PMID- 20891481 TI - The Ideal Physician. PMID- 20891480 TI - Shock. PMID- 20891482 TI - Serum Therapy: A Discourse: Some Clinical Observations in the Use of Neiser Bacterin and Mixed Infection Phylacogen. PMID- 20891483 TI - The Negro Woman and the Health Problem. PMID- 20891484 TI - Clinical Notes on a Case of Tetanus. PMID- 20891486 TI - On Dr. Taylor of Philadelphia. PMID- 20891485 TI - A Plea for the Lives of the Unborn. PMID- 20891488 TI - United States Census Bulletin No. 129. PMID- 20891487 TI - Our Chicago Meeting. PMID- 20891490 TI - Commencement and the Coming Years. PMID- 20891489 TI - The Editor Afield. PMID- 20891492 TI - Cancer. PMID- 20891491 TI - A Problem. PMID- 20891493 TI - N. M. A. Communications. PMID- 20891494 TI - Current Medical Thought. PMID- 20891495 TI - Current Medical Thought. PMID- 20891496 TI - Medico-Psychological Views of Infant and Adolescent Life. PMID- 20891497 TI - Eugenics and the School Teacher. PMID- 20891498 TI - Tetanus Resulting from Burn by Phosphorus, Successfully Treated with the Anti Tetanic Serum. PMID- 20891500 TI - Ophthalmia Neonatorum. PMID- 20891499 TI - Congenital Syphilis as a Possible Factor in the Etiology of Acute Chorea. PMID- 20891502 TI - Some Practical Remarks on Appendicitis. PMID- 20891501 TI - Where is That Fine Line of Demarcation Between Medicine and Dentistry? PMID- 20891503 TI - Oration in Pharmacy: The Conservation of Health by Restricting the Indiscriminate Use of Drugs. PMID- 20891504 TI - The National Medical Association: The Chicago Session. PMID- 20891505 TI - Notable Deaths. PMID- 20891506 TI - Progress and Prejudice. PMID- 20891507 TI - A Notable Incident. PMID- 20891508 TI - The Chicago Meeting. PMID- 20891509 TI - The President of the N. M. A. PMID- 20891512 TI - The Significance of the Anaphylaxis Reaction in Clinical Medicine. PMID- 20891510 TI - N. M. A. Communications. PMID- 20891513 TI - The Use and Abuse of Laboratory Findings. PMID- 20891514 TI - A Brief Review of Tubercular Peritonitis. PMID- 20891515 TI - The Medical Profession and its Relation to the General Public. PMID- 20891517 TI - Pellagra: Symptoms and Treatment. PMID- 20891516 TI - Surgery of the Uterus and Adnexa. PMID- 20891518 TI - Syphilis and the Effect of Salvarsan upon its Clinical Manifestations. PMID- 20891519 TI - A Gratuitous Falsehood and an Unwarranted Slander. PMID- 20891520 TI - A Pertinent Question. PMID- 20891522 TI - Progress or Atavism? PMID- 20891521 TI - "To Err is Human, to Forgive Divine". PMID- 20891524 TI - The Exceptional Man-An Appreciation. PMID- 20891523 TI - The Diagnoses and Treatment of the Complications of Urinary Calculi. PMID- 20891526 TI - Our Profession. PMID- 20891525 TI - Obiter Dicta. PMID- 20891527 TI - A Momentous Decision. PMID- 20891528 TI - Coprophagia. PMID- 20891529 TI - Startling Figures. PMID- 20891530 TI - Obiter Dicta. PMID- 20891531 TI - N. M. A. Communications. PMID- 20891532 TI - Current Medical Thought. PMID- 20891534 TI - Some Observations on Pellagra in Reply to the Report of the Public Health Committee. PMID- 20891535 TI - Report of Three Cases of Ectopic Gestation: One Being Twins at Term with Spontaneous Delivery. PMID- 20891537 TI - General Anesthesia. PMID- 20891536 TI - Cholelithiasis and Obstruction of Bile Ducts in Alcoholic Cirrhosis of Liver. PMID- 20891538 TI - Eclampsia. PMID- 20891539 TI - Omental Cysts: With Report of Case of Multilocular Cyst of Great Omentum. PMID- 20891540 TI - Diagnosis. PMID- 20891542 TI - Some Observations of Blood Pressure During Surgical Procedures, Especially Laparotomies. PMID- 20891541 TI - Interstitial Gingivitis and Pyorrhea Alveolaris. PMID- 20891543 TI - The Modern Hospital Largely Educational. PMID- 20891544 TI - Stay Out of the Uterus. PMID- 20891545 TI - Post-Operative Treatment of Cases by the Family Physician. PMID- 20891546 TI - Tonsillitis and Its Sequelae. PMID- 20891547 TI - "Health". PMID- 20891548 TI - Bubo: The Different Kinds and the Differential Diagnosis of the Same. PMID- 20891549 TI - Tetanus, With Report of a Case. PMID- 20891550 TI - The Druggist and the Doctor. PMID- 20891551 TI - The Medical Phase of the South's Ethnic Problem. PMID- 20891552 TI - Medical Bonhomie. PMID- 20891553 TI - New Sanitary Laws. PMID- 20891554 TI - Our Readers and Contributors. PMID- 20891556 TI - Obiter Dicta. PMID- 20891555 TI - The Editor Goes A-Maying. PMID- 20891557 TI - Anterior Poliomyelitis. PMID- 20891559 TI - N. M. A. Communications. PMID- 20891558 TI - On to Kansas City. PMID- 20891560 TI - Current Medical Thought. PMID- 20891562 TI - The Future of Medicine. PMID- 20891563 TI - The Relation Between the Physician and Surgeon. PMID- 20891564 TI - Scientific Researches into the Causes of Alcoholism and Inebriety. PMID- 20891565 TI - Primary and Secondary Joint Infection. PMID- 20891567 TI - The Kansas City Meeting. PMID- 20891566 TI - Leukemias. PMID- 20891568 TI - Our Literature-The Journal. PMID- 20891569 TI - The Grim Reaper. PMID- 20891571 TI - Our President. PMID- 20891570 TI - A Notable Anniversary. PMID- 20891573 TI - Obiter Dicta. PMID- 20891572 TI - Alcoholic Investigation. PMID- 20891574 TI - N. M. A. Communications. PMID- 20891576 TI - The Mechanical Equipment of the Modern Hospital. PMID- 20891575 TI - Blood Pressure. PMID- 20891577 TI - Ancient Medical Lore. PMID- 20891578 TI - An Obstetric Biography. PMID- 20891579 TI - Some Problems of Gynecological Surgery. PMID- 20891581 TI - Our Preventable Death-Rate. PMID- 20891580 TI - Current Advances in Surgery. PMID- 20891583 TI - Clinical Congress of Surgeons of North America. PMID- 20891582 TI - The Abuse of Therapeutic Vaccination. PMID- 20891584 TI - Obiter Dicta. PMID- 20891585 TI - Current Medical Thought. PMID- 20891586 TI - Laboratory in Diagnosis. PMID- 20891589 TI - Tissue Infiltration. PMID- 20891588 TI - A College Education as a Requisite Preparation for the Study of Medicine. PMID- 20891590 TI - The Relationship of Roentgenology to Gastro-Intestinal Diagnosis. PMID- 20891591 TI - Fifty Years' Progress of the American Negro in Health and Sanitation. PMID- 20891592 TI - Preventive Medicine in Obstetrics. PMID- 20891593 TI - Post-Partum Hemorrhage and Its Treatment. PMID- 20891594 TI - The Homogeneous Relations of Physicians and Pharmacists. PMID- 20891595 TI - The Diagnostic Value of Pain. PMID- 20891596 TI - A Few Practical and Dependable Therapeutic Suggestions. PMID- 20891597 TI - Report of the Pellagra Commission. PMID- 20891599 TI - Hydrometra-Report of a Case. PMID- 20891598 TI - The Indications for another Relative Value of Tonsillotomy and Tonsillectomy. PMID- 20891600 TI - Ancient Medical Lore. PMID- 20891602 TI - Birth Control. PMID- 20891601 TI - A Look Backward. PMID- 20891604 TI - Bridging the Chasm. PMID- 20891603 TI - The Journal of the A. M. A. PMID- 20891605 TI - Our Meeting in Memphis. PMID- 20891606 TI - Obiter Dicta. PMID- 20891608 TI - Splenectomy: Report of Case of Removal of Spleen with 10-Lb. Cyst. PMID- 20891607 TI - Current Medical Thought. PMID- 20891609 TI - Appendicitis. PMID- 20891610 TI - Oration on Medicine. PMID- 20891611 TI - A Case of Ectopic Pregnancy with Dermoid Cyst. PMID- 20891612 TI - The Relation of Dental Disease to Gastro Intestinal Disorders. PMID- 20891613 TI - Causes, Diagnosis, and Treatment of Pellagra. PMID- 20891614 TI - Why We Moved-A Roman Holiday. PMID- 20891615 TI - Come to Philadelphia. PMID- 20891616 TI - Health Week. PMID- 20891617 TI - Credulity. PMID- 20891618 TI - Our Next Meeting. PMID- 20891619 TI - Extra Professional Service. PMID- 20891620 TI - N. A. M. Communications. PMID- 20891621 TI - Current Medical Thought. PMID- 20891623 TI - Maternity and Infant Mortality. PMID- 20891624 TI - Diseases of the Bile Bearing Channels, Etc. PMID- 20891625 TI - Some Medical Aspects of Appendicitis. PMID- 20891626 TI - Some Peculiar Manifestations of Syphilis. PMID- 20891627 TI - Dr. U. G. Dailey. PMID- 20891628 TI - The Unsatisfied Valence. PMID- 20891630 TI - The Journal. PMID- 20891629 TI - The Philadelphia Session. PMID- 20891631 TI - The World War, Etc. PMID- 20891632 TI - The Philadelphia Meeting. PMID- 20891633 TI - Atlantic City. PMID- 20891634 TI - The New Amendments. PMID- 20891636 TI - Our President. PMID- 20891635 TI - The New Departure. PMID- 20891637 TI - The Pellagra Commission. PMID- 20891639 TI - Obiter Dicta. PMID- 20891638 TI - Tri-State Organization. PMID- 20891640 TI - N. M. A. Cummunications. PMID- 20891641 TI - Report of Pellagra Commission. PMID- 20891644 TI - The Evolution in the Standard of Medical Education. PMID- 20891643 TI - Hyperthyrosis. PMID- 20891645 TI - Peptic Ulcer. PMID- 20891647 TI - Gonorrheal Prophylaxis. PMID- 20891646 TI - Tuberculosis and Climate. PMID- 20891648 TI - Surgery in the Rural Districts: Some Helpful Hints. PMID- 20891649 TI - Intestinal Auto-Intoxication. PMID- 20891650 TI - Surgical Aspects of Typhoid Fever. PMID- 20891652 TI - The War-What Does it Mean? What Should We Do? PMID- 20891651 TI - Blood Picture in Tuberculosis. PMID- 20891653 TI - Racial Relationship. PMID- 20891654 TI - Death-Rate Among Physicians. PMID- 20891655 TI - American Murder Record. PMID- 20891657 TI - Intestinal Obstruction Resulting from Appendicitis. PMID- 20891656 TI - Border Lines Between Medicine and Surgery. PMID- 20891658 TI - Supra-Pubic Prostatectomy. PMID- 20891659 TI - Major Surgery in the Home. PMID- 20891660 TI - Interpretation of Abdominal Pain. PMID- 20891662 TI - A Case of Hemorrhagic Measles. PMID- 20891661 TI - Pelvic Surgery. PMID- 20891663 TI - Physiognomy in Diagnosis. PMID- 20891664 TI - The Management of Increased Blood Pressure. PMID- 20891665 TI - Remarks in Closing of a School Clinic. PMID- 20891666 TI - Clinical Study. PMID- 20891667 TI - The Acid Test. PMID- 20891669 TI - Obiter Dicta. PMID- 20891668 TI - An Explanation. PMID- 20891672 TI - Syllabus of Lecture to Colored Soldiers. PMID- 20891670 TI - N. M. A. Communications. PMID- 20891673 TI - Treatment of Fibroid Tumor of Uterus with Radium. PMID- 20891674 TI - Some Observation on Pellagra. PMID- 20891675 TI - Spastic Diplegia. PMID- 20891676 TI - Inflammation from Standpoint of Pathologist. PMID- 20891677 TI - Conservatism. PMID- 20891679 TI - Dr. Roman Retires. PMID- 20891678 TI - Richmond Meeting of N. M. A. PMID- 20891681 TI - The Influenza Epidemic. PMID- 20891680 TI - National Medical Commissions. PMID- 20891683 TI - N. M. A. Communications. PMID- 20891682 TI - The Passing of the Leonard School. PMID- 20891685 TI - Report of Pellagra Commission of The N. M. A. PMID- 20891686 TI - Typhoid Fever. PMID- 20891687 TI - Purulent Conjunctivitis with Report of Cases. PMID- 20891688 TI - The General Practitioner as Specialist. PMID- 20891690 TI - Our Tenth Anniversary. PMID- 20891689 TI - The Prevalence of Nephritis and the Necessity for Its Early Recognition. PMID- 20891691 TI - Benjamin Franklin as a Modern Sanitarian. PMID- 20891692 TI - Four Hundred Deaths from Diphtheria. PMID- 20891693 TI - Venereal Diseases. PMID- 20891694 TI - Epidemic Influenza and the Negro Physician. PMID- 20891695 TI - The Relationship that Should Exist Between the Physician and the Dentist. PMID- 20891696 TI - A Plea for Better Understanding Between Physicians and Pharmacists. PMID- 20891697 TI - Prophylactic Tonsillectomy. PMID- 20891698 TI - Study of 474 Venereal Diseases at Camp Humphreys. PMID- 20891699 TI - West Virginia State Colored Tuberculosis Sanatorium. PMID- 20891700 TI - The Pathology of N. M. A. PMID- 20891702 TI - An Important Duty. PMID- 20891701 TI - The Triumph of Democracy. PMID- 20891703 TI - The Venereal Problem. PMID- 20891704 TI - Not How Much but How Well. PMID- 20891706 TI - The West Virginia State Colored Tuberculosis Sanatorium. PMID- 20891705 TI - The Female Pelvis. PMID- 20891708 TI - Influenza and Pneumonia in Philadelphia. PMID- 20891707 TI - Dr. U. G. Dailey. PMID- 20891709 TI - Our Next Meeting. PMID- 20891710 TI - The Negro Medical Profession and United States Army. PMID- 20891711 TI - The Tidewater Colored Hospital. PMID- 20891712 TI - Reconstruction. PMID- 20891713 TI - Care of Eyes of New Born. PMID- 20891714 TI - Some Perversions of the Sexual Instinct. PMID- 20891715 TI - A Successful Remedy for the Relief of Odema in Cardio-Renal Conditions. PMID- 20891716 TI - Clinical Notes on the Influenza Epidemic. PMID- 20891718 TI - The Pus Tube. PMID- 20891717 TI - Historical Notes on Influenza. PMID- 20891719 TI - The Venereal Problem in Civil Life. PMID- 20891720 TI - Some Facts Concerning Negro Nurse Training Schools and Their Graduates. PMID- 20891721 TI - Climate, The Ignis Fatuus in the Treatment of Tuberculosis. PMID- 20891722 TI - The Venereal Situation. PMID- 20891723 TI - Influenza and Racial Susceptibility. PMID- 20891725 TI - Reciprocity. PMID- 20891724 TI - Recognition of the N. M. A. PMID- 20891727 TI - Patronize our Advertisers. PMID- 20891726 TI - Requirements for Membership in the N. M. A. PMID- 20891728 TI - A Half Million Endowment for Meharry. PMID- 20891729 TI - The Editor's Plea for Mercy. PMID- 20891730 TI - Letters to the Editor. PMID- 20891731 TI - N. M. A. Communications. PMID- 20891733 TI - Reconstruction. PMID- 20891735 TI - Mortality and Health, the Fruits of Intelligence and Self Control. PMID- 20891734 TI - The Effect of Strenuous Life Upon Health. PMID- 20891736 TI - Cancer of the Uterus. PMID- 20891738 TI - Reconstruction. PMID- 20891737 TI - The History and Problems of the Dental Profession. PMID- 20891740 TI - Better Preparation for Practitioners of Medicine. PMID- 20891739 TI - Negro Health. PMID- 20891742 TI - The Journal in Closer Affiliation with State Medical Associations. PMID- 20891741 TI - Progress in Gynecologic Surgery. PMID- 20891744 TI - Medical Book Buying and Journal Advertisers. PMID- 20891743 TI - Silent Influences. PMID- 20891746 TI - The Doctor's Vacation. PMID- 20891745 TI - The American Red Cross First Aid Course in Many of the Summer Normals. PMID- 20891748 TI - Improving Yank Hospitals. PMID- 20891747 TI - Our President. PMID- 20891749 TI - Summer Hygiene. PMID- 20891750 TI - Resolutions. PMID- 20891751 TI - The Nurse's Part in Winning the War. PMID- 20891753 TI - N. M. A. Communication. PMID- 20891752 TI - Hospital and Training School Methods. PMID- 20891754 TI - Some Lesions of the Alimentary Tract, with Report of Cases. PMID- 20891755 TI - Dysmenarrhea: Due to Appendicitis. PMID- 20891756 TI - Blood Pressure an Aid in Diagnosis. PMID- 20891757 TI - Some Points on Developing a Hospital. PMID- 20891758 TI - The Care of the Eyes of the Presbyopic. PMID- 20891760 TI - Public Health Education. PMID- 20891759 TI - Operative Surgery, etc. PMID- 20891761 TI - Spanish Influenza. PMID- 20891762 TI - Blood Pressure. PMID- 20891763 TI - Drugs and their Relation to the Physician. PMID- 20891764 TI - The Newark Meeting. PMID- 20891765 TI - The South and Negro Education. PMID- 20891766 TI - Our President. PMID- 20891767 TI - The Clinical Aspect of Dental Programs. PMID- 20891768 TI - Our President-Elect. PMID- 20891769 TI - Will the "Flu" Return? PMID- 20891770 TI - A Three-Cornered Campaign. PMID- 20891771 TI - More Complete Reports of Discussions. PMID- 20891772 TI - The N. M. A. Teaching the Public. PMID- 20891773 TI - N. M. A. Communications. PMID- 20891774 TI - Report of General Secretary. PMID- 20891775 TI - Report of the Secretary of the Executive Board. PMID- 20891776 TI - Report of the Editor and Manager of the Journal. PMID- 20891777 TI - Reconstruction. PMID- 20891778 TI - The Negro Doctor and The War. PMID- 20891780 TI - Medical Aspect of Gas Warfare. PMID- 20891781 TI - Dental Operation During Pregnancy. PMID- 20891782 TI - The X-Ray, A Potent Factor in Determining Important Decisions. PMID- 20891783 TI - The Arkansas Hot Springs Baths. PMID- 20891784 TI - The Gynecologist: Some of His Problems, etc. PMID- 20891785 TI - Hysteria. PMID- 20891787 TI - A Plea For A More Careful Consideration of the Pregnant Woman. PMID- 20891786 TI - Vaccine Therapy. PMID- 20891788 TI - A Racial Phase of Professional Obligation. PMID- 20891790 TI - A Phase of Birth Control. PMID- 20891789 TI - Commercializing Medicine. PMID- 20891791 TI - Why the Journal was late. PMID- 20891792 TI - United States Census. PMID- 20891794 TI - N. M. A. Communications. PMID- 20891793 TI - Report from the Manager of the Journal of the N. M. A. PMID- 20891796 TI - Reconstruction. PMID- 20891797 TI - The Negotiations of Medicine. PMID- 20891798 TI - Observations of Surgical Conditions of the Right Upper Quadrant. PMID- 20891800 TI - The Duty of the Physician to the Child. PMID- 20891799 TI - Ocular Symptoms as an Aid in Diagnosis. PMID- 20891801 TI - A Post-Graduate Course in Tuberculosis at the Piedmont Sanatorium, Burkeville, Va. PMID- 20891802 TI - The Effects of Certain Physical Impairments on Mortality. PMID- 20891803 TI - The Bacillus Tuberculosis: Its Morphological and Pathological Characteristics. PMID- 20891805 TI - Dr. Geo. W. Cabaniss. PMID- 20891804 TI - X-Ray as an Aid to Diagnosis. PMID- 20891807 TI - Exercise. PMID- 20891806 TI - The Busy Doctor. PMID- 20891808 TI - Dr. Perry's Paper. PMID- 20891809 TI - The Meharry Clinics. PMID- 20891811 TI - The Coming Meeting of the N. M. A. PMID- 20891810 TI - Sexual Impulse. PMID- 20891812 TI - N. M. A. Communications. PMID- 20891815 TI - The Care of the Eyes During Adolescence. PMID- 20891814 TI - Report of the Pellagra Commission of the National Medical Association. PMID- 20891816 TI - Importance of Early Diagnosis in Cancer of the Stomach. PMID- 20891817 TI - A Clinical Review of Four Types of Breast Tumors: Observed in the Surgical Wards of Freedmen's Hospital, Washington, D. C. PMID- 20891818 TI - Gastroptosis, Enteroptosis or Visceroptosis following hysterectomies. PMID- 20891820 TI - Radical Operation on the Female Reproductive Organs. PMID- 20891819 TI - Case Reports: Thoracic Aneurysms. PMID- 20891821 TI - Opium-Inebriety, Morphinism, Narcomania. PMID- 20891823 TI - The Editor Afield. PMID- 20891822 TI - Peridontaclasia. PMID- 20891824 TI - The Age I wish I Could Be. PMID- 20891825 TI - Howard University School of Medicine. PMID- 20891827 TI - The Atlanta Meeting of the National Medical Association. PMID- 20891826 TI - A Post-Graduate Course at the John A. Andrew Memorial Hospital. PMID- 20891828 TI - Our Shortcomings. PMID- 20891831 TI - Reconstruction. PMID- 20891829 TI - Some Observations on Pellagra with Special Reference to Therapy. PMID- 20891833 TI - Erysipelas. PMID- 20891832 TI - N. M. A. Communications. PMID- 20891834 TI - The Venereal Problem. PMID- 20891835 TI - Some Ramifications of the Sexual Impulse. PMID- 20891836 TI - Experiments in Vaccinotherapy. PMID- 20891838 TI - Acute Mastoiditis: With report of two cases. PMID- 20891837 TI - The Present Day Preparations of Salvarsan: With Special Reference to their Influence on the Wasserman Reaction. PMID- 20891839 TI - Embolic Abscess of the Lung: Secondary to a Mastoid Operation. PMID- 20891840 TI - Report of the Pellagra Commission of the N. M. A. PMID- 20891841 TI - The Early Diagnosis of Pulmonary Tuberculosis. PMID- 20891843 TI - Chronic Nephropathics. PMID- 20891842 TI - A Safe and Efficient Plan of Surgical Treatment for Prostatic Obstruction. PMID- 20891844 TI - Mastication and Saliva. PMID- 20891846 TI - Trip to Tuskegee. PMID- 20891845 TI - The Atlanta Meeting of the Nat'l Med. Asso'n. PMID- 20891848 TI - National Association of Colored Graduate Nurses. PMID- 20891847 TI - Our New President and President-elect. PMID- 20891850 TI - Chylo-Thorax: With report of a case. PMID- 20891849 TI - N. M. A. Communications. PMID- 20891852 TI - Personal Experiences with a Stricture of Stenson's Duct: A Salivary Calculus, Salivary Fistula and Enucleation of the Parotid Gland. PMID- 20891853 TI - The Early Recognition of Ectopic Pregnancy. PMID- 20891854 TI - Posterior Gastro-Enterostomy. PMID- 20891856 TI - Internal Medicine: Diagnosis-Laboratory. PMID- 20891855 TI - Rheumatism and the Phylacogens: Observations during their use. PMID- 20891857 TI - Influenza. PMID- 20891858 TI - Puerperal Eclampsia. PMID- 20891859 TI - Venereal Disease, A Problem of All Races. PMID- 20891861 TI - Dr. George W. Hubbard Retires. PMID- 20891860 TI - Popliteal Aneurism from a medical viewpoint: Report of a Case. PMID- 20891862 TI - The need of more Internists. PMID- 20891864 TI - A Trio of Events at the John A. Andrew Memorial Hospital. PMID- 20891863 TI - The Daniel Hale Williams Surgical and Oral Society. PMID- 20891865 TI - To Drain or not to Drain. PMID- 20891866 TI - The Venereal Problem. PMID- 20891868 TI - The Louisville Meeting of the N. M. A. PMID- 20891867 TI - Medico-Legal: Reporting Venereal Infection. PMID- 20891869 TI - N. M. A. Communications. PMID- 20891870 TI - Ectopic Gestation. PMID- 20891871 TI - Toxemias of Pregnancy. PMID- 20891872 TI - School Medical Inspection: Its object and results. PMID- 20891873 TI - Practical Points on the Nose, Throat and Ear. PMID- 20891874 TI - Case Reports. PMID- 20891875 TI - Our Secretary. PMID- 20891877 TI - The Clinic and Post Graduate Course at Tuskegee Institute. PMID- 20891876 TI - Losing our Advertising. PMID- 20891879 TI - N. M. A. Communications. PMID- 20891878 TI - Meharry in Mourning. PMID- 20891881 TI - The Early Diagnosis of Pulmonary Tuberculosis: With Roentgen Diagnosis (illustrated). PMID- 20891883 TI - Open Pneumothorax. PMID- 20891882 TI - The Value of the Paradoxical Reflex (Gordon Reflex): Apropos of a Case of Abscess in the Occipital Lobe. PMID- 20891884 TI - Pellagra. PMID- 20891885 TI - Unpunished Medical Crimes. PMID- 20891886 TI - Shock: Some Surgical observations with special reference to it. PMID- 20891887 TI - Some Phases in the Treatment of Lobar Pneumonia. PMID- 20891888 TI - Chorea. PMID- 20891889 TI - The Social Status of Medicine. PMID- 20891891 TI - The Tonsils-Gateways to Many Ills. PMID- 20891890 TI - The Diagnosis of Foreign Body in the Lung. PMID- 20891892 TI - Galvanism in Gynaecology and in Genito-Urinary Practice. PMID- 20891893 TI - The Advantages of Using U. S. P. and N. F. Preparations Instead of Patent and Proprietary Medicines. PMID- 20891894 TI - Heart Sounds and their Diagnostic Value. PMID- 20891895 TI - The Relation of Eye, Ear, Nose, and Throat Surgery to General Surgery. PMID- 20891896 TI - Letters to the Editor. PMID- 20891897 TI - Letters to the Editor. PMID- 20891900 TI - Progress. PMID- 20891898 TI - Letters to the Editor. PMID- 20891901 TI - Galvanism in Gynecology. PMID- 20891902 TI - The Louisville Meeting of the N. M. A. PMID- 20891903 TI - Clinics at Louisville. PMID- 20891904 TI - Meharry Medical College. PMID- 20891906 TI - Dr. Jackson and the Tulsa Riots. PMID- 20891905 TI - The Editor Afield. PMID- 20891907 TI - Gordonsville, Va. PMID- 20891908 TI - N. M. A. Communications. PMID- 20891909 TI - The Urethroscope in the Diagnosis and Treatment of Diseases of the Male Urethra. PMID- 20891911 TI - Hypernephroma of the Right Kidney: Report of a Case. PMID- 20891910 TI - Acute Intestinal Obstruction: Some aspects of. PMID- 20891912 TI - Luetic Popliteal Aneurysm: With Report of a Case. PMID- 20891914 TI - Diabetes Mellitus. PMID- 20891913 TI - Carcinoma of the Breast: Pre-operative and Post-operative X-Ray Treatment of. PMID- 20891915 TI - The Louisville Meeting of the National Medical Association. PMID- 20891916 TI - A Change in the Business Management of the Journal. PMID- 20891918 TI - Hospital Notes. PMID- 20891917 TI - The Indifference of the Negro Medical Profession. PMID- 20891920 TI - On Chartering the N. M. A. PMID- 20891919 TI - Dr. Garvin. PMID- 20891922 TI - N. M. A. Communications. PMID- 20891921 TI - Our New President. PMID- 20891923 TI - Syphilis of the Throat. PMID- 20891924 TI - Female Pelvic Disorders: Differential Diagnosis of. PMID- 20891925 TI - A New Responsibility for the Physician. PMID- 20891926 TI - Our Hospitals and their Standardization. PMID- 20891927 TI - The Motion Picture: Its Practical Value in Teaching Obstetrics. PMID- 20891928 TI - Nephritis. PMID- 20891930 TI - Sex, Suggestion and Society. PMID- 20891929 TI - Nephritis: The Conservative Treatment of. PMID- 20891931 TI - The Cancer Problem. PMID- 20891932 TI - Dr. G. W. Alexander. PMID- 20891933 TI - "Our Lay Bosses". PMID- 20891934 TI - Spare the Editor. PMID- 20891935 TI - National Negro Health Week. PMID- 20891936 TI - The Syphylitic Problem. PMID- 20891937 TI - Activities at John A. Andrew Memorial Hospital. PMID- 20891939 TI - Vacation. PMID- 20891938 TI - The Outlook for the N. M. A. PMID- 20891941 TI - The Wassermann Reaction: The Nature of, in Relation to its Clinical Value and the Standardization of Technic. PMID- 20891940 TI - N. M. A. Communications. PMID- 20891943 TI - Cancer,Facts and Figures about. PMID- 20891944 TI - Rickets, The Surgical Treatment of the Chronic Deformities of: With Emphasis on Bow-Legs and Knock-Knees. PMID- 20891945 TI - The Washington Meeting of the National Medical Association. PMID- 20891946 TI - On Pauperizing the Laity. PMID- 20891947 TI - Our Educational Congress. PMID- 20891949 TI - Does it Pay? PMID- 20891948 TI - School Diets. PMID- 20891950 TI - Lincoln University of Missouri. PMID- 20891951 TI - Post-Graduate Course in Nursing. PMID- 20891952 TI - N. M. A. Communications. PMID- 20891953 TI - Mental and Nervous Conditions Following Traumatism: Medico-Legal Consideration of. PMID- 20891954 TI - Why Report Communicable Diseases? PMID- 20891956 TI - Pellagra: Some Observation Upon More Than Fifty Cases of. PMID- 20891955 TI - Some Phenomena of Liver Pathology. PMID- 20891957 TI - Personality in Progress. PMID- 20891958 TI - Preventive Medicine: A Potent Asset in Our Social, Moral, Economic, and Intellectual Life. PMID- 20891959 TI - Syphilis of the Respiratory Tract and Lungs. PMID- 20891961 TI - Care of Infants. PMID- 20891960 TI - Neglected Anatomy: Hypertrophy of the Prostate. PMID- 20891962 TI - The Future of the Internist. PMID- 20891964 TI - The Tuning Fork Tests. PMID- 20891963 TI - Medicine-Past, Present and Future. PMID- 20891965 TI - State Control of Venereal Diseases. PMID- 20891966 TI - The Acute Abdomen. PMID- 20891967 TI - Abdominal Tumor: Report of an Unusual Case. PMID- 20891969 TI - Gastric and Duodenal Ulcers: With Report of Two Cases. PMID- 20891968 TI - Fractures of the Long Bones: With especial reference to Treatment by Suspension and Extension. PMID- 20891970 TI - The Normal Chest of the Child: X-Ray and Clinical Findings. PMID- 20891971 TI - Cardio-Vascular Syphilis. PMID- 20891972 TI - Syphilis: Diagnosis, Prognosis and Treatment. PMID- 20891973 TI - Carcinoma of the Undescended Abdominal Testicle : Report of a case. PMID- 20891974 TI - Bacterial Vaccines: In the Treatment of Infections. PMID- 20891975 TI - Allergy and Anaphylaxis. PMID- 20891976 TI - Pennsylvania on Top. PMID- 20891977 TI - Relation of State Associations to the Journal. PMID- 20891979 TI - Hospitals in Prospect. PMID- 20891978 TI - School of Public Health and Hygiene. PMID- 20891980 TI - Physicians and Post-Graduate work. PMID- 20891981 TI - Proposed Changes in the Education of Nurses. PMID- 20891982 TI - N. M. A. Communications. PMID- 20891984 TI - Skeletology. PMID- 20891985 TI - Ptosis of the Transverse Colon. PMID- 20891986 TI - Diagnosis Essential to Treatment. PMID- 20891987 TI - Problems in the Rehabilitation of Victims of War. PMID- 20891988 TI - Masters in Medicine. PMID- 20891989 TI - Basal Metabolism in Medical Practice. PMID- 20891990 TI - The Contra-Indications of Tonsillectomy. PMID- 20891991 TI - High Blood Pressure: The Role of High Frequency in the Treatment of. PMID- 20891992 TI - Reports of Three Cases. PMID- 20891993 TI - Did the Washington Meeting Justify Our Expectations? PMID- 20891994 TI - The John A. Andrew Clinic and Post-Graduate Course. PMID- 20891996 TI - The National Medical Association. PMID- 20891995 TI - Supporting Our Medical Schools. PMID- 20891997 TI - N. M. A. Communications. PMID- 20891998 TI - Therapeutic Notes: Social Hygiene. PMID- 20892000 TI - Medical and Surgical Pitfalls. PMID- 20891999 TI - Tuberculosis from the Standpoint of Pathology. PMID- 20892002 TI - A Standard of Cure in Gonorrheal Urethritis in the Male. PMID- 20892001 TI - Multiplex Pathology and the Cancer Problem. PMID- 20892003 TI - A Plea for More Careful Histories and Physical Examination of Venereal Disease Patients. PMID- 20892004 TI - Anesthesia. PMID- 20892005 TI - Organotherapy. PMID- 20892007 TI - Gunshot Wound of the Abdomen. PMID- 20892006 TI - Pneumoperitoneum as an Aid in Diagnosis. PMID- 20892009 TI - Some Possibilities and Opportunities in Medical Practice in the South. PMID- 20892008 TI - Dengue Fever: Presented through the Analysis of recent Epidemic Cases. PMID- 20892010 TI - Pulmonary Tuberculosis: Some Observations from a Study of three hundred Cases. PMID- 20892011 TI - Mortality from Tuberculosis 1921. PMID- 20892012 TI - The Washington Meeting. PMID- 20892013 TI - Our Next Meeting - St. Louis. PMID- 20892014 TI - House of Delegates. PMID- 20892016 TI - The Kahn Precipitation Test. PMID- 20892015 TI - Mental Abnormalities and the Problem of Eugenics. PMID- 20892018 TI - National Negro Health Week. PMID- 20892017 TI - "American Civilization and The Negro". PMID- 20892019 TI - N. M. A. Communications. PMID- 20892020 TI - Therapeutic Notes: Notes on Applied Therapeutics. PMID- 20892021 TI - Routine Examination of the Feces: With Special Reference to Parasites. PMID- 20892022 TI - Syphilis: Modern Diagnosis and Treatment of. PMID- 20892023 TI - General Anesthesia. PMID- 20892024 TI - Myotonia: Remarks on, apropos of a case of Paramyotonia limited to the Orbicularis Palpebrarum. PMID- 20892026 TI - The National Medical Association President. PMID- 20892025 TI - "A Grave Warmed by Glory". PMID- 20892028 TI - The John A. Andrew Clinics. PMID- 20892027 TI - Coueism, Hypnotism, Eddyism, et al. PMID- 20892030 TI - N. M. A. Communications. PMID- 20892029 TI - The Community Hospital, Wilmington, N. C. PMID- 20892031 TI - Thrombus of the Pelvis and Lower Extremities: Some Observations on. PMID- 20892033 TI - Basal Metabolism: A Few Observations on. PMID- 20892032 TI - The Treatment of Fractures. PMID- 20892034 TI - Calcium in the Treatment of Heart Diseases. PMID- 20892035 TI - Reflex Gastric Manifestations. PMID- 20892036 TI - Pathology and Diagnosis of Acute Pancreatitis. PMID- 20892038 TI - The National Medical Association Gets Recognition. PMID- 20892037 TI - Gonorrhea: From the Viewpoint of the Practitioner. PMID- 20892039 TI - Anti-Tuberculosis Work Among The Negroes of Philadelphia. PMID- 20892040 TI - Dengue Fever. PMID- 20892041 TI - N. M. A. Communications. PMID- 20892042 TI - The Principles of Bone Surgery. PMID- 20892043 TI - Non-Specific Immunity: A Note on the Increase of, and Preliminary Treatment in Operations with Latent Infections. PMID- 20892044 TI - Errors and Shortcomings in Diagnosis. PMID- 20892045 TI - The Prostate in General Practice. PMID- 20892046 TI - Hysterectomies for Fibro-Myoma: A Review of Forty-five Selected Cases. PMID- 20892047 TI - Public Health and the Negro. PMID- 20892048 TI - Typhoid Fever. PMID- 20892049 TI - Genius and Illness. PMID- 20892050 TI - Our New President. PMID- 20892051 TI - Public Health and The Negro. PMID- 20892052 TI - Our President-Elect. PMID- 20892053 TI - The St. Louis Meeting of The National Medical Association. PMID- 20892055 TI - N. M. A. Communications. PMID- 20892054 TI - A Plea for Support of Our Medical Schools. PMID- 20892057 TI - Summer Diarrhoea: (Acute Gastro-enteritis ). PMID- 20892056 TI - The Therapy of Erysipelas: A Note on, With Special Reference to the Supporting Influence of Red Light Rays. PMID- 20892058 TI - Pelvic Surgery: Time and Advisability of Operation in Certain Pathological Conditions. PMID- 20892060 TI - Pre-operative and Post-operative Treatment. PMID- 20892059 TI - Conservatism in Surgery. PMID- 20892061 TI - The Small Hospital: Some Observations and Conclusions. PMID- 20892062 TI - The Symptomatology of Tuberculosis. PMID- 20892063 TI - A Useful Diagnostic Aid in Syphilis. PMID- 20892065 TI - An Alarming Condition. PMID- 20892064 TI - Syphilis as Seen by the Ophthalmologist. PMID- 20892067 TI - Medical Economics. PMID- 20892066 TI - Our Medical Schools again. PMID- 20892068 TI - The Hampton Meeting. PMID- 20892070 TI - The Physiology of Vomiting. PMID- 20892069 TI - The Physiology of Digestion. PMID- 20892072 TI - The Sippy Treatment for Gastric Ulcer: (Compiled from directions of the Sippy Clinic). PMID- 20892071 TI - Mucous Colitis. PMID- 20892074 TI - In The Mountain City. PMID- 20892073 TI - Gastric Ulcer. PMID- 20892075 TI - Recognition. PMID- 20892076 TI - The Real Surgeon. PMID- 20892077 TI - Cervical Adenitis: The Diagnosis and Treatment of. PMID- 20892079 TI - Insulin Treatment of Diabetes. PMID- 20892078 TI - Syphilis: A Report of two Cases. PMID- 20892080 TI - Syphilis: The Role of the General Practitioner in the Treatment of. PMID- 20892081 TI - Malnutrition in Infancy and Early Childhood: With specific reference to the pathologic and physiologic actions of the Endocrines-A resume. PMID- 20892082 TI - Tuberculous Laryngitis: Some New Conclusions from a Study of 273 Cases. PMID- 20892083 TI - The Cultural Background of Modern Medicine. PMID- 20892085 TI - Hydronephrosis. PMID- 20892084 TI - Meningeal Hemorrhages in the Newly Born: And their Remote Consequences. PMID- 20892086 TI - Studies in Basal Metabolism Rate Determinations. PMID- 20892087 TI - The Responsibility of the Hospital to the Training School. PMID- 20892088 TI - Factors Fundamental in the Growth and Development of a People. PMID- 20892090 TI - Preventive Medicine. PMID- 20892089 TI - Exophthalmic Goiter-Hyperthyroidism. PMID- 20892092 TI - The Status of the National Medical Association. PMID- 20892091 TI - Diagnosis. PMID- 20892093 TI - The Chicago Session of the American Medical Association. PMID- 20892094 TI - The Doctor's Vacation. PMID- 20892095 TI - Dr. Jos. H. Ward heads Veterans Hospital. PMID- 20892096 TI - "Soul Sick". PMID- 20892097 TI - Chronic Intoxication with Valerian: Nervous and Mental Manifestations Following. PMID- 20892098 TI - Etiology and Pathogenesis of Primary Glaucoma. PMID- 20892099 TI - Hospital Economics. PMID- 20892100 TI - Physiotherapy: Is an Aid to Surgery and Internal Medicine. PMID- 20892101 TI - The Hampton Meeting. PMID- 20892102 TI - Our President. PMID- 20892104 TI - The New Secretary and Business Manager. PMID- 20892103 TI - The President-Elect. PMID- 20892105 TI - Mental Hygiene: Its Necessity and Socio-Economic Importance. PMID- 20892106 TI - Anaphylaxis: In its Relation to Hay-fever and Asthma. PMID- 20892107 TI - Neurasthenia. PMID- 20892108 TI - The Value of Blood Cultures in Streptococcic Infections. PMID- 20892109 TI - The Roentgen-ray Diagnosis of Pulmonary Tuberculosis. PMID- 20892111 TI - The John A. Andrew Clinics. PMID- 20892110 TI - Bright Prospects Ahead for the N. M. A. PMID- 20892112 TI - The Tragedy of Standard Life. PMID- 20892113 TI - Pollinosis. PMID- 20892114 TI - The "Nervous Child". PMID- 20892115 TI - Some Practical Suggestions from my Experience in Surgery and Gynecology. PMID- 20892116 TI - Simultaneous Dislocation of Both Shoulder Joints. PMID- 20892117 TI - Dionol. PMID- 20892119 TI - Dr. George E. Cannon. PMID- 20892118 TI - Acute Anterior Poliomyelitis. PMID- 20892120 TI - Lethargica Medicalis. PMID- 20892121 TI - The Colored Specialist. PMID- 20892123 TI - Sialorrhea as a Symptom of Chronic Pancreatitis. PMID- 20892122 TI - The Biological Aspects of Eugenics. PMID- 20892124 TI - Dean Balloch Honored. PMID- 20892125 TI - The Editor's Visit to Philadelphia. PMID- 20892126 TI - Experience in the Surgery of the Biliary Tract with Special Reference to Stone. PMID- 20892127 TI - Post Mortem Review of Heart Diagnoses. PMID- 20892128 TI - Traumatic Epilepsy. PMID- 20892130 TI - Rickets. PMID- 20892129 TI - Hematuria: Report of Cases. PMID- 20892131 TI - Local Anaesthesia in Tonsillectomy. PMID- 20892133 TI - Am I My Brother's Keeper? PMID- 20892132 TI - Case Reports. PMID- 20892135 TI - Mrs. Booker T. Washington. PMID- 20892134 TI - The Clinical Surgeon. PMID- 20892136 TI - Dr. George E. Cannon. PMID- 20892137 TI - The Acute Abdomen. PMID- 20892138 TI - The Hypophysis Gland: The Methods of Diagnosis in Functional and Pathological Changes of. PMID- 20892139 TI - Sarcoma of Superior Maxillary Bone and Pellagra. PMID- 20892140 TI - Anthropological Psychiatry. PMID- 20892142 TI - A Handmaid of Medicine. PMID- 20892141 TI - Some Personal Observations on Operative Technic. PMID- 20892144 TI - A Laboratory for the Study of the Abnormal Classes. PMID- 20892143 TI - The National Hospital Association. PMID- 20892145 TI - The Dawn of a Better Day. PMID- 20892146 TI - Our President-Elect. PMID- 20892147 TI - Young Men to the Front. PMID- 20892148 TI - The President of the N. M. A. PMID- 20892149 TI - Journal Advertising. PMID- 20892150 TI - The N. M. A. Visitors. PMID- 20892151 TI - In re the Trial of Dr. Sweet. PMID- 20892153 TI - Granuloma Inguinale : (Report of a Case). PMID- 20892152 TI - Leiomyofibroma of the Uterus : A Report of two Cases Complicating Pregnancy. PMID- 20892154 TI - Notes on Postgraduate Study in Europe. PMID- 20892156 TI - North Carolina Points the Way. PMID- 20892155 TI - Syphilis and the Negro. PMID- 20892157 TI - The National Medical Association Tour of European Clinics for 1927. PMID- 20892158 TI - Doctor Dailey Abroad. PMID- 20892160 TI - Mouth Hygiene. PMID- 20892159 TI - The Philadelphia Meeting of the N. M. A. PMID- 20892161 TI - The John A. Andrew Clinics. PMID- 20892162 TI - Hyperthyroidism : A Report of 125 Cases. PMID- 20892163 TI - Modern Aspects of the Treatment of Cancer. PMID- 20892165 TI - Exophthalmic Goiter: The Diagnosis of. PMID- 20892164 TI - The Medicolegal Aspect of Morbid Impulses. PMID- 20892167 TI - Bronchial Asthma. PMID- 20892166 TI - Roentgen Ray Diagnosis of the Diseases of the Thoracic Viscera. PMID- 20892168 TI - Inoperable Sarcoma of Leg: Report of a Case. PMID- 20892170 TI - Our Own Valhalla. PMID- 20892169 TI - Notes on Post-graduate Study in Europe. PMID- 20892171 TI - National Negro Health Week. PMID- 20892172 TI - The European Clinical Tour in 1927. PMID- 20892174 TI - The Piedmont Medical Bulletin. PMID- 20892173 TI - The National Hospital Association. PMID- 20892175 TI - Dr. A. M. Curtis Honored. PMID- 20892176 TI - Miss Jane E. Hunter. PMID- 20892177 TI - Treatment of Head Injuries. PMID- 20892179 TI - The Pediatric Department of Wheatley-Provident Hospital, Kansas City, Mo. PMID- 20892180 TI - Modern Surgery. PMID- 20892178 TI - Uterine Fibroids Complicating Pregnancy. PMID- 20892182 TI - Negro Death Rate in Boston. PMID- 20892181 TI - Notes on Postgraduate Study in Europe. PMID- 20892183 TI - John A. Andrew Clinic. PMID- 20892184 TI - Opening of State Hospital for Colored Insane in West Virginia. PMID- 20892186 TI - Mercy Hospital, Philadelphia. PMID- 20892185 TI - A Gratifying Accomplishment. PMID- 20892187 TI - Why a National Hospital Association. PMID- 20892188 TI - An Important Conference. PMID- 20892190 TI - The Surgical Treatment of Hemorrhoids: The Principles and Technic of. PMID- 20892192 TI - The Use of Insulin in Treatment of Diabetes Mellitus with Limited Laboratory Facilities. PMID- 20892191 TI - Some High Lights on Physiotherapy. PMID- 20892193 TI - The Aftermath. PMID- 20892194 TI - The Philadelphia Meeting and its Lessons. PMID- 20892196 TI - Dr. Carl G. Roberts. PMID- 20892195 TI - Some Impressions of the Philadelphia Meeting. PMID- 20892197 TI - The National Hospital Association. PMID- 20892198 TI - As Others See Us. PMID- 20892199 TI - Our President-Elect. PMID- 20892202 TI - The Treatment of Toxic Goiter in 1926. PMID- 20892200 TI - Current Medical Thought. PMID- 20892203 TI - The Enlarged Prostate. PMID- 20892205 TI - Altruism in Medicine. PMID- 20892204 TI - Surgical Conditions in the Right Side of the Female Abdomen: Some Points in the Differential Diagnosis of. PMID- 20892206 TI - Heart Disease, Apoplexy and High-Speed Living. PMID- 20892207 TI - Dr. Joseph J. France. PMID- 20892209 TI - Gastro-Intestinal Symptoms of Neurosyphilis. PMID- 20892208 TI - The X-Ray in Diagnosis. PMID- 20892210 TI - Heart Disease: A Few Points in the Management of. PMID- 20892211 TI - Dr. Alexander's Twenty Years: A Eulogy and Introduction. PMID- 20892212 TI - Hospitals. PMID- 20892213 TI - The Pituitary Gland: The Surgical Treatment of Diseases of. PMID- 20892215 TI - Our Medical Endowment Funds. PMID- 20892214 TI - Ammonium Chloride and Novasurol: The Use of, as a Diuretic. PMID- 20892216 TI - The Commission on Inter-Racial Co-Operation. PMID- 20892217 TI - Patronage for Our Advertisers. PMID- 20892218 TI - Current Medical Thought. PMID- 20892219 TI - The Treatment of Diabetes Mellitus by the General Practitioner. PMID- 20892220 TI - Pancreatic Cysts: With Report of a Case. PMID- 20892221 TI - The Acute Surgical Abdomen. PMID- 20892222 TI - Hernia. PMID- 20892223 TI - Uterine Fibroids. PMID- 20892225 TI - The Detroit Meeting. PMID- 20892224 TI - Cancer: A Brief Study in, with Special Reference to its Surgical Treatment. PMID- 20892226 TI - Simplicity in the Use of Insulin. PMID- 20892227 TI - A Plea for Meharry Endowment Fund. PMID- 20892228 TI - Howard Goes Over the Top. PMID- 20892229 TI - Cancer. PMID- 20892230 TI - Dr. A. W. Dumas Added to the Editorial Board. PMID- 20892231 TI - Current Medical Thought. PMID- 20892232 TI - Is Tubal Pregnancy Recognizable before Rupture? PMID- 20892233 TI - Trans-Uterine Insufflation for Determination of Patency of Fallopian Tubes. PMID- 20892234 TI - Diathermy in the Treatment of Gonorrhea. PMID- 20892236 TI - Our New President. PMID- 20892235 TI - Our President-Elect. PMID- 20892238 TI - Physicians' Liability Insurance. PMID- 20892237 TI - The Pullman Car Porters. PMID- 20892240 TI - The Detroit Meeting. PMID- 20892241 TI - Current Medical Thought. PMID- 20892239 TI - Dr. Eugene W. Lomax. PMID- 20892242 TI - Edema of the Larynx. PMID- 20892243 TI - The Underweight Child. PMID- 20892244 TI - An Unusual Gastric Neoplasm. PMID- 20892245 TI - High Blood Pressure in Insurance Examinations: The Significance of. PMID- 20892246 TI - A Needless Waste of Human Life. PMID- 20892248 TI - The Tuskegee Annual Clinic. PMID- 20892247 TI - National Negro Health and Clean-Up Week. PMID- 20892249 TI - The Provident Hospital and Free Dispensary of Baltimore. PMID- 20892250 TI - The Howard University Medical Endowment and Building Fund. PMID- 20892251 TI - The Thyroid, the Parathyroids and the Ovaries: The Functional Relation of. PMID- 20892252 TI - Granuloma Inguinale: (With Case Report). PMID- 20892253 TI - Non-Luetic Disorders in a Luetic Individual: Apropos of a Case of Jacksonian Epilepsy. PMID- 20892255 TI - Certain Aspects of the Diagnosis and Treatment of Brain Tumors. PMID- 20892254 TI - Current Medical Thought. PMID- 20892256 TI - Diagnosis of Pulmonary Tuberculosis. PMID- 20892257 TI - The Rational Management of Pelvic Infections. PMID- 20892258 TI - Some of the Problems of Hospital Administration. PMID- 20892259 TI - The Baltimore Meeting. PMID- 20892260 TI - Early Diagnosis of Tuberculosis. PMID- 20892262 TI - Dr. J. W. Jones Passes. PMID- 20892261 TI - Doctor L. L. Burwell. PMID- 20892263 TI - The Editor Reads Paper at Social Work Conference. PMID- 20892264 TI - Remarks on Chronic Ailments of the Colon. PMID- 20892265 TI - Fracture of the Pelvis and Rupture of the Bladder: Report of a Case. PMID- 20892266 TI - Protein (Milk) Therapy of Pelvic Inflammations: Report of First Hundred Cases. PMID- 20892267 TI - Importance of Early Diagnosis in Tuberculosis. PMID- 20892268 TI - Acute Perforated Gastric Ulcer: Diagnosis and Treatment of. PMID- 20892269 TI - The Relation of Goiter to the Borderline of Medicine. PMID- 20892270 TI - Surgery in the Diabetic. PMID- 20892271 TI - Turn on the Light. PMID- 20892272 TI - The National Medical Association's Surgical Clinics. PMID- 20892273 TI - Professional Esprit de Corps. PMID- 20892274 TI - The Ultimate Effects of War Gases. PMID- 20892275 TI - Meharry Dental Graduates Make Good Records. PMID- 20892276 TI - Surgery of the Intestines. PMID- 20892277 TI - Rene Theophile Hyacinthe Laennec. PMID- 20892278 TI - The Surgical Treatment of Peptic Ulcer: A Resume of Recent Concepts in. PMID- 20892279 TI - Prenatal Care. PMID- 20892280 TI - The Standardization of the Twenty-Five- to Thirty-Five-Bed Hospital. PMID- 20892281 TI - How Can We Reduce the Hospital Expenses Without Curtailing Its Services? PMID- 20892282 TI - Baltimore-The Aftermath. PMID- 20892283 TI - The National Medical Association Meets in Newark, 1929. PMID- 20892284 TI - Pre-Medical Education. PMID- 20892285 TI - National Medical Association Secretaries. PMID- 20892286 TI - Dr. Williston Passes Away. PMID- 20892288 TI - A Medical Officer in the President's Cabinet. PMID- 20892287 TI - Ex-Presidents' Council. PMID- 20892289 TI - Our New President and President-Elect. PMID- 20892291 TI - Hematuria, as a Result of Lesions Within, or Directly Affecting the Bladder. PMID- 20892290 TI - Essential Hypertension. PMID- 20892292 TI - The Hospital Survey. PMID- 20892293 TI - Should the Curette be Discarded? PMID- 20892294 TI - Fraudulent Advertising. PMID- 20892295 TI - The Influenza Epidemic. PMID- 20892297 TI - Dean Balloch Honored. PMID- 20892296 TI - National Negro Health Week. PMID- 20892298 TI - The 1929 Newark Meeting of the National Medical Association. PMID- 20892299 TI - The Conservation of Negro Infant Life. PMID- 20892300 TI - Treatment of Fractures. PMID- 20892302 TI - Secondary Syphilis. PMID- 20892301 TI - Primary Syphilis. PMID- 20892303 TI - Cardiovascular Syphilis: A Summary of Its Outstanding Features. PMID- 20892305 TI - Syphilis of the Bones. PMID- 20892304 TI - Meningo-Vascular Syphilis. PMID- 20892306 TI - Syphilis of the Parenchyma. PMID- 20892307 TI - Syphilis of the Brain and Cord. PMID- 20892308 TI - Obscure Syphilitic Manifestations. PMID- 20892310 TI - A Symposium on Syphilis. PMID- 20892309 TI - Comparative Therapy in Syphilis. PMID- 20892312 TI - The Newark Meeting of the National Medical Association. PMID- 20892311 TI - The U. S. Veterans' Hospital, Tuskegee, Ala., Colonel Joseph Henry Ward. PMID- 20892313 TI - For a Greater Meharry. PMID- 20892314 TI - X-Ray Treatment of Hyperthyroidism. PMID- 20892315 TI - Acidosis. PMID- 20892316 TI - Mastoid Disease. PMID- 20892317 TI - Cancer. PMID- 20892318 TI - The Diagnosis and Treatment of a Degenerated Fibroid Uterus and Its Complications. PMID- 20892319 TI - Our Hospital Problems. PMID- 20892320 TI - A Timely Editorial. PMID- 20892322 TI - The Doctor's Vacation. PMID- 20892321 TI - The Medical Profession. PMID- 20892323 TI - The Newark Meeting. PMID- 20892324 TI - Old North State Medical, Dental and Pharmaceutical Society. PMID- 20892325 TI - Acute Rheumatic Fever. PMID- 20892326 TI - Acute Rheumatism of Childhood. PMID- 20892327 TI - Discussion on Rheumatism. PMID- 20892329 TI - Treatment of Acute Rheumatic Fever. PMID- 20892328 TI - Diagnosis of Acute Rheumatic Fever. PMID- 20892330 TI - Intestinal Obstruction Caused by the Use of a Murphy Button---A Case. PMID- 20892332 TI - Acute Abdominal Attacks-Differential Diagnosis. PMID- 20892331 TI - Recent Advances in Medicine and Surgery. PMID- 20892334 TI - The Mirage of One Physiologic Positive From Two Pathologic Negatives. PMID- 20892333 TI - Malaria. PMID- 20892335 TI - Some Objective Symptoms of Syphilis in Infants. PMID- 20892336 TI - Apparent Circulatory Inpairments in Life Insurance Examinations. PMID- 20892337 TI - The Newark Meeting of the National Medical Association. PMID- 20892339 TI - Our New President and President-Elect. PMID- 20892338 TI - Social Events at the Newark Meeting. PMID- 20892341 TI - By the Way. PMID- 20892340 TI - Dr. Frank S. Hargrave, an Assemblyman. PMID- 20892342 TI - Some Problems Encountered in Surgery of the Intestines. PMID- 20892343 TI - Ethylene-The New General Anesthetic. PMID- 20892344 TI - The Medico-Legal Witness. PMID- 20892345 TI - Food Allergy-Two Unusual Cases. PMID- 20892346 TI - Curability of Tuberculosis. PMID- 20892347 TI - Tuberculosis in the Negro. PMID- 20892348 TI - Intravenous Therapy. PMID- 20892349 TI - Non-Surgical Treatment of Certain Gynecological Conditions. PMID- 20892350 TI - Some Facts Relative to Negro Mortality in the United States. PMID- 20892351 TI - Exploitation of the Sick. PMID- 20892352 TI - The Tuberculosis Problem. PMID- 20892353 TI - Conservative Gynecology. PMID- 20892354 TI - The Georgia State Medical Association Makes a New Move. PMID- 20892355 TI - The National Hospital Association. PMID- 20892356 TI - The Negro Death Rate. PMID- 20892358 TI - The John A. Andrew Clinics. PMID- 20892357 TI - National Negro Health Week. PMID- 20892359 TI - Gall-Bladder Surgery. PMID- 20892360 TI - Laceration of the Kidney; A Report of a Case. PMID- 20892361 TI - Health Service in a Negro District. PMID- 20892362 TI - Local Anesthesia. PMID- 20892363 TI - Syphilis, as Seen by the Ophthalmologist. PMID- 20892364 TI - The Eye Gone Astray. PMID- 20892365 TI - Synopsis of the Health Inventory of New York City From the Welfare Council of New York City. PMID- 20892366 TI - Some Significant Negro Movements to Lower their Mortality. PMID- 20892368 TI - Our Hospital Number. PMID- 20892367 TI - The Indianapolis Meeting. PMID- 20892370 TI - Attendance at Annual Sessions. PMID- 20892369 TI - The John A. Andrew Clinic. PMID- 20892371 TI - The Negro Hospital Renaissance. PMID- 20892372 TI - A Brief Study of the Hospital Situation Among Negroes. PMID- 20892373 TI - Hospitals and Health. PMID- 20892374 TI - Mercy Hospital. PMID- 20892375 TI - New Nurses' Home of Mercy Hospital and School for Nurses. PMID- 20892376 TI - Hospitals in Chicago. PMID- 20892377 TI - The Negro Physicians and the Hospitals of Cleveland. PMID- 20892378 TI - Kansas City (Missouri) Hospitals. PMID- 20892379 TI - The New Provident Hospital and Training School. PMID- 20892380 TI - Flint-Goodrich Hospital. PMID- 20892381 TI - The Hospital Situation in Nashville, Tenn. PMID- 20892382 TI - The Hospitals in New York State and Harlem. PMID- 20892383 TI - U. S. Veterans' Hospital. PMID- 20892384 TI - St. Agnes Hospital. PMID- 20892385 TI - The John A. Andrew Memorial Hospital. PMID- 20892386 TI - The Lincoln Hospital. PMID- 20892387 TI - The Missouri Hospital Situation. PMID- 20892389 TI - The L. Richardson Memorial Hospital. PMID- 20892388 TI - Some Educational Advantages of the Freedmen's Hospital and Asylum, Now a Prime Factor in Training Physicians and Nurses. PMID- 20892390 TI - Provident Hospital. PMID- 20892391 TI - The Hospital in Modern Communities. PMID- 20892392 TI - The New Meharry Medical College Plant. PMID- 20892393 TI - Working Benevolent Society Hospital. PMID- 20892394 TI - Mercy Hospital. PMID- 20892395 TI - Carson's Private Hospital. PMID- 20892396 TI - The Houston Negro Hospital. PMID- 20892397 TI - Dunbar Memorial Hospital. PMID- 20892398 TI - Whittaker Memorial Hospital and Training School for Nurses. PMID- 20892399 TI - Mercy Sanitarium. PMID- 20892401 TI - Kenney Memorial Hospital. PMID- 20892400 TI - Three Hospitals. PMID- 20892402 TI - The Dentist in the Hospital. PMID- 20892404 TI - The Willis Physio-Therapeutic Sanitarium. PMID- 20892403 TI - Burrell Memorial Hospital. PMID- 20892405 TI - Prairie View Hospital. PMID- 20892406 TI - The Home Infirmary. PMID- 20892407 TI - St. John Hospital. PMID- 20892408 TI - People's Hospital. PMID- 20892409 TI - Our Hospital Number. PMID- 20892410 TI - The New Hospital Era. PMID- 20892411 TI - Our Hospitals. PMID- 20892412 TI - Hospital Attaches. PMID- 20892413 TI - The Hospital-Its Duty to the Public. PMID- 20892414 TI - Necessity for Rural Hospitals. PMID- 20892415 TI - What will Indianapolis do for the National Medical Association? PMID- 20892416 TI - Report of Interesting Case of Septico Pyaemia Due to Staphylococcus Hemolyticus. PMID- 20892417 TI - Intestinal Obstruction. PMID- 20892418 TI - Provision for Training Colored Medical Students. PMID- 20892419 TI - The Surgical Clearing House. PMID- 20892420 TI - Experimental Acute Morphine Intoxication and Some Implications in Morphine Medication. PMID- 20892421 TI - Hospitals and their Effective Use. PMID- 20892422 TI - Report of the Editor of the Journal of the National Medical Association to the Executive Board. PMID- 20892424 TI - Our New President. PMID- 20892423 TI - What did Indianapolis do for the National Medical Association? PMID- 20892425 TI - Professional Liability. PMID- 20892426 TI - Dr. Perry Honored. PMID- 20892427 TI - Dr. Alan P. Smith Elected to Membership in the American Psychiatric Association. PMID- 20892428 TI - Dr. R. H. Brooks Passes. PMID- 20892430 TI - A Visit to the Plant of Eli Lilly & Company. PMID- 20892431 TI - An Opportunity. PMID- 20892432 TI - Comment on Hospital Edition of Journal. PMID- 20892433 TI - Mental Hygiene and the American Negro. PMID- 20892434 TI - Tularemia. PMID- 20892435 TI - Theoretic and Clinical Chemotherapy. PMID- 20892436 TI - Contribution of an Unknown Negro to Anesthesia. PMID- 20892437 TI - Lung Abscess. PMID- 20892439 TI - Entertaining the National Medical Association. PMID- 20892438 TI - The Drift to Specialism. PMID- 20892440 TI - Some Impressions of the White House Conference. PMID- 20892441 TI - The Selection of Surgery as a Career. PMID- 20892443 TI - National Negro Health. PMID- 20892442 TI - Our President-Elect. PMID- 20892444 TI - Physicians' Liability Insurance. PMID- 20892445 TI - Surgical Treatment of Congenital Malformations of the Colon. PMID- 20892446 TI - The Artificial Feeding of Infants. PMID- 20892447 TI - Sterility in the Male. PMID- 20892448 TI - Childhood Tuberculosis. PMID- 20892449 TI - Laminectomy for Paraplegia of Lower Extremities. PMID- 20892450 TI - Renal Tuberculosis with Report of a Case. PMID- 20892451 TI - Traumatic Rupture of Intestines due to Air Under Pressure : (With Report of Three Cases). PMID- 20892452 TI - Conservatism in Diseases of the Female Pelvis. PMID- 20892453 TI - Health Education in Public Schools. PMID- 20892454 TI - Cerebro-Spinal Fever. PMID- 20892455 TI - The Atlanta Meeting. PMID- 20892456 TI - Fibroplastic Diathesis. PMID- 20892457 TI - Isn't it Strange? PMID- 20892458 TI - The White House Conference: Explanation. PMID- 20892459 TI - The White House Conference. PMID- 20892460 TI - Professional Esprit de Corps. PMID- 20892461 TI - Our Salutation to the 1931 M.D.'s. PMID- 20892462 TI - On the Firing Line. PMID- 20892463 TI - It had to Come. PMID- 20892464 TI - The Inter-Racial Way. PMID- 20892465 TI - Save Your Cuts. PMID- 20892466 TI - A Plea for Dentistry. PMID- 20892467 TI - Neuropsychiatry in the Practice of Medicine and Surgery. PMID- 20892468 TI - Post-Graduate Study in Vienna. PMID- 20892469 TI - Tryparsamide Therapy of Neurosyphilis in Negroes. PMID- 20892470 TI - The Need for a Sound Professional Preparation for Colored Nurses. PMID- 20892472 TI - A Case Record of Osteomyelitis of the First Metatarsal Bone of the Right Foot. PMID- 20892471 TI - Acute Pericarditis with Effusion: (With Two Case Reports). PMID- 20892473 TI - Atlanta-Our Opportunity. PMID- 20892474 TI - Surgery as a Specialty. PMID- 20892475 TI - On to California! PMID- 20892476 TI - Isolation in Medicine. PMID- 20892477 TI - Society for Negro Specialists. PMID- 20892478 TI - A Recommended Hospital Program. PMID- 20892479 TI - Pellagra, Unemployment and Economic Depression. PMID- 20892481 TI - Editorial Squibb. PMID- 20892480 TI - Extract from Brief Sketch of the Life and Work of Dr. J. Edward Perry. PMID- 20892483 TI - The Inter-Racial Committee of Montclair, New Jersey: Report of Survey of Hospital Committee. PMID- 20892485 TI - Renaissance of the National Medical Association. PMID- 20892484 TI - Syphilitic Osteitis and Gummatous Ulcer of the Leg : (Report Of A Case). PMID- 20892486 TI - A Reasonable Program for our Hospitalization Movement. PMID- 20892488 TI - Surgical After-Care of the Parturient Woman. PMID- 20892487 TI - Maternal Care. PMID- 20892490 TI - Atlanta: What Next? PMID- 20892489 TI - The Negro Infant Mortality Rate and What the Well-Baby Clinics are doing to Lower It. PMID- 20892491 TI - Opportunity and Responsibility. PMID- 20892492 TI - Something Worth Reading. PMID- 20892493 TI - The President-Elect. PMID- 20892494 TI - A Unique and Auspicious Beginning. PMID- 20892495 TI - Unemployment Relief. PMID- 20892496 TI - Dr. Turner, a Police Surgeon. PMID- 20892497 TI - N. M. A. Executive Board and Cabinet Meetings. PMID- 20892498 TI - Neglected Fields for Research. PMID- 20892500 TI - Surgical Treatment of Benign Hypertrophy of the Prostate. PMID- 20892499 TI - The President's Column. PMID- 20892501 TI - Preventive and Reparative Surgery Before, During and After Delivery, in the Interest of Maternal and Child Welfare. PMID- 20892502 TI - A Study of Maternal and Child Welfare Work in North Carolina. PMID- 20892503 TI - Childhood Type of Tuberculosis in Negroes. PMID- 20892504 TI - Erythromelalgia Consequent to Hemiplegia : With Report of a Case. PMID- 20892505 TI - A Crisis a Verted. PMID- 20892507 TI - Dr. Michel O. Dumas. PMID- 20892506 TI - Cupidity in Medicine. PMID- 20892509 TI - Julius Rosenwald. PMID- 20892508 TI - Negro Health in 1940. PMID- 20892511 TI - The Tuskegee Clinics. PMID- 20892510 TI - Meharry Medical College 1876-1931. PMID- 20892512 TI - Our California Meeting. PMID- 20892513 TI - National Negro Health Week. PMID- 20892514 TI - A Thought. PMID- 20892515 TI - Just Human. PMID- 20892516 TI - Rupture of Bulbous Urethra. PMID- 20892518 TI - Goitre: Etiology, Symptoms and Diagnosis. PMID- 20892517 TI - The History of Anaesthesia. PMID- 20892519 TI - Cardiac Arhythmias. PMID- 20892520 TI - The Management of Chronic Pelvic Infections in Women. PMID- 20892521 TI - Some Clinical Lessons from a Year's Observation in the Department of Pathology of the University of Vienna. PMID- 20892523 TI - What Is Ours, We Should Conserve. PMID- 20892522 TI - The Fifth Year Training of the Negro Medical Student. PMID- 20892524 TI - Birth Control for the Negro-A Fad or a Necessity. PMID- 20892525 TI - Skull Fractures or Brain Injuries. PMID- 20892526 TI - Chronological Mutations Affecting Medicine. PMID- 20892528 TI - Health and Hygiene-Food Versus Clothing. PMID- 20892527 TI - An All-Important Health Problem. PMID- 20892529 TI - Editorial-Dr. Lanon's Appeal. PMID- 20892530 TI - The Presidents Column. PMID- 20892531 TI - Surgical Maggots in the Treatment of Osteomyelitis. PMID- 20892533 TI - A Pulmonary Case for Diagnosis. PMID- 20892532 TI - Observations from a Study of 200 Fracture Cases. PMID- 20892534 TI - What Future Is There for the Negro Pharmacist? PMID- 20892535 TI - The Treatment of Pulmonary Tuberculosis in the Negro With Artificial Pneumothorax. PMID- 20892536 TI - The veteran's Hospital Controversy. PMID- 20892537 TI - The Washington Meeting. PMID- 20892538 TI - The President-Elect. PMID- 20892540 TI - Dr. H. F. Gamble Passes. PMID- 20892539 TI - Dr. Julian H. Lewis. PMID- 20892541 TI - Functional Circulatory Stasis of the Cerebrospinal Axis. PMID- 20892543 TI - Chicago; The National Medical Association: An Appeal. PMID- 20892542 TI - Observations from the Study of Two Hundred Fracture Cases. PMID- 20892544 TI - Committee on the Cost of Medical Care: An Open Season in No Man's Land. PMID- 20892545 TI - Dr. Fishbein. PMID- 20892547 TI - Pharmaceutical Notes. PMID- 20892546 TI - The Negro Doctor and the Threatened Socialization of Medicine. PMID- 20892548 TI - Cavernous Sinus Thrombosis-Case Report. PMID- 20892549 TI - An Experimental Investigation of the Treatment of Acute Barbiturate Intoxication. PMID- 20892550 TI - Cholelithiasis and Carcinoma of the Gall Bladder : A Post-mortem Review with Report of a Case. PMID- 20892551 TI - Endometriosis-Report of a Spontaneously Ruptured Ovarian Cyst. PMID- 20892552 TI - Pelvic Neuritis, Its Pathology and Treatment. PMID- 20892553 TI - Tonsillectomy by the General Practitioner. PMID- 20892554 TI - Changing Conditions in Medical Practice. PMID- 20892556 TI - The John A. Andrew Clinics. PMID- 20892555 TI - Fundamentals of Oral Surgery. PMID- 20892558 TI - The Chicago Meeting of the N. M. A. PMID- 20892557 TI - The Post-Graduate Course in Medicine at St. Phillips Hospital. PMID- 20892560 TI - Constituent Association Fees. PMID- 20892559 TI - A National Medical Association Exhibit with a "Century of Progress". PMID- 20892562 TI - The New Constitution. PMID- 20892561 TI - A Neglected Asset of Our Profession. PMID- 20892563 TI - Surgical Mortality. PMID- 20892564 TI - Treatment of Cancer of the Breast. PMID- 20892565 TI - Pregnancy Tests. PMID- 20892567 TI - Comparison of Costs of Proprietary and Non-Proprietary Products. PMID- 20892566 TI - Acute Barbiturate Poisoning with Picrotoxin. PMID- 20892568 TI - Editor's Note. PMID- 20892569 TI - Narcotic Prescriptions. PMID- 20892570 TI - Therapeutic Suggestions. PMID- 20892572 TI - The Management of Fractures of the Spine. PMID- 20892571 TI - Etiology and Treatment of Carcinoma in the Female Generative Organs. PMID- 20892574 TI - Obstetric Amnesia and Analgesia : With Special Reference to the Use of Sodium Iso Amyl Ethyl Barbiturate. PMID- 20892573 TI - Coronary Disease. PMID- 20892575 TI - A Case Study of Negro Infant Mortality in Manhattan Due to Respiratory and Gastro Intestinal Diseases. PMID- 20892576 TI - Emotions as Functional Factors in the Etiology and Prognosis of Diseases. PMID- 20892577 TI - Our Twenty-fifth Anniversary. PMID- 20892579 TI - The Private Hospital. PMID- 20892578 TI - Last Call for Chicago Meeting. PMID- 20892581 TI - The Drunken Driver-A Menace. PMID- 20892580 TI - Free Membership to Recent Graduates in Medicine. PMID- 20892582 TI - Where Were We Born? PMID- 20892583 TI - Annual Meeting: 38th or 39th, Which? PMID- 20892584 TI - Current Medical Thought. PMID- 20892586 TI - The Necessity of Bronchoscopy in the Diagnosis and Treatment of the Lungs. PMID- 20892585 TI - Some Notes on the History of the National Medical Association. PMID- 20892587 TI - Carcinoma of the Esophagus. PMID- 20892588 TI - Gas Gangrene: Report of Two Cases. PMID- 20892589 TI - The Chicago Meeting. PMID- 20892590 TI - Goiter: 1. Historical Outline. PMID- 20892591 TI - Meharry, The Professional Mecca in 1934. PMID- 20892592 TI - Our General Secretary. PMID- 20892593 TI - Our President. PMID- 20892595 TI - Abstract; Spirochaetal Findings in the Brains of Paretics Treated with Malaria. PMID- 20892594 TI - Meharry and the National Board of Medical Examiners. PMID- 20892596 TI - Abstract; The Importance of Early Diagnosis in Cerebral Syphilis. PMID- 20892599 TI - Study of Twenty Cases of Gastric and Duodenal Ulcer in the Negro. PMID- 20892600 TI - An Interpretation of the Significance of the Homer G. Phillips Hospital. PMID- 20892601 TI - Statistics and Mortality Trends. PMID- 20892602 TI - Some Observations on and Lessons from the Experiences of the Past Ten Years. PMID- 20892603 TI - What Is a Nurse? PMID- 20892605 TI - "Go and Build One For Yourselves". PMID- 20892604 TI - The Journal and 1934. PMID- 20892606 TI - The Homer G. Phillips Hospital: A New Hope. PMID- 20892607 TI - Summary of the Nature of Goiter. PMID- 20892608 TI - The Nashville Meeting of the N. M. A. PMID- 20892609 TI - A Challenge to Organized Negro Medicine. PMID- 20892610 TI - President-Elect J. H. Hale, A.B., M.D. PMID- 20892612 TI - The National Pharmaceutical Association. PMID- 20892611 TI - National Negro Health Week. PMID- 20892614 TI - Our Staff Members. PMID- 20892613 TI - The John A. Andrew Clinic. PMID- 20892616 TI - "The Effect of Worry on Digestion". PMID- 20892615 TI - Some Neuropsychiatric Observations. PMID- 20892617 TI - Fixed Dermatitis Due to Tryparsamide. PMID- 20892618 TI - Talkie Films Help Diagnosis of Disease. PMID- 20892619 TI - Pneumothorax, A Radiographic Study. PMID- 20892621 TI - Treatment of Fractures of the Lower End of the Radius. PMID- 20892620 TI - The Art and the Science of Medicine. PMID- 20892622 TI - Acute Suppurative Thyroiditis: Presentation of Two Cases. PMID- 20892623 TI - A Brief History of the Origin of the John A. Andrew Clinics by the Founder. PMID- 20892624 TI - Management of Anhydremia in Infancy and Childhood from the Standpoint of the General Practitioner. PMID- 20892625 TI - Anaphylactoid Reactions in Relation to Trypanosome Infections and the Presence of Iso-Agglutinogens in White Rats. PMID- 20892627 TI - Honor To Whom Honor Is Due. PMID- 20892626 TI - Oslerism and Ye Editor. PMID- 20892629 TI - A Second Veterans Hospital for Our Group. PMID- 20892628 TI - Professional Ethics. PMID- 20892630 TI - Brain Abscess Consequent to Latent Head Trauma. PMID- 20892631 TI - Subperiosteal Osteogenic Sarcoma: (Report of three cases). PMID- 20892632 TI - Amebic Dysentery and its Treatment. PMID- 20892634 TI - Outline of the Present Status of the Surgical Treatment of Hyperthyroidism. PMID- 20892633 TI - Coronary Occlusion. PMID- 20892636 TI - Look to Nashville. PMID- 20892635 TI - Bony Gauges of Growth, Age and Disease. PMID- 20892637 TI - Our Professional Evaluation. PMID- 20892638 TI - State Medicine. PMID- 20892639 TI - The National Association of Colored Graduate Nurses. PMID- 20892641 TI - The Journal of the National Pharmaceutical Association. PMID- 20892640 TI - National Health Library. PMID- 20892642 TI - Department of Neuropsychiatry. PMID- 20892643 TI - Modern Methods in the Treatment of Pulmonary Tuberculosis. PMID- 20892644 TI - The Diagnosis and Collapse Therapy of Pulmonary Tuberculosis with Case Reports and Lantern Demonstrations. PMID- 20892646 TI - Dr. Charles Victor Roman. PMID- 20892645 TI - Appendicitis. PMID- 20892648 TI - Health Insurance. PMID- 20892647 TI - The Nashville Meeting of the N. M. A. PMID- 20892650 TI - The President-Elect. PMID- 20892649 TI - Professional Esprit De Corps. PMID- 20892652 TI - Item of Interest. PMID- 20892651 TI - Department of Neuropsychiatry. PMID- 20892653 TI - Radiation Therapy in Carcinoma of the Cervix. PMID- 20892655 TI - Report of Case of Tubercular Orchitis. PMID- 20892654 TI - The Operation. PMID- 20892656 TI - Aortic Regurgitation, Diagnosis and Differential Diagnosis. PMID- 20892658 TI - The Recovery of a Case of Acute Mercurial Poisoning by the Use of Sodium Thiosulphate. PMID- 20892657 TI - The Management of Appendicitis. PMID- 20892659 TI - Psychiatry and Medicine. PMID- 20892660 TI - Recognition of the Negro Medical Profession in Public Health Work. PMID- 20892662 TI - Federal Emergency Relief Administration as Affecting the Negro Professionals. PMID- 20892661 TI - "Bacillus Aerogenese Capsulatus". PMID- 20892664 TI - Dr. Baumgardner. PMID- 20892663 TI - National Negro Health Week. PMID- 20892665 TI - Dr. Louis T. Wright. PMID- 20892666 TI - The John A. Andrews Clinic. PMID- 20892667 TI - Tuberculosis of Bones and Joints. PMID- 20892669 TI - Canadian Letter. PMID- 20892668 TI - Therapeutic Suggestions. PMID- 20892670 TI - Ave Atque Vale, Romane. PMID- 20892671 TI - The Treatment of Fractures with Plaster of Paris Cast. PMID- 20892672 TI - The Incidence of Syphilis in Negroes. PMID- 20892673 TI - Simplified Diets and the Use of Insulin in the Treatment of Uncomplicated Diabetes Mellitus. PMID- 20892674 TI - The Perforated Appendix... Its Management. PMID- 20892675 TI - Neuronitis, a Complication of Pregnancy. PMID- 20892676 TI - Acute Intestinal Obstruction. PMID- 20892677 TI - Our Hospital Problem. PMID- 20892678 TI - Tuskegee's Clinic Goes Forward. PMID- 20892679 TI - Dr. H. M. Green: An Appreciation. A Practical Experiment. PMID- 20892680 TI - The Anesthetist. PMID- 20892681 TI - A Plea from without for Organized Negro Medicine. PMID- 20892682 TI - Present Status of the Negro Physician and Negro Patient. PMID- 20892683 TI - Patronize our Advertisers. PMID- 20892684 TI - Correction. PMID- 20892685 TI - Modern Treatment of Pulmonary Tuberculosis: Surgical. PMID- 20892686 TI - The Modern Concept of Acute Intestinal Obstruction. PMID- 20892687 TI - Artificial Pneumothorax in Children between 3 Years and 12 Years. PMID- 20892689 TI - The 41st Annual Session of the National Medical Association. PMID- 20892688 TI - Acute Aseptic Meningitis. PMID- 20892690 TI - New Orleans. PMID- 20892691 TI - Dr. D. A. Ferguson. PMID- 20892692 TI - Let's Go to New Orleans. PMID- 20892693 TI - Therapeutic Suggestions. PMID- 20892694 TI - Glaucoma with Special Reference to its Pathology and A Report of Two Cases of Secondary Glaucoma. PMID- 20892695 TI - Index Medicus of Negro Authors. PMID- 20892696 TI - Uterosalpingography. PMID- 20892697 TI - Food in Health and Disease. PMID- 20892698 TI - "Pneumococcus Septicemia". PMID- 20892699 TI - Dr. Daniel Williams takes priority in successful operation for Stab Wound of Human Heart. PMID- 20892700 TI - Dr. Frederick Douglas Patterson. PMID- 20892702 TI - Our President. PMID- 20892701 TI - Our New Orleans Meeting. PMID- 20892703 TI - The New Orleans Meeting. PMID- 20892704 TI - Are We Conscious for Better Hospitals? PMID- 20892705 TI - Sunday Programs. PMID- 20892706 TI - Dr. C. A. Lanon, General Secretary. PMID- 20892707 TI - Therapeutic Suggestions. PMID- 20892708 TI - Aneurysm With Report of a Case. PMID- 20892709 TI - A Few Excerpts of Recent Medical Progress as Found in the Literature. PMID- 20892710 TI - The Reflexes and Their Significance. PMID- 20892711 TI - Diabetic Management. PMID- 20892712 TI - The Red Cell Sedimentation Test as an Aid in the Diagnosis and Prognosis in Tuberculosis. PMID- 20892713 TI - The Rev. Amos Carnegie Hospital Scheme. PMID- 20892714 TI - "Man or Super-Man". PMID- 20892716 TI - Neurological Control of the Urinary Bladder. PMID- 20892715 TI - Total Thyroidectomy for Heart Disease. PMID- 20892717 TI - The Tuskegee Clinic. PMID- 20892718 TI - Roscoe Conkling Giles. PMID- 20892719 TI - Dr. J. R. Levy Passes. PMID- 20892720 TI - Some Medical Social Problems in Hospitals. PMID- 20892721 TI - Therapeutic Suggestions. PMID- 20892722 TI - Trichomonas Vaginitis in Pregnancy. PMID- 20892724 TI - Medical Economics. PMID- 20892723 TI - Report of Three Cases of Melanosarcoma in Negroes-One With Massive Hemorrhagic Cystic Degeneration of the Liver. PMID- 20892725 TI - The Evolution of Medicine; Present Requirements; Ideals; Is "State" Medicine Coming? PMID- 20892727 TI - Medical Economics. PMID- 20892726 TI - X-Rays and Fractures. PMID- 20892728 TI - A Message to our Constituency. PMID- 20892729 TI - A Dental Clinic at the John A. Andrew Clinic. PMID- 20892731 TI - National Negro Health Observance. PMID- 20892730 TI - Twenty-Fifth Anniversary of the John A. Andrew Clinic. PMID- 20892733 TI - Philadelphia, The Mecca of 1936. PMID- 20892732 TI - Over the Top. PMID- 20892734 TI - A Message to our Hospitals. PMID- 20892736 TI - Therapeutic Suggestions. PMID- 20892735 TI - Rural Nursing. PMID- 20892737 TI - A Plea for the Admittance of Negro Doctors to Municipal Hospital Staffs. PMID- 20892738 TI - Undulant Fever. PMID- 20892739 TI - The Organization of a Group Hospital Plan. PMID- 20892741 TI - The Present Status of the Diagnosis and Treatment of Carcinoma of Uterus. PMID- 20892740 TI - A Statistical Study of 407 Gynecic Operations-with Special References to Uterine Fibroids. PMID- 20892742 TI - Rheumatic Heart Disease in Children. PMID- 20892743 TI - Compound Fracture Complicated with Gas Bacillus Infection. PMID- 20892744 TI - The Crippled Child. PMID- 20892745 TI - Group Hospitalization. PMID- 20892746 TI - More About Removal of the Normal Thyroid Gland for Heart Disease. PMID- 20892747 TI - Liabilities and Assets. PMID- 20892748 TI - The Department of Neuro-Psychiatry. PMID- 20892749 TI - Therapeutic Suggestions. PMID- 20892750 TI - Glaucoma. PMID- 20892751 TI - A Comparison of the Subjective Effects of Hypnotic Doses-Bromural, Evipal and Ortal. PMID- 20892752 TI - Surgical Treatment of the Hypertrophied Prostate: Perineal and Suprapubic Prostatectomy. PMID- 20892754 TI - The Legal Aspects Of Medical Economics. PMID- 20892753 TI - The Treatment of Pelvic Inflammatory Disease On the Gynecological Service at Harlem Hospital. PMID- 20892755 TI - Dentistry and Pharmacy as a Vocation. PMID- 20892757 TI - The President-Elect. PMID- 20892756 TI - First Formal Instruction in Dentistry in America. PMID- 20892758 TI - Fundamentals of Hospital Administration. PMID- 20892760 TI - Gynecological Urology. PMID- 20892761 TI - Cases of Coma Showing Urinary Sugar. PMID- 20892762 TI - Recent Developments in the Specific Prophylaxis of Communicable Diseases. PMID- 20892763 TI - Clinical Aspects and Treatment of Lymphogranuloma Inguinale. PMID- 20892765 TI - There is Light. PMID- 20892764 TI - Professional Recognition. PMID- 20892767 TI - The John A. Andrew Clinics. PMID- 20892766 TI - A Lost Cane. PMID- 20892768 TI - Overactivity As A Potent Factor in the Etiology of Some Nervous Diseases. PMID- 20892769 TI - Pernicious Anemia in The Negro With Report of Four Cases. PMID- 20892770 TI - Some Subjective Symptoms in Dilaudid Medication. PMID- 20892772 TI - Some Results with the Elliott Treatment in Pelvic Inflammation and Prostatitis. PMID- 20892771 TI - Medical and Dental Economics. PMID- 20892773 TI - A Simple, Successful, Non-Operative Treatment for Fecal Fistula. PMID- 20892774 TI - Research and Scientific Medicine. PMID- 20892775 TI - A Prophecy in Ethnology. PMID- 20892776 TI - The Journal on Top. PMID- 20892777 TI - A Renewed Douglas Hospital. PMID- 20892779 TI - Who is Who. PMID- 20892778 TI - Vision Test to Reduce Automobile Accidents. PMID- 20892780 TI - Resume of "The Depression and Mental Disease". PMID- 20892781 TI - "Out of Darkness". PMID- 20892782 TI - Tobacco Ash. PMID- 20892783 TI - The Problems of the Rural Doctor. PMID- 20892784 TI - Colostomy. PMID- 20892786 TI - Meharry Professor Qualifies. PMID- 20892785 TI - Who is Who. PMID- 20892787 TI - Sudden Simultaneous Bilateral Embolism of the Popliteal Arteries. PMID- 20892789 TI - Advanced X-Ray Therapy. PMID- 20892788 TI - The Institutional Care of Negroes with Mental Diseases in the United States. PMID- 20892790 TI - Uterine Tumors : A Review With Case Summaries and Photographic Illustrations. PMID- 20892791 TI - The Institutional Care of Negroes with Mental Diseases in the United States. PMID- 20892792 TI - St. Louis Meeting. PMID- 20892793 TI - Insulin Hypoglycemic Shock in Treatment of Dementia Praecox. PMID- 20892794 TI - Syphilis and Some Statistics and Observations of Frequency Among Negroes. PMID- 20892796 TI - Who's Who. PMID- 20892795 TI - The Journal of the National Medical Association. PMID- 20892797 TI - The Journal of the National Hospital Association. PMID- 20892798 TI - Postgraduate Training of Negro Physicians in the Clinical Management and Public Health Control of Syphilis. PMID- 20892799 TI - Postgraduate Training of Negro Physicians in the Clinical Management and Public Health Control of Syphilis. PMID- 20892802 TI - St. Mary's Infirmary as a Hospital for Colored People. PMID- 20892801 TI - A Short History of Peoples Hospital. PMID- 20892803 TI - The Homer G. Phillips Hospital. PMID- 20892804 TI - Post Graduate Medical Education and the Negro Physician. PMID- 20892805 TI - The Future of the Negro in Dentistry and What can be Done about it. PMID- 20892807 TI - "Facing a Critical Year". PMID- 20892806 TI - Blood Transfusion. PMID- 20892809 TI - Conditions of the Cervical Spine Responsible for Segmental Neuritis. PMID- 20892808 TI - "Shadow on the Land". PMID- 20892810 TI - Negro Health Week. PMID- 20892811 TI - Tuskegee Annual Clinic. PMID- 20892812 TI - St. Louis Hospitals. PMID- 20892813 TI - Advances in Tuberculosis Work. PMID- 20892814 TI - Medical Libraries in Approved Hospitals for Negroes. PMID- 20892815 TI - A Consideration of the Effects of Focal Infection on the Susceptibility of Certain Endothelial Lined Cavities. PMID- 20892817 TI - Venereal Disease Control. PMID- 20892816 TI - Report of a Case of Heart Disease with Terminal Intestinal Perforation. PMID- 20892818 TI - The Control of Gonorrhea. PMID- 20892819 TI - The Prophylaxis of Genito-Urinary Diseases. PMID- 20892820 TI - Management of Acute Gonorrhea In the Male. PMID- 20892821 TI - Gonorrhea in the Female. PMID- 20892822 TI - Some Newer Remedies in the Treatment of Gonorrhea. PMID- 20892824 TI - From Atlanta 1895 to Hampton 1938. PMID- 20892823 TI - The Elliott Treatment as an Office Procedure. PMID- 20892825 TI - Douglas Hospital Receives "A" Rating. PMID- 20892827 TI - The Treatment of Pneumonia. PMID- 20892826 TI - Pulmonary Lympho-Sarcoma: Report of a Case. PMID- 20892828 TI - Lymphopathia Venereum: Case Report. PMID- 20892829 TI - Congenital Absence of the Upper Two-Thirds of the Vagina, with a Rudimentary, Unicornate Uterus. PMID- 20892830 TI - Remarkable Service Performed by Provident Hospital-Chicago Institution, Finest Voluntary Hospital Operated by Negroes. PMID- 20892832 TI - X-Ray Treatment of Inflammatory Diseases. PMID- 20892831 TI - A Plea for Independent Racial Thought and Action. PMID- 20892833 TI - A "Fireside Chat": Give the Journal a Break. PMID- 20892834 TI - Filling the Bill. PMID- 20892835 TI - Dumas' Ascitic Trocar. PMID- 20892836 TI - A Compliment and an Appeal. PMID- 20892837 TI - Granuloma of the Cervix. PMID- 20892839 TI - The National Health Program. PMID- 20892838 TI - J. Leonidas Leach-Incoming President. PMID- 20892840 TI - Opening of Squibb Institute for Medical Research. PMID- 20892841 TI - Our Thanks to Hampton. PMID- 20892842 TI - The Still Small Voice. PMID- 20892843 TI - Study of the National Health Program and Proceedings of the House of Delegates, A.M.A.-Advised. PMID- 20892844 TI - The Federal Government and Organized Medicine in Closer Accord. PMID- 20892845 TI - Bi-Monthly Journal. PMID- 20892846 TI - The Forgotten Tenth. PMID- 20892848 TI - Everyone a Partner. PMID- 20892847 TI - American Medical Association Joins American Hospital Association in Approving Pre payment Medical as well as Hospital Service. PMID- 20892849 TI - Dedication of Squibb Institute for Medical Research. PMID- 20892850 TI - The Use of Atropine and Digitalis in Certain Forms of Decompensated Heart Disease. PMID- 20892851 TI - Diagnosis and Treatment of Neurosyphilis. PMID- 20892852 TI - Compulsion Neurosis Terminating in Folie a Deux. PMID- 20892853 TI - Psychiatric Aspect of Crime-Causes and Management of Juvenile Delinquents. PMID- 20892855 TI - Conference of Special Committee of National Medical Association with Government Officials in Washington Representing the President's National Health Program. PMID- 20892854 TI - Salutatory To The Bi-Monthly. PMID- 20892856 TI - The Status of the Negro Doctor in the National Health Program. PMID- 20892858 TI - The Intern Shortage. PMID- 20892857 TI - Do Goiters Disappear? PMID- 20892859 TI - Case Review of Twenty-five Consecutive Cases of Acute Appendicitis. PMID- 20892861 TI - The Use of Insulin in Dementia Praecox. PMID- 20892860 TI - Urinary Extravasation: A Report of 17 Cases. PMID- 20892862 TI - Post Graduate Instruction in Venereal Diseases. PMID- 20892863 TI - A Plan for a Highly Correlated Course in Anatomy at Meharry Medical College. PMID- 20892864 TI - A Morbidity Study of 271 Rural Negro Families in The Mississippi Delta. PMID- 20892865 TI - Observations on Control of Prenatal Syphilis. PMID- 20892866 TI - Too Much Surgery. PMID- 20892868 TI - Dr. Louis T. Wright. PMID- 20892867 TI - The Pneumonia Program. PMID- 20892869 TI - Some of the Problems of Tuberculosis. PMID- 20892870 TI - Tuberculosis Among Negroes. PMID- 20892871 TI - The Negro Physician. PMID- 20892873 TI - The Clinical Value of Gastroscopy in Gastric Diseases. PMID- 20892872 TI - Oxygen in Delirium Tremens. PMID- 20892874 TI - The General Practitioner. PMID- 20892876 TI - The 1939 Clinic-Tuskegee Institute. PMID- 20892875 TI - S. O. S. Save the Clinic. PMID- 20892878 TI - Mid-Year Meeting of the Executive Board of the National Medical Ass'n., Tuskegee Institute, Alabama. PMID- 20892877 TI - Insulin Versus Metrazol. PMID- 20892879 TI - What is Goiter? PMID- 20892880 TI - A Racial Complaint and an Apology with Redress. PMID- 20892881 TI - Dr. Roscoe C. Giles Admitted to American Board of Surgery. PMID- 20892882 TI - Dr. Ira McCown Scores. PMID- 20892884 TI - The Health Bulletin. PMID- 20892883 TI - Silver Anniversary, National Negro Health Week. PMID- 20892885 TI - Tuberculosis as Observed in Our Municipal Tuberculosis Hospitals with Reference to Collapse Therapy in the Negro. PMID- 20892887 TI - Post-Operative Eviscerations of Abdominal Wounds. PMID- 20892886 TI - Closed Intrapleural Pneumolysis in the Treatment of Pulmonary Tuberculosis : A Preliminary Report of Forty Operations. PMID- 20892888 TI - Carcinoma of the Rectum, Its Diagnosis and Treatment. PMID- 20892889 TI - An Explanation which is not an Apology. PMID- 20892890 TI - Our Good-Will Committee. PMID- 20892891 TI - Punjab Medical Journal. PMID- 20892892 TI - The National Health Act of 1939. PMID- 20892894 TI - Housing in New York for Convention. PMID- 20892893 TI - Our Birthday. PMID- 20892895 TI - Visit Booths of Exhibitors. PMID- 20892896 TI - The Tuskegee Nurse Training School and Clinic. PMID- 20892897 TI - Syphilis in Combination with Certain Diseases. PMID- 20892898 TI - The Rationale of Otomastoiditis: The Need for Better Treatment of Otomastoiditis. PMID- 20892899 TI - Granuloma Inguinale, Complicated with Syphiloma of Vulva and Chancroidal Infection : Report of a Case. PMID- 20892900 TI - Medical Curiosities. PMID- 20892902 TI - Our Retiring President. PMID- 20892901 TI - Endocrinology and the Future of Man. PMID- 20892903 TI - A Lost Opportunity. PMID- 20892904 TI - A Catastrophe Averted. PMID- 20892905 TI - Observations on the Use of Mare Gonadotropic Hormone. PMID- 20892906 TI - The Menace of Injection Treatment of Hemorroids. PMID- 20892907 TI - Microphotography With Professional View Camera. PMID- 20892908 TI - Food Allergy. PMID- 20892909 TI - The Negro Doctor and Organized Medicine. PMID- 20892910 TI - The Dr. John A. Kenney Testimonial Dinner. PMID- 20892912 TI - The Health Insurance Doctor: His Role in Great Britain, Denmark and France. PMID- 20892911 TI - The Monthly Journal. PMID- 20892913 TI - The Commission on Medical Economics and the Wagner Bill. PMID- 20892914 TI - The Democracy of the American Hospital Association. PMID- 20892915 TI - The Editor Looks Southward. PMID- 20892916 TI - Editorial Flashes. PMID- 20892917 TI - Twenty-One Million Italians Insured Against Tuberculosis. PMID- 20892918 TI - Our President-Elect. PMID- 20892919 TI - Surgery In Hyperthyroidism. PMID- 20892920 TI - Acute Mastoiditis With Report of Cases. PMID- 20892921 TI - The Advance of Physio-Therapy in the Science of Medicine. PMID- 20892922 TI - Appendicitis-An Analysis of 655 Operative Cases. PMID- 20892923 TI - Internships, Residencies and Post Graduate Training. PMID- 20892924 TI - Minimal Tuberculosis. PMID- 20892925 TI - Trends In Dental Education. PMID- 20892926 TI - The Proposed Development of Teaching Centers for Negro Personnel in Psychiatry. PMID- 20892927 TI - The Tuskegee Institute Annual Clinic. PMID- 20892929 TI - The 1940 Decennial Census. PMID- 20892928 TI - Anent the Commission on Medical Economics and the Wagner Bill. PMID- 20892931 TI - Present and Future Prospects of Pharmaceutical Education. PMID- 20892930 TI - United States Department of the Interior. PMID- 20892932 TI - Stercoral Appendix in Negroes: A Surgical Problem. PMID- 20892933 TI - Pneumothorax Clinic In Macon County, Alabama. PMID- 20892934 TI - Diagnosis Of Spondylolisthesis. PMID- 20892936 TI - When to Operate for Gallbladder Disease. PMID- 20892935 TI - The 29th Annual Clinic-John A. Andrew Memorial Hospital. PMID- 20892937 TI - Sigmund Freud. PMID- 20892938 TI - Infantile Paralysis Unit of the John A. Andrew Memorial Hospital. PMID- 20892939 TI - An Apology. PMID- 20892941 TI - The Medical Aspect Of The Acute Abdomen. PMID- 20892940 TI - Differential Diagnosis of the Acute Abdomen. PMID- 20892942 TI - The Acute Abdomen - The Surgical Management. PMID- 20892943 TI - Surgical Management Of Hyperthyroidism. PMID- 20892944 TI - Shortage Of Negro Doctors : With Special Reference to Residents and Internes. PMID- 20892946 TI - On To Texas. PMID- 20892945 TI - The Texas State Medical Association Welcomes. PMID- 20892947 TI - The Forty-Sixth Annual Session of the National Medical Association, Houston, Texas, August 12-16, 1940. PMID- 20892948 TI - Increasing Opportunities for the Clinician in Public Health Work. PMID- 20892949 TI - The Etiology Of Acute Abdominal Pain. PMID- 20892950 TI - Case Study Of Left Retroperitoneal Kidney Mass. PMID- 20892951 TI - Traumatic Rupture Of Right Hydronephrotic Kidney. PMID- 20892952 TI - Acute Abscess Of The Lung. PMID- 20892953 TI - The Possibilities Of X-Ray Therapy In The Treatment Of Cancer. PMID- 20892954 TI - A Professional Father-Son Liaison. PMID- 20892956 TI - American Medical Directory. PMID- 20892955 TI - A Plea for Equality in our National Preparedness Program. PMID- 20892958 TI - The President Honored. PMID- 20892957 TI - The Abuse of Words. PMID- 20892959 TI - Who's Who. PMID- 20892960 TI - A. N. Vaughn, M.D., President-Elect, N. M. A., 1940-1941. PMID- 20892961 TI - Nicotinic Acid and Drugs in the Treatment of Pellagra. PMID- 20892962 TI - The Incidence Of Heart Disease Among Negroes. PMID- 20892964 TI - Bleeding in the Third Trimester. PMID- 20892963 TI - A Radiologist's View on the Treatment of Carcinoma of the Breast. PMID- 20892965 TI - The Medical Management of Gallbladder Disease. PMID- 20892966 TI - Further Studies in Dilaudid Medication. PMID- 20892967 TI - Case History Of Streptococcus Meningitis. PMID- 20892969 TI - The Houston Meeting. PMID- 20892968 TI - The 1939 Scientific Exhibit of the Howard University School of Medicine. PMID- 20892971 TI - Pacifist - Standpatter - Evolutionist - Revolutionist - Which? PMID- 20892970 TI - A Lost Opportunity. PMID- 20892972 TI - Psychiatry and General Medicine. PMID- 20892973 TI - Finances. PMID- 20892975 TI - The Misuse of Terms. PMID- 20892974 TI - The $7.00 Membership Fee. PMID- 20892976 TI - Dr. Adams Passes. PMID- 20892977 TI - The New Hospital Bill. PMID- 20892979 TI - "Preparedness for All". PMID- 20892978 TI - Progress in Professional Relationship. PMID- 20892980 TI - The Mammary Gland in 702 Autopsy and 9220 Surgical Specimens. PMID- 20892981 TI - Uterine Bleeding and Menstruation Its Causes and Treatment. PMID- 20892982 TI - The Treatment of Benign Lesions of the Cervix Uteri. PMID- 20892983 TI - Suggestive Psychotherapy in Psychoneurotic Disorders. PMID- 20892985 TI - Certificates Should Not Be Changed. PMID- 20892984 TI - Teaching the Social Component of Medical Care at Meharry Medical College. PMID- 20892987 TI - Our Liaison Committee. PMID- 20892986 TI - The Selective Draft Act of 1940. PMID- 20892988 TI - The Alcohol Problem. PMID- 20892989 TI - The Penalty of Leadership. PMID- 20892990 TI - Early Negro Hospitals: With Special Reference to Nurse's Training Schools. PMID- 20892992 TI - The Drinking Driver - A Menace. PMID- 20892991 TI - Postgraduate Course For Physicians : A Report on the First Five Years of Two-Week Courses Offered By Flint-Goodridge Hospital of Dillard University, New Orleans, Louisiana. PMID- 20892993 TI - Acute Coronary Occlusion in the Negro. PMID- 20892994 TI - Mycotic Dermatitis from Straw Slippers. PMID- 20892995 TI - Deficiency of Bed Space and Suggestions for Remedies. PMID- 20892996 TI - New Jersey State Health Program for Negroes. PMID- 20892998 TI - Opening of the Infantile Paralysis Unit of the John A. Andrew Memorial Hospital, Tuskegee Institute, Ala. PMID- 20892997 TI - Gastric and Ocular Symptoms in Diabetes Mellitus. PMID- 20892999 TI - A Mental Hygiene Society Organized at Tuskegee. PMID- 20893000 TI - The National Hospital Association. PMID- 20893001 TI - Cooperation Between the Races in the Practice of Medicine. PMID- 20893002 TI - Oration in Surgery: Indications for Operation in Biliary Tract Disease. PMID- 20893003 TI - Pneumoperitoneum in the Treatment of Pulmonary Tuberculosis. PMID- 20893004 TI - Carcinoma of the Cervix: Diagnosis and Treatment. PMID- 20893005 TI - Sulfanilamide: Its Therapeutic Value. PMID- 20893006 TI - Sixteen Months Experience With Intravenous Pentothal Sodium-Oxygen Anesthesia. PMID- 20893007 TI - Tuberculoma of the Cerebrum - Report of a Case. PMID- 20893008 TI - Facts of Interest in Connection with the Veterans Administration Facility, Tuskegee, Alabama. PMID- 20893009 TI - A Call to the John A. Andrew Clinic. PMID- 20893011 TI - The Liaison Committee of the N. M. A. PMID- 20893010 TI - Specific Racial Contributions. PMID- 20893012 TI - They Must Be White. PMID- 20893013 TI - What Price Medical Glory? PMID- 20893014 TI - Medical Preparedness and the National Defense. PMID- 20893015 TI - National Negro Health Week. PMID- 20893016 TI - Past the Cross-Roads. PMID- 20893017 TI - The Initial Lesion of Granuloma Inguinale: Report of a Case. PMID- 20893018 TI - Benign Tumors of the Breast. PMID- 20893019 TI - Diaphragmatic Hernia. PMID- 20893020 TI - Case Report of Orthostatic Hypotension. PMID- 20893021 TI - Case Report - Sickle Cell Anemia with Hemiplegia. PMID- 20893022 TI - Hyperthyroidism: A Question of Terms. PMID- 20893023 TI - The High Cost of Neurosyphilis. PMID- 20893024 TI - A Word to Our Lay Readers Preliminary to a Study of Vitamins. PMID- 20893025 TI - The Modern Neglect of the Tongue as an Aid in Diagnosis. PMID- 20893027 TI - Blood Plasma Reservoir. PMID- 20893026 TI - The Philosophies of the John A. Andrew Clinic. PMID- 20893029 TI - Association of Rheumatic Heart Disease and Exophthalmic Goitre. PMID- 20893028 TI - The Chicago Meeting of the N. M. A. PMID- 20893030 TI - The Coronary Artery Pain Syndromes. PMID- 20893032 TI - Standard Curative Treatment of Early and Late Syphilis. PMID- 20893031 TI - Traumatic Aneurysm of the Radial Artery. PMID- 20893033 TI - The Comparative Incidence of Umbilical Hernias in Colored and White Infants. PMID- 20893035 TI - Pneumoperitoneum in the Treatment of Pulmonary Tuberculosis. PMID- 20893034 TI - The Effect of Orange Juice on Gastric Acidity. PMID- 20893036 TI - Problems of the Negro in the Venereal Disease Control Program. PMID- 20893038 TI - Blacking Out Syphilis. PMID- 20893037 TI - Some Recent Observations of Certain Allergic Conditions. PMID- 20893039 TI - The Chicago Meeting of the N. M. A. PMID- 20893040 TI - National Health. PMID- 20893041 TI - No Time For Prejudice. PMID- 20893042 TI - It Can Be Done. PMID- 20893043 TI - It Is Uncle Sam's Job. PMID- 20893045 TI - Indications for Operation in Goiter. PMID- 20893044 TI - Second Annual Oration on Surgery : The Negro's Contribution to Surgery. PMID- 20893046 TI - Infantile Paralysis (Acute Anterior Poliomyelitis). PMID- 20893048 TI - What should be the Duties and Functions of the Head of the Department of Bacteriology in a University Community? PMID- 20893047 TI - Syphilis and Rectal Strictures. PMID- 20893050 TI - An Appreciation. PMID- 20893049 TI - Chicago Convention. PMID- 20893051 TI - Fiftieth Anniversary of the Founding of the National Medical Association. PMID- 20893052 TI - Our Challenge. PMID- 20893053 TI - Morale. PMID- 20893054 TI - Editor's Visit to New Jersey. PMID- 20893055 TI - At Armageddon-Let Us Battle. PMID- 20893056 TI - Cavernous Sinus Thrombosis Consequent to Furuncle of Face. PMID- 20893057 TI - Electrocardiography as an Aid to Cardiac Diagnosis. PMID- 20893058 TI - War Neurosurgery in Britain. PMID- 20893059 TI - Diagnosis of Lobar Pneumonia. PMID- 20893060 TI - A Plea for Conservatism in the Use of Anti-Luetic Therapy. PMID- 20893061 TI - National Defense and the Negro. PMID- 20893062 TI - Echoes from the Second Oration on Surgery "The Negro's Contribution on Surgery". PMID- 20893064 TI - Safer Methods of Thyroid Surgery. PMID- 20893063 TI - Two Case Reports. PMID- 20893065 TI - Management of Pelvic Inflammatory Diseases : With Report of An Unusual Case. PMID- 20893067 TI - Modern Treatment and the Rural Physician. PMID- 20893066 TI - Pitfalls, Diagnosis, Treatment of Cardiac Arrhythmias. PMID- 20893068 TI - An Epitome of the History of Pharmacology and Therapeutics. PMID- 20893070 TI - Post-Graduate Medical Education. PMID- 20893069 TI - Trends in Public Health Activities Among Negroes in 96 Southern Counties During 1930-1939: The Employment of Negro Professional Personnel and the Expenditure of Funds for Health Services to Negroes. PMID- 20893072 TI - An Example. PMID- 20893071 TI - Universal Over-Indulgence. PMID- 20893074 TI - Reclaiming Rejected Draftees. PMID- 20893073 TI - A New Method of Post-Graduate Study. PMID- 20893075 TI - The Negro Physician and National Defense. PMID- 20893076 TI - The John A. Andrew Clinics, Springtime at Tuskegee. PMID- 20893077 TI - Icterus Complicating Lobar Pneumonia In the Negro Patient: II. Experimental Production of Icterus-Confirmation of Maugeri's Experiments. PMID- 20893079 TI - The Scope of X-ray Examinations. PMID- 20893078 TI - Pulmonocardiac Failure. PMID- 20893080 TI - Psychiatry In General Practice. PMID- 20893081 TI - Heredity and Its Relation To Insanity. PMID- 20893082 TI - War Neurosis. PMID- 20893083 TI - Proctology, and Its Relationship to the General Practitioner. PMID- 20893084 TI - In Re A Proposed National Medical Association College of Physicians and a College of Surgeons. PMID- 20893085 TI - Proposals with Reference to the Idea of a Negro College of Surgeons. PMID- 20893086 TI - Registration of Medical Students and Physicians for the National Emergency. PMID- 20893087 TI - Physicians and Morale. PMID- 20893088 TI - The Present Status of Hypertension. PMID- 20893090 TI - The First Graduating Class of the Tuskegee School of Midwifery. PMID- 20893089 TI - Electroencephalography at Homer Phillips Hospital. PMID- 20893091 TI - Coronary Occlusion. PMID- 20893092 TI - Surgery on the Diabetic. PMID- 20893093 TI - The National Medical Association in National Defense. PMID- 20893095 TI - The Challenge to Democracy. PMID- 20893094 TI - The Negro in Medicine. PMID- 20893096 TI - Surgery for Hypertension. PMID- 20893097 TI - Some Observations on Human Nutrition. PMID- 20893098 TI - Vitamins in Nutrition and Health. PMID- 20893099 TI - A Greater Meharry. PMID- 20893100 TI - The John A. Andrew Clinics-1942. PMID- 20893101 TI - Vitamin B-Complex Deficiencies. PMID- 20893102 TI - Rheumatic Heart Disease. PMID- 20893103 TI - Cancer: A Challenge to the Medical Profession. PMID- 20893105 TI - A Plea for War on Syphilis. PMID- 20893104 TI - The Cancer Clinic Problem. PMID- 20893107 TI - Hypertensive Heart Disease. PMID- 20893106 TI - Newer Concepts of Heart Failure. PMID- 20893108 TI - An Unusual Bladder Injury. PMID- 20893109 TI - Obstetrical Analgesia. PMID- 20893110 TI - On to Cleveland: August 17 to 21, 1942. PMID- 20893111 TI - The Fort Huachuca Hospital. PMID- 20893112 TI - A Plea for Conservative Surgery. PMID- 20893113 TI - From Capt. William E. Allen, Jr. PMID- 20893114 TI - The Incoming President, T. Manuel Smith. PMID- 20893115 TI - Physical Anthropology and the Negro in the Present Crisis. PMID- 20893117 TI - Recurrent Rheumatic Endocarditis with Terminal Hyperpyrexia. PMID- 20893116 TI - One Stage Suprapubic Prostatectomy : Fifty-One Consecutive Cases of 1939 and 1940. PMID- 20893119 TI - Growth During Professional Life. PMID- 20893118 TI - Heredity and Its Relation to Insanity in Schizophrenics. PMID- 20893121 TI - The Journal Fund. PMID- 20893120 TI - Forty-Eighth Annual Convention National Medical Association, Cleveland, August 17 21, 1942. PMID- 20893123 TI - Nutrition and the Soldier. PMID- 20893122 TI - President H. E. Lee. PMID- 20893124 TI - Democracy in Action. PMID- 20893125 TI - Major Allergic Diseases and Their Treatment. PMID- 20893126 TI - The Sulfonamides in Acute Gonococcal Urethritis. PMID- 20893127 TI - Modern Obstetrics. PMID- 20893129 TI - Diagnosis in Acute Surgical Emergencies. PMID- 20893128 TI - Fractures of the Forearm: Their Complications and Treatment. PMID- 20893131 TI - An Open Letter to the American Red Cross. PMID- 20893130 TI - A Triple Responsibility. PMID- 20893132 TI - Vitamins in Human Nutrition. PMID- 20893134 TI - Item of Interest: Public Health Nurses Needed. PMID- 20893133 TI - Third Annual Oration on Surgery: The Fundamental Physiologic Concepts Underlying Major Surgery of the Chest. PMID- 20893136 TI - Report of Sub-Committee on Birth Control of the National Medical Association. PMID- 20893135 TI - Results and Observations on Insulin Shock Therapy in Negro Ex-Service Men. PMID- 20893137 TI - How the Facilities of Our Medical Schools Could Be Enlarged To Meet the Prospective Shortage of Negro Doctors. PMID- 20893138 TI - Pernicious Anemia. PMID- 20893140 TI - War, Science, and Medicine. PMID- 20893139 TI - Thoughtlessness or Ingratitude, Which? PMID- 20893141 TI - The 1943 "Fight Infantile Paralysis Campaign". PMID- 20893142 TI - Announcement of the E. S. Jones Prize. PMID- 20893143 TI - "Palliative Radical Surgery" of the Colon for Carcinoma. PMID- 20893144 TI - The Management of Cases of Phlegmon of the Scrotum At Freedmen's Hospital. PMID- 20893145 TI - Some Diagnostic Considerations in the Neuropsychiatric Examination of Selectees. PMID- 20893146 TI - War Neuroses. PMID- 20893148 TI - Approach to Cardiac Diagnosis. PMID- 20893147 TI - Heredity and Its Relation to Insanity in Manic-Depressives. PMID- 20893150 TI - The American Red Cross. PMID- 20893149 TI - A Plea for a Properly Balanced Diet. PMID- 20893152 TI - Again, The American Red Cross Blood Bank. PMID- 20893151 TI - The Uses of Stilbestrol in Endocrinology. PMID- 20893153 TI - Diet in War Time. PMID- 20893155 TI - The John A. Andrew Clinics. PMID- 20893154 TI - Invalid Diets and Food Rationing. PMID- 20893157 TI - Master Keys To Anatomy: Preliminary Notes. PMID- 20893156 TI - Military Affairs. PMID- 20893158 TI - Hypertension. PMID- 20893160 TI - The Basis of Therapeutics. PMID- 20893159 TI - Tuberculous Pericarditis : Report of a Case of Tuberculosis in Which the Tubercle Bacillus Was Recovered on Direct Smear From the Pericardial Effusion. PMID- 20893161 TI - The Problem of the Medical Insurance Examiner During The Post War Period. PMID- 20893162 TI - The Useful Fundamentals for the General Practitioner and General Tuberculosis Control. PMID- 20893163 TI - Phonocardiographic Studies On Heart Diseases. PMID- 20893164 TI - Indications for Tonsillectomy. PMID- 20893165 TI - Fungous Infections: Their Role in Clinical Medicine. PMID- 20893166 TI - Thrombopenia Purpura With Case Report. PMID- 20893167 TI - Planned Parenthood as a Health Measure. PMID- 20893168 TI - Large Scale Sedation in Postoperative Treatment. PMID- 20893169 TI - War, Syphilis and the State. PMID- 20893170 TI - Mental Hygiene Grows. PMID- 20893171 TI - Report of the Third Annual Meeting: The Committee for Mental Hygiene for Negroes. PMID- 20893172 TI - Democracy in Action. PMID- 20893173 TI - The Rather Prevalent Doctor's Disease. PMID- 20893174 TI - Abdominoperineal Proctosigmoidectomy for Cancer of the Rectum. PMID- 20893175 TI - Highlights in Mental Deficiency. PMID- 20893176 TI - A Few Principles of Fracture Therapy. PMID- 20893177 TI - Care and Treatment of Negro Veterans at Tuskegee. PMID- 20893178 TI - Priority For Suture of Heart. PMID- 20893179 TI - Headache. PMID- 20893180 TI - Red Cross Blood Discrimination in Limelight. PMID- 20893182 TI - Psychological Medicine of 1943. PMID- 20893181 TI - Sacrifice and Freedom. PMID- 20893183 TI - Social Service Management of Glaucoma. PMID- 20893185 TI - The History and Development of Aviation Medicine. PMID- 20893184 TI - Medicine, Fifty Years Ago and Now. PMID- 20893187 TI - The Education of Mothers of Well Babies Through Teaching at the Baby-Keep-Well Stations. PMID- 20893186 TI - Actinomycosis of the Leg: Report of a Case. PMID- 20893189 TI - The College and Tuberculosis. PMID- 20893188 TI - Nutrition and the Surgical Patient. PMID- 20893190 TI - Noon-Day. PMID- 20893191 TI - Tuberculosis in Wartime. PMID- 20893192 TI - Selecting Medical Students and the Elimination of Misfits. PMID- 20893193 TI - A Summary of the Venereal Disease Problem in New Jersey. PMID- 20893194 TI - The Maintenance of Good Arm Function in Cancer of the Breast Operations. PMID- 20893195 TI - Social Justice: Our Plea. PMID- 20893196 TI - John A. Andrew Annual Clinics. PMID- 20893197 TI - Some Observations on Nutrition. PMID- 20893198 TI - Is the Negro More Susceptible to Syphilis than the White Man. PMID- 20893199 TI - Post-War Medicine. PMID- 20893200 TI - An Acknowledgment. PMID- 20893201 TI - The Artistic Canons in the Teaching of Anatomy. PMID- 20893202 TI - Freedom Through Health. PMID- 20893204 TI - Pigmentogenesis and the Negro: Discussion of Recent Advances and Report of a Case. PMID- 20893203 TI - Penicillin. PMID- 20893205 TI - The Management of the Asthmatic Patient. PMID- 20893206 TI - The Treatment of Chronic Heart Disease. PMID- 20893207 TI - Vitamins in Human Nutrition. PMID- 20893209 TI - Making a Contribution. PMID- 20893208 TI - The Use of the X-Ray in the Diagnosis of Diseases of the Gastro-Intestinal Tract. PMID- 20893210 TI - Surgery of Today. PMID- 20893212 TI - Surgical Biopsy with Special Reference to Breast Lesions. PMID- 20893211 TI - The John A. Andrew Clinic: Adieu. PMID- 20893214 TI - We and the Wagner Bill. PMID- 20893213 TI - A Post-War Job for Negro Doctors. PMID- 20893215 TI - National Negro Health Week. PMID- 20893217 TI - The Renal Concentration Test with Posterior Pituitary Extract. PMID- 20893216 TI - Tribute to Dr. Walter Gray Crump. PMID- 20893218 TI - Public Health as a Professional Career. PMID- 20893219 TI - Lymphogranuloma in the Female. PMID- 20893220 TI - Priapism. PMID- 20893221 TI - Placenta Accreta. PMID- 20893222 TI - Perforating Gunshot Wound of the Abdomen. PMID- 20893223 TI - Atrophic Eye of Glaucoma in a Three Months Infant. PMID- 20893224 TI - A Review of Recent Advances in Chemotherapy. PMID- 20893226 TI - Medical Management of Peptic Ulcer. PMID- 20893225 TI - National Health Negro Week-A Radio Broadcast. PMID- 20893227 TI - The Modern Conception of Neuroses: Its Therapeutic Import. PMID- 20893228 TI - Fibroma Uteri in Relation to Pregnancy. PMID- 20893229 TI - Epilepsy. PMID- 20893230 TI - Fifty Years of Progress in Medicine: From Chattel to Citizenship. PMID- 20893231 TI - Julian Lewis and Transfusions. PMID- 20893232 TI - The Ulcer Patient. PMID- 20893234 TI - Fort Huachuca is Tops. PMID- 20893233 TI - Tribute to Dr. John A. Kenney. PMID- 20893235 TI - A Half Century Review of the National Medical Association. PMID- 20893236 TI - The Burned Patient. PMID- 20893237 TI - The Purpose of the Community Hospital. PMID- 20893238 TI - Fiftieth Anniversary N. M. A. PMID- 20893239 TI - The A.M.A. War Convention. PMID- 20893240 TI - Medicine and Politics. PMID- 20893241 TI - Some Sidelights on the St. Louis Meeting. PMID- 20893242 TI - Daniel Hale Williams-Pioneer and Innovator. PMID- 20893243 TI - Survey of the Common Diseases of the Rectum. PMID- 20893244 TI - Diagnosis and Prognosis of Bundle Branch Block. PMID- 20893245 TI - Summary of the Results of Combined Fever and X-Ray Therapy in the Treatment of Hopeless Malignancies. PMID- 20893247 TI - Ulcer of the Leg: Pathology of the Ulcer. PMID- 20893246 TI - Epidemic Lead Poisoning in Children from Storage Battery Casings. PMID- 20893249 TI - Dr. John A. Kenney Leaves Tuskegee. PMID- 20893248 TI - Tropical Diseases After the War-Diagnosis and Control. PMID- 20893251 TI - The Negro Medical Doctor and Organized Medicine. PMID- 20893250 TI - The Cost of Medical Education. PMID- 20893252 TI - Physical Examinations. PMID- 20893254 TI - The Present Status of Allergy. PMID- 20893253 TI - The Diagnosis of Peptic Ulcer. PMID- 20893255 TI - Beta Kappa Chi: A Challenge Not To Be Ignored. PMID- 20893257 TI - Food and Vitamins Again. PMID- 20893256 TI - Postwar Planning for "Negro" Hospitals. PMID- 20893259 TI - Cryptorchidism. PMID- 20893258 TI - Changing Trends in Medical Practice. PMID- 20893260 TI - Two Widespread Maladies: What Are We, As Physicians, Doing About Them? PMID- 20893261 TI - The Monthly Journal. PMID- 20893262 TI - A Surgical League of Nations. PMID- 20893264 TI - Medicine as a Professional Career. PMID- 20893263 TI - Discussion of Paper by Dr. H. M. Lambright on Surgical Treatment of Thyroid Diseases. PMID- 20893265 TI - Some Observations on the Treatment of Sterility in the Female. PMID- 20893267 TI - Ophthalmology at Tuskegee Army Air Field-Two Year Review. PMID- 20893266 TI - X-Ray Examination of the Abdomen: Without the use of contrast media. PMID- 20893268 TI - First Annual Report-Sydenham Hospital. PMID- 20893270 TI - Anti-Conventions Year. PMID- 20893269 TI - What The Negro Wants. PMID- 20893272 TI - Message to our Advertisers, Members, Contributors Subscribers, and Readers. PMID- 20893271 TI - A Worthy Veteran Retires. PMID- 20893274 TI - Letter to the Editor Re: Annual Convention. PMID- 20893273 TI - Correspondence. PMID- 20893275 TI - Practice for Sale. PMID- 20893276 TI - First Annual Report of the Trustees of Sydenham Hospital to the Organization Committee for an Interracial Voluntary Hospital in the Harlem Area. PMID- 20893277 TI - Causes of Death of Physicians. PMID- 20893278 TI - Prepaid Hospital Protection. PMID- 20893279 TI - Tribute to Dr. J. Edward Perry of Kansas City, Mo. PMID- 20893280 TI - Is Inflammatory Stricture of Urethra Decreasing? PMID- 20893281 TI - Medico-Chi: Whence and Whither? PMID- 20893282 TI - Distribution of Negro Physicians in Urban Communities with Less than 50,000 Negroes in 1942. PMID- 20893283 TI - Socialized Medicine: Pro and Con. PMID- 20893285 TI - The Running Ear. PMID- 20893284 TI - Pathological Gall Bladder and Eclampsism Complicating and Prematurely Terminating Pregnancy: Report of an Unusual Case. PMID- 20893286 TI - Ethmoiditis In Children. PMID- 20893287 TI - Sulfonamide Resistant Gonococcal Infections and the Negro. PMID- 20893288 TI - Can the Millennium be Approaching? PMID- 20893289 TI - The Clinical Value and Mechanism of Action of Certain Drugs in Gastro-Intestinal Disorders. PMID- 20893290 TI - Sulfonamides in Otolarngology and Ophthalmology. PMID- 20893291 TI - Observations on Vesical Schistosomiasis in West Africa. PMID- 20893292 TI - Ether in Oil Intramuscularly as Emergency and Supplementary Therapy in Bronchial Asthma. PMID- 20893293 TI - Recent Advances in the Treatment of Burns. PMID- 20893294 TI - A Plea for Interracial Cooperation. PMID- 20893296 TI - Program of the National Foundation for Infantile Paralysis. PMID- 20893295 TI - Your Unescapable Self. PMID- 20893297 TI - Service in Medicine. PMID- 20893298 TI - The Wagner-Murray-Dingell Senate Bill. PMID- 20893299 TI - The National Foundation for Infantile Paralysis. PMID- 20893300 TI - Wendell Wilkie and the Human Factor. PMID- 20893301 TI - Sickle-Cell Anemia. PMID- 20893302 TI - Birth Registration. PMID- 20893304 TI - Myomata of the Uterus : Report of Two Interesting Cases. PMID- 20893303 TI - The Treatment of Thyrotoxicosis : With Special Reference to Surgical Care. PMID- 20893306 TI - Post Traumatic Para Articular Calcification of the Knee Joint. PMID- 20893305 TI - Negro Nurses In Armed Forces. PMID- 20893307 TI - The Veterans Facility at Tuskegee. PMID- 20893309 TI - The Wagner-Dingell Bills. PMID- 20893308 TI - What About The Cervix? PMID- 20893310 TI - Buy A War Bond. PMID- 20893311 TI - Meeting of Board of Trustees. PMID- 20893312 TI - Dr. Dailey's Visit. PMID- 20893313 TI - Correspondence. PMID- 20893314 TI - Correspondence. PMID- 20893315 TI - A Report of Three Hundred and Forty-Two Consecutive Cases of Appendicitis. PMID- 20893316 TI - Methods of Administration of Penicillin Adaptable to Office Treatment of Gonococcal Infections. PMID- 20893317 TI - Pregnancy Complicated by Heart Disease. PMID- 20893318 TI - The Responsibility of the Private Physician in Tuberculosis Control. PMID- 20893320 TI - Medico-Chi And The National Selective Service. PMID- 20893319 TI - Report on Thiouracil Therapy in 26 Cases of Thyrotoxicosis. PMID- 20893322 TI - Chronic Cystic Mastitis-Should the Term be Discarded? PMID- 20893321 TI - The Challenge of Medicine in the Future. PMID- 20893323 TI - Service in Medicine. PMID- 20893324 TI - Professor Salomon. PMID- 20893325 TI - President Robinson's Activities. PMID- 20893326 TI - The Howard University Medical Alumni Association. PMID- 20893327 TI - Topical Application of Penicillin : Solution, Gentian-Violet and Heat in the Treatment of Extensive 1st and 2nd Degree Burns in Children. PMID- 20893329 TI - The Diagnosis and Management of Some Common Cardiac Arrhythmias. PMID- 20893328 TI - Frontiers of Mental Hygiene. PMID- 20893331 TI - The Campaign Against Cancer. PMID- 20893330 TI - Remarks for Health Service. PMID- 20893332 TI - Medicine Then and Now. PMID- 20893333 TI - Nothing is so Difficult as to Foresee Consequences. PMID- 20893334 TI - Should Cysts of the Breast be Aspirated? PMID- 20893335 TI - The American College of Surgeons-Breaking Down Barriers. PMID- 20893336 TI - The People's Health. PMID- 20893337 TI - The President's Plan for Medical Care. PMID- 20893339 TI - Access to a Hospital for Every Race Doctor. PMID- 20893338 TI - Mass Medical Treatment. PMID- 20893340 TI - The Meharry Alumni Hall. PMID- 20893341 TI - Blast Injuries. PMID- 20893342 TI - The Problem of Veteran's Facilities. PMID- 20893343 TI - National Association of Colored Graduate Nurses. PMID- 20893344 TI - Directory. PMID- 20893345 TI - Pneumococcus Meningitis: Treatment With Penicillin and Sulfonamide. PMID- 20893346 TI - A Control Program in a Metropolitan Area for Tuberculosis Among Negroes. PMID- 20893347 TI - Some Questions Text-Books Do Not Answer. PMID- 20893348 TI - Gastric Syphilis. PMID- 20893349 TI - Local Examination of the Thyroid Gland. PMID- 20893350 TI - Sickle Cell Anemia as a Clinical Entity. PMID- 20893351 TI - The Laboratory as a Necessity for a Conclusive Diagnosis. PMID- 20893352 TI - Federal Versus State Control. PMID- 20893354 TI - John A. Andrew Clinic. PMID- 20893353 TI - Streptomycin Moves Closer to Clinical Use. PMID- 20893355 TI - Directory. PMID- 20893356 TI - Thiouracil. PMID- 20893357 TI - Equal Opportunity. PMID- 20893358 TI - Shall We Improve Our Health Program? PMID- 20893360 TI - Who's Who Among Negro Lawyers. PMID- 20893359 TI - A Plea for More and Better Consultations. PMID- 20893361 TI - The Debt of Modern Medicine to Sir William Osler, Bart. PMID- 20893363 TI - When is Gonorrhea Cured? PMID- 20893362 TI - Some Uses of Nembutal in Obstetrics. PMID- 20893364 TI - Prophylaxis in Geriatrics. PMID- 20893366 TI - Acute Appendicitis with Complications. PMID- 20893365 TI - Periarteritis Nodosa With Case Report. PMID- 20893368 TI - The Diagnosis of Breast Lesions. PMID- 20893367 TI - The Doctor on the Witness Stand. PMID- 20893369 TI - Allantoin-Sulfanilamide Ointment in the General Practice of Medicine. PMID- 20893371 TI - Despise Not The Day of Small Beginnings. PMID- 20893370 TI - Post-War Adjustments in Medicine. PMID- 20893372 TI - Statement in Support of National Health Bill, S.1606, on Behalf of the National Association for the Advancement of Colored People. PMID- 20893373 TI - The Fifty-First Annual Meeting of the National Medical Association. PMID- 20893374 TI - Of Special Interest to Our Returning G. I.'s. PMID- 20893376 TI - Penicillin Recommended for Prospective Mothers. PMID- 20893375 TI - The Tuskegee Founders Day and Annual Clinic. PMID- 20893378 TI - Dr. Roscoe C. Giles: A Fellow of the International College of Surgeons. PMID- 20893377 TI - Launch Provident Medical Associates. PMID- 20893379 TI - Editorial Squib. PMID- 20893380 TI - A Graphic Approach to a Compleat Anatomy. PMID- 20893381 TI - Vibration Sense. PMID- 20893382 TI - Recent Advances in the Therapy of Glaucoma. PMID- 20893383 TI - Some Medical Observations from the Caribbean. PMID- 20893384 TI - The Histologic and Clinical Response of Human Cancer to Irradiation-Citation of Five Cases. PMID- 20893385 TI - "Doubtfully Indicated Hysterectomies". PMID- 20893386 TI - The Care of the Aged. PMID- 20893387 TI - Removing Barriers. PMID- 20893389 TI - Dr. Dibble Heads the John A. Andrew Memorial Hospital. PMID- 20893388 TI - Penicillin in Early Syphilis. PMID- 20893390 TI - Shall the Demobilized Doctor enter Medical Group Practice. PMID- 20893391 TI - Citation-Dr. W. S. Quinland. PMID- 20893392 TI - Correspondence. PMID- 20893393 TI - The Firestone Tire & Rubber Company. PMID- 20893394 TI - Letter of Appreciation. PMID- 20893395 TI - The Monthly Journal. PMID- 20893396 TI - The Louisville Meeting. PMID- 20893398 TI - Bed Rest in Tuberculosis. PMID- 20893397 TI - Let Us Be Consistent About the Principle of "Free Choice of Physician". PMID- 20893399 TI - The Late Booker T. Washington. PMID- 20893400 TI - Medicine in this Changing World. PMID- 20893401 TI - Hormonal Therapy in Peptic Ulcer. PMID- 20893402 TI - Masking Syphilis in Treatment of Gonococcic Infections with Penicillin. PMID- 20893403 TI - Digitalis Poisoning. PMID- 20893404 TI - Artistry in Medicine and Surgery. PMID- 20893405 TI - A Challenge to the American College of Physicians. PMID- 20893406 TI - Hospitals and Health Centers. PMID- 20893407 TI - Nathan Francis Mossell. PMID- 20893408 TI - Negro Fellows of the American College of Surgeons. PMID- 20893409 TI - Our Medical Heroes in the Hall of Fame. PMID- 20893410 TI - The 1946 Clinical Congress of the American College of Surgeons. PMID- 20893411 TI - Random Highlights of the American College of Surgeons Program, Thirty-Second Annual Session. PMID- 20893412 TI - Wanted: Candidates for Opportunity. PMID- 20893414 TI - Infectious (Epidemic) Hepatitis. PMID- 20893413 TI - Esprit de Corps in the National Medical Association. PMID- 20893415 TI - Segregation at Gallinger Hospital. PMID- 20893416 TI - National Negro Health Week: The Thirty-Third Annual Observance March 30 - April 6, 1947. PMID- 20893417 TI - The Diagnosis of Gonococcic Infections in Women. PMID- 20893418 TI - More Negro Physicians Needed. PMID- 20893419 TI - Recent National Health Legislation. PMID- 20893420 TI - Quinidine Sulfate. PMID- 20893422 TI - Our Nurses and the Nursing Situation. PMID- 20893421 TI - BAL: Its Use in Arsenic, Mercury, and Gold Poisoning. PMID- 20893423 TI - Senior Surgeon Poindexter, U.S.P.H.S. PMID- 20893424 TI - Dr. E. R. Alexander Elected to The New York Academy of Medicine. PMID- 20893425 TI - Table of Metric Doses with Approximate Apothecary Equivalents. PMID- 20893426 TI - Diet and the Surgical Patient. PMID- 20893427 TI - The Tuskegee Clinic. PMID- 20893428 TI - Paludrine-A New Synthetic Antimalarial Drug. PMID- 20893429 TI - The New Health Insurance Bill. PMID- 20893430 TI - Dr. W. S. Quinland Goes to the Veterans' Hospital at Tuskegee. PMID- 20893431 TI - Dr. J. Edward Perry and the Houston (Texas) Negro Hospital. PMID- 20893433 TI - Make Lynching a Federal Offense. PMID- 20893432 TI - United Negro College Fund. PMID- 20893434 TI - Advice Regarding Poliomyelitis. PMID- 20893435 TI - Medical Legislation. PMID- 20893436 TI - A Report on the Tuskegee Clinic. PMID- 20893437 TI - Inactive Rheumatic Heart Disease. PMID- 20893439 TI - An Appeal to the A.M.A. in Behalf of Negro Physicians in the South. PMID- 20893438 TI - A Hitherto Undescribed Form of Headache. PMID- 20893441 TI - The Pressing Need for Private Mental Hospitals. PMID- 20893440 TI - Sixtieth Annual Meeting of the Old North State Medical, Dental & Pharmaceutical Society, Inc. PMID- 20893442 TI - Dr. John P. Turner, Member of the Board of Education of Philadelphia. PMID- 20893443 TI - Howard University-Washington, D. C. PMID- 20893444 TI - Negro Physicians and the American Medical Association. PMID- 20893446 TI - The Journal of the American Medical Association-535 North Dearborn Street, Chicago 10. PMID- 20893445 TI - Howard University-Washington, D. C. PMID- 20893447 TI - The Treatment of Burns. PMID- 20893448 TI - American Medical Association. PMID- 20893449 TI - The Need for Advanced Training Opportunities for Physicians and Dentists in Training Institutions. PMID- 20893450 TI - Not Alms But Equal Opportunity. PMID- 20893451 TI - The New Antihistaminic Drugs-Pyribenzamine and Benadryl. PMID- 20893453 TI - An Oversupply of Physicians? PMID- 20893452 TI - Christmas Seals. PMID- 20893454 TI - A Health Hazard. PMID- 20893455 TI - The Independent Committee of Colored Physicians. PMID- 20893456 TI - Physicians Needed. PMID- 20893458 TI - Congresswoman Helen Gahagan Douglas on Health Legislation. PMID- 20893457 TI - Frederick Douglass Stubbs, 1906-1947: An Appreciation. PMID- 20893459 TI - The Common Cold. PMID- 20893460 TI - In Retrospect and Prospect. PMID- 20893462 TI - The John A. Andrew Clinic. PMID- 20893461 TI - "Cast Down Your Bucket...". PMID- 20893463 TI - Surgery for High Blood Pressure. PMID- 20893464 TI - "To Secure These Rights". PMID- 20893465 TI - Effective Utilization of Essential Amino Acids in Food Proteins. PMID- 20893467 TI - Our Salute to the Bulletin of the Medico-Chirurgical Society. PMID- 20893466 TI - "The Color Line in Medicine". PMID- 20893469 TI - Midian O. Bousfield, M.D., 1885-1948. PMID- 20893468 TI - The Senior Oration at Howard University Medical School, 1947. PMID- 20893470 TI - Edward Arthur Balloch, M.D., 1857-1948. PMID- 20893471 TI - The Southern Governors' Educational Plan. PMID- 20893472 TI - The International Congress on Mental Health. PMID- 20893473 TI - "A Special Kind of Membership". PMID- 20893474 TI - Dean Edward Arthur Balloch. PMID- 20893475 TI - The National Hospital Construction Program. PMID- 20893476 TI - Brig. General Spencer C. Dickerson, B.S., M.D., 1871-1948. PMID- 20893477 TI - Brig. General Spencer C. Dickerson, B.S., M.D., 1871-1948. PMID- 20893479 TI - The Internist in Medicine Among Negroes. PMID- 20893478 TI - Medical Education for Minority Groups. PMID- 20893481 TI - Dr. Kenney Resigns. PMID- 20893480 TI - Spencer C. Dickerson, M.D. PMID- 20893483 TI - The Editor's Spring Itinerary. PMID- 20893482 TI - Racial Progress-Mr. and Mrs. W. J. Edwards. PMID- 20893485 TI - College Presidents Urge Negro Students to Apply for Scholarships. PMID- 20893484 TI - Autobiographical Sketch of Dr. J. A. C. Lattimore. PMID- 20893486 TI - Oak Bluffs. PMID- 20893487 TI - Which Way? PMID- 20893488 TI - 100 Million Lost Years. PMID- 20893489 TI - The Frederick Douglass Stubbs Surgical Oration. PMID- 20893490 TI - Programs-or Politics? PMID- 20893491 TI - Penicillin: Benefits and Paradoxes. PMID- 20893492 TI - Folic Acid. PMID- 20893494 TI - President-Elect-Dr. C. Herbert Marshall. PMID- 20893493 TI - Race and Disease. PMID- 20893495 TI - The New President-Dr. C. Austin Whittier. PMID- 20893496 TI - The Pathologist. PMID- 20893497 TI - The General Practitioner and His Neurotic Patients. PMID- 20893499 TI - Atomic Energy and the Practice of Medicine. PMID- 20893498 TI - The Negro's Position in Medicine. PMID- 20893501 TI - Medical Portents of the National Election. PMID- 20893500 TI - Racism Rules AMA Policies. PMID- 20893503 TI - Our Past Presidents. PMID- 20893502 TI - Physicians and Neurosis. PMID- 20893504 TI - When the Slip gets by. PMID- 20893506 TI - My Eviscerectomy. PMID- 20893505 TI - Provident Hospital, Baltimore. PMID- 20893507 TI - Myocarditis. PMID- 20893508 TI - Hypertension and Pheochromocytomas. PMID- 20893509 TI - Our Exchanges. PMID- 20893511 TI - The Membership Drive. PMID- 20893510 TI - Are Physicians Particularly Suspect of Tax Fraud? PMID- 20893513 TI - Persident Whittier Activates the State Vice Presidents. PMID- 20893512 TI - Prenatal Care. PMID- 20893514 TI - Treatment of Obesity. PMID- 20893515 TI - Open Medical Schools. PMID- 20893517 TI - The Detroit Meeting. PMID- 20893516 TI - Qualified Medical Applicants. PMID- 20893518 TI - "Socialized Medicine". PMID- 20893519 TI - Why I Oppose Compulsory Health Insurance. PMID- 20893520 TI - Social Responsibility for Health. PMID- 20893521 TI - Our Past Presidents. PMID- 20893522 TI - A Neurotic Patient's Plea. PMID- 20893523 TI - Missouri Falls in Line. PMID- 20893524 TI - Blood Test for Cancer. PMID- 20893525 TI - The Distinguished Service Award. PMID- 20893526 TI - President's Column. PMID- 20893527 TI - Letters to the Editor. PMID- 20893528 TI - Letters to the Editor. PMID- 20893529 TI - Letters to the Editor. PMID- 20893530 TI - The Geneva Hippocratic Oath. PMID- 20893531 TI - The Detroit Session. PMID- 20893532 TI - Cancer Centers and Tumor Clinics. PMID- 20893533 TI - Recent Past Presidents. PMID- 20893534 TI - The Future of the Journal. PMID- 20893535 TI - Lest We Forget. PMID- 20893536 TI - Communication from President Marshall. PMID- 20893537 TI - Dr. Ulysses Grant Dailey Receives Distinguished Service Award for 1949. PMID- 20893538 TI - It's Up To You. PMID- 20893539 TI - Medical Deans and Discrimination. PMID- 20893540 TI - Glaring Premedical Needs. PMID- 20893542 TI - Medical Students Dropped for Poor Scholarship at Meharry Medical College 1938-48. PMID- 20893541 TI - Dr. Evarts Graham. PMID- 20893543 TI - Zone Directors and State Vice Presidents. PMID- 20893544 TI - General Practice Residency. PMID- 20893545 TI - AIMS-Activity Against Discrimination. PMID- 20893546 TI - The Hospital Situation in Miami, Florida. PMID- 20893547 TI - Perforated Peptic Ulcers. PMID- 20893549 TI - Carl Glennis Roberts, M.D., 1886-1950. PMID- 20893548 TI - Fetal Meconium Peritonitis with Intra-Abdominal Hernia. PMID- 20893550 TI - President's Column. PMID- 20893551 TI - An Age of Communications. PMID- 20893552 TI - No Room for the Moneychangers in the Temple of Aesculapius. PMID- 20893553 TI - Riches No Goal of Basic Discoverers. PMID- 20893554 TI - Persecution of Innovators. PMID- 20893555 TI - Hospital Personnel Shortages. PMID- 20893556 TI - Correspondence. PMID- 20893557 TI - Superfetation in Uterus Bicornis Unicollis: A Case Report. PMID- 20893558 TI - A Brighter Forecast for Patient Care: Coordination of Hospitals. PMID- 20893559 TI - Diagnosis and Treatment of Hepatocellular Diseases. PMID- 20893560 TI - Federal Aid to Medical Education. PMID- 20893561 TI - The Cardiac Patient as a Surgical or Obstetrical Risk. PMID- 20893562 TI - Interesting African Visitors. PMID- 20893563 TI - The Enigma of Peptic Ulcer. PMID- 20893564 TI - Cortisone and ACTH. PMID- 20893565 TI - The Diagnosis of Syphilis. PMID- 20893567 TI - Children's Hospital, Washington, D.C., Accepts First Colored Physician. PMID- 20893566 TI - President's Column. PMID- 20893568 TI - Legal Counsel. PMID- 20893569 TI - Correspondence. PMID- 20893570 TI - Correspondence. PMID- 20893572 TI - The NMA at the Crossroads. PMID- 20893571 TI - Correspondence. PMID- 20893573 TI - The Crisis in Medical Education. PMID- 20893574 TI - Anxiety and Disease. PMID- 20893575 TI - Clinical Interpretation of Heart Disease. PMID- 20893576 TI - President's Column. PMID- 20893577 TI - Legal Counsel. PMID- 20893578 TI - Chance for Service (?). PMID- 20893579 TI - Howard Pioneer in Nicaragua. PMID- 20893580 TI - Chance for Service (?). PMID- 20893581 TI - The AMA Resolutions. PMID- 20893582 TI - Speak for Yourself, John! PMID- 20893584 TI - The General Adaptation Syndrome. PMID- 20893583 TI - Exit the Race Statistic. PMID- 20893585 TI - New Light on the Formation of Melanin. PMID- 20893586 TI - President's Column. PMID- 20893587 TI - Legal Counsel. PMID- 20893589 TI - David's Hour. PMID- 20893588 TI - The Hampton Convention. PMID- 20893591 TI - Dr. Joseph G. Gathings, The President Elect. PMID- 20893590 TI - "Problem" Movies. PMID- 20893592 TI - Physician of the Eighties. PMID- 20893593 TI - Tuberculosis Due to Chlorine Irritation is "Poisoning". PMID- 20893595 TI - Medical Deans Static. PMID- 20893594 TI - Cultural Tachygenesis: A Need of the Hour. PMID- 20893596 TI - President's Column. PMID- 20893597 TI - Correspondence. PMID- 20893598 TI - Anyone Remember These Days? PMID- 20893600 TI - Sterile Meetings. PMID- 20893599 TI - Pernicious Anemia in the American Negro. PMID- 20893601 TI - The New Assistant Editor. PMID- 20893602 TI - President's Column. PMID- 20893603 TI - Rangoon to Mandalay. PMID- 20893604 TI - Appendicitis in Missouri. PMID- 20893605 TI - Swing around Africa. PMID- 20893606 TI - Appendicitis in Missouri. PMID- 20893607 TI - Liability of Operating Surgeon for Attending Interne's Negligence. PMID- 20893609 TI - National Negro Health Program Ends. PMID- 20893608 TI - The Henry Wisdom Cave Testimonial Dinner. PMID- 20893610 TI - Africa on the Medical Horizon. PMID- 20893611 TI - President's Column. PMID- 20893613 TI - Penicillin for Vaginal Discharge. PMID- 20893612 TI - Numa P. G. Adams. PMID- 20893614 TI - Numa P. G. Adams. PMID- 20893616 TI - The Federal Aid and Regional Plan Chimerae. PMID- 20893615 TI - "It is Later Than You Think!!". PMID- 20893618 TI - President's Column. PMID- 20893617 TI - Integration only Practicable Goal. PMID- 20893619 TI - N.A.A.C.P. Resolutions in Health Area. PMID- 20893621 TI - More from Burma. PMID- 20893620 TI - Pregnancy in Sickle Cell Anemia. PMID- 20893623 TI - Dr. Rivers Frederick Receives Distinguished Service Award for 1951. PMID- 20893622 TI - Deductions from Gross Income for Tax Purposes. PMID- 20893624 TI - The Philadelphia Convention. PMID- 20893625 TI - The Honorable Oscar Ross Ewing. PMID- 20893626 TI - President's Column. PMID- 20893627 TI - The President-Elect. PMID- 20893628 TI - Medicines for India. PMID- 20893630 TI - Army Taboo on Negro Obstetricians? PMID- 20893629 TI - Restrictions on Disclosure of Information Received While Treating Patients. PMID- 20893631 TI - Geriatrics and Medical Practice. PMID- 20893632 TI - Specialty Boards and Colleges. PMID- 20893633 TI - President's Column. PMID- 20893634 TI - Imhotep. PMID- 20893635 TI - Government Taboo on Negro Physicians? PMID- 20893637 TI - Carcinoma of the Esophagus. PMID- 20893636 TI - Forward Detroit! PMID- 20893638 TI - President's Column. PMID- 20893639 TI - Refusal of Race Identification on Birth Certificate. PMID- 20893640 TI - Medical History. PMID- 20893641 TI - Observations on the General Adaptation Syndrome: Surgery as Measured by the Eosinophil Response. PMID- 20893642 TI - 'Apartheid' and the Medical Profession. PMID- 20893643 TI - The Louis T. Wright Library of Harlem Hospital. PMID- 20893644 TI - Survival Under Anesthesia. PMID- 20893645 TI - Inactivity or Indecision? PMID- 20893647 TI - Memphis NAACP Branch Rescinds Endorsement of Negro Hospital. PMID- 20893646 TI - Greetings to the American Medical Association from the National Medical Association. PMID- 20893648 TI - Lambright Elected to Board of Academy of Medicine of Cleveland. PMID- 20893649 TI - Starke Story. PMID- 20893650 TI - Fourteen Colored Physicians Join Florida Medical Association. PMID- 20893651 TI - First Arkansas Medical Graduate to enter University Hospital. PMID- 20893652 TI - Alexander Thomas Augusta. PMID- 20893653 TI - The Crushing Irony of De Luxe Jim Crow. PMID- 20893654 TI - Medicine in our Democracy. PMID- 20893656 TI - Editor of Modern Hospital Attacks "Jim Crow". PMID- 20893655 TI - President's Column. PMID- 20893657 TI - Quality of the Journal. PMID- 20893659 TI - President's Column. PMID- 20893658 TI - Quality of the Journal. PMID- 20893661 TI - Nurses Shortage Eases Color Bar. PMID- 20893660 TI - Old North State Society Protests Omission. PMID- 20893663 TI - Salutes to Dr. Hinton. PMID- 20893662 TI - The Reclaimed Art of Physical Therapy. PMID- 20893664 TI - The New Community Hospital of Evanston, Illinois. PMID- 20893665 TI - University of Texas Admits Five. PMID- 20893666 TI - Georgia County Society Opens Doors Wide. PMID- 20893667 TI - Progress in Evanston, Illinois. PMID- 20893668 TI - Spotlight on Anesthesia. PMID- 20893669 TI - President's Column. PMID- 20893671 TI - Hospital Discrimination Must End! PMID- 20893670 TI - High Kilovoltage Radiographic Technique. PMID- 20893672 TI - Doctors and Defense. PMID- 20893673 TI - Greetings to Our Fellows and Colleagues. PMID- 20893675 TI - Integration in Orange, N. J., Hospital. PMID- 20893674 TI - Louisiana Medical Association Calls for Dropping of Racial Bars. PMID- 20893677 TI - No Time to Play Ostrich. PMID- 20893676 TI - Alabama Medical Association Votes to Admit Negroes. PMID- 20893679 TI - Council of Chief Consultants of the Veterans Administration. PMID- 20893678 TI - Texas Medical Association and Negro Physicians. PMID- 20893680 TI - The Liver in Medicine. PMID- 20893681 TI - Progress on Integration in Veterans Hospitals. PMID- 20893682 TI - Negro Voters Defeat Hospital Bond Issue. PMID- 20893683 TI - NAACP's Resolutions on Health, 1953. PMID- 20893684 TI - John Wesley Anderson, 1861-1947. PMID- 20893686 TI - President's Column. PMID- 20893685 TI - The Old Order Changeth. PMID- 20893688 TI - Detroit NAACP Opposes New Segregated Hospital. PMID- 20893687 TI - Integration Advances in Veterans Hospitals. PMID- 20893689 TI - Accomplishments of Ambulatory State Venereal Disease Clinic : A Ten Year Survey. PMID- 20893690 TI - John Henry Hale, 1878-1944. PMID- 20893691 TI - Ageing: A Special Problem. PMID- 20893692 TI - Lovers, Age, and Differential Mortality. PMID- 20893693 TI - President's Column. PMID- 20893694 TI - Veterans Hospital at Tuskegee. PMID- 20893695 TI - Admissions to Kentucky Medical Societies. PMID- 20893696 TI - Brewer Fighter With Ballot. PMID- 20893698 TI - Louis T. Wright Memorials. PMID- 20893697 TI - Support the "Fighting Fund For Freedom". PMID- 20893699 TI - Creative Destiny. PMID- 20893700 TI - President's Column. PMID- 20893701 TI - Louisiana Societies Static. PMID- 20893702 TI - South Carolina Association Open to Negro Nurses. PMID- 20893704 TI - The Seventeenth of May. PMID- 20893703 TI - George Cleveland Hall, 1864-1930. PMID- 20893705 TI - Physicians' $500 and $100 Memberships in NAACP. PMID- 20893707 TI - Mary Eliza Mahoney, First Negro Nurse. PMID- 20893706 TI - Austin Maurice Curtis, 1868-1939. PMID- 20893709 TI - Doctor Dan. PMID- 20893708 TI - Atomic Energy in Medicine. PMID- 20893711 TI - Dallas Hospital Admits Five Negro Physicians To Staff. PMID- 20893710 TI - Albert Porter Davis. PMID- 20893712 TI - Solomon Carter Fuller, 1872-1953. PMID- 20893713 TI - Dr. Peter Marshall Murray Receives Distinguished Service Award for 1954. PMID- 20893714 TI - The President-Elect. PMID- 20893715 TI - The Washington Convention. PMID- 20893716 TI - President's Column. PMID- 20893717 TI - Little Rock, Arkansas Hospital Admits Four to Staff. PMID- 20893718 TI - Three Washington Hospitals Open Staffs to Negro Physicians. PMID- 20893720 TI - North Carolina Society Drops Racial Bars. PMID- 20893719 TI - D.C. Tuberculosis Hospital Adds First Negro Staff Physicians. PMID- 20893721 TI - Dr. James F. Scott Named Ohio County Coroner. PMID- 20893723 TI - Slow Grinding Mills. PMID- 20893722 TI - Negro Members of Western Reserve Medical Faculty. PMID- 20893724 TI - New Accent on Youth. PMID- 20893725 TI - New Goals for the NMA. PMID- 20893726 TI - President's Column. PMID- 20893727 TI - St. Louis Ends Discriminatory Ambulances. PMID- 20893728 TI - The Distinguished Service Medal of the National Medical Association. PMID- 20893730 TI - "Stomachus Convivius" or Banquet Belly: An Ancient But Hitherto Undescribed Clinical Syndrome. PMID- 20893729 TI - William Harry Barnes, 1887-1945. PMID- 20893732 TI - William Frank Nelson, M.D. PMID- 20893731 TI - Letter from Liberia. PMID- 20893733 TI - Lawrence Winfield Long, M.D. PMID- 20893734 TI - Albert Schweitzer. PMID- 20893735 TI - Leffall Succeeds Cox as Assistant Editor. PMID- 20893737 TI - Oklahoma Medical Association President Decries Segregation. PMID- 20893736 TI - A Medical Viewpoint on the Proposal to Place a Branch of Cook County Hospital on the Southside of Chicago. PMID- 20893739 TI - Chicago N.A.A.C.P. Fights Hospital Bias. PMID- 20893738 TI - North Carolina Society Urges Public Service Appointments for Negro Physicians. PMID- 20893741 TI - Roanoke Academy of Medicine (Virginia) Opens Doors. PMID- 20893740 TI - Maxwell Heads Milwaukee Hospital Staff. PMID- 20893742 TI - Monroe Alpheus Majors, 1864. PMID- 20893743 TI - "Phimosis Corticis Atrophica" and "Myocallositis Chronica": Two Infrequently Recognized Causes of Cerebral Insufficiency. PMID- 20893744 TI - Roscoe Conkling Bryant, M.D. PMID- 20893745 TI - Emory Irving Robinson, M.D. PMID- 20893746 TI - National Scene in Ferment. PMID- 20893747 TI - Salk Vaccine Distribution. PMID- 20893748 TI - President's Column. PMID- 20893750 TI - Physicians' Life Memberships in the NAACP. PMID- 20893749 TI - Tests of Southern Negro High School Seniors. PMID- 20893751 TI - Progress in Kansas City. PMID- 20893752 TI - Providence Hospital, Washington, D.C., Admits Three Negro Physicians to Staff. PMID- 20893753 TI - Metropolitan Life Gives Same Insurance Rates to Whites and Negroes. PMID- 20893754 TI - First Negro Physician Appointed to District of Columbia Board of Examiners in Medicine and Osteopathy. PMID- 20893755 TI - William Wells Brown, M.D., 1816-1884. PMID- 20893757 TI - Texas Medical Association Opens Doors. PMID- 20893756 TI - The Growth and Future of the Journal. PMID- 20893758 TI - American Psychiatric Association Changes Meeting Place. PMID- 20893759 TI - Nashville Academy of Medicine Admits Three. PMID- 20893760 TI - Chicago Activity Against Hospital Discrimination Continues. PMID- 20893761 TI - Henry McKee Minton, 1870-1946. PMID- 20893762 TI - Clinico-Pathological Diagnostic Problems. PMID- 20893763 TI - Then and Now: Thomas Luther Zuber, Monarch of the Mound. PMID- 20893764 TI - Clinico-Pathological Diagnostic Problems. PMID- 20893765 TI - New Weapon Against Hospital Discrimination. PMID- 20893766 TI - Gift Subscriptions of the Journal. PMID- 20893767 TI - The Strait Gate: A Story of a Principle and the Adherence Thereto. PMID- 20893769 TI - Five Appointed to Staff of Savannah Hospital. PMID- 20893768 TI - Work, Wages and Welfare in Kansas City. PMID- 20893771 TI - Illinois Hospitals Required to Have Open Policy or Lose Tax Exemption. PMID- 20893770 TI - First Negro Graduates from Maryland and Virginia Medical Schools. PMID- 20893773 TI - Tell the Doctor Your Views. PMID- 20893772 TI - Cleveland Medical Reading Club Thirty Years Old. PMID- 20893774 TI - Numa Pompilius Garfield Adams, 1885-1940. PMID- 20893775 TI - On "Diagnostic Problems". PMID- 20893776 TI - Dr. William Montague Cobb Receives Distinguished Service Award For 1955. PMID- 20893778 TI - The President Elect. PMID- 20893777 TI - Clinico-Pathological Diagnostic Problems. PMID- 20893780 TI - The Los Angeles Convention. PMID- 20893779 TI - World Outlook in Medicine. PMID- 20893781 TI - President's Column. PMID- 20893782 TI - Arnold Hamilton Maloney, M.D., 1888-1955. PMID- 20893783 TI - Unusual Request for Employment. PMID- 20893785 TI - President's Column. PMID- 20893784 TI - Hearts and Hobbies. PMID- 20893786 TI - Harris County (Houston, Texas) Admits Two. PMID- 20893787 TI - Bexar County (San Antonio, Texas) Admits Third Negro Member-No Negro Applicants for Dental Society. PMID- 20893789 TI - Chicago Ordinance Against Hospital Discrimination Introduced. PMID- 20893788 TI - Cook County Physicians Association's Role in Illinois Hospital Segregation Ban. PMID- 20893790 TI - Negro Physicians in New York State. PMID- 20893791 TI - John Andrew Kenney, M.D., 1874-1950. PMID- 20893792 TI - Clinico-Pathological Diagnostic Problems. PMID- 20893794 TI - President's Column. PMID- 20893793 TI - Control of Differentiation. PMID- 20893795 TI - Texas Academy of General Practice Drops Bars. PMID- 20893796 TI - A.A.A.S. Will Meet No More in Segregating Cities. PMID- 20893797 TI - Interracial Justice in Hospitals : His Eminence Samuel Cardinal Stritch. PMID- 20893799 TI - Dr. Elihu D. Burke. PMID- 20893798 TI - Charles Richard Drew, M.D., 1904-1950. PMID- 20893800 TI - Dr. J. W. Parker, Sr. PMID- 20893801 TI - President's Column. PMID- 20893803 TI - Anglo-Saxon Ancestry of Americans. PMID- 20893802 TI - The Importance of Mutual Goodwill. PMID- 20893805 TI - Anthropological Science and Current Race Problems. PMID- 20893804 TI - Distribution of Negro Genes. PMID- 20893807 TI - Jackson Heads Connecticut Commission on Civil Rights. PMID- 20893806 TI - Wilmington, North Carolina, Physicians Sue for Hospital Privileges. PMID- 20893808 TI - Chicago Enacts Hospital Anti-Discrimination Ordinance. PMID- 20893810 TI - Clinico-Pathological Diagnostic Problems. PMID- 20893809 TI - Eugene Theodore Hinson, M.D., 1873-. PMID- 20893811 TI - President's Column. PMID- 20893812 TI - And Again New York. PMID- 20893814 TI - Young Recruits are Essential. PMID- 20893813 TI - Clinico-Pathological Diagnostic Problems. PMID- 20893815 TI - Poll of New Orleans Doctors Challenges Statements that School Integration will be Psychiatrically Dangerous. PMID- 20893817 TI - C.E.D. Holds Integration Banquet. PMID- 20893816 TI - Detroit Reports on Racial Factors in Health Areas. PMID- 20893819 TI - Freedmen's Cardiovascular Conferences. PMID- 20893818 TI - Freedmen's Cardiovascular Conferences. PMID- 20893821 TI - Gathings on Keloids. PMID- 20893820 TI - Julius Augustus McMillan, M.D., 1871-1949. PMID- 20893822 TI - Dr. Daniel Thomas Rolfe Receives Distinguished Service Award for 1956. PMID- 20893823 TI - Clinico-Pathological Diagnostic Problems. PMID- 20893824 TI - President's Column. PMID- 20893825 TI - The Imhotep Conference on Hospital Integration. PMID- 20893826 TI - Radioactive Fallout. PMID- 20893828 TI - Rivers Frederick, 1873-1954. PMID- 20893827 TI - The President-Elect. PMID- 20893829 TI - Mark Cox Newsletter. PMID- 20893830 TI - Clinico-Pathological Diagnostic Problems. PMID- 20893831 TI - President's Column. PMID- 20893832 TI - The General Practitioner-His Role Today. PMID- 20893833 TI - A Golden Opportunity. PMID- 20893834 TI - Reference List of Titles in This Journal, 1950-1956, Relating to Anti Discrimination Developments in Medicine. PMID- 20893835 TI - James Thomas Aldrich. PMID- 20893836 TI - David Ruggles, 1810-1849; Hydropathic Practitioner. PMID- 20893838 TI - Failure to Keep Records of Causes of Death. PMID- 20893837 TI - Tribute to Dr. Perry. PMID- 20893840 TI - On Getting into Medical School. PMID- 20893839 TI - President's Column. PMID- 20893841 TI - North Carolina Physicians Refuse Limited Membership. PMID- 20893843 TI - Statement on Hoxsey Cancer Treatment. PMID- 20893842 TI - The Responsibilities of the Student of Medicine to Medical Education. PMID- 20893844 TI - Absalom Jones, 1746-1818, and Richard Allen, 1760-1831. PMID- 20893845 TI - David Ruggles. PMID- 20893846 TI - Clinico-Pathological Diagnostic Problems. PMID- 20893847 TI - President's Column. PMID- 20893848 TI - An Appraisal of the Imhotep Conference. PMID- 20893849 TI - William Alonza Warfield, 1866-1951. PMID- 20893850 TI - Clinico-Pathological Diagnostic Problems. PMID- 20893852 TI - Anesthesia and Something Done. PMID- 20893851 TI - President's Column. PMID- 20893853 TI - Clinico-Pathological Diagnostic Problems. PMID- 20893854 TI - Clinico-Pathological Diagnostic Problems. PMID- 20893855 TI - President's Column. PMID- 20893856 TI - New Horizons. PMID- 20893857 TI - Ernest Everett Just, 1883-1941. PMID- 20893859 TI - Awards at the 1957 Convention of the National Medical Association. PMID- 20893858 TI - Jaundice. PMID- 20893861 TI - The Future of the National Medical Association. PMID- 20893860 TI - President's Column. PMID- 20893862 TI - Clinico-Pathological Diagnostic Problems. PMID- 20893863 TI - The President-Elect. PMID- 20893864 TI - William Augustus Hinton, M.D., 1883-. PMID- 20893866 TI - Our Golden Anniversary Volume. PMID- 20893865 TI - NMA Group Insurance Plans. PMID- 20893867 TI - Clinico-Pathological Diagnostic Problems. PMID- 20893868 TI - Resolution Concerning Alleged Discrimination Against Negro Physicians in Chicago Hospitals. PMID- 20893869 TI - Mental Health Week April 27-May 3, 1958. PMID- 20893870 TI - The Light of the Body. PMID- 20893871 TI - Clinico-Pathological Diagnostic Problems. PMID- 20893873 TI - Ernest Everett Just. PMID- 20893872 TI - Walter Gilbert Alexander, M.D., 1880-1953. PMID- 20893874 TI - Kansas City General Hospitals Nos. 1 and 2 Consolidated. PMID- 20893875 TI - President's Column. PMID- 20893876 TI - Guest Editorial. PMID- 20893878 TI - Radiation Needs Enlightenment. PMID- 20893877 TI - Good Out of Little Rock. PMID- 20893879 TI - Frederick Douglas Stubbs, M.D., 1906-1947. PMID- 20893880 TI - North Carolina Impasse. PMID- 20893881 TI - President's Column. PMID- 20893882 TI - Tomorrow's Scientists and Technicians. PMID- 20893883 TI - Clinico-Pathological Diagnostic Problems. PMID- 20893884 TI - Financial Problems of Medical Schools. PMID- 20893885 TI - State of the Union in Respect to Health. PMID- 20893886 TI - William Clarence McNeill, M.D., 1878-. PMID- 20893887 TI - Correspondence. PMID- 20893888 TI - In Retrospect. PMID- 20893889 TI - A Special Need In Mental Health. PMID- 20893890 TI - Inflation and the Crippled Child. PMID- 20893891 TI - Anderson William Cheatham, 1880-1936. PMID- 20893892 TI - Legal Counsel. PMID- 20893893 TI - NMA Greetings to NAACP Telegram. PMID- 20893894 TI - Hypothermia in Cardiovascular Surgery. PMID- 20893895 TI - Dr. Leonidas H. Berry Receives Distinguished Service Award for 1958. PMID- 20893896 TI - President's Column. PMID- 20893898 TI - Our Cardiovascular Problem. PMID- 20893897 TI - The Milwaukee Convention and the Future. PMID- 20893899 TI - Howard Dedicates Preclinical Medical Science Buildings. PMID- 20893900 TI - William McKinley Thomas, M.D. PMID- 20893901 TI - Clinico-Pathological Diagnostic Problems. PMID- 20893903 TI - New Horizons. PMID- 20893902 TI - Make Haste Slowly! PMID- 20893904 TI - The Arkansas Medical, Dental and Pharmaceutical Association. PMID- 20893905 TI - William Daniel Morman, M.D., 1901-1951. PMID- 20893906 TI - Single Trauma and Cancer. PMID- 20893907 TI - President's Column. PMID- 20893908 TI - Increase in Staff Appointments at Chicago Hospitals. PMID- 20893909 TI - Right Spirit Toward Integration. PMID- 20893910 TI - Clinico-Pathological Diagnostic Problems. PMID- 20893911 TI - On to Detroit. PMID- 20893912 TI - The Centennial of Physical Anthropology. PMID- 20893913 TI - Steering Wheel Injuries to the Heart. PMID- 20893914 TI - President's Column. PMID- 20893915 TI - Our Lady Members. PMID- 20893917 TI - Milwaukee Hospital Integration Story. PMID- 20893916 TI - Clinico-Pathological Diagnostic Problems. PMID- 20893919 TI - Chicago Hospital Staff Appointments. PMID- 20893918 TI - Hospital Integration in Columbus, Ohio. PMID- 20893920 TI - Arthur Melvin Townsend, M.D., 1875-1959. PMID- 20893921 TI - Restricting Hospital Privileges of Physicians. PMID- 20893923 TI - Reorientation in Medicine. PMID- 20893922 TI - Ocular Sarcoidosis. PMID- 20893924 TI - Something to Consider. PMID- 20893925 TI - Clinico-Pathological Diagnostic Problems. PMID- 20893926 TI - N.A.A.C.P. Resolutions on Health, 1959. PMID- 20893928 TI - Henry Rutherford Butler, M.D., 1860-1931. PMID- 20893927 TI - Mental Anguish: Two New Legal Approaches. PMID- 20893929 TI - Penetrating Thoraco-Abdominal Wounds : An Analysis of 136 Cases Treated in a Civilian General Hospital. PMID- 20893930 TI - Looking Ahead in Health and Medicine. PMID- 20893931 TI - The 1959 Awards of the National Medical Association. PMID- 20893932 TI - The President-Elect. PMID- 20893934 TI - Salute to Surgery. PMID- 20893933 TI - Doctors and Lawyers. PMID- 20893935 TI - The Physician: His Public Relations and Organization. PMID- 20893936 TI - Medical Practice Becoming Give-Away Program. PMID- 20893937 TI - Grossi Hamilton Francis, M.D., 1885-. PMID- 20893938 TI - What the Law Requires a Physician to Tell His Patients. PMID- 20893939 TI - Meetings and Reflections Thereon. PMID- 20893940 TI - The Third Detroit Convention. PMID- 20893941 TI - The Sons of Podalirius. PMID- 20893942 TI - Behavior Disorders in Children. PMID- 20893944 TI - Developments in Charlotte, North Carolina. PMID- 20893943 TI - Clinico-Pathological Diagnostic Problems. PMID- 20893945 TI - South Side Branch of County Hospital Opposed in Chicago. PMID- 20893946 TI - Doctors and Politics. PMID- 20893947 TI - The Need for Biological Toys. PMID- 20893948 TI - Carl Glennis Roberts, M.D., 1886-1950. PMID- 20893949 TI - Non-Paternity and Blood Grouping Tests. PMID- 20893951 TI - Biopsy in Modern Medical Practice. PMID- 20893950 TI - Stomachus Convivius Endemic Condition. PMID- 20893952 TI - Small Bowel Perforation in Regional Enteritis Secondary to the Administration of Steroids: A Case Report. PMID- 20893953 TI - The Negro Physician in a Sick Society. PMID- 20893954 TI - A Governor's Health Conference. PMID- 20893955 TI - Elimination of Racial Discrimination in Hospital Practices. PMID- 20893957 TI - Fort Lauderdale, Florida, Hospital Controversy. PMID- 20893956 TI - Charlotte Dentist Sues for Admission to North Carolina Dental Society. PMID- 20893959 TI - Detroit Medical Center Rehabilitation Project. PMID- 20893958 TI - Proposal for Separate Negro Hospital in St. Petersburg, Florida, Protested. PMID- 20893960 TI - X-Ray Machines and the Non-Radiologist. PMID- 20893961 TI - Julian Waldo Ross, M.D., 1884. PMID- 20893962 TI - It's Your Sit-Down Too! PMID- 20893963 TI - A Comparison of Small Arterial Anastomoses with and without Heparin. PMID- 20893964 TI - Southern Exposure. PMID- 20893965 TI - Blood Transfusion and Race. PMID- 20893967 TI - Ulysses Grant Dailey, M.D., 1885. PMID- 20893966 TI - Integration of Hospital Staffs and Medical Institutions in Louisville, Kentucky. PMID- 20893968 TI - Therapeutic Abortions and the Law. PMID- 20893970 TI - Clinico-Pathological Diagnostic Problems. PMID- 20893969 TI - Malpractice and the Physician. PMID- 20893972 TI - The Value of Medical History. PMID- 20893971 TI - Rehabilitation of the Chronically Ill. PMID- 20893973 TI - Indiana Hospitals Open to Negro Physicians. PMID- 20893974 TI - Hospital Discrimination in Columbus, Ohio. PMID- 20893975 TI - Proposed Chicago South Side County Hospital Branch Controversy Continues. PMID- 20893976 TI - Fort Lauderdale, Florida, Fiasco. PMID- 20893977 TI - A Short Method of Doing Cholesterols. PMID- 20893979 TI - Vasectomy and the Law. PMID- 20893978 TI - Clyde Donnell, M.D., 1890. PMID- 20893980 TI - Postpartum Hemorrhage. PMID- 20893981 TI - The Treatment of Abortions. PMID- 20893982 TI - Dr. John B. Johnson Distinguished Service Medalist for 1960. PMID- 20893983 TI - The President Elect: Vaughan Carrington Mason, M.D. PMID- 20893985 TI - Talent Recruitment Necessities. PMID- 20893984 TI - Medical Care. PMID- 20893986 TI - The Pittsburgh Convention. PMID- 20893987 TI - The Journal's Hospital Series. PMID- 20893989 TI - Clinico-Pathological Diagnostic Problems. PMID- 20893988 TI - Daniel Hale Williams Cardiac Operation Priority. PMID- 20893990 TI - Imhotep Conference Chairmen. PMID- 20893992 TI - Medical-Legal Consent by Minors. PMID- 20893991 TI - Killed-Virus vs. Live-Virus Vaccines Against Polio. PMID- 20893993 TI - Trustees, Administrators and Staff of Mercy-Douglass Hospital. PMID- 20893994 TI - Diabetes. PMID- 20893995 TI - Help for Emerging Africa. PMID- 20893996 TI - Mercy-Douglass Hospital. PMID- 20893997 TI - Clinico-Pathological Diagnostic Problems. PMID- 20893998 TI - Chicago Hospital Council Makes New Statement of Policy on Medical Staff Appointments. PMID- 20893999 TI - Call for Nationwide Formation of Local Imhotep Committees. PMID- 20894000 TI - The Electroencephalogram and Head Injuries. PMID- 20894001 TI - Cerebral Vascular Disease : A Preliminary Study. PMID- 20894002 TI - Emergency Management of Multiple Injury Patients. PMID- 20894003 TI - Clinico-Pathological Diagnostic Problems. PMID- 20894004 TI - Recruiting Program. PMID- 20894005 TI - John A. Andrew Memorial Hospital. PMID- 20894006 TI - Some Implications of the Need for Increased Production of Physicians. PMID- 20894007 TI - Community Imhotep Committees. PMID- 20894009 TI - Eight Physicians Arrested for Atlanta Cafeteria Stand-In. PMID- 20894008 TI - Chicago Physicians Sue for Admission to Hospital Staffs. PMID- 20894010 TI - The Need for New Construction at Freedmen's Hospital. PMID- 20894011 TI - The Patient's Right to Privacy. PMID- 20894012 TI - The Use of a Vaginal Detergent and pH Stabilizer in Treatment of Leucorrhea. PMID- 20894013 TI - Use of Sustained Release Prochlorperazine Therapy in the Treatment of Severely Disturbed Mental Patients. PMID- 20894014 TI - The March of Dimes Campaign for 1961. PMID- 20894015 TI - The Seventieth Anniversary of the Provident Hospital. PMID- 20894016 TI - Whither the Community Hospital? PMID- 20894017 TI - North Carolina Civil Rights Advisory Committee to Study State Health Programs. PMID- 20894018 TI - Detroit Group Desires Exchanges. PMID- 20894020 TI - Fee Collection and the Third Party "Stranger". PMID- 20894019 TI - Mercy Douglass Hospital Number. PMID- 20894021 TI - Vignettes of Life in Liberia. PMID- 20894022 TI - Ectopic Pregnancy. PMID- 20894023 TI - Diabetes in Pregnancy. PMID- 20894024 TI - Clinico-Pathological Diagnostic Problems. PMID- 20894025 TI - Medical Care Legislation. PMID- 20894026 TI - In Tribute to Alexander Meiklejohn. PMID- 20894027 TI - A Raleigh, North Carolina, Newspaper Comment on "Scientific Membership". PMID- 20894028 TI - Dr. Pierce S. Moten. PMID- 20894029 TI - Electric Shock Therapy and Relaxant Drugs. PMID- 20894030 TI - Hypnosis: A Useful Adjunct to Medicine and Dentistry. PMID- 20894031 TI - Clinical Experience with Hypnosis in Obstetrics and Gynecology. PMID- 20894032 TI - The Role of Psychiatry and Religion in the Treatment of Illness. PMID- 20894033 TI - Entrapment Neuropathy of Intercostal Nerve: A Case Report. PMID- 20894034 TI - The Challenge of Prenatal Care. PMID- 20894035 TI - Clinico-Pathological Diagnostic Problems. PMID- 20894036 TI - President's Column. PMID- 20894037 TI - Moral Rearmament a Necessity in Medicine. PMID- 20894038 TI - Visits of a Pharmacologist to Europe and South America. PMID- 20894039 TI - Second Suit Filed Against Wilmington, North Carolina, Hospital. PMID- 20894040 TI - New York Hospital Staff Appointment Survey Criticized. PMID- 20894041 TI - The Social Treatment of the Aged. PMID- 20894043 TI - Remarks Introducing Dr. Leonard W. Larson. PMID- 20894042 TI - The President-Elect. PMID- 20894044 TI - Medicine, the Patient and Government. PMID- 20894045 TI - Hill-Burton "Separate But Equal" Provision Unconstitutional. PMID- 20894047 TI - The 1961 Awards of the National Medical Association. PMID- 20894046 TI - NAACP 1961 Health Resolutions. PMID- 20894048 TI - Clinico-Pathological Diagnostic Problems. PMID- 20894050 TI - Joe Louis-Model for the Physician. PMID- 20894049 TI - Needs of the Hour. PMID- 20894051 TI - Javits Bill to End Hospital Discrimination Under Hill-Burton Act. PMID- 20894052 TI - D.C. Hospitals Tied to Anti-Bias Rule. PMID- 20894053 TI - NMA Physician Admitted to Virginia Hospital Staffs. PMID- 20894054 TI - Presence of Attorney During Medical Examination. PMID- 20894056 TI - Clinico-Pathological Diagnostic Problems. PMID- 20894055 TI - A Clinical Note on the Jarisch-Herxheimer Reaction. PMID- 20894057 TI - The Other Mantle of the Physician. PMID- 20894058 TI - Hospital Discrimination and the Sixth Imhotep Conference. PMID- 20894059 TI - Executive Procedure Without Effect in Hospital Area. PMID- 20894061 TI - Maryland Commission Report Cites Negro Health Needs. PMID- 20894060 TI - Greensboro, North Carolina, Group Files Historic Suit Against Hospital Exclusion. PMID- 20894062 TI - Johns Hopkins Medical School Open to Negro Students. PMID- 20894063 TI - Health Insurance Plans Silent on Racial Discrimination. PMID- 20894065 TI - Paul Dudley White as an Inspirational Force. PMID- 20894064 TI - A Broad View of Continued Education. PMID- 20894066 TI - Clinico-Pathological Diagnostic Problems. PMID- 20894067 TI - Dingell Bill to End Hospital Discrimination Under the Hill-Burton Act. PMID- 20894068 TI - Orangeburg, S. C., Hospital Sued for Segregation. PMID- 20894070 TI - Medical Care and the Negro: An Analysis and Report on the Greater Pittsburgh Area. PMID- 20894069 TI - Chicago Commission on Human Relations Reports on Negro Physicians on Chicago Hospital Staffs. PMID- 20894071 TI - The Unlicensed Employee. PMID- 20894072 TI - Technics For, and the Importance Of, Heart Size Determination in Infants and Children. PMID- 20894074 TI - Of Time and Truth. PMID- 20894073 TI - The Treatment of Depression with Meprobamate-Benactyzine (Deprol): Evaluation of a "Sliding Scale" Method of Dose Selection. PMID- 20894076 TI - Greetings to Imhotep. PMID- 20894075 TI - The Infinite Wealth of a Veteran Teacher. PMID- 20894077 TI - The President's Message. PMID- 20894078 TI - American Association of Physical Anthropologists Condemns Racist Literature. PMID- 20894079 TI - A Brief History of McRae Memorial Sanatorium. PMID- 20894081 TI - Correspondence. PMID- 20894080 TI - Medico-Legal Relationship of the Attending Surgeon to the Hospital Staff in the Operating Room. PMID- 20894082 TI - Clinico-Pathological Diagnostic Problems. PMID- 20894083 TI - Every Shoulder to the Wheel. PMID- 20894084 TI - Green Bill to End Hospital Discrimination Under the Hill-Burton Act. PMID- 20894085 TI - SAMA Adopts Anti-Discrimination Resolution. PMID- 20894086 TI - Blood Transfusions: A Sale or a Service. PMID- 20894088 TI - The President-Elect. PMID- 20894087 TI - Dr. Eugene Heriot Dibble, Jr., Distinguished Service Medalist for 1962. PMID- 20894089 TI - Living Within One's Means. PMID- 20894090 TI - No Need to Fear a Colossus. PMID- 20894091 TI - The Chicago Commission on Human Relations. PMID- 20894092 TI - Treatment of Patients in Desperate Heart Failure. PMID- 20894093 TI - The Treatment of Uremia With the Artificial Kidney. PMID- 20894094 TI - Dr. Franklin Chambers McLean: An Appreciation. PMID- 20894095 TI - Pearly Tumors of the Brain and Spinal Cord. PMID- 20894096 TI - A Strong America. PMID- 20894097 TI - The Government and the People's Health. PMID- 20894098 TI - Texts of the Atlanta and Butner, N. C., Hospital Suits. PMID- 20894099 TI - Discrimination in North Carolina Hospitals. PMID- 20894101 TI - Charlotte Physician Receives Hospital Staff Appointment. PMID- 20894100 TI - Greensboro Hospital to Accept Negro Physicians and Dentists. PMID- 20894103 TI - Chicago Hospital Ordinance Forbids Racial Discrimination in Appointment and Employment of Physicians. PMID- 20894102 TI - Key N.A.A.C.P. Leaders in Hospital Area. PMID- 20894104 TI - Chicago Commission Recommends Non-Discrimination Policy Statement for Voluntary Hospitals. PMID- 20894105 TI - Prudhomme Appointed to District of Columbia Mental Health Commission. PMID- 20894106 TI - The Hospital Situation in St. Louis. PMID- 20894108 TI - The Negro in the Practice of Medicine in Los Angeles. PMID- 20894107 TI - The Hospital Situation in Knoxville, Tennessee. PMID- 20894110 TI - Detroit Physician Voices Resentment of A.M.A. Indifference. PMID- 20894109 TI - Beaumont, Texas, Hospital Opens Doors. PMID- 20894111 TI - Theodore Wiprud-Medical Statesman. PMID- 20894112 TI - The Holy Family Hospital, Ensley, Alabama. PMID- 20894113 TI - The Palmetto Medical, Dental and Pharmaceutical Association. PMID- 20894115 TI - Cultural Variations in the Concepts of Sickness and Health. PMID- 20894114 TI - Three Medical Systems: China, the West, and the Middle East. PMID- 20894116 TI - The Partnership of Anthropology and Public Health. PMID- 20894118 TI - NMA Members Should Support Federal Aid to Education. PMID- 20894117 TI - Surgical Management of Cystic Disease of the Lung : Clinical Review of 108 Cases. PMID- 20894119 TI - Pro Lege Medicara: On Behalf of Medicare. PMID- 20894120 TI - Federal Hospital Council Recommends Anti-Bias Legislation. PMID- 20894121 TI - Dingell Bill to Bar Hospital Discrimination Under Hill-Burton Law. PMID- 20894122 TI - Organized Labor Issues Strong Policy Statement Against Hospital Discrimination. PMID- 20894123 TI - Medical School Admission Policies of the State University of New York. PMID- 20894125 TI - Collection Agency Violating Patient's Right to Privacy. PMID- 20894124 TI - D. C. Government Adds to Hospital Contracts Non-Discrimination Clause on Staff Appointments. PMID- 20894126 TI - Need For Postgraduate Study. PMID- 20894128 TI - The Student National Medical Association. PMID- 20894127 TI - National Medical Fellowships, Inc. PMID- 20894129 TI - Statement on Non-Discrimination of Health & Welfare Council of National Capital Area. PMID- 20894130 TI - The Negro Specialist and The Negro General Practitioner: Their Relationship to Each Other, the Profession and the Community. PMID- 20894131 TI - Suspension of Medical License for Tax Evasion. PMID- 20894132 TI - Burrell Memorial Hospital. PMID- 20894133 TI - Lysis of a Cerebral Thrombus with Fibrinolysin: A Case Report. PMID- 20894134 TI - Clinical Scleroderma in a Patient with Renal Lesions Described as Malignant Nephrosclerosis. PMID- 20894136 TI - Changing Concepts of Peptic Ulcer. PMID- 20894135 TI - A Clinical Appraisal of Some Sexually Promiscuous Females. PMID- 20894138 TI - Hospital Integration. PMID- 20894137 TI - Spontaneous Hypoglycemia. PMID- 20894139 TI - Physicians, Peace, Pickets and Powell. PMID- 20894140 TI - The president's Message. PMID- 20894142 TI - New Progress in Atlanta. PMID- 20894141 TI - Admission Policy of Catholic Hospitals of Atlanta. PMID- 20894143 TI - Javits Re-introduces His Bill To Amend Hill-Burton Law. PMID- 20894144 TI - New York Enacts Law to Prevent Discrimination Against Physicians in Private Institutions. PMID- 20894145 TI - Chicago Committee To Recruit Negro Medical Students. PMID- 20894146 TI - Appointments of Practicing Negro Physicians at Private, Non-Governmental Chicago Hospitals. PMID- 20894147 TI - Washington Urban League Findings on Appointment of Negro Physicians to Hospital Staffs. PMID- 20894148 TI - Catholic Hospital Association Passes Anti-Discrimination Resolution. PMID- 20894149 TI - N.A.A.C.P. Hospital Suits Pending. PMID- 20894150 TI - Physicians Contributions to Community Hospitals and the So-called "Bed Tax". PMID- 20894151 TI - Prepaid Medical Plans. PMID- 20894152 TI - Anemia Threatens Life of Civil Rights Bill. PMID- 20894153 TI - Health Facilities and Services Recommendations of the United States Commission on Civil Rights. PMID- 20894154 TI - Federal Court Rules Bias in Federally Aided Hospitals Unconstitutional. PMID- 20894155 TI - New York Hospital Association Anti-Discrimination Resolution. PMID- 20894156 TI - N.A.A.C.P. Resoluton on Hospitals and Health, 1963. PMID- 20894157 TI - AFL-CIO Department of Social Security Statement on Civil Rights Commission Report on Health Matters. PMID- 20894158 TI - Lawyers are Not Immune From Legal Actions by Physicians. PMID- 20894159 TI - Chicago Human Relations Commission Report of October 23, 1963: Negro Physicians and Medical Students Affiliated with Chicago Hospitals and Medical Schools. PMID- 20894160 TI - The Ojike Nigerian Hospital Project. PMID- 20894161 TI - Mental Illness in Workmen's Compensation Law. PMID- 20894162 TI - The Role of the Physician in Adoption. PMID- 20894164 TI - Washington State Medical Association Petition to A.M.A. Against Discrimination. PMID- 20894163 TI - Profession and Public Focus on Hospital Discrimination. PMID- 20894166 TI - Senate Rejection of Javits Anti-Discrimination Amendment to Hill-Burton Act. PMID- 20894165 TI - Cleveland Academy of Medicine Anti-Discrimination Resolution to A.M.A. PMID- 20894168 TI - Gadsden (Ala.) Freedom Movement Protests New Hill-Burton Hospital Arrangements. PMID- 20894167 TI - American Hospital Association Asks Amendment of Hill-Burton Law. PMID- 20894169 TI - Statement of President Lyndon B. Johnson to Senior Citizens. PMID- 20894170 TI - Smoking and Health. PMID- 20894171 TI - The Los Angeles Convention. PMID- 20894172 TI - Dentist and Physician Among Demonstrators Arrested in Atlanta. PMID- 20894173 TI - Chicago Court Agreement Reached. PMID- 20894174 TI - Hospital to Drop Bars Following NAACP Probe. PMID- 20894175 TI - Desmoid Tumor: A Tumor That Shaped a Career. PMID- 20894176 TI - Alcoholics and Vocational Rehabilitation. PMID- 20894177 TI - Assassination Could Have Been Prevented. PMID- 20894178 TI - Are Negro Schools of Nursing Needed Today? PMID- 20894179 TI - Mental Retardation. PMID- 20894181 TI - American Hospital Association Issues Statement on Rights. PMID- 20894180 TI - Message on Health. PMID- 20894183 TI - Clement Statement on A.M.A. Proposed Hill-Burton Amendment. PMID- 20894182 TI - Hospital Council of Maryland Moves Quietly For Integration. PMID- 20894184 TI - A.M.A. Proposes Hill-Burton Amendment Weakening Moses Cone Decision. PMID- 20894185 TI - Statistics on Negro Illegitimacy False Indices of Relative Standards of Morality. PMID- 20894186 TI - A Word of Thanks. PMID- 20894187 TI - Past Gains and New Challenges. PMID- 20894188 TI - Statement of Cleveland Physicians and Dentists on School Segregation. PMID- 20894190 TI - Civil Rights Committee Report On New York and Buffalo. PMID- 20894189 TI - Text of H.E.W. Order on Nondiscrimination By Hill-Burton Applicants. PMID- 20894192 TI - President Johnson Signs Hill-Burton Extension Act, H.R. 10041. PMID- 20894191 TI - The Legal Hazards of Golf. PMID- 20894194 TI - President Johnson and the Great Society. PMID- 20894193 TI - Tooling-Up for Progress. PMID- 20894195 TI - The Fifth Washington Convention. PMID- 20894197 TI - First Negro Resident at Cleveland Clinic. PMID- 20894196 TI - Baton Rouge Hospitals Integrate. PMID- 20894198 TI - New A.M.A. Antidiscrimination Resolution. PMID- 20894199 TI - Federal Medical Facilities Requested for Mississippi Civil Rights Workers. PMID- 20894201 TI - Confidential Relationship, Especially as to Infants. PMID- 20894200 TI - The Physician and The Social Security Disability Program. PMID- 20894202 TI - Dr. Hildrus Augustus Poindexter, Distinguished Service Medalist for 1964. PMID- 20894203 TI - Leonidas Harris Berry, B.S., M.S., M.D. PMID- 20894204 TI - The Power of Growth. PMID- 20894205 TI - The Changing Scene in Surgery. PMID- 20894206 TI - N.A.A.C.P. Health Resolutions, 1964. PMID- 20894207 TI - A Program in Health Careers. PMID- 20894208 TI - Toussaint Tourgee Tildon, Sr. PMID- 20894209 TI - Malpractice: Breach of Warranty vs. Action in Negligence. PMID- 20894211 TI - The journal covers. PMID- 20894210 TI - Bestriding the globe. PMID- 20894213 TI - Emergence. PMID- 20894212 TI - Bed of procrustes. PMID- 20894214 TI - Firm foundations. PMID- 20894215 TI - Challenge and hope. PMID- 20894216 TI - Journal of the royal society of medicine. PMID- 20894217 TI - Dermatitis artefacta. PMID- 20894219 TI - Whither vestibular tests? PMID- 20894218 TI - Causes of 'delayed' respiratory distress in infancy. PMID- 20894220 TI - Problems of communication of a drug regulatory authority. PMID- 20894221 TI - Thyroid eye disease. PMID- 20894222 TI - Causes of 'delayed' respiratory distress in infancy. PMID- 20894223 TI - Visual field examination. PMID- 20894224 TI - Evolution, environment and cancer: November 1977 Proceedings, 70, 753. PMID- 20894225 TI - The pelvic ureter. PMID- 20894227 TI - Treatment of perianal and anal condylomata acuminata: a new operative technique. PMID- 20894226 TI - Obturating balloon colostomy. PMID- 20894228 TI - Causes of 'delayed' respiratory distress in infancy. PMID- 20894229 TI - Immunofluorescent diagnosis of communicable diseases. PMID- 20894230 TI - Diffuse unilateral subacute neuroretinitis. PMID- 20894232 TI - International nomenclature of diseases. PMID- 20894231 TI - Computerized tomography in localization of abdominal malignancy. PMID- 20894233 TI - Role of the district or nonteaching hospital. PMID- 20894234 TI - Diabetes in pregnancy. PMID- 20894235 TI - British postgraduate medical Federation. PMID- 20894237 TI - General practice: a developing academic discipline. PMID- 20894236 TI - Problems of communication of a drug regulatory authority. PMID- 20894238 TI - Recurrence rate and survival time in carcinoma of the breast treated by biopsy excision alone. PMID- 20894239 TI - Cholesterol hydroperoxide - a potential cardiac hazard. PMID- 20894240 TI - Role of the district or non-teaching hospital. PMID- 20894241 TI - Role of the district or non-teaching hospital. PMID- 20894242 TI - Treatment of perianal and anal condylomata acuminata. PMID- 20894243 TI - The nature of diabetes. PMID- 20894244 TI - Internal fixation of wrist fractures. PMID- 20894246 TI - Role of the district or non-teaching hospital. PMID- 20894245 TI - The pharmaceutical industry and medical education. PMID- 20894247 TI - Recurrence rate and survival time of patients with carcinoma of the breast. PMID- 20894249 TI - Internal fixation of wrist fractures. PMID- 20894248 TI - Continent ileocaecal urinary reservoir. PMID- 20894250 TI - Grommets and glue ear. PMID- 20894251 TI - Immunofluorescent diagnosis of communicable diseases. PMID- 20894252 TI - Carbohydrate confusion. PMID- 20894253 TI - Clinical pharmacology in the National Health Service. PMID- 20894254 TI - The state of British medicine - 8. Medicine in the armed forces. PMID- 20894255 TI - Hearing conservation in the Royal Air Force. PMID- 20894256 TI - Preoperative diagnosis of renal masses. PMID- 20894257 TI - Trichlorethylene - relationship of metabolite levels to atmospheric concentrations: preliminary communication. AB - The search for a practical index of trichlorethylene exposure must take into account its degree of narcotic activity in turn related to air concentration. Trichloracetic acid level in urine provides a useful means of assessing exposure and it can be related to trichlorethylene in air. A small investigation of this relationship has been carried out on two continuously exposed subjects. PMID- 20894258 TI - Sachse optical urethrotome in management of urethral stricture in the male: preliminary communication. PMID- 20894259 TI - Childhood brain tumours: a review. PMID- 20894260 TI - Hairy cell leukaemia. PMID- 20894261 TI - Tufted folliculitis of the scalp. PMID- 20894263 TI - Sir Ronald Ross and his contemporaries. PMID- 20894262 TI - Resolution of actinic reticuloid with transition to photosensitive eczema. PMID- 20894264 TI - Inherited susceptibility to rheumatic disease. PMID- 20894265 TI - Electroencephalography today. PMID- 20894266 TI - The young chronic sick. PMID- 20894267 TI - Hearing conservation. PMID- 20894268 TI - Lateral subcutaneous sphincterotomy. PMID- 20894270 TI - General practice: a developing academic discipline. PMID- 20894269 TI - Pelvic pain. PMID- 20894271 TI - Male infertility. PMID- 20894272 TI - Internal fixation of wrist fractures. PMID- 20894273 TI - Perianal and anal condylomata. PMID- 20894274 TI - The general practitioner's contribution to undergraduate medical education. PMID- 20894275 TI - Clinical pharmacology in the NHS. PMID- 20894276 TI - Internal fixation of wrist fractures. PMID- 20894277 TI - Grommets and glue ear. PMID- 20894278 TI - The hospital nurse. PMID- 20894279 TI - DHSS policy. PMID- 20894281 TI - Misdiagnosis of testicular tumours. PMID- 20894280 TI - Sir ronald ross. PMID- 20894283 TI - Medical library in need. PMID- 20894282 TI - Perianal and anal condylomata. PMID- 20894284 TI - Perianal and anal condylomata. PMID- 20894285 TI - Hormonal status in postmenopausal women. PMID- 20894286 TI - Payment for medical authors. PMID- 20894287 TI - Malaria and the Maudsley Hospital: November 1978 Journal, pp 853-854. PMID- 20894288 TI - Treatment of Colles' fractures. PMID- 20894289 TI - Electroencephalography today. PMID- 20894290 TI - Electroencephalography today. PMID- 20894291 TI - Electroencephalography today. PMID- 20894292 TI - Closure of the abdominal wound. PMID- 20894293 TI - Arthroscopy: the first hundred are the worst. PMID- 20894294 TI - Payment for medical authors. PMID- 20894295 TI - Electroencephalography today. PMID- 20894296 TI - Clinical pharmacology in the NHS. PMID- 20894298 TI - Diagnosis of dyslexia. PMID- 20894297 TI - Clinical pharmacology in the NHS. PMID- 20894299 TI - General practice in inner-city areas: April Journal, p 299. PMID- 20894301 TI - Electroencephalography today. PMID- 20894300 TI - Adhesion of the labia minora in childhood: an early description. PMID- 20894302 TI - Community mental health centres. PMID- 20894303 TI - Frey's syndrome. PMID- 20894304 TI - The concept of disease in psychiatry. PMID- 20894305 TI - Prenatal care in Libya. PMID- 20894306 TI - Agricultural medicine. PMID- 20894307 TI - Otolaryngology in the curriculum. PMID- 20894308 TI - Community mental health centres. PMID- 20894309 TI - Inhalation sedation. PMID- 20894310 TI - Community mental health centres. PMID- 20894311 TI - Defence of invertebrates against bacterial infection. PMID- 20894312 TI - Future of community medicine. PMID- 20894314 TI - Medical Art Society exhibition. PMID- 20894313 TI - Napoleon's health. PMID- 20894315 TI - Pelvi-ureteric junction is effect not cause of primary pelvic hydronephrosis. PMID- 20894316 TI - Concept of disease in psychiatry. PMID- 20894317 TI - Mental health services and primary medical care: March Journal, pp 219-220. PMID- 20894318 TI - Problem with a Foley catheter: April Journal, p 305. PMID- 20894319 TI - Pelvi-ureteric junction and primary pelvic hydronephrosis. PMID- 20894321 TI - Napoleon's health. PMID- 20894320 TI - Doctors and civil litigation. PMID- 20894323 TI - The hospital ophthalmic service. PMID- 20894322 TI - Pelvi-ureteric junction and primary pelvic hydronephrosis. PMID- 20894324 TI - The hospital ophthalmic service. PMID- 20894325 TI - Epidemiology of minor psychiatric disorders. PMID- 20894326 TI - Finding anaesthesiology boring. PMID- 20894328 TI - Second ear stapedectomy. PMID- 20894327 TI - Doctors and civil litigation. PMID- 20894329 TI - The hospital ophthalmic service. PMID- 20894330 TI - Words and meanings. PMID- 20894331 TI - Hospice care and geriatric medicine. PMID- 20894332 TI - Words and meanings. PMID- 20894333 TI - Metachronous carcinomas of the large and small bowel. PMID- 20894334 TI - Acute abdominal pain in children. PMID- 20894336 TI - Psychiatric research. PMID- 20894335 TI - Psychiatric research. PMID- 20894337 TI - Incidence of various forms of organic dementia. PMID- 20894338 TI - Calcium metabolism in bone disease. PMID- 20894339 TI - Hypokalaemic thyrotoxic periodic paralysis. PMID- 20894340 TI - Hypnosis and psychiatry. PMID- 20894342 TI - Second ear stapedectomy. PMID- 20894341 TI - Calcium metabolism in bone disease. PMID- 20894343 TI - Towards the chemotherapeutic treatment of dental caries. PMID- 20894345 TI - Hypnosis and psychiatry. PMID- 20894344 TI - Severe myxoedema presenting with chondrocalcinosis and polymyositis. PMID- 20894346 TI - Effectiveness of amiodarone in resistant arrhythmias. PMID- 20894347 TI - Psychiatric research. PMID- 20894348 TI - Use of pressurized aerosol bronchodilators. PMID- 20894350 TI - Controlled clinical trials: the current ethical debate. PMID- 20894349 TI - Controlled clinical trials: the current ethical debate. PMID- 20894351 TI - Tympanoplasty. PMID- 20894353 TI - Hospice care and geriatric medicine. PMID- 20894352 TI - Severe myxoedema presenting with chondrocalcinosis and polymyositis. PMID- 20894354 TI - Use of pressurized aerosol bronchodilators. PMID- 20894356 TI - Tympanoplasty. PMID- 20894355 TI - Success of colorectal anastomosis. PMID- 20894357 TI - The hospice tradition. PMID- 20894359 TI - Success of colorectal anastomosis. PMID- 20894358 TI - Penicillamine-induced dermatomyositis. PMID- 20894360 TI - Urological cooperatives. PMID- 20894362 TI - Cost effectiveness of prophylaxis of venous thromboembolism. PMID- 20894361 TI - Crohn's disease and arthritis. PMID- 20894363 TI - Are patients shocked by ECT? PMID- 20894365 TI - Purple toe syndrome. PMID- 20894364 TI - Are patients shocked by ECT? PMID- 20894366 TI - Boiling water intake and gastric problems? PMID- 20894368 TI - Food hyposensitization. PMID- 20894367 TI - Use of pressurized bronchodilators. PMID- 20894369 TI - The hospice tradition. PMID- 20894370 TI - Pain relief during childbirth and development at 4 years. PMID- 20894371 TI - Post-traumatic syndrome. PMID- 20894372 TI - Purple toe syndrome. PMID- 20894373 TI - Donald winnicott. PMID- 20894374 TI - Reconstruction of the breast after mastectomy. PMID- 20894375 TI - No alternatives to Western medical care. PMID- 20894376 TI - Tympanoplasty. PMID- 20894378 TI - Is 'an' before 'h' still justified? PMID- 20894377 TI - Collagen, autoimmunity and disease. PMID- 20894379 TI - Scientific empiricism and clinical medicine. PMID- 20894380 TI - Oral complaints related to climacteric symptoms in oophorectomized women. PMID- 20894381 TI - Aetiology of gynaecological cancer. PMID- 20894382 TI - Hypnotherapy in the psychosomatic approach to illness. PMID- 20894383 TI - Carcinoma of the rectum in male homosexuals. PMID- 20894384 TI - Purple toe syndrome. PMID- 20894385 TI - Post-traumatic syndrome. PMID- 20894387 TI - Campylobacter infections in man. PMID- 20894386 TI - Post-traumatic syndrome. PMID- 20894388 TI - Smallpox eradication. PMID- 20894390 TI - Naloxone in anorexia nervosa. PMID- 20894389 TI - Ossification in abdominal scars. PMID- 20894391 TI - Is 'an' before 'h' still justified? PMID- 20894392 TI - Is 'an' before 'h' still justified? PMID- 20894393 TI - Abdominal wound closure: a choice of suture. PMID- 20894394 TI - Value of hormone measurements in gynaecology. PMID- 20894396 TI - Origins of palaeopathology. PMID- 20894395 TI - Sexually transmitted disease statistics. PMID- 20894397 TI - Urological misconceptions. PMID- 20894399 TI - Organophosphate poisoning and complete heart block. PMID- 20894398 TI - Lay participation in review of clinical judgment in psychiatry. PMID- 20894400 TI - Consent to treatment. PMID- 20894401 TI - What should be done about hearing impairments? PMID- 20894402 TI - What should be done about hearing impairments? PMID- 20894403 TI - Post-traumatic syndrome. PMID- 20894404 TI - Horner's syndrome with ipsilateral vocal cord and phrenic nerve palsies: newly recognized syndrome in the neck. PMID- 20894406 TI - Treatment of severe anaphylactic reactions to insect stings. PMID- 20894405 TI - Post-traumatic syndrome. PMID- 20894407 TI - James Neild's legacy. PMID- 20894409 TI - Newly recognized syndrome in the neck: Horner's syndrome with ipsilateral vocal cord and phrenic nerve palsies. PMID- 20894408 TI - Newly recognized syndrome in the neck. PMID- 20894410 TI - Newly recognized syndrome in the neck: Horner's syndrome with ipsilateral vocal cord and phrenic nerve palsies. PMID- 20894411 TI - The continuing problem of pain. PMID- 20894412 TI - Sexually transmitted disease statistics. PMID- 20894413 TI - Chronic perianal pain. PMID- 20894414 TI - Emotional stress and occlusal parafunction. PMID- 20894415 TI - 150 years of the BMA. PMID- 20894416 TI - Child abuse. PMID- 20894417 TI - Endogenous opioids and pain: a review. PMID- 20894418 TI - Homosexual transmission of amoebiasis. PMID- 20894419 TI - Needle aspiration technique to detect pancreatic abscess. PMID- 20894420 TI - Organophosphate poisoning and complete heart block. PMID- 20894421 TI - Triamcinolone acetonide in treatment of chronic back pain. PMID- 20894422 TI - Child abuse statistics. PMID- 20894423 TI - Post-traumatic syndrome. PMID- 20894425 TI - Chagas's disease. PMID- 20894424 TI - Treatment of thromboembolic disease. PMID- 20894427 TI - Lymphadenopathy mimicking lymphoma associated with cryoglobulinaemia and arteritis. PMID- 20894426 TI - Second European conference on clinical haemorheology. PMID- 20894428 TI - Medical education and disability. PMID- 20894430 TI - GP prescribing practices. PMID- 20894429 TI - Emotional stress, occlusal parafunction and swallowing. PMID- 20894431 TI - Debridement in wound treatment. PMID- 20894432 TI - Ranitidine and duodenal ulceration. PMID- 20894433 TI - Post lumbar puncture headache. PMID- 20894434 TI - Malignant fibrous histiocytoma treated by excision and repair with a free latissimus dorsi musculocutaneous flap. PMID- 20894435 TI - Modern trends in burns care. PMID- 20894436 TI - Post lumbar puncture headache. PMID- 20894437 TI - Lymphadenopathy mimicking lymphoma associated with cryoglobulinaemia and arteritis. PMID- 20894438 TI - History of writing and its relevance in dyslexia. PMID- 20894439 TI - Amoebiasis. PMID- 20894440 TI - Treatment of cramp. PMID- 20894441 TI - Hidradenitis suppurativa. PMID- 20894442 TI - Historical sources of surgical practice. PMID- 20894443 TI - Introduction. PMID- 20894444 TI - Hormonal, metabolic and biochemical changes following thermal injury. PMID- 20894445 TI - Catabolic processes in burned patients and compensatory nutrition. PMID- 20894446 TI - Large burns - transatlantic view. PMID- 20894447 TI - Management of the burn wound. PMID- 20894448 TI - Analgesia for burns dressing. PMID- 20894449 TI - Enflurane analgesia. AB - An air-enflurane mixture was used for inhalation analgesia in conscious patients undergoing painful procedures such as burns dressings. A preliminary study indicated that enflurane possessed definite analgesic properties, but that the concentration of the air-enflurane mixture was critical if restlessness was to be avoided and cooperation retained. Further studies established that 1% enflurane in air provided good analgesia in the absence of anaesthesia. The analgesic effects were similar to those produced by 0.35% methoxyflurane in air, but were produced in a much shorter time (about 3 minutes compared with 9 to 10 minutes). Preoperative starvation was unnecessary and nausea and vomiting were absent. Details are given of the use of enflurane analgesia in 32 conscious burned patients who underwent 101 burns dressing procedures. PMID- 20894450 TI - Measurement of toxic combustion products in fire survivors. PMID- 20894451 TI - Management of injury due to smoke inhalation. PMID- 20894452 TI - Fluid therapy in burns. PMID- 20894453 TI - Unreliable 'memories' under hypnosis. PMID- 20894454 TI - Management of scoliosis. PMID- 20894455 TI - Educational programmes on the problems of long-term disablement. PMID- 20894456 TI - Management of scoliosis. PMID- 20894458 TI - Meteorological factors affecting behaviour. PMID- 20894457 TI - Effects of acupuncture in bronchial asthma. PMID- 20894459 TI - Post lumbar puncture headache. PMID- 20894460 TI - Frozen shoulder. PMID- 20894461 TI - Muscle strain as a cause of abdominal pain in children. PMID- 20894462 TI - Biological materials used in reconstruction of the ear: 1982 JRSM 75, 691-698. PMID- 20894463 TI - Smoking and subarachnoid haemorrhage. PMID- 20894464 TI - Memory distortion under hypnosis. PMID- 20894465 TI - Historical sources of surgical practice. PMID- 20894466 TI - Amphotericin B versus miconazole in treatment of candidal infection. PMID- 20894467 TI - Emergency oesophageal transection to control bleeding varices. PMID- 20894468 TI - Smoking and subarachnoid haemorrhage. PMID- 20894469 TI - Newly recognized syndrome in the neck: 1981 JRSM 74, 814-818. PMID- 20894470 TI - Treatment of Fournier's gangrene in India. PMID- 20894471 TI - Post lumbar puncture headache. PMID- 20894472 TI - Epidural blood-patching to treat severe post lumbar puncture headache. PMID- 20894474 TI - Treatment of cramp. PMID- 20894473 TI - Amoebiasis. PMID- 20894475 TI - Calcium metabolism during rifampicin and isoniazid therapy for tuberculosis. PMID- 20894476 TI - Swimming and grommets. PMID- 20894478 TI - Globus hystericus and the masticatory apparatus. PMID- 20894477 TI - Unreliable 'memories' under hypnosis. PMID- 20894479 TI - Amphotericin B versus miconazole in treatment of candidal infection. PMID- 20894480 TI - Mammary tuberculosis. PMID- 20894481 TI - Mammary tuberculosis. PMID- 20894482 TI - Psychosocial function of accident and emergency departments. PMID- 20894483 TI - Continuing education in rheumatology. PMID- 20894484 TI - Continuing education in rheumatology. PMID- 20894485 TI - Epidurography for outpatients. PMID- 20894486 TI - Organophosphate poisoning and complete heart block. PMID- 20894487 TI - Newly recognized syndrome in the neck. PMID- 20894488 TI - From virus to cosmology. PMID- 20894490 TI - Grommets and swimming. PMID- 20894489 TI - Grommets and swimming. PMID- 20894491 TI - Role of community medicine. PMID- 20894492 TI - High incidence of rickets in children with wheezy bronchitis in a developing country: JRSM November 1982, 75, 884-887. PMID- 20894493 TI - Commonwealth association for mental handicap and developmental disabilities. PMID- 20894494 TI - Unusual physical sign of multiple myeloma. PMID- 20894495 TI - Contemporary problems in philosophy. PMID- 20894496 TI - Frozen shoulder. PMID- 20894497 TI - Newly recognized syndrome in the neck. PMID- 20894499 TI - Preservation of the body with fixatives after death. PMID- 20894498 TI - Functions of the temporal lobes. PMID- 20894500 TI - From virus to cosmology. PMID- 20894502 TI - Contemporary problems in philosophy. PMID- 20894501 TI - From virus to cosmology. PMID- 20894503 TI - Back pain research. PMID- 20894504 TI - Discovery of Horner's syndrome. PMID- 20894505 TI - Risks of hypertension. PMID- 20894506 TI - Cramp in pregnancy. PMID- 20894507 TI - Vestibular function tests in children. PMID- 20894508 TI - Apothecaries and their lodgers: their part in the development of the sciences and of medicine. PMID- 20894509 TI - Ligature applicator and tier. PMID- 20894510 TI - Resection of the prostate. PMID- 20894511 TI - Mozart's illnesses and death. PMID- 20894512 TI - Riboflavine products. PMID- 20894514 TI - World population. PMID- 20894513 TI - Salt and hypertension. PMID- 20894516 TI - From virus to cosmology. PMID- 20894515 TI - Psychosurgery. PMID- 20894517 TI - Mozart's illnesses and death. PMID- 20894518 TI - Frozen shoulder. PMID- 20894520 TI - Splenosis: a beneficial condition. PMID- 20894519 TI - Globus hystericus. PMID- 20894521 TI - Mental Health Act (1983): progress or vitiation? PMID- 20894522 TI - Ligature applicator and tier. PMID- 20894523 TI - Inpatient services in neurological practice. PMID- 20894524 TI - Training to care for the dying. PMID- 20894525 TI - Electrical stimulation of the brain: JRSM November 1983, p 905. PMID- 20894526 TI - Salt and hypertension. PMID- 20894527 TI - Bowel disease after radiotherapy. PMID- 20894528 TI - Inflammatory diseases and copper. PMID- 20894529 TI - From virus to cosmology. PMID- 20894530 TI - From virus to cosmology. PMID- 20894531 TI - Mental health of doctors. PMID- 20894532 TI - Inpatient services in neurological practice. PMID- 20894533 TI - Nutrition in medical education. PMID- 20894534 TI - Inpatient services in neurological practice. PMID- 20894535 TI - Mozart's illnesses and death. PMID- 20894536 TI - Myositis ossificans progressiva. PMID- 20894537 TI - Arabian medicine in the Middle Ages. PMID- 20894538 TI - Role of district community physicians in promoting prevention. PMID- 20894539 TI - Appropriate surgery for vesicocolic fistula. PMID- 20894540 TI - Compulsory psychiatric admissions. PMID- 20894541 TI - Frozen shoulder. PMID- 20894542 TI - Nocturnal enuresis. PMID- 20894543 TI - Frozen shoulder. PMID- 20894544 TI - From virus to cosmology. PMID- 20894545 TI - Day-case ophthalmic surgery. PMID- 20894546 TI - The unscientific surgeon. PMID- 20894547 TI - The sore mouth. PMID- 20894548 TI - National diabetes foundation. PMID- 20894549 TI - From virus to cosmology. PMID- 20894550 TI - Self-exposure treatment for phobics. PMID- 20894551 TI - From virus to cosmology. PMID- 20894553 TI - Appropriate surgery for vesicocolic fistula. PMID- 20894552 TI - Assessment of sutures for use in colonic surgery. PMID- 20894555 TI - The forgotten people: chronic younger sick in Welsh hospitals. PMID- 20894554 TI - AIDS and African Kaposi's sarcoma. PMID- 20894556 TI - AIDS and African Kaposi's sarcoma. PMID- 20894558 TI - Frozen shoulder. PMID- 20894557 TI - Tinnitus and the cervical spine. PMID- 20894559 TI - Encyclopaedia of occupational health and safety. PMID- 20894561 TI - Quick preparation of slides using a microcomputer. PMID- 20894560 TI - Fresh look at ischaemic heart disease. PMID- 20894563 TI - Quantum physics and the philosophy of medicine. PMID- 20894562 TI - Preface. PMID- 20894564 TI - User acceptance of computer systems. PMID- 20894565 TI - Self-exposure treatment for phobics. PMID- 20894566 TI - Pandemic influenza and the viral haemorrhagic fevers. PMID- 20894567 TI - Intestinal problems in childhood (correction): JRSM Supplement No. 3, 1984. PMID- 20894568 TI - A plea for the plaintiff. PMID- 20894569 TI - A plea for the plaintiff. PMID- 20894570 TI - Overwrapping as a possible cause of heamorrhagic shock and encephalopathy (HSE) in infants. PMID- 20894571 TI - Developmental screening. PMID- 20894572 TI - Psychiatry for all. PMID- 20894574 TI - Hybrids and hybridity: a correction. PMID- 20894573 TI - International society for lymphology. PMID- 20894575 TI - Osteosarcoma of the bladder. PMID- 20894576 TI - Psychiatry for all. PMID- 20894577 TI - Cardiopulmonary resuscitation: standards among junior hospital doctors. PMID- 20894579 TI - Clearinghouse for researchers into drug problems. PMID- 20894578 TI - Ocular manifestations of Graves' disease. PMID- 20894580 TI - Thorotrast granuloma of the neck. PMID- 20894581 TI - Developmental screening. PMID- 20894583 TI - Speech production after laryngectomy. PMID- 20894582 TI - Pesticide residues in food. PMID- 20894584 TI - Speech production after laryngectomy. PMID- 20894585 TI - Swallowing difficulties and iron deficiency. PMID- 20894586 TI - Schizophreniform psychosis and adrenomyeloneuropathy (AMN). PMID- 20894587 TI - Minneapolis hip prosthesis. PMID- 20894588 TI - Hutchison's litany. PMID- 20894589 TI - Tinnitus and the cervical spine. PMID- 20894590 TI - Turner's syndrome, cleft palate and skeletal disorders. PMID- 20894592 TI - Developmental screening. PMID- 20894591 TI - Sperm quality and pesticides. PMID- 20894593 TI - Developmental screening. PMID- 20894594 TI - Developmental screening. PMID- 20894595 TI - Speech production after laryngectomy. PMID- 20894596 TI - Foreign body sensation in the throat. PMID- 20894597 TI - Confidential enquiry into perioperative deaths. PMID- 20894598 TI - Counselling in general practice. PMID- 20894599 TI - Allergy to insect stings. PMID- 20894600 TI - Diffusion barriers in venous ulceration. PMID- 20894601 TI - Percutaneous and endoscopic biliary drainage in surgical jaundice. PMID- 20894602 TI - Pesticide residues in food. PMID- 20894603 TI - Register of UK alcoholic research projects 1985-86. PMID- 20894604 TI - Problems in diagnosis of popliteal aneurysms. PMID- 20894606 TI - Spontaneous passage of gallstones. PMID- 20894605 TI - Speech production after laryngectomy. PMID- 20894607 TI - Sperm counts and pesticides. PMID- 20894609 TI - Cartesian dualism and the current crisis in medicine. PMID- 20894608 TI - Overtreatment in surgery. PMID- 20894610 TI - Pesticide residues in food. PMID- 20894611 TI - Caring or curing: conflicts of choice. PMID- 20894612 TI - Amylase-rich ascites and pleural effusion. PMID- 20894614 TI - Introduction. PMID- 20894613 TI - Preface. PMID- 20894615 TI - Preface. PMID- 20894616 TI - Preface. PMID- 20894617 TI - Coagulation studies: a priority in unexplained bleeding. PMID- 20894618 TI - Foreign body sensation in the throat. PMID- 20894619 TI - Aetiology of leg ulcers. PMID- 20894620 TI - AIDS virus infection: prognosis and transmission. PMID- 20894621 TI - Units, symbols, and abbreviations. PMID- 20894622 TI - Heinemann's Integrated Clinical Science Essay Competition. PMID- 20894623 TI - Recombinant human gamma-interferon in primary hepatocellular carcinoma. PMID- 20894624 TI - Endocrine treatment of prostatic cancer. PMID- 20894625 TI - International medical practice newsletter. PMID- 20894626 TI - Amylase-rich ascites and pleural effusions. PMID- 20894627 TI - Questionable safety of pyloromyotomy in district general hospitals. PMID- 20894628 TI - Abdominal tuberculosis. PMID- 20894629 TI - CT versus ultrasound in diagnosing brain displacements. PMID- 20894630 TI - Unilateral ischaemic optic neuropathy following systemic hypotension. PMID- 20894631 TI - Safety of Ramstedt's pyloromyotomy in district hospitals. PMID- 20894632 TI - Haematuria due to urinary bladder metastases from carcinoma of the bronchus. PMID- 20894633 TI - Joan of Arc, creative psychopath: is there another explanation? PMID- 20894634 TI - Communication skills. PMID- 20894635 TI - Cancer research - the lessons from Hodgkin's disease. PMID- 20894636 TI - Motor neuron disease - a challenge to medical ethics. PMID- 20894637 TI - Meta-analysis in medicine. PMID- 20894638 TI - Employment during pregnancy. PMID- 20894639 TI - Pathogenesis of Alzheimer's disease. PMID- 20894640 TI - Health promotion; health education: postscript. PMID- 20894641 TI - Admission to medical school: from audit to action. PMID- 20894642 TI - 'Dry tap' in glue ears. PMID- 20894643 TI - Joan of Arc, creative psychopath: is there another explanation? PMID- 20894645 TI - Anaesthesia and monitoring for paediatric radiotherapy. PMID- 20894644 TI - Anaesthesia and monitoring for paediatric radiotherapy. PMID- 20894646 TI - Anaesthesia and monitoring for paediatric radiotherapy. PMID- 20894647 TI - Alzheimer's disease society. PMID- 20894648 TI - Mental hospitals and community care. PMID- 20894649 TI - Preventive medicine or disease prevention. PMID- 20894650 TI - Hyperbaric oxygen in multiple sclerosis. PMID- 20894651 TI - Early radiologists. PMID- 20894652 TI - Mucociliary function following inferior meatal antrostomy. PMID- 20894653 TI - Personality assessment of future doctors. PMID- 20894654 TI - Admission to medical school: from audit to action. PMID- 20894655 TI - Journals of psychological medicine. PMID- 20894656 TI - Communication in medical practice. PMID- 20894657 TI - Halley's Comet and astrospectroscopy. PMID- 20894658 TI - Iatrogenic anal ulceration. PMID- 20894659 TI - Deaths from choking on food in infancy. PMID- 20894660 TI - Scientific basis of caries prevention. PMID- 20894661 TI - Biblical ills and remedies. PMID- 20894662 TI - Biblical ills and remedies. PMID- 20894664 TI - Tenosynovitis and Sudeck's atrophy. PMID- 20894663 TI - Germs from space. PMID- 20894665 TI - Tenosynovitis and Sudeck's atrophy. PMID- 20894666 TI - 'Dry tap' in glue ears. PMID- 20894667 TI - Meigs' syndrome and pseudo-Meigs' syndrome. PMID- 20894668 TI - Negation of responsibility: a heavy price to pay? PMID- 20894669 TI - Autologous blood transfusion. PMID- 20894670 TI - Cause of small bowel obstruction. PMID- 20894671 TI - Iatrogenic psychosomatic illness. PMID- 20894672 TI - Hyperventilation syndromes in medicine and psychiatry. PMID- 20894673 TI - Plague, rats and the Bible. PMID- 20894674 TI - Predicting the outcome. PMID- 20894676 TI - Benign thoracic pain. PMID- 20894675 TI - The place of basic research in education. PMID- 20894677 TI - AIDS: origin, transmission and moral dilemmas. PMID- 20894678 TI - AIDS: origin, transmission and moral dilemmas. PMID- 20894679 TI - Is Occam's razor disposable? PMID- 20894680 TI - AIDS: origin, transmission and moral dilemmas. PMID- 20894681 TI - Is Occam's razor disposable? PMID- 20894682 TI - Unrecognized cervical subluxation. PMID- 20894683 TI - Intractable functional abdominal pain. PMID- 20894685 TI - Science versus non-science in medicine: fact or fiction? PMID- 20894684 TI - Should patients read their own medical records? PMID- 20894686 TI - Leprosy and the bible. PMID- 20894687 TI - Effect of oral iron on penicillamine absorption. PMID- 20894688 TI - 'Dry tap' in glue ears. PMID- 20894689 TI - Intractable functional abdominal pain. PMID- 20894691 TI - The consequences of hyperandrogenism in young women. PMID- 20894690 TI - CT scanning in orbital cellulitis. PMID- 20894692 TI - Ankle motion after external fixation of tibial fractures. PMID- 20894693 TI - The invaluable art of unlearning. PMID- 20894695 TI - Science versus non-science in medicine: fact or fiction? PMID- 20894694 TI - Reoperative surgery for early complications following abdominal and abdominothoracic operations. PMID- 20894696 TI - Should patients read their own medical records? PMID- 20894697 TI - The urological Damocles. PMID- 20894698 TI - General practitioner referral of patients with lower gastrointestinal symptoms. PMID- 20894700 TI - Assessment of self-poisoning patients by psychiatrists and junior medical staff. PMID- 20894699 TI - The anion gap as a screening procedure for occult myeloma in the elderly. PMID- 20894701 TI - General practitioner referral of patients with lower gastrointestinal symptoms. PMID- 20894702 TI - John Conolly: a reconsideration. PMID- 20894703 TI - Back pain at Greenwich. PMID- 20894704 TI - Numerical methods for decision-making in clinical care: where to now? PMID- 20894705 TI - Drug safety and the CSM. PMID- 20894706 TI - Accident and emergency medicine: an administrative convenience or a specialty? PMID- 20894707 TI - Haematuria analysed. PMID- 20894709 TI - Eye care and the medical student. PMID- 20894708 TI - Numerical methods for decision-making in clinical care: where to now? PMID- 20894710 TI - Amniotic bands: an unusual chest lesion. PMID- 20894711 TI - Perforated duodenal ulcer and cigarette smoking. PMID- 20894712 TI - Pseudoachalasia of the cardia. PMID- 20894713 TI - Death, dissection and the destitute. PMID- 20894714 TI - On the chemical death of Lot's wife. PMID- 20894715 TI - The calcite ploy from Illinois. PMID- 20894716 TI - The 'think test': a further technique to elicit hyperventilation. PMID- 20894717 TI - Biology and psychiatry. PMID- 20894718 TI - Accident and emergency medicine: an administrative convenience or a specialty? PMID- 20894719 TI - Rethinking the national health service. PMID- 20894720 TI - Eye care and the medical student. PMID- 20894721 TI - Amniotic bands: an unusual chest lesion. PMID- 20894722 TI - Cholecystectomy: ironmasters and eggheads. PMID- 20894723 TI - Unacceptable variation in the core diameters of some AO type cancellous screws. PMID- 20894724 TI - Do all minor excised lesions require histological examination? PMID- 20894725 TI - Do all minor excised lesions require histological examination? PMID- 20894726 TI - Fish oils-their significance to human health. PMID- 20894727 TI - Simplifying infusion chemotherapy. PMID- 20894728 TI - Sick doctors. PMID- 20894729 TI - Antoni Lesniowski and his contribution to regional enteritis (Crohn's disease). PMID- 20894730 TI - Corticosteroid replacement therapy: twice or thrice daily? PMID- 20894732 TI - On the chemical death of Lot's wife. PMID- 20894731 TI - The risks of staying in London. PMID- 20894733 TI - Wind of change. II. Medical journals in Britain in 1988. PMID- 20894735 TI - Intractable pain: a neglected area of medical education in the UK. PMID- 20894734 TI - Wind of change. II. Medical journals in Britain in 1988. PMID- 20894736 TI - The surgical instrument maker. PMID- 20894737 TI - Rethinking the NHS. PMID- 20894738 TI - Wind of change. III. The Royal Colleges. PMID- 20894739 TI - Cholecystectomy: ironmasters and eggheads. PMID- 20894740 TI - Seat belt injuries. PMID- 20894742 TI - Ethics of transsexuality. PMID- 20894741 TI - Biblical ills and remedies. PMID- 20894743 TI - Wind of change. III. The Royal Colleges. PMID- 20894744 TI - The chemical death of Lot's wife. PMID- 20894745 TI - Robert james minnitt. PMID- 20894746 TI - Kelvin's day. PMID- 20894747 TI - Wind of change II. Medical journals in Britain in 1988. PMID- 20894748 TI - Who needs toxicology? PMID- 20894749 TI - Gestalt theory and psychiatry. PMID- 20894750 TI - Medical audit. PMID- 20894751 TI - Wind of change II. Medical journals in Britain in 1988. PMID- 20894752 TI - Medical audit. PMID- 20894753 TI - Chair discussions. PMID- 20894754 TI - Chair discussions. PMID- 20894755 TI - Chair discussions. PMID- 20894756 TI - Chair discussions. PMID- 20894757 TI - Spontaneous rupture of the oesophagus (Boerhaave's syndrome). PMID- 20894759 TI - Transsexuality. PMID- 20894758 TI - Robert james minnitt 1889-1974. PMID- 20894760 TI - Pioneer health service, peckham. PMID- 20894761 TI - Tinted spectacles. PMID- 20894762 TI - Tinted spectacles. PMID- 20894763 TI - 'Kosher' tests. PMID- 20894764 TI - Management of abdominal hernias. PMID- 20894765 TI - Tinted spectacles. PMID- 20894766 TI - Myalgic encephalomyelitis. PMID- 20894767 TI - Terence millin. PMID- 20894768 TI - Tinted spectacles - sign of psychopathology? PMID- 20894769 TI - New-born circumcision: a long-term strategy for AIDS prevention. PMID- 20894770 TI - Modern cassandras. PMID- 20894772 TI - When is treatment for cancer economically justified? PMID- 20894771 TI - Seizure induction by alcohol. PMID- 20894773 TI - Sir william osler. PMID- 20894774 TI - Medical student section. PMID- 20894775 TI - Into europe. PMID- 20894776 TI - A new human virus with unusual effects. PMID- 20894777 TI - Spinal cord compression associated with pseudohypoparathyroidism. PMID- 20894779 TI - Kosher tests. PMID- 20894778 TI - Seizures and alcohol. PMID- 20894780 TI - Eccentricity of dieting. PMID- 20894781 TI - Immunology of the tonsil. PMID- 20894782 TI - The greenhouse effect and human population. PMID- 20894783 TI - Health effects of electromagnetic fields. PMID- 20894784 TI - Fish and olives. PMID- 20894785 TI - Postviral syndrome. PMID- 20894786 TI - Another look at holistic medicine. PMID- 20894787 TI - Medical student selection. PMID- 20894788 TI - The death of Mozart. PMID- 20894789 TI - The greenhouse effect and human population. PMID- 20894790 TI - The homeopathic conundrum. PMID- 20894792 TI - A tale of two paintings. PMID- 20894791 TI - I don't fancy cheiromancy. PMID- 20894793 TI - The homeopathic conundrum. PMID- 20894795 TI - Motivation to change. PMID- 20894794 TI - Lifeline and longevity. PMID- 20894796 TI - Medical histories of musicians. PMID- 20894797 TI - Pyoderma gangrenosum. PMID- 20894798 TI - Newborn circumcision and cancer of the penis. PMID- 20894799 TI - Medical student selection. PMID- 20894800 TI - Another look at holistic medicine. PMID- 20894801 TI - Epidemiology of shingles. PMID- 20894803 TI - A struggle for survival. PMID- 20894802 TI - Cairo Geniza: plus ca change.. PMID- 20894804 TI - Osler, beaumont and alexis st martin. PMID- 20894806 TI - Why do hospital doctors wear white coats? PMID- 20894805 TI - Why do hospital doctors wear white coats? PMID- 20894807 TI - Introduction. PMID- 20894808 TI - Adenocarcinoma of the gallbladder. PMID- 20894810 TI - Homo sapiens - a species too successful. PMID- 20894809 TI - Adenocarcinoma of the gallbladder. PMID- 20894811 TI - Prospects for the treatment of multiple sclerosis. PMID- 20894813 TI - Immunology of the tonsils. PMID- 20894812 TI - Death of mozart. PMID- 20894815 TI - Arthur conan doyle. PMID- 20894814 TI - Surgical roots and branches. PMID- 20894816 TI - Mozart. PMID- 20894817 TI - Sherlock holmes. PMID- 20894818 TI - Pathology: is it well taught? PMID- 20894819 TI - Pathology: is it well taught? PMID- 20894820 TI - Waiting list initiatives. PMID- 20894821 TI - Another look at holistic medicine. PMID- 20894822 TI - Munchausen. PMID- 20894823 TI - Doctors' dress. PMID- 20894824 TI - Audit of cervical cytology screening programmes. PMID- 20894826 TI - Compensation for injury-a reappraisal: comments. PMID- 20894825 TI - The European committee of the royal society of medicine. PMID- 20894827 TI - Into Europe: the road to Sevres. PMID- 20894828 TI - Dr Henry harington. PMID- 20894830 TI - He/she or hshe? PMID- 20894829 TI - He/she or hshe? PMID- 20894831 TI - The wart lady of Kansas. PMID- 20894833 TI - The one-track mind. PMID- 20894832 TI - How to avoid pitfalls in ethnic medical history, examination and diagnosis. PMID- 20894834 TI - Familial adenomatous polyposis. PMID- 20894835 TI - What's in a name? PMID- 20894836 TI - Patient denial in breast cancer. PMID- 20894837 TI - He/She etc. PMID- 20894838 TI - He/She etc. PMID- 20894839 TI - Modern medical writing. PMID- 20894840 TI - He/She or hshe. PMID- 20894841 TI - Implantation metastasis from adenocarcinoma of sigmoid colon into fistula in ano. PMID- 20894842 TI - Why do hospital doctors wear white coats? PMID- 20894843 TI - The laser in dentistry. PMID- 20894844 TI - Medical education and substance abuse. PMID- 20894845 TI - Nailbiters in the navy. PMID- 20894846 TI - Preface. PMID- 20894847 TI - Medicine in San'a, Yemen 1937-1943. PMID- 20894849 TI - Unilateral choanal atresia. PMID- 20894848 TI - The strange case of Ms Elizabeth Trevers. PMID- 20894850 TI - Early use of the thermometer. PMID- 20894851 TI - Nailbiting. PMID- 20894852 TI - Obturator hernia. PMID- 20894853 TI - Exclusion diets. PMID- 20894855 TI - Education and population control. PMID- 20894854 TI - Lightning and electrical injury. PMID- 20894856 TI - Should we ban the mercury thermometer? PMID- 20894857 TI - Undergraduate training in ENT-time for change? PMID- 20894858 TI - Delay in seeking treatment for breast cancer. PMID- 20894859 TI - Endotracheal intubation skills of medical students. PMID- 20894860 TI - The portrayal of the physician in non-medical literature. PMID- 20894862 TI - Double-blind trials and alternative medicine. PMID- 20894861 TI - Management of generalized faecal peritonitis. PMID- 20894863 TI - What's in a title - Mr or Dr? PMID- 20894864 TI - The edinburgh declaration. PMID- 20894865 TI - Non-sexist statements in medical literature. PMID- 20894867 TI - What's in a title - Mr or Dr? PMID- 20894866 TI - Oesophago-gastrectomy. PMID- 20894868 TI - Delay in seeking treatment for breast cancer. PMID- 20894869 TI - The plague of Athens. PMID- 20894870 TI - The physician and religion. PMID- 20894871 TI - Percutaneous endoscopic gastrostomy. PMID- 20894872 TI - Archbishop laud. PMID- 20894873 TI - White coats? PMID- 20894874 TI - Medico-legal reports. PMID- 20894875 TI - White coats? PMID- 20894876 TI - The Royal Society of Medicine Foundation, Inc: a celebration of 25 years of service. PMID- 20894878 TI - Introduction. PMID- 20894877 TI - Retroorbital metastasis. PMID- 20894879 TI - Evaluation of counselling in the National Health Service. PMID- 20894880 TI - Origins. PMID- 20894881 TI - Rheumatology writing. PMID- 20894882 TI - Amyand's hernia. PMID- 20894883 TI - Writing medical papers. PMID- 20894884 TI - Lightning and electrical injury. PMID- 20894886 TI - Sir frederick treves. PMID- 20894885 TI - Chronic nutmeg psychosis. PMID- 20894887 TI - What's in a title-Mr or Dr? PMID- 20894888 TI - Editorial note. PMID- 20894889 TI - The doctor's aim in a pluralistic society. PMID- 20894890 TI - Delay in seeking treatment for breast cancer. PMID- 20894892 TI - Changes in the perception of energy and mood in relation to sunshine. PMID- 20894891 TI - Endotracheal intubation skills of medical students. PMID- 20894893 TI - The physician who dislikes his trade. PMID- 20894895 TI - Preface. PMID- 20894894 TI - Advanced medical courses at the RSM. PMID- 20894896 TI - The inferior turbinate. PMID- 20894897 TI - Body and brain. PMID- 20894898 TI - He/she. PMID- 20894899 TI - Two hundred years of drug abuse. PMID- 20894900 TI - Lyme disease. PMID- 20894901 TI - The diagnosis and management of arteritis. PMID- 20894902 TI - Hartmanns procedure: an appraisal. PMID- 20894903 TI - A history of the use of arsenicals in man. PMID- 20894904 TI - What's in a title - Mr or Dr? PMID- 20894905 TI - Application of a general health policy model in the American health care crisis. PMID- 20894906 TI - Streetwise health: the press and the people. PMID- 20894907 TI - Mood changes and perceptions of vitality. PMID- 20894908 TI - Health promotion or confusion? PMID- 20894909 TI - Robert Norman thomson: 1935-1994. PMID- 20894910 TI - Transplantation and organ donors. PMID- 20894911 TI - Lesions of the internal auditory meatus. PMID- 20894912 TI - Mr or dr? PMID- 20894914 TI - Non-sexist grammar in medical literature. PMID- 20894913 TI - George frederic still. PMID- 20894915 TI - Writing medical papers. PMID- 20894916 TI - The origin of the Society's motto. PMID- 20894917 TI - Ears for flying and diving. PMID- 20894918 TI - Ears safe for diving. PMID- 20894919 TI - Glue ear. PMID- 20894921 TI - Eric Anthony Barker (1920-1993): cbe frcp frcsAnthony and Maggie Barker. PMID- 20894920 TI - Chronic nutmeg psychosis. PMID- 20894922 TI - Stone Age diet. PMID- 20894923 TI - Logic and magic in mainstream and fringe medicine. PMID- 20894924 TI - What's in a title - Mr or Dr? PMID- 20894926 TI - He/She, or they. PMID- 20894925 TI - What's in a title - Mr or Dr? PMID- 20894927 TI - Ears safe for diving. PMID- 20894928 TI - The portrayal of the physician in non-medical literature. PMID- 20894930 TI - A journey round my skull. PMID- 20894929 TI - Logic and magic in mainstream and fringe medicine. PMID- 20894931 TI - Control of neonatal group B streptococcal infection. PMID- 20894932 TI - Value of performing an autopsy in a teaching hospital. PMID- 20894934 TI - Botulinum toxin: dangerous terminology errors. PMID- 20894933 TI - Successful resuscitation from hypothermic induced cardiac arrest. PMID- 20894935 TI - Vestibular schwannoma. PMID- 20894936 TI - Breast cancer and pregnancy. PMID- 20894937 TI - A girl called georgina. PMID- 20894938 TI - Beethoven's illness. PMID- 20894939 TI - The origin of the Society's motto. PMID- 20894940 TI - Medical ethics and evolution. PMID- 20894941 TI - Cortico basal degeneration. PMID- 20894942 TI - Hartmann's procedure. PMID- 20894943 TI - The portrayal of the physician in non-medical literature: the physician in politics. PMID- 20894944 TI - The origin of the Society's motto. PMID- 20894945 TI - Beethoven's illness. PMID- 20894946 TI - 'Ring out...'. PMID- 20894947 TI - If Cytokines be the Food of Love. PMID- 20894948 TI - Junior doctors' hours. PMID- 20894950 TI - A response. PMID- 20894949 TI - Preface. PMID- 20894951 TI - The role of the media in reporting and shaping public expectations. PMID- 20894952 TI - Paternalism versus patient autonomy. PMID- 20894954 TI - A response. PMID- 20894953 TI - Consensus clinical practice guidelines. PMID- 20894955 TI - The cost of care and the role of health care delivery systems. PMID- 20894956 TI - A response. PMID- 20894957 TI - Charlatanry and fraud: influence on mutual trust. PMID- 20894959 TI - A response. PMID- 20894958 TI - A response. PMID- 20894960 TI - A response. PMID- 20894961 TI - A response. PMID- 20894962 TI - Preparation for medical school. PMID- 20894963 TI - A response. PMID- 20894964 TI - Concluding remarks: a conspectus of views expressed. PMID- 20894965 TI - The new public perception of health care and physicians. PMID- 20894966 TI - The Journal: tradition and change. PMID- 20894967 TI - He/She. PMID- 20894969 TI - The first medical publication. PMID- 20894968 TI - Issues of the day: what are they? PMID- 20894970 TI - British CME: a framework for the future. PMID- 20894971 TI - How negative are we to the idea of a suicide prevention? PMID- 20894973 TI - The new Journal-progress report. PMID- 20894972 TI - Karinthy's Journey Round My Skull. PMID- 20894974 TI - Aequanimitas. PMID- 20894975 TI - The gene hunters. PMID- 20894976 TI - Lead toxicity intervention in children. PMID- 20894977 TI - Medical ethics. PMID- 20894978 TI - Medical ethics. PMID- 20894979 TI - It couldn't happen here. PMID- 20894980 TI - Liver transplantation in cystic fibrosis. PMID- 20894981 TI - Dilemmas of life and death. PMID- 20894983 TI - The alex comfort lecture, 1995. PMID- 20894982 TI - Some parting words from the Deputy Editor. PMID- 20894984 TI - The meaning of words in the new health service. PMID- 20894985 TI - Sam Johnson's lung not in Baillie's Atlas. PMID- 20894987 TI - Panel and general discussion. PMID- 20894986 TI - A medical/scientific editor's view: a summary of a paper presented by Richard Smith, Editor, BMJ. PMID- 20894988 TI - Preface. PMID- 20894989 TI - The new journal: the first year. PMID- 20894990 TI - The illnesses of the great. PMID- 20894991 TI - Balancing primary and specialty care. PMID- 20894993 TI - The meaning of words in the new health service. PMID- 20894992 TI - The meaning of words in the new health service. PMID- 20894994 TI - Dr george C cathcart. PMID- 20894995 TI - Palliative care in the Third World. PMID- 20894996 TI - The meaning of words in the new health service. PMID- 20894997 TI - John Swales moves onward and upward. PMID- 20894998 TI - The medical history of Mozart. PMID- 20894999 TI - A celebration of women in anaesthesia 1894-1994. PMID- 20895000 TI - Smoking in restaurants. PMID- 20895001 TI - Pitfalls in accident and emergency chest pain evaluation. PMID- 20895002 TI - Syndrome. PMID- 20895004 TI - Get some research under your belt. PMID- 20895003 TI - A patient's view of asthma. PMID- 20895005 TI - Cases in clinical biochemistry. PMID- 20895006 TI - Instructive errors. PMID- 20895007 TI - Colleges versus academies. PMID- 20895008 TI - The meaning of words in the new health service. PMID- 20895009 TI - Physical activity and the compression of morbidity. PMID- 20895010 TI - Lithopaedion. PMID- 20895012 TI - Prenatal screening vouchers. PMID- 20895011 TI - Euthanasia. PMID- 20895013 TI - The meaning of words. PMID- 20895014 TI - Get some research under your belt. PMID- 20895015 TI - The meaning of words. PMID- 20895016 TI - A reunification. PMID- 20895018 TI - Clinical risks. PMID- 20895017 TI - Medical support for Afghanistan. PMID- 20895019 TI - Vaches folles? PMID- 20895020 TI - Audit and clinical research. PMID- 20895021 TI - What do patients want from medical research? PMID- 20895022 TI - Watsoniana. PMID- 20895024 TI - Smallpox and royalty. PMID- 20895023 TI - Toxic shock syndrome and burns. PMID- 20895026 TI - Medical students and history of medicine. PMID- 20895025 TI - Science versus quackery. PMID- 20895027 TI - Preface. PMID- 20895028 TI - Preface. PMID- 20895029 TI - Ancient alternative medicine and its modern survival. PMID- 20895030 TI - Ghosts. PMID- 20895031 TI - Jenner returns to his alma mater. PMID- 20895032 TI - The Gabo fountain, St Thomas' Hospital. PMID- 20895033 TI - Do community hospitals reduce use of DGH beds? PMID- 20895034 TI - Hospital-at-home. PMID- 20895035 TI - Sailors, scurvy and science. PMID- 20895037 TI - Medical scientism. PMID- 20895036 TI - Sailors, scurvy and science. PMID- 20895038 TI - The anatomy lesson of Professor Barge. PMID- 20895040 TI - Medical scientism. PMID- 20895039 TI - Attorney-at-the-gate in the year 2005. PMID- 20895041 TI - Privatization of the NHS. PMID- 20895042 TI - Paradigm shifts in the 16th and 17th centuries. PMID- 20895043 TI - Complementary medicine in the medical curriculum. PMID- 20895044 TI - Save the ESR. PMID- 20895045 TI - Richard feynman. PMID- 20895046 TI - Agues of essex. PMID- 20895048 TI - The genesis of the faculty of community medicine. PMID- 20895047 TI - Deafness-the visual component. PMID- 20895049 TI - Tender lungs. PMID- 20895050 TI - A cure for the ague. PMID- 20895051 TI - A view from the Web. PMID- 20895052 TI - Blank spaces. PMID- 20895055 TI - Indian centuplets. PMID- 20895056 TI - The lady. PMID- 20895054 TI - On the shoulders of giants. PMID- 20895057 TI - Markel cell tumour. PMID- 20895053 TI - Genesis of the faculty of community medicine. PMID- 20895058 TI - Stick symbolism. PMID- 20895060 TI - Destruction of a hospital. PMID- 20895059 TI - Surgery and the mental health act. PMID- 20895061 TI - Preface. PMID- 20895062 TI - Preface. PMID- 20895063 TI - Foreword. PMID- 20895064 TI - A portrait of 'The Lady': a life of Dorothy Russell. PMID- 20895065 TI - Gift relationships. PMID- 20895066 TI - Plastic stress. PMID- 20895068 TI - Moral dilemmas. PMID- 20895067 TI - Medical editors' trial amnesty. PMID- 20895069 TI - Sir geoffrey jefferson. PMID- 20895070 TI - Memoir: Richard Cohen: first Chief Scientist at the DHSS. PMID- 20895071 TI - Is she pregnant? PMID- 20895072 TI - Charges for RSM meetings. PMID- 20895073 TI - Duty of continuity. PMID- 20895074 TI - Hippocratism. PMID- 20895075 TI - Hippocratism. PMID- 20895076 TI - Charges for RSM meetings. PMID- 20895077 TI - Dorothy russell in oxford. PMID- 20895078 TI - King herod the great. PMID- 20895079 TI - Admission of a patient to hospital on a stretcher. PMID- 20895080 TI - Anniversaries and mensiversaries. PMID- 20895082 TI - New format for figures. PMID- 20895081 TI - The bosom serpent. PMID- 20895083 TI - Preface. PMID- 20895084 TI - Preface. PMID- 20895085 TI - Palliative medicine: is it really specialist territory? PMID- 20895086 TI - Great expectations. PMID- 20895088 TI - Missing inaction. PMID- 20895087 TI - Death in custody. PMID- 20895089 TI - Bereavement in children. PMID- 20895090 TI - Music as male competition. PMID- 20895091 TI - Echolocation and scurvy: facts before explanations. PMID- 20895093 TI - The handshake. PMID- 20895092 TI - This month in history: Jacques Louis Reverdin. PMID- 20895094 TI - An equal music. PMID- 20895095 TI - The struck-off mystery. PMID- 20895096 TI - A surrogate for smoking: forty years of mutilating cigarettes. PMID- 20895097 TI - Thoughts in an MRI scanner. PMID- 20895098 TI - East london college. PMID- 20895099 TI - This month in history: Patrick Manson. PMID- 20895100 TI - Multicentre research ethics committees. PMID- 20895102 TI - This month in history: Ephraim McDowell. PMID- 20895101 TI - Royal medical benevolent fund christmas appeal. PMID- 20895103 TI - Preface. PMID- 20895105 TI - On Gouty Concretions or Chalk Stones. PMID- 20895104 TI - A Case of Aneurism of the Carotid Artery. PMID- 20895107 TI - A case of violent and obstinate Cough, cured by a preparation of Iron. PMID- 20895106 TI - A case of Artificial Dilatation of the Female Urethra, &c. PMID- 20895108 TI - A case of Hydrophobia; with an Account of the Appearances after Death. PMID- 20895110 TI - A case of Intus-susceptio, with Remarks. PMID- 20895109 TI - An account of three Cases of Sudden Death, with the appearances on Dissection, and some additional observations. PMID- 20895111 TI - A description of two Muscles surrounding the membranous part of the Urethra. PMID- 20895112 TI - A case of Tumour in the Brain, with remarks on the Propagation of Nervous Influence. PMID- 20895113 TI - Second case of Carotid Aneurism. PMID- 20895115 TI - Case of a Foetus found in the Abdomen of a Boy. PMID- 20895114 TI - Some observations relative to the Treatment of Hooping Cough. PMID- 20895117 TI - On a diminution, in consequence of Disease, of the Area of the Aperture, by which the left Auricle of the Heart communicates with the Ventricle of the same side. PMID- 20895116 TI - Observations on the Distemper in Dogs. PMID- 20895118 TI - Two cases of Small-Pox Infection communicated to the Foetus in Utero under peculiar circumstances, with additional remarks. PMID- 20895119 TI - Historical account of Philip Howorth, a Boy in whom Signs of Puberty commenced at an early Age. PMID- 20895120 TI - Appendix. PMID- 20895122 TI - On the Gelatine of the Blood. PMID- 20895121 TI - An account of a peculiar Disease of the Heart. PMID- 20895123 TI - An Account of the Effects produced by a large quantity of Laudanum taken internally, and of the means used to counteract those effects. PMID- 20895125 TI - An account of a Case of Lithotomy, with Remarks. PMID- 20895124 TI - A case of Exposure to the Vapour of burning Charcoal. PMID- 20895126 TI - A case of Aneurism by Anastomosis in the Orbit, cured by the Ligature of the common Carotid Artery. PMID- 20895127 TI - A case of a Sailor, in the Muscles of whose Back the blade of a knife lodged above thirty years. PMID- 20895128 TI - A case of Fracture of the Occipital Bone, extending to the Great Foramen; in which that bone was trephined, and the Dura Mater of the Cerebellum punctured. PMID- 20895130 TI - Experiments on the Urine discharged in Diabetes Mellitus, with remarks on that disease. PMID- 20895129 TI - A case of premature Puberty in a Female. PMID- 20895131 TI - A case of Recovery from the Effects of Arsenic; with remarks on a new mode of detecting the presence of this metal. PMID- 20895132 TI - Experiments and Observations on the Serum of the Blood. PMID- 20895133 TI - A case of Hydrocephalus Internus. PMID- 20895134 TI - On the Mercurial Treatment of Dysentery, with observation on the same practice in Fevers. PMID- 20895135 TI - A case of Lithotomy, with remarks on the effect of that Operation; and on some cases of Fistula in Perineo. PMID- 20895136 TI - History of a singular Nervous or Paralytic Affection, attended with anomalous morbid sensations. PMID- 20895138 TI - On the Use of Oil of Turpentine in Taenia. PMID- 20895137 TI - Account of a singular and fatal Disease occurring in several persons of the same hamlet. PMID- 20895139 TI - Case of Dysphagia produced by Aneurism of the Aorta. PMID- 20895140 TI - Dissection of a Limb on which the Operation for Popliteal Aneurism had been performed. PMID- 20895141 TI - A case of Hydatid in the Brain. PMID- 20895143 TI - A case of Trismus following a contused wound in the Head. PMID- 20895142 TI - Case of Amputation at the Shoulder Joint. PMID- 20895144 TI - A case of Trismus successfully treated. PMID- 20895145 TI - Observations on Tumors within the Pelvis, occasioning difficult Parturition. PMID- 20895146 TI - Case of Fractured Cranium, when the Dura and Pia Mater were lacerated, and a great quantity of the Cerebrum protruded, which terminated favourably. PMID- 20895147 TI - A case of Secondary Small Pox, with references to some cases of a similar nature. PMID- 20895148 TI - Some Observations on Spina Bifida. PMID- 20895149 TI - A Chemical Account of Various Dropsical Fluids; with remarks concerning the nature of the Alkaline Matter contained in these Fluids, and in the Serum of the Blood. PMID- 20895150 TI - Case of a Woman who voided a large number of Worms by the Urethra; with a description of the Animals. PMID- 20895151 TI - Some Account of the Effects of Arsenic in counteracting the Poison of Serpents. PMID- 20895152 TI - Explanation of the Plates. PMID- 20895153 TI - A case of an Un-united Fracture of the Thigh, cured by sawing off the Ends of the Bone. PMID- 20895155 TI - A case of Wound of the Heart. PMID- 20895154 TI - A case of Malformation of the Head, constituting what is commonly called an acephalous foetus. PMID- 20895156 TI - History of an extraordinary Enlargement of the Right Lower Extremity; with a description of some morbid changes in the Papillae of the Cutis. PMID- 20895157 TI - An Account of a severe case of Erythema, unconnected with Mercurial Action. PMID- 20895158 TI - On Painful Affections of the Side from Tumid Spleen. PMID- 20895159 TI - Facts and Observations respecting Intermittent Fevers, and the exhalations which occasion them. PMID- 20895160 TI - Account of a case of spontaneous Extravasation within the Theca Vertebralis, which soon terminated fatally. PMID- 20895161 TI - Observations on Diabetes Insipidus. PMID- 20895163 TI - Experiments on the Bark of the Coccoloba Uvifera. PMID- 20895162 TI - Cases of premature Labour artificially induced in Women with distorted Pelvis; to which are subjoined, some observations on this method of practice. PMID- 20895164 TI - A case of Splenitis, with further remarks on that disease. PMID- 20895165 TI - Account of the Muscles of the Ureters, and their effects in the irritable states of the Bladder. PMID- 20895166 TI - History of a case in which a Calculus was voided from a Tumor in the Groin. PMID- 20895167 TI - General Views of the Composition of Animal Fluids. PMID- 20895169 TI - History of a severe affection of the Organs of Respiration; with the appearances on dissection, and remarks. PMID- 20895168 TI - A Case of Fungus Haematodes. PMID- 20895170 TI - An Account of a new mode of treatment in Chronic Rheumatism, and especially in Sciatica. PMID- 20895171 TI - Appendix to the Paper on Cynanche Laryngea, containing remarks on the distinction between that disease and Cynanche Trachealis. PMID- 20895172 TI - Appendix, containing remarks on the Comperative Health and Population of England and Wales, at different periods. PMID- 20895173 TI - Some Remarks on the Use of Nitrat of Silver, for the detection of minute portions of Arsenic. PMID- 20895174 TI - History of a case of remitting Ophthalmia, and its successful treatment by Opium. PMID- 20895176 TI - History of a remarkable case of Ovarian Dropsy. PMID- 20895175 TI - Explanation of the Plates. PMID- 20895178 TI - Case of diseased Appendix Vermiformis. PMID- 20895177 TI - A Case of difficult parturition, occasioned by a Dropsical Ovarium, forming a Tumor in the lower part of the Pelvis. PMID- 20895179 TI - A Case of diseased Testicle, accompanied with disease of the Lungs and Brain, and terminating fatally. PMID- 20895181 TI - Cases of Cynanche Laryngea. PMID- 20895180 TI - Description of an improved method of tying diseased Tonsils. PMID- 20895182 TI - History of a case of Anaesthesia. PMID- 20895183 TI - Observations on the Venereal Disease in Portugal, as affecting the Constitutions of the British Soldiery and Natives. PMID- 20895184 TI - On the Effects of evacuating the Aqueous Humor in Inflammation of the Eyes, and in some Diseases of the Cornea. PMID- 20895185 TI - Case of Paralysis of the Face, succeeded by certain Nervous Disorders. PMID- 20895186 TI - Case of Disease in the Brain, produced by external violence. PMID- 20895187 TI - Appendix to the foregoing paper. PMID- 20895188 TI - History of a case of Premature Puberty. PMID- 20895189 TI - Pathological Researches respecting the Diseases of Joints. PMID- 20895191 TI - Observations on the Cataract. PMID- 20895190 TI - A remarkable Instance of Spasmodic Affection of the Tongue and Mouth, successfully treated. PMID- 20895192 TI - Case of Contracted Wrist, successfully treated. PMID- 20895194 TI - History of a diseased Metacarpal Bone, removed by an operation, with the description of an instrument for sawing off the extremities or portions of the long bones. PMID- 20895193 TI - History and Dissection of a fatal Case of Cynanche Laryngea. PMID- 20895195 TI - Case of a double encysted Tumour, the posterior cyst of which, situated deeply between the eye-ball, and the floor of the orbit, was attached to, and partly contained a tooth. PMID- 20895196 TI - Two Cases of Strangulated Femoral Hernia, attended with some unusual circumstances. PMID- 20895197 TI - Case of Extravasation of Bile into the Abdomen, from rupture of the Liver or Gall Bladder. PMID- 20895198 TI - On the Muscularity of the Uterus. PMID- 20895199 TI - Two Examples of the beneficial effects of Mercury in some severe affections of the Brain. PMID- 20895200 TI - Some Observations on the Use of Opium in Uterine Hemorrhagy. PMID- 20895201 TI - Observations on the Vascular Appearance in the Human Stomach, which is frequently mistaken for inflammation of that organ. PMID- 20895202 TI - Analysis of the Bones of the Spine, in a Case of Mollities Ossium. PMID- 20895203 TI - An Account of the Anastomosis of the Arteries at the Groin. PMID- 20895204 TI - Observations on the Ligature of Arteries and the Causes of Secondary Hemorrhage, with a suggestion of a new method of employing the ligature in cases of Aneurism. PMID- 20895205 TI - Instance of the good effects of Arsenic in Chorea. PMID- 20895206 TI - Explanation of the Plates. PMID- 20895207 TI - An Example of Symptoms resembling Tic Douleureux, produced by a wound in the Radial Nerve. PMID- 20895209 TI - A Tabular Synopsis of Albuminous Fluids. PMID- 20895208 TI - On the Nature and Analysis of Animal Fluids. PMID- 20895210 TI - Cases of Periodical Jactitation or Chorea. PMID- 20895211 TI - The History of a Child retained in the Mother fifty-two years after the usual period of utero-gestation. PMID- 20895212 TI - An Account of some Diseases of the Toes and Fingers; with observations on their Treatment. PMID- 20895214 TI - Case of Cynanche Laryngea, with remarks. PMID- 20895213 TI - Observations on some of the Causes which destroy the Foetus in Utero; with an account of a case in which a successful mode of treatment was employed in preventing that accident. PMID- 20895215 TI - Account of a Child born without a Brain, which lived four days; with a sketch of the principal deviations from the ordinary formation of the body, remarks on their production, and a view of some physiological inferences, to which they lead. PMID- 20895216 TI - History of a Tubercular Eruption of a syphilitic appearance, but curable without Mercury. PMID- 20895217 TI - Case of Bubonocele, requiring a second operation five days after the first. PMID- 20895218 TI - On the Effects of large doses of Opium in a case of Diabetes Mellitus. PMID- 20895219 TI - Further Observations on the Diseases which affect the Synovial Membranes of Joints. PMID- 20895220 TI - Case of Abscess in the Brain. PMID- 20895221 TI - On the Muscae Volitantes of Nervous Persons. PMID- 20895222 TI - On the Treatment of Erysipelas by Incision. PMID- 20895223 TI - Case of obstructed Aorta. PMID- 20895224 TI - Account of an Epidemic Fever, which occurred at Gibraltar, in the years 1804, 1810, and 1813; taken from Official Documents, Military and Medical, and from the Communications of Joseph D. A. Gilpin, M.D. Deputy Inspector of Hospitals. PMID- 20895225 TI - A Practical Essay on Hemeralopia, or Night-Blindness, commonly called Nyctalopia; as it affects seaman and others, in the East and West Indies, China, the Mediterranean, and all Tropical Climates, in which a successful method of treating the disease is detailed. PMID- 20895226 TI - On the Diuretic Properties of the Pyrola Umbellata. PMID- 20895228 TI - Addition to the foregoing paper. PMID- 20895227 TI - Case where a Seton was introduced between the fractured extremities of a Femur, which had not united in the usual manner; with some observations on the methods which have been employed to produce reunion in fractured bones. PMID- 20895230 TI - A Case of Aneurism of the Glutaeal Artery cured by tying the internal Iliac. PMID- 20895229 TI - Further Observations on the Cataract. PMID- 20895231 TI - Report of the principal natural Diseases that have prevailed amongst the Children of the Royal Military Asylum at Chelsea, from its first establishment in 1804, to the 1st of January, 1814, including a period of ten years, with some remarks thereon. PMID- 20895233 TI - References to the Plates. PMID- 20895232 TI - Addition to the foregoing paper, being extracts from letters to Dr. Marcet, by William Henry, M.D. F.R.S. Physician to the Infirmary at Manchester. PMID- 20895234 TI - A Case of Cartilaginous Substances successfully extracted from the Cavity of the Knee-Joint; which occurred in the Detachment Hospital at Gosport, in the summer of 1809. PMID- 20895235 TI - Account of the Extraction of a loose Substance, consisting partly of Bone and partly of Cartilage, from the Elbow-Joint. PMID- 20895236 TI - Account of a Chemical Examination of the Urine and Serum of the Blood of a person who had taken large quantities of Soda. PMID- 20895238 TI - On contractions after Burns or extensive Ulcerations. PMID- 20895237 TI - Case of Laceration of the internal Coat of the Stomach and Duodenum, by vomiting. PMID- 20895239 TI - An Account of the origin and progress of the Plague of Malta, in the year 1813. PMID- 20895241 TI - A Case of Aneurism by Anastomosis in the left orbit, cured by tying the common trunk of the left carotid artery. PMID- 20895240 TI - A Case of Incontinence of Urine, of nine years' duration, cured by external pressure. PMID- 20895242 TI - Account of a Case in which parts of a Foetus were found in a tumour situated in the abdomen of a girl two years and a half old. PMID- 20895243 TI - A Case of Axillary Aneurism, for which the artery was tied below the clavicle. PMID- 20895244 TI - Successful treatment of a case of Cynanche Laryngea. PMID- 20895246 TI - Account of a case of Croup, in which the operation of Bronchotomy was successfully performed. PMID- 20895245 TI - Remarks on the preceding case of Cynanche Laryngea. PMID- 20895247 TI - A new method of tying the arteries in Aneurism, Amputation, and other Surgical Operations; with incidental remarks on some collateral points. PMID- 20895248 TI - Two Cases of the true Elephantiasis, or Lepra Arabum. PMID- 20895249 TI - On some affections of the Larynx, which require the operation of Bronchotomy. PMID- 20895250 TI - Experiments and Observations in order to ascertain the means employed by the animal economy in the formation of bone. PMID- 20895251 TI - Observations on the Mediterranean Fever. PMID- 20895252 TI - Further observations on the Ulceration of the Cartilages of the Joints. PMID- 20895253 TI - Case of Hernia Ventriculi, from external Violence, wherein the Diaphragm was lacerated without fracture of the ribs. PMID- 20895254 TI - Sketch of the Medical History of the British Armies in the Peninsula of Spain and Portugal, during the late campaigns. PMID- 20895255 TI - Statements of the comparative Health of the British Navy, from the year 1779 to the year 1814, with proposals for its farther improvement. PMID- 20895256 TI - Particulars of a case in which a very large Calculus was removed from the Urethra of a female without operation; with examples of analogous cases. PMID- 20895257 TI - Case of the successful treatment of the Incontinence of Urine consequent to sloughing or ulceration of the bladder from injury during labour, with observations. PMID- 20895258 TI - A Case of Mortification of the Uterus occurring a few hours after delivery, with some remarks on the causes that produced it. PMID- 20895260 TI - Some experiments on the chemical nature of Chyle, with a few observations upon Chyme. PMID- 20895259 TI - On the use of the Lactuca Virosa, in Hooping-Cough. PMID- 20895262 TI - A Case of Locked-Jaw cured by Oil of Turpentine given as a Glyster. PMID- 20895261 TI - Further observations on the Ligature of Arteries. PMID- 20895263 TI - Note on the use of Nitrate of Silver, for the detection of Arsenic, in reference to a paper on this subject in Vol. III. of the Society's Transactions. PMID- 20895264 TI - References to the Plates. PMID- 20895265 TI - A Case of an extraordinary enlargement of the Scrotum, with an operation successfully performed for its removal. PMID- 20895266 TI - On the use of Nicotiana in Retention of Urine. PMID- 20895267 TI - Case of obstruction in the large intestines, occasioned by a Biliary Calculus of extraordinary size. PMID- 20895268 TI - Chemical Analysis of the Mineral Waters of Spa. PMID- 20895270 TI - History of a Case of Wound in the Face, requiring the Operation of tying the Common Carotid Artery, which was performed with success. PMID- 20895269 TI - Case of Ununited Fracture of the Os Humeri, treated successfully by the Seton. PMID- 20895271 TI - History of a Tumor successfully removed from the Face and Neck, by previously tying the Carotid Artery. PMID- 20895272 TI - History of a Case of Aneurism of the Femoral Artery, for which the Operation of tying the External Iliac Artery was performed. PMID- 20895273 TI - Some Observations concerning the Medical Properties of the Pyrola Umbellata, and the Arbutus Uva Ursi, of Linnaeus. PMID- 20895274 TI - A Case of Ossification and Bony Growth of the Cartilages of the Larynx, preventing deglutition. PMID- 20895275 TI - Observationes quaedam de Hottentotis, praesertim de structura genitalium peculiari Hottentotarum. PMID- 20895276 TI - Case of Gunshot Wound of the Shoulder Joint, where the head of the Os Humeri, together with parts of the Humerus, were successfully removed. PMID- 20895277 TI - Cases and Observations illustrating the influence of the Nervous System, in regulating Animal Heat. PMID- 20895278 TI - Observations on the treatment of Varicose Veins of the Legs. PMID- 20895280 TI - Additional Particulars, connected with Professor de Saussure's Case. PMID- 20895279 TI - An Account of the Last Illness and Death of Professor H. Benedict de Saussure. PMID- 20895281 TI - History of a case of Chorea Sancti Viti, occurring in an adult, and cured in an unusual manner. PMID- 20895283 TI - Note by the Secretaries on the Above Communication. PMID- 20895282 TI - Particulars concerning the Structure of a Monstrous Foetus. PMID- 20895284 TI - History of a Case of Caesarean Operation. PMID- 20895285 TI - Of the Laceration of the Fibres of Muscles, particularly of the Gastrocnemius. PMID- 20895286 TI - Observations on a Change of Colour in the Skin, produced by the internal use of the Nitrate of Silver. PMID- 20895288 TI - Observations and Cases relating to the operation for Artificial Pupil; in a letter from Mr. Maunoir of Geneva, to Professor scarpa of pavia, with the professor's answer. PMID- 20895287 TI - Additional Facts relative to the subject of the preceding paper. PMID- 20895289 TI - Case of Inflammation in the Muscular Structure of the Heart. PMID- 20895290 TI - Case of a Wound of the Peroneal Artery, successfully treated by Ligature. PMID- 20895291 TI - Case of a Gunshot Wound and Fracture of the Tibia, in which a seton was successfully employed in promoting a cure. PMID- 20895292 TI - An account of a new method of operating for the cure of external Aneurism, with some Observations and Experiments illustrative of the effects of the different methods of procuring the obliteration of Arteries. PMID- 20895293 TI - A Sketch of the Medical History of the First Battalion of the First Regiment of Foot Guards, during the winter of 1812-13. PMID- 20895294 TI - Microscopic Observations on the Structure of Bone. PMID- 20895296 TI - Further Observations on Contractions succeeding to Ulceration of the Skin. PMID- 20895295 TI - Observations on the condition of the Bones in Rickets, with an account of some circumstances not before noticed relating to the processes of restoration which take place in them. PMID- 20895297 TI - Case of hernia of the Dura Mater connected with Hydrocephalus Internus. PMID- 20895298 TI - Description of an Extra-Uterine Foetus contained in the Fallopian Tube. PMID- 20895299 TI - Observations on Tetanus. PMID- 20895301 TI - Account of a case of curious imperfection of Vision. PMID- 20895300 TI - Copy of a Letter on the subject of Tetanus, from Duncan M'Arthur M.D. F.L.S. late Physician to the Naval Hospital at Deal, to the Commissioners for Transports, London. PMID- 20895302 TI - On the Treatment of Sinuous Ulcers. PMID- 20895303 TI - Some Observations on a Species of Pulmonary Consumption, very frequent in Great Britain. PMID- 20895304 TI - Case of Inguinal Aneurism, cured by tying the external Iliac Artery. PMID- 20895305 TI - Facts illustrating the effects of the Venereal Disease on the foetus in utero, and the modes of its communication. PMID- 20895307 TI - Supplementary Observations to the Paper on the Structure of Bone. PMID- 20895306 TI - On the Medicinal Properties of Stramonium; with illustrative cases. PMID- 20895308 TI - References to the Plates. PMID- 20895309 TI - History of two Cases of Angina Pectoris. PMID- 20895310 TI - History of a very fatal affection of the Pudendum of Female Children. PMID- 20895311 TI - Report of the State of the Wounded on board his Majesty's Ship Leander, in the action before Algiers, extracted from a letter from D. Quarrier, M.D. Surgeon to the Leander, to the Commissioners for Transports. PMID- 20895312 TI - An inquiry into the Origin and Nature of the Yellow Fever, as it has lately appeared in the West Indies, with Official Documents relating to this subject. PMID- 20895313 TI - Cases of Hernia Cerebri, with Observations. PMID- 20895314 TI - On the Internal and External Use of the Nitro-Muriatic Acid in the Cure of Diseases. PMID- 20895315 TI - History of a Case of ill-conditioned Ulcer of the Tongue, successfully treated by Arsenic. PMID- 20895316 TI - History of a Case of Lithotomy, with a few remarks on the best mode of making the incision in the Lateral operation. PMID- 20895317 TI - A case of fatal Haemorrhage from the Extraction of a Tooth. PMID- 20895318 TI - Rupture of the Stomach and escape of its Contents into the Cavity of the Abdomen. PMID- 20895319 TI - Additional Observations. PMID- 20895320 TI - Account of a Case where a severe Nervous Affection came on after a Punctured Wound of the Finger, and in which Amputation was successfully performed. PMID- 20895321 TI - An Account of some remarkable symptoms which were connected with a painful affection of the extremity of the left thumb, together with the mode of treatment. PMID- 20895322 TI - Cases of Fungus Haematodes, with Observations, by George Langstaff, Esq. and an Appendix, containing two cases of Analogous Affections. PMID- 20895323 TI - On the Pellagra, a Disease prevailing in Lombardy. PMID- 20895324 TI - Observations on the Treatment of Syphilis, with an account of several cases of that disease in which a cure was effected without the use of Mercury. PMID- 20895325 TI - Three Cases of Calculi, removed from the Urethra, without the use of Cutting Instruments. PMID- 20895326 TI - Some Cases of Diseases of the Heart, with an Inquiry into their Nature and Causes. PMID- 20895328 TI - A Case of Extra-Uterine Foetus, contained in the Fallopian Tube, with some Observations. PMID- 20895327 TI - Further Observations on the Ligature of Arteries, to which is added a Case of Popliteal Aneurism, attended with some unusual circumstances. PMID- 20895329 TI - The History of a Woman who bore a seven months' Foetus for seven years, was delivered of it per anum, and completely recovered. PMID- 20895330 TI - History of a Case of Rupture of the Brain and its Membranes, arising from the accumulation of Fluid, in Hydrocephalus Internus. PMID- 20895331 TI - On the Formation of New Joints. PMID- 20895332 TI - Observations on the Nature of some of the proximate Principles of the Urine; with a few remarks upon the means of preventing those diseases, connected with a morbid state of that fluid. PMID- 20895333 TI - Observations on the Treatment of the Venereal Disease, without Mercury. PMID- 20895335 TI - Explanation of the Plates. PMID- 20895334 TI - Observations on the morbid structure of Bones, and an attempt at an arrangement of their Diseases. PMID- 20895336 TI - A Case of Loss of Power over the Voluntary Muscles. PMID- 20895338 TI - Experiments and Observations on the Union of Fractured Bones. PMID- 20895337 TI - History of a Case of Caesarean Operation, in which the Lives of the Mother and Child were both preserved. PMID- 20895339 TI - Brief Notice presented to the Medico-Chirurgical Society with the original obstetric Instruments of the Chamberlins. PMID- 20895340 TI - Case of Aneurism in the Arm, cured by tying the Subclavian Artery. PMID- 20895341 TI - A singular Case of Expulsion of a blighted Foetus and Placenta at seven Months, a living Child still remaining to the full period of Utero-gestation. PMID- 20895343 TI - Case of Aneurism by Anastomosis of the Finger. PMID- 20895342 TI - Some Observations on one species of Naevus Maternus; with the case of an Infant where the Carotid Artery was tied. PMID- 20895344 TI - Notes of a case of Mercurial Erethism. PMID- 20895345 TI - On the Effect of Nitrate of Silver on the Complexion. PMID- 20895346 TI - Case of an extensive Wound from the Bite of a Shark. PMID- 20895347 TI - A Report of the principal Diseases which occurred among the Gentlemen Cadets in the Royal Military College, at Great Marlow, Bucks, and Sandhurst, Berkshire, during a period of seven years viz. from 3rd of September, 1809, to 2nd of September, 1816. PMID- 20895348 TI - A Case of Inguinal Aneurism cured after the use of Compression. PMID- 20895349 TI - References to the Plates. PMID- 20895350 TI - Case of Cynanche Laryngea. PMID- 20895351 TI - Some Observations on the Cure of Hydrocele of the Tunica Vaginalis Testis, without procuring an obliteration of the Sac. PMID- 20895352 TI - Case of Hereditary Ichthyosis. PMID- 20895353 TI - Experiments on the Transfusion of Blood by the Syringe. PMID- 20895354 TI - History of the Progress, and Inquiry into the Causes of the Yellow Fever, as it appeared in the Island of Antigua in the Year 1816. PMID- 20895355 TI - Cases of Fungus Haematodes Cancer, and Tuberculated Sarcoma, with Observations. PMID- 20895356 TI - Case of Hydrocephalus, successfully treated by the removal of the Water by Operation. PMID- 20895357 TI - Account of a Case of Defective Power to distinguish Colours. PMID- 20895359 TI - Further Account of the result of an Operation for performing an Artificial Pupil: Extracted from Letters addressed to Professor Scarpa. PMID- 20895358 TI - On the use of the actual Cautery as a remedy for the Cure of Diseases. PMID- 20895360 TI - Cases shewing the coincidence of Worms in the Intestines with Haemoptysis, and Remarks on the probability of the two affections having a connexion with each other. PMID- 20895361 TI - Two Cases of Aneurism, in which the temporary Ligature was employed. PMID- 20895362 TI - Observations on some points relating to the Physiology and Pathology of the Ear. PMID- 20895363 TI - Account of a Case in which some singular preternatural appearances were observed in the Ovarium and Female Bladder. PMID- 20895364 TI - An Account of a congenital Monstrosity. PMID- 20895365 TI - On the comparative Infrequency of Urinary Calculi among Seafaring People. PMID- 20895366 TI - Appendix to the foregoing Paper. PMID- 20895367 TI - Further Observations on the Proximate Principles of the Urine. PMID- 20895369 TI - On Urinary and other Morbid Concretions. PMID- 20895368 TI - Note subjoined as postscript to Mr. Rumsey's paper on the connexion between Worms and Haemoptysis. PMID- 20895370 TI - History of a Case of Nephritis Calculosa, in which the various periods and symptoms of the disease are strikingly illustrated; and an account of the Operation of Lithotomy, given by the Patient himself. PMID- 20895371 TI - Memoir on a New Mode of treating Bronchocele. PMID- 20895372 TI - Case of a Periodical Affection of the Eyes and Chest. PMID- 20895374 TI - Observations upon the Morbid Appearances and Structure of Bones, being the sequel of a former paper. PMID- 20895373 TI - A Case of Chronic Inflammation of the Larynx, in which Laryngotomy and Mercury were successfully employed. PMID- 20895375 TI - Case of Carotid Aneurism. PMID- 20895376 TI - On the Use of Arsenic in the Cure of Chorea. PMID- 20895377 TI - On a New Method of preparing Pharmaceutical Extracts. PMID- 20895378 TI - Explanation of the Figures. PMID- 20895379 TI - The Elephantiasis, as it appears in Hindostan. PMID- 20895380 TI - Observations on the Diseases of the Teeth. PMID- 20895382 TI - An Account of a Substance obtained from a diseased Ovarium, with some Remarks on diseased Secretions of an analogous nature. PMID- 20895381 TI - Cases of Tumors within the Pelvis impeding Parturition; with Remarks. PMID- 20895384 TI - On the Operation for Aneurism. PMID- 20895383 TI - Observations on the Changes which the Animal Body undergoes in a Hot Climate soon after Death. PMID- 20895385 TI - Account of the Rheumatic Inflammation of the Eye, with Observations on the Treatment of the Disease. PMID- 20895386 TI - Experiments on a few controverted points respecting the Physiology of Generation. PMID- 20895387 TI - Some observations on a mode of performing Operations on Irritable Patients, with a Case where the practice was successfully employed. PMID- 20895388 TI - History of a Case of Bony Tumor, successfully removed from the Head of a Female. PMID- 20895390 TI - Case of Bronchocele, in which the superior Thyroidal Artery was successfully tied. PMID- 20895389 TI - Some account of a Case of Obstinate Vomiting, in which an attempt was made to prolong Life by the Injection of Blood into the Veins. PMID- 20895391 TI - A Statement of Facts tending to establish an Estimate of the true Value and present State of Vaccination. PMID- 20895392 TI - On the Structure of the Membranous Part of the Urethra. PMID- 20895393 TI - Some Observations on Inversion of the Uterus; with a Case of successful Extirpation of that Organ. PMID- 20895394 TI - Description of an Urinary Calculus, composed of the Lithate or Urate of Ammonia. PMID- 20895395 TI - Case of a Presentation of a Bag of Water after Delivery, unconnected with plurality of Children. PMID- 20895396 TI - Observations on the relaxed Rectum. PMID- 20895397 TI - On Affections of the Meatus Auditorius Externus. PMID- 20895398 TI - Note subjoined as Postscript to Dr. Hall's Case of Chronic Inflammation of the Larynx. PMID- 20895399 TI - Reference to the Plate. PMID- 20895400 TI - A Statistical Inquiry into the Frequency of Stone in the Bladder, in Great Britain and Ireland. PMID- 20895401 TI - Case of Popliteal Aneurism, in which the Temporary Ligature was employed. PMID- 20895402 TI - On an Acute Form of Ulceration of the Cartilages of Joints. PMID- 20895403 TI - Account of the Epidemic Spasmodic Cholera, which has lately prevailed in India, and other adjacent countries and islands, and at sea. Communicated in a letter from Frederick Corbyn, Esq. Assistant Surgeon on the Bengal Establishment. With Communications on the same subject, by favor of the Chairman and Deputy Chairman of the East India Company; and from the islands of Mauritius and Ceylon, by favor of the Medical Board of the Army. With Remarks. PMID- 20895404 TI - Postscript. PMID- 20895405 TI - On the Causes of the Vacuity of the Arteries after Death. PMID- 20895406 TI - History of a Second Caesarean Operation, performed on the patient, whose case is related in the Ninth Volume of the Society's Transactions. PMID- 20895407 TI - Appendix. PMID- 20895408 TI - On Renal Calculi. PMID- 20895409 TI - Reference to the Plates. PMID- 20895410 TI - Successful Case of Lithotomy. PMID- 20895411 TI - History of a Case of Lithotomy. PMID- 20895413 TI - Case of Carotid Aneurism, successfully treated. PMID- 20895412 TI - Remarks on the Danger of Extracting Large Calculi, with the Description of an Instrument intended to facilitate the breaking down Stones of considerable magnitude. PMID- 20895414 TI - Cases of Bronchocele or Goitre, treated by Seton, with Observations. PMID- 20895416 TI - Case of fractured Os Pubis successfully treated. PMID- 20895415 TI - Observations on the Scrofulous Inflammation of the Peritonoeum occurring in Children, and frequently denominated Marasmus. PMID- 20895418 TI - A Case of Aneurism of the Carotid Artery. PMID- 20895417 TI - Case of Sudden Death, in which a Hydatid was found in the Substance of the Heart. PMID- 20895419 TI - Case of Malformation of the Heart. PMID- 20895421 TI - On the Efficacy of the Bark of the Pomegranate Tree in Cases of Taenia. PMID- 20895420 TI - A Case of Chorea successfully treated by Arsenic. PMID- 20895422 TI - On the Efficacy of the Bark of the Swietenia Febrifuga, as a Substitute for that of the Cinchona. PMID- 20895423 TI - On the Physiology of the Ear. PMID- 20895424 TI - Case of Amputation of Part of the Tarsus and Metatarsus, and Preservation of the Shape and Usefulness of the Foot. PMID- 20895425 TI - Note on the Subject of the preceding Paper. PMID- 20895426 TI - An Account of a Case in which numerous Calculi were extracted from the Urinary Bladder, without the Employment of cutting Instruments. PMID- 20895427 TI - On Sloughing Phagedaena. PMID- 20895428 TI - An Account of a Case of Tetanus successfully treated in the York Military Hospital at Chelsea. PMID- 20895429 TI - Case of a Separation of a Portion of the Uterus during severe labour. PMID- 20895430 TI - A Case of Inguinal Aneurism, successfully treated by tying the External Iliac Artery. PMID- 20895431 TI - On Lithotomy. PMID- 20895432 TI - Case of Cynanche Laryngea, in which Tracheotomy and Mercury were successfully employed, with Remarks. PMID- 20895434 TI - References to the Plates. PMID- 20895433 TI - Case of a large Adipose Tumor successfully extirpated. PMID- 20895436 TI - On Partial Paralysis. PMID- 20895435 TI - Four Cases of Children, who had attempted, by mistake, to drink boiling Water from the Spout of a Tea-kettle; with Observations on the Seat and Treatment of the Effects of this Accident. PMID- 20895437 TI - A Case of Aneurism, in which a Ligature was placed on the Subclavian Artery. PMID- 20895439 TI - Observations on Compound Fractures. PMID- 20895438 TI - An Account of some Circumstances, under which a Haemorrhage may occur, sufficient to produce alarming Symptoms, though the Uterus feels contracted in the ordinary degree. PMID- 20895440 TI - A Case of Umbilical Haemorrhage, which terminated fatally. PMID- 20895441 TI - Case of Vaccine Disease and Measles, existing at the same Time in the same Individual. PMID- 20895442 TI - Cases of Ununited Fracture of the Humerus, treated by Seton and the application of Caustic Potash. PMID- 20895444 TI - On the Varieties of Diseases comprehended under the Name of Carcinoma Mammae. PMID- 20895443 TI - Case of a Wounded Nerve of the Thumb, followed by severe Symptoms, which were relieved by a division of the Nerve. PMID- 20895445 TI - Account of a Stone and of a Portion of a Catheter extracted from the Female Bladder by a Dilator; with an Appendix by Mr. Chapman of Wandsworth, and by Mr. Birt, of Diss, Norfolk, on the removal of a Catheter and of a Stone from the Female Bladder by Dilatation. PMID- 20895447 TI - References to the Plates. PMID- 20895446 TI - Case of a Large Glandular Tumor in the Neck. PMID- 20895448 TI - A Case of Bronchotomy, successfully performed, for the Removal of a Pebble from the Trachea. PMID- 20895450 TI - Account of a singular Variety of Urine which turned black soon after being discharged; with some Particulars respecting its Chemical Properties. PMID- 20895449 TI - Observations on the preceding Case. PMID- 20895452 TI - Case of the Extraction of a living Foetus from a Woman killed by Violence. PMID- 20895451 TI - On the Chemical Properties of the Black Urine. PMID- 20895453 TI - Account of a Man who lived ten Years after having swallowed a number of Clasp Knives; with a Description of the Appearances of the Body after Death. PMID- 20895454 TI - Appendix, No 1. A Letter from Dr. Lara Surgeon to his Majesty's Ship Isis, dated Portsea, Hants, March 27, 1809. PMID- 20895455 TI - Appendix, No. 2. Narration of John Cummings, drawn up by himself. PMID- 20895456 TI - History of a Case of premature Puberty. PMID- 20895457 TI - Appendix to the preceding Paper. PMID- 20895458 TI - On the Product of Acute Inflammation. PMID- 20895459 TI - Note on the Preceding Paper. PMID- 20895460 TI - A Case of Inguinal Aneurism successfully treated, by tying the External Iliac Artery. PMID- 20895461 TI - Observations on the Use of the Cubebs, or Java Pepper, as a remedy for Gonorrhea. PMID- 20895463 TI - On the Influence of Local Irritation, in the production of Diseases resembling Cancer, and other morbid Alterations of Structure. PMID- 20895462 TI - AN Account of two Cases of Biliary Calculi, of extraordinary Dimensions. PMID- 20895465 TI - On the Destruction of the Foetal Brain. PMID- 20895464 TI - On Chimney-sweepers' Cancer. PMID- 20895466 TI - A Case of Bronchocele. PMID- 20895467 TI - On the Dilatation of the Male Urethra by Inflation, for the Extraction of Calculi from the Bladder, as practised in Egypt, nearly 250 years ago. PMID- 20895468 TI - Cursory Remarks on Small-Pox, as it occurs subsequent to Vaccination. PMID- 20895470 TI - Case of Stricture of the Urethra treated by Incision. PMID- 20895469 TI - On the Comparative Virtues of different Kinds of Sarsaparilla. PMID- 20895471 TI - On the occurrence in Persia of the Epidemic Cholera of India. PMID- 20895472 TI - Account of a rare Case of Complicated Labour, from Locking of the Heads of Twins; to which are subjoined Notices of two recorded Cases of the same Description; with a Suggestion of a Method for effecting Delivery under similar Circumstances. PMID- 20895473 TI - A Case of Ascites, connected with Utero-gestation, successfully treated by Operation. PMID- 20895474 TI - Further Account of the Extraction of Calculi from the Bladder, without the Use of any cutting Instrument. PMID- 20895475 TI - Some Observations on the Powers of Circulation, and the State of the Vessels in an inflamed Part. PMID- 20895476 TI - An Essay on the Proximate Cause of the Disease called Phlegmasia Dolens. PMID- 20895477 TI - On the Effects of Stricture of the Urethra, particularly of the sacculated State of the Bladder; with an Inquiry into the Mode of Treatment to avert this latter Consequence of Stricture, which is so often fatal. PMID- 20895478 TI - Appendix to Mr. Shaw's Paper. PMID- 20895479 TI - Inquiries respecting the Anatomy of the Eye. PMID- 20895481 TI - Account of a Case of Axillary Aneurism; in which the Operation of tying the Subclavian Artery was successfully performed. PMID- 20895480 TI - On Injuries of the Pelvis. PMID- 20895482 TI - Rupture of the Uterus, and subsequent Recovery of the Patient. PMID- 20895483 TI - Illustrations of the Medical Properties of Quinina. PMID- 20895484 TI - Case of Preternatural Growth in the Lining Membrane covering the Trunks of the Vessels proceeding from the Arch of the Aorta. PMID- 20895486 TI - Case of Axillary Aneurism successfully treated by tying the Subclavian Artery. PMID- 20895485 TI - Reference to the Plates. PMID- 20895487 TI - Remarks on the Diagnosis, and on the Inversion of the Foot, in Fracture of the Neck and Upper Part of the Thigh Bone. PMID- 20895488 TI - Case of Tumor in the Anterior Mediastinum, containing Bone and Teeth. PMID- 20895489 TI - On the Effects of Loss of Blood. PMID- 20895490 TI - Cases in which the Operation for the Removal of Cicatrices from the Neck, consequent on Burns, was successfully performed; with Remarks. PMID- 20895491 TI - Case of the Simultaneous Occurrence of Small-Pox and Measles, with Remarks on Measles as it prevailed epidemically at Exeter in 1824. PMID- 20895492 TI - A Case of Injury to the Blood-vessels of the Lower Extremity, producing Pale Dry Gangrene in the Foot. PMID- 20895493 TI - History of a Case of Hydrometra and Dry Gangrene, occurring in the Same Individual, with some Observations on these Diseases. PMID- 20895495 TI - Case of Epilepsy, attended with remarkable Slowness of the Pulse. PMID- 20895494 TI - Cases of Destructive Inflammation of the Eye, and of Suppurative Inflammation of the Integuments, occurring in the Puerperal State, and apparently from constitutional Causes. PMID- 20895497 TI - Case of Carotid Aneurism, successfully treated by tying the Artery Above the Aneurismal Tumour. PMID- 20895496 TI - Some Particulars of a Remarkable Disease of the Heart, attended with Partial Discoloration of the Skin. PMID- 20895498 TI - Appendix. Description of Mr. Bremner's Instrument for carrying a Ligature round deep-seated Arteries. PMID- 20895499 TI - On the Medical Properties of the Subcarbonate of Iron. PMID- 20895500 TI - Notes of a Case of Hydrophobia, with some Remarks on the Pathology of that Disease. PMID- 20895501 TI - Case of Ulceration and Rupture of the Stomach. PMID- 20895503 TI - Explanation of the Plates. PMID- 20895502 TI - Account of the Effects of the Bite of a Wild Jackal in a Rabid State, as the same occurred in the District of Kattywar in the East Indies, in 1822. PMID- 20895505 TI - A Case of Fallopian Tube Pregnancy. PMID- 20895504 TI - On a New Variety of Extra-uterine Pregnancy. PMID- 20895506 TI - On the Ligaments of the Human Ossicula Auditus. PMID- 20895507 TI - Observations on the Saliva during the action of Mercury upon the System. PMID- 20895508 TI - Case of Fungus Haematodes of the Brain. PMID- 20895509 TI - On a New Preparation of Croton Tiglium. PMID- 20895510 TI - Case in which a Piece of Iron was found in a Cyst within the Thorax, where it had remained Fourteen Years. PMID- 20895511 TI - Case of Injury of the Head. PMID- 20895512 TI - Case of Inflammation of the Iliac and Femoral Vein, with an Account of the Appearances after Death. PMID- 20895513 TI - Case of Hydrophobia, and the Appearance of the Body on Dissection, Fourteen Hours after Death, with some Remarks on the Nature and Treatment of the Disease. PMID- 20895514 TI - An Extraordinary Case of Ovarian Dropsy. PMID- 20895516 TI - A Case of Extra-Uterine Gestation, in which the Foetus was extracted through an Aperture made in the Posterior Part of the Vagina, between the Uterus and Rectum. PMID- 20895515 TI - Calculations respecting the Period of Parturition in Women. PMID- 20895517 TI - History of Two Cases of Laceration of the Uterus during Labour, after which one of the Women survived nearly Eight Weeks, and the other perfectly recovered; with some General Remarks. PMID- 20895518 TI - A Case of Rupture of the Uterus, successfully treated. PMID- 20895519 TI - On Dislocations of the Vertebrae. PMID- 20895520 TI - On the Treatment of Naevi Materni by Ligature. PMID- 20895521 TI - Observations on the Surgical Treatment of the Naevus Maternus, with Ligature. PMID- 20895522 TI - On the Use of the Sulphate of Copper in Chronic Diarrhoea. To which are added some Observations on the Use of Acupuncture in Rheumatism. PMID- 20895523 TI - History of a Fungous Eruption, curable by Mercury, but not of Venereal Origin. PMID- 20895524 TI - Cases of Fractured Neck of the Thigh-Bone within the Capsular Ligament, with the Dissections and Observations. PMID- 20895526 TI - The Particulars of a Case of Fracture of the Neck of the Femur. PMID- 20895525 TI - A Brief Notice of some Cases of Injury to the Hip-Joint. PMID- 20895527 TI - On Paraplegia. PMID- 20895529 TI - Case of Amputation of the Thigh at the Hip-Joint, successfully performed. PMID- 20895528 TI - Observations on the Necessity and Method of further investigating the Distinctions between Syphilis and other Varieties of Venereal Disease. PMID- 20895531 TI - Explanation of the Plates. PMID- 20895530 TI - Note to Dr. Merriman's Paper. PMID- 20895533 TI - Cases of simple Erysipelas treated by incision. PMID- 20895532 TI - Observations on the Nature and Treatment of Erysipelas, illustrated by Cases. PMID- 20895534 TI - Cases of simple Erysipelas Inflammation of the Cellular Structure. PMID- 20895535 TI - On the Treatment of Erysipelas by numerous Punctures in the affected Part. PMID- 20895536 TI - Case of Erysipelas, with some Remarks. PMID- 20895537 TI - Cases of Tumours in the Abdomen arising from Organic Disease of the Stomach, with Remarks. PMID- 20895539 TI - Observations on a Peculiar Inflammatory Disease of the Eye. PMID- 20895538 TI - Observations on Depositions of Pus and Lymph occurring in the Lungs and other Viscera, after Injuries of different Parts of the Body. PMID- 20895540 TI - Explanation of the Plates. PMID- 20895541 TI - Cases of simple Erysipelas. PMID- 20895542 TI - Pathological and Surgical Observations relating to Injuries of the Brain: Part I. PMID- 20895543 TI - Analysis of a specimen of Cutaneous Perspiration. PMID- 20895544 TI - Of the Catarrhus AEstivus, or Summer Catarrh. PMID- 20895546 TI - A pathological Inquiry into the Secondary Effects of Inflammation of the Veins. PMID- 20895545 TI - Case of Rupture of the Stomach produced by Vomiting, with some Observations. PMID- 20895547 TI - A Contribution to the Pathology of Phlegmasia Dolens. PMID- 20895549 TI - Analysis of a quantity of fluid drawn off from a Hydrocele of some years' standing. PMID- 20895548 TI - Appendix, containing cases and observations for the illustration of the pathology of Phlegmasia Dolens. PMID- 20895551 TI - An Account of a Case of Aneurism by Anastomosis of the Forehead, treated by the application of Ligatures. PMID- 20895550 TI - On the use of the Subcarbonate of Iron in Tetanus. PMID- 20895552 TI - Two Cases of Fracture of the Thigh-bone taking place without any violence, in which a diseased state of the bones appears to have been the predisposing cause of fracture, and concurring with cancer in the breasts in both patients. PMID- 20895554 TI - Observations on the Local Diseases termed Malignant: Part II. PMID- 20895553 TI - Observations on the Local Diseases termed Malignant: Part I. PMID- 20895555 TI - Explanation of the Plates. PMID- 20895556 TI - On the Anatomical Characters of some Adventitious Structures. PMID- 20895557 TI - Observations on the Statement made by Dr. Douglass of Cheselden's Improved Lateral Operation of Lithotomy, in a Letter to Sir Astley Cooper, Bart., F.R.S. PMID- 20895559 TI - Explanation of the Plates. PMID- 20895558 TI - Pathological Researches on Inflammation of the Veins of the Uterus, with additional Observations on Phlegmasia Dolens. PMID- 20895560 TI - Case of Aneurism of the External Iliac Artery, for which the Femoral Artery and subsequently the Aorta were tied. PMID- 20895561 TI - Practical Observations on the Healthy and Morbid Conditions of Stumps. PMID- 20895562 TI - A Case of Aneurism of the External Iliac Artery, in which a Ligature was applied to the Common Iliac Artery. PMID- 20895564 TI - An Account of the Removal of a Tumour situated on the Cheek. PMID- 20895563 TI - On the Glanders in the Human Subject. PMID- 20895565 TI - An Account of the Dissection of the Parts concerned in the Aneurism for the Cure of which Dr. Stevens tied the Internal Iliac Artery, at Santa Cruz, in the Year 1812. PMID- 20895566 TI - A Case of Ununited Fracture of the Thigh-Bone, cured by the application of a Silver Wire between the Fractured Extremities. PMID- 20895567 TI - An Account of a Concrete Oil existing as a Constituent Principle of Healthy Blood. In a Letter addressed to the Secretary of the Medico-Chirurgical Society. PMID- 20895568 TI - Case of Phlegmasia Dolens, caused by Inflammation of the Veins of the Lower Extremity, excited by Malignant Ulceration of the Cervix Uteri. PMID- 20895570 TI - History of a Case of Stammering, successfully treated by the long continued Use of Cathartics. PMID- 20895569 TI - Case of Extensive Inflammation and Obstruction of the Veins of the Right Inferior Extremity of a Phthisical Youth, accompanied by a Swollen State of the Limb. PMID- 20895571 TI - On the Pathology of Hooping Cough. PMID- 20895572 TI - A Further Inquiry into the Comparative Infrequency of Calculous Diseases among Sea-Faring People, with some Observations on their Frequency in Scotland. PMID- 20895573 TI - Remarks on Omental Hernia, with Cases. PMID- 20895574 TI - Some Considerations with respect to the Blood, founded on one or two very simple Experiments on that Fluid. PMID- 20895575 TI - Observations on the Symptoms attending the change of a Circumscribed Popliteal Aneurism into the diffused state; with some Particulars of an Aneurism of the Aorta that burst into the OEsophagus. PMID- 20895576 TI - Case of Axillary Aneurism, successfully treated. PMID- 20895577 TI - Observations on the Use of Tobacco, as a local application in Gout and other Cases of Constitutional Inflammation. PMID- 20895578 TI - Case of Axillary Aneurism, successfully treated by Tying the Subclavian Artery. PMID- 20895579 TI - History of a Case in which, on Examination after Death, the Pancreas was found in a state of Active Inflammation. PMID- 20895580 TI - Pathological and Practical Researches on Uterine Inflammation in Puerperal Women. PMID- 20895581 TI - Observations on Tumours, with Cases. PMID- 20895582 TI - History of the Case of a Man whose Spine was Fractured, with the Dissection. PMID- 20895583 TI - Account of some Experiments on the Use of Styptics in Haemorrhage from Arteries. PMID- 20895584 TI - On some Effects of Inflammation of the Membranous Lining of the Larynx; with Suggestions relative to the Operation of Bronchotomy; and Incidental Remarks on Spasm and Wounds of the Throat. PMID- 20895586 TI - An Account of some Cases of Chronic Abscess of the Tibia. PMID- 20895585 TI - Case of Extensive Ovarian Disease, complicated with Pregnancy. PMID- 20895587 TI - An Experimental Investigation of the Effects of Loss of Blood. PMID- 20895588 TI - Observations on the Local Diseases termed Malignant. Being a Sequel to the Paper Published in Vol. XV. of the Society's Transactions. PMID- 20895589 TI - On the Phenomena and Appearances from Partial Obstruction in the Cerebral Circulation. PMID- 20895590 TI - Of a Peculiarity in the Conformation of the Skeleton in Rickets. PMID- 20895592 TI - Case in which a Cyst containing Hydatids was found in the Substance of the Heart. PMID- 20895591 TI - A Description of the Appearances observed in a Case of Double Uterus in which Impregnation had taken place, with Remarks on the Structure and Formation of the Membranes of the Human Ovum. PMID- 20895593 TI - Some Account of a Case in which the Left Femur and the Fifth Rib on the Right Side were Fractured in consequence of Disease, the Bladder being at the same time in the State of Carcinomatous Ulceration, with Observations. PMID- 20895594 TI - Explanation of the Plates. PMID- 20895595 TI - History and Dissection of a Case in which there had been Dislocation of the Ankle with Fracture of the Fibula. PMID- 20895597 TI - On some Morbid Appearances of the Absorbent Glands and Spleen. PMID- 20895596 TI - Case of Polypus of the Uterus. PMID- 20895599 TI - Case of Aqueous Encysted Tumour of the Kidney, with a Supernumerary Gland attached to it. PMID- 20895598 TI - Cases and Observations connected with Disease of the Pancreas and Duodenum. PMID- 20895600 TI - An Account of Two Cases of Deep Seated Naevus, or Vascular Tumour of Large Size, treated by the Introduction of Setons. PMID- 20895601 TI - Additional Facts respecting Glanders in the Human Subject. PMID- 20895602 TI - On the Ulcerative Process in Joints. PMID- 20895603 TI - History of a Case of Medullary Sarcoma, which affected several important Viscera, with a Description of the Morbid Appearances which were observed on Dissection. PMID- 20895604 TI - Case of Bony Union of a Fracture of the Neck of the Femur within the Capsule, occurring in a Young Subject. PMID- 20895605 TI - On Irritation of the Spinal Cord and its Nerves, in connection with Disease in the Kidneys. PMID- 20895606 TI - On Malignant Tumours connected with the Heart and Lungs. PMID- 20895607 TI - Case of Jaundice with discharge of Fatty Matter from the Bowels, and a contracted State of the Duodenum. PMID- 20895608 TI - On the Discharge of Fatty Matters from the Alimentary Canal and Urinary Passages. PMID- 20895609 TI - Case of OEsophagotomy, with Remarks. PMID- 20895610 TI - Cases of Sloughing Abscess connected with the Liver, with some Remarks on Encysted Tumours of that Organ. PMID- 20895611 TI - Cases of Fracture of the Neck of the Femur; with the Appearances Observed after Death. PMID- 20895612 TI - Further Remarks on the Ulcerative Process. PMID- 20895613 TI - Some Remarks on Mal-formation of the Internal Ear; being the result of post mortem investigations performed in five cases of Congenital Deafness. PMID- 20895614 TI - Examination of the Organs of Hearing from the body of a boy, aged 13 years, who had been the subject of Congenital Deafness. PMID- 20895615 TI - A Relation of some Cases of Mental Derangement, successfully treated by the Acetate of Morphia. PMID- 20895616 TI - Cases and Observations illustrative of Diagnosis when Adhesions have taken place in the Peritoneum, with Remarks upon some other Morbid Changes of that Membrane. PMID- 20895617 TI - Cases of Warty Tumours in Cicatrices. PMID- 20895618 TI - On the Medicinal Properties of Creosote. PMID- 20895619 TI - On the Functions of the Foetal Kidney. PMID- 20895620 TI - Observations on Fractures of the Bones of the Pelvis. PMID- 20895621 TI - On Serous Effusion from the Membranes, and into the Ventricles of the Brain, and its connection with Apoplexy and other diseases of the Brain. PMID- 20895622 TI - On Hypertrophy and Atrophy of the Brain. PMID- 20895623 TI - A Case of Abdominal Tumour, with the Appearances on Dissection. PMID- 20895624 TI - On the Cure of Ramollissement of the Brain. PMID- 20895626 TI - Case of Pulmonary Phlebitis. PMID- 20895625 TI - Explanation of the Plates. PMID- 20895627 TI - Observations on Ulceration of the Cartilages of Joints, and on Anchylosis. PMID- 20895628 TI - A Case of sudden Illness in advanced Pregnancy, terminating in the delivery of Twins and Death; with an account of a singular Laceration of the Peritoneal Coat of the Uterus. PMID- 20895629 TI - On the Chemical Constitution of Calcareous Tumours of the Uterus, and other parts. PMID- 20895631 TI - Petition to his Majesty. PMID- 20895630 TI - Observations on Fibro-Calcareous Tumours and Polypi of the Uterus. PMID- 20895632 TI - Observations on Vascular Appearances of Mucous and Serous Membranes, as indicative of Inflammation. PMID- 20895634 TI - Pathological and Surgical Observations relating to Injuries of the Spinal Chord. PMID- 20895633 TI - A Case of unusual Dislocation of the Thigh-Bone, with Observations. PMID- 20895636 TI - Of Inflammation, Chronic Disease, and Perforative Ulceration of the Caecum, and of the Appendix Vermiformis caeci, with Symptomatic Peritonitis and Faecal Abscess. PMID- 20895635 TI - Observations on some Tumours of the Mouth and Jaws. PMID- 20895637 TI - On Black Expectoration, and the Deposition of Black Matter in the Lungs, particularly as occurring in Coal miners, &c. PMID- 20895638 TI - Sequel of the History of a Case in which the External Iliac Artery was Tied; with an account of the Condition of the Blood-vessels in the Limb after Death. PMID- 20895639 TI - Researches on some Points of the Pathology of Pulmonary Tubercles. PMID- 20895640 TI - History of a remarkable Case of Varicose Aneurism, with Observations. PMID- 20895642 TI - A brief account of the Subsequent Medical History of Mary Wren, whose case is detailed in the thirteenth volume of the Society's Transactions. PMID- 20895641 TI - Observations on some of the Forms of Atrophy of Bone. PMID- 20895644 TI - Explanation of the Plates. PMID- 20895643 TI - Case of Removal of a Portion of Lung which protruded through a Wound, &c. PMID- 20895645 TI - Case of Recovery from the Insensibility of Intoxication, by the performance of Tracheotomy. PMID- 20895647 TI - Account of a case of Fracture and Displacement of the Atlas. PMID- 20895646 TI - On the Treatment of Injuries received in Dissection. PMID- 20895648 TI - Some particulars of a Case in which the Patient was saved from the Destructive Influence of Opium, by Artificial Respiration. PMID- 20895649 TI - Remarks on two Forms of Atrophy of the Heart's Valves, which interfere with their Function: founded on a Series of Cases. PMID- 20895650 TI - On Necrosis; being an experimental inquiry into the agency ascribed to the absorbents, in the removal of the sequestrum. PMID- 20895651 TI - Nervous affections, peculiar to young women, causing contraction of the muscles of the extremities. PMID- 20895652 TI - Report of a case of secondary measles; with observations. PMID- 20895653 TI - Removal of the clavicle, with a tumour situated in that bone. PMID- 20895654 TI - Case of universal purulent deposition into the joints, with separation of the epiphyses, occurring as a sequel to small pox. PMID- 20895655 TI - Report of twenty cases of malignant cholera that occurred in the Seamen's Hospital Ship Dreadnought, in 1837. PMID- 20895656 TI - On aneurisms of the heart with cases. PMID- 20895657 TI - Note on the comparative prevalence of calculous diseases, &c. PMID- 20895658 TI - Observations on the constitution of the urine. PMID- 20895659 TI - History of a female who has four mammae and nipples. PMID- 20895660 TI - Results of poisoning by sulphuric acid. PMID- 20895661 TI - On the use of arsenic in some affections of the uterus. PMID- 20895662 TI - Description of a new instrument for closing vesico-vaginal and recto-vaginal fistulae, and fissures of the soft palate. PMID- 20895663 TI - Case of excision of the entire lower jaw, with observations. PMID- 20895665 TI - History of a case of popliteal aneurism, with observations. PMID- 20895664 TI - On increased thickness of the parietes of one of the ventricles of the heart with diminution of its cavity. PMID- 20895666 TI - Facts and inferences relative to the condition of the vital organs and viscera in general, as to their nutrition in certain chronic diseases. PMID- 20895667 TI - Case of hydatid cyst of the liver successfully tapped. PMID- 20895668 TI - On black expectoration and the deposition of black matter in the lungs, &c. Part II: Particularly as Occurring in Coal Miners and Moulders in Iron Works. PMID- 20895669 TI - Account of a case of enormous ventral aneurism, with Dissection: Post Mortem Appearances. PMID- 20895671 TI - On a successful plan of arresting the destruction of the transparent cornea from acute purulent inflammation of the conjunctiva. PMID- 20895670 TI - On the proportions of animal and earthy matter in the different bones of the human body. PMID- 20895672 TI - Explanation of the Plates. PMID- 20895673 TI - Remarks on malignant diseases of the skin of the face. PMID- 20895674 TI - On a peculiar symptom occurring in some cases of enlarged liver. PMID- 20895675 TI - Cases of spasmodic disease accompanying affections of the pericardium. PMID- 20895676 TI - Case of fracture of the coracoid process of the scapula, with partial dislocation of the humerus forwards, &c. PMID- 20895678 TI - Case of aneurismal tumour in the orbit, cured by tying the common carotid artery. PMID- 20895677 TI - Statistical account of cholera in the Seamen's Hospital, in 1832. PMID- 20895679 TI - On the softening of coagulated fibrine. PMID- 20895680 TI - Contributions to the pathology of the spinal cord. PMID- 20895681 TI - Memoirs on some principles of pathology in the nervous system. PMID- 20895682 TI - Case of malignant disease occupying one-half of the tongue, to which a ligature was applied from beneath the jaw. PMID- 20895683 TI - Case of enlargement from melanoid tumour of the prostate gland, in a child of five years of age. PMID- 20895684 TI - Case of congenital absence of the pericardium. PMID- 20895685 TI - On a peculiar form of congenital tumour of the neck. PMID- 20895686 TI - Cases of measles occurring oftener than once in the same individuals. PMID- 20895687 TI - Remarkable case of dry gangrene occurring in a child three years and seven months old. PMID- 20895688 TI - Statistical notices of one hundred and twenty cases of carcinoma uteri, with remarks. PMID- 20895689 TI - Case of a girl who voided from the urethra a number of entozootic worms, not hitherto described, with an account of the animals. PMID- 20895690 TI - Remarks on the acute form of anasarcous tumour of the scrotum. PMID- 20895691 TI - An account of a foetus of seven months, with its placenta partially adherent to a naevus occupying the scalp and dura mater. PMID- 20895692 TI - On the structure, physiology, and pathology of the persistent capsular investments and pulp of the tooth. PMID- 20895693 TI - On the structure of the corpus luteum. PMID- 20895694 TI - Memoir on tuphlo-enteritis; or inflammation and perforative ulceration of the caecum, and of the appendix vermiformis caeci. PMID- 20895695 TI - Explanation of the Plates. PMID- 20895696 TI - Case of carditis. PMID- 20895697 TI - Notices of the effects of lead upon the system. PMID- 20895699 TI - Case of strangulated hernia, in which the bowel was ruptured by the patient in his efforts to reduce it. PMID- 20895698 TI - Notices of the occurrences at the Small-Pox Hospital, London, during the year 1838. PMID- 20895700 TI - History of a case in which the operation of tracheotomy was performed, with observations. PMID- 20895702 TI - Third Memoir on same principles of pathology of the nervous system. PMID- 20895701 TI - Second Memoir on some principles of the pathology of the nervous system. PMID- 20895704 TI - Case of large osseous tumour of the uterus. PMID- 20895703 TI - On the presence of sulphur in cystic oxyde, and an account of a cystic oxyde calculus. PMID- 20895705 TI - Observations on the blood-corpuscles and pus-globules in certain animals. PMID- 20895706 TI - On the rapid organization of lymph in cachexia. PMID- 20895708 TI - On the structure of the human placenta, and its connexion with the uterus. PMID- 20895707 TI - A case of recovery from cut throat, in which both the larynx and pharynx were extensively opened. PMID- 20895709 TI - Termination of the case of William Chandler, afflicted with dry gangrene, of which an account was published in the twenty-second volume of the Transactions. PMID- 20895710 TI - Observations on injuries of joints, and their treatment. PMID- 20895712 TI - On aneurisms, and especially spontaneous varicose aneurisms of the ascending aorta, and sinuses of Valsalva, with cases. PMID- 20895711 TI - On white spots on the surface of the heart, and on the frequency of pericarditis. PMID- 20895713 TI - Remarks on emphysema of the lungs. PMID- 20895714 TI - Case of a rare species of hydatid, the echinococcus hominis, found in the human liver. PMID- 20895715 TI - Observations on the mode of union of fractures of flat bones. PMID- 20895716 TI - Case of aneurism of the arteria innominata, in which the carotid and subclavian arteries were tied. PMID- 20895717 TI - Case of tumour in the pelvis, impeding parturition. PMID- 20895718 TI - Explanation of the Plates. PMID- 20895719 TI - On a remarkable effect on the human gums, produced by the absorption of lead. PMID- 20895720 TI - A case of disease in the posterior columns of the spinal cord. PMID- 20895721 TI - On the arrangement of the intermediate vessels on surfaces secreting pus, with a note regarding the vascularity of inter-articular cartilages. PMID- 20895722 TI - Remarks on the diagnosis of foreign bodies in the larynx. PMID- 20895723 TI - Observations on the structure of the entozoa belonging to the genus cysticercus. PMID- 20895724 TI - Case of osseous union of a fracture of the neck of the femur within the capsule. PMID- 20895725 TI - On dislocations, especially of the hip-joint, accompanied by elongation of the capsule and ligaments. PMID- 20895726 TI - Observations on the anatomy of the lungs. PMID- 20895727 TI - Observations on vaccination and small-pox, more especially with reference to the theory of vaccine influence, and the relations subsisting between the cicatrix and the character of the consecutive variola. PMID- 20895728 TI - Results of amputations at University College Hospital, London, statistically arranged. PMID- 20895729 TI - Colica pictonum treated with warm water. PMID- 20895731 TI - Pathological and Surgical Observations on the Diseases of the ear. PMID- 20895730 TI - Case of malposition of the kidneys, absence of the vagina, uterus, and Fallopian tubes; disease of left ovary. PMID- 20895732 TI - Two cases of dislocation of the tendon of the long head of the biceps humeri from its groove. PMID- 20895733 TI - An account of two cases of aneurism of the superior mesenteric artery, in one of which jaundice was induced by pressure of the sac. PMID- 20895734 TI - On congenital tumours of the pelvis. PMID- 20895735 TI - Explanation of the Plates. PMID- 20895736 TI - On gouty concretions, with a new method of treatment. PMID- 20895737 TI - History of a remarkable case of phlebitis, with observations. PMID- 20895738 TI - Cases of cancerous or malignant disease of the spinal column, with remarks. PMID- 20895739 TI - A case of slow pulse with fainting fits, which first came on two years after an injury of the neck from a fall, with observations. PMID- 20895740 TI - Fourth memoirs on some principles of pathology in the nervous system. PMID- 20895741 TI - Case of cyanosis, depending upon transposition of the aorta and pulmonary artery. PMID- 20895742 TI - On diseases which affect corresponding parts of the body in a symmetrical manner. PMID- 20895743 TI - Case of aneurism of the ascending aorta, bursting into the right ventricle; with a communication between the two ventricles. PMID- 20895744 TI - Notice of cases of plague contracted in the Lazeretto of Constantinople, in a letter addressed to Dr. Davy. PMID- 20895746 TI - Case of local tubercular deposit upon the surface of the brain. PMID- 20895745 TI - Observations on tubercle of the brain in children, with a tabular view of thirty cases of the affection. PMID- 20895747 TI - On the structure and functions of the human placenta. PMID- 20895749 TI - History of a remarkable case of tumours, developed on the head and face; accompanied with a similar disease in the abdomen. PMID- 20895748 TI - A case of stricture of the trachea. PMID- 20895750 TI - Account of a case of irregular formation of the heart, accompanied with a supernumerary valve in the pulmonary artery. PMID- 20895751 TI - Notes of a case of petechial cow-pox, with observations on the development of the haemorrhagic diathesis. PMID- 20895752 TI - On acute ulceration of the duodenum, in cases of burn. PMID- 20895754 TI - Observations on a particular form of encysted tumour, which occurs in the neck, but is not necessarily connected with the thyroid body. PMID- 20895753 TI - Cases of malformation of the heart. PMID- 20895755 TI - On the relation between the symmetry and the diseases of the body. PMID- 20895756 TI - Explanation of the Plates. PMID- 20895757 TI - An account of a case of extensive disease of the pancreas. PMID- 20895758 TI - Remarks on typhus fever. PMID- 20895759 TI - Cases of laryngitis, relieved by operation. PMID- 20895760 TI - Peculiar symptoms affecting an entire family, and terminating in death. PMID- 20895761 TI - A case of congenital cataract, where sight was acquired by operation, at the age of twenty-three years. PMID- 20895762 TI - Case of paralysis without loss of sensation, from disease of the cervical medulla. PMID- 20895763 TI - Remarks on the calculi in St. George's Hospital. PMID- 20895764 TI - Case of ulceration of the internal jugular vein communicating with an abscess. PMID- 20895765 TI - Some account of an hysterical affection of the vocal apparatus, with several cases. PMID- 20895766 TI - Case of erectile tumour in the popliteal space.-Removal. PMID- 20895767 TI - Two cases of osteosarcoma of the thigh bone, requiring amputation of the limb in both instances. PMID- 20895768 TI - Remarks on cancrum oris and the gangrenous erosion of the cheek of Mr. Dease and Dr. Underwood, and more particularly on the efficacy of the chlorate of potash in the treatment of those diseases. PMID- 20895769 TI - Case of ulceration of the pulmonary artery into an abscess of the lungs. PMID- 20895770 TI - Cases of strangulated hernia reduced "en masse," with observations. PMID- 20895771 TI - Observations on the medicinal properties of the Cannabis Sativa of India. PMID- 20895772 TI - Case of bronchial calculus, with observations on disease of the bronchial glands. PMID- 20895773 TI - On the sugar in diabetic blood. PMID- 20895775 TI - Some account of an epidemic which prevailed at Teheran, in the months of January and February 1842. PMID- 20895774 TI - A few observations on encysted hydrocele. PMID- 20895776 TI - On the nature of the ossification of encysted tumours. PMID- 20895777 TI - On the anatomical characters of some adventitious structures, being an attempt to point out the relation between the microscopic characters and those which are discernible by the naked eye. PMID- 20895778 TI - An account of a case in which a foreign body was lodged in the right bronchus. PMID- 20895779 TI - On congestive pneumonia consequent upon surgical operations, diseases, and injuries. PMID- 20895780 TI - Second series of observations on the pathology of the ear, based on one hundred and twenty dissections of that organ. PMID- 20895781 TI - On the effects of rickets upon the growth of the skull. PMID- 20895782 TI - On the presence of spermatozoa in the fluid of hydrocele. PMID- 20895783 TI - Statistics of Bethlem Hospital, with remarks on insanity. PMID- 20895784 TI - Explanation of the Plates. PMID- 20895786 TI - An account of an unusually large biliary calculus voided from the rectum. PMID- 20895785 TI - Researches into the connection existing between an unnatural degree of compression of the blood contained in the renal vessels, and the presence of certain abnormal matters in the urine. PMID- 20895788 TI - An account of two cases of rupture of the ureter, or pelvis of the kidney, from external violence, followed by large effusion of urine into the abdomen. PMID- 20895787 TI - On fatty degeneration of the arteries, with a note on some other fatty degenerations. PMID- 20895789 TI - On the state in which the uric acid exists in the urine. PMID- 20895791 TI - Account of a case of cysticercus cellulosae of the brain. PMID- 20895790 TI - Case of extensive carcinoma of the lungs; with some practical remarks. PMID- 20895792 TI - An account of certain cases of acute disease in the throat and larynx, one of which was cured by tracheotomy. PMID- 20895793 TI - On the presence of oxalate of lime in the urine. PMID- 20895794 TI - On obstructions of the branches of the pulmonary artery. PMID- 20895796 TI - On the composition of the meconium, and of the vernix caseosa, or lubricating matter of the new-born infant. PMID- 20895795 TI - On the cause of the occasional presence of spermatozoa in the fluid drawn from the sac of common hydrocele of the tunica vaginalis. PMID- 20895797 TI - On paracentesis thoracis as a curative measure in empyema and inflammatory hydrothorax. PMID- 20895798 TI - Cases of carcinoma of the thyroid gland. PMID- 20895799 TI - Account of a case of empyema, which recovered after repeated punctures of the pleural sac. PMID- 20895800 TI - Observations on the omental sacs which are sometimes found in strangulated herniae, completely enveloping the intestine; with cases and dissections: to which has been added, a table of all the strangulated herniae operated on at St. George's Hospital, in 1842-43. PMID- 20895802 TI - Case of aneurism of the external iliac, in which a ligature was applied to the common iliac artery. PMID- 20895801 TI - Account of a case of a dissecting aneurism of the aorta innominata, and right carotid arteries, giving rise to suppression of urine, and white softening of the brain. PMID- 20895803 TI - Two cases of tubular expectoration from the bronchi, in the adult. PMID- 20895804 TI - A tabular view of the seat of tubercle, in 180 cases of tubercle of the lungs in children; with remarks on pulmonary phthisis in the young subject. PMID- 20895805 TI - Case of tumour in the right hypochondrium, occurring after injury, from which a large quantity of fluid resembling bile was repeatedly withdrawn by the operation of tapping. PMID- 20895807 TI - An account of the examination of a cyst containing seminal fluid. PMID- 20895806 TI - Peculiar case of gelatiniform cancer, in which nearly all the organs of the body contained colloid tumours; with the appearances on dissection. PMID- 20895808 TI - Some statistical records of the progress of the Asiatic cholera over the globe. PMID- 20895809 TI - Alarming syncope, from the admission of air into a vein during an amputation at the shoulder-joint. PMID- 20895810 TI - Case of necrosis of the lower jaw, recovered from, without deformity. PMID- 20895811 TI - Remarks on the pathology of mollities ossium; with cases. PMID- 20895812 TI - Case of fistulous communication between the intestinum ileum, and urinary bladder, simulating stone in the bladder. PMID- 20895813 TI - Observations on the recorded cases of operations for the extraction of ovarian tumours. PMID- 20895814 TI - Explanation of the Plates. PMID- 20895815 TI - Account of a horn developed from the human skin; with observations on the pathology of certain disorders of the sebaceous glands. PMID- 20895816 TI - On the early organisation of coagula and mixed fibrinous effusions, under certain conditions of the system. PMID- 20895817 TI - Case of extirpation of an ovarian cyst, terminating fatally. PMID- 20895818 TI - Case of the removal of a diseased ovarium, terminating fatally on the seventh day after the operation. PMID- 20895819 TI - Case in which the vena cava inferior was obstructed from the commencement of the common iliac veins, and its cavity entirely obliterated between the entrance of the emulgent and hepatic veins. PMID- 20895820 TI - On the mortality in prisons, and the diseases most frequently fatal to prisoners. PMID- 20895821 TI - On the classification, structure and development of the echinococcus hominis, showing reasons for regarding it as a species of cysticercus. PMID- 20895822 TI - Observations on cleft palate, and on staphyloraphy. PMID- 20895823 TI - On the pulsating tumours of bone, with the account of a case in which a ligature was placed around the common iliac artery. PMID- 20895824 TI - Description of a malformation of the duodenum, with notices of analogous cases. PMID- 20895825 TI - Case of remarkable hypertrophy of the fingers in a girl, with a notice of some similar cases. PMID- 20895826 TI - On the ophthalmia of puerperal women. PMID- 20895827 TI - Additional observations on obstructions of the pulmonary arteries. PMID- 20895828 TI - Two cases of anaesthesia and loss of motory function of the fifth nerve. PMID- 20895829 TI - A case of aneurism of the popliteal artery, cured by compression of the femoral artery. PMID- 20895830 TI - Account of a case of external and internal cephalhaematoma, complicated with fracture of the right parietal bone, in a new-born infant. PMID- 20895831 TI - Large opening into the anterior part of the urethra, caused by sloughing, and attended by considerable loss of structure, successfully treated by operation; with remarks. PMID- 20895832 TI - The pathology of mental diseases. PMID- 20895833 TI - On extravasations of blood into the cavity of the arachnoid, and on the formation of the false membrane which sometimes envelops these extravasations. PMID- 20895834 TI - On some of the causes of pericarditis, especially acute rheumatism, and Bright's disease of the kidneys, with incidental observations on the frequency, and on some of the causes of various other internal inflammations. PMID- 20895835 TI - Case of excision of the upper end of the femur, in an example of morbus coxarius. PMID- 20895836 TI - On the minute structure of the lungs, and on the formation of pulmonary tubercle. PMID- 20895837 TI - Two cases of aneurism, in which there was neither pulsation nor abnormal sound. PMID- 20895839 TI - Explanation of the Plates. PMID- 20895840 TI - On the colostrum of the cow. PMID- 20895838 TI - An account of a singular case, in which there was a black secretion from the skin of the forehead and upper part of the face. PMID- 20895841 TI - Case of obstruction of the large intestine, in which the ascending colon was opened with success; the patient dying three months afterwards of another disease. PMID- 20895842 TI - On the minute anatomy and pathology of Bright's disease of the kidney, and on the relation of the renal disease to those diseases of the liver, heart, and arteries, with which it is commonly associated. PMID- 20895843 TI - An account of a case of partial double monstrosity (ischiopage symelien of Geoffroy Saint-Hilaire, heteradelphia of Vrolik). PMID- 20895845 TI - A case in which a large tumour was developed in the substance of the fifth nerve and its ganglion. PMID- 20895844 TI - Some remarks on wounded arteries, secondary haemorrhage, and false aneurisms. PMID- 20895846 TI - On the capacity of the lungs, and on the respiratory functions, with a view of establishing a precise and easy method of detecting disease by the spirometer. PMID- 20895847 TI - History of a case of ligature of the left subclavian artery, between the scaleni muscles, attended with some peculiar circumstances. PMID- 20895848 TI - Hydatid cyst, either originating in, or pressing upon, the prostate gland. PMID- 20895849 TI - Cases of varicocele treated by pressure, with observations. PMID- 20895851 TI - On a particular derangement of the structure of the spleen. PMID- 20895850 TI - Account of a case of congenital deficiency of one kidney, with granular degeneration of the existing one. PMID- 20895852 TI - On a luminous appearance of the human eye, and its application to the detection of disease of the retina and posterior part of the eye. PMID- 20895853 TI - Account of a case in which an abscess in the neck communicated by an ulcerated opening with the arch of the aorta, and in which the haemorrhage did not prove fatal in less than forty-eight hours. PMID- 20895854 TI - On the intimate structure of the human kidney, and on the changes which its several component parts undergo in "Bright's disease". PMID- 20895855 TI - On the relation between the constituents of the food and the systems of animals. PMID- 20895856 TI - Two cases of disease of the brain, following the application of a ligature to the carotid artery. PMID- 20895857 TI - Case of punctured wound and ligature of the posterior tibial artery, in the upper third of its course. PMID- 20895859 TI - Case of aneurism, presenting some peculiarities, with remarks. PMID- 20895858 TI - An account of a case in which the corpus callosum, fornix, and septum lucidum, were imperfectly formed. PMID- 20895861 TI - On the ganglionic character of the arachnoid membrane of the brain and spinal marrow. PMID- 20895860 TI - Case of cyanosis of forty years' standing, depending upon congenital obstruction in the pulmonary artery, and patulous foramen ovale. PMID- 20895862 TI - Two remarkable cases of encephaloid disease of the heart, with observations. PMID- 20895863 TI - Case of enlargement of the left mamma: To which is added, an anatomical and pathological description of the tumour. PMID- 20895864 TI - Case of cyanosis, with a description of the appearances presented on dissection, illustrated by the preparation, and a drawing, of the heart. PMID- 20895865 TI - Observations on the co-existence of variola and scarlatina, with remarks on the co-existence of other eruptive fevers. PMID- 20895866 TI - Case of malformation of the heart, in which death resulted from obstruction in the trunk of the pulmonary artery. PMID- 20895867 TI - On sub-acute inflammation of the kidney. PMID- 20895868 TI - Penetrating wound of the neck, accompanied by profuse arterial haemorrhage, treated successfully by ligature of the common carotid artery. PMID- 20895870 TI - An account of the structure of a naevus. PMID- 20895869 TI - On the inflammatory diseases of the kidney. PMID- 20895871 TI - A case in which a large pouch was formed in the oesophagus, in connection with contraction of the canal. PMID- 20895872 TI - On the contractility or irritability of the muscles of paralysed limbs, and their excitability by the galvanic current, in comparison with the corresponding muscles of healthy limbs. PMID- 20895873 TI - Some instances of the contrast between delirium tremens and inflammation of the brain, as regards the quantity of phosphoric acid excreted by the kidneys. PMID- 20895875 TI - Note by Editor. PMID- 20895874 TI - Fatal case of dysphagia, produced by a polypous growth in the oesophagus. PMID- 20895876 TI - An account of a case of encephaloid disease of the endocardium. PMID- 20895878 TI - Case of elephantiasis. PMID- 20895877 TI - Case of internal strangulation of intestine relieved by operation. PMID- 20895879 TI - On tubercular pericarditis, with pathological and practical remarks. PMID- 20895880 TI - Case of tumour in the groin, where the testicle had not descended, and operation for its removal. PMID- 20895881 TI - Successful removal of an ovarian tumour, complicated with pregnancy. PMID- 20895882 TI - Observations on intestinal obstructions, depending on internal causes; and on the means to be employed for their relief. PMID- 20895883 TI - A case of very extensive gelatiniform cancer of the peritoneum, involving the lymphatic glands of the abdomen and the ovaries, and simulating ascites. PMID- 20895884 TI - Cases of ununited fracture, successfully treated. PMID- 20895885 TI - On the irritability of the muscular fibre in paralytic lymbs. PMID- 20895886 TI - Case of extra uterine foetation. PMID- 20895888 TI - Remarks on unnatural descent of the womb, with a proposed new instrument for its alleviation. PMID- 20895887 TI - Observations on some peculiarities of polypus of the uterus. PMID- 20895889 TI - Contributions to the statistics of valvular disease of the heart; with especial reference to affections of the several orifices, and the particular effects of certain recognised causes. PMID- 20895890 TI - On the anatomy and physiology of the cysticercus tenuicollis. PMID- 20895891 TI - Description of the dissection of a brain, in which the corpus callosum, fornix and septum lucidum were imperfectly developed. PMID- 20895892 TI - Report of a case in which gastrotomy was performed for the relief of obstruction of the bowels. PMID- 20895893 TI - Cases illustrative of some consequences of local injury. PMID- 20895894 TI - Account of a dislocation, in consequence of disease of the first and second cervical vertebrae. PMID- 20895895 TI - On the minute anatomy of the emphysematous lung. PMID- 20895896 TI - On the utility of trisnitrate of bismuth, in the diarrhoea accompanying phthisis. PMID- 20895897 TI - Case of resection of the scapula. PMID- 20895899 TI - Case of obturator hernia, simulating intestinal obstruction within the abdomen; to relieve which gastrotomy was performed. PMID- 20895898 TI - Case of a patient in whom a foreign body had been introduced into the pelvis through the vagina, and a description of a successful operation for its removal. PMID- 20895900 TI - The history of a case of dislocation of the head of the femur, backwards, with some observations on that form of dislocation. PMID- 20895901 TI - On the movements of respiration in disease, and on the use of a chest-measurer. PMID- 20895902 TI - Case of malignant tumour of the os uteri, excised during labour. PMID- 20895903 TI - Case of extensive laceration of the liver, with rupture of the gall-bladder, and other lesions, caused by external violence; terminating fatally on the ninth day; with remarks. PMID- 20895905 TI - Note in reference to a case of malformation of the heart. PMID- 20895904 TI - Case of laryngitis, accompanied by the formation of a false membrane in the trachea and bronchi, in which the operation of tracheotomy was performed. PMID- 20895906 TI - Case of destructive ophthalmia, with extensive suppuration of the cellular membrane, and severe affection of the knee-joint, occurring after premature delivery. PMID- 20895907 TI - Two cases in which the skin, hair and teeth were very imperfectly developed. PMID- 20895908 TI - Observations on certain pathological conditions of the blood and urine, in gout, rheumatism, and Bright's disease. PMID- 20895909 TI - On Petit's operation for the relief of strangulated hernia. PMID- 20895910 TI - On the Employment of Nitrate of Potash in Acute Rheumatism, with Suggestions for the Use of Saline Solutions as external Applications in Local Rheumatic Inflammation. PMID- 20895911 TI - A Case of Apoplexy of the Cerebellum. PMID- 20895913 TI - A Case of Hemiplegia, associated with great Hypertrophy of the Heart, and terminating by Rupture of the Aorta, producing Dissecting Aneurism. PMID- 20895912 TI - Remarks on the Causes and Morbid Anatomy of Mental Diseases. PMID- 20895914 TI - Case of Popliteal Aneurism, in which the Femoral Artery was tied after the Sac had burst. PMID- 20895915 TI - Case of Chronic Hiccup and Vomiting: Discovery of Oxalic Acid in the Blood. PMID- 20895916 TI - Note by the Editor. PMID- 20895918 TI - Case of Cysticercus Cellulosae, in the Anterior Chamber of the Human Eye. PMID- 20895917 TI - On the Causes of the Endemic Puerperal Fever of Vienna. PMID- 20895919 TI - On the Minute Anatomy of the Lung of the Bird, considered chiefly in Relation to the Structures with which the Air is in contact whilst traversing the ultimate Subdivisions of the Air-passages. PMID- 20895920 TI - An Extraordinary Case of Laesion within the Uterus, with partial Reparation before Birth. PMID- 20895921 TI - Appendix to a Case of "Successful Removal of an Ovarian Tumour, complicated with Pregnancy". PMID- 20895923 TI - Pathological Researches into the Diseases of the Ear. PMID- 20895922 TI - Case of Exfoliation of the Anterior Arch of the Atlas. PMID- 20895924 TI - Case of a foreign body impacted in the orifice of the third branch of the right Bronchus: with remarks. PMID- 20895925 TI - On the proximate cause of albuminous urine and dropsy, and on the pathology of the renal blood-vessels in Bright's Disease. PMID- 20895926 TI - On fatty diseases of the Heart. PMID- 20895927 TI - On Section of the Tendo Achillis in some cases of fracture of the bones of the leg. PMID- 20895928 TI - A Case of Gunshot wound, and subsequent extraction of a bullet from the bladder. PMID- 20895929 TI - A case of scrofulous abscess of the Anterior Mediastinum, communicating with both sides of the chest, the pericardium, and trachea; forming a tumour above the clavicle, and simulating aneurism of the Inominata artery or arch of the Aorta. With Observations. PMID- 20895930 TI - Case of Mollities and Fragilitas Ossium, accompanied with urine strongly charged with animal matter. PMID- 20895931 TI - On the Identity or Non-identity of the specific cause of Typhoid, Typhus, and Relapsing Fever. PMID- 20895932 TI - Case of very large Haematocele of the spermatic cord, proving fatal after Ten Years: To which is added, a Case of very large Haematocele of the tunica vaginalis, in an old Man, terminating fatally. PMID- 20895933 TI - Case of disarticulation of the left Condyle of the lower jaw, with excision of nearly the left half of the bone, on account of a very large cartilaginous tumour growing from, and occupying the site of all this part of the bone, save the condyle and neck. PMID- 20895934 TI - On excision of the Os Calcis, in incurable disease of that bone, as a substitute for amputation of the foot. With a case. PMID- 20895935 TI - A Case of Stricture of the Rectum, wherein an artificial anus was successfully established in the left lumbar region. PMID- 20895937 TI - Supplement to a paper on Fibro-Calcareous tumours, and Polypi of the uterus. Published in Volume XIX of the Medico-Chirurgical Transactions. PMID- 20895936 TI - On the use of the Speculum in the diagnosis and treatment of uterine diseases. PMID- 20895938 TI - Case of fatal poisoning by Sir William Burnett's fluid. PMID- 20895939 TI - Case in which the Urachus remained open, and a ring-shaped calculus, formed upon a hair in the bladder, was extracted through the umbilicus. PMID- 20895940 TI - Case of Ileus complicated by Hernia. PMID- 20895941 TI - Two Cases of absence of the Thyroid body, and symmetrical swellings of fat tissue at the sides of the neck, connected with defective cerebral development. PMID- 20895943 TI - On a Case of albuminous and fatty urine. PMID- 20895942 TI - Account of a case in which an Abscess formed in the Vesicula Seminalis, and proved fatal by perforation of the bladder and extravasation of pus into the abdominal cavity. PMID- 20895945 TI - A Case of complete intestinal obstruction, arising from disease of the Sigmoid Flexure, of the Colon and the Rectum; in which the descending colon was successfully opened in the loin. PMID- 20895944 TI - Observations on the prolonged expiratory murmur, as a sign of Incipient phthisis. PMID- 20895946 TI - A Case of complete intestinal obstruction, arising from disease of the Sigmoid Flexure of the Colon and the Rectum; in which the descending colon was successfully opened in the loin. PMID- 20895947 TI - Chemical researches on the nature and cause of Cholera. PMID- 20895948 TI - Case of Stricture of the OEsophagus, fatal, two years and three months after accidentally swallowing soap-lees. PMID- 20895949 TI - History of a successful case of Ovariotomy: With a Description of the Morbid Anatomy of the Sac. PMID- 20895950 TI - An Analysis of 108 Cases of Ovariotomy, which have occurred in Great Britain, with Appendix. PMID- 20895951 TI - Case of Extensive Necrosis of the Bones of the Cranium and removal of large portions thereof. PMID- 20895952 TI - An account of a Case of Fracture and Distortion of the Pelvis, combined with an unusual form of Dislocation of the Femur. PMID- 20895953 TI - Experiments on Chylous or Chylo-Serous Urine: With a History of the Patient. PMID- 20895954 TI - Cases illustrating some Difficulties in the Diagnosis of Pleuritic Effusion. PMID- 20895955 TI - Case of Popliteal Aneurism treated by Compression, with some Remarks upon this method of treating Aneurism, and a List of the Cases in which it has been employed in Dublin. PMID- 20895957 TI - On the Relation of Sleep to Convulsive Affections. PMID- 20895956 TI - Account of the Dissection of a case in which Two Popliteal Aneurisms had been treated by Compression of the Femoral Arteries. PMID- 20895958 TI - On Fatty Degeneration of the Placenta, and the Influence of this Disease in producing Abortion, Death of the Foetus, Haemorrhage, and Premature Labour. PMID- 20895959 TI - On some Secondary Physiological Effects produced by Atmospheric Electricity. PMID- 20895960 TI - On the Employment of the Heat of Electricity in Practical Surgery. PMID- 20895961 TI - A Case of Strangulated Obturator or Thyroideal Hernia, successfully relieved by Operation. PMID- 20895962 TI - Some Observations on the Pathology of those Affections of the Ear which produce Disease in the Brain. PMID- 20895963 TI - A Case of Obstruction of the Colon, relieved by an Operation performed at the Groin. PMID- 20895965 TI - Account of a case in which a Large Cyst containing Hydatids was developed at the Root of the Neck, death ensuing from Rupture of the Left Subclavian Artery. PMID- 20895964 TI - On the Variations of the Sulphates and Phosphates excreted in Acute Chorea, Delirium Tremens, and Inflammation of the Brain. PMID- 20895966 TI - A Case of Aneurismal Dilatation of the Posterior Tibial Vein, communicating indirectly with the Upper Part of the Popliteal Artery. PMID- 20895967 TI - On a New Method of Treatment applicable to certain Cases of Epiphora. PMID- 20895968 TI - A Case of Softening of the Spinal Marrow in a boy affected with Chorea. PMID- 20895969 TI - Case illustrating the difficulties of Diagnosis of Morbid Growths from the Upper Jaw: with Remarks. PMID- 20895970 TI - Cases of Rupture of the Liver or Spleen: with Remarks. PMID- 20895971 TI - Account of a case in which the Caesarean Section was performed; with Remarks on the peculiar sources of Danger attendant on the Operation. PMID- 20895975 TI - Statistical Report upon Cases of Disease of the Heart occurring in St. George's Hospital, especially in relation to rheumatism and albuminuria. PMID- 20895972 TI - A Case of Caesarean Section. PMID- 20895976 TI - Case of Inversion of the Uterus after Parturition, proving fatal in eighteen months, with a tabular statement of the results of cases treated by operation. PMID- 20895977 TI - On the Deposition of Fibrin on the Lining Membrane of Veins. PMID- 20895978 TI - On the Occasional Organic Union of Contiguous Teeth. PMID- 20895979 TI - An Account of Two Cases of Intestinal Obstruction, in which the operation for the formation of an artificial anus was performed; one in the ascending, the other in the descending colon. PMID- 20895980 TI - A Case of Intestinal Obstruction from Disease of the Rectum, treated successfully by opening the descending colon in the left loin. PMID- 20895981 TI - A Case of Intestinal Obstruction. PMID- 20895983 TI - On some of the principal effects resulting from the Detachment of Fibrinous Deposits from the interior of the heart, and their mixture with the circulating blood. PMID- 20895982 TI - Some Observations on the Effects of Cholagogue Medicines, and some remarks on Morbid Changes in the Liver. PMID- 20895984 TI - On the Diminution of the Chlorides in the Urine, or their absence from that fluid in cases of pneumonia; and on the chemical composition of the sputa in that disease. PMID- 20895985 TI - Case in which a communication appears to have existed for several months between the Stomach and Transverse Colon in a child five years old. PMID- 20895986 TI - A Memoir on the Pathology and Treatment of Leucorrhoea, based upon the Microscopical Anatomy of the Os and Cervix Uteri. PMID- 20895987 TI - On the Protection against Smallpox afforded by Vaccination, illustrated by the returns of the Army, the Navy, and the Royal Military Asylum. PMID- 20895988 TI - On Alkalescence of the Urine from fixed Alkali in some cases of disease of the Stomach. PMID- 20895989 TI - A Case of Haemorrhage from Inversion of the Uterus in which the Operation of Transfusion was successfully performed, with remarks on the employment of transfusion generally. PMID- 20895990 TI - An Analysis of One Hundred Cases of Cancerous Disease of the Uterus. PMID- 20895991 TI - An account of a Case of Pulsating Tumour in which the urine contained Cancer Cells. PMID- 20895992 TI - An account of a Case of Biliary Fistula. PMID- 20895993 TI - Supplemental Note. PMID- 20895994 TI - A Case of Constipation of nine days' duration from Scirrhous Rectum, relieved by opening the sigmoid flexure of the colon in the left groin. PMID- 20895995 TI - Remarkable Case of Foreign Bodies in the Stomach and Duodenum, complete obstruction of the bowel, and mechanical displacement of organs. PMID- 20895997 TI - On Granular and Fatty Degeneration of the Voluntary Muscles. PMID- 20895996 TI - A successful Case of Parturition in a patient who had previously undergone "Ovariotomy" by a "large incision". PMID- 20895998 TI - Case of Stricture of the Colon, successfully treated by operation, with an analysis of forty-four cases of Artificial Anus. PMID- 20895999 TI - A Comparative View of some of the more important points of the Pathology of Rheumatic and Non-Rheumatic Pericarditis, deduced from an Analysis of Cases. PMID- 20896000 TI - Hypertrophy and Prolapse of the Tongue. PMID- 20896002 TI - Case of Hypertrophy of the Tongue. PMID- 20896001 TI - Hypertrophy of the Tongue, being the account of a Case of that Disease, which was successfully treated by Ligature. PMID- 20896003 TI - Case of Popliteal Aneurism, cured by Compression of the Femoral Artery in the upper third of its course, the patient dying five months after of Aneurism of the Abdominal Aorta, with an Account of the Dissection of the affected Limb. PMID- 20896004 TI - A further Account of Fatty Degeneration of the Placenta, and the influence of this Disease in producing Death of the Foetus, Haemorrhage, and Abortion. PMID- 20896005 TI - Researches on the Pathology of Obstructive Phlebitis, and the Nature and Proximate Cause of Phlegmasia Dolens. PMID- 20896006 TI - On the Development of Torulae in the Urine, and on the relation of these Fungi to Albuminous and Saccharine Urine. PMID- 20896007 TI - On some points of the Pathology and Treatment of Yellow Fever. PMID- 20896008 TI - On the Treatment of Obstinate Strictures of the Urethra by External Incision upon a grooved Director. PMID- 20896009 TI - Further Researches on the Pathology of Phlegmasia Dolens. PMID- 20896010 TI - On the use of Two Needles at once in certain Operations on the Eye, especially in those for Capsular Cataract and Artificial Pupil. PMID- 20896011 TI - Analysis of the Cases of Injuries of the Head, examined after death in St. George's Hospital, from January, 1841, to January, 1851, with Pathological and Surgical Observations. PMID- 20896013 TI - On Small Pox and Vaccination: Analytical Examination of all the Cases admitted during sixteen years, at the Small Pox and Vaccination Hospital, London; with a view to illustrate the Pathology of Small Pox, and the protective influence of Vaccination, in degrees varying according as the Vaccination has been perfectly or imperfectly performed. PMID- 20896012 TI - A case of Perforating Ulcer of the OEsophagus, which caused Death by penetrating the Aorta. PMID- 20896014 TI - Observations on the State of the Blood and the Blood-Vessels in Inflammation. PMID- 20896015 TI - On Intermitting Diabetes, and on the Diabetes of Old Age. PMID- 20896016 TI - An Account of a Dissection of an Ovarian Cyst which contained Brain. PMID- 20896017 TI - An Account of an instance of remarkable Deformity of the Lower Limbs. PMID- 20896018 TI - Observations on Cystic Disease of the Testicle. PMID- 20896019 TI - Additional Experiments on the Excitability of Paralysed and Healthy Limbs by the Galvanic Current. PMID- 20896020 TI - Sequel to a Case of Albuminous and Fatty Urine, published in the 'Medico Chirurgical Transactions' for 1850, with some Account of two other Cases of so called Chylous Urine. PMID- 20896021 TI - On Degeneration of the Placenta at the end of Pregnancy. PMID- 20896022 TI - Scrofulous Caries of the Left Astralagus. Excision-cure, with formation of a Fresh Joint. PMID- 20896023 TI - Notice of a Case of Skin Disease, accompanied with partial Hypertrophy of the Mammary Gland. PMID- 20896024 TI - A Case of Fatal Asphyxia, caused by the detachment of a diseased Bronchial Gland which was impacted in the Larynx. PMID- 20896025 TI - Remarks on a peculiar form of Tumour of the Skin, denominated "Pachydermatocele," illustrated by Cases. PMID- 20896026 TI - Case of Distortion of the Spine, with observations on Rotation of the Vertebrae as a complication of Lateral Curvature. PMID- 20896027 TI - On Gout and Rheumatism. The differential Diagnosis, and the Nature of the so called Rheumatic Gout. PMID- 20896028 TI - Case of Mollities Ossium, preceded by Degeneration of the Muscles. PMID- 20896030 TI - English Statistics of Hooping-Cough. PMID- 20896029 TI - Case of Traumatic Aneurism of the Ophthalmic Artery, consequent on Injury of the Head, cured by Ligature of the common Carotid Artery. PMID- 20896031 TI - On the Keloid of Alibert, and on True Keloid. PMID- 20896032 TI - On the Blood and Effused Fluids in Gout, Rheumatism, and Bright's Disease. PMID- 20896033 TI - On Excision of the Knee-Joint. PMID- 20896034 TI - Pathological Remarks on the kind of Palpebral Tumour usually called, in England, Tarsal Tumour. PMID- 20896035 TI - On the Radical Cure of Reducible Inguinal Hernia, by a New Operation, with Cases and Remarks. PMID- 20896036 TI - Observations of Morbid Changes in the Mucous Membrane of the Stomach. PMID- 20896037 TI - Pathological Researches into the Diseases of the Ear; Fifth and Sixth Series. PMID- 20896038 TI - On the Relations of the Mortality from Cholera in London to the General Mortality and Temperature. PMID- 20896039 TI - On a Successful Method of Treating Acute Rheumatism by Large and Frequent Doses of Bicarbonate of Potash. PMID- 20896040 TI - Cases of Phlebitis with Pneumonia and Pleurisy from Chronic Disease of the Ear. PMID- 20896041 TI - Notes on Lithotrity, with an Account of the Results of the Operation in the Author's Practice. PMID- 20896042 TI - Observations respecting Degeneration of the Pancreas. PMID- 20896043 TI - Sequel of a Case of Extirpation of the Uterus. PMID- 20896044 TI - Cases of Disease of the Larynx, and some Observations on the Operation of Tracheotomy. PMID- 20896045 TI - Researches on Gout. PMID- 20896046 TI - Account of a Growth of Cartilage in a Testicle and its Lymphatics, and in other parts. PMID- 20896048 TI - Supplement to a Paper on the Use of the Speculum in the Diagnosis and Treatment of Uterine Diseases, published in the Thirty-third Volume of the Medico Chirurgical Transactions. PMID- 20896047 TI - Cases illustrating the Pathology of Mania and Dementia. PMID- 20896049 TI - Operation for Congenital Cataract on an Adult, followed by Division of the Recti Muscles for the purpose of controlling the Oscillation of the Globes. PMID- 20896050 TI - On Inguinal Tumour associated with Symptoms of Strangulated Hernia and Absence of the Testicle on the Affected Side. PMID- 20896051 TI - On the Juvantia and Laedentia in Diabetes. PMID- 20896052 TI - On a Plastic Operation for the Restoration of the Lower Lip. PMID- 20896053 TI - On Dislocation of the Femur, Upwards and Forwards, beneath the Crural Arch. PMID- 20896054 TI - On Bony Anchylosis between the Humerus and Scapula after Disease. PMID- 20896055 TI - On the Action of Digitalis upon the Uterus. PMID- 20896056 TI - Cases illustrative of the Pathology of the Ear. PMID- 20896057 TI - On Myeloid and Myelo-Cystic Tumours of Bone; their Structure, Pathology, and Mode of Diagnosis. PMID- 20896059 TI - Rate of Hourly Pulsation and Respiration in Phthisis, and its Relations to Sleep, Food, Sunlight, &c. PMID- 20896058 TI - History of a Case in which a Cedar Pencil was lodged in the Cavity of the Abdomen for Eight Months. PMID- 20896060 TI - Cases of Paraplegia, associated with Gonorrhoea and Stricture of the Urethra. PMID- 20896061 TI - Case of a Young Woman in whom the main Arteries of both Upper Extremities and of the Left Side of the Neck were throughout completely Obliterated. PMID- 20896062 TI - Analysis of Cases of Amputation of the Limbs in the Radcliffe Infirmary, Oxford. PMID- 20896063 TI - Wound of the Abdominal Parietes; Protrusion of Omentum and Transverse Colon; Division of the latter to the extent of Four-Fifths of its Circumference: Recovery. PMID- 20896064 TI - On the Structure and Nature of the so-called Colloid Cancer. PMID- 20896065 TI - Case of Fracture of Four Cervical Vertebrae, with Dislocation, produced by slight and unusual cause, and resulting in immediate Death; with Notes of a Case of Fracture of the Os Calcis. PMID- 20896066 TI - Two Cases of extensive Absorption of the Bones of the Head, followed, in one of them, by Hernia Cerebri. PMID- 20896067 TI - On Two Cases of Malformation of the Heart. PMID- 20896068 TI - On Encephalocele; being the History of a Case, with a Tabular Analysis of Seventy five Cases. PMID- 20896069 TI - Case of Detached Piece of Articular Cartilage existing as a Loose Substance in the Knee-Joint. PMID- 20896070 TI - An Account of the Arrangement of the Muscular Substance in the Urinary and certain of the Generative Organs of the Human Body. PMID- 20896071 TI - On Mercurial Fumigation in the Treatment of Syphilis. PMID- 20896072 TI - Hourly Pulsation and Respiration in Health. With Two Diagrams and Tables. PMID- 20896073 TI - On Atrophy of the Brain, with Cases in which there were remarkable Inequalities of the Cerebral Hemispheres, attended with Hemiplegia and Contraction of the Limbs on the side opposite the Atrophied Hemisphere. PMID- 20896075 TI - A Case of Destruction of the Entire Palate, successfully relieved by Mechanical Means. PMID- 20896074 TI - Observations on Congenital Deficiency of the Palate, and the Means to be used for its Relief. PMID- 20896076 TI - On the Treatment of Aneurism by Manipulation. PMID- 20896077 TI - On Disarticulation of the Scapula from the Shoulder-Joint. PMID- 20896078 TI - On a new Method of Operating for Impermeable Urethra. PMID- 20896080 TI - On Forcible Extension and Rupture of the Uniting Medium of partially Ankylosed Surfaces. PMID- 20896079 TI - Case of Double Talipes Varus in which the Cuboid Bone was partially removed from the Left Foot. PMID- 20896081 TI - On Scirrhus of the Male Breast. PMID- 20896082 TI - Analysis of Fifty-two Cases of Epilepsy observed by the Author. PMID- 20896083 TI - A Case of Disease of the Heart, with great Dilatation of the Auricles. PMID- 20896084 TI - Case of intense and long-continued Photophobia and Blepharospasm, relieved by the Inhalation of Chloroform. PMID- 20896085 TI - On the Effects of Twelve Weeks' Residence in Bulgaria (during the Months of June, July, and August, 1854) on the subsequent Health of the British Troops in the Crimea. PMID- 20896086 TI - Case in which a Large Cyst was successfully removed from the upper part of the Neck of a Young Woman, aged 27, who was considered at Birth to have been the subject of Spina Bifida. PMID- 20896087 TI - Further Observations on the Use of the Speculum in the Diagnosis and Treatment of Uterine Diseases. PMID- 20896088 TI - On the Determining Causes of Vesicular Emphysema of the Lung. PMID- 20896089 TI - Five Cases of Tracheotomy in Croup, with Remarks on certain points connected with the Operation; with a Postscript containing two additional Cases. PMID- 20896090 TI - Some Observations on the Anatomy and Pathology of the Adult Prostate, founded upon Fifty Preparations of the Organ, dissected by the Author, and accompanying the Paper; with Two Plates. PMID- 20896091 TI - An Account of a Case of Arterio-venous Aneurism of the Temporal Vessels, which was treated by Ligature of both the Artery and the Vein. PMID- 20896092 TI - Case of Communication with the Stomach, through the Abdominal Parietes, produced by Ulceration from External Pressure; with Observations on the Cases of Gastro cutaneous Fistulae already recorded. PMID- 20896093 TI - On some Points in the Pathology and Morbid Anatomy of Glaucoma. PMID- 20896094 TI - On the Analysis and Immediate Principles of Human Excrements in the Diseased State. PMID- 20896095 TI - On the Membrana Decidua which surrounds the Ovum in Cases of Tubal Gestation. PMID- 20896097 TI - On the Action of Galvanism upon the Contractile Structure of the Gravid Uterus, and its Remedial Powers in Obstetric Practice. PMID- 20896096 TI - Supplement to a Paper on the Membrana Decidua which surrounds the Ovum in Cases of Tubal Gestation. PMID- 20896098 TI - A Case of Complete Inversion of the Uterus, of nearly Twelve Years' Duration, successfully treated. PMID- 20896099 TI - On Excision of the Knee. PMID- 20896100 TI - Contributions to the Etiology of Continued Fever: or an Investigation of various Causes which influence the Prevalence and Mortality of its different Forms. PMID- 20896102 TI - A Case of Fibrous Polypus of the Urinary Bladder, with Observations, and a Table of the Recorded Cases. PMID- 20896101 TI - Case of Hydatids of the Tibia. PMID- 20896103 TI - Researches on Gout.-Part I. The Urine in the Different Forms of Gout.-Part II. The Influence of Colchicum upon the Urine. PMID- 20896104 TI - Contributions to the Pathology of the Glandular Structures of the Stomach. PMID- 20896105 TI - On the Influence of the Cervical Portions of the Sympathetic Nerve and Spinal Cord upon the Eye and its Appendages, illustrated by Clinical Cases, with Observations. PMID- 20896106 TI - An Account of a Case of Calculus in the Bladder removed by Lithotrity, in which a Communication existed between the Bladder and Intestine. PMID- 20896108 TI - On a Case of Premature Puberty. PMID- 20896107 TI - On a case of Dislocation of the Humerus, upwards and inwards, with Fracture of the Coracoid Process of the Scapula; accompanied by a Dissection of the Parts involved in the Injury. PMID- 20896109 TI - Therapeutic Communications.-No. I. On the Influence of Liquor Potassae, and other Caustic Alkaline Solutions, upon the Therapeutic Properties of Henbane, Belladonna, and Stramonium. PMID- 20896110 TI - Therapeutic Communications.-No. II. On the Influence of Liquor Potassae, and other Caustic Alkaline Solutions, upon the Therapeutic Properties of Henbane, Belladonna, and Stramonium. PMID- 20896111 TI - A Contribution to the Science of Teratology. PMID- 20896112 TI - Case of Excision of the Head of the Humerus (Decapitatiohumeri), with its results. PMID- 20896113 TI - Contribution to the Statistics of Cancer, collected from the Cancer Records of the Middlesex Hospital. PMID- 20896114 TI - Case of Encephaloid Cancer affecting a Testicle which had been retained within the Cavity of the Abdomen. PMID- 20896115 TI - On the Forms and Stages of Bright's Disease of the Kidneys, with especial Reference to Diagnosis and Prognosis; fourth Communication. PMID- 20896116 TI - Account of three Cases of Aneruism of or within the Orbit, treated by Ligature of the Common Carotid Artery, with Observations. PMID- 20896117 TI - Case of Aneurism of the Thoracic Aorta, which opened into the Trachea and left Bronchus; and in which Haemoptysis occurred four years and eight months before Death, with Remarks on the Circumstances attending the Rupture of Aneurisms, especially on Mucous Surfaces. PMID- 20896118 TI - A Case of Popliteal Aneurism, successfully treated by Flexion of the Knee-joint, with Remarks. PMID- 20896119 TI - A Case of Popliteal Aneurism, successfully treated by continued Flexion of the Knee-joint. PMID- 20896120 TI - On some of the Effects of Primary Cancerous Tumours within the Chest. PMID- 20896121 TI - Cases of Re-fracture of Bone, with Observations. PMID- 20896122 TI - Two Cases of Empyema, illustrating the Advantage of making two Openings and adopting the Plan of "Drainage" in the Operation of Paracentesis in that Disease. PMID- 20896124 TI - On the Administration of Belladonna, and on certain Causes which modify its Action. PMID- 20896123 TI - Inquiry into the Nature of those Cases of Strangulated Oblique Inguinal Hernia, termed "Reduction en bloc, ou en masse;" with special Relation to the Anatomy of the actual Lesion, and Practical Deductions derived from an Examination of the Cases. PMID- 20896125 TI - On the Reparative Process in Human Tendons, after Subcutaneous Division for the Cure of Deformities. PMID- 20896126 TI - Observation on the Medical Administration of Ozonized Oils. PMID- 20896127 TI - On the Connexion between the Heat of the Body and the excreted amounts of Urea, Chloride of Sodium, and Urinary Water, during a Fit of Ague. PMID- 20896128 TI - Cases of Disclocation of the Os Calcis and Scaphoid from the Astragalus, with Remarks on the Importance of dividing the Gastrocnemius and other Tendons, to facilitate Reduction in various Dislocations of the latter Bone. PMID- 20896129 TI - Case of Paralysis as to Voluntary Motor Power of the Limbs on one side of the Body, attended by Hyperaesthesia of the corresponding side of the Face, being the Result of Comparession of parts of the Brain from an Intra-cranial Aneurism, with Observations on "Induced" Cerebral Paralysis. PMID- 20896130 TI - Sequel of Case (published in vol. xli. of the 'Transactions') of Lithotrity, in which a Communication existed between the Bladder and Intestine. PMID- 20896131 TI - A Case of Vesical Calculus of unusual size, removed by the Recto-vesical Operation. PMID- 20896132 TI - On different Forms of Primary Syphilitic Inoculation. PMID- 20896133 TI - Description of the Organs of Generation of a Hermaphrodite Sheep. PMID- 20896134 TI - On the Causes of Death after Amputation. PMID- 20896135 TI - On Disarticulation of the Scapula from the Shoulder-joint, with removal of the Acromial end of the Clavicle. PMID- 20896136 TI - On some of the Cyclical Changes in the Human System connected with Season. PMID- 20896138 TI - Cases of Intra-Uterine Fracture, with Observations to show the Analogy between Fracture in Utero and Congenital Distortion. PMID- 20896137 TI - History of an additional Case of Tubal Gestation. PMID- 20896139 TI - Case Femoral Hernia, which had descended beneath the Pectineal Portion of the Fascia Lata, and was partially covered by the Pectineus Muscle. PMID- 20896140 TI - Case of Imperforate Arch of the Aorta, in which the Root of the Aorta was Ruptured. PMID- 20896141 TI - On the Treatment of Axillary Aneurism. PMID- 20896142 TI - Report on the Condition of the Prostate in Old Age, founded on the dissection of one hundred specimens. PMID- 20896143 TI - On the Condition of the Blood in Mania. PMID- 20896144 TI - Cases of Cerebral Affection caused by Disease in the Region of the Nose and Eyes. PMID- 20896145 TI - On Congestion of the Heart, and its Local Consequences. PMID- 20896146 TI - Case of Acute Caries of the Walls of the Tympanic Cavity, producing Ulceration of the Internal Carotid Artery. PMID- 20896147 TI - On Diseases of the Kidney accompanied by Albuminuria, in relation to their Origin in Change occurring in the Tubes or in the Intertubular Structure. PMID- 20896148 TI - Glaucoma, and its Surgical Treatment by Iridectomy. PMID- 20896149 TI - Contribution to the Study of Spirometry. PMID- 20896150 TI - Brief Notes of a Visit to the Leper Hospital, Granada. PMID- 20896151 TI - Inquiry into the Treatment of Congenital Imperfections of the Rectum by Operation, founded on an Analysis of One Hundred Cases, nine of which occurred in the Practice of the Author. PMID- 20896152 TI - On the relative amount of Sugar and Urea in the Urine in "Diabetes Mellitus". PMID- 20896153 TI - Tabular Statement of Seventy-two Cases of Haematemesis, with Remarks. PMID- 20896155 TI - Cases of Obstruction of the Veins of the Lower Extremities causing OEdema of the corresponding Limb, and occurring in Phthisical Patients. PMID- 20896154 TI - Account of a Fresh Dissection of a Preparation of Tubal Gestation, described by Dr. John Clarke in 1793. PMID- 20896156 TI - Case of Recurrent Anaesthesia of the Surface of the Body, with partial loss of Motor Power, from the effects upon the Spinal Nerves of effused products within the Spinal Canal. PMID- 20896157 TI - Observations on Stertor, the conditions upon which it is dependent, and its treatment. PMID- 20896158 TI - On the Etiology and Treatment of Peritonitis. PMID- 20896160 TI - On a New Method of Operating for the Radical Cure of Hernia. PMID- 20896159 TI - On a Form of Secondary Syphilitic Inoculation. PMID- 20896161 TI - On the Nature of Ovarian Cysts which contain Teeth, Hair, and Fatty Matter. PMID- 20896162 TI - A Case of Gastrotomy for Extra-uterine Gestation. PMID- 20896163 TI - Observations on the Growth of the Long Bones and of Stumps. PMID- 20896164 TI - On an Operation for Pervious Urachus, with Stillicidium Urinae. PMID- 20896165 TI - Researches on Asphyxia, with Observations on the effects produced by the Hot Bath in Asphyxiated Animals, and its use in the treatment of Suspended Animation. PMID- 20896166 TI - Letter relative to the preceding "Paper on Asphyxia, and the Use of the Hot Bath, by A. T. H. Waters, M.R.C.P.". PMID- 20896167 TI - Contribution to the Pathology of the Pons Varolii. PMID- 20896168 TI - On Disease of the Kidney, accompanied by Albuminuria (Second Paper). PMID- 20896169 TI - On a Case of Aneurismal Varix in the upper part of the Thigh, following the employment of Pressure for the Cure of an Aneurism of the Posterior Tibial Artery. PMID- 20896170 TI - Contributions to the subject of Compound Fracture, being an Analysis of three hundred and two Cases. PMID- 20896171 TI - On a Case of Aortic Aneurism, in which a Communication with the Pulmonary Artery was recognised during Life by means of Physical Diagnosis. PMID- 20896172 TI - Account of a Case in which the Corpus Callosum and Fornix were imperfectly formed, and the Septum Lucidum and Commissura Mollis were absent. PMID- 20896173 TI - Syphilitic Inoculation, and its relation to Diagnosis and Treatment. PMID- 20896174 TI - Cases illustrating the Causes and Effects of Fibrinous Obstructions in the Arteries, both of the Brain and of other Organs. PMID- 20896175 TI - Case of Irideremia Totalis. PMID- 20896176 TI - Case of Tetanus of Fourteen Months' Duration. PMID- 20896178 TI - On Pulsating Bronchocele. PMID- 20896177 TI - Analysis of fifty-two Cases of Epilepsy observed by the Author (Second Series). PMID- 20896179 TI - Remarks on the Cause of Closure of the Valves of the Heart. PMID- 20896180 TI - Pathological Researches into the Diseases of the Ear (Seventh Series): Sebaceous Tumours in the External Auditory Meatus, their effects upon the Organ of Hearing, the Petrous Bone, and the Brain, with Suggestions as to their Treatment. PMID- 20896181 TI - Further Observations on the Structure and Treatment of Uterine Polypi. PMID- 20896182 TI - Observations on the Discovery of the Original Obstetric Instruments of the Chamberlens. PMID- 20896183 TI - Additional Experiments on the Poisonous Effects of Coal-Gas upon the Animal System. PMID- 20896184 TI - On the Temperature, Urea, Chloride of Sodium, and Urinary Water in Scarlet Fever, and on a Cycle in Disease and Health. PMID- 20896186 TI - On Brass-Founders' Ague. PMID- 20896185 TI - On Pulse-Breath. PMID- 20896187 TI - On the Connection between a Local Affection of the Lymphatic System and Chylous Urine, with Remarks on the Pathology of the Disease. PMID- 20896188 TI - On a Case of Chylous Urine. PMID- 20896189 TI - Observations on the Tactile Sensibility of the Hand. PMID- 20896190 TI - On Certain Grave Evils attending Tenotomy, and on a new mode of curing Deformities of the Foot. PMID- 20896191 TI - On the Influence of Paralysis, Disease of the Joints, Disease of the Epiphysial Lines, Excision of the Knee, Rickets, &c., upon the Growth of the Bones. PMID- 20896192 TI - Analysis of 230 Cases of Lithotomy. PMID- 20896193 TI - On the Treatment of acute Rheumatism, considered with regard to the Liability to Affections of the Heart under different Remedies. PMID- 20896194 TI - Amaurosis, consequent on Acute Abscess of the Antrum, produced by a Carious Tooth. PMID- 20896195 TI - Two Cases of Extensive Arterial Obstruction from separated Cardiac Vegetations, followed by Gangrene of the lower Extremities and Death. PMID- 20896197 TI - Contribution to the Statistics of Cancer. PMID- 20896196 TI - Case of Iliac Aneurism. PMID- 20896198 TI - Report upon Syphilis, with reference to the more mixed and unusual forms of the Primary Symptoms. PMID- 20896199 TI - Congenital Malformation of the Eyes in three children of one family. PMID- 20896200 TI - Case of Aneurism of the External Iliac and Common Femoral Arteries, treated by Digital Pressure, with Observations. PMID- 20896201 TI - Report of the Committee appointed to investigate the subject of Suspended Animation. PMID- 20896202 TI - Observations on the Division of the Gustatory Nerve, and on Ligature of the Lingual Artery in the Treatment of Cancer of the Tongue. PMID- 20896203 TI - Case of Osteo-Malacia. PMID- 20896204 TI - On some Affections of the Caecal Portion of the Intestines, with Illustrative Cases. PMID- 20896205 TI - The Poisonous Effects of Coal-Gas upon the Animal System. PMID- 20896207 TI - Remarks on two Cases of Kelis. PMID- 20896206 TI - Account of a recent remarkable Case of Scrotal Elephantiasis, in which the Tumour was removed. PMID- 20896208 TI - On a Remarkable Case of Lesion of the Medulla Oblongata. PMID- 20896209 TI - A Contribution to the Pathology of the Crura Cerebri. PMID- 20896210 TI - Description of a Faetus born without Heart, Brain, Lungs, or Liver. PMID- 20896212 TI - Account of a Patient upon whom Ovariotomy was performed twice; with remarks. PMID- 20896211 TI - Case of Extreme Deformity of the Neck and Forearm, from the Cicatrices of a Burn, cured by Extension, Excision, and Transplantation of Skin, adjacent and remote. PMID- 20896213 TI - On the Induction of Premature Labour in Cases of Pregnancy, complicated with Albuminous Urine, Dropsy, and Amaurosis. PMID- 20896215 TI - A Case of Strangulation of the Stomach in an Umbilical Rupture, and of Death during its Reduction under Chloroform. PMID- 20896214 TI - Description of a New Iris Forceps. PMID- 20896216 TI - A Case of Transposition of the Great Vessels of the Heart. PMID- 20896217 TI - Supplement to a Paper, entitled an "Analysis of 162 Cases of Ovariotomy, which have occurred in Great Britain," published in vol. xxxiv of the Medico Chirurgical Transactions. PMID- 20896218 TI - Case of Popliteal Aneurism cured by Digital Compression. PMID- 20896219 TI - Cases of Ichthyosis Spuria vel Sebacea. PMID- 20896220 TI - Case of Poisoning by Oil of Wormwood (Artemisia absinthium). PMID- 20896221 TI - Contribution to the Natural History of Hereditary Transmission. PMID- 20896222 TI - Case of a Woman with three Hands; illustrated by Analogous Malformations in the lower Animals. PMID- 20896223 TI - On the History and Progress of Ovariotomy in Great Britain, with observations founded on personal experience of the operation in fifty cases. PMID- 20896224 TI - Case of White Fibro-serous Discharge from the Thigh. PMID- 20896226 TI - Case of Cancerous Infiltration of the Penis; with Cancerous Ulcer of the Bladder, and Secondary Deposits in the Lungs, Bones, and other parts of the Body. PMID- 20896225 TI - Observations upon Syphilis, in its Manifestations as a Constitutional Disease. PMID- 20896227 TI - On the Absorption of Dead Bone. PMID- 20896228 TI - Case of unusual difficulty in Lithotomy, arising from great Distortion of the Pelvis by Rickets. PMID- 20896229 TI - On a new operation for obtaining union of Ununited Fracture, with remarks on its application to certain cases of recent fracture. PMID- 20896231 TI - Two Cases of Stone in the Bladder of the Female, treated by rapid urethral dilatation; with remarks on the operation. PMID- 20896230 TI - On a new method of procuring the consolidation of Fibrin in certain incurable Aneurisms: With the Report of a case in which an Aneurism of the ascending Aorta was treated by the insertion of Wire. PMID- 20896232 TI - Statistics of Queen Charlotte's Lying-in Hospital. PMID- 20896233 TI - Account of some unusual occurrences during the cure of a Popliteal Aneurism. PMID- 20896234 TI - Account of a Case of Aneurism of the Abdominal Aorta, which was cured by compression of that artery immediately above the tumour. PMID- 20896235 TI - Case of Congenital Imperfection of the Mammae, Sexual Organs, Sternum, and Heart, in a woman aged twenty-two years. PMID- 20896236 TI - Pathological Researches into the Diseases of the Ear, Supplement to Seventh Series: Sebaceous Tumours in the External Auditory Meatus. PMID- 20896237 TI - On the condition of the Stomach and Intestines in Scarlatina. PMID- 20896238 TI - On the origin, structure, and mode of development of the Cystic Tumours of the Ovary. PMID- 20896239 TI - Case of Popliteal Aneurism successfully treated by Flexion of the Knee. PMID- 20896240 TI - A successful case of Paracentesis Capitis. PMID- 20896241 TI - Some Particulars of a Case of Popliteal Aneurism cured by Flexion of the Knee. PMID- 20896242 TI - On the Causes of Hernia. PMID- 20896243 TI - Note on the application of Indices to Aneurismal Clamps, and other pressure instruments. PMID- 20896244 TI - Report of the Scientific Committee on the Uses and the physiological, therapeutical, and toxical Effects of Chloroform, as well as into the best mode of administering it, and of obviating any ill consequences resulting from its administration. PMID- 20896245 TI - Clinical Observations illustrating the effects produced by the implication of Branches of the Pneumogastric Nerve in Aneurismal Tumours. PMID- 20896246 TI - On the Endemic Haematuria of the Cape of Good Hope. PMID- 20896247 TI - Case of a Mucous Cyst on the Laryngeal Aspect of the Epiglottis, successfully treated by incision. PMID- 20896248 TI - Some account of the Amputations performed at St. Bartholomew's Hospital, 1853-63. PMID- 20896250 TI - Remarkable instance of a Growth springing from the Epiglottis, which was successfully removed with the aid of the Laryngoscope. PMID- 20896249 TI - A Case of Strangulated Femoral Rupture, where, on a former occasion, the neck had been torn from the body of the sac, in the taxis, and the escaping bowel had formed a subperitoneal pouch which finally attained an extraordinary size. PMID- 20896251 TI - On Delirium or Acute Insanity during the decline of Acute Diseases, especially the Delirium of Collapse. PMID- 20896252 TI - On Vascular Protrusion of the Eyeball. PMID- 20896253 TI - On Intermittent Haematuria, with remarks upon its Pathology and Treatment. PMID- 20896254 TI - Notes of four cases of Intermittent Haematuria. PMID- 20896255 TI - Supplement to a Paper entitled "Further Observations on the Structure and Treatment of Uterine Polypi," published in volume XLIV of the Medico-Chirurgical Transactions. PMID- 20896256 TI - On Amputation of the Leg by a long Rectangular Flap from the Calf. PMID- 20896257 TI - Account of a case in which a Sixpence was lodged in the Larynx during ten weeks. PMID- 20896258 TI - On a Case of the "Haemorrhagic Diathesis". PMID- 20896259 TI - A Second Series of Fifty cases of Ovariotomy, with remarks on the selection of cases for the operation. PMID- 20896260 TI - On the obstacles to the re-establishment of Natural Respiration after the performance of Tracheotomy; cases with remarks. PMID- 20896261 TI - The application of Sutures to Bone in recent Gunshot Fractures, with cases; also remarks on their similar use in some other Fractures and Operations. PMID- 20896262 TI - On the Pathology of Tetanus; illustrated by cases and drawings. PMID- 20896264 TI - On Fibroid Degeneration of the Lung. PMID- 20896263 TI - On Morbid Changes in the Stomach and Intestinal Villi present in persons who have died of Cancer. PMID- 20896265 TI - Case of Ulcer in the lower portion of the Ileum, communicating with the Bladder. PMID- 20896266 TI - Remarks upon Osteo-myelitis consequent on Gunshot Wounds of the Upper and Lower Extremities, and especially upon the Treatment of Stumps affected with Osteomyelitis after Amputation necessitated by such Injuries. PMID- 20896267 TI - Case of Aneurism by Anastomosis of the Scalp, treated successfully by Ligature of the common Carotid and Setons. PMID- 20896269 TI - On the Solvent Treatment of Urinary Calculi; and experimental and clinical Inquiry. PMID- 20896268 TI - Congenital Hydronephrosis in a Boy four years old, repeatedly tapped; Recovery. PMID- 20896270 TI - Observations on the Effect of Coffee on the Urea and Chlorides in Health. PMID- 20896272 TI - Case of Premature Menstruation. PMID- 20896271 TI - Pathological and Surgical Observations on the Diseases of the Ear (Eighth Series): on Disconnection of the Incus and the Stapes, its effects upon the function of hearing and its treatment. PMID- 20896273 TI - Case of Myeloid Transformation of the Lungs. PMID- 20896275 TI - On a case of Elephantiasis Arabum, or Elephas, successfully treated by the application of a ligature to the main artery of the limb, with remarks. PMID- 20896274 TI - On Atrophy or Degeneration of the Muscles of the Upper and Lower Extremities from Disease of the Spinal Cord. PMID- 20896277 TI - Account of a second Case in which the Corpus Callosum was defective. PMID- 20896276 TI - Account of a Case of Oblique Inguinal Hernia on each side, in which, the testis remaining in the belly, the hernial sacs descended into the scrotum and also ascended upon the aponeurosis of the external oblique muscles. PMID- 20896278 TI - Remarks on Chronic Albuminuria originating during the convalescence from Scarlet Fever and other Eruptive Diseases. PMID- 20896279 TI - On the Detection of Lung-tissue in the Expectoration of Persons affected with Phthisis. PMID- 20896280 TI - Case in which the operation of Trephining of the Spine was performed. PMID- 20896281 TI - Account of an Arterio-venous Cyst in the Popliteal Nerve, for which the limb was amputated. PMID- 20896282 TI - Case of Multiple Neuromata affecting the nerves both within and external to the spinal canal, some of the tumours being of a cystic nature. PMID- 20896283 TI - On Granular Degeneration of the Voluntary Muscles. PMID- 20896284 TI - Notes and Observations on Fever during service on board H.M.'s screw corvette Pylades of 21 guns, on the west coast of Mexico, in 1860. PMID- 20896286 TI - On a Case of Hydatid Disease of the Liver, and remarks on the treatment of similar tumours. PMID- 20896285 TI - Case of Lumbar Colotomy (Amussat's operation) successfully performed for the relief of a vesico-intestinal fistula. PMID- 20896287 TI - A Case in which Ovariotomy was twice successfully performed on the same patient. PMID- 20896288 TI - On the Pathology and Treatment of Cholera. PMID- 20896289 TI - On the Treatment of Cholera and Epidemic Diarrhoea; with a record of Cases. PMID- 20896291 TI - A Study of the Influence of Weather and Season upon Public Health, made upon above 217,000 Cases of Sickness newly occurring at Institutions for the Sick Poor in Islington during 1857-65. I. The Influence of Atmospheric Temperature. PMID- 20896290 TI - Sequel to a Case of Colotomy for Vesico-Intestinal Fistula [in Vol. XLIX, p. 65], death having ensued from Affection of the Bowel higher up. PMID- 20896292 TI - Two Cases of Periodical Inflammation of the Right Knee-Joint, with Remarks. PMID- 20896294 TI - Record of Cases treated in the Lock Hospital by Syphilisation. PMID- 20896293 TI - On the Influence of Inadequate Operations on the Theory of Cancer. PMID- 20896295 TI - Observations on the Temperature and the Urine in Typhus Fever. PMID- 20896297 TI - Statistical Details of three years' experience in respect to the form of Amaurosis supposed to be due to Tobacco. PMID- 20896296 TI - On the Nature of the Waxy, Lardaceous, or Amyloid Deposit. PMID- 20896299 TI - On the Inoculation of Animals, as a means of Diagnosis in Tubercular Phthisis. PMID- 20896298 TI - A Case of Aneurism of the Femoral Artery, the Sac of which burst, and its treatment; with observations. PMID- 20896300 TI - Contributions to the Pathology of Aneurisms and Tumours, involving the upper portion of the Chest and root of the Neck. PMID- 20896301 TI - On the Repair of Arteries and Veins after Injury. PMID- 20896302 TI - On a Case of Muscular Atrophy, with Disease of the Spinal Cord and Medulla Oblongata. PMID- 20896303 TI - On a Case of Concussion-Lesion, with extensive secondary degenerations of the Spinal Cord, followed by General Muscular Atrophy. PMID- 20896305 TI - Report of the Scientific Committee appointed to investigate the Physiological and Therapeutical Effects of the Hypodermic Method of Injection. PMID- 20896304 TI - A Third and Fourth Series of Fifty Cases of Ovariotomy, with remarks on the situation and length of the Incision required in this operation. PMID- 20896306 TI - On Enucleation of Naevus. PMID- 20896307 TI - On a Case of Internal Strangulation of the Bowel by a Band, associated with a Reducible Hernia; successfully treated by operation. PMID- 20896308 TI - On the Condition of the Urine in three Cases of Epilepsy. PMID- 20896310 TI - Poisoning by Phosphorus; Jaundice; death in six days. Fatty Degeneration of Liver and Kidneys. PMID- 20896309 TI - Acute Poisoning by Phosphorus; Jaundice; death on the fifth day. Fatty Degeneration of the Liver, Kidneys, Gastric Follicles, Pancreas, Heart, &c. PMID- 20896311 TI - On some Analogies of Cholera, in which Suppression of Urine is not accompanied by symptoms of Uraemic Poisoning. PMID- 20896312 TI - Notes respecting Non-uniting Fractures. PMID- 20896313 TI - A case of Axillary Aneurism on the Right Side, for which the Subclavian Artery was successfully tied, the Left Subclavian Artery having been Ligatured in the same subject for an Axillary Aneurism about three years previously. PMID- 20896314 TI - Case of Cystic Disease of the Kidney simulating Ovarian Disease. PMID- 20896315 TI - A History of Seven Cases in which a Morbid Growth was removed from one of the Vocal Cords by the aid of the Laryngoscope. PMID- 20896316 TI - A Contribution to the Surgical Pathology of Sero-Sanguineous Cysts in the Neck and Axilla. PMID- 20896318 TI - Case of Perforation of the Mastoid Cells; subsequent Formation of an Abscess beneath the Sterno-Mastoid Muscle. PMID- 20896319 TI - On Paralysis of the Extensors. PMID- 20896317 TI - On the Torsion of Arteries as a means of arresting Haemorrhage, with Experiments. PMID- 20896320 TI - On a remarkable Case of Extreme Muscular Atrophy, with extensive Disease of the Spinal Cord. PMID- 20896321 TI - Description of the Spinal Cord in a case of Traumatic Tetanus. PMID- 20896322 TI - A Study of the Influence of Weather and Season upon Public Health, &c. II. Comparison of the Influence of Variation of Temperature upon General Sickness in the colder and warmer seasons of the year. PMID- 20896323 TI - A Study of the Influence of Weather and Season upon Public Health, &c. III. The Influence of Daily Range of Atmospheric Temperature. PMID- 20896324 TI - On Excess of Urea in the Urine as a guide to the Diagnosis and Treatment of certain forms of Dyspepsia and Nervousness. PMID- 20896325 TI - 1. On certain points in the Anatomy and Pathology of Bright's Disease of the Kidney. 2. On the Influence of the Minute Blood-vessels upon the Circulation. PMID- 20896326 TI - On the Cure of Cleft Palate by Operation in Children, with a description of an Instrument for facilitating the Operation. PMID- 20896327 TI - Case of Double Hernia in a Single Sac. PMID- 20896329 TI - On Excision of the Larger Joints, with a Table of Cases. PMID- 20896328 TI - On the State of the Optic Nerves and Retinae as seen in the Insane. PMID- 20896330 TI - The Results in Thirty-nine cases of Excision of the Knee. PMID- 20896331 TI - Description of a Dislocation of the Head of the Femur, complicated with its Fracture; with Remarks. PMID- 20896333 TI - A case illustrating the Physiology and Pathology of the Cervical Portion of the Sympathetic Nerve. PMID- 20896332 TI - On some New Double Salts of Carbolic Acid, particularly considered as Agents for the Treatment of Disease. PMID- 20896334 TI - On the Operations for the relief of Chronic Inversion of the Uterus; with the history of a case successfully treated by a New Method. PMID- 20896335 TI - A Third Series of One Hundred Cases of Ovariotomy, with remarks on Tapping Ovarian Cysts. PMID- 20896336 TI - Nephrotomy, as a means of Treating Renal Calculus. PMID- 20896337 TI - On the Treatment of Phthisis by Prolonged Residence in Elevated Regions. PMID- 20896338 TI - Cases of Iritis occurring in Syphilis treated without Mercury; with remarks on this Form of Iritis. PMID- 20896340 TI - On a Case of Fusiform and Tubular Aneurism of the Subclavian Artery, and its successful Treatment by indirect Digital Compression. PMID- 20896339 TI - On certain Points in the Physiology and Pathology of the Fifth Pair of Cerebral Nerves. PMID- 20896341 TI - A case of Double Aneurism affecting the Right External Iliac and Femoral, and the Right Popliteal, Arteries, cured by Pressure upon the Common Iliac and the Femoral Arteries. PMID- 20896342 TI - A Case of Aneurism of the Femoral Artery, treated by long-continued Compression of the Common Iliac; with Remarks. PMID- 20896343 TI - On Transverse Fractures of the Patella. PMID- 20896344 TI - A Case of Dissecting Aneurism of the Aorta. PMID- 20896345 TI - On the Enlargement of the Viscera which occurs in Rickets. PMID- 20896346 TI - A Second Communication on the Endemic Haematuria of the Cape of Good Hope and Natal. PMID- 20896348 TI - Remarks on the Natural History of Rheumatic Fever. PMID- 20896347 TI - Completion of the Case of Congenital Hydronephrosis in the Forty-eighth Volume of the 'Transactions' of the Society. PMID- 20896349 TI - On Fission and Extroversion of the Bladder with Epispadias; with the results of eight cases treated by Plastic Operations. PMID- 20896350 TI - On Amputation at the Knee-Joint. PMID- 20896351 TI - An Analysis of One Hundred and Eighty-four Cases of Stone in the Bladder of the Adult treated by Lithotrity. PMID- 20896352 TI - On Supra-condyloid Amputation of the Thigh. PMID- 20896353 TI - A Case of Extroversion of the Bladder in a Female treated by Operation. PMID- 20896354 TI - On Adenoid Vegetations in the Naso-pharyngeal Cavity: their Pathology, Diagnosis, and Treatment. PMID- 20896356 TI - On certain Morbid Changes in the Nervous System associated with Diabetes. PMID- 20896355 TI - On the Anatomy of a Case of Molluscum Fibrosum. PMID- 20896357 TI - Anosmia, or Cases illustrating the Physiology and Pathology of the Sense of Smell. PMID- 20896358 TI - Report of the Committee appointed to investigate Bain's and Pacini's Methods of Restoring Suspended Animation. PMID- 20896359 TI - Experiments on the Action of certain Diuretics (Citrate and Acetate of Potash, Spiritus AEtheris Nitrosi, and Oil of Juniper) on the Urine in Health. PMID- 20896360 TI - A Case of Compound Fracture of the Patella, with an Analysis of Sixty-nine Cases of that Injury. PMID- 20896361 TI - Case in which a Plate with Artificial Teeth was swallowed, detected in the Stomach, and extracted. PMID- 20896362 TI - On Excision of the Joints for Disease, and specially of the Knee, Hip, and Elbow; with the Histories of Twenty Typical Cases, and their Results. PMID- 20896363 TI - Three Cases of Injury to the Brain, with an appendix of Cases. PMID- 20896364 TI - On Neuritis of the Brachial Plexus. PMID- 20896365 TI - On Sporadic Cretinism, occurring in England. PMID- 20896366 TI - A Clinical Report on Xanthelasma Palpebrarum, and on its significance as a symptom. PMID- 20896367 TI - On the Classification and Tabulation of Injuries and Surgical Operations in time of war. PMID- 20896368 TI - A Case of Bony Ankylosis of the Knee-Joint, treated by Subcutaneous Section of the Bone. PMID- 20896369 TI - On the Removal of Tumours from Bone. PMID- 20896370 TI - A Fourth Series of One Hundred Cases of Ovariotomy, with Remarks on the Diagnosis of Uterine from Ovarian Tumours. PMID- 20896371 TI - On Dextral Pre-eminence. PMID- 20896372 TI - On the Modifications produced in the Temperature of the Body by the Local Application of Cold and Heat. PMID- 20896373 TI - On a Simple Method of Removing Silver Wire when employed in Cases of ununited Fracture. PMID- 20896375 TI - Report of a Sub-Committee of the Society on some of the Cases of Vaccino Syphilis, related by Mr. Hutchinson. PMID- 20896374 TI - Report on Two Series of Cases in which Syphilis was communicated in the Practice of Vaccination. PMID- 20896376 TI - Second Report of a Sub-Committee of the Society on some of the Cases of Vaccino Syphilis. PMID- 20896377 TI - A Third Communication on the Endemic Haematuria of the South-Eastern Coast of Africa, with remarks on the Topical medication of the Bladder. PMID- 20896378 TI - On Temporary Glycosuria as a sequel to Cholera. PMID- 20896379 TI - On the Duration of Phthisis Pulmonalis and on certain conditions which influence it. PMID- 20896380 TI - A Case of large Biliary Concretion in the Ileum. PMID- 20896382 TI - A Case of Complete Recovery after Necrosis of the Body of a Cervical Vertebra. PMID- 20896381 TI - The Pathology of Scarlatina, and the relation between Enteric and Scarlet Fevers. PMID- 20896383 TI - On the Cerebral Mechanism of Speech and Thought. PMID- 20896385 TI - On the Surgical Treatment of Suppurating Ovarian Cysts and on Pelvic Adhesions in Ovariotomy. PMID- 20896384 TI - On the Operation of Opening the Larynx by Section of the Cartilages, &c.,for the Removal of Morbid Growths. PMID- 20896386 TI - Account of a Case of Resection of the Shoulder and Elbow-Joints of the same arm for Gunshot Injury. PMID- 20896388 TI - A Case of Abdominal Aneurism treated by Distal Pressure, with remarks. PMID- 20896387 TI - On a Case of Abdominal Aneurism cured by Compression of the Aorta. PMID- 20896389 TI - On the Effects of Warm Climates in the Treatment of Pulmonary Consumption, as exemplified by an analysis of two hundred and fifty-one cases. PMID- 20896390 TI - An account of some Renal Calculi of unusual shape found in the Left Kidney of a Woman who died of Cancer of the Uterus, &c. PMID- 20896391 TI - Account of a Case of Intestinal Obstruction in which an Artificial Anus was made in the Small Intestine; recovery; and subsequent death from Cancer and Fatty Degeneration of the Heart. PMID- 20896392 TI - On the Pathology of the Morbid State commonly called Chronic Bright's Disease with Contracted Kidney, ("Arterio-capillary Fibrosis."). PMID- 20896393 TI - On Ether and Chloroform as Anaesthetics. PMID- 20896394 TI - On a Case of Unilateral Atrophy of the Tongue. PMID- 20896396 TI - Progressive Muscular Atrophy, accompanied by Muscular Rigidity and Contraction of Joints; examination of the Brain and Spinal Cord. PMID- 20896395 TI - On Non-Purulent Catarrh of the Middle Ear. PMID- 20896397 TI - A Fifth Series of one hundred Cases, with Remarks on the Results of five hundred Cases of Ovariotomy. PMID- 20896398 TI - Case of Subclavian Aneurism, in which Temporary Compression of the Innominate was tried, followed by Ligature of that Vessel. PMID- 20896399 TI - The Pathology of Chronic Bright's Disease with Contracted Kidney, with especial reference to the theroy of "Arterio-Capillary Fibrosis". PMID- 20896400 TI - An Analysis of Ship Air and its Effects. PMID- 20896401 TI - A Second Report on the Communication of Syphilis in the Practice of Vaccination; with two additional Cases. PMID- 20896402 TI - Removal of a Needle from the Heart; Recovery of the Patient. PMID- 20896403 TI - Case of Ovarian Dropsy, Operated on during an attack of acute peritonitis. PMID- 20896404 TI - Case of Excision of the Knee-Joint for Disease, in a woman fifty-three years of age, with successful result. PMID- 20896405 TI - Successful Case of Gastrotomy in Extra-Uterine Pregnancy. PMID- 20896407 TI - On three peculiar cases of Molluscum Fibrosum in Children in which one or more of the following conditions were observed: hypertrophy of the gums, enlargement of the ends of the fingers and toes, numerous connecive-tissue tumours on the scalp, &c. PMID- 20896406 TI - On Disseminated Suppuration of the Kidney, secondary to certain conditions of Urinary Disturbance. PMID- 20896408 TI - Report of a Case of Molluscum Fibrosum or Fibroma; with observations. PMID- 20896409 TI - The Pathology of Leprosy, with a note on the Segregation of Lepers in India. PMID- 20896410 TI - On the Morbid Effects of Alcohol, as shown in Persons who trade in Liquor. PMID- 20896411 TI - On the Elevated Health Resorts of the Southern Hemisphere; with special reference to South Africa. PMID- 20896412 TI - Preternatural Cavities in the Brain of the Sane and Insane. PMID- 20896413 TI - On the Infective Product of Acute Inflammation. PMID- 20896414 TI - Case of Abdominal Aneurism successfully treated by Proximal Pressure of the Aorta. PMID- 20896415 TI - Analysis of Observations on the Temperature, Pulse, and Respiration in Phthisis and Acute Tuberculization of the Lungs. PMID- 20896416 TI - On the Respiratory Movements in Man, with an account of a new Instrument for Measuring the movements of the Chest. PMID- 20896417 TI - Case of Imperfect Development of the Circular Muscular Fibres of the Rectum and Vagina. PMID- 20896418 TI - Remarks on Dislocations of the first and second Pieces of the Sternum. PMID- 20896420 TI - Cases of Disordered Muscular Movement, illustrating the Uses of Hemlock. PMID- 20896419 TI - Notes of a Case of Duchenne's Pseudo-hypertrophic Muscular Paralysis, with special reference to the Temperature of the Overgrown Limbs, and with General Remarks. PMID- 20896421 TI - Case of Primary Excision of the Ankle-joint, with Observations. PMID- 20896423 TI - Cases of (so-called) Ichthyosis Linguae. PMID- 20896422 TI - On the Treatment of Rickety Deformities of the Legs by Operation. PMID- 20896424 TI - On the Amount of Carbonic Acid found by Experiment in the Air on Board Wooden Frigates. PMID- 20896425 TI - A Case of Necrosis of the Jaw, and other Bones, from the Fumes of Phosphorus. PMID- 20896426 TI - On an Improved Method of Abscission of the Anterior Portion of the Eyeball. PMID- 20896428 TI - On the Acoustic Principles and Construction of Stethoscopes and Ear Trumpets. PMID- 20896427 TI - The Etiology of Bright's Disease and the Prealbuminuric Stage. PMID- 20896429 TI - On Septic Disease in and out of Hospitals. PMID- 20896430 TI - On a Disease of the Skin produced by the Acarus folliculorum, illustrated by Cases observed in the Dog. PMID- 20896431 TI - On a Case of Pseudo-hypertrophic Muscular Paralysis. PMID- 20896432 TI - A Contribution to the Natural History of Pulmonary Consumption, consisting of an Analysis of One Hundred Male Cases of Haemoptysis. PMID- 20896434 TI - Case of Idiopathic Hyalitis (Acute Inflammation of the Vitreous Humour of both Eyes). PMID- 20896433 TI - A Successful Case of Abdominal Section for Intussusception, with Remarks on this and other Methods of Treatment. PMID- 20896435 TI - A Case of Renal Calculi. PMID- 20896436 TI - The Successful Treatment of Aneurism by Position and Restricted Diet. PMID- 20896437 TI - Large Adenocele, complicated with Milk Cyst. PMID- 20896439 TI - Contribution to the History of Laryngeal Phthisis. PMID- 20896438 TI - Case of a Foreign Body Impacted for Twenty Months in the Female Pelvis; Recovery after its Removal. PMID- 20896440 TI - Urinary Crystals and Calculi: being Observations on some of the circumstances determining the Forms of Crystalline Deposits in Urine, and on some of the conditions under which Renal and Vesical Calculi are produced. PMID- 20896441 TI - A Case of Pulsating Tumour of the Left Orbit, consequent upon a Fracture of the Base of the Skull, Cured by Ligature of the Left Common Carotid Artery, subsequently to Injection of Perchloride of Iron, after Digital Compression and other means of Treatment had failed; with Remarks, and an Appendix containing a Chronological Resume of Recorded Cases of Intra-orbital Aneurism. PMID- 20896442 TI - On the Laryngeal Symptoms which Result from the Pressure of Aneurismal and other Tumours upon the Vagus and Recurrent Nerves. PMID- 20896443 TI - Observations upon the Elimination of Urea in certain Diseases. PMID- 20896444 TI - A Case of Left Subclavian Aneurism treated by Temporary Compression applied directly to the Artery in the First Part of its Course; with Remarks. PMID- 20896445 TI - On the Histology of the so-called Nutmeg Liver. PMID- 20896446 TI - On the Construction and Use of a New Form of Cardiograph. PMID- 20896447 TI - On a Case of Double Facial Palsy, with Observations on the Physiology of the Nerves supplying the Forepart of the Tongue. PMID- 20896448 TI - On the "so-called" Partial Dislocation of the Humerus. PMID- 20896449 TI - Notes on an Epidemic of Malarious Yellow Fever occurring on board H.M.S. 'Doris,' shortly after leaving Port Royal, Jamaica, May 18th, 1873. PMID- 20896450 TI - On the Pathology of Lupus Erythematosus. PMID- 20896451 TI - On the Temperature of Phthisis Pulmonalis, and on the Various Conditions influencing it. PMID- 20896452 TI - Cases of Syphilitic Reinfection; with Remarks. PMID- 20896453 TI - On the Pathology of Chorea. PMID- 20896454 TI - Note on Pathological Absorption Spectra. PMID- 20896455 TI - On the Minute Anatomy of Two Breasts, the Areolae of which had been the seat of long-standing Eczema. PMID- 20896456 TI - Case of Sphacelus of the Thyroid Gland, with recovery of the patient. PMID- 20896458 TI - Intermittent Haemorrhage from Malarial Influence. PMID- 20896457 TI - Notes on the Bouton de Biskra (Mycosis cutis chronica, auctoris). PMID- 20896459 TI - On the Estimation of Albumen in Urine by a New Method, adapted for clinical purposes. PMID- 20896460 TI - The Urea and Chlorides in the Urine of Jaundice. PMID- 20896461 TI - On some effects of Lung Elasticity in Health and Disease. PMID- 20896462 TI - On some of the Histological Changes found in Cancer of the Skin or Epithelioma, with special reference to the source of the newly formed epithelial cells. PMID- 20896464 TI - On a Case of Intermitting Hydronephrosis; with some remarks on Hydronephrosis as a Cause of Abdominal Tumours. PMID- 20896463 TI - On the Development of Spindle-Cells in "Nested Sarcomas.". PMID- 20896465 TI - On "Athetosis" and Post-Hemiplegic Disorders of Movement. PMID- 20896466 TI - On the Nature and Mode of Origin of the Lead Line in the Gums. PMID- 20896467 TI - On Ingravescent Apoplexy: a contribution to the Localisation of Cerebral Lesions. PMID- 20896468 TI - On the Causation of the Water-Hammer Pulse, and its Transformation in Different Arteries as illustrated by the Graphic Method. PMID- 20896469 TI - Observations on Box (Buxus sempervirens), with especial reference to the True Nature of Tetanus. PMID- 20896470 TI - On the Use of the Actual Cautery in the Enucleation of Fibroid Tumours of the Uterus. PMID- 20896471 TI - On Aortic Aneurism in the Army, and the conditions associated with it. PMID- 20896472 TI - A Case in which Abdominal Section was successfully performed for Intussusception in an Infant seven months old. PMID- 20896473 TI - A Case of Intussusception in an Adult, without symptoms of Strangulation, treated successfully by Abdominal Section. PMID- 20896475 TI - Subcutaneous Division of the Neck of the Femur for Anchylosis of the Hip-joint. PMID- 20896474 TI - Notes of a second Case of Abdominal Section for Intussusception into the Colon, with remarks on the details of the operation. PMID- 20896477 TI - Case of Resection of the Tarsal Bones for Double Congenital Talipes Equino-varus. PMID- 20896476 TI - A Case of General Teleangiectasis most developed in the left half of the body, associated with abnormalities of the large blood-vessels of the left lower limb and in the neck. PMID- 20896478 TI - A Case of Sclerema Adultorum. PMID- 20896480 TI - On the Minute Anatomy of Two Cases of Carcinoma of the Breast preceded by Eczema of the Nipple and Areola. PMID- 20896481 TI - Dislocations of the Thigh: their mode of occurrence as indicated by experiments, and the Anatomy of the Hip-joint. PMID- 20896479 TI - A Case of Simple Atrophic Sclerema, associated with Disorder of the Circulatory and Alimentary Functions. PMID- 20896483 TI - Notes of a Case of Pseudo-hypertrophic Paralysis, with a few observations on surface thermometry. PMID- 20896482 TI - On Necrosis without Suppuration, with a Case of Intraosseous Necrosis of the Femur without Suppuration, for which Amputation at the Hip-joint was performed. PMID- 20896484 TI - Three Hundred additional Cases of Ovariotomy, with Remarks on Drainage of the Peritoneal Cavity. PMID- 20896486 TI - On Direct Wounds of the Ureter. PMID- 20896485 TI - The Pathological Anatomy of Canine "Chorea.". PMID- 20896487 TI - Note on the Delhi Boil (Furunculus Delhinus). PMID- 20896488 TI - A Case of all but Universal Paralysis in a Child, following exposure to heat; with complete recovery. PMID- 20896489 TI - On an International Calculating Scale for Ophthalmological Purposes. PMID- 20896490 TI - Twenty-five Cases of Ovariotomy; with some Remarks on the Causes and Treatment of the Fever so frequently following the Operation. PMID- 20896491 TI - A Case of Primary Cylindrical Epithelioma of the Lung, with Secondary Deposits in the Pleura, Bronchial Glands, and Liver. PMID- 20896492 TI - On a Form of Chronic Inflammation of Bones (Osteitis Deformans). PMID- 20896493 TI - A Case of Complete Absence of both the Upper Limbs, and of Faulty Development of the Right Lower Limb. PMID- 20896494 TI - On the Use of Flexible Tracheotomy Tubes. PMID- 20896495 TI - A Case of Lodgment of a Tracheotomy Tube in the Right Bronchus, and its Extraction. PMID- 20896496 TI - On a Case in which a Flexible India-rubber Tracheotomy Tube was removed from the Right Bronchus. PMID- 20896497 TI - A Case in which a Silver Tracheotomy Tube was removed from the Left Bronchus, where it had been lodged seven weeks. PMID- 20896499 TI - A Second Communication on Simple Atrophic Sclerema. PMID- 20896498 TI - On a Case of Noma, in which Moving Bodies were observed in the Blood during Life. PMID- 20896500 TI - Analysis of Seventy-five Cases of "Writer's Cramp" and Impaired Writing Power. PMID- 20896501 TI - On a large Aneurism of the Aorta, Innominate, Subclavian, and Carotid Arteries, treated successfully by Double Distal Ligature. PMID- 20896503 TI - An Account of 500 Cases of Operation for Stone in the Bladder of the Male Adult, comprising his entire experience of such cases to January, 1877, with Remarks on the most important Incidents in connection with them. PMID- 20896502 TI - On a Case of Amnesia, with Post-mortem Examination. PMID- 20896504 TI - On the Condition of the Skin in Tinea tonsurans. PMID- 20896505 TI - One Hundred Cases of Paracentesis of the Tympanic Membrane, with the Results obtained therefrom, and Remarks on the Methods of Operation. PMID- 20896506 TI - On some Points in the Minute Anatomy of the Kidney and their relation to the Pathological Phenomenon of Tubular Casts. PMID- 20896507 TI - On Paralysis of the Internal Muscles of the Eye (Ophthalmoplegia Intima), a Group of Symptoms which probably indicates Disease of the Lenticular Ganglion. PMID- 20896508 TI - Treatment of Haemorrhage from Punctured Wounds of the Throat and Neck, especially considered with regard to Ligature of the External Carotid Artery. PMID- 20896509 TI - A Contribution to the Pathology of Haemophilia. PMID- 20896510 TI - On the Pathological Traces of Pulmonary Haemorrhage. PMID- 20896511 TI - Notes on the Spirillum Fever of Bombay, 1877. PMID- 20896513 TI - Appendix to Dr. John Harley's Paper, page 101, on Simple Atrophic Sclerema: Sequel of Case of Wm. W-, Post-mortem, &c. PMID- 20896512 TI - Case of Intussusception in which Abdominal Section was performed. PMID- 20896514 TI - On the Removal by Operation of a Hairy Mole occupying half the Forehead. PMID- 20896515 TI - Cases of Branchial Fistulae in the External Ears. PMID- 20896516 TI - The Microscopic Anatomy of the Smooth Tongue, "Chronic Superficial Glossitis.". PMID- 20896518 TI - On the Pathology of Tetanus and Hydrophobia. PMID- 20896517 TI - On Myxoedema, a term proposed to be applied to an essential condition in the "Cretinoid" Affection occasionally observed in Middle-aged Women. PMID- 20896519 TI - On the Proportion of Red Corpuscles in the Blood in some Skin Diseases. PMID- 20896520 TI - V. Dr. Dickinson's Tables of Cases, with remarks. PMID- 20896521 TI - VI. Dr. Hilton Fagge's Collection of Cases, with remarks. PMID- 20896522 TI - VII. Dr. Gee's Tables of Cases. PMID- 20896523 TI - VIII. List of Reports to the Medical Officers of the Privy Council and Local Government Board on Outbreaks of Diphtheria, and on subjects related thereto. PMID- 20896524 TI - A Case of Morphoea. PMID- 20896525 TI - On the Condition of the Skin in Tinea tonsurans. PMID- 20896526 TI - The Nature of Iodide-of-Potassium Eruption. PMID- 20896527 TI - Tracheotomy in Membranous Laryngitis: the indications for its adoption, and some special points as regards its after-treatment. PMID- 20896528 TI - On Three Cases of Distal Ligature of the Carotid and Subclavian Arteries for Aneurism involving the Innominate Artery. PMID- 20896529 TI - On Disease of the Mastoid Bone. PMID- 20896530 TI - Observations on the effect of Diet, Rest, Exercise, &c., in Chronic Nephritis. PMID- 20896531 TI - A Study of the so-called Tendon-Reflex Phemomena. PMID- 20896532 TI - On Ophthalmoplegia Externa, or Symmetrical Immobility (partial) of the Eyes, with Ptosis. PMID- 20896533 TI - Narrative of a Case of True Leprosy, in which complete recovery has taken place. PMID- 20896534 TI - On the Diagnosis and Treatment of Ruptured Bladder. PMID- 20896535 TI - Copies of Circulars of Inquiries. PMID- 20896536 TI - Remarks on One Hundred and Fifty Operations for Extraction of Cataract. PMID- 20896537 TI - A Case of Secondary Trephining for Traumatic Abscess of the Brain; recovery. PMID- 20896538 TI - On Deligation for Aortic Aneurism of the Right Carotid and Subclavian Arteries, with a new species of Ligature. PMID- 20896539 TI - On the Pathology of Lupus, with special reference to the appearances described as Giant Cells. PMID- 20896540 TI - Tumour in the Bladder removed by Perineal Incision; complete recovery. PMID- 20896541 TI - The Movements of the Eyelids. PMID- 20896542 TI - Observations on the Ophthalmoscopic Appearances in the Tubercular Meningitis of Children. PMID- 20896543 TI - III. Historical Sketch of Anatomical Distinctions which have been drawn between Croup and Diphtheria. PMID- 20896544 TI - IV. Report on the Histology of the Laryngeal and Tracheal False Membrane. PMID- 20896545 TI - An Account of a large Dermoid Cyst found in the Abdomen of a Man. PMID- 20896546 TI - Description of Malformations of the Genital Organs of a Man associated with Persistence of one of the Ducts of Muller. PMID- 20896547 TI - A Contribution to the Non-glandular Theory of Origin of Molluscum Contagiosum. PMID- 20896548 TI - The Antiseptic Theory tested by the Statistics of One Hundred Cases of Successful Ovariotomy. PMID- 20896549 TI - Case of Cholecystotomy preformed for Dropsy of the Gall-bladder due to impaction of a Gall-stone. PMID- 20896550 TI - Nephrectomy by Abdominal Section. PMID- 20896551 TI - On the Estimation of Uric Acid by its Reducing Action upon the Ammoniated Cupric Test. PMID- 20896552 TI - A Case of Extreme Pharyngeal Stenosis the Result of Syphilis. With Remarks. PMID- 20896554 TI - On the Partial Metabolism, by the Liver, of Leucin and Tyrosin into Urea. PMID- 20896553 TI - On Trephining for Traumatic Epilepsy, with an Illustrative Case. PMID- 20896555 TI - An Account of the Dissection of the Parts removed after Death from the Body of a Woman the subject of Congenital Malformation of the Spinal Column, Bony Thorax, and Left Scapular Arch; with Remarks on the probable nature of the Defects in Development producing the Deformities. PMID- 20896556 TI - Compound Fracture of the Femur twenty years after Excision of the Knee-joint for Disease, the line of Fracture being transversely one inch above the bony union. PMID- 20896557 TI - On the Treatment of Pelvic Suppuration by Abdominal Section and Drainage. PMID- 20896558 TI - A Case of Sub-coracoid Dislocation of the Humerus, with the Formation of an Indentation on the Posterior Surface of the Head, the Joint being unopened; with Remarks on the Mode of Production of Fracture of the Anatomical Neck, with Dislocation. PMID- 20896560 TI - On a Case of Basic Cavity of the Lung treated by Paracentesis. PMID- 20896559 TI - On a Case of Epithelioma of the Neck following a Patch of Chronic Skin Disease, in which the Cancer was twice Excised and the External and Internal Jugulars were Ligatured. PMID- 20896561 TI - On two Cases of Carcinoma of the Breast, preceded by so-called Eczema of the Nipple and Areola. PMID- 20896562 TI - Description of two Cases of direct Dislocation backwards of the Femur with Fracture of the Rim of the Acetabulum, with Remarks on the mode of production of Dislocations backwards. PMID- 20896563 TI - On a Case of Aneurism of the Subclavian Artery treated by Amputation at the Shoulder-joint and the introduction of Needles into the Sac. PMID- 20896565 TI - On a Case of Aneurism of the External Carotid, in which, after Failure of the Ligature of the Common Carotid, the old operation was successful. PMID- 20896564 TI - Contributions to the Experimental Pathology of Spirillum Fever. PMID- 20896566 TI - On Hyperpyrexia after "Listerian" Ovariotomy. PMID- 20896567 TI - One Hundred and Seventy-two Antiseptic Abdominal Sections, with Remarks on the Causes of Death in the Fatal Cases. PMID- 20896568 TI - Two Hundred Additional Cases, completing One Thousand Cases Of Ovariotomy, with Remarks on Recent Improvements in the Operation. PMID- 20896569 TI - Further Observations on the Value of Stethometry in the Prognosis of Chest Disease. PMID- 20896570 TI - A Case of Abscess in the Neck, which in its course destroyed a large portion of the Carotid Artery, Jugular Vein, and Pneumogastric Nerve. PMID- 20896571 TI - On a Probable Cause of Lead Colic. PMID- 20896572 TI - Experience and Specimens of Ox-aorta Ligature, and some Remarks on the Variability of Catgut. PMID- 20896573 TI - A Case of Innominate Aneurism treated by Simultaneous Distal Ligature of the Carotid and Subclavian Arteries; with Remarks on the Behaviour of a Tendon Ligature. PMID- 20896574 TI - On the Development of a Layer of Elastic Fibres in Duct Cancer of the Breast. PMID- 20896575 TI - Case of Vascular Protrusion of the Eyeball. PMID- 20896576 TI - Nephrectomy by Lumbar Section. PMID- 20896577 TI - An Unusual Case of Warty Growths on the Face. PMID- 20896578 TI - A Case of Urticaria Tuberosa, with unusual Symptoms. PMID- 20896579 TI - The Immediate Treatment of Fractures of the Leg by Plaster-of-Paris Splints. PMID- 20896580 TI - On the Pathology of Acute Periostitis. PMID- 20896581 TI - Amoeboid Movements of the Colourless Blood-corpuscles in Leuchaemia. PMID- 20896582 TI - On Artificial Respiration in Stillborn Children: the amount of Ventilation secured by different methods. An Experimental Inquiry. PMID- 20896584 TI - On Gangrenous Eruptions in connection with Vaccination and Chicken-pox. PMID- 20896583 TI - On Artificial Respiration in Stillborn Children, second communication: the Expansibility of various parts of the Lungs. An Experimental Inquiry. PMID- 20896585 TI - Two cases of Unreduced, and two cases of Reduced, Dislocation of the Hip. PMID- 20896586 TI - On the Variations in the amount of Sulphocyanide of Potassium in the Saliva of Persons affected with different Diseases. PMID- 20896587 TI - Two cases of Congenital Macrostoma accompanied by Malformation of the Auricles, and by the presence of Auricular Appendages. PMID- 20896589 TI - On a Case of Tumour of the Bladder (in the male) successfully removed through a Perineal Section of the Urethra; with remarks on the applicability of the operation in certain cases. PMID- 20896588 TI - A successful case of Lumbar Colectomy, or Excision of a Stricture of the Descending Colon through an incision made for a Left Lumbar Colotomy; with remarks. PMID- 20896590 TI - On Wounds of the Theca Vertebralis, with discharge of Cerebro-spinal fluid. PMID- 20896591 TI - Two Cases of Laryngeal Growths; in one of which numerous sessile, in part subglottic recurrent Papillomata, and in the other a large, hard, broad-based, vascular Fibroma were successfully removed by endolaryngeal, mainly galvano caustic operations. PMID- 20896592 TI - On Thyrotomy for the removal of Foreign Bodies impacted in the interior of the Thyroid Cartilage. PMID- 20896593 TI - Concerning the action of Salts of Potash, Soda, and Ammonia on the Frog's Heart. PMID- 20896595 TI - Additional Cases of Osteitis Deformans. PMID- 20896594 TI - A successful case of Simultaneous Ligature of the Carotid and Subclavian Arteries for Innominate Aneurism. PMID- 20896596 TI - Notes of two cases of Malignant Pustule, together with a table of seventeen cases which have been treated at Guy's Hospital: With a Report on the microscopical examination of sections from a portion of the skin of the cheek affected with malignant pustule, removed during life from a patient of Mr. Davies-Colley. PMID- 20896597 TI - Case of Excision of a Gravid Uterus, with Epithelioma of the Cervix, with remarks on the operations of Blundell, Freund, and Porro. PMID- 20896598 TI - A case of Lithotomy, where a Tumour of the Prostate was successfully enucleated; with remarks on the removal of such growths. PMID- 20896599 TI - A case of Fibrous Polypous Tumour of the Bladder successfully removed. PMID- 20896600 TI - Three cases of Tumour arising from Skin-glands in the Dog, showing the connection between disorder of the glandular structure and function, and cancerous invasion of the connective tissue. PMID- 20896601 TI - The Surgical Uses of Kangaroo Tendons. PMID- 20896602 TI - Third communication on Artificial Respiration in Still-born Children; Mediastinal Emphysema and Pneumothorax in connection with Tracheotomy; an experimental Inquiry. PMID- 20896604 TI - Ophthalmoplegia Externa complicating a case of Graves' Disease. PMID- 20896603 TI - On the Great Frequency of Cardiac Murmurs in the Puerperal State. PMID- 20896605 TI - On the Endemic Haematuria of the South-East Coast of Africa: With an introduction. PMID- 20896606 TI - A Contribution to the Pathology of Diphtheritic Paralysis. PMID- 20896607 TI - A Second Case of Malformation of the Left Shoulder-Girdle; removal of the abnormal portion of bone; with remarks on the probable nature of the deformity. PMID- 20896608 TI - On Cases Described as "Acute Rickets," which are probably a combination of Scurvy and Rickets, the Scurvy being an essential, and the rickets a variable, element. PMID- 20896610 TI - Cavernous Naevus of the Rectum, proving fatal in an adult from Haemorrhage. PMID- 20896609 TI - Subperiosteal Haemorrhage (probably scorbutic) of three long Bones in a Rickety Infant. PMID- 20896611 TI - I. A Case of Purulent Pericarditis Treated by Paracentesis and by Free Incision, with recovery. II. The Statistics of Paracentesis Pericardii, with remarks. PMID- 20896613 TI - A Case of Asymmetry of the Brain, presenting peculiarities which bear upon the question of the connection between the Optic Nerves and Certain definite areae of the Cerebral Cortex. PMID- 20896612 TI - Gliomatous enlargement of the Pons Varolii in Children. PMID- 20896614 TI - A Case of Excision of an Enlarged Cancerous Kidney. PMID- 20896615 TI - A Case of Suppurating Traumatic Haematoma connected with the left Kidney, treated by puncture and antiseptic drainage. PMID- 20896616 TI - On the Bacillus of Leprosy. PMID- 20896617 TI - On Urticaria Pigmentosa or Xanthelasmoidea; Urticaria Pigmentosa (Sangster), U. Perstans Pigmentosa (Pick), Xanthelasmoidea (Tilbury Fox). PMID- 20896618 TI - Twelve Cases of Tumour of the Bladder (ten in the male and two in the female) in all of which an operation has been performed for the removal of the growth, with their histories and the results. PMID- 20896619 TI - On Dislocation of the Foot, with version and torsion of the Astragalus. PMID- 20896621 TI - A Case of Aneurism of the External Carotid Artery; ligature of the Common Carotid, with cure of the Aneurism; death from Paralysis on the thirty-fifth day. PMID- 20896620 TI - On Resection of Portions of Intestine. PMID- 20896622 TI - Aneurism of the Arch of the Aorta; ligature of the right Subclavian and Carotid Arteries; death by rupture of the Sac on the fifty-first day after the operation. PMID- 20896623 TI - A Case of Aneurism of the Arch of the Aorta involving the Innominate Artery, with remarks on the Distal Ligature. PMID- 20896624 TI - Fourth communication on Artificial Respiration in Still-born Children. Certain minor points. An experimental inquiry. PMID- 20896625 TI - The direct treatment of Psoas Abscess with Caries of the Spine. PMID- 20896626 TI - Radical cure of a large Spina Bifida in an Adult. PMID- 20896627 TI - On a form of Alcoholic Spinal Paralysis. PMID- 20896628 TI - Neurectomy of the Second Division of the Fifth Nerve. PMID- 20896629 TI - On the value of Systematic Examination of Stillborn Children. PMID- 20896631 TI - The Pathology of Myxoedema as illustrated in a typical case. PMID- 20896630 TI - Three cases of Xeroderma Pigmentosum (Kaposi) or Atrophoderma Pigmentosum. PMID- 20896632 TI - An average or "Composite" Temperature Chart of Smallpox. PMID- 20896634 TI - On the treatment of Pus-secreting Basic Cavities of the Lung by the method of Paracentesis and Free Drainage. PMID- 20896633 TI - A case of Gangrene of the Lung following Necrosis of the Temporal Bone, the result of Scarlet Fever. Treatment by Drainage. Recovery. PMID- 20896635 TI - Three forms of Spinal Deformity. PMID- 20896636 TI - On a particular form of Amnesia. Loss of nouns. PMID- 20896637 TI - Embolism of the Right Middle Cerebral Artery, producing Left Hemiplegia and Hemianaesthesia: absorption of a large portion of the Right Hemisphere: death seven years later. PMID- 20896639 TI - On the Weight of the Thyroid Body in persons dying from various causes. PMID- 20896638 TI - On Albuminuria with Parametritis. PMID- 20896640 TI - Cerebral Localisation. A Review and Forecast. Being the Marshall Hall Prize Oration. PMID- 20896642 TI - Investigations into the action of the Digitalis Group. PMID- 20896641 TI - Case of Spontaneous Inguinal Aneurism in a boy aged twelve years; for which the external iliac artery was tied. With a table of all the other recorded cases of external aneurism in persons under twenty years of age. PMID- 20896643 TI - On High Amputation for Senile Gangrene. PMID- 20896645 TI - Case of Double Simultaneous Distal Ligature for Innominate Aneurysm. PMID- 20896644 TI - Cases in which Perforation of the Mastoid Cells is necessary. PMID- 20896646 TI - Case of Displacement and Fracture of the Axis. Life prolonged for ten years. PMID- 20896648 TI - An Account of Two Families, several Members of which are Ataxic. PMID- 20896647 TI - Observations on the Radical Cure of Club-Foot, and Exhibition of Cases which have been Operated on. PMID- 20896649 TI - Fatal Haemoptysis: the Statistics of the last Fifteen Years of the Chest Hospital, Victoria Park; with Remarks upon Profuse Non-fatal Haemoptysis. PMID- 20896650 TI - Acute Peritonitis treated by Abdominal Section. PMID- 20896651 TI - A Case of Abdominal Section for Acute Circumscribed Peritonitis. Recovery. PMID- 20896653 TI - On a Case of Aneurism of the Abdominal Aorta, which caused Gangrene of the Right Lower Extremity, partly by Embolism, and partly by Pressure of the Inferior Vena Cava. PMID- 20896652 TI - Aneurism of Abdominal Aorta. Distal Compression-Cure of the Aneurism-Death from Gangrene of the Jejunum on Eleventh Day- Necropy #x2014; Remarks. PMID- 20896654 TI - Three Cases (Progressive Muscular Atrophy and Infantile Paralysis) illustrating the Localisation of Motor Centres in the Brachial Enlargement of the Spinal Cord. PMID- 20896656 TI - Notes on So-called Non-Ovarian Dermoid Abdominal Tumours. PMID- 20896655 TI - On the Pathological Histology of the Semilunar and Superior Cervical Sympathetic Ganglia. PMID- 20896657 TI - Case of Cerebral Tumour. PMID- 20896658 TI - The Experimental Production of Chorea and other Results of Capillary Embolism of the Brain and Cord. PMID- 20896659 TI - Fatty Tumours. PMID- 20896660 TI - Case of Cirsoid Aneurism on the Dorsum of the Foot, with Remarks on the Disease. PMID- 20896661 TI - On a Case of very Large Lympho-Sarcomatous Tumour of the Tongue. PMID- 20896662 TI - On Expiratory Cervical Emphysema, that is, Emphysema of the Neck occurring during Labour and during violent Expiratory Efforts. An Experimental Inquiry. PMID- 20896664 TI - On the Distribution of the "Tubercle Bacilli" in the Lesions of Phthisis. PMID- 20896663 TI - A Successful Case of Lumbar Nephrectomy for Renal Calculus. PMID- 20896665 TI - On Some Points regarding the Distribution of Bacillus Anthracis in the Human Skin in Malignant Pustule. PMID- 20896666 TI - A Case of So-called Actinomycosis of the Liver. PMID- 20896667 TI - A Case of Destruction of a Portion of the Axillary Artery by Sarcoma. PMID- 20896669 TI - On the Increase in Number of White Corpuscles in the Blood in Inflammation, especially in those Cases accompanied by Suppuration. PMID- 20896668 TI - Amputation at the Knee-joint by Disarticulation; with Remarks on the Amputation of the Leg by Lateral Flaps. PMID- 20896670 TI - A Communication on the Removal of a Growth from the Brachial Plexus, affecting the Roots of the Eighth Cervical and First Dorsal Nerves at their Emergence from the Intervertebral Foramina. PMID- 20896671 TI - Statistics of Mortality in the Medical Profession. PMID- 20896672 TI - On the Tapetum Lucidum. PMID- 20896673 TI - Enteric Fever at Suakin, with Some Cases of Malarial-enteric, or Typho-malarial Fever. PMID- 20896674 TI - A Case of Thoracic Aneurism treated by the Introduction of Steel Wire into the Sac. PMID- 20896675 TI - On the Changes which Occur in Bone and Soft Tissues after Ampuration of a Limb, and from certain other Conditions. PMID- 20896676 TI - A Case of General Seborrhoea or "Harlequin" Foetus. PMID- 20896677 TI - On Cardiography, with Special Reference to the Relation of the Time of Duration of Ventricular Systole to that of Diastolic Interval. PMID- 20896678 TI - Two Cases of Bronchiectasis treated by Paracentesis, with Remarks on the Mode of Operation. PMID- 20896679 TI - On Supra-pubic Lithotomy. PMID- 20896680 TI - A Case of Encysted Vesical Calculus of Unusually Large Size removed by Supra pubic Cystotomy. PMID- 20896681 TI - A Case of Supra-pubic Lithotomy, with Remarks on the Operation. PMID- 20896683 TI - Two Cases of Splenectomy. PMID- 20896682 TI - The Chemical Pathology of Respiration in Cholera. PMID- 20896685 TI - On the Development of Mammary Functions by the Skin of Lying-in Women. PMID- 20896684 TI - Diffuse Lipoma. PMID- 20896686 TI - The Ligation of the Larger Arteries in their Continuity. An Experimental Inquiry. PMID- 20896687 TI - Congenital Absence of Hair and Mammary Glands with Atrophic Condition of the Skin and its Appendages, in a Boy whose Mother had been almost wholly Bald from Alopecia Areata from the age of Six. PMID- 20896688 TI - The Morbid Anatomy and Pathology of Encysted and Infantile Hernia. PMID- 20896689 TI - On a Case of Multiple Neuromata. PMID- 20896690 TI - Some Statistics of Pneumonia, with especial Reference to the Relations of Delirium and Temperature. PMID- 20896691 TI - A Case of Ligature of the Left Common Carotid Artery wounded by a Fish-bone which had penetrated the Pharynx; with Remarks and an Appendix containing Forty-five Cases of Wounds of Blood-vessels by Foreign Bodies. PMID- 20896692 TI - Scarlatinal Albuminuria, and the Pre-albuminuric Stage, Studied by Frequent Testing. PMID- 20896694 TI - A Case of Multiple Embolism of the Arteries of the Extremities followed by the Formation of Aneurisms. With Remarks on the Relations of Embolism to Aneurism. PMID- 20896693 TI - On the Active Principle of Castor Oil. PMID- 20896695 TI - On the Effect upon the Femoral Artery of its Ligature for the Cure of Popliteal Aneurism. PMID- 20896696 TI - Richter's Hernia or Partial Enterocele. PMID- 20896697 TI - Clinical Observations on "Induration" in the Primary Lesion of Syphilis in Women. PMID- 20896698 TI - On a Case in which the Urinary Bladder was twice Ruptured; the first time by Violence; the second time (seven years after the first) by the giving way of the Adhesion whereby the Rent had been closed. PMID- 20896700 TI - Some New Facts concerning Gouty Parotitis and Gouty Orchitis. PMID- 20896699 TI - On some Dangers connected with the Use of the Aspirator as a means of Relieving the Distended Urinary Bladder, with Suggestions for the Treatment of Certain Cases of Retention of Urine. PMID- 20896702 TI - On a Case of Obstruction of One Ureter by a Calculus, accompanied by Complete Suppression of Urine. PMID- 20896701 TI - A case of Empyema, with Pulmonary Gangrene following Enteric Fever, treated by Perflation: With Remarks on the Method of Perflation, and its Value in the Treatment of Empyema. PMID- 20896703 TI - On a Case of Suppression of Urine, following injury to a Sacculated Kidney containing Calculi, the other Kidney being entirely disorganised. PMID- 20896705 TI - A Case of Sacculated Aortic Aneurism treated by the Introduction into the Sac of Thirty-two Feet of Steel Wire. PMID- 20896704 TI - A Case of Aneurism of the Abdominal Aorta treated by Laparotomy and the Introduction of Steel Wire into the Sac. PMID- 20896706 TI - A Case of Aneurism at the Root of the Neck, and in the Upper Part of the Chest in a very advanced stage, treated by the Introduction of Steel Wire. PMID- 20896707 TI - An Analysis of Ninety-three Cases of Writers' Cramp and Impaired Writing Power; making, with Seventy-five Cases previously reported, a total of One Hundred and Sixty-eight Cases. PMID- 20896708 TI - A Case of Intussusception of the Upper End of the Rectum due to Obstruction by a New Growth. Excision of the Intussusception; Suture of the Remaining Bowel; Complete Recovery. PMID- 20896709 TI - Results of an Experimental Inquiry as to the Best Method of Restoring the Canal after Removing Portions of the Small Intestine. PMID- 20896711 TI - The Relation of a Certain Form of Headache to the Excretion of Uric Acid. PMID- 20896710 TI - A Case of Extra-Uterine Gestation. PMID- 20896712 TI - Three Cases of Alcoholic Paralysis (Multiple Neuritis). PMID- 20896714 TI - Three Hundred additional Cases of Complete Ovariotomy and Twenty Cases of Exploratory Operation. PMID- 20896713 TI - Multiple Gangrene of the Skin in Infants and its Causes. PMID- 20896715 TI - On a Form of Chronic Inflammation of the Lips and Mouth, which sometimes ends Fatally, and is Usually attended by Disease of the Skin and Nalls. PMID- 20896716 TI - On a Case of Early Disseminated Myelitis occurring in the Exanthem Stage of Measles and Fatal on the eleventh day of that Disease: Report on the Microscopical Examination of the Spinal Cord. PMID- 20896717 TI - On Three Cases of Acute Tubercular Ulceration of the Fauces. PMID- 20896718 TI - A Case of Neurotomy of the Third Division of the Fifth Nerve, where it issues from the Foramen Ovale. PMID- 20896719 TI - A Case of Occlusion of the Left Bronchus by a Metal Pencil Cap, and its Removal by Tracheotomy. PMID- 20896720 TI - Influence of Salicylic Acid and its Salts on the Excretion of Uric Acid. PMID- 20896721 TI - On the Occurrence of Tubercular Disease of the Testis as a Local Affection, particularly with reference to the Desirability of Early Castration in Certain Cases. PMID- 20896722 TI - A Case of Intra-Peritoneal Rupture of the Bladder; Abdominal Section; Suture of the Bladder; Recovery. PMID- 20896723 TI - Relapsing Typhlitis treated by Operation. PMID- 20896724 TI - A Case of Neglected Dislocation of the Humerus followed by Paralysis of the Nerves of the Hand and Forearm, treated by Excision of the Head of the Humerus. PMID- 20896725 TI - On the Naked-Eye and Microscopical Variations of the Human Thyroid Body. PMID- 20896726 TI - A Case of Extroversion of the Bladder treated by Preliminary Narrowing of the Gap existing in the Pubic Symphysis by means of Division of the Sacro-Iliac Synchondroses. PMID- 20896727 TI - A Case of Wound of the Femoral Artery and Vein. Traumatic Varicose Aneurism; Ligature of both Artery and Vein; Recovery. With remarks on the Treatment of Wounds of the Femoral Artery and Vein. PMID- 20896728 TI - A Case of Double Nephrolithotomy in which Lateral and Median Lithotomy had been previously Performed, with Remarks on Sympathy between the Kidneys. PMID- 20896729 TI - Remarks on Splenectomy, with a Report of a successful Case. PMID- 20896731 TI - Effects in Health and Disease of some Drugs which cause Retention of Uric Acid, in contrast with the Action of Salicylates, as shown in a previous Paper. PMID- 20896730 TI - A further Contribution to the Study of Rheumatoid Arthritis. PMID- 20896733 TI - On the Value of the Tubercle Bacillus in Clinical Diagnosis. PMID- 20896732 TI - On the Results of the Treatment of Pulmonary Consumption by Residence at High Altitudes, as exemplified by an Analysis of 141 Cases. PMID- 20896734 TI - On the Relations between the Function, Structure, Origin, and Distribution of the Nerve-Fibres, which compose the Spinal and Cranial Nerves, being the Marshall Hall Prize Oration. PMID- 20896735 TI - A Case of Tumour of the Spinal Cord. Removal; Recovery. PMID- 20896736 TI - The Condition and Management of the Intestine after Abdominal Section considered in the light of Physiological Facts. PMID- 20896737 TI - An Undescribed Method by which the Superjacent Weight of the Body is transmitted in United or Ununited Fracture of the Neck of the Femur through an acquired Ilio Femoral Articulation; and the bearing of the principle involved upon the Surgery of the Hip-Joint. PMID- 20896739 TI - A Contribution to the Theory of the Nervous Origin of Rheumatoid Arthritis. PMID- 20896738 TI - A Case of Excision of a Tubercular Movable Kidney. PMID- 20896740 TI - On Primary Union after excision of Tubercular Hip-joints. PMID- 20896741 TI - Eighty Cases of Chorea: Antecedents, Family History, State of the Heart, and Subsequent History. PMID- 20896742 TI - On the Relation of Chorea to Rheumatism, with Observations of Eighty Cases of Chorea. PMID- 20896743 TI - Back-knee, Knock-knee, Bow-knee, and other Deformities resulting from Defect of Growth at the Epiphysial Lines. PMID- 20896745 TI - Colectomy, or Resection of the large Intestine for Malignant Disease. PMID- 20896744 TI - On a Case of Actinomycosis Hominis: With an appended Report on the Morphology of the Fungus. PMID- 20896746 TI - Pemphigus Vegetans (Neumann). PMID- 20896747 TI - On the Clinical Significance of Colourless or Clay-coloured Stools unaccompanied by Jaundice, and their connection with Disease of the Pancreas; and on the part played by the Pancreas in Eliminating Bile from the Intestines. PMID- 20896748 TI - The Causation and Pathology of the more commonly observed forms of Lateral Curvature of the Spinal Column. PMID- 20896749 TI - Twenty-five Cases of Nephrectomy by Abdominal Section. PMID- 20896750 TI - Remarks on some points affecting the Mortality of Abdominal Section. With Tables of Cases. PMID- 20896751 TI - Dermoid Cyst of the right side of the Chest communicating with a Bronchus. PMID- 20896753 TI - Plastic Operations on the Neck and Arms for Severe Cicatricial Deformities after Burns. PMID- 20896752 TI - A Case in which Acute Spasmodic Pain in the Left Lower Extremity was completely relieved by Sub-dural Division of the Posterior Roots of certain Spinal Nerves, all other treatment having proved useless. Death from Sudden Collapse and Cerebral Haemorrhage on the Twelfth Day after the Operation, at the commencement of Apparent Convalescence. PMID- 20896754 TI - A Case of Gastro-enterostomy, together with a Table of the Cases hitherto recorded. PMID- 20896755 TI - Influence of Phosphate of Soda on the Excretion of Uric Acid and some of the Conditions which prevent its Action. PMID- 20896756 TI - The Resuscitation of the Apparently Drowned. PMID- 20896757 TI - Removal by Operation of a Gangrenous Appendix Vermiformis containing a Faecal Concretion. Secondary Laparotomy through the Linea Alba for Suppurative Peritonitis. Recovery. PMID- 20896758 TI - Two Cases of Partial Obstruction of a Bronchus by a Foreign Body, with Remarks on the Operation of Tracheotomy for its Removal. PMID- 20896759 TI - Arthrectomy; Erasion of Joints. PMID- 20896760 TI - The AEtiology of Puerperal Fever. PMID- 20896761 TI - Acetonuria and its Relation to Diabetic Coma. PMID- 20896762 TI - The Mechanism of Suspension in the Treatment of Locomotor Ataxy. PMID- 20896764 TI - Rheumatism, its Treatment Past and Present; with special reference to recent Experimental Research on Salicylic Acids and their Salts. PMID- 20896763 TI - A Case of Hernia of the Caecum, entirely wanting in a Peritoneal Sac, in which Strangulation at the Internal Abdominal Ring co-existed with an Intussusception through the Ileo-caecal Valve. PMID- 20896765 TI - On the Symptomatology of Total Transverse Lesions of the Spinal Cord; with special reference to the condition of the various Reflexes. PMID- 20896766 TI - Analysis of 964 Cases of Operation for Calculus in the Bladder by Lithotomy and Lithotrity, with Remarks. PMID- 20896767 TI - On the History of Uric Acid in the Urine, with reference to the Formation of Uric Acid Concretions and Deposits. PMID- 20896768 TI - A Study of Fifty Consecutive Cases of Operation for the Radical Cure of Non strangulated Herniae. PMID- 20896769 TI - Salicin compared with Salicylate of Soda as to effect on the Excretion of Uric Acid, and value in the Treatment of Acute Rheumatism; with some deductions as to the Causation of the Disease. PMID- 20896770 TI - On the Condition of the Reflexes in Cases of Injury to the Spinal Cord; with special reference to the Indications for Operative Interference. PMID- 20896771 TI - Senile Hypertrophy and Senile Atrophy of the Skull. PMID- 20896772 TI - An Analytical and Clinical Examination of Lead-Poisoning in its Acute Manifestations. PMID- 20896773 TI - A Contribution to the Chemistry of Gout. PMID- 20896775 TI - A Case of Tubal Pregnancy, with remarks on the cause of Early Rupture. PMID- 20896774 TI - On Four Hundred Cases of Amputation performed at St. George's Hospital, from October, 1874, to June, 1888; with especial reference to the diminished Rate of Mortality. PMID- 20896776 TI - A Case of Cholecystenterostomy. PMID- 20896778 TI - Successful Removal of the entire Upper Extremity for Osteo-Chondroma. PMID- 20896777 TI - On Blood Tumours (Angeiomata and Angeiosarcomata) of Bone. PMID- 20896779 TI - Clinical Observations upon Respiration during Anaesthesia, with Special Reference to the Causes of Embarrassed and Obstructed Breathing. PMID- 20896780 TI - Nephrolithotomy (following Nephrectomy) for Total Suppression of Urine lasting five days; Complete Recovery and Good health five years after the Operation. PMID- 20896781 TI - A Case in which Large Calculi were removed from both Kidneys, Fatal Haemorrhage following the Second Operation. PMID- 20896782 TI - The Therapeutical Value of Venesection; its Indications and its Limits. PMID- 20896783 TI - Macrodactyly, and some other Forms of Congenital Overgrowth, and their Relation to Tumours. PMID- 20896784 TI - Two Cases of Idioglossia, with Phonographic Demonstration of the Peculiarity of Speech. PMID- 20896786 TI - On the Treatment of Strangulated Hernia when the Intestine is Gangrenous or Ulcerated. PMID- 20896785 TI - A Case of Defective Articulation. PMID- 20896787 TI - On Measles as a Cause of Endocarditis; being an Account of Four Cases in which Organic Mitral Murmurs developed during the Course of the Disease. PMID- 20896788 TI - On the Value of Tuberculin in the Treatment of Surgical Diseases. PMID- 20896789 TI - Thirteen Cases of Paget's Disease of the Nipple, with Special Reference to the Causation of the Malady by Psorosperms. PMID- 20896790 TI - On the Changes observed in Healthy Medium-sized Arteries and in Tendon Ligatures during the First Four Weeks after Ligation. PMID- 20896791 TI - Seven Cases of Excision of the Hip combined with the Hot-water Flushing Method; Primary Union in Six. PMID- 20896792 TI - Symptoms and Pathology of a Case of Acute Inflammation of the Mucous Membrane of the Ileum from Climatic Causes. PMID- 20896793 TI - A Case of Pancreatic Cyst successfully treated by Abdominal Section and Drainage. PMID- 20896794 TI - The Causation and Mode of Production of Pes Cavus. PMID- 20896795 TI - Soot in Cells of Chimney-sweep's Cancer. PMID- 20896796 TI - Suppurative Affections of the Testicle and Epididymis. PMID- 20896797 TI - On One Hundred and Fourteen Consecutive Cases of Operation for Calculus in the Bladder, performed at the Hospital for Sick Children, and a Comparison of the Methods adopted. PMID- 20896798 TI - Report of the Building Committee, as amended and adopted by the Council, February 5th, 1891. PMID- 20896799 TI - A Case of Actinomycosis of the Face and Neck. Operation. Cure. PMID- 20896800 TI - On the occurrence of Pleural Effusion in association with Disease of the Abdomen. PMID- 20896801 TI - An Analysis of Seventy-two Cases of Ununited Fracture occurring in the Long Bones of Children. PMID- 20896802 TI - On Tetanus as a Complication of Ovariotomy. PMID- 20896803 TI - Glandular Swelling in Neck; Conversion into a Pulsating Tumour like Aneurism; Ligature of the Common and External Carotids and of the Internal Jugular Vein; Cure. PMID- 20896804 TI - Gelatiniform Degeneration of Hydatid Cysts. PMID- 20896805 TI - The Changes in the Blood in the course of Rheumatic Attacks. PMID- 20896806 TI - "Antiseptic" Preparations of Catgut and Silk; their relation to Wound Infection. PMID- 20896807 TI - Case of Torsion of the Spermatic Cord, with Strangulation of the Epididymis and Testicle in an incompletely descended organ. PMID- 20896808 TI - Case of Torsion of the Spermatic Cord in a Dog. PMID- 20896809 TI - The Operative Treatment of Congenital Dislocation of the Hip. PMID- 20896811 TI - On the Symptoms and Pathology of Psilosis (Linguae et Intestini). PMID- 20896810 TI - A Case of Ligature of the Second Part of the Left Subclavian Artery for the Cure of an Axillary Aneurysm. PMID- 20896812 TI - On Renal Dropsy, with especial reference to the Circulation; together with some Considerations relating to Pulmonary Apoplexy in Renal Disease. PMID- 20896814 TI - Upon Amputation in Diabetes Mellitus. PMID- 20896815 TI - Two Cases of Pylorectomy and one of Jejunostomy, with remarks, and with a suggested modification of the former operation. PMID- 20896813 TI - Note on the alleged occurrence of Ovarian Pregnancy; being an explanation of some cases which have been published as belonging to this variety of Ectopic Gestation. PMID- 20896816 TI - A Case of Limited Lesion of Certain Spinal Nerves by Secondary Carcinoma of the Vertebrae and Dura Mater. PMID- 20896817 TI - A Case of Actinomycosis of the Vermiform Appendix causing Perityphlitis. PMID- 20896819 TI - On some Points in the Supra-vaginal Amputation of the Cervix Uteri for Cancer, with Special Reference to the Methods adopted in Cases where for Two Years and upwards the Disease has not recurred. PMID- 20896818 TI - A Case of Actinomycosis Hominis of the Urinary and Alimentary Tracts. Recovery. PMID- 20896820 TI - The Effects of the iodides on Arterial Tension and the Excretion of Urates. PMID- 20896822 TI - On the Absence of Sugar from Normal Human Urine. PMID- 20896821 TI - Cases to illustrate the Relationship which exists between Wryneck and Congenital Haematoma of the Sterno-mastoid Muscle. PMID- 20896823 TI - Two Cases of Knee Trouble with Difficulty in Locomotion, depending upon an Elongation of the Ligamentum Patellae, treated by Transplantation of the Tubercle of the Tibia: with Remarks. PMID- 20896825 TI - A Case of Fracture of both Bones of the Leg, occasioned by a very slight cause, in a Woman the Subject of Tabes Dorsalis. PMID- 20896824 TI - Some Cases of Fracture of Long Bones from Slight Causes in connection with Tabes Dorsalis, Syphilis, and Paraplegia. PMID- 20896826 TI - Case of Fibrous Polypus of the Prostatic Portion of the Urethra, associated with Profuse Haematuria and Prostatic Enlargement. Removal of the Growth and Recovery. PMID- 20896827 TI - On Resection of the Intestine and Immediate Suture in the Treatment of Gangrenous Hernia. PMID- 20896828 TI - Acute Renal Dislocation. PMID- 20896830 TI - On the Influence of Various Diets upon the Composition of the Urine and the General Condition of Patients suffering from Chronic Bright's Disease. PMID- 20896829 TI - On the Removal of a "Pressure-pouch" of the OEsophagus. PMID- 20896831 TI - Large Cystic Myoma of Uterus of over Twelve Years' Duration removed by Enucleation; Recovery: with Notes on Cystic "Fibroids;". PMID- 20896832 TI - On Enterorhaphy by Invagination (Maunsell's Operation), with a Case of Artificial Anus treated by this Method. PMID- 20896833 TI - On the Use of Atropine in Cholera. PMID- 20896834 TI - On Amputation for Diabetic Gangrene. PMID- 20896836 TI - On the Advantages of an Amputation through the Thigh, either as a Preliminary Operation to, or, in some cases, instead of, Amputation through the Hip, where the Hip-joint is itself diseased and the Patient in very bad Condition. PMID- 20896835 TI - A Case of Malignant Disease of the Thyroid Gland, with most Unusual Course. PMID- 20896837 TI - Two Cases illustrating the Treatment of advanced Hip-joint Disease by Mr. Howse's Method of Preliminary Amputation at the Knee. PMID- 20896839 TI - The Radical Treatment of severe Talipes Equino-varus in Children. PMID- 20896838 TI - Bursting of a large Hepatic Abscess into the Peritoneal Sac; Incision of this latter; Evacuation of Pus; Flushing; Recovery. PMID- 20896840 TI - On Albuminuric Ulceration of the Bowels. PMID- 20896841 TI - Abdominal Section for Intestinal Obstruction due to Multiple Hydatid Cysts; Recovery. PMID- 20896842 TI - On the (so-called) Spontaneous Disappearance of Solid Abdominal Tumours; with Three Cases. PMID- 20896843 TI - On Nerve Stretching and Splitting in Localised Interstitial Neuritis, Leprous and otherwise. PMID- 20896844 TI - Two Cases of Intussusception of the Large Intestine, due to the presence of a Papillomatous Growth, successfully reduced by introduction of the hand into the rectum, after removal of the growth. PMID- 20896845 TI - Cases of Pleurisy caused by the Pneumococcus, and with Constitutional Symptoms resembling those of Pneumonia. PMID- 20896846 TI - Ruptured Gastric Ulcer treated by Laparotomy, Gastric Suture, and Washing Out of the Peritoneum; Recovery. PMID- 20896847 TI - A Case of Resection and Immediate Suture of Intestine which had been Strangulated eighty-one hours; Recovery. PMID- 20896848 TI - On Persistence of the Thyreoglossal Duct, with Remarks on Median Cervical Fistulae and Cysts due to Embryonic Remnants. PMID- 20896849 TI - A Case of Extra-peritoneal Vesical Hernia. PMID- 20896850 TI - An Operation for the Cure of Cleft of the Hard and Soft Palate. PMID- 20896852 TI - Upon Two Cases of Uretero-lithotomy. PMID- 20896851 TI - A Case of Extreme Prolapse of the Female Urethra in a Child aged Six, with Remarks. PMID- 20896853 TI - The Influence of Different Kinds of Soil on the Comma and Typhoid Organisms. PMID- 20896854 TI - A Review of Cases manifesting Pain at the Heart or Morbid Acceleration of the Heart's Contraction (Tachycardia) subsequently to Influenza. PMID- 20896855 TI - A Case of Acanthosis Nigricans. PMID- 20896856 TI - Disease of many Joints, probably of Syphilitic Origin. PMID- 20896857 TI - A Case of "False" Disseminated Sclerosis due to Measles, with remarks on the occurrence of certain wide-spread Nervous Disorders after this and other Infectious Diseases. PMID- 20896858 TI - On a Disseminated Fibrosis of the Kidney found in Cases of Infective Endocarditis, Aortitis, and allied disease; its Pathological Significance, and chief Clinical Features. PMID- 20896859 TI - Arthrectomy of Elbow and Ankle. PMID- 20896860 TI - The Surgical Treatment of Diffuse Septic Peritonitis; with successful cases. PMID- 20896861 TI - Varieties of Intestinal Obstruction dependent on Gall-stones, with a series of cases. PMID- 20896863 TI - On Nervous Symptoms and Morbid Changes in the Spinal Cord in Certain Cases of Profound Anaemia. PMID- 20896862 TI - The Causation of AEgophony. PMID- 20896864 TI - A Case of Large Pelvic Hydatid successfully treated by Perineal Incision and Drainage with observations. PMID- 20896866 TI - A Case of Actinomycosis Extensively Involving the Skin. PMID- 20896865 TI - On the Probable Pathological Identity of the various forms of Acute Septic Inflammations of the Throat and Neck, hitherto described as Acute OEdema of the Larynx, OEdematous Laryngitis, Erysipelas of the Pharynx and Larynx, Phlegmon of the Pharynx and Larynx, and Angina Ludovici. PMID- 20896867 TI - Micro-organisms in the Healthy Nose. PMID- 20896868 TI - Further Observations on the Development of Mammary Functions by the Skin of Lying in Women. PMID- 20896869 TI - A Case of Intra-peritoneal Rupture of the Bladder; Suture; Recovery. with Remarks on the Inflation test: with a Table of Twenty Cases of Rupture of the Bladder treated by Suture since 1888. PMID- 20896870 TI - The Treatment of Respiratory Affections by means of Large Medicinal Injections through the Larynx. PMID- 20896871 TI - A Year's Experience of the Use of Sulphur in Surgery. PMID- 20896872 TI - The Influence of Heredity in Phthisis. PMID- 20896873 TI - Illustrations of some Modes of Death after Ovariotomy. PMID- 20896874 TI - On Posture in its Relation to Surgical Operations under Anaesthetics. PMID- 20896875 TI - The Parasite of Malaria, as observed in the Malarial Fevers of the South of Spain. PMID- 20896876 TI - A Note on the Appearances found in the Tissues in a Fatal Case of Pernicious Malaria at Sierra Leone. PMID- 20896877 TI - Excision of a Portion of Liver for Tumour. PMID- 20896878 TI - A Case of Neoplasm Cyst of the Brain treated by Operation. PMID- 20896879 TI - On the Effects produced by the Retention of Foreign Bodies for Lengthened Periods in the Bronchial Tubes. PMID- 20896880 TI - Note on the Endemic Fever of the Mediterranean. PMID- 20896881 TI - Observations and Experiments on Intestinal and Gastrointestinal Anastomosis. PMID- 20896882 TI - On the Use of Guaiacum in the Treatment of Chronic Gouty Affections, and its Value in warding off Acute Attacks. PMID- 20896883 TI - Case of Splenic Anaemia (spleno-megalie primitive), with an account of the disease. PMID- 20896884 TI - Renal Colic in Infants. PMID- 20896885 TI - On Prevesical Abscess. PMID- 20896886 TI - Ecchymoses from Natural Causes. PMID- 20896887 TI - The Exceptions to Colles' Law. PMID- 20896888 TI - Locomotor Ataxy occurring in a Young Woman; Tabetic Arthropathy with Dislocation of both Hips; Six Pregnancies occurring in the course of the Disease. PMID- 20896889 TI - A Case of Perforating Typhoid Ulcer treated by Operation and Suture, and resulting in Recovery. PMID- 20896890 TI - Typhoid Fever; Convalescence; Symptoms of Perforation; Laparotomy; no Lesion found; Recovery. PMID- 20896891 TI - On Jaundice and on Perforation of the Gall-bladder in Typhoid Fever. PMID- 20896892 TI - On the Presence of the Typhoid Bacilli in the Urine of Patients suffering from Typhoid Fever. PMID- 20896893 TI - On some Affections of the Nervous System met with in Association with an Attack of Enteric Fever. PMID- 20896894 TI - On a Condition of Mixed Premature and Immature Development. PMID- 20896895 TI - On some Points in the Surgical Physiology of the Foot. PMID- 20896896 TI - On the Clinical Bearing of some Experiments on Peritoneal Infections. PMID- 20896897 TI - A Case of Large Solid Tumour removed with success from the Retro-peritoneal Space. PMID- 20896898 TI - The Parasite of Malaria in the Fevers of Sierra Leone. PMID- 20896899 TI - Pulsating Empyema (Empyema Pulsans). PMID- 20896901 TI - Non-tuberculous Posterior Basic Meningitis in Infants. PMID- 20896900 TI - Compound Depressed Fracture of the Skull; Cerebral Abscess; Hernia Cerebri; Recovery; with a consideration of the subject of Hernia Cerebri based upon One Hundred and Nine collected Cases. PMID- 20896902 TI - On the Relations between Bodily Development, Nutrition, and Brain Conditions in their Pathological Aspects. PMID- 20896903 TI - Case of Subclavian Aneurism successfully treated by Ligature. PMID- 20896904 TI - Case of Pharyngeal Abscess Haemorrhage; Ligature of Carotid Arteries. PMID- 20896905 TI - On Irreducible Hernia. PMID- 20896906 TI - On the Occurrence of Musical Mitral Murmurs in connection with Aortic Stenosis. PMID- 20896907 TI - On a Form of Chronic Joint Disease in Children. PMID- 20896908 TI - On a Case of Amnesia and other Speech Defects of Eighteen Years' Duration, with Autopsy. PMID- 20896909 TI - Infantile Cerebral Degeneration with Symmetrical Changes at the Macula. PMID- 20896910 TI - A Case of Calcareous Metamorphosis of the Tracheal Lymphatic Glands; formation of Mediastinal Abscess and establishment of Bronchial Fistula; subsequent Perforation of the Wall of the Arch of the Aorta; long-continued repeated Haemoptysis; death from Hemiplegia. PMID- 20896912 TI - Removal of the Entire Upper Extremity for Recurrent Carcinoma after Removal of the Breast. PMID- 20896911 TI - Latency and Freedom from Recurrence after Operations for Reputed Carcinoma of the Breast; illustrated by 108 tabulated cases. PMID- 20896913 TI - A Further Contribution towards the Pathology of the Pernicious Malarial Fevers of Sierra Leone, and our Knowledge of the Parasite with which they are associated. PMID- 20896914 TI - On the Epidemic Malarial Fever of Assam or Kala-azar. PMID- 20896915 TI - A Case of Albumosuria in which the Albumose was Spontaneously Precipitated. PMID- 20896916 TI - Intra-pleural Tension. PMID- 20896918 TI - Five Cases of Acute Leukaemia. PMID- 20896917 TI - A Case of Cyst of the Urachus, with Notes on Urachal and So-called "Allantoic Cysts". PMID- 20896920 TI - Acute Dilatation of the Heart in Rheumatic Fever. PMID- 20896919 TI - The Influence on Gout of the Mineral Constituents of various Vegetables. PMID- 20896921 TI - Obscure Cystic Tumour of the Bladder containing two Calculi successful removal by Supra-pubic Cystotomy. PMID- 20896922 TI - Acute Dilatation of the Heart in the Rheumatism and Chorea of Childhood. PMID- 20896923 TI - On Mesenteric Cysts, with two Cases in Young Children subjected to Operation. PMID- 20896924 TI - Discussion on the Prevention of Enteric Fever. PMID- 20896925 TI - Fibrinous or Membranous Rhinitis and its Relation to Diphtheria. PMID- 20896926 TI - Aortic Aneurysm as a Cause of Hypertrophy of the Left Ventricle. PMID- 20896928 TI - Gonococcus Joint Disease in Infants secondary to Purulent Ophthalmia; with Twenty three Cases. PMID- 20896927 TI - A Case of Aortic Aneurysm; Involvement of Sensory Nerve-roots; Spontaneous Fracture of Vertebral Column; Laminectomy; Death. PMID- 20896929 TI - On the Effects produced in the Human Subject by the Administration of Definite Mixtures of Nitrous Oxide and Air and of Nitrous Oxide and Oxygen. PMID- 20896930 TI - A Case of Extirpation of a Large Non-pulsating Aneurysm, involving the Common, Internal, and External Carotid Arteries of the Right Side of the Neck; with Remarks on Non-pulsation in Aneurysms and the Treatment of Aneurysms by Extirpation. PMID- 20896931 TI - The Morbid Anatomy and Pathology of Dr. Bradshaw's Case of Myelopathic Albumosuria. PMID- 20896932 TI - Two Cases where Multiple Calculi were removed from Large Narrow-necked Sacculi connected with the Male Urinary Bladder. PMID- 20896934 TI - On Prevesical Hernia, with the relation of a Case in which Subacute Strangulation Occurred. PMID- 20896933 TI - On the Treatment of Pulmonary Tuberculosis by Anti-tubercular Serum. PMID- 20896935 TI - The Clinical Examination of the Haemic Leucocytes. PMID- 20896936 TI - A Case of Rheumatic Pericarditis and Extreme Dilatation of the Heart, with an Investigation into the Microscopy of Rheumatic Heart Disease. PMID- 20896937 TI - A Contribution to the Study of Alkaptonuria. PMID- 20896938 TI - The Results of Segregation of Cases and Moving from Infected Sites in eradicating the Assam Epidemic Malarial Fever, or Kala-azar. PMID- 20896939 TI - The Remote Prognosis of Pericarditis. PMID- 20896940 TI - Congenital Hypertrophic Stenosis of the Pylorus. PMID- 20896942 TI - A Distinct Variety of Hip-joint Disease in Children and Young Persons. PMID- 20896941 TI - Address on the Spinal Animal. PMID- 20896943 TI - On an Improved Method of Treatment of Separation of the Lower Epiphysis of the Femur. PMID- 20896945 TI - An Investigation into the Nature of the Changes produced in the Nerve-cells of the Cerebral Cortex by the Action of Tetanus Toxin. PMID- 20896944 TI - Discussion on the Open-Air Treatment of Tuberculosis (November 14th, 28th, and December 12th). PMID- 20896946 TI - The Conduct of the Mastoid Operation for the Cure of Chronic Purulent Otorrhoea: Together with Remarks on the Cases which require the Operation. PMID- 20896947 TI - The Complete Mastoid Operation for the Cure of Chronic Suppurative Disease of the Middle Ear: Observations on the Selection of Cases for Operation. PMID- 20896948 TI - A Case of Acute Meniere's Symptoms in Splenomedullary Leucocythaemia, with Special Reference to the Anatomical Changes found in Acute Leucocythaemic Affections of the Ear: Including a Pathological Report on the Present Case. PMID- 20896949 TI - A Case of Spleno-medullary Leukaemia with Haemorrhage into the Cochlea and Semicircular Canals, associated with Deafness and Loss of Balance. PMID- 20896950 TI - The Skin Affections occurring in Bright's Disease. PMID- 20896951 TI - A Case of Rupture of the OEsophagus caused by Vomiting, together with a Table of Seventeen other Cases. PMID- 20896952 TI - A Case of Sarcomatous Tumour of the Gastro-hepatic Omentum removed by Operation, with Remarks on the Diagnosis of such Tumours. PMID- 20896954 TI - On the Wounded in the Transvaal War: an Address delivered before the Royal Medical and Chirurgical Society, May 22nd, 1900. PMID- 20896953 TI - On the Wounded in the Transvaal War: an Address delivered before the Royal Medical and Chirurgical Society, May 8th, 1900. PMID- 20896955 TI - On the Wounded in the Transvaal War: an Address delivered before the Royal Medical and Chirurgical Society, May 22nd, 1900. PMID- 20896957 TI - Ophthalmoplegia Externa complicating a Case of Graves's Disease. PMID- 20896956 TI - On some of the Medical and Surgical Complications of Pyorrhoea Alveolaris. PMID- 20896958 TI - On Two Cases bearing upon the Question of the Limitations of Enterectomy. PMID- 20896959 TI - On a Case of Intestinal Intoxication due to Appendicitis without Local Symptoms. PMID- 20896960 TI - A Case of Pernicious Anaemia; with Observations regarding Mode of Onset, Clinical Features, Infective Nature, Prognosis, and Antiseptic and Serum Treatment of the Disease. PMID- 20896961 TI - The Prognosis and Treatment of Cases of Ascites occurring in the course of Alcoholic Cirrhosis of the Liver; with Special Reference to the Treatment by Operation. PMID- 20896962 TI - Discussion on Immunity, on March 12th 1901. PMID- 20896963 TI - Suggestions for a Possible Improvement in the Method of Removing Stones and Morbid Growths from the Interior of the Bladder. PMID- 20896964 TI - The After-results in Forty Consecutive Cases of Vaginal Hysterectomy performed for Cancer of the Uterus. PMID- 20896965 TI - On Metabolism in Phthisis. PMID- 20896966 TI - Median Perineal Urethrotomy and Cystotomy through a Superficial Transverse Incision, after Celsus. PMID- 20896968 TI - A Contribution to the Study of Intestinal Sand, with Notes on a Case in which it was passed. PMID- 20896967 TI - Arterial Haemorrhage from the Ear and its Control by Ligature of the Common Carotid Artery. PMID- 20896969 TI - An Account of the Epidemic Outbreak of Arsenical Poisoning occurring in Beer Drinkers in the North of England and the Midland Counties in 1900. PMID- 20896970 TI - A Case of Acute Leukaemia. PMID- 20896971 TI - A Pharyngeal Pouch of large size removed by Operation. PMID- 20896972 TI - Recent Advances in the Knowledge of Malaria. PMID- 20896973 TI - Report on Two Experiments on the Mosquito-malaria Theory, instituted by the Colonial Office and the London School of Tropical Medicine. PMID- 20896974 TI - Wind Exposure and Phthisis. PMID- 20896976 TI - A Contribution to the Study of Tropical Abscess of the Liver. PMID- 20896975 TI - Acute Dilatation of the Stomach, with Illustrative Cases. PMID- 20896977 TI - Some General and Etiological Details concerning Leprosy in the Sudan. PMID- 20896978 TI - Leprosy in Natal and Cape Colony. PMID- 20896979 TI - The Possibility of Recovery from the Active Stage of Malignant Endocarditis, illustrated by Cases and Specimens. PMID- 20896980 TI - A Contribution to the Study of Malignant Endocarditis. PMID- 20896981 TI - Ulceration of the OEsophagus and Stomach due to swallowing Strong Hydrochloric Acid; Lessons of Treatment deduced from Three Cases. PMID- 20896982 TI - Modern Methods of Vaccination and their Scientific Basis; an Address. PMID- 20896983 TI - Clinical and Experimental Observations introducing a Discussion on the Regeneration of Peripheral Nerves; an Address. PMID- 20896984 TI - Ateleiosis, a Disease characterised by Conspicuous Delay of Growth and Development. PMID- 20896985 TI - Case of Intestinal Obstruction due to the Pressure of a Vesical Sacculus upon a Coil of Small Intestine. PMID- 20896986 TI - An Analysis of Forty-six Cases of Cancer of the Breast which have been operated upon and survived the Operation from Five to Thirty-five Years; with Remarks upon the Treatment of Recurrent Growths, including the Disease of the Second Breast, Operative and otherwise. PMID- 20896988 TI - Two Cases of Ligature of the Left Carotid for Aneurysm of the Arch of the Aorta, with the Post-mortem Specimens of Four Cases. PMID- 20896987 TI - About Alkaptonuria. PMID- 20896989 TI - The Surgical Treatment of Obstruction in the Common Bile-duct by Concretions, with especial reference to the Operation of Choledochotomy as modified by the Author, illustrated by Sixty Cases. PMID- 20896991 TI - The Clinical Associations of Reduplicated First Sounds, based on a Series of One Hundred and Nine Cases. PMID- 20896990 TI - A Note on the Causation and Treatment of Thrombosis occurring in connection with Typhoid Fever. PMID- 20896992 TI - The Clinical History and Symptoms of One Hundred and Twenty Cases of Exophthalmic Goitre. PMID- 20896993 TI - Paroxysmal Haemoglobinuria of Traumatic Origin. PMID- 20896994 TI - The Differentiation of the Continued and Remittent Fevers of the Tropics by the Blood Changes. PMID- 20896996 TI - Latent Empyema in Infants. PMID- 20896995 TI - On Acute Cerebro-spinal Meningitis caused by the Diplococcus intracellularis of Weichselbaum: a Clinical Study. PMID- 20896997 TI - A Statistical Inquiry into the Prognosis and Curability of Epilepsy based upon the results of treatment. PMID- 20896998 TI - A Further Report on the Remarkable Series of Cases of Molluscum Fibrosum in Children communicated to the Society by Dr. John Murray in 1873. PMID- 20896999 TI - A Report on Four Cases of Acute Septic Inflammation of the Throat, with Bacteriological Examination of each: a Sequel to a similar Paper read by Sir Felix Semon, April, 1895. PMID- 20897000 TI - Rise of Blood-pressure in Later Life. PMID- 20897001 TI - Supra-pubic Cystotomy in Cases of Tumour of the Bladder, with Special Reference to the Causes of Mortality and of Recurrence of the Growth. PMID- 20897002 TI - A Case of Aneurysm of the Abdominal Aorta treated by the Introduction of Silver Wire; with a Description of Instruments invented and constructed by Mr. G. H. Colt to facilitate the introduction of Wire into Aneurysms. PMID- 20897003 TI - The Treatment of Aneurysm by Subcutaneous Injection of Gelatine. PMID- 20897004 TI - A Case of Multiple Myeloma (Myelomatosis) with Bence-Jones Proteid in the Urine (Myelopathic Albumosuria of Bradshaw, Kahler's Disease),and a Summary of Published Cases of Bence-Jones Albumosuria: With a Report on the Chemical Pathology. PMID- 20897006 TI - The Operative Treatment of Gastric and Duodenal Ulcers. PMID- 20897005 TI - Congenital Hypertrophic Stenosis of the Pylorus and its Treatment by Pyloroplasty. PMID- 20897007 TI - Large Bile Cyst of the Liver: Jaundice without Cholelithiasis; incision and drainage; recovery. PMID- 20897009 TI - Observations on Metabolism in the Febrile State in Man. PMID- 20897008 TI - On Hour-glass Stomach. PMID- 20897010 TI - Remarks on Fifty Consecutive Cases of Perforated Gastric and Duodenal Ulcer treated by Laparotomy. PMID- 20897011 TI - The Cardiac Dulness in Cases of Cancer. PMID- 20897012 TI - Peptic Ulcer of the Jejunum. PMID- 20897013 TI - The Mental Condition in Epilepsy in Relation to Prognosis. PMID- 20897014 TI - The Economic Value of the Sanatorium Treatment for the Working Classes, based upon After-histories. PMID- 20897015 TI - The Surgical Anatomy of the Normal and Enlarged Prostate, and the Operation of Supra-pubic Prostatectomy. PMID- 20897016 TI - Anaemia Pseudo-leukaemica Infantum. PMID- 20897017 TI - Leucocyte Counts in Eighty-three Cases of Appendicitis: the Limitations of Leucocytosis as an indication for Laparotomy. PMID- 20897019 TI - The Anaemias of Infancy. PMID- 20897018 TI - On the Elasticity of the Aorta: being a Contribution to the Study of Arterial Sclerosis. PMID- 20897020 TI - The Effects of a Proteid Dietary (Raw Meat): an Experimental and Clinical Study. PMID- 20897021 TI - Protracted and Recrudescent Infection in Diphtheria and Scarlet Fever. PMID- 20897022 TI - On a Case of Properitoneal Hernia. PMID- 20897023 TI - Description of a Simple and Efficient Method of Performing Artificial Respiration in the Human Subject, especially in Cases of Drowning; to which is appended Instructions for the Treatment of the Apparently Drowned. PMID- 20897025 TI - The Pathology and Prevention of Secondary Parotitis. PMID- 20897024 TI - Hypertrophic Pulmonary Osteo-arthropathy. PMID- 20897026 TI - The Seventh Cervical Rib and its Effects upon the Brachial Plexus. PMID- 20897027 TI - The Influence of Stigmata of Degeneration upon the Prognosis of Epilepsy. PMID- 20897028 TI - An Analysis of Ninety-nine Cases of Inoperable Carcinoma of the Breast treated by Oophorectomy. PMID- 20897030 TI - Actinomycosis of the Gall-bladder. PMID- 20897029 TI - A Case of "Splenomegalic" or "Myelopathic" Polycythaemia, with True Plethora and Arterial Hypertonia, without Cyanosis. PMID- 20897031 TI - Adenoma of the Gall-bladder. PMID- 20897033 TI - A Series of 123 Cases of Choledochotomy for Calculi in the Common Duct. PMID- 20897032 TI - The Operation of Jejunostomy: With a Description of a New Method. PMID- 20897034 TI - A Case of Chronic Jaundice and Great Enlargement of the Liver due to Primary Carcinoma of the Extra-hepatic Bile-ducts commencing at the Junction of the Hepatic Ducts. PMID- 20897035 TI - The Reaction of Phenylhydrazin with other Substances than Dextrose occurring in the Urine. PMID- 20897036 TI - The Consumptive Working Man: A Study of the Social and Economic Conditions which Govern his Life. PMID- 20897037 TI - Abdominal Tuberculosis in Childhood: A Clinical Study. PMID- 20897038 TI - Symptomatic Parotitis. PMID- 20897039 TI - On a Group of Associated Congenital Malformations: Including almost complete absence of the Muscles of the Abdominal Wall, and Abnormalities of the Genito urinary Apparatus. PMID- 20897040 TI - Ankylostomiasis: Principally as affecting Coal and Metalliferous Miners. PMID- 20897041 TI - Some Changes which take place in the Lungs and Pleura, chiefly in Pulmonary Tuberculosis, as shown by Skiagraphy. PMID- 20897042 TI - Discussion on the Subsequent Course and Later History of Cases of Appendicitis after Operation. PMID- 20897043 TI - Torsion of the Great Omentum. PMID- 20897045 TI - Two Cases of Fungating Endocarditis followed by Convalescence. PMID- 20897044 TI - Chloroform Anaesthesia: A Special Discussion introduced by four short Papers describing Apparatus. PMID- 20897046 TI - Contributions to Centenary Fund, and Balance-sheet. PMID- 20897047 TI - On the General Principles of the Therapeutic Inoculation of Bacterial Vaccines as applied to the Treatment of Tuberculous Infection. PMID- 20897048 TI - Primary Malignant Disease of the Vermiform Appendix. PMID- 20897049 TI - Report on the Sections Submitted from the Two Cases (Nos. 11 and 42). PMID- 20897050 TI - "Interrupted Circulation" as a Therapeutic Agent: With Illustrative Cases of Rheumatoid Arthritis. PMID- 20897051 TI - The Use of Rectal Injections of an Antistreptococcus Serum in Gonorrhaeal Infections and in Certain Cases of Purpura Haemorrhagica. PMID- 20897052 TI - Capillary Circulation and Blood-Pressure and the Conditions that Control them. PMID- 20897053 TI - An Improved Method of Performing the "Pancreatic" Reaction in the Urine. PMID- 20897055 TI - The Influence of Posture on the Normal Cardiac Sounds and on the Normal Cardiac Dulness. PMID- 20897054 TI - Inflammation and Peritonitis Regarded as Physiological Processes. PMID- 20897056 TI - Influenzal Endocarditis: With an Account of Two Cases in which the Influenza Bacillus was repeatedly Cultivated from the Blood during Life. PMID- 20897058 TI - Achondroplasia. PMID- 20897057 TI - The Effects of Violet Infusion on Malignant Growths: An Interim Report. PMID- 20897059 TI - Three Cases of Myoclonus. PMID- 20897061 TI - A Study of some Points in Relation to the Administration of Tuberculin T.R: Controlled by Observation of the Opsonic Index in Pulmonary Tuberculosis. PMID- 20897060 TI - Observations on Endemic Goitre in the Chitral and Gilgit Valleys. PMID- 20897062 TI - A Review of 282 Operations for Non-malignant Diseases of the Stomach. PMID- 20897064 TI - Mitral Stenosis and Pregnancy. PMID- 20897063 TI - Notes on One Hundred Cases of Intra-Cranial Tumour, with Special Reference to the Ocular Symptoms. PMID- 20897065 TI - Appendicitis and Gangrene of the Vermiform Appendix Considered as Separate Diseases. PMID- 20897066 TI - Submucous Excision of Deviations and Spurs of the Nasal Septum: With a Report of 30 Operations. PMID- 20897067 TI - The Treatment of Tuberculosis by Tuberculin. PMID- 20897069 TI - Sequel to a Case of Subclavian Aneurysm reported in the 'Transactions,' 1897. PMID- 20897068 TI - A Paper on the Value of a Serum (Doyen's) in Cases of Malignant Disease. PMID- 20897070 TI - The Treatment of Tuberculosis of the Urinary System by Tuberculin (T.R.). PMID- 20897071 TI - On Some Aspects of Dilatation of the Heart. PMID- 20897072 TI - Observations on a Case of Chyluria Occurring in England: With a Report of the Post-mortem Examination. PMID- 20897073 TI - The Early Diagnosis and Cure of the Pre-Suppurative Stage of Amoebic Hepatitis. PMID- 20897074 TI - A Common Sporadic Seven-day Fever of Indian Ports Simulating Dengue. PMID- 20897075 TI - The Diagnosis of Addison's Disease. PMID- 20897076 TI - Discussion on the Operative Treatment of Non-malignant Ulcer of the Stomach and its Chief Complications, with Indications, Limitations, and Ultimate Results. PMID- 20897077 TI - Dr. Walter Bayley and His Works, 1529-1592. PMID- 20897078 TI - A Case of Cervical Myelopathic Trichosis. PMID- 20897079 TI - Ligature of the Renal Vessels by the Transperitoneal Method for the Cure of Persistent Urinary Renal Fistula: With Notes of One Successful Case. PMID- 20897080 TI - Changes Occurring in the Number of Red Corpuscles and their Haemoglobin Content in Cases of Pulmonary Tuberculosis Undergoing Sanatorium Treatment. PMID- 20897081 TI - Observations upon Cheyne-Stokes' Respiration. PMID- 20897083 TI - Idiopathic Cyanosis due to Sulph-haemoglobinaemia: Enterogenous Cyanosis. PMID- 20897082 TI - On the de novo Origin of Bacteria, Bacilli, Vibriones, Micrococci, Torulae, and Moulds, in Certain Previously Superheated Saline Solutions, Within Hermetically Sealed Vessels. PMID- 20897084 TI - On the Condition of the Blood-vessels During Shock. PMID- 20897085 TI - The Causes of Colitis, with Special Reference to its Surgical Treatment with an Account of 36 Cases. PMID- 20897086 TI - On Volvulus of the Entire Small Intestine, Caecum, and Ascending Colon: Operation and Recovery with an analysis of nine other cases of complete volvulus. PMID- 20897087 TI - Fractures of the Odontoid Process of the Axis. PMID- 20897088 TI - Experiments on Prolonged Protein Feeding with Special Reference to the Thyroid Gland and the Osseous System. PMID- 20897089 TI - Demonstration (by Epidiascope and Microscope) of the Bodies described by him in 1895 as "Protozoa" in Syphilitic Lesions, with subsequent observations. PMID- 20897090 TI - Demonstration of the variations of the Spirochaeta pallida, etc. (Epidiascope and Microscope). PMID- 20897092 TI - Demonstration of Series of Drawings and Radiographs illustrating Dislocations and Fractures of Thumb and Great Toe. PMID- 20897091 TI - Demonstration of a Case of Recovery after Operation for simultaneous-(a) Acute Obstruction by Band formed of Vermiform Appendix and Omentum, and (b) General Septic Peritonitis. PMID- 20897093 TI - Observations upon Two Cases of Cheyne-Stokes' Respiration. PMID- 20897095 TI - Report of the Hon. Treasurers on the Financial Position of the Society at the Date of Amalgamation. PMID- 20897094 TI - Human and Bovine Tuberculosis: With Special Reference to Treatment by Special Kinds of Tuberculin. PMID- 20897109 TI - Purpura haemorrhagica with Fatal Result from Cerebral Haemorrhage. PMID- 20897096 TI - Union of Medical Societies: Final Report of the Committee of Representatives; Draft of Scheme for Amalgamation. PMID- 20897111 TI - Fatal Lymphocythaemia in Early Life. PMID- 20897122 TI - OEdema of Hands and Feet with Mediastinal Affection. PMID- 20897123 TI - Haemangiectatic Hypertrophy of the Foot, possibly of Spinal Origin. PMID- 20897128 TI - Report on Dr. Essex Wynter's Case of Cyanotic Anaemia. PMID- 20897124 TI - Myxoedema with Optic Atrophy. PMID- 20897142 TI - Multiple Idiopathic Haemorrhagic Sarcoma of the Skin. PMID- 20897146 TI - Myxoedema, with Unusual Features. PMID- 20897149 TI - Pigmentation with Enlarged Spleen and Leucopenia (? Splenic Anaemia). PMID- 20897152 TI - Splenic Polycythaemia with Cyanosis. PMID- 20897156 TI - Methaemoglobinaemia of twelve years' standing. PMID- 20897163 TI - Polycythaemia, with Enlarged Spleen without Cyanosis, in a girl aged 18. PMID- 20897185 TI - Verrucose Naevus. PMID- 20897186 TI - Chronic OEdema of the Face. PMID- 20897194 TI - Sclerodermia (Morphoea). PMID- 20897219 TI - Two Cases of Congenital Syphilis with late Cutaneous and Mucous Membrane Lesions of the Gummatous or Phagedaenic type. PMID- 20897233 TI - Morphoea in a Woman aged 65. PMID- 20897256 TI - Glossitis in a Girl aged 31/2. PMID- 20897261 TI - Haemangiectatic Hypertrophy of the Foot, possibly of Spinal Origin. PMID- 20897258 TI - Two Cases of Elephantiasis graecorum. PMID- 20897270 TI - Bilateral Telangiectases of the Trunk with a History of Marked Epistaxis in Childhood and recent Rectal Haemorrhage. PMID- 20897285 TI - Unusually Generalized Naevus verrucosus zoniformis. PMID- 20897290 TI - Morphoea. PMID- 20897314 TI - The Treatment of Leukaemia, Exophthalmic Goitre, Sarcoma, &c., by X-rays. PMID- 20897316 TI - Gonorrhoeal Warts. PMID- 20897327 TI - Swelling of the Right Arytaenoid, with Loss of Movement of the Right Vocal Cord. PMID- 20897343 TI - Large Post-nasal Polypus removed from a Boy aged 141/2. PMID- 20897374 TI - Bilateral Sarcoma of the Upper Maxillae: (With Microscopical Section.). PMID- 20897381 TI - A Patient in whom an OEdematous Fibroma had been removed from the Left Vocal Cord. PMID- 20897409 TI - Swelling of the Arytaenoid. PMID- 20897393 TI - Multiple Hereditary Developmental Angeiomata (Telangiectases), with Recurring Haemorrhages. PMID- 20897446 TI - Suppurating Haematoma of the Septum Nasi, with a Fistulous Opening in the Gingivo labial Recess. PMID- 20897417 TI - Necrosis of the Arytaenoid Cartilage. PMID- 20897493 TI - Ischaemic Disturbance of the Right Upper Extremity. PMID- 20897511 TI - Haemangiectatic Hypertrophy of the Foot, possibly of Spinal Origin. PMID- 20897499 TI - Disease of the Cervical Vertebrae, with Pressure Symptoms. PMID- 20897555 TI - Haematosalpinx complicating Myoma. PMID- 20897549 TI - A Case of Caesarean Hysterectomy for Traumatic Atresia of the Vagina, the Patient having previously undergone a Successful Operation for a Vesico-vaginal Fistula due to the same Injury. PMID- 20897566 TI - Tumour of Foetal Head. PMID- 20897567 TI - A Case of Intra-uterine Death of the Foetus occurring in Six Consecutive Pregnancies, with Observations upon the Importance of the Examination of the Foetal Tissues for the presence of the Spirochaeta pallida. PMID- 20897570 TI - Haematosalpinx with Acute Symptoms following Retroversion of Fibroid Uterus. PMID- 20897604 TI - Placenta praevia with Delivery of Complete Gestation Sac at the twenty-eighth Week. PMID- 20897572 TI - Three Cases of Caesarean Hysterectomy for Stenosis of the Vagina. PMID- 20897606 TI - A Paravaginal Fibro-myoma weighing 21/2 lb. PMID- 20897612 TI - An Improved Demonstration Pelvis with attached Foetal Skull for Demonstrating to Students the Mechanism of Labour. PMID- 20897613 TI - Unilateral Haematometra removed by Operation. PMID- 20897620 TI - OEdematous Fibroma of Pelvis. PMID- 20897622 TI - Haemorrhage into the Pons varolii as the Immediate Cause of Death in the Eclampsia of Pregnancy. PMID- 20897628 TI - Some Clinical Notes on Pyorrhoea Alveolaris. PMID- 20897624 TI - Bilateral Haemorrhagic Ovarian Cysts. PMID- 20897652 TI - Unilateral Hysterical Nerve Deafness of Sudden Onset, with Hemianaesthesia and other allied Stigmata. PMID- 20897642 TI - A Case demonstrating a Point in the Treatment of Pyorrhoea. PMID- 20897666 TI - Notes on Partial Grafting, with the aid of Local Anaesthesia, in the After treatment of the Radical Mastoid Operation. PMID- 20897702 TI - Three Specimens of the Larvae of Eristalis tenax, passed by the Bowel. PMID- 20897757 TI - Demonstration of the use of Bruning's Instrument for the Direct Examination of the Larynx, Trachea, and OEsophagus. PMID- 20897761 TI - Two Brothers, one having Diffuse Periostitis of both Tibiae and the other an Affection of the Knee, probably due to Congenital Syphilis. PMID- 20897764 TI - Feet Deformed by Gonorrhoeal Rheumatism. PMID- 20897766 TI - Anaesthetic Leprosy. PMID- 20897788 TI - Uraemia or Meningitis? PMID- 20897783 TI - Three Cases illustrating the Treatment of Septicaemia by Vaccine Therapy. PMID- 20897797 TI - Trophoedema following Trauma. PMID- 20897796 TI - Scleroderma of the Extremities associated with Angioneurotic OEdema. PMID- 20897800 TI - Pernicious Anaemia treated by Lactobacillin. PMID- 20897810 TI - Congenital Heart Disease, with Extreme Secondary Polycythaemia and Orthostatic Albuminuria. PMID- 20897815 TI - Splenectomy for (?) Splenic Anaemia. PMID- 20897817 TI - Polycythaemia. PMID- 20897820 TI - Polycythaemia. PMID- 20897821 TI - Splenomegalic Polycythaemia. PMID- 20897835 TI - Two Cases of Congenital OEdema of a Family Type. PMID- 20897836 TI - So-called Trophoedema of the Left Lower Extremity. PMID- 20897837 TI - Persistent Hereditary OEdema confined to One Leg. PMID- 20897838 TI - General OEdema (Toxic) without Albuminuria. PMID- 20897841 TI - Variable OEdema of Lower Extremities. ? Wandering Thrombosis. PMID- 20897840 TI - Anomalous OEdema. PMID- 20897844 TI - Apparent Muscular Hypertrophy following OEdema of the Left Leg (due to Venous Thrombosis). PMID- 20897842 TI - Anomalous OEdema. PMID- 20897855 TI - Recurrent Whitlows and Bullae. PMID- 20897872 TI - Multiple Haemorrhages into the Skin and Subcutaneous Tissue in a Girl aged 10. PMID- 20897874 TI - Spontaneous Disappearance of an Endothelioma (Naevo-xanthoma). PMID- 20897880 TI - Leukaemic Nodules in the Skin in a Woman, aged 58. PMID- 20897883 TI - A Series of Cases Treated with Liquid Air, with a Demonstration of the Method of Application in a Case of Port-wine Naevus. PMID- 20897884 TI - Three Cases of Raised Vascular Naevi cured by Carbon-dioxide Snow. PMID- 20897890 TI - Cultures of Trichophyton Rosaceum from Two Cases of Tinea Barbae. PMID- 20897901 TI - Vascular Naevus of Unusual Type. PMID- 20897918 TI - Morphoea. PMID- 20897956 TI - The Treatment of Naevus by Electrical Methods, with Notes of 1,600 Cases. PMID- 20897992 TI - Inter-arytaenoid and Subglottic Infiltration of Fifteen Months' Duration, causing Difficulty of Breathing which necessitated Tracheotomy. PMID- 20897965 TI - Notes on the Value of Bismuth in the X-ray Examination of OEsophagus and Colon. PMID- 20898017 TI - Kuhn's Laryngeal Intubation Anaesthetic Apparatus for Administering Chloroform and Sealing the Larynx as a Substitute for Laryngotomy in Sanguinary Operations in the Mouth and Jaws, &c. PMID- 20898001 TI - Removal of Foreign Bodies by Bronchoscopy and OEsophagoscopy. PMID- 20898019 TI - Angeioneurotic OEdema. PMID- 20898031 TI - The "Teat" of a Comforter removed from the OEsophagus of a Child 4 days old. PMID- 20898033 TI - Fixation of the Left Cord, with Swelling of the Left Arytaenoid Region. PMID- 20898073 TI - Epithelioma; primary in Posterior Wall of Pharynx, now invading OEsophagus and Larynx. PMID- 20898035 TI - Foreign Body removed from the OEsophagus. PMID- 20898079 TI - Angioneurotic OEdema in a Male aged 48. PMID- 20898081 TI - Excision of Half the Larynx for Large Carcinomatous Tumour of the Arytaenoid. PMID- 20898124 TI - Haematoma of the Right Vocal Cord closely simulating a Fibroma. PMID- 20898169 TI - Myopathy with Gigantic OEdema and Albuminuria. PMID- 20898125 TI - The Further History of "A Case for Diagnosis. ? Continuous Fibroma of Neck and Larynx, or Malignant Disease of the Larynx with Enlargements of Glands in the Neck.". PMID- 20898192 TI - Apoplectiform Cerebral Haemorrhage. Operation. Evacuation of Blood. Slow Improvement. PMID- 20898197 TI - Dystocia due to Distension of the Urinary Bladder of the Foetus, with Remarks on Renal Secretion in utero. PMID- 20898200 TI - A Fatal Case of Accidental Haemorrhage, partly concealed, with Intraperitoneal Bleeding from both Fallopian Tubes. PMID- 20898204 TI - The Bacteria of the Puerperal Uterus, with especial reference to the Presence of Haemolytic Streptococci. PMID- 20898203 TI - Operation at End of Fifth Month for Extra-uterine Gestation with Living Foetus; Recovery without Recurrent or Secondary Haemorrhage. PMID- 20898221 TI - Haemorrhage into an Ovarian Sarcoma producing Symptoms resembling Torsion. PMID- 20898222 TI - Haemorrhage into the Great Omentum and Peritoneal Cavity following a Strain. PMID- 20898235 TI - Tumour of the Ovary. ? Adenofibroma or Endothelioma. PMID- 20898236 TI - Foetal Chondrodystrophia as a Cause of Brow Presentation and Dystocia. PMID- 20898250 TI - Caesarean Section and Total Abdominal Hysterectomy for Retroflexion of the Uterus at Term by Fibromyoma adherent in Douglas's Pouch. PMID- 20898253 TI - Parovarian Cyst with Intracystic Haemorrhage from Torsion of the Fallopian Tube. PMID- 20898268 TI - The Treatment of a Denture, Swallowed and Impacted in the OEsophagus, by means of Killian's OEsophageal Tube. PMID- 20898287 TI - Sections of the Human Cochlea through the Organ of Corti, showing Beaded Nerve fibril traversing the Tunnel of Corti, and Cell Fibrillae projecting from the Hair-cells. PMID- 20898291 TI - Cerebellar Abscess secondary to Infective Labyrinthitis associated with Acute Inflammatory OEdema of the Brain; Recovery; Details of Operative Procedures. PMID- 20898310 TI - Portal Thrombosis, associated with Stricture of the Urethra and Double Mitral Disease: fatal Haematemesis. PMID- 20898322 TI - The Action of Splenotoxic and Haemolytic Sera on the Blood and Tissues. PMID- 20898326 TI - Discussion on Proposed General Anaesthetics Act, 1908. PMID- 20898325 TI - Anaesthesia in the Human Subject, with known Percentages of Chloroform Vapour. PMID- 20898328 TI - Treatment of Shock during Anaesthesia. PMID- 20898327 TI - Discussion on the Proposed General Anaesthetics Act, 1908. PMID- 20898330 TI - The Bacteriology of Summer Diarrhoea. PMID- 20898332 TI - The AEtiology of Enteric Fever in Belfast in relation to Water Supply, Sanitary Circumstances, and Shellfish. PMID- 20898337 TI - Toxaemia apparently produced by Ascaris lumbricoides. PMID- 20898401 TI - AEtiology of that Dislocation of the Hip commonly regarded as Congenital. PMID- 20898395 TI - Symmetrical Bilateral Helical Fistulae, Unilateral Branchial Fistula, and Pre auricular Tubercle. PMID- 20898411 TI - Stenosis of the Isthmus Aortae, with Patent Ductus Arteriosus and Patent Interventricular Septum. PMID- 20898408 TI - Acute Leucocythaemia. PMID- 20898418 TI - A Girl aged 7 years showing Misplaced and Rudimentary Patellae, Congenital Dislocation of the Hip, and Coxa valga. PMID- 20898414 TI - Cerebral Haemorrhage in an Infant aged 2 months. PMID- 20898422 TI - Complete Ectopia vesicae. Transplantation of the Ureters into the Rectum by the Extraperitoneal Method. PMID- 20898457 TI - The British Pharmacopoeia: its Scope and Object. PMID- 20898447 TI - The Repeated Strangulation of an Obturator Hernia necessitating its Radical Cure, with Remarks upon Obturator Herniae in General. PMID- 20898460 TI - The Treatment of Acute Toxaemias. PMID- 20898491 TI - Pyaemic Knee- and Shoulder-joints treated by Tapping and Incision. PMID- 20898483 TI - Excision of both Maxillae. PMID- 20898492 TI - Traumatic Pancreatic Cyst cured by Operation, and followed twelve years later by Medullary Leukaemia. PMID- 20898500 TI - Spleno-medullary Leukaemia: Intercurrent Erysipelas. PMID- 20898516 TI - OEsophageal Growth under Treatment by Radium. PMID- 20898503 TI - Exophthalmic Goitre in a Man with Symmetrical Telangiectases of the Ocular Conjunctivae. PMID- 20898536 TI - Sequel of a Case of Pigmentation of the Circum-oral Skin and of the Buccal Mucosa in Pernicious Anaemia. PMID- 20898541 TI - Demonstration by the Ultra-microscope of living Treponema pallidum and various Spirochaetes. PMID- 20898545 TI - Sequel of a Case of Sclerodermia of the Extremities (Sclerodactylia, Acroteric Sclerodermia of Hutchinson) associated with a previous and family history of Angioneurotic OEdema. PMID- 20898551 TI - Excision of the Larynx, lower part of the Pharynx, and Upper End of the OEsophagus for Malignant Disease (Squamous-celled Carcinoma) of those Structures. PMID- 20898561 TI - Two Cases of Congenital OEdema with Cardiac Defect in Mother and Daughter. PMID- 20898552 TI - Pneumococcic Colitis with Hyperpyrexia; Severe Haemorrhage treated by Appendicostomy. PMID- 20898575 TI - Pigmentation of the Circum-oral Skin and of the Buccal Mucosa in Pernicious Anaemia. PMID- 20898567 TI - Transverse Fracture of both Patellae, with much separation of Fragments, treated by Operation. PMID- 20898587 TI - Linear Naevus with combined Verrucose and Vascular Elements. PMID- 20898591 TI - Sections from a Case of Linear Naevus. PMID- 20898611 TI - Symmetrical Plantar Naevoid Tumours in an Infant. PMID- 20898655 TI - Linear Naevus of Unusual Type (Naevus Acneiformis). PMID- 20898646 TI - Disseminated Lupus in a Girl aged 41/2. PMID- 20898668 TI - Myxoedema in a Woman aged 41. PMID- 20898660 TI - Specimen of Spirochaeta Pallida prepared with Indian ink, with Demonstration of Method. PMID- 20898681 TI - Electro-therapeutics in Gynaecology: (Presidential Address). PMID- 20898670 TI - Linear Naevus of Unusual Character in a Boy aged 18. PMID- 20898695 TI - The Treatment of Naevi by Electricity, Cautery, and Refrigeration. PMID- 20898724 TI - Vaccine Therapy: its Treatment, Value, and Limitations. PMID- 20898737 TI - Tuberculous Perichondritis of Cricoid and Arytaenoid Cartilages. PMID- 20898747 TI - OEsophageal Stenosis in a Man, aged 53. PMID- 20898739 TI - Papilloma of the Larynx in a Boy aged 61/2, of four years' duration, cured by Tracheotomy and repeated Operations by Direct Laryngoscopy. PMID- 20898791 TI - Tuberculosis of the Larynx, with considerable Dysphagia, treated and relieved by Congestion Hyperaemia. PMID- 20898788 TI - Loss of Voice with Dyspnoea in a Woman, aged 26. PMID- 20898792 TI - Large Globular Dilatation of the Upper Third of the OEsophagus above a Malignant Stricture. PMID- 20898799 TI - Swelling on Left Side of Neck, accompanied by Dyspnoea, in a Male aged 28. PMID- 20898809 TI - Ulcer of Doubtful Nature on the Left Arytaenoid Cartilage in a Man aged 63. PMID- 20898829 TI - Tuberculosis of all the Left Vocal Cord and Inter-arytaenoid Space, in a Lady aged 46, completely healed by Two Months' Silence and Sanatorium Treatment. PMID- 20898827 TI - Complete Occlusion of Left Nostril by Deflected Triangular Cartilage in a Girl aged 71/2. PMID- 20898835 TI - Extensive Tuberculosis of the Epiglottis, left Ary-epiglottic Fold, and Left Inter-arytaenoid Space, in a Gentleman aged 47, completely healed by the Galvano cautery and Sanatorium Treatment. PMID- 20898852 TI - Paresis of Palate, Pharynx, and OEsophagus. PMID- 20898841 TI - Two Cases of Foreign Bodies: (A) in Lung, (B) in OEsophagus. PMID- 20898895 TI - Syringomyelia with Total Anaesthesia. PMID- 20898875 TI - The Diagnostic Value of an Analysis of the Faeces in Diseases of the Pancreas. PMID- 20898910 TI - Cerebral Haemorrhage from Luetic Vessels. PMID- 20898917 TI - Pontine Thrombosis causing Anaesthesia of the Fifth Nerve and Hemianaesthesia of the same side. PMID- 20898931 TI - Pelvic Haematocele of Ovarian Origin. PMID- 20898939 TI - Extensive Retroperitoneal Haematocele complicating a large Uterine Fibroid: Operation: Cure. PMID- 20898932 TI - Placenta Praevia in which it was deemed advisable to perform Caesarean Section. PMID- 20898945 TI - Abscess of the Ovary probably due to Infection by the Amoeba coli. PMID- 20898949 TI - Points for the Use of, and Indications for, Electrotherapy in some Gynaecological Affections. PMID- 20898952 TI - The Place of Caesarean Section in the Treatment of Placenta Praevia. PMID- 20898959 TI - Caesarean Section in the Treatment of Eclampsia Gravidarum, with Notes of a Successful Case. PMID- 20898958 TI - Pregnancy in a Septate Uterus treated by Abdominal Hysterectomy 5 Months after the Death of Foetus at Full Term. PMID- 20898962 TI - Tubal Mole, with OEdema of the Connective Tissue of the Villi. PMID- 20898964 TI - Fibrosis of the Uterus causing Persistent Haemorrhagia. PMID- 20898965 TI - Double Uterus (Atresia of one-half) with Dysmenorrhoea. PMID- 20898976 TI - Myxofibroma of an Ovary removed under Spinal Anaesthesia. PMID- 20898966 TI - Leucoplakic Vulvitis and its Relation to Kraurosis Vulvae and Carcinoma Vulvae. PMID- 20898981 TI - Posterior Caesarean Section followed by Total Hysterectomy for Fibroids. PMID- 20899000 TI - Some Observations on the Bacteriology of Pyorrhoea Alveolaris, and the Treatment of the Disease by Bacterial Vaccines. PMID- 20899003 TI - The Vaccine Treatment of Early Cases of Pyorrhoea Alveolaris. PMID- 20899004 TI - The Bacteriology of Pyorrhoea Alveolaris and the Results of Treatment by Bacterial Vaccines: (Discussion). PMID- 20899026 TI - Twenty Specimens of Chronic Middle-ear Suppuration and its Sequelae, Eighteen of the Bones being of the Infantile types and two Cellular. PMID- 20899031 TI - Thickening of the Cartilage of both Auricles (?) Othaematoma. PMID- 20899041 TI - Deformity of both Pinnae resulting from Perichondritis following Double Mastoid Operation. PMID- 20899071 TI - Heart Massage in Heart Failure during Anaesthesia. PMID- 20899053 TI - Attempts to produce Chondromatous or Osteomatous Growths by the Grafting of Foetal Bones. PMID- 20899082 TI - The Choice of the Anaesthetic. PMID- 20899085 TI - Summer Diarrhoea and Enteric Fever. PMID- 20899087 TI - Discussion on Dr. Niven's paper on "Summer Diarrhoea and Enteric Fever.". PMID- 20899089 TI - Discussion on Dr. Niven's paper on "Summer Diarrhoea and Enteric Fever.". PMID- 20899088 TI - Discussion on Dr. Niven's paper on "Summer Diarrhoea and Enteric Fever.". PMID- 20899091 TI - Discussion on Dr. Niven's paper on "Summer Diarrhoea and Enteric Fever.". PMID- 20899090 TI - Discussion on Dr. Niven's paper on "Summer Diarrhoea and Enteric Fever.". PMID- 20899092 TI - Discussion on Dr. Niven's paper on "Summer Diarrhoea and Enteric Fever.". PMID- 20899093 TI - Discussion on Dr. Niven's paper on "Summer Diarrhoea and Enteric Fever.". PMID- 20899094 TI - Discussion on Dr. Niven's paper on "Summer Diarrhoea and Enteric Fever.". PMID- 20899095 TI - Discussion on Dr. Niven's paper on "Summer Diarrhoea and Enteric Fever.". PMID- 20899096 TI - Discussion on Dr. Niven's paper on "Summer Diarrhoea and Enteric Fever.". PMID- 20899121 TI - Pathological Report on Case of Myelogenous Leukaemia in an Infant, aged 18 months. PMID- 20899100 TI - The Communication of Diarrhoea from the Sick to the Healthy. PMID- 20899130 TI - Specimen of Peritoneal Growths from a Case of Lymphocythaemia, with blood-slides. PMID- 20899169 TI - Congenital OEdema with Dilatation of the Intestinal Lymphatics. PMID- 20899157 TI - Acute Inflammation in an Appendix, involuted into the Lumen of the Caecum, which then formed the Apex of an Intussusception; Operation; Recovery. PMID- 20899172 TI - Prolapse of Intestine through Ectopia Vesicae. PMID- 20899189 TI - Congenital OEdema of the Leg. PMID- 20899190 TI - Specimen of the Urinary Organs of a Boy who Died apparently from Uraemia; Diphtheritic Membrane being found in the Trachea after Death. PMID- 20899247 TI - A Fatal Case of Poisoning by Phosphorus, taken as an Abortifacient, with Unusual Subcutaneous Haemorrhages. PMID- 20899191 TI - Myelogenous Leukaemia in an Infant, aged 18 months. PMID- 20899287 TI - Two Cases of Secondary Anaemia associated with Achylia, with Comments. PMID- 20899282 TI - Splenomegaly (? Congenital Family Cholaemia). PMID- 20899288 TI - A Subsequent Report on a Case of Excision of the Larynx, Lower Part of the Pharynx, and Upper End of the OEsophagus for Malignant Disease (Squamous-celled Carcinoma) of those Structures. PMID- 20899295 TI - Ectopia Vesicae in a Female Child. PMID- 20899292 TI - Specimens illustrating the Removal of Foreign Bodies from the Air-passages and the OEsophagus. PMID- 20899305 TI - Morphoea affecting Right Frontal Region and Orbit. PMID- 20899303 TI - Urgent Dyspnoea and OEdema of the Glottis in a Woman, aged 50, due to Haemorrhage into the Thyroid. PMID- 20899323 TI - Double Proptosis due to a Growth, Lymphoma (Haemangio-lymphadenoma), invading each Orbit. PMID- 20899312 TI - "Addisonian Anaemia" (Idiopathic Pernicious Anaemia). PMID- 20899325 TI - The Treatment of Splenic Anaemia by Splenectomy. PMID- 20899331 TI - Large Cavernous Naevus of Foot. PMID- 20899354 TI - Gonorrhoeal Keratosis of Hands and Feet. PMID- 20899386 TI - Naevo-lipomata in an Infant. PMID- 20899357 TI - Cultures of Violet Endothrix Trichophyton from a Case of "Eczematoid" Ringworm of the Fungus associated with Tinea Barbae. PMID- 20899389 TI - Melanodermia associated with Pernicious Anaemia. PMID- 20899402 TI - An Unusual Case of Linear Naevus. PMID- 20899418 TI - Unilateral Pigmentary Naevus. PMID- 20899421 TI - Two Cases of Naevus Unius Lateris. PMID- 20899422 TI - Naevus Pigmentosus, Verrucosus et Pilosus. PMID- 20899437 TI - Maculo-anaesthetic Leprosy. PMID- 20899432 TI - Naevi of peculiar appearance in a Girl, aged 12. PMID- 20899441 TI - Functional Hysterical Trophoedema. PMID- 20899451 TI - Large Pigmented Vascular Sclerosing Naevus in a Girl, aged 10. PMID- 20899475 TI - Ulceration of the Pharynx, due to Pyorrhoea. PMID- 20899454 TI - The Rontgen-ray Examination of the OEsophagus. PMID- 20899476 TI - Party-wall Cancer of Larynx and OEsophagus. PMID- 20899490 TI - Carcinoma of OEsophagus. PMID- 20899489 TI - Permanent Styletted Oro-oesophago-gastric Tube which had been in situ for Thirteen Weeks. PMID- 20899534 TI - OEdema of Conjunctiva from Acute Frontal Sinusitis. PMID- 20899557 TI - Stricture of the Lower End of the OEsophagus-Spasmodic (?). PMID- 20899523 TI - Malignant Stricture of the OEsophagus. PMID- 20899562 TI - Carcinoma of OEsophagus. (?) Temporary Cure under Radium Treatment. PMID- 20899566 TI - Two Specimens of the Quadrilateral Cartilage (Nasal Septum) showing Fenestrae; Removed by Submucous Resection. PMID- 20899572 TI - A New Pattern Expanding OEsophagoscope. PMID- 20899567 TI - Denture removed from the OEsophagus. PMID- 20899573 TI - An Improved OEsophago-gastroscope, combining the Methods of Direct and Indirect Vision. PMID- 20899585 TI - Demonstration on a Living Subject of the Hill-Herschell Method of Combined Direct and Indirect Gastroscopy by Means of a New Type of OEsophago-gastroscope. PMID- 20899593 TI - Fungating Carcinoma of OEsophagus. Disappearance of Fungation and Ulceration after Treatment by Radium. PMID- 20899606 TI - Carcinoma of OEsophagus. Dysphagia Treated by a New Form of Intubation Apparatus. PMID- 20899598 TI - Malignant Stricture of the OEsophagus. PMID- 20899657 TI - Haematosalpinx with Torsion of the Tubes. PMID- 20899651 TI - Tic Douloureux illustrating the Anaesthesia produced by Alcohol Injection of the Superior Maxillary and Supra-orbital Nerves. PMID- 20899659 TI - Gravid Uterus ruptured through the Scar of a Caesarean Section. PMID- 20899664 TI - The Indications for, and Technique of, Caesarean Section and its Alternatives, in Women with Contracted Pelves, who have been long in Labour and exposed to Septic Infection: An Address Introductory to a Discussion on the Subject. PMID- 20899665 TI - Adenomatosis Vaginae: a hitherto undescribed condition. PMID- 20899666 TI - The Indications for, and Technique of, Caesarean Section and its Alternatives, in Women with Contracted Pelves, who have been long in Labour and exposed to Septic Infection. PMID- 20899668 TI - The Indications for, and Technique of, Caesarean Section and its Alternatives, in Women with Contracted Pelves, who have been long in Labour and exposed to Septic Infection. PMID- 20899667 TI - The Indications for, and Technique of, Caesarean Section and its Alternatives, in Women with Contracted Pelves, who have been long in Labour and exposed to Septic Infection. PMID- 20899670 TI - The Indications for, and Technique of, Caesarean Section and its Alternatives, in Women with Contracted Pelves, who have been long in Labour and exposed to Septic Infection. PMID- 20899669 TI - The Indications for, and Technique of, Caesarean Section and its Alternatives, in Women with Contracted Pelves, who have been long in Labour and exposed to Septic Infection. PMID- 20899671 TI - The Indications for, and Technique of, Caesarean Section and its Alternatives, in Women with Contracted Pelves, who have been long in Labour and exposed to Septic Infection. PMID- 20899672 TI - The Indications for, and Technique of, Caesarean Section and its Alternatives, in Women with Contracted Pelves, who have been long in Labour and exposed to Septic Infection. PMID- 20899673 TI - The Indications for, and Technique of, Caesarean Section and its Alternatives, in Women with Contracted Pelves, who have been long in Labour and exposed to Septic Infection. PMID- 20899674 TI - The Indications for, and Technique of, Caesarean Section and its Alternatives, in Women with Contracted Pelves, who have been long in Labour and exposed to Septic Infection. PMID- 20899675 TI - Discussion on the Indications for, and Technique of, Caesarean Section and its Alternatives, in Women with Contracted Pelves, who have been long in Labour and exposed to Septic Infection. PMID- 20899676 TI - Discussion on the Indications for, and Technique of, Caesarean Section and its Alternatives, in Women with Contracted Pelves, who have been long in Labour and exposed to Septic Infection. PMID- 20899678 TI - Discussion on the Indications for, and Technique of, Caesarean Section and its Alternatives, in Women with Contracted Pelves, who have been long in Labour and exposed to Septic Infection. PMID- 20899677 TI - Discussion on the Indications for, and Technique of, Caesarean Section and its Alternatives, in Women with Contracted Pelves, who have been long in Labour and exposed to Septic Infection. PMID- 20899679 TI - Discussion on the Indications for, and Technique of, Caesarean Section and its Alternatives, in Women with Contracted Pelves, who have been long in Labour and exposed to Septic Infection. PMID- 20899681 TI - Discussion on the Indications for, and Technique of, Caesarean Section and its Alternatives, in Women with Contracted Pelves, who have been long in Labour and exposed to Septic Infection. PMID- 20899680 TI - Discussion on the Indications for, and Technique of, Caesarean Section and its Alternatives, in Women with Contracted Pelves, who have been long in Labour and exposed to Septic Infection. PMID- 20899682 TI - Discussion on the Indications for, and Technique of, Caesarean Section and its Alternatives, in Women with Contracted Pelves, who have been long in Labour and exposed to Septic Infection. PMID- 20899684 TI - Discussion on the Indications for, and Technique of, Caesarean Section and its Alternatives, in Women with Contracted Pelves, who have been long in Labour and exposed to Septic Infection. PMID- 20899683 TI - Discussion on the Indications for, and Technique of, Caesarean Section and its Alternatives, in Women with Contracted Pelves, who have been long in Labour and exposed to Septic Infection. PMID- 20899685 TI - Discussion on the Indications for, and Technique of, Caesarean Section and its Alternatives, in Women with Contracted Pelves, who have been long in Labour and exposed to Septic Infection. PMID- 20899686 TI - Discussion on the Indications for, and Technique of, Caesarean Section and its Alternatives, in Women with Contracted Pelves, who have been long in Labour and exposed to Septic Infection. PMID- 20899693 TI - The Nature of Haematocolpos Fluid, with Deductions as to the Chemical Composition of the Menstrual Discharge and the Cause of its Normal Non-coagulability, also of the Acidity of the Vaginal Secretion; and the Character of the Obstructing Membrane, with its Bearing on the Development of the Vagina; together with a Report of Three Cases of Haematocolpos. PMID- 20899701 TI - Six Cases of "Utriculoplasty" for Uterine Haemorrhage, one of which was followed by pregnancy and Labour. PMID- 20899702 TI - A Foetus with Congenital Absence of the Sacrum. PMID- 20899703 TI - Cervical Glands in the Uterus of the Foetus at Term. PMID- 20899712 TI - The Rectum in Gynaecology. PMID- 20899756 TI - Notes on a Case of Temporary Deafness and Blindness due to Intestinal Toxaemia. PMID- 20899792 TI - The Comparative Neuropathology of Trypanosome and Spirochaete Infections, with a Resume of our Knowledge of Human Trypanosomiasis. PMID- 20899799 TI - Resection of the Caecum and Ascending Colon, showing Chronic Hypertrophy of the Mucous Membrane, with Stenosis simulating Cancer. PMID- 20899811 TI - Prolonged Anaesthesia maintained by Ether and Gas alternately. PMID- 20899814 TI - A Death due to Inspiration of Gummatous Material from a Gumma which had burst during Chloroform Anaesthesia. PMID- 20899813 TI - Hypnotism in Relation to Surgical Anaesthesia. PMID- 20899816 TI - Anaesthesia in Post-pharyngeal Abscess. PMID- 20899815 TI - Nasal Reflex during Anaesthesia. PMID- 20899819 TI - The Use of Scopolamine, Morphine, Atropine, and similar drugs by Hypodermic Injection before Inhalation Anaesthesia. PMID- 20899817 TI - Note on a Case of "Cheyne-Stokes" Respiration during Anaesthesia. PMID- 20899826 TI - The AEtiology and Epidemiology of Paratyphoid Fever and "Food-poisoning.". PMID- 20899844 TI - Chronic Pyaemia of Five Years' Duration following Suppurative Epiphysitis of the Upper End of the Humerus. PMID- 20899840 TI - Von Jaksch's Anaemia. PMID- 20899889 TI - Morphoea in Band Form in a Girl, aged 7 Years. PMID- 20899869 TI - Congenital Naevoid Condition of the Left Thigh. PMID- 20899909 TI - Embolism of the Central Artery of the Retina in a Girl, aged 113/4 Years. PMID- 20899894 TI - Naevus Verrucosus Linearis. PMID- 20899929 TI - Infantilism with Thyroid Inadequacy (Juvenile Myxoedema). PMID- 20899981 TI - Septicaemia Haemorrhagica. Severe Capillary and Parenchymatous Haemorrhages of Septic Origin. PMID- 20899982 TI - Gastric and Intestinal Haemorrhages (probably of Septic Origin) occurring after Abdominal Operations. PMID- 20899993 TI - On Drugs used as Local Anaesthetics in the Mouth. PMID- 20900026 TI - Anomalous OEdema. PMID- 20900055 TI - Relief following Bilateral Nephrotomy and Drainage for Acute Nephritis attended by Suppression of Urine and Uraemic Convulsions. PMID- 20900060 TI - Haemorrhagic Disease in a Child (? Scorbutic). PMID- 20900069 TI - Persistent OEdema of Right Hand and Forearm after Slight Tramautism. PMID- 20900076 TI - Enlarged Spleen with Recurring Haematemesis. PMID- 20900072 TI - Recurrent Attacks of Dyspnoea (Asthma), accompanied on each occasion by a Faint Erythematous Annular Rash on the Limbs and Body. PMID- 20900079 TI - Haemochromatosis with Diabetes. PMID- 20900073 TI - Haemorrhagic Pericardial Effusion. PMID- 20900081 TI - Two Cases of Malignant Anaemia. PMID- 20900100 TI - Haemochromatosis with Diabetes. PMID- 20900122 TI - Haemorrhage into the Nail-matrices and Nail-beds of the Finger-nails. PMID- 20900136 TI - Maculo-anaesthetic Leprosy in a Woman, aged 25. PMID- 20900131 TI - Hydroa Vacciniforme vel AEstivale in a Boy, aged 8. PMID- 20900155 TI - Note on the AEtiology of Leprosy. PMID- 20900153 TI - Developing Systematized Naevus on the Back and Front and Arms in a Boy, aged 8 months. PMID- 20900170 TI - Naevus Unius Lateris of Skin and Mucous Membrane. PMID- 20900185 TI - Granuloma Annulare in a Boy, aged 21/2. PMID- 20900207 TI - Case of Naevus. PMID- 20900215 TI - Striae Cutis Distensae. PMID- 20900214 TI - A peculiar Naevus. PMID- 20900222 TI - Extensive Naevus affecting chiefly the Left Side of the Body and partially the Right Side of the Neck in a Girl, aged 14. PMID- 20900226 TI - Small Linear Naevus on the Palm of the Hand of a Girl, aged 5. PMID- 20900232 TI - Morphoea Guttata. PMID- 20900280 TI - Tracheotomy performed Sixteen Years ago for Fixation of Cords in Mid-line, caused by (?) Inflammation of each Crico-arytaenoid Joint. PMID- 20900284 TI - Cystic Conditions of Left Arytaenoid in a Tuberculous Subject. PMID- 20900300 TI - Intrinsic Carcinoma of Larynx removed under Infusion Anaesthesia with Hedonal. PMID- 20900304 TI - Foreign Body, a Nail Two Inches long, in the Left Bronchus of a Child, aged 21/2, with Complete Transposition of Viscera. PMID- 20900323 TI - Specimen presenting Traction Diverticulum of OEsophagus and Atrophy of Left Vocal Cord, due to Infiltrated Gland beneath Arch of Aorta. PMID- 20900318 TI - Pneumococcic Laryngitis followed by Suppurative Arthritis, Endocarditis, Septicaemia, and Death. PMID- 20900324 TI - OEsophagus with Perforations due to Ulceration produced by Foreign Bodies. PMID- 20900326 TI - Cancer of OEsophagus projecting into Trachea. PMID- 20900325 TI - OEsophagus with Cicatricial Stenosis caused by Carbolic Acid. PMID- 20900353 TI - Skiagrams illustrating the Treatment of Two Cases of Non-malignant Stricture of Gullet by Endo-oesophageal Mechanical Dilatation. PMID- 20900337 TI - Chronic OEdema of the Fauces and Larynx in a Boy. PMID- 20900356 TI - Bilateral OEdema of the Ethmoidal Septum in Sinus Suppuration. PMID- 20900377 TI - Swelling in the Neck in a Child, aged 41/2. PMID- 20900379 TI - Two Cases of Carcinoma of the OEsophagus; Lower Thoracic with Superadded Pharyngeal Dysphagia;? Paretic or Spasmodic. PMID- 20900420 TI - Microscopical Section of a Malignant Columnar-celled Carcinoma of the OEsophagus. PMID- 20900423 TI - Tumour of Right Lateral Wall of the Pharynx involving the Right Arytaenoid. PMID- 20900442 TI - Nodular Leukaemia: with an Illustrative Case and References to over One Hundred others. PMID- 20900445 TI - Two Cases of Spontaneous Haematorrhachis, or Intrameningeal Spinal Haemorrhage one cured by Laminectomy. PMID- 20900482 TI - Presidential Address: The Past Work of the Obstetrical Society of London and some of the Obstetric and Gynaecological Problems still awaiting Solution. PMID- 20900484 TI - A Discussion on Amenorrhoeal Insanity. PMID- 20900483 TI - A Discussion on Amenorrhoeal Insanity. PMID- 20900486 TI - A Discussion on Amenorrhoeal Insanity. PMID- 20900485 TI - A Discussion on Amenorrhoeal Insanity. PMID- 20900487 TI - A Discussion on Amenorrhoeal Insanity. PMID- 20900488 TI - A Discussion on Amenorrhoeal Insanity. PMID- 20900489 TI - A Discussion on Amenorrhoeal Insanity. PMID- 20900491 TI - A Discussion on Amenorrhoeal Insanity. PMID- 20900490 TI - A Discussion on Amenorrhoeal Insanity. PMID- 20900497 TI - Extra-uterine Gestation; Death of Foetus near Term; Removal of whole Sac three months later. PMID- 20900510 TI - The Presence of Blood-pigment in the Faeces of the New-born. PMID- 20900518 TI - A Foetus with Congenital Hereditary Graves's Disease. PMID- 20900513 TI - The Treatment of Puerperal Septicaemia by Bacterial Vaccines. PMID- 20900521 TI - Sections of Ovarian Concretions (Haematoliths) and of the Cyst Wall in which they were contained. PMID- 20900524 TI - Uterus and Appendages from a Case of Primary Amenorrhoea. PMID- 20900522 TI - Caesarean Section for Dystocia due to Coils of the Cord around the Foetus. PMID- 20900532 TI - Extraperitoneal Caesarean Section. PMID- 20900527 TI - Retroversion of the Gravid Uterus complicated by Over-distension of the Bladder and Haematuria. PMID- 20900533 TI - Embryotomy after Version for Placenta Praevia. PMID- 20900538 TI - Generalized OEdema of the Foetus. PMID- 20900539 TI - Haematocele of the Canal of Nuck. PMID- 20900541 TI - Haematosalpinx and Haematometra, Bicornute Uterus. Atresia of the Vagina and Cervix Uteri. PMID- 20900558 TI - A Discussion on Amenorrhoeal Insanity: An Address Introductory to a Discussion on the Subject. PMID- 20900559 TI - A Discussion on Amenorrhoeal Insanity: Discussion. PMID- 20900576 TI - Local Anaesthesia, with Special Reference to Injection Methods. PMID- 20900662 TI - Tuberculous Disease of the Temporal Bone in a Boy, aged 71/2. PMID- 20900663 TI - Solid Symmetrical OEdema of both Auricles in a Woman, aged 36; Twelve Months' Duration. PMID- 20900669 TI - A Large Intra-abdominal Haematoma formed in an Accessory Spleen. PMID- 20900690 TI - Three Cases of Death under Anaesthesia. PMID- 20900687 TI - Sahli's Haemoglobinometer. PMID- 20900693 TI - The Systematic Use of a Mouth-prop and Tongue-clip in General Anaesthesia. PMID- 20900694 TI - Crawford Williamson Long (1815-1879): the Pioneer of Anaesthesia and the first to suggest and employ Ether Inhalation during Surgical Operations. PMID- 20900699 TI - Chloroform Toxaemia in a Child to whom Fat was Noxious. PMID- 20900700 TI - Notes of a Case of (?) Post-anaesthetic Poisoning. PMID- 20900701 TI - Ether Infusion Anaesthesia. PMID- 20900702 TI - Hedonal Infusion Anaesthesia; a Report on Seventy-five Cases. PMID- 20900710 TI - Certain AEtiological Considerations arising from Observations of the Behaviour of Poliomyelitis in Devon and Cornwall, 1911. PMID- 20900712 TI - Diarrhoea in 1911. PMID- 20900725 TI - Two Brothers with Haemophilia. PMID- 20900736 TI - Recurrent Unilateral OEdema. PMID- 20900747 TI - Diphtheria of OEsophagus. PMID- 20900770 TI - Congenital Absence of Patellae and Deformity of the Nails in a Mother and Three Children. PMID- 20900777 TI - Purpura in Infective Diarrhoea. PMID- 20900787 TI - Discussion on Partial Thyroidectomy under Local Anaesthesia, with Special Reference to Exophthalmic Goitre. PMID- 20900789 TI - Discussion on Partial Thyroidectomy under Local Anaesthesia, with Special Reference to Exophthalmic Goitre. PMID- 20900788 TI - Discussion on Partial Thyroidectomy under Local Anaesthesia, with Special Reference to Exophthalmic Goitre. PMID- 20900790 TI - Discussion on Partial Thyroidectomy under Local Anaesthesia, with Special Reference to Exophthalmic Goitre. PMID- 20900792 TI - Discussion on Partial Thyroidectomy under Local Anaesthesia, with Special Reference to Exophthalmic Goitre. PMID- 20900791 TI - Discussion on Partial Thyroidectomy under Local Anaesthesia, with Special Reference to Exophthalmic Goitre. PMID- 20900793 TI - Discussion on Partial Thyroidectomy under Local Anaesthesia, with Special Reference to Exophthalmic Goitre. PMID- 20900794 TI - Discussion on Partial Thyroidectomy under Local Anaesthesia, with Special Reference to Exophthalmic Goitre. PMID- 20900795 TI - Discussion on Partial Thyroidectomy under Local Anaesthesia, with Special Reference to Exophthalmic Goitre. PMID- 20900797 TI - Discussion on Partial Thyroidectomy under Local Anaesthesia, with Special Reference to Exophthalmic Goitre. PMID- 20900796 TI - Discussion on Partial Thyroidectomy under Local Anaesthesia, with Special Reference to Exophthalmic Goitre. PMID- 20900798 TI - Discussion on Partial Thyroidectomy under Local Anaesthesia, with Special Reference to Exophthalmic Goitre. PMID- 20900799 TI - Discussion on Partial Thyroidectomy under Local Anaesthesia, with Special Reference to Exophthalmic Goitre. PMID- 20900800 TI - Discussion on Partial Thyroidectomy under Local Anaesthesia, with Special Reference to Exophthalmic Goitre. PMID- 20900801 TI - Discussion on Partial Thyroidectomy under Local Anaesthesia, with Special Reference to Exophthalmic Goitre. PMID- 20900802 TI - Discussion on Partial Thyroidectomy under Local Anaesthesia, with Special Reference to Exophthalmic Goitre. PMID- 20900833 TI - A Discussion on Partial Thyroidectomy under Local Anaesthesia, with Special Reference to Exophthalmic Goitre: An Address Introductory to a Discussion on the Subject. PMID- 20900834 TI - A Discussion on Partial Thyroidectomy under Local Anaesthesia, with Special Reference to Exophthalmic Goitre: Discussion. PMID- 20900835 TI - A Discussion on Partial Thyroidectomy under Local Anaesthesia, with Special Reference to Exophthalmic Goitre. PMID- 20900836 TI - A Discussion on Partial Thyroidectomy under Local Anaesthesia, with Special Reference to Exophthalmic Goitre. PMID- 20900837 TI - A Discussion on Partial Thyroidectomy under Local Anaesthesia, with Special Reference to Exophthalmic Goitre. PMID- 20900838 TI - A Discussion on Partial Thyroidectomy under Local Anaesthesia, with Special Reference to Exophthalmic Goitre. PMID- 20900839 TI - Discussion on Partial Thyroidectomy under Local Anaesthesia, with Special Reference to Exophthalmic Goitre. PMID- 20900840 TI - Discussion on Partial Thyroidectomy under Local Anaesthesia, with Special Reference to Exophthalmic Goitre. PMID- 20900841 TI - Discussion on Partial Thyroidectomy under Local Anaesthesia, with Special Reference to Exophthalmic Goitre. PMID- 20900909 TI - Nephritis with Ascites, Bilateral Hydrothorax and General OEdema in Secondary Syphilis (Result). PMID- 20900914 TI - "Baggy" Subcutaneous Fat, simulating Symmetrical OEdema of the Legs. Disorder of Internal Secretions. PMID- 20900913 TI - Secondary Haemorrhages in the Retina in Secondary Anaemia. PMID- 20900940 TI - Purpura Haemorrhagica, a Fulminating Case; Gelatine Treatment. PMID- 20900955 TI - Oblique Fracture of Femur into the Knee-joint, and of both Tibiae and Fibulae; Arthrotomy and Union of Condyles of Femur by Screws. PMID- 20900963 TI - Acholuric Jaundice (Haemolytic Anaemia). PMID- 20900964 TI - Resection of Caecum, Appendix, Ileocaecal Valve, and 10 in. of Ileum for Chronic Appendicitis. PMID- 20900965 TI - Resection of Caecum, Ileocaecal Valve, and 5 in. of Ileum for Sarcoma; Anastomosis by Murphy's Button; Button retained for Four Years. PMID- 20900966 TI - Resection of Caecum, Ileocaecal Valve, Appendix, and 10 in. of Ileum for Obstruction following an Entero-anastomosis; subsequent Ventral Hernia cured by Filigree Inplantation. PMID- 20900967 TI - Gastro-enterostomy for Haematemesis followed by Ileus and Faecal Vomiting; Caecostomy; subsequent Ventral Hernia; Cure by Implantation of 6-in. Filigree. PMID- 20900988 TI - Chronic Acholuric Jaundice, with Anaemia, slight Splenomegaly, and Nervous Disorder. PMID- 20901001 TI - Framboesiform Syphilide of Palms. PMID- 20901007 TI - Hidradenomes Eruptifs (Syringoma). PMID- 20901008 TI - Localized Sclerodermia (Morphoea). PMID- 20901037 TI - Pigmented Naevi-like Freckles in a Girl, aged 16. PMID- 20901039 TI - Naevus Unius Lateris and Unusual Effects of Solid CO(2) (Dermatitis Repens). PMID- 20901072 TI - Note on the AEtiology of some Tropical Dermatomycoses (Tinea cruris, Tinea flava et nigra, Tinea imbricata). PMID- 20901094 TI - OEdema Neonatorum. PMID- 20901121 TI - The AEtiology of Gastric Ulcer. PMID- 20901148 TI - The Consequences and Treatment of Alimentary Toxaemia from an Odontological Point of View. PMID- 20901150 TI - A Discussion on Alimentary Toxaemia; its Sources, Consequences, and Treatment. PMID- 20901149 TI - A Discussion on Alimentary Toxaemia; its Sources, Consequences, and Treatment. PMID- 20901151 TI - A Discussion on Alimentary Toxaemia; its Sources, Consequences, and Treatment. PMID- 20901152 TI - A Discussion on Alimentary Toxaemia; its Sources, Consequences, and Treatment. PMID- 20901153 TI - A Discussion on Alimentary Toxaemia; its Sources, Consequences, and Treatment. PMID- 20901155 TI - A Discussion on Alimentary Toxaemia; its Sources, Consequences, and Treatment. PMID- 20901154 TI - A Discussion on Alimentary Toxaemia; its Sources, Consequences, and Treatment. PMID- 20901157 TI - A Discussion on Alimentary Toxaemia; its Sources, Consequences, and Treatment. PMID- 20901156 TI - A Discussion on Alimentary Toxaemia; its Sources, Consequences, and Treatment. PMID- 20901158 TI - A Discussion on Alimentary Toxaemia; its Sources, Consequences, and Treatment. PMID- 20901160 TI - A Discussion on Alimentary Toxaemia; its Sources, Consequences, and Treatment. PMID- 20901159 TI - A Discussion on Alimentary Toxaemia; its Sources, Consequences, and Treatment. PMID- 20901161 TI - A Discussion on Alimentary Toxaemia; its Sources, Consequences, and Treatment. PMID- 20901162 TI - A Discussion on Alimentary Toxaemia; its Sources, Consequences, and Treatment. PMID- 20901163 TI - A Discussion on Alimentary Toxaemia; its Sources, Consequences, and Treatment. PMID- 20901165 TI - A Discussion on Alimentary Toxaemia; its Sources, Consequences, and Treatment. PMID- 20901166 TI - A Discussion on Alimentary Toxaemia; its Sources, Consequences, and Treatment. PMID- 20901167 TI - A Discussion on Alimentary Toxaemia; its Sources, Consequences, and Treatment. PMID- 20901168 TI - A Discussion on Alimentary Toxaemia; its Sources, Consequences, and Treatment. PMID- 20901170 TI - A Discussion on Alimentary Toxaemia; its Sources, Consequences, and Treatment. PMID- 20901169 TI - A Discussion on Alimentary Toxaemia; its Sources, Consequences, and Treatment. PMID- 20901171 TI - A Discussion on Alimentary Toxaemia; its Sources, Consequences, and Treatment. PMID- 20901172 TI - A Discussion on Alimentary Toxaemia; its Sources, Consequences, and Treatment. PMID- 20901173 TI - A Discussion on Alimentary Toxaemia; its Sources, Consequences, and Treatment. PMID- 20901175 TI - A Discussion on Alimentary Toxaemia; its Sources, Consequences, and Treatment. PMID- 20901174 TI - A Discussion on Alimentary Toxaemia; its Sources, Consequences, and Treatment. PMID- 20901177 TI - A Discussion on Alimentary Toxaemia; its Sources, Consequences, and Treatment. PMID- 20901176 TI - A Discussion on Alimentary Toxaemia; its Sources, Consequences, and Treatment. PMID- 20901178 TI - A Discussion on Alimentary Toxaemia; its Sources, Consequences, and Treatment. PMID- 20901180 TI - A Discussion on Alimentary Toxaemia; its Sources, Consequences, and Treatment. PMID- 20901179 TI - A Discussion on Alimentary Toxaemia; its Sources, Consequences, and Treatment. PMID- 20901181 TI - A Discussion on Alimentary Toxaemia; its Sources, Consequences, and Treatment. PMID- 20901182 TI - A Discussion on Alimentary Toxaemia; its Sources, Consequences, and Treatment. PMID- 20901183 TI - A Discussion on Alimentary Toxaemia; its Sources, Consequences, and Treatment. PMID- 20901184 TI - A Discussion on Alimentary Toxaemia; its Sources, Consequences, and Treatment. PMID- 20901185 TI - A Discussion on Alimentary Toxaemia; its Sources, Consequences, and Treatment. PMID- 20901186 TI - A Discussion on Alimentary Toxaemia; its Sources, Consequences, and Treatment. PMID- 20901187 TI - A Discussion on Alimentary Toxaemia; its Sources, Consequences, and Treatment. PMID- 20901188 TI - A Discussion on Alimentary Toxaemia; its Sources, Consequences, and Treatment. PMID- 20901189 TI - A Discussion on Alimentary Toxaemia; its Sources, Consequences, and Treatment. PMID- 20901190 TI - A Discussion on Alimentary Toxaemia; its Sources, Consequences, and Treatment. PMID- 20901191 TI - A Discussion on Alimentary Toxaemia; its Sources, Consequences, and Treatment. PMID- 20901192 TI - A Discussion on Alimentary Toxaemia; its Sources, Consequences, and Treatment. PMID- 20901193 TI - A Discussion on Alimentary Toxaemia; its Sources, Consequences, and Treatment. PMID- 20901194 TI - A Discussion on Alimentary Toxaemia; its Sources, Consequences, and Treatment. PMID- 20901196 TI - A Discussion on Alimentary Toxaemia; its Sources, Consequences, and Treatment. PMID- 20901195 TI - A Discussion on Alimentary Toxaemia; its Sources, Consequences, and Treatment. PMID- 20901197 TI - A Discussion on Alimentary Toxaemia; its Sources, Consequences, and Treatment. PMID- 20901198 TI - A Discussion on Alimentary Toxaemia; its Sources, Consequences, and Treatment. PMID- 20901199 TI - The Consequences and Treatment of Alimentary Toxaemia from a Medical Point of View. PMID- 20901200 TI - A Discussion on Alimentary Toxaemia; its Sources, Consequences, and Treatment. PMID- 20901201 TI - A Discussion on Alimentary Toxaemia; its Sources, Consequences, and Treatment: Summary and Reply. PMID- 20901202 TI - The Consequences and Treatment of Alimentary Toxaemia from a Surgical Point of View. PMID- 20901207 TI - Brain, with large Pituitary Tumour, from Patient who died from Haemorrhage after Partial Removal of Floor of Sella Turcica. PMID- 20901227 TI - Haemorrhage into the Right Vocal Cord, the Result of an Accident at Football. PMID- 20901233 TI - Cyst of Arytaeno-epiglottidean Fold which has Burst Spontaneously. PMID- 20901231 TI - Cast of the Epithelial Lining of the OEsophagus, from a Case of CHCl(3) Poisoning. PMID- 20901234 TI - Cyst on Epiglottis, with Symptoms suggestive of OEsophageal Stricture. PMID- 20901241 TI - Double Abductor Paresis and Stricture of Deep Pharynx and Upper End of OEsophagus, after accidentally Swallowing Glacial Acetic Acid in October, 1912. PMID- 20901242 TI - Nearly Complete Paralysis of Left Vocal Cord of Unexplained AEtiology. PMID- 20901252 TI - Discussion on the AEtiology of Unilateral Paralysis of the Recurrent Laryngeal Nerve. PMID- 20901248 TI - Discussion on the AEtiology of Unilateral Paralysis of the Recurrent Laryngeal Nerve. PMID- 20901254 TI - Discussion on the AEtiology of Unilateral Paralysis of the Recurrent Laryngeal Nerve. PMID- 20901253 TI - Discussion on the AEtiology of Unilateral Paralysis of the Recurrent Laryngeal Nerve. PMID- 20901258 TI - Discussion on the AEtiology of Unilateral Paralysis of the Recurrent Laryngeal Nerve. PMID- 20901257 TI - Discussion on the AEtiology of Unilateral Paralysis of the Recurrent Laryngeal Nerve. PMID- 20901259 TI - Discussion on the AEtiology of Unilateral Paralysis of the Recurrent Laryngeal Nerve. PMID- 20901260 TI - Discussion on the AEtiology of Unilateral Paralysis of the Recurrent Laryngeal Nerve. PMID- 20901261 TI - Discussion on the AEtiology of Unilateral Paralysis of the Recurrent Laryngeal Nerve. PMID- 20901263 TI - Discussion on the AEtiology of Unilateral Paralysis of the Recurrent Laryngeal Nerve. PMID- 20901262 TI - Discussion on the AEtiology of Unilateral Paralysis of the Recurrent Laryngeal Nerve. PMID- 20901264 TI - Discussion on the AEtiology of Unilateral Paralysis of the Recurrent Laryngeal Nerve. PMID- 20901267 TI - Symmetrical Swellings on Anterior Aspect of Arytaenoids just above the Vocal Processes. PMID- 20901283 TI - Malignant Disease of the OEsophagus; Complete Paralysis of the Left Recurrent Nerve. PMID- 20901295 TI - Skiagram showing a Penny Coin impacted in the OEsophagus of a Woman, aged 25. PMID- 20901298 TI - Infiltration of Uvula, Epiglottis and Arytaenoids. PMID- 20901313 TI - A Chicken Bone 11/4 in. long removed from the Upper Part of the OEsophagus. PMID- 20901312 TI - The Fin of a Haddock extracted from the OEsophagus. PMID- 20901314 TI - Telescopic OEsophageal Tube with the Outer Tube Straight-ended and the Inner Tube Beaked. PMID- 20901348 TI - Two Cases of Bilateral OEdema of Nasal Septum. PMID- 20901319 TI - A Spicule of Rabbit Bone, 3/4 in. in Length, removed by Upper Bronchoscopy from the Trachea of a Boy, aged 5. PMID- 20901375 TI - Some Cases of Polycythaemia. PMID- 20901376 TI - The Prognostic Significance of Secondary Polycythaemia in Cardio-pulmonary Cases. PMID- 20901377 TI - Gout and Chronic Rheumatism: Their AEtiology from the Bacteriological Standpoint, and some Notes on Treatment. PMID- 20901443 TI - Uterine Mole showing Low Implantation of the Ovum (Placenta Praevia). PMID- 20901445 TI - Portion of Bone Knitting Needle, used to procure Abortion, removed by Operation from Abdominal Cavity; Development of a Pelvic Abscess, Faecal Fistula, Septic Pyelonephritis, and General Septic Infection, with ultimate Recovery. PMID- 20901475 TI - Chorionepithelioma following Hydatidiform Mole and giving rise to Intraperitoneal Haemorrhage from an Extension in the Right Mesosalpinx. PMID- 20901454 TI - The Cause of Internal Rotation of the Foetal Head. PMID- 20901484 TI - Bacterial Infection of the Foetal Membranes from a Case of Hydrorrhoea Gravidarum. PMID- 20901495 TI - Puerperal Eclampsia treated by Caesarean Section. PMID- 20901490 TI - Haematocolpos, with Remarks on the Structure of the Vaginal Wall. PMID- 20901502 TI - Rupture of a Haemorrhagic Corpus Luteum into a Broad Ligament Cyst. PMID- 20901498 TI - Urgent Caesarean Section for Prolapse of the Cord in a Case of Contracted Pelvis. PMID- 20901503 TI - Tubal Haematoma. PMID- 20901531 TI - An Improved Anaesthetic Facepiece. PMID- 20901545 TI - A Horsebean removed from the Middle Ear during a Radical Mastoid Operation for prolonged Otorrhoea in a Boy, aged 9; with two Sequestra, containing the Outer Wall or the Canal of the Facial Nerve. PMID- 20901580 TI - Deafness in a Case of Myxoedema. PMID- 20901581 TI - Epithelioma of Middle Ear invading the Middle and Posterior Fossae of the Skull in a Man, aged 56. PMID- 20901594 TI - Left Otorrhoea and Right Temporal Sphenoidal Abscess. PMID- 20901606 TI - An Account of a Bacillus of an Unusual Kind isolated from a Case of Septicaemia. PMID- 20901607 TI - A New Spirochaeta found in Human Blood. PMID- 20901614 TI - Death during Hedonal Infusion Anaesthesia. PMID- 20901610 TI - Some Points concerning the Vaccine Treatment of Gonorrhoea and the Regulation thereof by the Complement-fixation Test. PMID- 20901616 TI - Notes on the Administration of Anaesthetics in America, with Special Reference to the Practice at the Mayo Clinic. PMID- 20901621 TI - Technique in General Anaesthesia for Intranasal Operations. PMID- 20901622 TI - Scopolamine-Morphine-Atropine as a General Anaesthetic. PMID- 20901623 TI - Scopolamine-Morphine-Atropine as an Adjunct in Inhalation Anaesthesia. PMID- 20901646 TI - Formulae Medicamentorum Concinnatae. PMID- 20901702 TI - OEdema of the Thighs in a Katatoniac. PMID- 20901670 TI - Drawing of Semilunar Retinal Haemorrhages (so-called Subhyaloid Haemorrhages). PMID- 20901703 TI - Presenile Katatonia (? Dementia Praecox). PMID- 20901715 TI - Microscopical Investigation of the Nervous System in Three Cases of Spontaneous Myxoedema. PMID- 20901745 TI - Summer Diarrhoea and Summer Heat. PMID- 20901723 TI - Interstitial Keratitis and Osteo-periostitis of the Tibiae treated with Neo salvarsan. PMID- 20901764 TI - Operative Myxoedema-Cachexia Strumipriva. PMID- 20901787 TI - Ectopia Vesicae. PMID- 20901768 TI - Pathological Specimen; Diphtheria of the OEsophagus. PMID- 20901800 TI - Congenital Syphilis; Haematuria. PMID- 20901803 TI - Congenital OEsophageal Stenosis. PMID- 20901807 TI - Malformation of the Rectum (Complete Absence of the Post-allantoic Gut and the Proctodaeum); Operation; Result. PMID- 20901813 TI - Congenital Family Cholaemia. PMID- 20901809 TI - Pharynx and Larynx from Fatal Case of Haemorrhage from Throat. PMID- 20901849 TI - Excision of the Spleen for Splenic Anaemia. PMID- 20901817 TI - Excision of Spleen for Congenital Family Cholaemia. PMID- 20901906 TI - Haemolytic Jaundice complicated by Cholecystitis. PMID- 20901905 TI - Haemolytic Jaundice; Cholecystotomy; Splenectomy; Cure. PMID- 20901909 TI - Splenomegaly; Two Attacks of Haematemesis; Irregular Liver. PMID- 20901922 TI - Extradural Haemorrhage causing Slight Aphasia from Pressure over Broca's Convolution. PMID- 20901927 TI - Spleno-myelogenic Leukaemia. PMID- 20901932 TI - Spasmodic Stricture of the OEsophagus (Cardiospasm), with Fusiform Dilatation above it. PMID- 20901929 TI - Splenomegaly with Gastro-intestinal Haemorrhages. PMID- 20901940 TI - Haemophilia. PMID- 20901947 TI - Chronic Myelocytic Leukaemia treated by Benzol, &c. PMID- 20901968 TI - Splenic Enlargement, Haemorrhage, Anaemia, and Arteritis Obliterans with Oral Sepsis. PMID- 20901959 TI - Splenic Enlargement, Haemorrhage, Anaemia, with Oral Sepsis. PMID- 20901971 TI - Splenic Anaemia in a Father and Three Children. PMID- 20901972 TI - Splenic Anaemia treated by Splenectomy. PMID- 20901973 TI - Splenic Anaemia treated by Splenectomy. PMID- 20901974 TI - Splenic Anaemia treated by Splenectomy. PMID- 20901980 TI - Splenomegaly with Gastro-intestinal Haemorrhages. PMID- 20901987 TI - Naevus Linearis Bilateralis (Mixed Systemic Naevus). PMID- 20901981 TI - Splenic Anaemia with Ascites, treated by Splenectomy and Omentopexy. PMID- 20901995 TI - Polycythaemia Rubra. PMID- 20902031 TI - Hydroa AEstivale (et Hiemale). PMID- 20902033 TI - Bilateral Telangiectases (Naevus Araneus). PMID- 20902170 TI - Electrolysis in the Treatment of Haemorrhoids. PMID- 20902069 TI - Case of Trophoedema. PMID- 20902174 TI - On Some of the Recent Advances in the Field of Microbiology; with Demonstrations of the Pure Cultures of various Spirochaetes, of the Viruses of Rabies and Poliomyelitis, and of Treponema pallidum in the Brains of General Paralytics. PMID- 20902220 TI - Removal of Foreign Bodies from the OEsophagus. PMID- 20902201 TI - Fixed Circo-arytaenoid Joint; Phthisis; Healed Tertiary Syphilis. PMID- 20902221 TI - X-ray Photographs of Carcinoma of the OEsophagus in Two Patients, aged respectively 49 and 71. PMID- 20902223 TI - Inoperable Fungating Carcinoma of the OEsophagus in a Male Patient, aged 36. PMID- 20902244 TI - (a) Two Curettes for the removal of the Anterior Ethmoidal and "Agger" Cells. (b) A Collection of Foreign Bodies removed from the Lower Air Passages and OEsophagus. (c) Skiagrams illustrating Foreign Bodies in the Bronchi and Malignant Strictures of OEsophagus. PMID- 20902231 TI - An OEdematous Fibroma depending from the Left Vocal Cord. PMID- 20902247 TI - Skiagram showing a Farthing in the OEsophagus of a Child, aged 2. PMID- 20902277 TI - Specimen of Thyro-glossal Cyst, causing Dyspnoea, in a Woman, aged 54. PMID- 20902262 TI - Carcinoma of Arytaeno-epiglottic Fold and Pyriform Fossa removed by Transthyroid Pharyngotomy. PMID- 20902285 TI - Tooth-plates and Meat Bones removed from the OEsophagus. PMID- 20902280 TI - Polycythaemia rubra with Chronic Rhinitis. PMID- 20902294 TI - OEsophageal Diverticulum. PMID- 20902296 TI - Removal of a Large Pharyngeal Pouch under Local Anaesthesia in a Man, aged 70. PMID- 20902298 TI - Notes, Specimen and Drawing of Case of Cerebrospinal Rhinorrhoea, with subsequent Ethmoiditis, Mucocele, and Frontal Sinus Suppuration, indistinguishable from Ethmoidal Mucocele; Operation; Death. PMID- 20902317 TI - Inflammatory Fixation of the Left Arytaenoid following supposed Impaction of a Foreign Body in the Larynx. PMID- 20902329 TI - Pathological Specimens of Tonsils from a Case of Lymphatic Leukaemia. PMID- 20902332 TI - A Contribution to the Study of a Group of Cases of Chronic Recurrent Diarrhoea in Childhood. PMID- 20902339 TI - Paroxysmal Tachycardia in a Child, aged 23/4. PMID- 20902340 TI - Paroxysmal Tachycardia in a Boy, aged 41/2. PMID- 20902341 TI - Secondary or Symptomatic Leukaemia. PMID- 20902345 TI - Acute Aplastic Anaemia: With a Note on the Nomenclature of Plastic and Aplastic Anaemias. PMID- 20902367 TI - Sclerodermia; Neuropathic OEdema; Functional Hemiplegia. PMID- 20902348 TI - Pathological Changes in Case of Leukaemia from Prolonged Use of X-rays. PMID- 20902389 TI - "Pre-eclampsia" at the Twenty-fourth Week; Acute Toxaemia; Caesarean Section. PMID- 20902390 TI - "Caesarean Myomectomy"; Remarks on the Operation. PMID- 20902392 TI - A Specimen of Foetus Acardiacus Amorphus. PMID- 20902397 TI - Case of Haematometra. PMID- 20902401 TI - Uterine Fibroids; one impacted in the Pelvis obstructing Delivery; Caesarean Hysterectomy. PMID- 20902403 TI - Caesarean Section; Labour obstructed by One Half of a Uterus Didelphys. PMID- 20902402 TI - Eclampsia; Vaginal Caesarean Section. PMID- 20902405 TI - Uncontrollable Uterine Haemorrhage: A Report on 104 Uteri after Hysterectomy. PMID- 20902412 TI - Defective Ossification of Foetal Skull. PMID- 20902414 TI - Heart Disease complicating Pregnancy; Caesarean Section under Spinal Anaesthesia. PMID- 20902416 TI - Peritonitis in Foetus. PMID- 20902429 TI - Uterus with Multiple Fibroids showing Gestation Sac situated over internal Os (Placenta Praevia) and Empty Decidual Cavity in Upper Half of Uterus. PMID- 20902430 TI - Foetal Bones removed from the Uterus Three Years after a Miscarriage. PMID- 20902433 TI - The AEtiology of Eclampsia and Albuminuria and their Relation to Accidental Haemorrhage: (An Anatomical and Experimental Investigation.). PMID- 20902432 TI - Volvulus of the Caecum occurring in Connexion with Labour. PMID- 20902435 TI - A Lithopaedion removed from a Patient Six Months Pregnant. PMID- 20902479 TI - Lateral Sinus Thrombosis, with Pyaemia. PMID- 20902501 TI - Nerve Deafness associated with Anaemia. PMID- 20902488 TI - Haematoma Auris; Operative Treatment. PMID- 20902507 TI - Haematoma Auris. PMID- 20902533 TI - Intratracheal Anaesthesia. PMID- 20902532 TI - A Review of Inquests concerning Deaths during Anaesthesia, 1910-1913. PMID- 20902534 TI - Intratracheal Anaesthesia. PMID- 20902536 TI - Intratracheal Anaesthesia. PMID- 20902538 TI - Discussion on Posture in relation to General Anaesthesia. PMID- 20902537 TI - Physiological Observations upon Intratracheal Anaesthesia. PMID- 20902539 TI - Discussion on Posture in relation to General Anaesthesia. PMID- 20902540 TI - Discussion on Posture in relation to General Anaesthesia. PMID- 20902541 TI - Discussion on Posture in relation to General Anaesthesia. PMID- 20902542 TI - Discussion on Posture in relation to General Anaesthesia. PMID- 20902543 TI - Discussion on Posture in relation to General Anaesthesia. PMID- 20902545 TI - Discussion on Posture in relation to General Anaesthesia. PMID- 20902544 TI - Discussion on Posture in relation to General Anaesthesia. PMID- 20902546 TI - Discussion on Posture in relation to General Anaesthesia. PMID- 20902547 TI - Discussion on Posture in relation to General Anaesthesia. PMID- 20902548 TI - Discussion on Posture in relation to General Anaesthesia. PMID- 20902549 TI - Sudden Death under Light Chloroform Anaesthesia. PMID- 20902618 TI - Iritis-Rheumatic and Toxaemic. PMID- 20902637 TI - Korsakoff's Disease, with Systematized Anaesthesia. PMID- 20902645 TI - Case for Diagnosis: (?) Dementia Praecox. PMID- 20902654 TI - Congenital Deficiency of Vertebrae and Ribs. PMID- 20902675 TI - Benzol in the Treatment of Lymphatic Leukaemia. PMID- 20902677 TI - Case showing Bilateral Hare-lip, without Cleft Palate, and also Congenital Bilateral Mucous Fistulae in the Lower Lip. PMID- 20902694 TI - A Familial Case of Splenomegalic Anaemia with Infantilism. PMID- 20902695 TI - Fatal Haemoptysis in a Child, aged 4 Years. PMID- 20902719 TI - Case of Cephalhaematoma. PMID- 20902721 TI - Boy, aged 5 Years, with Two Femoral Herniae. PMID- 20902733 TI - Case for Diagnosis. Congenital Morbus Cordis or Erythraemia (?). PMID- 20902746 TI - Hemiplegia with very Extensive Naevus. PMID- 20902756 TI - Lymphocytic Leukaemia under Treatment by Benzol. PMID- 20902765 TI - Enlargement of the Mammary Gland in a Boy, aged 101/2 Years. PMID- 20902764 TI - Cyst of the Caecum in a Child, aged 3 Months, causing Intestinal Obstruction; Resection of Intestine; Recovery. PMID- 20902770 TI - Subacute Nephritis with Ascites and Uraemia. PMID- 20902773 TI - Urticaria followed by OEdema in an Infant, aged 2 Months. PMID- 20902776 TI - The Selection of the Incision in Coeliotomy. PMID- 20902798 TI - Congenital Absence of Tibiae. PMID- 20902826 TI - Haematoma of the Broad Ligament simulating Sarcoma of the Rectum. PMID- 20902843 TI - Case of Haemorrhagic Proctitis. PMID- 20902845 TI - Entire Caecum and Colon removed by Operation in a Case of very Severe Auto intoxication. PMID- 20902847 TI - Haemorrhagic Proctitis, with Notes of Cases. PMID- 20902858 TI - Recent Researches on Emetine and its Value as a Therapeutic Agent in Amoebiasis and other Diseases. PMID- 20902895 TI - Splenic Anaemia; Splenectomy. PMID- 20902881 TI - Splenomegaly with Anaemia and Haemorrhages. PMID- 20902896 TI - Double Osteotomy of Tibiae Ten Years after Operation. PMID- 20902904 TI - Naevus Linearis. PMID- 20902916 TI - Linear Naevus in Mother and Child. PMID- 20902974 TI - Acute Striae Atrophicae. PMID- 20902956 TI - Lymphatic Leukaemia. PMID- 20902977 TI - Morphoeic Sclerodermia. PMID- 20902981 TI - Hydroa AEstivalis. PMID- 20902983 TI - Lichen Planus Atrophicus, Sclerosus et Morphoeicus. PMID- 20903025 TI - Bristle from Hair-brush with Ova of Hoematopinus suis. PMID- 20902995 TI - Peculiar Zoniform Naevus of the Right Upper Extremity. PMID- 20903038 TI - Morphoeic Sclerodermia. PMID- 20903083 TI - Peptic Ulcer of the OEsophagus. PMID- 20903096 TI - Further Notes on a Case of a Gentleman, aged 59, with Malignant Stricture of the OEsophagus. PMID- 20903099 TI - Halfpenny embedded in OEsophagus. PMID- 20903151 TI - Fixation of Right Crico-arytaenoid Joint; (?) Traumatic. PMID- 20903124 TI - Haemostatic Guillotine. PMID- 20903153 TI - Dyspnoea, Perichondritis, Tumour (?) of the Mediastinum. PMID- 20903159 TI - Specimen and Skiagram of a Case of OEsophagotomy. PMID- 20903163 TI - Synechiae in the Nose treated by Diathermy. PMID- 20903168 TI - Male, aged 59, with Epithelioma of the OEsophagus, shown to illustrate the Benefits of Hill's Feeding Tube. PMID- 20903165 TI - Tuberculosis of Nasal Fossae. PMID- 20903171 TI - Synechiae and Contraction of the Vestibules. PMID- 20903170 TI - Specimens of Superior Maxillae, exhibiting Abnormal Conditions of the Nasal Fossae and Maxillary Antra. PMID- 20903179 TI - Two Cases of OEsophageal Stricture in Children. PMID- 20903180 TI - OEsophagus from a Child, aged 21/2, showing Escharotic Stenosis. PMID- 20903187 TI - A Case resembling Acute Lymphatic Leukaemia, ending in Complete Recovery. PMID- 20903188 TI - Notes on some Cases of Myelogenic Leukaemia. PMID- 20903189 TI - An Instance of Long Quiescence of Leukaemia. PMID- 20903190 TI - Bilateral Hypernephroma, with Secondary Thrombosis of the Inferior Vena Cava and Terminal Uraemia. PMID- 20903212 TI - Severe Haemorrhage after the Menopause from Rupture of a Vein in the Endometrium. PMID- 20903218 TI - Presidential Address: An Investigation of the Causes which determine the Lie of the Foetus in utero. PMID- 20903219 TI - Puerperal Eclampsia; Death due to Rupture of Subcapsular Haematoma of the Liver. PMID- 20903220 TI - Intestinal Fistulae made with a View to facilitating Recovery from certain Conditions which may follow Abdominal Operations. PMID- 20903226 TI - Two Cases of Hysterectomy for Ante-partum Haemorrhage. PMID- 20903227 TI - Placenta Praevia with Unusual Sequelae. PMID- 20903236 TI - Tubal Pregnancy showing Foetus undergoing Dissolution. PMID- 20903249 TI - The Discovery of Entamoeba buccalis in Pyorrhoea Pus, and Treatment by Emetin Hydrochloride. PMID- 20903299 TI - Anaesthetic Ether. PMID- 20903300 TI - A Discussion on the Methods of Induction of Anaesthesia. PMID- 20903301 TI - A Discussion on the Methods of Induction of Anaesthesia. PMID- 20903302 TI - A Discussion on the Methods of Induction of Anaesthesia. PMID- 20903303 TI - Discussion on the Influence of Preliminary Narcotics on (a) Induction, (b) Maintenance, (c) After-results of Anaesthesia. PMID- 20903304 TI - Discussion on the Influence of Preliminary Narcotics on (a) Induction, (b) Maintenance, (c) After-results of Anaesthesia. PMID- 20903305 TI - Discussion on the Influence of Preliminary Narcotics on (a) Induction, (b) Maintenance, (c) After-results of Anaesthesia. PMID- 20903306 TI - Discussion on the Influence of Preliminary Narcotics on (a) Induction, (b) Maintenance, (c) After-results of Anaesthesia. PMID- 20903307 TI - Discussion on the Influence of Preliminary Narcotics on (a) Induction, (b) Maintenance, (c) After-results of Anaesthesia. PMID- 20903308 TI - Discussion on the Influence of Preliminary Narcotics on (a) Induction, (b) Maintenance, (c) After-results of Anaesthesia. PMID- 20903309 TI - Discussion on the Influence of Preliminary Narcotics on (a) Induction, (b) Maintenance, (c) After-results of Anaesthesia. PMID- 20903310 TI - Discussion on the Influence of Preliminary Narcotics on (a) Induction, (b) Maintenance, (c) After-results of Anaesthesia. PMID- 20903404 TI - Giant Naevus. PMID- 20903311 TI - Discussion on the Influence of Preliminary Narcotics on (a) Induction, (b) Maintenance, (c) After-results of Anaesthesia. PMID- 20903405 TI - Splenomegaly (? Splenic Anaemia of Infancy) improved by Antisyphilitic Treatment. PMID- 20903424 TI - Specimen of Perforation of the Arch of the Aorta by Safety-pin Impacted in the OEsophagus. PMID- 20903415 TI - Nine Patches of Morphoea in a Child. PMID- 20903428 TI - Haematoma of the Lower Lid in an Infant, aged 5 Months (an Unusual Manifestation of Infantile Scurvy). PMID- 20903433 TI - Suprarenal Haemorrhage in an Infant. PMID- 20903454 TI - Child with Defective Patellae and Contraction of Limbs. Case for Diagnosis. PMID- 20903464 TI - Obscure Case of OEdema of the Sigmoid Mesocolon. PMID- 20903462 TI - Abdomino-perineal Excision of the Rectum for Carcinoma in a Woman, aged 763/4. PMID- 20903516 TI - Tuberculous Disease of the Face of Five Years' Duration in a Girl aged 181/2. PMID- 20903482 TI - Note on a Case of Anaemia and Purpura, with Greenish Coloration of the Bone marrow, and its Bearing on the Question of the Causation of the Green colour of Chloroma and the so-called Chloro-leukaemia. PMID- 20903532 TI - Sclerodermia occurring in a Case of Myxoedema while under Thyroid Treatment. PMID- 20903534 TI - Case of Morphoeo-sclerodermia (shown before) with recent Acute Symmetrical Involvement of the Soles of the Feet. PMID- 20903546 TI - Sclerodermia associated with Graves's Disease, and later Myxoedema, conspicuously benefiting by Implantation of Human Thyroid into the Bone-marrow. PMID- 20903602 TI - Radiogram of the OEsophagus of a Case of Carcinoma which presented itself as an Achalasia. PMID- 20903612 TI - Final Notes on a Case of Malignant Stricture of the OEsophagus, situated 3/4 in. above the Sternal Notch. PMID- 20903624 TI - Malignant Disease (?) of the Arytaeno-epiglottic Fold and Ventricular Region of the Left Side of Larynx. PMID- 20903625 TI - Halfpenny impacted for Five Days in the OEsophagus of a Child, aged 4. PMID- 20903628 TI - Tin Disk, 13/8 in. in Diameter, removed from the Gullet by the Direct Method. PMID- 20903640 TI - Long-continued Spasm of the OEsophagus. PMID- 20903629 TI - Large Irregular Piece of Bone, impacted in the OEsophagus, removed by Direct Method; Death from Sepsis Six Days later. PMID- 20903648 TI - Foreign Body (Fish-bone) in OEsophagus, followed by Abscess in Neck. PMID- 20903656 TI - Plumbism and Pyorrhoea associated with Passive OEdema and Thickening of the Uvula, Epiglottis, and Arytaenoids, with Enlargement of the Glands in the Parotid and Submaxillary Regions. PMID- 20903730 TI - A Wire-fed Tubular Needle for use in Closing Vesico-vaginal Fistulae. PMID- 20903728 TI - Acute Hepatic Toxaes complicating Pregnancy and Labour. PMID- 20903746 TI - Three Cases of Haematoma of the Abdominal Wall. PMID- 20903736 TI - Case of Glandular Carcinoma of Uterus in a Child, aged 21/2 Years. PMID- 20903801 TI - Fracture of the Base of the Skull in a Baby, aged 13/4 Years. PMID- 20903805 TI - Observations on the Influence of Anaesthetics on the Temperature of the Body. PMID- 20903807 TI - Studies on Egyptian Sand Amoebae: (Communicated and taken as read.). PMID- 20903830 TI - Retinitis Pigmentosa (Atypical), with OEdema of the Macula. PMID- 20903840 TI - A Fallacy in the Diagnosis of Glioma Retinae. PMID- 20903877 TI - Acute Nephritis without OEdema; Recovery. PMID- 20903860 TI - Case of Solid OEdema. PMID- 20903879 TI - Paroxysmal Haemoglobinuria. PMID- 20903966 TI - Persistent Hereditary OEdema of the Legs (Milroy's Disease) in Mother and Daughter. PMID- 20903972 TI - Case of Leucocythaemia Cutis. PMID- 20903979 TI - Case of OEdeme bleu de Charcot. PMID- 20903989 TI - Resistant Eczematous Eruption associated with Erythraemia. PMID- 20903991 TI - Case of Maculo-anaesthetic Lepra. PMID- 20904004 TI - Unilateral Striae Atrophicae (Striae Cutis Distensae) of the Thorax. PMID- 20904006 TI - Multiple Idiopathic Haemorrhagic Sarcoma (Kaposi). PMID- 20904007 TI - Case of Circumscribed Sclerodermia (Morphoea) in a Child. PMID- 20904010 TI - Case of Leucocythaemia Cutis. PMID- 20904020 TI - Case of Morphoeo-sclerodermia. PMID- 20904015 TI - Case of OEdematous Sclerodermia. PMID- 20904035 TI - Trauma in the AEtiology of Arthritis. PMID- 20904057 TI - A Method of Concentrating Entamoeba Cysts in Stools. PMID- 20904090 TI - Skiagrams illustrating Spasmodic Stricture of the Thoracic OEsophagus. PMID- 20904123 TI - Haematoma (?) of the Posterior End of the Inferior Turbinate. PMID- 20904124 TI - Specimen from a Case of Fatal Haemorrhage from Gunshot Wound involving the Superior Thyroid Artery. PMID- 20904129 TI - Cases and Specimens illustrating Work on Atrophic Rhinitis (Ozaena) and Tuberculosis. PMID- 20904139 TI - Six Cases of OEsophagectasia. PMID- 20904135 TI - Report of Two Cases of Mutton Bones impacted in the OEsophagus; OEsophagoscopy; Recovery. PMID- 20904169 TI - Concealed Accidental Haemorrhage with Intraperitoneal Bleeding. PMID- 20904174 TI - Acute Toxaemia of Pregnancy, with Acute Nephritis and Accidental Haemorrhage; Caesarean Hysterectomy; Recovery. PMID- 20904175 TI - Caesarean Section and Hysterectomy for Accidental Haemorrhage. PMID- 20904181 TI - Large Vesical Calculus, 31/2 oz., around a Slate Pencil. PMID- 20904193 TI - Mandibular Anaesthesia. PMID- 20904237 TI - Punctiform Haemorrhages of the Brain in Gas Poisoning. PMID- 20904232 TI - Note on an Amoeboid Body found in the Urine. PMID- 20904240 TI - Observations upon the Air under Masks during Ether Anaesthesia. PMID- 20904239 TI - Anaesthetics at a Casualty Clearing Station. PMID- 20904262 TI - DISCUSSION ON THE AETIOLOGY AND TREATMENT OF IRITIS: OPENING ADDRESS BY THE PRESIDENT. PMID- 20904245 TI - Recent Researches into the AEtiology of Typhus. PMID- 20904263 TI - DISCUSSION ON THE AETIOLOGY AND TREATMENT OF IRITIS. PMID- 20904264 TI - DISCUSSION ON THE AETIOLOGY AND TREATMENT OF IRITIS. PMID- 20904266 TI - DISCUSSION ON THE AETIOLOGY AND TREATMENT OF IRITIS. PMID- 20904267 TI - DISCUSSION ON THE AETIOLOGY AND TREATMENT OF IRITIS. PMID- 20904268 TI - DISCUSSION ON THE AETIOLOGY AND TREATMENT OF IRITIS. PMID- 20904269 TI - DISCUSSION ON THE AETIOLOGY AND TREATMENT OF IRITIS. PMID- 20904270 TI - DISCUSSION ON THE AETIOLOGY AND TREATMENT OF IRITIS. PMID- 20904271 TI - DISCUSSION ON THE AETIOLOGY AND TREATMENT OF IRITIS. PMID- 20904277 TI - Studies on Endocrine Organs of Dementia Praecox. PMID- 20904289 TI - Case of OEsophageal Stricture. PMID- 20904301 TI - Congenital Atresia of the OEsophagus. PMID- 20904300 TI - A Case of Cyclic Vomiting with Acetonaemia (Acidosis): Remarks on Non-diabetic Acetonuria and Diaceturia. PMID- 20904357 TI - Two Cases of Morphoea Guttata. PMID- 20904346 TI - Case for Diagnosis: possibly an early case of the miscalled Multiple Idiopathic Haemorrhagic Sarcoma of Kaposi. PMID- 20904400 TI - Case of Extensive Naevus of the Trunk and Extremities, involving the Palms and Soles. PMID- 20904401 TI - Case of Multiple Morphoeo-sclerodermia. PMID- 20904405 TI - Case of Guttate Morphoea-Striae et Maculae Atrophicae. PMID- 20904411 TI - Naevus treated by X-rays. PMID- 20904413 TI - Abnormal Condition of the OEsophagus, Stomach and Colon. PMID- 20904439 TI - Case of Hyper-adduction of the Left Arytaenoid Cartilage. PMID- 20904461 TI - Intranasal Frontal Sinus Operation under Nitrous Oxide Anaesthesia. PMID- 20904480 TI - Paralysis of the Arytaenoideus of a Woman, aged 24. PMID- 20904520 TI - Fusiform Dilatation of the OEsophagus, coated with Oidium albicans, in a Girl, aged 15, and apparently Idiopathic. PMID- 20904486 TI - Crossing of Arytaenoids. PMID- 20904532 TI - A Piece of Mutton Bone removed from the Entrance to the OEsophagus. PMID- 20904534 TI - Fracture of Four Rings of the Trachea; Urgent Dyspnoea; Operation; Recovery. PMID- 20904543 TI - Case of Tuberculosis of the Larynx in a Female Patient; Dyspnoea and Regurgitation of Liquids during Drinking relieved by Intralaryngeal Operation. PMID- 20904561 TI - Removal of Foreign Body Impacted in the OEsophagus. PMID- 20904550 TI - Case of Pre-tracheal Abscess of Acute Development, in a Middle-aged Woman, producing Dysphagia and Dyspnoea. PMID- 20904581 TI - REPORT OF THE COMMITTEE APPOINTED BY THE SECTION OF OBSTETRICS AND GYNAECOLOGY TO INVESTIGATE THE EFFECTS OF SCOPOLAMINE-MORPHINE NARCOSIS, "TWILIGHT SLEEP," IN CHILDBIRTH. PMID- 20904638 TI - Aural Bacteraemia, with Illustrative Cases : (Abstract). PMID- 20904662 TI - Some Considerations on the Physiology of Anaesthesia by Chloroform. PMID- 20904660 TI - The Administration of Anaesthetics in Home Military Hospitals. PMID- 20904700 TI - Case of Haemophilia with Effusion into Knee-joints. PMID- 20904707 TI - Case of Haemophilia with Effusion into Knee-joints. PMID- 20904704 TI - Case of Haemophilia. PMID- 20904708 TI - Case of Osteogenesis Imperfecta (Fragilitas Ossium, Foetal Rickets). PMID- 20904709 TI - Coagulation of the Blood in Purpura and Haemophilia: (Abstract). PMID- 20904718 TI - Case of Anaemia with unusual Blood Count. PMID- 20904720 TI - Note on Three Cases of Melaena Neonatorum successfully treated by the Injection of Whole Blood or Blood Serum. PMID- 20904741 TI - Case of Extensive Pigmented Naevi. PMID- 20904751 TI - Guttate Morphoea. PMID- 20904748 TI - White-spot Disease (Morphoea Guttata). PMID- 20904761 TI - Case of Unilateral Band Sclerodermia and Morphoeosclerodermia of the Left Leg. PMID- 20904760 TI - Case of Melanotic Naevo-carcinoma (previously shown). PMID- 20904766 TI - Case of Multiple Idiopathic Haemorrhagic Sarcoma of Kaposi. PMID- 20904765 TI - Another Probable Early Case of the Miscalled Multiple Idiopathic Haemorrhagic Sarcoma of Kaposi. PMID- 20904767 TI - Case of Erythrodermia with Lymphatic Leukaemia. PMID- 20904802 TI - An Enumerative Study of Entamoeba coli Cysts in Stools. PMID- 20904784 TI - Diathermy in Gynaecology. PMID- 20904856 TI - Tooth-plate in OEsophagus; OEsophagoscopy: Removal. PMID- 20904854 TI - Case of Long Fraenum Linguae. PMID- 20904863 TI - Two Cases of Dental Plates removed from the OEsophagus. PMID- 20904864 TI - Summary of Case of Foreign Body in OEsophagus, occurring at a Royal Naval Base Hospital. PMID- 20904869 TI - Angioma of the Left Arytaenoid. PMID- 20904885 TI - Removal by the Indirect Method of a Jagged Piece of Bone impacted in the OEsophagus. PMID- 20904898 TI - Four Cases of Atrophic Rhinitis with Ozaena undergoing Treatment by the Glycophylic Method. PMID- 20904923 TI - Spasm at the Entrance to the OEsophagus. PMID- 20904922 TI - A Method of treating Atrophic Rhinitis with Ozaena based on an Alteration in Composition and Reaction of the Substrate on which the Bacterial Ferments are acting: (Abstract). PMID- 20904929 TI - Pharyngeal Diverticula with Notes of Two Cases-in one the Pouch was Removed under Local, in the other under General, Anaesthesia. PMID- 20904936 TI - Appendix: Museum; Specimens and Cases exhibited: Electrodes for the Treatment of Ozaena of the Nose by Ionic Medication. PMID- 20904939 TI - Three Dental Plates removed from OEsophagus. PMID- 20904944 TI - DISCUSSION ON DILATATION OF THE OESOPHAGUS WITHOUT ANATOMICAL STENOSIS. PMID- 20904945 TI - DISCUSSION ON DILATATION OF THE OESOPHAGUS WITHOUT ANATOMICAL STENOSIS. PMID- 20904947 TI - DISCUSSION ON DILATATION OF THE OESOPHAGUS WITHOUT ANATOMICAL STENOSIS. PMID- 20904948 TI - DISCUSSION ON DILATATION OF THE OESOPHAGUS WITHOUT ANATOMICAL STENOSIS. PMID- 20904949 TI - DISCUSSION ON DILATATION OF THE OESOPHAGUS WITHOUT ANATOMICAL STENOSIS. PMID- 20904950 TI - DISCUSSION ON DILATATION OF THE OESOPHAGUS WITHOUT ANATOMICAL STENOSIS. PMID- 20904951 TI - DISCUSSION ON DILATATION OF THE OESOPHAGUS WITHOUT ANATOMICAL STENOSIS. PMID- 20904952 TI - DISCUSSION ON DILATATION OF THE OESOPHAGUS WITHOUT ANATOMICAL STENOSIS. PMID- 20904953 TI - DISCUSSION ON DILATATION OF THE OESOPHAGUS WITHOUT ANATOMICAL STENOSIS. PMID- 20904954 TI - DISCUSSION ON DILATATION OF THE OESOPHAGUS WITHOUT ANATOMICAL STENOSIS. PMID- 20904955 TI - DISCUSSION ON DILATATION OF THE OESOPHAGUS WITHOUT ANATOMICAL STENOSIS. PMID- 20904956 TI - DISCUSSION ON DILATATION OF THE OESOPHAGUS WITHOUT ANATOMICAL STENOSIS. PMID- 20904957 TI - DISCUSSION ON DILATATION OF THE OESOPHAGUS WITHOUT ANATOMICAL STENOSIS. PMID- 20904958 TI - DISCUSSION ON DILATATION OF THE OESOPHAGUS WITHOUT ANATOMICAL STENOSIS. PMID- 20904960 TI - The Pathology of OEsophagectasia (Dilatation of the OEsophagus without Anatomic Stenosis at the Cardiac Orifice). PMID- 20904959 TI - DISCUSSION ON DILATATION OF THE OESOPHAGUS WITHOUT ANATOMICAL STENOSIS. PMID- 20904961 TI - A Tooth-plate impacted in the OEsophagus divided by Irwin Moore's Cutting Shears. PMID- 20904962 TI - Tooth-plate impacted in the OEsophagus for Eight Weeks; Three Unsuccessful Attempts at Removal; Death from Perforation into the Pleural Cavity. PMID- 20904963 TI - Skiagram showing Reflex Achalasia of the OEsophagus due to the Irritation of a Gastric Ulcer. PMID- 20904965 TI - Spirochaetosis Icterohaemorrhagica: (Abstract). PMID- 20904964 TI - Dilatation of the OEsophagus without Stenosis. PMID- 20904983 TI - A Foetus undergoing Spontaneous Evolution removed by Laparotomy during Labour. PMID- 20904982 TI - Report to Council on Teaching of Obstetrics and Gynaecology to Medical Students and Graduates in London. PMID- 20904987 TI - Specimen of a Lower Limb of a Mature Foetus contained in an Osseous Cyst, and remaining in the Abdomen of the Mother for Fifty-two Years. PMID- 20905004 TI - The Teaching of Obstetrics and Gynaecology from the Standpoint of Preventive Medicine. PMID- 20904995 TI - Specimen of Subperitoneal Lipoma weighing 163/4 lb. PMID- 20905005 TI - The Teaching of Obstetrics and Gynaecology from the Point of View of a General Practitioner. PMID- 20905006 TI - DISCUSSION ON RECONSTRUCTION IN THE TEACHING OF OBSTETRICS AND GYNAECOLOGY TO MEDICAL STUDENTS. PMID- 20905007 TI - DISCUSSION ON RECONSTRUCTION IN THE TEACHING OF OBSTETRICS AND GYNAECOLOGY TO MEDICAL STUDENTS. PMID- 20905009 TI - DISCUSSION ON RECONSTRUCTION IN THE TEACHING OF OBSTETRICS AND GYNAECOLOGY TO MEDICAL STUDENTS. PMID- 20905008 TI - DISCUSSION ON RECONSTRUCTION IN THE TEACHING OF OBSTETRICS AND GYNAECOLOGY TO MEDICAL STUDENTS. PMID- 20905010 TI - DISCUSSION ON RECONSTRUCTION IN THE TEACHING OF OBSTETRICS AND GYNAECOLOGY TO MEDICAL STUDENTS. PMID- 20905011 TI - DISCUSSION ON RECONSTRUCTION IN THE TEACHING OF OBSTETRICS AND GYNAECOLOGY TO MEDICAL STUDENTS. PMID- 20905012 TI - DISCUSSION ON RECONSTRUCTION IN THE TEACHING OF OBSTETRICS AND GYNAECOLOGY TO MEDICAL STUDENTS. PMID- 20905013 TI - DISCUSSION ON RECONSTRUCTION IN THE TEACHING OF OBSTETRICS AND GYNAECOLOGY TO MEDICAL STUDENTS. PMID- 20905014 TI - DISCUSSION ON RECONSTRUCTION IN THE TEACHING OF OBSTETRICS AND GYNAECOLOGY TO MEDICAL STUDENTS. PMID- 20905015 TI - DISCUSSION ON RECONSTRUCTION IN THE TEACHING OF OBSTETRICS AND GYNAECOLOGY TO MEDICAL STUDENTS. PMID- 20905016 TI - DISCUSSION ON RECONSTRUCTION IN THE TEACHING OF OBSTETRICS AND GYNAECOLOGY TO MEDICAL STUDENTS. PMID- 20905017 TI - DISCUSSION ON RECONSTRUCTION IN THE TEACHING OF OBSTETRICS AND GYNAECOLOGY TO MEDICAL STUDENTS. PMID- 20905018 TI - DISCUSSION ON RECONSTRUCTION IN THE TEACHING OF OBSTETRICS AND GYNAECOLOGY TO MEDICAL STUDENTS. PMID- 20905019 TI - DISCUSSION ON RECONSTRUCTION IN THE TEACHING OF OBSTETRICS AND GYNAECOLOGY TO MEDICAL STUDENTS. PMID- 20905020 TI - DISCUSSION ON RECONSTRUCTION IN THE TEACHING OF OBSTETRICS AND GYNAECOLOGY TO MEDICAL STUDENTS. PMID- 20905021 TI - DISCUSSION ON RECONSTRUCTION IN THE TEACHING OF OBSTETRICS AND GYNAECOLOGY TO MEDICAL STUDENTS. PMID- 20905024 TI - On Local Anaesthesia in Dental Operations. PMID- 20905026 TI - An Experimental Inquiry into the Bacteriology of Pyorrhoea. PMID- 20905034 TI - Prosthetic Treatment of Old Injuries of the Maxillae. PMID- 20905080 TI - DISCUSSION ON THE PRESENT POSITION OF SPINAL ANAESTHESIA. PMID- 20905079 TI - DISCUSSION ON THE PRESENT POSITION OF SPINAL ANAESTHESIA. PMID- 20905081 TI - DISCUSSION ON THE PRESENT POSITION OF SPINAL ANAESTHESIA. PMID- 20905082 TI - DISCUSSION ON THE PRESENT POSITION OF SPINAL ANAESTHESIA. PMID- 20905084 TI - DISCUSSION ON THE PRESENT POSITION OF SPINAL ANAESTHESIA. PMID- 20905083 TI - DISCUSSION ON THE PRESENT POSITION OF SPINAL ANAESTHESIA. PMID- 20905091 TI - Case of Caesarean Section under Spinal Anaesthesia. PMID- 20905101 TI - President's Address: The Formation of Clear Lines in Nebulae : (Abstract). PMID- 20905155 TI - Trophoedema of Leg. PMID- 20905158 TI - Specimens from Case of Aplastic Anaemia. PMID- 20905163 TI - Case of Aplastic Anaemia. PMID- 20905169 TI - DISCUSSION ON THE AETIOLOGY, PREVENTION, AND NON-OPERATIVE TREATMENT OF ADENOIDS. PMID- 20905170 TI - DISCUSSION ON THE AETIOLOGY, PREVENTION, AND NON-OPERATIVE TREATMENT OF ADENOIDS. PMID- 20905171 TI - DISCUSSION ON THE AETIOLOGY, PREVENTION, AND NON-OPERATIVE TREATMENT OF ADENOIDS. PMID- 20905172 TI - DISCUSSION ON THE AETIOLOGY, PREVENTION, AND NON-OPERATIVE TREATMENT OF ADENOIDS. PMID- 20905173 TI - DISCUSSION ON THE AETIOLOGY, PREVENTION, AND NON-OPERATIVE TREATMENT OF ADENOIDS. PMID- 20905176 TI - DISCUSSION ON THE AETIOLOGY, PREVENTION, AND NON-OPERATIVE TREATMENT OF ADENOIDS. PMID- 20905175 TI - DISCUSSION ON THE AETIOLOGY, PREVENTION, AND NON-OPERATIVE TREATMENT OF ADENOIDS. PMID- 20905177 TI - DISCUSSION ON THE AETIOLOGY, PREVENTION, AND NON-OPERATIVE TREATMENT OF ADENOIDS. PMID- 20905178 TI - DISCUSSION ON THE AETIOLOGY, PREVENTION, AND NON-OPERATIVE TREATMENT OF ADENOIDS. PMID- 20905179 TI - DISCUSSION ON THE AETIOLOGY, PREVENTION, AND NON-OPERATIVE TREATMENT OF ADENOIDS. PMID- 20905181 TI - Discussion on the AEtiology, Prevention, and Non-operative Treatment of Adenoids. PMID- 20905180 TI - Discussion on the AEtiology, Prevention, and Non-operative Treatment of Adenoids. PMID- 20905183 TI - Discussion on the AEtiology, Prevention, and Non-operative Treatment of Adenoids. PMID- 20905185 TI - Discussion on the AEtiology, Prevention, and Non-operative Treatment of Adenoids. PMID- 20905184 TI - Discussion on the AEtiology, Prevention, and Non-operative Treatment of Adenoids. PMID- 20905187 TI - Discussion on the AEtiology, Prevention, and Non-operative Treatment of Adenoids. PMID- 20905186 TI - Discussion on the AEtiology, Prevention, and Non-operative Treatment of Adenoids. PMID- 20905189 TI - Discussion on the AEtiology, Prevention, and Non-operative Treatment of Adenoids. PMID- 20905188 TI - Discussion on the AEtiology, Prevention, and Non-operative Treatment of Adenoids. PMID- 20905195 TI - Aplastic Anaemia. PMID- 20905271 TI - Case of Intussusception caused by Papilloma at the Ileo-caecal Valve. PMID- 20905247 TI - The Role of Health Resorts in the State and their Use as "Temples of AEsculapius" for the Diagnosis and Treatment of Chronic and Functional Diseases. PMID- 20905272 TI - Case of Bony Anchylosis of the Knee; fixed at Right Angle; ? Gonococcus, or some other form of Arthritis. PMID- 20905280 TI - Myxoedema, with High Blood-pressure, preceded by Enlargement of the Thyroid Gland. PMID- 20905290 TI - A Case of Dislocation between the Fifth and Sixth Cervical Vertebrae. PMID- 20905294 TI - Hysterical Anaesthesia of the Eyeballs; Cutaneous Artefacts; Voluntary Regurgitation of Stomach Contents. PMID- 20905291 TI - Case of Malignant Endocarditis affecting the Pulmonary Valve in a Youth, aged 161/2. PMID- 20905295 TI - A Case of Trophoedema. PMID- 20905296 TI - A Case of Extreme OEsophagectasia (Hurst's Achalasia of the Cardia). PMID- 20905323 TI - So-called "Multiple Haemorrhagic Sarcoma" (Kaposi). PMID- 20905324 TI - Multiple Pigmented Haemorrhagic Sarcoma (?): a Case for Diagnosis. PMID- 20905326 TI - Two Cases of Bilateral (more or less Symmetrical) Morphoea in Children. PMID- 20905331 TI - Case of Morphoea and Hyperthyroidism. PMID- 20905334 TI - Case of Naevus Anaemicus (Vorner). PMID- 20905350 TI - Case of Linear Morphoea. PMID- 20905352 TI - Case of Haemorrhagic Lupus Erythematosus. PMID- 20905372 TI - Case of Anaesthetic Leprosy. PMID- 20905360 TI - Seborrhoeic Dermatitis of Unusual Severity following an Attack of Urticaria ab Ingestis. PMID- 20905375 TI - Case of Morphoea of Acute Onset. PMID- 20905376 TI - Case for Diagnosis; ? Cutaneous Sarcoid of Boeck. PMID- 20905380 TI - Extensive Vascular Naevus. PMID- 20905392 TI - Case of ? Mycosis Fungoides. PMID- 20905389 TI - Case of Morphoea Guttata (White-spot Disease). PMID- 20905440 TI - Haemorrhage during or after Thyro-fissure in the Removal of the Vocal Cord for Intrinsic Cancer of the Larynx and the Chief Vessel concerned; and its Control. PMID- 20905395 TI - Case of ? Lupus Erythematosus (anomalous type); ? Folliculitis Ulerythematosa Reticulata of McKee. PMID- 20905449 TI - Case of ? Neoplasm of Larynx. PMID- 20905461 TI - Fistula and Cicatrization in connexion with ? Thyroglossal Tract. PMID- 20905450 TI - Case of Streptococcal Ulcer on the Arytaenoid. PMID- 20905478 TI - Notes on a Case of Congenital Deformity of the OEsophagus. PMID- 20905493 TI - Carcinoma of the Post-Cricoid Region (Pars laryngea pharyngis) and the Upper End of the OEsophagus. PMID- 20905497 TI - OEsophageal Obstruction due to Hypertrophy of the Cardiac Sphincter and Narrowing of the Epicardia. PMID- 20905499 TI - Multiple Polypi (OEdematous Fibromata) of the Middle Third of the OEsophagus. PMID- 20905509 TI - Case of ? Lupus of the Larynx. PMID- 20905512 TI - Newly-designed Instruments for OEsophagoscopy and Bronchoscopy. PMID- 20905517 TI - Infiltration of Right Ventricular Band, Vocal Cord, and Pyriform Sinus; ? Malignant. PMID- 20905525 TI - Instruments used for Suturing the Pillars of the Fauces after Enucleation of the Tonsils in Case of Haemorrhage. PMID- 20905529 TI - (IX) OESophagus. PMID- 20905530 TI - The Control of Haemorrhage following Removal of the Tonsils. PMID- 20905531 TI - Anaemias of the Haemolytic Jaundice Group. PMID- 20905561 TI - Case of Combined Antepartum Haemorrhage: Placenta Praevia and Accidental Haemorrhage. PMID- 20905565 TI - A Note on the Value of Blood Transfusion before Operation in Severe Secondary Anaemias. PMID- 20905571 TI - Case of Recurrent Haemorrhage from Laceration of the Cervix, treated by Blood Transfusion and Hysterectomy. PMID- 20905582 TI - DISCUSSION ON THE REPORT ON THE TEACHING OF OBSTETRICS AND GYNAECOLOGY. PMID- 20905572 TI - Utero-placental (Accidental) Haemorrhage: A Clinical Report of Fifty Consecutive Cases. PMID- 20905583 TI - A Criticism of the Report of the Committee of the Council of the Section of Obstetrics and Gynaecology of the Royal Society of Medicine upon the Teaching of Obstetrics and Gynaecology in London. PMID- 20905585 TI - A Criticism of the Report of the Committee of the Council of the Section of Obstetrics and Gynaecology of the Royal Society of Medicine upon the Teaching of Obstetrics and Gynaecology in London. PMID- 20905584 TI - A Criticism of the Report of the Committee of the Council of the Section of Obstetrics and Gynaecology of the Royal Society of Medicine upon the Teaching of Obstetrics and Gynaecology in London. PMID- 20905586 TI - A Criticism of the Report of the Committee of the Council of the Section of Obstetrics and Gynaecology of the Royal Society of Medicine upon the Teaching of Obstetrics and Gynaecology in London. PMID- 20905587 TI - A Criticism of the Report of the Committee of the Council of the Section of Obstetrics and Gynaecology of the Royal Society of Medicine upon the Teaching of Obstetrics and Gynaecology in London. PMID- 20905588 TI - A Criticism of the Report of the Committee of the Council of the Section of Obstetrics and Gynaecology of the Royal Society of Medicine upon the Teaching of Obstetrics and Gynaecology in London. PMID- 20905589 TI - A Criticism of the Report of the Committee of the Council of the Section of Obstetrics and Gynaecology of the Royal Society of Medicine upon the Teaching of Obstetrics and Gynaecology in London. PMID- 20905590 TI - A Criticism of the Report of the Committee of the Council of the Section of Obstetrics and Gynaecology of the Royal Society of Medicine upon the Teaching of Obstetrics and Gynaecology in London. PMID- 20905591 TI - A Criticism of the Report of the Committee of the Council of the Section of Obstetrics and Gynaecology of the Royal Society of Medicine upon the Teaching of Obstetrics and Gynaecology in London. PMID- 20905593 TI - A Criticism of the Report of the Committee of the Council of the Section of Obstetrics and Gynaecology of the Royal Society of Medicine upon the Teaching of Obstetrics and Gynaecology in London. PMID- 20905592 TI - A Criticism of the Report of the Committee of the Council of the Section of Obstetrics and Gynaecology of the Royal Society of Medicine upon the Teaching of Obstetrics and Gynaecology in London. PMID- 20905594 TI - A Criticism of the Report of the Committee of the Council of the Section of Obstetrics and Gynaecology of the Royal Society of Medicine upon the Teaching of Obstetrics and Gynaecology in London. PMID- 20905610 TI - Chronic Infective Osteitis of Maxillae in a Male, aged 40. PMID- 20905673 TI - DISCUSSION ON ANAESTHESIA IN OPERATIONS ON THE THYROID GLAND. PMID- 20905674 TI - DISCUSSION ON ANAESTHESIA IN OPERATIONS ON THE THYROID GLAND. PMID- 20905675 TI - DISCUSSION ON ANAESTHESIA IN OPERATIONS ON THE THYROID GLAND. PMID- 20905677 TI - DISCUSSION ON ANAESTHESIA IN OPERATIONS ON THE THYROID GLAND. PMID- 20905676 TI - DISCUSSION ON ANAESTHESIA IN OPERATIONS ON THE THYROID GLAND. PMID- 20905678 TI - DISCUSSION ON ANAESTHESIA IN OPERATIONS ON THE THYROID GLAND. PMID- 20905679 TI - DISCUSSION ON ANAESTHESIA IN OPERATIONS ON THE THYROID GLAND. PMID- 20905680 TI - DISCUSSION ON ANAESTHESIA IN OPERATIONS ON THE THYROID GLAND. PMID- 20905688 TI - The Serbian Epidemics of Typhus and Relapsing Fever in 1915: Their Origin, Course, and Preventive Measures employed for their Arrest : (An AEtiological and Preventive Study based on Records of British Military Sanitary Mission to Serbia, 1915.). PMID- 20905702 TI - Macular Detachment of Retina; ? New Growth. PMID- 20905707 TI - The Radical Cure of Gonorrhoeal Iritis. PMID- 20905738 TI - Case of Leukaemia with Scalp Nodules. PMID- 20905735 TI - Studies in the Pathology of Dementia Praecox. PMID- 20905749 TI - Nasopharyngeal Toxaemia and the Examination of Swabs of the Nasopharynx. PMID- 20905740 TI - Cases of Anaemia with Enlarged Spleen. PMID- 20905754 TI - Two Cases of Melaena Neonatorum treated by Injection of Fresh Citrated Blood. PMID- 20905750 TI - OEsophageal Obstruction in Young Children. PMID- 20905770 TI - Notes of a Case of OEsophagectasis in an Infant, with Radiograms. PMID- 20905801 TI - Case of Sternomastoid Tumour in a Child born by Caesarean Section. PMID- 20905847 TI - Congenital Absence of the Tibiae. PMID- 20905952 TI - Case of Enlarged Ischial Bursae. PMID- 20905946 TI - Chronic Myeloid Leukaemia: Death from Acute Anaemia due to Massive Haemorrhages (Haematomata); Simulation of Slight Pyuria by Leukaemic Oozing in the Urine. PMID- 20905966 TI - Case of Cavernous Naevus of the Foot. PMID- 20905998 TI - Case of Multiple Idiopathic Haemorrhagic Sarcoma. PMID- 20905982 TI - Post-mortem Findings of Case of ? Neoplasm of Lung, shown at the Meeting of the Section on December 10, 1920. PMID- 20905999 TI - Leukaemia with Cutaneous Nodules. PMID- 20906009 TI - Case of (?) Kaposi's Haemorrhagic Sarcoma or Schamberg's Disease. PMID- 20906026 TI - Extensive Naevus of the Type Naevus Unius Lateris. PMID- 20906024 TI - Morphoea Guttata with Arthritis. PMID- 20906030 TI - Framboesiform Syphilis. PMID- 20906039 TI - Case of Morphoea Guttata et Areata. PMID- 20906040 TI - Case of Haematolymphangioma. PMID- 20906082 TI - Atrophic Condition of Skin following Treatment of Naevus. PMID- 20906119 TI - Case of OEdema of the Larynx for Diagnosis. PMID- 20906128 TI - Tumour of Nasopharynx extending Outwards into Zygomatic and Temporal Fossae (section shown). PMID- 20906120 TI - Fixation of the Arytaenoids in a Case of Osteo-arthritis. PMID- 20906136 TI - An Account of Two Cases of Obstruction of the OEsophagus by a Foreign Body acting as Ball-valve. PMID- 20906170 TI - Tuberculosis of Interarytaenoid Region, Right Vocal Cord, Right Vocal Band, and Left Vocal Process, treated with the Galvano-cautery. PMID- 20906167 TI - Foreign Body (Collar Stud) in the OEsophagus of an Infant, causing Spinal Osteomyelitis and Death. PMID- 20906222 TI - DISCUSSION ON THE TREATMENT OF ANTE-PARTUM HAEMORRHAGE. PMID- 20906175 TI - Subglottic Tumour. ? Cyst. PMID- 20906223 TI - DISCUSSION ON THE TREATMENT OF ANTE-PARTUM HAEMORRHAGE. PMID- 20906224 TI - DISCUSSION ON THE TREATMENT OF ANTE-PARTUM HAEMORRHAGE. PMID- 20906225 TI - DISCUSSION ON RUPTURE OF THE CAESAREAN SECTION SCAR IN SUBSEQUENT PREGNANCY OR LABOUR. PMID- 20906226 TI - DISCUSSION ON THE TREATMENT OF ANTE-PARTUM HAEMORRHAGE. PMID- 20906227 TI - DISCUSSION ON RUPTURE OF THE CAESAREAN SECTION SCAR IN SUBSEQUENT PREGNANCY OR LABOUR. PMID- 20906229 TI - DISCUSSION ON RUPTURE OF THE CAESAREAN SECTION SCAR IN SUBSEQUENT PREGNANCY OR LABOUR. PMID- 20906228 TI - DISCUSSION ON RUPTURE OF THE CAESAREAN SECTION SCAR IN SUBSEQUENT PREGNANCY OR LABOUR. PMID- 20906231 TI - DISCUSSION ON RUPTURE OF THE CAESAREAN SECTION SCAR IN SUBSEQUENT PREGNANCY OR LABOUR. PMID- 20906230 TI - DISCUSSION ON RUPTURE OF THE CAESAREAN SECTION SCAR IN SUBSEQUENT PREGNANCY OR LABOUR. PMID- 20906232 TI - DISCUSSION ON THE TREATMENT OF ANTE-PARTUM HAEMORRHAGE. PMID- 20906233 TI - DISCUSSION ON RUPTURE OF THE CAESAREAN SECTION SCAR IN SUBSEQUENT PREGNANCY OR LABOUR. PMID- 20906234 TI - DISCUSSION ON RUPTURE OF THE CAESAREAN SECTION SCAR IN SUBSEQUENT PREGNANCY OR LABOUR. PMID- 20906236 TI - DISCUSSION ON RUPTURE OF THE CAESAREAN SECTION SCAR IN SUBSEQUENT PREGNANCY OR LABOUR. PMID- 20906235 TI - DISCUSSION ON RUPTURE OF THE CAESAREAN SECTION SCAR IN SUBSEQUENT PREGNANCY OR LABOUR. PMID- 20906237 TI - DISCUSSION ON RUPTURE OF THE CAESAREAN SECTION SCAR IN SUBSEQUENT PREGNANCY OR LABOUR. PMID- 20906238 TI - DISCUSSION ON RUPTURE OF THE CAESAREAN SECTION SCAR IN SUBSEQUENT PREGNANCY OR LABOUR. PMID- 20906239 TI - DISCUSSION ON RUPTURE OF THE CAESAREAN SECTION SCAR IN SUBSEQUENT PREGNANCY OR LABOUR. PMID- 20906240 TI - DISCUSSION ON RUPTURE OF THE CAESAREAN SECTION SCAR IN SUBSEQUENT PREGNANCY OR LABOUR. PMID- 20906241 TI - DISCUSSION ON RUPTURE OF THE CAESAREAN SECTION SCAR IN SUBSEQUENT PREGNANCY OR LABOUR. PMID- 20906243 TI - DISCUSSION ON RUPTURE OF THE CAESAREAN SECTION SCAR IN SUBSEQUENT PREGNANCY OR LABOUR. PMID- 20906242 TI - DISCUSSION ON RUPTURE OF THE CAESAREAN SECTION SCAR IN SUBSEQUENT PREGNANCY OR LABOUR. PMID- 20906244 TI - The Pathology of Utero-placental (Accidental) Haemorrhage. PMID- 20906246 TI - DISCUSSION ON THE TREATMENT OF ANTE-PARTUM HAEMORRHAGE. PMID- 20906245 TI - DISCUSSION ON THE TREATMENT OF ANTE-PARTUM HAEMORRHAGE. PMID- 20906248 TI - DISCUSSION ON THE TREATMENT OF ANTE-PARTUM HAEMORRHAGE. PMID- 20906247 TI - DISCUSSION ON THE TREATMENT OF ANTE-PARTUM HAEMORRHAGE. PMID- 20906251 TI - Intravesical Repair of Inaccessible Vesico-vaginal Fistulae. PMID- 20906252 TI - Placenta Praevia, with Vasa Praevia; Caesarean Section. PMID- 20906254 TI - DISCUSSION ON THE TREATMENT OF ANTE-PARTUM HAEMORRHAGE. PMID- 20906257 TI - DISCUSSION ON THE TREATMENT OF ANTE-PARTUM HAEMORRHAGE. PMID- 20906259 TI - DISCUSSION ON RUPTURE OF THE CAESAREAN SECTION SCAR IN SUBSEQUENT PREGNANCY OR LABOUR. PMID- 20906269 TI - Sodium Bicarbonate Tolerance in the Toxaemias of Pregnancy. PMID- 20906271 TI - Case of Concealed Accidental Haemorrhage with Eclampsia. PMID- 20906272 TI - Further Observations on the AEtiology of Eclampsia and the Pre-eclamptic State. PMID- 20906293 TI - DISCUSSION ON THE TREATMENT OF ANTE-PARTUM HAEMORRHAGE. PMID- 20906294 TI - DISCUSSION ON THE TREATMENT OF ANTE-PARTUM HAEMORRHAGE. PMID- 20906295 TI - DISCUSSION ON THE TREATMENT OF ANTE-PARTUM HAEMORRHAGE. PMID- 20906322 TI - Pyorrhoea Alveolaris affecting the Ears. PMID- 20906326 TI - Zinc Ionization and Electrolysis in the Treatment of Chronic Otorrhoea. PMID- 20906335 TI - Two Cases of Lateral Sinus Thrombosis without Otorrhoea. PMID- 20906337 TI - The Psychology of Anaesthesia. PMID- 20906338 TI - Anaesthetics in the Plastic Surgery of the Face and Jaws. PMID- 20906339 TI - The Importance of an Examination of Patients by the Anaesthetist previous to Anaesthesia. PMID- 20906341 TI - A New General Anaesthetic: its Theory and Practice. PMID- 20906363 TI - Commotio Retinae with Extreme OEdema. PMID- 20906385 TI - Case of Severe Anaemia. PMID- 20906401 TI - Case of OEsophageal Obstruction in a Girl, aged 41/2 years. PMID- 20906443 TI - On the Occurrence of the Eggs of Mites in the Faeces of Miners in Cornwall and their Subsequent Development on Culture Media. PMID- 20906453 TI - Unilateral Haemorrhagic Interstitial Nephritis with slight Hydronephrosis. PMID- 20906446 TI - The Value of Laboratory Reports on Stools in Cases of Suspected Amoebic Dysentery, and their Interpretation by the Clinician; with a Special Note on the Diagnostic Significance of Charcot-Leyden Crystals. PMID- 20906454 TI - Haemato-nephrosis due to Papilloma of the Renal Pelvis. PMID- 20906483 TI - Results of an Experimental and Histological Investigation into Seventy-five Cases of Rectal Fistulae. PMID- 20906492 TI - Case of Haematocele of the Knee-joint. PMID- 20906565 TI - DISCUSSION ON THE PLACE OF BATHS AND HEALTH RESORTS IN GYNAECOLOGY. PMID- 20906555 TI - The Use of Pituitrin by Mouth in certain Cases of Uterine Haemorrhage. PMID- 20906566 TI - DISCUSSION ON THE PLACE OF BATHS AND HEALTH RESORTS IN GYNAECOLOGY. PMID- 20906573 TI - Case of Ectopia Vesicae. PMID- 20906567 TI - DISCUSSION ON THE PLACE OF BATHS AND HEALTH RESORTS IN GYNAECOLOGY. PMID- 20906581 TI - Addison's Disease, with Severe Anaemia, treated by Suprarenal Grafting. PMID- 20906592 TI - Case of Erythraemia (Vaquez-Osler Disease). PMID- 20906615 TI - Case of Morphoea Guttata. PMID- 20906594 TI - Case of von Recklinghausen's Disease, associated with Secondary Anaemia. PMID- 20906616 TI - Case of Multiple Naevi. PMID- 20906633 TI - Case of Unilateral Morphoeo-sclerodermia Faciei. PMID- 20906618 TI - Naevo-xantho-endothelioma (?) with Epidermolysis Bullosa. PMID- 20906639 TI - Lichenoid Linear Naevus. PMID- 20906643 TI - Hydroa AEstivale. PMID- 20906647 TI - Des Epitheliomes Primitifs de la Peau : (Abstract). PMID- 20906651 TI - Case of ? Erythromelalgia. PMID- 20906654 TI - Case of ? Angioma Serpiginosum. PMID- 20906673 TI - Electro-therapy in Gynaecology. PMID- 20906685 TI - Foreign Body (Piece of Wire) removed from Right Arytaenoid Cartilage by Indirect Method. PMID- 20906751 TI - Three Post-mortem Specimens of Acute Septic OEdema of the Larynx. PMID- 20906690 TI - Carcinoma of the OEsophagus perforating into the Trachea at the Bifurcation; Report of a Case and Demonstration of Specimen. PMID- 20906758 TI - Foreign Body (Toothplate) in the OEsophagus. PMID- 20906771 TI - Accessory Thyroid growing in the OEsophageal Lumen. PMID- 20906805 TI - Tubal Lithopaedion. PMID- 20906809 TI - Case of Haematoma of the Vulva following Labour. PMID- 20906811 TI - A Wandering Silk Suture removed from the Urethra as a Sequel to Caesarean Section. PMID- 20906817 TI - Chemical Observations on the Toxaemias of Pregnancy: (A REPORT TO THE MEDICAL RESEARCH COUNCIL.). PMID- 20906825 TI - Labour obstructed by a Solid Carcinomatous Tumour of the Left Ovary; Caesarean Hysterectomy, with Removal of the Tumour. PMID- 20906826 TI - Carcinoma of the Cervix following Gonorrhoea in a Young Woman. PMID- 20906836 TI - A Note on the Treatment of Haemorrhage after Tooth Extraction. PMID- 20906828 TI - The Essential Buttress of Practical Training in Obstetrics and Gynaecology. PMID- 20906854 TI - Otosclerosis-with a possible Bearing on the AEtiology of the Disease. PMID- 20906877 TI - Case of Unilateral Deafness with Anaesthesia of the same Side of the Face. PMID- 20906883 TI - Report on Visit as Official Representative of the Section of Anaesthetics to the First Meeting of the Canadian Society of Anaesthetists at Niagara, and to the Meeting of the American Society of Anaesthetists at Boston, in June, 1921. PMID- 20906884 TI - DISCUSSION ON THE UTILITY AND LIMITATIONS OF NITROUS OXIDE ANAESTHESIA. PMID- 20906885 TI - DISCUSSION ON THE UTILITY AND LIMITATIONS OF NITROUS OXIDE ANAESTHESIA. PMID- 20906887 TI - DISCUSSION ON THE UTILITY AND LIMITATIONS OF NITROUS OXIDE ANAESTHESIA. PMID- 20906886 TI - DISCUSSION ON THE UTILITY AND LIMITATIONS OF NITROUS OXIDE ANAESTHESIA. PMID- 20906888 TI - Anaesthesia in Intracranial Surgery. PMID- 20906889 TI - DISCUSSION ON THE UTILITY AND LIMITATIONS OF NITROUS OXIDE ANAESTHESIA. PMID- 20906890 TI - DISCUSSION ON THE UTILITY AND LIMITATIONS OF NITROUS OXIDE ANAESTHESIA. PMID- 20906900 TI - The Epidemiology of Summer Diarrhoea. PMID- 20906899 TI - The Relationship between Puerperal Septicaemia and other Infectious Diseases, with Reference to the Admission of Maternity Cases into Isolation Hospitals: (ABSTRACT.). PMID- 20906927 TI - Case of ? Retinitis or Choroiditis. PMID- 20906943 TI - Further Pathological Studies in Dementia Praecox, especially in relation to the Interstitial Cells of Leydig. PMID- 20906944 TI - The Morbid Histology of the Testes in Dementia Praecox. PMID- 20906949 TI - Splenomedullary Leukaemia. PMID- 20906950 TI - Case of OEsophageal Stricture. PMID- 20906963 TI - Case of ? Dyspituitarism, ? Hypernephroma. PMID- 20906962 TI - Specimen of Congenital Malformation of OEsophagus. PMID- 20906964 TI - Dermato-polyneuritis (Acrodynia: Erythroedema): (Abstract). PMID- 20906968 TI - Specimens from the Case of Obesity (? Dispituitarism, ? Hypernephroma), shown at last Meeting. PMID- 20906981 TI - Case of ? Tumour of Suprarenal Cortex. PMID- 20906987 TI - Case of Obesity of ? Suprarenal Origin. PMID- 20906990 TI - Case of Myelocytic Leukaemia. PMID- 20907003 TI - Observations on the Effect of Tartar Emetic on the Eggs and Miracidia of Bilharzia hoematobia. PMID- 20907002 TI - Eimeria oxyspora, Dobell, 1919, found in a Specimen of Human Faeces in England. PMID- 20907004 TI - Thermotropism in Ankylostome Larvae. PMID- 20907005 TI - A Simple Method of Experimentation for Skin Infection with Hook-worm Larvae. PMID- 20907009 TI - DISCUSSION ON AMOEBIC DYSENTERY. PMID- 20907010 TI - DISCUSSION ON AMOEBIC DYSENTERY. PMID- 20907011 TI - DISCUSSION ON AMOEBIC DYSENTERY. PMID- 20907012 TI - DISCUSSION ON AMOEBIC DYSENTERY. PMID- 20907013 TI - DISCUSSION ON AMOEBIC DYSENTERY. PMID- 20907014 TI - DISCUSSION ON AMOEBIC DYSENTERY. PMID- 20907015 TI - DISCUSSION ON AMOEBIC DYSENTERY. PMID- 20907016 TI - DISCUSSION ON AMOEBIC DYSENTERY. PMID- 20907088 TI - Case of ? Diverticulitis of Pelvic Colon, with Vesico-colic Fistula. PMID- 20907136 TI - Case of Retro-rectal Sarcoma (Chordoma ?). PMID- 20907162 TI - Case of Purpura Haemorrhagica. PMID- 20907175 TI - Case of Cysticercus Cellulosae. PMID- 20907183 TI - Two Cases of Erythraemia (Vaquez Disease) treated by Rontgen-Therapy. PMID- 20907189 TI - Hemiplegia occurring in Pregnant Woman at Full Term; Sudden Onset accompanied by Transient Albuminuria; Caesarean Section; Gradual Recovery. PMID- 20907202 TI - Case for Diagnosis: ? Papulonecrotic Tuberculides. PMID- 20907205 TI - Extensive Linear Naevus in a Man, aged 54. PMID- 20907207 TI - Case of Morphoea associated with Vitiligo. PMID- 20907216 TI - Case for Diagnosis (? Leukaemia Cutis). PMID- 20907255 TI - Idiopathic Haemorrhagic Sarcoma of Kaposi. PMID- 20907285 TI - Case for Diagnosis; ? Diphtheria of the Skin. PMID- 20907303 TI - Case of Atrophic Dermatitis of the Hands and Feet ? Lupus Erythematosus. PMID- 20907320 TI - Section of Obstetrics and Gynaecology: Joint Meeting with the Section of Therapeutics and Pharmacology: The Value of Ergot in Obstetrical and Gynaecological Practice; with Special Reference to its Present Position in the British Pharmacopoeia. PMID- 20907334 TI - Case of Myotonia Atrophica with Implication of Left Crico-arytaenoid Muscle. PMID- 20907350 TI - Case of OEdema of the Septum in association with Nasal Polypi. PMID- 20907360 TI - Skiagrams showing Simple Fibrous Strictures of the OEsophagus in a Child. PMID- 20907372 TI - Haemorrhagic Angiosarcoma of Upper Jaw. PMID- 20907380 TI - Specimen from the Post-mortem Room of a Large Cyst of the Orifice of the Larynx arising from the Arytaeno-epiglottidean Fold. PMID- 20907381 TI - Mounted Specimen showing a Threepenny-piece impacted in a Perforation between the OEsophagus and Trachea of a Baby, aged 3 months. PMID- 20907385 TI - Tumour of the Larynx; ? Malignant. PMID- 20907389 TI - Demonstration of Specimens of Tumours in the Inter-arytaenoid Space of the Larynx. PMID- 20907402 TI - Outgrowth from the Anterior Half of the Left Vocal Cord; ? Fibroma or Prolapse. PMID- 20907426 TI - Two Cases of Chronic OEdema of Orbit. PMID- 20907405 TI - Specimen of a Large Cyst of the Orifice of the Larynx arising from the Arytaeno epiglottidean Fold. PMID- 20907435 TI - Nasopharyngeal Tumour: ? A Cystic Adenoma, containing Cartilage (Wet Specimen and Section). PMID- 20907436 TI - Case of ? Clinically Malignant Disease of the Left Pyriform Sinus. PMID- 20907439 TI - The Nervous and Mental Disorders of Severe Anaemias in Relation to their Infective Lesions and Blood Changes. PMID- 20907454 TI - Case of Erythraemia (Polycythaemia Vera, Vaquez-Osler's Disease), with Cerebral Haemorrhage. PMID- 20907452 TI - Case of Acquired Chronic Haemolytic (Acholuric) Jaundice, seen Fifteen Years ago, with a Blood Picture at that time resembling one of Pernicious Anaemia. PMID- 20907457 TI - Case of Unusual Sequelae of Lethargic Encephalitis (Parkinsonian Syndrome associated with Right Hemiplegia, showing Peculiar Disturbances of Tone and Posture in the Limbs on the Hemiplegic Side). PMID- 20907500 TI - Report of a Committee of the Section of Obstetrics and Gynaecology of the Royal Society of Medicine upon the Prognosis and Treatment of Eclampsia. PMID- 20907503 TI - Stretching of the Epithelium of the Tubal Rugae by Blood effused into them in Torsion of Pedicle of Ovarian Tumour. PMID- 20907518 TI - Adenomatosis Vaginae. PMID- 20907505 TI - The Treatment of Dysmenorrhoea: An Analysis of 100 Cases. PMID- 20907520 TI - The Technique of Caesarean Section. PMID- 20907528 TI - The Treatment of Severe and Persistent Uterine Haemorrhage by Radium, with a Report upon Forty-five Cases. PMID- 20907521 TI - A Note on Two Cases of Caesarean Section under Spinal Anaesthesia with Tropacocaine. PMID- 20907530 TI - A Ruptured Haematoma of the Ovary, with Extensive Intra-peritoneal Haemorrhage. PMID- 20907534 TI - DISCUSSION ON "DENTAL SEPSIS AS AN AETIOLOGICAL FACTOR IN DISEASE OF OTHER ORGANS.". PMID- 20907536 TI - ADJOURNED DISCUSSION ON "DENTAL SEPSIS AS AN AETIOLOGICAL FACTOR IN DISEASE OF OTHER ORGANS.". PMID- 20907535 TI - DISCUSSION ON "DENTAL SEPSIS AS AN AETIOLOGICAL FACTOR IN DISEASE OF OTHER ORGANS.". PMID- 20907537 TI - ADJOURNED DISCUSSION ON "DENTAL SEPSIS AS AN AETIOLOGICAL FACTOR IN DISEASE OF OTHER ORGANS.". PMID- 20907538 TI - ADJOURNED DISCUSSION ON "DENTAL SEPSIS AS AN AETIOLOGICAL FACTOR IN DISEASE OF OTHER ORGANS.". PMID- 20907539 TI - ADJOURNED DISCUSSION ON "DENTAL SEPSIS AS AN AETIOLOGICAL FACTOR IN DISEASE OF OTHER ORGANS.". PMID- 20907540 TI - ADJOURNED DISCUSSION ON "DENTAL SEPSIS AS AN AETIOLOGICAL FACTOR IN DISEASE OF OTHER ORGANS.". PMID- 20907541 TI - ADJOURNED DISCUSSION ON "DENTAL SEPSIS AS AN AETIOLOGICAL FACTOR IN DISEASE OF OTHER ORGANS.". PMID- 20907542 TI - ADJOURNED DISCUSSION ON "DENTAL SEPSIS AS AN AETIOLOGICAL FACTOR IN DISEASE OF OTHER ORGANS.". PMID- 20907544 TI - ADJOURNED DISCUSSION ON "DENTAL SEPSIS AS AN AETIOLOGICAL FACTOR IN DISEASE OF OTHER ORGANS.". PMID- 20907543 TI - ADJOURNED DISCUSSION ON "DENTAL SEPSIS AS AN AETIOLOGICAL FACTOR IN DISEASE OF OTHER ORGANS.". PMID- 20907546 TI - ADJOURNED DISCUSSION ON "DENTAL SEPSIS AS AN AETIOLOGICAL FACTOR IN DISEASE OF OTHER ORGANS.". PMID- 20907545 TI - ADJOURNED DISCUSSION ON "DENTAL SEPSIS AS AN AETIOLOGICAL FACTOR IN DISEASE OF OTHER ORGANS.". PMID- 20907561 TI - DISCUSSION ON "DENTAL SEPSIS AS AN AETIOLOGICAL FACTOR IN DISEASE OF OTHER ORGANS.". PMID- 20907547 TI - ADJOURNED DISCUSSION ON "DENTAL SEPSIS AS AN AETIOLOGICAL FACTOR IN DISEASE OF OTHER ORGANS.". PMID- 20907593 TI - Cerebellar Abscess; Sudden Coma and Apnoea; Recovery after Operation during Artificial Respiration. PMID- 20907607 TI - The Anaesthetization of Patients for the Classical Caesarean Section. PMID- 20907608 TI - General Anaesthesia in Dental Surgery. PMID- 20907611 TI - DISCUSSION ON CORONERS' INQUESTS-THE CLASSIFICATION OF DEATHS UNDER ANAESTHETICS AS VIOLENT OR UNNATURAL. PMID- 20907612 TI - DISCUSSION ON CORONERS' INQUESTS-THE CLASSIFICATION OF DEATHS UNDER ANAESTHETICS AS VIOLENT OR UNNATURAL. PMID- 20907613 TI - DISCUSSION ON CORONERS' INQUESTS-THE CLASSIFICATION OF DEATHS UNDER ANAESTHETICS AS VIOLENT OR UNNATURAL. PMID- 20907614 TI - DISCUSSION ON CORONERS' INQUESTS-THE CLASSIFICATION OF DEATHS UNDER ANAESTHETICS AS VIOLENT OR UNNATURAL. PMID- 20907615 TI - DISCUSSION ON CORONERS' INQUESTS-THE CLASSIFICATION OF DEATHS UNDER ANAESTHETICS AS VIOLENT OR UNNATURAL. PMID- 20907616 TI - DISCUSSION ON CORONERS' INQUESTS-THE CLASSIFICATION OF DEATHS UNDER ANAESTHETICS AS VIOLENT OR UNNATURAL. PMID- 20907617 TI - DISCUSSION ON CORONERS' INQUESTS-THE CLASSIFICATION OF DEATHS UNDER ANAESTHETICS AS VIOLENT OR UNNATURAL. PMID- 20907618 TI - DISCUSSION ON CORONERS' INQUESTS-THE CLASSIFICATION OF DEATHS UNDER ANAESTHETICS AS VIOLENT OR UNNATURAL. PMID- 20907619 TI - Case of Cardiac Arrest under an Anaesthetic followed by Heart Massage. PMID- 20907620 TI - The Effects of Vagal Trauma on the Anaesthetized Patient. PMID- 20907641 TI - Haemangeioma of Orbit. PMID- 20907636 TI - Jabir ibn Hayyan. PMID- 20907650 TI - Case for Diagnosis (? Polycythaemia Rubra). PMID- 20907657 TI - Case of Subhyaloid Haemorrhage in a Girl. PMID- 20907659 TI - Atrophic Patches at the Macula Tuberculous; ? Cyst. PMID- 20907658 TI - Two Cases of Primary Band-shaped Opacity of both Corneae. PMID- 20907668 TI - Ischaemic Paralysis. PMID- 20907713 TI - Case of ? Charcot's Knee. PMID- 20907686 TI - Case of Haemophilic Arthritis of the Knee. PMID- 20907728 TI - Double Tumour, ? Lipoma, in the Perineal Region of an Infant. PMID- 20907719 TI - Specimen of Synostosis of Phalangeal Joint ? Congenital in Origin. PMID- 20907732 TI - Two Cases of Coeliac Infantilism in the Convalescent (Non-diarrhoeic) Stage. PMID- 20907731 TI - Case for Diagnosis; ? Renal Dwarfism. PMID- 20907735 TI - Pneumococcal Septicaemia and Enlargement of Liver and Spleen. PMID- 20907776 TI - Congenital Haemolytic Jaundice. PMID- 20907760 TI - Specimen of Congenital Stricture of the OEsophagus. PMID- 20907801 TI - Framboesia: History of its Introduction into India; with Personal Observations of over 200 Initial Lesions. PMID- 20907805 TI - Case of Spirochaetal Dysentery: (Abstract). PMID- 20907807 TI - Specimens from a Human Case of Infection with Dientamoeba fragilis, Jepps and Dobell, 1917. PMID- 20907812 TI - The Factors in Uraemia. PMID- 20907820 TI - Two Large Calculi removed from the Perinaeum of a Male, aged 62, in Margate Cottage Hospital. PMID- 20907848 TI - Gonorrhoeal Stricture of the Rectum: PRESIDENT'S ADDRESS. PMID- 20907853 TI - Case of Excision of an Adenoma of the Liver which had ruptured spontaneously, causing Internal Haemorrhage. PMID- 20907937 TI - A Case of Lymphogranulomatosis Maligna (Hodgkin's Disease) with Recurrent Purpura and Haemorrhagic Symptoms-also Remarks on Lymphogranulomatosis Maligna. PMID- 20907929 TI - Case of Juvenile Myxoedema. PMID- 20907948 TI - Two Cases of Hydroa AEstivale with Notes of Three Other Cases. PMID- 20907961 TI - Haematoporphyria Congenita with Hydroa-AEstivale. PMID- 20907962 TI - Striae Atrophicae. PMID- 20907972 TI - OEdema Perstans of Eyelids (Five Years). PMID- 20907981 TI - Case of Ulcerative Stomatitis; ? Nature. PMID- 20907999 TI - Case of Aleukaemic Lymphomata. PMID- 20907986 TI - Case of ? Darier's Disease. PMID- 20908045 TI - DISCUSSION ON "THE AETIOLOGY AND TREATMENT OF OSTEO-ARTHRITIS AND RHEUMATOID ARTHRITIS". PMID- 20908046 TI - DISCUSSION ON "THE AETIOLOGY AND TREATMENT OF OSTEO-ARTHRITIS AND RHEUMATOID ARTHRITIS". PMID- 20908047 TI - DISCUSSION ON "THE AETIOLOGY AND TREATMENT OF OSTEO-ARTHRITIS AND RHEUMATOID ARTHRITIS". PMID- 20908049 TI - DISCUSSION ON "THE AETIOLOGY AND TREATMENT OF OSTEO-ARTHRITIS AND RHEUMATOID ARTHRITIS.". PMID- 20908048 TI - DISCUSSION ON "THE AETIOLOGY AND TREATMENT OF OSTEO-ARTHRITIS AND RHEUMATOID ARTHRITIS.". PMID- 20908050 TI - DISCUSSION ON "THE AETIOLOGY AND TREATMENT OF OSTEO-ARTHRITIS AND RHEUMATOID ARTHRITIS.". PMID- 20908051 TI - DISCUSSION ON "THE AETIOLOGY AND TREATMENT OF OSTEO-ARTHRITIS AND RHEUMATOID ARTHRITIS.". PMID- 20908058 TI - DISCUSSION ON "THE AETIOLOGY AND TREATMENT OF OSTEO-ARTHRITIS AND RHEUMATOID ARTHRITIS". PMID- 20908081 TI - SPECIAL DISCUSSION ON "THE POSSIBLE SUBSTITUTES FOR COCAINE.": Local Anaesthetics in Rhinology. PMID- 20908070 TI - DISCUSSION ON "THE AETIOLOGY AND TREATMENT OF OSTEO-ARTHRITIS AND RHEUMATOID ARTHRITIS". PMID- 20908090 TI - Sections of Surgery, of Medicine, and of Therapeutics and Pharmacology: Discussion on "The Treatment of Severe Gastric and Duodenal Haemorrhage.". PMID- 20908094 TI - Sections of Study of Disease in Children, Neurology, Obstetrics and Gynaecology, and Orthopaedics: Discussion on "Birth Injuries, with Special Reference to Intracranial Injuries with Haemorrhage, and to Nerve Injuries.". PMID- 20908106 TI - A Case of Enlarged Tonsils complicated by a Venous Naevus of the Palate. PMID- 20908139 TI - Case of Laryngeal Tuberculosis in a Child aged 41/2 years. PMID- 20908186 TI - Haematemesis "Without Lesions". PMID- 20908195 TI - Symptoms following ? Encephalitis Lethargica. PMID- 20908191 TI - Case of ? Myopathy Confined to the Face. PMID- 20908201 TI - Case of ? Amyotonia Congenita. PMID- 20908205 TI - Spontaneous Sub-arachnoid Haemorrhage. PMID- 20908234 TI - Observations made at "Repeat" Caesarean Sections on the Uterine Scar (a) where the Previous Incision had been made through the Upper Contractile Part of the Uterus and (b) where the Previous Incision had been made through the Lower Non Contractile Part or Lower Uterine Segment. PMID- 20908213 TI - Case of Central Gliosis of Spinal Cord ? PMID- 20908236 TI - Venous Infarction in a Foetal Liver. PMID- 20908243 TI - Ruptured Caesarean Section Scar. PMID- 20908237 TI - Placenta Praevia in Four Successive Pregnancies. PMID- 20908247 TI - Radiography of the Foetus in Utero. PMID- 20908245 TI - Radiography of the Foetus in Utero. PMID- 20908248 TI - X-Ray Demonstration of Foetus in Utero. PMID- 20908251 TI - Dysmenorrhoea due to Haematometra in the Rudimentary Horn of a Uterus Bicornis Unicollis. PMID- 20908252 TI - Some Chemical Observations on the Toxaemias of Pregnancy, with Special Reference to Hepatic Function. PMID- 20908258 TI - Changes in the Polarity of the Foetus during the later weeks of pregnancy. PMID- 20908264 TI - DISCUSSION ON PYORRHOEA: ITS PREVENTION AND TREATMENT. PMID- 20908266 TI - DISCUSSION ON PYORRHOEA: ITS PREVENTION AND TREATMENT. PMID- 20908265 TI - DISCUSSION ON PYORRHOEA: ITS PREVENTION AND TREATMENT. PMID- 20908267 TI - DISCUSSION ON PYORRHOEA: ITS PREVENTION AND TREATMENT. PMID- 20908268 TI - DISCUSSION ON PYORRHOEA: ITS PREVENTION AND TREATMENT. PMID- 20908269 TI - DISCUSSION ON PYORRHOEA: ITS PREVENTION AND TREATMENT. PMID- 20908270 TI - DISCUSSION ON PYORRHOEA: ITS PREVENTION AND TREATMENT. PMID- 20908271 TI - DISCUSSION ON PYORRHOEA: ITS PREVENTION AND TREATMENT. PMID- 20908272 TI - DISCUSSION ON PYORRHOEA: ITS PREVENTION AND TREATMENT. PMID- 20908273 TI - DISCUSSION ON PYORRHOEA: ITS PREVENTION AND TREATMENT. PMID- 20908274 TI - DISCUSSION ON PYORRHOEA: ITS PREVENTION AND TREATMENT. PMID- 20908276 TI - DISCUSSION ON PYORRHOEA: ITS PREVENTION AND TREATMENT. PMID- 20908275 TI - DISCUSSION ON PYORRHOEA: ITS PREVENTION AND TREATMENT. PMID- 20908277 TI - DISCUSSION ON PYORRHOEA: ITS PREVENTION AND TREATMENT. PMID- 20908278 TI - DISCUSSION ON PYORRHOEA: ITS PREVENTION AND TREATMENT. PMID- 20908280 TI - Haemorrhage following Tooth Extraction. PMID- 20908302 TI - Case of Diabetes in which a Mastoid Operation was performed under Local Anaesthesia. PMID- 20908325 TI - Paralysis of the Sixth Cranial Nerve in a Patient suffering from Chronic Otorrhoea. PMID- 20908329 TI - Two Cases of Chronic Otorrhoea treated by Zinc Ionization. PMID- 20908333 TI - A Surgeon's Thoughts on Anaesthetics. PMID- 20908337 TI - Recent Experiences of Anaesthetics in America. PMID- 20908335 TI - The Preparation and Condensation of Di-methyl Ether, and its use as an Anaesthetic Agent. PMID- 20908383 TI - Case of Spleno-medullary Leukaemia (with Blood Films). PMID- 20908360 TI - Persistent Swelling of Conjunctivae. PMID- 20908423 TI - Case of Congenital Deformity of Dorsal and Cervical Vertebrae. PMID- 20908427 TI - Bony Ankylosis of Elbow at 125 degrees , and with Forearm Pronated. PMID- 20908464 TI - A Case of Anaemia in a Premature Infant treated by Intraperitoneal Injection of Blood. PMID- 20908483 TI - Case of Death from Uraemia due to Interstitial Nephritis (? of Congenital Origin): Renal Dwarfism. PMID- 20908473 TI - A Case of Progressive Lipodystrophia in a Boy aged 71/2 Years. PMID- 20908485 TI - Case of Myelogenous Leukaemia associated with Priapism. PMID- 20908490 TI - DISCUSS ON ON SPRUE AND COELIAC DISEASE. PMID- 20908492 TI - DISCUSS ON ON SPRUE AND COELIAC DISEASE. PMID- 20908491 TI - DISCUSS ON ON SPRUE AND COELIAC DISEASE. PMID- 20908493 TI - DISCUSS ON ON SPRUE AND COELIAC DISEASE. PMID- 20908494 TI - DISCUSS ON ON SPRUE AND COELIAC DISEASE. PMID- 20908495 TI - DISCUSS ON ON SPRUE AND COELIAC DISEASE. PMID- 20908496 TI - DISCUSS ON ON SPRUE AND COELIAC DISEASE. PMID- 20908497 TI - DISCUSS ON ON SPRUE AND COELIAC DISEASE. PMID- 20908499 TI - DISCUSS ON ON SPRUE AND COELIAC DISEASE. PMID- 20908498 TI - DISCUSS ON ON SPRUE AND COELIAC DISEASE. PMID- 20908500 TI - DISCUSS ON ON SPRUE AND COELIAC DISEASE. PMID- 20908524 TI - Subcapsular Haemorrhage (Renal). PMID- 20908501 TI - DISCUSS ON ON SPRUE AND COELIAC DISEASE. PMID- 20908544 TI - Three Specimens of "Atonic Caecum," removed by Operation. PMID- 20908553 TI - DISCUSSION ON THE TREATMENT OF HAEMORRHOIDS BY INJECTION: Pathological Changes produced by Carbolic Acid Injections and Mode of Action of Carbolic Acid. PMID- 20908554 TI - DISCUSSION ON THE TREATMENT OF HAEMORRHOIDS BY INJECTION. PMID- 20908556 TI - DISCUSSION ON THE TREATMENT OF HAEMORRHOIDS BY INJECTION. PMID- 20908555 TI - DISCUSSION ON THE TREATMENT OF HAEMORRHOIDS BY INJECTION. PMID- 20908557 TI - DISCUSSION ON THE TREATMENT OF HAEMORRHOIDS BY INJECTION. PMID- 20908558 TI - DISCUSSION ON THE TREATMENT OF HAEMORRHOIDS BY INJECTION. PMID- 20908560 TI - DISCUSSION ON THE TREATMENT OF HAEMORRHOIDS BY INJECTION. PMID- 20908559 TI - DISCUSSION ON THE TREATMENT OF HAEMORRHOIDS BY INJECTION. PMID- 20908561 TI - DISCUSSION ON THE TREATMENT OF HAEMORRHOIDS BY INJECTION. PMID- 20908562 TI - DISCUSSION ON THE TREATMENT OF HAEMORRHOIDS BY INJECTION. PMID- 20908602 TI - Some Aspects of Cardiac Dyspnoea; a Review. PMID- 20908607 TI - The Present-day Trend of Treatment of Gonorrhoea, with Special Reference to Cataphoretic Application of Colloid Silver. PMID- 20908626 TI - Case of Purpura Haemorrhagica. PMID- 20908635 TI - Case of "The Hairy, Black Tongue" (Nigrities-Hyperkeratosis Linguae). PMID- 20908644 TI - Case of "Polycythaemia Hypertonica". PMID- 20908652 TI - Psoriasis and Seborrhoeic Eczema: Pathological Anatomy and Diagnostic Histology of the Two Dermatoses. PMID- 20908661 TI - Case of Lymphatic Leukaemia with Erythrodermia. PMID- 20908659 TI - Case of Morphoea Guttata. PMID- 20908671 TI - Case of Macular Non-anaesthetic Leprosy. PMID- 20908665 TI - Case of Lupus Pernio (Sarcoid-Schaumann Type) associated with ? Lupus Vulgaris. PMID- 20908693 TI - Extensive Vascular Naevus of Face, treated by Radium. PMID- 20908673 TI - Naevus with Congenital Atrophic Lesions. PMID- 20908707 TI - Scaly Eruption ? Syphilitic. PMID- 20908739 TI - Chronic Purpura, Cutaneous "Striae," and Grave Endocrine Disturbance. PMID- 20908734 TI - Case of Hydroa AEstivale. PMID- 20908770 TI - Sections of Psychiatry, Neurology, Study of Disease in Children, and Epidemiology, Joint Discussion No. 2: Discussion on the Mental Sequelae of Encephalitis Lethargica. PMID- 20908744 TI - Technique Used in the Treatment of Gonorrhoeal Infections by Diathermy. PMID- 20908771 TI - Sections of Surgery, Anaesthetics, Medicine, Obstetrics and Gynaecology, and Pathology, Joint Discussion No. 3: Discussion on the Prevention and Treatment of Post-Operative Pulmonary Affections. PMID- 20908772 TI - Sections of Medicine, Surgery, and Pathology, Joint Discussion No. 4: Discussion on the Treatment of Septicaemia. PMID- 20908787 TI - Larynx Removed for Malignant Disease, under Local Anaesthesia. PMID- 20908798 TI - DISCUSSION ON PAROXYSMAL RHINORRHOEA. PMID- 20908800 TI - DISCUSSION ON PAROXYSMAL RHINORRHOEA. PMID- 20908803 TI - DISCUSSION ON PAROXYSMAL RHINORRHOEA. PMID- 20908801 TI - DISCUSSION ON PAROXYSMAL RHINORRHOEA. PMID- 20908804 TI - DISCUSSION ON PAROXYSMAL RHINORRHOEA. PMID- 20908805 TI - DISCUSSION ON PAROXYSMAL RHINORRHOEA. PMID- 20908807 TI - DISCUSSION ON PAROXYSMAL RHINORRHOEA. PMID- 20908806 TI - DISCUSSION ON PAROXYSMAL RHINORRHOEA. PMID- 20908808 TI - DISCUSSION ON PAROXYSMAL RHINORRHOEA. PMID- 20908825 TI - Specimen of Larynx and OEsophagus, from a Case of Paralysis of Left Recurrent Laryngeal Nerve and Tuberculous Ulcers of the OEsophagus, all caused by Caseous Tuberculous Glands. PMID- 20908819 TI - Naevus of the Epiglottis and Tongue. PMID- 20908835 TI - Pathological Specimens: (i) Myxo-chondroma of Base of Skull; (ii) Haemangioma of the Mid-brain; (iii) Neuro-fibroma of Auditory Nerve. PMID- 20908827 TI - An Instrument for the Application of Diathermy to the OEsophagus. PMID- 20908838 TI - DISCUSSION ON THE AETIOLOGY AND TREATMENT OF SUBACUTE COMBINED DEGENERATION OF THE SPINAL CORD: Pathogenesis and Treatment of Addison's (Pernicious) Anaemia and Subacute Combined Degeneration of the Spinal Cord. PMID- 20908839 TI - DISCUSSION ON THE AETIOLOGY AND TREATMENT OF SUBACUTE COMBINED DEGENERATION OF THE SPINAL CORD: Pathogenesis and Treatment of Addison's (Pernicious) Anaemia and Subacute Combined Degeneration of the Spinal Cord. PMID- 20908840 TI - DISCUSSION ON THE AETIOLOGY AND TREATMENT OF SUBACUTE COMBINED DEGENERATION OF THE SPINAL CORD: Pathogenesis and Treatment of Addison's (Pernicious) Anaemia and Subacute Combined Degeneration of the Spinal Cord. PMID- 20908841 TI - DISCUSSION ON THE AETIOLOGY AND TREATMENT OF SUBACUTE COMBINED DEGENERATION OF THE SPINAL CORD: Pathogenesis and Treatment of Addison's (Pernicious) Anaemia and Subacute Combined Degeneration of the Spinal Cord. PMID- 20908842 TI - DISCUSSION ON THE AETIOLOGY AND TREATMENT OF SUBACUTE COMBINED DEGENERATION OF THE SPINAL CORD: Pathogenesis and Treatment of Addison's (Pernicious) Anaemia and Subacute Combined Degeneration of the Spinal Cord. PMID- 20908843 TI - DISCUSSION ON THE AETIOLOGY AND TREATMENT OF SUBACUTE COMBINED DEGENERATION OF THE SPINAL CORD: Pathogenesis and Treatment of Addison's (Pernicious) Anaemia and Subacute Combined Degeneration of the Spinal Cord. PMID- 20908844 TI - DISCUSSION ON THE AETIOLOGY AND TREATMENT OF SUBACUTE COMBINED DEGENERATION OF THE SPINAL CORD: Pathogenesis and Treatment of Addison's (Pernicious) Anaemia and Subacute Combined Degeneration of the Spinal Cord. PMID- 20908853 TI - Case of Post-encephalitic Contractures and Paroxysmal Tachypnoea. PMID- 20908855 TI - Case of Post-encephalitic Myoclonus and Tachypnoea. PMID- 20908890 TI - Sarcoma Ulcerating through the Vagina and causing Severe Haemorrhage in a Girl aged 19. PMID- 20908904 TI - Retroplacental Haematoma from a Case of Toxaemia. PMID- 20908905 TI - A Case of Toxaemia in Early Pregnancy with Jaundice, Hyperemesis and Multiple Neuritis. Death three weeks after termination of Pregnancy. PMID- 20908912 TI - The Treatment of Placenta Praevia by Continuous Weight Traction-a Report of Seven Cases. PMID- 20908922 TI - A Report on Certain Drugs and Solutions used in Local Anaesthesia. PMID- 20908916 TI - A Note on Protagulin in Haemorrhage after Extraction. PMID- 20908931 TI - Septicaemia and Acute Infection of the Middle-ear Tract. PMID- 20908940 TI - Case of Naevoid Angioma of the Tympanum (? Endothelioma). Microscopical Section. PMID- 20908951 TI - Statistics of Results of Zinc Ionization in Chronic Otorrhoea in over 600 Cases. PMID- 20908966 TI - Some Morphological Factors governing the Incidence of Pernicious Anaemia. PMID- 20908967 TI - The Selection and Administration of Local and General Anaesthetics for Animals. PMID- 20908971 TI - Chloroform Anaesthesia. PMID- 20909009 TI - On the Relationship between Sub-arachnoid and Intra-ocular Haemorrhage. PMID- 20909030 TI - Two Cases for Diagnosis: ? Pseudocoxalgia. PMID- 20909028 TI - Case for Diagnosis; Multiple Arthritis (? Type) and ? Spastic Diplegia. PMID- 20909070 TI - Specimens from Three Cases of Cerebro-spinal Leptomeningitis due to Bacillus Influenzoe. PMID- 20909081 TI - A Case of Coeliac Disease with Glycosuria. PMID- 20909087 TI - Case of Myelogenous Leukaemia in a Child of 13. PMID- 20909124 TI - Some Flukes bred from Cercariae recurring in Schistosoma-transmitting Molluscs in South Africa. PMID- 20909108 TI - DISCUSSION: IS THE MODIFICATION OF COW'S MILK NECESSARY IN INFANT FEEDING ? PMID- 20909125 TI - Leptospirae in Tap Water. PMID- 20909133 TI - Haemorrhage from a Retropelvic Vessel during Pyelolithotomy. PMID- 20909181 TI - Case of Sacculitis of the Pelvic Colon with Localized Abscess. Death due to Portal Pyaemia. PMID- 20909184 TI - The Treatment of Certain Atonic and Atrophic Conditions of the Caecum. PMID- 20909190 TI - Carcinoma of the OEsophagus. PMID- 20909221 TI - A Further Communication on the Treatment of Gonorrhoea by Kataphoresis. PMID- 20909191 TI - Examination of the OEsophagus by X-rays. PMID- 20909229 TI - Remarks on the Incidence, AEtiology and Prevention of Rheumatic Fever in the Navy. PMID- 20909241 TI - Case of Polycythaemia Rubra Vera (Vaquez Disease) treated twice with application of X-rays to the Bones; Duration of Improvement. PMID- 20909250 TI - Case of Unusual Chronic OEdema. PMID- 20909255 TI - Splenectomy for Essential Thrombocytopenic Purpura Haemorrhagica in a Girl aged 10 years. PMID- 20909259 TI - Three Cases of Splenectomy for Essential Thrombocytopenic Purpura Haemorrhagica. PMID- 20909273 TI - Case of Mycosis Fungoides, (? Leukaemia Cutis). PMID- 20909264 TI - Congenital Auriculo-Ventricular Block in a Child aged 51/2 years. PMID- 20909283 TI - Case of Pigmentary Naevi. PMID- 20909324 TI - Unusual Case of Melanotic Naevi. PMID- 20909386 TI - SECTIONS OF COMPARATIVE MEDICINE, OBSTETRICS, AND GYNAECOLOGY, AND TROPICAL DISEASES AND PARASITOLOGY, JOINT DISCUSSION No. 1: DISCUSSION ON INFECTIVE ABORTION IN CATTLE AND ITS RELATION TO MALTA FEVER. PMID- 20909391 TI - SECTION OF DERMATOLOGY WITH THE SECTION FOR THE STUDY OF DISEASE IN CHILDREN, JOINT DISCUSSION No. 5: DISCUSSION ON THE AETIOLOGY AND TREATMENT OF INFANTILE ECZEMA. PMID- 20909398 TI - Case of Chronic Pharyngeal and OEsophageal Stenosis. PMID- 20909400 TI - A Case of OEsophageal Carcinoma treated by Intubation with Souttar's Tube. PMID- 20909399 TI - Extraction of Two Farthings from the OEsophagus. PMID- 20909401 TI - A Case of Chronic Lymphatic Leukaemia associated with enormous Enlargement of the Faucial Tonsils. PMID- 20909405 TI - An Instrument for the Application of Diathermy to the OEsophagus. PMID- 20909451 TI - Hypoglycaemia. PMID- 20909431 TI - Case of Ozaena apparently cured by Submucous Injection of Paraffin. PMID- 20909482 TI - A Contribution to the Technique of Caesarean Section. PMID- 20909490 TI - Gliosarcoma in a Full-time Stillborn Foetus. PMID- 20909495 TI - Hydatidiform Mole: Expulsion, and Death from Pulmonary Haemorrhage. PMID- 20909506 TI - A Revised Conception of Ante-partum Accidental Haemorrhage. PMID- 20909527 TI - Haemorrhagic Types of Ear Disease occurring during Epidemics of Influenza. PMID- 20909548 TI - Apnoea, Dyspnoea and Cyanosis in Relation to Anaesthesia: Part II.-Anaesthesia. PMID- 20909547 TI - DISCUSSION ON ANAESTHETICS IN CHILDREN. PMID- 20909550 TI - Anaesthesia in Relation to Disturbances of the Circulation. PMID- 20909551 TI - Some Bearings of the Physiology of the Respiration on the Administration of Anaesthetics. PMID- 20909552 TI - Recent Investigations concerning Nitrous Oxide, and the Ignition Points of some Anaesthetic Vapours. PMID- 20909554 TI - DISCUSSION ON ANAESTHETICS IN CHILDREN. PMID- 20909553 TI - On an Attempt to Alleviate the Acidosis of Anaesthesia. PMID- 20909556 TI - Gas-and-Oxygen Anaesthesia in Abdominal Surgery; and "Secondary Saturation.". PMID- 20909555 TI - Anaesthesia in Urological Surgery. PMID- 20909557 TI - DISCUSSION ON ANAESTHETICS IN CHILDREN. PMID- 20909559 TI - DISCUSSION ON ANAESTHETICS IN CHILDREN. PMID- 20909558 TI - DISCUSSION ON ANAESTHETICS IN CHILDREN. PMID- 20909561 TI - DISCUSSION ON ANAESTHETICS IN CHILDREN. PMID- 20909560 TI - DISCUSSION ON ANAESTHETICS IN CHILDREN. PMID- 20909563 TI - DISCUSSION ON ANAESTHETICS IN CHILDREN. PMID- 20909562 TI - DISCUSSION ON ANAESTHETICS IN CHILDREN. PMID- 20909581 TI - Glisson as an Orthopaedic Surgeon. PMID- 20909564 TI - Apnoea, Dyspnoea and Cyanosis in Relation to Anaesthesia: Part I.-Physiology. PMID- 20909628 TI - Case of Retinitis (? Result of Haemorrhage). PMID- 20909694 TI - A Case of Congenital Stenosis of the OEsophagus. PMID- 20909696 TI - Case of (?) Lymphocytic Leukaemia. PMID- 20909714 TI - Two Cases of Post-encephalitic Hyperpnoea. PMID- 20909716 TI - Case of Congenital OEdema of the Feet. PMID- 20909719 TI - Case of Splenic Anaemia (Banti's Disease). PMID- 20909738 TI - Case of Giant Naevus. PMID- 20909742 TI - Pseudoparasites in the Faeces of Man. PMID- 20909750 TI - Rupture of the Bladder in Acute Gonorrhoea. PMID- 20909759 TI - Case of Hydronephrosis with Intermittent Haematuria as Outstanding Symptom. PMID- 20909789 TI - Case of Ectopia Vesicae. PMID- 20909787 TI - Two Cases of Vesical Calculi following Caesarean Section. PMID- 20909856 TI - Orthopaedics at a Country Children's Hospital: President's Address. PMID- 20909853 TI - Some Important Differences in Gynaecological Practice. : President's Address. PMID- 20909868 TI - Pigmentation of the Thigh, with Varicose Veins and a Condition somewhat resembling so-called "Multiple Idiopathic Haemorrhagic (Pigment) Sarcoma" (Kaposi). PMID- 20909900 TI - DISCUSSION ON THE TREATMENT OF CANCER OF THE OESOPHAGUS. PMID- 20909871 TI - A Question on the Teaching of Ether Anaesthesia: With a Report of Four Deaths under Ether: President's Address. PMID- 20909901 TI - DISCUSSION ON THE TREATMENT OF CANCER OF THE OESOPHAGUS: THE INTUBATION METHOD. PMID- 20909902 TI - DISCUSSION ON THE TREATMENT OF CANCER OF THE OESOPHAGUS. PMID- 20909903 TI - DISCUSSION ON THE TREATMENT OF CANCER OF THE OESOPHAGUS. PMID- 20909907 TI - The Relative Numbers of Male and Female Gametocytes in Human Malaria (Plasmodium vivax, Plasmodium falciparum and Plasmodium malariae) and Hoemoproteus in Birds. PMID- 20909915 TI - Striae Patellares following Typhoid Fever. PMID- 20909925 TI - Haemangioma of Tongue. PMID- 20909967 TI - Interstitial Keratitis, with Marked Radial Deep Corneal Striation (Corneal OEdema). PMID- 20909968 TI - Patches of Choroiditis at the Maculae, Secondary to Double Antral Suppuration. PMID- 20910029 TI - Haemangiectatic Hypertrophy of the Arm. PMID- 20910030 TI - Bilateral OEdema of Feet. PMID- 20910036 TI - Case of Essential Thrombocytopenic Purpura Haemorrhagica a year after Splenectomy. PMID- 20910039 TI - Aleukaemic Lymphadenosis. PMID- 20910049 TI - Unusual Type of Naevus. PMID- 20910042 TI - Haemangioma Causing Jacksonian Epilepsy. PMID- 20910061 TI - Tumour of Upper Jaw originating in Maxillary Sinus, and Non-malignant Stricture of OEsophagus. PMID- 20910051 TI - Maculo-anaesthetic Lepra. PMID- 20910077 TI - Lateral Sinus Thrombosis, without Otorrhoea: Septicaemia; Subsequent Tonsillectomy; Acute Nephritis; Recovery. PMID- 20910113 TI - A Spirochaetic Infection with Necrosis and Perforation of Ileum. PMID- 20910112 TI - The Oocysts of a Coccidium in the Faeces of Laboratory and Wild Rats. PMID- 20910202 TI - Intermittent OEdema of the Foot for Diagnosis. PMID- 20910143 TI - Persistent Erythema, with Ischaemic Circulation, in the Left Foot, possibly in part connected with Prolonged Use of a Plaster Bandage for Tuberculous Disease of the Left Knee. PMID- 20910215 TI - Recurring Eruption: ? Artefact. PMID- 20910218 TI - Persistent Erythema, with Ischaemic Circulation in the Left Foot, possibly in part connected with Prolonged Use of a Plaster Bandage for Tuberculous Disease of the Left Knee. PMID- 20910220 TI - Papular Swellings on Eyelids and Forehead: ? Colloid Milium. PMID- 20910240 TI - Dysphagia for Three Months due to Foreign Body in the OEsophagus. PMID- 20910246 TI - Recurrent Intra-Ocular Haemorrhage in a Young Male. PMID- 20910279 TI - Large Temporo-sphenoidal Abscess following Injury: no Localizing Signs except Homolateral Papilloedema. PMID- 20910290 TI - Splenectomy for Essential Thrombocytopenic Purpura Haemorrhagica. PMID- 20910314 TI - Normal Variability of the Action of Pituitrin on the Contractile Power of the Caecum and Colon. PMID- 20910315 TI - The Value of Lipiodol in Determining the Extent of Fistulae-in ano. PMID- 20910317 TI - Volvulus of the Pelvic Colon and Blind Caecostomy. PMID- 20910320 TI - The Medical Aspects of Haematuria. PMID- 20910318 TI - Skin Grafts for Fistulae. PMID- 20910321 TI - DISCUSSION ON ANAESTHETICS IN DENTAL OPERATIONS. PMID- 20910345 TI - Case for Diagnosis: ? Boeck's Sarcoid. PMID- 20910337 TI - Case of ? Angioma Serpiginosum: for Diagnosis. PMID- 20910350 TI - Congenital Bilateral Occlusion of the Posterior Choanae. PMID- 20910349 TI - The Pathology of OEsophagectasia (Dilatation of the OEsophagus without Anatomic Stenosis at the Cardiac Orifice). PMID- 20910361 TI - A Pair of Haemostatic Clamp Forceps used in Enucleation of Tonsils. PMID- 20910362 TI - An OEsophageal Speculum with Distal and Proximal Illumination. PMID- 20910425 TI - Ulceration of Vocal Cord; ? Malignant. PMID- 20910453 TI - Case of ? Periostitis of Metatarsal. PMID- 20910481 TI - Fibromata (or ? Papilloma) of Larynx. PMID- 20910483 TI - The Pathology of OEsophagectasia (Dilatation of the OEsophagus without Anatomic Stenosis at the Cardiac Orifice). PMID- 20910503 TI - Case of Rare Seborrhoeide. PMID- 20910508 TI - Case for Diagnosis. ? Lupus Erythematosus. PMID- 20910524 TI - Aural Electrodes for Use in the Treatment of Chronic Otorrhoea by Zinc Ionization and Zinc Electrolysis. PMID- 20910526 TI - Acute Lateral Sinus Thrombosis Following Chronic Otorrhoea. PMID- 20910533 TI - Mass in Vitreous in a Boy aged 5, ? Glioma. PMID- 20910554 TI - Gastric Achlorhydria in a Woman who was under Observation over 19 years ago for Grave Anaemia. PMID- 20910585 TI - Congenital Abnormality of Cervical Vertebrae. PMID- 20910563 TI - Recent Investigations in the Treatment of Gonorrhoea. PMID- 20910590 TI - Case of ? Chloroma, ? Suprarenal Tumour. PMID- 20910612 TI - Tabes Dorsalis with Sudden Development of Local Anaesthesia. PMID- 20910615 TI - Laryngo-fissure for Intrinsic Carcinoma of the Larynx: Four cases in medical men, who are now in active practice, 21/4, 3, 41/2, and 51/2 years after operation. PMID- 20910618 TI - Extreme and Diffuse Dilatation of the OEsophagus. [X-ray Photographs and Lantern Slides]. PMID- 20910630 TI - Anaesthesia in Thyroid Surgery. PMID- 20910632 TI - A Case of Rupture of the Uterus After a Previous Caesarean Section. PMID- 20910661 TI - Splenomegaly. ? Diagnosis and Treatment. PMID- 20910663 TI - Notes on Blastomycosis: Its AEtiology and Clinical Varieties. PMID- 20910680 TI - Contusio Cerebri. ? Right Occipital Fracture. PMID- 20910668 TI - A Case of Intermittent Pyrexia associated with and probably due to Broncho spirochaetosis, Shown April 6, 1927. PMID- 20910681 TI - Polycythaemia: Cerebral Thrombosis. PMID- 20910694 TI - Coeliac Disease. PMID- 20910710 TI - A Case of Otitic Septicaemia. PMID- 20910719 TI - Case for Diagnosis. ? Mycosis Fungoides. PMID- 20910725 TI - Case for Diagnosis. ? Erythema Multiforme. PMID- 20910727 TI - Case for Diagnosis. ? Tertiary Yaws. PMID- 20910766 TI - Erythro-leukaemia. PMID- 20910781 TI - Volkmann's Ischaemic Myositis. PMID- 20910775 TI - Two Cases of Essential Thrombocytopenic Purpura Haemorrhagica two years after Splenectomy. PMID- 20910782 TI - The Medico-Legal Aspects of Deaths Under Anaesthetics. PMID- 20910788 TI - Hirschsprung's Disease with Faecal Incontinence. PMID- 20910790 TI - Rachitis Tarda following Treatment for Coeliac Disease. PMID- 20910794 TI - Double Optic Neuritis (Choked Discs), with Changes in the Maculae, in a Case of Cerebral Tumour. PMID- 20910796 TI - Tumour in Anterior Chamber with Recurrent Hyphaema. PMID- 20910822 TI - Congenital Deformities of Cervical and Upper Dorsal Vertebrae and Fusion of Upper Three Left Ribs. PMID- 20910833 TI - A Case of Diplococcal Infection of the Sphenoid Sinus with Associated Haemorrhages in the Stomach. PMID- 20910857 TI - The Haemorrhagic Diathesis. AB - The primary purpuras form a single clinical entity.Variations in the number of platelets can occur without the production of haemorrhages. These variations are the result of the condition of the capillaries and are not the cause of haemorrhages. The platelets may vary in any form of purpura, primary or secondary.The essential cause of the haemorrhagic state is a defect or increased permeability of the capillary endothelium.Purpura is allied to urticaria, the Henoch-Schonlein type being an intermediate state. PMID- 20910873 TI - DISCUSSION ON ANAESTHESIA IN OBSTETRICS. PMID- 20910889 TI - Leukaemic Erythrodermia. PMID- 20910894 TI - Ulceration of Nipple: ? Paget's Disease. PMID- 20910921 TI - DISCUSSION ON THE AETIOLOGY OF ALCOHOLISM. PMID- 20910920 TI - Eclampsia and Its Treatment: An Experience with Spinal Anaesthesia in One Case. PMID- 20910939 TI - Granuloma Fungoides. ? Case for Diagnosis. PMID- 20910944 TI - Haemangiectatic Hypertrophy (Parkes Weber). PMID- 20910947 TI - Bilharzia Haematobia of the Rectum. PMID- 20910952 TI - Case of Gangrene of the Rectum following Long-standing Prolapsing Haemorrhoids. PMID- 20910964 TI - Report of a Sub-Committee Appointed by the Council of the Section of Obstetrics and Gynaecology to Prepare a Scheme for the Unification of the Clinical Reports of Maternity Hospitals. PMID- 20910977 TI - A Further Contribution to the Subject of Aplastic Anaemia. AB - In the description of the condition of benign aplastic anaemia in pigs, attention is directed, among other things, to changes in the bone-marrow which seem of fundamental importance in understanding normal erythrogenesis.It is possible that an indirect van den Bergh reaction can be converted into an immediate direct by controlling the H-ion concentration suitably, either with buffer solutions or with less dissociable acids, such as acetic, used in preparing the van den Bergh reagent. The question of the interpretation of direct and indirect reactions, therefore, would seem to be reopened.Following Minot and Murphy's work, a pig with aplastic anaemia was fed with liver. The lesions in the liver, considered with the marked improvement in the blood which followed on liver feeding in this case, lead one to regard the condition as one of blood and marrow inefficiency due primarily to hepatic insufficiency.A comparison of pernicious anaemia with the benign aplastic anaemia of pigs seems to indicate that in pernicious anaemia there is more than a mere functional disturbance of the marrow. The marrow appears to be fundamentally and organically affected, and this appears to be the pathological basis of the disease-a point which has already been discussed more fully elsewhere [14]. A parallel may be drawn between the varieties of aplastic anaemia, such as already exists for ordinary anaemias. We have, thus, the secondary or benign anaemias on the one hand; and, on the other, the primary or malignant anaemias, such as pernicious anaemia. Correspondingly, we have such benign or secondary aplastic anaemias as that described in the pigs; and malignant or primary aplastic anaemias such as those in benzol poisoning, etc. That aplasia should be so marked a feature in iron deficiency, as compared with other secondary anaemias, is probably due to the persisting nature of the cause. PMID- 20910986 TI - DISCUSSION ON THE TREATMENT OF URETHRAL STRICTURE AND FISTULAE BY EXCISION. AB - For hard tunnel strictures and in cases of perineal fistula we should be bolder to adopt the principle of excision rather than that of mere external urethrotomy.A preliminary suprapubic cystotomy is advised, and also the avoidance, as far as possible, of the indwelling catheter. All fistulae should be excised completely, not merely opened, scraped and drained.The operator should not be in too great a hurry to pass sounds of too large a calibre after the operation, as in many cases there is little tendency to re-formation of the stricture. PMID- 20911003 TI - Congenital Anaemia with Jaundice. PMID- 20910992 TI - Morphoea with Root Distribution. PMID- 20911004 TI - A Case of Dysmenorrhoea due to Calcification of the Ovary. PMID- 20911017 TI - (?) Morphoea or Tuberculosis Cutis. PMID- 20911021 TI - Methods of Estimating the Liability to Post-operative Haemorrhage from Unsutured Wounds. PMID- 20911037 TI - Reconstruction of the Upper End of the OEsophagus. PMID- 20911048 TI - A Propos de la Colectomie pour Cancer. PMID- 20911055 TI - Intense Ascites. ? Hepatic Syphilis. PMID- 20911057 TI - Involuntary Movements of Arm. ? Psychoneurosis. PMID- 20911061 TI - Coeliac Rickets. PMID- 20911058 TI - Case for Diagnosis. ? Fibrocystic Disease of Femur. PMID- 20911092 TI - Anaemia of Obscure Origin. PMID- 20911105 TI - Myelogenous Leukaemia. PMID- 20911115 TI - Case for Diagnosis: ? Gummatous Osteitis of the Humerus. PMID- 20911125 TI - Anaemia and Jaundice in a Newborn Child. PMID- 20911122 TI - Muscular Hypotonia with Hypoglycaemia. PMID- 20911128 TI - Naevus and Hemiplegia. Shown for Comparison with previous Case. PMID- 20911127 TI - Naevus and Left-sided Hemiplegia. PMID- 20911140 TI - Aplastic Anaemia. PMID- 20911144 TI - Complete Occlusion of Posterior Choanae. PMID- 20911168 TI - Specimen of Carcinoma of Ascending Colon with great Dilatation of Caecum. Removed by Resection of the Distal Half of the Colon after Preliminary Short Circuit. PMID- 20911169 TI - Endotracheal Anaesthesia. AB - (1) With certain exceptions, endotracheal anaesthesia is the best method for operations on the head and neck and for any other operation in which there may be a difficulty in controlling the patient's air-way. (2) Expiration should be provided for, in endotracheal anaesthesia, either by means of a second tube or by a tube of calibre sufficient to permit to-and-fro respiration. (3) Cocainization of the upper air-passages has decided advantages in endotracheal anaesthesia. (4) "Blind" intubation through the nose renders the method possible in cases where it is impossible to use a speculum. (5) The insufflation method is not specially indicated in abdominal surgery. (6) The routine use of endotracheal anaesthesia in teaching-hospitals for every class of case is detrimental to the production of sound anaesthetic knowledge in students who are likely to become general practitioners. PMID- 20911170 TI - Simple Achromic Naevus, of Blotchy Distribution, on the Front of the Chest. PMID- 20911211 TI - Nutritional Anaemia in Infancy: Some Observations on a Common Deficiency Disease. AB - The prevalence of anaemia among London infants is shown by an investigation extending over the last three years and comprising about 770 cases with 3,100 haemoglobin estimations. This anaemia is largely nutritional in origin and is due to a deficiency of iron, possibly associated with other factors. It is known that an infant obtains its necessary iron not only from its milk, which is poor in iron, but also from a store in the liver. Our results lead us to suppose that this store may be unduly low in many London infants. The average haemoglobin percentage in the blood of fairly healthy artificially-fed London infants shows a sharp fall from its high level at birth to about 65 per cent. at 2 to 3 months of age, a rise to about 70 per cent. by 5 to 6 months, and then a steady fall reaching about 65 per cent. at 12 months. The continuous administration of iron, beginning when the infant is under 2 months old, raised the average haemoglobin percentage to 80 per cent. at 4 months of age and onwards. Infants whose birth weight is under 6 lb., twins and premature infants are specially in need of iron treatment. The selection of the iron salt is of importance, and iron and ammonium citrate proved effective. It was satisfactorily administered on a large scale by giving it incorporated in a dried milk.No evidence was obtained that want of light is an etiological factor in anaemia in infancy, and artificial light therapy did not cure it. No vitamin deficiency appeared to be involved. The value of liver treatment is still under investigation, but the results so far obtained can be explained on the assumption that liver treatment is efficacious only because it provides a source of iron. The routine administration of an iron salt to artificially-fed infants is advocated on the ground that, by preventing the anaemia from which most of them would otherwise suffer, the level of health of our infant population would be raised. PMID- 20911219 TI - Severe Rickets with ? Dyschondroplasia. PMID- 20911220 TI - Severe Anaemia and Bronzing. PMID- 20911232 TI - A Note on the Association of Extensive Haemangiomatous Naevus of the Skin with Cerebral (Meningeal) Haemangioma, especially Cases of Facial Vascular Naevus with Contralateral Hemiplegia. AB - The main type of the cases under consideration is that in which extensive capillary naevus of the skin, especially of trigeminal distribution, is associated with contralateral spastic hemiplegia, developing in early life, probably sometimes connected with intracranial haemorrhage from the abnormal blood-vessels of a diffuse leptomeningeal angioma on the same side as the main vascular naevus of the face. Various points related to such cases are referred to. PMID- 20911236 TI - The Excretion of the Constituent Ions of Sulphur Water in Faeces, Urine and Sweat. PMID- 20911238 TI - Naevus Anaemicus (Ischaemicus). PMID- 20911246 TI - Hyperplastic Laryngitis and Pharyngitis; ? Myxoedema (Shown a year ago, but not reported. PMID- 20911247 TI - Carcinoma of the OEsophagus treated by Radium. PMID- 20911248 TI - Specimen: OEsophagus from an Elderly Man, treated by Radium for Carcinoma. PMID- 20911249 TI - Specimen: OEsophagus from a Middle-aged Man, showing a Congenital Opening into the Trachea. PMID- 20911287 TI - Two Cases of Anaemia showing the Result of Liver Treatment. PMID- 20911291 TI - Preliminary Medication in Anaesthetics. PMID- 20911322 TI - Specimen: Prolapsed Haemorrhoids of Excessive Dimensions. PMID- 20911298 TI - Carcinoma of Middle Ear, apparently secondary to Carcinoma Mammae. PMID- 20911330 TI - Specimen. Fibrous Polypi associated with Internal Haemorrhoids. PMID- 20911323 TI - Prolapsed Haemorrhoids in an Erythraemic Patient with Psoriasis. PMID- 20911331 TI - Specimen. Tuberculous Ulcer of Caecum with large Enterolith. PMID- 20911362 TI - The Medical Aspects of the Mediaeval Monastery in England. PMID- 20911338 TI - Two Cases of Thrombocytopenic Purpura Haemorrhagica, three years after Splenectomy. PMID- 20911368 TI - Congenital Occlusion of OEsophagus (Specimen). PMID- 20911370 TI - Fusiform Dilatation of OEsophagus with Spasm; Leukoplakia of Walls. Specimen and Sections of Wall. PMID- 20911374 TI - Experiences of Radiological Treatment of Cancer in Gynaecology. PMID- 20911371 TI - Acute Pain and Fever following Chronic OEsophagitis, possibly Syphilitic, with Dilatation and OEsophagospasm. PMID- 20911376 TI - Treatment of Experimental Anaemias with Ultra-Violet Light. PMID- 20911391 TI - Deaths under Anaesthetics, with Special Relation to their Pathology. PMID- 20911395 TI - Myxoedema (presumably), confined to the Palate and Larynx. PMID- 20911422 TI - Clinical and Pathological Report of Bilateral Glioma Retinae. PMID- 20911451 TI - Foreign Body Impacted in OEsophagus; Paroesophageal Abscess. Removal of Foreign Body by Peroral Endoscopy, with Drainage of Abscess; Pneumonia; Death: (Specimen and Skiagrams). PMID- 20911448 TI - OEsophageal Obstruction probably Traumatic, treated by Gastrostomy and Retrograde Dilatation by Multiple Silk Threads. Improvement. PMID- 20911456 TI - Chronic Inflammation of Right Lachrymal Gland. ? Tuberculous. PMID- 20911455 TI - Specimen of Carcinoma of the OEsophagus treated with Diathermy. Gastrostomy. Death. PMID- 20911457 TI - Specimen: Tracheo-OEsophageal Fistula. PMID- 20911467 TI - The AEtiological Relationship of Achylia Gastrica to Pernicious Anaemia. PMID- 20911459 TI - Treatment by Hyperthermal Baths (104 degrees F. to 108 degrees F.) at the Royal Bath Hospital, Harrogate. PMID- 20911469 TI - Persistent Hypoglycaemia following Diabetes Mellitus treated with Insulin. PMID- 20911489 TI - Macroglossia, Right-sided. ? Cause. PMID- 20911491 TI - Splenic Anaemia. PMID- 20911495 TI - Ulcerative Condition of Throat and Nose. ? Actinomycosis. Case for Diagnosis. PMID- 20911496 TI - A Large Diverticulum of the OEsophagus at its Lower End [Skiagrams shown]. PMID- 20911497 TI - Carcinoma of Upper Part of OEsophagus treated by Radium. PMID- 20911502 TI - A Safety-pin removed from the Left Bronchus by a Fortunate Manoeuvre. PMID- 20911506 TI - Paresis of Left Vocal Cord. ? Chondroma of Larynx. PMID- 20911534 TI - Elephantiasis of the Penis and Scrotum due to Stricture of the Urethra and Fistulae. PMID- 20911546 TI - Thoracotomy in the Treatment of Malignant Disease of the OEsophagus by Radon. PMID- 20911547 TI - The Insertion and Use of Radon in Cancer of the OEsophagus. PMID- 20911548 TI - A Note on Two Cases of Carcinoma of the OEsophagus treated by Radon and Diathermy. PMID- 20911556 TI - Morphine-Scopolamine Narco-Anaesthesia in Nasal Operations. PMID- 20911557 TI - Gigantic Female Foetus Weighing 24 lb. 2 oz. at Birth. PMID- 20911599 TI - Pseudoleukaemia. Aleukaemic Lymphadenosis. PMID- 20911567 TI - Softening of the Upper Humeral Epiphyses. ? Typhoid Arthritis. PMID- 20911627 TI - Splenic Anaemia, treated by Splenectomy (previously shown March, 1926). PMID- 20911631 TI - Severe Rickets with Anaemia. PMID- 20911635 TI - Obesity. ? Cause. PMID- 20911642 TI - Erythraemia (Splenomegalic Polycythaemia) with a high degree of Acholuric Jaundice, probably a Manifestation of Compensatory "Hypersplenism.". PMID- 20911656 TI - President's Address: Diathermy Treatment of Puerperal Septicaemia and Pneumonia. PMID- 20911657 TI - A Patient who was Operated on in 1914 for Neo-natal Subdural Haemorrhage. PMID- 20911663 TI - DISCUSSION ON AVERTIN ANAESTHESIA. PMID- 20911673 TI - Juvenile Myxoedema. PMID- 20911668 TI - Splenic Anaemia. PMID- 20911675 TI - Erythroedema Polyneuriticum. PMID- 20911678 TI - Paroxysmal Haemoglobinuria (?). Case for Diagnosis. PMID- 20911677 TI - Scoliosis due to Absence of the Halves of Two Vertebrae. PMID- 20911681 TI - Haemophilia Treated by Liver Extract. PMID- 20911680 TI - Variable Heart Block with Cyanosis. ? Specific Pulmonary Arteritis (Ayerza Syndrome) or Congenital Lesion. Case for Diagnosis. PMID- 20911684 TI - Overgrowth of Bones of Face. ? Paget's Disease. PMID- 20911700 TI - Naevus of Bladder. PMID- 20911734 TI - Foreign Body (Halfpenny) in OEsophagus removed by Jackson's OEsophageal Speculum. PMID- 20911751 TI - Psoriasis. ? Pityriasis Rubra Pilaris. Case for Diagnosis. PMID- 20911748 TI - Leukaemide. Case for Diagnosis. PMID- 20911756 TI - OPENING PAPERS IN A DISCUSSION ON ANAESTHESIA IN RECTAL SURGERY. PMID- 20911759 TI - Polycythaemia Vera Treated with Phenylhydrazine. PMID- 20911762 TI - Combined Degeneration of Spinal Cord without Blood-picture of Pernicious Anaemia. PMID- 20911770 TI - DISCUSSION ON THE USE OF PHENYLHYDRAZINE IN THE TREATMENT OF POLYCYTHAEMIA. PMID- 20911765 TI - Congenital Morbus Cordis and Abdominal Tumour ? Causal Ascites. PMID- 20911782 TI - Two Cases of Spontaneous Haemorrhage into the Fossae of Inflamed Tonsils. PMID- 20911779 TI - Fibrous Stricture of the OEsophagus caused by Swallowing Lysol Five Years Ago. PMID- 20911823 TI - Two Cases of Essential Thrombocytopenic Purpura Haemorrhagica. PMID- 20911803 TI - Uterus with Fibromyoma, from which Haemorrhage occurred into the Peritoneal Cavity. PMID- 20911884 TI - DISCUSSION ON ANAESTHESIA IN THORACIC SURGERY. PMID- 20911899 TI - Erythema Circinatum, ? Erytheme Annulaire Centrifuge of Darier. PMID- 20911907 TI - Report on a Case of Purpura Haemorrhagica following Diphtheria. PMID- 20911934 TI - A Case of Invasion of the Intact Buccal Mucous Membrane by Spirochaetes. PMID- 20911912 TI - Cyst. ? Intracranial. PMID- 20911937 TI - Morphoea-type of Tuberculide. PMID- 20911935 TI - Typhus-like Fevers of Unknown AEtiology, with Special Reference to the Malay States. AB - Typhus exanthematicus, Rocky Mountain fever, and the tsutsugamushi disease have been classified in the "typhus group" by Megaw, as louse-typhus, tick-typhus, and mite-typhus. He has added a fourth-class, comprising typhus-like fevers, with unknown vectors. It is the diseases of this class with which this paper is concerned.Endemic typhus (Brill's disease) is very closely related to typhus fever; the Weil-Felix reaction is positive, typhus-like vascular lesions are present, and there is cross-immunity with typhus. In the exanthematic fever of Marseilles the relationship is more superficial; there is neither cross-immunity nor vascular lesion, and the Weil-Felix reaction is negative. Some, e.g., the scrub-typhus of Malaya (vector probably a mite), are more nearly related to tsutsugamushi than to typhus; others, e.g., Indian "tick-typhus" (vector probably a tick), to Rocky Mountain fever.All are non-contagious, non-epidemic, warm weather diseases. They are unassociated with dirt, squalor, or lice, and are restricted to definite foci. Probably rodents or other animals are the reservoirs of the virus. On the question of identity with typhus, health authorities decide that notification is unnecessary; typhus introduced into America spreads, Brill's disease does not.These typhus-like diseases are not the same in all the countries where they occur. There are two main groups: (1) an urban group, more closely related to typhus, in which the Weil-Felix reaction is positive; (2) a rural group, more closely related to tsutsugamushi and Rocky Mountain fever, in which the Weil-Felix reaction is negative. There is a special non-indologenic strain of B. proteus, which is agglutinated in some of the fevers belonging to the second group.TROPICAL TYPHUS IN THE MALAY STATES: (1) urban form, or "shop-typhus," resembling Brill's disease; (2) rural form or "scrub-typhus." Peculiar association with oil-palms and coarse grass. PMID- 20911938 TI - Leukaemia Cutis. PMID- 20911953 TI - DISCUSSION ON THE POSITION OF RADIUM IN THE TREATMENT OF GYNAECOLOGICAL CONDITIONS: Joint Discussion No. 7. PMID- 20911952 TI - Case of Recurring Meningitis three weeks after Septicaemic Type of Mastoiditis. PMID- 20912018 TI - Haemochromatosis. PMID- 20911998 TI - Atypical Leukaemia. PMID- 20912027 TI - Post-mortem Specimen from a Case variously reported on as Granuloma, Lymphosarcoma, Endothelioma. Treated by X-rays and Radium. Death from Haemorrhage. PMID- 20912059 TI - Microscopical Sections from a Case of Endothelioma arising in connection with a Naevoid Angioma. PMID- 20912070 TI - Ethylene Anaesthesia. PMID- 20912074 TI - Carotinaemia in a Male Diabetic. PMID- 20912073 TI - Solid OEdema of One Leg: Case for Diagnosis. PMID- 20912076 TI - Haemophilia treated by Liver Diet. PMID- 20912077 TI - Congenital Haemolytic Anaemia, with Splenomegaly in a Child: Controlled by Liver Treatment. PMID- 20912090 TI - Bilateral Congenital Elevation of the Scapulae. PMID- 20912089 TI - Two Cases of Coeliac Rickets. PMID- 20912093 TI - The Hereditary Transmission of Hypoglycaemia in Mice. PMID- 20912116 TI - Haemoptysis due to Cryptal Ulceration of Tonsils. PMID- 20912117 TI - A New OEsophagoscope and Bronchoscope. PMID- 20912142 TI - Lichen Planus associated with Lichen Spinulosus and Cicatricial Alopecia of the Scalp, Pubes, and Axillae. PMID- 20912148 TI - Periodontal Disease in Dogs: (Experimental Gingivitis and "Pyorrhoea"). PMID- 20912150 TI - Congenital Stenosis of the OEsophagus in Children, Associated with Diaphragmatic Hernia of the Stomach. PMID- 20912155 TI - A Case of Lithopaedion. PMID- 20912154 TI - The Toxaemias of Pregnancy: A New Conception: (Abstract). PMID- 20912172 TI - Coeliac Disease. PMID- 20912164 TI - Cerebral Haemorrhage in a Boy now aged 14 years. PMID- 20912200 TI - Naevus Unius Lateris. PMID- 20912184 TI - Three Cases of Congenital OEdema (Milroy's Disease) in Two Generations of the Same Family. PMID- 20912201 TI - Leukaemia Cutis. PMID- 20912227 TI - Anaemic Type of Haemolytic Jaundice without Familial History. PMID- 20912203 TI - Extensive Cicatricial Alopecia of Scalp. ? Lichen Planus. PMID- 20912229 TI - Fistula behind Left Ear: ? Branchial. PMID- 20912252 TI - Haemolytic Jaundice. PMID- 20912263 TI - Anaemia with Splenomegaly. PMID- 20912264 TI - Simple Achlorhydric Anaemia (L. J. Witts). PMID- 20912270 TI - Multiple Foreign Bodies in the Corneae. PMID- 20912280 TI - Cultivation of the Spirochaetes Associated with Tropical Ulcer. AB - Spirochaetes from cases of tropical ulcer have been cultured in a modified Wenyon media and have now been successfully passed through thirty-two subcultures.-A pure culture has not yet been obtained.-Five inocultation experiments are described in which it has been shown that the spirochaetes and fusiform bacilli, in mixed culture, are capable of proliferation and of producing ulcerated lesions in natives. PMID- 20912281 TI - Generalized Infection of Muscles with Cysticercus cellulosae; measurements of cysts and comparison with those of Trichinella spiralis. PMID- 20912306 TI - Aortic Aneurysm and ? Syphilis of the Lung. PMID- 20912323 TI - Report on Two Cases of Septicaemia following Tonsillectomy. PMID- 20912328 TI - Syphilitic Osteitis and Periostitis: Sabre Tibiae. PMID- 20912339 TI - Extensive Hairy Pigmented Naevus. PMID- 20912340 TI - Naevus Unius Lateralis involving the Sebaceous Glands and Pilo-sebaceous Follicles. PMID- 20912358 TI - Erythematous Patch on Soft Palate. ? Pre-carcinoma. PMID- 20912369 TI - Adenoma of the Kidney giving rise to a large Haemorrhage. PMID- 20912370 TI - Three Cases of Hydronephrosis Associated with Haematuria. PMID- 20912402 TI - Congenital Opacity of both Corneae with Slight Buphthalmos. PMID- 20912373 TI - Haemochromatosis, with Diabetes Mellitus, Hepatic Cirrhosis and Chronic Ascites. PMID- 20912404 TI - Section of Neoplasm shown at October meeting as ? Endothelioma of Foot. PMID- 20912413 TI - The AEtiology of Disseminate Sclerosis: Some criticisms of recent work, especially with regard to the "Spherula Insularis". PMID- 20912412 TI - Chronic Sub-dural Haematoma. PMID- 20912418 TI - Glaucoma associated with Facial Naevus. PMID- 20912437 TI - Mycosis Fungoides with Papillomatosis of the Areolae. PMID- 20912443 TI - Morphoea with Unusual Degree of Atrophy. PMID- 20912455 TI - General Enlargement of Lymph Glands; Splenomegaly, Enlargement of Head with OEdema of Face. PMID- 20912439 TI - Erythematous Lichen Planus, with Development of Bullae. PMID- 20912476 TI - Radium Necrosis of the Trachea following Insertion of Radon Seeds into a Carcinoma of the Thoracic Part of the OEsophagus. PMID- 20912480 TI - Tuberculous Empyema Necessitatis. Haemothorax due to Bleeding from a Cavity. PMID- 20912487 TI - (7, 8, 9) Three Cases of OEsophageal Diverticula Removed Successfully by Two stage Operation. PMID- 20912498 TI - Haemoptysis. Case for Diagnosis. PMID- 20912504 TI - DISCUSSION ON THE BARBITURATES IN ANAESTHESIA. PMID- 20912514 TI - Left Senile Macular Exudative Retinitis and Right Macular Haemorrhage. PMID- 20912529 TI - Two Cases of Essential Thrombocytopenic Purpura Haemorrhagica Five Years after Splenectomy. PMID- 20912534 TI - Splenic Enlargement in Simple Achlorhydric Anaemia (L. J. Witts). PMID- 20912533 TI - Polycythaemia Vera, with Cerebral Thrombosis. PMID- 20912537 TI - Polycythaemia Vera (Vaquez' Disease) treated by Benzol, Roentgen Therapy, and Phenylhydrazine. Complications. PMID- 20912536 TI - Polycythaemia Vera with Nervous and Ocular Disorders. PMID- 20912547 TI - The Injection Treatment of Hydrocele, Varicocele, Bursae, and Naevi. PMID- 20912572 TI - Old Crush Fracture of Lumbar Vertebrae. PMID- 20912579 TI - Tracheotomy in an Adult for OEdematous Laryngitis in Scarlet Fever. PMID- 20912594 TI - Pulsating Haemangioma on Dorsum of Nose. PMID- 20912619 TI - Extreme Cyanosis, Chronic Bronchitis, Emphysema, Polycythaemia, and Partial Block of a Branch of the Bundle of His. PMID- 20912613 TI - DISCUSSION ON THE PATHOLOGY AND TREATMENT OF HAEMOPATHIES, INCLUDING LEUKAEMIAS, OF MAN AND ANIMALS: The Haemopathies of Laboratory Animals. AB - The difference between haemopathies (which originate in the blood-forming tissues) and blood-diseases (which develop in the blood-stream) is explained and illustrated by examples and specimens.Primary anaemia caused by the hyperplasia of the erythroblastic tissues in the marrow occurs in fowls as erythromyelosis. This condition can be experimentally transmitted, though inoculation in fowls may reproduce the anaemic disease, or give rise to a persistent polyerythrocythaemia. On farms erythromyelosis is often, but not always, associated with the cestode, Davainea proglottina.Secondary anaemia develops in splenectomized rats following the invasion of the erythrocytes by Bartonella muris. The subsequent erythrocytolysis may induce haemoglobinuria, similar to that occurring in man and cattle as the result of certain haemic infections.Oligoerythrocythaemia is frequently seen in fowls associated with leucocythaemia; the deficiency of the red blood-corpuscles is due to the pressure on the erythroblastic sinusoids, by the proliferation of the myeloblastic or lymphoblastic tissues in the marrow.Lymphocythaemia (and lymphomatosis) have been observed in canaries, fowls, mice and guinea-pigs. The conditions can be experimentally transmitted within the species; inoculation with lymphocythaemic blood may reproduce the haemic type or induce the development of scattered tumour-like deposits (lymphomatosis). Whichever type of lesion results, the pathological cell unit is one of the lymphoblast-lymphocyte series.Fowl leucocythaemia originates through the morbid proliferation and premature entry into the circulation of cells of the myeloblast granulocyte series. On inoculation in fowls the original leucocythaemia may be reproduced; rarely there follows the development of localized deposits of myeloblastic cells in the skin.As these diseases of the blood-forming system, and those occurring in man and cattle offer many striking resemblances, it may be suggested that the determination of the origin of the particular type of cell encountered should serve as guide to diagnosis and classification in all haemopathies. PMID- 20912622 TI - Congenital Abnormalities at or near the Upper End of the OEsophagus. PMID- 20912623 TI - Obstruction at the Upper End of the OEsophagus. PMID- 20912624 TI - Carcinoma of Upper End of OEsophagus. External Exposure and Insertion of Radon Seeds. PMID- 20912625 TI - Two Cases of Dysphagia and Anaemia. PMID- 20912626 TI - Atrophic OEsophagitis in Region of Crico-pharyngeal Fold. PMID- 20912627 TI - Dysphagia associated with Anaemia. PMID- 20912629 TI - Carcinoma at Upper End of OEsophagus, following Intrinsic Carcinoma of Larynx, apparently cured for Ten Years. PMID- 20912635 TI - OEsophagus with Congenital Stenosis at Entrance. PMID- 20912639 TI - Recurring Pain after Frontal Sinus Operation, relieved by Injection of Eucaine beta Solution by means of Hartmann's Frontal Sinus Cannula. PMID- 20912645 TI - OEsophageal Speculum. PMID- 20912670 TI - Pubertas Praecox. PMID- 20912677 TI - Periostitis. ? Cause. PMID- 20912680 TI - Post-mortem Findings in a Case shown at the Meeting held on March 27, 1931, as one of "Enlargement of the Liver. ? Sarcoma". PMID- 20912682 TI - Thrombo-angiitis Obliterans of Lower Limbs with attacks of Urticaria and Angioneurotic OEdema. PMID- 20912729 TI - DISCUSSION ON THE RELATIVE VALUE OF THE INDUCTION OF PREMATURE LABOUR, TEST LABOUR AND CAESAREAN SECTION IN THE TREATMENT OF MINOR DEGREES OF CONTRACTED PELVIS. PMID- 20912731 TI - Modern Methods of Treatment of Intestinal Amoebiasis. PMID- 20912733 TI - Congenital Shortening of the OEsophagus and the Thoracic Stomach Resulting Therefrom. PMID- 20912735 TI - Treatment of Cicatricial Stenosis of the OEsophagus by Autodilatation. PMID- 20912751 TI - OEsophageal Spasm. PMID- 20912756 TI - Laryngeal Obstruction in a Man suffering from Lymphatic Leukaemia (Specimen). PMID- 20912763 TI - Broncho-OEsophagoscope. PMID- 20912764 TI - A Warty Condition of the Areolae Papillaris having Superficial Resemblance to Acanthosis Nigricans. PMID- 20912768 TI - Naevus Anaemicus of Hand. PMID- 20912771 TI - Atrophic Lichen Planus with Morphoea-like Lesions. PMID- 20912772 TI - Eruption on Feet. ? Erythema Elevatum Diutinum (Crocker). Case for Diagnosis. PMID- 20912786 TI - Congenital Jaundice in an Elderly Man-probably belonging to the Congenital Haemolytic Group. PMID- 20912788 TI - An Anaemic Breakdown or Crisis in a Child, not connected with definite Congenital Haemolytic Jaundice-Rapid Recovery. PMID- 20912790 TI - Cardiac Malformation with Compensatory Polycythaemia. ? Septal Deficiency. PMID- 20912789 TI - Erythraemia, with Frequent Jaundice, apparently of Haemolytic Nature. Slow Recovery from Extremely Severe Haematemesis. PMID- 20912806 TI - DISCUSSION ON ANAESTHESIA FOR DIATHERMY AND ENDOSCOPY. PMID- 20912807 TI - Pachymeningitis Haemorrhagica Interna. PMID- 20912808 TI - Nutritional Anaemia treated with Copper. PMID- 20912810 TI - Scorbutic Haemorrhage Beneath Periosteum of Femur. PMID- 20912828 TI - Cysticercus Cellulosae and Tabes Dorsalis. PMID- 20912816 TI - Persistent Haematuria. PMID- 20912831 TI - Essential Thrombocytopenic Purpura Haemorrhagica in a Girl. PMID- 20912843 TI - Diffuse Symmetrical Granuloma. ? Sarcoid. PMID- 20912842 TI - Two Cases of Striae Atrophicae following Typhoid Fever. PMID- 20912874 TI - Amoebic Abscess of the Liver: Its Diagnosis and Treatment. A Clinical Study. PMID- 20912871 TI - Syphilitic Stricture of OEsophagus. PMID- 20912875 TI - Operative Procedures in Amoebic Abscess of the Liver based on Recent Experiences. PMID- 20912900 TI - Unilateral Vascular Naevus (Angio-elephantiasis). PMID- 20912890 TI - Haemangioma in the Spleen. PMID- 20912947 TI - Resuscitation during Anaesthesia and of the Newly-born. PMID- 20912951 TI - Gonorrhoeal Conjunctivitis quickly cured. PMID- 20912981 TI - Focal Nephritis Simulating Haemangeioma. PMID- 20912961 TI - Recovery after Meningitis with Haemolytic Streptococci in the Cerebrospinal Fluid under Direct Observation. PMID- 20912989 TI - The Bearing of Recent Research on the Sex Hormones on Clinical Obstetrics and Gynaecology. PMID- 20912992 TI - Osteitis of the Tarsal Scaphoid (Bilateral). ? Cause. PMID- 20912995 TI - Spontaneous Hyperaemic Dislocation of the Atlas. PMID- 20912997 TI - Hypnosis and Anaesthesia. PMID- 20913012 TI - Seborrhoeic Verrucae and Multiple Basal-celled Epitheliomata. PMID- 20913015 TI - Acute Lupus Erythematosus with Bullae. PMID- 20913017 TI - Cavernous Naevus treated by Radon Seeds. PMID- 20913018 TI - Symmetrical Systematized Naevus. PMID- 20913022 TI - Retinitis Punctata, ? Albescens. PMID- 20913026 TI - Punctate Keratitis. ? Nature. PMID- 20913027 TI - Naevus of Conjunctiva. PMID- 20913036 TI - Four Cases of Typical well-marked Disciform Degeneration of the Maculae. PMID- 20913038 TI - Disciform Degeneration of Maculae. PMID- 20913043 TI - Three Cases of Obstruction of the OEsophagus. PMID- 20913044 TI - Severe Acute Haemoglobinuria in a Boy. PMID- 20913050 TI - Obesity and Hirsutes of ? Adrenal Origin. PMID- 20913058 TI - Haemorrhagic Hepatitis: AEtiology unknown. PMID- 20913059 TI - Pott's Disease of the 4th and 5th Lumbar Vertebrae. PMID- 20913062 TI - Polycythaemia Anaemica secondary to Congenital Cardiac Septal Defect, in association with an Anaemia-producing Agent. PMID- 20913064 TI - Multiple Naevi of the Hand. PMID- 20913068 TI - Association of Extensive Haemangiomatous Naevus of the Skin with Cerebral (Meningeal) Haemangioma. PMID- 20913067 TI - Obesity, ? Nature. PMID- 20913075 TI - An old Case of Pernicious Anaemia. PMID- 20913076 TI - Orthostatic OEdema of the Dorsum of both Feet of the Nonne and Milroy type. PMID- 20913080 TI - Haemolymphangeioma of Tongue. PMID- 20913081 TI - Striae Atrophicae following Rheumatic Fever. PMID- 20913082 TI - Suprarenal Virilism (Pubertas Praecox). PMID- 20913087 TI - DISCUSSION ON GONORRHOEA AND OTHER CERVICAL DISCHARGES. PMID- 20913089 TI - Severe Pannus of the Cornea. ?Trachoma: Case previously shown (November, 1927). PMID- 20913093 TI - DISCUSSION ON THE COMMON COLDS AND THEIR SEQUELAE. PMID- 20913114 TI - Erosions and Ulcers of the Tongue. ? Tuberculous. PMID- 20913102 TI - The Surgical Treatment of Pyorrhoea Alveolaris. AB - (1) The technique of eradicating the pockets and occasionally trimming the alveolar margin is described. (2) Instruments designed for the operation are illustrated. (3) The whole mouth can be treated at one sitting. (4) The flap operation, in which the gum is reflected before scraping the alveolus and finally sutured, is not advisable. (5) Pyorrhoea can be eradicated by surgical measures in cases favourable for treatment. (6) Recurrence of the disease is due to: (a) Lack of suitable preliminary treatment. (b) Insufficient attention to detail when performing the operation. (c) Lack of suitable post-operative care by dental surgeon or patient. (d) Selection of cases not suitable for operation. PMID- 20913119 TI - Seborrhoeic Verrucae and Multiple Basal-celled Epitheliomata. PMID- 20913120 TI - Thoracic Exposure of the Diaphragm and Lower OEsophagus. PMID- 20913123 TI - Two Specimens of Carcinoma of the Caecum removed by a Modification of the Classical Method of Ileocaecal Resection. PMID- 20913153 TI - The Operative Closure of Oro-Maxillary Fistulae. PMID- 20913166 TI - Anaesthesia for Major Throat Operations. PMID- 20913167 TI - Right Hemihypertrophy and Pubertas Praecox. PMID- 20913168 TI - Trigeminal Naevus and Homolateral Pial Angioma. PMID- 20913169 TI - Two Cases of Congenital OEdema. PMID- 20913174 TI - Two Cases of Essential Purpura Haemorrhagica Six Years after Splenectomy. PMID- 20913183 TI - The X-ray Treatment of Chronic Mastitis and Certain Leukaemias. PMID- 20913177 TI - Erythraemia or Erythro-leukaemia. PMID- 20913189 TI - Cyst. ? Tumour on the Iris. PMID- 20913194 TI - Haemangioma of Retina. PMID- 20913191 TI - Two cases of ? Doyne's Familial Choroiditis. PMID- 20913223 TI - The AEtiology and Treatment of Heat Exhaustion and Heat Hyperpyrexia, with special reference to Experiences in Iraq. PMID- 20913220 TI - A Case illustrating the Importance, when examining the OEsophagus, of seeing the Patient in the Recumbent, as well as the Erect, Position. PMID- 20913231 TI - DISCUSSION ON MILK FEVER, OR HYPOCALCAEMIA IN PARTURIENT COWS AND SIMILAR CONDITIONS IN OTHER ANIMALS AND MAN. PMID- 20913228 TI - Specimen of a Temporal Bone, with Pus in the Mastoid Antrum, from an Infant dying from Diarrhoea and Vomiting. PMID- 20913250 TI - Tubal Gestation as seen by the Gynaecologist: An Analytical Study of Certain Aspects, Clinical and Pathological, of a Consecutive Series of 146 cases. PMID- 20913259 TI - Coeliac Disease. PMID- 20913255 TI - Splenic Anaemia, with Thrombocytopenic Purpura. Cirrhosis of Liver. PMID- 20913269 TI - Two Cases of Slight Polycythaemia with Latent Jaundice. PMID- 20913263 TI - Lymphatic Leukaemia, simulating Aplastic Anaemia. PMID- 20913280 TI - Subconjunctival Prolapse of Iris: Dislocated Lens. ? Berger's Capsular Layer in Pupil. Good Vision. PMID- 20913306 TI - Delusional Insanity following Nembutal-Ether Anaesthesia. PMID- 20913321 TI - Pansinusitis with Orbital Cellulitis. Pyaemic Infection. Osteomyelitis of Frontal Bone. Operation. Recovery. PMID- 20913327 TI - Acute OEsophagitis in Infant. PMID- 20913353 TI - Ano-Rectal Fistulae. PMID- 20913354 TI - Bilateral Transplantation of Ureters and Colostomy for Vesico-vaginal and Vesico rectal Fistulae. PMID- 20913363 TI - DISCUSSION ON THE MEGALOCYTIC ANAEMIAS OF TROPICAL AND NON-TROPICAL COUNTRIES: Joint Discussion No. 6. PMID- 20913366 TI - Trigeminal Naevus and Haemangioma of Meninges. PMID- 20913372 TI - Calcifying Periosteal Haemorrhage, following Scurvy. PMID- 20913370 TI - Abdominal Foetal Implantation. PMID- 20913373 TI - Naevo-neurofibromatosis. PMID- 20913378 TI - Swelling on Right Cheek: Case for Diagnosis. ? Granuloma Annulare. PMID- 20913405 TI - Persistent OEdema of Both Legs. PMID- 20913408 TI - Persistent OEdema of Right Lower Limb. PMID- 20913413 TI - Multiple Fatty Herniae of the Feet. PMID- 20913415 TI - Epiphysitis of Upper End of Femur, associated later with ? Clutton's Joints. PMID- 20913424 TI - Hypoaemic (Anaemic) Naevus of the Trunk with Hypochromic Naevus of the Hairy Scalp. PMID- 20913438 TI - Cephalhaematoma Externum and Meningocele. PMID- 20913427 TI - Acute Circumscribed Allergic OEdema with Urticaria. PMID- 20913452 TI - Modern Aids to Anaesthesia: President's Address. PMID- 20913447 TI - Coeliac Rickets. PMID- 20913455 TI - DISCUSSION ON THE INDICATIONS FOR AND AGAINST CAESAREAN SECTION. PMID- 20913471 TI - Nasal Obstruction. ? Mycosis. PMID- 20913476 TI - Hernia of Tympanic Membrane. ? Cholesteatoma: Case for Diagnosis. PMID- 20913485 TI - Traumatic Haemopneumothorax treated by Continuous Suction Drainage. PMID- 20913484 TI - Subconjunctival Haemorrhage. PMID- 20913492 TI - Familial Rickets with Obscure AEtiology. PMID- 20913494 TI - Diabetes Insipidus and ? Anterior Pituitary Lobe Deficiency. PMID- 20913499 TI - Pemphigus of the Conjunctivae. PMID- 20913510 TI - A Successful Treatment for Toxic Symptoms resulting from Ether Anaesthesia, based on a Biochemical Investigation. AB - (1) Blood-sugar rises and blood-pressure falls as ether anaesthesia progresses. (2) Blood-sugar is high and blood-pressure low when symptoms of shock are present.-(3) There is some justification for thinking that the pancreatic hormone is deficient as the result of the ketosis produced in connection with ether anaesthesia.-(4) Insulin administration is a successful method of treatment for post-anaesthetic toxic symptoms, which are always associated with a high blood sugar, and also prevents these from developing. It tends to increase a fallen blood-pressure and reduce a raised blood-sugar during ether anaesthesia. PMID- 20913511 TI - Three Cases of Essential Purpura Haemorrhagica: Splenectomy. PMID- 20913512 TI - Acute Idiopathic Purpura Haemorrhagica Fourteen Months after Splenectomy. PMID- 20913515 TI - Splenectomy in Gaucher's Disease with Haemoglobinuria. PMID- 20913513 TI - Acute Idiopathic Purpura Haemorrhagica, Two Years and Ten Months after Splenectomy. PMID- 20913516 TI - Erythraemia, with Tortuous and Dilated Arteries in Arms. PMID- 20913517 TI - Erythraemia, with Recurrent Ophthalmic Migraine and Gout. PMID- 20913518 TI - Splenomegalic Polycythaemia treated with Minimal Doses of Phenylhydrazine. PMID- 20913519 TI - An Unusual Case of Polycythaemia Rubra Vera. PMID- 20913521 TI - Polycythaemia Vera. PMID- 20913527 TI - Splenomegaly with Anaemia. PMID- 20913526 TI - Non-familial Acholuric Jaundice (Haemolytic Anaemia). PMID- 20913530 TI - Chronic Lymphoid Leukaemia in a Woman. PMID- 20913531 TI - Splenectomy in Myeloid Leukaemia. PMID- 20913534 TI - Hepatomegaly, Splenomegaly. ? Hodgkin's Disease. PMID- 20913572 TI - Naevus Unius Lateralis. PMID- 20913579 TI - Nervous Sequelae of Spinal Anaesthesia. PMID- 20913581 TI - Haemoptysis: for diagnosis. ? Epituberculosis. PMID- 20913592 TI - OEsophageal Pouch. PMID- 20913593 TI - Exophthalmic Goitre successfully treated by X-rays 20 years ago, but now complicated by ? X-ray Epithelioma. PMID- 20913597 TI - Recurrent Haemoptysis due to ? Benign Bronchial Tumour. PMID- 20913596 TI - Lineae Atrophicae in Rheumatic Fever. PMID- 20913604 TI - DISCUSSION ON SOME ASPECTS OF ANAESTHESIA IN ANIMALS. PMID- 20913601 TI - Chronic OEdema of Legs with Large Turgid Hands. PMID- 20913621 TI - Incontinence of Faeces and Congenital Deformity of Anus. PMID- 20913619 TI - Obstructive and Haemolytic Jaundice in the Tropics. PMID- 20913636 TI - DISCUSSION ON RADIOTHERAPY IN THE TREATMENT OF NON-MALIGNANT GYNAECOLOGICAL CONDITIONS: Joint Discussion No. 3. PMID- 20913635 TI - DISCUSSION ON THE TREATMENT OF THE ANAEMIAS: Joint Discussion No. 2. PMID- 20913674 TI - Haemophilia; Tuberculous Hip; Haemophiliac Knee; Tuberculous Abscess of Abdominal Wall. PMID- 20913684 TI - Persistent OEdema of the Left Leg, with Anaemia. PMID- 20913698 TI - Intra-epidermal Carcinoma. ? Paget's Disease of the Nipple. PMID- 20913702 TI - DISCUSSION ON THE NEW PHARMACOPOEIA. PMID- 20913729 TI - Erythroedema. PMID- 20913737 TI - Lymphadenosis commencing with the clinical picture of Hypoplastic Anaemia. PMID- 20913735 TI - Recurring Collapse of Lung with Enlarged Mediastinal Glands. ? Epituberculosis. PMID- 20913741 TI - Cerebellar Tumour. ? Right Lobe. PMID- 20913753 TI - Two Cases of Angiomatosis Retinae. PMID- 20913742 TI - Cerebellar Tumour, ? Left Lobe. PMID- 20913754 TI - Glioma Retinae. PMID- 20913759 TI - Swelling of Optic Discs. ? Cause. PMID- 20913772 TI - DISCUSSION ON ANAESTHESIA IN INTRACRANIAL SURGERY. PMID- 20913765 TI - DISCUSSION ON THE DIAGNOSIS OF CHRONIC DIARRHOEAS. PMID- 20913774 TI - Some Observations on the Extraction of Teeth in Cases of Haemophilia. PMID- 20913791 TI - Bacteriaemia in Pneumonia. AB - (1) Tables are shown which record the course of bacteriaemia investigated by frequent blood-cultures in a series of cases of pneumonia.(2) The proportion of cases having a bacteriaemia in the course of the disease agrees fairly closely with other findings both in this country and in America.(3) Attention is drawn to the frequency with which the organisms disappear from the blood in the absence of any specific treatment, and to the frequency of recovery of bacteriaemic cases.(4) It is therefore submitted that it is unsafe to regard the disappearance of a bacteriaemia as the direct result of specific serum treatment, and that this cannot be used as evidence of successful serum therapy. PMID- 20913776 TI - AEtiology and Treatment of the Acute and Chronic Inflammatory Disorders of the Posterior Sinuses. PMID- 20913795 TI - A Case of Concealed Accidental Haemorrhage Associated with Spontaneous Complete Rupture of the Uterus. PMID- 20913796 TI - A Case of Concealed Accidental Haemorrhage associated with Spontaneous Complete Rupture of the Uterus. PMID- 20913835 TI - Carcinoma of OEsophagus in a Male aged 45 years, treated with Radon Seeds. Patient free from symptoms two years later. PMID- 20913839 TI - Congenital Shortening of OEsophagus. PMID- 20913841 TI - Congenital Tracheo-oesophageal Fistula in an Infant. PMID- 20913848 TI - The Anti-Anaemic Principle in Stomach Tissue. PMID- 20913858 TI - Severe Bilateral OEdema of the Eyelids for Thirteen Years. PMID- 20913849 TI - Cured Coeliac Disease: Achondroplasia. PMID- 20913864 TI - Three Types of Haemolytic Anaemia in the New-born. PMID- 20913862 TI - Anaemia of Von Jaksch. PMID- 20913866 TI - Chlorotic Type of Anaemia. PMID- 20913865 TI - Chlorotic Anaemia with Dwarfism and Rickets. PMID- 20913870 TI - Severe Anaemia in a New-born Child. PMID- 20913871 TI - Megalodactyly. ? Cause. PMID- 20913873 TI - Anaemia: probably Acholuric Jaundice. PMID- 20913883 TI - Volvulus of the Caecal Angle. PMID- 20913887 TI - Diverticulitis of the Caecum. PMID- 20913909 TI - Telangiectasia (Stellate Naevi) with Elastic Dystrophy. PMID- 20913927 TI - Restoration Appliances for use after Excision of the Maxillae and Partial Excision of the Mandible. PMID- 20913930 TI - Spread of Caries in Hypoplastic Dentine. (2) Structure of Enamel Lamellae. PMID- 20913938 TI - Erythro-leukaemia (Polycythaemia Rubra Vera-Vaquez's Disease-Associated with Myeloid Leukaemia). PMID- 20913939 TI - Erythraemia with Great Excess of Uric Acid in the Blood. PMID- 20913940 TI - Achlorhydric Anaemia with Pyrexia of Unknown Origin. PMID- 20913946 TI - OEdema in the Leg of a Child: Case for Diagnosis. PMID- 20913950 TI - Some Observations on Injuries to Joints: (Section of Orthopaedics). PMID- 20913955 TI - The Relationship Between Genito-Urinary Haemorrhage and Diseases of the Vascular System: (Section of Urology). AB - The diseases of the vascular system which cause haemorrhage from the genito urinary tract are:-(1) Those in which changes are noted in the blood and capillary endothelium, and(2) Those in which alterations of a pathological nature are taking place in the walls of both large and small blood-vessels, but in which there is no change in the blood itself.In the first group are the purpuras; in the second arteriosclerosis, hyperpiesis and atheroma.This paper is confined to a discussion of the latter group of diseases in relation to genito-urinary haemorrhage.Little attention has been paid to sudden loss of blood from the kidney, bladder, or genitalia in support of a diagnosis of a vascular lesion, other than angioma. Haemorrhage in these cases may be purely renal, vesical, or penile.Investigations consist of examination of the superficial arteries, estimation of the blood-pressure, examination of the blood and cystoscopy. Surgical lesions must be excluded by the usual well-known methods.A careful record has been kept of fifteen cases of arteriosclerosis in which haemorrhage from the genito-urinary tract has been the predominant manifestation of the disease. Details are given of nine patients with renal, one with vesical and three with urethral haemorrhage. Two cases of thrombosis of the penis are also included.From a study of the literature here the cases of urethral haemorrhage and thrombosis of the penis, recorded as due to arterial disease, appear to be unique. PMID- 20913958 TI - Sprue commencing at 111/2 years of age. PMID- 20913957 TI - Anaesthesia in Gynaecology: (Section of Anaesthetics). AB - The operations of gynaecology are divided into two classes: (1) Minor: including perineal repairs, colporrhaphies, vaginal hysterectomies, dilatations and curettings, etc., and (2) Major: abdominal sections. For both groups routine premedication is a combination of morphia and nembutal, the former in 1/6-grain, and the latter in 3-grain doses.For Group 1 three methods of anaesthesia are described: (a) Ethylene and oxygen, producing in nearly all cases an adequate depth of anaesthesia without the addition of ether. A safe type of anaesthesia and one from which recovery takes place quickly. (b) Planocaine in 20% solution, made up with sodium bisulphate, as a spinal anaesthetic, described by Mr. Dickson Wright. The dose usually injected is 0.5 c.c. (c) Sodium evipan given intravenously, though rather uncertain in action seems to serve well for such minor operations as curettage and insertion of radium.In Group 2 (major operations), the author's choice is between (a) ether administered with a little additional oxygen to counteract the asphyxial tendency which the Trendelenburg position occasions, and (b) spinal anaesthesia with percaine. For intra-abdominal pelvic surgery the latter is a very safe method for two reasons: (1) The dose required is comparatively small, and (2) the Trendelenburg position helps materially to prevent the fall of blood-pressure which a spinal anaesthetic tends to produce. PMID- 20913979 TI - Morphoea or Vitiligo: Case for Diagnosis. PMID- 20913976 TI - Syringocystadenoma ? Apocrine Gland Naevus. PMID- 20913984 TI - Case shown for Diagnosis as ? Acrodermatitis Chronica Atrophicans and later proved to be Kaposi's (so called) "Idiopathic Haemorrhagic Sarcoma". PMID- 20913989 TI - Pemphigus Conjunctivae. PMID- 20913993 TI - Familial Occurrence of Microcorneae Associated with Brachydactyly. PMID- 20914028 TI - Icterus Gravis Neonatorum and Allied Diseases: (Section of Obstetrics and Gynaecology). PMID- 20914027 TI - Neurospirochaetosis in the East African: (Section of Neurology). AB - (1) An inquiry was made at the Mathari Mental Hospital, Nairobi, into the validity in Kenya of the common belief that syphilitic infection of the nervous system is rare amongst Africans in their own environment.(2) The difficulties encountered by the inquiry are discussed, especially: (a) That arising from the presence of both yaws and syphilis in the colony; (b) that due to apparent unreliability of the Wassermann reaction under local conditions.(3) The incidence of a positive serum reaction in the general population was estimated.(4) The whole of the male adults in the hospital were selected for the inquiry.(5) The results are presented in tables showing: (a) Mental state and neurological and other signs; (b) serum reactions; (c) cerebrospinal fluid examination results, including those from the Lange colloidal gold reaction.(6) The post-mortem reports on four of the series who died during the inquiry are given.(7) The inquiry appears to allow the general conclusion that spirochoetal infection of the nervous system of the Kenya native is not uncommon.(8) Insufficient evidence is forthcoming for a decision as to whether the infection found was syphilitic, framboesial, or from an unknown source.(9) The question has much more than medical importance in view of the possibility that unchecked spirochaetal infection in the past may have been an environmental influence contributing to the present degree of cerebral deficiency found in the native by Dr. F. W. Vint and the writer, and reported elsewhere. (To the Eugenics Society on November 7, 1933, by the writer, and in the next issue of the Journal of Anatomy, by Dr. Vint.). PMID- 20914029 TI - Sympathectomy for Dysmenorrhoea: (Section of Obstetrics and Gynaecology). PMID- 20914036 TI - Multiple Symmetrical Fibro-Angiomatous Naevi of the Face and Hands. PMID- 20914058 TI - The Investigation and Treatment of the Toxaemias of Pregnancy: (Section of Obstetrics adn Gynaecology). PMID- 20914057 TI - Intrathecal Nerve Root Block. Some Contributions and a New Technique : (Section of Anaesthetics). PMID- 20914059 TI - Recent Advances in the Treatment of Carcinoma of the OEsophagus from the Surgical and Radiological Aspects: (Section of Laryngology). PMID- 20914061 TI - Method of Implanting Radon Seeds in OEsophageal Carcinoma. PMID- 20914060 TI - Carcinoma of the OEsophagus treated by Radiation. PMID- 20914064 TI - Carcinoma of OEsophagus in a Man aged 45 treated with Radon Seeds. Patient free from symptoms two years later. PMID- 20914062 TI - Carcinoma of Upper End of OEsophagus, apparently cured by the application of Radon Seeds. PMID- 20914080 TI - Specimen from Case of Suprarenal Haemorrhage following Breech Delivery. PMID- 20914090 TI - Report on Case and Specimen of Double Ureterocoele with Dilated Ureters and Early Hydronephrosis. PMID- 20914124 TI - Poikilodermia of the Face (Civatte's type) in a Girl aged 141/2 years. PMID- 20914127 TI - Respiratory Failure: (Section of Anaesthetics). PMID- 20914126 TI - Modern Views on Respiration: Normal Regulation of Respiration: (Section of Anaesthetics). PMID- 20914141 TI - Carotid Pulsation (Resembling Aneurysm) in a Woman with Hypertension and Myxoedema. PMID- 20914140 TI - OEdema: Milroy Type. PMID- 20914143 TI - Haemolytic Acholuric Jaundice with Splenomegaly and Normal Erythrocyte Fragility treated by Splenectomy. PMID- 20914171 TI - Tuberculous Laryngitis; Pulmonary Tuberculosis; Syphilitic Aortitis; ? Aneurysm of Innominate Artery; Heart Block. PMID- 20914177 TI - Post-menopausal Uterine Haemorrhage: (Section of Obstetrics and Gynaecology). PMID- 20914178 TI - Vaginal Hysterectomy: (Section of Obstetrics and Gynaecology). PMID- 20914181 TI - Naevus Unius Lateralis of the Mouth, associated with Multiple Naevi of Various Types. PMID- 20914184 TI - Epidemic of Obscure AEtiology occurring in a Coal Mine in Kent. PMID- 20914191 TI - The Failure of OEstrin as a Means of Inducing Labour: (Section of Therapeutics and Pharmacology). PMID- 20914199 TI - Complete Stapes thrown off during Chronic Suppurative Otitis Media, ? Tuberculosis. PMID- 20914221 TI - The AEtiology of Acute Rheumatism and Chorea in Relation to Social and Environmental Factors: (Section of Epidemiology and Section for the Study of Disease in Children): Joint Discussion No. 3. PMID- 20914206 TI - Colloid Carcinoma of Caecum with Chronic Intussusception producing Severe Anaemia, treated by Resection and Anastomosis after Specimen of Blood Transfusions. PMID- 20914222 TI - Fibrocystic Disease of Bone: (Section of Orthopaedics and Section of Surgery): Joint Discussion No. 4. PMID- 20914237 TI - Carcinoma of OEsophagus: Disappearance of Growth after Deep X-ray Therapy; ? Damage to Lungs by X-rays. PMID- 20914232 TI - Essential Purpura Haemorrhagica: (Previously shown October, 1931 ). PMID- 20914252 TI - Copper Therapy in Nutritional Anaemia: (Section of Therapeutics and Pharmacology). PMID- 20914256 TI - William Harvey's Knowledge of Literature-Classical, Mediaeval, Renaissance and Contemporary: (Section of the History of Medicine). PMID- 20914258 TI - Spontaneous Circumrenal Haematoma: (Section of Urology). AB - By spontaneous circum-renal haematoma is meant a condition of extensive extravasation of blood into the kidney bed and surrounding tissues, unassociated with trauma.Since this is manifested by a fairly uniform clinical picture, by similar operative findings, and by peculiar difficulties in treatment, I propose to discuss it as a clinical entity irrespective of its wide ultimate causation. Very few cases are reported in the English literature. Nevertheless, from the world literature I have collected 170 case reports, and on them, together with three further cases, I base the present paper.Etiologically the cases fall into three groups:-(1) Those due to definite disease of the kidney or its blood vessels, 58%.(2) Those due to extra-renal causes, 22%.(3) Those cases whose cause is obscure, 20%.In the first group neoplasms and inflammations of the kidney, aneurysms of the renal artery and arteriosclerosis are obvious causes. Many cases are due to obstruction of the renal veins.The classical triad of abdominal pain, signs of internal haemorrhage, and a tumour in the loin are often obscured by the resemblance of an acute abdominal catastrophe.In acute cases, expectant treatment is almost invariably fatal. Evacuation of the clot, tamponage and drainage has a mortality of about 40%, whilst nephrectomy in 55 cases showed a mortality of 22%. PMID- 20914262 TI - Pemphigus Conjunctivae. PMID- 20914263 TI - Pemphigus Conjunctivae. PMID- 20914268 TI - The History of Haematology: (Section of the History of Medicine). PMID- 20914273 TI - Anaesthesia in Urinary Surgery: (Section of Urology). PMID- 20914271 TI - The Physiology and Pathology of the Pelvic Joints in Relation to Child-bearing: (Section of Obstetrics and Gynaecology). PMID- 20914292 TI - The Scope of Evipan Anaesthesia: (Section of Surgery). PMID- 20914299 TI - Self-administered Analgesia or the Midwifery of General Practice: (Section of Anaesthetics). PMID- 20914300 TI - Congenital Syphilis and Splenic Anaemia in an Infant. PMID- 20914305 TI - Haemolytic Streptococcal Septicaemia complicating Mastoid Disease. Recovery. PMID- 20914302 TI - Cooley's Anaemia. PMID- 20914309 TI - Partial Congenital Absence of Sacrum and Coccyx and ? Lower Sacral Roots. PMID- 20914316 TI - Localized Myxoedema with Hyperthyroidism. PMID- 20914314 TI - Cutaneous Haemosiderotic Pigmentation from Purpura in a Woman with High Blood Pressure. PMID- 20914327 TI - Ovarian and Uterine Grafts: (Section of Obstetrics and Gynaecology). AB - Recent experience has convinced the author of the value of ovarian grafting. He gives the histories of a number of women upon whom he made implants of their own ovarian tissue in the course of operations for double oophorectomy. The subsequent state of these patients is contrasted with that of women after castration without grafting. When the uterus was left in position menstruation was re-established in over 80% of the grafted cases.The author and his co-workers maintain that the vitality of autogenous grafts of ovarian substance is enhanced by hormones produced by the uterine mucosa. He therefore advocates that grafts of uterus be made in conjunction with ovarian implants whenever possible. Experiments carried out on animals have proved the correctness of this opinion.The results of a series of cases of combined ovarian and uterine graftings are recorded, and the technique of uterine mucosa implants is described. PMID- 20914358 TI - The Zondek-Aschheim Test after Partial Hypophysectomy: (Section of Obstetrics and Gynaecology). PMID- 20914359 TI - Diffuse Round-celled Sarcoma of Uterus and Fallopian Tubes: (Section of Obstetrics and Gynaecology). PMID- 20914337 TI - Leprosy (Mixed Nodular and Anaesthetic). PMID- 20914361 TI - Renal Cortical Necrosis Associated with Pregnancy: (Section of Obstetrics and Gynaecology). PMID- 20914360 TI - An Unusual Cyst of the Uterus: (Section of Obstetrics and Gynaecology). PMID- 20914367 TI - Haematemesis: (Section of Surgery and Section of Medicine): Joint Discussion No. 7. PMID- 20914362 TI - Concealed Accidental Haemorrhage treated by Caesarean Hysterectomy: (Section of Obstetrics and Gynaecology). PMID- 20914398 TI - Sex: Its Nature and Abnormalities Considered from Biological and Legal Points of View: (Section of Obstetrics and Gynaecology with the Medico-Legal Society). PMID- 20914372 TI - Multiple Haemangiomata associated with Changes in the Central Nervous System. Case for Diagnosis. PMID- 20914415 TI - Bilateral Proptosis: ? due to Sphenoidal Fissure Syndrome. PMID- 20914425 TI - Factors, other than Anaesthetics, affecting Anaesthesia: (Section of Anaesthetics). PMID- 20914418 TI - Sarcoma ? Tuberculoma of Iris. PMID- 20914431 TI - Chronic Arsenical Poisoning. ? Carcinoma of the Liver. PMID- 20914429 TI - Erythro-leukaemia, in which the Myeloid Leukaemic Component is, as usual, of the Benignant Type. PMID- 20914432 TI - Cirrhosis of the Liver. ? Congenital Syphilis. PMID- 20914438 TI - Morphoea with Spontaneous Resolution. PMID- 20914442 TI - Two Cases of Cicatricial Alopecia. ? Pseudo-pelade of Brocq. PMID- 20914445 TI - The Treatment of Pes Cavus: (Section of Orthopaedics). AB - (A) REVIEW OF EARLIER METHODS: Manipulations; fasciotomy; Phelps' operation; Steindler's operation; anterior arch-plates.(B) Reasons for their relative failure.-(1) Correction of the deformity is imperfect, and (2) as they deal with the existing deformity only, and not with its cause, the result is not permanent; relapse occurs.(C) Evolution of the modern operation.-Two facts in connexion with the ordinary "idiopathic" type of pes cavus are constant, and therefore noteworthy, viz.: (a) the deformity is entirely a fore-foot deformity, consisting of dropping-down of the fore-foot, and (b) paralysis of the lumbrical or of the interosseous muscles is never found at operation.This suggests that a cause for the fore-foot drop should be sought. Pes cavus never occurs in flail foot, but may develop in mild cases of paralysis of the anterior tibial (extensor) group of muscles; this suggests that in less marked cases of paresis of these muscles, pes cavus may result; in fact, this has been observed.Finally, a case in which the legs were known to have been normal, and one was damaged, anteriorly (thereby weakening the long extensor action) resulted in the development of typical unilateral pes cavus.The part played by the interossei and lumbrical muscles is purely passive, and results from the dropping-down of the metatarsal heads beyond their line of action. This can be demonstrated on any case in which contracture of the soft parts of the toes has not occurred; pushing-up the anterior arch brings down the toes, and vice versa.The problem, then, seems to consist of finding a means to strengthen the relatively weak long extensors, and of giving them a stronger and more direct lifting action upon the metatarsal heads.(D) The modern operation.-This consists of two distinct parts: (a) the correction of existing deformity, and (b) the adoption of measures to prevent recurrence of the deformity. (a) Mere non-selective elongation of the structures of the sole is inadequate; those on the inner side must be lengthened and flattened more than those on the outer side; therefore, the joint-capsules, fasciae, tendon-sheaths, etc., are divided as freely as possible, by open operation, on the inner side of the foot. Steindler's section of all structures attached to the os calcis then allows the whole foot to elongate; this is followed by vigorous manipulation, and this completes stage (a).(b) The extensor tendons are then transplanted into holes bored through the necks of the metatarsal bones (Murk Jansen's operation, modified), and are sutured, the foot being held over-corrected meanwhile.If the toes are contracted, and the above method does not correct the deformity, arthrodesis of the proximal interphalangeal joints is performed; the fifth toe may perhaps be amputated.(E) After-treatment and results.-Other Points: The results seen to be permanent. At what age should this operation be performed? Treatment, at earlier ages, The type and degree of disability caused by pes cavus. Relief of advanced cases. PMID- 20914454 TI - Hepatomegaly. ? V. Gierke's Disease. PMID- 20914447 TI - Congenital Obstruction of OEsophagus. PMID- 20914457 TI - Coeliac Disease with Unusual Features. PMID- 20914458 TI - Graves' Disease in a Child aged 81/2 years. PMID- 20914482 TI - Specimen of Rectum and Colon from a Case of Faecal Impaction in a Girl aged 18. PMID- 20914501 TI - The AEtiology and Treatment of Asthma: (Section of Medicine). PMID- 20914484 TI - Specimen of Tuberculous Ulceration of Caecum with Large Stercolith. PMID- 20914515 TI - Erythro-leukaemia (Leukaemia following Long-standing Erythraemia-Polycythaemia Vera, Vaquez's Disease). PMID- 20914503 TI - Further Studies in Adult Rickets (Osteomalacia) and Foetal Rickets: (Section of Obstetrics and Gynaecology). PMID- 20914516 TI - Evipan as an Intravenous Anaesthetic: (Section of Anaesthetics). PMID- 20914517 TI - Evipan in Dental Anaesthesia: (Section of Anaesthetics). PMID- 20914531 TI - The Choice of an Anaesthetic under Conditions of Active Service: (United Services Section). PMID- 20914536 TI - Supravital Staining in the Diagnosis of the Leukaemias: (Section for the Study of Disease of Children). PMID- 20914538 TI - Congenital OEsophageal Stricture. PMID- 20914539 TI - Achalasia of the OEsophagus. PMID- 20914553 TI - Hypernephroma with Haemorrhage. PMID- 20914560 TI - Specimen of Acute Haemorrhagic Infarction of Duodenum. PMID- 20914573 TI - Columnar-celled Carcinoma of the Caecum in a Young Man. PMID- 20914577 TI - Gumma. ? of Parotid Gland. PMID- 20914579 TI - How Can the Results of Ante-natal Care be Improved?: (Section of Epidemiology and State Medicine and Section of Obstetrics and Gynaecology): Joint Discussion No. 1. PMID- 20914580 TI - The Role of Inorganic Elements in Nutritional Anaemia: (Section of Comparitive Medicine). PMID- 20914581 TI - Anaemias Due to a Deficiency of the Principle in Liver which is effective in the Treatment of Addisonian Pernicious Anaemia: (Section of Comparative Medicine). PMID- 20914582 TI - Contraction Ring: Treatment by Amyl Nitrite, with Observations on the Pharmacological Action of Nitrite: (Section of Obstetrics and Gynaecology). PMID- 20914583 TI - The Estimation of Foetal Maturity by a New Method of X-ray Cephalometry: Its Bearing on Clinical Midwifery: (Section of Obstetrics and Gynaecology). AB - A plea is made for routine use of X-rays in antenatal work. A new method of cephalometry is described, depending on the fact that the foetal head is a rough ovoid. It is shown that the shadows cast by ovoids may be oval or circular, but that always the diameter of the greatest circular section of an ovoid is represented in its shadow-by the diameter if the shadow be circular or by the short axis if oval. The results are applied to estimate the actual proportions of foetal head and maternal pelvis, and also to estimate foetal maturity.The accuracy of the method of cephalometry was tested in 100 cases of labour induced by rupture of membranes.A simple method of pelvimetry is described, and it is suggested that pelvimetry should be carried out in the early months and not later when the pelvis is obscured.No special apparatus is required and any cottage hospital X-ray set will serve. PMID- 20914586 TI - Morphoea. PMID- 20914611 TI - Acoustic Tumour, ? Meniere's Syndrome: Case for Diagnosis. PMID- 20914597 TI - Brown-Sequard Syndrome; Right Hemihaematomyelia. PMID- 20914618 TI - Transposition of Right Kidney as a Result of a Perinephric Haematoma. PMID- 20914632 TI - Movements of the Lumbar Vertebrae during Flexion and Extension: (Section of Orthopaedics). PMID- 20914637 TI - Coeliac Disease showing Unusual Features. PMID- 20914643 TI - Haemoglobinuria: (Section of Comparative Medicine). PMID- 20914644 TI - The Prevention and Treatment of Metastases in Carcinoma Mammae: (Section of Radiology). PMID- 20914670 TI - Accidental Injuries: Their Compensation and Rehabilitation in the United States: (Section of Orthopaedics). PMID- 20914646 TI - Some Gynaecological and Obstetrical Problems of European Women Resident in the Tropics: (Section of Tropical Diseases and Parasitology). PMID- 20914689 TI - Acute Haemoglobinuria and Anaemia in a Boy. PMID- 20914694 TI - Specimens from a Case of Congenital Obstruction of the OEsophagus. PMID- 20914692 TI - Hepatomegaly in an Infant. (? Hepatomegalia Glycogenica. ? Hypertrophic Steatosis). PMID- 20914695 TI - Specimens from a Case of Right-sided Hemihypertrophy associated with Pubertas Praecox. PMID- 20914698 TI - A Case of Obstructed Labour due to Radium Stenosis of the Cervix: (Section of Obstetrics and Gynaecology). PMID- 20914697 TI - The Glands of the Stomach in Relation to Pernicious Anaemia; with Special Reference to the Glands in the Pyloric Region: (Section of Medicine). AB - The researches have had in view the anatomical localization of the anti-anaemic factor (Castle's "intrinsic factor") in the stomach.As the pig's stomach is peculiarly constructed, having a so-called cardiac-gland region, a fundus-gland region and a pyloric gland region continued in the glands of Brunner in the duodenum, preparations have been made from each of these regions, and tests of the effectiveness of each of these separate portions have been made in cases of pernicious anaemia. It has previously been pointed out (Meulengracht and Schiodt) that the production of hydrochloric acid, pepsin and rennin was confined to the glands of the fundus region (peptic glands) with their oxyntic cells and chief cells.The experiments showed that the extract of the fundus-gland portion was inactive in cases of pernicious anaemia, that of the so-called cardiac-gland portion was mildly active, that of the pyloric-gland portion was strongly active, and that of the duodenal portion was also strongly active. The feebler activity of the cardiac portion might be shown to be a result of the smaller number of glands to the unit area in that region.The conclusion drawn from the experiments is that the so-called cardiac glands, the pyloric glands and the Brunner glands in the duodenum, which anatomically may be said to be very nearly identical, may also be taken to be functionally identical, at any rate with regard to the production of the anti-anaemic factor.This collective gland region, which it is proposed to call the pyloric-gland region, is the site of the production of the anti-anaemic factor. There is thus attributed to these glands a definite, well defined and vitally important function.It is further concluded from the experiments that pernicious anaemia in human beings is due to atrophy and inactivity of that part of the stomach which comprises the pyloric-gland region. The experiments may thus be said to have anatomically localized pernicious anaemia in human beings.Experimental pernicious anaemia will presumably be producible by the deliberate removal of the pyloric-gland region.Stomach preparations for the treatment of pernicious anaemia will with advantage be producible from the pyloric-gland region alone. PMID- 20914700 TI - The Birth of Chimpanzee at the Zoological Gardens, London: (Section of Obstetrics and Gynaecology). PMID- 20914699 TI - The Effects of Preconception Irradiation: (Section of Obstetrics and Gynaecology). PMID- 20914712 TI - The Sterilization of Women, including Indications (Medical and Eugenic), Technique and Legal Position: (Section of Obstetrics and Gynaecology with the Eugenics Society): Joint Discussion No. 3. PMID- 20914719 TI - Fusion of Lumbar Vertebrae. PMID- 20914721 TI - Fracture of the Tibia involving the Knee-joint: (Section of Orthopaedics). PMID- 20914731 TI - Intracranial Aneurysm. ? Cerebral Angioma. PMID- 20914725 TI - Aplastic Anaemia with Bronzing. PMID- 20914738 TI - Experiences in the Surgical Treatment of Lymphoedema: (Section of Tropical Diseases and Parasitology). PMID- 20914739 TI - An Explosion in Anaesthetic Apparatus: (Section of Anaesthetics). PMID- 20914741 TI - The Joint Anaesthetics Committee: A Retrospect of Eleven Years' Work: (Section of Anaesthetics). PMID- 20914740 TI - The Electrical Ignition of Explosive Anaesthetic Mixtures: (Section of Anaesthetics). PMID- 20914764 TI - Painful Recurrent Carcinoma Mammae treated by Selenium and X-rays with Immediate Relief from First Injection. PMID- 20914770 TI - A Follow-up Survey of the Cases of Hydatidiform Mole and Chorion-epithelioma treated at the London Hospital since 1912: (Section of Obstetrics and Gynaecology). PMID- 20914774 TI - The Manifold Effects of Testicular Hormones (as Extracted from Human Urine or Synthetically Prepared) and of OEstrone on the Male, as Judged by Experiments on Rats (Abstract): (Section of Therapeutics and Pharmacology). PMID- 20914775 TI - Microscopic Demonstration of Hypophyses of Rats, Normal, Castrated and after Injection of OEstrone or Synthetic Testicular Hormone (Abstract): (Section of Therapeutics and Pharmacology). PMID- 20914788 TI - Malignant Disease of the Liver. ? Secondary to a Suprarenal Tumour. PMID- 20914790 TI - Congenital Hypertrophy of Heart ? (Cardiomegalia Glycogenica): Specimen. PMID- 20914808 TI - Diet in Pregnancy: (Section of Obstetrics and Gynaecology). PMID- 20914815 TI - Polypoid Haemangioma of Pharynx. PMID- 20914820 TI - The Haemostatic Uses of Snake Venom: (Section of Medicine). PMID- 20914827 TI - Retinal Haemorrhages, of Doubtful AEtiology. PMID- 20914825 TI - Peripheral Neuritis and Pernicious Anaemia. PMID- 20914845 TI - Acrodermatitis Perstans: ? Pustular Psoriasis. PMID- 20914835 TI - Morphoea. PMID- 20914849 TI - Some Contributions to Mediaeval Veterinary Science in the Kitab al-Falahah and in Fleta: (Section of the History of Medicine). PMID- 20914864 TI - Lesions on Face. ? Artefacts: Case for Diagnosis. PMID- 20914881 TI - Idiopathic Steatorrhoea with Early Osteomalacia. PMID- 20914883 TI - Decidual Cast in Suspected Ectopic Gestation: (Section of Obstetrics and Gynaecology). PMID- 20914882 TI - The AEtiology of Fibrocystic Tumours of the Ovary: (Section of Obstetrics and Gynaecology). PMID- 20914884 TI - The Merits and Demerits of Oxytocic Drugs in the Post-partum Period: (Section of Obstetrics and Gynaecology). PMID- 20914889 TI - Sequelae following Injection Anaesthesia in the Mouth: A Bacteriological Investigation: (Section of Odontology). PMID- 20914904 TI - Porphyrinuria and Hydroa AEstivale. PMID- 20914910 TI - The Development of Orthopaedic Surgery: (Section of Orthopaedics). PMID- 20914918 TI - Case of Hepatomegaly and Mental Backwardness. ? AEtiology. PMID- 20914926 TI - Transpleural Removal of Total Thoracic OEsophagus. PMID- 20914937 TI - Cheilitis associated with Microcytic Hypochromic Anaemia. PMID- 20914938 TI - Radio-dermatitis. ? Artefact. Case for Diagnosis. PMID- 20914944 TI - Acquired Hydroa AEstivale with Haematoporphyrinuria. PMID- 20914945 TI - Mediaeval Arabic Pharmacology: (Section of the History of Medicine). PMID- 20914975 TI - Pemphigus Vegetans. ? Epithelioma. PMID- 20914948 TI - The Treatment of Breech Presentations, with Special Reference to Cases of Extended Legs and Arms: (Section of Obstetrics and Gynaecology). PMID- 20914979 TI - Recurrent Dislocation of the Shoulder: (Section of Orthopaedics). PMID- 20914980 TI - Cyclopropane: (Section of Anaesthetics). PMID- 20914984 TI - Snake Venom and Its Use in Dental Haemorrhage: (Section of Odontology). PMID- 20915001 TI - Foetus Removed from Mother's Thigh Following Rupture of the Uterus. PMID- 20915011 TI - Haematonephrosis and Carcinoma of the Renal Pelvis. PMID- 20915018 TI - Pyelitis of Pregnancy in the Light of Conditions Found in Mice after the Prolonged Administration of OEstrogenic Compounds (Abstract): (Section of Comparative Medicine). PMID- 20915049 TI - Chronic Anaemia, Leucopenia, Granulocytopenia and Thrombocytopenia, with Absolute Increase of Lymphocytes. PMID- 20915053 TI - Acroparaesthesia. PMID- 20915054 TI - Iron-Deficiency Anaemia responding to Liver Therapy and suggesting the co existence of a pernicious type of Anaemia. PMID- 20915055 TI - Persistent OEdema with Cyanosis. ? Nature. PMID- 20915069 TI - Idiopathic Steatorrhoea with Skin Lesions and Megalocytic Anaemia. PMID- 20915070 TI - Idiopathic Steatorrhoea with Osteoporosis, Tetany and Megalocytic Anaemia. PMID- 20915082 TI - Radiology in Relation to Obstetrics: (Section of Obstetrics and Gynaecology with Section of Radiology), Joint Discussion No. 3. PMID- 20915078 TI - Anaesthesia in Thoracic Surgery, with Special Reference to Lobectomy: (Section of Anaesthetics). PMID- 20915090 TI - Toxic Dermatitis. ? Arsenical. PMID- 20915091 TI - The Morbid Conditions which Cause Progressive Hyperglycaemic Glycosuria and the Circumstances which Modify its Course: (Section of Medicine). PMID- 20915092 TI - Jaundice and ? Hepatic Cirrhosis. PMID- 20915103 TI - Purpura Haemorrhagica: Splenectomy. PMID- 20915097 TI - Anaemia with Bone Changes in the Skull. PMID- 20915129 TI - Surgical Perforation in a Mediaeval Skull with Reference to Neolithic Holing: (Section of the History of Medicine). PMID- 20915131 TI - Non-Malignant Obstruction of the OEsophagus: (Section of Laryngology). PMID- 20915130 TI - A Case of Primitive Surgical Holing of the Cranium Practised in Great Britain in Mediaeval Times, with a Note on the Introduction of Trepanning Instruments: (Section of the History of Medicine). PMID- 20915146 TI - Naevus Spilus. PMID- 20915143 TI - Sub-epidermal Granuloma affecting the Skin of the Face: ? Sarcoid of Darier Roussy. PMID- 20915148 TI - Intrinsic Dysmenorrhoea: (Section of Obstetrics and Gynaecology). PMID- 20915149 TI - Atresia of the Vagina: Operation Followed by Pregnancy and Caesarean Section. PMID- 20915150 TI - Demonstration of a Number of Obstetrical and Gynaecological Models. PMID- 20915152 TI - Monocular Optic Neuritis, ? Neoplasm. PMID- 20915153 TI - Haemorrhage and Exudation into the Recessus Hyaloideo-capsulare in a Case of Septic Retino-choroiditis: (Section of Ophthalmology). PMID- 20915168 TI - Osteomyelitis of Mandible, complicated by Septicaemia and Secondary Abscesses of Elbow and Hip. PMID- 20915159 TI - Fractures in the Region of the Shoulder-Joint: (Section of Orthopaedics). PMID- 20915185 TI - The Prevention of Neo-Natal Death, Injury, And Disease: (Section for the Study of Disease in Children, Section of Obstetrics and Gynaecology and Section of Epidemiology and State Medicine), Joint Discussion No. 5. PMID- 20915186 TI - The Prevention and Treatment of Atelectasis in the Newborn Child: with Particular Reference to the Use of a New Inclined Receiving Table: (Section for the Study of Disease in Children, Section of Obstetrics and Gynaecology and Section of Epidemiology and State Medicine), Joint Discussion No. 5. PMID- 20915187 TI - Anaemia with Pigmentation of the Skin: Collapsed Left Lower Lobe. PMID- 20915204 TI - Myxoedema Resistant to Thyroid Treatment. PMID- 20915192 TI - Aplastic Anaemia. PMID- 20915206 TI - A Case of Polycythaemia Vera in which Phenyl hydrazine Treatment was followed by Acute Platelet Reactions. PMID- 20915207 TI - Chronic Meningococcal Septicaemia ending in Meningococcal Meningitis and Recovery. PMID- 20915210 TI - Subpectoral Sarcoma: ? Lymphosarcoma ? Myosarcoma. PMID- 20915220 TI - Microscopic Sections from two Cases of Blue Naevus (Jadassohn). PMID- 20915213 TI - Erythromyelosis in Fowls (Yellow Anaemia) and its Treatment by Liver Extracts: (Section of Comparative Medicine). PMID- 20915228 TI - Morphoea. PMID- 20915222 TI - Idiopathic Hypochromic Anaemia with Dermatitis Herpetiformis. PMID- 20915234 TI - OEsophageal Pouch. PMID- 20915235 TI - Tumours in Cheek. ? Fibro-myxoma. PMID- 20915240 TI - Circulatory Adjustments in Polycythaemia Rubra Vera: (Section of Medicine). PMID- 20915251 TI - Subarachnoid Haemorrhage (? of Traumatic Origin). PMID- 20915249 TI - Congenital Blindness: ? Bilateral Pseudo-glioma. PMID- 20915252 TI - Infantile Myxoedema. PMID- 20915261 TI - On the motion: "That induction of premature labour should not play any part in the treatment of pelvic contraction or disproportion in primigravidae": (Section of Obstetrics nd Gynaecology). PMID- 20915255 TI - The AEtiology and Treatment of Fibrous Stricture of the Rectum (including Lymphogranuloma Inguinale): (Section of Surgery: Sub-Section of Proctology). PMID- 20915283 TI - Hydroa AEstivale. PMID- 20915276 TI - Ulceration of the Leg and ? Myositis Ossificans. PMID- 20915289 TI - Technique of Lower Segment Caesarean Section, More Especially in "Suspect" and Infected Cases: (Section of Obstetrics and Gynaecology). PMID- 20915290 TI - Two Cases of Angular Pregnancy: (Section of Obstetrics and Gynaecology). PMID- 20915291 TI - Two Cases of Full-time Ectopic Pregnancy-I, Delivered by Vaginal Route: Child just Dead; II, Delivered Abdominally: Living Child: (Section of Obstetrics and Gynaecology). PMID- 20915297 TI - Rupture of a Tuberculous Spinal Abscess into the OEsophagus. PMID- 20915293 TI - Fusion of Transverse Processes of Third and Fourth Lumbar Vertebrae. PMID- 20915304 TI - Carbon Dioxide Absorption from Anaesthetic Atmospheres : (Section of Anaesthetics). AB - A safe and practical technique for the application of carbon dioxide absorption from anaesthetic atmospheres is described. It has been found satisfactory in over 20,000 administrations over a period of fifteen years. High-grade soda lime is utilized as the chemical absorbent. Granules are placed in a canister between face mask, and breathing bag. The canister is carefully checked for efficiency by both chemical analyses and physical experiments. Its size, shape and arrangement is shown to be important for safety and maximum efficiency. Detailed techniques are described for the use of various agents. Advantages of carbon dioxide absorption are set forth. The "Apnoea" suggested by Guedel is described under the term "Controlled Respiration" and attention is called to certain of its advantages. PMID- 20915316 TI - Metrochylorrhoea. PMID- 20915333 TI - Ectopia Vesicae Treated by Implanting Ureters into the Bowel. PMID- 20915335 TI - Resection of Lower OEsophagus and Cardia. PMID- 20915351 TI - Haemolymphangeioma. PMID- 20915346 TI - Leukaemic Erythrodermia. PMID- 20915368 TI - The Present Position of Hormones in Obstetrics and Gynaecology: (Section of Obstetrics and Gynaecology). PMID- 20915359 TI - The Effect of Removal of the Patella for Simple Transverse Fractures on the Function of the Knee-joint: (Section of Orthopaedics). PMID- 20915374 TI - The Ideal Structure of an Operating Theatre from the Point of View of an Anaesthetist: (Section of Anaesthetics). PMID- 20915369 TI - Retinal Haemorrhages in the Newborn: (Section of Ophthalmology). PMID- 20915385 TI - Symmetrical Follicular Naevus. PMID- 20915391 TI - Tonic Spasm of Arm. ? Effect of Encephalitis. PMID- 20915392 TI - Retrobulbar Neuritis. ? Devic's Disease. PMID- 20915398 TI - Febrile Anaemia of Obscure Origin. PMID- 20915401 TI - Hepato-splenomegaly: ? Idiopathic Cirrhosis. PMID- 20915407 TI - Internal Derangement of the Knee in Children and Adolescents: (Section of Orthopaedics). PMID- 20915409 TI - Bone Shortening for Inequality of Length in the Lower Limbs: (Section of Orthopaedics). PMID- 20915408 TI - Arthrodesis in Young Children: (Section of Orthopaedics). PMID- 20915414 TI - Three Renal Tumours successfully removed from Female Children aged 3 Months, 41/4 Years, and 14 Years respectively. PMID- 20915417 TI - I.-Large Adenoma of Kidney with Haemorrhage into Growth. PMID- 20915429 TI - Simplified OEsophagoscopy: OEsophagoscopy without Anaesthesia, without Head-rest, and without Assistance: (Section of Laryngology). PMID- 20915437 TI - Nodular Non-diabetic Cutaneous Xanthomatosis with Hypercholesterolaemia and Atypical Histological Features. PMID- 20915443 TI - The AEtiology and Diagnosis of Lymphadenoma: (Section of Medicine). PMID- 20915444 TI - The Relative Values of the Upper- and Lower-Segment Caesarean Operations: (Section of Obstetrics and Gynaecology). PMID- 20915449 TI - Foetus Amorphus (Anideus). PMID- 20915450 TI - An Operation for the Correction of Madelung's Deformity and Similar Conditions: (Section of Orthopaedics). PMID- 20915453 TI - Secondary Syringomyelia. ? Vertebral Aneurysm. PMID- 20915463 TI - Therapeutic Methods of Arresting Haemorrhage: (Section of Therapeutics and Pharmacology and Section of Medicine), Joint Discussion No. 2. PMID- 20915455 TI - Acute Syphilitic Meningitis with Papilloedema. PMID- 20915464 TI - Arabian Gynaecological, Obstetrical, and Genito-Urinary Practice illustrated from Albucasis: (Section of the History of Medicine). PMID- 20915483 TI - Sclerodermia (or ? Scleropanniculomyodermia). PMID- 20915480 TI - Splenomegaly with Lipaemia. PMID- 20915489 TI - A Case Clinically Resembling Morphoea with a Tuberculous Background and Indeterminate Histology, suggestive of Necrobiosis Lipoidica. PMID- 20915485 TI - Nodules. ?Tuberculous. PMID- 20915490 TI - Keratoderma Climactericum (Haxthausen) treated with OEstrone. PMID- 20915502 TI - Myocardial Ischaemia treated by Graft of Skeletal Muscle to the Heart. PMID- 20915540 TI - The Choice and Technique of Anaesthetics for Nose and Throat Operations: (Section of Laryngology and Section of Anaesthetics), Joint Discussion No. 3. PMID- 20915533 TI - Vinyl Ether for Dental Anaesthesia: (Section of Odontology). AB - Properties: Vinyl ether, CH(2):CH(2):O:CH(2):CH(2), a volatile liquid. Lipoidsoluble but highly inflammable.Toxicity.-Has little effect on liver function; overdoses produce respiratory paralysis, but not cardiac paralysis.Indications.-Replaces ethyl chloride for short operations, and can be added to gas and oxygen instead of ether or chloroform. Is a safe and portable anaesthetic for the general practitioner.Administration.-Open method convenient, but not very satisfactory, a closed method produces better anaesthesia. Special inhaler described and illustrated.Vinyl ether is obtainable in ampoules of 3 c.c., a sufficient quantity for the average case.Induction is rapid; signs of anaesthesia described. Patient's colour remains excellent.Apparatus required when vinyl ether is to be added to gas-and-oxygen. PMID- 20915541 TI - The Neurological Sequelae of Spinal Anaesthesia: (Section of Neurology). PMID- 20915545 TI - The Nonne-Milroy-Meige OEdema, of late onset, in Sisters. PMID- 20915548 TI - Impressions of Anaesthesia in U.S.A. and Canada: (Section of Anaesthetics). PMID- 20915550 TI - Haemorrhage from Vascular Growth of Orbit. PMID- 20915556 TI - Sarcoma of the Choroid. ? Retinitis Exudativa Externa. PMID- 20915570 TI - Atrophic Areas on Insteps and Soles with ? Telangiectases: Case for Diagnosis. PMID- 20915572 TI - The Prevention and Treatment of Ununited Fractures: (Section of Orthopaedics). PMID- 20915589 TI - Hepatomegaly. ? Cause. PMID- 20915595 TI - Coeliac Rickets. PMID- 20915602 TI - Polioencephalitis Haemorrhagica Superior. PMID- 20915604 TI - Spontaneous Haematomyelia: a Report of Two Cases, one in Association with an Intramedullary Angioma, and the other in Association with Syphilis. PMID- 20915611 TI - Tumour of the Spinal Cord in a Child aged 21/2 years: Specimens. PMID- 20915607 TI - Local and Remote Sequelae of Infection in the Parodontal Sulcus: (Section of Odontology). AB - (1) It is shown in this paper that the infecting organisms in the parodontal sulcus are confined to the surface, but may be forced into the blood and lymph stream by traumatic interference.2. Local and general disturbances may therefore arise both as a result of the absorption of soluble toxic matter from the pocket into the tissues and also as a result of this traumatic introduction of organisms into the blood-stream.3. The effect of toxic absorption on the local tissues is destruction of the attachment of the tooth-pyorrhoea.4. The remote effects of toxic absorption may be a similar destruction of the connective tissue generally arthritis and fibrositis. The liver and kidney may suffer since they excrete the toxic matter, and other susceptible tissues may also be involved.5. Traumatic bacteraemia may produce local bone necrosis or "dry" socket. Acute suppurative lymphangitis produces the "pyorrhoetic abscess".6. The remote effect of bacteraemia may be to produce osteomyelitis (e.g. of the tibia) or to convert a simple endocarditis into the bacterial type.7. The mechanism of bone absorption and deposition in response to irritation is discussed.8. Methods of eliminating parodontal infection are referred to and the importance of complete elimination is stressed. It is shown to be not incompatible with the conservation of the teeth. PMID- 20915613 TI - Hypochromic Anaemia, Congenital Heart Disease, and Peculiar Facies. PMID- 20915623 TI - Meckel's Diverticulum causing Severe Recurrent Haemorrhage from the Bowel. PMID- 20915647 TI - A New Type of Nitrous-oxide Machine for Self-induction of Analgesia during Labour: (Section of Obstetrics and Gynaecology). PMID- 20915649 TI - An Investigation into the Ocular Changes in Normal and Hypertensive Pregnancy: (Section of Obstetrics and Gynaecology). PMID- 20915648 TI - Modified Mayo Operation for Procidentia: (Section of Obstetrics and Gynaecology). PMID- 20915653 TI - Partial Resolution of Leukoplakia Vulvae under OEstrin Therapy. PMID- 20915658 TI - Dermatomyositis: ? Artefact. PMID- 20915662 TI - Two Cases of Carcinoma of the Cervix complicating Procidentia Uteri: (Section of Obstetrics and Gynaecology). PMID- 20915664 TI - Results of Radium Treatment in (1) Carcinoma of the Uterus; (2) Uterine Haemorrhage: (Section of Obstetrics and Gynaecology). PMID- 20915663 TI - Procidentia Recti Present for Twenty-three Years and Cured by Operation: (Section of Obstetrics and Gynaecology). PMID- 20915675 TI - The Spa Treatment of Pelvic Disorders: (Section of Physical Medicine with Section of Obstetrics and Gynaecology), Joint Discussion No. 5. PMID- 20915665 TI - The Prolapse Syndrome: (Section of Obstetrics and Gynaecology). PMID- 20915681 TI - The Initiation of Respiration in Asphyxia Neonatorum. A Clinical and Experimental Study Incorporating Foetal Blood Analyses and a Consideration of Important Methods of Resuscitation: (Section of Obstetrics and Gynaecology). PMID- 20915692 TI - Splenomegaly and Meningitis. ? Nature. PMID- 20915682 TI - Carcinoma of the Vagina Complicating a Complete Procidentia: (Section of Obstetrics and Gynaecology). PMID- 20915694 TI - A Condition resembling Rheumatic Fever, with Arthritis, in a Man aged 48. ? Nature. PMID- 20915707 TI - Two Cases of Chronic OEdema of Legs with High Blood-pressure. PMID- 20915697 TI - The Evolution of Orthopaedic Surgery in Great Britain: (Section of Orthopaedics). PMID- 20915715 TI - Bronchiectasis, with Repeated Haemoptysis treated by Postural Drainage followed by Pneumonectomy. PMID- 20915724 TI - The Neurological and Psychological Effects of Hypoglycaemia: (Section of Psychiatry). PMID- 20915728 TI - Multiple Pyaemic Abscesses in Scarlet Fever: Operations: Recovery. PMID- 20915735 TI - Chronic Leukaemic Dermatosis. PMID- 20915729 TI - Coeliac Disease with a Conditioned Vitamin Deficiency resembling, but not typical of Pellagra. PMID- 20915770 TI - Chronic Granuloma; ? Artefact. PMID- 20915765 TI - Maternity Work in L.C.C. Hospitals, 1931-1936: (Section of Obstetrics and Gynaecology). PMID- 20915772 TI - Lupus Erythematosus of the Face, with ? Lichen Planus or Lupus Erythematosus of Tongue and Buccal Mucosa. PMID- 20915780 TI - Pseudopapilloedema. PMID- 20915785 TI - Combined Degeneration of the Cord with Polycythaemia. PMID- 20915789 TI - OEsophageal Obstruction. PMID- 20915790 TI - Congenital Palatal Paralysis: ? Nuclear Agenesis. PMID- 20915798 TI - Multiple Subcutaneous Phleboliths over the Tibiae. PMID- 20915799 TI - Tumour of Cheek: ? Nature. PMID- 20915802 TI - Localized Myxoedema associated with Graves' Disease. PMID- 20915808 TI - Acute Rheumatism occurring in the course of a Staphylococcal Septicaemia. PMID- 20915803 TI - Poikilodermia. ? Chronic Atrophic Dermatitis: Case for Diagnosis. PMID- 20915811 TI - Two Cases of Monocytic Leukaemia. PMID- 20915817 TI - A Case of Acute Myeloid Leukaemia: (Section of Odontology). PMID- 20915821 TI - The Errors of Flow-meters and the Advantages of a New Type of Constriction: (Section of Anaesthetics). PMID- 20915823 TI - The Trend of Modern Anaesthesia for Upper Abdominal Surgery: (Section of Anaesthetics). PMID- 20915822 TI - The Continuous-Flow Administration of Cyclopropane: (Section of Anaesthetics). PMID- 20915824 TI - Lesions of the Supraspinatus: (Section of Orthopaedics). PMID- 20915825 TI - The Lorenz Bifurcation Osteotomy for Irreducible Congenital Dislocation of Hip: (Section of Orthopaedics). PMID- 20915826 TI - A Method of Grafting Long Bones: (Section of Orthopaedics). PMID- 20915828 TI - Hydradenome Eruptif of Darier. PMID- 20915835 TI - Pigmented Dermatitis associated with Pernicious Anaemia. PMID- 20915848 TI - Hepatomegaly in an Infant: ? Von Gierke's Disease. PMID- 20915836 TI - An Unusual Type of ? Lichen Planus. PMID- 20915857 TI - Case described as Acquired Acholuric (Haemolytic) Jaundice in 1909. PMID- 20915856 TI - Congenital Acholuric Jaundice, without Anaemia, Splenomegaly, or Fragility of Red Corpuscles. PMID- 20915863 TI - Two Cases of Infantile Myxoedema, with X-ray Findings. PMID- 20915891 TI - Diverticulitis of the Caecum. PMID- 20915903 TI - Mucocoele of Frontal Sinus. PMID- 20915914 TI - The Survey of Maternity Work in L.C.C. Hospitals 1931-1936 [Dr. Letitia Fairfield] : (Section of Obstetrics and Gynaecology). PMID- 20915906 TI - Unusual Coincidence of Bitemporal Hemianopia and Papilloedema, due to an Adamantinoma. PMID- 20915915 TI - The Problem of Post-Maturity: (Section of Obstetrics and Gynaecology). PMID- 20915916 TI - Lower Segment Caesarean Section (Cinematograph Demonstration). PMID- 20915917 TI - Fractures of the Metatarsals: (Section of Orthopaedics). PMID- 20915918 TI - Fractures of the Phalanges of the Hand and Metacarpals: (Section of Orthopaedics). PMID- 20915920 TI - A Historical, Epidemiological and AEtiological Study of Measles (Morbilli; Rubeola): (Section of Epidemiology and State Medicine). PMID- 20915924 TI - Cavernous Haemangioma of the Right Orbit, Removed by Kronlein's Operation. PMID- 20915928 TI - Morphoea. PMID- 20915940 TI - Lateral Sinus Thrombosis and Septicaemia. PMID- 20915937 TI - Hypo-ovarian Dermatosis, Responding to OEstrin. PMID- 20915949 TI - Endocrinal Obesity (Hypothyroidism) with OEdema of the Legs, Osteo-arthritis and Hypertension. PMID- 20915957 TI - The Treatment of Tuberculosis of the Hip in Adults: (Section of Orthopaedics). PMID- 20915958 TI - Treatment of Tuberculous Disease of the Spine in Adults: (Section of Orthopaedics). PMID- 20915963 TI - Radiotherapy in Non-malignant Gynaecological Disorders: (Section of Radiology with Section of Obstetrics and Gynaecology), Joint Discussion No. 4. PMID- 20915960 TI - Ether Narcosis and Carbohydrate Metabolism: (Section of Anaesthetics). PMID- 20915973 TI - Rectal Polyposis associated with Clubbing, Polydactyly, Hydrocephalus, Hepatomegaly and Hypochromic Anaemia. PMID- 20915980 TI - Leukoplakic Vulvitis and the Conditions Liable to be Confused With It: (Section of Obstetrics and Gynaecology). PMID- 20915981 TI - Hydrops Foetalis (Erythroblastosis): (Section of Obstetrics and Gynaecology). PMID- 20915982 TI - A Case of Diabetes Insipidus and Twin Pregnancy: (Section of Obstetrics and Gynaecology). PMID- 20915983 TI - Puerperal Femoral Thrombosis: (Section of Obstetrics and Gynaecology). PMID- 20916012 TI - Cerebral Sequelae, after Neonatal Jaundice, ascribed to Kernicterus. PMID- 20916013 TI - Microcytic Anaemia Resistant to Iron. PMID- 20916016 TI - Coeliac Rickets. PMID- 20916064 TI - Urinary Fistulae in Relation to the Colon and Rectum: (Section of Surgery: Sub Section of Proctology). PMID- 20916057 TI - Massive Collapse of the Lung as a Complication of Surgical Operations: (Sections of Surgery, Medicine, and Anaesthetics), Joint Discussion No. 5. PMID- 20916085 TI - Obstetric Shock: (Section of Obstetrics and Gynaecology). PMID- 20916072 TI - Haemochromatosis in a Woman. PMID- 20916086 TI - Large Mesenteric Cyst situated mainly behind the Caecum and resembling an Ovarian Cyst-Adenoma: (Section of Obstetrics and Gynaecology). PMID- 20916096 TI - Anatomical Variations in the Female Pelvis: Their Classification and Obstetrical Significance: (Section of Obstetrics and Gynaecology). PMID- 20916101 TI - The Femoral Neck in Childhood: (Section of Orthopaedics). PMID- 20916115 TI - Purpura and Angioneurotic OEdema in a Male, associated with Hypertrophy of the Breasts. PMID- 20916116 TI - Intermittent Metrochylorrhoea. PMID- 20916133 TI - Haemolytic Anaemia in a Newborn Infant. PMID- 20916117 TI - Two Cases of Dislocation of the Cervical Spine in Children Caused by Hyperaemic Decalcification of the Vertebrae following Cervical Adenitis. PMID- 20916142 TI - Vitamin-C Deficiency and Periostitis of Both Ulnae.? Scurvy. PMID- 20916144 TI - OEdema of Leg. PMID- 20916165 TI - Infantile Hemiplegia. Cerebral Angioma. Subarachnoid Haemorrhage. PMID- 20916173 TI - Kast's Syndrome (Multiple Haemangiomata associated with Chondromata or Ollier's Dyschondroplasia). PMID- 20916186 TI - Carcinoma of the Vulva: (Section of Obstetrics and Gynaecology). PMID- 20916185 TI - Further Studies in Adult Rickets (Osteomalacia) and Foetal Rickets: (Section of Obstetrics and Gynaecology). PMID- 20916187 TI - The Treatment of Carcinoma Vulvae: (Section of Obstetrics and Gynaecology). PMID- 20916188 TI - Epithelioma of the Vulva: (Section of Obstetrics and Gynaecology). PMID- 20916189 TI - Some Recent Work on Barbiturates: (Section of Anaesthetics). AB - Toxic effects are sometimes seen after the administration of quite small amounts of barbiturates. Factors concerned in their production are discussed under the following heads:-(1) Barbiturates can produce liver damage, even hepatitis.(2) Barbiturates may become toxic in the presence of liver damage, as shown by:-(a) Clinical and post-mortem experience.(b) Experimental evidence-the work of Pratt and Koppanyi in America and our own experiments showing that certain barbiturates may exert toxic effects not only when there is severe liver damage but also in the early stages of liver injury.(3) Other factors also seem to be concerned:-(a) Cold.(b) Haemorrhage.(c) Fasting.(d) Sepsis.(e) Tight bandage around upper abdomen.(f) Castration.The experimental evidence for this statement is given. PMID- 20916214 TI - Pigmented Naevi on the Skin, Lips, and Buccal Mucous Membrane. PMID- 20916193 TI - Congenital Steatorrhoea with Congenital Morbus Cordis. PMID- 20916219 TI - Melanodermia? Pigmentary Morphoea. PMID- 20916256 TI - Circumrenal Haematoma. PMID- 20916268 TI - Apyrexial Ulceration, Lung Abscess and Pyaemia. PMID- 20916280 TI - Myeloid Leukaemia. PMID- 20916274 TI - Precancerous Changes in the Cervix Uteri: (Section of Obstetrics and Gynaecology). PMID- 20916283 TI - Streptococcal Bacteriaemia. PMID- 20916281 TI - Chronic Lymphatic Leukaemia. PMID- 20916287 TI - Injuries to Both Semilunar Cartilages of the Knee-joint: (Section of Orthopaedics). PMID- 20916289 TI - The Operation of Intertrochanteric Osteotomy: (Section of Orthopaedics). PMID- 20916288 TI - Congenital Coxa Vara and the Short Femur: (Section of Orthopaedics). PMID- 20916290 TI - Fractures of the Shaft of the Humerus: (Section of Orthopaedics). PMID- 20916308 TI - Bacteriaemia and Oral Sepsis: (Section of Odontology). AB - Transient streptococcal bacteriaemias are a frequent sequel to dental extractions especially when the mouth is the seat of severe chronic gum infection. Bacteria may also gain admission to the blood-stream in such cases irrespective of operative procedures and probably as the result, in many instances, of minor degrees of gum injury such as is produced by biting on a loose tooth. Acute apical infections do not appear to be especially associated with blood infection of this kind, the focus of infection here apparently being effectively "walled off" by the associated inflammatory reaction.Of the two factors, infection and trauma, involved in the production of these post-operative bacteriaemias, infection appears to be the more important since, when it is marked, very slight degrees of gum injury are sufficient to produce blood-stream invasion. In the complete absence, however, of the type of trauma induced by the "rocking" of a tooth during its removal, extraction may be accomplished without producing a heavy bacterial shower in the blood.Usually these transient bacteriaemias produce no permanent ill-effect, but there is some evidence that, occurring in subjects with abnormal heart valves, they may lead to subacute infective endocarditis. Thirteen cases are reported where the valvular infection appeared to result from a post-operative dental bacteriaemia.Prevention of such bacteriaemias may be achieved by the reduction or elimination of infection and trauma. Complete elimination of the gum infection is difficult although preliminary treatment of the gum margin by some measure such as cauterization may lessen it and lead to a reduction of the post-operative bacterial shower. Similarly, by manipulating an infected tooth as little as possible during its extraction the incidence or degree of blood infection may be decreased. PMID- 20916309 TI - Subhyaloid OEdema of the Retina. PMID- 20916318 TI - Paget's Disease associated with Transverse Band Degeneration of both Corneae. PMID- 20916323 TI - Unilateral Papillitis of Obscure AEtiology. PMID- 20916349 TI - Cerebral Aneurysm with Papilloedema. PMID- 20916330 TI - Radium Treatment of Menopausal Haemorrhage Followed by Carcinoma of the Body of the Uterus Three Years Later. PMID- 20916364 TI - Solitary Diverticulum of the Caecum. PMID- 20916366 TI - Extensive Ano-Rectal and Urethral Fistulae with Plastic Repair: (Section of Surgery: Sub-Section of Proctology). PMID- 20916368 TI - I.-Diverticulitis of Caecum, Resembling Carcinoma. PMID- 20916370 TI - A Case of Amoebic Ulceration of the Rectum and Anus. PMID- 20916372 TI - Amoebic Ulceration of the Abdominal Wall. PMID- 20916379 TI - Serum and Vaccine Therapy in Combination with Sulphanilamide or M and B 693: (Section of Obstetrics and Gynaecology). PMID- 20916380 TI - The Effects of Injection of Pituitary Extract Immediately after Delivery: (Section of Obstetrics and Gynaecology). PMID- 20916381 TI - On the Effects of Pituitary Extract (Posterior Lobe) in the Third Stage of Labour: (Section of Obstetrics and Gynaecology). PMID- 20916382 TI - The Effects of Injections of Pituitary Extract Immediately after Delivery: (Section of Obstetrics and Gynaecology). PMID- 20916383 TI - Effective Methods of Using Oxytocic Drugs in Post-Partum Haemorrhage: (Section of Obstetrics and Gynaecology). PMID- 20916384 TI - The Elimination of the Breech Presentation from Private Practice: (Section of Obstetrics and Gynaecology). PMID- 20916386 TI - The Significance of Anoxaemia in Modern Psychiatric Treatment: (Section of Psychiatry). AB - Blood in its passage through the brain loses oxygen and glucose at relatively high rates, the amount of oxygen disappearing being approximately equivalent to the amount of glucose consumed, calculating on the basis that the sugar is completely oxidized. The respiratory quotient of brain in vivo is unity. These facts point to the dominance of carbohydrate oxidation in brain respiration in vivo and are similar to those found in studies of brain in vitro.Various factors influence glucose oxidation in brain, e.g. changes in the ionic environment of the cells, vitamin B(1), or the presence of narcotics. The latter bring about inhibitions of glucose oxidation in brain tissue which may in most cases be shown to be reversible in vitro. Glucose is not only important for the maintenance of respiration of brain but for enabling certain synthetic processes to occur. One of these is the formation of acetylcholine whose physiological significance is now well known and whose synthesis seems to be confined to the nervous system. This synthesis depends not only on the presence of glucose but on that of oxygen. The influence of glucose has been observed also in investigations on cortical potentials.An important feature of the nerve cell is its vulnerability to the lack of oxygen. Reversibility depends on the degree and duration of the anoxaemia.During insulin shock treatment studies of brain in vivo show lowered oxygen consumption and glucose utilization, these depending on the degree of hypoglycaemia. In cardiazol treatment, in vivo studies show that the oxygen content of the blood may fall to 42%. During the convulsion there is a greatly lowered arterial and venous blood-flow through the brain and cerebral anaemia becomes a marked feature. In narcosis treatment both in vitro and in vivo studies show a diminished ability of the brain to consume oxygen.It is suggested that the most significant facts to be taken into account are (1) the importance of glucose and oxygen for the metabolism and function of the nervous system, (2) the vulnerability and varying sensitivities of nerve cells to lack of oxygen and glucose, (3) the occurrence of varying degrees of cerebral anoxaemia in narcosis, insulin and cardiazol treatments. PMID- 20916387 TI - Coma Resistance and Adrenalaemia in the Insulin Treatment of Schizophrenia: (Section of Psychiatry). PMID- 20916400 TI - Surgery in Diabetic Patients: (Sections of Surgery, Medicine and Anaesthetics). PMID- 20916403 TI - Local Diffuse Myxoedema-like Area over Shin. PMID- 20916435 TI - Subarachnoid Haemorrhage. PMID- 20916413 TI - Lymphatic Leukaemia with Skin Deposits. PMID- 20916439 TI - Subdural Haematoma. PMID- 20916444 TI - On the Danger of Willett's Forceps in Placenta Praevia with Two Illustrative Cases: (Section of Obstetrics and Gynaecology). PMID- 20916447 TI - The Birth of Quadruplets: (Section of Obstetrics and Gynaecology). PMID- 20916446 TI - The Diagnostic Value of Hysterography: (Section of Obstetrics and Gynaecology). AB - Object of paper.-Clarification of position concerning clinical value of procedure. Conflicting views. Review of routine examination of all cases investigated during the past two years.Historical.-Suggested by Cary (1914) and Rubin (1915), made practicable by the invention of lipiodol-applied Heuser (1924).Technique.-Instruments employed, anaesthesia, X-ray figures, screening.Material.-Uterine fibroids and carcinomas, extra-uterine tumours and cysts, placental remains and polypi, moles, &c. Correlation with operative results.Physiology.-Normal shapes, sizes, and positions. Pseudo filling-defects and malformations.Pathology.-Appearances in various conditions. Correlation with specimens and radiography of same. Fallacies and contradictions.Conclusions. Method of value in diagnosis of placental remains may avoid diagnostic curettage in carcinoma of body; by localization of fibromata may allow of prediction of myomectomy, &c. But fallacies numerous and much more experience required to make diagnosis so accurate as to be of much real routine value. PMID- 20916448 TI - The Factors Influencing the Attitude of the Foetus in utero: (Section of Obstetrics and Gynaecology). PMID- 20916449 TI - The Effects of Stilboestrol on Labour: (Section of Obstetrics and Gynaecology). PMID- 20916467 TI - Routine Treatment of Congenital Dislocation of the Hip: (Section of Orthopaedics). PMID- 20916466 TI - Methaemalbumin in Man (Pseudo-methaemoglobin): (Section of Therapeutics and Pharmacology). PMID- 20916479 TI - Chronic Meningococcal Septicaemia, with old Hemiplegia. PMID- 20916481 TI - Pachymeningitis Interna Haemorrhagica. PMID- 20916488 TI - Achalasia of Cardia with Gross OEsophagus. PMID- 20916506 TI - Capillary Naevus treated by Grenz Rays. PMID- 20916520 TI - Chronic Lymphatic Leukaemia with Paraplegia. PMID- 20916523 TI - Simple Ulcer of the OEsophagus and Short OEsophagus: (Section of Medicine). PMID- 20916530 TI - Haemorrhagic Purpura (Essential Thrombocytopenia) as a Complication of Excision of the Rectum: (Section of Surgery: Sub-Section of Proctology). PMID- 20916535 TI - Anaesthetic Problems in Urology: (Section of Urology). PMID- 20916540 TI - Leukaemia with Nodules in the Skin. PMID- 20916546 TI - Striae Atrophicae.? Dyspituitarism. PMID- 20916551 TI - Atypical Psoriasis of Axillae, with a Remarkable Family History of Psoriasis. PMID- 20916552 TI - Naevus Unius Lateris of the Verrucosus and Hystrix Types. PMID- 20916558 TI - A Case of Mistaken Diagnosis of Malignancy in an Ovarian Cyst: (Section of Obstetrics and Gynaecology). PMID- 20916559 TI - Utero-Abdominal Fistula in a Young Woman: (Section of Obstetrics and Gynaecology). PMID- 20916560 TI - Pelvic Osteo-arthropathy of Pregnancy: (Section of Obstetrics and Gynaecology). AB - Excessive relaxation of the pelvic joints during pregnancy has as its chief symptoms chronic backache and locomotor disturbances. Goldthwait and others have for long drawn attention to the frequent part played by softening of the sacro iliac joint structures in the production of the common backache of pregnancy. The frequency of this symptom may be gauged by the fact that 114 women out of a successive series of 3,030 cases at the antenatal clinic, or 3.7%, suffered in such a degree as to lead them to call for treatment. In 69, or 60.5%, the pain commenced before the 28th week, whilst in the remaining 45 or 39.5%, it commenced later. PMID- 20916561 TI - The Effect of the Inclination of the Pelvic Brim and the Shape and Inclination of the Upper Sacrum on the Passage of the Head through the Upper Pelvis: (Section of Obstetrics and Gynaecology). AB - Engagement of the Head does not depend only on the size and shape of the brim, but also on the angle of inclination of the brim. The methods of determining this inclination are considered and the angle between the plane of the brim and the front of the body of the 5th lumbar vertebra is found to furnish the best index of the inclination. Analysis of a series of cases shows that this angle varies considerably. Its postural range is demonstrated.When the inclination is high the head does not easily engage although the measurements may be normal, and a high inclination is one of the commonest causes of unexpected dystocia.Because these cases are usually selected for a "trial of labour", criteria are necessary to select the cases suitable. Success or failure of trial labour in these cases depends on the amount of room in the upper pelvis. A part from the actual size of the true conjugate the amount of room is shown to depend both on the sacral inclination, a method of measuring which is described, and the shape of the upper sacrum, which shows considerable vriation. A common type of pelvis causing dystocia is one in which the inclination of the brim is high and the upper sacrum is relatively vertical and convex. Pelves of this type do not always fit into any of the standard classifications.The uses and limitations of postural treatment of these cases are discussed. PMID- 20916568 TI - Protruded Intervertebral Disc (Fibrocartilage): (Section of Orthopaedics and Section of Neurology). PMID- 20916570 TI - The Organization of Hospital Services for Casualties due to the Bombing of Cities, Based on Experience Gained in Barcelona-with Special Reference to the Classification of Casualties: (Section of Orthopaedics). AB - (1) Difference between modern "total population" war and old-fashioned war. Difference between bombing of (a) military objectives and (b) civilian population.(a) The heavy bomb, e.g. 750 lb., with large fragments, upward throw, great destruction of buildings.(b) The light bomb with finger nail fragments, horizontal throw, great velocity.There is in addition the incendiary bomb, little used in Barcelona because the buildings are built of stone and concrete.(2) Aerial bombing of a town produces injuries needing more immediate hospitalization than most front-line wounds. At the same time it is possible in a town to organize rapid collection of patients and their immediate transfer to hospital.(3) Experience shows that it is most desirable to make this transfer of patients to hospital a primary consideration. On arrival they are "sorted" and minor injuries are given First Aid treatment and sent home, others are fully examined, classified, and dispatched to the theatres on a priority list, to nearby wards for resuscitation, to wards for rest, or sent on to plaster rooms for splintage, or to a neurosurgical centre.(4) First-aid posts in a town should be in hospitals and treat superficial injuries, &c., after primary sorting in the hospital reception room.(5) First-aid posts in outlying areas should carry out the same function for the same type of cases; all the more seriously wounded, including those with tiny penetrating wounds, should be dispatched without first aid treatment direct to hospital.(6) Hospital arrangements, for circulation of ambulances, for sorting, undressing of patients, docketing of valuables, &c.(7) Classification must be carried out by surgeons of experience and judgment. They must regard not only a standard priority list but the particular clinical picture and prognosis in each case.(8) The surgeon will furthermore draft the cases with regard to the special abilities of the surgical units available, e.g. chest, abdomen, or limbs.(9) Review of wounds in limbs, chest, abdomen, and head, caused by fragments from heavy bombs or by splinters from small light bombs.(10) Injuries from falling masonry.(11) Standard classification by urgency of operation.(12) Classification re possible early evacuation. PMID- 20916571 TI - Yesterday and To-day in Children's Anaesthesia: (Section of Anaesthetics). PMID- 20916573 TI - On Injuries to the Brain and their Sequelae: (United Services Section). PMID- 20916577 TI - Status Lymphaticus: (Section of Anaesthetics). PMID- 20916585 TI - Intra-medullary Kirschner Wires in the Treatment of Fractures: (Section of Orthopaedics). PMID- 20916584 TI - Simplifications of Technique in Some Joint Operations: (Section of Orthopaedics). PMID- 20916586 TI - Treatment of Ununited Fractures by Bone Grafting without Resection of the Bone Ends: (Section of Orthopaedics). PMID- 20916597 TI - Premedication: (Section of Anaesthetics). PMID- 20916590 TI - The Radiological Diagnosis of Chronic Subdural Haematoma: (Section of Neurology). PMID- 20916602 TI - Fractured Lumber Vertebrae. PMID- 20916604 TI - Idiopathic Lymphoedema. PMID- 20916609 TI - Spasm of the OEsophagus. PMID- 20916608 TI - Congenital Megacolon treated by High Spinal Anaesthesia. PMID- 20916616 TI - Anaemia with Splenomegaly. PMID- 20916624 TI - Steatorrhoea with Radiological Changes in Vertebrae. PMID- 20916634 TI - Trotula and the Ladies of Salerno: A Contribution to the Knowledge of the Transition between Ancient and Mediaeval Physick (Abridged): (Section of the History of Medicine). PMID- 20916648 TI - Some Investigations on the Treatment of Sterility: (Section of Obstetrics and Gynaecology). PMID- 20916655 TI - Connective Tissue Naevus. PMID- 20916675 TI - Staphylococcus aureus Septicaemia with Recovery, treated with M & B 693. PMID- 20916680 TI - The Surgical Treatment of Idiopathic Ulcerative Colitis and its Sequelae: (Section of Proctology). PMID- 20916679 TI - A Method of Administering Continuous Intravenous Anaesthesia for Abdominal Surgery: (Section of Anaesthetics). PMID- 20916681 TI - Fractures and Dislocation of the Cervical Vertebrae: (Section of Orthopaedics). PMID- 20916682 TI - The Position of Radiotherapy in the Treatment of Malignant Disease of the Upper Respiratory and Alimentary Tracts, excluding the Tongue and OEsophagus: (Section of Laryngology). PMID- 20916690 TI - Radio-Opaque Calcification of the Fallopian Tubes with Tubal Patency: (Section of Obstetrics and Gynaecology). PMID- 20916691 TI - Brain Showing Cerebral Haemorrhage in a Case of Spontaneous Labour: (Section of Obstetrics and Gynaecology). PMID- 20916692 TI - Chronic Nephritis in Pregnancy: (Section of Obstetrics and Gynaecology). PMID- 20916702 TI - The Pathology of Cervicitis: (Section of Obstetrics and Gynaecology). PMID- 20916701 TI - Clinical Study of 40 Consecutive Cases of Extra-Uterine Pregnancy: (Section of Obstetrics and Gynaecology). PMID- 20916708 TI - The Treatment of Traumatic Haemothorax: (Section of Medicine). PMID- 20916707 TI - The AEtiology and Morbid Anatomy of Fowl Paralysis (Neurolymphomatosis): (Section of Comparative Medicine). PMID- 20916720 TI - Closed Plaster Treatment of Wounds in the Light of Recent Experience: (Section of Orthopaedics). PMID- 20916719 TI - The Functional Treatment of Congenital Dislocation of the Hip-joint: (Section of Orthopaedics). PMID- 20916721 TI - The Treatment of Burns: (Section of Orthopaedics). PMID- 20916735 TI - Some Little-known Medical Practitioners in Mediaeval Persia: (Section of the History of Medicine). PMID- 20916754 TI - Anaesthesia in Chest Surgery, with Special Reference to Controlled Respiration and Cyclopropane: (Section of Anaesthetics). AB - Problems in chest surgery: Cases with prolonged toxaemia or amyloid disease require an anaesthetic agent of low toxicity. When sputum or blood are present in the tracheobronchial tree the anaesthesia should abolish reflex distrubances and excessive sputum be removed by suction. The technique should permit the use of a high oxygen atmosphere; controlled respiration with cyclopropane or ether fulfil these requirements. Open pneumothorax is present when a wound of the chest wall allows air to pass in and out of the pleural cavity. The lung on the affected side collapses and the mediastinum moves over and partly compresses the other lung.The dangers of an open pneumothorax: (1) Paradoxical respiration-the lung on the affected side partially inflates on expiration and collapses on inspiration. Part of the air entering the good lung has been shuttled back from the lung on the affected side and is therefore vitiated. Full expansion of the sound lung is handicapped by the initial displacement of the mediastinum which increases on inspiration. The circulation becomes embarrassed.(2) Vicious circle coughing. During a paroxysm of coughing dyspnoea will occur. This accentuates paradoxical respiration and starts a vicious circle. Death from asphyxia may result.Special duties of the anaesthetist: (1) To carry out or supervise continuous circulatory resuscitation. During a thoracotomy a drip blood transfusion maintains normal blood-pressure and pulse-rate.(2) To maintain effcient respiration.Positive pressure anaesthesia: Risk of impacting secretions in smaller bronchi with subsequent atelectasis; eventual risk of CO(2) poisoning without premonitory signs.Controlled respiration: (1) How it is produced. (2) Its uses in chest surgery.Controlled respiration means that the anaesthetist, having abolished the active respiratory efforts of the patient, maintains an efficient tidal exchange by rhythmic squeezing of the breathing bag. This may be done mechanically by Crafoord's modification of Frenkner's spiropulsator or by hand.Active respiration will cease (i) if the patient's CO(2) is lowered sufficiently by hyperventilation, (ii) if the patient's respiratory centre is depressed sufficiently by sedative and anaesthetic drugs, and (iii) by a combination of (i) and (ii) of less degree.The author uses the second method, depressing the respiratory centre with omnoponscopolamine, pentothal sodium, and then cyclopropane. The CO(2) absorption method is essential for this technique, and this and controlled respiration should be mastered by the anaesthetist with a familiar agent and used at first only in uncomplicated cases.The significance of cardiac arrhythmias occuring with cyclopropane is discussed.The place of the other available anaesthetic agents is discussed particularly on the advisability of using local anaesthesia for the drainage of empyema or lung abscess.Pharyngeal airway or endotracheal tube? Anaesthesia may be maintained with a pharyngeal airway in many cases but intubation must be used when tracheobronchial suction may be necessary and when there may be difficulty in maintaining an unobstructed airway.A one-lung anaesthesia is ideal for pneumonectomy. This may be obtained by endotracheal anaesthesia after bronchial tamponage of the affected side (Crafoord, v. fig. 6b) or by an endobronchial intubation of the sound side (v. figs. 9b and 9c). Endobronchial placing of the breathing tube may be performed "blind". Before deciding on blind bronchial intubation, the anaesthetist must examine X-ray films for any abnormality deviating the trachea or bronchi. Though the right bronchus may be easily intubated blindly as a rule, there is the risk of occluding the orifice of the upper lobe bronchus (fig. 9d) when the patient will become cyanosed. If the tube bevel is facing its orifice the risk of occlusion will be decreased (fig. 9c).Greater accuracy in placing the tube can be effected by inserting it under direct vision. Instruments for performing this manoeuvre are described.In lobectomy for bronchiectasis the anaesthetist must try to prevent the spread of infection to other parts. Ideally, the bronchus of the affected lobe should be plugged with ribbon gauze (Crafoord, v. fig. 6c) or a suction catheter with a baby balloon on it placed in the affected bronchus. In the presence of a large bronchopleural fistula controlled respiration cannot be established during operation. As the surgeon is rarely able to plug the fistula, if pneumonectomy is to be performed intubation for a one-lung anaesthesia is the best method. During other procedures it is essential to maintain quiet respiration.In war casualties it is almost always possible, with the technique described, to leave the lung on the affected side fully expanded and thus frequently to restore normal respiratory physiology. Co-operation between surgeon and anaesthetist is essential. PMID- 20916769 TI - The Relationship of Nitrous Oxide Anaesthesia and Anoxia: (Section of Anaesthetics). PMID- 20916755 TI - Injuries to Peripheral Nerves: (Section of Orthopaedics). PMID- 20916770 TI - The Clinical Manifestations of Oxygen Lack: (Section of Anaesthetics). PMID- 20916771 TI - Spinal Anaesthesia with Heavy Percaine: (Section of Anaesthetics). PMID- 20916772 TI - Casualty Anaesthesia in the E.M.S: (Section of Anaesthetics). PMID- 20916775 TI - The Spread of Bacteria and Toxins from Infected Wounds; the Clinical Application of Laboratory Findings: (Section of Orthopaedics). PMID- 20916774 TI - A Report on Cases of Septic Arthritis: (Section of Orthopaedics). PMID- 20916776 TI - The Spread of Bacteria and Toxins from Infected Wounds; the Clinical Application of Laboratory Findings: (Section of Orthopaedics). PMID- 20916782 TI - Carcinoma of the OEsophagus. Results of Deep X-Ray Treatment. PMID- 20916780 TI - Chemotherapy, Serotherapy and Haemotherapy in Otology and Laryngology: (Sections of Otology and Laryngology). PMID- 20916803 TI - The Use of Vitallium in Surgery with Special Reference to Cup Arthroplasty: (Section of Orthopaedics). PMID- 20916804 TI - Sulphathiazole in the Treatment of War Wounds: (Section of Orthopaedics). PMID- 20916805 TI - Mechanical Fixation of Fractures: (Section of Orthopaedics). PMID- 20916806 TI - Orthopaedic Aspects of Plastic Surgery. The Early Replacement of Skin Losses in War Injuries of the Extremities: (Section of Orthopaedics). PMID- 20916807 TI - A Case of Osteomalacia: (Section of Obstetrics and Gynaecology). PMID- 20916813 TI - Idiopathic Steatorrhaea with Severe Anaemia and Pyrexia. PMID- 20916808 TI - Experience with the Intravenous Use of the Follicle-Stimulating Hormone of the Anterior Pituitary in Menstrual Disorders: (Section of Obstetrics and Gynaecology). PMID- 20916814 TI - Exophthalmic Ophthalmoplegia (Unilateral) with Papilloedema. PMID- 20916823 TI - Polycythaemia Rubra Vera. PMID- 20916816 TI - Fracture of the Skull in an Infant Associated with Haematoma Formation and Followed by Development of Encephalocele. PMID- 20916828 TI - Hydronephrosis Causing OEdema of the Legs. PMID- 20916846 TI - Some Orthopaedic Procedures Employed in the Treatment of Arthritis: (Section of Physical Medicine). AB - (1) A series of six cases of ankylosing spondylitis was shown to illustrate the benefit gained, even in very long-standing cases, by the following regime:(a) Complete rest in a plaster shell.(b) Gradual correction of kyphosis by adding thin layers of padding under the dorsolumbar junction, and subtracting similar layers of padding from under the head, to increase extension in the spine.(c) Deep-breathing exercises practised constantly while the patient is lying in a plaster shell.(d) Daily physiotherapy.(e) The fitting of a Goldthwaite spinal brace to maintain the position of maximum correction that has been obtained.The improvement was manifested in all cases by alleviation of symptoms, improvement in posture, and increased chest expansion.(2) A series of six cases of arthritis of the knee was shown, including rheumatoid arthritis, infective arthritis and osteo-arthritis, illustrating treatment by rest plasters, followed by:(a) Arthrotomy and lavage-where swelling and effusion persist, and(b) Bone drilling where bone changes are marked and there is constant pain at rest. Improvement was manifested by relief of symptoms, subsidence of signs of inflammation, and restoration of a considerable degree of movement.(3) A case of arthritis of the tarsal and metatarsal joints, illustrating relief of symptoms afforded by the application of a plaster boot. PMID- 20916862 TI - The Foot Problem in Service Cases: (Section of Orthopaedics). PMID- 20916863 TI - Psychological Reactions to Injury: (Section of Orthopaedics). PMID- 20916864 TI - Conditions of the Back Simulating Visceral Disease: (Section of Orthopaedics). PMID- 20916865 TI - Some Spinal Cases of Interest: (Section of Orthopaedics). PMID- 20916866 TI - Some Points in the Diagnosis of Osteochondritis of the Knee: (Section of Orthopaedics). PMID- 20916867 TI - Lumbar Puncture Injuries: (Section of Orthopaedics). PMID- 20916868 TI - The Role of Orthopaedics in Medical Education: (Section of Orthopaedics). PMID- 20916869 TI - The Conservative Treatment of Osteomyelitis: (Section of Orthopaedics). PMID- 20916870 TI - Physiotherapy and the Soldier's Foot: (Section of Orthopaedics). PMID- 20916871 TI - A Case of Degeneration of the Intervertebral Disc Following Lumbar Puncture: (Section of Orthopaedics). PMID- 20916872 TI - The Technique of Arthroplasty: (Section of Orthopaedics). PMID- 20916874 TI - Treatment of Fractures of the Shaft of the Femur: (Section of Orthopaedics). PMID- 20916891 TI - The Centenary of the First Anaethetic Use of Ether: (Section of Anaesthetics). PMID- 20916899 TI - Angiomatosis Retinae. Account of a Case, including the Histological Results of X Ray Treatment. PMID- 20916901 TI - Progress in Obstetrics and Gynaecology During the Present Century: President's Address. PMID- 20916905 TI - Cellular Naevus Resembling Lupus Vulgaris. PMID- 20916907 TI - Myxoedema Papulosum et Annulare. PMID- 20916914 TI - Discussion on Vitamins and Haemorrhagic States. PMID- 20916909 TI - Lichen Simplex Controlled by Stilboestrol. PMID- 20916930 TI - Discussion on Cerebral OEdema. PMID- 20916923 TI - Trichlorethylene as a General Analgesic and Anaesthetic. PMID- 20916948 TI - Haemospermia. PMID- 20916968 TI - Recurring Juvenile Vitreous Haemorrhage: President's Address. PMID- 20916982 TI - Discussion on Nutritional Anaemia in Children and Women: A War-time Problem. PMID- 20916974 TI - Naevus Flammeus Treated by Thorium X. PMID- 20917007 TI - R.C.A.M.C. Anaesthetic Experiences: Dieppe Raid Casualties, August 19-20, 1942. PMID- 20917010 TI - The AEtiology of Erythroblastosis Foetalis and Certain Haemolytic Transfusion Reactions, with Special Reference to the Rh Factor. PMID- 20917020 TI - Naevocarcinoma (Malignant Melanoma). PMID- 20917027 TI - Lichen Ruber Moniliformis (Morbus Moniliformis Lichenoides; Myxoedema Moniliforme.). PMID- 20917049 TI - The Emancipation of Orthopaedic Surgery. PMID- 20917058 TI - Carcinoma of OEsophagus-Treated by Excision and Reconstruction of Ante-thoracic OEsophagus. PMID- 20917059 TI - Specimen of Ante-thoracic OEsophagus. PMID- 20917060 TI - Hypoglycaemia as an Experimental Psychosis. PMID- 20917066 TI - Discussion on Medico-Legal Pitfalls in Obstetrical and Gynaecological Practice excluding Abortion. PMID- 20917073 TI - Recovery of Speech Following the Evacuation of Subcortical Haematoma-Report of Three Cases. PMID- 20917082 TI - Trichlorethylene Anaesthesia by the Single-Dose Method. PMID- 20917086 TI - A Method of Keeping Anaesthetic Records and Assessing Results. PMID- 20917097 TI - Discussion on the Present Position of the Lower Segment Caesarean Operation. PMID- 20917095 TI - Discussion on Anaesthesia and Analgesia in Obstetrical Practice. PMID- 20917098 TI - A Case of Pregnancy Complicated by Convulsions due to Cysticercosis Cellulosae. PMID- 20917099 TI - Discussion on the Diagnosis and Treatment of the Acute Abdomen from the Gynaecological Point of View. PMID- 20917103 TI - The AEtiology of Erythema Nodosum. Abstract. PMID- 20917118 TI - Idiopathic Haemorrhagic Sarcoma of Kaposi. PMID- 20917119 TI - Early Kraurosis Valvae in a Child. PMID- 20917139 TI - Carcinoma of OEsophagus: Resection and OEsophago-gastrostomy. PMID- 20917134 TI - The Cancer Problem from the Point of View of the Young Gynaecologist: President's Address. PMID- 20917140 TI - Case of Partial OEsophagectomy for Carcinoma with Extrathoracic Gastro oesophageal Anastomosis. PMID- 20917141 TI - Two Cases of OEsophagectomy and Anterior OEsophagoplasty. PMID- 20917142 TI - Transthoracic Resection of Carcinoma of the Cardia with Involvement of the Lower End of the OEsophagus, and OEsophago-gastrostomy. PMID- 20917143 TI - Haemangiectatic Hepatoma. PMID- 20917144 TI - Psoas Abscess Containing Gas and Faeces, Secondary to a Fistula from the Caecum. PMID- 20917185 TI - Mediastinal Tumour (? Thymoma) with Gynaecomastia. PMID- 20917187 TI - Haemangio-Endothelioma of Chest Wall. PMID- 20917203 TI - Orthopaedic Surgery and the Future [Abridged]. PMID- 20917202 TI - The Contribution of Orthopaedic Surgery to Hospital Development: President's Address. PMID- 20917215 TI - Amputation Under Ice Anaesthesia [Abridged]. PMID- 20917230 TI - Lepra Maculo-anaesthetica. PMID- 20917229 TI - Case for Diagnosis. ? Staphylococcal Eruption. PMID- 20917240 TI - Discussion on the Treatment of Carcinoma of the OEsophagus. PMID- 20917241 TI - The Diagnosis and Treatment of Infections of the Male Genital Organs other than Tuberculosis and Gonorrhoea [Abridged]. PMID- 20917267 TI - Epithelioma Adenoides Cysticum (Naevus Follicularis of Brooke). PMID- 20917292 TI - Discussion on Parenteral Diarrhoea. PMID- 20917264 TI - Leiomyoma. ? Fibrocellular naevus. PMID- 20917304 TI - Discussion on Anaesthesia and Analgesia in Abdominal Operations: Joint Discussion No. 4. PMID- 20917303 TI - Electrocardiographic Changes during Trilene Anaesthesia. PMID- 20917359 TI - Discussion on Advanced Cases of Carcinoma of the Breast treated by Stilboestrol. PMID- 20917369 TI - Haemorrhagic Coats's Disease. PMID- 20917381 TI - Staphylococcal Septicaemia. Osteomyelitis of Pelvis. Recovery. PMID- 20917383 TI - Staphylococcal Septicaemia. Osteomyelitis of Femur. Penicillin Therapy. PMID- 20917385 TI - Interauricular Septal Defect. Haemoptyses. PMID- 20917396 TI - Eosinophilic Granuloma. ? Sarcoid of Boeck. PMID- 20917400 TI - OEsophagectomy. PMID- 20917402 TI - Idiopathic Steatorrhoea: Osteomalacia. PMID- 20917403 TI - Massive Renal Calculi. Squamous-Celled Carcinoma in Lung, ? Primary. ? Secondary to Growth in Renal Pelvis. PMID- 20917425 TI - Left Conjunctival Epithelioma. ? Atypical Mooren's Ulcer Superimposed on Old Mustard-Gas Damage. PMID- 20917413 TI - Pigmentation. ? Pellagra. PMID- 20917451 TI - Discussion on Anaesthesia in the Dental Chair. PMID- 20917450 TI - Haemorrhagic Telangiectasia. PMID- 20917456 TI - Experimental Foetal Death: The Surviving Placenta. PMID- 20917463 TI - (I) Intrasternal Anaesthesia [Abridged]. PMID- 20917467 TI - Cases:-Sarcoma of Cervix. Primary Carcinoma of Fallopian Tube. Primary Sarcoma of Fallopian Tube. Grossesse Extramembraneuse. An Unusual Ectopic Pregnancy. Chocolate Cysts of the Ovary (Ovarian Endometriosis) and Pregnancy: A Report of Two Cases Occurring in Sisters. Acromegaly with Pregnancy. Anaemia in a Rhesus negative Woman during Pregnancy with a Rhesus-positive Foetus. Breech Presentation with Fracture of the Foetal Neck: Recovery. Ulceration of the Mouth Associated with Recurrent Ulceration of Vulva. Tuberculosis of the Cervix, Uterus and Appendages. Necrosis of the Liver and Massive Bilateral Suprarenal Haemorrhage in a Puerperal Woman. Torsion of the Pregnant Uterus. Rupture of the Symphysis Pubis. Symphyseal Osteo-arthropathy. Rupture of the Uterus Self produced. Hydatidiform Mole with a 16-Weeks Foetus. Papillary Cystic Carcinoma. Granulosa-cell Carcinoma. Papillomatous Adenoma. Retroperitoneal Haemorrhage Causing Death in a Woman near Term. PMID- 20917468 TI - Multiple Minute Fibro-angiomata of Face and Ears (Pringle's Disease, Darier's Type). ? Morphoea with Tuberculous Histology: ? Necrobiosis Lipoidica. Mucin in Granuloma Annulare. Angiokeratoma. A Form of "Mamillated Tongue". Sarcoidosis. PMID- 20917476 TI - Discussion on Subdural Haematoma in Infancy. PMID- 20917479 TI - Steatorrhoea due to Lymphatic Obstruction. PMID- 20917500 TI - Sudden Onset of Tachycardia and Arrhythmia. Paroxysmal Auricular Tachycardia with Atrio-Ventricular Block. ? Mitral Stenosis. PMID- 20917486 TI - The Force of Expiration as a Sign in Anaesthesia [Abbreviated]. PMID- 20917501 TI - Aplastic Anaemia Treated by Splenectomy. PMID- 20917507 TI - Carcinoma of the OEsophagus. Radical Resection with OEsophago-gastrostomy for a Midthoracic Growth by a Right Transpleural Approach. PMID- 20917506 TI - Carcinoma of Lower End of OEsophagus. Radical Resection with OEsophagogastrostomy by a Left Transpleural Approach. PMID- 20917525 TI - Anaesthesia in Operations for Closure of Patent Ductus Arteriosus [Abridged]. PMID- 20917527 TI - A Brief Account of Anaesthetics given in a Field Surgical Unit in the B.L.A. PMID- 20917532 TI - Rickets Resistant to Vitamin D: Healing with Very Heavy Dosage of Vitamin D, Fluctuations in Vitamin D Requirement, Development of Hypercalcaemia. PMID- 20917542 TI - Acroparaesthesia. [A Summary]. PMID- 20917545 TI - The Consideration of Functional Disabilities in Orthopaedics. PMID- 20917557 TI - Anaesthesia for Surgery of Nasal Sinuses. PMID- 20917581 TI - Conservative Treatment of Volkmann's Ischaemic Contracture. PMID- 20917609 TI - Multiple Chronic Ulcers of the Upper Trunk in a Young Woman. ? Acne Conglobata. PMID- 20917610 TI - Multiple Chronic Ulcers of the Arms and Trunk. ? Cause. PMID- 20917621 TI - Pulmonary Haemosiderosis. PMID- 20917622 TI - Refractory Anaemia. PMID- 20917623 TI - Nephrocalcinosis associated with Hyperchloraemia. PMID- 20917624 TI - Two Cases of Banti's Syndrome: Hepatomegaly with Anaemia. PMID- 20917627 TI - Trigeminal Naevus and Homolateral Intracranial Angioma associated with Hypertelorism. PMID- 20917642 TI - Spinal Anaesthesia and its Effect on a Case of Hydronephrosis and Hydro-ureter. PMID- 20917669 TI - Personnel Selection: By Whom ? PMID- 20917663 TI - Anaesthesia for Ear, Nose and Throat Surgery. PMID- 20917670 TI - Discussion on the Toxaemia of Gas Gangrene. PMID- 20917677 TI - Para-oesophageal Hernia as a Cause of Recurrent Gastro-intestinal Haemorrhage. PMID- 20917679 TI - Chronic Haemolytic Polycythaemia. PMID- 20917682 TI - OEsophagectomy for Carcinoma. Ante-thoracic Jejunal Graft. PMID- 20917684 TI - Chronic Myeloid Leukaemia: Goitre and Raised B.M.R. PMID- 20917713 TI - DISCUSSION ON ANAESTHETICS IN TROPICAL CLIMATES. PMID- 20917706 TI - Laryngeal Granuloma following Intratracheal Anaesthesia. PMID- 20917714 TI - A Milestone in Anaesthesia?: (d-Tubocurarine Chloride). PMID- 20917715 TI - DISCUSSION ON CARCINOMA OF LOWER OESOPHAGUS AND CARDIA. PMID- 20917737 TI - Gynaecomastia with Bilateral Undescended Testes in a Man aged 21. PMID- 20917741 TI - Male Gynaecomastia: Testicular Atrophy. PMID- 20917743 TI - Some Observations on the AEtiology and Treatment of Sprue. PMID- 20917750 TI - DISCUSSION ON BACTERIAEMIA IN PUERPERAL SEPSIS. PMID- 20917749 TI - DISCUSSION ON PLACENTA PRAEVIA. PMID- 20917768 TI - Intravenous Pentothal as the Sole Anaesthetic for Tonsillectomy. PMID- 20917761 TI - Suprarenal Haemorrhage Complicating the Puerperium. PMID- 20917782 TI - The Treatment of Coeliac Disease with Vitamin B Complex and Liver Extract. PMID- 20917781 TI - Spontaneous Hypoglycaemia in Infancy and Childhood. PMID- 20917793 TI - DISCUSSION ON LEUKAEMIA AND LEUKOSIS IN MAN AND ANIMALS. PMID- 20917790 TI - Arterial Advances of Orthopaedic Concern. PMID- 20917799 TI - The Surgical Complications of Amoebic Dysentery. PMID- 20917810 TI - A New OEsophagoscope. PMID- 20917825 TI - Case for Diagnosis.? Reticulosis.? Circumscribed Myxoedema. PMID- 20917832 TI - Haemorrhagic Telangiectasia of Rendu-Osler-Weber, with No Family History. PMID- 20917830 TI - Injuries of the Cervical Vertebrae: President's Address. PMID- 20917843 TI - Total Gastrectomy with OEsophagoduodenal Anastomosis. PMID- 20917834 TI - Haemorrhagic Telangiectasia of Rendu-Osler-Weber. PMID- 20917846 TI - The Development of Inhalation Anaesthesia in the Second Half of the Nineteenth Century. PMID- 20917857 TI - Myelosclerosis with Leukaemoid Blood Picture. PMID- 20917870 TI - Retinal Haemorrhage with Mitral Incompetence. PMID- 20917879 TI - Case for Diagnosis. ? Diabetes Mellitus with Diabetes Insipidus. PMID- 20917873 TI - Chromophobe Adenoma in a Male Aged 151/2 Years. PMID- 20917895 TI - DISCUSSION: SHOCK WITH SPECIAL REFERENCE TO ANAESTHESIA. PMID- 20917891 TI - Intracranial Haemangioma Causing Convulsions. PMID- 20917897 TI - Studies on the Haematology of the Horse, Ox and Sheep. PMID- 20917911 TI - Impetigo Herpetiformis. ? Pemphigus Vegetans. PMID- 20917914 TI - Erythrodermia in Lymphatic Leukaemia. (Malignant Erythrodermia). PMID- 20917915 TI - Epidermodysplasia of Lewandowski and Lutz. ? Abortive Form of Blastomycosis or Chromoblastomycosis. PMID- 20917921 TI - Myxoedema Circumscriptum. PMID- 20917922 TI - Nodules in Abdominal Wall for Diagnosis. ? Fibrosarcoma (Darier and Ferrand). PMID- 20917925 TI - DISCUSSION: ANAESTHESIA FOR ABDOMINO-PERINEAL OPERATIONS FOR CANCER OF THE RECTUM. PMID- 20917933 TI - Anterior Ethmoidal Haemorrhage. PMID- 20917953 TI - THE AETIOLOGY OF CHRONIC RHEUMATISM: Joint Discussion No. 1. PMID- 20917958 TI - DISCUSSION ON THE MANAGEMENT OF THE NORMAL THIRD STAGE OF LABOUR AND OF HAEMORRHAGE THEREIN. PMID- 20917971 TI - OEsophageal Carcinoma Treated by Resection and Presternal OEsophago-Gastrostomy. PMID- 20917970 TI - Sclerodactylia with OEsophageal Lesion (3 Cases). PMID- 20917983 TI - Poikiloderma ? Premycosis. PMID- 20917981 TI - Hyperkeratotic Systematized Naevus with ? Bromide Eruption. PMID- 20917987 TI - Leukaemia Cutis ? Myeloid Leukaemia. PMID- 20918000 TI - Raynaud's Phenomenon, with Paroxysmal Haemoglobinuria, Caused by Cold Haemagglutination. PMID- 20917995 TI - Chondro-osteodystrophy. ? Morquio. PMID- 20918006 TI - Morphoea Guttata. PMID- 20918005 TI - Blue Naevus in a Mongolian Patch. PMID- 20918015 TI - Congenital Defect of Scalp. PMID- 20918016 TI - Pneumatocoele Occurring During Pneumonia and Rupturing to Form a Pneumothorax. PMID- 20918022 TI - DISCUSSION ON ANAESTHESIA IN CHILDREN. PMID- 20918023 TI - DISCUSSION ON ANAESTHESIA FOR CAESAREAN SECTION. PMID- 20918030 TI - Skin Temperature as a Clinical Aid During Anaesthesia [Abridged]. PMID- 20918044 TI - DISCUSSION ON CEREBRAL OEDEMA. PMID- 20918051 TI - Myxoedema Papulosum. PMID- 20918057 TI - Three Cysts in the Same Mandible, Not of Dental Origin. ? Solitary Cysts or Osteitis Fibrosa. PMID- 20918063 TI - Hoemophilus influenzoe and its Relation to Epidemic Influenza: President's Address. PMID- 20918082 TI - Brief Note on the Contributions of the late Sir Henry Gauvain to Orthopaedic Surgery. PMID- 20918136 TI - Toxic Thyroid Adenoma. Generalized Osteoporosis with Collapse of Some Vertebrae. PMID- 20918149 TI - Chronic Lymphatic Leukaemia with Haemolytic Anaemia. Splenectomy. PMID- 20918157 TI - Nodular Subcutaneous Haemangiomatosis. PMID- 20918158 TI - Polycythaemia with Myelosclerosis. PMID- 20918172 TI - Spontaneous Hypoglycaemia, ? Hepatogenous. PMID- 20918160 TI - Malignant Exophthalmos with Ophthalmoplegia and Localized Myxoedema. PMID- 20918177 TI - Coarctation of the Aorta with Congenital OEdema of the Feet. PMID- 20918195 TI - Urethral Fistulae from Surgical Trauma [Abstract]. PMID- 20918212 TI - Neurological Sequelae in Repatriated Prisoners of War from Hong Kong: A Follow-up [Abstract]. PMID- 20918262 TI - The Significance of Haemophilus influenzae in Chronic Bronchiectasis of Children. PMID- 20918242 TI - The Reduction of Operative Bleeding by T-Piece Anaesthesia [Summary]. PMID- 20918267 TI - Haemangioma with Thrombocytopenia. PMID- 20918283 TI - Posture During Anaesthesia [Abstract]. PMID- 20918299 TI - Essential Hyperlipaemia and Primary Hypercholesterolaemia. PMID- 20918307 TI - Malignant Haemangioblastoma of Liver. Total Excision of Right Lobe of Liver. PMID- 20918304 TI - Injury as An AEtiological Factor in Tuberculosis. PMID- 20918330 TI - A Historical Note on Queen Charlotte's Maternity Hospital and its Paediatricians. PMID- 20918333 TI - Cardiospasm and Epithelioma of OEsophagus Treated by OEsophagectomy. PMID- 20918341 TI - The Changing AEtiology of Erythema Nodosum in Children [Summary]. PMID- 20918343 TI - The Association of Acute Appendicitis with Infective Diarrhoea. PMID- 20918345 TI - Medico-legal Adventures and Misadventures in Gynaecology and Obstetrics [Abridged]. PMID- 20918364 TI - Phaeochromocytoma. PMID- 20918365 TI - The Surgical and Prosthetic Importance of the Labial and Buccal Vestibule of the Maxillae [Abstract]. PMID- 20918395 TI - Painful Enteromegaly of Unknown AEtiology. PMID- 20918396 TI - Intracerebral Haemorrhage and Brain-stem Compression Treated Initially by Hypotension and Later by Evacuation of the Haematoma. PMID- 20918413 TI - Neonatal Ischaemic Gangrene of the Lower Leg. PMID- 20918418 TI - Discussion on the AEtiology of Mental Defect [Abridged]. PMID- 20918424 TI - Gynaecomastia Persisting after OEstrogen Therapy for Acne. PMID- 20918444 TI - Hereditary Haemorrhagic Telangiectasia. PMID- 20918449 TI - Urinary OEstrogen Metabolites of 19-Norethisterone and its Esters [Summary]. PMID- 20918451 TI - Some Thoughts on the Antibiotic Therapy of Orthopaedic Tuberculosis [Summary]. PMID- 20918458 TI - Some Observations on Neuromuscular Disorders of the OEsophagus [Summary]. PMID- 20918462 TI - A Prospective Study of the Leukaemia Mortality of Children Exposed to Ante-natal Diagnostic Radiography-A Preliminary Report [Summary]. PMID- 20918463 TI - Geographical Variation in Leukaemia Mortality in Relation to Background Radiation Epidemiological Studies [Summary]. PMID- 20918486 TI - Anaesthesia for Emergency Surgery in Children [Summary]. PMID- 20918500 TI - Congenital Tracheo-oesophageal Fistula. PMID- 20918514 TI - Pseudoxanthoma Elasticum:Severe Melaena from the Jejunum Treated by Resection. PMID- 20918530 TI - The Changing Pattern of Paediatrics in a Children's Hospital 1876-1961. PMID- 20918537 TI - Idiopathic Hyperlipaemia with Glycosuria. PMID- 20918565 TI - Myxoedema and Trauma (Two Cases). PMID- 20918566 TI - Epilepsy Due to Angioneurotic OEdema. PMID- 20918567 TI - Spontaneous Rupture of OEsophagus. PMID- 20918570 TI - Gout, Megaloblastic Anaemia and Steatorrhoea. PMID- 20918572 TI - Congenital Hypogammaglobulinaemia and Megaloblastic Anaemia Presenting as a Case of Bronchiectasis. PMID- 20918588 TI - Observations During Hypotensive Anaesthesia [Abridged]. PMID- 20918594 TI - Myxoedema with Thyroid Antibodies Presenting with Ascites. PMID- 20918599 TI - Acute Renal Failure and the Artificial Kidney in Obstetrics and Gynaecology. PMID- 20918600 TI - Hyperglobulinaemic Purpura. PMID- 20918750 TI - A Study of Healing in the Anal Canal and of the Severity of Post-operative Pain after Haemorrhoidectomy [Abridged]. PMID- 20918784 TI - Double Uterus with Unilateral Haematocolpos and Absence of the Ipsilateral Kidney. PMID- 20918788 TI - Diagnostic Problems in Pregnancy: Severe Laevorotation of the Uterus. PMID- 20918819 TI - Symposium: Haemolytic Anaemias. PMID- 20918807 TI - Hypercalcaemia and Hypoglycaemia Associated with Tumours. PMID- 20918821 TI - Symposium: Haemolytic Anaemias. PMID- 20918820 TI - Symposium: Haemolytic Anaemias. PMID- 20918839 TI - The Pathology and Chemistry of Experimental OEdema in the Brain. PMID- 20918848 TI - Haemorrhoidectomy, a New Method [Summary]. PMID- 20918860 TI - Infertility and the hypothalamus [abridged]. PMID- 20918861 TI - Asbestos and mesothelioma of the pleura [abridged]. PMID- 20918862 TI - Asbestos and mesothelioma of the pleura [abridged]. PMID- 20918863 TI - Polyps and cancer [abridged]. PMID- 20918864 TI - Polyps and cancer [abridged]. PMID- 20918865 TI - Polyps and cancer [abridged]. PMID- 20918866 TI - Polyps and cancer [abridged]. PMID- 20918867 TI - Haemorrhoids [abridged]. PMID- 20918868 TI - Haemorrhoids [abridged]. PMID- 20918869 TI - Chronic ulcerative colitis in childhood. PMID- 20918870 TI - Ivalon wrap operation for rectal prolapse. PMID- 20918871 TI - Management of a colostomy. PMID- 20918872 TI - Operations for Severe Ulcerative Colitis with Reference to Advantages of Ileorectal Anastomosis over Permanent Ileostomy. PMID- 20918873 TI - Disorders of colonic motility. PMID- 20918874 TI - Epidemiology of cancer of the large intestine. PMID- 20918875 TI - The origin of faecal fat. PMID- 20918876 TI - Cryptogenic ulcerous colitis and mucohaemorrhagic (later ulcerated) rectocolitis [summary]. PMID- 20918877 TI - Symposium: the handicapped child [abridged]. PMID- 20918878 TI - Symposium: the handicapped child [abridged]. PMID- 20918879 TI - Symposium: the handicapped child [abridged]. PMID- 20918880 TI - Symposium: the handicapped child [abridged]. PMID- 20918881 TI - Symposium: the handicapped child [abridged]. PMID- 20918882 TI - Symposium: the handicapped child [abridged]. PMID- 20918883 TI - Symposium: the handicapped child [abridged]. PMID- 20918884 TI - Symposium: the handicapped child [abridged]. PMID- 20918885 TI - The assessment of renal function tests. PMID- 20918886 TI - Rhesus Iso-immunization. PMID- 20918887 TI - Rhesus Iso-immunization. PMID- 20918888 TI - Rhesus Iso-immunization. PMID- 20918890 TI - An immunological approach to tumour therapy. PMID- 20918889 TI - Rhesus Iso-immunization. PMID- 20918891 TI - Treatment of carcinoma of the colon complicated by large abscesses [abstract]. PMID- 20918894 TI - Medical management of Crohn's disease: a 'holding operation'. PMID- 20918892 TI - Colonic exclusion for portasystemic encephalopathy. PMID- 20918895 TI - Reticulosis and steatorrhoea. PMID- 20918896 TI - Mental sequelae of head injury. PMID- 20918897 TI - Mental sequelae of head injury. PMID- 20918898 TI - Two surveys of children [abridged]. PMID- 20918899 TI - Tumours of the parotid gland. PMID- 20918900 TI - Anaesthesia for the respiratory cripple. PMID- 20918901 TI - The pattern of anaesthesia in a general hospital [abstract]. PMID- 20918903 TI - Inaugural meeting. PMID- 20918902 TI - Traumatic conductive deafness. PMID- 20918904 TI - Fundamental advances in dental ceramics [abstract]. PMID- 20918906 TI - Radioimmunoassays [abridged]. PMID- 20918905 TI - Radioimmunoassays [abridged]. PMID- 20918907 TI - Radioimmunoassays [abridged]. PMID- 20918908 TI - Backache in industry. PMID- 20918909 TI - Ischaemic diseases of the colon [abridged]. PMID- 20918911 TI - Ischaemic diseases of the colon [abridged]. PMID- 20918910 TI - Ischaemic diseases of the colon [abridged]. PMID- 20918912 TI - Ischaemic diseases of the colon [abridged]. PMID- 20918914 TI - Work in progress [abridged]. PMID- 20918913 TI - Ischaemic diseases of the colon [abridged]. PMID- 20918915 TI - Work in progress [abridged]. PMID- 20918917 TI - Work in progress [abridged]. PMID- 20918916 TI - Work in progress [abridged]. PMID- 20918918 TI - The significance of oxygen measurement. PMID- 20918920 TI - Vesicovaginal fistula [abridged]. PMID- 20918919 TI - Pulmonary hypersensitivity reactions to inhaled antigens [abridged]. PMID- 20918921 TI - Tissue conditioners and functional impression materials [abridged]. PMID- 20918922 TI - Stricture of the lower oesophagus. PMID- 20918924 TI - Biomechanics. PMID- 20918923 TI - The training and education of a surgeon. PMID- 20918925 TI - Anhydrotic ectodermal dysplasia. PMID- 20918926 TI - Generalized hyperkeratosis -? Ichthyosiform erythrodermia. Psoriasis. PMID- 20918928 TI - Dogger bank itch [abridged]. PMID- 20918927 TI - Applied electrophysiology in nerve and muscle disease [abridged]. PMID- 20918929 TI - A historical exhibition from the norfolk and norwich hospital. PMID- 20918930 TI - Medical Education in our Time [Synopsis]. PMID- 20918931 TI - Intensive care units [abridged]. PMID- 20918932 TI - Assessment of antitussives and limitation of measurements of sputum viscosity [abstract]. PMID- 20918933 TI - Scope and limitations of computers for the medical user [abstract]. PMID- 20918934 TI - The Critical Electrical Stimulus which Causes Uterine Pain. PMID- 20918935 TI - The effect of organochlorine pesticides on wildlife, domestic animals and man [abridged]. PMID- 20918936 TI - Value of prospective studies. PMID- 20918937 TI - One hundred years after john conolly. PMID- 20918938 TI - Studies with drugs and hormones on the human colon [abridged]. PMID- 20918939 TI - Terminal disinfection of infant feeds [summary]. PMID- 20918940 TI - Aspects of psychiatry in the elderly. PMID- 20918941 TI - Aspects of psychiatry in the elderly. PMID- 20918942 TI - Inaugural meeting. PMID- 20918944 TI - Rheumatoid pericarditis. PMID- 20918943 TI - Crohn's Disease, Presenting as Chronic Bartholin's Abscesses. PMID- 20918945 TI - Automation possibilities in ophthalmology [abstract]. PMID- 20918946 TI - Management of cardiac arrhythmia. PMID- 20918947 TI - The intrauterine contraceptive device. PMID- 20918948 TI - The intrauterine contraceptive device. PMID- 20918949 TI - The dawn of state medicine in britain. PMID- 20918950 TI - The dawn of state medicine in britain. PMID- 20918951 TI - Vocational training in general practice. PMID- 20918953 TI - Injuries of the leg in football and ballet. PMID- 20918952 TI - On some aspects of cerebral degeneration in later life. PMID- 20918954 TI - Injuries of the leg in football and ballet. PMID- 20918955 TI - Injuries of the leg in football and ballet. PMID- 20918956 TI - Odontology and malignancy. PMID- 20918957 TI - A Three-dimensional Approach to the Microscopy of the Periodontal Membrane. PMID- 20918958 TI - Tibial diaphysectomy for acute osteomyelitis. PMID- 20918959 TI - Phagedaenic ulcer of the thigh. PMID- 20918960 TI - Familial Recurrent Dislocation of the Head of the Fibula (2 cases). PMID- 20918961 TI - Traumatic thrombosis of the external iliac artery. PMID- 20918962 TI - Chondrosarcoma of scapula associated with diaphyseal aclasia. PMID- 20918963 TI - Leprosy finger. PMID- 20918964 TI - Recurrent dislocation of the elbow. PMID- 20918965 TI - Hydatid of sacrum. PMID- 20918966 TI - Osteosarcoma of left pubis. PMID- 20918967 TI - Bilateral avascular necrosis of femoral head. PMID- 20918968 TI - Mastocytosis: an unusual presentation. PMID- 20918969 TI - A psychological setting of somatic disease: the 'giving up - given up' complex. PMID- 20918970 TI - The pink spot. PMID- 20918972 TI - The experimental study of psychotic children. PMID- 20918971 TI - The pink spot. PMID- 20918973 TI - The experimental study of psychotic children. PMID- 20918974 TI - Some hazards of pelvic surgery. PMID- 20918975 TI - The Seed-bag and the Urn. PMID- 20918976 TI - The royal college of physicians of ireland and some of its famous personalities. PMID- 20918977 TI - Antibodies-structure and biological function. PMID- 20918978 TI - Antibodies-structure and biological function. PMID- 20918980 TI - Perforating injuries of the globe [abridged]. PMID- 20918979 TI - Antibodies-structure and biological function. PMID- 20918981 TI - Perforating injuries of the globe [abridged]. PMID- 20918982 TI - Perforating injuries of the globe [abridged]. PMID- 20918983 TI - Headache. PMID- 20918984 TI - The management of anaesthesia in sickle cell States [abridged]. PMID- 20918986 TI - Drug therapy of infertility. PMID- 20918985 TI - The management of anaesthesia in sickle cell States [abridged]. PMID- 20918987 TI - The remote effects of cancer on the nervous system. PMID- 20918988 TI - The remote effects of cancer on the nervous system. PMID- 20918990 TI - Specialist Training in Great Britain today as seen by a Trainee. PMID- 20918989 TI - Specialist Training in Great Britain today as seen by a Trainee. PMID- 20918991 TI - Three Hundred Cases of Parotid Tumours with Special Reference to the Management of Giant Cell Dumb-bell Tumours [Summary]. PMID- 20918992 TI - Medical research council radiation research at the hammersmith hospital. PMID- 20918993 TI - Medical research council radiation research at the hammersmith hospital. PMID- 20918994 TI - Auditory communication [summary]. PMID- 20918995 TI - Auditory communication [summary]. PMID- 20918996 TI - Auditory communication [summary]. PMID- 20918997 TI - Auditory communication [summary]. PMID- 20918998 TI - Mechanical and physiological properties of bone. PMID- 20918999 TI - Mechanical and physiological properties of bone. PMID- 20919000 TI - The northwick park project [abstract]. PMID- 20919001 TI - Surgical care of the hand. PMID- 20919002 TI - Surgical care of the hand. PMID- 20919003 TI - Symposium: speech, learning and child health. PMID- 20919005 TI - Early treatment of multiple injuries [abridged]. PMID- 20919004 TI - Early treatment of multiple injuries [abridged]. PMID- 20919006 TI - Early treatment of multiple injuries [abridged]. PMID- 20919008 TI - Early treatment of multiple injuries [abridged]. PMID- 20919007 TI - Early treatment of multiple injuries [abridged]. PMID- 20919009 TI - Early treatment of multiple injuries [abridged]. PMID- 20919010 TI - Protein metabolism. PMID- 20919011 TI - Protein metabolism. PMID- 20919012 TI - Impurities in nitrous oxide [abridged]. PMID- 20919013 TI - Impurities in nitrous oxide [abridged]. PMID- 20919014 TI - Impurities in nitrous oxide [abridged]. PMID- 20919015 TI - Impurities in nitrous oxide [abridged]. PMID- 20919016 TI - Ballistocardiography and ischaemic heart disease: predictive considerations and statistical evaluation. PMID- 20919017 TI - Diagnosis and treatment of monocytic leukaemia [summary]. PMID- 20919019 TI - Microangiography in retinal vascular occlusion [abstract]. PMID- 20919018 TI - The doubtful optic disc [summary]. PMID- 20919021 TI - The life cycle of the temporomandibular joint. PMID- 20919020 TI - Recent Advances in Neuro-ophthalmology [Summary]. PMID- 20919023 TI - An elastic vascular prosthesis. PMID- 20919022 TI - Ruptured aortic aneurysm as an abdominal emergency. PMID- 20919024 TI - Radiology in renal transplants [summary]. PMID- 20919026 TI - Inferior vena cavography after partial caval occlusion [summary]. PMID- 20919025 TI - Drip infusion cholangiography. PMID- 20919027 TI - Thermography [summary]. PMID- 20919028 TI - Anterior hypophysitis associated with autoimmune disease [summary]. PMID- 20919029 TI - The use of the placenta in human biochemical genetics with special reference to twin placentation and zygosity [summary]. PMID- 20919030 TI - Practical medical history [summary]. PMID- 20919031 TI - Are there emotional causes of obesity? [Summary]. PMID- 20919032 TI - Villous tumours of the rectosigmoid [abstracts]. PMID- 20919033 TI - Villous tumours of the rectosigmoid [abstracts]. PMID- 20919034 TI - Villous tumours of the rectosigmoid [abstracts]. PMID- 20919035 TI - Communication between Doctors and Patients. PMID- 20919036 TI - Communication between Doctors and Patients. PMID- 20919037 TI - Communication between Doctors and Patients. PMID- 20919038 TI - Hypernatraemia in a patient with ectopic pinealoma. PMID- 20919039 TI - Bladder emptying by nerve and muscle stimulation. PMID- 20919040 TI - Film on bladder stimulators. PMID- 20919041 TI - Record Linkage Techniques in Studies of the aetiology of Cancer. PMID- 20919042 TI - Use and abuse of advertising in medicine. PMID- 20919043 TI - Myasthenia gravis: clinical aspects. PMID- 20919045 TI - FructosaeMia [Summary]. PMID- 20919044 TI - Well-population Screening. PMID- 20919046 TI - Chromosomal deletion syndromes [summary]. PMID- 20919047 TI - Ultrasonic diagnosis of intraocular tumours. PMID- 20919049 TI - The Burnt Child and his Family [Abridged]. PMID- 20919048 TI - The Burnt Child and his Family [Abridged]. PMID- 20919050 TI - Salivary gland tumours [abridged]. PMID- 20919051 TI - Salivary gland tumours [abridged]. PMID- 20919052 TI - Salivary gland tumours [abridged]. PMID- 20919053 TI - Salivary gland tumours [abridged]. PMID- 20919054 TI - Diffuse pulmonary fibrosis [abstract]. PMID- 20919056 TI - Diffuse pulmonary fibrosis [abstract]. PMID- 20919055 TI - Diffuse pulmonary fibrosis [abstract]. PMID- 20919057 TI - Vocal disabilities of singers [abridged]. PMID- 20919059 TI - Chairman's Summing-up. PMID- 20919058 TI - Chairman's Introduction. PMID- 20919060 TI - Thyroid stimulating factor in the serum of immunized rabbits. PMID- 20919062 TI - Medical education and the common market. PMID- 20919061 TI - Toxic chemicals and peripheral neuropathy. PMID- 20919063 TI - Medical education and the common market. PMID- 20919064 TI - Medical education and the common market. PMID- 20919065 TI - Congestive Cardiac Failure due to Secondary Amyloidosis. PMID- 20919066 TI - Transient Choreo-athetosis Following Hypernatraemia [Summary]. PMID- 20919068 TI - Metrication in medical journals: a conference of editors. PMID- 20919067 TI - Introduction. PMID- 20919069 TI - An interdisciplinary approach to measurement. AB - This meeting had as its theme the importance of good communications between workers in different disciplines. Papers and demonstrations were presented on a range of topics as apparently unrelated as the intraocular pressure, the tension of nitrogen in blood, and the experimental production of mesothelial tumours. In his introduction Dr J C Gilson showed how these were some recent end-products of research into pneumoconiosis. The work of the Pneumoconiosis Research Unit was centred round the properties of airborne dust and the acute and long-term effects of its inhalation. Studies ranged from the immunological responses of coal workers to surveys of men in some of the world's major asbestos fields; the latter were selected on account of the exposure to dust differing from that of workers in the UK in being confined to a single type of fibre. One link between the different studies was the features of the chest radiographs. For rounded opacities these were now read using the ILO Classification which was largely developed at the Unit; Dr Gilson demonstrated a recent extension to include the irregular opacities which are associated with exposure to asbestos. PMID- 20919070 TI - Infectious complications of transplantation surgery. PMID- 20919072 TI - Still's Disease Followed into Adult Life. PMID- 20919075 TI - Chairman's Closing Remarks. PMID- 20919074 TI - Chairman's Introduction. PMID- 20919073 TI - Carcinoma of the urachus [summary]. PMID- 20919076 TI - Cutaneous ulceration in Crohn's disease [summary]. PMID- 20919077 TI - Embryology. PMID- 20919078 TI - A controlled trial of conservative treatment for early breast cancer. PMID- 20919080 TI - Subphrenic abscess: the place of antibiotics. PMID- 20919079 TI - The prognostic implication of treatment. PMID- 20919081 TI - Subphrenic abscess: the place of antibiotics. PMID- 20919083 TI - A USA-UK Comparison. PMID- 20919082 TI - Subphrenic abscess: the place of antibiotics. PMID- 20919084 TI - A USA-UK Comparison. PMID- 20919085 TI - Effect of abdominal decompression on the metabolism of the foetoplacental unit. PMID- 20919087 TI - Effect of abdominal decompression on the metabolism of the foetoplacental unit. PMID- 20919086 TI - Effect of abdominal decompression on the metabolism of the foetoplacental unit. PMID- 20919088 TI - Specialized training in communicable diseases: the army. PMID- 20919089 TI - Late Results of Adrenalectomy for Cushing's Syndrome. PMID- 20919090 TI - Surgical implications of medullary carcinoma of the thyroid. PMID- 20919091 TI - Surgical implications of medullary carcinoma of the thyroid. PMID- 20919092 TI - Congenital arteriovenous fistula within the tibia. PMID- 20919093 TI - Sir Terence Cawthorne at King's College Hospital. PMID- 20919094 TI - Sir Terence Cawthorne at King's College Hospital. PMID- 20919095 TI - Sir Terence Cawthorne at King's College Hospital. PMID- 20919096 TI - Glaucoma: A Fourteen-year Retrospective Study of Scheie and Flap Sclerotomies. PMID- 20919097 TI - The general practitioner and industrial absenteeism. PMID- 20919098 TI - The general practitioner and industrial absenteeism. PMID- 20919099 TI - Duration of recovery from minor injuries. PMID- 20919101 TI - Duration of recovery from minor injuries. PMID- 20919100 TI - Duration of recovery from minor injuries. PMID- 20919102 TI - Duration of recovery from minor injuries. PMID- 20919104 TI - Duration of recovery from minor injuries. PMID- 20919105 TI - Duration of recovery from minor injuries. PMID- 20919103 TI - Duration of recovery from minor injuries. PMID- 20919106 TI - Duration of recovery from minor injuries. PMID- 20919107 TI - Duration of recovery from minor injuries. PMID- 20919108 TI - Duration of recovery from minor injuries. PMID- 20919109 TI - Duration of recovery from minor injuries. PMID- 20919110 TI - The Employer's Point of View. PMID- 20919111 TI - The Employer's Point of View. PMID- 20919112 TI - The Employer's Point of View. PMID- 20919114 TI - The Employer's Point of View. PMID- 20919113 TI - The Employer's Point of View. PMID- 20919115 TI - The Employer's Point of View. PMID- 20919116 TI - President's Introduction. PMID- 20919118 TI - Impermeability of the human rectum to water and electrolytes [abstract]. PMID- 20919117 TI - Monitoring of adverse reactions to drugs in the United kingdom: some illustrative examples of the work done by the committee on safety of drugs. PMID- 20919119 TI - Chairman's Introduction. PMID- 20919120 TI - Release of oxytocin by the human foetus during labour abstract. PMID- 20919121 TI - Selective indications for ketamine anaesthesia. PMID- 20919122 TI - Selective indications for ketamine anaesthesia. PMID- 20919123 TI - Selective indications for ketamine anaesthesia. PMID- 20919124 TI - The Complementary Roles of ENT and Plastic Surgery in Major Malignancies of the Middle Ear. PMID- 20919126 TI - A Porter's View [Abridged]. PMID- 20919125 TI - Political biography. PMID- 20919127 TI - A Porter's View [Abridged]. PMID- 20919128 TI - A Parent's View [Abridged]. PMID- 20919129 TI - Diagnosis of deep vein thrombosis and fractures of femoral neck [summary]. PMID- 20919131 TI - Case summaries. PMID- 20919130 TI - Lupoid sclerosis [summary]. PMID- 20919132 TI - An immunological approach to the detection of neoplasia. PMID- 20919133 TI - The place of internal urethrotomy in the treatment of urinary incontinence in women. PMID- 20919134 TI - Eradication of smallpox: the critical year ahead. PMID- 20919135 TI - Granulomatous liver disease and portal hypertension. PMID- 20919136 TI - Acute hepatic sarcoidosis. PMID- 20919137 TI - Cerebral lesion in an adult coeliac. PMID- 20919138 TI - Tuberculosis, Crohn's disease and villous papilloma of the rectum. PMID- 20919139 TI - A Multi-disciplinary Approach to the Relief of Pain. PMID- 20919140 TI - Facial palsies: selection of cases for treatment. PMID- 20919141 TI - Recognition and management of facial nerve palsies of operative and traumatic origin [abridged]. PMID- 20919142 TI - Traumatic facial palsy. PMID- 20919143 TI - Amenorrhoea and galactorrhoea. PMID- 20919144 TI - 'Sphincter cripples' [abridged]. PMID- 20919145 TI - Treatment of malignant disease of the orbital region [abridged]. PMID- 20919146 TI - Treatment of malignant disease of the orbital region [abridged]. PMID- 20919147 TI - Immunity to schistosomiasis. PMID- 20919149 TI - Summing up. PMID- 20919148 TI - Dynamic Psychotherapy: Can it be Evaluated. PMID- 20919150 TI - The radiological diagnosis of adrenal tumours [abstract]. PMID- 20919151 TI - Parachuting injuries. PMID- 20919152 TI - Lipodystrophia centrifugalis abdominalis infantilis. PMID- 20919153 TI - Freiberg's Disease: A Review of the Long-term Results. PMID- 20919154 TI - Samuel dale (1659-1739), physician and geologist. PMID- 20919155 TI - Methods of mechanical ventilation for hyaline membrane disease. PMID- 20919157 TI - Methods of mechanical ventilation for hyaline membrane disease. PMID- 20919156 TI - Methods of mechanical ventilation for hyaline membrane disease. PMID- 20919158 TI - Methods of mechanical ventilation for hyaline membrane disease. PMID- 20919159 TI - Newer diagnostic methods. PMID- 20919160 TI - Newer diagnostic methods. PMID- 20919161 TI - Newer diagnostic methods. PMID- 20919162 TI - Newer diagnostic methods. PMID- 20919163 TI - Newer diagnostic methods. PMID- 20919164 TI - Endocrine therapy - the future. PMID- 20919165 TI - Endocrine therapy - the future. PMID- 20919166 TI - Endocrine therapy - the future. PMID- 20919167 TI - Endocrine therapy - the future. PMID- 20919168 TI - Endocrine therapy - the future. PMID- 20919170 TI - Endocrine therapy - the future. PMID- 20919169 TI - Endocrine therapy - the future. PMID- 20919172 TI - Chemotherapy in breast cancer. PMID- 20919171 TI - Chemotherapy in breast cancer. PMID- 20919173 TI - Chemotherapy in breast cancer. PMID- 20919175 TI - Chemotherapy in breast cancer. PMID- 20919174 TI - Chemotherapy in breast cancer. PMID- 20919176 TI - Chemotherapy in breast cancer. PMID- 20919177 TI - Immunotherapy in treatment of breast cancer. PMID- 20919178 TI - Immunotherapy in treatment of breast cancer. PMID- 20919180 TI - Immunotherapy in treatment of breast cancer. PMID- 20919179 TI - Immunotherapy in treatment of breast cancer. PMID- 20919181 TI - Immunotherapy in treatment of breast cancer. PMID- 20919182 TI - Immunotherapy in treatment of breast cancer. PMID- 20919183 TI - Intraoral malignancy with special reference to jaw replacement. PMID- 20919184 TI - The injured face. PMID- 20919185 TI - The work of ground staff [summary]. PMID- 20919186 TI - Combination chemotherapy. PMID- 20919187 TI - Combination chemotherapy. PMID- 20919189 TI - Immunopathological mechanisms. PMID- 20919188 TI - Assessment of head injuries for rehabilitation. PMID- 20919191 TI - The function of noise and retinal image quality in human photopic vision [summary]. PMID- 20919192 TI - Keratoconus. PMID- 20919193 TI - Conclusions. PMID- 20919194 TI - An introduction to optical processing and its applications [summary]. PMID- 20919190 TI - Autoimmunity in endocrine disease. PMID- 20919195 TI - The control system regulating breathing in health at sea level. PMID- 20919197 TI - Good general practice: icons and iconoclasts. PMID- 20919196 TI - A prospective view. PMID- 20919198 TI - Good general practice: icons and iconoclasts. PMID- 20919199 TI - Good general practice: icons and iconoclasts. PMID- 20919200 TI - Good general practice: icons and iconoclasts. PMID- 20919202 TI - Coronary care: home or hospital. PMID- 20919201 TI - Disease in the Tropics: Has the Problem Changed for the Epidemiologist since Ross? PMID- 20919203 TI - Coronary care: home or hospital. PMID- 20919205 TI - The general practitioner and the specialist. PMID- 20919204 TI - Coronary care: home or hospital. PMID- 20919206 TI - The general practitioner and the specialist. PMID- 20919207 TI - The general practitioner and the specialist. PMID- 20919208 TI - The general practitioner and the specialist. PMID- 20919210 TI - The general practitioner and the specialist. PMID- 20919209 TI - The general practitioner and the specialist. PMID- 20919211 TI - The general practitioner and the specialist. PMID- 20919213 TI - Report of the merrison committee. PMID- 20919212 TI - The general practitioner and the specialist. PMID- 20919215 TI - Report of the merrison committee. PMID- 20919214 TI - Report of the merrison committee. PMID- 20919216 TI - Adverse reactions to radiological contrast media. PMID- 20919218 TI - Coronary angiography. PMID- 20919217 TI - Anaesthesia for neuroradiology. PMID- 20919220 TI - Medicolegal aspects. PMID- 20919219 TI - Pulmonary oedema following translumbar aortography. PMID- 20919221 TI - Civil aviation. PMID- 20919222 TI - Life before death. PMID- 20919223 TI - Life before death. PMID- 20919224 TI - Life before death. PMID- 20919226 TI - Life before death. PMID- 20919225 TI - Life before death. PMID- 20919227 TI - Introduction. PMID- 20919228 TI - Summing up. PMID- 20919229 TI - Hysteroscopy. PMID- 20919230 TI - Samuel Pepys and his Stones [Abstract]. PMID- 20919231 TI - Cervical lymph node metastases. PMID- 20919232 TI - The birth of american neurology. PMID- 20919233 TI - Dr Thomas moffett and the sixteenth century origins of medical microbiology [abstract]. PMID- 20919234 TI - Pesticides in Perspective: Some Ecological Aspects of their Uses in Agriculture and Public Health. PMID- 20919235 TI - Pollution with sound. PMID- 20919236 TI - Exposure of man to microbes in industry. PMID- 20919237 TI - Fire risks in intensive care units and operating theatres: evacuation of surgical patients [summary]. PMID- 20919238 TI - Developmental assessment. PMID- 20919239 TI - The birth of american neurology. PMID- 20919240 TI - Cytological screening for cancer. PMID- 20919241 TI - Vertebral venography. PMID- 20919242 TI - Cervical lymph node metastases. PMID- 20919243 TI - The importance of cooperation in paediatric endoscopy. PMID- 20919244 TI - The birth of american neurology. PMID- 20919245 TI - Medicolegal aspects. PMID- 20919247 TI - Medicolegal aspects. PMID- 20919246 TI - Medicolegal aspects. PMID- 20919248 TI - Florence nightingale in buckinghamshire [abstract]. PMID- 20919249 TI - Wegener's granulomatosis presenting as rheumatoid arthritis. PMID- 20919250 TI - Osteosarcoma. PMID- 20919251 TI - Stage II Carcinoma of the Cervix. PMID- 20919252 TI - Circulating malignant cells and fibrinolysis. PMID- 20919253 TI - Offshore medicine. PMID- 20919254 TI - Medicine in the open university. PMID- 20919255 TI - Medicine in the open university. PMID- 20919256 TI - Medical disease and the anaesthetist. PMID- 20919257 TI - Stage II Carcinoma of the Cervix. PMID- 20919258 TI - Stage II Carcinoma of the Cervix. PMID- 20919259 TI - Cross-face Nerve Transplantation in Facial Palsy. PMID- 20919260 TI - Medical and legal aspects of the increasing demand for diagnostic radiology. PMID- 20919261 TI - A perspective of oral cancer. PMID- 20919262 TI - Oral manifestations of Crohn's disease: studies in the pathogenesis. PMID- 20919263 TI - Factors affecting Intraocular Pressure. PMID- 20919264 TI - Chairman's Summing Up. PMID- 20919265 TI - Chairman's Summing Up. PMID- 20919266 TI - Chairman's Summing Up. PMID- 20919267 TI - Clinical oncology. PMID- 20919269 TI - Too many hospital referrals? PMID- 20919268 TI - Simplification of laboratory and other reports. PMID- 20919270 TI - Project selection in the pharmaceutical industry. PMID- 20919271 TI - Ankylosing spondylitis and spinal osteotomy. PMID- 20919272 TI - A perspective of oral cancer. PMID- 20919273 TI - Letters to the editor. PMID- 20919274 TI - Periodic reregistration. PMID- 20919275 TI - Recurrent oral ulceration [abridged report]. PMID- 20919276 TI - Pioneers in obstetrics and hospital hygiene [abridged report]. PMID- 20919277 TI - On dying and dying well. PMID- 20919278 TI - A new look at thermoregulation in the newborn. PMID- 20919279 TI - Some reflections on book reviews. PMID- 20919280 TI - Management of the injured ureter. PMID- 20919281 TI - Outpatient thyrography: its value in the diagnosis of thyroid and mediastinal lesions. PMID- 20919283 TI - Outpatient percutaneous ligation of varicose veins. PMID- 20919282 TI - Sex difference and the mind. PMID- 20919285 TI - Early postoperative abdominal complications and reoperations after gallbladder, colonic and gastric surgery. PMID- 20919284 TI - Hormone replacement therapy and the general practitioner. PMID- 20919286 TI - The value of comparative pathology. PMID- 20919287 TI - Children's Feet. PMID- 20919288 TI - Academic General Practice: Is it relevant? PMID- 20919290 TI - The influence of litigation on medical practice. PMID- 20919289 TI - Anorexia nervosa. PMID- 20919291 TI - The Treatment of Pilonidal Sinus at St Mark's Hospital. PMID- 20919292 TI - Premyxoedema - a cause of preventable coronary heart disease. PMID- 20919293 TI - Sex difference and the mind. PMID- 20919294 TI - Letters to the editor. PMID- 20919295 TI - Breast cancer. PMID- 20919296 TI - Spina bifida: some problems of management. PMID- 20919297 TI - Medical research, reading, speaking and writing. PMID- 20919298 TI - Sex difference and the mind. PMID- 20919299 TI - Visual field examination. PMID- 20919301 TI - Visual field examination. PMID- 20919300 TI - Academic General Practice: Is it Relevant? PMID- 20919302 TI - Evaluation of preclinical hypothyroidism. PMID- 20919304 TI - Changing patterns in higher education. PMID- 20919303 TI - Section of medical and dental hypnosis. PMID- 20919305 TI - The leprosy study centre in london. PMID- 20919306 TI - Premyxoedema: entity or nonentity? PMID- 20919307 TI - Visual field examination. PMID- 20919308 TI - Introductory remarks. PMID- 20919309 TI - Round table discussion: miconazole(1)tolerance and toxicity (2) route of administration (3) indications for use. PMID- 20919310 TI - Chairman's Summing Up. PMID- 20919311 TI - Dopaminergic mechanisms in schizophrenia. PMID- 20919312 TI - The role of dopamine in the antipsychotic effect and the pathogenesis of schizophrenia. PMID- 20919314 TI - The clinical actions of major tranquillizers. PMID- 20919315 TI - Is an oral neuroleptic suitable for continuing drug treatment in schizophrenia? PMID- 20919313 TI - Neurochemical and psychoanalytical approaches to mania. PMID- 20919316 TI - Tardive dyskinesia and pimozide. PMID- 20919317 TI - Monosymptomatic hypochondriacal Psychosis: Presentation and Treatment. PMID- 20919319 TI - Pimozide in withdrawn chronic schizophrenics: preliminary observations. PMID- 20919318 TI - Open study to determine appropriate maintenance dosage of pimozide in patients with chronic schizophrenia. PMID- 20919321 TI - Chairman's Summing Up. PMID- 20919320 TI - Behavioural characterization of neuroleptic properties in the rodent. PMID- 20919322 TI - Chairman's Introduction. PMID- 20919323 TI - Chairman's Introduction. PMID- 20919324 TI - Effect of D-penicillamine Treatment on Certain Humoral Immunological Parameters in Clinical and Experimental Arthritis [Abstract]. PMID- 20919326 TI - Summing up. PMID- 20919325 TI - Concluding remarks. PMID- 20919327 TI - Summing up. PMID- 20919328 TI - Course of Chronic Active Hepatitis in Wilson's Disease [Abstract]. PMID- 20919329 TI - A Double-blind Controlled Trial of Penicillamine Therapy in Duchenne Muscular Dystrophy - Interim Comments [Abstract]. PMID- 20919331 TI - Foreword. PMID- 20919330 TI - A Controlled Trial of D-penicillamine Therapy in Primary Biliary Cirrhosis [Abstract]. PMID- 20919332 TI - Chairman's Introduction. PMID- 20919333 TI - Dose-response in hypertension in general practice. PMID- 20919334 TI - Placebo-controlled Multicentre Study in General Practice. PMID- 20919335 TI - Points arising from discussion. PMID- 20919337 TI - Comparison of atenolol (tenormin) and methyldopa (a multicentre study in general practice). PMID- 20919336 TI - Problems in the detection and management of hypertension. PMID- 20919338 TI - Hypertension - factors of relevance to trials design. PMID- 20919340 TI - Atenolol Compared with Other Beta-blocking Agents. PMID- 20919339 TI - Comparison of once daily atenolol with slow release oxprenolol in hypertension. PMID- 20919341 TI - Points arising from discussion. PMID- 20919342 TI - Why treat hypertension? PMID- 20919343 TI - Physiological aspects of blood pressure measurement. PMID- 20919344 TI - Atenolol-Once-daily Dosage. PMID- 20919345 TI - Effect of Acute and Chronic Dosing over 24 Hours. PMID- 20919346 TI - Points arising from discussion. PMID- 20919347 TI - Problems with Beta Adrenergic Blocking Drugs and other Antihypertensive Drugs. PMID- 20919349 TI - Cardioselectivity studies. PMID- 20919348 TI - Assessment and clinical implications of cardioselectivity. PMID- 20919350 TI - Review of clinical pharmacology of atenolol. PMID- 20919352 TI - Points arising from discussion. PMID- 20919351 TI - Effect of Atenolol and other Beta Blockers on Insulin-induced Hypoglycaemia. PMID- 20919353 TI - Interim report on a compliance study and review of side effects. PMID- 20919354 TI - Clinical use of atenolol. PMID- 20919355 TI - Clinical review of atenolol as an antihypertensive. PMID- 20919356 TI - Dose-response in hypertension. PMID- 20919357 TI - Pharmacology and toxicology of fenclofenac. PMID- 20919359 TI - Therapeutic dose range of fenclofenac. PMID- 20919358 TI - The methodology of the fenclofenac clinical research programme and results obtained with particular reference to the therapeutic dose range. PMID- 20919360 TI - The Use of Quantitative Thermography to Assess the Anti-inflammatory Dose Range for Fenclofenac. PMID- 20919361 TI - Studies on the Anti-inflammatory Effects of Fenclofenac Using 99-Technetium Joint Scanning. PMID- 20919362 TI - Fenclofenac in Rheumatoid Arthritis: Sequential Double-blind Cross-over Comparisons with Placebo and Naproxen. PMID- 20919363 TI - Fenclofenac and soluble aspirin in rheumatoid arthritis: a comparative trial. PMID- 20919364 TI - Fenclofenac in rheumatoid arthritis-comparative studies. PMID- 20919365 TI - Fenclofenac in osteoarthrosis. PMID- 20919366 TI - Fenclofenac in the treatment of rheumatoid arthritis and ankylosing spondylitis. PMID- 20919367 TI - Comparative Studies of Gastric Ulcerogenesis by Non-steroid Anti-inflammatory Drugs: Effects of Fenclofenac. PMID- 20919368 TI - Fenclofenac therapy in rheumatic diseases. PMID- 20919369 TI - Preliminary clinical evaluation of fenclofenac (32 patients). PMID- 20919370 TI - Analysis of the Side-effect Patterns Presenting During the Course of a Continuing Long-term Open Study of Fenclofenac. PMID- 20919371 TI - Fenclofenac tolerance in the dyspeptic patient. PMID- 20919372 TI - Side-effects of Fenclofenac with Special Reference to the Gastrointestinal Tract. PMID- 20919373 TI - Foreword. PMID- 20919374 TI - Modern techniques of venous occlusion plethysmography in the assessment of peripheral vascular disease. PMID- 20919375 TI - Vascular responses with cinnarizine to standard exercise in patients with intermittent claudication. PMID- 20919376 TI - Treatment of Peripheral Circulatory Disturbances with Cinnarizine: A Multi-centre Double-blind, Placebo-controlled Evaluation. PMID- 20919377 TI - Use of the ECG-triggered Venous Occlusion Plethysmograph to Study Hyperaemic Response Patterns in Patients with Intermittent Claudication treated with Cinnarizine. PMID- 20919378 TI - Action of cinnarizine on the hyperviscosity of blood in patients with peripheral obliterative arterial disease. PMID- 20919381 TI - Preliminary clinical experience with cefuroxime: report on one hundred cases. PMID- 20919379 TI - Can drug therapy alter the natural course of peripheral vascular disease?: a review. PMID- 20919380 TI - Cinnarizine in the treatment of peripheral vascular disease: mechanisms related to its clinical action. PMID- 20919382 TI - Cefuroxime: a clinical evaluation. PMID- 20919383 TI - An evaluation of cefuroxime in internal medicine. PMID- 20919384 TI - Clinical profile of cefuroxime in sixty-four patients. PMID- 20919385 TI - Activityin vitroof Cefuroxime and Six Other Antimicrobial Agents againstNeisseria gonorrhoeoeisolated in Belgium and Rwanda. PMID- 20919386 TI - In vitroSusceptibility of beta-Lactamase Positive and beta-Lactamase Negative Strains ofNeisseria gonorrhoeoeto Cefuroxime. PMID- 20919387 TI - Dose response evaluation of cefuroxime in the treatment of gonorrhoea in male and female patients. PMID- 20919388 TI - Treatment of Females with Acute Gonorrhoea using Cefuroxime. PMID- 20919390 TI - Experimental investigations of cefuroxime in renal tolerance and therapeutic efficacy in pyelonephritis. PMID- 20919389 TI - Cefuroxime and post-gonococcal urethritis. PMID- 20919391 TI - Cefuroxime in renal insufficiency: therapeutic results in various infections and pharmacokinetics including the effects of dialysis. PMID- 20919392 TI - Pharmacokinetic studies of cefuroxime and dosage recommendations in patients with impaired renal function. PMID- 20919393 TI - Clinical evaluation of the effect of cefuroxime in patients with pyelonephritis and osteomyelitis. PMID- 20919394 TI - The effect of Renal Failure and Dialysis on the Pharmacokinetics of Cefuroxime. PMID- 20919395 TI - Clinical evaluation of cefuroxime in patients with urinary tract infections. PMID- 20919396 TI - The efficacy of cefuroxime in urinary tract infections. PMID- 20919397 TI - Clinical studies in cefuroxime in the urological and surgical fields. PMID- 20919398 TI - Cefuroxime in chronic and acute cystitis. PMID- 20919399 TI - Cefuroxime in the treatment of urinary tract infections. PMID- 20919400 TI - Pharmacokinetic and clinical study of cefuroxime in infants. PMID- 20919401 TI - Pharmacokinetics and clinical efficacy of cefuroxime in the newborn period. PMID- 20919403 TI - Experience in the treatment of infections in infants and children with cefuroxime. PMID- 20919402 TI - A clinical study of cefuroxime in neonates. PMID- 20919405 TI - Experience in the use of cefuroxime in paediatric infections. PMID- 20919404 TI - Serum and skin blister concentrations of cefuroxime in relation to dose and in comparison to cephalothin. PMID- 20919406 TI - The microbiological assay of cefuroxime. PMID- 20919408 TI - In vitro Activity of Selected Cephalosporins and Penicillins against Bacteria of Importance in Infections of Infants and Children. PMID- 20919407 TI - Susceptibility to cefuroxime 450 bacterial strains resistant to gentamicin. PMID- 20919409 TI - In vitro Microbiological Evaluation of Cefuroxime and its Combinations with Gentamicin and Sisomicin. PMID- 20919410 TI - Chairmen's Summing Up and General Discussion. PMID- 20919411 TI - General summing up. PMID- 20919412 TI - Chairman's Closing Remarks. PMID- 20919413 TI - Phase one clinical study on cefuroxime. PMID- 20919414 TI - Pharmacokinetic and clinical studies on cefuroxime. PMID- 20919415 TI - Cefuroxime: pharmacokinetic study in bronchial secretions. PMID- 20919416 TI - Bioavailability of Cefuroxime in Various Sites including Bile, Sputum and Bone. PMID- 20919417 TI - Cefuroxime concentrations in serum, urine and bile: pharmacokinetic profile. PMID- 20919418 TI - Comparative in vitro Activity of Cefuroxime and its Interactions with Aminoglycoside Antibiotics. PMID- 20919419 TI - The in vitro and in vivo Antibacterial Activity of Cefuroxime. PMID- 20919420 TI - Cefuroxime, an in vitro Comparison with Six Other Cephalosporins. PMID- 20919422 TI - A clinical and bacteriological study of cefuroxime. PMID- 20919421 TI - Cefuroxime Resistance to Staphylococcal beta-Lactamases. PMID- 20919423 TI - beta-Lactamase Resistant Cephalosporins with Particular Reference to Cefuroxime. PMID- 20919424 TI - Cefuroxime treatment of patients with lower respiratory and urinary tract infections. PMID- 20919425 TI - Cefuroxime in the treatment of bacterial infections in seriously ill patients admitted to an intensive care unit. PMID- 20919426 TI - Clinical experience in the treatment of pneumonia with cefuroxime. PMID- 20919427 TI - Clinical trials with cefuroxime in chest disease. PMID- 20919428 TI - Biliary tract excretion of cefuroxime. PMID- 20919429 TI - Clinical evaluation of cefuroxime. PMID- 20919430 TI - Analysing contractual environments: lessons from Indigenous health in Canada, Australia and New Zealand. AB - Contracting in health care is a mechanism used by the governments of Canada, Australia and New Zealand to improve the participation of marginalized populations in primary health care and improve responsiveness to local needs. As a result, complex contractual environments have emerged. The literature on contracting in health has tended to focus on the pros and cons of classical versus relational contracts from the funder's perspective. This article proposes an analytical framework to explore the strengths and weaknesses of contractual environments that depend on a number of classical contracts, a single relational contract or a mix of the two. Examples from indigenous contracting environments are used to inform the elaboration of the framework. Results show that contractual environments that rely on a multiplicity of specific contracts are administratively onerous, while constraining opportunities for local responsiveness. Contractual environments dominated by a single relational contract produce a more flexible and administratively streamlined system. PMID- 20919431 TI - Tracing experiences of NHS change in England: a process philosophy perspective. AB - For over three decades public services have been the subject of unprecedented change. Nowhere has this been more evident than in the English National Health Service (NHS) where despite the effort expended on change there is growing evidence that such restructuring is largely ineffective. Drawing on a study of culture modification in the English NHS, this paper utilizes Chia's (1999) account of the metaphysics of processual change to consider why attempts to restructure public services are not always successful. The paper contributes to our understanding of public management reform by considering how an ontology of becoming, and a loosening of control, might alter how we approach reforming. Further, the paper offers a theoretical justification for the use of standard research methods for novel processual ends. The paper concludes with a reflection on the implications of a processual perspective for the future management, organization and study of change in public administration. PMID- 20919432 TI - Costs can be cut by providing high quality training in leg ulcer care. PMID- 20919433 TI - [Monitoring the quality of life in patients with varicose disease of the lower extremities in the use of venarus]. PMID- 20919434 TI - [The carcinoid tumor of appendix]. PMID- 20919435 TI - [Diagnostic and treatment of small peripheral lung neoplasms]. PMID- 20919436 TI - [Some aspects of pathogenesis of the multiple organ failure by acute bowel obstruction]. PMID- 20919437 TI - [Surgical diseases of earl L. N. Tolstoi (to the 100th anniversary of death)]. PMID- 20919438 TI - [Complicated laparoscopic hernioplasty be ventral hernia]. PMID- 20919439 TI - [Biliary complications after liver resections]. PMID- 20919440 TI - [Endocrine pancreatic tumors by type 1 syndrome of multiple endocrine neoplasia]. PMID- 20919441 TI - [The choice of synthetic prosthesis and fixation method by laparoscopic ventral hernia plasty]. PMID- 20919442 TI - TGF-beta promotes immune suppression by inhibiting Treg cell apoptosis. PMID- 20919443 TI - TLR7 and TLR8 as targets for tumor immunotherapy. PMID- 20919444 TI - Maintaining skeletal health among postmenopausal women. AB - The paradigm for prevention of osteoporotic fractures in postmenopausal women is changing. There are new ways of looking at prevention, diagnosis, and treatment. With diagnostic procedures, such as bone densitometry, and recently developed pharmacologic agents, such as bisphosphonates and selective estrogen receptor modulators, there is increasing optimism about osteoporosis prevention and treatment. Effective results have been demonstrated even when treatment is begun in women in their 60s and 70s. Bone can be regained and fractures can be prevented in patients in this age group and beyond. PMID- 20919445 TI - CAPD peritonitis after colonoscopy: follow the guidelines. AB - We present two cases of peritonitis shortly after endoscopic examination of the large bowel with polypectomy in patients on continuous ambulant peritoneal dialysis (CAPD) despite the standard preventive measure to drain the dialysate from the abdomen prior to the procedure. We have reviewed the current literature on this topic. These cases demonstrate that the administration of prophylactic broad-spectrum antibiotics next to the drainage of the abdomen prior to colonoscopy in CAPD patients should be considered as recommended in the International Society for Peritoneal Dialysis (IS PD) guidelines 2005. PMID- 20919446 TI - Hypoglycaemia in nondiabetic patients. PMID- 20919447 TI - Investigating bone morphogenetic protein (BMP) signaling in a newly established human cell line expressing BMP receptor type II. AB - Bone morphogenetic proteins (BMPs), members of the transforming growth factor beta cytokine superfamily, elicit various biological effects in different tissues. BMP receptor type II (BMPRII) contains a unique carboxyl-terminal region that interacts with multiple signaling molecules. However, expression of endogenous BMPRII is low in various mammalian cell lines, which hampers the analysis of BMP signaling. Therefore, we established a human cell line expressing BMPRII tagged with a Flag epitope (BMPRII-Flag) using the tetracycline-controlled Flp-In T-REx gene expression system. The BMPRII-Flag gene was introduced into the Flp-In T-REx 293 (FT293) cell line, a derivative of human 293 embryonic kidney fibroblasts. Then we analyzed the expression of key BMP target genes, inhibitors of DNA binding (Id) family members (Id1, Id2, and Id3) and the inhibitory Smads Smad6 and Smad7, in parental FT293 cells and an established cell line, FT293 BMPRII, by quantitative real-time PCR. Tetracycline treatment significantly increased the expression of BMPRII-Flag mRNA and protein in FT293-BMPRII cells, but induced no significant changes in expression of Id1, Id2, Id3, Smad6, or Smad7 mRNA. In contrast, treatment with a BMPRII ligand BMP2 induced the expression of Id1, Id2, Id3, and Smad6 in parental FT293 cells and FT293-BMPRII cells. Tetracycline-induced BMPRII-Flag expression significantly enhanced the induction of Id1, Id3, and Smad6 mRNA expression in FT293-BMPRII cells treated with BMP2. These findings provide evidence that although BMPRII has no obvious effect on the expression of representative BMP target genes, it differentially modulates the responsiveness of target genes to BMP2. PMID- 20919448 TI - Expanding the use of neurotoxins in facial aesthetics: a consensus panel's assessment and recommendations. AB - Injection of botulinum toxin type A (BoNTA) is the most common nonsurgical aesthetic procedure undertaken in the United States (U.S.). A new formulation of BoNTA (abobotulinumtoxinA, DysportTM) has recently been approved in the U.S. for the treatment of glabellar lines. This product has been used for facial aesthetics in other parts of the world for more than 15 years, whereas in the U.S. a different formulation (onabotulinumtoxinA, Botox(r) Cosmetic) has been used for many years. The various formulations of neurotoxins are unique and are not interchangeable nor are doses convertible from one product to another, so it is important that recommendations be developed to assist U.S. clinicians in understanding the differences between the two available formulations of BoNTA, which should ensure successful outcomes with these products. A group of worldwide experts on the aesthetic use of BoNTA convened in February 2009 in New York, NY, to review the use of BoNTA and to develop consensus recommendations for the use of the new formulation, since such guidelines previously had only been published in German. This publication summarizes key discussions from the meeting as well as recommendations and suggestions regarding the use of abobotulinumtoxinA in the areas of the face most commonly treated with BoNTA. PMID- 20919449 TI - Increased efficiency using the encapsulation-dehydration cryopreservation technique for Arabidopsis thaliana. AB - Arabidopsis thaliana shoot tips were successfully cryopreserved using encapsulation-dehydration cryopreservation methods. Between one and seven shoot tips were encapsulated within 4 mm calcium-alginate beads. Beads were formed in the presence of 2 M glycerol + 0.4 M sucrose. The time required to make 10 beads, each containing five shoot tips (4 min), was less than the time required to make 50 beads containing one shoot tip (12 min). Shoot tip regrowth after cryoexposure was between 60 and 68%, with one to seven shoot tips per bead. Using five Arabidopsis shoot tips per bead, alginate beads were formed either in the presence of 2 M glycerol + 0.4 M sucrose or 0.5 M sucrose. Beads formed in the presence of glycerol were immediately air-dried to moisture contents between 0.21 to 0.26 g H2O/g FW (0.27 to 0.38 g H2O/g DW). Alginate beads formed in 0.5 M sucrose were incubated in solutions of 0.5, 0.75, and 1 M sucrose for one day each prior to air-dehydration, achieving moisture contents of 0.19 to 0.21 g H2O/g FW (0.23 to 0.27 g H2O/g DW). Shoot tip regrowth after cryoexposure was between 42 and 65%, with no significant differences among treatments. We successfully reduced the amount of time needed for shoot tip processing for Arabidopsis by encapsulating five shoot tips per alginate bead and by using a glycerol-encapsulation method, without lowering shoot tip regrowth levels after cryopreservation. PMID- 20919450 TI - Recovery and characterisation of hybrid firs (Abies alba x A. cephalonica, Abies albax A. numidica) embryogenic tissues after cryopreservation. AB - Embryogenic tissues of hybrid firs were cryopreserved using a slow freezing protocol. The procedure involved preculture of tissues for 24, 48 or 72 h in media with different sorbitol concentrations (0.4 or 0.8 M) and addition of 5% (v/v) DMSO as cryoprotectant. The cell lines tested withstood cryopreservation, even though tissue regrowth after thawing was dependent on treatment and cell line. For cell line AN72, regrowth was 100% for all experimental conditions tested. With cell line AC78, regrowth was 100% except after shorter pretreatment durations, which produced 83% and 86% regrowth for 0.4 M and 0.8 M sorbitol pretreatment, respectively. Cell lines AC1 and AC4 were more sensitive to cryopreservation with 37.5 to 100% regrowth, respectively. Growth parameters evaluated 3 months after cryopreservation showed cell line and treatments effects. In most cases, cryopreservation had no negative effect on growth of tissues. Statistically significant differences in fresh mass accumulation were found for four samples out of 24 investigated, although growth increase of these tissues still reached 79.4-84.6%, compared with non-cryopreserved ones (100% increase). Maturation capacity and genetic fidelity were studied in tissues whose growth was not negatively influenced by cryopreservation. Maturation capacity of embryogenic tissues cryopreserved using the optimal protocol was comparable to that of non-frozen controls. RAPD analysis of 88 genomic regions per cell line did not reveal any changes in genetic fidelity of cryopreserved tissues compared to non-cryopreserved controls. PMID- 20919452 TI - Cryopreservation of zebrafish (Danio rerio) oocytes by vitrification. AB - Cryopreservation of fish oocytes is challenging because these oocytes have low membrane permeability to water and cryoprotectant and are highly chilling sensitive. Vitrification is considered to be a promising approach for their cryopreservation as it involves rapid freezing and thawing of the oocytes and therefore minimising the chilling injury. In the present study, vitrification properties and the toxicity of a range of vitrification solutions containing different concentrations of Me2SO, methanol, propylene glycol and ethylene glycol were investigated. Two different base media and vitrification methods were compared. The effect of different post-thaw dilution solutions together with incubation periods on oocyte viability were also investigated. Stage III zebrafish oocytes were equilibrated in increasing concentrations of cryoprotectants for 30 min in 3 steps. Oocytes were thawed rapidly in a water bath and cryoprotectants were removed in 4 steps. Oocyte viability was assessed using trypan blue staining. The results showed that vitrification solutions V3 and V4 in KCl buffer had low toxicity and vitrified well. The survivals of oocytes after stepwise dilution using solutions containing permeable cryoprotectants were significant higher than those diluted in 0.5M glucose, and the use of CVA65 vitrification system improved oocyte survival when compared with plastic straws after 30 min at 22 degrees C post-thawing. Cryopreservation of zebrafish oocytes by vitrification is reported here for the first time, although oocyte survivals after cryopreservation assessed by trypan blue staining were relatively high shortly after thawing, they became swollen and translucent after incubation in KCl buffer. Further studies are needed to optimise the post-thaw culturing conditions. PMID- 20919451 TI - Induction of phospho-Thr-172 AMPK in 3T3-L1 adipocytes exposed to cold or treated with anisomycin, mithramycin A, and ionic compounds. AB - Cold exposure induces cellular responses, including subcellular molecule expression and transport responses, similar to those stimulated by insulin in 3T3 L1 (L1) adipocytes. The transport response is induced in L1 adipocytes treated with translation inhibitors. We examined the level of phospho-Thr-172 AMPK (an active form of AMPK, a known energy-state sensor) in L1 adipocytes exposed to different temperatures of 4-37 degrees C or stressors, including chemical inhibitors and activators. The phospho-AMPK level increased in cold-exposed cells and their subcellular fractions and decreased after rewarming and serum depletion. The phospho-molecule was also induced by anisomycin, which induces protein kinase activation and translation inhibition; mithramycin A, an inhibitor of transcription factor binding; and ionic compounds, which stimulate molecular signaling and alter several gene expression. These results indicate that temperature responses are mimicked by metabolic stressors through phospho molecule alteration. Our results provide possible clues for clarifying the mechanisms underlying cold responses in L1 adipocytes. PMID- 20919453 TI - Ice-active proteins from New Zealand snow tussocks, Chionochloa macra AND C. rigida. AB - The ice active protein profile of New Zealand snow tussocks Chionochloa macra and C. rigida consisted of ice nucleation activity but no antifreeze or recrystallization inhibition activity. The ice nucleation activity was similar in the two species, despite them being collected at different altitudes and at different times. The activity is intrinsic to the plant and is associated with the surface of the leaves. Snow tussocks collect water from fog. Nucleation sites on the surface of their leaves may aid the efficiency of this process. PMID- 20919454 TI - Physiological, biochemical and molecular characteristics of cryopreserved Hypericum perforatum L. shoot tips. AB - Hypericum perforatum L. in vitro cultured shoot tips were characterised at the physiological, biochemical and molecular levels following recovery from cryogenic treatment using the plant vitrification solutions PVS2 and PVS3. This comparative study revealed an increase in recovery and regrowth of explants cryoprotected with PVS3. Among the physiological markers only lipid peroxidation in the regenerants treated with PVS2 significantly increased indicating membrane damage. Genotype-specific interactions were found in most characteristics studied, with some variation detected within control and cryopreserved samples. Analyses of metabolite biosynthesis and genetic stability showed no significant differences in hypericin content, RAPD and minisatellite amplification profiles between PVS2- and PVS3-treated explants. This study demonstrates and discusses the criteria selective for PVS3 to improve the cryopreservation of H. perforatum L. PMID- 20919455 TI - Effect of cryopreservation protocols on the phenotypic stability of yeast. AB - Eight cryopreservation protocols were assessed for their effects on the viability and phenotypic stability of the yeast Saccharomyces cerevisiae during a five-year study. It is found that viability and phenotypic features have remained largely unchanged when the yeast was preserved in glycerol, dimethyl sulphoxide, or sucrose at -80 degrees C or in liquid nitrogen. When sorbitol was used as a cryoprotectant, yeast cells frozen and stored at -80 degrees C manifested great decreases in viability after six months in storage and concomitantly large fluctuations in the rate of the trpl auxotrophic reversion. This phenotypic reversion was stable passage after passage. Such a degree of phenotypic fluctuations, however, was not observed for yeast cells preserved in the same sorbitol solution that went through a controlled freezing program and were subsequently stored in liquid nitrogen. These results indicate that some combinations of cryoprotective agent, freezing program, and storage temperature disturb biomaterials more profoundly during cryopreservation and imply a genetic basis of this phenotypic change. PMID- 20919456 TI - An improved pollen collection and cryopreservation method for highly recalcitrant tropical fruit species of mango (Mangifera indica L.) and litchi (Litchi chinensis Sonn.). AB - An improved method for pollen collection from freshly dehiscing anthers of mango (Mangifera indica L.) and litchi (Litchi chinensis Sonn.) using the organic solvent cyclohexane has been devised. Using this method pollen quantity sufficient for large scale pollinations could be collected and stored for future use. Transport of pollen in viable conditions over long distances, from site of collection (field genebank) to cryolab was successfully devised for both these fruit species. Cryopreservation was successfully applied to achieve long-term pollen storage over periods of up to four years. Pollen viability was tested using in vitro germination, the fluorochromatic reaction (FCR) method and by fruit set following field pollination. On retesting, four year cryostored pollen of different mango and litchi varieties showed high percentage viability as good as fresh control pollens. Pollens of more than 180 cultivars of mango and 19 cultivars of litchi have been stored in the cryogenebank using the technology developed, thus facilitating breeding programmes over the long-term. PMID- 20919457 TI - A universal self-adaptive time-varying function for extracellular concentration during osmotic shift for curve-fitting permeability coefficients of cell membrane. AB - A universal self-adaptive time-varying function of extracellular concentration history during osmotic shift for measuring cell membrane permeability was presented in this study. The feasibility and accuracy of the assumed function were verified based on the experimental data obtained from the microperfusion chamber method. It was found that the assumed function could always give out the very satisfactory coefficient of determination, and there were no significant differences between the hydraulic conductivity values fitted using the laser interferometer measured extracellular concentration profile and the predicted one by the assumed piecewise function (student's t test, p > 0.05). Due to the adaptive feature of the assumed function for the concentration of extracellular solution, the function was suggest to be used for all the similar studies for measurement of cell membrane permeability by osmotic shift. PMID- 20919458 TI - [WHO child growth standards for children 0-5 years and the possibility of their implementation in Poland]. AB - The origin of the WHO Child Growth Standards dates back to the early 1990s and the meticulous evaluation of the NCHS growth reference, which had been recommended for international use since the late 1970s. The review documented the deficiencies of the reference and led to a plan for developing new growth charts that would depict how children should grow in all countries rather than merely describing how they grew at a particular time and place. The outcome of this plan was the WHO Multicentre Growth Reference Study (1997-2003), which applied rigorous methods of data collection and which serves as a model of collaboration for conducting international research. The study provides a solid foundation for developing a standard because the sample is based on healthy the mothers of the children selected for the construction of the standards engaged in fundamental health promoting practices, namely breastfeeding and non smoking. Other important features of the study are that it included children from a diverse set of countries (Brazil, Ghana, India, Norway, Oman and USA) and explicitly identified breastfeeding as the biological norm and established the breastfed child as the normative model for growth and development. By replacing the NCHS reference, which is based on children from a single country, with one based on an international group of children, the new standards recognize that children all the world over grow similarly when their health and care needs are met. The WHO Child Growth Standards provide a technically robust tool for assessing the well being of infants and young children. The standards depict normal growth under optimal environmental conditions and can be used to assess children everywhere, regardless of ethnicity, socioeconomic status and type of feeding. In the paper the current status regarding growth reference (norms) in Poland and activities undertaken for implementation of the WHO Child Growth Standards in this country are presented. PMID- 20919459 TI - [Assessment of physical development of children and adolescents. Part I. Infants and children up to 5 years--national reference values or WHO standards?]. AB - INTRODUCTION: Growth and development assessment of infants and young children is a very important component of early prophylaxis in paediatric health care. In 2006 the World Health Organization published the new Child Growth Standards for children up to 5 years of age. They describe the optimal pattern of young children development. AIM OF THE STUDY: 1. To compare the cut-off points for selected anthropometric parameters in children up to 5 years between reference values for Polish children and WHO Child Growth Standards. 2. To attempt to answer the question whether the WHO Child Growth Standards can be implemented to assess health and development in children up to 5 years in Poland. METHODS: The differences for mean (50th percentile) and extreme values (3rd and 97th percentile) for length/height for age and weight for age were calculated for boys and girls. The differences in BMI units for overweight (mean + 1 SD) and obesity (mean + 2 SD) were compared using the z-score method. RESULTS: Comparisons of the WHO and Polish length/height and weight for age showed no differences in children aged 1-60 months. Small differences were seen in the 3rd percentile (less than 2%) in children aged 3 and 6 years. BMI values for overweight and obesity were slightly lower for Polish children in the first 6 months of life than in WHO standards. These differences have positive values for boys and girls starting at 9th month and increasing in toddlers. CONCLUSIONS: WHO standards reflect the optimal growth pattern for children from birth up to 5 years. Therefore these instruments should be adopted for Polish children to assessing their growth. PMID- 20919460 TI - [Assessment of physical development of children and adolescents. Part II. Children and adolescents aged 6-19 years--national references or WHO recommendations?]. AB - AIMS: 1. Comparison of cut-off points for selected anthropometric parameters in children and adolescents between reference values for Polish Institute of Mother and Child (IMD) and WHO growth METHODS: The accepted reference system were IMD reference values and the differences for mean (50th) and 3rd and 97th percentile for height and weight were calculated for boys and girls. The differences between BMI units for overweight (85th) and obesity (95th) percentile were compared. Warsaw 1980 reference values were used to estimate secular trend influence on differences between IMD and WHO cut-off points in stunting adolescents. RESULTS: Comparison of height-for-age showed the largest differences with positive values relative to 3rd percentile in the Polish population. Boys aged 16 years attain 4% (6.2 cm) of 3rd percentile height value and girls aged 14 years 2.3% (2.8 cm). Secular trend of the Polish population did not influence the differences between IMD and WHO values in stunting adolescents. The differences for 85th and 95th percentile of BMI were most pronounced in prepubescence and the largest values were for boys and girls aged 10 years. CONCLUSIONS: 1. National height-for-age references should be used for growth assessment in Polish school-aged children and adolescents especially in stunting adolescents identified in puberty. 2. WHO norms for BMI, can be used as a tool for identifying overweight and obesity in epidemiological studies in Poland and for international comparisons. 3. The usefulness of WHO norms for clinical evaluation of overweight and obesity should be discussed among experts. PMID- 20919461 TI - [Screening for developmental disorders of infants and young children in the primary care clinics--is there a need for standardized tools implementation?]. AB - Early identification of children with developmental delay is an important task for the primary care physicians. Different screening tests are used to detect developmental disorders in infants and young children. The authors describe screening tools currently available in Poland in the primary care setting. The review of the standardized developmental screening tests available in other countries is given: parent report instruments, such as Ages and Stages Questionnaires (ASQ), Parent's Evaluation of Developmental Status (PEDS) and instruments that require direct examination as the Denver-ll Developmental Screening Test (DDST) and Bayley Infant Neurodevelopmental Screener (BINS). The authors describe a proposed standardized developmental screening instrument of infants and young children for primary care pediatricians and family doctors in Poland. PMID- 20919462 TI - [Health status of mothers and children in Poland compared to other European Union countries on the basis of EURO-PERISTAT indicators]. AB - AIM: The aim of this study is an evaluation of perinatal health and data sources in Poland compared to other European Union countries on the basis of the results of the EURO-PERISTATproject for 2004. MATERIAL AND METHODS: The results obtained during the second phase of the EURO-PERISTAT project were used. Core and recommended indicators for Poland in 2004 were compared to the respective indicators for EU member countries before 2004 and Norway, and to the respective indicators for the EU members since 2004, separately. RESULTS: Poland has all the data for 10 core indicators and data for 5 of the 11 recommended indicators. Most of their values are within the range of other EU countries except total neonatal and infant mortality, which are higher in Poland than in the most developed EU countries. Higher total neonatal and infant mortality in Poland results from higher neonatal and infant mortality of prematurely born babies. Gestational age- specific neonatal mortality in Poland was 456.8 deaths per 1000 live births delivered between 24-27 weeks gestational age (against 107.3 -324.6 in the EU members before 2004), 124,7 deaths per 1000 live births delivered between 28-31 weeks (against 17,6 - 84,9 in the EU members before 2004) and 16,2 deaths per 1000 live births delivered between 32-36 weeks (against 2,5 - 10,0 in the EU members before 2004). Neonatal mortality of babies born at term, was within the range observed in EU members before 2004. CONCLUSIONS: Poland has incomplete data sources for perinatal health indicators, especially in respect to evaluation of the quality of health care. Data sources should be expanded. However, existing information indicate that neonatal and infant mortality among babies born (extremely, very and moderately) prematurely is higher in Poland than in the most developed European countries. To change the situation, a multidisciplinary evidence-based national intervention programme should be implemented. PMID- 20919463 TI - [Perinatal mortality of fetuses and newborns in Poland in the years 1999-2008]. AB - BACKGROUND: Procreation and perinatal health which includes maternal health, fetal growth and well being of newborns are a challenge for modern medicine. One of the indices of evaluation of perinatal health is perinatal mortality of fetuses and newborns. This has been emphasised in the National Health Programme in Poland for 2007-2015. AIM: Analysis of perinatal mortality in the period 1999 2008 of fetuses, newborn and stillborn, with MATERIAL AND METHODS: The analysis was based on data from the Central Statistical Office, from the Ministry of Health dokument MZ-29 and on data obtained from own studies. RESULTS: In the second part of the analysed period there was a reduction in the rate of fall of the number of newborn deaths. This was particulary marked in newborn with low and extremely low birthweight. Throughout the whole period of analysis there was a significant difference in the perinatal mortality between the newborn group with birthweight above 2500 g and the newborn group below 2500 g. Higher newborn mortality and particularly higher stillbirth rate was found in the group of mothers above 40 years of age. In the maternal group aged 15-19 years, these indices were slightly less increased. Throughout the analysis period it was noted that there were significant differences between individual voivodeships in perinatal mortality of newborn, as well as of still births. CONCLUSIONS: 1. In order to improve perinatal health and to further reduce the perinatal mortality and in particular to reduce the number of stillbirths and newborn with low and very low birthweight, it is essential to create a well functioning system of triple level perinatal care. There is on urgent need for elaboration of such a programme and finding financial resources for its implementation. 2. Part of this task is to modernise and improve the medical documentation concerning perinatal health. PMID- 20919464 TI - [Can implementation of intensified perinatal survey be effective in improving the quality of perinatal care?]. AB - INTRODUCTION: Intensive scientific research and rapid technical progress have influenced the rapid fall in term newborn mortality. At the same time new problems have arisen such as saving the lives of infants with low and very low birth weight. Solving these problems needs reorganization of perinatal care, better equipment, especially in reference units and in outpatient clinics, as well as more intensive staff training. AIM: to obtain information whether implementation of intensified perinatal survey of fetus and newborn mortality can improve the quality of perinatal care in Poland. MATERIAL AND METHODS: Implementation of the survey based on Central Statistics Office (GUS) data, Ministry of Health MZ-29 section X Document and the author's own studies. RESULTS AND DISCUSSION: In the year 2008 newborn with birth weight less than 2500 g, constituted 6,06% liveborn infants, newborn weighing from 1000 to 2499 g - 5%, those with weight from 500 to 999 g - 0.51% of all live born infants. These figures differ according to voivodeship. The intensive survey concerning birth weight and perinatal mortality indeces in voivodeshipPoland, as well as in individual voivodeships, showed differences between data from the Central Statistics Office and data from the Ministry of Health MZ-29 document. This may be due to different methods of registrating newborn deaths eg. newborns transfered in the first weekoflife from the maternity ward to intensive care neonatal ward or to other specialistic departaments. Another reason for the difference may be discharge of the newborn data according to the place of birth or the mother's place of permanent domicile registration. This causes disturbances in flow of infomation resulting in ineffective analysis of perinatal mortality and of perinatal care evaluation. In the ongoing analysis it was found that in Poland stillbirths occur twice as often as perinatal deaths (4.3 per thousands) stillbirths and 2.15 per thousands perinatal deaths), with significant differences between voivodeships. This makes it obligatory to conduct medical audit which is a form of specialistic supervision. It is probable that higher number of stillbirths and premature births may be caused by late start of perinatal care in pregnancy. In primary health care, insufficient objective parameters are investigated which lead to assessment of the quality of perinatal care. Correct filling up of the pregnancy chart could improve the quality of the management of prophylactic procedures leading to a fall in the number of premature births and stillbirths. This would also lead to a reduction of costs associated with life saving procedures and improving the quality of life in newborns with low and extremly low birth weight. CONCLUSIONS: 1. The survey of fetal and newborn perinatal mortality of fetuses and newborn should be the base for elaborating the perinatal care programme as well as the main source of data for medical audit. This is the instrument for evaluation of the three level perinatal care. It also serves to assess the effectivness of diagnostic and therapeutic recommendations and the programme of active prevention. 2. In order to obtain effectivness in functioning of the three step perinatal care within the framework of the National Health Programme the following steps are needed: - urgent elaboration of new or improved medical documentation which will become obligatory, - implementation of educational programmes and training of teachers. 3. Implementation of medical audit, carried out periodically at all three levels of perinatal care. PMID- 20919465 TI - [Perspectives on future decline in child and adolescent mortality in Poland]. AB - BACKGROUND: Mortality among children and adolescents is relatively low in higher developed countries, and the main causes of death reflect only a number of selected health problems among this population. However, it is worthwhile to refer to international statistics in order to show current trends and the distance that separates each country from the European average and the lowest rates noted in Europe. THE AIM of the study is to present current mortality data among children and adolescents aged 1-19 yrs in Poland compared to European Union statistics. METHODS: The study uses data published by the national Central Statistical Office and the interactive WHO HFA-MDB database (Health for All Mortality Database). RESULTS: The presently recorded number of deaths, among children and adolescents aged 1-19, is slightly below 2.5 thousand, that is 29 per 100 000 persons. A higher mortality rate among boys in comparison with girls continues to prevail, and a higher mortality rate in the rural areas in comparison with towns. In spite of the falling trend, mortality among children and young people in Poland continues to be higher than that observed in most European Union countries (Poland ranks 19th in a total of27). Poland occupies a particularly unfavourable position in statistics related to deaths from external causes and ill-defined symptoms. During the years 1990-2007 the strongest declining trend was noted with respect to the mortality of children aged 1-4, which is less dependent on external factors. In older age groups the declining trend detected in previous years came to a halt in the year 2000. CONCLUSIONS: A further fall of the mortality rate of children and young people could be achieved by consistently implementing programmes preventing accidental injuries (road accidents, drowning, poisoning) and intentional injuries, particularly suicide. In order to improve the health of the young generation it is necessary to implement the postulate of the European Strategy for Child and Adolescent Health and Development on a consistent basis, including prevention of the effects of chronic diseases, mental health disorders and risk behaviour. There is a need for more concern about inequalities in health, especially differences resulting from place of residence and social group. PMID- 20919466 TI - [Chronic diseases and perception of school demands among school children aged 11 15 years in Poland]. AB - BACKGROUND: There are children for whom because of chronic diseases, functioning in school is more difficult. They are absent more often, causing gaps in knowledge and isolation from peer group. These pupils need extra support in order to make normal school progress without the need to move to special schools or individual schooling. The aim of the study is to compare the stress and perception of school demands among healthy and ill schoolchildren. METHODS: The study concerned 5489 children aged 11-15 years who participated in the Polish part of the international study on health behaviour in schoolchildren (HBSC - Health Behaviour in School-aged Children) conducted in 2006. As outcome measures, three items concerning school stress and school-related demands were chosen. Chronically ill pupils were defined as those who suffered from prolonged health problems diagnosed by a doctor and, as a result, had to take medication on permanent basis and/ or stay away from school for this reason. Logistic regression was applied and odds ratio (OR) with 95% confidence interval (CI) was estimated. All analyses were adjusted for age, gender and family economic status measured by Family Affluence Scale (FAS). At first step FAS was included as independent variable, while at the second step three models specific for FAS groups were estimated. RESULTS: The studies revealed that schoolchildren suffering from chronic illness have greater problems with fulfilling their development tasks connected with education. The difference between ill and healthy children is significantly raised by a low family economic status. Students with chronic diseases are at increased risk of finding school work heavy. For the three FAS groups, the odds ratio was: in poor families OR = 1.62 (95% CI: < 1.10-2.38>), in average income families OR = 1.49 (95% C1: < 1.07-2.08 >), and in rich families OR = 1.26 (95% Cl:< 0.84- 1.88 >). CONCLUSION: Young people with chronic health problems are at a higher risk of poor school adjustment. There is only a weak relationship between family socio-economic status and the prevalence of chronic diseases in the population of schoolchildren. However, family economic status modifies the relationship between chronic diseases and perception of school demands. The way a sick child functions in the school environment should become part of a wider discussion among teachers, parents and pediatricians. PMID- 20919467 TI - [Social determinants of subjective health in school children aged 11-15 years in Poland in the light of European data]. AB - BACKGROUND: Adolescence is a particularly significant period due to the risk of psycho-social disorders, life-style formation and making many important decisions about the future. THE AIM of the study is to provide an overall assessment of the impact of various elements of the environment on the risk of disorders of subjective health of schoolchildren aged 11-15 yrs, and to compare of the Polish data with European Union statistics. METHODS: The data source is the last series of international studies on health related behaviour of schoolchildren (HBSC), conducted during the school year 2005/06. In general, the object of analysis comprises data related to 142 478 schoolchildren from a combined sample from 25 countries, on average aged 13.6 yrs (SD = 1.65), including 5489 Polish schoolchildren. The main outcome variable was the occurrence of at least one of three subjective health disorders: poor self-rated health, dissatisfaction with life and the intensity of recurrent subjective symptoms. The analysis included the impact of gender, age (in three age groups), country of residence (Poland vs. the other 24 countries) and the five components of the growing up environment: economic and social status of the family, communication with parents, functioning at school, peer support, problems in the area of domicile. Logistic regression models were estimated with a step-block procedure of variable selection, which provided relative risk indices (OR) with a 95% confidence interval (CI). RESULTS: The studies have shown that the strongest predictor of subjective health disorders consists of problems with functioning at school (OR = 3.14), disrupted communication with parents (OR = 2.15) and absence of peer support (OR = 1.87). However, after these factors were taken into account, the weak impact of the material status of the family (OR = 1.65) and area of residence (OR-= 1.94) continued to be noted. Young people in Poland report subjective health problems more often than their average European counterparts. In the analyses adjusted for socioeconomic and psychosocial factors the differences between Polish adolescents and their peers from EU countries are leveling. Analyzing the social environment in Poland we discover a better assessment of communication in the family, coupled with a lower than European average assessment of the other elements of that environment, especially in relation to material status. CONCLUSION: Intervention activities aimed at reducing health inequalities has to tackle inequalities in the broad socioeconomic context underlying child and adolescent environment. PMID- 20919468 TI - [Inequalities in access to preventive health care for school children]. AB - Access to health care, including preventive health care for pupils affects the health of society. Equal access to pupils'preventive health care means the same level of preventive services for all children and adolescents regardless of school type, place and region of domicile. AIM: To analyse the quality of preventive health care for pupils in school year 2007/2008 in all school types in Poland, giving special attention to inequalities and access of this healthcare. MATERIAL AND METHODS: Reports from national public statistics filled by school nurses regarding preventive healthcare for pupils were analysed. Special attention was given to inequalites in access to RESULT: Disparities in access to preventive health care were observed. They affected more often pupils from rural schools, basic vocational schools and special schools. As a result, 60% rural elementary schools did not have a school health office. School nurses working in these schools were overburdened, each of them had to look after excessive number of pupils. Nearly one-quarter of basic vocational school pupils didn't have periodic check-up. Pupils from these schools less frequently participated in health education conducted by school nurses compared with pupils from other school types. In special schools school nurses were overburdened. One school nurse from these schools had to look after above limit of pupils' number (above 25% in urban and above 75% in rural schools). CONCLUSIONS: 1. Inequalities in access to preventive health care affected pupils from rural, basic vocational schools and special schools. They reflected existing social disparities in Poland. 2. Inequalities exist mainly in the social groups, who are at risk of social exclusion. 3. Equal opportunity for pupils'preventive health care requires systemic solutions in health and educational cooperation at government level. PMID- 20919469 TI - [Are community clubs tutors and parents of children prepared for activities in field of improving health? Preliminary analysis of problem]. AB - Social exclusion constraints the development of individuals and groups. Especially endangered are inhabitants of villages and small towns. To prevent social exclusion of children and adolescents from poor families or with social dysfunctions, community clubs are being organized. THE PURPOSE of the study was a preliminary assessment of preparing community clubs tutors for health education and evaluation of parents' activities in preventive health care for children. MATERIAL AND METHODS: the questionnaire survey was carried out in a sample of 19 community centre tutors and 144 parents (in 84% these were mothers) of children attending these centres. Children of surveyed parents were aged 4-16 years (M = 10.5; SD = 2.5), 70% of them 7-12 years old. Community centre tutors were asked about their knowledge of preventive health care, the current health education activities, cooperation with parents, and local social care institutions. Parents were asked about the use of preventive health care facilities by their children. RESULTS: The largest group of community club tutors assessed their own knowledge about the children's preventive health care as sufficient or good. Their knowledge about active methods in health education was self-assessed as average. In practice, active methods in health education were used only by half of surveyed tutors. Periodic preventive health examinations were performed in 57-86% of the children and 56-75% were vaccinated. CONCLUSIONS: 1. There is a need to implement health education in community clubs, but this requires improving the knowledge of tutors, especially about using active methods. 2. Only a complex approach to prophylaxis can bring real advantages for child health and help in giving equal opportunities and eliminating health inequalities among children. PMID- 20919470 TI - [The role of physical education teachers to support overweight and obese pupils]. AB - INTRODUCTION: School-based physical education (PE) is often proposed as a strategy for obesity prevention and treatment. Thus the role of PE teachers is crucial on this field. OBJECTIVES: The purpose of this study was to investigate the perception of PE teachers towards overweight and obese pupils aged 13-15 years, especially psychosomatic problems and support for obese adolescents in realisation of physical activity programme. MATERIAL AND METHOD: A random sample of 185 PE teachers from 112 lower secondary schools in Poland were surveyed regarding their perception of pupils obesity and their support for obese adolescents. RESULTS: PE teachers observed many negative features among obese pupils: Two thirds of teachers (67% male and 74% teachers with work experience 6 10 years) observed decreased physical fitness and exercise capacity in this group of pupils. Body-related barriers in obese pupils and anxiety caused by weight related peer teasing were observed by respectively 30% and 20% teachers more often women teachers and teachers with shorter work experience. PE teachers were engaged in activities to support obese pupils: 90% of them assessed obese pupils by personal development, 70% conducted counseling and 20% cooperated with obese pupils' parents. Two third of teachers reported successes in their work with obese pupils. Their difficulties were connected with body-related barriers in pupils (24%), and aversion to exercise and physical efforts and location of PE lessons at school (9-16%). CONCLUSIONS: 1. The PE teachers can play an important role in preventing and combating obesity in pupils. 2. PE teachers should be motivated to organize interesting PE lessons, school sport and competitions for both normal and overweight pupils. PMID- 20919471 TI - ["Health for Pomeranians". A regional programme of maternal and child health prepared by a working group experts]. AB - The presented programme "Health for Pomeranians" is based on a number of legal acts and the agreement between the authorities of the Region and the Medical University of Gdansk. The main objective of its authors was to improve the three stage medical care of mother and child. Particular emphasis is placed on improving the preventive care of the pregnant woman and infant, and child who is in the developmental age, presenting the schedule and the range of recommended tests in relation to the patient's age. After an analysis of epidemiological data, the current ambulatory care and number of beds for patients in the Pomeranian region, the needs for the years 2009-2013 according to professional medical, instrumentation and the proposed changes in the diagnostic-therapeutic profile of outpatient clinic and hospitals were presented. In terms of outpatient care as the most important change was the proposal to create a pediatric clinic for consultation within the province, while in the hospital use the expansion of highly specialized care, particularly intensive care unit and rehabilitation. PMID- 20919472 TI - [BINet programme as a standard of modern health policy]. AB - Infectious diseases--despite significant progress, both in their management and prevention--are becoming an increasingly serious problem, and their extent and character frequently constitute a threat for public health. In addition, a significant part of medical decisions regarding treatment and prevention of invasive bacterial infections is not made on the basis of the etiological agent of infection, which increases the chance of therapeutic failures, and makes the right decisions regarding prophylaxis difficult. In June 2008 the National Reference Centre for Bacterial Meningitis (Krajowy Osrodek Referencyjny ds. Diagnostyki Bakteryjnych Zakazen Osrodkowego Ukladu Nerwowego, KOROUN) started the BINet programme, which is a network monitoring invasive bacterial infections acquired outside the hospital. The programme aims to improve the diagnostic and thus therapeutic standards, in community acquired invasive bacterial infections in Poland. The BINet programme is based on the cooperation of clinicians, epidemiologists, microbiologists, and is headed by a team of the National Reference Centre for Bacterial Meningitis. The BINet programme enables quick and appropriate microbiological diagnosis of infections which is the basis of rational therapy and plays a key role in dealing with the infected patient. In addition, accurate epidemiological data allow to take quick and effective preventive measures at local and national level. PMID- 20919473 TI - [Recommendations of prophylaxis of vitamin D deficiency in Poland (2009)]. AB - Adequate vitamin D intake and its status as well outdoor physical activity are important not only for normal bone development and Ca-P metabolism, but for optimal function of many organs and tissues throughout the body. Due to documented changes in dietary habits and physical activity level, both observed in growing children and adults, the prevalence of vitamin D insufficiency is continuously increasing. National Consultants and experts in this field established the Polish recommendations for prophylactic vitamin D supplementation in infants, toddlers, children and adolescents as well as in adults, including pregnant and lactating women based on current literature review. Taking into consideration pleyotropic vitamin D action and safety aspects serum 25 hydroxyvitamin D (25-OHD) level of 20-60 ng/ml (50-750 nmol/l) in children and 30 80 ng/ml (75-200 nmol/I) in adults is considered as optimal. Sunlight exposure inducing vitamin D production in the skin is main endogen source of vitamin D in the body but sunscreens may reduce skin synthesis by 90%. In Poland, skin synthesis is effective only from April to September so other sources of vitamin D such as diet and supplements play an important role. All newborns should be supplemented with 400 IU/d of vitamin D beginning from the first few days of life and continue during infancy. In formula fed infants vitamin D intake from the diet should be taken into account. In preterm infants higher total vitamin D intake (400-800 IU/day) is recommended till 40 weeks post conception. Total vitamin D intake in children and adolescents required from all sources (diet and/or supplements) should be 400 IU/d between October and March and throughout the whole year in case of inadequate vitamin D skin synthesis during the summer months. In overweight/obese children supplementation with higher dosage of vitamin D up to 800-1000 IU/d should be considered. Adults require 800-1000 IU/d of vitamin D. In pregnant and lactating women such supplementation is recommended in case of inadequate intake from diet and/or skin synthesis supplementation. Monitoring of serum 25-OHD level to define optimal dosage should be considered. PMID- 20919474 TI - [Revista Medica de Chile: A new member in the "International Committee of Medical Journal Editors"]. AB - After a worldwide call for applications that took place in 2009, two medical journals were selected to become new members of the "International Committee of Medical Journal Editors (ICMJE)": Chinese Medical Journal and Revista Medica de Chile. Both Editors: Getu Zhaori, MD, and Humberto Reyes, MD, respectively, attended the ICMJE Meeting, 12-14 April 2010, in Queenstown, New Zealand. The meeting agenda included several topics that had been studied in advance by the attendants: editors or deputy editors of the 14 journals integrating this Committee plus a representative for the U.S. National Library of Medicine and another one for the World Association of Medical Journal Editors (WAME). The Committee agreed in new recommendations tending to safeguard the integrity and transparency of every manuscript published in all journals that adhere to the "Uniform Requirements for Manuscripts Submitted to Biomedical Journals (URM)". These recommendations will be published shortly in ICMJE member journals. An important issue discussed refers to improvements in the "ICMJE Uniform Disclosure Form for Potential Conflicts of Interest"' that had some changes, a glossary of terms will be attached to it and the Instructions will be accompanied by translations into the official WHO languages as well as other languages used by ICMJE member journals. For our journal it is an honor and a great responsibility to become a member of this highly qualified Committee, the only journal published in Spanish and the first one from Latin America. PMID- 20919475 TI - [Prevalence of primary antiretroviral resistance among HIV infected patients in Chile]. AB - BACKGROUND: The main cause of virological failure during AIDS treatment is the resistance to antiretroviral medications (ARV). AIM: To search for mutations associated with ARV resistance in recently HIV-1 infected patients naive to treatment, in Chile. MATERIAL AND METHODS: Patients over 18 years old with HIV-1 infection, naive to anti-retroviral drugs before the study were included. Patients with CD4 cell counts less than 200 cells/mm3, viral load below 2000 copies/mL or any condition indicative of advanced AIDS were excluded. Criteria for diagnosis of recent infection (< 18 months) were a previous negative test for HIV antibodies or a history of an acute retroviral syndrome in the past 18 months. Resistance to drugs was analyzed using the TRUGENE HIV-1 assay from Bayer and the OpenGene DNA sequencing system. RESULTS: Ninety nine percent of patients had at least one mutation, 27% had 4 or more mutations, but high level resistance to ARV was found only in 2.7% of cases. Point mutations for non nucleoside reverse transcriptase inhibitors (NNRTI) were detected in 4.1% of cases (K103N in 1 patient, V179D in 2 patients), for nucleoside reverse transcriptase inhibitors (NRTI) in 8.1% of cases (T215S in 1 patient, V118I in 4 patients, M41L in 1 patient) and for protease inhibitors (PI) in 1.3% of cases. All mutations detected in the protease gene were secondary. Of these, the most common were L63P/T (38 patients), L10I/V (27 patients) and V77I (26 patients). Resistance to two or more antiretroviral classes was not detected. CONCLUSIONS: This study supports that, by now, primary resistance has a low prevalence in Chile. Therefore, a genotyping test before starting antiretroviral therapy is not necessary. PMID- 20919476 TI - [Evaluation of the undergraduate educational environment in six medical schools in Chile]. AB - BACKGROUND: The Dundee Ready Education Environment Measure (DREEM) is the most valid and reliable instrument to measure the educational environment (EE) in undergraduate medical education. AIM: To evaluate the EE perceived by undergraduate medical students in Chile, using a Spanish version of the DREEM questionnaire. MATERIAL AND METHODS: The DREEM was applied during 2008 in third, fourth and fifth undergraduate years of six medical schools. The individual results were calculated and means of both global and individual domain scores of the DREEM were compared, by year, gender and between different Schools. RESULTS: One thousand ninety two students (77% of the total universe of students), answered the questionnaire. The mean score of the six Schools was 113.9. The domains of Perception ofLearning and Social Self-Perception obtained the lower scores, with a global outcome indicating a more positive than negative EE. Two schools obtained mean scores of 128.32 and 126.87, that were significantly higher than the global scores obtained by other schools. No relevant differences by years or gender were observed. CONCLUSIONS: There is a significant variability between the six schools evaluated and two of these obtained significantly better scores than the rest. The identified positive and negative areas will orient the actions to improve the EE for undergraduate medical students. PMID- 20919477 TI - [An instrument in Spanish to evaluate the performance of clinical teachers by students]. AB - BACKGROUND: The modernization of clinical teaching has called for the creation of faculty development programs, and the design of suitable instruments to evaluate clinical teachers' performance. AIM: To report the development and validation of an instrument in Spanish designed to measure the students' perceptions of their clinical teachers' performance and to provide them with feedback to improve their teaching practices. MATERIAL AND METHODS: In a process that included the active participation of authorities, professors in charge of courses and internships, clinical teachers, students and medical education experts, we developed a 30-item questionnaire called MEDUC30 to evaluate the performance of clinical teachers by their students. The internal validity was assessed by factor analysis of 5214 evaluations of 265 teachers, gathered from 2004 to 2007. The reliability was measured with the Cronbach's alpha coefficient and the generalizability coefficient (g). RESULTS: MEDUC30 had good content and construct validity. Its internal structure was compatible with four factors: patient-centered teaching, teaching skills, assessment skills and learning climate, and it proved to be consistent with the structure anticipated by the theory. The scores were highly reliable (Cronbach's alpha: 0.97); five evaluations per teacher were sufficient to reach a reliability coefficient (g) of 0.8. CONCLUSIONS: MEDUC30 is a valid, reliable and useful instrument to evaluate the performance of clinical teachers. To our knowledge, this is the first instrument in Spanish for which solid validity and reliability evidences have been reported. We hope that MEDUC30 will be used to improve medical education in Spanish-speaking medical schools, providing teachers a specific feedback upon which to improve their pedagogical practice, and authorities with valuable information for the assessment of their faculty. PMID- 20919478 TI - [Association between hospital admissions due to affective disorders and solar activity. Analysis of 16 years]. AB - BACKGROUND: Exposure to solar activity may be associated with incidence of depressive and manic disorders. AIM: To assess the link between solar activity and appearance of affective disorders. MATERIAL AND METHODS: We examined 1862 clinical records of a psychiatric clinic located in Santiago, Chile. Patients with major depression and manic disorders were included in the study, only when they were admitted at the clinic for the first time. Solar activity was calculated using the Wolf number, which is given by the formula R = K(10g+f), where "g" stands for the groups of sunspots and "f" is the total number of sunspots. We examined the correlation between annual incidence of hospital admissions and average Wolf numbers for the period 1990-2005, which corresponds to approximately one and half solar cycles of 16 years. RESULTS: A total of 450 medical records corresponding to 299 patients (199 women) with depressive symptoms and 151 patients (73 women) with mania, were analyzed. There was a higher number of admissions for depression during the years with lower solar activity. Admissions due to mania tended to increase in the years with high solar activity. There was a negative correlation between the number of hospital admissions due to depression and solar activity (Spearman r = -0.812, p < 0.01). The association between the latter parameter and admissions due to mania did not reach statistical significance. CONCLUSIONS: There is a significant negative association between the rate of hospital admissions due to depressive disorders and solar activity. PMID- 20919479 TI - [Depressive symptoms among patients with acute myocardial infarction. Relationship with revascularization therapy]. AB - BACKGROUND: Persistence of depressive symptoms after myocardial infarction (MI) is associated with an adverse outcome. The relationship between depression and Invasive Revascularization Therapy (IRT) is not yet fully understood. AIM: To compare the frequency of depressive symptoms and other psychosocial variables among patients with MI, undergoing or not undergoing IRT. MATERIAL AND METHODS: Prospective evaluation of 45 patients aged 58 +/- 11 years (87% males) with a diagnosis of MI (Killip I and II). On admission to hospital and at follow up 3 months after discharge, all patients completed the Beck Depression Inventory (BDI), the Zung Anxiety Inventory (ASI), and the Medical Outcomes Study (MOS) social support survey. Depressive symptoms were considered to be present if the BDI score was over 10. RESULTS: Thirty seven percent were hypertensive, 15% diabetic and 44% smokers. Sixty four percent of patients underwent IRT (11.1% revascularization surgery and 53.3% coronary angioplasty). Forty four percent of patients scored over 10 in the BDI at baseline assessment and 26.5% at 3 months follow-up (p < 0.01). At baseline BDI score was 10.2 +/- 5.1 and 9.1 +/- 4.4 among patients subjected or not subjected to IRT, respectively (NS). The figures at 3 months of follow up were 9.9 +/- 5.6 and 4.1 +/- 2.5, respectively (p < 0.01). At baseline and three months BDI, anxiety and perceived social support were significantly correlated. CONCLUSIONS: Depressive symptoms were frequent after MI in this group of patients, and decreased at follow up only among patients not subjected to IRT. PMID- 20919480 TI - [Prevalence of metabolic syndrome among Chilean adults]. AB - BACKGROUND: There are several diagnostic criteria for Metabolic Syndrome (MS) definition. AIM: To study their application in the Chilean general adult population. MATERIAL AND METHODS: We analyzed data from a random sub sample of 1.833 adults aged 17 years and older surveyed during the First Chilean National Health Survey conducted in 2003. The prevalence of MS was estimated using the update Adult Treatment Panel III (ATP III) of the National Cholesterol Education Program (NCEP) and the International Diabetes Federation (IDF 2005) criteria. The distribution of MS was analyzed according to age, gender, educational level, geographic area, obesity and sedentary lifestyle. RESULTS: The overall prevalence of MS was 31.6% (95% CI 28.5-34.9) and 36.8% (95% CI 33.5-40.3), according to update ATPIII-NCEP and IDF criteria respectively. Both criteria had a 90% concordance. Demographic and socioeconomic distribution was similar for both criteria. The prevalence of high blood pressure, high fasting glucose, and low HDL cholesterol (MS components) were: 46, 22 and 53% respectively. The prevalence of abnormal waist circumference was 30 and 59% according to update ATPIII-NCEP and IDF criteria, respectively. Using update ATPIII-NCEP criteria, the gender, age and educational level adjusted odds ratio (OR) for having MS was 9.59 (95% IC 6.8-13.6) for obese subjects compared with normal weight subjects and 2.14 (95% IC 1.3-3.7) for sedentary subjects compared with non sedentary. CONCLUSIONS: There was a 90% agreement between update ATPIII-NCEP and IDF criteria for the diagnosis of MS. The overall prevalence of MS in this population was 32% usuing update ATPIII-NCEP criteria, with higher prevalence among obese and sedentary subjects. PMID- 20919481 TI - [Effects of an exercise training program on the quality of life of women with breast cancer on chemotherapy]. AB - BACKGROUND: Exercise may reduce anxiety and depression associated to the diagnosis and treatment of cancer. AIM: To assess the effects of a physical training program during chemotherapy among women with breast cancer. PATIENTS AND METHODS: Twenty two women aged 49 +/- 7 years with breast cancer voluntarily agreed to take part in the study, after surgical treatment. Functional capacity (Karnofsky Performance Status), psychological status (General Health Questionnaire, GHQ) and quality of life (EORTC QLQ-C30) were evaluated at baseline and at the end of the study. Before beginning with adjuvant chemotherapy, ten women were randomly assigned to a program of physical exercise and seven to a control group. The program lasted 18 to 22 weeks, depending on the duration of chemotherapy. RESULTS: Five women were lost from follow up. Before starting chemotherapy, 41% of women were working and all had to kit. At baseline all had a normal Karnofski score and quality of life was compromised. At the end of the study, the intervention group had an improvement of their quality of life, compared to the control group that did not experience significant changes. CONCLUSIONS: An exercise training program improves quality of life of women with breast cancer on chemotherapy. PMID- 20919482 TI - [Survival of patients with vulvar cancer]. AB - BACKGROUND: Vulvar cancer corresponds to 3 to 5% of all female reproductive tract malignancies. Therefore it is classified as a low frequency disease. AIM: To estimate overall and conditional survival one and two years after diagnosing women with vulvar cancer. MATERIAL AND METHODS: Retrospective cohort study. The patient database ofan oncological hospital was revised and patients with vulvar cancer diagnosed between 1997 and 2006 were selected. The clinical records of these women were reviewed. RESULTS: Eighty six women aged 32 to 92 years, were identified. Eighty percent had a squamous carcinoma, 46% were in stage III, 48% received incomplete treatment, 40% consulted due to the presence of a vulvar mass and 18% had lesions in labia majora or minora. Overall five years survival at 5 years was 41.8%. There were statistically significant differences in survival depending on the initial stage of cancer (p = 0.02). Five year conditional survival, one and two years after the diagnosis, was 59 and 79%, respectively. CONCLUSIONS: Five years overall survival of these group of women with vulvar cancer was 41.8%. The figures increased to 59 and 79% in patients who had survived one and two years after the diagnosis. The stage of the lesion and the initial survival are survival prognostic factors for vulvar cancer. PMID- 20919483 TI - [Effect of a tele-care model on self-management and metabolic control among patients with type 2 diabetes in primary care centers in Santiago, Chile]. AB - BACKGROUND: Telephone based self-management support may improve the metabolic control of patients with type2 (DM2) diabetes if it is coordinated with primary care centers, if telephone protocols and clinical guidelines are used and if it is provided by nurses trained in motivational interviewing. AIM: To assess the efficacy of a tele-care self-management support model (ATAS) on metabolic control of patients with DM2 attending primary care centers in a low income area in Santiago, Chile. MATERIAL AND METHODS: Two primary care centers were randomly assigned to continue with usual care (control group, CG) or to receive additionally 6 telecare self-management support interventions (IG) during a 15 month period. Glycosylated hemoglobin (HbA1c) was used to measure metabolic control of DM2; the "Summary of Diabetes Self-care Activities Measure" and the "Spanish Diabetes Self-efficacy" scale were used to measure self-management and self efficacy, respectively. Changes in the use of health services were also evaluated. RESULTS: The IG maintained its HbA1c level (baseline and final levels of 8.3 +/- 2.3% and 8.5 +/- 2.2% respectively) whereas it deteriorated in the CG (baseline and final levels of 7.4 +/- 2.3 and 8.8 +/- 2.3% respectively, p < 0.001). The perception of self-efficacy in the IG improved while remaining unchanged in the CG (p < 0.001). Adherence to medication, physical activity and foot care did not change in either group. In the IG, compliance to clinic visits increased while emergency care visits decreased. CONCLUSIONS: The ATAS intervention, in low income primary care centers, significantly increased the probability of stabilizing the metabolic control of patients with DM2 and improved their use of health services. PMID- 20919485 TI - [Endoluminal excision of an esophageal fibrovascular polyp. Report of one case]. AB - We report a 47-year-old woman presenting with dysphagia. A chest CAT scan and barium swallow showed an endoluminal mass that extended to four vertebrae. An endoluminal sonography localized the pediculum of the mass, that was excised endoscopically. The pathological study disclosed a fibrovascular polyp. After 18 months of follow up, the patient is asymptomatic. PMID- 20919484 TI - [Pancreatic metastasis from renal cell carcinoma: a case report]. AB - We report the case of a 60-year-old woman with multiple pancreatic nodules found on abdominal computed tomography. Thirteen years earlier she had undergone a left nephrectomy for renal cell carcinoma. The patient underwent surgery with a preoperative diagnosis of multifocal metastatic or neuroendocrine tumor. At surgery, two metastatic nodules of renal cell carcinoma were found and excised. After four years of follow up there is no evidence of recurrence. PMID- 20919486 TI - [Extensive cerebral vein thrombosis as first manifestation of Behcet's disease. Report of one case]. AB - Behcet's disease (BD) is a systemic inflammatory vascular disease with several clinical manifestations and geographical differences in disease expression. In Middle Eastern countries it is one of the most common causes of cerebral venous thrombosis. We report a 29-year-old female admitted for acute headache and vomiting. A magnetic resonance image showed a large thrombosis of sagital and transverse sinuses. She developed oral and genital ulcers a week later. Ophthalmologic examination revealed left anterior uveitis and ipsilateral papilledema. Multiple studies ruled out a hypercoagulability syndrome. The patient used oral contraceptives. Anticoagulant therapy was prescribed. A biopsy of a genital ulcer demonstrated diffuse lymphocytic infiltration with vasculitis. After treatment with topical and systemic corticoids, her condition improved. Venous sinus thrombosis followed by oral and genital ulcers is an unusual presentation of Behcet's disease. PMID- 20919487 TI - [Four-week Levitronix Centrimag bridge-to-transplant for post myocardial infarction cardiogenic shock. A case report]. AB - Cardiogenic shock after myocardial infarction has a high mortality even if early revascularization is achieved. Biventricular assist devices have not been used in Chile in this critical setting. We report a case of a 55-year-old diabetic man who suffered an acute chest pain and ventricular fibrillation. Prompt outside hospital defibrillation/reanimation restored pulse and allowed emergency room transfer on mechanical ventilation. Electrocardiogram showed an anterior myocardial infarction and early revascularization was achieved by anterior descending artery angioplasty. However, severe cardiogenic shock continued in spite of inotropic and intra aortic balloon pump support. Levitronix Centrimag biventricular mechanical circulatory support was inserted during reanimation for recurrent ventricular fibrillation and the patient listed for urgent cardiac transplantation upon stabilization. Heart transplantation was performed successfully 28 days later and the patient was discharged after a 21-day recovery period. Twelve months after transplant the patient is in NYHA functional class I with normal biventricular function. Levitronix Centrimag biventricular mechanical circulatory support could be used successfully as a bridge-to-transplant for myocardial infarction cardiogenic shock. PMID- 20919488 TI - Interleukin (IL)-35 is raising our expectations. AB - PURPOSE: To elucidate and discuss the role of IL-35 in immunity to parasitic and bacterial infections as well as in autoimmunity in terms of its anti-inflammatory properties, we highlight significant findings on this novel member of the IL-12 family. METHODS: Studies using genetically deficient mice have greatly enhanced our understanding of the biology of IL-35. On the basis of data derived from the analysis of these genetically deficient mice published by NIH, we focus on the key features of this heterodimeric cytokine, especially its relation to the other IL-12 family members, and discuss its potential relevance to the clinical usage. PRINCIPAL FINDINGS: IL-35 is required for the CD4+CD25+ Treg cells-mediated immune regulation, the alleviation of some inflammatory responses, as well as the expansion of CD4+CD25- Teff cells simultaneously. Moreover, administration or augmentation of IL-35 suppresses some diseases of autoimmune or allergic origin like collagen-induced arthritis or Helicobacter-induced colitis in animal models, demonstrating its potential in therapy of diseases mediated by inflammatory cytokines. However, some questions involving it are still unclear, including the composition of IL-35 receptor, IL-35-related cell signaling pathway, the different expression patterns of IL-35 between human and murine T cells, etc. CONCLUSION: As our understanding of the IL-35 is rapidly growing and changing, it will bring us more therapeutic strategies towards some intractable immune diseases such as Lupus Erythematosus. PMID- 20919489 TI - [Genetic markers in essential hypertension]. AB - Essential hypertension (HTA) is a multifactorial disease and in Chile, its prevalence is 33.7%. There is a genetic predisposition to develop hypertension, whose magnitude is approximately 30 to 50%. At present, some factors are known to increase the risk for cardiovascular disease, but widely accepted biomarkers for screening are missing. The first studies that looked for candidate genes have focused on the renin-angiotensin--aldosterone, aducina, adrenoreceptors beta, G protein subunits, G protein signaling regulators, kinases associated with G proteins and Rho kinases. Studies of DNA sequencing search for polymorphisms and variants through single nucleotide polymorphisms, have been used to seek partnerships with complex or multifactorial diseases, like HTA. Examples of these are: components of collagen proteins, genes related to cell myocardial proteins belonging to cytochrome P450 and growth factors, among others. It is still unlikely to count in a near future with a universal marker. Most probably, a series of markers that confer susceptibility to a specific individual will have to be used in prevention programs or personalized therapy. PMID- 20919490 TI - [Bipolar depression and unipolar depression: differential diagnosis in clinical practice]. AB - When assessing a patient with depression it is crucial not to miss a diagnosis of bipolar depression. In this review we suggest that it can be achieved, first, by consistently usingstandardised diagnostic criteria (e.g., DSM-IV-TR or ICD 10) and, second, by ascertaining the presence of some clinical features. The latter include previous episodes of mood elevation, current or past episodes of psychotic depression, onset of recurrent depressive disorder before the age of 25, a strong family history of mood disorder and suicide, lack of response or "wearing off" of response to well conducted antidepressant treatment, and an unusually fast response to antidepressants with features of elation. Although more and better research is required to establish the validity, sensitivity, specificity, and predictive value of each one of these features we suggest that from a practical point of view they would increase clinicians' awareness of bipolar depression. PMID- 20919491 TI - [When two consecutive laboratory results indicate a change in health status in a patient?]. AB - Sources of variation between two serial tests must be considered in interpreting if there was a clinically significant change. The main causes of variation are the biological variation coefficient (CVB) of the test in question, which must be obtained from the literature, and the analytical coefficient of variation (CVA) of the same test, which must be obtained from the internal quality control laboratory data. With both data we can calculate the critical difference or "reference change value" which helps us to decide whether there was a real change in the patient's health. PMID- 20919492 TI - [Absence of Chorein protein is the molecular basis of psychiatric and neurologic manifestations associated with acanthocytosis in a patient]. PMID- 20919494 TI - [Preliminary report of a governmental program on children psychosocial development care in Chile]. PMID- 20919493 TI - [Case study of monoclonal gammopathy of undetermined significance and multiple myeloma at "Hospital Naval Almirante Nef" vina del Mar, Chile]. PMID- 20919495 TI - [Clinical application of azithromycin extended-release (ER) formulation to treat female sexually transmitted infection]. AB - The prevalence of female sexually transmitted infection (STI) in Japan is in the decreasing tendency after 2002, however it still actualizes as a social problem. Azithromycin, which is 15-member macrolide antimicrobial agent, has indication to treat the chlamydia STI in a single dose of 1 g. In April 2009, a single dose of 2 g of azithromycin extended release (ER) formulation, which is improved formulation by the viewpoint of pharmacokinetics-pharmacodynamics, was approved and has indications to treat not only chlamydial STI but also gonococcal STI. We considered the clinical application of azithromycin ER to treat female STI, including our new our own experiences because the clinical studies of azithromycin ER for STI had not been conducted. In conclusion, azithromycin ER was suggested theoretically becoming one of the choices of new treatment STI caused by not only chlamydia but also gonococcus, more clinical consideration to treat STI will be necessary in the future. PMID- 20919496 TI - [Bacteria isolated from surgical infections and their susceptibilities to antimicrobial agents --special references to bacteria isolated between April 2008 and March 2009]. AB - Bacteria isolated from infections in abdominal surgery during the period from April 2008 to March 2009 were investigated in a multicenter study in Japan, and the following results were obtained. In this series, 712 strains including 18 strains of Candida spp. were isolated from 173 (80.5%) of 215 patients with surgical infections. Three hundred and sixty-six strains were isolated from primary infections, and 346 strains were isolated from postoperative infections. From primary infections, anaerobic Gram-negative bacteria were predominant, followed by aerobic Gram-negative bacteria, while from postoperative infections aerobic Gram-positive bacteria were predominant, followed by anaerobic Gram negative bacteria. Among aerobic Gram-positive bacteria, the isolation rate of Enterococcus spp. was highest, followed by Streptococcus spp., and Staphylococcus spp. in this order, from primary infections, while Enterococcus spp. was highest, followed by Staphylococcus spp. from postoperative infections. Among aerobic Gram negative bacteria, Escherichia coli was the most predominantly isolated from primary infections, followed by Klebsiella pneumoniae and Pseudomonas aeruginosa, in this order, and from postoperative infections, P aeruginosa was most predominantly isolated, followed by E. coli, Enterobacter cloacae, and K. pneumoniae. Among anaerobic Gram-positive bacteria, the isolation rate of Eggerthella lenta was the highest from primary infections, followed by Parvimonas micra, Streptococcus constellatus and Gemella morbillorum, and from postoperative infections, E. lenta was most predominantly isolated. Among anaerobic Gram negative bacteria, the isolation rate of Bacteroides fragilis was the highest from primary infections, followed by Bacteroides thetaiotaomicron, Bacteroides ovatus and Bilophila wadsworthia, and from postoperative infections, B. fragilis was most predominantly isolated, followed by B. thetaiotaomicron, B. wadsworthia and B. ovatus, in this order. In this series, we noticed no vancomycin-resistant methicillin-resistant S. aureus, and Enterococcus spp., nor multidrug-resistant P aeruginosa. We should carefully follow up B. wadsworthia which was resistant to various antibiotics, and also Bacteroides spp. which was resistant to many beta lactam antibiotics. PMID- 20919497 TI - [Antimicrobial activity of oral quinolones against clinical isolates of Bifidobacterium group and Clostridium difficile]. AB - Administrations of antimicrobial agent influence human intestinal flora, and sometimes lead to cause Clostridium difficile colitis (CDC). It has been well known that antimicrobial agents, such as clindamycin (CLDM), ampicillin (ABPC) and cephems, frequently cause C. difficile colitis, however, recently some respiratory quinolones, such as garenoxacin (GRNX) and moxifloxacin (MFLX), have paid to attention. Bifidobacterium species would be highly associated with the preservation of normal intestinal flora, while C. difficile would be associated with diarrhea related with antibiotics administration. We investigated antimicrobial activity of GRNX, MFLX and levofloxacin (LVFX) by agar dilution methods based on CLSI recommendations. Forty-seven strains Bifidobacterium species isolated from healthy human intestinal flora and 51 strains of C. difficile isolated from C. difficile colitis patients between 2004 and 2006 were subjected to this study. MIC ranges of Bifidobacterium species for GRNX, MFLX and LVFX were 0.5-16, 0.06-2, and 0.5-8 microg/mL, respectively. MIC50 s of GRNX, MFLX and LVFX against Bifidobacterium species were 2, 0.5 and 4 microg/mL, respectively. MIC90 s of GRNX, MFLX and LVFX against Bifidobacterium species were 8, 2 and 8 microg/mL, respectively. MIC ranges of C. difficile for GRNX, MFLX and LVFX were 0.5 - > 64, 1-64, and 0.125-32 microg/mL, respectively. MIC50s of GRNX, MFLX and LVFX against C. difficile were 2, 2 and 0.5 microg/mL, respectively. MIC90 s of GRNX, MFLX and LVFX against C. difficile were 64, 16 and 8 microg/mL, respectively. LVFX would preserve Bifidobacterium species, and also would be bactericidal for C. difficile, which might lead to the low rate of gastrointestinal disorder in LVFX. GRNX would preserve Bifidobacterium species, however, might be lead to CDC in some cases, since antimicrobial activity for C. difficile has been weak compared with LVFX. Since MFLX would be bactericidal for Bifidobacterium species and antibacterial activity of MFLX for C. difficile would be weak compared with LVFX, we have to pay attention to antibiotics associated diarrhea in MFLX treatment. PMID- 20919498 TI - [A historical story of the Japanese antibiotics world-development of penicillin]. PMID- 20919499 TI - [A proposal of a patient psychiatric treatment and hospitalisation consent form]. AB - The Polish medical law has accepted the rule of equivalence in the doctor-patient relationship. In this way it gave up on the medical paternalism". To a large extent, the newly passed or renewed Rules and Regulations were responsible for this. All Polish hospitals, the psychiatric ones amongst them, must abide the rules on patients' agreement to being hospitalised, examined and treated in accordance with the regulations on: the profession of the doctor and the dentist (passed on the 5th December 1996); on the patient's laws and the Speaker of Patient's Laws (passed on the 6th November 2008) and the Minister of Health Regulation on the type and range of medical records kept in the health care centres and the means of dealing with those records (from the 21st December 2006). Many hospitals have use their own adapted records, which are in accordance with those rules and regulations. There is no universal forms concerning the patient's consent to being admitted and treated in a psychiatric hospital. The problem that is taken on by the psychiatrists about the difference and specificity of psychiatric treatment and the situation of the patient being admitted onto a psychiatric ward, proves the general consent forms to be inadequate. The article shows the current and running regulations on the patient's consent to hospital admission, an agreement to receiving health care and receiving medical information and insight into medical records. The character, scope, types of patient's agreement and their forms have been discussed here. Appropriate form types and outlines are presented. PMID- 20919500 TI - [Incapacity to undertaking the essential marital duties due to causes of psychic nature. The forensic-psychiatric point of view]. AB - Since at least 20 years, most of the legal proceedings of marital incapacity are carried on by the church tribunals mainly of no 3 canon 1095 new law code, that is of mental incapacity to undertaking and performing the essential marital duties. Very often the legal proceedings are very difficult and the canonical lawyers need the forensic psychiatric or psychological opinions. The aim of this paper is to give the forensic psychiatrists and psychologists the essential knowledge connected with the new regulations listed in canon 1095 no 3 of the actual canon law code. According to the opinions of the notable canonical lawyers the author describes the legal and marital prerequisites for valid marriage, the ability for undertaking and performing the essential marital duties and the mental reasons for marital incapacity. The author points out several psychiatric reasons underlying the mental incapacity for undertaking and performing essential marital duties: personality disorders and alcoholism which preclude adequate interpersonal relations and sexually related personality disorders which preclude the exclusiveness and natural consumption of the marital agreement. At the end the author points out the conditions which should have good forensic opinion. PMID- 20919502 TI - [Transcranial direct current stimulation and related techniques in treatment of psychiatric disorders]. AB - Transcranial Direct Current Stimulation tDCS is one from many techniques of electrical head stimulation, which were or are subjected to clinical investigations for testing their mainly antidepressive efficacy, and which do not evoke the excessive stimulation of brain neurones with eliciting of the paroxysmal discharge. Despite the proven effectiveness of the convulsive techniques, amongst them electroconvulsive therapy ECT, investigations over sub(non) convulsive methods were continued. The paper describes and contains a systematisation trial of the sub(non)convulsive techniques applied in the period of past decades in the therapy of psychical disorders. Their clinical effectiveness is low, and investigations over them have mainly a cognitive value. PMID- 20919501 TI - [The evolution of the canons law code and the mental nature reasons of marital incapacity during the last 25 years]. AB - AIM: The aim of the article was to investigate how during the last 25 years of implementation of the new canons law code changed the use of these new law regulations by the church lawyers as well as the mental causes for marital incapacity. METHOD: The basis of investigation was the analysis of 135 forensic psychiatric opinions made by the author for the Metropolitan Tribunal of Gniezno in the legal proceedings carried out in the years 1984-2008. RESULTS AND CONCLUSIONS: On the basis of the analysis, the author got the following results. During the first 10 years of implementation of the new canon law code, the legal proceedings were carried on mostly of no 1 or together of no 1 and no 3 canon 1095, but during the last 15 years mostly of no 3 this canon of mental incapacity to undertaking the essentials marital duties. The mental causes of the marital incapacity also changed very significantly in this time. During the first 15 years, there were serious mental disorders such as schizophrenia, epilepsy or oligophrenia, but during the last 10 years the main causes of incapacity to undertaking the essential marital duties were personality disorders, alcohol dependences or psychosexual deviations. PMID- 20919503 TI - [Caregiving consequences in mental disorders--definitions and instruments of assessment]. AB - Severe mental illnesses have far-reaching consequences for both patients and their relatives. This paper reviews literature on the measures of caregiving consequences. Authors provide a condensed knowledge and research results in the area of caregiving consequences, especially both subjective and objective caregivers' burden. The consequences of care apply to carers' social and leisure activities, financial status, health condition. The burden of care has three fundamental causes: the reorganisation of mental health services, a social isolation of patients and their families and the lack of systemic support for caregivers. The problem of caregiving consequences has been investigated in several studies. In order to identify factors, which have impact on caregiver distress, a variety instruments have been developed. This paper focuses on questionnaires useful for the systematic assessment of both objective and subjective burden: Involvement Evaluation Questionnaire (IEQ), Perceived Family Burden Scale (PFBS), Zarit Caregiver Burden Scale (ZCBS), Experience of Caregiving Inventory (ECI), Family Problems Questionnaire (FPQ). The mentioned instruments proved to be a reliable instrument for measuring caregiver consequences in mental healthcare. PMID- 20919504 TI - [Psychological determinants of quality of life in women diagnosed with depressive disorders]. AB - The essential element of the functioning of patients is the assessment of quality of life and its determinants. Taking into account the depression process and its specific nature this seems to be of special importance. AIM: The aim of this paper was the assessment of importance of psychological determinants of quality of life in women with depressive disorders. METHODS: The tests were carried out on the basis of the analysis of medical documentation, including the psychiatric records. The following criteria were measured: depression level (Beck Hopelessness Scale), quality of life (The Life Satisfaction Questionnaire FLZ according to Fahrenberg), personality model (NEO Five-Factor Inventory), optimism (The Life Orientation Test-Revised LOT-R by M. Scheier, ChS. Carver and M. Bridges adapted by R. Poprawa and Z. Juczynski), purpose in life (The Purpose-in Life Test developed by Crumbaugh and Maholick according to the authorised translation by Z. Pluzek), social support (The Social Support Questionnaire by Sommer G, Fydrich T, 1989 adapted by Z. Juczynski), health satisfaction (General Health Questionnaire GHQ 28 by David Goldberg). Women diagnosed with depressive disorders were qualified for testing. The tested group of women included 80 patients in the age bracket of 40 to 60 years from the Outpatient Department of Mental Health, Regional Specialised Hospital in Zgierz. The reference group consisted of 30 women showing no symptoms of depressive disorders. RESULTS: The statistical analysis of variables taken into account in the tests showed essential statistical differences between the compared groups with regard to almost all parameters. Significant differences were found in respect of life satisfaction, personality variables, social support, health satisfaction and purpose in life. CONCLUSIONS: The obtained results showed significant differences regarding the assessment of quality of life between the group of women with depressive disorders and the group of women without any symptoms of such disorders in respect of the tested psychological determinants. The only exception was the "parent-child relationship satisfaction" where no differences were found. PMID- 20919505 TI - [Evaluation of quality of life, anxiety and depression in testicular cancer patients during chemotherapy and after anticancer treatment]. AB - AIM: Investigating quality of life, anxiety, aggression and depression disorders in testicular cancer during chemotherapy and after anticancer treatment. Evaluation of correlation between quality of life domains and mental disorders. METHOD: Participants were 111 men: 57 testicular cancer patients during chemotherapy and 54 survivors at least 6 months after treatment for testicular cancer. The World Health Organization Quality of Life Instrument (WHOQoL-BREF) and the Hospital Anxiety Depression Scale (HADS) were used to study. RESULTS: The assessment of general health was higher in survivors than in patients during chemotherapy. Anxiety and depression disorders were defined by a score > or = 8 on the HADS subscales. The prevalence of anxiety disorder was 40% (anxiety syndrome--15%) in patients during chemotherapy and 18.5% in patients after treatment. The prevalence of depression disorder was 14.6% in patients during chemotherapy and 9.3% in patients after treatment. The prevalence of aggression was 5.6% in patients during chemotherapy and 18.9% in survivors. Anxiety and depression disorders correlated with quality of life and self-health perception, psychological and social domains. CONCLUSION: Testicular cancer patients during chemotherapy assessed their health lower. Chemotherapy for testicular cancer was associated with higher levels of anxiety and depression. Survivors after testicular cancer therapy have an increased risk of a higher aggression level. PMID- 20919506 TI - [Comorbidity of aspirin-induced asthma, panic disorder and depression versus gender and presence of profound psychological traumas]. AB - AIM: The author examined psychiatrically a group of 100 ambulatory patients with asthma. The special interest of the study was the careful analysis of the time, context and content of different psychological traumas that the patients had throughout their lives. METHODS: 100 consecutive adults with confirmed, physician diagnosed aspirin-induced asthma underwent psychiatric interview and assessment using M.I.N.I 5.0, Beck Depression Inventory (BDI) and Panic And Agoraphobia Scale (PAS). Psychiatric assessment was performed by an experienced liaison psychiatrist according to ICD-10 and DSM-IV diagnosis. There were 66 women (66%) and 34 men (34%). The average age was 52.7 (SD = 12.3) for women and 48.8 (SD = 13.0) for men. RESULTS: In the group of 100 patients with asthma, women were a majority (66%) with higher level of anxiety and depressive symptoms than men. It may be due to specific trauma of suffering and/or death of an emotionally close person, which occurred in adulthood. This kind of trauma may have an impact on the aetiology of both panic disorder and depression. Women are more exposed to this sort of trauma due to their social role. CONCLUSIONS: It is possible, that psychological trauma affects the development, course and severity of anxiety and depressive symptoms in asthmatic patients. PMID- 20919507 TI - [Panic disorder and depression influence on the severity of aspirin-induced asthma]. AB - AIM: Studies have reported a high rate of depression (DD) and panic disorder (PD) among asthma patients, though the impact of these disorders on asthma severity remains unclear. This study evaluated the prevalence of psychiatric disorders in 100 patients with aspirin-induced asthma and association between psychiatric status and levels of asthma severity. METHODS: 100 consecutive adults with confirmed, physician-diagnosed aspirin-induced asthma underwent psychiatric interviews and assessment using M.I.N.I 5.0, Beck Depression Inventory (BDI) and Panic And Agoraphobia Scale (PAS). Psychiatric assessment was performed by an experienced liaison psychiatrist according to ICD-10 and DSM-IV diagnosis. Asthma severity was assessed according to NHLBI/NAEPP 2007. There were 66 women (66%) and 34 men (34%). The average age was 52.7 (SD = 12.3) for women and 49.8 (SD = 13.0) for men. RESULTS: 41% patients met the diagnostic criteria for panic disorder, and 30% of them met depression criteria. Analyses revealed that there is correlation between asthma severity and presence and intensity of psychiatric disorders. CONCLUSIONS: Results suggest that psychiatric disorders are prevalent among patients with aspirin-induced asthma and are associated with worse asthma severity. Physicians should consider the impact of these conditions when planning optimal treatment. PMID- 20919508 TI - [Prevalence of mental disorders and psychoactive substance use in metropolitan 17 year old youth population]. AB - AIM: To determine the extent to which mental disorders (depressive disorders, anxiety disorders, eating disorders) and psychoactive substance use are prevalent among Krakow secondary school adolescents in the late adolescent phase. METHOD: A representative sample of the population of Krakow secondary school pupils was tested. Two-stage draw method identified a group of 1933 2nd form pupils of all types of secondary schools: grammar schools, technical schools and vocational schools (17-year-olds). They were tested using the following screening questionnaires: Beck Depression Scale, EAT-26 eating disorders scale, Obsessive compulsive disorder (Leyton) scale and the author's drug questionnaire. RESULTS: Girls declared symptoms of mental disorders twice as often as boys (41.2% vs. 22.7%). Among girls, the most common disorders were: depressive symptoms (33.6%), eating disorder symptoms (18.7%) and obsessive-compulsive disorders (5.4%). And in the boys group: depressive symptoms (22.7%), eating disorder (7.3%) and obsessive-compulsive symptoms (3.4%). Findings were obtained concerning the prevalence of substance use in the boys and girls group (73% vs. 68%), mainly alcohol, as well as alcohol and cigarettes and alcohol, cigarettes and drugs. CONCLUSIONS: The prevalence of mental disorders in the population of 17-year-olds is significant; it concerns especially depressive symptoms and eating disorder symptoms. A significant prevalence of psychoactive substance use was found in this age group, mainly alcohol and mixed type substance use: alcohol and cigarettes and alcohol, cigarettes and drugs. PMID- 20919509 TI - [Specific phobia in early period of puerperium. Case report and its legal aspects]. AB - A 28 year old woman with a specific phobia of being in hospital, three hours after having given birth to her baby, demanded to be discharged from the hospital, in spite of having been informed by the obstetrician that her life was threatened because of an intrauterine infection that might cause sepsis. The patient decided to stay in hospital after several long-lasting psychiatric consultations including psychotherapeutic interventions. The patient did not recognise that her fear was excessive and unreasonable, i.e., did not meet one of the criteria of specific phobia. She gradually regained criticism toward her symptoms within approximately one day. This indicates that patients with specific phobia confronted with a phobic situation may temporarily loose awareness that their fears are unreasonable and/or too intensive and may express beliefs similar to psychotic delusions. This situation faced the team of doctors with potential legal problems that might appear if the patient had definitely refused to stay in the hospital. Polish law does not allow to treat such patients against their will on non-psychiatric hospital wards. However, in the case ofa definite phobia diagnosis there is no legal way to hospitalise a patient against his or her will on a psychiatric ward. PMID- 20919510 TI - [Detention--means of protection in psychiatry, law and reality]. PMID- 20919511 TI - Single-port laparoscopic surgery. AB - Laparoscopic surgery performed through a single-incision is gaining popularity. The demand from the public for even less invasive procedures will motivate surgeons, industry, and academic centers to explore the possibilities and refine the technology. Although the idea seems quite attractive, there are several technological obstacles that are yet to be conquered by improved technology or additional training. The question of safety has yet to be answered and will require well-designed randomized control trials. Opponents to the approach argue that the size of the single incision (see Table 1) is frequently larger than all the standard laparoscopy incisions combined. On the other hand, proponents remember a similar argument from traditional open surgeons during the initial development of laparoscopy. That argument was quickly discredited when the immediate benefits oflaparoscopy were compared with patients undergoing surgery with small laparotomy incisions. During the development of a new technique, the learning curve exposes patients to risk and society to expense. LESS pioneers appear to have reached a level of comfort with technology and techniques that paves the way for scientific scrutiny. Perhaps, the surgical community will capitalize on this situation with randomized, controlled studies and sound evidence to support or refute the benefits of LESS. If we do not seize this opportunity, patient demand and industry's dual edge message of financial success versus fear of losing referrals will lead to a scenario similar to the development of laparoscopic cholecystectomy in the 1990s. Regardless of its future, the surgical community will still benefit from a renewed excitement as surgeons aim to continually reduce the amount of pain and trauma our patients must endure. In addition, technological advances on instrumentation will benefit the field of laparoscopy and improve patient care. PMID- 20919512 TI - Combating stress and burnout in surgical practice: a review. AB - The practice of surgery offers the potential for tremendous personal and professional satisfaction. Few careers provide the opportunity to have such a profound effect on the lives of others and to derive meaning from work. Surgeons choose this arduous task to change the lives of individuals facing serious health problems, to experience the joy of facilitating healing, and to help support those patients for whom medicine does not yet have curative treatments. Despite its virtues, a career in surgery brings with it significant challenges, which can lead to substantial personal distress for the individual surgeons and their family. By identifying the priorities of their personal and professional life, surgeons can identify values, choose the optimal practice type, manage the stressors unique to that career path, determine the optimal personal work-life balance, and nurture their personal wellness. Being proactive is better than reacting to burnout after it has damaged one's professional life or personal wellness. Studies like the ACS survey can benefit surgeons going through a personal crisis by helping them to know that they are not alone and that many of their colleagues face similar issues. It is important that surgeons do not make the mistake of thinking: "I must not be tough enough," or "no one could possibly experience what I am going through." The available evidence suggests that those surgeons most dedicated to their profession and their patient may very well be most susceptible to burnout. Silence on career distress, as a strategy, simply does not work among professionals whose careers, well-being, and level of patient care may be in jeopardy. Additional research in these areas is needed to elucidate evidence-based interventions to address physician distress at both the individual and organizational level to benefit the individual surgeon and the patient they care for. Surgeons must also be able to recognize how and when their personal distress affects the quality of care they provide (both in the delivery of care and in the emotional support of patients and their families). There is no single formula for achieving a satisfying career in surgery. All surgeons deal with stressful times in their personal and professional life and must cultivate habits of personal renewal, emotional self-awareness, connection with colleagues, adequate support systems, and the ability to find meaning in work to combat these challenges. As surgeons, we also need to set an example of good health to our patients and future generations of surgeons. To provide the best care for our patients, we need to be alert, interested in our work, and ready to provide for our patient's needs. Maintaining these values and healthy habits is the work of a lifetime. PMID- 20919513 TI - Laparoscopic gastric bypass or gastric banding: which operation is best? AB - Data from the available published literature support that laparoscopic gastric bypass and laparoscopic adjustable gastric banding are safe and effective bariatric procedures for the treatment of morbid obesity. Compared with gastric bypass, gastric banding is commonly associated with a shorteroperative time and length of hospital stay, and lower perioperative morbidity. However, the medium- and long-term weight losses were consistently and dramatically better after gastric bypass. The 2 preoperative factors predictive of poor weight loss in patients with gastric banding were male gender and patients with a BMI greater than or equal to 50 kg/m2. With this knowledge, the final decision regarding gastric bypass versus gastric banding will rely on an in-depth discussion between patients and surgeons with regard to perioperative and late complication data, long-term weight loss and variability of weight loss between the 2 operations, as well as the data regarding the rate for remission of comorbidities between the 2 operations. At the current time, there is ample evidence for surgeons and patients to make a well-informed decision with regard to which operation is best for the individual patient. PMID- 20919514 TI - Prevention, detection, and management of leaks following gastric bypass for obesity. PMID- 20919515 TI - Distinguishing acute from ruptured appendicitis preoperatively in the pediatric patient. PMID- 20919516 TI - Screening criteria for breast cancer. AB - Breast cancer screening constitutes an integral part of surgical practice for many surgeons and is an important tool in the war against breast cancer. Among many modalities, mammography plays a central role, with MRI now being increasingly used for women with high risk for breast cancer. Current guidelines for screening are in the process of evolution as more scientific knowledge is gained. The challenge lies in developing cost-effective methods to reach the maximum number of the population at risk. PMID- 20919517 TI - Laparoscopic and thoracoscopic esophagectomy. AB - Over the past decade, our technique of MIE has evolved considerably. In the incipient phase of our experience, we used a totally laparoscopic approach similar to that described in the initial reports from DePaula and colleagues and Swanstrom and Hansen. However, it was soon apparent that there were several critical disadvantages to a purely laparoscopic approach. Laparoscopic transhiatal mobilization of the esophagus offers suboptimal visualization of important periesophageal structures, including the inferior pulmonary vein and the left mainstem bronchus. Moreover, decreased visibility hindered hemostatic division of periesophageal vessels and negatively impacted the completeness of the mediastinal lymph node dissection. These problems are further exacerbated in taller patients. In light of these considerations, we soon transitioned to a laparoscopic-thoracoscopic McKeown approach (thoracoscopic mobilization of the intrathoracic esophagus, laparoscopic gastric tube creation, cervical anastomosis). To this date, the great majority of our minimally invasive esophagectomies (>500 cases) have been performed with this 3-field technique. Indeed, the procedure has been the mainstay of our experience in the past 10 years with reduced perioperative morbidity and mortality compared with many other open series. In our experience, perhaps the most significant technical concern with this operation is the cervical dissection. Recurrent laryngeal nerve injuries, perturbations in pharyngeal transit, and swallowing dysfunction even in the absence of recurrent nerve injury are not infrequent. Moreover, as described in open series using a cervical anastomosis, anastomotic stricture and leak have been shown to occur with increased frequency [35]. In short, there is a significant learning curve with the cervical dissection. Out of these concerns emerged our more recent experience with completely thoracoscopic-laparoscopic Ivor Lewis esophagectomy. However, we did first evolve through a transition phase whereby a mini-thoracotomy (hybrid approach) was performed for creation of the intrathoracic anastomosis. We believe that the experience with totally thoracoscopic-laparoscopic Ivor Lewis esophagectomy will ultimately reproduce the low morbidity and mortality we have previously published with our established MIE technique. The omission of a cervical dissection has reduced our recurrent nerve injury rate to zero. From a theoretical standpoint, one would presume that pharyngeal transit problems and oropharyngeal swallowing dysfunction should be reduced as well with a chest anastomosis. It should be emphasized that there is a steep operator learning curve associated with this approach. Indeed, thoracoscopic port placement is critical, as poorly positioned trocars can result in difficulty maneuvering instruments through the rigid chest wall. Additionally, both blood and lung can obscure visualization of the esophagus, which lies at the dependent aspect of the operative field. Prone positioning has been described as an alternative approach that may facilitate operative exposure and address such technical concerns. Low rates of anastomotic leak (3%), low mortality (1.5%), and equivalent stage-specific survival compared with open series have been shown with this thoracoscopic prone approach [36]. In conclusion, our technique of MIE has evolved such that laparoscopic-thoracoscopic Ivor Lewis esophagectomy has become our preferred approach. Although somewhat early in our experience, we are convinced that this operative technique is feasible with reproducible results. Perioperative morbidity and mortality are comparable with our previously established MIE with cervical anastomosis while essentially eliminating recurrent nerve injury, limiting the length of the gastric conduit required, and allowing a more aggressive gastric resection margin. Recent data from other publications also suggests that lymph node yields may be improved, although insufficient data exist at this time to comment on oncologic results or outcomes with this technique. PMID- 20919518 TI - Biomedical and health informatics for surgery. AB - The application of biomedical and health informatics to surgery holds tremendous opportunities to enhance surgical care. Better use of information in surgical practice has the potential to streamline care, remove inefficiencies, and allow for improvements in surgical research. With greater EHR adoption, health care reform, and direct investment in HIT, an increasing opportunity exists for surgeons to access and use patient information more effectively. For this to happen, greater focus on the specific needs of surgeons is particularly important, alongside increasing the number of surgical informatics stakeholders. PMID- 20919519 TI - Does the type of pancreaticojejunostomy after Whipple alter the leak rate? AB - Despite the overwhelming limitations that plague the literature surrounding the optimal method of reestablishing pancreatico-enteric continuity following a Whipple operation, it is clear that all successful techniques conform to sound surgical principles. These principles include a water-tight and tension-free anastomosis, preservation of adequate blood supply for both organs involved in the anastomosis, and minimal trauma to the pancreas gland. Although surgeon experience, gland texture, and pancreatic duct size are clearly the dominate risk factors from a long list of variables associated with pancreatic leaks following pancreatoduodenectomy, these are nonmodifiable covariates. Although the plethora of current literature cannot provide a single definitive technical solution for restoring pancreatico-enteric continuity, a small number of well-designed RCTs support the use of transanastomotic external stenting for high-risk pancreatic glands and an end-to-side invaginated pancreaticojejunostomy. The truth remains that an individual surgeon's mastery of a specific anastomotic technique, in conjunction with a large personal experience, is likely to be the best predictor of a low pancreas leak rate following pancreatoduodenectomy. PMID- 20919520 TI - Adjuvant chemoradiation therapy for pancreas cancer: who really benefits? PMID- 20919521 TI - Real-time glucose monitoring in the hospital: future or now? PMID- 20919522 TI - Minimally invasive thyroid and parathyroid operations: surgical techniques and pearls. AB - With advances in technology and greater demand for minimally invasive procedures, novel minimally invasive approaches to thyroid and parathyroid glands increasingly have been described and practiced worldwide. For the MIT approaches, the direct/cervical approaches truly can be considered minimally invasive, as they require less surgical dissection than the conventional thyroidectomy. The indirect/extracervical approaches, however, only can be considered endoscopic, however, because they generally do require greater surgical dissection. Still, among the indirect/extracervical approaches, the axillary approach appears the preferred choice, as it requires the least amount of dissection while offering the advantage of being scarless in the neck. The addition of the robot such as the de Vinci surgical system could make some of the extracervical approaches technically less challenging and improve patient outcomes. Unlike MIT, MIP has become the standard approach for surgical management of primary hyperparathyroidism caused by localized solitary parathyroid adenoma. PMID- 20919523 TI - What's new in neoadjuvant therapy for breast cancer? AB - Neoadjuvant treatment of breast cancer is currently being used in patients with advanced disease as well as with increasing application in those that present with initially operable breast cancer. The current clinical benefits of the use of NAC include: NAC increases the possibility of the use of BCS, the safety of NAC is comparable with that of adjuvant chemotherapy, and pCR may be predictive of overall survival. Although there are still unresolved clinical questions regarding the use of neoadjuvant therapy in initially operable breast cancer, there appears to be equivalent survival to the standard of care. Future research should be aimed at tailoring treatment to individual patients using specific tumor characteristics that may predict response to different types of chemotherapy, molecular targeted therapy, and endocrine therapy. PMID- 20919524 TI - The impact of frailty in the elderly on the outcome of surgery in the aged. AB - As the population continues to age, we will continue to encounter issues involving aging and the elderly. Despite these issues, knowledge is expanding and evolving with new solutions to ongoing problems. Mechanistically, frailty at its root is a symptom of growing old, with cascades and circuitous feedback between organ systems at all levels. Clinically, frailty is as equally dynamic and its multifactorial nature represents a unique challenge to the surgical community and warrants the integration of geriatric assessment into clinical practice. Integration within clinical practice includes using an interdisciplinary approach, where surgeons work with anesthesiologists, geriatricians, nursing, rehabilitation, nutritionists, and other support staff to provide holistic assessment, efficient delivery, and higher quality of care. This in hand, recognition of frailty can occur in a timely fashion to initiate treatment, decreasing the risk of morbidity and mortality for improved surgical outcomes. PMID- 20919525 TI - Quality improvement in surgery: the American College of Surgeons National Surgical Quality Improvement Program approach. AB - The history and development of the NSQIP, from its inception in the Veterans Administration Health System to its implementation within the private sector sponsored by the ACS, documents the growth of a program that has substantially improved the quality of surgical care and has had a considerable influence on the culture of quality improvement in the profession. The success of the ACS NSQIP is the result of providing hospitals with rigorous, clinical data, networking opportunities, and resources to improve their risk-adjusted outcomes. In this manner, the ACS NSQIP challenges its hospitals and health care providers to continually improve the care they provide. In addition to reducing the complications and mortality experienced by patients after surgical procedures, hospitals that participate in the ACS NSQIP have seen the financial rewards of their quality improvement efforts. Continued growth of the ACS NSQIP will facilitate achievement of the primary goal surrounding the current health care reform debate: efficient, high-quality care. PMID- 20919526 TI - Management of disappearing colorectal hepatic metastases. AB - Disappearance of liver lesions during neoadjuvant chemotherapy is common and is the basis for the increasing number of patients suitable for potentially curative hepatectomy in patients with hepatic colorectal metastases. Many of the liver lesions disappearing on radiologic evaluation after successful chemotherapy for metastatic colorectal cancer are still present and alive. In patients with only some disappearing lesions, exploration should be undertaken to thoroughly evaluate all sites of previous disease. Because many small residual lesions are scars and complete pathologic responses, treatment should include not only complete treatment of all remaining lesions but also parenchymal conservation techniques such as ablations and limited resections. For patients with completely disappearing lesions, the standard therapy is still exploration and direct intraoperative assessment. However, if the patient chooses observation in the setting of negative CEA, MRI, and PET, close follow-up should be undertaken to avoid missing treatable and resectable recurrences. PMID- 20919527 TI - Endovascular repair of traumatic aortic injuries. AB - Endograft repair has clearly revolutionized the treatment of traumatic aortic injury. Numerous studies, both retrospective and prospective, have documented the advantages with respect to lower mortality and lower paraplegia rates as compared with traditional open repair. Additionally, 2 recent meta-analyses of the published literature both reported significantly lower mortality and paraplegia rates with endovascular repair. These clear improvements, however, come at an increased rate of device-related complications. Currently, newer devices designed to adapt to more acute bends in the proximal thoracic aorta are in the multicenter trial phase. These devices are also expected to be available in a wider range of diameters and lengths, including smaller diameter devices required to treat younger patients. A conformable Gore TAG design is undergoing trials in the United States. Trials of the Talent thoracic device for the treatment of blunt aortic injury are also ongoing. We await the results of the ongoing multicenter trials and expect that with improvements in technology, the vast majority of patients with traumatic aortic injury can be treated without open thoracic aortic surgery. The long-term durability and natural history of thoracic endograft devices, however, are unknown. Continued regular follow-up is recommended, although this can be difficult in this young population of patients. Because follow-up may be ongoing for decades, the need to identify a potential problem has to be weighed against the oncologic risks of repeated radiation exposure. PMID- 20919529 TI - The role of PET scanning in pancreatic cancer. AB - The strength of functional imaging lies in its ability to detect malignant disease irrespective of lesion morphology. In this setting, 18FDG-PET can complement management by providing a more accurate diagnosis. When combined as an adjunct to CT, 18FDG-PET can increase the sensitivity, specificity, and accuracy for detecting a pancreatic malignancy, especially in patients in whom CT alone fails to identify a discrete mass or in whom biopsy results are indeterminate. This capability is accentuated with small lesions of the pancreas. 18FDG-PET is significantly more sensitive in detecting metastatic disease than conventional CT imaging. Moreover, 18FDG-PET is able to differentiate tumor response to therapy in the postoperative setting, and could potentially serve to monitor recurrence patterns in the setting of neoadjuvant or adjuvant chemoradiotherapy. Finally, as 18FDG-PET/CT fusion modalities become more widespread and technical advances in image acquisition progress, 18FDG-PET will continue to have an increasing role in the diagnosis, staging, and surveillance of pancreatic cancer, integrating anatomic information with functional imaging. PMID- 20919530 TI - Reoperative surgery for the Zollinger-Ellison syndrome. AB - It is clear that a properly performed initial operation is the key to success in the management of a patient with ZES. However, reoperation is frequently a consideration in the management of patients with ZES because high rates of persistent and recurrent disease are manifest even with modern imaging and surgical approaches. In carefully selected patients, reoperation can result in durable biochemical cure and improved survival and should be considered. A thorough knowledge of the natural history of the sporadic form of ZES and ZES in the context of MEN-1, patterns of presentation, and sites of metastases are necessary to achieve the best outcome in patients with this unusual disease. PMID- 20919531 TI - Computerized physician order entry system in a surgical practice. PMID- 20919528 TI - Update on familial pancreatic cancer. PMID- 20919532 TI - [New concepts of pathogenesis, diagnosis, and treatment of neurodegenerative diseases]. AB - Millions of patients all over the world suffer from chronic neurodegenerative diseases (NDD) (Parkinson's disease, Alzheimer's disease, Huntington disease, hyperprolactinemia, etc.) which result first in disability and then in fatal outcome. The key component of NDD pathogenesis is the degeneration of specific neurons leading with time to dysfunction, e.g. cognitive problems in Alzheimer's disease, disturbed motor behavior in Parkinson's disease, etc. Over the initial twenty-thirty years, NDD are developed as a preclinical condition, and their first symptoms appear only after degeneration of a greater part of specific neurons. The lag in the manifestation of NDD at the organismic level is explained by late triggering mechanisms of brain plasticity serving to compensate functional insufficiency of dying neurons. In this context, the appearance of initial symptoms is considered as a manifestation of irreversible degradation of the specific regulatory brain system and the exhaustion of compensatory resources of the brain that probably explains low efficiency of pharmacotherapy. This implies the necessity to develop preclinical diagnostics and preventive therapy aimed at arresting or at least slowing down of the neurodegenerative process and prolongation of the preclinical stage for many years. The development of preclinical diagnostics is based on a search for specific clinical forerunners of NDD and endogenous peripheral markers circulating in cerebrospinal fluid and blood. NDD diagnostics in the preclinical stage should be developed by identification of risk groups during prophylactic examination of healthy population based on detection of disease markers. The final diagnosis can be made by non-invasive neurovisualizing techniques. The new concept of NDD pathogenesis promotes further development of novel approaches to their diagnostics and treatment. PMID- 20919533 TI - [A program for evaluation of severity of biliary sepsis and a choice for therapeutic and diagnostic methods]. AB - The program of actions for the assessment of severity of biliar sepsis and the choice of algorithms for relevant medical-diagnostic measures is presented. The account is taken of the traumatic factor of operation, the method of narcosis (endotracheal, local anaesthesia) and severity of the initial condition in individual patients. It is suggested to use this program in the form of computer software for the diagnosis of severity of the disease in septic patients, creation of the database and electron archives of the results of the treatment for the purpose of continuous monitoring the patients' conditions. PMID- 20919534 TI - [Pathogenesis of mucociliary clearance]. AB - The study of mucociliary clearance included 68 patients with bronchial asthma of different severity in whom viscoelastic properties of the sputum, motor activity of ciliary epithelium, glycosaminoglycans in peripheral blood and bronchial secretion at the B9-B10 level of the bronchial tree were determined. Simultaneously, morphofunctional state of bronchial mucosa was evaluated using DNA methylation-specific PCR. PMID- 20919535 TI - [Multiple and combined injuries to chest and abdomen as an unresolved surgical problem]. AB - Peculiar features of surgical treatment of gunshot, non-lethal arm, and cold steel wounds are formulated based on the 20-year experience with managing 20,000 injured subjects having multiple and combined injuries to neck, chest, and abdomen of suicidal and criminal character. The growth in the number of patients with suicidal wounds and hemocontact viral infections (hepatitis, HIV) is emphasized. It is concluded that assessment of the state of gas exchange, lipid peroxidation, antioxidative, and immune systems does not give full idea of pathogenetic mechanisms of traumatic diseases. PMID- 20919536 TI - [Electrophysiological characteristics of animal respiratory muscles after long term stay at high altitudes]. AB - Experiments were made using rats at different stages of readaptation after long term stay at high altitudes. Characteristics of bioelectrical activity of respiratory muscles were obtained for the first time, its spectral picture is described in different periods of readaptation. PMID- 20919537 TI - [Pathogenetic aspects of bronchial asthma]. AB - This review represents contemporary knowledge about pathogenetic aspects of evolvement and progress of human bronchial asthma. Main attention is given to cells and mediators of allergic inflammation, Th1/Th2-bias, remodeling of respiratory tract, genetic and exogenous risk markers. Moreover, opportunities and prospects for the use of laboratory animals in modeling bronchial asthma are assessed. PMID- 20919538 TI - [Polyneuropathy in intensive care patients]. AB - Critical illness polyneuropathy is an acquired critical illness syndrome of neuromuscular problems as polyneuropathy and/or myopathy that is caused by long term immobilization, clinically manifested by general muscle weakness and a main reason for difficulty weaning from the ventilator. The review gives an update on the history, epidemiology, etiology, pathogenesis, clinical picture, diagnosis, differential diagnosis, course, outcome, prevention, and treatment of critical illness care polyneuropathy. PMID- 20919539 TI - [Use of recombinant human erythropoietin preparations as a blood-saving method in neurosurgery]. AB - The paper gives the results of the first clinical use of recombinant human erythropoietin (rhEPO) within the blood-saving program in neurosurgical patients with preoperative anemia of various genesis and predictable massive intraoperative blood loss. A course of effective therapy with rhEPO is shown to increase hemoglobin and packed cell volume rather rapidly in all patients prior to surgery. This made it possible to effectively apply other blood-saving procedures (isovolemic hemodilution and instrumental reinfusion of washed red blood cells) and to reduce the volume required for the use of donor transfused media in these patients. Various clinical aspects of the use of rhEPO in these patients are discussed. PMID- 20919540 TI - [Systemic hemodynamic disorders in critically ill patients with intracranial hemorrhages]. AB - The paper analyzes systemic hemodynamic disorders in 45 victims of severe brain injury and patients with nontraumatic intracranial hemorrhages. The incidence of hypovolemia in patients with nontraumatic intracranial hemorrhages and victims of severe brain injury is 65.4% and 73.7%, respectively. Infusion therapy based on the estimation of routine hemodynamic parameters (blood pressure, heart rate, central venous pressure, daily fluid balance) could not prevent hypovolemia in the examinees and caused a high rate of sympathomimetic use in uncorrected volemic states. PMID- 20919541 TI - [Brain edema treatment procedure using continuous controlled infusion of mannitol in neurosurgical patients]. AB - The paper evaluates the efficiency and safety of the developed osmotherapy protocol using controlled continuous infusion of 15% mannitol solution. Two hundred and nine patients with intracranial hypertension (ICH) syndrome of various etiologies had 15% mannitol infusion, the rate of which was determined by clinical criteria. The infusion rate was 50 ml/hr with midline brain structure dislocation of 8 mm or more and major depression of consciousness (a Glasgow coma scale (GCS) score of less than 8) and 25 ml/hr with brain dislocation of 7-mm or less and a GCS score of 8 or higher. The monitoring program was as follows: Block 1 comprised the clinical and instrumental data characterizing the adequacy of brain perfusion (GCS, the magnitude of focal neurological symptoms, ICH, mean blood pressure, computed tomographic dislocation); Block 2 involved the clinical and laboratory data identifying the extracerebral complications of osmotherapy (packed cell volume, plasma osmolarity, urine density, and renal ultrasonography); Block 3 consisted of cerebral oximetry (CO) and Neurotrend. The authors' early proposed integral indicators of OC, such as interhemispheric asymmetry coefficient and hemodynamic conformity index, were used to estimate the adequacy of brain perfusion. In cerebral vasospasm, a Neurotrend microsensor was implanted at 3-cm depth for the direct quantitative determination of pO2, pCO2, pH, and brain temperature. ICH was characterized by natural changes in the CO indicators. In vasospasm, the mean linear blood flow velocity was 245 +/- 14 cm/sec in the basilar arteries, which was attended by low pO2 and metabolic acidosis, as shown by readings. Optimization of artificial ventilation, stabilization of hemodynamics, and the use of postural exposures and osmo diuretics promoted ICH normalization and central perfusion pressure optimization, which was accompanied by the disappearance of tissue hypoxia and acidosis, as suggested by Neurotrend reading. The duration of mannitol infusion averaged 6.6 days. No urinary tract complications were observed. The proposed procedure of osmotherapy is effective and safe if the scope of monitoring is adequate. PMID- 20919542 TI - [Effect of an original enteral feeding protocol on clinical outcome indicators in patients with acute cerebral damage of vascular and traumatic genesis]. AB - The prospective randomized controlled study enrolled 58 patients diagnosed as having brain injury and hemorrhagic stroke. Enteral feeding was started within the first 24 hours after admission to an intensive care unit (ICU); a control group (n = 28) was given an isocalorie formula while a study group (n = 28) received a combination of a hypercalorie formula and a fiber-containing formula. In the study group, the intestine was stimulated with erythromycin within the first 3 days. Glasgow coma scale (GCS) and APACHE II scores, the degree of a systemic inflammatory response (SIR) and multiple organ failure (MOF), serum albumin and glucose levels, energy expenditure and balance, and nitrogen excretion and balance were estimated on day 10. Treatment results on day 30, length of ICU stay, AV duration, mortality, and use of blood preparations were compared. On study day 10, nitrogen and energy balances and the pattern of signs of SIR and MOF were significantly better and fresh frozen plasma and albumin solutions were used less in the study group than in the control one. There were differences in APACHE II and GCS scores, energy expenditure and nitrogen loss, plasma albumin and glucose concentrations, mortality, and volume of used packed red blood cells. The original enteric feeding protocol based on the use of dietary fiber-fortified hypercalorie diets in combination with the new method of gastric motility stimulation makes it possible to reduce the accumulation of deficiency of energy and plastic substrates, to alleviate the manifestations of SIR and MOF and to decrease the consumption of blood components and preparations. PMID- 20919543 TI - [Characteristics of central hemodynamics and cerebrovascular circulation during various anesthesia modes in reconstructive surgeries for the extracranial vessels]. AB - The purpose of the study was to choose an optimal anesthetic method to ensure adequate cerebral blood flow and to reduce the number of perioperative complications during carotid endarterectomy. Total intravenous anesthesia with diprivan, combined cervical plexus block anesthesia, and inhaled sevoflurane anesthesia were assessed in 190 patients undergoing carotid endarterectomy. The study of cerebral blood flow and central hemodynamic parameters indicated that deprivan anesthesia suppressed the major hemodynamic parameters, causing associated cerebral circulation depression. The use of cervical plexus block as a major component of anesthesia after Pashchuk stabilized the mean blood pressure and cardiac index, causing the optimization of cerebral blood flow parameters with a considerable postload increase. During sevoflurane anesthesia, the most physiological conditions for the performance of the circulatory system were found at all stages of surgical treatment, which predetermined the stable parameters of central hemodynamics and cerebral blood flow. The studies revealed that deprivan anesthesia was followed by a considerable number of both cardiac and neurological complications. The patients with cervical plexus block had fewer neurological disorders, but the increased postload accompanying these changes caused an increase in the number of cardiac complications. The most optimal parameters of cerebral blood flow and central hemodynamics during sevoflurane anesthesia induced a statistically significant reduction in the number of cardiac and neurological complications. PMID- 20919545 TI - [Current technologies and changing the medical paradigm in aortic ruptures (analysis of clinical cases)]. AB - The paper describes two clinical cases of aortic rupture of traumatic and nontraumatic genesis, which was difficult to diagnose due to evident neurological symptoms. The analysis of these cases and the data available in the literature leads to the conclusion that aortic rupture is not a nosological entity with a known fatal outcome. Timely diagnosis based on widely practiced up-to-date ultrasound and radiological methods allows one to perform surgical or endovascular treatment in good time, by showing good long-term outcomes. PMID- 20919544 TI - [Continuous mechanical ventilation in a neurosurgical intensive care unit (one year analysis of results)]. AB - This was a retrospective study. Its inclusion criterion was mechanical ventilation (MV) for more than 48 hours. One hundred and eighty-four case records of 184 neurosurgical intensive care unit patients were analyzed. Ventilation modes, upper airway cares and prosthetic replacement were chosen by the protocol accepted at the Institute. Great differences were found in the structure of indications for MV and in the duration of respiratory support in relation to the neurosurgical nosological entity and the site of a major process. The upper airway care protocols accepted at the Institute were shown to reduce the incidence of ventilator-associated pneumonia. Some risk factors for ventilator associated pneumonia were identified. PMID- 20919546 TI - [Compression cervical spine cord injury in patients with posterior cranial fossa tumors operated on in the sitting position: two cases with different outcomes]. AB - The paper describes two cases of posterior cranial fossa pathology, operated on in the sitting position on the operating table. In one case, symptoms of cervical spine injury caused by undiagnosed preoperative cervical spine pathology emerged in a female patient in the early postoperative period. In the other case, cervical spine pathology was diagnosed before surgery and evoked potentials were monitored to prevent possible cervical spine injury in the sitting position during an operation. PMID- 20919547 TI - [Acute injuries to the upper gastrointestinal tract in patients with multiple cerebral arterial aneurysms]. AB - The paper describes a case of multiple cerebral arterial aneurysms in a patient with prior subarachnoidal hemorrhage, who developed postoperative acute upper gastrointestinal tract (GIT) lesion manifesting itself as bleeding and requiring multiple endoscopic treatment procedures and eventually a direct surgical intervention. The susceptibility of patients with cerebral pathology to upper GIT lesions and methods of their therapy and prevention are discussed. PMID- 20919548 TI - [Experimental optimization of learning and memory processes by selank]. AB - The effect of selank (Thr-Lys-Pro-Arg-Pro-Gly-Pro), which is a synthetic derivative of the endogenous tetrapeptide tuftsin (stable with respect to tissue peptidases), on the learning and memory processes and metabolism of serotonin (5 HT) have been experimentally studied on Wistar rats. The animals were trained with food reward in 30 trials per day. Selank (300 microg/kg) or saline were injected after the 10th trial. Elaboration of conditioned reflex with food reward was continued 30 min later. Retention was tested 24 h, 7 and 30 days after treatment. A single injection of selank activated the metabolism of 5-HT in the hypothalamus and caudal brain stem for 30 min to 2 h. It was established that selank induces an increase in memory trace stability during 30 days. These findings provide direct evidence that selank, when injected during consolidation phase, can enhance memory storage processes. Nootrope activity of the selank is probably caused by its obvious effect on the level of serotonin and its metabolite in the brain. PMID- 20919549 TI - [Effect of psychotropic drugs on activity of anticonvulsants in maximal electroshock test]. AB - The effect ofpsychotropic drugs on the pharmacological properties of anticonvulsants was studied on white mice under maximal electroshock (ME) test conditions. Changes in the anticonvulsant effect of phenobarbital, diphenin, carbamazepine, hexamidine were traced upon their joint administration with psychotropic drugs, including piracetam, aminalon, amitriptyline, imizine, levomepromazine, and lithium oxybutyrate. An important result of research is the fact, that in no one of combinations the basic pharmacological effect of anticonvulsants was decreased. Based on the results of experiments, the most rational combinations of anticonvulsants with psychotropic preparations were revealed as manifested in the ME test. As criterion of rational combination was the increase in the activity of anticonvulsants and reduction of their toxicity in combination or at least invariance of this parameter. Rational combinations include (i) phenobarbital with piracetam, amitriptyline, levomepromazine, and lithium oxybutyrate; (ii) carbamazepine with piracetam; and (iii) hexamidine with amitriptyline, levomepromazine and imizine. PMID- 20919550 TI - [Effects of phenibut on parameters of cerebral hemodynamics in swimmers with dysadaptation syndrome and various types of systemic hemodynamics]. AB - Administration of phenibut (0.25 g) during 4 weeks as a means of rehabilitation promoted optimization of the biochemical status and cerebral blood circulation in swimmers with various types of systemic hemodynamics, which were examined 20 minutes after warm-up. PMID- 20919551 TI - [Bizerine: new anticholinesterase drug with selective gastrointestinal action]. AB - Bizerine-oxalate of hexamethylene-bic-[N-methylcarbamic acid-3-(2 dimethylaminomethyl)pyridyl ether] exhibits the properties of acetylcholine esterase (AChE) inhibitor, being comparable in this respect in in vitro tests to aminostigmine. Bizerine is 2.5 and 6.7 times less active in these tests than proserine and distigmine, respectively, but it forms more stable complex with the enzyme. Bizerine is 10-80 times less toxic for laboratory mammals as compared to prozerine; it is 3-60 times more active on the isolated urinary bladder of rats, but it is 100-500 times less effective on the spinal muscle of leeches and skeletal muscles of mice and rats. Bizerine actively inhibits intestinal cholinesterase (ChE) of guinea pigs. In systematic use, it does not inhibit brain ChE of mice. Bizerine is a prolonged peripheral muscarinic potentiating inhibitor of ChE and activator of intestinal peristalsis. PMID- 20919552 TI - [Model study of afobazole distribution in pregnant and lactating female rats and infant rat pups]. AB - Afobazole and M-11, its major metabolite were detected in placental and embryonic rat tissues after single peroral administration to pregnant female rats at a dose of 100 mg/kg. The anxiolytic drug and its metabolite are also detected in rat milk and body of the breast-fed infant rat pups after 4 days of daily administration (200 mg/kg, per os) to lactating female rats. PMID- 20919553 TI - [Influence of new 1,3,4-thiadiazines on platelet aggregation in vitro and ex vivo]. AB - The influence of new original 1,3,4-thiadiazines on the human platelet aggregation in vitro was studied. All substances inhibited the platelet aggregation induced by both ADP and arachidonic acid. 1,3,4-Thiadiazines L-19, H 30 and L-37 were the most effective inhibitors. Effect of the intravenous injection of L-19 in various doses on platelet aggregation and some parameters of plasmatic hemostasis were studied ex vivo. PMID- 20919554 TI - [Effect of hypoglycemic drugs on hemostasis]. AB - The effects of hypoglycemic drugs (gliclazide, glibenclamide) and new sugar lowering drug diabenol on the coagulation chain of hemostasis and fibrinolytic system of blood have been studied in intact rats and in rats with experimental diabetes mellitus. Experiments revealed the ability of drugs to reduce thromboelastogram indices, which is probably related to the ability of hypoglycemic drugs to inhibit the platelet aggregation and prevent the subsequent activation of the coagulation chain of hemostasis. All drugs improve the thrombogenic potential (by decreasing the platelet activation) and increase the activity of the fibrinolytic system of blood. The activity of diabenol and gliclazide i s more pronounced as compared to that of glibenclamide. PMID- 20919555 TI - [Hemorheological properties of new xanthine derivative studied on model of streptozotocin induced diabetes mellitus]. AB - Influence of a new xanthine derivative SUM-55 on microrheological properties erythrocytes in rats with experimental diabetes has been investigated. It is shown that compound SUM-55 significantly reduces aggregation and increases deformability of erythrocytes. Comparative analysis showed that SUM-55 is comparable with pentoxyphylline in the ability to reduce aggregation of erythrocytes and is superior to the reference drug in increasing deformability of red bloodcells. PMID- 20919556 TI - [Hemorheological effects of thiophane on tetrachloromethane induced hepatic damage]. AB - Carbon tetrachloride-induced hepatitis in rats is accompanied by blood hyperviscosity syndrome development. A course intragastric administration of thiophane under these conditions prevents the increase in whole blood viscosity by normalizing the microrheological indices (deformability and aggregation of erythrocytes), which is manifested by increasing oxygen availability for tissues. PMID- 20919557 TI - [Experimental study of cytoprotector effect of succinate-containing drugs on functional activity of liver]. AB - Hepatoprotective effect of metabolism correctors has been studied on the model of experimental viral and toxic damage of the liver. Reamberin-based substrate compositions (cytoflavin and remaxol) exhibit antihypoxic effect, antioxidant activity, and cytoprotective action on the background of metabolic effect. Based on these results, the indicated preparations are recommended for clinical trials on acute and chronic viral liver disorders. PMID- 20919558 TI - [Use of interferon inducers for pharmacological correction of cytokine disturbances in patients with recurrent genital herpes]. AB - The level ofcytokines was studied in the blood of 111 women aged 18 to 56 with recurrent genital herpes caused by herpes simplex virus (HSV) type 1 or 2 (for the frequency of relapses within 6-9 year) treated with interferon inducers iodantipyrin, cycloferon and amixin in combination with basic aciclovir therapy. It is found that, in patients with clinical effect of treatment (decrease in the frequency of relapses) the level of cytokines of nonspecific immune response (alpha-interferon, beta-interferon, tumor necrosis factor-alpha) and Th1 profile gamma-interferon, interleukin-2) increased and the concentrations of interleukin 10 decreased 1.5-3 months after beginning of drug administration. A special feature of drug action for iodantipyrin was a relatively large increase in the blood level of alpha-interferon, for cycloferon--in the level of tumor necrosis factor-alpha, and for amixin--in the level of gamma-interferon. In the absence of any clinical effect, interferon inducers produced only small and brief (in 1.5 months after the beginning of treatment) increase in the blood content of proinflammatory cytokines (alpha-interferon, gamma-interferon, interleukin-2) at a stable high level of interleukin-10. PMID- 20919559 TI - [Mutagen properties of water-soluble polysaccharides from Acorus calamus]. AB - Mutagenic properties of water soluble polysaccharides (WSPS) extracted from Acorus calamus L. have been studied. Neither a single intravenous injection nor a course intraperitoneal introduction of WSPS in a dose of 1/2 LD50 to mice of the CBA/CaLac line increases the level of cytogenetic disorders in the bone marrow cells. The investigation of WSPS by means of the somatic mosaicism test showed that the given dose of WSPS does not increase the rate of mutant spots on Drosophila wings. PMID- 20919561 TI - [From the History of the Journal Clinical Medicine (1920-2010)]. PMID- 20919560 TI - [Pharmacokinetics of hopantenic acid upon peroral administration]. AB - A simple, specific and sensitive RP-HPLC method with UV detection for the determination of hopantenic acid in human blood plasma has been developed. The pharmacokinetics of drug pantocalcin upon single peroral administration was investigated on 18 healthy volunteers. The peak of hopantenic acid in blood plasma was achieved at 1.56 h and the elimination half life was 6.68 h. No hopantenic acid in blood plasma is found in 48 h. PMID- 20919562 TI - [Neurological problems highlighted in the Journal Clinical Medicine]. PMID- 20919564 TI - [Achievements and prospects of clinical gastroenterology]. PMID- 20919563 TI - [Diagnosis and choice of therapy of arterial hypertension]. AB - The clinical concept of evolvement, chronisation and development of hypertensive disease is expounded in the light of recent basic research with reference to the influence of hypotensive (symptomatic) and pathogenetic (basal) therapy on its clinical features. The main stages of pathogenesis, risk of complications, and concomitant diseases are discussed. Analysis of main physiological mechanisms underlying regulation of hemodynamics is presented at different steps of formation of the cardiovascular system and angiogenesis from fetal life to the outset of involutional processes. Effect of environmental factors on these processes and compensatory reactions are considered. Algorithm of differential diagnosis of arterial hypertension and hypertensive disease is proposed along with the approaches to the choice of adequate therapeutic modalities, their role in the treatment and prevention of complications. A review of distribution of hypertensive disease and cardiovascular disorders in developed countries is focused on the elucidation of their causes and prophylactic measures. PMID- 20919565 TI - [Gastroenterology in Russia: 1920-2010]. PMID- 20919566 TI - [Thromboses and antithrombotic therapy today]. AB - Current understanding of importance and danger of atherothrombosis and venous thromboembolism is illustrated. New preparations and methods for the management of these conditions are described. PMID- 20919567 TI - [Current problems of deontology]. AB - The scope of knowledge in medical ethics continues to extend. Deontology as a science needs systematization of the accumulated data. This review may give impetus to classification of problems pertaining to this important area of medical activity. PMID- 20919568 TI - [Microbial antagonism and rationale for the use of probiotics in combined therapy of Helicobacter pylori-related diseases]. AB - This review discusses methods of Helicobacter pylori (HP) eradication, causes and consequences of its steadily growing resistance to therapy recommended by Maastricht Consensus (2005) and alternative treatment schemes including "reserved" antibacterial preparations. Different approaches to the solution of this problem are recommended, such as the use of phenomenon of microbial antagonism between endosymbiotic microorgnisms (bifido- and lactobacteria) and opportunistic and pathogenic microflora, e.g. cytotoxic HP strains. The data are presented on the mechanisms of antimicrobial action of bifido- and lactobacteria, pathogenic activity of different HP cytotoxic strains, normal and pathological microbiocenosis of the stomach. Prospects for the use of antibiotics containing bifido- and lactobacteria for the treatment of HP-related conditions are discussed. PMID- 20919569 TI - [Disorders of lipid metabolism in patients with cholelithiasis and gallbladder cholesterosis depending on apolipoprotein E genotype]. AB - The work was aimed to study blood lipid spectrum in 133 patients with cholelithiasis (CL) and 159 with gallbladder cholesterosis (GC) as well as apoE genotypes (based on restriction fragment polymorphism) in 49 and 36 respectively. Lipid composition was shown to significantly differ in the two conditions. LDL cholesterol was increased in GC and TG in CL. A rise in LDL cholesterol in both groups was apparent before the age of 30 yr (34.6 +/- 8.4 and 52.6 +/- 12.9% respectively), that in TG and VLDL after 40 yr. E3/3 genotype (norm) was identified in 75.5 +/- 6.2% of the patients with CL and in 83.4 +/- 6.2% in those with GC (p < 0.05). e4 allele (mutation) equally frequently occurred in 10.2 +/- 4.3 and 8.1 +/- 4.5% of patients with CL and GC (p > 0.5), e2 allele in 14.5 +/- 5.0 and 8.1 +/- 4.5% (p < 0.05). These data suggest that patients of both groups equally frequently suffered disturbances in metabolism of saturated (e2 allele) and polyunsaturated (e4 allele) fatty acids predisposing for hypercholesterolemia and hyperlipidemia. They explain why CL is frequently associated with cholesterosis and GC with the formation of caliculi. However, the absence of significant correlation between CL, GC and alleles e2, e4 suggests participation of other factors in pathogenesis of these diseases (LP(a), LDL heterogeneity). PMID- 20919570 TI - [The role of hypothalomo-pituitary-adrenal system in pathogenesis of exogenous constitutional obesity]. PMID- 20919571 TI - [Clinico-pathogenetic significance of enzymes regulating nucleic metabolism in erythrocyte lysates and sera of patients with osteoarthrosis]. AB - Lysates of erythrocytes and sera of 52 patients with osteoarthrosis (OA) and 30 healthy subjects were used used to determine adenosine deaminidase (ADA, AMP deaminase (AMPDA) and adenine deaminidase (AD). Their activities were unrelated to the age and sex of the patients. At admission, patients with OA showed enhanced activity of ADA in sera and reduced activity of AMPDA and AD in lysates compared with normal values. These changes depended on clinical features of OA and were especially pronounced in patients with poly-OA and synovitis. These data suggest participation of enzymes of the adenyl branch of purine metabolism in pathogenesis of OA. Treatment of hospitalized patients allowed to achieve positive dynamics of the above activities coupled to their improved clinical conditions even though enzymatic activity of erythrocyte lysates remained different from that in healthy subjects. It is concluded that enzymatic assays used in the study may be used as additional diagnostic methods for the assessment of synovitis and optimizatic of control over efficiency of OA therapy. PMID- 20919572 TI - [Neuroendocrine changes in patients with inflammatory diseases and colonic cancer]. AB - The study included 60 patients of whom 20 presented with colonic cancer, 20 with ulcerative colitis UC), and 20 with Crohn's disease (CD). Control group was comprised of 20 healthy subjects. It was shown that UC and CD can be regarded as apudopathies based on reduced melatonin production associated with altered proliferative activity, apoptosis, and accumulation of free radicals. UC and CD patients with high p53, PCNA, and oxidative stress levels both with and without dysplasia of intestinal epithelium are at risk of developing colonic cancer and require efficacious preventive treatment with early diagnosis of oncological problems. PMID- 20919573 TI - [Therapeutic efficiency of cytoflavine solution for infusion in emergency conditions]. AB - The author reports results of clinical assessment of cytoflavin for injections in the treatment of different pathological condition including critical ones. It was shown that therapy reduces mortality among patients with acute disturbances of cerebral circulation to 4.8-9.6% compared with 11.7-17.1% in controls. Positive dynamic of neurologic status was documented in 79% of the patients with dyscirculatory encephalopathy versus 25% in control. Duration of comatose state decreased 1,7-fold, length of stay in resuscitation and intensive therapy wards 1.8-fold, and frequency of internal complications secondary to the effect of neurotropic poisons 2-fold. Cytoflavin corrected the level of metalloproteides and stabilized antioxidative potential of sera and cerebrospinal liquid in patient with meningitis including that of zoonotic etiology. In the period of post-narcosis rehabilitation cytoflavin restored conscience in 77% of the patients within 20 min. The drug also inhibited pathological alcohol addiction within 5 days after the onset of therapy as apparent from the improvement of intellectual-mnestic status and activization of attention. The frequency of infectious complications in patients with acute surgical abdominal pathology decreased by 5.1% and lethality by 3.6% compared with placebo group. Cytoflavin exhibited cardioprotective action in patients with myocardial infarction, during cardiosurgical intervention, and chronic brucellosis. It had hepatoprotective effect in iatrogenic hepatic conditions as well as ophthalmo- and oto-protective activity. PMID- 20919574 TI - [Reamberin for pathogenetic therapy of acute and chronic viral diseases of the liver]. AB - The study including 427 patients with acute and chronic viral hepatitis was designed to assess results of clinical and laboratory diagnostics of hepatic problems and the state of thiosulfide antioxidative system. It was shown that infusion of succinate-containing preparation reamberin (400 ml/day for 10 days) took less time to eliminate clinical manifestation of the disease (dispeptic and asthenovegetative syndromes) than conventional therapy. Simultaneously the levels of biochemical markers of hepatic cytolysis and cholestasis significantly decreased while serum antioxidative potential recovered. The normal size of the liver was achieved 3.4 times more frequently than in control. No side effects or adverse reactions other than listed in the instruction for use of reamberin occurred. The preparation had to be withdrawn only in one patient. PMID- 20919575 TI - [Clinical features and delayed aftereffects of Legionellosis pneumonia during an epidemic outbreak]. AB - The aim of this work was to study specific clinical features of legionellosis pneumonia during an epidemic outbreak of the disease in Sverdlovsk region and to assess its delayed effects. 202 patients applied for the treatment to the central hospital of the town of Verkhnyaya Pyshma in July-August 2007 Legionella pneumophila was identified in 61 adults aged 51.3-59.3 (mean 55.3) years. The following analyses were performed at admittance and discharge as well as 1 year after treatment: complete blood count, urinalysis, AST, ALT and sugar levels, breast X-ray and ECG. Patients with mild disease were given azithromycin per os (500 mg for 7days, n = 10) or levofloxacin (500 mg for 10 days, n = 5). Those with the severe form of the disease were treated with azithromycin (500 mg for 3 days, v/v, n = 17) or levofloxacin (750 mg for 2-3 days v/v and for 12 days per os, n = 29). The results were analysed using the STATA 5.0 software package (Stata Corporation, College Station, Texas, USA). Difference were considered significant at p < 0.05. It was shown that the outbreak resulted from the use of hot water from the public water supply system contaminated with L. pneumophila. The incubation period of infection was 4.48-6.01 (mean 5.3) days. Duration of hospitalization varied from 9.6-12.9 (mean 11.3) days. Most common clinical symptoms: general uneasiness, headache, non-productive cough, and fever lasting 3.8-6.6 (mean 5.2 days). Intrahospital lethality 6.6%. It is concluded that therapy with azithromycin and levofloxacin give good clinical effect leaving no systemic lesions in patients with legionellosis pneumonia. PMID- 20919576 TI - Bioterrorism and invasive species. AB - The risk of dispersing invasive species, especially human pathogens, through acts of bioterrorism, cannot be neglected. However, that risk appears quite low in comparison with the risk of dispersing animal pathogens that could dramatically burden the agricultural economy of food animal producing countries, such as Australia and countries in Europe and North and South America. Although it is not directly related to bioterrorism, the intentional release of non-native species, particularly undesired companion animals or wildlife, may also have a major economic impact on the environment and, possibly, on animal and human health, in the case of accidental release of zoonotic agents. PMID- 20919577 TI - Invasive mammals. AB - Every region of the world is concerned by potential mammal invasions, as humans are already present on all the world's land masses. All these invasions are a result of species introductions by humans for one reason or another. The authors briefly review the known movements and observed consequences of mammal-related invasions. They take examples from all five continents, as well as from a few island systems. The ancient introduction of game species, and later of domestic species, has been followed more recently by movements of commercial species. We are now seeing the emergence of what are known as entertainment species. In a number of cases, such introductions have led to the establishment of new epidemiological cycles that previously might never have been thought possible. According to current indicators, this phenomenon is not on the wane. PMID- 20919578 TI - Alien invasive birds. AB - A bird species is regarded as alien invasive if it has been introduced, intentionally or accidentally, to a location where it did not previously occur naturally, becomes capable of establishing a breeding population without further intervention by humans, spreads and becomes a pest affecting the environment, the local biodiversity, the economy and/or society, including human health. European Starling (Sturnus vulgaris), Common Myna (Acridotheres tristis) and Red-vented Bulbul (Pycnonotus cafer) have been included on the list of '100 of the World's Worst Invasive Alien Species', a subset of the Global Invasive Species Database. The 'Delivering Alien Invasive Species Inventories for Europe' project has selected Canada Goose (Branta canadensis), Ruddy Duck (Oxyura jamaicensis), Rose ringed Parakeet (Psittacula krameri) and Sacred Ibis (Threskiornis aethiopicus) as among 100 of the worst invasive species in Europe. For each of these alien bird species, the geographic range (native and introduced range), the introduction pathway, the general impacts and the management methods are presented. PMID- 20919579 TI - Invasive reptiles and amphibians. AB - Although they are frequently lumped together, reptiles and amphibians belong to two very different zoological groups. Nevertheless, one fact is clear: while numerous reptile and amphibian species on Earth are in decline, others have taken advantage of trade or human movements to become established in new lands, adopting different, and sometimes unusual, strategies. The authors have taken a few examples from these two zoological groups that illustrate the majority of cases. A brief analysis of the causes and effects of their introductions into new areas reveals connections with economic interests, trade in companion animals, medical research and public health. PMID- 20919580 TI - Invasive crayfish and freshwater fishes of the world. AB - After habitat destruction, invasive alien species are the second leading cause of biodiversity loss, particularly in freshwater ecosystems. They also alter the structure and functioning of ecosystems, lead to biotic homogenisation, and eventually threaten human economies and health. This review aims to synthesise some of the existing information about the world distribution, vectors of spread, and impacts of two important components of freshwater ecosystems, crayfish and fishes. Analysis of the available literature shows that crayfish and fish species, once moved outside their native range, are likely to establish self reproducing populations, spread from the point of introduction and become invasive. Efforts to manage these populations are difficult and expensive, which warrants the provision of effective preventative measures. Unfortunately, the state of our knowledge of the mechanisms in play in crayfish and fish invasions is still limited, which suggests that much greater attention and investment should be directed to studies in this field. PMID- 20919581 TI - Invasive processes, mosaics and the structure of helminth parasite faunas. AB - The biosphere in evolutionary and ecological time has been structured by episodes of geographic and host colonisation that have determined distributions of complex assemblages of microparasites and macroparasites, including helminths circulating among vertebrates. Biological invasion is an intricate phenomenon often involving 'extra-range dispersal' and establishment of exotic (non-indigenous) species and populations substantially beyond their native range. Invasion may also involve the expansion or shifting of host and geographic distributions of an endemic (indigenous) species or fauna under changing environmental conditions. Invasions result in faunal interchange occurring under influences from both natural and anthropogenic forces where expansion on spatial/temporal continua bridges continents, regions and landscapes. Drivers for invasion are idiosyncratic, multifactorial, interactive, and opportunistic, with a powerful role for historical contingency. The life history patterns of helminths interact with invasion pathways to determine the potential for introduction. Human-mediated events, such as the global expansion of pathogens linked to development of agriculture, domestication of food animals, and European exploration have had a pervasive influence on the distribution of helminths. Globalisation, broad transport networks and environmental perturbation linked to climate change, along with other drivers, have accelerated these processes. A consequence of invasion and establishment of exotic species is that faunal structure will be a mosaic that includes admixtures of indigenous and non-indigenous species and populations; exemplified by helminth faunas among domestic and free-ranging ungulates and a diversity of host-parasite systems among vertebrates. Contemporary mosaics are evident where human-mediated events have brought assemblages of new invaders and relatively old endemic species into sympatry, highlighting interactions at ecotones, particularly those at borderlands between managed and natural ecosystems. Understanding the historical origins and complex components of mosaics is essential in formulating predictions about future responses to environmental change. Powerful tools are available which support the study of invasive species, the most important being systematics and our capacity to accurately identify parasites and to define evolutionary and biogeographic history. Faunal baselines derived from arrays of biological specimens, integrated surveys and informatics are a permanent record of the biosphere when archived in museum collections. The absence of comprehensive taxonomic inventories of parasites, including molecular-genetic data, limits our ability to recognise the introduction of non-indigenous parasites, and to document patterns of expansion for local faunas under a regime of environmental perturbation. PMID- 20919582 TI - Invasive arthropods. AB - Many arthropod species have been transported around the globe and successfully invaded new regions. Invasive arthropods can have severe impacts on animal and human health, agriculture and forestry, and the biodiversity of natural habitats as well as those modified by humans. The economic and environmental effects of invasion can be both direct, through feeding and competition, and indirect, such as the transmission of pathogens. In this paper, the authors consider ten examples that illustrate the main mechanisms of introduction, the characteristics that enable species to rapidly expand their ranges and some of the consequences of their arrival. PMID- 20919583 TI - The consequences of introducing non-indigenous species: two case studies, the grey squirrel in Europe and the brushtail possum in New Zealand. AB - Two examples of the introduction of non-indigenous invasive species are reviewed: the grey squirrel in Europe (United Kingdom, Ireland and Italy) and the brushtail possum in New Zealand. Both have become very successful in their respective non native habitats since their introductions in the mid-to-late 19th Century. Both species impact extensively on native biodiversity, environmental sustainability, forestry, and agriculture through a range of direct and indirect mechanisms. Management is currently mainly by lethal control, namely poisoning, trapping and shooting. Such methods of control are, however, increasingly contentious for both species, and alternative, non-lethal methods of population control, e.g. fertility control, are being developed. The case studies highlight many of the issues in invasive animal control; for example, prevention being better than control, lack of good understanding of impacts and the success of control measures on reducing impacts, interactive impacts on native biodiversity and ecosystems, the telling influence of public opinion on management options and, lastly, the need to better inform and educate the public. PMID- 20919584 TI - Biosecurity measures to prevent the incursion of invasive alien species into Japan and to mitigate their impact. AB - The 2004 Japanese 'Invasive Alien Species Act' was enacted to control invasive alien species and prevent the damage that they cause to ecosystems. The Act defines invasive alien species as those recognised as, or suspected of, causing damage to ecosystems, human safety, agriculture, forestry and fisheries. Invasive alien species are carefully regulated: raising, planting, keeping or transporting them is prohibited without the express permission of the relevant minister. The Act represents a revolutionary advance for biological conservation in Japan. However, enforcing the Act is problematic. Dealing with the European bumblebee (Bombus terrestris), for example, involved resolving a bitter dilemma between biological conservation and agricultural productivity. The Act also has a serious loophole; it does not include alien micro-organisms. The incursion of amphibian chytridiomycosis into Japan caused confusion for scientists and the Japanese Government because control of such an alien micro-organism was not anticipated in the Act. Japan faces particular difficulties in attempting to control alien species because of its reliance on imports. PMID- 20919585 TI - Control and eradication of invasive mammals in Great Britain. AB - This paper provides a 'long view' of the eradication and control of invasive mammals by reviewing the management of 24 mammalian species that have been introduced into Great Britain since the Neolithic period and have subsequently established free-living populations in the wild. The approach provides examples of the issues faced when managing populations and examines some of the lessons that can be learned from successes and failures. The species are covered in the order of introduction, with the control/eradication of rabbit (Oryctolagus cuniculus), muskrat (Ondatra zibethicus), coypu (Myocastor coypus) and American mink (Mustela vison) considered in more detail. The species accounts are set within the context of commitments for the control of invasive alien species made by parties to the Convention on Biological Diversity and guidance provided by the International Union for Conservation of Nature and the Council of Europe. These have led to improvements in the process for assessing risks and co-ordinating action. However, despite some notable cases documented here, there have been few successful eradication programmes carried out in Europe. This paper argues that there is a case for building on the improved frameworks that are being developed in the United Kingdom and elsewhere and for being more ambitious with goals for the management of invasive alien species. PMID- 20919586 TI - Disease risks associated with the translocation of wildlife. AB - Translocation is defined as the human-managed movement of living organisms from one area for free release in another. Throughout the world, increasing numbers of animals are translocated every year. Most of these movements involve native mammals, birds and fish, and are made by private and national wildlife agencies to augment existing populations, usually for sporting purposes. The translocation of endangered species, often to reintroduce them into a part of the historical range from which they have been extirpated, has also become an important conservation technique. The main growth in reintroduction projects over the last decade has involved smaller animals, including amphibians, insects and reptiles. The success of potentially expensive, high-profile wildlife translocation projects depends to a large extent on the care with which wildlife biologists and their veterinary advisers evaluate the suitability of the animals and chosen release site, and on the ability of the translocated animals to colonise the area. The veterinary aspects of reintroduction projects are of extreme importance. There are instances of inadequate disease risk assessment resulting in expensive failures and, worse still, the introduction of destructive pathogens into naive resident wildlife populations. In this paper, some of the disease risks attending wildlife translocation are described. Risk assessment, involving the examination of founder and recipient populations and their habitats, is now a pre-requisite of managed movements of animals. PMID- 20919587 TI - Why own an exotic pet? AB - Even though people have owned a wide variety of companion animals since times of old, the modern craze for increasingly exotic and little-known species raises a number of questions, including some of an ethical nature. While trade in exotic animals is certainly profitable for these who practise it, it poses great risks of varying types: ecological risks, threats to biodiversity conservation and health risks. Several introduced animal populations have gone on to establish a line in their new host country. We are just starting to measure the adverse impact this has had, in some cases on a very large scale. The veterinary profession doubtless has a major role to play in endeavouring to reform this trade in living creatures that unfortunately results in many losses. PMID- 20919588 TI - Biological invasions and the conservation of biodiversity. AB - Consideration of definitions of 'biological invasion' and 'biodiversity' shows why invasions have recently generated great interest among conservationists. Many studies show that invasion numbers have increased drastically over the last five centuries, that this exponential increase is not levelling off, and that human activities are the only reason for the phenomenon. Many mechanisms are portrayed in an evolutionary framework and their consequences for biodiversity are described at three levels of life--gene, species and ecosystem. Examples from islands show that insular ecosystems are especially prone to damage from invasions; they also serve as 'laboratories' to elucidate the nature of invasion impacts. An important management approach--eradication--is discussed. Eradicating invaders not only aids understanding of their impacts on native species but also in understanding how ecosystems function. In fact, biological invasions can be seen as 'experiments', providing a rare opportunity to help answer certain fundamental scientific questions. PMID- 20919589 TI - The role of international organisations in controlling invasive species and preserving biodiversity. AB - Invasive alien species spread through the environment and threaten native biodiversity, assisted by the absence of natural enemies. Alien species may also carry pathogens, which can be transmitted to native species. About half of the known endangered species are under threat from invasive alien species. The Conference of the Parties to the Convention on Biological Diversity in 2008 invited relevant international organisations to work together to fill the gap in the international regulatory framework on invasive alien species. The Convention also reaffirmed the need for capacity and expertise to deal with invasive alien species in many countries, especially in developing countries. In this paper, the authors review the findings of this project. PMID- 20919590 TI - The role of the World Trade Organization and the 'three sisters' (the World Organisation for Animal Health, the International Plant Protection Convention and the Codex Alimentarius Commission) in the control of invasive alien species and the preservation of biodiversity. AB - The missions of the World Organisation for Animal Health (OIE) include the design of surveillance and control methods for infectious transboundary animal diseases (including zoonoses), the provision of guarantees concerning animal health and animal production food safety, and the setting of standards for, and promotion of, animal welfare. The OIE role in setting standards for the sanitary safety of international trade in animals and animal products is formally recognised in the World Trade Organization (WTO) Agreement on the Application of Sanitary and Phytosanitary Measures (the SPS Agreement). While the primary focus of the OIE is on animal diseases and zoonoses, the OIE has also been working within the WTO framework to examine possible contributions the organisation can make to achieving the goals of the Convention on Biological Diversity, particularly to preventing the global spread of invasive alien species (IAS). However, at the present time, setting standards for invasive species (other than those connected to the cause and distribution of diseases listed by the OIE) is outside the OIE mandate. Any future expansion of the OIE mandate would need to be decided by its Members and resources (expertise and financial contributions) for an extended standard-setting work programme secured. The other international standard-setting organisations referenced by the SPS Agreement are the International Plant Protection Convention (IPPC) and the Codex Alimentarius Commission (CAC). The IPPC mandate and work programme address IAS and the protection of biodiversity. The CAC is not involved in this field. PMID- 20919591 TI - Invasive species. Part 1: General aspects and biodiversity. Part 2: Concrete examples. PMID- 20919592 TI - Body weight, self-perception and mental health outcomes among adolescents. AB - BACKGROUND: The prevalence of childhood obesity in the United States has increased three-fold over the last thirty years. During the same period, the prevalence of depressive symptoms in children also rose significantly. Previous literature suggests an association between actual body weight and mental health, but there is little evidence on self-perception of weight and mental health status. AIM: To examine the relationship between actual body weight, self perception of body weight and mental health outcomes among adolescents. METHODOLOGY: Using data for a nationally-representative sample of adolescents in the United States, we ascertain the effect of body weight status on depressive symptoms by estimating endogeneity-corrected models including school-level fixed effects to account for bi-directionality and unobserved confounders. Actual body weight status was calculated using interviewer-measured height and weight. We also used a measure of self-perceived weight status to compare how actual versus self-perceived weight status affects mental health. The Rosenberg Self-Esteem (RSE) Scale, Center for Epidemiologic Studies Depression (CES-D) Scale, and a dichotomous version of self-reported indicator for depression were utilized as mental health indicators. Potential mediators between mental health and weight status such as levels of physical activity, participation in risky health behaviors and parental characteristics were also controlled for in the analysis. The analytical sample consisted of 13,454 adolescents aged 11 to 18. RESULTS AND DISCUSSION: After accounting for a wide array of relevant characteristics, we did not find a direct and significant association between actual weight status and mental health outcomes. Instead, our analysis revealed a strongly negative and significant relationship between self-perceived weight status and mental health. The negative relationship between self-perceived weight and depressive symptoms was more pronounced among females. The RSE scale was particularly correlated with body weight perceptions, suggesting a potentially important link between weight perception and self esteem. LIMITATIONS: While the data set has rich detail on body weight and mental health outcomes, it lacks information on weight stigmatization. The complex relationships between actual body weight, self perception of weight and weight stigmatization also limit determination of causality. CONCLUSION AND IMPLICATIONS: The results from this study highlight the role of body weight perceptions in influencing mental health outcomes independent of actual weight status, especially among female adolescents. This suggests that policies aimed at improving mental health outcomes among adolescents might benefit from a focus on increasing awareness about healthy attitudes towards weight. FUTURE RESEARCH: Recent studies have found evidence that weight stigmatization and body dissatisfaction are predictors of depressive symptoms. It may be that the causal pathway between perceived weight status and depression occurs through weight stigmatization and body dissatisfaction. Future studies should investigate this causal mechanism further. PMID- 20919593 TI - Should "standard gamble" and "'time trade off" utility measurement be used more in mental health research? AB - BACKGROUND: This review and discussion paper demonstrates that utility and preference measurement in mental health research is increasing. However there is still a general reluctance around using the methods due to methodological challenges and concerns around the capacity of users to understand utility methods during the research process. AIMS OF THE STUDY: This paper sets out to describe and review some of the previously documented difficulties of using utility measurements in mental health services research and to highlight where they have been used successfully as measures. Additionally the paper aims to discuss a means of improving the methods used to capture service user utility and preference measurement and why decision making would be better informed as a result. METHODS: International literature on utility measurement is reviewed, specifically examining the use of standard gamble and time trade off methods in mental health. RESULTS: Utility measurement in mental health is increasing though as the review demonstrates, concerns still exist over its application. A number of methods can be used to improve the approach overall and these are discussed as well as specific areas worthy of utility measurement including 'disutility' of admission, medication and medication side effects. DISCUSSION AND LIMITATIONS: Overall this paper argues that it is necessary to persist with efforts to conduct utility measurement calculation albeit with a critical eye on the methods in an attempt to ensure improvements are continually made. Utility and preference scores may be limited in that they only provide a rough score but they are defended as a means of providing some form of strength of preference for health states. The review is limited to English only texts. IMPLICATIONS FOR HEALTH CARE PROVISION: The debate on whether to use standard gamble and time trade off has implications for health services resource allocations, decision making, health economics research, policy making and health services research generally involving psychiatric service users. The paper argues that the absence of utility measurement in mental health runs the risk of mental health being disadvantaged in decisions around resource allocation. IMPLICATIONS FOR HEALTH POLICIES: Institutions involved in decision making like the United Kingdom's National Institute for Health and Clinical Excellence, would be better served in their decision making and calculation of Quality Adjusted Life Years if more utility measurement in psychiatric research was carried out. Other arguments for using utility measurement include the desirability of using utility measurement to elicit a patient dimension of risk. IMPLICATIONS FOR FURTHER RESEARCH: Future utility research should aim for better involvement of service users in the design stage, the changing of time frames offered to users in health state scenarios used, a greater need for comparative work of utilities scoring across illness and between standard gamble and time trade off and more staff training in the use of utility methodology with mental health service users. PMID- 20919594 TI - Evaluating mental health care and policy in Spain. AB - BACKGROUND: The reform and expansion of mental health care (MHC) systems is a key health policy target worldwide. Evidence informed policy aims to make use of a wide range of relevant data, taking into account past experience and local culture and context. AIMS: To discuss the organisation, provision and financing of MHC in Spain visa vis the goals of recent psychiatric reforms. METHOD: We draw upon existing literature, reports and empirical data from regional and national health plans, as well as European reports pertinent to Spain. In addition we have made use of iterative discussion by an expert panel on the features of Spanish MHC services, namely its history, characteristics and determinants in comparison to reforms in other European health systems. RESULTS: In contrast to most other European health systems, the Spanish case reveals that political regional devolution leads to a greater heterogeneity in MHC systems, with some of the 17 autonomous communities (ACs) or region states that make up the country moving more rapidly to full de-institutionalisation alongside coverage expansion and policy innovation. There remains a lack of specific earmarked budgets for MHC at a time of under-funding. There has been an imbalance in MHC reforms, with more focus on the principles underpinning the process of de-institutionalisation and less on the actual development of alternative community based mental health services. Moreover there has been a lack of monitoring of the reform process. Common to other countries, attempts to develop a more informed evidence policy have been hampered by a dislocation between the production of research evidence and the timing of actual policy reform implementation. DISCUSSION: Much of the focus of policy attention is on how to improve coordination within and across sectors, tackle socioeconomic inequalities and thus reduce the gap between perceived and observed need while monitoring any trends suggesting trans institutionalisation. Other issues include developing and strengthening services to meet the needs of new migrants, as well as those of the rural population. There is also a growing recognition of the need to strengthen the evidence base both through research capacity and mechanisms to encourage the use of health economic information as one key component in the assessment of the system. IMPLICATIONS FOR HEALTH POLICIES: The evolution of MHC in Spain may be regarded as a useful contextual case study for other countries embarking on reform, including some in Eastern Europe and Latin America. Spain is an example of a country that has undergone substantial economic and democratic transition in a short time frame; it has seen significant economic growth in some areas and has experienced mass immigration. While it is too early to judge the effectiveness of reforms in Spain, work to date clearly indicates some of the challenges that have to be overcome. These include better harmonisation and integration between health and social care, and more attention paid to the development or monitoring mechanisms to assess progress in reform implementation and better identify any widening of geographical disparities. PMID- 20919595 TI - Costs associated with attempted suicide among individuals with bipolar disorder. AB - BACKGROUND: Bipolar disorder is a chronic mood disorder associated with a high risk for suicide attempts, which carry personal, societal, and economical consequences. No information is available on the economic costs associated with suicide attempts among patients with bipolar disorder or the change in economic costs from before to following the suicide attempt. AIMS OF THE STUDY: The primary objective of this study was to estimate the total health care costs and cost components (inpatient, outpatient, emergency services, and medication) incurred by patients diagnosed with bipolar disorder who attempt suicide. Cost data included psychiatric and non-psychiatric costs. A secondary objective was to compare patients with and without attempted suicide on demographic and clinical characteristics. METHODS: Data for this retrospective study were obtained from the PharMetrics Integrated Outcomes Database (1995-2005). Patients diagnosed with bipolar disorder with (N = 352) and without (N = 15,102) a suicide attempt were identified and compared on demographics and psychiatric and medical comorbidities. T-tests and chi-square tests were used for group comparisons of patient characteristics. Among patients who attempted suicide and were continuously enrolled in the year before and following the suicide attempt (N = 352), Wilcoxon signed-rank tests were used to compare health care costs between the year prior and the year following the first suicide attempt. RESULTS: The average total health care cost for the year following the suicide attempt (N = 352) was $25,012, which was more than 2 times higher than the $11,476 incurred in the prior 1-year period (p. < 001). The total health care cost in the first month following the suicide attempt accounted for 28.9% of the total annual cost. The cost distribution over time showed a large spike for inpatient and emergency services costs in the month following the attempt with sustained increases in medication and outpatient costs. Patients with suicide attempt (N = 1,147) were significantly more likely than patients without (N = 15,102) to be younger, female, and to have comorbid psychiatric and medical diagnoses, especially depressive and substance use disorders. DISCUSSION: The substantial economic costs incurred by patients with bipolar disorder who attempt suicide are marked by an increase in costs of crisis services during the first month following the suicide attempt, along with sustained increases in medication and outpatient costs during the year following the suicide attempt. Limitations of the study include reliance on claims data and potential lack of generalizability beyond private payer data. IMPLICATIONS FOR HEALTH CARE PROVISION AND USE: Interventions designed to reduce the risk of suicide attempts among patients diagnosed with bipolar disorder may help decrease the related high economic costs, in addition to helping decrease adverse personal and societal consequences. IMPLICATIONS FOR HEALTH POLICIES: Cost-benefit analyses of treatment methods for bipolar disorder need to include the considerable expenses associated with suicide attempts. Current findings may also be of value for modeling the cost-effectiveness of treatment for bipolar disorder and of interest to payers and other health care decision makers, especially those involved in developing Medicare capitation models for patients with chronic conditions such as bipolar disorder. IMPLICATIONS FOR FURTHER RESEARCH: Additional research is needed on the cost of attempted suicide in the treatment of patients with bipolar disorder, especially studies that capture societal costs. PMID- 20919596 TI - Rosacea in patients with skin of color: uncommon but not rare. PMID- 20919597 TI - Treating patients with delusions of parasitosis: a blueprint for clinicians. AB - Dermatologists often inquire how to approach a patient with delusions of parasitosis. Avoiding negative countertransference and developing a therapeutic alliance with the patient are key steps for dermatologists. Even though each case is unique, this article serves as a blueprint for clinicians on how to approach and treat these patients. PMID- 20919598 TI - What is your diagnosis? The diagnosis: cutaneous metastic renal cell carcinoma. PMID- 20919599 TI - Underlying amelanotic lentigo maligna melanoma uncovered after a severe blistering sunburn. PMID- 20919600 TI - Porokeratosis of Mibelli with mutilation: a case report. AB - Porokeratosis is a rare keratinization disorder of the skin characterized by annular plaques with an atrophic center surrounded by a raised keratotic wall that spreads centrifugally. We report a case of porokeratosis of Mibelli with mutilation. A 30-year-old woman presented with atrophic plaques on the index fingers of both hands with a keratotic ridge in some margins of the plaques. There was loss of the distal phalanx of the left index finger. In the right hand, shortening of the right distal phalanx and flexion contracture of the distal interphalangeal joint were noted in the index finger. PMID- 20919601 TI - Facial hyperpigmentation caused by diltiazem hydrochloride. AB - Diltiazem hydrochloride, a member of the calcium channel blocker family of antihypertensive medications, has been found to produce many cutaneous reactions, such as photodistributed hyperpigmentation. We report a 53-year-old black woman who presented with facial darkening that began 6 months after starting diltiazem. Areas were not responsive to topical bleaching creams. Biopsy showed postinflammatory pigment alteration with a largely burned-out lichenoid dermatitis. The results of all laboratory evaluations were negative, including complete blood cell count, antinuclear antibodies, anti-Ro antibodies, and anti La antibodies. Patch testing and photo-patch testing to numerous drugs including diltiazem were negative. Phototesting revealed a normal minimal erythema dose to UVA but a slightly reduced minimal erythema dose to UVB. Diltiazem was then stopped and hydralazine hydrochloride was started. While UVA has been thought to be the main culprit in drug-induced photosensitive reactions, this case demonstrates that UVB may possibly play a role in diltiazem-induced photodistributed hyperpigmentation. PMID- 20919602 TI - Furuncular myiasis: a case report. AB - Most clinicians associate myiasis with travel to a tropical location. We report a case of endemic myiasis due to Cuterebra species to remind clinicians that myiasis can occur throughout North America. PMID- 20919603 TI - Oral mucosal melanoma of the mandibular gingiva: a case report. AB - Oral mucosal melanoma is rare and is reported to be more aggressive than cutaneous melanoma. The incidence of oral mucosal melanoma peaks at 41 to 60 years of age and the male to female ratio is 2 to 1. Preferred sites in the oral mucosa include the hard palate and maxillary alveolar crests. Risk factors have not been clearly identified, but melanotic pigmentation is present in one-third of patients prior to the diagnosis of melanoma. We report an unusual case of oral mucosal melanoma of the mandibular gingiva with the main characteristics of an in situ lesion and areas of superficial invasion in a 45-year-old woman. The patient was treated with surgical resection of the lesion and a 54-month follow-up shows no evidence of recurrence. Oral mucosal melanomas are aggressive neoplasms that may arise from prior pigmented lesions in the oral mucosa. Classification of these tumors is not well-established and the main prognostic factor appears to be lymph node compromise. The main treatment modality is surgical resection. PMID- 20919604 TI - Acne vulgaris in the United States: a descriptive epidemiology. AB - While acne vulgaris is a common skin disease, many misconceptions still exist. The purpose of this study is to provide epidemiologic data to accurately describe the US population affected with acne and its associated comorbidities. Patient information was obtained from a third-party database of administrative claims from more than 80 public and private healthcare plans, representing approximately 9.6 million unique patients, and analyzed using the Total Resource Utilization Benchmarks process. Benchmarks in this study included sex, age, comorbidities, medication, and cost. Nearly two-thirds of visits were made by females (65.2%). Teenagers (age range, 12-17 years) comprised only 36.5% of patients with acne, while patients 18 years or older comprised 61.9%. Depression was reported in 10.6% of females with acne. The average total episode cost across all age groups was determined to be $689.06, with a range of $361.25 (age range, 0-11 years) to $869.06 (age range, 15-17 years). The older patients (age 65+ years) more often were prescribed different medications than younger individuals. This analysis only included patients who sought treatment of their acne and may underestimate the total prevalence of acne in the population. Acne is a disease that affects all age groups, not just adolescents. Differences in age are associated with differences in pharmaceutical treatment as well as total healthcare utilization. Depression is a substantial comorbidity and patients seeking treatment of acne should be screened for depression. PMID- 20919605 TI - Osteoma cutis as a sequela to facial acne: a case report. AB - Secondary osteoma cutis of the face represents a late, rare, and often unrecognized complication of chronic inflammatory acne. We present the case of a 48-year-old woman with chronic inflammatory acne followed by osteoma cutis formation. The nodules were successfully removed by simple surgical excision. PMID- 20919606 TI - Simplifying regimens promotes greater adherence and outcomes with topical acne medications: a randomized controlled trial. AB - New combination topical formulations for the treatment of acne may improve outcomes by increasing adherence. We assessed adherence to and efficacy of a combination topical medication for acne applied once daily compared with daily applications of 2 separate generic subcomponents. Twenty-six participants with mild to moderate acne vulgaris were randomized to 12 weeks of once daily application of clindamycin phosphate 7.2%-tretinoin 0.025% gel (CTG) combination product or separate daily applications of clindamycin phosphate gel 1% and tretinoin cream 0.025% (C gel + T cream) for a total of 2 applications daily. Disease severity was measured at baseline and weeks 4, 8, and 12. Adherence was monitored using electronic monitoring caps on the medication tubes. Of the 26 participants enrolled, 21 completed the 12-week study. Median adherence in the CTG group was 88% compared with 61% in the C gel + T cream group. There was a 51% mean reduction in total lesions for the CTG group versus a 32% mean reduction for the C gel + T cream group by the end of the study. Both CTG and separate applications of C gel + T cream improved mild to moderate acne. The use of a once daily combination product has the advantage of promoting better adherence and clinical outcomes. PMID- 20919607 TI - Pediatric brain tumors: a histologic and genetic update on commonly encountered entities. AB - As our understanding of pediatric brain neoplasia flourishes, so does the development of diagnostic, prognostic, and predictive biomarkers. The neuropathologist uniquely stands at the crossroads between pathology and molecular genetics, often overseeing the creation, development, implementation, delivery, and reporting of the newest bioassays. This review serves to highlight the key microscopic and genetic features of the most common pediatric brain tumors. For example, INI-1 immunohistochemistry has assisted in identifying several previously unrecognized cases of rhabdoid cell-poor atypical teratoid rhabdoid tumor (ATRT). The latest discovery involving the tandem duplication and fusion BRAF-KIAA1549 on chromosome 7q34 in pilocytic astrocytoma has drawn attention to the MAPK-ERK pathway and its potential chemotherapeutic manipulation. The newly identified IDH1 mutation, which appears characteristic of "secondary astrocytomas," has yet to be studied in the pediatric population, but some researchers have extolled concomitant BRAF-KIAA1549/IDH1 analysis in the neuropathologic workup of many astrocytomas. Through these and other advances, our understanding of pediatric brain tumors will continue to expand exponentially, and as such will set the stage for truly effectual future treatments. PMID- 20919608 TI - Frequently asked questions concerning the use of whole-slide imaging telepathology for neuropathology frozen sections. AB - TP involves the provision of pathology services over a distance using the Internet to link pathologists at the "viewing site" with diagnostic material in a "remote site." Robotic microscopes were a mainstay of TP; however, this is now changing with the development of whole-slide imaging (WSI) systems which enable rapid production of digital slides that can be reviewed over a complete range of magnifications with a viewing experience closely replicating that of light microscopy. As such, WSI will undoubtedly become a viable option for pathology departments considering TP for remote frozen section (FS) coverage, and in the future for rapid consultation on difficult cases. For reasons to be discussed below, it may be particularly attractive to use WSI TP for neuropathology frozen sections (NPFS). We have been using WSI TP for primary NPFS diagnoses since 2006. This brief review provides answers to questions that we have frequently been asked about our program. The answers reflect our experience, and it is important to note that our recommendations may not be applicable in all institutions. The reader is directed to the recent literature for more detailed information on WSI as well as a complete description of our TP program. PMID- 20919609 TI - Parasitic diseases of the central nervous system. AB - Parasitic infections, though endemic to certain regions, have over time appeared in places far removed from their original sites of occurrence facilitated probably by the increase in world travel and the increasing migration of people from their native lands to other, often distant, countries. The frequency of occurrence of some of these diseases has also changed based on a variety of factors, including the presence of intermediate hosts, geographic locations, and climate. One factor that has significantly altered the epidemiology of parasitic diseases within the central nervous system (CNS) is the HIV pandemic. In this review of the pathology of parasitic infections that affect the CNS, each parasite is discussed in the sequence of epidemiology, life cycle, pathogenesis, and pathology. PMID- 20919610 TI - Nontumor lesions of spinal cord and spine. AB - Nontumor lesions of the spinal cord and spine include developmental disorders, cystic tumor-like lesions, vascular disorders, infective diseases, demyelinating diseases, degenerative diseases, metabolic and toxic disorders, and spinal cord injury. In addition, diseases of the spine and extradural spaces secondarily cause spinal cord injury. Aside from tumors, these include developmental abnormalities, inflammatory diseases, nontumor space-occupying lesions, and tumor like lesions such as lipomas, vascular malformations, and cysts. Awareness is required of hemostatic agents used during surgery and subsequently presenting as space-occupying lesions, which have to be differentiated from recurrent lesions. On the therapeutic front, stem cell transplantation into spinal cord for treatment of neurodegenerative disorders, spinal cord injury, and multiple sclerosis is a challenging prospect. PMID- 20919611 TI - The problems of protecting the neck from combat wounds. PMID- 20919612 TI - Traumatic diaphragmatic injury. AB - Traumatic diaphragmatic injury is a not uncommon accompaniment to blunt or penetrating trauma to the abdomen or thorax; it may present acutely with haemodynamic and respiratory compromise and be associated with significant injury to other organs or may not be diagnosed at the initial trauma at all and present later as a diaphragmatic hernia. This overview examines the incidence, pathophysiology and management of this condition. PMID- 20919613 TI - Anaesthetic and critical care management of thoracic injuries. AB - Thoracic wounding has been a relatively common presentation of military wounds throughout modern conflict. When civilian casualties are included the incidence has remained constant at around 10%, although the frequency and severity of wounds to combatants has been altered by modern body armour. Whilst thoracic injury has a high initial mortality on the battlefield, those surviving to reach hospital frequently have injuries that only require simple management. In addition to penetrating ballistic injury, blunt chest trauma frequently occurs on operations as a result of road traffic collisions or tertiary blast injury. The physiological impact of thoracic wounds, however, is often great and survivors often require intensive care management and, where available, complex strategies to ensure oxygenation and carbon dioxide removal. This review examines the incidence and patterns of thoracic trauma and looks at therapeutic options for managing these complex cases. PMID- 20919614 TI - British military experience of pre-hospital paediatric trauma in Afghanistan. AB - INTRODUCTION: Trauma is a leading cause of death in children. Life support courses have been developed to reduce the mortality and morbidity of children suffering trauma; differences in anatomy and physiology may produce different injury patterns to adults when children are exposed to trauma, challenging the care providers. METHODS: A retrospective analysis of all paediatric patients transported by the helicopter-borne MERT between 01 May 2006 and 31 December 2007 in Helmand Province, Afghanistan. RESULTS: 78 children were brought in over the study period by the MERT team representing 7.3% of MERT casualties and 2.2% of the total seen in the Emergency Department. Breakdown by demographics, triage category, mechanism of injury, and treatment is given. CONCLUSION: A significant number of paediatric patients are treated by the deployed pre-hospital team. All military pre-hospital care providers should gain training and experience in the care of the seriously injured child prior to deployment. PMID- 20919615 TI - The development of bacteriology, sanitation science and allied research in the British Army 1850-1918: equipping the RAMC for war. AB - The recent 90 year anniversary of the end of the First World War is an opportune time to reconsider the important role of the Royal Army Medical Corps in this conflict. One area which has been neglected is the role of the Royal Army Medical Corps in responding to infectious diseases and to understand this properly it is important to consider the development of bacteriology, sanitation science and allied research in the British Army up to the Great War. The context of the home front is also central, with the British population from 1880-1914 increasingly benefiting from improved public sanitation and the new science of bacteriology. Historians acknowledge that the British campaign in the Crimea in the 1850s was pursued with inadequate medical provision and as a result, the Army suffered severely from infectious diseases. Limited changes were introduced after the Crimean War, such as the establishment of the Army Medical School, with its high quality instruction in military hygiene and later bacteriology. Army medics also led the way in various branches of scientific research, through research in the colonies. As compared with the continental powers, however, the application of bacteriology and sanitation to field craft in the British Army was delayed. It took the experiences of the South African and Russo-Japanese Wars for the importance of these sciences to be recognised by the Army as a whole. These subjects began to form part of the education of army Medical Officers, but training was basic and few trainees had specialised in bacteriology by 1914. In spite of these limitations, the Royal Army Medical Corps responded well to the demands placed upon it by World War One, recruiting civilian bacteriologists to its ranks, developing technological innovations such as mobile bacteriological laboratories for them to work in, forming a sanitation service and fostering medical research. PMID- 20919616 TI - Advanced airway management--a medical emergency response team perspective. AB - OBJECTIVES: To determine the number of medical emergency response team (MERT) patients undergoing advanced airway management in the peri-evacuation phase and to determine the indications for airway interventions undertaken in flight. METHODS: This was a retrospective study. Data was collected from patient report and mission debrief forms completed after each MERT mission during Operation HERRICK 10 (April-October 2009). All patients that received advanced airway interventions before or during evacuation were identified. RESULTS: MERTs were involved in the primary transfer of 534 patients during the period studied, 56 (10.5%) underwent advanced airway management, of which 31 (5.8% of total) were initiated by the MERT in the peri-evacuation phase. Twenty five cases (4.7%) underwent advanced airway management by other pre-hospital providers prior to MERT arrival. Of the 31 advanced airway interventions undertaken in-flight, cardiac arrest was the primary indication in only nine cases. CONCLUSIONS: The figure of 56 patients requiring advanced airway management is at the higher end of the range expected from the study of historical military data. This may reflect the doctrine of "intelligent tasking", that is sending this physician-led team to the most seriously injured casualties. PMID- 20919617 TI - UK Role 4 military infectious diseases at Birmingham Heartlands Hospital in 2005 9. AB - OBJECTIVES: Infectious diseases affecting British troops are mostly due to gastrointestinal and respiratory illnesses, but these are usually minor in severity, easy to manage and short in duration. To assess the importance of infections that are more severe, difficult to manage or longer in duration, it is necessary to look at military cases that are evacuated or otherwise referred to the UK Role 4 (definitive care) medical facility for infectious diseases. METHODS: Case notes from military infectious disease patients seen at Birmingham Heartlands Hospital in 2005-2009 were reviewed to extract data on demographics, origin of infection, diagnostic categories, exact diagnoses, type and duration of care, time off duty, quality of care and costs incurred. RESULTS: Over a 4-year period, 138 cases were referred, 131 (95%) were male and 98 (71%) were from the Army. The origin of infection was Afghanistan in 52 (38%) and Belize in 19 (14%). From 131 patients (95%) that attended, 59 (45%) had dermatological illnesses and 38 (29%) had undifferentiated febrile illnesses. Diagnoses included 35 (27%) with cutaneous leishmaniasis and 21 (16%) with "Helmand Fever" due to sandfly fever, acute Q fever or rickettsial infection. For 51 in-patients, the median (range) length of stay was 3 (1-17) days and time off duty was 20 (5-127) days. For 80 out-patients, the median (range) number of attendances was 1 (1-23) and time off duty was 22 (1-228) days. All cases were seen promptly (within 7 days for in patients and 28 days for out-patients), but only 59 (45%) had appropriate letters sent to the referring medical officer and none had F Med 85 notifications of infectious disease submitted. Aeromedical evacuation costs could not be calculated, but UK hospital care cost approximately pound 78 000 per year. CONCLUSIONS: Dermatological infections and undifferentiated febrile illnesses that require management at a UK Role 4 facility are important causes of disease non-battle injury. Prospective collection of this data in the future will be a valuable asset. PMID- 20919618 TI - Force generation--deployment-aligned MIACs. AB - As the pressure mounts to supply more ground forces in Afghanistan, the Defence Medical Services (DMS) are directly supporting surge activity through ensuring the provision of deployable personnel. Delivery of this goal requires a change in the practice, focus and resources of the DMS. Identification, treatment and rehabilitation of injured service personnel is a priority in improving the pool of personnel available for deployment on Operations. This paper details the drivers, process and potential benefits of aligning Multi-Disciplinary Injury Assessment Clinic's activity with a unit's formation readiness cycle, to more appropriately and proactively manage injured service personnel to improve both the quality and quantity of Force Generation. PMID- 20919619 TI - A travel misadventure--visceral leishmaniasis in an immunocompetent patient. AB - Visceral leishmaniasis is one of the world's most neglected diseases. Over 90% of the 500,000 annual new cases occur in only five countries: India, Nepal, Bangladesh, Sudan and North-Eastern Brazil, but the disease remains endemic in Southern Europe. We report a case of visceral leishmaniasis in an immunocompetent serviceman after a seven-day stay in the Marseilles region of South-Eastern France. This case is intended to alert clinicians to the possibility of visceral leishmaniasis in patients who develop a febrile illness after returning from travel in Southern European countries. PMID- 20919620 TI - Cardiology. AB - Cardiac disease remains a significant threat to both local and deployed military populations. In this article we present several cardiac case reports which may be of educational use to the military clinician. PMID- 20919621 TI - The Indian mutiny--Part 2. PMID- 20919622 TI - The Army Primary Health Care Service: from foundation to future. AB - Following the British Government's implementation of policies to improve quality and introduce clinical governance into healthcare delivery in the late 1990s, the British Army commissioned a study into how primary healthcare for the Regular Army should best be delivered in UK. The study recommended a unitary command structure, with more central control based upon a model of a main headquarters and seven regions. The change has been largely successful and has been subject to external scrutiny. Areas still to be developed include improving information management and benchmarking standards against the NHS, improvements in practice management, plus developments in occupational health and the nursing cadres. The forthcoming Strategic Defence and Security Review and other ongoing studies are likely to have a profound influence on how the current Army Primary Health Care Service develops. PMID- 20919623 TI - General practice training in the Army. PMID- 20919624 TI - Preparing for an operational tour as a medical officer in southern. AB - At the time of writing, Afghanistan is the pre-eminent theatre of operations for UK military forces, which form a lead element in the International Security Assistance Force. Many junior medical officers (MOs) can expect to see service on Operation HERRICK in the south of the country, in support of deployed battlegroup formations. MO's will often find themselves supporting Company Group formations, either within the Company Aid Post, or on dismounted/vehicle borne operations. This article presents some of the challenges faced by those deployed in such circumstances, and proposes possible strategies to address them. PMID- 20919625 TI - Detecting post-deployment mental health problems in primary care. AB - Post-deployment mental health problems are a source of potential concern for health professionals and politicians in military forces in the world; the UK Armed Forces are no exception. This article examines practical ways in which General Practitioners in Primary Care can enhance their ability to detect post deployment mental health problems and offers suggestions on immediate management and assessment, based on contemporary evidence and clinical experience. PMID- 20919626 TI - Opportunities in pre hospital emergency care for the Armed Forces in the UK. PMID- 20919627 TI - The general practitioner trainer exchange as an innovative approach to peer review. AB - There are various formal peer review schemes to assess the quality of primary care practices and several special approval and re-approval programmes exist for General Practitioner (GP) trainers and primary care training practices. The Defence Postgraduate Medical Deanery (DPMD) has its own General Practice Education Committee (GPEC) approval and re-approval programme. Part of this programme is related to the New Membership of the Royal College of Practitioners (nMRCGP). There is limited published information related to GP trainer exchanges as a means of peer review and as such as preparation for GPEC in the British Forces. This paper provides a review of a GP trainer exchange involving a visit of a GP trainer from British Forces Germany (BFG) to the practices of Dhekelia and Ay Nik on Cyprus in January 2010. It concludes that a GP trainer exchange is cost neutral and may be a valuable experience for both the host and visiting GP trainer, the local GP trainers' group, the practice teams and above all, for the GP trainee. PMID- 20919628 TI - The doctor vs. the Command: can disagreement arise? AB - Doctors have long since assisted the Command on operations and in providing day to day bespoke medical care to the UK Armed Forces. Doctors and the Command work along different models that confer different obligations and priorities. For doctors the patient and their wellbeing is of primary importance and for the Command, the Unit as a whole with its military goals are of primary concern. Most of the time these two models work in harmony. However occasionally disagreement can arise. This article examines the models guiding their respective practice in order to understand the underpinnings of these disagreements, and offers some discussion of the issues, particularly as they pertain to the deployed environment. Finally, some recommendations are made to equip doctors and the Command to contain any disagreements. PMID- 20919629 TI - Refractive errors in the UK Armed Forces. PMID- 20919630 TI - Hoffman II external fixator techniques--a work-around to use small pins in large clamps. AB - We describe a novel technique to allow use of small pins in medium pin size clamps. Slipping a second 3 mm pin into the same clamp hole as the first allows the 5 mm clamp to bite securely on a 3 mm pin. This enables construction of an external fixator frame utilising 3 mm and 5 mm pins, as required to span the elbow, wrist and ankle. This extends the capabilities of the 5 mm clamp and reduces the need for extra materiel such as sets containing damps to connect 3 mm pins to standard size rods. PMID- 20919631 TI - The ecological impact of invasive cane toads (Bufo marinus) in Australia. AB - Although invasive species are viewed as major threats to ecosystems worldwide, few such species have been studied in enough detail to identify the pathways, magnitudes, and timescales of their impact on native fauna. One of the most intensively studied invasive taxa in this respect is the cane toad (Bufo marinus), which was introduced to Australia in 1935. A review of these studies suggests that a single pathway-lethal toxic ingestion of toads by frog-eating predators-is the major mechanism of impact, but that the magnitude of impact varies dramatically among predator taxa, as well as through space and time. Populations of large predators (e.g., varanid and scincid lizards, elapid snakes, freshwater crocodiles, and dasyurid marsupials) may be imperilled by toad invasion, but impacts vary spatially even within the same predator species. Some of the taxa severely impacted by toad invasion recover within a few decades, via aversion learning and longer-term adaptive changes. No native species have gone extinct as a result of toad invasion, and many native taxa widely imagined to be at risk are not affected, largely as a result of their physiological ability to tolerate toad toxins (e.g., as found in many birds and rodents), as well as the reluctance of many native anuran-eating predators to consume toads, either innately or as a learned response. Indirect effects of cane toads as mediated through trophic webs are likely as important as direct effects, but they are more difficult to study. Overall, some Australian native species (mostly large predators) have declined due to cane toads; others, especially species formerly consumed by those predators, have benefited. For yet others, effects have been minor or have been mediated indirectly rather than through direct interactions with the invasive toads. Factors that increase a predator's vulnerability to toad invasion include habitat overlap with toads, anurophagy, large body size, inability to develop rapid behavioral aversion to toads as prey items, and physiological vulnerability to bufotoxins as a result of a lack of coevolutionary history of exposure to other bufonid taxa. PMID- 20919632 TI - Toward a conceptual framework for biology. AB - Science progresses faster when researchers operate within an explicit framework of concepts and theories, but currently biology has no explicit, overarching conceptual framework and few general theories. The single general theory currently recognized is that of evolution, which was put forth by Charles Darwin 150 years ago. Recently, Scheiner and Willig (2008) explicated a similarly general theory of ecology. In this paper, using the theory of evolution as an exemplar, I discuss the nature of theory in biology and put forth an overarching theory, as well as new general theories for cells, organisms, and genetics. Along with the theories of evolution and ecology, these constitute a general conceptual framework for the biological sciences. This framework reveals linkages among the various parts of biology, makes explicit the assumptions behind more narrow theories and models, and provides new insights into the structures of biological theories. This framework can also be used as a teaching tool, moving the teaching of biology beyond the transference of a vast compendium of facts. My hope is that this essay will lead to a vigorous discussion and debate across all of biology about the nature and structure of its theories. PMID- 20919633 TI - Assessing macroinvertebrate biodiversity in freshwater ecosystems: advances and challenges in DNA-based approaches. AB - Assessing the biodiversity of macroinvertebrate fauna in freshwater ecosystems is an essential component of both basic ecological inquiry and applied ecological assessments. Aspects of taxonomic diversity and composition in freshwater communities are widely used to quantify water quality and measure the efficacy of remediation and restoration efforts. The accuracy and precision of biodiversity assessments based on standard morphological identifications are often limited by taxonomic resolution and sample size. Morphologically based identifications are laborious and costly, significantly constraining the sample sizes that can be processed. We suggest that the development of an assay platform based on DNA signatures will increase the precision and ease of quantifying biodiversity in freshwater ecosystems. Advances in this area will be particularly relevant for benthic and planktonic invertebrates, which are often monitored by regulatory agencies. Adopting a genetic assessment platform will alleviate some of the current limitations to biodiversity assessment strategies. We discuss the benefits and challenges associated with DNA-based assessments and the methods that are currently available. As recent advances in microarray and next generation sequencing technologies will facilitate a transition to DNA-based assessment approaches, future research efforts should focus on methods for data collection, assay platform development, establishing linkages between DNA signatures and well-resolved taxonomies, and bioinformatics. PMID- 20919634 TI - BCL-2 protein family. Essential regulators of cell death. Preface. PMID- 20919635 TI - Homeostatic functions of BCL-2 proteins beyond apoptosis. AB - Since its introduction in 1930 by physiologist Walter Bradford Cannon, the concept of homeostasis remains the cardinal tenet of biologic regulation. Cells have evolved a highly integrated network of control mechanisms, including positive and negative feedback loops, to safeguard homeostasis in face of a wide range of stimuli. Such control mechanisms ultimately orchestrate cell death, division and repair in a manner concordant with cellular energy and ionic balance to achieve proper biologic fitness. The interdependence of these homeostatic pathways is also evidenced by shared control points that decode intra- and extracellular cues into defined effector responses. As critical control points of the intrinsic apoptotic pathway, the BCL-2 family of cell death regulators plays an important role in cellular homeostasis. The different anti- and pro-apoptotic members of this family form a highly selective network of functional interactions that ultimately governs the permeabilization of the mitochondrial outer membrane and subsequent release of apoptogenic factors such as cytochrome c. The advent of loss- and gain-of-function genetic models for the various BCL-2 family proteins has not only provided important insights into apoptosis mechanisms but also uncovered unanticipated roles for these proteins in other physiologic pathways beyond apoptosis (Fig. 1). Here, we turn our attention to these alternative cellular functions for BCL-2 proteins. We begin with a brief introduction of the cast of characters originally known for their capacity to regulate apoptosis and continue to highlight recent advances that have shaped and reshaped our views on their physiologic relevance in integration of apoptosis with other homeostatic pathways. PMID- 20919636 TI - Alternative functions of the BCL-2 protein family at the endoplasmic reticulum. AB - Apoptosis is essential for maintenance of tissue homeostasis and its deregulation results in a variety of disease conditions. The BCL-2 family of proteins is a group of evolutionarily conserved regulators of cell death that comprises both anti- and pro-apoptotic members, that operate at the mitochondrial membrane to control caspase activation. Different BCL-2-related proteins are also located in the endoplasmic reticulum (ER), where important roles in organelle physiology are proposed. Adaptation to ER stress is mediated by the activation of a complex signal transduction pathway known as the unfolded protein response (UPR). Recent reports indicate that the ER stress sensor IRE1alpha, signals through the formation of a protein complex platform at the ER membrane, here termed the "UPRosome". Alternatively, BCL-2 family members are contained in other multiprotein complexes at the ER that are involved in the control of diverse cellular processes including calcium homeostasis, autophagy and ER morphogenesis. Here we describe the emerging concept that BCL-2 family members are important regulators of essential cellular processes beyond apoptosis. PMID- 20919638 TI - Endoplasmic reticulum stress and BCL-2 family members. AB - In the eukaryotic cell, the endoplasmic reticulum (ER) plays an important role as the site of lipid synthesis, protein folding and protein maturation. Stringent regulation of redox and calcium homeostasis is paramount, failure of which leads accumulation of unfolded and aggregating proteins resulting in a condition known as ER stress. Eukaryotic cells deal with ER stress by eliciting the unfolded protein response (UPR). This pathway splits into two streams depending on the severity and longevity of the ER stress, where the cell must make a choice for the good of the organism between survival and programmed cell death. The BCL-2 family of proteins is central to the cell death arm of the UPR pathway. This chapter discusses the recent findings on the involvement of BCL-2 family members in the apoptotic process initiated by ER stress and a related process called autophagy. Understanding the molecular mechanisms involved in ER stress and autophagy could have a profound implications developing new therapies for many ER stress associated diseases and cancer. PMID- 20919639 TI - Targeting survival pathways in lymphoma. AB - Targeting cellular death pathways including apoptosis is a promising strategy for cancer drug discovery. To date at least three major types of cell death have been distinguished, including: apoptosis, autophagy, and necrosis. Increasing evidence has begun to support a role of Bcl-2-family members in the cellular pathways involved in each of these processes. The induction of apoptosis in different types of tissue and in response to various stressors is a complex process that is controlled by different BCL-2 family members. Pharmacologic modulation of BCL-2 proteins and apoptosis can be achieved through different ways including the use of: (1) Modified peptides; (2) Small molecule inhibitors ofanti-apoptotic proteins; (3) Antisense strategies; and (4) TRAIL targeting. Non-peptide based small-molecule inhibitors of signaling pathways are at present the strategy of choice given their low antigenicity and generally more favorable pharmacokinetic and pharmacodynamic features, especially as they pertain to volume of distribution and intracellular accumulation. Bcl2-family inhibitors are showing impressive preclinical efficacy in animal models and are moving rapidly towards phase I and II clinical trials. Appropriate preclinical studies will need to identify the optimal strategies for combining these agents, with an emphasis on the importance of dose and schedule dependency. PMID- 20919640 TI - The interplay between BCL-2 family proteins and mitochondrial morphology in the regulation of apoptosis. AB - Apoptosis is a highly regulated process where key players such as BCL-2 family members control the recruitment of the mitochondrial subroutine. This culminates in the release of cytochrome c from the organelle in the cytoplasm, where it is required for the activation of effector caspases. The complete release of cytochrome c is the result of the combined action of proapoptotic BCL-2 family members and of changes in the complex morphology and ultrastructure of the organelle, controlled by the balance between fusion and fission processes. Here we discuss recent findings pointing to a role for changes in mitochondrial morphology during apoptosis and how these might be regulated by members of the BCL-2 family. PMID- 20919641 TI - Noncanonical functions of BCL-2 proteins in the nervous system. AB - BCL-2 family proteins form heterodimers or homo-oligomers to inhibit or induce apoptotic cell death, respectively. They often relocalize from the cytoplasm to mitochondria to carry out these functions. The traditional model is that in healthy cells, anti-death family members hold pro-death BCL-2 family members in check. Upon receiving a death stimulus, another set of proteins (BH3-only proteins) inactivate the protective BCL-2 proteins, forcing them to release their pro-death partners that are subsequently triggered to oligomerize and porate the mitochondrial outer membrane leading to cell death. In support of this traditional view, there is a preponderance of supporting evidence derived from the study of events that occur following treatment of cells with a death stimulus. Knockout and mutant mice also exhibit many developmental and treatment induced phenotypes consistent with this model of antagonism between BCL-2 family proteins. Emphasis is logically placed on those phenotypes that support the model. However, this working model of BCL-2 family interactions has become so engrained that alternative, potentially valid interpretations are sometimes dismissed. Therefore, it is useful to consider the evidence that seems contrary to accepted models. In particular, the analysis of BCL-2 family functions in the nervous system has revealed unexpected outcomes that can serve to further stimulate critical probing of the yet unknown biochemical functions of BCL-2 proteins. PMID- 20919637 TI - BH3-only proteins and their effects on cancer. AB - Apoptosis, a form of cellular suicide is a key mechanism involved in the clearance of cells that are dysfunctional, superfluous or infected. For this reason, the cell needs mechanisms o sense death cues and relay death signals to the apoptotic machinery involved in cellular execution. In the intrinsic apoptotic pathway, a subclass of BCL-2 family proteins called the BH3 onlyproteins are responsible for triggering apoptosis in response to varied cellular stress cues. The mechanisms by which they are regulated are tied to the type of cellular stress they sense. Once triggered, they interact with other BCL 2 family proteins to cause mitochondrial outer membrane permeabilization which in turn results in the activation ofserine proteases necessary for cell killing. Failure to properly sense death cues and relay the death signal can have a major impact on cancer. This chapter will discuss our current models of how BH3-only proteins function as well as their impact on carcinogenesis and cancer treatment. PMID- 20919642 TI - Mitochondria on guard: role of mitochondrial fusion and fission in the regulation of apoptosis. AB - Mitochondria are highly dynamic organelles that constantly change shape and structure in response to different stimuli and metabolic demands of the cell. Mitochondrial structure in the cell is predominantly regulated by cycles of fusion and fission. These two processes are tightly regulated and under physiological conditions, mitochondrial fusion is evenly counterbalanced by fission. During apoptosis, mitochondria undergo extensive fragmentation, which precedes caspase activation, whereas inhibition of the mitochondrial fission machinery blocks or delays cell death. Aberrant mitochondrial fusion and fission have also emerged as important mechanisms in the development of disease. In this chapter we will briefly discuss mechanisms of mitochondrial fusion and fission in mammalian cells, the mitochondrial morphogenesis proteins that may be involved in these processes and role of these processes in cell viability. This will be followed by a review of recent work connecting mitochondrial morphogenesis proteins with the progression of the mitochondrial steps in apoptosis, as well as stimulating findings showing that certain proteins associated with apoptosis regulation can also participate in the regulation ofmitochondrial fusion and fission in healthy cells. PMID- 20919644 TI - Sphingolipid transport. AB - Sphingolipids are a family of ubiquitous membrane components that exhibit multiple functional properties fundamental to cell properties. Sphingolipid transport represents a crucial aspect in the metabolism, signaling and biological role of sphingolipids. Different mechanisms of sphingolipid movements contribute to their selective localization in different membranes but also in different portions and sides of the same membrane, thus ensuring and regulating their interaction with different enzymes and target molecules. In this chapter we will describe the knowledge of the different mechanisms ofsphingolipid movements within and between membranes, focusing on the recent advances in this field and considering the role played by selective sphingolipid molecules in the regulation of these mechanisms. PMID- 20919645 TI - Sphingolipid analysis by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). AB - Sphingolipid (SPL) metabolism (Fig. 1) serves a key role in the complex mechanisms regulating cellular stress responses to environment. Several SPL metabolites, especially ceramide (Cer), sphingosine (Sph) and sphingosinel phosphate (S1P) act as key bioactive molecules governing cell growth and programmed cell death (Fig. 2). Perturbations in sphingolipids of one type may enhance or interfere with the action of another. To monitor changes in SPL composition therefore, reliable analytical methods are necessary. Here we present the liquid chromatography tandem mass spectrometry (LC-MS/MS) approach for simultaneous qualitative and quantitative monitoring of SPL components (classes and molecular species) in biological material as an effective tool to study sphingolipid signaling events. The LC-MS/MS methodology is the only available technique that provides high specificity and sensitivity, along with a wealth of structural identification information. PMID- 20919646 TI - Ceramide synthases: roles in cell physiology and signaling. AB - Ceramide synthases (CerS) are integral membrane proteins of the endoplasmic reticulum. Six mammalian CerS have been described, with each utilizing fatty acyl CoAs of relatively defined chain lengths for N-acylation of the sphingoid long chain base. In this chapter, we review the main functional features of the CerS proteins, discuss their fatty acid specificity, kinetics, tissue distribution and mode of inhibition, as well as possible posttranslational modifications. We then address the reason that mammals contain six distinct CerS, whereas most other enzymes in the sphingolipid biosynthetic pathway only occur in one or two isoforms. Finally, we discuss the putative roles of CerS and the ceramide derived from the CerS, in signaling pathways and in development of disease. PMID- 20919643 TI - An overview of sphingolipid metabolism: from synthesis to breakdown. AB - Sphingolipids constitute a class of lipids defined by their eighteen carbon amino alcohol backbones which are synthesized in the ER from nonsphingolipid precursors. Modification of this basic structure is what gives rise to the vast family of sphingolipids that play significant roles in membrane biology and provide many bioactive metabolites that regulate cell function. Despite the diversity of structure and function of sphingolipids, their creation and destruction are governed by common synthetic and catabolic pathways. In this regard, sphingolipid metabolism can be imagined as an array of interconnected networks that diverge from a single common entry point and converge into a single common breakdown pathway. In their simplest forms, sphingosine, phytosphingosine and dihydrosphingosine serve as the backbones upon which further complexity is achieved. For example, phosphorylation of the C1 hydroxyl group yields the final breakdown products and/or the important signaling molecules sphingosine-1 phosphate, phytosphingosine-1-phosphate and dihydrosphingosine-1-phosphate, respectively. On the other hand, acylation of sphingosine, phytosphingosine, or dihydrosphingosine with one of several possible acyl CoA molecules through the action of distinct ceramide synthases produces the molecules defined as ceramide, phytoceramide, or dihydroceramide. Ceramide, due to the differing acyl CoAs that can be used to produce it, is technically a class of molecules rather than a single molecule and therefore may have different biological functions depending on the acyl chain it is composed of. At the apex of complexity is the group of lipids known as glycosphingolipids (GSL) which contain dozens of different sphingolipid species differing by both the order and type of sugar residues attached to their headgroups. Since these molecules are produced from ceramide precursors, they too may have differences in their acyl chain composition, revealing an additional layer of variation. The glycosphingolipids are divided broadly into two categories: glucosphingolipids and galactosphingolipids. The glucosphingolipids depend initially on the enzyme glucosylceramide synthase (GCS) which attaches glucose as the first residue to the C1 hydroxyl position. Galactosphingolipids, on the other hand, are generated from galactosylceramide synthase (GalCerS), an evolutionarily dissimilar enzyme from GCS. Glycosphingolipids are further divided based upon further modification by various glycosyltransferases which increases the potential variation in lipid species by several fold. Far more abundant are the sphingomyelin species which are produced in parallel with glycosphingolipids, however they are defined by a phosphocholine headgroup rather than the addition of sugar residues. Although sphingomyelin species all share a common headgroup, they too are produced from a variety of ceramide species and therefore can have differing acyl chains attached to their C 2 amino groups. Whether or not the differing acyl chain lengths in SMs dictate unique functions or important biophysical distinctions has not yet been established. Understanding the function of all the existing glycosphingolipids and sphingomyelin species will be a major undertaking in the future since the tools to study and measure these species are only beginning to be developed (see Fig 1 for an illustrated depiction of the various sphingolipid structures). The simple sphingolipids serve both as the precursors and the breakdown products of the more complex ones. Importantly, in recent decades, these simple sphingolipids have gained attention for having significant signaling and regulatory roles within cells. In addition, many tools have emerged to measure the levels of simple sphingolipids and therefore have become the focus of even more intense study in recent years. With this thought in mind, this chapter will pay tribute to the complex sphingolipids, but focus on the regulation of simple sphingolipid metabolism. PMID- 20919647 TI - Tales and mysteries of the enigmatic sphingomyelin synthase family. AB - In the last five years tremendous progress has been made toward the understanding of the mechanisms that govern sphingomyelin (SM) synthesis in animal cells. In line with the complexity of most biological processes, also in the case of SM biosynthesis, the more we learn the more enigmatic and finely tuned the system appears. Therefore with this review we aim first, at highlighting the most significant discoveries that advanced our knowledge and understanding of SM biosynthesis, starting from the discovery of SM to the identification of the enzymes responsible for its production; and second, at discussing old and new riddles that such discoveries pose to current investigators. PMID- 20919648 TI - Ceramide in stress response. AB - Evidence has consistently indicated that activation of sphingomyelinases and/or ceramide synthases and the resulting accumulation of ceramide mediate cellular responses to stressors such as lipopolysaccharide, interleukin 1beta, tumor necrosis factor alpha, serum deprivation, irradiation and various antitumor treatments. Recent studies had identified the genes encoding most of the enzymes responsible for the generation of ceramide and ongoing research is aimed at characterizing their individual functions in cellular response to stress. This chapter discusses the seminal and more recent discoveries in regards to the pathways responsible for the accumulation of ceramide during stress and the mechanisms by which ceramide affects cell functions. The former group includes the roles of neutral sphingomyelinase 2, serine palmitoyltransferase, ceramide synthases, as well as the secretory and endosomal/lysosomal forms of acid sphingomyelinase. The latter summarizes the mechanisms by which ceramide activate its direct targets, PKCzeta, PP2A and cathepsin D. The ability of ceramide to affect membrane organization is discussed in the light of its relevance to cell signaling. Emerging evidence to support the previously assumed notion that ceramide acts in a strictly structure-specific manner are also included. These findings are described in the context of several physiological and pathophysiological conditions, namely septic shock, obesity-induced insulin resistance, aging and apoptosis of tumor cells in response to radiation and chemotherapy. PMID- 20919649 TI - Animal models for studying the pathophysiology of ceramide. AB - Bioactive sphingolipids play key roles in the regulation of several fundamental biological processes such as proliferation, apoptosis and transformation. The recent development of genetically engineered mouse (GEM) models has enabled the study of functional roles of sphingolipids in normal development and disease. In this chapter, we review the phenotypes of GEM models (knockout mice) that lack sphingolipid metabolism-related enzymes, discuss what we have learned from animal models and describe future directions of animal models in sphingolipid research. PMID- 20919650 TI - Ceramide-1-phosphate in cell survival and inflammatory signaling. AB - An important metabolite of ceramide is ceramide-1-phosphate (C1P). This lipid second messenger was first demonstrated to be mitogenic for fibroblasts and macrophages and later shown to have antiapoptotic properties. C1P is also an important mediator of the inflammatory response, by stimulating the release of arachidonic acid through activation of group IVA cytosolic phospholipase A2, the initial rate-limiting step of eicosanoid biosynthesis. C1P is formed from ceramide by the action of a specific ceramide kinase (CerK), which is distinct from the sphingosine kinases that synthesize sphingosine-1-phosphate. CerK is specific for natural ceramides with the erythro configuration in the base component and esterified to long-chain fatty acids. CerK can be activated by different agonists, including interleukin 1-beta, macrophage colony stimulating factor, or calcium ions. Most of the effects of C1P so far described seem to take place in intracellular compartments; however, the recent observation that C1P stimulates cell migration implicates a specific plasma membrane receptor that is coupled to a G(i) protein. Therefore, C1P has a dual regulatory capacity acting as an intracellular second messenger to regulate cell survival, or as extracellular receptor ligand to stimulate chemotaxis. PMID- 20919651 TI - Ceramide-1-phosphate in phagocytosis and calcium homeostasis. AB - Sphingolipids are well established sources of important signaling molecules. For example, ceramide (Cer) has been described as a potent inhibitor of cell growth and inducer of apoptosis. In contrast, ceramide-1-phosphate (C1P) has been reported to have mitogenic properties and to inhibit apoptosis. Our understanding of the distinct biological roles of C1P in the regulation of DNA synthesis, inflammation, membrane fusion and intracellular Ca2+ increase has rapidly expanded. C1P is a bioactive sphingolipid formed by the phosphorylation of ceramide catalyzed by ceramide kinase (CERK). This chapter specifically focuses on the role of C1P in phagocytosis and Ca2+ homeostasis. Studies of the metabolism of C1P during phagocytosis, may lead to a better understanding of its role in signaling. Potentially, the inhibition of CERK and C1P formation may be a therapeutic target for inflammation. PMID- 20919653 TI - Glucosylceramide in humans. AB - Glucosylceramide has a unique and often ambiguous role in mammalian cells. Activation of glucosylceramide synthase, the enzyme that places a glucosyl moiety onto ceramide, is the first pathway-committed step to the production of more complex glycosphingolipids such as lactosylceramide and gangliosides. Alterations in the level of glucosylceramide are noted in cells and tissues in response to cardiovascular disease, diabetes, skin disorders and cancer. Overall, upregulation of glucosylceramide offers cellular protection and primes certain cells for proliferation. However, prolonged overabundance of glucosylceramide is detrimental, as seen in Gaucher disease in humans. PMID- 20919652 TI - Extracellular and intracellular actions of sphingosine-1-phosphate. AB - Sphingosine-1-phosphate (S1P) is a bioactive lipid mediator with crucial roles in a wide variety of cellular functions across a broad range of organisms. Though a simple molecule in structure, S1P functions are complex. The formation of S1P is catalyzed by one of two sphingosine kinases that have differential cellular distributions as well as both overlapping and opposing functions and which are activated by many different stimuli. S1P can act on a family of G protein-coupled receptors (S1PRs) that are also differentially expressed in different cell types, which influences the cellular responses to S1P. In addition to acting on receptors located on the plasma membrane, S1P can also function inside the cell, independently of S1PRs. It also appears that both the intracellular location and the isotype of sphingosine kinase involved are major determinants of inside-out signaling of S1P in response to many extracellular stimuli. This chapter is focused on the current literature on extracellular and intracellular actions of S1P. PMID- 20919654 TI - Gangliosides as regulators of cell membrane organization and functions. AB - Gangliosides, characteristic complex lipids present in the external layer of plasma membranes, deeply influence the organization of the membrane as a whole and the function of specific membrane associated proteins due to lipid-lipid and lipid-protein lateral interaction. Here we discuss the basis for the membrane organizing potential of gangliosides, examples of ganglioside-regulated membrane protein complexes and the mechanisms for the regulation of ganglioside membrane composition. PMID- 20919656 TI - Therapeutic strategies for diabetes and complications: a role for sphingolipids? AB - Diabetes is a debilitating chronic disease that has no cure and can only be managed by pharmaceutical or nutritional interventions. Worldwide, the incidence of diabetes and diabetic complications is dramatically increasing. This may reflect the incomplete knowledge base underlying the role of inflammatory or nutritional stresses to exacerbate diabetic complications. Despite the knowledge that hyperlipidemia is a cardinal feature of both Type 1 and 2 diabetes, the actual lipid species that contribute to complications such as diabetic nephropathy, retinopathy, neuropathy and cardiovascular disease have not been well defined, or have not elucidated new treatment strategies. Sphingolipids comprise only a fraction of total lipids but a body of evidence has now identified dysfunctional sphingolipid metabolism and/or generation of specific sphingolipid metabolites as contributors to diabetic complications. This review suggests that pharmacological therapies that target dysfunctional sphingolipid metabolism and/or signaling may prove beneficial in decreasing the chronic pathology of hyperglycemia and hyperlipidemia. Moreover, the review suggests that these treatment options may also prove beneficial to ameliorate or delay pancreatic beta cell failure. PMID- 20919655 TI - Cancer treatment strategies targeting sphingolipid metabolism. AB - Ceramide and sphingosine-1-phosphate are related sphingolipid metabolites that can be generated through a de novo biosynthetic route or derived from the recycling of membrane sphingomyelin. Both these lipids regulate cellular responses to stress, with generally opposing effects. Sphingosine-1-phosphate functions as a growth and survival factor, acting as a ligand for a family of G protein-coupled receptors, whereas ceramide activates intrinsic and extrinsic apoptotic pathways through receptor-independent mechanisms. A growing body of evidence has implicated ceramide, sphingosine-1-phosphate and the genes involved in their synthesis, catabolism and signaling in various aspects of oncogenesis, cancer progression and drug- and radiation resistance. This may be explained in part by the finding that both lipids impinge upon the PI3K/ AKT pathway, which represses apoptosis and autophagy. In addition, sphingolipids influence cell cycle progression, telomerase function, cell migration and stem cell biology. Considering the central role of ceramide in mediating physiological as well as pharmacologically stimulated apoptosis, ceramide can be considered a tumor suppressor lipid. In contrast, sphingosine-1-phosphate can be considered a tumor promoting lipid, and the enzyme responsible for its synthesis functions as an oncogene. Not surprisingly, genetic mutations that result in reduced ceramide generation, increased sphingosine-1-phosphate synthesis or which reduce steady state ceramide levels and increase sphingosine-1-phosphate levels have been identified as mechanisms of tumor progression and drug resistance in cancer cells. Pharmacological tools for modulating sphingolipid pathways are being developed and represent novel therapeutic strategies for the treatment of cancer. PMID- 20919658 TI - Sphingolipid signaling in fungal pathogens. AB - Sphingolipid involvement in infectious disease is a new and exciting branch of research. Various microbial pathogens have been shown to synthesize their own sphingolipids and some have evolved methods to "hijack" host sphingolipids for their own use. For instance, Sphingomonas species are bacterial pathogens that lack the lipopolysaccharide component typical but instead contain glycosphingolipids (Kawahara 1991, 2006). In terms of sphingolipid signaling and function, perhaps the best-studied group of microbes is the pathogenic fungi. Pathogenic fungi still represent significant problems in human disease, despite treatments that have been used for decades. Because fungi are eukaryotic, drug targets in fungi can have many similarities to mammalian processes. This often leads to significant side effects of antifungal drugs that can be dose limiting in many patient populations. The search for fungal-specific drugs and the need for better understanding of cellular processes of pathogenic fungi has led to a large body of research on fungal signaling. One particularly interesting and rapidly growing field in this research is the involvement of fungal sphingolipid pathways in signaling and virulence. In this chapter, the research relating to sphingolipid signaling pathogenic fungi will be reviewed and summarized, in addition to highlighting pathways that show promise for future research. PMID- 20919657 TI - Roles for sphingolipids in Saccharomyces cerevisiae. AB - Studies using Saccharomyces cerevisiae, the common baker's or brewer's yeast, have progressed over the past twenty years from knowing which sphingolipids are present in cells and a basic outline of how they are made to a complete or nearly complete directory of the genes that catalyze their anabolism and catabolism. In addition, cellular processes that depend upon sphingolipids have been identified including protein trafficking/exocytosis, endocytosis and actin cytoskeleton dynamics, membrane microdomains, calcium signaling, regulation of transcription and translation, cell cycle control, stress resistance, nutrient uptake and aging. These will be summarized here along with new data not previously reviewed. Advances in our knowledge of sphingolipids and their roles in yeast are impressive but molecular mechanisms remain elusive and are a primary challenge for further progress in understanding the specific functions of sphingolipids. PMID- 20919660 TI - Biosynthesis of sphingolipids in plants (and some of their functions). AB - Our knowledge of plant sphingolipid metabolism and function has significantly increased over the past years. This applies mainly to the identification and the functional characterization of genes and enzymes involved in sphingolipid biosynthesis. In addition a number of plant mutants have provided new insights into sphingolipid functions. Very little is still known about intracellular transport, spatial distribution, degradation and signaling functions of sphingolipids. However, combination of Arabidopsis genetics with lipidomics and cell biology will soon bring our understanding of these issues to a new level. PMID- 20919661 TI - Computational analysis of sphingolipid pathway systems. AB - Sphingolipid metabolism constitutes a complex pathway system that includes biosynthesis of different types of sphingosines and ceramides, the formation and recycling of complex sphingolipids and the supply of materials for remodeling. Many of the metabolites have several roles, for instance, as substrates and as modulators of reactions in other parts of the system. The large number of sphingolipid compounds and the different types of nonlinear interactions among them render it difficult to predict responses of the sphingolipid pathway system to perturbations, unless one utilizes mathematical models. The sphingolipid pathway system not only invites modeling as a useful tool, it is also a very suitable test bed for developing detailed modeling techniques and analyses, due to several features. First, the reaction network is relatively well understood and many of the steps have been characterized, at least in vitro. Second, sphingolipid metabolism constitutes a relatively closed system, such that most reactions occur within the system rather than between the system and other pathways. Third, the basic structure of the pathway is conserved throughout evolution, but some of the details vary among differentspecies. This degree of similarity permits comparative analyses and may one day elucidate the gradual evolution toward superior system designs. We discuss here some reasons that make sphingolipid modeling an appealing companion to experimental researchand sketch out applications of sphingolipid models that are different from typical model uses. PMID- 20919659 TI - Sphingolipids in parasitic protozoa. AB - The surface of most protozoan parasites relies heavily upon lipid-anchored molecules, to form protective barriers and play critical functions required for infectivity. Sphingolipids (SLs) play important roles through their abundance and involvement in membrane microdomain formation, as well as serving as the lipid anchor for many of these molecules and in some but possibly not all species, as important signaling molecules. Interactions of parasite sphingolipid metabolism with that of the host may potentially contribute to parasite survival and/or host defense. In this chapter we summarize current knowledge of SL structure, synthesis and function in several of the major parasitic protozoan groups. PMID- 20919662 TI - Introduction to tools and techniques for ceramide-centered research. AB - Sphingolipids are important components of eukaryotic cells, many of which function as bioactive signaling molecules. As thoroughly discussed elsewhere in this volume, ceramide, central metabolite of the sphingolipid pathway, plays key roles in a variety of cellular responses. Since the discovery of the bioactive function of ceramide, a growing number of tools and techniques have been and still are being developed in order to better decipher the complexity and implications of ceramide-mediated signaling. With this chapter it is our intention to provide new comers to the sphingolipid arena with a short overview of tools and techniques currently available for the study ofsphingolipid metabolism, with the focus on ceramide. PMID- 20919663 TI - Issues and politics related to vascular education in the United States. PMID- 20919664 TI - Does a concomitant Cox-maze procedure improve survival in atrial fibrillation? AB - In this review paper, the authors briefly describe the pathophysiology of atrial fibrillation. The original technique to restore sinus rhythm is cited, with its subsequent technical variations. A literature review summarizes the outcome of patients who benefited from the Cox-MAZE procedure. PMID- 20919665 TI - The World Health Organisation surgical checklist. A surgeon's viewpoint. PMID- 20919666 TI - Do we need a new carotid artery stenting trial? AB - Four well-conducted carotid artery trials comparing carotid artery stenting with carotid artery endarterectomy (EVA-3S, SPACE, ICSS and CREST) could not demonstrate the superiority of carotid artery stenting (CAS) over carotid artery endarterectomy (CEA). There is at the moment no level-I evidence to support widespread use of endovascular management of carotid artery disease in routine practice. In order to shead some light on the continuing debate on the role of carotid artery stenting, the authors conducted a search in contemporary published literature concerning carotid artery stenting. This extensive literature review reveals a higher peri-procedural stroke-death rate after CAS and a higher cost. Two other events hamper the value of CAS: a higher late restenosis rate and a higher risk of micro-embolisation during the procedure, compared with CEA. The authors conclude that the prevailing overenthusiasm of interventionalists (vascular surgeons, radiologists, cardiologists) for carotid artery stenting is not justified. PMID- 20919667 TI - Thrombolysis of occluded infra-inguinal bypass grafts: is it worthwhile? AB - BACKGROUND: Thrombosis of an infra-inguinal bypass graft often results in a limb threatening ischemia. There is no consensus on the optimal management strategy. AIM OF THE STUDY: To analyse safety and efficacy of catheter-guided intra arterial thrombolysis to re-open thrombosed infra-inguinal bypass grafts and to identify factors that influence graft patency and limb salvage rate after thrombolytic procedures. METHODS: A continuous cohort-study of 106 thrombolytic procedures between 1993 to 2008. RESULTS: Despite a high initial success rate (76%), the mid-term results are less convincing, with a 58% re-occlusion rate at 45 months follow-up. Thrombosed vein grafts, old (2 weeks or more) occlusions, poor run-off and failure to identify or rectify an underlying causative stenosis are determinant for a poor long-term outcome of thrombolytic procedures. COMMENTS: The outcome results of author's experience are consistent with literature reports. Thrombolysis of occluded infra-inguinal bypass grafts should be limited to selective cases (recent occlusion, prosthetic or vein graft in place since 1 year or more, critical limb ischemia). Despite its obvious advantages, the long-term outcome of thrombolytic procedures is deceiving. The inherent risk of hemorrhagic complications should also be taken in account at the decision making of treatment strategy. The question whether, in general, catheter guided selective intra-arterial thrombolysis offers a significant advantage over operative revascularisation (thrombectomy or new bypass) remains unanswered. A more selective approach seems to favour thrombolysis as most appropriate strategy in the management of recent (< 2 weeks) thromboses of grafts in place since at least 1 year. PMID- 20919668 TI - Do different abdominal incision techniques play a role in wound complications in patients operated on for gastrointestinal malignancies ? "Scalpel vs. electrocautery". AB - BACKGROUND: Despite the studies of animals that demonstrate better wound healing after abdominal incisions with the use of a scalpel rather than electocautery, clinical experience does not confirm these findings. The purpose of this study was to compare the early postoperative and late-term wound complication rates between the scalpel and electrocautery in patients with gastrointestinal malignancies undergoing midline abdominal incisions. METHODS: Patients undergoing midline abdominal incisions for gastrointestinal malignancies were randomly divided into two groups according to the method used to perform the incisions: scalpel or electrocautery. Complications were investigated, diagnosed and compared in the early postoperative and late-term follow-up periods. The independent samples, chi-square, and Student's t tests were used for statistical analysis. RESULTS: Two hundred and eighteen patients were included to this study, of whom 97 (44.5%) were in the scalpel group and 121 (55.5%) in the electrocautery group. Both groups were similar with respect to their demographic, operative and postoperative characteristics. The analysis revealed no significant statistical differences in consideration of the incidences of either wound infection in the early postoperative period or incisional hernia in the late-term follow-up period between these two study groups (p > 0.05). CONCLUSIONS: Scalpel and electrocautery are similar in terms of early postoperative and late-term wound complications when used to perform midline abdominal incisions. Therefore, the choice of method remains a matter of the surgeon's preference. PMID- 20919669 TI - Subcutaneous closed-suction drainage does not affect surgical site infection rate following elective abdominal operations: a prospective randomized clinical trial. AB - PURPOSE: To evaluate whether subcutaneous closed-suction drainage (SCSD) would decrease the SSI rate in elective abdominal operations. METHODS: Participants were randomly assigned to have subcutaneous drains or not following elective abdominal surgery. The fascia and incision closure technique and antimicrobial prophylaxis were standardised. In the drain cohort, SCSD was applied after fascia closure. The drain was removed on postoperative day three. Patient characteristics, body mass index (BMI) and the depth of subcutaneous fatty tissue (SCFT) were noted. The incisional SSI rates were analysed. RESULTS: There were 210 patients in the drain group and 192 in the no-drain group. There was no significant difference between groups in terms of demographics, BMI or SCFTs. The overall SSI rate was 7.7% and was 5.7% in the drain group and 9.9% in the no drain group (p = 0.116). Neither BMI nor subcutaneous skin depth affected the SSI rate. However, subgroup analysis revealed that the SSI rate was lower in patients with drains who had undergone resection of colorectal malignancies or had lower abdominal incisions (p< 0.03). CONCLUSIONS: The overall incisional SSI rate was comparable between the drain and no-drain groups. However, subcutaneous closed suction drainage was not found effective in preventing SSI in our study except in a subgroup of patients with colorectal malignancies and lower abdominal incisions. PMID- 20919670 TI - Success of minimally invasive single-gland exploration using the quick intraoperative parathyroid assay. AB - OBJECTIVE: Using accurate localization techniques and the quick intra-operative parathyroid assay (QPTH), surgery for primary hyperparathyroidism due to a solitary adenoma has moved from the traditional wide bilateral neck exploration to more limited approaches such as minimally invasive single-gland exploration (MISGE) and minimally invasive radio-guided parathyroidectomy (MIRP). This study investigated whether the MISGE could take the place of MIRP with the help of the QPTH. DESIGN: From 2007 to 2009, 56 patients with primary hyperparathyroidism were studied. All patients were pre-operatively investigated by imaging techniques to improve the pre-operative determination of adenomas. Twenty-five patients were in the MIRP group and 31 in the MISGE group. QPTH was routinely measured; a 50% reduction in the QPTH level indicated complete excision. RESULTS: There were no differences in the complication rates, surgical time, anaesthesia time or mean length of hospital stay between the groups. However, total hospital charges were more favourable in the MISGE group with a mean saving of $400 per case. CONCLUSION: This study demonstrates that with the additon of the QPTH, MISGE can be performed as a quick and reliable procedure in correct adenoma removal instead of MIRP. Moreover MISGE achieves the optimal time interval between injection and exploration, reduces the radiation exposure of both patient and surgeon, decreases the cost, and decreases usage of pre-operative imaging and intra-operative equipment. PMID- 20919671 TI - The effect of the psychological status of breast cancer patients on the short term clinical outcome after mastectomy. AB - PURPOSE: to analyze the effect of anxiety and depression on the postoperative complications and length of hospitalization of patients with breast cancer. Beck's Depression Inventory (BDI) and Hospital Anxiety and Depression Scale (HADS) were filled out by the patients pre-operatively. Patients were asked to rate their pain by the visual analogue scale (VAS) after surgery. Age, seroma volume, day of drain withdrawal, complications, and pathological stages were noted. The median age of 49 patients with the diagnosis of breast cancer was 51 (36-80). There was a significant correlation between the pain score and Beck, HADS, HADS (anxiety) and HADS (depression) (8 hours ; p = 0.021, 0.001, 0.004, 0.005 and 24 hours ; p = 0.005, 0.012, 0.006, 0.120). The mean HADS depression score in those patients with complications was 9.1 +/- 4.2 and that of patients with no complications was 6.6 +/- 3.1 (p = 0.047). The mean hospital stay of patients with a normal HADS score (< 19) was 2.9 +/- 1.1 days, whilst that of patients with an abnormal HADS score was 3.8 +/- 1.2 days (p = 0.016). Patients with abnormal HADS anxiety and abnormal HADS (total) scores had an earlier stage of breast cancer (p = 0.077, p = 0.063). The psychological status of breast cancer patients effects their postoperative recovery period and it is easy to diagnose these patients by some brief questionnaires. PMID- 20919672 TI - Traumatic abdominal wall hernia: case report and review of the literature. AB - Traumatic abdominal wall hernia (TAWH) is a rare type of hernia that occurs after an impact of the abdominal wall against a blunt object. The first case described was reported in 1906 and ever since, 46 cases have been reported. CT scan is mandatory in the diagnosis of TAWH but also because of a frequent association with significant intra-abdominal injuries. We report here the case of a 61-year old man with a TAWH developed after impact against a bicycle handlebar. Hemodynamically stable and without associated injuries, the patient was monitored for 24 hours before hospital discharge. A successful elective hernia repair with a prosthetic mesh was performed 6 weeks later once cicatrisation was achieved. PMID- 20919673 TI - A 71-year-old woman with a pigmented nail bed, which persisted after trauma. AB - A 71-year-old woman presented in our out-patients department with pigmentation of the nail bed of her left large toe, which had persisted after a trauma two years earlier. An inconclusive biopsy showed melanoma in situ. The lesion was excised with amputation of the big toe at the IP-joint and closed primarily. The pathological diagnosis was melanoma in situ and lentigo maligna. The lesion had been radically excised. PMID- 20919674 TI - Selective conservative management of penetrating hollow viscus injuries: a report of three cases. AB - In this manuscript, we report three cases of penetrating abdominal injury: one with pellet injury, one with pellet injury after a bomb explosion and one with gunshot injury. All three patients were successfully managed nonoperatively. A 30 year-old male was admitted to our trauma and emergency service with a pellet injury. His physical examination revealed multiple pellet injuries in the left upper abdominal quadrant, left hemithorax, left axilla, dorsal side of the abdomen, left upper extremity, and left gluteus. The second case was a 16-year old male admitted with a shrapnel injury after a bomb explosion. His physical examination revealed multiple shrapnel injuries in the thoracal and abdominal regions, extremities and left eye. The third case was a 30-year-old male admitted with gunshot and stab wound injury. He had multiple stab wound injuries in both lower extremities and a gunshot wound in the left posterosuperior hemithorax, left upper abdomen and left dorsolumbar region. All these cases were treated non operatively. We advocate a policy of selective conservatism based on careful initial and subsequent serial clinical examinations and imaging techniques as needed. PMID- 20919675 TI - Pituitary apoplexy following coronary artery bypass grafting: report of a case. AB - Abstract. Pituitary apoplexy can rarely occur after surgical procedures, mainly due to severe haemorrhage or hypotension. It is a serious condition that may lead to devastating complications and even to death. We present a 60-year-old male patient in whom pituitary apoplexy developed due to protamine anaphylaxis during coronary artery bypass surgery. PMID- 20919676 TI - Techniques for coverage of infected vascular grafts in the groin. AB - Plastic surgeons expertise is requested for treatment of vascular graft exposures. Exposure within the femoral triangle (Scarpa) represents the majority of those cases. We intend to share our experience in the coverage of exposed vascular grafts: through the most common and safe procedures we are currently using, illustrated by some of our clinical cases. Our experience leaded us to formulate some guidelines and conclusions, to ensure vascular surgeons that coverage of a vascular graft can always be successfully done. PMID- 20919677 TI - Art, medicine and surgery: puncture of ascites. PMID- 20919678 TI - Design, synthesis, and evaluation of indolinones as inhibitors of the transforming growth factor beta receptor I (TGFbetaRI). AB - Inhibition of transforming growth factor beta (TGFbeta) type I receptor (Alk5) offers a novel approach for the treatment of fibrotic diseases and cancer. Indolinones substituted in position 6 were identified as a new chemotype inhibiting TGFbetaRI concomitant with a low cross-reactivity among the human kinome. A subset of compounds showed additional inhibition of platelet-derived growth factor receptor alpha (PDGFRalpha), contributing to an interesting pharmacological profile. In contrast, p38 kinase, which is often inhibited by TGFbetaRI inhibitors, was not targeted by derivatives based on the indolinone chemotype. Guided by an X-ray structure of lead compound 5 (BIBF0775) soaked into the kinase domain of TGFbetaRI, optimization furnished potent and selective inhibitors of TGFbetaRI. Potent inhibition translated well into good inhibition of TGFbetaRI-mediated phosphorylation of Smad2/3, demonstrating efficacy in a cellular setting. Optimized compounds were extensively profiled on a 232-kinase panel and showed low cross-reactivities within the human kinome. PMID- 20919679 TI - Engineered biocompatible nanoparticles for in vivo imaging applications. AB - Iron-platinum alloy nanoparticles (FePt NPs) are extremely promising candidates for the next generation of contrast agents for magnetic resonance (MR) diagnostic imaging and MR-guided interventions, including hyperthermic ablation of solid cancers. FePt has high Curie temperature, saturation magnetic moment, magneto crystalline anisotropy, and chemical stability. We describe the synthesis and characterization of a family of biocompatible FePt NPs suitable for biomedical applications, showing and discussing that FePt NPs can exhibit low cytotoxicity. The importance of engineering the interface of strongly magnetic NPs using a coating allowing free aqueous permeation is demonstrated to be an essential parameter in the design of new generations of diagnostic and therapeutic MRI contrast agents. We report effective cell internalization of FePt NPs and demonstrate that they can be used for cellular imaging and in vivo MRI applications. This opens the way for several future applications of FePt NPs, including regenerative medicine and stem cell therapy in addition to enhanced MR diagnostic imaging. PMID- 20919680 TI - Protein biomarkers for in vitro testing of embryotoxicity. AB - There are new challenges for hazard and risk assessment in the chemical industry with regard to REACH legislation in Europe and related activities in the U.S. and Japan, which require the development of novel in vitro models for the molecular characterization of drug- or chemical-related effects replacing conventional animal testing. In the frame of a European FP6 project on reproductive toxicology ( www.reprotect.eu ), we prepared protein samples from mouse embryonic stem cells differentiated into contracting cardiomyocytes according to the validated embryonic stem cell test (EST) protocol, which had been exposed to toxic substances selected by an expert committee from different in vivo categories of embryotoxicity. Lysates were used to carry out the following investigations: (i) identify optimal dose range conditions in the EST that are suitable for (ii) performing a differential quantitative proteomic study of underlying molecular pathways, (iii) define classes of substances with similar proteomic response patterns, (iv) relate these classes to the traditional in vivo categories of embryotoxicity with (v) the final goal to identify novel surrogate protein biomarker candidates for embryo toxicity. We found two distinct classes of toxic substances (Dinoseb, Ochratoxin-A, and Nitrofen vs beta-aminoproprionitril, Metoclopramide, Doxylamine succinate, and d-penicillamine) with clear pathway related differences in their proteomic patterns. Most notably, different responses to cluster 1 and cluster 2 substances were observed for Heat shock protein beta-1, Ras-GTPase-activating protein SH3-domain binding protein, Ran binding protein 5, and Calreticulin, Dihydropyrimidinase-like 2 (Ulip2 protein). On the other hand, Heat shock protein 8 and Fscn1 protein were down-regulated by all compounds from both clusters. PMID- 20919682 TI - Enhanced photoluminescence and photoconductivity of ZnO nanowires with sputtered Zn. AB - We have sputtered Zn onto quasi-one-dimensional ZnO nanowires (NWs) in order to investigate the effect of Zn diffusion on the photoluminescence and photoconduction properties of ZnO NWs. Elemental mapping clearly indicates higher Zn concentration in the NWs due to diffusion of Zn. The Zn-sputtered NWs show an enhanced ultraviolet emission with 7 nm red shift. Since the ionization energy of Zni is 51 meV, the enhanced PL emission with a red shift is correlated to the coupling between free exciton and zinc interstitials (Zni) defects. The photocurrent transients show almost 20 times more photocurrent generation in Zn/ZnO NWs compared to the as-grown NWs. In contrast, the thin film shows no significant change in the photoluminescence and photoconductivity. Based on the photoconductivity and photoluminescence results, we predict that Zn diffusion in the NWs occurs easily compared to the films because of the smaller dimensions of the NWs. PMID- 20919681 TI - Assessment of glycoprotein interactions with 4-[(2 aminoethyl)carbamoyl]phenylboronic acid surfaces using surface plasmon resonance spectroscopy. AB - Reported here are analyses of the interactions between a select group of solution phase glycoproteins and a unique boronic acid capture surface. The boronic acid derivative, 4-[(2-aminoethyl)carbamoyl]phenylboronic acid, AECPBA, was synthesized and then immobilized on carboxymethyl dextran surfaces using simple coupling methods. From surface plasmon resonance spectroscopy responses, it is found that model glycoproteins interact strongly with the AECPBA surface and subsequently can be readily released from the AECPBA surface using borate buffer. A striking difference between the glycoproteins fetuin and asialofetuin (desialylated fetuin), in terms of glycoprotein binding to the AECPBA surface, indicates that the interaction of glycoproteins with the immobilized AECPBA is dictated by the terminal saccharide of the heteroglycan chain. Surprisingly, secondary interactions of glycosylated and nonglycosylated proteins with the carboxymethyl dextran hydrogel matrix are observed. Importantly, it is demonstrated that use of tris(hydroxymethyl)aminomethane buffer allows for decreased secondary interactions of nonglycosylated proteins on the AECPBA/dextran surface, as noted with the model protein ExtrAvidin. PMID- 20919684 TI - Interlayer interactions induced by amphiphilicities of a rod-like molecule produce frustrated structures in conventional calamitic phases. AB - We prepared a rod-like molecule, 4-[4-(7-hydroxyheptyloxy)phenyl]-1-(4 hexylphenyl)-2,3-difluorobenzene, and investigated its physical properties using polarized optical microscopy (POM), differential scanning calorimetry (DSC), and X-ray diffraction (XRD). The compound was found to exhibit nematic, smectic A, and smectic C phases. A smectic-like layer ordering was detected using XRD at low temperatures of the nematic phase. The nematic phase changed to a smectic A phase when cooled, with no accompanying enthalpy change. Analyses using XRD and POM revealed that the smectic C phase consists of three states: conventional SmC with a monolayered structure, monolayered SmC' possessing an additional weak bilayered character, and SmC'' possessing both monolayered and bilayered structures. Furthermore, a discontinuous increase in birefringence of a homeotropically aligned sample of the compound was observed in the SmC'' phase. Interlayer interactions organized by hydrophobic-hydrophilic amphiphilicity and orthogonal tilt amphiphilicity are discussed to explain the appearance of the unusual liquid crystalline phases with a hierarchical structure. PMID- 20919683 TI - Effect of surface charge on the cellular uptake and cytotoxicity of fluorescent labeled cellulose nanocrystals. AB - Probing of cellular uptake and cytotoxicity was conducted for two fluorescent cellulose nanocrystals (CNCs): CNC-fluorescein isothiocyanate (FITC) and newly synthesized CNC-rhodamine B isothiocyanate (RBITC). The positively charged CNC RBITC was uptaken by human embryonic kidney 293 (HEK 293) and Spodoptera frugiperda (Sf9) cells without affecting the cell membrane integrity. The cell viability assay and cell-based impedance spectroscopy revealed no noticeably cytotoxic effect of the CNC-RBITC conjugate. However, no significant internalization of negatively charged CNC-FITC was observed at physiological pH. Indeed, the effector cells were surrounded by CNC-FITC, leading to eventual cell rupture. As the surface charge of CNC played an important role in cellular uptake and cytotoxicity, facile surface functionalization together with observed noncytotoxicity rendered modified CNC as a promising candidate for bioimaging and drug delivery systems. PMID- 20919686 TI - Evaluation of catalyst acidity and substrate electronic effects in a hydrogen bond-catalyzed enantioselective reaction. AB - A modular catalyst structure was applied to evaluate the effects of catalyst acidity in a hydrogen bond-catalyzed hetero Diels-Alder reaction. Linear free energy relationships between catalyst acidity and both rate and enantioselectivity were observed, where greater catalyst acidity leads to increased activity and enantioselectivity. A relationship between reactant electronic nature and rate was also observed, although there is no such correlation to enantioselectivity, indicating the system is under catalyst control. PMID- 20919687 TI - The CO formation reaction pathway in steam methane reforming by rhodium. AB - Three different pathways toward CO formation from adsorbed CH and O are compared by quantum-chemical density functional theory (DFT) calculations for planar and stepped Rh surfaces. The conventional pathway competes with the pathway involving a formyl (CHO) species. This holds for both types of surfaces. The barrier for carbon-oxygen bond formation for the planar surface (180 kJ/mol) is substantially higher than that for the stepped surface (90 kJ/mol). The reaction path through intermediate formyl formation competes with direct formation of CO from recombination via adsorbed C and O atoms. Calculations are used as a basis for the analysis of the overall kinetics of the methane steam reforming reaction as a function of the particle size and the metal. PMID- 20919688 TI - The impact of multivalent counterions, Al3+, on the surface adsorption and self assembly of the anionic surfactant alkyloxyethylene sulfate and anionic/nonionic surfactant mixtures. AB - The impact of multivalent counterions, Al(3+), on the surface adsorption and self assembly of the anionic surfactant sodium dodecyl dioxyethylene sulfate, SLES, and the anionic/nonionic surfactant mixtures of SLES and monododecyl dodecaethylene glycol, C(12)E(12), has been investigated using neutron reflectivity, NR, and small angle neutron scattering, SANS. The addition of relatively low concentrations of Al(3+) counterions induces a transition from a monolayer to well-defined surface bilayer, trilayer, and multilayer structures in the adsorption of SLES at the air-water interface. The addition of the nonionic cosurfactant, C(12)E(12), partially inhibits the evolution in the surface structure from monolayer to multilayer interfacial structures. This surface phase behavior is strongly dependent upon the surfactant concentration, solution composition, and concentration of Al(3+) counterions. In solution, the addition of relatively low concentrations of Al(3+) ions promotes significant micellar growth in SLES and SLES/C(12)E(12) mixtures. At the higher counterion concentrations, there is a transition to lamellar structures and ultimately precipitation. The presence of the C(12)E(12) nonionic cosurfactant partially suppresses the aggregate growth. The surface and solution behaviors can be explained in terms of the strong binding of the Al(3+) ions to the SLES headgroup to form surfactant-ion complexes (trimers). These results provide direct evidence of the role of the nonionic cosurfactant in manipulating both the surface and solution behavior. The larger EO(12) headgroup of the C(12)E(12) provides a steric hindrance which disrupts and ultimately prevents the formation of the surfactant-ion complexes. The results provide an important insight into how multivalent counterions can be used to manipulate both solution self-assembly and surface properties. PMID- 20919689 TI - Graphene oxide thin films for flexible nonvolatile memory applications. AB - There has been strong demand for novel nonvolatile memory technology for low cost, large-area, and low-power flexible electronics applications. Resistive memories based on metal oxide thin films have been extensively studied for application as next-generation nonvolatile memory devices. However, although the metal oxide based resistive memories have several advantages, such as good scalability, low-power consumption, and fast switching speed, their application to large-area flexible substrates has been limited due to their material characteristics and necessity of a high-temperature fabrication process. As a promising nonvolatile memory technology for large-area flexible applications, we present a graphene oxide based memory that can be easily fabricated using a room temperature spin-casting method on flexible substrates and has reliable memory performance in terms of retention and endurance. The microscopic origin of the bipolar resistive switching behavior was elucidated and is attributed to rupture and formation of conducting filaments at the top amorphous interface layer formed between the graphene oxide film and the top Al metal electrode, via high resolution transmission electron microscopy and in situ X-ray photoemission spectroscopy. This work provides an important step for developing understanding of the fundamental physics of bipolar resistive switching in graphene oxide films, for the application to future flexible electronics. PMID- 20919690 TI - Mapping octahedral tilts and polarization across a domain wall in BiFeO3 from Z contrast scanning transmission electron microscopy image atomic column shape analysis. AB - Oxygen octahedral tilts underpin the functionality of a large number of perovskite-based materials and heterostructures with competing order parameters. We show how a precise analysis of atomic column shapes in Z-contrast scanning transmission electron microscopy images can reveal polarization and octahedral tilt behavior across uncharged and charged domain walls in BiFeO(3). This method is capable of visualizing octahedral tilts to much higher thicknesses than phase contrast imaging. We find that the octahedral tilt transition across a charged domain wall is atomically abrupt, while the associated polarization profile is diffuse (1.5-2 nm). Ginzburg-Landau theory then allows the relative contributions of polarization and the structural order parameters to the wall energy to be determined. PMID- 20919691 TI - Enhancing sensitivity of a single ZnO micro-/nanowire photodetector by piezo phototronic effect. AB - We demonstrate the piezoelectric effect on the responsivity of a metal semiconductor-metal ZnO micro-/nanowire photodetector. The responsivity of the photodetector is respectively enhanced by 530%, 190%, 9%, and 15% upon 4.1 pW, 120.0 pW, 4.1 nW, and 180.4 nW UV light illumination onto the wire by introducing a -0.36% compressive strain in the wire, which effectively tuned the Schottky barrier height at the contact by the produced local piezopotential. After a systematic study on the Schottky barrier height change with tuning of the strain and the excitation light intensity, an in-depth understanding is provided about the physical mechanism of the coupling of piezoelectric, optical, and semiconducting properties. Our results show that the piezo-phototronic effect can enhance the detection sensitivity more than 5-fold for pW levels of light detection. PMID- 20919692 TI - Contribution toward comprehension of contact angle values on single polydimethylsiloxane and poly(ethylene oxide) polymer networks. AB - The large application ranges of polydimethylsiloxane (PDMS) and poly(ethylene oxide) (PEO) based materials justify the importance of controlling polymer surface properties including morphology and wettability behavior. However, it appears that the reported contact angle values of PDMS surfaces show significant scattering which cannot always be interpreted in terms of sole chemical data. In addition, few values are reported concerning pure PEO surfaces, since the polymer generally swells in the presence of water. Thus, in order to correlate surface properties with sample preparation, several single PDMS and PEO polymer networks were synthesized with varying cross-linkers and different cross-linking densities. First, the sample surface topography was systematically analyzed by atomic force microscopy (AFM). It was proven that the removal process of the polymer film from the mold plays a significant role in surface topography according to the vitreous or rubbery state of the given polymer network at room temperature irrespective of mold surface treatment. AFM-scale smooth surfaces can be obtained for all the samples by removing them systematically from the mold at a temperature below the alpha-relaxation temperature. Dynamic water contact angles were then measured and the values analyzed as a function of cross-linker nature and cross-linking density. PMID- 20919693 TI - Toward drug delivery into the brain: synthesis, characterization, and preliminary in vitro assessment of alkylglyceryl-functionalized chitosan nanoparticles. AB - A series of O-substituted alkylglyceryl chitosans with systematically varied degrees of grafting was prepared through synthetic steps that involved the protection of amino moieties via phthaloylation and employed for the formulation of aqueous nanoparticulate systems that may be capable of delivering drugs to the brain. Dynamic light scattering studies have shown that nanoparticles with physiologically relevant aqueous stabilities may be prepared following the partial quaternization of these alkylglyceryl-modified chitosans. Preliminary in vitro tests using a mouse-brain endothelial cell model have indicated the efficient cellular uptake of these nanoparticles and identified butylglyceryl chitosan and butylglyceryl N,N,N-trimethyl chitosan as promising materials for the formulation of colloidal systems that could act as drug carriers into the brain. PMID- 20919694 TI - Transition metal complexes as linkages for assembly of supertetrahedral T4 clusters. AB - Tn clusters are usually connected into frameworks by sulfur bridges. A new type of T4 compounds in which the clusters are linked by both sulfur bridges and transition metal complexes are described. PMID- 20919695 TI - Tunable visible and near-IR emission from sub-10 nm etched single-crystal Si nanopillars. AB - Visible and near-IR photoluminescence (PL) is reported from sub-10 nm silicon nanopillars. Pillars were plasma etched from single crystal Si wafers and thinned by utilizing strain-induced, self-terminating oxidation of cylindrical structures. PL, lifetime, and transmission electron microscopy were performed to measure the dimensions and emission characteristics of the pillars. The peak PL energy was found to blue shift with narrowing pillar diameter in accordance with a quantum confinement effect. The blue shift was quantified using a tight binding method simulation that incorporated the strain induced by the thermal oxidation process. These pillars show promise as possible complementary metal oxide semiconductor compatible silicon devices in the form of light-emitting diode or laser structures. PMID- 20919696 TI - Computational study of the mechanisms of the photoisomerization reactions of bicycloalkene. AB - The mechanisms of the photochemical isomerization reactions were investigated theoretically using a model system, bicyclo[4,1,0]hept-3-ene (1), with the CASSCF (six-electron/six-orbital active space) and MP2-CAS methods and the 6-311(d,p) basis set. The structures of the conical intersections, which play a decisive role in such phototranspositions, were obtained. The intermediates and transition structures of the ground state were also calculated to assist in providing a qualitative explanation of the reaction pathways. Our model investigations suggest that the preferred reaction route for bicyclo[4,1,0]hept-3-ene is as follows: reactant -> Franck-Condon region -> conical intersection -> intermediate -> transition state -> photoproduct. Two reaction paths, which lead to final photoproducts, have been identified: (path I) ring expansion and (path II) ring closure. The former is more favorable than the latter. Also, our theoretical findings strongly indicate that there is a substantial interaction between the cyclopropane moiety and the isolated carbon-carbon double bond in the excited state of 1. PMID- 20919697 TI - Sensitive detection of nucleic acids with rolling circle amplification and surface-enhanced Raman scattering spectroscopy. AB - Detection of specific DNA sequences is important to molecular biology research and clinical diagnostics. To improve the sensitivity of surface-enhanced Raman scattering spectroscopy (SERS), a variety of signal amplification methods has been developed, including Raman-active-dye, polymerase chain reaction (PCR) technology, molecular beacon, SERS-active substrates, and SERS-tag. However, the combination of rolling circle amplification (RCA) with SERS for nucleic acid detection has not been reported. Herein, we describe a new approach for nucleic acid detection by the combination of RCA reaction with SERS. Because of the binding of abundance repeated sequences of RCA products with gold nanoparticle (Au NP) and Rox-modified detection probes, SERS signal is significantly amplified and the detection limit of 10.0 pM might be achieved. The sensitivity of RCA based SERS has increased by as much as 3 orders of magnitude as compared to PCR based SERS and is also comparable with or even exceeds that of both RCA-based electrochemical and RCA-based fluorescent methods. This RCA-based SERS might discriminate perfect matched target DNA from 1-base mismatched DNA with high selectivity. The high sensitivity and selectivity of RCA-based SERS makes it a potential tool for early diagnosis of gene-related disease and also offers a great promise for multiplexed assays with DNA microarrays. PMID- 20919698 TI - Probing the topological tolerance of multimeric protein interactions: evaluation of an estrogen/synthetic ligand for FK506 binding protein conjugate. AB - Bivalent small molecules composed of a targeting element and an element that recruits endogenous proteins have been shown to block protein-protein interactions in some systems. We have attempted to apply such an approach to disrupt the interaction of the estrogen receptor alpha with either its associated coactivators or its dimerization partner (i.e., another estrogen receptor). We show here that a conjugate capable of simultaneously binding both the estrogen receptor and a recruited protein (FK506 Binding Protein 12 kDa) is, however, incapable of disrupting the multimeric estrogen receptor dimer/coactivator complex both in vitro and in cell-based reporter gene assays. We postulate why it may not be possible to disrupt this particular protein-protein complex-as well as other systems having high topological tolerance-with such bivalent inhibitors. PMID- 20919700 TI - Protein-protein binding site prediction by local structural alignment. AB - Generalization of an earlier algorithm has led to the development of new local structural alignment algorithms for prediction of protein-protein binding sites. The algorithms use maximum cliques on protein graphs to define structurally similar protein regions. The search for structural neighbors in the new algorithms has been extended to all the proteins in the PDB and the query protein is compared to more than 60,000 proteins or over 300,000 single-chain structures. The resulting structural similarities are combined and used to predict the protein binding sites. This study shows that the location of protein binding sites can be predicted by comparing only local structural similarities irrespective of general protein folds. PMID- 20919699 TI - Adhesive performance of biomimetic adhesive-coated biologic scaffolds. AB - Surgical repair of a discontinuity in traumatized or degenerated soft tissues is traditionally accomplished using sutures. A current trend is to reinforce this primary repair with surgical grafts, meshes, or patches secured with perforating mechanical devices (i.e., sutures, staples, or tacks). These fixation methods frequently lead to chronic pain and mesh detachment. We developed a series of biodegradable adhesive polymers that are synthetic mimics of mussel adhesive proteins (MAPs), composed of 3,4-dihydroxyphenylalanine (DOPA)-derivatives, polyethylene glycol (PEG), and polycaprolactone (PCL). These polymers can be cast into films, and their mechanical properties, extent of swelling, and degradation rate can be tailored through the composition of the polymers as well as blending with additives. When coated onto a biologic mesh used for hernia repair, these adhesive constructs demonstrated adhesive strengths significantly higher than fibrin glue. With further development, a precoated bioadhesive mesh may represent a new surgical option for soft tissue repair. PMID- 20919701 TI - Immobilization of penicillin G acylase in epoxy-activated magnetic cellulose microspheres for improvement of biocatalytic stability and activities. AB - We prepared magnetic cellulose porous microspheres (MCM) with mean diameter of ~200 MUm by employing the sol-gel transition (SGT) method from a mixture of magnemite ferrofluid and cellulose dissolved in 7 wt % NaOH/12% urea aqueous solvent precooled to -12 degrees C. Subsequently, the cellulose microspheres were activated with epoxy chloropropane to enhance loading efficiency of biomacromolecules. Their morphology, structure, and properties were characterized by Fourier transform infrared spectroscopy, scanning electron microscopy, X-ray diffraction, and vibrating-sample magnetometer. The results indicated that the spherical magnetic gamma-Fe2O3 nanoparticles with mean size of 10 nm were uniformly dispersed and embedded in the cellulose substrate of MCM, and the structure and nature of gamma-Fe2O3 were conserved perfectly. Penicillin G acylase (PGA) as a biocatalyst was immobilized successfully in the porous microspheres, as a result of the existence of the cavity and affinity forces in the activated cellulose matrix. The immobilized PGA exhibited highly effective catalytic activity, thermal stability, and enhanced tolerance to pH variations. Furthermore, the cellulose microspheres loaded with the enzymes could be removed and recovered easily by introducing a magnetic field, leading to an acceptable reusability. Therefore, we have provided a simple and biocompatible support for the enzyme immobilization, which will be promising for the applications in the biomaterial fields. PMID- 20919702 TI - Low-temperature preparation of highly conductive thin films from acrylic acid stabilized silver nanoparticles prepared through ligand exchange. AB - The preparation of AcA-stabilized Ag nanoparticles and its application to make highly conductive thin films are reported. The AcA-stabilized Ag nanoparticles were prepared through a ligand exchange of original oleylamine (OLA)-coated Ag nanoparticles with acrylic acid (AcA), which acted as both an antisolvent and a modifying ligand during the ligand exchange process. Efficiencies of the ligand exchange as well as the properties of Ag nanoparticles were analyzed using various techniques including TEM, FT-IR, XPS, TGA, and UV-vis methods. The thin films were fabricated by annealing spin-coated AcA-stabilized Ag nanoparticles. Further, the effects of annealing temperature, time, and film thickness on both the film morphology and electrical conductivity have been investigated. In this work, due to the low boiling temperature of stabilizer (AcA) and adjustment of annealing conditions, high electrical conductivity was obtained for the Ag thin films. For example, when annealing at 175 degrees C for 30 min, a 70 nm thick film showed a maximum electrical conductivity of 1.12 * 10(5) S cm(-1). A conductive layer on a flexible polymer substrate (e.g., PET) sheet has been successfully prepared by annealing a spin-coated film at 140 degrees C for 30 min. The combined advantages of long-term stability of the AcA-stabilized Ag nanoparticles, low annealing temperature, and high conductivity of the prepared thin films make this relatively simple method attractive for applications in flexible electronics. PMID- 20919703 TI - Synthesis of recognition matrix from 4-methylamino-N-allylnaphthal-imide with fluorescent effect for the imprinting of creatinine. AB - 4-Methylamino-N-allylnaphthalimide (4-MAANI), a functional monomer with fluorescent effect, was synthesized for the imprinting and specific uptake of creatinine, an important clinical marker for kidney function. 4-Methylamino-N allylnaphthalimide was synthesized from the reaction of 4-bromo-1,8-naphthalic anhydride with allylamine to form 4-bromo-N-allylnaphthalimide and further to react with methylamine. Excitation and emission of the fluorescent monomer was investigated by both a three-dimensional plot of fluorescent intensity versus excited and emitted wavelengths and a corresponding contour plot. The photoluminescence properties of the as-prepared conjugated species were also studied. 4-Methylamino-N-allylnaphthalimide (4-MAANI) fluorescent monomer, methacrylic acid (MAA) functional monomer, ethylene glycol dimethylacrylate (EGDMA) cross-linker, and 2,2'-azobisisobutyronitrile (AIBN) initiator were then utilized in the presence of creatinine template for the processing of heat induced polymerization. FT-IR analysis was used to confirm the successful synthesis of 4-MAANI. The specific recognition cavity for creatinine was then created from the polymer matrix after the removal of creatinine by proper solvent. The imprinting effect as well as selectivity from the creatinine containing mixture was also evaluated. The grouped clusters from the emitted fluorescent intensities of the imprinted and nonimprinted polymers before and after rebinding of creatinine were obtained and discussed. Serum spiked with a different concentration of creatinine was also used to confirm the feasibility of clinical applications in the future. Successful recognition of the creatinine molecule via the combined effect of molecular imprinting and photoluminescence of the imprinted polymeric material was thus confirmed in this work. PMID- 20919704 TI - Influence of water content on the acidities in acetonitrile. Quantifying charge delocalization in anions. AB - The effect of traces of water on the relative strengths of acids (DeltapK(a) values) in acetonitrile was quantitatively evaluated experimentally and computationally (COSMO-RS). Water affects first of all the anions by selective solvation. Expectedly, the more localized is the charge in acid anions the higher is the effect of water. The energetic effect of increasing water content from 0 to ca. 10,000 ppm on solvation enthalpies of anions ranged from 0.2-0.4 kcal mol 1 (anions with delocalized charges) to 15 kcal mol-1 in the case of the highly charge-localized acetate ion. In the case of DeltapK(a) values the change ranges from 0.01 to ca. 1.7 pK(a) units (acid pair involving acetic acid). The COSMO-RS method was found to satisfactorily describe the trends in DeltapK(a) values. To quantify the extent of charge localization/delocalization in anions a parameter, weighted average positive sigma (WAPS), was introduced, which can be conveniently computed using the COSMO approach. WAPS characterizes the distribution of charge density across the molecular surface and was found to correlate well with the extent of water influence on the dissociation of the respective acid. PMID- 20919705 TI - Ambipolar hexa-peri-hexabenzocoronene-fullerene hybrid materials. AB - A new class of self-assembling hexa-peri-hexbenzocoronene (HBC)-fullerene hybrid materials has been synthesized and characterized. Photoluminescence experiments indicate that energy transfer processes can be tuned in these donor-acceptor systems by varying the length and nature of the linker group. In preliminary device testing, ambipolar charge transport behavior is observed in organic field effect transistors, while single active component organic photovoltaic devices consisting of these materials achieved a maximum external quantum efficiency of 30%. PMID- 20919706 TI - A chiral 6-membered N-heterocyclic carbene copper(I) complex that induces high stereoselectivity. AB - A chiral 6-membered annulated N-heterocyclic (6-NHC) copper complex that catalyzes beta-borylations with high yield and enantioselectivity was developed. The chiral 6-NHC copper complex is easy to prepare on the gram scale and is very active, showing 10,000 turnovers at 0.01 mol % of catalyst without significant decrease of enantioselectivity and with useful reaction rates. PMID- 20919708 TI - Molecular approach to understand the tacticity effects on the hydrophilicity of poly(N-isopropylacrylamide): solubility of dimer model compounds in water. AB - Although it has been suggested that the tacticity affects the hydrophilicity of poly(N-isopropylacrylamide) (PNiPA), little is known about the physical background of this phenomenon. In this study, we investigated the solubility of the dimer model compounds (DNiPA). The partition coefficient of DNiPA in the two phases of a water/chloroform mixture has indicated that DNiPA with the racemo configuration (r-DNiPA) is more soluble in water than DNiPA with the meso configuration (m-DNiPA). The difference of the hydration free energy between m- and r-DNiPA is estimated to be 1.2 kJ mol(-1). The molecular mechanics (MM) calculations with the GB/SA model have revealed that r-DNiPA in water is more stable by ca. 1 kJ mol(-1) than m-DNiPA, which is in excellent agreement with the experimental result. The MM calculations have also indicated that the intramolecular interaction of m-DNiPA is stronger than that of r-DNiPA, while r DNiPA is advantageous in terms of the hydration free energy and conformational entropy. PMID- 20919707 TI - A biosynthetic route to photoclick chemistry on proteins. AB - Light-induced chemical reactions exist in nature, regulating many important cellular and organismal functions, e.g., photosensing in prokaryotes and vision formation in mammals. Here, we report the genetic incorporation of a photoreactive unnatural amino acid, p-(2-tetrazole)phenylalanine (p-Tpa), into myoglobin site-specifically in E. coli by evolving an orthogonal tRNA/aminoacyl tRNA synthetase pair and the use of p-Tpa as a bioorthogonal chemical "handle" for fluorescent labeling of p-Tpa-encoded myoglobin via the photoclick reaction. Moreover, we elucidated the structural basis for the biosynthetic incorporation of p-Tpa into proteins by solving the X-ray structure of p-Tpa-specific aminoacyl tRNA synthetase in complex with p-Tpa. The genetic encoding of this photoreactive amino acid should make it possible in the future to photoregulate protein function in living systems. PMID- 20919710 TI - Wettability patterning by UV-initiated graft polymerization of poly(acrylic acid) in closed microfluidic systems of complex geometry. AB - Many microfluidic applications require modified surface wettability of the microchannels. Patterning of wettability within enclosed microfluidic structures at high spatial resolution has been challenging in the past. In this paper, we report an improved method for altering the surface wettability in poly(dimethylsiloxane) (PDMS) microchannels by UV-induced graft polymerization of poly(acrylic acid). Our method presents significant improvements in terms of wettability contrast and spatial resolution of the patterned structures as compared to recent literature and is in particular applicable to complex microfluidic structures with a broad range of channel sizes and aspect ratios. A key part of our work is the clear description of the surface treatment process with the identification of key parameters, some of which have been overlooked, neglected, or misinterpreted in previous works. We have studied these key parameters in detail and provide recommended values for each parameter supported by experimental results. This detailed understanding of the treatment process and the effects of the critical parameters on it allowed us to significantly improve quality and reliability of the treatment process. PMID- 20919709 TI - A high-nuclearity 3d/4f metal oxime cluster: an unusual Ni(8)Dy(8) "core-shell" complex from the use of 2-pyridinealdoxime. AB - The initial employment of 2-pyridinealdoxime in 3d/4f chemistry has led to a Ni(II)(8)Dy(III)(8) cluster with an unprecedented metal topology; the compound has an unusual structure, is the highest-nuclearity metal oxime cluster to date, and exhibits slow magnetization relaxation. PMID- 20919711 TI - Dynamic investigation of protein metal active sites: interplay of XANES and molecular dynamics simulations. AB - The effect of structural disorder on the X-ray absorption near-edge structure (XANES) spectrum of a heme protein has been investigated using the dynamical description of the system derived from molecular dynamics (MD) simulations. The XANES spectra of neuroglobin (Ngb) and carbonmonoxy-neuroglobin (NgbCO) have been quantitatively reproduced, starting from the MD geometrical configurations, without carrying out any optimization in the structural parameter space. These results provide an important experimental validation of the reliability of the potentials used in the MD simulations and accordingly corroborate the consistency of the structural dynamic information on the metal center, related to its biological function. This analysis allowed us to demonstrate that the configurational disorder associated with the distortion of the heme plane and with the different orientations of the axial ligands can affect the XANES features at very low energy. Neglecting configurational disorder in the XANES quantitative analysis of heme proteins is a source of systematic errors in the determination of Fe coordination geometry. The combined use of XANES and MD is a novel strategy to enhance the resolution and reliability of the structural information obtained on metalloproteins, making the combination of these techniques powerful for metalloprotein investigations. PMID- 20919712 TI - Cerium(IV), neptunium(IV), and plutonium(IV) 1,2-phenylenediphosphonates: correlations and differences between early transuranium elements and their proposed surrogates. AB - The in situ hydrothermal reduction of Np(VI) to Np(IV) and Pu(VI) to Pu(IV) in the presence of 1,2-phenylenediphosphonic acid (PhP2) results in the crystallization of Np[C(6)H(4)(PO(3)H)(2)](2).2H(2)O (NpPhP2) and Pu[C(6)H(4)(PO(3)H)(PO(3)H(2))][C(6)H(4)(PO(3)H)(PO(3))].2H(2)O (PuPhP2), respectively. Similar reactions have been explored with Ce(IV) resulting in the isolation of the Ce(IV) phenylenediphosphonate Ce[C(6)H(4)(PO(3)H)(PO(3)H(2))][C(6)H(4)(PO(3)H)(PO(3))].2H(2)O (CePhP2). Single crystal diffraction studies reveal that although all these three compounds all crystallize in the triclinic space group P1, only PuPhP2 and CePhP2 are isotypic, whereas NpPhP2 adopts a distinct structure. In the cerium and plutonium compounds edge-sharing dimers of MO(8) polyhedra are bridged by the diphosphonate ligand to create one-dimensional chains. NpPhP2 also forms chains. However, the NpO(8) units are monomeric. The protonation of the ligands is also different in the two structure types. Furthermore, the NpO(8) polyhedra are best described as square antiprisms (D(4d)), whereas the CeO(8) and PuO(8) units are trigonal dodecahedra (D(2d)). Bond-valence parameters of R(o) = 1.972 and b = 0.538 have been derived for Np(4+) using a combination of the data reported in this work with that available in crystallographic databases. The UV-vis-NIR absorption spectra of NpPhP2 and PuPhP2 are also reported and used to confirm the tetravalent oxidation states. PMID- 20919713 TI - Citric acid adsorption on TiO2 nanoparticles in aqueous suspensions at acidic and circumneutral pH: surface coverage, surface speciation, and its impact on nanoparticle-nanoparticle interactions. AB - Citric acid plays an important role as a stabilizer in several nanomaterial syntheses and is a common organic acid found in nature. Here, the adsorption of citric acid onto TiO(2) anatase nanoparticles with a particle diameter of ca. 4 nm is investigated at circumneutral and acidic pHs. This study focuses on both the details of the surface chemistry of citric acid on TiO(2), including measurements of surface coverage and speciation, and its impact on nanoparticle behavior. Using macroscopic and molecular-based probes, citric acid adsorption and nanoparticle interactions are measured with quantitative solution phase adsorption measurements, attenuated total reflection-FTIR spectroscopy, dynamic light scattering techniques, and zeta-potential measurements as a function of solution pH. The results show that surface coverage is a function of pH and decreases with increasing pH. Surface speciation differs from the bulk solution and is time dependent. After equilibration, the fully deprotonated citrate ion is present on the surface regardless of the highly acidic solution pH indicating pK(a) values of surface adsorbed species are lower than those in solution. Nanoparticle interactions are also probed through measurements of aggregation and the data show that these interactions are complex and depend on the detailed interplay between bulk solution pH and surface chemistry. PMID- 20919714 TI - Electronic transitions of protonated benzene and fulvene, and of C6H7 isomers in neon matrices. AB - Electronic transitions of protonated benzene (A (1)B(2)<-X (1)A(1), origin at 325 nm) and alpha-protonated fulvene (A (1)A'<-X (1)A', at 335 nm) trapped in 6 K neon matrices have been detected. The cations were produced from several different precursors, mass-selected, and co-deposited with neon. After neutralization of the cations, the electronic transitions of cyclohexadienyl (onsets at 549 and 310 nm) and alpha-hydrogenated fulvene (532 and 326 nm) radicals were identified. Upon excitation of cyclohexadienyl to the B (2)B(1) state, photoisomerization to an open-chain structure and alpha-hydrogenated fulvene was observed. PMID- 20919715 TI - B(C6F5)3-promoted tandem silylation and intramolecular hydrosilylation: diastereoselective synthesis of oxasilinanes and oxasilepanes. AB - B(C(6)F(5))(3) promotes regio- and stereoselective cyclizations of unsaturated alkoxysilanes to generate oxasilinanes and oxasilepanes. The same products are available directly from alkenols via tandem silylation and hydrosilylation. PMID- 20919716 TI - Multidimensional molecular steric opacity function for XeCl*(B, C) formation in the oriented Xe* (3P2, MJ = 2) + oriented CCl3F reaction. AB - The steric effect for the XeCl*(B, C) formations in the oriented Xe* (3P2, MJ = 2) + oriented CCl3F reaction has been observed as a function of the mutual configuration between the molecular orientation and the atomic orbital alignment in the collision frame. Molecular steric opacity functions have been determined as a function of the atomic orbital alignment (M(L)') in the collision frame. The XeCl*(B, C) channels show similar molecular steric opacity functions at M(L)' = 0 but not at |M(L)'| = 1. The large molecular alignment dependence (i.e., the reactivity of the Cl3 end and the F end is comparable, but a very poor reactivity for the sideway) is recognized for the XeCl*(B, C) channels except for the XeCl*(C) channel at |M(L)'| = 1, which shows an almost isotropic molecular orientation dependence. The M(L)' selectivity is different between the XeCl*(B, C) channels. At the molecular axis direction, the XeCl*(B) channel has little M(L)' selectivity whereas the XeCl*(C) channel is significantly favorable at M(L)' = 0. On the other hand, |M(L)'| = 1 is favorable at the sideway for the XeCl*(B, C) channels. PMID- 20919717 TI - Rate coefficients for the gas-phase reaction of hydroxyl radicals with 2 methoxyphenol (guaiacol) and related compounds. AB - 2-Methoxyphenol (guaiacol) and its derivatives are potential marker compounds for wood smoke emissions in the atmosphere. To investigate the atmospheric reactivity of this type of compounds, rate coefficients for their reactions with hydroxyl (OH) radicals have been determined at 294 +/- 2 K and 1 atm using the relative rate method with gas chromatography for chemical analysis. The rate coefficients (in units of cm3 molecule-1 s-1) are: 2-methoxyphenol, (7.53 +/- 0.41) * 10-11; 3 methoxyphenol, (9.80 +/- 0.46) * 10-11; 4-methoxyphenol, (9.50 +/- 0.55) * 10-11; 2-methoxy-4-methylphenol, (9.45 +/- 0.59) * 10-11; and methoxybenzene, (2.20 +/- 0.15) * 10-11. The estimated atmospheric lifetime for 2-methoxyphenol is ~2 h, indicating that it is too reactive to be used as a tracer for wood smoke emissions. The reactivity of the methoxyphenols is compared with other substituted aromatics and interpreted in relation to the type, number, and positions of the different substituents on the aromatic ring. The atmospheric implications of the reactions are also discussed. PMID- 20919718 TI - Formation and characterization of amyloid-like fibrils from soy beta-conglycinin and glycinin. AB - The fibrillar aggregation at pH 2.0 of soy beta-conglycinin, glycinin, and the 1:1 mixture thereof, induced by heating at 80 degrees C for various periods of time, was investigated using Th T and Congo Red spectroscopic techniques. The morphology of the formed fibrillar aggregates was characterized using atomic force microscopy (AFM), whereas the conformational changes and the polypeptide hydrolysis of the proteins upon heating were also evaluated. Th T fluorescence analysis indicated that beta-conglycinin had a much higher potential to form heat induced amyloid-like aggregates than glycinin. AFM analyses showed that all of the soy globulins could form twisted screw-structure fibrils with heights of 1.4 2.2 nm, but the morphology of the amyloid-like fibrils considerably varied among various soy proteins. Significantly lower width at half-heights and higher coil periodicity values were observed for the beta-conglycinin fibrils than the glycinin counterpart. Far-UV CD spectral analysis indicated that upon heating, the secondary conformations of the proteins changed considerably, especially during initial heating (e.g., <4 h), and the changes were much more distinct in the beta-conglycinin case than in the glycinin case. Furthermore, reducing electrophoresis analyses indicated that progressive polypeptide hydrolysis occurred upon heating, but the polypeptide hydrolysis for the beta-conglycinin was much more severe than that of glycinin. The data suggest that soy beta conglycinin exhibited a much higher potential to form thermally fibrillar aggregates than glycinin, and the differences seem to be mainly associated with the differences in their conformational changes and extent of polypeptide hydrolysis by the heating. The results would be of vital importance for the utilization of soy proteins to produce thermally induced fibrillar gels with excellent properties. PMID- 20919719 TI - Simultaneous quantification of flavonoids and phenolic acids in plant materials by a newly developed isocratic high-performance liquid chromatography approach. AB - A simple reversed-phase high-performance liquid chromatographic (RP-HPLC) method based on isocratic elution has been developed and validated for the simultaneous quantitation of flavonols (myricetin, quercetin, kaempferol, and isorhamnetin), flavones (luteolin and apigenin), and phenolic acids (chlorogenic, caffeic, ellagic, and rosmarinic acids) as important constituents in fruits, vegetables, and medicinal plants. Analysis was achieved on a C18 column at ambient temperature. The wavelengths used for the detection of flavonols, flavones, and phenolic acids were 370, 350, and 325 nm, respectively. After acid hydrolysis, the flavonoid aglycones were quantified straightforwardly in 20 dry herbal samples. The plants with the highest flavonoids were Rosa damascena, Solidago virgaurea, Ginkgo biloba, and Camellia sinensis. The contents of flavonoids aglycons ranged from 0.54 to 11.10 mg/g, from 0.03 to 14.80 mg/g, from 0.19 to 2.76 mg/g, from 0.15 to 2.36 mg/g, from 0.27 to 2.05 mg/g, and from 0.42 to 1.82 mg/g for quercetin, kaempferol, isorhamnetin, luteolin, apigenin, and myricetin in dry plant samples, respectively. PMID- 20919720 TI - Discovery of novel 2-aryl-4-benzoyl-imidazoles targeting the colchicines binding site in tubulin as potential anticancer agents. AB - A series of 2-aryl-4-benzoyl-imidazoles (ABI) was synthesized as a result of structural modifications based on the previous set of 2-aryl-imidazole-4 carboxylic amide (AICA) derivatives and 4-substituted methoxylbenzoyl-aryl thiazoles (SMART). The average IC(50) of the most active compound (5da) was 15.7 nM. ABI analogues have substantially improved aqueous solubility (48.9 MUg/mL for 5ga vs 0.909 MUg/mL for SMART-1, 0.137 MUg/mL for paclitaxel, and 1.04 MUg/mL for combretastatin A4). Mechanism of action studies indicate that the anticancer activity of ABI analogues is through inhibition of tubulin polymerization by interacting with the colchicine binding site. Unlike paclitaxel and colchicine, the ABI compounds were equally potent against multidrug resistant cancer cells and the sensitive parental melanoma cancer cells. In vivo results indicated that 5cb was more effective than DTIC in inhibiting melanoma xenograph tumor growth. Our results suggest that the novel ABI compounds may be developed to effectively treat drug-resistant tumors. PMID- 20919721 TI - Characterization of the influence of the ionic liquid 1-butyl-3-methylimidazolium chloride on the structure and thermal stability of green fluorescent protein. AB - Ionic liquids (ILs) are finding a vast array of applications as novel solvents for a wide variety of processes that include enzymatic chemistry, particularly as more biocompatible ILs are designed and discovered. While it is assumed that a native or near-native structure is required for enzymatic activity, there is some evidence that ILs alter protein structure and oligomerization states in a manner than can negatively impact function. The IL 1-butyl-3-methylimidazolium chloride, [bmim]Cl, is a well-studied, water-miscible member of the popular 1-alkyl-3 methylimidazolium IL family. To improve our understanding of the impact of water miscible ILs on proteins, we have characterized the structure and oligomerization state of green fluorescent protein (GFP) in aqueous solutions containing 25 and 50 vol % [bmim]Cl using a combination of optical spectroscopy and small-angle neutron scattering (SANS). Measurements were also performed as a function of temperature to provide insight into the effect of the IL on the thermal stability of GFP. While GFP exists as a dimer in water, the presence of 25 vol % [bmim]Cl causes GFP to transition to a monomeric state. The SANS data indicate that GFP is a great deal less compact in 50 vol % [bmim]Cl than in neat water, indicative of unfolding from the native structure. The oligomerization state of the protein in IL-containing aqueous solution changes from a dimer to a monomer in response to the IL, but does not change as a function of temperature in the IL-containing solution. The SANS and spectroscopic results also demonstrate that the addition of [bmim]Cl to the solution decreases the thermal stability of GFP, allowing the protein to unfold at lower temperatures than in aqueous solution. PMID- 20919722 TI - Assessment of environmental tobacco smoke contamination in public premises: significance of 2,5-dimethylfuran as an effective marker. AB - Contamination by environmental tobacco smoke (ETS) on premises where smoking is permitted is evaluated. Although all target VOCs evaluated show significant differences between smoking and nonsmoking indoors, the results obtained indicate that 2,5-dimethylfuran is the most appropriate and effective marker of ETS contamination given that this compound is only detected in environments where people have smoked and so the detection of this compound cannot be attributed to other contamination sources such as traffic. Moreover, the air levels of this compound due to coffee aroma are below the detection limits for this methodology. A preliminary study is performed to evaluate whether 2,5-dimethylfuran, a smoking breath biomarker, can be detected in passive smokers working in smoking environments. The compound was continuously detected in the breath of nonsmoking employees after being in direct contact with ETS for just a few hours. The Tedlar gas sampling bags had 5% loss of 2,5-dimethylfuran after 3 h of storage, which we took as the maximum recommended period for air sample storage. PMID- 20919723 TI - Expedient enantioselective synthesis of the delta4-oxocene cores of (+)-laurencin and (+)-prelaureatin (?). AB - An expedient enantioselective synthesis of the Delta(4)-oxocene cores present in (+)-laurencin and (+)-prelaureatin was accomplished in eight steps via a novel one-pot regio- and stereoselective ring cyclization-fragmentation-expansion cascade from the tetrahydrofuran precursors which were prepared by stereocontrolled cyclization from vinylsilanes. This process is highlighted by an intramolecular oxo-carbenoid insertion and a beta-silyl fragmentation sequence. PMID- 20919725 TI - Enantioselective Pd-catalyzed hydrogenation of fluorinated imines: facile access to chiral fluorinated amines. AB - An enantioselective hydrogenation of simple fluorinated imines has been developed using Pd(OCOCF(3))(2)/(R)-Cl-MeO-BIPHEP as a catalyst, and up to 94% ee was achieved. This method provides an efficient route to enantioenriched fluorinated amines. PMID- 20919724 TI - Control of proton and electron transfer in de novo designed, biomimetic beta hairpins. AB - Tyrosine side chains are involved in proton coupled electron transfer reactions (PCET) in many complex proteins, including photosystem II (PSII) and ribonucleotide reductase. For example, PSII contains two redox-active tyrosines, TyrD (Y160D2) and TyrZ (Y161D1), which have different protein environments, midpoint potentials, and roles in catalysis. TyrD has a midpoint potential lower than that of TyrZ, and its protein environment is distinguished by potential pi cation interactions with arginine residues. Designed biomimetic peptides provide a system that can be used to investigate how the protein matrix controls PCET reactions. As a model for the redox-active tyrosines in PSII, we are employing a designed, 18 amino acid beta hairpin peptide in which PCET reactions occur between a tyrosine (Tyr5) and a cross-strand histidine (His14). In this peptide, the single tyrosine is hydrogen-bonded to an arginine residue, Arg16, and a second arginine, Arg12, has a pi-cation interaction with Tyr5. In this report, the effect of these hydrogen bonding and electrostatic interactions on the PCET reactions is investigated. Electrochemical titrations show that histidine substitutions change the nature of PCET reactions, and optical titrations show that Arg16 substitution changes the pK of Tyr5. Removal of Arg16 or Arg12 increases the midpoint potential for tyrosine oxidation. The effects of Arg12 substitution are consistent with the midpoint potential difference, which is observed for the PSII redox-active tyrosine residues. Our results demonstrate that a pi-cation interaction, hydrogen bonding, and PCET reactions alter redox active tyrosine function. These interactions can contribute equally to the control of midpoint potential and reaction rate. PMID- 20919726 TI - Self-assembled E(2)L(3) cryptands (E = P, As, Sb, Bi): transmetalation, homo- and heterometallic assemblies, and conformational isomerism. AB - A series of Group 15-containing homometallic (E(2)L(3), E = P, As, Sb, Bi) and heterometallic (AsSbL(3), AsBiL(3), PSbL(3)) supramolecular cryptands were prepared by the self-assembly of pnictogen halides with dithiolate ligand or by direct transmetalation from a heavier congener. Structural characterization by single crystal X-ray diffraction shows that the E-S bond distances and S-E-S bond angles are significantly affected by the identity of the pnictogen. (1)H NMR spectroscopy reveals that the homometallic cryptands are dynamic in solution: surprisingly one ligand "flips", perturbing the C(3) symmetry of the complex and giving a new asymmetric conformer. Density functional theory calculations were carried out on both the symmetric and the asymmetric conformations of the cryptands, and the energies were compared to those observed by NMR spectroscopy. It was found that the relative stability of the asymmetric cryptand to its symmetric conformer increases with increasing size of the Group 15 element. Finally, it is reported that if two metals are present during the self-assembly process, heterometallic cryptands form. These supramolecular cryptands are reminiscent of their organic analogues, but result from a self-assembly process rather than a stepwise synthesis. Surprisingly, they possess conformational isomerism and exhibit dynamic transmetalation in their reactivity which provides access to otherwise unattainable assemblies. PMID- 20919727 TI - Photoinduced electron transfer in Zn(II)porphyrin-bridge-Pt(II)acetylide complexes: variation in rate with anchoring group and position of the bridge. AB - The synthesis and photophysical characterization of two sets of zinc porphyrin platinum acetylide complexes are reported. The two sets of molecules differ in the way the bridging phenyl-ethynyl unit is attached to the porphyrin ring. One set is attached via an ethynyl unit on the beta position, while the other set is attached via a phenyl unit on the meso position of the porphyrin. These were compared with previously studied complexes where attachment was made via an ethynyl unit on the meso position. Femtosecond transient absorption measurements showed in all systems a rapid quenching of the porphyrin singlet state. Electron transfer is suggested as the quenching mechanism, followed by an even faster recombination to form both the porphyrin ground and triplet excited states. This is supported by the variation in quenching rate and porphyrin triplet yield with solvent polarity, and the observation of an intermediate state in the meso-phenyl linked systems. The different linking motifs between the dyads resulted in significant variations in electron transfer rates. PMID- 20919728 TI - Boronic acid flux synthesis and crystal growth of uranium and neptunium boronates and borates: a low-temperature route to the first neptunium(V) borate. AB - Molten methylboronic acid has been used as a reactive flux to prepare the first neptunium(V) borate, NpO(2)[B(3)O(4)(OH)(2)] (NpBO-1), and the first actinide boronate, UO(2)(CH(3)BO(2))(H(2)O) (UCBO-1). NpBO-1 contains cation-cation interactions between the neptunyl units. In contrast, the presence of the methyl groups in the uranyl boronate leads to a one-dimensional structure. PMID- 20919729 TI - Charge transport in dual gated bilayer graphene with Corbino geometry. AB - The resistance of dual-gated bilayer graphene is measured as a function of temperature and gating electric fields in the Corbino geometry which precludes edge transport. The temperature-dependent resistance is quantitatively described by a two-channel conductance model including parallel thermal activation and variable range hopping channels, which gives the electric-field-dependent band gap whose magnitude is found to be in good agreement with infrared absorption experiments. Low-temperature transport is similar to that seen in previous studies of dual-gated bilayer graphene with edges, suggesting that edge transport does not play an important role. PMID- 20919730 TI - Control performance and biomembrane disturbance of carbon nanotube artificial water channels by nitrogen-doping. AB - To establish ways to control the performance of artificial water channels is a big challenge. With molecular dynamics studies, we found that water flow inside the water channels of carbon nanotubes (CNTs) can be controlled by reducing or intensifying interaction energy between water molecules and the wall of the CNTs channel. A way of example toward this significant goal was demonstrated by the doping of nitrogen into the wall of CNTs. Different ratios of nitrogen doping result in different controllable water performance which is dominated mainly through a gradient of van der Waals forces created by the heteroatom doping in the wall of CNTs. Further results revealed that the nitrogen-doped CNT channels show less influence on the integrality of biomembrane than the pristine one, while the nitrogen-doped double-walled carbon nanotube exhibits fewer disturbances to the cellular membrane integrality than the nitrogen-doped single walled carbon nanotube when interacting with biomembranes. PMID- 20919731 TI - Chromene "lock", thiol "key", and mercury(II) ion "hand": a single molecular machine recognition system. AB - A regenerative, molecular machine-like "ON-OFF-ON" chemosensor based on a chromene molecule with the pyran ring "OFF-ON-OFF" cycle is reported for the first time. It behaves as a molecular lock that requires a thiol "key" to open the lock and a mercury(II) ion "hand" that unlatches the key for unsheathing the key to close the lock. PMID- 20919732 TI - The first naturally occurring thiepinols and thienol from an endolichenic fungus Coniochaeta sp. AB - Coniothiepinols A (1) and B (2) and coniothienol A (3), the first naturally occurring thiepinols (1 and 2) and thienol (3), have been isolated from the crude extract of an endolichenic fungus Coniochaeta sp. 1 possesses a unique 8-oxa-2 thia-bicyclo[3.2.1]octane skeleton, and its structure was assigned by NMR spectroscopy and X-ray crystallography. 1 showed significant activity against the gram-positive bacteria, Enterococcus faecium and Enterococcus faecalis. PMID- 20919733 TI - Secondary organic aerosol from photooxidation of polycyclic aromatic hydrocarbons. AB - Secondary organic aerosol (SOA) formation from the photooxidation of five polycyclic aromatic hydrocarbons (PAHs, naphthalene, 1- and 2-methylnaphthalene, acenaphthylene, and acenaphthene) was investigated in a 9-m(3) chamber in the presence of nitrogen oxides and the absence of seed aerosols. Aerosol size distributions and PAH decay were monitored by a scanning mobility particle sizer and a gas chromatograph with a flame ionization detector. Over a wide range of conditions, the aerosol yields for the investigated PAHs were observed to be in the range of 2-22%. The observed evolution of aerosol and PAH decay indicate that light and oxidant sources influence the time required to form aerosol and the required threshold reacted concentration of the PAHs. The SOA yields also were related to this induction period and the hydroxyl radical concentrations, particularly for smaller aerosol loadings (<~6 MUg m(-3)). Estimation of SOA production from oxidation of PAHs emitted from mobile sources in Houston shows that PAHs could account for more than 10% of the SOA formed from emissions from mobile sources in this region. PMID- 20919734 TI - Metal impurities dominate the sorption of a commercially available carbon nanotube for Pb(II) from water. AB - Numerous studies suggested carbon nanotubes (CNTs) as a type of promising sorbent for heavy metals from water and explained the sorption mechanism mainly by oxygen containing functional groups on CNT surfaces but neglected the potential role of metal catalyst residues in CNTs. This is a first study showing that metal impurities could dominate the sorption of one type of commercially available CNTs (P-CNTs) for Pb(II) from water, which will help to understand and guide environmental applications of CNTs as a sorbent. Sorption capacity of P-CNTs (27.3 mg g(-1)) for Pb(II) was much higher than that of the water-washed P-CNTs (W-CNTs, 4.7 mg g(-1)). SEM-EDS and ICP-MS analyses showed that both P-CNTs and W CNTs contained metal impurities (mainly Co and Mo) which released into the solutions during the sorption, especially P-CNTs. XAFS examination and precipitation experiments demonstrated that PbMoO(4) formation between Pb(II) and CNT-released MoO(4)(2-) and subsequent precipitation in the sorptive solutions was the dominant mechanism for the apparent sorption of Pb(II) by P-CNTs. PMID- 20919735 TI - Fabrication and superhydrophobic behavior of fluorinated microspheres. AB - We describe the preparation of fluorinated microspheres by precipitation polymerization and their use to fabricate superhydrophobic surfaces. For that purpose, two different approaches have been employed. In the first approach, a fluorinated monomer (either 4-fluorostyrene or 2,3,4,5,6-pentafluorostyrene) was added to the initial mixture of monomers constituted by styrene (S) and divinylbenzene (DVB). The second approach is based on the encapsulation of a block copolymer, polystyrene-b-poly(2,3,4,5,6-pentafluorostyrene), during the polymerization of the monomers (S and DVB), thus enabling the formation of particles with perfluorinated chains instead of single functional groups at the interface. Both approaches led to narrow polydisperse particles with fluoro functional groups at the interface as demonstrated by scanning electron microscopy (SEM), infrared (IR) spectroscopy, and X-ray photoelectron spectroscopy (XPS). Surface array of particles obtained by simple solvent casting presented superhydrophobic behavior with contact angles of water droplets of ca. 160-165 degrees . PMID- 20919736 TI - Molecular design of dinotefuran with unique insecticidal properties. AB - Dinotefuran, (RS)-1-methyl-2-nitro-3-(tetrahydro-3-furylmethyl)guanidine, is a neonicotinoid insecticide developed by Mitsui Chemicals Agro. Dinotefuran provides a tetrahydrofuran (THF) moiety distinct from other neonicotinoids with a chloropyridine or chlorothiazole ring, which is considered to be an essential structural element for the neonicotinoid action. The molecular design strategy based on acetylcholine ester moiety as a lead structure has successfully led to the discovery of dinotefuran with the cyclic ether THF functional group. The unique chemical and excellent biological properties and favorable toxicological profile make dinotefuran available for pest management in wide range of crops with a variety of application methods. PMID- 20919737 TI - Glyphosate degradation in glyphosate-resistant and -susceptible crops and weeds. AB - High levels of aminomethylphosphonic acid (AMPA), the main glyphosate metabolite, have been found in glyphosate-treated, glyphosate-resistant (GR) soybean, apparently due to plant glyphosate oxidoreductase (GOX)-like activity. AMPA is mildly phytotoxic, and under some conditions the AMPA accumulating in GR soybean correlates with glyphosate-caused phytotoxicity. A bacterial GOX is used in GR canola, and an altered bacterial glyphosate N-acetyltransferase is planned for a new generation of GR crops. In some weed species, glyphosate degradation could contribute to natural resistance. Neither an isolated plant GOX enzyme nor a gene for it has yet been reported in plants. Gene mutation or amplification of plant genes for GOX-like enzyme activity or horizontal transfer of microbial genes from glyphosate-degrading enzymes could produce GR weeds. Yet, there is no evidence that metabolic degradation plays a significant role in evolved resistance to glyphosate. This is unexpected, considering the extreme selection pressure for evolution of glyphosate resistance in weeds and the difficulty in plants of evolving glyphosate resistance via other mechanisms. PMID- 20919738 TI - Two-dimensional self-assemblies of silica nanoparticles formed using the "bubble deposition technique". AB - Two-dimensional silica nanoparticle assemblies were obtained by deposition of bubble made from a surfactant solution containing nanoparticles onto hydrophobic silicon substrate. The morphologies of the nanoparticle assemblies can be finely controlled by several experimental parameters, including surfactant concentration, nanoparticle concentration, and deposition time. Monolayer of nanoparticles with surface coverage of about 100% can be obtained under appropriate conditions. The method can also be applied to another hydrophobic substrate, HMDS (hexamethyldisilazane)-modified silicon substrate. Furthermore, it can be applied directly to lithography patterned substrates, meaning a high compatibility with the well-developed conventional top-down approaches to nanodevices. This bubble deposition technique is expected to be a promising method in the field of nano-object assembly and organization and has great application potentials. PMID- 20919739 TI - Synthesis in ionic liquids: [Bi2Te2Br](AlCl4), a direct gap semiconductor with a cationic framework. AB - The Lewis acidic ionic liquid EMIMBr-AlCl(3) (EMIM = 1-ethyl-3-methylimidazolium) allows a novel synthetic route to the semiconducting layered metal chalcogenides halide [Bi(2)Te(2)Br](AlCl(4)) and its Sb analogue. [Bi(2)Te(2)Br](AlCl(4)) is a direct band gap, strongly anisotropic semiconductor and consists of cationic infinite layers of [Bi(2)Te(2)Br](+) and [AlCl(4)](-) anions inserted between the layers. PMID- 20919741 TI - HKGreen-3: a rhodol-based fluorescent probe for peroxynitrite. AB - A novel fluorescent probe, HKGreen-3, for sensing peroxynitrite is designed on the basis of the rhodol scaffold and a peroxynitrite-specific oxidation reaction. The probe turns out to be highly sensitive and selective for detecting peroxynitrite in both chemical and biological systems. PMID- 20919740 TI - CHOBIMALT: a cholesterol-based detergent. AB - Cholesterol and its hemisuccinate and sulfate derivatives are widely used in studies of purified membrane proteins but are difficult to solubilize in aqueous solution, even in the presence of detergent micelles. Other cholesterol derivatives do not form conventional micelles and lead to viscous solutions. To address these problems, a cholesterol-based detergent, CHOBIMALT, has been synthesized and characterized. At concentrations above 3-4 MUM, CHOBIMALT forms micelles without the need for elevated temperatures or sonic disruption. Diffusion and fluorescence measurements indicated that CHOBIMALT micelles are large (210+/-30 kDa). The ability to solubilize a functional membrane protein was explored using a G-protein coupled receptor, the human kappa opioid receptor type 1 (hKOR1). While CHOBIMALT alone was not found to be effective as a surfactant for membrane extraction, when added to classical detergent micelles CHOBIMALT was observed to dramatically enhance the thermal stability of solubilized hKOR1. PMID- 20919743 TI - Dissection of DEN-induced platelet proteome changes reveals the progressively dys regulated pathways indicative of hepatocarcinogenesis. AB - Due to the lack of precise markers indicative of its occurrence, progression, and malignant stages, hepatocellular carcinoma (HCC) is currently associated with high mortality. Given the fact that thrombocytopenia is associated with chronic liver diseases, and the multifunctional nature of platelets we reason that phenotype-specific platelets could be the systemic barometer for hepato carcinogenesis. The mass spectrometry (MS)-based proteomic efforts to discover novel biomarkers in plasma or serum are largely compromised by a few of the overwhelmingly abundant proteins that comprise over 95% of the total protein mass of plasma or sera. Platelets however are free of these MS signal-suppressing proteins. On the basis of a HCC animal model where diethyl nitrosamine (DEN) administration on male rats specifically induces HCC, by using a multiplex quantitative proteomic approach, we profiled the phase-to-phase proteome changes in a series of viable phenotype-specific platelets along with the DEN-induced progressive liver transformation. The platelet proteome was found highly responsive to each physiological stage of liver inflammation or pathogenesis. Using data-dependent bioinformatics network analysis, we found that certain pathway modules involved in immune response, tissue wound repair, apoptosis, cell proliferation, and catabolism and metabolism were differentially regulated, which were uncovered by the DEN-induced differential expression of the corresponding pathway components. The phase-specific presentations of these pathways suggested that the DEN-induced progression of immune suppression and apoptosis resistance is dynamically coordinated in the platelets. These novel platelet signatures are interconnected in the dynamic networks along with HCC progression and could be identified noninvasively for HCC prognosis and early diagnosis. PMID- 20919744 TI - Disruption of the mucus barrier by topically applied exogenous particles. AB - The mucus barrier is well established as a formidable barrier to exogenous substances and forms the first line of defense for mucosal surfaces. Drugs and particle systems are known to be significantly hindered via a variety of interactions with mucus, and some efforts have been reported that can mitigate these interactions. We investigated topically applied particulate systems (nano and micro) for their potential to interact with mucus and influence on the diffusion of model drugs across the mucus barrier. Functionalized polystyrene nanoparticles and microparticles and diesel particulate matter were topically applied to established in vitro mucus models. Particle treated mucus was then assessed, compared to controls, for drug permeation rates. The average permeation rate of drugs increased 2-fold following the application of particles to mucus compared to permeation of the same drug through mucus alone. In some cases permeation enhancement of small model drugs was over 5 times that of controls. Assessment of particle physicochemical properties also indicated that significant interactions occurred between mucus and the particles as determined by zeta potential changes and size changes. Collectively this work supports the hypothesis that topically applied particles interact with the mucus barrier causing disruption of this barrier allowing for increased drug permeation. These findings have implications for improved drug delivery and enhanced environmental exposure to exogenous substances. PMID- 20919742 TI - LDL receptor-related protein 1 regulates the abundance of diverse cell-signaling proteins in the plasma membrane proteome. AB - LDL receptor-related protein 1 (LRP1) is an endocytic receptor, reported to regulate the abundance of other receptors in the plasma membrane, including uPAR and tissue factor. The goal of this study was to identify novel plasma membrane proteins, involved in cell-signaling, that are regulated by LRP1. Membrane protein ectodomains were prepared from RAW 264.7 cells in which LRP1 was silenced and control cells using protease K. Peptides were identified by LC-MS/MS. By analysis of spectral counts, 31 transmembrane and secreted proteins were regulated in abundance at least 2-fold when LRP1 was silenced. Validation studies confirmed that semaphorin4D (Sema4D), plexin domain-containing protein-1 (Plxdc1), and neuropilin-1 were more abundant in the membranes of LRP1 gene silenced cells. Regulation of Plxdc1 by LRP1 was confirmed in CHO cells, as a second model system. Plxdc1 coimmunoprecipitated with LRP1 from extracts of RAW 264.7 cells and mouse liver. Although Sema4D did not coimmunoprecipitate with LRP1, the cell-surface level of Sema4D was increased by RAP, which binds to LRP1 and inhibits binding of other ligands. These studies identify Plxdc1, Sema4D, and neuropilin-1 as novel LRP1-regulated cell-signaling proteins. Overall, LRP1 emerges as a generalized regulator of the plasma membrane proteome. PMID- 20919745 TI - Effects of oxidation on structural stability and remodeling of human very low density lipoprotein. AB - Very low density lipoproteins (VLDL) are triglyceride-rich precursors of low density lipoproteins (LDL) and a risk factor for atherosclerosis. The effects of oxidation on VLDL metabolism may be pro- or antiatherogenic. To understand the underlying biophysical basis, we determined the effects of copper (that preferentially oxidizes lipids) and hypochlorite (that preferentially oxidizes proteins) on the heat-induced VLDL remodeling. This remodeling involves VLDL fusion, rupture, and fission of apoE-containing high-density lipoprotein- (HDL-) like particles; HDL with similar size, density, and protein composition are formed upon VLDL remodeling by lipoprotein lipase, a key enzyme in triglyceride metabolism. Circular dichroism, turbidity, and electron microscopy show that mild oxidation promotes VLDL fusion and rupture, while advanced oxidation hampers these reactions. VLDL destabilization upon moderate oxidation results, in part, from the exchangeable apolipoprotein modifications, including proteolysis and limited cross-linking. VLDL stabilization against fusion and rupture upon advanced oxidation probably results from massive protein cross-linking on the particle surface. Electron microscopy and gel electrophoresis reveal that oxidation promotes fission of apoE-containing HDL-size particles; hydrolysis of apolar core lipids probably contributes to this effect. Copper and hypochlorite have similar effects on VLDL remodeling, suggesting that these effects may be produced by other oxidants. In summary, moderate oxidation that encompasses in vivo conditions destabilizes VLDL and promotes fission of HDL-size particles. Consequently, mild oxidation may be synergistic with lipoprotein lipase reaction and, hence, may help to accelerate VLDL metabolism. PMID- 20919747 TI - Key features for designing phosphodiesterase-5 inhibitors. AB - Phosphodiesterase superfamily is the key regulator of 3',5'-cyclic guanosine monophosphate (cGMP) decomposition in human body. Phosphodiesterase-5 (PDE-5) inhibitors, sildenafil, vardenafil and tadalafil, are well known oral treatment for males with erectile dysfunction. To investigate the inhibitory effects of traditional Chinese medicine (TCM) compounds to PDE-5, we performed both ligand based and structure-based studies on this topic. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) studies were conducted to construct three dimensional quantitative structure activity relationship (3D-QSAR) models of series of known PDE-5 inhibitors. The predictive models had cross-validated, q(2), and non cross-validated coefficient, r(2), values of 0.791 and 0.948 for CoMFA and 0.724 and 0.908 for CoMSIA. These two 3D-QSAR models were used to predict activity of TCM compounds. Docking simulations were performed to further analyze the binding mode of training set and TCM compounds. A putative binding model was proposed based on CoMFA and CoMSIA contour maps and docking simulations; formation of pi-stacking, water bridge and specific hydrogen bonding were deemed important interactions between ligands and PDE-5. Of our TCM compounds, engeletin, satisfied our binding model, and hence, emerged as PDE-5 inhibitor candidate. Using this study as an example, we demonstrated that docking should be conducted for qualitative purposes, such as identifying protein characteristics, rather than for quantitative analyses that rank compound efficacy based on results of scoring functions. Prediction of compound activity should be reserved for QSAR analyses, and scoring functions and docking scores should be used for preliminary screening of TCM database (http://tcm.cmu.edu.tw/index.php). PMID- 20919746 TI - A conformationally constrained peptidomimetic binds to the extracellular region of HER2 protein. AB - Human epidermal growth factor receptor 2 (HER2) is a member of the human epidermal growth factor receptor kinases (other members include EGFR or HER1, HER3, and HER4) that are involved in signaling cascades for cell growth and differentiation. It is well established that HER2-mediated heterodimerization has important implications in cancer. Deregulation of signaling pathways and overexpression of HER2 is known to occur in cancer cells, indicating a role of HER2 in tumorigenesis. Therefore, blocking HER2-mediated signaling has potential therapeutic value. We have designed several peptidomimetics to inhibit HER2 mediated signaling for cell growth. One of the compounds (HERP5, Arg-beta Naph Phe) exhibited antiproliferative activity with IC(50) values in the micromolar-to nanomolar range in breast cancer cell lines. Binding of fluorescently labeled HERP5 to HER2 protein was evaluated by fluorescence assay, microscopy, and circular dichroism spectroscopy. Results indicated that HERP5 binds to the extracellular region of the HER2 protein. Structure of the peptidomimetic HERP5 was studied by NMR and molecular dynamics simulations. Based on these results a model was proposed for HER2-EGFR dimerization and possible blocking by HERP5 peptidomimetic using a protein-protein docking method. PMID- 20919748 TI - Anti-infectious bronchitis virus (IBV) activity of 1,8-cineole: effect on nucleocapsid (N) protein. AB - In the present study, anti-IBV (infectious bronchitis virus) activity of 1,8 cineole was studied by MTT assay, as well as docking and molecular dynamic (MD) simulations. The CC50 of 1,8-cineole was above 10 mM. And the maximum noncytotoxic concentration (TD0) of 1,8-cineole was determined to be 3.90 +/- 0.22 mM, which was much higher than that of ribavirin (0.78 +/- 0.15 mM). 1,8 cineole could inhibit IBV with an IC(50) of 0.61 mM. MTT assay showed that the inhibition of IBV by 1, 8-cineole appears to occur moderately before entering the cell but much strongly after penetration of the virus into the cell. In silico simulations indicated that the binding site of 1,8-cineole was located at the N terminus of phosphorylated nucleocapsid (N) protein, with interaction energy equaling -40.33 kcal mol(-1). The residues TyrA92, ProA134, PheA137, AspA138 and TyrA140 had important roles during the binding process and are fully or partially conserved in various IBV strains. Based on spatial and energetic criteria, 1,8 cineole interfered with the binding between RNA and IBV N-protein. Results presented here may suggest that 1,8-cineole possesses anti-IBV properties, and therefore is a potential source of anti-IBV ingredients for the pharmaceutical industry. PMID- 20919749 TI - Effect of oligosaccharides and their monosaccharide mixtures on the stability of proteins: a scaled particle study. AB - Experimental results of RNase-A stabilization by sugar osmolytes show that the change in the Gibbs free energy (DeltaGD) associated with the equilibrium, N (native) state <-> D (denatured) state of the protein in the presence of equimolar mixture of monosaccharides is larger than that of the corresponding oligosaccharides at a given temperature and pH. However, at the molar scale, DeltaGD obtained in the presence of an oligosaccharide is much higher as compared with DeltaGD obtained using individual monosaccharide. We used scaled particle theory (SPT) to explain these experimental observations. The effective length, called Tolman's length that describes the curvature correlations to a surface area or surface tension and in turn contributes to the change in free energy, is discussed. Tolman's length is higher for corresponding monomer mixture than the oligosaccharide molecules. Based on SPT analysis, a geometrical model is proposed for clustering of monosaccharides in the mixture due to high particle density. The cluster is presumed to have weak interaction among them due to larger hydrodynamic radius than that of the bonded molecules of oligosaccharides. PMID- 20919750 TI - Effects of pH and temperature on the structural and thermodynamic character of alpha-syn12 peptide in aqueous solution. AB - The structural and thermodynamic characters of alpha-syn12 peptide in aqueous solution at different pH and temperatures have been investigated through temperature replica exchange molecular dynamics (T-REMD) simulations with GROMOS 43A1 force field. The two independent T-REMD simulations were completed at pH = 7.0 and 10.0, respectively. Each replica was run for 300 ns. The structural and thermodynamic characters of alpha syn12 peptide were studied based on the distributions of backbone dihedral angles, the free energy surface, and the stability of different type structure and the favorite conformations of the peptide. The results showed that the simulation at pH = 10.0 produced more sampling in alpha region than the simulation at pH = 7.0. The temperature changes from 283 K to 308 K result in negligible effects on the distributions of backbone dihedral angle. The beta hairpin conformation with Turn(9-6) and four hydrogen bonds (HB(4-11), HB(6-9), HB(9-6) and HB(11-4)) is the lowest free energy state in the simulation at pH = 7.0. However, for the simulation at pH = 10.0, the lowest free energy state corresponds to a structure with Turn(9-6) and two hydrogen bonds (HB(6-10) and HB(10-6)) induced by an overly strong residue residue interaction effect between lysine residues. For the simulation at pH = 7.0, the free energy change of the alpha-syn12 peptide from the unfolded state to the beta hairpin state was in good agreement with the experiments and molecular dynamics simulation results for the other beta-peptides, the beta hairpin state of the alpha-syn12 peptide included the conformations that not only the Turn(9-6) is formed, but also the terminus are closed together in space. However, the subtle balances between lysine-lysine interactions and lysine-solvent interaction are disrupted in the simulation at pH = 10.0, which induced the assembly of lysine residues, the beta hairpin conformation is destabilized by the deprotonation of the Lys side chain. This study can help us to understand the conformation changes and the thermodynamic character of alpha;-syn12 peptide at atomic level induced by changing pH and temperature, which is propitious to reveal the nosogenesis of Parkinson disease. In our knowledge, this is the first report to study the influence of pH and temperature on isolated alpha-syn12 peptide in water by T-REMD. PMID- 20919751 TI - Exposure of hydrophobic core in human prion protein pathogenic mutant H187R. AB - Pathogenesis studies have revealed that H187R mutation of human prion protein (huPrP) is related to GSS type of TSE diseases. Its pathogenic mechanism is still unclear. We here studied the globular domain of this mutant protein by molecular dynamics simulations. Compared to the wide-type protein, the mutant has similar dynamics and stability profiles in our simulation. Conformational rearrangements are concentrated around the mutation site, due to the introduction the positively charged side chain of Arg187. The strong electrostatic repulsion between Arg156 and Arg187 drives both side chains away from their original positions, leaving its hydrophobic core to be solvent accessible. Such a unfavorable conformational change may destabilize the mutant protein and make it more susceptible to unfolding. PMID- 20919752 TI - Homology modeling of Cry10Aa toxin from B. thuringiensis israelensis and B. thuringiensis subsp. LDC-9. AB - A three dimensional model was developed for Cry10Aa protein sequence of B. thuringiensis LDC-9 and B. thuringiensis israelensis that has not been solved empirically by X-ray crystallography or NMR. Homology modeling was employed for the structure prediction using Cry2Aa as template protein, a high-resolution X ray crystallography structure. The model predicted for the B. thuringiensis LDC-9 Cry10Aa protein reveals a partial N-terminal domain only due to its partial sequence of 104 amino acids. B. thuringiensis israelensis Cry10Aa model contains three domains such as domain I, a bundle of eight alpha helices with the central relatively hydrophobic helix surrounded by amphipathic helices while domain II and III contain mostly beta-sheets. Significant structural differences within domain II in this model among all Cry protein structures indicates that it is involved in recognition and binding to cell surfaces. Comparison of B. thuringiensis israelensis predicted structure with available experimentally determined Cry structures reveals identical folds. The distribution of electrostatic potential on the surface of the molecules in the model is non uniform and identifies one side of the alpha-helical domain as negatively charged indicating orientation of toxic molecules toward the cell membrane during the initial binding with a cell surface receptor. The collective knowledge of Cry toxin structures will lead to a more critical understanding of the structural basis for receptor binding and pore formation, as well as allowing the scope of diversity to be better appreciated. This model will serve as a starting point for the design of mutagenesis experiments aimed to improve the toxicity and to provide a new tool for the elucidation of the mechanism of action of these mosquitocidal proteins. PMID- 20919753 TI - Homology modeling and docking studies of human Bcl-2L10 protein. AB - Cancer, an unrestrained proliferation of cells, is one of the lead cause of death. Nearly 12.5 million people are diagnosed with cancer worldwide, 7.5 million people die of which 2.5 million cases are from India. Major cause for cancer is restriction of programmed cell death (apoptosis). Multiple signaling pathways regulate apoptosis. Bcl-2 (B - Cell Lymphomas-2) family proteins play a vital role as central regulators of apoptosis. Bcl-2L10, a novel anti-apoptotic protein, blocks apoptosis by mitochondrial dependent mechanism. The present study evaluates the 3D structure of Bcl-2L10 protein using homology modeling and aims to understand plausible functional and binding interactions between Bcl-2L10 with BH3 domain of BAX using protein - protein docking. The docking studies show binding of BH3 domain at Lys 110, Trp-111, Pro-115, Glu-119 and Asp-127 in the groove of BH 1, 2 and 3 domains of Bcl-2L10. Heterodimerization of anti-apoptotic Bcl-2 and BH3 domain of pro-apoptotic Bcl-2 proteins instigates apoptosis. Profound understanding of Bcl-2 pathway may prove useful in identification of future therapeutic targets for cancer. PMID- 20919754 TI - Influence of the acetylcholinesterase active site protonation on omega loop and active site dynamics. AB - Existence of alternative entrances in acetylcholinesterase (AChE) could explain the contrast between the very high AChE catalytic efficiency and the narrow and long access path to the active site revealed by X-ray crystallography. Alternative entrances could facilitate diffusion of the reaction products or at least water and ions from the active site. Previous molecular dynamics simulations identified side door and back door as the most probable alternative entrances. The simulations of non-inhibited AChE suggested that the back door opening events occur only rarely (0.8% of the time in the 10ns trajectory). Here we present a molecular dynamics simulation of non-inhibited AChE, where the back door opening appears much more often (14% of the time in the 12ns trajectory) and where the side door opening was observed quite frequently (78% of trajectory time). We also present molecular dynamics, where the back door does not open at all, or where large conformational changes of the AChE omega loop occur together with alternative passage opening events. All these differences in AChE dynamical behavior are caused by different protonation states of two glutamate residues located on bottom of the active site gorge (Glu202 and G450 in Mus musculus AChE). Our results confirm the results of previous molecular dynamics simulations, expand the view and suggest the probable reasons for the overall conformational behavior of AChE omega loop. PMID- 20919755 TI - SMpred: a support vector machine approach to identify structural motifs in protein structure without using evolutionary information. AB - Knowledge of three dimensional structure is essential to understand the function of a protein. Although the overall fold is made from the whole details of its sequence, a small group of residues, often called as structural motifs, play a crucial role in determining the protein fold and its stability. Identification of such structural motifs requires sufficient number of sequence and structural homologs to define conservation and evolutionary information. Unfortunately, there are many structures in the protein structure databases have no homologous structures or sequences. In this work, we report an SVM method, SMpred, to identify structural motifs from single protein structure without using sequence and structural homologs. SMpred method was trained and tested using 132 proteins domains containing 581 motifs. SMpred method achieved 78.79% accuracy with 79.06% sensitivity and 78.53% specificity. The performance of SMpred was evaluated with MegaMotifBase using 188 proteins containing 1161 motifs. Out of 1161 motifs, SMpred correctly identified 1503 structural motifs reported in MegaMotifBase. Further, we showed that SMpred is useful approach for the length deviant superfamilies and single member superfamilies. This result suggests the usefulness of our approach for facilitating the identification of structural motifs in protein structure in the absence of sequence and structural homologs. The dataset and executable for the SMpred algorithm is available at http://www3.ntu.edu.sg/home/EPNSugan/index_files/SMpred.htm. PMID- 20919756 TI - The MBLOSUM: a server for deriving mutation targets and position-specific substitution rates. AB - To facilitate mutagenesis study, it is necessary to be able to derive mutation targets and associated substitution rates in the sequence of interest regardless of the availability of corresponding structure. It is also important to obtain these data depending on the specific aims of the mutation process. The MBLOSUM server determines candidate positions for mutations and derives position-specific substitution rates given only a protein sequence. Different sets of complete genomes collected according to their phylogeny or specificity of environments along with compete set of non-redundant sequences can be used in calculations depending on the experimental task. MBLOSUM server is available at: http://apps.cbu.uib.no/mblosum. PMID- 20919757 TI - Conformational analysis of genotoxic benzo[a]pyrene-7,8-dione-duplex DNA adducts using a molecular dynamics method (II). AB - The conformations of the benzo[a]pyrene-7,8-quinone (BPQ) modified oligonucleotide were investigated using molecular dynamic simulation. In the initial structures, the central guanine base was modified with BPQ resulting in the formation of four structurally distinguishable 10-(N2-deoxyguanosyl)-9,10 dihydro-9-hydroxy benzo[a]pyrene-7,8-dione adducts (BPQ-G3,4). Each of the oligonucleotide adduct consisted of two conformers, namely syn and anti conformations, depending on the rotation around the glycosidic bond between BPQ and the guanine base. The results revealed that the BPQ moiety was located in the major groove for all four syn conformers. The relative energies of these conformers were high, and the backbone largely deviated from the B-form. On the other hand, BPQ was located in the minor groove with relatively low energies, and backbone was retained in all of the anti conformer cases. The most conceivable BPQ-modified double stranded oligonucleotide structure was proposed from the energy calculation and the structural analysis. PMID- 20919758 TI - RNA stability under different combinations of amber force fields and solvation models. AB - The proper matching of force field and solvent is critical to obtain correct result in molecular dynamics simulation of bio-molecules. This problem has been intensively investigated for protein but not for RNA yet. In this paper, we use standard molecular dynamics and replica exchange molecular dynamics to take a series of tests on the RNA stability under different combinations of Amber force field parameters (ff98, ff99 and ff99bsc0) and the general Born implicit solvent models (igb1, igb2 and igb5). It is found that only ff98 and ff99bsc0 with igb1 can keep the native conformations of RNA hairpin and duplex. Our results suggest that ff98 plus igb1 may be reasonable choice for molecular dynamics simulation of RNA dynamics. PMID- 20919759 TI - Family and individual factors associated with substance involvement and PTS symptoms among adolescents in greater New Orleans after Hurricane Katrina. AB - OBJECTIVE: This study examined the influence of hurricane impact as well as family and individual risk factors on posttraumatic stress (PTS) symptoms and substance involvement among clinically referred adolescents affected by Hurricane Katrina. METHOD: A total of 80 adolescents (87% male; 13-17 years old; mean age = 15.6 years; 38% minorities) and their parents were interviewed at the adolescent's intake into substance abuse treatment, 16 to 46 months postdisaster. Independent measures included hurricane impact variables (initial loss/disruption and perceived life threat); demographic and predisaster variables (family income, gender, predisaster adolescent substance use, predisaster trauma exposure, and parental substance abuse); postdisaster family factors (parental psychopathology, family cohesion, and parental monitoring); and postdisaster adolescent delinquency. RESULTS: Hierarchical multivariate regression analyses showed that adolescent substance involvement was associated with higher family income, lower parental monitoring (adolescent report), and more adolescent delinquency. Adolescent-reported PTS symptoms were associated with greater hurricane-related initial loss/disruption, lower family cohesion (adolescent report), and more adolescent delinquency, whereas parent-reported adolescent PTS symptoms were associated with greater parental psychopathology, lower parental monitoring (adolescent report), and lower family cohesion (parent report). CONCLUSIONS: The results suggest that hurricane impact was related only to adolescent-reported PTS. However, certain postdisaster family and individual risk factors (low family cohesion and parental monitoring, more adolescent delinquency) were associated both with adolescent substance involvement and with PTS symptoms. Identification of these factors suggests directions for future research as well as potential target areas for screening and intervention with substance-abusing adolescents after disasters. PMID- 20919760 TI - The Treatment Advocacy Program: a randomized controlled trial of a peer-led safer sex intervention for HIV-infected men who have sex with men. AB - OBJECTIVE: Primary care may be an effective venue for delivering behavioral interventions for sexual safety among HIV-positive men who have sex with men (MSM); however, few studies show efficacy for such an approach. We tested the efficacy of the Treatment Advocacy Program (TAP), a 4-session, primary-care based, individual counseling intervention led by HIV-positive MSM "peer advocates" in reducing unprotected sex with HIV-negative or unknown partners (HIV transmission risk). METHOD: We randomized 313 HIV-positive MSM to TAP or standard care. HIV transmission risk was assessed at baseline, 6 months, and 12 months (251 participants completed all study waves). We conducted intent-to-treat analyses using general estimating equations to test the interaction of group (TAP vs. standard care) by follow-up period. RESULTS: At study completion, TAP participants reported greater transmission risk reduction than did those receiving standard care, chi2(2, N = 249) = 6.6, p = .04. Transmission risk among TAP participants decreased from 34% at baseline to about 20% at both 6 and 12 months: Transmission risk ranged from 23% to 25% among comparison participants. CONCLUSIONS: TAP reduced transmission risk among HIV-positive MSM, although results are modest. Many participants and peer advocates commented favorably on the computer structure of the program. We feel that the key elements of TAP computer-based and individually tailored session content, delivered by peers, in the primary care setting-warrant further exploration. PMID- 20919761 TI - Naming from definition, semantic relevance and feature type: the effects of aging and Alzheimer's disease. AB - OBJECTIVE: The principal aim of the present study was to evaluate the impact of semantic relevance and feature type on the ability to name from definition. METHOD: Thirty-two normal young subjects (Study 1) and 20 probable Alzheimer's disease patients (pAD) with 20 matched older controls (Study 2) were tested with verbal definitions consisting of 4 features, combining feature type (sensory vs. nonsensory) and semantic relevance (high vs. low). The subjects were asked to provide a name corresponding to the definition and to select which individual features they considered most important in justifying their answer. RESULTS: Feature selection results showed that high-relevance features first (d = 2.13 in Study 1; d = 1.44 in Study 2) and nonsensory features second (d = 0.81 in Study 1; d = 0.36 in Study 2) were the main dimensions driving correct performance. Overall, naming performance was affected by the age of acquisition (AoA) of the concept, and differences between the groups in all measures were mainly quantitative. CONCLUSIONS: These findings suggest that semantic relevance and feature type are important feature dimensions in conceptual representation and in conceptual access and retrieval. Moreover, results suggest that the former dimension may be more important than the latter, at least in the case of naming from definition. Finally, these results extend previous findings with other tasks, supporting the importance of AoA for correct performance and suggesting that the poorer performance of pAD patients on semantic tasks may represent an exaggeration of difficulties found also in normal older subjects. PMID- 20919762 TI - Deficits in emotional and social cognition in amyotrophic lateral sclerosis. AB - OBJECTIVE: These studies investigated whether non-demented ALS patients display impairments on tests of emotional decision making and social and emotional cognition, sensitive to frontal variant Frontotemporal Dementia (fvFTD). Previous studies have shown predominant executive dysfunction and dorsolateral prefrontal involvement in ALS, but evidence of other prefrontal dysfunction implicated in fvFTD is sparse. METHOD: In Study A, 19 ALS patients and 20 healthy controls undertook a test of affective decision making, modified Iowa Gambling Task (IGT). Behavioral measures included the Frontal Systems Behavior Scale. In Study B, 14 ALS patients and 20 controls undertook tests of social and emotional cognition (Judgment of Preference based on eye gaze, the Mind in the Eyes, recognition of Facial Expressions of Emotion). RESULTS: In Study A, ALS patients demonstrated a significantly different performance profile from healthy controls on the IGT and did not learn to avoid the disadvantageous stimuli (Block 3, d = 0.60, Block 4 days = 0.68). Behavior ratings showed increased apathy from premorbid levels. In Study B, ALS patients were impaired on attentionally demanding (d = 3.12) and undemanding (d = 7.52) conditions of the Judgment of Preference task, despite many showing intact executive functions. A smaller subset showed impaired emotion recognition. Behavior change was also evident. CONCLUSIONS: The findings reveal a Theory of Mind deficit on a simple test that was dissociated from the presence of executive dysfunction and suggests a profile of cognitive and behavioral dysfunction indicative of a subclinical fvFTD syndrome. The relative contribution of prefrontal pathways to the cognitive profile in ALS is considered. PMID- 20919763 TI - Task switching performance reveals heterogeneity amongst patients with mild cognitive impairment. AB - OBJECTIVE: To assess executive function in patients with mild cognitive impairment (MCI) and to determine whether task switching ability is associated with transition to Alzheimer's disease. METHODS: Twenty-seven MCI patients and 19 older controls were tested using a cued letter-digit classification switching task. Sixteen patients could perform the task (MCI-able), 6 could not (MCI unable), and 5 were able only with cognitive support (MCI-cue). Demographic, neuropsychological, event-related potential (ERP), MRI, and genetic data were also collected. RESULTS: The four groups did not differ on age, gender, and APO E4 frequency. Compared to the controls, the MCI-unable group had significantly poorer performance on the Trail Making task (eta2 = .430), lower education (eta2 = .234), and smaller cortical volume (eta2 = .245). Most MCI patients exhibited task-switching deficits but to vastly different degrees and with varying outcomes. The combined pattern of neuropsychological and task switching performance indicates that the MCI-able patients displayed memory retrieval difficulties (F(2,39) = 3.6, p = .036, MSE = 1.44), generally preserved task switching abilities, and had a high probability of remaining dementia-free at follow-up. The MCI-cue patients had increased mixing costs, F(2,39) = 11.0, p < .001, MSE = .07; the MCI-unable patients showed episodic memory deficits, and both groups had a high probability of poor outcome (i.e., developing AD or dying within four years). CONCLUSION: This study demonstrates that variability in performance on measures of task-switching can highlight important heterogeneity in the MCI population. PMID- 20919765 TI - Neuromotor outcomes at school age after extremely low birth weight: early detection of subtle signs. AB - OBJECTIVE: Motor impairments are prevalent in children born at extremely low birth weight (ELBW; <1,000 g). Rarely studied are subtle motor deficits that indicate dysfunction or delay in neural systems critical for optimal cognitive, academic, and behavioral function. We aimed to examine quantifiable signs of subtle neuromotor dysfunction in an early school-aged ELBW cohort that coincidentally had age-appropriate cognition and design copying. METHOD: We studied 97 participants born between 1998 and 2001; 74 ELBW (6.7 years +/- 0.75) compared with 23 term-born (6.6 years +/- 0.29). Neuromotor outcomes were assessed using the Physical and Neurological Examination of Subtle Signs-Revised, and measures of dexterity/coordination and visual-motor integration. RESULTS: ELBW participants performed worse than term-born on design-copying and dexterity, were age-appropriate compared to normative data, and had slower timed movements and more subtle overflow movements. Those ELBW born <26 weeks performed most poorly compared with those born 26-34 weeks and term-born. CONCLUSION: Subtle motor dysfunctions are detectable and quantifiable in ELBW children by school age, even in the presence of average cognition. Early age assessment of incoordination, motor speed, and overflow movements should aid initiation of timely therapies to prepare at-risk ELBW children for subsequent school entry and facilitate design of optimal early treatment strategies. PMID- 20919764 TI - Enhanced facilitation of spatial attention in schizophrenia. AB - OBJECTIVE: While attentional functions are usually found to be impaired in schizophrenia, a review of the literature on the orienting of spatial attention in schizophrenia suggested that voluntary attentional orienting in response to a valid cue might be paradoxically enhanced. We tested this hypothesis with orienting tasks involving the cued detection of a laterally presented target stimulus. METHOD: Subjects were chronic schizophrenia patients (SZ) and matched healthy control subjects (HC). In Experiment 1 (15 SZ, 16 HC), cues were endogenous (arrows) and could be valid (100% predictive) or neutral with respect to the subsequent target position. In Experiment 2 (16 SZ, 16 HC), subjects performed a standard orienting task with unpredictive exogenous cues (brightening of the target boxes). RESULTS: In Experiment 1, SZ showed a larger attentional facilitation effect on reaction time than HC. In Experiment 2, no clear sign of enhanced attentional facilitation was found in SZ. CONCLUSIONS: The voluntary, facilitatory shifting of spatial attention may be relatively enhanced in individuals with schizophrenia in comparison to healthy individuals. This effect bears resemblance to other relative enhancements of information processing in schizophrenia such as saccade speed and semantic priming. PMID- 20919766 TI - Spatial location memory discriminates children born at extremely low birth weight and late-preterm at age three. AB - OBJECTIVE: The spatial location memory of preschool-aged children born preterm has rarely been studied primarily due to an absence of developmentally sensitive measures. This study aimed to address this gap in the literature. METHOD: We administered a modification of the Hopkins Board to 135 children at age 3 who were born extremely low birth weight (ELBW) (n = 20), late-preterm (LPT) (n = 75), or at term (TERM) (n = 40). Five measures were obtained: naming, trials-to criterion, errors-to-criterion, delayed item recall, and delayed location recall. RESULTS: ANCOVA indicated that the groups differed in naming (p = .019), errors to-criterion (p = .002), and delayed item recall (p = .025). For these measures, ELBW performed worse than TERM and LPT, but LPT did not differ from TERM. Corrected age and sociodemographic factors did not eliminate the deficit in spatial location learning for ELBW participants. A MANCOVA found a significant difference in learning, with post hoc tests indicating significant learning across trials in the LPT and TERM groups, but not in the ELBW group. CONCLUSIONS: ELBW is a significant risk factor for developmental delay or impairment of spatial location learning. These findings suggest that the modified Hopkins Board identifies at-risk premature children. This modification may be more broadly useful to assess preschoolers' neurodevelopmental maturation. PMID- 20919767 TI - Recovery of time estimation following moderate to severe traumatic brain injury. AB - OBJECTIVE: Accurate time estimation abilities are thought to play an important role in efficient performance of many daily activities. This study investigated the role of episodic memory in the recovery of time estimation abilities following moderate to severe traumatic brain injury (TBI). METHOD: Using a prospective verbal time estimation paradigm, TBI participants were tested in the early phase of recovery from TBI and then again approximately one year later. Verbal time estimations were made for filled intervals both within (i.e., 10 s, 25 s) and beyond (i.e., 45 s 60 s) the time frame of working memory. RESULTS: At baseline, when compared to controls, the TBI group significantly underestimated time durations at the 25 s, 45 s and 60 s intervals, indicating that the TBI group perceived less time as having passed than actually had passed. At follow up, despite the presence of continued episodic memory impairment and little recovery in episodic memory performance, the TBI group exhibited estimates of time passage that were similar to controls. CONCLUSION: The pattern of data was interpreted at suggesting that episodic memory performance did not play a noteworthy role in the recovery of temporal perception in TBI participants. PMID- 20919768 TI - Neurocognitive signs in prodromal Huntington disease. AB - OBJECTIVE: PREDICT-HD is a large-scale international study of people with the Huntington disease (HD) CAG-repeat expansion who are not yet diagnosed with HD. The objective of this study was to determine the stage in the HD prodrome at which cognitive differences from CAG-normal controls can be reliably detected. METHOD: For each of 738 HD CAG-expanded participants, we computed estimated years to clinical diagnosis and probability of diagnosis in 5 years based on age and CAG-repeat expansion number (Langbehn, Brinkman, Falush, Paulsen, & Hayden, 2004). We then stratified the sample into groups: NEAR, estimated to be <=9 years; MID, between 9 and 15 years; and FAR, >=15 years. The control sample included 168 CAG-normal participants. Nineteen cognitive tasks were used to assess attention, working memory, psychomotor functions, episodic memory, language, recognition of facial emotion, sensory-perceptual functions, and executive functions. RESULTS: Compared with the controls, the NEAR group showed significantly poorer performance on nearly all of the cognitive tests and the MID group on about half of the cognitive tests (p = .05, Cohen's d NEAR as large as 1.17, MID as large as -0.61). One test even revealed significantly poorer performance in the FAR group (Cohen's d = -0.26). Individual tasks accounted for 0.2% to 9.7% of the variance in estimated proximity to diagnosis. Overall, the cognitive battery accounted for 34% of the variance; in comparison, the Unified Huntington's Disease Rating Scale motor score accounted for 11.7%. CONCLUSIONS: Neurocognitive tests are robust clinical indicators of the disease process prior to reaching criteria for motor diagnosis of HD. PMID- 20919769 TI - Subjective cognitive complaints and longitudinal changes in memory and brain function. AB - OBJECTIVE: Subjective cognitive complaints are often used in the diagnosis of memory and other cognitive impairment. This study examined whether cognitive complaints are associated with longitudinal changes in cognition and cross sectional differences in regional brain function during memory performance in 98 participants with a mean age of 75. METHOD: The Cognitive Failures Questionnaire (CFQ) assessed cognitive complaints and mixed effects regression models were used to determine whether mean CFQ scores predicted rates of change in cognitive function over a period of 11.5 years. RESULTS: Higher CFQ scores, reflecting increased subjective complaints, were associated with steeper rates of decline in immediate and delayed recall on the California Verbal Learning Test. Voxel-based regression analysis was used to determine the cross-sectional relationship between CFQ scores and regional cerebral blood flow measured by PET during a resting condition and during verbal and figural memory tasks. Higher levels of cognitive complaints were associated with increased activity in insular, lingual and cerebellar areas during memory tasks. CONCLUSIONS: These findings offer some support for the validity of subjective cognitive complaints as markers of age related changes in memory and brain activity. PMID- 20919770 TI - Further validation of the MMPI-2 and MMPI-2-RF Response Bias Scale: findings from disability and criminal forensic settings. AB - The present study extends the validation of the Minnesota Multiphasic Personality Inventory-2 (MMPI-2) and the Minnesota Multiphasic Personality Inventory-2 Restructured Form (MMPI-2-RF) Response Bias Scale (RBS; R. O. Gervais, Y. S. Ben Porath, D. B. Wygant, & P. Green, 2007) in separate forensic samples composed of disability claimants and criminal defendants. Using cognitive symptom validity tests as response bias indicators, the RBS exhibited large effect sizes (Cohen's ds = 1.24 and 1.48) in detecting cognitive response bias in the disability and criminal forensic samples, respectively. The scale also added incremental prediction to the traditional MMPI-2 and the MMPI-2-RF overreporting validity scales in the disability sample and exhibited excellent specificity with acceptable sensitivity at cutoffs ranging from 90T to 120T. The results of this study indicate that the RBS can add uniquely to the existing MMPI-2 and MMPI-2-RF validity scales in detecting symptom exaggeration associated with cognitive response bias. PMID- 20919771 TI - The risk-taking and self-harm inventory for adolescents: development and psychometric evaluation. AB - In this study, we report on the development and psychometric evaluation of the Risk-Taking (RT) and Self-Harm (SH) Inventory for Adolescents (RTSHIA), a self report measure designed to assess adolescent RT and SH in community and clinical settings. 651 young people from secondary schools in England ranging in age from 11.6 years to 18.7 years and 71 young people referred to mental health services for SH behavior in London between the ages of 11.9 years and 17.5 years completed the RTSHIA along with standardized measures of adolescent psychopathology. Two factors emerged from the principal axis factoring, and RT and SH were further validated by a confirmatory factor analysis as related, but different, constructs, rather than elements of a single continuum. Inter-item and test retest reliabilities were high for both components (Cronbach's alpha = .85, ru = .90; Cronbach's alpha .93, ru = .87), and considerable evidence emerged in support of the measure's convergent, concurrent, and divergent validity. The findings are discussed with regard to potential usefulness of the RTSHIA for research and clinical purposes with adolescents. PMID- 20919772 TI - How leaders self-regulate their task performance: evidence that power promotes diligence, depletion, and disdain. AB - When leaders perform solitary tasks, do they self-regulate to maximize their effort, or do they reduce effort and conserve their resources? Our model suggests that power motivates self-regulation toward effective performance-unless the task is perceived as unworthy of leaders. Our 1st studies showed that power improves self-regulation and performance, even when resources for self-regulation are low (ego depletion). Additional studies showed that leaders sometimes disdain tasks they deem unworthy, by withholding effort (and therefore performing poorly). Ironically, during ego depletion, leaders skip the appraisal and, therefore, work hard regardless of task suitability, so that depleted leaders sometimes outperform nondepleted ones. Our final studies replicated these patterns with different tasks and even with simple manipulation of framing and perception of the same task (Experiment 5). Experiment 4 also showed that the continued high exertion of leaders when depleted takes a heavy toll, resulting in larger impairments later. The judicious expenditure of self-control resources among powerful people may help them prioritize their efforts to pursue their goals effectively. PMID- 20919773 TI - The effect of negative performance stereotypes on learning. AB - Stereotype threat (ST) research has focused exclusively on how negative group stereotypes reduce performance. The present work examines if pejorative stereotypes about women in math inhibit their ability to learn the mathematical rules and operations necessary to solve math problems. In Experiment 1, women experiencing ST had difficulty encoding math-related information into memory and, therefore, learned fewer mathematical rules and showed poorer math performance than did controls. In Experiment 2, women experiencing ST while learning modular arithmetic (MA) performed more poorly than did controls on easy MA problems; this effect was due to reduced learning of the mathematical operations underlying MA. In Experiment 3, ST reduced women's, but not men's, ability to learn abstract mathematical rules and to transfer these rules to a second, isomorphic task. This work provides the first evidence that negative stereotypes about women in math reduce their level of mathematical learning and demonstrates that reduced learning due to stereotype threat can lead to poorer performance in negatively stereotyped domains. PMID- 20919774 TI - Mere social categorization modulates identification of facial expressions of emotion. AB - The ability of the human face to communicate emotional states via facial expressions is well known, and past research has established the importance and universality of emotional facial expressions. However, recent evidence has revealed that facial expressions of emotion are most accurately recognized when the perceiver and expresser are from the same cultural ingroup. The current research builds on this literature and extends this work. Specifically, we find that mere social categorization, using a minimal-group paradigm, can create an ingroup emotion-identification advantage even when the culture of the target and perceiver is held constant. Follow-up experiments show that this effect is supported by differential motivation to process ingroup versus outgroup faces and that this motivational disparity leads to more configural processing of ingroup faces than of outgroup faces. Overall, the results point to distinct processing modes for ingroup and outgroup faces, resulting in differential identification accuracy for facial expressions of emotion. PMID- 20919776 TI - Motivated information processing, social tuning, and group creativity. AB - The extent to which groups are creative has wide implications for their overall performance, including the quality of their problem solutions, judgments, and decisions. To further understanding of group creativity, we integrate the motivated information processing in groups model (De Dreu, Nijstad, & Van Knippenberg, 2008) with work on epistemic social tuning (Lunn, Sinclair, Whitchurch, & Glenn, 2007). Three propositions were advanced: (a) Groups produce more ideas when members have high rather than low epistemic motivation, especially when members also have a prosocial rather than pro-self motivation; (b) these ideas are more original, appropriate, or feasible when a group norm favors originality, appropriateness, or feasibility; and (c) originality is valued more in individualistic cultures (e.g., the Netherlands), whereas appropriateness is valued more in collectivist cultures (e.g., Korea). Four studies involving 3-person groups generating ideas supported these propositions: Epistemic motivation (mild vs. intense time pressure; presence vs. absence of process accountability) stimulated production and originality, especially when prosocial rather than pro-self motives were present and participants were Dutch or originality norms were experimentally primed. When appropriateness norms were primed or participants were Korean, epistemic motivation stimulated production and appropriateness, especially when prosocial rather than pro-self motives were present. We discuss implications for research on group processes and for work on culture and creativity. PMID- 20919777 TI - A joke is just a joke (except when it isn't): cavalier humor beliefs facilitate the expression of group dominance motives. AB - Past research reveals preferences for disparaging humor directed toward disliked others. The group-dominance model of humor appreciation introduces the hypothesis that beyond initial outgroup attitudes, social dominance motives predict favorable reactions toward jokes targeting low-status outgroups through a subtle hierarchy-enhancing legitimizing myth: cavalier humor beliefs (CHB). CHB characterizes a lighthearted, less serious, uncritical, and nonchalant approach toward humor that dismisses potential harm to others. As expected, CHB incorporates both positive (affiliative) and negative (aggressive) humor functions that together mask biases, correlating positively with prejudices and prejudice-correlates (including social dominance orientation [SDO]; Study 1). Across 3 studies in Canada, SDO and CHB predicted favorable reactions toward jokes disparaging Mexicans (low-status outgroup). Neither individual difference predicted neutral (nonintergroup) joke reactions, despite the jokes being equally amusing and more inoffensive overall. In Study 2, joke content targeting Mexicans, Americans (high-status outgroup), and Canadians (high-status ingroup) was systematically controlled. Although Canadians preferred jokes labeled as anti American overall, an underlying subtle pattern emerged at the individual difference level: Only those higher in SDO appreciated those jokes labeled as anti-Mexican (reflecting social dominance motives). In all studies, SDO predicted favorable reactions toward low-status outgroup jokes almost entirely through heightened CHB, a subtle yet potent legitimatizing myth that "justifies" expressions of group dominance motives. In Study 3, a pretest-posttest design revealed the implications of this justification process: CHB contributes to trivializing outgroup jokes as inoffensive (harmless), subsequently contributing to postjoke prejudice. The implications for humor in intergroup contexts are considered. PMID- 20919778 TI - Generalization versus contextualization in automatic evaluation. AB - Research has shown that automatic evaluations can be highly robust and difficult to change, highly malleable and easy to change, and highly context dependent. We tested a representational account of these disparate findings, which specifies the conditions under which automatic evaluations reflect (a) initially acquired information, (b) subsequently acquired, counterattitudinal information, or (c) a mixture of both. The account postulates that attention to contextual cues during the encoding of evaluative information determines whether this information is stored in a context-free representation or a contextualized representation. To the extent that attention to context cues is low during the encoding of initial information but is enhanced by exposure to expectancy-violating counterattitudinal information, initial experiences are stored in context-free representations, whereas counterattitudinal experiences are stored in contextualized representations. Hence, automatic evaluations tend to reflect the valence of counterattitudinal information only in the context in which this information was learned (occasion setting) and the valence of initial experiences in any other context (renewal effect). Four experiments confirmed these predictions, additionally showing that (a) the impact of initial experiences was reduced for automatic evaluations in novel contexts when context salience during the encoding of initial information was enhanced, (b) context effects were eliminated altogether when context salience during the encoding of counterattitudinal information was reduced, and (c) enhanced context salience during the encoding of counterattitudinal information produced context-dependent automatic evaluations even when there was no contingency between valence and contextual cues. Implications for automatic evaluation, learning theory, and interventions in applied settings are discussed. PMID- 20919780 TI - Why additional presentations help identify a stimulus. AB - Nosofsky (1983) reported that additional stimulus presentations within a trial increase discriminability in absolute identification, suggesting that each presentation creates an independent stimulus representation, but it remains unclear whether exposure duration or the formation of independent representations improves discrimination in such conditions. Experiment 1 replicated Nosofsky's result. Experiments 2 (masking the ISI between two-presentations) and 3 (manipulating stimulus duration without changing number of presentations or overall trial duration) ruled out an explanation in terms of extended opportunities for stimulus sampling, from either a sensory buffer during additional ISIs or increased stimulus exposure, respectively. Experiment 4 (comparing two and three-presentations, other factors controlled) provided some limited additional support for Nosofsky's original claim that additional stimulus presentations can create either independent or duplicate representations. Experiments 5 and 6 (both manipulating ISI) demonstrated that a key factor in the additional stimulus presentation effect is the overall trial duration. We discuss the results in relation to models of absolute identification, their relative emphasis on stimulus sampling versus response selection, and the mechanisms by which duplicate representations could be created. PMID- 20919779 TI - Surprise-induced blindness: a stimulus-driven attentional limit to conscious perception. AB - The cost of attending to a visual event can be the failure to consciously detect other events. This processing limitation is well illustrated by the attentional blink paradigm, in which searching for and attending to a target presented in a rapid serial visual presentation stream of distractors can impair one's ability to detect a second target presented soon thereafter. The attentional blink critically depends on 'top-down' attentional settings, for it does not occur if participants are asked to ignore the first target. Here we show that 'bottom-up' attention can also lead to a profound but ephemeral deficit in conscious perception: Presentation of a novel, unexpected, and task-irrelevant stimulus virtually abolishes conscious detection of a target presented within half a second after the 'Surprise' stimulus, but only for its earliest occurrences (generally 1 to 2 presentations). This powerful but short-lived deficit contrasts with a milder but more enduring form of attentional capture that accompanies singleton presentations in rapid serial visual presentations. We conclude that the capture of stimulus-driven attention alone can limit explicit perception. PMID- 20919781 TI - The role of relational information in contingent capture. AB - On the contingent capture account, top-down attentional control settings restrict involuntary attentional capture to items that match the features of the search target. Attention capture is involuntary, but contingent on goals and intentions. The observation that only target-similar items can capture attention has usually been taken to show that the content of the attentional control settings consists of specific feature values. In contrast, the present study demonstrates that the top-down target template can include information about the relationship between the target and nontarget features (e.g., redder, darker, larger). Several spatial cuing experiments show that a singleton cue that is less similar to the target but that shares the same relational property that distinguishes targets from nontargets can capture attention to the same extent as cues that are similar to the target. Moreover, less similar cues can even capture attention more than cues that are identical to the target when they are relationally better than identical cues. The implications for current theories of attentional capture and attentional guidance are discussed. PMID- 20919782 TI - Assessing the concreteness of relational representation. AB - Research has shown that people's ability to transfer abstract relational knowledge across situations can be heavily influenced by the concrete objects that fill relational roles. This article provides evidence that the concreteness of the relations themselves also affects performance. In 3 experiments, participants viewed simple relational patterns of visual objects and then identified these same patterns under a variety of physical transformations. Results show that people have difficulty generalizing to novel concrete forms of abstract relations, even when objects are unchanged. This suggests that stimuli are initially represented as concrete relations by default. In the 2nd and 3rd experiments, the number of distinct concrete relations in the training set was increased to promote more abstract representation. Transfer improved for novel concrete relations but not for other transformations such as object substitution. Results indicate that instead of automatically learning abstract relations, people's relational representations preserve all properties that appear consistently in the learning environment, including concrete objects and concrete relations. PMID- 20919783 TI - Hierarchical control and skilled typing: evidence for word-level control over the execution of individual keystrokes. AB - Routine actions are commonly assumed to be controlled by hierarchically organized processes and representations. In the domain of typing theories, word-level information is assumed to activate the constituent keystrokes required to type each letter in a word. We tested this assumption directly using a novel single letter probe technique. Subjects were primed with a visual or auditory word or a visually presented random consonant string and then probed to type a single letter from the prime or another randomly selected letter. Relative to randomly selected letters, probe responses were speeded for first, middle, and last letters contained in visual and auditory word primes but not for middle and last letters contained in random consonant primes. This suggests that word-level information causes parallel activation of constituent keystrokes, consistent with hierarchical processing. The role of hierarchical processing in typing and routine action is discussed. PMID- 20919784 TI - Effects of iconicity and semantic relatedness on lexical access in american sign language. AB - Iconicity is a property that pervades the lexicon of many sign languages, including American Sign Language (ASL). Iconic signs exhibit a motivated, nonarbitrary mapping between the form of the sign and its meaning. We investigated whether iconicity enhances semantic priming effects for ASL and whether iconic signs are recognized more quickly than noniconic signs are (controlling for strength of iconicity, semantic relatedness, familiarity, and imageability). Twenty deaf signers made lexical decisions to the 2nd item of a prime-target pair. Iconic target signs were preceded by prime signs that were (a) iconic and semantically related, (b) noniconic and semantically related, or (c) semantically unrelated. In addition, a set of noniconic target signs was preceded by semantically unrelated primes. Significant facilitation was observed for target signs when they were preceded by semantically related primes. However, iconicity did not increase the priming effect (e.g., the target sign PIANO was primed equally by the iconic sign GUITAR and the noniconic sign MUSIC). In addition, iconic signs were not recognized faster or more accurately than were noniconic signs. These results confirm the existence of semantic priming for sign language and suggest that iconicity does not play a robust role in online lexical processing. PMID- 20919785 TI - Paradoxical effects of testing: retrieval enhances both accurate recall and suggestibility in eyewitnesses. AB - Although retrieval practice typically enhances memory retention, it can also impair subsequent eyewitness memory accuracy (Chan, Thomas, & Bulevich, 2009). Specifically, participants who had taken an initial test about a witnessed event were more likely than nontested participants to recall subsequently encountered misinformation-an effect we called retrieval-enhanced suggestibility (RES). Here, we sought to test the generality of RES and to further elucidate its underlying mechanisms. To that end, we tested a dual mechanism account, which suggests that RES occurs because initial testing (a) enhances learning of the later misinformation by reducing proactive interference and (b) causes the reactivated memory trace to be more susceptible to later interference (i.e., a reconsolidation account). Three major findings emerged. First, RES was found after a 1-week delay, where a robust testing benefit occurred for event details that were not contradicted by later misinformation. Second, blockage of reconsolidation was unnecessary for RES to occur. Third, initial testing enhanced learning of the misinformation even when proactive interference played a minimal role. PMID- 20919786 TI - The influence of consistency, frequency, and semantics on learning to read: an artificial orthography paradigm. AB - Two experiments explored learning, generalization, and the influence of semantics on orthographic processing in an artificial language. In Experiment 1, 16 adults learned to read 36 novel words written in novel characters. Posttraining, participants discriminated trained from untrained items and generalized to novel items, demonstrating extraction of individual character sounds. Frequency and consistency effects in learning and generalization showed that participants were sensitive to the statistics of their learning environment. In Experiment 2, 32 participants were preexposed to the sounds of all items (lexical phonology) and to novel definitions for half of these items (semantics). Preexposure to either lexical phonology or semantics boosted the early stages of orthographic learning relative to Experiment 1. By the end of training, facilitation was restricted to the semantic condition and to items containing low-frequency inconsistent vowels. Preexposure reduced generalization, suggesting that enhanced item-specific learning was achieved at the expense of character-sound abstraction. The authors' novel paradigm provides a new tool to explore orthographic learning. Although the present findings support the idea that semantic knowledge supports word reading processes, they also suggest that item-specific phonological knowledge is important in the early stages of learning to read. PMID- 20919787 TI - Can I trust you? Negative affective priming influences social judgments in schizophrenia. AB - Successful social interactions rely on the ability to make accurate judgments based on social cues as well as the ability to control the influence of internal or external affective information on those judgments. Prior research suggests that individuals with schizophrenia misinterpret social stimuli and this misinterpretation contributes to impaired social functioning. We tested the hypothesis that for people with schizophrenia, social judgments are abnormally influenced by affective information. Twenty-three patients with schizophrenia and 35 healthy control participants rated the trustworthiness of faces following the presentation of neutral, negative (threat-related), or positive affective primes. Results showed that all participants rated faces following negative affective primes as less trustworthy than faces following neutral or positive primes. Importantly, this effect was significantly more pronounced for participants with schizophrenia, suggesting that schizophrenia may be characterized by an exaggerated influence of negative affective information on social judgment. Furthermore, the extent that the negative affective prime influenced trustworthiness judgments was significantly associated with patients' severity of positive symptoms, particularly feelings of persecution. These findings suggest that for people with schizophrenia, negative affective information contributes to an interpretive bias, consistent with paranoid ideation, when judging the trustworthiness of others. This bias may contribute to social impairments in schizophrenia. PMID- 20919789 TI - Challenges associated with a polythetic diagnostic system: criteria combinations in the personality disorders. AB - Converging research on the diagnostic criteria for personality disorders (PDs) reveals that most criteria have different psychometric properties. This finding is inconsistent with the PD diagnostic system according to the Diagnostic and Statistical Manual of Mental Disorders (4th ed.; American Psychiatric Association, 1994), which weights each criterion equally. The purpose of the current study was to examine the potential effects of using equal weights for differentially functioning criteria. Data from over 2,100 outpatients were used to analyze and score response patterns to the diagnostic criteria for 9 PDs within an item response theory framework. Results indicated that combinations that included the same number of endorsed criteria yielded differing estimates of PD traits, depending on which criteria were met. Moreover, trait estimates from subthreshold criteria combinations often overlapped with diagnostic (at-threshold or higher) combinations, indicating that there were subthreshold combinations of criteria that indicated as much or more PD than did some combinations at the diagnostic threshold. These results suggest that counting the number of criteria an individual meets provides only a coarse estimation of his or her PD trait level. Implications for the assessment of polythetically defined mental disorders and for the PD proposal for the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders are discussed. PMID- 20919788 TI - Developmental trajectories of delinquency symptoms in childhood: the role of marital conflict and autonomic nervous system activity. AB - Trajectories of delinquency symptoms across middle and late childhood were examined through latent growth modeling, with a focus on the role of interactions among parental marital conflict, child sex, and multiple indices (baseline, reactivity) of either parasympathetic nervous system activity, indexed by respiratory sinus arrhythmia (RSA), or sympathetic nervous system activity, indexed by skin conductance level (SCL), as predictors of growth. At Time 1, 128 girls and 123 boys (mean age = 8.23 yrs +/- 0.73) and their parents participated. The sample comprised 64% European American and 36% African American children. Families participated in second and third waves of data collection with a 1-year lag between each wave. Interactions among marital conflict, sex, baseline RSA, and RSA reactivity from baseline to a frustrating lab task were significant predictors of growth in delinquent behavior from age 8 to age 10, with overall patterns indicating increasing symptoms for boys who lived in high-conflict homes and had an RSA response profile comprising lower RSA during the baseline and RSA augmentation (increase from baseline to the frustrating task). Furthermore, increases in delinquency symptoms over time were observed for children from high conflict homes and with an SCL profile characterized by higher baseline levels and lower reactivity (less pronounced SCL increases from baseline) to the frustrating task. Findings highlight the importance of contemporaneous assessments of resting and reactivity levels when examining relations among the environment, physiological functioning, and psychopathology. Results are discussed in the context of interactions between biology and environment as relevant to the development of psychopathology. PMID- 20919791 TI - Effects of organizational citizenship behaviors on selection decisions in employment interviews. AB - This article reports on an experiment examining the effects of job candidates' propensity to exhibit organizational citizenship behaviors (OCBs) on selection decisions made in the context of a job interview. We developed videos that manipulated candidate responses to interview questions tapping task performance and citizenship behavior content in 2 administrative positions. Results obtained from 480 undergraduates provided support for our hypotheses that job candidates who exhibited higher levels of helping, voice, and loyalty behaviors were generally rated as more competent, received higher overall evaluations, and received higher salary recommendations than job candidates who exhibited lower levels of these behaviors. These effects held even after taking into account candidate responses regarding task performance. We also found that candidate responses to OCB-related questions tended to have a greater effect on selection decisions for the higher level position (supervisor of administrative personnel) than for the lower level one (administrative assistant). Finally, content analyses of open-ended responses indicated that participants' selection decisions were particularly sensitive to candidates who exhibited low levels of voice and helping behaviors. Implications and future research are discussed. PMID- 20919790 TI - Mediators of aggression among young adult offspring of depressed mothers. AB - The current article explores the connection between maternal depression and offspring aggression during the transition to adulthood, expanding the scope of prior research on this topic. Both family-level factors (including parent-child relationship quality and maternal romantic relationship quality) and youth factors (including depression history and social functioning in midadolescence) were tested as potential mediators in a longitudinal community sample of 710 youth at ages 15 and 20. The results suggest that maternal depression confers a risk for higher levels of aggressive behavior by offspring at age 20. Structural equation models suggested that the association between maternal depression and youth aggression is fully mediated by youth history of depression by midadolescence, even when accounting for the stability of aggression between ages 15 and 20. Parent-child relationship quality, youth social functioning, and maternal relationship quality were not unique mediators of this association. Limitations and implications are discussed. PMID- 20919792 TI - The power of "we": effects of psychological collectivism on team performance over time. AB - We examined the influences of different facets of psychological collectivism (Preference, Reliance, Concern, Norm Acceptance, and Goal Priority) on team functioning at 3 different performance depictions: initial team performance, end state team performance, and team performance change over time. We also tested the extent to which team-member exchange moderated the relationships between facets of psychological collectivism and performance change over time. Results from multilevel growth modeling of 66 teams (N = 264) engaged in a business simulation revealed differential effects across facets of psychological collectivism and across different performance measurements. Whereas facets concerned with affiliation (Preference and Concern) were positively related to initial team performance, reliance was negatively related to initial team performance. Goal Priority was a strong predictor of end-state performance. Team-member exchange moderated the relationship between performance change and 3 of the 5 facets of psychological collectivism (Preference, Reliance, Norm Acceptance). Implications for team composition and team training are discussed. PMID- 20919793 TI - Unraveling the daily stress crossover between unemployed individuals and their employed spouses. AB - This study examined the dynamic relationship of distress levels between spouses when one is unemployed (and looking for a job) while the other is engaged in full time employment. Using the diary survey method, we sampled 100 couples in China for 10 days and tested a model comprising three stress crossover mechanisms: the direct crossover, the mediating crossover, and the common stressor mechanisms. Results supported the direct crossover and common stressor mechanisms. Other stressors (e.g., work-family conflict and negative job search experience) were also related to distress of the unemployed individuals and their employed spouses. Additionally, we found a three-way interaction involving gender, marital satisfaction, and distress levels of employed spouses. We discuss how the study contributes to the unemployment and stress crossover literatures. PMID- 20919794 TI - Reconsidering vocational interests for personnel selection: the validity of an interest-based selection test in relation to job knowledge, job performance, and continuance intentions. AB - Although vocational interests have a long history in vocational psychology, they have received extremely limited attention within the recent personnel selection literature. We reconsider some widely held beliefs concerning the (low) validity of interests for predicting criteria important to selection researchers, and we review theory and empirical evidence that challenge such beliefs. We then describe the development and validation of an interests-based selection measure. Results of a large validation study (N = 418) reveal that interests predicted a diverse set of criteria-including measures of job knowledge, job performance, and continuance intentions-with corrected, cross-validated Rs that ranged from .25 to .46 across the criteria (mean R = .31). Interests also provided incremental validity beyond measures of general cognitive aptitude and facets of the Big Five personality dimensions in relation to each criterion. Furthermore, with a couple exceptions, the interest scales were associated with small to medium subgroup differences, which in most cases favored women and racial minorities. Taken as a whole, these results appear to call into question the prevailing thought that vocational interests have limited usefulness for selection. PMID- 20919795 TI - Updating the trainability tests literature on Black-White subgroup differences and reconsidering criterion-related validity. AB - A number of applied psychologists have suggested that trainability test Black White ethnic group differences are low or relatively low (e.g., Siegel & Bergman, 1975), though data are scarce. Likewise, there are relatively few estimates of criterion-related validity for trainability tests predicting job performance (cf. Robertson & Downs, 1989). We review and clarify the existing (and limited) literature on Black-White group differences on trainability tests, provide new trainability test data from a recent video-based trainability exam, and present archival data about how trainability test scores relate to cognitive ability, Black-White differences, and job performance. Consistent with hypotheses, our results suggest large correlations of trainability tests with cognitive ability (e.g., .80) and larger standardized ethnic group differences than previously thought (ds of 0.86, 1.10, and 1.21 for 3 samples). Results also suggest that trainability tests have higher validity than previously thought. Overall, our analysis provides a substantial amount of data to update our understanding of the use of trainability tests in personnel selection. PMID- 20919797 TI - Maternal work early in the lives of children and its distal associations with achievement and behavior problems: a meta-analysis. AB - This meta-analysis of 69 studies (1,483 effect sizes) used random effects models to examine maternal employment during infancy/early childhood in relation to 2 major domains of child functioning: achievement and behavior problems. Analyses of studies that spanned 5 decades indicated that, with a few exceptions, early employment was not significantly associated with later achievement or internalizing/externalizing behaviors. The exceptions were for teacher ratings of achievement and internalizing behaviors: Employment was associated with higher achievement and fewer internalizing behaviors. Substantial heterogeneity among the effect sizes prompted examination of moderators. Sample-level moderator analyses pointed to the importance of socioeconomic and contextual variables, with early employment most beneficial when families were challenged by single parenthood or welfare status. Maternal employment during Years 2 and 3 was associated with higher achievement. Some moderator analyses indicated negative effects of employment for middle-class and 2-parent families and for very early employment (child's first year). Associations also differed depending on whether effect sizes were adjusted for contextual variables. Only 1 study-level moderator (sex of first author) was significant after adjusting for other moderators. The small effect size and primarily nonsignificant results for main effects of early maternal employment should allay concerns about mothers working when children are young. However, negative findings associated with employment during the child's first year are compatible with calls for more generous maternal leave policies. Results highlight the importance of social context for identifying under which conditions and for which subgroups early maternal employment is associated with positive or negative child outcomes. PMID- 20919798 TI - Prevention of malathion-induced depletion of cardiac cells mitochondrial energy and free radical damage by a magnetic magnesium-carrying nanoparticle. AB - The present work was designed to examine the effect of a new (25)Mg(2+)-carrying nanoparticle (PMC16) on energy and oxidative stress parameters inside the heart of the rats exposed to acute mild toxic dose of malathion, a widely used organophosphate. Post a single intraperitoneal (ip) injection of malathion (0.25 of LD50), PMC16 at different doses (0.05, 0.1, and 0.2 of LD50) was administered intravenously (iv) as a supplement to standard therapy of atropine and pralidoxime. MgSO(4) was used as another supplement for comparison with PMC16. Oxidative stress biomarkers including lipid peroxidation (LPO) and reactive oxygen species (ROS), antioxidant enzymes including superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT), ATP/ADP ratio, and Mg in the cardiac cells were determined. Results indicated a significant increase in LPO, ROS, ADP/ATP ratio, and a decrease in Mg post-malathion poisoning in comparison to controls. All of these parameters were improved by use of standard therapy either with MgSO4 or various doses of PMC16. The activities of SOD, CAT, and GPx did not change significantly in the present acute malathion poisoning model and neither MgSO(4) or PMC16 had no considerable improvement on these parameters. Comparing groups that received normal Mg and those of various doses of PMC16, a significant difference was found with the PMC16 (0.2 LD50) group. PMC16 0.2 reduced cardiac cells LPO and ROS of Mal-exposed animals rather than that of MgSO4. PMC16 0.2 was also significantly better than MgSO(4) in improving MAL induced changes in ADP/ATP ratio and also intracellular Mg levels. This study illustrates that malathion-induced cardiac cells toxicity is improved by administration of Mg as a result of increasing cardiac ATP through active transport of Mg inside the cells. Finally, the results of this study support positive effects of this magnetic Mg nanoparticle carrier but do not confirm its absolute efficacy that remains to be explored by further tests in different animal models and organs before moving to a phase I human trial. PMID- 20919799 TI - Partition coefficients for nonane and its isomers in the rat. AB - Jet Fuel 8 (JP-8) is a major fuel source used by US and NATO military. JP-8 is a complex mixture of aliphatic and aromatic isomers of hydrocarbons. Tissue/blood partition coefficient (PC) values are chemical-specific parameters used in modeling the kinetic behavior of chemicals. The partition coefficient values for n-alkanes tend to increase with the increasing carbon number, but less is known about the trend for isomers of n-alkanes. PC values were obtained for the n alkane nonane (C9) and five of its isomers, namely 3-methyloctane, 4 ethylheptane, 2,3-dimethylheptane, 2,2,4-trimethylhexane, 2,2,4,4 tetramethylpentane. The blood:air and tissue:air PC values correlated with the published log octanol/water (O:W) PC values for n-nonane and its isomers. Experimentally determined blood:air and tissue:air PC values for n-nonane with the largest O:W value were greatest and smallest for the isomer 2,2,4,4 tetramethylpentane with the lowest O:W value. As expected the fat tissue had the highest PC values and muscle the lowest for n-nonane and its isomers. For each tissue, a linear relationship was observed between the tissue/blood PC values for the isomers of n-nonane and n-nonane. This suggests that tissue/blood PC values for all isomers of an alkane could be estimated using data collected from only a sub-set of alkanes of equal carbon number. These reported tissue/blood PC values will support the development of a jet fuel physiologically-based pharmacokinetic (PBPK) model. PMID- 20919800 TI - Targeting B cells with biologics in systemic lupus erythematosus. AB - IMPORTANCE OF THE FIELD: The use of biologics as immune modulators in several autoimmune diseases has provided new tools to the physician's therapeutic armamentiarium and has led to improved patients' outcomes and quality of life. By producing autoantibodies, B cells in systemic lupus erythematosus (SLE) are key players in the pathogenesis of the disease and in its clinical manifestations. Therefore, biologics that target B cells in SLE aim at reducing the activity of these cells for the induction of remissions and/or amelioration of disease activity, reduction of organ involvement, and limitation of the complications and side effects caused by immunosuppressive therapies. AREAS COVERED IN THIS REVIEW: This review describes the past and current clinical trials with B-cell-targeted biologics in SLE, to provide a historical perspective and the state-of-the-art on the topic. WHAT THE READER WILL GAIN: We review how the disappointment in the field from promising agents has been instrumental in providing valuable lessons leading to an improved design of new trials that are now giving encouraging results. TAKE HOME MESSAGE: In systemic lupus erythematosus (SLE), the use of B cell-based biologics in clinical trials has shown both disappointment and promise. PMID- 20919801 TI - Comparison of extracellular striatal acetylcholine and brain seizure activity following acute exposure to the nerve agents cyclosarin and tabun in freely moving guinea pigs. AB - Organophosphorus nerve agents like cyclosarin and tabun are potent cholinesterase inhibitors. The inhibition of acetylcholinesterase, which is responsible for breaking down acetylcholine (ACh) at the synapse and neuromuscular junction, leads to a build-up of extracellular ACh and a series of toxic consequences including hypersecretion, tremor, convulsion/seizure, respiratory distress, coma, and death. This study employed simultaneous and continuous electroencephalographic recording and striatal microdialysis collection for quantification of ACh changes (via subsequent HPLC analysis) during acute exposure to a 1.0 * LD(50) subcutaneous dose of either cyclosarin or tabun to investigate differences in cholinergic and behavioral effects. Information about the unique mechanisms and consequences of different nerve agents is intended to aid in the development of broad-spectrum medical countermeasures for nerve agents. At the dose administered, non-seizure and sustained seizure responses were observed in both agent groups and in the tabun-exposed group some subjects experienced an unsustained seizure response. Significant extracellular ACh increases were only observed in seizure groups. Cyclosarin and tabun were found to exhibit some unique cholinergic and ictogenic characteristics. Lethality only occurred in subjects experiencing sustained seizure, and there was no difference in lethality between agent groups that progressed to sustained seizure. PMID- 20919802 TI - Comment and reply on: Atorvastatin: safety and tolerability. Statins and polymyositis: a neglected link? PMID- 20919804 TI - Comparative study of a barbed suture, poliglecaprone and stapler in Pfannenstiel incisions performed for benign gynecological procedures: a randomized trial. AB - OBJECTIVE: To compare a novel barbed suture, poliglecaprone-25 suture and stapler in Pfannenstiel incisions performed for benign gynecological procedures. DESIGN: A randomized controlled non-inferiority trial with randomization in a 1:1:1 ratio. SETTING: Istanbul Dr. Lutfi Kirdar Kartal Research and Training Hospital, Department of Obstetrics and Gynecology. POPULATION: Patients between 18 and 45 years of age without prior lower abdominal incision and undergoing Pfannenstiel incisions for benign gynecological procedures. METHODS: A total of 117 female patients randomized into barbed (n = 39), poliglecaprone-25 (n = 39) and stapler (n = 39) groups according to suture type. Skin closure techniques were compared in terms of length of incision (cm), adverse events (wound dehiscence, incisional infection, seroma and hematoma), subjective pain scores, patient satisfaction and postoperative scar cosmesis. MAIN OUTCOME MEASURES. The difference between three suture materials in terms of postoperative incision pain, patient satisfaction and scar cosmesis. RESULTS: Skin closure techniques were similar in terms of length of incision (cm), adverse events and pain scores and Modified Hollander Cosmesis Score. Barbed (p < 0.001) and poliglecaprone-25 (p < 0.01) sutures were significantly better than staplers in terms of patient satisfaction. CONCLUSION: The three different methods of skin closure revealed comparable outcome except for a significant superiority of sutures to the stapler method in terms of patient satisfaction scores. PMID- 20919803 TI - Production latencies of morphologically simple and complex verbs in aphasia. AB - There are several accounts of why some individuals with post-stroke aphasia experience difficulty in producing morphologically complex verbs. Although a majority of these individuals also produce syntactically flawed utterances, at least two accounts focus on word-level encoding operations. One account proposes a difficulty with rule-governed affixation, predicting that verbs without affixes (stems and irregular past) should be produced with ease. The second account emphasises the contribution of phonological encoding, noting that morphological complexity is often confounded by phonological complexity. The present study investigated the effect of morphological complexity (presence vs. absence of affixes) on verb production when phonological complexity and lexical frequency was controlled. A novel delayed repetition paradigm was used, accuracy and latency of production were the dependent measures. Data from nine agrammatic aphasic and nine unimpaired participants revealed no effects of morphological complexity, but a significant effect of frequency on production latency. The results indicate that morphological complexity plays little role, if any, in production difficulty, at least for this experimental task and this group of non apraxic agrammatic aphasic individuals. A difficulty in usage of contextually appropriate verb inflections, rather than in morphophonological encoding, is suggested. PMID- 20919805 TI - Patterns of stuttering in a Spanish/English bilingual: A case report. AB - Stuttering patterns may differ when comparing two languages. In bilinguals, specific patterns of stuttering in each one of the languages may potentially be found. This study reports on the case of a 27-year-old Spanish/English simultaneous bilingual whose dominant language is English. Speech and language testing was performed in both languages (language repetition, language understanding, vocabulary, reading, verbal fluency, spontaneous speech and conversational speech). Some differences in the stuttering distribution were found: stuttering in adjectives, adverbs and conjunctions occurred at least twice as much in Spanish as in English; stuttering was also more frequent in verbs in Spanish. Some hypotheses are presented to explain the differences in stuttering severity in both languages. It seems that when comparing stuttering in two different languages in the same subject, it is possible to find similarities in the stuttering pattern, suggesting general stuttering laws; but also differences, associated not only with language-specific idiosyncrasies but also with the individual's bilingualism characteristics. PMID- 20919807 TI - Prevalence of overweight and obesity among Portuguese youth: a study in a representative sample of 10-18-year-old children and adolescents. AB - PURPOSE: The aim of this research was to report the prevalence of overweight and obesity in a representative sample of Portuguese youth. METHODS: This was a school-based study performed in Portugal. A total of 22 048 children and adolescents aged 10-18 years were included in the study. The World Health Organization (WHO) and the International Obesity Task Force (IOTF) cut-offs were used to categorise overweight and obese participants. RESULTS: Using IOTF cut offs the prevalence of overweight and obesity was 17.0 and 4.6% in girls, and 17.7 and 5.8% in boys, respectively (p < 0.001 for overweight and p > 0.05 for obesity), whereas WHO cut-offs resulted in overweight and obesity prevalence scores of 23.1 and 9.6% in girls, and 20.4 and 10.3% in boys, respectively (p < 0.001 for overweight and p >0.05 for obesity). With IOTF cut-offs, a lower prevalence of obesity and overweight was observed at higher ages, in both genders. With the WHO cut-offs, a lower prevalence of obesity and overweight was observed at higher ages, in boys. In girls, the prevalence of overweight and obesity increases from 10 to 12 years of age and decreases from the age of 13 to 18 years. CONCLUSION: The prevalence for overweight/obesity among Portuguese children and adolescents vary according to the cut-off points used and are also of concern requiring strategies to promote healthy weight gain among children and adolescents. PMID- 20919806 TI - Obesity is associated with impaired cardiac autonomic modulation in children. AB - OBJECTIVE: To examine the cross-sectional association between measurements of obesity and subclinical impairment of cardiac autonomic modulation (CAM) in a population-based sample of children. METHODS: Data from 616 grade K-5 children randomly selected from Central Pennsylvania were utilized. Obesity was defined using the International Obesity Task Force (IOTF) age- and sex-specific cut-off criteria and classified as normal weight, overweight, and obese. CAM was measured by heart rate variability (HRV) analysis of beat-to-beat RR intervals, including time domain measures i.e., the standard deviation of all RR intervals (SDNN), the square root of the mean of the sum of squares of differences between adjacent RR intervals (RMSSD), and mean heart rate (HR); and frequency domain measures i.e., high frequency power (HF), low frequency power (LF), and LF/HF ratio. RESULTS: The prevalence of obesity and overweight in children was 12.3%, and 16.5%, respectively. Age, race, sex, and sleep disorder breathing (SDB) adjusted means (standard error, SE) of SDNN were 98 (1.24), 90.2 (2.58), and 81.9 (3.03) milliseconds (ms) in normal weight, overweight, and obese groups, respectively; and that for (log) HF were 6.83 (0.04), 6.56 (0.08), and 6.35 (0.09) ms(2), respectively. Comparing the magnitude of effects from body mass index (BMI), weight, and height percentiles, and waist circumference on HRV indices revealed that body weight was the strongest correlate of HRV indices. CONCLUSION: Childhood obesity is significantly associated with lower HRV, indicative of sympathetic overflow unopposed by parasympathetic modulation. These findings support the need to target childhood-obesity before traditional "high risk age" for cardiac events. PMID- 20919808 TI - Intraarticular location predicts cartilage filling and subchondral bone changes in a chondral defect. AB - BACKGROUND AND PURPOSE: The natural history of, and predictive factors for outcome of cartilage restoration in chondral defects are poorly understood. We investigated the natural history of cartilage filling subchondral bone changes, comparing defects at two locations in the rabbit knee. ANIMALS AND METHODS: In New Zealand rabbits aged 22 weeks, a 4-mm pure chondral defect (ICRS grade 3b) was created in the patella of one knee and in the medial femoral condyle of the other. A stereo microscope was used to optimize the preparation of the defects. The animals were killed 12, 24, and 36 weeks after surgery. Defect filling and the density of subchondral mineralized tissue was estimated using Analysis Pro software on micrographed histological sections. RESULTS: The mean filling of the patellar defects was more than twice that of the medial femoral condylar defects at 24 and 36 weeks of follow-up. There was a statistically significant increase in filling from 24 to 36 weeks after surgery at both locations. The density of subchondral mineralized tissue beneath the defects subsided with time in the patellas, in contrast to the density in the medial femoral condyles, which remained unchanged. INTERPRETATION: The intraarticular location is a predictive factor for spontaneous filling and subchondral bone changes of chondral defects corresponding to ICRS grade 3b. Disregarding location, the spontaneous filling increased with long-term follow-up. This should be considered when evaluating aspects of cartilage restoration. PMID- 20919809 TI - Competing risks survival analysis applied to data from the Australian Orthopaedic Association National Joint Replacement Registry. AB - BACKGROUND AND PURPOSE: The Kaplan-Meier (KM) method is often used in the analysis of arthroplasty registry data to estimate the probability of revision after a primary procedure. In the presence of a competing risk such as death, KM is known to overestimate the probability of revision. We investigated the degree to which the risk of revision is overestimated in registry data. PATIENTS AND METHODS: We compared KM estimates of risk of revision with the cumulative incidence function (CIF), which takes account of death as a competing risk. We considered revision by (1) prosthesis type in subjects aged 75-84 years with fractured neck of femur (FNOF), (2) cement use in monoblock prostheses for FNOF, and (3) age group in patients undergoing total hip arthroplasty (THA) for osteoarthritis (OA). RESULTS: In 5,802 subjects aged 75-84 years with a monoblock prosthesis for FNOF, the estimated risk of revision at 5 years was 6.3% by KM and 4.3% by CIF, a relative difference (RD) of 46%. In 9,821 subjects of all ages receiving an Austin Moore (non-cemented) prosthesis for FNOF, the RD at 5 years was 52% and for 3,116 subjects with a Thompson (cemented) prosthesis, the RD was 79%. In 44,365 subjects with a THA for OA who were less than 70 years old, the RD was just 1.4%; for 47,430 subjects > 70 years of age, the RD was 4.6% at 5 years. INTERPRETATION: The Kaplan-Meier method substantially overestimated the risk of revision compared to estimates using competing risk methods when the risk of death was high. The bias increased with time as the incidence of the competing risk of death increased. Registries should adopt methods of analysis appropriate to the nature of their data. PMID- 20919810 TI - Alteration of the material properties of the normal supraspinatus tendon by nicotine treatment in a rat model. AB - BACKGROUND AND PURPOSE: Several studies have shown that nicotine has a detrimental effect on the development of rotator cuff tear. However, little is known about its mechanism. We evaluated the effect of nicotine on the maximum tensile load, the maximum tensile stress, and the elastic modulus of the supraspinatus tendon in a rat model. METHODS: 27 rats were randomly assigned to 3 groups. Subcutaneously implanted osmotic pumps delivered two different concentrations of nicotine solution (high dose: 45 ng/mL; low dose: 22.5 ng/mL) or saline solution (controls) over a 12-week period. The level of serum cotinine, a breakdown product of nicotine, was evaluated. We performed tensile testing using the left supraspinatus tendon in each rat. The maximum load of the supraspinatus tendon was measured, and the maximum tensile stress and elastic modulus were calculated. RESULTS: Serum cotinine levels showed controlled systemic release of nicotine. The maximum tensile load and stress were similar in the three groups. The elastic modulus was, however, higher in the nicotine groups than in the control group. INTERPRETATION: In a rat model, nicotine caused a change in the material properties of the supraspinatus tendon. This change may predispose to a tear in the supraspinatus tendon. PMID- 20919811 TI - Stem torsion in total hip replacement. AB - BACKGROUND AND PURPOSE: The clinical results of THR may be improved by correct femoral torsion. We evaluated the stem position by postoperative CT examination in 60 patients. METHODS: 60 patients requiring total hip arthroplasty were prospectively enrolled in this study. Minimally invasive THR was performed (anterior approach) in a lateral decubitus position and each patient underwent a postoperative CT examination. The position of the stem was evaluated by an independent external institution. RESULTS: Stem torsion ranged from - 19 degrees retrotorsion to 33 degrees antetorsion. Normal antetorsion (i.e 10-15 degrees according to Tonnis) was present in 5 of 60 patients, so the prevalence of abnormal stem antetorsion was 92% (95% CI: 82-97). We found a stem antetorsion outside the range of 0-25 degrees in 21 of 60 hips. Women had a higher mean stem antetorsion (8.0 degrees (SD 11)) than men (1.5 degrees (SD 10)). INTERPRETATION: Postoperative stem antetorsion shows a high variability and is gender-related. We suggest precise assessment of stem antetorsion intraoperatively by means of computer navigation, preparing the femur first. In abnormal stem antetorsion, the cup position can be adjusted using a combined anteversion concept; alternatively, modular femoral components or stems with retroverted or anteverted necks ("retrostem") could be used. PMID- 20919812 TI - Inferior outcome after hip resurfacing arthroplasty than after conventional arthroplasty. Evidence from the Nordic Arthroplasty Register Association (NARA) database, 1995 to 2007. AB - BACKGROUND AND PURPOSE: The reported outcomes of hip resurfacing arthroplasty (HRA) vary. The frequency of this procedure in Denmark, Norway, and Sweden is low. We therefore determined the outcome of HRA in the NARA database, which is common to all 3 countries, and compared it to the outcome of conventional total hip arthroplasty (THA). METHODS: The risk of non-septic revision within 2 years was analyzed in 1,638 HRAs and compared to that for 172,554 conventional total hip arthroplasties (THAs), using Cox regression models. We calculated relative risk (RR) of revision and 95% confidence interval. RESULTS: HRA had an almost 3 fold increased revision risk compared to THA (RR = 2.7, 95% CI:1.9-3.7). The difference was even greater when HRA was compared to the THA subgroup of cemented THAs (RR = 3.8, CI: 2.7-5.3). For men below 50 years of age, this difference was less pronounced (HRA vs. THA: RR = 1.9, CI: 1.0-3.9; HRA vs. cemented THA: RR = 2.4, CI: 1.1-5.3), but it was even more pronounced in women of the same age group (HRA vs. THA: RR = 4.7, CI: 2.6-8.5; HRA vs. cemented THA: RR = 7.4, CI: 3.7-15). Within the HRA group, risk of non-septic revision was reduced in hospitals performing >= 70 HRAs annually (RR = 0.3, CI: 0.1-0.7) and with use of Birmingham hip resurfacing (BHR) rather than the other designs as a group (RR = 0.3, CI: 0.1 0.7). Risk of early revision was also reduced in males (RR = 0.5, CI: 0.2-0.9). The femoral head diameter alone had no statistically significant influence on the early revision rate, but it eliminated the significance of male sex in a combined analysis. INTERPRETATION: In general, our results do not support continued use of hip resurfacing arthroplasty. Men had a lower early revision rate, which was still higher than observed for all-cemented hips. Further follow-up is necessary to determine whether HRA might be useful as an alternative in males. PMID- 20919813 TI - The role of mucosal flaps in external dacryocystorhinostomy. AB - PURPOSE: To determine whether a mucosal anastomosis fashioned at the time of external dacryocystorhinostomy (DCR) influences postoperative outcome. METHODS: The clinical records of all patients who underwent external DCR at Sydney Eye Hospital between May 2000 and August 2007 were reviewed. Data were collected in regards to surgical technique, clinical outcomes and postoperative management. Chi-square statistical analysis was done to determine the significance of the different flap techniques on surgical success. RESULTS: A total of 260 medical records were reviewed. The main outcome measure was postoperative resolution of symptoms. The mean final follow-up time was 11 months. There was no statistically significant difference in outcome between patients who had both anterior and posterior flaps sutured, compared to those who had anterior flap sutures only (73% vs 79%, p = 0.51). Patients who had no sutured flaps had an overall success rate of 89% compared to those that had at least the anterior flaps sutured together (76%); this difference was not significant (p = 0.45). CONCLUSION: There was no statistical difference in symptom outcome between patients in whom both mucosal flaps were sutured, those who had only the anterior flap sutured, or those who did not have either flap sutured at the time of surgery. PMID- 20919814 TI - Graves' orbitopathy and oxidative stress. PMID- 20919815 TI - Low risk of thromboembolic complications after fast-track hip and knee arthroplasty. AB - BACKGROUND AND PURPOSE: Pharmacological prophylaxis can reduce the risk of deep venous thrombosis (DVT), pulmonary embolism (PE), and death, and it is recommended 10-35 days after total hip arthroplasty (THA) and at least 10 days after total knee arthroplasty (TKA). However, early mobilization might also reduce the risk of DVT and thereby the need for prolonged prophylaxis, but this has not been considered in the previous literature. Here we report our results with short-duration pharmacological prophylaxis combined with early mobilization and reduced hospitalization. PATIENTS AND METHODS: 1,977 consecutive, unselected patients were operated with primary THA, TKA, or bilateral simultaneous TKA (BSTKA) in a well-described standardized fast-track set-up from 2004-2008. Patients received DVT prophylaxis with low-molecular-weight heparin starting 6-8 h after surgery until discharge. All re-admissions and deaths within 30 and 90 days were analyzed using the national health register, concentrating especially on clinical DVT (confirmed by ultrasound and elevated D-dimer), PE, or sudden death. Numbers were correlated to days of prophylaxis (LOS). RESULTS: The mean LOS decreased from 7.3 days in 2004 to 3.1 days in 2008. 3 deaths (0.15%) were associated with clotting episodes and overall, 11 clinical DVTs (0.56%) and 6 PEs (0.30%) were found. The vast majority of events took place within 30 days; only 1 death and 2 DVTs occurred between 30 and 90 days. During the last 2 years (854 patients), when patients were mobilized within 4 h postoperatively and the duration of DVT prophylaxis was shortest (1-4 days), the mortality was 0% (95% CI: 0-0.5). Incident cases of DVT in TKA was 0.60% (CI: 0.2-2.2), in THA it was 0.51% (CI: 0.1-1.8), and in BSTKA it was 0% (CI: 0-2.9). Incident cases of PE in TKA was 0.30% (CI: 0.1-1.7), in THA it was 0% (CI: 0-1.0), and in BSTKA it was 0% (CI: 0-2.9). INTERPRETATION: The risk of clinical DVT, and of fatal and non-fatal PE after THA and TKA following a fast-track set-up with early mobilization, short hospitalization, and short duration of DVT prophylaxis compares favorably with published regimens with extended prophylaxis (up to 36 days) and hospitalization up to 11 days. This calls for a reconsideration of optimal duration of chemical thromboprophylaxis. PMID- 20919816 TI - Incidence of low-grade infection in aseptic loosening of total hip arthroplasty. AB - PURPOSE: We investigated the hypothesis that many total hip arthroplasty revisions that are classified as aseptic are in fact low-grade infections missed with routine diagnostics. METHODS: In 7 Dutch hospitals, 176 consecutive patients with the preoperative diagnosis of aseptic loosening of their total hip arthroplasty were enrolled. During surgery, between 14 and 20 tissue samples were obtained for culture, pathology, and broad-range 16S rRNA PCR with reverse line blot hybridization. Patients were classified as either not being infected, suspected of having infection, or infected according to strict, predefined criteria. Each patient had a follow-up visit after 1 year. RESULTS: 7 patients were classified as infected, 4 of whom were not identified by routine culture. 15 additional patients were suspected of having infection. 20 of these 22 patients received a cemented prosthesis, fixated with antibiotic-loaded bone cement. All 22 patients received prophylactic systemic antibiotics. 7 of them reported complaints one year after surgery, but only one showed signs of early loosening. However, additional surgery was not performed in any of the patients. INTERPRETATION: Although the proportions were not as high as previously reported in the literature, between 4% and 13% of patients with the preoperative diagnosis of aseptic loosening were infected. However, as thorough debridement was performed during surgery and prophylactic antibiotics were used, the diagnosis of infection did not have any obvious clinical consequences, as most patients performed well at the 1-year follow-up. Whether this observation has implications for long-term implant survival remains to be seen. PMID- 20919817 TI - Aerobic granular sludge: characterization, mechanism of granulation and application to wastewater treatment. AB - Aerobic granular sludge can be classified as a type of self-immobilized microbial consortium, consisting mainly of aerobic and facultative bacteria and is distinct from anaerobic granular methanogenic sludge. Aerobic granular technology has been proposed as a promising technology for wastewater treatment, but is not yet established as a large-scale application. Aerobic granules have been cultured mainly in sequenced batch reactors (SBR) under hydraulic selection pressure. The factors influencing aerobic granulation, granulation mechanisms, microbial communities and the potential applications for the treatment of various wastewaters have been studied comprehensively on the laboratory-scale. Aerobic granular sludge has shown a potential for nitrogen removal, but is less competitive for the high strength organic wastewater treatments. This technology has been developed from the laboratory-scale to pilot scale applications, but with limited and unpublished full-scale applications for municipal wastewater treatment. The future needs and limitations for aerobic granular technology are discussed. PMID- 20919818 TI - Superoxide dismutase: an industrial perspective. AB - The application of enzyme technologies to industrial research, development, and manufacturing has become a very important field. Since the production of crude rennet in 1874, several enzymes have been commercialized, and used for therapeutic, supplementary, and other applications. Recent advancements in biotechnology now allow companies to produce safer and less expensive enzymes with enhanced potency and specificity. Antioxidant enzymes are emerging as a new addition to the pool of industrial enzymes and are surpassing all other enzymes in terms of the volume of research and production. In the 1990s, an antioxidant enzyme--superoxide dismutase (SOD)--was introduced into the market. Although the enzyme initially showed great promise in therapeutic applications, it did not perform up to expectations. Consequently, its use was limited to non-drug applications in humans and drug applications in animals. This review summarizes the rise and fall of SOD at the industrial level, the reasons for this, and potential future thrust areas that need to be addressed. The review also focuses on other industrially relevant aspects of SOD such as industrial importance, enzyme engineering, production processes, and process optimization and scale-up. PMID- 20919819 TI - CBF-dependent signaling pathway: a key responder to low temperature stress in plants. AB - Plants under low temperature (LT) stress exhibit a C-repeat binding factor (CBF) dependent responsive pathway. The transcription factors in the CBF family, existing in multiple plant species, are the key regulators of the cold-responsive (COR) genes. CBF1 and CBF3 are regulated in a different way from CBF2, and CBF4 is the only known CBF gene definitely involved in abscisic acid (ABA)-dependent signaling pathways. RAP2.1 and RAP2.6 are the downstream regulators under CBFs. The upstream regulators of the CBF named inducer of CBF expression (ICE) acts as a positive regulator of CBFs. Meanwhile, these CBF signaling pathway components could associate with many other transcription activators and repressors in regulating gene expression when plants are under LT stress. HOS1 negatively regulates ICE1, which down regulates MYB15, an upstream repressor of CBFs. ZAT12 participates in the repression of CBFs, while ZAT10 and FRY2 negatively regulate the CBF-target genes. ADF5 was recently also found to repress CBFs. LOS2 works against ZAT10, and LOS4 positively regulates CBFs. SFR6 is involved in the modification of CBFs to activate the COR genes, and SIZ1-dependent sumoylation plays a positive role in the regulation of ICE1. The utilization of CBF-dependent signaling components has a broad perspective in the field of plant breeding for enhancing crop LT tolerance. PMID- 20919820 TI - Long-term cardiovascular risk following platinum-based chemotherapy for germ cell tumors. PMID- 20919821 TI - How estrogen fuels breast cancer. PMID- 20919822 TI - First results of largest study of genomes and cancer treatments available. PMID- 20919823 TI - Sunitinib for metastatic renal cell carcinoma. AB - Sunitinib is an orally available, multitargeted tyrosine kinase inhibitor licensed for the treatment of metastatic renal cell carcinoma. This article is an in-depth review of the mechanism of action of sunitinib, rationale for dose and schedule, toxicity and clinical efficacy. Other targeted therapies and treatment combinations for renal cell carcinoma are discussed. The use of sunitinib for other indications, biomarkers of response and future directions are explored. PMID- 20919824 TI - The trifunctional antibody catumaxomab in treatment of malignant ascites and peritoneal carcinomatosis. AB - Peritoneal carcinomatosis remains an unsolved medical problem in modern oncologic treatment. Excruciating symptoms such as malignant ascites, ileus, nausea, vomiting, dyspnoea and pain deteriorate the quality of life for affected patients. There is still no effective standard treatment for peritoneal carcinomatosis. The trifunctional antibody catumaxomab (antiepithelial cell adhesion molecule x anti-CD3) is able to direct T lymphocytes and Fcg-receptor positive accessory cells to epithelial cell adhesion molecule-positive tumor cells. Intraperitoneal catumaxomab therapy was shown to be the first effective therapy against accumulation of malignant ascites in patients with peritoneal carcinomatosis of epithelial cancer, reducing the need of paracentesis and prolonging puncture-free survival. This paper reviews the mode of action of catumaxomab and analyzes different fields of local immunotherapy in patients with peritoneal carcinomatosis. A summary of completed and ongoing studies is included. Catumaxomab is discussed to be an outstanding option for local control and therapy of peritoneal carcinomatosis, which could be an optimal modular therapy in addition to systemic chemotherapy and surgical tumor resection. PMID- 20919825 TI - Metabolomics and detection of colorectal cancer in humans: a systematic review. AB - Metabolomics represents one of the new omics sciences and capitalizes on the unique presence and concentration of small molecules in tissues and body fluids to construct a 'fingerprint' that can be unique to the individual and, within that individual, unique to environmental influences, including health and disease states. As such, metabolomics has the potential to serve an important role in diagnosis and management of human conditions. Colorectal cancer is a major public health concern. Current population-based screening methods are suboptimal and whether metabolomics could represent a new tool of screening is under investigation. The purpose of this systematic review is to summarize existing literature on metabolomics and colorectal cancer, in terms of diagnostic accuracies and distinguishing metabolites. Eight studies are included. A total of 12 metabolites (taurine, lactate, choline, inositol, glycine, phosphocholine, proline, phenylalanine, alanine, threonine, valine and leucine) were found to be more prevalent in colorectal cancer and glucose was found to be in higher proportion in control specimens using tissue metabolomics. Serum and urine metabolomics identified several other differential metabolites between controls and colorectal cancer patients. This article highlights the novelty of the field of metabolomics in colorectal oncology. PMID- 20919827 TI - DNA methylation profiling in acute myeloid leukemia: from recent technological advances to biological and clinical insights. AB - Acute myeloid leukemia represents a heterogeneous malignant hematological disease with a complex underlying biology suggesting multiple patterns of genetic and epigenetic alterations. Recent evidence suggests that epigenetic mechanisms, especially deregulation of DNA methylation, play an important pathogenic role in leukemogenesis and the first epigenetic drugs have entered the clinic. Therefore, an improved understanding of the impact of altered epigenetic patterns on leukemogenesis represents a pre-requisite for improved patient management and outcome. Here, we provide an overview of current advances in deciphering the leukemic epigenome and its clinical relevance. Recent high-throughput analyses and genome-wide studies provide an optimal starting point for future epigenetic and integrative analyses that will further the development and use of predictive and prognostic epigenetic markers in acute myeloid leukemia. PMID- 20919826 TI - Should biomarkers be used to design personalized medicine for the treatment of glioblastoma? AB - Significant progress has been made in understanding the molecular pathogenesis of gliomas and in predicting general outcome depending on a limited set of clinical parameters and molecular markers. However, methylation of the O6-methylguanine DNA methyltransferase (MGMT) gene promoter is the only molecular marker linked to sensitivity of a specific treatment, that is, alkylating agent chemotherapy, and this predictive value may be limited to glioblastoma. Moreover, in the absence of potent alternative drugs, temozolomide chemotherapy should not be withheld from patients with newly diagnosed glioblastoma without MGMT promoter methylation in general practice. In the context of clinical trials, however, irrespective of whether classical cytotoxic drugs, tyrosine kinase inhibitors or antiangiogenic agents are used, tissue should be centrally collected. Appropriate research programs should seek to define enriched patient populations for future trials and ultimately facilitate individualized cancer treatments. PMID- 20919828 TI - Germline genetic markers for urinary bladder cancer risk, prognosis and treatment response. AB - After decades of research using a candidate gene approach, only NAT2 and GSTM1 have consistently been demonstrated to be germline genetic susceptibility markers for urinary bladder cancer (UBC). The recent shift to an agnostic genome-wide association approach led to the identification of several UBC susceptibility loci, and provided valuable leads for new mechanistic insights into UBC carcinogenesis. The markers do not have sufficient discriminatory ability yet to be applied for risk assessment in the population and the question is whether they ever will. Prognostic and predictive studies in UBC are still in their infancy compared with etiologic studies. In the future, focus on a genome-wide association approach possibly using whole-genome sequence data, consortia formation and meta-analyses, and blood and tumor tissue collection, preferably in the context of randomized controlled trials will stimulate well designed and sufficiently powered studies, and thereby enhance the elucidation of genetic prognostic and predictive markers. PMID- 20919830 TI - The potential of immunomodulatory drugs in the treatment of solid tumors. AB - Lenalidomide (REVLIMID(r)) CC-5013 (Celgene, NJ, USA) is approved, in both the USA and Europe, in combination with dexamethasone for the treatment of multiple myeloma patients who have received at least one prior therapy, and is rapidly being accepted worldwide for this condition. Lenalidomide is also approved in the USA and Canada for use in transfusion-dependent anemia in patients with low- and intermediate-1-risk myelodysplastic syndromes associated with del (5q) abnormality with or without additional abnormalities. Lenalidomide is an IMiD(r) immunomodulatory compound, incorporating structural modification of the drug thalidomide, which is active against a wide variety of autoimmune Th-2-dependent disorders, including erythema nodosum of leprosy, leishmaniasis, as well as severe ulcerative disorders such as Behcet's syndrome. Unfortunately, long-term use of thalidomide is limited, particularly by neurotoxicity. To date, results suggest that lenalidomide is more active than thalidomide and does not cause the neurotoxicity seen with thalidomide. Lenalidomide has multiple properties, including anti-inflammatory, antiangiogenic and costimulatory effects, as well as being able to inhibit T-regulatory cells, all of which are properties deemed desirable for anticancer activity. This article covers the evidence that lenalidomide may have a major role in the treatment and control of many cancer types other than del (5q) myelodysplastic syndrome and multiple myeloma. PMID- 20919831 TI - Role of cell cycle perturbations in the combination therapy of chemotherapeutic agents and radiation. AB - The combination of radiotherapy with chemotherapeutic agents that sensitize tumor cells to ionizing radiation has long been regarded as a promising strategy to enhance cancer therapy. Many chemotherapeutic agents interact with radiation and enhance the cytotoxic or anti-tumor effect of radiation through a number of mechanisms. These include an increase in initial radiation damage, inhibition of cellular repair, cell cycle redistribution, enhancement of apoptosis, counteracting hypoxia and overcoming accelerated repopulation. This article focuses on the role of cell cycle perturbations in the radiosensitivity of cancer cells. PMID- 20919832 TI - Extracorporeal, low-energy focused ultrasound for noninvasive and nondestructive targeted hyperthermia. AB - The benefits of hyperthermia are well known as both a primary treatment modality and adjuvant therapy for treating cancer. Among the different techniques available, high-intensity focused ultrasound is the only noninvasive modality that can provide local hyperthermia precisely at a targeted location at any depth inside the body using image guidance. Traditionally, focused ultrasound exposures have been provided at high rates of energy deposition for thermal ablation of benign and malignant tumors. At present, exposures are being evaluated in pulsed mode, which lower the rates of energy deposition and generate primarily mechanical effects for enhancing tissue permeability to improve local drug delivery. These pulsed exposures can be modified for low-level hyperthermia as an adjuvant therapy for drug and gene delivery applications, as well as for more traditional applications such as radiosensitization. In this review, we discuss the manner by which focused ultrasound exposures at low rates of energy deposition are being developed for a variety of clinically translatable applications for the treatment of cancer. Specific preclinical studies will be highlighted. Additional information will also be provided for optimizing these exposures, including computer modeling and simulations. Various techniques for monitoring temperature elevations generated by focused ultrasound will also be reviewed. PMID- 20919829 TI - Why target PIM1 for cancer diagnosis and treatment? AB - The highly conserved proto-oncogenic protein PIM1 is an unusual serine or threonine kinase, in part because it is constitutively active. Overexpression of PIM1 experimentally leads to tumor formation in mice, while complete knockout of the protein has no observable phenotype. It appears to contribute to cancer development in three major ways when it is overexpressed; by inhibiting apoptosis, by promoting cell proliferation and by promoting genomic instability. Expression in normal tissues is nearly undetectable. However, in hematopoietic malignancies and in a variety of solid tumors, increased PIM1 expression has been shown to correlate with the stage of disease. This characteristic suggests it can serve as a useful biomarker for cancer diagnosis and prognosis. Several specific and potent inhibitors of PIM1’s kinase activity have also been shown to induce apoptotic death of cancer cells, to sensitize cancer cells to chemotherapy and to synergize with other anti-tumor agents, thus making it an attractive therapeutic target. PMID- 20919833 TI - Ultrasound-guided excision of nonpalpable malignant soft tissue tumors of the abdomen. AB - The use of intraoperative ultrasound to guide the excision of sonographically visible but nonpalpable lesions is a newer modality. Its use in intraoperative localization of recurrent malignant soft tissue tumors has not been reported. This report describes a technique of intraoperative localization by ultrasound to guide the excision of recurrent nonpalpable malignant soft tissue tumors of the abdominal wall in two patients. Tumors of both patients were successfully localized intraoperatively by ultrasonography and excised with adequate margins. This technique leads to reduced patient discomfort and anxiety, the avoidance of organizational requirements on the day of surgery, and allows for adequate margins of resection. PMID- 20919834 TI - Intramedullary spinal cord metastases in breast cancer are associated with improved longer-term systemic control. AB - Intramedullary spinal cord metastases are a rare complication of malignancy, associated with a poor prognosis. We describe three cases with extensively pretreated advanced breast cancer developing intramedullary spinal cord metastases two of whom were receiving trastuzumab, one of whom was a male. As therapeutic advances increase overall survival for patients with metastatic breast cancer, patterns of disease are changing with improved systemic control. The incidence of intramedullary spinal cord metastases is likely to increase but management strategies remain unclear. PMID- 20919838 TI - Questions prerequisite for certification by new specialty organization. PMID- 20919839 TI - The vanishing veterinarian-scientist? PMID- 20919840 TI - What is your diagnosis? Transitional cell carcinoma. PMID- 20919841 TI - What is your diagnosis? Paragonimus kellicotti infection. PMID- 20919842 TI - Pathology in practice. Ranavirus infection. PMID- 20919843 TI - Use of a number-needed-to-ban calculation to illustrate limitations of breed specific legislation in decreasing the risk of dog bite-related injury. PMID- 20919844 TI - Employment, starting salaries, and educational indebtedness of year-2010 graduates of US veterinary medical colleges. PMID- 20919845 TI - Evaluation of the use of baseline cortisol concentration as a monitoring tool for dogs receiving trilostane as a treatment for hyperadrenocorticism. AB - OBJECTIVE: To determine whether a single measurement of cortisol concentration can be used to monitor dogs receiving trilostane for hyperadrenocorticism. DESIGN: Controlled drug efficacy trial. ANIMALS: 103 client-owned dogs. PROCEDURES: Results of ACTH stimulation tests before and during trilostane treatment were evaluated. Each cortisol concentration after ACTH stimulation was classified as indicative of excessive, acceptable, or inadequate control of adrenal gland function, as outlined by the trilostane manufacturer. Baseline cortisol concentrations before and during trilostane treatment were evaluated; target variables were defined, and sensitivity, specificity, and predictive values were determined. RESULTS: Results of 103 and 342 ACTH stimulation tests before and during treatment were evaluated. In this population, baseline cortisol concentrations >= 1.3 ug/dL accurately excluded excessive suppression (defined by cortisol concentration after ACTH stimulation < 1.5 ug/dL) in 254 of 259 (98%) dogs. In addition, baseline cortisol concentrations <= 2.9 ug/dL correctly excluded inadequate control (defined by cortisol concentration after ACTH stimulation > 9.1 ug/dL) in 200 of 211 (95%) dogs. During trilostane treatment, baseline cortisol concentrations between 1.3 and either 2.9 ug/dL or <= 50% of the pretreatment baseline cortisol concentration correctly predicted acceptable control of adrenal gland function in 147 of 168 (88%) dogs. CONCLUSIONS AND CLINICAL RELEVANCE: Evaluation of a baseline cortisol concentration collected 4 to 6 hours after trilostane administration in dogs with hyperadrenocorticism provided clinically useful information about control of adrenal gland function. Many dogs receiving trilostane may be adequately monitored without the expense and inconvenience of an ACTH stimulation test. PMID- 20919846 TI - Comparison of plasma cardiac troponin I concentrations among dogs with cardiac hemangiosarcoma, noncardiac hemangiosarcoma, other neoplasms, and pericardial effusion of nonhemangiosarcoma origin. AB - OBJECTIVE: To determine whether plasma cardiac troponin I (cTnl) concentrations can be used to identify cardiac involvement in dogs with hemangiosarcoma, exclude cardiac hemangiosarcoma in dogs with noncardiac hemangiosarcoma, and identify cardiac hemangiosarcoma in dogs with pericardial effusion. DESIGN: Cohort study. ANIMALS: 57 dogs (18 with confirmed [5 dogs] or suspected [13] cardiac hemangiosarcoma, 14 with confirmed hemangiosarcoma involving sites other than the heart [noncardiac hemangiosarcoma], 10 with pericardial effusion not caused by hemangiosarcoma, and 15 with noncardiac nonhemangiosarcoma neoplasms). PROCEDURES: Plasma cTnl concentration was measured, and thoracic radiography, abdominal ultrasonography, and echocardiography were performed in each dog. The cTnl concentration was compared among groups. RESULTS: Median plasma cTnl concentration in dogs with cardiac hemangiosarcoma was significantly higher than the concentration in each of the other groups. A plasma cTnl concentration > 0.25 ng/mL could be used to identify cardiac involvement in dogs with hemangiosarcoma at any site (sensitivity, 78%; specificity, 71 %). A plasma cTnl concentration > 0.25 ng/mL could be used to identify cardiac hemangiosarcoma in dogs with pericardia effusion (sensitivity, 81%; specificity, 100%). CONCLUSIONS AND CLINICAL RELEVANCE: The median plasma cTnl concentration was higher in dogs with cardiac hemangiosarcoma, compared with the median concentration in dogs with hemangiosarcoma at other sites, dogs with other neoplasms, and dogs with pericardial effusion not caused by hemangiosarcoma. The plasma cTnl concentration may be used to identify cardiac involvement in dogs with hemangiosarcoma and to identify cardiac hemangiosarcoma in dogs with pericardial effusion. PMID- 20919847 TI - Multicenter case-control study of signalment, diagnostic features, and outcome associated with cervical vertebral malformation-malarticulation in horses. AB - OBJECTIVE: To compare signalment of horses with cervical vertebral malformation malarticulation (CVM) with that of control horses and to describe results of clinical examination, diagnostic imaging and necropsy findings, and reported outcome in horses with CVM. DESIGN: Retrospective case-control study. ANIMALS: 270 horses with CVM and 608 control horses admitted to 6 veterinary hospitals from 1992 through 2007. PROCEDURES: Medical records of participating hospitals were reviewed to identify horses with CVM (ie, case horses) and contemporaneous control (non-CVM-affected) horses that were admitted for treatment. Signalment was compared between case horses and control horses. Results of clinical examination, laboratory and diagnostic imaging findings, necropsy results, and outcome were assessed for horses with CVM. RESULTS: Case horses were younger (median age, 2 years) than were control horses (median age, 7 years). Thoroughbreds, warmbloods, and Tennessee Walking Horses were overrepresented in the CVM group. Gait asymmetry and cervical hyperesthesia were frequently detected in horses with CVM. Vertebral canal stenosis and articular process osteophytosis were commonly observed at necropsy; agreement between the results of radiographic or myelographic analysis and detection of lesions at necropsy was 65% to 71% and 67% to 78%, respectively. Of 263 horses with CVM for which outcome was recorded, 1 died and 172 (65.4%) were euthanatized. CONCLUSIONS AND CLINICAL RELEVANCE: Odds of a diagnosis of CVM were greater in young horses and horses of specific breeds. Detection of gait asymmetry and cervical hyperesthesia were frequently reported in association with CVM. Accurate diagnosis of lesions associated with CVM by use of radiography and myelography can be challenging. PMID- 20919848 TI - Diagnosis and management of cranial and caudal nuchal bursitis in four horses. AB - CASE DESCRIPTION: 4 horses with a history of neck pain, abnormal head carriage, and related inability to perform were examined. Cranial nuchal bursitis was diagnosed in 2 horses, and caudal nuchal bursitis was diagnosed in the other 2. CLINICAL FINDINGS: All 4 horses had prominent swelling in the region between the frontal bone and temporal fossa (ie, the poll) and abnormal head carriage. Ultrasonographic examination revealed fluid distention and synovial thickening of the cranial or caudal nuchal bursa in all 4 horses. Ultrasonography-guided aspiration of the affected region was performed successfully in 3 horses. Radiography revealed bony remodeling and mineralization over the dorsal aspect of the atlas in 1 horse and a radiolucency at the axis in another. Nuclear scintigraphy revealed an increase in radioisotope uptake at the level of C2 in 1 horse. Although a septic process was considered among the differential diagnoses in all horses, a septic process could only be confirmed in 1 horse. TREATMENT AND OUTCOME: All horses were refractory to conservative management consisting of intrabursal injection of anti-inflammatory medications. Bursoscopic debridement and lavage of the affected bursae resulted in resolution of the clinical signs in all horses, and they all returned to their intended use. CLINICAL RELEVANCE: Cranial and caudal nuchal bursitis, of nonseptic or septic origin, should be considered as a differential diagnosis in horses with head and neck pain. Horses undergoing surgical intervention consisting of nuchal bursoscopy have the opportunity to return to their original degree of exercise. PMID- 20919849 TI - Severe phenylephrine-associated hemorrhage in five aged horses. AB - CASE DESCRIPTION: 5 aged (>= 17 years old) horses developed life-threatening Internal hemorrhage following IV administration of phenylephrine at 3 hospitals. CLINICAL FINDINGS: All 5 horses developed severe hemothorax, hemoabdomen, or both within minutes to hours following administration of phenylephrine. TREATMENT AND OUTCOME: Four of 5 horses died of hemorrhagic shock, and 1 horse survived with a blood transfusion. The exact source of hemorrhage was Identified In only 1 horse. Medical records of all horses with nephrosplenic entrapment of the large colon and treated with phenylephrine at the University of Florida Veterinary Medical Center between 2000 and 2008 (n = 74) were reviewed. Three of these 74 (4%) horses developed fatal hemorrhage (horses 1 through 3 of this report). The risk of developing phenylephrine-associated hemorrhage was 64 times as high (95% confidence interval, 3.7 to 1,116) in horses >= 15 years old than in horses < 15 years old. CLINICAL RELEVANCE: The potential risks versus benefits of phenylephrine administration should be evaluated carefully, especially In old horses. PMID- 20919850 TI - Clinical and pathological differences between human immunodeficiency virus positive and human immunodeficiency virus-negative patients with plasmablastic lymphoma. AB - Plasmablastic lymphoma (PBL) is a distinct variant of diffuse large B-cell lymphoma initially described in HIV-positive patients. Several studies have reported the occurrence of PBL in HIV-negative patients, but comparative data are lacking. The goal of this study was to compare the characteristics of HIV positive and HIV-negative patients with PBL. A MEDLINE search was undertaken through August 2009 for cases of PBL in HIV-positive and HIV-negative patients. Cases were identified and clinicopathological data were gathered. chi(2) was used to compare categorical and t-test to compare continuous variables between groups. Calculated Kaplan-Meier survival estimates were compared using the log-rank test. Cox proportional-hazard regression was used for multivariate analysis. From 228 identified cases of PBL, 157 were HIV-positive and 71 HIV-negative. HIV-positive patients were younger, and more likely to be men, present with oral involvement, respond to chemotherapy, and express CD20, CD56, and EBV-encoded RNA than HIV negative patients. In univariate analysis, age >=60, advanced stage, bone marrow involvement, no chemotherapy, Ki-67 expression >80%, and HIV-negative status were associated with worse overall survival. In multivariate analysis, advanced stage and no chemotherapy were independent adverse prognostic factors. In conclusion, HIV-positive and HIV-negative patients with PBL have different clinicopathological characteristics, including a better response to chemotherapy and longer survival in HIV-positive patients. PMID- 20919851 TI - SOX11 expression in mantle cell lymphoma. AB - SOX11 is a transcription factor involved in embryonic neurogenesis and tissue remodeling. Its role in lymphopoiesis is still unknown. Recent studies have shown the specific overexpression of SOX11 mRNA and nuclear protein in both cyclin D1 positive and -negative mantle cell lymphoma (MCL). In addition to MCL, SOX11 is strongly expressed in hairy cell leukemia, Burkitt lymphoma, and immature lymphocytic neoplasms. Expression of SOX11 in MCL is not only a new diagnostic marker, but may also carry information related to the clinical and biological behavior. Further study of the biology may reveal common pathways to neoplasia related to SOX11 expression. PMID- 20919853 TI - Caspase 3a: new prognostic marker for diffuse large B-cell lymphoma in the rituximab era. AB - Fewer than half of patients with diffuse large B-cell lymphoma (DLBCL) can be cured. Molecular prognostic factors in the rituximab era must be re-evaluated, because there are few molecular indicators with prognostic value. Samples of DLBCL from 41 newly diagnosed patients with a median follow-up of 52 months were studied. Immunohistochemical staining was performed to investigate the expression of apoptosis-related proteins (Bcl-2 and caspase 3a), cell proliferation (Ki-67), and tumor microenvironmental factors. Two groups were analysed, 23 cases (56%) treated with CHOP and 18 (44%) treated with R-CHOP. Survival analysis showed that cases with overexpression of Bcl-2 had worse overall survival (OS) in the CHOP group. However, OS in the R-CHOP group was adversely affected by lack of caspase 3a staining. In the entire series, cases positive for caspase 3a showed significantly better OS, without significance for other parameters, and caspase 3 was associated with parameters of prognosis and OS in R-CHOP. This is the first study that relates caspase 3a and prognosis in DLBCL. PMID- 20919852 TI - Phase I study of dose-escalated busulfan with fludarabine and alemtuzumab as conditioning for allogeneic hematopoietic stem cell transplant: reduced clearance at high doses and occurrence of late sinusoidal obstruction syndrome/veno occlusive disease. AB - Disease recurrence after allogeneic hematopoietic cell transplant (alloHCT) remains common, making improvements in conditioning regimens desirable. A dose response relationship between busulfan exposure and outcome is known. Using individual real-time monitoring of the busulfan area under the curve (AUC), we aimed to determine the maximum-tolerated busulfan AUC in a conditioning regimen with fludarabine/alemtuzumab. Thirty-six patients with advanced hematologic malignancies were treated. Busulfan levels after a test dose and conditioning dose 1 allowed targeting of subsequent AUCs and dose-escalation above the starting AUC of 4800 umol-min/L. Clearance of busulfan test doses was not always sufficiently predictive of treatment dose AUC and, on average, test dose clearance was faster than treatment dose clearance. When the study was modified to use conditioning dose 1 pharmacokinetics instead, accurately targeted treatment AUCs were achieved, and dose-escalation was possible. Severe, late occurring sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) was the dose-limiting toxicity seen in 5/8 patients at an AUC level of 6800 umol min/L. The risk for SOS/VOD correlated with the highest observed AUC (AUC(max)) rather than with the average cumulative AUC (AUC(avg)). Busulfan dose-escalation to a maximum-tolerated AUC of 5800 umol-min/L-higher than that achieved by current standard busulfan regimens-was accurate and achievable using real-time pharmacokinetics monitoring of the first conditioning dose. This AUC is now being studied in phase II for patients receiving busulfan/fludarabine/alemtuzumab as alloHCT conditioning. PMID- 20919854 TI - Fish oil delays lymphoma progression in the TLL mouse. AB - The objective was to investigate the effects of omega-3 fatty acids, known for their anti-inflammatory effects, on time to lymphoma progression and survival in the TLL mouse, a strain genetically prone to developing aggressive T-cell lymphoma. Compared to mice fed a standard diet, TLL mice fed omega-3 (menhaden fish oil) experienced a significant delay in disease progression and were more likely to remain alive and symptom free during the first 8 months of the study. In contrast, omega-6 supplementation (corn oil) did not significantly affect lymphoma progression. Irrespective of diet, all mice eventually progressed, and 1 year survival was not different between the groups. Immunological analysis demonstrated a significantly altered B-cell compartment and fewer NK cells in healthy C57Black6 mice fed omega-3, compared to controls. In conclusion, a diet rich in omega-3 fatty acids delays lymphoma development in the TLL mouse possibly by mechanisms that include complex effects on immune function. PMID- 20919855 TI - Long-term survival following allogeneic or syngeneic stem cell transplant for follicular lymphoma in Sweden. PMID- 20919856 TI - A DNA methylation study of the amyloid precursor protein gene in several brain regions from patients with familial Alzheimer disease. AB - Presence of extracellular amyloid plaques is a neuropathological hallmark of Alzheimer disease. Here the authors have compared the methylation status of a CpG island in the amyloid precursor protein gene (APP) in DNA extracted from the more plaque-vulnerable cortex regions with DNA from the more plaque-resistant cerebellum using material from six familial Alzheimer disease cases. Bisulfite sequencing of a 188 bp fragment in the APP associated CpG-island showed no methylation in any sample, suggesting that APP is not transcriptionally regulated by methylation in any of the investigated brain regions. PMID- 20919858 TI - Hypertonic conditions trigger transient plasmolysis, growth arrest and blockage of transporter endocytosis in Aspergillus nidulans and Saccharomyces cerevisiae. AB - By using Aspergillus nidulans strains expressing functional GFP-tagged transporters under hypertonic conditions, we noticed the rapid appearance of cortical, relatively static, fluorescent patches (0.5-2.3 MUm). These patches do not correspond to transporter microdomains as they co-localize with other plasma membrane-associated molecules, such as the pleckstrin homology (PH) domain and the SsoA t-Snare, or the lipophilic markers FM4-64 and filipin. In addition, they do not show characteristics of lipid rafts, MCCs or other membrane microdomains. Deconvoluted microscopic images showed that fluorescent patches correspond to plasma membrane invaginations. Transporters remain fully active during this phenomenon of localized plasmolysis. Plasmolysis was however associated with reduced growth rate and a dramatic blockage in transporter and FM4-64 endocytosis. These phenomena are transient and rapidly reversible upon wash-out of hypertonic media. Based on the observation that block in endocytosis by hypertonic treatment altered dramatically the cellular localization of tropomyosin (GFP-TpmA), although it did not affect the cortical appearance of upstream (SlaB-GFP) or downstream (AbpA-mRFP) endocytic components, we conclude that hypertonicity modifies actin dynamics and thus acts indirectly on endocytosis. This was further supported by the effect of latrunculin B, an actin depolymerization agent, on endocytosis. We show that the phenomena observed in A. nidulans also occur in Saccharomyces cerevisiae, suggesting that they constitute basic homeostatic responses of ascomycetes to hypertonic shock. Finally, our work shows that hypertonic treatments can be used as physiological tools to study the endocytic down-regulation of transporters in A. nidulans, as non-conditional genetic blocks affecting endocytic internalization are lethal or severely debilitating. PMID- 20919859 TI - Unresolved issues in the comparison of therapies and determination of responses in Waldenstrom macroglobulinemia. PMID- 20919857 TI - Genetic feminization of the thoracic nervous system disrupts courtship song in male Drosophila melanogaster. AB - Despite the growing research investigating the sex-specific organization of courtship behavior in Drosophila melanogaster, much remains to be understood about the sex-specific organization of the motor circuit that drives this behavior. To investigate the sex-specification of a tightly patterned component of courtship behavior, courtship song, the authors used the GAL4/UAS targeted gene expression system to feminize the ventral ganglia in male Drosophila and analyzed the acoustic properties of courtship song. More specifically, the authors used the thoracic-specifying teashirt promoter (tsh(GAL4)) to express feminizing transgenes specifically in the ventral ganglia. When tsh(GAL4) drove expression of transformer (tra), males were unable to produce prolonged wing extensions. Transgenic expression of an RNAi construct directed against male specific fruitless (fru(M)) transcripts resulted in normal wing extension, but highly defective courtship song, with 58% of males failing to generate detectable courtship song. Of those that did sing, widths of individual pulses were significantly broader than controls, suggesting thoracic fru(M) function serves to mediate proprioceptive-dependent wing vibration damping during pulse song. However, the most critical signal in the song, the interpulse interval, remained intact. The inability to phenocopy this effect by reducing fru(M) expression in motor neurons and proprioceptive neurons suggests thoracic interneurons require fru(M) for proper pulse song execution and patterning of pulse structure, but not for pulse timing. This provides evidence that genes establishing sex-specific activation of complex behaviors may also be used in establishing pattern generating motor networks underlying these sex-specific behaviors. PMID- 20919860 TI - Pneumocystis jiroveci pneumonia in relation to CD4+ lymphocyte count in patients with B-cell non-Hodgkin lymphoma treated with chemotherapy. AB - An increasing incidence of Pneumocystis jiroveci pneumonia (PCP) in patients with B-cell non-Hodgkin lymphoma (B-NHL) receiving rituximab treatment has been reported. We reviewed patients with B-NHL who underwent chemotherapy from 2004 to 2008 at our institution to identify risk factors for PCP development during and after chemotherapy. Among 297 patients with B-NHL, six developed PCP. Of 121 patients (41%) who received PCP prophylaxis with sulfamethoxazole-trimethoprim during chemotherapy, none developed PCP (0%), while among 176 patients (59%) who had no prophylaxis, six (3.4%) developed PCP at a median of 2 months (range: 1-3 months) after starting chemotherapy. Patients with CD4+ lymphocyte counts <=200/mm3 before chemotherapy had a higher risk of developing PCP (p=0.045), while a history of rituximab treatment was not related to PCP. CD4+ lymphocyte counts <=200/mm3 during and after chemotherapy were observed in 18.9% of patients. PMID- 20919861 TI - Variation at 7p12.2 and 10q21.2 influences childhood acute lymphoblastic leukemia risk in the Thai population and may contribute to racial differences in leukemia incidence. AB - Recent genome-wide association (GWA) studies of childhood acute lymphoblastic leukemia (ALL) have identified 7p12.2, 9p21.3, 10q21.2, and 14q11.2 SNPs that confer modest risks of ALL. These studies have been conducted in European populations, and it is unclear whether these observations generalize to other populations with a lower incidence of ALL. To explore the impact of these variants on ALL risk in the Thai population, we genotyped 190 cases of ALL and 182 controls for SNPs rs4132601 (7p12.2), rs3731217 (9p21.3), rs7089424 and rs10821938 (10q21.2), and rs2239633 (14q11.2). Consistent with findings in European populations, rs4132601 genotype was significantly associated with risk of ALL (odds ratio [OR] = 1.57, 95% confidence interval [CI]: 1.01-2.44; p = 0.04), and rs10821938 genotype was significantly associated with B-cell precursor ALL (OR = 0.73, 95% CI: 0.55-0.97; p = 0.03). There were, however, differences in allele frequencies in SNPs observed between Thai and Caucasian populations (e.g. IKZF1, rs4132601; risk allele frequency [RAF] ratio of 0.36 for Thai/Caucasian). These differences, combined with differences in linkage disequilibrium structure between populations or differences in effect size between populations, may contribute to racial differences in ALL incidence. PMID- 20919862 TI - Refractory cytopenias with unilineage dysplasia: a retrospective analysis of refractory neutropenia and refractory thrombocytopenia. PMID- 20919875 TI - Chronic disease self-management for individuals with stroke, multiple sclerosis and spinal cord injury. AB - PURPOSE: The purpose of this study was to explore the experience of people with neurological conditions who take the chronic disease self-management (CDSM) programme. The CDSM programme is used to teach skills to manage chronic conditions, and prevent secondary conditions. Few studies have explored the use of the CDSM programme with people with neurological conditions, in spite of the long standing and sometimes unpredictable nature of those conditions. METHOD: This qualitative study explored the experience of people with stroke, multiple sclerosis (MS) and spinal cord injury (SCI) who participated in the CDSM programme. We completed individual interviews using a semi-structured interview guide with 22 individuals with stroke, MS and SCI. RESULTS: Five categories emerged from the interview discussions including: (1) pre-programme influences; (2) group; (3) factors affecting learning opportunities; (4) workshop content and (5) outcomes. CONCLUSIONS: The results of this study provide insights regarding the optimal way to present the CDSM programme to people with neurological conditions. PMID- 20919880 TI - High altitude medicine and biology in Peru. PMID- 20919876 TI - Recombinant adeno-associated virus-mediated in utero gene transfer gives therapeutic transgene expression in the sheep. AB - Somatic in utero gene therapy aims to treat congenital diseases where pathology develops in perinatal life, thereby preventing permanent damage. The aim of this study was to determine whether delivery of self-complementary (sc) adeno associated virus (AAV) vector in utero would provide therapeutic long-term transgene expression in a large animal model. We performed ultrasound-guided intraperitoneal injection of scAAV2/8-LP1-human Factor IX (hFIX)co (1 * 10(12) vector genomes/kg) in early (n = 4) or late (n = 2) gestation fetal sheep. The highest mean hFIX levels were detected 3 weeks after injection in late gestation (2,055 and 1,687.5 ng/ml, n = 2) and 3 days after injection in early gestation (435 ng/ml, n = 1). Plasma hFIX levels then dropped as fetal liver and lamb weights increased, although low levels were detected 6 months after late gestation injection (75 and 52.5 ng/ml, n = 2). The highest vector levels were detected in the fetal liver and other peritoneal organs; no vector was present in fetal gonads. hFIX mRNA was detectable only in hepatic tissues after early and late gestation injection. Liver function tests and bile acid levels were normal up to a year postnatal; there was no evidence of liver pathology. No functional antibodies to hFIX protein or AAV vector were detectable, although lambs mounted an antibody response after injection of hFIX protein and Freund's adjuvant. In conclusion, hFIX expression is detectable up to 6 months after delivery of scAAV vector to the fetal sheep using a clinically applicable method. This is the first study to show therapeutic long-term hFIX transgene expression after in utero gene transfer in a large animal model. PMID- 20919884 TI - Can patients with coronary heart disease go to high altitude? AB - Tourism to high altitude is very popular and includes elderly people with both manifest and subclinical coronary heart disease (CHD). Thus, risk assessment regarding high altitude exposure of patients with CHD is of increasing interest, and individual recommendations are expected despite the lack of sufficient scientific evidence. The major factor increasing cardiac stress is hypoxia. At rest and for a given external workload, myocardial oxygen demand is increased at altitude, particularly in nonacclimatized individuals, and there is some evidence that blood-flow reserve is reduced in atherosclerotic coronary arteries even in the absence of severe stenosis. Despite a possible imbalance between oxygen demand and oxygen delivery, studies on selected patients have shown that exposure and exercise at altitudes of 3000 to 3500 m is generally safe for patients with stable CHD and sufficient work capacity. During the first days at altitude, patients with stable angina may develop symptoms of myocardial ischemia at slightly lower heart rate x blood-pressure products. Adverse cardiac events, however, such as unstable angina coronary syndromes, do not occur more frequently compared with sea level except for those who are unaccustomed to exercise. Therefore, training should start before going to altitude, and the altitude related decrease in exercise capacity should be considered. Travel to 3500 m should be avoided unless patients have stable disease, preserved left ventricular function without residual capacity, and above-normal exercise capacity. CHD patients should avoid travel to elevations above 4500 m owing to severe hypoxia at these altitudes. The risk assessment of CHD patients at altitude should always consider a possible absence of medical support and that cardiovascular events may turn into disaster. PMID- 20919885 TI - Altitude illness in Qinghai-Tibet railroad passengers. AB - It takes ~24 h to travel the ~3000-km-long Qinghai-Tibet railroad of which 85% is situated above 4000 m with a pass at 5072 m. Each year about 2 million passengers are rapidly exposed to high altitude traveling on this train. The aim of this study was to quantify the occurrence of altitude illness on the train. Three subject groups were surveyed: 160 Han lowlanders, 62 Han immigrants living at 2200 to 2500 m, and 25 Tibetans living at 3700 to 4200 m. Passengers reached 4768 m from 2808 m in less than 1.5 h, after which 78% of the passengers reported symptoms, 24% reaching the Lake Louise criterion score for AMS. AMS incidence was 31% in nonacclimatized Han compared to 16% in Han altitude residents and 0% in Tibetans. Women and older subjects had a slightly greater risk for AMS. Most cases of AMS were mild and self-limiting, resolving within days upon arrival in Lhasa. Some cases of more severe AMS necessitated medical attention. To curb the health risk of rapid travel to altitude by train, prospective travelers should be better informed, medical train personnel should be well trained, and staged travel with 1 to 2 days at intermediate altitudes should be suggested to nonacclimatized subjects. PMID- 20919886 TI - Hematological and physiological adaptations following 46 weeks of moderate altitude residence. AB - Although acclimatization to moderate altitude (MA) is thought to be unnecessary or to require minimal adaptation, retrospective data from the U.S. Air Force Academy (USAFA), a military college located at 2210 m, suggested otherwise. To further examine the utility of USAFA as a model for MA acclimatization, a longitudinal experimental design was prospectively utilized to determine the magnitude and time course of selected hematological and performance parameters following 46 weeks at this unique MA setting. Incoming USAFA male freshmen (n=55) were divided into experimental groups based on prior residence at sea level (SL) or MA. Hematological and performance parameters were repeatedly assessed during their entire first year at MA. Hematological data consisted of a complete blood count (CBC) with reticulocyte parameters, as well as determination of serum levels of ferritin, erythropoietin, and soluble transferrin receptor (sTfR). Performance testing included aerobic (1.5-mile run) and physical (push-ups, sit ups, pull-ups, and standing long jump) fitness tests, maximal aerobic capacity, and running economy. Significant (p<0.05; main effect) hematological differences between SL and MA subjects were observed for the majority of the study. MA subjects had a significantly higher hemoglobin concentration ([Hb], +5.5%), hematocrit (+2.8%), and serum ferritin (+59.0%) and significantly lower sTfR ( 11.4%) values than their SL peers. Although both serum ferritin and sTfR demonstrated a significant altitude group x time interaction, [Hb] and hematocrit did not. A significant main effect of altitude without interaction was also observed for performance parameters, with SL subjects having a significantly lower Vo2peak (-5.9%), slower 1.5- mile run time (+5.4%), poorer running economy (+6.6%), and lower composite physical fitness test score (-13.9%) than MA subjects. These results suggest that complete acclimatization to 2210 m by former SL residents may require lengthy physiological adaptations, as both hematological and physical performance differences persisted between groups. Further research at this uniquely well controlled MA setting is warranted. PMID- 20919887 TI - The physiological basis of reduced VO2max in Operation Everest II. AB - While it is well-known that maximal VO2 falls progressively with increasing altitude, discussion continues on how each step of the O2 transport pathway contributes to this loss in exercise capacity. By analyzing the O2 transport pathway as an in-series system of four transport processes (ventilation, alveolar capillary diffusion, circulation, and muscle capillary-mitochondrial diffusion) and applying this analysis to published data from Operation Everest II, it is concluded that in OE II the passive diffusive steps in the lungs and muscles explain most of the decrement in O2 availability, while changes in the mostly convective processes of ventilation and blood flow contribute little or no impediment to O2 transport. Potentially deleterious effects of decreased maximal cardiac output and mitigating effects of increased [Hb] on circulatory O2 transport are likely offset by corresponding changes in diffusion equilibration in the lungs and muscles. These conclusions are consistent with the laws of diffusion that depend on partial pressure, which falls progressively with increasing hypoxia. PMID- 20919888 TI - Incidence and predictors of acute mountain sickness among trekkers on Mount Kilimanjaro. AB - We investigated the incidence of AMS amongst a general population of trekkers on Mount Kilimanjaro, using the Lake Louise consensus scoring system (LLS). Additionally we examined the effect of prophylactic acetazolamide and different ascent profiles. Climbers on 3 different ascent itineraries were recruited. At 2743 m we recruited 177 participants (mean age 31, range [18-71]) who completed LLS together with an epidemiological questionnaire. At 4730 m participants (n=189, male=108, female=68, mean age 33, range [1871]) completed LLS, 136 of whom had been followed up from 2730 m. At 2743 m, 3% (5/177) of climbers were AMS positive, and 47% (89/189) of climbers from all itineraries were AMS positive at 4730 m. Of climbers attempting the Marangu itineraries, 33% (45/136) were taking acetazolamide. This group had a similar rate of AMS and no statistical difference in severity of LLS when compared with those not taking prophylactic drugs. We also did not demonstrate a difference between the incidence of AMS in climbers who did or did not take a rest day at 3700 m. However, there was a significant reduction in the incidence of AMS amongst pre-acclimatized subjects. Consistent with previous work, we found that the rate of AMS on Mount Kilimanjaro is high. Furthermore, at these fast ascent rates, there was no evidence of a protective effect of acetazolamide or a single rest day. There is a need to increase public awareness of the risks of altitude sickness and we advocate a pragmatic "golden rules" approach (http://www.altitude.org/altitude_sickness.php). PMID- 20919889 TI - Demographic, geographic, and expedition determinants of reaching the summit of denali. AB - Mount McKinley, or Denali as it is called by the native people of Alaska, is the highest mountain in North America and its summit is attempted by over 1000 climbers annually. Many factors affect the likelihood of achieving the summit of high peaks such as Denali: climber age, experience, weather, team characteristics, and many others. We analyzed the characteristics of mountaineers who gained the summit of Denali versus those who did not during the climbing seasons of 1990 to 2008. Of the 21,809 climbers who attempted to summit Denali during the study period, 11,297 (51.8%) achieved the summit. We found that male mountaineers were slightly more likely to attain the summit than females. Climbers older than 40 had a decreasing trend of summit success. Climbers from continents other than North America had better odds of achieving the summit. Our results help to better predict those who are more likely to achieve the summit of North America's highest peak. The information can be used by mountaineers during expedition planning so that team selection, route choice, and expedition style may be considered when evaluating chances for summit success. National Park Service administrative personnel and rescue staff may be able to identify climbing teams with a lower likelihood of summit success for proactive discussion or intervention prior to an expedition's departure for this unique and often very inhospitable mountain. PMID- 20919890 TI - Role of oxidative stress and inflammation in hypoxia-induced cerebral edema: a molecular approach. AB - The present study reports the possible role of oxidative stress and inflammation (role of nuclear factor, NFkB) in hypoxia-induced transvascular leakage in brain of rats. The rats were exposed to a simulated altitude of 25,000 ft for different durations: 0, 3, 6, 12, 24, and 48h. Brain water content, transvascular leakage, oxidative stress, and proinflammatory parameters were studied at different durations of hypoxic exposure. The results revealed that maximum increase in transvascular leakage in brain of rats was observed at 24h of hypoxic exposure (240.16 +/- 1.95 relative fluorescence units (r.f.u)/g tissue) compared with control (100.58 +/- 1.79 r.f.u/g tissue). There was a significant increase in reactive oxygen species (ROS) and lipid peroxidation (MDA), with concomitant reduction in antioxidants. Hypoxic exposure resulted in a significant increase in NFkappaB protein expression levels and in the DNA binding activity in the 24-h hypoxic exposure (p<0.001) compared with control. There was a significant increase in proinflammatory cytokines, with concomitant upregulation of cell adhesion molecules. Simultaneously, to rule out the fact that inflammation causes cerebral edema, the rats were pretreated with curcumin (100 mg/kg body weight) 1h prior to 24-h hypoxia. Curcumin pretreatment significantly attenuated the hypoxia induced cerebral transvascular leakage (p<0.05), with concomitant downregulation in the expression of brain NFkappaB levels (p<0.001). The present study therefore reveals that inflammation (NFkappaB) plays a significant role in hypoxia-induced cerebral edema. PMID- 20919892 TI - 'This constant being woken up is the worst thing' - experiences of sleep in fibromyalgia syndrome. AB - PURPOSE: Sleep disturbance affects a high proportion of people with fibromyalgia syndrome (FMS). This study aims to explore people's perceptions of their sleep quality and the influence sleep has on their symptoms and daily lives. METHOD: Semi-structured interviews were conducted with sixteen participants diagnosed with primary FMS, covering all aspects of the sleep experience. The audio recorded qualitative interviews were transcribed verbatim and analysed using interpretative phenomenological analysis. RESULTS: Poor sleep dominated participants' lives, affecting levels of pain and fatigue, engagement in daily activities and ability to cope. Participants reported experiencing blocks of sleep, with the most profound difficulty for participants being able to go back to sleep after a night time awakening. They also felt a lack of control in their ability to manage their sleep difficulties and use of day-time napping appeared to be the only perceived beneficial coping strategy for relieving daytime sleepiness and symptoms of fatigue. CONCLUSIONS: Greater emphasis on screening for sleep disorders and how to manage poor sleep is needed in rehabilitation programmes provided for patients with FMS. PMID- 20919895 TI - Evaluation of a three-dimensional kinematic model for canine gait analysis. AB - OBJECTIVE: To evaluate a 3-D kinematic model of the hind limb developed by use of a joint coordinate system in dogs. ANIMALS: 6 clinically normal adult mixed-breed dogs. PROCEDURES: 17 retroreflective markers were affixed to the skin on the right hind limb of each dog. Eight infrared cameras were arranged around a gait platform to record marker locations as dogs were recorded moving through the calibrated space 5 times during a walk and trot at velocities of 0.9 to 1.2 m/s and 1.7 to 2.1 m/s, respectively. Local and global coordinate systems were established, and a segmental rigid-body model of the canine hind limb was produced. Dynamic 3-D joint kinematic measurements were collected for the hip, stifle, and tarsal joints. RESULTS: Sagittal (flexion-extension), transverse (internal-external rotation), and frontal (abduction-adduction) plane kinematic measurements were acquired during each trial for the hip, stifle, and tarsal joints. CONCLUSIONS AND CLINICAL RELEVANCE: The joint coordinate system allowed acquisition of 3-D kinematic measurements of the hip, stifle, and tarsal joints of the canine hind limb. Methods were described to model 3-D joint motion of the canine hind limb. PMID- 20919896 TI - Evaluation of a milk-flow assessment technique in dairy cows with normal teat canals or stenotic teat canals. AB - OBJECTIVE: To assess the usefulness and reliability of a milk-flow measurement technique and the values obtained in unobstructed teats and teats with teat canal stenosis in dairy cows. ANIMALS: 16 Holstein cows. PROCEDURES: Teats were assessed via hand milking and classified as unobstructed or partially obstructed. Partially obstructed teats were further categorized according to the anatomic location of the obstruction via ultrasonography into teat canal obstruction (TCO) and obstruction at the proximal portion of the teat canal (Furstenberg rosette obstruction [FRO]) The milk-flow characteristics of the teat canal were assessed by measuring the intracisternal pressure at the start (PSL) and at cessation (PCL) of leakage of an infused solution. RESULTS: The PSL and PCL values among unobstructed teats were not significantly different between lactating and nonlactating cows nor among quarters. In assessment of test-retest intrarater reliability, a high degree of correlation was detected for PSL (correlation coefficient, 0.94; 95% confidence interval, 0.90 to 0.96) and PCL (correlation coefficient, 0.92; 95% confidence interval, 0.86 to 0.95). Teats with TCO and FRO had higher PSL and PCL values, compared with unobstructed teats. Teats with FRO had significantly higher PSL but lower PCL than teats with TCO. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated the usefulness and reliability of the technique in assessing the milk-flow characteristics of the teat canal. The milk flow pattern of teats with teat canal stenosis varies depending on the location of obstruction. This technique may be a valuable tool in evaluating the effectiveness of teat canal surgery. PMID- 20919897 TI - Pharmacokinetics of fentanyl administered transdermally and intravenously in sheep. AB - OBJECTIVE: To investigate the pharmacokinetics of fentanyl administered transdermally and IV in sheep. ANIMALS: 21 adult female sheep. PROCEDURES: Fentanyl was administered IV to 6 healthy sheep. Transdermal fentanyl patches (TFPs) were applied to 15 sheep 12 hours prior to general anesthesia and surgery. Seria blood samples were collected for 18 hours after IV injection and 84 hours after TFP application. Fentanyl concentrations were quantified via liquid chromatography-mass spectrometry, and pharmacokinetic values were estimated. RESULTS: All sheep completed the study without complications. Following a dose of 2.5 g/kg administered IV, the half-life was 3.08 hours (range, 2.20 to 3.36 hours), volume of distribution at steady state was 8.86 L/kg (range, 5.55 to 15.04 L/kg), and systemic clearance was 3.62 L/kg/h (range, 2.51 to 5.39 L/kg/h). The TFPs were applied at a mean dose of 2.05 g/kg/h. Time to maximum plasma concentration and maximal concentration were 12 hours (range, 4 to 24 hours) and 1.30 ng/mL (range, 0.62 to 2.73 ng/mL), respectively. Fentanyl concentrations were maintained at >0.5 ng/mL for 40 hours after TFP application. CONCLUSIONS AND CLINICAL RELEVANCE: IV administration of fentanyl resulted in a short half-life. Application of a TFP resulted in stable blood fentanyl concentrations in sheep. PMID- 20919898 TI - Hemodynamic effects in dogs anesthetized with isoflurane and remifentanil isoflurane. AB - OBJECTIVE: To compare hemodynamic effects in dogs anesthetized with remifentanilisoflurane and with isoflurane alone. ANIMALS: 6 adult dogs. PROCEDURES: Mechanically ventilated, isoflurane-anesthetized dogs received increasing constant rate infusions (CRIs) of remifentanil (0.15, 0.30, 0.60, and 0.90 MUg/kg/min) or physiologic saline (0.9% NaCl) solution (control treatment), with a 1-week washout interval between treatments. Each CRI of remifentanil or saline solution was maintained for 60 minutes with equipotent end-tidal isoflurane concentrations that corresponded to 1.3 times the minimum alveolar concentration. Hemodynamic measurements and plasma vasopressin concentrations were determined before and at the end of each CRI and 60 minutes after the end of the infusion regimen. RESULTS: Compared with the control treatment, remifentanil CRIs significantly decreased heart rate (HR) and cardiac index (CI) and significantly increased systemic vascular resistance index (SVRI) and plasma vasopressin concentration. Greatest differences in mean values between treatments were recorded for remifentanil at 0.60 MUg/kg/min (HR and Cl were 55% and 47% lower, respectively, and SVRI was 91% higher than for the control treatment). Mean arterial pressure increased significantly during the highest remifentanil CRI (9% higher than for the control treatment). The increase in vascular resistance was positively correlated with increases in vasopressin concentrations (coefficient of determination, 0.65) during anesthesia with remifentanil isoflurane. CONCLUSIONS AND CLINICAL RELEVANCE: Anesthesia maintained with remifentanil-isoflurane may decrease tissue perfusion as a result of a decrease in Cl. However, hypotension may not develop because of systemic vasoconstriction. An increase in plasma vasopressin concentration was associated with the vasoconstriction observed in dogs anesthetized with remifentanil-isoflurane. PMID- 20919899 TI - Evaluation of anti-inflammatory and chondroprotective effects of peroxisome proliferator-activated receptor gamma agonists in cartilage and synovial explants from dogs. AB - OBJECTIVE: To evaluate the effects of peroxisome proliferator-activated receptor gamma (PPARgamma) agonists on tissue metabolism in cartilage and synovial explants from dogs. SAMPLE POPULATION: Cartilage-synovial membrane expiants from 12 dogs. PROCEDURES: Expiants were cultured for 21 days without (negative control) or with interleukin (IL)-1beta (positive control) or with IL-1beta and 2 concentrations of 2 PPARgamma agonists (15-deoxy-Delta 12,14-prostaglandin J2 [PGJ2] and pioglitazone). Media were collected on days 3, 7, 9, 12, 15, 18, and 21 and assessed for glycosaminoglycan (GAG), nitric oxide (NO), and prostaglandin E2 (PGE2) concentrations. Tissue GAG and hydroxyproline concentrations were determined in cartilage expiants collected on day 21. RESULTS: The GAG concentrations of cartilage expiants cultured in IL-1beta (100 ng/mL) with 2 concentrations of PGJ2 were significantly higher than those in all other groups, whereas media GAG concentrations were significantly lower in the high concentration PGJ2-treated groups, compared with all other groups. The PGE2 concentrations were significantly lower in the PGJ2 treatment groups, compared with the positive control and the pioglitazone treatment groups on days 3 to 21. The NO concentrations were significantly lower in PGJ2 treatment groups, compared with the other groups on days 3 and 12 to 21. CONCLUSIONS AND CLINICAL RELEVANCE: PGJ2, an endogenous PPARgamma agonist, may have anti-inflammatory and chondroprotective effects in an osteosteoarthritic joint environment. PMID- 20919900 TI - Analysis of the subchondral microarchitecture of the distopalmar aspect of the third metacarpal bone in racing Thoroughbreds. AB - OBJECTIVE: To determine the anisotropic characteristics of the microarchitecture of the subchondral bone (SCB) plate and trabecular bone (TBB) of the distopalmar aspect of the metacarpal condyles in horses with different stages of SCB disease. SAMPLE POPULATION: 12 third metacarpal bone pairs from racing Thoroughbreds euthanized for diverse reasons. PROCEDURES: Both metacarpi were collected from horses with SCB changes that were mild (sclerosis and focal radiolucencies; n=6) or severe (multifocal radiolucencies and articular surface defects; 6). Sample blocks of SCB plate and TBB were collected from the distopalmar aspect of both condyles and the sagittal ridge and examined via 3-D micro-computed tomography at 45-?m isotropic voxel resolution. For each sample, the angle between the principal orientation of trabeculae and the sagittal plane and the degree of anisotropy (DA) were calculated from mean intercept length measurements. RESULTS: Condylar samples had significantly lower angle (mean, 8.9 degrees ; range, 73 degrees to 10.9 degrees ) than sagittal ridge samples (mean, 40.7 degrees ; range, 33.6 degrees to 49.2 degrees ), TBB had significantly higher DA (mean+/ SE, 1.75+/-0.04) than SCB plate (1.29+/-0.04), and mildly diseased TBB had higher DA (1.85+/-0.06) than severely diseased TBB (1.65+/-0.06). CONCLUSIONS AND CLINICAL RELEVANCE: The highly ordered appearance of trabeculae within the condyles supports the concept that joint loading is primarily transmitted through the condyles and not the sagittal ridge. The sharp changes in the trajectories of the SCB trabeculae at the condylar grooves may be indicative of hypothetical tensile forces at this location contributing to the pathogenesis of condylar fractures. PMID- 20919901 TI - Evaluation of a flow-mediated vasodilation measurement technique in healthy dogs. AB - OBJECTIVE: To evaluate the between- and within-dog repeatability of a flow mediated vasodilation (FMD) measurement technique in healthy dogs. ANIMALS: 43 male and female dogs of various breeds (weight range, 6.9 to 31.7 kg; age range, 11 months to 11 years). PROCEDURES: 5 dogs were used to refine the technique; other dogs were classified as large (>15 kg) or small (>=15 kg) before use in the main study. In each dog, a brachial artery was occluded for 5 minutes by inflating a blood pressure cuff (applied pressure was more than 50 mm Hg greater than that required to occlude flow). Two-dimensional ultrasonographic images of the artery were recorded during a 30-second period prior to cuff inflation (baseline) and during a 3-minute period after cuff deflation by each of 2 sonographers. Relative percentage increases in luminal size from baseline (ie, FMD) were calculated. Independent contributing factors to FMD (eg, body weight, age, and room temperature) were assessed. RESULTS: Median FMD was significantly greater in small dogs (77%; range, 0% to 19.3%) than it was in large dogs (2.2%; range, -2.2% to 10.6%); values were significantly greater in dogs<6 years old, compared with dogs>6 years old. Weight was the only independent contributing factor for FMD. Coefficients of variation for between- and within-dog repeatability were 99.7% and 62.8%, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Application of the FMD measurement technique used in humans appears to be feasible in dogs and may provide a means of assessing canine endothelial function, although between and within-dog variations were large. PMID- 20919902 TI - Expression of genes associated with inflammation induced by ex vivo exposure to lipopolysaccharide in peripheral blood leukocytes from horses with gastrointestinal disease. AB - OBJECTIVE: To investigate the effect of ex vivo exposure to lipopolysaccharide (LPS) on the expression of inflammatory genes in leukocytes from horses with gastrointestinal (Gl) disease and determine whether the pattern or magnitude of the response to LPS correlated with the type of disease and outcome. ANIMALS: 49 horses with Gl disease and 10 healthy horses PROCEDURES: Leukocytes were isolated from blood samples and submitted to 3 protocols: immediate freezing, freezing after 4-hour incubation in medium, and freezing after 4-hour incubation in medium containing LPS. Expression of 14 genes associated with inflammation was assessed via PCR assay. Results were compared by disease type and outcome RESULTS: Horses with Gl disease had colic of unknown etiology (n=8), Gl inflammation or strangulation (18), or nonstrangulating Gl obstruction (23). Among the 44 horses receiving treatment, 38 were discharged from the hospital and 6 died or were euthanized. Incubation of leukocytes in medium alone changed the expression of several genes. Incubation with LPS resulted in increased expression of interleukin-10 and monocyte chemotactic protein-3 in leukocytes from healthy and sick horses. Leukocytes from horses with nonstrangulating obstruction and horses that survived had less pronounced LPS-induced increases in interleukin-10 expression than did cells from healthy horses. The opposite was evident for monocyte chemotactic protein-3. CONCLUSIONS AND CLINICAL RELEVANCE: No evidence existed for a reduced response of leukocytes from horses with gastrointestinal disease to ex vivo exposure to LPS. Leukocyte expression of inflammatory genes after ex vivo incubation with LPS appeared to be related to pathogenesis and prognosis. PMID- 20919903 TI - Evaluation of the pathogenicity and virulence of three strains of Salmonella organisms in calves and pigs. AB - OBJECTIVE: To assess in pigs the pathogenicity and virulence of 3 strains of Salmonella spp capable of causing atypical salmonellosis in cattle. ANIMALS: 36 Holstein calves and 72 pigs experimentally infected with Salmonella spp. PROCEDURES: Representative Salmonella strains associated with 3 new disease phenotypes (protozoa-mediated hypervirulence, multisystemic cytopathicity, and encephalopathy) that have been characterized in cattle during the past 10 years were orally inoculated into pigs. Clinical manifestations were compared with those observed in cattle. Samples were collected from various tissues, and the presence of Salmonella organisms was assessed qualitatively and quantitatively by use of Salmonella-selective media. RESULTS: Of the 3 unique Salmonella disease phenotypes observed in cattle, only protozoa-mediated hypervirulence was observed in pigs. Hypervirulence was related to a more rapid onset of disease and higher pathogen burden in pigs than in cattle. This phenotype was observed in pigs inoculated with multiresistant Salmonella enterica serotypes Typhimurium or Choleraesuis bearing the Salmonella genomic island 1 (SGI1) integron. CONCLUSIONS AND CLINICAL RELEVANCE: Salmonella hypervirulence was identified in pigs noculated with SGI1-bearing strains exposed to free-living protozoa. Additionally, an SGI1-bearing strain of Salmonella Choleraesuis was detected that resulted in augmented virulence in pigs. Therefore, it appeared that protozoa associated salmonellosis was analogous in pigs and cattle. Salmonella-mediated encephalopathy and multisystemic cytopathicity did not appear to be relevant diseases in pigs. PMID- 20919904 TI - Comparison of iatrogenic transmission of Anaplasma marginale in Holstein steers via needle and needle-free injection techniques. AB - OBJECTIVE: To compare iatrogenic transmission of Anaplasma marginale during sham vaccination between needle and needle-free injection techniques. ANIMALS: 26 Holstein steers confirmed negative for anaplasmosis by use of a competitive ELISA (cELISA) and an A marginale-specific reverse transcription (RT)-PCR assay. PROCEDURES: An isolate of A marginale was propagated to a circulating parasitemia of 2.0% in a splenectomized steer. Sham vaccination was performed in the left cervical muscles of the splenectomized parasitemic steer with a hypodermic needle fitted to a multiple-dose syringe. The same needle and syringe were used to sham vaccinate a naive steer. This 2-step procedure was repeated until 10 naive steers (group ND) were injected. Similarly, sham vaccination of the left cervical muscles of the splenectomized parasitemic steer and another group of 10 naive steers (group NF) was performed by use of a needle-free injection system. Five control steers were not injected. Disease status was evaluated twice weekly for 61 days by use of light microscopy, a cELISA, and an A marginale-specific RT-PCR assay. RESULTS: Iatrogenic transmission was detected in 6 of 10 steers in group ND. Disease status did not change in the NF or control steers. Sensitivity of light microscopy, cELISA, and RT-PCR assay was 100% on days 41, 41, and 20 after sham vaccination, respectively; however, only cELISA and RT-PCR assay sustained a sensitivity of 100% thereafter. CONCLUSIONS AND CLINICAL RELEVANCE: Needle-free injection was superior to needle injection for the control of iatrogenic transmission of A marginale. PMID- 20919905 TI - Prevalence of antimicrobial resistance and association with toxin genes in Clostridium difficile in commercial swine. AB - OBJECTIVE: To estimate prevalence and determine association between antimicrobia resistance and toxin gene profile of Clostridium difficile in commercial pigs at the preharvest food-safety level. ANIMALS: 68 sows and 251 young pigs from 5 farms in North Carolina and 3 in Ohio. PROCEDURES: Fecal samples were collected from sows (8/farm) and matched young pigs (32/farm) at farrowing and again at the nursery and finishing stages. Clostridium difficile isolates were tested for susceptibility to 6 antimicrobials. A PCR assay was used to detect genes coding for enterotoxin A (tcdA), cytotoxin B (tcdB), and binary toxin (cdtB). RESULTS: C difficile prevalence in young pigs at farrowing was 73% (n=183) with significantly higher prevalence in Ohio (875%) than in North Carolina (64%). Clostridium difficile was isolated from 32 (47%) sows with no significant difference between the 2 regions. A single pig had a positive test result at the nursery, and no isolate was recovered at the finishing farms. Resistance to ciprofloxacin was predominant in young pigs (91.3% of isolates) and sows (94%). The antimicrobial resistance profile ciprofloxacin-erythromycin-tetracycline was detected in 21.4% and 11.7% of isolates from young pigs and sows, respectively. Most isolates had positive results for tcdA (65%), tcdB (84%), and the binary toxin cdtB (77%) genes. Erythromycin resistance and tetracycline resistance were significantly associated with toxin gene profiles. CONCLUSIONS AND CLINICAL RELEVANCE: The common occurrence of antimicrobial-resistant C difficile and the significant association of toxigenic strains with antimicrobial resistance could contribute to high morbidity in farms with farrowing pigs. PMID- 20919906 TI - Evaluation of peptide- and recombinant protein-based assays for detection of anti Ehrlichia ewingii antibodies in experimentally and naturally infected dogs. [corrected] AB - OBJECTIVE: To evaluate microtiter-plate format ELISAs constructed by use of different diagnostic targets derived from the Ehrlichia ewingii p28 outer membrane protein for detection of E ewingii antibodies in experimentally and naturally infected dogs. SAMPLE POPULATION: Serum samples from 87 kenneled dogs, 9 dogs experimentally infected with anti-E ewingii, and 180 potentially naturally exposed dogs from Missouri. PROCEDURES: The capacities of the synthetic peptide and truncated recombinant protein to function as detection reagents in ELISAs were compared by use of PCR assay, western blot analysis, and a full-length recombinant protein ELISA. Diagnostic targets included an E ewingii synthetic peptide (EESP) and 2 recombinant proteins: a full-length E ewingii outer membrane protein (EEp28) and a truncated E ewingii outer membrane protein (EETp28) RESULTS: A subset of Ehrlichia canis-positive samples cross-reacted in the EEp28 ELISA; none were reactive in the EESP and EETp28 ELISAs. The EESP- and EETp28 based ELISAs detected E ewingii seroconversion at approximately the same time after infection as the EEp28 ELISAs. In afield population, each of the ELISAs identified the same 35 samples as reactive and 27 samples as nonreactive. Anaplasma and E can is peptides used in a commercially available ELISA platform did not detect anti-E ewingii antibodies in experimentally infected dogs. CONCLUSIONS AND CLINICAL RELEVANCE: The EESP and EETp28 ELISAs were suitable for specifically detecting anti-E ewingii antibodies in experimentally and naturally infected dogs. PMID- 20919907 TI - Pharmacokinetics of metformin after enteral administration in insulin-resistant ponies. AB - OBJECTIVE: To determine pharmacokinetics and plasma steady-state kinetics of metformin after oral or nasogastric administration in insulin-resistant (IR) ponies. ANIMALS: 8 IR ponies. PROCEDURES: Metformin (30 mg/kg) was administered to 8 ponies via nasogastric tube Blood samples were collected at intervals for 24 hours. Plasma concentrations of metformin were measured via liquid chromatography electrospray tandem mass spectroscopy Pharmacokinetic variables were determined via noncompartmental analysis. Metformin (15 mg/kg, PO, twice daily [8 am and 5 pm]) was administered to 4 ponies for an additional 20 days, and blood samples were obtained every 2 days. Plasma concentration at steady state (Css) was determined. RESULTS: Mean+/-SD elimination half-life (t1/2) of metformin was 11.7+/-5.2 hours, maxima plasma concentration was 748+/-269 ng/mL at 54+/-32 minutes, mean area under the curve was 355+/-92 microg.h/mL, and apparent clearance was 90.6+/-28.1 mL/min/kg. The Css was 122+/-22 ng/mL. CONCLUSIONS AND CLINICAL RELEVANCE: Metformin reportedly enhances insulin sensitivity of peripheral tissues without stimulating insulin secretion, but bioavailability in horses is low. The t1/2 of metformin in IR ponies was similar to that in humans. Actual clearance of metformin adjusted for bioavailability in IR ponies was similar to that in humans; however, during chronic oral administration at dosages reported in efficacy studies, the Css of metformin was less than values associated with therapeutic efficacy in humans The apparent lack of long-term efficacy of metformin in horses is likely attributable to low bioavailability, rather than to rapid clearance. PMID- 20919909 TI - Evaluation of exercise-induced changes in concentrations of C-reactive protein and serum biochemical values in sled dogs completing a long-distance endurance race. AB - OBJECTIVE: To determine whether long-distance endurance exercise in sled dogs causes increases in serum concentrations of C-reactive protein (CRP) and whether such increases are correlated with other markers of the exercise-induced acute phase response. ANIMALS: 25 sled dogs. PROCEDURES: Serum was obtained from 25 sled dogs approximately 48 hours before and immediately after completing a race of 557 km. Serum was analyzed to determine concentrations of CRP and interleukin (IL)-6, and serum biochemical analysis (and iron homeostasis analysis) also was performed. RESULTS: CRP concentrations increased significantly from a mean+/-SD concentration of 22.4+/-16.3 microg/mL before racing to a mean of 263.3+/-103.8 microg/mL immediately after racing Serum IL-6 concentrations were unchanged; however, there was a modest but significant correlation (r=0.50) between the increase in CRP concentration and an overall decrease in serum albumin concentration, which suggested an inverse relationship between hepatic synthesis of the 2 proteins. Differences in CRP concentrations among teams of dogs revealed that concentrations before racing may be influenced by previous episodes of exercise. Serum iron concentration had only a mild decrease, which may have been attributable to iron-rich diets consumed by the dogs. CONCLUSIONS AND CLINICAL RELEVANCE: CRP concentrations may serve as a potential marker for exercise induced inflammation. The exact amount of exercise required to induce such a response is unknown, but dogs apparently have a more robust acute-phase response than do humans. Clinical evaluation of CRP concentrations must account for physical activity when those concentrations are used as a potential marker for systemic inflammation. PMID- 20919910 TI - Effects of administration of caffeine on metabolic variables in neonatal pigs with peripartum asphyxia. AB - OBJECTIVE: To determine effects of 2 doses of caffeine on metabolic variables in neonatal pigs with peripartum asphyxia. ANIMALS: 180 neonatal pigs. PROCEDURES: Neonatal pigs were assigned to 2 groups (groups P and F) on the basis of results for a vitality scale (passed or failed, respectively). Within each group, there were 3 subgroups of 30 pigs each. Within each group, the 3 subgroups received a placebo that consisted of an empty gelatin capsule, a gelatin capsule that contained 20 mg of caffeine, and a gelatin capsule that contained 35 mg of caffeine, respectively; all capsules were administered orally (0 hours). Blood samples were collected immediately before and 24 hours after capsule administration. RESULTS: Pigs in groups P and F that received 20 or 35 mg of caffeine had significant increases in triglyceride concentrations. All pigs in groups P and F had a significant decrease in lactate concentrations, although the placebo-treated pigs in group F had larger decreases than did the group F pigs treated with 20 or 35 mg of caffeine. Glucose concentrations increased significantly in group F pigs treated with 20 or 35 mg of caffeine (30% and 50%, respectively), whereas glucose concentrations remained unchanged in group P pigs. In pigs treated with 35 mg of caffeine, the final weight obtained for group F was approximately 8% lower than that obtained for group P. CONCLUSIONS AND CLINICAL RELEVANCE: Administering caffeine immediately after birth to neonatal pigs with severe oxygen restriction resulted in significant improvements in metabolic variables. PMID- 20919911 TI - Effects of renal autograft ischemic storage and reperfusion on intraoperative hemodynamic patterns and plasma renin concentrations in clinically normal cats undergoing renal autotransplantation and contralateral nephrectomy. AB - OBJECTIVE: To evaluate the effect of the duration of cold Ischemia on the renin angiotensin system during renal transplantation In cats and to define the potential Influence of vasoactive factors in renal tissue following cold ischemic storage versus warm ischemic storage. ANIMALS: 10 purpose-bred 6-month-old sexually Intact female cats. PROCEDURES: 10 cats underwent renal autotransplantation after 30 minutes (n=5) or 3 hours (5) of simple, ex vivo cold storage of renal autographs. Following autograft reperfusion, direct hemodynamic variables were measured with a telemetric Implant and samples were collected for plasma renin concentration. Activation of vascular-related genes (renin, endothelin, and angiotensin converting enzyme) relative to 2-hour simple cold or warm ischemia was also evaluated. RESULTS: No significant difference between groups was detected In any of the hemodynamic variables or postreperfusion plasma renin concentrations measured in this study relative to the duration of cold ischemic storage. There was also no difference between warm- and cold-stored kidneys in the expression of vascular-related genes. CONCLUSIONS AND CLINICAL RELEVANCE: Prolonged renal Ischemia for clinically relevant durations does not appear to predispose clinically normal cats to altered hemodynamics or high plasma renin concentrations following graft reperfusion. Activation of vasoactive genes does not appear to be Influenced by type of Ischemia over 2 hours. PMID- 20919912 TI - Evaluation of the osteogenic and chondrogenic differentiation capacities of equine adipose tissue-derived mesenchymal stem cells. AB - OBJECTIVE: To evaluate the proliferative behavior, telomere length, immunophenotype, and differentiation capacity of equine adipose tissue-derived mesenchymal stem cells (AT-MSCs). ANIMALS: 6 adult racing horses treated for articular Injury but otherwise healthy. PROCEDURES: AT-MSCs were Isolated from horses and expanded In Dulbecco modified Eagle medium enriched with fetal bovine serum and antimicrobials. Expression of cell surface antigens and telomere length were Investigated via flow cytometry Differentiation of MSCs Into chondrocytes, osteoblasts, and adipocytes was Induced In vitro by specific stimuli and was evaluated by analyzing marker genes with quantitative reverse transcriptase PCR assays and immunocytochemical and cytologie evaluations. RESULTS: Equine MSCs could be cultured up to the fifth passage before signs of senescence, apoptosis, and detachment Indicated cellular exhaustion. However, the AT-MSCs from 2 of 6 horses survived to later passages with Increased doubling rates and telomere lengths. The cells had a typical phenotype, with expression of CD14, CD73, CD90, CD105, CD140b, and CD164 antigens and a lack of CD34 and CD45 antigens. The cells also had a strong potential to differentiate Into osteoblasts, as characterized by Intense von Kossa and alizarin red staining as well as high Induction of osteopontin. Chondrogenic differentiation was detected via Alelan blue staining and expression of aggrecan and type II collagen Adipogenesis was Induced in AT MSCs by supplementation of differentiation media with rabbit serum. CONCLUSIONS AND CLINICAL RELEVANCE: Equine AT-MSCs representa suitable cellular source for regenerative treatment of bone or cartilage defects, particularly when expanded In vitro for only a few passages. PMID- 20919913 TI - Comparison of the osteogenic potential of equine mesenchymal stem cells from bone marrow, adipose tissue, umbilical cord blood, and umbilical cord tissue. AB - OBJECTIVE: To determine the optimal osteogenic source of equine mesenchymal stem cells (eMSCs) and optimize collection of and expansion conditions for those cells. ANIMALS: 10 adult Quarter Horses and 8 newborn Thoroughbred foals. PROCEDURES: eMSCs were isolated from bone marrow (BM), adipose tissue, and umbilical cord blood and tissue, and the osteogenic potential of each type was assessed. Effects of anatomic site, aspiration volume, and serum type on eMSC yield from BM were investigated. RESULTS: BM-eMSCs had the highest overall expression of the osteogenic genes Cbfa1, Osx, and Omd and staining for ALP activity and calcium deposition. There was no significant difference in BM-eMSC yield from the tuber coxae or sternum, but yield was significantly greater from the first 60-mL aspirate than from subsequent aspirates. The BM-eMSC expansion rate was significantly higher when cells were cultured in fetal bovine serum instead of autologous serum (AS). CONCLUSIONS AND CLINICAL RELEVANCE: eMSCs from BM possessed the highest in vitro osteogenic potential; eMSCs from adipose tissue also had robust osteogenic potential. The tuber coxae and the sternum were viable sources of BM-eMSCs in yearlings, and 60 mL of BM aspirate was sufficient for culture and expansion. Expanding BM-eMSCs in AS to avoid potential immunologic reactions decreased the total yield because BM-eMSCs grew significantly slower in AS than in fetal bovine serum. Additional studies are needed to determine optimal ex vivo eMSC culture and expansion conditions, including the timing and use of growth factor-supplemented AS. PMID- 20919914 TI - Early detection of ketoprofen-induced acute kidney injury in sheep as determined by evaluation of urinary enzyme activities. AB - OBJECTIVE: To evaluate early indicators of renal tissue destruction and changes in urinary enzyme activities in sheep during the first hours after acute kidney injury induced by administration of an overdose of an NSAID. ANIMALS: 12 adult female sheep. PROCEDURES: Acute kidney injury was induced in 6 sheep by administration of ketoprofen (30 mg/kg, IV) and detected by evaluation of urinary protein concentration, iohexol clearance, and results of histologic examination. Six sheep served as control animals. Blood and urine samples were collected for up to 24 hours after administration of ketoprofen. Plasma concentrations of urea, creatinine, albumin, and total protein; plasma activities of alkaline phosphatase, acid phosphatase, gamma-glutamyl transpeptidase (GGT), matrix metalloproteinase (MMP)-2, and MMP-9; and urinary creatinine and protein concentrations, specific gravity, and activities of alkaline phosphatase, acid phosphatase, GGT lactate dehydrogenase, N-acetyl-beta-D-glucosaminidase (NAG), MMP-2, and MMP-9 were measured. Urinary protein concentration and enzyme activities were normalized on the basis of urinary creatinine concentrations and reported as ratios. RESULTS: Many urinary enzyme-to-creatinine ratios increased before the plasma creatinine concentration exceeded the reference value. Urine NAG, lactate dehydrogenase, and acid phosphatase activities were increased beginning at 2 hours after ketoprofen administration, and alkaline phosphatase, GGT, and MMP-2 activities were increased beginning at 4 hours after ketoprofen administration. Most peak urinary enzyme-to-creatinine ratios were detected earlier than were the highest plasma creatinine and urea concentrations. CONCLUSIONS AND CLINICAL RELEVANCE: Urinary enzyme activities were sensitive early indicators of acute kidney injury induced by an overdose of an NSAID in sheep. PMID- 20919915 TI - Contemporary experience in the management of angiomyolipoma. AB - PURPOSE: We review our single center experience in the management of renal angiomyolipoma (AML) in patients who were treated with active surveillance (AS) or invasive treatment protocols. PATIENTS AND METHODS: A prospectively evaluated database was reviewed, and we identified 91 patients with the diagnosis of renal AML who presented between June 1985 and February 2009. Patient characteristics, clinical presentation, treatment modalities, and patient outcomes were evaluated. Patients on AS were analyzed for successful completion of the surveillance protocol considering age, symptomatic presentation, and tumor size as potential predictors of invasive treatment. RESULTS: A total of 91 patients with AMLs were identified. The mean patient age was 57 years. Seventy-three (83.9%) patients presented incidentally, and 14 (16%) patients were symptomatic at presentation. Forty-five patients were treated with AS, 4 underwent embolization, and 38 patients had extirpative surgery. After a median follow-up of 54.8 months (range 0.2-211.7 mos), there was a mean growth rate of 0.088 cm/year in the group who were treated with AS. AS failed in three patients. Two patients had retroperitoneal bleeding during the observation period, and one patient manifested an expeditious growth rate of 0.7 cm/year and underwent a radical nephrectomy. CONCLUSIONS: AML is a renal tumor that usually exhibits a benign course. Surgical removal and embolization are the standard invasive treatment modalities. AS for AMLs is associated with a slow and consistent growth rate (0.088 cm/year), typically has minimal morbidity, and is a reasonable option in selected patients. Symptomatic presentation and size (> 3 cm) are not predictive for necessitating an invasive procedure. PMID- 20919916 TI - Extracorporeal shockwave lithotripsy in elderly: impact of age and comorbidity on stone-free rate and complications. AB - INTRODUCTION: The aim of this study was to investigate and compare the success and complication rates of extracorporeal shockwave lithotripsy (SWL) in three cohorts of patients older than 60 years. PATIENTS AND METHODS: Our study included 444 patients older than 60 years who were treated with SWL between May 2001 and May 2008 at the Croatian Referential Center for Urolythiasis in Osijek. Three groups were formed: group I (60-65 years old), group II (66-70), and group III (> 70). There were 175, 151, and 118 patients in groups I, II, and III, respectively, with a mean age of 67.7 +/- 5.4 years for all patients. Demographic data, comorbidities, kidney function, stone characteristics, treatment details, complications, and stone-free rate (SFR) were analyzed. RESULTS: We performed 1.7 +/- 1.12 sessions per patient, with 3166 +/- 571.3 impulses per session and a mean energy of 18.78 +/- 0.64 kV. Three groups did not differ in number of SWL sessions (p = 0.78), number of impulses (p = 0.34), energy level (p = 0.5), stone size (p = 0.3), and pretreatment creatinine level (p = 0.88). Comorbidities were found in 55% of patients, with almost every third patient having two or more ones present. Complications were noted in 6% of patients, with no significant difference when comparing complication rates between the groups. An overall SFR of 67.98% was found. There was no statistically significant difference when comparing SFRs between the studied groups, even after dividing patients into those with renal and ureteral stones. CONCLUSION: Our study shows that good SFR and low rate of complications can be achieved with proper patient selection for SWL, regardless of patients' age and comorbidities. PMID- 20919917 TI - Retroperitoneoscopic living donor nephrectomy: experience of 425 cases at a single center. AB - BACKGROUND AND PURPOSE: Laparoscopic living donor nephrectomy (LLDN) is a standard method of donor nephrectomy. Most cases of LLDN are transperitoneal. Retroperitoneal access, however, implies a direct approach to the retroperitoneal organs without interfering with any of them. Since 2001, we have been trying to establish the technique of retroperitoneoscopic live donor nephrectomy (RPLDN). To assess the safety, feasibility, and usefulness of RPLDN, we reviewed the experience with this technique at our institution. PATIENTS AND METHODS: From July 2001 to March 2009, 425 patients underwent live donor renal transplantation at our institution with allografts procured by RPLDN. Study variables included operative time, time to retrieval of the kidney, blood loss, warm ischemia time, length of hospital stay, number and length of renal vessels, graft function, and complications. RESULTS: Mean follow-up was 53 months. Donor nephrectomy was performed successfully in all patients. The complication rate was 4.9%. In one case, the procedure was changed to open donor nephrectomy because of severe adhesion in the renal hilum from previous surgery. Ureteral complications occurred in four patients, who were successfully treated with retrograde ureteral stent placement. None of the donors needed readmission. Mean warm ischemia time was 4.8 minutes. Creatinine levels returned to normal in all patients, and long term allograft function was good. Serum creatinine levels at postoperative days 1, 7, and 14 were 3.7 mg/dL, 1.4 mg/dL, and 1.4 mg/dL on average, respectively. Slow graft function was noted in four (1.1%) cases but returned to the normal level within 2 weeks after surgery. One-year donor survival was 99%, and 1-year graft survival was 98.2%. CONCLUSIONS: Excellent donor safety and allograft function were obtained with RPLDN. These results suggest that RPLDN could be an option for LLDN. PMID- 20919918 TI - Blood loss during transurethral resection of the prostate as measured by the chromium-51 method. AB - PURPOSE: To evaluate blood loss during transurethral resection of the prostate (TURP), and its predictive factors, using the chromium 51 (51Cr) labeling method. PATIENTS AND METHODS: From January to June 2008, 41 patients who underwent TURP for symptomatic benign prostatic hyperplasia (BPH) at four French urology centers were included in the analysis. Red cells volume was measured by the 51Cr method 1 day before TURP, and on postoperative day 3. Overall blood loss was estimated by multiplication of red cells volume loss and preoperative venous hematocrit value. RESULTS: Mean preoperative red cells volume was 1997 mL. Mean loss of red cells volume was 209 ml, which corresponds to an estimated blood loss of 507 mL. Mean delta of hematocrit and hemoglobin were 1.4% and 0.71 g/dL, respectively. In univariate analysis, prostate volume, weight of resected tissue, preoperative red cells volume, and resection time were significantly and directly associated with loss of red cells volume (P = 0.038, P = 0.004, P = 0.002, and P = 0.039, respectively). Bipolar and monopolar TURP did not lead to significant difference of red cells loss. In multivariate analysis, both preoperative red cells volume and weight of resected tissue were independent predictors of red cells loss (P = 0.017 and P = 0.048 respectively). CONCLUSION: We present the first study to measure blood loss secondary to TURP using the 51Cr method. This technique allowed evaluating blood loss not only during the surgical procedure but also during the postoperative period. We learned from this study that, on average, blood loss from the procedure until postoperative day 3 was more than 500 mL, which is larger than previously reported amounts as measured by other methods. Because significant blood loss might occur during the postoperative period, the 51Cr method should be used to measure blood loss when evaluating new emerging techniques to manage BPH. PMID- 20919919 TI - Renal access by urologist or radiologist during percutaneous nephrolithotomy. AB - PURPOSE: We evaluated percutaneous access for percutaneous nephrolithotomy (PCNL) that was obtained by interventional radiologists or urologists at a single academic institution and compared access outcomes and complications. PATIENTS AND METHODS: The records of 233 patients who underwent PCNL at the University of Pittsburgh Medical Center between 2000 and 2008 were retrospectively reviewed. Patients were stratified according to percutaneous access by urologists (group 1) or a group of interventional radiologists (group 2) in 195 and 38 patients, respectively. Radiologist-acquired access was performed for collecting system decompression in 33.3% of patients in group 2. A predicted access difficulty score was calculated using demographic, stone, and operative variables. Percutaneous access complications and stone-free rates were compared between groups. RESULTS: Mean patient age was 53 +/- 16 years (51% male, range 19-90 y) and 58 +/- 17 years (62% male, range 25-95 y) in groups 1 and 2, respectively. Use of multiple access tracts (4.3% vs 5.4%; P = 0.54), mean stone diameter (3.5 +/- 1.8 cm vs 3.6 +/- 1.9 cm; P = 0.97), and percentage of supracostal tracts (36% vs 35%; P = 0.63) were comparable between groups. Mean access difficulty parameters were comparable between groups. The percentage of staghorn calculi (39% vs 30%; P = 0.28) and number of obese (body mass index > 30) patients (30% vs 38%; P = 0.34) were also comparable between groups 1 and 2. The complication rate was the same in the two groups (14.3% vs 13.5%; P = 0.52). The overall stone free rate was significantly greater in the urology access group (99% vs 92.1%; P = 0.033) on univariate analysis. Radiologist-obtained access could not be used in 36.8% of patients, necessitating additional access tract placement at the time of surgery. CONCLUSIONS: Urologist-obtained access is safe and effective for PCNL. Access obtained by radiologists for decompression of infected or obstructed systems often is not adequate for PCNL. Despite similar stone complexity and access difficulty, urologist-obtained access was associated with a statistically significant improvement in overall stone-free rate. PMID- 20919920 TI - HIV type 1-mediated downregulation of HLA-B*57/B*5801 proteins on elite suppressor CD4+ T cells. AB - Elite controllers or suppressors (ES) are HIV-1-infected patients who maintain viral loads of <50 copies/ml without antiretroviral therapy. While HLA-B*57 and B*5801 alleles are overrepresented in ES, many HLA-B*57/B*5801 patients become chronic progressors (CP). We show here that HIV-1 infection results in similar levels of downregulation of HLA-B*57 and HLA-B*5801 molecules on primary CD4(+) T cells from ES and CP. Thus, differences in HIV-1-mediated downregulation of HLA B*57/B*5801 molecules do not distinguish ES from CP. PMID- 20919921 TI - Maternal exposure to domestic violence and pregnancy and birth outcomes: a systematic review and meta-analyses. AB - BACKGROUND: Pregnant women who experience domestic violence are at increased risk of adverse outcomes in addition to the risks to themselves. Inadequate prenatal care, higher incidences of high-risk behaviors, direct physical trauma, stress, and neglect are postulated mechanisms. Our objective was to systematically review birth outcomes among women who experienced domestic violence. METHODS: Medline, Embase, CINAHL, and bibliographies of identified articles were searched for English language studies. Studies reporting rates of low birth weight, preterm birth, small for gestational age births, birth weight, or gestational age at birth were included. Study quality was assessed for selection, exposure assessment, confounder adjustment, analyses, outcomes assessment, and attrition biases. Unadjusted and adjusted data from included studies were extracted by two reviewers. Summary odds ratio (OR) and confidence intervals (CI) were calculated using the random effects model. Population-attributable risk was calculated. RESULTS: Thirty studies of low to moderate risk of biases were included. Low birth weight (adjusted OR 1.53, 95% CI 1.28-1.82) and preterm births (adjusted OR 1.46, 95% CI 1.27-1.67) were increased among women exposed to domestic violence. As the prevalence of reported domestic violence during pregnancy was low, the population-attributable risk was low. Prospective cohort studies provided robust and consistent results. CONCLUSIONS: Maternal exposure to domestic violence was associated with significantly increased risk of low birth weight and preterm birth. Underreporting of domestic violence is hypothesized. Effective programs to identify violence and intervene during pregnancy are essential. PMID- 20919922 TI - Sustained profile of transmitted drug resistance mutations for more than 10 years in an HIV type 1-infected patient. AB - We present an HIV-1-infected patient with a profile of transmitted drug resistance (RT M41L, E44D, V118I, L210W, T215D) sustained during more than 10 years in the absence of treatment. Clonal analysis of different plasma and cellular samples within this period did not reveal any reversion to the wild-type genotype. PMID- 20919923 TI - A genomic and bioinformatics analysis of the integration of HIV in peripheral blood mononuclear cells. AB - The mechanistic basis of the target-site preference of lentivirus DNA integration is not well understood. In the present in silico study, we describe the integrational profile of simultaneous HIV-1 and HIV-2 infection. A total of 352 genomic DNA sequences from human peripheral blood mononuclear cells (PBMCs) obtained from GenBank and possessing the 5' LTR of HIV were used to characterize the structure and composition of local chromatin associated with high frequency integration sites. These sequences were aligned with the draft human genome (hg18) using BLAST (NCBI) and BLAT (UCSC) in order to derive information about chromosome localization, functional aspects of coding protein genes, CpG island number, and repetitive elements flanking integration sites. No significant differences in the integrational profile between HIV-1 and HIV-2 were found. However, we observed a tendency in both lentiviruses to integrate in the vicinity of protein coding genes. Multiple regression analysis showed a strong correlation between the number of genes and the number of CpG islands in regions with high integration frequency, mainly in chromosome 17 (R = 0.95, p < 0.05). Our results provide strong evidence that HIV-1 and HIV-2 have common genomic environments in the local chromatin regions with high gene density and CpG islands. The understanding of local genomic environments with a high frequency of integration would be the starting point to develop novel antiviral strategies for lentiviral infection. PMID- 20919924 TI - Short Communication: Hepatitis B Virus Harboring Nucleotide Deletions in the Basal Core Promoter in HBe-Positive HIV-Coinfected Patients Under Lamivudine Therapy. AB - The presence of HBV genomes with deletions at the basal core promoter (BCP) is associated with more aggressive liver disease. This 3-year longitudinal analysis of two HIV-HBV-coinfected patients allowed identification of three deletions with dissimilar abundance and permanence into the HBV quasispecies composition. These deletions may contribute to HBV pathogenesis in HIV-coinfected individuals. PMID- 20919925 TI - Effects of autologous stem cell transplantation in HIV: searching for the origins of viral replication in settings of profound CD4(+) T cell depletion. PMID- 20919927 TI - Does 1-(R)-aminoindan possess neuroprotective properties against experimental Parkinson's disease? AB - The anti-Parkinsonian, monoamine oxidase-B inhibitor drug, rasagiline (Azilect(r)), is primarily metabolized by hepatic cytochrome P450 isoenzyme 1A2 mediated N-dealkylation to form its major metabolite, 1-(R)-aminoindan. The present study was undertaken to further investigate, for the first time, the possible neuroprotective effect of 1-(R)-aminoindan in two rat models of Parkinson's disease, the 6-hydroxydopamine- and lactacystin (a proteasomal inhibitor)-induced nigrostriatal degeneration. 1-(R)-aminoindan reversed behavioral asymmetry and restored striatal catecholamine levels in these two rat models and significantly protected neurons from hydrogen peroxide-induced oxidative stress. These observations indicate that 1-(R)-aminoindan may contribute to the overall neuroprotective activity of its parental compound, rasagiline. PMID- 20919926 TI - Analysis of HIV type 1 BF recombinant sequences from South America dates the origin of CRF12_BF to a recombination event in the 1970s. AB - HIV-1 epidemics in South America are believed to have originated in part from the subtype B epidemic initiated in the Caribbean/North America region. However, circulation of BF recombinants in similar proportions was extensively reported. Information currently shows that many BF recombinants share a recombination structure similar to that found in the CRF12_BF. In the present study, analyzing a set of 405 HIV sequences, we identified the most likely origin of the BF epidemic in an early event of recombination. We found that the subtype B epidemics in South America analyzed in the present study were initiated by a founder event that occurred in the early 1970s, a few years after the introduction of these strains in the Americas. Regarding the F/BF recombinant epidemics, by analyzing a subtype F genomic segment within the viral gene gag present in the majority of the BF recombinants, we found evidence of a geographic divergence very soon after the introduction of subtype F strains in South America. Moreover, through analysis of a subtype B segment present in all the CRF12_BF-like recombination structure, we estimated the circulation of the subtype B strain that gave rise to that recombinant structure around the same time period estimated for the introduction of subtype F strains. The HIV epidemics in South America were initiated in part through a founder event driven by subtype B strains coming from the previously established epidemic in the north of the continent. A second introduction driven by subtype F strains is likely to have encountered the incipient subtype B epidemic that soon after their arrival recombined with them, originating the BF epidemic in the region. These results may explain why in South America the majority of F sequences are found as BF recombinants. PMID- 20919928 TI - Two-component mediated peroxide sensing and signal transduction in fission yeast. AB - Two-component related proteins play a major role in regulating the oxidative stress response in the fission yeast, Schizosaccharomyces pombe. For example, the peroxide-sensing Mak2 and Mak3 histidine kinases regulate H(2)O(2)-induced activation of the Sty1 stress-activated protein kinase pathway, and the Skn7 related response regulator transcription factor, Prr1, is essential for activation of the core oxidative stress response genes. Here, we investigate the mechanism by which the S. pombe two-component system senses H(2)O(2), and the potential role of two-component signaling in the regulation of Prr1. Significantly, we demonstrate that PAS and GAF domains present in the Mak2 histidine kinase are essential for redox-sensing and activation of Sty1. In addition, we find that Prr1 is required for the transcriptional response to a wide range of H(2)O(2) concentrations and, furthermore, that two-component regulation of Prr1 is specifically required for the response of cells to high levels of H(2)O(2). Significantly, this provides the first demonstration that the conserved two-component phosphorylation site on Skn7-related proteins influences resistance to oxidative stress and oxidative stress-induced gene expression. Collectively, these data provide new insights into the two-component mediated sensing and signaling mechanisms underlying the response of S. pombe to oxidative stress. PMID- 20919929 TI - Process optimization by response surface design and characterization study on geniposide pharmacosomes. AB - The objective of this study was to prepare and characterize geniposide pharmcosomes (GP-PMS) and optimize the process and formulation variables using response surface methodology. Tetrahydrofuran was used as a reaction medium, GP and phospholipids were resolved into the medium, and GP-PMS was formed after the organic solvent was evaporated off under vacuum condition. The process and formulation variables were optimized by central composite design (CCD) of response surface methodology (RSM). The phospholipid-to-drug ratio (X(1)), reaction temperature (X(2)) and the drug concentration (X(3)) were selected as independent variables and the yield (%) of GP 'present as a complex' in the PMS was used as the dependent variable. The physico-chemical properties of the complex obtained by optimal parameters were investigated by means of Fourier transform infrared spectrophotometry (FT-IR), differential scanning calorimetry, n-octanol/water partition coefficient (P) and particle size analysis. Multiple linear regression analysis for optimization by CCD revealed that the higher the yield of GP 'present as a complex' in the GP-PMS was obtained wherein the optimal settings of X(1), X(2) and X(3) are 3, 50 degrees C and 5.5 mg/mL, respectively. The DSC and IR studies of GP-PMS by the optimal settings demonstrated that GP and phospholipids in the GP-PMS were combined by non-covalent bond, not forming a new compound. GP-PMS could significantly increased the lipophilicify of GP, and P of GP-PMS in n-octanol and water was about 20 multiples more than that of GP material. Pharmacosomes could be an alternative approach to improve the absorption and permeation of biologically active constituents. PMID- 20919930 TI - Multiple functions of peroxiredoxins: peroxidases, sensors and regulators of the intracellular messenger H2O2, and protein chaperones. AB - Peroxiredoxins (Prxs) are a family of peroxidases that reduce peroxides, with a conserved cysteine residue (the peroxidatic Cys) serving as the site of oxidation by peroxides. Peroxides oxidize the peroxidatic Cys-SH to Cys-SOH, which then reacts with another cysteine residue (typically the resolving Cys [C(R)]) to form a disulfide that is subsequently reduced by an appropriate electron donor. On the basis of the location or absence of the C(R), Prxs are classified into 2-Cys, atypical 2-Cys, and 1-Cys Prx subfamilies. In addition to their peroxidase activity, members of the 2-Cys Prx subfamily appear to serve as peroxide sensors for other proteins and as molecular chaperones. During catalysis, the peroxidatic Cys-SOH of 2-Cys Prxs is occasionally further oxidized to Cys-SO(2)H before disulfide formation, resulting in inactivation of peroxidase activity. This hyperoxidation, which is reversed by the ATP-dependent enzyme sulfiredoxin, modulates the sensor and chaperone functions of 2-Cys Prxs. The peroxidase activity of 2-Cys Prxs is extensively regulated via tyrosine and threonine phosphorylation, which allows modulation of the local concentration of the intracellular messenger H(2)O(2). Finally, 2-Cys Prxs interact with a variety of proteins, with such interaction having been shown to modulate the function of the binding partners in a reciprocal manner. PMID- 20919931 TI - Chronic exposure to a high-fat diet induces hepatic steatosis, impairs nitric oxide bioavailability, and modifies the mitochondrial proteome in mice. AB - Obesity-related pathologies, such as nonalcoholic fatty liver disease, are linked to mitochondrial dysfunction and nitric oxide (NO) deficiency. Herein, we tested the hypothesis that a high-fat diet (HFD) modifies the liver mitochondrial proteome and alters proteins involved in NO metabolism, namely arginase 1 and endothelial NO synthase. Male C57BL/6 mice were fed a control or HFD and liver mitochondria were isolated for proteomics and reactive oxygen species measurements. Steatosis and hepatocyte ballooning were present in livers of HFD mice, with no pathology observed in the controls. HFD mice had increased serum glucose and decreased adiponectin. Mitochondrial reactive oxygen species was increased after 8 weeks in the HFD mice, but decreased at 16 weeks compared with the control, which was accompanied by increased uncoupling protein 2. Using proteomics, 22 proteins were altered as a consequence of the HFD. This cohort consists of oxidative phosphorylation, lipid metabolism, sulfur amino acid metabolism, and chaperone proteins. We observed a HFD-dependent increase in arginase 1 and decrease in activated endothelial NO synthase. Serum and liver nitrate + nitrite were decreased by HFD. In summary, these data demonstrate that a HFD causes steatosis, alters NO metabolism, and modifies the liver mitochondrial proteome; thus, NO may play an important role in the processes responsible for nonalcoholic fatty liver disease. PMID- 20919932 TI - Peroxiredoxin 6: a bifunctional enzyme with glutathione peroxidase and phospholipase A2 activities. AB - Peroxiredoxin 6 (Prdx6) is the prototype and the only mammalian 1-Cys member of the Prdx family. Major differences from 2-Cys Prdxs include the use of glutathione (GSH) instead of thioredoxin as the physiological reductant, heterodimerization with piGSH S-transferase as part of the catalytic cycle, and the ability either to reduce the oxidized sn-2 fatty acyl group of phospholipids (peroxidase activity) or to hydrolyze the sn-2 ester (alkyl) bond of phospholipids (phospholipase A(2) [PLA(2)] activity). The bifunctional protein has separate active sites for peroxidase (C47, R132, H39) and PLA(2) (S32, D140, H26) activities. These activities are dependent on binding of the protein to phospholipids at acidic pH and to oxidized phospholipids at cytosolic pH. Prdx6 can be phosphorylated by MAP kinases at T177, which markedly increases its PLA(2) activity and broadens its pH-activity spectrum. Prdx6 is primarily cytosolic but also is targeted to acidic organelles (lysosomes, lamellar bodies) by a specific targeting sequence (amino acids 31-40). Oxidant stress and keratinocyte growth factor are potent regulators of Prdx6 gene expression. Prdx6 has important roles in both antioxidant defense based on its ability to reduce peroxidized membrane phospholipids and in phospholipid homeostasis based on its ability to generate lysophospholipid substrate for the remodeling pathway of phospholipid synthesis. PMID- 20919934 TI - Neuronal death and oxidative stress in the developing brain. AB - The developing brain is particularly vulnerable to reactive oxygen and reactive nitrogen species-mediated damage because of its high concentrations of unsaturated fatty acids, high rate of oxygen consumption, low concentrations of antioxidants, high content of metals catalyzing free radical formation, and large proportion of sensitive immature cells. In this review, we outline the dynamic changes of energy resources, metabolic requirements, and endogenous free radical scavenging systems during physiologic brain development. We further discuss the involvement of oxidative stress in the pathogenesis of neuronal death after exposure of the infant brain to hyperoxia, hypoxia/ischemia, sedative drugs, ethanol, and mechanical trauma. Several approaches have been developed to combat oxidative stress, but neuroprotective treatment strategies are limited in the clinical setting. PMID- 20919935 TI - Redox regulation of protein tyrosine phosphatases: structural and chemical aspects. AB - Protein tyrosine phosphatases (PTPs) are important targets of the H(2)O(2) that is produced during mammalian signal transduction. H(2)O(2)-mediated inactivation of PTPs also may be important in various pathophysiological conditions involving oxidative stress. Here we review the chemical and structural biology of redox regulated PTPs. Reactions of H(2)O(2) with PTPs convert the catalytic cysteine thiol to a sulfenic acid. In PTPs, the initially generated sulfenic acid residues have the potential to undergo secondary reactions with a neighboring amide nitrogen or cysteine thiol residue to yield a sulfenyl amide or disulfide, respectively. The chemical mechanisms by which formation of sulfenyl amide and disulfide linkages can protect the catalytic cysteine residue against irreversible overoxidation to sulfinic and sulfonic oxidation states are described. Due to the propensity for back-door and distal cysteine residues to engage with the active-site cysteine after oxidative inactivation, differences in the structures of the oxidatively inactivated PTPs may stem, to a large degree, from differences in the number and location of cysteine residues surrounding the active site of the enzymes. PTPs with key cysteine residues in structurally similar locations may be expected to share similar mechanisms of oxidative inactivation. PMID- 20919936 TI - Autophagy: a story of live or let die. PMID- 20919938 TI - NOX2 complex-derived ROS as immune regulators. AB - Reactive oxygen species (ROS) are a heterogeneous group of highly reactive molecules that oxidize targets in a biologic system. During steady-state conditions, ROS are constantly produced in the electron-transport chain during cellular respiration and by various constitutively active oxidases. ROS production can also be induced by activation of the phagocyte NADPH oxidase 2 (NOX2) complex in a process generally referred to as an oxidative burst. The induced ROS have long been considered proinflammatory, causing cell and tissue destruction. Recent findings have challenged this inflammatory role of ROS, and today, ROS are also known to regulate immune responses and cell proliferation and to determine T-cell autoreactivity. NOX2-derived ROS have been shown to suppress antigen-dependent T-cell reactivity and remarkably to reduce the severity of experimental arthritis in both rats and mice. In this review, we discuss the role of ROS and the NOX2 complex as suppressors of autoimmunity, inflammation, and arthritis. PMID- 20919937 TI - Hydrogen peroxide regulates extracellular superoxide dismutase activity and expression in neonatal pulmonary hypertension. AB - We previously demonstrated that superoxide and H(2)O(2) promote pulmonary arterial vasoconstriction in a lamb model of persistent pulmonary hypertension of the newborn (PPHN). Because extracellular superoxide dismutase (ecSOD) augments vasodilation, we hypothesized that H(2)O(2)-mediated ecSOD inactivation contributes to pulmonary arterial vasoconstriction in PPHN lambs. ecSOD activity was decreased in pulmonary arterial smooth muscle cells (PASMCs) isolated from PPHN lambs relative to controls. Exposure to 95% O(2) to mimic hyperoxic ventilation reduced ecSOD activity in control PASMCs. In both cases, these events were associated with increased protein thiol oxidation, as detected by the redox sensor roGFP. Accordingly, exogenous H(2)O(2) decreased ecSOD activity in control PASMCs, and PEG-catalase restored ecSOD activity in PPHN PASMCs. In intact animal studies, ecSOD activity was decreased in fetal PPHN lambs, and in PPHN lambs ventilated with 100% O(2) relative to controls. In ventilated PPHN lambs, administration of a single dose of intratracheal PEG-catalase enhanced ecSOD activity, reduced superoxide levels, and improved oxygenation. We propose that H(2)O(2) generated by PPHN and hyperoxia inactivates ecSOD, and intratracheal catalase enhances enzyme function. The associated decrease in extracellular superoxide augments vasodilation, suggesting that H(2)O(2) scavengers may represent an effective therapy in the clinical management of PPHN. PMID- 20919939 TI - Oxidative modifications of DAMPs suppress inflammation: the case for S100A8 and S100A9. AB - Several S100 Ca(2+)-binding proteins are considered damage-associated molecular pattern molecules (DAMPs). They are actively secreted or released from necrotic cells in response to tissue injury or stress and have various functions important in innate immunity. Here, we review several DAMPs, with particular focus on S100A8 and S100A9, which are susceptible to oxidative modifications by various forms of reactive oxygen species. We discuss the unique posttranslational modifications generated in S100A8 by hypochlorite and the likely structural consequences that alter function. We propose that some reversible modifications act as regulatory switches, representing a mechanism to arrest their novel antiinflammatory activities. These may be important in dampening mast cell activation and altering properties of the activated microcirculation to limit leukocyte adhesion, transmigration, and accumulation. S-nitrosylation of S100A8 in the vasculature could regulate nitric oxide transport and contribute to vessel reflow during resolution of inflammation. PMID- 20919933 TI - The redox basis of epigenetic modifications: from mechanisms to functional consequences. AB - Epigenetic modifications represent mechanisms by which cells may effectively translate multiple signaling inputs into phenotypic outputs. Recent research is revealing that redox metabolism is an increasingly important determinant of epigenetic control that may have significant ramifications in both human health and disease. Numerous characterized epigenetic marks, including histone methylation, acetylation, and ADP-ribosylation, as well as DNA methylation, have direct linkages to central metabolism through critical redox intermediates such as NAD(+), S-adenosyl methionine, and 2-oxoglutarate. Fluctuations in these intermediates caused by both normal and pathologic stimuli may thus have direct effects on epigenetic signaling that lead to measurable changes in gene expression. In this comprehensive review, we present surveys of both metabolism sensitive epigenetic enzymes and the metabolic processes that may play a role in their regulation. To close, we provide a series of clinically relevant illustrations of the communication between metabolism and epigenetics in the pathogenesis of cardiovascular disease, Alzheimer disease, cancer, and environmental toxicity. We anticipate that the regulatory mechanisms described herein will play an increasingly large role in our understanding of human health and disease as epigenetics research progresses. PMID- 20919940 TI - Oscillatory shear stress induces mitochondrial superoxide production: implication of NADPH oxidase and c-Jun NH2-terminal kinase signaling. AB - Fluid shear stress is intimately linked with vascular oxidative stress and atherosclerosis. We posited that atherogenic oscillatory shear stress (OSS) induced mitochondrial superoxide (mtO2*-) production via NADPH oxidase and c-Jun NH(2)-terminal kinase (JNK-1 and JNK-2) signaling. In bovine aortic endothelial cells, OSS (+/-3 dyn/cm2) induced JNK activation, which peaked at 1 h, accompanied by an increase in fluorescein isothiocyanate-conjugated JNK fluorescent and MitoSOX Red (specific for mtO2*- production) intensities. Pretreatment with apocynin (NADPH oxidase inhibitor) or N-acetyl cysteine (antioxidant) significantly attenuated OSS-induced JNK activation. Apocynin further reduced OSS-mediated dihydroethidium and MitoSOX Red intensities specific for cytosolic O2*- and mtO2*- production, respectively. As a corollary, transfecting bovine aortic endothelial cells with JNK siRNA (siJNK) and pretreating with SP600125 (JNK inhibitor) significantly attenuated OSS-mediated mtO2*- production. Immunohistochemistry on explants of human coronary arteries further revealed prominent phosphorylated JNK staining in OSS-exposed regions. These findings indicate that OSS induces mtO2*- production via NADPH oxidase and JNK activation relevant for vascular oxidative stress. PMID- 20919941 TI - "Go with the flow": how Kruppel-like factor 2 regulates the vasoprotective effects of shear stress. AB - Laminar shear stress is known to confer potent anti-inflammatory, antithrombotic, and antiadhesive effects by differentially regulating endothelial gene expression. The identification of Kruppel-like factor 2 as a flow-responsive molecule has greatly advanced our understanding of molecular mechanisms governing vascular homeostasis. This review summarizes the current understanding of Kruppel like factor 2 action in endothelial gene expression and function. PMID- 20919943 TI - Interaction of p53 with tumor suppressive and oncogenic signaling pathways to control cellular reactive oxygen species production. AB - p53 is a crucial transcription factor with tumor suppressive properties that elicits its function through specific target genes. It constitutes a pivotal system that integrates information received by many signaling pathways and subsequently orchestrates cell fate decisions, namely, growth-arrest, senescence, or apoptosis. Reactive oxygen species (ROS) production in cells can play a key role in signal transduction, being able to trigger different processes as cell death or cell proliferation. Sustained oxidative stress can induce genomic instability and collaborates with cancer development, whereas acute enhancement of high ROS levels leads to toxic oxidative cell damage and cell death. Here, it has been considered p53 broad potential contribution through its ability to regulate selected key cancer signaling pathways, where ROS participate as inductors or effectors of the final biological outcome. Further, we have discussed how p53 could play a role in preventing potentially harmful oxidative state and cell proliferation by pro-oncogenic pathways such as PI3K/AKT/mTOR and WNT/beta-catenin or under hypoxia state. In addition, we have considered potential mechanisms by which p53 could collaborate with signal transduction pathways such as transforming growth factor-beta (TGF-beta) and stress-activated protein kinases (SAPK) that produce ROS, to stop or eliminate uncontrolled proliferating cells. PMID- 20919944 TI - Determinants of absence of osteoarthritis in old age. AB - OBJECTIVE: To investigate factors associated with absence of osteoarthritis (OA). METHODS: In 82 well-functioning 90-year-old participants from a cross-sectional birth cohort, radiographs of hands, hips, and knees were acquired and scored according to the Kellgren and Lawrence (K-L) method for determining OA. A score of >= 2 was considered as OA. 'Free from OA' was defined as no hip or knee OA and less than three hand joints with OA. Logistic regression analyses were used to investigate associations with absence of OA. RESULTS: Absence of hip, knee, and hand OA was seen in 63, 51, and 29% of participants, respectively. Joints on the left and right side of the body were equally affected. Sixteen per cent of 90 year old participants were 'free from OA'. Absence of knee OA was associated with being male. A family history of finger nodes was negatively associated with absence of hip and hand OA. Body mass index (BMI) was negatively associated with 'free from OA', and also with absence of hip and knee OA. A history of heavy occupational work was associated with 'free from OA' [odds ratio (OR) 7.2, 95% confidence interval (CI) 1.3-39.9] and with absence of hand OA in particular (OR 2.7, 95% CI 1.0-7.1). CONCLUSIONS: In 90-year-olds, absence of OA is associated with male sex, a normal BMI, absence of familial predisposition for OA, and, contrary to our expectation, heavy work. Further research in protective genetic factors is needed. PMID- 20919942 TI - p53, aerobic metabolism, and cancer. AB - p53 regulates the cell cycle and deoxyribonucleic acid (DNA) repair pathways as part of its unequivocally important function to maintain genomic stability. Intriguingly, recent studies show that p53 can also transactivate genes involved in coordinating the two major pathways of energy generation to promote aerobic metabolism, but how this serves to maintain genomic stability is less clear. In an attempt to understand the biology, this review presents human epidemiologic data on the inverse relationship between aerobic capacity and cancer incidence that appears to be mirrored by the impact of p53 on aerobic capacity in mouse models. The review summarizes mechanisms by which p53 regulates mitochondrial respiration and proposes how this might contribute to maintaining genomic stability. Although disparate in nature, the data taken together suggest that the promotion of aerobic metabolism by p53 serves as an important tumor suppressor activity and may provide insights for cancer prevention strategies in the future. PMID- 20919945 TI - Immunogenetic aspects of erosive osteoarthritis of the hand in patients from northern Italy. AB - OBJECTIVES: To compare the distribution of human leucocyte antigen (HLA) class I and II alleles in patients with erosive hand osteoarthritis (EHOA) to that of patients with non-erosive hand OA (non-EHOA) and in healthy Italian Bone Marrow Donors (IBMDs), in order to evaluate possible immunogenetic associations with EHOA. In the EHOA group we also sought possible associations between HLA alleles and disease severity. METHODS: Ninety-four patients with EHOA (82 women, 12 men; mean age 61.4 +/- 8.45 years) and 37 with non-EHOA (28 women, nine men; mean age 59.21 +/- 9.07 years) were studied. Disease severity was measured by the number of clinically active joints (NCAJ) and by the radiographic score (RS) using the Kallman scale. HLA typing was undertaken for A, B, C, and DRB1 loci; HLA-DRB1* genotyping was determined using polymerase chain reaction (PCR) with sequence specific primers. Frequencies were compared with those of the healthy IBMDs. RESULTS: The alleles found more frequently in EHOA patients than in non-EHOA patients and healthy controls were: A23, A26, and A29; B38, B44, and HLA DRB1*01 and *07. The RS was more severe in the EHOA compared to the non-EHOA group (63.60 +/- 23.14 vs. 34.34 +/- 20.24, p < 0.001). Within the EHOA group, HLA-DRB1*07 was associated with a higher RS (67.36 +/- 23 vs. 64.5 +/- 18.5, p = 0.029). CONCLUSION: In this study of North Italian patients affected with EHOA, the HLA DRB1*07 allele was found to be associated with both the development and greater severity of the disease. PMID- 20919946 TI - Enlarged right-sided dimensions and fibrosis of the right ventricular insertion point on cardiovascular magnetic resonance imaging is seen early in patients with pulmonary arterial hypertension associated with connective tissue disease. AB - OBJECTIVES: To describe the findings of cardiovascular magnetic resonance (CMR) imaging in patients with pulmonary arterial hypertension (PAH) associated with connective tissue disease (CTD) and in consecutive patients with systemic sclerosis (SSc) without PAH. METHODS: The study comprised nine consecutive patients who were admitted for right heart catheterization (RHC) under a suspicion of CTD-PAH and 25 consecutive patients who were admitted for evaluation because of a clinical suspicion of SSc. In addition to the regular assessment, they also underwent examination by CMR. RESULTS: CMR measurements of right ventricular (RV) volumes and function showed severe pathology in patients with CTD-PAH. Patients with SSc without PAH had similar but much less severe findings. Right ventricular end-diastolic volume (RVEDV) and right ventricular ejection fraction (RVEF) were abnormal in all patients with CTD-PAH. In eight out of nine patients with CTD-PAH, fibrosis was seen in the RV insertion point, probably caused by increased tension, but only in one of the consecutive SSc patients. This patient was diagnosed with CTD-PAH 20 months later. CONCLUSIONS: In CTD-PAH, CMR shows severe changes in RV volumes and function, but also fibrosis in the RV insertion point. Similar abnormalities, although much less severe, may be seen at diagnosis of SSc. Further evaluation is warranted to determine whether these findings are of value in screening for early signs of PAH in SSc. PMID- 20919947 TI - The presence of rheumatoid nodules at early rheumatoid arthritis diagnosis is a sign of extra-articular disease and predicts radiographic progression of joint destruction over 5 years. AB - OBJECTIVE: Radiographic damage is an important outcome in rheumatoid arthritis (RA). The disease course varies considerably, and there is a need for simple and reliable prognostic markers. The aim of the study was to determine the utility of early signs of extra-articular disease, manifested as rheumatoid nodules (RN), in predicting radiographic outcome. METHODS: In a cohort (n = 1589) of consecutive, newly diagnosed patients with RA, 112 cases with RN at inclusion (7%) were identified. Each case was compared to two age- and sex-matched controls without nodules from the same cohort. Radiographs of the hands and feet were performed at inclusion, after 1, 2, and 5 years and scored according to the modified Sharp van der Heijde Score (SHS; range 0-448). RESULTS: Fifty-two cases with RN and 139 controls without RN had available radiographs at baseline and after 5 years. Cases were more often rheumatoid factor (RF) positive and anti-cyclic citrullinated peptide (anti-CCP) positive, and had higher disease activity and radiographic damage scores at baseline (7.9 vs. 2.5). After 5 years, there was more extensive radiographic damage among the cases (mean SHS progression 21.7 vs. 13.5). In bivariate analysis, positive RF, positive anti-CCP, SHS, and RN were strong baseline predictors for radiographic progression up to 5 years. In multivariate analysis, positive anti-CCP and SHS at baseline were independently associated with radiographic progression. CONCLUSION: The presence of RN at baseline is a marker of extra-articular involvement and severe disease, and a predictor of subsequent joint damage. PMID- 20919950 TI - Amniotic fluid-derived mesenchymal stem cells lead to bone differentiation when cocultured with dental pulp stem cells. AB - Mesenchymal stem cells are present in many tissues of the human body, including amniotic fluid (AF) and dental pulp (DP). Stem cells of both AF and DP give rise to a variety of differentiated cells. In our experience, DP stem cells (DPSCs) display a high capacity to produce bone. Therefore, our aim was to investigate if AF-derived stem cells (AFSCs) were able to undergo bone differentiation in the presence of DPSCs. AFSCs were seeded under three different conditions: (i) cocultured with DPSCs previously differentiated into osteoblasts; (ii) cultured in the conditioned medium of osteoblast-differentiated DPSCs; (iii) cultured in the osteogenic medium supplemented with vascular endothelial growth factor and bone morphogenetic protein-2 (BMP-2). Results showed that AFSCs were positive for mesenchymal markers, and expressed high levels of Tra1-60, Tra1-80, BMPR1, BMPR2, and BMP-2. In contrast, AFSCs were negative for epithelial and hematopoietic/endothelial markers. When AFSCs were cocultured with DPSCs-derived osteoblasts, they differentiated into osteoblasts. A similar effect was observed when AFSCs were cultured in the presence of a conditioned medium originated from DPSCs. We found that osteoblasts derived from DPSCs released large amounts of BMP 2 and vascular endothelial growth factor into the culture medium and that those morphogens significantly upregulate RUNX-2 gene, stimulating osteogenesis. This study highlights the mechanisms of osteogenesis and strongly suggests that the combination of AFSCs with DPSCs may provide a rich source of soluble proteins useful for bone engineering purposes. PMID- 20919949 TI - Engineered pullulan-collagen composite dermal hydrogels improve early cutaneous wound healing. AB - New strategies for skin regeneration are needed to address the significant medical burden caused by cutaneous wounds and disease. In this study, pullulan collagen composite hydrogel matrices were fabricated using a salt-induced phase inversion technique, resulting in a structured yet soft scaffold for skin engineering. Salt crystallization induced interconnected pore formation, and modification of collagen concentration permitted regulation of scaffold pore size. Hydrogel architecture recapitulated the reticular distribution of human dermal matrix while maintaining flexible properties essential for skin applications. In vitro, collagen hydrogel scaffolds retained their open porous architecture and viably sustained human fibroblasts and murine mesenchymal stem cells and endothelial cells. In vivo, hydrogel-treated murine excisional wounds demonstrated improved wound closure, which was associated with increased recruitment of stromal cells and formation of vascularized granulation tissue. In conclusion, salt-induced phase inversion techniques can be used to create modifiable pullulan-collagen composite dermal scaffolds that augment early wound healing. These novel biomatrices can potentially serve as a structured delivery template for cells and biomolecules in regenerative skin applications. PMID- 20919951 TI - Bioactive porous beads as an injectable urethral bulking agent: their in vitro evaluation on smooth muscle cell differentiation. AB - Growth factor (basic fibroblast growth factor or vascular endothelial growth factor)-immobilized polycaprolactone (PCL)/Pluronic F127 porous beads were prepared as an injectable bulking agent for effective treatment of urinary incontinence. The growth factor-immobilized porous beads may stimulate smooth muscle cell (SMC) differentiation of muscle-derived stem cells or defect tissues around urethra to improve the sphincter function (bioactive therapy) as well as to provide a bulking effect (passive therapy). The porous PCL/F127 beads were fabricated by an isolated particle-melting/melt-molding particulate-leaching method. The growth factors were easily immobilized onto the surfaces of the PCL/F127 porous beads via heparin binding and were continuously released for up to 28 days. Both growth factor-immobilized porous beads had a positive effect for the SMC differentiation of muscle-derived stem cells, as were demonstrated by the analyses of quantitative polymerase chain reactions, Western blot using SMC specific markers, and immunohistochemical staining. In particular, the basic fibroblast growth factor-immobilized porous beads showed desirable SMC differentiation behavior that can be applied as an injectable bulking agent for the treatment of urinary incontinence. PMID- 20919952 TI - Operating bioreactors for microbial exopolysaccharide production. AB - There is considerable interest in exploiting the novel physical and biological properties of microbial exopolysaccharides in industry and medicine. For economic and scientific reasons, large scale production under carefully monitored and controlled conditions is required. Producing exopolysaccharides in industrial fermenters poses several complex bioengineering and microbiological challenges relating primarily to the very high viscosities of such culture media, which are often exacerbated by the producing organism's morphology. What these problems are, and the strategies for dealing with them are discussed critically in this review, using pullulan, curdlan, xanthan, and fungal beta-glucans as examples of industrially produced microbial exopolysaccharides. The role of fermenter configuration in their production is also examined. PMID- 20919953 TI - Genomic large rearrangement screening of BRCA1 and BRCA2 genes in high-risk Turkish breast/ovarian cancer patients by using multiplex ligation-dependent probe amplification assay. AB - In this study, MLPA assay was performed for detection of large rearrangements of BRCA1 and BRCA2 genes in 16 familial, 29 early onset, 3 male breast cancer, and 2 bilateral breast/ovarian cancer high risk Turkish index cases. MLPA assay for all exons of both genes and for 1100delC variant of CHEK2 gene were performed. Analyses, revealed no large genomic rearrangements in both genes, and, no 1100del variant in CHEK2 gene. Our data which represents the first results for Turkish patients, suggest that, the frequency of BRCA1 and BRCA2 genes' large rearrangements is very low. PMID- 20919954 TI - Reduced expression of DNA repair and redox signaling protein APE1/Ref-1 impairs human pancreatic cancer cell survival, proliferation, and cell cycle progression. AB - Pancreatic cancer is a deadly disease that is virtually never cured. Understanding the chemoresistance intrinsic to this cancer will aid in developing new regimens. High expression of APE1/Ref-1, a DNA repair and redox signaling protein, is associated with resistance, poor outcome, and angiogenesis; little is known in pancreatic cancer. Immunostaining of adenocarcinoma shows greater APE1/Ref-1 expression than in normal pancreas tissue. A decrease in APE1/Ref-1 protein levels results in pancreatic cancer cell growth inhibition, increased apoptosis, and altered cell cycle progression. Endogenous cell cycle inhibitors increase when APE1/ Ref-1 is reduced, demonstrating its importance to proliferation and growth of pancreatic cancer. PMID- 20919955 TI - Current trends of lectins from microfungi. AB - Lectins are widespread in nature and have been isolated from plants, animals, microorganisms, and viruses. Although several lectins have been reported from microfungi, many more genera still remain unexplored and their physiological role is also uncertain. Microfungal lectins show wide disparity regarding their specificity to erythrocytes. Only a few lectins display specificity to particular human blood types. In addition, they also show agglutination to various animal erythrocytes. Many lectins from microfungi exhibit stringent specificity to animal glycoproteins, while a few have much more simplified sugar binding properties. The role of few microfungal lectins in host-parasite interactions, as storage proteins, and in growth and morphogenesis has been proposed. The current review focuses on an overview of lectins from microfungi, their specificity towards erythrocytes and carbohydrates, physicochemical characteristics, and their possible role and applications. PMID- 20919956 TI - Evidence-based checklists: intended and unintended consequences for interprofessional care. PMID- 20919957 TI - Conflicts and conflict management in the collaboration between nurses and physicians - a qualitative study. AB - In health care, optimal collaboration between nurses and physicians is crucial in the quality of the care process – but not self-generating. Little is known about how health-care professionals cope with conflicts within their collaboration. This qualitative study investigates the way nurses and physicians cope with conflict and clarifies the determinants of conflict management styles. All respondents formulate clear expectations which in their opinion are essential to collaboration. When collaboration leads to disagreement, physicians and nurses choose between ignoring the conflict or engaging in it. Choice is determined by five factors: the influence of oneself, the influence of the other, the nature of the conflict, the context of conflict, and personal motives. PMID- 20919958 TI - Discharge preparation: do healthcare professionals differ in their opinions? AB - Discharge preparation is a multiprofessional activity that is not always conducted efficiently. Perspectives of staff provide an insight into challenges and solutions for this organizational process. The study aimed to examine current discharge practice in one hospital and to compare perceptions of this activity between healthcare workers from different professions. A questionnaire was sent to 1344 staff in an English hospital. It consisted of items related to discharge, which were rated on a Likert scale, and included space for free text. Data were analyzed using descriptive and inferential statistics. The survey method has a number of limitations and conclusions must be considered with caution. A total of 455 usable questionnaires were returned from nurses/midwives, doctors and therapists/allied health professionals. Although respondents showed agreement on a number of areas, differences did arise, which could be linked, in part, to values and roles associated with specific healthcare disciplines. Tensions between professional groups were evident, especially between social workers, nurses and medics. Differences of opinion also appeared between practitioners, patients and carers. Different views among practitioners of discharge preparation could impede efficient joint working. Better understanding of the roles and expertise of team members might improve this process. Factors affecting discharge preparation need to be understood to reduce staff and consumer dissatisfaction and to avoid potential readmissions. PMID- 20919959 TI - Interprofessional primary care protocols: a strategy to promote an evidence-based approach to teamwork and the delivery of care. AB - Primary care reform involving interprofessional team-based care is a global phenomenon. In Ontario, Canada, 150 Family Health Teams (FHTs) have been approved in the past few years. The transition to a FHT is complex involving many changes and the processes for collaborative teamwork are not clearly delineated. To support the transition to team-based care in FHTs, a project was undertaken to develop and implement a series of interprofessional protocols in four clinical areas. These interprofessional protocols would contain relevant and evidence based resources to support both a team and evidence-based approach to care. This paper reports on a qualitative study to examine the process of interprofessional protocol development and pilot implementation. Adopting an exploratory case study approach (Robson, 2002 ), 36 interviews were conducted with health professionals and community group members who participated in the creation and piloting of the protocols, and with project managers. In addition, observational and documentary data were gathered on the protocol development and implementation processes. The findings from the protocol development stage demonstrate the value of the focus on evidence and team, the process of assessing and targeting FHT needs, inter organizational and interprofessional sharing, the importance of facilitation and support, and expectations for implementation. The findings from the pilot implementation stage report on the importance of champions and leaders, the implementation strategies used, FHT and organizational factors affecting implementation, and outcomes achieved. Findings are discussed in relation to the knowledge translation and interprofessional literature. Research is ongoing to examine the effectiveness of dissemination of the protocols to FHTs across the province of Ontario and its impact on health care outcomes. PMID- 20919960 TI - Functional roles of intrinsic neurotrophin-3 in spinal neuroplasticity of cats following partial ganglionectomy. AB - This study detected the effects of endogenous neurotrophin-3 (NT-3) on the collateral sprouting derived from the L6 dorsal root ganglion (DRG) after unilateral removal of adjacent DRGs (L1–L5 and L7) in cats. Cholera toxin B tracing revealed significant neurite growth from the spared L6 DRG and axonal sprouting in the dorsal column. There was a significant increase in the number of NT-3 and trkC immunopositive neurons as well as in NT-3 protein level in the spared DRG by immunohistochemistry and enzyme-linked immunoadsorbent assay. NT-3 and its mRNA and trkC were located mainly in large- and medium-sized DRG neurons. NT-3 antibody neutralization in vivo and in vitro results in marked reduction in sprouted fibers. These findings point to an important role of NT-3 in neural plasticity at dorsal column axons. PMID- 20919961 TI - Reg2 protects mouse insulinoma cells from streptozotocin-induced mitochondrial disruption and apoptosis. AB - We reported previously that pancreas-specific ablation of IGF-I in mice induced an increased expression of regenerating family proteins Reg2 and Reg3β in the pancreas and protected them from streptozotocin (Stz)-induced β-cell damage. We, therefore, assessed the effect of ectopically introduced Reg2 on Stz induced apoptosis in MIN6 mouse insulinoma cells and report here that Reg2 protects MIN6 cells from Stz-induced apoptosis by attenuating its ability to disrupt mitochondrial membrane integrity, activate caspase-3 and promote poly-ADP ribose polymerase cleavage, and induce apoptosis. These changes correlated with suppression of c-jun N-terminal kinase (JNK) phosphorylation by Stz. Reg2 inhibited Stz-induced proapoptotic events as well as the inactivation of JNK. Inclusion of chemical inhibitor of JNK to Reg2 expressing cells rendered them sensitive to Stz. These data demonstrate that Reg2 protects insulin-producing cells against Stz-induced apoptosis by interfering with its cytotoxic signaling upstream of the intrinsic proapoptotic events by preventing its ability to inactivate JNK. PMID- 20919962 TI - Second AKT: the rise of SGK in cancer signalling. AB - The serum and glucocorticoid kinase (SGK) family of serine/threonine kinases consists of three isoforms, SGK-1, SGK-2 and SGK-3. This family of kinases is highly homologous to the AKT kinase family, sharing similar upstream activators and downstream targets. SGKs have been implicated in the regulation of cell growth, proliferation, survival and migration: cellular processes that are dysregulated in cancer. Furthermore, SGKs lie downstream of phosphoinositide-3 kinase (PI3Kinase) signalling and interact at various levels with RAS/RAF/ERK signalling, two pathways that are involved in promoting tumorigenesis. Recent evidence suggests that mutant PI3Kinase can induce tumorigenesis through an AKT independent but SGK3-dependent mechanism, thus implicating SGKs as potential players in malignant transformation. Here, we will review the current state of knowledge on the regulation of the SGKs and their role in normal cell physiology and transformation with a particular focus on SGK3. PMID- 20919963 TI - Thiopurines in Crohn's disease, is there something new? AB - IMPORTANCE OF THE FIELD: traditional immunosuppressants, including azathioprine, remain the mainstay of therapy in steroid dependent/refractory patients with inflammatory bowel diseases (IBD). The main limitations of its use are its side effects appearing in about a fifth of the patients, including myelosuppression and liver toxicity. Major complications occur in patients with low thiopurine-S methyltransferase (TPMT) enzyme activity; however, the clinical relevance of these tests remains conflictive. AREAS COVERED IN THIS REVIEW: in this review, the authors aim to summarize the new data regarding the relationship between the pharmacology of thiopurines and pathogenesis of adverse events. WHAT THE READER WILL GAIN: readers will gain an understanding of the metabolism of thiopurines, side effect profile, pharmacological background of side effects, importance of metabolite monitoring, clinical relevance of inherited differences in drug metabolism and other conditions (e.g., concomitant use of allopurinol) which can modify enzyme activity. By gaining an understanding of the pharmacology and metabolism of thiopurines, clinicians will be able to optimize thiopurine therapy in IBD. TAKE HOME MESSAGE: TPMT testing and metabolite monitoring are still not considered the standard of care, and clinicians will continue to choose the approach that best suits their clinical practice and patient needs. Regardless of what strategy is chosen, patients need to be carefully monitored and well informed about the potential risks. PMID- 20919964 TI - Testosterone and male ageing: spinning the wheels. PMID- 20919965 TI - The NICS care bundle: aiming to improve the initial care of patients with stroke and transient ischaemic attack. PMID- 20919966 TI - Implications of bed reduction in an acute psychiatric service. AB - OBJECTIVE: To evaluate the impact of psychiatric inpatient bed closures, accompanied by a training program aimed at enhancing team effectiveness and incorporating data-driven practices, in a mental health service. DESIGN AND SETTING: Retrospective comparison of the changes in services within three consecutive financial years: baseline period - before bed reduction (2006-07); observation period - after bed reduction (2007-08); and intervention period - second year after bed reduction (2008-09). The study was conducted at Cramond Clinic, Queen Elizabeth Hospital, Adelaide. MAIN OUTCOME MEASURES: Length of stay, 28-day readmission rates, discharges, bed occupancy rates, emergency department (ED) presentations, ED waiting time, seclusions, locality of treatment, and follow-up in the community within 7days. RESULTS: Reduced bed numbers were associated with reduced length of stay, fewer referrals from the community and subsequently shorter waiting times in the ED, without significant change in readmission rates. A higher proportion of patients was treated in the local catchment area, with improved community follow-up and a significant reduction in inpatient seclusions. CONCLUSION: Our findings should reassure clinicians concerned about psychiatric bed numbers that service redesign with planned bed reductions will not necessarily affect clinical care, provided data literacy and team training programs are in place to ensure smooth transition of patients across ED, inpatient and community services. PMID- 20919967 TI - Prevalence and treatment of osteoporosis in older Australian men: findings from the CHAMP study. AB - OBJECTIVE: To determine the proportion of older Australian men who meet the Pharmaceutical Benefits Scheme (PBS) criteria for osteoporosis treatment and are receiving effective treatment. DESIGN AND SETTING: A population-based, cross sectional analysis of the baseline phase of the Concord Health and Ageing in Men Project (CHAMP), a large epidemiological study focusing on the health of older men. Data were collected through questionnaires and clinical assessments. Bone mineral density (BMD) of the hip and spine was measured by dual x-ray absorptiometry (DXA). Vertebral deformities were identified from DXA lateral vertebral fracture assessment images. The study was conducted at Concord Hospital, Sydney, between January 2005 and May 2007. PARTICIPANTS: 1705 community dwelling men aged 70 years or over from a defined geographical region around Concord Hospital. MAIN OUTCOME MEASURES: Prevalence of vertebral deformities; previous minimal trauma fractures; BMD T-scores <= - 3; falls in the previous 12 months; use of bisphosphonates and calcium and vitamin D supplements. RESULTS: Of the 1705 men seen at baseline, 1626 completed all DXA scans and 401 (25%) met one or more of the PBS criteria for osteoporosis treatment. Ninety per cent of the men who met the PBS criteria were unaware they had osteoporosis. Of the men eligible for PBS-subsidised treatment, 39 (10%) reported use of a bisphosphonate, 56 (14%) had taken calcium supplements, and 28 (7%) had taken vitamin D supplements. Only three men had taken calcium, vitamin D and bisphosphonates in combination. CONCLUSIONS: Despite a high prevalence of osteoporosis in elderly Australian men, awareness, diagnosis and treatment of the condition remain very low. PMID- 20919968 TI - Invasive pneumococcal disease in non-Indigenous people in north Queensland, 2001 2009. AB - OBJECTIVE: To compare trends in invasive pneumococcal disease (IPD) in non Indigenous people in north Queensland before and after the introduction of funded pneumococcal vaccines, and to examine the proportion of cases that occurred after vaccine roll-out that could be vaccine-preventable. DESIGN, SETTING AND PARTICIPANTS: In 2005, a 7-valent pneumococcal conjugate vaccine (7vPCV) for non Indigenous children and a 23-valent pneumococcal polysaccharide vaccine (23vPPV) for non-Indigenous adults aged >= 65 years were made freely available. Trends in IPD in the non-Indigenous estimated resident population in north Queensland (about 581 850 in 2006) were compared between the 4 years before (2001-2004) and after (2006-2009) the vaccines were rolled out. MAIN OUTCOME MEASURES: Incidences and serotypes of IPD in non-Indigenous people. RESULTS: After the introduction of the vaccines, there were significant declines for all ages in the average annual incidence of IPD (- 34%; P < 0.05) and 7vPCV serotype IPD (- 77%; P < 0.05). In children aged < 5 years, there was a 91% decline in the incidence of 7vPCV serotype IPD (P < 0.05); in adults aged 15-64 years and >= 65 years there were 62% and 77% declines, respectively, in 7vPCV and 23vPPV common-serotype IPD (P < 0.05). There was a 188% increase in 23vPPV-only serotype IPD in adults aged 15-64 years (P < 0.05), whereas there was no significant change in adults aged >= 65 years. Serotype 19A was the most frequently identified serotype in 2006-2009, causing 19% of all IPD in those 4 years. CONCLUSIONS: There is circumstantial evidence that 7vPCV has had a powerful indirect effect in preventing IPD in adults in north Queensland; 23vPPV may have had a direct effect in adults aged >= 65 years. It is likely that with combined direct and indirect effects, newer conjugate vaccines could prevent more IPD than could be prevented with the two current vaccines. PMID- 20919969 TI - E-health in Australia: time to plunge into the 21st century. AB - E-health is the health care buzzword of the moment, with a person-controlled electronic health record funded in the 2010 federal Budget and legislation to introduce health identifiers recently passed by Parliament. E-health can ease the patient journey, improve quality of care and reduce costs. Australia's health care system lags behind all other sectors of our economy in the use of computerised systems. While general practice and community pharmacy are highly computerised, the hospital sector is not. Adopting e-health is likely to result in higher quality practice, but general practice and hospitals need a mechanism for securely sharing patient data. Uncoordinated implementation of differing, incompatible systems within and between hospitals compounds a dire lack of national coordination of effort. Multiple funding streams and jurisdictions and the lack of an implementation strategy have slowed e-health development. Government programs underestimate the costs of change management and the need for training and technology. Confusion reigns about responsibilities, but governments must ensure connectivity between health care providers and recognise that the benefits will accrue into the future. The National E-Health Transition Authority has developed national open-access standards, and its foundation projects and the National Broadband Network are now coming into place. To ensure the clinical relevance, utility, safety and acceptability of e-health systems, health professionals urgently need technical capacity and expert guidance. PMID- 20919970 TI - Will information and communication technology disrupt the health system and deliver on its promise? AB - Investment in information and communication technology (ICT) in the health sector can bring important benefits. To date, the focus has been on automating clinical work practices such as ordering tests and prescriptions, which significantly improves efficiency and safety. Uptake of ICT has been slow and the results less favourable than anticipated for various reasons, including poor integration of systems into complex clinical work processes, limited training, and the intermittent nature of ICT funding. As a result, many health care organisations have been operating hybrid paper and computer systems that introduce new patient risks, staff frustration, and outcomes below expectation. The focus must shift from automation of clinical work to innovation; from evolutionary application of ICT to revolutionary uses. Health professionals must embrace ICT as a "disruptive technology" that will produce significant changes in their roles and responsibilities and lead to real health reform with new, innovative models of health care delivery. As other industries have shown, substitution and role changes are areas in which ICT can lead to the greatest gains. PMID- 20919971 TI - Pandemic (H1N1) 2009 influenza vaccination coverage in Western Australia. AB - OBJECTIVE: To assess pandemic (H1N1) 2009 influenza vaccination coverage in Western Australians, up to 31 January 2010. DESIGN, SETTING AND PARTICIPANTS: Vaccination data for Western Australians aged 10 years and older were obtained from two sources: the WA Pandemic Influenza Vaccination Database (PIVD; which collected reports of pandemic influenza vaccinations from vaccination providers statewide) for the period 30 September 2009 to 31 January 2010, and the WA Health and Wellbeing Surveillance System (HWSS; a continuous population-based telephone survey) for the period 1 December 2009 to 31 January 2010. Data from the PIVD was used to input vaccination coverage estimates for at-risk subpopulations not assessed in the HWSS interviews. MAIN OUTCOME MEASURES: Vaccination coverage of Western Australians aged 10 years and older and of subgroups targeted by the national pandemic (H1N1) 2009 influenza vaccination campaign. RESULTS: A total of 171,789 pandemic influenza vaccinations were reported to the PIVD by 31 January 2010 and 88% of these were administered by 1 December 2009. Based on HWSS data, vaccination coverage of persons aged 10 years and older was 14.5% (95% CI, 12.6% 16.6%) and of persons aged 18 years and older was 15.3% (95% CI, 13.3%-17.6%). Based on PIVD data, coverage in adults ranged from 10.3% in pregnant women to 52.8% in health care workers. CONCLUSIONS: Our estimate of pandemic influenza vaccination coverage in the adult population of WA is comparable to the national estimate of 19%, but it did not reach levels considered sufficient to interrupt community transmission. Future influenza vaccination programs should target groups at increased risk of severe influenza, such as pregnant women. PMID- 20919972 TI - Pandemic (H1N1) 2009 influenza vaccine uptake in pregnant women entering the 2010 influenza season in Western Australia. AB - OBJECTIVE: To audit the uptake of pandemic (H1N1) 2009 influenza vaccine in pregnant women entering the 2010 influenza season in Western Australia, and to identify why some women did not receive the vaccine. DESIGN, SETTING AND PARTICIPANTS: Cross-sectional study of consecutive patients attending the Joondalup Health Campus public antenatal clinics in WA in January 2010. INTERVENTION: Audit of uptake of the H1N1-specific vaccine. MAIN OUTCOME MEASURES: Rate of H1N1-specific vaccination, and reasons for not being the vaccinated. RESULTS: 479 of 541 women who attended the clinics (88.5%) were included in the audit. Three women had been infected with pandemic influenza in the preceding influenza season, leaving 476 women who were eligible for vaccination in pregnancy. Of these 476 women, only 33(6.9%) had been vaccinated. Of the remaining 443 women who were eligible to receive the vaccine but had not been vaccinated, 63.9% had not been offered vaccination despite multiple visits to their general practitioners during pregnancy, 19.6% had been advised by their GPs against vaccination in pregnancy, and 61.6% stated that they would decline vaccination if offered because of safety concerns. CONCLUSIONS: Uptake of H1N1 specific influenza vaccine in pregnant women was poor. Reasons for this relate both to vaccination not being offered to or actively sought by the women, as well as concerns - of both the women and their GPs - about vaccine safety in pregnancy. Uptake in this setting may improve if vaccination is offered through public antenatal clinics with concurrent safety education for obstetricians and vaccination providers. PMID- 20919973 TI - Implementing pay-for-performance in Australian primary care: lessons from the United Kingdom and the United States. AB - We identify key lessons learned from the international experience of pay-for performance and use them to formulate questions for Australia to consider before such a scheme is introduced. Discussion of lessons learned is based on a narrative review of the literature. We examined international evidence on factors to consider when designing pay-for-performance schemes, and the impact of these schemes on primary care practitioner behaviour and on primary care funding. Pay for-performance schemes evolve over time, and usually involve several complex interventions including accreditation, education, quality improvement programs, investment in information technology and data collection systems, professional support and regional structures. These are all necessary conditions for linking financial incentives to quality of care. There is a strong argument for changing the existing service incentive payments program and investing the resources into revised outcome payments that provide rewards for annual improvements in numbers of patients receiving completed cycles of care. If pay-for-performance is to be introduced in Australia, several key lessons should be learned from the experiences of other countries. Pay-for-performance should be used as part of a wider strategy for quality improvement; it should not be seen as a panacea. Pay for-performance should be used to drive quality improvement, not simply to reward those who are already providing high-quality care. PMID- 20919974 TI - Iodine toxicity from soy milk and seaweed ingestion is associated with serious thyroid dysfunction. AB - We report a series of cases of thyroid dysfunction in adults associated with ingestion of a brand of soy milk manufactured with kombu (seaweed), and a case of hypothyroidism in a neonate whose mother had been drinking this milk. We also report two cases of neonatal hypothyroidism linked to maternal ingestion of seaweed made into soup. These products were found to contain high levels of iodine. Despite increasing awareness of iodine deficiency, the potential for iodine toxicity, particularly from sources such as seaweed, is less well recognised. PMID- 20919975 TI - A rare case of primary hyperparathyroidism and osteitis fibrosa cystica. PMID- 20919976 TI - Catching a chameleon: IgG4-related systemic disease. AB - IgG4-related systemic disease (IRSD) is a recently described entity with protean manifestations. We describe a patient who developed inflammation and fibrosis in multiple organs over 20 years, sequentially involving his pancreas, bile ducts, gallbladder, submandibular and lacrimal glands, and kidneys. He had an elevated serum IgG4 level. Retrospective analysis of biopsies showed strongly positive tissue immunostaining for IgG4, confirming the diagnosis of IRSD. This case illustrates the natural history of partially treated IRSD and its varied clinical presentations. Early diagnosis and treatment is important, as the condition is highly steroid-responsive. PMID- 20919978 TI - World cup fever. PMID- 20919977 TI - Otosyphilis: a cause of hearing loss in adults with HIV. PMID- 20919979 TI - Prevalence of allergen avoidance advisory statements on packaged processed foods in a supermarket. PMID- 20919980 TI - Generic medicines literacy - minimising the potential for patient confusion. PMID- 20919981 TI - Congenital anomalies - why bother? PMID- 20919982 TI - National approaches for medical school entry. PMID- 20919983 TI - Family history: the neglected risk factor in disease prevention. PMID- 20919984 TI - Reducing the burden of inherited disease: the Human Variome Project. PMID- 20919985 TI - Suicide and mental disorder: the legal perspective. PMID- 20919986 TI - Has PSA testing truly been a "public health disaster"? PMID- 20919987 TI - Suicide in Australia: meta-analysis of rates and methods of suicide between 1988 and 2007. PMID- 20919988 TI - Swimming pool filter-induced transrectal evisceration in children: Australian experience. PMID- 20919989 TI - Macrocycles in medicinal chemistry and drug discovery. PMID- 20919990 TI - The immunoproteasome, the 20S proteasome and the PA28alphabeta proteasome regulator are oxidative-stress-adaptive proteolytic complexes. AB - Oxidized cytoplasmic and nuclear proteins are normally degraded by the proteasome, but accumulate with age and disease. We demonstrate the importance of various forms of the proteasome during transient (reversible) adaptation (hormesis), to oxidative stress in murine embryonic fibroblasts. Adaptation was achieved by 'pre-treatment' with very low concentrations of H2O2, and tested by measuring inducible resistance to a subsequent much higher 'challenge' dose of H2O2. Following an initial direct physical activation of pre-existing proteasomes, the 20S proteasome, immunoproteasome and PA28alphabeta regulator all exhibited substantially increased de novo synthesis during adaptation over 24 h. Cellular capacity to degrade oxidatively damaged proteins increased with 20S proteasome, immunoproteasome and PA28alphabeta synthesis, and was mostly blocked by the 20S proteasome, immunoproteasome and PA28 siRNA (short interfering RNA) knockdown treatments. Additionally, PA28alphabeta-knockout mutants achieved only half of the H2O2-induced adaptive increase in proteolytic capacity of wild-type controls. Direct comparison of purified 20S proteasome and immunoproteasome demonstrated that the immunoproteasome can selectively degrade oxidized proteins. Cell proliferation and DNA replication both decreased, and oxidized proteins accumulated, during high H2O2 challenge, but prior H2O2 adaptation was protective. Importantly, siRNA knockdown of the 20S proteasome, immunoproteasome or PA28alphabeta regulator blocked 50-100% of these adaptive increases in cell division and DNA replication, and immunoproteasome knockdown largely abolished protection against protein oxidation. PMID- 20919991 TI - Structural insights into the catalytic mechanism of the yeast pyridoxal 5 phosphate synthase Snz1. AB - In most eubacteria, fungi, apicomplexa, plants and some metazoans, the active form of vitamin B6, PLP (pyridoxal 5-phosphate), is de novo synthesized from three substrates, R5P (ribose 5-phosphate), DHAP (dihydroxyacetone phosphate) and ammonia hydrolysed from glutamine by a complexed glutaminase. Of the three active sites of DXP (deoxyxylulose 5-phosphate)independent PLP synthase (Pdx1), the R5P isomerization site has been assigned, but the sites for DHAP isomerization and PLP formation remain unknown. In the present study, we present the crystal structures of yeast Pdx1/Snz1, in apo-, G3P (glyceraldehyde 3-phosphate)- and PLP bound forms, at 2.3, 1.8 and 2.2 A (1 A=0.1 nm) respectively. Structural and biochemical analysis enabled us to assign the PLP-formation site, a G3P-binding site and a G3P-transfer site. We propose a putative catalytic mechanism for Pdx1/Snz1 in which R5P and DHAP are isomerized at two distinct sites and transferred along well-defined routes to a final destination for PLP synthesis. PMID- 20919992 TI - Identification of novel species-selective agonists of the G-protein-coupled receptor GPR35 that promote recruitment of beta-arrestin-2 and activate Galpha13. AB - The poorly characterized G-protein-coupled receptor GPR35 has been suggested as a potential exploratory target for the treatment of both metabolic disorders and hypertension. It has also been indicated to play an important role in immune modulation. A major impediment to validation of these concepts and further study of the role of this receptor has been a paucity of pharmacological tools that interact with GPR35. Using a receptor-beta-arrestin-2 interaction assay with both human and rat orthologues of GPR35, we identified a number of compounds possessing agonist activity. These included the previously described ligand zaprinast. Although a number of active compounds, including cromolyn disodium and dicumarol, displayed similar potency at both orthologues of GPR35, a number of ligands, including pamoate and niflumic acid, had detectable activity only at human GPR35 whereas others, including zaprinast and luteolin, were markedly selective for the rat orthologue. Previous studies have demonstrated activation of Galpha13 by GPR35. A Saccharomyces cerevisiae-based assay employing a chimaeric Gpa1-Galpha13 G-protein confirmed that all of the compounds active at human GPR35 in the beta-arrestin-2 interaction assay were also able to promote cell growth via Galpha13. Each of these ligands also promoted binding of [35S]GTP[S] (guanosine 5'-[gamma-[35S]thio]triphosphate) to an epitope-tagged form of Galpha13 in a GPR35-dependent manner. The ligands identified in these studies will be useful in interrogating the biological actions of GPR35, but appreciation of the species selectivity of ligands at this receptor will be vital to correctly attribute function. PMID- 20919994 TI - The critical role of nurses in lactation support. PMID- 20919993 TI - Postconditioning attenuates myocardial injury by reducing nitro-oxidative stress in vivo in rats and in humans. AB - In the present study, we hypothesized that postcon (postconditioning) confers cardioprotection in vivo by reducing the production of ONOO- (peroxynitrite) and nitro-oxidative stress subsequent to the inhibition of the iNOS (inducible NO synthase). Patients with AMI (acute myocardial infarct) were randomly assigned to undergo percutaneous coronary intervention without (control) or with ischaemic postcon by three episodes of 30-s inflation and 30-s deflation of the angioplasty balloon. Animal models of MI/R (myocardial ischaemia/reperfusion) injury were induced in rats by occluding the left coronary artery for 40 min followed by 4-h reperfusion. Rats were randomized to receive vehicle, postcon (three cycles of 10 s reperfusion and 10-s coronary re-occlusion preceding full reperfusion), the selective iNOS inhibitor 1400W or postcon plus 3-morpholinosydnonimine (an ONOO- donor). Postcon in patients reduced iNOS activity in white blood cells, decreased plasma nitrotyrosine, a fingerprint of ONOO- and an index of nitro-oxidative stress, and improved cardiac function (P<0.01 compared with control). In rats, postcon reduced post-ischaemic myocardial iNOS activity and nitrotyrosine formation, reduced myocardial infarct size (all P<0.05 compared with control) and improved cardiac function. Administration of 1400W resembled, whereas 3 morpholinosydnonimine abolished, the effects of postcon. In conclusion, reduction in ONOO--induced nitro-oxidative stress subsequent to the inhibition of iNOS represents a major mechanism whereby postcon confers cardioprotection in vivo. PMID- 20919995 TI - On "current resources for evidence-based practice". PMID- 20919996 TI - Is neonatal abstinence syndrome related to the amount of opiate used? AB - OBJECTIVE: To determine if a relationship exists between the dose of heroin and/or substitute medication used in pregnancy and neonatal abstinence syndrome (NAS). DATA SOURCES: Ovid online was used to search the following: EMBASE, Ovid MEDLINE, CINHAL, PscyINFO, Cochrane Database of Systematic Reviews. STUDY SELECTION: English language journal articles reporting original research undertaken and published between 1995 and 2009 that examined relationships between NAS and opiate use in pregnancy and with patterns of substance abuse that reflect those of the United Kingdom and other high-resource settings. DATA EXTRACTION: The studies were reviewed independently by two authors using predefined quality criteria. DATA SYNTHESIS: This was a narrative review; key messages from included studies were discussed in the context of the diversity and commonality of findings in relation to NAS. CONCLUSIONS: No correlation between the amount of fetal opioid exposure and expression of NAS was reported in eight of the 10 studies. This observation was consistent across international boundaries, and studies that included both methadone and buprenorphine. PMID- 20919997 TI - A historical overview of preeclampsia-eclampsia. AB - Preeclampsia is a hypertensive, multisystem disorder of pregnancy whose etiology remains unknown. Although management is evidence-based, preventative measures/screening tools are lacking, treatment remains symptomatic, and delivery remains the only cure. Past hypotheses/scientific contributions have influenced current understanding of preeclampsia pathophysiology and guided management strategies and classification criteria. To provide insight into how past hypotheses/scientific contributions have shaped current practice trends, this article provides a historical overview of preeclampsia-eclampsia. PMID- 20919998 TI - Sucking patterns and behavioral state in 1- and 2-day-old full-term infants. AB - OBJECTIVE: To provide a comprehensive analysis of the temporal structure of sucking in full-term neonates. DESIGN: Descriptive study. SETTING: Newborn nursery in a city teaching institution. PATIENTS/PARTICIPANTS: Fifty-six full term infants with a mean birth weight of 3,128+/-370 g completed sucking assessments on the first and second day of life. METHODS: A 5-minute sucking assessment was completed on the first and second day of life. Instruments included an Infant Nutritive Sucking Apparatus and the Anderson Behavioral Assessment Scale. RESULTS: The number of sucks (p<.001), intersuck width (p=.008) and interburst width (p<.05) were significantly different between the first and second day of life. On the second day of life the infants generated significantly more sucks, a decrease in interburst width and a decrease in intersuck width. There was a significant increase in the presence of an alert behavioral state from the first to second sucking assessment (p<.01). In addition, with a more alert infant state there was an increased time spent bursting (p<.001). CONCLUSION: Our results show that sucking analysis is sensitive to infant status and suggest that the development of sucking methodology can be considered as a useful clinical tool to assess the normal developmental course of sucking patterns. PMID- 20919999 TI - The effects of prenatal secondhand smoke exposure on preterm birth and neonatal outcomes. AB - OBJECTIVE: To examine the relationship between prenatal secondhand smoke (SHS) exposure, preterm birth and immediate neonatal outcomes by measuring maternal hair nicotine. DESIGN: Cross-sectional, observational design. SETTING: A metropolitan Kentucky birthing center. PARTICIPANTS: Two hundred and ten (210) mother-baby couplets. METHODS: Nicotine in maternal hair was used as the biomarker for prenatal SHS exposure collected within 48 hours of birth. Smoking status was confirmed by urine cotinine analysis. RESULTS: Smoking status (nonsmoking, passive smoking, and smoking) strongly correlated with low, medium, and high hair nicotine tertiles (rho=.74; p<.001). Women exposed to prenatal SHS were more at risk for preterm birth (odds ratio [OR]=2.3; 95% Confidence Interval [CI] [.96, 5.96]), and their infants were more likely to have immediate newborn complications (OR=2.4; 95% CI [1.09, 5.33]) than nonexposed women. Infants of passive smoking mothers were at increased risk for respiratory distress syndrome (RDS) (OR=4.9; 95% CI [1.45, 10.5]) and admission to a Neonatal Intensive Care Unit (NICU) (OR=6.5; CI [1.29, 9.7]) when compared to infants of smoking mothers (OR=3.9; 95% CI [1.61, 14.9]; OR=3.5; 95% CI [2.09, 20.4], respectively). Passive smokers and/or women with hair nicotine levels greater than .35 ng/ml were more likely to deliver earlier (1 week), give birth to infants weighing less (decrease of 200-300 g), and deliver shorter infants (decrease of 1.1-1.7 cm). CONCLUSIONS: Prenatal SHS exposure places women at greater risk for preterm birth, and their newborns are more likely to have RDS, NICU admissions, and immediate newborn complications. PMID- 20920001 TI - Time from pregnancy recognition to prenatal care and associated newborn outcomes. AB - OBJECTIVE: To examine the relationship between newborn outcomes and late prenatal care initiation after recognition of pregnancy. DESIGN: Secondary data analysis of the Pregnancy Risk Assessment and Monitoring System (PRAMS) data for the United States. SETTING: Twenty-nine states. PARTICIPANTS: Women of childbearing age (135,623) who resided in 29 states in the PRAMS study who received prenatal care and had live births. METHODS: Population-based survey from 2000 through 2004 that examined four newborn outcomes: prematurity, low birth weight (LBW), admission into Neonatal Intensive Care Unit (NICU), and infant mortality. RESULTS: The average time lag (difference between the time of pregnancy recognition and initiation of prenatal care) for the study was 3.2 weeks (99% CI [3.12, 3.21]). Women who recognized their pregnancies before 6 weeks had a longer lag time (3.5 weeks, 99% CI [3.43, 3.53]) than women who recognized their pregnancies later (2.1 weeks, 99% CI [1.96, 2.15]). After adjusting for confounders including the timing of pregnancy recognition, longer time lag was associated with reduced risks of prematurity (odds ratio [OR]=0.99, 99% Confidence Interval [CI] [0.97, 1.00], p<.01), LBW (OR=0.98, 99% CI [0.97, 0.99], p<.01) and NICU admission (OR=0.99, 99% CI [0.98, 1.00], p<.01) but not with infant mortality (OR=1.00, 99% CI [0.95, 1.05], p>.01). CONCLUSION: Average time lag from pregnancy recognition to prenatal care was not associated with poor newborn outcomes once results were adjusted for time of pregnancy recognition and other confounders. PMID- 20920000 TI - Effects of gender on the health and development of medically at-risk infants. AB - OBJECTIVES: To examine gender-differentiated health and cognitive/motor/language developmental outcomes among medically at-risk infants. DESIGN: Longitudinal descriptive and comparative secondary analysis. SETTING: Neonatal Intensive Care Unit, intermediate care unit, and infectious disease clinic of tertiary medical centers in the southeast and east United States. PARTICIPANTS: One hundred eight (108) premature infants, 67 medically fragile infants, and 83 infants seropositive for HIV. METHODS: Neonatal and later health variables were obtained from the medical record to determine the technology dependence scores and frequency of common health problems. Data for physical growth and cognitive/motor/language development were obtained through the physical measurement, including the Bayley Scales of Infant Development-Second Edition, the Vineland Adaptive Behavior Scale, the Toll Control Developmental Checklist, and the Preschool Language Scale-3 during home visits between 6 and 27 months corrected ages. RESULTS: Fewer effects on health and developmental outcomes related to gender were observed with medically fragile infants than the other two groups of infants. The cognitive/motor/language scores were decreased with increasing age of the infants in all groups. CONCLUSION: Male gender can be considered a significant biological risk factor for infants' cognitive and motor development, especially for premature infants. Because of their increased risk, it is recommended that male infants who are born prematurely or seropositive for HIV have early and advanced developmental screening tests by trained personnel through periodic pediatric clinic. PMID- 20920004 TI - Editorial: The changing face of nursing in a developing country. PMID- 20920002 TI - Agreement on perceptions of quality of life in couples dealing with infertility. AB - OBJECTIVE: To examine the extent to which men and women seeking treatment for infertility were able to accurately perceive their partners' ratings of their quality of life (QOL). DESIGN: Cross-sectional prospective study. Quality of life was measured as a multidimensional construct. SETTING: Assisted reproduction clinic of a university hospital. PARTICIPANTS: One hundred and sixty-two couples participated. The men's and women's mean ages were 36.1 and 32.1 years, respectively. Most participants had no children, and no previous assisted reproduction attempts. METHODS: Men and women completed the World Health Organization-Quality of Life-Brief (WHOQOL-Brief) and the Beck Depression Inventory independently. Paired t tests were used to explore men's perceptions of their wives' QOL ratings and wives' perceptions of their husbands' ratings. Multiple regression and repeated-measures ANCOVA were used to examine the role of depression. RESULTS: Proxy assessments were consistently lower than self-reports on the domains of QOL. The influence of depression on agreement was minimal, and no gender effect was observed. CONCLUSION: Findings indicated little agreement in perceptions of the partner's QOL, with each partner tending to underrate the other's view. Practitioners need to consider the differences between partners to enable partners to better understand and support each other. PMID- 20920005 TI - Metastatic spinal cord compression: a review of practice and care. AB - AIM AND OBJECTIVES: The aim of this review was to address: (1) How is spinal stability assessed? (2) What is the role of bracing/should braces be used? (3) When is it safe to mobilise the patient? (4) What position should the patient be nursed in? BACKGROUND: Controversy surrounds the care for patients with metastatic spinal cord compression (MSCC). There is some evidence to indicate that care for patients with MSCC is based on individual clinician preference rather than evidence-based guidelines which has been shown to cause delays and discrepancies in patient treatment. DESIGN: A structured literature review to synthesise the available evidence about the management of MSCC. METHODS: The following databases were searched: Medline, EMBASE, Cochrane Systematic Reviews Database, SIGN (Scottish Intercollegiate Guidelines Network), NICE (National Institute for Clinical Excellence), AMED (Allied and Complementary Medicine), CINAHL (Cumulative Index to Nursing and Allied Health Literature) and BNI (British Nursing Index). Publications were selected from the past 10 years. The search yielded a total of 1057 hits, 755 abstracts were screened, and 73 articles were retrieved and examined. Thirty-five articles were included. RESULTS: The findings identified a gap and evidence relating to spinal stability, bracing, patient mobilisation, and positioning is limited and may be inconclusive. It is important for patients with a poor prognosis that their preferences and quality of life are considered. CONCLUSION: Currently, the evidence base to underpin care is limited, and further research in this area is necessary for patients and healthcare professionals alike. RELEVANCE TO CLINICAL PRACTICE: Patients who suffer from MSCC suffer numerous physical, psychological and social issues. Because of lack of consensus, the current guidelines to inform clinical decision making of professional staff are of limited benefit. PMID- 20920006 TI - Satisfaction with care in oncology outpatient clinics: psychometric characteristics of the Icelandic EORTC IN-PATSAT32 version. AB - AIM AND OBJECTIVES: To assess the psychometric characteristics of the Icelandic European Organisation for Research and Treatment of Cancer IN-PATSAT32 (EORTC IN PATSAT32) version and to compare satisfaction with care between gender and different age groups. BACKGROUND: The majority of patients with cancer receive either chemotherapy or radiotherapy on an outpatient basis. There is a need to evaluate satisfaction with care and service for these patients using reliable and valid instruments. DESIGN: Cross-sectional comparative study. METHOD: Participants (n=217) who received treatment for cancer as outpatients answered the EORTC IN-PATSAT32 questionnaire. Participants were 22-91 years old and 57% of them were female. RESULTS: Overall high satisfaction was found with communication, information and care that patients receive from doctors and nurses. Principal component analysis extracted four factors: 'satisfaction with nurses' conduct', 'satisfaction with doctors' conduct', 'satisfaction with information' and 'satisfaction with service and care organisation'. Patients were most satisfied with nurses' conduct but least satisfied with service and care organisation. Cronbach's alpha for the four factors ranged from 0.95-0.67. CONCLUSION: Although the validity of this instrument including its sensitivity to patients' level of dissatisfaction as well as satisfaction with care and service was evident, this needs to be further explored in future studies. The psychometric strengths of the EORTC IN-PATSAT32 are its internal consistency and its construct validity, but there are several issues indicating a need to change and develop the instrument and specifically adopting it to outpatient care. RELEVANCE TO CLINICAL PRACTICE: Outpatient treatment options offered to cancer patients have increased, and this calls for knowledge of their satisfaction with care and service. Sparse studies are available, and there is a need for further development of reliable instruments. Our study indicates that outpatients with cancer are quite satisfied with the care they receive. Findings may contribute to improvement in outpatients' clinics that provide treatment to patients with cancer. PMID- 20920007 TI - Perception of risk factors and DXA T score among at-risk females of osteoporosis. AB - AIM: This paper reports a study to investigate the relationships among bone mineral density, demographics, knowledge of osteoporosis, beliefs concerning osteoporosis and preventive behaviours of at-risk females with family histories of osteoporosis. BACKGROUND: Strong evidence demonstrates that genetics is a significant determinant of peak bone mass, with a heritability of 50-90%. However, few studies have examined the bone mineral density of at-risk females with family histories of osteoporosis, particularly in an Asian population. DESIGN: Telephone survey. METHODS: The study population (n=2890) was recruited from a radiology department at a national university medical centre in northern Taiwan during 2005-2006. In total, 886 females completed a questionnaire via the telephone; the participation rate was 30.7%. RESULTS: The bone mineral density of at-risk females was close to osteopenia status (T score of -1 to -2.49). Most subjects were aware of osteoporosis-related information; however, few clearly understood osteoporosis. Furthermore, subjects reported difficult implementing strategies to improve bone mineral density. Variation in bone mineral density was correlated with self-rated health (r=0.56, p<0.05), knowledge of osteoporosis (r=0.66, p<0.05) and preventive behaviours (r=0.68, p<0.05). CONCLUSIONS: This study is to examine risk factors associated with bone mineral density of females with family histories of osteoporosis. Early identification of risk factors for osteoporosis and development of prevention programmes are required to halt the increasing in the incidence of osteoporosis and improve the bone mineral density of at-risk females. RELEVANCE TO CLINICAL PRACTICE: Nursing care professionals, who emphasise primary, secondary and tertiary prevention with individuals and families, should develop effective prevention strategies for women with family the history of osteoporosis to protect the health of these vulnerable populations at-risk for osteoporosis. PMID- 20920008 TI - Implementation of a guideline for pressure ulcer prevention in home care: pretest post-test study. AB - AIMS AND OBJECTIVES: To investigate the effect of the implementation of a patient and family education programme for pressure ulcer prevention in an organisation for home care nursing on guideline adherence and on prevalence and severity of pressure ulcers and to examine the determining factors for the application of measures for pressure ulcer prevention. BACKGROUND: Quality improvement programmes in pressure ulcer prevention are not always successful. DESIGN: Implementation study using a pretest-post-test design. Data were collected in three probability samples. The first post-test data collection was held after six months, the second after 18 months. METHOD: Statistical analysis was used, comparing the pretest sample and the second post-test sample. RESULTS: After 18 months, the proportion of subjects with adherent measures had increased from 10.4 13.9%, the proportion of subjects with non-adherent measures decreased from 45.7 36.0%, the proportion of subjects without pressure ulcer prevention increased from 43.9-50.1% (p<0.0001, Chi-square test). Sub-analysis revealed that a positive change in guideline adherence was observed principally in the group at risk. Better process-of-care indicators were associated by lower pressure ulcer prevalence and less severe skin lesions. The nurses' judgement of a patient risk status was the most important factor for applying preventive measures. Furthermore, application of pressure ulcer prevention was determined by higher age (from the age category of 70-79 years), higher dependency for the activities of daily living, higher than baseline mobility score and the presence of a pressure ulcer. CONCLUSIONS: Guideline adherence in pressure ulcer prevention changed significantly after implementation of the education programme. There might have been inconsistencies in the nurses' risk judgement. RELEVANCE TO CLINICAL PRACTICE: Quality of pressure ulcer prevention improved, but several items for improvement remain. Adaptation of risk assessment procedures is needed. PMID- 20920009 TI - Starting a care improvement journey: focusing on the essentials of bedside nursing care in an Australian teaching hospital. AB - AIMS AND OBJECTIVES: To evaluate and improve patient assessment practices, care practices, recognition of patient deterioration and communication in the acute ward environment. BACKGROUND: A growing recognition of patient safety-related concerns in acute hospitals, a nursing shortage and a reduction in availability of skill and experience levels at the bedside led a group of clinicians to explore the issues that impacted on patient care at a ward level within their organisation. DESIGN: Multimethod practice development study. This paper reports phase one of concept development. METHOD: A practice review was conducted using clinical audit processes that examined practice and documentation in relation to patient assessment parameters and care planning, specifically identifying whether changes in clinical parameters were identified and acted on. RESULTS: Results highlighted a clear discrepancy between the care that was identified on the nursing care plan and the care the patient was receiving. Actions as a result of the disappointing audit results included changes to education programmes, strategies to improve critical discussion regarding clinical practices and the development of assessable domains of nursing care that were relevant and realistic to ward-based nurses. CONCLUSION: The results enabled the identification of eight domains of care and associated care outcomes that target strategies for care improvement. Emancipatory practice development methodology will be used to further progress this work and ensure successful implementation into clinical units. RELEVANCE TO CLINICAL PRACTICE: This paper examines the critical discussions, audit processes and actions that took place, leading to the development of care outcomes for nurses. PMID- 20920010 TI - Malnutrition prevalence and precision in nutritional care: an intervention study in one teaching hospital in Iceland. AB - AIM: The aim of this study was to explore the point prevalence of malnutrition and the targeting of nutritional interventions in relation to undernutrition risk before and after an intervention. BACKGROUND: Malnutrition risk and the precision in targeting nutritional treatment are indicators of quality of care. Knowledge regarding the in-hospital prevalence of malnutrition and nutritional treatment is meagre for Iceland. DESIGN: Pre- and postintervention study. METHODS: The study was performed during one day in 2006 (March) and one day in 2007 (April). In total, 95 (89%) and 92 (88%) patients agreed to participate. Moderate/high undernutrition risk was defined as the occurrence of at least two of the following: involuntary weight loss, body mass index below limit and eating difficulties according to Minimal Eating Observation Form - Version II. Being overweight was graded based on body mass index. Specific nutritional care actions were recorded. INTERVENTION: A five-point programme for nutrition and eating was implemented. RESULTS: Moderate/high risk for undernutrition was found in 25 and 17% in the two years (ns, not significant). A high body mass index was found in 53 and 54% (ns). The number of patients with a documented body mass index significantly increased between the two surveys (1 and 30%, p-value <0.0005). The use of oral supplements increased from 11-40% (p<0.0005) and especially among those at no/low undernutrition risk, with ingestion or deglutition difficulties (p<0.0005 in both cases) but not among those with appetite and energy problems (ns). CONCLUSION: Implementing a nutritional programme does not necessarily affect the number of in-patients with malnutrition, but it is likely to increase the precision of nutritional care to some extent. RELEVANCE TO CLINICAL PRACTICE: Greater efforts need to be taken to increase the precision of nutritional care among patients at moderate/high undernutrition risk and among those with appetite and energy problems. PMID- 20920011 TI - Functional constipation: implications for nursing interventions. AB - AIMS: To verify the correlation between anorectal function and psychological conditions of depression/anxiety in patients with functional constipation. The aim of this study is to explore why people with depression/anxiety have higher incidence of functional constipation and recommend innovative interventions to advance patient care of functional constipation. DESIGN: A prospective correlational design. METHODS: Anorectal manometry was performed on functional constipation patients (n=70) through the Medtronic Synectics PC Polygraf, while the psychological condition was tested by Self-Rating Anxiety Scale and Self Rating Depression Scale. Twenty normal controls were also studied. RESULTS: Compared with controls, (1) functional constipation patients displayed higher squeezing pressure, defaecation thresholds and maximal volume of tolerance (p<0.01), and there was no significant difference in anorectal resting pressure, defaecating pressure, minimum relaxation volume and first sensation (p>0.05). (2) Functional constipation patients showed higher depression/anxiety scores (p<0.01). (3) The anorectal squeezing pressure was negatively correlated with anxiety and depression scores, while the first sensation and maximal volume of tolerance was positively correlated with depression score (p<0.05). CONCLUSIONS: Abnormal anorectal function correlates to depression/anxiety levels indicating that depression/anxiety may contributes to functional constipation. The possible pathology is via brain-gut axis. RELEVANCE TO CLINICAL PRACTICE: The study indicates that nurses should pay attention to the patients' psychological needs, especially to those interested in seeing the physician and doing unnecessary examinations repeatedly to find any organic disease. Integrated nursing intervention should be applied to improve patients' psychological adaptation and boost the functional constipation therapeutic effect. PMID- 20920012 TI - Quality of life in chronic disease: a comparison between patients with heart failure and patients with aphasia after stroke. AB - OBJECTIVES: This study aimed to describe the impact of heart failure and of stroke with aphasia on quality of life (QoL) and to compare the different domains of QoL in these groups. BACKGROUND: The prevalence of chronic conditions has increased during the last decades, and chronic diseases such as stroke and heart failure may have a great impact on QoL. DESIGN: Comparative study of patients from two randomised controlled studies. METHOD: Seventy-nine patients with heart failure and 70 patients with aphasia after stroke were evaluated concerning the severity of their disease and by QoL, as measured with the Nottingham Health Profile, in the acute phase and after six months. RESULTS: The severity of the disease improved between baseline and six month for both groups. Correlations between New York Heart Association (NYHA) class and all QoL domains were seen in patients with heart failure after six months. The degree of aphasia correlated to mobility, social, emotional and total score after six month. QoL in patients with heart failure was more affected in the domains of sleep and energy in the acute phase and in the energy domain at six months. CONCLUSION: Although low energy is more frequent among patients with heart failure, both groups report poor QoL. Improvement in severity of the disease is not necessarily accompanied by improvement in QoL. RELEVANCE TO CLINICAL PRACTICE: Nottingham Health Profile can easily be used as a screening instrument, aiming to identify patients at risk for adverse effects on QoL. A better understanding of the subjective QoL of patients with chronic disease is fundamental for health care professionals to be able to identify and support vulnerable patients. PMID- 20920013 TI - The effect of clothes on sphygmomanometric blood pressure measurement in hypertensive patients. AB - AIMS: To test whether there is any difference between blood pressure readings with patients wearing clothes under the manometer's cuff and not wearing clothes. BACKGROUND: The few studies published on this subject have shown that blood pressure measurements give similar results whether the patients' arm is covered by clothing or not. However, it has not been clarified whether this is also true in hypertensive patients. METHOD: Blood pressure was measured on non-sleeved arm, sleeved arm and again on non-sleeved arm in 258 hypertensive patients using a mercury-filled column sphygmomanometer. Three nurses who were experienced and specially trained for the study performed blood pressure measurements. They were unaware of the purpose of the research. RESULTS: Measuring blood pressure with the manometer's cuff over participant's sleeved arm did not differ significantly from non-sleeved arm measurements. RELEVANCE TO CLINICAL PRACTICE: Sleeves have no effect on blood pressure results. Blood pressure readings taken over the sleeves will be much more practical and time saving in busy departments like emergency rooms, during disasters like earthquake where decisions have to make in minutes. Additionally, it will be time saving for general health screening surveys. Finally, it may have preferable because of hygiene concerns, patient privacy and religious beliefs. PMID- 20920014 TI - Nurses' experiences in the relief of postoperative nausea and vomiting. AB - AIM: The aim of the study was to illuminate the experience of nurses in relieving postoperative nausea and vomiting. BACKGROUND: Postoperative nausea and vomiting has been shown to be one of the most common and distressing side effects of surgery. In spite of this, there has been little research on the role of nurses in caring for patients with postoperative nausea and vomiting. DESIGN: Qualitative approach using narratives. METHODS: Ten female nurses from two general surgical departments were interviewed. The transcribed interviews were analysed using the hermeneutic narrative method inspired by Polkinghorne. RESULTS: The nurses report that they have what may be described as a set of different tools at their disposal. These tools can be entitled 'listen and understand', 'information', 'the clinical eye' and 'availability', all of which can be used in solving several needs. However, some nurses have better skills or more opportunities to use the available tools than do others. By using these tools, the nurses can increase their possibilities for enhancing the patients' efforts to gain control over their own situation and thereby increase the quality of their care. CONCLUSION: Nurses use different types of tools to relieve postoperative nausea and vomiting and it is possible to create a positive nursing care situation if patients are given the opportunity to be in control and handle their own situation. RELEVANCE TO CLINICAL PRACTICE: When it comes to relieving postoperative nausea and vomiting, the findings of this study are important as the study highlights the practical actions taken by nurses and their experiences. When nurses have the possibility to use their nursing tools in an optimal way, together with their experience and knowledge and then follow their nursing actions by being able to reflect on them, they can further develop their approach to nursing and thereby increase their competence as nurses. PMID- 20920015 TI - Risk factors for deep sternal wound infections after cardiac surgery in Jordan. AB - AIM: The purpose of this study was to assess rates of and risk factors for deep sternal wound infection after coronary artery bypass grafting surgery. BACKGROUND: Deep sternal wound infection is one of the most devastating complications of cardiac surgery, resulting in multiple operative and non operative procedures and increased hospital costs. DESIGN: A retrospective design using an existing coronary artery surgery database of adults (n=206) who had undergone coronary artery bypass grafting surgeries between January 2004-January 2006 at a university affiliated hospital, northern Jordan was used. METHOD: Multiple logistic regression analyses were used to asses rates of and risk factors for deep sternal wound infection. RESULTS: Deep sternal wound infection incidence rate was 22% of the total sample. Risk factors of deep sternal wound infection include: (1) diabetes (OR=0.317, p=0.048), (2) Obesity (OR=0.275, p=0.011), (3) duration of surgery (OR=4.22, p=0.032) and (4) use of intraaortic balloon pump (OR=0.033, p=0.001). CONCLUSION: The proposed model provides a preliminary indication of risk factors placing coronary artery bypass grafting patients at risk of DSWI. Further investigations and testing of the model are needed. RELEVANCE TO CLINICAL PRACTICE: Determining patients who are at risk of developing deep sternal wound infection after cardiac surgeries is the first step towards its prevention. PMID- 20920016 TI - A comprehensive training programme for nurse endoscopist performing flexible sigmoidoscopy in Hong Kong. AB - AIMS: To describe the process and explore the feasibility of training a colorectal nurse in Hong Kong to perform flexible sigmoidoscopy. BACKGROUND: Given the shortage and high turnover rate of medical staff, a pilot programme was designed to train and expand the role of colorectal nurse clinicians. It was hoped that such nurses could share some of the clinical duties of the medical staff. An advanced practice nurse was selected for the programme. One of the training components was the performance of flexible sigmoidoscopy. DESIGN: This was a descriptive, case review study. METHOD: A one-year-structured endoscopic training programme was designed for the nurse clinician. Weekly sessions were conducted by one of the trainers. The training process included the following: (1) procedural observation; (2) supervised withdrawal, advancement and manipulation of the sigmoidoscope and (3) a final assessment of the nurse's competency in performing sigmoidoscopy independently. RESULTS: In total, 119 outpatients (58 male and 61 female) with a mean age of 57.02 years (SD 14.6 years; range: 18-83 years) underwent flexible sigmoidoscopy by the nurse over 11 months. The mean procedural time was 9.38 minutes (SD 3.5 minutes; range 3-26 minutes). The procedure was terminated prematurely if it could not be tolerated by the patient or if the bowel preparation was inadequate. The mean depth of insertion was 53.5 cm (SD 12.2 cm; range 6-60 cm). In total, 82 patients had a normal exam, 32 patients had abnormalities. There were no procedural complications, and no patient required an unplanned hospital admission after the procedure. CONCLUSION: In Queen Mary Hospital, nurses can be trained to perform flexible sigmoidoscopy in a safe and effective manner. RELEVANCE TO CLINICAL PRACTICE: Nurse endoscopists could increase the use of flexible sigmoidoscopy in colorectal cancer screening and can also enhance the professional development of colorectal nurses. PMID- 20920017 TI - User involvement in in-patient mental health services: operationalisation, empirical testing, and validation. AB - AIMS: This study presents development, empirical testing and validation of an instrument measuring service user involvement in in-patient mental health from the mental health professionals' perspective. BACKGROUND: Service user involvement is high on the agenda in European mental health policies. In Norway, focus is on enhanced service user involvement at both the individual and organisational levels of in-patient mental health services. Mental health professionals are in an important position to ensure opportunities for real user involvement in in-patient mental health care. However, there is a need for more empirical knowledge on how mental health professionals attend to service user involvement. DESIGN: Survey. METHODS: A self-report questionnaire was designed and administered to 121 mental health professionals, with 98 responses, working in a community-based mental health centre in western Norway. Factor analysis procedures together with reliability testing were performed. RESULTS: A 30-items instrument was developed. The instrument contains four components/subscales: (1) Democratic patient involvement (mean score 3.74, Cronbach's alpha 0.81), (2) Carer involvement (mean score 3.67, Cronbach's alpha 0.82), (3) Assisted patient involvement (mean score 4.05, Cronbach's alpha 0.78) and (4) Management support (mean score 4.10, Cronbach's alpha 0.75). These subscales were found to be essential to service user involvement in the context of in-patient mental health care. The total mean score for the instrument was 3.88, Cronbach's alpha 0.88. CONCLUSION: Empirical testing of the instrument demonstrates that the measurement of mental health professionals' perception of service user involvement has a reasonable level of construct validity and reliability. RELEVANCE TO CLINICAL PRACTICE: We have developed a measurement instrument with items reflecting essential characteristics to user involvement in in-patient mental health services. We believe that answering this questionnaire on the subject user involvement can act as one step towards enhancing awareness of this issue and to assess user-oriented practices in treatment and services. PMID- 20920018 TI - Research priorities for nursing care of infants, children and adolescents: a West Australian Delphi study. AB - AIMS AND OBJECTIVES: This paper describes a study that aimed to identify research priorities for the care of infants, children and adolescents at the sole tertiary referral hospital for children in Western Australia. The secondary aim was to stimulate nurses to explore clinical problems that would require further inquiry. BACKGROUND: Planning for research is an essential stage of research development; involving clinicians in this exercise is likely to foster research partnerships that are pertinent to clinical practice. Nursing research priorities for the paediatric population have not previously been reported in Australia. DESIGN: Delphi study. METHOD: Over 12 months in 2005-2006, a three-round questionnaire, using the Delphi technique, was sent to a randomly selected sample of registered nurses. This method was used to identify and prioritise nursing research topics relevant to the patient and the family. Content analysis was used to analyse Round I data and descriptive statistics for Round II and III data. RESULTS: In Round I, 280 statements were identified and reduced to 37 research priorities. Analysis of data in subsequent rounds identified the top two priority research areas as (1) identification of strategies to reduce medication incidents (Mean=6.47; SD 0.88) and (2) improvement in pain assessment and management (Mean=6; SD 1.38). Additional comments indicated few nurses access the scientific literature or use research findings because of a lack of time or electronic access. CONCLUSIONS: Thirty-seven research priorities were identified. The identification of research priorities by nurses provided research direction for the health service and potentially other similar health institutions for children and adolescents in Australia and internationally. RELEVANCE TO CLINICAL PRACTICE: The nurse participants showed concern about the safety of care and the well-being of children and their families. This study also enabled the identification of potential collaborative research and development of pain management improvement initiatives. PMID- 20920019 TI - Reliability and validity of the scale of patient perception of hospital experience with nursing care in a Turkish population. AB - AIM AND OBJECTIVES: This study aimed to adapt an English version of the survey tool Patient Perception of Hospital Experience with Nursing Care for Turkish patients and to evaluate its psychometric properties. BACKGROUND: Patient satisfaction is used as an important indicator of care quality and frequently included in health care planning and evaluation. In Turkey, although a review of the literature identified several tests that measured patient satisfaction with hospitalisation services, there are few studies that measured both patients' satisfaction and patients' perceptions. DESIGN: This study was conducted at the Research and Application Hospital of Ataturk University in Erzurum, Turkey with a convenience sample of 150 patients who were discharged from medical and surgical clinical units. METHODS: Experts' viewpoints were used to determine language validity of the scale, and factor analysis was used to determine the structural validity of the scale. Cronbach's alpha reliability coefficient, item analysis, test-retest analysis were conducted to evaluate the reliability of the scale. Data were collected using the Patient Perception of Hospital Experience with Nursing Care Scale and Socio-demographic form. RESULTS: It was determined that Patient Perception of Hospital Experience with Nursing Care showed a one-factor structure, Cronbach's alpha reliability coefficient was 0.92 and item-total point correlations were between 0.36-0.74. In addition, it was found that the test retest correlation value was 0.90, which was found to be statistically significant (p<0.001). CONCLUSIONS: The validity and the reliability of the Patient Perception of Hospital Experience with Nursing Care Scale are extremely high, and it is an adequate measurement scale to determine patients' satisfaction with nursing care. RELEVANCE TO CLINICAL PRACTICE: We suggest that the scale can be used in nursing research projects to evaluate the patient satisfaction and the quality of nursing care. PMID- 20920020 TI - Actively involving people with dementia in qualitative research. AB - AIMS AND OBJECTIVES: This paper aims to: * Consider the major challenges to involving people with dementia in qualitative research. * Critique a process consent framework. * Demonstrate the need for nurses and researchers to explore these issues in research and practice with people with dementia. * Consider the impact of the Mental Capacity Act 2005 on research with people with dementia. To achieve its aims, the authors will draw on current literature and use examples which explores the use of life story work with people with dementia by taking a qualitative approach. BACKGROUND: There is acceptance that researchers should consider ways of actively involving people with dementia in research as participants where appropriate to answering specific research questions. Process consent methods have been advocated as an ethical way forward in recruiting and gaining consent for people with dementia, the Mental Capacity Act offers guidance to both practitioners and researchers. DESIGN AND METHOD: This paper does not seek to be a comprehensive review of the current literature but is a discussion paper appraising a process consent framework against current literature and drawing on the lead author's PhD study, exploring life story work with older people with dementia. RESULTS AND CONCLUSIONS: The Mental Capacity Act and process consent frameworks compliment one another, and their use should be considered when researching issues affecting older people with dementia. Researchers and practitioners should work more closely to ensure that the principles of process consent are achieved. Process consent models can equally be applied to everyday nursing practice. RELEVANCE TO CLINICAL PRACTICE: Process consent models can provide an ethical and practical framework to ensure that consent is continually assessed in people with dementia with all clinical interventions. The paper also draws on literature exploring practical ways of involving people with dementia in evaluating service delivery. PMID- 20920021 TI - Multi-institutional study of barriers to research utilisation and evidence-based practice among hospital nurses. AB - AIMS: The study aims were to explore the relationships between perceived barriers to research use and the implementation of evidence-based practice among hospital nurses and to investigate the barriers as predictors of implementation of evidence-based practice. BACKGROUND: Evidence-based practice is critical in improving healthcare quality. Although barriers to research use have been extensively studied, little is known about the relationships between the barriers and the implementation of evidence-based practice in nursing. DESIGN: Cross sectional study. METHOD: Data were collected between December 2006-January 2007 for this cross-sectional study using computerised Evidence-Based Practice Questionnaire and BARRIERS surveys. A convenience sample (n=1301) of nurses from four hospitals in southern California, USA, participated. Hierarchical multiple regression analyses were performed for each of the three dependent variables: practice, attitude and knowledge/skills associated with evidence-based practice. BARRIERS subscales were used as predictor variables. RESULTS: The perceived barriers to research use predicted only 2.7, 2.4 and 4.5% of practice, attitude and knowledge/skills associated with evidence-based practice. Conclusions. It was unexpected that the barriers to research use predicted such small fractions of practice, attitude and knowledge/skills associated with evidence-based practice. The barriers appear to have minimal influence over the implementation of evidence-based practice for most hospital nurses. RELEVANCE TO CLINICAL PRACTICE: In implementing evidence-based practice, the focus on barriers to research use among general nursing staff may be misplaced. Further studies are needed to identify the predictors of evidence-based practice and to identify the subset of nurses who are most amenable to adopting evidence-based practice. PMID- 20920022 TI - Mothers' experience with 1st-3rd-grade children with asthma assisting their child's adaptation of school life in Taiwan. AB - AIMS AND OBJECTIVES: This study used purposive sampling through semi-structured interviews to obtain the experiences of mothers of 7-11-year-old children with asthma who were assisting their child's adaptation to school life. BACKGROUND: Children with asthma often have problems with social adaptation, including school absenteeism, limits to their activity and bullying by peers. From kindergarten to elementary school, it is a transitional process where the child experiences multiple changes in the body, mind and social situations. It can be difficult for mothers of children with asthma to assist their children with their adaptation to school life. DESIGN: A qualitative enquiry design was used. METHODS: A total of 15 mothers having elementary school children with asthma in grades 1-3 were interviewed. Participants were contacted at the outpatient department of a medical centre in Taiwan. Verbatim transcriptions of the interviews were examined by the content analysis method. After analysis of the interview data of the 15 informants, no new themes had emerged. Lincoln and Guba's trustworthiness criteria were employed to evaluate methodological rigour. RESULTS: There were four themes that formed part of the mothers' experiences. Those were: (1) being concerned about the child's adaptation to school life, (2) improving attitudes and relieving symptoms, (3) establishing the child's self-management abilities and (4) bearing role strain and normalising the life of the child. CONCLUSIONS: The findings of this study should help health professionals and schoolteachers to understand the needs of families and mothers who have a child with asthma. The findings provide appropriate information and resources to assist the children's adjustment to school life. RELEVANCE TO CLINICAL PRACTICE: The findings indicate that nursing professionals should provide child-focused and family-centred care that will assist parents of children with asthma to adjust to school life. PMID- 20920023 TI - Processing the first birth: journeying into 'motherland'. AB - AIMS AND OBJECTIVES: To explore first-time mothers' experiences of birth at home and in hospital in Australia. BACKGROUND: The first birth has unique physical and psychological impacts on women. With the first birth, women become mothers. DESIGN: A grounded theory methodology was used. Data were generated from in-depth interviews with women in their own homes. METHODS: Nineteen women were interviewed in Sydney, Australia. The experiences of seven women who gave birth for the first time in a public hospital and seven women who gave birth for the first time at home were contrasted with two mothers who gave birth for the first time in birth centres, one mother who gave birth for the first time in a private hospital and two women who had given birth more than once. RESULTS: Following the birth, women 'processed the birth' by 'remembering', 'talking (storytelling)' and 'feeling'. This activity appeared to help most women resolve their feelings about the birth and understand what it actually means to be a new mother. 'Personal and social integration' occurred for most women as they entered 'motherland'. CONCLUSION: First-time mothers appear to 'process the birth' to a greater extent than multiparous women because they are experiencing this for the first time. These women also have limited social networks in 'motherland', and these are facilitated through sharing the experiences of their labour or 'processing the birth'. RELEVANCE TO CLINICAL PRACTICE: Identifying the novice status of first time mothers and understanding the way they process the birth can help health providers to be sensitive to the specific needs of primiparous women. In particular, their need to tell their birth stories following birth; understanding that these stories help women to process the birth and connect to other women. PMID- 20920024 TI - Lesbians' attitudes and beliefs regarding overweight and weight reduction. AB - AIM AND OBJECTIVE: This article presents data on attitudes and beliefs about overweight/weight reduction in lesbians. The project was developed to have information on which to base future culturally sensitive interventions to reduce cardiovascular risk in lesbians. BACKGROUND: Lesbians have been found to have high rates of obesity/overweight and to be more accepting of it. Researchers have hypothesised that this is attributed to different attitudes towards body weight and shape in lesbians than heterosexuals. Little is known about acceptable ways to intervene to decrease cardiovascular risk in lesbians in view of these attitudes. DESIGN: omen over 21 who self-identified as lesbian and reported one or more cardiovascular risk factors were recruited from medical providers and community resources. Twenty-five women participated in five focus groups that explored practices, attitudes and beliefs about cardiovascular risk and culturally acceptable strategies to reduce cardiovascular risk in lesbians. METHOD: Demographic and risk factor information was collected from focus group members by questionnaire. Focus groups were audiotaped and transcribed. Investigators reviewed the transcripts and identified, coded and categorised data to begin to identify emergent themes. RESULTS: Lesbian participants with risk factors for cardiovascular risk expressed concern about the health consequences of weight but want a focus on their general health rather than exclusively on the BMI. There is not homogeneity in attitudes and beliefs about weight and overweight among lesbians, and generational differences were found. Minority stress, anxiety and depression and homophobia were major factors in health behaviours and barriers to changing unhealthy behaviours. RELEVANCE TO CLINICAL PRACTICE: Lesbian participants with risk factors for cardiovascular disease were eager to be involved in individual and group culturally sensitive programs that focus on improved health and well being. Recommended interventions include lesbian specific multidimensional group interventions that could deal with the multiple factors involved in causing and maintaining the behaviours. PMID- 20920025 TI - Disrupted sense of self: young women and sexually transmitted infections. AB - AIM: This article is an exploration of young women's experiences of having a sexually transmitted infection. BACKGROUND: Sexually transmitted infections are prevalent worldwide and have serious physical and psychological sequelae. Although some aspects of having sexually transmitted infections have been identified in the literature, the stigmatised nature of these infections means that relatively little is known about the experiential aspects of these conditions. DESIGN: This research used a qualitative feminist approach. METHODS: Data were collected in 2007 via online interviews with ten women. Thematic analysis was guided by a feminist narrative technique. RESULTS: Findings revealed the women had not believed themselves to be at risk of sexually transmitted infections because of perceptions they held about the sorts of women who contract these infections. Because these perceptions were incompatible with their self perceived views, the women initially experienced a disruption in their sense of self. To facilitate the restoration of their previously held sense of self, these women engaged in wishful thinking and denial. CONCLUSION: This study illuminates how perceptions of sexually transmitted infections influence the way young women perceive themselves in the context of these infections. Awareness of the detrimental impact contracting sexually transmitted infections can have on young women can help nurses to provide services that facilitate positive and effective coping strategies among this group. RELEVANCE TO CLINICAL PRACTICE: Nurses providing care to women with sexually transmitted infections should promote positive coping strategies that could help curb non-disclosure and denial among young women who contract these infections. Education focused on sexually transmitted infections should emphasis that all sexually active individuals are at risk of these infections, which could potentially minimise the shame felt by persons who contract these infections. Further, recognition of the gender issues that limit women's ability to practise safer sex should be incorporated into safer sex education and campaigns. PMID- 20920026 TI - Recovering from a stroke: a longitudinal, qualitative study of older Norwegian women. AB - AIM: To illuminate older women's experiences and the characteristics of the recovery process following a stroke. BACKGROUND: Patients with stroke face serious challenges related to bodily changes, existential aspects and daily life after stroke. Few qualitative longitudinal studies have examined the recovery process from the perspective of the patient. Knowledge about older women's experiences in coping with life after a stroke is limited. DESIGN: Prospective, longitudinal, case-study design. METHODS: Six women aged 68-83 suffering from first-time stroke were recruited from two stroke units. Each participant was interviewed in-depth 12-14 times during the first two years post stroke. The interviews addressed how they experienced their body, their self-understanding, daily life and how this had changed over time. Most interviews took place in the participants' homes. Gadamer's philosophical hermeneutics informed the analyses. RESULTS: Post stroke recovery was slow and complex and evolved through four distinct phases. In the first phase (0-2 months post stroke), the participants' main concerns were their bodily changes; in the second phase (2-6 months), activities of daily life; in the third phase (6-12 months), self-understanding and in the fourth phase (12-24 months), going on with life. The transition between phases was gradual. CONCLUSION: Recovery from stroke evolves over time through four distinct phases, which differ depending on significant experiences and associated meanings. Psychological and social resources are equally critical in the women's process of recovery. RELEVANCE TO CLINICAL PRACTICE: The four phases of rehabilitation suggest at what points various concerns require increased therapeutic attention. Psychological and social resources must be vitalised at an early phase similar to bodily resources. This knowledge may assist professionals in offering adequate help throughout the recovery process even beyond the established rehabilitation period. PMID- 20920027 TI - Perceptions of breastfeeding and planned return to work or school among low income pregnant women in the USA. AB - AIMS AND OBJECTIVES: To describe the perceptions of breastfeeding in low-income pregnant women to understand their needs better as they plan to return to work or school. BACKGROUND: Maternal employment has a negative impact on breastfeeding duration. Yet there is insufficient research on challenges and facilitators regarding breastfeeding and employment issue among low-income women in the USA. Knowing the perceptions of breastfeeding among low-income pregnant women and their plan to return to work or school may have implications for nurses and midwives in providing quality care. DESIGN: Qualitative study using focus group interviews. METHODS: The research setting consisted of three Women, Infants and Children clinics (WIC) in a midwestern city of the USA. Seventeen pregnant women (aged 19-35) participated in focus group interviews. Data were coded and analysed for themes and patterns using the QSR software - NVivo 6. RESULTS: Eleven participants were single. Ten women were primigravida, and seven were multipara. The following five themes were identified: (1) perceived benefits of breastfeeding; (2) general perceptions of breastfeeding; (3) maternal concerns; (4) having the right support; and (5) anticipated challenges of combining breastfeeding and work. Conclusions. Low-income women anticipated substantial barriers for breastfeeding when they planned to combine breastfeeding and work or school. The results of this study have many implications for public health practice, research and policy. Educating employers and the public at large about the health and economic benefits derived from long-term breastfeeding could help promote breastfeeding awareness. RELEVANCE TO CLINICAL PRACTICE: Strategies supporting breastfeeding among low-income working women must be provided at multiple levels to help overcome the barriers they concern. Health care providers should help women gain confidence by minimising their uncertainties and fears about breastfeeding to prepare them to continue breastfeeding successfully after returning to work. PMID- 20920028 TI - Treatment decision-making in cancer care: the role of the carer. AB - AIMS AND OBJECTIVES: This study explores the role of the carer in treatment decision-making in cancer care. BACKGROUND: Literature about involvement in treatment decision-making tends to focus on patients and clinicians, with the carer rarely included. The absence of carers is problematic because the management of illness is often carried out in the context of complex networks of relationships. Although current policy encourages health care practitioners to work in partnership with family members, implementation is troubled by a lack of understanding of the significance of interpersonal relationships and interactions and the role of the relationship throughout the course of the illness experience. Despite awareness, there is little systematic, coherent analysis of the complexity of these interactional dynamics and, in particular, consideration of the implications for involvement and treatment decision-making. DESIGN: Qualitative, longitudinal. METHODS: Three serial semi-structured interviews with 66 patients and 43 carers within the first year following a diagnosis of cancer. A descriptive and thematic approach to data analysis was adopted. RESULTS: Carers are involved in treatment decision-making in cancer care and contribute to the involvement of patients through their actions during, before and after consultations with clinicians. Carers can act as conduits for information from patient to clinician and from clinician to patient. They can also act as facilitators during deliberations, helping patients to consider whether to have treatment or not and which treatment. CONCLUSIONS: Our study has highlighted the deficiency of models that fail to acknowledge the role of the carer in the treatment decision-making process. We propose the adoption of a relational approach by the inclusion of the carer in conceptual frameworks and recommend triadic (patient, carer and professional) models of involvement. RELEVANCE TO CLINICAL PRACTICE: Cancer care clinicians should recognise and actively involve the carer as well as the patient in treatment decision-making. PMID- 20920029 TI - An exploratory study of anxiety in carers of stroke survivors. AB - AIMS AND OBJECTIVES: To investigate anxiety in informal carers of stroke survivors in the first three months after discharge. BACKGROUND: Informal carers, also called caregivers, play a vital role in supporting stroke survivors. However, caring for stroke survivors can have adverse consequences amongst carers such as burden, stress and reduced quality of life. Emotional distress is also commonly reported but anxiety has received less attention than depression. DESIGN: Prospective, longitudinal, descriptive study. METHOD: Forty-five carers completed the Hospital Anxiety and Depression Scale on two occasions - within one month and at three months after discharge from stroke and rehabilitation units. RESULTS: Carers were more likely to have scores indicating anxiety than depression. In the first month, half the carers (51.1%) scored in the cut-off for anxiety and a third were in the cut-off for depression (31.1%). At three months, the picture was very similar with nearly identical proportions in the anxious and depressed categories (48.9% and 28.9%, respectively). Changes in numbers of cases of anxiety and depression and in mean anxiety scores were non-significant but there was a significant decrease in depression scores (p=0.048). Fourteen carers (31.1%) at one month and eleven (24.4%) at three months fell into both anxious and depressed categories. CONCLUSIONS: Anxiety is a relatively neglected emotional outcome in stroke carers. Our study suggests anxiety is an important issue very early in caring whilst other research suggests it remains prevalent for many months. Given the significant role carers play in rehabilitation of stroke survivors, greater recognition of their emotional state is required. Further, longitudinal research with larger sample sizes from a range of geographical areas and improved understanding of factors associated with anxiety is needed. RELEVANCE TO CLINICAL PRACTICE: Nurses working in the community are ideally placed to identify and support carers suffering from anxiety. PMID- 20920030 TI - Patient perceptions of helpful communication in the context of advanced cancer. AB - AIMS AND OBJECTIVES: Based on a secondary analysis of data from a large qualitative study on cancer care communication, we address the question: what do patients with advanced cancer identify as helpful in their communication encounters with health care providers? BACKGROUND: Communication is of critical importance to the care of patients with advanced cancer. A better understanding of what such patients identify as helpful in their communication encounters with nurses and other health care providers seems critical to creating evidence informed recommendations for best practices. DESIGN: Secondary analysis of qualitative interview data. METHODS: Data from 18 participants interviewed individually and 16 focus group participants, with advanced cancer in the palliative phase of care. Interpretive description methodology informed data collection and analysis. RESULTS: Findings suggest four key elements are critically important to consider in communications with patients in an advanced or palliative phase - respecting the importance of time, demonstrating caring, acknowledging fear and balancing hope and honesty in the provision of information. CONCLUSIONS: Communication is an important element in the provision of advanced cancer care. RELEVANCE TO CLINICAL PRACTICE: Findings emphasise the complex meanings inherent in cancer care communication and identify central themes that are fundamental to effective cancer care communication. PMID- 20920031 TI - 'Again': the impact of recurrence on survivors of cancer and family members. AB - AIM: To examine the psychosocial impact of recurrence on survivors of cancer and their family members. BACKGROUND: Cancer recurrence is described as one of the most stressful phases of cancer. Recurrence brings back many negative emotions, which are different and may be more intense than those after first diagnosis of cancer. Survivors and their family members have to deal with new psychological distress. DESIGN: A qualitative descriptive study was conducted in four cancer units of two hospitals in North of Spain. METHODS: Fifteen survivors of cancer with a recent diagnosis of recurrence, 13 family members and 14 nurses were interviewed. Data collection and analysis were based on the constant comparative method of grounded theory. RESULTS: Four major categories were found: (1) 'Again': when cancer comes back, (2) the shock of recurrence, (3) the impact of the diagnosis on family life, and (4) factors that influence the impact of recurrence. Learning that cancer had come back was, for most of the families, more devastating than hearing that they had cancer for the first time. Signs of shock and suffering were experienced by families as an initial response to recurrence. The new diagnosis often entailed a change in the family life. Survivorship period and age seemed also significant in the psychosocial experience of recurrence. CONCLUSIONS: The term 'again', used by all the participants to describe a recurrence of the disease, symbolised a beginning and a continuation with cancer; it implied a re-encounter with health services, and it represented new suffering for the families. RELEVANCE TO CLINICAL PRACTICE: Therapeutic nursing interventions should be planned and provided to both patients with recurrent cancer and their family members. Family nursing can play an important role in helping families master the impact of the recurrent illness. PMID- 20920032 TI - Why carers of frail older people are not using available respite services: an Australian study. AB - AIM: The purpose of this study was to explore the limiting and motivating factors that influence carers' use of respite services and the ability of currently available respite services to meet the needs of carers of frail older people. BACKGROUND: The development of community carer support services, their availability and usage and the common barriers that affect or impact on carers' use of community services in general and respite services in particular need to be examined to ensure they meet client needs. DESIGN: A qualitative descriptive approach informed by critical social theory was used to expose the inequities inherent in community services. METHODS: A qualitative examination of carer relationships with respite services was informed and guided by critical theory. Sixteen carers took part in four focus groups. A purposeful sampling strategy was adopted to engage with carers not currently using respite services. Study participants were recruited from a state-wide carer support organisation and a community service organisation in Queensland, Australia. RESULTS: Three themes emerged from the data: 'Commitment' characterised by reciprocity, role definition and role frustration, 'Needing Help' discussed in terms of trust, confidence in service, fear and resistance, and 'Support' discussed in relation to informal networking, misinformation and lack of knowledge. CONCLUSION: This study improves our understanding of the caring role, its significance in carer's lives and how this shapes their formal service expectations and use. The findings suggest that further investigation of the factors involved in carers' service expectations and service-seeking is warranted to develop a deeper understanding of how care giving influences the ways carers seek help from formal services. RELEVANCE TO CLINICAL PRACTICE: Service delivery changes towards a model of care, which engages and promotes user control and fosters genuine participatory relations between informal and professional carers may improve uptake of respite services. PMID- 20920033 TI - Parental management of childhood complaints: over-the-counter medicine use and advice-seeking behaviours. AB - AIMS AND OBJECTIVES: To explore parental management of childhood complaints with respect to factors associated with the purchase of over-the-counter medicines and sources of information accessed by parents. BACKGROUND: The use of over-the counter medicines is extensive, but this practice is not without risks. To ensure safe use, nurses and other healthcare providers need to understand parental reasons for purchase and sources of information they access regarding management practices. DESIGN: A cross-sectional survey. METHOD: Three-hundred and twenty five parents of children (aged birth to 24 months) were recruited between September 2006-June 2007 from three recruitment sites across Melbourne, Australia. These included the following: outpatient clinics at a major paediatric hospital, maternal and child health centres and a childcare service of a tertiary education institution. Data were collected using a self-administered questionnaire. RESULT: Most parents (82%) purchased over-the-counter medicines if suggested by the doctor and if it had been effective in the past. Doctors were the most frequently cited source of advice for management of complaints such as an ear ache (95%), wheeziness (90%) and rash (77%). Advice from maternal and child health nurses was frequently sought for sleep difficulties (60%), while family or friends were sought for advice on irritability or crankiness (47%) and teething pain (44%). CONCLUSIONS: The findings revealed the impact of healthcare provider recommendations on parental purchase of over-the-counter medicines. Parents mainly sought information and advice from doctors, followed by maternal and child health nurses and family or friends, which appeared to be dependent on the type of childhood complaint. RELEVANCE TO CLINICAL PRACTICE: The use of over the-counter medicines for symptom management is likely to increase with enhanced focus on self-care. It is important for all healthcare providers to proactively provide accurate, consistent and evidence-based information to parents regarding appropriate management of symptomatic and behavioural complaints. PMID- 20920034 TI - Obesity and diabetes: never say never again! PMID- 20920035 TI - Screening for type 2 diabetes: an update of the evidence. AB - A growing body of evidence on diabetes screening has been published during the last 10 years. Type 2 diabetes meets many but not all of the criteria for screening. Concerns about potential harms of screening have largely been resolved. Screening identifies a high-risk population with the potential to gain from widely available interventions. However, in spite of the findings of modelling studies, the size of the benefit of earlier initiation of treatment and the overall cost-effectiveness remains uncertain, in contrast to other screening programmes (such as for abdominal aortic aneurysms) that are yet to be fully implemented. There is also uncertainty about optimal specifications and implementation of a screening programme, and further work to complete concerning development and delivery of individual- and population-level preventive strategies. While there is growing evidence of the net benefit of earlier detection of individuals with prevalent but undiagnosed diabetes, there remains limited justification for a policy of universal population-based screening for type 2 diabetes at the present time. Data from ongoing studies should inform the key assumptions in existing modelling studies and further reduce uncertainty. PMID- 20920036 TI - A review of treatment response in type 2 diabetes: assessing the role of patient heterogeneity. AB - The response to treatment for type 2 diabetes typically varies among individuals within a study population. This variation is known as heterogeneity of treatment response. We conducted a comprehensive literature review to identify factors that account for heterogeneity of treatment response in patients treated for type 2 diabetes. Three databases (PubMed, EMBASE and Cochrane Library) were searched for articles published in the last 10 years describing investigations of factors associated with treatment response and outcomes among people with type 2 diabetes receiving pharmacological treatment. Of the 43 articles extracted and summarized, 35 (81%) discussed clinical factors, 31 (72%) described sociodemographic factors and 17 (40%) reported on comorbidity or behavioural factors. Clinical factors identified included baseline glycated hemoglobin A1c or fasting plasma glucose (FPG) levels, insulin response or sensitivity, C-peptide, body composition, adipose tissue proteins, lipid profile, plasma albumin levels and duration of disease or insulin treatment. Other factors identified included age, sex, race, socioeconomic status and comorbidities. This review identified the following research gaps: use of multiple definitions for response, few patient-reported measures and lack of evidence regarding whether factors were associated with treatment response for only specific medications or across pharmacological therapies. Furthermore, identification of factors associated with type 2 diabetes treatment response was generally a secondary objective in the research reviewed. Understanding which patient subgroups are more likely to respond to treatment and identifying factors associated with response may result in targeted treatment decisions and alter the interpretation of efficacy or effectiveness of results. In conclusion, accounting for these factors in clinical trials and when making clinical treatment decisions may improve therapy selection and individual patient outcomes. PMID- 20920037 TI - Managing diabetes in cystic fibrosis. AB - Cystic fibrosis related diabetes (CFRD) is the most common co-morbidity in persons with cystic fibrosis (CF). As the life expectancy of persons with CF continues to increase, the need to proactively diagnose and aggressively treat CFRD and its potential complications has become more apparent. CFRD negatively impacts lung function, growth and mortality, making its diagnosis and management crucial in a population already at high risk for early mortality. Compared to type 1 and type 2 diabetes, CFRD is a unique entity, requiring a thorough understanding of its unique pathophysiology to facilitate the creation and utilization of an effective medical treatment plan. The physiology of CFRD is complex, likely consisting of a combination of insulin deficiency, insulin resistance and a genetic predisposition towards the development of diabetes. However, the hallmark of CFRD is insulin deficiency, necessitating the use of exogenous insulin as the mainstay of therapy. Insulin administration, in combination with a multidisciplinary team of health professionals with expertise in the care of patients with CF and CFRD, is the cornerstone of the care for these patients. The goals of treatment of the CFRD population are to reverse protein catabolism, maintain a healthy weight, and reduce acute and chronic diabetes complications. Creating a partnership between the treatment team and the patient is the ideal way to accomplish these goals and is essential for successful diabetes care. PMID- 20920038 TI - Predictors of responders to insulin therapy at 1 year among adults with type 2 diabetes. AB - BACKGROUND: The effectiveness of insulin therapy to lower blood glucose levels in patients with type 2 diabetes (T2D) may depend on a variety of factors. This study aims to determine baseline parameters including body mass index (BMI) threshold that might predict responders to insulin therapy. METHODS: This was a retrospective UK population-based study derived from 358 general practices electronic dataset. We included all patients with T2D, diagnosed at the age of >18 years old and who were initiated on insulin from January 2000 to December 2006. Insulin responders were defined as HbA1c <7.5% and/or HbA1c reduction by >1% at 12 months postinsulin initiation. RESULTS: Results are expressed in mean (s.d.). A total of 6032 patients were identified. Baseline age was 63 years (11.7). In all, 61% of patients (3696) responded to insulin. At 1-year postinsulin initiation, HbA1c was significantly reduced (9.8 vs. 8.4%, p < 0.001) and weight increased (85.7 vs. 87.9 kg, p < 0.001). Using logistic regression model, older age (p < 0.001), lower BMI (p = 0.046), higher HbA1c (p < 0.001), basal-bolus insulin therapy and premixed insulin compared to basal insulin alone at baseline were independent predictors of responders to insulin. Gender and social class were not significant predictors of insulin responders. A BMI of <35.3 was derived as a cut-point for response to insulin (p = 0.038). CONCLUSION: Overall, insulin therapy confers significant HbA1c reduction and weight increase in patients with T2D. The responsiveness to insulin therapy however appears to depend on baseline age, BMI, HbA1c and insulin regime. Clinicians should take these factors into consideration when making a decision to initiate insulin therapy in patients with T2D. PMID- 20920039 TI - Intranasal delivery of mouse [D-Leu-4]-OB3, a synthetic peptide amide with leptin like activity, improves energy balance, glycaemic control, insulin sensitivity and bone formation in leptin-resistant C57BLK/6-m db/db mice. AB - BACKGROUND: We have recently shown that intranasal administration of mouse [D-Leu 4]-OB3 reconstituted in Intravail((r)) to male Swiss Webster mice resulted in significantly higher uptake and bioavailability when compared with commonly used injection methods of delivery. AIM AND METHODS: In this study, we examined the effects of intranasal delivery of mouse [D-Leu-4]-OB3 in Intravail((r)) on energy balance, glucose regulation, insulin secretion and serum levels of osteocalcin, a specific and sensitive marker of bone formation. Genetically obese C57BLK/6-m db/db mice were allowed food and water ad libitum and given either Intravail((r)) alone or mouse [D-Leu-4]-OB3 in Intravail((r)) for 14 days by intranasal instillation. RESULTS: Mouse [D-Leu-4]-OB3 reduced body weight gain, daily food intake, daily water intake and serum glucose by 11.5, 2.2, 4.0 and 61.9%, respectively. Serum insulin levels in db/db mice given mouse [D-Leu-4]-OB3 were approximately threefold lower than those in mice receiving Intravail((r)) alone. Mouse [D-Leu-4]-OB3 elevated serum osteocalcin in db/db mice by 28.7% over Intravail((r)) treated control mice. CONCLUSIONS: The results of our study indicate that intranasal delivery of biologically active mouse [D-Leu-4]-OB3 in Intravail((r)) is feasible and has significant effects on regulating body weight gain, food and water intake, serum glucose, insulin sensitivity and bone formation in leptin-resistant C57BLK/6-m db/db mice. PMID- 20920040 TI - Randomized controlled trial to investigate the effects of a newly developed formulation of phentermine diffuse-controlled release for obesity. AB - AIM: To evaluate the efficacy and safety of a newly developed formulation of phentermine diffuse-controlled release (DCR) in patients with obesity. METHODS: This was a randomized, double-blind, placebo-controlled trial of 12 weeks of treatment with phentermine DCR 30 mg (n = 37) or placebo (n = 37), administered once daily in patients with obesity with controlled diabetes, hypertension or dyslipidaemia. The efficacy was evaluated by changes in body weight and waist circumference from baseline at 12 weeks and also changes in metabolic parameters, including lipid profiles and blood pressure. RESULTS: The participants in the phentermine DCR group showed significant reductions in body weight (-8.1 +/- 3.9 vs. -1.7 +/- 2.9 kg, p < 0.001) and waist circumference (7.2 +/- 0.5 vs. 2.1 +/- 0.6 cm, p < 0.001) compared with those in the placebo group. Weight reductions of 5% or greater from the baseline (95.8 vs. 20.8%, p < 0.001) and 10% or more (62.5 vs. 4.7%, p < 0.001) were achieved in the DCR phentermine group and placebo group, respectively. Total cholesterol and low-density lipoprotein cholesterol (LDL-C) levels were significantly improved in the phentermine DCR group. However, there were no significant differences in systolic and diastolic blood pressure between the groups. Dry mouth and insomnia were the most common adverse events, but these were mild to moderate and transient. CONCLUSIONS: Short-term phentermine DCR treatment resulted in significant reduction in weight and improvement of metabolic parameters, including waist circumference and some lipid profiles, without clinically severe adverse events. Further study is needed to show long-term efficacy and safety of phentermine DCR in Korean patients with obesity. PMID- 20920041 TI - Cerebellin1 is a novel orexigenic peptide. AB - AIM: Cerebellin1 (Cbln1) is highly expressed in the hypothalamus, a region of the brain involved in appetite regulation. However, the effects of Cbn1 on food intake are not known. The present study aimed to investigate the effect of Cbln1 on appetite regulation in rats. METHODS: We determined the effect of (i) intracerebroventricular (ICV) injection of Cbln1 on food intake, behaviour and plasma pituitary hormone levels in male Wistar rats; (ii) Cbln1 on the release of hypothalamic neuropeptides known to modulate food intake from hypothalamic explants and (iii) fasting on hypothalamic Cbln1 mRNA expression. RESULTS: (i) ICV administration of Cbln1 significantly increased food intake in rats and caused no adverse behaviours. ICV administration of Cbln1 significantly reduced plasma thyroid stimulating hormone (TSH) levels 10 min postinjection in rats. (ii) Cbln1 significantly increased the release of neuropeptide Y (NPY) from hypothalamic explants. (iii) Cbln1 mRNA expression levels were increased in the ventromedial nucleus of the hypothalamus in fasted rats. CONCLUSIONS: These data suggest that Cbln1 is a novel orexigenic peptide, which may mediate its effects via hypothalamic NPY. PMID- 20920042 TI - Four weeks administration of Liraglutide improves memory and learning as well as glycaemic control in mice with high fat dietary-induced obesity and insulin resistance. AB - AIM: Liraglutide is a long-acting glucagon-like peptide-1 (GLP-1) mimetic which is a treatment option for type 2 diabetes. GLP-1 peptides, including Liraglutide, cross the blood-brain barrier and may additionally act to improve brain function. The present study tested the hypothesis that, in addition to its antihyperglycaemic actions, peripheral administration of Liraglutide exerts positive actions on cognitive function in mice with high fat dietary-induced obesity and insulin resistance. METHODS: Young Swiss TO mice maintained on high fat diet for 20 weeks received twice-daily injections of Liraglutide (200 ug/kg bw; sc) or saline vehicle over 28 days. An additional group of mice on standard diet received twice-daily saline injections. Energy intake, bodyweight, non fasting plasma glucose and insulin concentrations were monitored at regular intervals. Glucose tolerance, open field assessment, object recognition testing and electrophysiological long-term potentiation (LTP) were performed at termination of the study. RESULTS: Liraglutide treatment resulted in significant time-dependent reduction in bodyweight and energy intake, whilst improving non fasting glucose and normalizing glucose tolerance. Although Liraglutide did not alter general behaviour, treated mice exhibited marked increase in recognition index (RI) during object recognition testing, indicative of enhanced learning and memory ability. Furthermore, Liraglutide rescued the deleterious effects of high fat diet on hippocampal LTP of neurotransmission following both chronic and direct intracerebroventricular (icv) administration. CONCLUSION: Liraglutide administered peripherally not only improves metabolic parameters but exerts additional beneficial effects on cognitive function and hippocampal synaptic plasticity. Whether therapy with GLP-1 mimetics has similar effects in humans with type 2 diabetes needs to be established. PMID- 20920043 TI - Effects of central administration of insulin or l-NMMA on rat skeletal muscle microvascular perfusion. AB - AIM: Intracerebroventricular (ICV) administration of a nitric oxide synthase (NOS) inhibitor to rats has been reported to raise blood pressure (BP) and cause insulin resistance, suggestive of a central effect of insulin that is NO dependent. Herein we test whether ICV insulin has peripheral haemodynamic and metabolic effects and whether peripheral effects of systemic insulin are affected by the ICV administration of the NOS inhibitor N(G) -methyl-l-arginine (l-NMMA). METHODS: Anaesthetized rats were fitted with an ICV cannula for insulin, artificial cerebrospinal fluid (aCSF) or l-NMMA infusion. Rats receiving ICV l NMMA (500 ug) underwent systemic insulin clamp (10 mU/min/kg) or saline treatment for 70 min and were compared with animals receiving an equal amount of l-NMMA infused systemically. RESULTS: ICV aCSF or insulin (135 mU/min/kg brain) for 70 min or systemic l-NMMA (500 ug) had no effect on BP, heart rate (HR), femoral blood flow (FBF), glucose infusion rate, muscle 2-deoxyglucose uptake, microvascular perfusion or plasma insulin. However, ICV l-NMMA reduced systemic insulin-mediated increases in FBF (2.05 +/- 0.08 to 1.55 +/- 0.15 ml/min), 2 deoxyglucose uptake (17.7 +/- 0.15 to 10.0 +/- 0.03 ug/g/min) and microvascular perfusion (10.5 +/- 0.5 to 6.6 +/- 1.1 mol/min) (each mean +/- SE, p < 0.05); plasma insulin, HR and BP were unaffected. CONCLUSIONS: Central insulin administration had no effect on skeletal muscle haemodynamics or glucose metabolism. However, systemic insulin-mediated increases in limb blood flow, muscle microvascular perfusion and glucose uptake may be regulated by a central pathway that is NO dependent. PMID- 20920044 TI - Initial short-term intensive insulin therapy as a strategy for evaluating the preservation of beta-cell function with oral antidiabetic medications: a pilot study with sitagliptin. AB - AIM: Studies evaluating the effects of oral antidiabetic drugs (OADs) on beta cell function in type 2 diabetes mellitus (T2DM) are confounded by an inability to establish the actual baseline degree of beta-cell dysfunction, independent of the deleterious effects of hyperglycaemia (glucotoxicity). Because intensive insulin therapy (IIT) can induce normoglycaemia, we reasoned that short-term IIT could enable evaluation of the beta-cell protective capacity of OADs, free from confounding hyperglycaemia. We applied this strategy to assess the effect of sitagliptin on beta-cell function. METHODS: In this pilot study, 37 patients with T2DM of 6.0 + 6.4 years duration and A1c 7.0 + 0.8% on 0-2 OADs were switched to 4-8 weeks of IIT consisting of basal detemir and premeal insulin aspart. Subjects achieving fasting glucose <7.0 mmol/l 1 day after completing IIT (n = 21) were then randomized to metformin with either sitagliptin (n = 10) or placebo (n = 11). Subjects were followed for 48 weeks, with serial assessment of beta-cell function [ratio of AUC(Cpep) to AUC(gluc) over Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) (AUC(Cpep/gluc) /HOMA-IR)] on 4-h meal tests. RESULTS: During the study, fasting glucagon-like-peptide-1 was higher (p = 0.003) and A1c lower in the sitagliptin arm (p = 0.016). Nevertheless, although beta cell function improved during the IIT phase, it declined similarly in both arms over time (p = 0.61). By study end, AUC(Cpep/gluc) /HOMA-IR was not significantly different between the placebo and sitagliptin arms (median 71.2 vs 80.4; p = 0.36). CONCLUSIONS: Pretreatment IIT can provide a useful strategy for evaluating the beta-cell protective capacity of diabetes interventions. In this pilot study, improved A1c with sitagliptin could not be attributed to a significant effect on preservation of beta-cell function. PMID- 20920045 TI - Addition of insulin lispro protamine suspension or insulin glargine to oral type 2 diabetes regimens: a randomized trial. AB - AIMS: The addition of basal insulin to existing oral therapy can help patients with type 2 diabetes (T2D) achieve glycaemic targets. This study compares the efficacy and safety of insulin lispro protamine suspension (ILPS) and insulin glargine in insulin-naive patients with T2D and inadequate control on oral antihyperglycaemic medication (OAM). MATERIALS AND METHODS: An open-label, randomized, multicentre, multinational 24-week study of 471 patients receiving >=2 OAMs for >=3 months with a body mass index between 25 and 45 kg/m(2) and HbA1c 7.5-10.0% was conducted. ILPS was injected once or twice daily vs. glargine injected once daily plus prestudy OAMs. Primary objective compared the HbA1c change from baseline. RESULTS: HbA1c change from baseline to endpoint was similar in both groups [-1.46% (ILPS) and -1.41% (glargine)]. Least-squares mean difference (95% CI) for HbA1c (-0.05 [-0.21, 0.11]%), glycaemic variability (0.06 [-0.06, 0.19] mmol/l) and weight change (-0.01 [-0.61, 0.59] kg) showed non inferiority (margins of 0.4%, 0.8 mmol/l and 1.5 kg, respectively). Percentages of patients achieving HbA1c <7.0% were 43.8% ILPS and 41.2% glargine. Mean daily insulin dose was 0.39 vs. 0.35 U/kg (p = 0.02) and weight gain was 1.04 vs. 1.07 kg for ILPS vs. glargine (p = 0.98). Overall hypoglycaemia (episodes/patient/year) was similar for ILPS and glargine (24.2 +/- 28.8 vs. 23.0 +/- 30.9); nocturnal (6.1 +/- 10.6 vs. 4.1 +/- 9.4, p < 0.001) rates were higher for ILPS. Severe hypoglycaemia was higher for ILPS vs. glargine (n = 9 vs. n = 2; p = 0.04). CONCLUSIONS: At endpoint, ILPS was non-inferior to glargine in HbA1c change from baseline, but associated with increased risk of hypoglycaemia. PMID- 20920046 TI - Continuation versus discontinuation of insulin secretagogues when initiating insulin in type 2 diabetes. AB - We compared the combined use of basal insulin, metformin and insulin secretagogues with a combination of basal insulin and metformin in patients with type 2 diabetes starting basal insulin analogue therapy. This analysis was part of a 24-week trial, in which 964 insulin-naive patients with type 2 diabetes inadequately controlled on oral agents (including metformin) were randomized to insulin glargine or detemir. Secretagogues were stopped or maintained at the site investigators' discretion. During the study, 57.6% of patients continued their secretagogue treatment. Compared with patients stopping secretagogues, those who continued experienced significantly more hypoglycaemia and weight gain. Insulin doses, however, were significantly lower: 0.6 +/- 0.4 versus 0.8 +/- 0.4 U/kg/day (p < 0.001). The difference between groups in mean HbA1c reduction was not statistically significant. In conclusion, in type 2 diabetic patients starting basal insulin analogue therapy, continuing both metformin and secretagogues results in more hypoglycaemia and weight gain and lower insulin doses than only maintaining metformin. PMID- 20920047 TI - Response to Fritsche et al. (GINGER study). PMID- 20920048 TI - Level of concern and precaution taking among Australians regarding travel during pandemic (H1N1) 2009: results from the 2009 Queensland Social Survey. AB - BACKGROUND: Global disease outbreaks, such as the recent Pandemic (H1N1) 2009 (the so-called Swine flu), may have an impact on travel, including raising the concerns of travelers. The objective of this study was to examine the level of concern of Australians regarding travel during Pandemic (H1N1) 2009 and how this impacted on their travel. METHODS: Data were collected by interviews as part of the Queensland Social Survey (QSS) 2009. Specific questions were incorporated regarding travel and Pandemic (H1N1) 2009. Multivariate logistic regression was used to analyze associations between demographic variables and concern and likelihood of cancelling travel. RESULTS: There were 1,292 respondents (41.5% response rate). The sample was nearly equally divided between males and females (50.2% vs 49.8%). Younger people (18-34 y) were under-represented in the sample; older people (> 55 y) were over-represented in the sample. About half (53.2%) of respondents indicated some level of concern about Pandemic (H1N1) 2009 when traveling and just over one-third (35.5%) indicated they would likely cancel their air travel if they had a cough and fever that lasted more than one day. When cross-tabulating these responses, people who expressed concern regarding Pandemic (H1N1) 2009 when they traveled were more likely than those without concern to cancel their air travel if they had a cough and fever lasting more than one day (44.7% vs 27.7%, chi2 = 33.53, p < 0.001). People with higher levels of education [adjusted odds ratio (AOR): 0.651], people with higher incomes (AOR: 0.528) and people living outside of metropolitan Southeast Queensland (AOR: 0.589) were less likely to be concerned about Pandemic (H1N1) 2009 when traveling, and younger people (AOR: 0.469) were less likely than others to cancel travel if they had a cough and fever. CONCLUSIONS: Pandemic (H1N1) 2009 was of some concern to more than half of Queensland travelers. None-the-less, the majority of Queenslanders would not have postponed their own travel, even if they exhibited symptoms consistent with Pandemic (H1N1) 2009. PMID- 20920049 TI - Illness in French travelers to Senegal: prospective cohort follow-up and sentinel surveillance data. AB - OBJECTIVE: To investigate travel-associated illnesses in French travelers to Senegal. METHODS: A prospective cohort follow-up was conducted in 358 travelers recruited at a pre-travel visit in Marseille and compared to data from ill travelers collected from the GeoSentinel data platform in two clinics in Marseille. RESULTS: In the cohort survey, 87% of travelers experienced health complaints during travel, which most frequently included arthropod bites (75%), diarrhea (46%), and sunburns (36%). Severe febrile illness cases, notably malaria and salmonella, were detected only through the surveillance system, not in the cohort follow-up. Food hygiene was inefficient in preventing diarrhea. Arthropod bites were more frequent in younger patients and in patients with pale phototypes. Sunburns were also more frequent in younger patients. Finally, we demonstrate that mild travel-related gastrointestinal symptoms and the lack of arthropod bites are significantly associated with poor observance of antimalarial prophylaxis. CONCLUSIONS: In this study, we suggest the complementary nature of using cohort surveys and sentinel surveillance data. Effective protection of skin from arthropod bites and sun exposure should result in significantly reduced travel-associated diseases in Senegal. Travelers to Senegal should be informed that diarrhea is extremely common despite preventive measures, but it is mild and transitory and should not lead to the disruption of malaria chemoprophylaxis. PMID- 20920050 TI - Clinical and epidemiological characteristics of imported infectious diseases in Spanish travelers. AB - INTRODUCTION: Spain could be a potential area in Europe for the development and spread of emerging diseases from the tropics due to its geoclimatic characteristics, but there is little information on infectious diseases imported by travelers. The aim of this article was to analyze clinical-epidemiological characteristics of infectious diseases imported by Spanish travelers from the tropics. METHODS: A retrospective descriptive study of 2,982 travelers seeking medical advice who return ill from the tropics was conducted. Demographic data, details of travel (destination, type, and duration), preventive measures, clinical syndromes, and diagnoses were analyzed. RESULTS: Nearly half (46.5%) the travelers had traveled to sub-Saharan Africa; 46.5% reported a stay exceeding 1 month (and almost a quarter more than 6 months). Following pre-travel advice, 69.1% received at least one vaccine and 35.5% took malarial chemoprophylaxis with variations according to geographical area of travel. In all, 58.8% of this took chemoprophylaxis correctly. Most common syndromes were fever 1,028 (34.5%), diarrhea 872 (29.3%), and cutaneous syndrome 684 (22.9%). Most frequent diagnoses were traveler's diarrhea (17.2%), malaria (17%), and intestinal parasites (10.4%). The three main syndromes in travelers to the Caribbean-Central America, Indian subcontinent-Southeast Asia, and other areas were diarrhea, fever, and cutaneous syndrome (p < 0.05); in sub-Saharan Africa were fever, cutaneous syndrome, and diarrhea (p < 0.05); and in South America were cutaneous syndrome, diarrhea, and fever (p < 0.05). Travelers to sub-Saharan Africa showed a higher frequency of malaria, rickettsiosis, filariasis, and schistosomiasis (p < 0.05); those to South America showed cutaneous larva migrants, other ectoparasitosis, and cutaneous/mucocutaneous leishmaniasis; and those to the Indian subcontinent Southeast Asia showed intestinal parasitosis, arboviriasis, and enteric fever (p < 0.05). CONCLUSIONS: Increased international travel is a key factor for the development and spread of emerging pathogens. Information on these diseases is essential to establish early warning mechanisms and action plans. Spain represents a unique setting for this. PMID- 20920051 TI - Murine typhus as a cause of Fever in travelers from Tunisia and mediterranean areas. AB - BACKGROUND: Travelers are exposed to a variety of health risks in unfamiliar environments and fever is a common problem in patients returning from travel abroad. Rickettsial diseases are increasingly frequently being reported among international travelers. Here we present cases of Rickettsia typhi infection, the agent of murine typhus, that were identified in our laboratory the last year, in travelers from Tunisia. METHODS: For each patient we tested an acute-phase serum sample and for one patient we tested a convalescent-phase serum sample. IgG and IgM antibody titers were estimated with use of the microimmunofluorescence (MIF) assay. Western blot (WB) assay was performed for all the patients. RESULTS: We identified three cases of murine typhus after a travel in Tunisia. All cases were observed during late summer and early autumn and patients were suffering by persistent fever. None of them presented rash or inoculation eschar. MIF was positive for Rickettsia sp. in the acute-phase serum samples of two patients. In one patient, two acute-phase serum samples were Rickettsia sp. negative whereas a third convalescent-phase serum sample that was obtained 2 weeks after was Rickettsia sp. positive. By WB assay we identified infection by R typhi. A treatment was immediately started and patients became apyretic. CONCLUSIONS: In the countries of North Europe, although autochthones cases of murine typhus have not been described, sporadic cases of R typhi infection are identified in travelers who visited murine typhus endemic areas. Murine typhus should be considered in the diagnosis of febrile illness without rash in travelers returning from disease endemic areas, like the south Mediterranean area. PMID- 20920052 TI - Travel characteristics and risk-taking attitudes in youths traveling to nonindustrialized countries. AB - BACKGROUND: International travel to developing countries is increasing with rising levels of disposable income; this trend is seen in both adults and children. Risk-taking attitude is fundamental to research on the prevention of risky health behaviors, which can be an indicator of the likelihood of experiencing illness or injury during travel. The aim of this study is to investigate whether risk-taking attitudes of youths are associated with travel characteristics and likelihood of experiencing illness or injury while traveling to nonindustrialized countries. METHODS: Data were analyzed from the 2008 YouthStyles survey, an annual mail survey gathering demographics and health knowledge, attitudes, and practices of individuals from 9 through 18 years of age. Travelers were defined as respondents who reported traveling in the last 12 months to a destination other than the United States, Canada, Europe, Japan, Australia, or New Zealand. Risk-taking attitude was measured by using a four-item Brief Sensation-Seeking Scale. All p values <= 0.05 were considered significant. RESULTS: Of 1,704 respondents, 131 (7.7%) traveled in the last 12 months. Females and those with higher household income were more likely to travel (odds ratio = 1.6,1.1). Of those who traveled, 16.7% reported seeking pretravel medical care, with most visiting a family doctor for that care (84.0%). However, one-fifth of respondents reported illness and injury during travel; of these, 83.3% traveled with their parents. Males and older youths had higher mean sensation-seeking scores. Further, travelers had a higher mean sensation-seeking score than nontravelers. Those who did not seek pretravel medical care also had higher mean sensation-seeking scores (p = 0.1, not significant). CONCLUSIONS: Our results show an association between risk-taking attitudes and youth travel behavior. However, adult supervision during travel and parental directives prior to travel should be taken into consideration. Communication messages should emphasize the importance of pretravel advice, target parents of children who are traveling, and be communicated through family doctors. PMID- 20920053 TI - Fecal-orally transmitted diseases among travelers are decreasing due to better hygienic standards at travel destination. AB - OBJECTIVE: To evaluate whether changes in attack rates of fecal-orally transmitted diseases among travelers are related to changes in pretravel vaccination practices or better hygienic standards at travel destination. METHODS: National surveillance data on all laboratory-confirmed cases of travel related hepatitis A, shigellosis, and typhoid fever diagnosed in the Netherlands from 1995 to 2006 were matched with the number of Dutch travelers to developing countries to calculate region-specific annual attack rates. Trends in attack rates of non-vaccine-preventable shigellosis were compared with those of vaccine preventable hepatitis A and typhoid fever. Trends were also compared with three markers for hygienic standards of the local population at travel destinations, drawn from the United Nations Development Programme database: the human development index, the sanitation index, and the water source index. RESULTS: Attack rates among Dutch travelers to developing regions declined for hepatitis A, shigellosis, and typhoid fever. Region-specific trends in attack rates of shigellosis resembled trends of hepatitis A and typhoid fever. Declining attack rates of the three fecal-orally transmitted diseases correlated with improvements in socioeconomic, sanitary, and water supply conditions of the local population at travel destination. CONCLUSIONS: These findings suggest that improved hygienic standards at travel destination strongly contributed to the overall decline in attack rates of fecal-orally transmitted diseases among visiting travelers. PMID- 20920054 TI - Health and well-being factors associated with international business travel. AB - BACKGROUND: International travel by US business travelers is continuing to increase with the globalization of the economy. The objective of this study was to determine if the frequency and duration of international business travel is associated with differences in travelers' health and well-being. This study expands our limited knowledge of the impact of long-haul travel on healthy lifestyle choices and traveler's perceptions of their health and well-being. METHODS: 12,942 unique health risk appraisal (HRA) records of US employees of a multinational corporation were analyzed according to self-reported (objective and subjective) travel history and lifestyle habits. RESULTS: Comparing 2,962 international travelers and 9,980 non-travelers, international business travel was significantly associated with a lower body mass index, lower blood pressure, excess alcohol consumption, sleep deprivation, and diminished confidence to keep up with the pace of work. CONCLUSIONS: This study demonstrated both positive and negative associations on the health risks and well-being of a large sample of US based international business travelers from an US multinational company. This study identifies targeted areas for pretrip screening and counseling to proactively address potential negative effects of travel and may assist in the design of corporate travel health and employee assistance programs. PMID- 20920055 TI - Pediatric malaria: 8-year case series in Atlanta, Georgia, and review of the literature. AB - BACKGROUND: Although malaria is frequent in travelers, it is often misdiagnosed on initial presentation, especially in children. The objective of this study is to describe epidemiology, clinical and laboratory presentation, and treatment of children with malaria in the United States. METHODS: We performed a retrospective review of 50 confirmed cases of malaria from two pediatric metropolitan hospitals in Atlanta, GA, from 2000 to 2008. RESULTS: Malarial smears were performed in 385 unique patients; 50 (12.6%) were positive. American children who had visited family and friends in malaria-endemic countries comprised 62% of our cases. Most cases visited Nigeria or Cameroon; all but three traveled to Africa. Three patients presented 8 to 12 months following travel. Plasmodium falciparum was diagnosed most frequently (72%). Most patients had low-level parasitemia (<1%). Gametocytes were rarely identified. Treatment was primarily with quinine and either doxycycline or clindamycin, and transfusion was rare. All patients responded rapidly to treatment. Although seven (14%) had hyperparasitemia (> 5%), no fatalities or long-term sequelae were seen. CONCLUSIONS: Malarial diagnosis can be difficult in children because parasitemia is usually below 1%. A high index of suspicion is required in patients who have traveled to Africa. PMID- 20920056 TI - A cohort study of risk factors for malaria among healthcare workers in equatorial Guinea: stay away from the ground floor. AB - BACKGROUND: Nonimmune long-term travelers to sub-Saharan Africa are at a high risk of contracting malaria. Most previous studies described risk factors and spatial distribution only in short-term travelers. This study describes the epidemiology and spatial distribution of malaria cases among expatriate healthcare workers in Equatorial Guinea. METHODS: We conducted a cohort study evaluating the risk factors for malaria among healthcare personnel working in a hospital in Bata, Equatorial Guinea. Demographic data were recorded for all workers, and the spatial distribution of malaria cases within the hospital perimeters was determined. RESULTS: During 2008 noncomplicated falciparum malaria was diagnosed in 13/102 workers (12.75%). On univariate analysis, the factors negatively associated with the risk of contracting malaria were living above the first floor and being older than 30 years. This association remained significant in multivariate analysis [hazard ratio (HR) = 0.24, 95% confidence interval [CI] = 0.06-0.91 for subjects living above the first floor and HR = 0.14, 95% CI = 0.04-0.52 for subjects above 30 years old]. Males and smokers had increased risk of contracting malaria on univariate analysis. However, this association was not significant in multivariate analysis (HR = 3.37, 95% CI = 0.87-13.1 and HR = 3.12, 95% CI = 0.83-11.75, for univariate and multivariate analysis, respectively). Low compliance with malaria prevention guidelines was observed in the study cohort. CONCLUSIONS: Living on the ground floor of apartment buildings in sub-Saharan Africa, as opposed to living on the top floors, confers an increased risk of acquiring malaria in long-term travelers with low compliance to prophylaxis. These findings should be discussed in advance with people intending to stay in sub-Saharan Africa for an extended period of time. The association between belonging to a younger age group and an increased risk of acquiring malaria, and the marginally significant increased risk of malaria in males and smokers, can probably be explained by increased exposure to malaria vectors. The compliance of healthcare workers with malaria prophylaxis is extremely low, as was previously described for other long-term residents. PMID- 20920057 TI - A review of risk factors for imported malaria in the European African diaspora. PMID- 20920058 TI - Fever in a soldier returned from Afghanistan. AB - We present a case of Plasmodium vivax infection in a soldier, 4 months after returning from Afghanistan. Primary care physicians should be reminded of the possible delay in presentation of P. vivax when evaluating fever and the importance of terminal prophylaxis with primaquine to prevent relapse following return from malarious regions. PMID- 20920059 TI - Malaria outbreak among French army troops returning from the Ivory Coast. AB - In 2006, a French Army unit reported 39 malaria cases among service persons returning from Ivory Coast. Thirty, including three serious forms, occurred after the return to France. The risk of post-return malaria was higher than the risk in Ivory Coast. Half of the imported cases had stopped post-return chemoprophylaxis early. PMID- 20920060 TI - Murine typhus in two travelers returning from Bali, Indonesia: an underdiagnosed disease. AB - Two Japanese travelers from Bali were diagnosed with murine typhus in Japan during the same period. Although one had only mild illness, the other experienced liver and kidney dysfunction. Murine typhus may be missed not only in endemic areas around the world, but also in travelers, especially those returning from marine resorts in these areas. PMID- 20920061 TI - Acute neuroschistosomiasis: a cerebral vasculitis to treat with corticosteroids not praziquantel. PMID- 20920062 TI - Re: Immunity against poliomyelitis in refugees in Italy. PMID- 20920065 TI - Editorial: Madonna and child. PMID- 20920066 TI - Literature review: should antipyretic therapies routinely be administered to patients with [corrected] fever? AB - AIMS AND OBJECTIVES: To determine whether the practices of routinely treating fever with antipyretic medications or physical cooling methods are supported by the literature. BACKGROUND: Fever is one of the commonest symptoms presented to caregivers. Previous research suggests that treating fever with antipyretic medications or physical cooling methods is often routine practice. This article considers that fever and the febrile response may have been preserved through evolution because of its advantage for host defences and that fever may have an adaptive value. It is questioned whether the administration of antipyretic therapies could prolong the duration of illness, as interventions to lower body temperature are acting against the body's natural response to infection. DESIGN: Literature review. METHOD: Electronic databases and the Internet were searched, supplemented by citation tracking. Articles were eligible if the participants studied had received pharmacological or physical cooling interventions to reduce their body temperature during fever. The interventions were evaluated in regard to whether they prolonged duration of illness. RESULTS: Results were inconsistent. None of the studies found that antipyretic therapies reduced duration of illness in patients with fever. Evidence suggests that antipyretic therapies do not reduce the duration of illness, but can prolong it. CONCLUSIONS: The evidence on which to base recommendations for practice is weak but does not support the current practice of administering antipyretic therapies routinely to patients with fever. Physical cooling methods alone should never be used. Nurses should assess patients with fever on an individualised basis and use antipyretic therapies selectively. RELEVANCE TO CLINICAL PRACTICE: The administration of antipyretics to patients with fever is an important issue, and nurses are at the forefront of decision-making. Evidence-based care delivery is expected by the NMC. A protocol to assist decision-making when caring for patients with pyrexia is suggested. PMID- 20920067 TI - A literature review of the potential of telephone follow-up in colorectal cancer. AB - AIMS: The aim of this review is to examine the potential of telephone follow-up for patients with colorectal cancer. BACKGROUND: More people are surviving cancer and entering into follow-up care. It is recognised that improvements in cancer follow-up care are needed in the UK. Telephone use has proved a very successful medium for conducting health care in other specialties and may offer an acceptable alternative to face-to-face follow-up appointments. Nurse specialists could assume responsibility for patients' follow-up by offering telephone consultations. DESIGN: A literature review was conducted via a systematic electronic and hand search of relevant literature. METHOD: Thematic content analysis was used to achieve the objectives of the review. Results. The findings demonstrate that telephone follow-up conducted by an experienced nurse specialist is cost-effective and accepted by the majority of patients. Aspects of care such as symptom management and reassurance are possible over the phone. CONCLUSION: Telephone follow-up meets patients' satisfaction, support and information needs and has potential to deliver high standards of aftercare when conducted by a nurse specialist. It is at least equivalent to traditional follow-up in meeting the needs of patients with cancer. Because of the disparity of the studies examined, further research in the area of nurse-led telephone follow-up vs. nurse led traditional follow-up would be constructive in the development of this new initiative. RELEVANCE TO CLINICAL PRACTICE: Nurses are now increasingly involved in patient follow-up care and telephone dialogue after hospital discharge. However, the ideal structure, method and timing of telephone follow-up as well as the skills required to carry out such care over the phone are often not considered and have not been articulated. The option of telephone follow-up could, for some patients, dramatically improve their care experience. PMID- 20920068 TI - 'Cool friends': an evaluation of a community befriending programme for young people with cystic fibrosis. AB - AIM: To evaluate the impact of a community youth befriending programme on a group of young people with chronic illness and their carers. BACKGROUND: Befriending is said to be highly valued by those who are befriended, improving self-esteem and offering opportunities for increasing skills and social activities. DESIGN: A qualitative longitudinal pilot study of young people with cystic fibrosis, their carers, their befrienders and other personnel, closely involved with the families. METHODS: Seventeen participants were interviewed over one-year to explore their experiences of befriending. Ten of these were either befriendees (aged 8-18 years) or their parents. Half of these families were interviewed twice; once at the beginning of the befriending relationship and another at one year later. Seven other personnel, closely involved with the young people, were interviewed; two play therapists and two education liaison personnel. A focus group was also held with three befrienders. This range of data sought to reveal a wide perspective on the impact of befriending. RESULTS: Befriending was seen as a good thing by all parties involved. It offered a distraction from illness, respite for carers and helped young people to raise issues of personal importance. Befriending was challenging for the befrienders given the diagnosis of this group of befriendees. Negative experiences could result if pairs are poorly matched or if befrienders are not committed to the process. Exit strategies were not addressed. CONCLUSION: Sustainable befriending relationships are dependent on commitment from both parties and transparency about the expected practices and processes from the beginning to the end of the relationship. RELEVANCE TO PRACTICE: The evidence that is available in support of befriending is mixed. To date this is the first study in relation to people with cystic fibrosis and will add to the body of knowledge of befriending in young people with a life-threatening chronic illness. PMID- 20920069 TI - Evaluation of the feasibility of a school-based asthma management programme in Taiwan. AB - AIMS AND OBJECTIVES: To investigate the feasibility of a school-based asthma management programme for middle school children. BACKGROUND: Asthma rates are increasing among school-aged children. Successful asthma treatment in children depends in part on clear communication and effective education. DESIGN: This feasibility study employed a one-group only longitudinal design with four time points over 18 months. METHODS: Nineteen female and twelve male (n = 31) seventh grade children with asthma (13 SD 0.71 years) were identified using a six-stage asthma case-finding approach. Teachers and school staff were trained in the principles and methods of the proposed school-based asthma management programme. An individualised guided asthma self-management programme was developed for each child by a clinical team at a major academic medical centre. We assisted teachers in implementing the school programme; building a support network and monitoring children's activities. Outcome measures included lung function tests (at 0, six, 12 and 18 months), disease-related symptoms, psychosocial status and impact of asthma on learning (at 0 and 18 months). School provided data on academic achievement and school absences at 0, six, 12 and 18 months. RESULTS: Significant improvements were noted at six, 12 and 18 months on forced vital capacity (FVC)% of predicted (p = 0.001, 0.015, 0.015, respectively), forced expiratory volume in one second (FEV(1) )% of predicted (p = 0.001, 0.006, 0.088, respectively) and FEV(1) /FVC% of predicted (p = 0.001, 0.015, 0.099, respectively). There was a trend towards improved asthma symptoms (p = 0.050) and a significant decrease in positive perception of curriculum (p = 0.017) at 18 months after adjustment for covariates. CONCLUSIONS: This programme was associated with respiratory benefits on physiological asthma markers commonly, with a trend for symptom control. Academic and psychosocial outcomes are subject of further inquiry. RELEVANCE TO CLINICAL PRACTICE: School-based asthma management holds promise as a feasible clinical option for middle school children with asthma in the Taiwanese school system. PMID- 20920071 TI - Factors influencing the practice of exclusive breastfeeding among Hong Kong Chinese women: a questionnaire survey. AB - AIMS AND OBJECTIVES: The purpose of this article is to explore the relationships between breastfeeding knowledge, self-efficacy and demographic factors on breastfeeding patterns among Hong Kong Chinese primiparous women. Background. There is substantial evidence showing that maternal education, social class, ethnic background and religion are related to the decision to initiate as well as continue breastfeeding. Nevertheless, not much is known about how the controllable factors are able to influence the practice with the Hong Kong Chinese population. DESIGN: A cross-sectional and correlational design. METHODS: A convenience sample of 82 subjects who had normal vaginal delivery in the maternity unit of a regional hospital in Hong Kong was recruited. RESULTS: Linear regression analysis showed that subjects who lived with their mothers-in-law, had higher household income and higher gravida would be associated with a higher score in the Breastfeeding Self-Efficacy Scale. On the other hand, decisions to breastfeed made later in the pregnancy, father-in-law to 'pei-yue' (the Chinese practice whereby the new mother is expected to stay at home and to avoid all household chores and social activities during the first month after giving birth) and older in age would be associated with a lower score. Pei-yue is Chinese ritual of which the woman who has delivered should stay at home for one month and being taken care by others (this Chinese term is used throughout the article to indicate the time period described). Generalised estimating equations model revealed that women who had searched through the Internet for breastfeeding information, who had husbands to 'pei yue', lived in private housing, were married, had a domestic helper to 'pei yue' and who had attained higher education were more likely to practice exclusive breastfeeding. CONCLUSION: The social support from the family and breastfeeding self-efficacy have implications for continuing the practice of breastfeeding for primiparous women. RELEVANCE TO CLINICAL PRACTICE: Future efforts aimed at promoting exclusive breastfeeding could include the modifiable factors into consideration to better tailor interventions for successful, exclusive breastfeeding. PMID- 20920070 TI - Analysis of pelvic floor musculature function during pregnancy and postpartum: a cohort study: (a prospective cohort study to assess the PFMS by perineometry and digital vaginal palpation during pregnancy and following vaginal or caesarean childbirth). AB - AIM: To compare the measurements of women's pelvic floor musculature strength (PFMS) during pregnancy and postpartum period. BACKGROUND: Pregnancy and childbirth can have an influence on the muscles and pelvic floor and can cause morbidities of women's genito-urinary tract. DESIGN: A prospective cohort study. METHODS: There were included 226 primigravidae women, attended by community health services in the city of Itapecerica da Serra, Sao Paulo, Brazil. The participants were followed in four stages: (1) within 12 weeks of pregnancy; (2) between 36-40 weeks of pregnancy; (3) within 48 hours after childbirth; (4) 42-60 days after childbirth. Data were collected from February 2007-August 2008. The pelvic floor musculature strength was evaluated by perineometry and digital vaginal palpation in stages 1, 2 and 4. The final sample included 110 women who completed all four stages of the study. RESULTS: The pelvic floor musculature strength of the women did not change significantly during pregnancy or after delivery (anova: p = 0.78). In all three examined stages, a low-intensity pelvic floor musculature strength was prevalent (in mmHg: stage 1 = 15.9; stage 2 = 15.2, stage 4 = 14.7), with scores from 0-3 on the Oxford scale. The pelvic floor musculature strength did not differ in relation to maternal age, skin colour, conjugal status, dyspareunia, stool characteristics, type of delivery, or conditions of the perineum. An interaction between maternal nutritional state and newborn's weight may affect the pelvic floor musculature strength (manova: p = 0.04). CONCLUSION: Pregnancy and childbirth did not reduce significantly pelvic floor musculature strength. The perineometry and digital vaginal palpation used to assess the pelvic floor musculature strength were well accepted by the women. RELEVANCE TO CLINICAL PRACTICE: In clinical practice, digital vaginal palpation is effective for supporting the diagnosis of urinary, intestinal and sexual dysfunctions. Perineometry use is particularly important together with the performance of perineal exercises with biofeedback in the treatment these disorders. PMID- 20920072 TI - Attitudes towards gestational diabetes among a multiethnic cohort in Australia. AB - AIMS: This study aimed to examine the attitudes and beliefs towards gestational diabetes of a multiethnic sample of pregnant women with gestational diabetes. BACKGROUND: Women from non-Caucasian background are disproportionately represented in gestational diabetes statistics. This is of particular importance in multicultural Australia, where increasing numbers of non-Caucasian women give birth. DESIGN: Cross-sectional survey. METHODS: The Diabetes Attitude Scale, version 3 was administered to 200 women with gestational diabetes from Vietnamese, Indian, Filipino and Caucasian backgrounds. RESULTS: A total of 143 questionnaires were returned indicating a response rate of 71.5%. There were significant between group differences in terms of educational level (p = 0.001) and English fluency (p = 0.001). Lower educational level, though not English language fluency, was associated with poorer appreciation of gestational diabetes as a serious condition and also with a lower valuing of tight glucose control. This effect was seen irrespective of ethnic group. Indian and Vietnamese women indicated a lower valuing of patient autonomy and also reported less negative psychological effects than Caucasian and Filipino women. CONCLUSIONS: Women from non-Caucasian ethnicities may be at risk of poorer self-management of gestational diabetes related to lower education, lower health literacy and a lower appreciation of gestational diabetes as a serious condition. RELEVANCE TO CLINICAL PRACTICE: Nurses and midwives provide information and advice to women with gestational diabetes. Knowledge about factors that impact on attitude towards gestational diabetes among multiethnic populations is important for developing educational programmes to address their needs. PMID- 20920073 TI - Cannabis use in palliative care - an examination of the evidence and the implications for nurses. AB - AIM AND OBJECTIVE: Examine the pharmaceutical qualities of cannabis including a historical overview of cannabis use. Discuss the use of cannabis as a clinical intervention for people experiencing palliative care, including those with life threatening chronic illness such as multiple sclerosis and motor neurone disease [amyotrophic lateral sclerosis] in the UK. BACKGROUND: The non-medicinal use of cannabis has been well documented in the media. There is a growing scientific literature on the benefits of cannabis in symptom management in cancer care. Service users, nurses and carers need to be aware of the implications for care and treatment if cannabis is being used medicinally. DESIGN: A comprehensive literature review. METHOD: Literature searches were made of databases from 1996 using the term cannabis and the combination terms of cannabis and palliative care; symptom management; cancer; oncology; chronic illness; motor neurone disease/amyotrophic lateral sclerosis; and multiple sclerosis. Internet material provided for service users searching for information about the medicinal use of cannabis was also examined. RESULTS: The literature on the use of cannabis in health care repeatedly refers to changes for users that may be equated with improvement in quality of life as an outcome of its use. This has led to increased use of cannabis by these service users. However, the cannabis used is usually obtained illegally and can have consequences for those who choose to use it for its therapeutic value and for nurses who are providing care. RELEVANCE TO CLINICAL PRACTICE: Questions and dilemmas are raised concerning the role of the nurse when caring and supporting a person making therapeutic use of cannabis. PMID- 20920074 TI - Decibel levels and noise generators on four medical/surgical nursing units. AB - AIMS AND OBJECTIVES: The study was designed to determine daytime decibel levels on the hospital's four medical/surgical nursing units, daytime decibel levels in patient rooms in corresponding nursing units, whether the nursing unit noise levels differed and to identify what generated noise on those units. BACKGROUND: Nurses are responsible for components of patients' physical environments, particularly those that promote patient safety and well-being. Numerous studies have linked hospital noise to negative physiological outcomes for both patients and staff. However, decisions related to managing patient acoustic environments continue to rely on nursing judgment, rather than objective evidence. DESIGN: Non human subject, observational/descriptive design. METHOD: Using noise dosimeters, weekday day shift decibel levels were measured on four nursing units, sequentially. Measures were made continuously over 12 hours, in three patient rooms and over five minutes every 45 minutes, at the corresponding nurses' station. Noise generators were documented at the nurses' station. RESULTS: Nursing units had average measured sound levels of 62.2, 63.3, 61.7 and 64.6 decibels, respectively, and were not significantly different from one another (p = 0.07). Nurses' designation of 'quiet', 'typical' and 'noisy' patient rooms was not consistently confirmed by the measured decibel levels. The range of minimum to maximum decibel levels was significantly greater in patient rooms than the nurses' station (54.4 versus 27.7 decibels, p < 0.01), and on average, more than 12 noise generators were identified during any one-five-minute study period. CONCLUSIONS: Patient care areas in today's hospitals are as noisy as a busy office. Nursing judgment is not sufficient to make informed decisions directed towards controlling inpatients' acoustic environment. Standards applied across studies to measure and characterise acoustic environments are urgently needed. RELEVANCE TO CLINICAL PRACTICE: Objective measures, not nursing judgment alone, are required to assess acoustic environments and to direct interventions that improve them. PMID- 20920075 TI - Post-discharge health care needs of patients after lung cancer resection. AB - AIMS AND OBJECTIVE: To determine the health care needs of patients after surgical resection of lung cancer at discharge and evaluate the significance of factors associated with such needs. BACKGROUND: Other studies have found that symptom distress level, social supports and health beliefs are associated with health care needs. Design. Sixty-two participants were recruited from a thoracic surgery clinic at a medical centre in Taipei from July-December 2005. Data related to demographic variables, disease characteristics, functional status, symptom distress and social support were collected. METHODS: The patients were administered the Karnofsky Performance Scale, the Symptom Distress Scale-Chinese Modified Form, the Social Support Scale (adapted from the Interpersonal Support Evaluation List), the Health Needs Scale and self-reported rating scales for pain. Data were analysed using Pearson's correlation coefficients and linear regression models. RESULTS: Pulmonary function was found to be correlated with the level of need for health care information and physiological care. Self perceived symptom distress and degree of distress were also correlated with levels of need for information, physiological care and psychosocial care. The level of pain was found to be correlated with the level of need for health care information and physiological care. After controlling for pain level, multivariate analysis revealed that self-perceived symptom severity (p = 0.032) and degree of distress (p = 0.043) were modestly correlated with the need for health care. CONCLUSIONS: Pulmonary function, self-perceived symptom distress, degree of distress and level of pain were correlated with the level of need for health care information and physiological care. Self-perceived symptom severity and degree of distress were independent predictors of health care needs. RELEVANCE TO CLINICAL PRACTICE: Administration of relevant questionnaires to assess postoperative symptom distress may be necessary for optimal disease management. PMID- 20920076 TI - A structured observation of the interaction between nurses and patients during the administration of medication in an acute mental health unit. AB - AIMS: This aims of this study are to describe current practice in the administration of medication in an acute psychiatric unit and explore factors that influence nurses' decisions regarding the administration of medication during 'rounds'. Background. Medication 'rounds' form part of the ward routine in many inpatient mental health settings. Nurses make several clinical decisions about administrating medication; yet, concerns have been raised about the poor assessment of patients' needs and the quality of the information exchanged. DESIGN: A structured non-participant observational design was used for this research. METHOD: This study involved the observation of 20 medication 'rounds' over three months. The Ward Administration of Medication Schedule was used to report on the interactions between nurses and patients and aspects of their communication during each round. RESULTS: From the rounds observed nurses appeared adept at communicating a positive interpersonal style but less so in demonstrating skills portraying collaboration and information giving. For example whilst nurses communicated warmth in 97% of cases, using non-verbal behaviours such as good eye contact, the provision of information was only initiated in 46% of cases. Enquiries regarding the patient's general health and medication taking (35% and 17% respectively) were less commonly observed. Verbal consent was sought in only 25% of cases. Procedural matters were adhered to overall. CONCLUSIONS: Findings suggest limited collaboration between nurses and patients and the poor monitoring of health status and medication effects. Information exchange could be improved; however, this may be related to medication procedures that make it difficult to explore sensitive information with patients, rather than nursing skills and behaviour. RELEVANCE TO CLINICAL PRACTICE: The Ward Administration of Medication Schedule can be used as a clinical or educational tool in the administration of medication. In both instances, it may be self-administered and used to reflect on personal skills or employed as an observational tool during peer review and audit. PMID- 20920077 TI - Population-specific Mini Nutritional Assessment can improve mortality-risk predicting ability in institutionalised older Taiwanese. AB - AIM AND OBJECTIVES: The study determined whether a new version of the Mini Nutritional Assessment that adopted population-specific anthropometric cut-points would improve the mortality-predicting ability in institutionalised Taiwanese older people. BACKGROUND: Routine screening is the key for detecting emerging malnutrition, but the tool must be simple, reliable and easy-to-use to be well accepted. The Mini Nutritional Assessment can meet these requirements, but for non-Western populations, modifications based on anthropometric considerations are needed. DESIGN: The study purposively sampled 208 residents, aged >65 years, of a long-term care institution in Central Taiwan. Subjects were free of acute infection/disease and able to communicate. A university human-subject-study ethics committee approved the protocol. METHODS: The study included biochemical measurements and a structured questionnaire for eliciting personal data and answers to questions in the Mini Nutritional Assessment. Follow-up survival/mortality was tracked for two consecutive six-month periods and analysed according to nutritional statuses graded with the original or a modified Mini Nutritional Assessment. The modified version adopted population-specific anthropometric cut-points and was without body mass index. RESULTS: The modification improved the mortality-predictive ability. Mortality rates for the first six months were 8.7, 3.9 and 0% according to the original Mini Nutritional Assessment and 10.6, 3.4 and 0% according to the modified version for subjects rated malnourished, at risk of malnutrition and normal, respectively. The mortality-predictive ability of both versions weakened after six months. CONCLUSION: Both versions can predict follow-up mortality, but the modified version has improved ability. For best results, the tool should be applied every six months or less (shorter for more frail older people) to screen for new cases of at-risk individuals. RELEVANCE TO CLINICAL PRACTICE: The Mini Nutritional Assessment that adopts population-specific anthropometric cut-points may have improved nutritional-risk and mortality-risk predictive abilities. The tool can help care-workers detect emerging nutritional problems and enable timely intervention. Routine use of the tool may help improve the quality of care. PMID- 20920078 TI - Effectiveness of resource-enhancing family-oriented intervention. AB - AIM: The purpose of the study was to assess the effectiveness of a resource enhancing family-oriented intervention. BACKGROUND: There is very little empirical knowledge of how nurses working in a home context develop relationships with families, what methods they use to enhance families' resources and how such relationships affect the families' health outcomes. DESIGN: The study was designed as a descriptive service evaluation. METHODS: A total of 129 family members from 30 families with small children participated in the study. Data were collected with family care plans and client reports in 2004-2005. Data were analysed by qualitative content analysis and by descriptive statistical methods. Resource-enhancing discussions were carried out in all family meetings. Other methods were video guidance, creation of a family tree and parents' role map, network collaboration, observation and parent-child group activity. RESULTS: The families needed support mostly in parents' health and well-being, coping with parenthood, upbringing and child care, parents' relationships, social relations and children's health and growth. The families had an average of five support needs at the beginning of the intervention and 1.8 needs at the completion. The families set on average 3.6 and achieved 4.5 goals during the family nursing process. CONCLUSION: The resource-enhancing family nursing can be used for supporting parenthood, the raising of and caring for the children, strengthening of social support networks, decreasing the need for support from the authorities and enhancing the parents' resources to manage the duties related to their work and studies. RELEVANCE TO CLINICAL PRACTICE: The study resulted in empirically based concepts that can be used in the future to construct instruments to evaluate the effectiveness of resource-enhancing family nursing from the perspective of families and family health. The findings add to our professional understanding of resource-enhancing family nursing. PMID- 20920079 TI - Relationship between diabetes mellitus, hypertension and obesity, and health related quality of life in Gaziantep, a central south-eastern city in Turkey. AB - AIMS AND OBJECTIVES: The main goal of nursing care should be to increase health related quality of life as well as improve the medical status of patients with chronic disease. For this reason, this study aims to evaluate and compare the health-related quality of life of patients with diabetes mellitus, hypertension and obesity in Gaziantep, a south-eastern city in Turkey. BACKGROUND: Diabetes mellitus, hypertension and obesity are the most decisive factors in terms of adversely affecting health-related quality of life. DESIGN: A cross-sectional, descriptive design was used. METHOD: In this study, the research population included a total of 1601 diabetes mellitus, hypertension and obesity patients. To evaluate health-related quality of life of patients, Short Form-36 (SF-36) was used. Student's t-test, one-way anova and chi-square analyses were used for comparisons between groups. RESULTS: In total, 18.1% of patients had combined obesity, hypertension and diabetes mellitus; 16.1% had hypertension and diabetes mellitus. Approximately 16.1% had only hypertension; 15.4% had obesity and hypertension; 13.3% had diabetes mellitus; 12.7% had obesity and diabetes mellitus; and 8.4% had obesity. The health-related quality of life physical component mean scores of patients with combined obesity and hypertension were lower than that of the other groups (p < 0.05). Health-related quality of life physical component mean scores were determined as 34.5 (SD 0.4), and mental component mean scores were determined as 43.9 (SD 4.4). Health-related quality of life physical component mean scores of moderately active patients were higher, while older age and lower educational and income levels had a negative effect on health-related quality of life (p < 0.05). CONCLUSION: Diabetes, hypertension and obesity decrease patient health-related quality of life while physical activity increases it. The coexistence of obesity and hypertension, in particular, has a more negative effect on health-related quality of life. RELEVANCE TO CLINICAL PRACTICE: Patients with hypertension, obesity and diabetes mellitus need professional support from nurse. Frequent health-related quality of life evaluation and support is required for chronic patients, especially for those who are older, have lower educational and income levels and those with more than one chronic disease. PMID- 20920080 TI - Life values and self-regulation behaviours among adults with type 2 diabetes. AB - AIM: The aim of this study was to identify life values in adults with type 2 diabetes and to describe their experiences of how these values may influence self regulation behaviours. BACKGROUND: Daily self-regulation behaviours have been described as challenging, because the individuals try to find a balance between them and life values. However, little is known about how life values may influence the motivation for necessary self-regulation behaviours. DESIGN AND METHODS: A descriptive/explorative qualitative design that included focus groups was used to collect data. The sample consisted of 19 adults with type 2 diabetes. Data were analysed using qualitative content analysis. RESULTS: The findings revealed six themes: maintaining health and longevity, a feeling of bodily well being, preserving a positive body image, self-determination, maintaining the ability to work and belonging. The results reflect the fact that many life values have a major influence on self-regulation behaviours. CONCLUSIONS: The findings indicate that several of the life values can conflict with self-regulation behaviours, which in turn may influence the motivation for self-regulation of type 2 diabetes. Some of these values could be considered to be related to self worth, which is regarded as an important motivational component for engaging in a task. Moreover, this study highlights the fact that goals related to self regulation behaviours were formulated in more general than in specific terms. RELEVANCE TO CLINICAL PRACTICE: This study may help health professionals to understand how adults' life values influence their motivation for adequate self regulation. The findings indicate that the existing support structures should make an effort to learn about people's life values and take them into account when giving advice about self-regulation behaviours. Moreover, people with type 2 diabetes should be supported by health professionals to set more specific self regulation goals that are consistent with their life values. PMID- 20920081 TI - Reasons why women choose a medical practice or a women's health centre for routine health screening: worker and client perspectives. AB - AIMS AND OBJECTIVES: This article aims to explore the stories and perceptions of consumers and health care workers in an area with a low uptake rate of women's health screening. Further, this article explores what factors influence women's choices for women's health screening in relation to the type of services they access. BACKGROUND: Routine women's health screening, using mammography and Papanicolaou (Pap) testing, is known to assist in the early detection of cancer and thereby has the potential to increase positive health outcomes for women. However, traditionally, compliance rates to women's health screening are lower than desired because of multiple barriers. Previous studies have largely been quantitative and few have been conducted in areas of low compliance to women's health screening. Furthermore, previous research has not identified the type of service offered, or gender of the professional providing this service, as potential barriers to women's health screening. DESIGN: Qualitative, storytelling design. METHOD: Participants from a socioeconomically disadvantaged area were recruited into the study via media releases. Data were collected during conversational, face to face interviews which were between 30 and 90 minutes in duration, digitally recorded and transcribed verbatim. During the process of analysis, dominant stories became obvious through the repetition or emphasis of women's accounts, and it is these stories that are presented in the findings. RESULTS: Findings suggest that women's decisions about care for routine health screening are guided by three major concerns. Women are seeking a woman friendly and woman-centred service, a safe environment and continuity of care. All these factors informed women's decision-making around where to seek care for routine health screening. CONCLUSIONS: Additional specialised women's health services are required to meet the needs of women. The provision of accessible women-centred environments has the potential to enhance compliance with women's health screening. RELEVANCE TO CLINICAL PRACTICE: It is possible that generalist medical practises as well as specialised women's health centres can provide woman-centred care. This as well as further access to education and training that supports nurses to become specialised competent and confident women's health practitioners may enhance screening rates. PMID- 20920082 TI - Between being and doing - the nature of leadership of first-line nurse managers and registered nurses. AB - AIMS AND OBJECTIVES: The aim of this study was to describe first-line nurse managers' (F-LNMs) and subordinate registered nurses' (RNs) conceptions and experiences of their routine work and how leadership was exercised. BACKGROUND: Extensive changes in health care organisations have had a powerful impact on leadership in nursing management. Nursing leadership, in turn, has an affect on both the quality of care and the subordinates' work environment. Therefore, it is important to enhance our understanding of current leadership in nursing management. DESIGN: This is a descriptive qualitative study carried out in three units at three Swedish hospitals. METHODS: Three F-LNMs and 14 RNs participated. Interviews were used to collect data. The interviews were analysed using qualitative content analysis. RESULTS: The result of this study was illustrated in one main theme referred to in this study as between being and doing. The RNs and F-LNMs described what it was to be a good professional (being), how they were engaged in creating a good work climate (doing) and personal outcomes of this project (gaining). CONCLUSION: The reciprocal relation between being and doing, which can be described as the development of virtues, was a central point in the professional work of the F-LNMs and RNs. The development of virtues is also a strategy to attain the goals of nursing and establish a work climate that motivates staff and improves performance. RELEVANCE TO CLINICAL PRACTICES: The implication for nursing management is to create ample space to develop strategies and knowledge about how leadership in nursing management can stimulate the development of a common perspective of good care and professional virtues appropriate for health care praxis. PMID- 20920083 TI - Questioning family-centred care. AB - AIMS: This article poses topics for discussion around family-centred care as a model of care delivery to children and families in health services. BACKGROUND: Family-centred care developed over three decades following awakening awareness that excluding parents during a child's hospital admission was detrimental to the child's mental health. Using resources from both past and current literature and existing research, I argue that it is time for a revision of practices and policies that espouse family-centred care as the optimum model of care in paediatrics. Once the historical development of family-centred care is discussed, current research shows a dearth of evidence about family-centred care, its use, implementation and applicability across cultures and nations. DESIGN: Discursive. METHODS: Five questions are discussed: is family-centred care relevant now? is it relevant only in Western countries?, what does it mean to implement family centred care?, is family-centred care implemented effectively?, does it make a difference? Exemplars of good family-centred care practice are provided. RESULTS: At this stage, it is difficult to know whether using family-centred care makes a difference to a child's and family's health outcomes, as there is no rigorous evidence to answer the question 'does it work?' CONCLUSIONS: Nurses must undertake studies so we can either support the successful implementation of family-centred care, or abandon it in the best interests of children, families and health services. RELEVANCE TO CLINICAL PRACTICE: Practitioners must be aware that family-centred care is a wonderful ideal that is almost impossible to implement and so new ways of delivering care to children may be needed. PMID- 20920084 TI - Student experiences in learning person-centred care of patients with Alzheimer's disease as perceived by nursing students and supervising nurses. AB - AIMS AND OBJECTIVES: The aims and objectives of this paper are to illuminate and discuss the experiences and perceptions of nursing students and supervising nurses regarding the students' learning of person- centred care of patients with Alzheimer's disease in a teaching nursing home. This information is then used to develop recommendations as to how student learning could be improved. BACKGROUND: The clinical experiences of nursing students are an important part of learning person-centred care. Caring for patients with Alzheimer's disease may cause frustration, sadness, fear and empathy. Person-centred care can be learned in clinical practice. DESIGN: A qualitative study. METHODS: The study was performed in 2006 using field work with field notes and qualitative interviews with seven fifth-semester nursing students and six supervising nurses. RESULTS: This study determined the variation in the perceptions of nursing students and supervising nurses with regards to the students' expertise in caring for patients with Alzheimer's disease. The nursing students experienced limited learning regarding person-centred approaches in caring for patients with Alzheimer's disease. However, the supervising nurses perceived the teaching nursing home as a site representing multiple learning opportunities in this area. CONCLUSIONS: Nursing students perceived limited learning outcomes because they did not observe or experience systematic person-centred approaches in caring for patients with Alzheimer's disease. It is important that measures of quality improvements in the care of patients with Alzheimer's disease are communicated and demonstrated for nursing students working in clinical practices in a teaching nursing home. RELEVANCE TO CLINICAL PRACTICE: Introduction of person-centred approaches is vital regarding learning outcomes for nursing students caring for patients with Alzheimer's disease. PMID- 20920085 TI - Role of a clinical nurse specialist within a paediatric multidisciplinary weight management programme team. PMID- 20920086 TI - The effect of educational intervention on pain beliefs and postoperative pain relief among Chinese patients with fractured limbs. PMID- 20920087 TI - Reliability and validity of three Chinese-version tasks of Mayer-Salovey-Caruso Emotional Intelligence Test. PMID- 20920088 TI - Medicine information sources used by nurses at the point of care. PMID- 20920090 TI - Commentary on ictal epileptic tachycardia and bradycardia. PMID- 20920092 TI - Authors' reply to the comments by Rheims et al., 2010. PMID- 20920097 TI - Research methods - most common reason for rejection. PMID- 20920096 TI - Differential regulation of oestrogen receptor beta isoforms by 5' untranslated regions in cancer. AB - Oestrogen receptors (ERs) are critical regulators of the behaviour of many cancers. Despite this, the roles and regulation of one of the two known ERs - ERbeta- are poorly understood. This is partly because analyses have been confused by discrepancies between ERbeta expression at mRNA and proteins levels, and because ERbeta is expressed as several functionally distinct isoforms. We investigated human ERbeta 5' untranslated regions (UTRs) and their influences on ERbeta expression and function. We demonstrate that two alternative ERbeta 5'UTRs have potent and differential influences on expression acting at the level of translation. We show that their influences are modulated by cellular context and in carcinogenesis, and demonstrate the contributions of both upstream open reading frames and RNA secondary structure. These regulatory mechanisms offer explanations for the non-concordance of ERbeta mRNA and protein. Importantly, we also demonstrate that 5'UTRs allow the first reported mechanisms for differential regulation of the expression of the ERbeta isoforms 1, 2 and 5, and thereby have critical influences on ERbeta function. PMID- 20920098 TI - Investigation of febrile passengers detected by infrared thermal scanning at an international airport. AB - OBJECTIVE: To determine the best approach for the evaluation of fever, detected by infrared thermal scanning, at an international airport. METHODS: Arriving passengers with fever were divided into three groups: community evaluation by a GP, with or without cost compensation, or evaluation at the airport by a health practitioner. Uptake of offered evaluations was measured, diagnoses were recorded, and region-specific rates of fever measured. Observations were made on practical aspects of thermal screening. RESULTS: Over a six-month period, 181,759 passengers were screened for fever at the Cairns international airport, Queensland, Australia. Fever was identified in 118 (0.06%) of the arriving passengers and 76 were enrolled in the study. Only 19 of these passengers (25%) voluntarily underwent further evaluation. No differences were observed in the three approaches. CONCLUSIONS: Public health surveillance of febrile passengers arriving at an international airport should not rely on voluntary passenger participation for the detection of imported contagious diseases. PMID- 20920099 TI - Chronic disease profiles in remote Aboriginal settings and implications for health services planning. AB - OBJECTIVE: To report the short-term experiences and outcomes of a program to support chronic disease management in three remote communities in Top End Northern Territory and in two Aboriginal Medical Services (AMSs) in Western Australia, and to discuss the implications of findings for health service delivery and policy. METHODS: Programs were health-worker centred. They espoused regular screening of all adults for chronic disease, initiation and modification of treatment where indicated and rigorous documentation. Process measures were documented and rates of hypertension, renal disease and diabetes among adults were calculated. RESULTS: Rates of hypertension, proteinuria and diabetes rose throughout adult life and multiple diagnoses were common. Most people with these conditions were young or middle age adults. Rates were uniformly excessive relative to AusDiab data, but varied greatly among settings. Adherence to protocols improved, many new diagnoses were made, treatments were started or modified and blood pressures in treated hypertensive people fell. In the NT, productivity was seriously limited by lack of health workers and their absenteeism. In the WA AMSs, executive and staff support carried the programs forward to a sustainable future, despite various challenges. CONCLUSIONS: Integrated chronic disease testing must be repeated throughout adult life for timely diagnosis. Health workers can perform all tasks well, with appropriate supports. Blood pressure outcomes alone predict lower cardiovascular and renal mortality. The findings support incorporation of chronic disease into lifetime health care plans. PMID- 20920100 TI - Cricket: notching up runs for food and alcohol companies? AB - OBJECTIVE: To analyse sports sponsorship by food and alcohol companies by quantifying the proportion of time that the main sponsor's logo was seen during each of three cricket telecasts, the extent of paid advertising during the telecast and the contribution by the main sponsor to this, and to describe the associated ground advertising. METHODS: DVD recordings of the three telecasts were analysed for visibility of the main sponsor's logo during actual playing time and for each sponsor's proportion of the advertising time during breaks in telecast. RESULTS: The main sponsor's logo was visible on a range of equipment and clothing that resulted in it being clearly identifiable from 44% to 74% of the game time. The proportion of paid advertising time in these three telecasts varied from 3% to 20%, reflecting the difference in advertising content of paid television versus free-to-air. IMPLICATIONS: While television food advertising to children is under review, sporting telecasts also reach children and, until recently, have avoided scrutiny. This content analysis of three recent cricket telecasts reveals an unacceptable level of exposure to food and alcohol marketing, particularly in the form of the main sponsor's logo. Sponsorship is not covered by the voluntary codes of practice that address some forms of advertising. A new system of regulation is required to reduce this unacceptable level of exposure. PMID- 20920101 TI - From hypothetical scenario to tragic reality: A salutary lesson in risk communication and the Victorian 2009 bushfires. AB - OBJECTIVE: To investigate the ways that the risk of a bushfire emergency and communication strategies are perceived by different community segments. METHODS: A brief questionnaire preceded focus group discussion of a bushfire scenario with four communications from different sources. Groups were recruited to represent different community segments within a bushfire-prone peri-urban Shire in Victoria. RESULTS: Four groups (28 participants) were recruited. Bushfire experience was highest in the over 40-year-olds, who would use a variety of information sources, preferred to receive information from trusted local sources, such as emergency services and the council, and were more likely to be a member of a local organisation than the under 40s. Younger people used television, local papers, and friends, family and neighbours as information sources. Young parents felt disempowered through lack of local knowledge, and trusted government departments less than older residents. All wanted clear, current, specific local information about ground conditions and actions to be taken during a fire outbreak. CONCLUSIONS/IMPLICATIONS: Knowledge of and preparedness for bushfire is unequally spread throughout a bushfire community. There is a need in public health risk and emergency situations to focus on community development, information and consultation. PMID- 20920102 TI - Dietary intakes of Pacific, Maori, Asian and European adolescents: the Auckland High School Heart Survey. AB - OBJECTIVE: To compare dietary intakes of European, Maori, Pacific Island and Asian adolescents living in Auckland. METHODS: A self-administered food frequency questionnaire was used to assess daily nutrient intakes of 2,549 14- to 21-year old high-school students in Auckland (1,422 male and 1,127 female) in a cross sectional survey carried out between 1997 and 1998. RESULTS: Compared with Europeans, Maori and Pacific Islanders consumed more energy per day. Carbohydrate, protein and fat intakes were higher in Maori and Pacific Islanders than in Europeans. Cholesterol intakes were lowest in Europeans and alcohol intakes were highest in Europeans and Maori. When nutrient intakes were expressed as their percentage contribution to total energy, many ethnic differences in nutrient intakes between Europeans and Maori or Pacific Islanders were eliminated. After adjustment for energy intake and age, Europeans ate the fewest eggs, and Pacific Islanders and Asians ate more servings of chicken and fish, and fewer servings of milk and cereal than Europeans. Compared to Europeans, Pacific Islanders consumed larger portion sizes for nearly every food item. CONCLUSION: There were marked differences in nutrient intakes between Pacific, Maori, Asian and European adolescents. Ethnic differences in food selections, frequency of food servings and portion sizes contribute to the differences in nutrient intakes between these ethnic groups. These differences generally matched those of other studies in children and adults from these ethnic groups. IMPLICATIONS: Interventions that reduce frequency of food consumption and serving sizes and promote less-fatty food choices in Maori and Pacific adolescents are needed. PMID- 20920103 TI - Evaluating performance of and organisational capacity to deliver brief interventions in Aboriginal and Torres Strait Islander medical services. AB - OBJECTIVE: This study assessed brief intervention (BI) activity and organisation capacity for smoking, nutrition, alcohol and physical activity (SNAP framework) and key clinical prevention activities in four Aboriginal and Torres Strait Islander medical services in Queensland. METHODS: A mixed methods design was used including: staff surveys of knowledge and attitudes (n=39), focus groups to discuss perceived barriers and enablers and chart audits (n=150) to quantify existing BI activity. RESULTS: Of 50 clinical staff, 46 participated in the staff survey and focus groups across the four sites. BI was perceived to be important. There was significant variation in completion of records for SNAP risk factors, key clinical and BI activities across the sites. At least one SNAP factor status was recorded in 130/150 (86.7%) patient charts audited and there was a significant trend of increased recording of SNAP factors with increasing number of patient visits. Of those identified at risk 78% received at least one BI. Where risk was identified 65/96 (67.7%) patients required multiple BIs. BI for tobacco use was consistently high across all sites. Only one site recorded regular care planning and Adult Health Checks. Impacting factors included leadership, high staff turnover, multiple medical records and staff health status. CONCLUSIONS: Inflexible staff training, competing health priorities and high levels of staff turnover were identified as key barriers to the delivery of BI in clinical settings. The data suggests a good base of existing BI activity for smoking and key clinical activities which may improve with further support. PMID- 20920104 TI - Lessons for Aboriginal tobacco control in remote communities: an evaluation of the Northern Territory 'Tobacco Project'. AB - OBJECTIVE: To evaluate a Northern Territory (NT) government-led pilot 'Tobacco Project' in six remote communities. METHODS: Monthly surveys of staff, semi structured interviews with staff and community members, observation of the delivery of tobacco control interventions, review of Project documents, and monitoring of tobacco consumption using sales (or wholesale orders) of tobacco. RESULTS: There was a substantive amount of tobacco control activity delivered in three of the Project communities. In two of these locations, the majority of work was primarily driven and undertaken by resident staff. Overall, most of the Project's efforts related to community education and awareness-raising. There was variable impact of the Project on tobacco consumption across the six communities. More tobacco control activity was consistently associated with a greater reduction in tobacco consumption. An important predictor of local activity was the presence of strong community drivers. A significant obstacle to the Project was the lack of new resources. CONCLUSIONS: Despite the minimal impact of this Project on tobacco consumption overall, there was a consistent association between on-the-ground tobacco control activity and reductions in tobacco consumption. IMPLICATIONS: New initiatives will not only need to provide new funding, but identify and then support local staff, who are central to improving local tobacco control activity and so reducing smoking and smoking-related illnesses and deaths. PMID- 20920105 TI - The comparison of health status and health services utilisation between Indigenous and non-Indigenous infants in Australia. AB - OBJECTIVE: To examine the differences in health services utilisation and the associated risk factors between Indigenous and non-Indigenous infants at a national level in Australia. METHODS: We analysed data from a national representative longitudinal study, the Longitudinal Study for Australian Children (LSAC) starting in 2004. We used survey logistic regression and survey multiple linear regression to examine the factors associated with health services utilisation. RESULTS: Health status of Indigenous infants was poorer than that of non-Indigenous. In comparison to non-Indigenous infants, in the previous 12-month period, the Indigenous infants were significantly less likely to use the following health services: maternal and child health centre or help lines (OR=0.35, 95%CI: 0.24-0.49); maternal and child health nurse visits (OR=0.45, 95%CI: 0.32-0.63); general practitioners (GPs) (OR=0.45, 95%CI: 0.31-0.64); and paediatrician (OR=0.52, 95%CI: 0.35-0.77). In contrast, they were more likely to visit a hospital outpatient clinic (OR=1.82, 95%CI: 1.16-2.85). Mothers' age, education and marital status were associated with certain health services use. Financial status and residential location were the important predictors of the use of health services. CONCLUSION: The rates of health services utilisation by Indigenous infants were lower and were associated with mothers' characteristics and socio-economic status. IMPLICATIONS: The gaps in health services utilisation between Indigenous and non-Indigenous infant requires immediate policy initiatives. Further research is needed to explore the causal pathways between health status, health services utilisation and multiple risk factors at different levels. PMID- 20920106 TI - Interpretation of two nutrition content claims: a New Zealand survey. AB - OBJECTIVE: To determine how various population groups in New Zealand interpret the nutrition content claims '97% fat free' and 'no added sugar' on food labels. METHODS: A survey of adult supermarket shoppers was conducted at 25 Auckland supermarkets over a six-week period in 2007. Supermarkets were located in areas where greater than 10% of the resident population were known to be Maori, Pacific or Asian, based on 2001 Census meshblock data. Four questions in the survey assessed understanding and interpretation of the nutrition content claims '97% fat free' and 'no added sugar'. RESULTS: There were 1,525 people who completed the survey, with approximately equal representation from Maori, Pacific, Asian and New Zealand European and Other ethnicities. Nearly three-quarters (72%) of participants correctly estimated the fat content of a 100 g product that was '97% fat free', and understood that a product with 'no added sugars' could contain natural sugar. However, up to three-quarters of Maori, Pacific, and Asian shoppers assumed that if a food carried a '97% fat free' or 'no added sugar' claim it was therefore a healthy food. Similarly, low-income shoppers were significantly more likely than medium- or high-income shoppers to assume that the presence of a claim meant a food was definitely healthy. CONCLUSION: Percentage fat free and no added sugar nutrition content claims on food are frequently misinterpreted by shoppers as meaning the food is healthy overall and appear to be particularly misleading for Maori, Pacific, Asian and low-income groups. IMPLICATIONS: Nutrition content claims have potential for harm if the food they are placed on is not healthy overall. Such claims should therefore only be permitted to be placed on healthy foods. PMID- 20920107 TI - Prevalence of risk and protective factors for falls in the home environment in a population-based survey of young and middle-aged adult New Zealanders. AB - OBJECTIVE: To estimate the prevalence of hazards in the home environment that may contribute to unintentional falls among young and middle-aged New Zealanders. METHODS: A random sample of 352 young and middle-aged people (25-60 years) residing in Auckland was drawn from the electoral roll. The prevalence of environmental factors that may have an impact on risk of falls was investigated using a structured interviewer-administered questionnaire. RESULTS: Potential risk factors for falls were common in the study population (ladder use in the past year - 64%; inability to reach a light from bed - 21%; lack of handrails for stairs - 54%). Only 9% and 11% of baths and showers, respectively, had grab or hand rails; 42% and 56% had anti-skid mats/surfaces. Compared to those reporting no socio-economic deprivation characteristics, respondents reporting one or more such characteristics were less likely to use a ladder and have indoor stairs, but more likely to have outdoors stairs. There was no significant relationship between socio-economic status and presence of a grab/handrail or antiskid mats/surfaces in or near showers/baths. CONCLUSION AND IMPLICATIONS: Structural hazards that are likely to result in falls at home are common in New Zealand. The greater prevalence of some environmental risk factors for falls among the least socially deprived population may account for the inconsistent association between socio-economic deprivation and fall-related injuries reported in previous research. Information regarding the contribution of these and associated factors to the occurrence of falls can help target and reduce the risks involved. PMID- 20920108 TI - Estimating the number of unlicensed brothels operating in Melbourne. AB - OBJECTIVE: To estimate the number of unlicensed brothels operating in Melbourne, Australia, and the sexual health of the women working in them. METHODS: Advertisements from Melbourne newspapers published in July 2006 were systematically analysed based on the language used to identify premises likely to be unlicensed brothels. A visit was made to each of the businesses where an address was available. Participating sex workers were tested for Neisseria gonorrhoeae, Chlamydia trachomatis, Mycoplasma genitalium and Trichomonas vaginalis using self-collected tampons and polymerase chain reaction. RESULTS: There were 438 advertisements collated, representing 174 separate establishments. Of these, 78 were not considered likely to be brothels. Of the remaining 96, addresses were available for 42 and all of these premises were visited. Thirteen were confirmed as unlicensed brothels. We estimate there were between 13 and 70 unlicensed brothels in Melbourne. Twenty-three women were recruited from four brothels. Only 56% (95% confidence interval (CI) 35-77%) reported having regular sexual health checks and only 13% (95%CI 3-36%) reported prior testing for HIV. Among the 22 women tested, one had chlamydia while another had gonorrhoea, a prevalence of 4.5% (95%CI: 2.3-20.4%) for each infection. CONCLUSIONS: The number of unlicensed brothels in Melbourne is much smaller than is generally believed. Women in the sector are infrequently tested for STIs. IMPLICATIONS: As long as a licensing system persists, promotion of sexual health among women in this sector is likely to face hurdles. Further research is needed into the best model for regulating or not regulating sex industries. PMID- 20920109 TI - Markers of hepatitis B virus infection and immunity in Victoria, Australia, 1995 to 2005. AB - OBJECTIVE: Estimating the prevalence of chronic hepatitis B virus (HBV) infection in generally low-prevalence populations containing communities with a higher disease burden is difficult. This study was conducted to estimate the prevalence of serological markers of infection with, and immunity to, HBV in the Victorian population and to analyse trends in these estimates over time. METHODS: A serological survey of 3,212 samples of convenience collected in the years 1995, 2000 and 2005 was conducted using a selection procedure designed to reduce selection bias. All samples were tested for hepatitis B surface and core antibodies; all core antibody positive samples (indicating previous infection) were then tested for the presence of hepatitis B surface antigen (HBsAg). RESULTS: HBsAg prevalence was 1.1% (95%CI 0.8-1.6%) with significant differences observed by area of residence, age, gender and test year. Serological evidence of immunisation in infants and adolescents were lower than established estimates following the introduction of universal vaccination for these groups. CONCLUSIONS: This study emphasises the significant and growing problem of chronic HBV infection in Victoria and suggests lower than expected population immunity deriving from universal vaccination programs. IMPLICATIONS: Greater efforts are needed to formulate a comprehensive public health response to address this relatively neglected blood borne viral infection, the burden of which is very significant in some marginalised sections of our community. Increased attention to improving the universality of our immunisation programs is also needed. PMID- 20920110 TI - A serosurvey of Coxiella burnetii infection in children and young adults in South West Queensland. AB - OBJECTIVE: To describe the seroepidemiology of Coxiella burnetii, the causative agent of Q fever, in those under 25 years of age in South West Queensland. METHODS: A convenience sample of residual sera from a diagnostic laboratory was tested for C. burnetii antibodies by immunofluorescence at 1:10 dilution. Prevalence and annual incidence were calculated from the results. RESULTS: Twenty nine of 447 (6.5%, 95% CI 4.5%-9.2%) samples were positive. Seropositivity increased from 2.5% in those <15 (95% CI 1.0%-5.5%) to 11.0% in those 15-24 years old (95% CI 7.4%-16.0%). The estimated annual incidence for the latter age group was 7.7 per 1,000. CONCLUSIONS: Q fever is a relatively common infection in South West Queensland, even in those aged <15 years for whom the vaccine is not recommended. IMPLICATIONS: Vaccination programs, such as the federally funded National Q fever Management Program, are needed in this and similar high risk rural areas. PMID- 20920111 TI - The power of policy to influence behaviour change: daylight saving and its effect on physical activity. AB - OBJECTIVE: To measure the impact of the introduction of daylight saving in Western Australia in December 2006 on when during the day adults engaged in physical activity. METHODS: In early December 2006, 1,300 Western Australian adults were telephoned and asked about how the introduction of daylight saving would influence when during the day they typically engaged in physical activity. At the end of the daylight saving period in March 2007, 1,083 of the baseline cohort agreed to answer questions relating to how daylight saving had affected when during the day they were physically active. RESULTS: Almost half the cohort (45.5%) reported that daylight saving had affected when during the day they were physically active. During daylight saving fewer people exercised in the morning and more people exercised in the evening. When analysed at the individual level, 23% of the cohort ceased to exercise in the morning during daylight saving and 22% exercised in the evening only during daylight saving. In addition, to changes in when during the day people exercised, there was also an overall reduction in the average number of daily exercise sessions, with 8% not exercising at all during daylight saving. CONCLUSIONS: The results suggest that the introduction of daylight saving, a relatively modest compulsory change to increase daylight by one hour had an impact on patterns of when during the day people were physically active. IMPLICATIONS: The study results reinforce the value of focusing on policy as an effective means of supporting population behaviour change. PMID- 20920112 TI - A climate-based early warning system to predict outbreaks of Ross River virus disease in the Broome region of Western Australia. PMID- 20920113 TI - Re: 'An overview of cancer and beliefs about the disease in Indigenous people of Australia, Canada, New Zealand and the US'Aust NZ J Public Health. 2009; 33: 109 18. PMID- 20920115 TI - The importance of public education campaigns in raising awareness and support for smoke-free car legislation in Western Australia. PMID- 20920116 TI - The risks of diverted take-home methadone. PMID- 20920117 TI - Australian medical students unaware of global development goals. PMID- 20920118 TI - Letter to the Editor in response to "Please don't Spit". PMID- 20920119 TI - Respiratory health issues in the Asia-Pacific region: an overview. AB - The Asia-Pacific region is home to a large heterogeneous population whose respiratory health is influenced by diverse social, economic and environmental factors. Despite this variability, the most prevalent causes of respiratory morbidity and mortality are tobacco smoking, infection, and air pollution. This review aims to summarize current respiratory health issues in the region including smoking-related diseases especially COPD, lung cancer and infectious problems such as pandemic influenza, the severe acute respiratory syndrome coronavirus, bacterial pneumonia and tuberculosis, as well as the contribution of air pollution to respiratory disease. Published data on trends in the epidemiology and management of respiratory diseases and are summarized; finally, the limitations of available data and projections for the future of respiratory health in the region are discussed. PMID- 20920120 TI - The debate on CXR utilization and interpretation is only just beginning: a Pro/Con debate. AB - The CXR is the most commonly performed radiographic examination worldwide. Its ease of performance, apparent ease of interpretation and low radiation dose, alongside its great spatial resolution would suggest that it should be the first investigation performed in all patients presenting with thoracic disease. But, the advent of ever-improving multislice CT and increasing scanner availability has resulted in some patients being referred directly for scanning, bypassing the CXR. This has resulted in an inexorable rise in the number of scans performed, with an increase in patient radiation exposure and concerns among legislators and physicians that the number of scans needs to be regulated. A key role in the reduction of unnecessary scanning in patients with thoracic disease is the understanding of the place of the CXR, its ability to help in disease detection and monitoring, and its limitations. PMID- 20920121 TI - Six-minute walk test in pulmonary rehabilitation: do all patients need a practice test? AB - BACKGROUND AND OBJECTIVE: The six-minute walk test (6MWT) is widely used as an outcome measure in pulmonary rehabilitation programs (PRP). A learning effect for the test has been reported in COPD; however, limited data exist in patients with other respiratory diagnoses. The objectives of this study were to: (i) report the magnitude of change in 6MWD with test repetition in patients referred to an outpatient PRP, and (ii) compare the magnitude of change in 6MWD with test repetition in patients with COPD, interstitial lung disease (ILD), bronchiectasis and asthma. METHODS: Retrospective study of 349 patients with stable COPD (n = 245), ILD (n = 21), bronchiectasis (n = 33) or asthma (n = 50) who performed two 6MWT at enrollment into a PRP. RESULTS: 6MWD increased in all groups on the second test (all P < 0.001). At least 80% of patients in each diagnostic group walked further on their second 6MWT. The magnitude of change (mean, 95% CI) was greater (P < 0.05) in the COPD (37 m, 95% CI: 33-41 m) and ILD (41 m, 95% CI: 27 55 m) cohorts compared with the bronchiectasis (22 m, 95% CI: 14-31 m) and asthma (19 m, 95% CI: 11-27 m) cohorts. CONCLUSIONS: Respiratory diagnosis influences the magnitude of the learning effect for the 6MWT. The findings support the recommendation of a practice 6MWT at baseline assessment in order to provide an accurate measure of the effects of rehabilitation on 6MWD. PMID- 20920122 TI - PET scanning is important in lung cancer; but it has its limitations. PMID- 20920123 TI - Acute fibrinous and organizing pneumonia in a patient with HIV infection and Pneumocystis jiroveci pneumonia. AB - Acute fibrinous and organizing pneumonia (AFOP) is a disease of the small airways that is characterized by deposition of fibrin within the alveolar spaces. The histological pattern is described as a variant of cryptogenic organizing pneumonia (COP). Although COP has been occasionally described in patients with HIV infection, the variant form, AFOP, has not been previously reported in such patients. This report describes an intriguing case of AFOP in a patient with HIV infection and Pneumocystis jiroveci pneumonia. AFOP was diagnosed after tapering of corticosteroid therapy. This case illustrates that non-infectious pulmonary infiltrates should be considered in the differential diagnosis of lung disease in patients with HIV infection. PMID- 20920124 TI - Measurement of exhaled nitric oxide: comparison of different analysers. AB - BACKGROUND AND OBJECTIVE: Exhaled nitric oxide (NO) is used as a surrogate marker to monitor eosinophilic airway inflammation, assist in diagnosis, and support treatment decisions for asthma patients. The aim of this study was to compare five NO analysers: Medisoft (M), Aerocrine Niox (N), Aerocrine Niox flex (NF), Aerocrino Niox mino (NM) and EcoMedics (E). METHODS: In 85 subjects (25 asthma patients, 25 COPD patients, 35 healthy volunteers; median age 36.5 years, range 23-79, 47% female), three NO measurements per individual were performed, using each analyser according to the American Thoracic Society/European Respiratory Society guidelines. Subjects evaluated the devices on the basis of comfort and ease of performing the measurement. RESULTS: Median NO concentrations were 24.8 parts per billion (ppb) (range 6.3-262.7) for M, 14.5 ppb (0.0-196.6) for N, 15.2 ppb (5.6-67.7) for NF, 16.3 ppb (5.0-208.3) for NM, and 13.1 ppb (4.0-103.0) for E. There was significant correlation among the absolute NO values measured with all the devices (0.743 for M vs NF < r < 0.979 for N vs NF). Bland-Altman plots suggested an acceptable degree of agreement among the results obtained with the three Niox analysers. Measurements obtained with the Medisoft and Ecomedics analysers were not directly comparable with those obtained with the other devices. The greatest differences in absolute NO levels for individual patients were between measurements with the M and E analysers (8.3 ppb, range 27.4-159.7, P < 0.001). Acceptance of the measurements by patients was high, independent of the device used. CONCLUSIONS: Exhaled NO values obtained with different devices were not directly comparable and may differ to a clinically relevant extent, depending on which device is used. PMID- 20920125 TI - Iodine-123 metaiodobenzylguanidine scintigraphic assessment of pulmonary vascular status in patients with chronic obstructive pulmonary disease. AB - BACKGROUND AND OBJECTIVE: Lung uptake of iodine-123 metaiodobenzylguanidine (123I MIBG) is used as an indicator of pulmonary endothelial function. Decreased lung uptake of 123I-MIBG has been demonstrated in patients with COPD as compared with normal subjects. The present study was performed to examine the relationship between lung uptake of 123I-MIBG and pulmonary artery pressure (Ppa) at rest and during exercise, in patients with COPD. METHODS: 123I-MIBG scintigraphy was performed in 19 patients with COPD. Anterior planar images were acquired 15 min after the injection of 123I-MIBG, and the total lung to upper mediastinum ratio (LMR) was calculated for both lungs. Right heart catheters were used to monitor Ppa continuously at rest and during exercise. Exercise was performed on an electrically braked bicycle ergometer at a constant workload of 25 W for 3 min. RESULTS: In COPD patients the LMR were not correlated with the pulmonary function parameters measured before exercise, including FEV1, PaO2, DL(CO), or Ppa at rest. However, the percentage increase in Ppa during exercise was significantly correlated with LMR. CONCLUSIONS: Evaluation of the kinetics of lung uptake of 123I-MIBG may be a novel scintigraphic tool for the assessment of exercise induced pulmonary hypertension in patients with COPD. PMID- 20920126 TI - Haemodynamic effects of proportional assist ventilation during high-intensity exercise in patients with chronic obstructive pulmonary disease. AB - BACKGROUND AND OBJECTIVE: Proportional assist ventilation (PAV) has been proposed as a more physiological modality of non-invasive ventilation, thereby reducing the potential for deleterious cardio-circulatory effects during exercise, in patients with COPD. We therefore evaluated whether PAV modulates the kinetic and 'steady-state' haemodynamic responses to exercise in patients with moderate-to severe COPD. METHODS: Twenty patients underwent constant-load (75-80% peak work rate) cycle ergometer exercise testing to the limit of tolerance (T(lim)), while receiving PAV or breathing spontaneously. Stroke volume (SV), heart rate (HR) and cardiac output (CO) were monitored by impedance cardiography. RESULTS: Compared with unassisted breathing, PAV increased T(lim) in 8/20 patients (median improvement 113% (range 8 to 212) vs -20% (range -40 to -9)). PAV had no significant effects on 'steady-state' haemodynamic responses either in patients with or those without increased T(lim) (P > 0.05). However, at the onset of exercise, SV kinetics were slowed with PAV, in 13/15 patients with analysable data. HR dynamics remained unaltered or failed to accelerate sufficiently in nine of these patients, thereby slowing CO kinetics (T(1/2) 61 s (range 81-30) vs 89 s (range 100-47)). These deleterious effects were not, however, associated with PAV induced changes in T(lim) (P > 0.05). CONCLUSIONS: PAV slowed the SV and CO kinetics at the onset of high-intensity exercise in selected patients with moderate-to-severe COPD. However, these adverse effects of PAV disappeared during the stable phase of exercise, and were not related to the ergogenic potential of PAV in this patient population. PMID- 20920127 TI - State of the art: how to set up a pulmonary rehabilitation program. AB - Pulmonary rehabilitation plays an essential role in the management of symptomatic patients with COPD. The benefits of rehabilitation include a decrease in dyspnoea and fatigue, and improvements in exercise tolerance and health-related quality of life. Importantly, rehabilitation reduces hospitalization for acute exacerbations and is cost-effective. Although most of the evidence for pulmonary rehabilitation has been obtained in patients with COPD, symptomatic individuals with other respiratory diseases have been shown to benefit. In this review we outline a stepwise approach to establish, deliver and evaluate a pulmonary rehabilitation program (PRP) that would be feasible in most settings. Throughout the review we have specified the minimum requirements for a PRP to facilitate the establishment of programs using limited resources. Recommendations for staffing and other resources required for a PRP are presented in the first section. Exercise training is a focus of the section on program delivery as this is the component of rehabilitation that has the strongest level of evidence for benefit. Program considerations for patients with respiratory conditions other than COPD are described. Different approaches for delivering the education component of a PRP are outlined and recommendations are made regarding topics for group and individual sessions. The problems commonly encountered in pulmonary rehabilitation, together with recommendations to avoid these problems and strategies to assist in their resolution, are discussed. The review concludes with recommendations for evaluating a PRP. PMID- 20920128 TI - Effect of the alveolar recruitment manoeuvre on haemodynamic parameters in patients with acute respiratory distress syndrome: relationship with oxygenation. AB - BACKGROUND AND OBJECTIVE: Although the alveolar recruitment manoeuvre (ARM) is considered to be an optimal method of recruiting collapsed alveoli in a short period, the haemodynamic effects of the ARM have not been investigated. The aim of this study was to assess whether the ARM causes haemodynamic instability in patients with ARDS, and any relationship this might have with arterial oxygenation. METHODS: Twenty-eight patients with ARDS (16 responders and 12 non responders), who were admitted to the medical intensive care unit of a university affiliated hospital, were enrolled in the study. ARM, using the extended sigh method, was performed within 48 h of the onset of ARDS. Haemodynamic parameters were measured at baseline, during the ARM, and at 2 min, 30 min and 1 h after the ARM. RESULTS: Responders and non-responders showed no significant changes in blood pressure or cardiac index during or after ARM. Mean pulmonary artery pressure (MPAP), pulmonary vascular resistance index (PVRI) and right ventricular stroke work index (RVSWI) were transiently increased compared with baseline, in responders and non-responders. During and after ARM, the systemic vascular resistance index was significantly higher in non-responders than in responders. CONCLUSIONS: Some haemodynamic parameters (MPAP, PVRI and RVSWI) changed significantly during ARM. However, these haemodynamic changes were minimal, transient and probably have no clinical significance. PMID- 20920129 TI - Alveolar proteinosis with hypersensitivity pneumonitis: a new clinical phenotype. AB - BACKGROUND AND OBJECTIVE: The aim of the present study was to report the features of five patients with concurrent histopathological features of pulmonary alveolar proteinosis (PAP) and hypersensitivity pneumonitis (HP) and their high-resolution CT (HRCT) appearances. METHODS: Patients with histopathological features of both HP and PAP on surgical lung biopsy referred for tertiary review were retrospectively identified. The pathology and HRCT images were semi quantitatively scored to evaluate the relative contribution to HP and PAP. RESULTS: Five patients had histopathological features of HP and PAP but had varied HRCT appearances. All had imaging features of PAP to a varying degree with two patients also showing characteristics of HP but three patients had ill defined thickened interlobular septa, not typical of either disease. CONCLUSIONS: We describe the coexistence of PAP and HP in five patients and discuss possible linkages between these two distinct pathologies. PMID- 20920130 TI - Lecithinized superoxide dismutase treatment improves steroid-refractory interstitial pneumonia. AB - Pulmonary fibrosis associated with amyopathic dermatomyositis is known to have a generally aggressive course and is ultimately fatal. We report the case of a 50 year-old patient with amyopathic dermatomyositis, who developed progressive interstitial pneumonia that was unresponsive to corticosteroids and multiple immunosuppressive agents, including cyclosporine and tacrolimus hydrate. Five courses of lecithinized superoxide dismutase were administered without adverse effects. Improvements in physiological parameters, such as pulmonary function and exercise tolerance, as well as the serum Krebs von den Lungen 6 level, were observed. This is the first report of a case of steroid-refractory interstitial pneumonia treated with lecithinized superoxide dismutase. PMID- 20920131 TI - Lung function testing in health and disease: issues pertaining to Asia-Pacific populations. AB - The Asia-Pacific region comprise of diverse ethnic populations and healthcare systems of highly variable developmental stages. We face challenges in lung function testing, many of which are different from the issues encountered in the west. In some places, access to proper lung function testing facilities is very limited due to resource constraints or geographic inconvenience. It is important to note the potential differences of normative values in Asia-Pacific populations, compared with established values derived from populations of Caucasian ethnicity, hence the need to choose from available prediction formulae the ones that most closely approximate the subjects being tested. The criteria for defining abnormality is a hot topic globally. In the Asia-Pacific region, the trade-off between simplicity and thus ease of application and the pitfall of under- or over-diagnosis based on fixed cut-off values has to be recognized. The promotion of wider availability and proper utilization of lung function testing will go a long way in the enhancement of respiratory health and disease management in the region. PMID- 20920132 TI - Fibrotic idiopathic interstitial pneumonias: mortality is linked to a decline in gas transfer. AB - BACKGROUND AND OBJECTIVE: Baseline clinical and physiological features and changes in these parameters over time are known predictors of survival in patients with fibrotic idiopathic interstitial pneumonia (IIP). Pulmonary hypertension is common in advanced fibrotic IIP, and has a negative impact on survival. Serial pulmonary function profiles, indicative of increasing vascular impairment in patients with IIP, and in particular, selective reductions in gas transfer, have not been studied previously. METHODS: Predictors of event-free survival time were investigated in a cohort of Dutch patients with IPF and fibrotic non-specific interstitial pneumonia (n = 117). Pulmonary function test data were prospectively collected from November 1993 to December 2005. Multivariate Cox regression models were developed to identify the prognostic relevance to survival of variables related to baseline demographics, histopathology, pulmonary function and the 6- and 12-month changes in pulmonary function parameters. RESULTS: Different survival patterns were observed for patients with different histopathological diagnoses. At baseline, FVC was the most important prognostic factor. At the 6-month follow up, change in transfer coefficient (K(CO), DL(CO)/V(A)), and at the 12-month follow up, age, baseline K(CO) and 12-month change in FVC and K(CO), were independent predictors of event free survival. CONCLUSIONS: Apart from histopathology, change in K(CO) over time appeared to be the most consistent and powerful predictor of survival in these patients. The decline in K(CO) may be indicative of increasing vascular impairment, which may have a major impact on survival, in patients with fibrotic IIP. PMID- 20920133 TI - Cough challenge tests involving mechanical stimulation of the cervical trachea in patients with cough as a leading symptom. AB - BACKGROUND AND OBJECTIVE: Challenge tests involving chemical stimulation by inhalation of capsaicin or citric acid are currently used to assess cough sensitivity. We investigated the clinical usefulness of cough challenge tests based on mechanical stimulation. METHODS: A total of 347 patients (126 men and 221 women) were enrolled in the study, including 161 patients with asthma, 116 with cough-variant asthma, 27 with acute upper respiratory tract viral infections, 25 with acute bronchitis, four with pneumonia, three with chronic bronchitis and 11 with cough of unknown aetiology. Three modes of mechanical stimulation were assessed: the cervical trachea was compressed softly with the fingers several times (tracheal compression test); the trachea was stretched by retroflexion of the neck for 5 s (tracheal stretch test); and a vibrating tuning fork was placed on the cervical trachea for 20 s (tuning fork test). The relationships between phonation-induced cough and the results of these tests were assessed. RESULTS: The cough detection rate was 27.7% with the tracheal compression test, 39.8% with the tracheal stretch test and 36.9% with the tuning fork test. An itchy sensation with or without cough was noted by about 50% of subjects undergoing each of the tests. Provocation of cough and an itchy sensation during each test was significantly more frequent in subjects with phonation-induced cough. Tests were usually negative after improvement of the cough with treatment. CONCLUSIONS: Mechanical stimulation of the cervical trachea is a feasible cough challenge test that may be useful for evaluating disease activity. PMID- 20920134 TI - Detection and prevalence of chronic obstructive pulmonary disease in a cardiovascular clinic: evaluation using a hand held FEV1/FEV6 meter and questionnaire. AB - BACKGROUND AND OBJECTIVE: COPD is one of the leading causes of morbidity and mortality worldwide, and its prevalence continues to increase. Although spirometry is indispensable for the diagnosis of COPD, other simple and reliable tools are necessary for screening of COPD because spirometry is not widely available. This study investigated the usefulness of a combination of an electronic FEV1/FEV6 meter (PiKo-6) with a COPD questionnaire as a screening method in patients with cardiovascular diseases. METHODS: The PiKo-6 and the COPD questionnaire of the International Primary Care Airways Group were used to screen patients attending a cardiovascular outpatient clinic. Patients with FEV1/FEV6 < 70% were defined as having airflow limitation. Patients diagnosed with airflow limitation underwent spirometry. Using data from the PiKo-6 and the COPD questionnaire, patients were assigned to a COPD group or a non-COPD group. The relationship between PiKo-6 measurements and spirometry was also evaluated. RESULTS: Among 753 patients, 82 (10.9%) showed airflow limitation when assessed with the PiKo-6. Of these patients, 79 (10.5%) were assigned to the COPD group. FEV1, FEV6 and FEV1/FEV6, as measured with the PiKo-6, correlated significantly with FEV1, FVC and FEV1/FVC, respectively, as measured by spirometry (r = 0.865, 0.751 and 0.57). Among the cardiovascular comorbidities, heart failure and ischaemic heart disease showed slightly stronger associations with airflow limitation (13.8% and 12.5%, respectively). CONCLUSIONS: Combination of the PiKo 6 with a COPD questionnaire may be a useful and feasible method of identifying undiagnosed COPD patients attending a cardiovascular outpatient clinic. PMID- 20920135 TI - The central motor conductivity of genioglossus in obstructive sleep apnoea. AB - BACKGROUND AND OBJECTIVE: During wakefulness, the electromyography (EMG) activities of upper airway dilator muscles are higher in OSA syndrome (OSAS) patients than those in normal subjects. This is believed to be related to central compensatory mechanisms. This study aimed to assess the central motor conductivity of genioglossus (GG) during wakefulness and to evaluate the compensatory site in OSAS patients. METHODS: Twelve OSAS patients and 12 normal subjects were recruited to record motor evoked potential (MEP) of GG to transcranial magnetic stimulation applied at dominant-sided anterolateral area and GG response to magnetic stimulation at the third cervical level. Stimuli were delivered at the end of expiration and inspiration respectively. The central motor conduction time (CMCT) was calculated by the latency difference between cortical and cervical stimulations. RESULTS: The MEP latency and CMCT of GG in OSAS patients were shorter than those in normal subjects at the end of expiration (MEP latency: 6.08 +/- 2.06 ms and 8.24 +/- 2.66 ms, respectively, P < 0.05; CMCT: 2.41 +/- 1.20 ms and 3.58 +/- 1.53 ms, respectively, P < 0.05). However, only in normal subjects, GG MEP latency and CMCT showed significant decrease from the end of expiration to the end of inspiration. GG CMCT of OSAS patients at the end of expiration was closely correlated with AHI (r = -0.797, P = 0.002), the nadir oxygen saturation (r = 0.76, P = 0.003) and the longest apnoea time (r = 0.68, P = 0.02). CONCLUSIONS: OSAS patients have an increased central motor conductivity of GG than normal subjects. Furthermore, this increased central motor conductivity of GG is related to the severity of OSAS. PMID- 20920136 TI - Pilot randomized study comparing two techniques of airway anaesthesia during curvilinear probe endobronchial ultrasound bronchoscopy (CP-EBUS). AB - BACKGROUND AND OBJECTIVE: This study evaluates two different techniques for topically anaesthetizing the airway with lidocaine during curvilinear probe endobronchial ultrasound bronchoscopy (CP-EBUS): standard injection through the working channel and spray catheter application. METHODS: This was a randomized, non-blinded, single-centre pilot study. Patients with plans for CP-EBUS under moderate sedation were enrolled. All patients received nebulized lidocaine followed by posterior oropharyngeal lidocaine via atomizer and a cotton ball swab using McGill forceps. Patients were then randomly assigned to lidocaine administration using spray catheter instillation or direct application through the working channel. Lidocaine was administered in a uniform fashion by a single investigator throughout the study. The primary end-point was the number of significant coughing episodes in the first 30 min of bronchoscopy. Other end points included lidocaine and intravenous sedation medication dosage; severe coughing session; and number of transbronchial needle aspirations. RESULTS: Forty patients were included in the study: 20 patients in each group. The median numbers of coughing episodes in the first 30 min were 1 (spray catheter group) and 2 (standard injection group) (P < 0.004). Six patients in the standard installation group experienced severe coughing sessions, while there was none in the spray catheter group (P = 0.02). There were no statistical differences between the groups in the dosage of lidocaine or intravenous sedation medications used. There were a greater number of transbronchial needle aspirations performed in the spray catheter group (P = 0.008). CONCLUSIONS: Lidocaine delivery via the spray catheter reduced the number of significant coughing episodes compared with standard working channel injection during CP-EBUS. Larger studies are needed to confirm these exploratory findings. PMID- 20920137 TI - Single photon emission computed tomography in chronic thromboembolic pulmonary hypertension. AB - BACKGROUND AND OBJECTIVE: The management of chronic thromboembolic pulmonary hypertension (CTEPH) is largely dependent on the extent of obstruction in the pulmonary arteries. Planar perfusion scans are commonly used to quantify perfusion defects in CTEPH patients. However, planar scans typically under represent the extent of vascular obstruction in CTEPH. We conducted this study to test the hypothesis that SPECT lung perfusion scans are more accurate than planar scans for determining the location and extent of perfusion defects in patients with CTEPH. METHODS: Planar ventilation scans, planar and SPECT perfusion scans were performed preoperatively in patients undergoing pulmonary thromboendarterectomy for treatment of CTEPH. Two clinical experts independently documented the segmental anatomy of the vascular obstructions by reviewing clinical records, pulmonary and CT angiograms, and surgical specimens. A nuclear medicine expert documented the segmental anatomy of the perfusion defects observed by planar and SPECT scans independently. RESULTS: Clinical/pathological evaluation disclosed 241 obstructed and 99 unobstructed lung segments in 17 patients. Sensitivity for detecting obstructed segments was significantly higher for SPECT than for planar scanning (63.5 +/- 3.1% vs. 42.7 +/- 3.2%, respectively; P < 0.01). Specificities of SPECT and planar scanning were not significantly different (62.6 +/- 4.8% vs. 76.8 +/- 4.2%, respectively; P = 0.092). CONCLUSIONS: The SPECT is more sensitive than planar perfusion scanning for identifying obstructed segments in CTEPH. However, even SPECT under represents the true extent of the vascular occlusions in CTEPH. PMID- 20920138 TI - Tracheal aspirate Gram stain has limited sensitivity and specificity for detecting Staphylococcus aureus. AB - BACKGROUND AND OBJECTIVE: The increasing incidence of respiratory infections due to methicillin resistant Staphylococcus aureus has resulted in increased empirical use of antibiotics active against this pathogen. There are limited data available as to whether the Gram stain of respiratory tract secretions accurately predicts growth of S. aureus. We theorized that the distinctive morphology of S. aureus would allow rapid, accurate identification of the organism in respiratory secretions. METHODS: The authors reviewed all available Gram stains of tracheal aspirates sent to our hospital's microbiology laboratory between 1 April 2008 and 31 October 2008, while blinded to the culture result, and recorded the presence or absence of organisms with a morphology consistent with S. aureus. These results were correlated with the semiquantitative culture result. RESULTS: Among 136 tracheal aspirates studied, 50 (37%) grew S. aureus. The Gram stain was read as positive for organisms consistent with S. aureus in 34 of these. Among 86 samples that did not grow S. aureus, the Gram stain was read as negative in 62. Therefore, the Gram stain had a sensitivity of 68%, a specificity of 72%, a negative predictive value of 80% and a positive predictive value of 59% for culture of S. aureus. False negative Gram stains were more likely when the culture revealed only rare or small growth of S. aureus (P = 0.01). CONCLUSIONS: In this study, the tracheal aspirate Gram stain read by an experienced clinician who was not a microbiologist, was not accurate enough to reliably predict the growth of S. aureus. PMID- 20920139 TI - The use of sildenafil to treat pulmonary hypertension associated with interstitial lung disease. AB - BACKGROUND AND OBJECTIVE: Limited data suggest a benefit following sildenafil treatment in patients with pulmonary hypertension (PH) and interstitial lung disease (ILD). The role of sildenafil in the management of PH in ILD is not clear. We report our experience of ILD patients with PH after 6-month sildenafil therapy. METHODS: We reviewed 15 patients (mean age 55 +/- 15 years; 8 men) with ILD (mean FVC 52.6 +/- 15.4%) and PH (mean right ventricular systolic pressure 73.8 +/- 17.8 mm Hg). Median brain natriuretic peptide: 37 (5-452) pmol/L; mean 6MWD: 156 +/- 101 m. RESULTS: Following 6-month treatment with sildenafil, brain natriuretic peptide levels were lower (n = 12, P = 0.03), 6MWD was higher (n = 6, P < 0.05), but no change in right ventricular systolic pressure (n = 11) was demonstrated. CONCLUSIONS: Our observations suggest that sildenafil may be useful in the management of PH in ILD. Controlled trials are warranted before therapeutic recommendations can be made. PMID- 20920140 TI - Predicting early mortality in acute exacerbation of chronic obstructive pulmonary disease using the CURB65 score. AB - BACKGROUND AND OBJECTIVE: Hospitalization for exacerbation of COPD is associated with a high risk of mortality. A risk-prediction model using information easily obtained on admission could help to identify high-risk individuals. The CURB65 score was developed to predict mortality risk in community acquired pneumonia. A retrospective study found that this score was also associated with mortality in COPD exacerbations. We conducted a prospective study to assess the utility of the CURB65 score in acute COPD exacerbations. METHODS: Consecutive patients with physician diagnosed COPD exacerbations admitted to a public hospital during a 1 year period were studied prospectively. The CURB65 scores were calculated from information obtained at initial hospital presentation. CURB65 = one point each for Confusion, Urea > 7 mmol/L, Respiratory rate >= 30/min, low Blood pressure, age >= 65 years. RESULTS: 30-day mortality data were available for 249 of 252 patients. CURB65 scores on admission significantly predicted risk of death during the hospital admission and at 30 days. The 30-day mortality by score groups were: low risk (scores 0-1) 2.0% (2/98), moderate risk (score 2) 6.7% (6/90) and high risk (scores 3-5) 21.3% (13/61). CURB65 scores were not predictive of 1-year mortality. CONCLUSIONS: A simple 6-point score based on confusion, blood urea, respiratory rate, blood pressure and age can be used to stratify patients with COPD exacerbation into different management groups. The CURB65 score was as effective in predicting early mortality in our cohort of acute COPD exacerbations as it was in previous cohorts with community acquired pneumonia. Our findings suggest that CURB65 scores can help clinicians to assess patients with exacerbation of COPD. PMID- 20920141 TI - Comparison of 21-gauge and 22-gauge aspiration needle during endobronchial ultrasound-guided transbronchial needle aspiration. AB - BACKGROUND AND OBJECTIVE: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has typically been performed using the 22 gauge (G) dedicated TBNA needle. Recently a new 21G TBNA needle has been introduced. The efficacy of using a larger gauge biopsy needle during EBUS-TBNA has not been reported. The purpose of this study was to compare the diagnostic yield and utility of 21G and 22G needles during EBUS-TBNA. METHODS: EBUS-TBNA was performed using both 21G and 22G needles. Cytological and histological findings were recorded for each samples obtained by an independent cytologist and pathologist. The cellularity and blood contamination were evaluated in the cytological samples. The quality of the histological core was evaluated by the amount of blood clots versus the actual tissue. Each factor was compared within two slides from the two different size needles. The diagnostic yield and the differences of the cytology and histology were analysed. RESULTS: The evaluation of 45 lesions by EBUS-TBNA revealed that tumour cells were equally detected by both 21G and 22G needles. Two patients of adenocarcinoma were histologically diagnosed only by the 21G needle. Although histological structure was better preserved in five lesions collected by the 21G needle, there was more blood contamination with the 21G needle (P < 0.0001). CONCLUSIONS: There were no differences in the diagnostic yield between the 21G and 22G needles during EBUS-TBNA. The preserved histological structure of the samples obtained by the 21G needle may be useful for the diagnosis of mediastinal and hilar adenopathy of unknown aetiology which may be a challenge with the 22G needle. PMID- 20920142 TI - Effects of adding salmeterol/fluticasone propionate to tiotropium on airway dimensions in patients with chronic obstructive pulmonary disease. AB - BACKGROUND AND OBJECTIVE: Although salmeterol/fluticasone propionate combination (SFC) therapy has been widely used for the treatment of COPD, the relationship between airway dimensions and improvement in pulmonary function remains unknown. The aim of this study was to compare the effects of SFC in combination with tiotropium (Tio) and Tio alone, on airway dimensions and pulmonary function in COPD patients. METHODS: Thirty COPD patients were randomized to receive inhaled Tio (18 ug once daily) or inhaled SFC (50/250 ug twice daily) plus Tio for 12 weeks. Spirometry and CT were performed, and the St. George's Respiratory Questionnaire (SGRQ) was completed, before and after the trial. Airway dimensions were assessed by a validated CT technique, and airway wall area (WA) corrected for body surface area (BSA), percentage wall area (WA%), absolute wall thickness T/?BSA, and luminal area Ai/BSA at the right apical segmental bronchus, were measured. RESULTS: Treatment with SFC plus Tio significantly decreased WA/BSA (P < 0.05), WA% (P < 0.01) and T/?BSA (P < 0.01), and increased Ai/BSA (P < 0.01), whereas treatment with Tio alone had no effect. The changes in WA/BSA and Ai/BSA were significantly correlated with increases in FEV1 (r = 0.48, P < 0.05, and r = 0.36, P < 0.05, respectively). There were significant improvements in SGRQ scores after treatment with SFC plus Tio. CONCLUSIONS: Airway wall thickening and airway narrowing decreased after treatment with SFC plus Tio, and the changes in airway dimensions were proportional to the improvements in FEV1 . These results suggest that SFC plus Tio is more effective than Tio alone in the management of COPD patients. PMID- 20920143 TI - The effects of bushfire smoke on respiratory health. AB - Bushfire smoke has the potential to affect millions of people and is therefore a major public health problem. The air pollutant that increases most significantly as a result of bushfire smoke is particulate matter (PM). During bushfire smoke episodes, PM concentrations are usually much higher than urban background concentrations, at which effects on respiratory health have been observed. The smoke can cover large areas including major cities and even small increases in the risk of respiratory health effects can cause large public health problems. The association between respiratory morbidity and exposure to bushfire smoke is consistent with the associations found with urban air pollution. Although using different methods, all studies looking at Emergency Department presentations in relation to a bushfire smoke event have found associations and most studies have also found an association with hospital admissions. However, only a few studies have distinguished between the effects of bushfire PM(10) (particles with a median aerodynamic diameter less than 10 um) and background PM(10). These studies suggest that PM(10) from bushfire smoke is at least as toxic as urban PM(10), but more research is needed. PMID- 20920144 TI - Biomarkers of lung injury after one-lung ventilation for lung resection. AB - BACKGROUND AND OBJECTIVE: Acute lung injury contributes to the mortality of patients after lung resection and one-lung ventilation (OLV). The objective of this study was to characterise the effect of lung resection and OLV on proposed biomarkers of lung injury in exhaled breath condensate (EBC) and plasma. METHODS: In adults undergoing lung resection, EBC was collected before and at 30-min intervals during OLV. Inflammatory mediators were assayed in plasma samples taken preoperatively, immediately postoperatively and 24 h postoperatively. RESULTS: EBC pH decreased from 6.51 +/- 0.43 preoperatively, to 6.17 +/- 0.78 and 6.09 +/- 0.83 at 30 and 60 min, respectively (mean +/- SD, P = 0.034, n = 20). Plasma concentrations of the receptor for advanced glycation end-products, von Willebrand factor and interleukin-6 increased comparing preoperative and postoperative samples (all P < 0.001, n = 30). By contrast, levels of Krebs von den Lungen-6 and surfactant protein-D decreased (P < 0.001, n=30), and correlated inversely with the extent of lung resected. CONCLUSIONS: Lung resection and OLV was associated with a rapid reduction in EBC pH and differential changes in plasma biomarkers of lung injury. Further investigation of EBC pH as a marker of ventilator-induced lung injury is warranted. PMID- 20920145 TI - Pulmonary hypertension in sarcoidosis: a review. AB - Pulmonary hypertension (PH) is a well-recognized complication of sarcoidosis. Patients with sarcoidosis-associated PH (SAPH) have poorer functional status and greater supplemental oxygen requirements than sarcoidosis patients without PH, and are more likely to be listed for lung transplantation. PH is an independent risk factor for mortality in sarcoidosis patients awaiting lung transplantation. The pathophysiology of SAPH is complex, with multiple mechanisms contributing to pathogenesis, including the fibrous destruction of the pulmonary vascular bed, extrinsic compression of the central pulmonary vessels and an intrinsic vasculopathy. Recognition of SAPH may be delayed as it can be masked by the clinical picture of underlying pulmonary sarcoidosis, and right heart catheter remains the gold-standard for diagnosis. Management of SAPH is based on reversal of resting hypoxaemia, treatment of comorbidities and treatment of the underlying sarcoidosis. The use of corticosteroids in SAPH is controversial. Specific PH therapy is not routinely recommended in SAPH as there are no successful placebo controlled trials, although there is limited data to suggest that endothelin receptor antagonists and phosphodiesterase-5 inhibitors may be useful. PMID- 20920146 TI - Low zinc in drinking water is associated with the risk of type 1 diabetes in children. AB - AIM: To explore if drinking water may influence the development of type 1 diabetes in children, either via enterovirus spread via drinking water or quality of drinking water related to acidity or concentration of certain minerals. METHODS: One hundred and forty-two families with a child with diabetes and who lived either in seven municipalities with a high annual diabetes incidence during 1977-2001 and in six municipalities with the lowest incidence during those 25 yr were asked to participate. Three hundred and seventy-three families in these communities were used as controls. The families filled a 200-mL plastic bottle with their tap drinking water and returned it by mail. The water samples were analyzed for pH, zinc, iron, nitrate, nitrite, nitrate-nitrogen and nitrite nitrogen, and occurrence of enterovirus RNA. RESULTS: Enterovirus RNA was not found in the tap water samples. The concentration of zinc, nitrate, and nitrate nitrogen was lower in the municipalities with high incidence of type 1 diabetes. The water samples from families with a child with diabetes had lower concentration of zinc than water samples from control families. CONCLUSION: Low zinc in drinking water is associated with the risk of developing type 1 diabetes during childhood. Enterovirus does not seem to be spread via drinking water in a country with modern water works. PMID- 20920147 TI - Assessing the progression of mild cognitive impairment to Alzheimer's disease: current trends and future directions. AB - With the advent of advances in biomarker detection and neuropsychological measurement, prospects have improved for identifying and tracking the progression of Alzheimer's disease (AD) from its earliest stages through dementia. While new diagnostic techniques have exciting implications for initiating treatment earlier in the disease process, much work remains to be done to optimize the contributions of the expanding range of tools at the disposal of researchers and clinicians. The present paper examines recent work in cerebrospinal fluid biomarkers, magnetic resonance imaging, positron emission tomography, neuropsychological measures, and functional assessment. The strengths and weaknesses of current methodologies are explored and discussed. It is concluded that AD from its mild cognitive impairment state through dementia represents a continuous process, and that progression over time can best be accomplished by interval-level variables. Biomarkers that are most sensitive to early AD may not be the most optimal for monitoring longitudinal change, and it is likely that multivariate models incorporating cognitive measures, functional variables and biomarker data will be the most fruitful avenues for future research. PMID- 20920148 TI - A cautionary tale of virus and disease. AB - The recent identification of the gammaretrovirus XMRV and a second gammaretrovirus of a different subtype in chronic fatigue syndrome has aroused much interest, not least among sufferers. However, it remains highly controversial whether the detection of these viruses represents true infection or laboratory artifacts. PMID- 20920149 TI - Host transcription in active and latent tuberculosis. AB - A recent study has identified a transcriptional signature for active tuberculosis, suggesting that the distinction between active and latent forms may not be absolute. PMID- 20920151 TI - Inotropes in goal-directed therapy: do we need 'goals'? AB - There is substantial evidence to demonstrate the benefits of goal-directed hemodynamic optimization using fluid loading or inotropic support or both to improve outcome during major surgery. However, until now, only limited pathophysiological data have been available to explain this benefit. The maintenance of adequate tissue perfusion and global oxygen delivery is an essential goal for therapy. In an interesting study, Jhanji and colleagues provided additional data that emphasize the roles of optimization of intravascular fluid status and low doses of inotropes to improve microvascular blood flow and tissue oxygenation. This commentary aims to highlight some issues raised by this important study and provides additional elements to further position these results. PMID- 20920150 TI - Focusing on optic tectum circuitry through the lens of genetics. AB - The visual pathway is tasked with processing incoming signals from the retina and converting this information into adaptive behavior. Recent studies of the larval zebrafish tectum have begun to clarify how the 'micro-circuitry' of this highly organized midbrain structure filters visual input, which arrives in the superficial layers and directs motor output through efferent projections from its deep layers. The new emphasis has been on the specific function of neuronal cell types, which can now be reproducibly labeled, imaged and manipulated using genetic and optical techniques. Here, we discuss recent advances and emerging experimental approaches for studying tectal circuits as models for visual processing and sensorimotor transformation by the vertebrate brain. PMID- 20920152 TI - Sleep quality, the neglected outcome variable in clinical studies focusing on locomotor system; a construct validation study. AB - BACKGROUND: In addition to general health and pain, sleep is highly relevant to judging the well-being of an individual. Of these three important outcome variables, however, sleep is neglected in most outcome studies.Sleep is a very important resource for recovery from daily stresses and strains, and any alteration of sleep will likely affect mental and physical health, especially during disease. Sleep assessment therefore should be standard in all population based or clinical studies focusing on the locomotor system. Yet current sleep assessment tools are either too long or too specific for general use. METHODS: Based on a literature review and subsequent patient-based rating of items, an expert panel designed a four-item questionnaire about sleep. Construct validation of the questionnaire in a random sample of the German-speaking Swiss population was performed in 2003. Reliability, correlation, and tests for internal consistency and validity were analyzed. RESULTS: Overall, 16,634 (70%) out of 23,763 eligible individuals participated in the study. Test-retest reliability coefficients ranged from 0.72 to 0.87, and a Cronbach's alpha of 0.83 indicates good internal consistency. Results show a moderate to good correlation between sleep disturbances and health perception, and between sleep disturbances and overall pain. CONCLUSIONS: The Sleep Standard Evaluation Questionnaire (SEQ Sleep) is a reliable and short tool with confirmed construct validity for sleep assessment in population-based observational studies. It is easy to administer and therefore suitable for postal surveys of the general population. Criterion validity remains to be determined. PMID- 20920153 TI - Position-specific propensities of amino acids in the beta-strand. AB - BACKGROUND: Despite the importance of beta-strands as main building blocks in proteins, the propensity of amino acid in beta-strands is not well-understood as it has been more difficult to determine experimentally compared to alpha-helices. Recent studies have shown that most of the amino acids have significantly high or low propensity towards both ends of beta-strands. However, a comprehensive analysis of the sequence dependent amino acid propensities at positions between the ends of the beta-strand has not been investigated. RESULTS: The propensities of the amino acids calculated from a large non-redundant database of proteins are found to be highly position-specific and vary continuously throughout the length of the beta-strand. They follow an unexpected characteristic periodic pattern in inner positions with respect to the cap residues in both termini of beta-strands; this periodic nature is markedly different from that of the alpha-helices with respect to the strength and pattern in periodicity. This periodicity is not only different for different amino acids but it also varies considerably for the amino acids belonging to the same physico-chemical group. Average hydrophobicity is also found to be periodic with respect to the positions from both termini of beta strands. CONCLUSIONS: The results contradict the earlier perception of isotropic nature of amino acid propensities in the middle region of beta-strands. These position-specific propensities should be of immense help in understanding the factors responsible for beta-strand design and efficient prediction of beta strand structure in unknown proteins. PMID- 20920154 TI - Periodic assessment of plasma sFlt-1 and PlGF concentrations and its association with placental morphometry in gestational hypertension (GH) - a prospective follow-up study. AB - BACKGROUND: Hypertensive disorders in pregnancy contributes to about 12% of maternal deaths in Malaysia and similarly worldwide. Early detection and adequate management are preventable strategies. Biochemical markers of abnormal angiogenesis would be more specific in early detection than routine blood pressure and proteinuria measurements. The aim of this study was to estimate maternal plasma PlGF and sFlt-1 levels in pregnant women with gestational hypertension at three intervals of pregnancy and correlate these biomarker levels with placental morphometry. METHODS: Venous blood samples (antepartum, intrapartum and post partum periods) were drawn to estimate for sFlt-1 and PlGF levels while placental tissue samples were examined for placental morphometry. RESULTS: PlGF levels were lower in gestational hypertension (GH) compared to normotensive during antepartum and intrapartum period, whereas sFlt-1 levels were elevated in GH at antepartum, intrapartum and postpartum intervals during pregnancy. An inverse relationship between these two biomarkers was observed through correlation analysis. PlGF levels were inversely correlated with total villous surface area of the placental periphery (TCsa-C) and villous capillarization (VC-C) of the placental periphery. CONCLUSION: We established periodic values of for sFlt-1 and PlGF levels for the first time in an ethnically diverse Malaysian setting. We suggest the development of GH in women is related to defective capillarization. In demonstrating periodic changes, this study suggest the possibility of developing GH and other long term health complications as a result of prolonged exposure to sFlt-1. The correlation between PlGF levels and morphometric findings also support possible capillarization defect. PMID- 20920155 TI - Further cautions for the use of ventilatory-induced changes in arterial pressures to predict volume responsiveness. AB - Variations in systemic arterial pressure with positive-pressure breathing are frequently used to guide fluid management in hemodynamically unstable patients. However, because of the complex physiology that determines the response, there are important limitations to their use. Two papers in a previous volume add pulmonary hypertension as limitations. Uncritical use of ventilatory-induced changes in arterial pressure can lead to excessive volume therapy and potential clinical harm, and they must be used with respect and thought. PMID- 20920156 TI - Treatment of moderate to severe restless legs syndrome: 2-year safety and efficacy of rotigotine transdermal patch. AB - BACKGROUND: Rotigotine is a unique dopamine agonist with activity across D1 through D5 receptors as well as select adrenergic and serotonergic sites. This study reports the 2-year follow-up safety and efficacy data of an ongoing open label multicenter extension study (NCT00498186) of transdermal rotigotine in patients with moderate to severe restless legs syndrome (RLS). METHODS: Patients received a once-daily patch application of an individually optimized dose of rotigotine between 0.5 mg/24 h to 4 mg/24 h. Safety assessments included adverse events (AEs) and efficacy was measured by the International RLS Study Group Severity Rating Scale (IRLS), RLS-6 scales and Clinical Global Impression (CGI). Quality of life (QoL) was measured by QoL-RLS. RESULTS: Of 310 patients who completed a 6-week placebo-controlled trial (SP709), 295 (mean age 58 +/- 10 years, 66% females) were included in the open-label trial SP710. 64.7% (190/295 patients) completed the 2-year follow-up; 29 patients discontinued during the second year. Mean daily rotigotine dose after 2 years was 2.93 +/- 1.14 mg/24 h with a 2.9% dose increase from year 1. Rotigotine was generally well tolerated. The rate of typical dopaminergic side effects, nausea and fatigue, was low (0.9% and 2.3%, respectively) during the second year; application site reactions were frequent but lower than in year 1 (16.4% vs. 34.5%). The IRLS total score improved from baseline of SP709 (27.8 +/- 5.9) by 17.2 +/- 9.2 in year 2 completers. Similar improvements were observed in RLS-6 scales, CGI scores and QoL-RLS. The responder rate in the CGI change item 2 ("much" and "very much" improved) was 95% after year 2. CONCLUSIONS: Transdermal rotigotine is an efficacious and well-tolerated long-term treatment option for patients with moderate to severe RLS with a high retention rate during 2 years of therapy. TRIAL REGISTRATION: NCT00498186. PMID- 20920157 TI - Quantitative phosphoproteomic analysis of prion-infected neuronal cells. AB - Prion diseases or transmissible spongiform encephalopathies (TSEs) are fatal diseases associated with the conversion of the cellular prion protein (PrPC) to the abnormal prion protein (PrPSc). Since the molecular mechanisms in pathogenesis are widely unclear, we analyzed the global phospho-proteome and detected a differential pattern of tyrosine- and threonine phosphorylated proteins in PrPSc-replicating and pentosan polysulfate (PPS)-rescued N2a cells in two-dimensional gel electrophoresis. To quantify phosphorylated proteins, we performed a SILAC (stable isotope labeling by amino acids in cell culture) analysis and identified 105 proteins, which showed a regulated phosphorylation upon PrPSc infection. Among those proteins, we validated the dephosphorylation of stathmin and Cdc2 and the induced phosphorylation of cofilin in PrPSc-infected N2a cells in Western blot analyses. Our analysis showed for the first time a differentially regulated phospho-proteome in PrPSc infection, which could contribute to the establishment of novel protein markers and to the development of novel therapeutic intervention strategies in targeting prion-associated disease. PMID- 20920158 TI - Bone marrow transplantation in AML, and socioeconomic class: a UK population based cohort study. AB - BACKGROUND: We have previously shown that in the UK mortality in people with Acute Myeloid Leukaemia (AML) was nearly 50% greater among the most socio economically deprived. The aim of this study was to determine whether AML patients from lower socioeconomic classes had a lower chance of receiving a bone marrow transplant. METHODS: Using Hospital Episode Statistics (HES) data, we identified all incident cases of AML admitted to UK hospitals between 1998 and 2007. We calculated the number of bone marrow transplantations undertaken in AML patients, stratifying our results by gender, age at diagnosis, year of diagnosis, degree of socioeconomic deprivation and co-morbidity. We used logistic regression to calculate odds ratios for bone marrow transplantation, adjusting for gender, age at diagnosis, year of diagnosis, degree of socioeconomic deprivation and co morbidity score. RESULTS: We identified a total of 23 910 incident cases of AML over this 10-year time period, of whom 1 140 (4.8%) underwent BMT. Bone marrow transplantation declined with increasing socioeconomic deprivation (p for trend < 0.001) such that people in the most deprived socioeconomic quintile were 40% less likely to have a transplant than those in the most advantaged group (Odds Ratio 0.60, 95% confidence interval 0.49, 0.73), even after adjusting for gender, age at diagnosis, year of diagnosis and co-morbidity. CONCLUSION: This large cohort study demonstrates that AML patients from lower socioeconomic classes are less likely to undergo bone marrow transplantation than their better off counter parts. PMID- 20920159 TI - Violence toward physicians in emergency departments of Morocco: prevalence, predictive factors, and psychological impact. AB - INTRODUCTION: Anyone working in the hospital may become a victim of violence. The effects of violence can range in intensity and include the following: minor physical injuries, serious physical injuries, temporary or permanent physical disability, psychological trauma, and death. The aim of this study was to determine the frequency of exposure, characteristics, and psychological impact of violence toward hospital-based emergency physicians in Morocco. METHODS: This was a survey including emergency physicians who ensured emergency service during the last fortnight. The variables studied were those related to the victim (age and gender), and those related to aggression: assaulter gender, number, time, reason (delay of consultation and/or care, acute drunkenness, neuropsychiatric disease), and type (verbal abuse, verbal threat and/or physical assault). After the questionnaire was completed, State-Trait Anxiety Inventory (STAI) of Spielberg was applied to all participants. RESULTS: A total of 60 physicians have achieved permanence in emergency department during the 15 days preceding the questionnaire response. The mean age was 24 +/- 1 year and 57% were male. A total of 42 (70%) had been exposed to violence. The violence occurred at night n = 16 (27%), afternoon n = 13 (22%), evening n = 7 (12%) and morning n = 6 (10%). Reasons for violence were: the delay of consultation or care in n = 31 (52%) cases, acute drunkenness in n = 10 (17%) cases and neuropsychiatric disease in n = 3 (5%) cases. Twenty eight (47%) participants stated that they experienced verbal abuse, n = 18 (30%) verbal threat and n = 5 (8.3%) physical assault. Exposure to some form of violence was related to a higher median [interquartile range, IQR] state anxiety point (SAP); (51 [46-59] vs 39 [34-46]; P < 0,001), and trait anxiety point (TAP) (48 [41-55] vs 40,5 [38-53]; P = 0,01). CONCLUSIONS: This study revealed a high prevalence (70%) of violence toward doctors in Morocco emergency departments. The exposure of physicians to some form of violence is greater among doctors with anxiety trait and was related to significant degree of anxiety state. PMID- 20920160 TI - Refeeding syndrome influences outcome of anorexia nervosa patients in intensive care unit: an observational study. AB - INTRODUCTION: Data on the epidemiology and management of anorexia nervosa (AN) in the intensive care unit (ICU) are scarce. The aim of this study was to evaluate the prevalence and associated morbidity and mortality of AN in French ICUs. METHODS: We randomly selected 30 ICUs throughout France. Thereafter, we retrospectively analyzed all patients with AN admitted to any of these 30 ICUs between May 2006 and May 2008. We considered demographic data, diagnosis at admission and complications occurring during the stay, focusing on refeeding syndrome and management of refeeding. RESULTS: Eleven of the 30 ICUs participated in the retrospective study, featuring 68 patients, including 62 women. Average body mass index at the admission was 12 +/- 3 kg/m2. Twenty one were mechanically ventilated, mainly for neurological reasons. The reported average calorie intake was 22.3 +/- 13 kcal/kg/24 h. Major diagnoses at admission were metabolic problems, refeeding survey and voluntary drug intoxication and infection. The most common complications were metabolic, hematological, hepatic, and infectious events, of which 10% occurred during refeeding. Seven patients developed refeeding syndrome. At day one, the average calorie intake was higher for patients who developed refeeding syndrome (23.2 +/- 5 Kcal/kg/j; n = 7) versus patients without refeeding syndrome (14.1 +/- 3 Kcal/kg/j; n = 61) P = 0.02. Seven patients died, two from acute respiratory distress syndrome and five from multiorgan-failure associated with major hydroelectrolytic problems. CONCLUSIONS: The frequency of AN in ICU patients is very low and the crude mortality in this group is about 10%. Prevention and early-detection of refeeding syndrome is the key point. PMID- 20920161 TI - Inferring the conservative causal core of gene regulatory networks. AB - BACKGROUND: Inferring gene regulatory networks from large-scale expression data is an important problem that received much attention in recent years. These networks have the potential to gain insights into causal molecular interactions of biological processes. Hence, from a methodological point of view, reliable estimation methods based on observational data are needed to approach this problem practically. RESULTS: In this paper, we introduce a novel gene regulatory network inference (GRNI) algorithm, called C3NET. We compare C3NET with four well known methods, ARACNE, CLR, MRNET and RN, conducting in-depth numerical ensemble simulations and demonstrate also for biological expression data from E. coli that C3NET performs consistently better than the best known GRNI methods in the literature. In addition, it has also a low computational complexity. Since C3NET is based on estimates of mutual information values in conjunction with a maximization step, our numerical investigations demonstrate that our inference algorithm exploits causal structural information in the data efficiently. CONCLUSIONS: For systems biology to succeed in the long run, it is of crucial importance to establish methods that extract large-scale gene networks from high throughput data that reflect the underlying causal interactions among genes or gene products. Our method can contribute to this endeavor by demonstrating that an inference algorithm with a neat design permits not only a more intuitive and possibly biological interpretation of its working mechanism but can also result in superior results. PMID- 20920162 TI - Antitumour activity of a potent MEK inhibitor RDEA119/BAY 869766 combined with rapamycin in human orthotopic primary pancreatic cancer xenografts. AB - BACKGROUND: Combining MEK inhibitors with other signalling pathway inhibitors or conventional cytotoxic drugs represents a promising new strategy against cancer. RDEA119/BAY 869766 is a highly potent and selective MEK1/2 inhibitor undergoing phase I human clinical trials. The effects of RDEA119/BAY 869766 as a single agent and in combination with rapamycin were studied in 3 early passage primary pancreatic cancer xenografts, OCIP19, 21, and 23, grown orthotopically. METHODS: Anti-cancer effects were determined in separate groups following chronic drug exposure. Effects on cell cycle and downstream signalling were examined by flow cytometry and western blot, respectively. Plasma RDEA119 concentrations were measured to monitor the drug accumulation in vivo. RESULTS: RDEA119/BAY 869766 alone or in combination with rapamycin showed significant growth inhibition in all the 3 models, with a significant decrease in the percentage of cells in S phase, accompanied by a large decrease in bromodeoxyuridine labelling and cell cycle arrest predominantly in G1. The S6 ribosomal protein was inhibited to a greater extent with combination treatment in all the three models. Blood plasma pharmacokinetic analyses indicated that RDEA119 levels achieved in vivo are similar to those that produce target inhibition and cell cycle arrest in vitro. CONCLUSIONS: Agents targeting the ERK and mTOR pathway have anticancer activity in primary xenografts, and these results support testing this combination in pancreatic cancer patients. PMID- 20920164 TI - Rasch analysis of the Psychiatric Out-Patient Experiences Questionnaire (POPEQ). AB - BACKGROUND: The Psychiatric Out-Patient Experiences Questionnaire (POPEQ) is an 11-item core measure of psychiatric out-patients experiences of the perceived outcome of the treatment, the quality of interaction with the clinician, and the quality of information provision. The POPEQ was found to have evidence for reliability and validity following the application of classical test theory but has not previously been assessed by Rasch analysis. METHODS: Two national postal surveys of psychiatric outpatients took place in Norway in 2004 and 2007. The performance of the POPEQ, including item functioning and differential item functioning, was assessed by Rasch analysis. Principal component analysis of item residuals was used to assess the presence of subdimensions. RESULTS: 6,677 (43.3%) and 11,085 (35.2%) psychiatric out patients responded to the questionnaire in 2004 and 2007, respectively. All items in the scale were retained after the Rasch analysis. The resulting scale had reasonably good fit to the Rasch model. The items performed the same for the two survey years and there was no differential item functioning relating to patient characteristics. Principal component analysis of the residuals confirmed that the measure to a high degree is unidimensional. However, the data also reflects three potential subscales, each relating to one of the three included aspects of health care. CONCLUSIONS: The POPEQ had excellent psychometric properties and Rasch analysis further supported the construct validity of the scale by also identifying the three subdimensions originally included as components in the instrument development. The 11-item instrument is recommended in future research on psychiatric out-patient experiences. Future development may lead to the construction of more precise measures of the three subdomains that the POPEQ is based on. PMID- 20920163 TI - Heritability patterns in hand osteoarthritis: the role of osteophytes. AB - INTRODUCTION: The objective of the present study was to assess heritability of clinical and radiographic features of hand osteoarthritis (OA) in affected patients and their siblings. METHODS: A convenience sample of patients with clinical and radiographic hand OA and their siblings were evaluated by examination and radiography. Radiographs were scored for hand OA features by radiographic atlas. The heritability of hand OA phenotypes was assessed for clinical and radiographic measures based on anatomic locations and radiographic characteristics. Phenotypic data were transformed to reduce non-normality, if necessary. A variance components approach was used to calculate heritability. RESULTS: One hundred and thirty-six probands with hand OA and their sibling(s) were enrolled. By anatomic location, the highest heritability was seen with involvement of the first interphalangeal joint (h2 = 0.63, P = 0.00004), the first carpometacarpal joint (h2 = 0.38, P = 0.01), the distal interphalangeal joints (h2 = 0.36, P = 0.02), and the proximal interphalangeal joints (h2 = 0.30, P = 0.03) with osteophytes. The number and severity of joints with osteophyte involvement was heritable overall (h2 = 0.38, P = 0.008 for number and h2 = 0.35, P = 0.01 for severity) and for all interphalangeal joints (h2 = 0.42, P = 0.004 and h2 = 0.33, P = 0.02). The severity of carpometacarpal joint involvement was also heritable (h2 = 0.53, P = 0.0006). Similar results were obtained when the analysis was limited to the Caucasian sample. CONCLUSIONS: In a population with clinical and radiographic hand OA and their siblings, the presence of osteophytes was the most sensitive biomarker for hand OA heritability. Significant heritability was detected for anatomic phenotypes by joint location, severity of joint involvement with osteophytes as well as for overall number and degree of hand OA involvement. These findings are in agreement with the strong genetic predisposition for hand OA reported by others. The results support phenotyping based on severity of osteophytes and a joint-specific approach. More specific phenotypes may hold greater promise in the study of genetics in hand OA. PMID- 20920165 TI - Three-day dendritic cells for vaccine development: antigen uptake, processing and presentation. AB - BACKGROUND: Antigen-loaded dendritic cells (DC) are capable of priming naive T cells and therefore represent an attractive adjuvant for vaccine development in anti-tumor immunotherapy. Numerous protocols have been described to date using different maturation cocktails and time periods for the induction of mature DC (mDC) in vitro. For clinical application, the use of mDC that can be generated in only three days saves on the costs of cytokines needed for large scale vaccine cell production and provides a method to produce cells within a standard work week schedule in a GMP facility. METHODS: In this study, we addressed the properties of antigen uptake, processing and presentation by monocyte-derived DC prepared in three days (3d mDC) compared with conventional DC prepared in seven days (7d mDC), which represent the most common form of DC used for vaccines to date. RESULTS: Although they showed a reduced capacity for spontaneous antigen uptake, 3d mDC displayed higher capacity for stimulation of T cells after loading with an extended synthetic peptide that requires processing for MHC binding, indicating they were more efficient at antigen processing than 7d DC. We found, however, that 3d DC were less efficient at expressing protein after introduction of in vitro transcribed (ivt)RNA by electroporation, based on published procedures. This deficit was overcome by altering electroporation parameters, which led to improved protein expression and capacity for T cell stimulation using low amounts of ivtRNA. CONCLUSIONS: This new procedure allows 3d mDC to replace 7d mDC for use in DC-based vaccines that utilize long peptides, proteins or ivtRNA as sources of specific antigen. PMID- 20920166 TI - Identification and characterization of microRNAs in Clonorchis sinensis of human health significance. AB - BACKGROUND: Clonorchis sinensis is a zoonotic parasite causing clonorchiasis associated human disease such as biliary calculi, cholecystitis, liver cirrhosis, and it is currently classified as carcinogenic to humans for cholangiocarcinoma. MicroRNAs (miRNAs) are non-coding, regulating small RNA molecules which are essential for the complex life cycles of parasites and are involved in parasitic infections. To identify and characterize miRNAs expressed in adult C. sinensis residing chronically in the biliary tract, we developed an integrative approach combining deep sequencing and bioinformatic predictions with stem-loop real-time PCR analysis. RESULTS: Here we report the use of this approach to identify and clone 6 new and 62,512 conserved C. sinensis miRNAs which belonged to 284 families. There was strong bias on families, family members and sequence nucleotides in C. sinensis. Uracil was the dominant nucleotide, particularly at positions 1, 14 and 22, which were located approximately at the beginning, middle and end of conserved miRNAs. There was no significant "seed region" at the first and ninth positions which were commonly found in human, animals and plants. Categorization of conserved miRNAs indicated that miRNAs of C. sinensis were still innovated and concentrated along three branches of the phylogenetic tree leading to bilaterians, insects and coelomates. There were two miRNA strategies in C. sinensis for its parasitic life: keeping a large category of miRNA families of different animals and keeping stringent conserved seed regions with high active innovation in other places of miRNAs mainly in the middle and the end, which were perfect for the parasite to perform its complex life style and for host changes. CONCLUSIONS: The present study represented the first large scale characterization of C. sinensis miRNAs, which have implications for understanding the complex biology of this zoonotic parasite, as well as miRNA studies of other related species such as Opisthorchis viverrini and Opisthorchis felineus of human and animal health significance. PMID- 20920167 TI - Long term follow up after surgery in congenitally corrected transposition of the great arteries with a right ventricle in the systemic circulation. AB - AIM OF THE STUDY: To investigate the long-term outcome of surgical treatment for congenitally corrected transposition of the great arteries (CCTGA), in patients with biventricular repair with the right ventricle as systemic ventricle. METHODS: A total of 32 patients with CCTGA were operated between January 1972 and October 2008. These operations comprised 18 patients with a repair with a normal left ventricular outflow tract, 11 patients with a Rastelli repair of the left ventricle to the pulmonary artery and 3 patients with a cardiac transplantation. RESULTS: Excluding the cardiac transplantation patients, mean age at operation was 16 years (sd 15 years, range 1 week - 49 years). Median follow-up was 12 years (sd 10 years, range 7 days - 32 years). Survival obtained from Kaplan-Meier analysis at 20 years after surgery was 63% (CI 53-73%). For the non-Rastelli group these data at 20 years were 62% (CI 48-76%) and for the Rastelli group 67% (CI 51-83%). Freedom of reoperation at 20 years was 32% (CI 19-45%) in the overall group. In the non-Rastelli group the data at 20 years were 47% (CI 11 83%) and for the Rastelli group 21% (CI 0-54%) after almost 19 years. CONCLUSIONS: Long term follow up confirms that surgery in CCTGA with the right ventricle as systemic ventricle has a suboptimal survival and limited freedom of reoperation. Death occurred mostly as a result of cardiac failure. PMID- 20920168 TI - Development of a practical guide for the early recognition for malignant melanoma of the foot and nail unit. AB - BACKGROUND: Malignant melanoma is a rare but potentially lethal form of cancer which may arise on the foot. Evidence suggests that due to misdiagnosis and later recognition, foot melanoma has a poorer prognosis than cutaneous melanoma elsewhere. METHODS: A panel of experts representing podiatry and dermatologists with a special interest in skin oncology was assembled to review the literature and clinical evidence to develop a clinical guide for the early recognition of plantar and nail unit melanoma. RESULTS: A systematic review of the literature revealed little high quality data to inform the guide. However a significant number of case reports and series were available for analysis. From these, the salient features were collated and summarised into the guide. Based on these features a new acronym "CUBED" for foot melanoma was drafted and incorporated in the guide. CONCLUSIONS: The use of this guide may help clinicians in their assessment of suspicious lesions on the foot (including the nail unit). Earlier detection of suspicious pedal lesions may facilitate earlier referral for expert assessment and definitive diagnosis. The guide is currently being field tested amongst practitioners. PMID- 20920169 TI - Overproduced Brucella abortus PdhS-mCherry forms soluble aggregates in Escherichia coli, partially associating with mobile foci of IbpA-YFP. AB - BACKGROUND: When heterologous recombinant proteins are produced in Escherichia coli, they often precipitate to form insoluble aggregates of unfolded polypeptides called inclusion bodies. These structures are associated with chaperones like IbpA. However, there are reported cases of "non-classical" inclusion bodies in which proteins are soluble, folded and active. RESULTS: We report that the Brucella abortus PdhS histidine kinase fused to the mCherry fluorescent protein forms intermediate aggregates resembling "non-classical" inclusion bodies when overproduced in E. coli, before forming "classical" inclusion bodies. The intermediate aggregates of PdhS-mCherry are characterized by the solubility of PdhS-mCherry, its ability to specifically recruit known partners fused to YFP, suggesting that PdhS is folded in these conditions, and the quick elimination (in less than 10 min) of these structures when bacterial cells are placed on fresh rich medium. Moreover, soluble PdhS-mCherry foci do not systematically colocalize with IpbA-YFP, a marker of inclusion bodies. Instead, time-lapse experiments show that IbpA-YFP exhibits rapid pole-to-pole shuttling, until it partially colocalizes with PdhS-mCherry aggregates. CONCLUSION: The data reported here suggest that, in E. coli, recombinant proteins like PdhS-mCherry may transit through a soluble and folded state, resembling previously reported "non-classical" inclusion bodies, before forming "classical" inclusion bodies. The dynamic localization of IbpA-YFP foci suggests that the IbpA chaperone could scan the E. coli cell to find its substrates. PMID- 20920170 TI - Detection of sexually transmitted infection and human papillomavirus in negative cytology by multiplex-PCR. AB - BACKGROUND: The aim of this study was to determine the prevalence of human papillomavirus (HPV) and 15 species that cause sexually transmitted infections (STIs) in negative cytology. In addition, we compared the diagnostic performance of multiplex polymerase chain reaction (PCR) with widely available techniques used to detect HPV. METHODS: We recruited 235 women of reproductive age who had negative cytology findings in a liquid-based cervical smear. STIs were identified by multiplex PCR, and HPV genotypes by multiplex PCR, hybrid capture 2, and DNA microaray; discordant results were analyzed by direct sequencing. RESULTS: Approximately 96.6% of patients with negative cytology results were positive for pathogens that cause STIs. The pathogens most frequently detected were Gardnerella vaginalis, Ureaplasma urealyticum. The incidence of HPV in negative cytology was 23.3%. Low-risk HPV infection was significantly correlated with Chalmaydia trachomatis, and high-risk HPV infection was significantly correlated with Group beta streptococcus. The analytical sensitivities of the multiplex PCR and DNA microarray were higher than 80%, and the analytical specificity was nearly 100% for all tests. CONCLUSIONS: Multiplex PCR yielded results that most of patients with negative cytology were positive for pathogens that cause STIs, and were more similar to that of DNA microarray, than that of hybrid capture 2 in terms of analytical sensitivity and prediction value of HPV infection. PMID- 20920171 TI - Psychometric properties of the DISABKIDS Chronic Generic Module (DCGM-37) when used in children undergoing treatment for cancer. AB - BACKGROUND: The aim was to evaluate data quality and psychometric properties of an instrument for measurement of health-related quality of life: DISABKIDS Chronic Generic Module (DCGM-37) used in school-aged children with cancer. METHODS: All school-children diagnosed with cancer in Sweden during a two-and-a half year period were invited to participate in the study. Analysis was performed on combined data from two assessments, two and-a-half and five months after start of cancer treatment (n = 170). The instrument was examined with respect to feasibility, data quality, reliability and construct and criterion-based validity. RESULTS: Missing items per dimension ranged from 0 to 5.3 percent, with a majority below three percent. Cronbach's alpha values exceeded 0.70 for all dimensions. There was support for the suggested groupings of items into dimensions for all but six of the 36 items of the DCGM-37 included in this study. The instrument discriminated satisfactorily between diagnoses reflecting treatment burden. CONCLUSIONS: The results indicate satisfactory data quality and reliability of the DCGM-37 when used in children undergoing treatment for cancer. Evaluation of construct validity showed generally acceptable results, although not entirely supporting the suggested dimensionality. Continued psychometric evaluation in a larger sample of children during and after treatment for cancer is recommended. PMID- 20920172 TI - Social determinants of rest deprivation amongst Ghanaian women: national and urban-rural comparisons with data from a cross-sectional nationally representative survey. AB - BACKGROUND: Rest deprivation (rest/napping/sleep 6 or less hours daily) is a clinically recognised risk factor for poor health, but its epidemiology is little studied. This study reports prevalence's and social correlates of rest deprivation in Ghana. METHODS: Data are from the 2008 Ghana Demographic and Health Survey. Women ages 15-49 were recruited in a national sampling design. Respondents were 4,916 women in the national sample, a sub-sample of 530 women in the three northernmost rural regions and a sub-sample of 853 women in urban Greater Accra. RESULTS: Prevalence's of rest deprivation were 0.13% nationally, 14.5% in Greater Accra and 16.8% in the North. The significant correlates nationally were age, education, wealth index, Christian religion and literacy. In Accra, they were age, wealth index, having household electricity, and possession of a refrigerator, a stove and a mobile phone. In the North, they were education, occupation, drinking water source, possession of motorcycle/scooter, Christian religion, literacy, and possession of a clock and a cupboard. In logistic regression analyses controlling for age in the national sample, the significant odds ratios were 1.40 for no education compared to secondary and higher education, 0.78-0.43 for the four poorer wealth quintiles compared to the richest wealth index quintile, and 0.55 for Christian religion compared to all others.Also controlling for age, the significant odds ratios in Accra were 2.15 for the second richest wealth quintile compared to the richest quintile and 0.16 for possession of a mobile phone. In the North they were 0.49 for Christian religion compared to all others, 1.87 for having a protected compared to an unprotected water source, and 0.41 for having a cupboard in the home. CONCLUSIONS: Education, wealth and religion were related to rest deprivation nationally but not in the urban and rural regions (except for religion in the North). This suggests caution in generalising about the social correlates of rest deprivation at a regional level, based on national-level data. Qualitative research in local contexts is needed in order to illuminate the social determinants of rest pattern, and to provide guidance about better ways to measure such determinants in future survey research. PMID- 20920173 TI - Small artery elasticity is decreased in patients with systemic lupus erythematosus without increased intima media thickness. AB - INTRODUCTION: The objectives of this study were to determine small arterial elasticity (SAE) in systemic lupus erythematosus (SLE) and to investigate its relationship with intima media thickness (IMT), accumulation of advanced glycation end products (AGEs), endothelial activation and inflammation. METHODS: Thirty SLE patients with inactive disease and 30 age- and sex-matched healthy controls were included. Twenty patients with essential hypertension (EH) served as positive control. SAE was assessed by pulse-wave analysis using tonometric recordings of the radial artery. IMT of the carotid arteries was measured by ultrasound. AGE accumulation was assessed with an AGE-reader. Endothelial activation markers and C-reactive protein (CRP) were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: SAE was decreased in SLE (P = 0.01) and further decreased in EH (P < 0.01) compared to healthy controls. IMT was increased in EH (P < 0.05), but not in SLE. AGE accumulation was increased in SLE (P < 0.05) and further increased in EH (P < 0.01) compared to healthy controls. Endothelial activation markers and CRP were increased in SLE but not in EH. SAE related to AGE accumulation (r = -0.370, P < 0.05), CRP (r = -0.429, P < 0.05) and creatinine clearance (r = 0.440, P < 0.05), but not to IMT and endothelial activation markers. In multivariate analysis SLE was an independent predictor of SAE. CONCLUSIONS: SAE is decreased in SLE patients without increased IMT, independently of traditional cardiovascular risk factors. Longitudinal studies are needed to investigate whether SAE, endothelial activation and AGE accumulation are early markers for cardiovascular disease in SLE. PMID- 20920174 TI - Polymorphisms of genes coding for ghrelin and its receptor in relation to colorectal cancer risk: a two-step gene-wide case-control study. AB - BACKGROUND: Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor (GHSR), has two major functions: the stimulation of the growth hormone production and the stimulation of food intake. Accumulating evidence also indicates a role of ghrelin in cancer development. METHODS: We conducted a case control study to examine the association of common genetic variants in the genes coding for ghrelin (GHRL) and its receptor (GHSR) with colorectal cancer risk. Pairwise tagging was used to select the 11 polymorphisms included in the study. The selected polymorphisms were genotyped in 680 cases and 593 controls from the Czech Republic. RESULTS: We found two SNPs associated with lower risk of colorectal cancer, namely SNPs rs27647 and rs35683. We replicated the two hits, in additional 569 cases and 726 controls from Germany. CONCLUSION: A joint analysis of the two populations indicated that the T allele of rs27647 SNP exerted a protective borderline effect (Ptrend = 0.004). PMID- 20920175 TI - Clinical characteristics and outcomes of patients with acute myelogenous leukemia admitted to intensive care: a case-control study. AB - BACKGROUND: There is limited epidemiologic data on patients with acute myelogenous (myeloid) leukemia (AML) requiring life-sustaining therapies in the intensive care unit (ICU). Our objectives were to describe the clinical characteristics and outcomes in critically ill AML patients. METHODS: This was a retrospective case-control study. Cases were defined as adult patients with a primary diagnosis of AML admitted to ICU at the University of Alberta Hospital between January 1st 2002 and June 30th 2008. Each case was matched by age, sex, and illness severity (ICU only) to two control groups: hospitalized AML controls, and non-AML ICU controls. Data were extracted on demographics, course of hospitalization, and clinical outcomes. RESULTS: In total, 45 AML patients with available data were admitted to ICU. Mean (SD) age was 54.8 (13.1) years and 28.9% were female. Primary diagnoses were sepsis (32.6%) and respiratory failure (37.3%). Mean (SD) APACHE II score was 30.3 (10.3), SOFA score 12.6 (4.0) with 62.2% receiving mechanical ventilation, 55.6% vasoactive therapy, and 26.7% renal replacement therapy. Crude in-hospital, 90-day and 1-year mortality was 44.4%, 51.1% and 71.1%, respectively. AML cases had significantly higher adjusted hazards of death (HR 2.23; 95% CI, 1.38-3.60, p = 0.001) compared to both non-AML ICU controls (HR 1.69; 95% CI, 1.11-2.58, p = 0.02) and hospitalized AML controls (OR 1.0, reference variable). Factors associated with ICU mortality by univariate analysis included older age, AML subtype, higher baseline SOFA score, no change or an increase in early SOFA score, shock, vasoactive therapy and mechanical ventilation. Active chemotherapy in ICU was associated with lower mortality. CONCLUSIONS: AML patients may represent a minority of all critically ill admissions; however, are not uncommonly supported in ICU. These AML patients are characterized by high illness severity, multi-organ dysfunction, and high treatment intensity and have a higher risk of death when compared with matched hospitalized AML or non-AML ICU controls. The absence of early improvement in organ failure may be a useful predictor for mortality for AML patients admitted to ICU. PMID- 20920176 TI - ExaCT: automatic extraction of clinical trial characteristics from journal publications. AB - BACKGROUND: Clinical trials are one of the most important sources of evidence for guiding evidence-based practice and the design of new trials. However, most of this information is available only in free text - e.g., in journal publications - which is labour intensive to process for systematic reviews, meta-analyses, and other evidence synthesis studies. This paper presents an automatic information extraction system, called ExaCT, that assists users with locating and extracting key trial characteristics (e.g., eligibility criteria, sample size, drug dosage, primary outcomes) from full-text journal articles reporting on randomized controlled trials (RCTs). METHODS: ExaCT consists of two parts: an information extraction (IE) engine that searches the article for text fragments that best describe the trial characteristics, and a web browser-based user interface that allows human reviewers to assess and modify the suggested selections. The IE engine uses a statistical text classifier to locate those sentences that have the highest probability of describing a trial characteristic. Then, the IE engine's second stage applies simple rules to these sentences to extract text fragments containing the target answer. The same approach is used for all 21 trial characteristics selected for this study. RESULTS: We evaluated ExaCT using 50 previously unseen articles describing RCTs. The text classifier (first stage) was able to recover 88% of relevant sentences among its top five candidates (top5 recall) with the topmost candidate being relevant in 80% of cases (top1 precision). Precision and recall of the extraction rules (second stage) were 93% and 91%, respectively. Together, the two stages of the extraction engine were able to provide (partially) correct solutions in 992 out of 1050 test tasks (94%), with a majority of these (696) representing fully correct and complete answers. CONCLUSIONS: Our experiments confirmed the applicability and efficacy of ExaCT. Furthermore, they demonstrated that combining a statistical method with 'weak' extraction rules can identify a variety of study characteristics. The system is flexible and can be extended to handle other characteristics and document types (e.g., study protocols). PMID- 20920177 TI - Glucose uptake regulation in E. coli by the small RNA SgrS: comparative analysis of E. coli K-12 (JM109 and MG1655) and E. coli B (BL21). AB - BACKGROUND: The effect of high glucose concentration on the transcription levels of the small RNA SgrS and the messenger RNA ptsG, (encoding the glucose transporter IICBGlc), was studied in both E. coli K-12 (MG1655 and JM109) and E. coli B (BL21). It is known that the transcription level of sgrS increases when E. coli K-12 (MG1655 and JM109) is exposed to the non-metabolized glucose alpha methyl glucoside (alphaMG) or when the bacteria with a defective glycolysis pathway is grown in presence of glucose. The increased level of sRNA SgrS reduces the level of the ptsG mRNA and consequently lowers the level of the glucose transporter IICBGlc. The suggested trigger for this action is the accumulation of the corresponding phospho-sugars. RESULTS: In the course of the described work, it was found that E. coli B (BL21) and E. coli K-12 (JM109 and MG1655) responded similarly to alphaMG: both strains increased SgrS transcription and reduced ptsG transcription. However, the two strains reacted differently to high glucose concentration (40 g/L). E. coli B (BL21) reacted by increasing sgrS transcription and reducing ptsG transcription while E. coli K-12 (JM109 and MG1655) did not respond to the high glucose concentration, and, therefore, transcription of sgrS was not detected and ptsG mRNA level was not affected. CONCLUSIONS: The results suggest that E. coli B (BL21) tolerates high glucose concentration not only by its more efficient central carbon metabolism, but also by controlling the glucose transport into the cells regulated by the sRNA SgrS, which may suggest a way to control glucose consumption and increase its efficient utilization. PMID- 20920178 TI - Lipofibromatous hamartoma of the median nerve. AB - Lipofibromatous hamartoma is a rare tumour of peripheral nerves which is characterised by an excessive infiltration of the epineurium and perineurium by fibroadipose tissue. To the best of our knowledge, only approximately 88 cases are reported in the literature. We report a rare case of lipofibromatous hamartoma of the median nerve causing secondary carpal tunnel syndrome in a 25 year old patient. This patient was treated conservatively with decompression and biopsy and experienced a complete resolution of symptoms post-operatively. Magnetic resonance imaging may be used to diagnose this lesion as it has very distinctive characteristics. Multiple conditions have been associated with this lesion and a greater understanding of these associations may clarify the pathogenesis. The architecture of the tumour makes excision very challenging and the surgical management remains controversial. A review of the literature regarding the etiology, pathogenesis and surgical management of lipofibromatous hamartoma is included. PMID- 20920179 TI - Predictors of switching antipsychotic medications in the treatment of schizophrenia. AB - BACKGROUND: To identify patient characteristics and early changes in patients' clinical status that best predict subsequent switching of antipsychotic agents in the long-term treatment of schizophrenia. METHODS: This post-hoc analysis used data from a one-year randomized, open-label, multisite study of antipsychotics in the treatment of schizophrenia. The study protocol permitted switching of antipsychotics when clinically warranted after the first eight weeks. Baseline patient characteristics were assessed using standard psychiatric measures and reviews of medical records. The prediction model included baseline sociodemographics, comorbid psychiatric and non-psychiatric conditions, body weight, clinical and functional variables, as well as change scores on standard efficacy and tolerability measures during the first two weeks of treatment. Cox proportional hazards modeling was used to identify the best predictors of switching from the initially assigned antipsychotic medication. RESULTS: About one-third of patients (29.5%, 191/648) switched antipsychotics before the end of the one-year study. There were six variables identified as the best predictors of switching: lack of antipsychotic use in the prior year, pre-existing depression, female gender, lack of substance use disorder, worsening of akathisia (as measured by the Barnes Akathisia Scale), and worsening of symptoms of depression/anxiety (subscale score on the Positive and Negative Syndrome Scale) during the first two weeks of antipsychotic therapy. CONCLUSIONS: Switching antipsychotics appears to be prevalent in the naturalistic treatment of schizophrenia and can be predicted by a small and distinct set of variables. Interestingly, worsening of anxiety and depressive symptoms and of akathisia following two weeks of treatment were among the more robust predictors of subsequent switching of antipsychotics. PMID- 20920180 TI - Individual patient data meta-analysis of acupuncture for chronic pain: protocol of the Acupuncture Trialists' Collaboration. AB - BACKGROUND: The purpose of clinical trials of acupuncture is to help clinicians and patients make decisions about treatment. Yet this is not straightforward: some trials report acupuncture to be superior to sham (placebo) acupuncture while others show evidence that acupuncture is superior to usual care but not sham, and still others conclude that acupuncture is no better than usual care. Meta analyses of these trials tend to come to somewhat indeterminate conclusions. This appears to be because, until recently, acupuncture research was dominated by small trials of questionable quality. The Acupuncture Trialists' Collaboration, a group of trialists, statisticians and other researchers, was established to synthesize patient-level data from several recently published large, high-quality trials. METHODS: There are three distinct phases to the Acupuncture Trialists Collaboration: a systematic review to identify eligible studies; collation and harmonization of raw data; statistical analysis. To be eligible, trials must have unambiguous allocation concealment. Eligible pain conditions are osteoarthritis; chronic headache (tension or migraine headache); shoulder pain; and non-specific back or neck pain. Once received, patient-level data will undergo quality checks and the results of prior publications will be replicated. The primary analysis will be to determine the effect size of acupuncture. Each trial will be evaluated by analysis of covariance with the principal endpoint as the dependent variable and, as covariates, the baseline score for the principal endpoint and the variables used to stratify randomization. The effect size for acupuncture from each trial--that is, the coefficient and standard error from the analysis of covariance--will then be entered into a meta-analysis. We will compute effect sizes separately for comparisons of acupuncture with sham acupuncture, and acupuncture with no acupuncture control for each pain condition. Other analyses will investigate the impact of different sham techniques, styles of acupuncture or frequency and duration of treatment sessions. DISCUSSION: Individual patient data meta-analysis of high-quality trials will provide the most reliable basis for treatment decisions about acupuncture. Above all, however, we hope that our approach can serve as a model for future studies in acupuncture and other complementary therapies. PMID- 20920181 TI - Proteomic analysis of Salmonella enterica serovar Enteritidis following propionate adaptation. AB - BACKGROUND: Salmonella Enteritidis is a highly prevalent and persistent foodborne pathogen and is therefore a leading cause of nontyphoidal gastrointestinal disease worldwide. A variety of stresses are endured throughout its infection cycle, including high concentrations of propionate (PA) within food processing systems and within the gut of infected hosts. Prolonged PA exposure experienced in such milieus may have a drastic effect on the proteome of Salmonella Enteritidis subjected to this stress. RESULTS: In this study, we used 2 D gel electrophoresis to examine the proteomes of PA adapted and unadapted S. Enteritidis and have identified five proteins that are upregulated in PA adapted cultures using standard peptide mass fingerprinting by MALDI-TOF-MS and sequencing by MALDI LIFT-TOF/TOF tandem mass spectrometry. Of these five, two significant stress-related proteins (Dps and CpxR) were shown (via qRT-PCR analysis) to be upregulated at the transcriptional level as well. Unlike the wild type when adapted to PA (which demonstrates significant acid resistance), PA adapted S. Enteritidis ?dps and S. Enteritidis ?cpxR were at a clear disadvantage when challenged to a highly acidic environment. However, we found the acid resistance to be fully restorable after genetic complementation. CONCLUSIONS: This work reveals a significant difference in the proteomes of PA adapted and unadapted S. Enteritidis and affirms the contribution of Dps and CpxR in PA induced acid resistance. PMID- 20920182 TI - Axis I comorbidity in adolescent inpatients referred for treatment of substance use disorders. AB - BACKGROUND: To assess comorbid DSM-IV-TR Axis I disorders in adolescent inpatients referred for treatment of substance use disorders. METHODS: 151 patients (mean age 16.95 years, SD = 1.76; range 13 - 22) were consecutively assessed with the Composite International Diagnostic Interview (CIDI) and standardized clinical questionnaires to assess mental disorders, symptom distress, psychosocial variables and detailed aspects of drug use. A consecutively referred subgroup of these 151 patients consisting of 65 underage patients (mean age 16.12, SD = 1.10; range 13 - 17) was additionally assessed with the modules for attention-deficit/hyperactivity disorder (ADHD) and conduct disorder (CD) using The Schedule for Affective Disorders and Schizophrenia for school-aged children (K-SADS-PL). RESULTS: 128 (84.8%) of the 151 patients were dependent on at least one substance, the remaining patients fulfilled diagnostic criteria for abuse only. 40.5% of the participants fulfilled criteria for at least one comorbid present Axis I disorder other than substance use disorders (67.7% in the subgroup additionally interviewed with the K-SADS-PL). High prevalences of present mood disorder (19.2%), somatoform disorders (9.3%), and anxiety disorders (22.5%) were found. The 37 female participants showed a significantly higher risk for lifetime comorbid disorders; the gender difference was significantly pronounced for anxiety and somatoform disorders. Data from the underage subgroup revealed a high prevalence for present CD (41.5%). 33% of the 106 patients (total group) who were within the mandatory school age had not attended school for at least a two-month period prior to admission. In addition, 51.4% had been temporarily expelled from school at least once. CONCLUSIONS: The present data validates previous findings of high psychiatric comorbidity in adolescent patients with substance use disorders. The high rates of school refusal and conduct disorder indicate the severity of psychosocial impairment. PMID- 20920183 TI - Do patients think cannabis causes schizophrenia? - A qualitative study on the causal beliefs of cannabis using patients with schizophrenia. AB - BACKGROUND: There has been a considerable amount of debate among the research community whether cannabis use may cause schizophrenia and whether cannabis use of patients with schizophrenia is associated with earlier and more frequent relapses. Considering that studies exploring patients' view on controversial topics have contributed to our understanding of important clinical issues, it is surprising how little these views have been explored to add to our understanding of the link between cannabis and psychosis. The present study was designed to elucidate whether patients with schizophrenia who use cannabis believe that its use has caused their schizophrenia and to explore these patients other beliefs and perceptions about the effects of the drug. METHODS: We recruited ten consecutive patients fulfilling criteria for paranoid schizophrenia and for a harmful use of/dependence from cannabis (ICD-10 F20.0 + F12.1 or F12.2) from the in- and outpatient clinic of the Psychiatric University Hospital Zurich. They were interviewed using qualitative methodology. Furthermore, information on amount, frequency, and effects of use was obtained. A grounded theory approach to data analysis was taken to evaluate findings. RESULTS: None of the patients described a causal link between the use of cannabis and their schizophrenia. Disease models included upbringing under difficult circumstances (5) or use of substances other than cannabis (e. g. hallucinogens, 3). Two patients gave other reasons. Four patients considered cannabis a therapeutic aid and reported that positive effects (reduction of anxiety and tension) prevailed over its possible disadvantages (exacerbation of positive symptoms). CONCLUSIONS: Patients with schizophrenia did not establish a causal link between schizophrenia and the use of cannabis. We suggest that clinicians consider our findings in their work with patients suffering from these co-occurring disorders. Withholding treatment or excluding patients from certain treatment settings like day-care facilities or in patient care because of their use of cannabis, may cause additional harm to this already heavily burdened patient group. PMID- 20920184 TI - Identification of Burkholderia mallei and Burkholderia pseudomallei adhesins for human respiratory epithelial cells. AB - BACKGROUND: Burkholderia pseudomallei and Burkholderia mallei cause the diseases melioidosis and glanders, respectively. A well-studied aspect of pathogenesis by these closely-related bacteria is their ability to invade and multiply within eukaryotic cells. In contrast, the means by which B. pseudomallei and B. mallei adhere to cells are poorly defined. The purpose of this study was to identify adherence factors expressed by these organisms. RESULTS: Comparative sequence analyses identified a gene product in the published genome of B. mallei strain ATCC23344 (locus # BMAA0649) that resembles the well-characterized Yersinia enterocolitica autotransporter adhesin YadA. The gene encoding this B. mallei protein, designated boaA, was expressed in Escherichia coli and shown to significantly increase adherence to human epithelial cell lines, specifically HEp2 (laryngeal cells) and A549 (type II pneumocytes), as well as to cultures of normal human bronchial epithelium (NHBE). Consistent with these findings, disruption of the boaA gene in B. mallei ATCC23344 reduced adherence to all three cell types by ~50%. The genomes of the B. pseudomallei strains K96243 and DD503 were also found to contain boaA and inactivation of the gene in DD503 considerably decreased binding to monolayers of HEp2 and A549 cells and to NHBE cultures.A second YadA-like gene product highly similar to BoaA (65% identity) was identified in the published genomic sequence of B. pseudomallei strain K96243 (locus # BPSL1705). The gene specifying this protein, termed boaB, appears to be B. pseudomallei-specific. Quantitative attachment assays demonstrated that recombinant E. coli expressing BoaB displayed greater binding to A549 pneumocytes, HEp2 cells and NHBE cultures. Moreover, a boaB mutant of B. pseudomallei DD503 showed decreased adherence to these respiratory cells. Additionally, a B. pseudomallei strain lacking expression of both boaA and boaB was impaired in its ability to thrive inside J774A.1 murine macrophages, suggesting a possible role for these proteins in survival within professional phagocytic cells. CONCLUSIONS: The boaA and boaB genes specify adhesins that mediate adherence to epithelial cells of the human respiratory tract. The boaA gene product is shared by B. pseudomallei and B. mallei whereas BoaB appears to be a B. pseudomallei-specific adherence factor. PMID- 20920185 TI - In vivo whole-cell patch-clamp recording of sensory synaptic responses of cingulate pyramidal neurons to noxious mechanical stimuli in adult mice. AB - The anterior cingulate cortex (ACC) plays important roles in emotion, learning, memory and persistent pain. Our previous in vitro studies have demonstrated that pyramidal neurons in layer II/III of the adult mouse ACC can be characterized into three types: regular spiking (RS), intermediate (IM) and intrinsic bursting (IB) cells, according to their action potential (AP) firing patterns. However, no in vivo information is available for the intrinsic properties and sensory responses of ACC neurons of adult mice. Here, we performed in vivo whole-cell patch-clamp recordings from pyramidal neurons in adult mice ACC under urethane anesthetized conditions. First, we classified the intrinsic properties and analyzed their slow oscillations. The population ratios of RS, IM and IB cells were 10, 62 and 28%, respectively. The mean spontaneous APs frequency of IB cells was significantly greater than those of RS and IM cells, while the slow oscillations were similar among ACC neurons. Peripheral noxious pinch stimuli induced evoked spike responses in all three types of ACC neurons. Interestingly, IB cells showed significantly greater firing frequencies than RS and IM cells. In contrast, non-noxious brush did not induce any significant response. Our studies provide the first in vivo characterization of ACC neurons in adult mice, and demonstrate that ACC neurons are indeed nociceptive. These findings support the critical roles of ACC in nociception, from mice to humans. PMID- 20920186 TI - Zinc and vitamin A supplementation fails to reduce sputum conversion time in severely malnourished pulmonary tuberculosis patients in Indonesia. AB - BACKGROUND: A previous study showed that combination of zinc and vitamin A reduced sputum conversion time in pulmonary tuberculosis (TB) patients. OBJECTIVE: We studied the efficacy of which single micronutrient contributed more to the sputum conversion time. METHODS: In a double-blind randomized community trial, newly sputum smear positive pulmonary TB patients were assigned randomly to receive zinc, vitamin A, zinc + vitamin A or placebo on top of TB treatment. Patients were asked to deliver their sputum on weekly basis to measure positivity of the bacteria. Nutritional status, chest x-ray, hemoglobin, C-reactive protein (CRP), retinol and zinc level were examined prior to, after 2 and 6 months of treatment. RESULTS: Initially, 300 patients were enrolled, and 255 finished the treatment. Most patients were severely malnourished (mean BMI 16.5 +/- 2.2 Kg/m2). Patients in the zinc + vitamin A group showed earlier sputum conversion time (mean 1.9 weeks) compared with that in the other groups; however the difference was not significant. Also, no benefit could be demonstrated of any of the used supplementations on clinical, nutritional, chest x-ray, or laboratory findings. CONCLUSIONS: This study among severely malnourished TB patients, did not confirm that single or combined supplementation of zinc and vitamin A significantly reduced sputum conversion time or had other significant benefit. PMID- 20920187 TI - Selective amplification of Brucella melitensis mRNA from a mixed host-pathogen total RNA. AB - BACKGROUND: Brucellosis is a worldwide anthropozoonotic disease caused by an in vivo intracellular pathogen belonging to genus Brucella. The characterization of brucelae transcriptome's during host-pathogen interaction has been limited due to the difficulty of obtaining an adequate quantity of good quality eukaryotic RNA free pathogen RNA for downstream applications. FINDINGS: Here, we describe a combined protocol to prepare RNA from intracellular B. melitensis in a quantity and quality suitable for pathogen gene expression analysis. Initially, B. melitensis total RNA was enriched from a host:pathogen mixed RNA sample by reducing the eukaryotic RNA..Then, to increase the Brucella RNA concentration and simultaneously minimize the contaminated host RNA in the mixed sample, a specific primer set designed to anneal to all B. melitensis ORF allows the selective linear amplification of sense-strand prokaryotic transcripts in a previously enriched RNA sample. CONCLUSION: The novelty of the method we present here allows analysis of the gene expression profile of B. melitensis when limited amounts of pathogen RNA are present, and is potentially applicable to both in vivo and in vitro models of infection, even at early infection time points. PMID- 20920188 TI - Evolutionary lability of a complex life cycle in the aphid genus Brachycaudus. AB - BACKGROUND: Most aphid species complete their life cycle on the same set of host plant species, but some (heteroecious species) alternate between different hosts, migrating from primary (woody) to secondary (herbaceous) host plants. The evolutionary processes behind the evolution of this complex life cycle have often been debated. One widely accepted scenario is that heteroecy evolved from monoecy on woody host plants. Several shifts towards monoecy on herbaceous plants have subsequently occurred and resulted in the radiation of aphids. Host alternation would have persisted in some cases due to developmental constraints preventing aphids from shifting their entire life cycle to herbaceous hosts (which are thought to be more favourable). According to this scenario, if aphids lose their primary host during evolution they should not regain it. The genus Brachycaudus includes species with all the types of life cycle (monoecy on woody plants, heteroecy, monoecy on herbs). We used this genus to test hypotheses concerning the evolution of life cycles in aphids. RESULTS: Phylogenetic investigation and character reconstruction suggest that life cycle is evolutionary labile in the genus. Though ancestral character states can be ambiguous depending on optimization methods, all analyses suggest that transitions from monoecy on herbs towards heteroecy have occurred several times. Transitions from heteroecy towards monoecy, are also likely. There have been many shifts in feeding behaviour but we found no significant correlation between life cycle changes and changes in diet. CONCLUSIONS: The transitions from monoecy on herbs towards heteroecy observed in this study go against a widely accepted evolutionary scenario: aphids in the genus Brachycaudus seem to be able to recapture their supposedly ancestral woody host. This suggests that the determinants of host alternation are probably not as complicated as previously thought. Definitive proofs of the lability of life cycle in Brachycaudus will necessitate investigation of these determinants. Life cycle changes, whether corresponding to the loss or acquisition of a primary host, necessarily promote speciation, by inducing shifts of the reproductive phase on different plants. We suggest that the evolutionary lability of life cycle may have driven speciation events in the Brachycaudus genus. PMID- 20920189 TI - Quercetin prevents progression of disease in elastase/LPS-exposed mice by negatively regulating MMP expression. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by chronic bronchitis, emphysema and irreversible airflow limitation. These changes are thought to be due to oxidative stress and an imbalance of proteases and antiproteases. Quercetin, a plant flavonoid, is a potent antioxidant and anti inflammatory agent. We hypothesized that quercetin reduces lung inflammation and improves lung function in elastase/lipopolysaccharide (LPS)-exposed mice which show typical features of COPD, including airways inflammation, goblet cell metaplasia, and emphysema. METHODS: Mice treated with elastase and LPS once a week for 4 weeks were subsequently administered 0.5 mg of quercetin dihydrate or 50% propylene glycol (vehicle) by gavage for 10 days. Lungs were examined for elastance, oxidative stress, inflammation, and matrix metalloproteinase (MMP) activity. Effects of quercetin on MMP transcription and activity were examined in LPS-exposed murine macrophages. RESULTS: Quercetin-treated, elastase/LPS-exposed mice showed improved elastic recoil and decreased alveolar chord length compared to vehicle-treated controls. Quercetin-treated mice showed decreased levels of thiobarbituric acid reactive substances, a measure of lipid peroxidation caused by oxidative stress. Quercetin also reduced lung inflammation, goblet cell metaplasia, and mRNA expression of pro-inflammatory cytokines and muc5AC. Quercetin treatment decreased the expression and activity of MMP9 and MMP12 in vivo and in vitro, while increasing expression of the histone deacetylase Sirt-1 and suppressing MMP promoter H4 acetylation. Finally, co-treatment with the Sirt 1 inhibitor sirtinol blocked the effects of quercetin on the lung phenotype. CONCLUSIONS: Quercetin prevents progression of emphysema in elastase/LPS-treated mice by reducing oxidative stress, lung inflammation and expression of MMP9 and MMP12. PMID- 20920190 TI - Interaction of sleep quality and psychosocial stress on obesity in African Americans: the Cardiovascular Health Epidemiology Study (CHES). AB - BACKGROUND: Compared with whites, sleep disturbance and sleep deprivation appear more prevalent in African Americans (AA). Long-term sleep deprivation may increase the risk of obesity through multiple metabolic and endocrine alterations. Previous studies have reported contradictory results on the association between habitual sleep duration and obesity. Accordingly, we aimed to assess whether sleep quality and duration are inversely associated with body mass index (BMI) and obesity and test whether these associations are modified by psychosocial stress, known to influence sleep quality. METHODS: A sample of 1,515 AA residents of metropolitan Atlanta, aged 30-65 years, was recruited by a random digit-dialing method in 2007-08. The outcome obesity was defined by BMI (kg/m2) continuously and categorically (BMI >= 30 versus BMI < 30). Global sleep quality (GSQ) score was computed as the sum of response values for the seven components of the Pittsburgh Sleep Quality Index (PSQI) scale. GSQ score was defined as a continuous variable (range 0-21) and as tertiles. The general perceived stress (GPS), derived from the validated Cohen scale, was categorized into tertiles to test the interaction. Chi-square tests, correlation coefficients and weighted multiple linear and logistic regression were used to assess the associations of GSQ, GPS and obesity. RESULTS: The mean (standard deviation) age was 47.5 (17.0) years, and 1,096 (72%) were women. GSQ score categorized into tertiles was associated with BMI. Among women, after multivariable adjustment that included age, gender, physical activity, smoking status, education, total family income, financial stress and history of hypertension, hypercholesterolemia, diabetes and myocardial infarction, obesity was associated with sleep quality as assessed by GSQ continuous score, [odds ratio, OR (95% C.I.): 1.08 (1.03 - 1.12)], and with a worse sleep disturbance subcomponent score [OR (95% C.I.): 1.48 (1.16 - 1.89)]. Among all participants, stress modified the association between obesity and sleep quality; there was an increased likelihood of obesity in the medium stress category, OR (95% C.I.): 1.09 (1.02 - 1.17). CONCLUSION: Sleep quality was associated with obesity in women. The association of sleep quality with obesity was modified by perceived stress. Our results indicate the need for simultaneous assessment of sleep and stress. PMID- 20920192 TI - Plant sterols, marine-derived omega-3 fatty acids and other functional ingredients: a new frontier for treating hyperlipidemia. AB - As hyperlipidemia, including hypercholesterolemia (HC) and hypertriglyceridemia (HTN), continue to challenge North America's healthcare systems, patients continue to seek efficacious and safe natural therapies that complement pharmaceutical interventions. However, despite the ever-growing body of research supporting the use of functional foods and nutraceuticals (FFN) for the prevention and treatment of hyperlipidemia, reception amongst the medical community regarding the implementation of FFN into clinical guidelines continues to lag. Research demonstrates that specific FFN target and modulate molecular processes that perpetuate hyperlipidemia. In addition, studies consistently demonstrate that combining certain FFN such as marine-derived omega-3 fatty acids or plant sterols/stanols with statins enhances triglyceride and cholesterol lowering efficacy, respectively. Thus, the purpose of this commentary is to contend that efficacious FFN not only reduce HC and HTG but also boost the lipid lowering effects of pharmaceutical hypolipidemic medications. Finally, this editorial aims to challenge current medical guidelines to emphasize efficacious FFN during all stages of treatment of hyperlipidemias as adjuncts to pharmacotherapy. PMID- 20920191 TI - An improved, high-quality draft genome sequence of the Germination-Arrest Factor producing Pseudomonas fluorescens WH6. AB - BACKGROUND: Pseudomonas fluorescens is a genetically and physiologically diverse species of bacteria present in many habitats and in association with plants. This species of bacteria produces a large array of secondary metabolites with potential as natural products. P. fluorescens isolate WH6 produces Germination Arrest Factor (GAF), a predicted small peptide or amino acid analog with herbicidal activity that specifically inhibits germination of seeds of graminaceous species. RESULTS: We used a hybrid next-generation sequencing approach to develop a high-quality draft genome sequence for P. fluorescens WH6. We employed automated, manual, and experimental methods to further improve the draft genome sequence. From this assembly of 6.27 megabases, we predicted 5876 genes, of which 3115 were core to P. fluorescens and 1567 were unique to WH6. Comparative genomic studies of WH6 revealed high similarity in synteny and orthology of genes with P. fluorescens SBW25. A phylogenomic study also placed WH6 in the same lineage as SBW25. In a previous non-saturating mutagenesis screen we identified two genes necessary for GAF activity in WH6. Mapping of their flanking sequences revealed genes that encode a candidate anti-sigma factor and an aminotransferase. Finally, we discovered several candidate virulence and host association mechanisms, one of which appears to be a complete type III secretion system. CONCLUSIONS: The improved high-quality draft genome sequence of WH6 contributes towards resolving the P. fluorescens species, providing additional impetus for establishing two separate lineages in P. fluorescens. Despite the high levels of orthology and synteny to SBW25, WH6 still had a substantial number of unique genes and represents another source for the discovery of genes with implications in affecting plant growth and health. Two genes are demonstrably necessary for GAF and further characterization of their proteins is important for developing natural products as control measure against grassy weeds. Finally, WH6 is the first isolate of P. fluorescens reported to encode a complete T3SS. This gives us the opportunity to explore the role of what has traditionally been thought of as a virulence mechanism for non-pathogenic interactions with plants. PMID- 20920193 TI - Extreme loss of immunoreactive p-Akt and p-Erk1/2 during routine fixation of primary breast cancer. AB - INTRODUCTION: Very few studies have investigated whether the time elapsed between surgical resection and tissue fixation or the difference between core-cut and excision biopsies impact on immunohistochemically measured biomarkers including phosphorylated proteins in primary breast cancer. The aim of this study was to characterize the differences in immunoreactivity of common biomarkers that may occur (a) due to tissue handling at surgery and (b) between core-cuts and resected tumours. METHODS: Core-cuts taken from surgical breast cancer specimens immediately after resection (sample A) and after routine X-ray of the excised tumour (sample B) were formalin-fixed and paraffin-embedded and compared to the routinely fixed resection specimen (sample C). The variation in immunohistochemical expression of Ki67, oestrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor 2 (HER2), p-Akt and p-Erk were investigated. RESULTS: Twenty-one tissue sets with adequate tumour were available. Median time between collection of core-cuts A and B was 30 minutes (range 20 to 80). None of the markers showed significant differences between samples A and B. Similarly, Ki67, ER, PgR and HER2 did not differ significantly between core-cuts and main resection specimen although there was a trend for lower resection values for ER (P=0.06). However, p-Akt and p-Erk1/2 were markedly lower in resections than core-cuts (median 27 vs 101 and 69 vs 193, respectively; both P<0.0001 [two-sided]). This difference was significantly greater in mastectomy than lumpectomy specimens for p-Erk1/2 (P=0.01). CONCLUSIONS: The delay in fixation in core-cuts taken after post-operative X-ray of resection specimens has no significant impact on expression of Ki67, ER, PgR, HER2, p-Akt or p-Erk1/2. However extreme loss of phospho-staining can occur during routine fixation of resection specimens. These differences are likely attributable to suboptimal fixation and may have major repercussions for clinical research involving these markers. PMID- 20920194 TI - Cytotoxic activity of Thai medicinal plants against human cholangiocarcinoma, laryngeal and hepatocarcinoma cells in vitro. AB - BACKGROUND: Cholangiocarcinoma is a serious public health in Thailand with increasing incidence and mortality rates. The present study aimed to investigate cytotoxic activities of crude ethanol extracts of a total of 28 plants and 5 recipes used in Thai folklore medicine against human cholangiocarcinoma (CL-6), human laryngeal (Hep-2), and human hepatocarcinoma (HepG2) cell lines in vitro. METHODS: Cytotoxic activity of the plant extracts against the cancerous cell lines compared with normal cell line (renal epithelial cell: HRE) were assessed using MTT assay. 5-fluorouracil was used as a positive control. The IC50 (concentration that inhibits cell growth by 50%) and the selectivity index (SI) were calculated. RESULTS: The extracts from seven plant species (Atractylodes lancea, Kaempferia galangal, Zingiber officinal, Piper chaba, Mesua ferrea, Ligusticum sinense, Mimusops elengi) and one folklore recipe (Pra-Sa-Prao-Yhai) exhibited promising activity against the cholangiocarcinoma CL-6 cell line with survival of less than 50% at the concentration of 50 MUg/ml. Among these, the extracts from the five plants and one recipe (Atractylodes lancea, Kaempferia galangal, Zingiber officinal, Piper chaba, Mesua ferrea, and Pra-Sa-Prao-Yhai recipe) showed potent cytotoxic activity with mean IC50 values of 24.09, 37.36, 34.26, 40.74, 48.23 and 44.12 MUg/ml, respectively. All possessed high activity against Hep-2 cell with mean IC50 ranging from 18.93 to 32.40 MUg/ml. In contrast, activity against the hepatoma cell HepG2 varied markedly; mean IC50 ranged from 9.67 to 115.47 MUg/ml. The only promising extract was from Zingiber officinal (IC50=9.67 MUg/ml). The sensitivity of all the four cells to 5-FU also varied according to cell types, particularly with CL-6 cell (IC50=757 micromolar). The extract from Atractylodes lancea appears to be both the most potent and most selective against cholangiocarcinoma (IC50=24.09 MUg/ml, SI = 8.6). CONCLUSIONS: The ethanolic extracts from five plants and one folklore recipe showed potent cytotoxic activity against CL-6 cell. Sensitivity to other cancerous cell lines varied according to cell types and the hepatocarcinoma cell line. HepG2 appears to be the most resistant to the tested extracts. PMID- 20920195 TI - Study of inter- and intra-individual variations in the salivary microbiota. AB - BACKGROUND: Oral bacterial communities contain species that promote health and others that have been implicated in oral and/or systemic diseases. Culture independent approaches provide the best means to assess the diversity of oral bacteria because most of them remain uncultivable. RESULTS: The salivary microbiota from five adults was analyzed at three time-points by means of the 454 pyrosequencing technology. The V1-V3 region of the bacterial 16S rRNA genes was amplified by PCR using saliva lysates and broad-range primers. The bar-coded PCR products were pooled and sequenced unidirectionally to cover the V3 hypervariable region. Of 50,708 obtained sequences, 31,860 passed the quality control. Non bacterial sequences (2.2%) were removed leaving 31,170 reads. Samples were dominated by seven major phyla: members of Firmicutes, Proteobacteria, Actinobacteria, Bacteroidetes and candidate division TM7 were identified in all samples; Fusobacteria and Spirochaetes were identified in all individuals, but not at all time-points. The dataset was represented by 3,011 distinct sequences (100%-ID phylotypes) of ~215 nucleotides and 583 phylotypes defined at >=97% identity (97%-ID phylotypes). We compared saliva samples from different individuals in terms of the phylogeny of their microbial communities. Based on the presence and absence of phylotypes defined at 100% or 97% identity thresholds, samples from each subject formed separate clusters. Among individual taxa, phylum Bacteroidetes and order Clostridiales (Firmicutes) were the best indicators of intraindividual similarity of the salivary flora over time. Fifteen out of 81 genera constituted 73 to 94% of the total sequences present in different samples. Of these, 8 were shared by all time points of all individuals, while 15-25 genera were present in all three time-points of different individuals. Representatives of the class Sphingobacteria, order Sphingobacteriales and family Clostridiaceae were found only in one subject. CONCLUSIONS: The salivary microbial community appeared to be stable over at least 5 days, allowing for subject-specific grouping using UniFrac. Inclusion of all available samples from more distant time points (up to 29 days) confirmed this observation. Samples taken at closer time intervals were not necessarily more similar than samples obtained across longer sampling times. These results point to the persistence of subject-specific taxa whose frequency fluctuates between the time points. Genus Gemella, identified in all time-points of all individuals, was not defined as a core-microbiome genus in previous studies of salivary bacterial communities. Human oral microbiome studies are still in their infancy and larger-scale projects are required to better define individual and universal oral microbiome core. PMID- 20920196 TI - Determination of quality of life in adolescents with idiopathic scoliosis subjected to conservative treatment. AB - INTRODUCTION AND OBJECTIVES: Physical deformities caused by adolescent idiopathic scoliosis (AIS) coupled with conservative treatment of AIS with orthesis unavoidably impacts on patients' quality of life (QoL). The present study aimed at evaluating the QoL in patients affected by AIS treated with brace. The study also sought to determine the ability of different QoL questionnaires to monitor QoL over the course of treatment. MATERIALS AND METHODS: Data were collected in 108 consecutive patients (96 females, 16 males) affected by AIS admitted to the outpatient orthopaedic clinic of the Catholic University of the Sacred Heart in Rome (Italy). Patients were subjected to full-time (i.e., 22 hrs per day) conservative treatment with the progressive action short brace (PASB), the Lyon brace or a combination of PASB + Lyon brace. Three instruments were used for QoL determination: the Scoliosis Research Society 22 (SRS-22), Bad Sobernheim Stress Questionnaire (BSSQ) and the Brace Questionnaire (BrQ). RESULTS: A significant correlation was detected among the 3 scores (p < 0.001). The BrQ possesses a higher capacity to detect changes in QoL in relation to the patient gender, type of brace, curve severity at baseline and at the completion of treatment, and curve type. Overall, boys displayed a higher QoL than girls. In all 3 questionnaires, higher QoL scores were determined in patients treated with the PASB compared with those using the Lyon brace. QoL scores were significantly correlated with the curve severity. Higher QoL scores were obtained by participants with thoraco-lumbar curves as compared with those with other curves. CONCLUSIONS: The 3 questionnaires are effective in capturing changes in QoL in AIS patients subjected to conservative treatment. However, the BrQ possesses a higher discriminatory capacity compared with the other questionnaires tested. PASB-based treatment is associated with better QoL than the Lyon bracing. PMID- 20920197 TI - Genetic linkage map of a wild genome: genomic structure, recombination and sexual dimorphism in bighorn sheep. AB - BACKGROUND: The construction of genetic linkage maps in free-living populations is a promising tool for the study of evolution. However, such maps are rare because it is difficult to develop both wild pedigrees and corresponding sets of molecular markers that are sufficiently large. We took advantage of two long-term field studies of pedigreed individuals and genomic resources originally developed for domestic sheep (Ovis aries) to construct a linkage map for bighorn sheep, Ovis canadensis. We then assessed variability in genomic structure and recombination rates between bighorn sheep populations and sheep species. RESULTS: Bighorn sheep population-specific maps differed slightly in contiguity but were otherwise very similar in terms of genomic structure and recombination rates. The joint analysis of the two pedigrees resulted in a highly contiguous map composed of 247 microsatellite markers distributed along all 26 autosomes and the X chromosome. The map is estimated to cover about 84% of the bighorn sheep genome and contains 240 unique positions spanning a sex-averaged distance of 3051 cM with an average inter-marker distance of 14.3 cM. Marker synteny, order, sex averaged interval lengths and sex-averaged total map lengths were all very similar between sheep species. However, in contrast to domestic sheep, but consistent with the usual pattern for a placental mammal, recombination rates in bighorn sheep were significantly greater in females than in males (~12% difference), resulting in an autosomal female map of 3166 cM and an autosomal male map of 2831 cM. Despite differing genome-wide patterns of heterochiasmy between the sheep species, sexual dimorphism in recombination rates was correlated between orthologous intervals. CONCLUSIONS: We have developed a first generation bighorn sheep linkage map that will facilitate future studies of the genetic architecture of trait variation in this species. While domestication has been hypothesized to be responsible for the elevated mean recombination rate observed in domestic sheep, our results suggest that it is a characteristic of Ovis species. However, domestication may have played a role in altering patterns of heterochiasmy. Finally, we found that interval-specific patterns of sexual dimorphism were preserved among closely related Ovis species, possibly due to the conserved position of these intervals relative to the centromeres and telomeres. This study exemplifies how transferring genomic resources from domesticated species to close wild relative can benefit evolutionary ecologists while providing insights into the evolution of genomic structure and recombination rates of domesticated species. PMID- 20920198 TI - The construct validity of the health utilities index mark 3 in assessing health status in lung transplantation. AB - PURPOSE: To assess the cross-sectional construct validity of the Health Utilities Index Mark 3 (HUI3) in lung transplantation. METHODS: Two hundred and thirteen patients (103 pre-transplant and 110 post-transplant) with mean age 53 years old (SD 13) were recruited during a randomized controlled clinical trial at the out patient clinic in a tertiary institution. At baseline, patients self-completed measures that included the HUI3, EuroQol EQ-5D, Hospital Anxiety and Depression Scale (HADS) and socio-demographic questionnaire. Six-minute walk test scores and forced expiratory volume in 1 second data were collected from patient's medical records. A priori hypotheses were formulated by members of the transplant team about the expected degree of association between the measures. Correlation coefficients of < 0.1 were considered as negligible, 0.1 to < 0.3 as small, 0.3 to < 0.5 as medium, and >= 0.5 as large. RESULTS: Of the ninety predictions made, forty three were correct but in 31 the correlation was slightly lower than predicted and in 7 the correlations were much higher than predicted. In 48% of the cases, predicted and observed associations were in agreement. Predictions of associations were off by one category in 42% of the cases; in 10% of the cases the predictions were off by two categories. CONCLUSIONS: This is the first study providing evidence of cross-sectional construct validity of HUI3 in lung transplantation. Results indicate that the HUI3 was able to capture the burden of lung disease before transplantation and that post-transplant patients enjoyed higher health-related quality of life than pre-transplant patients. PMID- 20920200 TI - Progressive multifocal leukoencephalopathy in a patient without apparent immunosuppression. AB - An 80-year-old man with no history of an immune-compromising disorder was diagnosed with progressive multifocal leukoencephalopathy (PML). He presented with dysphagia and left-sided weakness; magnetic resonance imaging demonstrated marked signal abnormality in the subcortical white matter of the left frontal lobe and in the posterior limb of the right internal capsule. Polymerase chain reaction (PCR) analysis of the cerebrospinal fluid (CSF) was negative for John Cunningham (JC) virus. On brain biopsy, foamy macrophages infiltrating the white matter were identified, staining positive for anti-simian virus 40 antibodies. Postoperatively, PCR for JC viral DNA in the CSF was positive, establishing the diagnosis of PML. Extensive investigation for an occult immunocompromising disorder was negative. The patient's neurologic deficits rapidly increased throughout his hospital stay, and he died 3.5 months after his diagnosis. PMID- 20920199 TI - The relationship among acute-phase response proteins, cytokines and hormones in cachectic patients with colon cancer. AB - BACKGROUND: Acute-phase response proteins (APRP), cytokines and hormones have been claimed to be an independent prognostic factor of malignancies, however the basis for their association with prognosis remains unexplained. We suggest that in colon malignancies, as similar to pancreatic and lung cancers, changes in APRP are associated with angiogenesis. METHODS: C-reactive protein (CRP), albumin, IL 1alpha, IL-1beta, IL-6, IL-8, IL-10, TNF-alpha, midkine, VEGF-A, VEGF-C, leptin, adiponectin, and ghrelin serum levels are studied in 126 colon cancer patients and 36 healthy subjects. RESULTS: We found statistically significant difference and correlations between two groups. We found significantly higher serum CRP, IL 1alpha, IL-1beta, IL-6, IL-8, IL-10, TNF-alpha, VEGF-A, VEGF-C and leptin concentrations in patients relative to controls (p < 0.001). We found lower levels of the serum albumin, midkine, adiponectin and ghrelin in patients compared to control subjects (p < 0.001). CONCLUSIONS: Cachexia in patients with colon cancers is associated with changes in APRP, cytokines and hormone concentrations. These biomarkers and cachexia together have a direct relationship with accelerated angiogenesis. This may lead to a connection between the outcomes in malignancies and the biomarkers. PMID- 20920201 TI - The CAZyome of Phytophthora spp.: a comprehensive analysis of the gene complement coding for carbohydrate-active enzymes in species of the genus Phytophthora. AB - BACKGROUND: Enzymes involved in carbohydrate metabolism include Carbohydrate esterases (CE), Glycoside hydrolases (GH), Glycosyl transferases (GT), and Polysaccharide lyases (PL), commonly referred to as carbohydrate-active enzymes (CAZymes). The CE, GH, and PL superfamilies are also known as cell wall degrading enzymes (CWDE) due to their role in the disintegration of the plant cell wall by bacterial and fungal pathogens. In Phytophthora infestans, penetration of the plant cells occurs through a specialized hyphal structure called appressorium; however, it is likely that members of the genus Phytophthora also use CWDE for invasive growth because hyphal forces are below the level of tensile strength exhibited by the plant cell wall. Because information regarding the frequency and distribution of CAZyme coding genes in Phytophthora is currently unknown, we have scanned the genomes of P. infestans, P. sojae, and P. ramorum for the presence of CAZyme-coding genes using a homology-based approach and compared the gene collinearity in the three genomes. In addition, we have tested the expression of several genes coding for CE in cultures grown in vitro. RESULTS: We have found that P. infestans, P. sojae and P. ramorum contain a total of 435, 379, and 310 CAZy homologs; in each genome, most homologs belong to the GH superfamily. Most GH and PL homologs code for enzymes that hydrolyze substances present in the pectin layer forming the middle lamella of the plant cells. In addition, a significant number of CE homologs catalyzing the deacetylation of compounds characteristic of the plant cell cuticle were found. In general, a high degree of gene location conservation was observed, as indicated by the presence of sequential orthologous pairs in the three genomes. Such collinearity was frequently observed among members of the GH superfamily. On the other hand, the CE and PL superfamilies showed less collinearity for some of their putative members. Quantitative PCR experiments revealed that all genes are expressed in P. infestans when this pathogen grown in vitro. However, the levels of expression vary considerably and are lower than the expression levels observed for the constitutive control. CONCLUSIONS: In conclusion, we have identified a highly complex set of CAZy homologs in the genomes of P. infestans, P. sojae, and P. ramorum, a significant number of which could play roles critical for pathogenicity, by participating in the degradation of the plant cell wall. PMID- 20920203 TI - Acute dyspnoea and single tracheal localisation of mantle cell lymphoma. AB - BACKGROUND: Mantle cell lymphoma is a lymphoid entity characterized by adenopathy, blood and bone marrow involment which only recurrent mucosal localisation is the lymphomatoid polyposis. Few other mucosal infiltrations have been already reported. RESULTS: We report here the first case of a unique tracheal localisation of mantle cell lymphoma at presentation of the disease. The presence of classical t(11;14)(q13;q32) confirmed the diagnosis of mantle cell lymphoma by eliminating MALT or cancer localisation. CONCLUSION: This case illustrates the necessity to ensure the diagnosis of mucosal lymphoma versus MCL since these diseases need different treatment regimens and prognoses. PMID- 20920202 TI - Unusual conservation among genes encoding small secreted salivary gland proteins from a gall midge. AB - BACKGROUND: In most protein-coding genes, greater sequence variation is observed in noncoding regions (introns and untranslated regions) than in coding regions due to selective constraints. During characterization of genes and transcripts encoding small secreted salivary gland proteins (SSSGPs) from the Hessian fly, we found exactly the opposite pattern of conservation in several families of genes: the non-coding regions were highly conserved, but the coding regions were highly variable. RESULTS: Seven genes from the SSSGP-1 family are clustered as one inverted and six tandem repeats within a 15 kb region of the genome. Except for SSSGP-1A2, a gene that encodes a protein identical to that encoded by SSSGP-1A1, the other six genes consist of a highly diversified, mature protein-coding region as well as highly conserved regions including the promoter, 5'- and 3'-UTRs, a signal peptide coding region, and an intron. This unusual pattern of highly diversified coding regions coupled with highly conserved regions in the rest of the gene was also observed in several other groups of SSSGP-encoding genes or cDNAs. The unusual conservation pattern was also found in some of the SSSGP cDNAs from the Asian rice gall midge, but not from the orange wheat blossom midge. Strong positive selection was one of the forces driving for diversification whereas concerted homogenization was likely a mechanism for sequence conservation. CONCLUSION: Rapid diversification in mature SSSGPs suggests that the genes are under selection pressure for functional adaptation. The conservation in the noncoding regions of these genes including introns also suggested potential mechanisms for sequence homogenization that are not yet fully understood. This report should be useful for future studies on genetic mechanisms involved in evolution and functional adaptation of parasite genes. PMID- 20920204 TI - A semi-nonparametric mixture model for selecting functionally consistent proteins. AB - BACKGROUND: High-throughput technologies have led to a new era of proteomics. Although protein microarray experiments are becoming more common place there are a variety of experimental and statistical issues that have yet to be addressed, and that will carry over to new high-throughput technologies unless they are investigated. One of the largest of these challenges is the selection of functionally consistent proteins. RESULTS: We present a novel semi-nonparametric mixture model for classifying proteins as consistent or inconsistent while controlling the false discovery rate and the false non-discovery rate. The performance of the proposed approach is compared to current methods via simulation under a variety of experimental conditions. CONCLUSIONS: We provide a statistical method for selecting functionally consistent proteins in the context of protein microarray experiments, but the proposed semi-nonparametric mixture model method can certainly be generalized to solve other mixture data problems. The main advantage of this approach is that it provides the posterior probability of consistency for each protein. PMID- 20920206 TI - Association between -238 but not -308 polymorphism of Tumor necrosis factor alpha (TNF-alpha)v and unexplained recurrent spontaneous abortion (URSA) in Chinese population. AB - OBJECTIVES: TNF-alpha is a critical cytokine produced by Th1 cells while altered T helper 1 (Th1)-Th2 balance is found crucial for a successful pregnancy. STUDY DESIGN: A cohort of 132 Southern Chinese Han RSA patients and 152 controls constituted the subjects of this study. Two functional polymorphisms -308 and 238 of TNF-alpha were studied by association analysis. RESULTS: lack of association was found in TNF-alpha -308 SNP yet a significant difference was discovered in -238 polymorphism. CONCLUSION: This study suggested that TNF-alpha may be a risk factor in Chinese RSA patients. However the ethnic differences may also contribute to the results. PMID- 20920205 TI - Behavioural symptoms in patients with Alzheimer's disease and their association with cognitive impairment. AB - BACKGROUND: Behavioural and psychological symptoms of dementia (BPSD) are non cognitive symptoms commonly associated to Alzheimer's disease (AD). The characterization of the clinical profile of AD patients might help to better understand disease evolution and to improve diagnosis and treatment. Thus, the aim of the present study is to describe the clinical profile of AD patients, and to correlate the presence of BPSD with the severity of the disease. METHODS: A cross-sectional, observational and multicenter study was conducted at 115 centres in Spain. Patients suffering from AD with higher and lower BPSD scores (ADAS Noncog score 26-50 and <=25, respectively) were included. Demographic and clinical data were collected, and dementia severity was assessed by the Mini Mental State Examination (MMSE) [mild 27-21, moderate 20-11, severe <=10]. The use of ADAS-Noncog in clinical practice was also explored. RESULTS: A total of 1014 patients (463 with higher and 551 with lower BPSD scores) were included (mean age 77 +/- 7 years, 65% women). Almost all patients (90%) had BPSD at inclusion, 17% of which reported psychotic outbreaks. The most prevalent symptoms were lack of concentration (56%), tremors (56%), depression (44%), lack of cooperation (36%), and delusions (32%). Patients with higher BPSD scores showed a significantly higher prevalence of psychotic symptoms (delusions, hallucinations, and delirium) and tremors, while emotional symptoms (tearfulness and apathy) predominated in patients with lower BPSD scores. MMSE and ADAS-Noncog scores were negatively associated (p = 0.0284), suggesting a correlation between cognitive impairment and BPSD. Lack of concentration and appetite change significantly correlated with MMSE (p = 0.0472 and p = 0.0346, respectively). Rivastigmine and donepezil were the first choice therapies in mild to moderate dementia. ADAS Noncog was generally considered better or similar to other scales (82%), and 68% of the investigators were willing to use it in the future. CONCLUSIONS: Our study shows that patients with AD have a high prevalence of noncognitive symptoms, and that cognitive impairment and BPSD are correlated. Therefore, ADAS-Noncog is a useful evaluation tool. PMID- 20920207 TI - Therapeutic versus neuroinflammatory effects of passive immunization is dependent on Abeta/amyloid burden in a transgenic mouse model of Alzheimer's disease. AB - BACKGROUND: Passive immunization with antibodies directed to Abeta decreases brain Abeta/amyloid burden and preserves memory in transgenic mouse models of Alzheimer's disease (AD). This therapeutic strategy is under intense scrutiny in clinical studies, but its application is limited by neuroinflammatory side effects (autoimmune encephalitis and vasogenic edema). METHODS: We intravenously administered the monoclonal Abeta protofibril antibody PFA1 to aged (22 month) male and female 3 * tg AD mice with intermediate or advanced AD-like neuropathologies, respectively, and measured brain and serum Abeta and CNS cytokine levels. We also examined 17 month old 3 * tg AD female mice with intermediate pathology to determine the effect of amyloid burden on responses to passive immunization. RESULTS: The 22 month old male mice immunized with PFA1 had decreased brain Abeta, increased serum Abeta, and no change in CNS cytokine levels. In contrast, 22 month old immunized female mice revealed no change in brain Abeta, decreased serum Abeta, and increased CNS cytokine levels. Identical experiments in younger (17 month old) female 3 * tg AD mice with intermediate AD like neuropathologies revealed a trend towards decreased brain Abeta and increased serum Abeta accompanied by a decrease in CNS MCP-1. CONCLUSIONS: These data suggest that passive immunization with PFA1 in 3 * tg AD mice with intermediate disease burden, regardless of sex, is effective in mediating potentially therapeutic effects such as lowering brain Abeta. In contrast, passive immunization of mice with a more advanced amyloid burden may result in potentially adverse effects (encephalitis and vasogenic edema) mediated by certain proinflammatory cytokines. PMID- 20920208 TI - Analysis of lifestyle and metabolic predictors of visceral obesity with Bayesian Networks. AB - BACKGROUND: The aim of this study was to provide a framework for the analysis of visceral obesity and its determinants in women, where complex inter-relationships are observed among lifestyle, nutritional and metabolic predictors. Thirty-four predictors related to lifestyle, adiposity, body fat distribution, blood lipids and adipocyte sizes have been considered as potential correlates of visceral obesity in women. To properly address the difficulties in managing such interactions given our limited sample of 150 women, bootstrapped Bayesian networks were constructed based on novel constraint-based learning methods that appeared recently in the statistical learning community. Statistical significance of edge strengths was evaluated and the less reliable edges were pruned to increase the network robustness. To allow accessible interpretation and integrate biological knowledge into the final network, several undirected edges were afterwards directed with physiological expertise according to relevant literature. RESULTS: Extensive experiments on synthetic data sampled from a known Bayesian network show that the algorithm, called Recursive Hybrid Parents and Children (RHPC), outperforms state-of-the-art algorithms that appeared in the recent literature. Regarding biological plausibility, we found that the inference results obtained with the proposed method were in excellent agreement with biological knowledge. For example, these analyses indicated that visceral adipose tissue accumulation is strongly related to blood lipid alterations independent of overall obesity level. CONCLUSIONS: Bayesian Networks are a useful tool for investigating and summarizing evidence when complex relationships exist among predictors, in particular, as in the case of multifactorial conditions like visceral obesity, when there is a concurrent incidence for several variables, interacting in a complex manner. The source code and the data sets used for the empirical tests are available at http://www710.univ lyon1.fr/~aaussem/Software.html. PMID- 20920209 TI - Bleeding from gastrointestinal angioectasias is not related to bleeding disorders - a case control study. AB - BACKGROUND: Angioectasias in the gastrointestinal tract can be found in up to 3% of the population. They are typically asymptomatic but may sometimes result in severe bleeding. The reasons for why some patients bleed from their angioectasias are not fully understood but it has been reported that it may be explained by an acquired von Willebrand syndrome (AVWS). This condition has similar laboratory findings to congenital von Willebrand disease with selective loss of large von Willebrand multimers. The aim of this study was to find out if AVWS or any other bleeding disorder was more common in patients with bleeding from angioectasias than in a control group. METHODS: We compared bleeding tests and coagulation parameters, including von Willebrand multimers, from a group of 23 patients with anemia caused by bleeding from angioectasias, with the results from a control group lacking angioectasias. RESULTS: No significant differences between the two groups were found in coagulation parameters, bleeding time or von Willebrand multimer levels. CONCLUSION: These results do not support a need for routine bleeding tests in cases of bleeding from angioectasias and do not show an overall increased risk of AVWS among these patients. PMID- 20920210 TI - Salivary gland derived peptides as a new class of anti-inflammatory agents: review of preclinical pharmacology of C-terminal peptides of SMR1 protein. AB - The limitations of steroidal and non steroidal anti-inflammatory drugs have prompted investigation into other biologically based therapeutics, and identification of immune selective anti-inflammatory agents of salivary origin. The traditional view of salivary glands as accessory digestive structures is changing as their importance as sources of systemically active immunoregulatory and anti-inflammatory factors is recognized. Salivary gland involvement in maintenance of whole body homeostasis is regulated by the nervous system and thus constitutes a "neuroendocrine axis". The potent anti-inflammatory activities, both in vivo and in vitro, of the tripeptide Phe-Glu-Gly (FEG) are reviewed. FEG is a carboxyl terminal peptide of the prohormone SMR1 identified in the rat submandibular salivary gland, The D-isomeric form (feG) mimics the activity of its L-isomer FEG. Macropharmacologically, feG attenuates the cardiovascular and inflammatory effects of endotoxemia and anaphylaxis, by inhibition of hypotension, leukocyte migration, vascular leak, and disruption of pulmonary function and intestinal motility. Mechanistically, feG affects activated inflammatory cells, especially neutrophils, by regulating integrins and inhibiting intracellular production of reactive oxygen species. Pharmacodynamically, feG is active at low doses (100 MUg/kg) and has a long (9-12 hour) biological half life. As a therapeutic agent, feG shows promise in diseases characterized by over exuberant inflammatory responses such as systemic inflammatory response syndrome and other acute inflammatory diseases. Arthritis, sepsis, acute pancreatitis, asthma, acute respiratory inflammation, inflammatory bowel disease, and equine laminitis are potential targets for this promising therapeutic peptide. The term "Immune Selective Anti-Inflammatory Derivatives" (ImSAIDs) is proposed for salivary-derived peptides to distinguish this class of agents from corticosteroids and nonsteroidal anti-inflammatory drugs. PMID- 20920211 TI - Whole genome sequencing of enriched chloroplast DNA using the Illumina GAII platform. AB - BACKGROUND: Complete chloroplast genome sequences provide a valuable source of molecular markers for studies in molecular ecology and evolution of plants. To obtain complete genome sequences, recent studies have made use of the polymerase chain reaction to amplify overlapping fragments from conserved gene loci. However, this approach is time consuming and can be more difficult to implement where gene organisation differs among plants. An alternative approach is to first isolate chloroplasts and then use the capacity of high-throughput sequencing to obtain complete genome sequences. We report our findings from studies of the latter approach, which used a simple chloroplast isolation procedure, multiply primed rolling circle amplification of chloroplast DNA, Illumina Genome Analyzer II sequencing, and de novo assembly of paired-end sequence reads. RESULTS: A modified rapid chloroplast isolation protocol was used to obtain plant DNA that was enriched for chloroplast DNA, but nevertheless contained nuclear and mitochondrial DNA. Multiply-primed rolling circle amplification of this mixed template produced sufficient quantities of chloroplast DNA, even when the amount of starting material was small, and improved the template quality for Illumina Genome Analyzer II (hereafter Illumina GAII) sequencing. We demonstrate, using independent samples of karaka (Corynocarpus laevigatus), that there is high fidelity in the sequence obtained from this template. Although less than 20% of our sequenced reads could be mapped to chloroplast genome, it was relatively easy to assemble complete chloroplast genome sequences from the mixture of nuclear, mitochondrial and chloroplast reads. CONCLUSIONS: We report successful whole genome sequencing of chloroplast DNA from karaka, obtained efficiently and with high fidelity. PMID- 20920212 TI - The RAD51 and DMC1 homoeologous genes of bread wheat: cloning, molecular characterization and expression analysis. AB - BACKGROUND: Meiotic recombination in eukaryotes requires two homologues of the E. coli RecA proteins: Rad51 and Dmc1. Both proteins play important roles in the binding of single stranded DNA, homology search, strand invasion and strand exchange. Meiotic recombination has been well studied in Arabidopsis, rice, maize and the orthologues of RAD51 and DMC1 have been characterized. However genetic analysis of the RAD51 and DMC1 genes in bread wheat has been hampered due to the absence of complete sequence information and because of the existence of multiple copies of each gene in the hexaploid wheat genome. FINDINGS: In this study we have identified that TaRAD51 and TaDMC1 homoeologues are located on group 7 and group 5 chromosomes of hexaploid wheat, respectively. Comparative sequence analysis of cDNA derived from the TaRAD51 and TaDMC1 homoeologues revealed limited sequence divergence at both the nucleotide and the amino acid level. Indeed, comparisons between the predicted amino acid sequences of TaRAD51 and TaDMC1 and those of other eukaryotes reveal a high degree of evolutionary conservation. Despite the high degree of sequence conservation at the nucleotide level, genome-specific primers for cDNAs of TaRAD51 and TaDMC1 were developed to evaluate expression patterns of individual homoeologues during meiosis. QRT-PCR analysis showed that expression of the TaRAD51 and TaDMC1 cDNA homoeologues was largely restricted to meiotic tissue, with elevated levels observed during the stages of prophase I when meiotic recombination occurs. All three homoeologues of both strand-exchange proteins (TaRAD51 and TaDMC1) are expressed in wheat. CONCLUSIONS: Bread wheat contains three expressed copies of each of the TaRAD51 and TaDMC1 homoeologues. While differences were detected between the three cDNA homoeologues of TaRAD51 as well as the three homoeologues of TaDMC1, it is unlikely that the predicted amino acid substitutions would have an effect on the protein structure, based on our three-dimensional structure prediction analyses. There are differences in the levels of expression of the three homoeologues of TaRAD51 and TaDMC1 as determined by QRT-PCR and if these differences are reflected at the protein level, bread wheat may be more dependent upon a particular homoeologue to achieve full fertility than all three equally. PMID- 20920214 TI - A novel framework for validating and applying standardized small area measurement strategies. AB - BACKGROUND: Local measurements of health behaviors, diseases, and use of health services are critical inputs into local, state, and national decision-making. Small area measurement methods can deliver more precise and accurate local-level information than direct estimates from surveys or administrative records, where sample sizes are often too small to yield acceptable standard errors. However, small area measurement requires careful validation using approaches other than conventional statistical methods such as in-sample or cross-validation methods because they do not solve the problem of validating estimates in data-sparse domains. METHODS: A new general framework for small area estimation and validation is developed and applied to estimate Type 2 diabetes prevalence in US counties using data from the Behavioral Risk Factor Surveillance System (BRFSS). The framework combines the three conventional approaches to small area measurement: (1) pooling data across time by combining multiple survey years; (2) exploiting spatial correlation by including a spatial component; and (3) utilizing structured relationships between the outcome variable and domain specific covariates to define four increasingly complex model types - coined the Naive, Geospatial, Covariate, and Full models. The validation framework uses direct estimates of prevalence in large domains as the gold standard and compares model estimates against it using (i) all available observations for the large domains and (ii) systematically reduced sample sizes obtained through random sampling with replacement. At each sampling level, the model is rerun repeatedly, and the validity of the model estimates from the four model types is then determined by calculating the (average) concordance correlation coefficient (CCC) and (average) root mean squared error (RMSE) against the gold standard. The CCC is closely related to the intraclass correlation coefficient and can be used when the units are organized in groups and when it is of interest to measure the agreement between units in the same group (e.g., counties). The RMSE is often used to measure the differences between values predicted by a model or an estimator and the actually observed values. It is a useful measure to capture the precision of the model or estimator. RESULTS: All model types have substantially higher CCC and lower RMSE than the direct, single-year BRFSS estimates. In addition, the inclusion of relevant domain-specific covariates generally improves predictive validity, especially at small sample sizes, and their leverage can be equivalent to a five- to tenfold increase in sample size. CONCLUSIONS: Small area estimation of important health outcomes and risk factors can be improved using a systematic modeling and validation framework, which consistently outperformed single-year direct survey estimates and demonstrated the potential leverage of including relevant domain-specific covariates compared to pure measurement models. The proposed validation strategy can be applied to other disease outcomes and risk factors in the US as well as to resource-scarce situations, including low-income countries. These estimates are needed by public health officials to identify at-risk groups, to design targeted prevention and intervention programs, and to monitor and evaluate results over time. PMID- 20920213 TI - Comparison of different sampling techniques and of different culture methods for detection of group B streptococcus carriage in pregnant women. AB - BACKGROUND: Streptococcus agalactiae (group B streptococcus; GBS) is a significant cause of perinatal and neonatal infections worldwide. To detect GBS colonization in pregnant women, the CDC recommends isolation of the bacterium from vaginal and anorectal swab samples by growth in a selective enrichment medium, such as Lim broth (Todd-Hewitt broth supplemented with selective antibiotics), followed by subculture on sheep blood agar. However, this procedure may require 48 h to complete. We compared different sampling and culture techniques for the detection of GBS. METHODS: A total of 300 swabs was taken from 100 pregnant women at 35-37 weeks of gestation. For each subject, one rectovaginal, one vaginal and one rectal ESwab were collected. Plating onto Columbia CNA agar (CNA), group B streptococcus differential agar (GBSDA) (Granada Medium) and chromID Strepto B agar (CA), with and without Lim broth enrichment, were compared. The isolates were confirmed as S. agalactiae using the CAMP test on blood agar and by molecular identification with tDNA-PCR or by 16S rRNA gene sequence determination. RESULTS: The overall GBS colonization rate was 22%. GBS positivity for rectovaginal sampling (100%) was significantly higher than detection on the basis of vaginal sampling (50%), but not significantly higher than for rectal sampling (82%). Direct plating of the rectovaginal swab on CNA, GBSDA and CA resulted in detection of 59, 91 and 95% of the carriers, respectively, whereas subculturing of Lim broth yielded 77, 95 and 100% positivity, respectively. Lim broth enrichment enabled the detection of only one additional GBS positive subject. There was no significant difference between GBSDA and CA, whereas both were more sensitive than CNA. Direct culture onto GBSDA or CA (91 and 95%) detected more carriers than Lim broth enrichment and subculture onto CNA (77%). One false negative isolate was observed on GBSDA, and three false positives on CA. CONCLUSIONS: In conclusion, rectovaginal sampling increased the number GBS positive women detected, compared to vaginal and/or rectal sampling. Direct plating on CA and/or GBSDA provided rapid detection of GBS that was at least as sensitive and specific as the CDC recommended method of Lim broth subcultured onto non chromogenic agar. PMID- 20920215 TI - Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers. AB - Familial hypocholesterolemia, namely abetalipoproteinemia, hypobetalipoproteinemia and chylomicron retention disease (CRD), are rare genetic diseases that cause malnutrition, failure to thrive, growth failure and vitamin E deficiency, as well as other complications. Recently, the gene implicated in CRD was identified. The diagnosis is often delayed because symptoms are nonspecific. Treatment and follow-up remain poorly defined.The aim of this paper is to provide guidelines for the diagnosis, treatment and follow-up of children with CRD based on a literature overview and two pediatric centers 'experience.The diagnosis is based on a history of chronic diarrhea with fat malabsorption and abnormal lipid profile. Upper endoscopy and histology reveal fat-laden enterocytes whereas vitamin E deficiency is invariably present. Creatine kinase (CK) is usually elevated and hepatic steatosis is common. Genotyping identifies the Sar1b gene mutation.Treatment should be aimed at preventing potential complications. Vomiting, diarrhea and abdominal distension improve on a low-long chain fat diet. Failure to thrive is one of the most common initial clinical findings. Neurological and ophthalmologic complications in CRD are less severe than in other types of familial hypocholesterolemia. However, the vitamin E deficiency status plays a pivotal role in preventing neurological complications. Essential fatty acid (EFA) deficiency is especially severe early in life. Recently, increased CK levels and cardiomyopathy have been described in addition to muscular manifestations. Poor mineralization and delayed bone maturation do occur. A moderate degree of macrovesicular steatosis is common, but no cases of steatohepatitis cirrhosis. Besides a low-long chain fat diet made up uniquely of polyunsaturated fatty acids, treatment includes fat-soluble vitamin supplements and large amounts of vitamin E. Despite fat malabsorption and the absence of postprandial chylomicrons, the oral route can prevent neurological complications even though serum levels of vitamin E remain chronically low. Dietary counseling is needed not only to monitor fat intake and improve symptoms, but also to maintain sufficient caloric and EFA intake. Despite a better understanding of the pathogenesis of CRD, the diagnosis and management of the disease remain a challenge for clinicians. The clinical guidelines proposed will helpfully lead to an earlier diagnosis and the prevention of complications. PMID- 20920216 TI - Potential threat of malaria epidemics in a low transmission area, as exemplified by Sao Tome and Principe. AB - BACKGROUND: Plasmodium falciparum is the major cause of malaria infection in the island of Sao Tome, in the Republic of Sao Tome and Principe (STP), with an incidence of 40 - 50% before 2004. Since 2004, through the coordination of the Ministry of Health of STP and their Centro Nacional de Endemias (CNE), an integrated malaria control programme has been intensively deployed on the island of Sao Tome. Malaria morbidity and mortality decreased by 95% after three years of effective intervention. In the low transmission settings, however, malaria seasonal fluctuation can be a potential problem directly related to epidemics if ongoing control measures are interrupted. Studies on a number of associated factors with malaria epidemics and the measures taken to respond to outbreaks are presented. METHODS: The integrated malaria control programme included indoor residual spraying (IRS), long-lasting insecticidal nets (LLINs), intermittent preventive therapy for pregnant women, as well as early diagnosis and prompt treatment with artemisinin-based combination therapy (ACT). Regular implementation of an island-wide IRS programme was carried out yearly in 2004 2007, and enhanced throughout the island in 2009. Malaria incidence and prevalence were estimated based on passive case detection and mass screening, respectively. Slide positivity rates were used for monitoring the beginning of a malaria epidemic or a seasonal peak. RESULTS: A steep decline of ca. 95% of malaria morbidity and mortality was observed between 2004 and 2008 with use of the combined control methods. Malaria incidence was 2.0%, 1.5%, and 3.0% for 2007, 2008, and 2009, respectively. In April 2008, a cross-sectional country-wide surveillance showed malaria prevalence of 3.5%, of which 95% cases were asymptomatic carriers. Only 50% of asymptomatic carriers were cured with ACT treatment, while 90% of the symptomatic patients were cured by ACT treatment as confirmed with a follow up study. Malaria morbidity increased by three-fold during the first half of 2009 as compared to the same period in 2008. Over this period of six months, severe malaria was also noted in all age groups and malaria mortality increased by two-fold in children less than five years old. After an emergency IRS was deployed, with increased use of LLINs, and an active search of asymptomatic carriers was followed and given complete ACT treatment, malaria incidence decreased to less than 1% in the second half of 2009. CONCLUSION: At the initial stage of the integrated malaria control programme, IRS contributed to the visible effect on the rapid reduction of malaria morbidity and mortality, while this programme highlights an urgent demand for the improvement of other measures, particularly promotion of LLINs usage, with close monitoring of asymptomatic carriers and with ACT treatment in malaria transmission hotspots. In addition, both daily reports and a regular active surveillance to prevent malaria outbreaks should be established permanently, so that a fast response to epidemics can be effectively made when necessary. PMID- 20920217 TI - The utility of the Historical Clinical Risk-20 Scale as a predictor of outcomes in decisions to transfer patients from high to lower levels of security--a UK perspective. AB - BACKGROUND: Structured Professional Judgment (SPJ) approaches to violence risk assessment are increasingly being adopted into clinical practice in international forensic settings. The aim of this study was to examine the predictive validity of the Historical Clinical Risk -20 (HCR-20) violence risk assessment scale for outcome following transfers from high to medium security in a United Kingdom setting. METHODS: The sample was predominately male and mentally ill and the majority of cases were detained under the criminal section of the Mental Health Act (1986). The HCR-20 was rated based on detailed case file information on 72 cases transferred from high to medium security. Outcomes were examined, independent of risk score, and cases were classed as "success or failure" based on established criteria. RESULTS: The mean length of follow up was 6 years. The total HCR-20 score was a robust predictor of failure at lower levels of security and return to high security. The Clinical and Risk management items contributed most to predictive accuracy. CONCLUSIONS: Although the HCR-20 was designed as a violence risk prediction tool our findings suggest it has potential utility in decisions to transfer patients from high to lower levels of security. PMID- 20920218 TI - Novel beta-N-acetylglucosaminidases from Vibrio harveyi 650: cloning, expression, enzymatic properties, and subsite identification. AB - BACKGROUND: Since chitin is a highly abundant natural biopolymer, many attempts have been made to convert this insoluble polysaccharide into commercially valuable products using chitinases and beta-N-acetylglucosaminidases (GlcNAcases). We have previously reported the structure and function of chitinase A from Vibrio harveyi 650. This study t reports the identification of two GlcNAcases from the same organism and their detailed functional characterization. RESULTS: The genes encoding two new members of family-20 GlcNAcases were isolated from the genome of V. harveyi 650, cloned and expressed at a high level in E. coli. VhNag1 has a molecular mass of 89 kDa and an optimum pH of 7.5, whereas VhNag2 has a molecular mass of 73 kDa and an optimum pH of 7.0. The recombinant GlcNAcases were found to hydrolyze all the natural substrates, VhNag2 being ten fold more active than VhNag1. Product analysis by TLC and quantitative HPLC suggested that VhNag2 degraded chitooligosaccharides in a sequential manner, its highest activity being with chitotetraose. Kinetic modeling of the enzymic reaction revealed that binding at subsites (-2) and (+4) had unfavorable (positive) binding free energy changes and that the binding pocket of VhNag2 contains four GlcNAc binding subsites, designated (-1),(+1),(+2), and (+3). CONCLUSIONS: Two novel GlcNAcases were identified as exolytic enzymes that degraded chitin oligosaccharides, releasing GlcNAc as the end product. In living cells, these intracellular enzymes may work after endolytic chitinases to complete chitin degradation. The availability of the two GlcNAcases, together with the previously-reported chitinase A from the same organism, suggests that a systematic development of the chitin-degrading enzymes may provide a valuable tool in commercial chitin bioconversion. PMID- 20920219 TI - Maximum growth and survival of estrogen receptor-alpha positive breast cancer cells requires the Sin3A transcriptional repressor. AB - BACKGROUND: Sin3A is an evolutionarily conserved transcriptional repressor which regulates gene expression as part of the multi-protein Sin3 repressive complex. It functions as a scaffold upon which proteins with enzymatic activity dock, including chromatin modifying histone deacetylases. Although regulation of transcription by Sin3A has been studied in detail, little is understood about the function of Sin3A in cancer cells. We previously showed that Sin3A is expressed in breast cancer cells and is a repressor of estrogen receptor-alpha (ERalpha, ESR1) gene expression. Here, we expand our previous studies to elucidate the function of Sin3A in the control of gene expression and growth of breast cancer cells. RESULTS: Analysis of gene expression following knockdown of Sin3A revealed changes in both basal and regulated gene transcription. Genes of known importance in breast cancer and estrogen signaling, including ERBB2, PGR, MYC, CLU, and NCOA2, were among those identified as Sin3A-responsive. The mechanism of Sin3A action varied among genes and was found to be mediated through both HDAC1/2 dependent and -independent activities. Loss of Sin3A inhibited breast cancer cell growth by increasing apoptosis without affecting cell cycle progression. Analysis of both ERalpha-positive and ERalpha-negative cell lines revealed that the effects of Sin3A on growth were cell-type specific, as Sin3A expression promoted maximum growth of only the ERalpha-positive cells, and, notably, Sin3A protein itself was increased by estrogen. Further gene expression experiments revealed that Sin3A repressed expression of key apoptotic genes, including TRAIL, TRAILR1, CASP10, and APAF1, in ERalpha-positive, but not ERalpha-negative, cell lines, which could provide a mechanistic explanation for cell-type differences in growth. CONCLUSIONS: This study identifies Sin3A as a regulator of gene expression, survival, and growth in ERalpha-positive breast cancer cells. Sin3A regulates the transcription of genes involved in breast cancer and apoptosis and acts through multiple mechanisms not limited to histone deacetylase function. These findings reveal previously undescribed functions of Sin3A in breast cancer and provide evidence for an important role of this transcriptional repressor in ERalpha-positive tumor cell growth. PMID- 20920220 TI - An interdisciplinary intervention for older Taiwanese patients after surgery for hip fracture improves health-related quality of life. AB - BACKGROUND: The effects of intervention programs on health-related quality of life (HRQOL) of patients with hip fracture have not been well studied. We hypothesized that older patients with hip fracture who received our interdisciplinary intervention program would have better HRQOL than those who did not. METHODS: A randomized experimental design was used. Older patients with hip fracture (N = 162), 60 to 98 years old, from a medical center in northern Taiwan were randomly assigned to an experimental (n = 80) or control (n = 82) group. HRQOL was measured by the SF-36 Taiwan version at 1, 3, 6, and 12 months after discharge. RESULTS: The experimental group had significantly better overall outcomes in bodily pain (beta = 9.38, p = 0.002), vitality (beta = 9.40, p < 0.001), mental health (beta = 8.16, p = 0.004), physical function (beta = 16.01, p < 0.001), and role physical (beta = 22.66, p < 0.001) than the control group at any time point during the first year after discharge. Physical-related health outcomes (physical functioning, role physical, and vitality) had larger treatment effects than emotional/mental- and social functioning-related health outcomes. CONCLUSIONS: This interdisciplinary intervention program may improve health outcomes of elders with hip fracture. Our results may provide a reference for health care providers in countries using similar programs with Chinese/Taiwanese immigrant populations. TRIAL REGISTRATION: NCT01052636. PMID- 20920221 TI - Japanese experience of hydrogen sulfide: the suicide craze in 2008. AB - Most of hydrogen sulfide poisoning has been reported as industrial accidents in Japan. However, since January 2008, a burgeoning of suicide attempts using homemade hydrogen sulfide gas has become evident. By April 2008, the fad escalated into a chain reaction nationwide. Mortality of the poisoning was very high. There were 220 cases of attempted gas suicides during the period of March 27 to June 15, killing 208. An introduction of new method of making the gas, transmitted through message boards on the internet, was blamed for this "outbreak". The new method entailed mixing bath additive and toilet detergent. The National Police Agency instructed internet providers to remove information that could be harmful. Of the victims of the fad in 2008, several cases were serious enough that family members were involved and died. Paramedics and caregivers were also injured secondarily by the gas. This fad has rapidly spread by internet communication, and can happen anywhere in the world. PMID- 20920222 TI - The role of the bronchial microvasculature in the airway remodelling in asthma and COPD. AB - In recent years, there has been increased interest in the vascular component of airway remodelling in chronic bronchial inflammation, such as asthma and COPD, and in its role in the progression of disease. In particular, the bronchial mucosa in asthmatics is more vascularised, showing a higher number and dimension of vessels and vascular area. Recently, insight has been obtained regarding the pivotal role of vascular endothelial growth factor (VEGF) in promoting vascular remodelling and angiogenesis. Many studies, conducted on biopsies, induced sputum or BAL, have shown the involvement of VEGF and its receptors in the vascular remodelling processes. Presumably, the vascular component of airway remodelling is a complex multi-step phenomenon involving several mediators. Among the common asthma and COPD medications, only inhaled corticosteroids have demonstrated a real ability to reverse all aspects of vascular remodelling. The aim of this review was to analyze the morphological aspects of the vascular component of airway remodelling and the possible mechanisms involved in asthma and COPD. We also focused on the functional and therapeutic implications of the bronchial microvascular changes in asthma and COPD. PMID- 20920225 TI - Statins and clinical outcome of acute ischemic stroke: a systematic review. AB - BACKGROUND: Statin therapy is considered an effective measure for the prevention of ischemic stroke. Several recent studies have indicated that treatment with statins, prior to the onset of acute ischemic stroke, may also substantially reduce the severity of stroke and the degree of patient disability. The purpose of the present review is to systematically evaluate the effectiveness of statin pretreatment on functional outcome of acute ischemic stroke and to assess potential adverse events associated with statin use. METHODS: Relevant articles on the role of statins in acute ischemic stroke were identified via MEDLINE/PubMed, EMBASE, CENTRAL, and by manual searches of the references of identified papers. Clinical studies (most were prospective cohort studies) assessing statin therapy for acute ischemic stroke were selected for the review. Only two randomized controlled clinical trials met the criteria to be included in the analysis. Clinical outcome was assessed based on the degree of disability determined with the modified Rankin Scale (mRS) and Barthel index (BI). The National Institutes of Health Stroke Scale (NIHSS) was used to measure stroke severity. Recurrence of stroke in patients who had suffered from a previous stroke was analyzed with and without statin therapy. Incidence and severity of adverse reactions was reviewed. Because there were too many differences in study outcome measures, a quantitative analysis of data was deemed inappropriate. A qualitative summary of the data was consequently completed. RESULTS: Thirteen reports were systematically reviewed to evaluate the efficacy and safety of statins in the pretreatment of acute ischemic stroke. Pretreatment with statins was found to reduce the recurrence of stroke and to result in more favorable outcomes for patients. The beneficial effects of prior statin therapy in acute ischemic stroke were shown to be especially profound in whites, diabetics, elderly patients with hypertension and other vascular diseases, and in patients with ideal low density lipoprotein (LDL) levels. There were few incidences of adverse reactions with statin pretreatment, most of which were not statistically significant. CONCLUSIONS: Pretreatment with statins was associated with a favorable outcome in acute ischemic stroke, with few incidences of adverse reactions. PMID- 20920224 TI - The effects of background white noise on memory performance in inattentive school children. AB - BACKGROUND: Noise is typically conceived of as being detrimental for cognitive performance; however, a recent computational model based on the concepts of stochastic resonance and dopamine related internal noise postulates that a moderate amount of auditive noise benefit individuals in hypodopaminergic states. On the basis of this model we predicted that inattentive children would be enhanced by adding background white noise while attentive children's performance would deteriorate. METHODS: Fifty-one secondary school pupils carried out an episodic verbal free recall test in two noise conditions. In the high noise condition, verb-noun sentences were presented during auditory background noise (white noise, 78 dB), and in the low noise condition sentences were presented without noise. RESULTS: Exposure to background noise improved performance for inattentive children and worsened performance for attentive children and eliminated episodic memory differences between attentive and inattentive school children. CONCLUSIONS: Consistent with the model, our data show that cognitive performance can be moderated by external background white noise stimulation in a non-clinical group of inattentive participants. This finding needs replicating in a larger sample using more noise levels but if replicated has great practical applications by offering a non-invasive way to improve school results in children with attentional problems. PMID- 20920223 TI - Maternal separation with early weaning: a novel mouse model of early life neglect. AB - BACKGROUND: Childhood adversity is associated with increased risk for mood, anxiety, impulse control, and substance disorders. Although genetic and environmental factors contribute to the development of such disorders, the neurobiological mechanisms involved are poorly understood. A reliable mouse model of early life adversity leading to lasting behavioral changes would facilitate progress in elucidating the molecular mechanisms underlying these adverse effects. Maternal separation is a commonly used model of early life neglect, but has led to inconsistent results in the mouse. RESULTS: In an effort to develop a mouse model of early life neglect with long-lasting behavioral effects in C57BL/6 mice, we designed a new maternal separation paradigm that we call Maternal Separation with Early Weaning (MSEW). We tested the effects of MSEW on C57BL/6 mice as well as the genetically distinct DBA/2 strain and found significant MSEW effects on several behavioral tasks (i.e., the open field, elevated plus maze, and forced swim test) when assessed more than two months following the MSEW procedure. Our findings are consistent with MSEW causing effects within multiple behavioral domains in both strains, and suggest increased anxiety, hyperactivity, and behavioral despair in the MSEW offspring. Analysis of pup weights and metabolic parameters showed no evidence for malnutrition in the MSEW pups. Additionally, strain differences in many of the behavioral tests suggest a role for genetic factors in the response to early life neglect. CONCLUSIONS: These results suggest that MSEW may serve as a useful model to examine the complex behavioral abnormalities often apparent in individuals with histories of early life neglect, and may lead to greater understanding of these later life outcomes and offer insight into novel therapeutic strategies. PMID- 20920226 TI - Metabolic syndrome in Russian adults: associated factors and mortality from cardiovascular diseases and all causes. AB - BACKGROUND: Metabolic syndrome (MetS) is a cluster of four major obesity-related risk factors for cardiovascular disease (CVD). Russia has one of the highest CVD mortality in the world, but its association with MetS remains unknown. Also little is known about factors associated with MetS and its components in Russia. METHODS: Data on 3555 adults aged 18-90 years were collected in a cross-sectional study in 2000. MetS was defined by the International Diabetes Federation (IDF) and National Cholesterol Education Program (NCEP) criteria. Sex-specific associations between the IDF-defined MetS, its components, and life-style, socio economic factors and laboratory indicators, were analysed using multivariable Poisson regression. Vital status of the study participants was identified by July 2009. Sex-specific associations between MetS and stroke, Coronary Heart Disease (CHD), CVD and all-cause death, were studied by Poisson regression adjusted for age, smoking, alcohol and history of CVDs. RESULTS: After adjustment for all studied factors except BMI, age, serum GGT, C-reactive protein and AST-to-ALT ratio were associated with MetS in both genders. Additionally, MetS was associated with sedentary lifestyle in women and with smoking in men. In the same regression model drinking alcohol 2-4 times a month and consumption of five or more alcohol units at one occasion in men, and drinking alcohol 5 times or more a month in women were inversely associated with MetS. After a 9-year follow-up, MetS was associated with higher risk of death from stroke (RR = 3.76, 95% CI:1.35 10.46) and from either stroke or myocardial infarction (MI, RR = 2.87, 95% CI:1.32-6.23) in men. No associations between MetS and any of the studied causes of death were observed in women. CONCLUSION: Factors associated with MetS in both genders were age, GGT, C-reactive protein, and AST-to-ALT ratio. Moderate frequency of alcohol consumption and binge drinking in men and higher leisure time physical activity in women, were inversely associated with MetS.Positive associations between MetS and mortality were only observed for deaths from stroke and either stroke or MI in men. PMID- 20920227 TI - Prognostic value of continuous EEG monitoring during therapeutic hypothermia after cardiac arrest. AB - INTRODUCTION: Continuous EEG (cEEG) is increasingly used to monitor brain function in neuro-ICU patients. However, its value in patients with coma after cardiac arrest (CA), particularly in the setting of therapeutic hypothermia (TH), is only beginning to be elucidated. The aim of this study was to examine whether cEEG performed during TH may predict outcome. METHODS: From April 2009 to April 2010, we prospectively studied 34 consecutive comatose patients treated with TH after CA who were monitored with cEEG, initiated during hypothermia and maintained after rewarming. EEG background reactivity to painful stimulation was tested. We analyzed the association between cEEG findings and neurologic outcome, assessed at 2 months with the Glasgow-Pittsburgh Cerebral Performance Categories (CPC). RESULTS: Continuous EEG recording was started 12 +/- 6 hours after CA and lasted 30 +/- 11 hours. Nonreactive cEEG background (12 of 15 (75%) among nonsurvivors versus none of 19 (0) survivors; P < 0.001) and prolonged discontinuous "burst-suppression" activity (11 of 15 (73%) versus none of 19; P < 0.001) were significantly associated with mortality. EEG seizures with absent background reactivity also differed significantly (seven of 15 (47%) versus none of 12 (0); P = 0.001). In patients with nonreactive background or seizures/epileptiform discharges on cEEG, no improvement was seen after TH. Nonreactive cEEG background during TH had a positive predictive value of 100% (95% confidence interval (CI), 74 to 100%) and a false-positive rate of 0 (95% CI, 0 to 18%) for mortality. All survivors had cEEG background reactivity, and the majority of them (14 (74%) of 19) had a favorable outcome (CPC 1 or 2). CONCLUSIONS: Continuous EEG monitoring showing a nonreactive or discontinuous background during TH is strongly associated with unfavorable outcome in patients with coma after CA. These data warrant larger studies to confirm the value of continuous EEG monitoring in predicting prognosis after CA and TH. PMID- 20920228 TI - Novel venom gene discovery in the platypus. AB - BACKGROUND: To date, few peptides in the complex mixture of platypus venom have been identified and sequenced, in part due to the limited amounts of platypus venom available to study. We have constructed and sequenced a cDNA library from an active platypus venom gland to identify the remaining components. RESULTS: We identified 83 novel putative platypus venom genes from 13 toxin families, which are homologous to known toxins from a wide range of vertebrates (fish, reptiles, insectivores) and invertebrates (spiders, sea anemones, starfish). A number of these are expressed in tissues other than the venom gland, and at least three of these families (those with homology to toxins from distant invertebrates) may play non-toxin roles. Thus, further functional testing is required to confirm venom activity. However, the presence of similar putative toxins in such widely divergent species provides further evidence for the hypothesis that there are certain protein families that are selected preferentially during evolution to become venom peptides. We have also used homology with known proteins to speculate on the contributions of each venom component to the symptoms of platypus envenomation. CONCLUSIONS: This study represents a step towards fully characterizing the first mammal venom transcriptome. We have found similarities between putative platypus toxins and those of a number of unrelated species, providing insight into the evolution of mammalian venom. PMID- 20920229 TI - DNA methylation epigenotypes in breast cancer molecular subtypes. AB - INTRODUCTION: Identification of gene expression based breast cancer subtypes is considered as a critical means of prognostication. Genetic mutations along with epigenetic alterations contribute to gene expression changes occurring in breast cancer. So far, these epigenetic contributions to sporadic breast cancer subtypes have not been well characterized, and there is only a limited understanding of the epigenetic mechanisms affected in those particular breast cancer subtypes. The present study was undertaken to dissect the breast cancer methylome and deliver specific epigenotypes associated with particular breast cancer subtypes. METHODS: Using a microarray approach we analyzed DNA methylation in regulatory regions of 806 cancer related genes in 28 breast cancer paired samples. We subsequently performed substantial technical and biological validation by Pyrosequencing, investigating the top qualifying 19 CpG regions in independent cohorts encompassing 47 basal-like, 44 ERBB2+ overexpressing, 48 luminal A and 48 luminal B paired breast cancer/adjacent tissues. Using all-subset selection method, we identified the most subtype predictive methylation profiles in multivariable logistic regression analysis. RESULTS: The approach efficiently recognized 15 individual CpG loci differentially methylated in breast cancer tumor subtypes. We further identify novel subtype specific epigenotypes which clearly demonstrate the differences in the methylation profiles of basal-like and human epidermal growth factor 2 (HER2)-overexpressing tumors. CONCLUSIONS: Our results provide evidence that well defined DNA methylation profiles enables breast cancer subtype prediction and support the utilization of this biomarker for prognostication and therapeutic stratification of patients with breast cancer. PMID- 20920230 TI - A global optimization algorithm for protein surface alignment. AB - BACKGROUND: A relevant problem in drug design is the comparison and recognition of protein binding sites. Binding sites recognition is generally based on geometry often combined with physico-chemical properties of the site since the conformation, size and chemical composition of the protein surface are all relevant for the interaction with a specific ligand. Several matching strategies have been designed for the recognition of protein-ligand binding sites and of protein-protein interfaces but the problem cannot be considered solved. RESULTS: In this paper we propose a new method for local structural alignment of protein surfaces based on continuous global optimization techniques. Given the three dimensional structures of two proteins, the method finds the isometric transformation (rotation plus translation) that best superimposes active regions of two structures. We draw our inspiration from the well-known Iterative Closest Point (ICP) method for three-dimensional (3D) shapes registration. Our main contribution is in the adoption of a controlled random search as a more efficient global optimization approach along with a new dissimilarity measure. The reported computational experience and comparison show viability of the proposed approach. CONCLUSIONS: Our method performs well to detect similarity in binding sites when this in fact exists. In the future we plan to do a more comprehensive evaluation of the method by considering large datasets of non-redundant proteins and applying a clustering technique to the results of all comparisons to classify binding sites. PMID- 20920231 TI - Diagnostic value of triggering receptor expressed on myeloid cells-1 and C reactive protein for patients with lung infiltrates: an observational study. AB - BACKGROUND: Differential diagnosis of patients with lung infiltrates remains a challenge. Triggering receptor expressed on myeloid cells (TREM)-1 is a neutrophil and monocyte receptor up-regulated during infection. The aim of this study was to evaluate the diagnostic accuracy of TREM-1 and of C-reactive protein (CRP) from patients with lung infiltrates to discern community acquired lung infections. METHODS: 68 patients admitted to a medical ward with acute respiratory illness were enrolled in the study. Neutrophil and monocyte TREM-1 expression were measured by flow cytometry, sTREM-1 by an enzyme immunoassay and C-reactive protein by nephelometry. Clinical pulmonary infection score was recorded. RESULTS: 34 patients were diagnosed with bacterial community acquired pneumonia (group A) and 34 with non-bacterial pulmonary disease (group B). Median serum TREM-1 concentration was 102.09 pg/ml in group A and lower than 15.10 pg/ml (p < 0.0001) in group B. Mean+/-SE neutrophil TREM-1 expression was 4.67 +/- 0.53 MFI in group A and 2.64 +/- 0.25 MFI (p = 0.001) in group B. Monocyte TREM-1 expression was 4.2 +/- 0.42 MFI in group A and 2.64 +/- 0.35 MFI (p = 0.007) in group B and mean+/-SE CRP was 18.03 +/- 2 mg/ml in group A and 7.1 +/- 1.54 mg/ml (p < 0.001) in group B. A cut-off of 19.53 pg/ml of sTREM-1 with sensitivity 82.6% and specificity 63% to discriminate between infectious and non-infectious pulmonary infiltrates was found. sTREM-1 at admission greater than 180 pg/ml was accompanied with unfavourable outcome. CONCLUSION: TREM-1 myeloid expression and sTREM-1 are reliable markers of bacterial infection among patients with pulmonary infiltrates; sTREM-1 is a predictor of final outcome. PMID- 20920232 TI - Perceptions of primary healthcare professionals towards their role in type 2 diabetes mellitus patient education in Brazil. AB - BACKGROUND: The aim of the current study was to analyze the perceptions, knowledge, and practices of primary healthcare professionals in providing patient education to people with type 2 diabetes mellitus. METHODS: A total of 23 health professionals working in primary healthcare units in Belo Horizonte, Minas Gerais State, Brazil, participated in a focus group in order to discuss their patient education practices and the challenges for effective patient education in diabetes self-management. RESULTS: The results were categorized as follows: 1) lack of preparation and technical knowledge among the health professionals on some aspects of diabetes mellitus and the health professionals' patient education practices; 2) work conditions and organization; 3) issues related or attributed to the clientele themselves; and 4) diabetes care model. CONCLUSIONS: This study highlights the importance of reorienting the patient education practices, health professionals' skills and work goals, and evaluation of the educational interventions, in order to establish strategies for health promotion and prevention and control of the disease. DESCRIPTORS: Health Education; Prevention of Diabetes Mellitus; Primary Healthcare. PMID- 20920233 TI - Is there an association between low dose aspirin and anemia (without overt bleeding)? Narrative review. AB - BACKGROUND: Overt bleeding associated with low dose aspirin (LDA) is well recognized, little attention is given to the possibility of association between LDA and occult bleeding, although this is known to occur in healthy volunteers. LDA is used increasingly in primary and secondary prevention of a number of medical conditions, many of which are common in older people, as is anemia. Anemia in older people is associated with adverse outcomes including disability, morbidity and mortality. The purpose of this study was to review the evidence that LDA might cause anemia without overt bleeding. METHODS: An extensive narrative review was carried out. Electronic searching (including database links) and reference lists of reports were used to identify studies reporting on use of aspirin <=325 mg/day and anemia or change in hemoglobin (Hb) without overt bleeding. Data were extracted from reports of trials, adverse drug reactions (ADRs) and prevalence studies of adults aged >=18 years, published since 1980. RESULTS: There are few relevant data, with considerable heterogeneity among trial designs, duration, and patient characteristics in studies of LDA. In five randomised trials (n = 5879) in (mostly secondary) prevention, the majority of patients were men without peptic ulcer disease aged 50-70 years and no consistent association between LDA and change in Hb was found. In two smaller studies (n = 609) of primary prevention in healthy patients aged >=70 years, there was a small but statistically significant fall in Hb with LDA. Observational studies, and data from trials in which use of LDA was not a primary focus of the study, were inconclusive. CONCLUSIONS: It is not clear whether there is an association between LDA and anemia in the absence of overt bleeding, but there may be an association between LDA and fall in Hb in (a subset of) older patients. The available evidence has significant limitations, which are discussed; studies including more older patients, and publication of individual patient data, would help clarify this important matter. PMID- 20920235 TI - Computationally efficient flux variability analysis. AB - BACKGROUND: Flux variability analysis is often used to determine robustness of metabolic models in various simulation conditions. However, its use has been somehow limited by the long computation time compared to other constraint-based modeling methods. RESULTS: We present an open source implementation of flux variability analysis called fastFVA. This efficient implementation makes large scale flux variability analysis feasible and tractable allowing more complex biological questions regarding network flexibility and robustness to be addressed. CONCLUSIONS: Networks involving thousands of biochemical reactions can be analyzed within seconds, greatly expanding the utility of flux variability analysis in systems biology. PMID- 20920234 TI - Epigenetic regulation of CD44 in Hodgkin and non-Hodgkin lymphoma. AB - BACKGROUND: Epigenetic inactivation of tumor suppressor genes (TSG) by promoter CpG island hypermethylation is a hallmark of cancer. To assay its extent in human lymphoma, methylation of 24 TSG was analyzed in lymphoma-derived cell lines as well as in patient samples. METHODS: We screened for TSG methylation using methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) in 40 lymphoma-derived cell lines representing anaplastic large cell lymphoma, Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), Hodgkin lymphoma and mantle cell lymphoma (MCL) as well as in 50 primary lymphoma samples. The methylation status of differentially methylated CD44 was verified by methylation-specific PCR and bisulfite sequencing. Gene expression of CD44 and its reactivation by DNA demethylation was determined by quantitative real-time PCR and on the protein level by flow cytometry. Induction of apoptosis by anti-CD44 antibody was analyzed by annexin-V/PI staining and flow cytometry. RESULTS: On average 8 +/- 2.8 of 24 TSG were methylated per lymphoma cell line and 2.4 +/- 2 of 24 TSG in primary lymphomas, whereas 0/24 TSG were methylated in tonsils and blood mononuclear cells from healthy donors. Notably, we identified that CD44 was hypermethylated and transcriptionally silenced in all BL and most FL and DLBCL cell lines, but was usually unmethylated and expressed in MCL cell lines. Concordant results were obtained from primary lymphoma material: CD44 was not methylated in MCL patients (0/11) whereas CD44 was frequently hypermethylated in BL patients (18/29). In cell lines with CD44 hypermethylation, expression was re-inducible at mRNA and protein levels by treatment with the DNA demethylating agent 5-Aza-2'-deoxycytidine, confirming epigenetic regulation of CD44. CD44 ligation assays with a monoclonal anti-CD44 antibody showed that CD44 can mediate apoptosis in CD44+ lymphoma cells. CD44 hypermethylated, CD44- lymphoma cell lines were consistently resistant towards anti-CD44 induced apoptosis. CONCLUSION: Our data show that CD44 is epigenetically regulated in lymphoma and undergoes de novo methylation in distinct lymphoma subtypes like BL. Thus CD44 may be a promising new epigenetic marker for diagnosis and a potential therapeutic target for the treatment of specific lymphoma subtypes. PMID- 20920236 TI - Efficacy and safety of combined prolonged-release oxycodone and naloxone in the management of moderate/severe chronic non-malignant pain: results of a prospectively designed pooled analysis of two randomised, double-blind clinical trials. AB - BACKGROUND: Two randomised 12-week, double-blind, parallel-group, multicenter studies comparing oxycodone PR/naloxone PR and oxycodone PR alone on symptoms of opioid-induced bowel dysfunction in patients with moderate/severe non-malignant pain have been conducted. METHODS: These studies were prospectively designed to be pooled and the primary outcome measure of the pooled data analysis was to demonstrate non-inferiority in 12-week analgesic efficacy of oxycodone PR/naloxone PR versus oxycodone PR alone. Patients with opioid-induced constipation were switched to oxycodone PR and then randomised to fixed doses of oxycodone PR/naloxone PR (n = 292) or oxycodone PR (n = 295) for 12 weeks (20-80 mg/day). RESULTS: No statistically significant differences in analgesic efficacy were observed for the two treatments (p = 0.3197; non-inferiority p < 0.0001; 95% CI -0.07, 0.23) and there was no statistically significant difference in frequency of analgesic rescue medication use. Improvements in Bowel Function Index score were observed for oxycodone PR/naloxone PR by Week 1 and at every subsequent time point (-15.1; p < 0.0001; 95% CI -17.3, -13.0). AE incidence was similar for both groups (61.0% and 57.3% of patients with oxycodone PR/naloxone PR and oxycodone PR alone, respectively). CONCLUSIONS: Results of this pooled analysis confirm that oxycodone PR/naloxone PR provides effective analgesia and suggest that oxycodone PR/naloxone PR improves bowel function without compromising analgesic efficacy. TRIAL REGISTRATION NUMBERS: ClinicalTrials.gov identifier: NCT00412100 and NCT00412152. PMID- 20920237 TI - PpiD is a player in the network of periplasmic chaperones in Escherichia coli. AB - BACKGROUND: The inner membrane-anchored periplasmic folding factor PpiD is described as a parvulin-like peptidyl prolyl isomerase (PPIase) that assists in the maturation of the major beta-barrel outer membrane proteins (OMPs) of Escherichia coli. More recent work however, calls these findings into question. Here, we re-examined the role of PpiD in the E. coli periplasm by analyzing its functional interplay with other folding factors that influence OMP maturation as well as general protein folding in the periplasmic compartment of the cell, such as SurA, Skp, and DegP. RESULTS: The analysis of the effects of both deletion and overexpression of ppiD on cell envelope phenotypes revealed that PpiD in contrast to prior observations plays only a minor role, if any, in the maturation of OMPs and cannot compensate for the lack of SurA in the periplasm. On the other hand, our results show that overproduction of PpiD rescues a surA skp double mutant from lethality. In the presence of increased PpiD levels surA skp cells show reduced activities of both the SigmaE-dependent and the Cpx envelope stress responses, and contain increased amounts of folded species of the major OMP OmpA. These effects require the anchoring of PpiD in the inner membrane but are independent of its parvulin-like PPIase domain. Moreover, a PpiD protein lacking the PPIase domain also complements the growth defects of an fkpA ppiD surA triple PPIase mutant and exhibits chaperone activity in vitro. In addition, PpiD appears to collaborate with DegP, as deletion of ppiD confers a temperature-dependent conditional synthetic phenotype in a degP mutant. CONCLUSIONS: This study provides first direct evidence that PpiD functions as a chaperone and contributes to the network of periplasmic chaperone activities without being specifically involved in OMP maturation. Consistent with previous work, our data support a model in which the chaperone function of PpiD is used to aid in the early periplasmic folding of many newly translocated proteins. PMID- 20920238 TI - BPDA - a Bayesian peptide detection algorithm for mass spectrometry. AB - BACKGROUND: Mass spectrometry (MS) is an essential analytical tool in proteomics. Many existing algorithms for peptide detection are based on isotope template matching and usually work at different charge states separately, making them ineffective to detect overlapping peptides and low abundance peptides. RESULTS: We present BPDA, a Bayesian approach for peptide detection in data produced by MS instruments with high enough resolution to baseline-resolve isotopic peaks, such as MALDI-TOF and LC-MS. We model the spectra as a mixture of candidate peptide signals, and the model is parameterized by MS physical properties. BPDA is based on a rigorous statistical framework and avoids problems, such as voting and ad hoc thresholding, generally encountered in algorithms based on template matching. It systematically evaluates all possible combinations of possible peptide candidates to interpret a given spectrum, and iteratively finds the best fitting peptide signal in order to minimize the mean squared error of the inferred spectrum to the observed spectrum. In contrast to previous detection methods, BPDA performs deisotoping and deconvolution of mass spectra simultaneously, which enables better identification of weak peptide signals and produces higher sensitivities and more robust results. Unlike template-matching algorithms, BPDA can handle complex data where features overlap. Our experimental results indicate that BPDA performs well on simulated data and real MS data sets, for various resolutions and signal to noise ratios, and compares very favorably with commonly used commercial and open-source software, such as flexAnalysis, OpenMS, and Decon2LS, according to sensitivity and detection accuracy. CONCLUSION: Unlike previous detection methods, which only employ isotopic distributions and work at each single charge state alone, BPDA takes into account the charge state distribution as well, thus lending information to better identify weak peptide signals and produce more robust results. The proposed approach is based on a rigorous statistical framework, which avoids problems generally encountered in algorithms based on template matching. Our experiments indicate that BPDA performs well on both simulated data and real data, and compares very favorably with commonly used commercial and open-source software. The BPDA software can be downloaded from http://gsp.tamu.edu/Publications/supplementary/sun10a/bpda. PMID- 20920239 TI - Two-year changes in quality of life in elderly patients with low-energy hip fractures. A case-control study. AB - BACKGROUND: The long-term effect of hip fracture on health-related quality of life (HRQOL) and global quality of life (GQOL) has not been thoroughly studied in prospective case-control studies. AIMS: a) to explore whether patients with low energy hip fracture regain their pre-fracture levels in HRQOL and GQOL compared with changes in age- and sex-matched controls over a two year period; b) to identify predictors of changes in HRQOL and GQOL after two years. METHODS: We examined 61 patients (mean age = 74 years, SD = 10) and 61 matched controls (mean age = 73 years, SD = 8). The Short Form 36 assessed HRQOL and the Quality of Life Scale assessed GQOL. Paired samples t tests and multiple linear regression analyses were applied. RESULTS: HRQOL decreased significantly between baseline and one-year follow-up in patients with hip fractures, within all the SF-36 domains (p < 0.04), except for social functioning (p = 0.091). There were no significant decreases within the SF-36 domains in the controls. Significantly decreased GQOL scores (p < 0.001) were observed both within patients and within controls between baseline and one-year follow-up. The same pattern persisted between baseline and two-year follow-up, except for the HRQOL domain mental health (p = 0.193). The patients with hip fractures did not regain their HRQOL and GQOL. Worsened physical health after two years was predicted by being a patient with hip fracture (B = -5.8, p < 0.001) and old age (B = -1.0, p = 0.015), while worsened mental health was predicted by co-morbidity (B = -2.2, p = 0.029). No significant predictors of differential changes in GQOL were identified. CONCLUSION: A hip fracture has a long-term impact on HRQOL and is a strong predictor of worsened physical health. Our data emphasize the importance of preventing hip fracture in the elderly to maintain physical health. This knowledge should be included in decision-making and health care plans. PMID- 20920240 TI - How are "teaching the teachers" courses in evidence based medicine evaluated? A systematic review. AB - BACKGROUND: Teaching of evidence-based medicine (EBM) has become widespread in medical education. Teaching the teachers (TTT) courses address the increased teaching demand and the need to improve effectiveness of EBM teaching. We conducted a systematic review of assessment tools for EBM TTT courses. To summarise and appraise existing assessment methods for teaching the teachers courses in EBM by a systematic review. METHODS: We searched PubMed, BioMed, EmBase, Cochrane and Eric databases without language restrictions and included articles that assessed its participants. Study selection and data extraction were conducted independently by two reviewers. RESULTS: Of 1230 potentially relevant studies, five papers met the selection criteria. There were no specific assessment tools for evaluating effectiveness of EBM TTT courses. Some of the material available might be useful in initiating the development of such an assessment tool. CONCLUSION: There is a need for the development of educationally sound assessment tools for teaching the teachers courses in EBM, without which it would be impossible to ascertain if such courses have the desired effect. PMID- 20920241 TI - Multi-centred mixed-methods PEPFAR HIV care & support public health evaluation: study protocol. AB - BACKGROUND: A public health response is essential to meet the multidimensional needs of patients and families affected by HIV disease in sub-Saharan Africa. In order to appraise current provision of HIV care and support in East Africa, and to provide evidence-based direction to future care programming, and Public Health Evaluation was commissioned by the PEPFAR programme of the US Government. METHODS/DESIGN: This paper described the 2-Phase international mixed methods study protocol utilising longitudinal outcome measurement, surveys, patient and family qualitative interviews and focus groups, staff qualitative interviews, health economics and document analysis. Aim 1) To describe the nature and scope of HIV care and support in two African countries, including the types of facilities available, clients seen, and availability of specific components of care [Study Phase 1]. Aim 2) To determine patient health outcomes over time and principle cost drivers [Study Phase 2]. The study objectives are as follows. 1) To undertake a cross-sectional survey of service configuration and activity by sampling 10% of the facilities being funded by PEPFAR to provide HIV care and support in Kenya and Uganda (Phase 1) in order to describe care currently provided, including pharmacy drug reviews to determine availability and supply of essential drugs in HIV management. 2) To conduct patient focus group discussions at each of these (Phase 1) to determine care received. 3) To undertake a longitudinal prospective study of 1200 patients who are newly diagnosed with HIV or patients with HIV who present with a new problem attending PEPFAR care and support services. Data collection includes self-reported quality of life, core palliative outcomes and components of care received (Phase 2). 4) To conduct qualitative interviews with staff, patients and carers in order to explore and understand service issues and care provision in more depth (Phase 2). 5) To undertake document analysis to appraise the clinical care procedures at each facility (Phase 2). 6) To determine principle cost drivers including staff, overhead and laboratory costs (Phase 2). DISCUSSION: This novel mixed methods protocol will permit transparent presentation of subsequent dataset results publication, and offers a substantive model of protocol design to measure and integrate key activities and outcomes that underpin a public health approach to disease management in a low-income setting. PMID- 20920242 TI - Comparative transcriptional profiling of the limbal epithelial crypt demonstrates its putative stem cell niche characteristics. AB - BACKGROUND: The Limbal epithelial crypt (LEC) is a solid cord of cells, approximately 120 microns long. It arises from the undersurface of interpalisade rete ridges of the limbal palisades of Vogt and extends deeper into the limbal stroma parallel or perpendicular to the palisade. There are up to 6 or 7 such LEC, variably distributed along the limbus in each human eye. Morphological and immunohistochemical studies on the limbal epithelial crypt (LEC) have demonstrated the presence of limbal stem cells in this region. The purpose of this microarray study was to characterise the transcriptional profile of the LEC and compare with other ocular surface epithelial regions to support our hypothesis that LEC preferentially harbours stem cells (SC). RESULTS: LEC was found to be enriched for SC related Gene Ontology (GO) terms including those identified in quiescent adult SC, however similar to cornea, limbus had significant GO terms related to proliferating SC, transient amplifying cells (TAC) and differentiated cells (DC). LEC and limbus were metabolically dormant with low protein synthesis and downregulated cell cycling. Cornea had upregulated genes for cell cycling and self renewal such as FZD7, BTG1, CCNG, and STAT3 which were identified from other SC populations. Upregulated gene expression for growth factors, cytokines, WNT, Notch, TGF-Beta pathways involved in cell proliferation and differentiation were noted in cornea. LEC had highest number of expressed sequence tags (ESTs), downregulated and unknown genes, compared to other regions. Genes expressed in LEC such as CDH1, SERPINF1, LEF1, FRZB1, KRT19, SOD2, EGR1 are known to be involved in SC maintenance. Genes of interest, in LEC belonging to the category of cell adhesion molecules, WNT and Notch signalling pathway were validated with real-time PCR and immunofluorescence. CONCLUSIONS: Our transcriptional profiling study identifies the LEC as a preferential site for limbal SC with some characteristics suggesting that it could function as a 'SC niche' supporting quiescent SC. It also strengthens the evidence for the presence of "transient cells" in the corneal epithelium. These cells are immediate progeny of SC with self-renewal capacity and could be responsible for maintaining epithelial turn over in normal healthy conditions of the ocular surface (OS). The limbus has mixed population of differentiated and undifferentiated cells. PMID- 20920243 TI - Prediction of two month modified Rankin Scale with an ordinal prediction model in patients with aneurysmal subarachnoid haemorrhage. AB - BACKGROUND: Aneurysmal subarachnoid haemorrhage (aSAH) is a devastating event with a frequently disabling outcome. Our aim was to develop a prognostic model to predict an ordinal clinical outcome at two months in patients with aSAH. METHODS: We studied patients enrolled in the International Subarachnoid Aneurysm Trial (ISAT), a randomized multicentre trial to compare coiling and clipping in aSAH patients.Several models were explored to estimate a patient's outcome according to the modified Rankin Scale (mRS) at two months after aSAH. Our final model was validated internally with bootstrapping techniques. RESULTS: The study population comprised of 2,128 patients of whom 159 patients died within 2 months (8%). Multivariable proportional odds analysis identified World Federation of Neurosurgical Societies (WFNS) grade as the most important predictor, followed by age, sex, lumen size of the aneurysm, Fisher grade, vasospasm on angiography, and treatment modality. The model discriminated moderately between those with poor and good mRS scores (c statistic = 0.65), with minor optimism according to bootstrap re-sampling (optimism corrected c statistic = 0.64). CONCLUSION: We presented a calibrated and internally validated ordinal prognostic model to predict two month mRS in aSAH patients who survived the early stage up till a treatment decision. Although generalizability of the model is limited due to the selected population in which it was developed, this model could eventually be used to support clinical decision making after external validation. TRIAL REGISTRATION: International Standard Randomised Controlled Trial, Number ISRCTN49866681. PMID- 20920244 TI - Association of an INSIG2 obesity allele with cardiovascular phenotypes is gender and age dependent. AB - BACKGROUND: The INSIG2 gene has been implicated in cholesterol metabolism and a single nucleotide polymorphism (SNP) near INSIG2 has been shown to be associated with obesity. We sought to determine the relationship of the INSIG2 SNP to cardiovascular disease (CVD) related phenotypes. METHODS AND RESULTS: Nine hundred forty six patients undergoing percutaneous coronary intervention (PCI) in wave 5 of the multicenter NHLBI Dynamic Registry were genotyped using RT PCR/TaqMan/allelic discrimination for the rs7566605 SNP near the INSIG2 gene. Clinical variables analyzed include demographics, medical history, and procedural details. The prevalence of peripheral vascular disease (PVD) was significantly higher in older men (>=65 years) who were either homozygous or carriers of the obesity/lipid risk allele ("C") compared to non-carriers (odds ratio 3.4, p = 0.013) using a logistic regression model incorporating history of hypercholesterolemia, history of hypertension, cerebrovascular disease, history of diabetes, and BMI. A similar relationship with cerebrovascular disease was found in older (>65) women (odds ratio 3.4, p = 0.013). The INSIG2 SNP was not associated with BMI, nor with other clinical variables. CONCLUSION: Age and gender may influence the association of the INSIG2 obesity SNP with PVD and cerebrovascular disease in patients with pre-existing CVD. PMID- 20920245 TI - Transformation of metabolism with age and lifestyle in Antarctic seals: a case study of systems biology approach to cross-species microarray experiment. AB - BACKGROUND: The metabolic transformation that changes Weddell seal pups born on land into aquatic animals is not only interesting for the study of general biology, but it also provides a model for the acquired and congenital muscle disorders which are associated with oxygen metabolism in skeletal muscle. However, the analysis of gene expression in seals is hampered by the lack of specific microarrays and the very limited annotation of known Weddell seal (Leptonychotes weddellii) genes. RESULTS: Muscle samples from newborn, juvenile, and adult Weddell seals were collected during an Antarctic expedition. Extracted RNA was hybridized on Affymetrix Human Expression chips. Preliminary studies showed a detectable signal from at least 7000 probe sets present in all samples and replicates. Relative expression levels for these genes was used for further analysis of the biological pathways implicated in the metabolism transformation which occurs in the transition from newborn, to juvenile, to adult seals. Cytoskeletal remodeling, WNT signaling, FAK signaling, hypoxia-induced HIF1 activation, and insulin regulation were identified as being among the most important biological pathways involved in transformation. CONCLUSION: In spite of certain losses in specificity and sensitivity, the cross-species application of gene expression microarrays is capable of solving challenging puzzles in biology. A Systems Biology approach based on gene interaction patterns can compensate adequately for the lack of species-specific genomics information. PMID- 20920246 TI - The core genome of the anaerobic oral pathogenic bacterium Porphyromonas gingivalis. AB - BACKGROUND: The Gram negative anaerobic bacterium Porphyromonas gingivalis has long been recognized as a causative agent of periodontitis. Periodontitis is a chronic infectious disease of the tooth supporting tissues eventually leading to tooth-loss. Capsular polysaccharide (CPS) of P. gingivalis has been shown to be an important virulence determinant. Seven capsular serotypes have been described. Here, we used micro-array based comparative genomic hybridization analysis (CGH) to analyze a representative of each of the capsular serotypes and a non encapsulated strain against the highly virulent and sequenced W83 strain. We defined absent calls using Arabidopsis thaliana negative control probes, with the aim to distinguish between aberrations due to mutations and gene gain/loss. RESULTS: Our analyses allowed us to call aberrant genes, absent genes and divergent regions in each of the test strains. A conserved core P. gingivalis genome was described, which consists of 80% of the analyzed genes from the sequenced W83 strain. The percentage of aberrant genes between the test strains and control strain W83 was 8.2% to 13.7%. Among the aberrant genes many CPS biosynthesis genes were found. Most other virulence related genes could be found in the conserved core genome. Comparing highly virulent strains with less virulent strains indicates that hmuS, a putative CobN/Mg chelatase involved in heme uptake, may be a more relevant virulence determinant than previously expected. Furthermore, the description of the 39 W83-specific genes could give more insight in why this strain is more virulent than others. CONCLUSION: Analyses of the genetic content of the P. gingivalis capsular serotypes allowed the description of a P. gingivalis core genome. The high resolution data from three types of analysis of triplicate hybridization experiments may explain the higher divergence between P. gingivalis strains than previously recognized. PMID- 20920247 TI - Population dynamics of an RNA virus and its defective interfering particles in passage cultures. AB - BACKGROUND: Viruses can fall prey to their defective interfering (DI) particles. When viruses are cultured by serial passage on susceptible host cells, the presence of virus-like DI particles can cause virus populations to rise and fall, reflecting predator-prey interactions between DI and virus particles. The levels of virus and DI particles in each population passage can be determined experimentally by plaque and yield-reduction assays, respectively. RESULTS: To better understand DI and virus particle interactions we measured vesicular stomatitis virus and DI particle production during serial-passage culture on BHK cells. When the multiplicity of infection (MOI, or ratio of infectious virus particles to cells) was fixed, virus yields followed a pattern of progressive decline, with higher MOI driving earlier and faster drops in virus level. These patterns of virus decline were consistent with predictions from a mathematical model based on single-passage behavior of cells co-infected with virus and DI particles. By contrast, the production of virus during fixed-volume passages exhibited irregular fluctuations that could not be described by either the steady state or regular oscillatory dynamics of the model. However, these irregularities were, to a significant degree, reproduced when measured host-cell levels were incorporated into the model, revealing a high sensitivity of virus and DI particle populations to fluctuations in available cell resources. CONCLUSIONS: This study shows how the development of mathematical models, when guided by quantitative experiments, can provide new insight into the dynamic behavior of virus populations. PMID- 20920248 TI - Computational analysis of LexA regulons in Cyanobacteria. AB - BACKGROUND: The transcription factor LexA plays an important role in the SOS response in Escherichia coli and many other bacterial species studied. Although the lexA gene is encoded in almost every bacterial group with a wide range of evolutionary distances, its precise functions in each group/species are largely unknown. More recently, it has been shown that lexA genes in two cyanobacterial genomes Nostoc sp. PCC 7120 and Synechocystis sp. PCC 6803 might have distinct functions other than the regulation of the SOS response. To gain a general understanding of the functions of LexA and its evolution in cyanobacteria, we conducted the current study. RESULTS: Our analysis indicates that six of 33 sequenced cyanobacterial genomes do not harbor a lexA gene although they all encode the key SOS response genes, suggesting that LexA is not an indispensable transcription factor in these cyanobacteria, and that their SOS responses might be regulated by different mechanisms. Our phylogenetic analysis suggests that lexA was lost during the course of evolution in these six cyanobacterial genomes. For the 26 cyanobacterial genomes that encode a lexA gene, we have predicted their LexA-binding sites and regulons using an efficient binding site/regulon prediction algorithm that we developed previously. Our results show that LexA in most of these 26 genomes might still function as the transcriptional regulator of the SOS response genes as seen in E. coli and other organisms. Interestingly, putative LexA-binding sites were also found in some genomes for some key genes involved in a variety of other biological processes including photosynthesis, drug resistance, etc., suggesting that there is crosstalk between the SOS response and these biological processes. In particular, LexA in both Synechocystis sp. PCC6803 and Gloeobacter violaceus PCC7421 has largely diverged from those in other cyanobacteria in the sequence level. It is likely that LexA is no longer a regulator of the SOS response in Synechocystis sp. PCC6803. CONCLUSIONS: In most cyanobacterial genomes that we analyzed, LexA appears to function as the transcriptional regulator of the key SOS response genes. There are possible couplings between the SOS response and other biological processes. In some cyanobacteria, LexA has adapted distinct functions, and might no longer be a regulator of the SOS response system. In some other cyanobacteria, lexA appears to have been lost during the course of evolution. The loss of lexA in these genomes might lead to the degradation of its binding sites. PMID- 20920249 TI - Polo-like kinase 4: the odd one out of the family. AB - Polo-like kinase 4 (PLK4) is a unique member of the Polo-like family of kinases that shares little homology with its siblings and has an essential role in centriole duplication. The turn-over of this kinase must be strictly controlled to prevent centriole amplification. This is achieved, in part, by an autoregulatory mechanism, whereby PLK4 autophosphorylates residues in a PEST sequence located carboxy-terminal to its catalytic domain. Phosphorylated PLK4 is subsequently recognized by the SCF complex, ubiquitinylated and targeted to the proteasome for degradation. Recent data have also shown that active PLK4 is restricted to the centrosome, a mechanism that could serve to prevent aberrant centriole assembly elsewhere in the cell. While significant advances have been made in understanding how PLK4 is regulated it is certain that additional regulatory mechanisms exist to safeguard the fidelity of centriole duplication. Here, we overview past and present data discussing the regulation and functions of PLK4. PMID- 20920251 TI - Frequent epigenetic inactivation of RASSF2 in thyroid cancer and functional consequences. AB - BACKGROUND: The Ras association domain family (RASSF) encodes for distinct tumor suppressors and several members are frequently silenced in human cancer. In our study, we analyzed the role of RASSF2, RASSF3, RASSF4, RASSF5A, RASSF5C and RASSF6 and the effectors MST1, MST2 and WW45 in thyroid carcinogenesis. RESULTS: Frequent methylation of the RASSF2 and RASSF5A CpG island promoters in thyroid tumors was observed. RASSF2 was methylated in 88% of thyroid cancer cell lines and in 63% of primary thyroid carcinomas. RASSF2 methylation was significantly increased in primary thyroid carcinoma compared to normal thyroid, goiter and follicular adenoma (0%, 17% and 0%, respectively; p < 0.05). Patients which were older than 60 years were significantly hypermethylated for RASSF2 in their primary thyroid tumors compared to those younger than 40 years (90% vs. 38%; p < 0.05). RASSF2 promoter hypermethylation correlated with its reduced expression and treatment with a DNA methylation inhibitor reactivated RASSF2 transcription. Over-expression of RASSF2 reduced colony formation of thyroid cancer cells. Functionally our data show that RASSF2 interacts with the proapoptotic kinases MST1 and MST2 and induces apoptosis in thyroid cancer cell lines. Deletion of the MST interaction domain of RASSF2 reduced apoptosis significantly (p < 0.05). CONCLUSION: These results suggest that RASSF2 encodes a novel epigenetically inactivated candidate tumor suppressor gene in thyroid carcinogenesis. PMID- 20920252 TI - A survey of variable selection methods in two Chinese epidemiology journals. AB - BACKGROUND: Although much has been written on developing better procedures for variable selection, there is little research on how it is practiced in actual studies. This review surveys the variable selection methods reported in two high ranking Chinese epidemiology journals. METHODS: Articles published in 2004, 2006, and 2008 in the Chinese Journal of Epidemiology and the Chinese Journal of Preventive Medicine were reviewed. Five categories of methods were identified whereby variables were selected using: A--bivariate analyses; B--multivariable analysis; e.g. stepwise or individual significance testing of model coefficients; C--first bivariate analyses, followed by multivariable analysis; D--bivariate analyses or multivariable analysis; and E--other criteria like prior knowledge or personal judgment. RESULTS: Among the 287 articles that reported using variable selection methods, 6%, 26%, 30%, 21%, and 17% were in categories A through E, respectively. One hundred sixty-three studies selected variables using bivariate analyses, 80% (130/163) via multiple significance testing at the 5% alpha-level. Of the 219 multivariable analyses, 97 (44%) used stepwise procedures, 89 (41%) tested individual regression coefficients, but 33 (15%) did not mention how variables were selected. Sixty percent (58/97) of the stepwise routines also did not specify the algorithm and/or significance levels. CONCLUSIONS: The variable selection methods reported in the two journals were limited in variety, and details were often missing. Many studies still relied on problematic techniques like stepwise procedures and/or multiple testing of bivariate associations at the 0.05 alpha-level. These deficiencies should be rectified to safeguard the scientific validity of articles published in Chinese epidemiology journals. PMID- 20920250 TI - Multi-species integrative biclustering. AB - We describe an algorithm, multi-species cMonkey, for the simultaneous biclustering of heterogeneous multiple-species data collections and apply the algorithm to a group of bacteria containing Bacillus subtilis, Bacillus anthracis, and Listeria monocytogenes. The algorithm reveals evolutionary insights into the surprisingly high degree of conservation of regulatory modules across these three species and allows data and insights from well-studied organisms to complement the analysis of related but less well studied organisms. PMID- 20920253 TI - Transcriptome analysis of various flower and silique development stages indicates a set of class III peroxidase genes potentially involved in pod shattering in Arabidopsis thaliana. AB - BACKGROUND: Plant class III peroxidases exist as a large multigenic family involved in numerous functions suggesting a functional specialization of each gene. However, few genes have been linked with a specific function. Consequently total peroxidase activity is still used in numerous studies although its relevance is questionable. Transcriptome analysis seems to be a promising tool to overcome the difficulties associated with the study of this family. Nevertheless available microarrays are not completely reliable for this purpose. We therefore used a macroarray dedicated to the 73 class III peroxidase genes of A. thaliana to identify genes potentially involved in flower and fruit development. RESULTS: The observed increase of total peroxidase activity during development was actually correlated with the induction of only a few class III peroxidase genes which supports the existence of a functional specialization of these proteins. We identified peroxidase genes that are predominantly expressed in one development stage and are probable components of the complex gene networks involved in the reproductive phase. An attempt has been made to gain insight into plausible functions of these genes by collecting and analyzing the expression data of different studies in plants. Peroxidase activity was additionally observed in situ in the silique dehiscence zone known to be involved in pod shattering. Because treatment with a peroxidase inhibitor delayed pod shattering, we subsequently studied mutants of transcription factors (TF) controlling this mechanism. Three peroxidases genes -AtPrx13, AtPrx30 and AtPrx55- were altered by the TFs involved in pod shatter. CONCLUSIONS: Our data illustrated the problems caused by linking only an increase in total peroxidase activity to any specific development stage or function. The activity or involvement of specific class III peroxidase genes needs to be assessed. Several genes identified in our study had not been linked to any particular development stage or function until now. Notably AtPrx13, which is one of the peroxidase genes not present on commercially available microarrays. A systematic survey of class III peroxidase genes expression is necessary to reveal specific class III peroxidase gene functions and the regulation and evolution of this key multifunctional enzyme family. The approach used in this study highlights key individual genes that merit further investigation. PMID- 20920254 TI - A prevalent mutation with founder effect in Spanish Recessive Dystrophic Epidermolysis Bullosa families. AB - BACKGROUND: Recessive Dystrophic Epidermolysis Bullosa (RDEB) is a genodermatosis caused by more than 500 different mutations in the COL7A1 gene and characterized by blistering of the skin following a minimal friction or mechanical trauma.The identification of a cluster of RDEB pedigrees carrying the c.6527insC mutation in a specific area raises the question of the origin of this mutation from a common ancestor or as a result of a hotspot mutation. The aim of this study was to investigate the origin of the c.6527insC mutation. METHODS: Haplotypes were constructed by genotyping nine single nucleotides polymorphisms (SNPs) throughout the COL7A1 gene. Haplotypes were determined in RDEB patients and control samples, both of Spanish origin. RESULTS: Sixteen different haplotypes were identified in our study. A single haplotype cosegregated with the c.6527insC mutation. CONCLUSION: Haplotype analysis showed that all alleles carrying the c.6527insC mutation shared the same haplotype cosegregating with this mutation (CCGCTCAAA_6527insC), thus suggesting the presence of a common ancestor. PMID- 20920255 TI - Reduced levels of SCD1 accentuate palmitate-induced stress in insulin-producing beta-cells. AB - BACKGROUND: Stearoyl-CoA desaturase 1 (SCD1) is an ER resident enzyme introducing a double-bond in saturated fatty acids. Global knockout of SCD1 in mouse increases fatty acid oxidation and insulin sensitivity which makes the animal resistant to diet-induced obesity. Inhibition of SCD1 has therefore been proposed as a potential therapy of the metabolic syndrome. Much of the work has focused on insulin target tissue and very little is known about how reduced levels of SCD1 would affect the insulin-producing beta-cell, however. The aim of the present study was therefore to investigate how reduced levels of SCD1 affect the beta cell. RESULTS: Insulin-secreting MIN6 cells with reduced levels of SCD1 were established by siRNA mediated knockdown. When fatty acid oxidation was measured, no difference between cells with reduced levels of SCD1 and mock-transfected cells were found. Also, reducing levels of SCD1 did not affect insulin secretion in response to glucose. To investigate how SCD1 knockdown affected cellular mechanisms, differentially regulated proteins were identified by a proteomic approach. Cells with reduced levels of SCD1 had higher levels of ER chaperones and components of the proteasome. The higher amounts did not protect the beta cell from palmitate-induced ER stress and apoptosis. Instead, rise in levels of p eIF2alpha and CHOP after palmitate exposure was 2-fold higher in cells with reduced levels of SCD1 compared to mock-transfected cells. Accordingly, apoptosis rose to higher levels after exposure to palmitate in cells with reduced levels of SCD1 compared to mock-transfected cells. CONCLUSIONS: In conclusion, reduced levels of SCD1 augment palmitate-induced ER stress and apoptosis in the beta cell, which is an important caveat when considering targeting this enzyme as a treatment of the metabolic syndrome. PMID- 20920256 TI - A novel spliced fusion of MLL with CT45A2 in a pediatric biphenotypic acute leukemia. AB - BACKGROUND: Abnormalities of 11q23 involving the MLL gene are found in approximately 10% of human leukemias. To date, nearly 100 different chromosome bands have been described in rearrangements involving 11q23 and 64 fusion genes have been cloned and characterized at the molecular level. In this work we present the identification of a novel MLL fusion partner in a pediatric patient with de novo biphenotypic acute leukemia. METHODS: Cytogenetics, fluorescence in situ hybridization (FISH), molecular studies (RT-PCR and LDI-PCR), and bioinformatic sequence analysis were used to characterize the CT45A2 gene as novel MLL fusion partner in pediatric acute leukemia. RESULTS: Fluorescence in situ hybridization of bone marrow G-banded metaphases demonstrated a cryptic insertion of 11q23 in Xq26.3 involving the MLL gene. Breakpoint fusion analysis revealed that a DNA fragment of 653 kb from 11q23, containing MLL exons 1-9 in addition to 16 other 11q23 genes, was inserted into the upstream region of the CT45A2 gene located at Xq26.3. In addition, a deletion at Xq26.3 encompassing the 3' region of the DDX26B gene (exons 9-16) and the entire CT45A1 gene was identified. RNA analysis revealed the presence of a novel MLL-CT45A2 fusion transcript in which the first 9 exons of the MLL gene were fused in-frame to exon 2 of the CT45A2 gene, resulting in a spliced MLL fusion transcript with an intact open reading frame. The resulting chimeric transcript predicts a fusion protein where the N-terminus of MLL is fused to the entire open reading frame of CT45A2. Finally, we demonstrate that all breakpoint regions are rich in long repetitive motifs, namely LINE/L1 and SINE/Alu sequences, but all breakpoints were exclusively identified outside these repetitive DNA sequences. CONCLUSION: We have identified CT45A2 as a novel spliced MLL fusion partner in a pediatric patient with de novo biphenotypic acute leukemia, as a result of a cryptic insertion of 11q23 in Xq26.3. Since CT45A2 is the first Cancer/Testis antigen family gene found fused with MLL in acute leukemia, future studies addressing its biologic relevance for leukemogenesis are warranted. PMID- 20920257 TI - Combination of measures distinguishes pre-miRNAs from other stem-loops in the genome of the newly sequenced Anopheles darlingi. AB - BACKGROUND: Efforts using computational algorithms towards the enumeration of the full set of miRNAs of an organism have been limited by strong reliance on arguments of precursor conservation and feature similarity. However, miRNA precursors may arise anew or be lost across the evolutionary history of a species and a newly sequenced genome may be evolutionarily too distant from other genomes for an adequate comparative analysis. In addition, the learning of intricate classification rules based purely on features shared by miRNA precursors that are currently known may reflect a perpetuating identification bias rather than a sound means to tell true miRNAs from other genomic stem-loops. RESULTS: We show that there is a strong bias amongst annotated pre-miRNAs towards robust stem loops in the genomes of Drosophila melanogaster and Anopheles gambiae and we propose a scoring scheme for precursor candidates which combines four robustness measures. Additionally, we identify several known pre-miRNA homologs in the newly sequenced Anopheles darlingi and show that most are found amongst the top-scoring precursor candidates. Furthermore, a comparison of the performance of our approach is made against two single-genome pre-miRNA classification methods. CONCLUSIONS: In this paper we present a strategy to sieve through the vast amount of stem-loops found in metazoan genomes in search of pre-miRNAs, significantly reducing the set of candidates while retaining most known miRNA precursors. This approach makes no use of conservation data and relies solely on properties derived from our knowledge of miRNA biogenesis. PMID- 20920258 TI - Acro-cardio-facial syndrome. AB - Acro-cardio-facial syndrome (ACFS) is a rare genetic disorder characterized by split-hand/split-foot malformation (SHFM), facial anomalies, cleft lip/palate, congenital heart defect (CHD), genital anomalies, and mental retardation. Up to now, 9 patients have been described, and most of the reported cases were not surviving the first days or months of age. The spectrum of defects occurring in ACFS is wide, and both interindividual variability and clinical differences among sibs have been reported. The diagnosis is based on clinical criteria, since the genetic mechanism underlying ACFS is still unknown. The differential diagnosis includes other disorders with ectrodactyly, and clefting conditions associated with genital anomalies and heart defects. An autosomal recessive pattern of inheritance has been suggested, based on parental consanguinity and disease's recurrence in sibs in some families. The more appropriate recurrence risk of transmitting the disease for the parents of an affected child seems to be up to one in four. Management of affected patients includes treatment of cardiac, respiratory, and feeding problems by neonatal pediatricians and other specialists. Prognosis of ACFS is poor. PMID- 20920259 TI - Cell-specific occupancy of an extended repertoire of CREM and CREB binding loci in male germ cells. AB - BACKGROUND: CREB and CREM are closely related factors that regulate transcription in response to various stress, metabolic and developmental signals. The CREMtau activator isoform is selectively expressed in haploid spermatids and plays an essential role in murine spermiogenesis. RESULTS: We have used chromatin immunoprecipitation coupled to sequencing (ChIP-seq) to map CREM and CREB target loci in round spermatids from adult mouse testis and spermatogonia derived GC1 spg cells respectively. We identify more than 9000 genomic loci most of which are cell-specifically occupied. Despite the fact that round spermatids correspond to a highly specialised differentiated state, our results show that they have a remarkably accessible chromatin environment as CREM occupies more than 6700 target loci corresponding not only to the promoters of genes selectively expressed in spermiogenesis, but also of genes involved in functions specific to other cell types. The expression of only a small subset of these target genes are affected in the round spermatids of CREM knockout animals. We also identify a set of intergenic binding loci some of which are associated with H3K4 trimethylation and elongating RNA polymerase II suggesting the existence of novel CREB and CREM regulated transcripts. CONCLUSIONS: We demonstrate that CREM and CREB occupy a large number of promoters in highly cell specific manner. This is the first study of CREM target promoters directly in a physiologically relevant tissue in vivo and represents the most comprehensive experimental analysis of CREB/CREM regulatory potential to date. PMID- 20920260 TI - Non-coding RNA detection methods combined to improve usability, reproducibility and precision. AB - BACKGROUND: Non-coding RNAs gain more attention as their diverse roles in many cellular processes are discovered. At the same time, the need for efficient computational prediction of ncRNAs increases with the pace of sequencing technology. Existing tools are based on various approaches and techniques, but none of them provides a reliable ncRNA detector yet. Consequently, a natural approach is to combine existing tools. Due to a lack of standard input and output formats combination and comparison of existing tools is difficult. Also, for genomic scans they often need to be incorporated in detection workflows using custom scripts, which decreases transparency and reproducibility. RESULTS: We developed a Java-based framework to integrate existing tools and methods for ncRNA detection. This framework enables users to construct transparent detection workflows and to combine and compare different methods efficiently. We demonstrate the effectiveness of combining detection methods in case studies with the small genomes of Escherichia coli, Listeria monocytogenes and Streptococcus pyogenes. With the combined method, we gained 10% to 20% precision for sensitivities from 30% to 80%. Further, we investigated Streptococcus pyogenes for novel ncRNAs. Using multiple methods--integrated by our framework--we determined four highly probable candidates. We verified all four candidates experimentally using RT-PCR. CONCLUSIONS: We have created an extensible framework for practical, transparent and reproducible combination and comparison of ncRNA detection methods. We have proven the effectiveness of this approach in tests and by guiding experiments to find new ncRNAs. The software is freely available under the GNU General Public License (GPL), version 3 at http://www.sbi.uni rostock.de/moses along with source code, screen shots, examples and tutorial material. PMID- 20920262 TI - Reference values for lysosomal enzymes activities using dried blood spots samples - a Brazilian experience. AB - BACKGROUND: Lysosomal storage diseases (LSD) are inherited disorders caused by deficiency of lysosomal enzymes in which early diagnosis is essential to provide timely treatment. This study reports interval values for the activity of lysosomal enzymes that are deficient in Mucopolysaccharidosis type I, Fabry, Gaucher and Pompe disease, using dried blood spots on filter paper (DBS) samples in a Brazilian population. RESULTS: Reference activity values were obtained from healthy volunteers samples for alpha-galactosidase A (4.57 +/- 1.37 umol/L/h), beta-glucosidase (3.06 +/- 0.99 umol/L/h), alpha-glucosidase (ratio: 13.19 +/- 4.26; % inhibition: 70.66 +/- 7.60), alpha-iduronidase (3.45 +/- 1.21 umol/L/h) and beta-galactosidase (14.09 +/- 4.36 umol/L/h). CONCLUSION: Reference values of five lysosomal enzymes were determined for a Brazilian population sample. However, as our results differ from other laboratories, it highlights the importance of establishing specific reference values for each center. PMID- 20920261 TI - Design of the xylitol for adult caries trial (X-ACT). AB - BACKGROUND: Dental caries incidence in adults is similar to that in children and adolescents, but few caries preventive agents have been evaluated for effectiveness in adults populations. In addition, dentists direct fewer preventive services to their adult patients. Xylitol, an over-the-counter sweetener, has shown some potential as a caries preventive agent, but the evidence for its effectiveness is not yet conclusive and is based largely on studies in child populations. METHODS/DESIGN: X-ACT is a three-year, multi center, placebo controlled, double-blind, randomized clinical trial that tests the effects of daily use of xylitol lozenges versus placebo lozenges on the prevention of adult caries. The trial has randomized 691 participants (ages 21 80) to the two arms. The primary outcome is the increment of cavitated lesions. DISCUSSION: This trial should help resolve the overall issue of the effectiveness of xylitol in preventing caries by contributing evidence with a low risk of bias. Just as importantly, the trial will provide much-needed information about the effectiveness of a promising caries prevention agent in adults. An effective xylitol-based caries prevention intervention would represent an easily disseminated method to extend caries prevention to individuals not receiving caries preventive treatment in the dental office. TRIAL REGISTRATION: ClinicalTrials.Gov NCT00393055. PMID- 20920263 TI - Graduates from a reformed undergraduate medical curriculum based on Tomorrow's Doctors evaluate the effectiveness of their curriculum 6 years after graduation through interviews. AB - BACKGROUND: In 1996 Liverpool reformed its medical curriculum from a traditional lecture based course to a curriculum based on the recommendations in Tomorrow's Doctors. A project has been underway since 2000 to evaluate this change. This paper focuses on the views of graduates from that reformed curriculum 6 years after they had graduated. METHODS: Between 2007 and 2009 45 interviews took place with doctors from the first two cohorts to graduate from the reformed curriculum. RESULTS: The interviewees felt like they had been clinically well prepared to work as doctors and in particular had graduated with good clinical and communication skills and had a good knowledge of what the role of doctor entailed. They also felt they had good self directed learning and research skills. They did feel their basic science knowledge level was weaker than traditional graduates and perceived they had to work harder to pass postgraduate exams. Whilst many had enjoyed the curriculum and in particular the clinical skills resource centre and the clinical exposure of the final year including the "shadowing" and A & E attachment they would have liked more "structure" alongside the PBL when learning the basic sciences. CONCLUSION: According to the graduates themselves many of the aims of curriculum reform have been met by the reformed curriculum and they were well prepared clinically to work as doctors. However, further reforms may be needed to give confidence to science knowledge acquisition. PMID- 20920264 TI - The structural and content aspects of abstracts versus bodies of full text journal articles are different. AB - BACKGROUND: An increase in work on the full text of journal articles and the growth of PubMedCentral have the opportunity to create a major paradigm shift in how biomedical text mining is done. However, until now there has been no comprehensive characterization of how the bodies of full text journal articles differ from the abstracts that until now have been the subject of most biomedical text mining research. RESULTS: We examined the structural and linguistic aspects of abstracts and bodies of full text articles, the performance of text mining tools on both, and the distribution of a variety of semantic classes of named entities between them. We found marked structural differences, with longer sentences in the article bodies and much heavier use of parenthesized material in the bodies than in the abstracts. We found content differences with respect to linguistic features. Three out of four of the linguistic features that we examined were statistically significantly differently distributed between the two genres. We also found content differences with respect to the distribution of semantic features. There were significantly different densities per thousand words for three out of four semantic classes, and clear differences in the extent to which they appeared in the two genres. With respect to the performance of text mining tools, we found that a mutation finder performed equally well in both genres, but that a wide variety of gene mention systems performed much worse on article bodies than they did on abstracts. POS tagging was also more accurate in abstracts than in article bodies. CONCLUSIONS: Aspects of structure and content differ markedly between article abstracts and article bodies. A number of these differences may pose problems as the text mining field moves more into the area of processing full-text articles. However, these differences also present a number of opportunities for the extraction of data types, particularly that found in parenthesized text, that is present in article bodies but not in article abstracts. PMID- 20920265 TI - Recruitment and retention of women in a large randomized control trial to reduce repeat preterm births: the Philadelphia Collaborative Preterm Prevention Project. AB - BACKGROUND: Recruitment and retention of patients for randomized control trial (RCT) studies can provide formidable challenges, particularly with minority and underserved populations. Data are reported for the Philadelphia Collaborative Preterm Prevention Project (PCPPP), a large RCT targeting risk factors for repeat preterm births among women who previously delivered premature (< 35 weeks gestation) infants. METHODS: Design of the PCPPP incorporated strategies to maximize recruitment and retention. These included an advanced database system tracking follow-up status and assessment completion rates; cultural sensitivity training for staff; communication to the community and eligible women of the benefits of participation; financial incentives; assistance with transportation and supervised childcare services; and reminder calls for convenient, flexibly scheduled appointments. Analyses reported here: 1) compare recruitment projections to actual enrollment 2) explore recruitment bias; 3) validate the randomization process 4) document the extent to which contact was maintained and complete assessments achieved 5) determine if follow-up was conditioned upon socio-economic status, race/ethnicity, or other factors. RESULTS: Of eligible women approached, 1,126 (77.7%) agreed to participate fully. Of the 324 not agreeing, 118 (36.4%) completed a short survey. Consenting women were disproportionately from minority and low SES backgrounds: 71.5% consenting were African American, versus 38.8% not consenting. Consenting women were also more likely to report homelessness during their lifetime (14.6% vs. 0.87%) and to be unmarried at the time of delivery (81.6% versus 47.9%). First one-month postpartum assessment was completed for 83.5% (n = 472) of the intervention group (n = 565) and 76% (426) of the control group. Higher assessment completion rates were observed for the intervention group throughout the follow-up. Second, third, fourth and fifth postpartum assessments were 67.6% vs. 57.5%, 60.0% vs. 48.9%, 54.2% vs. 46.3% and 47.3% vs. 40.8%, for the intervention and control group women, respectively. There were no differences in follow-up rates according to race/ethnicity, SES or other factors. Greater retention of the intervention group may reflect the highly-valued nature of the medical and behavior services constituting the intervention arms of the Project. CONCLUSION: Findings challenge beliefs that low income and minority women are averse to enrolling and continuing in clinical trials or community studies. PMID- 20920267 TI - Population uptake of antiretroviral treatment through primary care in rural South Africa. AB - BACKGROUND: KwaZulu-Natal is the South African province worst affected by HIV and the focus of early modeling studies investigating strategies of antiretroviral treatment (ART) delivery. The reality of antiretroviral roll-out through primary care has differed from that anticipated and real world data are needed to inform the planning of further scaling up of services. We investigated the factors associated with uptake of antiretroviral treatment through a primary healthcare system in rural South Africa. METHODS: Detailed demographic, HIV surveillance and geographic information system (GIS) data were used to estimate the proportion of HIV positive adults accessing antiretroviral treatment within northern KwaZulu Natal, South Africa in the period from initiation of antiretroviral roll-out until the end of 2008. Demographic, spatial and socioeconomic factors influencing the likelihood of individuals accessing antiretroviral treatment were explored using multivariable analysis. RESULTS: Mean uptake of ART among HIV positive resident adults was 21.0% (95%CI 20.1-21.9). Uptake among HIV positive men (19.2%) was slightly lower than women (21.8%, P = 0.011). An individual's likelihood of accessing ART was not associated with level of education, household assets or urban/rural locale. ART uptake was strongly negatively associated with distance from the nearest primary healthcare facility (aOR = 0.728 per square root transformed km, 95%CI 0.658-0.963, P = 0.002). CONCLUSIONS: Despite concerns about the equitable nature of antiretroviral treatment rollout, we find very few differences in ART uptake across a range of socio-demographic variables in a rural South African population. However, even when socio-demographic factors were taken into account, individuals living further away from primary healthcare clinics were still significantly less likely to be accessing ART. PMID- 20920266 TI - Premature terminator analysis sheds light on a hidden world of bacterial transcriptional attenuation. AB - BACKGROUND: Bacterial transcription attenuation occurs through a variety of cis regulatory elements that control gene expression in response to a wide range of signals. The signal-sensing structures in attenuators are so diverse and rapidly evolving that only a small fraction have been properly annotated and characterized to date. Here we apply a broad-spectrum detection tool in order to achieve a more complete view of the transcriptional attenuation complement of key bacterial species. RESULTS: Our protocol seeks gene families with an unusual frequency of 5' terminators found across multiple species. Many of the detected attenuators are part of annotated elements, such as riboswitches or T-boxes, which often operate through transcriptional attenuation. However, a significant fraction of candidates were not previously characterized in spite of their unmistakable footprint. We further characterized some of these new elements using sequence and secondary structure analysis. We also present elements that may control the expression of several non-homologous genes, suggesting co transcription and response to common signals. An important class of such elements, which we called mobile attenuators, is provided by 3' terminators of insertion sequences or prophages that may be exapted as 5' regulators when inserted directly upstream of a cellular gene. CONCLUSIONS: We show here that attenuators involve a complex landscape of signal-detection structures spanning the entire bacterial domain. We discuss possible scenarios through which these diverse 5' regulatory structures may arise or evolve. PMID- 20920268 TI - Overexpression of a natural chloroplast-encoded antisense RNA in tobacco destabilizes 5S rRNA and retards plant growth. AB - BACKGROUND: The roles of non-coding RNAs in regulating gene expression have been extensively studied in both prokaryotes and eukaryotes, however few reports exist as to their roles in organellar gene regulation. Evidence for accumulation of natural antisense RNAs (asRNAs) in chloroplasts comes from the expressed sequence tag database and cDNA libraries, while functional data have been largely obtained from artificial asRNAs. In this study, we used Nicotiana tabacum to investigate the effect on sense strand transcripts of overexpressing a natural chloroplast asRNA, AS5, which is complementary to the region which encodes the 5S rRNA and tRNAArg. RESULTS: AS5-overexpressing (AS5ox) plants obtained by chloroplast transformation exhibited slower growth and slightly pale green leaves. Analysis of AS5 transcripts revealed four distinct species in wild-type (WT) and AS5ox plants, and additional AS5ox-specific products. Of the corresponding sense strand transcripts, tRNAArg overaccumulated several-fold in transgenic plants whereas 5S rRNA was unaffected. However, run-on transcription showed that the 5S-trnR region was transcribed four-fold more in the AS5ox plants compared to WT, indicating that overexpression of AS5 was associated with decreased stability of 5S rRNA. In addition, polysome analysis of the transformants showed less 5S rRNA and rbcL mRNA associated with ribosomes. CONCLUSIONS: Our results suggest that AS5 can modulate 5S rRNA levels, giving it the potential to affect Chloroplast translation and plant growth. More globally, overexpression of asRNAs via chloroplast transformation may be a useful strategy for defining their functions. PMID- 20920269 TI - Cardiovascular and inflammatory effects of intratracheally instilled ambient dust from Augsburg, Germany, in spontaneously hypertensive rats (SHRs). AB - RATIONALE: Several epidemiological studies associated exposure to increased levels of particulate matter in Augsburg, Germany with cardiovascular mortality and morbidity. To elucidate the mechanisms of cardiovascular impairments we investigated the cardiopulmonary responses in spontaneously hypertensive rats (SHR), a model for human cardiovascular diseases, following intratracheal instillation of dust samples from Augsburg. METHODS: 250 MUg, 500 MUg and 1000 MUg of fine ambient particles (aerodynamic diameter <2.5 MUm, PM2(.)5-AB) collected from an urban background site in Augsburg during September and October 2006 (PM2(.)5 18.2 MUg/m3, 10,802 particles/cm3) were instilled in 12 months old SHRs to assess the inflammatory response in bronchoalveolar lavage fluid (BALF), blood, lung and heart tissues 1 and 3 days post instillation. Radio-telemetric analysis was performed to investigate the cardiovascular responses following instillation of particles at the highest dosage based on the inflammatory response observed. RESULTS: Exposure to 1000 MUg of PM2(.)5-AB was associated with a delayed increase in delta mean blood pressure (DeltamBP) during 2(nd) 4(th) day after instillation (10.0 +/- 4.0 vs. -3.9 +/- 2.6 mmHg) and reduced heart rate (HR) on the 3rd day post instillation (325.1 +/- 8.8 vs. 348.9 +/- 12.5 bpm). BALF cell differential and inflammatory markers (osteopontin, interleukin-6, C-reactive protein, and macrophage inflammatory protein-2) from pulmonary and systemic level were significantly induced, mostly in a dose dependent way. Protein analysis of various markers indicate that PM2(.)5-AB instillation results in an activation of endothelin system (endothelin1), renin angiotensin system (angiotensin converting enzyme) and also coagulation system (tissue factor, plasminogen activator inhibitor-1) in pulmonary and cardiac tissues during the same time period when alternation in DeltamBP and HR have been detected. CONCLUSIONS: Our data suggests that high concentrations of PM2(.)5-AB exposure triggers low grade PM mediated inflammatory effects in the lungs but disturbs vascular homeostasis in pulmonary tissues and on a systemic level by affecting the renin angiotensin system, the endothelin system and the coagulation cascade. These findings are indicative for promotion of endothelial dysfunction, atherosclerotic lesions, and thrombogeneis and, thus, provide plausible evidence that susceptible-predisposed individuals may develop acute cardiac events like myocardial infarction when repeatedly exposed to high pollution episodes as observed in epidemiological studies in Augsburg, Germany. PMID- 20920270 TI - The rate of the molecular clock and the cost of gratuitous protein synthesis. AB - BACKGROUND: The nature of the protein molecular clock, the protein-specific rate of amino acid substitutions, is among the central questions of molecular evolution. Protein expression level is the dominant determinant of the clock rate in a number of organisms. It has been suggested that highly expressed proteins evolve slowly in all species mainly to maintain robustness to translation errors that generate toxic misfolded proteins. Here we investigate this hypothesis experimentally by comparing the growth rate of Escherichia coli expressing wild type and misfolding-prone variants of the LacZ protein. RESULTS: We show that the cost of toxic protein misfolding is small compared to other costs associated with protein synthesis. Complementary computational analyses demonstrate that there is also a relatively weaker, but statistically significant, selection for increasing solubility and polarity in highly expressed E. coli proteins. CONCLUSIONS: Although we cannot rule out the possibility that selection against misfolding toxicity significantly affects the protein clock in species other than E. coli, our results suggest that it is unlikely to be the dominant and universal factor determining the clock rate in all organisms. We find that in this bacterium other costs associated with protein synthesis are likely to play an important role. Interestingly, our experiments also suggest significant costs associated with volume effects, such as jamming of the cellular environment with unnecessary proteins. PMID- 20920271 TI - Hypotheses, rationale, design, and methods for prognostic evaluation in type 2 diabetic patients with angiographically normal coronary arteries. The MASS IV-DM Trial. AB - BACKGROUND: The MASS IV-DM Trial is a large project from a single institution, the Heart Institute (InCor), University of Sao Paulo Medical School, Brazil to study ventricular function and coronary arteries in patients with type 2 diabetes mellitus. METHODS/DESIGN: The study will enroll 600 patients with type 2 diabetes who have angiographically normal ventricular function and coronary arteries. The goal of the MASS IV-DM Trial is to achieve a long-term evaluation of the development of coronary atherosclerosis by using angiograms and coronary-artery calcium scan by electron-beam computed tomography at baseline and after 5 years of follow-up. In addition, the incidence of major cardiovascular events, the dysfunction of various organs involved in this disease, particularly microalbuminuria and renal function, will be analyzed through clinical evaluation. In addition, an effort will be made to investigate in depth the presence of major cardiovascular risk factors, especially the biochemical profile, metabolic syndrome inflammatory activity, oxidative stress, endothelial function, prothrombotic factors, and profibrinolytic and platelet activity. An evaluation will be made of the polymorphism as a determinant of disease and its possible role in the genesis of micro- and macrovascular damage. DISCUSSION: The MASS IV-DM trial is designed to include diabetic patients with clinically suspected myocardial ischemia in whom conventional angiography shows angiographically normal coronary arteries. The result of extensive investigation including angiographic follow-up by several methods, vascular reactivity, pro thrombotic mechanisms, genetic and biochemical studies may facilitate the understanding of so-called micro- and macrovascular disease of DM. PMID- 20920272 TI - Consumption of diets high in prebiotic fiber or protein during growth influences the response to a high fat and sucrose diet in adulthood in rats. AB - BACKGROUND: Early dietary exposure can influence susceptibility to obesity and type 2 diabetes later in life. We examined the lasting effects of a high protein or high prebiotic fiber weaning diet when followed by a high energy diet in adulthood. METHODS: At birth, litters of Wistar rats were culled to 10 pups. At 21 d pups were weaned onto control (C), high prebiotic fiber (HF) or high protein (HP) diet. Rats consumed the experimental diets until 14 wk when they were switched to a high fat/sucrose (HFHS) diet for 6 wk. Body composition and energy intake were measured and an oral glucose tolerance test (OGTT) performed. Blood was analyzed for satiety hormones and tissues collected for real-time PCR. RESULTS: Weight gain was attenuated in male rats fed HF from 12 wk until study completion. In females there were early reductions in body weight that moderated until the final two wk of HFHS diet wherein HF females weighed less than HP. Final body weight was significantly higher following the high fat challenge in male and female rats that consumed HP diet from weaning compared to HF. Lean mass was higher and fat mass lower with HF compared to HP and compared to C in males. Energy intake was highest in HP rats, particularly at the start of HFHS feeding. Plasma glucose was higher in HP rats compared to HF during an OGTT. Plasma amylin was higher in HF females compared to C and glucagon-like peptide-1 (GLP-1) was higher in HF rats during the OGTT. Leptin was higher in HP rats during the OGTT. HF upregulated GLUT 5 mRNA expression in the intestine and downregulated hepatic hydroxymethylglutaryl coenzyme A reductase. Male rats fed HP had higher hepatic triglyceride content than C or HF. CONCLUSION: These data suggest that while a long-term diet high in protein predisposes to an obese phenotype when rats are given a high energy diet in adulthood, consumption of a high fiber diet during growth may provide some protection. PMID- 20920273 TI - Tigecycline use in serious nosocomial infections: a drug use evaluation. AB - BACKGROUND: Tigecycline is a novel antibiotic with activity against multidrug resistant bacteria. The aim of this study was to assess the efficacy of tigecycline use in serious hospital-acquired infections (HAI) CASE PRESENTATION: Prospective observational study of tigecycline use was conducted in a 1500 beds university hospital. From January 1, 2007 and January 31, 2010, 207 pts were treated with tigecycline for the following indications: intra-abdominal, pneumonia, bloodstream and complicated skin and soft tissue infections and febrile neutropenia. The therapy was targeted in 130/207 (63%) and empirical in 77/207 (37%) patients. All bacteria treated were susceptible to tigecycline. Median duration of tigecycline therapy was 13 days (range, 6-28). Clinical success was obtained in 151/207 (73%) cases, with the highest success rate recorded in intra-abdominal infections [81/99 (82%)]. Microbiological success was achieved in 100/129 (78%) treated patients. Adverse clinical events were seen in 16/207 patients (7.7%): CONCLUSIONS: Considering the lack of data on tigecycline for critically ill patients, we think that the reported data of our clinical experience despite some limitations can be useful for clinicians. PMID- 20920274 TI - The evolution of euhermaphroditism in caridean shrimps: a molecular perspective of sexual systems and systematics. AB - BACKGROUND: The hippolytid genus Lysmata is characterized by simultaneous hermaphroditism, a very rare sexual system among Decapoda. Specialized cleaning behavior is reported in a few pair-living species; these life history traits vary within the genus. Unfortunately, the systematics of Lysmata and the Hippolytidae itself are in contention, making it difficult to examine these taxa for trends in life history traits. A phylogeny of Lysmata and related taxa is needed, to clarify their evolutionary relationships and the origin of their unique sexual pattern. In this study, we present a molecular phylogenetic analysis among species of Lysmata, related genera, and several putative hippolytids. The analysis is based upon DNA sequences of two genes, 16S mtDNA and nuclear 28S rRNA. Phylogenetic trees were estimated using Bayesian Inference, Maximum Likelihood, and Maximum Parsimony. RESULTS: Phylogenetic analysis of 29 species of Lysmata, eight genera of Hippolytidae and two genera of Barbouriidae based on a single (16S, 28S) and combined gene approach (16S+28S) indicates that three groups of Lysmata differentiate according to antennular morphology: (1) Lysmata, having a multi-segmented accessory branch, (2) Hippolysmata (prior to Chace 1972), with a one-segmented accessory branch, and (3) a third group of Lysmata outliers, with one-segmented unguiform accessory branch, and close affinity to the genera Exhippolysmata and Lysmatella. The monophyly of the clade bearing a multi-segmented accessory branch is robust. Within the short accessory branch clade, species with specialized cleaning behaviors form a monophyletic clade, however, the integrity of the clade was sensitive to alignment criteria. Other hippolytid and barbouriid genera used in the analysis are basal to these three groups, including one displaying simultaneous hermaphroditism (Parhippolyte). The two barbouriid species occur in a separate clade, but among hippolytid taxa. CONCLUSIONS: The data support the historical morphological division of Lysmata into clades based on accessory branch morphology. The position of the "cleaner" shrimps, indicates that specialized cleaning behavior is a derived trait. The topologies of the cladograms support the monophyly of the barbouriids, but do not support their elevation to familial status. Taxa ancestral to the genus Lysmata display simultaneous hermaphroditism, suggesting that this life history trait evolved outside the genus Lysmata. PMID- 20920275 TI - Make Better Choices (MBC): study design of a randomized controlled trial testing optimal technology-supported change in multiple diet and physical activity risk behaviors. AB - BACKGROUND: Suboptimal diet and physical inactivity are prevalent, co-occurring chronic disease risk factors, yet little is known about how to maximize multiple risk behavior change. Make Better Choices, a randomized controlled trial, tests competing hypotheses about the optimal way to promote healthy change in four bundled risk behaviors: high saturated fat intake, low fruit and vegetable intake, low physical activity, and high sedentary leisure screen time. The study aim is to determine which combination of two behavior change goals--one dietary, one activity--yields greatest overall healthy lifestyle change. METHODS/DESIGN: Adults (n = 200) with poor quality diet and sedentary lifestyle will be recruited and screened for study eligibility. Participants will be trained to record their diet and activities onto a personal data assistant, and use it to complete two weeks of baseline. Those who continue to show all four risk behaviors after baseline recording will be randomized to one of four behavior change prescriptions: 1) increase fruits and vegetables and increase physical activity, 2) decrease saturated fat and increase physical activity, 3) increase fruits and vegetable and decrease saturated fat, or 4) decrease saturated fat and decrease sedentary activity. They will use decision support feedback on the personal digital assistant and receive counseling from a coach to alter their diet and activity during a 3-week prescription period when payment is contingent upon meeting behavior change goals. They will continue recording on an intermittent schedule during a 4.5-month maintenance period when payment is not contingent upon goal attainment. The primary outcome is overall healthy lifestyle change, aggregated across all four risk behaviors. DISCUSSION: The Make Better Choices trial tests a disseminable lifestyle intervention supported by handheld technology. Findings will fill a gap in knowledge about optimal goal prescription to facilitate simultaneous diet and activity change. Results will shed light on which goal prescription maximizes healthful lifestyle change. TRIAL REGISTRATION: Clinical Trials Gov. Identifier NCT00113672. PMID- 20920276 TI - Long-term results from a randomized phase II trial of neoadjuvant combined modality therapy for locally advanced rectal cancer. AB - BACKGROUND: This study evaluated the effectiveness and safety of preoperative chemoradiotherapy with capecitabine in patients with locally advanced resectable rectal cancer. This report summarizes the results of the phase II study together with long-term (5-year) follow-up. METHODS: Between June 2004 and January 2005, 57 patients with operable, clinical stage II-III adenocarcinoma of the rectum entered the study. Radiation dose was 45 Gy delivered as 25 fractions of 1.8 Gy. Concurrent chemotherapy with oral capecitabine 825 mg/m2 twice daily was administered during radiotherapy and at weekends. Surgery was scheduled 6 weeks after the completion of the chemoradiotherapy. Patients received four cycles of postoperative chemotherapy comprising either capecitabine 1250 mg/m2 bid days 1 14 every 3 weeks or bolus i.v. 5-fluorouracil 425 mg/m2/day and leucovorin 20 mg/m2/day days 1-5 every 4 weeks (choice was at the oncologist's discretion). Study endpoints included complete pathological remission, proportion of R0 resections and sphincter-sparing procedures, toxicity, survival parameters and long-term (5-year) rectal and urogenital morbidity assessment. RESULTS: One patient died after receiving 27 Gy because of a pulmonary embolism. Fifty-six patients completed radiochemotherapy and had surgery. Median follow-up time was 62 months. No patients were lost to follow-up. R0 resection was achieved in 55 patients. A complete pathological response was observed in 5 patients (9.1%); T-, N- and overall downstaging rates were 40%, 52.9% and 49.1%, respectively. The 5 year overall survival rate, recurrence-free survival, and local control was 61.4% (95% CI: 48.9-73.9%), 52.4% (95% CI: 39.3-65.5%), and 87.4% (95% CI: 75.0-99.8%), respectively. In 5 patients local relapse has occurred; dissemination was observed in 19 patients and secondary malignancies have occurred in 2 patients. The most frequent side-effect of the preoperative combined therapy was dermatitis (grade 3 in 19 patients). The proportion of patients with severe late (SOMA grade 3 and 4) rectal, bladder and sexual toxicity was 40%, 19.2% and 51.7%, respectively. CONCLUSIONS: This study confirms data from other non-randomised studies that capecitabine-based preoperative chemoradiation is a feasible treatment option for locally advanced rectal cancer, with positive 5-year overall survival, recurrence-free survival, and local control rates. PMID- 20920277 TI - Using the theory of planned behaviour as a process evaluation tool in randomised trials of knowledge translation strategies: A case study from UK primary care. AB - BACKGROUND: Randomised trials of knowledge translation strategies for professional behaviour change can provide robust estimates of effectiveness, but offer little insight into the causal mechanisms by which any change is produced. To illustrate the applicability of causal methods within randomised trials, we undertook a theory-based process evaluation study within an implementation trial to explore whether the cognitions of primary care doctors' predicted their test requesting behaviours and, secondly, whether the trial results were mediated by the theoretical constructs. METHODS: The process evaluation comprised a cross sectional questionnaire survey of a random 50% sample of the randomised groups of primary care practices in Grampian (NHS Grampian), UK, who took part in a trial of the effect of enhanced feedback and brief educational reminders on test requesting behaviour. The process evaluation was based upon the Theory of Planned Behaviour and focussed on three of the test requesting behaviours that were targeted in the trial -- ferritin, follicle stimulating hormone (FSH), and Helicobacter Pylori serology (HPS). RESULTS: The questionnaire was completed by 131 primary care doctors (56%) from 42 (98%) of the sampled practices. Behavioural intention, attitude, and subjective norm were highly correlated for all the tests. There was no evidence that perceived behavioural control was correlated with any of the other measures. Simple linear regression analysis of the rate of test requests on minimum behavioural intentions had R2 of 11.1%, 12.5%, and 0.1% for ferritin, FSH, and HPS requesting, respectively. Mediational analysis showed that the trial results for ferritin and FSH were partially mediated (between 23% and 78% mediation) through intentions. The HPS trial result was not mediated through intention. CONCLUSIONS: This study demonstrated that a theory-based process evaluation can provide useful information on causal mechanisms that aid not only interpretation of the trial but also inform future evaluations and intervention development. PMID- 20920279 TI - Assessing data availability for the development of REDD-plus national reference levels. AB - BACKGROUND: Data availability in developing countries is known to be extremely varied and is one of the constraints for setting the national reference levels (RLs) for the REDD-plus (i.e. 'Policy approaches and positive incentives on issues relating to reducing emissions from deforestation and forest degradation in developing countries; and the role of conservation, sustainable management of forests and enhancement of forest carbon stocks in developing countries') under the UNFCCC. Taking Thailand as a case study country, this paper compares three types of RLs, which require different levels of datasets, including a simple historic RL, a projected forest-trend RL, and a business-as-usual (BAU) RL. RESULTS: Other than the finding that different RLs yielded different estimations on future deforestation areas, the analysis also identified the characteristics of each RL. The historical RL demanded simple data, but can be varied in accordance with a reference year or period. The forest-trend RL can be more reliable than the historical RL, if the country's deforestation trend curve is formed smoothly. The complicated BAU RL is useful as it can demonstrate the additionality of REDD-plus activities and distinguish the country's unintentional efforts. CONCLUSIONS: With the REDD-plus that involves widespread participation, there should be steps from which countries choose the appropriate RL; ranging from simpler to more complex measures, in accordance with data availability in each country. Once registered with REDD-plus, the countries with weak capacity and capability should be supported to enhance the data collection system in that country. PMID- 20920278 TI - Nicotinic receptors on rat alveolar macrophages dampen ATP-induced increase in cytosolic calcium concentration. AB - BACKGROUND: Nicotinic acetylcholine receptors (nAChR) have been identified on a variety of cells of the immune system and are generally considered to trigger anti-inflammatory events. In the present study, we determine the nAChR inventory of rat alveolar macrophages (AM), and investigate the cellular events evoked by stimulation with nicotine. METHODS: Rat AM were isolated freshly by bronchoalveolar lavage. The expression of nAChR subunits was analyzed by RT-PCR, immunohistochemistry, and Western blotting. To evaluate function of nAChR subunits, electrophysiological recordings and measurements of intracellular calcium concentration ([Ca2+]i) were conducted. RESULTS: Positive RT-PCR results were obtained for nAChR subunits alpha3, alpha5, alpha9, alpha10, beta1, and beta2, with most stable expression being noted for subunits alpha9, alpha10, beta1, and beta2. Notably, mRNA coding for subunit alpha7 which is proposed to convey the nicotinic anti-inflammatory response of macrophages from other sources than the lung was not detected. RT-PCR data were supported by immunohistochemistry on AM isolated by lavage, as well as in lung tissue sections and by Western blotting. Neither whole-cell patch clamp recordings nor measurements of [Ca2+]i revealed changes in membrane current in response to ACh and in [Ca2+]i in response to nicotine, respectively. However, nicotine (100 MUM), given 2 min prior to ATP, significantly reduced the ATP-induced rise in [Ca2+]i by 30%. This effect was blocked by alpha-bungarotoxin and did not depend on the presence of extracellular calcium. CONCLUSIONS: Rat AM are equipped with modulatory nAChR with properties distinct from ionotropic nAChR mediating synaptic transmission in the nervous system. Their stimulation with nicotine dampens ATP-induced Ca2+-release from intracellular stores. Thus, the present study identifies the first acute receptor-mediated nicotinic effect on AM with anti-inflammatory potential. PMID- 20920280 TI - Helicobacter pylori infection and gastroduodenal diseases in Vietnam: a cross sectional, hospital-based study. AB - BACKGROUND: The rate of H. pylori infection in Vietnam is reportedly high, but the spectrum of H. pylori-associated gastroduodenal diseases has not been systematically investigated. Moreover, despite the similarities of ethnicity and diet, the age-standardized incidence rate of gastric cancer in the northern city of Hanoi is higher than that in the southern city of Ho Chi Minh, but the reason for this phenomenon is unknown. The virulence of Vietnamese H. pylori has also not been investigated in detail. METHODS: Individuals undergoing esophagogastroduodenoscopy were randomly recruited. H. pylori infection status was determined based on the combined results of culture, histology, immunohistochemistry, rapid urine test and serum ELISA. Peptic ulcer (PU) and gastroesophageal reflux disease was diagnosed by endoscopy, and chronic gastritis was determined histologically. H. pylori virulence factors were investigated by PCR and sequencing. RESULTS: Among the examined patients, 65.6% were infected with H. pylori. The prevalence of infection was significantly higher in those over 40 years of age than in those aged <=40. Chronic gastritis was present in all H. pylori-infected individuals, 83.1% of whom had active gastritis, and 85.3% and 14.7% had atrophy and intestinal metaplasia, respectively. PU was present in 21% of infected patients, whereas its incidence was very low in non-infected individuals. The prevalence of PU was significantly higher in Hanoi than in Ho Chi Minh. The prevalence of vacA m1, which has been identified as an independent risk factor for PU in Vietnam, was significantly higher among H. pylori isolates from Hanoi than among those from Ho Chi Minh. CONCLUSIONS: H. pylori infection is common in Vietnam and is strongly associated with PU, active gastritis, atrophy and intestinal metaplasia. vacA m1 is associated with an increased risk for PU and might contribute to the difference in the prevalence of PU and gastric cancer between Hanoi and Ho Chi Minh. PMID- 20920281 TI - Three novel beta-galactosidase gene mutations in Han Chinese patients with GM1 gangliosidosis are correlated with disease severity. AB - BACKGROUND: GM1 gangliosidosis (GM1) is an autosomal recessive lysosomal storage disease caused by deficiency of acid beta-galactosidase (GLB1; EC3.2.1.23). Here, we identify three novel mutations in the GLB1 gene from two Han Chinese patients with GM1 that appear correlated with clinical phenotype. METHODS: One of the two Han Chinese patients with GM1 presented with the juvenile form, and the other with the infantile form with cardiac involvement. Sequencing of the entire GLB1 gene revealed three novel mutations (p.H102 D, p.G494V, c.495_497delTCT), which were absent in 94 normal controls. Transient expression of cDNA encoding these variants was performed in COS-1 cells to evaluate beta-galactosidase activities. RESULTS: The first case (patient 1) with the juvenile form contained two missense mutations, p.H102 D and p.A301V. Patient 2 diagnosed with the infantile form of the disease with cardiac involvement was compound heterozygous for p.G494V and c.495_497delTCT mutations. All mutant beta-galactosidases exhibited significantly reduced activity (12%, 0%, 0%, and 0% for p.H102 D, p.A301V, p.G494V, and c.495_497delTCT), compared with the wild-type beta-galactosidase cDNA clone. The mutations identified in patient 2 with cardiomyopathy were localized in the GLB1 gene region common to both lysosomal beta-galactosidase and elastin binding protein (EBP), and caused a deletion in the elastin-binding domain of EBP. CONCLUSIONS: All four mutations identified in Han Chinese patients induce significant suppression of beta-galactosidase activity, correlating with severity of disease and presence of cardiomyopathy. PMID- 20920282 TI - TNFRSF11B computational development network construction and analysis between frontal cortex of HIV encephalitis (HIVE) and HIVE-control patients. AB - BACKGROUND: TNFRSF11B computational development network construction and analysis of frontal cortex of HIV encephalitis (HIVE) is very useful to identify novel markers and potential targets for prognosis and therapy. METHODS: By integration of gene regulatory network infer (GRNInfer) and the database for annotation, visualization and integrated discovery (DAVID) we identified and constructed significant molecule TNFRSF11B development network from 12 frontal cortex of HIVE control patients and 16 HIVE in the same GEO Dataset GDS1726. RESULTS: Our result verified TNFRSF11B developmental process only in the downstream of frontal cortex of HIVE-control patients (BST2, DGKG, GAS1, PDCD4, TGFBR3, VEZF1 inhibition), whereas in the upstream of frontal cortex of HIVE (DGKG, PDCD4 activation) and downstream (CFDP1, DGKG, GAS1, PAX6 activation; BST2, PDCD4, TGFBR3, VEZF1 inhibition). Importantly, we datamined that TNFRSF11B development cluster of HIVE is involved in T-cell mediated immunity, cell projection organization and cell motion (only in HIVE terms) without apoptosis, plasma membrane and kinase activity (only in HIVE-control patients terms), the condition is vital to inflammation, brain morphology and cognition impairment of HIVE. Our result demonstrated that common terms in both HIVE-control patients and HIVE include developmental process, signal transduction, negative regulation of cell proliferation, RNA-binding, zinc-finger, cell development, positive regulation of biological process and cell differentiation. CONCLUSIONS: We deduced the stronger TNFRSF11B development network in HIVE consistent with our number computation. It would be necessary of the stronger TNFRSF11B development function to inflammation, brain morphology and cognition of HIVE. PMID- 20920283 TI - QEEG characteristics and spectrum weighted frequency for children diagnosed as autistic spectrum disorder. AB - BACKGROUND: Autistic spectrum disorders are a group of neurological and developmental disorders associated with social, communication, sensory, behavioral and cognitive impairments, as well as restricted, repetitive patterns of behavior, activities, or interests.The aim of this study was a) to analyze QEEG findings of autistic patients and to compare the results with data base; and b) to introduce the calculation of spectrum weighted frequency (brain rate) as an indicator of general mental arousal in these patients. RESULTS: Results for Q-EEG shows generally increased delta-theta activity in frontal region of the brain. Changes in QEEG pattern appeared to be in a non-linear correlation with maturational processes.Brain rate measured in CZ shows slow brain activity (5. 86) which is significantly lower than normal and corresponds to low general mental arousal.Recent research has shown that autistic disorders have as their basis disturbances of neural connectivity. Neurofeedback seems capable of remediating such disturbances when these data are considered as part of treatment planning. CONCLUSIONS: Prognosis of this pervasive disorder depends on the intellectual abilities: the better intellectual functioning, the possibilities for life adaptation are higherQEEG shows generally increased delta-theta activity in frontal region of the brain which is related to poor cognitive abilities.Brain rate measured in CZ shows slow brain activity related to under arousal.Pharmacotherapy combined with behavior therapy, social support and especially neurofeedback technique promise slight improvements. PMID- 20920284 TI - Using Chinese version of MYMOP in Chinese medicine evaluation: validity, responsiveness and minimally important change. AB - BACKGROUND: Measure Yourself Medical Outcome Profile (MYMOP) is a patient generated outcome instrument applicable in the evaluation of both allopathic and complementary medicine treatment. This study aims to adapt MYMOP into Chinese, and to assess its validity, responsiveness and minimally important change values in a sample of patients using Chinese medicine (CM) services. METHODS: A Chinese version of MYMOP (CMYMOP) is developed by forward-backward-forward translation strategy, expert panel assessment and pilot testing amongst patients. 272 patients aged 18 or above with subjective symptoms in the past 2 weeks were recruited at a CM clinic, and were invited to complete a set of questionnaire containing CMYMOP and SF-36. Follow ups were performed at 2nd and 4th week after consultation, using the same set of questionnaire plus a global rating of change question. Criterion validity of CMYMOP was assessed by its correlation with SF-36 at baseline, and responsiveness was evaluated by calculating the Cohen effect size (ES) of change at two follow ups. Minimally important difference (MID) values were estimated via anchor based method, while minimally detectable difference (MDC) figures were calculated by distribution based method. RESULTS: Criterion validity of CMYMOP was demonstrated by negative correlation between CMYMOP Profile scores and all SF-36 domain and summary scores at baseline. For responsiveness between baseline and 4th week follow up, ES of CMYMOP Symptom 1, Activity and Profile reached the moderate change threshold (ES>0.5), while Symptom 2 and Wellbeing reached the weak change threshold (ES>0.2). None of the SF-36 scores reached the moderate change threshold, implying CMYMOP's stronger responsiveness in CM setting. At 2nd week follow up, MID values for Symptom 1, Symptom 2, Wellbeing and Profile items were 0.894, 0.580, 0.263 and 0.516 respectively. For Activity item, MDC figure of 0.808 was adopted to estimate MID. CONCLUSIONS: The findings support the validity and responsiveness of CMYMOP for capturing patient centred clinical changes within 2 weeks in a CM clinical setting. Further researches are warranted (1) to estimate Activity item MID, (2) to assess the test-retest reliability of CMYMOP, and (3) to perform further MID evaluation using multiple, item specific anchor questions. PMID- 20920285 TI - Validity, responsiveness and the minimal clinically important difference for the de Morton Mobility Index (DEMMI) in an older acute medical population. AB - BACKGROUND: The de Morton Mobility Index (DEMMI) is a new mobility instrument that overcomes the limitations of existing instruments. It is the first mobility instrument that accurately measures the mobility of all older adults. The aim of this study was to provide a detailed report of investigations of the validity, responsiveness to change and minimal clinically important difference (MCID) of the DEMMI during its development in an older acute medical population. METHODS: This study was conducted using a head to head comparison design in two independent samples of older acute medical patients (development sample, n = 86; validation sample, n = 106). Consecutive patients (>= 65 years) were assessed using the DEMMI, Barthel Index (BI) and Hierarchical Assessment of Balance and Mobility (HABAM) within 48 hours of hospital admission and discharge. Convergent and discriminant validity were investigated using Spearman's rho and known groups validity was investigated using a independent t test to compare DEMMI scores for patients who were discharged to home compared to inpatient rehabilitation. Criterion and distribution based methods were employed for estimating instrument responsiveness to change and the MCID. RESULTS: Significant moderate to high correlations were identified between DEMMI and BI scores (r = 0.76 and r = 0.68) and DEMMI and HABAM scores (r = 0.91 and r = 0.92) in both samples. In both samples, DEMMI scores for patients who were discharged to home were significantly higher than for patients discharged to inpatient rehabilitation and provided evidence of known groups validity. Patients who were discharged to inpatient rehabilitation (n = 8) had a mean DEMMI score of 50.75 (sd = 11.29) at acute hospital discharge compared to patients who were discharged to home (n = 70) with a mean DEMMI score of 62.14 (sd = 18.41). MCID estimates were similar across samples using distribution and criterion based methods. The MCID for the DEMMI was 10 points on the 100 point interval scale. The DEMMI was significantly more responsive to change than the BI using criterion and distribution based methods in the validation sample. CONCLUSION: This study has validated the DEMMI in two independent samples of older acute medical patients. Estimates of its responsiveness and MCID have also been established. This study confirms that the DEMMI overcomes the limitations of the BI and HABAM and provides an advanced method for objectively assessing mobility for older acute medical patients. PMID- 20920286 TI - Impacts of mutation effects and population size on mutation rate in asexual populations: a simulation study. AB - BACKGROUND: In any natural population, mutation is the primary source of genetic variation required for evolutionary novelty and adaptation. Nevertheless, most mutations, especially those with phenotypic effects, are harmful and are consequently removed by natural selection. For this reason, under natural selection, an organism will evolve to a lower mutation rate. Overall, the action of natural selection on mutation rate is related to population size and mutation effects. Although theoretical work has intensively investigated the relationship between natural selection and mutation rate, most of these studies have focused on individual competition within a population, rather than on competition among populations. The aim of the present study was to use computer simulations to investigate how natural selection adjusts mutation rate among asexually reproducing subpopulations with different mutation rates. RESULTS: The competition results for the different subpopulations showed that a population could evolve to an "optimum" mutation rate during long-term evolution, and that this rate was modulated by both population size and mutation effects. A larger population could evolve to a higher optimum mutation rate than could a smaller population. The optimum mutation rate depended on both the fraction and the effects of beneficial mutations, rather than on the effects of deleterious ones. The optimum mutation rate increased with either the fraction or the effects of beneficial mutations. When strongly favored mutations appeared, the optimum mutation rate was elevated to a much higher level. The competition time among the subpopulations also substantially shortened. CONCLUSIONS: Competition at the population level revealed that the evolution of the mutation rate in asexual populations was determined by both population size and mutation effects. The most striking finding was that beneficial mutations, rather than deleterious mutations, were the leading force that modulated the optimum mutation rate. The initial configuration of the population appeared to have no effect on these conclusions, confirming the robustness of the simulation method developed in the present study. These findings might further explain the lower mutation rates observed in most asexual organisms, as well as the higher mutation rates in some viruses. PMID- 20920287 TI - All-cause mortality among people with serious mental illness (SMI), substance use disorders, and depressive disorders in southeast London: a cohort study. AB - BACKGROUND: Higher mortality has been found for people with serious mental illness (SMI, including schizophrenia, schizoaffective disorders, and bipolar affective disorder) at all age groups. Our aim was to characterize vulnerable groups for excess mortality among people with SMI, substance use disorders, depressive episode, and recurrent depressive disorder. METHODS: A case register was developed at the South London and Maudsley National Health Services Foundation Trust (NHS SLAM), accessing full electronic clinical records on over 150,000 mental health service users as a well-defined cohort since 2006. The Case Register Interactive Search (CRIS) system enabled searching and retrieval of anonymised information since 2008. Deaths were identified by regular national tracing returns after 2006. Standardized mortality ratios (SMRs) were calculated for the period 2007 to 2009 using SLAM records for this period and the expected number of deaths from age-specific mortality statistics for the England and Wales population in 2008. Data were stratified by gender, ethnicity, and specific mental disorders. RESULTS: A total of 31,719 cases, aged 15 years old or more, active between 2007-2009 and with mental disorders of interest prior to 2009 were detected in the SLAM case register. SMRs were 2.15 (95% CI: 1.95-2.36) for all SMI with genders combined, 1.89 (1.64-2.17) for women and 2.47 (2.17-2.80) for men. In addition, highest mortality risk was found for substance use disorders (SMR = 4.17; 95% CI: 3.75-4.64). Age- and gender-standardised mortality ratios by ethnic group revealed huge fluctuations, and SMRs for all disorders diminished in strength with age. The main limitation was the setting of secondary mental health care provider in SLAM. CONCLUSIONS: Substantially higher mortality persists in people with serious mental illness, substance use disorders and depressive disorders. Furthermore, mortality risk differs substantially with age, diagnosis, gender and ethnicity. Further research into specific risk groups is required. PMID- 20920288 TI - A note on Youden's J and its cost ratio. AB - BACKGROUND: The Youden index, the sum of sensitivity and specificity minus one, is an index used for setting optimal thresholds on medical tests. DISCUSSION: When using this index, one implicitly uses decision theory with a ratio of misclassification costs which is equal to one minus the prevalence proportion of the disease. It is doubtful whether this cost ratio truly represents the decision maker's preferences. Moreover, in populations with a different prevalence, a selected threshold is optimal with reference to a different cost ratio. SUMMARY: The Youden index is not a truly optimal decision rule for setting thresholds because its cost ratio varies with prevalence. Researchers should look into their cost ratio and employ it in a decision theoretic framework to obtain genuinely optimal thresholds. PMID- 20920289 TI - Integrating clinicians, knowledge and data: expert-based cooperative analysis in healthcare decision support. AB - BACKGROUND: Decision support in health systems is a highly difficult task, due to the inherent complexity of the process and structures involved. METHOD: This paper introduces a new hybrid methodology Expert-based Cooperative Analysis (EbCA), which incorporates explicit prior expert knowledge in data analysis methods, and elicits implicit or tacit expert knowledge (IK) to improve decision support in healthcare systems. EbCA has been applied to two different case studies, showing its usability and versatility: 1) Bench-marking of small mental health areas based on technical efficiency estimated by EbCA-Data Envelopment Analysis (EbCA-DEA), and 2) Case-mix of schizophrenia based on functional dependency using Clustering Based on Rules (ClBR). In both cases comparisons towards classical procedures using qualitative explicit prior knowledge were made. Bayesian predictive validity measures were used for comparison with expert panels results. Overall agreement was tested by Intraclass Correlation Coefficient in case "1" and kappa in both cases. RESULTS: EbCA is a new methodology composed by 6 steps:. 1) Data collection and data preparation; 2) acquisition of "Prior Expert Knowledge" (PEK) and design of the "Prior Knowledge Base" (PKB); 3) PKB-guided analysis; 4) support-interpretation tools to evaluate results and detect inconsistencies (here Implicit Knowledg -IK- might be elicited); 5) incorporation of elicited IK in PKB and repeat till a satisfactory solution; 6) post-processing results for decision support. EbCA has been useful for incorporating PEK in two different analysis methods (DEA and Clustering), applied respectively to assess technical efficiency of small mental health areas and for case-mix of schizophrenia based on functional dependency. Differences in results obtained with classical approaches were mainly related to the IK which could be elicited by using EbCA and had major implications for the decision making in both cases. DISCUSSION: This paper presents EbCA and shows the convenience of completing classical data analysis with PEK as a mean to extract relevant knowledge in complex health domains. One of the major benefits of EbCA is iterative elicitation of IK.. Both explicit and tacit or implicit expert knowledge are critical to guide the scientific analysis of very complex decisional problems as those found in health system research. PMID- 20920290 TI - Wound contraction and macro-deformation during negative pressure therapy of sternotomy wounds. AB - BACKGROUND: Negative pressure wound therapy (NPWT) is believed to initiate granulation tissue formation via macro-deformation of the wound edge. However, only few studies have been performed to evaluate this hypothesis. The present study was performed to investigate the effects of NPWT on wound contraction and wound edge tissue deformation. METHODS: Six pigs underwent median sternotomy followed by magnetic resonance imaging in the transverse plane through the thorax and sternotomy wound during NPWT at 0, -75, -125 and -175 mmHg. The lateral width of the wound and anterior-posterior thickness of the wound edge was measured in the images. RESULTS: The sternotomy wound decreased in size following NPWT. The lateral width of the wound, at the level of the sternum bone, decreased from 39 +/- 7 mm to 30 +/- 6 mm at -125 mmHg (p = 0.0027). The greatest decrease in wound width occurred when switching from 0 to -75 mmHg. The level of negative pressure did not affect wound contraction (sternum bone: 32 +/- 6 mm at -75 mmHg and 29 +/ 6 mm at -175 mmHg, p = 0.0897). The decrease in lateral wound width during NPWT was greater in subcutaneous tissue (14 +/- 2 mm) than in sternum bone (9 +/- 2 mm), resulting in a ratio of 1.7 +/- 0.3 (p = 0.0423), suggesting macro deformation of the tissue. The anterior-posterior thicknesses of the soft tissue, at 0.5 and 2.5 cm laterally from the wound edge, were not affected by negative pressure. CONCLUSIONS: NPWT contracts the wound and causes macro-deformation of the wound edge tissue. This shearing force in the tissue and at the wound-foam interface may be one of the mechanisms by which negative pressure delivery promotes granulation tissue formation and wound healing. PMID- 20920291 TI - The DNA relaxation activity and covalent complex accumulation of Mycobacterium tuberculosis topoisomerase I can be assayed in Escherichia coli: application for identification of potential FRET-dye labeling sites. AB - BACKGROUND: Mycobacterium tuberculosis topoisomerase I (MtTOP1) and Escherichia coli topoisomerase I have highly homologous transesterification domains, but the two enzymes have distinctly different C-terminal domains. To investigate the structure-function of MtTOP1 and to target its activity for development of new TB therapy, it is desirable to have a rapid genetic assay for its catalytic activity, and potential bactericidal consequence from accumulation of its covalent complex. RESULTS: We show that plasmid-encoded recombinant MtTOP1 can complement the temperature sensitive topA function of E. coli strain AS17. Moreover, expression of MtTOP1-G116 S enzyme with the TOPRIM mutation that inhibits DNA religation results in SOS induction and loss of viability in E. coli. The absence of cysteine residues in the MtTOP1 enzyme makes it an attractive system for introduction of potentially informative chemical or spectroscopic probes at specific positions via cysteine mutagenesis. Such probes could be useful for development of high throughput screening (HTS) assays. We employed the AS17 complementation system to screen for sites in MtTOP1 that can tolerate cysteine substitution without loss of complementation function. These cysteine substitution mutants were confirmed to have retained the relaxation activity. One such mutant of MtTOP1 was utilized for fluorescence probe incorporation and fluorescence resonance energy transfer measurement with fluorophore-labeled oligonucleotide substrate. CONCLUSIONS: The DNA relaxation and cleavage complex accumulation of M. tuberculosis topoisomerase I can be measured with genetic assays in E. coli, facilitating rapid analysis of its activities, and discovery of new TB therapy targeting this essential enzyme. PMID- 20920292 TI - Clinical significance of Polycomb gene expression in brain tumors. AB - Polycomb group (PcG) proteins are crucial for neural cancer stem cell (NCSC) self renewal. However, the relative expression levels of PcG genes in different subtypes of brain tumors, their prognostic role and their effects on cellular pathways have not been investigated. For this purpose, we queried the Oncomine database and found that 4 PcG genes (EZH2, RBBP7, SUZ12, YY1) are specifically expressed in brain tumors. EZH2 expression increases with tumor grade in adult and pediatric brain tumors, and is a poor prognostic factor. In glioblastoma, EZH2 inhibits differentiation, and activates cancer-, cell cycle- and cellular movement-related genes. In keeping with previously published data, our results suggest that EZH2 is both a prognostic factor and a promising therapy target in brain tumors. PMID- 20920293 TI - Gerbode defect following endocarditis and misinterpreted as severe pulmonary arterial hypertension. AB - A Gerbode-type defect is a ventricular septal defect communicating directly between the left ventricle and right atrium. It is usually congenital, but rarely is acquired, as a complication of endocarditis. This can be anatomically possible because the normal tricuspid valve is more apically displaced than the mitral valve. However, identification of an actual communication is often extremely difficult, so a careful and meticulous echocardiogram should be done in order to prevent echocardiographic misinterpretation of this defect as pulmonary arterial hypertension. The large systolic pressure gradient between the left ventricle and the right atrium would expectedly result in a high velocity systolic Doppler flow signal in right atrium and it can be sometimes mistakably diagnosed as tricuspid regurgitant jet simulating pulmonary arterial hypertension. We present a rare case of young woman, with endocarditis who presented with severe pulmonary arterial hypertension. The preoperative diagnosis of left ventricle to right atrial communication (acquired Gerbode defect) was suspected initially by echocardiogram and confirmed at the time of the surgery. A point of interest, apart from the diagnostic problem, was the explanation for its mechanism and presentation. The probability of a bacterial etiology of the defect is high in this case. PMID- 20920294 TI - Sequence-structure-function relations of the mosquito leucine-rich repeat immune proteins. AB - BACKGROUND: The discovery and characterisation of factors governing innate immune responses in insects has driven the elucidation of many immune system components in mammals and other organisms. Focusing on the immune system responses of the malaria mosquito, Anopheles gambiae, has uncovered an array of components and mechanisms involved in defence against pathogen infections. Two of these immune factors are LRIM1 and APL1C, which are leucine-rich repeat (LRR) containing proteins that activate complement-like defence responses against malaria parasites. In addition to their LRR domains, these leucine-rich repeat immune (LRIM) proteins share several structural features including signal peptides, patterns of cysteine residues, and coiled-coil domains. RESULTS: The identification and characterisation of genes related to LRIM1 and APL1C revealed putatively novel innate immune factors and furthered the understanding of their likely molecular functions. Genomic scans using the shared features of LRIM1 and APL1C identified more than 20 LRIM-like genes exhibiting all or most of their sequence features in each of three disease-vector mosquitoes with sequenced genomes: An. gambiae, Aedes aegypti, and Culex quinquefasciatus. Comparative sequence analyses revealed that this family of mosquito LRIM-like genes is characterised by a variable number of 6 to 14 LRRs of different lengths. The "Long" LRIM subfamily, with 10 or more LRRs, and the "Short" LRIMs, with 6 or 7 LRRs, also share the signal peptide, cysteine residue patterning, and coiled-coil sequence features of LRIM1 and APL1C. The "TM" LRIMs have a predicted C-terminal transmembrane region, and the "Coil-less" LRIMs exhibit the characteristic LRIM sequence signatures but lack the C-terminal coiled-coil domains. CONCLUSIONS: The evolutionary plasticity of the LRIM LRR domains may provide templates for diverse recognition properties, while their coiled-coil domains could be involved in the formation of LRIM protein complexes or mediate interactions with other immune proteins. The conserved LRIM cysteine residue patterns are likely to be important for structural fold stability and the formation of protein complexes. These sequence-structure-function relations of mosquito LRIMs will serve to guide the experimental elucidation of their molecular roles in mosquito immunity. PMID- 20920295 TI - Pharmacokinetic comparability of Prolastin(r)-C to Prolastin(r) in alpha1 antitrypsin deficiency: a randomized study. AB - BACKGROUND: Alpha1-antitrypsin (AAT) deficiency is characterized by low blood levels of alpha1-proteinase inhibitor (alpha1-PI) and may lead to emphysema. Alpha1-PI protects pulmonary tissue from damage caused by the action of proteolytic enzymes. Augmentation therapy with Prolastin(r) (Alpha1-Proteinase Inhibitor [Human]) to increase the levels of alpha1-PI has been used to treat individuals with AAT deficiency for over 20 years. Modifications to the Prolastin manufacturing process, incorporating additional purification and pathogen reduction steps, have led to the development of an alpha1-PI product, designated Prolastin(r)-C (Alpha1-Proteinase inhibitor [Human]). The pharmacokinetic comparability of Prolastin-C to Prolastin was assessed in subjects with AAT deficiency. METHODS: In total, 24 subjects were randomized to receive 60 mg/kg of functionally active Prolastin-C or Prolastin by weekly intravenous infusion for 8 weeks before crossover to the alternate treatment for another 8 weeks. Pharmacokinetic plasma samples were drawn over 7 days following last dose in the first treatment period and over 10 days following the last dose in the second period. The primary end point for pharmacokinetic comparability was area under the plasma concentration versus time curve over 7 days post dose (AUC0-7 (days)) of alpha1-PI determined by potency (functional activity) assay. The crossover phase was followed by an 8-week open-label treatment phase with Prolastin-C only. RESULTS: Mean AUC0-7 (days) was 155.9 versus 152.4 mg*h/mL for Prolastin-C and Prolastin, respectively. The geometric least squares mean ratio of AUC0-7 (days) for Prolastin-C versus Prolastin had a point estimate of 1.03 and a 90% confidence interval of 0.97-1.09, demonstrating pharmacokinetic equivalence between the 2 products. Adverse events were similar for both treatments and occurred at a rate of 0.117 and 0.078 per infusion for Prolastin-C (double-blind treatment phase only) and Prolastin, respectively (p = 0.744). There were no treatment-emergent viral infections in any subject for human immunodeficiency virus, hepatitis B or C, or parvovirus B19 during the course of the study. CONCLUSION: Prolastin-C demonstrated pharmacokinetic equivalence and a comparable safety profile to Prolastin. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00295061. PMID- 20920296 TI - Determinants of menarche. AB - Menarche is a milestone in a woman's life as it denotes the start of reproductive capacity. Aim of this report is to review the recent developments and the current knowledge in the neuroendocrinology of pubertal onset and the factors, genetic and environmental, that influence menarcheal age. We also review the implications of early or late menarcheal age on a young woman's life. PMID- 20920297 TI - Characterization of an H3N2 triple reassortant influenza virus with a mutation at the receptor binding domain (D190A) that occurred upon virus transmission from turkeys to pigs. AB - The hemagglutinin (HA) protein of influenza virus mediates essential viral functions including the binding to host receptor and virus entry. It also has the antigenic sites required for virus neutralization by host antibodies. Here, we characterized an H3N2 triple reassortant (TR) influenza virus (A/turkey/Ohio/313053/04) with a mutation at the receptor binding domain (Asp190Ala) that occurred upon virus transmission from turkeys to pigs in an experimental infection study. The mutant virus replicated less efficiently than the parental virus in human, pig and turkey primary tracheal/bronchial epithelial cells, with more than 3-log10 difference in virus titer at 72 hours post infection. In addition, the mutant virus demonstrated lower binding efficiency to plasma membrane preparations from all three cell types compared to the parental virus. Antisera raised against the parental virus reacted equally to both homologous and heterlogous viruses, however, antisera raised against the mutant virus showed 4-8 folds lower reactivity to the parental virus. PMID- 20920298 TI - Molecular determinants of improved cathepsin B inhibition by new cystatins obtained by DNA shuffling. AB - BACKGROUND: Cystatins are inhibitors of cysteine proteases. The majority are only weak inhibitors of human cathepsin B, which has been associated with cancer, Alzheimer's disease and arthritis. RESULTS: Starting from the sequences of oryzacystatin-1 and canecystatin-1, a shuffling library was designed and a hybrid clone obtained, which presented higher inhibitory activity towards cathepsin B. This clone presented two unanticipated point mutations as well as an N-terminal deletion. Reversing each point mutation independently or both simultaneously abolishes the inhibitory activity towards cathepsin B. Homology modeling together with experimental studies of the reverse mutants revealed the likely molecular determinants of the improved inhibitory activity to be related to decreased protein stability. CONCLUSION: A combination of experimental approaches including gene shuffling, enzyme assays and reverse mutation allied to molecular modeling has shed light upon the unexpected inhibitory properties of certain cystatin mutants against Cathepsin B. We conclude that mutations disrupting the hydrophobic core of phytocystatins increase the flexibility of the N-terminus, leading to an increase in inhibitory activity. Such mutations need not affect the inhibitory site directly but may be observed distant from it and manifest their effects via an uncoupling of its three components as a result of increased protein flexibility. PMID- 20920299 TI - A cell-permeable dominant-negative survivin protein induces apoptosis and sensitizes prostate cancer cells to TNF-alpha therapy. AB - BACKGROUND: Survivin is a member of the inhibitor-of-apoptosis (IAP) family which is widely expressed by many different cancers. Overexpression of survivin is associated with drug resistance in cancer cells, and reduced patient survival after chemotherapy and radiotherapy. Agents that antagonize the function of survivin hold promise for treating many forms of cancer. The purpose of this study was to investigate whether a cell-permeable dominant-negative survivin protein would demonstrate bioactivity against prostate and cervical cancer cells grown in three dimensional culture. RESULTS: A dominant-negative survivin (C84A) protein fused to the cell penetrating peptide poly-arginine (R9) was expressed in E. coli and purified by affinity chromatography. Western blot analysis revealed that dNSurR9-C84A penetrated into 3D-cultured HeLa and DU145 cancer cells, and a cell viability assay revealed it induced cancer cell death. It increased the activities of caspase-9 and caspase-3, and rendered DU145 cells sensitive to TNF alpha via by a mechanism involving activation of caspase-8. CONCLUSIONS: The results demonstrate that antagonism of survivin function triggers the apoptosis of prostate and cervical cancer cells grown in 3D culture. It renders cancer cells sensitive to the proapoptotic affects of TNF-alpha, suggesting that survivin blocks the extrinsic pathway of apoptosis. Combination of the biologically active dNSurR9-C84A protein or other survivin antagonists with TNF alpha therapy warrants consideration as an approach to cancer therapy. PMID- 20920300 TI - Context-dependent functions of specific microRNAs in neuronal development. AB - MicroRNAs (miRNAs) are small noncoding RNAs that regulate multiple developmental processes at the post-transcriptional level. Recent rapid progresses have demonstrated critical roles for a number of miRNAs in neuronal development and function. In particular, miR-9 and miR-124 are specifically expressed in the mammalian nervous system, and their respective nucleotide sequences are 100% identical among many species. Yet, their expression patterns and mRNA targets are less conserved throughout evolution. As a consequence, these miRNAs exhibit diverse context-dependent functions in different aspects of neuronal development, ranging from early neurogenesis and neuronal differentiation to dendritic morphogenesis and synaptic plasticity. Some other neuronal miRNAs also exhibit context-dependent functions in development. Thus, post-transcriptional regulation of spatial and temporal expression levels of protein-coding genes by miRNAs contributes uniquely to the proper development and evolution of the complex nervous system. PMID- 20920302 TI - Suicide prevention in primary care: General practitioners' views on service availability. AB - BACKGROUND: Primary care may be a key setting for suicide prevention. However, comparatively little is known about the services available in primary care for suicide prevention. The aims of the current study were to describe services available in general practices for the management of suicidal patients and to examine GPs views on these services. We carried out a questionnaire and interview study in the North West of England. We collected data on GPs views of suicide prevention generally as well as local mental health service provision. FINDINGS: During the study period (2003-2005) we used the National Confidential Inquiry Suicide database to identify 286 general practitioners (GPs) who had registered patients who had died by suicide. Data were collected from GPs and practice managers in 167 practices. Responses suggested that there was greater availability of services and training for general mental health issues than for suicide prevention specifically. The three key themes which emerged from GP interviews were: barriers accessing primary or secondary mental health services; obstacles faced when referring a patient to mental health services; managing change within mental health care services CONCLUSIONS: Health professionals have an important role to play in preventing suicide. However, GPs expressed concerns about the quality of primary care mental health service provision and difficulties with access to secondary mental health services. Addressing these issues could facilitate future suicide prevention in primary care. PMID- 20920301 TI - Drosophila type II neuroblast lineages keep Prospero levels low to generate large clones that contribute to the adult brain central complex. AB - Tissue homeostasis depends on the ability of stem cells to properly regulate self renewal versus differentiation. Drosophila neural stem cells (neuroblasts) are a model system to study self-renewal and differentiation. Recent work has identified two types of larval neuroblasts that have different self renewal/differentiation properties. Type I neuroblasts bud off a series of small basal daughter cells (ganglion mother cells) that each generate two neurons. Type II neuroblasts bud off small basal daughter cells called intermediate progenitors (INPs), with each INP generating 6 to 12 neurons. Type I neuroblasts and INPs have nuclear Asense and cytoplasmic Prospero, whereas type II neuroblasts lack both these transcription factors. Here we test whether Prospero distinguishes type I/II neuroblast identity or proliferation profile, using several newly characterized Gal4 lines. We misexpress prospero using the 19H09-Gal4 line (expressed in type II neuroblasts but no adjacent type I neuroblasts) or 9D11 Gal4 line (expressed in INPs but not type II neuroblasts). We find that differential prospero expression does not distinguish type I and type II neuroblast identities, but Prospero regulates proliferation in both type I and type II neuroblast lineages. In addition, we use 9D11 lineage tracing to show that type II lineages generate both small-field and large-field neurons within the adult central complex, a brain region required for locomotion, flight, and visual pattern memory. PMID- 20920303 TI - Renal protection in diabetes: lessons from ONTARGET. AB - Hypertension is an important independent risk factor for renal disease. If hypertension and chronic renal disease co-exist, as is common in patients with diabetes mellitus, the risk of cardiovascular disease is heightened. The importance of rigorous blood pressure control is recognized in current guidelines, with a recommended target of office blood pressure of < 130/80 mmHg; although ambulatory blood pressure may be more appropriate in order to identify the 24-hour hypertensive burden. Even lower blood pressure may further reduce the progression of chronic kidney disease, but the incidence of cardiovascular events may increase. Albuminuria not only indicates renal damage, but is also a powerful predictor of cardiovascular morbidity and mortality at least in patients with high cardiovascular risk and potentially pre-existing vascular damage. Management of the multiple factors for renal and cardiovascular disease is mandatory in the diabetic patient. The renin-angiotensin system (RAS) plays a pivotal role in the progression of renal disease, as well as in hypertension and target-organ damage. The use of agents that target the RAS confer renoprotection in addition to antihypertensive activity. There is extensive evidence of the renoprotective effect of angiotensin II receptor blockers (ARBs), and specifically telmisartan. In addition to providing 24-hour blood pressure control, clinical studies in patients with diabetes show that telmisartan improves renal endothelial function, prevents progression from microalbuminuria to macroalbuminuria, slows the decline in glomerular filtration rate and reduces proteinuria in overt nephropathy. These effects cannot be solely attributed to blood pressure control. In contrast to other members of the ARB class, the renoprotective effect of telmisartan is not confined to the management of diabetic nephropathy; slowing the progression of albuminuria has been demonstrated in the ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET), which included diabetic and non-diabetic patients at high risk of cardiovascular events. PMID- 20920304 TI - Scoring of senescence signalling in multiple human tumour gene expression datasets, identification of a correlation between senescence score and drug toxicity in the NCI60 panel and a pro-inflammatory signature correlating with survival advantage in peritoneal mesothelioma. AB - BACKGROUND: Cellular senescence is a major barrier to tumour progression, though its role in pathogenesis of cancer and other diseases is poorly understood in vivo. Improved understanding of the degree to which latent senescence signalling persists in tumours might identify intervention strategies to provoke "accelerated senescence" responses as a therapeutic outcome. Senescence involves convergence of multiple pathways and requires ongoing dynamic signalling throughout its establishment and maintenance. Recent discovery of several new markers allows for an expression profiling approach to study specific senescence phenotypes in relevant tissue samples. We adopted a "senescence scoring" methodology based on expression profiles of multiple senescence markers to examine the degree to which signals of damage-associated or secretory senescence persist in various human tumours. RESULTS: We first show that scoring captures differential induction of damage or inflammatory pathways in a series of public datasets involving radiotherapy of colon adenocarcinoma, chemotherapy of breast cancer cells, replicative senescence of mesenchymal stem cells, and progression of melanoma. We extended these results to investigate correlations between senescence score and growth inhibition in response to ~1500 compounds in the NCI60 panel. Scoring of our own mesenchymal tumour dataset highlighted differential expression of secretory signalling pathways between distinct subgroups of MPNST, liposarcomas and peritoneal mesothelioma. Furthermore, a pro inflammatory signature yielded by hierarchical clustering of secretory markers showed prognostic significance in mesothelioma. CONCLUSIONS: We find that "senescence scoring" accurately reports senescence signalling in a variety of situations where senescence would be expected to occur and highlights differential expression of damage associated and secretory senescence pathways in a context-dependent manner. PMID- 20920305 TI - Relationship between severe obesity and gut inflammation in children: what's next? AB - BACKGROUND: Preliminary evidence suggests an association between obesity and gut inflammation. AIMS: To evaluate the frequency of glucose abnormalities and their correlation with systemic and intestinal inflammation in severely obese children. PATIENTS AND METHODS: Thirty-four children (25 males; median age 10.8 +/- 3.4 yrs) with severe obesity (BMI >95%) were screened for diabetes with oral glucose tolerance test (OGTT), systemic inflammation with C-reactive protein (CRP) and gut inflammation with rectal nitric oxide (NO) and faecal calprotectin. RESULTS: BMI ranged from 23 to 44 kg/m2, and BMI z-score between 2.08 e 4.93 (median 2.69 +/- 0.53). Glucose abnormalities were documented in 71% of patients: type 2 diabetes in 29%, impaired fasting glucose (IFG) in 58%, and impaired glucose tolerance (IGT) in 37.5%. Thirty-one patients (91%) were hyperinsulinemic. CRP was increased in 73.5% with a correlation between BMI z-score and CRP (p 0.03). Faecal calprotectin was increased in 47% patients (mean 77 +/- 68), and in 50% of children with abnormal glucose metabolism (mean 76 +/- 68 MUg/g), with a correlation with increasing BMI z-score. NO was pathological in 88%, and in 87.5% of glucose impairment (mean 6.8 +/- 5 MUM). CONCLUSIONS: In this study, the prevalence of glucose abnormalities in obese children is higher than in other series; furthermore, a correlation is present between markers of systemic and intestinal inflammation and glucose abnormalities. PMID- 20920306 TI - Evidence at a glance: error matrix approach for overviewing available evidence. AB - BACKGROUND: Clinical evidence continues to expand and is increasingly difficult to overview. We aimed at conceptualizing a visual assessment tool, i.e., a matrix for overviewing studies and their data in order to assess the clinical evidence at a glance. METHODS: A four-step matrix was constructed using the three dimensions of systematic error, random error, and design error. Matrix step I ranks the identified studies according to the dimensions of systematic errors and random errors. Matrix step II orders the studies according to the design errors. Matrix step III assesses the three dimensions of errors in studies. Matrix step IV assesses the size and direction of the intervention effect. RESULTS: The application of this four-step matrix is illustrated with two examples: peri operative beta-blockade initialized in relation to surgery versus placebo for major non-cardiac surgery, and antiarrhythmics for maintaining sinus rhythm after cardioversion of atrial fibrillation. When clinical evidence is deemed both internally and externally valid, the size of the intervention effect is to be assessed. CONCLUSION: The error matrix provides an overview of the validity of the available evidence at a glance, and may assist in deciding which interventions to use in clinical practice. PMID- 20920307 TI - Non-viral siRNA delivery into the mouse retina in vivo. AB - BACKGROUND: Gene silencing in the retina using RNA interference could open broad possibilities for functional studies of genes in vivo and for therapeutic interventions in eye disorders. Therefore, there is a considerable demand for protocols to deliver siRNA into the vertebrate retina. In this work we explored a possibility to deliver synthetic 21 bp siRNA into the mouse retina after intravitreal application using a non-viral carrier. METHODS: Fluorescently labelled synthetic 21 bp siRNA duplex was combined with Transit-TKO transfection reagent and injected intravitreally into adult mice eyes. Eyes cryostat sections and whole mount retinas were prepared 24-48 h post-injection, stained with either Hoechst 33342 (cell nuclei) or immunostained with anti-GFAP antibody (astroglia cells marker). Distribution of fluorescent siRNA signal in the retina was investigated. RESULTS: Single intravitreal injection of as little as 5 ng of siRNA combined with Transit-TKO transfection reagent by a modified protocol provided robust and non-toxic delivery of the siRNA into the retina. However, siRNA accumulation was predominantly confined to ganglion cells layer as analysed 24 h post-injection. Furthermore, siRNA containing particles were localized along GFAP cytoskeleton of retinal astroglial cells hinting on intracellular localization of the siRNA CONCLUSIONS: In this work we demonstrated that siRNA can be efficiently delivered into the vertebrate retina in vivo with low-toxicity using a non-viral carrier, specifically Transit-TKO transfection reagent. However, the capacity of siRNA delivered by our protocol to induce gene silencing in the retina has to be further evaluated. Our report could raise a closer look on Transit-TKO transfection reagent as a promising siRNA carrier in vivo and be of interest for the researchers and companies who work on development of ocular RNAi techniques. PMID- 20920308 TI - Targeting neurotensin as a potential novel approach for the treatment of autism. AB - The pathophysiology of autism remains obscure. Recently, serum neurotensin levels in children with autistic disorder have been found to be higher than those of normal children. Neurotensin is known to intensify neuronal NMDA-mediated glutamate signaling, which may cause apoptosis in autism. Further, an imbalance of glutamate/GABAergic system in autism has been described. These observations lead to a postulate that neurotensin may accentuate the hyperglutaminergic state in autism, leading to apoptosis. Targeting neurotensin might be a possible novel approach for the treatment of autism. PMID- 20920309 TI - Valuation of scleroderma and psoriatic arthritis health states by the general public. AB - OBJECTIVE: Psoriatic arthritis (PsA) and scleroderma (SSc) are chronic rheumatic disorders with detrimental effects on health-related quality of life. Our objective was to assess health values (utilities) from the general public for health states common to people with PsA and SSc for economic evaluations. METHODS: Adult subjects from the general population in a Midwestern city (N = 218) completed the SF-12 Health Survey and computer-assisted 0-100 rating scale (RS), time trade-off (TTO, range: 0.0-1.0) and standard gamble (SG, range: 0.0 1.0) utility assessments for several hypothetical PsA and SSc health states. RESULTS: Subjects included 135 (62%) females, 143 (66%) Caucasians, and 62 (28%) African-Americans. The mean (SD) scores for the SF-12 Physical Component Summary scale were 52.9 (8.3) and for the SF-12 Mental Component Summary scale were 49.0 (9.1), close to population norms. The mean RS, TTO, and SG scores for PsA health states varied with severity, ranging from 20.2 to 63.7 (14.4-20.3) for the RS 0.29 to 0.78 (0.24-0.31) for the TTO, and 0.48 to 0.82 (0.24-0.34) for the SG. The mean RS, TTO, and SG scores for SSc health states were 25.3-69.7 (15.2-16.3) for the RS, 0.36-0.80 (0.25-0.31) for the TTO, and 0.50-0.81 (0.26-0.32) for the SG, depending on disease severity. CONCLUSION: Health utilities for PsA and SSc health states as assessed from the general public reflect the severity of the diseases. These descriptive findings could have implications regarding comparative effectiveness research for tests and treatments for PsA and SSc. PMID- 20920310 TI - A potential role for intragenic miRNAs on their hosts' interactome. AB - BACKGROUND: miRNAs are small, non-coding RNA molecules that mainly act as negative regulators of target gene messages. Due to their regulatory functions, they have lately been implicated in several diseases, including malignancies. Roughly half of known miRNA genes are located within previously annotated protein coding regions ("intragenic miRNAs"). Although a role of intragenic miRNAs as negative feedback regulators has been speculated, to the best of our knowledge there have been no conclusive large-scale studies investigating the relationship between intragenic miRNAs and host genes and their pathways. RESULTS: miRNA containing host genes were three times longer, contained more introns and had longer 5' introns compared to a randomly sampled gene cohort. These results are consistent with the observation that more than 60% of intronic miRNAs are found within the first five 5' introns. Host gene 3'-untranslated regions (3'-UTRs) were 40% longer and contained significantly more adenylate/uridylate-rich elements (AREs) compared to a randomly sampled gene cohort. Coincidentally, recent literature suggests that several components of the miRNA biogenesis pathway are required for the rapid decay of mRNAs containing AREs. A high confidence set of predicted mRNA targets of intragenic miRNAs also shared many of these features with the host genes. Approximately 20% of intragenic miRNAs were predicted to target their host mRNA transcript. Further, KEGG pathway analysis demonstrated that 22 of the 74 pathways in which host genes were associated showed significant overrepresentation of proteins encoded by the mRNA targets of associated intragenic miRNAs. CONCLUSIONS: Our findings suggest that both host genes and intragenic miRNA targets may potentially be subject to multiple layers of regulation. Tight regulatory control of these genes is likely critical for cellular homeostasis and absence of disease. To this end, we examined the potential for negative feedback loops between intragenic miRNAs, host genes, and miRNA target genes. We describe, how higher-order miRNA feedback on hosts' interactomes may at least in part explain correlation patterns observed between expression of host genes and intragenic miRNA targets in healthy and tumor tissue. PMID- 20920311 TI - Carbohydrate antigens in nipple aspirate fluid predict the presence of atypia and cancer in women requiring diagnostic breast biopsy. AB - BACKGROUND: The goal of this prospective study was to determine (a) concentrations of the carbohydrate biomarkers Thomsen Friedenreich (TF) antigen and its precursor, Tn antigen, in nipple discharge (ND) collected from women requiring biopsy because of a suspicious breast lesion; and (b) if concentration levels predicted pathologic diagnosis. METHODS: Adult women requiring biopsy to exclude breast cancer were enrolled and ND obtained. The samples from 124 women were analyzed using an anti-TF and anti-Tn monoclonal antibodies in direct immunoassay. RESULTS: The highest median concentration in ND for TF and Tn was in women with ductal carcinoma in situ (DCIS). TF was higher in women with 1) cancer (DCIS or invasive) vs. either no cancer (atypia or benign pathology, p = .048), or benign pathology (p = .018); and 2) abnormal (atypia or cancer) versus benign pathology (p = .016); and was more predictive of atypia or cancer in post- compared to premenopausal women. Tn was not predictive of disease. High TF concentration and age were independent predictors of disease, correctly classifying either cancer or abnormal vs. benign pathology 83% of the time in postmenopausal women. CONCLUSIONS: TF concentrations in ND were higher in women with precancer and cancer compared to women with benign disease, and TF was an independent predictor of breast atypia and cancer. TF may prove useful in early breast cancer detection. PMID- 20920312 TI - A systematic study of genome context methods: calibration, normalization and combination. AB - BACKGROUND: Genome context methods have been introduced in the last decade as automatic methods to predict functional relatedness between genes in a target genome using the patterns of existence and relative locations of the homologs of those genes in a set of reference genomes. Much work has been done in the application of these methods to different bioinformatics tasks, but few papers present a systematic study of the methods and their combination necessary for their optimal use. RESULTS: We present a thorough study of the four main families of genome context methods found in the literature: phylogenetic profile, gene fusion, gene cluster, and gene neighbor. We find that for most organisms the gene neighbor method outperforms the phylogenetic profile method by as much as 40% in sensitivity, being competitive with the gene cluster method at low sensitivities. Gene fusion is generally the worst performing of the four methods. A thorough exploration of the parameter space for each method is performed and results across different target organisms are presented. We propose the use of normalization procedures as those used on microarray data for the genome context scores. We show that substantial gains can be achieved from the use of a simple normalization technique. In particular, the sensitivity of the phylogenetic profile method is improved by around 25% after normalization, resulting, to our knowledge, on the best-performing phylogenetic profile system in the literature. Finally, we show results from combining the various genome context methods into a single score. When using a cross-validation procedure to train the combiners, with both original and normalized scores as input, a decision tree combiner results in gains of up to 20% with respect to the gene neighbor method. Overall, this represents a gain of around 15% over what can be considered the state of the art in this area: the four original genome context methods combined using a procedure like that used in the STRING database. Unfortunately, we find that these gains disappear when the combiner is trained only with organisms that are phylogenetically distant from the target organism. CONCLUSIONS: Our experiments indicate that gene neighbor is the best individual genome context method and that gains from the combination of individual methods are very sensitive to the training data used to obtain the combiner's parameters. If adequate training data is not available, using the gene neighbor score by itself instead of a combined score might be the best choice. PMID- 20920313 TI - Assessment of orthologous splicing isoforms in human and mouse orthologous genes. AB - BACKGROUND: Recent discoveries have highlighted the fact that alternative splicing and alternative transcripts are the rule, rather than the exception, in metazoan genes. Since multiple transcript and protein variants expressed by the same gene are, by definition, structurally distinct and need not to be functionally equivalent, the concept of gene orthology should be extended to the transcript level in order to describe evolutionary relationships between structurally similar transcript variants. In other words, the identification of true orthology relationships between gene products now should progress beyond primary sequence and "splicing orthology", consisting in ancestrally shared exon intron structures, is required to define orthologous isoforms at transcript level. RESULTS: As a starting step in this direction, in this work we performed a large scale human- mouse gene comparison with a twofold goal: first, to assess if and to which extent traditional gene annotations such as RefSeq capture genuine splicing orthology; second, to provide a more detailed annotation and quantification of true human-mouse orthologous transcripts defined as transcripts of orthologous genes exhibiting the same splicing patterns. CONCLUSIONS: We observed an identical exon/intron structure for 32% of human and mouse orthologous genes. This figure increases to 87% using less stringent criteria for gene structure similarity, thus implying that for about 13% of the human RefSeq annotated genes (and about 25% of the corresponding transcripts) we could not identify any mouse transcript showing sufficient similarity to be confidently assigned as a splicing ortholog. Our data suggest that current gene and transcript data may still be rather incomplete - with several splicing variants still unknown. The observation that alternative splicing produces large numbers of alternative transcripts and proteins, some of them conserved across species and others truly species-specific, suggests that, still maintaining the conventional definition of gene orthology, a new concept of "splicing orthology" can be defined at transcript level. PMID- 20920314 TI - Therapeutic approach to bronchiolitis: why pediatricians continue to overprescribe drugs? AB - BACKGROUND: Bronchiolitis guidelines suggest that neither bronchodilators nor corticosteroids, antiviral and antibacterial agents should be routinely used. Although recommendations, many clinicians persistently prescribe drugs for bronchiolitis. AIM OF THE STUDY: To unravel main reasons of pediatricians in prescribing drugs to infants with bronchiolitis, and to possibly correlate therapeutic choices to the severity of clinical presentation. Also possible influence of socially deprived condition on therapeutic choices is analyzed. METHODS: Patients admitted to Pediatric Division of 2 main Hospitals of Naples because of bronchiolitis in winter season 2008-2009 were prospectively analyzed. An RDAI (Respiratory Distress Assessment Instrument) score was assessed at different times from admission. Enrollment criteria were: age 1-12 months; 1st lower respiratory infection with cough and rhinitis with/without fever, wheezing, crackles, tachypnea, use of accessory muscles, and/or nasal flaring, low oxygen saturation, cyanosis. Social deprivation status was assessed by evaluating school graduation level of the origin area of the patients. A specific questionnaire was submitted to clinicians to unravel reasons of their therapeutic behavior. RESULTS: Eighty-four children were enrolled in the study. Mean age was 3.5 months. Forty-four per cent of patients presented with increased respiratory rate, 70.2% with chest retractions, and 7.1% with low SaO2. Mean starting RDAI score was 8. Lung consolidation was found in 3.5% on chest roentgenogram. Data analysis also unraveled that 64.2% matched clinical admission criteria. Social deprivation status analysis revealed that 72.6% of patients were from areas "at social risk". Evaluation of length of stay vs. social deprivation status evidenced no difference between "at social risk" and "not at social risk" patients. Following therapeutic interventions were prescribed: nasal suction (64.2%), oxygen administration (7.1%), antibiotics (50%), corticosteroids (85.7%), bronchodilators (91.6%). Statistically significant association was not found for any used drug with neither RDAI score nor social deprivation status. The reasons of hospital pediatricians to prescribe drugs were mainly the perception of clinical severity of the disease, the clinical findings at chest examination, and the detection of some improvement after drug administration. CONCLUSIONS: We strongly confirm the large use of drugs in bronchiolitis management by hospital pediatricians. Main reason of this wrong practice appears to be the fact that pediatricians recognize bronchiolitis as a severe condition, with consequent anxiety in curing so acutely ill children without drugs, and that sometimes they feel forced to prescribe drugs because of personal reassurance or parental pressure. We also found that social "at risk" condition represents a main reason for hospitalization, not correlated to clinical severity of the disease neither to drug prescription. Eventually, we suggest a "step-by-step" strategy to rich a more evidence based approach to bronchiolitis therapy, by adopting specific and shared resident guidelines. PMID- 20920316 TI - Are component positioning and prosthesis size associated with hip resurfacing failure? AB - BACKGROUND: Recent studies suggest that there is a learning curve for metal-on metal hip resurfacing. The purpose of this study was to assess whether implant positioning changed with surgeon experience and whether positioning and component sizing were associated with implant longevity. METHODS: We evaluated the first 361 consecutive hip resurfacings performed by a single surgeon, which had a mean follow-up of 59 months (range, 28 to 87 months). Pre and post-operative radiographs were assessed to determine the inclination of the acetabular component, as well as the sagittal and coronal femoral stem-neck angles. Changes in the precision of component placement were determined by assessing changes in the standard deviation of each measurement using variance ratio and linear regression analysis. Additionally, the cup and stem-shaft angles as well as component sizes were compared between the 31 hips that failed over the follow-up period and the surviving components to assess for any differences that might have been associated with an increased risk for failure. RESULTS: Surgeon experience was correlated with improved precision of the antero-posterior and lateral positioning of the femoral component. However, femoral and acetabular radiographic implant positioning angles were not different between the surviving hips and failures. The failures had smaller mean femoral component diameters as compared to the non-failure group (44 versus 47 millimeters). CONCLUSIONS: These results suggest that there may be differences in implant positioning in early versus late learning curve procedures, but that in the absence of recognized risk factors such as intra-operative notching of the femoral neck and cup inclination in excess of 50 degrees, component positioning does not appear to be associated with failure. Nevertheless, surgeons should exercise caution in operating patients with small femoral necks, especially when they are early in the learning curve. PMID- 20920315 TI - Bilateral posterior RION after concomitant radiochemotherapy with temozolomide in a patient with glioblastoma multiforme: a case report. AB - BACKGROUND: Radiation induced optic neuropathy (RION) is a rare but severe consequence of radiation therapy that is associated with adjuvant chemotherapy, specifically therapy with vincristine or nitrosoureas. However, there is very little evidence regarding the occurrence of RION after concomitant radiochemotherapy with temozolomide. CASE PRESENTATION: The case of a 63 year old woman with glioblastoma multiforme and concomitant radiochemotherapy with temozolomide is described. Due to a slight depressive episode the patient also took hypericum perforatum. Five months after cessation of fractionated radiation and adjuvant chemotherapy with temozolomide (cumulative dose of 11040 mg) the patient developed bilateral amaurosis due to RION. Tumor regrowth was excluded by magnetic resonance imaging. After the application of gadolinium a pathognomonic contrast enhancement of both prechiasmatic optic nerves could be observed. CONCLUSIONS: In this patient, the occurrence of RION may have been the result of radiosensitization by temozolomide, which could have been strengthened by hypericin. Consequently, physicians should avoid a concomitant application of hypericum perforatum and radiochemotherapy. PMID- 20920317 TI - Molecular targets for the protodynamic action of cis-urocanic acid in human bladder carcinoma cells. AB - BACKGROUND: cis-urocanic acid (cis-UCA) is an endogenous amino acid metabolite capable of transporting protons from the mildly acidic extracellular medium into the cell cytosol. The resulting intracellular acidification suppresses many cellular activities. The current study was aimed at characterizing the molecular mechanisms underlying cis-UCA-mediated cytotoxicity in cultured cancer cells. METHODS: 5367 bladder carcinoma cells were left untreated or treated with cis UCA. Cell death was assessed by measuring caspase-3 activity, mitochondrial membrane polarization, formation and release of cytoplasmic histone-associated DNA fragments, and cellular permeabilization. Cell viability and metabolic activity were monitored by colorimetric assays. Nuclear labelling was used to quantify the effects of cis-UCA on cell cycle. The activity of the ERK and JNK signalling pathways was studied by immunoblotting with specific antibodies. Phosphatase activity in cis-UCA-treated cells was determined by assay kits measuring absorbance resulting from the dephosphorylation of an artificial substrate. All statistical analyses were performed using the two-way Student's t test (p < 0.05). RESULTS: Here we report that treatment of the 5637 human bladder carcinoma cells with 2% cis-UCA induces both apoptotic and necrotic cell death. In addition, metabolic activity of the 5637 cells is rapidly impaired, and the cells arrest in cell cycle in response to cis-UCA. Importantly, we show that cis UCA promotes the ERK and JNK signalling pathways by efficiently inhibiting the activity of serine/threonine and tyrosine phosphatases. CONCLUSIONS: Our studies elucidate how cis-UCA modulates several cellular processes, thereby inhibiting the proliferation and survival of bladder carcinoma cells. These anti-cancer effects make cis-UCA a potential candidate for the treatment of non-muscle invasive bladder carcinoma. PMID- 20920319 TI - Barriers towards insulin therapy in type 2 diabetic patients: results of an observational longitudinal study. AB - BACKGROUND: The course of barriers towards insulin therapy was analysed in three different groups of type 2 diabetic patients. This observational longitudinal study surveyed a three-month follow-up. METHODS: Participants in this study totalled 130 type 2 diabetic patients. The first subgroup was on insulin therapy at baseline (group 1: n = 57, age 55.6 +/- 8.7 yrs, disease duration 12.7 +/- 7.2 yrs, HbA1c 8.5 +/- 1.6%) and remained on insulin at follow-up. Of an initial 73 insulin-naive patients, 44 were switched to insulin therapy (group 2: age 58.1 +/ 6.8 yrs, disease duration 7.7 +/- 5.0 yrs, HbA1c 9.1 +/- 1.7%) and 29 patients remained on an oral regimen (group 3: age 52.7 +/- 10.7 yrs, disease duration 5.3 +/- 4.6 yrs, HbA1c 8.3 +/- 1.4%). Barriers towards insulin therapy were measured using the Insulin Treatment Appraisal Scale (ITAS). As generic instruments of health related quality of life patients completed also the Problem Areas of Diabetes Questionnaire (PAID), the WHO-5 Well-Being Scale (WHO-5), the Centre for Epidemiologic Studies Depression Scale (CES-D) and the Trait Version of the State Trait Anxiety Inventory (STAI) at baseline and at three-month follow-up. RESULTS: At the three-month follow-up, HbA1c had improved in all three groups (7.7 +/- 1.2% vs. 7.1 +/- 1.1% vs. 6.7 +/- 0.8%). The course of negative appraisal of insulin therapy was significantly different in the three groups (p > .003): the ITAS score increased in patients remained on oral antidiabetic drugs (51.2 +/- 12.2 to 53.6 +/- 12.3), whereas it decreased in patients switched to insulin therapy (49.2 +/- 9.8 to 46.2 +/- 9.9) or remained on insulin treatment (45.8 +/- 8.3 to 44.5 +/- 8.0). Diabetes-related distress, trait anxiety, and well-being, showed a similar course in all three groups. The depression score improved significantly in patients switched to insulin treatment compared with patients remaining on insulin therapy. CONCLUSIONS: In summary, this study suggests that a negative appraisal of insulin treatment is modifiable by the initiation of insulin therapy. This finding indicates that barriers to insulin are a rather temporary than a stable phenomenon. PMID- 20920318 TI - Molecular signature of response and potential pathways related to resistance to the HSP90 inhibitor, 17AAG, in breast cancer. AB - BACKGROUND: HSP90 may be a favorable target for investigational therapy in breast cancer. In fact, the HSP90 inhibitor, 17AAG, currently has entered in phase II clinical trials as an anticancer agent in breast and other tumors. Since HSP90 inhibition leads to global depletion of oncogenic proteins involved in multiple pathways we applied global analysis using gene array technology to study new genes and pathways involved in the drug response in breast cancer. METHODS: Gene expression profiling using Whole Human Genome Agilent array technology was applied to a total of six sensitive and two resistant breast cancer cell lines pre-treatment and treated with the 17AAG for 24 and 48 hours. RESULTS: We have identified a common molecular signature of response to 17AAG composed of 35 genes which include novel pharmacodynamic markers of this drug. In addition, different patterns of HSP90 client transcriptional changes after 17AAG were identified associated to the sensitive cell lines, which could be useful to evaluate drug effectiveness. Finally, we have found differentially expressed pathways associated to resistance to 17AAG. We observed significant activation of NF kappaB and MAPK pathways in resistant cells upon treatment, indicating that these pathways could be potentially targeted to overcome resistance. CONCLUSIONS: Our study shows that global mRNA expression analysis is a useful strategy to examine molecular effects of drugs, which allowed us the discovery of new biomarkers of 17AAG activity and provided more insights into the complex mechanism of 17AAG resistance. PMID- 20920320 TI - C-reactive protein serum levels as an early predictor of outcome in patients with pandemic H1N1 influenza A virus infection. AB - BACKGROUND: Data for predicting which patients with pandemic influenza A (H1N1) infection are likely to run a complicated course are sparse. We retrospectively studied whether the admission serum C-reactive protein (CRP) levels can serve as a predictor of illness severity. METHODS: Included were all consecutive adult patients who presented to the emergency department (ED) between May-December, 2009 with a flu-like illness, a confirmed diagnosis of pandemic influenza A (H1N1) infection and a serum CRP level measured within 24 hours of presentation. Patients with a proven additional concurrent acute illness (e.g., bacteremia) were excluded. We used the ROC curve analysis, Kaplan-Meier curves and the Cox proportional hazard model to evaluate the predictive ability of CRP as a prognostic factor. RESULTS: Seventeen (9%) of the 191 enrolled patients were admitted to the intensive care unit (ICU), of whom eight (4%) required mechanical ventilation and three (2%) died. The median admission serum CRP levels were significantly higher among patients who required subsequent ICU care and mechanical ventilation than among patients who did not (123 mg/L and 112 mg/L vs. 40 mg/L, p < .001 and 43 mg/L, p = .017, respectively). A Cox proportional hazard model identified admission serum CRP levels and auscultatory findings over the lungs as independent prognostic factors for ICU admission. Admission serum CRP levels were the only independent prognostic factor for mechanical ventilation. Thirty days after presenting to the ED, none of the patients with admission serum CRP level <28 mg/L (lower tertile) required either ICU admission or mechanical ventilation. At the same time point, 19% of the patients with admission serum CRP level >=70 mg/L (upper tertile) needed to be admitted to the ICU and 8% of the same upper tertile group required mechanical ventilation. The differences in the rates between the lower vs. upper tertile groups were significant (Log-Rank p < .001 for ICU and p < .024 for mechanical ventilation). CONCLUSIONS: In our study group, serum CRP levels obtained in the early ED admission stage from patients presenting with pandemic H1N1 influenza A infection were found to serve as a useful gauge for predicting disease course and assisting in patient management. PMID- 20920321 TI - Microsatellite typing and susceptibilities of serial Cryptococcus neoformans isolates from Cuban patients with recurrent cryptococcal meningitis. AB - BACKGROUND: Cryptococcus neoformans is commonly associated with meningoencephalitis in immunocompromised patients and occasionally in apparently healthy individuals. Recurrence of infection after initial treatment is not uncommon. We studied C. neoformans isolates from 7 Cuban patients with recurrent cryptococcal meningitis. Antifungal susceptibility and genotyping with microsatellite molecular typing were carried out. METHODS: Isolates (n = 19) were recovered from cerebrospinal fluid, blood, urine and semen. Antifungal susceptibilities for amphotericin B, fluconazole, flucytosine, itraconazole, voriconazole, posaconazole and isavuconazole were tested by CLSI M27A3 broth microdilution method. Genotyping was done using a panel of 9 microsatellite (STR) markers: (CT)n, (TG)n, (TA)n, (CTA)n, (TCT)n, (CCA)n, (TTAT)n, (ATCC)n and (TATT)n. RESULTS: The average number of isolates/patient was 2.71. The mean time interval between the collection of any two isolates was 52.5 days. All strains were identified as C. neoformans var. grubii (serotype Aalpha). Although none of the strains were resistant to the studied drugs, in serial isolates from two patients, MICs values of triazoles increased 4-5 log2 dilutions over time. STR patterns showed 14 distinctive profiles. In three patients the recurrent infection was associated with genotypically identical isolates. The four other patients had relapse isolates which were genotypically different from the initial infecting strain. CONCLUSION: Recurrences of cryptococcal meningitis in our series of patients was not associated with development of drug resistance of the original strain but by an initial infection with different strains or a reinfection with a new strain. PMID- 20920322 TI - On-ward participation of a hospital pharmacist in a Dutch intensive care unit reduces prescribing errors and related patient harm: an intervention study. AB - INTRODUCTION: Patients admitted to an intensive care unit (ICU) are at high risk for prescribing errors and related adverse drug events (ADEs). An effective intervention to decrease this risk, based on studies conducted mainly in North America, is on-ward participation of a clinical pharmacist in an ICU team. As the Dutch Healthcare System is organized differently and the on-ward role of hospital pharmacists in Dutch ICU teams is not well established, we conducted an intervention study to investigate whether participation of a hospital pharmacist can also be an effective approach in reducing prescribing errors and related patient harm (preventable ADEs) in this specific setting. METHODS: A prospective study compared a baseline period with an intervention period. During the intervention period, an ICU hospital pharmacist reviewed medication orders for patients admitted to the ICU, noted issues related to prescribing, formulated recommendations and discussed those during patient review meetings with the attending ICU physicians. Prescribing issues were scored as prescribing errors when consensus was reached between the ICU hospital pharmacist and ICU physicians. RESULTS: During the 8.5-month study period, medication orders for 1,173 patients were reviewed. The ICU hospital pharmacist made a total of 659 recommendations. During the intervention period, the rate of consensus between the ICU hospital pharmacist and ICU physicians was 74%. The incidence of prescribing errors during the intervention period was significantly lower than during the baseline period: 62.5 per 1,000 monitored patient-days versus 190.5 per 1,000 monitored patient-days, respectively (P < 0.001). Preventable ADEs (patient harm, National Coordinating Council for Medication Error Reporting and Prevention severity categories E and F) were reduced from 4.0 per 1,000 monitored patient-days during the baseline period to 1.0 per 1,000 monitored patient-days during the intervention period (P = 0.25). Per monitored patient-day, the intervention itself cost ?3, but might have saved ?26 to ?40 by preventing ADEs. CONCLUSIONS: On-ward participation of a hospital pharmacist in a Dutch ICU was associated with significant reductions in prescribing errors and related patient harm (preventable ADEs) at acceptable costs per monitored patient-day. TRIAL REGISTRATION NUMBER: ISRCTN92487665. PMID- 20920323 TI - Anthracycline and concurrent radiotherapy as adjuvant treatment of operable breast cancer: a retrospective cohort study in a single institution. AB - BACKGROUND: Concurrent chemoradiotherapy (CCRT) after breast surgery was investigated by few authors and remains controversial, because of concerns of toxicity with taxanes/anthracyclines and radiation. This treatment is not standard and is more commonly used for locally advanced breast cancer. The aim of our study was to evaluate the efficacy and safety of the concomitant use of anthracycline with radiotherapy (RT). FINDINGS: Four hundred women having operable breast cancer, treated by adjuvant chemotherapy (CT) and RT in concomitant way between January 2001 and December 2003, were included in this retrospective cohort study. The study compares 2 adjuvant treatments using CCRT, the first with anthracycline (group A) and the second with CMF (group B). The CT treatment was repeated every 21 days for 6 courses and the total delivered dose of RT was 50 Gy, divided as 2 Gy daily fractions. Locoregional recurrence free (LRFS), event free (EFS), and overall survivals (OS) were estimated by the Kaplan Meier method. The log-rank test was used to compare survival events. Multivariate Cox-regression was used to evaluate the relationship between patient characteristics, treatment and survival.In the 2 groups (A+B) (n = 400; 249 in group A and 151 in group B), the median follow-up period was 74.5 months. At 5 years, the isolated LRFS was significantly higher in group A compared to group B (98.7% vs 95.3%; hazard ratio [HR] = 0.258; 95% CI, 0.067 to 0.997; log-rank P = .034). In addition, the use of anthracycline regimens was associated with a higher rate of 5 years EFS (80.4% vs 75.1%; HR = 0.665; 95% CI, 0.455 to 1.016; log-rank P = .057). The 5 years OS was 83.2% and 79.2% in the anthracycline and CMF groups, respectively (HR = 0.708; 95% CI, 0.455 to 1.128; log-rank P = .143). Multivariate analysis confirmed the positive effect of anthracycline regimens on LRFS (HR = 0.347; 95% CI, 0.114 to 1.053; log-rank P = .062), EFS (HR = 0.539; 95% CI, 0.344 to 0.846; P = 0.012), and OS (HR = 0.63; 95% CI, 0.401 to 0.991; P = .046). LRFS, EFS and OS were significantly higher in the anthracycline group where the patients (n = 288) received more than 1 cycle of concurrent CT (P = .038, P = .026 and P = .038, respectively). LRFS and EFS were significantly higher in the anthracycline group within the BCT subgroup (P = .049 and P = .04, respectively). There were more hematologic, and more grade 2/3/4 skin toxicity in the anthracycline group. CONCLUSIONS: After mastectomy or BCT, the adjuvant treatment based on anthracycline and concurrent RT reduced breast cancer relapse rate, and significantly improved LRFS, EFS and OS in the patients receiving more than 1 cycle of concurrent CT. There were more hematologic and non hematologic toxicities in the anthracycline group. PMID- 20920324 TI - Partial trisomy 9p22 to 9p24.2 in combination with partial monosomy 9pter in a Syrian girl. AB - BACKGROUND: Partial trisomy of the short arm of chromosome 9 is among the most common autosomal structural chromosomal anomalies leading to chromosomal imbalance in human. Clinical characteristics are craniofacial dysmorphism including hypertelorism, prominent nose, deep-set eyes, and down-slanting palpebral fissures. The degree of clinical severity in partial trisomy 9p roughly correlates with the size of the chromosomal imbalance. Therefore, breakpoints as well as clinical findings need to be precisely defined for differential diagnosis. RESULTS: Chromosomes of a young female were analyzed due to primary amenorrhea, short stature, developmental delay and a characteristic facial appearance. Cytogenetic analysis using GTG banding identified a karyotype 46, XX, add(9pter). Surprisingly the application of high resolution molecular cytogenetic techniques characterized a partial trisomy 9p24.2-p22 and partial monosomy 9pter p24.2. To the best of our knowledge only four similar case were reported by now. CONCLUSION: Attempts for genotype-phenotype correlations for partial trisomy 9p might have been hampered by the fact that more complex, cryptic aberrations were neither considered nor detected in comparable clinical cases. PMID- 20920325 TI - Carbon ion radiotherapy for basal cell adenocarcinoma of the head and neck: preliminary report of six cases and review of the literature. AB - BACKGROUND: Basal cell adenocarcinoma accounts for approximately 1.6% of all salivary gland neoplasms. In this report, we describe our experiences of treatment for BCAC with carbon ion radiotherapy in our institution. METHODS: Case records of 6 patients with diagnosis of basal cell adenocarcinoma of the head and neck, who were treated by carbon ion radiotherapy with 64.0 GyE/16 fractions in our institution, were retrospectively reviewed. RESULTS: In a mean follow-up period of 32.1 months (14.0-51.3 months), overall survival and local control rates of 100% were achieved. Only one grade 4 (CTCAE v3.0) late complication occurred. There was no other grade 3 or higher toxicity. CONCLUSIONS: Carbon ion radiotherapy should be considered as an appropriate curative approach for treatment of basal cell adenocarcinoma in certain cases, particularly in cases of unresectable disease and postoperative gross residual or recurrent disease. PMID- 20920326 TI - Acute hiatal hernia: a late complication following gastrectomy. AB - INTRODUCTION: We describe a case of acute hiatal hernia during chemotherapy, in a female patient previously treated with gastrectomy. CASE PRESENTATION: After gastric resection, the patient underwent chemotherapy, developing important emetic symptoms. A radiograph of the abdomen was performed because of acute epigastrial pain and it showed a marked left diaphragm elevation.A CT scan carried out 24 hours later identified an occlusion with herniation in the left hemi thorax. Subsequent surgical investigation resulted in a diagnosis of hiatal hernia with volvulus. CONCLUSIONS: This case represents a rare, late complication occurring after gastrectomy. PMID- 20920327 TI - Elevated expression of Dickkopf-1 increases the sensitivity of human glioma cell line SHG44 to BCNU. AB - BACKGROUND: Studies have shown that Dickkopf-1 (DKK-1) is involved in tumorigenesis. Recently, we found that 9 out of 12 human glioma cell lines had high level of DKK-1 protein while the other 3 had very low or non-detectable level of DKK-1. The aim of this study is to further examine the function of DKK-1 in glioma cells. MATERIALS AND METHODS: The glioma cell line SHG44 was obtained from a patient with grade II-III astrocytoma. SHG44 cells were transfected with a human DKK-1 gene. Transfection of the empty vector pcDNA3.1 was used as negative control. Sensitivity to BCNU was measured by Annexin-V staining. Expression of bax, bcl-2 and caspase-3 of three groups was determined by immunohistochemistry. RESULTS: The tranfection was confirmed by PCR, RT-PCR and Western blot. More apoptotic cell death was observed in the DKK-1 transfected cells, comparing to the non-transfected cells, or cells with empty vector. The expression of bax and caspase-3 of the SHG44 -DDK-1 increased, whereas the expression of bcl-2 decreased CONCLUSION: Our results indicated that DKK-1 has a pro-apoptotic function of in glioma. PMID- 20920328 TI - A method of active case detection to target reservoirs of asymptomatic malaria and gametocyte carriers in a rural area in Southern Province, Zambia. AB - BACKGROUND: Asymptomatic reservoirs of malaria parasites are common yet are difficult to detect, posing a problem for malaria control. If control programmes focus on mosquito control and treatment of symptomatic individuals only, malaria can quickly resurge if interventions are scaled back. Foci of parasite populations must be identified and treated. Therefore, an active case detection system that facilitates detection of asymptomatic parasitaemia and gametocyte carriers was developed and tested in the Macha region in southern Zambia. METHODS: Each week, nurses at participating rural health centres (RHC) communicated the number of rapid diagnostic test (RDT) positive malaria cases to a central research team. During the dry season when malaria transmission was lowest, the research team followed up each positive case reported by the RHC by a visit to the homestead. The coordinates of the location were obtained by GPS and all consenting residents completed a questionnaire and were screened for malaria using thick blood film, RDT, nested-PCR, and RT-PCR for asexual and sexual stage parasites. Persons who tested positive by RDT were treated with artemether/lumefantrine (Coartem). Data were compared with a community-based study of randomly selected households to assess the prevalence of asymptomatic parasitaemia in the same localities in September 2009. RESULTS: In total, 186 and 141 participants residing in 23 case and 24 control homesteads, respectively, were screened. In the case homesteads for which a control population was available (10 of the 23), household members of clinically diagnosed cases had a 8.0% prevalence of malaria using PCR compared to 0.7% PCR positive individuals in the control group (p = 0.006). The case and control groups had a gametocyte prevalence of 2.3% and 0%, respectively but the difference was not significant (p = 0.145). CONCLUSIONS: This pilot project showed that active case detection is feasible and can identify reservoirs of asymptomatic infection. A larger sample size, data over multiple low transmission seasons, and in areas with different transmission dynamics are needed to further validate this approach. PMID- 20920329 TI - Inflammation and adipose tissue: effects of progressive load training in rats. AB - INTRODUCTION: Cytokines (IL-6, IL-10 and TNF-alpha) are increased after exhaustive exercise in the rat retroperitoneal (RPAT) and mesenteric adipose tissue (MEAT) pads. On the other hand, these cytokines show decreased expression in these depots in response to a chronic exercise protocol. However, the effect of exercise with overload combined with a short recovery period on pro- and anti inflammatory cytokine expression is unknown. In the present study, we investigated the regulation of cytokine production in the adipose tissue of rats after an overtraining-inducing exercise protocol. METHODS: Male Wistar rats were divided into four groups: Control (C), Trained (Tr), Overtrained (OT) and recovered overtrained (R). Cytokines (IL-6, TNF-alpha and IL-10) levels and Toll Like Receptor 4 (TLR4), Nuclear Factor kBp65 (NF-kBp65), Hormone Sensitive Lipase (HSL) and, Perilipin protein expression were assessed in the adipose tissue. Furthermore, we analysed plasma lipid profile, insulin, testosterone, corticosterone and endotoxin levels, and liver triacylglycerol, cytokine content, as well as apolipoprotein B (apoB) and TLR4 expression in the liver. RESULTS: OT and R groups exhibited reduced performance accompanied by lower testosterone and increased corticosterone and endotoxin levels when compared with the control and trained groups. IL-6 and IL-10 protein levels were increased in the adipose tissue of the group allowed to recover, in comparison with all the other studied groups. TLR-4 and NF-kBp65 were increased in this same group when compared with both control and trained groups. The protein expression of HSL was increased and that of Perilipin, decreased in the adipose in R in relation to the control. In addition, we found increased liver and serum TAG, along with reduced apoB protein expression and IL-6 and IL-10 levels in the of R in relation to the control and trained groups. CONCLUSION: In conclusion, we have shown that increases in pro inflammatory cytokines in the adipose tissue after an overtraining protocol may be mediated via TLR-4 and NF-kBp65 signalling, leading to an inflammatory state in this tissue. PMID- 20920330 TI - Association between the Cytotoxic T-lymphocyte antigen 4 +49G > A polymorphism and cancer risk: a meta-analysis. AB - BACKGROUND: As a key gene in the immunosurveillance of cell malignancy, Cytotoxic T-lymphocyte antigen 4 (CTLA-4 is an important negative regulator of T cell activation and proliferation. The CTLA-4 +49G > A polymorphism is one of the most commonly studied polymorphisms in this gene due to its association with cancer risks, but previous results have been conflicting. METHODS: We preformed a meta analysis using 22 eligible case-control studies (including 32 datasets) with a total of 11,273 patients and 13,179 controls to summarize the existing data on the association between the CTLA-4 +49G > A polymorphism and cancer risk. RESULTS: Compared with the common CTLA-4 +49G > A GG genotype, the carriers of variant genotypes (CTLA-4 +49 GC/CC) had a 1.24-fold elevated risk of cancer (95% CI = 1.18-1.32, P < 0.05) under the dominant genetic model, as estimated using a fixed effect model. The effect of the CTLA-4 +49G > A polymorphism was further evaluated using stratification analysis. In four breast cancer studies, patients with the variant genotypes had a significantly increased risk of breast cancer (OR = 1.31, 95% CI = 1.17-1.48, P < 0.00001). A similar result was found in three skin cancer studies (OR = 1.30, 95% CI = 1.10-1.52, P = 0.001). In 26 solid tumor studies, subjects with the variant genotypes had a significantly higher risk of developing solid tumors (OR = 1.25, 95% CI = 1.18-1.33, P < 0.00001) compared with the 6 non-solid tumor studies (OR = 1.08, 95% CI = 0.79-1.48, P = 0.62). Patients with variant genotypes had significantly increased risk of non epithelial tumors and epithelial tumors, with ORs of 1.23 (95% CI = 1.14-1.32, P < 0.00001) and 1.29 (95% CI = 1.17-1.41, P < 0.00001), respectively. It was also demonstrated that the increased risk of cancer associated with CTLA-4 +49G > A variant genotypes was more pronounced in Caucasians (OR = 1.29, 95% CI = 1.13 1.47, P = 0.0002), Asians (OR = 1.23, 95% CI = 1.16-1.32, P < 0.00001) and Chinese (OR = 1.23, 95% CI = 1.15-1.31, P < 0.00001). CONCLUSION: Our meta analysis suggests that the CTLA-4 +49G > A polymorphism genotypes (GA + AA) might be associated with an increased risk of cancer, especially in Caucasians and Chinese. PMID- 20920331 TI - Distribution and persistence of pleural penetrations by multi-walled carbon nanotubes. AB - BACKGROUND: Multi-walled carbon nanotubes (MWCNT) are new manufactured nanomaterials with a wide spectrum of commercial applications. The durability and fiber-like dimensions (mean length 3.9 MUm long * 49 nm diameter) of MWCNT suggest that these fibers may migrate to and have toxicity within the pleural region. To address whether the pleura received a significant and persistent exposure, C57BL/6J mice were exposed by pharyngeal aspiration to 10, 20, 40 and 80 MUg MWCNT or vehicle and the distribution of MWCNT penetrations determined at 1, 7, 28 and 56 days after exposure. Following lung fixation and sectioning, morphometric methods were used to determine the distribution of MWCNT and the number of MWCNT fiber penetrations of three barriers: alveolar epithelium (alveolar penetrations), the alveolar epithelium immediately adjacent to the pleura (subpleural tissue), and visceral pleural surface (intrapleural space). RESULTS: At 1 day 18%, 81.6% and 0.6% of the MWCNT lung burden was in the airway, the alveolar, and the subpleural regions, respectively. There was an initial, high density of penetrations into the subpleural tissue and the intrapleural space one day following aspiration which appeared to decrease due to clearance by alveolar macrophages and/or lymphatics by day 7. However, the density of penetrations increased to steady state levels in the subpleural tissue and intrapleural from day 28 - 56. At day 56 approximately 1 in every 400 fiber penetrations was in either the subpleural tissue or intrapleural space. Numerous penetrations into macrophages in the alveolar airspaces throughout the lungs were demonstrated at all times but are not included in the counts presented. CONCLUSIONS: The results document that MWCNT penetrations of alveolar macrophages, the alveolar wall, and visceral pleura are both frequent and sustained. In addition, the findings demonstrate the need to investigate the chronic toxicity of MWCNT at these sites. PMID- 20920332 TI - Association between treated/untreated traumatic dental injuries and impact on quality of life of Brazilian schoolchildren. AB - BACKGROUND: Traumatic dental injury (TDI) could have physical and psychosocial consequences for children. Thus, it is important to measure the impact of TDI on the quality of life of children (QoL). The aim of the present study was to investigate the association between treated/untreated TDI and the impact on the quality of life of 11-to-14-year-old Brazilian schoolchildren. METHODS: A cross sectional study was carried out involving 1612 male and female schoolchildren aged 11 to 14 years attending public and private elementary schools in the city of Belo Horizonte, Brazil. A multi-stage sampling technique was adopted to select the children. Three calibrated examiners used the Andreasen classification for the diagnosis of TDI. Oral health-related quality of life was assessed using the Brazilian version of the Child Perceptions Questionnaire (CPQ11-14) - Impact Short Form (ISF:16), composed of 16 items and self-administered by all children. Other oral conditions (dental caries and malocclusion) and the Social Vulnerability Index were determined and used as controlling variables. RESULTS: Two hundred nineteen children were diagnosed with untreated TDI and 64 were diagnosed with treated TDI. There were no statistically significant associations between untreated or treated TDI and overall CPQ11-14 (Fisher = 0.368 and Fisher = 0.610, respectively). Children with an untreated TDI were 1.4-fold (95% CI = 1.1-2.1) more likely to report impact on the item "avoided smiling/laughing" than those without TDI, whereas children with a treated TDI were twofold (95% CI = 1.1 3.5) more likely to report impact on the item "other children asked questions" than those without TDI. CONCLUSIONS: Neither treated nor untreated TDI was associated with oral symptoms, functional limitations or emotional wellbeing. However, children with a TDI in the anterior teeth experienced a negative impact on social wellbeing, mainly with regard to avoiding smiling or laughing and being concerned about what other people may think or say. PMID- 20920333 TI - Discovering joint associations between disease and gene pairs with a novel similarity test. AB - BACKGROUND: Genes in a functional pathway can have complex interactions. A gene might activate or suppress another gene, so it is of interest to test joint associations of gene pairs. To simultaneously detect the joint association between disease and two genes (or two chromosomal regions), we propose a new test with the use of genomic similarities. Our test is designed to detect epistasis in the absence of main effects, main effects in the absence of epistasis, or the presence of both main effects and epistasis. RESULTS: The simulation results show that our similarity test with the matching measure is more powerful than the Pearson's chi2 test when the disease mutants were introduced at common haplotypes, but is less powerful when the disease mutants were introduced at rare haplotypes. Our similarity tests with the counting measures are more sensitive to marker informativity and linkage disequilibrium patterns, and thus are often inferior to the similarity test with the matching measure and the Pearson's chi2 test. CONCLUSIONS: In detecting joint associations between disease and gene pairs, our similarity test is a complementary method to the Pearson's chi2 test. PMID- 20920334 TI - The intriguing cyclophilin A-HIV-1 Vpr interaction: prolyl cis/trans isomerisation catalysis and specific binding. AB - BACKGROUND: Cyclophilin A (CypA) represents a potential target for antiretroviral therapy since inhibition of CypA suppresses human immunodeficiency virus type 1 (HIV-1) replication, although the mechanism through which CypA modulates HIV-1 infectivity still remains unclear. The interaction of HIV-1 viral protein R (Vpr) with the human peptidyl prolyl isomerase CypA is known to occur in vitro and in vivo. However, the nature of the interaction of CypA with Pro-35 of N-terminal Vpr has remained undefined. RESULTS: Characterization of the interactions of human CypA with N-terminal peptides of HIV-1 Vpr has been achieved using a combination of nuclear magnetic resonace (NMR) exchange spectroscopy and surface plasmon resonance spectroscopy (SPR). NMR data at atomic resolution indicate prolyl cis/trans isomerisation of the highly conserved proline residues Pro-5, 10, -14 and -35 of Vpr are catalyzed by human CypA and require only very low concentrations of the isomerase relative to that of the peptide substrates. Of the N-terminal peptides of Vpr only those containing Pro-35 bind to CypA in a biosensor assay. SPR studies of specific N-terminal peptides with decreasing numbers of residues revealed that a seven-residue motif centred at Pro-35 consisting of RHFPRIW, which under membrane-like solution conditions comprises the loop region connecting helix 1 and 2 of Vpr and the two terminal residues of helix 1, is sufficient to maintain strong specific binding. CONCLUSIONS: Only N terminal peptides of Vpr containing Pro-35, which appears to be vital for manifold functions of Vpr, bind to CypA in a biosensor assay. This indicates that Pro-35 is essential for a specific CypA-Vpr binding interaction, in contrast to the general prolyl cis/trans isomerisation observed for all proline residues of Vpr, which only involve transient enzyme-substrate interactions. Previously suggested models depicting CypA as a chaperone that plays a role in HIV-1 virulence are now supported by our data. In detail the SPR data of this interaction were compatible with a two-state binding interaction model that involves a conformational change during binding. This is in accord with the structural changes observed by NMR suggesting CypA catalyzes the prolyl cis/trans interconversion during binding to the RHFP35RIW motif of N-terminal Vpr. PMID- 20920336 TI - Polymorphisms of XRCC4 are involved in reduced colorectal cancer risk in Chinese schizophrenia patients. AB - BACKGROUND: Genetic factors related to the regulation of apoptosis in schizophrenia patients may be involved in a reduced vulnerability to cancer. XRCC4 is one of the potential candidate genes associated with schizophrenia which might induce colorectal cancer resistance. METHODS: To examine the genetic association between colorectal cancer and schizophrenia, we analyzed five SNPs (rs6452526, rs2662238, rs963248, rs35268, rs2386275) covering ~205.7 kb in the region of XRCC4. RESULTS: We observed that two of the five genetic polymorphisms showed statistically significant differences between 312 colorectal cancer subjects without schizophrenia and 270 schizophrenia subjects (rs6452536, p = 0.004, OR 0.61, 95% CI 0.44-0.86; rs35268, p = 0.028, OR 1.54, 95% CI 1.05-2.26). Moreover, the haplotype which combined all five markers was the most significant, giving a global p = 0.0005. CONCLUSIONS: Our data firstly indicate that XRCC4 may be a potential protective gene towards schizophrenia, conferring reduced susceptibility to colorectal cancer in the Han Chinese population. PMID- 20920337 TI - An introduction to standardized clinical nomenclature for dysmorphic features: the Elements of Morphology project. AB - Human structural malformations (anomalies or birth defects) have an enormous and complex range of manifestations and severity. The description of these findings can be challenging because the variation of many of the features is continuous and only some of them can be objectively assessed (that is, measured), among other factors. An international group of clinicians resolved to develop a set of terms that could be used to describe human structural malformations, under the general project name 'Elements of Morphology'. Here, the background to the project, progress to date, and the practical implementation of the terminology in research reporting is discussed. PMID- 20920335 TI - Expression and biological-clinical significance of hTR, hTERT and CKS2 in washing fluids of patients with bladder cancer. AB - BACKGROUND: at present, pathogenesis of bladder cancer (BC) has not been fully elucidated. Aim of this study is to investigate the role of human telomerase RNA (hTR), human telomerase reverse transcriptase (hTERT) and CDC28 protein kinase regulatory subunit 2 (CKS2) in bladder carcinogenesis and their possible clinical significance; METHODS: the transcript levels of hTR, hTERT and CKS2 were quantified by Real time reverse transcriptase chain reaction in exfoliated cells from bladder washings of 36 patients with BC and 58 controls. The statistical significance of differences between BC bearing patients and control groups, in the general as well as in the stratified analysis (superficial or invasive BC), was assessed by Student's t test. Non parametric Receiver Operating Characteristics analysis (ROC) was performed to ascertain the accuracy of study variables to discriminate between BC and controls. The clinical value of concomitant examination of hTR, hTERT and CKS2 was evaluated by logistic regression analysis; RESULTS: a significant decrease in hTR and a significant increase in hTERT or CKS2 gene expression were found between BC bearing patients and controls, as well as in the subgroups analysis. The area under the curve (AUC) indicated an average discrimination power for the three genes, both in the general and subgroups analysis, when singularly considered. The ability to significantly discriminate between superficial and invasive BC was observed only for hTR transcript levels. A combined model including hTR and CKS2 was the best one in BC diagnosis; CONCLUSIONS: our results, obtained from a sample set particularly rich of exfoliated cells, provide further molecular evidence on the involvement of hTR, hTERT and CKS2 gene expression in BC carcinogenesis. In particular, while hTERT and CKS2 gene expression seems to have a major involvement in the early stages of the disease, hTR gene expression, seems to be more involved in progression. In addition, our findings suggest that the studied genes have a clinical role in discriminating between BC and controls in the general as well as in the stratified analysis, when singularly considered. A combined model improved over the single marker BC diagnosis. PMID- 20920338 TI - An ELISA-based high throughput protein truncation test for inherited breast cancer. AB - INTRODUCTION: Breast cancer is the most diagnosed and second leading cause of cancer deaths in the U.S. female population. An estimated 5 to 10 percent of all breast cancers are inherited, caused by mutations in the breast cancer susceptibility genes (BRCA1/2). As many as 90% of all mutations are nonsense mutations, causing a truncated polypeptide product. A popular and low cost method of mutation detection has been the protein truncation test (PTT), where target regions of BRCA1/2 are PCR amplified, transcribed/translated in a cell-free protein synthesis system and analyzed for truncated polypeptides by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and autoradiography. We previously reported a novel High Throughput Solid-Phase PTT (HTS-PTT) based on an enzyme-linked immunosorbent assay (ELISA) format that eliminates the need for radioactivity, SDS-PAGE and subjective interpretation of the results. Here, we report the next generation HTS-PTT using triple-epitope tagged proteins and demonstrate, for the first time, its efficacy on clinical genomic DNA samples for BRCA1/2 analysis. METHODS: Segments of exons 11 of BRCA1/2 open reading frames were PCR amplified from either blood derived genomic DNA or cell line mRNA. PCR primers incorporate elements for cell-free transcription/translation and epitope tagging. Cell-free expressed nascent proteins are then antibody-captured onto the wells of a microtiter plate and the relative amount of truncated polypeptide measured using antibodies against the N- and C-terminal epitope tags in an ELISA format. RESULTS: 100% diagnostic sensitivity and 96% specificity for truncating mutations in exons 11 of BRCA1/2 was achieved on one hundred blood-derived clinical genomic DNA samples which were previously assayed using the conventional gel based PTT. Feasibility of full gene coverage for BRCA1/2 using mRNA source material is also demonstrated. CONCLUSIONS: Overall, the HTS-PTT provides a simple, quantitative, objective, low cost and high throughput method for analysis of truncating mutations as an alternative to gel based PTT for BRCA analysis. The technology is readily accessible to virtually any laboratory, with the only major instrumentation required being a PCR thermocycler and a basic micro-well plate reader. When compared to conventional gel based PTT, the HTS-PTT provides excellent concordance. PMID- 20920339 TI - Mapping HIV/STI behavioural surveillance in Europe. AB - BACKGROUND: Used in conjunction with biological surveillance, behavioural surveillance provides data allowing for a more precise definition of HIV/STI prevention strategies. In 2008, mapping of behavioural surveillance in EU/EFTA countries was performed on behalf of the European Centre for Disease prevention and Control. METHOD: Nine questionnaires were sent to all 31 member States and EEE/EFTA countries requesting data on the overall behavioural and second generation surveillance system and on surveillance in the general population, youth, men having sex with men (MSM), injecting drug users (IDU), sex workers (SW), migrants, people living with HIV/AIDS (PLWHA), and sexually transmitted infection (STI) clinics patients. Requested data included information on system organisation (e.g. sustainability, funding, institutionalisation), topics covered in surveys and main indicators. RESULTS: Twenty-eight of the 31 countries contacted supplied data. Sixteen countries reported an established behavioural surveillance system, and 13 a second generation surveillance system (combination of biological surveillance of HIV/AIDS and STI with behavioural surveillance). There were wide differences as regards the year of survey initiation, number of populations surveyed, data collection methods used, organisation of surveillance and coordination with biological surveillance. The populations most regularly surveyed are the general population, youth, MSM and IDU. SW, patients of STI clinics and PLWHA are surveyed less regularly and in only a small number of countries, and few countries have undertaken behavioural surveys among migrant or ethnic minorities populations. In many cases, the identification of populations with risk behaviour and the selection of populations to be included in a BS system have not been formally conducted, or are incomplete. Topics most frequently covered are similar across countries, although many different indicators are used. In most countries, sustainability of surveillance systems is not assured. CONCLUSION: Although many European countries have established behavioural surveillance systems, there is little harmonisation as regards the methods and indicators adopted. The main challenge now faced is to build and maintain organised and functional behavioural and second generation surveillance systems across Europe, to increase collaboration, to promote robust, sustainable and cost-effective data collection methods, and to harmonise indicators. PMID- 20920340 TI - Enhancer of zeste homolog 2 (EZH2) expression is an independent prognostic factor in renal cell carcinoma. AB - BACKGROUND: The enhancer of zeste homolog 2 (EZH2) gene exerts oncogene-like activities and its (over)expression has been linked to several human malignancies. Here, we studied a possible association between EZH2 expression and prognosis in patients with renal cell carcinoma (RCC). METHODS: EZH2 protein expression in RCC specimens was analyzed by immunohistochemistry using a tissue microarray (TMA) containing RCC tumor tissue and corresponding normal tissue samples of 520 patients. For immunohistochemical assessment of EZH2 expression, nuclear staining quantity was evaluated using a semiquantitative score. The effect of EZH2 expression on cancer specific survival (CSS) was assessed by univariate and multivariate Cox regression analyses. RESULTS: During follow-up, 147 patients (28%) had died of their disease, median follow-up of patients still alive was 6.0 years (range 0-16.1 years). EZH2 nuclear staining was present in tumor cores of 411 (79%) patients. A multivariate Cox regression analysis revealed that high nuclear EZH2 expression was an independent predictor of poor CSS (> 25-50% vs. 0%: HR 2.72, p = 0.025) in patients suffering from non metastatic RCC. Apart from high nuclear EZH2 expression, tumor stage and Fuhrman's grading emerged as significant prognostic markers. In metastatic disease, nuclear EZH2 expression and histopathological subtype were independent predictive parameters of poor CSS (EZH2: 1-5%: HR 2.63, p = 0.043, >5-25%: HR 3.35, p = 0.013, >25%-50%: HR 4.92, p = 0.003, all compared to 0%: HR 0.36, p = 0.025, respectively). CONCLUSIONS: This study defines EZH2 as a powerful independent unfavourable prognostic marker of CSS in patients with metastatic and non-metastatic RCC. PMID- 20920341 TI - Residential self-selection bias in the estimation of built environment effects on physical activity between adolescence and young adulthood. AB - BACKGROUND: Built environment research is dominated by cross-sectional designs, which are particularly vulnerable to residential self-selection bias resulting from health-related attitudes, neighborhood preferences, or other unmeasured characteristics related to both neighborhood choice and health-related outcomes. METHODS: We used cohort data from the National Longitudinal Study of Adolescent Health (United States; Wave I, 1994-95; Wave III, 2001-02; n = 12,701) and a time varying geographic information system. Longitudinal relationships between moderate to vigorous physical activity (MVPA) bouts and built and socioeconomic environment measures (landcover diversity, pay and public physical activity facilities per 10,000 population, street connectivity, median household income, and crime rate) from adolescence to young adulthood were estimated using random effects models (biased by unmeasured confounders) and fixed effects models (within-person estimator, which adjusts for unmeasured confounders that are stable over time). RESULTS: Random effects models yielded null associations except for negative crime-MVPA associations [coefficient (95% CI): -0.056 ( 0.083, -0.029) in males, -0.061 (-0.090, -0.033) in females]. After controlling for measured and time invariant unmeasured characteristics using within-person estimators, MVPA was higher with greater physical activity pay facilities in males [coefficient (95% CI): 0.024 (0.006, 0.042)], and lower with higher crime rates in males [coefficient (95% CI): -0.107 (-0.140, -0.075)] and females [coefficient (95% CI): -0.046 (-0.083, -0.009)]. Other associations were null or in the counter-intuitive direction. CONCLUSIONS: Comparison of within-person estimates to estimates unadjusted for unmeasured characteristics suggest that residential self-selection can bias associations toward the null, as opposed to its typical characterization as a positive confounder. Differential environment MVPA associations by residential relocation suggest that studies examining changes following residential relocation may be vulnerable to selection bias. The authors discuss complexities of adjusting for residential self-selection and residential relocation, particularly during the adolescent to young adult transition. PMID- 20920342 TI - Autoimmune conditions and hairy cell leukemia: an exploratory case-control study. AB - BACKGROUND: Case reports suggest that hairy cell leukemia (HCL) may be associated with autoimmune conditions, however no systematic investigations in this area have been undertaken. METHODS: Using the United States Surveillance, Epidemiology, and End Results Medicare linked database, we conducted an exploratory study comparing autoimmune conditions in 418 HCL cases (aged >=65 years) and 160,086 controls. RESULTS: Overall, the proportion with autoimmune conditions was similar between HCL cases and controls (n = 79 (18.9%) and n = 29,284 (18.3%), respectively). Before diagnosis/selection, there was no overall difference in the prevalence of autoimmune conditions in HCL cases (n = 37, 8.9%) compared with controls (n = 14,085, 8.8%), p = 0.969. However, compared with controls, HCL cases more frequently had sarcoidosis (OR 9.6, 95%CI 2.4-39.5), Sjogren syndrome (OR 6.1, 95%CI 2.0-19.3) and erythema nodosum (OR 37, 95%CI 4.9 284) before diagnosis. Autoimmune conditions were also more common in HCL cases than controls around the time of diagnosis/selection (p < 0.001) but not subsequently. CONCLUSIONS: The findings do not support an overall relationship between autoimmune conditions and HCL, although the association with some autoimmune conditions prior to HCL diagnosis may warrant further investigation. Our findings also suggest that autoimmune conditions in HCL patients may be detected around the time of diagnosis. PMID- 20920344 TI - Cigarette smoke induces PTX3 expression in pulmonary veins of mice in an IL-1 dependent manner. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is associated with abnormal inflammatory responses and structural alterations of the airways, lung parenchyma and pulmonary vasculature. Since Pentraxin-3 (PTX3) is a tuner of inflammatory responses and is produced by endothelial and inflammatory cells upon stimuli such as interleukin-1beta (IL-1beta), we hypothesized that PTX3 is involved in COPD pathogenesis. METHODS AND RESULTS: We evaluated whether cigarette smoke (CS) triggers pulmonary and systemic PTX3 expression in vivo in a murine model of COPD. Using immunohistochemical (IHC) staining, we observed PTX3 expression in endothelial cells of lung venules and veins but not in lung arteries, airways and parenchyma. Moreover, ELISA on lung homogenates and semi quantitative scoring of IHC-stained sections revealed a significant upregulation of PTX3 upon subacute and chronic CS exposure. Interestingly, PTX3 expression was not enhanced upon subacute CS exposure in IL-1RI KO mice, suggesting that the IL 1 pathway is implicated in CS-induced expression of vascular PTX3. Serum PTX3 levels increased rapidly but transiently after acute CS exposure.To elucidate the functional role of PTX3 in CS-induced responses, we examined pulmonary inflammation, protease/antiprotease balance, emphysema and body weight changes in WT and Ptx3 KO mice. CS-induced pulmonary inflammation, peribronchial lymphoid aggregates, increase in MMP-12/TIMP-1 mRNA ratio, emphysema and failure to gain weight were not significantly different in Ptx3 KO mice compared to WT mice. In addition, Ptx3 deficiency did not affect the CS-induced alterations in the pulmonary (mRNA and protein) expression of VEGF-A and FGF-2, which are crucial regulators of angiogenesis. CONCLUSIONS: CS increases pulmonary PTX3 expression in an IL-1 dependent manner. However, our results suggest that either PTX3 is not critical in CS-induced pulmonary inflammation, emphysema and body weight changes, or that its role can be fulfilled by other mediators with overlapping activities. PMID- 20920345 TI - Caspase-1 is involved in the genesis of inflammatory hypernociception by contributing to peripheral IL-1beta maturation. AB - BACKGROUND: Caspase-1 is a cysteine protease responsible for the processing and secretion of IL-1beta and IL-18, which are closely related to the induction of inflammation. However, limited evidence addresses the participation of caspase-1 in inflammatory pain. Here, we investigated the role of caspase-1 in inflammatory hypernociception (a decrease in the nociceptive threshold) using caspase-1 deficient mice (casp1-/-). RESULTS: Mechanical inflammatory hypernociception was evaluated using an electronic version of the von Frey test. The production of cytokines, PGE2 and neutrophil migration were evaluated by ELISA, radioimmunoassay and myeloperoxidase activity, respectively. The interleukin (IL) 1beta and cyclooxygenase (COX)-2 protein expression were evaluated by western blotting. The mechanical hypernociception induced by intraplantar injection of carrageenin, tumour necrosis factor (TNF)alpha and CXCL1/KC was reduced in casp1 /- mice compared with WT mice. However, the hypernociception induced by IL-1beta and PGE2 did not differ in WT and casp1-/- mice. Carrageenin-induced TNF-alpha and CXCL1/KC production and neutrophil recruitment in the paws of WT mice were not different from casp1-/- mice, while the maturation of IL-1beta was reduced in casp1-/- mice. Furthermore, carrageenin induced an increase in the expression of COX-2 and PGE2 production in the paw of WT mice, but was reduced in casp1-/- mice. CONCLUSION: These results suggest that caspase-1 plays a critical role in the cascade of events involved in the genesis of inflammatory hypernociception by promoting IL-1beta maturation. Because caspase-1 is involved in the induction of COX-2 expression and PGE2 production, our data support the assertion that caspase 1 is a key target to control inflammatory pain. PMID- 20920347 TI - The homeodomain complement of the ctenophore Mnemiopsis leidyi suggests that Ctenophora and Porifera diverged prior to the ParaHoxozoa. AB - BACKGROUND: The much-debated phylogenetic relationships of the five early branching metazoan lineages (Bilateria, Cnidaria, Ctenophora, Placozoa and Porifera) are of fundamental importance in piecing together events that occurred early in animal evolution. Comparisons of gene content between organismal lineages have been identified as a potentially useful methodology for phylogenetic reconstruction. However, these comparisons require complete genomes that, until now, did not exist for the ctenophore lineage. The homeobox superfamily of genes is particularly suited for these kinds of gene content comparisons, since it is large, diverse, and features a highly conserved domain. RESULTS: We have used a next-generation sequencing approach to generate a high quality rough draft of the genome of the ctenophore Mnemiopsis leidyi and subsequently identified a set of 76 homeobox-containing genes from this draft. We phylogenetically categorized this set into established gene families and classes and then compared this set to the homeodomain repertoire of species from the other four early branching metazoan lineages. We have identified several important classes and subclasses of homeodomains that appear to be absent from Mnemiopsis and from the poriferan Amphimedon queenslandica. We have also determined that, based on lineage-specific paralog retention and average branch lengths, it is unlikely that these missing classes and subclasses are due to extensive gene loss or unusually high rates of evolution in Mnemiopsis. CONCLUSIONS: This paper provides a first glimpse of the first sequenced ctenophore genome. We have characterized the full complement of Mnemiopsis homeodomains from this species and have compared them to species from other early branching lineages. Our results suggest that Porifera and Ctenophora were the first two extant lineages to diverge from the rest of animals. Based on this analysis, we also propose a new name - ParaHoxozoa - for the remaining group that includes Placozoa, Cnidaria and Bilateria. PMID- 20920348 TI - Variations in the length of stay of intensive care unit nonsurvivors in three Scandinavian countries. AB - INTRODUCTION: The length of stay (LOS) in intensive care unit (ICU) nonsurvivors is not often reported, but represents an important indicator of the use of resources. LOS in ICU nonsurvivors may also be a marker of cultural and organizational differences between units. In this study based on the national intensive care registries in Finland, Sweden, and Norway, we aimed to report intensive care mortality and to document resource use as measured by LOS in ICU nonsurvivors. METHODS: Registry data from 53,305 ICU patients in 2006 were merged into a single database. ICU nonsurvivors were analyzed with regard to LOS within subgroups by univariate and multivariate analysis (Cox proportional hazards regression). RESULTS: Vital status at ICU discharge was available for 52,255 patients. Overall ICU mortality was 9.1%. Median LOS of the nonsurvivors was 1.3 days in Finland and Sweden, and 1.9 days in Norway. The shortest LOS of the nonsurvivors was found in patients older than 80 years, emergency medical admissions, and the patients with the highest severity of illness. Multivariate analysis confirmed the longer LOS in Norway when corrected for age group, admission category, sex, and type of hospital. LOS in nonsurvivors was found to be inversely related to the severity of illness, as measured by APACHE II and SAPS II. CONCLUSIONS: Despite cultural, religious, and educational similarities, significant variations occur in the LOS of ICU nonsurvivors among Finland, Norway, and Sweden. Overall, ICU mortality is low in the Scandinavian countries. PMID- 20920346 TI - Accelerated Partial Breast Irradiation (APBI): A review of available techniques. AB - Breast conservation therapy (BCT) is the procedure of choice for the management of the early stage breast cancer. However, its utilization has not been maximized because of logistics issues associated with the protracted treatment involved with the radiation treatment. Accelerated Partial Breast Irradiation (APBI) is an approach that treats only the lumpectomy bed plus a 1-2 cm margin, rather than the whole breast. Hence because of the small volume of irradiation a higher dose can be delivered in a shorter period of time. There has been growing interest for APBI and various approaches have been developed under phase I-III clinical studies; these include multicatheter interstitial brachytherapy, balloon catheter brachytherapy, conformal external beam radiation therapy and intra-operative radiation therapy (IORT). Balloon-based brachytherapy approaches include Mammosite, Axxent electronic brachytherapy and Contura, Hybrid brachytherapy devices include SAVI and ClearPath. This paper reviews the different techniques, identifying the weaknesses and strength of each approach and proposes a direction for future research and development. It is evident that APBI will play a role in the management of a selected group of early breast cancer. However, the relative role of the different techniques is yet to be clearly identified. PMID- 20920349 TI - Genomic insights into Wnt signaling in an early diverging metazoan, the ctenophore Mnemiopsis leidyi. AB - BACKGROUND: Intercellular signaling pathways are a fundamental component of the integrating cellular behavior required for the evolution of multicellularity. The genomes of three of the four early branching animal phyla (Cnidaria, Placozoa and Porifera) have been surveyed for key components, but not the fourth (Ctenophora). Genomic data from ctenophores could be particularly relevant, as ctenophores have been proposed to be one of the earliest branching metazoan phyla. RESULTS: A preliminary assembly of the lobate ctenophore Mnemiopsis leidyi genome generated using next-generation sequencing technologies were searched for components of a developmentally important signaling pathway, the Wnt/beta-catenin pathway. Molecular phylogenetic analysis shows four distinct Wnt ligands (MlWnt6, MlWnt9, MlWntA and MlWntX), and most, but not all components of the receptor and intracellular signaling pathway were detected. In situ hybridization of the four Wnt ligands showed that they are expressed in discrete regions associated with the aboral pole, tentacle apparati and apical organ. CONCLUSIONS: Ctenophores show a minimal (but not obviously simple) complement of Wnt signaling components. Furthermore, it is difficult to compare the Mnemiopsis Wnt expression patterns with those of other metazoans. mRNA expression of Wnt pathway components appears later in development than expected, and zygotic gene expression does not appear to play a role in early axis specification. Notably absent in the Mnemiopsis genome are most major secreted antagonists, which suggests that complex regulation of this secreted signaling pathway probably evolved later in animal evolution. PMID- 20920351 TI - Oral squamous cell carcinoma in non-smoking and non-drinking patients. AB - INTRODUCTION: Of the many different factors associated with an increased risk for oral squamous cell carcinoma (SCC), tobacco and alcohol seem to be the most studied. The aim of the current study was to evaluate the clinicopathologic characteristics of patients without the mentioned risk factors. PATIENTS AND METHODS: Out of 278 patients (159 male and 119 female patients) with oral SCC, 67 patients had no history of tobacco or alcohol use. The minimum follow-up time was 12 months. RESULTS: Of the 67 patients, 45 (67.2%) were women, and the mean age was 70 years. The most common tumor sites were mandibular alveolar ridge (22) and maxilla (18). Fifteen patients experienced a recurrence, and 10 developed lymph node metastases during the follow-up period. CONCLUSION: The group of patients with no tobacco and alcohol use tends toward a higher proportion of females, a higher proportion of patients over 70 years, and a higher number of oral maxillary SCC. PMID- 20920350 TI - SHMT1 1420 and MTHFR 677 variants are associated with rectal but not colon cancer. AB - BACKGROUND: Association between rectal or colon cancer risk and serine hydroxymethyltransferase 1 (SHMT1) C1420T or methylenetetrahydrofolate reductase (MTHFR) C677T polymorphisms was assessed. The serum total homocysteine (HCY), marker of folate metabolism was also investigated. METHODS: The SHMT1 and MTHFR genotypes were determined by real-time PCR and PCR-RFLP, respectively in 476 patients with rectal, 479 patients with colon cancer and in 461 and 478, respective controls matched for age and sex. Homocysteine levels were determined by HPLC kit. The association between polymorphisms and cancer risk was evaluated by logistic regression analysis adjusted for age, sex and body mass index. The population stratification bias was also estimated. RESULTS: There was no association of genotypes or diplotypes with colon cancer. The rectal cancer risk was significantly lower for SHMT1 TT (OR = 0.57, 95% confidence interval (CI) 0.36-0.89) and higher for MTHFR CT genotypes (OR = 1.4, 95%CI 1.06-1.84). A gene dosage effect was observed for SHMT1 with progressively decreasing risk with increasing number of T allele (p = 0.014). The stratified analysis according to age and sex revealed that the association is mainly present in the younger (< 60 years) or male subgroup. As expected from genotype analysis, the SHMT1 T allele/MTHFR CC diplotype was associated with reduced rectal cancer risk (OR 0.56, 95%CI 0.42-0.77 vs all other diplotypes together). The above results are unlikely to suffer from population stratification bias. In controls HCY was influenced by SHMT1 polymorphism, while in patients it was affected only by Dukes' stage. In patients with Dukes' stage C or D HCY can be considered as a tumor marker only in case of SHMT1 1420CC genotypes. CONCLUSIONS: A protective effect of SHMT1 1420T allele or SHMT1 1420 T allele/MTHFR 677 CC diplotype against rectal but not colon cancer risk was demonstrated. The presence of SHMT1 1420 T allele significantly increases the HCY levels in controls but not in patients. Homocysteine could be considered as a tumor marker in SHMT1 1420 wild type (CC) CRC patients in Dukes' stage C and D. Further studies need to clarify why SHMT1 and MTHFR polymorphisms are associated only with rectal and not colon cancer risk. PMID- 20920352 TI - The incidence of malaria in travellers to South-East Asia: is local malaria transmission a useful risk indicator? AB - BACKGROUND: The presence of ongoing local malaria transmission, identified though local surveillance and reported to regional WHO offices, by S-E Asian countries, forms the basis of national and international chemoprophylaxis recommendations in western countries. The study was designed to examine whether the strategy of using malaria transmission in a local population was an accurate estimate of the malaria threat faced by travellers and a correlate of malaria in returning travellers. METHODS: Malaria endemicity was described from distribution and intensity in the local populations of ten S-E Asian destination countries over the period 2003-2008 from regionally reported cases to WHO offices. Travel acquired malaria was collated from malaria surveillance reports from the USA and 12 European countries over the same period. The numbers of travellers visiting the destination countries was based on immigration and tourism statistics collected on entry of tourists to the destination countries. RESULTS: In the destination countries, mean malaria rates in endemic countries ranged between 0.01 in Korea to 4:1000 population per year in Lao PDR, with higher regional rates in a number of countries. Malaria cases imported into the 13 countries declined by 47% from 140 cases in 2003 to 66 in 2008. A total of 608 cases (27.3% Plasmodium falciparum (Pf)) were reported over the six years, the largest number acquired in Indonesia, Thailand and Korea. Four countries had an incidence > 1 case per 100,000 traveller visits; Burma (Myanmar), Indonesia, Cambodia and Laos (range 1 to 11.8-case per 100,000 visits). The remaining six countries rates were < 1 case per 100,000 visits. The number of visitors arriving from source countries increased by 60% from 8.5 Million to 13.6 million over the 6 years. CONCLUSION: The intensity of malaria transmission particularly sub-national activity did not correlate with the risk of travellers acquiring malaria in the large numbers of arriving visitors. It is proposed to use a threshold incidence of > 1 case per 100,000 visits to consider targeted malaria prophylaxis recommendations to minimize use of chemoprophylaxis for low risk exposure during visits to S-E Asia. Policy needs to be adjusted regularly to reflect the changing risk. PMID- 20920353 TI - Reconstructing the evolutionary history of the radiation of the land snail genus Xerocrassa on Crete based on mitochondrial sequences and AFLP markers. AB - BACKGROUND: A non-adaptive radiation triggered by sexual selection resulted in ten endemic land snail species of the genus Xerocrassa on Crete. Only five of these species and a more widespread species are monophyletic in a mitochondrial gene tree. The reconstruction of the evolutionary history of such closely related species can be complicated by incomplete lineage sorting, introgression or inadequate taxonomy. To distinguish between the reasons for the nonmonophyly of several species in the mitochondrial gene tree we analysed nuclear AFLP markers. RESULTS: Whereas six of the eleven morphologically delimited Xerocrassa species from Crete are monophyletic in the mitochondrial gene tree, nine of these species are monophyletic in the tree based on AFLP markers. Only two morphologically delimited species could not be distinguished with the multilocus data and might have diverged very recently or might represent extreme forms of a single species. The nonmonophyly of X. rhithymna with respect to X. kydonia is probably the result of incomplete lineage sorting, because there is no evidence for admixture in the AFLP data and the mitochondrial haplotype groups of these species coalesce deeply. The same is true for the main haplotype groups of X. mesostena. The nonmonophyly of X. franciscoi might be the result of mitochondrial introgression, because the coalescences of the haplotypes of this species with some X. mesostena haplotypes are shallow and there is admixture with neighbouring X. mesostena. CONCLUSION: The most likely causes for the nonmonophyly of species in the mitochondrial gene tree of the Xerocrassa radiation on Crete could be inferred using AFLP data by a combination of several criteria, namely the depth of the coalescences in the gene tree, the geographical distribution of shared genetic markers, and concordance with results of admixture analyses of nuclear multilocus markers. The strongly subdivided population structure increases the effective population size of land snail species and, thus, the likelihood of a long persistence of ancestral polymorphisms. Our study suggests that ancestral polymorphisms are a frequent cause for nonmonophyly of species with a strongly subdivided population structure in gene trees. PMID- 20920354 TI - Primary glomangiosarcoma of the lung: A case report. AB - BACKGROUND: Glomus tumor is an uncommon neoplasm derived from cells of the neuromyoarterial glomus or glomus body. Most glomus tumours occur in the dermis and subcutaneous tissues. A case of a primary pulmonary glomus tumour originating in the right upper lobe is presented. CASE PRESENTATION: A 74-yr-old male was admitted with siccus cough, dyspnea and right-sided chest pain. Computed tomography of the thorax revealed a 4 cm growth of the right upper lobe. Fiberoptic bronchoscopy demonstrated an endobronchial hypervascular mass causing obstruction of the apical segmental bronchus. Pathology report was consistent with pulmonary glomus tumor. The patient underwent a typical right upper lobectomy with mediastinal lymph node dissection. Twelve months later he is free of disease. CONCLUSION: Occasionally glomus tumors can occur in extracutaneous sites such as the gastrointestinal tract, bone, genitourinary system and respiratory tract. Primary pulmonary glomus tumors are very rare (our case is the 19th one presented in the international literature) and are often confused with other solid neoplasms such as carcinoids, hemangiopericytomas and tumors belonging to the family of Ewing's sarcoma/primitive neuroectodermal tumours. PMID- 20920356 TI - aeGEPUCI: a database of gene expression in the dengue vector mosquito, Aedes aegypti. AB - BACKGROUND: Aedes aegypti is the principal vector of dengue and yellow fever viruses. The availability of the sequenced and annotated genome enables genome wide analyses of gene expression in this mosquito. The large amount of data resulting from these analyses requires efficient cataloguing before it becomes useful as the basis for new insights into gene expression patterns and studies of the underlying molecular mechanisms for generating these patterns. FINDINGS: We provide a publicly-accessible database and data-mining tool, aeGEPUCI, that integrates 1) microarray analyses of sex- and stage-specific gene expression in Ae. aegypti, 2) functional gene annotation, 3) genomic sequence data, and 4) computational sequence analysis tools. The database can be used to identify genes expressed in particular stages and patterns of interest, and to analyze putative cis-regulatory elements (CREs) that may play a role in coordinating these patterns. The database is accessible from the address http://www.aegep.bio.uci.edu. CONCLUSIONS: The combination of gene expression, function and sequence data coupled with integrated sequence analysis tools allows for identification of expression patterns and streamlines the development of CRE predictions and experiments to assess how patterns of expression are coordinated at the molecular level. PMID- 20920355 TI - A three-way comparative genomic analysis of Mannheimia haemolytica isolates. AB - BACKGROUND: Mannhemia haemolytica is a Gram-negative bacterium and the principal etiological agent associated with bovine respiratory disease complex. They transform from a benign commensal to a deadly pathogen, during stress such as viral infection and transportation to feedlots and cause acute pleuropneumonia commonly known as shipping fever. The U.S beef industry alone loses more than one billion dollars annually due to shipping fever. Despite its enormous economic importance there are no specific and accurate genetic markers, which will aid in understanding the pathogenesis and epidemiology of M. haemolytica at molecular level and assist in devising an effective control strategy. DESCRIPTION: During our comparative genomic sequence analysis of three Mannheimia haemolytica isolates, we identified a number of genes that are unique to each strain. These genes are "high value targets" for future studies that attempt to correlate the variable gene pool with phenotype. We also identified a number of high confidence single nucleotide polymorphisms (hcSNPs) spread throughout the genome and focused on non-synonymous SNPs in known virulence genes. These SNPs will be used to design new hcSNP arrays to study variation across strains, and will potentially aid in understanding gene regulation and the mode of action of various virulence factors. CONCLUSIONS: During our analysis we identified previously unknown possible type III secretion effector proteins, clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated sequences (Cas). The presence of CRISPR regions is indicative of likely co-evolution with an associated phage. If proven functional, the presence of a type III secretion system in M. haemolytica will help us re-evaluate our approach to study host pathogen interactions. We also identified various adhesins containing immuno dominant domains, which may interfere with host-innate immunity and which could potentially serve as effective vaccine candidates. PMID- 20920357 TI - Glycogen Synthase Kinase-3 regulates multiple myeloma cell growth and bortezomib induced cell death. AB - BACKGROUND: Glycogen Synthase Kinase-3 (GSK-3) alpha and beta are two serine threonine kinases controlling insulin, Wnt/beta-catenin, NF-kappaB signaling and other cancer-associated transduction pathways. Recent evidence suggests that GSK 3 could function as growth-promoting kinases, especially in malignant cells. In this study, we have investigated GSK-3alpha and GSK-3beta function in multiple myeloma (MM). METHODS: GSK-3 alpha and beta expression and cellular localization were investigated by Western blot (WB) and immunofluorescence analysis in a panel of MM cell lines and in freshly isolated plasma cells from patients. MM cell growth, viability and sensitivity to bortezomib was assessed upon treatment with GSK-3 specific inhibitors or transfection with siRNAs against GSK-3 alpha and beta isoforms. Survival signaling pathways were studied with WB analysis. RESULTS: GSK-3alpha and GSK-3beta were differently expressed and phosphorylated in MM cells. Inhibition of GSK-3 with the ATP-competitive, small chemical compounds SB216763 and SB415286 caused MM cell growth arrest and apoptosis through the activation of the intrinsic pathway. Importantly, the two inhibitors augmented the bortezomib-induced MM cell cytotoxicity. RNA interference experiments showed that the two GSK-3 isoforms have distinct roles: GSK-3beta knock down decreased MM cell viability, while GSK-3alpha knock down was associated with a higher rate of bortezomib-induced cytotoxicity. GSK-3 inhibition caused accumulation of beta-catenin and nuclear phospho-ERK1, 2. Moreover, GSK-3 inhibition and GSK-3alpha knockdown enhanced bortezomib-induced AKT and MCL-1 protein degradation. Interestingly, bortezomib caused a reduction of GSK-3 serine phosphorylation and its nuclear accumulation with a mechanism that resulted partly dependent on GSK-3 itself. CONCLUSIONS: These data suggest that in MM cells GSK-3alpha and beta i) play distinct roles in cell survival and ii) modulate the sensitivity to proteasome inhibitors. PMID- 20920358 TI - Gene discovery for the bark beetle-vectored fungal tree pathogen Grosmannia clavigera. AB - BACKGROUND: Grosmannia clavigera is a bark beetle-vectored fungal pathogen of pines that causes wood discoloration and may kill trees by disrupting nutrient and water transport. Trees respond to attacks from beetles and associated fungi by releasing terpenoid and phenolic defense compounds. It is unclear which genes are important for G. clavigera's ability to overcome antifungal pine terpenoids and phenolics. RESULTS: We constructed seven cDNA libraries from eight G. clavigera isolates grown under various culture conditions, and Sanger sequenced the 5' and 3' ends of 25,000 cDNA clones, resulting in 44,288 high quality ESTs. The assembled dataset of unique transcripts (unigenes) consists of 6,265 contigs and 2,459 singletons that mapped to 6,467 locations on the G. clavigera reference genome, representing ~70% of the predicted G. clavigera genes. Although only 54% of the unigenes matched characterized proteins at the NCBI database, this dataset extensively covers major metabolic pathways, cellular processes, and genes necessary for response to environmental stimuli and genetic information processing. Furthermore, we identified genes expressed in spores prior to germination, and genes involved in response to treatment with lodgepole pine phloem extract (LPPE). CONCLUSIONS: We provide a comprehensively annotated EST dataset for G. clavigera that represents a rich resource for gene characterization in this and other ophiostomatoid fungi. Genes expressed in response to LPPE treatment are indicative of fungal oxidative stress response. We identified two clusters of potentially functionally related genes responsive to LPPE treatment. Furthermore, we report a simple method for identifying contig misassemblies in de novo assembled EST collections caused by gene overlap on the genome. PMID- 20920359 TI - Viral replication is enhanced by an HIV-1 intersubtype recombination-derived Vpu protein. AB - BACKGROUND: Multiple HIV-1 intersubtype recombinants have been identified in human populations. Previous studies from our lab group have shown that the epidemic in Argentina is characterized by the high prevalence of a circulating recombinant form, CRF12_BF, and many related BF recombinant forms. In these genomic structures a recombination breakpoint frequently involved the vpu coding region. Due to the scarce knowledge of Vpu participation in the virion release process and its impact on pathogenesis and of the functional capacities of intersubtype recombinant Vpu proteins, the aim of this work was to perform a comparative analysis on virion release capacity and relative replication capacity among viral variants harboring either a BF recombinant Vpu or a subtype B Vpu. RESULTS: Our results showed that BF recombinant Vpu was associated to an increased viral particles production when compared to WT B variant in tetherin expressing cell lines. This observation was tested in the context of a competition assay between the above mentioned variants. The results showed that the replication of the BF Vpu-harboring variant was more efficient in cell cultures than subtype B, reaching a higher frequency in the viral population in a short period of time. CONCLUSION: This study showed that as a result of intersubtype recombination, a structurally re-organized HIV-1 Vpu has an improved in vitro capacity of enhancing viral replication, and provides evidence of the changes occurring in this protein function that could play an important role in the successful spread of intersubtype recombinant variants. PMID- 20920360 TI - The synergy between TB and HIV co-infection on perceived stigma in Ethiopia. AB - BACKGROUND: The synergy between tuberculosis (TB) and human immunodeficiency virus (HIV) co-infection on perceived stigma is not well studied. The objective of this study was to assess the effect of TB/HIV co-infection on perceived stigma in selected hospitals of Oromiya region, Ethiopia. A cross sectional study was conducted from February to April, 2009 in Adama, Nekemet and Jimma Specialized hospitals. Data were collected by trained HIV counselors. A structured questionnaire which consisted of socio-demographic variables, clinical information, perceived stigma, and depression was used to collect the data FINDINGS: A total of 591 participants were included in the study of whom 124 (20.9%) were co-infected with TB/HIV. The stigma items were highly reliable (Cronbach's alpha = 0.93) and had strong inter dimension correlation. Respondents who were co-infected with TB and HIV were more likely to have perceived stigma compared to non-co-infected HIV patients, [OR = 1.4, (95% CI: 1.2, 2.0)]. Non literate individuals [OR = 1.9, (95% CI: 1.2, 3.0)] and females [OR = 1.6, (95% CI: 1.2, 2.3)] had also more perceived stigma. CONCLUSIONS: TB/HIV co-infected patients, non-literate individuals and females were more likely to have high perceived stigma. Behavioral Change Communication should focus on these segments of the population to rectify the high perceived stigma. PMID- 20920361 TI - Social cohesion through football: a quasi-experimental mixed methods design to evaluate a complex health promotion program. AB - Social isolation and disengagement fragments local communities. Evidence indicates that refugee families are highly vulnerable to social isolation in their countries of resettlement. Research to identify approaches to best address this is needed. Football United is a program that aims to foster social inclusion and cohesion in areas with high refugee settlement in New South Wales, Australia, through skills and leadership development, mentoring, and the creation of links with local community and corporate leaders and organisations. The Social Cohesion through Football study's broad goal is to examine the implementation of a complex health promotion program, and to analyse the processes involved in program implementation. The study will consider program impact on individual health and wellbeing, social inclusion and cohesion, as well as analyse how the program by necessity interacts and adapts to context during implementation, a concept we refer to as plasticity. The proposed study will be the first prospective cohort impact study to our knowledge to assess the impact of a comprehensive integrated program using football as a vehicle for fostering social inclusion and cohesion in communities with high refugee settlement. METHODS/DESIGN: A quasi-experimental cohort study design with treatment partitioning involving four study sites. The study employs a 'dose response' model, comparing those with no involvement in the Football United program with those with lower or higher levels of participation. A range of qualitative and quantitative measures will be used in the study. Study participants' emotional well being, resilience, ethnic identity and other group orientation, feelings of social inclusion and belonging will be measured using a survey instrument complemented by relevant data drawn from in-depth interviews, self reporting measures and participant observation. The views of key informants from the program and the wider community will also be solicited. DISCUSSION: The complexity of the Football United program poses challenges for measurement, and requires the study design to be responsive to the dynamic nature of the program and context. Assessment of change is needed at multiple levels, drawing on mixed methods and multidisciplinary approaches in implementation and evaluation. Attention to these challenges has underpinned the design and methods in the Social Cohesion through Football study, which will use a unique and innovative combination of measures that have not been applied together previously in social inclusion/cohesion and sport and social inclusion/cohesion program research. PMID- 20920362 TI - Gaseous air pollution and emergency hospital visits for hypertension in Beijing, China: a time-stratified case-crossover study. AB - BACKGROUND: A number of epidemiological studies have been conducted to research the adverse effects of air pollution on mortality and morbidity. Hypertension is the most important risk factor for cardiovascular mortality. However, few previous studies have examined the relationship between gaseous air pollution and morbidity for hypertension. METHODS: Daily data on emergency hospital visits (EHVs) for hypertension were collected from the Peking University Third Hospital. Daily data on gaseous air pollutants (sulfur dioxide (SO2) and nitrogen dioxide (NO2)) and particulate matter less than 10 MUm in aerodynamic diameter (PM10) were collected from the Beijing Municipal Environmental Monitoring Center. A time stratified case-crossover design was conducted to evaluate the relationship between urban gaseous air pollution and EHVs for hypertension. Temperature and relative humidity were controlled for. RESULTS: In the single air pollutant models, a 10 MUg/m3 increase in SO2 and NO2 were significantly associated with EHVs for hypertension. The odds ratios (ORs) were 1.037 (95% confidence interval (CI): 1.004-1.071) for SO2 at lag 0 day, and 1.101 (95% CI: 1.038-1.168) for NO2 at lag 3 day. After controlling for PM10, the ORs associated with SO2 and NO2 were 1.025 (95% CI: 0.987-1.065) and 1.114 (95% CI: 1.037-1.195), respectively. CONCLUSION: Elevated urban gaseous air pollution was associated with increased EHVs for hypertension in Beijing, China. PMID- 20920363 TI - Single-cell and coupled GRN models of cell patterning in the Arabidopsis thaliana root stem cell niche. AB - BACKGROUND: Recent experimental work has uncovered some of the genetic components required to maintain the Arabidopsis thaliana root stem cell niche (SCN) and its structure. Two main pathways are involved. One pathway depends on the genes SHORTROOT and SCARECROW and the other depends on the PLETHORA genes, which have been proposed to constitute the auxin readouts. Recent evidence suggests that a regulatory circuit, composed of WOX5 and CLE40, also contributes to the SCN maintenance. Yet, we still do not understand how the niche is dynamically maintained and patterned or if the uncovered molecular components are sufficient to recover the observed gene expression configurations that characterize the cell types within the root SCN. Mathematical and computational tools have proven useful in understanding the dynamics of cell differentiation. Hence, to further explore root SCN patterning, we integrated available experimental data into dynamic Gene Regulatory Network (GRN) models and addressed if these are sufficient to attain observed gene expression configurations in the root SCN in a robust and autonomous manner. RESULTS: We found that an SCN GRN model based only on experimental data did not reproduce the configurations observed within the root SCN. We developed several alternative GRN models that recover these expected stable gene configurations. Such models incorporate a few additional components and interactions in addition to those that have been uncovered. The recovered configurations are stable to perturbations, and the models are able to recover the observed gene expression profiles of almost all the mutants described so far. However, the robustness of the postulated GRNs is not as high as that of other previously studied networks. CONCLUSIONS: These models are the first published approximations for a dynamic mechanism of the A. thaliana root SCN cellular pattering. Our model is useful to formally show that the data now available are not sufficient to fully reproduce root SCN organization and genetic profiles. We then highlight some experimental holes that remain to be studied and postulate some novel gene interactions. Finally, we suggest the existence of a generic dynamical motif that can be involved in both plant and animal SCN maintenance. PMID- 20920364 TI - Development of the lateral ventricular choroid plexus in a marsupial, Monodelphis domestica. AB - BACKGROUND: Choroid plexus epithelial cells are the site of blood/cerebrospinal fluid (CSF) barrier and regulate molecular transfer between the two compartments. Their mitotic activity in the adult is low. During development, the pattern of growth and timing of acquisition of functional properties of plexus epithelium are not known. METHODS: Numbers and size of choroid plexus epithelial cells and their nuclei were counted and measured in the lateral ventricular plexus from the first day of its appearance until adulthood. Newborn Monodelphis pups were injected with 5-bromo-2-deoxyuridine (BrdU) at postnatal day 3 (P3), P4 and P5. Additional animals were injected at P63, P64 and P65. BrdU-immunopositive nuclei were counted and their position mapped in the plexus structure at different ages after injections. Double-labelling immunocytochemistry with antibodies to plasma protein identified post-mitotic cells involved in protein transfer. RESULTS: Numbers of choroid plexus epithelial cells increased 10-fold between the time of birth and adulthood. In newborn pups each consecutive injection of BrdU labelled 20-40 of epithelial cells counted. After 3 injections, numbers of BrdU positive cells remained constant for at least 2 months. BrdU injections at an older age (P63, P64, P65) resulted in a smaller number of labelled plexus cells. Numbers of plexus cells immunopositive for both BrdU and plasma protein increased with age indicating that protein transferring properties are acquired post mitotically. Labelled nuclei were only detected on the dorsal arm of the plexus as it grows from the neuroependyma, moving along the structure in a 'conveyor belt' like fashion. CONCLUSIONS: The present study established that lateral ventricular choroid plexus epithelial cells are born on the dorsal side of the structure only. Cells born in the first few days after choroid plexus differentiation from the neuroependyma remain present even two months later. Protein-transferring properties are acquired post-mitotically and relatively early in plexus development. PMID- 20920365 TI - Indacaterol provides 24-hour bronchodilation in COPD: a placebo-controlled blinded comparison with tiotropium. AB - BACKGROUND: Indacaterol is a novel, inhaled, once-daily, ultra-long-acting beta2 agonist for the treatment of chronic obstructive pulmonary disease (COPD). This randomized, double-blind study compared the bronchodilator efficacy of indacaterol with that of placebo and tiotropium in patients with moderate-to severe COPD. METHODS: In an incomplete-block, multi-dose, three-period, crossover design, patients received three of the following four treatments: indacaterol 150 MUg, indacaterol 300 MUg, tiotropium 18 MUg and placebo, each once-daily for 14 days. Each treatment period was separated by a 14-day washout. Study drug was supplied daily by blinded, third party study personnel to maintain blinding of patients and investigators. The primary efficacy variable was trough forced expiratory volume in one second (FEV1) at 24 h post-dose after 14 days. The study was powered to demonstrate non-inferiority of indacaterol to tiotropium for this variable. RESULTS: A total of 169 patients were randomized (mean age 65 years); 153 (90.5%) completed. Trough FEV1 after 14 days with indacaterol 150 MUg and 300 MUg was statistically and clinically superior to placebo, with differences (95% CI) of 170 (120-220) and 150 (100-200) mL respectively (both p < 0.001). For this endpoint, both doses of indacaterol not only met the criterion for non inferiority compared with tiotropium, but also achieved numerically higher values, with differences versus tiotropium of 40 and 30 mL for indacaterol 150 and 300 MUg, respectively. At 5 min post-dose on Day 1, the mean FEV1 for both indacaterol doses was significantly higher than placebo (by 120 and 130 mL for indacaterol 150 and 300 MUg, respectively; p < 0.001) and tiotropium (by 80 mL for both doses; p < 0.001). Adverse events were reported by similar proportions of patients: 31.4%, 29.5%, 28.3% and 28.5% for indacaterol 150 MUg and 300 MUg, tiotropium and placebo treatments, respectively. CONCLUSIONS: Once-daily indacaterol provided clinically and statistically significant 24-h bronchodilation. Indacaterol was at least as effective as tiotropium, with a faster onset of action (within 5 min) on the first day of dosing. Indacaterol should prove useful in patients with moderate-to-severe COPD, for whom treatment with one or more classes of long-acting bronchodilator is recommended. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00615459, EudraCT number: 2007-004071-19. PMID- 20920366 TI - Circadian blood pressure variability in type 1 diabetes subjects and their nondiabetic siblings - influence of erythrocyte electron transfer. AB - BACKGROUND: Normotensive non-diabetic relatives of type 1 diabetes (T1D) patients have an abnormal blood pressure response to exercise testing that is associated with indices of metabolic syndrome and increased oxidative stress. The primary aim of this study was to investigate the circadian variability of blood pressure and the ambulatory arterial stiffness index (AASI) in healthy siblings of T1D patients vs healthy control subjects who had no first-degree relative with T1D. Secondary aims of the study were to explore the influence of both cardiovascular autonomic function and erythrocyte electron transfer activity as oxidative marker on the ambulatory blood pressure profile. METHODS: Twenty-four hour ambulatory blood pressure monitoring (ABPM) was undertaken in 25 controls, 20 T1D patients and 20 siblings. In addition to laboratory examination (including homeostasis model assessment of insulin sensitivity) and clinical testing of autonomic function, we measured the rate of oxidant-induced erythrocyte electron transfer to extracellular ferricyanide (RBC vfcy). RESULTS: Systolic blood pressure (SBP) midline-estimating statistic of rhythm and pulse pressure were higher in T1D patients and correlated positively with diabetes duration and RBC vfcy; autonomic dysfunction was associated with diastolic BP ecphasia and increased AASI. Siblings had higher BMI, lower insulin sensitivity, larger SBP amplitude, and higher AASI than controls. Daytime SBP was positively, independently associated with BMI and RBC vfcy. Among non-diabetic people, there was a significant correlation between AASI and fasting plasma glucose. CONCLUSIONS: Siblings of T1D patients exhibited a cluster of sub-clinical metabolic abnormalities associated with consensual perturbations in BP variability. Moreover, our findings support, in a clinical setting, the proposed role of transplasma membrane electron transport systems in vascular pathobiology. PMID- 20920367 TI - Favorable response to doxorubicin combination chemotherapy does not yield good clinical outcome in patients with metastatic breast cancer with triple-negative phenotype. AB - BACKGROUND: We analyzed the responses to first line treatment and clinical outcomes of metastatic breast cancer patients treated with palliative doxorubicin/cyclophosphamide (AC) according to molecular cancer subtype. METHODS: A retrospective analysis was performed for 110 metastatic breast cancer patients selected on the basis of palliative AC treatment and the availability of immunohistochemical data for estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER-2/neu) status. RESULTS: Of the 110 patients analyzed, 71 (64.5%) were hormone receptor positive (HR+), 14 (12.7%) were HER2+, and 25 (22.7%) were triple negative (TN). There were no differences in age, stage at diagnosis, total number of cycles of palliative chemotherapy, incidence of visceral metastasis, and metastatic sites with the exception of liver among breast cancer subtypes. The overall response rates to AC were 55.9% for the HR+ subgroup, 42.9% for the HER2+ subgroup, and 56.5% for the TN subgroup. The progression-free survival (PFS) in patients with HER2+ and TN were significantly shorter than in the HR+ (median PFS, 9.1 vs 8.1 vs 11.5 months, respectively; p = 0.0002). The overall survival (OS) was 25.4 months in the TN subgroup and 27.3 months in HER2+ subgroup. The median OS for these two groups was significantly shorter than for patients in the HR+ subgroup (median, 38.5 months; 95% CI, 30.1-46.9 months; p < 0.0001). CONCLUSIONS: The response to palliative AC chemotherapy did not differ among breast cancer subtypes. Despite chemosensitivity for palliative AC, the TN subtype has a shorter overall survival than non-TN subtypes. Innovative treatment strategies should be developed to slow the course of disease. PMID- 20920368 TI - Molecular analysis of phosphomannomutase (PMM) genes reveals a unique PMM duplication event in diverse Triticeae species and the main PMM isozymes in bread wheat tissues. AB - BACKGROUND: Phosphomannomutase (PMM) is an essential enzyme in eukaryotes. However, little is known about PMM gene and function in crop plants. Here, we report molecular evolutionary and biochemical analysis of PMM genes in bread wheat and related Triticeae species. RESULTS: Two sets of homologous PMM genes (TaPMM-1 and 2) were found in bread wheat, and two corresponding PMM genes were identified in the diploid progenitors of bread wheat and many other diploid Triticeae species. The duplication event yielding PMM-1 and 2 occurred before the radiation of diploid Triticeae genomes. The PMM gene family in wheat and relatives may evolve largely under purifying selection. Among the six TaPMM genes, the transcript levels of PMM-1 members were comparatively high and their recombinant proteins were all enzymatically active. However, PMM-2 homologs exhibited lower transcript levels, two of which were also inactive. TaPMM-A1, B1 and D1 were probably the main active isozymes in bread wheat tissues. The three isozymes differed from their counterparts in barley and Brachypodium distachyon in being more tolerant to elevated test temperatures. CONCLUSION: Our work identified the genes encoding PMM isozymes in bread wheat and relatives, uncovered a unique PMM duplication event in diverse Triticeae species, and revealed the main active PMM isozymes in bread wheat tissues. The knowledge obtained here improves the understanding of PMM evolution in eukaryotic organisms, and may facilitate further investigations of PMM function in the temperature adaptability of bread wheat. PMID- 20920369 TI - Diagnosis delay and follow-up strategies in colorectal cancer. Prognosis implications: a study protocol. AB - BACKGROUND: Controversy exists with regard to the impact that the different components of diagnosis delay may have on the degree of invasion and prognosis in patients with colorectal cancer. The follow-up strategies after treatment also vary considerably. The aims of this study are: a) to determine if the symptoms-to diagnosis interval and the treatment delay modify the survival of patients with colorectal cancer, and b) to determine if different follow-up strategies are associated with a higher survival rate. METHODS/DESIGN: Multi-centre study with prospective follow-up in five regions in Spain (Galicia, Balearic Islands, Catalonia, Aragon and Valencia) during the period 2010-2012. Incident cases are included with anatomopathological confirmation of colorectal cancer (International Classification of Diseases 9th revision codes 153-154) that formed a part of a previous study (n = 953).At the time of diagnosis, each patient was given a structured interview. Their clinical records will be reviewed during the follow-up period in order to obtain information on the explorations and tests carried out after treatment, and the progress of these patients.Symptoms-to diagnosis interval is defined as the time calculated from the diagnosis of cancer and the first symptoms attributed to cancer. Treatment delay is defined as the time elapsed between diagnosis and treatment. In non-metastatic patients treated with curative intention, information will be obtained during the follow-up period on consultations performed in the digestive, surgery and oncology departments, as well as the endoscopies, tumour markers and imaging procedures carried out.Local recurrence, development of metastases in the follow-up, appearance of a new tumour and mortality will be included as outcome variables.Actuarial survival analysis with Kaplan-Meier curves, Cox regression and competitive risk survival analysis will be performed. DISCUSSION: This study will make it possible to verify if the different components of delay have an impact on survival rate in colon cancer and rectal cancer. In consequence, this multi-centre study will be able to detect the variability present in the follow-up of patients with colorectal cancer, and if this variability modifies the prognosis. Ideally, this study could determine which follow-up strategies are associated with a better prognosis in colorectal cancer. PMID- 20920370 TI - Therapeutic efficacy of alpha-1 antitrypsin augmentation therapy on the loss of lung tissue: an integrated analysis of 2 randomised clinical trials using computed tomography densitometry. AB - BACKGROUND: Two randomised, double-blind, placebo-controlled trials have investigated the efficacy of IV alpha-1 antitrypsin (AAT) augmentation therapy on emphysema progression using CT densitometry. METHODS: Data from these similar trials, a 2-center Danish-Dutch study (n = 54) and the 3-center EXAcerbations and CT scan as Lung Endpoints (EXACTLE) study (n = 65), were pooled to increase the statistical power. The change in 15th percentile of lung density (PD15) measured by CT scan was obtained from both trials. All subjects had 1 CT scan at baseline and at least 1 CT scan after treatment. Densitometric data from 119 patients (AAT [Alfalastin(r) or Prolastin(r)], n = 60; placebo, n = 59) were analysed by a statistical/endpoint analysis method. To adjust for lung volume, volume correction was made by including the change in log-transformed total lung volume as a covariate in the statistical model. RESULTS: Mean follow-up was approximately 2.5 years. The mean change in lung density from baseline to last CT scan was -4.082 g/L for AAT and -6.379 g/L for placebo with a treatment difference of 2.297 (95% CI, 0.669 to 3.926; p = 0.006). The corresponding annual declines were -1.73 and -2.74 g/L/yr, respectively. CONCLUSIONS: The overall results of the combined analysis of 2 separate trials of comparable design, and the only 2 controlled clinical trials completed to date, has confirmed that IV AAT augmentation therapy significantly reduces the decline in lung density and may therefore reduce the future risk of mortality in patients with AAT deficiency related emphysema. TRIAL REGISTRATION: The EXACTLE study was registered in ClinicalTrials.gov as 'Antitrypsin (AAT) to Treat Emphysema in AAT-Deficient Patients'; ClinicalTrials.gov Identifier: NCT00263887. PMID- 20920371 TI - Exploring recruitment, willingness to participate, and retention of low-SES women in stress and depression prevention. AB - BACKGROUND: Recruitment, willingness to participate, and retention in interventions are indispensable for successful prevention. This study investigated the effectiveness of different strategies for recruiting and retaining low-SES women in depression prevention, and explored which sociodemographic characteristics and risk status factors within this specific target group are associated with successful recruitment and retention. METHODS: The process of recruitment, willingness to participate, and retention was structurally mapped and explored. Differences between women who dropped out and those who adhered to the subsequent stages of the recruitment and retention process were investigated. The potential of several referral strategies was also studied, with specific attention paid to the use of GP databases. RESULTS: As part of the recruitment process, 12.1% of the target population completed a telephone screening. The most successful referral strategy was the use of patient databases from GPs working in disadvantaged neighborhoods. Older age and more severe complaints were particularly associated with greater willingness to participate and with retention. CONCLUSIONS: Low-SES women can be recruited and retained in public health interventions through tailored strategies. The integration of mental health screening within primary care might help to embed preventive interventions in low-SES communities. PMID- 20920372 TI - Increased matrix metalloproteinase activation in esophageal squamous cell carcinoma. AB - BACKGROUND: Esophageal squamous cell carcinomas (ESCC) are usually asymptomatic and go undetected until they are incurable. Cytological screening is one strategy to detect ESCC at an early stage and has shown promise in previous studies, although improvement in sensitivity and specificity are needed. Proteases modulate cancer progression by facilitating tumor invasion and metastasis. In the current study, matrix metalloproteinases (MMPs) were studied in a search for new early detection markers for ESCC. METHODS: Protein expression levels of MMPs were measured using zymography in 24 cases of paired normal esophagus and ESCC, and in the tumor-associated stroma and tumor epithelium in one sample after laser capture microdissection (LCM). MMP-3 and MMP-10 transcripts in both the epithelium and stroma in five cases were further analyzed by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). RESULTS: Gelatin zymography showed bands corresponding in size to MMP-2, MMP-3, MMP-9, and MMP-10 enzymes in each of the 24 cancer cases. MMP levels tended to be higher in tumors than paired normal tissue; however, only the 45 kDa band that corresponds to the activated form of MMP-3 and MMP-10 was strongly expressed in all 24 tumors with little or no expression in the paired normal foci. LCM-based analysis showed the 45 kDA band to be present in both the stromal and epithelial components of the tumor microenvironment, and that MMP-3 and MMP-10 mRNA levels were higher in tumors than paired normal tissues for each compartment. CONCLUSIONS: Increased levels of MMPs occur in ESCC suggesting their up-regulation is important in esophageal tumorigenesis. The up-regulated gene products have the potential to serve as early detection markers in the clinic. PMID- 20920373 TI - Three-dimensional echocardiography using single-heartbeat modality decreases variability in measuring left ventricular volumes and function in comparison to four-beat technique in atrial fibrillation. AB - BACKGROUND: Three dimensional echocardiography (3DE) approaches the accuracy of cardiac magnetic resonance in measuring left ventricular (LV) volumes and ejection fraction (EF). The multibeat modality in comparison to single-beat (SB) requires breath-hold technique and regular heart rhythm which could limit the use of this technique in patients with atrial fibrillation (AF) due to stitching artifact. The study aimed to investigate whether SB full volume 3DE acquisition reduces inter- and intraobserver variability in assessment of LV volumes and EF in comparison to four-beat (4B) ECG-gated full volume 3DE recording in patients with AF. METHODS: A total of 78 patients were included in this study. Fifty-five with sinus rhythm (group A) and 23 having AF (group B). 4B and SB 3DE was performed in all patients. LV volumes and EF was determined by these two modalities and inter- and intraobserver variability was analyzed. RESULTS: SB modality showed significantly lower inter- and intraobserver variability in group B in comparison to 4B when measuring LV volumes and EF, except for end-systolic volume (ESV) in intraobserver analysis. There were significant differences when calculating the LV volumes (p < 0.001) and EF (p < 0.05) with SB in comparison to 4B in group B. CONCLUSION: Single-beat three-dimensional full volume acquisition seems to be superior to four-beat ECG-gated acquisition in measuring left ventricular volumes and ejection fraction in patients having atrial fibrillation. The variability is significantly lower both for ejection fraction and left ventricular volumes. PMID- 20920374 TI - Ventricular septal defect in a child with Alport syndrome: a case report. AB - BACKGROUND: Alport syndrome (AS) is a rare inherited disorder characterized by an inflammation of the kidneys and damage to the glomerular capillaries, ultimately leading to renal failure at an early age. To date, rare reports of cardiac involvement in AS have been described, due in the majority of cases to the higher risk of heart conduction abnormalities in these patients, at times requiring implantation of a transcutaneous pacemaker. An increased risk of hypertension is likewise commonly featured. CASE PRESENTATION: We report the case of a 17-year old female affected by a very severe early form of AS. A previously unreported association of the syndrome with congenital heart disease (CHD), (in this case membranous ventricular septal defect), is also reported. A possible pathophysiological mechanism underlying the concomitant manifestation of these two disorders is suggested. Complications implicated in surgical treatment of CHD are described. Clinical and therapeutic management of AS with cardiovascular involvement are discussed, and a short literature review performed. CONCLUSIONS: This first report of a cardiovascular association highlights the possible involvement of collagen mutations in the two pathologies. Even when drug resistance appears to be responsible for the failure to control secondary hypertension in AS, clonidine may represent a safe, effective option in the normalization of high blood pressure. PMID- 20920376 TI - Prebiotic effects: metabolic and health benefits. AB - The different compartments of the gastrointestinal tract are inhabited by populations of micro-organisms. By far the most important predominant populations are in the colon where a true symbiosis with the host exists that is a key for well-being and health. For such a microbiota, 'normobiosis' characterises a composition of the gut 'ecosystem' in which micro-organisms with potential health benefits predominate in number over potentially harmful ones, in contrast to 'dysbiosis', in which one or a few potentially harmful micro-organisms are dominant, thus creating a disease-prone situation. The present document has been written by a group of both academic and industry experts (in the ILSI Europe Prebiotic Expert Group and Prebiotic Task Force, respectively). It does not aim to propose a new definition of a prebiotic nor to identify which food products are classified as prebiotic but rather to validate and expand the original idea of the prebiotic concept (that can be translated in 'prebiotic effects'), defined as: 'The selective stimulation of growth and/or activity(ies) of one or a limited number of microbial genus(era)/species in the gut microbiota that confer(s) health benefits to the host.' Thanks to the methodological and fundamental research of microbiologists, immense progress has very recently been made in our understanding of the gut microbiota. A large number of human intervention studies have been performed that have demonstrated that dietary consumption of certain food products can result in statistically significant changes in the composition of the gut microbiota in line with the prebiotic concept. Thus the prebiotic effect is now a well-established scientific fact. The more data are accumulating, the more it will be recognised that such changes in the microbiota's composition, especially increase in bifidobacteria, can be regarded as a marker of intestinal health. The review is divided in chapters that cover the major areas of nutrition research where a prebiotic effect has tentatively been investigated for potential health benefits. The prebiotic effect has been shown to associate with modulation of biomarkers and activity(ies) of the immune system. Confirming the studies in adults, it has been demonstrated that, in infant nutrition, the prebiotic effect includes a significant change of gut microbiota composition, especially an increase of faecal concentrations of bifidobacteria. This concomitantly improves stool quality (pH, SCFA, frequency and consistency), reduces the risk of gastroenteritis and infections, improves general well-being and reduces the incidence of allergic symptoms such as atopic eczema. Changes in the gut microbiota composition are classically considered as one of the many factors involved in the pathogenesis of either inflammatory bowel disease or irritable bowel syndrome. The use of particular food products with a prebiotic effect has thus been tested in clinical trials with the objective to improve the clinical activity and well-being of patients with such disorders. Promising beneficial effects have been demonstrated in some preliminary studies, including changes in gut microbiota composition (especially increase in bifidobacteria concentration). Often associated with toxic load and/or miscellaneous risk factors, colon cancer is another pathology for which a possible role of gut microbiota composition has been hypothesised. Numerous experimental studies have reported reduction in incidence of tumours and cancers after feeding specific food products with a prebiotic effect. Some of these studies (including one human trial) have also reported that, in such conditions, gut microbiota composition was modified (especially due to increased concentration of bifidobacteria). Dietary intake of particular food products with a prebiotic effect has been shown, especially in adolescents, but also tentatively in postmenopausal women, to increase Ca absorption as well as bone Ca accretion and bone mineral density. Recent data, both from experimental models and from human studies, support the beneficial effects of particular food products with prebiotic properties on energy homaeostasis, satiety regulation and body weight gain. Together, with data in obese animals and patients, these studies support the hypothesis that gut microbiota composition (especially the number of bifidobacteria) may contribute to modulate metabolic processes associated with syndrome X, especially obesity and diabetes type 2. It is plausible, even though not exclusive, that these effects are linked to the microbiota-induced changes and it is feasible to conclude that their mechanisms fit into the prebiotic effect. However, the role of such changes in these health benefits remains to be definitively proven. As a result of the research activity that followed the publication of the prebiotic concept 15 years ago, it has become clear that products that cause a selective modification in the gut microbiota's composition and/or activity(ies) and thus strengthens normobiosis could either induce beneficial physiological effects in the colon and also in extra-intestinal compartments or contribute towards reducing the risk of dysbiosis and associated intestinal and systemic pathologies. PMID- 20920377 TI - Using microscopy to assess chorion structural integrity and parasitoid oviposition sites on stink bug (Hemiptera: Pentatomidae) eggs. AB - Previous efficacy studies found that many insecticides used by growers could be having an adverse effect on egg parasitoids (Telenomus podisi) developing in the eggs of the brown stink bug (Euschistus servus), while unhatched stink bugs experienced lower levels of mortality. One plausible explanation for this was that insecticides might enter parasitized eggs more readily via oviposition wounds. Parasitized E. servus eggs, as well as nonparasitized stink bug (Acrosternum hilare, E. servus, Murgantia histrionica, and Podisus maculiventris) eggs, were examined using electron microscopy. Egg response to perforation by a tungsten probe served as a control. Microscopy images depicted the chorion surface as characterized by a matrix of ridges and micropylar processes in a ring around the margin of the operculum. Observations of oviposition sites showed a "scab" formed where the ovipositor penetrated the chorion, and at sites penetrated by the probe. These formations appeared to be the result of fluids from inside the egg leaking out, drying, and hardening after oviposition or probe perforation, suggesting that the response was not due to substances secreted by the parasitoid. Further, no open wounds or holes were seen to increase the possibility of insecticides entering parasitized eggs. PMID- 20920375 TI - Immunogenicity and efficacy of oral vaccines in developing countries: lessons from a live cholera vaccine. AB - Oral vaccines, whether living or non-living, viral or bacterial, elicit diminished immune responses or have lower efficacy in developing countries than in developed countries. Here I describe studies with a live oral cholera vaccine that include older children no longer deriving immune support from breast milk or maternal antibodies and that identify some of the factors accounting for the lower immunogenicity, as well as suggesting counter-measures that may enhance the effectiveness of oral immunization in developing countries. The fundamental breakthrough is likely to require reversing effects of the 'environmental enteropathy' that is often present in children living in fecally contaminated, impoverished environments. PMID- 20920378 TI - Effect of the insertion and polymerization technique in composite resin restorations: analysis of marginal gap by atomic force microscopy. AB - This in vitro study evaluated the marginal gap at the composite tooth/resin interface in class V cavities under the influence of two insertion techniques and a curing system by means of atomic force microscopy (AFM). Forty enamel and dentin cavities were prepared on the buccal surface in bovine teeth with quadratic forms measuring 2 mm * 2 mm and depth of 1.5 mm. The teeth were then divided into four groups: group A, 10 cavities were restored in one increment, light cured by halogen light; group B, 10 cavities filled with bulk filling, light cured by the light emitting diodes (LED); group C, 10 cavities were restored by the incremental technique, light cured by halogen light; group D, 10 cavities were restored by the incremental technique, light cured by the LED. The teeth underwent the polishing procedure and were analyzed by AFM for tooth/restoration interface evaluation. The data were compared between groups using the nonparametric Kruskall-Wallis and Mann-Whitney tests (p < 0.05). The results showed a statistically significant difference between groups A and B and groups A and C. It was concluded that no insertion and polymerization technique was able to completely seal the cavity. PMID- 20920379 TI - P-wave dispersion between transcatheter and surgical closure of secundum-type atrial septal defect in childhood. AB - Patients with atrial septal defect have an increased risk for atrial fibrillation. Increased P-wave dispersion predicts the development of atrial fibrillation. The aim of this study was to determine difference in P dispersion between transcatheter closure with Amplatzer septal occluder and surgical closure in childhood. A total of 68 children (the mean age was 7.2 plus or minus 3.3 years; the mean secundum atrial septal defects diameter was 17.3 plus or minus 5.4 millimetres) were evaluated in this study. Transcatheter closure was attempted in 41 children with secundum atrial septal defects, and the defect in 27 patients was closed by surgical techniques. P maximum, P minimum and P dispersion were measured by the 12-lead surface electrocardiography. P maximum, P minimum and P dispersion were found to be similar in patients with pre- and post procedure (98.0 plus or minus 19.3 versus 95.1 plus or minus 23.0 milliseconds; 68.0 plus or minus 20.8 versus 67.6 plus or minus 24.3 milliseconds, 29.9 plus or minus 11.0 versus 27.1 plus or minus 12.1 milliseconds, respectively). There was no statistical significance in the comparison of P dispersion between the two groups. But in the surgical group, P-wave dispersion was decreased more significantly compared with baseline values (p-value equal to 0.03). In conclusion, there is no P dispersion between transcatheter closure with Amplatzer septal occluder and surgical closure of secundum atrial septal defect. PMID- 20920380 TI - Pandemic A(H1N1) 2009 influenza: review of the Southern Hemisphere experience. AB - We sought to systematically review the published literature describing the epidemiological aspects of the first wave of pandemic A(H1N1) 2009 influenza in the Southern Hemisphere. Fifteen studies were included in this review, originating from South America, Australia or New Zealand, and Africa. Across the different studies, 16.8-45.3% of the laboratory-confirmed cases were admitted to hospital, and 7.5-26.0% of these cases were admitted to intensive care units (ICUs). The fatality rate was 0.5-1.5% for laboratory-confirmed cases in 6/8 studies reporting specific relevant data, and 14.3-22.2% for cases admitted to ICUs in 5/7 studies, respectively. In 4/5 studies the majority of laboratory confirmed cases were observed in young and middle-aged adults, the percentage of older adults increased the higher the level of healthcare the cases received (e.g. laboratory confirmation, hospitalization or ICU admission) or for fatal cases. Many of the cases had no prior comorbidity, including conditions identified as risk factors for seasonal influenza. Pregnant women represented 7.4 9.1% and 7.1-9.1% of unselected laboratory-confirmed cases and of those admitted to ICUs, respectively. Obesity and morbid obesity were more commonly reported as the level of healthcare increased. PMID- 20920381 TI - Health service resource needs for pandemic influenza in developing countries: a linked transmission dynamics, interventions and resource demand model. AB - We used a mathematical model to describe a regional outbreak and extrapolate the underlying health-service resource needs. This model was designed to (i) estimate resource gaps and quantities of resources needed, (ii) show the effect of resource gaps, and (iii) highlight which particular resources should be improved. We ran the model, parameterized with data from the 2009 H1N1v pandemic, for two provinces in Thailand. The predicted number of preventable deaths due to resource shortcomings and the actual resource needs are presented for two provinces and for Thailand as a whole. The model highlights the potentially huge impact of health-system resource availability and of resource gaps on health outcomes during a pandemic and provides a means to indicate where efforts should be concentrated to effectively improve pandemic response programmes. PMID- 20920382 TI - Maintaining high rates of measles immunization in Africa. AB - Supplementary immunization activities (SIAs) are important in achieving high levels of population immunity to measles virus. Using data from a 2006 survey of measles vaccination in Lusaka, Zambia, we developed a model to predict measles immunity following routine vaccination and SIAs, and absent natural infection. Projected population immunity was compared between the current programme and alternatives, including supplementing routine vaccination with a second dose, or SIAs at 1-, 2-, 3-, 4- and 5-year intervals. Current routine vaccination plus frequent SIAs could maintain high levels of population immunity in children aged <5 years, even if each frequent SIA has low coverage (e.g. >= 72% for bi-annual 60% coverage SIAs vs. >= 69% for quadrennial 95% coverage SIAs). A second dose at 12 months with current coverage could achieve 81% immunity. Circulating measles virus will only increase population immunity. Public health officials should consider frequent SIAs when resources for a two-dose strategy are unavailable. PMID- 20920383 TI - The Q fever epidemic in The Netherlands: history, onset, response and reflection. AB - The 2007-2009 human Q fever epidemic in The Netherlands attracted attention due to its magnitude and duration. The current epidemic and the historical background of Q fever in The Netherlands are reviewed according to national and international publications. Seroprevalence studies suggest that Q fever was endemic in The Netherlands several decades before the disease was diagnosed in dairy goats and dairy sheep. This was in 2005 and the increase in humans started in 2007. Q fever abortions were registered on 30 dairy goat and dairy sheep farms between 2005 and 2009. A total of 3523 human cases were notified between 2007 and 2009. Proximity to aborting small ruminants and high numbers of susceptible humans are probably the main causes of the human Q fever outbreak in The Netherlands. In general good monitoring and surveillance systems are necessary to assess the real magnitude of Q fever. PMID- 20920384 TI - The impact of training for day-care educators on childhood anaemia in nurseries: an institutional randomised clinical trial. AB - OBJECTIVE: To test the impact of training for educators on the health of children enrolled in public and philanthropic day-care nurseries. DESIGN: A randomised, institutional, non-blind clinical trial was conducted. An educational intervention was performed in four day-care centres and the control group consisted of four other day-care centres. Interviews with the mothers, collection of blood from the children by digital puncture and anthropometry were performed. The chosen indicator for the improvement of health was anaemia (Hb <11 g/dl). An unconditional logistic regression model was set for the risk factors for anaemia, considering associations with P <= 0.05 as statistically significant. SETTING: Eight day-care centres in the city of Sao Paulo, Brazil. SUBJECTS: Two hundred and fifty-two children from day-care nurseries. RESULTS: The children from the day-care centres that were not subject to intervention presented a 2.11 times greater risk (95% CI 1.04, 4.30; P = 0.40) of having anaemia at the end of the study independent of the control variables (sex, age, time in the day-care centre, anaemia at the beginning of the study, maternal age, use of oral iron supplements, number of siblings, per capita family income, use of antibiotics and the necessity of avoidable hospitalisations) used in the construction of the final logistical model. CONCLUSIONS: The assessed educational intervention promoted significant changes in the health status of the children, reinforcing the importance of training for professionals who care for young children in day care centres in developing countries in order to promote child health. PMID- 20920385 TI - Low prevalence of iron-deficiency anaemia among Inuit preschool children: Nunavut Inuit Child Health Survey, 2007-2008. AB - OBJECTIVE: To report the prevalence rates and correlates for anaemia, iron deficiency (ID) and iron-deficiency anaemia (IDA) among Inuit preschool-aged children. DESIGN: A cross-sectional study assessed iron intake, demographic information, medical history, anthropometrics, Hb, ferritin, C-reactive protein and antibodies to Helicobacter pylori. SETTING: Sixteen selected Inuit communities in Nunavut Territory, Canada. SUBJECTS: Inuit (n 388) aged 3-5 years randomly recruited from communities. RESULTS: Anaemia (3-4 years: Hb < 110 g/l; 5 years: Hb < 115 g/l) was prevalent in 16.8 % of children. The prevalence of ID (ferritin < 12 MUg/l) was 18.0 % and that of IDA was 5.4 %. When ID was defined as ferritin <10 MUg/l, 10.8 % of children were iron deficient and 3.3 % had IDA. In multiple logistic regression, boys were more likely to be iron deficient (OR = 2.28, 95 % CI 1.17, 8.25), but no other risk factor emerged for ID. Three- to 4 year-olds were less likely than 5-year-olds to have anaemia from causes other than ID (OR = 0.11, 95 % CI 0.08, 0.58). Anaemia from other causes was more common among children residing in crowded homes (OR = 2.30, 95 % CI 1.37, 12.31) and those treated for past-year ear infection (OR = 1.35, 95 % CI 1.05, 7.21). CONCLUSIONS: The low prevalence of ID and IDA is encouraging, but efforts are still needed to reduce rates as they continue to be higher than general population rates. Household crowding and infections may contribute to anaemia and warrant further research. PMID- 20920387 TI - Sugar-sweetened beverage intake and overweight in children from a Mediterranean country. AB - OBJECTIVE: To assess the association between sugar-sweetened beverage (SSB) consumption and overweight in children from a Mediterranean country. DESIGN: The children's dietary intake was measured using a semi-quantitative FFQ completed by the parents. Overall, 2512 questionnaires were returned and 837 children were removed, leaving a final sample of 1675 children, aged between 5 and 10 years. Height and weight were measured according to international standards, and BMI was calculated. The definition of overweight and obesity was based on average centiles according to the International Obesity Task Force cut-offs. To determine the magnitude of the association between SSB consumption and overweight, OR estimates, including CI, were computed using unconditional logistic regression, adjusting for confounders. SETTING: Elementary schools throughout the city of Porto, Portugal. SUBJECTS: We invited 5867 children, randomly selected, and their parents to participate in the study. Of those schools that agreed to take part, 3391 parents signed and returned the fully filled out consent form. RESULTS: The prevalence of overweight (including obesity) was 36.6 % for girls and 38.8 % for boys. With regard to SSB consumption (serving/d), no differences between with overweight and non-overweight children were found even after adjustment for confounders (1-2 servings/d: OR = 1.67, 95 % CI 0.76, 3.66, in girls; OR = 1.63, 95 % CI 0.76, 3.47, in boys; and >2 servings/d: OR = 0.63, 95 % CI 0.33, 1.22, in girls; OR = 0.64, 95 % CI 0.33, 1.52, in boys). CONCLUSIONS: The intake of SSB was not associated with increased risk of overweight in Portuguese schoolchildren. PMID- 20920386 TI - Healthy food purchasing among African American youth: associations with child gender, adult caregiver characteristics and the home food environment. AB - OBJECTIVE: To examine how factors related to the home food environment and individual characteristics are associated with healthy food purchasing among low income African American (AA) youth. SUBJECTS: A total of 206 AA youth (ninety-one boys and 115 girls), aged 10-14 years, and their primary adult caregivers. SETTING: Fourteen Baltimore recreation centres in low-income neighbourhoods. DESIGN: Cross-sectional study. We collected information about food purchasing, the home food environment, sociodemographic and psychosocial factors drawn from social cognitive theory. Multivariable logistic regression was used to examine the factors associated with the frequency and proportion of healthy food purchases in all youth and stratified by gender. Low-fat or low-sugar foods were defined as healthy. RESULTS: Youth purchased an average of 1.5 healthy foods (range=0-15) in the week before the interview, comprising an average of 11.6% (range=0-80%) of total food purchases. The most commonly purchased healthy foods included water and sunflower seeds/nuts. Healthier food-related behavioural intentions were associated with a higher frequency of healthy foods purchased (OR=1.4, P<0.05), which was stronger in girls (OR=1.9, P<0.01). Greater caregiver self-efficacy for healthy food purchasing/preparation was associated with increased frequency of healthy purchasing among girls (OR=1.3, P<0.05). Among girls, more frequent food preparation by a family member (OR=6.6, P<0.01) was associated with purchasing a higher proportion of healthy foods. No significant associations were observed for boys. CONCLUSIONS: Interventions focused on AA girls should emphasize increasing food-related behavioural intentions. For girls, associations between caregiver self-efficacy and home food preparation suggest the importance of the caregiver in healthy food purchasing. PMID- 20920388 TI - Waist circumference percentiles for Kuwaiti children and adolescents. AB - OBJECTIVE: Abdominal obesity is a major risk factor for chronic diseases. Yet there are no waist circumference (WC) cut-offs for children in the Arabian Gulf. We developed smoothed WC percentiles for 5-19-year-old Kuwaiti children and adolescents, which could be used in clinical and public health practice. We also examined the percentages of children who had WC >= 90th percentile, a value commonly associated with an elevated risk of CVD. DESIGN: This is a cross sectional study that was conducted by the Kuwait National Nutrition Surveillance System. SETTING: Data were collected from representative primary-, intermediate- and secondary-school children as part of the yearly nutrition and health monitoring. Least mean square regression was used to develop smoothed WC curves. SUBJECTS: A total of 9593 healthy 5.0-18.9-year-old children of both sexes were studied from all areas of Kuwait. Age, gender, residency, education level, weight, height and WC were collected for all participants. RESULTS: We developed the first smoothed WC curves for Kuwaiti children. Male children had higher WC than female children. WC increased with age in both genders, but larger percentages of male children had WC >= 90th percentile. Male children aged >10 years have higher WC percentiles than do female children at the 50th, 75th, 90th and 97th percentiles. CONCLUSIONS: Male children (especially those aged >10 years) are at higher risk than female children. Few health-care professionals routinely measure WC. WC measurement should be promoted as an important tool in paediatric primary care practice. The use of these age- and gender-specific percentiles can impact public health recommendations for Kuwaiti and other Arab children from the Gulf. PMID- 20920391 TI - [Diagnosis of malignant pleural mesothelioma]. PMID- 20920389 TI - A multiscale approach to assess the complex surface of polyurethane catheters and the effects of a new plasma decontamination treatment on the surface properties. AB - Polyurethane catheters made of Pellethane 2363-80AE(r) were treated with a low temperature plasma developed for the decontamination of reusable polymer devices in hospitals. We investigated the modifications of the polymer surface by studying the topographic modifications, the chemical modifications, and their consequences on the wettability and bacterial adhesion. This study showed that plasma treatment modified the topography and grafted oxygen and nitrogen species onto the surface, resulting in an increase in the surface polarity. This effect could be correlated to the number of nitrogen atoms interacting with the surface. Moreover, this study demonstrated the significance of multiscale heterogeneities, and the complexity of industrial medical devices made from polymers. Their surface can be heterogeneous, and they contain additives that can migrate and change the surface composition. PMID- 20920392 TI - [Sarcomatoid mesothelioma--a diagnostic challenge]. AB - This is the case of a 62-year-old carpenter in whom a computed tomography showed a widespread "mesothelioma-like" tumour of the pleura. Needle biopsy and later autopsy showed malignant sarcomatoid tumour. The tumour stained negatively for calretinin and other "mesothelial markers". Diagnosis has important legal implications for the relatives, we therefore find it important to stress that sarcomatoid mesothelioma is usually calretinin-negative. PMID- 20920393 TI - [Severe acute malnutrition in children]. AB - Severe acute malnutrition (SAM) affects approx. 19 million children below five years of age in low and middle income countries. Both shortage and low quality of foods are important determinants of SAM. With the development of special ready-to use foods and by using simple treatment protocols, it is now possible to treat SAM successfully outside hospitals and treatment centers thereby reducing the case-fatality rate. However, only a small percentage of children with SAM have access to correct treatment. PMID- 20920394 TI - [Good results after Hartmann's operation for rectal cancer in high risk patients]. AB - INTRODUCTION: The purpose of this study was to evaluate the incidence of per- and postoperative complications of low anterior resection and Hartmann's operation (HO) for rectal cancer. The study was performed in a department with a high frequency of HO. MATERIAL AND METHODS: Patients who had undergone low anterior resection (LA) or HO for rectal cancer at the Department of Surgery, Gentofte Hospital, between 1 January 2001 and 31 December 2007. RESULTS: A total of 187 patients were operated using LA or HO technique during this period. LA was performed in 103 patients and HO in 84 patients. ASA-scores were significantly higher for patients who underwent HO (p = 0.0066). There was no significant difference in complication rates between the two groups (p = 0.385). The 30-day mortality rate was 3.2% (n = 6) for all patients, and it was not significantly different between the two groups (HO 3.6% (n = 3) and LA= 2.9% (n = 3), p = 1). One ASA III patient who underwent LA died from anastomotic leakage whereas no ASA III patients operated with HO died. There was no significant difference between the groups for any other per- and postoperative complication. CONCLUSION: In this material, HO rather than LA seems to be the safer choice for high risk rectal cancer patients with ASA > 3 in terms of mortality rate compared with the national index. PMID- 20920395 TI - [Prolonged symptoms following mild traumatic brain injury]. AB - INTRODUCTION: Patients with mild traumatic brain injury (MTBI) do not undergo consistent follow-up in Denmark and the risk factors for long-term symptoms are not fully known. The purpose of this study was to look into symptom frequency, sick-leave frequency and to try to identify risk factors for long-term symptoms following MTBI. MATERIAL AND METHODS: Patients were recruited from the emergency room at Viborg Hospital. Initial data were registered and telephone interviews were conducted one month and one year after trauma. RESULTS: 60% were asymptomatic within the first month; an additional 11% became asymptomatic within the next year, leaving 29% with residual symptoms one year after trauma. 70% reported a sick leave period < 2 days, 19% > one month and 2% > one year. The average trauma-to-emergency room contact reached 158 min (median 65 min). Gender, age, blood pressure (BP), pulse, Glasgow coma score (GCS), admission to hospital, unconsciousness, amnesia, alcohol intake, time or type of trauma were not associated with long term symptoms. CONCLUSION: Even patients with minor head trauma have a relatively high risk of long-term symptoms regardless of gender, age, BP, pulse, GCS, admission to hospital, unconsciousness, amnesia, alcohol intake, time or type of trauma. Nevertheless, the risk of long-term sick leave is relatively small. PMID- 20920396 TI - [Autopsy and blood testing for alcohol and drugs/medicine after traffic fatalities is not routinely conducted]. AB - INTRODUCTION: In some road traffic crashes with fatal outcome, the police investigations lead to charges against and prosecution of a person. The police can request a medico-legal autopsy as well as a toxicological examination, but the extent to which this is done, and the role here of in the legal setting is unknown. MATERIAL AND METHODS: Information concerning traffic crashes with fatal outcome in the period 2000-2004 in Aarhus Police District was retrieved and compared. The information included comprised crash specific and legal information, as well as medical data concerning autopsy, examination for alcohol, drugs and/or medicine. RESULTS: In all, 81 traffic crashes had a fatal outcome for 92 persons, of whom 17 (18%) were autopsied, 55 (60%) were tested for alcohol, and five (5%) were examined for drugs/medicine. Twenty-six were charged with negligent homicide, of which 18 were convicted. Autopsy was performed in four of these cases, 19 were tested for alcohol and one was tested for drugs/medicine. CONCLUSION: This study shows that the police requests few medico legal autopsies following road traffic fatalities, and that testing for alcohol as well as drugs/medicine is not conducted routinely. As a consequence, important information may not come to the knowledge of the police in cases of negligent homicide. We recommend that postmortem examination be conducted routinely in traffic-related homicide cases to secure the best possible conditions for a legal evaluation. PMID- 20920397 TI - [Perioperative care of patients with stage IIIC ovarian cancer]. AB - INTRODUCTION: Besides intraoperative efforts, the perioperative care is essential to improve the postoperative outcome following ovarian cancer surgery. Multimodal evidence-based care within the fast-track methodology significantly enhances postoperative recovery and reduces morbidity. The purpose of this study was to assess and discuss perioperative care principles in patients undergoing ovarian cancer surgery with stage IIIC at the six centres in Denmark performing this surgical procedure. MATERIAL AND METHODS: The study was a retrospective audit. The study included 90 consecutive patients, 15 from each of the centres at which operations were performed in 2007. Data was obtained from medical and nursing files. The extent of the surgical procedure was recorded. RESULTS: For patients without extensive surgery effort, the median hospital stay was six days; for patients with extensive surgery, the median hospital stay was 13 days. A total of 48 percent of the patients without maximal surgery effort fulfilled the goals for mobilization on the day of surgery, and 19 percent on the first postoperative day. A total of 35 percent of the patients with maximal surgery effort fulfilled the goals for mobilization on the day of the surgery, and 24 percent on the first postoperative day. Less than half of the patients had regular oral diet and protein enriched drinks on or before the third postoperative day. CONCLUSION: Mobilization, nutrition, nausea and pain are severe problems for patients undergoing ovarian cancer surgery. Optimized perioperative care is needed including a procedure-specific, evidence-based clinical guideline for patients receiving extensive surgery. PMID- 20920398 TI - [Evidence-based pedagogical principles used at medical specialist workshop]. AB - How should a theoretical postgraduate course be organized to obtain maximum effect? We report an example of a two-day course planned and implemented according to educational approaches previously shown to be effective. The theme of the course is "The old patient", and the course is compulsory for residents in internal medicine. This case study showed that the methods used were feasible, and the participants gained knowledge. A multiple-choice test before and after the course showed 44% (before) and 64% (after) correct answers, p < 0.001. PMID- 20920400 TI - [Stem cells--belief, hope and knowledge]. PMID- 20920399 TI - [Subcutaneous emphysema of upper limb]. AB - Subcutaneous emphysema involving the upper limb can result from infection with gas-producing microorganisms or from a variety of non-infective causes. This case illustrates the reflections that should be made in such cases to avoid over- or undertreating the patient. PMID- 20920401 TI - [An introduction to stem cell research]. AB - Stem cells (SC) are characterized by the ability of self renewal as well as specialization into different cell types. Stem cells are present in most organs, and can be isolated from adult tissue, embryonic tissue and can be created by a new technology named induced pluripotency. The three types of SC have different potentials in terms of advancing regenerative medicine, but also raise serious safety concerns that need to be addressed before SC can fulfill the expectations by being developed into new cures and treatments for a range of serious cell degenerative diseases. PMID- 20920402 TI - [Cancer stem cells in the haematopoietic system]. AB - Cancer is dependent on so-called cancer stem cells that initiate and maintain the cancer cell population. Stem cells are described in normal tissue as low frequent, self-renewing cells with a multi- or pluripotent differentiation potential. The true characteristics of the cancer-initiating cells are still not entirely known, but it is obvious that identifying these cells will enable us to better understand the biology of cancer. In this article, we focus on normal haematopoietic stem cells and cancer stem cells in leukaemia and multiple myeloma. PMID- 20920403 TI - [Basic stem cell biology and cancer]. AB - The finding that tumours, like normal tissues, are endowed with varying degrees of cellular heterogeneity has far-reaching consequences for our understanding of cancer. The cancer stem cell and clonal evolution models have both been proposed to explain tumour-associated cellular heterogeneity. Here, we briefly review these two non-exclusive models with special emphasis on how they aid our understanding of cancer and their implications for therapeutic strategies. Finally, we discuss the close association between basic stem cell biology and cancer, focusing on the role of self-renewal. PMID- 20920404 TI - [Stem cell therapy for neurodegenerative disorders]. AB - Intrastriatal, foetal neural transplants can ameliorate symptoms in patients with Parkinson's and Huntington's disease, although not stop the primary cell-loss. Several issues must, however, be addressed before general or extended clinical use of cell therapy in neurodegenerative diseases can become a reality. Improvements include standardized and safe master cell-lines derived from human embryonic stem cells, induced pluripotent stem cells and neural stem cells. Cells from these sources are expected to become available for cell replacement therapies or therapeutic production of trophic, anti-inflammatory and restorative factors within a few years. PMID- 20920405 TI - [From stem cells to functional beta cells in type 1 diabetes]. AB - Although the reconstitution of a functional beta-cell mass by transplantation of isolated islets can restore euglycaemia in the absence of insulin treatment, a shortage of donor material is preventing the use of cell replacement therapy for treatment of type 1 diabetes. Advances in directed differentiation of stem cells towards beta-cells via stepwise recapitulation of embryonic development demonstrate that stem cells may be an appropriate source for the generation of therapeutic cells. In the present article, we highlight some of the critical issues impeding the translation of stem cell-based therapies to the clinic. PMID- 20920406 TI - [Cardiovascular regeneration using mesenchymal stem cells]. AB - Treatment with stem cells with a regenerative potential is a new form of therapy that is being studied intensively. Mesenchymal stem cells or stromal cells (MSC) are a promising source of stem cells for regenerative therapy. MSC are easy to isolate and culture, expand in vitro and have a multipotent differentiation capacity. Clinical MSC studies on patients with ischaemic heart disease have shown improved left ventricular function and perfusion and also a reduction in infarct size and symptoms. In this short review we provide a status on MSC regenerative treatment in cardiovascular disease. PMID- 20920407 TI - [Bone and cartilage repair using stem cells]. AB - Mesenchymal stem cells (MSC) are capable of multilineage differentiation into cells like osteoblasts, chondrocytes or adipocytes. MSCs can be isolated from bone marrow and expanded ex vivo for up to 25-40 population doublings while maintaining genetic stability and differentiation potential. MSCs have great potential in the field of tissue engineering and regenerative medicine where cartilage and bone conditions which are non-treatable or show very slow improvement can be effectively handled. Several clinical trials have been performed using MSC and show very promising results. PMID- 20920408 TI - Microvesicle formulations used in topical drugs and cosmetics affect product efficiency, performance and allergenicity. AB - Attempts to improve the formulations of topical products are continuing processes (ie, to increase cosmetic performance, enhance effects, and protect ingredients from degradation). The development of micro- and nanovesicular systems has led to the marketing of topical drugs and cosmetics that use these technologies. Several articles have reported improved clinical efficacy by the encapsulation of pharmaceuticals in vesicular systems, and the numbers of publications and patents are rising. Some vesicular systems may deliver the drug deeper in the skin as compared to conventional vehicles, or even make transdermal delivery more efficient for a number of drugs. Vesicular systems may also allow a more precise drug delivery to the site of action (ie, the hair follicles) and thereby minimize the applied drug concentration, reducing potential side effects. On the other hand, this may increase the risk of other side effects. Few case reports have suggested that microvesicle formulations may affect the allergenicity of topical products. This article gives an overview of the current knowledge about the topical use of microvesicular systems and the dermatoallergologic aspects. PMID- 20920409 TI - "Dermatitis" defined. AB - BACKGROUND: The term "dermatitis" can be defined narrowly or broadly, clinically or histologically. A common and costly condition, dermatitis is underresourced compared to other chronic skin conditions. The lack of a collectively understood definition of dermatitis and its subcategories could be the primary barrier. OBJECTIVE: To investigate how dermatologists define the term "dermatitis" and determine if a consensus on the definition of this term and other related terms exists. METHODS: A seven-question survey of dermatologists nationwide was conducted. RESULTS: Of respondents (n = 122), half consider dermatitis to be any inflammation of the skin. Nearly half (47.5%) use the term interchangeably with "eczema." Virtually all (> 96%) endorse the subcategory "atopic" under the terms "dermatitis" and "eczema," but the subcategories "contact," "drug hypersensitivity," and "occupational" are more highly endorsed under the term "dermatitis" than under the term "eczema." Over half (55.7%) personally consider "dermatitis" to have a broad meaning, and even more (62.3%) believe that dermatologists as a whole define the term broadly. CONCLUSION: There is a lack of consensus among experts in defining dermatitis, eczema, and their related subcategories. PMID- 20920410 TI - Patch testing in atopic dermatitis. AB - BACKGROUND: Because atopic dermatitis (AD) patients differ from non-AD patients in immunologic responses (they lack beta-defensins, are more likely to react to protein allergens, and are harder to experimentally sensitize to the nonprotein allergens), patch-test responses to commercially available patch test series may differ in AD patients. OBJECTIVE: To compare responses to conventional patch tests in AD and non-AD patients and to assess the importance of specific allergens in AD. METHODS: AD patients were strictly defined by history of childhood flexural dermatitis. Patients with active disease were routinely pretreated with systemic antistaphylococcal and antiyeast antibiotics before patch testing unless contraindicated. All final patch-test readings occurred at day 7. RESULTS: The overall number of positive patch-test results did not differ significantly in AD patients (n = 146) versus non-AD patients (n = 1,003). There was no significant increase in nickel sensitivity. There was a nonsignificant trend toward an increased number of positive patch-test reactions to tixocortol pivalate, Compositae mix, and propylene glycol in AD patients. CONCLUSION: In AD patients treated with antibiotics and systemic azoles before patch testing, the number of positive patch-test reactions is almost identical to that of non-AD patients. Patch-test reactions to components of topical medicaments may be more frequent in AD as compared to non-AD patients. PMID- 20920411 TI - Effects of occlusion on the skin of atopic dermatitis patients. AB - BACKGROUND: Atopic dermatitis (AD) may be exacerbated by occlusion from items such as occlusive gloves or textiles, especially if the occlusion is removed suddenly, creating a steep humidity gradient. Most previous studies of occlusion have focused on normal skin. Occlusion has been shown to be beneficial in psoriatic skin, but many atopic patients complain of increased inflammation after occlusion. OBJECTIVE: To evaluate the response of noninflamed AD skin to occlusion. METHODS: Six patients with AD were patch-tested with occlusive polyethylene wrap and sodium lauryl sulfate (SLS) in standard Finn Chambers taped to noninflamed skin of the back. Cytokine and chemokine messenger ribonucleic acid (mRNA) for interleukin-8 (IL-8), interleukin-1 alpha (IL-1alpha), and interleukin-1 receptor antagonist (IL-1RA), as well as the 18S rRNA housekeeping gene, was obtained via tape-stripping the skin and measured using quantitative real-time polymerase chain reaction. We also measured transepidermal water loss after removal of occlusion. RESULTS: Polyethylene occlusion alone with abrupt removal induced IL-8 and IL-1alpha levels similar to or exceeding that of SLS. IL 1RA was up-regulated by SLS and occlusion, with SLS showing a stronger response. CONCLUSION: Removal of occlusion with polyethylene film up-regulates the inflammatory cytokines IL-8, IL-1alpha, and IL-1RA in patients with AD. This may explain the worsening of AD with the use of occlusive gloves, athletic equipment, and fabrics. PMID- 20920412 TI - Irritant and sensitizing potential of eight surfactants commonly used in skin cleansers: an evaluation of 105 patients. AB - BACKGROUND: Irritation from surfactants contained in detergents is a frequent adverse reaction to cosmetics. Sensitization to surfactants is also possible. In the literature, comparative studies about irritant and sensitizing potential of different surfactants are heterogeneous and inconclusive about the best molecules to use. OBJECTIVES: We compared the irritant and sensitizing potential of some surfactants that are usual components in marketed synthetic detergents (syndets) to obtain practical information regarding commonly used detergents. METHODS: We patch-tested eight surfactants of the different types (anionic, cationic, amphoteric, and non-ionic) in 105 patients. Assessment of allergic reactions of tested surfactants was carried out in accordance with the recommendations of the International Contact Dermatitis Research Group; assessment of irritant power followed the amended Draize classification. RESULTS: None of the eight surfactants in our series gave positive allergic reactions. Only cocamidopropyl betaine from the Italian standard (Societa Italiana di Dermatologia Allergologica, Professionale e Ambientale [SIDAPA]) series gave five positive reactions among 105 patients. None of the eight studied surfactants induced skin irritation. The most tolerated are two new mild anionics (sodium cocoyl glutamate and sodium lauroyl oat amino acids) and an amphoteric agent (disodium cocoamphodiacetate). CONCLUSION: From this study, we deduce that cosmetic companies' efforts to search for and market new products with very mild surfactants have been generally successful. PMID- 20920413 TI - Patch-testing with plastics and glues series allergens. AB - BACKGROUND: Few US studies have reported results of patch testing with plastics and glues. OBJECTIVE: To report our institution's results of testing patients suspected of allergy to plastics and glues with a comprehensive plastics and glues series and to compare these results with previously published data. METHODS: Retrospective review of results of patch-testing with plastics and glues allergens at our institution between 2000 and 2007. In total, 444 patients were patch-tested with up to 56 plastics and glues allergens in the specialized series and up to five plastics and glues allergens in a baseline series. Positive reaction rates were compared to other patch testing reports. RESULTS: Of patients, 97 (22%) had irritant reactions, and 201 (45%) had at least one allergic reaction. Bis(2-dimethylaminoethyl) ether 1%, benzoyl peroxide 1%, epoxy resin, bisphenol F 0.25%, 2-hydroxyethyl methacrylate 2%, and 2-hydroxyethyl acrylate 0.1% had the highest allergy reaction rates. Testing with specialized series identified 193 patients with plastics and glues allergy, of whom 162 were not identified by testing with baseline series alone. CONCLUSION: For patients suspected of allergy to plastics and glues, patch-testing with specialized series of plastics and glues allergens is an important adjunct to patch-testing with baseline series. PMID- 20920414 TI - Physician-patient agreement in the assessment of allergen relevance. AB - BACKGROUND: The efficacy of patch testing may be enhanced by data allowing the physician to estimate the likelihood that results of a patch-test reading are relevant to a patient's dermatitis. OBJECTIVE: The goal of this study was to compare the rates of agreement between the physician's assessment of relevance at the time of final reading and the patients' report 3 months to 3 years later in regard to whether avoidance of an allergen was needed to remain free of dermatitis. We hypothesize that the agreement rates between the physician and patient relevance assessments will vary based on properties both intrinsic and extrinsic to the allergen in question. METHODS: We mailed 407 Institutional Review Board-approved questionnaires to patients and analyzed results for the 92 patients reporting greater than 80% improvement of their dermatitis. Cross reacting allergens tested on the same patient were combined for analysis. Percent agreement was used to assess interrater concordance. RESULTS: Percent agreement regarding relevance for each allergen or group of allergens was as follows: formaldehyde and formaldehyde-releasing preservatives, 88%; neomycin sulfate, 78%; nickel sulfate hexahydrate, 71%; fragrance mix and related products, 65%; and gold sodium thiosulfate, 56%. CONCLUSION: Relevance varies between allergens. Physician assessment of relevance at the time of final reading is not the ideal method for determining allergen relevance. This has implications for when best to determine the relevance of certain allergens. For allergens with lower agreement, in particular, extended follow-up is recommended to accurately determine an allergen's contribution to a patient's allergic contact dermatitis, especially in those circumstances in which a patient's condition has not improved. PMID- 20920415 TI - Publication of abstracts presented at Annual American Contact Dermatitis Society Meetings. AB - BACKGROUND: Medical meetings provide a forum for the open discussion and sharing of new information for attendees. Peer-reviewed publication provides greater distribution of vetted information. OBJECTIVE: The aim of this study was to analyze the publication of presentations from annual American Contact Dermatitis Society meetings. METHODS: Abstracts presented at the 2000, 2003, and 2006 American Contact Dermatitis Society meetings were identified. By keywords and author names, PubMed was searched for published papers corresponding to the work presented at these annual meetings. Matches were confirmed by comparing the content of the abstracts with the fully published articles. RESULTS: Of 115 presented abstracts, 55% resulted in the publication of an article by November 2009; 5% of abstracts had been published prior to presentation. Time to publication was 0.25 to 6.0 years. Mean time to publication was 1.8 years. CONCLUSIONS: Over one-half of all American Contact Dermatitis Society presentations resulted in the publication of an original article. Most were published within 2 years. The great majority of abstracts were published in Dermatitis (formerly the American Journal of Contact Dermatitis). PMID- 20920416 TI - Occupational airborne allergic contact dermatitis caused by gold. AB - Airborne allergic contact dermatitis caused by gold is rare, often not even suspected and hence not investigated. Our purpose was to elucidate the clinical relevance of gold-induced airborne contact dermatitis. We analyzed and discussed the occupational dermatitis of two women working as restorers. Both patients' test results showed positive reactions to gold sodium thiosulfate only. The stop and-relapse test confirmed the diagnostic hypothesis of airborne contact allergy. Our patients turned out to be gold sensitized because of occupational exposure to gold dust and gold leaf. PMID- 20920417 TI - Allergic contact dermatitis from epoxy resin in solder mask coating in an individual working with printed circuit boards. PMID- 20920418 TI - Shiitake mushroom dermatitis. PMID- 20920419 TI - Allergic contact dermatitis from N,N-methylenebismorpholine in a cutting oil. PMID- 20920420 TI - The role of patch testing in oral disease. PMID- 20920421 TI - Palladium sensitization in the United States: dermatology and dentistry connection. PMID- 20920422 TI - Assisted monitoring of blood glucose: special safety needs for a new paradigm in testing glucose. PMID- 20920423 TI - Quantifying the composition of human skin for glucose sensor development. AB - BACKGROUND: Glucose is heterogeneously distributed within human skin. In order to develop a glucose measurement method for human skin, both a good quantification of the different compartments of human skin and an understanding of glucose transport processes are essential. This study focused on the composition of human skin. In addition, the extent to which intersubject variability in skin composition alters glucose dynamics in human skin was investigated. METHODS: To quantify the composition of the three layers of human skin-epidermis, dermis, and adipose tissue-cell and blood vessel volumes were calculated from skin biopsies. These results were combined with data from the literature. The composition was applied as input for a previously developed computational model that calculates spatiotemporal glucose dynamics in human skin. The model was used to predict the physiological effects of intersubject variability in skin composition on glucose profiles in human skin. RESULTS: According to the model, the lag time of glucose dynamics in the epidermis was sensitive to variation in the volumes of interstitial fluid, cells, and blood of all layers. Data showed most variation/uncertainty in the volume composition of the adipose tissue. This variability mainly influences the dynamics in the adipose tissue. CONCLUSIONS: This study identified the intersubject variability in human skin composition. The study shows that this variability has significant influence on the glucose dynamics in human skin. In addition, it was determined which volumes are most critical for the quantification and interpretation of measurements in the different layers. PMID- 20920424 TI - Impact of tissue heterogeneity on noninvasive near-infrared glucose measurements in interstitial fluid of rat skin. AB - BACKGROUND: Movement of the optical interface used to collect noninvasive near infrared spectra is known to dramatically increase prediction errors for glucose concentration measurements within the interstitial fluid of living rat skin. Prediction errors increase by more than 2.5-fold when the interface is moved before each non-invasive measurement compared to measurements where the interface position is constant throughout. Chemical heterogeneity of the skin matrix is examined as a possible mechanism for the strong sensitivity to the interface placement during noninvasive measurements conducted from transmission near infrared absorption spectroscopy. METHOD: Microspectroscopy was performed over a region of the near-infrared spectrum (4000-5000 cm(-1)) to map the concentrations of water, collagen protein, fat, and keratin protein within the skin tissue matrix through which noninvasive spectra are collected. Maps were created for multiple samples of skin excised from male and female animals. Sets of near infrared spectra were constructed to simulate noninvasive spectra in accord with the basic tissue composition found from the microspectroscopic maps with added information corresponding to a span of glucose concentrations ranging from 5 to 35 mM and Gaussian-distributed noise. RESULTS: Microspectroscopic maps of rat skin reveal similar patterns of heterogeneity for major chemical components of skin samples excised from both male and female animals. These maps demonstrate concentration domains with dimensions similar to the size of the fiber interface used to collect noninvasive spectra. Partial least squares calibration models generated from sets of simulated spectra demonstrate increases in prediction errors for glucose when the spectral matrix is changed in accord with the degree of chemical heterogeneity displayed in the skin maps. Prediction errors typically increase between 100 and 1000% when comparing errors generated from spectra that represent a single tissue composition versus spectra that represent a varied skin composition in accord with the distribution displayed in the skin maps. CONCLUSIONS: The distribution of the major components of skin is not uniform, but establishes domains within the skin matrix that strongly impact prediction errors for the noninvasive spectroscopic measurement of glucose within the interstitial fluid of rat dermis tissue. The observed increase in prediction error (>2.5-fold) determined from actual noninvasive measurements is within the lower range of prediction error increases demonstrated by this simulation study. These findings implicate that chemical heterogeneity within the tissue matrix is a major factor in the sensitivity of the location of the fiber interface used to collect noninvasive spectral data. PMID- 20920425 TI - Bioluminescence imaging of glucose in tissue surrounding polyurethane and glucose sensor implants. AB - BACKGROUND: The bioluminescence technique was used to quantify the local glucose concentration in the tissue surrounding subcutaneously implanted polyurethane material and surrounding glucose sensors. In addition, some implants were coated with a single layer of adipose-derived stromal cells (ASCs) because these cells improve the wound-healing response around biomaterials. METHODS: Control and ASC coated implants were implanted subcutaneously in rats for 1 or 8 weeks (polyurethane) or for 1 week only (glucose sensors). Tissue biopsies adjacent to the implant were immediately frozen at the time of explant. Cryosections were assayed for glucose concentration profile using the bioluminescence technique. RESULTS: For the polyurethane samples, no significant differences in glucose concentration within 100 MUm of the implant surface were found between bare and ASC-coated implants at 1 or 8 weeks. A glucose concentration gradient was demonstrated around the glucose sensors. For all sensors, the minimum glucose concentration of approximately 4 mM was found at the implant surface and increased with distance from the sensor surface until the glucose concentration peaked at approximately 7 mM at 100 MUm. Then the glucose concentration decreased to 5.5-6.5 mM more than 100 MUmm from the surface. CONCLUSIONS: The ASC attachment to polyurethane and to glucose sensors did not change the glucose profiles in the tissue surrounding the implants. Although most glucose sensors incorporate a diffusion barrier to reduce the gradient of glucose and oxygen in the tissue, it is typically assumed that there is no steep glucose gradient around the sensors. However, a glucose gradient was observed around the sensors. A more complete understanding of glucose transport and concentration gradients around sensors is critical. PMID- 20920426 TI - Analyte flux at a biomaterial-tissue interface over time: implications for sensors for type 1 and 2 diabetes mellitus. AB - OBJECTIVE: The very presence of an implanted sensor (a foreign body) causes changes in the adjacent tissue that may alter the analytes being sensed. The objective of this study was to investigate changes in glucose availability and local tissue metabolism at the sensor-tissue interface in patients with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). METHOD: Microdialysis was used to model implanted sensors. Capillary glucose and subcutaneous (sc) microdialysate analytes were monitored in five T1DM and five T2DM patients. Analytes included glucose, glycolysis metabolites (lactate, pyruvate), a lipolysis metabolite (glycerol), and a protein degradation byproduct (urea). On eight consecutive days, four measurements were taken during a period of steady state blood glucose. RESULTS: Microdialysate glucose and microdialysate to-blood-glucose ratio increased over the first several days in all patients. Although glucose recovery eventually stabilized, the lactate levels continued to rise. These trends were explained by local inflammatory and microvascular changes observed in histological analysis of biopsy samples. Urea concentrations mirrored glucose trends. Urea is neither produced nor consumed in sc tissue, and so the initially increasing urea trend is explained by increased local capillary presence during the inflammatory process. Pyruvate in T2DM microdialysate was significantly higher than in T1DM, an observation that is possibly explained by mitochondrial dysfunction in T2DM. Glycerol in T2DM microdialysate (but not in T1DM) was higher than in healthy volunteers, which is likely explained by sc insulin resistance (insulin is a potent antilipolytic hormone). Urea was also higher in microdialysate of patients with diabetes mellitus compared to healthy volunteers. Urea is a byproduct of protein degradation, which is known to be inhibited by insulin. Therefore, insulin deficiency or resistance may explain the higher urea levels. To our knowledge, this is the first histological evaluation of a human tissue biopsy containing an implanted glucose monitoring device. CONCLUSIONS: Monitoring metabolic changes at a material-tissue interface combined with biopsy histology helped to formulate an understanding of physiological changes adjacent to implanted glucose sensors. Microdialysate glucose trends were similar over 1-week in T1DM and T2DM; however, differences in other analytes indicated wound healing and metabolic activities in the two patient groups differ. We propose explanations for the specific observed differences based on differential insulin insufficiency/resistance and mitochondrial dysfunction in T1DM versus T2DM. PMID- 20920427 TI - Importance of interleukin-1 and interleukin-1 receptor antagonist in short-term glucose sensor function in vivo. AB - BACKGROUND: The importance of the interleukin (IL)-1 cytokine family in inflammation and immunity is well established as a result of extensive in vitro and in vivo studies. In fact, much of our understanding of the in vivo importance of interleukin-1beta (IL-1B) is the result of research utilizing transgenic mice, such as overexpression or deficiencies of the naturally occurring inhibitor of IL 1 known as interleukin-1 receptor antagonist (IL-1RA). For the present studies, we utilized these transgenic mice to determine the role of IL-1B in glucose sensor function in vivo. METHODS: To investigate the role of IL-1B in glucose sensor function in vivo, we compared glucose sensor function in trans-genic mice that (1) overexpressed IL-1RA [B6.Cg-Tg(II1rn)1Dih/J] and (2) are deficient in IL 1RA (B6.129S-Il1rn(tm1Dih)/J), with mice that have normal levels of IL-1RA (C57BL/6). RESULTS: Our studies demonstrated that, during the first 7 days post sensor implantation (PSI), mice deficient in IL-1RA had extensive inflammation and decreased sensor function when compared to normal or IL-1RA-overexpressing mice. CONCLUSION: These data directly support our hypothesis that the IL-1 family of cytokines and antagonists play a critical role in controlling tissue reactions and thereby sensor function in vivo during the first 7 days PSI. PMID- 20920428 TI - Use of subcutaneous interstitial fluid glucose to estimate blood glucose: revisiting delay and sensor offset. AB - BACKGROUND: Estimates for delays in the interstitial fluid (ISF) glucose response to changes in blood glucose (BG) differ substantially among research groups. We review these findings along with arguments that continuous glucose monitoring (CGM) devices used to measure ISF delay contribute to the variability. We consider the impact of the ISF delay and review approaches to correct for it, including strategies pursued by the manufacturers of these devices. The focus on how the manufacturers have approached the problem is motivated by the observation that clinicians and researchers are often unaware of how the existing CGM devices process the ISF glucose signal. METHODS: Numerous models and simulations were used to illustrate problems related to measurement and correction of ISF glucose delay. RESULTS: We find that (1) there is no evidence that the true physiologic ISF glucose delay is longer than 5-10 min and that the values longer than this can be explained by delays in CGM filtering routines; (2) the primary impact of the true ISF delay is on sensor calibration algorithms, making it difficult to estimate calibration factors and offset (OS) currents; (3) inaccurate estimates of the sensor OS current result in overestimation of sensor glucose at low values, making it difficult to detect hypoglycemia; (4) many device companies introduce nonlinear components into their filters, which can be expected to confound attempts by investigators to reconstruct BG using linear deconvolution; and (5) algorithms advocated by academic groups are seldom compared to algorithms pursued by industry, making it difficult to ascertain their value. CONCLUSIONS: The absence of any direct comparisons between existing and new algorithms for correcting ISF delay and sensor OS current is, in part, due to the difficulty in extracting relevant details from industry patents and/or extracting unfiltered sensor signals from industry products. The model simulation environment, where all aspects of the signal can be derived, may be more appropriate for developing new filtering and calibration strategies. Nevertheless, clinicians, academic researchers, and the industry would benefit from collaborating when evaluating those strategies. PMID- 20920429 TI - Hyperspectral imaging in diabetic foot wound care. AB - Diabetic foot ulceration is a major complication of diabetes and afflicts as many as 15 to 25% of type 1 and 2 diabetes patients during their lifetime. If untreated, diabetic foot ulcers may become infected and require total or partial amputation of the affected limb. Early identification of tissue at risk of ulcerating could enable proper preventive care, thereby reducing the incidence of foot ulceration. Furthermore, noninvasive assessment of tissue viability around already formed ulcers could inform the diabetes caregiver about the severity of the wound and help assess the need for amputation. This article reviews how hyperspectral imaging between 450 and 700 nm can be used to assess the risk of diabetic foot ulcer development and to predict the likelihood of healing noninvasively. Two methods are described to analyze the in vivo hyperspectral measurements. The first method is based on the modified Beer-Lambert law and produces a map of oxyhemoglobin and deoxyhemoglobin concentrations in the dermis of the foot. The second is based on a two-layer optical model of skin and can retrieve not only oxyhemoglobin and deoxyhemoglobin concentrations but also epidermal thickness and melanin concentration along with skin scattering properties. It can detect changes in the diabetic foot and help predict and understand ulceration mechanisms. PMID- 20920430 TI - Utilization of advanced modalities in the management of diabetic Charcot neuroarthropathy. AB - Technological advances have allowed reconstructive foot and ankle surgeons greater opportunity to provide significant limb salvage options to those patients who present with significant lower extremity deformity due to diabetic Charcot neuroarthropathy. Paradigms that promote the utilization of these advanced modalities have demonstrated significant improved limb salvage outcomes in this challenging patient population and have consequently improved the quality of life for patients. The purpose of this review is to discuss current concepts in Charcot reconstruction. PMID- 20920431 TI - Novel use of platelet-rich plasma to augment curative diabetic foot surgery. AB - Autologous platelet-rich plasma (PRP) may enhance wound healing through the formation of a platelet plug that provides both hemostasis and the secretion of biologically active proteins, including growth factors such as platelet-derived growth factor, transforming growth factor (TGF)-beta, TGF-beta2, and epidermal growth factor. The release of these growth factors into the wound may create an environment more conducive to tissue repair and could accelerate postoperative wound healing. To our knowledge, there are no reports of combining the use of PRP with curative diabetic foot surgery. This article provides a summary of the literature regarding PRP and wound healing and presents a case of a 49-year-old man with diabetes and a three-month history of a deep, nonhealing plantar hallux wound in which PRP was combined with a first metatarsophalangeal joint arthroplasty. Through the use of the PRP and bioengineered tissue to supplement curative diabetic foot surgery, the patient healed uneventfully at seven weeks. PMID- 20920432 TI - A new classification of diabetic gait pattern based on cluster analysis of biomechanical data. AB - BACKGROUND: The diabetic foot, one of the most serious complications of diabetes mellitus and a major risk factor for plantar ulceration, is determined mainly by peripheral neuropathy. Neuropathic patients exhibit decreased stability while standing as well as during dynamic conditions. A new methodology for diabetic gait pattern classification based on cluster analysis has been proposed that aims to identify groups of subjects with similar patterns of gait and verify if three dimensional gait data are able to distinguish diabetic gait patterns from one of the control subjects. METHOD: The gait of 20 nondiabetic individuals and 46 diabetes patients with and without peripheral neuropathy was analyzed [mean age 59.0 (2.9) and 61.1(4.4) years, mean body mass index (BMI) 24.0 (2.8), and 26.3 (2.0)]. K-means cluster analysis was applied to classify the subjects' gait patterns through the analysis of their ground reaction forces, joints and segments (trunk, hip, knee, ankle) angles, and moments. RESULTS: Cluster analysis classification led to definition of four well-separated clusters: one aggregating just neuropathic subjects, one aggregating both neuropathics and non neuropathics, one including only diabetes patients, and one including either controls or diabetic and neuropathic subjects. CONCLUSIONS: Cluster analysis was useful in grouping subjects with similar gait patterns and provided evidence that there were subgroups that might otherwise not be observed if a group ensemble was presented for any specific variable. In particular, we observed the presence of neuropathic subjects with a gait similar to the controls and diabetes patients with a long disease duration with a gait as altered as the neuropathic one. PMID- 20920433 TI - Use of sugar on the healing of diabetic ulcers: a review. AB - With the advent of several innovative wound care management tools, the choice of products and treatment modalities available to clinicians continues to expand. High costs associated with wound care, especially diabetic foot wounds, make it important for clinician scientists to research alternative therapies and optimally incorporate them into wound care protocols appropriately. This article reviews using sugar as a treatment option in diabetic foot care and provides a guide to its appropriate use in healing foot ulcers. In addition to a clinical case study, the physiological significance and advantages of sugar are discussed. PMID- 20920434 TI - Hypoglycemia prevention via pump attenuation and red-yellow-green "traffic" lights using continuous glucose monitoring and insulin pump data. AB - BACKGROUND: Hypoglycemia has been identified as a primary barrier to optimal management of diabetes. This observation, in conjunction with the introduction of continuous glucose monitoring (CGM) devices, has set the stage for achieving tight glycemic control with systems that adjust the insulin pump settings based on measured glucose concentrations. Because system safety and system reliability are key considerations, there is a need for algorithms that reduce the risk of hypoglycemia in closed-loop, open-loop, and advisory-mode systems. More specifically, the algorithm presented here is formulated as a component of the independent safety system module proposed in the modular control-to-range architecture. METHODS: We developed two algorithms for attenuating insulin pump injections, which we refer to as Brakes and Power Brakes: Brakes is a pump attenuation function computed using CGM information only, while Power Brakes is an attenuation function in which a metabolic state observer with insulin input is used in addition to CGM information to inform the level of pump attenuation. These algorithms modulate the insulin pump delivery so that the insulin injection rate is dramatically reduced when the risk of hypoglycemia is high. Additionally, we combined these algorithms with an alert system that indicates a level of hypoglycemic risk to the user. RESULTS: We demonstrated the effectiveness of Brakes and Power Brakes in reducing the incidence of hypoglycemia in two simulated scenarios: an elevated basal rate scenario and a scenario in which a bolus is delivered for a meal that is skipped. For these scenarios, the incidence of hypoglycemia using Power Brakes was reduced by 88 and 94%, respectively, where we defined hypoglycemia based on the American Diabetes Association guidelines for defining and reporting as 70 mg/dl. In the elevated basal rate scenario, no rebounds above 180 mg/dl (the desired upper limit of the control-to-range protocol) following hypoglycemia were shown to occur. We demonstrated the way the hypoglycemia alert system can trigger the intake of carbohydrates to reduce the incidence of hypoglycemia by 98%. CONCLUSIONS: This article offers, for the first time, a method for smoothly reducing insulin delivery rate to prevent hypoglycemia in individuals with type 1 diabetes mellitus based on a mathematically formal assessment of hypoglycemic risk. In silico, we demonstrate the way this method can prevent hypoglycemia while avoiding hyperglycemia rebounds that exceed 180 mg/dl. In conjunction with the pump attenuation algorithms, this article also proposes a system for alerting an individual of their hypoglycemic risk that contains three "levels" of alerts in the form of a traffic light. This alert system can be used in an advisory mode setting to alert the user to take action when hypoglycemia is imminent ("red" light) or in a closed-loop setting where initiation of rescue action begins when the red light alert is triggered. PMID- 20920435 TI - Diabetes in the desert: what do patients know about the heat? AB - BACKGROUND: This study aims to identify self-management strategies used by patients with diabetes in hot weather, examine knowledge of safe temperatures and exposure times, and evaluate comprehension of weather data. METHODS: Patients attending an endocrinology clinic in southwestern United States were surveyed. RESULTS: One hundred fifty-two surveys completed from November 30 to December 31, 2009 were analyzed. Mean patient age was 64 years; diabetes duration e analyzed 15 years; 51% were women 83% had type 2 diabetes, 58% were non Hispanic white, and 77% were on insulin injections. Mean hemoglobin A1c was 7.9%; 38% had hemoglobin A1c values of 8.0% or higher. Patients used an array of personal protective measures during hot weather, and 71% limited heat exposure to less than one hour. Respondents typically took steps to protect their diabetes medication and supplies, but 37% chose to leave medications and supplies at home. Although 73% of respondents had received information regarding the effect of heat on insulin, only 39% had received information about the effect of heat on oral medications, 41% on glucose meters, and 38% on glucose test strips. The temperature at which patients took protective measures varied. Only 55% knew the definition of the heat index. CONCLUSION: Most survey participants took measures to protect themselves from the heat, although gaps in knowledge were evident. Many patients had suboptimal glycemic control, placing them potentially at risk for dehydration during the hottest months. Increased public awareness of this topic is needed, and diabetes education programs should include information about the heat where appropriate. PMID- 20920436 TI - Pharmacokinetic characterization of the novel pulmonary delivery excipient fumaryl diketopiperazine. AB - BACKGROUND: Technosphere(r) [Bis-3,6(4-fumarylaminobutyl)-2,5-diketopiperazine (FDKP)] microparticles, the integral component of the Technosphere inhalation system, deliver drugs to the deep lung and have been used to administer insulin and glucagon-like peptide-1 via inhalation in clinical studies. Three studies were conducted to characterize FDKP pharmacokinetics, including assessments in subjects with diabetic nephropathy (DNP), in subjects with chronic liver disease (CLD), and in healthy subjects. METHODS: An open-label, nonrandomized, two period, fixed-sequence crossover absorption, distribution, metabolism, and excretion (ADME) study was conducted in six healthy nonsmoking men who received single intravenous and oral doses of [(14)C]FDKP solution, with serial sampling of blood, urine, feces, and expired air. Additionally, two single-dose, open label, parallel-design studies with 20 mg of inhaled FDKP were conducted in (1) 12 diabetic subjects with normal renal function and 24 DNP subjects and (2) 12 healthy subjects and 21 CLD subjects. RESULTS: In the ADME study, >95% of the intravenous dose and <3% of the oral dose were recovered in urine, with no evidence of metabolism. No significant pharmacokinetic differences were observed between healthy subjects and CLD subjects [geometric mean (% coefficient of variation) area under the curve from time 0 to 480 minutes (AUC(0-480)): 26,710 (34.8) and 31,477 (28.8) ng/ml.min, respectively]. Maximum observed drug concentration (C(max)) and AUC(0-480) were higher in DNP subjects than in subjects with normal renal function [C(max): 159.9 (59.4) ng/ml versus 147.0 (44.3) ng/ml; AUC(0-480): 36,869 (47.2) ng/ml.min versus 30,474 (31.8) ng/ml.min]. None of the differences observed were considered clinically significant. CONCLUSIONS: Fumaryl diketopiperazine is predominantly cleared unchanged by the kidney with essentially no oral bioavailability. Technosphere is a safe delivery vehicle for medications administered via inhalation. PMID- 20920437 TI - Guidelines for insulin dosing in continuous subcutaneous insulin infusion using new formulas from a retrospective study of individuals with optimal glucose levels. AB - BACKGROUND: Successful insulin pump therapy depends on correct insulin doses based on an optimal total daily dose (TDD) and optimal pump settings for basal infusion, carbohydrate factor (CarbF), and glucose correction factor (CorrF) based on the TDD. There are limited data in the literature to guide providers and patients regarding methods to optimize these critical parameters for glucose control. METHODS: Anonymous data downloads from 1020 insulin pumps used throughout the United States and overseen by a variety of clinicians were analyzed retrospectively to find insulin doses that provided the best glucose control. A subset of 396 pumps was chosen for glucose data reliability, with over 85% of their glucose data directly entered from a meter. This subset was divided into tertiles based on glucose levels, and the low glucose tertile was analyzed to derive formulas for optimal insulin pump settings. RESULTS: An inconsistent clustering of pump settings was found for the CarbF and the CorrF. This was less pronounced when CarbFs and CorrFs were determined from the actual bolus doses delivered once adjustments were made to the initial dose calculations by users and, to a larger extent, internally by the bolus calculator itself. Common beliefs that hyperglycemia is related to less carb counting, fewer carb boluses, or delivery of less insulin per day were not substantiated in this data. New or verified insulin dosing formulas presented include basal U/day = TDD * 0.48; CarbF = [2.6 * Wt(lb)]/TDD; and CorrF = 1960/TDD. CONCLUSIONS: Insulin pump users cannot reap full benefit from their pump bolus calculator if the settings on which bolus doses are based are less than optimal. Our data show that CarbFs and CorrFs tend to be unevenly distributed, suggesting that these factors are not selected in a systematic manner through use of formulas. Poor glucose outcomes among insulin pump users appear to be related to pump setting errors and being relatively underinsulinized, even though those in poor control use more total insulin per day. We have developed a model with the hypothesis that improved glucose outcomes will result from the use of formulas to derive appropriate pump settings. Prospective validation of these concepts is needed. PMID- 20920438 TI - Evaluating the clinical accuracy of GlucoMen(r)Day: a novel microdialysis-based continuous glucose monitor. AB - BACKGROUND: The objective of this work was to determine the clinical accuracy of GlucoMen(r)Day, a new microdialysis-based continuous glucose monitoring system (CGMS) from A. Menarini Diagnostics (Florence, Italy). Accuracy evaluation was performed using continuous glucose-error grid analysis (CG-EGA), as recommended by the Performance Metrics for Continuous Interstitial Glucose Monitoring; Approved Guideline (POCT05-A). METHODS: Two independent clinical trials were carried out on patients with types 1 and 2 diabetes mellitus, the glycemic levels of whom were monitored in an in-home setting for 100-hour periods. A new multiparametric algorithm was developed and used to compensate in real-time the GlucoMen(r)Day signal. The time lag between continuous glucose monitoring (CGM) and reference data was first estimated using the Poincare plot method. The entire set of CGM/reference data pairs was then evaluated following the CG-EGA criteria, which allowed an estimation of the combined point and rate accuracy stratified by glycemic ranges. RESULTS: With an estimated time lag of 11 minutes, the linear regression analysis of the CGM/reference glucose values yielded r = 0.92. The mean absolute error (MAE) was 11.4 mg/dl. The calculated mean absolute rate deviation (MARD) was 0.63 mg/dl/min. The data points falling within the A+B zones of CG-EGA were 100% in hypoglycemia, 95.7% in euglycemia, and 95.2% in hyperglycemia. CONCLUSIONS: The GlucoMen(r)Day system provided reliable, real time measurement of subcutaneous glucose levels in patients with diabetes for up to 100 hours. The device showed the ability to follow rapid glycemic excursions and detect severe hypoglycemic events accurately. Its accuracy parameters fitted the criteria of the state-of-the-art consensus guideline for CGMS, with highly consistent results from two independent studies. PMID- 20920439 TI - Analysis of GlucoMen(r)Day: a novel microdialysis-based continuous glucose monitor. AB - In this issue of Journal of Diabetes Science and Technology, Valgimigli and colleagues present promising data on the clinical accuracy of the new microdialysis-based continuous glucose monitoring device GlucoMen(r)Day. In this analysis, two issues are addressed: first, the established way data analyses may obscure interindividual variability in terms of a glucose monitoring system's accuracy; and second, to fully appreciate the future merits of the new system, data on accuracy, while a clearly necessary prerequisite, are not sufficient and need to be augmented by patient-reported outcome data as highlighted by recent U.S. Food and Drug Administration guidelines. PMID- 20920440 TI - Accuracy and reliability of the Nova StatStrip(r) glucose meter for real-time blood glucose determinations during glucose clamp studies. AB - AIMS/HYPOTHESIS: The Andres clamp technique, which requires accurate and timely determination of glucose, utilizes the Beckman or Yellow Springs Instruments (YSI) glucose analyzers. Both instruments require maintenance, a dedicated operator, preparation of a plasma sample, and a duplicate measurement that takes >=2 minutes. The Nova StatStrip glucose meter was evaluated for accuracy, reliability, and near-real-time availability of glucose. METHODS: Blood samples from 24 patients who underwent 6-hour clamp studies and 12 patients who had a standardized meal tolerance test (SMT) were measured. Specimens were analyzed simultaneously and immediately upon collection by Beckman, YSI, and Nova. RESULTS: Of 1004 data pairs for the Nova device versus Beckman, the Nova data points ranged from 32 to 444, while Beckman ranged from 42 to 412. The coefficient for the slope of Beckman versus Nova was 1.009 (r = 0.978). Using error grid analysis, the number and percentage of values for Nova were 976 (97.2%) in the A zone and 28 (2.8%) in the B zone. Of 399 data pairs for the Nova device versus YSI, the Nova data points ranged from 46 to 255, whereas YSI ranged from 47 to 231. The coefficient for the slope of YSI versus Nova was 1.023 (r = 0.989). All Nova readings fell in the A zone. Time required for final reading, in duplicate, was 15 seconds for Nova and 120-180 seconds for Beckman and YSI. CONCLUSIONS: The simplicity of Nova and its reliability, accuracy, and speed make it an acceptable replacement device for Beckman and YSI in the conduct of clamps, especially when perturbations require rapid glucose determination. PMID- 20920441 TI - Analysis of the Nova Stat Strip(r) glucose meter for real-time blood glucose determinations during glucose clamp studies: "don't swap horses in midstream". AB - Proper performance of glucose clamps is critically dependent on reliable blood glucose (BG) measurements. A number of requirements have to be fulfilled by a system that aims to replace the laboratory devices that are currently in use. Many more aspects need to be taken into account besides the accuracy of BG measurement. It might very well be that the BG meter studied by Rabiee and colleagues in this issue of Journal of Diabetes Science and Technology fulfills most or all of such requirements; however, these aspects have to be tested more thoroughly before one switches from an established measurement method to the Nova Stat Strip(r) glucometer. PMID- 20920442 TI - Validation of a deconvolution procedure (AutoDecon) for identification and characterization of fasting insulin secretory bursts. AB - BACKGROUND: Insulin secretion is pulsatile, and has been shown to be altered in both physiologic and pathophysiologic conditions. The identification and characterization of such pulses have been challenging, partially because of the low concentrations of insulin during fasting and its short half-life. Existing pulse detection algorithms used to identify insulin pulses either cannot separate hormone pulses into their secretory burst and clearance components, or have been limited by both the subjective nature of initial peak selection and a lack of statistical verification of bursts. METHODS: To address these concerns, we have developed AutoDecon, a novel deconvolution computer program. RESULTS: AutoDecon was applied to synthetic insulin concentration-time series modeled on data derived from normal fasting subjects and simulated to reflect several sampling frequencies, sampling durations, and assay replicates. The operating characteristics of AutoDecon were compared to those obtained with Cluster, a standard pulse detection algorithm. AutoDecon performed considerably better than Cluster with regard to sensitivity and secretory burst detection rates for true positives, false positives, and false negatives. As expected, given the short half-life of insulin, sampling at 30-second intervals is required for optimal analytical results. The choice of sampling duration is more flexible and relates to the number of replicates assayed. CONCLUSION: AutoDecon represents a viable alternative to standard pulse detection algorithms for the appraisal of fasting insulin pulsatility. PMID- 20920443 TI - Modeling the effects of subcutaneous insulin administration and carbohydrate consumption on blood glucose. AB - BACKGROUND: Estimation of the magnitude and duration of effects of carbohydrate (CHO) and subcutaneously administered insulin on blood glucose (BG) is required for improved BG regulation in people with type 1 diabetes mellitus (T1DM). The goal of this study was to quantify these effects in people with T1DM using a novel protocol. METHODS: The protocol duration was 8 hours: a 1-3 U subcutaneous (SC) insulin bolus was administered and a 25-g CHO meal was consumed, with these inputs separated by 3-5 hours. The DexCom SEVEN(r) PLUS continuous glucose monitor was used to obtain SC glucose measurements every 5 minutes and YSI 2300 Stat Plus was used to obtain intravenous glucose measurements every 15 minutes. RESULTS: The protocol was tested on 11 subjects at Sansum Diabetes Research Institute. The intersubject parameter coefficient of variation for the best identification method was 170%. The mean percentages of output variation explained by the bolus insulin and meal models were 68 and 69%, respectively, with root mean square error of 14 and 10 mg/dl, respectively. Relationships between the model parameters and clinical parameters were observed. CONCLUSION: Separation of insulin boluses and meals in time allowed unique identification of model parameters. The wide intersubject variation in parameters supports the notion that glucose-insulin models and thus insulin delivery algorithms for people with T1DM should be personalized. This experimental protocol could be used to refine estimates of the correction factor and the insulin-to-carbohydrate ratio used by people with T1DM. PMID- 20920444 TI - Correct use of a new reusable insulin injection pen by patients with diabetes: a design validation study. AB - BACKGROUND: Insulin pen devices are currently being used by approximately half of insulin users worldwide. ClikSTAR(r) (sanofi-aventis) is a novel reusable insulin pen for injecting either long-acting insulin glargine or short-acting insulin glulisine. The objective of this study was to demonstrate that individuals with diabetes could use the ClikSTAR pen correctly. METHODS: In this open-label, single-center study, people with diabetes delivered three 40 U insulin doses after receiving training from a diabetes specialist (group A, n = 256) or after self-training (group B, n = 47). Administration of a dose of 75-115% of the intended dose was considered successful. Adverse events (AEs) and product technical complaints (PTCs) were recorded. RESULTS: In group A (68% females, 93% Hispanic ethnicity, 97% type 2 diabetes mellitus, mean +/- standard deviation age 52 +/- 11 years, diabetes duration 11 +/- 7 years), half of the participants had prior experience in using insulin pen devices. All except one participant (99.6%) in group A successfully delivered three insulin doses. The lower one-tailed 95% confidence limit for the success rate (98.2%) was higher than the predefined target of 90%. Demographic/baseline characteristics were similar in group B, but 70% had not previously used an injection pen. Group B also showed success; 93.6% of participants successfully completed three dose deliveries. No AEs were reported, although one participant (0.4%) in group A reported one PTC during the training period that was due to a blocked needle. CONCLUSIONS: This study successfully validated the ClikSTAR pen for use by individuals with diabetes. PMID- 20920445 TI - Analysis: including visually impaired participants in validation design studies of diabetes technology. AB - In an article in this issue of Journal of Diabetes Science and Technology, Sherwyn Schwartz, M.D., presents a study to validate the design of the ClikSTAR(r) insulin pen from sanofi-aventis and demonstrates that the device can be used correctly by participants with diabetes. Concern with this article lies with the selection of participants, which was meant to reflect the intended audience for the insulin pen device but does not address the inclusion of visually impaired individuals, who comprise over 20% of the adult diabetes population. Visually impaired individuals need to be included as part of the intended audience for insulin administration technology, and manufacturers of these devices need to design their products for safe use by all people, including those who are visually impaired. The study demonstrated successful use of the ClikSTAR insulin pen in a population that did not include subjects with severe visual impairment. We believe that future validation studies for insulin administration technology should also include samples of visually impaired users and that visually impaired patients will embrace the use of insulin pens designed with their needs in mind. PMID- 20920447 TI - The Sardinian way to type 1 diabetes. AB - Sardinia and Finland are the "hottest" areas for type 1 diabetes mellitus (T1DM) worldwide. Its genetic and epidemiological background make Sardinia an ideal region for investigating environmental, immunological, and genetic factors related to the etiopathogenesis of T1DM. Consequently, in 1990, the Insulin Dependent Diabetes Mellitus Sardinia Project was launched in order to map the geographical distribution of T1DM in the island and to investigate preclinical phases of T1DM in a large cohort of people genetically at risk. The final goal would be to design models of prediction and to formulate safe preventive measures, especially addressed to the general population living in areas at high risk. PMID- 20920446 TI - Enhancing clinical islet transplantation through tissue engineering strategies. AB - Clinical islet transplantation (CIT), the infusion of allogeneic islets within the liver, has the potential to provide precise and sustainable control of blood glucose levels for the treatment of type 1 diabetes. The success and long-term outcomes of CIT, however, are limited by obstacles such as a nonoptimal transplantation site and severe inflammatory and immunological responses to the transplant. Tissue engineering strategies are poised to combat these challenges. In this review, emerging methods for engineering an optimal islet transplantation site, as well as novel approaches for improving islet cell encapsulation, are discussed. PMID- 20920448 TI - Obesity Reduction and Awareness and Screening of Noncommunicable Diseases through Group Education in children and adolescents (ORANGE): methodology paper (ORANGE 1). AB - AIM: Our goal is to estimate the prevalence of obesity, glucose intolerance, hypertension, dyslipidemia, and metabolic syndrome among urban children and adolescents aged 6-19 years and to raise awareness about noncommunicable diseases (NCDs) among school children in Chennai, South India. METHODS: The Obesity Reduction and Awareness and Screening of Noncommunicable Diseases through Group Education project plans to reach out to children and adolescents using two approaches: the school and the community approach. The school approach aims to reach out to a representative sample of approximately 20,000 urban school children and adolescents, aged 6-19 years, covering 50 schools from all parts of Chennai. Anthropometric measures will include height, weight, waist, body fat, and blood pressure. Data on demographics, family profile, behavioral aspects, physical activity, and food pattern will be obtained by using a validated questionnaire. Awareness about metabolic NCDs like obesity and diabetes will be increased by educating the children and adolescents about healthy lifestyles. Through the community approach, 2000 children and adolescents from randomly selected residential colonies in Chennai will be screened for obesity, glucose intolerance, hypertension, dyslipidemia, and metabolic syndrome. EXPECTED OUTCOMES: Awareness about NCDs will be increased among children and their parents in Chennai. This study will also provide valuable epidemiological data on obesity, glucose intolerance, dyslipidemia, hypertension and metabolic syndrome in children and adolescents in urban India. PMID- 20920449 TI - We need tighter regulatory standards for blood glucose monitoring, but they should be for accuracy disclosure. AB - Regulatory interest has focused on the accuracy of blood glucose monitoring systems. Currently, almost all systems meet the International Organization for Standardization (ISO) 15197 clinical standard (>=95% of the values within 20% of the reference for values above 75 mg/dl and within 15 mg/dl below that level). Should the systems have to meet one of the extended ISO standards of 15%, 10%, or even 5%? There is a wide variety of people with diabetes doing glucose monitoring, and the majority do not need better accuracy. Indeed, when selecting an insulin dose, the inaccuracy of the glucose reading has little effect compared with the inaccuracy in counting carbohydrates and the variability in insulin absorption. It might be far better to evaluate the accuracy in a standard method and provide the accuracy values on a standard label. Patients and health care providers could then select the monitoring system that best meets their needs. PMID- 20920450 TI - Glucose information for tight glycemic control: different methods with different challenges. AB - Rigorous glucose control is essential for prevention of diabetes-related complications in diabetes patients. Even without diabetes, tight glucose control is beneficial in hospitalized, critically ill patients. Actually, three different glucose measurement methods are used: (1) hand held devices, (2) blood-gas analyzers, and (3) laboratory analyzers in core laboratories. Each method is subject to specific challenges and limitations that can affect the overall system performance. In this article, we aim to demonstrate that even glucose measurement results from core laboratories (professional laboratory systems) do not necessarily reflect the absolute "true" glucose level of a patient. PMID- 20920451 TI - Missing elements revisited: information engineering for managing quality of care for patients with diabetes. AB - INTRODUCTION: Advances in information technology offer new avenues for assembling data about diet and care regimens of diabetes patients "in the field." This creates a challenge for their doctors and the diabetes care community--how to organize and use new data to produce better long-term outcomes for diabetes patients. METHODS: iAbetics approaches the challenge as a quality management problem, drawing on total quality concepts, which in turn are grounded in application of the scientific method. We frame the diabetes patient's quality-of care problem as an ongoing scientific investigation aimed at quantifying and predicting relationships between specific care-management actions and their outcomes for individual patients in their ordinary course of life. RESULTS: Framing diabetes quality-of-care management as a scientific investigation leads to a seven-step model termed "adaptive empirical iteration." Adaptive empirical iteration is a deliberate process to perfect the patient's choices, decisions, and actions in routine situations that make up most day-to-day life and to systematically adapt across differences in individual patients and/or changes in their physiology, diet, or environment. The architecture incorporates care protocol management and version control, structured formats for data collection using mobile smart phones, statistical analysis on secure Web sites, tools for comparing alternative protocols, choice architecture technology to improve patient decisions, and information sharing for doctor review. CONCLUSIONS: Adaptive empirical iteration is a foundation for information architecture designed to systematically improve quality-of-care provided to diabetes patients who act as their own day-to-day care provider under supervision and with support from their doctor. The approach defines "must-have" capabilities for systems using new information technology to improve long-term outcomes for diabetes patients. PMID- 20920452 TI - Bovine fasciolosis in the human fasciolosis hyperendemic Binh Dinh province in Central Vietnam. AB - A cross-sectional survey on bovine fasciolosis was conducted in the Binh Dinh province of Central Vietnam that was previously identified as hyperendemic for human fasciolosis. In Vietnam, both pure Fasciola gigantica and hybrid and/or introgressed populations of liverflukes bearing genetic material from both Fasciola hepatica and F. gigantica infect humans and animals. In this study, 825 cattle were randomly selected from 8 of the 11 provincial districts for faecal collection; blood samples were taken from 400 of these animals. Fasciola eggs and antibodies against Fasciola were detected by a quantitative sedimentation method and an Enzyme Linked Immunosorbent Assay, respectively. Overall, 54.9% of the animals were shedding Fasciola eggs while 72.2% were Fasciola seropositive. Animals under two years showed lower Fasciola infection rates than older animals. There were no differences in infection rates between districts. These results indicate a very high prevalence of Fasciola infections in cattle in Binh Dinh province. It is concluded that a fasciolosis control programme should be designed in this region aiming at reducing infection in both cattle and humans. PMID- 20920453 TI - Capacity building for the modified filarial hydrocelectomy technique in West Africa. AB - To harmonise the technique of filarial hydrocelectomy throughout the West African subregion, training workshops were organized in 10 endemic West African countries involving surgeries on Filarial hydrocele patients (Filariceles). Countries included Ghana, Nigeria, Niger, Burkina Faso, Senegal, Mali, Liberia, Gambia, Sierra Leone and Togo. Patients were recruited by the Filariasis programme managers in all these countries and workshops were done to train surgeons from teaching, government and district hospitals with funding mainly from the West African Filariasis Project. A total of 16 workshops were held in 10 West African Countries, and a total of 500 filarial hydrocele/chylocele cases were operated using the technique of total tunical resection without drainage with excellent postoperative results. The average operating time for a unilateral hydrocele was 45 min to 1h and for bilateral hydrocele was 11/2 h to 2h depending on the size of the hydrocele .All patients were admitted for a minimum of 5 days postoperative. Training workshops were successfully organized in 10 out of the envisaged 12 west African Countries with 214 surgeons trained. Since 2004 till date the trained surgeons have also operated 2500 filaricele cases bringing it to a total of 3000 cases operated so far. Evaluation studies revealed that the infection rates in one country was initially 60% and then it later dropped to 20% and this was actually attributed to poor follow up by the selected National Coordinator. However complication rates in all the Countries where workshops were done ranged between 5% and 7% made up of infection, haematoma and or delayed wound healing. Recurrence rates have been very low about 3-5% per Country. PMID- 20920454 TI - Sequence-specific detection using a universal probe system based on the formation of a four-way junction structure. AB - We have developed a novel hybridization detection system using a universal probe based on the formation of a four-way junction (4WJ) structure. This methodology employs a combination of two sequence-specific probes and a universal quenching probe, and the same universal probe can be used for any target gene, allowing cost-effective assays. This 4WJ detection is ideal for extensive parallel identification of nucleic acids such as in multiplex polymerase chain reaction (PCR) systems. Compared with gel electrophoresis, this detection procedure is not only sensitive and rapid but also free of hazardous chemicals such as ethidium bromide. In addition, the 4WJ hybridization technology is more specific as an identifier than the size of a band on an agarose gel. We used a model multiplex PCR method that detected eight different virulence genes in Escherichia coli isolates, demonstrating that our 4WJ detection system is rapid, sensitive, and specific. PMID- 20920455 TI - Sodium dodecyl sulfate-agarose gel electrophoresis for the detection and isolation of amyloid curli fibers. AB - Curli are amyloid-like fibers on the surface of some strains of Escherichia coli and Salmonella enteritidis. We tested the use of horizontal sodium dodecyl sulfate (SDS)-agarose gel electrophoresis to detect, isolate, and quantitate curli. Cell extracts fractionated in SDS-agarose gels and stained with Coomassie blue exhibited a soluble fraction that entered the gel and an insoluble fraction that remained in the well. Much more insoluble material was observed with curli proficient strains than with strains that do not make curli. Both highly purified curli and the insoluble material isolated from an SDS-agarose gel could be dissociated into monomers when treated with formic acid. For quantitation, we immobilized samples in SDS-agarose prior to electrophoresis. This avoids losses during the staining of the gel. Our methods provide a rapid and simple fractionation of curli using equipment that is readily available. PMID- 20920456 TI - A high-affinity recombinant antibody permits rapid and sensitive direct detection of myeloperoxidase. AB - Over the past 10 years, a growing field of research supporting the value of myeloperoxidase (MPO) as a prognostic indicator in acute cardiac pathophysiologies has emerged. The availability of a rapid and disposable MPO detection platform would enable research clinicians to more readily assess MPO indications for guiding therapy and also facilitate clinicians at the patient interface to readily adopt MPO testing and potentially drive more informed prognoses. Here we describe the isolation of a high-affinity avian MPO-specific recombinant antibody panel using phage display. Rapid isolation of a suitable single-chain variable fragment (scFv) antibody was facilitated using a surface plasmon resonance (SPR)-based "off-rate ranking" screening process. The selected scFv was then successfully incorporated into a rapid, simple, and sensitive one step lateral flow immunoassay (LFIA) for the detection of MPO. This "one-step" feature of the developed assay was made possible by the scFv's strong affinity for MPO, obviating the need for sandwich signal enhancement steps. The assay's rapid performance was also further enhanced by exploiting the intrinsic enzymatic properties of MPO in its final detection. Use of the optimized LFIA facilitated the sensitive detection of MPO in MPO-depleted serum within clinically relevant reference ranges. PMID- 20920457 TI - Engineering of a broad-specificity antibody: detection of eight fluoroquinolone antibiotics simultaneously. AB - Recombinant sarafloxacin-recognizing antibody was engineered with the use of novel fluoroquinolone (FQ) derivatives. A monoclonal FQ antibody, 6H7, was targeted to random mutagenesis to broaden the specificity of the antibody in development of a generic assay for FQ antibiotics. Engineering involved the synthesis of different small-sized FQ molecules to immobilize and detect the mutant antibodies. Selections with labeled FQs resulted in several mutant antibodies with increased affinity or wider specificity toward different FQs. The best characterized mutant antibody was capable of recognizing seven of eight targeted FQs below maximum residue limits set by the European Union. The results are promising in regard to the development of a multiresidue immunoassay for FQs based on a single antibody. PMID- 20920459 TI - Vitamin B(12) incorporated with multiwalled carbon nanotube composite film for the determination of hydrazine. AB - Electrochemically active composite film containing multiwalled carbon nanotubes (MWCNTs) and vitamin B(12) was synthesized on glassy carbon, gold, and indium tin oxide electrodes by the potentiodynamic method. The presence of MWCNTs in the composite film (MWCNT-B(12)) modified electrode mediates vitamin B(12)'s redox reaction, whereas vitamin B(12)'s redox reaction does not occur at bare electrode. The electrochemical impedance spectroscopy studies reveal that MWCNTs present in MWCNT-B(12) film enhance electron shuttling between the reactant and electrode surface. The surface morphology of bare electrode, MWCNT film. and MWCNT-B(12) composite film was studied using atomic force microscopy, which reveals vitamin B(12) incorporated with MWCNTs. The MWCNT-B(12) composite film exhibits promising enhanced electrocatalysis toward hydrazine. The electrocatalysis response of hydrazine at MWCNT film and MWCNT-B(12) composite film was measured using cyclic voltammetry and amperometric current-time (i-t) curve techniques. The linear concentration range of hydrazine obtained at MWCNT B(12) composite film using the i-t curve technique is 2.0 MUM-1.95 mM. Similarly, the sensitivity of MWCNT-B(12) composite film for hydrazine determination using the i-t curve technique is 1.32 mA mM(-1)cm(-2), and the hydrazine's limit of detection at MWCNT-B(12) composite film is 0.7 MUM. PMID- 20920458 TI - Comparison of metalloproteinase protein and activity profiling. AB - Proteolytic enzymes play fundamental roles in many biological processes. Members of the matrix metalloproteinase (MMP) family have been shown to take part in processes crucial in disease progression. The current study used the ExcelArray Human MMP/TIMP Array to quantify MMP and tissue inhibitor of metalloproteinase (TIMP) production in the lysates and media of 14 cancer cell lines and 1 normal cell line. The overall patterns were very similar in terms of which MMPs and TIMPs were secreted in the media versus associated with the cells in the individual samples. However, more MMP was found in the media (in both amount and variety). TIMP-1 was produced in all cell lines. MMP activity assays with three different fluorescence resonance energy transfer (FRET) substrates were then used to determine whether protein production correlated with function for the WM-266-4 and BJ cell lines. Metalloproteinase activity was observed for both cell lines with a general MMP substrate (Knight SSP), consistent with protein production data. However, although both cell lines promoted the hydrolysis of a more selective MMP substrate (NFF-3), metalloproteinase activity was confirmed only in the BJ cell line. The use of inhibitors to confirm metalloproteinase activities pointed to the strengths and weaknesses of in situ FRET substrate assays. PMID- 20920460 TI - PHK from phenol hydroxylase of Pseudomonas sp. OX1. Insight into the role of an accessory protein in bacterial multicomponent monooxygenases. AB - Bacterial multicomponent monooxygenases (BMMs) are members of a wide family of diiron enzymes that use molecular oxygen to hydroxylate a variety of aromatic compounds. The presence of genes encoding for accessory proteins not involved in catalysis and whose role is still elusive, is a common feature of the gene clusters of several BMMs, including phenol hydroxylases and several soluble methane monooxygenases. In this study we have expressed, purified, and partially characterized the accessory component PHK of the phenol hydroxylase from Pseudomonas sp. OX1, a bacterium able to degrade several aromatic compounds. The phenol hydroxylase (ph) gene cluster was expressed in Escherichia coli/JM109 cells in the absence and in the presence of the phk gene. The presence of the phk gene lead to an increase in the hydroxylase activity of whole recombinant cells with phenol. PHK was assessed for its ability to interact with the active hydroxylase complex. Our results show that PHK is neither involved in the catalytic activity of the phenol hydroxylase complex nor required for the assembly of apo-hydroxylase. Our results suggest instead that this component may be responsible for enhancing iron incorporation into the active site of the apo hydroxylase. PMID- 20920461 TI - Modulation of expression and polymerization of hemoglobin Polytaur, a potential blood substitute. AB - Chemically or genetically modified hemoglobins are a therapeutic class indicated for the treatment of a variety of hypo-oxygenation pathologies, severe trauma related hemorrhages or elective surgery when blood transfusions are refused or not available. Recombinant heterologous hemoglobins offer the possibility of a potentially unlimited production and genetically optimized properties in terms of oxygen affinity, NO reactivity and resistance to autoxidation. Hemoglobin Polytaur is an autopolymerizing human-bovine hybrid mutant, previously obtained as a 500kDa polymer, shown to reduce the infarct volume from focal cerebral ischemia in in vivo animal models. In this work, hemoglobin Polytaur polymerization, carried out under conditions to minimize heme oxidation and modification, resulted in a 180kDa cyclic homogeneous trimer of hemoglobin tetramers. This novel oligomer was characterized by electrophoresis, MALDI-TOF mass spectrometry and gel filtration. The size and the oxygen binding properties were shown to be ideally suited for its use as a blood substitute. Co-expression with the human alpha hemoglobin-stabilizing protein (AHSP), a chaperone that assists hemoglobin folding in vivo, resulted in an unexpected decrease in yield and in unusual spectroscopic and functional properties, suggesting the formation of strong protein-protein interactions that reduce the expression, hinder the tetramer assembly and prevent purification. PMID- 20920462 TI - Unusual P450 reactions in plant secondary metabolism. AB - Plant cytochromes P450 (P450s) participate in a variety of biochemical pathways to produce a vast diversity of plant natural products. The number of P450 genes in plant genomes is estimated to be up to 1% of the total gene annotations of each plant species, implying that plants are huge sources for various P450 dependent reactions. Plant P450s catalyze a wide variety of monooxygenation/hydroxylation reactions in secondary metabolism, and some of them are involved in unusual reactions such as methylenedioxy-bridge formation, phenol coupling reactions, oxidative rearrangement of carbon skeletons, and oxidative C C bond cleavage. Here, we summarize unusual P450 reactions in various plant secondary metabolisms, and describe their proposed reaction mechanisms. PMID- 20920463 TI - The structure and function of eukaryotic photosystem I. AB - Eukaryotic photosystem I consists of two functional moieties: the photosystem I core, harboring the components for the light-driven charge separation and the subsequent electron transfer, and the peripheral light-harvesting complex (LHCI). While the photosystem I-core remained highly conserved throughout the evolution, with the exception of the oxidizing side of photosystem I, the LHCI complex shows a high degree of variability in size, subunits composition and bound pigments, which is due to the large variety of different habitats photosynthetic organisms dwell in. Besides summarizing the most current knowledge on the photosystem I core structure, we will discuss the composition and structure of the LHCI complex from different eukaryotic organisms, both from the red and the green clade. Furthermore, mechanistic insights into electron transfer between the donor and acceptor side of photosystem I and its soluble electron transfer carrier proteins will be given. This article is part of a Special Issue entitled: Regulation of Electron Transport in Chloroplasts. PMID- 20920464 TI - Interaction of chromium(III) complexes with model lipid bilayers: implications on cellular uptake. AB - To understand molecular cytotoxicity of chromium(III) and how it affects the stability of biological membranes, studies on the interaction of chromium(III) complexes aquapentaminechromium complex (complex I) and trans- [Cr(5 methoxysalcyclohex) (H(2)O) (2)] ClO(4) (complex II) with model biomembranes have been carried out. Langmuir films of dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidic acid (DPPA), dioctadecyldimethylammoniumbromide (DOMA) at air/water interface interacting with the chromium(III) complexes have been characterized using the surface pressure-molecular area (pi-A) isotherms. Initial surface pressures changes for the two complexes show that the chromium(III) complexes inserted in the Langmuir films and complex I interacted strongly compared to complex II. Supported bilayers (SB) of the lipids on solid substrates formed by hydrating their Langmuir-Blodgett films (LB films) have been characterized using linear dichroic spectra, low angle X-ray diffraction and steady state fluorescence anisotropy. Depending on the geometry of the ligands and concentration, the complexes either insert in the alkyl or in the head group region of the SB and sometimes in both regions. The Supported lipid bilayers are well-layered and at low concentration, the metal complexes are incorporated near the head group region. Order and increase in lamellar spacing show stronger interaction of complex I with the lipids compared with complex II. This study provides some insights into the mechanism of chromium(III) toxicity and uptake of chromium(III) by the cells. PMID- 20920465 TI - Different membrane behaviour and cellular uptake of three basic arginine-rich peptides. AB - Cell penetrating peptides (CPPs) are peptides displaying the ability to cross cell membranes and transport cargo molecules inside cells. Several uptake mechanisms (endocytic or direct translocation through the membrane) are being considered, but the interaction between the CPP and the cell membrane is certainly a preliminary key point to the entry of the peptide into the cell. In this study, we used three basic peptides: RL9 (RRLLRRLRR-NH(2)), RW9 (RRWWRRWRR NH(2)) and R9 (RRRRRRRRR-NH(2)). While RW9 and R9 were internalised into wild type Chinese Hamster Ovary cells (CHO) and glycosaminoglycan-deficient CHO cells, at 4 degrees C and 37 degrees C, RL9 was not internalised into CHO cells. To better understand the differences between RW9, R9 and RL9 in terms of uptake, we studied the interaction of these peptides with model lipid membranes. The effect of the three peptides on the thermotropic phase behaviour of a zwitterionic lipid (DMPC) and an anionic lipid (DMPG) was investigated with differential scanning calorimetry (DSC). The presence of negative charges on the lipid headgroups appeared to be essential to trigger the peptide/lipid interaction. RW9 and R9 disturbed the main phase transition of DMPG, whereas RL9 did not induce significant effects. Isothermal titration calorimetry (ITC) allowed us to study the binding of these peptides to large unilamellar vesicles (LUVs). RW9 and R9 proved to have about ten fold more affinity for DSPG LUVs than RL9. With circular dichroism (CD) and NMR spectroscopy, the secondary structure of RL9, RW9 and R9 in aqueous buffer or lipid/detergent conditions was investigated. Additionally, we tested the antimicrobial activity of these peptides against Escherichia coli and Staphylococcus aureus, as CPPs and antimicrobial peptides are known to share several common characteristics. Only RW9 was found to be mildly bacteriostatic against E. coli. These studies helped us to get a better understanding as to why R9 and RW9 are able to cross the cell membrane while RL9 remains bound to the surface without entering the cell. PMID- 20920466 TI - Effect of trehalose on the interaction of Alzheimer's Abeta-peptide and anionic lipid monolayers. AB - The interaction of amyloid beta-peptide (Abeta) with cell membranes is believed to play a central role in the pathogenesis of Alzheimer's disease. In particular, recent experimental evidence indicates that bilayer and monolayer membranes accelerate the aggregation and amyloid fibril formation rate of Abeta. Understanding that interaction could help develop therapeutic strategies for treatment of the disease. Trehalose, a disaccharide of glucose, has been shown to be effective in preventing the aggregation of numerous proteins. It has also been shown to delay the onset of certain amyloid-related diseases in a mouse model. Using Langmuir monolayers and molecular simulations of the corresponding system, we study several thermodynamic and kinetic aspects of the insertion of Abeta peptide into DPPG monolayers in water and trehalose subphases. In the water subphase, the insertion of the Abeta peptide into the monolayer exhibits a lag time which decreases with increasing temperature of the subphase. In the presence of trehalose, the lag time is completely eliminated and peptide insertion is completed within a shorter time period compared to that observed in pure water. Molecular simulations show that more peptide is inserted into the monolayer in the water subphase, and that such insertion is deeper. The peptide at the monolayer interface orients itself parallel to the monolayer, while it inserts with an angle of 50 degrees in the trehalose subphase. Simulations also show that trehalose reduces the conformational change that the peptide undergoes when it inserts into the monolayer. This observation helps explain the experimentally observed elimination of the lag time by trehalose and the temperature dependence of the lag time in the water subphase. PMID- 20920467 TI - Corepressor MMTR/DMAP1 is an intrinsic negative regulator of CAK kinase to regulate cell cycle progression. AB - We have previously reported that MMTR (MAT1-mediated transcriptional repressor) is a co-repressor that inhibits TFIIH-mediated transcriptional activity via interaction with MAT1 (Kang et al., 2007). Since MAT1 is a member of the CAK kinase complex that is crucial for cell cycle progression and that regulates CDK phosphorylation as well as the general transcription factor TFIIH, we investigated MMTR function in cell cycle progression. We found that MMTR over expression delayed G1/S and G2/M transitions, whereas co-expression of MAT1 and MMTR rescued the cell growth and proliferation rate. Moreover, MMTR was required for inhibition of CAK kinase-mediated CDK1 phosphorylation. We also showed that the expression level of MMTR was modulated during cell cycle progression. Our data support the notion that MMTR is an intrinsic negative cell cycle regulator that modulates the CAK kinase activity via interaction with MAT1. PMID- 20920468 TI - The inhibition of the T-cell immunoglobulin and mucin domain 3 (Tim3) pathway enhances the efficacy of tumor vaccine. AB - T-cell immunoglobulin and mucin domain 3 (Tim3) plays an important role in the Th1-mediated immune response; however, its effect on the efficacy of tumor vaccines has not been fully evaluated. Here, we demonstrate the effect of Tim3 pathway inhibition on tumor growth in mice. Lewis lung carcinoma (3LL) cells expressing a Tim3 pathway inhibitor, when injected into mice, showed suppressed tumor growth and a reduced frequency of CD4(+)CD25(+)Foxp3(+) T-cells. Furthermore, Tim3 pathway inhibition significantly enhanced the efficacy of a prophylactic tumor vaccine and marginally enhanced the efficacy of a therapeutic tumor vaccine. However, when given in combination with the chemotherapeutic agent, 5-fluorouracil, the therapeutic tumor vaccine capable of Tim3 pathway inhibition had no additional anti-tumor effect. Our results show that Tim3 pathway inhibition can enhance tumor vaccine efficacy. PMID- 20920469 TI - Regulatory T cells as a potent target for controlling bone loss. AB - Metabolic bone diseases, such as rheumatoid arthritis (RA) and osteoporosis, affect hundreds and millions of people worldwide leading causes of long-term pain and disability. Effective clinical treatment for bone destruction in bone diseases is lacking because the knowledge about molecular mechanisms leading to bone destruction are incompletely understood. Recently, it has been confirmed that regulatory T cells (Tregs) play a crucial role in suppressing the immune response in the pathogenesis of various autoimmune diseases. In vitro, Tregs directly inhibit osteoclasts and differentiation and function. In mice, the injection of Tregs into the TNF transgenic results in enhanced systemic bone density. In addition, it has been shown that increase of Tregs numbers by overexpressing the FoxP3 is effective in the prevention of local and systemic bone destruction. In vivo treatment with anti-CD28 superagonist antibody leading to a stronger increase in Tregs numbers protect against TNF-a-induced bone loss in TNF-transgenic mice. In agreement, Tregs can control ovariectomy-induced bone loss in FoxP3-transgenic mice. In this paper, we will briefly discuss the biological features of Tregs and summarize recent advances on the role of Tregs in the pathogenesis and treatment of bone loss in metabolic bone diseases. PMID- 20920470 TI - Molecular expression of Ly6k, a putative glycosylphosphatidyl-inositol-anchored membrane protein on the mouse testicular germ cells. AB - Ly6k, a putative mouse glycosylphosphatidyl-inositol (GPI)-anchored membrane protein is specifically associated with a unique germ-cell marker, TEX101. Although a human orthologue LY6K has been proposed as a novel cancer/testis antigen, its molecular nature is largely obscure, because its characteristics have been gleaned mainly from qualitative studies of gene structure. The aim of this study is to characterize molecular nature of Ly6k more precisely, especially, to focus on the molecular expression during testicular development. The present study have shown that: (1) Ly6k was strongly observed in testis, but faint expression was broadly noticed in other tissues; (2) Ly6k was weakly detected in testes from 18-day postcoitus to 1-day postpartum (dpp), with a plateau starting around 8-dpp; and (3) testicular Ly6k showed two-peak expression at around 14-dpp and 24-dpp, then exhibited stable expression from 6-week after birth onward. Western blot and immunohistochemical analyses revealed that Ly6k exists in at least two forms: a GPI-anchored form (17kDa) and a water-soluble (non-membrane) form (12kDa), and the 17-kDa mature form is expressed in the testicular germ cells beginning approximately 10days after birth. This information is essential for the molecular classification of Ly6k, and may help uncover the detailed physiological role of Ly6k in gametogenesis, or cancer biology. PMID- 20920471 TI - Temperature dependence rigidity of non-taxol stabilized single microtubules. AB - Because microtubules are the structural elements of cells, it is essential to study the mechanical properties of single microtubules under physiological conditions. Previously, we measured the effect of temperature on the flexural rigidity of a single taxol-stabilized microtubule and found that the flexural rigidity is 2.5*10(-24)Nm(2), independent of temperature in the 20-35 degrees C range. Employing the same technique here, we have measured the flexural rigidity of microtubules polymerized in the presence of guanylyl-(a,b)-methylene diphosphonate (GMPCPP, the slowly hydrolyzable GTP analogue) and in the presence of GTP only; both of the states were taxol-free. The obtained values were approximately 5-fold (for GMPCPP) and three- to 4-fold (for GTP) greater than those of taxol-stabilized microtubules. Interestingly, rigidity decreased as temperature increased, that is, temperature dependence was only observed in taxol free microtubules. Length dependence was also observed. These results indicate that the transition of microtubule's rigidity is associated with the tubulin conformation change from a GTP-bound state to a GDP-bound state in the alpha/beta subunit. We discuss the relationship of the regulation mechanism of the microtubules in the cell body to the changes in rigidity through hydrolysis. PMID- 20920472 TI - ATP synthesis is impaired in isolated mitochondria from myotubes established from type 2 diabetic subjects. AB - To date, it is unknown whether mitochondrial dysfunction in skeletal muscle from subjects with type 2 diabetes is based on primarily reduced mitochondrial mass and/or a primarily decreased mitochondrial ATP synthesis. Mitochondrial mass were determined in myotubes established from eight lean, eight obese and eight subjects with type 2 diabetes precultured under normophysiological conditions. Furthermore, mitochondria were isolated and ATP production was measured by luminescence at baseline and during acute insulin stimulation with or without concomitant ATP utilization by hexokinase. Mitochondrial mass and the ATP synthesis rate, neither at baseline nor during acute insulin stimulation, were not different between groups. The ratio of ATP synthesis rate at hexokinase versus ATP synthesis rate at baseline was lower in diabetic mitochondria compared to lean mitochondria. Thus the lower content of muscle mitochondria in type 2 diabetes in vivo is an adaptive trait and mitochondrial dysfunction in type 2 diabetes in vivo is based both on primarily impaired ATP synthesis and an adaptive loss of mitochondrial mass. PMID- 20920473 TI - Thr 3 phosphorylated histone H3 concentrates at centromeric chromatin at metaphase. AB - Thr 3 was one of the newly characterized phosphorylation sites on histone H3. However, the functional significance of histone H3 Thr 3 phosphorylation during mitosis is unclear. In this study, SDS-PAGE and Western blotting analysis showed that histone H3 Thr 3 was phosphorylated specially during mitosis in MCF-10A and ECV-304 cells. Using indirect immunofluorescence labeling and laser confocal microscopy, we demonstrated that histone H3 Thr 3 phosphorylation occurred from prophase to anaphase and dephosphorylated completely in telophase. Remarkably, Thr 3 phosphorylated histone H3 mostly concentrated at centromeric chromatin at metaphase, which was distinct with Ser 10 phosphorylation aggregated at the telomere, but similar to that characteristic of Thr 11 phosphorylated H3 which is largely restricted to the centromeric chromatin. Using chromatin immunoprecipitation (ChIP) assay, we provided direct evidence that the Thr 3 phosphorylated H3 is associated with centromeric DNA at metaphase. These findings suggested that at metaphase Thr 3 phosphorylated histone H3 may also participate in kinetochore assembly to promote faithful chromosome segregation and serve as another recognition code for kinetochore proteins. PMID- 20920474 TI - The tick saliva immunosuppressor, Salp15, contributes to Th17-induced pathology during Experimental Autoimmune Encephalomyelitis. AB - Salp15 is a tick saliva protein that inhibits CD4(+) T cell differentiation through its interaction with CD4. The protein inhibits early signaling events during T cell activation and IL-2 production. Because murine Experimental Autoimmune Encephalomyelitis development is mediated by central nervous system infiltrating CD4(+) T cells that are specific for myelin-associated proteins, we sought to determine whether the treatment of mice with Salp15 during EAE induction would prevent the generation of proinflammatory T cell responses and the development of the disease. Surprisingly, Salp15-treated mice developed more severe EAE than control animals. The treatment of EAE-induced mice with the tick saliva protein did not result in increased infiltration of T cells to the central nervous system, indicating that Salp15 had not affected the permeability of the blood-brain barrier. Salp15 treatment did not affect the development of antibody responses against the eliciting peptide or the presence of IFNgamma in the sera. The treatment with Salp15 resulted, however, in the increased differentiation of Th17 cells in vivo, as evidenced by higher IL-17 production from PLP(139-151) specific CD4(+) T cells isolated from the central nervous system and the periphery. In vitro, Salp15 was able to induce the differentiation of Th17 cells in the presence of IL-6 and the absence of TGFbeta These results suggest that a conductive milieu for the differentiation of Th17 cells can be achieved by restriction of the production of IL-2 during T cell differentiation, a role that may be performed by TGFbeta and other immunosuppressive agents. PMID- 20920475 TI - Promoter-exon relationship of H3 lysine 9, 27, 36 and 79 methylation on pluripotency-associated genes. AB - Evidence links pluripotency to a gene regulatory network organized by the transcription factors Oct4, Nanog and Sox2. Expression of these genes is controlled by epigenetic modifications on regulatory regions. However, little is known on profiles of trimethylated H3 lysine residues on coding regions of these genes in pluripotent and differentiated cells, and on the interdependence between promoter and exon occupancy of modified H3. Here, we determine how H3K9, H3K27, H3K36 and H3K79 methylation profiles on exons of OCT4, NANOG and SOX2 correlate with expression and promoter occupancy. Expression of OCT4, SOX2 and NANOG in embryonal carcinoma cells is associated with a looser chromatin configuration than mesenchymal progenitors or fibroblasts, determined by H3 occupancy. Promoter H3K27 trimethylation extends into the first exon of repressed OCT4, NANOG and SOX2, while H3K9me3 occupies the first exon of these genes irrespective of expression. Both H3K36me3 and H3K79me3 are enriched on exons of expressed genes, yet with a distinct pattern: H3K36me3 increases towards the 3' end of genes, while H3K79me3 is preferentially enriched on first exons. Down-regulation of the H3K36 methyltransferase SetD2 by siRNA causes global and gene-specific H3K36 demethylation and global H3K27 hypermethylation; however it does not affect promoter levels of H3K27me3, suggesting for the genes examined independence of occupancy of H3K27me3 on promoters and H3K36me3 on exons. mRNA levels are however affected, raising the hypothesis of a role of SetD2 on transcription elongation and/or termination. PMID- 20920476 TI - A Novel mouse model of enhanced proteostasis: Full-length human heat shock factor 1 transgenic mice. AB - The heat shock response (HSR) is controlled by the master transcriptional regulator heat shock factor 1 (HSF1). HSF1 maintains proteostasis and resistance to stress through production of heat shock proteins (HSPs). No transgenic model exists that overexpresses HSF1 in tissues of the central nervous system (CNS). We generated a transgenic mouse overexpressing full-length non-mutant HSF1 and observed a 2-4-fold increase in HSF1 mRNA and protein expression in all tissues studied of HSF1 transgenic (HSF1(+/0)) mice compared to wild type (WT) littermates, including several regions of the CNS. Basal expression of HSP70 and 90 showed only mild tissue-specific changes; however, in response to forced exercise, the skeletal muscle HSR was more elevated in HSF1(+/0) mice compared to WT littermates and in fibroblasts following heat shock, as indicated by levels of inducible HSP70 mRNA and protein. HSF1(+/0) cells elicited a significantly more robust HSR in response to expression of the 82 repeat polyglutamine-YFP fusion construct (Q82YFP) and maintained proteasome-dependent processing of Q82YFP compared to WT fibroblasts. Overexpression of HSF1 was associated with fewer, but larger Q82YFP aggregates resembling aggresomes in HSF1(+/0) cells, and increased viability. Therefore, our data demonstrate that tissues and cells from mice overexpressing full-length non-mutant HSF1 exhibit enhanced proteostasis. PMID- 20920477 TI - Low concentration of 4-hydroxy hexenal increases heme oxygenase-1 expression through activation of Nrf2 and antioxidative activity in vascular endothelial cells. AB - Large-scale clinical studies have shown that n-3 polyunsaturated fatty acids (n-3 PUFAs) such as eicosapentaenoic and docosahexaenoic acids reduce cardiovascular events without improving classical risk factors for atherosclerosis. Recent studies have proposed that direct actions of n-3 PUFAs themselves, or of their enzymatic metabolites, have antioxidative and anti-inflammatory effects on vascular cells. Although a recent study showed that plasma 4-hydroxy hexenal (4 HHE), a peroxidation product of n-3 PUFA, increased after supplementation of docosahexaenoic acid, the antiatherogenic effects of 4-HHE in vascular cells remain unclear. In the present study, we tested the hypothesis that 4-HHE induces the antioxidative enzyme heme oxygenase-1 (HO-1) through activation of nuclear factor erythroid 2-related factor 2 (Nrf2), a master regulatory transcriptional factor, and prevents oxidative stress-induced cytotoxicity in vascular endothelial cells. This mechanism could partly explain the cardioprotective effects of n-3 PUFAs. Human umbilical vein endothelial cells were stimulated with 1-10MUM 4-HHE or 4-hydroxy nonenal (4-HNE), a peroxidation product of n-6 PUFAs. Both 4-HHE and 4-HNE dose-dependently increased HO-1 mRNA and protein expression, and intranuclear expression and DNA binding of Nrf2 at 5MUM. Small interfering RNA for Nrf2 significantly reduced 4-HHE- or 4-HNE-induced HO-1 mRNA and protein expression. Furthermore, pretreatment with 4-HHE or 4-HNE prevented tert-butyl hydroperoxide-induced cytotoxicity. In conclusion, 4-HHE, a peroxidation product of n-3 PUFAs, stimulated expression of the antioxidant enzyme HO-1 through the activation of Nrf2 in vascular endothelial cells. This resulted in prevention of oxidative stress-induced cytotoxicity, and may represent a possible mechanism to partly explain the cardioprotective effects of n-3 PUFAs. PMID- 20920478 TI - Differentiation of neural stem cells into Schwann-like cells in vitro. AB - Neural stem cells (NSCs) are multipotent stem cells that have the potential to differentiate into different cells of the neural lineage like neurons, astrocytes and oligodendrocytes. In the current work, we explored whether NSCs could be differentiated into functional Schwann-like cells, which has not been investigated up to date. NSCs were harvested from the hippocampus of rats and identified by single cell cloning and immunofluorescence staining. Then NSCs were treated with DMEM/F12 supplemented with forskolin, heregulin, bFGF, PDGF-AA and retinoic acid (RA). Differentiated NSCs (dNSCs) exhibited a spindle-like morphology similar to Schwann cells and expressed the glial markers p75 and S100. We also found that dNSCs could enhance neurite outgrowth when co-cultured with NG108-15 cells. These results indicated that NSCs, derived from hippocampus of rats, could differentiate into Schwann-like cells with morphological, phenotypic and functional similarities. PMID- 20920479 TI - Signaling through LRP1: Protection from atherosclerosis and beyond. AB - The low-density lipoprotein receptor-related protein (LRP1) is a multifunctional cell surface receptor that belongs to the LDL receptor (LDLR) gene family and that is widely expressed in several tissues. LRP1 consists of an 85-kDa membrane bound carboxyl fragment (beta chain) and a non-covalently attached 515-kDa (alpha chain) amino-terminal fragment. Through its extracellular domain, LRP1 binds at least 40 different ligands ranging from lipoprotein and protease inhibitor complex to growth factors and extracellular matrix proteins. LRP-1 has also been shown to interact with scaffolding and signaling proteins via its intracellular domain in a phosphorylation-dependent manner and to function as a co-receptor partnering with other cell surface or integral membrane proteins. LRP-1 is thus implicated in two major physiological processes: endocytosis and regulation of signaling pathways, which are both involved in diverse biological roles including lipid metabolism, cell growth/differentiation processes, degradation of proteases, and tissue invasion. The embryonic lethal phenotype obtained after target disruption of the LRP-1 gene in the mouse highlights the biological importance of this receptor and revealed a critical, but yet undefined role in development. Tissue-specific gene deletion studies also reveal an important contribution of LRP1 in vascular remodeling, foam cell biology, the central nervous system, and in the molecular mechanisms of atherosclerosis. PMID- 20920480 TI - Thioredoxin reductase 1 knockdown enhances selenazolidine cytotoxicity in human lung cancer cells via mitochondrial dysfunction. AB - Thioredoxin reductase (TR1) is a selenoprotein that is involved in cellular redox status control and deoxyribonucleotide biosynthesis. Many cancers, including lung, overexpress TR1, making it a potential cancer therapy target. Previous work has shown that TR1 knockdown enhances the sensitivity of cancer cells to anticancer treatments, as well as certain selenocompounds. However, it is unknown if TR1 knockdown produces similar effect on the sensitivity of human lung cancer cells. To further elucidate the role of TR1 in the mechanism of selenocompounds in lung cancer, a lentiviral microRNA delivery system to knockdown TR1 expression in A549 human lung adenocarcinoma cells was utilized. Cell viability was assessed after 48 hr treatment with the selenocysteine prodrug selenazolidines 2 butylselenazolidine-4(R)-carboxylic acid (BSCA) and 2-cyclohexylselenazolidine-4 (R)-carboxylic acid (ChSCA), selenocystine (SECY), methylseleninic acid (MSA), 1,4-phenylenebis(methylene)selenocyanate (p-XSC), and selenomethionine (SEM). TR1 knockdown increased the cytotoxicity of BSCA, ChSCA, and SECY but did not sensitize cells to MSA, SEM, or p-XSC. GSH and TR1 depletion together decreased cell viability, while no change was observed with GSH depletion alone. Reactive oxygen species generation was induced only in TR1 knockdown cells treated with the selenazolidines or SECY. These three compounds also decreased total intracellular glutathione levels and oxidized thioredoxin, but in a TR1 independent manner. TR1 knockdown increased selenazolidine and SECY-induced mitochondrial membrane depolarization, as well as DNA strand breaks and AIF translocation from the mitochondria. These results indicate the ability of TR1 to modulate the cytotoxic effects of BSCA, ChSCA and SECY in human lung cancer cells through mitochondrial dysfunction. PMID- 20920481 TI - Antiangiogenic agents and targets: A perspective. AB - The first generation of clinically useful antiangiogenic agents focused on VEGF and targets in the VEGF pathway. The strengths and limitations of these therapeutics are now clear. Some tumors do not respond to VEGF-directed therapies de novo and others become non-responsive or resistant over time by switching to other angiogenic pathways. The next generation of angiogenesis-directed therapeutics will expand the field beyond the VEGF pathway and become more disease selective. Placental growth factor, a protein closely related to VEGF, is induced as tumors lose responsiveness to VEGF-directed therapies. Angiopoietins 1 and 2 are being targeted with a unique peptibody, a human recombinant Fc constant region fused to peptides, in clinical trials. The HGF/c-Met pathway is upregulated in some tumors as an alternate angiogenic pathway. The CXCL12 (SDF 1)/CXCR4 pathway represents a stromal chemokine axis involved in tumor angiogenesis. CXCR2 is a G-protein coupled receptor with several ligands including interleukin-8 and other angiogenic cytokines and may represent a useful target for antiangiogenic agents. The notch pathway is being investigated as a target in the setting of tumor angiogenesis. Sphingosine-1-phosphate is a bioactive lipid that can be neutralized with a monoclonal antibody. The anti-S-1 P antibody is under investigation as an antiangiogenic agent. Finally, several multi-targeted kinase inhibitors each with a unique pattern of inhibitory potency are in clinical trial with a focus on antiangiogenic activity. The expansion of the scope of potential antiangiogenic agents in or entering clinical trial should allow the development of antiangiogenic combination regimens and single agents that address diseases refractory to VEGF-directed therapeutics. PMID- 20920483 TI - Chronic antidepressant administration alleviates frontal and hippocampal BDNF deficits in CUMS rat. AB - Stress activates the hypothalamo-pituitary-adrenal (HPA) axis, regulates the expression of brain-derived neurotrophic factor (BDNF) in the brain, and mediates mood. Antidepressants alleviate stress and up-regulate BDNF gene expression. In this study, we investigated the effect of chronic unpredictable mild stress (CUMS) and the different kinds of antidepressant treatments on the HPA axis and the BDNF expression in the rat brain. Adult Wistar male rats were exposed to a six-week CUMS procedure and received different antidepressant treatments including venlafaxine, mirtazapine, and fluoxetine. Immunohistochemistry and real time PCR were used to measure BDNF expression levels in the rat brain, and ELISAs were used to investigate the plasma corticosterone (CORT) and adrenocorticotropic hormone (ACTH) levels. CUMS significantly decreased the BDNF protein level in the DG, CA1, and CA3 of the hippocampus and increased plasma CORT level. Chronic antidepressant treatments all significantly increased BDNF protein levels in the hippocampus and the pre-frontal cortex. In addition, venlafaxine and mirtazapine inhibited the increase of plasma CORT level. These results suggested that an increase in the BDNF level in the brain could be a pivotal mechanism of various antidepressants to exert their therapeutic effects. PMID- 20920484 TI - Pre-attentive and attentive processing of French vowels. AB - This study aimed at investigating the effects of acoustic distance and of speaker variability on the pre-attentive and attentive perception of French vowels by French adult speakers. The electroencephalogram (EEG) was recorded while participants watched a silent movie (Passive condition) and discriminated deviant vowels (Active condition). The auditory sequence included 4 French vowels, /u/ (standard) and /o/, /y/ and /o/ as deviants, produced by 3 different speakers. As the vowel /o/ is closer to /u/ than the other deviants in acoustic distance, we predicted smaller mismatch negativity (MMN) and smaller N1 component, as well as higher error rate and longer reaction times. Results were in line with these predictions. Moreover, the MMN was elicited by all deviant vowels independently of speaker variability. By contrast, the Vowel by Speaker interaction was significant in the Active listening condition thereby showing that subtle within category differences are processed at the attentive level. These results suggest that while vowels are categorized pre-attentively according to phonemic representations and independently of speaker variability, participants are sensitive to between-speaker differences when they focus attention on vowel processing. PMID- 20920485 TI - A reinforcement learning approach to model interactions between landmarks and geometric cues during spatial learning. AB - In contrast to predictions derived from the associative learning theory, a number of behavioral studies suggested the absence of competition between geometric cues and landmarks in some experimental paradigms. In parallel to these studies, neurobiological experiments suggested the existence of separate independent memory systems which may not always interact according to classic associative principles. In this paper we attempt to combine these two lines of research by proposing a model of spatial learning that is based on the theory of multiple memory systems. In our model, a place-based locale strategy uses activities of modeled hippocampal place cells to drive navigation to a hidden goal, while a stimulus-response taxon strategy, presumably mediated by the dorso-lateral striatum, learns landmark-approaching behavior. A strategy selection network, proposed to reside in the prefrontal cortex, implements a simple reinforcement learning rule to switch behavioral strategies. The model is used to reproduce the results of a behavioral experiment in which an interaction between a landmark and geometric cues was studied. We show that this model, built on the basis of neurobiological data, can explain the lack of competition between the landmark and geometry, potentiation of geometry learning by the landmark, and blocking. Namely, we propose that the geometry potentiation is a consequence of cooperation between memory systems during learning, while blocking is due to competition between the memory systems during action selection. PMID- 20920482 TI - Identified GnRH neuron electrophysiology: a decade of study. AB - Over the past decade, the existence of transgenic mouse models in which reporter genes are expressed under the control of the gonadotropin-releasing hormone (GnRH) promoter has made possible the electrophysiological study of these cells. Here, we review the intrinsic and synaptic properties of these cells that have been revealed by these approaches, with a particular regard to burst generation. Advances in our understanding of neuromodulation of GnRH neurons and synchronization of this network are also discussed. PMID- 20920486 TI - Attentional demand and processing of relevant visual information during simulated driving: a MEG study. AB - It is a well-known fact that attention is crucial for driving a car. This innovative study aims to assess the impact of attentional workload modulation on cerebral activity during a simulated driving task using magnetoencephalography (MEG). A car simulator equipped with a steering wheel, turn indicators, an accelerator and a brake pedal has been specifically designed to be used with MEG. Attentional demand has been modulated using a radio broadcast. During half of the driving scenarios, subjects could ignore the broadcast (simple task, ST) and during the other half, they had to actively listen to it in order to answer 3 questions (dual task, DT). Evoked magnetic responses were computed in both conditions separately for two visual stimuli of interest: traffic lights (from green to amber) and direction signs (arrows to the right or to the left) shown on boards. The cortical sources of these activities have been estimated using a minimum-norm current estimates modeling technique. Results show the activation of a large distributed network similar in ST and DT and similar for both the traffic lights and the direction signs. This network mainly involves sensory visual areas as well as parietal and frontal regions known to play a role in selective attention and motor areas. The increase of attentional demand affects the neuronal processing of relevant visual information for driving, as early as the perceptual stage. By demonstrating the feasibility of recording MEG activity during an interactive simulated driving task, this study opens new possibilities for investigating issues regarding drivers' activity. PMID- 20920487 TI - The impact of agrin on the formation of orthogonal arrays of particles in cultured astrocytes from wild-type and agrin-null mice. AB - Astrocytic endfeet membranes are studded with aquaporin-4 (AQP4) containing orthogonal arrays of particles (OAP) which can be visualized exclusively by the freeze-fracturing method. They are predominantly expressed where the astroglial membrane is in contact with the superficial and perivascular basal lamina. This polarity seems to be essential for the integrity of the blood-brain barrier (BBB). The basal lamina containing many extracellular matrix (ECM) components such as collagen, laminin and heparansulfate proteoglycans like agrin is thought to influence this OAP-related polarity of astrocytes. Recently, we have shown that agrin, in particular the neuronal isoform A4B8, is capable of influencing the formation of OAPs in astrocytes when cultured in the presence of agrin conditioned media. In this paper we wanted to investigate whether coating with exogenous agrin compared to coating with other ECM components would induce OAP formation in astrocytes of the agrin-null mouse. For this purpose, we cultured astrocytes from agrin-null and wild-type mice on agrin- or ECM-coated surfaces. Immunofluorescent cytochemical staining of AQP4 indicated a higher AQP4 expression level in cultures with agrin- or ECM-coated than in cultures with uncoated surfaces, whereas western blot analyses and PCR showed no differences. alpha-Dystroglycan is thought to be a potential receptor of agrin and was immunostained in wild-type as well as in agrin-null astrocytes. In freeze fracture replicas, we observed an increase in OAP density in astrocytes when growing on agrin- and ECM-coatings. These results concurred with other experiments in which changes in volume were measured following hypotonic stress, which supported the positive influence of exogenous agrin on AQP4 insertion into the membrane, on OAP formation and on water transport. PMID- 20920488 TI - Visuomotor mental rotation: reaction time is determined by the complexity of the sensorimotor transformations mediating the response. AB - In the visuomotor mental rotation (VMR) task, participants point to a location that deviates from a visual target by a predetermined angle. A seminal investigation of the VMR task reported a linear increase in reaction time (RT) as a function of increasing angle, for 5 degrees , 10 degrees , 15 degrees , 35 degrees , 70 degrees , 105 degrees , and 140 degrees (Georgopoulos and Massey, 1987). This finding led to the development of the mental rotation model (MRM) and the assertion that response preparation is mediated via the imagined rotation of a movement vector. To determine if the MRM can be extrapolated to perceptually familiar angles (e.g., 90 degrees and 180 degrees ) within a range of equally spaced angles, we evaluated two independent sets of angles: 5 degrees , 10 degrees , 15 degrees , 35 degrees , 70 degrees , 105 degrees , and 140 degrees (experiment one) and 30 degrees , 60 degrees , 90 degrees , 120 degrees , 150 degrees , 180 degrees , and 210 degrees (experiment two). Consistent with the MRM, experiment one revealed a linear increase in RT as a function of increasing angle; however, a non-linear relation was revealed for experiment two. RTs were fastest for 180 degrees , followed by 30 degrees , 90 degrees , 60 degrees , 150 degrees , 210 degrees , and 120 degrees . Such results demonstrate that response preparation was not uniquely mediated via a mental rotation process. Instead, the present work provides evidence of a temporally demanding and cognitively mediated response substitution process, wherein the computational demands of response preparation are determined by the complexity of the sensorimotor transformations mediating the response. PMID- 20920489 TI - Neural correlates of task switching in paternal 15q11-q13 deletion Prader-Willi syndrome. AB - We report a first study of brain activity linked to task switching in individuals with Prader-Willi syndrome (PWS). PWS individuals show a specific cognitive deficit in task switching which may be associated with the display of temper outbursts and repetitive questioning. The performance of participants with PWS and typically developing controls was matched in a cued task switching procedure, and brain activity was contrasted on switching and non-switching blocks using fMRI. Individuals with PWS did not show the typical frontal-parietal pattern of neural activity associated with switching blocks, with significantly reduced activation in regions of the posterior parietal and ventromedial prefrontal cortices. We suggest that this is linked to a difficulty in PWS in setting appropriate attentional weights to enable task-set reconfiguration. In addition to this, PWS individuals did not show the typical pattern of deactivation, with significantly less deactivation in an anterior region of the ventromedial prefrontal cortex. One plausible explanation for this is that individuals with PWS show dysfunction within the default mode network, which has been linked to attentional control. The data point to functional changes in the neural circuitry supporting task switching in PWS even when behavioural performance is matched to controls and thus highlight neural mechanisms that may be involved in a specific pathway between genes, cognition and behaviour. PMID- 20920491 TI - Effect of menstrual cycle phase on corticolimbic brain activation by visual food cues. AB - Food intake is decreased during the late follicular phase and increased in the luteal phase of the menstrual cycle. While a changing ovarian steroid milieu is believed to be responsible for this behavior, the specific mechanisms involved are poorly understood. Brain activity in response to visual food stimuli was compared during the estrogen dominant peri-ovulatory phase and the progesterone dominant luteal phase of the menstrual cycle. Twelve women underwent functional magnetic resonance imaging during the peri-ovulatory and luteal phases of the menstrual cycle in a counterbalanced fashion. Whole brain T2* images were collected while subjects viewed pictures of high calorie (HC) foods, low calorie (LC) foods, and control (C) pictures presented in a block design. Blood oxygen level dependent (BOLD) signal in the late follicular phase and luteal phase was determined for the contrasts HC-C, LC-C, HC-LC, and LC-HC. Both HC and LC stimuli activated numerous corticolimbic brain regions in the follicular phase, whereas only HC stimuli were effective in the luteal phase. Activation of the nucleus accumbens (NAc), amygdala, and hippocampus in response to the HC-C contrast and the hippocampus in response to the LC-C contrast was significantly increased in the late follicular phase compared to the luteal phase. Activation of the orbitofrontal cortex and mid cingulum in response to the HC-LC contrast was greater during the luteal phase. These results demonstrate for the first time that brain responses to visual food cues are influenced by menstrual cycle phase. We postulate that ovarian steroid modulation of the corticolimbic brain contributes to changes in ingestive behavior during the menstrual cycle. PMID- 20920490 TI - Brain growth across the life span in autism: age-specific changes in anatomical pathology. AB - Autism is marked by overgrowth of the brain at the earliest ages but not at older ages when decreases in structural volumes and neuron numbers are observed instead. This has led to the theory of age-specific anatomic abnormalities in autism. Here we report age-related changes in brain size in autistic and typical subjects from 12 months to 50 years of age based on analyses of 586 longitudinal and cross-sectional MRI scans. This dataset is several times larger than the largest autism study to date. Results demonstrate early brain overgrowth during infancy and the toddler years in autistic boys and girls, followed by an accelerated rate of decline in size and perhaps degeneration from adolescence to late middle age in this disorder. We theorize that underlying these age-specific changes in anatomic abnormalities in autism, there may also be age-specific changes in gene expression, molecular, synaptic, cellular, and circuit abnormalities. A peak age for detecting and studying the earliest fundamental biological underpinnings of autism is prenatal life and the first three postnatal years. Studies of the older autistic brain may not address original causes but are essential to discovering how best to help the older aging autistic person. Lastly, the theory of age-specific anatomic abnormalities in autism has broad implications for a wide range of work on the disorder including the design, validation, and interpretation of animal model, lymphocyte gene expression, brain gene expression, and genotype/CNV-anatomic phenotype studies. PMID- 20920492 TI - Cross-regional cortical synchronization during affective image viewing. AB - Affective perception has been suggested to involve the coordinated activation of widely distributed cortical networks, including those involved in sensory storage/analysis and higher-order structures, such as the prefrontal cortex that regulate these processes. We measured regional electroencephalogram (EEG) activity while young adult participants viewed images varying in arousal and valence (pleasant, neutral, and unpleasant). Viewing highly arousing images led to a significant enhancement of EEG coherence between prefrontal and posterior electrodes in both cerebral hemispheres. Long distance interhemispheric coherence also increased during affective image viewing, but only among females. Increases in coherent brain electrical activity were specific to oscillations in the beta (14 to 30Hz) bandwidth, while right hemispheric networks oscillating in the theta (4 to 7Hz) range tended to de-synchronize during viewing of affective images. Although directionality could not be inferred, analyses of lead-lag relations showed the prefrontal electrodes leading the posterior clusters, consistent with top-down modulation. Our results suggest large-scale synchronization of cortical cells during affective viewing and emphasize the role of beta oscillations in mediating such binding. PMID- 20920493 TI - Neural mechanisms mediating circadian phase resetting by activation of 5-HT(7) receptors in the dorsal raphe: roles of GABAergic and glutamatergic neurotransmission. AB - 5-HT(7) receptors in the dorsal raphe nucleus (DRN) influence circadian rhythms, sleep, and serotonin release. Because interactions between 5-HT(7) receptors and glutamatergic and GABAergic neurons have been demonstrated previously, the current studies tested the hypothesis that GABAergic and/or glutamatergic neurons mediate phase shifts induced by activation of DRN 5-HT(7) receptors. Hamsters were fitted with guide cannulae aimed at the DRN, housed in cages with running wheels, and exposed to 14h light (L):10h dark (D). In Experiment 1, hamsters received DRN pretreatment with muscimol (87.6 pmol) or vehicle before DRN 8-OH DPAT (6 pmol) microinjections at ZT6. After exposure to constant darkness (10 days), phase shifts were calculated and animals were re-exposed to 14L:10D. The procedure was repeated to give each animal the alternate pretreatment. In Experiment 2, hamsters received DRN pretreatment with NMDA (20 pmol) or vehicle before 8-OH-DPAT at ZT 6. Other experiments tested the effects of single DRN microinjections of muscimol, bicuculline (136 pmol), NMDA, MK-801 (10 pmol) or vehicle. Phase shifts (mean +/- S.E.M., h) in muscimol/8-OH-DPAT-microinjected hamsters (1.02 +/- 0.30) were not different (P=0.11) from those in vehicle/8-OH DPAT-microinjected hamsters (1.34 +/- 0.30), while those in NMDA/8-OH-DPAT microinjected hamsters (0.67 +/- 0.17) were smaller (P<0.05) than those in vehicle/8-OH-DPAT-microinjected hamsters (0.97 +/- 0.10). DRN single microinjections of bicuculline, but not muscimol, NMDA, or MK-801 induced phase advances. Bicuculline also potentiated 8-OH-DPAT-induced phase advances (P<0.05). These finding suggest that the mechanism mediating DRN 5-HT(7) receptor induction of phase advances involves decreased glutamatergic neurotransmission, and furthermore, that inhibition of DRN GABAergic neurotransmission causes a phase advance. PMID- 20920494 TI - Lipopolysaccharide-induced cytokine expression in alveolar epithelial cells: role of PKCzeta-mediated p47phox phosphorylation. AB - Chronic inflammation incited by bacteria in the saccular lung of premature infants contributes to the pathogenesis of bronchopulmonary dysplasia (BPD). LPS mediated type II alveolar epithelial cell (AEC) injury induces the expression of pro-inflammatory cytokines that trigger pulmonary neutrophil influx, alveolar matrix degradation and lung remodeling. We hypothesized that NADPH oxidase (Nox) dependent mechanisms mediate LPS-induced cytokine expression in AEC. We examined the role of p47phox in mediating LPS-dependent inflammatory cytokine expression in A549 cells (which exhibit phenotypic features characteristic of type II AEC) and elucidated the proximal signaling events by which Nox is activated by LPS. LPS-induced ICAM-1 and IL-8 expression was associated with increased superoxide formation in AEC. LPS-mediated oxidative stress and cytokine expression was inhibited by apocynin and augmented by PMA demonstrating that Nox-dependent redox signaling regulates LPS-dependent pro-inflammatory signaling in AEC. In LPS treated cells, p47phox translocated from the cytoplasm to the perinuclear region and co-localized with gp91phox. LPS also induced a temporal increase in p47phox serine304 phosphorylation in AEC. While inhibition of classical PKC and novel PKC with calphostin and rottlerin did not inhibit ICAM-1 or IL-8 expression, the myristolyated PKCzeta pseudosubstrate peptide (a specific inhibitor of PKCzeta) inhibited LPS-induced cytokine expression in AEC. Inhibition of PKCzeta also attenuated LPS-mediated p47phox phosphorylation and perinuclear translocation in AEC. Consistent with these data, LPS activated PKCzeta in AEC as evidenced by increased threonine410 phophorylation. We conclude that PKCzeta-mediated p47phox activation regulates LPS-dependent cytokine expression in AEC. Selective inhibition of PKCzeta or p47phox might attenuate LPS-mediated inflammation and alveolar remodeling in BPD. PMID- 20920495 TI - Enzymes that hydrolyze adenine nucleotides in patients with ischemic heart disease. AB - BACKGROUND: The extracellular nucleotides, ATP and ADP, as well as the nucleoside adenosine have been implicated in a great number of pathologic and physiological functions. However, extracellular adenine nucleotide levels are controlled by a complex cell surface-located group of enzymes called ectonucleotidases. We evaluated activities of enzymes that hydrolyze adenine nucleotides and nucleosides in platelets from patients with ischemic heart disease (IHD). METHODS: Sixty IHD patients were selected for the study. The activities of ectonucleoside triphosphate diphosphohydrolase (NTPDase, CD39), ectonucleotide pyrophosphatase/phosphodiesterase (E-NPP), ecto-5'-nucleotidase and adenosine deaminase (ADA) were studied in isolated platelets of these patients, as well as the platelet aggregation and NTPDase expression. RESULTS: The results show that NTPDase, ecto-5'-nucleotidase, E-NPP activities and NTPDase expression were increased in platelets of IHD patients when compared with the control group (p < 0.05). On the other hand, ADA activity and platelet aggregation were decreased in IHD patients, when compared with the control group (p < 0.05). CONCLUSIONS: The pathological condition in IHD generates alterations in ectonucleotidase activities as a compensatory organic response to thrombotic events that occur in IHD. PMID- 20920496 TI - Co-peptin: Role as a novel biomarker in clinical practice. AB - BACKGROUND: Arginine vasopressin (AVP) is a key regulator of water balance, but its instability makes reliable measurement difficult and precludes its routine use. Co-peptin is the C-terminal part of the AVP precursor which plays an important role in the correct structural formation of the AVP precursor and its efficient proteolytic maturation. Because of its stoichiometric generation, co peptin mirrors the release of AVP and measurement of more stable co-peptin may be an indicator of AVP levels. METHOD: A comprehensive literature search was conducted from the websites of the National Library of Medicine (http://www.ncbl.nlm.nih.gov) and Pubmed Central, the US National Library of Medicine's digital archive of life sciences literature (http://www.pubmedcentral.nih.gov/). The data was assessed from books and journals that published relevant articles in this field. RESULT: Recent and ongoing research indicates the diagnostic and prognostic roles of co-peptin in various clinical settings especially in critically ill patients. CONCLUSION: Co peptin levels are altered in various physiological and pathological conditions indicating its possible role as a biomarker. However, further research using co peptin in various clinical settings will prove its cost-effectiveness and clinical usefulness. PMID- 20920497 TI - Use of likelihood ratios improves clinical interpretation of IgG and IgA anti-DGP antibody testing for celiac disease in adults and children. AB - OBJECTIVE: To evaluate whether taking into account anti-deamidated gliadin peptide (DGP) antibody concentrations improves clinical interpretation. DESIGN AND METHODS: We calculated likelihood ratios (LR) using data from two previously published studies for assays from EUROIMMUN and INOVA. RESULTS: LRs markedly increased with increasing IgG anti-DGP concentrations. LRs also increased with increasing IgA anti-DGP concentrations, although they were lower than for IgG anti-DGP. CONCLUSIONS: Use of LRs for different test result intervals improves clinical interpretation. PMID- 20920498 TI - Mice lacking FABP9/PERF15 develop sperm head abnormalities but are fertile. AB - The male germ cell-specific fatty acid-binding protein 9 (FABP9/PERF15) is the major component of the murine sperm perforatorium and perinuclear theca. Based on its cytoskeletal association and sequence homology to myelin P2 (FABP8), it has been suggested that FABP9 tethers sperm membranes to the underlying cytoskeleton. Furthermore, its upregulation in apoptotic testicular germ cells and its increased phosphorylation status during capacitation suggested multiple important functions for FABP9. Therefore, we investigated specific functions for FABP9 by means of targeted gene disruption in mice. FABP9(-/-) mice were viable and fertile. Phenotypic analysis showed that FABP9(-/-) mice had significant increases in sperm head abnormalities (~8% greater than their WT cohorts); in particular, we observed the reduction or absence of the characteristic structural element known as the "ventral spur" in ~10% of FABP9(-/-) sperm. However, deficiency of FABP9 affected neither membrane tethering to the perinuclear theca nor the fatty acid composition of sperm. Moreover, epididymal sperm numbers were not affected in FABP9(-/-) mice. Therefore, we conclude that FABP9 plays only a minor role in providing the murine sperm head its characteristic shape and is not absolutely required for spermatogenesis or sperm function. PMID- 20920500 TI - Ofd1 is required in limb bud patterning and endochondral bone development. AB - Oral-facial-digital type I (OFDI) syndrome is an X-linked male lethal developmental disorder. It is ascribed to ciliary dysfunction and characterized by malformation of the face, oral cavity, and digits. Conditional inactivation using different Cre lines allowed us to study the role of the Ofd1 transcript in limb development. Immunofluorescence and ultrastructural studies showed that Ofd1 is necessary for correct ciliogenesis in the limb bud but not for cilia outgrowth, in contrast to what was previously shown for the embryonic node. Mutants with mesenchymal Ofd1 inactivation display severe polydactyly with loss of antero-posterior (A/P) digit patterning and shortened long bones. Loss of digit identity was found to be associated with a progressive loss of Shh signaling and an impaired processing of Gli3, whereas defects in limb outgrowth were due to defective Ihh signaling and to mineralization defects during endochondral bone formation. Our data demonstrate that Ofd1 plays a role in regulating digit number and identity during limb and skeletal patterning increasing insight on the functional role of primary cilia during development. PMID- 20920499 TI - BMP signaling modulates hedgehog-induced secondary heart field proliferation. AB - Sonic hedgehog signaling in the secondary heart field has a clear role in cardiac arterial pole development. In the absence of hedgehog signaling, proliferation is reduced in secondary heart field progenitors, and embryos predominantly develop pulmonary atresia. While it is expected that proliferation in the secondary heart field would be increased with elevated hedgehog signaling, this idea has never been tested. We hypothesized that up-regulating hedgehog signaling would increase secondary heart field proliferation, which would lead to arterial pole defects. In culture, secondary heart field explants proliferated up to 6-fold more in response to the hedgehog signaling agonist SAG, while myocardial differentiation and migration were unaffected. Treatment of chick embryos with SAG at HH14, just before the peak in secondary heart field proliferation, resulted unexpectedly in stenosis of both the aortic and pulmonary outlets. We examined proliferation in the secondary heart field and found that SAG-treated embryos exhibited a much milder increase in proliferation than was indicated by the in vitro experiments. To determine the source of other signaling factors that could modulate increased hedgehog signaling, we co-cultured secondary heart field explants with isolated pharyngeal endoderm or outflow tract and found that outflow tract co-cultures prevented SAG-induced proliferation. BMP2 is made and secreted by the outflow tract myocardium. To determine whether BMP signaling could prevent SAG-induced proliferation, we treated explants with SAG and BMP2 and found that BMP2 inhibited SAG-induced proliferation. In vivo, SAG-treated embryos showed up regulated BMP2 expression and signaling. Together, these results indicate that BMP signaling from the outflow tract modulates hedgehog-induced proliferation in the secondary heart field. PMID- 20920501 TI - Investigation of Toxoplasma gondii presence in farmed shellfish by nested-PCR and real-time PCR fluorescent amplicon generation assay (FLAG). AB - To evaluate the presence of Toxoplasma gondii in edible farmed shellfish, 1734 shellfish specimens i.e., 109 Crassostrea gigas (6 pools), 660 Mytilus galloprovincialis (22 pools), 804 Tapes decussatus (28 pools) and 161 Tapes philippinarum (6 pools), were collected from the Varano Lagoon (Apulia, Italy). Shellfish from 62 pools were subjected to two molecular techniques: a nested-PCR assay, and a fluorescent amplicon generation (FLAG) real-time PCR assay, both based on the multi-copy B1 target, were performed. One pooled sample of gills from C. gigas and one pooled sample of haemolymphs from T. decussatus were assessed as positive for T. gondii DNA by both techniques. The results demonstrated the presence of T. gondii in edible farmed C. gigas and T. decussatus and indicate that there may be a considerable health threat involved in eating contaminated raw shellfish. PMID- 20920502 TI - The dissociation activation model of B cell antigen receptor triggering. AB - To detect its cognate antigen, each B lymphocyte contains up to 120000 B cell antigen receptor (BCR) complexes on its cell surface. How these abundant receptors remain silent on resting B cells and how they can be activated by a molecularly diverse set of ligands is poorly understood. The antigen-specific activation of the BCR is currently explained by the cross-linking model (CLM). This model predicts that the many BCR complexes on the surface of a B cell are dispersed signalling-inert monomers and that it is BCR dimerization that initiates signalling from the receptor. The finding that the BCR forms auto inhibited oligomers on the surface of resting B cells falsifies these predictions of the CLM. We propose the dissociation activation model (DAM), which fits better with the existing body of experimental data. PMID- 20920503 TI - Identification and characterization of mesotocin and V1a-like vasotocin receptors in a urodele amphibian, Taricha granulosa. AB - The cDNA sequences encoding the mesotocin receptor (MTR) and vasotocin 1a receptor (VTR-1a) were identified in a urodele amphibian, the rough-skinned newt, Taricha granulosa. Saturation binding of [(3)H]oxytocin (OT) to the Taricha MTR (tMTR) was best fit by a two-state model; a high affinity-low abundance site and a lower affinity-high abundance site. Competition-binding studies found the following rank-order affinities for the tMTR: mesotocin (MT)>OT~vasotocin (VT)>vasopressin (VP)>isotocin (IT). Inositol phosphate (IP) accumulation studies demonstrated functional activity of both the tMTR and Taricha VTR-1a (tVTR-1a) in a heterologous cell culture system. The rank-order potencies for the tMTR were MT>OT>VT~VP>IT. The combined binding and IP results indicate that VT may act as a partial agonist of the tMTR. Rank-order potencies for the tVTR-1a were VT>VP>MT~OT>IT. For both receptors, stimulation of IP accumulation was blocked by d(CH(2))(5)[Tyr(Me)(2)]AVP (Manning compound) and d(CH(2))(5)[Tyr(Me)(2),Thr(4),Tyr-NH(2)]OVT (OTA). OTA was a more potent antagonist for the transiently expressed tMTR while Manning compound was relatively more potent at inhibiting IP accumulation in tVTR-1a expressing cells. In contradiction to earlier assumptions, the absolute IC(50) of Manning compound was lower for the tMTR (27nM+/-13) than the tVTR-1a (586nM+/-166) indicating its potential higher affinity for the tMTR, a finding with special relevance to interpretation of comparative studies investigating the behavioral and physiological actions of neurohypophysial peptides in non-mammalian species. PMID- 20920504 TI - Sex differences in the analgesic effects of ICI 182,780 and Flutamide on ureteral calculosis in rats. AB - To better define the involvement of gonadal hormones in the sex differences observed in experimental visceral pain, we administered antagonists of estrogen receptors (ICI 182,780 [ICI]) or androgen receptors (Flutamide [FLU]) to adult male and female rats suffering from artificial ureteral calculosis. Subjects were divided into groups and treated with one of the substances (ICI, FLU) or sweet almond oil (OIL, vehicle) for 5 days, starting 2 days before surgery. On day 3, animals underwent surgery, with half receiving an artificial calculosis (Stone) and half only a sham procedure. The animals' behavior (number and duration of ureteral crises) and blood hormone levels (estradiol and testosterone) were determined in all groups. In OIL-treated rats the number and duration of crises were higher in females than in males. The administration of ICI or FLU resulted in hormonal effects in males and behavioral effects in females. In males ICI treatment increased estradiol plasma levels and FLU increased testosterone plasma levels; in females ICI and FLU treatments both decreased the number and duration of the ureteral crises. These results, confirming previous findings of higher sensitivity of females than males to urinary tract pain, showed the modulatory effects of estrogen and androgen antagonists on the behavioral responses induced by pain but only in females. PMID- 20920505 TI - Comparing the relative amount of testosterone required to restore sexual arousal, motivation, and performance in male rats. AB - It is well established that male rat reproductive behaviors including sexual arousal, motivation, and performance are dependent on circulating levels of testosterone (T). The present study was designed to (1) compare the relative amount of T required to restore these different aspects of behavior in castrated rats, and (2) create an animal model for clinical populations with sexual impairments. Twenty-nine male Long-Evans rats were tested before and after castration for sexual performance (copulation), motivation (partner preference), and arousal (50 kHz ultrasonic vocalizations; measured together with scent marking). Sexual arousal was also inferred from copulation data. Rats were then assigned to one of four groups, and T was re-introduced via Silastic capsule implants varying in length and content: No T (empty capsules), Low T (2mm capsules), Medium T (5mm capsules), or High T (two 10mm capsules). The highest dose was intended to restore physiological levels. Results indicate that High T is required for 50 kHz vocalizations, while Medium T was sufficient for the restoration of copulation, partner preference, and scent marking. These data suggest that sexual arousal may be most sensitive to reductions in testosterone. The role of T levels in measures of generalized and specific (sexual) arousal is discussed in the context of other reproductive behaviors. Furthermore, because the Low T group showed impairments across all behaviors during post-implant tests, we propose that these animals may provide a good animal model for studying clinical conditions marked by reduced motivation and arousal, including Hypoactive Sexual Desire Disorder. PMID- 20920506 TI - The evolution of virulence in primate malaria parasites based on Bayesian reconstructions of ancestral states. AB - Plasmodium parasites, the causative agents of malaria, are generally considered as harmful parasites, but many of them cause mild symptoms. Little is known about the evolutionary history and phylogenetic constraints that generate this interspecific variation in virulence due to uncertainties about the phylogenetic associations of parasites. Here, to account for such phylogenetic uncertainty, phylogenetic methods based on Bayesian statistics were followed in combination with sequence data from five genes to estimate the ancestral state of virulence in primate Plasmodium parasites. When recent parasites were categorised according to the damage caused to the host, Bayesian estimates of ancestral states indicated that the acquisition of a harmful host exploitation strategy is more likely to be a recent evolutionary event than a result of an ancient change in a character state altering virulence. On the contrary, there was more evidence for moderate host exploitation having a deep origin along the phylogenetic tree. Moreover, the evolution of host severity is determined by the phylogenetic relationships of parasites, as severity gains did not appear randomly on the evolutionary tree. Such phylogenetic constraints can be mediated by the acquisition of virulence genes. As the impact of a parasite on a host is the result of both the parasite's investment in reproduction and host sensitivity, virulence was also estimated by calculating peak parasitemia after eliminating host effects. A directional random-walk evolutionary model showed that the ancestral primate malarias reproduced at very low parasitemia in their hosts. Consequently, the extreme variation in the outcome of malaria infection in different host species can be better understood in light of the phylogeny of parasites. PMID- 20920507 TI - MHC-I prediction using a combination of T cell epitopes and MHC-I binding peptides. AB - We propose a novel learning method that combines multiple experimental modalities to improve the MHC Class-I binding prediction. Multiple experimental modalities are often accessible in the context of a binding problem. Such modalities can provide different labels of data, such as binary classifications, affinity measurements, or direct estimations of the binding profile. Current machine learning algorithms usually focus on a given label type. We here present a novel Multi-Label Vector Optimization (MLVO) formalism to produce classifiers based on the simultaneous optimization of multiple labels. Within this methodology, all label types are combined into a single constrained quadratic dual optimization problem. We apply the MLVO to MHC class-I epitope prediction. We combine affinity measurements (IC50/EC50), binary classifications of epitopes as T cell activators and existing algorithms. The multi-label vector optimization algorithms produce classifiers significantly better than the ones resulting from any of its components. These matrix based classifiers are better or equivalent to the existing state of the art MHC-I epitope prediction tools in the studied alleles. PMID- 20920508 TI - Longevity and aging in insects: Is reproduction costly; cheap; beneficial or irrelevant? A critical evaluation of the "trade-off" concept. AB - The most prevalent hypothesis concerning the relationship between reproduction and longevity predicts that reproduction is costly, particularly in females. Specifically, egg production and sexual harassment of females by males reduce female longevity. This may apply to some short-lived species such as Drosophila, but not to some long-lived species such as the queens of ants and bees. Bee queens lay up to 2000 eggs a day for several years, but they nevertheless live at least 20 times longer than their sisters, the sterile workers. This discrepancy necessitates a critical reevaluation of the validity of both the trade-off concept as such, and of the current theories of aging. The widely accepted oxidative stress theory of aging with its links to metabolism and the insulin/IGF I system has been disproven in Caenorhabditis elegans and mice, but not in Drosophila, necessitating other approaches. The recent spermidine/mitophagy theory is gaining momentum. Two major mechanisms may have been largely overlooked, namely epigenetic control of longevity by imprinting through DNA methylation as suggested by recent data in the honey bee, and especially, a mechanism of which the principles are outlined here, the progressive weakening of the "electrical dimension" of cells up to the point of total collapse, namely death. PMID- 20920509 TI - Rhythmic beating of stem cell-derived cardiac cells requires dynamic coupling of electrophysiology and Ca cycling. AB - There is an intense interest in differentiating embryonic stem cells to engineer biological pacemakers as an alternative to electronic pacemakers for patients with cardiac pacemaker function deficiency. Embryonic stem cell-derived cardiocytes (ESCs), however, often exhibit dysrhythmic excitations. Using Ca(2+) imaging and patch-clamp techniques, we studied requirements for generation of spontaneous rhythmic action potentials (APs) in late-stage mouse ESCs. Sarcoplasmic reticulum (SR) of ESCs generates spontaneous, rhythmic, wavelet-like Local Ca(2+)Releases (LCRs) (inhibited by ryanodine, tetracaine, or thapsigargin). L-type Ca(2+)current (I(CaL)) induces a global Ca(2+) release (CICR), depleting the Ca(2+) content SR which resets the phases of LCR oscillators. Following a delay, SR then generates a highly synchronized spontaneous Ca(2+)release of multiple LCRs throughout the cell. The LCRs generate an inward Na(+)/Ca(2+)exchanger (NCX) current (absent in Na(+)-free solution) that ignites the next AP. Interfering with SR Ca(2+) cycling (ryanodine, caffeine, thapsigargin, cyclopiazonic acid, BAPTA-AM), NCX (Na(+)-free solution), or I(CaL) (nifedipine) results in dysrhythmic excitations or cessation of automaticity. Inhibition of cAMP/PKA signaling by a specific PKA inhibitor, PKI, decreases SR Ca(2+) loading, substantially reducing both spontaneous LCRs (number, size, and amplitude) and rhythmic AP firing. In contrast, enhancing PKA signaling by cAMP increases the LCRs (number, size, duration) and converts irregularly beating ESCs to rhythmic "pacemaker-like" cells. SR Ca(2+) loading and LCR activity could be also increased with a selective activation of SR Ca(2+) pumping by a phospholamban antibody. We conclude that SR Ca(2+) loading and spontaneous rhythmic LCRs are driven by inherent cAMP/PKA activity. I(CaL) synchronizes multiple LCR oscillators resulting in strong, partially synchronized diastolic Ca(2+) release and NCX current. Rhythmic ESC automaticity can be achieved by boosting "coupling" factors, such as cAMP/PKA signaling, that enhance interactions between SR and sarcolemma. PMID- 20920510 TI - Mitochondrial complex II participates in normoxic and hypoxic regulation of alpha keto acids in the murine heart. AB - alpha-Keto acids (alpha-KAs) are not just metabolic intermediates but are also powerful modulators of different cellular pathways. Here, we tested the hypothesis that alpha-KA concentrations are regulated by complex II (succinate dehydrogenase=SDH), which represents an intersection between the mitochondrial respiratory chain for which an important function in cardiopulmonary oxygen sensing has been demonstrated, and the Krebs cycle, a central element of alpha-KA metabolism. SDH subunit D heterozygous (SDHD(+/-)) and wild-type (WT) mice were housed at normoxia or hypoxia (10% O(2)) for 4 days or 3 weeks, and right ventricular pressure, right ventricle/(left ventricle+septum) ratio, cardiomyocyte ultrastructure, pulmonary vascular remodelling, ventricular complex II subunit expression, SDH activity and alpha-KA concentrations were analysed. In both strains, hypoxia induced increases in right ventricular pressure and enhanced muscularization of distal pulmonary arteries. Right ventricular hypertrophy was less severe in SDHD(+/-) mice although the cardiomyocyte ultrastructure and mitochondrial morphometric parameters were unchanged. Protein amounts of SDHA, SDHB and SDHC, and SDH activity were distinctly reduced in SDHD(+/-) mice. In normoxic SDHD(+/-) mice, alpha-ketoisocaproate concentration was lowered to 50% as compared to WT animals. Right/left ventricular concentration differences and the hypoxia-induced decline in individual alpha-KAs were less pronounced in SDHD(+/-) animals indicating that mitochondrial complex II participates in the adjustment of cardiac alpha-KA concentrations both under normoxic and hypoxic conditions. These characteristics are not related to the hemodynamic consequences of hypoxia-induced pulmonary vascular remodelling, since its extent and right ventricular pressure were not affected in SDHD(+/-) mice albeit right ventricular hypertrophy was attenuated. PMID- 20920511 TI - The therapeutic potential of heat shock proteins in cardiomyopathies due to mutations in cardiac structural proteins. PMID- 20920512 TI - The human amygdala is necessary for developing and expressing normal interpersonal trust. AB - The human amygdala is known to be involved in processing social, emotional, and reward-related information. Previous reports have indicated that the amygdala is involved in extracting trustworthiness information from faces. Interestingly, functional neuroimaging research using economic tasks that presumably require developing and/or expressing interpersonal trust, such as the Trust Game (TG), have not routinely identified involvement of the amygdala. The present study sought to explore the role of the amygdala in developing and expressing interpersonal trust, via a multi-round, multiplayer economic exchange, a version of the TG, in a large sample of participants with focal brain damage. Participants with unilateral damage to the amygdala displayed increased benevolent behavior in the TG, and specifically, they tended to increase trust in response to betrayals. On the other hand, neurologically normal adults tended to repay trust in kind, i.e., they decreased interpersonal trust in response to betrayals or increased trust in response to increases from others. Comparison participants, with brain damage that does not include the amygdala, ventromedial prefrontal or insular cortices, tended to behave ambivalently to the expressed trust or betrayal of others. Our data suggest that the amygdala is necessary for developing and expressing normal interpersonal trust. This increased tendency to behave benevolently in response to defections from others may be related to the abnormal social behavior observed in this group. Moreover, increased benevolence may increase the likelihood or opportunity to be taken advantage of by others. PMID- 20920514 TI - A review on the effects of environmental conditions on growth and toxin production of Ostreopsis ovata. AB - Since the end of the 1990s the occurrence of blooms of the benthic dinoflagellates Ostreopsis spp. is spreading in many tropical and temperate regions worldwide, sometimes causing benthonic biocenosis suffering and occasional human distress. Ostreopsis ovata has been found to produce palytoxin like compounds, a class of highly potent toxins. As general, the highest abundances of Ostreopsis spp. are recorded during warmer periods characterized by high temperature, salinity, and water column stability. Moreover, as these cells are easily resuspended in the water column, the role of hydrodynamism in the blooms development and decline has been highlighted. The environmental conditions appear, therefore, to be one of the main factors determining the proliferation of these species as testified by several field surveys. Laboratory studies on the effect of environmental parameters on growth and toxicity of O. ovata are rather scarce. With regard to the effects of temperature, culture results indicate that different strains blooming along Italian coasts displayed different optima, in accordance to blooming periods, and that higher toxin levels correlated with best growth conditions. Additionally, in relation to an Adriatic strain, cell growth positively correlated with the increase in salinity, while toxicity was lowest at the highest salinity value (i.e. 40). For the same strain, both nitrogen and phosphorus limitation determined a decrease in cell toxicity showing different behaviour with respect to many other toxic dinoflagellates. PMID- 20920515 TI - Electrophysiological characterization of a novel small peptide from the venom of Conus californicus that targets voltage-gated neuronal Ca2+ channels. AB - Conus californicus belongs to a genus of marine gastropods with more than 700 extant species. C. californicus has been shown to be distantly related to all Conus species, but showing unusual biological features. We report a novel peptide isolated from C. californicus with a significant inhibitory action over neuronal voltage-gated calcium channels. The new toxin is formed by 13-amino acid residues with two disulfide bonds, whose sequence (NCPAGCRSQGCCM) is strikingly different from regular omega-conotoxins. In the HPLC purification procedure, the venom fraction eluted in the first 10-15 min produced a significant decrease (54% +/- 3%) of the Ca(2+) current in Xenopus laevis oocytes transfected with purified rat brain mRNA. A specific peptide obtained from the elution at 13 min decreased the Ca(2+) current in the adult rat dorsal-root ganglion neurons in a primary culture by 34% +/- 2%. The cysteine pattern of this peptide corresponds to the framework XVI described for the M-superfamily of conopeptides and is unprecedented among Conus peptides acting on Ca(2+) channels. PMID- 20920513 TI - The amygdala and decision-making. AB - Decision-making is a complex process that requires the orchestration of multiple neural systems. For example, decision-making is believed to involve areas of the brain involved in emotion (e.g., amygdala, ventromedial prefrontal cortex) and memory (e.g., hippocampus, dorsolateral prefrontal cortex). In this article, we will present findings related to the amygdala's role in decision-making, and differentiate the contributions of the amygdala from those of other structurally and functionally connected neural regions. Decades of research have shown that the amygdala is involved in associating a stimulus with its emotional value. This tradition has been extended in newer work, which has shown that the amygdala is especially important for decision-making, by triggering autonomic responses to emotional stimuli, including monetary reward and punishment. Patients with amygdala damage lack these autonomic responses to reward and punishment, and consequently, cannot utilize "somatic marker" type cues to guide future decision making. Studies using laboratory decision-making tests have found deficient decision-making in patients with bilateral amygdala damage, which resembles their real-world difficulties with decision-making. Additionally, we have found evidence for an interaction between sex and laterality of amygdala functioning, such that unilateral damage to the right amygdala results in greater deficits in decision-making and social behavior in men, while left amygdala damage seems to be more detrimental for women. We have posited that the amygdala is part of an "impulsive," habit type system that triggers emotional responses to immediate outcomes. PMID- 20920516 TI - Late hematologic toxicity following treatment of rattlesnake envenomation with crotalidae polyvalent immune Fab antivenom. AB - BACKGROUND: North American rattlesnake envenomations commonly produce defibrination, coagulopathy and/or thrombocytopenia, which may be reversed following treatment with Crotalidae Polyvalent Immune Fab Ovine (FabAV). Despite initial resolution with FabAV, late onset or recurrence of venom-induced hematologic effects may occur. Time at which onset of late hematotoxicity may first be detected is unknown. The purpose of this study was to identify the incidence and time of onset of recurrent or new late hypofibrinogenemia, coagulopathy, or thrombocytopenia in a cohort of rattlesnake envenomation patients seen in outpatient follow-up after treatment with FabAV, and to report hematologic outcomes in these patients. METHODS: Review of 66 charts of patients with rattlesnake envenomation who were treated with FabAV, and subsequently had outpatient follow-up evaluation at least 48 h after last FabAV, was performed. Demographic information, rattlesnake and bite characteristics, dose and timing of antivenom administration, adverse events, in-patient laboratory values, length of hospital stay, and follow-up laboratory values were collected. The primary outcome parameters were recurrent or delayed onset coagulopathy, hypofibrinogenemia, or thrombocytopenia identified no sooner than 48 h after last dose of FabAV. RESULTS: Prior to control of the envenomation with FabAV, 42 patients (63.6%) experienced hematologic toxicity. At follow-up, 21 patients (32%) were found to have late coagulopathy, hypofibrinogenemia, or thrombocytopenia. Of twenty-three patients (35%) with more than one follow-up visit, fifteen had normal laboratory findings at the first follow-up visit. Five of these 15 patients (8% of total study group; 33% of this subgroup) with normal hematologic studies at first follow-up exhibited late hematologic toxicity at second follow-up. Severe late hematologic toxicity developed in five of 66 (8%) patients. One patient was retreated with FabAV for late severe thrombocytopenia. CONCLUSION: Recurrent and delayed onset of hematologic toxicity in rattlesnake envenomation victims treated with FabAV is common. Follow-up more than three days after treatment is necessary to detect all cases of late hematologic toxicity. PMID- 20920518 TI - Topology modification for surgical simulation using precomputed finite element models based on linear elasticity. AB - Surgical simulators provide another tool for training and practising surgical procedures, usually restricted to the use of cadavers. Our surgical simulator utilises Finite Element (FE) models based on linear elasticity. It is driven by displacements, as opposed to forces, allowing for realistic simulation of both deformation and haptic response at real-time rates. To achieve demanding computational requirements, the stiffness matrix K, which encompasses the geometrical and physical properties of the object, is precomputed, along with K 1. Common to many surgical procedures is the requirement of cutting tissue. Introducing topology modifications, such as cutting, into these precomputed schemes does however come as a challenge, as the precomputed data needs to be modified, to reflect the new topology. In particular, recomputing K-1 is too costly to be performed during the simulation. Our topology modification method is based upon updating K-1 rather than entirely recomputing the matrix. By integrating condensation, we improve efficiency to allow for interaction with larger models. We can further enhance this by redistributing computational load to improve the system's real-time response. We exemplify our techniques with results from our surgical simulation system. PMID- 20920517 TI - Contributions of ideal observer theory to vision research. AB - An ideal observer is a hypothetical device that performs optimally in a perceptual task given the available information. The theory of ideal observers has proven to be a powerful and useful tool in vision research, which has been applied to a wide range of problems. Here I first summarize the basic concepts and logic of ideal observer analysis and then briefly describe applications in a number of different areas, including pattern detection, discrimination and estimation, perceptual grouping, shape, depth and motion perception and visual attention, with an emphasis on recent applications. Given recent advances in mathematical statistics, in computational power, and in techniques for measuring behavioral performance, neural activity and natural scene statistics, it seems certain that ideal observer theory will play an ever increasing role in basic and applied areas of vision science. PMID- 20920519 TI - SSR181507, a dopamine D2 receptor and 5-HT(1A) receptor ligand: evidence for mixed anxiolytic- and antidepressant-like activities. AB - SSR181507, a dopamine D2 receptor antagonist/partial agonist and 5-HT(1A) receptor agonist, is active in animal models of schizophrenia. Furthermore, it shows activity in several anxiety and/or depression models (Depoortere et al. 2003). Presently, we sought to further characterize the latter two activities in rats, using a step-down passive avoidance procedure, a shock-induced ultrasonic vocalization (UV) test in adult subjects and a social interaction test. SSR181507 (0.3 & 1 mg/kg ip), but not the atypical antipsychotics clozapine and olanzapine, decreased the latency time to step-down from a "safety" platform. Effects of SSR181507 were reversed by the selective 5-HT(1A) receptor antagonist SL88.0338. SSR181507 also reduced UV (0.3 & 1 mg/kg ip), an effect not reversed by SL88.0338, and observed with olanzapine, haloperidol, fluoxetine and the 5-HT(1A) receptor agonists 8-OH-DPAT and buspirone, but not diazepam. Furthermore, SSR181507 remained active following 3 weeks of administration (1 mg/kg ip, once daily) in the UV test. Lastly, SSR181507 (3 mg/kg ip) potentiated social interaction, an effect shared by diazepam and buspirone, but not by olanzapine, clozapine, haloperidol and 8-OH-DPAT. These data further strengthen previous findings that the putative atypical antipsychotic SSR181507 has mixed antidepressant and anxiolytic activities. PMID- 20920520 TI - How to analyze longitudinal multilevel physical activity data with many zeros? AB - BACKGROUND: Physical activity (PA) is a modifiable lifestyle factor for many chronic diseases with established health benefits. PA outcomes are measured and assessed in many longitudinal studies, but their analyses often pose difficulties due to the presence of many zeros, extreme skewness, and lack of independence, which render standard regression methods inappropriate. METHODS: A two-part multilevel modeling approach is used to analyze the heterogeneous and correlated PA data. In the first part, a logistic mixed regression model is fitted to estimate the prevalence of PA and factors associated with PA participation over time. For subjects engaging in PA, a gamma mixed regression model is adopted in the second part to assess the effects of predictor variables on the repeated PA outcomes nested within clusters. Extra variations are accommodated within the modeling process by random effects assigned to each cluster and each subject in the cohort. RESULTS: The findings in a longitudinal multilevel study of a community-based PA intervention for older adults demonstrate the effectiveness of the intervention program and enable the identification of pertinent factors affecting participation and PA levels over time. CONCLUSIONS: The two-part mixed regression approach provides a practical and statistically valid method to analyze the skewed and correlated PA data with many zeros. The methodology can be extended to handle complex hierarchical or multilevel settings by suitable specification of the covariance structure in the random components, model fitting of which can be performed in STATA using GLLAMM with various user-specified options. PMID- 20920521 TI - Comparison of women's breast cancer risk factors in Geneva, Switzerland and Shanghai, China. AB - BACKGROUND: We compared the prevalence of known and suspected breast cancer risk factors among women in Geneva, Switzerland, where the annual incidence of breast cancer is high, to women in Shanghai, China, where incidence is lower. METHODS: Different translations of the same woman's health questionnaire were administered to women aged 35 to 74 years in Shanghai (n=631) and Geneva (n=1,212) during 1996 1997 and reproductive and lifestyle factors compared. RESULTS: Shanghai women reported older age at menarche (median 15 vs. 13 years), fewer nulliparity (7.3 vs. 21.6%), younger age at first live birth (median 25.7 vs. 28.4 years), and shorter duration of reproductive life (median 35.7 vs. 38.4 years). Geneva women had a greater prevalence of current cigarette smoking (22.4 vs. 1.8%), oral contraceptive use (61.1 vs. 10.0%), hormone replacement therapy use (23.4 vs. 0.8%), and family history of breast cancer (8.6 vs. 1.4%). Among women who breastfed, Shanghai women had more than twice the duration of breastfeeding than Geneva women (median 48 vs. 21 weeks). CONCLUSIONS: Differences in the prevalence of breast cancer risk factors, in particular reproductive characteristics, may contribute to the large contrast in cumulative risk between women living in Geneva and Shanghai. PMID- 20920522 TI - Influence of laminarin polysaccahrides on oxidative damage. AB - Laminarin is a tropical plant traditionally used in Chinese medicine. In this experiment, Laminarin polysaccharides were analysed using GC-MS method and result showed that the polysaccharides contained mannose (3.27%), arabinose (8.61%), glucose (4.23%), galactose (12.12%), fucose (46.93%). Laminarin polysaccharides were tested to evaluate their effect on lung oxidative stress and lipid peroxidation in rats. The animal were divided into model and polysaccharides treated animal. Laminarin polysaccharides were administered by gavage over a 14 day period. The results indicated that Laminarin polysaccharides significantly normalized catalase (CAT) activity (P<0.01), increased glutathione peroxidase (GPx) activity (P<0.05), superoxide dismutase (SOD) activity and reduced malondialdehyde (MDA) concentrations in animal. It could be concluded that Laminarin polysaccharides appeared to be more effective in reducing sepsis induced oxidative stress, lipid peroxidation in animal. PMID- 20920523 TI - Molecular characterization and enzymatic hydrolysis of naringin extracted from kinnow peel waste. AB - Kinnow peel, a waste rich in glycosylated phenolic substances, is the principal by-product of the citrus fruit processing industry and its disposal is becoming a major problem. This peel is rich in naringin and may be used for rhamnose production by utilizing alpha-L-rhamnosidase (EC 3.2.1.40), an enzyme that catalyzes the cleavage of terminal rhamnosyl groups from naringin to yield prunin and rhamnose. In this work, infrared (IR) spectroscopy confirmed molecular characteristics of naringin extracted from kinnow peel waste. Further, recombinant alpha-L-rhamnosidase purified from Escherichia coli cells using immobilized metal-chelate affinity chromatography (IMAC) was used for naringin hydrolysis. The purified enzyme was inhibited by Hg2+ (1 mM), 4 hydroxymercuribenzoate (0.1 mM) and cyanamide (0.1 mM). The purified enzyme established hydrolysis of naringin extracted from kinnow peel and thus endorses its industrial applicability for producing rhamnose. PMID- 20920525 TI - Physical properties of edible emulsified films based on carboxymethyl cellulose and oleic acid. AB - Glycerol and oleic acid (OA) were incorporated into carboxymethyl cellulose (CMC) films by an emulsification method. Films containing different amounts of glycerol and OA were examined for mechanical properties, water vapor permeability (WVP), and moisture uptake, optical and thermal properties. Addition of OA to the CMC films significantly improved the barrier property. However, the effect of OA on the mechanical properties was lower than glycerol. By increasing of OA content, the cloudiness of the CMC films was intensified and Hunter value (b) of the films increased (by ca. 35.8%). PMID- 20920524 TI - Bacterial cellulose nanocrystals exhibiting high thermal stability and their polymer nanocomposites. AB - Nanocrystals prepared from bacterial cellulose are considered as 'green nanomaterials' depending on their renewable nature and ease of production without the involvement of hazardous chemical treatments. In this investigation, a top down approach was followed for the preparation of bacterial cellulose nanocrystals (BCNC) using a commercially available cellulase enzyme so as to retain native properties of bacterial cellulose even in its nanodimensional form. The morphological and dimensional parameters of BCNC were studied using atomic force microscope (AFM) and transmission electron microscope (TEM). Thermal properties of BCNC produced using the novel enzyme treatment and conventional sulfuric acid hydrolysis were compared. The thermal stability of enzyme processed BCNC was almost two fold higher than sulfuric acid processed ones. Further, the activation energy required for decomposition of enzyme processed BCNC was much higher than the other. Using this enzyme processed BCNC, Polyvinylalcohol (PVA) nanocomposite films were prepared and characterized. Incorporation of these nanocrystals in polymer matrix resulted in a remarkable improvement in the thermal stability as well as mechanical properties of nanocomposite films. These nanocomposites exhibited higher melting temperature (Tm) and enthalpy of melting (DeltaHm) than those of pure PVA, suggesting that the addition of nanocrystals modified the thermal properties of PVA. The effective load transfer from polymer chains to the BCNC resulted in an improved tensile strength from 62.5 MPa to 128 MPa, by the addition of just 4 wt% of BCNC. Furthermore, the elastic modulus was found to increase from 2 GPa to 3.4 GPa. The BCNC obtained through cellulose treatment under controlled conditions were associated with several desirable properties and appear to be superior over the conventional methods of nanocrystals production. The enzymatic method followed in this study is expected to contribute the fabrication of high performance polymer nanocomposites in a much greener and innovative manner. PMID- 20920526 TI - Characterization and immune function of two intracellular sensors, HmTLR1 and HmNLR, in the injured CNS of an invertebrate. AB - Unlike mammals, the CNS of the medicinal leech can regenerate damaged neurites, thus restoring neural functions. Our group recently demonstrated that the injured leech nerve cord is able to mount an immune response, which promotes the regenerative processes. This defense mechanism is microorganism-specific, suggesting that the leech CNS is able to discriminate among microbial components. We report here the characterization of two receptors potentially implicated in this detection: HmTLR1 and HmNLR. Interestingly, HmTLR1 presents an endosomal distribution in neurons and appears as a chimera combining the mammalian intraendosomal domain of TLR3 and the cytoplasmic section of TLR13, while HmNLR is cytosolic and has the highest homology to NLRC3 receptors. Both receptors show patterns of induction upon stimulation that suggest their involvement in the leech neuroimmune response. This work constitutes the first demonstration in an invertebrate of (i) an intracellular TLR and (ii) a cytosolic PRR related to the NLR family. PMID- 20920527 TI - Alkhumra (Alkhurma) virus outbreak in Najran, Saudi Arabia: epidemiological, clinical, and laboratory characteristics. AB - OBJECTIVE: After its first appearance in Alkhumra district of Jeddah in 1994 1995, and then in Makkah in 2001-2003, the new hemorrhagic fever virus, known as Alkhumra (misnamed as Alkhurma) virus (ALKV), has subsequently been reported from Najran, in the south border of Saudi Arabia. METHODS: This is a descriptive cohort study summarizing the epidemiological, clinical, and laboratory characteristics of ALKV infected patients diagnosed in Najran from 1 August 2003 through 31 December 2009. RESULTS: A total of 148 suspected cases were reported, of which 78 (52.7%) cases were laboratory confirmed; 2 cases in 2003, 1 case in 2004, 4 cases in 2005, 1 case in 2007, 12 cases in 2008, and 58 cases in 2009. The cases were reported year round but 64.1% (50/78) of them occurred in the summer time. Twenty-five (32.1%) cases occurred as clusters in 5 families. The virus seemed to be transmitted from livestock animals to humans by direct contact with these animals and likely by mosquito bites. Ticks did not seem to be involved in the transmission of infection from animals to humans. Clinical and laboratory features included fever (100%), headache (85.9%), malaise (85.9%), arthralgia (83.3%), anorexia (82.1%), myalgia (82.1%), backache (71.8%), nausea and vomiting (71.8%), chills (60.3%), retro-orbital pain (55.1%), diarrhea (51.3%), abdominal pain (48.7%), hemorrhagic manifestations (25.6%), central nervous system manifestations (23.1%), leucopenia (87.7%), elevated liver enzymes (85.7%), prolonged partial thromboplastin time (52.6%), thrombocytopenia (46.2%), elevated creatine kinase level (45.7%), and elevated lactate dehydrogenase (25.0%). CONCLUSION: ALKV infection has now been recognized outside its original boundaries in Saudi Arabia which may herald its identification in other countries. PMID- 20920528 TI - Adipocytokines, cardiovascular pathophysiology and myocardial protection. AB - Reducing myocardial damage resulting from ischaemia-reperfusion (I/R) is vital in ensuring patient recovery and survival. It relies upon the activation of the so called Reperfusion Injury Salvage Kinase (RISK) pathway. Experimentally various treatments, both mechanical and chemical, have been shown to protect the myocardium against I/R injury. Chemical facilitators of myocardial preservation include endogenous factors such as insulin, erythropoietin and glucagon-like peptide 1. The adipocytokines, products of white adipose tissue, are important peptide hormones with respect to metabolic control and satiety, and were formerly considered in the context of obesity and metabolic disease. More recently, however, evidence has been presented indicating that the adipocytokines play significant roles in cardiac function and, as we have suggested, in myocardial protection. To date leptin, adiponectin, apelin and visfatin have all been shown to protect against I/R injury. Significantly, the protection afforded by these peptides involves the activation of kinases which are key elements of the mechanisms underlying tissue preservation, including the RISK pathway components PI3K-Akt and p44/42, and inhibition of the mitochondrial permeability transition pore (MPTP). In this article we examine the roles played by the adipocytokines in cardiovascular function and disease. In particular, we focus on the evidence that these peptides promote myocardial survival, much of it having been obtained in this laboratory. To conclude, we discuss some future directions in the field, including the prospects for some of the adipocytokines finding application as therapeutic agents in myocardial infarction. PMID- 20920529 TI - Roles of prostanoids in the pathogenesis of cardiovascular diseases: Novel insights from knockout mouse studies. AB - Prostanoids consisting of prostaglandins (PGs) and thromboxanes (TXs) are produced from arachidonic acids, representative fatty acids contained in cell membrane, by the sequential actions of phospholipase A(2), cyclooxygenases and respective prostanoid synthases. Prostanoids are released outside of the cells immediately after biosynthesis and exert a wide range of actions in the body. These actions are mediated by their respective G protein-coupled receptors expressed in the target cells, which receptors include the DP, EP, FP, IP and TP receptors for PGD(2), PGE(2), PGF(2)alpha, PGI(2) and TXA(2), respectively. In addition, there are four subtypes of the EP receptors: EP(1), EP(2), EP(3) and EP(4). Recently, roles of prostanoids in the pathogenesis of cardiovascular diseases have been widely examined using mice lacking each prostanoid receptor individually or enzyme participating in prostanoid biosynthesis. These studies have revealed important and novel roles of prostanoids in the development of cardiovascular diseases, such as acute myocardial infarction, cardiac hypertrophy, atherosclerosis, vascular remodeling, hypertension and cerebral thrombosis. Roles of prostanoids in the generation of inflammatory tachycardia and the regulation of platelet function have also been clarified. In this review, we summarize these roles of prostanoids revealed from knockout mouse studies. PMID- 20920530 TI - Dabigatran etexilate versus warfarin as the oral anticoagulant of choice? A review of clinical data. AB - For many years, warfarin was the only effective oral anticoagulant to prevent and treat thromboembolism. Nevertheless, its clinical use is limited by a narrow therapeutic window, extensive drug interactions, need of strict dietary control and frequent monitoring. The pharmacological response is also unpredictable and highly variable among patients. Suboptimal anticoagulation can lead to detrimental thromboembolic events or life-threatening bleeding. Direct thrombin inhibitor (DTI) activity represents a new class of anticoagulant activity that was intended to replace warfarin. Ximelagatran was the first DTI shown to have similar efficacy to warfarin, but failed to replace it because of a high incidence of liver toxicity. Dabigatran etexilate is another novel DTI with a more predictable pharmacokinetic profile and fewer drug interactions compared with warfarin. Recent large-scaled, randomized studies have shown that it does not share ximelagatran's hepatotoxicity, and is as effective as conventional anticoagulants for venous thromboembolism (VTE) and prophylaxis in atrial fibrillation (AF). These findings led to the approval of dabigatran etexilate for thromboprophylaxis following hip or knee replacement surgery in Europe, Canada and the United Kingdom. Here we summarize the latest evidence concerning the use of dabigatran etexilate in VTE (BISTRO, RE-MODEL, RE-NOVATE, RE-MOBILIZE and RECOVER) and AF (PETRO and RELY). Potential problems related to dabigatran use are also discussed to examine whether it can truly replace warfarin as the gold standard. PMID- 20920531 TI - A role for hypocretin/orexin in motivation. AB - Obesity and drug addiction, both a result of aberrant motivated behavior, are growing problems in western society. Increased dopamine neurotransmission occurs with both drug-seeking and ingestive behaviors and has been linked to effort related functions. Hypocretin/orexin (Hcrt/ox) neurons have long been known to mediate arousal and feeding. Over the last 5 years, hcrt/ox has been demonstrated to play a novel role in mediating a variety of reward-seeking behaviors and can modulate the activity and output of dopamine neurons. Here, we propose that hcrt/ox action on mesolimbic dopamine circuitry serves to promote effort to obtain highly salient natural or drug rewards. PMID- 20920532 TI - Interaction between early postnatal neurosteroid manipulations and adult infusion of neurosteroids into CA1 hippocampal region on the open field behaviour. AB - Recent findings suggest that neurosteroids acting as GABAA modulators, as allopregnanolone (AlloP), not only play an important role in brain development, especially in the maturation of the hippocampus, but also in adult behaviour. The aim of the present work is to investigate whether the effects of adult CA1 intrahippocampal administrations of AlloP and pregnenolone sulphate (PregS), GABAA positive and negative modulators, respectively, on behavioural novelty responses measured in the open field test can be different depending on neonatal alterations (increase or decrease) of physiological AlloP levels. Rat pups received AlloP and a 5alpha-reductase inhibitor (finasteride) from the fifth to the ninth postnatal day. At maturity, a bilateral cannula was implanted into the hippocampus (CA1). Intrahippocampal AlloP and PregS decreased total locomotor activity in neonatal control rats. Instead, in neonatal AlloP rats only PregS decreased open field activity, whereas in neonatal finasteride rats the intrahippocampal injections (AlloP and PregS) did not affect locomotor activity. Also, the decrease in activity induced by PregS infusion was higher in neonatal AlloP rats than in controls. However, neonatal treatments did not affect any of the anxiety scores. Although intrahippocampal AlloP and PregS decreased inner activity and time spent in the first 5 min independently of the neonatal treatment, the extremely low inner values do not allow a conclusion of anxiogenic effects. Results indicate that neonatal AlloP administration potentiates and neonatal finasteride decreases the effects of adult intrahippocampal PregS administration on open field locomotion, suggesting neurobiological adaptations that remain until adult age. PMID- 20920533 TI - Evidence that the reward attenuating effect of the D1-like antagonist, SCH-23390, is not mediated by its agonist action at the 5-HT2c receptors. AB - This study investigated the effect of the 5-HT2c receptor antagonist, SB-242,084, on the attenuation of brain stimulation reward by SCH-23390. An additional experiment determined the effectiveness of SB-242,084 at blocking the reward attenuating effect of 5-HT2c agonist, CP-809,101. Results show that SB-242,084 blocked the reward attenuating effect of CP-809,101 but failed to alter that of SCH-23390. These findings provide evidence that the agonist action of SCH-23390 at the 5-HT2c receptors does not contribute to its attenuating effect on reward. PMID- 20920534 TI - Reprint of: Chromogranin A: a new proposal for trafficking, processing and induction of granule biogenesis. AB - Chromogranin A (CgA), a member of the granin family serves several important cell biological roles in (neuro)endocrine cells which are summarized in this review. CgA is a "prohormone" that is synthesized at the rough endoplasmic reticulum and transported into the cisternae of this organelle via its signal peptide. It is then trafficked to the Golgi complex and then to the trans-Golgi network (TGN) where CgA aggregates at low pH in the presence of calcium. The CgA aggregates provide the physical driving force to induce budding of the TGN membrane resulting in dense core granule (DCG) formation. Within the granule, a small amount of the CgA is processed to bioactive peptides, including a predicted C terminal peptide, serpinin. Upon stimulation, DCGs undergo exocytosis and CgA and its derived peptides are released. Serpinin, acting extracellularly is able to signal the increase in transcription of a serine protease inhibitor, protease nexin-1 (PN-1) that protects DCG proteins against degradation in the Golgi complex, which then enhances DCG biogenesis to replenish those that were released. Thus CgA and its derived peptide, serpinin, plays a significant role in granule formation and regulation of granule biogenesis, respectively, in (neuro) endocrine cells. PMID- 20920535 TI - Phosphorylation/dephosphorylation of human SULT4A1: role of Erk1 and PP2A. AB - SULT4A1 is a cytosolic sulfotransferase that shares little homology with other human sulfotransferases but is highly conserved between species. It is found in neurons located in several regions of the brain. Recently, the stability of SULT4A1 was shown to be regulated by Pin1, a peptidyl-prolyl cis-trans isomerase implicated in several neurodegenerative diseases. Since Pin1 binds preferentially to phosphoproteins, these findings suggested that SULT4A1 is post-translationally modified. In this study, we show that the Thr(11) residue of SULT4A1, which is involved in Pin1 binding is phosphorylated. MEK inhibition was shown to abolish Pin1 mediated degradation of SULT4A1 while in vitro phosphorylation assays using alanine substitution mutants of SULT4A1 demonstrated phosphorylation of Thr(11) by ERK1. We also show that dephosphorylation was catalyzed by the protein phosphatase 2A. The PP2A regulatory subunit, Bbeta was identified from a yeast-2 hybrid screen of human brain cDNA as a SULT4A1 interacting protein. This was further confirmed by GST pull-downs and immunoprecipitation. Other members of the B subunit (alpha??delta??gamma) did not interact with SULT4A1. Taken together, these studies indicate that SULT4A1 stability is regulated by post-translational modification that involves the ERK pathway and PP2A. The phosphorylation of SULT4A1 allows interaction with Pin1, which then promotes degradation of the sulfotransferase. PMID- 20920537 TI - PCR-linked reverse DNA hybridization using oligonucleotide-specific probes of rpoB for identification of Mycobacterium avium and Mycobacterium intracellulare. AB - A PCR-linked reverse DNA hybridization method using two different specific rpoB DNA probes (Avp and Intp) of Mycobacterium avium and Mycobacterium intracellulare, respectively, were evaluated for the differentiation and identification of M. avium and M. intracellulare culture isolates. Among the 504 culture isolates tested by this method, 48 strains showed positive results for M. avium and 60 strains showed positive results for M. intracellulare. The other 396 culture isolates showed negative results for both M. avium and M. intracellulare. These results were consistent with those obtained from partial rpoB (306 bp) sequence analysis and biochemical tests. The negative strains obtained by this DNA hybridization method were identified as M. tuberculosis (366 strains), M. peregrinum (11 strains), M. abscessus (9 strains), M. fortuitum (8 strains), and M. flavescens (2 strains) by rpoB DNA sequence analysis. Due to the high sensitive and specific result obtained by this assay, we suggest that this PCR linked reverse DNA hybridization method using two different specific rpoB DNA probes of M. avium and M. intracellulare would be used for the rapid and precise method for differentiation and identification of M. avium and M. intracellulare. PMID- 20920536 TI - Role of hypoxia and EGF on expression, activity, localization and phosphorylation of carbonic anhydrase IX in MDA-MB-231 breast cancer cells. AB - Carbonic anhydrase IX (CAIX) is a zinc metalloenzyme that catalyzes the reversible hydration of CO(2). CAIX is overexpressed in many types of cancer, including breast cancer, but is most frequently absent in corresponding normal tissues. CAIX expression is strongly induced by hypoxia and is significantly associated with tumor grade and poor survival. Herein, we show that hypoxia induces a significant increase in CAIX protein in MDA-MB-231 breast cancer cells. Using a unique mass spectrophotometric assay, we demonstrate that CAIX activity in plasma membranes isolated from MDA-MB-231 is correlated with CAIX content. We also show that CAIX exists predominantly as a dimeric, high-mannose N-linked glycoprotein. While there is some evidence that the dimeric form resides specifically in lipid rafts, our data do not support this hypothesis. EGF, alone, did not affect the distribution of CAIX into lipid rafts. However, acute EGF treatment in the context of hypoxia increased the amount of CAIX in lipid rafts by about 5-fold. EGF did not stimulate tyrosine phosphorylation of CAIX, although EGFR and down-stream signaling pathways were activated by EGF. Interestingly, hypoxia activated Akt independent of EGF action. Together, these data demonstrate that the active form of CAIX in the MDA-MB-231 breast cancer cell line is dimeric but that neither lipid raft localization nor phosphorylation are likely required for its dimerization or activity. PMID- 20920538 TI - In vitro anaerobic biofilms of human colonic microbiota. AB - The human gastrointestinal tract hosts a complex community of microorganisms that grow as biofilms on the intestinal mucosa. These bacterial communities are not well characterized, although they are known to play an important role in human health. This study aimed to develop a model for culturing biofilms (surface adherent communities) of intestinal microbiota. The model utilizes adherent mucosal bacteria recovered from colonic biopsies to create multi-species biofilms. Culture on selective media and confocal microscopy indicated the biofilms were composed of a diverse community of bacteria. Molecular analyses confirmed that several phyla were represented in the model, and demonstrated stability of the community over 96 h when cultured in the device. This model is novel in its use of a multi-species community of mucosal bacteria grown in a biofilm mode of growth. PMID- 20920539 TI - PACAP up-regulates the expression of apolipoprotein D in 3T3-L1 adipocytes. DRG/3T3-L1 co-cultures study. AB - The existence of a cross-talk between nerves and fatty tissue is increasingly recognized. Using co-cultures of dorsal root ganglion (DRG)-derived cells and 3T3 L1 adipocytes, we have previously shown that the presence of fat cells enhances neurite outgrowth and number of synapses. Vice versa, neural cells induced expression of neurotrophic adipokines apolipoprotein D and E (ApoD, ApoE) and angiopoietin-1 (Ang-1) by adipocytes. Here, we tested whether pituitary adenylate cyclase-activating peptide (PACAP), which is released by sensory fibres and causes Ca(2+) influx into fat cells, is involved in ApoD induction. Using 3T3-L1 cell cultures, we found that PACAP at a dose of 1 nM up-regulated the expression of ApoD protein and mRNA approx. 2.5 fold. This effect was driven by ERK1/2 acting upon PAC1/VPAC2 receptors. In turn, PACAP-treated 3T3-L1 adipocytes in co cultures with DRG cells enhanced neurite ramification of neurofilament 200 (NF200)-positive neurons (measured using fluorescence microscopy) and neurofilament 68 protein levels (measured using Western blot analysis). This effect could be blocked using the PAC1/VPAC2 antagonist PACAP(6-38). Scanning cytometry revealed PACAP/ApoD induced low density lipoprotein receptors (LDLR) and ApoE receptor 2 (apoER2) in NF200-positive cells. Thus, a bidirectional loop seems to exist regulating the innervation of fatty tissues: PACAP released from sensory fibres might stimulate fat cells to synthesize neurotrophic adipokines, which, in turn, support peripheral innervation. PMID- 20920541 TI - The Wnt signaling pathway in cellular proliferation and differentiation: A tale of two coactivators. AB - Wnt signaling pathways play divergent roles during development, normal homeostasis and disease. The responses that result from the activation of the pathway control both proliferation and differentiation. Tight regulation and controlled coordination of the Wnt signaling cascade is required to maintain the balance between proliferation and differentiation. The non-redundant roles of the coactivator proteins CBP and p300, within the context of Wnt signaling are discussed. We highlight their roles as integrators of the various inputs that a cell receives to elicit the correct and coordinated response. We propose that essentially all cellular information - i.e. from other signaling pathways, nutrient levels, etc. - is funneled down into a choice of coactivators usage, either CBP or p300, by their interacting partner beta-catenin (or catenin-like molecules in the absence of beta-catenin) to make the critical decision to either remain quiescent, or once entering cycle to proliferate without differentiation or to initiate the differentiation process. PMID- 20920542 TI - Computational analysis for hepatic safety signals of constituents present in botanical extracts widely used by women in the United States for treatment of menopausal symptoms. AB - Black cohosh, red clover, hops, and chasteberry are botanicals commonly used to alleviate menopausal symptoms in the US, and are examined in this study as part of a FDA Office of Women's Health research collaboration to expand knowledge on the safety of these botanical products. Computational approaches using classic (quantitative) structure-activity relationships ((Q)SAR), probabilistic reasoning, machine learning methods, and human expert rule-based systems were employed to deliver human hepatobiliary adverse effect predictions. The objective is to profile and analyze constituents that are alerting for the human hepatobiliary adverse effects. Computational analysis of positively predicted constituents showed that common structural features contributing to the hepatobiliary adverse effect predictions contain phenolic, flavone, isoflavone, glucoside conjugated flavone and isoflavone, and 4-hydroxyacetophenone structures. Specifically, protocatechuic acid from black cohosh, benzofuran and 4 vinylphenol from chasteberry, and xanthohumol I from hops were botanical constituents predicted positive for liver toxicity endpoints and were also confirmed with literature findings. However, comparison between the estimated human exposure to these botanical constituents and the LOAEL and NOAEL in published animal liver toxicology studies for these constituents demonstrated varying margins of safety. This study will serve as regulatory decision support information for regulators at the FDA to help with the process of prioritizing chemicals for testing. PMID- 20920540 TI - Mesenchymal stem cells for the sustained in vivo delivery of bioactive factors. AB - Mesenchymal stem cells (MSC) are a promising tool for cell therapy, either through direct contribution to the repair of bone, tendon and cartilage or as an adjunct therapy through protein production and immune mediation. They are an attractive vehicle for cellular therapies due to a variety of cell intrinsic and environmentally responsive properties. Following transplantation, MSC are capable of systemic migration, are not prone to tumor formation, and appear to tolerize the immune response across donor mismatch. These attributes combine to allow MSC to reside in many different tissue types without disrupting the local microenvironment and, in some cases, responding to the local environment with appropriate protein secretion. We describe work done by our group and others in using human MSC for the sustained in vivo production of supraphysiological levels of cytokines for the support of cotransplanted hematopoietic stem cells and enzymes that are deficient in animal models of lysosomal storage disorders such as MPSVII. In addition, the use of MSC engineered to secrete protein products has been reviewed in several fields of tissue injury repair, including but not limited to revascularization after myocardial infarction, regeneration of intervertebral disc defects and spine therapy, repair of stroke, therapy for epilepsy, skeletal tissue repair, chondrogenesis/knee and joint repair, and neurodegenerative diseases. Genetically engineered MSC have thus proven safe and efficacious in numerous animal models of disease modification and tissue repair and are poised to be tested in human clinical trials. The potential for these interesting cells to secrete endogenous or transgene products in a sustained and long-term manner is highly promising and is discussed in the current review. PMID- 20920543 TI - Paliperidone-induced leukopenia and neutropenia: a case report. PMID- 20920544 TI - Effects of Salacia chinensis extract on reproductive outcome in rats. AB - Salaciachinensis is a traditional South and Southeast Asian herb medicine and has been reported to have an antidiabetic function via alpha-glucosidases inhibitory activity. In this study, the effects of S. chinensis extract (SCE) on reproductive functions of F0 males and females and the effects on survival and growth of F1 offspring were examined using Sprague-Dawley rats. SCE was administered at dose levels of 0, 500, 1000 and 2000 mg/kg/day orally to groups consisting of 25 males and 25 females. Males were dosed once a day in the morning from 8 weeks before mating, throughout the mating period and until the day before necropsy and females were dosed once a day in the morning for 2 weeks before mating and through the mating, gestation and lactation periods (until day 20 of lactation). In all SCE treatment groups, no toxic signs were noted on reproductive outcome such as estrous cycle of F0 females or any parameters for reproductive function or survival, growth, sensory reflex or function development of F1 pups. Therefore, we concluded that SCE has no effects on the reproductive outcome even at a remarkably high dosage level, 2000 mg/kg/day, in Sprague-Dawley rats. PMID- 20920545 TI - Gene expression profiling of DEHP-treated cardiomyocytes reveals potential causes of phthalate arrhythmogenicity. AB - BACKGROUND: Di-(2-ethylhexyl)-phthalate (DEHP) is a widely used plasticizer that imparts flexibility to polyvinyl chloride. We have recently reported that clinically relevant concentrations of DEHP can affect electrical coupling between cardiac myocytes causing significant rhythm disturbances. The underlying causes for this effect are currently unknown. OBJECTIVES: To use data on global mRNA expression as a tool to reveal possible pathways leading to arrhythmogenic effects of DEHP. METHODS: Rat neonatal cardiomyocytes were treated with 50 MUg/mL DEHP for 72 h. Extracted RNA samples were hybridized onto Affymetrix Rat Gene 1.0 ST arrays. The mRNA expression of a subset of genes was validated by qRT-PCR. In a second set of experiments, cells were treated in a concentration dependent manner to identify genes affected by low DEHP concentrations. RESULTS: DEHP exposure is associated with global changes in mRNA expression, with differentially expressed genes overrepresented in 47 Gene Ontology categories. Modified expression was detected for genes associated with cell electrical activity, calcium handling, adhesion and microtubular transport. For a number of key proteins, including kinesin, TGFbeta2, alpha-tubulin, and alpha1 & beta1 integrins, changes in mRNA levels were confirmed on the level of the protein expression. A number of genes associated with cell adhesion and electrical activity were identified as early DEHP targets as they were affected by concentrations as low as 1 MUg/mL. CONCLUSIONS: Exposure of neonatal rat cardiomyocytes to clinically relevant DEHP concentrations leads to global changes in mRNA expression. These changes help to explain the arrhythmogenic effects of phthalates on these cells. PMID- 20920546 TI - Mechanisms and genes involved in enhancement of HIV infectivity by tobacco smoke. AB - HIV infection is more common among smokers than nonsmokers, and, remarkably, HIV infected individuals are about 3 times more likely to smoke than the uninfected general population. However, the relationship between tobacco smoking and HIV/AIDS disease progression remains controversial. In this study, we demonstrate a potent enhancing effect of aqueous tobacco smoke extract (TSE) on HIV infectivity that is nicotine-independent. This increased infectivity is neither NF-kappaB mediated nor a direct result of oxidative stress, as it cannot be blocked by antioxidants. On the contrary, TSE itself was found to possess significant antioxidant potential, enabling it to protect the viability of both infected cells and HIV virions in the presence of peroxide. Assessment of TSE induced alterations in cellular gene expression that may be involved in increasing HIV infectivity in T cells showed that TSE up-regulates some genes known to be capable of enhancing HIV and HCV infection, or protecting HIV, but down-regulates several genes involved in cellular defense and antigen presentation. These results demonstrate that tobacco smoke can enhance HIV infectivity, possibly by a combination of direct (antioxidant) and indirect (gene based) mechanisms. This raises the concern that smoking may thereby increase the risk of acquisition or progression of HIV infection. PMID- 20920547 TI - Mutagenesis analyses explore residues responsible for the neurotoxic and anticoagulant activities of Trimucrotoxin, a pit-viper venom Asn6-phospholipase A2. AB - Trimucrotoxin (TmCT) is an Asn(6)-containing phospholipase A(2) (PLA(2)) from Protobothrops mucrosquamatus (pit-viper) venom. In an attempt to characterize the amino acid residues responsible for the neurotoxic and anticoagulant activities of TmCT, the recombinant fusion proteins of TmCT wild type and mutants were expressed in Escherichia coli. Correct refolding and processing of 37 TmCT mutants were confirmed by their HPLC retention times, circular dichroism spectra, and masses obtained from ESI-MS spectrometry. Each mutant was assayed by pH-stat titration using zwitterionic as well as anionic micelle substrates, and the neurotoxicity was evaluated by using the contractile responses of chick biventer cervicis muscles. The results demonstrated that the residues Asn(1), Asn(6), Lys(7), Ile(11), Met(12), Gly(53), Thr(79), His(108) and Met(118) are important to TmCT neurotoxicity. Through various tests, we also confirmed that enzymatic activity, as opposed to binding to Factor Xa, was a necessary part of TmCT's anticoagulant effect. In addition, pulldown assays of the WT and selected mutants revealed that TmCT's in vitro binding to crotoxin acidic subunit may involve a broad surface area. We conclude that the hot spot mutations at specific positions 53, 79, 108, and 118 during the pit-viper Asn(6)-PLA(2) evolution regulate their neurotoxicities, and that many of the neurotoxic site residues and the anticoagulant mechanism of TmCT are different from those of ammodytoxin A (a true viper venom neurotoxic PLA(2)). PMID- 20920548 TI - Lack of association between the 5-HTTLPR and the error-related negativity (ERN). AB - The error-related negativity (ERN) is a negative waveform that occurs approximately 50ms after an incorrect response. Pharmacological manipulations and theoretical accounts suggest that the ERN reflects reward-related dopamine activity; however, it is likely that several neurotransmitters contribute to the generation of the ERN. Two studies have found an association between the ERN and the serotonin transporter-linked promoter region (5-HTTLPR) polymorphism. In order to investigate this further, 86 participants performed an arrow version of the flanker task and were genotyped for the 5-HTTLPR and the A/G SNP (rs25531) located within the L allele. Despite using multiple methods to group subjects by genotype and score the ERN, no reliable associations between the ERN and the 5 HTTLPR were found. The current study casts doubt on the relationship between ERN and 5-HTTLPR; reasons for this discrepancy with previous work are discussed. PMID- 20920549 TI - Emergence of robust regulatory motifs from in silico evolution of sustained oscillation. AB - The relationship between robustness and evolvability (easiness to evolve), and the evolutionary emergence of robust genetic circuits in biology have attracted much attention in systems biology. This paper investigates in silico the influence of the cis-regulation logic and the coupling of feedback loops on the evolvability and robustness of gene regulatory motifs that can generate sustained oscillation. Our simulation results indicate that both evolvability and robustness of the considered regulatory motifs depend on the cis-regulation logic and the way in which positive and negative feedback loops are coupled. Most interestingly, our findings suggest that robust regulatory motifs can emerge from evolution without an explicit selection pressure on robustness and adding noise in the parameters during the evolution is likely to promote the evolution of sustained oscillation. PMID- 20920550 TI - Evidence for a role of calcineurin in the development of retinocollicular fine topography. AB - The fine-tuning of topographically organized projections in sensory systems is strongly influenced by electrical activity and use-dependent modifications in synaptic strength. Since calcineurin (CaN), a Ca(2+)-calmodulin dependent serine/threonine phosphatase has been associated with activity-dependent modifications in synaptic efficacy we studied the effects of systemic and local administration of CaN inhibitors during the critical period of development of the uncrossed retinocollicular projection in pigmented rats. We found that the expression of the catalytic subunit of calcineurin (CaNA) occurs throughout early development in the visual layers of the superior colliculus and peaks at PND14 when eye opening is complete. The functional blockade of CaN activity by means of a systemic treatment with cyclosporine A (CsA) during the second postnatal week, induces sprouting of uncrossed retinal axons outside their main terminal zones. Additionally, the local treatment with intracranial implants of Elvax loaded with either CsA or a cell-permeable CaN inhibitory peptide (CIP) resulted in a similar expansion of retinocollicular terminal fields. Taken together, these results suggest CaN as a key element for the development of fine tuning of retinocollicular topography. PMID- 20920551 TI - Knockdown of glycogen synthase kinase 3 beta attenuates 6-hydroxydopamine-induced apoptosis in SH-SY5Y cells. AB - Glycogen synthase kinase 3 beta (GSK3beta) plays a critical role in signal transductions concerning neuronal death. In the present study, we investigated the potential role of GSK3beta in 6-hydroxydopamine (6-OHDA)-induced toxicity in human neuroblastoma cell line SH-SY5Y. We assessed the apoptotic proteins and the relative levels of pGSK3beta (Ser9) and pGSK3beta (Tyr216) to GSK3beta in 6-OHDA treated SH-SY5Y. Furthermore, we downregulated the expression of GSK3beta by short hairpin RNA (shRNA) interference and compared the cell viability and expression of apoptotic proteins in knockdown group with those in control group under the treatment of 6-OHDA. We found that 6-OHDA increased the expression of caspase-3 and caspase-9 but not caspase-8. Additionally, 6-OHDA decreased the ratio of pGSK3beta (Ser9)/GSK3beta and increased the ratio of pGSK3beta (Tyr216)/GSK3beta. Moreover, 6-OHDA induced less cell viability loss and lower expression of caspase-9 and caspase-3 in GSK3beta knockdown group compared with control. The present data indicate that 6-OHDA may induce apoptosis in SH-SY5Y via the intrinsic death pathway and GSK3beta knockdown can partly attenuate 6 OHDA-induced neuronal death and apoptosis, suggesting that GSK3beta may have the potential to serve as a therapeutic target for PD. PMID- 20920552 TI - Enhancement of long-term memory expression by a single trial during consolidation. AB - Before the memory trace is stored long term, it must undergo a phase of consolidation during which it remains susceptible to modifications. It has previously been proposed that during consolidation, memories are kept from being stored long term, and can therefore be modified with additional information resulting from ongoing behavior. The Chasmagnathus associative memory model is used here to test whether it is possible during consolidation to modify the long term expression of a memory generated by a weak training procedure. In this memory model, long-term memory expression is achieved after strong training protocols, a 15-spaced trial procedure. After a weak training protocol (WTP, six spaced trials), crabs do not show memory retention when tested in the long term. Nevertheless, the WTP builds a long-term memory that it is indeed consolidated, but remains unexpressed. Here we show that memory can be modified by experience during this short period after learning: memory expression can be enhanced by a Single Trial Session, on the condition that this session takes place contingent upon the consolidation period. We also found that during this time, the memory built by the WTP is behaviorally expressed, in contrast with what occurs at long term. Our results support the idea that during consolidation memories can be evaluated in the background of concurrent experiences. In particular, we propose that during the consolidation period it is possible for crabs to assess which experiences, among those stored long term, will be expressed long term. PMID- 20920554 TI - Modulation of spindle discharge from jaw-closing muscles during chewing foods of different hardness in awake rabbits. AB - The relationships between jaw-closing muscle spindle unit discharge and the hardness of foods were evaluated during chewing in awake rabbits. Spindle unit discharges recorded from the left mesencephalic trigeminal nucleus were correlated with the simultaneous recording of jaw movements and electromyographic (EMG) activities of the left masseter (jaw-closing) muscle during chewing soft and hard foods. A chewing cycle was divided into the fast-closing (FC), slow closing (SC) and opening (OP) phases according to jaw movements. The chewing was classified as ipsilateral and contralateral chewing according to ipsilateral and contralateral to the recording side of the neuron, respectively. Spindle unit discharge was significantly higher during the FC and SC phases of the hard food than the soft food during both ipsilateral and contralateral chewing. The discharge was observed to be higher when the masseter muscle activity was higher. A comparison between the chewing sides reveals that the discharge was significantly higher during the slow-closing phase of ipsilateral chewing than contralateral chewing. From the above findings, the relationship of the spindle unit discharge with the hardness of foods was observed. Moreover, this relationship exists even when an animal chews food on the contralateral side suggesting the significance of the muscle spindle information for smooth chewing. In addition, the phase dependent difference of the spindle unit discharge between chewing sides suggests the distinct roles of the spindle information on the chewing and non-chewing sides. PMID- 20920553 TI - Kv4.2 block of long-term potentiation is partially dependent on synaptic NMDA receptor remodeling. AB - Proper expression of synaptic NMDA receptors (NMDARs) is necessary to regulate synaptic Ca2(+) influx and the induction the long-term potentiation (LTP) in the mammalian hippocampus. Previously we reported that expressing the A-type K(+) channel subunit Kv4.2 in CA1 neurons of organotypic slice cultures reduced synaptic NR2B-containing NMDAR expression and completely blocked LTP induced by a pairing protocol. As pretreatment with an NMDAR antagonist (APV) overnight blocked the reduction of NR2B-containing receptors in neurons expressing EGFP labeled Kv4.2 (Kv4.2g), we hypothesized that LTP would be rescued in Kv4.2g neurons by overnight treatment with APV. We report here that the overnight APV pretreatment in Kv4.2g-expressing neurons only partially restored potentiation. This partial potentiation was completely blocked by inhibition of the CAMKII kinase. These results indicate that A-type K(+) channels must regulate synaptic integration and plasticity through another mechanism in addition to their regulation of synaptic NR2 subunit composition. We suggest that dendritic excitability, which is regulated by Kv4.2 expression, also contributes to synaptic plasticity. PMID- 20920555 TI - A slowing effect on visual search by advance information in pigeons (Columba livia): a comparison with humans (Homo sapiens). AB - A comparative study was conducted to investigate whether the search for a target letter was facilitated when the target and prime (preceding stimulus) letters were identical. Pigeons (Section 2) and human participants (Section 3) were first trained to search for "A" among "Y"s and "E" among "D"s in a condition in which a square shape appeared as the prime (Neutral condition). In subsequent testing, a prime was identical either to the corresponding target (Target-priming condition) or to the distractor (Distractor-priming condition). Humans and pigeons responded differently to the two priming conditions. On early trials, the Target prime facilitated search in humans, reducing reaction times (RTs) to targets. In pigeons, however, RTs were longer with Target primes, suggesting that pre exposure to target letters may directly inhibit the search for targets in subsequent search displays. Furthermore, pre-exposure to the distractor letters may inhibit the processing of the distractor. On later trials, RTs of humans were faster in both priming conditions than in the Neutral condition, suggesting that expectation of a target facilitated search ("Y" predicted "A" and "D" predicted "E"). In contrast, the pigeons showed no evidence of expectation-based facilitation, with constant slowing effects of the Target prime extending across sessions. Possible mechanisms underlying such a slowing priming effect in pigeons were discussed. PMID- 20920556 TI - Prior exposure to organophosphorus and organochlorine pesticides increases the allergic potential of environmental chemical allergens in a local lymph node assay. AB - The dysregulation of immune functions by some pesticides leads to various immune disorders, including immunodeficiency, tumorigenesis, allergies, and autoimmunity. This study's primary objective was to examine the relationship between immune disorders and the immunosuppression induced by immunosuppressive pesticides. We focused on the modulation of allergic potential by the organophosphorus pesticide parathion, organochlorine pesticide methoxychlor, phenoxyacetic acid herbicide 2,4-d-butyl, and benzoic acid fungicide eugenol, as detected by a local lymph node assay (LLNA), which was developed initially for hazard identification of skin sensitization. Parathion and methoxychlor are immunosuppressive chemicals, and 2,4-d-butyl and eugenol are contact allergens. After the immunosuppressive characteristics of parathion and methoxychlor were confirmed in a pilot study, 4-week-old mice were orally administered parathion (0, 0.4, 1.2mg/kg) or methoxychlor (0, 100, 300 mg/kg). Four weeks after the last administration, an LLNA was conducted using 2,4-d-butyl (0%, 2.5%, 5%, and 10%) and eugenol (0%, 5%, 10%, and 25%). In addition, detailed analysis of their auricular lymph nodes for number of surface antigen expression of T cells and local cytokine production were performed using 5% 2,4-d-butyl and 5% eugenol treatment groups. EC3 values (estimated concentration to yield a stimulation index of 3) of 2,4-d-butyl and eugenol decreased markedly in parathion- and methoxychlor-pretreated groups. Parathion- and methoxychlor-pretreated groups induced marked increase in number of surface antigen expression of T cells and levels of Th1 cytokines (IFN-gamma, TNF-alpha, and IL-17) produced by ex vivo restimulated lymph node cells. According to our results, the allergic potentials of 2,4-d-butyl and eugenol are increased by prior exposure to parathion and methoxychlor. PMID- 20920557 TI - Irciniastatin A induces JNK activation that is involved in caspase-8-dependent apoptosis via the mitochondrial pathway. AB - Irciniastatin A (ISA)/psymberin, a pederin-type natural product isolated from marine sponge, exhibits extremely potent and selective cytotoxicity against certain human cancer cell lines, but its molecular target and cytotoxic mechanisms are still unknown. Here we show that ISA is a potent inhibitor of protein translation, and induces apoptosis accompanied with activation of the stress-activated protein kinases via the mitochondrial pathway in human leukemia Jurkat cells. ISA potently inhibited protein translation, and induced a slow but prolonged activation of the stress-activated protein kinases, JNK and p38, at between 1h and 6h after treatment. In Bcl-x(L)-transfected cells, the activation of JNK and p38 by ISA was shortened. The same results were obtained in the cells treated with N-acetyl-L-cysteine, suggesting that the prolonged activation of JNK and p38 by ISA is mediated by reactive oxygen species generated from mitochondria. ISA strongly induced apoptosis, which was partially suppressed by the JNK inhibitor SP600125, but not by the p38 inhibitor SB202190. Apoptosis induction by ISA was partially reduced, but not suppressed by SP600125 in caspase 8-deficient Jurkat cells. These results suggest that ISA activates stress activated kinases by a mitochondria-mediated mechanism, and that activation of JNK is required for caspase-8-dependent apoptosis. PMID- 20920558 TI - Pyrrolidine dithiocarbamate (PDTC)/Cu complex induces lung epithelial cell apoptosis through mitochondria and ER-stress pathways. AB - Pyrrolidine dithiocarbamate (PDTC) is widely used in pesticides, fungicides, insecticides, and herbicides. Copper (Cu) is a toxic heavy metal in the environment, and an essential trace metal element in the body, which is involved in many biological processes as a catalytic cofactor. The present study is designed to investigate the cellular toxicity of PDTC, CuCl(2), and PDTC/Cu complex exposure in lung alveolar epithelial cells that serve primary structural and functional roles in the lungs. The results showed that PDTC or CuCl(2) alone did not affect cell viability, but PDTC/Cu complex significantly decreased lung alveolar epithelial cell viability. PDTC/Cu complex also significantly increased intracellular copper concentration, but PDTC or CuCl(2) alone had low levels of copper. PDTC/Cu complex dramatically enhanced the JNK protein phosphorylation and ERK protein phosphorylation proteins. PDTC/Cu complex did not affect the p38 protein phosphorylation. PDTC/Cu complex was capable of activating the apoptosis related caspases including caspase-9, caspase-7, and caspase-3, which could be reversed by the addition of JNK inhibitor SP600125 or transfection of MAPK8 short hairpin RNA. PDTC/Cu complex also increased cytosolic cytochrome c and decreased mitochondrial transmembrane potential. The Bcl-2 mRNA and protein expressions were decreased in lung epithelial cells treated with PDTC/Cu complex, which could be reversed by SP600125. Furthermore, PDTC/Cu complex could trigger the expressions of ER stress-associated signaling molecules including Grp78, Grp94, caspase-12, ATF4, and CHOP, which could be reversed by SP600125. Taken together, these results indicate that exposure to PDTC/Cu complex induces cytotoxicity and apoptosis in alveolar epithelial cells via the mitochondria- and ER-stress related signaling pathways. PMID- 20920559 TI - Ovotoxicity and PPAR-mediated aromatase downregulation in female Sprague-Dawley rats following combined oral exposure to benzo[a]pyrene and di-(2-ethylhexyl) phthalate. AB - The aim of the present study was to determine the ovotoxicity of female Sprague Dawley (SD) rats exposed to benzo[a]pyrene (B[a]P) and di-(2-ethylhexyl) phthalate (DEHP), either alone or in combination; the molecular mechanism and the combined effects were also evaluated. Female rats were given intragastric administration of control (corn oil), B[a]P (5 and 10mg/kg), DEHP (300 and 600 mg/kg) and B[a]P+DEHP (at 5mg/kg and 300 mg/kg respectively, or at 10mg/kg and 600 mg/kg respectively) on alternate days for 60 days. Relative ovary weight, estrous cycle, 17beta-estradiol blood level, ovarian follicle populations, granulosa cell apoptosis, and gene and protein expression of P450Arom and PPAR were investigated. Our study demonstrated that the combination of B[a]P and DEHP exerts ovotoxicity in female rats and suppression of sex hormone secretion and homeostasis, which is associated with prolonged estrous cycles, decreases in ovarian follicle populations and granulosa cell apoptosis involving a PPAR mediated signaling pathway of action of the two chemicals. In addition, based on qualitative assessment of the combined toxicity, no interaction effects were observed following combined B[a]P and DEHP administration. PMID- 20920560 TI - Comparison of in vitro cell models in predicting in vivo brain entry of drugs. AB - Although several in vitro models have been reported to predict the ability of drug candidates to cross the blood-brain barrier, their real in vivo relevance has rarely been evaluated. The present study demonstrates the in vivo relevance of simple unidirectional permeability coefficient (P(app)) determined in three in vitro cell models (BBMEC, Caco-2 and MDCKII-MDR1) for nine model drugs (alprenolol, atenolol, metoprolol, pindolol, entacapone, tolcapone, baclofen, midazolam and ondansetron) by using dual probe microdialysis in the rat brain and blood as an in vivo measure. There was a clear correlation between the P(app) and the unbound brain/blood ratios determined by in vivo microdialysis (BBMEC r=0.99, Caco-2 r=0.91 and MDCKII-MDR1 r=0.85). Despite of the substantial differences in the absolute in vitro P(app) values and regardless of the method used (side-by side vs. filter insert system), the capability of the in vitro models to rank order drugs was similar. By this approach, thus, the additional value offered by the true endothelial cell model (BBMEC) remains obscure. The present results also highlight the need of both in vitro as well as in vivo methods in characterization of blood-brain barrier passage of new drug candidates. PMID- 20920561 TI - Salidroside promotes erythropoiesis and protects erythroblasts against oxidative stress by up-regulating glutathione peroxidase and thioredoxin. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Rhodiola rosea is commonly used in China and Tibet folk medicine for the treatment of high altitude sickness, anoxia and mountain malhypoxia. AIM OF STUDY: Salidroside (SDS) is an active ingredient of Rhodiola rosea. This study attempted to examine the potential erythropoiesis stimulating and anti-oxidative effect of SDS in TF-1 erythroblasts. MATERIALS AND METHODS: The erythropoiesis-promoting effect was determined by treating human TF 1 cells, one of the popular in vitro models for studying erythropoiesis, with SDS in the presence and absence of erythropoietin (EPO) through the measurement of the expression of a series of erythroid markers such as glycophorin A (GPA), transferrin receptor (CD71) and hemoglobin (Hb). The potential protective effect of SDS against H(2)O(2)-induced apoptosis and its underlying mechanism in TF-1 erythroblasts were examined by flow cytometry and Western blot analysis. RESULTS: SDS promotes erythropoiesis in the EPO-treated cells and it also reduces the number of apoptotic cells in TF-1 erythroblasts after H(2)O(2) treatment probably through the up-regulation of protective proteins thioredoxin-1 (Trx1) and glutathione peroxidase-1 (GPx1). CONCLUSION: Our study provides evidence to explain the ethnopharmacological role of SDS and Rhodiola rosea in Chinese medicine. Our findings also support the use of SDS as an erythropoiesis-adjuvant agent to correct anemia and malhypoxia. PMID- 20920562 TI - Screening of Caesalpinia bonduc leaves for antipsoriatic activity. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Leaves of Caesalpinia bonduc (L.) Roxb. (Caesalpiniaceae) have been used by traditional Siddha healer of Malabar region for psoriasis treatment. AIM OF THE STUDY: To evaluate the Caesalpinia bonduc decoction (CBD), Caesalpinia bonduc hydroalcoholic extract (CBHA) for antipsoriatic activity. MATERIALS AND METHODS: Mouse tail test for psoriasis was used for the evaluation of antipsoriatic activity. Extracts were tested at a dose of 500 mg/kg b.w. and fractions at 250 mg/kg b.w. in Swiss albino mice. Parameters studied in the mouse tail test were changes in epidermal thickness and percentage orthokeratotic values. In vitro antiproliferant assay on HaCaT cell lines and in vitro lipoxygenase inhibition were also carried out. RESULTS: Butanol fraction of Caesalpinia bonduc hydroalcoholic extract (CBHAB) and water fraction of Caesalpinia bonduc hydroalcoholic extract (CBHAW) produced significant orthokeratosis (p<0.001). In relative epidermal thickness, a significant (p<0.05) reduction with respect to control was observed in groups treated with retinoic acid, CBD, butanol fraction of Caesalpinia bonduc decoction (CBDB), water fraction of Caesalpinia bonduc hydroalcoholic extract (CBHAW). Maximum antiproliferant activity was shown by CBHA (IC(50), 77.5+/-12.7 MUg/ml). In lipoxygenase inhibition assay, water fraction of Caesalpinia bonduc decoction (CBDW) showed maximum activity with an IC(50) value of 164.71+/-4.57 MUg/ml. CONCLUSIONS: Among all the tested samples only CBHAW showed good activity in the mouse tail test, antiproliferant activity in HaCaT cells and lipoxygenase inhibition assay. Other extracts and fractions showed varying degrees of activity. The present study supports the traditional use of Caesalpinia bonduc leaves for psoriasis treatment. PMID- 20920563 TI - Bronchospasm potentiating effect of methanolic extract of Ficus religiosa fruits in guinea pigs. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The sacred tree Peepal (Ficus religiosa family: Moraceae) has numerous therapeutic utility in folk medicine. AIM OF THE STUDY: It has been reported to be used in ethno medical treatment of asthma and also in epilepsy due to its high serotonin content, which has been implicated in pathophysiology of asthma, this led us to carry out the present study. MATERIALS AND METHODS: The in vivo studies of histamine induced bronchospasm in guinea pigs and in vitro isolated guinea pig tracheal chain and ileum preparation. RESULTS: Pre-treatment of guinea pigs with ketotifen (1 mg/kg, p.o.) has significantly delayed the onset of histamine aerosol induced pre-convulsive dyspnea, compared with vehicle control (281.8(a)+/-11.7 vs. 112.2+/-9.8). The administration of methanolic extract (125, 250 and 500 mg/kg, p.o.) did not produced any significant effect on latency to develop histamine induced pre-convulsive dyspnea. On the other hand, methanolic extract of the fruits at the doses employed (i.e., 0.5, 1 and 2 mg/ml) has significantly potentiate the EC(50) doses of both histamine and acetylcholine in isolated guinea pig tracheal chain and ileum preparation. In addition, HPLC analysis of the methanolic extract showed the presence of high amounts of serotonin (2.89%, w/w). CONCLUSIONS: On the basis of data, it may be concluded that Ficus religiosa fruits have been found to be ineffective against histamine induced bronchospasm in guinea pigs. In addition, methanolic extract of the fruits have shown to potentiate the bronchoconstriction induced by both histamine and acetylcholine on guinea pig tracheal chain preparation. PMID- 20920564 TI - Bioactivity-guided fractionation for anti-fatigue property of Acanthopanax senticosus. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The root of Acanthopanax senticosus (also called Eleutherococcus senticosus or Siberian ginseng) has been used extensively in China, Russia and Japan as an adaptogen to fight against stress and fatigue. AIM OF THE STUDY: The present study was designed to ascertain the anti-fatigue property of Acanthopanax senticosus by load-weighted swimming test, sleep deprivation test, also to isolate and characterize the active constituents. MATERIALS AND METHODS: Animals were orally administered with the extract of Acanthopanax senticosus. The anti-fatigue effects of the four fractions with different polarities from the 80% ethanol extract, and the different eluates collected from D101 macroporous resin chromatography and eleutheroside E, were examined based on the weight-loaded swimming capacity (physical fatigue) and the change of biochemical parameters in ICR mice. Moreover, the active fraction was later submitted to sleep-deprived mice (mental fatigue). RESULTS: The results shown that the n-butanol fraction significant extends the swimming time of mice to exhaustion. Furthermore, the 60% ethanol-water eluate, more purified eleutherosides (including eleutheroside E, E(2) and derivatives), were the exactly active constituents. Two compounds were isolated, which were identified as eleutheroside E, E(2). CONCLUSIONS: The eleutherosides possess the potent abilities to alleviate fatigue both in physical and mental fatigue. Eleutheroside E may be responsible for the pharmacological effect of anti-fatigue. Furthermore, the possible mechanisms were reduced the level of TG by increasing fat utilization, delayed the accumulation of blood urea nitrogen (BUN), and increased the LDH to reduce the accumulation of lactic acid in muscle and then protect the muscle tissue. PMID- 20920565 TI - Anti-angiogenesis effect of essential oil from Curcuma zedoaria in vitro and in vivo. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Curcuma zedoaria (Berg.) Rosc., a traditional Chinese herb, was used widely but absolutely prohibited for the pregnant in clinic. Based on that there is abundant angiogenesis in endometrium and placenta during gestation period, we hypothesized that some components from it could inhibit angiogenesis and then damaged the supply of oxygen and nutrition to the embryo, which finally led to gestation failure. AIM OF THE STUDY: This study was set to demonstrate whether essential oil, major components of Curcuma zedoaria had anti-angiogenic effect. MATERIALS AND METHODS: Essential oil of Curcuma zedoaria (EO-CZ) was abstracted by steam distillation extraction. Cell proliferation assay and two angiogenic models, rat aortic ring assay and chick embryo chorioallantoic membrane assay were presented. Furthermore, melanoma growth and experimental lung metastasis assay in mice were performed to evaluate its anti-angiogenesis effect in vivo. Immunohistochemical analysis and enzyme linked immunosorbent assay (ELISA) were used to respectively detect the expression of CD34 and matrix metalloproteinases (MMPs). RESULTS: EO-CZ exhibited anti-proliferative effect on B16BL6 and SMMC-7721 cells, the IC(50), respectively was 41.8 MUg/ml and 30.7 MUg/ml, and on HUVEC (Human Umbilical Vein Endothelial Cells) cells with IC(50) of far more than 120 MUg/ml. Both 20 MUg/ml and 40 MUg/ml EO-CZ indicated significant suppression on sprouting vessels of aortic ring and formation of microvessels in chick embryo chorioallantoic membrane in vitro. Moreover, solid melanoma grown in left oxter of mice was obviously inhibited after oral intake of 100 and 200 mg/kg of EO-CZ a day for 28 days, and CD34 expression indicating angiogenesis in melanoma reduced significantly compared with control; melanoma metastatic nodules in lung were detected to be inhibited, as well as MMP-2 and MMP-9 expression in serum. CONCLUSIONS: Essential oil, a fat-soluble fraction of Curcuma zedoaria, presented anti-angiogenic activity in vitro and in vivo, resulting in suppressing melanoma growth and lung metastasis. And this was associated with down-regulating MMPs. PMID- 20920566 TI - Euchresta horsfieldii Benn. activates peroxisome proliferator-activated receptor alpha and regulates expression of genes involved in fatty acid metabolism in human HepG2 cells. AB - AIM OF THE STUDY: Euchresta horsfieldii Benn., an oriental medicinal plant, has been used for the traditional treatment of hyperlipidemia and has been reported to possess bioactive isoflavones; however, the molecular mechanism underlying its hypolipidemic effects remains unclear. In the present study, we investigated the effect of Euchresta horsfieldii on peroxisome proliferator-activated receptor alpha (PPARalpha) activation and fatty acid metabolism in HepG2 hepatocytes. MATERIALS AND METHODS: The dried Euchresta horsfieldii fruits were extracted with 100% ethanol, and the ethanol evaporated to produce Euchresta horsfieldii extract (EHX). The effect of EHX on fatty acid metabolism was evaluated by PPARalpha transactivation assay, real-time reverse transcription-polymerase chain reaction, and Western blot analysis. RESULTS: We demonstrated that EHX significantly increased PPARalpha activation in a dose-dependent manner. In human HepG2 hepatocytes, EHX increased mRNA levels of the following genes involved in fatty acid oxidation: carnitine palmitoyltransferase 1, liver form (CPT1L), acyl-CoA synthetase (ACS), medium-chain acyl-CoA dehydrogenase (MCAD), 3-hydroxy-3 methylglutaryl-CoA synthase 2 (HMGCS2), acyl-CoA 1 (ACO1), acyl-CoA 2 (ACO2), and enoyl-CoA hydratase 1 (ECH1). EHX treatment also increased levels of proteins related to fatty acid oxidation, such as CPT1L, PPARalpha, and uncoupling protein 2 (UCP2). In contrast, sterol regulatory element binding protein 1 (SREBP1), a key lipogenic transcription factor, was downregulated. CONCLUSION: Consistent with significant PPARalpha activation, EHX increased PPARalpha target genes expression and regulated protein expression for lipid metabolism. Taken together, these results indicate that Euchresta horsfieldii shows potential as a natural lipid-lowering agent. PMID- 20920567 TI - Pentacyclic triterpenoids and ceramide mediate the vasorelaxant activity of Vitex cienkowskii via involvement of NO/cGMP pathway in isolated rat aortic rings. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Vitex cienkowskii Kotschy & Peyritsch is a deciduous tree, prescribed by Cameroonian traditional healers as one of the most popular plant widely used in many disorders including cardiovascular diseases. The preliminary pharmacological studies carried out on Vitex cienkowskii showed its vasorelaxant activities on guinea-pig aortic rings. AIM OF THE STUDY: The present work evaluated the vasorelaxant activity of extract and isolated compounds from Vitex cienkowskii. MATERIALS AND METHODS: Rat aortic rings were used to evaluate the in vitro vascular effect of the extract. The antioxidant activity was determined by measuring the reduction of the free radical 1,1 diphenyl-1-picryl-hydrazyl (DPPH). RESULTS: Vitex cienkowskii induced significant relaxation in a concentration- and endothelium-dependent manner (EC(50)=12.12 MUg/ml, CH(2)Cl(2)-MeOH, 1:1) and did not produce a vasorelaxant effect on contraction evoked by KCl (60 mM). In order to determine its mode of action, Vitex cienkowskii-induced relaxant effect was evaluated in the presence of indomethacin (10 MUM), L-NAME (100 MUM), ODQ (1 MUM) and SQ22356 (100 MUM). Relaxation was significantly blocked by L-NAME and ODQ. These results indicate that Vitex cienkowskii-mediated relaxation is endothelium dependent, probably due to NO release, and the consequent activation of vascular smooth muscle soluble guanylate cyclase (sGC), a signal transduction enzyme that forms the second messenger cGMP. Bio-guided study of Vitex cienkowskii allowed the isolation of the known pentacyclic triterpenoids and a ceramide. It is the first report of salvin A, maslinic acid and a ceramide from Vitex cienkowskii. The activity induced by these compounds indicated that they may be partly responsible for the vasorelaxant effect of the plant extract. A dose of 40 mg/kg of CH(2)Cl(2)-MeOH (1:1) extract administered intravenously induced a decrease of mean arterial pressure but did not affect the heart rate. Moreover the plant extracts were found to be highly active in the DPPH radical scavenging assay. CONCLUSION: Vitex cienkowskii extract possesses antioxidant property, vasorelaxing, and hypotensive effect linked to the endothelium related factors, where nitric oxide is involved. PMID- 20920568 TI - The herbal market of Cyprus: traditional links and cultural exchanges. AB - AIM OF THE STUDY: Directive 2004/24/EC sets the frame for the herbal trade in Europe emphasizing the need of the botanical characterization of herbal substances intended for human consumption. Thus, the aim of the present study is to survey and identify taxonomically the herbs sold in the market of Cyprus and to document and evaluate their uses. Moreover, the relationship of the nowadays market to the local ethnobotanical tradition, as well as to other eastern Mediterranean markets (i.e. Greece, Israel, Jordan, Turkey) is also traced. MATERIAL AND METHODS: Herbs sold in 15 shops scattered in three major cities of Cyprus were surveyed. Data concerning their uses were collected through interviews with the herbal traders and studied quantitatively by the use of ethnobotanical indices (informant consensus factor, use value, relative importance value, fidelity level) and statistical tests (Spearman's correlation coefficient, Kruskal-Wallis test, paired-sample t-test). Comparisons to published information concerning other eastern Mediterranean markets were performed by multivariate tests (Ward's hierarchical cluster). RESULTS: A total number of 57 taxa were surveyed from 15 selected shops, out of which 32 are cultivated, 14 are collected from the wild and 11 are imported. The highest Informant Consensus Factors were presented by the neuropsychiatric (0.78), gastrointestinal (0.76) and respiratory ailments (0.71). The comparison of our results to published information has shown that 40 of the traded taxa have also been used traditionally, while a considerable number of herbs are also found in the markets of Greece and Turkey (35 and 29 taxa, respectively); a lower number of the taxa traded, is found in the markets of the Middle East. CONCLUSIONS: The nowadays herbal trade in Cyprus is still linked to the local ethnobotanical legacy. Moreover the similarities between the Cypriot herbal market and the markets of Greece and Turkey are more prominent than those between Cyprus and the Middle East, reflecting the cultural exchanges among the three neighbouring countries. PMID- 20920569 TI - Evaluation of the disease modifying activity of Colchicum luteum Baker in experimental arthritis. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Colchicum luteum (CL) has been traditionally used in the Unani system of medicine as a chief ingredient of many polyherbal formulations for the treatment of joint pain and rheumatoid arthritis (RA). AIM OF THE STUDY: To evaluate the antiarthritic activity of CL hydroalcoholic extract (CLHE) in formaldehyde and complete Freund's adjuvant (CFA) induced arthritis. MATERIALS AND METHODS: Arthritis was induced by administration of either formaldehyde (2% v/v) or CFA into the subplantar surface of the hind paw of the animal. Joint swelling was measured on days 8, 9 and 10 in formaldehyde induced arthritis and days 3, 7, 14 and 21 in CFA induced arthritis. In order to evaluate the effect of CLHE on disease progression, serum TNF-alpha level and synovial expression of proinflammatory mediators (TNF-R1, IL-6 and IL-1beta) was determined in CFA induced arthritis. RESULTS: CLHE produced a significant and dose dependent inhibition of joint swelling during the entire duration of the study in both, formaldehyde and CFA induced arthritis. Serum TNF-alpha level was also reduced significantly in a dose dependent manner in all the CLHE treated groups. The expression of proinflammatory mediators (TNF-R1, IL-6 and IL-1beta) was also found to be less in the CLHE treated group as compared to control. CONCLUSION: We believe that the antiarthritic activity of CLHE was due to its modulatory effect on the expression of proinflammatory cytokine in the synovium. Our results contribute towards validation of the traditional use of CL in the treatment of RA and other inflammatory joint disorders. PMID- 20920570 TI - Antinociceptive activity of methanolic extract of Acmella uliginosa (Sw.) Cass. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Acmella uliginosa (Sw.) Cass. is a medicinal herbaceous plant that is commonly used by the Malay community in Malaysia to relieve pain often associated with mouth ulcers, toothache, sore throat, and stomach ache. AIM: The study was carried out to investigate the antinociceptive effect of the methanolic extract of A. uliginosa (Sw.) Cass. flowers (MEAU) using murine models of chemicals and thermal nociception. MATERIALS AND METHODS: Chemicals (acetic acid-induced abdominal constriction and formalin-, capsaicin-, glutamate-induced paw licking test) and thermal models (hot plate test) of nociception in mice were employed to evaluate the MEAU analgesic effect. The extract was given via oral administration at doses of 3, 10, 30 and 100 mg/kg. RESULTS: It was demonstrated that MEAU produced significant antinociceptive response in all the chemical- and thermal-induced nociception models, which indicates the presence of both centrally and peripherally mediated activities. Furthermore, the reversal of antinociception of MEAU by naloxone suggests the involvement of opioid system in its centrally mediated analgesic activity. Moreover, MEAU-treated mice did not show any significant motor performance alterations. No mortality and signs of toxicity were recorded following treatment of the MEAU. CONCLUSION: The results from the present study appear to support the folkloric belief in the medicinal properties of A. uliginosa (Sw.) Cass. which against pain at both central and peripheral levels, in which the central antinociception is probably due to the participation of the opioid receptors. PMID- 20920571 TI - The lipid peroxidation products as possible markers of Alzheimer's disease in blood. AB - Oxidative stress, which is present in Alzheimer's disease (AD), results in the formation of various end-products of free radical reactions with proteins and lipids. At present there are no reliable diagnostic biomarkers of AD in the blood. Therefore, specific products of lipid peroxidation in the blood of AD patients were investigated. Lipophilic extracts of erythrocytes in the group of patients with AD (n = 44) and age-matched controls (n = 16) were studied. The end products of lipid peroxidation, so called lipofuscin-like pigments (LFP), were analysed by fluorescence spectroscopy. It was found that the level of these products is significantly increased in erythrocytes of AD patients compared to controls. LFP were further separated by means of HPLC into individual fractions to study their composition in AD and controls. The specific fraction of LFP in AD patients, which was isolated, might represent a disease-specific product in the blood. PMID- 20920572 TI - Protection in mice passively immunized with serum from cynomolgus macaques and humans vaccinated with recombinant plague vaccine (rF1V). AB - Passive transfer models were developed to evaluate the ability of antibodies generated in cynomolgus macaques and humans vaccinated with a recombinant plague vaccine (rF1V) to protect naive Swiss Webster mice against pneumonic plague. Development of the passive transfer model is intended to support clinical and nonclinical development of the rF1V vaccine. To evaluate protection, unfractionated serum collected from rF1V vaccinated cynomolgus macaques and human volunteers with known antibody titers to rF1, rV and rF1V was transferred into naive Swiss Webster mice via the intraperitoneal route. Results of these studies demonstrated that passive immunization protected mice from challenge or extended mean survival time and that the passive transfer assay can be used to evaluate the functional role of antibodies induced by rF1V vaccination in protection against aerosol exposure. PMID- 20920573 TI - Temporal changes in the gene signatures of BCG-vaccinated guinea pigs in response to different mycobacterial antigens. AB - Mycobacterium bovis BCG-vaccination in the guinea pig model of tuberculosis (TB) is sufficiently protective that candidate TB vaccines are judged against this. Little is understood about how the BCG vaccine works and, in the absence of a definitive correlate of protection, it is difficult to interpret the significance of novel vaccine induced host responses. Here an extended custom-made microarray (86 guinea pig genes) was used to dissect temporal changes in BCG-vaccine induced gene signatures to different mycobacterial antigens. Initially at 4h, pro inflammatory genes such as IL-1alpha, IL-1beta, IL-8 and GRO were up-regulated (P<0.001) and these were then superseded by IFN-gamma and GM-CSF (at 12 and 20h) post-stimulation, ex vivo with PPD. Similar genes were seen following stimulation with viable BCG but with the addition of IL-23 (P<0.01) after 8h. Our results suggest that temporal changes in the up- and down-regulation of a variety of genes are required to trigger a successful protective response to TB in guinea pigs. This provides base-line information against which new TB vaccines can be compared. PMID- 20920574 TI - A new murine model for testing vaccines against genital Chlamydia trachomatis infections in males. AB - Two groups of 50 BALB/c male mice were immunized with live Chlamydia trachomatis mouse pneumonitis (MoPn) using the intranasal (i.n.) or the meatus urethra (intraurethral: i.u.) routes. As a control group, 100 male mice were sham immunized in parallel. Both groups of animals vaccinated with live organisms developed strong Chlamydia-specific humoral and cell mediated immune responses. Based on the IgG2a/IgG1 ratio and the levels of IFN-gamma both groups mounted a Th1 immune response. At six weeks following the immunization, all mice were challenged in the meatus urethra. The urethra, urinary bladder, testes and epididymides were harvested at weekly intervals and tested for the presence of C. trachomatis. Based on the culture results from these four organs both groups of Chlamydia-immunized mice showed significant protection. In the group immunized i.u., 10% (5/50) had positive cultures, while in the group immunized i.n. 28% (14/50) had positive cultures during the 5 weeks of observation. In contrast, in the sham-immunized animals 47% (47/100) had positive cultures (P<0.005) during the study period. In addition, the number of positive organs, the length of time that the animal had positive cultures, and the total number of inclusion forming units (IFU) recovered were overall significantly lower in the i.u. or i.n. groups in comparison with the sham-immunized animals. However, in relation to the i.u. immunized group, the protection elicited in the i.n. group was delayed and not as robust. In conclusion, immunization of mice in the meatus urethra may provide the gold standard for testing Chlamydia vaccines in a male model. PMID- 20920577 TI - No effect of sustained systemic growth retardation on the distribution of Reelin expressing interneurons in the neuron-producing hippocampal dentate gyrus in rats. AB - Reelin signaling plays a role in neuronal migration and positioning during brain development. To clarify the effect of systemic growth retardation on the distribution of Reelin-expressing interneurons in the hilus of the hippocampal dentate gyrus, pregnant rats were fed a synthetic diet with either a normal (20% casein) or low (10% casein) protein concentration from gestational day 10 to postnatal day (PND) 21 at weaning. Male offspring were immunohistochemically examined at PND 21 and on PND 77. Protein-restricted offspring displayed systemic growth retardation through PND 77 and had decreased absolute brain weights and an increased number of external granular cells in the cerebellar cortex, suggestive of retarded brain growth at weaning. However, maternal protein restriction did not change the cellular distribution of immunoreactivity for Reelin, Calbindin-D 28K, or glutamic acid decarboxylase 67 or of NeuN-positive postmitotic neurons in the dentate hilus either at PND 21 or PND 77, which suggests that the population of gamma-aminobutyric acid-ergic interneurons involving synthesis of Reelin was not affected. Furthermore, as well as the distribution of hilar neurons expressing neurogenesis-related FoxG1, cell proliferation and apoptosis in the subgranular zone were unaffected through PND 77. These results suggest that systemic growth retardation caused by maternal protein restriction does not affect neuronal migration and postnatal neurogenesis of the dentate gyrus resulting in unaltered distribution of Reelin-synthesizing interneurons. PMID- 20920575 TI - Effects of developmental stress and lead (Pb) on corticosterone after chronic and acute stress, brain monoamines, and blood Pb levels in rats. AB - Despite restrictions, exposure to lead (Pb) continues. Moreover, exposure varies and is often higher in lower socioeconomic status (SES) families and remains a significant risk to cognitive development. Stress is another risk factor. Lower SES may be a proxy for stress in humans. When stress and Pb co-occur, risk may be increased. A few previous experiments have combined Pb with intermittent or acute stress but not with chronic stress. To determine if chronic developmental stress affects outcome in combination with Pb, we tested such effects on growth, organ weight, brain monoamines, and response to an acute stressor. Sprague Dawley rats were gavaged with Pb acetate (1 or 10 mg/kg) or vehicle every other day from postnatal day (P)4-29 and reared in standard or barren cages. Subsets were analyzed at different ages (P11, 19, 29). Chronic stress did not alter blood Pb levels but altered HPA axis response during early development whereas Pb did not. Pb treatment and rearing each altered organ-to-body weight ratios, most notably of thymus weights. Both Pb and rearing resulted in age- and region-dependent changes in serotonin and norepinephrine levels and in dopamine and serotonin turnover. The model introduced here may be useful for investigating the interaction of Pb and chronic developmental stress. PMID- 20920579 TI - Regulation of MKP-1 expression and MAPK activation by PARP-1 in oxidative stress: a new mechanism for the cytoplasmic effect of PARP-1 activation. AB - Previously, it was suggested that the release of nuclearly formed ADP-ribose polymers or ADP-ribosylated proteins could be responsible for the cytosolic and mitochondrial effects of poly(ADP-ribose) polymerase (PARP)-1 activation in oxidative stress. In this report, we provide a novel alternative mechanism. We found that reactive oxygen species-activated PARP-1 regulated the activation of JNK and p38 mitogen-activated protein kinases (MAPKs) because inhibition of PARP 1 by pharmacons, small interfering RNA silencing of PARP-1 expression, or the transdominant expression of enzymatically inactive PARP-1 resulted in the inactivation of these MAPKs. This regulation was achieved by increased expression and enlarged cytoplasmic localization of MAPK phosphatase-1 (MKP-1) upon PARP-1 inhibition in oxidative stress because changes in MKP-1 expression were reflected in the phosphorylation states of JNK and p38. Furthermore, we found that in MKP-1 silenced cells, PARP inhibition was unable to exert its protective effect, indicating the pivotal roles of JNK and p38 in mediating the oxidative-stress induced cell death as well as that of increased MKP-1 expression in mediating the protective effect of PARP inhibition. We suggest that regulation of a protein that can directly influence cytoplasmic signaling cascades at the expression level represents a novel mechanism for the cytoplasmic action of PARP-1 inhibition. PMID- 20920580 TI - Zebrafish as a tool in Alzheimer's disease research. AB - Alzheimer's disease is the most prevalent form of neurodegenerative disease. Despite many years of intensive research our understanding of the molecular events leading to this pathology is far from complete. No effective treatments have been defined and questions surround the validity and utility of existing animal models. The zebrafish (and, in particular, its embryos) is a malleable and accessible model possessing a vertebrate neural structure and genome. Zebrafish genes orthologous to those mutated in human familial Alzheimer's disease have been defined. Work in zebrafish has permitted discovery of unique characteristics of these genes that would have been difficult to observe with other models. In this brief review we give an overview of Alzheimer's disease and transgenic animal models before examining the current contribution of zebrafish to this research area. This article is part of a Special Issue entitled Zebrafish Models of Neurological Diseases. PMID- 20920578 TI - Redox modulation of diaphragm contractility: Interaction between DHPR and RyR channels. AB - Previous reports indicate that reactive oxygen species (ROS) may modulate contractility in skeletal muscle. Although Ca(2+)-sensitivity of the contractile apparatus appears to be a primary site of regulation, dihydropyridine receptor (DHPR or L-type Ca(2+) channels) and calcium efflux in isolated sarcoplasmic reticulum (SR) vesicles appear to be redox sensitive as well. However, DHPR as a target is poorly understood in intact muscles at body temperature, particularly in the diaphragm, a muscle more dependent on external Ca(2+) than locomotor muscles. Previously, we reported that oxidant challenge via xanthine oxidase (XO) alters the K(+) contractures in diaphragm fiber bundles, suggestive of a role of L-type Ca(2+) channels. Contractility of isolated rat diaphragm fiber bundles revealed a biphasic response to ROS challenge that was dose and time dependent. Potentiation of twitch and low-frequency diaphragm fiber bundle contractility with 0.02 U*ml(-1) XO was reversible or partially preventable with washout, dithiothreitol, and the SOD/catalase mimetic EUK-134. The RyR antagonist ruthenium red inhibited xanthine oxidase-induced potentiation, while the RyR agonist caffeine elevated diaphragm twitch and low-frequency tension in a non additive manner by 55% when introduced simultaneously with ROS challenge. The DHPR antagonist nitrendipine (15 MUM) inhibited elevation in low-frequency diaphragm tension produced by ROS challenge. Caffeine threshold tension curves were shifted to the left with 0.02 U*ml(-1) XO, but this effect was partially reversed with 15 MUM nitrendipine. These results are consistent with the hypothesis that DHPR redox state and RyR function are modulated in an interactive manner, affecting contractility in intact diaphragm fiber bundles. PMID- 20920576 TI - The 22q11.2 microdeletion: fifteen years of insights into the genetic and neural complexity of psychiatric disorders. AB - Over the last fifteen years it has become established that 22q11.2 deletion syndrome (22q11DS) is a true genetic risk factor for schizophrenia. Carriers of deletions in chromosome 22q11.2 develop schizophrenia at rate of 25-30% and such deletions account for as many as 1-2% of cases of sporadic schizophrenia in the general population. Access to a relatively homogeneous population of individuals that suffer from schizophrenia as the result of a shared etiological factor and the potential to generate etiologically valid mouse models provides an immense opportunity to better understand the pathobiology of this disease. In this review we survey the clinical literature associated with the 22q11.2 microdeletions with a focus on neuroanatomical changes. Then, we highlight results from work modeling this structural mutation in animals. The key biological pathways disrupted by the mutation are discussed and how these changes impact the structure and function of neural circuits is described. PMID- 20920581 TI - Both UDP N-acetylglucosamine pyrophosphorylases of Tribolium castaneum are critical for molting, survival and fecundity. AB - A bioinformatics search of the genome of the red flour beetle, Tribolium castaneum, resulted in the identification of two genes encoding proteins closely related to UDP-N-acetylglucosamine pyrophosphorylases (UAPs), which provide the activated precursor, UDP-N-acetylglucosamine, for the synthesis of chitin, glycoproteins and glycosylphosphoinositide (GPI) anchors of some membrane proteins as well as for the modification of other substrates. This is in contrast to other arthropods whose genomes have been completely sequenced, all of which have only a single copy of this gene. The two T. castaneum UAP genes, TcUAP1 and TcUAP2, share both nucleotide and amino acid sequence identities of about 60%. RT PCR analysis revealed that the two genes differ in their developmental and tissue specific patterns of expression. RNA interference (RNAi) indicated roles for TcUAP1 and TcUAP2 at the molt and intermolt stages, respectively: RNAi for TcUAP1 resulted in specific arrest at the larval-larval, larval-pupal or pupal-adult molts, depending on time of injection of double-stranded RNAs, whereas RNAi for TcUAP2 prevented larval growth or resulted in pupal paralysis. Analysis of elytral cuticle indicated loss of structural integrity and chitin staining after RNAi for TcUAP1, but not after RNAi for TcUAP2. Loss of peritrophic matrix (PM) associated chitin was also observed following RNAi for TcUAP1, but not after RNAi for TcUAP2. Down-regulation of transcripts for either TcUAP gene at the mature adult stage resulted in cessation of oviposition in females, as well as fat body depletion and eventual death in both sexes. These results demonstrate that both TcUAP genes are critical for beetle development and survival, but that only TcUAP1 is clearly associated with synthesis of cuticular or PM chitin. However, both of these genes appear to have additional critical role(s) unrelated to chitin synthesis, presumably in the glycosylation of proteins and/or secondary metabolites. PMID- 20920582 TI - T-cell function in chronic lymphocytic leukaemia. AB - According to the immune-surveillance hypothesis, cancer cells evolve strategies to evade or suppress the immune system as part of the development of this disease. The malignant B-cells of chronic lymphocytic leukaemia are prime examples of this premise, having been shown to generate a variety of ways of suppressing T-cell anti-tumour immune responses and these are summarized here. These mechanisms range from impairment of antigen presentation by the tumour cells themselves, to suppression of the immune microenvironment by contact dependent pathways and alterations in the cytokine milieu. By understanding these defects, novel targeted therapies can be developed with the aim of restoring T cell function. Indeed, some of the recent advances in the treatment of chronic lymphocytic leukaemia have been demonstrated to have profound immunomodulatory effects, repairing these defects in T-cell function. PMID- 20920583 TI - Macromolecular docking restrained by a small angle X-ray scattering profile. AB - While many structures of single protein components are becoming available, structural characterization of their complexes remains challenging. Methods for modeling assembly structures from individual components frequently suffer from large errors, due to protein flexibility and inaccurate scoring functions. However, when additional information is available, it may be possible to reduce the errors and compute near-native complex structures. One such type of information is a small angle X-ray scattering (SAXS) profile that can be collected in a high-throughput fashion from a small amount of sample in solution. Here, we present an efficient method for protein-protein docking with a SAXS profile (FoXSDock): generation of complex models by rigid global docking with PatchDock, filtering of the models based on the SAXS profile, clustering of the models, and refining the interface by flexible docking with FireDock. FoXSDock is benchmarked on 124 protein complexes with simulated SAXS profiles, as well as on 6 complexes with experimentally determined SAXS profiles. When induced fit is less than 1.5A interface C(alpha) RMSD and the fraction residues of missing from the component structures is less than 3%, FoXSDock can find a model close to the native structure within the top 10 predictions in 77% of the cases; in comparison, docking alone succeeds in only 34% of the cases. Thus, the integrative approach significantly improves on molecular docking alone. The improvement arises from an increased resolution of rigid docking sampling and more accurate scoring. PMID- 20920584 TI - Poly(lactic-co-glycolic acid) nanoparticles as candidate DNA vaccine carrier for oral immunization of Japanese flounder (Paralichthys olivaceus) against lymphocystis disease virus. AB - In order to protect DNA vaccine against degradation in alimentary tract of fish, poly(lactic-co-glycolic acid) (PLGA) nanoparticles encapsulating vaccine were prepared using W/O/W emulsification combined with spray drying technique in our laboratory. The characteristics of PLGA nanoparticles were described as follows: (1) shape, spherical; (2) size, <500 nm; (3) yield, ~96.2%; loading percentage, ~0.5%; encapsulation efficiency, ~63.7%; supercoiled conformation percentage, ~65%; (4) release dynamics, gradual release. In vitro transfection in SISK cells showed that PLGA nanoparticles could be utilized to transfect eukaryotes. After oral administration, FITC-labeled PLGA nanoparticles were detected in blood of fish, and RNA containing major capsid protein (MCP) gene information existed in various tissues of fish 10-90 days. In addition, the analysis of immune parameters in sera of treatment fish showed that: (1) infection rate of LCDV post challenge, ~16.7%; (2) prophenoloxidase, superoxide dismutase, respiratory burst, lysozyme and antibody levels, increased significantly (p<0.05); (3) activities of serum complement, changed a little (p>0.05). Pearson's correlation displayed that correlation of immune factors mentioned above (not including serum complement) were all positive for fish vaccinated. The data in this study suggested that PLGA nanoparticles were promising carriers for plasmid DNA vaccine and might be used to vaccinate fish by oral approach. PMID- 20920585 TI - Dietary nucleotides influence immune responses and intestinal morphology of red drum Sciaenops ocellatus. AB - Dietary nucleotides have been shown to benefit many physiological and nutritional functions in higher vertebrates and fish. Therefore, a 6-week feeding trial was conducted to evaluate the effects of graded levels of a commercial nucleotide product on growth performance, immune responses and intestinal morphology of juvenile red drum (initial average weight of 7.1g). The basal diet was formulated to contain 40% protein, 10% lipid and a digestible energy level of 3.5 kcal g( 1). Two levels of nucleotide (Ascogen P((r)), 0.5% and 1% of diet) were added to the basal diet with menhaden fishmeal and menhaden oil adjusted to provide isonitrogenous and isolipidic diets. Nucleotide supplementation tended to improve weight gain and survival of red drum, but not at a significant level. Neutrophil oxidative radical anion production and serum lysozyme activity tended to be higher for fish fed diets supplemented with nucleotide, while extracellular superoxide anion production of head kidney macrophages from fish fed diets with 1% nucleotide was significantly (P<0.05) increased, although no significant differences were observed between fish fed 0.5% nucleotide diet and the basal diet. Nucleotide supplementation significantly (P<0.05) increased fold height in the proximal intestine, and enterocyte height in the pyloric caeca, proximal and distal enteric sections. A significantly (P<0.05) higher microvilli height was observed in all evaluated enteric sections of fish fed with diets supplemented with nucleotides. It is therefore possible to use dietary nucleotides supplementation to significantly enhance the intestinal structure of red drum. Likewise, nucleotides in the diet may improve some components of the non-specific immune response of this sciaenid fish. PMID- 20920586 TI - Callosal tracts and patterns of hemispheric dominance: a combined fMRI and DTI study. AB - Left-hemispheric dominance for language and right-hemispheric dominance for spatial processing are distinctive characteristics of the human brain. However, variations of these hemispheric asymmetries have been observed, with a minority showing crowding of both functions to the same hemisphere or even a mirror reversal of the typical lateralization pattern. Here, we used diffusion tensor imaging and functional magnetic imaging to investigate the role of the corpus callosum in participants with atypical hemispheric dominance. The corpus callosum was segmented according to the projection site of the underlying fibre tracts. Analyses of the microstructure of the identified callosal segments revealed that atypical hemispheric dominance for language was associated with high anisotropic diffusion through the corpus callosum as a whole. This effect was most evident in participants with crowding of both functions to the right. The enhanced anisotropic diffusion in atypical hemispheric dominance implies that in these individuals the two hemispheres are more heavily interconnected. PMID- 20920587 TI - Voltage-sensitive dye imaging analysis of functional development of the neonatal rat corticostriatal projection. AB - We examined the feasibility of voltage-sensitive dye imaging for detecting the neuronal activity in the neonatal rat corticostriatal projection and analyzed postnatal development of synaptic function in this projection. Coronal slice preparations were dissected from postnatal 3 to 14 day (P3-14) rats and were then stained with the voltage-sensitive absorption dye, NK2761. The transmembrane voltage-related optical changes evoked by cortical stimulation using a bipolar electrode could be recorded simultaneously from many loci in the preparation, using a 464ch hexagonal diode array system. In the striatum, the optical signal was composed of a fast spike-like signal and a slow signal. The slow signal was blocked by DL-2-amino-5-phosphonovaleric acid (APV) and 6-cyano-7 nitroquinoxaline-2,3-dione (CNQX) and enhanced by bicuculline, suggesting that (1) the slow signal includes glutamatergic excitatory postsynaptic potentials (EPSPs) and that (2) inhibitory gamma-aminobutyric acid A (GABA(A)) receptor function is expressed in the corticostriatal pathway from the early postnatal stage. We compared the excitatory and inhibitory synaptic responses between the first and second postnatal week preparations, and we showed that (1) in the first postnatal week, excitatory transmission in the corticostriatal pathway is mostly mediated by glutamate, (2) in addition to glutamatergic transmission, other excitatory transmission mechanisms emerge in this pathway until the second postnatal week, and (3) the inhibitory transmission mediated by GABA rapidly develops during the postnatal 2 weeks. PMID- 20920588 TI - Correlation between baseline regional gray matter volume and global gray matter volume decline rate. AB - Evaluating whole-brain or global gray matter volume decline rate is important in distinguishing neurodegenerative diseases from normal aging and in anticipating cognitive decline over a given period in non-demented subjects. Whether a significant negative correlation exists between baseline regional gray matter volume of several regions and global gray matter volume decline in the subsequent time period in healthy subjects has not yet been clarified. Therefore, we analyzed the correlation between baseline regional gray matter volumes and the rate of global gray matter volume decline in the period following baseline using magnetic resonance images of the brains of 381 healthy subjects by applying a longitudinal design over 6 years using voxel-based morphometry. As a result, the annual percentage change in gray matter ratio (GMR, APC(GMR)), in which GMR represents the percentage of gray matter volume in the intracranial volume, showed a significant negative correlation with the baseline regional gray matter volumes of the right posterior cingulate cortex/precuneus and the left hippocampus. Additionally, baseline regional gray matter volume of both the right PCC/precuneus and the left hippocampus significantly distinguished whether the APC(GMR) was above or below the mean of APC(GMR). Our results suggest that baseline regional gray matter volume predicts the rate of global gray matter volume decline in the subsequent period in healthy subjects. Our study may contribute to distinguishing neurodegenerative diseases from normal aging and to predicting cognitive decline. PMID- 20920590 TI - A mini-cap for simultaneous EEG and fMRI recording in rodents. AB - Simultaneous recording of electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) is now widely accepted as a prevailing tool to study brain functions. For over a decade, EEG caps with high-dense arrays of electrodes for EEG-fMRI studies in humans have been commercially available. However, simultaneous EEG and fMRI recording in rodents has been limited to only a few electrodes due mainly to two technical reasons, i.e. a small available scalp area and the proximity of the electrodes to the brain tissue. In this paper, we introduce both a new EEG mini-cap and a protocol to obtain whole scalp EEG recordings simultaneously with 7 T fMRI signals in rodents. We provide methodological protocol to evaluate a number of problems emerging from the particulars of using rodents in simultaneous EEG and fMRI recording. The quality and reproducibility of both EEG and fMRI signals were demonstrated using a conventional forepaw stimulation paradigm in Wistar rats. Based on this quantitative analysis, we conclude that simultaneous EEG-fMRI recordings are achievable in rodents without significant signal loss. In light of the contemporary transgenic models and advanced drug administration protocols in rodents, the proposed methodology could be remarkable as a futurist experimental platform. PMID- 20920589 TI - Quantitative analysis of brain pathology based on MRI and brain atlases- applications for cerebral palsy. AB - We have developed a new method to provide a comprehensive quantitative analysis of brain anatomy in cerebral palsy patients, which makes use of two techniques: diffusion tensor imaging and automated 3D whole brain segmentation based on our brain atlas and a nonlinear normalization technique (large-deformation diffeomorphic metric mapping). This method was applied to 13 patients and normal controls. The reliability of the automated segmentation revealed close agreement with the manual segmentation. We illustrate some potential applications for individual characterization and group comparison. This technique also provides a framework for determining the impact of various neuroanatomic features on brain functions. PMID- 20920591 TI - Pulmonate phylogeny based on 28S rRNA gene sequences: a framework for discussing habitat transitions and character transformation. AB - Pulmonate snails occupy a wide range of marine, estuarine, freshwater and terrestrial environments. Non-terrestrial forms are supposed to be basal in pulmonate evolution but the group's phylogeny is not well resolved either morphologically or on the basis of available DNA sequence data. The lack of a robust phylogeny makes it difficult to understand character polarization and habitat transformation in pulmonates. We have investigated pulmonate relationships using 27 new sequences of 28S rRNA from pulmonates and outgroups, augmented with data from GenBank. The complete alignments comprised about 3.8kb. Maximum parsimony, maximum likelihood and Bayesian analyses of alignments generated under different assumptions are reported. Complete alignments appear to have a degree of substitution saturation so where there is conflict between hypothesised relationships more weight is given to analyses where regions of random similarity are excluded and which are not affected by this complication. Monophyly of the five main pulmonate groups was robustly supported in almost all analyses. The marine group Amphiboloidea and the freshwater Glacidorbidae are the most basal. The remaining pulmonates (Siphonariidae, Hygrophila and Eupulmonata) form a moderately-supported monophyletic group in all analyses bar one probably affected by saturation of substitutions. Siphonariidae, a predominantly marine and intertidal family, and Eupulmonata (mainly terrestrial with marine, estuarine and freshwater species) form a strongly supported clade that is the sister group to Hygrophila (freshwater). Multiple colonizations of freshwater and terrestrial habitats by pulmonate snails are suggested. No analyses strongly support the possibility of habitat reversions. The colonizations of freshwater by Hygrophila and of land by Stylommatophora were apparently phylogenetically independent although it cannot yet be excluded that there were transient terrestrial phases in the history of the former group or freshwater phases in the latter. PMID- 20920592 TI - Phylogeny, biogeography, and host-plant association in the subfamily Apaturinae (Insecta: Lepidoptera: Nymphalidae) inferred from eight nuclear and seven mitochondrial genes. AB - The subfamily Apaturinae consists of 20 genera and shows disjunct distributions and unique host-plant associations. Most genera of this subfamily are distributed in Eurasia South-East Asia and Africa, whereas the genera Doxocopa and Asterocampa are distributed mainly in South America and North America, respectively. Although the Apaturinae larvae mainly feed on the Cannabaceae, those of the genus Apatura are associated with Salix and Populus (Salicaceae), which are distantly related to the Cannabaceae. Here, we infer the phylogeny of Apaturinae and reconstruct the history of host shifting and of colonization in the New World. We analyzed 9761 bp of nuclear and mitochondrial DNA sequence data, including the genes encoding EF1a, Wg, ArgK, CAD, GAPDH, IDH, MDH, RpS5, COI, COII, ATPase8, ATPase6, COIII, ND3, and ND5 for 12 apaturine genera. We also inferred the phylogeny with six additional genera using mitochondrial sequence data alone. Within the Apaturinae, two major clades are recovered in all the datasets. These clades separate the New World genera, Doxocopa and Asterocampa, indicating that dispersal to the New World occurred at least twice. According to our divergence time estimates, these genera originated during the Early Oligocene to the Early Miocene, implying that they migrated across the Bering Land Bridge rather than the Atlantic Land Bridge. The temporal estimates also show that host shifting to Salix or Populus in Apatura occurred more than 15 million years after the divergence of their host plants. Our phylogenetic results are inconsistent with the previously accepted apaturine genus groups and indicate that their higher classification should be reconsidered. PMID- 20920593 TI - Endoplasmic reticulum protein 29 (ERp29): An emerging role in cancer. AB - The endoplasmic reticulum protein 29 (ERp29) is a molecule that facilitates processing and transport of proteins in the early secretory pathway. Structural and functional analyses have suggested a biological role as a putative chaperone in the endoplasmic reticulum. The N-terminal domain of ERp29 resembles the thioredoxin domain of protein disulfide isomerase, but lacks its redox-active function due to the absence of an active motif consisting of double cysteines. In the context of carcinogenesis, the role of ERp29 in cancer progression has not been fully elucidated. However, recent studies indicate that high expression of ERp29 inversely correlates to tumor progression. In addition, over-expression of ERp29 significantly inhibits proliferation and suppresses tumorigenesis by modulating ER stress signaling and the mesenchymal-epithelial transition in breast cancer cells. In this review, we summarize the biological properties of ERp29 and its novel function as a tumor suppressor. PMID- 20920594 TI - Regulation of mammalian desaturases by myristic acid: N-terminal myristoylation and other modulations. AB - Myristic acid, the 14-carbon saturated fatty acid (C14:0), usually accounts for small amounts (0.5%-1% weight of total fatty acids) in animal tissues. Since it is a relatively rare molecule in the cells, the specific properties and functional roles of myristic acid have not been fully studied and described. Like other dietary saturated fatty acids (palmitic acid, lauric acid), this fatty acid is usually associated with negative consequences for human health. Indeed, in industrialized countries, its excessive consumption correlates with an increase in plasma cholesterol and mortality due to cardiovascular diseases. Nevertheless, one feature of myristoyl-CoA is its ability to be covalently linked to the N terminal glycine residue of eukaryotic and viral proteins. This reaction is called N-terminal myristoylation. Through the myristoylation of hundreds of substrate proteins, myristic acid can activate many physiological pathways. This review deals with these potentially activated pathways. It focuses on the following emerging findings on the biological ability of myristic acid to regulate the activity of mammalian desaturases: (i) recent findings have described it as a regulator of the Delta4-desaturation of dihydroceramide to ceramide; (ii) studies have demonstrated that it is an activator of the Delta6 desaturation of polyunsaturated fatty acids; and (iii) myristic acid itself is a substrate of some fatty acid desaturases. This article discusses several topics, such as the myristoylation of the dihydroceramide Delta4-desaturase, the myristoylation of the NADH-cytochrome b5 reductase which is part of the whole desaturase complex, and other putative mechanisms. PMID- 20920595 TI - Incorporation profiles of conjugated linoleic acid isomers in cell membranes and their positional distribution in phospholipids. AB - Although the conjugated linoleic acids (CLA) have several isomer-specific biological effects including anti-carcinogenic and anti-adipogenic effects, their mechanisms of action remain unclear. To determine their potential effects on membrane structure and function, we studied the incorporation profiles of four CLA isomers (trans-10 cis-12 (A), trans-9 trans-11 (B), cis-9 trans-11 (C), and cis-9 cis-11 (D)) in CHO and HepG2 cells. All four isomers were incorporated into cellular lipids as efficiently as linoleic acid (LA), with the majority of the incorporated CLA present in membrane rafts. Of the four isomers, only CLA-A increased the cholesterol content of the raft fraction. Over 50% of the incorporated CLAs were recovered in phosphatidylcholine of CHO cells, but in HepG2 the neutral lipids contained the majority of CLA. The desaturation index (18:1/18:0 and 16:1/16:0) was reduced by CLA-A, but increased by CLA-B, the effects being apparent mostly in raft lipids. The Delta9 desaturase activity was inhibited by CLAs A and C. Unlike LA, which was mostly found in the sn-2 position of phospholipids, most CLAs were also incorporated significantly into the sn-1 position in both cell types. These studies show that the incorporation profiles of CLA isomers differ significantly from that of LA, and this could lead to alterations in membrane function, especially in the raft-associated proteins. PMID- 20920596 TI - Colon neoplasms develop early in the course of inflammatory bowel disease and primary sclerosing cholangitis. AB - BACKGROUND & AIMS: Colon cancer surveillance guidelines for patients with inflammatory bowel disease (IBD) and primary sclerosing cholangitis (PSC) suggest annual colonoscopy once the diagnosis of concomitant disease is made, but there is little evidence to support this recommendation. We conducted a retrospective review of patients with colonic neoplasms (colon cancer or dysplasia) to test this guideline's validity and determined when colonic neoplasms occurred in the population. METHODS: Records were retrospectively reviewed from 54 patients with IBD, PSC, and colonic neoplasia for dates of diagnosis of IBD, PSC, and colon neoplasia and descriptive information about the colon neoplasms that developed. RESULTS: The occurrence of colon neoplasms within 2 years of diagnosis of IBD and PSC (21.5 per 100 patient years of follow-up) was similar to the occurrence within 8 to 10 years from diagnosis of IBD and PSC (20.4 per 100 patient years of follow-up). The colonic neoplasms that developed in this population were spread throughout the colon. CONCLUSIONS: Patients with IBD and PSC have a risk of developing colonic neoplasms soon after the coexistence of the 2 diseases is discovered. This finding supports the current colon cancer surveillance guideline recommendations of yearly colonoscopies for this patient population, beginning at the time of diagnosis of PSC in patients with IBD or with the diagnosis of IBD in patients with PSC. PMID- 20920597 TI - CT and MRI improve detection of hepatocellular carcinoma, compared with ultrasound alone, in patients with cirrhosis. AB - BACKGROUND & AIMS: In patients with cirrhosis, hepatocellular carcinoma (HCC) is detected by ultrasound (US), computed tomography (CT), or magnetic resonance imaging (MRI); US is recommended for screening and surveillance. We performed a retrospective analysis of the abilities of these cross-sectional imaging modalities to detect HCC. METHODS: We analyzed data from 638 consecutive adult patients with cirrhosis who received liver transplants within 6 months of imaging at a tertiary care institution. Imaging reports and serum alpha-fetoprotein levels were compared with results from pathology analysis of explants as the reference standard. Sensitivities of US, CT, and MRI were calculated overall and in defined size categories. False-positive imaging results and patient-based specificities were evaluated. RESULTS: Of the 638 patients, 225 (35%) had HCC, confirmed by pathology analysis of liver explants. In 23 cases, the lesions were infiltrative or extensively multifocal. In the remaining 202 explants (337 numerable, discrete nodules), respective lesion-based sensitivities of US, CT, and MRI were 46%, 65%, and 72% overall and 21%, 40%, and 47% for small (<2 cm) HCC. The sensitivity of US increased with the availability of CT or MRI data (P = .049); sensitivity values were 62% and 85% for lesions 2-4 and >= 4 cm, respectively. Patient-based specificities of US, CT, and MRI were 96%, 96%, and 87%, respectively. CONCLUSIONS: US, CT, and MRI did not detect small HCC lesions with high levels of sensitivity, although CT and MRI provide substantial improvements over unenhanced US in patients with cirrhosis who received liver transplants. PMID- 20920598 TI - Umbilical metastasis: Sister Mary Joseph's nodule. PMID- 20920599 TI - Esophageal eosinophilic infiltration responds to proton pump inhibition in most adults. AB - BACKGROUND & AIMS: Despite consensus recommendations, eosinophilic esophagitis (EoE) is commonly diagnosed upon esophageal eosinophilic infiltration (EEI; based on >= 15 eosinophils per high power field; eo/HPF). We evaluated the prevalence of EEI before and after proton pump inhibitor (PPI) therapy and assessed the accuracy of EEI and pH monitoring analyses. METHODS: Biopsies were taken from the upper-middle esophagus of 712 adults with upper gastrointestinal symptoms who were referred for endoscopy due to upper gastrointestinal symptoms. Patients with EEI were treated with rabeprazole (20 mg, twice daily) for 2 months. EoE was defined by persistent symptoms and >15 eo/HPF following PPI therapy. RESULTS: Thirty-five patients (4.9%) had EEI, of whom 55% had a history of allergies, and 70% had food impaction or dysphagia as their primary complaint. Twenty-six EEI patients (75%) achieved clinicopathological remission with PPI therapy; of these, 17 had GERD-like profile (EEI <35 eo/HPF and objective evidence of reflux, based on endoscopy or pH monitoring), and 9 had EoE-like profile (EEI 35-165 eo/HPF, typical EoE symptoms and endoscopic findings). The PPI response was 50% in the EoE-like profile patients. The PPI-response was 50% in EoE-like profile patients. Likewise, PPI-responsive EEI occurred with normal (33%) and pathologic (80%) pH monitoring. Higher histologic cut-off values improved specificity and positive predictive for EoE (35%-35% for >20 eo/HPF; 46%-39% for >24 eo/HPF; 65%-50% for 35 eo/HPF). CONCLUSIONS: In adults with EEI, 75% of unselected patients and 50% with an EoE phenotype respond to PPI therapy; pH monitoring is poorly predictive of response. Patients with PPI-responsive EEI >35 eo/HPF are phenotypically undistinguishable from EoE patients. EoE might be overestimated without clinical and pathologic follow-up of patient response to PPI. PMID- 20920600 TI - Incidence of sports-related sudden cardiac death: the Danish paradox. PMID- 20920601 TI - Current-to-load mismatch, Brugada ECG pattern, and the associated arrhythmogenesis. PMID- 20920602 TI - First experience with rotational angiography of the right ventricle to guide ventricular tachycardia ablation. AB - BACKGROUND: Rotational angiography with three-dimensional reconstruction (3DRA) is a new imaging tool recently introduced to guide mapping and ablation of the left atrium. OBJECTIVE: The purpose of this study was to determine the utility of 3DRA for imaging the ventricles and guiding ventricular tachycardia (VT) ablation. METHODS: Using the Philips Allura Xper FD10 system, 3DRA was performed in eight patients referred for right ventricular outflow tract (RVOT) VT ablation. The imaging protocol for right ventricular (RV) injection is described. IV contrast was injected at the RA/IVC junction over 4 sec and 3DRA was obtained immediately. Images were segmented manually on the EP Navigator workstation and registered on live fluoroscopy. Intracardiac electrograms were superimposed on 3DRA creating a true electroanatomic map (ElectroNav). CARTO mapping and echocardiograms were performed on all patients, cardiac computed tomography (CT) in 4, and magnetic resonance imaging (MRI) in 1. RESULTS: Three-dimensional rotational angiography was successful in 7 of 8 patients. Image interpretation was unsuccessful in one patient due to poor isocentering. RV imaging was performed with 82 +/- 18 mL of contrast. RV image segmentation required 19 +/- 5 minutes. CARTO maps of the RVOT required 43 +/- 12 minutes and additional fluoroscopy. Three-dimensional rotational angiography was used to guide VT ablation by providing realistic anatomic images of the pulmonary valve plane, endo-views of the ventricle, and ablation point tagging. Anatomic detail provided by 3DRA was qualitatively superior to CARTO. VT ablation was acutely successful in all patients. Close concordance between echocardiographic, CT/MRI, and 3DRA measurements of the RVOT was observed (r = 0.9, P <.01). CONCLUSION: Three dimensional rotational angiography of the RV and RVOT is a feasible imaging technique that utilizes a protocol of timed angiography, manual segmentation, image registration, and superimposition of intracardiac electrograms to create an angiogram-based electroanatomic model of these structures. PMID- 20920603 TI - Case of coronary perforation with epicardial access for ablation of ventricular tachycardia. PMID- 20920605 TI - Statistical methods for a phase II oncology trial with a growth modulation index (GMI) endpoint. AB - For cytostatic cancer therapies, alternatives to traditional phase II endpoints are needed. Von Hoff (1998) proposed an intrapatient progression-free survival (PFS) ratio, the growth modulation index (GMI). Current practice in estimation of the GMI success rate is conservative and omits a measure of uncertainty. We investigated nonparametric and parametric methods to estimate the GMI success rate, including an approach using midranks for paired survival outcomes (Hudgens and Satten (2002)). Estimators were applied to a phase II GMI dataset (Bonetti et al. (2001)). From simulation studies, it was determined that a rank-based estimator had the most favorable statistical properties. Its point estimate bias was consistently within 1.5%; its bias and precision were robust over a range of effect and censoring scenarios. Using a proof of concept criterion of {P(GMI>=1)>=theta}, a simulation investigation found that a theta of 50%, for sample sizes between 20 and 30 patients, had type I error of <=20% and a power to detect Von Hoff's 1.33 effect of >=80%. When the amount of censoring was >=20%, the midrank estimator had a minimum of 14% greater power over the simple percentage estimator for the GMI success rate. Future investigations reporting the GMI should consider adopting the midrank methodology. PMID- 20920607 TI - IS6110-based global phylogeny of Mycobacterium tuberculosis. AB - IS6110, a Mycobacterium tuberculosis complex species-specific insertion element, is targeted primarily for DNA fingerprinting of M. tuberculosis strains. The number and chromosomal positions of copies of this element have been found to be highly variable between unrelated strains and have been exploited for molecular epidemiological purpose but the utility of IS6110 as an informative marker of strain phylogeny has yet to be demonstrated. In the current study, a recently proposed IS6110-targetting PCR based typing methodology, fluorescent amplified fragment length polymorphism (fAFLP) was applied to a global panel of 166 of the clinically more predominant 'modern' strains characterised by spoligotype and, where available, Variable Number Tandem Repeat (VNTR) to identify potentially evolutionarily informative common fragments that could define strains as belonging to established genetic lineages. These common fragments are hereby proposed to be ancestral insertion sites present in common ancestors of these strains rather than preferential insertion sites or 'hot spots'. Results indicate that the exact same spoligotype and VNTR-defined lineages are reflected in the fragment patterns but with greater resolution and are able to clearly define the very distinct Haarlem, LAM, X and also the currently ill-defined T and S and lineages and spoligotypes designated as U, or unknown, without ambiguity. The biogeographical patterns generated reflect the migration of mankind across the globe and indicate that only four successful clones (or individual bacteria) gave rise to virtually all of the tuberculosis in Europe and the Americas. Potential lies in the application of the data to determine IS6110 evolutionary events that have occurred during the evolution of these lineages. PMID- 20920606 TI - Distinct tissue distributions and subcellular localizations of differently phosphorylated forms of the myosin regulatory light chain in Drosophila. AB - Nonmuscle myosin II (myosin hereafter) has well-established roles in generating contractile force on actin filaments during morphogenetic processes in all metazoans. Myosin activation is regulated by phosphorylation of the myosin regulatory light chain (MRLC, encoded by spaghettisquash or sqh in Drosophila) first on Ser21 and subsequently on Thr20. These phosphorylation events are positively controlled by a variety of kinases including myosin light chain kinase, Rho kinase, citron kinase, and AMP kinase and are negatively regulated by myosin phosphatase. The activation of myosin is thus highly regulated and likely developmentally controlled. In order to monitor the activity of myosin during development, we have generated antibodies against the monophosphorylated (Sqh1P) and diphosphorylated (Sqh2P) forms of Sqh. We first show that the antibodies are highly specific. We then used these antibodies to monitor myosin activation in wild type Drosophila tissues. Interestingly, Sqh1P and Sqh2P show distinct patterns of expression in embryos. Sqh1P is expressed nearly ubiquitously and outlines cells consistent with a junctional localization, whereas Sqh2P is strongly expressed on the apical surfaces and in filopodia of tissues undergoing extensive cell shape change or cell movements including the invaginating fore- and hindgut, the invaginating tracheal system, the dorsal pouch and the dorsal most row of epidermal (DME) cells during dorsal closure. In imaginal discs, Sqh1P predominantly localizes in the adherens junction, whereas Sqh2P locates to the apical domain. These antibodies thus have the potential to be very useful in monitoring myosin activation for functional studies of morphogenesis in Drosophila. PMID- 20920608 TI - EuPathDomains: the divergent domain database for eukaryotic pathogens. AB - Eukaryotic pathogens (e.g. Plasmodium, Leishmania, Trypanosomes, etc.) are a major source of morbidity and mortality worldwide. In Africa, one of the most impacted continents, they cause millions of deaths and constitute an immense economic burden. While the genome sequence of several of these organisms is now available, the biological functions of more than half of their proteins are still unknown. This is a serious issue for bringing to the foreground the expected new therapeutic targets. In this context, the identification of protein domains is a key step to improve the functional annotation of the proteins. However, several domains are missed in eukaryotic pathogens because of the high phylogenetic distance of these organisms from the classical eukaryote models. We recently proposed a method, co-occurrence domain detection (CODD), that improves the sensitivity of Pfam domain detection by exploiting the tendency of domains to appear preferentially with a few other favorite domains in a protein. In this paper, we present EuPathDomains (http://www.atgc-montpellier.fr/EuPathDomains/), an extended database of protein domains belonging to ten major eukaryotic human pathogens. EuPathDomains gathers known and new domains detected by CODD, along with the associated confidence measurements and the GO annotations that can be deduced from the new domains. This database significantly extends the Pfam domain coverage of all selected genomes, by proposing new occurrences of domains as well as new domain families that have never been reported before. For example, with a false discovery rate lower than 20%, EuPathDomains increases the number of detected domains by 13% in Toxoplasma gondii genome and up to 28% in Cryptospordium parvum, and the total number of domain families by 10% in Plasmodium falciparum and up to 16% in C. parvum genome. The database can be queried by protein names, domain identifiers, Pfam or Interpro identifiers, or organisms, and should become a valuable resource to decipher the protein functions of eukaryotic pathogens. PMID- 20920609 TI - Statistical phylogeography of Chagas disease vector Triatoma infestans: testing biogeographic hypotheses of dispersal. AB - Chagas disease is one of the most important vector-borne diseases in Latin America. The disease, caused by the flagellate protozoan Trypanosoma cruzi, is commonly transmitted to humans by Triatoma infestans in South America. Using mitochondrial DNA sequences, we assessed alternative biogeographic scenarios of dispersal of T. infestans using coalescence simulations. We also assessed phylogeographic structure and spatial genetics of T. infestans in Chile. Two major routes of dispersal in southern South America were supported including a dual-origin of T. infestans in Chile. Phylogeographic analyses identified two primary clades with Chilean haplotypes partitioned into either a northern cluster with Peruvian and Bolivian haplotypes or a north-central cluster with Argentinean and Uruguayan haplotypes. The north-central clade is further divided into two subgroups. Domestic and sylvatic T. infestans in central Chile were not segregated in the phylogeographic reconstruction. Spatial genetic analyses show higher distances in northern Chile, congruent with the presence of two divergent lineages of T. infestans. Phylogenetic evidence does not unequivocally support the hypothesized Bolivian origin of T. infestans, so we discuss alternative scenarios. PMID- 20920610 TI - Complex V TMEM70 deficiency results in mitochondrial nucleoid disorganization. AB - Mutations in the TMEM70 gene are responsible for a familial form of complex V deficiency presenting with 3-methylglutaconic aciduria, lactic acidosis, cardiomyopathy and mitochondrial myopathy. Here we present a case of TMEM70 deficiency due to compound heterozygous mutations, who displayed abnormal mitochondria with whorled cristae in muscle. Immunogold electron microscopy and tomography shows for the first time that nucleoid clusters of mtDNA are disrupted in the abnormal mitochondria, with both nucleoids and mitochondrial respiratory chain complexes confined to the outer rings of the whorls. This could explain the differential effects on the expression and assembly of complex V in different tissues. PMID- 20920611 TI - Why docosahexaenoic acid and aspirin supplementation could be useful in women as a primary prevention therapy against Alzheimer's disease? AB - The assumption that disease specific risk factors are similar or the same in men and women may lead to incorrect primary prevention strategies. This study focused on the evaluation of gender-specific Alzheimer's disease (AD) risk factors. In AD, female gender appears to be an important risk factor associated with the aberrant production of beta amyloid (betaA) peptides. Although decreased levels in plasma DHA concentration are associated with cognitive decline in healthy elderly and Alzheimer's patients, pre-treatment with DHA significantly reduced the survival of cortical neurons incubated with beta amyloid (betaA). Hence, in the presence of an increasing amount of betaA, paradoxically women - who have higher plasma levels of DHA - are more likely to develop AD. Aspirin (ASA) converts cyclooxygenase (COX)-2 into a form that generates new neuroprotective docosanoids from DHA; therefore, ASA might positively resolve the paradoxical effect of the concomitant presence of DHA and betaA. PMID- 20920612 TI - Catastrophic antiphospholipid syndrome in a community-acquired methicillin resistant Staphylococcus aureus infection: a review of pathogenesis with a case for molecular mimicry. AB - Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) has remarkable pathogenicity and can cause severe infections, such as necrotizing pneumonia, necrotizing fasciitis, and sepsis. To our knowledge, no case of CA MRSA resulting in catastrophic antiphospholipid syndrome (CAPS) has been reported. Furthermore, no specific pathogenic link between these two disorders has been described. Staphylococcal sequence homologies and binding capabilities to plasma protein beta2-glycoprotein I (beta2-GPI) may result in anti-beta2-GPI antibody production. These antibodies represent the critical prothrombotic factor in pathogenesis of antiphospholipid syndrome and CAPS. However, the development of CAPS requires additional prothrombotic activities. In our case, sepsis and CA MRSA-induced leukocytolysis likely represent the activity required to transform a hypercoagulable state into the life threatening, diffusely thrombotic CAPS. The presence of anti-beta2GPI-antibodies and diffuse microvascular occlusion are characteristic of CAPS. However, other life threatening syndromes cause microvascular thrombi and multiorgan failure, and more studies are needed to determine the frequency of antiphospholipid antibodies and clinical syndromes consistent with CAPS in patients with staphylococcal infections. PMID- 20920613 TI - Devic's syndrome and SLE: challenges in diagnosis and therapeutic possibilities based on two overlapping cases. AB - Neuromyelitis optica (NMO, Devic's disease), an uncommon demyelinating neuro immunological disease, can be associated with autoimmune diseases. In SLE associated forms anti-aquaporin-4 antibody positivity can help differentiating between SLE nerve system manifestation and NMO. In the literature rituximab, or immunoablative dose cyclophosphamide (CYC) was effective for the therapy resistant forms. Authors present 2 SLE overlapping NMO cases, one of them with SLE associated interstitial lung disease (ILD). In both cases neurological manifestations anticipated other SLE symptoms. Patients previously were treated with high dose corticosteroid therapy, plasmapheresis, and one of them with azathioprine, and the other one with oral CYC (which could not prevent flares). 0.5 g/m2 body-surface monthly parenteral inductive CYC therapy was administered, in one patient followed by quarterly maintenance therapy. This patient completed her 18 month maintenance treatment and has been in neurological remission, but required steroid pulse and plasmapheresis for lung symptoms. The second patient had urogenital infection after the induction phase, followed by an exacerbation, requiring plasmapheresis and high dose parenteral corticosteroid treatment. After it he refused CYC therapy and has been taking azathioprine. He has no new symptoms, only residual ones. In our two patients conventional dose CYC therapy proved to be effective for NMO/SLE overlap, required only transient supportive therapy. PMID- 20920614 TI - Insights into the mechanism of magnetic particle assisted gene delivery. AB - In magnetic particle assisted gene delivery DNA is complexed with polymer-coated aggregated magnetic nanoparticles (AMNPs) to effect transfection. In vitro studies based on COS-7 cells were carried out using pEGFP-N1 and pMIR-REPORT complexed, polyethylenimine (PEI)-coated iron oxide magnetic nanoparticles (MNPs). PEI-coated AMNPs (PEI-AMNPs) with average individual particle diameters of 8, 16 and 30 nm were synthesized. Normal, reverse and retention magnetic transfection experiments and cell wounding assays were performed. Our results show that the optimum magnetic field yields maximum transfection efficiency with good viability. The results of the normal, reverse and retention magnetic transfection experiments show that the highest transfection efficiency was achieved in normal magnetic transfection mode due to clustering of the PEI-AMNPs on the cells. Cell wounding assay results suggest that the mechanism of magnetic transfection is endocytosis rather than cell wounding. PMID- 20920615 TI - Effects of humidity on the mechanical properties of gecko setae. AB - We tested the hypothesis that an increase in relative humidity (RH) causes changes in the mechanical properties of the keratin of adhesive gecko foot hairs (setae). We measured the effect of RH on the tensile deformation properties, fracture, and dynamic mechanical response of single isolated tokay gecko setae and strips of the smooth lamellar epidermal layer. The mechanical properties of gecko setae were strongly affected by RH. The complex elastic modulus (measured at 5 Hz) of a single seta at 80% RH was 1.2 GPa, only 39% of the value when dry. An increase in RH reduced the stiffness and increased the strain to failure. The loss tangent increased significantly with humidity, suggesting that water absorption produces a transition to a more viscous type of deformation. The influence of RH on the properties of the smooth epidermal layer was comparable with that of isolated seta, with the exception of stress at rupture. These values were two to four times greater for the setae than for the smooth layer. The changes in mechanical properties of setal keratin were consistent with previously reported increases in contact forces, supporting the hypothesis that an increase in RH softens setal keratin, which increases adhesion and friction. PMID- 20920616 TI - Structural and material approaches to bone tissue engineering in powder-based three-dimensional printing. AB - This article reviews the current state of knowledge concerning the use of powder based three-dimensional printing (3DP) for the synthesis of bone tissue engineering scaffolds. 3DP is a solid free-form fabrication (SFF) technique building up complex open porous 3D structures layer by layer (a bottom-up approach). In contrast to traditional fabrication techniques generally subtracting material step by step (a top-down approach), SFF approaches allow nearly unlimited designs and a large variety of materials to be used for scaffold engineering. Today's state of the art materials, as well as the mechanical and structural requirements for bone scaffolds, are summarized and discussed in relation to the technical feasibility of their use in 3DP. Advances in the field of 3DP are presented and compared with other SFF methods. Existing strategies on material and design control of scaffolds are reviewed. Finally, the possibilities and limiting factors are addressed and potential strategies to improve 3DP for scaffold engineering are proposed. PMID- 20920617 TI - Penicillium oxalicum SAEM-51: a mutagenised strain for enhanced production of chitin deacetylase for bioconversion to chitosan. AB - A novel chitin deacetylase (CDA) producing strain Penicillium oxalicum ITCC 6965 was isolated from residual materials of sea food processing industries. Strain following mutagenesis using ethidium bromide (EtBr) and microwave irradiation had resulted into a mutant P. oxalicum SAE(M)-51 having improved levels of chitin deacetylase (210.71 +/- 1.65 Ul(-1)) as compared to the wild type strain (108.26 +/- 1.98 Ul(-1)). Maximum enzyme production was achieved in submerged fermentation following 144 hours of incubation with notably improved productivity of 1.46 +/- 0.82 Ul(-1) h(-1) as compared to the wild type strain (0.75 +/- 0.53 Ul(-1)h(-1)). Scanning electron micrographs of mutant and wild type strains had revealed distinct morphological features. Evaluation of kinetic parameters viz. Q(s), Q(p), Y(p/x), Y(p/s), q(p), q(s) had denoted that strain P. oxalicum SAE(M) 51 is a hyper producer of chitin deacetylase. Glucose as compared to chitin or colloidal chitin had resulted in increased levels of enzyme production. However, replacement of glucose with chitinous substrates had prolonged the duration for enzyme production. The mutant strain had two pH optima that is 6.0 and 8.0 and had an optimum temperature of 30 degrees C for growth and enzyme production. PMID- 20920618 TI - Nutritional regulation of protease production by the feather-degrading bacterium Chryseobacterium sp. kr6. AB - The effects of nutritional conditions on growth and protease production by the feather-degrading Chryseobacterium sp. kr6 were investigated. Higher growth was observed on feather-containing or tryptone (TR) medium when compared to casein (CA) or glucose-nitrogen (GN) base medium. Protease production occurred during growth on feather-containing and TR media, whereas no protease activity was detected on CA or GN medium, indicating that protease production is not constitutive, depending on the presence of specific complex nitrogen sources. Supplementation of whole feathers (WF) medium with glucose (WFG) or NH(4)Cl (WFN) did not result in major differences in growth and protease production, whereas soluble protein was lower in supplemented media. Glucose consumption and growth were higher on WFG than on GN medium, suggesting that the absence of a specific complex nitrogen source limited bacterial growth. On WF medium, this strain grew closely attached to the feather structures, initially on the barbules and subsequently on the feather rachis. It was observed, through zymogram analysis, that strain kr6 produced diverse proteolytic enzymes in response to different growth substrates. These results were confirmed by the differential behaviors of crude proteases towards protease inhibitors. PMID- 20920623 TI - Nitrogen-containing bisphosphonates can inhibit angiogenesis in vivo without the involvement of farnesyl pyrophosphate synthase. AB - Nitrogen-containing bisphosphonates (N-BPs) are widely used to block bone destruction associated with bone metastasis because they are effective inhibitors of osteoclast-mediated bone resorption. More specifically, once internalized by osteoclasts, N-BPs block the activity of farnesyl pyrophosphate synthase (FPPS), a key enzyme in the mevalonate pathway. In addition to their antiresorptive activity, preclinical evidence shows that N-BPs have antiangiogenic properties. However, the exact reasons for which N-BPs inhibit angiogenesis remain largely unknown. Using different angiogenesis models, we examined here the effects of zoledronate, risedronate and three structural analogs of risedronate (NE-58025, NE-58051 and NE-10790) with lower potencies to inhibit FPPS activity. Risedronate and zoledronate were much more potent than NE-compounds at inhibiting both endothelial cell proliferation in vitro and vessel sprouting in the chicken egg chorioallantoic membrane (CAM) assay. In addition, only risedronate and zoledronate inhibited the revascularization of the prostate gland in testosterone stimulated castrated rats. Moreover, as opposed to NE-compounds, risedronate and zoledronate induced intracellular accumulation of isopentenyl pyrophosphate (IPP) in endothelial cells by blocking the activity of the IPP-consuming enzyme FPPS. Thus, these results indicated that N-BPs inhibited angiogenesis in a FPPS dependent manner. However, drug concentrations used to inhibit angiogenesis, both in vitro and in the CAM and prostate gland assays, were high. In contrast, a low concentration of risedronate (1 MUM) was sufficient to inhibit blood vessel formation in the ex vivo rat aortic ring assay. Moreover, NE-58025 (which had a 7 fold lower potency than risedronate to inhibit FPPS activity) was as effective as risedronate to reduce angiogenesis in the rat aortic ring assay. In conclusion, our results suggest that low concentrations of N-BPs inhibit angiogenesis in a FPPS-independent manner, whereas higher drug concentrations were required to inhibit FPPS activity in vivo. PMID- 20920628 TI - SPECT V/Q imaging of the lungs. PMID- 20920629 TI - Why SPECT for V/Q lung scanning? PMID- 20920630 TI - Transition from planar to SPECT V/Q scintigraphy: rationale, practicalities, and challenges. AB - Compared with planar imaging, ventilation/perfusion scintigraphy performed with single-photon emission computed tomography (SPECT) has a greater sensitivity and specificity, greater accuracy, improved reproducibility, and a lower number of inconclusive reports in the detection of pulmonary embolism. Despite these improvements, there are several challenges that must be overcome for the transition from planar imaging to SPECT imaging to be successful, including a lack of familiarity with 3D imaging of the lungs by some reporting specialists, the selection of a ventilation agent appropriate for SPECT acquisitions, and a different approach in the image reporting. The transition to SPECT imaging can be facilitated by generating planar-like images from the SPECT data, with which many reporting specialists are more familiar. SPECT ventilation/perfusion acquisition times are generally equal to or shorter than conventional planar imaging, studies are easier for technologists to acquire, and modern computing provides several new approaches to image processing and display. PMID- 20920631 TI - V/Q imaging in 2010: a quick start guide. AB - In this article we review protocols for ventilation-perfusion (V/Q) imaging with current generation technology. Although many groups have expressed interest in moving from planar lung V/Q imaging to single-photon emission computed tomography (SPECT) methods, few resources or guidelines exist for suggested protocols. Here, we provide an introduction to help establish protocols for planar and SPECT V/Q imaging and display that should be readily transferable into a clinical department's routine practice. We emphasize, in particular, the need for a good ventilation study and that acquiring planar images as well as SPECT can be negated by producing acceptable planar-like images from the SPECT data. PMID- 20920632 TI - Methodology for ventilation/perfusion SPECT. AB - Ventilation/perfusion single-photon emission computed tomography (V/Q SPECT) is the scintigraphic technique of choice for the diagnosis of pulmonary embolism and many other disorders that affect lung function. Data from recent ventilation studies show that the theoretic advantages of Technegas over radiolabeled liquid aerosols are not restricted to the presence of obstructive lung disease. Radiolabeled macroaggregated human albumin is the imaging agent of choice for perfusion scintigraphy. An optimal combination of nuclide activities and acquisition times for ventilation and perfusion, collimators, and imaging matrix yields an adequate V/Q SPECT study in approximately 20 minutes of imaging time. The recommended protocol based on the patient remaining in an unchanged position during the initial ventilation study and the perfusion study allows presentation of matching ventilation and perfusion slices in all projections as well as in rotating volume images based upon maximum intensity projections. Probabilistic interpretation of V/Q SPECT should be replaced by a holistic interpretation strategy on the basis of all relevant information about the patient and all ventilation/perfusion patterns. PE is diagnosed when there is more than one subsegment showing a V/Q mismatch representing an anatomic lung unit. Apart from pulmonary embolism, other pathologies should be identified and reported, for example, obstructive disease, heart failure, and pneumonia. Pitfalls exist both with respect to imaging technique and scan interpretation. PMID- 20920633 TI - V/Q SPECT and computed tomographic pulmonary angiography. AB - Planar ventilation and perfusion (V/Q) scintigraphy has been largely displaced by computed tomography pulmonary angiography (CTPA) in recent years for the diagnosis of pulmonary embolism (PE). This change can be attributed to multiple studies that demonstrate CTPA has a reasonable sensitivity and good prognostic value in negative cases, associated with the ability to deliver few indeterminate results and provide an alternate diagnosis in a significant number of patients. However, the technique has significant limitations. The Prospective Investigation of Pulmonary Embolism Diagnosis II (PIOPED II) study has shown a sensitivity of 83%, which is not optimal. However, CT technology has greatly progressed since this time, and therefore it is likely that this number has improved. The PIOPED II study has also shown that there may be a problem in positive or negative predictive value when the imaging results are discordant with the clinical probability. Additional concerns include allergies, contrast nephropathy associated with the use of intravenous contrast in patients with impaired creatinine clearance, suboptimal results in pregnant women, and high radiation exposure. In recent years, V/Q single-photon emission computed tomography has emerged as a mature technique for the diagnosis of PE and has been shown to be clearly superior to planar V/Q. The technique has excellent sensitivity for PE and is not associated with most of the limitations of CTPA, although it has its own set of limitations in patients with very severe chronic obstructive pulmonary disease or with a severely abnormal chest x-ray. V/Q single-photon emission computed tomography can be used as the initial modality for PE diagnosis in a wide variety of situations although CTPA remains invaluable in specific scenarios. PMID- 20920634 TI - Radiation dosimetry and safety issues in the investigation of pulmonary embolism. AB - When considering the investigation of the patient with possible pulmonary embolism, one needs to balance the likelihood of disease and the diagnostic utility of the test against the risks associated with the investigation. Both computed tomography pulmonary angiography (CTPA) and the ventilation/perfusion (V/Q) scan involve exposure to ionizing radiation. The effect of low-level ionizing radiation remains an issue of some controversy. CTPA delivers a greater effective dose and, in particular, greater doses to breast tissue, than the V/Q scan (typically 10-70 mGy for CTPA vs <1.5 mGy for V/Q to breast). Since breast tissue is particularly radiosensitive in younger women, the V/Q study has an advantage over CTPA in this group. In the pregnant patient, fetal exposure has been raised as a concern. In fact, there is typically only low fetal exposure from either study (<1 mGy). The CTPA does deliver less fetal exposure, particularly in the first trimester, but the difference between CTPA and V/Q scan is small when compared with the difference in dose to maternal breast from the 2 investigations. The "as low as reasonably achievable" (ie, ALARA) principle favors the use of V/Q scans in young women, assuming the diagnostic power of the 2 tests is comparable. CTPA requires a contrast injection that can cause adverse reactions in a small number of patients. No significant risk, however, has been demonstrated with the radiopharmaceuticals involved in V/Q scans. PMID- 20920635 TI - SPECT/CT in V/Q scanning. AB - Combining the functional data provided by single-photon emission computed tomography (SPECT) with the anatomical information provided by CT has been shown to improve overall diagnostic accuracy in many areas of nuclear medicine. Although planar lung scans have often relied on correlation with a chest x-ray to help optimize scan interpretation, the advent of 3D lung imaging with SPECT provides the opportunity to combine lung perfusion data with CT images. This can be done by performing the study on a hybrid SPECT/CT scanner, with the CT acquisition typically performed with the use of low-dose parameters, rather than full diagnostic quality settings, or by software fusion with a fully diagnostic CT or a contrast-enhanced CT pulmonary angiogram. Such an approach has been shown to improve specificity and overall accuracy of ventilation/perfusion scintigraphy as well as facilitating more accurate clot localization. With the increased availability of hybrid SPECT/CT scanners, such an approach can be implemented in most imaging departments with little additional acquisition time or radiation dose. Misregistration caused by respiratory motion can impact combined studies, although this can be minimized with attention to patient breathing patterns during image acquisition. For patients with lung cancer, ventilation/perfusion SPECT/CT may have a role in allowing the optimal selection of radiotherapy fields and can improve the preoperative quantification of lung function before resection. PMID- 20920636 TI - V/Q SPECT: utility for investigation of pulmonary physiology. AB - Single-photon emission computed tomography (SPECT) is being increasingly used as a tool in respiratory research, in particular ventilation SPECT. Much of the basic understanding of pulmonary physiology has been derived from inhaled radioactive inert gases because, as the lung behaves in an asymmetric manner, the nature of regional differences in ventilation is ideally studied with the use of imaging. It is well known to clinicians that ventilation is patchy in patients who have airways disease. However, the relevance to the disease mechanisms itself only started to be studied with the use of 3-dimensional imaging and with advances in quantitative image analysis. The measurements of both ventilation distribution and nonventilation (airway closure) have become very topical in the study of asthma, and accurate quantification of those parameters is of relevance to disease mechanisms. In chronic obstructive pulmonary disease, the drive is towards better characterization of disease groups ("phenotypes") and, again, description of ventilation patterns may prove to be useful. This is a review, therefore, on pulmonary SPECT imaging in respiratory research which includes a focus on methodology in relation to respiratory physiology. There has been relatively little published in this area but there is great potential for advances in the understanding of airways disease to be gained from SPECT imaging. PMID- 20920637 TI - SPECT imaging of pulmonary emboli with radiolabeled thrombus-specific imaging agents. AB - The safe and accurate diagnosis of acute pulmonary embolism (PE) remains challenging, and many PE-related deaths still occur before the detection of PE. Current techniques detect PE as "negative images," ie, the absence of contrast or downstream perfusion. There would be advantages to obtaining "positive images" of PE, by targeting imaging agents to components that are present primarily on thromboemboli. In addition to providing alternative means of diagnosing acute PE, they would also enable acute PE to be distinguished from other types of pulmonary arterial obstruction, such as unresolved intravascular defects attributable to previous PE. Positive images of PE require imaging agents to bind onto target antigens that are present predominantly on thromboemboli. The "D dimer" regions of polymerized fibrin are present in high concentrations on thromboemboli and are sufficiently accessible to binding. (99m)Tc-lableled anti-D-dimer deimmunized monoclonal antibody Fab' fragments (DI-DD-3B6/22-80B3) bind specifically to thromboemboli, with a thrombus: blood labeling ratio that allows scintigraphic detection. Another thrombus-specific imaging agent is (99m)Tc-labeled apcitide, a synthetic peptide that binds with a high affinity and specificity to the glycoprotein IIb/IIIa receptor on the membrane of activated platelets. Both of these agents have enabled the detection of lower extremity deep vein thrombi by planar scintigraphy. However, even highly radiolabeled PEs are difficult to distinguish by planar scintigraphy from the large blood pool in the heart and lungs. The spatial and contrast resolution inherent to single-photon emission computed tomography (SPECT) scanning allow the in situ imaging of pulmonary emboli that have been bound by radiolabeled thrombus-specific imaging agents. Preliminary trials in humans with acute PE have shown that the emboli can be detected after intravenous administration of (99m)Tc-lableled anti-D dimer, followed by SPECT scanning. Although clinical results are still preliminary, it appears that imaging of pulmonary emboli with SPECT, after administration of radiolabeled thrombus-specific antibody fragments, is accurate and clinically feasible. PMID- 20920638 TI - Antiplatelet therapy in acute coronary syndrome (ACS): applying new science to clinical decisions. AB - The platelet is central to the pathogenesis of acute coronary syndromes (ACS), and antiplatelet therapy has demonstrated a significant reduction in the risk for ischemic events in patients with ACS. For patients with unstable angina or non-ST elevation myocardial infarctions, regardless of whether a conservative or invasive (i.e., percutaneous intervention) treatment approach is used, current guidelines recommend combination antiplatelet therapies, including aspirin with the thienopyridines clopidogrel or prasugrel and/or a glycoprotein IIb/IIIa inhibitor. However, there remains a significant incidence of arterial thrombosis in patients receiving currently available antiplatelet therapy, indicating the need for improved and/or alternative agents and targets. Recent landmark clinical trials of new oral antiplatelet therapies, including the thienopyridine prasugrel and the investigational reversible oral adenosine diphosphate antagonist ticagrelor, indicate they have a faster onset of action, result in a more predictable response, and provide improved efficacy compared to clopidogrel, the current standard of care. Other promising potential targets under investigation to reduce the contribution of the platelet to ACS pathophysiology include von Willebrand factor, thromboxane A(2), and protease-activated receptor-1. Of these, the protease-activated receptor-1 antagonist vorapaxar (SCH 530348) is furthest along in clinical development, with phase II data showing profound inhibition of platelet aggregation and a large phase III development program under way. A fundamental lingering issue is whether improved prevention and treatment of thrombosis can be separated from an increase in hemorrhage or bleeding, and clinicians must continue to consider the potential risks and benefits when individualizing antiplatelet therapy for patients with ACS. PMID- 20920639 TI - Low-density lipoprotein cholesterol level in patients with acute myocardial infarction having percutaneous coronary intervention (the cholesterol paradox). AB - The relation between low-density lipoprotein (LDL) cholesterol levels and clinical outcomes after percutaneous coronary intervention (PCI) in patients with acute myocardial infarction (AMI) has not been described. A total of 9,571 eligible patients (mean age 62.6 +/- 12.5 years, 6,967 men) who underwent PCI with a final diagnosis of AMI from the Korea Acute Myocardial Infarction Registry (KAMIR) were divided into 5 groups according to LDL cholesterol level: < 70, 70 to 99, 100 to 129, 130 to 159, and >= 160 mg/dl. Clinical outcomes in hospital and 1 and 12 months after PCI in patients with AMI were examined. Age and co morbidities decreased as LDL cholesterol increased. Patients with higher LDL cholesterol levels had favorable hemodynamic status and laboratory findings. Lifesaving medications, including lipid-lowering drugs, were underused in patients with lower LDL cholesterol levels. Clinical outcomes in hospital and 1 and 12 months after PCI showed better results as LDL cholesterol increased, except for patients with LDL cholesterol levels >= 160 mg/dl. In a Cox proportional-hazards model, LDL cholesterol level was not an independent predictor of mortality at 12 months, after adjusting for clinical characteristics including demographics and biologic data. In conclusion, the cholesterol paradox in patients with AMI is related to confounding by baseline characteristics associated with survival. More intensive treatment including lipid-lowering therapy for AMI in patients with lower LDL cholesterol level may result in better clinical outcomes. PMID- 20920640 TI - Correlates and consequences of gastrointestinal bleeding complicating percutaneous coronary intervention. AB - Gastrointestinal bleeding (GIB) complicating percutaneous coronary intervention (PCI) results in high mortality, but clinical factors associated with and long term outcomes of GIB are poorly understood. We sought to examine clinical and procedural factors associated with GIB complicating PCI. We also examined the impact of GIB on 30-day mortality and 1-year major adverse cardiac events (MACEs). Patients undergoing PCI from January 2000 to January 2010 were retrospectively analyzed for the occurrence of in-hospital GIB. Multivariable logistic regression and Cox proportional hazards regression were used to identify predictors of in-hospital GIB and 30-day mortality. Landmark analysis of patients surviving to hospital discharge was performed to assess the impact of GIB on 1 year MACEs. Of 20,621 patients who underwent PCI, 147 (0.72%) who developed in hospital GIB were identified. Variables associated with increased risk of GIB included older age, shock, acute myocardial infarction, chronic renal insufficiency, lower baseline hematocrit, and glycoprotein IIb/IIIa inhibitors; bivalirudin decreased the risk. Unadjusted 30-day mortality rate of patients with GIB was 20.5% compared to 2.4% of patients without GIB. After multivariable adjustment, GIB and shock (and an interaction between the 2) were the most important correlates of 30-day mortality. In the population surviving to discharge, however, GIB was not associated with adjusted mortality or MACEs. In conclusion, GIB complicating PCI has a dramatic impact on 30-day mortality, and bivalirudin was associated with lower rates of GIB. PMID- 20920641 TI - Meta-analysis of incidence, clinical characteristics and implications of stent fracture. AB - A meta-analysis of published studies was conducted to evaluate the incidence, predictors, and clinical outcomes of stent fractures. Eight studies with 108 stent fractures in 5,321 patients were analyzed using the Bayesian method. Study end points included in-stent restenosis (ISR) and target lesion revascularization (TLR). The mean incidence of stent fracture per patient was 4.0% (95% confidence interval 0.4% to 16.3%). All cases, except 1, were reported with sirolimus eluting stents. The incidence of stent fracture was 30.4% in the left anterior descending coronary artery, 10.9% in the left circumflex coronary artery, 56.4% in the right coronary artery, < 0.01% in the left main coronary artery, and 1.7% in saphenous vein grafts. The probability of stent fracture was significantly higher in the right coronary artery than in the left anterior descending and left circumflex lesions (p < 0.01). Left main stents were less likely to fracture compared to those in all other vessels (p < 0.01). The probability of stent fracture was significantly increased in overlapping stents (7.5% vs 2.1%, p = 0.01) and long stents (46 vs 32.5 mm, p < 0.01). Lesions with stent fractures had higher rates of ISR (38% vs 8.2%, p < 0.01) and TLR (17% vs 5.6%, p < 0.01). Conversely, the probability of stent fractures was higher in patients with ISR (12.8% vs 2.1%, p < 0.01) and TLR (8.8% vs 2.7%, p < 0.01). In conclusion, although not always associated with clinical sequelae, the probability of ISR and TLR is increased with stent fracture. Conversely, the probability of stent fractures is increased in lesions with ISR or TLR, thus raising the need for surveillance and management guidelines for at-risk patients. PMID- 20920642 TI - Acute myocardial infarction due to left circumflex artery occlusion and significance of ST-segment elevation. AB - Acute occlusion of the left circumflex (LC) artery can be difficult to diagnose. The aim of the present study was to assess the incidence of LC occlusion in patients with acute myocardial infarction (AMI) requiring percutaneous coronary intervention (PCI), the frequency of ST-segment versus non-ST-segment elevation presentation among them, and to correlate the electrocardiographic findings with the outcomes. The clinical characteristics and outcomes of consecutive patients from November 2001 through December 2007 with AMI within 7 days before PCI of a single acutely occluded culprit vessel were included in the present analysis. Of the 1,500 patients, the culprit lesion was located in the right coronary artery, left anterior descending artery, or LC artery in 44.7%, 35.8%, and 19.5% of patients, respectively. Of the 1,500 patients, 72% presented with ST-segment elevation AMI, but only 43% were patients with a LC lesion (n = 127). PCI was significantly less likely (80%, 83%, and 70% for right coronary, left anterior descending, and LC artery, respectively; p < 0.001) to be performed within 24 hours for LC occlusions than for occlusions in the other territories. Among those with a non-ST-segment elevation AMI, the highest post-PCI troponin levels were in patients with a LC artery occlusion (median 1.4, 1.3, and 2.5 ng/ml; p < 0.001). No significant difference was found in the in-hospital mortality (4.4%, 7.4%, and 6.5%; p = 0.66) or major adverse cardiovascular event (9.2%, 13.9%, and 11.6%; p = 0.53) rates for right, left anterior descending, and LC occlusions, respectively. In conclusion, our results have demonstrated that in clinical practice, the LC artery is the least frequent culprit vessel among patients treated invasively for AMI. Patients with LC occlusion are less likely to present with ST-segment elevation AMI and have emergency PCI. The study results suggest that detection of these patients has been suboptimal, highlighting the need to improve the diagnostic approach toward the detection of an acutely occluded LC artery. PMID- 20920643 TI - Long-term outcomes after percutaneous coronary intervention of left main coronary artery for treatment of cardiac allograft vasculopathy after orthotopic heart transplantation. AB - The present study evaluated the safety and efficacy of percutaneous coronary intervention (PCI) of the unprotected left main coronary artery (ULMCA) for the treatment of cardiac allograft vasculopathy (CAV) in consecutive unselected patients with orthotopic heart transplantation (OHT). PCI in patients with OHT and develop CAV has been associated with greater restenosis rates compared to PCI in patients with native coronary artery disease. A paucity of short- and long term data is available from patients with OHT who have undergone PCI for ULMCA disease. The present retrospective, multicenter, international registry included 21 patients with OHT and CAV who underwent ULMCA PCI from 1997 to 2009. Angiographic success was achieved in all patients. Drug-eluting stents were used in 14 of the 21 patients. No major adverse cardiac events or repeat OHT occurred within the first 30 days. At a mean follow-up of 4.9 +/- 3.2 years, 3 patients (14%) had died, myocardial infarction had occurred in 1 patient (5%), and target lesion revascularization had been required in 4 patients (19%). Follow-up angiography was performed in 16 patients (76%), and restenosis was observed in 4 (19%). No stent thrombosis of the ULMCA was observed. One patient (5%) underwent coronary artery bypass grafting, and 5 patients (24%) underwent repeat OHT. In conclusion, the results of our study have shown ULMCA PCI to be safe and reasonably effective in patients with OHT and represents a viable treatment strategy for CAV in these patients. PMID- 20920644 TI - Aspirin adherence, aspirin dosage, and C-reactive protein in the first 3 months after acute coronary syndrome. AB - Persistent elevation of inflammatory markers such as C-reactive protein (CRP) has been associated with an increased risk of recurrent cardiac events after acute coronary syndromes (ACS). Conflicting evidence is available regarding whether aspirin can reduce CRP after ACS. We investigated whether the dosage and adherence to aspirin was associated with the CRP level 3 months after ACS. Adherence to aspirin was monitored for 3 months in a cohort of 105 patients enrolled within 1 week of an ACS using an electronic chip stored in the pill bottle cap. The CRP level was measured at baseline and 3 months. Logistic regression analysis was used to test whether poor adherence to aspirin and a lower aspirin dosage were associated with increased CRP levels, controlling for age, ACS type, disease co-morbidity, baseline CRP level, use of clopidogrel and statins, depressive symptoms, smoking, and adherence to other medications. Aspirin adherence was inversely correlated with the CRP level at 3 months (Spearman's r = -0.36, p < 0.001). In the adjusted model, every 10% decrease in aspirin adherence was associated with a 1.7 increased risk (95% confidence interval 1.2 to 2.4) of a CRP level of >= 3.0 mg/L at 3 months. Low-dose aspirin was associated with a 7.1 increased risk (95% confidence interval 1.5 to 33.3) of a CRP level of >= 3.0 mg/L. The Charlson co-morbidity index, depressive symptoms, and baseline CRP level were also predictive of a CRP level of >= 3.0 mg/L at 3 months. The association between aspirin adherence and CRP level was not attenuated by controlling for other risk-reducing behaviors. In conclusion, a strong association was found between aspirin adherence and the CRP level after an ACS. PMID- 20920645 TI - Trends in incidence and mortality rates of ventricular septal rupture during acute myocardial infarction. AB - Since the introduction of reperfusion in the treatment of acute myocardial infarction (AMI), rates of ventricular septal rupture (VSR) and associated mortality have decreased, but it is not known if incidence and mortality have continued to decrease. We describe trends in incidence and mortality rates of patients with postinfarction VSR during the previous 2 decades and identify risk factors that predict the development and mortality of this rare but catastrophic complication. We analyzed occurrence and mortality rates in patients with first AMI with (n = 408) and without VSR (n = 148,473) who were hospitalized from 1990 to 2007 using the New Jersey Myocardial Infarction Data Acquisition System (MIDAS) database. The annual rate of VSR in AMI was 0.25% to 0.31%. Compared to patients with AMI without VSR, patients with VSR were older, more likely to be women, had increased rate of chronic renal disease, congestive heart failure, and cardiogenic shock, and were less likely to be hypertensive or diabetic (all p values < 0.0001). During the 18-year study period, we found no change in hospital and 1-year mortalities, which were 41% and 60% in 1990 to 1992 and 44% and 56% in 2005 to 2007, respectively. The survival benefit associated with VSR surgical repair was seen only in hospital (hazard ratio 0.66, 95% confidence interval 0.45 to 0.95) but not at 30 days or 1 year. In conclusion, despite improvement in medical treatment and revascularization techniques, the rate of VSR complicating AMI has not changed during the previous 2 decades, and the mortality associated with VSR has remained high and relatively constant. PMID- 20920646 TI - Relation of alcohol consumption to angiographically proved coronary artery disease in chinese men. AB - Light-to-moderate alcohol consumption is believed to be protective against coronary artery disease (CAD) in many studies. However, the cardioprotective effects of alcohol intake lack epidemiologic evidence in a Chinese population. The present case-control study was designed to explore the relation between alcohol consumption and angiographically proved CAD in Chinese men. The study population consisted of 1,476 consecutive men 36 to 84 years of age who underwent coronary arteriography. Participants were categorized as nondrinkers, light drinkers, moderate drinkers, and heavy drinkers. Adjusted odds ratios for light, moderate, and heavy drinking were 1.16 (95% confidence interval 0.68 to 1.94), 1.78 (1.35 to 2.27), and 2.18 (1.46 to 3.25). Adjusted odds ratios were 1.36 (1.08 to 1.83) for drinking alcohol 2 to 3 days/week, 1.58 (1.17 to 2.26) for 4 to 5 days/week, and 2.03 (1.36 to 3.27) for 6 to 7 days/week. Compared to nondrinking, adjusted odds ratios were 1.03 (0.54 to 1.87) for drinking 0 to 15 years, 1.61 (1.28 to 2.14) for 16 to 30 years, and 1.98 (1.23 to 3.05) for > 30 years. In conclusion, moderate-to-heavy alcohol consumption increased the risk of CAD in Chinese men. CAD risk tended to increase with an increase in frequency and duration of drinking. PMID- 20920647 TI - Depressive symptoms and all-cause mortality in unstable angina pectoris (from the Coronary Psychosocial Evaluation Studies [COPES]). AB - Although depression is clearly associated with increased mortality after acute myocardial infarction, there is a paucity of data examining the impact of depression on patients with unstable angina (UA). We analyzed the relation between depressive symptoms and all-cause mortality in patients with UA who were enrolled in a prospective multicenter study of depression and acute coronary syndrome (ACS). Depressive symptoms were measured with the Beck Depression Inventory (BDI) within 1 week of the ACS event, and patients were selected for a BDI score 0 to 4 or >= 10. Our sample included 209 patients with UA, with 104 (50%) having a BDI score >= 10. Proportional hazards analyses adjusted for variables including left ventricular ejection fraction, Global Registry of Acute Coronary Events risk score, and Charlson co-morbidity index. In multivariable analyses, a BDI score >= 10 was associated with increased risk of 42-month all cause mortality (hazard ratio 2.04, 95% confidence interval 1.20 to 3.46, p = 0.008) compared to a BDI score 0 to 4. In conclusion, our results confirm and extend previous evidence linking depression to worse outcomes in UA and suggest that interventions that address depression may be worth examining across the spectrum of risk in ACS. PMID- 20920648 TI - Variation in hospital mortality rates for patients with acute myocardial infarction. AB - Hospitals vary by twofold in their hospital-specific 30-day risk-stratified mortality rates (RSMRs) for Medicare beneficiaries with acute myocardial infarction (AMI). However, we lack a comprehensive investigation of hospital characteristics associated with 30-day RSMRs and the degree to which the variation in 30-day RSMRs is accounted for by these characteristics, including the socioeconomic status (SES) profile of hospital patient populations. We conducted a cross-sectional national study of hospitals with >=15 AMI discharges from July 1, 2005 to June 20, 2008. We estimated a multivariable weighted regression using Medicare claims data for hospital-specific 30-day RSMRs, American Hospital Association Survey of Hospitals for hospital characteristics, and the United States Census data reported by Neilsen Claritas, Inc., for zip code level estimates of SES status. Analysis included 2,908 hospitals with 513,202 AMI discharges. Mean hospital 30-day RSMR was 16.5% (SD 1.7 percentage points). Our multivariable model explained 17.1% of the variation in hospital specific 30-day RSMRs. Teaching status, number of hospital beds, AMI volume, cardiac facilities available, urban/rural location, geographic region, ownership type, and SES profile of patients were significantly (p < 0.05) associated with 30-day RSMRs. In conclusion, substantial variation in hospital outcomes for patients with AMI remains unexplained by measurements of hospital characteristics including SES patient profile. PMID- 20920649 TI - Usefulness of intravascular low-power laser illumination in preventing restenosis after percutaneous coronary intervention. AB - Despite the several years of studies, no factor that could reduce the restenosis rate without significant limitations has been introduced. The aim of the present study was to evaluate the influence of low-power 808-nm laser illumination of coronary vessels after percutaneous angioplasty in preventing restenosis. The procedure of laser intravascular illumination was performed on 52 patients (laser group), and another 49 patients formed the control group. All patients were monitored for major adverse cardiac events (MACE) at the 6- and 12-month follow up points. The MACE rate after 6 and 12 months was 7.7% in the laser group at both points. The MACE rate was 14.3% and 18.5% at 6 and 12 months of follow-up in the control group, respectively (p = NS). Follow-up coronary angiography was performed after 6 months. The difference in the restenosis rate was insignificant (15.0% vs 32.4%); however, significant differences were observed in the minimal lumen diameter (2.18 +/- 0.70 vs 1.76 +/- 0.74 mm; p < 0.05), late lumen loss (0.53 +/- 0.68 vs 0.76 +/- 0.76 mm; p < 0.01), and the late lumen loss index (0.28 +/- 0.39 vs 0.46 +/- 0.43; p < 0.005) in favor of the laser group. In conclusion, the new therapy seemed effective and safe. Marked differences between late loss, late loss index, and minimal lumen diameter were observed. The late lumen loss in the laser group was only slightly greater than that in studies of drug-eluting stents, and MACE rate remained within very comparable ranges. This suggests that intravascular laser illumination could bring advantages comparable to those of drug-eluting stents without the risk of late thrombosis. PMID- 20920650 TI - Relation of plasma fatty acid binding proteins 4 and 5 with the metabolic syndrome, inflammation and coronary calcium in patients with type-2 diabetes mellitus. AB - Fatty acid-binding proteins (FABPs) 4 and 5 play coordinated roles in rodent models of inflammation, insulin resistance, and atherosclerosis, but little is known of their role in human disease. The aim of this study was to examine the hypothesis that plasma adipocyte and macrophage FABP4 and FABP5 levels would provide additive value in the association with metabolic and inflammatory risk factors for cardiovascular disease as well as subclinical atherosclerosis. Using the Penn Diabetes Heart Study (PDHS; n = 806), cross-sectional analysis of FABP4 and FABP5 levels with metabolic and inflammatory parameters and with coronary artery calcium, a measure of subclinical coronary atherosclerosis, was performed. FABP4 and FABP5 levels had strong independent associations with the metabolic syndrome (for a 1-SD change in FABP levels, odds ratio [OR] 1.85, 95% confidence interval [CI] 1.43 to 2.23, and OR 1.66, 95% CI 1.41 to 1.95, respectively) but had differential associations with metabolic syndrome components. FABP4 and FABP5 were also independently associated with C-reactive protein and interleukin-6 levels. FABP4 (OR 1.26, 95% CI 1.05 to 1.52) but not FABP5 (OR 1.13, 95% CI 0.97 to 1.32) was associated with the presence of coronary artery calcium. An integrated score combining FABP4 and FABP5 quartile data had even stronger associations with the metabolic syndrome, C-reactive protein, interleukin-6, and coronary artery calcium compared to either FABP alone. In conclusion, this study provides evidence for an additive relation of FABP4 and FABP5 with the metabolic syndrome, inflammatory cardiovascular disease risk factors, and coronary atherosclerosis in type 2 diabetes mellitus. These findings suggest that FABP4 and FABP5 may represent mediators of and biomarkers for metabolic and cardiovascular disease in type 2 diabetes mellitus. PMID- 20920651 TI - Prevalence and spectrum of large deletions or duplications in the major long QT syndrome-susceptibility genes and implications for long QT syndrome genetic testing. AB - Long QT syndrome (LQTS) is a cardiac channelopathy associated with syncope, seizures, and sudden death. Approximately 75% of LQTS is due to mutations in genes encoding for 3 cardiac ion channel alpha-subunits (LQT1 to LQT3). However, traditional mutational analyses have limited detection capabilities for atypical mutations such as large gene rearrangements. We set out to determine the prevalence and spectrum of large deletions/duplications in the major LQTS susceptibility genes in unrelated patients who were mutation negative after point mutation analysis of LQT1- to LQT12-susceptibility genes. Forty-two unrelated, clinically strong LQTS patients were analyzed using multiplex ligation-dependent probe amplification, a quantitative fluorescent technique for detecting multiple exon deletions and duplications. The SALSA multiplex ligation-dependent probe amplification LQTS kit from MRC-Holland was used to analyze the 3 major LQTS associated genes, KCNQ1, KCNH2, and SCN5A, and the 2 minor genes, KCNE1 and KCNE2. Overall, 2 gene rearrangements were found in 2 of 42 unrelated patients (4.8%, confidence interval 1.7 to 11). A deletion of KCNQ1 exon 3 was identified in a 10-year-old Caucasian boy with a corrected QT duration of 660 ms, a personal history of exercise-induced syncope, and a family history of syncope. A deletion of KCNQ1 exon 7 was identified in a 17-year-old Caucasian girl with a corrected QT duration of 480 ms, a personal history of exercise-induced syncope, and a family history of sudden cardiac death. In conclusion, because nearly 5% of patients with genetically elusive LQTS had large genomic rearrangements involving the canonical LQTS-susceptibility genes, reflex genetic testing to investigate genomic rearrangements may be of clinical value. PMID- 20920652 TI - Annual incidence of atrial fibrillation and related factors in adults. AB - The aim of this study was to investigate the annual incidence of atrial fibrillation (AF) and related factors from health surveys in 2006 and 2007. Participants (aged >= 40 years) were examined from annual health surveys provided by the Kurashiki Public Health Center twice, in 2006 and 2007. Participants were classified into 2 groups: a control group without AF in 2006 and 2007, and an AF group with documented AF in 2007 but not in 2006. Annual AF incidence (per 1,000 patient-years) was calculated, and baseline characteristics were compared between groups. Independent factors for new documented AF were analyzed using multivariate logistic regression modeling. Health surveys were performed for 30,449 participants in 2006 and 2007. Excluding 439 participants with AF in 2006, newly documented AF was observed in 278 participants (0.9%), while the control group comprised 29,732 participants. The overall incidence of newly documented AF was 9.3/1,000 patient-years. Newly documented AF was significantly associated with age >= 80 years (odds ratio [OR] 1.57, 95% confidence interval [CI] 1.20 to 2.06, p = 0.001), history of cardiac disease (OR 7.47, 95% CI 5.79 to 9.63, p < 0.001), increasing estimated glomerular filtration rate of 10 ml/min/1.73 m(2) (OR 0.93, 95% CI 0.87 to 0.99, p = 0.025), and hypercholesterolemia (OR 0.75, 95% CI 0.58 to 0.96, p = 0.023). PMID- 20920654 TI - Impact of worsening renal function during hospital admission on resource utilization in patients with heart failure. AB - Renal impairment frequently accompanies heart failure (HF) and is a recognized independent risk factor for morbidity and mortality. Few data are available assessing the impact of worsening renal function (WRF) during hospitalization on health care resource use in patients with HF. Health Insurance Portability and Accountability Act-compliant, de-identified, clinical, laboratory, and economic data for patients admitted to a tertiary care medical center with a primary diagnosis of HF were extracted by MedMining and reviewed retrospectively by the authors. Patients were excluded if they had no previous HF or were admitted for acute coronary syndrome or coronary artery bypass grafting within 30 days of index hospitalization. WRF was defined as >= 0.3 mg/dl increase in serum creatinine from baseline at any time during hospitalization. Of 5,803 hospitalized patients with primary HF diagnosis, 827 patients (14%) fulfilled all prespecified inclusion and exclusion criteria (74 +/- 14 years of age, 43% men, 98% white, admission serum creatinine 1.4 +/- 0.9 mg/dl, estimated glomerular filtration rate < 90 ml/min/1.73 m(2) at admission in 83%). During index hospitalization, WRF was identified in nearly 33%. Compared to patients without WRF, those with WRF had greater prevalence of diabetes (54% vs 43%), lower estimated glomerular filtration rate (44 +/- 30 vs 62 +/- 35 ml/min/1.73 m(2)), higher serum potassium (4.3 +/- 0.7 vs 4.2 +/- 0.7 mEq/L), and higher B-type natriuretic peptide (845 +/- 821 vs 795 +/- 947 pg/ml) at baseline (all p values < 0.05). Patients developing WRF incurred higher total inpatient costs ($10,977, range 671 to 212,819, vs $7,820, range 697 to 269,797, p < 0.001) and longer hospital stay (8.2 +/- 6.8 vs 5.7 +/- 5.5 days, p < 0.001). In conclusion, occurrence of WRF during HF-related hospitalization is associated with higher hospitalization costs and longer hospital stay. PMID- 20920653 TI - Effect of serum insulin on the association between hyperuricemia and incident heart failure. AB - Increased serum uric acid (UA) is associated with incident heart failure (HF). However, whether it is a direct effect of UA or an effect of increased xanthine oxidase (XO) is unknown. Because hyperuricemia in hyperinsulinemia is primarily due to impaired renal UA excretion, its association with incident HF would suggest a direct UA effect. In contrast, hyperuricemia in normoinsulinemia is likely due to increased UA production and thus its association with incident HF would suggest an XO effect. To clarify this, we examined the association of hyperuricemia with centrally adjudicated incident HF in Cardiovascular Health Study participants with and without hyperinsulinemia. Of the 5,411 participants >= 65 years of age without baseline HF, 1,491 (28%) had hyperuricemia (serum UA >= 6 mg/dl for women and >= 7 mg/dl for men). Propensity scores for hyperuricemia were estimated using 63 baseline characteristics. Mean serum UA levels were 6.0 and 5.3 mg/dl in those with (n = 2,731) and those without (n = 2,680) hyperinsulinemia (median serum insulin >= 13 mU/L), respectively (p < 0.001). Propensity-adjusted hazard ratios (95% confidence intervals) for hyperuricemia associated incident HF during 8 years of median follow-up were 0.99 (0.83 to 1.18, p = 0.886) and 1.32 (1.04 to 1.67, p = 0.021) for those with and without hyperinsulinemia respectively (p for interaction = 0.014). In conclusion, the absence of an association of hyperuricemia with incident HF in those with hyperinsulinemia (despite a significantly higher mean serum UA) and a significant association in normoinsulinemia suggest that UA has no intrinsic association with incident HF and that it may predict incident HF when it is a marker of increased of XO activity. PMID- 20920655 TI - Effect of cardiac resynchronization therapy in patients with New York Heart Association functional class IV heart failure. AB - Cardiac resynchronization therapy (CRT) is considered a class I indication in treatment of patients with New York Heart Association (NYHA) functional class III and IV heart failure. However, only small numbers of patients in large clinical trials have been in NYHA functional class IV. Therefore, little is known about the effects of CRT in this group. Therefore, we evaluated the effects of CRT in patients with NYHA functional class IV heart failure. Of all patients referred for CRT implantation, 61 patients with symptoms according to NYHA functional class IV were included. All patients were evaluated before implantation and at 6 month follow-up for clinical changes according to the clinical composite score and changes in left ventricular (LV) volumes and function. In addition, survival was evaluated during long-term follow-up. At 6-month follow-up, 9 patients (15%) had died and 2 patients (3%) were admitted for worsening heart failure. The remaining 39 patients (64%) showed improvement according to the clinical composite score. Decreases in LV end-systolic volume (from 167 +/- 88 to 147 +/- 93 ml, p = 0.009) and LV end-diastolic volume (from 211 +/- 100 to 199 +/- 113 ml, p = 0.135) were observed, as was a significant increase in LV ejection fraction (from 22 +/- 8% to 28 +/- 9%, p <0.001). During a mean follow-up of 30 +/- 26 months, 36 patients (59%) died, 27 (75%) from worsening heart failure. Respective 1- and 2-year mortality rates were 25% and 38%. In conclusion, CRT decreases LV volumes and improves cardiac function in patients with NYHA functional class IV heart failure. Nevertheless, (heart failure) mortality remains high in these patients. PMID- 20920656 TI - Usefulness of left atrial volume versus diameter to assess thromboembolic risk in mitral stenosis. AB - In patients with mitral stenosis (MS) in sinus rhythm (SR), guidelines recommend anticoagulation if the left atrium is enlarged based on diameter measurements. We sought to compare the association of left atrial (LA) diameter and LA volume with markers of thromboembolic risk (peak LA appendage emptying velocity [LAAv] and LA spontaneous contrast density) measured during transesophageal echocardiography in 152 patients with moderate to severe MS. High thromboembolic risk was defined by a peak LAAv < 25 cm/s and/or dense spontaneous contrast. Mean LA diameter (50 +/- 7 mm, 32 to 77) and LA volume (152 +/- 70 ml, 67 to 720) were significantly correlated (r = 0.71, p < 0.0001), but the relation was curvilinear and the 95% confidence interval increased with LA diameter. In the subset of 80 patients in SR who underwent clinically indicated transesophageal echocardiography, body surface area (BSA)-indexed LA volume but not LA diameter differentiated patients with normal from those with low LAAv (86 +/- 17 vs 71 +/- 17 ml/m(2), p < 0.01, and 50 +/- 6 vs 48 +/- 6 mm, p = 0.13, respectively) and patients with dense spontaneous contrast from those with no or mild spontaneous contrast (81 +/- 16 vs 63 +/- 15 ml/m(2), p < 0.01, and 49 +/- 6 vs 46 +/- 5 mm, p = 0.11, respectively). BSA-indexed LA volume provided the highest area under the curve (0.85) for high thromboembolic risk and LA diameter the lowest (0.65). A BSA indexed LA volume > 60 ml/m(2) provided an excellent 90% sensitivity despite 44% specificity, 76% positive predictive value, and 70% negative predictive value. Use of this threshold instead of 50 or 55 mm would have changed the indication for anticoagulation in 51% to 77% of patients. In conclusion, LA volume was more strongly associated with markers of thromboembolic risk than LA diameter, which poorly reflected LA size. Our results support the use of BSA-indexed LA volume to guide the decision for anticoagulation in patients with MS in SR, which may lead to significant change in the management of those patients. We suggest a threshold of 60 ml/m(2), which has good sensitivity, albeit with low specificity. PMID- 20920657 TI - Impact of aortic valve stenosis on left atrial phasic function. AB - The aim of this study was to determine the impact of aortic stenosis (AS) on the different components of left atrial (LA) function. The study consisted of a total of 52 consecutive patients with severe AS (aortic valve area < 1 cm(2)) and 20 normal subjects matched for gender, heart rate, body surface area, and baseline systolic blood pressure. Phasic LA longitudinal function was assessed using tissue Doppler imaging. LA peak systolic (reservoir function), early diastolic (conduit function), and late diastolic (active function) strain rates were measured. During late diastole, LA peak strain (active function) was also measured. Mitral annular systolic, early diastolic (Ea), and late diastolic (Aa) velocities were also measured. Compared with controls, all strain values were significantly reduced in patients with AS. By multivariate regression analysis, mitral E-wave deceleration time (p = 0.033) and E/Ea ratio (p = 0.02, R(2) = 0.43) emerged as independently associated with LA peak systolic strain rate. Ea was the sole determinant of LA early diastolic strain rate (p < 0.0001, R(2) = 0.42), whereas LA late diastolic strain rate was independently related to aortic valve area (p = 0.031) and Aa (p = 0.022, R(2) = 0.51). In conclusion, in patients with severe AS, the 3 components of LA function are reduced. LA reservoir dysfunction is related to left ventricular filling pressures, whereas LA conduit dysfunction depends on left ventricular relaxation. Active LA dysfunction is related to the severity of AS and late left ventricular diastolic function. PMID- 20920658 TI - Sexuality in adult patients with congenital heart disease and their partners. AB - Data on relational and sexuality issues in adult patients with congenital heart disease (CHD) are scarce. The present study aimed to evaluate relational and sexual behaviors, satisfaction, and functioning in a representative sample of patients with CHD and their partners. In addition, we aimed to evaluate the relation between sexuality parameters and quality of life. Relational and sexuality issues were assessed using a sexuality questionnaire in 133 patients (52% men, 37 +/- 13 years old) with CHD (43 with coarctation of the aorta, 42 with transposition of great arteries, 36 with Marfan syndrome, and 12 with Eisenmenger syndrome), and 74 partners. Quality of life was assessed using the Dutch translation of the Medical Outcomes Study Short Form 36-Item Health Survey. Data were compared to an age- and gender-matched control group (n = 3,642). Seventy-one percent of patients with CHD were involved in a relationship, which was significantly less compared to controls (79%, p < 0.05). Nonetheless, patients perceived their relationship as more satisfactory compared to controls (p < 0.05). Overall, sexual satisfaction was equal in patients compared to controls, although they perceived lower body esteem (p < 0.001), decreased sexual esteem (p < 0.05), and more distress during sex (p < 0.001). Patients reported no more erectile and lubrication problems compared to partners and to controls. We found significant associations between most relational and sexual parameters and quality of life. In conclusion, many aspects of sexuality are affected in adult patients with CHD, whereas their partners remain relatively unaffected. Moreover, sexuality is an important aspect of quality of life in these patients. We advise physicians to be receptive to discuss sexuality issues and provide patients with adequate therapy. PMID- 20920659 TI - Relation of cardiac ventricular repolarization and global cognitive performance in a community population. AB - Atherosclerosis is a risk factor for dementia. However, little is known about the association between cognitive performance and a widely used indicator of coronary heart disease, at rest electrocardiography. We identified 839 older residents (mean age 81 years, 58% black) from a geographically defined biracial community in Chicago, Illinois, who had undergone extensive cognitive performance testing and met the electrocardiographic eligibility criteria, including a QRS duration of < 120 ms. We then examined multivariate regression coefficients that described the associations between global cognitive performance and 4 novel descriptors of ventricular repolarization waveforms. All analyses were adjusted for age, gender, education, and race. The T wave nondipolar voltage had a significant association with global cognitive performance (p = 0.01), and this association largely remained after adjustment for cardiovascular disease risk factors (p = 0.03). In contrast, global cognitive performance was not significantly associated with the rate-adjusted QT interval, the voltage change from the beginning to end of the ST segment in lead V(5), or the spatial angle between the mean QRS and T wave vectors. In conclusion, the strengths of the associations varied between the novel electrocardiographic descriptors of ventricular repolarization and global cognitive performance. Nevertheless, the significant association observed with T wave nondipolar voltage suggests that the cardiac effects of heart disease are associated with cognitive declines. PMID- 20920660 TI - Differentiation between spontaneous echocardiographic contrast and left atrial appendage thrombus in patients with suspected embolic stroke using two-phase multidetector computed tomography. AB - The detection of a thrombus at the left atrial appendage (LAA) is an important step for management in a patient with a suspected embolic infarction. However, spontaneous echocardiographic contrast (SEC), which can mimic thrombus, can confuse clinicians in many cases. We examined electrocardiographic-gated 64-slice multidetector computed tomography with a 2-phase scan and transesophageal echocardiography in 314 patients with suspected embolic stroke. The transesophageal echocardiographic findings were classified using a 5-grade scale and the multidetector computed tomographic findings were categorized as no filling defect, an early filling defect (a filling defect seen on early-phase images without considering the late-phase images), and a persistent filling defect (a filling defect seen on added late-phase images, as well as on early phase images). For quantitative analysis, the ratio of Hounsfield units in the LAA to the ascending aorta (AA) was calculated for each early-phase and late phase image (LAA/AA(L)). Using transesophageal echocardiography as the reference standard, for no filling defect seen on early-phase images, the presence of a thrombus, including severe SEC, could be ruled out with 100% sensitivity and a 100% negative predictive value. When considering the addition of late-phase images, all persistent filling defects had resulted from the presence of a thrombus and severe SEC. However, using the optimal cutoff value of 0.5 for the LAA/AA(L) ratio, thrombi could be distinguished from severe SEC where all thrombi had a LAA/AA(L) ratio < 0.5. In conclusion, our findings suggest that 2-phase multidector computed tomography is useful for the detection and differentiation of a thrombus from SEC at the LAA in patients with suspected embolic stroke. PMID- 20920661 TI - Effect of increasing body mass index on image quality and positive predictive value of 100-kV coronary computed tomographic angiography. AB - Lowering the voltage to 100 kV is an effective method of reducing the radiation of coronary computed tomographic angiography (CTA). It is unknown, however, whether one could use a 100-kV CTA protocol with overweight or obese patients. We, thus, evaluated the effect of increasing body mass index (BMI) on various image quality parameters of 100-kV CTA. We also compared the radiation dose and diagnostic accuracy of 100-kV CTA with CTA performed at 120 kV. Three different protocols were studied: 120 kV, retrospective; 100 kV, retrospective; and 100 kV, prospective. The image quality and radiation doses were analyzed for each protocol. The effect of increasing BMI was also examined. A worsening of the noise, contrast-to-noise, and signal-to-noise ratios occurred with increasing BMI and decreasing voltages. The radiation exposure was significantly lowered with the 100-kV protocol and with prospective gating. Despite this image degradation, however, diagnostic images were obtained with 100-kV CTA, even in overweight and many obese subjects. Of the 66 subjects referred for invasive angiography because of the findings from CTA, 55 were correctly characterized (overall positive predictive value [PPV] of 83.3%). This PPV remained reasonable, irrespective of the voltage, until a BMI of 35 kg/m(2) was reached (PPV for 100-kV protocol 90.0% [27 of 30]; PPV for a BMI of >= 25 kg/m(2) but < 30 kg/m(2) 84.4% [27 of 32]; and PPV for a BMI of >= 30 kg/m(2) but < 35 kg/m(2) 81.8% [18 of 22]). In conclusion, 100-kV coronary CTA is feasible in overweight and many obese subjects. PMID- 20920662 TI - Usefulness of a Z-score of E' versus raw E' velocities to detect left ventricular dysfunction in patients with mitral or aortic regurgitation or dilated cardiomyopathy. AB - Despite their potential as a sensitive measure of ventricular performance, tissue Doppler velocities vary with normal aging. This is inconvenient for nonspecialists to interpret and makes it difficult to use as an entry criterion for clinical studies. The age-adjusted tissue Doppler Z-scores might avoid these disadvantages and be more discriminant for myocardial impairment than the raw velocities. We conducted a meta-regression of studies reporting age-specific normal tissue Doppler velocities to determine a consensus formula for Z-scores (8 studies, 1,867 patients) that we then tested in an independent study at our institution. We next compared the Z-scores head-to-head with the raw velocities for their ability to distinguish a fresh set of 81 healthy subjects from groups in whom subtle ventricular dysfunction might be expected, including 50 patients with dilated cardiomyopathy, 50 with aortic regurgitation, and 50 with mitral regurgitation. The discriminant capacity, assessed by the area under the receiver operating characteristic curves, was higher for the Z-scores than for the raw velocities in each patient group. At the septal angle of the mitral annulus: dilated cardiomyopathy 0.95 versus 0.92 (p = 0.03), aortic regurgitation 0.83 versus 0.78 (p = 0.02), mitral regurgitation 0.85 versus 0.81 (p = 0.04). At the lateral angle: dilated cardiomyopathy 0.94 versus 0.88 (p = 0.005), aortic regurgitation 0.92 versus 0.83 (p = 0.001), mitral regurgitation 0.87 versus 0.85 (p = 0.31). In conclusion, the Z-scores of the tissue Doppler velocities were better than the raw velocities at detecting myocardial impairment in valvular or heart muscle disease. The calculation needs only the raw velocity and patient age. Tissue Doppler Z-scores could be used to create a novel, more sensitive, definition of ventricular dysfunction and might make it easier for nonspecialists to interpret the reports. PMID- 20920663 TI - Profound left ventricular remodeling associated with LAMP2 cardiomyopathy. AB - Lysosome-associated membrane protein (LAMP2) cardiomyopathy is an X-linked and highly progressive myocardial storage disorder associated with diminished survival, which clinically resembles sarcomeric hypertrophic cardiomyopathy. As shown here in a young woman, the natural history of LAMP2 may demonstrate an extreme profile of left ventricular remodeling with regression of hypertrophy (i.e. marked wall thinning), chamber dilatation, and severe systolic dysfunction, all of which are associated with widespread transmural scarring. PMID- 20920664 TI - Understanding FDA regulation of DTC genetic tests within the context of administrative law. AB - How the FDA should regulate direct-to-consumer genetic tests is fiercely contested. Passing a rule or issuing an order is only one down in the series. There is more to the regulatory game. PMID- 20920665 TI - Identification of copy number variation hotspots in human populations. AB - Copy number variants (CNVs) in the human genome contribute to both Mendelian and complex traits as well as to genomic plasticity in evolution. The investigation of mutational rates of CNVs is critical to understanding genomic instability and the etiology of the copy number variation (CNV)-related traits. However, the evaluation of the CNV mutation rate at the genome level poses an insurmountable practical challenge that requires large samples and accurate typing. In this study, we show that an approximate estimation of the CNV mutation rate could be achieved by using the phylogeny information of flanking SNPs. This allows a genome-wide comparison of mutation rates between CNVs with the use of vast, readily available data of SNP genotyping. A total of 4187 CNV regions (CNVRs) previously identified in HapMap populations were investigated in this study. We showed that the mutation rates for the majority of these CNVRs are at the order of 10-5 per generation, consistent with experimental observations at individual loci. Notably, the mutation rates of 104 (2.5%) CNVRs were estimated at the order of 10-3 per generation; therefore, they were identified as potential hotspots. Additional analyses revealed that genome architecture at CNV loci has a potential role in inciting mutational hotspots in the human genome. Interestingly, 49 (47%) CNV hotspots include human genes, some of which are known to be functional CNV loci (e.g., CNVs of C4 and beta-defensin causing autoimmune diseases and CNVs of HYDIN with implication in control of cerebral cortex size), implicating the important role of CNV in human health and evolution, especially in common and complex diseases. PMID- 20920666 TI - Mutations in the SPTLC2 subunit of serine palmitoyltransferase cause hereditary sensory and autonomic neuropathy type I. AB - Hereditary sensory and autonomic neuropathy type I (HSAN-I) is an axonal peripheral neuropathy associated with progressive distal sensory loss and severe ulcerations. Mutations in the first subunit of the enzyme serine palmitoyltransferase (SPT) have been associated with HSAN-I. The SPT enzyme catalyzes the first and rate-limiting step in the de novo sphingolipid synthesis pathway. However, different studies suggest the implication of other genes in the pathology of HSAN-I. Therefore, we screened the two other known subunits of SPT, SPTLC2 and SPTLC3, in a cohort of 78 HSAN patients. No mutations were found in SPTLC3, but we identified three heterozygous missense mutations in the SPTLC2 subunit of SPT in four families presenting with a typical HSAN-I phenotype. We demonstrate that these mutations result in a partial to complete loss of SPT activity in vitro and in vivo. Moreover, they cause the accumulation of the atypical and neurotoxic sphingoid metabolite 1-deoxy-sphinganine. Our findings extend the genetic heterogeneity in HSAN-I and enlarge the group of HSAN neuropathies associated with SPT defects. We further show that HSAN-I is consistently associated with an increased formation of the neurotoxic 1 deoxysphinganine, suggesting a common pathomechanism for HSAN-I. PMID- 20920667 TI - Mutations disrupting selenocysteine formation cause progressive cerebello cerebral atrophy. AB - The essential micronutrient selenium is found in proteins as selenocysteine (Sec), the only genetically encoded amino acid whose biosynthesis occurs on its cognate tRNA in humans. In the final step of selenocysteine formation, the essential enzyme SepSecS catalyzes the conversion of Sep-tRNA to Sec-tRNA. We demonstrate that SepSecS mutations cause autosomal-recessive progressive cerebellocerebral atrophy (PCCA) in Jews of Iraqi and Moroccan ancestry. Both founder mutations, common in these two populations, disrupt the sole route to the biosynthesis of the 21st amino acid, Sec, and thus to the generation of selenoproteins in humans. PMID- 20920668 TI - Compound heterozygosity for loss-of-function lysyl-tRNA synthetase mutations in a patient with peripheral neuropathy. AB - Charcot-Marie-Tooth (CMT) disease comprises a genetically and clinically heterogeneous group of peripheral nerve disorders characterized by impaired distal motor and sensory function. Mutations in three genes encoding aminoacyl tRNA synthetases (ARSs) have been implicated in CMT disease primarily associated with an axonal pathology. ARSs are ubiquitously expressed, essential enzymes responsible for charging tRNA molecules with their cognate amino acids. To further explore the role of ARSs in CMT disease, we performed a large-scale mutation screen of the 37 human ARS genes in a cohort of 355 patients with a phenotype consistent with CMT. Here we describe three variants (p.Leu133His, p.Tyr173SerfsX7, and p.Ile302Met) in the lysyl-tRNA synthetase (KARS) gene in two patients from this cohort. Functional analyses revealed that two of these mutations (p.Leu133His and p.Tyr173SerfsX7) severely affect enzyme activity. Interestingly, both functional variants were found in a single patient with CMT disease and additional neurological and non-neurological sequelae. Based on these data, KARS becomes the fourth ARS gene associated with CMT disease, indicating that this family of enzymes is specifically critical for axon function. PMID- 20920669 TI - Exome sequencing in Brown-Vialetto-van Laere syndrome. PMID- 20920671 TI - Changes in 24-hour ambulatory blood pressure monitoring during the 2009 earthquake at L'Aquila. PMID- 20920672 TI - Morgagni-type diaphragmatic hernia presenting as an abnormal cardiac silhouette. PMID- 20920673 TI - No association of catastrophic events with Advair. PMID- 20920675 TI - Notification of abnormal and critical values: the road ahead. PMID- 20920677 TI - Presence of other autoimmune diseases in subjects with autoimmune thyroid disease. PMID- 20920679 TI - We can reduce US health care costs: a resident's perspective. PMID- 20920681 TI - Right intra-atrial and ventricular polymethylmethacrylate embolus after balloon kyphoplasty. PMID- 20920682 TI - Papillary fibroelastoma of the subvalvular apparatus of the mitral valve found on echocardiography after the clinical presentation of embolic CVA. PMID- 20920683 TI - Trivial chest injury leading to azygos vein pseudoaneurysm. PMID- 20920684 TI - Aortic stenosis in the 21st century. PMID- 20920685 TI - Drug-induced osteoporosis: mechanisms and clinical implications. AB - Drug-induced osteoporosis is common and has a significant impact on the prognosis of patients suffering from chronic debilitating diseases. Glucocorticoids are the drugs causing osteoporotic fractures most frequently, but osteoporosis with fractures is observed also in women treated with aromatase inhibitors for breast cancer, in men receiving anti-androgen therapy for prostate cancer, in postmenopausal women treated with high doses of thyroxine, and in men and women treated with thiazolinediones for type 2 diabetes mellitus. Bone loss with fractures also occurs in patients treated with drugs targeting the immune system, such as calcineurin inhibitors, antiretroviral drugs, selective inhibitors of serotonin reuptake, anticonvulsants, loop diuretics, heparin, oral anticoagulants, and proton pump inhibitors. PMID- 20920686 TI - Adult nonhepatic hyperammonemia: a case report and differential diagnosis. AB - This article presents a case report of nonhepatic hyperammonemia, i.e., elevated serum ammonia secondary to a nonhepatic etiology. It then discusses the importance of broadening one's differential diagnosis to include such nonhepatic causes of elevated ammonia levels, and provides a short review of rarer causes of hyperammonemia in the adult population. Treating the underlying condition is the best way to prevent recurrence of hyperammonemia. However, symptomatic treatment should not be delayed while investigating the underlying source. PMID- 20920687 TI - Treating mixed hyperlipidemia and the atherogenic lipid phenotype for prevention of cardiovascular events. AB - Statins reduce cardiovascular events and cardiovascular and total mortality in persons at risk for and with coronary disease, but there remains a significant residual event rate, particularly in those with the atherogenic lipid phenotype that is characterized by a low high-density lipoprotein (HDL) cholesterol and increase in non-HDL cholesterol. Large outcome trials designed to assess the value of combining statins with other agents to target HDL cholesterol and non HDL cholesterol will not be completed for a few years, but there is ample evidence for the clinician to consider combination therapy. The choices for therapies to supplement statins include niacin, fibrates, and omega-3 fatty acids. We present the argument that after therapeutic lifestyle changes, the first priority should be the maximally tolerated effective dose of a potent statin. Evidence supports the addition of niacin as the second agent. In some situations, high-dose omega-3 fatty acid therapy could be the first agent added to statins. Although fibrate monotherapy alone or in combination with non-statin low-density lipoprotein cholesterol-lowering agents can be effective in mixed hyperlipidemia when statins are not tolerated, the combination of statin+fibrate should be considered second-line therapy until the efficacy and safety are established. PMID- 20920688 TI - Improving abdominal aortic aneurysm screening with an electronic clinical reminder. PMID- 20920689 TI - Painless lumps: a manifestation of granulocytic sarcoma. PMID- 20920690 TI - Images in dermatology. A plethora of protein. Primary localized cutaneous nodular amyloidosis. PMID- 20920691 TI - ECG image of the month. A childhood illness ... in an adult. Complete atrioventricular block. PMID- 20920692 TI - Images in radiology. An element of surprise. Mercury poisoning. PMID- 20920693 TI - Etiology and diagnosis of systolic murmurs in adults. AB - BACKGROUND: It is unknown whether echocardiography can provide insights into the origin of systolic murmurs and the modern value of bedside cardiovascular diagnosis. METHODS: The author examined 376 inpatients and compared their physical findings to transthoracic echocardiography, exploring the associations between echocardiography and systolic murmurs and investigating the diagnostic accuracy of physical examination for pathologic murmurs. RESULTS: Four echocardiographic variables predict the presence of systolic murmurs: peak aortic velocity (P <.001); mitral regurgitation severity (P <.001); mitral valve E-point velocity (P=.09); and absence of pericardial effusion (P=.09). When diagnosing murmurs, the most helpful finding is its distribution on the chest wall with respect to the 3(rd) left parasternal space, a landmark that distinguishes murmurs into 6 patterns. The "apical-base" pattern indicates increased aortic velocity (likelihood ratio [LR] 9.7; 95% confidence interval [CI]; 6.7-14): a delayed carotid upstroke (LR 6.8; 95% CI; 4.0-11.5); absent S2 (LR 12.7; 95% CI; 5.3-30.4); and humming quality to the murmur (LR 8.5; 95% CI; 4.3-16.5) further increase the probability of aortic valve disease. The "broad apical" murmur pattern suggests significant mitral regurgitation (LR 6.8; 95% CI; 3.9-11.9); and the "left lower sternal" murmur pattern indicates significant tricuspid regurgitation (LR 8.4; 95% CI; 3.5-20.3): additional bedside observations refine these diagnoses. Nonetheless, this study shows that some classic physical findings are no longer accurate, that physical examination cannot reliably distinguish severe aortic stenosis from less severe stenosis, and that classic physical findings, despite having proven value, are absent in many patients with significant cardiac lesions. CONCLUSIONS: In the diagnosis of systolic murmurs, physical examination has limitations but also unappreciated value. A simple system using onomatopoeia and classifying systolic murmurs into 1 of 6 patterns is diagnostically helpful. PMID- 20920694 TI - Outcomes in patients with rheumatoid arthritis and myocardial infarction. AB - BACKGROUND: Patients with rheumatoid arthritis have an increased risk for accelerated atherosclerosis. It is unknown, however, whether rheumatoid arthritis also increases in-hospital mortality after a myocardial infarction or influences the therapy patients receive. METHODS: A cross-sectional analysis of 1,112,676 patients with myocardial infarction in the 2003-2005 Nationwide Inpatient Sample was performed. RESULTS: Patients with rheumatoid arthritis were 39% more likely to receive medical therapy (odds ratio [OR], 1.39; 95% confidence interval [CI], 1.30-1.49) than interventional therapy. By using logistic regression, we adjusted for confounding variables to determine the effect of rheumatoid arthritis on the selection of therapy and found that rheumatoid arthritis itself was associated with a 38% increased likelihood of undergoing thrombolysis (OR, 1.38; 95% CI, 1.10-1.71) and a 27% increased likelihood of undergoing percutaneous coronary intervention (OR, 1.27; 95% CI, 1.17-1.39). For the primary outcome measure, we determined that patients with rheumatoid arthritis overall had a 24% better in hospital mortality compared with other patients with a myocardial infarction (OR, 0.76; 95% CI, 0.68-0.86), which was 34% better after adjusting for confounding variables (OR, 0.66; 95% CI, 0.59-0.74). This better in-hospital mortality was seen in patients with rheumatoid arthritis undergoing medical therapy (adjusted OR, 0.67; 95% CI, 0.59-0.75) and percutaneous coronary intervention (adjusted OR, 0.47; 95% CI, 0.32-0.70), but not in patients undergoing thrombolysis or coronary artery bypass grafting. CONCLUSIONS: Among patients with myocardial infarction, rheumatoid arthritis was associated with an increased use of thrombolysis and percutaneous coronary intervention. Moreover, patients with rheumatoid arthritis had an in-hospital survival advantage, particularly those undergoing medical therapy and percutaneous coronary intervention. PMID- 20920695 TI - Adherence to oral contraception in women on Category X medications. AB - BACKGROUND: Over 6% of women become pregnant when taking teratogenic medications, and contraceptive counseling appears to occur at suboptimal rates. Adherence to contraception is an important component in preventing unwanted pregnancy and has not been evaluated in this population. We undertook a pharmacy claims-based analysis to evaluate the degree to which women of childbearing age who receive Category X medications adhere to their oral contraception. METHODS: We evaluated the prescription medication claims for over 6 million women, age 18-44 years, with prescription benefits administered by a pharmacy benefits manager. Women with 2 or more claims for a Category X medication and 2 or more claims for oral contraception were evaluated in further detail. Adherence to oral contraception was measured by analyzing pharmacy claims. Multivariable logistic regression was performed to identify factors associated with adherence. RESULTS: There were 146,758 women of childbearing age who received Category X medications, of which 26,136 also took oral contraceptive medication. Women who received Category X medications were prescribed oral contraception (18%) at rates similar to others of childbearing age (17%). Women prescribed both Category X and oral contraception demonstrated adherence similar to the overall population. Age, class of Category X medication, number of medications, prescriber's specialty, and ethnicity correlated with lower adherence rates. CONCLUSIONS: Despite added risk associated with unintended pregnancy, many women who receive Category X medications have refill patterns suggesting nonadherence to oral contraception. Compared with all women age 18-44 years, women receiving teratogenic medications do not have better adherence to oral contraception. PMID- 20920696 TI - Incidence and risk factors of venous thromboembolic events in lymphoma. AB - BACKGROUND: Cancer patients are at increased risk of venous thromboembolism; however, the incidence and risk factors for venous thromboembolism in lymphoma patients are not well defined. METHODS: Medical records of 422 newly referred lymphoma patients at our institution were reviewed over 2-year follow-up for all venous thromboembolism events and potential risk factors. Multivariate logistic regression model was used to identify risk factors predictive of venous thromboembolism. RESULTS: Among 422 patients, 72 (17.1 %) had 80 new episodes of venous thromboembolism: 59 had deep vein thrombosis, 17 had pulmonary embolism, and 4 had combined deep vein thrombosis and pulmonary embolism. Only 18 of 422 patients (4.3%) were on thromboprophylaxis at baseline. Interestingly, 64% (51/80) of the episodes occurred by the third cycle of chemotherapy. By multivariate logistic regression, female sex (odds ratio [OR] 3.51, P=.001), high hemoglobin (OR 1.26, P=.020), high serum creatinine (OR 3.23, P=.009), and doxorubicin- or methotrexate-based chemotherapy (OR 3.47, P=0.003) were important risk factors for new venous thromboembolism. CONCLUSIONS: Lymphoma patients are at high risk for venous thromboembolism in the initial cycles of chemotherapy; the risk was higher for women, patients with elevated hemoglobin or creatinine, or those receiving doxorubicin or methotrexate. Future studies might focus on validation of these risk factors to identify the high-risk cohort and the potential role of thromboprophylaxis, particularly during initial cycles of chemotherapy. PMID- 20920697 TI - Empiric outpatient therapy with trimethoprim-sulfamethoxazole, cephalexin, or clindamycin for cellulitis. AB - BACKGROUND: Limited data exist on optimal empiric oral antibiotic treatment for outpatients with cellulitis in areas with a high prevalence of community associated methicillin-resistant Staphylococcus aureus (MRSA) infections. METHODS: We conducted a 3-year retrospective cohort study of outpatients with cellulitis empirically treated at a teaching clinic of a tertiary-care medical center in Hawaii. Patients who received more than 1 oral antibiotic, were hospitalized, or had no follow-up information were excluded. Treatment success rates for empiric therapy were compared among commonly prescribed antibiotics in our clinic: cephalexin, trimethoprim-sulfamethoxazole, and clindamycin. Risk factors for treatment failure were evaluated using multivariate logistic regression analysis. RESULTS: Of 544 patients with cellulitis, 405 met the inclusion criteria. The overall treatment success rate of trimethoprim sulfamethoxazole was significantly higher than the rate of cephalexin (91% vs 74%; P<.001), whereas clindamycin success rates were higher than those of cephalexin in patients who had subsequently culture-confirmed MRSA infections (P=.01), had moderately severe cellulitis (P=.03), and were obese (P=.04). Methicillin-resistant S. aureus was recovered in 72 of 117 positive culture specimens (62%). Compliance and adverse drug reaction rates were not significantly different among patients who received these 3 antibiotics. Factors associated with treatment failure included therapy with an antibiotic that was not active against community-associated MRSA (adjusted odds ratio 4.22; 95% confidence interval, 2.25-7.92; P<.001) and severity of cellulitis (adjusted odds ratio 3.74; 95% confidence interval, 2.06-6.79; P<.001). CONCLUSION: Antibiotics with activity against community-associated MRSA, such as trimethoprim sulfamethoxazole and clindamycin, are preferred empiric therapy for outpatients with cellulitis in the community-associated MRSA-prevalent setting. PMID- 20920698 TI - Diabetes enhances hepatocarcinogenesis in noncirrhotic, interferon-treated hepatitis C patients. AB - BACKGROUND: This retrospective cohort study assessed the impact of diabetes mellitus on hepatocarcinogenesis and determined the predictors of hepatocarcinogenesis in noncirrhotic, interferon-treated patients with hepatitis C virus infection. METHODS: A total of 2058 hepatitis C virus-positive, noncirrhotic patients treated with interferon were enrolled. The median follow-up period was 6.7 years. The primary end point was the onset of hepatocellular carcinoma. The cumulative rate of new hepatocellular carcinoma cases was computed by the Kaplan-Meier method and Cox proportional hazard analysis according to diabetic state and response to interferon therapy. RESULTS: The cumulative rates of hepatocellular carcinoma in diabetic patients (3.2% at 4 years, 8.5% at 8 years, and 24.4% at 12 years) were significantly higher than those of nondiabetic patients (1.3% at 4 years, 2.2% at 8 years, and 5.6% at 12 years, P<.001). In patients with a sustained virologic response, diabetes had no significant effect on the rate of hepatocarcinogenesis. In contrast, the rate in patients with a nonsustained virologic response was significantly higher in diabetic than in nondiabetic patients. Multivariate analysis identified lack of sustained virologic response (hazard ratio [HR] 7.28; 95% confidence interval [CI], 3.28 16.15; P<.001) and diabetes as independent risk factors for hepatocarcinogenesis (HR 2.00; 95% CI, 1.05-3.84; P=.036). CONCLUSIONS: Our results highlight the enhancing effect of diabetes mellitus on hepatocarcinogenesis in noncirrhotic, interferon-treated patients with hepatitis C virus. The sustained virologic response induced by interferon therapy eliminates the influence of diabetes and markedly reduces the rate of hepatocarcinogenesis in such patients. PMID- 20920700 TI - Should we systematically perform central nervous system imaging in patients with Whipple's endocarditis? AB - BACKGROUND: Whipple's endocarditis is an uncommon disease, with approximately 100 cases reported to date. Case series suggest that Whipple's endocarditis usually presents without extracardiac manifestations of Whipple's disease. METHODS: We report 4 consecutive cases of Whipple's endocarditis associated with brain lesions. All patients fulfilled Duke Criteria for definite endocarditis. Whipple's disease was diagnosed through 16S rRNA polymerase chain reaction assays on valves excised from patients with culture-negative endocarditis (n=3) or through polymerase chain reaction and periodic acid staining-positive foamy macrophages on duodenal biopsy (n=1). RESULTS: All patients were male, aged 56 to 72 years. They presented with mitral (n=1), aortic (n=1), mitral and aortic (n=1), and tricuspid (n=1) endocarditis. Brain magnetic resonance imaging was performed because of mild-to-moderate cognitive disorders (n=3) or ataxia (n=1) and revealed multiple (n=3) or solitary (n=1) contrast-enhancing lesions. Cerebrospinal fluid studies revealed meningitis in 1 case. Polymerase chain reaction assays on cerebrospinal fluid were negative for all patients. All patients received intravenous ceftriaxone (2-4 weeks) associated with gentamicin (2 weeks), followed by 1 year of oral trimethoprim-sulfamethoxazole, with favorable outcomes. CONCLUSION: Whipple's associated central nervous system disease may be common but frequently undiagnosed, in patients with Whipple's endocarditis. Because treatment is different when neurologic disease is present (ie, trimethoprim-sulfamethoxazole vs doxycycline/hydroxychloroquine), clinicians should consider brain imaging in patients diagnosed with Whipple's endocarditis. PMID- 20920699 TI - Serum uric acid levels and the risk of type 2 diabetes: a prospective study. AB - PURPOSE: To evaluate the impact of serum uric acid levels on the future risk of developing type 2 diabetes independent of other factors. METHODS: We used prospective data from the Framingham Heart Study original (n=4883) and offspring (n=4292) cohorts to examine the association between serum uric acid levels and the incidence of diabetes. We used Cox proportional hazards models to estimate the relative risk of incident diabetes adjusting for age, sex, physical activity, alcohol consumption, smoking, hypertension, body mass index, and blood levels of glucose, cholesterol, creatinine, and triglycerides. RESULTS: We identified 641 incident cases of diabetes in the original cohort and 497 cases in the offspring cohort. The incidence rates of diabetes per 1000 person-years for serum uric acid levels <5.0, 5.0-5.9, 6.0-6.9, 7.0-7.9 and >=8.0 mg/dL were 3.3, 6.1, 8.7, 11.5, and 15.9, respectively, in the original cohort; and 2.9, 5.0, 6.6, 8.7, and 10.9, respectively, in the offspring cohort (P-values for trends <.001). Multivariable relative risks per mg/dL increase in serum uric acid levels were 1.20 (95% confidence interval; 1.11-1.28) for the original cohort and 1.15 (95% confidence interval; 1.06-1.23) for the offspring cohort. CONCLUSIONS: These prospective data from 2 generations of the Framingham Heart Study provide evidence that individuals with higher serum uric acid; including younger adults, are at a higher future risk of type 2 diabetes independent of other known risk factors. These data expand on cross-sectional associations between hyperuricemia and the metabolic syndrome, and extend the link to the future risk of type 2 diabetes. PMID- 20920701 TI - AAIM report on master teachers and clinician educators Part 3: finances and resourcing. PMID- 20920702 TI - Juvenile central ossifying fibroma of the mandible: a case report. AB - Central ossifying fibroma is a rare fibro-osseous neoplasm in young children. It is highly aggressive and has a strong tendency to recur. We describe an 11-year old girl with juvenile central ossifying fibromas of the mandible that caused obstruction of tooth eruption of the lower left second premolar. Oral examination revealed the presence of the primary lower left second molar and a small bony hard swelling over the left side of the mandibular body. After a computed tomographic scan, an incisional biopsy was performed, and the lesion proved to be a juvenile ossifying fibroma. Although this tumor often recurs early, and many authors suggest radical en bloc resection, we performed a more conservative procedure to avoid damage to the mandibular nerve. There has been no evidence of recurrence 1 year later. PMID- 20920703 TI - Distinct features of teratoid Wilms tumor. AB - Teratoid Wilms tumor is an unusual variant of nephroblastoma in which heterologous tissue predominates. Typically, histopathologic examination shows a mixture of mature squamous and mucus-producing columnar epithelium and a prominent component of mature adipose tissue. The treatment of this tumor has not been established because of its rarity with some reports doubting the value of chemotherapy. We report 3 new cases and review the 23 previously reported cases that we were able to identify. The first case was a 2-year-old boy with a huge tumor that occupied most of the abdominal cavity. The second case was a 5-year old girl with a metastatic tumor in association with horseshoe kidney and is the first case of teratoid Wilms tumor with brain metastasis. The third case was an 11-month-old girl with bilateral involvement. Imaging studies of our patients were similar to those reported in the literature with areas of fat attenuation and calcification. Failure to respond to preoperative chemotherapy was seen in our patients and in most previously reported cases that were treated with preoperative chemotherapy. We recommend treating this entity with protocols designed for Wilms tumor and to conduct further basic research to understand its biologic nature. PMID- 20920704 TI - Lipoblastoma with unique localization requiring tracheal and esophageal resection. AB - Lipoblastoma and lipoblastomatosis are rare tumors of infancy. They originate from embryonic fat and localize in soft tissues. We present the case of a lipoblastoma of the neck with localization in tracheal and esophageal walls that required an extended laryngotracheal and esophageal resection. To our knowledge, this is the first report of such localization of this tumor. PMID- 20920705 TI - Compound colonic intussusception: a reason for failure of pneumatic reduction. AB - Intussusception is the most common cause of bowel obstruction in infants older than 3 months. The authors report a case of idiopathic compound (ileocolic/colocolic) intussusception in a 5-month-old girl that was resistant to nonsurgical pneumatic (enema) reduction and necessitated open surgery. Compound intussusception is extremely rare but represents a form of intussusception that is likely to be aggravated by attempts at pneumatic reduction with obvious dangers for the unwary. The literature is reviewed, and the terminology was discussed. PMID- 20920706 TI - Excision of ganglioneuroma from skull base to aortic arch. AB - High retropharyngeal neuroblastic tumors in children have been excised and debulked transorally or cervically, often with a covering tracheostomy. Although we and others have approached high thoracic lesions thoracoscopically, the trapdoor incision (or modification thereof) is generally reserved for cervicothoracic tumors with significant vessel encasement around the thoracic inlet. We report a case of symptomatic ganglioneuroma extending from the nasopharynx, at the level of the skull base, down to the aortic arch: macroscopic clearance was achieved via an extended trapdoor incision and without recourse to tracheostomy, transoral surgery, or transfusion. PMID- 20920707 TI - A retroperitoneal gastric duplication cyst mimicking a simple exophytic renal cyst in an adolescent. AB - Gastric duplications are rare anomalies and usually occur along the greater curvature of the stomach. The authors herein describe an uncommon case of a retroperitoneal gastric duplication, which was not found during previous emergency laparotomy for suspected peritonitis at another institution. On subsequent computed tomography scan, the lesion was misinterpreted as a simple exophytic renal cyst. Laparoscopy was undertaken because of unresolved symptoms, and a retroperitoneal duplication cyst was successfully excised. It was lined with gastric mucosa and islands of pancreatic tissue on pathologic examination. PMID- 20920708 TI - Differential diagnosis of tendon tumors: xanthomas caused by hyperlipidemia in children. AB - Tumors of tendons and tendon sheaths causing pain and mechanical problems are often because of overstraining, and in most cases the resulting common ganglia can be easily removed. We describe an 8-year-old child in whom the tumor's origin had remained undetected and was related to a homozygous familial hypercholesterolemia, which can be associated with multiple xanthomas of the skin and tendons. After a thorough investigation and therapy, a program to prevent arteriosclerosis and myocardial infarct in this patient was initiated. PMID- 20920709 TI - Heparin-binding epidermal growth factor-like growth factor overexpression in transgenic mice increases resistance to necrotizing enterocolitis. AB - BACKGROUND: Necrotizing enterocolitis (NEC) is the most common gastrointestinal emergency and the leading surgical cause of death in premature infants. We have shown that administration of exogenous heparin-binding epidermal growth factor like growth factor (HB-EGF) in mice protects the intestines from experimental NEC. The aim of the current study was to evaluate the effect of gain-of-function of endogenous HB-EGF on susceptibility to NEC. METHODS: Neonatal HB-EGF transgenic (TG) mice and their wild-type (WT) counterparts were exposed to experimental NEC. An additional group of HB-EGF TG pups were also exposed to NEC, but received the HB-EGF antagonist cross-reacting material 197 (CRM197) injected subcutaneously immediately after birth. To examine gut barrier function, HB-EGF TG and WT pups received intragastric fluorescein isothiocyanate-labeled dextran under basal and stressed conditions, and serum fluorescein isothiocyanate-labeled dextran levels were measured. RESULTS: Wild-type mice had an incidence of NEC of 54.2%, whereas HB-EGF TG mice had a significantly decreased incidence of NEC of 22.7% (P = .03). Importantly, administration of CRM197 to HB-EGF TG pups significantly increased the incidence of NEC to 65% (P = .004). HB-EGF TG mice had significantly decreased intestinal permeability compared to WT mice both under basal and stressed conditions. CONCLUSIONS: Our results provide evidence that overexpression of the HB-EGF gene decreases susceptibility to NEC and that administration of the HB-EGF antagonist CRM197 reverses this protective effect. PMID- 20920710 TI - The current state of evidence-based pediatric surgery. AB - BACKGROUND: The efficiency of medical care in the United States has become intensely scrutinized with expectations from patients, families, payors, lawmakers, and, currently, the President. The most effective vehicle to bring more efficient care is the employment of evidence-based medicine whenever possible. Evidence-based medicine is dependent on best evidence, and best evidence is generated from prospective trials. To evaluate current state of evidence based practice in pediatric surgery we reviewed the literature for trials conducted in our field the past 10 years. METHODS: All randomized controlled trials from January 1999 through December 2009 published in the English literature were identified through a literature search using PubMed (www.pubmed.com). We included only those in pediatric general surgery excluding transplant, oncology, and the other nongeneral subspecialties. RESULTS: The search criteria produced 56 manuscripts, of which 51 described appropriate randomization techniques. A definitive trial design with a sample size calculation was utilized in only 19 studies (34%). A statistically significant difference between treatment arms was identified in 29 of the 56 (52%) trials. There were 26 different journals of publication, with the Journal of Pediatric Surgery being most common (20) followed by Pediatric Surgery International (7). The combined total publications from January 1999 through December 2009 for the 26 journals these randomized trials represent 0.04% of all publications. Appendicitis was the most common condition that was studied (n = 10) followed by pyloric stenosis (n = 4). Trials originated in 19 different countries led by the United States (28%), United Kingdom (14%), and Turkey (12%). There was a generally progressive increase in published trials from 1999 to 2009, however, the percentage of prospective articles published in pediatric surgery was similar to a previous review published in 1999. CONCLUSIONS: The current state of evidence-based surgery in pediatric surgery has remained stable in the first decade of the 21st century. Randomized controlled trials represent less than 0.05% of all publications involving pediatric surgery. Some of the hurdles to evidence based surgery are identified and reviewed. PMID- 20920711 TI - Influence of lymph node metastases on survival in pediatric medullary thyroid cancer. AB - PURPOSE: Lymph node metastases (LNM) from medullary thyroid cancer (MTC) are common in adults and are a poor prognostic factor. Less is known about LNM in children, who often have hereditary forms of MTC. Guidelines recommend prophylactic thyroidectomy in early childhood, but randomized prospective trials are not feasible. We hypothesized that LNM is associated with poor prognosis in children. METHODS: Patients with MTC 21 years or younger from the National Cancer Data Base from 1985 to 2007 were studied. Multivariable logistic regression was used to identify factors associated with lymph node evaluation. Survival was estimated using the Kaplan-Meier method. RESULTS: Of 430 patients, 276 (64.2%) had nodal evaluation with LNM present in 121 (28.1%). Older patients, those with tumors larger than 2 cm, and those with involved margins were more likely to have LNM (all P < .05). Patients undergoing total thyroidectomy, those with involved margins, and older patients were more likely to undergo lymph node evaluation after controlling for patient, tumor, and hospital factors (all P < .05). Over time an increasing number of patients with MTC have undergone total thyroidectomy. Patients 16 to 21 years of age had lower 10-year overall survival compared to patients 0 to 15 years old (88.7% vs 98.1%, P = .005). Lymph node metastases were also associated with decreased 10-year overall survival (84.4% vs 100%, P < .001). CONCLUSIONS: In pediatric MTC, LNM predict poorer overall survival. Adequate lymph node assessment can provide valuable prognostic information for the pediatric MTC patient. Lymph node assessment should be considered for older pediatric patients undergoing surgery for hereditary MTC or biopsy confirmed MTC. PMID- 20920712 TI - Pediatric borderline ovarian tumors: a retrospective analysis. AB - BACKGROUND/PURPOSE: Borderline ovarian tumors (BOTs) are uncommon in the pediatric population, and there have been limited studies that have included a small number of patients. In present study, we evaluated the clinical outcomes and the rates of recurrence of pediatric BOTs with larger sample size than those in previous studies. METHODS: A retrospective chart review was performed on 29 patients who were treated for histopathologically confirmed BOTs at our institution between January 1997 and December 2009. RESULTS: Twenty-nine patients (median age, 18 years) had a large-sized tumor (median, 19.8 cm). Abdominal pain was the most common symptom, seen in 82.8% of the patients, followed by abdominal distension. The permanent section histology revealed 25 mucinous (86.2%) and 4 serous type tumors (13.8%). There was considerable discordance between the permanent and frozen sections (rate of concordance, 55.1%). Disease stage was IA in 26 patients (89.7%) and stage IC in the other 3 patients (10.3%). All patients underwent fertility-preserving surgery. Overall, 4 patients (13.8%) experienced a clinically suspicious recurrence requiring surgery. In 2 cases, the suspected recurrences were found to be other benign ovarian tumors. In one case that was initially treated with left ovarian cystectomy for a mucinous BOT, subsequent left salpingo-oophorectomy confirmed recurrence of a mucinous BOT at 16-month follow-up. The last case was a newly developed primary ovarian mucinous carcinoma with no evidence of recurrence of a previous mucinous BOT at 26-month follow-up. CONCLUSIONS: This study shows that BOTs in pediatric populations can be successfully treated conservatively to preserve fertility with no apparent increased risk of morbidity or mortality compared with those of more radical surgical options. PMID- 20920713 TI - Preliminary results of a phase I trial of prophylactic ethanol-lock administration to prevent mediport catheter-related bloodstream infections. AB - BACKGROUND: Catheter-related bloodstream infections remain costly with no simple prevention. We report preliminary results of a phase I trial of ethanol-lock administration to prevent mediport catheter-related bloodstream infections in children. METHODS: Twelve patients receiving intravenous antibody treatments for neuroblastoma were enrolled. On 4 days of each 5-day antibody cycle, 70% ethanol was administered instead of heparin to dwell in each patient's mediport overnight. We used clinical monitoring/questionnaires to assess symptoms and measured blood ethanol levels and liver functions. Patients were tracked for positive blood cultures. Time to infection for ethanol-lock-treated patients was compared with historical controls. RESULTS: We administered 123 ethanol-locks. No adverse symptoms attributable to ethanol occurred; one patient's urticaria worsened. Blood ethanol levels averaged 11 mg/dL. The study was voluntarily suspended after 3 patients' catheters became occluded, 1 of which fractured. A positive blood culture occurred in 1 (8%) of 12 patients, but suspension of the study precluded statistical power to detect impact on time to infection. CONCLUSIONS: Although children with mediport catheters exhibited nontoxic blood ethanol levels and a low rate of bloodstream infections following prophylactic ethanol-lock use, there was a high incidence of catheter occlusion. Adjustments are necessary before adopting ethanol-locks for routine prophylaxis against catheter infections in children. PMID- 20920714 TI - Emergence of community-acquired methicillin-resistant Staphylococcus aureus skin and soft tissue infections as a common cause of hospitalization in United States children. AB - BACKGROUND: Community-acquired methicillin-resistant Staphylococcus aureus (CA MRSA) was first observed in pediatric patients in the late 1990s. Since then, possible risk factors for contracting CA-MRSA have been hypothesized, but supporting studies are limited. METHODS: We analyzed hospital discharge records for patients with a principal International Classification of Diseases, Ninth Revision code for skin and soft tissue infections, collected from 1996 to 2006 by the United States National Center for Health Statistics. Noninstitutional, short stay hospitals in the United States participated. The sample was limited to patients aged <=19 years. Staphylococcus aureus and CA-MRSA were defined by International Classification of Diseases, Ninth Revision codes. Data weights were used to derive regional and national estimates. Population estimates were obtained from the US Bureau of the Census, and incidence rates were reported per 100,000 persons. Risk factors for CA-MRSA were first identified using chi(2) and chi(2) goodness-of-fit tests, then by multivariable logistic regression. RESULTS: These data represent 616,375 pediatric discharges for skin and soft tissue infections from U.S. hospitals between 1996 and 2006. This represents approximately 69.9 hospitalizations for skin and soft tissue infections per 100,000 U.S. children per year. Staphylococcus aureus and CA-MRSA accounted for 19.6% and 9.6% of these cases, respectively. The rate of hospitalization for CA MRSA skin and soft tissue infections increased dramatically over the study period; from less than one case per 100,000 in 1996 to 25.5 cases per 100,000 in 2006. Rates of CA-MRSA varied by region, with the South region having the highest rate (11.5 per 100,000 US children), followed by the West (5.2), Northeast (3.4), and Midwest (3.2). Peak CA-MRSA incidence occurred from May to December; however, the incidence in the South region was consistently higher than other regions for most months and the period of peak incidence was longer than other regions. Independent risk factors for CA-MRSA included survey year, race, geographic region, hospital size, and health insurance status (P < .0001 for all risk factors). CONCLUSIONS: Pediatric hospitalizations for methicillin-susceptible S. aureus and CA-MRSA skin and soft tissue infections are on the rise. Possible risk factors for CA-MRSA infection include White race, residence in the South region of the United States, and lack of health insurance. PMID- 20920715 TI - State of the practice for pediatric surgery--career satisfaction and concerns. A report from the American Pediatric Surgical Association Task Force on Family Issues. AB - BACKGROUND: There has been increasing interest and concern raised in the surgical literature regarding changes in the culture of surgical training and practice, and the impact these changes may have on surgeon stress and the appeal of a career in surgery. We surveyed pediatric surgeons and their partners to collect information on career satisfaction and work-family balance. METHODS: The American Pediatric Surgical Association Task Force on Family Issues developed separate survey instruments for both pediatric surgeons and their partners that requested demographic data and information regarding the impact of surgical training and practice on the surgeon's opportunity to be involved with his/her family. RESULTS: We found that 96% of pediatric surgeons were satisfied with their career choice. Of concern was the lack of balance, with little time available for family, noted by both pediatric surgeons and their partners. CONCLUSION: The issues of work-family balance and its impact on surgeon stress and burnout should be addressed in both pediatric surgery training and practice. The American Pediatric Surgical Association is positioned to play a leading role in this effort. PMID- 20920716 TI - Research interests and funding of members of the American Pediatric Surgical Association: report from 2010 American Pediatric Surgical Association Outcomes and Clinical Trials Committee. AB - OBJECTIVE: There is lack of data relating to the research interests and funding of pediatric surgeons within the United States and Canada. These data may be helpful in promoting basic and clinical research among pediatric surgeons. METHODS: The American Pediatric Surgical Association (APSA) Outcomes and Clinical Trials Committee developed and administered an online survey via e-mail to the APSA membership to help characterize research activities and funding. The survey was available for completion during December of 2009. The survey contained 10 items with a drop-down menu for multiple choice answers and required 5 to 10 minutes to complete. Results based on research interests as well as funding sources were compiled and analyzed. RESULTS: A total of 275 members, which comprises 27.4% of the APSA membership, completed the survey. Of the respondents, 177 (64%) described being in an academic practice, 44 (16%) in an academically associated private practice, 9 (3.3%) in a private solo practice, 17 (6.2%) in private group practice, and 3 (1%) in the military. A total of 189 (68.7%) respondents stated that they participated in formal research. Respondents also categorized their research interests, and the following were the most common subjects of study (decreasing order of frequency): appendicitis, trauma and critical care, outcomes, minimally invasive surgery, and congenital diaphragmatic hernia. Of those participating in research, 64.5% stated that they have no formal financial support. Of those supported through the National Institutes of Health, funding grants achieved were as follows: R01 (n = 29), K08 (n = 9), K23 (n = 2), and U01 (n = 8). CONCLUSIONS: Research activities are common among APSA members and encompass a wide range of pediatric surgery topics. Strikingly, the overall financial support of these efforts is limited, predominantly supported by the surgeons themselves. Funded respondents attained grants through Public Health Service grants, departmental grants, or private institutions. PMID- 20920717 TI - Abnormal platelet-derived growth factor signaling accounting for lung hypoplasia in experimental congenital diaphragmatic hernia. AB - PURPOSE: The pathogenesis of pulmonary hypoplasia in congenital diaphragmatic hernia (CDH) is not fully understood. Platelet-derived growth factor A (PDGFA) and platelet-derived growth factor receptor alpha (PDGFRalpha) play a crucial role in lung development. It has been reported that PDGF induces H(2)O(2) production and that oxidative stress may be an important mechanism for the impaired lung development in the nitrofen rat model. We hypothesized that pulmonary expression of PDGFA and PDGFRalpha is altered in the nitrofen induced CDH model. MATERIALS AND METHODS: Pregnant rats received 100 mg nitrofen or vehicle on gestational day 9 (D9) and were sacrificed on D15, D18 or D21. RNA was extracted from fetal left lungs and mRNA levels of PDGFA and PDGFRalpha were determined using real-time polymerase chain reaction. Immunohistochemistry for protein expression of PDGFA and PDGFRalpha was performed. Pulmonary H(2)O(2) was measured colorimetrically. RESULTS: mRNA levels of PDGFRalpha at D15 (4.50 +/- 0.87) and PDGFA at D18 (2.90 +/- 1.38) were increased in the nitrofen group (P < .05). Immunohistochemistry revealed increased pulmonary expression of PDGFRalpha and PDGFA. H(2)O(2) content was significantly higher in the nitrofen group. CONCLUSIONS: Increased expression of PDGFA and PDGFRalpha suggests that pulmonary hypoplasia in the nitrofen CDH model may be owing to PDGF-induced oxidative stress during lung development. PMID- 20920718 TI - Factors associated with survival in pediatric extracorporeal membrane oxygenation -a single-center experience. AB - AIM: We aimed to examine outcomes of extracorporeal membrane oxygenation (ECMO) therapy in the pediatric population and identify pre-ECMO and on-ECMO characteristics that are associated with survival. METHODS: We retrospectively reviewed the ECMO records at our institution between 1999 and 2008 and selected pediatric patients who were cannulated for respiratory failure or hemodynamic instability resistant to conventional interventions. We recorded details of pre ECMO clinical characteristics, including blood gas variables and mechanical ventilatory support, and details of ECMO therapy including survival off ECMO and to hospital discharge. Predictors of survival were analyzed using logistic regression modeling and a prediction algorithm was developed. RESULTS: Of the 445 ECMO runs, data from 58 consecutive patients were analyzed: 57% were successfully decannulated, and 48% survived to discharge from the hospital. The cohort included 32 (55%) female patients, 22 postoperative patients (38%), and 15 (26%) with an immunosuppressive condition, with a median age of 5 years and weight 19.5 kg, The mean duration of pre-ECMO respiratory support was 3 days, in the form of high-frequency oscillatory ventilation (n = 28, 48%) and conventional mechanical ventilation (n = 13, 22%). The median duration (interquartile range) of ECMO support was 142 hours (60, 321) or 5.9 days. Pre-ECMO pH above 7.2 (P < .001) and oxygenation index below 35 (P = .021) were associated with the highest survival rates. Pre-ECMO PaCO(2) and duration of mechanical ventilation were not associated with survival. CONCLUSIONS: Based on our results, ECMO therapy should be considered early in children with oxygenation index greater than 35 with worsening metabolic status. The restriction of ECMO based on ventilator days alone needs to be revisited in this era of lung protective ventilation. PMID- 20920719 TI - Maternal diabetes and risk of esophageal atresia. AB - BACKGROUND: The etiology of esophageal atresia is poorly understood. The incidence of some congenital malformations is increased in children of mothers with diabetes, but the role of maternal diabetes in esophageal atresia development in the infant is unknown. We hypothesized that maternal diabetes increases the risk of esophageal atresia in the infant. METHODS: A population based, matched case-control study, nested within a cohort of neonates born in Sweden in January 1, 1982 through December 31, 2007, was undertaken. Conditional logistic regression was used to calculate relative risks, expressed as odds ratios with 95% confidence intervals. Adjustment for confounding was made through matching and by multivariable regression. RESULTS: Among 2,625,436 newborn infants in the study cohort, there were 780 cases of esophageal atresia, and 7,800 infants were matched and randomly selected as controls. Exposure to preexisting or gestational diabetes was more frequent in the mothers of the case group (n = 18; 2.3%) than in those of the control group (n = 103; 1.3%). The adjusted risk of esophageal atresia was 70 % higher among infants of women with diabetes than among women without diabetes (odds ratio, 1.7; 95% confidence interval, 1.0-2.9). CONCLUSIONS: Maternal diabetes might increase the risk of esophageal atresia in the child. PMID- 20920720 TI - Experience in treating congenital esophageal atresia in China. AB - PURPOSE: The aim of the study was to evaluate our recent experience in treating esophageal atresia (EA) and the outcomes observed at a single center for pediatric surgery. MATERIALS AND METHODS: The records of infants with EA from 2006 to 2009 were reviewed. Birth weight, associated anomalies, details of management, complications, and outcomes were examined. RESULTS: Forty-eight consecutive infants with EA were identified from 2006 to 2009, of which 33 (69%) were boys. Mean birth weight was 2668 g (range, 1700-3800 g). Common associated malformations (35%) were cardiac anomalies, imperforate anus, limb anomalies, and chromosomal anomalies. Forty-seven were Gross type C, and one was Gross type A. Forty-five infants underwent ligation of the tracheoesophageal fistula and end-to side primary anastomosis, and one received a colonic interposition. Six patients died (12.5% mortality). Three died before or during operation because of severe pneumonia and complex cardiac anomalies, and 3 died during recovery (within 1 month after repair) because of aspiration and severe pneumonia (early postoperative mortality was 6.67%). Complications included pneumonia, anastomotic leakage (16%, all recovered after conservative treatment), wound sepsis (11%), recurrent tracheoesophageal fistula (9%) (3/4 recovered after conservative treatment), anastomotic stricture (10%), and gastroesophageal reflux in about 2 of 3 patients. Preoperative computed tomographic imaging and 3-dimensional graphic reconstruction used in 15 patients were useful. CONCLUSIONS: Most patients with EA have excellent short- to midterm surgical outcomes. The main factors for mortality are complex cardiac anomalies, aspiration, and pneumonia. Computed tomographic imaging and 3-dimensional graphic reconstruction can provide surgeons with excellent preoperative reference about the anatomy of the defect. Most anastomotic related complications resolve with conservative treatment. Patients of low-risk prognosis group with type A and long gap EA can be managed with a primary colonic interposition with good results. The main midterm complications are gastroesophageal reflux and stricture. PMID- 20920721 TI - Overgrowth of costal cartilage is not the etiology of pectus excavatum. AB - PURPOSE: The etiology of pectus excavatum (PE) has not been clarified. In 1944, Sweet (Sweet RH. Pectus excavatum. Ann Surg 1944;119:922-934) mentioned about the possibility of the overgrowth of costal cartilage being involved. However, no additional report that supports his hypothesis is available. In this study, we investigated whether the overgrowth of costal cartilage was an actual cause of PE through measurement of the costal cartilage length in PE patients and healthy controls. MATERIALS AND METHODS: We investigated the length of the fifth and sixth costal cartilages and ribs in PE patients from reconstructed images of 3 dimensional computed tomography. To examine the relative costal cartilage length, we calculated the C/R ratio, defined as the quotient of the costal cartilage length divided by the adjacent rib length, and compared it between PE patients and healthy controls. RESULTS: In PE patients, the C/R ratios were not larger than in healthy controls at any level. At the left sixth, the C/R ratio was significantly smaller in patients than in the healthy control group. DISCUSSION: The results revealed that, in PE patients, relative costal cartilage lengths were not longer than in healthy controls. We conclude that the overgrowth of costal cartilage is not the etiology of PE. PMID- 20920722 TI - Repeat abdominal computed tomography scans after pediatric blunt abdominal trauma: missed injuries, extra costs, and unnecessary radiation exposure. AB - PURPOSE: We hypothesized that pediatric blunt trauma patients, initially evaluated at nontrauma centers with abdominal computed tomography (CT) scans, often undergo repeat scans after transfer. This study was designed to quantify this phenomenon, assess consequences, and elucidate possible causes. METHODS: This article is an institutional review board-approved, retrospective chart review of pediatric blunt abdominal trauma patients transferred to a level I trauma center from 2002 to 2007 and evaluated with abdominal CT at the trauma center or at a referring facility. RESULTS: A total of 388 patients met the study criteria, with 6 patients being excluded because of inability to verify outside records resulting in study group of 382 patients. Of those 382 patients, 199 (52%) underwent abdominal CT before transfer. Thirty-six (18%) of those 199 patients underwent repeat CT scanning at our level I trauma center. Of these 36 patients, 19 (53%) were transferred without their outside CT scans, with 10 (53%) of these 19 having significant abdominal injuries. Of the remaining 17, 6 (17%) had repeat scans to assess changes in vital signs, or patient condition, or because of inadequate outside imaging. The remaining 11 (30%) were repeated despite an acceptable outside CT and no change in patient condition. Only 2 of 11 resulted in changed management. Additional radiation delivered from these repeat scans totaled 180 mSv, and additional patient charges totaled more than $110,000. There was an apparent trend toward increased repeat scanning (from 6.7% in 2002 to 16.7% in 2007). CONCLUSIONS: Abdominal CT scans, for evaluation of pediatric blunt trauma, are frequently repeated after transfer from outside hospitals. In many cases, repeat scans provide useful diagnostic information. However, more than 80% of repeat scanning is potentially preventable with better education of transport personnel (paramedics, emergency medical technicians, and nurses) and emergency department physicians. PMID- 20920723 TI - Pathogenic implications of remnant vitelline structures in gastroschisis. AB - PURPOSE: The pathogenesis of gastroschisis is unknown. It may be helpful in understanding its pathogenesis to know the structural relationships among umbilical components including umbilical vessels, urachus, and vitelline structures, and thus, the authors investigated the remnants of vitelline structures in a series of cases of gastroschisis. METHODS: Medical records of 41 cases with gastroschisis treated in our institute from 1979 to 2009 were retrospectively reviewed. RESULTS: Paraumbilical bands, possible remnants of vitelline structures, were observed in 4 cases (9.8%). All 4 bands were attached to the skin edge of the abdominal defect without incorporation into the umbilical cord. The band ended at the mesentery in 3 cases and at the antimesenteric site of the ileum in the remaining case. Histologic findings showed fibrous tissues in all cases. One was possibly associated with the development of colonic atresia. Another was noticed after silo reduction when herniated bowels became strangulated by the band. The other 2 cases were uncomplicated. CONCLUSIONS: Our findings may support the recently proposed hypothesis that the developmental failure of the yolk sac and related vitelline structures to merge with or to be incorporated into the umbilical stalk might be associated with the pathogenesis of the abdominal wall defect in gastroschisis. Paraumbilical bands derived from vitelline structures may possibly cause intestinal ischemia prenatally or postnatally. PMID- 20920724 TI - Perturbation of Fgf10 signal pathway in mouse embryonic palate by dexamethasone and vitamin B12 in vivo. AB - BACKGROUND/PURPOSE: The Fgf10 signaling pathway plays an important role in early stages of mouse embryonic palatal development, which is associated with cell proliferation and differentiation. The objective of this study was to assess whether dexamethasone and vitamin B(12) affected the Fgf10 signal pathway of mouse embryonic palate. MATERIALS AND METHODS: Immunohistochemical studies were performed for expression of Fgf10, Fgfr2b, and sonic hedgehog and for cell proliferation and apoptosis of mouse embryonic palate. RESULTS: The expression of Fgf10, Fgfr2b, and sonic hedgehog was changed in mouse embryonic palate after dexamethasone and vitamin B(12) treatment, resulting in reduced and restored proliferation of mesenchymal cells. CONCLUSIONS: Dexamethasone and vitamin B(12) affected the Fgf10 signaling pathway and cell proliferation of mouse embryonic palate. Cell apoptosis was not altered after dexamethasone and vitamin B(12) exposure. PMID- 20920725 TI - Long-term outcome after free autogenous muscle transplantation for anal incontinence in children with anorectal malformations. AB - PURPOSE: Patients with high anorectal anomalies are often incontinent after reconstruction, particularly with the older forms of surgical treatment, that is, anorectal pull-through or Stephen's operations. In 1974, a new treatment for anal incontinence in children was introduced at the Akademiska Hospital: free autogenous muscle transplantation (FAMT) to the perirectal area. All the patients receiving FAMT were totally incontinent before the procedure and had no rectal sensitivity. The aim of this study was to evaluate the long-term functional outcome of this procedure. METHODS: Twenty-two patients (17 males) operated on with FAMT below the age of 15 years were identified through records. One of the patients had died, and 2 were not available for follow-up. The remaining 19 were sent a validated bowel function questionnaire, and 15 (78.9%) of 19 patients responded (12 males). These 15 patients were compared with 15 patients with the same sex, age, and a similar malformation from our patient database. RESULTS: At follow-up, after an average of 30 years postoperatively, 2 of 15 patients with FAMT had a stoma compared with 3 of 15 in the control group. The Miller incontinence score had a mean of 6.2 (median, 6; range, 0-15) in the FAMT group and 3.7 (median, 4; range, 0-12) in the control group. All patients in both groups could sense stool, and 11 of 13 patients in the FAMT group could distinguish between feces and flatus. CONCLUSIONS: The patients with FAMT had a slightly inferior anorectal function compared with the controls. Considering they were all totally incontinent before FAMT, we conclude that FAMT has an acceptable effect 30 years postoperatively. Therefore, we find that FAMT could be an alternative for anorectal malformation patients who are totally incontinent. PMID- 20920726 TI - Umbilicoplasty with 3 triangular skin flaps and excised diamond-shaped skin flap. AB - PURPOSE: In cases of large umbilical hernias, standard surgical techniques have proven inadequate for diminishing the diameter of the umbilicus. We have modified the 3- and 4-triangular-skin-flap techniques to diminish the diameter of the umbilicus and achieve a cosmetically acceptable umbilicus. MATERIALS AND METHODS: Umbilicoplasty was performed in 149 children (median age, 2.5 years; range, 3 months-10 years) between 2003 and 2008. We created 4 skin flaps 1.5 cm in length on the umbilicus and excised the cranial diamond-shaped skin flap. After closure of the fascial defect, the diameter of the umbilicus was diminished by suturing the opened cranial part of the diamond-shaped skin flap vertically. The tips of the 3 remaining flaps were then anchored to the closed fascia. RESULTS: Postoperatively, granulation tissue occurred in 18 cases (12%), transient erythema of a flap in 15 cases (10%), and bulging of a skin flap in 15 cases (10%). These complications were reduced by suturing adjoining skin flaps. No recurrent hernias were encountered. The postoperative umbilical appearance was satisfactory in all cases. CONCLUSION: This surgical technique is effective for diminishing the diameter of the umbilicus and creating a cosmetically acceptable shaped umbilicus, even for large umbilical hernias. PMID- 20920727 TI - Metastatic neuroblastoma mimicking infantile hemangioma. AB - Many lesions can masquerade as deep infantile hemangioma, the most common tumor of infancy. We describe an infant with infantile hemangioma and concomitant metastatic subcutaneous neuroblastoma mimicking deep hemangioma. The patient presented at 8 months of age with 3 superficial infantile hemangiomas as well as 3 subcutaneous masses. History, physical examination, and ultrasonography of the deep lesions were consistent with subcutaneous hemangioma. New masses appeared at 10 months of age that prompted biopsy; histopathology demonstrated metastatic neuroblastoma. Deviation from the predictable clinical features of a deep infantile hemangioma should prompt consideration for other causes of a subcutaneous mass in infancy, including metastatic neuroblastoma. PMID- 20920728 TI - Case report: actinomycosis of the appendix--an unusual cause of acute appendicitis in children. AB - Abdominal actinomycosis in children is a rare disease, which is occasionally found on histologic examination after an operation for acute appendicitis. Because of its nonspecific clinical and radiological signs and symptoms and low prevalence, the diagnosis is hardly ever made before the patient undergoes an operation and tissue is available for pathologic evaluation. When the diagnosis is made, the patient should be treated with the appropriate long-term antibiotics. With antibiotic therapy, the prognosis is favorable. We describe a 13-year-old girl who presented with acute appendicitis and was found to have abdominal actinomycosis after undergoing open appendectomy, which was treated successfully with penicillin and piperacillin-tazobactam. PMID- 20920729 TI - Magnetic resonance nephrography for planning of laparoscopic partial nephrectomy in a pediatric case of ureteral triplication. AB - We present the case of ureteral triplication with vesicoureteral reflux into the lowest and middle pole in a 5-year-old girl. Magnetic resonance (MR) nephrography depicted loss of function of the lowest pole, which could not be assessed through MAG3 renal scan. Morphologic analyses revealed organ structure and vascular anatomy in superior quality. A laparoscopic partial nephroureterectomy of the lower pole was performed. Intraoperative findings correlated exactly with morphologic data obtained through MR nephrography. Dynamic MR nephrography should be considered as diagnostic tool of choice for selected kidney anomalies before surgery. PMID- 20920730 TI - Dermoid cyst of the spermatic cord in children. AB - Most of inguinal masses in children correspond to inguinal indirect hernias, but other pathologic entities may be found. Dermoid cysts of the spermatic cord are very rare, with only 9 clear cases reported in the literature to date, all of them in adults. We present a case of dermoid cyst of the spermatic cord in a 2 year-old boy, the youngest patient reported so far. Dermoid cysts of the spermatic cord should be considered as part of the differential diagnosis of inguinal masses in children, especially in cases of long-standing, nontender, and irreducible inguinal mass. PMID- 20920731 TI - Carcinoid tumor of the common bile duct in children: a case report. AB - Carcinoid tumors of common bile duct (CBD) are rare, with fewer than 60 cases reported worldwide. Typically, jaundice is the most common presenting symptom. Preoperative diagnosis is difficult because methods for obtaining adequate specimens for histologic analysis are limited. Surgery is the primary treatment for CBD carcinoids to have disease-free survival. This is a case report concerning a 10-year-old boy with a carcinoid tumor of the CBD. An overview of the clinical presentation, diagnosis, radiologic workup, surgical treatment, histologic features, and prognosis of carcinoid tumor is provided. PMID- 20920732 TI - Herniation of the brain after conservative treatment of a large congenital skull defect in an infant with Adams-Oliver syndrome. AB - We report the case of a newborn baby with a large congenital skull defect owing to Adams-Oliver syndrome. An initial attempt at conservative treatment failed and led to disruption of the leptomeningeal membrane and prolapse of the brain. After local debridement, delayed and stepwise surgical closure was complicated by cerebrospinal fluid leakage, which required the insertion of a cerebrospinal fluid shunt. This case report highlights the potential serious risks of nonsurgical management of largely extended congenital skull defects. PMID- 20920733 TI - Esophegeal replacement in children with AIDS. AB - We report 2 human immunodeficiency virus-positive patients with refractory esophageal strictures secondary to candidiasis. They presented with progressive dysphagia and had suffered from oropharyngeal and/or esophageal candidiasis within the preceding 3 months. Both failed conservative management of these strictures, including systemic antifungal therapy, administration of proton pump inhibitors, and numerous attempts at stricture dilation, ultimately progressing to open transhiatal esophagectomy. Although challenging in the immunocompromised host, successful treatment of these strictures by gastric interposition is achievable with minimal morbidity. PMID- 20920734 TI - Acute pancreatitis induced by ifosfamide therapy. AB - Ifosfamide used in the treatment of pediatric solid tumors is known to have serious adverse effects, including acute pancreatitis, a rare complication of therapy. This report describes a young girl who developed acute pancreatitis while being treated for recurrent Wilms tumor with the ifosfamide, carboplatin, and etoposide regimen. She recovered completely and without sequelae from ifosfamide-induced pancreatitis soon after the drug was stopped. Abdominal pain in patients on anticancer treatment is a common occurrence, but it is rarely investigated. Patients who receive ifosfamide as part of a chemotherapy regimen should be carefully monitored, and symptoms or signs suggestive of acute pancreatitis should be promptly investigated. Withholding the drug usually leads to complete recovery. PMID- 20920735 TI - What is new in cryptorchidism and hypospadias--a critical review on the testicular dysgenesis hypothesis. AB - It has been hypothesized that poor semen quality, testis cancer, undescended testis, and hypospadias are symptoms of one underlying entity--the testicular dysgenesis syndrome--leading to increasing male fertility impairment. Though testicular cancer has increased in many Western countries during the past 40 years, hypospadias rates have not changed with certainty over the same period. Also, recent studies demonstrate that sperm output may have declined in certain areas of Europe but is probably not declining across the globe as indicated by American studies. However, at the same time, there is increasing recognition of male infertility related to obesity and smoking. There is no certain evidence that the rates of undescended testes have been increasing with time during the last 50 years. In more than 95% of the cases, hypospadias is not associated with cryptorchidism, suggesting major differences in pathogenesis. Placental abnormality may occasionally cause both cryptorchidism and hypospadias, as it is also the case in many other congenital malformations. The findings of early orchidopexy lowering the risk of both infertility and testicular cancer suggest that the abnormal location exposes the cryptorchid testis to infertility and malignant transformation, rather than there being a primary abnormality. Statistically, 5% of testicular cancers only are caused by cryptorchidism. These data point to the complexity of pathogenic and epidemiologic features of each component and the difficulties in ascribing them to a single unifying process, such as testicular dysgenesis syndrome, particularly when so little is known of the actual mechanisms of disease. PMID- 20920736 TI - Vaginal replacement in the pediatric age group: a 34-year experience of intestinal vaginoplasty in children and young girls. AB - BACKGROUND/PURPOSE: The absence of vagina is rare in the pediatric population. It can occur as a result of congenital malformations such as an aplasia of mullerian ducts (46,XX Mayer-Rokitansky-Kuster-Hauser syndrome) or a complete androgen insensitivity syndrome (46,XY testicular feminizing syndrome). Intersex patients, who underwent reassessment of a female sex, need a genital reconstruction toward a feminine phenotype. Patients with congenital adrenogenital syndrome with high urogenital sinus could have a severe hypoplastic vagina. In all these cases, a vaginal replacement is required. We reviewed our experience of vaginal replacement using a sigmoid conduit. METHODS: In 34 years, we evaluated 47 patients. The observation period was from 1 to 34 years (mean: 12 years). The preoperative diagnosis was Mayer-Rokitansky-Kuster-Hauser syndrome in 17 cases, androgen insensitivity syndrome in 24 cases, adrenogenital syndrome with high urogenital sinus in 5 and 1 patient was affected by penile agenesis. Forty-six patients were treated with vaginal reconstruction by interposition of sigmoid colon. Only in 1 case we performed a vaginal construction with an ileal loop: in this case, the sigmoid colon was extremely dilated by a chronic constipation secondary to a high anorectal malformation corrected at birth. RESULTS: The outcome for 47 patients is excellent: 18 are sexually active and 4 are married. Only 1 patient with adrenogenital syndrome died of endocrine problems. Complications occurred in 17 cases: in 1 patient a necrosis of the replaced vagina occurred, thus requiring vaginal exeresis; now she is waiting for a second operation. Another patient had an abdominal abscess, which was surgically treated. In 12 cases a second procedure was required: 6 had stenotic new-vaginal introitus, 4 had new-vaginal prolapse, and 2 had intestinal obstruction. CONCLUSIONS: We believe that the preferable technique for vaginal replacement is the use of intestinal conduit. The sigmoid colon is the best intestinal tract to be used owing to its size, location and preserved blood supply. Our experience leads us to believe that the sigmoid segment is the segment of choice, although we consider ileal loop as a good alternative when the sigmoid colon is not available. PMID- 20920737 TI - Three-dimensional magnetic resonance imaging of Kommerell diverticulum in a child with recurrent dysphagia. AB - We report a case of a 3-year-old girl with a history of recurrent dysphagia and feeding difficulties. After chest x-ray and esophagogram examination, magnetic resonance imaging revealed the presence of a right-sided aortic arch with an aberrant retroesophageal left subclavian artery arising from a Kommerell diverticulum. PMID- 20920738 TI - Pilomatrixomas presenting as vascular tumors on color Doppler ultrasound. AB - Diagnosis of pilomatrixomas may be difficult because they can mimic other clinical conditions. Color Doppler ultrasound had been proven useful in the study of localized lesions of the skin and can both define lesion morphology and determine blood flow changes in real time, and may thus help differentiate primary from secondary vascular skin lesions. We present 3 cases of pilomatrixomas that mimic vascular lesions of the skin on physical examination. Clinical, sonographic, intraoperative, and histologic images are provided to highlight the nature of these challenging cases. PMID- 20920739 TI - Laparoscopic-assisted clearance of protein plugs in the common channel in children with choledochal cysts. AB - BACKGROUND: The purpose of the study was to assess the efficacy of laparoscopic assisted removal of protein plugs from the common channel in choledochal cysts. METHODS: Between 2001 and 2009, 34 patients with choledochal cysts (mean age, 4.98 years) with protein plugs in the common channel successfully underwent laparoscopic cyst excision and Roux-en-Y hepatojejunostomy. Under direct vision during laparoscopy, urethroscopes or catheters were inserted into the common channel to irrigate and remove the protein plugs. Complete clearance was confirmed by either direct urethroscopic visualization or cholangiogram that demonstrated (1) no filling defects in the common channel, (2) significant reduction of common channel diameter, (3) free passage of contrast agent into the duodenum, and (4) no pancreatic duct reflux. Operative time and blood loss, postoperative hospital stay, duration of drainage, postoperative complications, perioperative ultrasonographic findings, and laboratory results were reviewed. RESULTS: Protein plugs were completely removed in all the patients. The mean operative time, postoperative hospital stay, and drainage duration were 3.51 hours, 7.08 days, and 3.41 days, respectively. The median follow-up period was 32 months. Neither mortality nor complications of pancreatic juice leak, pancreatitis, or stone formation were observed. Liver function parameters and serum amylase levels returned to normal postoperatively. CONCLUSIONS: Laparoscopic-assisted clearance of the protein plugs in the common channel in choledochal cyst is effective, with good medium-term results observed. PMID- 20920740 TI - Laparoscopic suture rectopexy for full-thickness anorectal prolapse in children: an effective outpatient procedure. AB - BACKGROUND/PURPOSE: Our approach to full-thickness anorectal prolapse has transitioned to laparoscopic suture rectopexy (LSRP). The purpose of this study was to describe the indications, technique, and postoperative outcomes for LSRP. METHODS: Rectopexy was performed using 3 or 4 laparoscopic ports. Redundant rectum was retracted from the pelvis, and the posterior rectal wall was secured to the sacral promontory using 3 permanent sutures. RESULTS: Nineteen children (7 girls) underwent LSRP from March 2003 to January 2008. Mean age was 6.2 +/- 3.6 years. Three patients had prior perineal operations: 2 sacrococcygeal teratoma resections and 1 pull-through for Hirschsprung disease. One patient had cystic fibrosis, and another had Prader-Willi syndrome. The remaining children had either chronic constipation or idiopathic prolapse. All patients were treated preoperatively with laxatives. Two patients received antegrade continent enemas. Length of stay was 1 +/- 0.8 days, with only the first 5 patients admitted to the hospital. The patient with Prader-Willi syndrome had a full-thickness recurrence (5%) owing to obsessive-compulsive behavior. Partial mucosal prolapse occurred in 2 patients. There were no other complications. CONCLUSIONS: Laparoscopic suture rectopexy is an effective minimally invasive method to treat full-thickness rectal prolapse in children from various etiologies. It can be performed as an outpatient procedure with minimal morbidity and low recurrence rate (5%). PMID- 20920741 TI - "To illustrate and increase Chyrurgerie": Ambroise Pare (1510-1590). AB - The quincentenary of Ambroise Pare's birth celebrates a man who rose from a humble origin to become the leading surgeon of the Renaissance. Now remembered as a celebrated war surgeon, especially for his gentle treatment of gunshot wounds, it is generally forgotten that Pare also treated children and wrote about them. Despite his little schooling, Pare was appointed as the Head of the French College of Surgeons in 1567. Pare's contributions to child health include conservative management of childhood deformities, such as clubfoot and scoliosis. He also gave descriptions of conjoined twins and intersex. Pare managed childhood trauma and bladder stones using devices that he invented. This article will briefly demonstrate Pare's wide-ranging contribution to pediatric surgery, adding new insights and material to earlier work. PMID- 20920743 TI - Introduction: epigenetics and cancer. AB - The field of epigenetics has witnessed a recent explosion in our knowledge on the importance of epigenetic events in the control of both normal cellular processes and abnormal events associated with diseases, moving this field to the forefront of biomedical research. Advances in the field of cancer epigenetics and epigenomics have turned academic, medical, and public attention to the potential application of epigenetics in cancer control. A tremendous pace of discovery in this field requires that these recent conceptual breakthroughs and technological state-of-the-art in epigenetics and epigenomics are updated and summarized in one book with cancer focus. This book is primarily intended to academic and professional audience; however, an attempt has been made to make it understandable by and appealing to a wider audience among healthcare workers. The main aim of this book is to produce an authoritative and comprehensive reference source in print and online, covering all critical aspects of epigenetics and epigenomics and their implications in cancer research. This book discusses the state of science and determines the future research needs, covering most recent advances, both conceptual and technological, and their implication for better understanding of molecular mechanisms of cancer development and progression, early detection, risk assessment, and prevention of cancer. In this chapter, we describe the main aim and scope of this book and provide a brief emphasis of each of 22 chapters regrouped into eight major parts. PMID- 20920744 TI - DNA methylation and cancer. AB - DNA methylation is one of the most intensely studied epigenetic modifications in mammals. In normal cells, it assures the proper regulation of gene expression and stable gene silencing. DNA methylation is associated with histone modifications and the interplay of these epigenetic modifications is crucial to regulate the functioning of the genome by changing chromatin architecture. The covalent addition of a methyl group occurs generally in cytosine within CpG dinucleotides which are concentrated in large clusters called CpG islands. DNA methyltransferases are responsible for establishing and maintenance of methylation pattern. It is commonly known that inactivation of certain tumor suppressor genes occurs as a consequence of hypermethylation within the promoter regions and a numerous studies have demonstrated a broad range of genes silenced by DNA methylation in different cancer types. On the other hand, global hypomethylation, inducing genomic instability, also contributes to cell transformation. Apart from DNA methylation alterations in promoter regions and repetitive DNA sequences, this phenomenon is associated also with regulation of expression of noncoding RNAs such as microRNAs that may play role in tumor suppression. DNA methylation seems to be promising in putative translational use in patients and hypermethylated promoters may serve as biomarkers. Moreover, unlike genetic alterations, DNA methylation is reversible what makes it extremely interesting for therapy approaches. The importance of DNA methylation alterations in tumorigenesis encourages us to decode the human epigenome. Different DNA methylome mapping techniques are indispensable to realize this project in the future. PMID- 20920745 TI - Histone modifications and cancer. AB - It is now widely recognized that epigenetic events are important mechanisms underlying cancer development and progression. Epigenetic information in chromatin includes covalent modifications (such as acetylation, methylation, phosphorylation, and ubiquitination) of core nucleosomal proteins (histones). A recent progress in the field of histone modifications and chromatin research has tremendously enhanced our understanding of the mechanisms underlying the control of key physiological and pathological processes. Histone modifications and other epigenetic mechanisms appear to work together in establishing and maintaining gene activity states, thus regulating a wide range of cellular processes. Different histone modifications themselves act in a coordinated and orderly fashion to regulate cellular processes such as gene transcription, DNA replication, and DNA repair. Interest in histone modifications has further grown over the last decade with the discovery and characterization of a large number of histone-modifying molecules and protein complexes. Alterations in the function of histone-modifying complexes are believed to disrupt the pattern and levels of histone marks and consequently deregulate the control of chromatin-based processes, ultimately leading to oncogenic transformation and the development of cancer. Consistent with this notion, aberrant patterns of histone modifications have been associated with a large number of human malignancies. In this chapter, we discuss recent advances in our understanding of the mechanisms controlling the establishment and maintenance of histone marks and how disruptions of these chromatin-based mechanisms contribute to tumorigenesis. We also suggest how these advances may facilitate the development of novel strategies to prevent, diagnose, and treat human malignancies. PMID- 20920746 TI - Epigenetics and miRNAs in human cancer. AB - Epigenetic factors and microRNAs (miRNAs) are regulators of gene expression. Their regulatory function is frequently aberrant in cancer. In this chapter, we show that a tight connection occurs between miRNAs and epigenetics. Epigenetic factors can be responsible for the aberrancies of the miRNome (defined as the full spectrum of miRNAs for a specific genome) observed in cancer. Indeed, miRNAs undergo the same epigenetic regulatory laws like any other protein-coding gene. Moreover, a specific group of miRNAs (defined as epi-miRNAs) can directly target effectors of the epigenetic machinery (such as DNA methyltransferases, histone deacetylases, and polycomb repressive complex genes) and indirectly affect the expression of tumor suppressor genes, whose expression is controlled by epigenetic factors. The result of this epigenetic-miRNA interaction is a new layer of complexity in gene regulation, whose comprehension opens new avenues to understand human cancerogenesis and to achieve new cancer treatments. PMID- 20920747 TI - Interplay between different epigenetic modifications and mechanisms. AB - Cellular functions including transcription regulation, DNA repair, and DNA replication need to be tightly regulated. DNA sequence can contribute to the regulation of these mechanisms. This is exemplified by the consensus sequences that allow the binding of specific transcription factors, thus regulating transcription rates. Another layer of regulation resides in modifications that do not affect the DNA sequence itself but still results in the modification of chromatin structure and properties, thus affecting the readout of the underlying DNA sequence. These modifications are dubbed as "epigenetic modifications" and include, among others, histone modifications, DNA methylation, and small RNAs. While these events can independently regulate cellular mechanisms, recent studies indicate that joint activities of different epigenetic modifications could result in a common outcome. In this chapter, I will attempt to recapitulate the best known examples of collaborative activities between epigenetic modifications. I will emphasize mostly on the effect of crosstalks between epigenetic modifications on transcription regulation, simply because it is the most exposed and studied aspect of epigenetic interactions. I will also summarize the effect of epigenetic interactions on DNA damage response and DNA repair. The involvement of epigenetic crosstalks in cancer formation, progression, and treatment will be emphasized throughout the manuscript. Due to space restrictions, additional aspects involving histone replacements [Park, Y. J., and Luger, K. (2008). Histone chaperones in nucleosome eviction and histone exchange. Curr. Opin. Struct. Biol.18, 282-289.], histone variants [Boulard, M., Bouvet, P., Kundu, T. K., and Dimitrov, S. (2007). Histone variant nucleosomes: Structure, function and implication in disease. Subcell. Biochem. 41, 71-89; Talbert, P. B., and Henikoff, S. (2010). Histone variants-Ancient wrap artists of the epigenome. Nat. Rev. Mol. Cell Biol.11, 264-275.], and histone modification readers [de la Cruz, X., Lois, S., Sanchez-Molina, S., and Martinez-Balbas, M. A. (2005). Do protein motifs read the histone code? Bioessays27, 164-175; Grewal, S. I., and Jia, S. (2007). Heterochromatin revisited. Nat. Rev. Genet.8, 35-46.] will not be addressed in depth in this chapter, and the reader is referred to the reviews cited here. PMID- 20920748 TI - Genomic imprinting syndromes and cancer. AB - Genomic imprinting represents a form of epigenetic control of gene expression in which one allele of a gene is preferentially expressed according to the parent-of origin of the allele. Genomic imprinting plays an important role in normal growth and development. Disruption of imprinting can result in a number of human imprinting syndromes and predispose to cancer. In this chapter, we describe a number of human imprinting syndromes to illustrate the concepts of genomic imprinting and how loss of imprinting of imprinted genes their relationship to human neoplasia. PMID- 20920749 TI - Epigenetic codes in stem cells and cancer stem cells. AB - Definition of stemness states that a stem cell population should be maintained over long periods of time, while generating all differentiated cell types of the corresponding tissues. Epigenetic regulation plays an important role in such process because the context of genome sequences is generally unchanged by differentiation process. Recent evidence indicates that an abnormal control of cellular differentiation is involved in the process of carcinogenesis [Hochedlinger, K., Yamada, Y., Beard, C., and Jaenisch, R. (2005). Ectopic expression of Oct-4 blocks progenitor-cell differentiation and causes dysplasia in epithelial tissues. Cell 121, 465-477]. Therefore, understanding how cellular differentiation is controlled would be useful for obtaining a better understanding of the mechanisms underlying carcinogenesis. In this chapter, we will describe recent advances in understanding the epigenetic codes that govern differentiation of stem cells, especially focusing on embryonic stem cells. We will also discuss the concept of cancer stem cells, in which the epigenetic regulations control differentiation of tumor cells and such regulations play a central role in the determination of whether a tumor cell is capable of tumor initiation or not. PMID- 20920750 TI - Inheritance of epigenetic aberrations (constitutional epimutations) in cancer susceptibility. AB - The pathogenic role for heritable mutations in the DNA sequence of tumor suppressor and DNA repair genes has been well established in familial cancer syndromes. These germ line mutations confer a high risk of developing particular types of cancer, according to the gene affected, at a young age of onset when compared to sporadically arising cancers of a similar type. The widespread role for epigenetic dysregulation in the development and progression of sporadic cancers is also well recognized. However, it has only become apparent in recent years that epigenetic aberrations can also occur constitutionally to confer a similar cancer phenotype as a genetic mutation within the same gene. These epigenetic errors are termed "constitutional epimutations" and are characterized by promoter methylation and transcriptional silencing of a single allele of the gene in normal somatic tissues in the absence of a sequence mutation within the affected locus. This is best exemplified in Lynch syndrome, which is an autosomal dominant cancer susceptibility syndrome characterized by the early development of colorectal, uterine, and additional cancers exhibiting microsatellite instability due to impaired mismatch repair. Lynch syndrome is usually caused by heterozygous loss-of-function germ line mutations of the mismatch repair genes, namely MLH1, MSH2, MSH6, and PMS2. Tumors develop following an acquired somatic loss of the remaining functional allele. However, a subset of Lynch syndrome cases without genetic mutations instead has a constitutional epimutation of MLH1 or MSH2. These epimutations are associated with distinct patterns of inheritance depending on the nature of the mechanisms underlying them. PMID- 20920751 TI - Cancer epigenome. AB - Cancer is a heterogeneous disease caused largely by abnormalities of the genome and the epigenome. Typically, such abnormalities include genetic changes such as mutations and other genomic rearrangements or epigenetic changes such as aberrant DNA methylation and histone modifications that are frequently mediated by exposure to environmental or lifestyle factors. Therefore, comprehensive genetic and epigenetic analysis of cancer genomes is the most effective way to identify causative changes involved in tumorigenesis, irrespective of whether they are inherited or acquired. In this chapter, we review recent progress in the field and discuss some of the pilot studies that have already established epigenomic analysis as integral part of modern cancer research and present a major step toward personalized treatment of this disease in the future. PMID- 20920753 TI - Epigenetic drivers of genetic alterations. AB - DNA methylation plays a key role in the silencing of cancer-related genes, thereby affecting numerous cellular processes, including the cell cycle checkpoint, apoptosis, signal transduction, cell adhesion, and angiogenesis. DNA methylation also affects the expression of genes involved in maintaining the integrity of the genome through DNA repair and detoxification of reactive oxygen species. Here, we discuss how epigenetic changes lead to genetic alterations, including microsatellite instability and nucleotide and chromosomal alterations. Epigenetic inactivation of hMLH1 is a major cause of microsatellite instability in sporadic colorectal cancers, and germline epimutation of hMLH1 and hMSH2 is a cause of hereditary nonpolyposis colorectal cancers, which do not show mutation of mismatch repair genes. Epigenetic inactivation of MGMT is often associated with G:C-to-A:T mutations in K-ras and p53, while epigenetic inactivation of BRCA1, WRN, FANCF, and CHFR impairs the machinery involved in maintaining genomic integrity. Epigenetic alteration of the genes involved in the induction of senescence is often associated with cancers showing mutations in the Ras signaling pathway. In addition to regional hypermethylation, global hypomethylation is also a common feature of tumors. Hypomethylation of short and long interspersed repetitive elements has been reported, and hypomethylation affecting the integrity of the genome has been observed in ICF syndrome and various cancers. Dissection of the epigenetic drivers of genetic instability may be important for the development of novel approaches to the treatment of cancer. PMID- 20920754 TI - DNA demethylating agents and epigenetic therapy of cancer. AB - Epigenetic events have been associated with virtually every step of tumor development and progression, and epigenetic alterations are believed to occur early in tumor development and may precede the malignant process. In contrast to genetic changes, epigenetic alterations arise in a gradual manner, leading to a progressive silencing of specific genes. An important distinction between epigenetic and genetic alterations is intrinsic reversibility of the former, making cancer-associated changes in DNA methylation, histone modifications, and expression of noncoding RNAs attractive targets for therapeutic intervention. This realization has triggered an impressive quest for the development of "epigenetic drugs" and epigenetic therapies. A number of agents have been subjected to an intensive investigation, many of which have been found capable of altering epigenetic states, including DNA methylation patterns and histone modification states. Many of these agents are currently being tested in clinical trials, while several of them are already used in clinics. This review will focus on the recent advances in the development of epigenetic drugs based on the inhibition of DNA methylation. Combinatorial therapies that couple DNA demethylating agents with histone deacetylase inhibitors will also be discussed. PMID- 20920755 TI - Histone modification therapy of cancer. AB - The state of modification of histone tails plays an important role in defining the accessibility of DNA for the transcription machinery and other regulatory factors. It has been extensively demonstrated that the posttranslational modifications of the histone tails, as well as modifications within the nucleosome domain, regulate the level of chromatin condensation and are therefore important in regulating gene expression and other nuclear events. Together with DNA methylation, they constitute the most relevant level of epigenetic regulation of cell functions. Histone modifications are carried out by a multipart network of macromolecular complexes endowed with enzymatic, regulatory, and recognition domains. Not surprisingly, epigenetic alterations caused by aberrant activity of these enzymes are linked to the establishment and maintenance of the cancer phenotype and, importantly, are potentially reversible, since they do not involve genetic mutations in the underlying DNA sequence. Histone modification therapy of cancer is based on the generation of drugs able to interfere with the activity of enzymes involved in histone modifications: new drugs have recently been approved for use in cancer patients, clinically validating this strategy. Unfortunately, however, clinical responses are not always consistent and do not parallel closely the results observed in preclinical models. Here, we present a brief overview of the deregulation of chromatin-associated enzymatic activities in cancer cells and of the main results achieved by histone modification therapeutic approaches. PMID- 20920752 TI - Identification of driver and passenger DNA methylation in cancer by epigenomic analysis. AB - Human cancer genomes are characterized by widespread aberrations in DNA methylation patterns including DNA hypomethylation of mostly repetitive sequences and hypermethylation of numerous CpG islands. The analysis of DNA methylation patterns in cancer has progressed from single gene studies examining potentially important candidate genes to a more global analysis where all or almost all promoter and CpG island sequences can be analyzed. We provide a brief overview of these genome-scale methylation-profiling techniques, summarize some of the information that has been obtained with these approaches, and discuss what we have learned about the specificity of methylation aberrations in cancer at a genome-wide level. The challenge is now to identify those methylation changes that are thought to be crucial for the processes of tumor initiation, tumor progression, or metastasis and distinguish these from methylation changes that are merely passenger events that accompany the transformation process but have no effect per se on the process of carcinogenesis. PMID- 20920756 TI - Floquet theory in solid-state nuclear magnetic resonance. PMID- 20920757 TI - Radial sampling for fast NMR: Concepts and practices over three decades. PMID- 20920758 TI - Random sampling in multidimensional NMR spectroscopy. PMID- 20920760 TI - Airway obstructive diseases in older adults: from detection to treatment. AB - Asthma and chronic obstructive pulmonary disease occur commonly and may overlap among older adults. Smoking, air pollution, and bronchial hyperresponsiveness are the main risk factors. The treatment of these diseases in older adults does not differ from the available guidelines but may be complicated by the presence of comorbidities. Smoking cessation is essential for smokers, and pulmonary rehabilitation must be considered regardless of the age of the patient. PMID- 20920759 TI - Age-related changes in immune function: effect on airway inflammation. AB - Immunosenescence is defined as changes in the innate and adaptive immune response associated with increased age. The clinical consequences of immunosenescence include increased susceptibility to infection, malignancy and autoimmunity, decreased response to vaccination, and impaired wound healing. However, there are several immune alterations that might facilitate persistence of asthma into late adulthood or development of asthma after the age of 50 to 60 years. Asthma in older patients is not uncommon, and this is a growing population as the average lifespan increases. Specific innate changes that might affect severity of asthma in older patients or be involved in the development of late-onset asthma include impaired mucociliary clearance and changes in airway neutrophil, eosinophil, and mast cell numbers and function. Additionally, age-related altered antigen presentation and decreased specific antibody responses might increase the risk of respiratory tract infections. Respiratory tract infections exacerbate asthma in older patients and possibly play a role in the pathogenesis of late-onset asthma. Furthermore, cytokine profiles might be modified with aging, with some investigators suggesting a trend toward T(H)2 cytokine expression. This review examines specific innate and adaptive immune responses affected by aging that might affect the inflammatory response in older adults with asthma. PMID- 20920762 TI - Alveolar nitric oxide concentration, small airways inflammation, and targeted asthma therapy: are we there yet? PMID- 20920763 TI - Does suppression of IL-4 synthesis by aspirin explain the therapeutic benefit of aspirin desensitization treatment? PMID- 20920765 TI - Statins enhance the anti-inflammatory effects of inhaled corticosteroids in asthmatic patients through increased induction of indoleamine 2, 3-dioxygenase. AB - BACKGROUND: We have previously shown that inhaled corticosteroids activate indoleamine 2, 3-dioxygenase (IDO) activity through increased IL-10 secretion. Statins might enhance the anti-inflammatory effects of corticosteroids. OBJECTIVE: In a double-blind study we added simvastatin to patients with mild asthma receiving a low dose of inhaled budesonide and evaluated sputum eosinophil counts, IL-10 secretion, and IDO activity, as well as their putative signaling pathways. METHODS: After a 2-week run-in period without treatment, 50 asthmatic patients were treated with 200 MUg of budesonide and randomly assigned to either 10 mg of simvastatin or matched placebo for 8 weeks. Inflammation was evaluated through eosinophil counts, secretory signaling molecules, and immunocytochemistry of macrophages in sputum. RESULTS: Sputum eosinophil percentages were reduced significantly by the combined therapy with budesonide and simvastatin compared with budesonide alone (P = .02). Corticosteroids activated glucocorticoid-induced TNF receptor ligand, which induces activation of p52 through the noncanonical nuclear factor kappaB pathway, leading to the increased transcription and activation of IDO. Simvastatin enhanced corticosteroid-activated noncanonical nuclear factor kappaB-dependent induction of IDO by activating type I interferons and also enhanced the effect of corticosteroid on IL-10 release. CONCLUSION: A statin enhances the anti-inflammatory effect of an inhaled corticosteroid in asthma, and this was mediated through the alteration of IDO activity in macrophages. PMID- 20920764 TI - A trial of clarithromycin for the treatment of suboptimally controlled asthma. AB - BACKGROUND: PCR studies have demonstrated evidence of Mycoplasma pneumoniae and Chlamydophila pneumoniae in the lower airways of patients with asthma. OBJECTIVE: To test the hypothesis that clarithromycin would improve asthma control in individuals with mild-to-moderate persistent asthma that was not well controlled despite treatment with low-dose inhaled corticosteroids. METHODS: Adults with an Asthma Control Questionnaire score >=1.5 after a 4-week period of treatment with fluticasone propionate were entered into a PCR-stratified randomized, controlled trial to evaluate the effect of 16 weeks of either clarithromycin or placebo, added to fluticasone, on asthma control in individuals with or without lower airway PCR evidence of M pneumoniae or C pneumoniae. RESULTS: A total of 92 participants were randomized. Twelve (13%) subjects demonstrated PCR evidence of M pneumoniae or C pneumoniae in endobronchial biopsies; 80 were PCR-negative for both organisms. In PCR-positive participants, clarithromycin yielded a 0.4 +/- 0.4 unit improvement in the Asthma Control Questionnaire score, with a 0.1 +/- 0.3 unit improvement in those allocated to placebo. This between-group difference of 0.3 +/- 0.5 (P = .6) was neither clinically nor statistically significant. In PCR-negative participants, a nonsignificant between-group difference of 0.2 +/- 0.2 units (P = .3) was observed. Clarithromycin did not improve lung function or airway inflammation but did improve airway hyperresponsiveness, increasing the methacholine PC(20) by 1.2 +/- 0.5 doubling doses (P = .02) in the study population. CONCLUSION: Adding clarithromycin to fluticasone in adults with mild to-moderate persistent asthma that was suboptimally controlled by low-dose inhaled corticosteroids alone did not further improve asthma control. Although there was an improvement in airway hyperresponsiveness with clarithromycin, this benefit was not accompanied by improvements in other secondary outcomes. PMID- 20920766 TI - The immunostimulant OM-85 BV prevents wheezing attacks in preschool children. AB - BACKGROUND: No reagents have been shown to be effective in preventing wheezing attacks provoked by acute respiratory tract illnesses (ARTIs) in preschool children. New therapeutic agents and preventive strategies are needed. OBJECTIVES: We assessed the effect of OM-85 BV (Broncho-Vaxom; OM Pharma, Geneva, Switzerland) in preventing ARTI-provoked wheezing attacks in preschool children with recurrent wheezing. METHODS: A randomized, double-blind, placebo-controlled, parallel-group study was carried out between August 2007 and September 2008. The study included 75 children with recurrent wheezing who were 1 to 6 years old. Participants were randomly assigned to groups given either OM-85 BV or a placebo (1 capsule per day for 10 days each month for 3 consecutive months) at the start of the trial. Participants were followed for 12 months, which included the administration period of the test article. RESULTS: Subjects given OM-85 BV had a lower rate of wheezing attacks. The cumulative difference in wheezing attacks between the 2 groups was 2.18 wheezing attacks per patient in 12 months; there was a 37.9% reduction in the group given OM-85 BV compared with the group given placebo (P < .001). Stepwise multiple (linear) regression analysis showed that the main difference between the OM-85 BV and placebo groups was a reduction the number of ARTIs (R = -0.805, P < .001). The duration of each wheezing attack was 2 days shorter in the group given OM-85 BV than in the group given placebo (P = .001). CONCLUSION: Administration of OM-85 BV significantly reduced the rate and duration of wheezing attacks in preschool children with ARTIs. PMID- 20920767 TI - Can we prevent exacerbations of asthma caused by common cold viruses? PMID- 20920768 TI - Risk of perinatal mortality associated with inhaled corticosteroid use for the treatment of asthma during pregnancy. AB - BACKGROUND: Four studies investigating the association between inhaled corticosteroid (ICS) use during pregnancy and perinatal mortality reported no significantly increased risk. These studies must be interpreted with caution because they have insufficient statistical power and a lack of adjustment for potential confounders. OBJECTIVES: We sought to evaluate whether asthmatic women exposed to ICSs during pregnancy are more at risk of perinatal mortality than asthmatic women not exposed. We also sought to estimate the risk of perinatal mortality as a function of the daily ICS dose taken during pregnancy. METHODS: From the linkage of 3 administrative databases from Quebec, a cohort including 13,004 single pregnancies from asthmatic women was constructed. We used a 2-stage sampling cohort design to obtain information on cigarette smoking from the medical charts of 487 mothers. The final estimates of the odds ratios (ORs) of perinatal mortality were estimated with a logistic regression model. RESULTS: The cohort was formed of 4,140 women who used greater than 0 to 250 MUg/d ICS, 1,140 women who used greater than 250 MUg/d ICS, and 7,724 nonusers of ICSs during pregnancy. Women exposed to ICSs (any dose) had a nonsignificant increased risk of perinatal mortality (OR, 1.07; 95% CI, 0.70-1.61). The use of greater than 250 MUg/d ICS was associated with a nonsignificant 52% increased risk of perinatal mortality (OR, 1.52; 95% CI, 0.62-3.76). CONCLUSION: The risk of perinatal mortality was not found to be significantly associated with ICS use during pregnancy. The result associated with higher doses of ICSs is limited due to a lack of statistical power and a possibility of residual confounding by asthma severity and control. PMID- 20920769 TI - The epidemiology of ocular and nasal allergy in the United States, 1988-1994. AB - BACKGROUND: Allergies give rise to the fifth-leading group of chronic diseases. However, the specific prevalence of ocular allergy is poorly described. OBJECTIVE: We sought to provide a more accurate representation of the epidemiology of ocular allergy in the United States. METHODS: The National Health And Nutrition Examination Survey III performed in the United States from 1988 1994 was the source for the data collected. Items from the questionnaire regarding ocular and nasal allergy symptoms in relation to skin prick testing were stratified by age, race, region, and sex. RESULTS: The sample size is 20,010: 1,285 (6.4%) reported ocular symptoms, 3,294 (16.5%) reported nasal symptoms, 5,944 (29.7%) reported both ocular and nasal symptoms, and 9.487 (47.4%) were asymptomatic. Forty percent of the population reported at least 1 occurrence of ocular symptoms in the past 12 months. Those 50 years and older have a higher frequency of isolated ocular symptoms (P < .001). There is an increase in the frequency of symptoms in those younger than 50 years in the populations of subjects with ocular and nasal symptoms combined and isolated nasal symptoms (P < .001). Ocular symptoms are more frequent than nasal symptoms in relation to animals (P < .001), household dust (P < .001), and pollen (P < .001). CONCLUSION: This analysis provides the first representation of the epidemiology of ocular allergy in the United States. Up to 40% of the population, the highest reported to date, have experienced ocular symptoms at least once in their lifetime, with a peak of symptoms in the months of June and July. PMID- 20920770 TI - National prevalence and risk factors for food allergy and relationship to asthma: results from the National Health and Nutrition Examination Survey 2005-2006. AB - BACKGROUND: The national prevalence and patterns of food allergy (FA) in the United States are not well understood. OBJECTIVE: We developed nationally representative estimates of the prevalence of and demographic risk factors for FA and investigated associations of FA with asthma, hay fever, and eczema. METHODS: A total of 8203 participants in the National Health and Nutrition Examination Survey 2005-2006 had food-specific serum IgE measured to peanut, cow's milk, egg white, and shrimp. Food-specific IgE and age-based criteria were used to define likely FA (LFA), possible FA, and unlikely FA and to develop estimates of clinical FA. Self-reported data were used to evaluate demographic risk factors and associations with asthma and related conditions. RESULTS: In the United States, the estimated prevalence of clinical FA was 2.5% (peanut, 1.3%; milk, 0.4%; egg, 0.2%; shrimp, 1.0%; not mutually exclusive). Risk of possible FA/LFA was increased in non-Hispanic blacks (odds ratio, 3.06; 95% CI, 2.14-4.36), males (1.87; 1.32-2.66), and children (2.04; 1.42-2.93). Study participants with doctor diagnosed asthma (vs no asthma) exhibited increased risk of all measures of food sensitization. Moreover, in those with LFA, the adjusted odds ratio for current asthma (3.8; 1.5-10.7) and an emergency department visit for asthma in the past year (6.9; 2.4-19.7) were both notably increased. CONCLUSION: Population-based serologic data on 4 foods indicate an estimated 2.5% of the US population has FA, and increased risk was found for black subjects, male subjects, and children. In addition, FA could be an under-recognized risk factor for problematic asthma. PMID- 20920771 TI - Can early introduction of egg prevent egg allergy in infants? A population-based study. AB - BACKGROUND: Infant feeding guidelines have long recommended delaying introduction of solids and allergenic foods to prevent allergy in high-risk infants, despite a paucity of evidence. OBJECTIVE: We aimed to determine whether confirmed egg allergy in 12-month-old infants is associated with (1) duration of breast-feeding and (2) ages of introducing egg and solids. METHODS: In a population-based cross sectional study (HealthNuts) parents reported on infant feeding and potential confounding factors before skin prick testing for egg white. Egg-sensitized infants were then offered an egg oral food challenge. Multiple logistic regression was used to investigate associations between diet and egg allergy adjusted for possible confounding factors. RESULTS: A total of 2589 infants (73% response) participated. Compared with introduction at 4 to 6 months, introducing egg into the diet later was associated with higher risks of egg allergy (adjusted odds ratios [ORs], 1.6 [95% CI, 1.0-2.6] and 3.4 [95% CI, 1.8-6.5] for introduction at 10-12 and after 12 months, respectively). These findings persisted even in children without risk factors (OR, 3.3 [95% CI, 1.1-9.9]; 10-12 months). At age 4 to 6 months, first exposure as cooked egg reduced the risk of egg allergy compared with first exposure as egg in baked goods (OR, 0.2 [95% CI, 0.06-0.71]). Duration of breast-feeding and age at introduction of solids were not associated with egg allergy. CONCLUSIONS: Introduction of cooked egg at 4 to 6 months of age might protect against egg allergy. Changes in infant feeding guidelines could have a significant effect on childhood egg allergy and possibly food allergy more generally. PMID- 20920772 TI - Recombinant human C1-inhibitor for the treatment of acute angioedema attacks in patients with hereditary angioedema. AB - BACKGROUND: Hereditary angioedema (HAE) results from a genetic deficiency of C1 inhibitor. Two similar independent, randomized, saline controlled, double-blind studies were conducted to evaluate the efficacy and safety of recombinant human C1-inhibitor (rhC1INH) as a treatment of acute angioedema attacks in patients with HAE. OBJECTIVE: Analysis of pooled study results. METHODS: Patients with an eligible attack were randomized to a single intravenous dose of rhC1INH or saline. Efficacy was assessed by using patient-reported visual analog scale outcomes, and safety was assessed by using adverse events and immunogenicity of rhC1INH. RESULTS: rhC1INH at 100 (n = 29) and 50 (n = 12) U/kg body weight resulted in a significant reduction for both the primary endpoint time to the beginning of relief of symptoms compared with saline (n = 29): median, 66 (95% CI, 61-122) minutes, 122 (72-136) minutes, and 495 (245-520) minutes, P < .001 and P = .013, respectively; and for the secondary endpoint time to minimal symptoms, median, 266 (242-490) minutes, 247 (243-484) minutes, and 1210 (970 1500) minutes, P < .001 and P = .001, respectively. Therapeutic failure occurred in 59% (17/29) of the saline group compared with 0% (0/12) of the 50 U/kg group and 10% (3/29) of the 100 U/kg group. Treatment-emergent adverse events were unremarkable and tended to be reported more frequently in the saline group. No postexposure antibody responses against rhC1INH or host-related impurities were observed. CONCLUSION: Administration of rhC1INH at 100 or 50 U/kg was highly effective as a treatment of acute attacks in patients with HAE and appeared to be safe and well tolerated. PMID- 20920773 TI - Ambient air pollution impairs regulatory T-cell function in asthma. AB - BACKGROUND: Asthma is the most frequent chronic disease in children, and children are at high risk for adverse health consequences associated with ambient air pollution (AAP) exposure. Regulatory T (Treg) cells are suppressors of immune responses involved in asthma pathogenesis. Treg-cell impairment is associated with increased DNA methylation of Forkhead box transcription factor 3 (Foxp3), a key transcription factor in Treg-cell activity. Because AAP exposure can induce epigenetic changes, we hypothesized that Treg-cell function would be impaired by AAP, allowing amplification of an inflammatory response. OBJECTIVES: To assess whether exposure to AAP led to hypermethylation of the Foxp3 gene, causing impaired Treg-cell suppression and worsened asthma symptom scores. METHODS: Children with and without asthma from Fresno, Calif (high pollution, Fresno Asthma Group [FA], n = 71, and Fresno Non Asthmatic Group, n = 30, respectively), and from Stanford, Calif (low pollution, Stanford Asthma Group, n = 40, and Stanford Non Asthmatic Group, n = 40), were enrolled in a cross-sectional study. Peripheral blood Treg cells were used in functional and epigenetic studies. Asthma outcomes were assessed by Global Initiative in Asthma score. RESULTS: Fresno Asthma Group Treg-cell suppression was impaired and FA Treg-cell chemotaxis were reduced compared with other groups (P <= .05). Treg-cell dysfunction was associated with more pronounced decreases in asthma Global Initiative in Asthma score in FA versus the Stanford Asthma Group. Foxp3 was decreased in FA compared with the Fresno Non Asthmatic Group (P <= .05). FA also contained significantly higher levels of methylation at the Foxp3 locus (P <= .05). CONCLUSION: Increased exposure to AAP is associated with hypermethylation of the Foxp3 locus, impairing Treg-cell function and increasing asthma morbidity. AAP could play a role in mediating epigenetic changes in Treg cells, which may worsen asthma by an immune mechanism. PMID- 20920774 TI - Eoxins: a new inflammatory pathway in childhood asthma. AB - BACKGROUND: Increased levels of leukotrienes (LTs) in exhaled breath condensate (EBC) are associated with asthma and bronchial hyperresponsiveness (BHR), whereas eicosanoids generated through the 15-lipoxygenase (LO) pathway (15 hydroxyeicosatetraenoic acid [HETE] and eoxins) have been less studied. OBJECTIVE: We investigated whether metabolites of the 5- and 15-LO pathways in EBC are associated with childhood asthma, asthma severity, and clinical parameters. METHODS: The present study included 131 school-aged children (27 children with problematic severe asthma, 80 children with mild-to-moderate asthma, and 24 healthy children) from the Severe Asthma Recognized in Childhood study and 19 children with other nonasthmatic chronic lung diseases. Clinical work-up included spirometry, fractional exhaled nitric oxide measurements, skin prick testing, and methacholine challenge. Eicosanoids were analyzed in EBC by using mass spectrometry and are reported as concentrations (in picograms per milliliter) and eicosanoid/palmitic acid (PA) ratios. RESULTS: Eoxin C4/PA, eoxin D4/PA, eoxin E4/PA, 15-HETE/PA, and LTC4/PA ratios were significantly increased in asthmatic versus healthy children. Eoxin D4/PA and LTE4/PA ratios were also significantly higher in children with BHR. A nonsignificant trend was observed toward higher eoxin/PA ratios with increasing asthma severity. In contrast to asthma, children with chronic lung disease had the highest 15-HETE/PA, LTC4/PA, LTE4/PA, and LTB4/PA ratios. CONCLUSION: The results point to increased activity of the 15-LO inflammatory pathway in childhood asthma. Mass spectrometric analyses of EBC demonstrate that increased eoxin levels not only accompany the increased 5-LO product LTC4 but are also associated with BHR. These markers might represent a new therapeutic target for asthma treatment. PMID- 20920775 TI - Methacholine is more sensitive than mannitol for evaluation of bronchial hyperresponsiveness in children with asthma. PMID- 20920776 TI - PDE11A associations with asthma: results of a genome-wide association scan. PMID- 20920777 TI - Ineffectiveness of telephone-based environmental control intervention to improve asthma outcomes. PMID- 20920778 TI - IL-4 receptor alpha polymorphisms are predictors of a pharmacogenetic response to a novel IL-4/IL-13 antagonist. PMID- 20920779 TI - The need for standardization in exercise challenge testing for exercise-induced asthma/bronchoconstriction. PMID- 20920780 TI - Curcumin attenuates the effects of transport stress on serum cortisol concentration, hippocampal NO production, and BDNF expression in the pig. AB - Curcumin, the active component of curcuma longa, has been reported to be effective in alleviating chronic stress-induced disorders in rodents by modulating neuroprotection and neuroendocrine functions of the central nervous system, especially hippocampus. However, it is unclear whether curcumin can attenuate the subacute stress response induced by 2 h of road transport in the pig. Therefore, the present study was designed to identify the changes of serum cortisol concentration, hippocampal nitric oxide (NO) production, and related gene expression in response to 2 h of transport and to explore whether curcumin treatment (8 mg/kg, p.o.) for 21 d before transport may alleviate the stress induced responses in the hippocampus of pigs. We found that 2 h of transport elevated serum cortisol concentration (P < 0.01), increased hippocampal NO content, and reduced brain-derived neurotrophic factor (BDNF) mRNA expression in pigs not treated with curcumin, whereas these stress responses were all reversed or attenuated in curcumin-treated pigs. In addition, the stress-induced increase in the expression of constitutive nitric oxide synthase (cNOS) and enzyme activities of total NOS, cNOS, and inducible NOS (iNOS) was also reversed or attenuated in curcumin-treated pigs. However, neither transport nor curcumin caused significant alterations in hippocampal expression of 11beta-hydroxysteroid dehydrogenase type 1 and type 2 (11beta-HSD1 and 2), glucocorticoid and mineralocorticoid receptors (GR and MR), or pro-/anti-apoptotic molecules (Bax alpha and Bcl-xL). These results suggest that curcumin can alleviate subacute stress response in pigs through its neuroprotective effects on modulating hippocampal NO production and BDNF expression. PMID- 20920781 TI - Impacts of maternal selenium and nutritional level on growth, adiposity, and glucose tolerance in female offspring in sheep. AB - To examine effects of maternal nutrition and Se intake on adiposity and insulin sensitivity in female offspring, treatments were imposed during gestation on 82 pregnant primiparous Rambouillet ewe lambs (52.2 +/- 0.8 kg) allotted randomly to 1 of 6 treatments in a 2 * 3 factorial arrangement. Factors were adequate (9.5 MUg Se.kg BW(-1).d(-1); ASe) or high (81.8 MUg Se.kg BW(-1).d(-1); HSe) levels of dietary Se (Se-enriched yeast) and maternal nutritional intake (100% of metabolizable energy [ME] requirement [MOD], 60% of MOD [LOW], and 140% of MOD [HIGH]). Selenium treatments were initiated at breeding and global nutritional treatments at day 50 of gestation. At parturition, lambs were removed from ewes before nursing and managed similarly. Glucose tolerance tests were performed at 107 and 148 d of age. Necropsies were performed at 180 d of age. Although there was no effect of Se on maternal body condition or weight during gestation, both maternal nutritional intake and selenium treatment influenced (P <= 0.04) offspring growth and response to a glucose tolerance test. Female lambs from HSe ewes were heavier (P = 0.04) at birth. There were nutritional intake and Se interactions (P <= 0.05) on the growth rate of the lambs and their insulin response to a glucose bolus at 2 different times during growth. By 180 d, ewe lambs from HSe ewes had more (P <= 0.07) internal fat stores than lambs from ASe ewes. It appears that both maternal nutritional level and Se intake can influence insulin sensitivity, and maternal Se intake alone can enhance fat deposition in female offspring. PMID- 20920782 TI - Fibroblast growth factor-10 maintains the survival and promotes the growth of cultured goat preantral follicles. AB - The aim of the present study was to investigate the effects of fibroblast growth factor-10 (FGF-10) on the survival, activation (transition from primordial to primary follicles), and growth of goat preantral follicles cultured in vitro. Pieces of ovarian cortex were cultured for 1 and 7 d in the absence or presence of FGF-10 (0, 1, 10, 50, 100, and 200 ng/mL). Noncultured and cultured tissues were processed and analyzed by histology, transmission electron microscopy, and viability testing. Results showed that after 7 d, a greater percentage (79.9%) of morphologically normal follicles (containing an oocyte with regular shape and uniform cytoplasm, and organized layers of granulosa cells without a pyknotic nucleus) was observed when cultured with 50 ng/mL of FGF-10 when compared with other concentrations of FGF-10 (0 ng/mL, 67.3%; 1 ng/mL, 68.2%; 10 ng/mL, 63.3%; 100 ng/mL, 64.4%; 200 ng/mL, 52.7%). Ultrastructural analyses and viability testing using fluorescent markers confirmed the follicular integrity of FGF-10 (50 ng/mL)-treated fragments after 7 d of culture. After 7 d, all FGF-10 concentrations reduced the percentage of primordial follicles and increased the percentage of developing follicles. In the presence of 50 ng/mL of FGF-10, follicles increased in diameter after 7 d of culture when compared with other concentrations tested. In conclusion, this study demonstrates that FGF-10 maintains the morphological integrity of goat preantral follicles and stimulates the growth of activated follicles in culture. The culture conditions identified here contribute to the understanding of the factors involved in goat early follicular development. PMID- 20920783 TI - Expression of the ACTH receptor, steroidogenic acute regulatory protein, and steroidogenic enzymes in canine cortisol-secreting adrenocortical tumors. AB - Studies of human adrenocortical tumors (ATs) causing Cushing's syndrome suggest that hypersecretion of cortisol is caused by altered expression of steroidogenic enzymes and that steroidogenesis can only be maintained when there is expression of the ACTH receptor (ACTH-R). Here we report the screening for the mRNA expression of the ACTH-R, steroidogenic acute regulatory protein (StAR), cholesterol side-chain cleavage enzyme, 3beta-hydroxysteroid dehydrogenase, 21 hydroxylase (all in 38 cortisol-secreting ATs), 17alpha-hydroxylase, and 11beta hydroxylase (both in 28 cortisol-secreting ATs). Real-time PCR (RT-PCR) was applied in all samples and was compared with that in normal canine adrenal glands. Messenger-RNA encoding StAR, steroidogenic enzymes, and ACTH-R were present in both normal adrenal glands and cortisol-secreting ATs. The amounts of mRNA encoding StAR and enzymes of the steroidogenic cluster needed for cortisol production did not differ significantly between either adenomas or carcinomas and normal adrenal glands. The amount of mRNA encoding ACTH-R was significantly lower in carcinomas than in normal adrenal glands (P = 0.008). In conclusion, RT-PCR analysis revealed no overexpression of StAR and steroidogenic enzymes in canine cortisol-secreting ATs. Significant downregulation of ACTH-R in carcinomas might be associated with the malignant character of the AT. PMID- 20920784 TI - Small molecule ion channel match making: a natural fit for new ASIC ligands. AB - ASICs (acid-sensing ion channels) are proton-gated channels that are important for pain sensation. New work by Yu and coworkers in this issue of Neuron identifies synthetic ligands and related small molecules found in the inflammatory soup that activate ASICs. These new findings highlight the power of small molecule screening to find new compounds that can control channel function. They also demonstrate how the discovery and characterization of such molecules can lead to new insights regarding channel mechanism and natural ligands. PMID- 20920785 TI - Snapin snaps into the dynein complex for late endosome-lysosome trafficking and autophagy. AB - Late endosome-lysosome trafficking plays a key role in regulating cell surface signaling and degradation of intracellular components by autophagy. New work by Cai and coworkers in this issue of Neuron provides evidence that snapin regulates the recruitment of late endosomes to the dynein motor complex for retrograde trafficking along microtubules and maturation of lysosomes. PMID- 20920786 TI - VGLUTs--potential targets for the treatment of seizures? AB - Vesicular glutamate transporters (VGLUTs) load glutamate into synaptic vesicles. In this issue of Neuron, Juge et al. report that ketone bodies compete with chloride-dependent activation of VGLUTs, leading to suppression of glutamate release and seizures. These findings provide a surprising explanation for the efficacy of the ketogenic diet in controlling epilepsy. PMID- 20920787 TI - Molecular mechanisms of synaptic specificity in developing neural circuits. AB - The function of the brain depends on highly specific patterns of connections between populations of neurons. The establishment of these connections requires the targeting of axons and dendrites to defined zones or laminae, the recognition of individual target cells, the formation of synapses on particular regions of the dendritic tree, and the differentiation of pre- and postsynaptic specializations. Recent studies provide compelling evidence that transmembrane adhesion proteins of the immunoglobulin, cadherin, and leucine-rich repeat protein families, as well as secreted proteins such as semaphorins and FGFs, regulate distinct aspects of neuronal connectivity. These observations suggest that the coordinated actions of a number of molecular signals contribute to the specification and differentiation of synaptic connections in the developing brain. PMID- 20920788 TI - Regulation of tau pathology by the microglial fractalkine receptor. AB - Aggregates of the hyperphosphorylated microtubule-associated protein tau (MAPT) are an invariant neuropathological feature of tauopathies. Here, we show that microglial neuroinflammation promotes MAPT phosphorylation and aggregation. First, lipopolysaccharide-induced microglial activation promotes hyperphosphorylation of endogenous mouse MAPT in nontransgenic mice that is further enhanced in mice lacking the microglial-specific fractalkine receptor (CX3CR1) and is dependent upon functional toll-like receptor 4 and interleukin-1 (IL-1) receptors. Second, humanized MAPT transgenic mice lacking CX3CR1 exhibited enhanced MAPT phosphorylation and aggregation as well as behavioral impairments that correlated with increased levels of active p38 MAPK. Third, in vitro experiments demonstrate that microglial activation elevates the level of active p38 MAPK and enhances MAPT hyperphosphorylation within neurons that can be blocked by administration of an interleukin-1 receptor antagonist and a specific p38 MAPK inhibitor. Taken together, our results suggest that CX3CR1 and IL-1/p38 MAPK may serve as novel therapeutic targets for human tauopathies. PMID- 20920789 TI - Presynaptic activity and CaMKII modulate retrograde semaphorin signaling and synaptic refinement. AB - Establishing synaptic connections often involves the activity-dependent withdrawal of off-target contacts. We describe an in vivo role for temporally patterned electrical activity, voltage-gated calcium channels, and CaMKII in modulating the response of Drosophila motoneurons to the chemorepellent Sema-2a during synaptic refinement. Mutations affecting the Sema-2a ligand, the plexin B receptor (plexB), the voltage-gated Ca(v)2.1 calcium channel (cac), or the voltage-gated Na(v)1 sodium channel (mle(nap-ts);tipE) each result in ectopic neuromuscular contacts. Sema-2a interacts genetically with both of the channel mutations. The cac phenotype is enhanced by the Sema-2a mutation and is suppressed by either plexB overexpression or patterned, low-frequency (0.01 Hz) bouts of electrical activity in the embryo. The calcium-dependent suppression of ectopic contacts also depends on the downstream activation of CaMKII. These results indicate a role for patterned electrical activity and presynaptic calcium signaling, acting through CaMKII, in modulating a retrograde signal during the refinement of synaptic connections. PMID- 20920790 TI - Nna1 mediates Purkinje cell dendritic development via lysyl oxidase propeptide and NF-kappaB signaling. AB - The molecular pathways controlling cerebellar Purkinje cell dendrite formation and maturation are poorly understood. The Purkinje cell degeneration (pcd) mutant mouse is characterized by mutations in Nna1, a gene discovered in an axonal regenerative context, but whose actual function in development and disease is unknown. We found abnormal development of Purkinje cell dendrites in postnatal pcd(Sid) mice and linked this deficit to a deletion mutation in exon 7 of Nna1. With single cell gene profiling and virus-based gene transfer, we analyzed a molecular pathway downstream to Nna1 underlying abnormal Purkinje cell dendritogenesis in pcd(Sid) mice. We discovered that mutant Nna1 dramatically increases intranuclear localization of lysyl oxidase propeptide, which interferes with NF-kappaB RelA signaling and microtubule-associated protein regulation of microtubule stability, leading to underdevelopment of Purkinje cell dendrites. These findings provide insight into Nna1's role in neuronal development and why its absence renders Purkinje cells more vulnerable. PMID- 20920791 TI - A nonproton ligand sensor in the acid-sensing ion channel. AB - Acid-sensing ion channels (ASICs) have long been considered as extracellular proton (H(+))-gated cation channels, and peripheral ASIC3 channels seem to be a natural sensor of acidic pain. Here, we report the identification of a nonproton sensor on ASIC3. We show first that 2-guanidine-4-methylquinazoline (GMQ) causes persistent ASIC3 channel activation at the normal pH. Using GMQ as a probe and combining mutagenesis and covalent modification analysis, we then uncovered a ligand sensor lined by residues around E423 and E79 of the extracellular "palm" domain of the ASIC3 channel that is crucial for activation by nonproton activators. Furthermore, we show that GMQ activates sensory neurons and causes pain-related behaviors in an ASIC3-dependent manner, indicating the functional significance of ASIC activation by nonproton ligands. Thus, natural ligands beyond protons may activate ASICs under physiological and pathological conditions through the nonproton ligand sensor, serving for channel activation independent of abrupt and marked acidosis. PMID- 20920792 TI - Snapin-regulated late endosomal transport is critical for efficient autophagy lysosomal function in neurons. AB - Neuron maintenance and survival require late endocytic transport from distal processes to the soma where lysosomes are predominantly localized. Here, we report a role for Snapin in attaching dynein to late endosomes through its intermediate chain (DIC). snapin(-/-) neurons exhibit aberrant accumulation of immature lysosomes, clustering and impaired retrograde transport of late endosomes along processes, reduced lysosomal proteolysis due to impaired delivery of internalized proteins and hydrolase precursors from late endosomes to lysosomes, and impaired clearance of autolysosomes, combined with reduced neuron viability and neurodegeneration. The phenotypes are rescued by expressing the snapin transgene, but not the DIC-binding-defective Snapin-L99K mutant. Snapin overexpression in wild-type neurons enhances late endocytic transport and lysosomal function, whereas expressing the mutant defective in Snapin-DIC coupling shows a dominant-negative effect. Altogether, our study highlights new mechanistic insights into how Snapin-DIC coordinates retrograde transport and late endosomal-lysosomal trafficking critical for autophagy-lysosomal function, and thus neuronal homeostasis. PMID- 20920793 TI - Circadian and homeostatic regulation of structural synaptic plasticity in hypocretin neurons. AB - Neurons exhibit rhythmic activity that ultimately affects behavior such as sleep. In living zebrafish larvae, we used time-lapse two-photon imaging of the presynaptic marker synaptophysin in hypocretin/orexin (HCRT) neurons to determine the dynamics of synaptic modifications during the day and night. We observed circadian rhythmicity in synapse number in HCRT axons. This rhythm is regulated primarily by the circadian clock but is also affected by sleep deprivation. Furthermore, NPTX2, a protein implicated in AMPA receptor clustering, modulates circadian synaptic changes. In zebrafish, nptx2b is a rhythmic gene that is mostly expressed in hypothalamic and pineal gland cells. Arrhythmic transgenic nptx2b overexpression (hcrt:NPTX2b) increases synapse number and abolishes rhythmicity in HCRT axons. Finally, hcrt:NPTX2b fish are resistant to the sleep promoting effects of melatonin. This behavioral effect is consistent with NPTX2b mediated increased activity of HCRT circuitry. These data provide real-time in vivo evidence of circadian and homeostatic regulation of structural synaptic plasticity. PMID- 20920794 TI - Metabolic control of vesicular glutamate transport and release. AB - Fasting has been used to control epilepsy since antiquity, but the mechanism of coupling between metabolic state and excitatory neurotransmission remains unknown. Previous work has shown that the vesicular glutamate transporters (VGLUTs) required for exocytotic release of glutamate undergo an unusual form of regulation by Cl(-). Using functional reconstitution of the purified VGLUTs into proteoliposomes, we now show that Cl(-) acts as an allosteric activator, and the ketone bodies that increase with fasting inhibit glutamate release by competing with Cl(-) at the site of allosteric regulation. Consistent with these observations, acetoacetate reduced quantal size at hippocampal synapses and suppresses glutamate release and seizures evoked with 4-aminopyridine in the brain. The results indicate an unsuspected link between metabolic state and excitatory neurotransmission through anion-dependent regulation of VGLUT activity. PMID- 20920795 TI - Endocannabinoids potentiate synaptic transmission through stimulation of astrocytes. AB - Endocannabinoids and their receptor CB1 play key roles in brain function. Astrocytes express CB1Rs that are activated by endocannabinoids released by neurons. However, the consequences of the endocannabinoid-mediated neuron astrocyte signaling on synaptic transmission are unknown. We show that endocannabinoids released by hippocampal pyramidal neurons increase the probability of transmitter release at CA3-CA1 synapses. This synaptic potentiation is due to CB1R-induced Ca(2+) elevations in astrocytes, which stimulate the release of glutamate that activates presynaptic metabotropic glutamate receptors. While endocannabinoids induce synaptic depression in the stimulated neuron by direct activation of presynaptic CB1Rs, they indirectly lead to synaptic potentiation in relatively more distant neurons by activation of CB1Rs in astrocytes. Hence, astrocyte calcium signal evoked by endogenous stimuli (neuron-released endocannabinoids) modulates synaptic transmission. Therefore, astrocytes respond to endocannabinoids that then potentiate synaptic transmission, indicating that astrocytes are actively involved in brain physiology. PMID- 20920796 TI - Spatial representation along the proximodistal axis of CA1. AB - CA1 cells receive direct input from space-responsive cells in medial entorhinal cortex (MEC), such as grid cells, as well as more nonspatial cells in lateral entorhinal cortex (LEC). Because MEC projects preferentially to the proximal part of the CA1, bordering CA2, whereas LEC innervates only the distal part, bordering subiculum, we asked if spatial tuning is graded along the transverse axis of CA1. Tetrodes were implanted along the entire proximodistal axis of dorsal CA1 in rats. Data were recorded in cylinders large enough to elicit firing at more than one location in many neurons. Distal CA1 cells showed more dispersed firing and had a larger number of firing fields than proximal cells. Phase-locking of spikes to MEC theta oscillations was weaker in distal CA1 than in proximal CA1. The findings suggest that spatial firing in CA1 is organized transversally, with the strongest spatial modulation occurring in the MEC-associated proximal part. PMID- 20920798 TI - Neural responses to ingroup and outgroup members' suffering predict individual differences in costly helping. AB - Little is known about the neurobiological mechanisms underlying prosocial decisions and how they are modulated by social factors such as perceived group membership. The present study investigates the neural processes preceding the willingness to engage in costly helping toward ingroup and outgroup members. Soccer fans witnessed a fan of their favorite team (ingroup member) or of a rival team (outgroup member) experience pain. They were subsequently able to choose to help the other by enduring physical pain themselves to reduce the other's pain. Helping the ingroup member was best predicted by anterior insula activation when seeing him suffer and by associated self-reports of empathic concern. In contrast, not helping the outgroup member was best predicted by nucleus accumbens activation and the degree of negative evaluation of the other. We conclude that empathy-related insula activation can motivate costly helping, whereas an antagonistic signal in nucleus accumbens reduces the propensity to help. PMID- 20920799 TI - Practitioners of Western herbal medicine and their practice in the UK: beginning to sketch the profession. AB - OBJECTIVE: To profile the profession of Western herbal medicine (WHM) in the UK. DESIGN: A self-completion postal questionnaire sent to a sample of practitioners of WHM in England. RESULTS: A typical practitioner of WHM in the UK is female, aged 41-50, white, and practises part-time from a shared clinic or from home. Motivations to embark on a career in WHM are grounded in an interest in natural healing and the desire to help others. The practice of WHM in the UK responds extensively to women's health needs. Tensions in the practice of WHM are identified between a framework of healthcare that is described as 'traditional' and the influences of evidence-based developments in healthcare. CONCLUSION: Women, both as practitioners and as patients, and women's health needs play a central role in the contemporary practice of WHM in the UK. PMID- 20920797 TI - Preserved functional specialization for spatial processing in the middle occipital gyrus of the early blind. AB - The occipital cortex (OC) of early-blind humans is activated during various nonvisual perceptual and cognitive tasks, but little is known about its modular organization. Using functional MRI we tested whether processing of auditory versus tactile and spatial versus nonspatial information was dissociated in the OC of the early blind. No modality-specific OC activation was observed. However, the right middle occipital gyrus (MOG) showed a preference for spatial over nonspatial processing of both auditory and tactile stimuli. Furthermore, MOG activity was correlated with accuracy of individual sound localization performance. In sighted controls, most of extrastriate OC, including the MOG, was deactivated during auditory and tactile conditions, but the right MOG was more activated during spatial than nonspatial visual tasks. Thus, although the sensory modalities driving the neurons in the reorganized OC of blind individuals are altered, the functional specialization of extrastriate cortex is retained regardless of visual experience. PMID- 20920800 TI - A randomised controlled trial of yoga for the treatment of chronic low back pain: results of a pilot study. AB - OBJECTIVE: To conduct a pilot trial of yoga for the treatment of chronic low back pain (LBP) to inform the feasibility and practicality of conducting a full-scale trial in the UK; and to assess the efficacy of yoga for the treatment of chronic low back pain. DESIGN: A pragmatic randomised controlled trial was undertaken comparing yoga to usual care. PARTICIPANTS: Twenty participants who had presented to their GP with chronic low back pain in the previous 18 months were recruited via GP records from one practice in York, UK. INTERVENTIONS: Twenty patients were randomised to either 12 weekly 75-min sessions of specialised yoga plus written advice, or usual care plus written advice. Allocation was 50/50. MAIN OUTCOME MEASURES: Recruitment rate, levels of intervention attendance, and loss to follow up were the main non-clinical outcomes. Change as measured by the Roland and Morris disability questionnaire was the primary clinical outcome. Changes in the Aberdeen back pain scale, SF-12, EQ-5D, and pain self-efficacy were secondary clinical outcomes. Data were collected via postal questionnaire at baseline, 4 weeks, and 12 weeks follow-up. RESULTS: Of the 286 patients identified from the GP database, 52 (18%) consented and returned the eligibility questionnaire, out of these 20 (6.9%) were eligible and randomised. The total percentage of patients randomised from the GP practice population was 0.28%. Ten patients were randomised to yoga, receiving an average of 1.7 sessions (range 0-5), and 10 were randomised to usual care. At 12 weeks follow-up data was received from 60% of patients in the yoga group and 90% of patients in the usual care group (75% overall). No significant differences were seen between groups in clinical outcomes apart from on the Aberdeen back pain scale at four weeks follow-up where the yoga group reported significantly less pain. CONCLUSION: This pilot study provided useful data and information to inform the design and development of a full-scale trial of yoga for CLBP in the UK. A key finding is the calculation of GP practice total list size required for patient recruitment in a full-scale trial, and the need to implement methods to increase class attendance. PMID- 20920801 TI - Development of ethical rules for boundaries of touch in complementary medicine- outcomes of a Delphi process. AB - The practice of complementary medicine (CAM) often involves touch. The unique philosophy of many CAM therapies, and the setting in which treatments are provided create a therapeutic space which may be less clearly defined than in conventional settings - a space in which the boundaries between professional touch and personal/intimate touch may become easily obscured. Thus, complementary therapists need clear definitions and firm boundaries in order to maintain therapeutic efficacy and commitment. The aim of the process described in this article, was to develop ethical guidelines for boundaries of touch that will promote the safety and protection of the public which use CAM. Through a modified Delphi process, a diverse group of CAM practitioners, physicians, ethicists, legal consultants, health policy specialists, and representatives from the public, developed Ethical Rules for Boundaries of Touch in CAM. These guidelines may be implemented in ethical codes of professional CAM organizations, and also serve as a foundation for curriculums in ethics in CAM schools. PMID- 20920802 TI - Effect of acupressure at the Sanyinjiao point on primary dysmenorrhea: a randomized controlled trial. AB - OBJECTIVE: We conducted this study to assess the effect of acupressure at the Sanyinjiao point on primary dysmenorrhea. METHODS: Eighty-six students participated in the study. All participants met the inclusion criteria. The study group received acupressure at Sanyinjiao point, while the control received sham acupressure. The severity of dysmenorrhea was assessed at the following time periods: prior to the intervention, 30 min, 1, 2 and 3h following the intervention. Data were analyzed using SPSS. RESULTS: The acupressure caused decline in the severity of dysmenorrhea immediately after intervention in both groups during their first menstrual cycle, although, there difference was not significant (p>0.05). In addition, during the same cycle, the severity of the dysmenorrhea decreased more in study group rather than control group at 30 min, 1, 2 and 3h after intervention (p<0.05). During the second menstrual cycle, acupressure made dysmenorrhea reduced in both study and control groups; however, the decline was more salient among participants of the study group at all stages after the intervention (p<0.05). CONCLUSIONS: Acupressure at Sanyinjiao point can be an effective, feasible, cost-effective intervention for improving primary dysmenorrhea. PMID- 20920803 TI - Neuro-linguistic programming and application in treatment of phobias. AB - Phobias are a prevalent and often debilitating mental health problem all over the world. This article aims to explore what is known about the use of Neuro linguistic Programming (NLP) as a treatment for this condition. Whilst there is abundant experiential evidence from NLP practitioners attesting to the efficacy of this method as a treatment for phobias, experimental research in this area is somewhat limited. This paper reviews evidence available in literature produced in the UK and US and reveals that NLP is a successful treatment for phobias as well as being particularly efficient due to the relatively brief time period it takes to effect an improvement. PMID- 20920804 TI - The use of herbal preparations as complementary and alternative medicine (CAM) in a sample of patients with cancer in Jordan. AB - PURPOSE: This study sought to describe the type, frequency, purpose and pattern of herbal preparation use as complementary medicine in a sample of patients with cancer in Jordan. METHOD: The study took the form of a cross-sectional survey of patients attending the outpatient departments at King Hussein Cancer Centre (KHCC), a specialist cancer centre in Amman. The method was based on using a semi structured questionnaire. RESULTS: A total of 1138 patients with cancer were interviewed, out of which 404 (35.5%) reported using botanicals based complementary and alternative medicine (CAM) primarily bought form Jordan (85.1%) and used in the crude form as infusions (73.3%). Only 6.8% used herbal products in a dosage form. Most of CAM users were above 40 years of age (63.1%). Recommendation of a friend was the main factor that prompted them to use CAM (41.8%). CONCLUSION: This study revealed that CAM use is common among patients with cancer in Jordan. PMID- 20920805 TI - Medicinal leech therapy (hirudotherapy): a brief overview. AB - Hirudotherapy is a treatment using medicinal leeches. Hirudo medicinali, have been used to treat patients for centuries. In the past, leeches have proved to be an effective treatment for a number of conditions including battle wound treatment. Currently leeches may be used to assist in the treatment of abscesses, arthritis, glaucoma, myasthenia gravis, thrombosis and some venous disorders. Medical leeches may also be used in plastic surgery and in some blood circulatory problems. During feeding, leeches secrete a complex mixture of different biologically and pharmacologically active substances into the wound. Hirudin is the prominent constituent of leech saliva. It is sometimes used to describe all the active constituents in the leech saliva. This paper outlines the potential use of leech therapy in current medical care in India. PMID- 20920806 TI - Sho-saiko-to-ka-kikyo-sekko as an alternative treatment for chronic tonsillitis to avoid surgery. AB - Sho-saiko-to-ka-kikyo-sekko (TJ-109) is composed of 9 herbs (gypsum, Bupleurum root, Pinellia tuber, Scutellaria root, Platycodon root, jujube fruit, ginseng root, Glycyrrhiza root, and ginger rhizome). It is a folk medicine that has been used to treat pharyngitis or acute tonsillitis. The efficacy of TJ-109 for treating patients with chronic tonsillitis was investigated. Ten outpatients who experienced chronic tonsillitis for more than 2 years were recruited. TJ-109 was prescribed, and after one year of daily treatment the incidence of acute tonsillitis before and after the treatment was compared. The incidence of acute tonsillitis due to chronic tonsillitis decreased in all 7 patients who were followed up. No adverse events were observed in any of the patients. In conclusion, the herbal medicine TJ-109 effectively reduced the incidence of acute tonsillitis. In some cases, planned tonsillectomy was avoided. PMID- 20920807 TI - Bathing in a bathtub and health status: a cross-sectional study. AB - BACKGROUND: Bathing, or soaking, in a bathtub is a popular and often habitual pastime that has its roots in the culture of the Japanese people. The purpose of this study was to examine the effects of such bathing on health status. METHODS: We conducted a population-based cross-sectional study involving 617 Japanese participants who took routine medical checkups. The frequency of bathing in a bathtub was categorized into two levels: "less than seven times a week" (less frequent bathing group) and "seven or more times a week" (frequent bathing group). We compared the following characteristics between the two groups: age, body mass index, blood pressure, blood chemistry findings, self-rated health, and sleep quality. RESULTS: The frequent bathing group reported better self-rated health and sleep quality than the less frequent bathing group, with age- and sex adjusted odds ratios (95% confidence interval) of 2.11 (1.28-3.48) for self-rated health and 1.55 (0.98-2.44) for sleep quality. Other survey items were similar between the two groups. CONCLUSIONS: The findings of this study suggested that bathing in a bathtub every day or more frequently was associated with a good state of self-rated health and sleep quality. PMID- 20920808 TI - The integration of healing into conventional cancer care in the UK. AB - Healing encompasses Reiki, therapeutic touch and healing touch, and is often used by cancer patients to supplement their health care, but the extent of healing provision in conventional cancer care is unknown. This study used snowball sampling to map the healing provision in UK conventional cancer care settings. Sixty-seven individuals at 38 centres were identified who provided healing within conventional care, 16 NHS-based. Less than half were paid or had specialist cancer training. Self-referral was the usual route to healing, followed by hospital nurse referral. Healing was perceived as well accepted and useful by healers. Providing healing in conventional cancer care may improve patient empowerment and choice. Despite the value to patients, staff and healers, many services receive little financial support. Exchange of information and communication on referral possibilities between healers and conventional staff needs to be improved. Voluntary healer self-regulation will facilitate the safe incorporation of healing into conventional care. PMID- 20920809 TI - Nurses' knowledge, attitudes, and professional use of complementary and alternative medicine (CAM): a survey at five metropolitan hospitals in Adelaide. AB - PURPOSE: To determine nurses' knowledge, attitudes, and professional use of complementary and alternative medicine (CAM) at five metropolitan hospitals in Adelaide, while also investigating the relationships between socio-demographic factors and use of CAM domains. METHOD: Information on nurses' demographics, knowledge, attitudes, and professional use of CAM was obtained using a self administered questionnaire. Data were analysed using descriptive and non parametric statistics. RESULTS: Almost 50% of nurses were using CAM for patients, with mind-body interventions being the most common form of CAM domain used in practice (31.4%). While 59% of nurses were positive about CAM, more than 60% of them had very little or no knowledge of CAM. Nurses' professional use of CAM was also associated with diverse socio-demographic factors, and a positive association was found between the nurses' knowledge and their attitudes towards CAM. CONCLUSION: Nurses have limited knowledge of CAM but remain open towards CAM use. Nurses' positive attitudes towards CAM use could be an indication that they are poised for further integration of clinically approved CAM into nursing care of patients. PMID- 20920810 TI - Tai chi/yoga effects on anxiety, heartrate, EEG and math computations. AB - OBJECTIVE: To determine the immediate effects of a combined form of Tai chi/yoga. DESIGN: 38 adults participated in a 20-min Tai chi/yoga class. The session was comprised of standing Tai chi movements, balancing poses and a short Tai chi form and 10 min of standing, sitting and lying down yoga poses. MAIN OUTCOME MEASURES: The pre- and post- Tai chi/yoga effects were assessed using the State Anxiety Inventory (STAI), EKG, EEG and math computations. RESULTS: Heartrate increased during the session, as would be expected for this moderate-intensity exercise. Changes from pre to post-session assessments suggested increased relaxation including decreased anxiety and a trend for increased EEG theta activity. CONCLUSIONS: The increased relaxation may have contributed to the increased speed and accuracy noted on math computations following the Tai chi/yoga class. PMID- 20920811 TI - Healing crisis in reflexology: becoming worse before becoming better. AB - PURPOSE: In the previous study the effects of reflexology on symptoms of fibromyalgia (FM) were investigated. In this paper it will be explored whether healing crisis is experienced after reflexology in the same sample of women. METHODS: Multiple case study method as developed by Stake was used to investigate the effects of reflexology on six cases of women with FM who were given ten weekly sessions of reflexology. Data were collected with observation, interviews and diary. Within and across case data analysis was employed. RESULTS: Several different symptoms were experienced by all of the women after reflexology sessions, although differently for each of them. The symptoms presented as mixture of pain, fatigue, and flu like along with a variety of some other symptoms. This constellation of symptoms was more in tune with descriptions of the healing crisis phenomenon than with fibromyalgia. It gradually became worse until rather abruptly started to diminish around the seventh and eighth session. CONCLUSIONS: For the majority of the women the healing crisis symptoms gradually became worse before they started to decrease. This has similarities with other health professionals' accounts in the literature. Nurses and health professionals need to be aware of healing crisis effects when offering reflexology to patients. PMID- 20920812 TI - Transfer of skill engendered by complex task training under conditions of variable priority. AB - We explored the theoretical underpinnings of a commonly used training strategy by examining issues of training and transfer of skill in the context of a complex video game (Space Fortress, Donchin, 1989). Participants trained using one of two training regimens: Full Emphasis Training (FET) or Variable Priority Training (VPT). Transfer of training was assessed with a large battery of cognitive and psychomotor tasks ranging from basic laboratory paradigms measuring reasoning, memory, and attention to complex real-world simulations. Consistent with previous studies, VPT accelerated learning and maximized task mastery. However, the hypothesis that VPT would result in broader transfer of training received limited support. Rather, transfer was most evident in tasks that were most similar to the Space Fortress game itself. Results are discussed in terms of potential limitations of the VPT approach. PMID- 20920813 TI - Long-term follow-up after submandibular gland transplantation in severe dry eyes secondary to cicatrizing conjunctivitis. AB - PURPOSE: To evaluate the long-term results of autologous submandibular gland transplantation in eyes with cicatrizing conjunctivitis and to determine biomechanical and biochemical features of the resulting salivary tear film. DESIGN: Prospective, observational case series. METHODS: Fifteen eyes with cicatrizing conjunctivitis with a viable autologous submandibular gland transplantation were compared with 10 eyes with cicatrizing conjunctivitis and a failed submandibular gland transplantation or no submandibular gland transplantation. Best-corrected visual acuity, frequency of tear substitute instillation, severity of dry eye discomfort, lid margin erythema, conjunctival hyperemia, corneal epithelial edema, tear film break-up time, Schirmer test results, and corneal fluorescein and conjunctival Rose Bengal staining were evaluated. In a subgroup central corneal thickness and sensitivity, corneal epithelial barrier function, conjunctival and lid margin flora, and conjunctival impression cytologic analysis results were evaluated. In 3 patients, preoperative and postoperative tear samples were analyzed for viscosity, surface tension, and presence of mucins. RESULTS: Submandibular gland autotransplantation resulted in long-term improvement of subjective, objective, and some ocular surface parameters. Salivary mucins were detectable in salivary tears after submandibular gland transplantation. The viscosity of salivary tears was more similar to normal saliva and the surface tension was intermediate between the 2 original secretions. CONCLUSIONS: Submandibular gland autotransplantation provides long term relief from pain and reduces the need for frequent installation of lubricants. PMID- 20920814 TI - Neuromuscular complications of hepatitis A virus infection and vaccines. AB - The hepatitis A virus (HAV) infects millions of people worldwide every year. Case histories report on various acute neuropathy syndromes in the context of acute HAV infection, but any causal link has not been established. Epidemiological data also cast doubt on the importance of HAV as a trigger for Guillain-Barre syndrome. The virtual absence of a chronic HAV-infected state likely explains the rare occurrence of extrahepatic immune-mediated diseases, including an absence of chronic autoimmune neuromuscular disorders. Several vaccines against HAV provide effective protection against natural infection. Isolated case histories report on an unconvincing association between HAV vaccination and neuropathy. Medical and epidemiological data show insufficient evidence to support a causal relationship between HAV vaccines and neuropathy syndromes. Aluminum hydroxide, a HAV vaccine adjuvant, is considered a trigger of the macrophagic myofasciitis syndrome. This review concludes that it seems unnecessary to routinely consider HAV infection or vaccination as triggers of neuromuscular diseases. PMID- 20920815 TI - Decisions on multiple sclerosis immunotherapy: new treatment complexities urge patient engagement. AB - For patients with multiple sclerosis (MS) involvement in treatment decisions becomes ever more imperative. Recently new therapeutic options have become available for the treatment of MS and more will be licensed in the near future. Although more efficacious and easier to administer, the new drugs pose increased risks of severe side effects. Also, new diagnostic criteria lead to more and earlier MS diagnoses. Facing increasingly complex decisions, patients need up-to date evidence-based information and decision support systems in order to make informed decision together with physicians based on their autonomy preferences. This article summarizes recently terminated and ongoing trials on MS patient education and decision aids conducted by the authors' study groups. Programs on relapse management, immunotherapy, and for patients with suspected and early MS have been developed and evaluated in randomized controlled clinical trials. It could be shown that the programs successfully increase knowledge and allow patients to make informed decisions based on their preferences. For the near future, we aim to develop a modular program for all relevant decisions in MS to increase patients' self-management and empower patients to develop their individual approach with the disease. Faced by a disease with many uncertainties, this should enhance patients' sense of control. Still, it remains a challenge to adequately assess decision quality. Therefore, a study in six European and one Australian centers will start soon aiming to establish adequate tools to assess decision-making quality. PMID- 20920816 TI - Toward a pathological definition of vascular dementia. AB - To date, there are no widely accepted neuropathological criteria for vascular dementia, although creating such a standard is ranked high on the wish list of all the researchers in this field. Such criteria would make it possible to perform large multicentre clinicopathological studies and, consequently, to better understand which, how, and where vascular brain lesions lead to cognitive decline, as it is possible to do in Alzheimer's disease or Parkinson's disease. However, a major obstacle in the standardization of diagnosis is the fact that vascular brain lesions are a large group comprising heterogeneous changes that have different pathogeneses. Although it is accepted that some kinds of vascular changes cause cognitive impairment, it is not uncommon to find reports of the assumed same histological changes in control subjects. An indispensable first step in the unequivocal establishment of neuropathological criteria is to uniform the definitions used for each one of the lesions, preferably based on its pathogenesis. In the present, non-standardized state of ambiguity, a given lesion is designated by different names between and within the clinical, radiological, and pathological settings, and several definitions simply overlap. Before attempting to create new criteria, a multidisciplinary group-task is urged to identify and minimize the uncontrolled proliferation of definitions. Only then, it will be possible to advance the understanding of how vascular brain changes affect cognition. PMID- 20920817 TI - Cross-species extrapolation of chronic nickel Biotic Ligand Models. AB - The use of Biotic Ligand Models (BLMs) to normalize metal ecotoxicity data and predict effects in non-BLM organisms should be supported by quantitative evidence. This study determined the ability of chronic nickel BLMs developed for the cladocera Daphnia magna and Ceriodaphnia dubia to predict chronic nickel toxicity to three invertebrates for which no specific BLMs were developed. Those invertebrates were the snail Lymnaea stagnalis, the insect Chironomus tentans, and the rotifer Brachionus calyciflorus. Similarly, we also determined the ability of chronic nickel BLMs developed for the alga Pseudokirchneriella subcapitata and the terrestrial vascular plant Hordeum vulgare to predict chronic nickel toxicity to the aquatic vascular plant Lemna minor. Chronic nickel toxicity to the three invertebrates and the aquatic plant were measured in five natural waters that varied in pH, Ca, Mg, and dissolved organic carbon (DOC), which are known to affect chronic nickel toxicity and are the important input variables for the chronic nickel BLMs. Nickel toxicity to the three invertebrates varied considerably among the test waters, i.e., a 14-fold variation of EC50s in L. stagnalis, a 3-fold variation in EC20s in C. tentans, and a 10-fold variation in EC20s in B. calyciflorus, but the cladoceran BLMs were able to predict nickel effect concentrations within a factor of two. Nickel toxicity (EC50s) to L. minor varied by 6-fold among the test waters. Although the P. subcapitata and H. vulgare BLMs offered reasonable predictions of nickel EC50s to L. minor, the D. magna and C. dubia BLM showed better predictions. Our results confirm the influence of site-specific pH, hardness, and DOC on chronic nickel toxicity to aquatic organisms, and support the use of chronic nickel BLMs to manage this influence through normalizations of ecotoxicity data. PMID- 20920818 TI - Sensitivity-related illness: the escalating pandemic of allergy, food intolerance and chemical sensitivity. AB - The prevalence of allergic-related diseases, food intolerance, and chemical sensitivities in both the pediatric and adult population has increased dramatically over the last two decades, with escalating rates of associated morbidity. Conditions of acquired allergy, food intolerance and chemical hypersensitivity are frequently the direct sequelae of a toxicant induced loss of tolerance (TILT) in response to a significant initiating toxic exposure. Following the primary toxicant insult, the individuals become sensitive to low levels of diverse and unrelated triggers in their environment such as commonly encountered chemical, inhalant or food antigens. Among sensitized individuals, exposure to assorted inciting stimuli may precipitate diverse clinical and/or immune sequelae as may be evidenced by clinical symptoms as well as varied lymphocyte, antibody, or cytokine responses in some cases. Recently recognized as a mechanism of disease development, TILT and resultant sensitivity-related illness (SRI) may involve various organ systems and evoke wide-ranging physical or neuropsychological manifestations. With escalating rates of toxicant exposure and bioaccumulation in the population-at-large, an increasing proportion of contemporary illness is the direct result of TILT and ensuing SRI. Avoidance of triggers will preclude symptoms, and desensitization immunotherapy or immune suppression may ameliorate symptomatology in some cases. Resolution of SRI generally occurs on a gradual basis following the elimination of bioaccumulated toxicity and avoidance of further initiating adverse environmental exposures. As has usually been the case throughout medical history whenever new evidence regarding disease mechanisms emerges, resistance to the translation of knowledge abounds. PMID- 20920819 TI - Management of deep vein thrombosis diagnosed during active labour. PMID- 20920820 TI - Protein C and protein S changes in GH-deficient adults on r-HGH replacement therapy: correlations with PAI-1 and t-PA plasma levels. AB - BACKGROUND: In the rat liver, growth hormone (GH) affects the synthesis of vitamin-K-dependent factors, including Protein C (prot.C) and protein S (prot.S), two natural anticoagulants that prevent hypercoagulable states. Adults with GH deficiency (GHD) are at risk of thrombotic events. High circulating levels of PAI 1 and t-PA, that reflect hypercoagulable states, may contribute to such risk. In GHD adults on replacement therapy with recombinant human GH (r-HGH), %Delta PAI-1 and %Delta t-PA are related to %Delta insulin changes. OBJECTIVES: To evaluate changes in vitamin-K-dependent factors in GHD on r-HGH replacement. METHODS: In 60 GHD adults, to relate plasma levels of vitamin-K-dependent factors with those of PAI-1, t-PA and insulin before and after 6-month (6-mo) replacement therapy with r-HGH. RESULTS: After 6-mo r-HGH replacement, %Delta insulin enhancements occurred in 36/60 subjects. PAI-1, t-PA, Prot.C, Prot.S and FVIIact did not change in them. In the 24/40 subjects that experienced %Delta insulin reductions, Prot.C (p=0.025), Prot.S (p=0.031) and FVIIact (p=0.049) decreased significantly. PAI-1 (p=0.019) and t-PA antigen (p=0.009) behaved similarly. In a multivariate analysis, %? PAI-1 (beta=0.436, p<0.01) was the strongest predictor of %? prot.S, wheras %? t-PA (beta=0.385, p<0.008) and %? insulin (beta=0.429, p<0.004) were the strongest predictors of %? prot.C. In all cases, regardless of %Delta insulin changes, FII, FVII Ag and FIX levels did not change from baseline. CONCLUSIONS: In GHD adults on r-HGH replacement, changes in vitamin-K-dependent factors reflect a subtle adaptation of the natural anticoagulant system to PAI-1 and t-PA changes, via the response of insulin to r-HGH. PMID- 20920821 TI - Combined risk stratification with computerized tomography /echocardiography and biomarkers in patients with normotensive pulmonary embolism. AB - BACKGROUND: Right ventricular dysfunction (RVD) detected by computerized tomography (CT)/echocardiography or elevated biomarkers is associated with a poor prognosis for pulmonary embolism (PE). However, these prognostic factors have not previously been concomitantly elucidated in the same patient group. METHODS: This prospective study included 108 consecutive patients with normotensive PE confirmed by CT pulmonary angiography (CTPA). On admission, patient serum NT proBNP and troponin T (Tn-T) levels were measured, and echocardiography was performed within 24 hours after diagnosis of PE. Receiver operating characteristic (ROC) analysis was performed to determine the optimal echocardiographic end-diastolic diameters of the right ventricle, the ratio of the right ventricle to left ventricle (RV/LV ratio) on CTPA, and NT-proBNP and Tn T cut-off levels with regard to prognosis. RESULTS: All-cause 30-day mortality was 13% and PE-related mortality was 5.6%. RVD was defined as a right/left ventricular dimension ratio>=1.1 on CTPA and RV>30 mm on echocardiography by ROC analysis. A cut-off level of NT-proBNP<=90 pmol/ml had a high positive predictive value of 98% for survival, whereas NT-proBNP>300 and Tn-T>=0.027 had a negative predictive value, for all-cause deaths, of 95% and 96%, respectively. PE mortality in patients with NT-proBNP>300 and Tn-T>=0.027 reached 64%. In univariable analysis, the combination of Tn-T>=0.027 ng/ml with a echocardiographic RVD were the most significant predictors of overall mortality and PE-related death [HR: 14 (95% CI: 4.6-42,) and HR: 37.6 (95% CI: 4.4-324)], respectively. In multivariable Cox's regression analysis, NT-proBNP>300 and Tn T>=0.027 HR: 26.5 (95% CI: 4.1-169.9, p<0.001) were the best combination to predict all-cause of mortality. CONCLUSIONS: The combination of NT-proBNP and Tn T clearly appears to be a better risk stratification predictor than biomarkers plus RVD on CT/ echocardiography in patients with normotensive PE. PMID- 20920822 TI - Nitric oxide production and blood corpuscle dynamics in response to the endocrine status of female rats. AB - INTRODUCTION: Menopause is associated with marked changes in the endocrine profile, and increases the risk of vascular disease. However, the effect of hormones on the vascular system is still unclear. Therefore, the aim of this study was to examine the effects of endocrine status in female rats on nitric oxide (NO) production, inflammatory reactions and thrombus organization potency in the mesenteric microcirculation. MATERIALS AND METHODS: Female Wistar rats were divided into four groups: proestrus, metestrus, ovariectomized (OVX) and OVX plus estradiol treatment (OVX+E2). NO was imaged using an NO-sensitive dye. The leukocyte and platelet velocities relative to the erythrocyte velocity (VW/VRC and VP/VRE, respectively) and thrombi sizes created by laser radiation were measured as thrombogenesis indices. RESULTS: Changes in endocrine status did not affect vascular function in the arterioles. However, in venules, NO production, VW/VRC and VP/VRE were decreased in the OVX group compared with the proestrus and metestrus states. Thrombus size was significantly greater in the OVX group than in the proestrus and metestrus states. Administration of E2 for 2 weeks restored NO production, VW/VRC and VP/VRE to control levels. CONCLUSIONS: Changes in endocrine status did not affect arterioles. In contrast, in venules, reduced estrogen levels led to a decrease in NO production, thereby increasing thrombogenesis. Estrogen replacement restored NO production and leukocyte and platelet velocities, reducing thrombus formation relative to OVX. Although it is unclear how E2 reduces thrombus formation, our results indicate that leukocyte and platelet adhesion to the endothelium is a target for E2 via NO. PMID- 20920823 TI - Audiovisual communication and therapeutic jurisprudence: Cognitive and social psychological dimensions. AB - The effects of audiovisual communications on the emotional and psychological well being of participants in the legal system have not been previously examined. Using as a framework for analysis what Slobogin (1996) calls internal balancing (of therapeutic versus antitherapeutic effects) and external balancing (of therapeutic jurisprudence [TJ] effects versus effects on other legal values), this brief paper discusses three examples that suggest the complexity of evaluating courtroom audiovisuals in TJ terms. In each instance, audiovisual displays that are admissible based on their arguable probative or explanatory value - day-in-the-life movies, victim impact videos, and computer simulations of litigated events - might well reduce stress and thus improve the psychological well-being of personal injury plaintiffs, survivors, and jurors, respectively. In each situation, however, other emotional and cognitive effects may prove antitherapeutic for the target or other participants, and/or may undermine other important values including outcome accuracy, fairness, and even the conception of the legal decision maker as a moral actor. PMID- 20920824 TI - Ability of cirrus HD-OCT optic nerve head parameters to discriminate normal from glaucomatous eyes. AB - PURPOSE: To determine the ability of optic nerve head (ONH) parameters measured with spectral domain Cirrus HD-OCT (Carl Zeiss Meditec, Inc., Dublin, CA) to discriminate between normal and glaucomatous eyes and to compare them with the discriminating ability of peripapillary retinal nerve fiber layer (RNFL) thickness measurements performed with Cirrus HD-OCT. DESIGN: Evaluation of diagnostic test or technology. PARTICIPANTS: Seventy-three subjects with glaucoma and 146 age-matched normal subjects. METHODS: Peripapillary ONH parameters and RNFL thickness were measured in 1 randomly selected eye of each participant within a 200 * 200 pixel A-scan acquired with Cirrus HD-OCT centered on the ONH. MAIN OUTCOME MEASURES: Optic nerve head topographic parameters, peripapillary RNFL thickness, and area under receiver operating characteristic curves (AUCs). RESULTS: To distinguish normal from glaucomatous eyes, regardless of disease stage, the 6 best parameters (expressed as AUC) were vertical rim thickness (VRT, 0.963), rim area (0.962), RNFL thickness at clock-hour 7 (0.957), RNFL thickness of the inferior quadrant (0.953), vertical cup-to-disc ratio (VCDR, 0.951), and average RNFL thickness (0.950). The AUC for distinguishing between normal eyes and eyes with mild glaucoma was greatest for RNFL thickness of clock-hour 7 (0.918), VRT (0.914), rim area (0.912), RNFL thickness of inferior quadrant (0.895), average RNFL thickness (0.893), and VCDR (0.890). There were no statistically significant differences between AUCs for the best ONH parameters and RNFL thickness measurements (P > 0.05). CONCLUSIONS: Cirrus HD-OCT ONH parameters are able to discriminate between normal eyes and eyes with glaucoma or even mild glaucoma. There is no difference in the ability of ONH parameters and RNFL thickness measurement, as measured with Cirrus OCT, to distinguish between normal and glaucomatous eyes. PMID- 20920825 TI - Characteristics of patients losing vision after 2 years of monthly dosing in the phase III ranibizumab clinical trials. AB - PURPOSE: To investigate the cause of visual acuity (VA) loss in patients with neovascular age-related macular degeneration (AMD) receiving monthly ranibizumab injections in the pivotal ranibizumab phase III trials. DESIGN: Retrospective analysis. PARTICIPANTS: The Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab In the treatment of Neovascular AMD (MARINA) and Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in AMD (ANCHOR) trials. METHODS: Demographics and lesion characteristics at baseline and month 24 were compared in patients with >=15 letters VA loss and patients with >=15 letters VA gain from baseline to month 24. Additional evaluations of fundus photographs from these patients were performed to assess features of non-exudative AMD, such as geographic atrophy (GA) and retinal pigment epithelium (RPE) abnormalities. MAIN OUTCOME MEASURES: Differences in lesion characteristics between patients who lost versus gained >=15 letters of VA from baseline to month 24. RESULTS: At month 24, 9% of ranibizumab-treated patients from MARINA and 10% of ranibizumab-treated patients from ANCHOR had lost >=15 letters VA; 30% of ranibizumab-treated patients from MARINA and 38% of ranibizumab-treated patients from ANCHOR had gained >=15 letters VA. Baseline characteristics associated with VA loss at month 24 included older age, better VA, and larger lesions. At month 24, an increased area of RPE abnormality was associated with VA loss in both the MARINA (P = 0.0008) and ANCHOR (P = 0.0046) trials. Increased total lesion area at month 24 was associated with VA loss in both trials. In MARINA, the increase in total lesion area was attributable to an increase in the angiographic designation of atrophic scar among VA losers (P = 0.0043), but in ANCHOR it was attributable to an increased area of choroidal neovascularization (CNV) (P = 0.039) but not an increased area of leakage (P = 0.17). Increased areas of GA, fibrosis, and hemorrhage were not associated with VA loss. CONCLUSIONS: Vision loss after 2 years of monthly ranibizumab therapy was associated with lesion characteristics commonly associated with suppressed CNV, such as pigmentary abnormalities, atrophic scar, and the absence of leakage. Future VA improvements in patients receiving ranibizumab therapy may require preservation of photoreceptor and RPE function rather than strategies that target CNV. PMID- 20920826 TI - Analysis of peripapillary atrophy using spectral domain optical coherence tomography. AB - OBJECTIVE: To study retinal morphologic changes around the optic disc in patients with peripapillary atrophy (PPA) with high-resolution spectral domain optical coherence tomography (SD OCT). DESIGN: Cross-sectional, retrospective analysis. PARTICIPANTS: A total of 103 eyes of 73 patients with PPA and 21 eyes of 12 normal patients seen at the New England Eye Center, Tufts Medical Center, between January 2007 and August 2009. METHODS: Spectral domain optical coherence tomography images taken through the region of PPA were quantitatively and qualitatively analyzed. Inclusion criteria included eyes with at least 300 MUm of temporal PPA as detected on color fundus photographs. The study population was divided into subgroups according to the following clinical diagnoses: glaucoma (n=13), age-related macular degeneration (n=11), high myopia (n=11), glaucoma and high myopia (n=3), and optic neuropathy (n=11). Fifty-four patients were classified with other diagnoses. By using OCT software, retinal thickness and retinal nerve fiber layer (RNFL) thickness were both manually measured perpendicular to the internal limiting membrane and retinal pigment epithelium (RPE) 300 MUm temporal to the optic disc, within the region of PPA. Qualitative analysis for morphologic changes in the atrophic area was also performed. MAIN OUTCOME MEASURES: Qualitative assessment and quantitative measures of retinal and RNFL thickness in PPA. RESULTS: The study group was categorized by 6 characteristics demonstrated in the area of PPA by SD OCT: RPE loss with accompanying photoreceptor loss, RPE disruption, RNFL thickening with plaque-like formation, intraretinal cystic changes, inner and outer retinal thinning, and abnormal retinal sloping. Statistical analysis of measurements revealed a statistically significant difference in the total retinal thickness between normal eyes and eyes with PPA (P=0.0005), with normal eyes 15% thicker than the eyes with PPA; however, the RNFL thickness was not significantly different between the normal eyes and the eyes with PPA (P=0.05). CONCLUSIONS: Eyes with PPA manifest characteristic retinal changes that can be described via SD OCT. PMID- 20920827 TI - Reversal of retinal ganglion cell dysfunction after surgical reduction of intraocular pressure. AB - PURPOSE: The pattern electroretinogram optimized for glaucoma screening (PERGLA) is a noninvasive method of objectively measuring retinal ganglion cell (RGC) function. This study was undertaken to quantify the RGC response to intraocular pressure (IOP) reduction after glaucoma surgery. DESIGN: Prospective cohort study. PARTICIPANTS: Forty-seven eyes of 47 patients with uncontrolled IOP or progressive glaucomatous optic neuropathy receiving maximal medical therapy requiring trabeculectomy or aqueous drainage device implantation who met eligibility criteria. METHODS: Eyes with visual acuity less than 20/30, corneal or retinal pathologic features, or unreliable standard automated perimetry (SAP) results were excluded. All patients underwent complete ocular examination, arterial blood pressure, SAP, and PERGLA at 2 sessions before surgery and at 3 months after surgery. Mean ocular perfusion pressure (MOPP) was calculated. Each measure of PERGLA amplitude and phase was an average of 600 artifact-free signal registrations. MAIN OUTCOME MEASURES: Intraocular pressure and PERGLA amplitude and phase. RESULTS: Forty-seven eyes of 47 patients (mean age +/- standard deviation [SD], 69.9 +/- 11.3 years) were enrolled. Thirty-four eyes (72%) underwent trabeculectomy with antifibrosis therapy; 13 eyes (28%) underwent glaucoma drainage implant surgery. Mean +/- SD postoperative IOP (10.4 +/- 4.6 mmHg) was significantly (P< 0.001) reduced compared with that before surgery (19.7 +/- 8.6 mmHg). Mean +/- SD postoperative PERGLA amplitude (0.46 +/- 0.22 MUV) was significantly (P = 0.001) increased compared with preoperative PERGLA amplitude (0.37 +/- 0.18 MUV). Mean +/- SD postoperative PERGLA phase (1.72 +/- 0.20 pi-radian) was significantly (P = 0.01) reduced compared with preoperative PERGLA phase (1.81 +/- 0.22 pi-radian). Mean +/- SD postoperative MOPP (53.1 +/- 6.4 mmHg) was significantly (P < 0.001) increased compared with mean +/- SD preoperative MOPP (45.8 +/- 10.1 mmHg). No correlation (P > 0.05) was identified between change in PERGLA amplitude and change in IOP or MOPP. CONCLUSIONS: Reversal of RGC dysfunction occurs after surgical reduction of IOP and may be quantified using PERGLA. PMID- 20920828 TI - Retinal and optic nerve head pathology in Susac's syndrome. AB - PURPOSE: This article describes the first retinal histopathologic findings in a patient with Susac's syndrome (SS). DESIGN: Observational case report. PARTICIPANT: A 51-year-old white woman diagnosed with SS. METHODS: Eyes from a 51 year-old white woman diagnosed with SS were obtained at autopsy. One retina was dissected and processed for adenosine diphosphatase (ADPase) flat embedding. Selected areas were processed further for transmission electron microscopy. MAIN OUTCOME MEASURES: Histopathologic examination using ADPase flat-embedding technique. RESULTS: There were vaso-occlusive changes in the retinal periphery resulting in small areas of capillary dropout. Cross-sections demonstrated serous filled spaces between the retinal blood vessels and the internal limiting membrane. Lumens adjacent to these spaces appeared compressed and sometimes closed, but without thrombosis. Decreased ADPase activity in some peripheral blood vessels suggested endothelial cell dysfunction and vaso-occlusion. In the optic nerve head, numerous corpora amylacea were observed in the vicinity of capillaries with thickened walls and narrow lumens. Transmission electron microscopy demonstrated thickened and amorphous vascular basal lamina and open endothelial cell junctions in some retinal blood vessels. CONCLUSIONS: The serous deposits with compression of retinal vessel lumens observed histologically probably represent the so-called string of pearls described clinically in SS. Chronic extension of these serous deposits along the vessel wall possibly are the cause of retinal arterial wall plaques as described by Gass and other investigators. In the optic nerve head, corpora amylacea are probably a result of microinfarcts resulting from optic nerve head capillary angiopathy. Accumulation of amorphous material in the basal lamina, loss of viable endothelial cells, and capillary dropout suggest that SS may be an endotheliopathy. PMID- 20920829 TI - Relationship between malnutrition and depression or anxiety in Anorexia Nervosa: a critical review of the literature. AB - BACKGROUND: Depression, anxiety and obsessive-compulsive disorder (OCD) frequently co-occur with Anorexia Nervosa (AN). Clinical consensus admits that depressive symptoms and anxiety are the sequelae of malnutrition in AN. This review presents a critical assessment of the literature that looked into the link between depression/anxiety symptoms in relation to malnutrition and their improvement throughout the treatment. METHODS: We performed a systematic search of literature in Medline and PsychInfo for all the studies done to investigate psychological factors in relation to malnutrition in AN using the keywords "Anorexia Nervosa", "depression", "anxiety", "obsessive-compulsive disorder" and "malnutrition". Only articles published between 1980 and 2010 in English or French were reviewed. From the articles on AN and depression, anxiety, and/or OCD, only the ones which investigated on the relation with malnutrition were kept. This search was complemented by a manual search. We also checked the reference lists of the articles we found. RESULTS: Seven papers were analyzed and critically reviewed for their methods and results. Results are contradictory and inconsistent at all levels of assessment. CONCLUSIONS: Evidence based data is very rare. From the 7 reviewed studies, none of them draw the same conclusion. This is mainly due to the large differences in the samples' populations and the studies' protocols. Future studies are needed to focus on the relationship between depression/anxiety symptoms and malnutrition. A more critical nutritional assessment should be undertaken with multiple psychological assessment scales. PMID- 20920830 TI - Invariant NKT cells in adrenoleukodystrophy patients and mice. AB - X-linked adrenoleukodystrophy (X-ALD) is a severe neurological disease characterized by progressive demyelination within the CNS, adrenal insufficiency, and is associated with an accumulation of saturated very long chain fatty acids in plasma and tissues of patients. iNKT cells, a distinct lineage of T cells recognizing glycolipid antigens through CD1d molecules, exert immunoregulatory functions and can prevent various immune mediated-pathologies. In ALD patients, but not in ALD deficient mice, iNKT cell frequency and CD1d expression on the surface of B cells are slightly decreased. However, such minor differences might not influence the pathogenesis of the disease. PMID- 20920831 TI - IVIg inhibits classical pathway activity and anti-GM1 IgM-mediated complement deposition in MMN. AB - The effects of intravenous immunoglobulins (IVIg) on anti-GM1 IgM titer and function, classical complement pathway activity, and antibody-complement interaction were investigated in 62 patients with multifocal motor neuropathy (MMN). In vitro, IVIg decreased complement deposition by anti-GM1 IgM antibodies. First IVIg treatment (2 g/kg) decreased C1q and C4 concentrations and classical pathway activity in serum. In sera from patients receiving IVIg maintenance therapy (0.4 g/kg) C4 concentrations and classical pathway activity were generally lower at higher IgG concentrations. The beneficial effects of IVIg in MMN may be explained by reduced antibody-mediated complement deposition in nerves amplified by a systemically attenuated classical pathway. PMID- 20920832 TI - Differences in exon expression and alternatively spliced genes in blood of multiple sclerosis compared to healthy control subjects. AB - Using whole genome exon microarrays 120 exons were differentially expressed between medication-free multiple sclerosis (MS) subjects in remission and healthy control subjects (HS) (p<0.001, fold change>|1.2|). These exons differentiated MS from HS using cluster analyses, principal components analyses (PCAs) and cross validation. In addition, 340 genes (transcripts) were predicted to be alternatively spliced in MS compared to HS. These findings may provide insight into the pathophysiology of MS and potentially provide prognostic and diagnostic biomarkers. However, given that multiple comparisons were performed on a very small sample, these preliminary findings require confirmation using a much larger independent cohort. PMID- 20920833 TI - Protective effects of Lactobacilli, Bifidobacteria and Staphylococci on the infection of cultured HT29 cells with different enterohemorrhagic Escherichia coli serotypes are strain-specific. AB - In this study, we investigated the interaction of 19 benign strains of lactic acid bacteria (LAB), bifidobacteria and staphylococci with enterohemorrhagic Escherichia coli (EHEC) strains of different serotypes and virulence gene spectrum in a HT29 cell culture infection model. As markers of infection, the secretion of interleukin 8 (IL-8) and the activation of the transcription factor NF-kappaB by the infected cells were determined. With 12 of 19 tested strains, a weak reduction <30% of IL-8 secretion of HT29 cells after co-infection with EHEC O157:H7 strain EDL933 was observed. Six strains reduced the IL-8 secretion up to 60% and the strain B. adolescentis DSMZ 20086 decreased the IL-8 production about 73%. In further co-infection assays with EHEC strains of the serotypes O103:H2, O26:H-, 0157:H- and O113:H21, different abilities of the LAB strains to influence the infection with the different EHEC strains were noted. Therefore, the protective anti-inflammatory effect is strain specific for LAB and also depends on the application of EHEC strains with different sero- and virulence types. The differences in efficacy of protective bacteria against certain EHEC strains were unexpected and have not been shown so far. Furthermore, we could show that the inhibitory effects were not attributed to lower adhesion abilities of EHEC to the production of organic acids by the benign bacteria. In addition, viable bacteria are needed to inhibit the IL-8 secretion. Moreover, the NF-kappaB activation was reduced significantly by all tested LAB strains in co-infection trials, but was not strain-specific. The model described here is useful to screen for basic effects of protective bacteria that are able to counteract EHEC-mediated effects on human cells, and to study the molecular interaction between bacteria as well as between bacteria and human cultured cells. PMID- 20920834 TI - Efficacy of short-term psychotherapy for multiple medically unexplained physical symptoms: a meta-analysis. AB - Multiple medically unexplained physical symptoms (MUPS) are considered to be difficult and costly to treat. The current meta-analysis therefore investigates the efficacy of short-term psychotherapy for MUPS. Based on a multiple-phase literature search, studies were selected according to a-priori defined inclusion criteria. The standardized mean gain was used as the effect size index. Separate data aggregation of between- and within-group contrasts was performed on the basis of a mixed effects model. Outcome variables were physical symptoms, disorder specific emotions, cognitions and behaviors, depressive symptoms, general psychopathology, functional impairment, and health care utilization. Based on 27 included studies, small between-group effect sizes (range: d(+)=0.06 d(+)=0.40) and small to large within-group effect sizes (range: d(+)=0.36 d(+)=0.80) were found for post-treatment and follow-up assessments for the different outcome variables. Significant moderator variables were identified as the type, mode, and setting of therapy, number of therapy sessions, profession of therapist, age and sex of patients, quality of diagnostic procedure, and the control of concomitant treatments. Implications of the results for clinical practice and future research are discussed. PMID- 20920835 TI - Use of dietary vitamin E and selenium (Se) to increase the shelf life of modified atmosphere packaged light lamb meat. AB - The aim of this work was to determine the increase in the shelf life of modified atmosphere packaged fresh lamb meat due to the effect of dietary vitamin E and selenium supplementation on colour and lipid oxidation. 128 lambs were fed on a concentrate with standard levels of vitamin E (C), a concentrate enriched with vitamin E (V), a concentrate with sodium selenite (S) and a concentrate enriched with both vitamin E and sodium selenite (VS). The lambs were slaughtered at 27.3+/-1.45 kg LW, and chops stored on MAP for 7, 9, 11 and 13 days. CIELab colour and TBARs were studied on these days. Use of dietary vitamin E extended the shelf life a further 4 days from the commercial sell-by date in terms of lightness, hue angle, metmyoglobin formation and lipid oxidation. Selenium could be used to increase the lightness of meat without vitamin E supplementation in lambs' diets. PMID- 20920836 TI - A biomechanical comparison of the pullout strength of No. 2 FiberWire suture and 2-mm FiberWire tape in bovine rotator cuff tendons. AB - PURPOSE: To biomechanically compare No. 2 polyblend suture with 2-mm polyblend tape in a bovine rotator cuff model as well as in isolation. METHODS: Ten paired bovine infraspinatus specimens were randomly assigned to simple suture fixation with either No. 2 polyblend suture or 2-mm polyblend tape. Each specimen was subjected to cyclic testing followed by load-to-failure testing. Elongation, ultimate tensile load, and stiffness were determined. The failure method was recorded. Isolated suture specimens were also cycled and tested with the same protocol. RESULTS: For tendon-suture specimens, testing showed no significant difference for elongation (1.44 +/- 0.41 mm v 1.90 +/- 1.15 mm, P = .192) or stiffness (67 +/- 13 N/mm v 66 +/- 11 N/mm, P = .757). Statistical significance was found for ultimate tensile load (168 +/- 73 N v 184 +/- 83 N, P = .046). The most common mode of failure for both groups of specimens was disruption of the tendon by the suture. Isolated suture specimens showed significant differences for ultimate tensile load (349 +/- 7 N v 937 +/- 93 N, P = .001) and stiffness (85 +/- 12 N/mm v 218 +/- 20 N/mm, P = .002) but not for elongation (0.26 +/- 0.05 mm v 0.19 +/- 0.04 mm, P = .124). CONCLUSIONS: Using the described testing method in bovine rotator cuff specimens, we found no difference in ultimate tensile load, stiffness, or elongation between the 2 tested sutures. Testing of the sutures in isolation showed that the 2-mm tape was approximately 3 times as stiff as the No. 2 suture and failed at 3 times the loads of the No. 2 suture. CLINICAL RELEVANCE: The larger 2-mm tape does not diminish the biomechanical performance of rotator cuff-suture specimens in comparison to No. 2 suture. Although the effect of tape on the vascularity of the rotator cuff is not known, the larger tape does not negatively affect elongation, ultimate tensile load, or stiffness in this in vitro animal model. PMID- 20920837 TI - The anterior cruciate ligament provides resistance to externally applied anterior tibial force but not to internal rotational torque during simulated weight bearing flexion. AB - PURPOSE: We investigated knee kinematics during simulated weight-bearing flexion and determined the effect of 3 different parameters of external tibial loading on the kinematics of the anterior cruciate ligament (ACL)-intact and ACL-deficient knee. METHODS: Ten human knee specimens were mounted on a dynamic knee simulator, and weight-bearing muscle-loaded knee flexions were simulated while a robotic/universal force sensor system was used to provide external tibial loads during the motion. Three different loading conditions were simulated: partial body weight only, an additional 50 N of anterior tibial force (ATD), or an additional 5 Nm of internal rotational tibial torque (IRT). After arthroscopic transection of the ACL, these 3 trials were repeated. The kinematics were measured with an ultrasonic measuring system for 3-dimensional motion analysis, and different loading and knee conditions were examined. RESULTS: When the ACL was intact, ATD and IRT barely changed the anterior tibial translation. However, in the absence of the ACL, ATD significantly increased the anterior tibial translation by 5 mm whereas IRT did not. The application of IRT increased the internal tibial rotation of ACL-intact knees, but there was no difference in the internal rotation before and after transection of the ACL. Regardless of ACL status, the difference in the anterior tibial translation and the internal tibial rotation across different external tibial loadings was greater at lower flexion angles and gradually diminished with increasing flexion angles. CONCLUSIONS: We established an experimental protocol, incorporating a dynamic knee simulator and a robotic/universal force sensor system, to successfully measure the kinematics of the knee joint while applying external forces in weight-bearing flexion. Our findings suggest that, in muscle-loaded knee flexion, the ACL provides substantial resistance to externally applied ATD but not to IRT. CLINICAL RELEVANCE: Information from this study allows us to better understand the function of the ACL and, hence, treatment of injuries to this important stabilizing ligament. PMID- 20920838 TI - Magnetic resonance imaging evidence of meniscal extrusion in medial meniscus posterior root tear. AB - PURPOSE: The purpose of this study was to evaluate the relation between meniscal extrusion on magnetic resonance imaging (MRI) and tearing of the posterior root of the medial meniscus, as well as to understand the relation between meniscal extrusion and chondral lesions. METHODS: From January 2007 to December 2008, 387 consecutive cases of medial meniscal tears were treated arthroscopically. Of these cases, 248 (64.1%) with MRI were reviewed. Arthroscopic findings were reviewed for the type of tear and medial compartment cartilage lesion. Root tear was defined as a radial tear in the posterior horn of the medial meniscus near the tibial spine (i.e., within 5 mm of the root attachment). An MRI scan of the knee was used to evaluate the presence and extent of meniscal extrusion. Meniscal extrusion of 3 mm or greater was considered pathologic. Arthroscopic findings were compared with respect to the extent of meniscal extrusion. RESULTS: There were 98 male patients and 150 female patients. The mean age was 53.5 years (range, 15 to 81 years). The results showed 127 cases (51.2%) in which the medial meniscus had meniscal extrusion of 3 mm or greater. Posterior root tears were found in 66 (26.6%) of the 248 knees. The mean meniscal extrusion in patients with root tear was 3.8 +/- 1.4 mm, whereas the mean extrusion of those who had no root tear was 2.7 +/- 1.3 mm. We found an association between pathologic meniscal extrusion and root tear (P < .001). Meniscal extrusion showed a low positive predictive value (39%) and specificity (58%) with regard to the meniscal root tear. Meniscal extrusion was also significantly correlated with severity of chondral lesions (P < .001). CONCLUSIONS: Considerable extrusion (>=3 mm) can be associated with tearing of the medial meniscus root and chondral lesion of the medial femoral condyle. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 20920839 TI - Endovascular treatment of acute limb ischemia secondary to fracture of a popliteal artery stent. AB - The authors report the case of a patient with acute lower limb ischemia (category IIa) after occlusion of the popliteal artery due to fracture of a long indwelling stent. The patient refused surgical therapy for religious reasons, and an interventional revascularization was performed as acute rescue therapy. After reentry into the distal popliteal artery was achieved, the artery was dilated, and the fragmented stent was crushed, followed by implantation of two helical nitinol stents with high radial force and a third self-expandable nitinol stent. Sufficient primary technical success was achieved, and stent patency was present at midterm follow-up. PMID- 20920841 TI - Comparing strategies for operator eye protection in the interventional radiology suite. AB - PURPOSE: To evaluate the impact of common radiation-shielding strategies, used alone and in combination, on scattered dose to the fluoroscopy operator's eye. MATERIALS AND METHODS: With an operator phantom positioned at the groin, upper abdomen, and neck, posteroanterior low-dose fluoroscopy was performed at the phantom patient's upper abdomen. Operator lens radiation dose rate was recorded with a solid-state dosimeter with and without a leaded table skirt, nonleaded and leaded (0.75 mm lead equivalent) eyeglasses, disposable tungsten-antimony drapes (0.25 mm lead equivalent), and suspended and rolling (0.5 mm lead equivalent) transparent leaded shields. Lens dose measurements were also obtained in right and left 15 degrees anterior obliquities with the operator at the upper abdomen and during digital subtraction angiography (two images per second) with the operator at the patient's groin. Each strategy's shielding efficacy was expressed as a reduction factor of the lens dose rate compared with the unshielded condition. RESULTS: Use of leaded glasses alone reduced the lens dose rate by a factor of five to 10; scatter-shielding drapes alone reduced the dose rate by a factor of five to 25. Use of both implements together was always more protective than either used alone, reducing dose rate by a factor of 25 or more. Lens dose was routinely undetectable when a suspended shield was the only barrier during low-dose fluoroscopy. CONCLUSIONS: Use of scatter-shielding drapes or leaded glasses decreases operator lens dose by a factor of five to 25, but the use of both barriers together (or use of leaded shields) provides maximal protection to the interventional radiologist's eye. PMID- 20920840 TI - High-fidelity computer models for prospective treatment planning of radiofrequency ablation with in vitro experimental correlation. AB - PURPOSE: To evaluate the accuracy of computer simulation in predicting the thermal damage region produced by a radiofrequency (RF) ablation procedure in an in vitro perfused bovine liver model. The thermal dose end point in the liver model is used to assess quantitatively computer prediction for use in prospective treatment planning of RF ablation procedures. MATERIALS AND METHODS: Geometric details of the tri-cooled tip electrode were modeled. The resistive heating of a pulsed voltage delivery was simulated in four dimensions using finite element models (FEM) implemented on high-performance parallel computing architectures. A range of physically realistic blood perfusion parameters, 3.6-53.6 kg/sec/m(3), was considered in the computer model. An Arrhenius damage model was used to predict the thermal dose. Dice similarity coefficients (DSC) were the metric of comparison between computational predictions and T1-weighted contrast-enhanced images of the damage obtained from a RF procedure performed on an in vitro perfused bovine liver model. RESULTS: For a perfusion parameter greater than 16.3 kg/sec/m(3), simulations predict the temporal evolution of the damaged volume is perfusion limited and will reach a maximum value. Over a range of physically meaningful perfusion values, 16.3-33.1 kg/sec/m(3), the predicted thermal dose reaches the maximum damage volume within 2 minutes of the delivery and is in good agreement (DSC > 0.7) with experimental measurements obtained from the perfused liver model. CONCLUSIONS: As measured by the computed volumetric DSC, computer prediction accuracy of the thermal dose shows good correlation with ablation lesions measured in vitro in perfused bovine liver models over a range of physically realistic perfusion values. PMID- 20920842 TI - Adenosine signaling via the adenosine 2B receptor is involved in bronchiolitis obliterans development. AB - BACKGROUND: Adenosine is produced in response to ischemia or inflammation and protects tissues from injury. Four adenosine receptors are critical in the physiologic negative-feedback mechanism for limitation and termination of tissue specific and systemic inflammatory responses. Accumulating evidence has focused on the anti-inflammatory and immunosuppressive role of the adenosine 2A receptor (A(2A)R), and we have previously reported on its role in the development of bronchiolitis obliterans (BO) after lung transplantation. Few studies, however, have reported the role of the adenosine 2B receptor (A(2B)R) in BO. Data suggests that the A(2B)R has pro-inflammatory and pro-fibrotic roles. We hypothesized that adenosine signaling through A(2B)R is involved in the development of BO. METHODS: A murine heterotopic tracheal model across a total alloantigenic mismatch was used to study A(2B)R signaling in BO. Tracheal transplants consisted of Balb/c donor tracheas transplanted into wild-type or A(2B)R knockout (KO) C57BL/6 recipients. Transplanted tracheas were removed 3, 7, 12, and 21 days after transplantation. The luminal obliteration was evaluated through hematoxylin and eosin staining, and the cellular infiltration (macrophage, neutrophil, CD3+ and Foxp3+ regulatory T cell) was detected by immunohistochemical staining. RESULTS: Compared with allografts in wild-type recipients, tracheas transplanted into A(2B)R KO mice displayed less BO development on Day 21. A(2B)R KO mice had an increase in CD3+ T cells and CD4+/CD25+/Foxp3+ regulatory T cells than did wild type mice on Day 7. By Day 12, more CD3+ T cells were present in the wild-type trachea compared with the A(2B)R KO, but the percentage of CD4+/CD25+/Foxp3+ regulatory T cells remained higher in the tracheas of A(2B)R KO mice. CONCLUSIONS: A(2B)R stimulation may promote the development of BO by inhibiting CD4+/CD25+/Foxp3+ regulatory T-cell infiltration. PMID- 20920844 TI - The Dutch Objective Burden Inventory: validity and reliability in a Canadian population of caregivers for people with heart failure. AB - Evidence suggests that caregivers of people with heart failure (HF) often experience caregiver burden and emotional distress. However, these studies measured the caregiving experience using generic tools since a disease-specific tool was not available. Recently, the Dutch Objective Burden Inventory (DOBI) was developed as a disease-specific tool measuring objective caregiver burden in a Dutch HF population of caregivers. Using a cross-sectional design, caregivers of HF patients attending an outpatient HF clinic completed the DOBI, the Hosptial Anxiety and Depression Scale (HADS) and the Caregiver Reaction Assessment (CRA). Caregivers (n=47) were mainly female (72%) and spouses (72%) of the HF patients with a mean age of 63.1 (+/-10.4) years. Patients were older (mean age 72.7; +/ 10.6), 64% male and had advanced HF. Feasibility for the objective portion of the DOBI was excellent with <10% missing values. The subjective component of the DOBI was incomplete and could not be used in the analyses. Seven items had minimal variability. Significant relationships emerged between the DOBI, CRA and HADS revealing construct validity for all subscales of the DOBI. Cronbach's alpha was >.80 for all DOBI subscales. The DOBI is the only disease-specific tool that measures burden for caregivers of HF patients. The objective portion of the DOBI showed evidence of adequate internal consistency and construct validity in a Canadian population of caregivers of HF patients attending a HF Clinic. Further testing is needed to determine floor and ceiling effects for DOBI items and responsiveness of this tool. PMID- 20920843 TI - Adventitious shoot regeneration from juvenile cotyledons of a biodiesel producing Plant, Jatropha curcas L. AB - An efficient and rapid adventitious shoot regeneration system from young cotyledons of Jatropha curcas L. was developed. After testing several combinations of plant growth regulators, the highest regeneration frequency was obtained for the medium supplemented with 3 mg/l BA and 0.1 mg/l IBA. This system will be useful for promoting genetic improvement efforts in J. curcas. PMID- 20920845 TI - A simplified method to assess affinity of insulin autoantibodies. AB - Insulin autoantibodies (IAA) precede type 1 diabetes, but not all IAA-positive children develop other islet autoantibodies and disease. Diabetes risk can be stratified by laborious IAA affinity measurement using competition with multiple ligand concentrations. Here, we identify a single competitor concentration that discriminates low- and high-affinity IAA. Discrimination was achieved among 122 IAA-positive sera using 7.0 nM competitor which is 54-fold that of the assay radioligand concentration. Relative-binding <60% at this competitor concentration identified all 85 sera with affinities >=1.0*108 L/mol and none with lower affinities (P<0.0001), and 45 (96%) of 47 multiple islet autoantibody-positive sera (P<0.0001). IAA competition was further tested in a second set of 119 IAA positive sera. Of these, 99 fulfilled high-affinity competition criteria of <60% relative-binding at 7.0 nM competitor including 89 (94%) of 95 sera with multiple islet autoantibodies (P<0.0001). Thus, increased IAA specificity can be achieved with simple modification to existing assays. PMID- 20920846 TI - Administration of lithium and magnesium chloride inhibited tolerance to the anticonvulsant effect of morphine on pentylenetetrazole-induced seizures in mice. AB - Although morphine has an anticonvulsant effect in several animal models of seizures, its potential clinical application in epilepsy may be hindered by its adverse effects like opioid tolerance. The present study evaluated the development of tolerance to the anticonvulsant effect of morphine in a model of clonic seizures induced with pentylenetetrazole (PTZ) in male Swiss mice. We also examined whether administration of either lithium chloride (LiCl) or magnesium chloride (MgCl(2)) was able to prevent the probable tolerance. Our data demonstrated that the anticonvulsant effect of a potent dose of morphine (1mg/kg) was abolished in chronic morphine-treated mice (mice administered the same dose of morphine intraperitoneally twice daily for 4 days). Four days of pretreatment with low and noneffective doses of MgCl(2) (2 and 5mg/kg) and LiCl (5mg/kg) inhibited the development of tolerance to the anticonvulsant effect of morphine (1mg/kg, ip). Moreover, a single acute injection of the aforementioned agents at the same doses reversed the expression of tolerance to the anticonvulsant effects of morphine (1mg/kg, ip). Chronic 17-day treatment with LiCl (600 mg/L in drinking water) also inhibited the development of tolerance to the anticonvulsant effects of 1mg/kg morphine. These results demonstrate that the anticonvulsant effect of morphine is subject to tolerance after repeated administration. Both development and expression of tolerance are inhibited by either LiCl or MgCl(2). As both LiCl and MgCl(2) can modulate the function of N-methyl-d-aspartate (NMDA) receptors, we discuss how NMDA receptor functioning might be involved in the effects of LiCl and MgCl(2) on the development of tolerance to the anticonvulsant effect of morphine. PMID- 20920847 TI - Absence of gender effect on amygdala volume in temporal lobe epilepsy. AB - Sexual dimorphism has already been described in temporal lobe epilepsy with mesial temporal sclerosis (TLE-MTS). This study evaluated the effect of gender on amygdala volume in patients with TLE-MTS. One hundred twenty-four patients with refractory unilateral or bilateral TLE-MTS who were being considered for epilepsy surgery underwent a comprehensive presurgical evaluation and MRI. Amygdalas of 67 women (27 with right; 32 with left, and 8 with bilateral TLE) and 57 men (22 with right, 30 with left, and 5 with bilateral TLE) were manually segmented. Significant ipsilateral amygdala volume reduction was observed for patients with right and left TLE. No gender effect on amygdala volume was observed. Contralateral amygdalar asymmetry was observed for patients with right and left TLE. Although no gender effect was observed on amygdala volume, ipsilateral amygdala volume reductions in patients with TLE might be related to differential rates of cerebral maturation between hemispheres. PMID- 20920848 TI - Twice vs three-times daily antibiotics in the treatment of pulmonary exacerbations of cystic fibrosis. AB - BACKGROUND: Once daily dosing of aminoglycosides is widely used but is limited by the inconvenience of the slow infusion it requires and the associated three-times daily infusion of a beta-lactam. Twice daily tobramycin can be given as a slow IV bolus and may be more convenient. This study compares twice with three-times daily dosing of both tobramycin and ceftazidime. METHODS: This was a randomised, open-label, parallel group trial. CF patients presenting with an infective exacerbation were randomised to either twice or three-times daily ceftazidime and tobramycin. Markers of treatment efficacy and safety were measured in the two groups. The primary outcome measure was improvement in FEV1. RESULTS: 146 patients were randomised into the study. There was no significant difference in the two groups for improvement in FEV1% predicted (9.93% and 7.98% for twice daily and three-times daily respectively) and similar times to next exacerbation. There were no differences in the incidence of treatment failure, nephrotoxicity and ototoxicity. DISCUSSION: This study confirms that twice daily dosing of both tobramycin and ceftazidime is safe and effective and may be considered more convenient than current dosing schedules. PMID- 20920849 TI - Proteome analysis of the leukocytes from the American alligator (Alligator mississippiensis) using mass spectrometry. AB - Mass spectrometry was used in conjunction with gel electrophoresis and liquid chromatography, to determine peptide sequences from American alligator (Alligator mississippiensis) leukocytes and to identify similar proteins based on homology. The goal of the study was to generate an initial database of proteins related to the alligator immune system. We have adopted a typical proteomics approach for this study. Proteins from leukocyte extracts were separated using two-dimensional gel electrophoresis and the major bands were excised, digested and analyzed by on line nano-LC MS/MS to generate peptide sequences. The sequences generated were used to identify proteins and characterize their functions. The protein identity and characterization of the protein function were based on matching two or more peptides to the same protein by searching against the NCBI database using MASCOT and Basic Local Alignment Search Tool (BLAST). For those proteins with only one peptide matching, the phylum of the matched protein was considered. Forty-three proteins were identified that exhibit sequence similarities to proteins from other vertebrates. Proteins related to the cytoskeletal system were the most abundant proteins identified. These proteins are known to regulate cell mobility and phagocytosis. Several other peptides were matched to proteins that potentially have immune-related function. PMID- 20920850 TI - [Translational research in clinical oncology: challenges and opportunities]. AB - The principal objective of the translational research in Oncology is to translate the knowledge derived from the basic research to the clinical practice as soon as possible. The goal is to develop and maximize the concepts of oncopharmacogenomic and oncopharmacogenetic. In this context it will be absolutely necessary that hospitals integrate the basic and clinical research in translational research units with the appropriate resources. PMID- 20920851 TI - [Antineoplastic drug-induced neutropenia: use of granulocyte colony stimulating factors]. AB - Neutropenia is a frequent adverse event of the pharmacologic treatment of cancer. Morbidity and mortality-associated neutropenia can be successfully treated and prevented with granulocyte-colony stimulating factors (G-CSF). European and American Guidelines recommend their prophylactic use when the expected percentage of febrile neutropenia exceeds 20% or there are concomitant risk factors. Afebrile neutropenia is not considered to benefit from G-CSF treatment. Other approved indications include stem cell mobilization, and an adequate delivery of dose-intense and dose-dense chemotherapy regimens. PMID- 20920852 TI - [Pharmacoeconomics and cost of cancer drugs]. AB - Cancer is a disease of high incidence, which determines that the health systems will be forced to allocation a significant amount of resources. In an era of evidence-based medicine and increasing cost pressures, it is important to understand the relative clinical and economic impact of the many drug treatment strategies available for cancer patients. Currently, resources that may be spent in pharmacoeconomics expenditure are limited so it is necessary to rationalize their consumption and priorize in the allocation of these resources to the options with higher economic advantages. Pharmacoeconomic studies will permit us to know what is the efficiency of different therapeutic alternatives so they will help to determine the therapeutic options that we should use in routine medical practice. PMID- 20920853 TI - [Biosimilars: regulatory status for approval]. AB - Biotecnological drugs represents the future treatment in medicine. Since the expiry of the patent of the fi rst approved biotech drug, "copying" and marketing of them can be offered by any other biotech company, these new medicines are known as biosimilar medicines. They are approved by the EMEA (European Medicines Evaluation Agency) through the European centralised procedure, the EMEA issued several stringent guidelines to approve a biosimilar drug on the European market, preclinical and clinical studies are necessary to asses the highest standards in quality, efficacy and patient safety. The World Health Organization has determined that biosimilar have the same INN than the original product. PMID- 20920854 TI - [Biosimilar filgrastim: from development to record]. AB - Ratiograstim(r) is the first filgrastim biosimilar approved by EMEA. The reference medicinal product is Neupogen(r). The active substance is filgrastim (the manufacturing laboratory, ratiopharm, is using the name XM02). Filgrastim is a non glycosylated recombinant methionyl human granulocyte colony stimulating factor expressed in E. coli. Differences with human granulocyte-colony stimulating factor (G-CSF) are a N-terminal methionyl extension and be a non glycosylated protein. Ratiograstim(r) has the same indications as the reference product: - Cytotoxic chemotherapy induced neutropenia. - Neutropenia caused by myeloablative therapy followed by BMT. - Mobilisation of peripheral blood progenitor cells (PBPC). - Congenital, cyclic or idiopathic neutropenia. - Persistant neutropenia in HIV-patients. Authorisation according to the EMEA guidelines for biosimilars by centralized approval procedure, to demonstrate quality, efficacy and safety compared to the reference product Neupogen(r). Comprehensive phase I and phase III clinical studies involving 880 subjects and patients have been completed (table 1). PMID- 20920855 TI - [Biosimilars: assessment of efficacy, safety and cost]. AB - A biosimilar medicinal product is a successor to a biological medicinal product for which patent protection no longer applies. Manufactured by recombinant DNA technology (insertion of gene into the host cell to produce the protein). Comparable with the selected comparator, reference product, in terms of quality, safety and efficacy. The biosimilar product is usually approved for the same indications as the comparator reference product given that they share the same mode of actions. PMID- 20920856 TI - [Biosimilar medicines. Scientific and legal disputes]. AB - Patent expiry dates for early biotechnological drugs is giving rise to the availability of biosimilar drugs. According to the EMEA, these are defined as drugs with a biotechnological origin that have proven comparable to their reference product once the latter's patent expired. Modifications in the manufacturing process of biotechnological medications or treatment changes from one biotechnological molecule to another have not been debated until these biosimilar drugs have become available. It is then that, among other issues, the potential risks of their substitution for reference molecules became controversial. EMEA guidelines for biosimilar drug approval grant that these will be as effective and safe as any other newly available biotechnological medicinal product, or as any other drug undergoing changes in its manufacturing processes once marketed. Their availability will promote competition and reduce the high financial impact healthcare systems endure following the introduction of new therapies based on biotechnological drugs. PMID- 20920857 TI - [Consensus document on the use of granulocyte colony stimulating factor biosimilars for correction of neutropenia in cancer patients]. PMID- 20920858 TI - A new computerized measurement approach of carotid artery stenosis on tomographic image sequence. AB - RATIONALE AND OBJECTIVES: The stenosis degree of carotid artery (CA) can be a critical factor for treatment of cerebrovascular disease and for determining candidate of carotid endarterectomy. Currently, three different measuring methods are applied only on projectional cervical images. These measurement methods introduce several demerits such as a thromboembolic event, and three reference positions provide the different measurement results even on same subject. In addition, projection image could not provide the most severe stenosis position by nature; and the manual measurements also provide the inter-observer and intra observer variability. Therefore, a computerized measuring scheme is necessary to overcome these drawbacks. MATERIALS AND METHODS: By applying local adaptive thresholding technique on cervical magnetic resonance angiogram image sequence, CA objects are initially identified. These are used to determine the three dimensional central axis of CA by using circumscribed quadrangle. The oblique slices are reformatted into two-dimensional image planes, which are perpendicular to the central axis of CA, to provide the circular shape of blood vessel provided that the artery runs horizontally across the scanning axis. After that, region growing technique is applied on obliquely reformatted image sequence followed by geometrically restoration of segmented CA objects. RESULTS: The percentage of stenosis can be defined by the area ratio of segmented CA to restored CA object. The stenosis grading of is [(A-B)/A]*100%, where A represents area measure of restored object, B represents area measure of segmented CA object. Experiments have been conducted on both phantom that simulated the mild (30%), moderate (50%), and severe (70%) stenosis degree for validation of proposed measurement approach and 86 carotid arteries from 43 clinical data sets (including 5 occlusion cases). CONCLUSIONS: The automated approach is recommended to measure the carotid stenosis by using axial image sequence. This technique is not only accurate as possible but also robust, simple to handle, and less time consuming as compared to manual measurements. In addition, a computerized carotid stenosis measuring method is necessary to overcome the drawbacks introduced by using the projectional image and measurement variability of inter-observer, intra-observer. PMID- 20920859 TI - Cost analysis and feasibility of high-fidelity simulation based radiology contrast reaction curriculum. AB - RATIONALE AND OBJECTIVES: Radiology residents have variable training in managing acute nonrenal adverse reactions to iodinated contrast media because of their rarity. Preliminary results show positive feedback and knowledge gain with high fidelity simulation-based training. Financial costs and the time required to implement a high-fidelity simulation curriculum are higher than for a lecture series. The objective of this study was to provide a financial and time cost benefit analysis for high-fidelity simulation training of acute adverse reactions to iodinated contrast media. MATERIALS AND METHODS: Forty-four radiology residents were divided into lecture and simulation groups. Five simulation scenarios were created, with core education content mirrored in the lecture. Lengths of faculty time commitment and resident training were recorded. Financial costs, including manikin and simulation facility rates, were recorded and divided by the number of residents to obtain per resident simulation and lecture costs. A written evaluation of the experience, with Likert-type items and unstructured response items, was conducted. RESULTS: Cost per resident for simulation training setup was $259.76, and $203.46 for subsequent years, compared to <$5 for lecture. Faculty time was 7 academic days for simulation versus 2 days for lecture format. Resident simulation commitment was 3 hours 30 minutes. Time to train technologists to run the simulation was 3 hours. All residents provided positive feedback regarding the simulation curriculum, with mean feedback scores statistically higher than lecture group (P < .05). CONCLUSIONS: This study illustrates that financial costs of implementation are low compared to the potential cost of morbidity associated with the life-threatening event of an acute adverse reaction to iodinated contrast media. PMID- 20920860 TI - Inframalleolar bypass grafts for limb salvage. AB - OBJECTIVE: To report our experience of long-term results of inframalleolar bypass. DESIGN: Retrospective analysis. MATERIALS AND METHODS: We analysed 122 inframalleolar bypasses performed between January 1991 and June 2005 in 116 patients. Most patients were treated for critical ischaemia (97%). The indication for the use of podalic arteries was a lack of tibial arteries with run-off to the foot. The dorsalis pedis was predominantly used for distal anastomoses (62.3%) and the greater saphenous vein (84.4%) as the conduit. The follow-up periods ranged from 1 to 60 months. The endpoints analysed were graft patency, limb salvage, preservation of deambulation and survival rate. RESULTS: The cumulative patency was 58.2% at 3 years and 53.4% at 5 years. The best results were achieved with the devalvulated greater saphenous veins. Limb salvage was 70.0% at 3 years and 50.4% at 5 years, with preserved deambulation rates of 57.3% and 47.1%, respectively. There were 36 major and 45 minor amputations. At 3 years, the survival rate was 50.2% and the surgical mortality 13%. Female sex was associated with worse results for cumulative patency and limb salvage (P<0.01). CONCLUSIONS: In the long term, inframalleolar bypass is a satisfactory option for limb salvage. PMID- 20920861 TI - Hybrid repair of the aortic arch in patients with extensive aortic disease. AB - OBJECTIVE: To evaluate the outcome of hybrid treatment of the aortic arch with supra-aortic debranching and endovascular stent-graft repair in a selected group of patients with complex disease. DESIGN: Case series study with retrospective analysis of prospectively collected non-randomised data. METHODS: Patients with hybrid repair of complex arch disease at a single centre over a 6-year period were enrolled in the study. Only patients with extensive arch pathologies requiring debranching of at least the left carotid artery were considered. Patients were divided into those who underwent complete and partial supra-aortic revascularisation. The chi2 test was used to evaluate differences in outcomes. Logistic regression analyses were applied to identify predictors of poor outcome. RESULTS: A total of 33 patients were included in the study. Complete and partial arch repair was performed in nine and 24 patients, respectively. The aortic disease extended to the thoracic and abdominal aorta in 39% and 52% of the patients, respectively. One-third of the patients (30%) were treated on an urgent/emergency basis. Elective 30-day mortality and morbidity rates were 13% and 35%, respectively. Early mortality was significantly higher in the complete arch repair group (p=0.046). Pre-existing renal impairment was identified as a poor prognostic factor. All extra-anatomic bypasses remained patent and no aortic disease-related deaths occurred during a mean follow-up period of 23 months (range, 1.5-58 months). Complete arch repair was associated with an increased incidence of late endoleak (p=0.018). CONCLUSIONS: Hybrid treatment of the aortic arch provides a feasible alternative treatment in patients who are high risk for conventional open surgical repair. Careful selection of patients is required to achieve satisfactory results. PMID- 20920862 TI - International psychometric validation of the Chronic Venous Disease quality of life Questionnaire (CIVIQ-20). AB - OBJECTIVE: To review the psychometric validation of the Chronic Venous dIsease quality of life Questionnaire (CIVIQ-20) in the countries that have used it since 1996. DESIGN: Prospective, clinical, international study in 18 countries. PATIENTS: Patients with venous disease of the lower limb in the clinical, aetiological, anatomical and pathophysiological (CEAP) clinical stages C0s to C4 presenting to surgical outpatient departments and general practices and receiving drug treatment for 6 months. METHODS: Quantification of symptoms on a four-point scale and pain on a visual analogue scale, and self-administration of CIVIQ-20 to patients before visit (baseline, 2, 4 and 6 months). RESULTS: In 3956 patients, CIVIQ-20 showed good internal consistency and reliability (above 0.80) through test-retest correlations. The discriminating power of items was good in known groups of patients. Factor analysis identified physical, psychological and pain factors as important, but revealed instability of the social factor. CIVIQ-20 was highly sensitive to changes in the quality of life of patients clinically improved after drug treatment. CONCLUSION: CIVIQ-20 is valuable in assessing treatment effects in longitudinal, multinational studies, but comparisons of different populations should use the global score rather than scores per dimension. PMID- 20920863 TI - The CAESAR trial--highlighting the need for different end points. PMID- 20920864 TI - Vitamin D Receptor (VDR) polymorphic variants in patients with cancer and Gaucher disease. AB - BACKGROUND: An increased risk has been reported in Gaucher disease genotype N370S/N370S for multiple myeloma, hematologic and other malignancies, as well as skeletal involvement. The purpose of this study is to ascertain whether VDR genotype which is involved in the risk for many cancers including multiple myeloma is also correlated with cancers in patients with Gaucher disease. METHODS: VDR polymorphisms (ApaI, TaqI, BsmI, FokI) were analyzed by standard methods from 29 Gaucher patients (some on enzyme therapy) with various cancers and from 70 healthy Ashkenazi Jews. Associations between VDR and categorical variables were analyzed by chi-square and Fisher's exact tests; associations with quantitative variables used ANOVA and Scheffe post-hoc tests. Non-parametric Kruskal-Wallis ANOVA was used when one category was small. IRB Committee approval was received for this study. FINDINGS: There was a trend for statistical significance (p=0.04) between patients and controls for the ApaI aa genotype. There were no correlations between VDR polymorphic genotypes and disease severity, need for ERT, splenectomy, or bone disease except a trend associating TaqI TT genotype with Zimran's severity score (p=0.06). CONCLUSION: This survey highlights the possibility that Gaucher disease in itself may not be the only important risk factor for cancers (other than multiple myeloma) and that other modifiers may affect cancer morbidity in Gaucher disease. PMID- 20920865 TI - Screening for proteinuria in cats using a conventional dipstick test after removal of cauxin from urine with a Lens culinaris agglutinin lectin tip. AB - Proteinuria is an important indicator of urinary tract disease and urine dipsticks are simple and sensitive tools to screen for this marker. However, the use of dipsticks to screen for proteinuria may not be appropriate in cats, since cauxin, a 70 kDa glycoprotein, is secreted by the kidneys in clinically normal animals of this species. To circumvent this problem, a Lens culinaris agglutinin (LCA) lectin tip was developed to remove cauxin from feline urine, followed by conventional urine dipstick testing for proteinuria. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) with Coomassie brilliant blue R-250 staining indicated that >90% cauxin in the urine of 13 clinically normal cats was trapped by the LCA lectin tip, so that the dipstick protein 'score' changed from 'positive' (>=30 mg/dL) for untreated urine to 'negative' (<=10 mg/dL) for lectin tip-treated urine. In contrast, SDS-PAGE indicated that lectin tip-treated samples from 20 animals with renal disease contained high concentrations of albumin and low-molecular weight proteins; dipstick testing of lectin tip-treated urine resulted in a consistently positive protein score. The accuracy of the dipstick method for detecting cats with abnormal proteinuria is enhanced if dipsticks are used with urine samples that have first been passed through the LCA lectin tip. PMID- 20920866 TI - White noise: pigment-associated deafness. PMID- 20920867 TI - Autism in monogenic disorders. PMID- 20920868 TI - Z-spectroscopy with Alternating-Phase Irradiation. AB - Magnetization transfer (MT) MRI and Z-spectroscopy are tools to study both water macromolecule interactions and pH-sensitive exchange dynamics between water and the protons of mobile chemical groups within these macromolecules. Both rely on saturation of frequencies offset from water and observation of the on-resonance water signal. In this work, an RF saturation method called Z-spectroscopy with Alternating-Phase Irradiation (ZAPI) is introduced. Based on the T(2)-selectivity of the irradiation pulse, ZAPI can be used to separate the different contributions to a Z-spectrum, as well as to study the T(2) distribution of the macromolecules contributing to the MT signal. ZAPI can be run at resonance for water and with low power, thus minimizing problems with specific absorption rate (SAR) limits in clinical applications. In this paper, physical and practical aspects of ZAPI are discussed and the sequence is applied in vitro to sample systems and in vivo to rat head to demonstrate the method. PMID- 20920869 TI - Characteristics of zero-quantum correlation spectroscopy in MAS NMR experiments. AB - Zero-quantum coherence generation and reconversion in magic-angle spinning solid state NMR is analyzed. Two methods are discussed based on implementations using symmetry-based pulse sequences that utilize either isotropic J couplings or dipolar couplings. In either case, the decoupling of abundant proton spins plays a crucial role for the efficiency of the zero-quantum generation. We present optimized sequences for measuring zero-quantum single-quantum correlation spectra in solids, achieving an efficiency of 50% in ubiquitin. The advantages and disadvantages of zero-quantum single-quantum over single-quantum single-quantum correlation spectroscopy are explored, and similarities and differences with double-quantum single-quantum correlation spectroscopy are discussed. Finally, possible application of zero-quantum single-quantum experiments to polypeptides, where it can lead to better spectral resolution is investigated using ubiquitin, where we find high efficiency and high selectivity, but also increased line widths in the MQ dimension. PMID- 20920870 TI - IGF(CA)19 and IGFBP-3-202A/C gene polymorphism in patients with acromegaly. AB - OBJECTIVE: We aimed to investigate IGF-1 and IGFBP-3 gene polymorphisms in patients with acromegaly. DESIGN: We included 34 patients with acromegaly and 37 healthy subjects to study. At baseline examinations, antropometric measurements were done. Genomic DNA from the patients and controls were prepared. Serum, glucose, insulin, total cholesterol, triglyceride, HDL cholesterol, LDL cholesterol, growth hormone (GH), Insulin-like growth factor I (IGF-I) and IGFBP 3 levels of subjects were analyzed. RESULTS: The frequency of genotype IGF 1(CA)19 and IGFBP3-202 A/C gene was significantly different between control and patients. In acromegalic patients, a significant difference in the serum IGF-1 levels and LDL cholesterol levels among the three IGF(CA)19 genotype. LDL levels were positively correlated with IGF-1. Subjects having >194 bp genotype had higher IGF-1 and LDL cholesterol levels. We observed that the patients with 194 bp genotype have more invasive and bigger tumors and they require adjunctive therapies. Clinical characteristics among the three IGFBP3-202 A/C genotype, AA, AC and CC, did not display any significant difference. CONCLUSIONS: In our study, 194 bp allele (20 CA repeats) of the IGF-I promoter have higher circulating IGF-I levels than others. We have found that the patients with 194 bp genotype are the resistant patients with active disease and they required high dose medication. We think this study may help to define the patients, who are resistant to drug therapy, and possible cardiovascular disease. PMID- 20920871 TI - Mutation spectrum of phenylketonuria in Iranian population. AB - Identification of molecular basis of phenylketonuria (PKU) in Iran has been accomplished through the analysis of 248 unrelated chromosomes from 124 Iranian classic PKU subjects. Phenylalanine hydroxylase (PAH) gene mutations were analyzed through a combined approach in which p.S67P, p.R252W, p.R261Q, p.R261X, p.L333F, IVS10-11G>A, IVS11+1G>C, p.L364del, p.R408Q and p.R408W mutations were first screened by PCR of PAH gene exons 3, 7, 10, 11 and 12, followed by digestion with the appropriate digestion enzymes. Subsequently SSCP analysis for exons 2, 6, 7 and 11 of the PAH gene and finally, sequencing of 13 PAH gene exons have been used to study uncharacterized PKU chromosomes. 26 different mutations were found. The predominant mutation in this population sample was IVS10-11G>A, with a frequency of 24.6%. Nine mutations (IVS10-11G>A, p.R261Q, p.P281L, IVS11+1G>C, p.K363>NFS, p.R243X, IVS2+5G>C, p.R261X and p.R252W) represent almost 84% of all PKU chromosomes studied. IVS10-11G>A mutation is the major PKU-causing mutation throughout the Mediterranean region. The finding of the high prevalence of this mutation in Iranian population is consistent with the historical and geographical links between Iranian and Mediterranean populations. PMID- 20920872 TI - [Expression of the elastic fibers components during the foetal liver development]. AB - Elastic fibers are composed of microfibrils containing fibrillin-1 and an elastic component, elastin. Microfibrils may not be associated with elastin. In the adult liver, fibrillin-1 and elastin are coexpressed within the stroma and portal tracts vessel walls. Fibrillin-1 is expressed alone around the bile ducts and within the Disse space. There is little work that has studied the elastic fiber organization during the foetal liver development. Here, we studied the expression of fibrillin-1 and elastin by immunohistochemistry on 20 cases of foetal liver. During the development of the portal tract, the two components are coexpressed on interstitial elastic fibers and within vessel walls. Fibrillin-1 is expressed alone around the bile structures during their maturation. Unlike adult liver, fibrillin-1 is expressed on thin and very irregular microfibrils within the Disse space. Our study shows that the elastic matrix development in the portal tract follows the development of the different structures, notably biliary structures. In the Disse space, microfibrils are not continuous. Their maturation may be in relation with the change of the hepatic blood flow after birth. PMID- 20920873 TI - A rapid and efficient ultrasound-assisted synthesis of 5,5-diphenylhydantoins and 5,5-diphenyl-2-thiohydantoins. AB - To obtain a rapid, efficient and mild synthesis of 5,5-diphenylhydantoin and 5,5 diphenyl-2-thiohydantoin derivatives, ultrasonic irradiation has been applied to the reaction mixtures containing substituted benzils and urea or thiourea derivatives catalyzed by KOH in DMSO/H(2)O, which allowed us to achieve products at room temperature in a good yield and short time without any side product. This convenient procedure will allow a further increase of the diversity within the hydantoin family. PMID- 20920874 TI - Recovery of bone strength in young pigs from an induced short-term dietary calcium deficit followed by a calcium replete diet. AB - This study investigated whether the deficits in bone strength of pre-pubertal pigs, induced by short-term deficits in dietary calcium can be recovered if followed by a calcium-fortified diet. Young pigs were divided into two groups based on diet: a marginal Ca diet (70% of established Ca requirements) or an excess Ca diet (150% of established Ca requirements) for 4 weeks. Each group was then randomly sub-divided into two groups and fed diets with either marginal or excess dietary Ca for 6 weeks in a cross-over design, resulting in four treatment groups: H150-H150, H150-L70, L70-H150, and L70-L70. Animals were DXA scanned at 2 week intervals during the 10-week period to obtain whole body bone mineral content (BMC) and density (BMD). After animals were euthanized, right femurs were collected for this study. Traits such as bone mineral density, mass, volume, area moment of inertia (MI) and the section modulus (SM) were computed from computed tomography (CT) data and failure load was measured from four-point bending tests. DXA results showed significant reduction in BMC (61.6%) and BMD (37.5%) in the (L70-L70) group compared to the (H150-H150) group. DXA results additionally showed that deficiencies induced by the 4-week marginal Ca diet in the (L70-H150) group were not recovered with a subsequent excess Ca diet. While mechanical test results also showed significant reduction (75%) in strength in the L70-L70 group, compared to the H150-H150 group, they revealed no differences between the failure loads of the (L70-H150) group and the (H150-H150) group. Similar results were also found for bone mineral mass and volume, indicating that recovery from a short-term dietary Ca deficiency is possible at the pre-pubertal stage. Furthermore, bone mineral content and bone volume calculated from CT data correlated highly with failure load (R(2)=0.78 and 0.84, respectively), while density, MI and SM only showed weak-to-moderate correlations (R(2)=0.40-0.56), implying that bone mineral mass and volume calculated from CT data are good non invasive surrogates for strength of growing bones. PMID- 20920875 TI - Automatic microvolt T-wave alternans identification in relation to ECG interferences surviving preprocessing. AB - The aim was to investigate the effect of interferences surviving preprocessing (residual noise, baseline wanderings, respiration modulation, replaced beats, missed beats and T-waves misalignment) on automatic identification of T-wave alternans (TWA), an ECG index of risk for sudden cardiac death. The procedures denominated fast-Fourier-transform spectral method (FFTSM), complex-demodulation method (CDM), modified-moving-average method (MMAM), Laplacian-likelihood-ratio method (LLRM), and adaptive-match-filter method (AMFM) were applied to interferences-corrupted synthetic ECG tracings and Holter ECG recordings from control-healthy subjects (CH-group; n=25) and acute-myocardial-infarction patients (AMI group; n=25). The presence of interferences in simulated data caused detection of false-positive TWA by all techniques but the FFTSM and AMFM. Clinical applications evidenced a discrepancy in that the FFTSM and LLRM detected no more than one TWA case in each population, whereas the CDM, MMAM, and AMFM detected TWA in all CH-subjects and AMI-patients, with significantly lower TWA amplitude in the former group. Because the AMFM is not prone to false-positive TWA detections, the latter finding suggests TWA as a phenomenon having continuously changing amplitude from physiological to pathological conditions. Only occasional detection of TWA by the FFTSM and LLRM in clinics can be ascribed to their limited ability in identifying TWA in the presence of interferences surviving preprocessing. PMID- 20920876 TI - Autophagy induction by the 30-100kDa fraction of areca nut in both normal and malignant cells through reactive oxygen species. AB - Areca nut (AN) is an addictive carcinogen used by about 200-600 million people worldwide. Some AN components are shown to induce apoptosis; however, we previously demonstrated that AN extract (ANE) and the 30-100kDa fraction of ANE (ANE 30-100K) induced autophagy-like responses, such as swollen cell morphology, empty cytoplasm, acidic vesicles, and LC3-II accumulation, in an oral cancer cell line, OECM-1. To further assess the responses of other cell types to ANE 30-100K, we used both normal and malignant cells as the targets of ANE 30-100K and found that normal oral fibroblasts (CMT415), peripheral blood lymphocytes (PBLs), Jurkat leukemia T cells, and esophageal carcinoma cells (CE81T/VGH) exhibited similar responses after ANE 30-100K challenge. ANE 30-100K drastically increased acidic vesicle-containing PBLs isolated from two independent donors (from 0.1% to 92.1% and 2.9% to 64.2%). Furthermore, both ANE- and ANE 30-100K-induced LC3-II accumulation in CMT415 and CE81T/VGH was further increased in the presence of the lysosomal protease inhibitors (pepstatin A, E64d, and leupeptin). On the other hand, ANE 30-100K also increased the level of intracellular reactive oxygen species (ROS), and the ROS scavengers, N-acetylcysteine (NAC) and Tiron, inhibited ANE 30-100K-induced cell death and LC3-II accumulation. Collectively, these results suggest the existence of an autophagy-inducing AN ingredient (AIAI) in ANE 30-100K, which renders ANE as an autophagic flux inducer through ROS in both normal and malignant cells. PMID- 20920877 TI - Phase II study of vinorelbine/cetuximab in patients with recurrent/metastatic squamous cell carcinoma of the head and neck progressing after at least two chemotherapy regimens. AB - The aim of the present study was to identify a potentially effective new treatment regimen for patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck in disease progression after at least two previous chemotherapy regimens. The "novel" regimen was Cetuximab administered weekly plus Vinorelbine on days 1, 8, 15 every 28days. The regimen was administered to patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck previously treated with surgery, radiotherapy or both and progressing after at least two chemotherapy regimens. Twenty-four patients with histologically confirmed tumors of oral cavity, oropharynx, hypopharynx and larynx were enrolled. All patients were stage IV and 91.6% had an ECOG PS 0-1. After 3 cycles of treatment 23 patients (95.8%) were evaluable for response: 4 patients had partial response; 12 stable disease and 7 progressive disease. Disease control rate was 69.5%. At a median follow-up of 21.3months, the median progression-free survival was 5.8months. Median duration of response was 5.2months. At May 2010, 11/24 (45.8%) patients were alive. The safety profile was quite good. The present study shows that the combination of Vinorelbine and Cetuximab in recurrent and/or metastatic squamous cell carcinoma of the head and neck patients is effective, feasible and has a good safety profile. Our findings warrant further investigation in a wider patient population. PMID- 20920878 TI - Oropharyngeal squamous cell carcinoma: a unique disease on the rise? AB - Despite successful efforts to control tobacco and alcohol consumption in the western world, several developed countries report rising oropharyngeal squamous cell carcinoma (OPSCC) incidence figures, specifically in young individuals. Similar to anogenital cancers, a significant proportion of OPSCC (up to 60%) is caused by sexually acquired HPV infection and the rise in OPSCC has been attributed to changing sexual behaviours in the Western World. Accordingly, patients with HPV-positive OPSCC report divergent sexual histories and absence of classical risk factors as tobacco and alcohol exposure compared to patients with HPV-negative OPSCC. The profile of HPV-positive OPSCC differs from HPV-negative OPSCC in several other significant aspects, including a unique molecular biologic tumor characteristics and improved clinical behaviour. Thus, a further increase in HPV-positive OPSCC will impact significantly upon clinical management of OPSCC, unless it is halted by adequate preventive measures aimed at reduction of HPV-associated disease. HPV vaccination has been recently offered to young females in an attempt to reduce HPV-induced cervical cancer and may ultimately result in a decline of OPSCC incidence as well. Until then, close collaboration between otolaryngologists/head and neck surgeons and anogenital/genitourinary specialists is warranted to optimize clinical management of HPV-induced malignancy and improve detection of second primary tumor development. PMID- 20920879 TI - Impact of different surgical margin conditions on local recurrence of oral squamous cell carcinoma. AB - The purpose of this study was to analyze the impact of different surgical margin conditions on local recurrence of oral squamous cell carcinoma (SCC) in 148 consecutive patients who underwent planned radical resection of oral SCC. The patients were classified into four categories according to the status of the surgical margin: clear (no SCC within 5mm, n=103), close (SCC within 5mm, n=21), dysplasia (dysplastic epithelium at margin, n=13), and involved (SCC at margin, n=11). Cox's proportional hazard model showed that the status of the surgical margin had a significant impact on local recurrence (p<0.003); hazard ratio was 3.79 (95%CI: 1.17-12.28) with a close and 7.89 (2.38-26.17) with an involved margin. The presence of mucosal dysplasia at the surgical margin was also a significant predictor of local recurrence (hazard ratio: 5.29, 95%CI: 1.31 21.29). Local recurrence was observed only with severe dysplasia, while no recurrence with mild and moderate dysplasia. In the patients with a clear and closed surgical margin, local recurrence was related with T4 tumor and an advanced mode of tumor invasion. The results of this study suggested that the presence of tumor cells at or close to the surgical margin increased the risk of local recurrence. The presence of dysplastic epithelium (especially severe dysplasia) at the mucosal surgical margin has a significant impact on local control. It was also suggested that not simply the width of the free margin but also clinical and histological risk factors should be included in deciding the necessity for adjuvant radiotherapy. PMID- 20920880 TI - Criteria to define true second primary oral squamous cell carcinoma. PMID- 20920881 TI - Phototropin signaling and stomatal opening as a model case. AB - Phototropins are plant-specific light-activated receptor kinases that regulate diverse blue-light-induced responses, and serve to optimize plant growth under various light environments. Phototropins undergo autophosphorylation as an essential step for their signaling and induce a variety of tissue-specific or organ-specific responses, but the divergent mechanisms for these responses are unknown. It is most likely that the phototropins generate a specific output after the event of autophosphorylation. In this report, we will review the common steps of phototropin signaling and the numerous interactive proteins of phototropins, which may act as signal transducers for the diverse responses. We also describe the phototropin-mediated signaling process of stomatal guard cells and its crosstalk with abscisic acid signaling. PMID- 20920882 TI - Alarming beta-lactamase-mediated resistance in multidrug-resistant Enterobacteriaceae. AB - Resistance to beta-lactams and other antibiotics in the Enterobacteriaceae is frequently associated with plasmidic resistance determinants that are easily transferred among species. beta-Lactamase-mediated resistance is increasingly associated with plasmid-encoded extended-spectrum beta-lactamases (ESBLs) and carbapenemases, specifically the CTX-M family of ESBLs, the KPC family of serine carbapenemases, and the VIM, IMP, and NDM-1 metallo-beta-lactamases. Although clonal dispersion of resistant isolates was seen initially, more diverse genetic platforms are being observed as variations of mobile elements are transferred worldwide. These enzymes are now appearing in multiple combinations of ESBLs and carbapenemases, thereby conferring resistance to virtually all beta-lactam antibiotics. PMID- 20920883 TI - Glycopeptide biosynthesis in the context of basic cellular functions. AB - Using molecular genetics, biochemistry and organic chemistry the biosynthesis of glycopeptides has been elucidated in detail. It can be categorised in three parts: precursor supply, linking of the peptide backbone and modification reactions. The important steps of the biosynthesis are carried out at a multi enzyme complex consisting of three non-ribosomal peptide synthetases (NRPS), three oxygenases and one halogenase. Novel derivatives can be generated by precursor-directed biosynthesis or combinatorial approaches and the knowledge can be used to optimise the yield of production by metabolic engineering approaches. To protect themselves glycopeptide producers seem to have developed strategies which may differ from those of the resistant pathogens. PMID- 20920884 TI - Endocytosis in filamentous fungi: Cinderella gets her reward. AB - Endocytosis has been the Cinderella of membrane trafficking studies in filamentous fungi until recent work involving genetically tractable models has boosted interest in the field. Endocytic internalization predominates in the hyphal tips, spatially coupled to secretion. Early endosomes (EEs) show characteristic long-distance motility, riding on microtubule motors. The fungal tip contains a region baptised the 'dynein loading zone' where acropetally moving endosomes reaching the tip shift from a kinesin to dynein, reversing the direction of their movement. Multivesicular body biogenesis starts from these motile EEs. Maturation of EEs into late endosomes and vacuoles appears to be essential. The similarities between fungal and mammalian endocytic trafficking suggest that conditional mutant genetic screens would yield valuable information. PMID- 20920885 TI - Synthesis, characterization, spectrophotometric, structural and antimicrobial studies of the newly charge transfer complex of p-phenylenediamine with pi acceptor picric acid. AB - Charge transfer complex (CTC) of donor, p-phenylenediamine (PPD) and acceptor, 2,4,6-trinitrophenol (picric acid) has been studied in methanol at room temperature. The CT complex was synthesized and characterized by elemental analysis, FTIR spectra, 1H NMR spectroscopy and electronic absorption spectra which indicate the CT interaction associated with proton migration from the acceptor to the donor followed by hydrogen bonding via N+-H?O-. The thermal stability of CT complex was studied using TGA and DTA analyses techniques. The CT complex was screened for its antifungal activity against Aspergillus niger (Laboratory isolate), Candida albicans (IQA-109) and Penicillium sp. (Laboratory isolate) and antibacterial activity against two Gram-positive bacteria Staphylococcus aureus (MSSA 22) and Bacillus subtilis (ATCC 6051) and two Gram negative bacteria Escherichia coli (K 12) and Pseudomonas aeruginosa (MTCC 2488). It gives good antimicrobial activity. The stoichiometry of the CT complex was found to be 1:1. The physical parameters of CT complex were evaluated by the Benesi-Hildebrand equation. On the basis of the studies, the structure of CT complex is [(PPDH)+(PA)-], and a general mechanism for its formation is proposed. PMID- 20920887 TI - TMS-induced artifacts on EEG can be reduced by rearrangement of the electrode's lead wire before recording. AB - OBJECTIVE: Our purpose was to establish a technique to reduce residual artifacts after transcranial magnetic stimulation (TMS) from electroencephalographic (EEG) signals. METHODS: We investigated the effects of coil direction and stimulus intensity on residual artifacts in an artificial circuit, and tested whether or not the size of the circuit area affects the residual artifact (the model study). Based on the results, the optimization by rearranging the electrode's lead wire was tested on the human scalp (the human study). RESULTS: The residual artifact after TMS was dependent on the direction of the figure-of-eight coil, and on the artificial circuit area size. CONCLUSIONS: In accordance with the model study, the scalp EEG shows that TMS-induced artifacts can be reduced dramatically before the amplifier input stages in TMS-EEG experiments by a step-wise procedure rearranging the lead wires relative to the fixed coil orientation. SIGNIFICANCE: Our technique makes it possible to significantly reduce the residual artifacts from recordings of short-latency TMS-evoked potentials. PMID- 20920888 TI - Nightmare and sleep paralysis among Japanese adolescents: a nationwide representative survey. AB - OBJECTIVE: The objective of this study was to clarify the prevalence of nightmares and sleep paralysis and associated factors among Japanese adolescents. METHODS: This study was designed as a cross-sectional sampling survey. The targets were junior and senior high schools throughout Japan. Self-reported anonymous questionnaires were sent to schools for all students to complete. RESULTS: A total of 90,081 questionnaires were analyzed. The overall response rate was 62.6%, and the prevalence of nightmares and sleep paralysis was 35.2% and 8.3%, respectively. Multiple logistic analyses revealed that female sex, drinking alcohol, poor mental health, difficulty initiating sleep, low subjective sleep assessment, presence of excessive daytime sleepiness, and presence of sleep paralysis had higher odds ratios than others for nightmares. Male sex, poor mental health, drinking alcohol, taking a long daytime nap, early or late bedtime, difficulty initiating sleep, low subjective sleep assessment, presence of excessive daytime sleepiness, and presence of nightmares had higher odds ratios than other factors for sleep paralysis. CONCLUSIONS: This study has revealed the prevalence of nightmares and sleep paralysis among Japanese adolescents. Furthermore, the results of this study suggest that it is important to maintain regular sleep habits for preventing these symptoms. We propose that health education about regular sleep habits should be promoted among Japanese adolescents. PMID- 20920889 TI - Humoral 'reactome' profiles using peptide microarray chips. PMID- 20920890 TI - Piggy-backing the concept of cancer drugs for schistosomiasis treatment: a tangible perspective? AB - The fear that schistosomes will become resistant to praziquantel (PZQ) motivates the search for alternatives to treat schistosomiasis. Recent studies of signaling proteins in schistosomes uncovered a way of achieving this goal relatively quickly. It was shown that protein kinases (PKs) control important biological processes in schistosomes. Concurrently, the involvement of mutant forms of PKs was demonstrated in the etiology of cancer. Therefore, different anticancer drugs have been developed to inhibit deregulated PKs. These can also inhibit schistosome PKs, thus blocking parasite development. Recent studies characterizing schistosome PKs are summarized and we discuss the concept of PK inhibitors, including approved cancer drugs, as novel candidate anti-schistosome agents. This is also likely to be of significance for other worm infections. PMID- 20920891 TI - Outcomes of vitrified-warmed day-4 embryos after day-3 cleavage-stage biopsy. AB - The objective of this study was to compare the post-warming survival rates of biopsied and non-biopsied day-3 embryos vitrified on day 4 and to evaluate the clinical outcomes of following transfers. This study included 18 preimplantation genetic diagnosis (PGD) patients and 18 non-PGD patients treated between January 2005 and January 2009 who had not achieved live births during their fresh embryo transfer cycles and whose surplus embryos were cryopreserved on day 4. The embryo survival rate after warming in the PGD and non-PGD groups was similar (53/59, 89.8% versus 55/64, 85.9%, respectively; difference of 3.9% 95% CI -7.3 to 13.4). Vitrified embryo-transfer cycles yielded no significant differences between PGD and non-PGD groups in implantation rates (12/46, 26.1% versus 9/47, 19.1%, respectively; difference of 6.9%, 95% CI -9.7 to 22.2), clinical pregnancy rates (11/18, 61.1% versus 9/18, 50%, respectively; difference of 11.1%, 95% CI -20.6 to 40.6) and live birth rates (9/18, 50% versus 6/18, 33.3%, respectively; difference of 16.7%, 95% CI -15.1 to 44.8). These results showed that, in PGD cycles, embryos can be vitrified effectively on day 4 after biopsy on day 3. The objective of this study was to compare the post-warming survival rates of biopsied and non-biopsied day-3 embryos that vitrified on day 4 and to evaluate the clinical outcomes of following transfers. This retrospective study included 18 preimplantation genetic diagnosis (PGD) and 18 non-PGD patients treated between January 2005 and January 2009 who had not achieved live births during their fresh embryo transfer cycles and whose surplus were frozen on day 4. After warming in frozen embryo-transfer cycles, embryo survival with respect to embryo grades, implantation, clinical pregnancy and live birth rates were compared. The embryo survival rate after warming in the PGD group was similar to the survival rate in the non-PGD group (53/59, 89.8% versus 55/64, 85.9%, respectively; difference of 3.9%, 95% CI -7.3 to 13.4, P=0.701). Frozen embryo transfer yielded no significant differences between PGD and non-PGD groups in implantation rates (12/46, 26.1% versus 9/47, 19.1%, respectively; difference of 6.9%, 95% CI -9.7 to 22.2, P=0.581), clinical pregnancy rates (11/18, 61.1% versus 9/18, 50%, respectively; difference of 11.1%, 95% CI -20.6 to 40.6, P=0.737) or live birth rates (9/18, 50% versus 6/18, 33.3%, respectively; difference of 16.7%, 95% CI 15.1 to 44.8, P=0.499). These results showed that, in PGD cycles, embryos can be vitrified effectively on day 4 after biopsy on day 3. PMID- 20920892 TI - Differences in corpus callosum volume and diffusivity between temporal and frontal lobe epilepsy. AB - We analyzed volume and diffusivity measures of the corpus callosum (CC) in patients with temporal (TLE) and frontal (FLE) lobe epilepsy in comparison with healthy subjects. On high-resolution T1-weighted scans of 18 controls and 44 patients the volumes (cm(3)) of Witelson regions (WRs) and the entire CC were measured. The apparent diffusion coefficients (ADCs, 10(-5)mm(2)s(-1)) for the entire CC and three areas of interest were measured from co-registered ADC maps. The CC of patients with TLE and FLE, corrected for total brain volume, was smaller than that of controls. Patients' ADC values were higher than those of controls. Findings were significant for WR1, WR2, and WR6, the CC regions connecting the frontal and temporal lobes. Patients with FLE had smaller WR1 and higher ADC values; in patients with TLE, the findings were similar for WR6. Atrophy and increased diffusivity in subregions of the CC connecting homotopic contralateral cortical regions indicate anatomical abnormalities extending beyond the epileptogenic zone in FLE and TLE. PMID- 20920893 TI - Ictal consciousness in epilepsy and nonepileptic attack disorder. AB - Exploration of subjective experiences during seizures may enhance knowledge of the differing natures of epilepsy and nonepileptic attack disorder (NEAD). We performed a quantitative evaluation of both the general level of awareness and the specific contents of consciousness during seizures using the Ictal Consciousness Inventory (ICI). Ninety-five adult outpatients attending general neuropsychiatry and epilepsy clinics with established diagnoses of either epilepsy (n = 66) or NEAD (n = 29) completed one ICI for each witnessed seizure recalled. Patients with a dubious/dual diagnosis were excluded. ICI Level (ICI-L) and ICI Content (ICI-L) scores were calculated for the 167 questionnaires generated by patients with epilepsy (n = 119, of which 58 from patients with temporal lobe epilepsy, 14 frontal lobe epilepsy, and 47 idiopathic 30 generalized epilepsy) and patients with NEAD (n = 48). Mann-Whitney U tests revealed statistically significant higher ICI-L and ICI-C scores for patients with NEAD (both P = 0.01). Subjective reports of consciousness experiences varied between epilepsy and NEAD, with patients with NEAD reporting significantly greater levels of general awareness/responsiveness and more vivid subjective experiences during attacks. The ICI is proposed as a potentially useful self report instrument to supplement clinical and instrumental tests for the differential diagnosis of epilepsy and NEAD. PMID- 20920894 TI - Cannabinoid subtype-2 receptors modulate the antihyperalgesic effect of WIN 55,212-2 in rats with neuropathic spinal cord injury pain. AB - BACKGROUND CONTEXT: There is increasing evidence for a role of the cannabinoid (CB) system in the development of neuropathic pain (NP) after spinal cord injury (SCI). The nonspecific CB1 and CB2 receptor agonists, WIN 55, 212-2 (WIN), have previously been shown to alleviate both mechanical and thermal hyperalgesia (TH) after peripheral nerve injury. PURPOSE: The present study was designed to identify the CB receptors involved in the antihyperalgesic effect of WIN by using selective antagonists for CB1 and CB2 receptors. STUDY DESIGN: This is an in vivo and behavioral study using a moderate T9 contusion SCI. After injury, TH of the hind paws was measured on postinjury days 21 through 42. METHODS: Sprague-Dawley rats underwent a contusion SCI using the Multicenter Animal Spinal Cord Injury Study (MASCIS) weight-drop impactor, which induced a moderate T9 SCI. Only animals showing consistent plantar stepping and consistent forelimb and hind limb coordination (Basso, Beattie, and Bresnahan score=15) were tested for TH. Animals exhibiting decreased withdrawal latency time, indicating TH, on or before Day 42, were selected for pharmacological intervention. Animals not exhibiting TH did not receive pharmacological intervention and were sacrificed. Rats underwent hind paw testing before any drug administration (after injury), 45 minutes after selective CB antagonist (AM 251 or AM 630) administration (postantagonist) and again 45 minutes after WIN administration (post-WIN). There were a total of seven treatment groups: saline vehicle control; Dimethyl sulfoxide (DMSO) vehicle control; low-dose WIN (0.2 mg/kg); and high-dose WIN (2.0 mg/kg); AM 251 (3 mg/kg) and AM 630 (1 mg/kg) were given subcutaneously in a total volume of 0.5 mL. Followed by intraperitoneal injection of WIN after each antagonist, sham operated rats repeated pharmacological intervention used with treatment Groups 5 and 6. RESULTS: Thermal hyperalgesia was significantly ameliorated in a dose dependent manner with systemically administered WIN. Cannabinoid receptor Type 1 antagonist AM 251 pretreatment did not affect the antihyperalgesic effect of WIN. By contrast, pretreatment with the CB2 receptor antagonist AM 630 significantly attenuated the effect of WIN. CONCLUSION: Taken together, these results suggest a role of the CB2 receptor in modulating SCI-induced TH. Selective activation of the CB2 receptor could potentially lead to analgesic effects on NP while avoiding psychotropic side effects in patients with SCI. PMID- 20920895 TI - Abnormal electrochemical skin conductance in cystic fibrosis. AB - BACKGROUND: Electrochemical skin conductance measurement is an active electrophysiologic method in which incremental low direct voltage is applied on the skin. It generates a current due to reverse iontophoresis which previous studies suggested to be mostly related to chloride anion movements. As sweat chloride movements upon electric stimulation were likely to be impaired in cystic fibrosis (CF) patients, we designed a proof-of-concept study to measure electrochemical skin conductance in CF patients and control subjects and to test the ability of this method to discriminate CF from controls. METHODS: Electrochemical skin conductance was measured in 41 adult patients with classical CF and 20 healthy control subjects. Patients placed their hands and feet on nickel electrodes and an incremental low direct voltage was applied on the anode during 2min. The resulting voltage on the cathode and the current generated between anode and cathode were measured and from them, two electrochemical skin conductance variables were calculated: ESC, obtained when a low voltage of 1.6V was applied, and dESC which took into account electrochemical skin conductances obtained when low and high voltages were applied. RESULTS: ESC measurements on hands and feet were significantly different in CF patients (on feet: 75+/ 10MUSi), as compared with control subjects (62+/-13MUSi, p<0.0001); dESC was also significantly different and more discriminative in CF patients (on feet: 34+/ 24MUSi), as compared with control subjects (93+/-24MUSi, p<0.0001). dESC measurement provided a diagnostic specificity of 1 and a sensitivity of 0.93. CONCLUSIONS: These results show that electrochemical skin conductance which is easily and rapidly measured is abnormal in CF patients. Trial registry name in the European Clinical Trials Database (eudraCT): "EZSCAN MUCO1: Mesure de la conductance cutanee par chronoamperometrie", N degrees EUDRACT: 2007-A00221-52. PMID- 20920896 TI - Improved early diagnosis of Pseudomonas aeruginosa by real-time PCR to prevent chronic colonisation in a paediatric cystic fibrosis population. AB - Early detection of Pseudomonas aeruginosa in children with cystic fibrosis is hampered by the need to process a sub-optimal specimen type, namely cough swabs, which are known to have a lower positive yield than sputa or more invasive samples. This delay in the detection of low levels of P. aeruginosa could potentially result in the loss of an opportunity to initiate early aggressive antibiotic therapy and result in chronic colonisation, with a poorer overall prognosis. Quantitative real-time PCR (qPCR) offers an opportunity to increase the detection rate of P. aeruginosa compared to traditional culture techniques. This study examined 500 cough swabs and 42 sputum samples from paediatric patients and showed that detection of P. aeruginosa could be increased in both sample types by 100% and 45% respectively. Overall the sensitivity was 100% and specificity of 58% when compared to culture as a gold standard. These results although initially promising require careful consideration both from a treatment and infection control standpoint as the significance of detection of very low levels of P. aeruginosa is unclear. PMID- 20920897 TI - [Peritoneal dialysis: a satisfactory experience of a misknown technique in Rabat University Hospital]. AB - Peritoneal dialysis (PD) is a renal replacement therapy method that could be proposed in the first intention for the treatment of end stage renal disease (ESRD). The aim of the study is to describe the beginning and development of PD in "Ibn Sina" University Hospital in Rabat, and to evaluate the outcome of the patients treated by this technique. PATIENTS AND METHODS: It is a descriptive study between July 2006 and December 2009, including 41 ESRD patients treated by PD. PD parameters as well as clinical and biological data were collected and analyzed. RESULTS: The average age of our patients was 45.8+/-17.4-year-old. The sex-ratio (M/F) was 1.9. Professionally active patients (50%) as well as students (14) kept their activity throughout the study. Initially, 68.2% of the patients had hypertension whereas, at the end of the study, only 25.8% still suffered from hypertension. A better quality of dialysis as well as the conservation of a residual renal function were ensured in PD with 92.6% of the patients having a residual clearance higher than 2 mL/min. A correction of anemia was noted with higher rates of hemoglobin after the beginning of the treatment by peritoneal dialysis. None of our cases presented a denutrition and all our diabetic patients did not worsen with the exchanges in PD. DISCUSSION AND CONCLUSION: PD has recently been introduced in Morocco. It must be encouraged and sustained. In our study, we noted a good quality of dialysis and a conservation of the residual renal function. These results should encourage the promotion of this technique, especially that there is an inequality of distribution of hemodialysis centers in Morocco and the inability to deal with all ESRD patients. Furthermore, renal transplantation is not always possible in our country. For that, a specific program of information of both generalists and specialists, especially nephrologists must be established. PMID- 20920898 TI - [Acute renal failure due to malignant lymphoma infiltration]. AB - We present two cases of renal lymphoma revealed by acute renal failure (ARF), which remains a rare clinical entity. Case 1 was a 29-year-old man with an ARF. The diagnosis was a primitive kidney immunophenotype B lymphoma. The patient died after three courses of chemotherapy due to rapid spread lymphoma. The second case was a high-grade renal lymphomatous infiltration, with an unusual computer tomography image of two large kidneys compressing the stomach. Death happened early before initiating therapy. In both cases the diagnosis has been established by renal pathology. Early diagnosis is a key component of therapeutic success, however, the rapid spread of lymphoma worsened renal and vital prognosis. PMID- 20920899 TI - Effect of chromosome instability on the maintenance and differentiation of human embryonic stem cells in vitro and in vivo. AB - The therapeutic potential of human embryonic stem cells (hESCs) has long been appreciated, and the recent FDA approval of hESC derivatives for cell-based therapy encourages the clinical application of hESCs. Here, using CHA3-hESCs with normal and abnormal karyotypes, we report the importance of maintaining normal chromosomes during in vitro culture and the differentiation of hESCs for minimization of posttransplantation complications. We found that undifferentiated CHA3-hESCs with trisomy chromosome 12 undergo abnormal cell division with multiple spindles in comparison to the bipolar cell division of the karyotypically normal CHA3-hESCs. Transplanted karyotypically abnormal CHA3-hESC derivatives formed a tumor-like tissue 6weeks after transplantation in two out of seven mice tested. Our results demonstrate that the preservation of normal chromosomes is indispensable for maintaining the true properties of hESCs in vitro and abolishing adverse effects posttransplantation. Thus, the development of optimized techniques for stabilizing the chromosome state during in vitro hESC culture is a prerequisite for the therapeutic application of hESCs. PMID- 20920900 TI - One-step generation of murine embryonic stem cell-derived mesoderm progenitors and chondrocytes in a serum-free monolayer differentiation system. AB - Cartilage defects have limited capacity for repair and are often replaced by fibrocartilage with inferior mechanical properties. To overcome the limitations of artificial joint replacement, high-throughput screens (HTS) could be developed to identify molecules that stimulate differentiation and/or proliferation of articular cartilage for drug therapy or tissue engineering. Currently embryonic stem cells (ESCs) can differentiate into articular cartilage by forming aggregates (embryoid body (EB), pellet, micromass), which are difficult to image. We present a novel, single-step method of generating murine ESC-derived chondrocytes in monolayer cultures under chemically defined conditions. Mesoderm induction was achieved in cultures supplemented with BMP4, activin A, or Wnt3a. Prolonged culture with sustained activin A, TGFbeta3, or BMP4 supplementation led to robust chondrogenic induction. A short pulse of activin A or BMP4 also induced chondrogenesis efficiently while Wnt3a acted as a later inducer. Long-term supplementation with activin A or with activin A followed by TGFbeta3 promoted articular cartilage formation. Thus, we devised a serum-free (SF) culture system to generate ESC-derived chondrocytes without the establishment of 3D cultures or the aid of cell sorting. Cultures were governed by the same signaling pathways as 3D ESC differentiation systems and limb bud mesenchyme or articular cartilage explant cultures. PMID- 20920901 TI - Impact of the Quality assured Mamma Diagnostic (QuaMaDi) programme on survival of breast cancer patients. AB - OBJECTIVE: To evaluate the effect of the Quality assured Mamma Diagnostic programme (QuaMaDi) introduced in 2001 on breast cancer and mortality on a population basis. QuaMaDi provides a standardized diagnostic process for symptomatic or at risk women of all ages. The process includes independent double reading of mammograms, additional ultrasound, and if suspicious an expert reading and assessment. We tested the hypothesis that QuaMaDi has influenced breast cancer epidemiology and survival positively. METHODS: The QuaMaDi cohort of breast cancer patients, diagnosed within the programme between 2001 and 2007, was linked to the cancer registry dataset of all breast cancer cases in Schleswig Holstein, Germany. By this record-linkage procedure participants of QuaMaDi could be marked in the cancer registry data. Overall survival rates of 3096 patients diagnosed within QuaMaDi were compared to 5417 patients diagnosed outside QuaMaDi, matched by year of diagnosis, using multivariate Cox proportional hazard models. RESULTS: Crude hazard ratio for overall survival was HR 0.43 (95% CI 0.35 0.52) for breast cancer cases detected inside QuaMaDi versus those diagnosed outside the programme. After stepwise adjustment for age, grading, histology, treatment, and tumour stage, the survival advantage in QuaMaDi diagnosed breast cancer patients was still statistically significant (HR 0.78, 95% CI 0.64-0.96). CONCLUSION: Evidence is provided that the QuaMaDi programme has a beneficial impact on the first 5-year overall survival rate after breast cancer beyond a favourable tumour stage distribution. Thus, we conclude that QuaMaDi contributes to improved health care for women, who are not eligible for mammography screening. PMID- 20920902 TI - Conservative treatment of big yolk sac tumour of the ovary in young girl. AB - We present the case of a large yolk sac tumour of the ovary in a 14-year-old girl with high level of serum alpha-feto-protein (AFP). Multidisciplinary care is important to do appropriate surgical treatment with the aim of fertility preservation. PMID- 20920903 TI - Surgical approach to the juxtahepatic veins. PMID- 20920904 TI - Risk of biliary complications in bariatric surgery. AB - Gallstones are commonly observed after rapid weight loss, particularly after bariatric surgery. Preventive measures of gallstone formation and potential related complications are still debated. This study aimed to propose a standardized strategy according to the results of the literature. Thus, preventive measures should be determined according to patient status (evaluated clinically and by routine ultrasound) and the type of bariatric surgery. Cholecystectomy should be performed in patients with symptomatic gallstones irrespective of the planned operation, or for asymptomatic gallstones during a gastric by-pass. In other settings, ursodesoxycholic acid should be given postoperatively for 6 months. PMID- 20920905 TI - Single umbilical incision laparoscopic cholecystectomy: initial experience of the Coelio Club. AB - AIM: To assess the initial results of single umbilical incision laparoscopic cholecystectomies (SUILC) performed by the members of the Club Coelio. PATIENTS AND METHODS: This multicenter study involved 65 consecutive patients undergoing SUILC between September 2008 and December 2009. The operation was performed with a 0 degrees scope in 35 and with a 30 degrees scope in 30 patients. There were 56 women and nine men with a mean age of 49 +/- 14 years and a mean body mass index of 25 +/- 4. The main perioperative parameters analyzed were duration of operation, conversion, morbidity and duration of hospitalization. One month after surgery, the esthetic result was assessed by each patient on a visual analogue scale (VAS). A VAS score between 9 and 10 was considered as an excellent result. RESULTS: During laparoscopy, some degree of cholecystitis was seen in 10 patients. Intraoperative cholangiography was performed in 57 patients and the mean duration of operation was 68 +/- 22 min. Conversion to conventional laparoscopic cholecystectomy (CLC) was required in eight patients (12%). We noted three complications (4%): two wound abscesses and one hemoperitoneum. The mean hospital stay was 2 +/- 1 days. The esthetic result was considered as excellent by 45 patients (69%). Multivariable analysis revealed that duration of operation was shorter after five procedures (61 +/- 25 vs. 72 +/- 18 min, regression coefficient: -7, P<0.032) and when a 30 degrees scope was used (56 +/- 18 vs. 76 +/- 20 min, regression coefficient: -14, P<0.011), the conversion rate was higher in cholecystitis (60% [6/10] vs. 4% [2/55], OR: 33, P<0.002) and the percentage of excellent esthetic results was greater in patients who did not required a conversion to CLC (77% [44/57] vs. 12% [1/8], OR: 18, P<0.012). CONCLUSIONS: Our study showed that SUILC is feasible with low morbidity but duration of operation is long and conversion to CLC is frequent in cholecystitis. However, duration of operation decreases with rising experience of the surgeon and when a 30 degrees scope is used. The major value of this technique is cosmetic. PMID- 20920906 TI - Patient positioning in laparoscopic surgery: tricks and tips. PMID- 20920907 TI - Gastric bypass. Principles, complications, and results. PMID- 20920908 TI - Where eagles dare. PMID- 20920910 TI - A newly identified transcriptional network for mesenchymal transformation of brain tumors: potential targets for therapeutic intervention. PMID- 20920912 TI - An international initiative to define the role for surgery for spinal metastases: the GSTSG. PMID- 20920913 TI - Transcranial magnetic stimulation may provide benefit in acute ischemic stroke. PMID- 20920914 TI - Neurosciences on Everest. PMID- 20920915 TI - Clipping versus coiling: the total hospital cost of aneurysm treatment. PMID- 20920916 TI - Expanding nepalese neurosurgery: challenges and opportunities. PMID- 20920917 TI - Devastation after the Haiti Earthquake: a neurosurgeon's Journal. PMID- 20920918 TI - The musical brain: myth and science. PMID- 20920919 TI - The magical power of music. PMID- 20920920 TI - Mind-Brain Identity Theory and the musical experience. PMID- 20920921 TI - Music and the brain. PMID- 20920922 TI - Microneurosurgical management of anterior choroidal artery aneurysms. PMID- 20920923 TI - Erythropoietin and subarachnoid hemorrhage. PMID- 20920924 TI - Erythropoietin: will it improve outcome after subarachnoid hemorrhage? PMID- 20920925 TI - The quantitative time-resolved near infrared spectroscopy (TR-NIRs) for bedside cerebrohemodynamic monitoring after aneurysmal subarachnoid hemorrhage: can we predict delayed neurological deficits? PMID- 20920926 TI - Why do we not have resolution on an ancient disease of the spine? PMID- 20920927 TI - Treatment of isthmic spondylolisthesis: still controversial. PMID- 20920928 TI - Using lumbar interspinous anchor with transforaminal lumbar interbody fixation. PMID- 20920929 TI - Extradural spinal nerve transfer for bladder reinnervation. PMID- 20920930 TI - Arab Islamic medical revelations. PMID- 20920931 TI - From atom to brain: applications of molecular imaging to neurosurgery. AB - Molecular imaging is a field born out of the happy marriage of molecular biology and radiology. The first installment of this two-part series on molecular imaging demonstrated basic principles for practitioners in the field of the neurosciences. This installment seeks to provide some illustrative examples, insights, and specific applications to the neurosciences. The fields of functional neurosurgery including the treatment of neuropsychiatric disorders, novel treatments and imaging of tumors, neuroregenerative medicine, and nanotechnology in vascular disorders are covered. Finally, we give some parting thoughts on the future of molecular imaging, including advances in the imaging of neurodegenerative disorders. PMID- 20920932 TI - Microneurosurgical management of anterior choroid artery aneurysms. AB - OBJECTIVE: Anterior choroid artery aneurysms (AChAAs) constitute 2%-5% of all intracranial aneurysms. They are usually small, thin walled with one or several arteries originating at their base, and often associated with multiple aneurysms. In this article, we review the practical microsurgical anatomy, the preoperative imaging, surgical planning, and the microneurosurgical steps in the dissection and the clipping of AChAAs. METHODS: This review, and the whole series on intracranial aneurysms (IAs), are mainly based on the personal microneurosurgical experience of the senior author (J.H.) in two Finnish centers (Helsinki and Kuopio) that serve, without patient selection, the catchment area in Southern and Eastern Finland. RESULTS: These two centers have treated more than 10,000 patients with IAs since 1951. In the Kuopio Cerebral Aneurysm Database of 3005 patients with 4253 IAs, 831 patients (28%) had altogether 980 internal carotid artery (ICA) aneurysms, of whom 95 patients had 99 (2%) AChAAs. Ruptured AChAAs, found in 39 patients (41%), with median size of 6 mm (range = 2-19 mm), were associated with intracerebral hematoma (ICH) in only 1 (3%) patient. Multiple aneurysms were seen in 58 (61%) patients. CONCLUSIONS: The main difficulty in microneurosurgical management of AChAAs is to preserve flow in the anterior choroid artery originating at the base and often attached to the aneurysm dome. This necessitates perfect surgical strategy based on preoperative knowledge of 3 dimensional angioarchitecture and proper orientation during the microsurgical dissection. PMID- 20920933 TI - Erythropoietin for the treatment of subarachnoid hemorrhage: a review. AB - OBJECTIVE: Subarachnoid hemorrhage (SAH) has a worldwide incidence of approximately 10.5 cases per 100,000 person-years and constitutes 3% of all strokes. Erythropoietin (EPO) has recently been proposed for the treatment of a variety of brain diseases, including SAH, because of its neuroprotective effects. Hence, the current evidence in the published literature was reviewed to determine the potential utility of EPO in the treatment of SAH. METHODS: A careful retrospective review of the literature was performed to determine the potential benefit of employing EPO in the treatment of SAH and its sequelae. RESULTS: Careful literature review revelaed that the use of EPO may not necessarily reduce the incidence of vasospasm after SAH, but it may reduce the severity and its eventual outcome. CONCLUSION: Given the recent trial results, a dose-escalation study and subsequent randomized trial should be considered. PMID- 20920934 TI - Bedside monitoring of cerebral blood oxygenation and hemodynamics after aneurysmal subarachnoid hemorrhage by quantitative time-resolved near-infrared spectroscopy. AB - BACKGROUND: Early detection of vasospasm is essential for the treatment of delayed ischemic neurological deficits in subarachnoid hemorrhage (SAH). We evaluated cerebral blood oxygenation (CBO) changes after SAH employing quantitative time-resolved near-infrared spectroscopy (TR-NIRS) for this purpose. METHODS: We investigated 11 age-matched controls and 14 aneurysmal SAH patients, including 10 patients with WFNS grade V and 4 patients with grade II. Employing TR-NIRS, we measured the cortical oxygen saturation (CoSO(2)) and baseline hemoglobin concentrations in the middle cerebral artery territory. Measurements of TR-NIRS and transcranial Doppler sonography (TCD) were performed repeatedly after SAH. RESULTS: In six patients, the CoSO(2) and hemoglobin concentrations remained stable after SAH; digital subtraction angiography (DSA) did not reveal vasospasm in these patients. In eight patients, however, CoSO(2) and total hemoglobin decreased abruptly between 5 and 9 days after SAH. DSA revealed diffuse vasospasms in six of eight patients. The reduction of CoSO(2) predicted occurrence of vasospasm at a cutoff value of 3.9%-6.4% with 100% of sensitivity and 85.7% of specificity. TCD failed to detect the vasospasm in four cases, which TR-NIRS could detect. Finally, TR-NIRS performed on Day 1 after SAH revealed significantly higher CoSO(2) than that of controls (p = .048), but there was no significant difference in total hemoglobin. CONCLUSION: TR-NIRS detected vasospasm by evaluating the CBO in the cortex and may be more sensitive than TCD, which assesses the blood flow velocity in the M1 portion. The cerebral oxygen metabolism in SAH might be reduced by brain damage due to aneurysmal rupture. PMID- 20920935 TI - Traumatic carotid-cavernous fistulas treated with covered stents: experience of 12 cases. AB - OBJECTIVE: Covered stents have recently become available for intracranial use, such as aneurysms, arterial dissections and carotid-cavernous fistulas (CCFs). However, there have been few reports of the successful application of covered stents for the treatment of traumatic CCFs (TCCFs). The purpose of this study is to investigate the efficacy and safety of endovascular treatment of TCCFs with covered stent. METHODS: Twelve consecutive patients with TCCFs treated with covered stent after initial failure of traditional techniques are presented. All the patients were followed up both clinically and angiographically for a mean of 22.5 months. RESULTS: Eleven of the 12 patients had covered stents placed successfully. In one case, the covered stent placement failed after multiple attempts because of the tortuous anatomy of the internal carotid artery (ICA). Complete occlusion was achieved in nine cases immediately after stent deployment. Endoleak was observed in case 4 and redilation was performed to avoid the endoleak. In case 8, improved symptoms recurred the next morning, and cerebral angiogram revealed a small endoleak; redilation was performed to eliminate the endoleak successfully. Spasm of the ICA was observed in six cases, but angioplasty was not required. Symptoms improved in all cases after stent placement. Angiographic follow-up demonstrated complete occlusion of the TCCFs and patency of ICA, and no intra-stent stenosis or embolization occurred in the 11 patients who received successful stent placement. CONCLUSION: Although larger sample and long-term follow-up are required, our series shows that covered stent is an effective, safe, and microinvasive method to treat TCCFs. PMID- 20920936 TI - Microroll retractor for surgical resection of brainstem cavernomas. AB - BACKGROUND: Safe and complete surgical resection of brainstem cavernoma is difficult without injury surrounding normal structures because the lesions are deep and intra-axial. In this article, the authors describe the "microroll retractor" technique for brainstem cavernoma surgery. METHODS: The microroll retractor is made of expanded polytetrafluoroethylene sheet. The sheet is cut in several sizes of square piece and transformed into a tubular shape. We insert this roll retractor via minimal brain incision and keep surgical corridor without usual spatulas during lesionectomy. RESULTS: This technique was adopted for 7 patients with brainstem cavernomas. In all patients, we achieved total excision; improvement was recorded in 6 patients, and no change was recorded in 1 patient. CONCLUSIONS: The microroll retractor is extremely simple but provides enough surgical corridors for safe total resection of brainstem cavernomas. PMID- 20920937 TI - Surgical management of trigeminal neuralgia patients with recurrent or persistent pain despite three or more prior operations. AB - OBJECTIVE: To compare facial pain outcomes from different surgical techniques for patients with idiopathic trigeminal neuralgia (TN) who continue to have persistent or recurrent TN despite multiple operations. METHODS: Review of a prospective surgical database identified 62 TN patients with ongoing facial pain despite having undergone three or more prior operations (mean = 3.4) from July 1999 to March 2008. The mean patient age was 66.5 years and the mean pain duration was 11.8 years. Twenty-six patients (42%) underwent 33 additional procedures during the follow-up period. In total, 95 operations were performed: posterior fossa exploration (PFE; n = 37, 39%), stereotactic radiosurgery (n = 31, 33%), glycerol rhizotomy (n = 18, 19%), and balloon compression (n = 9, 10%). Follow-up (median = 35 months; range = 1 day to 103 months) was censored at time of subsequent surgery, last patient contact, or death. RESULTS: Complete pain relief after surgery (no pain, no medications) was 66% at 1 year and 50% at 3 years. Patients having PFE had better facial pain outcomes (70% complete relief at 3 years) compared to other procedures (36% at 3 years) (hazard ratio = 2.6, 95% CI = 1.3-5.1, P < .01). No difference was noted between radiosurgery and the percutaneous techniques. Additional surgery was performed in 8 patients after PFE (22%) compared to 25 patients (48%) after radiosurgery (n = 16), glycerol rhizotomy (n = 7), or balloon compression (n = 2; P = .02). CONCLUSIONS: Although no procedure is best for all patients, PFE gives the operating surgeon the option of performing either a nondestructive (microvascular decompression) or destructive (partial sensory rhizotomy) procedure and is associated with better facial pain outcomes for this difficult patient group. PMID- 20920938 TI - A functional magnetic resonance imaging study of factors influencing motor function after surgery for gliomas in the rolandic region. AB - BACKGROUND: Pre- and postoperative fMRI was performed in patients with rolandic gliomas to evaluate factors influencing motor function after surgery. METHODS: The study population consisted of 9 right-handed patients (mean age, 43.3 years; range, 25-67, 2 female/7 male) affected by high-grade gliomas growing within or adjacent to the rolandic cortex. Patients had a diverse onset and evolution of their disease. All patients underwent morphological imaging and fMRI on a 3-T scanner before and after surgery. Postprocessed imaging data were analyzed off line using SPM. RESULTS: Patterns of activation in real-time maps and SPM were similar when coregistered head motion artifacts did not exceed more than 50% voxel size of the echo-planar imaging sequence. Movements of the hand opposite the affected hemisphere showed activation of the cMI in all patients. Coactivation of the iMI occurred in 5 patients. The cMII was activated in 4 patients, all with excellent postoperative motor function. The iMII and SMA were activated in patients with a good functional outcome. When the unaffected hand was tested, this activation pattern was similar. Postoperative fMRIs were comparable with the preoperative scans. CONCLUSIONS: Postoperative evaluation is feasible and may add confirmatory information to preoperative findings in selected patients. Bilateral activation of primary and secondary motor areas may be the correlate for compensatory recruitment of additional functional areas and a predictor for better functional outcome. PMID- 20920939 TI - Occult middle fossa encephaloceles in patients with temporal lobe epilepsy. AB - OBJECTIVE: Middle fossa encephaloceles are rare structural defects previously reported to cause complex partial seizures. Their debated etiology is either by failed union of temporal and sphenoid bone ossification centers or by erosion of the middle fossa floor secondary to pressure phenomena. Although magnetic resonance imaging (MRI) often reveals abnormalities, the actual encephalocele may not be identified preoperatively. METHODS: We present three cases of middle fossa encephaloceles that were identified intraoperatively and provide a review of the relevant literature. RESULTS: All three of our case presentations demonstrate patients with medically intractable epilepsy and intraoperative findings of middle fossa encephaloceles. In all patients, careful retrospective analysis of preoperative imaging provided clues to these encephaloceles, although none were suspected before surgery. After resection of the area all patients had improved seizure outcome. CONCLUSION: Middle fossa encephaloceles should be recognized as a potential source of epileptic pathology in patients with complex partial seizures. Although only 12 cases are reported in the literature, we believe that this phenomenon may be more common than previously recognized. We suggest that simple resection of the encephalocele alone may result in long-lasting, excellent seizure outcomes without amygdalohippocampectomy. PMID- 20920940 TI - Awake craniotomy, electrophysiologic mapping, and tumor resection with high-field intraoperative MRI. AB - BACKGROUND: Awake craniotomy and electrophysiologic mapping (EPM) is an established technique to facilitate the resection of near eloquent cortex. Intraoperative magnetic resonance imaging (iMRI) is increasingly used to aid in the resection of intracranial lesions. Standard draping protocols in high-field iMRI units make awake craniotomies challenging, and only two groups have previously reported combined EPM and high-field iMRI. METHODS: We present an illustrative case describing a simple technique for combining awake craniotomy and EPM with high-field iMRI. A movable platter is used to transfer the patient from the operating table to a transport trolley and into the adjacent MRI and still maintaining the patient's surgical position. This system allows excess drapes to be removed, facilitating awake craniotomy. RESULTS: A 57-year-old right handed man presented with new onset seizures. Magnetic resonance imaging demonstrated a large left temporal mass. The patient underwent an awake, left frontotemporal craniotomy. The EPM demonstrated a single critical area for speech in his inferior frontal gyrus. After an initial tumor debulking, the scalp flap was loosely approximated, the wound was covered with additional drapes, and the excess surrounding drapes were trimmed. An iMRI was obtained. The image-guidance system was re-registered and the patient was redraped. Additional resection was performed, allowing extensive removal of what proved to be an anaplastic astrocytoma. The patient tolerated this well without any new neurological deficits. CONCLUSIONS: Standard protocols for positioning and draping in high field iMRI units make awake craniotomies problematic. This straightforward technique for combined awake EPM and iMRI may facilitate safe removal of large lesions in eloquent cortex. PMID- 20920941 TI - Effectiveness and safety of subcutaneous abdominal preservation of autologous bone flap after decompressive craniectomy: a prospective pilot study. AB - BACKGROUND: The aim was to assess the effectiveness and safety of reconstructing a cranial bone defect after decompressive craniectomy using an autologous bone flap banked in a subcutaneous pocket in the patient's abdominal wall. METHODS: A prospective pilot study was performed on 12 of 15 consecutive patients who had undergone decompressive craniotomy and subsequent autologous bone flap replacement. The bone flap had been stored in the abdominal wall for an average period of 40 days. To assess the safety of this method, we evaluated the infections rate and the need for a surgical revision. Efficacy was evaluated under different points of view: 1) clinical standpoint, as the cosmetic reconstructive result at 6 months after the replacement; 2) imaging point of view, as the extent of residual bony gap detectable on a three-dimensional computed tomography scan as well as the extent of the bone flap revascularization, detected with a three-phase technetium bone scan. All the bone flaps were evaluated to assess their viability by histological investigations. RESULTS: There was no bone flap infection. The only significant complication encountered in two cases was the formation of a collection under the bone flap, which required its removal. CONCLUSIONS: This preliminary and limited experience has led us to believe that the subcutaneous preservation of autologous bone flap is feasible. This method may be a very inexpensive option that preserves the viability of the bone flap, which can be ultimately responsible for the good cosmetic results and the very low infection rate. PMID- 20920942 TI - Posttraumatic human cerebral myiasis. AB - OBJECTIVE: Only eight cases of cerebral myiasis in humans have been reported worldwide and only one in the United States. Presented here is a case of cerebral myiasis in the setting of head trauma in suburban Los Angeles. METHODS: The article includes chart review and description of a clinical case presentation. RESULTS: A 42-year-old HIV-positive man was found in a ditch after 2 weeks, the victim of apparent assault. He had multiple facial fractures along with open depressed bifrontal sinus fractures with necrotic bone, eroded dura, exposed cortex, and extensive maggot infestation of the left frontal lobe. The patient was taken urgently to the operating room, where the maggots where evacuated by irrigation and suction. Debridement of necrotic bone, dura, and brain was performed, the frontal sinuses were exenterated, and skull defects plated with titanium mesh. Intraoperative cultures revealed a polymicrobial meningitis/encephalitis, which was treated postoperatively with antibiotics. The patient's neurologic exam stabilized and the patient was transferred to a rehabilitation facility for further care, ultimately achieving functionality and holding a job. CONCLUSION: This is the first published case of cerebral myiasis secondary to trauma, and to our knowledge, the first documented long-term survivor of extensive cerebral myiasis. Wide debridement to normal brain followed by 6 weeks of broad-spectrum antibiotic treatment is effective in managing this condition. A well-functioning outcome can be expected with prompt recognition and treatment of the disease. Larval infestation may have a protective effect against bacterial infection and may allow for greater tolerance of treatment delay. PMID- 20920943 TI - Chemotherapy in anterior instrumentation for spinal tuberculosis: highlighting a 9-month three-drug regimen. AB - BACKGROUND: Anterior instrumentation has been used for surgical treatment of spinal tuberculosis, but there are different regimens of antituberculous chemotherapy used in combination with surgical intervention. The objective of this prospective study was to determine the efficacy of an antituberculous chemotherapy regimen by following a series of patients with spinal tuberculosis, for a minimum of 3 years, who underwent single-stage anterior radical debridement, autogenous bone grafting, and instrumentation. METHODS: The clinical and radiographic outcomes of these patients were analyzed with special reference to postoperative chemotherapy with a 9-month three-drug regimen. A total of 57 consecutive patients were treated surgically with single-stage anterior radical debridement, autogenous bone grafting, and instrumentation between 1999 and 2004. These patients received postoperative antituberculous chemotherapy with a 9-month three-drug regimen of isoniazid, rifampicin, and ethambutol. They were followed for 3-8 years (average = 5.5 years) with clinical and radiologic outcomes examined at each follow-up visit. RESULTS: All patients received postoperative chemotherapy for 9 months except two for whom postoperative chemotherapy was discontinued 4 and 6 months after surgery because of noncompliance. All patients experienced complete or significant relief of cervical or back pain, rapid improvement of neurologic function, and kyphotic correction. Bony fusion and eradication of the infection were achieved in all patients, with no recurrence of the tuberculosis. CONCLUSIONS: In conclusion, postoperative chemotherapy with the 9-month three-drug regimen of isoniazid, rifampicin, and ethambutol is effective when combined with surgical treatment of spinal tuberculosis using single-stage anterior autogenous bone grafting and instrumentation. PMID- 20920944 TI - Comparison study of the instrumented circumferential fusion with instrumented anterior lumbar interbody fusion as a surgical procedure for adult low-grade isthmic spondylolisthesis. AB - BACKGROUND: Instrumented circumferential fusion has been used as a primary and salvage procedure in lumbar spine fusion, especially for adult low-grade isthmic spondylolisthesis. Recently, instrumented anterior lumbar interbody fusion (ALIF) has been shown to provide good clinical and radiologic results that are comparable with those attained with traditional lumbar fusion. However, there have been no reports available that compare instrumented circumferential fusion with instrumented ALIF. METHODS: Between January 2003 and November 2004, a total of 43 consecutive patients underwent instrumented ALIF (group I) at one hospital of the authors. Between February 2003 and October 2006, a total of 32 consecutive patients underwent instrumented circumferential fusion (group II) at the other hospital of the authors. The authors retrospectively reviewed clinical and radiologic data from patients. The time spent on the operation, blood loss, blood transfusions, the length of hospital stay, complications, clinical results, and radiologic results, including disc height (DH), degree of listhesis, segmental lordosis (SL), and whole lumbar lordosis (WL), were analyzed and compared. Clinical outcomes were graded using visual analog scale (VAS) scores. Functional outcomes were measured using Oswestry Disability Index (ODI) scores and return-to work status. RESULTS: The mean follow-up period was 41.1 and 32.9 months in group I and group II, respectively. Radiologic evidence of fusion was noted in 42 of 43 patients in group I and in 32 of 32 patients in group II. In both groups, all of the radiologic data, including the DH, degree of listhesis, SL, and WL significantly changed from the preoperative to postoperative period except for WL in group II. In both groups, VAS scores for back and leg pain and ODI scores significantly changed from the preoperative to postoperative period. There was no significant difference for VAS scores for back ODI scores in the two treatment groups after surgery. The mean time until return to work was 3.7 months in group I and 3.6 months in group II (p < .05). The mean hospital stay for group I (7.4 days) was shorter than that for group II (15.2 days) (p < .05). The mean operation time in group I (190 minutes) was shorter than that in group II (260.8 minutes) (p < .05). The mean blood loss in group I (300 mL) was less than that in group II (379 mL) (p < .05). CONCLUSIONS: According to the present clinical outcome, instrumented ALIF is at least as effective as instrumented circumferential fusion for the treatment of back pain in adult patients with low grade isthmic spondylolisthesis. Moreover, in terms of operative data including the duration of operation and hospital stay, as well as blood loss, instrumented ALIF demonstrates better results. PMID- 20920945 TI - Biomechanics of a lumbar interspinous anchor with transforaminal lumbar interbody fixation. AB - OBJECT: To study the stability offered by a clamping lumbar interspinous anchor (ISA) for transforaminal lumbar interbody fusion (TLIF). METHODS: Seven human cadaveric lumbosacral specimens were tested: 1) intact; 2) after placing ISA; 3) after TLIF with ISA; 4) with TLIF, ISA, and unilateral pedicle screws-rod; 5) with TLIF and unilateral pedicle screws-rod (ISA removed); and 6) with TLIF and bilateral pedicle screws-rods. Pure moments (7.5 Nm maximum) were applied in each plane to induce flexion-extension, axial rotation, and lateral bending while recording angular motion optoelectronically. Compression (400 N) was applied while upright foraminal height was measured. RESULTS: All instrumentation reduced angular range of motion (ROM) significantly from normal. The loading modes in which the ISA limited ROM most effectively were flexion and extension, where the ROM allowed was equivalent to that of pedicle screws-rods (P > .08). The ISA was least effective in reducing lateral bending, with this mode reduced to 81% of normal. TLIF with unilateral pedicle screws-rod was the least stable configuration. Addition of the ISA to this construct significantly improved stability during flexion, extension, lateral bending, and axial rotation (P < .008). Constructs that included the ISA increased the foraminal height an average of 0.7 mm more than the other constructs (P < .05). CONCLUSIONS: In cadaveric testing, the ISA limits flexion and extension equivalently to pedicle screws rods. It also increases foraminal height. When used with TLIF, a construct of ISA or ISA plus unilateral pedicle screws-rod may offer an alternative to bilateral pedicle screws-rods for supplemental posterior fixation. PMID- 20920946 TI - How does chronic endocrine disease affect cost in spine surgery? AB - BACKGROUND: Previous research has suggested that increases in length of stay and hospital cost in patients undergoing spine surgery can be due to comorbidities, especially diabetes mellitus. To study how endocrine comorbidities impact spine surgery cost, we conducted the further analysis. METHODS: We reviewed the charts of 787 patients operated between 2005 and 2008 and their treatment cost. Patients underwent one of three of the most common types of spine surgery: lumbar microdiskectomy (N = 237), anterior cervical decompression and fusion (N = 339), and lumbar decompression and fusion (N = 211). Patients were 14 to 92 years of age (mean 54.5 years), nearly equally divided by gender and mostly white. Demographics, body mass index, and comorbidities were studied versus length of stay and hospital charges. Data were analyzed using the Mann-Whitney and Pearson chi(2) tests with the help of the SPSS v16 software. RESULTS: Among the 653 patients who had their glycosylated hemoglobin (HbA1c) level measured, 32.5% had an HbA1c level >=6.1% and 4.3% had high HbA1c level and hypothyroidism. These two comorbidities increased with age. Cost analysis showed that in the lumbar decompression and fusion group, length of stay and hospital cost significantly increased with these comorbidities. Without HbA1c elevation or hypothyroidism, the average length of stay for lumbar decompression and fusion patients was 5 days. This increased to 6 days with hypothyroidism. With both comorbidities the average length of stay increased to 8 days (P < .01). Regarding hospital cost, without these comorbidities the average was approximately $52,449. With elevated HbA1c the cost increased to $56,176 and with hypothyroidism to $63,278 (P < .01 and P < .05, respectively). When both comorbidities were present the average hospital cost was $71,352. It was also noted that 89.7% of the patients with hypothyroidism were women. Cost and length of stay increased with age in the female lumbar decompression and fusion group. In addition, there was a surge in length of stay and cost in the >=70-year-old female group with hypothyroidism undergoing anterior cervical decompression and fusion. CONCLUSIONS: HbA1c elevation and hypothyroidism have an additive effect on hospital cost in lumbar decompression and fusion female patients. The finding of a surge in hospital cost parameters in elderly female hypothyroid patients undergoing surgery on their cervical spine needs more investigation. PMID- 20920947 TI - Reinnervation of atonic bladder after conus medullaris injury using a modified nerve crossover technique in canines. AB - BACKGROUND: Neurogenic bladder represents a major cause of morbidity in patients with spinal cord injuries (SCI). Herein, we evaluated a novel reconstructive surgical technique designed to restore afferent and efferent nerve function in atonic bladder caused by conus medullaris injury. MATERIALS AND METHODS: A new reflex pathway was established by extradural transfer of the left L5 ventral root (VR) to the left S2 VR root together with extradural postganglionic spinal nerve transfer of the L5 dorsal root (DR) to the S2 DR with a nerve graft in a canine model. The corresponding nerves on the right side were kept intact and served as a control. After the new reflex pathway was reestablished, the early function of the reflex arc was evaluated by electrophysiologic study, intravesical pressure, and histologic examination. RESULTS: Action potential (AP) curves were recorded with single focal stimulation of the left S2 DR before and after the spinal cord was destroyed horizontally between the L6 and S3 levels. Bladder contraction was successfully initiated by trains of stimuli targeting the left L5-S2 DR anastomosis. Achievable bladder pressures and the amplitude of bladder smooth muscle complex action potentials were unchanged before and after induced paraplegia and were comparable to those of the control. Prominent axonal sprouting was observed in the distal region of the nerve graft. CONCLUSION: Both afferent and efferent nerve pathways in the atonic bladder were reconstructed by suprasacral motor-to-motor and sensory-to-sensory extradural nerve transfer in canines. Taken together, these findings suggest a new potential clinical approach for restoring bladder function in individuals with paraplegia. PMID- 20920948 TI - From anesthetic sponge to nonsinking skull perforator, unitary work neurosurgery in the ancient Arabic and Islamic world. AB - During the Middle Ages, the work of Middle Eastern physicians such as Avicenna, Albucasis, and Rhazes was of paramount importance in guarding the knowledge that had been accumulated throughout history, particularly the contributions of Greek and Roman scholars, and it is well known that the Arabic versions of all of the works by Hippocrates and Galen by Islamic and Arabic scholars are the only copies that have survived until now. In addition to preserving this wealth of knowledge, these Middle Eastern scholars made significant contributions of their own to both medicine and neurosurgery. Many points regarding ancient Arabic and Islamic science need to be discussed and clarified, such as cadaver dissections, anatomic studies, neurosurgical practice and instruments, Arabic translations of Hippocratic and other works, and the influence of the Islamic civilization on Western civilization, especially the Renaissance. PMID- 20920949 TI - Reversed apical rotation and paradoxical increased left ventricular torsion in children with left ventricular non-compaction. PMID- 20920950 TI - Tobacco smoke exposure and altered nasal responses to live attenuated influenza virus. AB - BACKGROUND: Epidemiologic evidence links tobacco smoke and increased risk for influenza in humans, but the specific host defense pathways involved are unclear. OBJECTIVE: We developed a model to examine influenza-induced innate immune responses in humans and test the hypothesis that exposure to cigarette smoke alters nasal inflammatory and antiviral responses to live attenuated influenza virus (LAIV). METHODS: This was an observational cohort study comparing nasal mucosal responses to LAIV among young adult active smokers (n = 17), nonsmokers exposed to secondhand smoke (SHS; n = 20), and unexposed controls (n = 23). Virus RNA and inflammatory factors were measured in nasal lavage fluids (NLF) serially after LAIV inoculation. For key end points, peak and total (area under curve) responses were compared among groups. RESULTS: Compared with controls, NLF interleukin-6 (IL-6) responses to LAIV (peak and total) were suppressed in smokers. Virus RNA in NLF cells was significantly increased in smokers, as were interferon-inducible protein 10:virus ratios. Responses in SHS-exposed subjects were generally intermediate between controls and smokers. We observed significant associations between urine cotinine and NLF IL-6 responses (negative correlation) or virus RNA in NLF cells (positive correlation) for all subjects combined. CONCLUSIONS: Nasal inoculation with LAIV results in measurable inflammatory and antiviral responses in human volunteers, thus providing a model for investigating environmental effects on influenza infections in humans. Exposure to cigarette smoke was associated with suppression of specific nasal inflammatory and antiviral responses, as well as increased virus quantity, after nasal inoculation with LAIV. These data suggest mechanisms for increased susceptibility to influenza infection among persons exposed to tobacco smoke. PMID- 20920951 TI - Private drinking water wells as a source of exposure to perfluorooctanoic acid (PFOA) in communities surrounding a fluoropolymer production facility. AB - BACKGROUND: The C8 Health Project was established in 2005 to collect data on perfluorooctanoic acid (PFOA, or C8) and human health in Ohio and West Virginia communities contaminated by a fluoropolymer production facility. OBJECTIVE: We assessed PFOA exposure via contaminated drinking water in a subset of C8 Health Project participants who drank water from private wells. METHODS: Participants provided demographic information and residential, occupational, and medical histories. Laboratory analyses were conducted to determine serum-PFOA concentrations. PFOA data were collected from 2001 through 2005 from 62 private drinking water wells. We examined the relationship between drinking water and PFOA levels in serum using robust regression methods. As a comparison with regression models, we used a first-order, single-compartment pharmacokinetic model to estimate the serum:drinking-water concentration ratio at steady state. RESULTS: The median serum PFOA concentration in 108 study participants who used private wells was 75.7 MUg/L, approximately 20 times greater than the levels in the U.S. general population but similar to those of local residents who drank public water. Each 1 MUg/L increase in PFOA levels in drinking water was associated with an increase in serum concentrations of 141.5 MUg/L (95% confidence interval, 134.9-148.1). The serum:drinking-water concentration ratio for the steady-state pharmacokinetic model was 114. CONCLUSIONS: PFOA contaminated drinking water is a significant contributor to PFOA levels in serum in the study population. Regression methods and pharmacokinetic modeling produced similar estimates of the relationship. PMID- 20920952 TI - Meeting report: Estimating the benefits of reducing hazardous air pollutants- summary of 2009 workshop and future considerations. AB - BACKGROUND: Quantifying the benefits of reducing hazardous air pollutants (HAPs, or air toxics) has been limited by gaps in toxicological data, uncertainties in extrapolating results from high-dose animal experiments to estimate human effects at lower doses, limited ambient and personal exposure monitoring data, and insufficient economic research to support valuation of the health impacts often associated with exposure to individual air toxics. OBJECTIVES: To address some of these issues, the U.S. Environmental Protection Agency held the Workshop on Estimating the Benefits of Reducing Hazardous Air Pollutants (HAPs) in Washington, DC, from 30 April to 1 May 2009. DISCUSSION: Experts from multiple disciplines discussed how best to move forward on air toxics benefits assessment, with a focus on developing near-term capability to conduct quantitative benefits assessment. Proposed methodologies involved analysis of data-rich pollutants and application of this analysis to other pollutants, using dose-response modeling of animal data for estimating benefits to humans, determining dose-equivalence relationships for different chemicals with similar health effects, and analysis similar to that used for criteria pollutants. Limitations and uncertainties in economic valuation of benefits assessment for HAPS were discussed as well. CONCLUSIONS: These discussions highlighted the complexities in estimating the benefits of reducing air toxics, and participants agreed that alternative methods for benefits assessment of HAPs are needed. Recommendations included clearly defining the key priorities of the Clean Air Act air toxics program to identify the most effective approaches for HAPs benefits analysis, focusing on susceptible and vulnerable populations, and improving dose-response estimation for quantification of benefits. PMID- 20920953 TI - Examining the joint effect of multiple risk factors using exposure risk profiles: lung cancer in nonsmokers. AB - BACKGROUND: Profile regression is a Bayesian statistical approach designed for investigating the joint effect of multiple risk factors. It reduces dimensionality by using as its main unit of inference the exposure profiles of the subjects that is, the sequence of covariate values that correspond to each subject. OBJECTIVES: We applied profile regression to a case-control study of lung cancer in nonsmokers, nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, to estimate the combined effect of environmental carcinogens and to explore possible gene-environment interactions. METHODS: We tailored and extended the profile regression approach to the analysis of case-control studies, allowing for the analysis of ordinal data and the computation of posterior odds ratios. We compared and contrasted our results with those obtained using standard logistic regression and classification tree methods, including multifactor dimensionality reduction. RESULTS: Profile regression strengthened previous observations in other study populations on the role of air pollutants, particularly particulate matter <= 10 MUm in aerodynamic diameter (PM10), in lung cancer for nonsmokers. Covariates including living on a main road, exposure to PM10 and nitrogen dioxide, and carrying out manual work characterized high-risk subject profiles. Such combinations of risk factors were consistent with a priori expectations. In contrast, other methods gave less interpretable results. CONCLUSIONS: We conclude that profile regression is a powerful tool for identifying risk profiles that express the joint effect of etiologically relevant variables in multifactorial diseases. PMID- 20920955 TI - [Severe respiratory disease in an intensive care unit during influenza A(H1N1) 2009 pandemia]. AB - We describe characteristics of patients admitted to our intensive care unit with severe acute respiratory illness and influenza-like syndrome during the first months of the pandemic influenza A(H1N1) 2009 in Argentina. We analyzed clinical data, severity scores, laboratory tests, microbiological and radiological findings at admission, clinical outcomes and in-hospital mortality. H1N1 was confirmed by RT-PCR. Data from positive and negative PCR patients were compared. We admitted 31 adult patients between June and July 2009; median age: 54 years (IQR 33-66). A 54% (17) had positive PCR; 16 patients presented underlying medical conditions. Bilateral interstitial opacities were observed in chest radiography in 20 cases; 5 had unilateral lobar consolidation. Bacterial co infection (isolation or IgM antibodies for bacterial infections) was found in 21 patients. Mechanical ventilation was required in 23 patients and 18 developed ARDS. Lymphopenia and increased creatine kinase levels were frequently observed (83% and 65% among PCR+ and PCR- respectively). Six patients died (19%); they were all over 75 years old, had cancer or immune-suppression. Early antiviral treatment (<= 48 hours from symptoms onset) was associated with less frequency of mechanical ventilation (54% vs. 89%, p: 0.043). There were no differences in analyzed variables when comparing H1N1 positive and H1N1 negative patients; which suggests this approach as a most correct in future epidemic outbreaks. H1N1 infection was associated with severe respiratory illness and ARDS. Fatal outcome was observed in very old patients, or in those with major co-morbidities. PMID- 20920954 TI - The dichloroacetate dilemma: environmental hazard versus therapeutic goldmine- both or neither? AB - BACKGROUND: Dichloroacetate (DCA) is known to environmental scientists as a by product of water chlorination and as a metabolite of industrial solvents, including Superfund chemicals. In contrast, DCA is studied by clinical investigators for its therapeutic potential in several life-threatening conditions, including genetic mitochondrial diseases, pulmonary arterial hypertension, and cancer. Thus, DCA holds an almost unique position at the interface between environmental science and allopathic medicine. OBJECTIVE: I critically reviewed laboratory and clinical pharmacological research on DCA to address questions about the current and future status of DCA in relation to human health. DISCUSSION: Recent information on the clinical toxicogenetics of DCA is interpreted particularly in light of its use as an investigational drug. Adverse effects from chronic DCA exposure have been identified in several target organs in animals. However, in humans, toxicity has so far been limited to reversible effects on the nervous system and liver. DCA is primarily biotransformed to glyoxylate by the bifunctional enzyme glutathione transferase zeta1 and maleylacetoacetate isomerase (GSTz1/MAAI), which also catalyzes the penultimate step in the phenylalanine and tyrosine catabolic pathway. DCA is a suicide inhibitor of GSTz1/MAAI, which can result in delayed plasma clearance of DCA and the accumulation of potentially toxic tyrosine intermediates. Age and GSTz1/MAAI haplotype can markedly affect the toxicokinetics of DCA in humans and rodents. CONCLUSIONS: I have defined new potential avenues of research that focus on discrete human populations that may be at increased health risk or that may receive increased health benefit from chronic exposure to DCA at both environmentally and clinically relevant concentrations. PMID- 20920956 TI - [Primary hyperparathyroidism: postoperative long-term evolution]. AB - The long-term postoperative outcome of 87 patients with primary hyperparathyrodism is here presented. Of the total 78 were females and 9 males, ratio: 8.7:1. Mean age 55.3 +/- 10.2 years. Before surgery, 44% had kidney stones, 70% had osteopenia or osteoporosis and 71.2% had hypercalciuria. Decrease renal glomerular filtration was found in 12.6%. Of the total, 72 patients had a single adenoma, two double adenoma, two hyperplasia, four had normal histology and seven could not dispose of the result. Serum calcium, ionized calcium, phosphorus and intact parathyroid hormone were normalized in all post surgery patients. Bone mineral density increased by 6.9% in lumbar spine and 3% in femoral neck. Markers of bone remodeling were normalized and persisted normal 23 months of follow-up, coinciding with the normal intact parathyroid hormone. Same thing happened with the values of 25 OH D. When patients whith initial hypercalciuria were compared with those with normocalciuria, no differences were found in the basal values and postsurgery in both groups. In 11 patients with previous renal glomerular filtration < 60 ml / min, we found a higher intact parathyroid hormone and lower bone mineral density than the rest. The glomerular filtration rate did not change significantly after surgery. In conclusion, the surgical primary hyperparathyroidism, operated by specialized surgeons has an excellent long-term outcome, with normalization of all parameters of phosphocalcic metabolism and bone remodeling and significant improvement in bone mineral density. Adverse effects were scarce and had spontaneous resolution. PMID- 20920957 TI - [Analysis of a pituitary adenoma registry]. AB - Collection and analysis of data obtained during the clinical treatment of pituitary tumours are of great utility in the decision making process, when facing clinical situations. We report here data on 519 from 670 patients with pituitary adenomas obtained from a computerized registry. Three hundred and forty five were females (66%) and 174 males (34%), aged 14-80. Final diagnosis was acromegaly in 176, Cushing's disease in 153, prolactinoma in 101 and clinically non-functioning adenoma in 89. Mean age at diagnosis was 43.9 +/- 13.5 (16-80) for acromegalics, 35.7 +/- 12.9 (14-72) for Cushing's, 30.0 +/- 13.4 (15-79) for prolactinoma and 52.1 +/- 15.2 (17-79), for non-functioning tumours. The setup of an institutional registry on pituitary tumours constitutes a useful tool to analyze clinical experience, optimize the cost/benefit ratio of procedures used for diagnosis and to ameliorate therapeutic strategies, improving patient's care. It greatly contributes to teaching medical students as well as to post-graduate physicians and provides a basis for developing clinical research. PMID- 20920958 TI - [Prevalence of thrombocytopenia in HIV infected children]. AB - Thrombocytopenia is a common hematologic finding in patients infected with the human immunodeficiency virus. Multiple mechanisms may contribute to the development of chronic thrombocytopenia as immune-mediated platelet destruction, enhanced platelet splenic sequestration and impaired platelet production. Acute thrombocytopenia is frequently associated with coexisting disorders. In this study, the prevalence of thrombocytopenia was evaluated in a cohort of HIV infected children analyzing the clinical features and the association with the immunological and virological status of the disease in a 14 year-follow-up period. Thrombocytopenia prevalence was of 8.5% (29 out 339 children evaluated). Chronic and acute thrombocytopenia was observed in 22 and 7 children respectively. The percentages of CD4+ T cells were variable and not related with the presence of thrombocytopenia. Thrombocytopenic patients showed viral load levels significantly increased; being the thrombocytopenia the initial clinical manifestation of HIV infection in 10 out 29 children. Mild chronic thrombocytopenia bleeding found in 23% of children evaluated was not correlated with the immunologic status of the disease. In contrast, the severity of acute thrombocytopenia depended on the evolution of associated clinical conditions. Constant viral activity and failure in the use of antiretroviral agents might induce the development of thrombocytopenia in HIV-infected children. PMID- 20920959 TI - [Adverse drug reactions in multidrug-resistant tuberculosis]. AB - Multidrug-resistant tuberculosis (MDRTB) poses difficulties in diagnosis and treatment, including increased frequency of adverse reactions to antituberculosis drugs (ADRAs), which compromise the effectiveness of treatment. This is specially complicated in the treatment of patients co-infected with HIV which includes the antiretroviral therapy plus the treatment of eventual comorbidities. A total of 121 MDRTB patients, 87 HIV-negative and 34 HIV positive, assisted in the Hospital F. J. Muniz, Buenos Aires, during the period 2003-2007 were retrospectively studied. The incidence of ADRAs among the two groups of patients was compared. All the patients with adherence to treatment (no more than one abandon, recovered) were included in the study. Antituberculosis drugs used were: ethambutol, pyrazinamide, ofloxacin, moxifloxacin, cycloserine, ethionamide, PAS, streptomycin, kanamycin, amikacin and linezolid. The emergence of ADRAs and the proportion of severe reactions attributed to antituberculosis drugs were similar in both groups: 44.8% in HIV negative and 44.1% in HIV positive, but it was observed an additional 23.5% of adverse reactions to antiretroviral therapy in the second group. There were differences in the type of reactions and time of occurrence between the two groups. One HIV positive patient died of epidermolysis. The proportion of adverse reactions in HIV/AIDS patients increased 50% when those attributed to antiretroviral treatment were included. We conclude that the studied population showed a frequency of ADRAs higher than it would be expected in the treatment of susceptible TB, but there was no difference in its frequency among HIV-negative and positive patients. PMID- 20920961 TI - [Pneumococcal surface protein A (PspA) families. Relation with serotypes and clinical site of infection]. AB - PspA, a pneumococcal surface protein, is highly immunogenic and common to all serotypes. Although pspA gene shows a great heterogeneity at the N-terminal region, PspA protein has conserved epytopes which are able to elicit protective cross-reaction against various serotypes presenting different PspA. In spite of the high polimorfism of the PspA, three majority families can be identified. These properties convert PspA as ideal candidate for the formulation of a pneumococcal vaccine. Investigations of the PspA families were mostly carried out on prevalent serotypes in other countries. The aim of this study was to identify PspA families from Streptococcus pneumoniae isolates of our region as well as to associate them to prevalent serotypes or pathologies. We studied 70 isolates from pediatric patients with invasive infections. PCR was performed using specific primers for each family. In these studies we observed that 60% were PspA family 1, 34% were PspA family 2 and 6% remained unclassified. Serotypes 1 and 5 presented only family 1; serotypes 14, 6B, 19F y 18C showed genes from both families. Family 1 was observed respectively in 60 y 50% of pneumonias and meningitis. The family 2 was identified in 33 and 50% of pneumonias and meningitis. This information about the PspA family distribution could become a valuable contribution to develop an effective regional vaccine using recombinant PspA as immunogen. PMID- 20920960 TI - [Lower lung field tuberculosis]. AB - Tuberculosis (TB) that affects lower lung fields (LLFTB) is infrequent in the adult population and is generally associated with immunodeficiency. The objective of our study was to determine the incidence of LLFTB in our patients population and compare the characteristics of these pa-tients with those who presented TB of typical pulmonary localization. We studied 42 patients with LLFTB retrospec tively between 2004 and 2008 and compared them to 84 patients with TB of typical localization (control group). HIV-positive patients were excluded. LLFTB represented 6% of the pulmonary TB cases. No significant differences were found with respect to age, sex, the presence of cavities in chest x-rays, days of evolution, and albumin levels. LLFTB had a significantly greater proportion of comorbilities (p < 0.001), the presence of condensation (p < 0.001), and unilateral involvement (p < 0.001), with a higher number of hospital admissions (p = 0.02). The observation that only 16 of the 42 patients with LLFTB (38%) had a notable comorbility is important. Thus, LLFTB can be present without associated comorbilities and must be suspected in pneumonias that have a torpid evolution regardless of pulmonary localization. PMID- 20920962 TI - [Systemic sclerosis complicated with syncope and complete AV block]. AB - Systemic sclerosis is a complex disease that affects the connective tissue, the vascular system and the immune system. It typically produces skin and organ fibrosis. Cardiac bundle branch blocks and fascicular blocks occur in 25-75% of the cases and were found to be independent predictors of mortality. Second and third degree atrioventricular block are very rare. We present the case of a 47 year-old female with diagnosis of systemic sclerosis, presented with syncope secondary to complete atrioventricular block requiring permanent pacemaker implantation. PMID- 20920963 TI - [Primary lung lymphoma]. PMID- 20920964 TI - [Effect of a single dose of zoledronic acid in a case of Paget bone disease]. AB - Paget's disease is a chronic disorder of bone remodeling characterized by increase of bone resorption by atypical osteoclasts, followed by rapid increase in bone formation resulting in a disorganized mosaic bone. The biochemical marker for early diagnosis and monitoring is serum alkaline phosphatase (ALP). We report the case of a 90 year old male, with diagnose of Paget's disease. Pamidronate treatment was started orally with partial response, so it was switched to intravenous pamidronate. Pain intensity and FAL levels diminished. The scyntigraphic scan, however, though improved, persisted abnormal. After several years of treatment, with adequate calcium and vitamin D support, the patient presents pain and increase of FAL. We administered intravenous zoledronic acid (4 mg) in a single dose. After this treatment we observed clinical and biochemical remission during four years and a significantly improvement in the scintigraphy. We report a case of Paget's disease, resistant to pamidronate treatment in whom a single dose of zoledronic acid produced clinical and biochemical remission during 4 years and a significant improvement in the scintigraphic scan. PMID- 20920965 TI - [Hyperperfusion syndrome after carotid angioplasty and stenting with cerebral hemorrhage]. PMID- 20920966 TI - [The importance of early diagnosis for the survival of HIV positive patients]. AB - In Argentina, HIV diagnosis is reached by voluntary testing or symptom-based case findings. However, because of the high proportion of infected individuals unaware of their serologic status new strategies are required. In this article we show how a mathematic model predicts the impact of expanding HIV testing in Argentina. The model is based on time-dependent Markov matrixes and applies parameters dependent transition-probabilities obtained from both national and international cohort studies. Outputs include time on clinical stages and therapy regime, CD4 count, viral-load, infection-state and age; mortality rates and proportion of unidentified infection at a population-level. Simulations were performed for current testing strategy and for a theoretical scenario with earlier diagnosis. We show how our prediction suggests that diagnosis before onset of symptoms would increase life expectancy by 10.7 years. Also, we show how a reduction of time to diagnosis to 5 or less years from infection would reduce mortality rates in the first year of HAART from 7.6% to 2.1%, the proportion of unrecognized infection from 43.2% to 23.8% and the proportion of individuals with unaware infection needing treatment from 12% to 0.2%. Based on this prediction we stress the importance of implementing health policies aimed at detecting HIV infection in early stages in Argentina. PMID- 20920967 TI - Molecular mechanisms of glucocorticoid receptor signaling. AB - This review highlights the most recent findings on the molecular mechanisms of the glucocorticoid receptor (GR). Most effects of glucocorticoids are mediated by the intracellular GR which is present in almost every tissue and controls transcriptional activation via direct and indirect mechanisms. Nevertheless the glu-cocorticoid responses are tissue -and gene- specific. GR associates selectively with corticosteroid ligands produced in the adrenal gland in response to changes of humoral homeostasis. Ligand interaction with GR promotes either GR binding to genomic glucocorticoid response elements, in turn modulating gene transcription, or interaction of GR monomers with other transcription factors activated by other signalling pathways leading to transrepression. The GR regulates a broad spectrum of physiological functions, including cell differentiation, metabolism and inflammatory responses. Thus, disruption or dysregulation of GR function will result in severe impairments in the maintenance of homeostasis and the control of adaptation to stress. PMID- 20920969 TI - [Defining sex]. PMID- 20920968 TI - [Update on interventional treatment of acute ischemic stroke]. AB - New options have been developed for the prevention and treatment of acute ischemic stroke in the last 20 years, such as carotid endarterectomy and intravenous thrombolysis with tissue plasminogen activator. Scientific evidence has supported their use in developed countries, while there is an evident delay in their use among emerging countries. Other promising modalities require the conclusion of ongoing randomized, controlled trials. Malignant middle or carotid cerebral artery infarction accounts for 10 to 15% ischemic strokes and constitutes a devastating event associated with high morbidity and mortality. Decompressive craniectomy seems to be an effective and safe approach for rapidly lowering intracranial pressure. Although randomized trials are lacking, there is enough evidence to support this surgical procedure in appropriately selected patients. PMID- 20920970 TI - [The two cultures: hard science versus social sciences]. PMID- 20920971 TI - [Two cultures or multiple cultures? Hard science, soft science and science studies]. PMID- 20920972 TI - [Two cultures? or none]. PMID- 20920973 TI - [Communication in sanitary crisis]. PMID- 20920974 TI - [Pharmacogenomics and the path towards personalized medicine]. PMID- 20920977 TI - Tailored local-regional treatment for early-stage breast cancer. PMID- 20920979 TI - Ixabepilone plus capecitabine for breast cancer patients with an early metastatic relapse after adjuvant chemotherapy: two clinical trials. AB - BACKGROUND: Despite recent advances in treating patients with metastatic breast cancer (MBC), outcomes remain poor. Ixabepilone is a semisynthetic analogue of epothilone B with low susceptibility to multiple mechanisms of tumor-cell resistance. This review examined the results of 2 phase III clinical trials of ixabepilone in patients with drug-resistant or heavily pretreated, locally advanced breast cancer or MBC. PATIENTS AND METHODS: In both studies, women with locally advanced breast cancer or MBC pretreated with, or resistant to, taxanes or anthracyclines were randomly assigned to ixabepilone plus capecitabine, or capecitabine alone, until disease progression or unacceptable toxicity occurred. RESULTS: Ixabepilone plus capecitabine significantly prolonged progression-free survival (PFS) compared with capecitabine alone. The median PFS was prolonged by 1.5 months and 1.8 months in the 2 studies (hazard ratio, < 0.8 in both studies; P >= .001). These observations remained valid within several patient subsets: those receiving ixabepilone as first-line therapy, those with taxane-resistant disease, and those with particularly poor prognostic features. Ixabepilone plus capecitabine significantly improved overall survival (OS) compared with capecitabine in patients with symptomatic disease (12.3 vs. 9.5 months, respectively; P = .015). Peripheral neuropathy with ixabepilone was generally reversible and was effectively managed by dosage reduction in most patients. Ixabepilone did not exacerbate capecitabine-induced hand-foot syndrome or diarrhea. CONCLUSION: The results of these 2 large phase III trials suggest that ixabepilone plus capecitabine may improve treatment outcomes for patients with locally advanced breast cancer or MBC resistant to, or heavily pretreated with, taxanes or anthracyclines, even in those with poor prognostic features. PMID- 20920980 TI - Bisphosphonates as anticancer therapy for early breast cancer. AB - Bisphosphonates (BPs) are approved for preventing the skeletal-related events associated with malignant bone disease. Several studies indicate that they may also prevent cancer therapy-induced bone loss. Multiple preclinical and early clinical studies provide evidence of the anticancer activity of BPs, including an inhibition of tumor cell proliferation and survival, a reduction of angiogenesis, and a stimulation of innate anticancer immunity. In addition to their evident single-agent activity, BPs may also act synergistically with other antineoplastic agents. Translational studies corroborate the effects of bisphosphonates on angiogenesis and innate immunity. Moreover, many of these anticancer effects occur at clinically relevant drug concentrations. Indeed, clinical data suggest that in addition to being well-tolerated and efficacious in maintaining bone health, BPs including clodronate, pamidronate, and zoledronic acid also improve cancer-related outcomes such as tumor response, disease-free survival, and overall survival in patients with breast cancer. Among the BPs, zoledronic acid is the most extensively studied in the adjuvant and neoadjuvant settings and has accumulated the most data pointing to anticancer activity, although a survival benefit has not been documented. Future studies are necessary to elucidate the anticancer activity of BPs. Other aspects of BP therapy that require further study include the optimization of dosing regimens for single agents and combinations in various clinical settings and the identification of prognostic factors that predict treatment outcomes. This review summarizes the preclinical and clinical evidence of anticancer activity of BPs, with a focus on zoledronic acid. PMID- 20920981 TI - Association of DNMT1 gene polymorphisms in exons with sporadic infiltrating ductal breast carcinoma among Chinese Han women in the Heilongjiang Province. AB - BACKGROUND: Infiltrating ductal carcinoma (IDC) is the most common malignant breast cancer in women, and genetic factors appear to play a significant role in the susceptibility to IDC. Alteration of DNA methylation is an epigenetic change in human cancers, including breast cancer. DNA-methyltransferase 1 (DNMT1) is a major enzyme that determines genomic methylation patterns. In order to clarify the association of DNMT1 polymorphisms with IDC, a case-control study was conducted in women from the Heilongjiang Province, in the northeast of China. PATIENTS AND METHODS: We scrutinized the 2 genetic polymorphisms in exons of DNMT1 that may influence the activity of DNMT1. Our research subjects consisted of 305 patients with IDC and 314 age-matched healthy controls. Genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism. Data were analyzed using the chi2 test by SPSS, version 13.0, and Haploview, version 4.1. The association between DNMT1 polymorphisms and the clinical features of IDC was analyzed. RESULTS: In rs16999593, the frequency of CT genotype and C allele were lower in patients than in controls (P = .028 and P = .017, respectively). Also, rs2228611 AG genotype was higher in patients than in controls (P = .015). The frequency of haplotype CA was lower in patients than in controls (P = .034). Significant association was shown between the 2 single nucleotide polymorphisms of the DNMT1 gene and progesterone receptor (PgR) and p53 status. No association was found between DNMT1 gene polymorphisms and tumor size or estrogen receptor status. CONCLUSION: Our results was a previous study, which suggested that DNMT1 gene polymorphisms in exons may provide valuable information for predicting the sporadic IDC risk and may be associated with prognosis factors such as PgR and p53 status in Chinese Han women in the Heilongjiang Province. PMID- 20920982 TI - Disseminated tumor cells in bone marrow assessed by TWIST1, cytokeratin 19, and mammaglobin A mRNA predict clinical outcome in operable breast cancer patients. AB - PURPOSE: To investigate the prognostic relevance of disseminated tumor cells (DTCs) in bone marrow (BM) assessed by a multimarker mRNA panel consisting of TWIST1, cytokeratin 19 (CK19) and human mammaglobin A (hMAM) mRNA, in patients with early breast cancer. PATIENTS AND METHODS: TWIST1 (gene name: TWIST1), CK19 (gene name: KRT19), and hMAM (gene name: SCGB2A2) mRNA was quantitated in BM samples from 191 operable breast cancer patients by real-time reverse transcriptase polymerase chain reaction (RT-PCR). RESULTS: Using the highest relative mRNA concentration of TWIST1 in the control population as a cut-off, 5 of the 191 breast cancer patients showed elevated TWIST1 mRNA levels in their BM by real-time RT-PCR. Two of these patients experienced a systemic relapse during a median follow-up of 98 months. Combining these results with previous hMAM and CK19 mRNA quantifications in the same BM samples, 12 (40%) of the 30 patients with BM positive for at least 1 marker (multimarker positive) experienced a systemic relapse as compared with 18 (11%) of the 161 patients with multimarker negative BMs. The patients with multimarker-positive BM had significantly shorter systemic recurrence-free survival (P < .001, log-rank test), breast cancer specific survival (P < .001), and overall survival (P = .03). The prognostic relevance of BM multimarker detection appeared to be independent of adjuvant treatment, although the difference was not statistically significant in the subgroup of patients who received adjuvant chemotherapy. Multivariate analysis demonstrated the BM multimarker panel status to be a strong independent predictor of clinical outcome. CONCLUSION: Our results demonstrated the prognostic relevance of BM DTCs assessed by a multimarker mRNA panel consisting of TWIST1, CK19, and hMAM in operable breast cancer patients. PMID- 20920983 TI - Compliance differences between patients with breast cancer in university and county hospitals. AB - PURPOSE: Compliance with recommended breast cancer treatments outside the context of a clinical trial differs from that in study populations. The purpose of this study was to examine differences in compliance of breast cancer treatments. PATIENTS AND METHODS: We conducted a retrospective review of 529 patients treated at 2 teaching hospitals in the same city from 2003 to 2006. Compliance with adjuvant therapy recommendations and choice of breast-conserving operations were compared between a university hospital (UH) and a county hospital (CH). RESULTS: The 2 populations demonstrated similar rates of breast conservation (72% vs. 69%). Although use of radiation therapy at the CH was acceptable (82%), patients at the UH were more likely to undergo radiation therapy (95%). The use of hormone therapy was similar at the UH and the CH (> 93%). Patients were more likely to follow physician recommendations for adjuvant chemotherapy at the UH (89%) compared with the CH (70%; P = .0005). Univariate analysis revealed that patient age, tumor size, stage, grade, and estrogen receptor status were all significant predictors of patient compliance with chemotherapy. Preoperative chemotherapy was a strong predictor of patient compliance with chemotherapy (P < .0001). In multivariate analysis, all of the factors predictive of patient compliance in univariate analysis remained significant except tumor grade. CONCLUSION: Preoperative chemotherapy appeared to increase compliance compared with adjuvant chemotherapy in the CH population. Compared with national standards, breast conserving operations and radiation therapy compliance can be accomplished in an acceptable percentage of underinsured patients. PMID- 20920984 TI - Changes of HER2 status in circulating tumor cells compared with the primary tumor during treatment for advanced breast cancer. AB - BACKGROUND: HER2/neu status of tumor cells at metastatic sites in patients with advanced disease may differ from that of the primary tumor. Assessing the presence of target antigens on circulating tumor cells (CTCs) might affect treatment choice. PATIENTS AND METHODS: From June 2007 to October 2008, we collected 23 mL of blood from each of the 76 consecutive patients before and during chemotherapy to determine CTC numbers and HER2 overexpression. CTCs were isolated with the CellSearch System(r) (Veridex, LLC; Raritan, NJ) and fluorescently stained with the Epithelial Cell Kit(r). Tumor Phenotyping Reagent(r) was used to investigate HER2/neu overexpression. RESULTS: Concordance of HER2 status between the primary tumor and CTCs was 86% (49 out of 57 patients) at baseline and 82% (50 out of 61 patients) in the treatment samples. HER2 overexpression in CTCs was acquired in 8 out of 45 patients (18%) and lost in 3 out of 16 patients (19%) during a treatment containing trastuzumab. The overall discordance rate between the primary tumor and CTCs was 18% (11 out of 61 patients). Patients with HER2 overexpression in CTCs had poorer progression-free survival compared with those without CTCs or with HER2- CTCs (log-rank P =.036). CONCLUSION: Information on the presence or absence of HER2 overexpression can be obtained in CTCs. Larger trials are needed to evaluate the activity of HER2 targeted therapy in patients with acquired HER2 overexpression in CTCs. PMID- 20920985 TI - Discrepancy between preference and actual adjuvant therapy for breast cancer. AB - PURPOSE: Pretreatment preferences for adjuvant therapy were examined and compared with actual treatment received. PATIENTS AND METHODS: Before definitive surgery, women with node-negative breast cancer were asked to indicate their preference for adjuvant therapy in response to 3 different clinical scenarios. The scenarios provided precise risk, benefit, and side effect information with low-, moderate-, or high-risk risk of death from breast cancer. Contingency table and Spearman rank correlation coefficients were used to examine associations. Kruskal-Wallis rank sum tests were used for group comparisons, with the Friedman rank sum test being used for correlated samples. RESULTS: A total of 75 women enrolled between February 2002 and April 2005; 24% were aged > 65 years. After definitive surgery, 21% of women had ductal carcinoma in situ, and 89% had receptor-positive disease. There was a significant correlation between risk of recurrence and aggressiveness of treatment preferred (P < .001). After surgical staging, the high-risk group received more aggressive treatment compared with the low-risk group (P = .004). In the 51 women with invasive receptor-positive tumors, there was a significant difference (P = .002) in aggressiveness of treatment received based on risk of recurrence. Only 45% of the women received what they had preferred for the level of their risk before surgery. Women were more likely to receive a less aggressive therapy than they preferred initially (P = .0002). CONCLUSION: This study is among the first to correlate pretreatment preference for therapy with the actual therapy received. Less than half of women received their indicated preference before definitive surgery, with most women receiving less aggressive therapy. Future studies will need to examine this discrepancy. PMID- 20920986 TI - Levofloxacin-induced radiation recall dermatitis: a case report and a review of the literature. AB - Radiation recall dermatitis (RRD) is a rare phenomenon. There are a few reports in the literature reporting RRD triggered by quinolones administration after external beam radiation therapy (EBRT). We present an unusual case of RRD induced by levofloxacin 7 months after completion of EBRT. A 56-year-old Caucasian female was treated with EBRT for stage I carcinoma of the right breast with whole breast irradiation followed by the boost to the tumor bed to a total dose of 6080 cGy. Seven months post completion of EBRT, levofloxacin was administered for an upper respiratory tract infection. On day 8 of levofloxacin, the patient developed a blistering RRD in the skin overlying the area of previous radiation portals. Discontinuation of the RRD-inducing antibiotic and appropriate therapy led to the resolution of the condition. We review literature emphasizing this quinolone antibiotic as a causative of RRD. PMID- 20920989 TI - Microsatellite instability and mismatch repair genes in colorectal cancer: useful tools for managing patients and counseling their relatives. PMID- 20920991 TI - Diagnosing hereditary colorectal cancer. AB - Although progress in the treatment of patients with colorectal cancer (CRC) has resulted in improved median survival, most patients with metastatic CRC still die of their disease, and essentially all patients with early-stage disease must undergo surgical resection and subsequently face the possibility of adjuvant chemotherapy. As effective screening and prevention strategies for CRC have been developed, identification of individuals with a hereditary predisposition to developing CRC is especially important and provides the opportunity to reduce disease burden in this high-risk population. Increased awareness and improved diagnostic techniques for hereditary CRC syndromes have facilitated more frequent diagnosis and management of a small number of highly penetrant syndromes within families. However, known high-penetrance genetic predisposition syndromes account for a minority of all familial CRC, leaving much of the genetic basis of CRC unexplained. Recent advances in high-throughput genotyping have made possible genome-wide association studies, which have identified novel genetic variants associated with modest increases in CRC risk. While these associations have helped to identify potentially important pathways in CRC carcinogenesis, at the current time, the clinical use of such genetic risk variants in colon cancer risk stratification remains limited. PMID- 20920992 TI - The timing of chemotherapy and surgery for the treatment of colorectal liver metastases. AB - Combining surgery and chemotherapy in the treatment of patients with colorectal hepatic metastases is increasingly becoming the standard of care. However, controversy remains regarding the juxtapositioning of chemotherapy and surgery, the duration of chemotherapy, and particularly, the use of preoperative chemotherapy in the treatment of patients with initially resectable metastases. The arguments for and against the different approaches presented are based on the data published in the medical literature and on the data presented at the most recent major oncology meetings, coupled with the personal experience of the authors. For patients with liver metastases that are resectable at presentation, perioperative chemotherapy has become the standard treatment in many institutions, with the recommendation that surgery is performed after a maximum of 6 cycles of systemic therapy. In the case of patients with initially unresectable liver metastases receiving preoperative systemic therapy, patients should be carefully monitored and surgery performed as soon as the metastases become resectable. All patients should, where possible, be treated by a multidisciplinary team. Going forward, it needs to be established whether more intensive treatment (ie, perioperative versus postoperative systemic therapy) is merited for the treatment of patients with initially resectable disease, and what the precise contribution of new therapeutic agents in these settings is, based on new prospective randomized trial data. PMID- 20920993 TI - The insulin-like growth factor signaling pathway as a target for treatment of colorectal carcinoma. AB - The insulin-like growth factors (IGFs), IGF1 and IGF2, are peptide hormones that bind to the insulin-like growth factor 1 receptor (IGF1R) and cause intracellular signaling that ultimately results in cellular growth and proliferation. Evidence from epidemiologic and preclinical studies suggests that IGF signaling may be of importance in the pathogenesis of colorectal cancer (CRC). In recent years, agents that target the IGF1R pathway have been developed. These agents are currently under evaluation for the treatment of CRC. PMID- 20920994 TI - Routine dihydropyrimidine dehydrogenase testing for anticipating 5-fluorouracil related severe toxicities: hype or hope? AB - 5-Fluorouracil (5-FU) is a mainstay for treating colorectal cancer, alone or more frequently as part of combination therapies. However, its efficacy/toxicity balance is often limited by the occurrence of severe toxicities, showing in about 15%-20% of patients. Several clinical reports have shown the deleterious effect of dihydropyrimidine dehydrogenase (DPD) genetic polymorphism, a condition that reduces the liver detoxification step of standard dosages of 5-FU, in patients undergoing fluoropyrimidine-based therapy. Admittedly, DPD deficiency accounts for 50%-75% of the severe and sometimes life-threatening toxicities associated with 5-FU (or oral 5-FU). However, technical consensus on the best way to identify patients with DPD deficiency before administrating 5-FU is far from being achieved. Consequently, no regulatory step has been undertaken yet to recommend DPD testing as part of routine clinical practice for securing the administration of 5-FU. This review covers the limits and achievements of the various strategies proposed so far for determining DPD status in patients scheduled for 5-FU therapy. PMID- 20920995 TI - Patients with locally advanced and metastatic colorectal cancer treated with capecitabine versus 5-fluorouracil as monotherapy or combination therapy with oxaliplatin: a cost comparison. AB - INTRODUCTION: This study quantified the costs associated with the acquisition of chemotherapy, its administration, and the management of chemotherapy-related complications, and their effect on total patient expenditures. PATIENTS AND METHODS: Patients with locally advanced and metastatic colorectal cancer treated with capecitabine or 5-fluorouracil/leucovorin (5-FU/LV) as monotherapy or combination therapy with oxaliplatin from 2003-2006 were identified in the Thomson Reuters MarketScan(r) databases. Selection bias between treatment groups was addressed by propensity score matching, assessment of the risk of complications using Cox models, and an estimate of expenditures using general linear models. RESULTS: In respect to monotherapy, capecitabine users (n = 1272) were propensity score matched to 5-FU/LV users on a 1:1 ratio. The adjusted mean monthly cost was significantly lower for patients treated with capecitabine versus 5-FU/LV ($6683 vs. $9304, respectively; P < .0001). Although the cost of drug acquisition was significantly higher for capecitabine than for 5-FU/LV (unadjusted P < .0001), significantly lower costs of capecitabine administration (unadjusted P < .0001) and management of complications (adjusted costs, P < .0001) offset the difference, and drove a lower overall cost. In regard to combination therapy, capecitabine/oxaliplatin users (n = 263) were propensity score matched to 5-FU/LV/oxaliplatin users (n = 526) on a 1:2 ratio. The adjusted mean monthly cost was significantly lower for capecitabine/oxaliplatin than for 5 FU/LV/oxaliplatin ($11,436 vs. $14,320, respectively; P < .0001). The cost difference was driven by the significantly lower administration costs of capecitabine-based chemotherapy (unadjusted P < .0001) and management of complications (adjusted P < .0001). CONCLUSION: The monthly cost per patient during capecitabine or capecitabine/oxaliplatin treatment is significantly lower than during 5-FU/LV or 5-FU/LV/oxaliplatin treatment because of lower costs for the administration of chemotherapy and for the management of complications. PMID- 20920996 TI - Efficacy and toxicity of chemoradiation in the treatment of HIV-associated anal cancer. AB - PURPOSE: The purpose of this retrospective study is to determine the results and the toxicity of concurrent chemoradiation for squamous cell carcinoma of the anal canal in HIV-positive patients treated at a single institution. PATIENTS AND METHODS: HIV-positive patients with squamous cell carcinoma of the canal treated at Continuum Cancer Centers-affiliated hospitals were identified from tumor registries. We reviewed hospital and treatment charts to gather data relating to demographics, HIV status including cluster of differentiation 4 (CD4) count and viral load, tumor stage, radiation and chemotherapy treatment, toxicity and local control, and survival. RESULTS: Thirty-four patients were identified. All patients received radiation and concurrent chemotherapy consisting of either mitomycin-C and 5-fluorouracil (5-FU; 20 patients), cisplatin and 5-FU (13 patients), or 5-FU alone (1 patient). The most frequently reported severe toxicities were dermatologic (50% grade 3 or 4 toxicity) and hematologic (36% grade 3 or 4 toxicity). Actuarial local control and overall survival (OS) at 3 years were 63% and 69%, respectively. CONCLUSION: Concurrent chemoradiation with cisplatin or mitomycin and 5-FU in HIV-positive patients provides local control and OS comparable to that observed in the HIV-negative population, with acceptable toxicity. PMID- 20920997 TI - Differences in efficacy and safety between capecitabine and infusional 5 fluorouracil when combined with irinotecan for the treatment of metastatic colorectal cancer. AB - BACKGROUND: Capecitabine is an oral fluoropyrimidine that is shown to have similar efficacy to 5-fluorouracil (5-FU) when used both alone and in combination with oxaliplatin in the treatment of colorectal cancer (CRC). Capecitabine and irinotecan combinations (XELIRI) have been developed for the treatment of this disease but randomized comparisons with standard infusional 5-FU and irinotecan (FOLFIRI) showed conflicting results. PATIENTS AND METHODS: We searched the literature for randomized controlled trials comparing XELIRI to FOLFIRI for the treatment of metastatic colorectal cancer. Odds ratios with 95% confidence intervals were used to analyze dichotomous variables. Hazard ratios for progression and death were combined with an inverse variance method based on logarithmic conversion. The fixed-effect model and Mantel-Haenszel method were used. Heterogeneity was investigated with the Q-test and I2. Sensitivity analyses were performed. RESULTS: Only 3 studies were identified, involving a total of 450 patients. XELIRI was associated with significantly shorter progression-free survival (PFS) and increased grade 3/4 gastrointestinal toxicities such as nausea, vomiting, and diarrhea. Severe neutropenia, however, was significantly more frequent with FOLFIRI. No differences in responses and febrile neutropenia events were observed. CONCLUSION: Our analysis suggest that the 2 regimens are not equivalent. XELIRI remains an option for the first-line treatment of metastatic CRC but FOLFIRI should be preferred as it confers more benefits in terms of PFS and induces fewer GI toxicities. PMID- 20920998 TI - Evaluation of the combination 5-fluorouracil, dacarbazine, and epirubicin in patients with advanced well-differentiated neuroendocrine tumors. AB - INTRODUCTION: The aim of this study was to retrospectively analyze the efficacy and safety of the combination of 5-fluorouracil (5-FU), dacarbazine, and epirubicin (FDE) in 39 patients with advanced, well-differentiated neuroendocrine tumors (NETs). PATIENTS AND METHODS: The primary sites of the disease were the pancreas (16 cases), gastrointestinal tract (12 cases), and extradigestive sites (11 cases). Out of these, 54% of the patients were chemotherapy naive and 74% were progressive. The treatment was a combination of 5-FU 500 mg/m2/day, dacarbazine 250 mg/m2/day for 5 days, and epirubicin 50 mg/m2 on day 1, administered every 21 days. Tumoral response was assessed with response evaluation criteria in solid tumors. RESULTS: Partial response was seen in 17 out of the 39 patients (44%) and the median response duration was 12 months. The median progression-free survival and overall survival were 11 and 21 months, respectively. Disease control was achieved in 83% of the 29 patients in progression at the beginning of the treatment. Objective responses were 58%, 25%, and 36%, for pancreatic, gastrointestinal, and extradigestive NETs, respectively. The sole grade 3/4 toxicity was hematologic. CONCLUSION: The FDE regimen is effective in advanced well-differentiated NETs and represents an interesting alternative to streptozocin-based regimens as first- or second-line therapy. PMID- 20920999 TI - Prospective immunohistochemical analysis of primary colorectal cancers for loss of mismatch repair protein expression. AB - BACKGROUND: Evaluation of patients for Lynch syndrome includes assessment of age and family cancer history as well as testing for microsatellite instability and alterations in mismatch repair (MMR) genes. We examined the value of routine immunohistochemistry (IHC) for MMR proteins in patients with colorectal cancer (CRC) undergoing resection at a single institution. PATIENTS AND METHODS: Beginning in July 2006, all patients aged < 50 years who were undergoing resection of primary CRC had their specimens routinely examined by IHC for MMR proteins. Patients aged 50-60 years were examined if histopathology suggestive of Lynch syndrome was reported, and patients of any age were examined if strong clinical suspicion was present. Family cancer history was analyzed and fulfillment of Amsterdam II criteria determined. RESULTS: Over an 18-month period, 96 patients aged < 50 years underwent CRC resection. Out of these, 72 patients (75%) had immunohistochemical testing, with an overall MMR protein loss rate of 19%. In selected patients aged 50-60 years and > 60 years, loss rates were 26% and 65%, respectively. Of all patients with MMR protein loss, 10 (32%) had reported histopathology, and 3 (10%) had family histories suggesting Lynch syndrome. CONCLUSION: We demonstrate the feasibility of routine immunohistochemical testing for MMR proteins in patients with CRC. As only a minority of patients with MMR protein loss met Amsterdam II criteria or had suggestive histopathology reported, routine IHC may identify patients with Lynch syndrome who might otherwise be missed. PMID- 20921001 TI - Demographic, behavioral, and psychosocial correlates of using the website component of a worksite physical activity and healthy nutrition promotion program: a longitudinal study. AB - BACKGROUND: Internet-delivered behavior change programs have the potential to reach a large population. However, low participation levels and high levels of attrition are often observed. The worksite could be a setting suitable for reaching and retaining large numbers of people, but little is known about reach and use of Internet-delivered health promotion programs in the worksite setting. OBJECTIVE: This study aimed (1) to gain more insight in the use of the website component of a worksite behavior change intervention and (2) to identify demographic, behavioral, and psychosocial factors associated with website use. METHODS: The study was an observational study among participants from 5 workplaces in a cluster randomized controlled trial. At baseline, all participants visited a study website to fill out the baseline questionnaire. Then a physical health check was done followed by face-to-face advice. After this contact, all participants received an email to promote visiting the website to view their health check results and the personal advice based on the baseline questionnaire. In the subsequent period, only participants in the intervention group received monthly email messages to promote website visits and were offered additional Web-based tools (self-monitors and a food frequency questionnaire [FFQ] assessing saturated fat intake) to support their behavior change. Website use was monitored by website statistics registering website access. Complete data were available for 726 employees. Logistic regression analyses were conducted to identify characteristics of employees who visited and used the website. RESULTS: In total, 43% of the participants visited the website after the email to promote website visits. Participants who were insufficiently physically active were less likely to visit the website (odds ratio [OR] 0.63, 95% confidence interval [CI] 0.45-0.88), whereas individuals with an elevated total cholesterol level visited the website more often (OR 1.44, 95% CI 1.05-1.98). The monthly emails in the intervention group resulted in higher website use during a 3-month period (18% versus 5% in the reference group, OR 3.96, 95% CI 2.30-6.82). Participants with a positive attitude toward increasing physical activity were less likely to visit the website (OR 0.54, 95% CI 0.31-0.93) or to use the self-monitor and FFQ (OR 0.50, 95% CI 0.25-0.99). Female workers visited the website more often to monitor their behavior and to receive advice on fat intake (OR 2.36, 95% CI 1.14-4.90). CONCLUSIONS: Almost half of the participants used the website component of a worksite behavior change program. Monthly emails were a prompt to visit the website, but website use remained low. More women than men used the website to obtain personalized advice for behavior change. No consistently higher participation was found among those with healthier behaviors. This health promotion program did not provide an indication that healthier subjects are more susceptible to health promotion. TRIAL REGISTRATION: ISRCTN52854353; http://www.controlled-trials.com/ISRCTN52854353 (Archived by WebCite at http://www.webcitation.org/5smxIncB1). PMID- 20921002 TI - A new technique for complete intraluminal repair of iatrogenic posterior tracheal lacerations. AB - Tracheal laceration is a rare complication of endotracheal intubation. Early surgical treatment is mandatory in cases of pneumomediastinum with difficulty in ventilation to prevent mediastinitis and stricture. Surgical access to the posterior tracheal wall is via a right posterolateral thoracotomy, transcervical tracheotomy or tracheostomy, each of which is associated with specific morbidities. We developed a new optical needle holder consisting of a 12 degrees HOPKINS telescope in a fixed attachment with an endoscopic needle holder to allow for complete intraluminal repair of posterior tracheal wall lacerations. Four patients were admitted with an iatrogenic tracheal laceration due to emergency intubation. In all cases, the repair of the tracheal laceration started with the introduction of a 14-mm rigid tracheoscope and subsequent jet-ventilation. Three of the tears were successfully repaired endotracheally with a running suture. In one case, the repair had to be converted to an open closure via posterolateral thoracotomy. Two patients were discharged extubated for further treatment of their underlying diseases. One patient died from a third cardiac infarction two days after the tracheal repair. We think that an exclusively endoluminal repair of longitudinal tracheal lacerations is feasible. This repair has convincing advantages including little surgical trauma, lack of scars and diminished postoperative pain. PMID- 20921003 TI - Theory of hybrid dynamical systems and its applications to biological and medical systems. AB - In this introductory article, we survey the contents of this Theme Issue. This Theme Issue deals with a fertile region of hybrid dynamical systems that are characterized by the coexistence of continuous and discrete dynamics. It is now well known that there exist many hybrid dynamical systems with discontinuities such as impact, switching, friction and sliding. The first aim of this Issue is to discuss recent developments in understanding nonlinear dynamics of hybrid dynamical systems in the two main theoretical fields of dynamical systems theory and control systems theory. A combined study of the hybrid systems dynamics in the two theoretical fields might contribute to a more comprehensive understanding of hybrid dynamical systems. In addition, mathematical modelling by hybrid dynamical systems is particularly important for understanding the nonlinear dynamics of biological and medical systems as they have many discontinuities such as threshold-triggered firing in neurons, on-off switching of gene expression by a transcription factor, division in cells and certain types of chronotherapy for prostate cancer. Hence, the second aim is to discuss recent applications of hybrid dynamical systems in biology and medicine. Thus, this Issue is not only general to serve as a survey of recent progress in hybrid systems theory but also specific to introduce interesting and stimulating applications of hybrid systems in biology and medicine. As the introduction to the topics in this Theme Issue, we provide a brief history of nonlinear dynamics and mathematical modelling, different mathematical models of hybrid dynamical systems, the relationship between dynamical systems theory and control systems theory, examples of complex behaviour in a simple neuron model and its variants, applications of hybrid dynamical systems in biology and medicine as a road map of articles in this Theme Issue and future directions of hybrid systems modelling. PMID- 20921004 TI - Discontinuity-induced bifurcations of piecewise smooth dynamical systems. AB - This paper presents an overview of the current state of the art in the analysis of discontinuity-induced bifurcations (DIBs) of piecewise smooth dynamical systems, a particularly relevant class of hybrid dynamical systems. Firstly, we present a classification of the most common types of DIBs involving non-trivial interactions of fixed points and equilibria of maps and flows with the manifolds in phase space where the system is non-smooth. We then analyse the case of limit cycles interacting with such manifolds, presenting grazing and sliding bifurcations. A description of possible classification strategies to predict and analyse the scenarios following such bifurcations is also discussed, with particular attention to those methodologies that can be applied to generic n dimensional systems. PMID- 20921005 TI - Stability analysis and controller synthesis for hybrid dynamical systems. AB - Wherever continuous and discrete dynamics interact, hybrid systems arise. This is especially the case in many technological systems in which logic decision-making and embedded control actions are combined with continuous physical processes. Also for many mechanical, biological, electrical and economical systems the use of hybrid models is essential to adequately describe their behaviour. To capture the evolution of these systems, mathematical models are needed that combine in one way or another the dynamics of the continuous parts of the system with the dynamics of the logic and discrete parts. These mathematical models come in all kinds of variations, but basically consist of some form of differential or difference equations on the one hand and automata or other discrete-event models on the other hand. The collection of analysis and synthesis techniques based on these models forms the research area of hybrid systems theory, which plays an important role in the multi-disciplinary design of many technological systems that surround us. This paper presents an overview from the perspective of the control community on modelling, analysis and control design for hybrid dynamical systems and surveys the major research lines in this appealing and lively research area. PMID- 20921006 TI - Robust dynamics in minimal hybrid models of genetic networks. AB - Many gene-regulatory networks necessarily display robust dynamics that are insensitive to noise and stable under evolution. We propose that a class of hybrid systems can be used to relate the structure of these networks to their dynamics and provide insight into the origin of robustness. In these systems, the genes are represented by logical functions, and the controlling transcription factor protein molecules are real variables, which are produced and destroyed. As the transcription factor concentrations cross thresholds, they control the production of other transcription factors. We discuss mathematical analysis of these systems and show how the concepts of robustness and minimality can be used to generate putative logical organizations based on observed symbolic sequences. We apply the methods to control of the cell cycle in yeast. PMID- 20921007 TI - Piecewise affine systems approach to control of biological networks. AB - In terms of a piecewise affine system representation, which is a kind of hybrid system model, this article discusses a series of approaches to modelling, analysing and synthesizing a biological network such as a gene-regulatory network. First, the input assignment problem, the controllable state set problem (CSP) and the input trajectory generation problem are emphasized as control problems to be addressed for biological networks. Subsequently, after the modelling issue on biological networks developed in the systems and control community is briefly explained, the CSP is described in detail with reference to control of the quorum-sensing system in the pathogen Pseudomonas aeruginosa. Finally, an optimal control design method to the quorum-sensing system is proposed as a solution to the input trajectory generation problem. PMID- 20921008 TI - Stochastic hybrid systems for studying biochemical processes. AB - Many protein and mRNA species occur at low molecular counts within cells, and hence are subject to large stochastic fluctuations in copy numbers over time. Development of computationally tractable frameworks for modelling stochastic fluctuations in population counts is essential to understand how noise at the cellular level affects biological function and phenotype. We show that stochastic hybrid systems (SHSs) provide a convenient framework for modelling the time evolution of population counts of different chemical species involved in a set of biochemical reactions. We illustrate recently developed techniques that allow fast computations of the statistical moments of the population count, without having to run computationally expensive Monte Carlo simulations of the biochemical reactions. Finally, we review different examples from the literature that illustrate the benefits of using SHSs for modelling biochemical processes. PMID- 20921009 TI - A hybrid approach to multi-scale modelling of cancer. AB - In this paper, we review multi-scale models of solid tumour growth and discuss a middle-out framework that tracks individual cells. By focusing on the cellular dynamics of a healthy colorectal crypt and its invasion by mutant, cancerous cells, we compare a cell-centre, a cell-vertex and a continuum model of cell proliferation and movement. All models reproduce the basic features of a healthy crypt: cells proliferate near the crypt base, they migrate upwards and are sloughed off near the top. The models are used to establish conditions under which mutant cells are able to colonize the crypt either by top-down or by bottom up invasion. While the continuum model is quicker and easier to implement, it can be difficult to relate system parameters to measurable biophysical quantities. Conversely, the greater detail inherent in the multi-scale models means that experimentally derived parameters can be incorporated and, therefore, these models offer greater scope for understanding normal and diseased crypts, for testing and identifying new therapeutic targets and for predicting their impacts. PMID- 20921010 TI - Mathematical modelling of prostate cancer growth and its application to hormone therapy. AB - Hormone therapy in the form of androgen deprivation is a major treatment for advanced prostate cancer. However, if such therapy is overly prolonged, tumour cells may become resistant to this treatment and result in recurrent fatal disease. Long-term hormone deprivation also is associated with side effects poorly tolerated by patients. In contrast, intermittent hormone therapy with alternating on- and off-treatment periods is a possible clinical strategy to delay progression to hormone-refractory disease with the advantage of reduced side effects during the off-treatment periods. In this paper, we first overview previous studies on mathematical modelling of prostate tumour growth under intermittent hormone therapy. The model is categorized into a hybrid dynamical system because switching between on-treatment and off-treatment intervals is treated in addition to continuous dynamics of tumour growth. Next, we present an extended model of stochastic differential equations and examine how well the model is able to capture the characteristics of authentic serum prostate-specific antigen (PSA) data. We also highlight recent advances in time-series analysis and prediction of changes in serum PSA concentrations. Finally, we discuss practical issues to be considered towards establishment of mathematical model-based tailor made medicine, which defines how to realize personalized hormone therapy for individual patients based on monitored serum PSA levels. PMID- 20921011 TI - Piecewise affine systems modelling for optimizing hormone therapy of prostate cancer. AB - Prostate cancer is one of the most common malignant neoplasms in men with an overall incidence of approximately 15 per cent during the normal life span. Androgen-deprivation therapy (hormone therapy) is an effective treatment of this disease when progressed to an advanced stage. Despite impressive responses, such treatment when applied on a continuous basis is not curative and eventually culminates in androgen-independent disease. On the other hand, intermittent androgen suppression (IAS) was first conceived as a potential way of delaying progression to androgen-independence, in addition offering the possibility of reducing adverse effects and improving the quality of life. Although the validity of this approach has been confirmed in several clinical studies, the optimal scheduling of the cycles of on- and off-treatment remains to be explored. In the present article, we show that IAS lends itself to mathematical modelling with hybrid dynamical systems and that the model we have developed can be used to select the best strategy for keeping prostate cancer in an androgen-dependent state as long as possible. Our results also suggest that the current way of using IAS exceeds what is necessary for optimal control; in fact, we have found that to achieve optimal control, the amount of therapy (dose and duration of drugs) can be reduced by a factor of one half. PMID- 20921012 TI - Hybrid spiking models. AB - I review a class of hybrid models of neurons that combine continuous spike generation mechanisms and a discontinuous 'after-spike' reset of state variables. Unlike Hodgkin-Huxley-type conductance-based models, the hybrid spiking models have a few parameters derived from the bifurcation theory; instead of matching neuronal electrophysiology, they match neuronal dynamics. I present a method of after-spike resetting suitable for hardware implementation of such models, and a hybrid numerical method for simulations of large-scale biological spiking networks. PMID- 20921013 TI - Hybrid discrete-time neural networks. AB - Hybrid dynamical systems combine evolution equations with state transitions. When the evolution equations are discrete-time (also called map-based), the result is a hybrid discrete-time system. A class of biological neural network models that has recently received some attention falls within this category: map-based neuron models connected by means of fast threshold modulation (FTM). FTM is a connection scheme that aims to mimic the switching dynamics of a neuron subject to synaptic inputs. The dynamic equations of the neuron adopt different forms according to the state (either firing or not firing) and type (excitatory or inhibitory) of their presynaptic neighbours. Therefore, the mathematical model of one such network is a combination of discrete-time evolution equations with transitions between states, constituting a hybrid discrete-time (map-based) neural network. In this paper, we review previous work within the context of these models, exemplifying useful techniques to analyse them. Typical map-based neuron models are low-dimensional and amenable to phase-plane analysis. In bursting models, fast-slow decomposition can be used to reduce dimensionality further, so that the dynamics of a pair of connected neurons can be easily understood. We also discuss a model that includes electrical synapses in addition to chemical synapses with FTM. Furthermore, we describe how master stability functions can predict the stability of synchronized states in these networks. The main results are extended to larger map-based neural networks. PMID- 20921014 TI - A phase-reduced neuro-mechanical model for insect locomotion: feed-forward stability and proprioceptive feedback. AB - In earlier work, we have developed an integrated model for insect locomotion that includes a central pattern generator (CPG), nonlinear muscles, hexapedal geometry and a representative proprioceptive sensory pathway. Here, we employ phase reduction and averaging theory to replace 264 ordinary differential equations (ODEs), describing bursting neurons in the CPG, their synaptic connections to motoneurons, muscle activation dynamics and sensory neurons, with 24 one dimensional phase oscillators that describe motoneuronal activation of agonist antagonist muscle pairs driving the jointed legs. Reflexive feedback is represented by stereotypical spike trains with rates proportional to joint torques, which change phase relationships among the motoneuronal oscillators. Restriction to the horizontal plane, neglect of leg mass and use of Hill-type muscle models yield a biomechanical body-limb system with only three degrees of freedom, and the resulting hybrid dynamical system involves 30 ODEs: reduction by an order of magnitude. We show that this reduced model captures the dynamics of unperturbed gaits and the effects of an impulsive perturbation as accurately as the original one. Moreover, the phase response and coupling functions provide an improved understanding of reflexive feedback mechanisms. PMID- 20921015 TI - Optic nerve gliomas: role of Ki-67 staining of tumour and margins in predicting long-term outcome. AB - BACKGROUND: Although optic nerve gliomas (ONGs) are generally slow-growing with a good prognosis, factors for identifying cases that may pursue a more aggressive course are not well established. The authors investigated cell proliferation markers for prognostic significance in a series of resected ONGs. METHODS: Twelve cases of resected ONG were identified out of a total of 38 examined at the authors' institution between 1981 and 2008. Clinical data were reviewed. Ki-67 and p53 immunohistochemical staining was performed on the tumour mass and the proximal resection margin. RESULTS: All of the tumours were low-grade pilocytic astrocytomas. Six patients were suspected to have histologically positive proximal resection margins. Ki-67 labelling indices (LI) ranged from 0.3% to 5.9% (mean 2.4%) for the tumour mass and from 0 to 2.1% (mean 0.9%) for the proximal resection margins. One patient had evidence of progression 25 months after subtotal surgical resection. The Ki-67 LI of the proximal resection margin in this case was similar to the main tumour value. The other six patients with histologically negative proximal resection margins all had lower relative proliferation indices at the resection margin when compared with the tumour mass and are currently stable with no evidence of progression. CONCLUSIONS: Routine histological examination of resection margins may be difficult to interpret in the setting of reactive gliosis. A resection margin with a Ki-67 LI similar to the tumour bulk value may have an adjunctive role in identifying cases with the potential for growth thereby facilitating the decision-making process for future management and surveillance. PMID- 20921016 TI - Young age as a risk factor for complicated course and visual outcome in intermediate uveitis in children. AB - OBJECTIVE: To identify prognostic factors in intermediate uveitis (IU) in children. METHODS: Retrospective case series of 35 patients with onset of IU <=16 years and a minimum follow-up of 1 year. Demographic and numerous clinical data were documented. Visual outcomes and development of complications were analysed in relation to age of onset and ocular signs at presentation. RESULTS: Forty-six per cent of patients had onset <=7 years, and 54% >7 years. The younger-onset group had a shorter event-free survival for secondary glaucoma (p=0.04) and vitreous haemorrhage (p=0.01). The mean age of onset in children with cataract (5.9 vs 8.7 years), glaucoma (5.0 vs 8.4) and vitreous haemorrhage (5.6 vs 8.5) was lower than in children without these complications (all p=0.03). Frequencies of other complications did not differ between both groups. The younger-onset group had worse BCVAs at presentation (0.3 vs 0.6), at 1 year (0.4 vs 0.9) and at 3 years' follow-up (0.6 vs 0.9; all p<=0.04), and they needed longer treatment (p=0.01). Children with young onset of IU reached remission less frequently (p=0.05). Development of cystoid macular oedema was independently associated with papillitis (adjusted HR=3.4; p=0.02) and snowbanking (adjusted HR=3.3; p=0.03) at presentation. Other complications at onset were not predictive for future complications. CONCLUSIONS: Children with young onset of IU carry a higher risk of complications and worse visual outcome. The authors would recommend considering more intensive monitoring and earlier threshold for systemic treatment in those children with risk factors as early onset, papillitis and/or snowbanking at initial presentation. PMID- 20921017 TI - An evaluation of echo in life support (ELS): is it feasible? What does it add? AB - BACKGROUND: Emergency physicians were trained to perform echo in life support (ELS)--that is, limited transthoracic echocardiography during advanced life support (ALS) management of cardiac arrest. METHODS: Data were collected on the adequacy of views obtained and timing of the scan, as well as the clinical findings of pericardial effusion and ventricular wall motion. Any intervention performed as a result of the scan was also noted. ELS was performed on 50 patients during cardiac arrest. RESULTS: Adequate views were obtained in 47 (94%) scans, and 45 (90%) were obtained within the 10 s rhythm check. Twenty patients (40%) had ventricular wall motion (VWM), three (6%) had pericardial effusions and six patients (12%) had an intervention performed as a direct result of the scan. These included pericardiocentesis, thrombolysis and insertion of a chest drain. The presence of VWM had a positive predictive value of 55%. The absence of VWM resulted in a negative predictive value of 97% for predicting return of spontaneous circulation (ROSC). CONCLUSION: It is concluded that ELS is feasible and that the scan findings may guide further interventions. PMID- 20921018 TI - Effects of pre-arrest comorbidities on 90-day survival of patients resuscitated from out-of-hospital cardiac arrest. AB - BACKGROUND: Factors that affect prognosis in successfully resuscitated out-of hospital cardiopulmonary arrest (OHCA) patients in the intensive care unit (ICU) who survived the initial 24 h period of post-resuscitation have not been established. This study was conducted to evaluate the clinical prognostic factors associated with 90-day survival in patients who were successfully resuscitated from OHCA. METHODS: This study was conducted at a tertiary large university hospital. Clinical data were obtained from the medical records of 224 adult non traumatic patients who were successfully resuscitated from OHCA and who survived the initial 24 h post-resuscitation phase. Univariate and multivariate analyses were performed to identify independent predictors associated with 90-day survival. RESULTS: Significant adverse prognosticators included liver cirrhosis (HR 4.36, 95% CI 1.76 to 10.79), prolonged cardiopulmonary resuscitation (CPR) duration >20 min (HR 1.95, 95% CI 1.27 to 3.00) and underlying malignancy (HR 1.64, 95% CI 1.06 to 2.54). Favourable prognostic factors included the best Glasgow Coma Scale within 24-48 h after return of spontaneous circulation >5 (HR 0.16, 95% CI 0.04 to 0.68), mean arterial pressure on ICU admission >100 mmHg (HR 0.81, 95% CI 0.43 to 0.94) and the presenting rhythm of pulseless electrical activity (HR 0.44, 95% CI 0.1 to 0.63). A high burden of comorbidities (by Charlson score >5) was associated with significantly poorer 90-day survival (HR 1.60, 95% CI 1.03 to 2.49). CONCLUSIONS: Underlying comorbidities have a significant influence on survival. CPR duration, post-resuscitative blood pressure and early neurological recovery may serve as practical clinical predictors of short-term survival. PMID- 20921019 TI - Health utility and survival after hospital admission with acute cardiogenic pulmonary oedema. AB - BACKGROUND: The aim of this study was to measure health utility and survival in patients with acute cardiogenic pulmonary oedema (ACPO), identify predictors of outcome and determine the effect of initial treatment with non-invasive ventilation (NIV) upon outcomes. METHODS: A randomised controlled trial was conducted at 26 hospitals in the UK. 1069 adults with ACPO were randomised to continuous positive airway pressure (CPAP), non-invasive positive pressure ventilation (NIPPV) or standard oxygen therapy. The main outcome measures were survival to 1-5 years, health utility measured using the EQ-5D survey at 1, 3 and 6 months, and quality-adjusted life years (QALYs). RESULTS: Median survival was 771 days (95% CI 669 to 875), with no difference between the three treatment groups (p = 0.827). Age (HR 1.042, 95% CI 1.031 to 1.052), chronic obstructive pulmonary disease (HR 1.13, 95% CI 1.06 to 1.62), cerebrovascular disease (HR 1.41, 95% CI 1.14 to 1.73) and diabetes mellitus (HR 1.31, 95% CI 1.01 to 1.63) independently predicted mortality. Mean EQ-5D scores were 0.578, 0.576 and 0.582 at 1, 3 and 6 months, respectively, with no significant difference between the treatment groups. Male gender (+0.045 QALYs, 95% CI 0.009 to 0.081) and cerebrovascular disease (-0.080 QALYs, 95% CI -0.131 to -0.029) independently predicted health utility. CONCLUSION: Patients with ACPO have high mortality and reduced health utility. Initial treatment with CPAP or NIPPV does not alter subsequent survival or health utility. PMID- 20921020 TI - Cohen syndrome diagnosis using whole genome arrays. AB - BACKGROUND: Cohen syndrome is a rare autosomal recessive disorder with a complex phenotype including psychomotor retardation, microcephaly, obesity with slender extremities, joint laxity, progressive chorioretinal dystrophy/myopia, intermittent isolated neutropenia, a cheerful disposition, and characteristic facial features. The COH1 gene, which contains 62 exons, is so far the only gene known to be associated with Cohen syndrome. Point mutations, deletions and duplications have been described in this gene. Oligonucleotide arrays have reached a resolution which allows the detection of intragenic deletions and duplications, especially in large genes such as COH1. METHOD AND RESULTS: High density oligonucleotide array data from patients with unexplained mental retardation (n=1523) and normal controls (n=1612) were analysed for copy number variation (CNV) changes. Intragenic heterozygous deletions in the COH1 gene were detected in three patients but no such changes were detected in the controls. Subsequent sequencing of the COH1 gene revealed point mutations in the second allele in all three patients analysed. CONCLUSION: Genome-wide CNV screening with high density arrays provides a tool to detect intragenic deletions in the COH1 gene. This report presents an example of how microarrays can be used to identify autosomal recessive syndromes and to extend the phenotypic and mutational spectrum of recessive disorders. PMID- 20921021 TI - Germline mutations in CDH1 are infrequent in women with early-onset or familial lobular breast cancers. AB - BACKGROUND: Germline mutations in CDH1 are associated with hereditary diffuse gastric cancer; lobular breast cancer also occurs excessively in families with such condition. METHOD: To determine if CDH1 is a susceptibility gene for lobular breast cancer in women without a family history of diffuse gastric cancer, germline DNA was analysed for the presence of CDH1 mutations in 318 women with lobular breast cancer who were diagnosed before the age of 45 years or had a family history of breast cancer and were not known, or known not, to be carriers of germline mutations in BRCA1 or BRCA2. Cases were ascertained through breast cancer registries and high-risk cancer genetic clinics (Breast Cancer Family Registry, the kConFab and a consortium of breast cancer genetics clinics in the United States and Spain). Additionally, Multiplex Ligation-dependent Probe Amplification was performed for 134 cases to detect large deletions. RESULTS: No truncating mutations and no large deletions were detected. Six non-synonymous variants were found in seven families. Four (4/318 or 1.3%) are considered to be potentially pathogenic through in vitro and in silico analysis. CONCLUSION: Potentially pathogenic germline CDH1 mutations in women with early-onset or familial lobular breast cancer are at most infrequent. PMID- 20921023 TI - Ancestry informative markers for fine-scale individual assignment to worldwide populations. AB - BACKGROUND AND AIMS: The analysis of large-scale genetic data from thousands of individuals has revealed the fact that subtle population genetic structure can be detected at levels that were previously unimaginable. Using the Human Genome Diversity Panel as reference (51 populations - 650,000 SNPs), this works describes a systematic evaluation of the resolution that can be achieved for the inference of genetic ancestry, even when small panels of genetic markers are used. METHODS AND RESULTS: A comprehensive investigation of human population structure around the world is undertaken by leveraging the power of Principal Components Analysis (PCA). The problem is dissected into hierarchical steps and a decision tree for the prediction of individual ancestry is proposed. A complete leave-one-out validation experiment demonstrates that, using all available SNPs, assignment of individuals to their self-reported populations of origin is essentially perfect. Ancestry informative genetic markers are selected using two different metrics (In and correlation with PCA scores). A thorough cross validation experiment indicates that, in most cases here, the number of SNPs needed for ancestry inference can be successfully reduced to less than 0.1% of the original 650,000 while retaining close to 100% accuracy. This reduction can be achieved using a novel clustering-based redundancy removal algorithm that is also introduced here. Finally, the applicability of our suggested SNP panels is tested on HapMap Phase 3 populations. CONCLUSION: The proposed methods and ancestry informative marker panels, in combination with the increasingly more comprehensive databases of human genetic variation, open new horizons in a variety of fields, ranging from the study of human evolution and population history, to medical genetics and forensics. PMID- 20921022 TI - Recurrent microdeletions of 15q25.2 are associated with increased risk of congenital diaphragmatic hernia, cognitive deficits and possibly Diamond- Blackfan anaemia. AB - BACKGROUND: Congenital diaphragmatic hernia (CDH) can occur in isolation or in association with other abnormalities. We hypothesised that some cases of non isolated CDH are caused by novel genomic disorders. METHODS AND RESULTS: In a cohort of >12, 000 patients referred for array comparative genomic hybridisation testing, we identified three individuals-two of whom had CDH--with deletions involving a ~2.3 Mb region on chromosome 15q25.2. Two additional patients with deletions of this region have been reported, including a fetus with CDH. Clinical data from these patients suggest that recurrent deletions of 15q25.2 are associated with an increased risk of developing CDH, cognitive deficits, cryptorchidism, short stature and possibly Diamond-Blackfan anaemia (DBA). Although no known CDH-associated genes are located on 15q25.2, four genes in this region--CPEB1, AP3B2, HOMER2 and HDGFRP3--have been implicated in CNS development/function and may contribute to the cognitive deficits seen in deletion patients. Deletions of RPS17 may also predispose individuals with 15q25.2 deletions to DBA and associated anomalies. CONCLUSIONS: Individuals with recurrent deletions of 15q25.2 are at increased risk for CDH and other birth defects. A high index of suspicion should exist for the development of cognitive defects, anaemia and DBA-associated malignancies in these individuals. PMID- 20921025 TI - Manual therapy versus usual GP care for chronic tension-type headache: we now have better evidence, but important questions remain. PMID- 20921024 TI - Organic fertilization leads to increased peach root production and lifespan. AB - We evaluated the effects of mineral and organic fertilizers on peach root dynamics in the growing season from 2003 to 2006 in a nectarine (Prunus persica L.) orchard, planted in 2001 and located in the Po valley, northeastern Italy. Very few studies have conducted long-term investigations of root dynamics of fruit crops. Our main objective was to determine whether organic fertilizers affect root dynamics differently than mineral fertilizers. The experiment was a completely randomized block design with four replicates of three treatments: unfertilized, mineral fertilized and composted with municipal waste. Mineral fertilizers included P (100 kg ha(-1) year(-1)) and K (200 kg ha(-1) year(-1)) applied only at planting and N (70-130 kg ha(-1) year(-1)) split into two applications, one at 40 days after full bloom (60%) and the other in September (40%) each year. The compost fertilization represented a yearly rate of 10 metric tons (t) dry weight ha(-1), which approximates (in kg ha(-1) year(-1)) 240 N, 100 P and 200 K, split similarly to that described for the mineral fertilization of N. Both root growth and survival were evaluated at 20-day intervals during the growing season by the minirhizotron technique. Compost increased the production of new roots compared with the other treatments (P < 0.01). Roots were mainly produced at a depth of 41-80 cm and from March to May and in late summer. An analysis of covariance indicated no significant effect of soil nitrate on root production (P = 0.47). The root lifespan was longer in compost-treated trees than in mineral-fertilized or unfertilized trees (P < 0.01) and it was strongly affected by time of birth; roots born later in the summer lived longer than those born in the spring. Across years and treatments, the average root lifespan was positively correlated with soil nitrate (r = 0.60; P < 0.001). Variation in root lifespan with method of fertilization could be accounted for by variation in soil nitrate concentration as indicated by no effect of fertilizer treatment on root lifespan when soil nitrate was included as a covariate. These results reveal how shifting from mineral to organic fertilizers may shift both soil properties and nutrient availability, leading to changes in both root production and lifespan. PMID- 20921026 TI - Mendelian and complex causes of migraine: bridging the gap. PMID- 20921027 TI - Predicting the probability of relapse after discontinuation of migraine preventive treatment with topiramate. PMID- 20921028 TI - Spasticity and contractures at the wrist after stroke: time course of development and their association with functional recovery of the upper limb. AB - OBJECTIVE: To investigate the time course of development of spasticity and contractures at the wrist after stroke and to explore if these are associated with upper limb functional recovery. DESIGN: Longitudinal observational study using secondary data from the control group of a randomized controlled trial. SETTING: The Acute Stroke Unit at the University Hospital of North Staffordshire. SUBJECTS: Patients without useful arm function (Action Research Arm Test - ARAT) score of 0 within 6 weeks of a first stroke. MAIN MEASURES: Spasticity was measured by quantifying muscle activity during passively imposed stretches at two velocities. Contractures were measured by quantifying passive range of movement and stiffness. Upper limb functional movement was assessed using the ARAT. All assessments were conducted at baseline, and at 6, 12, 24 and 36 weeks after recruitment. RESULTS: Thirty patients (43% male, median age 70 (range 52-90) years, median time since stroke onset 3 (range 1-5) weeks) were included. Twenty eight (92%) demonstrated signs of spasticity throughout the study period. Participants who recovered arm function (n = 5) showed signs of spasticity at all assessment points but did not develop contractures. Patients who did not recover useful arm function (n = 25) had signs of spasticity and changes associated with contracture formation at all time points tested. CONCLUSION: In this group of patients who had no arm function within the first 6 weeks of stroke, spasticity was seen early, but did not necessarily hinder functional recovery. Contractures were more likely to develop in patients who did not recover arm function. PMID- 20921029 TI - Comparison of an intermittent high-intensity vs continuous low-intensity physiotherapy service over 12 months in community-dwelling people with stroke: a randomized trial. AB - OBJECTIVE: This study compared two modes of physiotherapy service over 12 months in community-dwelling people with stroke, either following a train-wait train paradigm by providing bouts of intense physiotherapy, or a continuous less intense programme. DESIGN: Randomized trial. SETTING: Community-dwelling people with stroke. INTERVENTIONS: Fifty patients, first-time stroke, discharged home, following inpatient rehabilitation, allocated to two groups, A and B. Over 12 months, Group A (n = 25) received three two-month blocks of therapy at home, each block contained four 30 to 45 minute sessions per week, totalling 96 sessions. Group B (n = 25) continuously received two 30 to 45 minute sessions per week, totalling 104 sessions. MAIN OUTCOME MEASURES: Primary Rivermead Mobility Index (0-15), secondary upper- and lower-limb motor functions, Activities of Daily Living competence, tone and number of falls. RESULTS: Both groups were comparable at onset, the mean age in Group A (B) was 62.4 (61.9) years. A and B patients equally improved functions over time, between group differences did not occur. The initial (terminal) Rivermead Mobility Index was 9.4 +/- 2.8 (12.2 +/- 2.1) in Group A, and 8.5 +/- 3.5 (11.2 +/- 2.7) in Group B. More Group B patients fell seriously (7 versus 1). CONCLUSIONS: The intermittent high-intensity and continuous low-intensity therapy protocols were equally effective, the sheer intensity seems more important than the time-mode of application. The relatively young patients functionally improved in the first year after stroke, the reduced risk of serious falls in the intermittent high-intensity group should be validated. PMID- 20921030 TI - The relationship between objectively and subjectively measured activity levels in people with chronic low back pain. AB - OBJECTIVE: To compare self-report measures of daily activities with objective activity data to determine whether patients with chronic lower back pain report their activity levels as accurately as controls do. DESIGN: A cross-sectional study was performed in patients and controls. SETTING: The study was carried out in the daily environment of the subjects. SUBJECTS: Thirty-two chronic lower back pain patients with symptoms more than three months and 20 healthy controls from the Netherlands, aged 18-65 years. MAIN MEASURES: A tri-axial accelerometer was worn for five weekdays and the Baecke Physical Activity Questionnaire was filled in. Pearson's correlation was calculated to get insight in the awareness of patients and controls. Comparisons of the relationship between the objective and subjective scores of each individual patient with those of the group of controls were used to allocate each patient into subgroups: overestimators, underestimators and aware patients. Physical and psychological characteristics of these groups were explored. RESULTS: Patients showed weak correlations between the objective and subjective scores of physical activity and appear to have problems in estimating their activity levels (r = -0.27), in contrast to controls who showed strong correlations between the objective and subjective scores (r = 0.66). Comparison of the individual relationships of patients with those of controls showed that 44% of the patients were not aware of their activity level. There were relatively more underestimators (30%) than overestimators (14%). Physical characteristics between the three groups tended to be different. CONCLUSIONS: Patient self-reports about their activity level are relatively inaccurate when compared to objective measurements. PMID- 20921031 TI - Normative data, preliminary inter-rater reliability and predictive validity of the Drive Home Maze Test. AB - OBJECTIVE: The Drive Home Maze Test has been developed as part of a clinic-based driver assessment battery. This article reports normative data and preliminary inter-rater reliability for this test together with predictive validity for a clinical sample. SUBJECTS AND SETTING: 223 individuals contributed to the normative data. Of these, data from 42 clients undergoing driver assessment as part of their rehabilitation or health care plan were used to ascertain the predictive validity of the Drive Home Maze Test for on-road driving performance (Pass/ Fail). MAIN MEASURE: The Drive Home Maze Test was developed for occupational therapy driver assessors to use with all older and/ or functionally impaired drivers prior to on-road testing. The test assesses a person s executive function, attention and visuoconstructive skills. RESULTS: The normative data indicated that time taken and number of errors on the maze increases with age. Performance on this test was strongly indicative of driver assessment outcome using the regression model: ln(Odds of failing on road) = 5.9451 + 2.7047 (log10 time taken to complete the maze). Excellent preliminary inter-rater reliability was also found using Ordinary Least Products linear regression analysis to test for bias between two raters for time taken and number of errors on the maze, with values ranging from r = 0.858 to 0.999. CONCLUSIONS: The Drive Home Maze Test provides useful information concerning a person's cognitive skills prior to undertaking an on-road assessment. Time taken to complete this test is indicative of the outcome of an on-road driver assessment. PMID- 20921032 TI - Higher-intensity treadmill walking during rehabilitation after stroke in feasible and not detrimental to walking pattern or quality: a pilot randomized trial. AB - OBJECTIVE: To determine whether higher-intensity treadmill walking during rehabilitation in those newly able to walk after stroke is feasible, is detrimental to walking or is beneficial. DESIGN: A single-blind, randomized trial. SETTING: Two rehabilitation units. PARTICIPANTS: Thirty people with first stroke. INTERVENTIONS: Experimental group received 30 minutes of higher-intensity treadmill walking, three times per week for six weeks, in addition to usual physiotherapy. Control group received usual physiotherapy only. MAIN OUTCOME MEASURES: Feasibility was measured by examining compliance and adverse events. Detriment to walking was measured by examining pattern and quality. Benefit to walking was measured as capacity using six-minute walk test and speed, at baseline (Week 0), immediately after (Week 6) and at three months (Week 18). RESULTS: Overall compliance was 89%, with no adverse events reported. There was no between-group difference in walking pattern and quality. By Week 6, the experimental group improved walking capacity by 62 m (95% confidence interval (CI) 10 to 114), comfortable walking speed by 0.18 m/s (95% CI 0.07 to 0.29) and fast walking speed by 0.18 m/s (95% CI 0.03 to 0.35) more than the control group. By Week 18, the experimental group was still walking 0.26 m/s (95% CI 0.12 to 0.41) faster than the control group. CONCLUSIONS: Higher-intensity treadmill walking during rehabilitation after stroke is feasible and not detrimental to walking pattern and quality in those newly able to walk. 94 participants are required to detect a between-group difference of 75 m on six-minute walk test (alpha 0.05, beta 0.90) in future trials. TRIAL REGISTRATION: ACTRN12607000412437. PMID- 20921033 TI - Social networks, social capital and chronic illness self-management: a realist review. AB - BACKGROUND: Existing literature on the design of interventions and health policy about self-management have tended to focus on individual-centred definitions of self-care and there is growing recognition of the need to extend consideration beyond individual factors, which determine self-care, to examine wider influences such as the health service, the family and the wider social context. AIMS: To explore the theoretical and empirical links between social networks, social capital and the self-care practices associated with chronic illness work and management in the context of people's everyday lives. METHOD: A realist review method was used to search and appraise relevant quantitative and qualitative literature. FINDINGS: The review findings indicate that social networks play an important part in the management of long-term conditions. We found that social networks tend to be defined narrowly and are primarily used as a way of acknowledging the significance of context. There is insufficient discussion in the literature of the specific types of networks that support or undermine self care as well as an understanding of the processes involved. This necessitates shifting the emphasis of self-care towards community and network-centred approaches, which may also prove more appropriate for engaging people in socially and economically deprived contexts. PMID- 20921034 TI - Active living--the perception of older people with chronic conditions. AB - OBJECTIVES: To describe and understand factors which enhance and impede participation in physical activity for older adults with and without chronic illness and develop a framework of health behaviours for 'active living'. METHODS: A contrasting group framework was used to compare discussions in two sets of focus groups with relatively healthy and less healthy older adults. The thematic analysis was informed by the Transtheoretical Model, the Health Belief Model and Social Cognitive Theory. RESULTS: All participants affirmed the health benefits of physical activity and there was broad agreement that social support and conductive environments contributed to the promotion of opportunities for physical activity. However, perceptions of specific factors needed to maintain and promote good health differed between healthy and less healthy participants. Connection to community, sense of place and 'walkability' of neighbourhoods were identified as motivators for undertaking physical activity, whilst barriers were associated with health, the environment, family and attitudes to physical activity. DISCUSSIONS: The focus groups highlighted the importance of social, behavioural and contextual factors in promoting opportunities for physical activity in older adults with and without chronic illness. The findings were used to propose an Active Living Framework which is the subject of ongoing research. PMID- 20921036 TI - A model of the process of transformation in primary care for people living with chronic illnesses. AB - OBJECTIVES: The objective of the research was to construct a conceptual framework that explains the process of personal transformation within a primary care context for people living with chronic illnesses. METHODS: A literature search of articles published from 1990 to 2007 in CINAHL, ERIC, Healthstar, MEDLINE, PsycINFO, dissertation abstracts and SocINFO databases, was conducted to identify qualitative research studies investigating personal change in chronic illness or disability. Five hundred and fifty-six articles were identified; the researchers conducted a metasynthesis of a subgroup of these articles whose focus was on transformation in primary care (n = 5). RESULTS: The metasynthesis project presents a model of the conceptualizations of transformation. Transformation in chronic illness is presented as a process of learning about self and the chronic illness in an iterative and continually changing manner. The primary care context has its greatest influence on critical reflection, which occurs in the first phase (initial response). DISCUSSION: This model illustrates the complex processes that occur for someone living with a chronic illness. Health practitioners who understand why and how people transform in living with chronic illnesses will be able to apply this model in determining people's needs and how to assist people during the transformative process. PMID- 20921035 TI - How effective are the linkages between self-management programmes and primary care providers, especially for disadvantaged patients? AB - OBJECTIVES: To describe the extent and effectiveness of strategies that have been used to improve linkages between primary healthcare (PHC) and chronic disease self-management programmes, especially for disadvantaged patients. METHODS: A systematic review of the published peer-reviewed literature. Studies conducted in an Organisation for Economic Co-operation and Development country evaluating a group self-management programme of at least 4-week duration with some linkage between PHC and the programme were included. Linkage strategies were qualitatively derived. Studies were descriptively analysed in terms of the type of self-management programme, strategy for linking with PHC, culturally and linguistically diverse and socio-economic status and impact on health service usage. RESULTS: Sixteen studies were identified that used linkage strategies for a variety of functions-supporting communication, ongoing clinical care, programme development, recruitment or implementation. Of the four studies that evaluated impact on health service use, only one reported a positive change. DISCUSSION: Few programmes of self-management support included specific strategies to increase linkages with PHC as part of their intervention. There is insufficient evidence to determine which strategies or linkages are more effective and in what context. PMID- 20921037 TI - Self-managing versus self-management: reinvigorating the socio-political dimensions of self-management. AB - In Australia, self-management predominantly refers to education programmes that, theoretically, equip people with chronic disease with the necessary information and skills to manage their own healthcare, maintain optimal health, and minimize the consequences of their condition. These programmes are designed, and often delivered, by practitioners. Our research has demonstrated that for consumers, self-management involves navigating and responding to a myriad of information sources and experiences, many of which originate in their own lived bodily experiences and personal knowledge. In contrast to this organic and dynamic version of self-managing that is naturally practised by consumers, common practitioner and policy representations of self-management tend to discount consumer agency and overlook the daily ways in which people manage their own body, experiences and health choices. We argue that if the self-management movement is to tackle health inequalities (rather than creating new ones), health professionals and policy-makers must examine the potentially damaging assumptions that are inherent in contemporary self-management discourse. PMID- 20921038 TI - Patient engagement with a diabetes self-management intervention. AB - OBJECTIVES: To explore how people living with type 2 diabetes self-manage their condition in everyday life and the impact of the Diabetes Manual programme, a one to-one structured educational intervention aiming to increase skills and confidence for self-management. METHOD: Semi-structured interviews with 12 participants on the Diabetes Manual trial, sampled purposively according to baseline self-efficacy and educational attainment. RESULTS: When describing their experience of living with diabetes, there was little difference between intervention and control participants, although those who had received the programme talked more about the use of blood glucose self-assessment. Programme users were grouped into three categories, Programme Engagers (n = 2), Programme Browsers (n = 4) and Information Seekers (n = 6). Of the two participants engaging with the programme, one described a very positive experience, the other felt unsupported by their practice. None noticed a difference in the approach used by their health professional. Participants' approach to the Diabetes Manual programme suggests they will continue to use it as a resource in the future. CONCLUSION: Participants used the Diabetes Manual programme in different ways, choosing the timing and depth of engagement. Their experience suggests that the programme requires close communication and openness towards collaborative approaches to improve skills and confidence for self-management. PMID- 20921039 TI - The cross-informant concordance and concurrent validity of the Borderline Personality Features Scale for Children in a community sample of boys. AB - The Borderline Personality Disorder Features Scale for Children (BPFSC) is currently the only dimensional measure specifically developed to assess borderline features in children and adolescents. Few studies have investigated this measure for its concurrent validity and concordance between youth self report and parent-report versions. To this end, the current study had two aims: (1) to investigate the cross-informant concordance (youth self-report vs. parent report) of the BPFSC; and (2) to examine the concurrent validity of the BPFSC by showing that youth scoring high on the BPFSC also show poor clinical and psychosocial functioning, as measured by a standard Axis I scale. A community sample (N = 171) of boys between the ages of 8 and 18 completed the BPFSC and a self-report measure of Axis I psychopathology. Parents completed a newly developed parent-report version of the BPFSC (BPFSP) and a standard measure of Axis I psychopathology to index clinical and psychosocial functioning. Findings confirmed expectations. Modest concordance between parent- and self-report ratings were found. In addition, youth with borderline features showed poorer clinical and psychosocial functioning in all domains, especially where externalizing problems were concerned. Concurrent validity and modest parent child concordance were demonstrated for the BPFSC. The BPFSC and BPFSP show promise as dimensional measures to assess borderline features in boys. However, a criterion validity study is needed before the measure can be used. PMID- 20921040 TI - Rebuilding relationships: a pilot study of the effectiveness of the Mellow Parenting Programme for children with Reactive Attachment Disorder. AB - Mellow Parenting is an intensive parenting programme which has been shown to be effective in improving the psychosocial functioning of very vulnerable babies and preschool children. We used a complex interventions model to evaluate its use with school-age children with Reactive Attachment Disorder (RAD), a serious disorder of social functioning associated with maltreatment. The programme had a positive effect on mothers' mental health, but had no measurable effects on symptoms of RAD or on parent-child interaction, although the variation between families after the group suggested that some had responded more than others. Mellow Parenting is an effective programme for vulnerable families with younger children and may be a useful adjunct in the treatment of school-age children with RAD, but it cannot be considered a definite treatment for RAD in this age group. The search continues for safe and effective treatments for RAD in school-age children. PMID- 20921041 TI - Re: Gene expression-based prognostic signatures in lung cancer: ready for clinical use? PMID- 20921042 TI - Dynamic energy budget theory restores coherence in biology. AB - We present the state of the art of the development of dynamic energy budget theory, and its expected developments in the near future within the molecular, physiological and ecological domains. The degree of formalization in the set-up of the theory, with its roots in chemistry, physics, thermodynamics, evolution and the consistent application of Occam's razor, is discussed. We place the various contributions in the theme issue within this theoretical setting, and sketch the scope of actual and potential applications. PMID- 20921043 TI - Subcellular metabolic organization in the context of dynamic energy budget and biochemical systems theories. AB - The dynamic modelling of metabolic networks aims to describe the temporal evolution of metabolite concentrations in cells. This area has attracted increasing attention in recent years owing to the availability of high-throughput data and the general development of systems biology as a promising approach to study living organisms. Biochemical Systems Theory (BST) provides an accurate formalism to describe biological dynamic phenomena. However, knowledge about the molecular organization level, used in these models, is not enough to explain phenomena such as the driving forces of these metabolic networks. Dynamic Energy Budget (DEB) theory captures the quantitative aspects of the organization of metabolism at the organism level in a way that is non-species-specific. This imposes constraints on the sub-organismal organization that are not present in the bottom-up approach of systems biology. We use in vivo data of lactic acid bacteria under various conditions to compare some aspects of BST and DEB approaches. Due to the large number of parameters to be estimated in the BST model, we applied powerful parameter identification techniques. Both models fitted equally well, but the BST model employs more parameters. The DEB model uses similarities of processes under growth and no-growth conditions and under aerobic and anaerobic conditions, which reduce the number of parameters. This paper discusses some future directions for the integration of knowledge from these two rich and promising areas, working top-down and bottom-up simultaneously. This middle-out approach is expected to bring new ideas and insights to both areas in terms of describing how living organisms operate. PMID- 20921045 TI - The impact of metabolism on stable isotope dynamics: a theoretical framework. AB - Stable isotope analysis is a powerful tool used for reconstructing individual life histories, identifying food-web structures and tracking flow of elemental matter through ecosystems. The mechanisms determining isotopic incorporation rates and discrimination factors are, however, poorly understood which hinders a reliable interpretation of field data when no experimental data are available. Here, we extend dynamic energy budget (DEB) theory with a limited set of new assumptions and rules in order to study the impact of metabolism on stable isotope dynamics in a mechanistic way. We calculate fluxes of stable isotopes within an organism by following fluxes of molecules involved in a limited number of macrochemical reactions: assimilation, growth but also structure turnover that is here explicitly treated. Two mechanisms are involved in the discrimination of isotopes: (i) selection of molecules occurs at the partitioning of assimilation, growth and turnover into anabolic and catabolic sub-fluxes and (ii) reshuffling of atoms occurs during transformations. Such a framework allows for isotopic routing which is known as a key, but poorly studied, mechanism. As DEB theory specifies the impact of environmental conditions and individual state on molecule fluxes, we discuss how scenario analysis within this framework could help reveal common mechanisms across taxa. PMID- 20921044 TI - Dynamic energy budget approaches for modelling organismal ageing. AB - Ageing is a complex multifactorial process involving a progressive physiological decline that, ultimately, leads to the death of an organism. It involves multiple changes in many components that play fundamental roles under healthy and pathological conditions. Simultaneously, every organism undergoes accumulative 'wear and tear' during its lifespan, which confounds the effects of the ageing process. The scenario is complicated even further by the presence of both age dependent and age-independent competing causes of death. Various manipulations have been shown to interfere with the ageing process. Calorie restriction, for example, has been reported to increase the lifespan of a wide range of organisms, which suggests a strong relation between energy metabolism and ageing. Such a link is also supported within the main theories for ageing: the free radical hypothesis, for instance, links oxidative damage production directly to energy metabolism. The Dynamic Energy Budgets (DEB) theory, which characterizes the uptake and use of energy by living organisms, therefore constitutes a useful tool for gaining insight into the ageing process. Here we compare the existing DEB based modelling approaches and, then, discuss how new biological evidence could be incorporated within a DEB framework. PMID- 20921046 TI - Modelling the ecological niche from functional traits. AB - The niche concept is central to ecology but is often depicted descriptively through observing associations between organisms and habitats. Here, we argue for the importance of mechanistically modelling niches based on functional traits of organisms and explore the possibilities for achieving this through the integration of three theoretical frameworks: biophysical ecology (BE), the geometric framework for nutrition (GF) and dynamic energy budget (DEB) models. These three frameworks are fundamentally based on the conservation laws of thermodynamics, describing energy and mass balance at the level of the individual and capturing the prodigious predictive power of the concepts of 'homeostasis' and 'evolutionary fitness'. BE and the GF provide mechanistic multi-dimensional depictions of climatic and nutritional niches, respectively, providing a foundation for linking organismal traits (morphology, physiology, behaviour) with habitat characteristics. In turn, they provide driving inputs and cost functions for mass/energy allocation within the individual as determined by DEB models. We show how integration of the three frameworks permits calculation of activity constraints, vital rates (survival, development, growth, reproduction) and ultimately population growth rates and species distributions. When integrated with contemporary niche theory, functional trait niche models hold great promise for tackling major questions in ecology and evolutionary biology. PMID- 20921047 TI - Modelling effects of diquat under realistic exposure patterns in genetically differentiated populations of the gastropod Lymnaea stagnalis. AB - Pesticide use leads to complex exposure and response patterns in non-target aquatic species, so that the analysis of data from standard toxicity tests may result in unrealistic risk forecasts. Developing models that are able to capture such complexity from toxicity test data is thus a crucial issue for pesticide risk assessment. In this study, freshwater snails from two genetically differentiated populations of Lymnaea stagnalis were exposed to repeated acute applications of environmentally realistic concentrations of the herbicide diquat, from the embryo to the adult stage. Hatching rate, embryonic development duration, juvenile mortality, feeding rate and age at first spawning were investigated during both exposure and recovery periods. Effects of diquat on mortality were analysed using a threshold hazard model accounting for time varying herbicide concentrations. All endpoints were significantly impaired at diquat environmental concentrations in both populations. Snail evolutionary history had no significant impact on their sensitivity and responsiveness to diquat, whereas food acted as a modulating factor of toxicant-induced mortality. The time course of effects was adequately described by the model, which thus appears suitable to analyse long-term effects of complex exposure patterns based upon full life cycle experiment data. Obtained model outputs (e.g. no-effect concentrations) could be directly used for chemical risk assessment. PMID- 20921048 TI - How far details are important in ecosystem modelling: the case of multi-limiting nutrients in phytoplankton-zooplankton interactions. AB - We try to answer the question of to what extent details in nutrient uptake and phytoplankton physiology matter for population and community dynamics. To this end, we study how two nutrients interact in limiting phytoplankton growth. A popular formulation uses a product-rule for nutrient uptake, which we compare with that on the basis of synthesizing units. We first fit different nutrient uptake models to a dataset and conclude that the quantitative differences between the models are small. Then we study the sensitivity of phytoplankton growth and zooplankton-phytoplankton interactions (ZPi) models to uptake formulations. Two population models are compared; they are based on different assumptions on the relation between nutrient uptake and phytoplankton growth. We find that the population and community models are sensitive to uptake formulations. According to the uptake formulation used in the ZPi models, qualitative differences can be observed. Indeed, although two models based on functions with similar shapes have close equilibria, these can differ in stability properties. Since stability involves the derivatives of formulas, even if two formulas provide close values, large numerical differences in the stability criterion may occur after derivation. We conclude that mechanistic details can be of importance for community modelling. PMID- 20921049 TI - Stylized facts in microalgal growth: interpretation in a dynamic energy budget context. AB - A dynamic energy budget (DEB) model for microalgae is proposed. This model deviates from the standard DEB model as it needs more reserves to cope with the variation of assimilation pathways, requiring a different approach to growth based on the synthesizing unit (SU) theory for multiple substrates. It is shown that the model is able to accurately predict experimental data in constant and light-varying conditions with most of the parameter values taken directly from the literature. Also, model simulations are shown to be consistent with stylized facts (SFs) concerning NC ratio. These SFs are reinterpreted and the general conclusion is that all forcing variables (dilution rate, temperature and irradiance) impose changes in the nitrogen or carbon limitation status of the population, and consequently on reserve densities. Model predictions are also evaluated in comparison with SFs on chlorophyll concentration. It is proposed that an extra structure, more dependent on the nitrogen reserve, is required to accurately model chlorophyll dynamics. Finally, SFs concerning extracellular polymeric substances (EPSs) production by benthic diatoms are collected and interpreted and a formulation based on product synthesis and rejection flux is proposed for the EPSs production rate. PMID- 20921050 TI - How to lift a model for individual behaviour to the population level? AB - The quick answer to the title question is: by bookkeeping; introduce as p(opulation)-state a measure telling how the individuals are distributed over their common i(ndividual)-state space, and track how the various i-processes change this measure. Unfortunately, this answer leads to a mathematical theory that is technically complicated as well as immature. Alternatively, one may describe a population in terms of the history of the population birth rate together with the history of any environmental variables affecting i-state changes, reproduction and survival. Thus, a population model leads to delay equations. This delay formulation corresponds to a restriction of the p-dynamics to a forward invariant attracting set, so that no information is lost that is relevant for long-term dynamics. For such equations there exists a well-developed theory. In particular, numerical bifurcation tools work essentially the same as for ordinary differential equations. However, the available tools still need considerable adaptation before they can be practically applied to the dynamic energy budget (DEB) model. For the time being we recommend simplifying the i dynamics before embarking on a systematic mathematical exploration of the associated p-behaviour. The long-term aim is to extend the tools, with the DEB model as a relevant goal post. PMID- 20921051 TI - Extrapolating toxic effects on individuals to the population level: the role of dynamic energy budgets. AB - The interest of environmental management is in the long-term health of populations and ecosystems. However, toxicity is usually assessed in short-term experiments with individuals. Modelling based on dynamic energy budget (DEB) theory aids the extraction of mechanistic information from the data, which in turn supports educated extrapolation to the population level. To illustrate the use of DEB models in this extrapolation, we analyse a dataset for life cycle toxicity of copper in the earthworm Dendrobaena octaedra. We compare four approaches for the analysis of the toxicity data: no model, a simple DEB model without reserves and maturation (the Kooijman-Metz formulation), a more complex one with static reserves and simplified maturation (as used in the DEBtox software) and a full-scale DEB model (DEB3) with explicit calculation of reserves and maturation. For the population prediction, we compare two simple demographic approaches (discrete time matrix model and continuous time Euler-Lotka equation). In our case, the difference between DEB approaches and population models turned out to be small. However, differences between DEB models increased when extrapolating to more field-relevant conditions. The DEB3 model allows for a completely consistent assessment of toxic effects and therefore greater confidence in extrapolating, but poses greater demands on the available data. PMID- 20921052 TI - Dynamic energy budget theory and population ecology: lessons from Daphnia. AB - Dynamic energy budget (DEB) theory offers a perspective on population ecology whose starting point is energy utilization by, and homeostasis within, individual organisms. It is natural to ask what it adds to the existing large body of individual-based ecological theory. We approach this question pragmatically- through detailed study of the individual physiology and population dynamics of the zooplankter Daphnia and its algal food. Standard DEB theory uses several state variables to characterize the state of an individual organism, thereby making the transition to population dynamics technically challenging, while ecologists demand maximally simple models that can be used in multi-scale modelling. We demonstrate that simpler representations of individual bioenergetics with a single state variable (size), and two life stages (juveniles and adults), contain sufficient detail on mass and energy budgets to yield good fits to data on growth, maturation and reproduction of individual Daphnia in response to food availability. The same simple representations of bioenergetics describe some features of Daphnia mortality, including enhanced mortality at low food that is not explicitly incorporated in the standard DEB model. Size structured, population models incorporating this additional mortality component resolve some long-standing questions on stability and population cycles in Daphnia. We conclude that a bioenergetic model serving solely as a 'regression' connecting organismal performance to the history of its environment can rest on simpler representations than those of standard DEB. But there are associated costs with such pragmatism, notably loss of connection to theory describing interspecific variation in physiological rates. The latter is an important issue, as the type of detailed study reported here can only be performed for a handful of species. PMID- 20921053 TI - Temperature tolerance and energetics: a dynamic energy budget-based comparison of North Atlantic marine species. AB - Temperature tolerance and sensitivity were examined for some North Atlantic marine species and linked to their energetics in terms of species-specific parameters described by dynamic energy budget (DEB) theory. There was a general lack of basic information on temperature tolerance and sensitivity for many species. Available data indicated that the ranges in tolerable temperatures were positively related to optimal growth temperatures. However, no clear relationships with temperature sensitivity were established and no clear differences between pelagic and demersal species were observed. The analysis was complicated by the fact that for pelagic species, experimental data were completely absent and even for well-studied species, information was incomplete and sometimes contradictory. Nevertheless, differences in life-history strategies were clearly reflected in parameter differences between related species. Two approaches were used in the estimation of DEB parameters: one based on the assumption that reserve hardly contributes to physical volume; the other does not make this assumption, but relies on body-size scaling relationships, using parameter values of a generalized animal as pseudo-data. Temperature tolerance and sensitivity seemed to be linked with the energetics of a species. In terms of growth, relatively high temperature optima, sensitivity and/or tolerance were related to lower relative assimilation rates as well as lower maintenance costs. Making the step from limited observations to underlying mechanisms is complicated and extrapolations should be carefully interpreted. Special attention should be devoted to the estimation of parameters using body-size scaling relationships predicted by the DEB theory. PMID- 20921054 TI - Modelling shellfish growth with dynamic energy budget models: an application for cockles and mussels in the Oosterschelde (southwest Netherlands). AB - Dynamic energy budget models for growth of individual cockles (Cerastoderma edule) and mussels (Mytilus edulis) are adjusted and calibrated to the Oosterschelde by formulating and parametrizing their functional responses using an extensive set of field observations. The resulting model predictions fit the observations satisfactorily. Results indicate that food quality and the importance of detritus as a food source are site-specific as well as species specific. Despite these differences in their calibrated parameter values, both species show a very similar functional response. Compared with other systems, however, the functional responses of mussels in the present study are clearly higher than those of mussels in other systems. This may be explained by the absence of intra-specific competition in the measurement set-up that was used, and therefore supports the idea that the generally small functional response of M. edulis is caused by intra-specific competition. PMID- 20921055 TI - Bifurcation theory, adaptive dynamics and dynamic energy budget-structured populations of iteroparous species. AB - In this paper, we describe a technique to evaluate the evolutionary dynamics of the timing of spawning for iteroparous species. The life cycle of the species consists of three life stages, embryonic, juvenile and adult whereby the transitions of life stages (gametogenesis, birth and maturation) occur at species specific sizes. The dynamics of the population is studied in a semi-chemostat environment where the inflowing food concentration is periodic (annual). A dynamic energy budget-based continuous-time model is used to describe the uptake of the food, storage in reserves and allocation of the energy to growth, maintenance, development (embryos, juveniles) and reproduction (adults). A discrete-event process is used for modelling reproduction. At a fixed spawning date of the year, the reproduction buffer is emptied and a new cohort is formed by eggs with a fixed size and energy content. The population consists of cohorts: for each year one consisting of individuals with the same age which die after their last reproduction event. The resulting mathematical model is a finite dimensional set of ordinary differential equations with fixed 1-year periodic boundary conditions yielding a stroboscopic map. We will study the evolutionary development of the population using the adaptive dynamics approach. The trait is the timing of spawning. Pairwise and mutual invasibility plots are calculated using bifurcation analysis of the stroboscopic map. The evolutionary singular strategy value belonging to the evolutionary endpoint for the trait allows for an interpretation of the reproduction strategy of the population. In a case study, parameter values from the literature for the bivalve Macoma balthica are used. PMID- 20921056 TI - Bioaccumulation of heavy metals in mullet (Mugil cephalus) and oyster (Crassostrea madrasensis) from Pulicat lake, south east coast of India. AB - The accumulation of six heavy metals (Cr, Cd, Cu, Zn, Pb and Ni) in sediment, water and in tissue parts of Mugil cephalus and Crassostrea madrasensis was studied in two locations of Pulicat lake, Southeast coast of India, which receives considerable quantity of effluents from industries located in North Chennai coastal region. The results reveal that the metal concentration in water is decreasing in the following order of Zn > Ni > Cu > Cr > Pb > Cd both in lake and barmouth and highest concentration was observed for Zn (32.5 MUg L(-1) in lake and 25.2 MUg L(-1) in bar mouth). Metals were highly concentrated in sediments when compared to water and biota. Metals abundance in sediments has following sequential order of Cr > Ni > Zn > Cu > Pb > Cd and the accumulation pattern in barmouth showed minor variation indicating the following pattern of Zn > Ni > Cr > Cu > Pb > Cd. The geoaccumulation index (I(geo)) for Pulicat lake sediments indicate that the sediments are extremely contaminated with Cd and moderately contaminated with Cu and Ni. Bioaccumulation of heavy metals in Mugil cephalus and Crassostrea madrasensis showed marked differences in the accumulation patterns. It is observed that Zn, Cu and Pb are accumulated in elevated concentrations in various parts of the fish and oyster when compared with other metals. PMID- 20921057 TI - The protective role of zinc and calcium in Vicia faba seedlings subjected to cadmium stress. AB - The aim of the present study was to evidence the possible antagonistic effect of Zinc (Zn(2+)) and Calcium (Ca(2+)) against cadmium (Cd(2+))-induced DNA damage by using random amplification of polymorphic DNA (RAPD) and metabolic activities in Vicia faba. The results showed that all doses of Cd(2+) (10( -3) M, 10(-5) M) caused an increase in polymorphism value and a decrease in genomic template stability (GTS %). In addition, when 10( -4)-10(-6) M Ca(2+), 10(-6) M Zn(2+) were added together with 10(-3) M, 10(-4) M, 10(-5) M of Cd(2+), polymorphism value decreased besides GTS, total protein and chlorophyll content increased. Results suggested that Zn(2+) and Ca(2+) have an antagonistic effect against Cd(2+). The order of the antagonisms of Ca(2+), Zn(2+) against Cd(2+) toxicity was Ca(2+) > Zn(2+). Especially, the degree of antagonistic effect of Zn(2+) against Cd(2+) is probably related to its concentration ratio. PMID- 20921058 TI - Organic amendment based on vermicompost and compost: differences on soil properties and maize yield. AB - The objective of the present study was to study the effect of two vermicomposts [animal (VCD) and vegetal origin (VGF)] and a cotton gin compost (C) at rates of 1780 and 3560 kg fresh organic matter ha(-1) for 3 years on an Typic Xerofluvent located near Seville (Spain) on soil biological properties, nutrition (leaf N, P and K concentration, pigments and soluble carbohydrate concentrations) and yield parameters of maize (Zea mays cv. Tundra) crop. All organic waste materials had a positive effect on the soil biological properties, plant nutrition and crop yield parameters, although at the end of the experimental period and at the high organic matter rate, the soil microbial biomass and dehydrogenase, urease, beta glucosidase, phosphatase and arylsulfatase activities increased more significantly in the VCD-amended soils (86.4, 85.8, 94.5, 99.3, 70.1 and 63.8%, respectively) respect to the control soil, followed by VGF-amended soils (84.8, 80.6, 92.7, 99.1, 68.3 and 61.6%, respectively) and CC-amended soils (80.5, 75.9, 89.7, 99, 65.7 and 59.9%, respectively). Leaf N, P and K contents and pigments and soluble carbohydrate contents were highest in VCD-amended soils, followed by VGF and CC treatments. Compared with the control soil, the application of VCD in soils at high doses increased the crop yield parameters, followed by VGF and CC treatments. This may have been due to a greater labile fraction of organic matter in the VCD than the VGF and CC, respectively. PMID- 20921059 TI - Landfill sustainability and aftercare completion criteria. AB - Although many countries are increasing their efforts to recycle and to re-use waste materials, landfilling will still be needed in order to dispose of wastes which cannot be recycled or treated in other ways. Since landfills will most probably be present for a long time, measures will have to be taken to reduce their (long-term) emissions. The European Commission has delegated the competent authorities to decide to end aftercare and several member states have provided regulations for this purpose. However, there is currently no guidance for long term risk assessment to support an aftercare completion procedure for landfills. The aim of this study is to provide examples of current regulations and to demonstrate an alternative approach for a quantitative risk assessment of landfill leachate. The presented modelling approach clearly demonstrates the added value of site specific risk assessments of the long-term emissions from landfills and might provide a basis for application when the acceptance criteria for landfill will be revisited in the future. In addition, the modelling approach can be used as one of the toolboxes to perform assessments of the long-term emissions from landfill leachates and might help the competent authorities to decide whether the remaining emission potential is acceptable or not. Moreover, the results imply that local environmental conditions contribute to the acceptability of landfill emissions and are important factors in choosing a landfill location. PMID- 20921060 TI - Littering--a persistent problem. PMID- 20921061 TI - Nanotechnology risk assessment from a waste management perspective: are the current tools adequate? AB - The burgeoning nanotechnology industry is rapidly generating new forms of waste streams generically referred herein as nanowastes. However, little is known about the fate and behavior of these waste streams and their impacts thereof in different ecological systems despite their increasingly widespread dispersion into the environment through production, distribution, handling, and nanomaterials (NMs) incorporation into bulk products processes. In this paper, risk assessment of nanotechnology from a waste management perspective was examined to elucidate potential new forms of challenges nanowastes may likely pose to the current legislative and waste management systems. This was through the identification of several knowledge gaps that merit urgent attention in order to increase our collective understanding of managing nanowastes safely, responsibly, and sustainably. The paper presents the identified gaps and consequently proposes a qualitative risk assessment of nanowastes to address some of the current challenges. The applicability of the proposed model is illustrated through several examples. In addition, the first nanowastes classification protocol presented in this article show that a given nanomaterial may result in generating nanowaste streams of different forms with variant hazard levels ranging from benign to extremely being hazardous waste streams - a dramatic phenomenon from the conventional waste streams due to macroscale chemicals. The study shows that it is in the early days to draw broad generic classification of different nanowastes, and each stream may require their risk profile be assessed on a case-by-case basis. We conclude by presenting several recommendations on what needs to be done in dealing with nanowastes as means of avoiding unintended long-term consequences of nanotechnology. PMID- 20921062 TI - The efficacy of high doses of vitamin C in patients with paraquat poisoning. AB - Paraquat (PQ) poisoning is an extremely difficult condition to manage clinically because of the lack of effective treatments. The purpose of this study was to assess the effect of high doses of vitamin C in combination with anti inflammatory and immunosuppressant therapy in patients with PQ poisoning. The medical records of 134 patients who presented to the emergency department within 24 hours after PQ poisoning were reviewed retrospectively. The 57 patients presented between January 2004 and September 2005 were group 1; they received pulse therapy, which included cyclophosphamide and methylprednisolone, followed by the administration of dexamethasone over 2 weeks. The 77 patients that presented between October 2005 and January 2008 were group 2; they received the above-mentioned therapy and high-dose vitamin C for 2 weeks. There was no difference in the distribution of baseline variables between the 2 groups. However, group 2 showed a significant reduction in acute kidney injury related to PQ. Furthermore, a multivariate logistic regression analysis showed that the addition of vitamin C to the treatment was significantly associated with an increased survival of the patients. Larger trials will be needed to verify the effect of high-dose vitamin C on survival in patients with PQ poisoning. PMID- 20921063 TI - Enhancement of gallic acid-induced human pulmonary fibroblast cell death by N acetyl cysteine and L-buthionine sulfoximine. AB - Gallic acid (GA) has various biological properties including anti-cancer effect. However, little is known about the toxicological effect of GA in primary normal cells. Here, we evaluated the effects of GA on human pulmonary fibroblast (HPF) cells in relation to reactive oxygen species (ROS) and glutathione (GSH). GA inhibited the growth of HPF cells at 24 hours in a dose-dependent manner. GA also induced HPF cell death, which was accompanied by the loss of mitochondrial membrane potential (MMP; DeltaPsi(m)). GA increased ROS levels including O(2)(*-) and GSH-depleted cell numbers in HPF cells at 24 hours. Treatment with 2 mM N acetyl-cysteine (NAC) intensified growth inhibition and death in GA-treated HPF cells. NAC decreased ROS levels and increased GSH depletion in these cells. Treatment with 10 MUM L-buthionine sulfoximine (BSO) also enhanced growth inhibition and death in GA-treated HPF cells. BSO increased ROS levels and GSH depletion in these cells. In conclusion, GA-induced HPF cell death was accompanied by ROS increase and GSH depletion. The changes of ROS and GSH levels by NAC and BSO appeared to affect cell growth and death in GA-treated HPF cells. PMID- 20921066 TI - An observational study of an employer intervention for children's healthy weight behaviors. AB - OBJECTIVE: This observational study was undertaken to assess whether changes in healthy weight behaviors could be advanced in a short-term intervention involving parents and children at IBM. METHODS: IBM's Children's Health Rebate offered a cash incentive for parents to complete a 12-week program of self-selected activities in family food planning and meals, family physical activity, and sedentary time related to electronic entertainment ("screen time"). A preprogram/postprogram comparison of self-reported activities was used to assess behavior change. RESULTS: A total of 22,265 (52.3%) employees elected to participate, 11,631 (52.2%) of whom completed all program requirements and earned a $150 cash rebate. Families completing the program reported significant changes in levels of physical activity, amount of entertainment screen time, and proportion of healthy meals. For example, family physical activity >3 times per week increased by 17.1 percentage points (from 23.2% to 40.3%), eating healthy dinners >= 5 days/week increased by 11.8 percentage points (from 74.9% to 86.7%), and entertainment screen time <1 hour/day increased by 8.3 percentage points for children (from 22.4% to 30.7%) and by 6.1 percentage points for adults (from 18.1% to 24.2%). CONCLUSIONS: The results of this short-term observational study suggest that healthy weight behaviors in children, adolescents, and parents can be improved by using a Web-based intervention linked with a cash incentive. The results also show that employers can activate parents and support a role for employers in community-based strategies for obesity prevention in children. Experimental designs with biometric data would strengthen the suggestion of positive impact. PMID- 20921065 TI - Isothermal DNA amplification using the T4 replisome: circular nicking endonuclease-dependent amplification and primase-based whole-genome amplification. AB - In vitro reconstitution of the bacteriophage T4 replication machinery provides a novel system for fast and processive isothermal DNA amplification. We have characterized this system in two formats: (i) in circular nicking endonuclease dependent amplification (cNDA), the T4 replisome is supplemented with a nicking endonuclease (Nb.BbvCI) and a reverse primer to generate a well-defined uniform double-stranded linear product and to achieve up to 1100-fold linear amplification of a plasmid in 1 h. (ii) The T4 replisome with its primase (gp61) can also support priming and exponential amplification of genomic DNA in primase based whole-genome amplification (T4 pWGA). Low amplification biases between 4.8 and 9.8 among eight loci for 0.3-10 ng template DNA suggest that this method is indeed suitable for uniform whole-genome amplification. Finally, the utility of the T4 replisome for isothermal DNA amplification is demonstrated in various applications, including incorporation of functional tags for DNA labeling and immobilization; template generation for in vitro transcription/translation and sequencing; and colony screening and DNA quantification. PMID- 20921064 TI - Chronic ethanol ingestion induces aortic inflammation/oxidative endothelial injury and hypertension in rats. AB - The study aim was to investigate the relationship of chronic ethanol-induced inflammation leading to vascular endothelial injury and elevation of blood pressure (BP) in a rat model. Male Fisher rats were divided into two groups of six animals each and treated as follows: (1) Control (5% sucrose, orally) daily for 12 weeks and (2) 20% ethanol (4 g kg(-1), orally) daily for 12 weeks. The mean arterial blood pressure was recorded every week. The animals were anesthetized with pentobarbital after 12 weeks; thoracic aorta were isolated and analyzed for aortic reactivity response, inflammatory mediators, oxidant/antioxidant enzyme protein expression and endothelial nitric oxide generating system. The results show that the mean BP was significantly elevated 12 weeks after ethanol ingestion. The increased BP was related to increased aortic inflammation (tumor necrosis factor [TNF]-alpha; nitric oxide synthase [iNOS], COX-2 and MCP-1 protein expression) and elevated angiotensin II levels in alcohol-treated group compared to control. Aortic Nicotinamide adenine dinucleotide phosphate reduced (NADPH) oxidase activity, membrane and cytosolic subunits p22(phox) and p47(phox) expression and Mn-SOD activity and protein expression significantly increased, whereas nitric oxide (NO), endothelial NO synthase (eNOS), vascular endothelial growth factor (VEGF)-A and CuZn-SOD activity and protein expression significantly decreased in alcohol-treated group compared to control. The acetylcholine-mediated vasorelaxation response was depressed in the aorta of ethanol-treated rats compared to control. In conclusion, chronic ethanol-induced elevation in BP is related to increased aortic inflammation, elevated angiotensin II levels, induction of NADPH oxidase causing endothelial injury, depletion of CuZn-SOD, down-regulation of endothelial NO generating system and impaired vascular relaxation in rats. PMID- 20921067 TI - Developmental trajectories from birth to school age in healthy term-born children. AB - OBJECTIVE: To determine the stability of the scores obtained on tests of motor development from birth until school age in healthy, term singletons and to determine if early motor scores are associated with more complex cognitive functions at school age, such as attention and memory. PATIENTS AND METHODS: This longitudinal, prospective cohort study included 77 infants. The motor development of these infants was assessed during the neonatal period with Prechtl's neurologic examination; in early infancy with Touwen's neurologic examination and general movement assessment; at toddler age with Hempel's neurologic examination and the Psychomotor Developmental Index from the Bayley Scales of Infant Development; and at school age with the Movement Assessment Battery for Children. Cognition was determined at toddler age with the Mental Developmental Index from the Bayley Scales of Infant Development; and at school age with an intelligence test and attention and memory tests. RESULTS: The mean absolute difference in standardized motor scores for all time points was 1.01 SD (95% confidence interval: 0.91-1.11). Only the explained proportions of variance of maternal socioeconomic status and verbal intelligence were significant for sustained attention and verbal memory (r(2) = 0.104, P = .030 and r(2) = 0.074, P = .027), respectively. The children's scores on early motor tests added little value for their motor and cognitive development at school age. CONCLUSIONS: In healthy children the stability of motor development from birth until school age is low. Maternal socioeconomic status and verbal intelligence rather than the infants' scores on early motor tests signified added value for complex cognitive functions at school age. PMID- 20921068 TI - Laptop computer-induced erythema ab igne in a child and review of the literature. AB - We report here the case of a 12-year-old boy with erythema ab igne on his left thigh caused by the use of a laptop computer. This is the youngest of the 10 reported patients with this laptop-induced dermatosis since its first description in 2004. Erythema ab igne is a reticular, pigmented, sometimes telangiectatic dermatosis that is caused by prolonged exposure to a heat or infrared source. In laptop-induced erythema ab igne, the localization on the thighs and asymmetry are characteristic. The heat originates from the optical drive, the battery, or the ventilation fan of the computer. PMID- 20921069 TI - Retinal hemorrhage in abusive head trauma. AB - Retinal hemorrhage is a cardinal manifestation of abusive head trauma. Over the 30 years since the recognition of this association, multiple streams of research, including clinical, postmortem, animal, mechanical, and finite element studies, have created a robust understanding of the clinical features, diagnostic importance, differential diagnosis, and pathophysiology of this finding. The importance of describing the hemorrhages adequately is paramount in ensuring accurate and complete differential diagnosis. Challenges remain in developing models that adequately replicate the forces required to cause retinal hemorrhage in children. Although questions, such as the effect of increased intracranial pressure, hypoxia, and impact, are still raised (particularly in court), clinicians can confidently rely on a large and solid evidence base when assessing the implications of retinal hemorrhage in children with concern of possible child abuse. PMID- 20921070 TI - A systematic review of faces scales for the self-report of pain intensity in children. AB - CONTEXT: Numerous faces scales have been developed for the measurement of pain intensity in children. It remains unclear whether any one of the faces scales is better for a particular purpose with regard to validity, reliability, feasibility, and preference. OBJECTIVES: To summarize and systematically review faces pain scales most commonly used to obtain self-report of pain intensity in children for evaluation of reliability and validity and to compare the scales for preference and utility. METHODS: Five major electronic databases were systematically searched for studies that used a faces scale for the self-report measurement of pain intensity in children. Fourteen faces pain scales were identified, of which 4 have undergone extensive psychometric testing: Faces Pain Scale (FPS) (scored 0-6); Faces Pain Scale-Revised (FPS-R) (0-10); Oucher pain scale (0-10); and Wong-Baker Faces Pain Rating Scale (WBFPRS) (0-10). These 4 scales were included in the review. Studies were classified by using psychometric criteria, including construct validity, reliability, and responsiveness, that were established a priori. RESULTS: From a total of 276 articles retrieved, 182 were screened for psychometric evaluation, and 127 were included. All 4 faces pain scales were found to be adequately supported by psychometric data. When given a choice between faces scales, children preferred the WBFPRS. Confounding of pain intensity with affect caused by use of smiling and crying anchor faces is a disadvantage of the WBFPRS. CONCLUSIONS: For clinical use, we found no grounds to switch from 1 faces scale to another when 1 of the scales is in use. For research use, the FPS-R has been recommended on the basis of utility and psychometric features. Data are sparse for children below the age of 5 years, and future research should focus on simplified measures, instructions, and anchors for these younger children. PMID- 20921071 TI - Recombinant human growth hormone in the treatment of patients with cystic fibrosis. AB - CONTEXT: Recombinant human growth hormone (rhGH) improves growth in patients with growth hormone deficiency or idiopathic short stature. Its role in patients with cystic fibrosis (CF) is unclear. OBJECTIVE: To review the effectiveness of rhGH in the treatment of patients with CF. METHODS: Medline and the Cochrane Central Register of Controlled Trials were searched from the earliest date through April 2010. Randomized controlled trials, observational studies, systematic reviews/meta-analyses, or case reports were included if rhGH therapy was administered to patients with CF and data on prespecified harms, intermediate outcomes, or final health outcomes were reported. When applicable, end points were pooled by using a random-effects model. The overall body of evidence was graded for each outcome as insufficient, low, moderate, or high. RESULTS: Ten unique controlled trials (n = 312) and 8 observational studies (n = 58) were included. On quantitative synthesis of controlled trials, several markers of pulmonary function, anthropometrics, and bone mineralization were significantly improved versus control. Results of single-arm observational studies for the aforementioned outcomes were generally supportive of findings in clinical trials. There is insufficient evidence to determine the effect of rhGH on intravenous antibiotic use during therapy, pulmonary exacerbations, health-related quality-of life, bone consequences, or total mortality, but moderate evidence suggests that rhGH therapy reduces the rate of hospitalization versus control. CONCLUSIONS: rhGH improved almost all intermediate measures of pulmonary function, height, and weight in patients with CF. Improvements in bone mineral content are also promising. However, with the exception of hospitalizations, the benefits on final health outcomes cannot be directly determined at this time. PMID- 20921073 TI - Should NHS mental health services fear the private sector? Yes. PMID- 20921074 TI - Should NHS mental health services fear the private sector? No. PMID- 20921075 TI - President Obama apologises to Guatemala over 1940s syphilis study. PMID- 20921076 TI - Dengue outbreak affects more than 7000 people in Nepal. PMID- 20921078 TI - Dutch groups appeal against "irresponsible" plan to exempt small cafes from smoking ban. PMID- 20921079 TI - Bacteria in the respiratory tract and wheeze in children. PMID- 20921082 TI - Tobacco giant fails to prevent Scottish ban on display in shops. PMID- 20921080 TI - Association of bacteria and viruses with wheezy episodes in young children: prospective birth cohort study. AB - OBJECTIVE: To study the association between wheezy symptoms in young children and the presence of bacteria in the airways. DESIGN: Birth cohort study. SETTING: Clinical research unit in Copenhagen. PARTICIPANTS: Children of asthmatic mothers, from age 4 weeks to 3 years, with planned visits and acute admissions to the research clinic. MAIN OUTCOME MEASURE: Frequency of bacteria and virus carriage in airway aspirates during wheezy episodes and at planned visits without respiratory symptoms. RESULTS: 984 samples (361 children) were analysed for bacteria, 844 (299 children) for viruses, and 696 (277 children) for both viruses and bacteria. Wheezy episodes were associated with both bacterial infection (odds ratio 2.9, 95% confidence interval 1.9 to 4.3; P<0.001) and virus infection (2.8, 1.7 to 4.4; P<0.001). The associations of bacteria and viruses were independent of each other. CONCLUSION: Acute wheezy episodes in young children were significantly associated with bacterial infections similar to but independent of the association with virus infections. PMID- 20921083 TI - Obstetricians defend safety of childbirth in Italy. PMID- 20921084 TI - The effect of oxygenator mechanical characteristics on energy transfer during clinical cardiopulmonary bypass. AB - The hollow-fibre oxygenator is a key component of any extracorporeal circuit used to provide cardiopulmonary bypass (CPB) during open-heart surgery. Since the oxygenator is placed downstream of the pump, the energy losses over it have a direct impact on the quality of pulsatile pressure and flow waveforms. The objective of this study was to describe the effects of hydrodynamic characteristics of the oxygenator on energy transfer during pulsatile, normothermic CPB. Twenty-three adult patients scheduled for coronary bypass surgery were divided randomly into two groups, using either an oxygenator (Group 1) with a relatively high-resistance and low-compliance (2079 +/- 148 dyn.s.cm( 5) and 0.00348 +/- 0.00071 ml.mmHg(-1), respectively) or an oxygenator (Group 2) with a relatively low-resistance and high-compliance (884 +/- 464 dyn.s.cm(-5) and 0.01325 +/- 0.00161 ml.mmHg(-1), respectively). During perfusion, pre- and post-oxygenator pressures, radial artery pressure, and blood flow were recorded simultaneously. A 32% decline of mean pressure was observed in Group 1 and a 16% decline in Group 2 (p<0.0001). Another decrease by approximately 73% in mean pressure in the rest of the perfusion system was noted in both groups. The mean radial artery pressure did not differ between the groups (74 +/- 6 mmHg in Group 1 and 73 +/- 6 mmHg in Group 2, p=0.608). Although lower total energy transfer indices were noticed through the low-resistance oxygenator (Group 2), both oxygenators showed a decrease of the generated pump oscillatory energy of approximately 50%. Despite the differences in resistance and compliance of the hollow-fibre oxygenators used, both oxygenators cause a comparable loss of generated oscillatory energy. Exclusion of the oxygenator downstream of the pulsatile pump would improve energy transfer during CPB. PMID- 20921085 TI - Steroids and statins: an old and a new anti-inflammatory strategy compared. AB - OBJECTIVES: This study compared the anti-inflammatory effects of methylprednisolone (MP) and atorvastatin and analysed their influences on clinical variables in patients undergoing coronary revascularization. METHODS: Ninety patients with compromised left ventricular ejection fraction (<=30%) undergoing elective coronary surgery were equally randomized to one of three groups: statin group, treatment with atorvastatin (20 mg/day) 3 weeks before surgery; methylprednisolone group, a single shot of methylpredniosolone (10mg/kg); and control group. RESULTS: Postoperative IL-6 was higher in the control group when compared to the methylprednisolone and statin groups (p<0.01). IL-6 was higher in the statin-treated patients (p<0.05 versus methylprednisolone). Administration of methylprednisolone as well as statin treatment increased postoperative cardiac index, left ventricular stroke work index, decreased postoperative atrial fibrilation rate and reduced ICU stay (p<0.05 versus control). The number of patients requiring inotropic support was lower in the methylprednisolone group when compared with the other two groups (p<0.01). Tracheal intubation time was reduced in patients who received methylprednisolone (p<0.01 versus control). CONCLUSIONS: Preoperative administration of either methylprednisolone or atorvastatin reduced pro inflammatory cytokine release, improved haemodynamics, decreased postoperative atrial fibrilation rate and reduced ICU stay in patients with significantly impaired cardiac function undergoing coronary revascularization. Treatment with methylprednisolone was associated with less inotropic support requirements and reduced mechanical ventilation time. PMID- 20921086 TI - Open aortic arch surgery: how to reduce air embolism risk during antegrade cerebral perfusion. AB - Antegrade cerebral perfusion (ACP) is used widely, with the aim of obtaining cerebral protection during open aortic arch surgery. ACP is considered by many to be the reason for improvements in the clinical outcome of this type of surgery. However, perioperative cerebral complications may still occur. Cerebral complications during ACP are considered to be due mainly to embolic events rather than hypoperfusion. We believe that many of the embolic events during ACP may be due to air embolism rather than to vessel manipulation only. To reduce the risk of air embolism during ACP, we propose an easy technique, with the suggested steps to be followed in an exact sequence. PMID- 20921087 TI - Troubleshooting a missing intra-cardiac tumor at the time of bypass. AB - BACKGROUND: Primary cardiac tumors are rare and the only curative treatment consists of complete excision under cardiopulmonary bypass (CPB). This case report presents an unusual case of an intra-cardiac tumor which was missing at the time of surgical excision. METHOD AND RESULTS: The patient was scheduled to undergo surgical tumor removal and double coronary artery bypass grafting (CABG). Intraoperatively, transesophageal echocardiography (TEE) demonstrated a mobile and pediculated tumor in the left ventricular outflow tract (LVOT). Unfortunately, at the time of tumor excision under CPB, this was missing. Before confirming tumor embolization, the CPB system was inspected. The tumor was found on the lateral part of the defoaming filter. CONCLUSION: Careful mobilization of the heart is recommended during surgery. In this case, it was unexpected that the tumor made its way through the vent line and unidirectional valve up to the venous reservoir where it was fortunately found. PMID- 20921088 TI - Iopromide-induced encephalopathy following coronary angioplasty. AB - Non-ionic agents have pharmacological side effects, such as seizure, alteration of cerebral function, confusion, short-term memory loss, mental aberrations and ophthalmoplegia. In this report, we present two cases that developed contrast induced encephalopathy following coronary angioplasty by the non-ionic contrast agent, iopromide (Ultravist((r))). As a result, we concluded that iopromide induced encephalopathy may occur during angioplasty in patients with no particular predispositions. In addition to that, contrast-induced encephalopathy should be considered as a new-onset neurological disorder. PMID- 20921089 TI - Skeletal muscle myoblasts possess a stretch-responsive local angiotensin signalling system. AB - A paucity of information exists regarding the presence of local renin-angiotensin systems (RASs) in skeletal muscle and associated muscle stem cells. Skeletal muscle and muscle stem cells were isolated from C57BL/6 mice and examined for the presence of a local RAS using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), immunohistochemistry (IHC), Western blotting and liquid chromatography-mass spectrometry (LC-MS). Furthermore, the effect of mechanical stimulation on RAS member gene expression was analysed. Whole skeletal muscle, primary myoblasts and C2C12 derived myoblasts and myotubes differentially expressed members of the RAS including angiotensinogen, angiotensin-converting enzyme (ACE), angiotensin II (Ang II) type 1 (AT(1)) and type 2 (AT(2)). Renin transcripts were never detected, however, mRNA for the 'renin-like' enzyme cathepsin D was observed and Ang I and Ang II were identified in cell culture supernatants from proliferating myoblasts. AT(1) appeared to co-localise with polymerised actin filaments in proliferating myoblasts and was primarily found in the nucleus of terminally differentiated myotubes. Furthermore, mechanical stretch of proliferating and differentiating C2C12 cells differentially induced mRNA expression of angiotensinogen, AT(1) and AT(2). Proliferating and differentiated muscle stem cells possess a local stress-responsive RAS in vitro. The precise function of a local RAS in myoblasts remains unknown. However, evidence presented here suggests that Ang II may be a regulator of skeletal muscle myoblasts. PMID- 20921090 TI - Platelet abnormalities in diabetes mellitus. AB - Patients with diabetes mellitus (DM) have accelerated atherosclerosis, which is the main underlying factor contributing to the high risk of atherothrombotic events in these patients. Atherothrombotic complications are the leading cause of morbidity and mortality in patients with DM. Among factors contributing to the prothrombotic condition which characterise patients with DM, platelet hyperreactivity plays a pivotal role. Platelets of DM patients are characterised by dysregulation of several signalling pathways leading to intensified adhesion, activation and aggregation. Multiple mechanisms are involved in platelet dysfunction of patients with DM, which can be categorised as follows: a) hyperglycaemia, b) insulin deficiency and resistance, c) associated metabolic conditions, and d) other cellular abnormalities.The present manuscript aims to provide an overview on the current status of knowledge on platelet abnormalities that characterise patients with DM. PMID- 20921091 TI - Antithrombotic therapy in patients with diabetes mellitus and coronary artery disease. AB - Currently approved antiplatelet treatment strategies have proved successful for reducing cardiovascular adverse events in patients with CAD. However, despite the use of recommended antiplatelet treatment strategies, the presence of DM has been consistently associated with a negative impact on outcomes and a high rate of adverse cardiovascular events continue to occur in patients with DM. The elevated prevalence of low response to standard oral antiplatelet agents contribute to these impaired outcomes. Thus, the search for more potent antiplatelet treatment strategies is warranted in high-risk patients, such as those with DM. The present manuscript provides an overview on the current status of knowledge on currently available antiplatelet agents, focusing on the benefits and limitations of these therapies in DM patients, and evaluating the potential role of new antithrombotic agents and treatment strategies currently under development to overcome these limitations. PMID- 20921093 TI - Using a prediction of death in the next 12 months as a prompt for referral to palliative care acts to the detriment of patients with heart failure and chronic obstructive pulmonary disease. PMID- 20921092 TI - Efficacy and tolerability of olmesartan/amlodipine combination therapy in patients with mild-to-severe hypertension: focus on 24-h blood pressure control. AB - European guidelines recommend that treating patients with hypertension to blood pressure (BP) goal is an important target for cardiovascular (CV) risk reduction. However, office BP may be a suboptimal target, given its limitations. Indeed, there is evidence that 24-h ambulatory BP monitoring (ABPM) parameters may score better in this regard, representing more accurate predictors of CV risk. In particular, mean 24-h BP and BP variability both correlate closely with hypertension end-organ damage and rate of CV events, which suggests that antihypertensive therapy should provide smooth BP control over the full 24-h dosing interval. The use of ABPM has demonstrated that fixed-dose combination therapy, comprising agents with complementary mechanisms of action, may overcome the challenge of suboptimal BP control by providing improvements in antihypertensive efficacy and tolerability throughout the 24-h period. Olmesartan/amlodipine is one of the latest combination therapies to be approved, and a number of large clinical trials have demonstrated the efficacy and tolerability of this combination in patients with mild-to-severe hypertension. Furthermore, recent ABPM studies of olmesartan/amlodipine-based treatment algorithms have shown the satisfactory 24-h antihypertensive efficacy of this fixed-dose combination. This review provides an overview of recent clinical data on the efficacy and tolerability of fixed-dose olmesartan/amlodipine combination therapy for the treatment of mild-to-severe hypertension, with a focus on sustained 24-h BP control. PMID- 20921094 TI - Sinus bradycardia related to methadone in a patient with myeloma receiving thalidomide therapy. PMID- 20921095 TI - Physicians' attitudes towards euthanasia in Finland: would training in palliative care make a difference? PMID- 20921098 TI - Temporal isolation effects in recognition and serial recall. AB - Recent temporal distinctiveness models of memory predict that temporally isolated items will be recalled better than temporally crowded items. The effect has been found in some tasks (free recall, memory for serial order when report order is unconstrained, running memory span) but not in others (forward serial recall). Such results suggest that the attentional weighting given to a temporal dimension in memory may vary with task demands. Here, we find robust temporal isolation effects in recognition memory (Experiment 1) and a smaller isolation effect in forward serial recall when an open pool of items is used (Experiment 2). Analysis of 26 temporal isolation effects suggests that the phenomenon occurs in a range of tasks but is larger when it is useful to attend to a temporal dimension in memory. The overall pattern of results is taken to favor memory models that rely on multiple weighted dimensions in memory, one of which is temporal. PMID- 20921099 TI - Prospective memory: are preparatory attentional processes necessary for a single focal cue? AB - The preparatory attentional and memory processes theory of prospective memory (PM) assumes that PM retrieval requires resource-demanding preparatory attentional processes, whereas the multiprocess theory assumes that retrieval can also occur spontaneously. On the basis of showing slowing on an ongoing task (i.e., task interference)-even when the PM cue was highly salient (i.e., the participant's own name)-Smith, Hunt, McVay, and McConnell (2007) concluded that preparatory attentional processes are always necessary for PM retrieval. We argue that the presence of preparatory attentional processes cannot be used to rule out the existence of spontaneous retrieval processes, and the goal of the present research was to examine whether PM retrieval can occur in the absence of preparatory attentional processes. We varied whether we emphasized the importance of the PM task or the ongoing task, and we assessed task interference across quarters of the ongoing task. Our results showed no evidence of task interference and, hence, no evidence of preparatory attentional processes in the periods proximal to the target event, and yet participants showed high PM performance. Thus, the results suggest the existence of spontaneous retrieval processes and support the multiprocess theory. PMID- 20921097 TI - False memories and fantastic beliefs: 15 years of the DRM illusion. AB - This article reviews research using the Deese/Roediger-McDermott (DRM) associative memory illusion, whereby people falsely remember words that were not presented. This illusion has broadly influenced basic theories of memory in cognitive psychology and neuroscience and naturally raises the question as to how these theories apply to more complex autobiographical memories. Some applicability is evident from research linking individual differences in the DRM illusion to false autobiographical memories (e.g., misremembering public events) and fantastic autobiographical beliefs (e.g., memories from past lives). But which aspects generalize? Here it is argued that a process-oriented approach is needed in order to answer this question. Many productive years of DRM research indicate that multiple and often opposing psychological processes cause even the most basic false memories. In light of these discoveries, more researchers need to use methods that isolate these component processes if the goal is to understand false memories both in the lab and in life. PMID- 20921101 TI - Working memory and insight in the nine-dot problem. AB - In the present article, we examine the contribution of working memory (WM) to solution of the nine-dot problem, a classic insight problem. Prior research has generally demonstrated a limited role for WM in the solution of insight problems, which are typically assumed to be solved without conscious planning. However, MacGregor, Ormerod, and Chronicle (2001) proposed an information-processing model that solves the nine-dot problem by relying on a visual WM mechanism, which they term lookahead. In the present research, we examine whether performance on the nine-dot problem is indeed predicted by WM capacity. The results indicated that spatial WM capacity predicted the tendency to draw lines outside the configuration of dots and predicted the solution on a hint-aided version of the problem. Furthermore, within those solving the problem, higher spatial WM capacity was also related to faster solutions. The results support the information-processing model and suggest a more essential role for WM and planning in insight problem solving than has previously been acknowledged. PMID- 20921100 TI - The influence of complex working memory span task administration methods on prediction of higher level cognition and metacognitive control of response times. AB - Participants between the ages of 18 and 80 were tested on a complex working memory span task that was administered either using a typical experimenter-paced method or using a method in which the processing component was presented at a fixed, limited-pace presentation rate. Path analyses revealed that even after controlling for individual differences in general processing speed, the limited pace task predicted unique variance in episodic memory, executive functioning, and fluid intelligence, whereas the experimenter-paced task did not. For the experimenter-paced task, slower responses on the processing component of the task were associated with better recall, but only when individual differences in processing speed were controlled. These findings suggest that metacognitive control of response times affects recall from working memory span tasks, as well as the relationship between span task recall and high-level cognition. These results support resource-sharing explanations of working memory and suggest that limiting processing times using computer pacing of complex span tasks can be an effective way to efficiently measure working memory capacity. PMID- 20921102 TI - Selective attention and response set in the Stroop task. AB - Response set membership contributes much to the interference in the color-word Stroop task. This may be due to selective allocation of attention to eligible responses or, alternatively, to greater inhibition of distractors that are not responses. In the present article, we report two experiments that were designed to adjudicate between these accounts. In Experiment 1, membership was manipulated on a trial-by-trial basis by cuing the possible responses for each trial. Response time (RT) was longer for distractors that corresponded to a cued, eligible response than to an ineligible one. This cuing effect was independent of the number of different responses. In Experiment 2, the distractor was cued on half the trials. Cuing the distractor decreased RTs on both incongruent and congruent trials. Vincentile analyses in both experiments revealed that the effects were constant throughout the entire RT distributions. These results suggest that response set effects arise because of selective allocation of attention to eligible responses. PMID- 20921103 TI - Implicit learning of fifth- and sixth-order sequential probabilities. AB - Serial reaction time (SRT) task studies have established that people can implicitly learn sequential contingencies as complex as fourth-order probabilities. The present study examined people's ability to learn fifth-order (Experiment 1) and sixth-order (Experiment 2) probabilities. Remarkably, people learned fifth- and sixth-order probabilities. This suggests that the implicit sequence learning mechanism can operate over a range of at least seven sequence elements. PMID- 20921104 TI - Classification response times in probabilistic rule-based category structures: contrasting exemplar-retrieval and decision-boundary models. AB - Experiments were conducted to contrast the predictions from exemplar models and rule-based decision-boundary models of perceptual classification. Observers classified multidimensional stimuli into categories that could be described in terms of easily verbalized logical rules. The critical manipulation was that some pairs of stimuli received probabilistic feedback, whereas other control pairs received deterministic feedback. Despite the probabilistic feedback, the probabilistic pairs and the deterministic pairs were the same distance from ideal observer, rule-based decision boundaries. Across two experiments with varying category structures, observers classified the probabilistic pairs with slower response times (RTs) and lower accuracies than the comparison deterministic pairs. The effects were relatively long term, extending into test blocks in which all feedback was withheld. The results were as predicted by exemplar models, but challenged models that posit that RT is a function solely of the distance of a stimulus from rule-based boundaries. The studies add considerable generality to previous ones and suggest that, even in domains involving rule-based category structures, exemplar-retrieval processes play a significant role. Supplemental materials related to this article may be downloaded from http://mc.psychonomic journals.org/content/supplemental. PMID- 20921105 TI - Belief-based and analytic processing in transitive inference depends on premise integration difficulty. AB - Three experiments investigated belief-based versus analytic processing in transitive inference. Belief-based and analytic processing were inferred from conclusion acceptance rates for problems with conclusions that were either valid or invalid and believable or unbelievable. Premise integration difficulty was manipulated by varying premise integration time (Experiment 1), premise presentation order (Experiment 2), and the markedness of the relational terms in the premises (Experiment 3). In all the conditions, reasoning accuracy and rated confidence were lower on conflict problems, where belief-based and analytic processes yielded different responses. Participants relied more on analytic processing and less on belief-based processing in conditions in which premise integration was easier. Fluid intelligence and premise integration ability predicted analytical reasoning on conflict problems after reasoning on the no conflict problems was controlled for. The findings were related to three dual process models of belief bias. They provide the first evidence of belief bias in transitive inference. PMID- 20921106 TI - Broadening the study of inductive reasoning: confirmation judgments with uncertain evidence. AB - Although evidence in real life is often uncertain, the psychology of inductive reasoning has, so far, been confined to certain evidence. The present study extends previous research by investigating whether people properly estimate the impact of uncertain evidence on a given hypothesis. Two experiments are reported, in which the uncertainty of evidence is explicitly (by means of numerical values) versus implicitly (by means of ambiguous pictures) manipulated. The results show that people's judgments are highly correlated with those predicted by normatively sound Bayesian measures of impact. This sensitivity to the degree of evidential uncertainty supports the centrality of inductive reasoning in cognition and opens the path to the study of this issue in more naturalistic settings. PMID- 20921107 TI - Scaffolding feedback to maximize long-term error correction. AB - Scaffolded feedback was tested against three other feedback presentation methods (standard corrective feedback, minimal feedback, and answer-until-correct multiple-choice feedback) over both short- and long-term retention intervals in order to assess which method would produce the most robust gains in error correction. Scaffolded feedback was a method designed to take advantage of the benefits of retrieval practice by providing incremental hints until the correct answer could be self-generated. In Experiments 1 and 3, on an immediate test, final memory for the correct answer was lowest for questions given minimal feedback, moderate for the answer-until-correct condition, and equally high in the scaffolded feedback condition and the standard feedback condition. However, tests of the maintenance of the corrections over a 30-min delay (Experiment 2) and over a 1-day delay (Experiment 3) demonstrated that scaffolded feedback gave rise to the best memory for the correct answers at a delay. PMID- 20921108 TI - Geometric and featural representations in semantic concepts. AB - We explore the adequacy of two types of similarity representation in the context of semantic concepts. To this end, we evaluate different categorization models, assuming either a geometric or a featural representation, using categorization decisions involving familiar and unfamiliar foods and animals. The study aims to assess the optimal stimulus representation as a function of the familiarity of the stimuli. For the unfamiliar stimuli, the geometric categorization models provide the best account of the categorization data, whereas for the familiar stimuli, the featural categorization models provide the best account. This pattern of results suggests that people rely on perceptual information to assign an unfamiliar stimulus to a category but rely on more elaborate conceptual knowledge when assigning a familiar stimulus. PMID- 20921109 TI - Body part representations in verbal semantics. AB - Embodied theories of language propose that word meaning is inextricably tied to grounded in-mental representations of perceptual, motor, and affective experiences of the world. The four experiments described in this article demonstrate that accessing the meanings of action verbs like smile, punch, and kick requires language understanders to activate modality-specific cognitive representations responsible for performing and perceiving those same actions. The main task used is a word-image matching task, where participants see an action verb and an image depicting an action. Their task is to decide as quickly as possible whether the verb and the image depict the same action. Of critical interest is participants' behavior when the verb and image do not match, in which case the two actions can use the same effector or different effectors. In Experiment 1, we found that participants took significantly longer to reject a verb-image pair when the actions depicted by the image and denoted by the verb used the same effector than when they used different effectors. Experiment 2 yielded the same result when the order of presentation was reversed, replicating the effect in Cantonese. Experiment 3 replicated the effect in English with a verb-verb near-synonym task, and in Experiment 4, we once again replicated the effect with learners of English as a second language. This robust interference effect, whereby a shared effector slows discrimination, shows that language understanders activate effector-specific neurocognitive representations during both picture perception and action word understanding. PMID- 20921110 TI - The role of animacy in spatial transformations. AB - We present evidence that different mental spatial transformations are used to reason about three different types of items representing a spectrum of animacy: human bodies, nonhuman animals, and inanimate objects. Participants made two different judgments about rotated figures: handedness judgments ("Is this the left or right side?") and matching judgments ("Are these figures the same?"). Perspective-taking strategies were most prevalent when participants made handedness judgments about human bodies and animals. In contrast, participants generally did not imagine changes in perspective to perform matching judgments. Such results suggest that high-level information about semantic categories, including information about a thing's animacy, can influence how spatial representations are transformed when performing online problem solving. Supplemental materials for this article may be downloaded from http://mc.psychonomic-journals.org/content/supplemental. PMID- 20921111 TI - Effect of mental health courts on arrests and jail days: a multisite study. AB - CONTEXT: Mental health courts are growing in popularity as a form of jail diversion for justice system-involved people with serious mental illness. This is the first prospective multisite study on mental health courts with treatment and control groups. OBJECTIVES: To determine if participation in a mental health court is associated with more favorable criminal justice outcomes than processing through the regular criminal court system and to identify defendants for whom mental health courts produce the most favorable criminal justice outcomes. DESIGN: Longitudinal study. SETTING: Four mental health courts in San Francisco County, CA, Santa Clara County, CA, Hennepin County (Minneapolis), MN, and Marion County (Indianapolis), IN. PARTICIPANTS: A total 447 persons in the mental health court (MHC) and 600 treatment-as-usual (TAU) controls. INTERVENTION: Eighteen months of pre-entry and postentry data for 4 jurisdictions. All subjects were interviewed at baseline, and 70% were interviewed at 6 months. Objective outcome data were obtained on all subjects from Federal Bureau of Investigation arrest records, jails, prisons, and community treatment providers. MAIN OUTCOME MEASURES: Annualized rearrest rates, number of rearrests, and postentry incarceration days. RESULTS: The MHC and TAU samples are similar on the major outcome measures in the pre-entry 18-month period. In the 18 months following treatment, defined as entry into mental health court, the MHC group has a lower annualized rearrest rate, fewer post-18-month arrests, and fewer post-18-month incarceration days than the TAU group. The MHC graduates had lower rearrest rates than participants whose participation was terminated both during MHC supervision and after supervision ended. Factors associated with better outcomes among the MHC participants include lower pre-18-month arrests and incarceration days, treatment at baseline, not using illegal substances, and a diagnosis of bipolar disorder rather than schizophrenia or depression. CONCLUSIONS: Mental health courts meet the public safety objectives of lowering posttreatment arrest rates and days of incarceration. Both clinical and criminal justice factors are associated with better public safety outcomes for MHC participants. PMID- 20921112 TI - Evidence that familial liability for psychosis is expressed as differential sensitivity to cannabis: an analysis of patient-sibling and sibling-control pairs. AB - CONTEXT: Individual differences in cannabis sensitivity may be associated with genetic risk for psychotic disorder. OBJECTIVES: To demonstrate and replicate, using 2 conceptually different genetic epidemiological designs, that (familial) liability to psychosis is associated with sensitivity to cannabis. DESIGN, SETTING, AND PARTICIPANTS: Sibling-control and cross-sibling comparisons using samples of patients with a psychotic disorder (n = 1120), their siblings (n = 1057), and community controls (n = 590) in the Netherlands and Flanders. MAIN OUTCOME MEASURES: Positive and negative schizotypy using the Structured Interview for Schizotypy-Revised (for siblings and controls) and self-reported positive and negative psychotic experiences using the Community Assessment of Psychic Experiences (for siblings and patients). Cannabis use was assessed as current use (by urinalysis) and lifetime frequency of use (by Composite International Diagnostic Interview). RESULTS: In the sibling-control comparison, siblings displayed more than 15 times greater sensitivity to positive schizotypy associated with particularly current cannabis use by urinalysis (adjusted B = 0.197, P < .001) than controls (adjusted B = 0.013, P = .86) (P interaction = .04) and a similar difference in sensitivity to its effect on negative schizotypy (siblings: adjusted B = 0.120, P < .001; controls: B = -0.008, P = .87; P interaction = .03). Similarly, siblings exposed to cannabis resembled their patient relative nearly 10 times more closely in the positive psychotic dimension of the Community Assessment of Psychic Experiences (adjusted B = 0.278, P < .001) compared with nonexposed siblings (adjusted B = 0.025, P = .12) (P interaction < .001). No significant effect was apparent for the Community Assessment of Psychic Experiences negative domain, although the association was directionally similar (2 times more resemblance; P interaction = .17). Cross-sibling, cross-trait analyses suggested that the mechanism underlying these findings was moderation (familial risk increasing sensitivity to cannabis) rather than mediation (familial risk increasing use of cannabis). CONCLUSIONS: Genetic risk for psychotic disorder may be expressed in part as sensitivity to the psychotomimetic effect of cannabis. Cannabis use may synergistically combine with preexisting psychosis liability to cause positive and negative symptoms of psychosis. PMID- 20921113 TI - Postdisaster course of alcohol use disorders in systematically studied survivors of 10 disasters. AB - CONTEXT: Although several studies have suggested that alcohol use may increase after disasters, it is unclear whether any apparent postdisaster increases regularly translate into new cases of alcohol use disorders. OBJECTIVE: To determine the relationship of predisaster and postdisaster prevalence of alcohol use disorders and to examine the incidence of alcohol use disorders in relation to disasters. DESIGN: Data from 10 disasters, studied within the first few postdisaster months and at 1 to 3 years postdisaster, were merged and examined. PARTICIPANTS: Six hundred ninety-seven directly exposed survivors of 10 disasters. MEASURES: The Diagnostic Interview Schedule for DSM-III-R provided lifetime diagnoses of alcohol abuse and dependence, and onset and recency questions allowed a determination of whether the disorder had been present either prior to or following the event, or both. RESULTS: While the postdisaster prevalence of alcohol use disorders was 19%, only 0.3% of the sample developed an acute new postdisaster alcohol use disorder. Most of those in recovery, however, consumed alcohol after the disaster (83%) and coped with their emotions by drinking alcohol (22%). Those with a postdisaster alcohol use disorder were more than 4 times as likely as those without to cope with their disaster-related emotions by drinking alcohol (40% vs 9%). CONCLUSIONS: The vast majority of postdisaster alcohol use disorders represented the continuation or recurrence of preexisting problems. Findings suggest that those in recovery as well as those who drink to cope with their emotions represent groups warranting potential concern for postdisaster mental health intervention. Further research is needed to clarify the clinical significance of changes in alcohol use after disasters. PMID- 20921114 TI - Camillo Golgi, nobel laureate: the olfactory bulb. PMID- 20921115 TI - Biological validation of increased schizophrenia risk with NRG1, ERBB4, and AKT1 epistasis via functional neuroimaging in healthy controls. AB - CONTEXT: NRG1 is a schizophrenia candidate gene and plays an important role in brain development and neural function. Schizophrenia is a complex disorder, with etiology likely due to epistasis. OBJECTIVE: To examine epistasis between NRG1 and selected N-methyl-d-aspartate-glutamate pathway partners implicated in its effects, including ERBB4, AKT1, DLG4, NOS1, and NOS1AP. DESIGN: Schizophrenia case-control sample analyzed using machine learning algorithms and logistic regression with follow-up using neuroimaging on an independent sample of healthy controls. PARTICIPANTS: A referred sample of schizophrenic patients (n = 296) meeting DSM-IV criteria for schizophrenia spectrum disorder and a volunteer sample of controls for case-control comparison (n = 365) and a separate volunteer sample of controls for neuroimaging (n = 172). MAIN OUTCOME MEASURES: Epistatic association between single-nucleotide polymorphisms (SNPs) and case-control status; epistatic association between SNPs and the blood oxygen level-dependent physiological response during working memory measured by functional magnetic resonance imaging. RESULTS: We observed interaction between NRG1 5' and 3' SNPs rs4560751 and rs3802160 (likelihood ratio test P = .00020) and schizophrenia, which was validated using functional magnetic resonance imaging of working memory in healthy controls; carriers of risk-associated genotypes showed inefficient processing in the dorsolateral prefrontal cortex (P = .015, familywise error corrected). We observed epistasis between NRG1 (rs10503929; Thr286/289/294Met) and its receptor ERBB4 (rs1026882; likelihood ratio test P = .035); a 3-way interaction with these 2 SNPs and AKT1 (rs2494734) was also observed (odds ratio, 27.13; 95% confidence interval, 3.30-223.03; likelihood ratio test P = .042). These same 2- and 3-way interactions were further biologically validated via functional magnetic resonance imaging: healthy individuals carrying risk genotypes for NRG1 and ERBB4, or these 2 together with AKT1, were disproportionately less efficient in dorsolateral prefrontal cortex processing. Lower-level interactions were not observed between NRG1 /ERBB4 and AKT1 in association or neuroimaging, consistent with biological evidence that NRG1 * ERBB4 interaction modulates downstream AKT1 signaling. CONCLUSION: Our data suggest complex epistatic effects implicating an NRG1 molecular pathway in cognitive brain function and the pathogenesis of schizophrenia. PMID- 20921116 TI - Regional brain volume in depression and anxiety disorders. AB - CONTEXT: Major depressive disorder (MDD), panic disorder, and social anxiety disorder are among the most prevalent and frequently co-occurring psychiatric disorders in adults and may have, at least in part, a common etiology. OBJECTIVE: To identify the unique and shared neuroanatomical profile of depression and anxiety, controlling for illness severity, medication use, sex, age of onset, and recurrence. DESIGN: Cross-sectional study. SETTING: Netherlands Study of Depression and Anxiety. PARTICIPANTS: Outpatients with MDD (n = 68), comorbid MDD and anxiety (n = 88), panic disorder, and/or social anxiety disorder without comorbid MDD (n = 68) and healthy controls (n = 65). MAIN OUTCOME MEASURES: Volumetric magnetic resonance imaging was conducted for voxel-based morphometry analyses. We tested voxelwise for the effects of diagnosis, age at onset, and recurrence on gray matter density. Post hoc, we studied the effects of use of medication, illness severity, and sex. RESULTS: We demonstrated lower gray matter volumes of the rostral anterior cingulate gyrus extending into the dorsal anterior cingulate gyrus in MDD, comorbid MDD and anxiety, and anxiety disorders without comorbid MDD, independent of illness severity, sex, and medication use. Furthermore, we demonstrated reduced right lateral inferior frontal volumes in MDD and reduced left middle/superior temporal volume in anxiety disorders without comorbid MDD. Also, patients with onset of depression before 18 years of age showed lower volumes of the subgenual prefrontal cortex. CONCLUSIONS: Our findings indicate that reduced volume of the rostral-dorsal anterior cingulate gyrus is a generic effect in depression and anxiety disorders, independent of illness severity, medication use, and sex. This generic effect supports the notion of a shared etiology and may reflect a common symptom dimension related to altered emotion processing. Specific involvement of the inferior frontal cortex in MDD and lateral temporal cortex in anxiety disorders without comorbid MDD, on the other hand, may reflect disorder-specific symptom clusters. Early onset of depression is associated with a distinct neuroanatomical profile that may represent a vulnerability marker of depressive disorder. PMID- 20921118 TI - Randomized clinical trial comparing family-based treatment with adolescent focused individual therapy for adolescents with anorexia nervosa. AB - CONTEXT: Evidence-based treatment trials for adolescents with anorexia nervosa are few. OBJECTIVE: To evaluate the relative efficacy of family-based treatment (FBT) and adolescent-focused individual therapy (AFT) for adolescents with anorexia nervosa in full remission. DESIGN: Randomized controlled trial. SETTING: Stanford University and The University of Chicago (April 2005 until March 2009). PARTICIPANTS: One hundred twenty-one participants, aged 12 through 18 years, with DSM-IV diagnosis of anorexia nervosa excluding the amenorrhea requirement. Intervention Twenty-four outpatient hours of treatment over 12 months of FBT or AFT. Participants were assessed at baseline, end of treatment (EOT), and 6 months' and 12 months' follow-up posttreatment. MAIN OUTCOME MEASURES: Full remission from anorexia nervosa defined as normal weight (>=95% of expected for sex, age, and height) and mean global Eating Disorder Examination score within 1 SD of published means. Secondary outcome measures included partial remission rates (>85% of expected weight for height plus those who were in full remission) and changes in body mass index percentile and eating-related psychopathology. RESULTS: There were no differences in full remission between treatments at EOT. However, at both the 6- and 12-month follow-up, FBT was significantly superior to AFT on this measure. Family-based treatment was significantly superior for partial remission at EOT but not at follow-up. In addition, body mass index percentile at EOT was significantly superior for FBT, but this effect was not found at follow-up. Participants in FBT also had greater changes in Eating Disorder Examination score at EOT than those in AFT, but there were no differences at follow-up. CONCLUSION: Although both treatments led to considerable improvement and were similarly effective in producing full remission at EOT, FBT was more effective in facilitating full remission at both follow-up points. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00149786. PMID- 20921119 TI - Attention-deficit/hyperactivity disorder symptoms in offspring of mothers with impaired serotonin production. AB - CONTEXT: Exposure to adverse events during prenatal and postnatal development, as well as serotonin deficiency, have been implicated in disturbances of mood and impulsivity, but the underlying mechanisms are unknown. OBJECTIVE: To investigate the long-term effects of an impaired serotonin synthesis on the developing human brain, we studied the effects of nonsynonymous mutations affecting tryptophan hydroxylase (TPH) enzymes responsible for serotonin production in maternal reproductive tissues (TPH1) and the brain (TPH2). DESIGN: Family-based case control and functional studies of candidate genes. SETTING: Adult outpatients with attention-deficit/hyperactivity disorder (ADHD), their family members, and random control subjects were recruited across Norway. PARTICIPANTS: Nine pedigrees with TPH1 and TPH2 mutation carriers were identified among 459 patients with ADHD and 187 controls. The TPH genes were then sequenced in 97 additional family members, and information about psychiatric diagnoses and symptoms was obtained from 606 controls, the 459 patients, and their relatives. MAIN OUTCOME MEASURES: The effects of maternal vs paternal TPH1 mutations compared in all families. RESULTS: Nine different TPH1 and TPH2 mutations were found by sequencing in 646 individuals (1.0% and 0.2% allele frequency, respectively). In vitro studies showed that 8 TPH mutants had significantly impaired enzyme function. Family analysis of 38 TPH1 mutation carriers and 41 of their offspring revealed that offspring of mothers carrying TPH1 mutations reported 1.5- to 2.5 times-higher ADHD scores and related symptoms during childhood and as adults than did controls (P < 10(-6)) or offspring of fathers with the corresponding TPH1 mutations (P < .001). CONCLUSIONS: Impaired maternal serotonin production may have long-term consequences for brain development and increase the risk of ADHD related symptoms and behavior in offspring. Replication studies are required to form conclusions about the clinical implications of mutations affecting serotonin biosynthesis. PMID- 20921117 TI - A meta-analysis of depression during pregnancy and the risk of preterm birth, low birth weight, and intrauterine growth restriction. AB - CONTEXT: Maternal depressive symptoms during pregnancy have been reported in some, but not all, studies to be associated with an increased risk of preterm birth (PTB), low birth weight (LBW), and intrauterine growth restriction (IUGR). OBJECTIVE: To estimate the risk of PTB, LBW, and IUGR associated with antenatal depression. DATA SOURCES AND STUDY SELECTION: We searched for English-language and non-English-language articles via the MEDLINE, PsycINFO, CINAHL, Social Work Abstracts, Social Services Abstracts, and Dissertation Abstracts International databases (January 1980 through December 2009). We aimed to include prospective studies reporting data on antenatal depression and at least 1 adverse birth outcome: PTB (<37 weeks' gestation), LBW (<2500 g), or IUGR (<10th percentile for gestational age). Of 862 reviewed studies, 29 US-published and non-US-published studies met the selection criteria. DATA EXTRACTION: Information was extracted on study characteristics, antenatal depression measurement, and other biopsychosocial risk factors and was reviewed twice to minimize error. DATA SYNTHESIS: Pooled relative risks (RRs) for the effect of antenatal depression on each birth outcome were calculated using random-effects methods. In studies of PTB, LBW, and IUGR that used a categorical depression measure, pooled effect sizes were significantly larger (pooled RR [95% confidence interval] = 1.39 [1.19 1.61], 1.49 [1.25-1.77], and 1.45 [1.05-2.02], respectively) compared with studies that used a continuous depression measure (1.03 [1.00-1.06], 1.04 [0.99 1.09], and 1.02 [1.00-1.04], respectively). The estimates of risk for categorically defined antenatal depression and PTB and LBW remained significant when the trim-and-fill procedure was used to correct for publication bias. The risk of LBW associated with antenatal depression was significantly larger in developing countries (RR = 2.05; 95% confidence interval, 1.43-2.93) compared with the United States (RR = 1.10; 95% confidence interval, 1.01-1.21) or European social democracies (RR = 1.16; 95% confidence interval, 0.92-1.47). Categorically defined antenatal depression tended to be associated with an increased risk of PTB among women of lower socioeconomic status in the United States. CONCLUSIONS: Women with depression during pregnancy are at increased risk for PTB and LBW, although the magnitude of the effect varies as a function of depression measurement, country location, and US socioeconomic status. An important implication of these findings is that antenatal depression should be identified through universal screening and treated. PMID- 20921120 TI - Very early predictors of adolescent depression and suicide attempts in children with attention-deficit/hyperactivity disorder. AB - CONTEXT: Major depression and dysthymia in adolescence are associated with substantial disability, need for mental health services, and risk for recurrence. Concrete suicidal ideation and attempts during adolescence are particularly associated with significant distress, morbidity, and risk for completed suicide. OBJECTIVES: To test the hypothesis that young children with attention deficit/hyperactivity disorder (ADHD) are at increased risk for depression and suicidal ideation and attempts during adolescence and to identify early predictors of which young children with ADHD are at greatest risk. DESIGN: Prospective follow-up study. SETTING: Chicago, Illinois, and Pittsburgh, Pennsylvania. Patients A cohort of 125 children who met DSM-IV criteria for ADHD at 4 to 6 years of age and 123 demographically matched comparison children without ADHD were prospectively followed up in 7 structured diagnostic assessments of depression and suicidal behavior in assessment years 6 through 14, spanning 9 through 18 years of age. MAIN OUTCOME MEASURES: DSM-IV criteria for depressive disorders and suicidal behavior. RESULTS: Children with ADHD at 4 to 6 years of age were at greatly increased risk for meeting DSM-IV criteria for major depression or dysthymia (hazard ratio, 4.32) and for attempting suicide (hazard ratio, 3.60) through the age of 18 years relative to comparison children. There were marked variations in risk for these outcomes among children with ADHD, however. Within the ADHD group, children with each subtype of ADHD were at risk but for different adverse outcomes. Girls were at greater risk for depression and suicide attempts. Maternal depression and concurrent child emotional and behavior problems at 4 to 6 years of age predicted depression and suicidal behavior. CONCLUSIONS: All subtypes of ADHD in young children robustly predict adolescent depression and/or suicide attempts 5 to 13 years later. Furthermore, female sex, maternal depression, and concurrent symptoms at 4 to 6 years of age predict which children with ADHD are at greatest risk for these adverse outcomes. Identifying high-risk young children with ADHD sets the stage for early prevention trials to reduce risk for later depression and suicidal behavior. PMID- 20921121 TI - Similar white matter aberrations in children with autism and their unaffected siblings: a diffusion tensor imaging study using tract-based spatial statistics. AB - CONTEXT: Autism is a neurobiological condition with a strong genetic component. Recent diffusion tensor imaging (DTI) studies have indicated that white matter structure is aberrant in autism. To date, white matter structure has not been assessed in family members of children with autism. OBJECTIVE: To determine whether white matter structure is aberrant in children with autism and their unaffected siblings compared with controls, and to test the hypothesis that white matter structure in autism is correlated with autism spectrum symptomatology. DESIGN: Cross-sectional, case-control, voxel-based, whole-brain DTI analysis using Tract-Based Spatial Statistics. SETTING: University research center. Patients A sample of 37 children: 13 subjects with autism, 13 of their unaffected siblings, and 11 controls. Controls were age- and intelligence quotient-matched to the unaffected siblings; all groups were age matched. Main Outcome Measure Fractional anisotropy (FA) and axial and radial diffusivities. In addition, behavioral correlation analyses were conducted using the Autism Diagnostic Interview and Autism Diagnostic Observation Schedule subscales and FA values, as well as axial diffusivity values in the autism group. RESULTS: Compared with the control group, both the autism and sibling groups had widespread, significantly reduced white matter FA values (P <= .05, corrected) in the frontal parietal and temporal lobes and included, but were not restricted to, regions known to be important for social cognition. Within regions of reduced FA, significant reductions in axial diffusivity, but not radial diffusivity, were observed. There were no significant differences in white matter structure between the autism and sibling groups. There were no significant correlations between autism symptomatology and white matter FA or axial diffusivity. CONCLUSIONS: Our findings suggest that white matter structure may represent a marker of genetic risk for autism or vulnerability to development of this disorder. PMID- 20921122 TI - Deep brain stimulation of the nucleus accumbens for treatment-refractory obsessive-compulsive disorder. AB - CONTEXT: Obsessive-compulsive disorder (OCD) is a chronic psychiatric disorder that affects 2% of the general population. Even when the best available treatments are applied, approximately 10% of patients remain severely afflicted and run a long-term deteriorating course of OCD. OBJECTIVE: To determine whether bilateral deep brain stimulation of the nucleus accumbens is an effective and safe treatment for treatment-refractory OCD. DESIGN: The study consisted of an open 8-month treatment phase, followed by a double-blind crossover phase with randomly assigned 2-week periods of active or sham stimulation, ending with an open 12-month maintenance phase. SETTING: Academic research. Patients Sixteen patients (age range, 18-65 years) with OCD according to DSM-IV criteria meeting stringent criteria for refractoriness to treatment were included in the study. INTERVENTIONS: Treatment with bilateral deep brain stimulation of the nucleus accumbens. MAIN OUTCOME MEASURES: Primary efficacy was assessed by score change from baseline on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS). Responders were defined by a score decrease of at least 35% on the Y-BOCS. RESULTS: In the open phase, the mean (SD) Y-BOCS score decreased by 46%, from 33.7 (3.6) at baseline to 18.0 (11.4) after 8 months (P < .001). Nine of 16 patients were responders, with a mean (SD) Y-BOCS score decrease of 23.7 (7.0), or 72%. In the double-blind, sham-controlled phase (n = 14), the mean (SD) Y-BOCS score difference between active and sham stimulation was 8.3 (2.3), or 25% (P = .004). Depression and anxiety decreased significantly. Except for mild forgetfulness and word-finding problems, no permanent adverse events were reported. CONCLUSION: Bilateral deep brain stimulation of the nucleus accumbens may be an effective and safe treatment for treatment-refractory OCD. CLINICAL TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN23255677. PMID- 20921123 TI - Effect of acamprosate on magnetic resonance spectroscopy measures of central glutamate in detoxified alcohol-dependent individuals: a randomized controlled experimental medicine study. AB - CONTEXT: Acamprosate is approved for the treatment of alcoholism, but its mechanism of action remains unclear. Results of animal studies suggest that a persistent hyperglutamatergic state contributes to the pathogenesis of alcoholism and that acamprosate may exert its actions by intervening in this process. Human translation of these findings is lacking. OBJECTIVE: To examine whether acamprosate modulates indices of central glutamate levels in recently abstinent alcohol-dependent patients as measured using proton nuclear magnetic resonance spectroscopy (1H-MRS). DESIGN: A 4-week, double-blind, placebo-controlled, randomized controlled experimental medicine study, with 1H-MRS measures obtained on days 4 and 25. SETTING: An inpatient research unit at the NIH Clinical Center. Patients Thirty-three patients who met the DSM-IV criteria for alcohol dependence and who were admitted for medically supervised withdrawal from ongoing alcohol use. Intervention Four weeks of acamprosate (initial oral loading followed by 1998 mg daily) or matched placebo, initiated at the time of admission. MAIN OUTCOME MEASURES: The glutamate to creatine ratio as determined using single voxel 1H-MRS in the anterior cingulate. Exploratory neuroendocrine, biochemical, and behavioral outcomes were also collected, as were safety- and tolerability related measures. RESULTS: There was a highly significant suppression of the glutamate to creatine ratio across time by acamprosate (time * treatment interaction: F1(,)29 = 13.5, P < .001). Cerebrospinal fluid levels of glutamate obtained in a subset of patients 4 weeks into abstinence were uncorrelated with the MRS measures and unaffected by treatment but were strongly correlated (R2 = 0.48, P < .001) with alcohol dependence severity. Other exploratory outcomes, including repeated dexamethasone-corticotropin-releasing hormone tests, and psychiatric ratings were unaffected. Among tolerability measures, gastrointestinal symptoms were significantly greater in acamprosate-treated individuals, in agreement with the established profile of acamprosate. CONCLUSION: The MRS measures of central glutamate are reduced across time when acamprosate therapy is initiated at the onset of alcohol abstinence. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00106106. PMID- 20921124 TI - Economic costs of neuroticism: a population-based study. AB - CONTEXT: The importance of neuroticism for mental health care use and public health is well established. However, most research has focused on the association between neuroticism and a single specific disorder or health outcome, and the overall effect of neuroticism on use of somatic and mental health care and on society is not clear. OBJECTIVE: To examine the economic costs of neuroticism to get an impression of the overall effect of neuroticism on mental health care and on society in general. DESIGN: Cross-sectional population-based study. SETTING: General population. PARTICIPANTS: A large representative sample (N = 5504) of the Dutch general population. MAIN OUTCOME MEASURES: The costs (health service uptake in primary and secondary mental health care, out-of-pocket costs, and production losses) associated with neuroticism. RESULTS: The total per capita excess costs were $12 362 per year for the reference year 2007 in the 5% highest scorers of neuroticism, $8243 in the 10% highest scorers, and $5572 in the 25% highest scorers. The per capita excess costs of neuroticism are considerably higher than those of mental disorders. The total excess costs of neuroticism per 1 million inhabitants resulting from the 25% highest scorers ($1.393 billion) were approximately 2.5 times as high as the excess costs of common mental disorders ($585 million). CONCLUSIONS: The economic costs of neuroticism are enormous and exceed those of common mental disorders. We should start thinking about interventions that focus not on each of the specific negative outcomes of neuroticism but rather on the starting point itself. PMID- 20921125 TI - In utero smoking exposure warrants further investigation. PMID- 20921126 TI - Fall prevention practices in adult medical-surgical nursing units described by nurse managers. AB - The purpose of this article was to describe nursing practices (e.g., assessment, interventions) around fall prevention, as perceived by nurse managers in adult, medical-surgical nursing units. One hundred forty nurse managers from 51 hospitals from across the United States participated. Descriptive frequencies are used to describe nurse manager responses. The most commonly used fall risk assessment tool was the Morse Fall Risk Assessment Tool (40%). The most common fall prevention interventions included bed alarms (90%), rounds (70%), sitters (68%), and relocating the patient closer to the nurses' station (56%). Twenty nine percent of nurse managers identified physical restraints as an intervention to prevent falls whereas only 10% mentioned ambulation. No nurse manager identified that RN hours per patient-day were adjusted to prevent falls or fall related injuries. More work is needed to build systems that ensure evidence-based nursing interventions are consistently applied in acute care. PMID- 20921127 TI - Risk behaviors among adolescent girls in an HIV prevention trial. AB - Adolescent girls remain vulnerable to HIV and other sexually transmitted infections. Understanding their sexual and substance use behaviors is essential to designing effective interventions to reduce their risk. In this study, baseline data were analyzed from 738 adolescent girls ages 15 to 19 years in Rochester, New York. Data on sexual behavior and substance use (lifetime, past 3 months, and most recent sexual experience) were collected. Nearly one half of recent vaginal (42%) and anal (45%) sex acts were not condom protected; 39% had a prior sexually transmitted infection (STI) and 12% were currently infected with an STI. Approximately one third (31%) of girls had more than one sex partner in the past 3 months. Girls with multiple partners reported that their recent sexual experiences were more likely to involve drug and alcohol use by themselves and partners. Adolescent girls, particularly those with multiple sexual partners, continue to report high-risk sexual behaviors and need focused risk-reduction interventions. PMID- 20921128 TI - Using the TRIP model to disseminate an IT-based pressure ulcer intervention. AB - Pressure ulcers (PUs) are among the most common harms experienced by patients in health care facilities. Despite the existence of evidence-based guidelines and protocols for PU prevention and treatment, the sustained success in reducing the development of PUs is elusive. The purpose of this article is to describe how the Translating Research Into Practice (TRIP) model was used to support implementation of a care management solution (i.e., the Daily Project) aimed at preventing PUs. Using a case study approach, the development and implementation of the Daily Project is described in relation to the TRIP model. Initial success was evidenced by a 34% reduction in PU rates and an 86% reduction in missed patient turns 3 months postimplementation of the Daily intervention. Based on our experiences, the TRIP model successfully can assist with the implementation and diffusion of a tool that addresses a complex clinical issue such as PU prevention and treatment. PMID- 20921129 TI - Implementing and sustaining evidence-based nursing practice to reduce pediatric cardiopulmonary arrest. AB - Rapid response teams (RRTs) improve outcomes for patients through early escalation of care. However, subtle signs of clinical deterioration in children may not be consistently recognized by the bedside acute care nurse and therefore the RRT may not be activated. The Pediatric Early Warning Score (PEWS), an evidence-based tool, provides nurses with a mechanism for early detection using quantitative data. We describe our process and outcomes of implementing and sustaining the use of PEWS at the unit and organizational level using the Plan-Do Check-Act methodology for performance improvement. Our outcome data indicate that cardiopulmonary arrests were reduced by 31% at the pilot unit level and subsequently 23.4% at the organizational level. Data also suggest that bedside nurses effectively escalated patient care needs without activating RRTs (19.4% reduction in RRT activations after PEWS implementation). Strategies to sustain the positive outcomes of PEWS at the unit and organizational levels are also described. PMID- 20921130 TI - Evidence-based practice day: an innovative educational opportunity. AB - To maximize patient outcomes, the latest research and practice updates must be disseminated across the patient care continuum to include all members of the nursing team. The Clinical Research Council (CRC) recognized the need to bridge the gap between nursing research and practice, using evidence to decrease variation in practice. To meet this challenge, a Magnet-designated, rural community hospital developed an innovative educational program. This article describes Evidence-Based Practice (EBP) day, an interactive learning environment that engages nursing staff and strengthens their understanding of the science that guides practice. Topics for inclusion were selected based on staff requests, current research, quality improvement data, and institutional priorities. Evidence was provided in a format that supported rapid implementation into practice. Key components of the program included a clinical scenario, internal and external data, nursing interventions, patient outcomes (nursing-sensitive and organizational), and regulatory requirement updates. PMID- 20921131 TI - Friends, colleagues, authors, lend us your data. PMID- 20921132 TI - Bettina Winckler: neuronal polarity on her mind. Interviewed by Caitlin Sedwick. PMID- 20921133 TI - The two faces of serotonin in bone biology. AB - The serotonin molecule has some remarkable properties. It is synthesized by two different genes at two different sites, and, surprisingly, plays antagonistic functions on bone mass accrual at these two sites. When produced peripherally, serotonin acts as a hormone to inhibit bone formation. In contrast, when produced in the brain, serotonin acts as a neurotransmitter to exert a positive and dominant effect on bone mass accrual by enhancing bone formation and limiting bone resorption. The effect of serotonin on bone biology could be harnessed pharmacologically to treat diseases such as osteoporosis. PMID- 20921135 TI - Sds22 regulates aurora B activity and microtubule-kinetochore interactions at mitosis. AB - We have studied Sds22, a conserved regulator of protein phosphatase 1 (PP1) activity, and determined its role in modulating the activity of aurora B kinase and kinetochore-microtubule interactions. Sds22 is required for proper progression through mitosis and localization of PP1 to mitotic kinetochores. Depletion of Sds22 increases aurora B T-loop phosphorylation and the rate of recovery from monastrol arrest. Phospho-aurora B accumulates at kinetochores in Sds22-depleted cells juxtaposed to critical kinetochore substrates. Sds22 modulates sister kinetochore distance and the interaction between Hec1 and the microtubule lattice and, thus, the activation of the spindle assembly checkpoint. These results demonstrate that Sds22 specifically defines PP1 function and localization in mitosis. Sds22 regulates PP1 targeting to the kinetochore, accumulation of phospho-aurora B, and force generation at the kinetochore microtubule interface. PMID- 20921134 TI - BMI1-mediated histone ubiquitylation promotes DNA double-strand break repair. AB - Polycomb group (PcG) proteins are major determinants of cell identity, stem cell pluripotency, and epigenetic gene silencing during development. The polycomb repressive complex 1, which contains BMI1, RING1, and RING2, functions as an E3 ubuiquitin ligase. We found that BMI1 and RING2 are recruited to sites of DNA double-strand breaks (DSBs) where they contribute to the ubiquitylation of gamma H2AX. In the absence of BMI1, several proteins dependent on ubiquitin signaling, including 53BP1, BRCA1, and RAP80, are impaired in recruitment to DSBs. Loss of BMI1 sensitizes cells to ionizing radiation to the same extent as loss of RNF8. The simultaneous depletion of both proteins revealed an additive increase in radiation sensitivity. These data uncover an unexpected link between the polycomb and the DNA damage response pathways, and suggest a novel function for BMI1 in maintaining genomic stability. PMID- 20921136 TI - The differential interaction of snRNPs with pre-mRNA reveals splicing kinetics in living cells. AB - Precursor messenger RNA (pre-mRNA) splicing is catalyzed by the spliceosome, a large ribonucleoprotein (RNP) complex composed of five small nuclear RNP particles (snRNPs) and additional proteins. Using live cell imaging of GFP-tagged snRNP components expressed at endogenous levels, we examined how the spliceosome assembles in vivo. A comprehensive analysis of snRNP dynamics in the cell nucleus enabled us to determine snRNP diffusion throughout the nucleoplasm as well as the interaction rates of individual snRNPs with pre-mRNA. Core components of the spliceosome, U2 and U5 snRNPs, associated with pre-mRNA for 15-30 s, indicating that splicing is accomplished within this time period. Additionally, binding of U1 and U4/U6 snRNPs with pre-mRNA occurred within seconds, indicating that the interaction of individual snRNPs with pre-mRNA is distinct. These results are consistent with the predictions of the step-wise model of spliceosome assembly and provide an estimate on the rate of splicing in human cells. PMID- 20921137 TI - JunB transcription factor maintains skeletal muscle mass and promotes hypertrophy. AB - The size of skeletal muscle cells is precisely regulated by intracellular signaling networks that determine the balance between overall rates of protein synthesis and degradation. Myofiber growth and protein synthesis are stimulated by the IGF-1/Akt/mammalian target of rapamycin (mTOR) pathway. In this study, we show that the transcription factor JunB is also a major determinant of whether adult muscles grow or atrophy. We found that in atrophying myotubes, JunB is excluded from the nucleus and that decreasing JunB expression by RNA interference in adult muscles causes atrophy. Furthermore, JunB overexpression induces hypertrophy without affecting satellite cell proliferation and stimulated protein synthesis independently of the Akt/mTOR pathway. When JunB is transfected into denervated muscles, fiber atrophy is prevented. JunB blocks FoxO3 binding to atrogin-1 and MuRF-1 promoters and thus reduces protein breakdown. Therefore, JunB is important not only in dividing populations but also in adult muscle, where it is required for the maintenance of muscle size and can induce rapid hypertrophy and block atrophy. PMID- 20921138 TI - Kinesin-1 and dynein at the nuclear envelope mediate the bidirectional migrations of nuclei. AB - Kinesin-1 and dynein are recruited to the nuclear envelope by the Caenorhabditis elegans klarsicht/ANC-1/Syne homology (KASH) protein UNC-83 to move nuclei. The mechanisms of how these motors are coordinated to mediate nuclear migration are unknown. Time-lapse differential interference contrast and fluorescence imaging of embryonic hypodermal nuclear migration events were used to characterize the kinetics of nuclear migration and determine microtubule dynamics and polarity. Wild-type nuclei display bidirectional movements during migration and are also able to roll past cytoplasmic granules. unc-83, unc-84, and kinesin-1 mutants have severe nuclear migration defects. Without dynein, nuclear migration initiates normally but lacks bidirectional movement and shows defects in nuclear rolling, implicating dynein in resolution of cytoplasmic roadblocks. Microtubules are highly dynamic during nuclear migration. EB1::green fluorescence protein imaging demonstrates that microtubules are polarized in the direction of nuclear migration. This organization of microtubules fits with our model that kinesin-1 moves nuclei forward and dynein functions to move nuclei backward for short stretches to bypass cellular roadblocks. PMID- 20921139 TI - The dynamic interaction of AMBRA1 with the dynein motor complex regulates mammalian autophagy. AB - Autophagy is an evolutionary conserved catabolic process involved in several physiological and pathological processes such as cancer and neurodegeneration. Autophagy initiation signaling requires both the ULK1 kinase and the BECLIN 1 VPS34 core complex to generate autophagosomes, double-membraned vesicles that transfer cellular contents to lysosomes. In this study, we show that the BECLIN 1 VPS34 complex is tethered to the cytoskeleton through an interaction between the BECLIN 1-interacting protein AMBRA1 and dynein light chains 1/2. When autophagy is induced, ULK1 phosphorylates AMBRA1, releasing the autophagy core complex from dynein. Its subsequent relocalization to the endoplasmic reticulum enables autophagosome nucleation. Therefore, AMBRA1 constitutes a direct regulatory link between ULK1 and BECLIN 1-VPS34, which is required for core complex positioning and activity within the cell. Moreover, our results demonstrate that in addition to a function for microtubules in mediating autophagosome transport, there is a strict and regulatory relationship between cytoskeleton dynamics and autophagosome formation. PMID- 20921140 TI - Otoferlin is a calcium sensor that directly regulates SNARE-mediated membrane fusion. AB - Otoferlin is a large multi-C2 domain protein proposed to act as a calcium sensor that regulates synaptic vesicle exocytosis in cochlear hair cells. Although mutations in otoferlin have been associated with deafness, its contribution to neurotransmitter release is unresolved. Using recombinant proteins, we demonstrate that five of the six C2 domains of otoferlin sense calcium with apparent dissociation constants that ranged from 13-25 uM; in the presence of membranes, these apparent affinities increase by up to sevenfold. Using a reconstituted membrane fusion assay, we found that five of the six C2 domains of otoferlin stimulate membrane fusion in a calcium-dependent manner. We also demonstrate that a calcium binding-deficient form of the C2C domain is incapable of stimulating membrane fusion, further underscoring the importance of calcium for the protein's function. These results demonstrate for the first time that otoferlin is a calcium sensor that can directly regulate soluble N-ethyl maleimide sensitive fusion protein attachment protein receptor-mediated membrane fusion reactions. PMID- 20921141 TI - Distinct structural rearrangements of the VSV glycoprotein drive membrane fusion. AB - The entry of enveloped viruses into cells requires the fusion of viral and cellular membranes, driven by conformational changes in viral glycoproteins. Many studies have shown that fusion involves the cooperative action of a large number of these glycoproteins, but the underlying mechanisms are unknown. We used electron microscopy and tomography to study the low pH-induced fusion reaction catalyzed by vesicular stomatitis virus glycoprotein (G). Pre- and post-fusion crystal structures were observed on virions at high and low pH, respectively. Individual fusion events with liposomes were also visualized. Fusion appears to be driven by two successive structural rearrangements of G at different sites on the virion. Fusion is initiated at the flat base of the particle. Glycoproteins located outside the contact zone between virions and liposomes then reorganize into regular arrays. We suggest that the formation of these arrays, which have been shown to be an intrinsic property of the G ectodomain, induces membrane constraints, achieving the fusion reaction. PMID- 20921142 TI - Protein turnover of the Wallenda/DLK kinase regulates a retrograde response to axonal injury. AB - Regenerative responses to axonal injury involve changes in gene expression; however, little is known about how such changes can be induced from a distant site of injury. In this study, we describe a nerve crush assay in Drosophila melanogaster to study injury signaling and regeneration mechanisms. We find that Wallenda (Wnd), a conserved mitogen-activated protein kinase (MAPK) kinase kinase homologous to dual leucine zipper kinase, functions as an upstream mediator of a cell-autonomous injury signaling cascade that involves the c-Jun NH(2)-terminal kinase MAPK and Fos transcription factor. Wnd is physically transported in axons, and axonal transport is required for the injury signaling mechanism. Wnd is regulated by a conserved E3 ubiquitin ligase, named Highwire (Hiw) in Drosophila. Injury induces a rapid increase in Wnd protein concomitantly with a decrease in Hiw protein. In hiw mutants, injury signaling is constitutively active, and neurons initiate a faster regenerative response. Our data suggest that the regulation of Wnd protein turnover by Hiw can function as a damage surveillance mechanism for responding to axonal injury. PMID- 20921143 TI - Evidence for the horizontal transfer of an unusual capsular polysaccharide biosynthesis locus in marine bacteria. AB - The most intensely studied of the Vibrio vulnificus virulence factors is the capsular polysaccharide (CPS). All virulent strains produce copious amounts of CPS. Acapsular strains are avirulent. The structure of the CPS from the clinical isolate ATCC 27562 is unusual. It is serine modified and contains, surprisingly, N-acetylmuramic acid. We identified the complete 25-kb CPS biosynthesis locus from ATCC 27562. It contained 21 open reading frames and was allelic to O-antigen biosynthesis loci. Two of the genes, murA(CPS) and murB(CPS), were paralogs of the murA(PG) and murB(PG) genes of the peptidoglycan biosynthesis pathway; only a single copy of these genes is present in the strain CMCP6 and YJ016 genomes. Although MurA(CPS) and MurB(CPS) were functional when expressed in Escherichia coli, lesions in either gene had no effect on CPS production, virulence, or growth in V. vulnificus; disruption of 8 other genes within the locus resulted in an acapsular phenotype and attenuated virulence. Thus, murA(CPS) and murB(CPS) were functional but redundant. Comparative genomic analysis revealed that while completely different CPS biosynthesis loci were found in the same chromosomal region in other V. vulnificus strains, most of the CPS locus of ATCC 27562 was conserved in another marine bacterium, Shewanella putrefaciens strain 200. However, the average GC content of the CPS locus was significantly lower than the average GC content of either genome. Furthermore, several of the encoded proteins appeared to be of Gram-positive and archaebacterial origin. These data indicate that the horizontal transfer of intact and partial CPS loci drives CPS diversity in marine bacteria. PMID- 20921144 TI - Increased Pho regulon activation correlates with decreased virulence of an avian pathogenic Escherichia coli O78 strain. AB - Avian pathogenic Escherichia coli (APEC) strains are associated with respiratory infections, septicemia, cellulitis, peritonitis, and other conditions, since colibacillosis manifests in many ways. The Pho regulon is jointly controlled by the two-component regulatory system PhoBR and by the phosphate-specific transport (Pst) system. To determine the specific roles of the PhoBR regulon and the Pst system in the pathogenesis of the APEC O78 strain chi7122, different phoBR and pst mutant strains were tested in vivo in chickens and in vitro for virulence traits. Mutations resulting in constitutive activation of the Pho regulon rendered strains more sensitive than the wild type to hydrogen peroxide and to the bactericidal effects of rabbit serum. In addition, production of type 1 fimbriae was also impaired in these strains. Using a chicken competitive infection model, all PhoB constitutive mutants were outcompeted by the wild-type parent, including strains containing a functional Pst system. Cumulative inactivation of the Pst system and the PhoB regulator resulted in a restoration of virulence. In addition, loss of the PhoB regulator alone did not affect virulence in the chicken infection model. Interestingly, the level of attenuation of the mutant strains correlated directly with the level of activation of the Pho regulon. Overall, results indicate that activation of the Pho regulon rather than phosphate transport by the Pst system plays a major role in the attenuation of the APEC O78 strain chi7122. PMID- 20921145 TI - Role of adrenomedullin in Lyme disease. AB - Borrelia burgdorferi stimulates a strong inflammatory response during infection of a mammalian host. To understand the mechanisms of immune regulation employed by the host to control this inflammatory response, we focused our studies on adrenomedullin, a peptide produced in response to bacterial stimuli that exhibits antimicrobial activity and regulates inflammatory responses by modulating the expression of inflammatory cytokines. Specifically, we investigated the effect of B. burgdorferi on the expression of adrenomedullin as well as the ability of adrenomedullin to dampen host inflammatory responses to the spirochete. The concentration of adrenomedullin in the synovial fluid of untreated Lyme arthritis patients was elevated compared with that in control osteoarthritis patient samples. In addition, coculture with B. burgdorferi significantly increased the expression of adrenomedullin in RAW264.7 macrophages through MyD88-, phosphatidylinositol 3-kinase (PI3-K)-, and p38-dependent signaling cascades. Furthermore, the addition of exogenous adrenomedullin to B. burgdorferi stimulated RAW264.7 macrophages resulted in a significant decrease in the induction of proinflammatory cytokines. Taken together, these results suggest that B. burgdorferi increases the production of adrenomedullin, which in turn negatively regulates the B. burgdorferi-stimulated inflammatory response. PMID- 20921146 TI - Surface expression of MPT64 as a fusion with the PE domain of PE_PGRS33 enhances Mycobacterium bovis BCG protective activity against Mycobacterium tuberculosis in mice. AB - To improve the current vaccine against tuberculosis, a recombinant strain of Mycobacterium bovis bacillus Calmette-Guerin (rBCG) expressing a Mycobacterium tuberculosis vaccine candidate antigen (MPT64) in strong association with the mycobacterial cell wall was developed. To deliver the candidate antigen on the surface, we fused the mpt64 gene to the sequence encoding the PE domain of the PE_PGRS33 protein of M. tuberculosis (to create strain (H)PE-DeltaMPT64-BCG), which we have previously shown to transport proteins to the bacterial surface. In a series of protection experiments in the mouse model of tuberculosis, we showed that (i) immunization of mice with (H)PE-DeltaMPT64-BCG provides levels of protection significantly higher than those afforded by the parental BCG strain, as assessed by bacterial colonization in lungs and spleens and by lung involvement (at both 28 and 70 days postchallenge), (ii) rBCG strains expressing MPT64 provide better protection than the parental BCG strain only when this antigen is surface expressed, and (iii) the (H)PE-DeltaMPT64-BCG-induced MPT64 specific T cell repertoire when characterized by beta chain variable region-beta chain joining region (BV-BJ) spectratyping indicates that protection is correlated with the ability to recruit gamma interferon (IFN-gamma)-secreting T cells carrying the BV8.3-BJ1.5 (172 bp) shared rearrangement. These results demonstrate that (H)PE-DeltaMPT64-BCG is one of the most effective new vaccines tested so far in the mouse model of tuberculosis and underscore the impact of antigen cellular localization on the induction of the specific immune response induced by rBCG. PMID- 20921147 TI - Nod1 and Nod2 regulation of inflammation in the Salmonella colitis model. AB - The pattern recognition molecules Nod1 and Nod2 play important roles in intestinal homeostasis; however, how these proteins impact on the development of inflammation during bacterial colitis has not been examined. In the streptomycin treated mouse model of Salmonella colitis, we found that mice deficient for both Nod1 and Nod2 had attenuated inflammatory pathology, reduced levels of inflammatory cytokines, and increased colonization of the mucosal tissue. Nod1 and Nod2 from both hematopoietic and nonhematopoietic sources contributed to the pathology, and all phenotypes were recapitulated in mice deficient for the signaling adaptor protein Rip2. However, the influence of Rip2 was strictly dependent on infection conditions that favored expression of the Salmonella pathogenicity island 2 (SPI-2) type III secretion system (TTSS), as Rip2 was dispensable for inflammation when mice were infected with bacteria grown under conditions that promoted expression of the SPI-1 TTSS. Thus, Nod1 and Nod2 can modulate inflammation and mediate efficient clearance of bacteria from the mucosal tissue during Salmonella colitis, but their role is dependent on the expression of the SPI-2 TTSS. PMID- 20921148 TI - Effects of the putative transcriptional regulator IclR on Francisella tularensis pathogenesis. AB - Francisella tularensis is a highly virulent Gram-negative bacterium and is the etiological agent of the disease tularemia. IclR, a presumed transcriptional regulator, is required for full virulence of the animal pathogen, F. tularensis subspecies novicida U112 (53). In this study, we investigated the contribution of IclR to the intracellular growth, virulence, and gene regulation of human pathogenic F. tularensis subspecies. Deletion of iclR from the live vaccine strain (LVS) and SchuS4 strain of F. tularensis subsp. holarctica and F. tularensis subsp. tularensis, respectively, did not affect their abilities to replicate within macrophages or epithelial cells. In contrast to F. tularensis subsp. novicida iclR mutants, LVS and SchuS4 DeltaiclR strains were as virulent as their wild-type parental strains in intranasal inoculation mouse models of tularemia. Furthermore, wild-type LVS and LVSDeltaiclR were equally cytotoxic and induced equivalent levels of interleukin-1beta expression by infected bone marrow derived macrophages. Microarray analysis revealed that the relative expression of a limited number of genes differed significantly between LVS wild-type and DeltaiclR strains. Interestingly, many of the identified genes were disrupted in LVS and SchuS4 but not in their corresponding F. tularensis subsp. novicida U112 homologs. Thus, despite the impact of iclR deletion on gene expression, and in contrast to the effects of iclR deletion on F. tularensis subsp. novicida virulence, IclR does not contribute significantly to the virulence or pathogenesis of F. tularensis LVS or SchuS4. PMID- 20921149 TI - Interleukin-17 is not required for classical macrophage activation in a pulmonary mouse model of Cryptococcus neoformans infection. AB - Cryptococcus neoformans is an opportunistic fungal pathogen that causes disease in individuals with suppressed cell-mediated immunity. Recent studies in our laboratory have shown that increases in pulmonary Th1-type and interleukin-17A (IL-17A) cytokine production, classical macrophage activation, and sterilizing immunity are elicited in response to infection with a gamma interferon (IFN gamma)-producing C. neoformans strain, H99gamma. IL-17A-treated macrophages, compared to IL-4-treated macrophages, have been demonstrated to exhibit increased microbicidal activity in vitro, a characteristic consistent with classical macrophage activation. The purpose of these studies is to determine the role of IL-17A in the induction of classically activated macrophages following infection with C. neoformans. Immunohistochemistry and real-time PCR were used to characterize the macrophage activation phenotype in lung tissues of mice treated with isotype control or anti-IL-17A antibodies and given an experimental pulmonary infection with C. neoformans strain H99gamma. The pulmonary fungal burden was resolved, albeit more slowly, in mice depleted of IL-17A compared to the fungal burden in isotype control-treated mice. Nonetheless, no difference in classical macrophage activation was observed in IL-17A-depleted mice. Similarly, classical macrophage activation was evident in mice deficient in IL-17A or the IL 17 receptor A, which mediates IL-17A signaling, following pulmonary infection with wild-type C. neoformans strain H99 or H99gamma. These studies suggest that IL-17A may play a role in the early immune response to C. neoformans but is not required for classical macrophage activation in mice experimentally infected with C. neoformans. PMID- 20921151 TI - Is there a relationship between forefoot alignment and ingrown toenail? A case control study. AB - Biomechanical imbalance between the hallux and the second toe and external compression of the lateral nail fold are proposed as the main reasons for ingrown toenail. Therefore, any anatomical predisposition facilitating this compression may play a role in the occurrence of ingrown toenail. The purpose of this study is to investigate the relationship between forefoot alignment and ingrown toenail. The authors retrospectively reviewed radiographs of 81 patients with ingrown toenails and compared them with 100 healthy subjects regarding forefoot alignment. Hallux valgus angle (HVA), intermetatarsal angle (IMA), and interphalangeal angle (IPA) were measured, and feet were classified according to digital formula as Egyptian, Greek, and square. The mean HVA was 14.5 degrees +/ 5.0 degrees in the case group and 13.2 degrees +/- 5.9 degrees in the control group. The mean IMA was 9.1 degrees +/- 2.5 degrees in the case group and 8.6 degrees +/- 3.1 degrees in the control group. The mean IPA was 11.9 degrees +/ 4.1 degrees in the case group and 12.0 degrees +/- 5.1 degrees in the control group. There was no statistically significant difference between the groups regarding HVA, IMA, or IPA (P = .123, P = .198, and P = .925, respectively). The distribution of foot types between groups was also similar (P = .967). This study has failed to demonstrate any abnormality in forefoot alignment in patients with symptomatic ingrowing toenails, and it is suggested that treatment should not be based on the correction of the anatomy if no abnormality exists. PMID- 20921150 TI - CD46 engagement on human CD4+ T cells produces T regulatory type 1-like regulation of antimycobacterial T cell responses. AB - Understanding the regulation of human immune responses is critical for vaccine development and treating infectious diseases. We have previously shown that simultaneous engagement of the T cell receptor (TCR) and complement regulator CD46 on human CD4(+) T cells in the presence of interleukin-2 (IL-2) induces potent secretion of the immunomodulatory cytokine IL-10. These T cells mediate IL 10-dependent suppression of bystander CD4(+) T cells activated in vitro with anti CD3 and anti-CD28 costimulation, reflecting a T regulatory type 1 (Tr1)-like phenotype. However, CD46-mediated negative regulation of pathogen-specific T cells has not been described. Therefore, we studied the ability of CD46-activated human CD4(+) T cells to suppress T cell responses to Mycobacterium bovis BCG, the live vaccine that provides infants protection against the major human pathogen Mycobacterium tuberculosis. Our results demonstrate that soluble factors secreted by CD46-activated human CD4(+) T cells suppress mycobacterium-specific CD4(+), CD8(+), and gamma(9)delta(2) TCR(+) T cells. Dendritic cell functions were not downregulated in our experiments, indicating that CD46-triggered factors directly suppress pathogen-specific T cells. Interestingly, IL-10 appeared to play a less pronounced role in our system, especially in the suppression of gamma(9)delta(2) TCR(+) T cells, suggesting the presence of additional undiscovered soluble immunoregulatory factors. Blocking endogenous CD46 signaling 3 days after mycobacterial infection enhanced BCG-specific T cell responses in a subset of volunteers. Taken together, these results indicate that CD46-dependent negative regulatory mechanisms can impair T cell responses vital for immune defense against mycobacteria. Therefore, modulating CD46-induced immune regulation could be integral to the development of improved tuberculosis therapeutics or vaccines. PMID- 20921152 TI - Bilateral atraumatic sequential rupture of tibialis anterior tendons. AB - Tibialis anterior tendon ruptures are rare but debilitating injuries. A high index of suspicion is warranted in patients presenting with atraumatic anterior ankle pain, especially in conjunction with diabetes or inflammatory disease. The authors present a case report of bilateral sequential rupture of tibialis anterior tendons, a discussion of management, and a review of the literature. PMID- 20921153 TI - Diffuse edema and bilateral massive pleural effusion as the presentation of systemic lupus erythematosus. AB - A rare case of systemic lupus erythematosus (SLE), with massive bilateral pleural effusions and generalized edema as the first manifestations, is reported. The patient was a previously healthy 13-year-old boy. He presented with a history of fever, lack of appetite, gradually increasing fatigue, cough, diffuse edema, and moderate dyspnea. He responded well to corticosteroids with resolution of the pleural effusions, and edema. SLE should always be kept in mind in cases of massive pleural effusions and/or diffuse edema, even in the absence of other clinical manifestations of the disease. PMID- 20921154 TI - Acute scrotum in a neonate caused by renal vein thrombosis. AB - The authors report on a rare case of neonatal scrotal oedema occurring concurrently with pain upon palpation of the spermatic cord on the first day of life. An ultrasound examination showed poor perfusion of the left testicle and a thrombosis of the left renal vein; intraoperative exploration indicated necrosis of the left testicle without signs of torsion. Gorged vessels with paravasal bleeding were found in the spermatic cord. The authors hypothesise that necrosis of the testicle may result from haemorrhagic infarction caused by renal venous thrombosis. Acute scrotal discolouration with pain upon palpation in neonates is usually attributed to testicular torsion. The authors report a case where these symptoms had a different cause. PMID- 20921155 TI - Cross talk between the KNOX and ethylene pathways is mediated by intron-binding transcription factors in barley. AB - In the barley (Hordeum vulgare) Hooded (Kap) mutant, the duplication of a 305-bp intron sequence leads to the overexpression of the Barley knox3 (Bkn3) gene, resulting in the development of an extra flower in the spikelet. We used a one hybrid screen to identify four proteins that bind the intron-located regulatory element (Kap intron-binding proteins). Three of these, Barley Ethylene Response Factor1 (BERF1), Barley Ethylene Insensitive Like1 (BEIL1), and Barley Growth Regulating Factor1 (BGRF1), were characterized and their in vitro DNA-binding capacities verified. Given the homology of BERF1 and BEIL1 to ethylene signaling proteins, we investigated if these factors might play a dual role in intron mediated regulation and ethylene response. In transgenic rice (Oryza sativa), constitutive expression of the corresponding genes produced phenotypic alterations consistent with perturbations in ethylene levels and variations in the expression of a key gene of ethylene biosynthesis. In barley, ethylene treatment results in partial suppression of the Kap phenotype, accompanied by up regulation of BERF1 and BEIL1 expression, followed by down-regulation of Bkn3 mRNA levels. In rice protoplasts, BEIL1 activates the expression of a reporter gene driven by the 305-bp intron element, while BERF1 can counteract this activation. Thus, BEIL1 and BERF1, likely in association with other Kap intron binding proteins, should mediate the fine-tuning of Bkn3 expression by ethylene. We propose a hypothesis for the cross talk between the KNOX and ethylene pathways. PMID- 20921157 TI - Plant Physiology celebrates its 25,000th article! PMID- 20921156 TI - The Arabidopsis Botrytis Susceptible1 Interactor defines a subclass of RING E3 ligases that regulate pathogen and stress responses. AB - We studied the function of Arabidopsis (Arabidopsis thaliana) Botrytis Susceptible1 Interactor (BOI) in plant responses to pathogen infection and abiotic stress. BOI physically interacts with and ubiquitinates Arabidopsis BOS1, an R2R3MYB transcription factor previously implicated in stress and pathogen responses. In transgenic plants expressing the BOS1-beta-glucuronidase transgene, beta-glucuronidase activity could be detected only after inhibition of the proteosome, suggesting that BOS1 is a target of ubiquitin-mediated degradation by the proteosome. Plants with reduced BOI transcript levels generated through RNA interference (BOI RNAi) were more susceptible to the necrotrophic fungus Botrytis cinerea and less tolerant to salt stress. In addition, BOI RNAi plants exhibited increased cell death induced by the phytotoxin alpha-picolinic acid and by a virulent strain of the bacterial pathogen Pseudomonas syringae, coincident with peak disease symptoms. However, the hypersensitive cell death associated with different race-specific resistance genes was unaffected by changes in the level of BOI transcript. BOI expression was enhanced by B. cinerea and salt stress but repressed by the plant hormone gibberellin, indicating a complex regulation of BOI gene expression. Interestingly, BOI RNAi plants exhibit reduced growth responsiveness to gibberellin. We also present data revealing the function of three Arabidopsis BOI-RELATED GENES (BRGs), which contribute to B. cinerea resistance and the suppression of disease-associated cell death. In sum, BOI and BRGs represent a subclass of RING E3 ligases that contribute to plant disease resistance and abiotic stress tolerance through the suppression of pathogen induced as well as stress-induced cell death. PMID- 20921158 TI - Early evolution of photosynthesis. PMID- 20921159 TI - Basal signaling regulates plant growth and development. PMID- 20921160 TI - Emerging complexity in reactive oxygen species production and signaling during the response of plants to pathogens. PMID- 20921161 TI - Understanding lignification: challenges beyond monolignol biosynthesis. PMID- 20921162 TI - Flavonoids and isoflavonoids: from plant biology to agriculture and neuroscience. PMID- 20921164 TI - Opportunities to explore plant membrane organization with super-resolution microscopy. PMID- 20921163 TI - Endoplasmic reticulum: the rising compartment in auxin biology. PMID- 20921165 TI - Plant biology in the fourth dimension. PMID- 20921166 TI - Ubiquitin ligase-coupled receptors extend their reach to jasmonate. PMID- 20921167 TI - Genome-enabled research on the ecology of plant-insect interactions. PMID- 20921168 TI - Abscisic acid receptors. PMID- 20921169 TI - Plant cell walls. PMID- 20921170 TI - The perception of cytokinin: a story 50 years in the making. PMID- 20921171 TI - Climbing the branches of the strigolactones pathway one discovery at a time. PMID- 20921172 TI - Twenty-first century plant biology: impacts of the Arabidopsis genome on plant biology and agriculture. PMID- 20921173 TI - The power of auxin in plants. PMID- 20921174 TI - Do transcription factors play special roles in adaptive variation? PMID- 20921175 TI - The elements of plant micronutrients. PMID- 20921176 TI - The timing of flowering. PMID- 20921177 TI - Oxidative stress: antagonistic signaling for acclimation or cell death? PMID- 20921178 TI - How do we improve crop production in a warming world? PMID- 20921179 TI - Gene clusters for secondary metabolic pathways: an emerging theme in plant biology. PMID- 20921180 TI - Plant immunity: it's the hormones talking, but what do they say? PMID- 20921181 TI - The past, present, and future of vegetative phase change. PMID- 20921182 TI - Understanding plant vacuolar trafficking from a systems biology perspective. PMID- 20921183 TI - Pathogen-associated molecular pattern-triggered immunity: veni, vidi...? PMID- 20921184 TI - Lignin and biomass: a negative correlation for wood formation and lignin content in trees. PMID- 20921185 TI - Discover and connect cellular signaling. PMID- 20921186 TI - Gibberellin-GID1-DELLA: a pivotal regulatory module for plant growth and development. PMID- 20921187 TI - Molecular basis of plant cold acclimation: insights gained from studying the CBF cold response pathway. PMID- 20921188 TI - The puzzle of phloem pressure. PMID- 20921189 TI - Quantitative trait loci, epigenetics, sugars, and microRNAs: quaternaries in phosphate acquisition and use. PMID- 20921190 TI - Enhancing C3 photosynthesis. PMID- 20921191 TI - From endosymbiosis to synthetic photosynthetic life. PMID- 20921192 TI - Evolution of C4 photosynthesis--looking for the master switch. PMID- 20921193 TI - Retraction. PMID- 20921194 TI - Expression of early growth response protein 1 in vasopressin neurones of the rat anterior olfactory nucleus following social odour exposure. AB - The anterior olfactory nucleus (AON), a component of the main olfactory system, is a cortical region that processes olfactory information and acts as a relay between the main olfactory bulbs and higher brain regions such as the piriform cortex. Utilizing a transgenic rat in which an enhanced green fluorescent protein reporter gene is expressed in vasopressin neurones (eGFP-vasopressin), we have discovered a population of vasopressin neurones in the AON. These vasopressin neurones co-express vasopressin V1 receptors. They also co-express GABA and calbinin-D28k indicating that they are neurochemically different from the newly described vasopressin neurons in the main olfactory bulb. We utilized the immediate early gene product, early growth response protein 1 (Egr-1), to examine the functional role of these vasopressin neurons in processing social and non social odours in the AON. Exposure of adult rats to a conspecific juvenile or a heterospecific predator odour leads to increases in Egr-1 expression in the AON in a subregion specific manner. However, only exposure to a juvenile increases Egr-1 expression in AON vasopressin neurons. These data suggest that vasopressin neurones in the AON may be selectively involved in the coding of social odour information. PMID- 20921195 TI - Lung volume does not alter the distribution of pulmonary perfusion in dependent lung in supine humans. AB - There is a gravitational influence on pulmonary perfusion, including in the most dependent lung, where perfusion is reduced, termed Zone 4. Studies using xenon 133 show Zone 4 behaviour, present in the dependent 4 cm at total lung capacity (TLC), affects the dependent 11 cm at functional residual capacity (FRC) and almost all the lung at residual volume (RV). These differences were ascribed to increased resistance in extra-alveolar vessels at low lung volumes although other mechanisms have been proposed. To further evaluate the behaviour of perfusion in dependent lung using a technique that directly measures pulmonary perfusion and corrects for tissue distribution by measuring regional proton density, seven healthy subjects (age = 38 +/- 6 years, FEV1 = 104 +/- 7% predicted) underwent magnetic resonance imaging in supine posture. Data were acquired in the right lung during breath-holds at RV, FRC and TLC. Arterial spin labelling quantified regional pulmonary perfusion, which was normalized for regional proton density measured using a fast low-angle shot technique. The height of the onset of Zone 4 behaviour was not different between lung volumes (P = 0.23). There were no significant differences in perfusion (expressed as ml min-1 g-1) between lung volumes in the gravitationally intermediate (RV = 8.9 +/- 3.1, FRC = 8.1 +/- 2.9, TLC = 7.4 +/- 3.6; P = 0.26) and dependent lung (RV = 6.6 +/- 2.4, FRC = 6.1 +/- 2.1, TLC = 6.4 +/- 2.6; P = 0.51). However, at TLC perfusion was significantly lower in non-dependent lung than at FRC or RV (3.6 +/- 3.3, 7.7 +/- 1.5, 7.9 +/- 2.0, respectively; P < 0.001). These data suggest that the mechanism of the reduction in perfusion in dependent lung is unlikely to be a result of lung volume related increases in resistance in extra-alveolar vessels. In supine posture, the gravitational influence on perfusion is remarkably similar over most of the lung, irrespective of lung volume. PMID- 20921196 TI - Repeated transient mRNA bursts precede increases in transcriptional and mitochondrial proteins during training in human skeletal muscle. AB - Exercise training induces mitochondrial biogenesis, but the time course of molecular sequelae that accompany repetitive training stimuli remains to be determined in human skeletal muscle. Therefore, throughout a seven-session, high intensity interval training period that increased (12%), we examined the time course of responses of (a) mitochondrial biogenesis and fusion and fission proteins, and (b) selected transcriptional and mitochondrial mRNAs and proteins in human muscle. Muscle biopsies were obtained 4 and 24 h after the 1st, 3rd, 5th and 7th training session. PGC-1alpha mRNA was increased >10-fold 4 h after the 1st session and returned to control within 24 h. This 'saw-tooth' pattern continued until the 7th bout, with smaller increases after each bout. In contrast, PGC-1alpha protein was increased 24 h after the 1st bout (23%) and plateaued at +30-40% between the 3rd and 7th bout. Increases in PGC-1beta mRNA and protein were more delayed and smaller, and did not persist. Distinct patterns of increases were observed in peroxisome proliferator-activated receptor (PPAR) alpha and gamma protein (1 session), PPAR beta/delta mRNA and protein (5 sessions) and nuclear respiratory factor-2 protein (3 sessions) while no changes occurred in mitochondrial transcription factor A protein. Citrate synthase (CS) and beta-HAD mRNA were rapidly increased (1 session), followed 2 sessions later (session 3) by increases in CS and beta-HAD activities, and mitochondrial DNA. Changes in COX-IV mRNA (session 3) and protein (session 5) were more delayed. Training also increased mitochondrial fission proteins (fission protein-1, >2 fold; dynamin-related protein-1, 47%) and the fusion protein mitofusin-1 (35%) but not mitofusin-2. This study has provided the following novel information: (a) the training-induced increases in transcriptional and mitochondrial proteins appear to result from the cumulative effects of transient bursts in their mRNAs, (b) training-induced mitochondrial biogenesis appears to involve re-modelling in addition to increased mitochondrial content, and (c) the 'transcriptional capacity' of human muscle is extremely sensitive, being activated by one training bout. PMID- 20921197 TI - Differential sensitivity of Ca2+ wave and Ca2+ spark events to ruthenium red in isolated permeabilised rabbit cardiomyocytes. AB - Spontaneous Ca2(+) waves in cardiac muscle cells are thought to arise from the sequential firing of local Ca2(+) sparks via a fire-diffuse-fire mechanism. This study compares the ability of the ryanodine receptor (RyR) blocker ruthenium red (RuR) to inhibit these two types of Ca2(+) release in permeabilised rabbit ventricular cardiomyocytes. Perfusing with 600 nm Ca2(+) (50 MUm EGTA) caused regular spontaneous Ca2(+) waves that were imaged with the fluorescence from Fluo 5F using a laser-scanning confocal microscope. Addition of 4 MUm RuR caused complete inhibition of Ca2(+) waves in 50% of cardiomyocytes by 2 min and in 100% by 4 min. Separate experiments used 350 MUm EGTA (600 nm Ca2(+)) to limit Ca2(+) diffusion but allow the underlying Ca(2+) sparks to be imaged. The time course of RuR-induced inhibition did not match that of waves. After 2 min of RuR, none of the characteristics of the Ca2(+) sparks were altered, and after 4 min Ca2(+) spark frequency was reduced ~40%; no sparks could be detected after 10 min. Measurements of Ca(2+) within the SR lumen using Fluo-5N showed an increase in intra-SR Ca2(+) during the initial 2-4 min of perfusion with RuR in both wave and spark conditions. Computational modelling suggests that the sensitivity of Ca2(+) waves to RuR block depends on the number of RyRs per cluster. Therefore inhibition of Ca2(+) waves without affecting Ca2(+) sparks may be explained by block of small, non-spark producing clusters of RyRs that are important to the process of Ca2(+) wave propagation. PMID- 20921198 TI - The sense of self-motion, orientation and balance explored by vestibular stimulation. AB - The sense of orientation during locomotion is derived from our spatial relationship with the external environment, sensed predominantly by sight and sound, and from internal signals of motion, generated by the vestibular sense and the pattern of efferent and afferent signals to the muscles and joints. The sensory channels operate in different reference frames and have different time dependent adaptive properties and yet the inputs are combined by the central nervous system to create an internal representation of self-motion. In normal circumstances vestibular, visual and proprioceptive cues provide congruent information on locomotor trajectory; however, in cases of sensory discord there must be a recalibration of sensory signals to provide a unitary representation. We develop a means of studying these fusion processes by perturbing each channel in isolation about a consistent behavioural axis. This review focuses on creating the vestibular perturbation of the orientation sense by transmastoidal galvanic stimulation, a technique generally used to evoke balance reflexes. Vector summation across the population of semicircular canal afferents creates a net signal that is interpreted by the brain as a vector of angular acceleration in a craniocentric reference frame. The signal feeds perceptual processes of orientation after transformation that resolves the 3-D signal onto the terrestrial or behavioural plane. Changing head posture changes the interpretation of the galvanic vestibular signal for balance and orientation responses. With appropriate head alignments during locomotion, the galvanic stimulus can be used to either steer trajectory over the terrestrial plane or perturb balance. PMID- 20921199 TI - The neglected role of insulin-like growth factors in the maternal circulation regulating fetal growth. AB - Maternal insulin-like growth factors (IGFs) play a pivotal role in modulating fetal growth via their actions on both the mother and the placenta. Circulating IGFs influence maternal tissue growth and metabolism, thereby regulating nutrient availability for the growth of the conceptus. Maternal IGFs also regulate placental morphogenesis, substrate transport and hormone secretion, all of which influence fetal growth either via indirect effects on maternal substrate availability, or through direct effects on the placenta and its capacity to supply nutrients to the fetus. The extent to which IGFs influence the mother and/or placenta are dependent on the species and maternal factors, including age and nutrition. As altered fetal growth is associated with increased perinatal morbidity and mortality and a greater risk of developing degenerative diseases in adult life, understanding the role of maternal IGFs during pregnancy is essential in order to identify mechanisms underlying altered fetal growth and offspring programming. PMID- 20921200 TI - Correlated firing among major ganglion cell types in primate retina. AB - Retinal ganglion cells exhibit substantial correlated firing: a tendency to fire nearly synchronously at rates different from those expected by chance. These correlations suggest that network interactions significantly shape the visual signal transmitted from the eye to the brain. This study describes the degree and structure of correlated firing among the major ganglion cell types in primate retina. Correlated firing among ON and OFF parasol, ON and OFF midget, and small bistratified cells, which together constitute roughly 75% of the input to higher visual areas, was studied using large-scale multi-electrode recordings. Correlated firing in the presence of constant, spatially uniform illumination exhibited characteristic strength, time course and polarity within and across cell types. Pairs of nearby cells with the same light response polarity were positively correlated; cells with the opposite polarity were negatively correlated. The strength of correlated firing declined systematically with distance for each cell type, in proportion to the degree of receptive field overlap. The pattern of correlated firing across cell types was similar at photopic and scotopic light levels, although additional slow correlations were present at scotopic light levels. Similar results were also observed in two other retinal ganglion cell types. Most of these observations are consistent with the hypothesis that shared noise from photoreceptors is the dominant cause of correlated firing. Surprisingly, small bistratified cells, which receive ON input from S cones, fired synchronously with ON parasol and midget cells, which receive ON input primarily from L and M cones. Collectively, these results provide an overview of correlated firing across cell types in the primate retina, and constraints on the underlying mechanisms. PMID- 20921201 TI - Hyperoxia blunts counterregulation during hypoglycaemia in humans: possible role for the carotid bodies? AB - Chemoreceptors in the carotid bodies sense arterial oxygen tension and regulate respiration. Isolated carotid body glomus cells also sense glucose, and animal studies have shown the carotid bodies play a role in the counterregulatory response to hypoglycaemia. Thus, we hypothesized that glucose infusion rate would be augmented and neuro-hormonal counterregulation blunted during hypoglycaemia when the carotid bodies were desensitized by hyperoxia. Seven healthy adults (four male, three female) underwent two 180 min hyperinsulinaemic (2 mU (kg fat free mass (FFM))(-1) min(-1)), hypoglycaemic (3.33 mmol l(-1)) clamps 1 week apart, randomized to either normoxia (arterial P(O2) (P(aO2)) 111 +/- 6.3 mmHg) or hyperoxia (P(aO2) 345 +/- 80.6 mmHg) (P < 0.05). Plasma glucose concentrations were similar during normoxia and hyperoxia at baseline (5.52 +/- 0.15 vs. 5.55 +/ 0.13 MUmol ml(-1)) and during the clamp (3.4 +/- 0.05 vs. 3.3 +/- 0.05 MUmol ml( 1)). The glucose infusion rate was 44.2 +/- 3.5% higher (P < 0.01) during hyperoxia than normoxia at steady state during the clamp (28.2 +/- 0.15 vs. 42.7 +/- 0.65 MUmol (kg FFM)(-1) min(-1); P < 0.01). Area under the curve values (expressed as percentage normoxia response) for counterregulatory hormones during hypoglycaemia were significantly suppressed by hyperoxia (noradrenaline 50.7 +/- 5.2%, adrenaline 62.6 +/- 3.3%, cortisol 63.2 +/- 2.1%, growth hormone 53.1 +/- 2.7%, glucagon 48.6 +/- 2.1%, all P < 0.05 vs. normoxia). These data support the idea that the carotid bodies respond to glucose and play a role in the counterregulatory response to hypoglycaemia in humans. PMID- 20921203 TI - Multisensory space: from eye-movements to self-motion. AB - We perceive the world around us as stable. This is remarkable given that our body parts as well as we ourselves are constantly in motion. Humans and other primates move their eyes more often than their hearts beat. Such eye movements lead to coherent motion of the images of the outside world across the retina. Furthermore, during everyday life, we constantly approach targets, avoid obstacles or otherwise move in space. These movements induce motion across different sensory receptor epithels: optical flow across the retina, tactile flow across the body surface and even auditory flow as detected from the two ears. It is generally assumed that motion signals as induced by one's own movement have to be identified and differentiated from the real motion in the outside world. In a number of experimental studies we and others have functionally characterized the primate posterior parietal cortex (PPC) and its role in multisensory encoding of spatial and motion information. Extracellular recordings in the macaque monkey showed that during steady fixation the visual, auditory and tactile spatial representations in the ventral intraparietal area (VIP) are congruent. This finding was of major importance given that a functional MRI (fMRI) study determined the functional equivalent of macaque area VIP in humans. Further recordings in other areas of the dorsal stream of the visual cortical system of the macaque pointed towards the neural basis of perceptual phenomena (heading detection during eye movements, saccadic suppression, mislocalization of visual stimuli during eye movements) as determined in psychophysical studies in humans. PMID- 20921202 TI - Neuroeffector apparatus in gastrointestinal smooth muscle organs. AB - Control of gastrointestinal (GI) movements by enteric motoneurons is critical for orderly processing of food, absorption of nutrients and elimination of wastes. Work over the past several years has suggested that motor neurotransmission is more complicated than simple release of transmitter from nerve terminals and binding of receptors on smooth muscle cells. In fact the 'neuro-effector' junction in the tunica muscularis might consist of synaptic-like connectivity with specialized cells, and contributions from multiple cell types in integrated post-junctional responses. Interstitial cells of Cajal (ICC) were proposed as potential mediators in motor neurotransmission based on reduced post-junctional responses observed in W mutants that have reduced populations of ICC. More recent studies on W mutants have contradicted the original findings, and suggested that ICC may not be significant players in motor neurotransmission. This review examines the evidence for and against the role of ICC in motor neurotransmission and outlines areas for additional investigation that would help further resolve this controversy. PMID- 20921205 TI - Therapeutic potential of ketotifen in irritable bowel syndrome (IBS) may involve changes in mast cells at sites beyond the rectum. PMID- 20921206 TI - Autologous bone marrow-derived mesenchymal stromal cell treatment for refractory luminal Crohn's disease: results of a phase I study. AB - BACKGROUND AND AIM: Mesenchymal stromal cells (MSCs) are pluripotent cells that have immunosuppressive effects both in vitro and in experimental colitis. Promising results of MSC therapy have been obtained in patients with severe graft versus host disease of the gut. Our objective was to determine the safety and feasibility of autologous bone marrow derived MSC therapy in patients with refractory Crohn's disease. PATIENTS AND INTERVENTION: 10 adult patients with refractory Crohn's disease (eight females and two males) underwent bone marrow aspiration under local anaesthesia. Bone marrow MSCs were isolated and expanded ex vivo. MSCs were tested for phenotype and functionality in vitro. 9 patients received two doses of 1-2*10(6) cells/kg body weight, intravenously, 7 days apart. During follow-up, possible side effects and changes in patients' Crohn's disease activity index (CDAI) scores were monitored. Colonoscopies were performed at weeks 0 and 6, and mucosal inflammation was assessed by using the Crohn's disease endoscopic index of severity. RESULTS: MSCs isolated from patients with Crohn's disease showed similar morphology, phenotype and growth potential compared to MSCs from healthy donors. Importantly, immunomodulatory capacity was intact, as Crohn's disease MSCs significantly reduced peripheral blood mononuclear cell proliferation in vitro. MSC infusion was without side effects, besides a mild allergic reaction probably due to the cryopreservant DMSO in one patient. Baseline median CDAI was 326 (224-378). Three patients showed clinical response (CDAI decrease >=70 from baseline) 6 weeks post-treatment; conversely three patients required surgery due to disease worsening. CONCLUSIONS: Administration of autologous bone marrow derived MSCs appears safe and feasible in the treatment of refractory Crohn's disease. No serious adverse events were detected during bone marrow harvesting and administration. PMID- 20921207 TI - Colorectal cancer molecular biology moves into clinical practice. AB - The promise of personalised medicine is now a clinical reality, with colorectal cancer genetics at the forefront of this next major advance in clinical medicine. This is no more evident than in the recent advances in testing of colorectal cancers for specific molecular alterations in order to guide treatment with the monoclonal antibody therapies cetuximab and panitumumab, which target the epidermal growth factor receptor. In this review, genetic mechanisms of colorectal cancer and how these alterations relate to emerging biomarkers for early detection and risk stratification (diagnostic markers), prognosis (prognostic markers) and the prediction of treatment responses (predictive markers) are examined. PMID- 20921208 TI - Lack of TRPM2 impaired insulin secretion and glucose metabolisms in mice. AB - OBJECTIVE: TRPM2 is a Ca2(+)-permeable nonselective cation channel activated by adenosine dinucleotides. We previously demonstrated that TRPM2 is activated by coapplication of heat and intracellular cyclic adenosine 5'-diphosphoribose, which has been suggested to be involved in intracellular Ca2(+) increase in immunocytes and pancreatic beta-cells. To clarify the involvement of TRPM2 in insulin secretion, we analyzed TRPM2 knockout (TRPM2-KO) mice. RESEARCH DESIGN AND METHODS: Oral and intraperitoneal glucose tolerance tests (OGTT and IPGTT) were performed in TRPM2-KO and wild-type mice. We also measured cytosolic free Ca2(+) in single pancreatic cells using fura-2 microfluorometry and insulin secretion from pancreatic islets. RESULTS: Basal blood glucose levels were higher in TRPM2-KO mice than in wild-type mice without any difference in plasma insulin levels. The OGTT and IPGTT demonstrated that blood glucose levels in TRPM2-KO mice were higher than those in wild-type mice, which was associated with an impairment in insulin secretion. In isolated beta-cells, smaller intracellular Ca2(+) increase was observed in response to high concentrations of glucose and incretin hormone in TRPM2-KO cells than in wild-type cells. Moreover, insulin secretion from the islets of TRPM2-KO mice in response to glucose and incretin hormone treatment was impaired, whereas the response to tolbutamide, an ATP sensitive potassium channel inhibitor, was not different between the two groups. CONCLUSIONS: These results indicate that TRPM2 is involved in insulin secretion stimulated by glucose and that further potentiated by incretins. Thus, TRPM2 may be a new target for diabetes therapy. PMID- 20921209 TI - Combination of temsirolimus (CCI-779) with chemoradiation in newly diagnosed glioblastoma multiforme (GBM) (NCCTG trial N027D) is associated with increased infectious risks. AB - PURPOSE: The mammalian target of rapamycin (mTOR) functions within the phosphoinositide 3-kinase/Akt signaling pathway as a critical modulator of cell survival. METHODS: The mTOR inhibitor temsirolimus (CCI-779) was combined with chemoradiotherapy in glioblastoma multiforme (GBM) patients in a dose-escalation phase I trial. The first 12 patients were treated with CCI-779 combined with radiation/temozolomide and adjuvant temozolomide. A second cohort of 13 patients was treated with concurrent CCI-779/radiation/temozolomide followed by adjuvant temozolomide monotherapy. RESULTS: Concomitant and adjuvant CCI-779 was associated with a high rate (3 of 12 patients) of grade 4/5 infections. By limiting CCI-779 treatment to the radiation/temozolomide phase and using antibiotic prophylaxis, the rate of infections was reduced, although 2 of 13 patients developed exacerbation of pre-existing fungal or viral infections. Dose limiting toxicities were observed in 2 of 13 patients with this modified schedule. Weekly CCI-779 (50 mg/week) combined with radiation/temozolomide is the recommended phase II dose and schedule. The immune profile of patients in the second cohort was assessed before, during, and after CCI-779 therapy. There was robust suppression of helper and cytotoxic T cells, B cells, natural killer, cells and elevation of regulatory T cells during CCI-779/radiation/temozolomide therapy with recovery to baseline levels during adjuvant temozolomide of cytotoxic T cells, natural killer cells, and regulatory T cells. CONCLUSIONS: The increased infection rate observed with CCI-779 combined with chemoradiotherapy in GBM was reduced with antibiotic prophylaxis and by limiting the duration of CCI 779 therapy. The combined suppressive effects of CCI-779 and temozolomide therapy on discrete immune compartments likely contributed to the increased infectious risks observed. PMID- 20921210 TI - Intratumoral mediated immunosuppression is prognostic in genetically engineered murine models of glioma and correlates to immunotherapeutic responses. AB - PURPOSE: Preclinical murine model systems used for the assessment of therapeutics have not been predictive of human clinical responses, primarily because their clonotypic nature does not recapitulate the heterogeneous biology and immunosuppressive mechanisms of humans. Relevant model systems with mice that are immunologically competent are needed to evaluate the efficacy of therapeutic agents, especially immunotherapeutics. EXPERIMENTAL DESIGN: Using the RCAS/Ntv-a system, mice were engineered to coexpress platelet-derived growth factor B (PDGF B) receptor + B-cell lymphoma 2 (Bcl-2) under the control of the glioneuronal specific Nestin promoter. The degree and type of tumor-mediated immunosuppression were determined in these endogenously arising gliomas on the basis of the presence of macrophages and regulatory T cells. The immunotherapeutic agent WP1066 was tested in vivo to assess therapeutic efficacy and immunomodulation. RESULTS: Ntv-a mice were injected with RCAS vectors to express PDGF-B + Bcl-2, resulting in both low- and high-grade gliomas. Consistent with observations in human high-grade gliomas, mice with high-grade gliomas also developed a marked intratumoral influx of macrophages that was influenced by tumor signal transducer and activator of transduction 3 (STAT3) expression. The presence of intratumoral F4/80 macrophages was a negative prognosticator for long-term survival. In mice coexpressing PDGF-B + Bcl-2that were treated with WP1066, there was 55.5% increase in median survival time (P < 0.01), with an associated inhibition of intratumoral STAT3 and macrophages. CONCLUSIONS: Although randomization is necessary for including mice in a therapeutic trial, these murine model systems are more suitable for testing therapeutics, especially immunotherapeutics, in the context of translational studies. PMID- 20921211 TI - Neuromuscular responses to hydration in moderate to warm ambient conditions during self-paced high-intensity exercise. AB - OBJECTIVE: To examine the neuromuscular responses to 60 minutes of self-paced high-intensity exercise punctuated with 6 * 1-minute "all-out" sprints at 10 minute intervals in moderate (19.8 degrees C, SEM 0.3) and warm (33.2, SEM 0.1), humid (~64% relative humidity) conditions with either complete hydration (CH) or without hydration (NF). DESIGN: Seven subjects (mean age 20.6 years (SE 1.1), mass 73.8 kg (SE 4.5), peak power 288 W (SE 11.3)) performed the time trial on four separate occasions, which were differentiated by ambient temperature and fluid ingestion. For each sprint interval, distance, power output and electromyographic (EMG) data from the rectus femoris and vastus lateralis muscles were recorded. RESULTS: The NF trials resulted in a reduction in body mass for the moderate and warm conditions of 1.7% and 2.1%, respectively. Final rectal temperatures were not different among conditions (~38.7 degrees C). Total body sweating was higher in the warm condition (19.1-21.3 ml/kg per hour) compared with the moderate condition (16.1-16.5 ml/kg per hour; p<0.05). Neither fluid ingestion nor ambient temperature altered total distance cycled for any of the trials (range 30.1-32.6 km). The normalised integrated EMG (as percentage of maximal voluntary contraction) when compared with the first sprint increased from sprint three for the rectus femoris muscle in both no and complete hydration but decreased for the vastus lateralis muscle. The mean percentile frequency shift increased for both the vastus lateralis and rectus femoris muscles in both no and complete hydration. CONCLUSIONS: These results suggest that the integrity of the neuromuscular system is adjusted according to hydration status and ambient temperatures during intense self-paced cycling. PMID- 20921212 TI - A-Z of nutritional supplements: dietary supplements, sports nutrition foods and ergogenic aids for health and performance--Part 13. PMID- 20921213 TI - A rare cause of acute abdominal pain in a young kickboxer. PMID- 20921214 TI - Serum uric acid levels predict new-onset type 2 diabetes in hospitalized patients with primary hypertension: the MAGIC study. AB - OBJECTIVE: Recent studies suggest that uric acid may predict the development of diabetes in the general population. Whether this association holds true in primary hypertension and is independent of renal function and metabolic syndrome is not clear at present. RESEARCH DESIGN AND METHODS: In a prospective, observational study, 758 untreated hypertensive patients were evaluated at baseline and followed-up for 11 years. RESULTS: A total of 8,332 person-years of follow-up revealed that slightly elevated uric acid levels (i.e., >=318 MUmol/l for women and >=420 MUmol/l for men) at baseline were associated with a significantly higher risk of developing diabetes (hazard ratio 3.65 [95% CI 1.99 6.69], P < 0.0001), even after adjustment for several confounding factors such as metabolic syndrome (2.78 [1.35-5.70], P = 0.0054). CONCLUSIONS: Uric acid is an independent predictor of diabetes in primary hypertension. PMID- 20921215 TI - Frequent monitoring of A1C during pregnancy as a treatment tool to guide therapy. AB - OBJECTIVE: No guidelines for A1C measurement exist for women with gestational diabetes mellitus (GDM). The aim of this study was to document the rate of A1C decline in women with GDM. RESEARCH DESIGN AND METHODS: Women with GDM in the Santa Barbara County Endocrine Clinic are managed with a carbohydrate-restricted diet and self-monitored blood glucose before and 1-h postprandial. Insulin is started if the preprandial glucose concentration is >=90 mg/dl and/or a 1-h postprandial glucose concentration is >=120 mg/dl. Capillary A1C was tested weekly using the DCA2000+ analyzer. RESULTS: Twenty-four women with GDM (aged 29.0 +/- 7.3 years) with initial A1C >=7.0% were recruited. Baseline A1C was 8.8 +/- 1.8%. Mean A1C decline was 0.47% per week (range 0.10-1.15%); the maximum was 4.3% in 4 weeks. CONCLUSIONS: This study documents rapid decline in A1C during pregnancy and the utility of weekly A1C to guide therapy. PMID- 20921216 TI - Exercise-induced changes in metabolic intermediates, hormones, and inflammatory markers associated with improvements in insulin sensitivity. AB - OBJECTIVE: To understand relationships between exercise training-mediated improvements in insulin sensitivity (S(I)) and changes in circulating concentrations of metabolic intermediates, hormones, and inflammatory mediators. RESEARCH DESIGN AND METHODS: Targeted mass spectrometry and enzyme-linked immunosorbent assays were used to quantify metabolic intermediates, hormones, and inflammatory markers at baseline, after 6 months of exercise training, and 2 weeks after exercise training cessation (n = 53). A principal components analysis (PCA) strategy was used to relate changes in these intermediates to changes in S(I). RESULTS: PCA reduced the number of intermediates from 90 to 24 factors composed of biologically related components. With exercise training, improvements in S(I) were associated with reductions in by-products of fatty acid oxidation and increases in glycine and proline (P < 0.05, R2 = 0.59); these relationships were retained 15 days after cessation of exercise training (P < 0.05, R2 = 0.34). CONCLUSIONS: These observations support prior observations in animal models that exercise training promotes more efficient mitochondrial beta-oxidation and challenges current hypotheses regarding exercise training and glycine metabolism. PMID- 20921217 TI - Do physical activity and aerobic fitness moderate the association between birth weight and metabolic risk in youth?: the European Youth Heart Study. AB - OBJECTIVE: Lower birth weight has been associated with a greater risk of metabolic diseases. The aim of this study was examine whether physical activity and aerobic fitness may modify associations between birth weigh and metabolic risk. RESEARCH DESIGN AND METHODS: The European Youth Heart Study is a population based study of 9 and 15 year olds (n = 1,254). Birth weight was maternally reported. Skin fold measures were used to calculate body fat and fat mass index (FMI = fat mass [kilograms]/height2). Insulin was measured using fasting blood samples. Physical activity was measured using a hip-worn accelerometer (MTI Actigraph) for >600 min/day for >=3 days and is expressed as "average activity" (counts per minute) and time spent in above moderate intensity activity (>2000 cpm). Aerobic fitness was assessed using a maximal cycle ergometry test (watts per kilogram fat-free mass). RESULTS: Higher birth weight was associated with higher FMI (beta = 0.49 [95% CI 0.21-0.80]; P = 0.001) and greater waist circumference (0.90 [0.32-1.47]; P < 0.001), adjusted for sex, age-group, sexual maturity, height, and socioeconomic status. Lower birth weight was associated with higher fasting insulin only after further adjustment for adolescent waist circumference and height (-0.059 [-0.107 to -0.011]; P = 0.016). There was no evidence for any modification of the associations after adjustment for physical activity or aerobic fitness. CONCLUSIONS: The present study did not find any evidence that physical activity or aerobic fitness can moderate the associations among higher birth weight and increased fat mass and greater waist circumference or between lower birth weight and insulin resistance in healthy children and adolescents. PMID- 20921218 TI - Defective in cuticular ridges (DCR) of Arabidopsis thaliana, a gene associated with surface cutin formation, encodes a soluble diacylglycerol acyltransferase. AB - A key step in the triacylglycerol (TAG) biosynthetic pathway is the final acylation of diacylglycerol (DAG) by DAG acyltransferase. In silico analysis has revealed that the DCR (defective in cuticular ridges) (At5g23940) gene has a typical HX(4)D acyltransferase motif at the N-terminal end and a lipid binding motif VX(2)GF at the middle of the sequence. To understand the biochemical function, the gene was overexpressed in Escherichia coli, and the purified recombinant protein was found to acylate DAG specifically in an acyl-CoA dependent manner. Overexpression of At5g23940 in a Saccharomyces cerevisiae quadruple mutant deficient in DAG acyltransferases resulted in TAG accumulation. At5g23940 rescued the growth of this quadruple mutant in the oleate-containing medium, whereas empty vector control did not. Lipid particles were localized in the cytosol of At5g23940-transformed quadruple mutant cells, as observed by oil red O staining. There was an incorporation of 16-hydroxyhexadecanoic acid into TAG in At5g23940-transformed cells of quadruple mutant. Here we report a soluble acyl-CoA-dependent DAG acyltransferase from Arabidopsis thaliana. Taken together, these data suggest that a broad specific DAG acyltransferase may be involved in the cutin as well as in the TAG biosynthesis by supplying hydroxy fatty acid. PMID- 20921219 TI - Quality control of photosystem II: FtsH hexamers are localized near photosystem II at grana for the swift repair of damage. AB - The reaction center-binding D1 protein of Photosystem II is oxidatively damaged by excessive visible light or moderate heat stress. The metalloprotease FtsH has been suggested as responsible for the degradation of the D1 protein. We have analyzed the distribution and subunit structures of FtsH in spinach thylakoids and various membrane fractions derived from the thylakoids using clear native polyacrylamide gel electrophoresis and Western blot analysis. FtsH was found not only in the stroma thylakoids but also in the Photosystem II-enriched grana membranes. Monomeric, dimeric, and hexameric FtsH proteases were present as major subunit structures in thylakoids, whereas only hexameric FtsH proteases were detected in Triton X-100-solubilized Photosystem II membranes. Importantly, among the membrane fractions examined, hexameric FtsH proteases were most abundant in the Photosystem II membranes. In accordance with this finding, D1 degradation took place in the Photosystem II membranes under light stress. Sucrose density gradient centrifugation analysis of thylakoids and the Photosystem II membranes solubilized with n-dodecyl-beta-d-maltoside and a chemical cross-linking study of thylakoids showed localization of FtsH near the Photosystem II light-harvesting chlorophyll-protein supercomplexes in the grana. These results suggest that part of the FtsH hexamers are juxtapositioned to PSII complexes in the grana in darkness, carrying out immediate degradation of the photodamaged D1 protein under light stress. PMID- 20921220 TI - Mutation analysis of the presenilin 1 N-terminal domain reveals a broad spectrum of gamma-secretase activity toward amyloid precursor protein and other substrates. AB - The gamma-secretase protein complex executes the intramembrane proteolysis of amyloid precursor protein (APP), which releases Alzheimer disease beta-amyloid peptide. In addition to APP, gamma-secretase also cleaves several other type I membrane protein substrates including Notch1 and N-cadherin. gamma-Secretase is made of four integral transmembrane protein subunits: presenilin (PS), nicastrin, APH1, and PEN2. Multiple lines of evidence indicate that a heteromer of PS derived N- and C-terminal fragments functions as the catalytic subunit of gamma secretase. Only limited information is available on the domains within each subunit involved in the recognition and recruitment of diverse substrates and the transfer of substrates to the catalytic site. Here, we performed mutagenesis of two domains of PS1, namely the first luminal loop domain (LL1) and the second transmembrane domain (TM2), and analyzed PS1 endoproteolysis as well as the catalytic activities of PS1 toward APP, Notch, and N-cadherin. Our results show that distinct residues within LL1 and TM2 domains as well as the length of the LL1 domain are critical for PS1 endoproteolysis, but not for PS1 complex formation with nicastrin, APH1, and PEN2. Furthermore, our experimental PS1 mutants formed gamma-secretase complexes with distinct catalytic properties toward the three substrates examined in this study; however, the mutations did not affect PS1 interaction with the substrates. We conclude that the N-terminal LL1 and TM2 domains are critical for PS1 endoproteolysis and the coordination between the putative substrate-docking site and the catalytic core of the gamma secretase. PMID- 20921221 TI - Analysis of three-dimensional systems for developing and mature kidneys clarifies the role of OAT1 and OAT3 in antiviral handling. AB - The organic anion transporters OAT1 (SLC22A6, originally identified by us as NKT) and OAT3 (SLC22A8) are critical for handling many toxins, metabolites, and drugs, including antivirals (Truong, D. M., Kaler, G., Khandelwal, A., Swaan, P. W., and Nigam, S. K. (2008) J. Biol. Chem. 283, 8654-8663). Although microinjected Xenopus oocytes and/or transfected cells indicate overlapping specificities, the individual contributions of these transporters in the three-dimensional context of the tissues in which they normally function remain unclear. Here, handling of HIV antivirals (stavudine, tenofovir, lamivudine, acyclovir, and zidovudine) was analyzed with three-dimensional ex vivo functional assays using knock-out tissue. To investigate the contribution of OAT1 and OAT3 in various nephron segments, the OAT-selective fluorescent tracer substrates 5-carboxyfluorescein and 6 carboxyfluorescein were used. Although OAT1 function (uptake in oat3(-/-) tissue) was confined to portions of the cortex, consistent with a proximal tubular localization, OAT3 function (uptake in oat1(-/-) tissue) was apparent throughout the cortex, indicating localization in the distal as well as proximal nephron. This functional localization indicates a complex three-dimensional context, which needs to be considered for metabolites, toxins, and drugs (e.g. antivirals) handled by both transporters. These results also raise the possibility of functional differences in the relative importance of OAT1 and OAT3 in antiviral handling in developing and mature tissue. Because the HIV antivirals are used in pregnant women, the results may also help in understanding how these drugs are handled by developing organs. PMID- 20921222 TI - Aggregation of detergent-insoluble tau is involved in neuronal loss but not in synaptic loss. AB - Neurofibrillary tangles (NFTs), which consist of highly phosphorylated tau, are hallmarks of neurodegenerative diseases including Alzheimer disease (AD). In neurodegenerative diseases, neuronal dysfunction due to neuronal loss and synaptic loss accompanies NFT formation, suggesting that a process associated with NFT formation may be involved in neuronal dysfunction. To clarify the relationship between the tau aggregation process and synapse and neuronal loss, we compared two lines of mice expressing human tau with or without an aggregation prone P301L mutation. P301L tau transgenic (Tg) mice exhibited neuronal loss and produced sarcosyl-insoluble tau in old age but did not exhibit synaptic loss and memory impairment. By contrast, wild-type tau Tg mice neither exhibited neuronal loss nor produced sarcosyl-insoluble tau but did exhibit synaptic loss and memory impairment. Moreover, P301L tau was less phosphorylated than wild-type tau, suggesting that the tau phosphorylation state is involved in synaptic loss, whereas the tau aggregation state is involved in neuronal loss. Finally, increasing concentrations of insoluble tau aggregates leads to the formation of fibrillar tau, which causes NFTs to form. PMID- 20921223 TI - Nucleocytoplasmic shuttling of dysbindin-1, a schizophrenia-related protein, regulates synapsin I expression. AB - Dysbindin-1 is a 50-kDa coiled-coil-containing protein encoded by the gene DTNBP1 (dystrobrevin-binding protein 1), a candidate genetic factor for schizophrenia. Genetic variations in this gene confer a susceptibility to schizophrenia through a decreased expression of dysbindin-1. It was reported that dysbindin-1 regulates the expression of presynaptic proteins and the release of neurotransmitters. However, the precise functions of dysbindin-1 are largely unknown. Here, we show that dysbindin-1 is a novel nucleocytoplasmic shuttling protein and translocated to the nucleus upon treatment with leptomycin B, an inhibitor of exportin-1/CRM1 mediated nuclear export. Dysbindin-1 harbors a functional nuclear export signal necessary for its nuclear export, and the nucleocytoplasmic shuttling of dysbindin-1 affects its regulation of synapsin I expression. In brains of sandy mice, a dysbindin-1-null strain that displays abnormal behaviors related to schizophrenia, the protein and mRNA levels of synapsin I are decreased. These findings demonstrate that the nucleocytoplasmic shuttling of dysbindin-1 regulates synapsin I expression and thus may be involved in the pathogenesis of schizophrenia. PMID- 20921225 TI - Interaction of calcium-dependent activator protein for secretion 1 (CAPS1) with the class II ADP-ribosylation factor small GTPases is required for dense-core vesicle trafficking in the trans-Golgi network. AB - Ca(2+)-dependent activator protein for secretion (CAPS) regulates exocytosis of catecholamine- or neuropeptide-containing dense-core vesicles (DCVs) at secretion sites, such as nerve terminals. However, large amounts of CAPS protein are localized in the cell soma, and the role of somal CAPS protein remains unclear. The present study shows that somal CAPS1 plays an important role in DCV trafficking in the trans-Golgi network. The anti-CAPS1 antibody appeared to pull down membrane fractions, including many Golgi-associated proteins, such as ADP ribosylation factor (ARF) small GTPases. Biochemical analyses of the protein protein interaction showed that CAPS1 interacted specifically with the class II ARF4/ARF5, but not with other classes of ARFs, via the pleckstrin homology domain in a GDP-bound ARF form-specific manner. The pleckstrin homology domain of CAPS1 showed high affinity for the Golgi membrane, thereby recruiting ARF4/ARF5 to the Golgi complex. Knockdown of either CAPS1 or ARF4/ARF5 expression caused accumulation of chromogranin, a DCV marker protein, in the Golgi, thereby reducing its DCV secretion. In addition, the overexpression of CAPS1 binding deficient ARF5 mutants induced aberrant chromogranin accumulation in the Golgi and consequently reduced its DCV secretion. These findings implicate a functional role for CAPS1 protein in the soma, a major subcellular localization site of CAPS1 in many cell types, in regulating DCV trafficking in the trans-Golgi network; this activity occurs via protein-protein interaction with ARF4/ARF5 in a GDP-dependent manner. PMID- 20921224 TI - Deceleration of the E1P-E2P transition and ion transport by mutation of potentially salt bridge-forming residues Lys-791 and Glu-820 in gastric H+/K+ ATPase. AB - A lysine residue within the highly conserved center of the fifth transmembrane segment in P(IIC)-type ATPase alpha-subunits is uniquely found in H,K-ATPases instead of a serine in all Na,K-ATPase isoforms. Because previous studies suggested a prominent role of this residue in determining the electrogenicity of non-gastric H,K-ATPase and in pK(a) modulation of the proton-translocating residues in the gastric H,K-ATPases as well, we investigated its functional significance for ion transport by expressing several Lys-791 variants of the gastric H,K-ATPase in Xenopus oocytes. Although the mutant proteins were all detected at the cell surface, none of the investigated mutants displayed any measurable K(+)-induced stationary currents. In Rb(+) uptake measurements, replacement of Lys-791 by Arg, Ala, Ser, and Glu substantially impaired transport activity and reduced the sensitivity toward the E(2)-specific inhibitor SCH28080. Furthermore, voltage clamp fluorometry using a reporter site in the TM5/TM6 loop for labeling with tetra-methylrhodamine-6-maleimide revealed markedly changed fluorescence signals. All four investigated mutants exhibited a strong shift toward the E(1)P state, in agreement with their reduced SCH28080 sensitivity, and an about 5-10-fold decreased forward rate constant of the E(1)P <-> E(2)P conformational transition, thus explaining the E(1)P shift and the reduced Rb(+) transport activity. When Glu-820 in TM6 adjacent to Lys-791 was replaced by non charged or positively charged amino acids, severe effects on fluorescence signals and Rb(+) transport were also observed, whereas substitution by aspartate was less disturbing. These results suggest that formation of an E(2)P-stabilizing interhelical salt bridge is essential to prevent futile proton exchange cycles of H(+) pumping P-type ATPases. PMID- 20921226 TI - Dioxygenase activity of epidermal lipoxygenase-3 unveiled: typical and atypical features of its catalytic activity with natural and synthetic polyunsaturated fatty acids. AB - Epidermal lipoxygenase-3 (eLOX3) exhibits hydroperoxide isomerase activity implicated in epidermal barrier formation, but its potential dioxygenase activity has remained elusive. We identified herein a synthetic fatty acid, 9E,11Z,14Z 20:3omega6, that was oxygenated by eLOX3 specifically to the 9S-hydroperoxide. Reaction showed a pronounced lag phase, which suggested that eLOX3 is deficient in its activation step. Indeed, we found that high concentrations of hydroperoxide activator (e.g. 65 MUM) overcame a prolonged lag phase (>1 h) and unveiled a dioxygenase activity with arachidonic acid; the main products were the 5-, 9-, and 7-hydroperoxyeicosatetraenoic acids (HPETEs). These were R/S mixtures (ranging from ~50:50 to 73:27), and as the bis-allylic 7-HPETE can be formed only inside the enzyme active site, the results indicate there is oxygen availability along either face of the reacting fatty acid radical. That the active site oxygen supply is limited is implied from the need for continuous re-activation, as carbon radical leakage leaves the enzyme in the unactivated ferrous state. An Ala to-Gly mutation, known to affect the positioning of O(2) in the active site of other lipoxygenase enzymes, led to more readily activated reaction and a significant increase in the 9R- over the 5-HPETE. Activation and cycling of the ferric enzyme are thus promoted using the 9E,11Z,14Z-20:3omega6 substrate, by continuous hydroperoxide activation, or by the Ala-to-Gly mutation. We suggest that eLOX3 represents one end of a spectrum among lipoxygenases where activation is inefficient, favoring hydroperoxide isomerase cycling, with the opposite end represented by readily activated enzymes in which dioxygenase activity is prominent. PMID- 20921227 TI - Three- and four-repeat Tau coassemble into heterogeneous filaments: an implication for Alzheimer disease. AB - Tau filaments are the pathological hallmark of numerous neurodegenerative diseases including Alzheimer disease, Pick disease, and progressive supranuclear palsy. In the adult human brain, six isoforms are expressed that differ by the presence or absence of the second of four semiconserved repeats. As a consequence, half of the tau isoforms have three repeats (3R tau), whereas the other half of the isoforms have four repeats (4R tau). Tauopathies can be characterized based on the isoform composition of their filaments. Alzheimer disease filamentous inclusions contain all isoforms. Pick disease filaments contain 3R tau. Progressive supranuclear palsy filaments contain 4R tau. Here, we used site-directed spin labeling of recombinant tau in conjunction with electron paramagnetic resonance spectroscopy to obtain structural insights into these filaments. We find that filaments of 4R tau and 3R tau share a highly ordered core structure in the third repeat with parallel, in-register arrangement of beta strands. This structure is conserved regardless of whether full-length isoforms (htau40 and htau23) or truncated constructs (K18 and K19) are used. When mixed, 3R tau and 4R tau coassemble into heterogeneous filaments. These filaments share the highly ordered core in the third repeat; however, they differ in their overall composition. Our findings indicate that at least three distinct types of filaments exist: homogeneous 3R tau, homogeneous 4R tau, and heterogeneous 3R/4R tau. These results suggest that individual filaments found in Alzheimer disease are structurally distinct from those in the 3R and 4R tauopathies. PMID- 20921228 TI - Increase in 4-coumaryl alcohol units during lignification in alfalfa (Medicago sativa) alters the extractability and molecular weight of lignin. AB - The lignin content of biomass can impact the ease and cost of biomass processing. Lignin reduction through breeding and genetic modification therefore has potential to reduce costs in biomass-processing industries (e.g. pulp and paper, forage, and lignocellulosic ethanol). We investigated compositional changes in two low-lignin alfalfa (Medicago sativa) lines with antisense down-regulation of p-coumarate 3-hydroxylase (C3H) or hydroxycinnamoyl-CoA:shikimate hydroxycinnamoyltransferase (HCT). We investigated whether the difference in reactivity during lignification of 4-coumaryl alcohol (H) monomers versus the naturally dominant sinapyl alcohol and coniferyl alcohol lignin monomers alters the lignin structure. Sequential base extraction readily reduced the H monomer content of the transgenic lines, leaving a residual lignin greatly enriched in H subunits; the extraction profile highlighted the difference between the control and transgenic lines. Gel permeation chromatography of isolated ball-milled lignin indicated significant changes in the weight average molecular weight distribution of the control versus transgenic lines (CTR1a, 6000; C3H4a, 5500; C3H9a, 4000; and HCT30a, 4000). PMID- 20921229 TI - Casein aggregates built step-by-step on charged polyelectrolyte film surfaces are calcium phosphate-cemented. AB - The possible mechanism of casein aggregation and micelle buildup was studied in a new approach by letting alpha-casein adsorb from low concentration (0.1 mg.ml( 1)) solutions onto the charged surfaces of polyelectrolyte films. It was found that alpha-casein could adsorb onto both positively and negatively charged surfaces. However, only when its negative phosphoseryl clusters remained free, i.e. when it adsorbed onto a negative surface, could calcium phosphate (CaP) nanoclusters bind to the casein molecules. Once the CaP clusters were in place, step-by-step building of multilayered casein architectures became possible. The presence of CaP was essential; neither Ca(2+) nor phosphate could alone facilitate casein aggregation. Thus, it seems that CaP is the organizing motive in the casein micelle formation. Atomic force microscopy revealed that even a single adsorbed casein layer was composed of very small (in the range of tens of nanometers) spherical forms. The stiffness of the adsorbed casein layer largely increased in the presence of CaP. On this basis, we can imagine that casein micelles emerge according to the following scheme. The amphipathic casein monomers aggregate into oligomers via hydrophobic interactions even in the absence of CaP. Full scale, CaP-carrying micelles could materialize by interlocking these casein oligomers with CaP nanoclusters. Such a mechanism would not contradict former experimental results and could offer a synthesis between the submicelle and the block copolymer models of casein micelles. PMID- 20921230 TI - Direct and specific activation of human inward rectifier K+ channels by membrane phosphatidylinositol 4,5-bisphosphate. AB - Many ion channels are modulated by phosphatidylinositol 4,5-bisphosphate (PIP(2)), but studies examining the PIP(2) dependence of channel activity have been limited to cell expression systems, which present difficulties for controlling membrane composition. We have characterized the PIP(2) dependence of purified human Kir2.1 and Kir2.2 activity using (86)Rb(+) flux and patch clamp assays in liposomes of defined composition. We definitively show that these channels are directly activated by PIP(2) and that PIP(2) is absolutely required in the membrane for channel activity. The results provide the first quantitative description of the dependence of eukaryotic Kir channel function on PIP(2) levels in the membrane; Kir2.1 shows measureable activity in as little as 0.01% PIP(2), and open probability increases to ~0.4 at 1% PIP(2). Activation of Kir2.1 by phosphatidylinositol phosphates is also highly selective for PIP(2); PI, PI(4)P, and PI(5)P do not activate channels, and PI(3,4,5)P(3) causes minimal activity. The PIP(2) dependence of eukaryotic Kir activity is almost exactly opposite that of KirBac1.1, which shows marked inhibition by PIP(2). This raises the interesting hypothesis that PIP(2) activation of eukaryotic channels reflects an evolutionary adaptation of the channel to the appearance of PIP(2) in the eukaryotic cell membrane. PMID- 20921231 TI - MST1 promotes apoptosis through phosphorylation of histone H2AX. AB - MST1 (mammalian STE20-like kinase 1) is a serine/threonine kinase that is cleaved and activated by caspases during apoptosis. Overexpression of MST1 induces apoptotic morphological changes such as chromatin condensation, but the mechanism is not clear. Here we show that MST1 induces apoptotic chromatin condensation through its phosphorylation of histone H2AX at Ser-139. During etoposide-induced apoptosis in Jurkat cells, the cleavage of MST1 directly corresponded with strong H2AX phosphorylation. In vitro kinase assay results showed that MST1 strongly phosphorylates histone H2AX. Western blot and kinase assay results with a mutant S139A H2AX confirmed that MST1 phosphorylates H2AX at Ser-139. Direct binding of MST1 and H2AX can be detected when co-expressed in HEK293 cells and was also confirmed by an endogenous immunoprecipitation study. When overexpressed in HeLa cells, both the MST1 full-length protein and the MST1 kinase domain (MST1-NT), but not the kinase-negative mutant (MST1-NT-KN), could induce obvious endogenous histone H2AX phosphorylation. The caspase-3 inhibitor benzyloxycarbonyl-DEVD fluoromethyl ketone (Z-DEVD-fmk) attenuates phosphorylation of H2AX by MST1 but cannot inhibit MST1-NT-induced histone H2AX phosphorylation, indicating that cleaved MST1 is responsible for H2AX phosphorylation during apoptosis. Histone H2AX phosphorylation and DNA fragmentation were suppressed in MST1 knockdown Jurkat cells after etoposide treatment. Taken together, our data indicated that H2AX is a substrate of MST1, which functions to induce apoptotic chromatin condensation and DNA fragmentation. PMID- 20921233 TI - Young proteins experience more variable selection pressures than old proteins. AB - It is well known that young proteins tend to experience weaker purifying selection and evolve more quickly than old proteins. Here, we show that, in addition, young proteins tend to experience more variable selection pressures over time than old proteins. We demonstrate this pattern in three independent taxonomic groups: yeast, Drosophila, and mammals. The increased variability of selection pressures on young proteins is highly significant even after controlling for the fact that young proteins are typically shorter and experience weaker purifying selection than old proteins. The majority of our results are consistent with the hypothesis that the function of a young gene tends to change over time more readily than that of an old gene. At the same time, our results may be caused in part by young genes that serve constant functions over time, but nevertheless appear to evolve under changing selection pressures due to depletion of adaptive mutations. In either case, our results imply that the evolution of a protein-coding sequence is partly determined by its age and origin, and not only by the phenotypic properties of the encoded protein. We discuss, via specific examples, the consequences of these findings for understanding of the sources of evolutionary novelty. PMID- 20921232 TI - Conservation of an RNA regulatory map between Drosophila and mammals. AB - Alternative splicing is generally controlled by proteins that bind directly to regulatory sequence elements and either activate or repress splicing of adjacent splice sites in a target pre-mRNA. Here, we have combined RNAi and mRNA-seq to identify exons that are regulated by Pasilla (PS), the Drosophila melanogaster ortholog of mammalian NOVA1 and NOVA2. We identified 405 splicing events in 323 genes that are significantly affected upon depletion of ps, many of which were annotated as being constitutively spliced. The sequence regions upstream and within PS-repressed exons and downstream from PS-activated exons are enriched for YCAY repeats, and these are consistent with the location of these motifs near NOVA-regulated exons in mammals. Thus, the RNA regulatory map of PS and NOVA1/2 is highly conserved between insects and mammals despite the fact that the target gene orthologs regulated by PS and NOVA1/2 are almost entirely nonoverlapping. This observation suggests that the regulatory codes of individual RNA binding proteins may be nearly immutable, yet the regulatory modules controlled by these proteins are highly evolvable. PMID- 20921234 TI - Rapidly progressive course of very late onset multiple sclerosis presenting with Parkinsonism: case report. AB - Multiple sclerosis mainly affects young adolescents, making late-onset multiple sclerosis a rarity and diagnostic challenge, particularly for cases after age 80 years. We present an 82-year-old patient with multiple sclerosis with very late onset. As well as spastic paraplegia, additional Parkinsonism secondary to demyelination in the basal ganglia was observed in this case. In most publications, spinal cord lesions were more common in late-onset multiple sclerosis which, in contrast, could not be found in our case. Despite different treatment strategies, rapid clinical deterioration and death after about 2 years of disease course occurred. Further discrimination in late-onset multiple sclerosis (50-70 years) and multiple sclerosis with very late onset (above 70 years) might be considered. Future trials to elucidate potential benefit of immunosuppressive (and neuroprotective) therapies in these age groups are mandatory. PMID- 20921235 TI - Lower levels of glutathione in the brains of secondary progressive multiple sclerosis patients measured by 1H magnetic resonance chemical shift imaging at 3 T. AB - BACKGROUND: Disability levels for patients with secondary progressive multiple sclerosis (SPMS) often worsen despite a stable MRI T(2) lesion burden. The presence of oxidative stress in the absence of measurable inflammation could help explain this phenomenon. In this study, the assessment of an in vivo marker of oxidative stress, cerebral glutathione (GSH), using magnetic resonance chemical shift imaging (CSI) is described, and GSH levels were compared in patients with SPMS and healthy controls. OBJECTIVE: To assess whether GSH, a key antioxidant in the brain, is lower in the SPMS patients compared to matched controls. METHODS: Seventeen patients with SPMS (Expanded Disability Status Scale=4.0-7.0; length of MS diagnosis=19.4 +/- 7 years) and 17 age- and gender-matched healthy controls were studied. GSH levels were measured in the fronto-parietal regions of the brain using a specially designed magnetic resonance spectroscopy technique, CSI of GSH, at 3T. RESULTS: The levels of GSH were lower for SPMS patients than for controls, the largest reduction (18.5%) being in the frontal region (p=0.001). CONCLUSION: The lower GSH levels in these patients indicate the presence of oxidative stress in SPMS. This process could be at least partially responsible for ongoing functional decline in SPMS. PMID- 20921236 TI - Autologous hematopoietic cell transplantation for multiple sclerosis: a systematic review. AB - BACKGROUND AND OBJECTIVES: The purpose of this systematic review was to evaluate the safety and efficacy of autologous hematopoietic cell transplantation in patients with progressive multiple sclerosis (MS) refractory to conventional medical treatment. METHODS: Eight case series met our a priori inclusion criteria for the primary outcome of progression-free survival. Individual study quality was rated using an 11-item scale for case series. The strength of the overall body of evidence for each outcome was rated using a system developed by the ECRI Institute. Data from different studies were statistically combined using meta analysis. An additional six studies were included for a summary of mortality and morbidity. RESULTS: For secondary progressive MS, immunoablative therapy with autologous bone marrow/peripheral blood stem cell transplantation was associated with higher progression-free survival (up to 3 years following treatment) when using intermediate-intensity conditioning regimens compared with high-intensity conditioning regimens. The evidence was insufficient to determine whether the treatment was effective in patients with other types of MS. Treatment-related mortality was about 2.7%. CONCLUSIONS: Patients with secondary progressive MS refractory to conventional medical treatment have longer progression-free survival following autologous stem cell transplantation with intermediate intensity conditioning regimens than with high-intensity conditioning regimens. PMID- 20921238 TI - Osteopontin concentrations are increased in cerebrospinal fluid during attacks of multiple sclerosis. AB - BACKGROUND: The cytokine osteopontin (OPN) is a potential key player in the immunopathogenesis of multiple sclerosis (MS) and a candidate biomarker for disease activity. OBJECTIVE: The objective of this study was to examine concentrations of OPN in the cerebrospinal fluid (CSF) across the clinical spectrum of MS. METHODS: Our research consisted of a cross-sectional study of patients from two randomized, placebo-controlled trials. Concentrations of OPN and other blood and CSF markers were determined using an enzyme-linked immunosorbent assay (ELISA). Samples were obtained from untreated patients with exacerbation of clinically isolated syndrome (CIS) (n = 25) and relapsing remitting MS (RRMS) (n = 41) of whom 48 participated in clinical trials, randomly allocated to treatment with placebo or methylprednisolone (MP) and undergoing repeated sampling after 3 weeks. Furthermore, we obtained CSF and blood samples from patients with primary progressive MS (PPMS, n = 9), secondary progressive MS (SPMS, n = 28) and other neurological disorders (OND, n = 44), and blood samples from 24 healthy subjects. RESULTS: OPN concentrations were significantly increased in the CSF of patients with CIS (p = 0.02) and RRMS (p < 0.001) in exacerbation compared to patients with OND, and increased levels of OPN were associated with high values of other biomarkers of inflammation. At 3-week follow up CSF OPN concentrations had decreased significantly from baseline regardless treatment with placebo or MP. Patients with PPMS had increased OPN levels in the CSF (p = 0.004) and high CSF levels of OPN were associated with high degrees of disability. CONCLUSIONS: OPN concentration in the CSF is a dynamic indicator of disease activity in RRMS, presumably reflecting ongoing inflammation. Increased CSF OPN concentrations in PPMS may indicate ongoing inflammation even in these patients. PMID- 20921239 TI - Internet intervention for increasing physical activity in persons with multiple sclerosis. AB - BACKGROUND: Physical activity has been associated with improvements in walking mobility and quality of life in persons with multiple sclerosis (MS), and yet this population is largely sedentary and inactive compared with the general population. OBJECTIVES: We conducted a pilot, randomized controlled trial (RCT) for examining the effect of an Internet intervention based on social cognitive theory (SCT) for favorably increasing physical activity among persons with MS. We further examined variables from SCT as possible mediators of the Internet intervention. METHODS: We randomly allocated 54 persons with MS into either an Internet intervention condition or a waitlist control condition. The participants completed measures of physical activity, self-efficacy, outcome expectations, functional limitations, and goal setting before and after the 12-week period. RESULTS: The intervention group reported a statistically significant (p = 0.01) and large increase in physical activity over time (d = 0.72), whereas the control group had a small (d = 0.04) and non-significant change in physical activity (p = 0.71). The intervention group further reported a statistically significant (p = 0.001) and large increase in goal setting over time (d = 0.97), whereas the control group had a small (d = -0.13) and non-significant change (p = 0.17). The change in goal setting over time mediated the effect of the Internet intervention on physical activity behavior. CONCLUSIONS: This pilot study sets the stage for a subsequent RCT that includes a larger sample of persons with MS, longer intervention period along with a follow-up, objective measure of physical activity, and secondary outcomes of walking mobility and QOL. PMID- 20921240 TI - Fetal head circumference growth in children with specific language impairment. AB - OBJECTIVE: To characterise fetal brain growth in children with specific language impairment (SLI). DESIGN: A nested case-control study. SETTING: Perth, Western Australia. PARTICIPANTS: Thirty children meeting criteria for SLI at age 10 years were individually matched with a typically developing comparison child on sex, non-verbal ability, fetal gestational age, maternal age at conception, smoking and alcohol intake during pregnancy. MAIN OUTCOME MEASURES: Occipitofrontal head circumference (HC) was measured using ultrasonography at approximately 18 weeks gestation. Femur length provided a measure of fetal length. Occipitofrontal HC was measured at birth and at the 1-year postnatal follow-up using a precise paper tape measure, while crown-heel length acted as an index of body length at both time points. Raw data were transformed to z-scores using reference norms. RESULTS: The SLI group had a significantly smaller mean HC than the typically developing comparison children at birth, but there was no group difference at 18 weeks gestation or at the 1-year postnatal follow-up. Individual analyses found that 12 SLI children had an HC z-score less than -1 at birth, with three of these cases meeting criteria for microcephaly. There was no group difference in the indices of overall body size at any time point. CONCLUSIONS: Children with SLI are more likely to have a small HC at birth but not at 18 weeks gestation or infancy, suggesting growth asynchrony in brain development during the second half of pregnancy. PMID- 20921241 TI - The temporal relationship between glucose-corrected serum sodium and neurological status in severe diabetic ketoacidosis. AB - OBJECTIVE: Cerebral oedema is a potentially devastating complication of diabetic ketoacidosis (DKA). The relationship between osmolar changes, acid-base changes and development of cerebral oedema during therapy is unclear. DESIGN: Retrospective cohort study on 53 children with severe DKA (mean pH at presentation 6.92+/-0.08). Cerebral oedema was diagnosed using neurological status, response to osmotherapy, and neuroimaging, and classified as: early (occurring <=1 h after presentation, n=15), late (1-48 h, n=17) or absent (controls, n=21). The temporal profiles for various osmolar and acid-base profiles were examined using a random coefficients fractional polynomial mixed model, adjusted for known risk factors. RESULTS: The three groups could not be differentiated by demographic, osmolar or acid-base variables at presentation. All osmolar and acid-base variables showed non-linear temporal trajectories. Children who developed late onset oedema showed dramatically different temporal profiles for effective osmolality and glucose-corrected serum sodium (both p<0.001). Glucose-corrected sodium provided better qualitative discrimination, in that it typically fell in children who developed late oedema and rose in controls. The maximum between-group difference for both variables approximated the median time of clinical cerebral oedema onset. Blood glucose and acid-base temporal profiles did not differ between the groups. Late onset oedema patients received more fluid in the first 4 h, but this did not influence the osmolar or glucose-corrected sodium trajectories in a predictable fashion. CONCLUSIONS: Glucose-corrected serum sodium may prove a useful early warning for the development of cerebral oedema in DKA. PMID- 20921242 TI - New communication media for professional support, discussion and education. PMID- 20921243 TI - Mapping of AF1 transactivation domains in duplicated rainbow trout glucocorticoid receptors. AB - The glucocorticoid receptor (GR) is a ligand-dependent transcription factor mediating the genomic effects of glucocorticoids. Two activation functions (AFs) are present in the GR. While the N-terminal AF1 is ligand independent, the C terminal AF2 overlaps with the ligand-binding domain and is ligand dependent. In this study, we have mapped AF1 in duplicated rainbow trout GRs, called rtGR1 and rtGR2, showing a limited homology (24.5%) in the N-terminal domain. Ablation of this domain from rtGR1 or rtGR2 resulted in a marked decrease (>97%) in maximal hormone-dependent transactivation, but did not affect dexamethasone-binding activity or expression levels. This suggested that, similar to the situation in the human GR (hGR), AF1 is the main AF in the trout GRs. Sequence alignments with hGR suggested a localisation of AF1 to residues 70-230 of rtGR1 and 1-119 of rtGR2. These assignments were generally confirmed in the transactivation experiments with rtGR1- and rtGR2-derived mutants showing partial deletions of their N-terminal domains. In dexamethsone-treated cells (10-7 M, 2 h), the subcellular distribution of rtGR1 and rtGR2 mutants lacking the entire N-terminal domain, as well that of an rtGR1 mutant lacking the most N-terminal 234 amino acids, was similar to that of the corresponding wild-type GRs, suggesting that the disruption of transactivation activity was not caused by impairment of nuclear access of the mutants. Bioinformatic analyses predicted the presence of potential helical segments in the core of AF1 of rtGR1 and rtGR2, and further revealed that AF1 in rtGR1, rtGR2, and hGR shares a motif composed of hydrophobic and acidic amino acids. PMID- 20921244 TI - Has the time come to phase out codeine? PMID- 20921245 TI - Herpes zoster and postherpetic neuralgia. PMID- 20921246 TI - Simple stuff. PMID- 20921249 TI - Defining priorities for improving end-of-life care in Canada. AB - BACKGROUND: High-quality end-of-life care should be the right of every Canadian. The objective of this study was to identify aspects of end-of-life care that are high in priority as targets for improvement using feedback elicited from patients and their families. METHODS: We conducted a multicentre, cross-sectional survey involving patients with advanced, life-limiting illnesses and their family caregivers. We administered the Canadian Health Care Evaluation Project (CANHELP) questionnaire along with a global rating question to measure satisfaction with end-of-life care. We derived the relative importance of individual questions on the CANHELP questionnaire from their association with a global rating of satisfaction, as determined using Pearson correlation coefficients. To determine high-priority issues, we identified questions that had scores indicating high importance and low satisfaction. RESULTS: We approached 471 patients and 255 family members, of whom 363 patients and 193 family members participated, with response rates of 77% for patients and 76% for families. From the perspective of patients, high-priority areas needing improvement were related to feelings of peace, to assessment and treatment of emotional problems, to physician availability and to satisfaction that the physician took a personal interest in them, communicated clearly and consistently, and listened. From the perspective of family members, similar areas were identified as high in priority, along with the additional areas of timely information about the patient's condition and discussions with the doctor about final location of care and use of end-of-life technology. INTERPRETATION: End-of-life care in Canada may be improved for patients and their families by providing better psychological and spiritual support, better planning of care and enhanced relationships with physicians, especially in aspects related to communication and decision-making. PMID- 20921250 TI - Chronic cough: tracheobronchopathia osteochondroplastica. PMID- 20921252 TI - Is bigger better? An argument for very low starting doses. PMID- 20921251 TI - The impact of herpes zoster and postherpetic neuralgia on health-related quality of life: a prospective study. AB - BACKGROUND: Vaccination against herpes zoster is being considered in many countries. We conducted a multicentre prospective study to describe the impact of herpes zoster and postherpetic neuralgia on health-related quality of life. METHODS: From October 2005 to July 2006, 261 outpatients aged 50 years or older with herpes zoster were recruited from the clinical practices of 83 physicians within 14 days after rash onset. The Zoster Brief Pain Inventory was used to measure severity of pain and interference with activities of daily living because of pain. The EuroQol EQ-5D assessment tool was used to measure quality of life. These outcomes were assessed at recruitment and on days 7, 14, 21, 30, 60, 90, 120, 150 and 180 following recruitment. RESULTS: Acute herpes zoster interfered in all health domains, especially sleep (64% of participants), enjoyment of life (58%) and general activities (53%). The median duration of pain was 32.5 days. The median duration of interference with activities of daily living because of pain varied between 27 and 30 days. Overall, 24% of the participants had postherpetic neuralgia (pain for more than 90 days after rash onset). Anxiety and depression, enjoyment of life, mood and sleep were most frequently affected during the postherpetic neuralgia period. The mean EQ-5D score was 0.59 at enrolment and remained at 0.67 at all follow-up points among participants who reported clinically significant pain. INTERPRETATION: These data support the need for preventive strategies and additional early intervention to reduce the burden of herpes zoster and postherpetic neuralgia. PMID- 20921253 TI - The red eye. PMID- 20921254 TI - Self-governance threatened, provincial association says. PMID- 20921255 TI - Regulation of genetic tests unnecessary, government says. PMID- 20921256 TI - "Blue button" access to medical records. PMID- 20921257 TI - China's "left behind" children often suffer health consequences. PMID- 20921258 TI - Britain's libel fighter. PMID- 20921259 TI - Clinical guidelines may need ethical component. PMID- 20921260 TI - Advertising campaigns for cystic fibrosis. PMID- 20921261 TI - Disclosure: only a first step. PMID- 20921262 TI - Prostitution gender. PMID- 20921263 TI - A new perspective for delinquency: culture conflict measured by seriousness perceptions. AB - Numerous theories have attempted to analyze and understand the factors and etiology of juvenile delinquency. The present study is the first to suggest the use of Sellin's "culture conflict" theory as a possible cultural explanation for the phenomenon of juvenile delinquency. According to Sellin, crime in many instances is a product of culture conflict between the values and norms of a certain subculture in a given society and those of the general culture. Following Sellin's rationale, this study argues that youths constitute a social subculture with certain values, norms, and stances toward the criminal law that is not necessarily concordant with the moral values and formal norms of the general culture of adults, who determine the content of the criminal law. These assertions are analyzed via a crime seriousness study, in which adult and teenage respondents from a national (Israeli) sample were asked to evaluate the seriousness of various criminal offenses committed by adolescents. Generally, significant differences were found between the seriousness and punishment values given by the adult and juvenile respondents to violent offenses (high) and self use of illegal drugs (low), with adult respondents providing significantly higher seriousness values and punishment options for them. Moreover, in a regression analysis, the variable of respondents' age was found as decisive in understanding both dependent variables. The implications of these findings are discussed in this study. PMID- 20921264 TI - Can a 12-step program work in methadone maintenance treatment? AB - Three consecutive, professionally led (as opposed to self-help) groups following the 12-step program (TSP) were integrated into a methadone maintenance treatment (MMT) program that included 32 heroin-addicted individuals in recovery. This report describes our experience in meeting the challenges that arose and our conclusions regarding the therapeutic potential of this integration. A professional therapeutic staff guided the groups. In-depth interviews of 10 participants and the reflections of the group leaders provided data for learning about the groups' experience. Initially the participants rejected the concepts of Step 1, powerlessness and unmanageability of life. The assimilation of Step 4 (defining character defect) also aroused some resistance. The participants eventually adopted the pragmatic aspects of TSP, including its terminology. The establishment of a common language of recovery helped to create group coherence and a sense of belonging, and helped to meet the needs of those who felt stigmatized by both the nonaddicted and addicted population undergoing nonmethadone recovery. TSP could be adapted to various aspects of daily life, produced a sense of self-efficacy, and stimulated motivation for change. Therapeutic implications are discussed. PMID- 20921266 TI - Importance of biomarkers for long-term mortality prediction in acutely dyspneic patients. AB - BACKGROUND: Although numerous biomarkers may be prognostically meaningful in patients with acute dyspnea, few comparative analyses have addressed possible associations between a wide range of candidate biomarkers and clinical variables. METHODS: Vital status was obtained for 517 acutely dyspneic patients at 4 years after emergency department presentation. A wide array of biomarkers was measured in this cohort, including natriuretic peptides, necrosis markers, inflammatory markers, hematologic markers, and renal markers. We performed statistical evaluation by using minimization of the Bayesian information criterion to evaluate predictors of 4-year mortality. Cox proportional hazards analysis was used to confirm results from the Bayesian information criterion. A final risk model was derived, and this model was then validated by applying it to patients from a separate cohort of acutely dyspneic patients. RESULTS: By 4 years, there were 186 deaths (36%). In addition to several clinical variables, several biomarkers were significant predictors of death, including log-transformed concentrations of hemoglobin (hazard ratio=0.77; P < 0.001), soluble ST2 (hazard ratio=1.38; P < 0.001), and amino-terminal pro-B-type natriuretic peptide (hazard ratio=1.19; P < 0.001). Risk models that used these significant variables were accurate in predicting 4-year mortality in both the training and validation sets. CONCLUSIONS: When added to traditional clinical variables, selected biomarkers added significant value for long-term prognostication in acute dyspnea. PMID- 20921267 TI - A bioluminescent microbial biosensor for in vitro pretreatment assessment of cytarabine efficacy in leukemia. AB - BACKGROUND: The nucleoside analog cytarabine (Ara-C [cytosine arabinoside]) is the key agent for treating acute myeloid leukemia (AML); however, up to 30% of patients fail to respond to treatment. Screening of patient blood samples to determine drug response before commencement of treatment is needed. This project aimed to construct and evaluate a self-bioluminescent reporter strain of Escherichia coli for use as an Ara-C biosensor and to design an in vitro assay to predict Ara-C response in clinical samples. METHODS: We used transposition mutagenesis to create a cytidine deaminase (cdd)-deficient mutant of E. coli MG1655 that responded to Ara-C. The strain was transformed with the luxCDABE operon and used as a whole-cell biosensor for development an 8-h assay to determine Ara-C uptake and phosphorylation by leukemic cells. RESULTS: Intracellular concentrations of 0.025 MUmol/L phosphorylated Ara-C were detected by significantly increased light output (P < 0.05) from the bacterial biosensor. Results using AML cell lines with known response to Ara-C showed close correlation between the 8-h assay and a 3-day cytotoxicity test for Ara-C cell killing. In retrospective tests with 24 clinical samples of bone marrow or peripheral blood, the biosensor-based assay predicted leukemic cell response to Ara-C within 8 h. CONCLUSIONS: The biosensor-based assay may offer a predictor for evaluating the sensitivity of leukemic cells to Ara-C before patients undergo chemotherapy and allow customized treatment of drug-sensitive patients with reduced Ara-C dose levels. The 8-h assay monitors intracellular Ara-CTP (cytosine arabinoside triphosphate) levels and, if fully validated, may be suitable for use in clinical settings. PMID- 20921268 TI - Statistical Methods in Medical Research. Editorial. PMID- 20921269 TI - Long-range tertiary interactions in single hammerhead ribozymes bias motional sampling toward catalytically active conformations. AB - Enzymes generally are thought to derive their functional activity from conformational motions. The limited chemical variation in RNA suggests that such structural dynamics may play a particularly important role in RNA function. Minimal hammerhead ribozymes are known to cleave efficiently only in ~ 10-fold higher than physiologic concentrations of Mg(2+) ions. Extended versions containing native loop-loop interactions, however, show greatly enhanced catalytic activity at physiologically relevant Mg(2+) concentrations, for reasons that are still ill-understood. Here, we use Mg(2+) titrations, activity assays, ensemble, and single molecule fluorescence resonance energy transfer (FRET) approaches, combined with molecular dynamics (MD) simulations, to ask what influence the spatially distant tertiary loop-loop interactions of an extended hammerhead ribozyme have on its structural dynamics. By comparing hammerhead variants with wild-type, partially disrupted, and fully disrupted loop-loop interaction sequences we find that the tertiary interactions lead to a dynamic motional sampling that increasingly populates catalytically active conformations. At the global level the wild-type tertiary interactions lead to more frequent, if transient, encounters of the loop-carrying stems, whereas at the local level they lead to an enrichment in favorable in-line attack angles at the cleavage site. These results invoke a linkage between RNA structural dynamics and function and suggest that loop-loop interactions in extended hammerhead ribozymes-and Mg(2+) ions that bind to minimal ribozymes-may generally allow more frequent access to a catalytically relevant conformation(s), rather than simply locking the ribozyme into a single active state. PMID- 20921271 TI - Light at night and health: the perils of rotating shift work. PMID- 20921270 TI - Optimization of enzymatic reaction conditions for generating representative pools of cDNA from small RNA. AB - Small regulatory RNA repertoires in biological samples are heterogeneous mixtures that may include species arising from varied biosynthetic pathways and modification events. Small RNA profiling and discovery approaches ought to capture molecules in a way that is representative of expression level. It follows that the effects of RNA modifications on representation should be minimized. The collection of high-quality, representative data, therefore, will be highly dependent on bias-free sample manipulation in advance of quantification. We examined the impact of 2'-O-methylation of the 3'-terminal nucleotide of small RNA on key enzymatic reactions of standard front-end manipulation schemes. Here we report that this common modification negatively influences the representation of these small RNA species. Deficits occurred at multiple steps as determined by gel analysis of synthetic input RNA and by quantification and sequencing of derived cDNA pools. We describe methods to minimize the effects of 2'-O-methyl modification of small RNA 3'-termini using T4 RNA ligase 2 truncated, and other optimized reaction conditions, demonstrating their use by quantifying representation of miRNAs and piRNAs in cDNA pools prepared from biological samples. PMID- 20921272 TI - 'Dippers' flu' and its relationship to PON1 polymorphisms. AB - OBJECTIVES: Sheep-dippers report an acute flu-like condition (dippers' flu: DF) but the cause and relation to chronic disability are unknown. METHODS: In a case referent study previously reported, 175 sheep dippers with chronic disability and 234 referents, sheep dippers in good health, completed an interview with information on dipping, type of pesticide used and health for each year 1970-2000 and gave blood for typing of PON1 polymorphisms. RESULTS: Reports of DF were much higher (66.3% 116/175) in the chronically unwell than in those without chronic ill-health (18.0% 42/234: OR=8.99 95% CI 5.69-14.21). No significant relation was seen between reported exposures and DF in those with chronic illness, but risk was higher with concentrate handling in those without. An R allele at position 192 on PON1 related to reports of DF both in those with chronic illness (OR=2.04 95% CI 1.08-3.87) and in those who started dipping after 1969 and were not chronically unwell (OR=2.52 95%CI 1.00-6.37). Interaction between handling diazinon concentrate and PON1 (192R) increased the risk of DF. No precipitating factor was identified in a case-crossover analysis. In the group without chronic illness those with 192R developed DF earlier (risk ratio 2.49 95%CI 1.03-6.02). CONCLUSION: 'Dippers' flu' and chronic ill-health attributed to dipping share a common polymorphism (192R). The interaction between handling diazinon concentrate and PON1 genotype supports the conclusion that organophosphates may cause DF. Sheep dippers who are still healthy but experience 'dippers' flu' may be wise to further limit exposures to organophosphates. PMID- 20921273 TI - Air conditioning and intrahospital mortality during the 2003 heatwave in Portugal: evidence of a protective effect. AB - OBJECTIVES: The objective of the study was to analyse the association between the presence of air conditioning in hospital wards and the intrahospital mortality during the 2003 heatwave, in mainland Portugal. METHODS: Historical cohort study design including all patients aged 45 or more who were hospitalised in the 7 days before the heatwave. The outcome was survival during the 18 days the heatwave lasted and during the 2 days after the end of the heatwave. A comparison group was also selected in four analogous periods without any heatwave event during January to May 2003. Data were obtained from the 2003 hospital discharges database. Air conditioning presence in hospital wards was determined using a survey sent to hospital administrations. A Cox-regression model was used to estimate the confounder-adjusted HR of death, during the heatwave and the comparison period, in patients in wards with air conditioning (AC+) versus patients in wards without air conditioning (AC-). RESULTS: 41 hospitals of mainland Portugal (49% of all hospitals in mainland Portugal) participated, and 2093 patients were enrolled. The overall confounder-adjusted HR of death in AC+ patients versus AC- patients was 0.60 (95% CI 0.37 to 0.97) for the heatwave period and 1.05 (95% CI 0.84 to 1.32) for the comparison group. CONCLUSIONS: The study found strong evidence that, during the August 2003 heatwave, the presence of air conditioning in hospital wards was associated with an increased survival of patients admitted before the beginning of the climate event. The reduction of the risk of dying is estimated to be 40% (95% CI 3% to 63%). PMID- 20921274 TI - Commonly consumed and specialty dietary mushrooms reduce cellular proliferation in MCF-7 human breast cancer cells. AB - Worldwide, over one million women will be newly diagnosed with breast cancer in the next year. Moreover, breast cancer is the second leading cause of cancer death in the USA. An accumulating body of evidence suggests that consumption of dietary mushrooms can protect against breast cancer. In this study, we tested and compared the ability of five commonly consumed or specialty mushrooms to modulate cell number balance in the cancer process using MCF-7 human breast cancer cells. Hot water extracts (80 degrees C for 2 h) of maitake (MT, Grifola frondosa), crimini (CRIM, Agaricus bisporus), portabella (PORT, Agaricus bisporus), oyster (OYS, Pleurotus ostreatus) and white button (WB, Agaricus bisporus) mushrooms or water alone (5% v/v) were incubated for 24 h with MCF-7 cells. Cellular proliferation determined by bromodeoxyuridine incorporation was significantly (P < 0.05) reduced up to 33% by all mushrooms, with MT and OYS being the most effective. MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) reduction, an often used mitochondrion-dependent marker of proliferation, was unchanged although decreased (P > 0.05) by 15% with OYS extract. Lactate dehydrogenase release, as a marker of necrosis, was significantly increased after incubation with MT but not with other test mushrooms. Furthermore, MT extract significantly increased apoptosis, or programmed cell death, as determined by terminal deoxynucleotidyl end labeling method, whereas other test mushrooms displayed trends of ~15%. The total numbers of cells per flask, determined by hemacytometry, were not different from control cultures. Overall, all test mushrooms significantly suppressed cellular proliferation, with MT further significantly inducing apoptosis and cytotoxicity in human breast cancer cells. This suggests that both common and specialty mushrooms may be chemoprotective against breast cancer. PMID- 20921275 TI - Renal and metabolic effects of three months of decarbonated cola beverages in rats. AB - Epidemiological studies have shown an association between the intake of cola beverages and chronic kidney diseases. Experimental evidence for the negative effects of cola intake on kidneys is lacking. Male Wistar rats had ad libitum access to water (control group) or three different sugar-sweetened cola beverages for three months. Despite very high cola intake (daily cca 140 mL), no differences were found in body weight, kidney weight, glomerular morphology, oxidative and carbonyl stress or expression of selected marker genes in the renal cortex. Interestingly, all groups consuming cola beverages had lower blood glucose levels during an oral glucose tolerance test, suggesting improved insulin sensitivity. Despite hyperfiltration (5-6-fold increase in diuresis), cola beverages had no effect on assessed parameters of renal function, histology, gene expression or oxidative stress. Moreover, cola intake seems to increase creatinine clearance and to decrease plasma levels of urea. In our study increased insulin sensitivity and altered renal functional parameters were observed in rats receiving cola beverages for three months. Whether the findings are due to the short duration of the study or interspecies metabolic differences should be uncovered in further studies. Even more interesting might be the analysis of effects of cola intake in animal models of diabetes. PMID- 20921276 TI - Dietary soy protein benefit in experimental kidney disease is preserved after isoflavone depletion of diet. AB - Soy diet ameliorates renal injury in the Han:SPRD-cy rat. The relative roles of protein, isoflavones and changes in polyunsaturated fatty acid (PUFA) status are not determined. We fed male Han:SPRD-cy heterozygotes casein (C), high isoflavone soy protein (HIS), alcohol-extracted low isoflavone soy protein (LIS) or mixed soy protein diet (MIS). LIS and MIS were associated with a small decrease in animal weight compared with HIS or C. Soy diets preserved normal renal function and reduced relative renal weight (10.9-14.6 g/kg, cf. 23.6, P < 0.001), scores for cystic change (0.168-0.239, cf. 0.386, P < 0.05), fibrosis (0.013-0.015, cf. 0.032, P < 0.05), tissue oxidized LDL content (0.012-0.021, cf. 0.048, P < 0.05), inflammation (8.5-12.9, cf. 31.2, P < 0.05) and epithelial cell proliferation (6.5-13.8, cf. 26.3, P < 0.05). In post hoc testing, LIS produced a greater reduction in relative renal weight, cystic change and epithelial proliferation, whereas HIS produced a significantly greater reduction in oxidized-LDL. Soy diets were associated with increased hepatic content of 18C PUFA (P < 0.001). LIS and HIS diets were associated with a small increase in body fat content (P < 0.001). Alcohol-extracted soy protein retains its major protective effects in this model with subtle differences attributable to isoflavones. PMID- 20921279 TI - How the adoption of impression management goals alters impression formation. AB - Five experiments (N = 390) tested the hypothesis that adopting an impression management goal leads the impression manager to view an interaction partner as having less of the trait he or she is attempting to express. This hypothesis was confirmed for the impression management goals of appearing introverted, extraverted, smart, confident, and happy. Experiment 2 shows that adoption of the impression goal could alter judgments even when participants could not act on the goal. Experiment 3 provides evidence that adopting an impression management goal prompted a comparison mind-set and that this comparison mind-set activation mediated target judgments. Experiment 4 rules out a potential alternative explanation and provides more direct evidence that comparison of the impression manager's self-concept mediates the impression of the target. Experiment 5 eliminates a potential confound and extends the effect to another impression goal. These experiments highlight the dynamic interplay between impression management and impression formation. PMID- 20921277 TI - Characterization of Puma-dependent and Puma-independent neuronal cell death pathways following prolonged proteasomal inhibition. AB - Proteasomal stress and the accumulation of polyubiquitinated proteins are key features of numerous neurodegenerative disorders. Previously we demonstrated that stabilization of p53 and activation of its target gene, puma (p53-upregulated mediator of apoptosis), mediated proteasome inhibitor-induced apoptosis in cancer cells. Here we demonstrated that Puma also contributed to proteasome inhibitor induced apoptosis in mouse neocortical neurons. Although protection afforded by puma gene deletion was incomplete, we found little evidence indicating contributions from other proapoptotic BH3-only proteins. Attenuation of bax expression did not further reduce Puma-independent apoptosis, suggesting that pathways other than the mitochondrial apoptosis pathway were activated. Real-time imaging experiments in wild-type and puma-deficient neurons using a fluorescence resonance energy transfer (FRET)-based caspase sensor confirmed the involvement of a second cell death pathway characterized by caspase activation prior to mitochondrial permeabilization and, more prominently, a third, caspase independent and Puma-independent pathway characterized by rapid cell shrinkage and nuclear condensation. This pathway involved lysosomal permeabilization in the absence of autophagy activation and was sensitive to cathepsin but not autophagy inhibition. Our data demonstrate that proteasomal stress activates distinct cell death pathways in neurons, leading to both caspase-dependent and caspase independent apoptosis, and demonstrate independent roles for Puma and lysosomal permeabilization in this model. PMID- 20921278 TI - Dual functions of Nbs1 in the repair of DNA breaks and proliferation ensure proper V(D)J recombination and T-cell development. AB - Immunodeficiency and lymphoid malignancy are hallmarks of the human disease Nijmegen breakage syndrome (NBS; OMIM 251260), which is caused by NBS1 mutations. Although NBS1 has been shown to bind to the T-cell receptor alpha (TCRalpha) locus, its role in TCRbeta rearrangement is unclear. Hypomorphic mutations of Nbs1 in mice and patients result in relatively mild T-cell deficiencies, raising the question of whether the truncated Nbs1 protein might have clouded a certain function of NBS1 in T-cell development. Here we show that the deletion of the entire Nbs1 protein in T-cell precursors (Nbs1(T-del)) results in severe lymphopenia and a hindrance to the double-negative 3 (DN3)-to-DN4 transition in early T-cell development, due to abnormal TCRbeta coding and signal joints as well as the functions of Nbs1 in T-cell expansion. Chromatin immunoprecipitation (ChIP) analysis of the TCR loci reveals that Nbs1 depletion compromises the loading of Mre11/Rad50 to V(D)J-generated DNA double-strand breaks (DSBs) and thereby affects resection of DNA termini and chromatin conformation of the postcleavage complex. Although a p53 deficiency relieves the DN3->DN4 transition block, neither a p53 deficiency nor ectopic expression of TCRalphabeta rescues the major T-cell loss in Nbs1(T-del) mice. All together, these results demonstrate that Nbs1's functions in both repair of V(D)J-generated DSBs and proliferation are essential for T-cell development. PMID- 20921280 TI - Fluorodesoxyglucose uptake in the remaining adrenal glands during the follow-up of patients with adrenocortical carcinoma: do not consider it as malignancy. AB - OBJECTIVE: To make the specificity of fluorodesoxyglucose ((18)FDG) positron emission tomography (PET) precise, in the follow-up of patients with adrenal cancer. DESIGN: This single centre retrospective study assessed the frequency and outcome of (18)FDG uptake in the remaining adrenal glands after adrenalectomy for adrenocortical carcinoma (ACC) or malignant phaeochromocytoma (PH). RESULTS: Two hundred and ten (18)FDG PET scans in 62 ACC patients, all under 1,ortho-1,para' dichloro-diphenyl-dichloro-ethane (o,p'-DDD) treatment, and 30 (18)FDG PET scans in 8 PH patients were reviewed. Abnormal (18)FDG uptake in the remaining adrenal glands was found in 19 (8%) (18)FDG PET scans, in 10 (16%) ACC patients and in none of the PH patients. (18)FDG uptake was found in 4% of the patients before the onset of o,p'-DDD, in 29% of the patients 0-6 months after the onset of o,p' DDD (P=0.05), in 26% of the patients 6-12 months (P=0.072) after the onset of o,p'-DDD and in 14% of the patients 12-24 months after the onset of o,p'-DDD. It was never found later than 24 months after the onset of o,p'-DDD. Adrenal glands with (18)FDG uptake were normal on computed tomography scans with i.v. contrast agent in all cases. (18)FDG uptake in the remaining adrenal glands decreased and disappeared on subsequent FDG PET imaging in eight of the patients with follow-up available. CONCLUSIONS: (18)FDG uptake in the remaining adrenal glands occurred in 14-29% of the patients followed for ACC within 24 months after adrenalectomy and onset of o,p'-DDD. This uptake is transient and should not be considered as suspicious for malignancy. PMID- 20921281 TI - The Valpha14 invariant natural killer T cell TCR forces microbial glycolipids and CD1d into a conserved binding mode. AB - Invariant natural killer T cells (iNKT cells) rapidly produce effector cytokines. In this study, we report the first crystal structures of the iNKT cell T cell receptor (TCR) bound to two natural, microbial glycolipids presented by CD1d. Binding of the TCR induced CDR3-alpha-dependent structural changes in the F' roof of CD1d; these changes resemble those occurring in the absence of TCR engagement when the highly potent synthetic antigen alpha-galactosylceramide (alpha-GalCer) binds CD1d. Furthermore, in the Borrelia burgdorferi alpha-galactosyl diacylglycerol-CD1d complex, TCR binding caused a marked repositioning of the galactose sugar into an orientation that closely resembles alpha-GalCer. The TCR dependent reorientation of the sugar, together with the induced CD1d fit, may explain the weaker potency of the microbial antigens compared with alpha-GalCer. We propose that the TCR of iNKT cells binds with a conserved footprint onto CD1d, regardless of the bound glycolipid antigen, and that for microbial antigens this unique binding mode requires TCR-initiated conformational changes. PMID- 20921283 TI - Pathogenic virus-specific T cells cause disease during treatment with the calcineurin inhibitor FK506: implications for transplantation. AB - Recently, several cases of fatal lymphocytic choriomeningitis virus (LCMV) infection occurred in transplant recipients being treated with the immunosuppressive calcineurin inhibitor FK506. These findings were surprising because LCMV is a noncytolytic virus. To understand how a noncytolytic virus can cause disease under conditions of immunosuppression, we used the mouse LCMV model and found that, similar to the observations in human transplant recipients, LCMV infection of FK506-treated mice resulted in a lethal disease characterized by viremia, lack of seroconversion, and minimal lymphocytic infiltrates in the tissues. However, despite the apparent absence of an antiviral immune response, this disease was orchestrated by virus-specific T cells. FK506 did not prevent the generation and proliferation of LCMV-specific T cells but instead altered their differentiation so that these effector T cells lost the ability to control virus but were still capable of mediating disease. These pathogenic T cells initiated a cytokine storm characterized by high levels of tumor necrosis factor (TNF) and interleukin 6 (IL-6), and depletion of T cells or blockade of these inflammatory cytokines prevented the lethal disease. Our study shows that inhibiting calcineurin can generate pathogenic T cells and indicates that T cell mediated viral disease can occur even under conditions of immunosuppression. Furthermore, we identify a potential strategy (blockade of TNF and IL-6) for treatment of transplant recipients who have acute complications of viral infection. PMID- 20921282 TI - Macrophage-dependent nitric oxide expression regulates tumor cell detachment and metastasis after IL-2/anti-CD40 immunotherapy. AB - Using an orthotopic model of renal cell carcinoma, we showed previously that IL 2/anti-CD40 immunotherapy resulted in synergistic anti-tumor responses, whereas IL-2 or alpha-CD40 alone mediated partial transient anti-tumor effects. We now show that treatment of tumor-bearing mice with IL-2/alpha-CD40, but not IL-2 or alpha-CD40, induced significant nitric oxide synthase (NOS) 2 expression in tumor associated macrophages. In control-treated mice (low NO), NOS2 inhibition reduced tumor burden. However, during immunotherapy (high NO), NOS2 inhibition or macrophage depletion reversed the ability of IL-2/alpha-CD40 treatment to reduce lung metastases but had no effect on primary tumor burden. Furthermore, IL 2/alpha-CD40 induced the IFN-gamma- and NO-dependent decrease in matrix metalloproteinase (MMP) expression and activity, concomitant with increases in tissue inhibitor of metalloproteinase (TIMP) 1 and E-cadherin expression within tumors. Finally, treatment of tumor-bearing mice with the NO donor JS-K significantly reduced metastases. These data differentiate the mechanism for primary anti-tumor effects of IL-2/alpha-CD40 immunotherapy, which are independent of NO, from the NO-dependent inhibition of metastases. Furthermore, reduced MMP9 activity implicates M1-polarized macrophages within the tumor microenvironment as critical components of therapeutic response. Our data demonstrate the mechanistic basis for IL-2/alpha-CD40-mediated control of metastases and suggest that the context-dependent application of NO donors may hold promise for prevention of metastatic disease. PMID- 20921284 TI - A critical role for regulatory T cell-mediated control of inflammation in the absence of commensal microbiota. AB - Suppression mediated by regulatory T cells (T reg cells) represents a unique, cell-extrinsic mechanism of in-trans negative regulation that restrains multiple types of immune cells. The loss of T reg cells leads to fatal, highly aggressive, and widespread immune-mediated lesions. This severe autoimmunity may be driven by commensal microbiota, the largest source of non-self ligands activating the innate and adaptive immune systems. Alternatively, T reg cells may primarily restrain T cells with a diverse self-major histocompatibility complex (MHC) restricted T cell receptor repertoire independently of commensal microbiota. In this study, we demonstrate that in germ-free (GF) mice, ablation of the otherwise fully functional T reg cells resulted in a systemic autoimmune lympho- and myeloproliferative syndrome and tissue inflammation comparable with those in T reg cell-ablated conventional mice. Importantly, there were two exceptions: in GF mice deprived of T reg cells, the inflammation in the small intestine was delayed, whereas exocrine pancreatitis was markedly accelerated compared with T reg cell-ablated conventional mice. These findings suggest that the main function of T reg cells is restraint of self-MHC-restricted T cell responsiveness, which, regardless of the presence of commensal microbiota, poses a threat of autoimmunity. PMID- 20921285 TI - A requirement for FcgammaR in antibody-mediated bacterial toxin neutralization. AB - One important function of humoral immunity is toxin neutralization. The current view posits that neutralization results from antibody-mediated interference with the binding of toxins to their targets, a phenomenon viewed as dependent only on antibody specificity. To investigate the role of antibody constant region function in toxin neutralization, we generated IgG2a and IgG2b variants of the Bacillus anthracis protective antigen-binding IgG1 monoclonal antibody (mAb) 19D9. These antibodies express identical variable regions and display the same specificity. The efficacy of antibody-mediated neutralization was IgG2a > IgG2b > IgG1, and neutralization activity required competent Fcgamma receptor (FcgammaR). The IgG2a mAb prevented lethal toxin cell killing and mitogen-activated protein kinase/extracellular signal-regulated kinase kinase cleavage more efficiently than the IgG1 mAb. Passive immunization with IgG1 and IgG2a mAb protected wild type mice, but not FcgammaR-deficient mice, against B. anthracis infection. These results establish that constant region isotype influences toxin neutralization efficacy of certain antibodies through a mechanism that requires engagement of FcgammaR. These findings highlight a new parameter for evaluating vaccine responses and the possibility of harnessing optimal FcgammaR interactions in the design of passive immunization strategies. PMID- 20921286 TI - Bystander killing of cancer requires the cooperation of CD4(+) and CD8(+) T cells during the effector phase. AB - Cancers frequently evade cytotoxic T lymphocyte-mediated destruction through loss or down-regulation of tumor antigens and antigen-presenting major histocompatibility complex molecules. Therefore, we have concentrated our efforts on immunological strategies that destroy nonmalignant stromal cells essential for the survival and growth of cancer cells. In this study, we developed a non-T cell receptor transgenic, immunocompetent tumor model to determine whether tumor bearing hosts' own immune systems could eliminate cancer cells through stromal targeting and what role CD4(+) T cells play alongside CD8(+) T cells in this process. We found that aggressive cancers could be eradicated by T cell targeting of tumor stroma. However, successful elimination required the cooperation of CD4(+) and CD8(+) T cells not only during the induction phase but also during the effector phase in the tumor microenvironment, implying a new role for CD4(+) T cells that has not been previously described. Our study demonstrates the potential of stromal targeting as a cancer immunotherapy and suggests that successful anticancer strategies must facilitate cooperation between CD4(+) and CD8(+) T cells at the right times and the right places. PMID- 20921287 TI - A novel subset of CD4(+) T(H)2 memory/effector cells that produce inflammatory IL 17 cytokine and promote the exacerbation of chronic allergic asthma. AB - The inflammatory cytokine interleukin (IL)-17 is involved in the pathogenesis of allergic diseases. However, the identity and functions of IL-17-producing T cells during the pathogenesis of allergic diseases remain unclear. Here, we report a novel subset of T(H)2 memory/effector cells that coexpress the transcription factors GATA3 and RORgammat and coproduce T(H)17 and T(H)2 cytokines. Classical T(H)2 memory/effector cells had the potential to produce IL-17 after stimulation with proinflammatory cytokines IL-1beta, IL-6, and IL-21. The number of IL-17 T(H)2 cells was significantly increased in blood of patients with atopic asthma. In a mouse model of allergic lung diseases, IL-17-producing CD4(+) T(H)2 cells were induced in the inflamed lung and persisted as the dominant IL-17-producing T cell population during the chronic stage of asthma. Treating cultured bronchial epithelial cells with IL-17 plus T(H)2 cytokines induced strong up-regulation of chemokine eotaxin-3, Il8, Mip1b, and Groa gene expression. Compared with classical T(H)17 and T(H)2 cells, antigen-specific IL-17-producing T(H)2 cells induced a profound influx of heterogeneous inflammatory leukocytes and exacerbated asthma. Our findings highlight the plasticity of T(H)2 memory cells and suggest that IL-17-producing T(H)2 cells may represent the key pathogenic T(H)2 cells promoting the exacerbation of allergic asthma. PMID- 20921288 TI - Expanding the ecological validity of WAIS-IV and WMS-IV with the Texas functional living scale. AB - Assessment of functional status is an important aspect of clinical evaluation. As part of the standardization of the Wechsler Adult Intelligence Scale-Fourth Edition (WAIS-IV) and Wechsler Memory Scale-Fourth Edition (WMS-IV), participants completed the Texas Functional Living Scale (TFLS), a measure of Instrumental Activities of Daily Living. The relationships between TFLS and WAIS-IV and WMS-IV were examined in both normally developing and clinical samples. In general, the highest correlations were between TFLS and measures of general cognitive ability (WAIS-IV FSIQ [Full Scale IQ] and GAI [General Ability Index]) and working memory (WAIS-IV WMI [Working Memory Index] and WMS-IV VWMI [Visual Working Memory Index]). Across the clinical populations, working memory subtests were generally strongly related to TFLS performance, although this relationship was more consistent with WAIS-IV than WMS-IV. Contrast scaled scores are presented for the TFLS based on WAIS-IV or WMS-IV performance. These scores allow the evaluation of functional abilities within the context of cognitive and memory ability, enhancing and expanding the utility of the WAIS-IV and WMS-IV. PMID- 20921289 TI - A pilot study on tertiary teledermatology: feasibility and acceptance of telecommunication among dermatologists. AB - Tertiary teledermatology (TTD), where a general dermatologist consults a specialized dermatologist on difficult cases, is a relatively new telemedicine service. We evaluated TTD in a Dutch university hospital, where 13 general dermatologists used TTD to consult 11 specialized dermatologists and two residents at the university medical centre. We measured the avoided referrals to the university centre, the usability of the system and the user acceptance of it. During a three-month study, general dermatologists consulted via TTD 28 times. In 17 of the consultations (61%), the general dermatologists would have referred their patients to the university centre if teledermatology had not been available. Referral was not necessary after teledermatology for 12 of these 17 consultations (71%). The mean usability score (0-100) of all the users was 80. All dermatologists were satisfied with TTD (mean satisfaction of 7.6 on a 10 point scale) and acceptance was high. The baseline measurements showed that half of tertiary referrals were suitable for TTD. These results suggest that TTD reduces unnecessary physical referrals and that users are satisfied with it. A large-scale evaluation is now required. PMID- 20921290 TI - Paediatric health calls to Swedish telenurses: a descriptive study of content and outcome. AB - We collected data about telephone triage calls concerning children in Sweden. A sample of 110 paediatric calls were recorded. The transcribed data were analysed regarding word count, reasons for calling, results of calls, ages and gender of children, and gender of parents. The median call length was 4.4 min and the median child's age was 3.5 years. Mothers made 73% of calls, but mothers and fathers called to the same extent about daughters and sons, and regardless of age. The most common reasons for calls were ear problems, rash/wound or fever. In nearly half the calls, the telenurses provided self-care advice. Call length, word count or caller's part of word count did not differ according to gender of parents or children. However, mothers were more likely to receive self-care advice while fathers were more often referred to other health services by the telenurses. Telenurses might need to improve their gender competence, and more male telenurses in the service would potentially be beneficial to callers. PMID- 20921291 TI - The effect of sevelamer carbonate and lanthanum carbonate on the pharmacokinetics of oral calcitriol. AB - BACKGROUND: Lanthanum carbonate and sevelamer carbonate are non-calcium-based phosphate binders used to manage hyperphosphataemia in patients with chronic kidney disease (CKD). Patients with CKD may require intravenous or oral active vitamin D. We investigated the effects of lanthanum carbonate and sevelamer carbonate on the bioavailability of oral calcitriol. METHODS: This was a three period, crossover study in healthy volunteers. Forty-one individuals were randomized to one of six possible sequences, each consisting of three treatment periods separated by washouts. The treatments were calcitriol (1 MUg at lunch), calcitriol with lanthanum carbonate (3000 mg/day) and calcitriol with sevelamer carbonate (7200 mg/day). Serum calcitriol levels were assessed at baseline and throughout the study. RESULTS: Co-administration of lanthanum carbonate with calcitriol had no significant effect on area under the curve over 48 h (AUC(0 48)) for serum exogenous calcitriol [least-squares (LS) mean, calcitriol with lanthanum carbonate vs calcitriol alone: 429 pg h/mL vs 318 pg h/mL, respectively; P = 0.171]. Similarly, there was no significant effect on maximum concentration (C(max)). In contrast, co-administration with sevelamer was associated with a significant reduction in bioavailability parameters for calcitriol (calcitriol with sevelamer carbonate vs calcitriol alone, LS mean AUC(0-48): 137 pg h/mL vs 318 pg h/mL, respectively; P = 0.024; LS mean C(max): 40.1 pg/mL vs 49.7 pg/mL, respectively; P < 0.001). CONCLUSIONS: Sevelamer carbonate significantly reduces serum concentrations of exogenous calcitriol when administered concomitantly with oral calcitriol, whereas lanthanum carbonate has no significant effect. This should be considered when treating CKD patients who require phosphate binders and oral vitamin D. PMID- 20921292 TI - Aliskiren improves insulin resistance and ameliorates diabetic vascular complications in db/db mice. AB - BACKGROUND: Aliskiren is a direct renin inhibitor (DRI) and provides an organ protective effect in human and animal experiments. However, there is no current evidence of the effect of DRI on insulin resistance and metabolic abnormalities in type 2 diabetic animals. Methods. We investigated the effects and molecular mechanism of aliskiren in db/db mice and cultured mesangial cells (MCs). RESULTS: Aliskiren treatment for 3 months at a dose of 25 mg/kg/day via an osmotic mini pump did not induce significant changes in blood glucose levels, systolic blood pressure, serum creatinine and electrolyte levels. However, aliskiren treatment improved insulin resistance confirmed by insulin tolerance test and various biomarkers including homeostasis model assessment index levels and lipid abnormalities. The treated group also exhibited significant improvement in cardiac functional and morphological abnormalities including left ventricular hypertrophy, and induced phenotypic changes in adipose tissue. Aliskiren treatment also markedly decreased urinary albumin excretion, glomerulosclerosis and suppressed profibrotic and proinflammatory cytokine synthesis and improved renal lipid metabolism. In cultured MCs, high glucose stimulation increased MC renin concentration. Furthermore, renin treatment directly up-regulates synthesis of proinflammatory and profibrotic cytokines, which were abolished by prior treatment with aliskiren and angiotensin receptor (AT1) antagonist. These results suggest that the beneficial effect of aliskiren is mediated by an angiotensin dependent mechanism. CONCLUSIONS: Together, these results imply that aliskiren provides an organ-protective effect through improvement in insulin resistance and lipid abnormality, as well as direct anti-fibrotic effect in target organ in db/db mice. Aliskiren may be a useful new therapeutic agent in the treatment of type 2 diabetes mellitus and diabetic nephropathy. PMID- 20921293 TI - Matrix metalloproteinase levels in the drained dialysate reflect the peritoneal solute transport rate: a multicentre study in Japan. AB - BACKGROUND: Long-term peritoneal dialysis (PD) leads to peritoneal injury with high solute transport of the peritoneal membrane. At worst, peritoneal injury leads to encapsulating peritoneal sclerosis with an extremely high mortality rate. To perform PD safely and adequately, it is necessary to monitor peritoneal injury. The aim of this study was to investigate the potential of matrix metalloproteinases (MMPs) as new indicators of peritoneal injury. METHODS: The subjects included 215 PD patients with end-stage renal disease at 20 centres in Japan. MMPs or tissue inhibitors of MMP (TIMPs) in the drained dialysate were quantified with enzyme-linked immunosorbent assay. The peritoneal solute transport rate was assessed to estimate peritoneal injury and PD efficiency by the peritoneal equilibration test (PET). RESULTS: MMP-2, MMP-3 and TIMP-1 levels in the drained dialysate obtained by the PET were correlated with the D/P Cr ratios (rho = 0.69, rho = 0.52, rho = 0.55, respectively) and the D/D0 glucose ratios (rho = -0.60, rho = -0.47, rho = -0.48, respectively). The measured D/S ratios of MMP-2 and TIMP-1 were significantly higher than the expected D/S ratios when MMP-2 and TIMP-1 would have been transported from only the circulation. The measured D/S ratios of MMP-3 nearly corresponded to the expected ratios. MMP-1 and TIMP-2 in the drainage were undetected in most patients. CONCLUSIONS: From these results, most MMP-2 in the drained dialysate may be produced from the peritoneum, and MMP-2 is expected to be a useful marker of peritoneal injury or change in peritoneal solute transport. PMID- 20921294 TI - An association between depressive symptoms and survival in incident dialysis patients. AB - BACKGROUND: Depression in end-stage renal disease patients is detrimental to quality of life, and is also associated with adverse clinical outcomes. The aim of this study was to examine whether depression symptoms in 'incident dialysis' patients predicted survival. METHODS: One hundred and sixty incident haemodialysis and peritoneal dialysis patients completed a self-report depression questionnaire (Beck Depression Inventory-II, BDI) at a point soon after dialysis initiation. Over the study period (May 2007-December 2009), patients were followed up with all-cause mortality recorded as the end point. RESULTS: The median follow-up time for the cohort was 511 days (min 47 days and max 1027 days). There were 27 deaths (16.9%). Depression symptoms were evaluated both as a continuous variable and using a defined cut-off for depressed patients (BDI >= 16). In a Cox proportional hazards model, adjusted for several covariates including albumin and extra renal comorbidity, depression score was an independent predictor of mortality (HR = 1.07, 95% CI 1.02-1.11, P = 0.002). In an additional adjusted model, a BDI score >= 16 was associated with a 2.7 times increase in the hazard for death (HR = 2.7, 95% CI 1.06-6.8, P = 0.037). CONCLUSIONS: The severity of depression symptoms following the start of dialysis treatment is an independent predictor of survival. Further studies will be required to determine whether the treatment of depression would alter health related outcomes, including survival. PMID- 20921295 TI - Relations between malnutrition-inflammation-atherosclerosis and volume status. The usefulness of bioimpedance analysis in peritoneal dialysis patients. AB - BACKGROUND: Chronic fluid overload (FO) is frequently present in peritoneal dialysis (PD) patients and is associated with hypertension and left ventricular hypertrophy and dysfunction, which are important predictors of death in dialysis patients. In the present study, we investigated the relationship between nutrition, inflammation, atherosclerosis and body fluid volumes measured by multi frequency bioimpedance analysis (m-BIA) in PD patients. In addition, we analysed the relationship of extracellular volume values by m-BIA to echocardiographic parameters in order to define its usefulness as a measure of FO. METHODS: Ninety five prevalent PD patients (mean age 50 +/- 13 years, 10 of them diabetic) were enrolled. Extracellular water (ECW), total body water (TBW), dry lean mass (DLM) and phase angle (PA) were measured by m-BIA. Volume status was determined by measuring left atrium diameter (LAD) and left ventricular end-diastolic diameter (LVEDD). Measurement of carotid artery intima-media thickness (CA-IMT) was used to assess the presence of subclinical atherosclerosis. Serum albumin was used as a nutritional marker, and serum C-reactive protein (CRP) was used as an inflammatory marker. RESULTS: Mean ECW/height was 10.0 +/- 1.0 L/m for whole group and 9.3 +/- 0.6 L/m in patients with normal clinical hydration parameters. In correlation analysis, markers of nutrition, inflammation and atherosclerosis correlated well with m-BIA parameters. When we used echographically measured LAD (> 40 mm) or LVEDD (> 55 mm) as a confirmatory parameter, a cut-off value of 10.48 L/m ECW/height (78% specificity, with a sensitivity of 77% for LAD and 72% specificity, with a sensitivity of 70% for LVEDD) was found in ROC analysis for the diagnosis of FO. Patients with FO were older and had higher systolic blood pressure, cardiothoracic index, serum CRP level and mean CA-IMT than patients without FO. Patients with inflammation had higher CA-IMT values. In multivariate analysis, only two factors-low urine output and ECW/height-were independently associated with the presence of inflammation. CONCLUSIONS: FO defined by m-BIA is significantly correlated with markers of malnutrition, inflammation and atherosclerosis in PD patients. The indices obtained from m-BIA, especially ECW/height, correlated well with volume overload as assessed by echocardiography and might be a measure worth testing in a properly designed clinical study. PMID- 20921296 TI - Comparing automated peritoneal dialysis with continuous ambulatory peritoneal dialysis: survival and quality of life differences? AB - BACKGROUND: There is a wide disparity in the use of automated peritoneal dialysis (APD) or continuous ambulatory peritoneal dialysis (CAPD) in the UK. This may be due to a perceived quality of life and technique survival advantage with APD, although evidence is lacking. METHODS: We conducted a single-centre retrospective study of incident end-stage renal disease initiating APD and CAPD with data collected prospectively over 5 years. PD modality was based on patient preference. Health status was assessed using SF-36 questionnaires at initial and 1-year follow-up appointments. RESULTS: Three hundred and seventy-two patients were included: 194 patients chose APD, and 178 patients chose CAPD. CAPD patients were generally older and more dependent than APD patients. Univariate analysis for technique survival was inferior for CAPD (relative risk for failure 1.46, 95% CI 1.08-1.97). But on multivariate analysis when comorbidity was added into the model, PD modality was no longer a significant predictor of technique survival. There was no difference in decline in residual renal function. Baseline CAPD patients had worse health status (HS); mean (SEM) physical and social composite scores were 32.3 (0.9) vs 36.5 (0.9) and 33.3 (1.2) vs 40.3 (1.2). After 1 year, HS scores for CAPD and APD patients were similar, but the improvement in HS scores correlated with baseline scores (PD modality was not an independent predictor of the change in HS). CONCLUSIONS: This study did not show any advantages of APD over CAPD in terms of technique survival or HS. There is no evidence to support physician bias towards one PD modality, and both should be available to allow patient choice. PMID- 20921297 TI - Fresh and cryopreserved, uncultured adipose tissue-derived stem and regenerative cells ameliorate ischemia-reperfusion-induced acute kidney injury. AB - BACKGROUND: Acute kidney injury (AKI) represents a major clinical problem with high mortality and limited causal treatments. The use of cell therapy has been suggested as a potential modality to improve the course and outcome of AKI. METHODS: We investigated the possible renoprotection of freshly isolated, uncultured adipose tissue-derived stem and regenerative cells (ADRCs) before and after cryopreservation in a rat ischemia-reperfusion (I-R) model of AKI. RESULTS: We demonstrated that ADRC therapy drastically reduced mortality (survival 100% vs. 57%, ADRC vs. controls, respectively) and significantly reduced serum creatinine (sCr on Day 3: 3.03 +/- 1.58 vs. 7.37 +/- 2.32 mg/dL, ADRC vs. controls, respectively). Histological analysis further validated a significantly reduced intratubular cast formation, ameliorated acute tubular epithelial cell necrosis and mitigated macrophage infiltration. Furthermore, a reduced RNA expression of CXCL2 and IL-6 was found in the ADRC group which could explain the reduced macrophage recruitment. Use of cryopreserved ADRCs resulted in an equally high survival (90% vs. 33% in the control group) and similarly improved renal function (sCr on Day 3: 4.64 +/- 2.43 vs. 7.24 +/- 1.40 mg/dL in controls). CONCLUSIONS: Collectively, these results suggest a potential clinical role for ADRC therapy in patients with AKI. Importantly, cryopreservation of ADRCs could offer an autologous treatment strategy for patients who are at high risk for AKI during planned interventions. PMID- 20921300 TI - Gastric bypass in patients with chronic kidney disease. PMID- 20921298 TI - Chronic kidney disease and 1-year survival in elderly patients discharged from acute care hospitals: a comparison of three glomerular filtration rate equations. AB - BACKGROUND: Glomerular filtration rate (GFR) is directly associated with survival. However, the prognostic significance of GFR might be different according to the formula used to estimate it. We aimed at comparing the association between GFR estimated using three different formulas and 1-year survival in elderly patients discharged from acute care hospitals. METHODS: Our series consisted of 439 patients aged 65 and older admitted to 11 acute care medical wards enrolled in a multicentre prospective observational study. GFR was estimated by body surface area-adjusted Cockcroft-Gault (CG-BSA), Modification of Diet in Renal Disease study (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formulas. The relative risk of mortality in patients with estimated GFR = 30-59.9 or < 30 mL/min/1.73 m(2) compared to people with estimated GFR >= 60 mL/min/1.73 m(2) was calculated using Cox regression analysis. RESULTS: Participants with reduced GFR showed an increased mortality, regardless of the equation used, and the highest one was associated with CG-BSA estimated GFR < 30 mL/min/1.73 m(2). After adjusting for potential confounders, CKD-EPI-estimated GFR remained significantly associated with the outcome [30-59.9 mL/min/1.73 m(2), hazard ratio (HR) = 1.70, 95% confidence interval (95% CI) = 1.02-2.98; < 30 mL/min/1.73 m(2), HR = 2.60, 95% CI = 1.20-5.66], while the strength of the association was clearly reduced for MDRD (30-59.9 mL/min/1.73 m(2), HR = 1.47, 95% CI = 0.83-2.38; < 30 mL/min/1.73 m(2), HR = 2.07, 95% CI = 1.01-4.30) and CG-BSA (30-59.9 mL/min/1.73 m(2), HR = 1.79, 95% CI = 0.67-4.53; < 30 mL/min/1.73 m(2), HR = 2.68, 95% CI = 0.92-7.55). CONCLUSION: GFR adds to the list of prognostic indicators in elderly and frail people, and CKD-EPI-derived GFR, which outperforms to some extent MDRD and CG-BSA-derived GFR in a multivariable predictive model, seems worthy of testing in wider populations. PMID- 20921301 TI - Elevated salivary potassium in paediatric CKD patients, a novel excretion pathway. AB - BACKGROUND: Hyperkalaemia is one of the complications of chronic renal failure. Gastrointestinal excretion and cellular uptake are two adaptive mechanisms for extra-renal potassium (K) disposal in these patients. The salivary glands' secretion system can actively excrete K into the oral cavity. METHODS: We examined salivary K levels in four groups of paediatric chronic kidney disease (CKD) patients: 25 pre-dialytic (PreD) patients, 18 patients on maintenance dialysis (D), and 31 transplanted patients with a functioning graft (T), compared with 32 healthy children (C). RESULTS: Salivary K levels were significantly higher in the D and PreD groups than the C group (P = 0.03 and P = 0.0004, respectively). Interestingly, a significant negative correlation was found between glomerular filtration rate and salivary K in PreD and T patients. CONCLUSIONS: We suggest an extension of the gastrointestinal adaptive K pathway via salivary gland secretion in patients suffering from hyperkalaemia. PMID- 20921302 TI - Fractional excretions of albumin and IgG are the best predictors of progression in primary glomerulonephritis. AB - BACKGROUND: Proteinuria is the most sensitive predictor of development of progressive renal insufficiency, with increasing focus on the composition of proteinuria, particularly high molecular weight proteins such as immunoglobulin G (IgG) (molecular weight 150 kDa). Differing methods of assessing excretion of proteinuria molecules have limited interpretation of results. We aimed to assess the utility of available indices of IgG, total proteinuria and albumin excretions as predictors of chronic kidney disease (CKD) progression in patients with primary glomerulonephritis. METHODS: We recruited 97 patients with primary glomerulonephritis and measured 24-h urinary protein excretion, 24-h urinary albumin excretion, selectivity index, albumin:creatinine ratio, urinary IgG:creatinine ratio, fractional excretion of albumin (FE Alb) and fractional excretion of IgG (FE IgG) at baseline. The composite endpoint was developing stage 5 CKD, requiring RRT or death. Receiver operating characteristics curve analysis was used to assess the value of each measure in predicting outcome. From this analysis, high- and low-risk patient groups according to each measure were established. These were then tested using Kaplan-Meier and Cox survival analysis. RESULTS: During a median follow-up of 7.07 years, 23 patients developed the primary endpoint. FE IgG and FE Alb were the most sensitive predictive tests. The hazard ratios (HR) of developing the primary endpoint using FE IgG [HR 37.1 (95% CI 8.6-158.8)] and FE Alb [HR 35.2 (95% CI 8.2-150.8)] cut-offs were double those using the other measures. CONCLUSIONS: FE IgG and FE Alb are superior to conventional measures of proteinuria in predicting outcome in patients with primary glomerulonephritis, possibly because they are more accurate indicators of impairment of glomerular permselectivity. FE Alb should be used, in conjunction with other measures of proteinuria, in future studies of prediction of CKD progression. PMID- 20921303 TI - Pregnancy decreases rat CYP1A2 activity and expression. AB - Pregnancy results in increased CYP3A- and CYP2D6-mediated clearance but decreases the clearance of CYP1A2 probe drugs. The aim of this study was to determine whether the decreased CYP1A2 activity during human pregnancy could be explained by decreased expression of CYP1A2 protein and mRNA using the rat as a model. Potential mechanisms leading to decreased CYP1A2 activity and expression were also investigated. Hepatic CYP1A2 activity, protein, and mRNA were measured during mid- and late gestation and compared to nonpregnant control levels. In addition, the effect of 17-beta-estradiol and progesterone on CYP1A2 mRNA levels was assessed using rat hepatocytes, and the effect of estrogens or progesterone on CYP1A2 activity in vitro was tested. CYP1A2-mediated probe clearance decreased between 48 and 62% (p < 0.05) during pregnancy, with no difference in CYP1A2 activity between mid- and late pregnancy. This decrease in probe clearance was accompanied by a 33 +/- 8% (midpregnancy) and 29 +/- 27% (late pregnancy) decrease in CYP1A2 protein expression (p < 0.05) and a 53% decline in methoxyresorufin O-demethylation V(max) (p < 0.05). CYP1A2 mRNA was not significantly different from controls at midpregnancy and decreased by 27 +/- 20% (p < 0.05) of control during late pregnancy. Estradiol and progesterone had no effect on CYP1A2 mRNA in rat hepatocytes and did not inhibit CYP1A2 activity. These data demonstrate that pregnancy decreases CYP1A2 activity and expression with a modest effect on CYP1A2 mRNA and suggest that the rat can be used as a model to study mechanisms by which pregnancy decreases CYP1A2 activity in humans. PMID- 20921304 TI - Mechanism of antifungal activity of terpenoid phenols resembles calcium stress and inhibition of the TOR pathway. AB - Terpenoid phenols, including carvacrol, are components of oregano and other plant essential oils that exhibit potent antifungal activity against a wide range of pathogens, including Candida albicans, Staphylococcus aureus, and Pseudomonas aeruginosa. To gain a mechanistic view of the cellular response to terpenoid phenols, we used Saccharomyces cerevisiae as a model organism and monitored temporal changes in metabolic activity, cytosolic and vacuolar pH, and Ca(2+) transients. Using a panel of related compounds, we observed dose-dependent Ca(2+) bursts that correlated with antifungal efficacy. Changes in pH were long lasting and followed the Ca(2+) transients. A vma mutant lacking functional vacuolar H(+) ATPase (V-ATPase) and defective in ion homeostasis was hypersensitive to carvacrol toxicity, consistent with a role for ionic disruptions in mediating cell death. Genomic profiling within 15 min of exposure revealed a robust transcriptional response to carvacrol, closely resembling that of calcium stress. Genes involved in alternate metabolic and energy pathways, stress response, autophagy, and drug efflux were prominently upregulated, whereas repressed genes mediated ribosome biogenesis and RNA metabolism. These responses were strongly reminiscent of the effects of rapamycin, the inhibitor of the TOR pathway of nutrient sensing. The results point to the activation of specific signaling pathways downstream of cellular interaction with carvacrol rather than a nonspecific lesion of membranes, as has been previously proposed. PMID- 20921305 TI - Testing nucleoside analogues as inhibitors of Bacillus anthracis spore germination in vitro and in macrophage cell culture. AB - Bacillus anthracis, the etiological agent of anthrax, has a dormant stage in its life cycle known as the endospore. When conditions become favorable, spores germinate and transform into vegetative bacteria. In inhalational anthrax, the most fatal manifestation of the disease, spores enter the organism through the respiratory tract and germinate in phagosomes of alveolar macrophages. Germinated cells can then produce toxins and establish infection. Thus, germination is a crucial step for the initiation of pathogenesis. B. anthracis spore germination is activated by a wide variety of amino acids and purine nucleosides. Inosine and l-alanine are the two most potent nutrient germinants in vitro. Recent studies have shown that germination can be hindered by isomers or structural analogues of germinants. 6-Thioguanosine (6-TG), a guanosine analogue, is able to inhibit germination and prevent B. anthracis toxin-mediated necrosis in murine macrophages. In this study, we screened 46 different nucleoside analogues as activators or inhibitors of B. anthracis spore germination in vitro. These compounds were also tested for their ability to protect the macrophage cell line J774a.1 from B. anthracis cytotoxicity. Structure-activity relationship analysis of activators and inhibitors clarified the binding mechanisms of nucleosides to B. anthracis spores. In contrast, no structure-activity relationships were apparent for compounds that protected macrophages from B. anthracis-mediated killing. However, multiple inhibitors additively protected macrophages from B. anthracis. PMID- 20921306 TI - In vivo selection of a missense mutation in adeR and conversion of the novel blaOXA-164 gene into blaOXA-58 in carbapenem-resistant Acinetobacter baumannii isolates from a hospitalized patient. AB - The mechanism of stepwise acquired multidrug resistance in Acinetobacter baumannii isolates from a hospitalized patient was investigated. Thirteen consecutive multidrug-resistant isolates were recovered from the same patient over a 2-month period. The Vitek 2 system identified the isolates as meropenem sensitive Acinetobacter lwoffii; however, molecular identification showed that the isolates were A. baumannii. Etest revealed that the isolates were meropenem resistant. The presence of oxacillinase (OXA)-type enzymes were investigated by sequencing. The clonal relatedness of isolates was assessed by pulsed-field gel electrophoresis (PFGE). Expression of the genes encoding the efflux pumps AdeB and AdeJ was performed by semiquantitative real-time reverse transcription-PCR (qRT-PCR). The adeRS two-component system was sequenced. All isolates had identical PFGE fingerprints, suggesting clonal identity. The first six isolates were positive for the novel bla(OXA-164) gene. The following seven isolates, recovered after treatment with a combination of meropenem, amikacin, ciprofloxacin, and co-trimoxazole showed an increase of >7-fold in adeB mRNA transcripts and a missense mutation in bla(OXA-164), converting it to bla(OXA 58). Sequencing revealed a novel mutation in adeR. These data illustrate how A. baumannii can adapt during antimicrobial therapy, leading to increased antimicrobial resistance. PMID- 20921307 TI - Population pharmacokinetic modeling of the association between 63396C->T pregnane X receptor polymorphism and unboosted atazanavir clearance. AB - Atazanavir (ATV) plasma concentrations are influenced by CYP3A4 and ABCB1, which are regulated by the pregnane X receptor (PXR; NR1I2). PXR expression is correlated with CYP3A4 in liver in the absence of enzyme inducers. The PXR single nucleotide polymorphism (SNP) 63396C->T (rs2472677) alters PXR expression and CYP3A4 activity in vitro, and we previously showed an association of this polymorphism with unboosted ATV plasma concentrations. The aim of this study was to develop a population pharmacokinetic analysis to quantify the impact of 63396C >T and diurnal variation on ATV clearance. A population analysis was performed with 323 plasma samples from 182 randomly selected patients receiving unboosted ATV. Two hundred fifty-nine of the blood samples were collected at random time points, and 11 patients had a full concentration-time profile at steady state. Nonlinear mixed effects modeling was applied to explore the effects of PXR 63396C >T, patient demographics, and diurnal variation. A one-compartment model with first-order absorption and lag time best described the data. Population clearance was 19.7 liters/h with interpatient variability or coefficient of variation (CV) of 21.5%. Homozygosity for the T allele for PXR 63396 was associated with a 17.0% higher clearance that was statistically significant. Evening dosing was associated with 34% higher bioavailability than morning dosing. Patient demographic factors had no effect on ATV clearance. These data show an association of PXR 63396C->T and diurnal variation on unboosted ATV clearance. The association is likely to be mediated through an effect on hepatic PXR expression and therefore expression of its target genes (e.g., CYP3A4, SLCO1B1, and ABCB1), which are known to be involved in ATV clearance. PMID- 20921308 TI - In vitro evaluation of viability, integrity, and inflammation in genital epithelia upon exposure to pharmaceutical excipients and candidate microbicides. AB - The use of microbicides is a promising approach for the prevention of HIV-1 transmission. Unfortunately, various candidates failed in clinical trials. In some cases, the candidate microbicide even resulted in enhanced virus transmission. Therefore, there is an urgent need to develop more predictive preclinical strategies to anticipate the in vivo efficiency/toxicity rate, including in vitro assays that evaluate effects on epithelial integrity and inflammation. The present study aims to identify potential safety issues concerning the use of microbicides and excipients commonly used in vaginal microbicide preparations. The toxicities of various active pharmaceutical ingredients (APIs; TMC-120, UC-781, tenofovir [PMPA], PRO-2000, and glycerol monolaurate [GML]) and excipients (preservatives, cosolvents, surfactants, and cyclodextrins) were evaluated using an in vitro dual-chamber model and uterine cervical explants. Epithelial viability and permeation of fluorescent virus-sized beads, as well as induction of interleukin-8 (IL-8; as a sensitive marker of an inflammatory response), were assessed. Surprisingly, cell viability and epithelial layer integrity were compromised by most excipients at concentrations near the typical concentration used in vaginal gels, and a significant increase in the production of IL-8 was observed at subtoxic concentrations. Within the APIs, TMC-120, UC-781, and PMPA showed higher selectivity indices than PRO-2000 and GML. In conclusion, identification of safety issues concerning the use of pharmaceutical excipients could help to formulate less toxic vaginal microbicide preparations. PMID- 20921309 TI - Rv1218c, an ABC transporter of Mycobacterium tuberculosis with implications in drug discovery. AB - Efflux systems are important in determining the efficacy of antibiotics used in the treatment of bacterial infections. In the last decade much attention has been paid to studying the efflux pumps of mycobacteria. New classes of compounds are under investigation for development into potential candidate drugs for the treatment of tuberculosis. Quite often, these have poor bactericidal activities but exhibit excellent target (biochemical) inhibition. Microarray studies conducted in our laboratories for deciphering the mode of action of experimental drugs revealed the presence of putative ABC transporters. Among these transporters, Rv1218c was chosen for studying its physiological relevance in mediating efflux in Mycobacterium tuberculosis. A DeltaRv1218c mutant of M. tuberculosis displayed a 4- to 8-fold increase in the inhibitory and bactericidal potency for different classes of compounds. The MICs and MBCs were reversed to wild-type values when the full-length Rv1218c gene was reintroduced into the DeltaRv1218c mutant on a multicopy plasmid. Most of the compound classes had significantly better bactericidal activity in the DeltaRv1218c mutant than in the wild-type H37Rv, suggesting the involvement of Rv1218c gene product in effluxing these compounds from M. tuberculosis. The implication of these findings on tuberculosis drug discovery is discussed. PMID- 20921310 TI - Efficacy of a doxycycline treatment regimen initiated during three different phases of experimental ehrlichiosis. AB - Doxycycline is the treatment of choice for canine monocytic ehrlichiosis (CME), a well-characterized disease and valuable model for tick-borne zoonoses. Conflicting reports of clearance of Ehrlichia canis after treatment with doxycycline suggested that the disease phase during which treatment is initiated influences outcomes of these treatments. The purpose of this study was to evaluate the efficacy of a 28-day doxycycline regimen for clearance of experimental E. canis infections from dogs treated during three phases of the disease. Ten dogs were inoculated with blood from E. canis carriers and treated with doxycycline during acute, subclinical, or chronic phases of CME. Daily rectal temperatures and semiweekly blood samples were monitored from each dog, and Rhipicephalus sanguineus ticks were acquisition fed on each dog for xenodiagnosis. Blood collected from dogs treated during acute or subclinical CME became PCR negative for E. canis as clinical parameters improved, but blood samples collected from dogs treated during chronic CME remained intermittently PCR positive. R. sanguineus ticks fed on dogs after doxycycline treatments became PCR positive for E. canis, regardless of when treatment was initiated. However, fewer ticks became PCR positive after feeding on two persistently infected dogs treated with doxycycline followed by rifampin, suggesting that antibiotic therapy can reduce tick acquisition of E. canis. PMID- 20921311 TI - In vivo pharmacodynamic activity of tomopenem (formerly CS-023) against Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus in a murine thigh infection model. AB - Tomopenem (formerly CS-023) is a novel carbapenem with broad-spectrum activities against diverse hospital pathogens, including Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus (MRSA). We examined the in vivo pharmacodynamic characteristics of tomopenem against P. aeruginosa and MRSA by using a neutropenic murine thigh infection model with P. aeruginosa 12467 (MIC, 1 MUg/ml) and MRSA 12372 (MIC, 2 MUg/ml). The mice had 10(6) to 10(7) CFU/thigh of each strain 2 h after inoculation and were treated for 24 h with a fractionated administration of tomopenem given at intervals of 3, 6, 12, and 24 h. The serum protein binding of tomopenem was 17.4%. The efficacy of tomopenem in both infection models was enhanced by frequent dosing, which indicates that the efficacy is driven by the time above MIC (T(MIC)). In a sigmoid model, the cumulative percentages of the 24-h period that the concentrations of free, unbound fractions of the drug exceeded the MIC under steady-state pharmacokinetic conditions (f%T(MIC)s) were best correlated with efficacy when R(2) was 0.79 and 0.86 against P. aeruginosa and MRSA, respectively. Other pharmacokinetic and pharmacodynamic (PK-PD) indexes for the free, unbound fractions, the area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC/MIC) and the maximum concentration of the drug in serum divided by the MIC (C(max)/MIC), showed poor correlation with efficacy when R(2) was <=0.42. The f%T(MIC) values required for a static effect, 1-log kill, and 2-log kill against P. aeruginosa were 29, 39, and 51, respectively, which were similar to those for meropenem, for which the values were 24, 33, and 45, respectively. Against MRSA, the values for tomopenem were 27, 35, and 47. In conclusion, the pharmacodynamic characteristics of tomopenem were similar to those of meropenem against P. aeruginosa, and there was no difference between the target values for P. aeruginosa and MRSA required for efficacy in this study. PMID- 20921312 TI - Tissue penetration and pharmacokinetics of tigecycline in diabetic patients with chronic wound infections described by using in vivo microdialysis. AB - Tissue penetration of systemic antibiotics is an important consideration for positive outcomes in diabetic patients. Herein we describe the exposure profile and penetration of tigecycline in the interstitial fluid of wound margins versus that of uninfected thigh tissue in 8 adult diabetic patients intravenously (IV) administered 100 mg and then 50 mg of tigecycline twice daily for 3 to 5 doses. Prior to administration of the first dose, 2 microdialysis catheters were inserted into the subcutaneous tissue, the first within 10 cm of the wound margin and the second in the thigh of the same extremity. Samples for determination of plasma and tissue concentrations were simultaneously collected over 12 h under steady-state conditions. Tissue concentrations were corrected for percent in vivo recovery by the retrodialysis technique. Plasma samples were also collected for determination of protein binding at 1, 6, and 12 h postdose for each patient. Protein binding data were corrected using a fitted polynomial equation. The mean patient weight was 95.1 kg (range, 63.6 to 149.2 kg), the mean patient age was 63.5 +/- 9.4 years, and 75% of the patients were males. The mean values for the plasma, thigh, and wound free area under the concentration-time curve from 0 to 24 h (fAUC(0-24)) were 2.65 +/- 0.33, 2.52 +/- 1.15, and 2.60 +/- 1.02 MUg.h/ml, respectively. Protein binding was nonlinear, with the percentage of free drug increasing with decreasing serum concentrations. Exposure values for thigh tissue and wound tissue were similar (P = 0.986). Mean steady-state tissue concentrations for the thigh and wound were similar at 0.12 +/- 0.02 MUg/ml, and clearance from the tissues appeared similar to that from plasma. Tissue penetration ratios (tissue fAUC/plasma fAUC) were 99% in the thigh and 100% in the wound (P = 0.964). Tigecycline penetrated equally well into wound and uninfected tissue of the same extremity. PMID- 20921313 TI - Effect of antacids on the pharmacokinetics of raltegravir in human immunodeficiency virus-seronegative volunteers. AB - Raltegravir's divalent metal ion chelating motif may predispose the drug to interactions with divalent cations. We determined whether a divalent cation containing antacid interacted with raltegravir. Twelve HIV-1-seronegative subjects were enrolled in this randomized, prospective, crossover study of single dose raltegravir (400 mg) with and without an antacid. Subjects underwent two intensive pharmacokinetic visits in the fasted state separated by a 5- to 12-day washout period. With simultaneous antacid administration, time to peak raltegravir concentration occurred 2 h sooner (P = 0.002) and there was a 67% lower raltegravir concentration at 12 h postdose (P < 0.0001) than with administration of raltegravir alone. The raltegravir area under the-concentration time curve from 0 to 12 h and maximum concentration were unchanged with the addition of an antacid. Studies are needed to determine the clinical relevance of this interaction, whether it remains after multiple dosing to steady state, whether it is mitigated by temporal separation, and whether raltegravir interacts with divalent cation-containing vitamins, supplements, or foods. PMID- 20921314 TI - Serotype distribution and susceptibility of Streptococcus pneumoniae isolates from pleural fluid in Spain from 1997 to 2008. AB - Trends in serotype incidence and susceptibility (1997 to 2008) of Spanish Streptococcus pneumoniae pleural isolates (n = 831) were explored. Penicillin (oral) nonsusceptibility rates and the incidence of 7-valent pneumococcal conjugate vaccine (PCV-7) serotypes showed decreasing trends (R(2) >= 0.600; P <= 0.002). The incidence of serotypes 1 and 19A showed increasing trends (R(2) >= 0.759; P < 0.001), with no trends for serotype 3. Serotypes 19A, 1, and 3 represented 85% of pediatric isolates in 2008. In serotype 19A, the penicillin nonsusceptibility rate was 82.4% in 2008, associated with amoxicillin and cefotaxime nonsusceptibility in 21.4% of isolates. Inclusion of these serotypes in new vaccines offers the broadest coverage. PMID- 20921315 TI - Tigecycline population pharmacokinetics in patients with community- or hospital acquired pneumonia. AB - Tigecycline is a new-generation of tetracycline (glycylcyclines) and is active in vitro against bacteria that possess any of the classical genes that confer tetracycline resistance through ribosomal protection or efflux pumps. Herein, tigecycline disposition in patients with community- or hospital-acquired pneumonia was described using a population pharmacokinetic model. Additionally, the influence of covariates, such as body surface area, severity of illness, and clinical laboratory measures, on tigecycline disposition was evaluated. An intravenous loading dose of 100 mg was followed by 50 mg of tigecycline every 12 h. The final population pharmacokinetic model was a two-compartment model with linear elimination and with a relationship between tigecycline clearance and body surface area and creatinine clearance. The model was parameterized using total clearance (CL), the volume of the central compartment, distributional clearance from the central to the peripheral compartment, and volumes of distribution at steady state. Relationships between body surface area and creatinine clearance were identified as significant predictors of interindividual variability on CL. This model will serve as the basis for estimating tigecycline exposure for pharmacokinetic-pharmacodynamic analyses for efficacy and safety among patients with community- or hospital-acquired pneumonia. PMID- 20921316 TI - Mechanistic studies of the inactivation of TEM-1 and P99 by NXL104, a novel non beta-lactam beta-lactamase inhibitor. AB - NXL104 is a potent inhibitor of class A and C serine beta-lactamases, including KPC carbapenemases. Native and NXL104-inhibited TEM-1 and P99 beta-lactamases analyzed by liquid chromatography-electrospray ionization-time of flight mass spectrometry revealed that the inactivated enzymes formed a covalent adduct with NXL104. The principal inhibitory characteristics of NXL104 against TEM-1 and P99 beta-lactamases were determined, including partition ratios, dissociation constants (K), rate constants for deactivation (k(2)), and reactivation rates. NXL104 is a potent inhibitor of TEM-1 and P99, characterized by high carbamylation efficiencies (k(2)/K of 3.7 * 10(5) M(-1) s(-1) for TEM-1 and 1 * 10(4) M(-1) s(-1) for P99) and slow decarbamylation. Complete loss of beta lactamase activity was obtained at a 1/1 enzyme/NXL104 ratio, with a k(3) value (rate constant for formation of product and free enzyme) close to zero for TEM-1 and P99. Fifty percent inhibitory concentrations (IC(50)s) were evaluated on selected beta-lactamases, and NXL104 was shown to be a very potent inhibitor of class A and C beta-lactamases. IC(50)s obtained with NXL104 (from 3 nM to 170 nM) were globally comparable on the beta-lactamases CTX-M-15 and SHV-4 with those obtained with the comparators (clavulanate, tazobactam, and sulbactam) but were far lower on TEM-1, KPC-2, P99, and AmpC than those of the comparators. In-depth studies on TEM-1 and P99 demonstrated that NXL104 had a comparable or better affinity and inactivation rate than clavulanate and tazobactam and in all cases an improved stability of the covalent enzyme/inhibitor complex. PMID- 20921318 TI - Novel daptomycin combinations against daptomycin-nonsusceptible methicillin resistant Staphylococcus aureus in an in vitro model of simulated endocardial vegetations. AB - Reduced susceptibility to daptomycin has been reported in patients with infections due to methicillin-resistant Staphylococcus aureus (MRSA). Although infections with daptomycin-nonsusceptible (DNS) MRSA are infrequent, optimal therapy of these strains has not been determined. We investigated the killing effects of novel antibiotic combinations with daptomycin (DAP) against two clinical DNS MRSA isolates (SA-684 and R6003) in a 72-h in vitro pharmacokinetic/pharmacodynamic (PK/PD) model with simulated endocardial vegetations (SEV). Simulated regimens included DAP at 6 mg/kg every 24 h (q24h) alone or in combination with trimethoprim-sulfamethoxazole (TMP/SMX) at 160/800 mg q12h, linezolid (LIN) at 600 mg q12h, cefepime (CEF) at 2 g q12h, and nafcillin (NAF) at 4 g q4h. Bactericidal activity was defined as a >=3-log(10) CFU/g kill. Differences in CFU/g were evaluated between 4 and 72 h by analysis of variance with the Bonferroni post hoc test. DAP MICs were 4 and 2 mg/liter for SA 684 and R6003, respectively. In the PK/PD model, DAP alone was slowly bactericidal, achieving a 3-log(10) kill at 24 and 50 h for SA-684 and R6003, respectively. Against SA-684, DAP plus TMP/SMX, CEF, LIN, or NAF was bactericidal at 4, 4, 8, and 8 h, respectively, and maintained this activity for the 72-h study duration. DAP plus TMP/SMX or CEF exhibited superior killing than DAP alone against SA-684 between 4 and 72 h, and overall this was significant (P < 0.05). Against R6003, DAP plus TMP/SMX was bactericidal (8 h) and superior to DAP alone between 8 and 72 h (P < 0.001). The unique combination of DAP plus TMP/SMX was the most effective and rapidly bactericidal regimen against the two isolates tested and may provide a clinical option to treat DNS S. aureus infections. PMID- 20921317 TI - Identification and characterization of the multidrug resistance gene cfr in a Panton-Valentine leukocidin-positive sequence type 8 methicillin-resistant Staphylococcus aureus IVa (USA300) isolate. AB - The staphylococcal cfr gene mediates resistance to phenicols, lincosamides, oxazolidinones, pleuromutilins, and streptogramin A, a phenotype that has been termed PhLOPS(A). The cfr gene has mainly been associated with coagulase-negative staphylococcal isolates from animals, and only a few cfr-positive methicillin resistant Staphylococcus aureus (MRSA) isolates have been described so far. This study reports the first description of a cfr-positive MRSA isolate (M05/0060) belonging to the pandemic Panton-Valentine leukocidin (PVL)-positive sequence type 8 MRSA IVa/USA300 (ST8-MRSA-IVa/USA300) clone. The cfr gene was detected in M05/0060 using a DNA microarray which was used to screen PVL-positive MRSA isolates for the presence of virulence genes, typing markers, and antimicrobial resistance genes. Antimicrobial susceptibility testing revealed that M05/0060 exhibited the cfr-associated resistance phenotype. Molecular analysis identified the presence of cfr and a second phenicol resistance gene, fexA, on a novel 45-kb conjugative plasmid, which was designated pSCFS7. Within pSCFS7, a DNA segment consisting of cfr, a truncated copy of insertion sequence IS21-558, and a region with homology to the DNA invertase gene bin3 of transposon Tn552 from Bacillus mycoides was integrated into the transposase gene tnpB of the fexA-carrying transposon Tn558. The emergence of a multidrug-resistant cfr-positive variant of ST8-MRSA-IVa/USA300 is alarming and requires ongoing surveillance. Moreover, the identification of a novel conjugative plasmid carrying the cfr gene indicates the ability of cfr to spread to other MRSA strains. PMID- 20921319 TI - Photolysis of hydrogen peroxide, an effective disinfection system via hydroxyl radical formation. AB - The relationship between the amount of hydroxyl radicals generated by photolysis of H(2)O(2) and bactericidal activity was examined. H(2)O(2) (1 M) was irradiated with laser light at a wavelength of 405 nm to generate hydroxyl radicals. Electron spin resonance spin trapping analysis showed that the amount of hydroxyl radicals produced increased with the irradiation time. Four species of pathogenic oral bacteria, Staphylococcus aureus, Aggregatibacter actinomycetemcomitans, Streptococcus mutans, and Enterococcus faecalis, were used in the bactericidal assay. S. mutans in a model biofilm was also examined. Laser irradiation of suspensions in 1 M H(2)O(2) resulted in a >99.99% reduction of the viable counts of each of the test species within 3 min of treatment. Treatment of S. mutans in a biofilm resulted in a >99.999% reduction of viable counts within 3 min. Other results demonstrated that the bactericidal activity was dependent on the amount of hydroxyl radicals generated. Treatment of bacteria with 200 to 300 MUM hydroxyl radicals would result in reductions of viable counts of >99.99%. PMID- 20921320 TI - Ultra-performance liquid chromatography mass spectrometry and sensitive bioassay methods for quantification of posaconazole plasma concentrations after oral dosing. AB - Posaconazole (POS) is a new antifungal agent for prevention and therapy of mycoses in immunocompromised patients. Variable POS pharmacokinetics after oral dosing may influence efficacy: a trough threshold of 0.5 MUg/ml has been recently proposed. Measurement of POS plasma concentrations by complex chromatographic techniques may thus contribute to optimize prevention and management of life threatening infections. No microbiological analytical method is available. The objective of this study was to develop and validate a new simplified ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method and a sensitive bioassay for quantification of POS over the clinical plasma concentration range. The UPLC-MS/MS equipment consisted of a triple quadrupole mass spectrometer, an electrospray ionization (ESI) source, and a C(18) analytical column. The Candida albicans POS-hypersusceptible mutant (MIC of 0.002 MUg/ml) Deltacdr1 Deltacdr2 Deltaflu Deltamdr1 Deltacan constructed by targeted deletion of multidrug efflux transporters and calcineurin genes was used for the bioassay. POS was extracted from plasma by protein precipitation with acetonitrile-methanol (75%/25%, vol/vol). Reproducible standard curves were obtained over the range 0.014 to 12 (UPLC-MS/MS) and 0.028 to 12 MUg/ml (bioassay). Intra- and interrun accuracy levels were 106% +/- 2% and 103% +/- 4% for UPLC-MS/MS and 102% +/- 8% and 104% +/- 1% for bioassay, respectively. The intra- and interrun coefficients of variation were 7% +/- 4% and 7% +/- 3% for UPLC-MS/MS and 5% +/- 3% and 4% +/- 2% for bioassay, respectively. An excellent correlation between POS plasma concentrations measured by UPLC-MS/MS and bioassay was found (concordance, 0.96). In 26 hemato-oncological patients receiving oral POS, 27/69 (39%) trough plasma concentrations were lower than 0.5 MUg/ml. The UPLC-MS/MS method and sensitive bioassay offer alternative tools for accurate and precise quantification of the plasma concentrations in patients receiving oral posaconazole. PMID- 20921321 TI - Efficacy of usual and high doses of daptomycin in combination with rifampin versus alternative therapies in experimental foreign-body infection by methicillin-resistant Staphylococcus aureus. AB - The treatment of prosthetic joint infections caused by methicillin-resistant Staphylococcus aureus (MRSA) continues to be a challenge for the clinician. The aim of this study was to evaluate the efficacies of daptomycin at usual and high doses (equivalent to 6 and 10 mg/kg of body weight/day, respectively, in humans) and in combination with rifampin and to compare the activities to those of conventional anti-MRSA therapies. We used MRSA strain HUSA 304, with the following MICs and minimal bactericidal concentrations (MBCs), respectively: daptomycin, 1 MUg/ml and 4 MUg/ml; vancomycin, 2 MUg/ml and 4 MUg/ml; linezolid, 2 MUg/ml and >32 MUg/ml; and rifampin, 0.03 MUg/ml and 0.5 MUg/ml. In time-kill curves, only daptomycin and its combinations with rifampin achieved a bactericidal effect in log and stationary phases. For in vivo studies, we used a rat foreign-body infection model. Therapy was administered for 7 days with daptomycin at 100 mg/kg/day and 45/mg/kg/day, vancomycin at 50 mg/kg/12 h, rifampin at 25 mg/kg/12 h, and linezolid at 35 mg/kg/12 h, and each antibiotic was also combined with rifampin. Among monotherapies, daptomycin at 100 mg/kg/day and rifampin performed better than vancomycin and linezolid. In combination with rifampin, both dosages of daptomycin were significantly better than all other combinations, but daptomycin at 100 mg/kg/day plus rifampin achieved better cure rates at day 11 (P < 0.05) than daptomycin at 45 mg/kg/day plus rifampin. Resistant strains were found in monotherapies with rifampin and daptomycin at 45 mg/kg/day. In conclusion, daptomycin at high doses was the most effective monotherapy and also improved the efficacy of the combination with rifampin against foreign-body infections by MRSA. Clinical studies should confirm whether this combination may be considered the first-line treatment for foreign-body infections by MRSA in humans. PMID- 20921323 TI - Experimental transmission of h-type bovine spongiform encephalopathy to bovinized transgenic mice. AB - To characterize the biological and biochemical properties of H-type bovine spongiform encephalopathy (BSE), a transmission study with a Canadian H-type isolate was performed with bovinized transgenic mice (TgBoPrP), which were inoculated intracerebrally with brain homogenate from cattle with H-type BSE. All mice exhibited characteristic neurologic signs, and the subsequent passage showed a shortened incubation period. The distribution of disease-associated prion protein (PrP(Sc)) was determined by immunohistochemistry, Western blot, and paraffin-embedded tissue (PET) blot. Biochemical properties and higher molecular weight of the glycoform pattern were well conserved within mice. Immunolabeled granular PrP(Sc), aggregates, and/or plaque-like deposits were mainly detected in the following brain locations: septal nuclei, subcallosal regions, hypothalamus, paraventricular nucleus of the thalamus, interstitial nucleus of the stria terminalis, and the reticular formation of the midbrain. Weak reactivity was detected by immunohistochemistry and PET blot in the cerebral cortex, most thalamic nuclei, the hippocampus, medulla oblongata, and cerebellum. These findings indicate that the H-type BSE prion has biological and biochemical properties distinct from those of C-type and L-type BSE in TgBoPrP mice, which suggests that TgBoPrP mice constitute a useful animal model to distinguish isolates from BSE-infected cattle. PMID- 20921322 TI - Novel betapapillomavirus associated with hand and foot papillomas in a cynomolgus macaque. AB - Betapapillomavirus is a genus of papillomaviruses (PVs) commonly found in human skin and associated with both benign and malignant skin lesions. Only 2 previous beta-PVs have been fully characterized in nonhuman species. This report describes a novel beta-PV, named Macaca fascicularis PV type 2 (MfPV2), isolated from exophytic skin papillomas on the hands and feet of a 2-year-old male cynomolgus monkey (M. fascicularis). On histology the papillomas were composed of diffusely thickened epidermis with superficial foci of cytomegaly, cytoplasmic pallor, marginalized chromatin, and rare eosinophilic intranuclear inclusion bodies. Positive immunostaining for p16 and the proliferation marker Ki67 was present multifocally within affected epidermis, most prominently within basal-type cells. Complete sequence identity (100%) was noted between PV genomes fully sequenced from hand and foot lesions. The MfPV2 genome was 7632 base pairs in length and included putative open reading frames (ORFs) for E1, E2, E4, E6, E7, L1, and L2 genes, similar to other PVs. The closest relatives to MfPV2 based on the L1 ORF sequence were all beta-PVs. These included human PV (HPV) 9, HPV115, HPV76, HPV75, and MfPV1 (60-70% pairwise identity for all), the latter of which was also isolated from hand and foot papillomas in a cynomolgus macaque. Phylogenetic analysis placed MfPV2 in a new species group (beta-6), distinct from HPVs (beta-1 to beta-5) and MfPV1 (beta-1). These findings characterize a new nonhuman beta-PV and provide additional support for the idea that tissue tropism among ancestral primate PVs developed prior to divergence of certain Old World primate lineages. PMID- 20921324 TI - Effects of wrist tendon vibration on targeted upper-arm movements in poststroke hemiparesis. AB - BACKGROUND: Impaired motor control of the upper extremity after stroke may be related to lost sensory, motor, and integrative functions of the brain. Artificial activation of sensory afferents might improve control of movement by adding excitatory drive to sensorimotor control structures. The authors evaluated the effect of wrist tendon vibration (TV) on paretic upper-arm stability during point-to-point planar movements. METHODS: TV (70 Hz) was applied to the forearm wrist musculature of 10 hemiparetic stroke patients as they made center-out planar arm movements. End-point stability, muscle activity, and grip pressure were compared as patients stabilized at the target position for trials completed before, during, and after the application of the vibratory stimulus. RESULTS: Prior to vibration, hand position fluctuated as participants attempted to maintain the hand at the target after movement termination. TV improved arm stability, as evidenced by decreased magnitude of hand tangential velocity at the target. Improved stability was accompanied by a decrease in muscle activity throughout the arm as well as a mean decrease in grip pressure. CONCLUSIONS: These results suggest that vibratory stimulation of the distal wrist musculature enhances stability of the proximal arm and can be studied further as a mode for improving end-point stability during reaching in hemiparetic patients. PMID- 20921325 TI - Influence of task-oriented training content on skilled arm-hand performance in stroke: a systematic review. AB - OBJECTIVE: This review evaluates the underlying training components currently used in task-oriented training and assesses the effects of these components on skilled arm-hand performance in patients after a stroke. METHODS: A computerized systematic literature search in 5 databases (PubMed, CINAHL, EMBASE, PEDro, and Cochrane) identified randomized clinical trials, published through March 2009, evaluating the effects of task-oriented training. Relevant article references listed in publications included were also screened. The methodological quality of the selected studies was assessed with the Van Tulder Checklist. For each functional outcome measure used, the effect size (bias corrected Hedges's g) was calculated. RESULTS: The intervention results in 528 patients (16 studies) were studied. From these, 15 components were identified to characterize task-oriented training. An average of 7.8 (standard deviation = 2.1) components were used in the included trials. There was no correlation between the number of task-oriented training components used in a study and the treatment effect size. "Distributed practice" and "feedback" were associated with the largest postintervention effect sizes. "Random practice" and "use of clear functional goals" were associated with the largest follow-up effect sizes. CONCLUSION: The task-oriented training was operationalized with 15 components. The number of components used in an intervention aimed at improving arm-hand performance after stroke was not associated with the posttreatment effect size. Certain components, which optimize storage of learned motor performance in the long-term memory, occurred more in studies with larger treatment effects. PMID- 20921326 TI - Control of a visual keyboard using an electrocorticographic brain-computer interface. AB - OBJECTIVE: Brain-computer interfaces (BCIs) are devices that enable severely disabled people to communicate and interact with their environments using their brain waves. Most studies investigating BCI in humans have used scalp EEG as the source of electrical signals and focused on motor control of prostheses or computer cursors on a screen. The authors hypothesize that the use of brain signals obtained directly from the cortical surface will more effectively control a communication/spelling task compared to scalp EEG. METHODS: A total of 6 patients with medically intractable epilepsy were tested for the ability to control a visual keyboard using electrocorticographic (ECOG) signals. ECOG data collected during a P300 visual task paradigm were preprocessed and used to train a linear classifier to subsequently predict the intended target letters. RESULTS: The classifier was able to predict the intended target character at or near 100% accuracy using fewer than 15 stimulation sequences in 5 of the 6 people tested. ECOG data from electrodes outside the language cortex contributed to the classifier and enabled participants to write words on a visual keyboard. CONCLUSIONS: This is a novel finding because previous invasive BCI research in humans used signals exclusively from the motor cortex to control a computer cursor or prosthetic device. These results demonstrate that ECOG signals from electrodes both overlying and outside the language cortex can reliably control a visual keyboard to generate language output without voice or limb movements. PMID- 20921327 TI - Exploring the factors that influence functional performance among nursing home residents. AB - OBJECTIVE: To promote healthy aging in older nursing home (NH) residents, it is important to identify factors that impact functional performance. Using the Disablement Process Model, it was hypothesized that variables from all levels of the model would significantly impact the ability of a NH resident to get up from a chair. METHOD: A stepwise multiple logistic regression model was used to test the impact of sociodemographic, physiologic, physical, psychosocial, and environmental factors on chair rise. RESULTS: Analysis indicated that three factors, strength, gait, and self-efficacy, were significantly associated with chair-rise ability and together explained approximately 64% of the variance and successfully classified 88.4% of the chair-rise cases. DISCUSSION: These findings indicate that identifying physical and psychosocial variables early in the disablement process will help health care providers tailor medical and restorative care interventions that may help older adults maintain the ability to chair rise. PMID- 20921329 TI - Recommendations for publishing case studies of cell transplantation for spinal cord injury. AB - BACKGROUND: Cellular transplantation for subacute and chronic spinal cord injury (SCI) continues to proceed around the world, but clinicians and patients have only 10 English language publications of case reports and self-serving Web page anecdotes to guide them. METHODS: Recent publications about the use of olfactory ensheathing, bone marrow stromal, and fetal tissue stem cells in human subjects are examined to assess the adequacy of their designs, conclusions, and interpretation. RESULTS: Case series reports to date reveal adverse responses to cellular therapy when clinicians look for these and no clear functional effects when a matched group that is not treated is compared. Rehabilitation that focuses on potential targets for sensorimotor and functional gains must precede a transplantation until a plateau of change is reached and then continue for at least 6 months if not a year. CONCLUSION: Criteria are listed as the minimum requirements for any further case series reports to be considered by journals in regard to cellular interventions for SCI. Based on available reports, the published interventions should not be given to additional patients. One or two of the strategies can be considered for testing in a randomized trial with blinded assessors and an independent data monitoring committee to examine for biological activity in patients with motor complete SCI of greater than 4 to 6 months duration. PMID- 20921331 TI - Abstracts of the Societa Italiana di Patologia XXX National Congress. October 14 17, 2010. Salerno, Italy. PMID- 20921330 TI - Olfactory ensheathing cells for human spinal cord injury. PMID- 20921332 TI - A clinical study of ADHD symptoms with relation to symptoms of learning disorders in schoolchildren in Bogota, Colombia. AB - OBJECTIVE: To investigate possible relationships between symptoms of ADHD and of learning disorder (LD) in a population geographically, culturally, and linguistically distinct from previous studies. METHOD: The authors evaluated a cross section of 834 Colombian schoolchildren for childhood neurological pathologies on the basis of a medical examination and performance with reference to the Diagnostic and Statistical Manual (4th ed.) attention checklist, the General and Differential Aptitudes Battery, and the Visual-Motor Integration (VMI) test. RESULTS: Of the total sample, 382 were classified as "ADHD only," 54 as "LD only," and 75 as "ADHD + LD." A total of 459 had low VMI scores. ADHD, LD, and low VMI were significantly interrelated. Among the children with ADHD, the attention deficit subtype tended to have more learning problems than the hyperactive subtype, who showed no major deficiencies in their learning ability. CONCLUSIONS: This study provides additional evidence demonstrating a relationship between LD and ADHD, particularly with respect to verbal reasoning, visual auditory memory, and VMI. PMID- 20921333 TI - Circulating MicroRNA-208b and MicroRNA-499 reflect myocardial damage in cardiovascular disease. AB - BACKGROUND: Small RNA molecules, called microRNAs, freely circulate in human plasma and correlate with varying pathologies. In this study, we explored their diagnostic potential in a selection of prevalent cardiovascular disorders. METHODS AND RESULTS: MicroRNAs were isolated from plasmas from well-characterized patients with varying degrees of cardiac damage: (1) acute myocardial infarction, (2) viral myocarditis, (3) diastolic dysfunction, and (4) acute heart failure. Plasma levels of selected microRNAs, including heart-associated (miR-1, -133a, 208b, and -499), fibrosis-associated (miR-21 and miR-29b), and leukocyte associated (miR-146, -155, and -223) candidates, were subsequently assessed using real-time polymerase chain reaction. Strikingly, in plasma from acute myocardial infarction patients, cardiac myocyte-associated miR-208b and -499 were highly elevated, 1600-fold (P<0.005) and 100-fold (P<0.0005), respectively, as compared with control subjects. Receiver operating characteristic curve analysis revealed an area under the curve of 0.94 (P<10(-10)) for miR-208b and 0.92 (P<10(-9)) for miR-499. Both microRNAs correlated with plasma troponin T, indicating release of microRNAs from injured cardiomyocytes. In viral myocarditis, we observed a milder but significant elevation of these microRNAs, 30-fold and 6-fold, respectively. Plasma levels of leukocyte-expressed microRNAs were not significantly increased in acute myocardial infarction or viral myocarditis patients, despite elevated white blood cell counts. In patients with acute heart failure, only miR-499 was significantly elevated (2-fold), whereas no significant changes in microRNAs studied could be observed in diastolic dysfunction. Remarkably, plasma microRNA levels were not affected by a wide range of clinical confounders, including age, sex, body mass index, kidney function, systolic blood pressure, and white blood cell count. CONCLUSIONS: Cardiac damage initiates the detectable release of cardiomyocyte-specific microRNAs-208b and -499 into the circulation. PMID- 20921334 TI - Formation of cholesterol ozonolysis products in vitro and in vivo through a myeloperoxidase-dependent pathway. AB - 3beta-Hydroxy-5-oxo-5,6-secocholestan-6-al (secosterol-A) and its aldolization product 3beta-hydroxy-5beta-hydroxy-B-norcholestane-6beta-carboxaldehyde (secosterol-B) were recently detected in human atherosclerotic tissues and brain specimens, and they may play pivotal roles in the pathogenesis of atherosclerosis and neurodegenerative diseases. However, as their origin remains unidentified, we examined the formation mechanism, the stability, and the fate of secosterols in vitro and in vivo. About 40% of secosterol-A remained unchanged after 3 h incubation in the FBS-free medium, whereas 20% and 40% were converted to its aldehyde-oxidation product, 3beta-hydroxy-5-oxo-secocholestan-6-oic acid, and secosterol-B, respectively. In the presence of FBS, almost all secosterol-A was converted immediately to these compounds. Secosterol-B in the medium, with and without FBS, was relatively stable, but ~30% was converted to its aldehyde oxidation product, 3beta-hydroxy-5beta-hydroxy-B-norcholestane-6-oic acid (secoB COOH). When neutrophil-like differentiated human leukemia HL-60 (nHL-60) cells activated with PMA were cultured in the FBS-free medium containing cholesterol, significantly increased levels of secosterol-A and its aldehyde-oxidation product, but not secosterol-B, were formed. This secosterol-A formation was decreased in the culture of PMA-activated nHL-60 cells containing several reactive oxygen species (ROS) inhibitors and scavengers or in the culture of PMA activated neutrophils isolated from myeloperoxidase (MPO)-deficient mice. Our results demonstrate that secoterol-A is formed by an ozone-like oxidant generated with PMA-activated neutrophils through the MPO-dependent mechanism. PMID- 20921336 TI - Volumetric breast density from full-field digital mammograms and its association with breast cancer risk factors: a comparison with a threshold method. AB - INTRODUCTION: Breast density, a strong breast cancer risk factor, is usually measured on the projected breast area from film screen mammograms. This is far from ideal, as breast thickness and technical characteristics are not taken into account. We investigated whether volumetric density measurements on full-field digital mammography (FFDM) are more strongly related to breast cancer risk factors than measurements with a computer-assisted threshold method. METHODS: Breast density was measured on FFDMs from 370 breast cancer screening participants, using a computer-assisted threshold method and a volumetric method. The distribution of breast cancer risk factors among quintiles of density was compared between both methods. We adjusted for age and body mass index (BMI) with linear regression analysis. RESULTS: High percent density was strongly related to younger age, lower BMI, nulliparity, late age at first delivery and pre/perimenopausal status, to the same extent with both methods (all P < 0.05). Similarly strong relationships were seen for the absolute dense area but to a lesser extent for absolute dense volume. A larger dense volume was only significantly associated with late age at menopause, use of menopausal hormone therapy, and, in contrast to the other methods, high BMI. CONCLUSION: Both methods related equally well to known breast cancer risk factors. IMPACT: Despite its alleged higher precision, the volumetric method was not more strongly related to breast cancer risk factors. This is in agreement with other studies. The definitive relationship with breast cancer risk still needs to be investigated. PMID- 20921335 TI - Bulky DNA adducts in white blood cells: a pooled analysis of 3,600 subjects. AB - BACKGROUND: Bulky DNA adducts are markers of exposure to genotoxic aromatic compounds, which reflect the ability of an individual to metabolically activate carcinogens and to repair DNA damage. Polycyclic aromatic hydrocarbons (PAHs) represent a major class of carcinogens that are capable of forming such adducts. Factors that have been reported to be related to DNA adduct levels include smoking, diet, body mass index (BMI), genetic polymorphisms, the season of collection of biologic material, and air pollutants. METHODS: We pooled 11 studies (3,600 subjects) in which bulky DNA adducts were measured in human white blood cells with similar (32)P-postlabeling techniques and for which a similar set of variables was available, including individual data on age, gender, ethnicity, batch, smoking habits, BMI, and season of blood collection, and a limited set of gene variants. RESULTS: Lowest DNA adduct levels (P = 0.006) were observed in the spring (median = 0.50 adducts per 10(8) nucleotides), followed by summer (0.64), autumn (0.70), and winter (0.85). The same pattern emerged in multivariate analysis but only among never smokers (P = 0.02). Adduct levels were significantly lower (P = 0.001) in northern Europe (the Netherlands and Denmark; mean = 0.60, median = 0.40) than in southern Europe (Italy, Spain, France, and Greece; mean = 0.79, median = 0.60). CONCLUSIONS: In this large pooled analysis, we have found only weak associations between bulky DNA adducts and exposure variables. Seasonality (with higher adducts levels in winter) and air pollution may partly explain some of the interarea differences (north vs. south Europe), but most inter-area and interindividual variations in adduct levels still remain unexplained. IMPACT: Our study describes the largest pooled analysis of bulky DNA adducts so far, showing that interindividual variation is still largely unexplained, though seasonality seems to play a role. PMID- 20921337 TI - Remuneration of hematopoietic stem cell donors: principles and perspective of the World Marrow Donor Association. AB - Hematopoietic stem cell transplantation is a curative procedure for life threatening hematologic diseases. Donation of hematopoietic stem cells (HSCs) from an unrelated donor, frequently residing in another country, may be the only option for 70% of those in need of unrelated hematopoietic stem cell transplantation. To maximize the opportunity to find the best available donor, individual donor registries collaborate internationally. To provide homogeneity of practice among registries, the World Marrow Donor Association (WMDA) sets standards against which registries are accredited and provides guidance and regulations about unrelated donor safety and care. A basic tenet of the donor registries is that unrelated HSC donation is an altruistic act; nonpayment of donors is entrenched in the WMDA standards and in international practice. In the United States, the prohibition against remuneration of donors has recently been challenged. Here, we describe the reasons that the WMDA continues to believe that HSC donors should not be paid because of ethical concerns raised by remuneration, potential to damage the public will to act altruistically, the potential for coercion and exploitation of donors, increased risk to patients, harm to local transplantation programs and international stem cell exchange, and the possibility of benefiting some patients while disadvantaging others. PMID- 20921338 TI - Endogenous oncogenic Nras mutation promotes aberrant GM-CSF signaling in granulocytic/monocytic precursors in a murine model of chronic myelomonocytic leukemia. AB - Oncogenic NRAS mutations are frequently identified in myeloid diseases involving monocyte lineage. However, its role in the genesis of these diseases remains elusive. We report a mouse bone marrow transplantation model harboring an oncogenic G12D mutation in the Nras locus. Approximately 95% of recipient mice develop a myeloproliferative disease resembling the myeloproliferative variant of chronic myelomonocytic leukemia (CMML), with a prolonged latency and acquisition of multiple genetic alterations, including uniparental disomy of oncogenic Nras allele. Based on single-cell profiling of phospho-proteins, a novel population of CMML cells is identified to display aberrant granulocyte-macrophage colony stimulating factor (GM-CSF) signaling in both the extracellular signal-regulated kinase (ERK) 1/2 and signal transducer and activator of transcription 5 (Stat5) pathways. This abnormal signaling is acquired during CMML development. Further study suggests that aberrant Ras/ERK signaling leads to expansion of granulocytic/monocytic precursors, which are highly responsive to GM-CSF. Hyperactivation of Stat5 in CMML cells is mainly through expansion of these precursors rather than up-regulation of surface expression of GM-CSF receptors. Our results provide insights into the aberrant cytokine signaling in oncogenic NRAS-associated myeloid diseases. PMID- 20921340 TI - Combination of HOXB4 and Delta-1 ligand improves expansion of cord blood cells. AB - Umbilical cord blood (UCB) is an attractive cell source for hematopoietic cell transplantation (HCT). Here we examine whether the combination of homeobox B4 (HOXB4) and Delta-1 ligand (DL) synergize when used together. Monkey and human UCB CD34(+) cells were transduced with a HOXB4-expressing gammaretroviral vector and cultured with DL. Individual and combined effects of HOXB4 and DL were assessed by colony-forming unit assays, flow cytometry, and nonobese diabetic/severe combined immune deficienct mouse transplantation. The presence of DL yielded higher percentage of CD34(+) and CD7(+) cells and lower percentages of CD14(+) cells than non-DL cultures. Furthermore, HOXB4 yielded higher percentages of CD34(+) and CD14(+) cells than non-HOXB4 cultures. Interestingly, coculture with DL-expressing OP9 cells resulted in better maintenance of HOXB4 than culture in DL-conditioned medium. Culture of HOXB4-transduced human cells in the presence of DL yielded enhanced generation of repopulating cells with higher levels of engraftment of human CD45(+), CD34(+), CD3(+), CD20(+), and CD41(+) cells compared with either factor individually. Our results demonstrate enhanced generation of hematopoietic progenitors by combining HOXB4 and DL; addition of DL further enhances expansion of multipotent cells capable of repopulating lymphoid and megakaryocyte lineages, which is not observed with HOXB4 alone. PMID- 20921339 TI - A liver enhancer in the fibrinogen gene cluster. AB - The plasma concentration of fibrinogen varies in the healthy human population between 1.5 and 3.5 g/L. Understanding the basis of this variability has clinical importance because elevated fibrinogen levels are associated with increased cardiovascular disease risk. To identify novel regulatory elements involved in the control of fibrinogen expression, we used sequence conservation and in silico predicted regulatory potential to select 14 conserved noncoding sequences (CNCs) within the conserved block of synteny containing the fibrinogen locus. The regulatory potential of each CNC was tested in vitro using a luciferase reporter gene assay in fibrinogen-expressing hepatoma cell lines (HuH7 and HepG2). 4 potential enhancers were tested for their ability to direct enhanced green fluorescent protein expression in zebrafish embryos. CNC12, a sequence equidistant from the human fibrinogen alpha and beta chain genes, activates strong liver enhanced green fluorescent protein expression in injected embryos and their transgenic progeny. A transgenic assay in embryonic day 14.5 mouse embryos confirmed the ability of CNC12 to activate transcription in the liver. While additional experiments are necessary to prove the role of CNC12 in the regulation of fibrinogen, our study reveals a novel regulatory element in the fibrinogen locus that is active in the liver and may contribute to variable fibrinogen expression in humans. PMID- 20921341 TI - Effects of adverse events on the projected population benefits and cost effectiveness of using live attenuated influenza vaccine in children aged 6 months to 4 years. AB - OBJECTIVE: To evaluate the effect of adverse events associated with live attenuated influenza vaccine (LAIV) in children younger than 5 years on the cost effectiveness of influenza vaccination. DESIGN: A decision analytic model was developed to predict costs and health effects of no vaccination, vaccination with LAIV, and vaccination with inactivated influenza vaccine (IIV). Probabilities, costs, and quality adjustments for uncomplicated influenza, outpatient visits, hospitalizations, deaths, vaccination, and vaccine adverse events were based on primary and published data. The analysis included the possible increased incidence of adverse events following vaccination with LAIV for children younger than 5 years, including fever, wheezing, and hospitalization. A societal perspective was used. Sensitivity analyses, including probabilistic sensitivity analysis, were conducted. SETTING: Vaccination in the physician office setting in the United States. PARTICIPANTS: Hypothetical cohorts of healthy children aged 6 months to 4 years. INTERVENTION: Vaccination with LAIV or IIV. MAIN OUTCOME MEASURE: Incremental cost-effectiveness ratio in dollars per quality-adjusted life-year (QALY). RESULTS: Cost-effectiveness ratios ranged from $20 000/QALY (age 6-23 months) to $33 000/QALY (age 3-4 years) for LAIV and from $21 000/QALY to $37 000/QALY for IIV for healthy children aged 6 months to 4 years. Inclusion of possible new adverse events for LAIV had varying effects on cost-effectiveness results. Results were not sensitive to the inclusion of wheezing as an adverse event but were sensitive to a possible increase in the probability of hospitalization. CONCLUSION: Live attenuated influenza vaccine had comparable cost-effectiveness compared with IIV for children younger than 5 years under a wide range of assumptions about the incidence of adverse events. PMID- 20921342 TI - Relationship between neighborhood disadvantage and social function of Wisconsin 2 and 3-year-olds born at very low birth weight. AB - OBJECTIVE: To examine whether (1) neighborhood disadvantage is associated with social function in 2- and 3-year-olds born at very low birth weight (<1500 g) and (2) the association between social function and child's health-related quality of life (HRQoL) is moderated by neighborhood disadvantage. DESIGN: Cross-sectional study using the Newborn Lung Project, a cohort of infants born at very low birth weight in 2003 and 2004 in Wisconsin. SETTING: Wisconsin. PARTICIPANTS: This study includes the subgroup of 626 non-Hispanic black or white infants who were followed up at ages 24 to 43 months with parent-reported health and developmental information. MAIN EXPOSURE: An index of neighborhood disadvantage was derived by principal component analysis of 5 census tract variables (percentage of families in poverty, percentage of households with income higher than the state median, percentage of women with bachelor's degree or more, percentage of single mothers, and percentage of mothers of young children unemployed). Children were then classified (based on index tertiles) as living in either disadvantaged, middle advantage, or advantaged neighborhoods. Children's HRQoL was measured using the Pediatric Quality of Life Inventory. MAIN OUTCOME MEASURE: Social function was measured using the Pediatric Evaluation of Disability Inventory. RESULTS: Adjusting for child medical and family socioeconomic attributes, social function was lower (mean difference, -4.60; 95% confidence interval, -8.4 to -0.8) for children living in disadvantaged vs advantaged neighborhoods. We also found that the ill effects of lower HRQoL are particularly bad for children living in a disadvantaged neighborhood. CONCLUSION: Children born at very low birth weight have disparities in social function at ages 2 and 3 years that are associated with both HRQoL and neighborhood characteristics. PMID- 20921343 TI - Cultural and gender convergence in adolescent drunkenness: evidence from 23 European and North American countries. AB - OBJECTIVE: To investigate time-trend changes in the frequency of drunkenness among European and North American adolescents. DESIGN: Cross-sectional surveys in the 1997/1998 and 2005/2006 Health Behaviour in School-Aged Children Study (HBSC). SETTING: High schools in 23 countries. PARTICIPANTS: A sample of 77 586 adolescents aged 15 years was analyzed by means of hierarchical linear modeling. MAIN OUTCOME MEASURE: The frequency of drunkenness. RESULTS: We observed a significant increase of about 40% in the mean frequency of drunkenness in all 7 participating Eastern European countries. This increase was evident among both genders, but most consistently among girls. Meanwhile, it declined in 13 of 16 Western countries, about 25% on average. Declines in Western countries were particularly notable among boys and in North America, Scandinavia, the United Kingdom, and Ireland. Despite this gender convergence, with few exceptions (Greenland, Norway, United Kingdom) boys continued to have a higher frequency of drunkenness in 2005/2006 than girls. CONCLUSIONS: The confirmed cultural convergence implies that adoption and implementation of evidence-based measures to mitigate the frequency of adolescent drunkenness such as tax increases and restricting alcohol access and advertisement should get the same priority in Eastern European countries as in Western countries. Policy measures that might facilitate decreases in drunkenness such as server training and the promotion of alcohol-free leisure-time activities should be reinforced in Western countries. The gender convergence implies that prevention policy should be less exclusively focused on male adolescents. PMID- 20921344 TI - The promise of maternal vaccination to prevent influenza in young infants. PMID- 20921345 TI - Maternal influenza vaccination and effect on influenza virus infection in young infants. AB - OBJECTIVE: To assess the effect of seasonal influenza vaccination during pregnancy on laboratory-confirmed influenza in infants to 6 months of age. DESIGN: Nonrandomized, prospective, observational cohort study. SETTING: Navajo and White Mountain Apache Indian reservations, including 6 hospitals on the Navajo reservation and 1 on the White Mountain Apache reservation. PARTICIPANTS: A total of 1169 mother-infant pairs with mothers who delivered an infant during 1 of 3 influenza seasons. MAIN EXPOSURE: Maternal seasonal influenza vaccination. MAIN OUTCOME MEASURES: In infants, laboratory-confirmed influenza, influenza-like illness (ILI), ILI hospitalization, and influenza hemagglutinin inhibition antibody titers. RESULTS: A total of 1160 mother-infant pairs had serum collected and were included in the analysis. Among infants, 193 (17%) had an ILI hospitalization, 412 (36%) had only an ILI outpatient visit, and 555 (48%) had no ILI episodes. The ILI incidence rate was 7.2 and 6.7 per 1000 person-days for infants born to unvaccinated and vaccinated women, respectively. There was a 41% reduction in the risk of laboratory-confirmed influenza virus infection (relative risk, 0.59; 95% confidence interval, 0.37-0.93) and a 39% reduction in the risk of ILI hospitalization (relative risk, 0.61; 95% confidence interval, 0.45-0.84) for infants born to influenza-vaccinated women compared with infants born to unvaccinated mothers. Infants born to influenza-vaccinated women had significantly higher hemagglutinin inhibition antibody titers at birth and at 2 to 3 months of age than infants of unvaccinated mothers for all 8 influenza virus strains investigated. CONCLUSIONS: Maternal influenza vaccination was significantly associated with reduced risk of influenza virus infection and hospitalization for an ILI up to 6 months of age and increased influenza antibody titers in infants through 2 to 3 months of age. PMID- 20921346 TI - My special daughter. PMID- 20921347 TI - Six-year follow-up of a preventive intervention for parentally bereaved youths: a randomized controlled trial. AB - OBJECTIVE: To evaluate the efficacy of the Family Bereavement Program (FBP) to prevent mental health problems in parentally bereaved youths and their parents 6 years later. DESIGN: Randomized controlled trial. SETTING: Arizona State University Prevention Research Center from November 2002 to July 2005. PARTICIPANTS: Two hundred eighteen bereaved youths (89.34% of 244 enrolled in the trial 6 years earlier) and 113 spousally bereaved parents. INTERVENTIONS: The FBP includes 12 group sessions for caregivers and youths; the literature control (LC) condition includes bereavement books for youths and caregivers. MAIN OUTCOME MEASURES: Comparisons of youths in the FBP and LC on a measure of mental disorder diagnosis, 5 measures of mental health problems, and 4 measures of competent functioning; and comparisons of spousally bereaved parents on 2 measures of mental health problems. RESULTS: Youths in the FBP as compared with those in the LC had significantly lower externalizing problems as reported by caregivers and youths (adjusted mean, -0.06 vs 0.13, respectively; P = .02) and on teacher reports of externalizing problems (adjusted mean, 52.69 vs 56.27, respectively; P = .001) and internalizing problems (adjusted mean, 47.29 vs 56.27, respectively; P = .002), and they had higher self-esteem (adjusted mean, 33.93 vs 31.91, respectively; P = .005). Parents in the FBP had lower depression scores than those in the LC (adjusted mean, 5.48 vs 7.83, respectively; P = .04). A significant moderated program effect indicated that for youths with lower baseline problems, the rate of diagnosed mental disorder was lower for those in the FBP than in the LC. CONCLUSION: This study demonstrates efficacy of the FBP to reduce mental health problems of bereaved youths and their parents 6 years later. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01008189. PMID- 20921348 TI - Recurrent wheezing in the third year of life among children born at 32 weeks' gestation or later: relationship to laboratory-confirmed, medically attended infection with respiratory syncytial virus during the first year of life. AB - OBJECTIVE: To quantify the relationship between recurrent wheezing (RW) in the third year of life and respiratory syncytial virus (RSV) infection, prematurity, and neonatal oxygen exposure. DESIGN: Retrospective cohort study linking inpatient, outpatient, and laboratory databases for cohort assembly and logistic regression analysis. SETTING: Integrated health care delivery system in Northern California. PARTICIPANTS: A total of 71,102 children born from 1996 to 2002 at 32 weeks' gestational age or later who were health plan members for 9 or more months in their first and third years. MAIN EXPOSURES: Laboratory-confirmed, medically attended RSV infection during first year and supplemental oxygen during birth hospitalization. OUTCOME MEASURES: Recurrent wheezing, quantified through outpatient visits, inpatient hospital stays, and asthma prescriptions. RESULTS: The rate of RW in the third year of life was 16.23% among premature infants with RSV and 6.22% among those without RSV. The risk of RW increased among infants who had an RSV outpatient encounter (adjusted odds ratio [AOR], 2.07; 95% CI, 1.61 2.67), uncomplicated RSV hospitalization (AOR, 4.66; 95% CI, 3.55-6.12), or prolonged RSV hospitalization (AOR, 3.42; 95% CI, 2.01-5.82) compared with infants without RSV encounters. Gestational age of 34 to 36 weeks was associated with increased risk of RW (AOR, 1.23; 95% CI 1.07-1.41) compared with 38 to 40 weeks, while a gestational age of 41 weeks or more was protective (AOR, 0.90; 95% CI, 0.81-0.99). Supplemental oxygen exposure was associated with increased risk at all levels. CONCLUSION: Laboratory-confirmed, medically attended RSV infection, prematurity, and exposure to supplemental oxygen during the neonatal period have independent associations with the development of RW in the third year of life. PMID- 20921349 TI - School-based randomized controlled trial of an HIV/STD risk-reduction intervention for South African adolescents. AB - OBJECTIVE: To test the efficacy of a school-based human immunodeficiency virus/sexually transmitted disease (HIV/STD) risk-reduction intervention for South African adolescents. DESIGN: A cluster-randomized, controlled design with assessments of self-reported sexual behavior collected before intervention and 3, 6, and 12 months after intervention. SETTING: Primary schools in a large, black township and a neighboring rural settlement in Eastern Cape Province, South Africa. PARTICIPANTS: Nine of 17 matched pairs of schools were randomly selected. Sixth-grade students with parent or guardian consent were eligible. INTERVENTIONS: Two 6-session interventions based on behavior-change theories and qualitative research. The HIV/STD risk-reduction intervention targeted sexual risk behaviors; the attention-matched health promotion control intervention targeted health issues unrelated to sexual behavior. OUTCOME MEASURES: The primary outcome was self report of unprotected vaginal intercourse in the previous 3 months averaged over the 3 follow-ups. Secondary outcomes were other sexual behaviors. RESULTS: A total of 1057 (94.5%) of 1118 eligible students (mean age, 12.4 years) participated, with 96.7% retained at the 12-month follow up. Generalized estimating equation analyses adjusted for clustering from 18 schools revealed that, averaged over the 3 follow-ups, a significantly smaller percentage of HIV/STD risk-reduction intervention participants reported having unprotected vaginal intercourse (odds ratio [OR], 0.51; 95% confidence interval [CI], 0.30-0.85), vaginal intercourse (OR, 0.62; 95% CI, 0.42-0.94), and multiple sexual partners (OR, 0.50; 95% CI, 0.28-0.89), when adjusted for baseline prevalences, compared with health-promotion control participants. CONCLUSION: This is the first large-scale, community-level, randomized intervention trial to show significant effects on the HIV/STD sexual risk behavior of South African adolescents in the earliest stages of entry into sexual activity. PMID- 20921350 TI - Association between attention-deficit/hyperactivity disorder in adolescence and substance use disorders in adulthood. AB - OBJECTIVES: To determine whether attention-deficit/hyperactivity disorder (ADHD) in adolescence is related to substance use disorders (SUDs) in adulthood and whether conduct disorder (CD) mediates this relationship. DESIGN: A prospective design incorporating 5 assessments in participants spanning the mean ages of 14 to 37 years. Two baseline assessments were taken at ages 14 and 16 years, and 3 outcome assessments were taken between ages 27 and 37 years. SETTING: United States. PARTICIPANTS: A community sample of individuals initially drawn from upstate New York in 1975 and observed to a mean age of 37 years. INTERVENTIONS: The Diagnostic Interview Schedule for Children was used to assess ADHD and CD and the University of Michigan Composite International Diagnostic Interview was used to assess SUDs. MAIN OUTCOME MEASURE: A diagnosis of SUDs given to participants in adulthood. RESULTS: The odds ratios for ADHD and CD in adolescence as related to SUDs in adulthood were 1.9 and 3.5, respectively. The association between ADHD and SUDs, however, was indirect because CD served as a mediator between ADHD and SUDs. CONCLUSIONS: Pediatricians should focus on adolescent ADHD when it progresses to CD because CD is a major predictor of SUDs in adulthood. PMID- 20921351 TI - The effect of perceived and structural neighborhood conditions on adolescents' physical activity and sedentary behaviors. AB - OBJECTIVE: To test whether physical activity and sedentary behaviors are associated with perceived and structural neighborhood conditions. DESIGN: Secondary analysis of data from wave I (1994-1995) of the National Longitudinal Study of Adolescent Health in the United States. SETTING: In-home interviews of adolescents and their parents. PARTICIPANTS: Thirteen thousand six hundred sixty eight adolescents (6794 adolescent boys and 6874 adolescent girls; grades 7-12). MAIN EXPOSURES: Perceived neighborhood conditions (public nuisance, acquaintanceship, and informal control measured at both individual and census tract levels) and structural neighborhood characteristics (concentrated poverty, immigrant concentration, and residential stability at the census tract level). OUTCOME MEASURES: Failure to meet moderate to vigorous physical activity (MVPA) guidelines (<5 bouts of MVPA per week) and excessive screen time (>2 hours per day). RESULTS: Individual-level perception of intermediate (adjusted odds ratio [OR], 0.76; 95% confidence interval [CI], 0.68-0.84) or high (OR, 0.56; 95% CI, 0.50-0.61) acquaintanceship and high informal control (OR, 0.90; 95% CI, 0.82 0.99) in the neighborhood were negatively associated with failure to meet the MVPA guidelines compared with lower levels. At the census tract level, high informal control (OR, 1.16; 95% CI, 1.04-1.29) and intermediate (OR, 1.13; 95% CI, 1.01-1.26) and high (OR, 1.22; 95% CI, 1.06-1.40) concentrated poverty compared with lower levels were also associated with failing to meet the MVPA guidelines (when adjusted for sociodemographic characteristics). Compared with the lowest levels, high public nuisance (OR, 1.19; 95% CI, 1.04-1.36) and immigrant concentration (OR, 1.18; 95% CI, 1.01-1.38) at the census tract level were associated with excessive screen time. CONCLUSION: These findings suggest that both perceptual and structural neighborhood factors should be considered to understand adolescents' physical activity and sedentary behaviors. PMID- 20921353 TI - Relationship between the cognitive environment and vocabulary development during the second year of life. AB - OBJECTIVE: To examine the relationship between characteristics of the cognitive environment at age 10 to 18 months and vocabulary at age 18 to 30 months. DESIGN: Analysis of baseline and follow-up data on 157 families participating in a comparison of 2 anticipatory guidance programs. SETTING: Children's Hospital outpatient department serving low-income families. PARTICIPANTS: Parents of children aged 10 to 18 months at baseline who participated in a follow-up telephone interview at age 18 to 30 months. MAIN OUTCOME MEASURES: Three subscales of the StimQ (reading, parental involvement in developmental activities, and parental verbal responsivity [PVR]) and the short form of the MacArthur Communicative Development Inventories. RESULTS: Vocabulary score percentiles dropped significantly between baseline and follow-up, with scores for bilingual families showing a greater decrease than those for English speaking only families. StimQ subscale scores increased with maternal education and increased between baseline and follow-up. Multiple regression analysis showed that baseline variables accounted for 25% of the variance in follow-up vocabulary score percentile, with significant contributions from baseline expressive vocabulary (P < .001), PVR (P = .01), and home language (P = .03) scores. Seventy seven percent of children with PVR scores less than 4 had follow-up vocabulary scores at or less than the 25th percentile, with an associated likelihood ratio of 4.33. However, 35% of children with a PVR score of 4 also had vocabulary scores less than the 25th percentile at follow-up, with an associated likelihood ratio of 0.67. CONCLUSIONS: The StimQ is a clinically useful method for assessing early environmental factors that influence vocabulary development. The PVR subscale score was the best StimQ predictor of later vocabulary delay and may be useful in identifying children needing referral for evaluation. PMID- 20921352 TI - Household, family, and child risk factors after an investigation for suspected child maltreatment: a missed opportunity for prevention. AB - OBJECTIVE: To determine whether a Child Protection Services investigation for suspected child maltreatment is associated with subsequent improvements in household, caregiver, and child risk factors. DESIGN: Retrospective cohort study. SETTING: The Longitudinal Studies of Child Abuse and Neglect, a multicenter cohort study of the antecedents and consequences of child maltreatment. PARTICIPANTS: A total of 595 children with the same maternal caregiver responding to Longitudinal Studies of Child Abuse and Neglect surveys at ages 4 and 8 years. MAIN EXPOSURE: Investigation for suspected child maltreatment between ages 4 and 8 years. MAIN OUTCOME MEASURES: Adjusted differences in 7 modifiable risk factors (social support, family functioning, poverty, maternal education, maternal depressive symptoms, anxious or depressive child behaviors, and aggressive or destructive child behaviors) at age 8 years. RESULTS: Of 595 subjects, 164 (27.6%) experienced an investigation for suspected child maltreatment between ages 4 and 8 years. At age 8 years, investigated subjects were not perceptibly different from noninvestigated subjects in social support, family functioning, poverty, maternal education, or child behavior problems after adjusting for baseline risk factors. Mothers of investigated subjects did have more depressive symptoms than mothers of noninvestigated peers at the child's age of 8 years. Substantiation of child maltreatment by Child Protective Services did not alter these findings. CONCLUSIONS: Our finding that an investigation for suspected child maltreatment is not associated with relative improvements in common, modifiable risk factors suggests that we may be missing an opportunity for secondary prevention of maltreatment and maltreatment consequences. PMID- 20921354 TI - Improving evidence-based care in cystic fibrosis through quality improvement. AB - OBJECTIVE: To increase clinician adherence to prescribing guidelines for pulmonary medications in children with cystic fibrosis (CF). DESIGN: Quality improvement project with multiple time series design. SETTING: The CF center at a tertiary care pediatric hospital in the United States. PATIENTS: Children with CF who were eligible to receive oral azithromycin, nebulized dornase alfa, or inhaled tobramycin sulfate based on prescribing guidelines for CF lung disease. INTERVENTION: Evidence-based prescribing guidelines were designed by a local committee to reflect consensus recommendations from the CF Foundation. Clinicians and families were educated about guidelines. Adherence to prescribing guidelines was tracked using a local CF database and record reviews. Weekly meetings were used to highlight adherence failures and promote clinician accountability. MAIN OUTCOME MEASURE: The rate of clinician adherence to prescribing guidelines. RESULTS: One hundred seventy patients with CF were included. At the start of the project, the rate of clinician adherence to prescribing guidelines was 62%. After 3 months of the project, the rate of clinician adherence to prescribing guidelines was 87% (odds ratio = 4.6; 95% confidence interval, 3.0-7.0). The improvements in adherence to prescribing guidelines were sustained for 21 months of follow-up. CONCLUSIONS: Educating clinicians about prescribing guidelines, sharing guidelines with families, and monitoring clinician adherence improve prescribing adherence to evidence-based recommendations. PMID- 20921355 TI - Longitudinal assessment of the timing of career choice among pediatric residents. AB - OBJECTIVE: To determine the timing of and key factors in resident decision making to pursue either a career in general pediatrics or subspecialty training. DESIGN: We used a 10-item fixed-choice questionnaire that focused on exploring how and when pediatric residents make career choices. SETTING: The survey was administered to all categorical pediatric residents in the United States and Canada as part of the General Pediatrics In-Training Examination in 2007 and 2009. The 2007 level 1 residents and 2009 level 3 residents were matched by a unique person identifier to create a longitudinal data set. PARTICIPANTS: A total of 2305 individuals completed the survey as level 1 residents in 2007 and level 3 residents in 2009, representing a retention rate of 83.5%. MAIN OUTCOME MEASURES: Change in individual and aggregate pediatric resident response over time. RESULTS: A similar number of individuals planned to pursue fellowship training in 2007 and 2009 (1026 vs 1062). Among this group, 745 (72.6%) of the 2009 residents were the same individuals who had indicated that they planned to pursue fellowship training in 2007. A total of 258 (71.9%) of all residents who reported in 2007 that they intended to pursue careers in general pediatrics with little or no inpatient care were still planning to do so in 2009. CONCLUSIONS: Most pediatricians make their decisions regarding pursuit of a career in primary care or to complete a fellowship before they ever enter residency training. It is unknown whether a similar timeline of decision making is consistent across specialties. PMID- 20921357 TI - Picture of the month--quiz case. Ruptured hydatid lung cyst. PMID- 20921356 TI - Burden of anxiety disorders in pediatric medical settings: prevalence, phenomenology, and a research agenda. AB - The current review describes the phenomenology of several common anxiety disorders in children and adolescents as they present in medical settings. Anxiety disorders and associated features in children are described, along with epidemiology, functional impairment, common somatic complaints, medical comorbidity, health care utilization, and presentation in general and in specialty pediatric medical settings. Recommendations for clinical management in pediatric settings are presented, and evidence-based interventions and emerging treatments for pediatric anxiety disorders are described. The review concludes with a discussion of future research directions that may lead to increased recognition and improved management of anxiety disorders in pediatric medical settings. PMID- 20921358 TI - Protecting families from harm. PMID- 20921359 TI - Child protective services has outlived its usefulness. PMID- 20921360 TI - Anxiety disorders in children and adolescents. PMID- 20921361 TI - Three-dimensional tracking of single mRNA particles in Saccharomyces cerevisiae using a double-helix point spread function. AB - Optical imaging of single biomolecules and complexes in living cells provides a useful window into cellular processes. However, the three-dimensional dynamics of most important biomolecules in living cells remains essentially uncharacterized. The precise subcellular localization of mRNA-protein complexes plays a critical role in the spatial and temporal control of gene expression, and a full understanding of the control of gene expression requires precise characterization of mRNA transport dynamics beyond the optical diffraction limit. In this paper, we describe three-dimensional tracking of single mRNA particles with 25-nm precision in the x and y dimensions and 50-nm precision in the z dimension in live budding yeast cells using a microscope with a double-helix point spread function. Two statistical methods to detect intermittently confined and directed transport were used to quantify the three-dimensional trajectories of mRNA for the first time, using ARG3 mRNA as a model. Measurements and analysis show that the dynamics of ARG3 mRNA molecules are mostly diffusive, although periods of non Brownian confinement and directed transport are observed. The quantitative methods detailed in this paper can be broadly applied to the study of mRNA localization and the dynamics of diverse other biomolecules in a wide variety of cell types. PMID- 20921362 TI - Structures of aminoacylase 3 in complex with acetylated substrates. AB - Trichloroethylene (TCE) is one of the most widespread environmental contaminants, which is metabolized to N-acetyl-S-1,2-dichlorovinyl-L-cysteine (NA-DCVC) before being excreted in the urine. Alternatively, NA-DCVC can be deacetylated by aminoacylase 3 (AA3), an enzyme that is highly expressed in the kidney, liver, and brain. NA-DCVC deacetylation initiates the transformation into toxic products that ultimately causes acute renal failure. AA3 inhibition is therefore a target of interest to prevent TCE induced nephrotoxicity. Here we report the crystal structure of recombinant mouse AA3 (mAA3) in the presence of its acetate byproduct and two substrates: N(alpha)-acetyl-L-tyrosine and NA-DCVC. These structures, in conjunction with biochemical data, indicated that AA3 mediates substrate specificity through van der Waals interactions providing a dynamic interaction interface, which facilitates a diverse range of substrates. PMID- 20921364 TI - Satellite-based global-ocean mass balance estimates of interannual variability and emerging trends in continental freshwater discharge. AB - Freshwater discharge from the continents is a key component of Earth's water cycle that sustains human life and ecosystem health. Surprisingly, owing to a number of socioeconomic and political obstacles, a comprehensive global river discharge observing system does not yet exist. Here we use 13 years (1994-2006) of satellite precipitation, evaporation, and sea level data in an ocean mass balance to estimate freshwater discharge into the global ocean. Results indicate that global freshwater discharge averaged 36,055 km(3)/y for the study period while exhibiting significant interannual variability driven primarily by El Nino Southern Oscillation cycles. The method described here can ultimately be used to estimate long-term global discharge trends as the records of sea level rise and ocean temperature lengthen. For the relatively short 13-year period studied here, global discharge increased by 540 km(3)/y(2), which was largely attributed to an increase of global-ocean evaporation (768 km(3)/y(2)). Sustained growth of these flux rates into long-term trends would provide evidence for increasing intensity of the hydrologic cycle. PMID- 20921363 TI - Engineering of self-assembled nanoparticle platform for precisely controlled combination drug therapy. AB - The genomic revolution has identified therapeutic targets for a plethora of diseases, creating a need to develop robust technologies for combination drug therapy. In the present work, we describe a self-assembled polymeric nanoparticle (NP) platform to target and control precisely the codelivery of drugs with varying physicochemical properties to cancer cells. As proof of concept, we codelivered cisplatin and docetaxel (Dtxl) to prostate cancer cells with synergistic cytotoxicity. A polylactide (PLA) derivative with pendant hydroxyl groups was prepared and conjugated to a platinum(IV) [Pt(IV)] prodrug, c,t,c [Pt(NH(3))(2)(O(2)CCH(2)CH(2)COOH)(OH)Cl(2)] [PLA-Pt(IV)]. A blend of PLA-Pt(IV) functionalized polymer and carboxyl-terminated poly(D,L-lactic-co-glycolic acid) block-poly(ethylene glycol) copolymer in the presence or absence of Dtxl, was converted, in microfluidic channels, to NPs with a diameter of ~100 nm. This process resulted in excellent encapsulation efficiency (EE) and high loading of both hydrophilic platinum prodrug and hydrophobic Dtxl with reproducible EEs and loadings. The surface of the NPs was derivatized with the A10 aptamer, which binds to the prostate-specific membrane antigen (PSMA) on prostate cancer cells. These NPs undergo controlled release of both drugs over a period of 48-72 h. Targeted NPs were internalized by the PSMA-expressing LNCaP cells via endocytosis, and formation of cisplatin 1,2-d(GpG) intrastrand cross-links on nuclear DNA was verified. In vitro toxicities demonstrated superiority of the targeted dual-drug combination NPs over NPs with single drug or nontargeted NPs. This work reveals the potential of a single, programmable nanoparticle to blend and deliver a combination of drugs for cancer treatment. PMID- 20921365 TI - Controlling the growth and shape of chiral supramolecular polymers in water. AB - A challenging target in the noncovalent synthesis of nanostructured functional materials is the formation of uniform features that exhibit well-defined properties, e.g., precise control over the aggregate shape, size, and stability. In particular, for aqueous-based one-dimensional supramolecular polymers, this is a daunting task. Here we disclose a strategy based on self-assembling discotic amphiphiles that leads to the control over stack length and shape of ordered, chiral columnar aggregates. By balancing out attractive noncovalent forces within the hydrophobic core of the polymerizing building blocks with electrostatic repulsive interactions on the hydrophilic rim we managed to switch from elongated, rod-like assemblies to small and discrete objects. Intriguingly this rod-to-sphere transition is expressed in a loss of cooperativity in the temperature-dependent self-assembly mechanism. The aggregates were characterized using circular dichroism, UV and 1H-NMR spectroscopy, small angle X-ray scattering, and cryotransmission electron microscopy. In analogy to many systems found in biology, mechanistic details of the self-assembly pathways emphasize the importance of cooperativity as a key feature that dictates the physical properties of the produced supramolecular polymers. PMID- 20921366 TI - Mimicking nature by codelivery of stimulant and inhibitor to create temporally stable and spatially restricted angiogenic zones. AB - Nature frequently utilizes opposing factors to create a stable activator gradient to robustly control pattern formation. This study employs a biomimicry approach, by delivery of both angiogenic and antiangiogenic factors from spatially restricted zones of a synthetic polymer to achieve temporally stable and spatially restricted angiogenic zones in vivo. The simultaneous release of the two spatially separated agents leads to a spatially sharp angiogenic region that is sustained over 3 wk. Further, the contradictory action of the two agents leads to a stable level of proangiogenic stimulation in this region, in spite of significant variations in the individual release rates over time. The resulting spatially restrictive and temporally sustained profiles of active signaling allow the creation of a spatially heterogeneous and functional vasculature. PMID- 20921367 TI - Direct and enantioselective {alpha}-allylation of ketones via singly occupied molecular orbital (SOMO) catalysis. AB - The first enantioselective organocatalytic alpha-allylation of cyclic ketones has been accomplished via singly occupied molecular orbital catalysis. Geometrically constrained radical cations, forged from the one-electron oxidation of transiently generated enamines, readily undergo allylic alkylation with a variety of commercially available allyl silanes. A reasonable latitude in both the ketone and allyl silane components is readily accommodated in this new transformation. Moreover, three new oxidatively stable imidazolidinone catalysts have been developed that allow cyclic ketones to successfully participate in this transformation. The new catalyst platform has also been exploited in the first catalytic enantioselective alpha-enolation and alpha-carbooxidation of ketones. PMID- 20921368 TI - Structure, function, and folding of phosphoglycerate kinase are strongly perturbed by macromolecular crowding. AB - We combine experiment and computer simulation to show how macromolecular crowding dramatically affects the structure, function, and folding landscape of phosphoglycerate kinase (PGK). Fluorescence labeling shows that compact states of yeast PGK are populated as the amount of crowding agents (Ficoll 70) increases. Coarse-grained molecular simulations reveal three compact ensembles: C (crystal structure), CC (collapsed crystal), and Sph (spherical compact). With an adjustment for viscosity, crowded wild-type PGK and fluorescent PGK are about 15 times or more active in 200 mg/ml Ficoll than in aqueous solution. Our results suggest a previously undescribed solution to the classic problem of how the ADP and diphosphoglycerate binding sites of PGK come together to make ATP: Rather than undergoing a hinge motion, the ADP and substrate sites are already located in proximity under crowded conditions that mimic the in vivo conditions under which the enzyme actually operates. We also examine T-jump unfolding of PGK as a function of crowding experimentally. We uncover a nonmonotonic folding relaxation time vs. Ficoll concentration. Theory and modeling explain why an optimum concentration exists for fastest folding. Below the optimum, folding slows down because the unfolded state is stabilized relative to the transition state. Above the optimum, folding slows down because of increased viscosity. PMID- 20921369 TI - Nucleosome depletion at yeast terminators is not intrinsic and can occur by a transcriptional mechanism linked to 3'-end formation. AB - Genome-wide mapping of nucleosomes generated by micrococcal nuclease (MNase) suggests that yeast promoter and terminator regions are very depleted of nucleosomes, predominantly because their DNA sequences intrinsically disfavor nucleosome formation. However, MNase has strong DNA sequence specificity that favors cleavage at promoters and terminators and accounts for some of the correlation between occupancy patterns of nucleosomes assembled in vivo and in vitro. Using an improved method for measuring nucleosome occupancy in vivo that does not involve MNase, we confirm that promoter regions are strongly depleted of nucleosomes, but find that terminator regions are much less depleted than expected. Unlike at promoter regions, nucleosome occupancy at terminators is strongly correlated with the orientation of and distance to adjacent genes. In addition, nucleosome occupancy at terminators is strongly affected by growth conditions, indicating that it is not primarily determined by intrinsic histone DNA interactions. Rapid removal of RNA polymerase II (pol II) causes increased nucleosome occupancy at terminators, strongly suggesting a transcription-based mechanism of nucleosome depletion. However, the distinct behavior of terminator regions and their corresponding coding regions suggests that nucleosome depletion at terminators is not simply associated with passage of pol II, but rather involves a distinct mechanism linked to 3'-end formation. PMID- 20921370 TI - Structure of bacterial cellulose synthase subunit D octamer with four inner passageways. AB - The cellulose synthesizing terminal complex consisting of subunits A, B, C, and D in Acetobacter xylinum spans the outer and inner cell membranes to synthesize and extrude glucan chains, which are assembled into subelementary fibrils and further into a ribbon. We determined the structures of subunit D (AxCeSD/AxBcsD) with both N- and C-terminal His(6) tags, and in complex with cellopentaose. The structure of AxCeSD shows an exquisite cylinder shape (height: ~65 A, outer diameter: ~90 A, and inner diameter: ~25 A) with a right-hand twisted dimer interface on the cylinder wall, formed by octamer as a functional unit. All N termini of the octamer are positioned inside the AxCeSD cylinder and create four passageways. The location of cellopentaoses in the complex structure suggests that four glucan chains are extruded individually through their own passageway along the dimer interface in a twisted manner. The complex structure also shows that the N-terminal loop, especially residue Lys6, seems to be important for cellulose production, as confirmed by in vivo assay using mutant cells with axcesD gene disruption and N-terminus truncation. Taking all results together, a model of the bacterial terminal complex is discussed. PMID- 20921371 TI - Impacts of wind farms on surface air temperatures. AB - Utility-scale large wind farms are rapidly growing in size and numbers all over the world. Data from a meteorological field campaign show that such wind farms can significantly affect near-surface air temperatures. These effects result from enhanced vertical mixing due to turbulence generated by wind turbine rotors. The impacts of wind farms on local weather can be minimized by changing rotor design or by siting wind farms in regions with high natural turbulence. Using a 25-y long climate dataset, we identified such regions in the world. Many of these regions, such as the Midwest and Great Plains in the United States, are also rich in wind resources, making them ideal candidates for low-impact wind farms. PMID- 20921372 TI - Asian dust particles converted into aqueous droplets under remote marine atmospheric conditions. AB - The chemical history of dust particles in the atmosphere is crucial for assessing their impact on both the Earth's climate and ecosystem. So far, a number of studies have shown that, in the vicinity of strong anthropogenic emission sources, Ca-rich dust particles can be converted into aqueous droplets mainly by the reaction with gaseous HNO(3) to form Ca(NO(3))(2). Here we show that other similar processes have the potential to be activated under typical remote marine atmospheric conditions. Based on field measurements at several sites in East Asia and thermodynamic predictions, we examined the possibility for the formation of two highly soluble calcium salts, Ca(NO(3))(2) and CaCl(2), which can deliquesce at low relative humidity. According to the results, the conversion of insoluble CaCO(3) to Ca(NO(3))(2) tends to be dominated over urban and industrialized areas of the Asian continent, where the concentrations of HNO(3) exceed those of HCl ([HNO(3)/HCl] > ~ 1). In this regime, CaCl(2) is hardly detected from dust particles. However, the generation of CaCl(2) becomes detectable around the Japan Islands, where the concentrations of HCl are much higher than those of HNO(3) ([HNO(3)/HCl] < ~ 0.3). We suggest that elevated concentrations of HCl in the remote marine boundary layer are sufficient to modify Ca-rich particles in dust storms and can play a more important role in forming a deliquescent layer on the particle surfaces as they are transported toward remote ocean regions. PMID- 20921373 TI - DNA conformational changes at the primer-template junction regulate the fidelity of replication by DNA polymerase. AB - Local conformational changes in primer-template (P/T) DNA are involved in the selective incorporation of dNTP by DNA polymerases (DNAP). Here we use near UV CD and fluorescence spectra of pairs of base analogue probes, substituted either at the primer terminus or in the coding region of the template strand, to monitor and interpret conformational changes at and near the coding base of the template in P/T DNA complexes with Klenow fragment (KF) DNAP as the polymerase moves through the nucleotide addition cycle. Incoming dNTPs and rNTPs encounter binary complexes in which the 3'-end of the primer shuttles between the polymerization (pol) and exonuclease (exo) sites of DNAPs, even for perfectly complementary P/T DNA sequences. We have used spectral changes of probes inserted in both strands to monitor this two-state distribution and determine how it depends on the formation of ternary complexes with both complementary ("correct") and noncomplementary ("incorrect") NTPs and on the local sequence of the P/T DNA. The results show that the relative occupancy of the exo and pol sites is coupled to conformational changes in the P/T DNA of the complex that are partially regulated by the incoming NTP. We find that the coding base on the template strand is unperturbed by the binding of incorrect dNTPs, while binding of complementary rNTPs induces a novel template conformation. We conclude that, in addition to its editing function, primer strand occupancy of the 3'-exo site may also serve as a regulatory checkpoint for accurate dNTP selection in DNA synthesis. PMID- 20921374 TI - Injectable hydrogel microbeads for fluorescence-based in vivo continuous glucose monitoring. AB - Fluorescent microbeads hold great promise for in vivo continuous glucose monitoring with wireless transdermal transmission and long-lasting activity. The full potential of fluorescent microbeads has yet to be realized due to insufficient intensity for transdermal transmission and material toxicity. This paper illustrates the highly-sensitive, biostable, long-lasting, and injectable fluorescent microbeads for in vivo continuous glucose monitoring. We synthesized a fluorescent monomer composed of glucose-recognition sites, a fluorogenic site, spacers, and polymerization sites. The spacers are designed to be long and hydrophilic for increasing opportunities to bind glucose molecules; consequently, the fluorescent monomers enable high-intensive responsiveness to glucose. We then fabricated injectable-sized fluorescent polyacrylamide hydrogel beads with high uniformity and high throughput. We found that our fluorescent beads provide sufficient intensity to transdermally monitor glucose concentrations in vivo. The fluorescence intensity successfully traced the blood glucose concentration fluctuation, indicating our method has potential uses in highly-sensitive and minimally invasive continuous blood glucose monitoring. PMID- 20921375 TI - Forecasting potential global environmental costs of livestock production 2000 2050. AB - Food systems--in particular, livestock production--are key drivers of environmental change. Here, we compare the contributions of the global livestock sector in 2000 with estimated contributions of this sector in 2050 to three important environmental concerns: climate change, reactive nitrogen mobilization, and appropriation of plant biomass at planetary scales. Because environmental sustainability ultimately requires that human activities as a whole respect critical thresholds in each of these domains, we quantify the extent to which current and future livestock production contributes to published estimates of sustainability thresholds at projected production levels and under several alternative endpoint scenarios intended to illustrate the potential range of impacts associated with dietary choice. We suggest that, by 2050, the livestock sector alone may either occupy the majority of, or significantly overshoot, recently published estimates of humanity's "safe operating space" in each of these domains. In light of the magnitude of estimated impacts relative to these proposed (albeit uncertain) sustainability boundary conditions, we suggest that reining in growth of this sector should be prioritized in environmental governance. PMID- 20921376 TI - Recruitment of genes and enzymes conferring resistance to the nonnatural toxin bromoacetate. AB - Microbial niches contain toxic chemicals capable of forcing organisms into periods of intense natural selection to afford survival. Elucidating the mechanisms by which microbes evade environmental threats has direct relevance for understanding and combating the rise of antibiotic resistance. In this study we used a toxic small-molecule, bromoacetate, to model the selective pressures imposed by antibiotics and anthropogenic toxins. We report the results of genetic selection experiments that identify nine genes from Escherichia coli whose overexpression affords survival in the presence of a normally lethal concentration of bromoacetate. Eight of these genes encode putative transporters or transmembrane proteins, while one encodes the essential peptidoglycan biosynthetic enzyme, UDP-N-acetylglucosamine enolpyruvoyl transferase (MurA). Biochemical studies demonstrate that the primary physiological target of bromoacetate is MurA, which becomes irreversibly inactivated via alkylation of a critical active-site cysteine. We also screened a comprehensive library of E. coli single-gene deletion mutants and identified 63 strains displaying increased susceptibility to bromoacetate. One hypersensitive bacterium lacks yliJ, a gene encoding a predicted glutathione transferase. Herein, YliJ is shown to catalyze the glutathione-dependent dehalogenation of bromoacetate with a k(cat)/K(m) value of 5.4 * 10(3) M(-1) s(-1). YliJ displays exceptional substrate specificity and produces a rate enhancement exceeding 5 orders of magnitude, remarkable characteristics for reactivity with a nonnatural molecule. This study illustrates the wealth of intrinsic survival mechanisms that can be exploited by bacteria when they are challenged with toxins. PMID- 20921377 TI - Escherichia coli condensin MukB stimulates topoisomerase IV activity by a direct physical interaction. AB - In contrast to the current state of knowledge in the field of eukaryotic chromosome segregation, relatively little is known about the mechanisms coordinating the appropriate segregation of bacterial chromosomes. In Escherichia coli, the MukB/E/F complex and topoisomerase IV (Topo IV) are both crucial players in this process. Topo IV removes DNA entanglements following the replication of the chromosome, whereas MukB, a member of the structural maintenance of chromosomes protein family, serves as a bacterial condensin. We demonstrate here a direct physical interaction between the dimerization domain of MukB and the C-terminal domain of the ParC subunit of Topo IV. In addition, we find that MukB alters the activity of Topo IV in vitro. Finally, we isolate a MukB mutant, D692A, that is deficient in its interaction with ParC and show that this mutant fails to rescue the temperature-sensitive growth phenotype of a mukB( ) strain. These results show that MukB and Topo IV are linked physically and functionally and indicate that the activities of these proteins are not limited to chromosome segregation but likely also play a key role in the control of higher-order bacterial chromosome structure. PMID- 20921378 TI - Alkyltransferase-like protein (eATL) prevents mismatch repair-mediated toxicity induced by O6-alkylguanine adducts in Escherichia coli. AB - O(6)-alkylG adducts are highly mutagenic due to their capacity to efficiently form O(6)-alkylG:T mispairs during replication, thus triggering G->A transitions. Mutagenesis is largely prevented by repair strategies such as reversal by alkyltransferases or excision by nucleotide excision repair (NER). Moreover, methyl-directed mismatch repair (MMR) is known to trigger sensitivity to methylating agents via a mechanism that involves recognition by MutS of the O(6) mG:T replication intermediates. We wanted to investigate the mechanism by which MMR controls the genotoxicity of environmentally relevant O(6)-alkylG adducts formed by ethylene oxide and propylene oxide. Recently, the alkyltransferase-like gene ybaZ (eATL) was shown to enhance repair of these slightly larger O(6)-alkylG adducts by NER. We analyzed the toxicity and mutagenesis induced by these O(6) alkylG adducts using single-adducted plasmid probes. We show that the eATL gene product prevents MMR-mediated attack of the O(6)-alkylG:T replication intermediate for the larger alkyl groups but not for methyl. In vivo data are compatible with the occurrence of repeated cycles of MMR attack of the O(6) alkylG:T intermediate. In addition, in vitro, the eATL protein efficiently prevents binding of MutS to the O(6)-alkylG:T mispairs formed by the larger alkyl groups but not by methyl. In conclusion, eATL not only enhances the efficiency of repair of these larger adducts by NER, it also shields these adducts from MMR mediated toxicity. PMID- 20921379 TI - Demonstration of the importance for cellulose hydrolysis of CelS, the most abundant cellulosomal cellulase in Clostridium thermocellum [corrected]. PMID- 20921380 TI - Cancer stem cells from human breast tumors are involved in spontaneous metastases in orthotopic mouse models. AB - To examine the role of breast cancer stem cells (BCSCs) in metastasis, we generated human-in-mouse breast cancer orthotopic models using patient tumor specimens, labeled with optical reporter fusion genes. These models recapitulate human cancer features not captured with previous models, including spontaneous metastasis in particular, and provide a useful platform for studies of breast tumor initiation and progression. With noninvasive imaging approaches, as few as 10 cells of stably labeled BCSCs could be tracked in vivo, enabling studies of early tumor growth and spontaneous metastasis. These advances in BCSC imaging revealed that CD44(+) cells from both primary tumors and lung metastases are highly enriched for tumor-initiating cells. Our metastatic cancer models, combined with noninvasive imaging techniques, constitute an integrated approach that could be applied to dissect the molecular mechanisms underlying the dissemination of metastatic CSCs (MCSCs) and to explore therapeutic strategies targeting MCSCs in general or to evaluate individual patient tumor cells and predict response to therapy. PMID- 20921381 TI - EEG microstate sequences in healthy humans at rest reveal scale-free dynamics. AB - Recent findings identified electroencephalography (EEG) microstates as the electrophysiological correlates of fMRI resting-state networks. Microstates are defined as short periods (100 ms) during which the EEG scalp topography remains quasi-stable; that is, the global topography is fixed but strength might vary and polarity invert. Microstates represent the subsecond coherent activation within global functional brain networks. Surprisingly, these rapidly changing EEG microstates correlate significantly with activity in fMRI resting-state networks after convolution with the hemodynamic response function that constitutes a strong temporal smoothing filter. We postulate here that microstate sequences should reveal scale-free, self-similar dynamics to explain this remarkable effect and thus that microstate time series show dependencies over long time ranges. To that aim, we deploy wavelet-based fractal analysis that allows determining scale free behavior. We find strong statistical evidence that microstate sequences are scale free over six dyadic scales covering the 256-ms to 16-s range. The degree of long-range dependency is maintained when shuffling the local microstate labels but becomes indistinguishable from white noise when equalizing microstate durations, which indicates that temporal dynamics are their key characteristic. These results advance the understanding of temporal dynamics of brain-scale neuronal network models such as the global workspace model. Whereas microstates can be considered the "atoms of thoughts," the shortest constituting elements of cognition, they carry a dynamic signature that is reminiscent at characteristic timescales up to multiple seconds. The scale-free dynamics of the microstates might be the basis for the rapid reorganization and adaptation of the functional networks of the brain. PMID- 20921382 TI - On the swimming of Dictyostelium amoebae. PMID- 20921383 TI - Bacterial Na+-translocating ferredoxin:NAD+ oxidoreductase. AB - The anaerobic acetogenic bacterium Acetobacterium woodii carries out a unique type of Na(+)-motive, anaerobic respiration with caffeate as electron acceptor, termed "caffeate respiration." Central, and so far the only identified membrane bound reaction in this respiration pathway, is a ferredoxin:NAD(+) oxidoreductase (Fno) activity. Here we show that inverted membrane vesicles of A. woodii couple electron transfer from reduced ferredoxin to NAD(+) with the transport of Na(+) from the outside into the lumen of the vesicles. Na(+) transport was electrogenic, and accumulation was inhibited by sodium ionophores but not protonophores, demonstrating a direct coupling of Fno activity to Na(+) transport. Results from inhibitor studies are consistent with the hypothesis that Fno activity coupled to Na(+) translocation is catalyzed by the Rnf complex, a membrane-bound, iron-sulfur and flavin-containing electron transport complex encoded by many bacterial and some archaeal genomes. Fno is a unique type of primary Na(+) pump and represents an early evolutionary mechanism of energy conservation that expands the redox range known to support life. In addition, it explains the lifestyle of many anaerobic bacteria and gives a mechanistic explanation for the enigma of the energetic driving force for the endergonic reduction of ferredoxin with NADH plus H(+) as reductant in a number of aerobic bacteria. PMID- 20921384 TI - Initiation context modulates autoregulation of eukaryotic translation initiation factor 1 (eIF1). AB - The central feature of standard eukaryotic translation initiation is small ribosome subunit loading at the 5' cap followed by its 5' to 3' scanning for a start codon. The preferred start is an AUG codon in an optimal context. Elaborate cellular machinery exists to ensure the fidelity of start codon selection. Eukaryotic initiation factor 1 (eIF1) plays a central role in this process. Here we show that the translation of eIF1 homologs in eukaryotes from diverse taxa involves initiation from an AUG codon in a poor context. Using human eIF1 as a model, we show that this poor context is necessary for an autoregulatory negative feedback loop in which a high level of eIF1 inhibits its own translation, establishing that variability in the stringency of start codon selection is used for gene regulation in eukaryotes. We show that the stringency of start codon selection (preferential utilization of optimal start sites) is increased to a surprising degree by overexpressing eIF1. The capacity for the cellular level of eIF1 to impact initiation through the variable stringency of initiation codon selection likely has significant consequences for the proteome in eukaryotes. PMID- 20921385 TI - Correlation of brain amyloid with "aerobic glycolysis": A question of assumptions? PMID- 20921386 TI - Genome-wide analysis reveals methyl-CpG-binding protein 2-dependent regulation of microRNAs in a mouse model of Rett syndrome. AB - MicroRNAs (miRNAs) are a class of small, noncoding RNAs that function as posttranscriptional regulators of gene expression. Many miRNAs are expressed in the developing brain and regulate multiple aspects of neural development, including neurogenesis, dendritogenesis, and synapse formation. Rett syndrome (RTT) is a progressive neurodevelopmental disorder caused by mutations in the gene encoding methyl-CpG-binding protein 2 (MECP2). Although Mecp2 is known to act as a global transcriptional regulator, miRNAs that are directly regulated by Mecp2 in the brain are not known. Using massively parallel sequencing methods, we have identified miRNAs whose expression is altered in cerebella of Mecp2-null mice before and after the onset of severe neurological symptoms. In vivo genome wide analyses indicate that promoter regions of a significant fraction of dysregulated miRNA transcripts, including a large polycistronic cluster of brain specific miRNAs, are DNA-methylated and are bound directly by Mecp2. Functional analysis demonstrates that the 3' UTR of messenger RNA encoding Brain-derived neurotrophic factor (Bdnf) can be targeted by multiple miRNAs aberrantly up regulated in the absence of Mecp2. Taken together, these results suggest that dysregulation of miRNAs may contribute to RTT pathoetiology and also may provide a valuable resource for further investigations of the role of miRNAs in RTT. PMID- 20921387 TI - NADPH oxidase-4 mediates protection against chronic load-induced stress in mouse hearts by enhancing angiogenesis. AB - Cardiac failure occurs when the heart fails to adapt to chronic stresses. Reactive oxygen species (ROS)-dependent signaling is implicated in cardiac stress responses, but the role of different ROS sources remains unclear. Here we report that NADPH oxidase-4 (Nox4) facilitates cardiac adaptation to chronic stress. Unlike other Nox proteins, Nox4 activity is regulated mainly by its expression level, which increases in cardiomyocytes under stresses such as pressure overload or hypoxia. To investigate the functional role of Nox4 during the cardiac response to stress, we generated mice with a genetic deletion of Nox4 or a cardiomyocyte-targeted overexpression of Nox4. Basal cardiac function was normal in both models, but Nox4-null animals developed exaggerated contractile dysfunction, hypertrophy, and cardiac dilatation during exposure to chronic overload whereas Nox4-transgenic mice were protected. Investigation of mechanisms underlying this protective effect revealed a significant Nox4-dependent preservation of myocardial capillary density after pressure overload. Nox4 enhanced stress-induced activation of cardiomyocyte hypoxia inducible factor 1 and the release of vascular endothelial growth factor, resulting in increased paracrine angiogenic activity. These data indicate that cardiomyocyte Nox4 is a unique inducible regulator of myocardial angiogenesis, a key determinant of cardiac adaptation to overload stress. Our results also have wider relevance to the use of nonspecific antioxidant approaches in cardiac disease and may provide an explanation for the failure of such strategies in many settings. PMID- 20921388 TI - Bifidobacterium animalis subsp. lactis fermented milk product reduces inflammation by altering a niche for colitogenic microbes. AB - Intestinal health requires the coexistence of eukaryotic self with the gut microbiota and dysregulated host-microbial interactions can result in intestinal inflammation. Here, we show that colitis improved in T-bet(-/-)Rag2(-/-) mice that consumed a fermented milk product containing Bifidobacterium animalis subsp. lactis DN-173 010 strain. A decrease in cecal pH and alterations in short chain fatty acid profiles occurred with consumption, and there were concomitant increases in the abundance of select lactate-consuming and butyrate-producing bacteria. These metabolic shifts created a nonpermissive environment for the Enterobacteriaceae recently identified as colitogenic in a T-bet(-/-)Rag2(-/-) ulcerative colitis mouse model. In addition, 16S rRNA-based analysis of the T bet(-/-)Rag2(-/-) fecal microbiota suggest that the structure of the endogenous gut microbiota played a key role in shaping the host response to the bacterial strains studied herein. We have identified features of the gut microbiota, at the membership and functional level, associated with response to this B. lactis containing fermented milk product, and therefore this model provides a framework for evaluating and optimizing probiotic-based functional foods. PMID- 20921389 TI - Network-level structural covariance in the developing brain. AB - Intrinsic or resting state functional connectivity MRI and structural covariance MRI have begun to reveal the adult human brain's multiple network architectures. How and when these networks emerge during development remains unclear, but understanding ontogeny could shed light on network function and dysfunction. In this study, we applied structural covariance MRI techniques to 300 children in four age categories (early childhood, 5-8 y; late childhood, 8.5-11 y; early adolescence, 12-14 y; late adolescence, 16-18 y) to characterize gray matter structural relationships between cortical nodes that make up large-scale functional networks. Network nodes identified from eight widely replicated functional intrinsic connectivity networks served as seed regions to map whole brain structural covariance patterns in each age group. In general, structural covariance in the youngest age group was limited to seed and contralateral homologous regions. Networks derived using primary sensory and motor cortex seeds were already well-developed in early childhood but expanded in early adolescence before pruning to a more restricted topology resembling adult intrinsic connectivity network patterns. In contrast, language, social-emotional, and other cognitive networks were relatively undeveloped in younger age groups and showed increasingly distributed topology in older children. The so-called default-mode network provided a notable exception, following a developmental trajectory more similar to the primary sensorimotor systems. Relationships between functional maturation and structural covariance networks topology warrant future exploration. PMID- 20921390 TI - In an early branching metazoan, bacterial colonization of the embryo is controlled by maternal antimicrobial peptides. AB - Early embryos of many organisms develop outside the mother and are immediately confronted with myriads of potential colonizers. How these naive developmental stages control and shape the bacterial colonization is largely unknown. Here we show that early embryonic stages of the basal metazoan Hydra are able to control bacterial colonization by using maternal antimicrobial peptides. Antimicrobial peptides of the periculin family selecting for a specific bacterial colonization during embryogenesis are produced in the oocyte and in early embryos. If overexpressed in hydra ectodermal epithelial cells, periculin1a drastically reduces the bacterial load, indicating potent antimicrobial activity. Unexpectedly, transgenic polyps also revealed that periculin, in addition to bactericidal activity, changes the structure of the bacterial community. These findings delineate a role for antimicrobial peptides both in selecting particular bacterial partners during development and as important components of a "be prepared" strategy providing transgenerational protection. PMID- 20921391 TI - SNARE tagging allows stepwise assembly of a multimodular medicinal toxin. AB - Generation of supramolecular architectures through controlled linking of suitable building blocks can offer new perspectives to medicine and applied technologies. Current linking strategies often rely on chemical methods that have limitations and cannot take full advantage of the recombinant technologies. Here we used SNARE proteins, namely, syntaxin, SNAP25, and synaptobrevin, which form stable tetrahelical complexes that drive fusion of intracellular membranes, as versatile tags for irreversible linking of recombinant and synthetic functional units. We show that SNARE tagging allows stepwise production of a functional modular medicinal toxin, namely, botulinum neurotoxin type A, commonly known as BOTOX. This toxin consists of three structurally independent units: Receptor-binding domain (Rbd), Translocation domain (Td), and the Light chain (Lc), the last being a proteolytic enzyme. Fusing the receptor-binding domain with synaptobrevin SNARE motif allowed delivery of the active part of botulinum neurotoxin (Lc-Td), tagged with SNAP25, into neurons. Our data show that SNARE-tagged toxin was able to cleave its intraneuronal molecular target and to inhibit release of neurotransmitters. The reassembled toxin provides a safer alternative to existing botulinum neurotoxin and may offer wider use of this popular research and medical tool. Finally, SNARE tagging allowed the Rbd portion of the toxin to be used to deliver quantum dots and other fluorescent markers into neurons, showing versatility of this unique tagging and self-assembly technique. Together, these results demonstrate that the SNARE tetrahelical coiled-coil allows controlled linking of various building blocks into multifunctional assemblies. PMID- 20921392 TI - Somatic sex determination in Caenorhabditis elegans is modulated by SUP-26 repression of tra-2 translation. AB - Translational repression mediated by RNA-binding proteins or micro RNAs has emerged as a major regulatory mechanism for fine-tuning important biological processes. In Caenorhabditis elegans, translational repression of the key sex determination gene tra-2 (tra, transformer) is controlled by a 28-nucleotide repeat element, the TRA-2/GLI element (TGE), located in its 3' untranslated region (UTR). Mutations that disrupt TGE or the germline-specific TGE-binding factor GLD-1 increase TRA-2 protein expression and inhibit sperm production in hermaphrodites. Here we report the characterization of the sup-26 gene, which regulates sex determination in the soma and encodes an RNA recognition motif (RRM)-containing protein. We show that SUP-26 regulates the level of the TRA-2 protein through TGE in vivo and binds directly to TGE in vitro through its RRM domain. Interestingly, SUP-26 associates with poly(A)-binding protein 1 (PAB-1) in vivo and may repress tra-2 expression by inhibiting the translation stimulating activity of PAB-1. Taken together, our results provide further insight into how mRNA-binding factors repress translation and modulate sexual development in different tissues of C. elegans. PMID- 20921393 TI - Surprising flexibility in a conserved Hox transcription factor over 550 million years of evolution. AB - Although metazoan body plans are remarkably diverse, the structure and function of many embryonic regulatory genes are conserved because large changes would be detrimental to development. However, the fushi tarazu (ftz) gene has changed dramatically during arthropod evolution from Hox-like to a pair-rule segmentation gene in Drosophila. Changes in both expression and protein sequence contributed to this new function: ftz expression switched from Hox-like to stripes and changes in Ftz cofactor interaction motifs led to loss of homeotic and gain of segmentation potential. Here, we reconstructed ftz changes in a rigorous phylogenetic context. We found that ftz did not simply switch from Hox-like to segmentation function; rather, ftz is remarkably labile, having undergone multiple changes in sequence and expression. The segmentation LXXLL motif was stably acquired in holometabolous insects after the appearance of striped expression in early insect lineages. The homeotic YPWM motif independently degenerated multiple times. These "degen-YPWMs" showed varying degrees of homeotic potential when expressed in Drosophila, suggesting variable loss of Hox function in different arthropods. Finally, the intensity of ftz Hox-like expression decreased to marginal levels in some crustaceans. We propose that decreased expression levels permitted ftz variants to arise and persist in populations without disadvantaging organismal development. This process, in turn, allowed evolutionary transitions in protein function, as weakly expressed "hopeful gene variants" were coopted into alternative developmental pathways. Our findings show that variation of a pleiotropic transcription factor is more extensive than previously imagined, suggesting that evolutionary plasticity may be widespread among regulatory genes. PMID- 20921394 TI - Connexin 43 is critical to maintain the homeostasis of the blood-testis barrier via its effects on tight junction reassembly. AB - In mammalian testes, the blood-testis barrier (BTB) or Sertoli cell barrier created by specialized junctions between Sertoli cells near the basement membrane confers an immunological barrier by sequestering the events of meiotic division and postmeiotic germ cell development from the systemic circulation. The BTB is constituted by coexisting tight junctions (TJs), basal ectoplasmic specializations, desmosomes, and gap junctions. Despite being one of the tightest blood-tissue barriers, the BTB has to restructure cyclically during spermatogenesis. A recent study showed that gap junction protein connexin 43 (Cx43) and desmosome protein plakophilin-2 are working synergistically to modulate the BTB integrity by regulating the distribution of TJ-associated proteins at the Sertoli-Sertoli cell interface. However, the precise role of Cx43 in regulating the cyclical restructuring of junctions remains obscure. In this report, the calcium switch and the bisphenol A (BPA) models were used to induce junction restructuring in primary cultures of Sertoli cells isolated from rat testes that formed a TJ-permeability barrier that mimicked the BTB in vivo. The removal of calcium by EGTA perturbed the Sertoli cell tight junction barrier, but calcium repletion allowed the "resealing" of the disrupted barrier. However, a knockdown of Cx43 in Sertoli cells by RNAi significantly reduced the kinetics of TJ-barrier resealing. These observations were confirmed using the bisphenol A model in which the knockdown of Cx43 by RNAi also perturbed the TJ-barrier reassembly following BPA removal. In summary, Cx43 is crucial for TJ reassembly at the BTB during its cyclic restructuring throughout the seminiferous epithelial cycle of spermatogenesis. PMID- 20921395 TI - Correction of respiratory disorders in a mouse model of Rett syndrome. AB - Rett syndrome (RTT) is an autism spectrum disorder caused by mutations in the X linked gene that encodes the transcription factor methyl-CpG-binding protein 2 (MeCP2). A major debilitating phenotype in affected females is frequent apneas, and heterozygous Mecp2-deficient female mice mimic the human respiratory disorder. GABA defects have been demonstrated in the brainstem of Mecp2-deficient mice. Here, using an intact respiratory network, we show that apnea in RTT mice is characterized by excessive excitatory activity in expiratory cranial and spinal nerves. Augmenting GABA markedly improves the respiratory phenotype. In addition, a serotonin 1a receptor agonist that depresses expiratory neuron activity also reduces apnea, corrects the irregular breathing pattern, and prolongs survival in MeCP2 null males. Combining a GABA reuptake blocker with a serotonin 1a agonist in heterozygous females completely corrects their respiratory defects. The results indicate that GABA and serotonin 1a receptor activity are candidates for treatment of the respiratory disorders in Rett syndrome. PMID- 20921396 TI - Neurotoxic lupus autoantibodies alter brain function through two distinct mechanisms. AB - Damaging interactions between antibodies and brain antigenic targets may be responsible for an expanding range of neurological disorders. In the case of systemic lupus erythematosus (SLE), patients generate autoantibodies (AAbs) that frequently bind dsDNA. Although some symptoms of SLE may arise from direct reactivity to dsDNA, much of the AAb-mediated damage originates from cross reactivity with other antigens. We have studied lupus AAbs that bind dsDNA and cross-react with the NR2A and NR2B subunits of the NMDA receptor (NMDAR). In adult mouse models, when the blood-brain barrier is compromised, these NMDAR reactive AAbs access the brain and elicit neuronal death with ensuing cognitive dysfunction and emotional disturbance. The cellular mechanisms that underlie these deleterious effects remain incompletely understood. Here, we show that, at low concentration, the NMDAR-reactive AAbs are positive modulators of receptor function that increase the size of NMDAR-mediated excitatory postsynaptic potentials, whereas at high concentration, the AAbs promote excitotoxicity through enhanced mitochondrial permeability transition. Other synaptic receptors are completely unaffected by the AAbs. NMDAR activation is required for producing both the synaptic and the mitochondrial effects. Our study thus reveals the mechanisms by which NMDAR-reactive AAbs trigger graded cellular alterations, which are likely to be responsible for the transient and permanent neuropsychiatric symptoms observed in patients with SLE. Our study also provides a model in which local AAb concentration determines the exact nature of the cellular response. PMID- 20921398 TI - Bird communities in future bioenergy landscapes of the Upper Midwest. AB - Mandates for biofuel and renewable electricity are creating incentives for biomass production in agricultural landscapes of the Upper Midwest. Different bioenergy crops are expected to vary in their effects on biodiversity and ecosystem services. Here, we use data from the North American Breeding Bird Survey to forecast the impact of potential bioenergy crops on avian species richness and the number of bird species of conservation concern in Midwestern landscapes. Our analysis suggests that expanded production of annual bioenergy crops (e.g., corn and soybeans) on marginal land will lead to declines in avian richness between 7% and 65% across 20% of the region, and will make managing at risk species more challenging. In contrast, replacement of annual with diverse perennial bioenergy crops (e.g., mixed grasses and forbs) is expected to bring increases in avian richness between 12% and 207% across 20% of the region, and possibly aid the recovery of several species of conservation concern. PMID- 20921397 TI - Development of a highly efficacious vaccinia-based dual vaccine against smallpox and anthrax, two important bioterror entities. AB - Bioterrorism poses a daunting challenge to global security and public health in the 21st century. Variola major virus, the etiological agent of smallpox, and Bacillus anthracis, the bacterial pathogen responsible for anthrax, remain at the apex of potential pathogens that could be used in a bioterror attack to inflict mass casualties. Although licensed vaccines are available for both smallpox and anthrax, because of inadequacies associated with each of these vaccines, serious concerns remain as to the deployability of these vaccines, especially in the aftermath of a bioterror attack involving these pathogens. We have developed a single vaccine (Wyeth/IL-15/PA) using the licensed Wyeth smallpox vaccine strain that is efficacious against both smallpox and anthrax due to the integration of immune-enhancing cytokine IL-15 and the protective antigen (PA) of B. anthracis into the Wyeth vaccinia virus. Integration of IL-15 renders Wyeth vaccinia avirulent in immunodeficient mice and enhances anti-vaccinia immune responses. Wyeth/IL-15/PA conferred sterile protection against a lethal challenge of B. anthracis Ames strain spores in rabbits. A single dose of Wyeth/IL-15/PA protected 33% of the vaccinated A/J mice against a lethal spore challenge 72 h later whereas a single dose of licensed anthrax vaccine protected only 10%. Our dual vaccine Wyeth/IL-15/PA remedies the inadequacies associated with the licensed vaccines, and the inherent ability of Wyeth vaccinia virus to be lyophilized without loss of potency makes it cold-chain independent, thus simplifying the logistics of storage, stockpiling, and field delivery in the event of a bioterror attack involving smallpox or anthrax. PMID- 20921399 TI - Long-running German panel survey shows that personal and economic choices, not just genes, matter for happiness. AB - Psychologists and economists take contradictory approaches to research on what psychologists call happiness or subjective well-being, and economists call subjective utility. A direct test of the most widely accepted psychological theory, set-point theory, shows it to be flawed. Results are then given, using the economists' newer "choice approach"--an approach also favored by positive psychologists--which yields substantial payoffs in explaining long-term changes in happiness. Data come from the German Socio-Economic Panel (1984-2008), a unique 25-y prospective longitudinal survey. This dataset enables direct tests of theories explaining long-term happiness. PMID- 20921400 TI - Decreased ENaC expression compensates the increased NCC activity following inactivation of the kidney-specific isoform of WNK1 and prevents hypertension. AB - Mutations in WNK1 and WNK4 lead to familial hyperkalemic hypertension (FHHt). Because FHHt associates net positive Na(+) balance together with K(+) and H(+) renal retention, the identification of WNK1 and WNK4 led to a new paradigm to explain how aldosterone can promote either Na(+) reabsorption or K(+) secretion in a hypovolemic or hyperkalemic state, respectively. WNK1 gives rise to L-WNK1, an ubiquitous kinase, and KS-WNK1, a kinase-defective isoform expressed in the distal convoluted tubule. By inactivating KS-WNK1 in mice, we show here that this isoform is an important regulator of sodium transport. KS-WNK1(-/-) mice display an increased activity of the Na-Cl cotransporter NCC, expressed specifically in the distal convoluted tubule, where it participates in the fine tuning of sodium reabsorption. Moreover, the expression of the ROMK and BKCa potassium channels was modified in KS-WNK1(-/-) mice, indicating that KS-WNK1 is also a regulator of potassium transport in the distal nephron. Finally, we provide an alternative model for FHHt. Previous studies suggested that the activation of NCC plays a central role in the development of hypertension and hyperkalemia. Even though the increase in NCC activity in KS-WNK1(-/-) mice was less pronounced than in mice overexpressing a mutant form of WNK4, our study suggests that the activation of Na-Cl cotransporter is not sufficient by itself to induce a hyperkalemic hypertension and that the deregulation of other channels, such as the Epithelial Na(+) channel (ENaC), is probably required. PMID- 20921401 TI - Prefrontal cortex and basal ganglia contributions to visual working memory. AB - Visual working memory (VWM) is a remarkable skill dependent on the brain's ability to construct and hold an internal representation of the world for later comparison with an external stimulus. The prefrontal cortex (PFC) and basal ganglia (BG) interact within a cortical and subcortical network supporting VWM. We used scalp electroencephalography in groups of patients with unilateral PFC or BG lesions to provide evidence that these regions play complementary but dissociable roles in VWM. PFC patients show behavioral and electrophysiological deficits manifested by attenuation of extrastriate attention and VWM-related neural activity only for stimuli presented to the contralesional visual field. In contrast, patients with BG lesions show behavioral and electrophysiological VWM deficits independent of the hemifield of stimulus presentation but have intact extrastriate attention activity. The results support a model wherein the PFC is critical for top-down intrahemispheric modulation of attention and VWM with the BG involved in global support of VWM processes. PMID- 20921402 TI - Development of the malaria parasite in the skin of the mammalian host. AB - The first step of Plasmodium development in vertebrates is the transformation of the sporozoite, the parasite stage injected by the mosquito in the skin, into merozoites, the stage that invades erythrocytes and initiates the disease. The current view is that, in mammals, this stage conversion occurs only inside hepatocytes. Here, we document the transformation of sporozoites of rodent infecting Plasmodium into merozoites in the skin of mice. After mosquito bite, ~50% of the parasites remain in the skin, and at 24 h ~10% are developing in the epidermis and the dermis, as well as in the immunoprivileged hair follicles where they can survive for weeks. The parasite developmental pathway in skin cells, although frequently abortive, leads to the generation of merozoites that are infective to erythrocytes and are released via merosomes, as typically observed in the liver. Therefore, during malaria in rodents, the skin is not just the route to the liver but is also the final destination for many inoculated parasites, where they can differentiate into merozoites and possibly persist. PMID- 20921403 TI - Characterization of mononuclear phagocytic cells in medaka fish transgenic for a cxcr3a:gfp reporter. AB - Chemokines and chemokine receptors are key evolutionary innovations of vertebrates. They are involved in morphogenetic processes and play an important role in the immune system. Based on an analysis of the chemokine receptor gene family in teleost genomes, and the expression patterns of chemokine receptor genes during embryogenesis and the wounding response in young larvae of Oryzias latipes, we identified the chemokine receptor cxcr3a as a marker of innate immune cells. Cells expressing cxcr3a were characterized in fish transgenic for a cxcr3a:gfp reporter. In embryos and larvae, cxcr3a-expressing cells are motile in healthy and damaged tissues, and phagocytic; the majority of these cells has the morphology of tissue macrophages, whereas a small fraction has a dendritic phenotype. In adults, cxcr3a-positive cells continue to specifically express myeloid-associate markers and genes related to antigen uptake and presentation. By light microscopy and ultrastructural analysis, the majority of cxcr3a expressing cells has a dendritic phenotype, whereas the remainder resembles macrophage-like cells. After challenge of adult fish with bacteria or CpG oligonucleotides, phagocytosing cxcr3a-positive cells in the blood up-regulated il12p40 genes, compatible with their function as part of the mononuclear phagocytic system. Our results identify a marker of teleost mononuclear phagocytic cells and suggest a surprising degree of morphological and functional similarity between the innate immune systems of lower and higher vertebrates. PMID- 20921404 TI - Dopamine modulates synaptic plasticity in dendrites of rat and human dentate granule cells. AB - The mechanisms underlying memory formation in the hippocampal network remain a major unanswered aspect of neuroscience. Although high-frequency activity appears essential for plasticity, salience for memory formation is also provided by activity in ventral tegmental area (VTA) dopamine projections. Here, we report that activation of dopamine D1 receptors in dentate granule cells (DGCs) can preferentially increase dendritic excitability to both high-frequency afferent activity and high-frequency trains of backpropagating action potentials. Using whole-cell patch clamp recordings, calcium imaging, and neuropeptide Y to inhibit postsynaptic calcium influx, we found that activation of dendritic voltage dependent calcium channels (VDCCs) is essential for dopamine-induced long-term potentiation (LTP), both in rat and human dentate gyrus (DG). Moreover, we demonstrate previously unreported spike-timing-dependent plasticity in the human hippocampus. These results suggest that when dopamine is released in the dentate gyrus with concurrent high-frequency activity there is an increased probability that synapses will be strengthened and reward-associated spatial memories will be formed. PMID- 20921405 TI - NF-kappaB inhibits T-cell activation-induced, p73-dependent cell death by induction of MDM2. AB - NF-kappaB is a key transcription factor involved in the regulation of T-cell activation and proliferation upon engagement of the T-cell receptor (TCR). T cells that lack the IkappaB kinase (IKKbeta) are unable to activate NF-kappaB, and rapidly undergo apoptosis upon activation. NF-kappaB activation following T cell receptor engagement induces the expression of Mdm2 through interaction with NF-kappaB sites in its P1 promoter, and enforced expression of Mdm2 protected T cells deficient for NF-kappaB activation from activation-induced cell death. In T cells with intact NF-kappaB signaling, ablation or pharmacologic inhibition of Mdm2 resulted in activation-induced apoptosis. Mdm2 coprecipitates with p73 in activated T cells, and apoptosis induced by inhibition of Mdm2 was p73-dependent. Further, Bim was identified as a p73 target gene required for cell death induced by Mdm2 inhibition, and a p73-responsive element in intron 1 of Bim was characterized. Our results demonstrate a pathway for survival of activated T cells through NF-kappaB-induced Mdm2, which blocks Bim-dependent apoptosis through binding and inhibition of p73. PMID- 20921406 TI - Duration of antigen receptor signaling determines T-cell tolerance or activation. AB - The early events that determine the decision between lymphocyte tolerance and activation are not well-understood. Using a model of systemic self-antigen recognition by CD4(+) T cells, we show, using single-cell biochemical analyses, that tolerance is characterized by transient signaling events downstream of T cell receptor engagement in the mammalian target of rapamycin (mTOR) and NF kappaB pathways. Parallel studies done by live cell imaging show that the key difference between tolerance and activation is the duration of the T cell-antigen presenting cell (APC) interaction, as revealed by stable T-cell immobilization on antigen encounter. Brief T cell-APC interactions result in tolerance, and prolonged interactions are associated with activation and the development of effector cells. These studies show that the duration of T cell-APC interactions and magnitude of associated TCR-mediated signaling are key determinants of lymphocyte tolerance vs. activation. PMID- 20921407 TI - Loss of Goosecoid-like and DiGeorge syndrome critical region 14 in interpeduncular nucleus results in altered regulation of rapid eye movement sleep. AB - Sleep and wakefulness are regulated primarily by inhibitory interactions between the hypothalamus and brainstem. The expression of the states of rapid eye movement (REM) sleep and non-REM (NREM) sleep also are correlated with the activity of groups of REM-off and REM-on neurons in the dorsal brainstem. However, the contribution of ventral brainstem nuclei to sleep regulation has been little characterized to date. Here we examined sleep and wakefulness in mice deficient in a homeobox transcription factor, Goosecoid-like (Gscl), which is one of the genes deleted in DiGeorge syndrome or 22q11 deletion syndrome. The expression of Gscl is restricted to the interpeduncular nucleus (IP) in the ventral region of the midbrain-hindbrain transition. The IP has reciprocal connections with several cell groups implicated in sleep/wakefulness regulation. Although Gscl(-/-) mice have apparently normal anatomy and connections of the IP, they exhibited a reduced total time spent in REM sleep and fewer REM sleep episodes. In addition, Gscl(-/-) mice showed reduced theta power during REM sleep and increased arousability during REM sleep. Gscl(-/-) mice also lacked the expression of DiGeorge syndrome critical region 14 (Dgcr14) in the IP. These results indicate that the absence of Gscl and Dgcr14 in the IP results in altered regulation of REM sleep. PMID- 20921408 TI - Dated molecular phylogenies indicate a Miocene origin for Arabidopsis thaliana. AB - Dated molecular phylogenies are the basis for understanding species diversity and for linking changes in rates of diversification with historical events such as restructuring in developmental pathways, genome doubling, or dispersal onto a new continent. Valid fossil calibration points are essential to the accurate estimation of divergence dates, but for many groups of flowering plants fossil evidence is unavailable or limited. Arabidopsis thaliana, the primary genetic model in plant biology and the first plant to have its entire genome sequenced, belongs to one such group, the plant family Brassicaceae. Thus, the timing of A. thaliana evolution and the history of its genome have been controversial. We bring previously overlooked fossil evidence to bear on these questions and find the split between A. thaliana and Arabidopsis lyrata occurred about 13 Mya, and that the split between Arabidopsis and the Brassica complex (broccoli, cabbage, canola) occurred about 43 Mya. These estimates, which are two- to threefold older than previous estimates, indicate that gene, genomic, and developmental evolution occurred much more slowly than previously hypothesized and that Arabidopsis evolved during a period of warming rather than of cooling. We detected a 2- to 10 fold shift in species diversification rates on the branch uniting Brassicaceae with its sister families. The timing of this shift suggests a possible impact of the Cretaceous-Paleogene mass extinction on their radiation and that Brassicales codiversified with pierid butterflies that specialize on mustard-oil-producing plants. PMID- 20921409 TI - Sequential action of Caenorhabditis elegans Rab GTPases regulates phagolysosome formation during apoptotic cell degradation. AB - Phagocytosis of apoptotic cells requires recognition of cell corpses followed by internalization and enclosure within plasma membrane-derived phagosomes. Phagosomes undergo maturation to generate phagolysosomes in which cell corpses are degraded; however, regulation of the maturation process is poorly understood. Here, we identified Rab GTPase 14, which regulates apoptotic cell degradation in Caenorhabditis elegans. rab-14 mutants accumulate many persistent cell corpses owing to defective cell corpse clearance. Loss of rab-14 function affects several steps of phagosome maturation including phagosomal acidification and phagolysosome formation. RAB-14 and UNC-108/RAB2 are recruited to phagosomes at a similar stage and function redundantly to regulate phagosome maturation. Three Rabs, RAB-14, UNC-108/RAB2, and RAB-7, act in sequential steps to control phagolysosome formation. RAB-14 and UNC-108 recruit lysosomes, whereas RAB-7 mediates fusion of lysosomes to phagosomes. Our data reveal the sequential action of Rab GTPases in regulating tethering, docking, and fusion of lysosomes to apoptotic cell-containing phagosomes. PMID- 20921410 TI - Arc regulates spine morphology and maintains network stability in vivo. AB - Long-term memory relies on modulation of synaptic connections in response to experience. This plasticity involves trafficking of AMPA receptors (AMPAR) and alteration of spine morphology. Arc, a gene induced by synaptic activity, mediates the endocytosis of AMPA receptors and is required for both long-term and homeostatic plasticity. We found that Arc increases spine density and regulates spine morphology by increasing the proportion of thin spines. Furthermore, Arc specifically reduces surface GluR1 internalization at thin spines, and Arc mutants that fail to facilitate AMPAR endocytosis do not increase the proportion of thin spines, suggesting that Arc-mediated AMPAR endocytosis facilitates alterations in spine morphology. Thus, by linking spine morphology with AMPAR endocytosis, Arc balances synaptic downscaling with increased structural plasticity. Supporting this, loss of Arc in vivo leads to a significant decrease in the proportion of thin spines and an epileptic-like network hyperexcitability. PMID- 20921411 TI - Anaphase-promoting complex/cyclosome-Cdh1 coordinates glycolysis and glutaminolysis with transition to S phase in human T lymphocytes. AB - Cell proliferation is accompanied by an increase in the utilization of glucose and glutamine. The proliferative response is dependent on a decrease in the activity of the ubiquitin ligase anaphase-promoting complex/cyclosome (APC/C) Cdh1 which controls G1-to-S-phase transition by targeting degradation motifs, notably the KEN box. This occurs not only in cell cycle proteins but also in the glycolysis-promoting enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase isoform 3 (PFKFB3), as we have recently demonstrated in cells in culture. We now show that APC/C-Cdh1 controls the proliferative response of human T lymphocytes. Moreover, we have found that glutaminase 1 is a substrate for this ubiquitin ligase and appears at the same time as PFKFB3 in proliferating T lymphocytes. Glutaminase 1 is the first enzyme in glutaminolysis, which converts glutamine to lactate, yielding intermediates for cell proliferation. Thus APC/C-Cdh1 is responsible for the provision not only of glucose but also of glutamine and, as such, accounts for the critical step that links the cell cycle with the metabolic substrates essential for its progression. PMID- 20921412 TI - Endocytosis is required for Toll signaling and shaping of the Dorsal/NF-kappaB morphogen gradient during Drosophila embryogenesis. AB - Dorsoventral cell fate in the Drosophila embryo is specified by activation of the Toll receptor, leading to a ventral-to-dorsal gradient across nuclei of the NF kappaB transcription factor Dorsal. Toll receptor has been investigated genetically, molecularly, and immunohistologically, but much less is known about its dynamics in living embryos. Using live imaging of fluorescent protein chimeras, we find that Toll is recruited from the plasma membrane to Rab5(+) early endosomes. The distribution of a constitutively active form of Toll, Toll(10b), is shifted from the plasma membrane to early endosomes. Inhibition of endocytosis on the ventral side of the embryo attenuates Toll signaling ventrally and causes Dorsal to accumulate on the dorsal side of the embryo, essentially inverting the dorsal/ventral axis. Conversely, enhancing endocytosis laterally greatly potentiates Toll signaling locally, altering the shape of the Dorsal gradient. Photoactivation and fluorescence recovery after photobleaching studies reveal that Toll exhibits extremely limited lateral diffusion within the plasma membrane, whereas Toll is highly compartmentalized in endosomes. When endocytosis is blocked ventrally, creating an ectopic dorsal signaling center, Toll is preferentially endocytosed at the ectopic signaling center. We propose that Toll signals from an endocytic compartment rather than the plasma membrane. Our studies reveal that endocytosis plays a pivotal role in the spatial regulation of Toll receptor activation and signaling and in the correct shaping of the nuclear Dorsal concentration gradient. PMID- 20921413 TI - Climate mitigation and the future of tropical landscapes. AB - Land-use change to meet 21st-century demands for food, fuel, and fiber will depend on many interactive factors, including global policies limiting anthropogenic climate change and realized improvements in agricultural productivity. Climate-change mitigation policies will alter the decision-making environment for land management, and changes in agricultural productivity will influence cultivated land expansion. We explore to what extent future increases in agricultural productivity might offset conversion of tropical forest lands to crop lands under a climate mitigation policy and a contrasting no-policy scenario in a global integrated assessment model. The Global Change Assessment Model is applied here to simulate a mitigation policy that stabilizes radiative forcing at 4.5 W m(-2) (approximately 526 ppm CO(2)) in the year 2100 by introducing a price for all greenhouse gas emissions, including those from land use. These scenarios are simulated with several cases of future agricultural productivity growth rates and the results downscaled to produce gridded maps of potential land-use change. We find that tropical forests are preserved near their present-day extent, and bioenergy crops emerge as an effective mitigation option, only in cases in which a climate mitigation policy that includes an economic price for land-use emissions is in place, and in which agricultural productivity growth continues throughout the century. We find that idealized land-use emissions price assumptions are most effective at limiting deforestation, even when cropland area must increase to meet future food demand. These findings emphasize the importance of accounting for feedbacks from land-use change emissions in global climate change mitigation strategies. PMID- 20921414 TI - Genome-wide association study (GWAS)-identified disease risk alleles do not compromise human longevity. AB - A set of currently known alleles increasing the risk for coronary artery disease, cancer, and type 2 diabetes as identified by genome-wide association studies was tested for compatibility with human longevity. Here, we show that nonagenarian siblings from long-lived families and singletons older than 85 y of age from the general population carry the same number of disease risk alleles as young controls. Longevity in this study population is not compromised by the cumulative effect of this set of risk alleles for common disease. PMID- 20921415 TI - Both sides retaliate in the Israeli-Palestinian conflict. AB - Ending violent international conflicts requires understanding the causal factors that perpetuate them. In the Israeli-Palestinian conflict, Israelis and Palestinians each tend to see themselves as victims, engaging in violence only in response to attacks initiated by a fundamentally and implacably violent foe bent on their destruction. Econometric techniques allow us to empirically test the degree to which violence on each side occurs in response to aggression by the other side. Prior studies using these methods have argued that Israel reacts strongly to attacks by Palestinians, whereas Palestinian violence is random (i.e., not predicted by prior Israeli attacks). Here we replicate prior findings that Israeli killings of Palestinians increase after Palestinian killings of Israelis, but crucially show further that when nonlethal forms of violence are considered, and when a larger dataset is used, Palestinian violence also reveals a pattern of retaliation: (i) the firing of Palestinian rockets increases sharply after Israelis kill Palestinians, and (ii) the probability (although not the number) of killings of Israelis by Palestinians increases after killings of Palestinians by Israel. These findings suggest that Israeli military actions against Palestinians lead to escalation rather than incapacitation. Further, they refute the view that Palestinians are uncontingently violent, showing instead that a significant proportion of Palestinian violence occurs in response to Israeli behavior. Well-established cognitive biases may lead participants on each side of the conflict to underappreciate the degree to which the other side's violence is retaliatory, and hence to systematically underestimate their own role in perpetuating the conflict. PMID- 20921416 TI - Regional differences in cellular mechanisms of adipose tissue gain with overfeeding. AB - Body fat distribution is an important predictor of the metabolic consequences of obesity, but the cellular mechanisms regulating regional fat accumulation are unknown. We assessed the changes in adipocyte size (photomicrographs) and number in response to overfeeding in upper- and lower-body s.c. fat depots of 28 healthy, normal weight adults (15 men) age 29 +/- 2 y. We analyzed how these changes relate to regional fat gain (dual energy X-ray absorptiometry and computed tomography) and baseline preadipocyte proliferation, differentiation [peroxisome proliferator-activated receptor-gamma2 (PPARgamma2) and CCAAT/enhancer binding protein-alpha (C/EBPalpha) mRNA]), and apoptotic response to TNF-alpha. Fat mass increased by 1.9 +/- 0.2 kg in the upper body and 1.6 +/- 0.1 kg in the lower body. Average abdominal s.c. adipocyte size increased by 0.16 +/- 0.06 MUg lipid per cell and correlated with relative upper-body fat gain (r = 0.74, P < 0.0001). However, lower-body fat responded to overfeeding by fat-cell hyperplasia, with adipocyte number increasing by 2.6 +/- 0.9 * 10(9) cells (P < 0.01). We found no depot-differences in preadipocyte replication or apoptosis that would explain lower-body adipocyte hyperplasia and abdominal s.c. adipocyte hypertrophy. However, baseline PPARgamma2 and C/EBPalpha mRNA were higher in abdominal than femoral s.c. preadipocytes (P < 0.005 and P < 0.03, respectively), consistent with the ability of abdominal s.c. adipocytes to achieve a larger size. Inherent differences in preadipocyte cell dynamics may contribute to the distinct responses of different fat depots to overfeeding, and fat-cell number increases in certain depots in adults after only 8 wk of increased food intake. PMID- 20921417 TI - GAPDH regulates cellular heme insertion into inducible nitric oxide synthase. AB - Heme proteins play essential roles in biology, but little is known about heme transport inside mammalian cells or how heme is inserted into soluble proteins. We recently found that nitric oxide (NO) blocks cells from inserting heme into several proteins, including cytochrome P450s, hemoglobin, NO synthases, and catalase. This finding led us to explore the basis for NO inhibition and to identify cytosolic proteins that may be involved, using inducible NO synthase (iNOS) as a model target. Surprisingly, we found that GAPDH plays a key role. GAPDH was associated with iNOS in cells. Pure GAPDH bound tightly to heme or to iNOS in an NO-sensitive manner. GAPDH knockdown inhibited heme insertion into iNOS and a GAPDH mutant with defective heme binding acted as a dominant negative inhibitor of iNOS heme insertion. Exposing cells to NO either from a chemical donor or by iNOS induction caused GAPDH to become S-nitrosylated at Cys152. Expressing a GAPDH C152S mutant in cells or providing a drug to selectively block GAPDH S-nitrosylation both made heme insertion into iNOS resistant to the NO inhibition. We propose that GAPDH delivers heme to iNOS through a process that is regulated by its S-nitrosylation. Our findings may uncover a fundamental step in intracellular heme trafficking, and reveal a mechanism whereby NO can govern the process. PMID- 20921418 TI - Epithelial cell proliferation in the developing zebrafish intestine is regulated by the Wnt pathway and microbial signaling via Myd88. AB - Rates of cell proliferation in the vertebrate intestinal epithelium are modulated by intrinsic signaling pathways and extrinsic cues. Here, we report that epithelial cell proliferation in the developing zebrafish intestine is stimulated both by the presence of the resident microbiota and by activation of Wnt signaling. We find that the response to microbial proliferation-promoting signals requires Myd88 but not TNF receptor, implicating host innate immune pathways but not inflammation in the establishment of homeostasis in the developing intestinal epithelium. We show that loss of axin1, a component of the beta-catenin destruction complex, results in greater than WT levels of intestinal epithelial cell proliferation. Compared with conventionally reared axin1 mutants, germ-free axin1 mutants exhibit decreased intestinal epithelial cell proliferation, whereas monoassociation with the resident intestinal bacterium Aeromonas veronii results in elevated epithelial cell proliferation. Disruption of beta-catenin signaling by deletion of the beta-catenin coactivator tcf4 partially decreases the proliferation-promoting capacity of A. veronii. We show that numbers of intestinal epithelial cells with cytoplasmic beta-catenin are reduced in the absence of the microbiota in both WT and axin1 mutants and elevated in animals' monoassociated A. veronii. Collectively, these data demonstrate that resident intestinal bacteria enhance the stability of beta-catenin in intestinal epithelial cells and promote cell proliferation in the developing vertebrate intestine. PMID- 20921419 TI - Inhibition of brain tumor growth by intravenous poly (beta-L-malic acid) nanobioconjugate with pH-dependent drug release [corrected]. AB - Effective treatment of brain neurological disorders such as Alzheimer's disease, multiple sclerosis, or tumors should be possible with drug delivery through blood brain barrier (BBB) or blood-brain tumor barrier (BTB) and targeting specific types of brain cells with drug release into the cell cytoplasm. A polymeric nanobioconjugate drug based on biodegradable, nontoxic, and nonimmunogenic polymalic acid as a universal delivery nanoplatform was used for design and synthesis of nanomedicine drug for i.v. treatment of brain tumors. The polymeric drug passes through the BTB and tumor cell membrane using tandem monoclonal antibodies targeting the BTB and tumor cells. The next step for polymeric drug action was inhibition of tumor angiogenesis by specifically blocking the synthesis of a tumor neovascular trimer protein, laminin-411, by attached antisense oligonucleotides (AONs). The AONs were released into the target cell cytoplasm via pH-activated trileucine, an endosomal escape moiety. Drug delivery to the brain tumor and the release mechanism were both studied for this nanobiopolymer. Introduction of a trileucine endosome escape unit resulted in significantly increased AON delivery to tumor cells, inhibition of laminin-411 synthesis in vitro and in vivo, specific accumulation in brain tumors, and suppression of intracranial glioma growth compared with pH-independent leucine ester. The availability of a systemically active polymeric drug delivery system that passes through the BTB, targets tumor cells, and inhibits glioma growth gives hope for a successful strategy of glioma treatment. This delivery system with drug release into the brain-specific cell type could be useful for treatment of various brain pathologies. PMID- 20921420 TI - Claudin-4 forms paracellular chloride channel in the kidney and requires claudin 8 for tight junction localization. AB - Tight junctions (TJs) play a key role in mediating paracellular ion reabsorption in the kidney. The paracellular pathway in the collecting duct of the kidney is a predominant route for transepithelial chloride reabsorption that determines the extracellular NaCl content and the blood pressure. However, the molecular mechanisms underlying the paracellular chloride reabsorption in the collecting duct are not understood. Here we showed that in mouse kidney collecting duct cells, claudin-4 functioned as a Cl(-) channel. A positively charged lysine residue at position 65 of claudin-4 was critical for its anion selectivity. Claudin-4 was observed to interact with claudin-8 using several criteria. In the collecting duct cells, the assembly of claudin-4 into TJ strands required its interaction with claudin-8. Depletion of claudin-8 resulted in the loss of paracellular chloride conductance, through a mechanism involving its recruitment of claudin-4 during TJ assembly. Together, our data show that claudin-4 interacts with claudin-8 and that their association is required for the anion-selective paracellular pathway in the collecting duct, suggesting a mechanism for coupling chloride reabsorption with sodium reabsorption in the collecting duct. PMID- 20921421 TI - An atypical member of the light-harvesting complex stress-related protein family modulates diatom responses to light. AB - Diatoms are prominent phytoplanktonic organisms that contribute around 40% of carbon assimilation in the oceans. They grow and perform optimally in variable environments, being able to cope with unpredictable changes in the amount and quality of light. The molecular mechanisms regulating diatom light responses are, however, still obscure. Using knockdown Phaeodactylum tricornutum transgenic lines, we reveal the key function of a member of the light-harvesting complex stress-related (LHCSR) protein family, denoted LHCX1, in modulation of excess light energy dissipation. In contrast to green algae, this gene is already maximally expressed in nonstressful light conditions and encodes a protein required for efficient light responses and growth. LHCX1 also influences natural variability in photoresponse, as evidenced in ecotypes isolated from different latitudes that display different LHCX1 protein levels. We conclude, therefore, that this gene plays a pivotal role in managing light responses in diatoms. PMID- 20921422 TI - Control of salicylic acid synthesis and systemic acquired resistance by two members of a plant-specific family of transcription factors. AB - Salicylic acid (SA) is a defense hormone required for both local and systemic acquired resistance (SAR) in plants. Pathogen infections induce SA synthesis through up-regulating the expression of Isochorismate Synthase 1 (ICS1), which encodes a key enzyme in SA production. Here we report that both SAR Deficient 1 (SARD1) and CBP60g are key regulators for ICS1 induction and SA synthesis. Whereas knocking out SARD1 compromises basal resistance and SAR, overexpression of SARD1 constitutively activates defense responses. In the sard1-1 cbp60g-1 double mutant, pathogen-induced ICS1 up-regulation and SA synthesis are blocked in both local and systemic leaves, resulting in compromised basal resistance and loss of SAR. Electrophoretic mobility shift assays showed that SARD1 and CBP60g represent a plant-specific family of DNA-binding proteins. Both proteins are recruited to the promoter of ICS1 in response to pathogen infections, suggesting that they control SA synthesis by regulating ICS1 at the transcriptional level. PMID- 20921423 TI - Salt and aldosterone: a concert of bad effects. PMID- 20921424 TI - DORADO: opportunity postponed: lessons from studies of endothelin receptor antagonists in treatment-resistant hypertension. PMID- 20921425 TI - Enhanced Ca2+-dependent activation of phosphoinositide 3-kinase class IIalpha isoform-Rho axis in blood vessels of spontaneously hypertensive rats. AB - Rho-mediated inhibition of myosin light chain (MLC) phosphatase (MLCP), together with Ca(2+)-dependent MLC kinase activation, constitutes the major signaling mechanisms for vascular smooth muscle contraction. We recently unveiled the involvement of Ca(2+)-induced, phosphoinositide 3-kinase (PI3K) class IIalpha isoform (PI3K-C2alpha)-dependent Rho activation and resultant Rho kinase dependent MLCP suppression in membrane depolarization- and receptor agonist induced contraction. It is unknown whether Ca(2+)- and PI3K-C2alpha-dependent regulation of MLCP is altered in vascular smooth muscle of hypertensive animals and is involved in hypertension. Therefore, we studied the role of the Ca(2+) PI3K-C2alpha-Rho-MLCP pathway in spontaneously hypertensive rats (SHRs). PI3K C2alpha was readily detected in various vascular beds of Wistar-Kyoto rats and activated by high KCl. High KCl also stimulated vascular Rho activity and phosphorylation of the MLCP regulatory subunit MYPT1 at Thr(853) in a PI3K inhibitor wortmannin-sensitive manner. In mesenteric and other vessels of SHRs at the hypertensive but not the prehypertensive stage, the activity of PI3K-C2alpha but not class I PI3K p110alpha was elevated with concomitant rises of Rho activity and Thr(853)-phosphorylation of MYPT1, as compared with normotensive controls. Infusion of the Ca(2+) channel antagonist nicardipine reduced blood pressure with suppression of vascular activity of PI3K-C2alpha-Rho and phosphorylation of MYPT1 in hypertensive SHRs. Infusion of wortmannin lowered blood pressure with inhibition of PI3K-C2alpha-Rho activities and MYPT1 phosphorylation in hypertensive SHRs. These observations suggest that an increased activity of the Ca(2+)-PI3K-C2alpha-Rho signaling pathway with resultant augmented MLCP suppression contributes to hypertension in SHRs. The Ca(2+)- and PI3K-C2alpha-dependent Rho stimulation in vascular smooth muscle may be a novel, promising target for treating hypertension. PMID- 20921426 TI - New recommendations for treating hypertension in black patients: evidence and/or consensus? PMID- 20921427 TI - Does interleukin 6 contribute to renal hemodynamic changes during angiotensin II dependent hypertension? PMID- 20921428 TI - Dietary sodium, aldosterone, and left ventricular mass changes during long-term inhibition of the renin-angiotensin system. AB - In essential hypertension, the regression of left ventricular hypertrophy is an important goal of treatment. In addition to treatment-associated changes in blood pressure (BP), the roles of other determinants of left ventricular hypertrophy regression, including dietary sodium intake, deserve investigation. In the present study, the change in echographic left ventricular mass index (LVMI) was assessed in 182 patients with never-treated essential hypertension at baseline and after 3 years of treatment by angiotensin converting enzyme inhibitors or angiotensin II receptor antagonists given at recommended doses and associated with other antihypertensive agents. Treatment was associated with satisfactory control of BP (<140/90 mm Hg) in 64% of patients, and left ventricular hypertrophy prevalence decreased from 56% to 39%. Twenty-four-hour urinary sodium was positively related to LVMI at baseline and at the end of the study, independently of age, sex, and systolic BP. Supine plasma aldosterone concentration was correlated with LVMI only at baseline but not in multivariate analysis. In response to treatment, the percentage of change in LVMI was positively correlated with the absolute changes in systolic BP, urinary sodium, and plasma aldosterone concentration, independently of baseline LVMI. The population was divided into 3 tertiles according to final values of gender specific urinary sodium. When, within each urinary sodium tertile, patients were divided into those with plasma aldosterone concentration below and above the median (11.6 ng/dL), LVMI progressively increased across sodium tertiles only in patients with high plasma aldosterone concentration. Systolic BP was similar across all of the groups. In conclusion, aldosterone requires the presence of high dietary salt for the expression of its unfavorable effect on the heart. PMID- 20921429 TI - Interleukin 6 knockout prevents angiotensin II hypertension: role of renal vasoconstriction and janus kinase 2/signal transducer and activator of transcription 3 activation. AB - Chronic angiotensin II (Ang II) infusion stimulates interleukin (IL) 6 release, and we and others have shown that preventing the increase in IL-6 significantly attenuates Ang II hypertension. This study measured renal blood flow (RBF) chronically, using Transonic flow probes in wild-type (WT) and IL-6 knockout (KO) mice, to determine the role of RBF regulation in that response. Ang II infusion at 200, 800, and 3600 ng/kg per minute caused a dose-dependent decrease in RBF in WT mice, and the response at 800 ng/kg per minute was compared between WT and IL 6 KO mice. Ang II infusion increased plasma IL-6 concentration in WT mice and increased mean arterial pressure (19 h/d with telemetry) from 113+/-4 to 149+/-4 mm Hg (Delta36 mm Hg) over the 7-day infusion period, and that effect was blocked in IL-6 KO mice (119+/-7 to 126+/-7 mm Hg). RBF decreased to an average of 61+/ 8% of control over the 7-day period (control: 0.86+/-0.02 mL/min) in the WT mice; however, the average decrease to 72+/-6% of control (control: 0.88+/-0.02 mL/min) in the KO mice was not significantly different. There also was no difference in afferent arteriolar constriction by Ang II in blood-perfused juxtamedullary nephrons in WT versus KO mice. Phosphorylation of janus kinase 2 and signal transducer and activator of transcription 3 in renal cortex homogenates increased significantly in Ang II-infused WT mice, and that effect was prevented completely in Ang II-infused IL-6 KO mice. These data suggest that IL-6-dependent activation of the renal janus kinase 2/signal transducer and activator of transcription 3 pathway plays a role in Ang II hypertension but not by mediating the effect of Ang II to decrease total RBF. PMID- 20921430 TI - Divergent results using clinic and ambulatory blood pressures: report of a darusentan-resistant hypertension trial. AB - Patients with resistant hypertension are at increased risk for cardiovascular events. The addition of new treatments to existing therapies will help achieve blood pressure (BP) goals in more resistant hypertension patients. In the current trial, 849 patients with resistant hypertension receiving >=3 antihypertensive drugs, including a diuretic, at optimized doses were randomized to the selective endothelin A receptor antagonist darusentan, placebo, or the central alpha-2 agonist guanfacine. The coprimary end points of the study were changes from baseline to week 14 in trough, sitting systolic BP, and diastolic BP measured in the clinic. Decreases from baseline to week 14 in systolic BP for darusentan ( 15+/-14 mm Hg) were greater than for guanfacine (-12+/-13 mm Hg; P<0.05) but not greater than placebo (-14+/-14 mm Hg). Darusentan, however, reduced mean 24-hour systolic BP (-9+/-12 mm Hg) more than placebo (-2+/-12 mm Hg) or guanfacine (-4+/ 12 mm Hg) after 14 weeks of treatment (P<0.001 for each comparison). The most frequent adverse event associated with darusentan was fluid retention/edema at 28% versus 12% in each of the other groups. More patients withdrew because of adverse events on darusentan as compared with placebo or guanfacine. We conclude that darusentan provided greater reduction in systolic BP in resistant hypertension patients as assessed by ambulatory BP monitoring, in spite of not meeting its coprimary end points. The results of this trial highlight the importance of ambulatory BP monitoring in the design of hypertension clinical studies. PMID- 20921431 TI - Estrogen metabolomics: a physiologist's perspective. PMID- 20921433 TI - Management of high blood pressure in Blacks: an update of the International Society on Hypertension in Blacks consensus statement. AB - Since the first International Society on Hypertension in Blacks consensus statement on the "Management of High Blood Pressure in African American" in 2003, data from additional clinical trials have become available. We reviewed hypertension and cardiovascular disease prevention and treatment guidelines, pharmacological hypertension clinical end point trials, and blood pressure lowering trials in blacks. Selected trials without significant black representation were considered. In this update, blacks with hypertension are divided into 2 risk strata, primary prevention, where elevated blood pressure without target organ damage, preclinical cardiovascular disease, or overt cardiovascular disease for whom blood pressure consistently <135/85 mm Hg is recommended, and secondary prevention, where elevated blood pressure with target organ damage, preclinical cardiovascular disease, and/or a history of cardiovascular disease, for whom blood pressure consistently <130/80 mm Hg is recommended. If blood pressure is <=10 mm Hg above target levels, monotherapy with a diuretic or calcium channel blocker is preferred. When blood pressure is >15/10 mm Hg above target, 2-drug therapy is recommended, with either a calcium channel blocker plus a renin-angiotensin system blocker or, alternatively, in edematous and/or volume-overload states, with a thiazide diuretic plus a renin angiotensin system blocker. Effective multidrug therapeutic combinations through 4 drugs are described. Comprehensive lifestyle modifications should be initiated in blacks when blood pressure is >=115/75 mm Hg. The updated International Society on Hypertension in Blacks consensus statement on hypertension management in blacks lowers the minimum target blood pressure level for the lowest-risk blacks, emphasizes effective multidrug regimens, and de-emphasizes monotherapy. PMID- 20921435 TI - Diversity in cardiovascular outcomes among Chinese and South Asian patients. PMID- 20921436 TI - Perhexiline and hypertrophic cardiomyopathy: a new horizon for metabolic modulation. PMID- 20921434 TI - Candidate genes and mechanisms for 2-methoxyestradiol-mediated vasoprotection. AB - 2-Methoxyestradiol (2-ME; estradiol metabolite) inhibits vascular smooth muscle cell (VSMC) growth and protects against atherosclerosis and vascular injury; however, the mechanisms by which 2-ME induces these actions remain obscure. To assess the impact of 2-ME on biochemical pathways regulating VSMC biology, we used high-density oligonucleotide microarrays to identify differentially expressed genes in cultured human female aortic VSMCs treated with 2-ME acutely (4 hours) or long term (30 hours). Both single gene analysis and Gene Set Enrichment Analysis revealed 2-ME-induced downregulation of genes involved in mitotic spindle assembly and function in VSMCs. Also, Gene Set Enrichment Analysis identified effects of 2-ME on genes regulating cell-cycle progression, cell migration/adhesion, vasorelaxation, inflammation, and cholesterol metabolism. Transcriptional changes were associated with changes in protein expression, including inhibition of cyclin D1, cyclin B1, cyclin-dependent kinase 6, cyclin-dependent kinase 4, tubulin polymerization, cholesterol and steroid synthesis, and upregulation of cyclooxygenase 2 and matrix metalloproteinase 1. Microarray data suggested that 2-ME may activate peroxisome proliferator activated receptors (PPARs) in VSMCs, and 2-ME has structural similarities with rosiglitazone (PPARgamma agonist). However, our finding of weak activation and lack of binding of 2-ME to PPARs suggests that 2-ME may modulate PPAR-associated genes via indirect mechanisms, potentially involving cyclooxygenase 2. Indeed, the antimitogenic effects of 2-ME at concentrations that do not inhibit tubulin polymerization were blocked by the PPAR antagonist GW9662 and the cyclooxygenase 2 inhibitor NS398. Finally, we demonstrated that 2-ME inhibited hypoxia-inducible factor 1alpha. Identification of candidate genes that are positively or negatively regulated by 2-ME provides important leads to investigate and better understand the mechanisms by which 2-ME induces its vasoprotective actions. PMID- 20921432 TI - Common variants in the ATP2B1 gene are associated with susceptibility to hypertension: the Japanese Millennium Genome Project. AB - Hypertension is one of the most common complex genetic disorders. We have described previously 38 single nucleotide polymorphisms (SNPs) with suggestive association with hypertension in Japanese individuals. In this study we extend our previous findings by analyzing a large sample of Japanese individuals (n=14 105) for the most associated SNPs. We also conducted replication analyses in Japanese of susceptibility loci for hypertension identified recently from genome wide association studies of European ancestries. Association analysis revealed significant association of the ATP2B1 rs2070759 polymorphism with hypertension (P=5.3*10(-5); allelic odds ratio: 1.17 [95% CI: 1.09 to 1.26]). Additional SNPs in ATP2B1 were subsequently genotyped, and the most significant association was with rs11105378 (odds ratio: 1.31 [95% CI: 1.21 to 1.42]; P=4.1*10(-11)). Association of rs11105378 with hypertension was cross-validated by replication analysis with the Global Blood Pressure Genetics consortium data set (odds ratio: 1.13 [95% CI: 1.05 to 1.21]; P=5.9*10(-4)). Mean adjusted systolic blood pressure was highly significantly associated with the same SNP in a meta-analysis with individuals of European descent (P=1.4*10(-18)). ATP2B1 mRNA expression levels in umbilical artery smooth muscle cells were found to be significantly different among rs11105378 genotypes. Seven SNPs discovered in published genome-wide association studies were also genotyped in the Japanese population. In the combined analysis with replicated 3 genes, FGF5 rs1458038, CYP17A1, rs1004467, and CSK rs1378942, odds ratio of the highest risk group was 2.27 (95% CI: 1.65 to 3.12; P=4.6*10(-7)) compared with the lower risk group. In summary, this study confirmed common genetic variation in ATP2B1, as well as FGF5, CYP17A1, and CSK, to be associated with blood pressure levels and risk of hypertension. PMID- 20921438 TI - Chemokine receptor 7 knockout attenuates atherosclerotic plaque development. AB - BACKGROUND: Atherosclerosis is a systemic inflammatory disease characterized by the formation of atherosclerotic plaques. Both innate immunity and adaptive immunity contribute to atherogenesis, but the mode of interaction is poorly understood. Chemokine receptor 7 (CCR7) is critically involved in the transition from innate to adaptive immune activation by coordinating the migration to and positioning of antigen-presenting dendritic cells and T cells in secondary lymphoid organs. More recently, it was shown that CCR7 is also responsible for T cell migration into inflamed tissues and T-cell egress from these tissues via the afferent lymph. Thus, we investigated the influence of a systemic CCR7 deficiency on atherogenesis in atherosclerosis-prone low-density lipoprotein receptor (ldlr) knockout mice. METHODS AND RESULTS: CCR7 deficiency resulted in reduced atherosclerotic plaque development. CCR7(-/-) T cells showed impaired entry and exit behavior from atherosclerotic lesions. Oxidized low-density lipoprotein, a key molecule for atherogenesis with antigenic features, was used to pulse dendritic cells and to expand T cells ex vivo. Adoptive transfer of C57BL/6 wild type T cells but not ccr7(-/-)-derived T cells primed with oxidized low-density lipoprotein-pulsed dendritic cells resulted in a reconstitution of atherogenesis in ccr7(-/-)/ldlr(-/-) mice. CONCLUSION: These results demonstrate that both CCR7 dependent T-cell priming in secondary lymphoid organs and CCR7-dependent recirculation of T cells between secondary lymphoid organs and inflamed tissue are crucially involved in atherosclerotic plaque development. PMID- 20921437 TI - Complication rates associated with pacemaker or implantable cardioverter defibrillator generator replacements and upgrade procedures: results from the REPLACE registry. AB - BACKGROUND: Prospective studies defining the risk associated with pacemaker or implantable cardioverter-defibrillator replacement surgeries do not exist. These procedures are generally considered low risk despite results from recent retrospective series reporting higher rates. METHODS AND RESULTS: We prospectively assessed predefined procedure-related complication rates associated with elective pacemaker or implantable cardioverter-defibrillator generator replacements over 6 months of follow-up. Two groups were studied: those without (cohort 1) and those with (cohort 2) a planned transvenous lead addition for replacement or upgrade to a device capable of additional therapies. Complications were adjudicated by an independent events committee. Seventy-two US academic and private practice centers participated. Major complications occurred in 4.0% (95% confidence interval, 2.9 to 5.4) of 1031 cohort 1 patients and 15.3% (95% confidence interval, 12.7 to 18.1) of 713 cohort 2 patients. In both cohorts, major complications were higher with implantable cardioverter-defibrillator compared with pacemaker generator replacements. Complications were highest in patients who had an upgrade to or a revised cardiac resynchronization therapy device (18.7%; 95% confidence interval, 15.1 to 22.6). No periprocedural deaths occurred in either cohort, although 8 later procedure-related deaths occurred in cohort 2. The 6-month infection rates were 1.4% (95% confidence interval, 0.7 to 2.3) and 1.1% (95% confidence interval, 0.5 to 2.2) for cohorts 1 and 2, respectively. CONCLUSIONS: Pacemaker and implantable cardioverter-defibrillator generator replacements are associated with a notable complication risk, particularly those with lead additions. These data support careful decision making before device replacement, when managing device advisories, and when considering upgrades to more complex systems. PMID- 20921439 TI - Pediatric metabolic syndrome predicts adulthood metabolic syndrome, subclinical atherosclerosis, and type 2 diabetes mellitus but is no better than body mass index alone: the Bogalusa Heart Study and the Cardiovascular Risk in Young Finns Study. AB - BACKGROUND: The clinical utility of identifying pediatric metabolic syndrome (MetS) is controversial. This study sought to determine the status of pediatric MetS as a risk factor for adult subclinical atherosclerosis (carotid intima-media thickness [cIMT]) and type 2 diabetes mellitus (T2DM) and compare and contrast this prediction with its individual components. METHODS AND RESULTS: Using data from the population-based, prospective, observational Bogalusa Heart and Cardiovascular Risk in Young Finns studies, we examined the utility of 4 categorical definitions of youth MetS and their components in predicting adult high cIMT and T2DM among 1781 participants aged 9 to 18 years at baseline (1984 to 1988) who were then examined 14 to 27 years later (2001-2007) when aged 24 to 41 years. Youth with MetS were at 2 to 3 times the risk of having high cIMT and T2DM as adults compared with those free of MetS at youth. Risk estimates with the use of high body mass index were similar to those of MetS phenotypes in predicting adult outcomes. Comparisons of area under the receiver operating characteristic curve and net reclassification index suggested that prediction of adult MetS, high cIMT, and T2DM in adulthood with the use of youth MetS was either equivalent or inferior to classification based on high body mass index or overweight and obesity. CONCLUSIONS: Youth with MetS are at increased risk of meaningful adult outcomes; however, the simplicity of screening for high BMI or overweight and obesity in the pediatric setting offers a simpler, equally accurate alternative to identifying youth at risk of developing adult MetS, high cIMT, or T2DM. PMID- 20921440 TI - Metabolic modulator perhexiline corrects energy deficiency and improves exercise capacity in symptomatic hypertrophic cardiomyopathy. AB - BACKGROUND: Hypertrophic cardiomyopathy patients exhibit myocardial energetic impairment, but a causative role for this energy deficiency in the pathophysiology of hypertrophic cardiomyopathy remains unproven. We hypothesized that the metabolic modulator perhexiline would ameliorate myocardial energy deficiency and thereby improve diastolic function and exercise capacity. METHODS AND RESULTS: Forty-six consecutive patients with symptomatic exercise limitation (peak Vo(2) <75% of predicted) caused by nonobstructive hypertrophic cardiomyopathy (mean age, 55+/-0.26 years) were randomized to perhexiline 100 mg (n=24) or placebo (n=22). Myocardial ratio of phosphocreatine to adenosine triphosphate, an established marker of cardiac energetic status, as measured by (31)P magnetic resonance spectroscopy, left ventricular diastolic filling (heart rate normalized time to peak filling) at rest and during exercise using radionuclide ventriculography, peak Vo(2), symptoms, quality of life, and serum metabolites were assessed at baseline and study end (4.6+/-1.8 months). Perhexiline improved myocardial ratios of phosphocreatine to adenosine triphosphate (from 1.27+/-0.02 to 1.73+/-0.02 versus 1.29+/-0.01 to 1.23+/-0.01; P=0.003) and normalized the abnormal prolongation of heart rate normalized time to peak filling between rest and exercise (0.11+/-0.008 to -0.01+/-0.005 versus 0.15+/-0.007 to 0.11+/-0.008 second; P=0.03). These changes were accompanied by an improvement in primary end point (peak Vo(2)) (22.2+/-0.2 to 24.3+/-0.2 versus 23.6+/-0.3 to 22.3+/-0.2 mL . kg(-1) . min(-1); P=0.003) and New York Heart Association class (P<0.001) (all P values ANCOVA, perhexiline versus placebo). CONCLUSIONS: In symptomatic hypertrophic cardiomyopathy, perhexiline, a modulator of substrate metabolism, ameliorates cardiac energetic impairment, corrects diastolic dysfunction, and increases exercise capacity. This study supports the hypothesis that energy deficiency contributes to the pathophysiology and provides a rationale for further consideration of metabolic therapies in hypertrophic cardiomyopathy. PMID- 20921441 TI - Conditional overexpression of neuronal nitric oxide synthase is cardioprotective in ischemia/reperfusion. AB - BACKGROUND: We previously demonstrated that conditional overexpression of neuronal nitric oxide synthase (nNOS) inhibited L-type Ca2+ channels and decreased myocardial contractility. However, nNOS has multiple targets within the cardiac myocyte. We now hypothesize that nNOS overexpression is cardioprotective after ischemia/reperfusion because of inhibition of mitochondrial function and a reduction in reactive oxygen species generation. METHODS AND RESULTS: Ischemia/reperfusion injury in wild-type mice resulted in nNOS accumulation in the mitochondria. Similarly, transgenic nNOS overexpression caused nNOS abundance in mitochondria. nNOS translocation into the mitochondria was dependent on heat shock protein 90. Ischemia/reperfusion experiments in isolated hearts showed a cardioprotective effect of nNOS overexpression. Infarct size in vivo was also significantly reduced. nNOS overexpression also caused a significant increase in mitochondrial nitrite levels accompanied by a decrease of cytochrome c oxidase activity. Accordingly, O(2) consumption in isolated heart muscle strips was decreased in nNOS-overexpressing nNOS(+)/alphaMHC-tTA(+) mice already under resting conditions. Additionally, we found that the reactive oxygen species concentration was significantly decreased in hearts of nNOS-overexpressing nNOS(+)/alphaMHC-tTA(+) mice compared with noninduced nNOS(+)/alphaMHC-tTA(+) animals. CONCLUSION: We demonstrated that conditional transgenic overexpression of nNOS resulted in myocardial protection after ischemia/reperfusion injury. Besides a reduction in reactive oxygen species generation, this might be caused by nitrite-mediated inhibition of mitochondrial function, which reduced myocardial oxygen consumption already under baseline conditions. PMID- 20921442 TI - Enhanced external counterpulsation improves peripheral artery flow-mediated dilation in patients with chronic angina: a randomized sham-controlled study. AB - BACKGROUND: Mechanisms responsible for anti-ischemic benefits of enhanced external counterpulsation (EECP) remain unknown. This was the first randomized sham-controlled study to investigate the extracardiac effects of EECP on peripheral artery flow-mediated dilation. METHODS AND RESULTS: Forty-two symptomatic patients with coronary artery disease were randomized (2:1 ratio) to thirty-five 1-hour sessions of either EECP (n=28) or sham EECP (n=14). Flow mediated dilation of the brachial and femoral arteries was performed with the use of ultrasound. Plasma levels of nitrate and nitrite, 6-keto-prostaglandin F(1alpha), endothelin-1, asymmetrical dimethylarginine, tumor necrosis factor alpha, monocyte chemoattractant protein-1, soluble vascular cell adhesion molecule, high-sensitivity C-reactive protein, and 8-isoprostane were measured. EECP increased brachial (+51% versus +2%) and femoral (+30% versus +3%) artery flow-mediated dilation, the nitric oxide turnover/production markers nitrate and nitrite (+36% versus +2%), and 6-keto-prostaglandin F(1alpha) (+71% versus +1%), whereas it decreased endothelin-1 (-25% versus +5%) and the nitric oxide synthase inhibitor asymmetrical dimethylarginine (-28% versus +0.2%) in treatment versus sham groups, respectively (all P<0.05). EECP decreased the proinflammatory cytokines tumor necrosis factor-alpha (-16% versus +12%), monocyte chemoattractant protein-1 (-13% versus +0.2%), soluble vascular cell adhesion molecule-1 (-6% versus +1%), high-sensitivity C-reactive protein (-32% versus +5%), and the lipid peroxidation marker 8-isoprostane (-21% versus +1.3%) in treatment versus sham groups, respectively (all P<0.05). EECP reduced angina classification (-62% versus 0%; P<0.001) in treatment versus sham groups, respectively. CONCLUSIONS: Our findings provide novel mechanistic evidence that EECP has a beneficial effect on peripheral artery flow-mediated dilation and endothelial-derived vasoactive agents in patients with symptomatic coronary artery disease. PMID- 20921443 TI - In vivo therapeutic gas delivery for neuroprotection with echogenic liposomes. AB - BACKGROUND: Ischemia-related neurological injury is a primary cause of stroke disability. Studies have demonstrated that xenon (Xe) may have potential as an effective and nontoxic neuroprotectant. Xe delivery is, however, hampered by lack of suitable administration methods. We have developed a pressurization-freeze method to encapsulate Xe into echogenic liposomes (Xe-ELIP) and have modulated local gas release with transvascular ultrasound exposure. METHODS AND RESULTS: Fifteen microliters of Xe were encapsulated into each 1 mg of liposomes (70% Xe and 30% argon). Xe delivery from Xe-ELIP into cells and consequent neuroprotective effects were evaluated with oxygen/glucose-deprived and control neuronal cells in vitro. Xe-ELIP were administered into Sprague-Dawley rats intravenously or intra-arterially after right middle cerebral artery occlusion. One-megahertz low-amplitude (0.18 MPa) continuous wave ultrasound directed onto the internal carotid artery triggered Xe release from circulating Xe-ELIP. Effects of Xe delivery on ischemia-induced neurological injury and disability were evaluated. Xe-ELIP delivery to oxygen/glucose-deprived neuronal cells improved cell viability in vitro and resulted in a 48% infarct volume decrease in vivo. Intravenous Xe-ELIP administration in combination with the ultrasound directed onto the carotid artery enhanced local Xe release from circulating Xe ELIP and demonstrated 75% infarct volume reduction. This was comparable to the effect after intra-arterial administration. Behavioral tests on limb placement and grid and beam walking correlated with infarct reduction. CONCLUSIONS: This novel methodology may provide a noninvasive strategy for ultrasound-enhanced local therapeutic gas delivery for cerebral ischemia-related injury while minimizing systemic side effects. PMID- 20921444 TI - Outcomes after acute myocardial infarction in South Asian, Chinese, and white patients. AB - BACKGROUND: Cardiac mortality rates vary substantially between countries and ethnic groups. It is unclear, however, whether South Asian, Chinese, and white populations have a variable prognosis after acute myocardial infarction (AMI). To clarify this association, we compared mortality, use of revascularization procedures, and risk of recurrent AMI and hospitalization for heart failure between these ethnic groups in a universal-access healthcare system. METHODS AND RESULTS: We used a population cohort study design using hospital administrative data linked to cardiac procedure registries from British Columbia and the Calgary Health Region Area in Alberta (1994 to 2003) to identify AMI cases. Patient ethnicity was categorized using validated surname algorithms. There were 2190 South Asian, 946 Chinese, and 38479 white patients with AMI identified. There was no significant difference in use of revascularization procedures between ethnic groups at 30 d and 1 year. Short-term (30-day) mortality was higher among Chinese relative to white patients (odds ratio, 1.23; 95% confidence interval, 1.02 to 1.48). There was no significant difference in 30-day mortality between South Asian and white patients. South Asian patients had a 35% lower relative risk of long-term mortality compared with white patients (hazard ratio, 0.65; 95% confidence interval, 0.57 to 0.72). There was no significant difference in long term mortality between Chinese and white patients. Among AMI survivors, Chinese patients had a lower risk of recurrent AMI, whereas there was no difference between South Asian and white patients. CONCLUSION: The ethnic groups studied have striking differences in outcomes after AMI, with South Asian patients having significantly lower long-term mortality after AMI. PMID- 20921445 TI - Arteriotomy closure devices for cardiovascular procedures: a scientific statement from the American Heart Association. PMID- 20921446 TI - Bypass graft stent fracture leading to saphenous vein graft pseudoaneurysm. PMID- 20921447 TI - Letter by Gurbel et al regarding article, "Cytochrome 2C19*17 allelic variant, platelet aggregation, bleeding events, and stent thrombosis in clopidogrel treated patients with coronary stent placement". PMID- 20921449 TI - Drug-induced arrhythmia. PMID- 20921450 TI - Aortic root pseudoaneurysm 1 year after transapical aortic valve implantation. PMID- 20921451 TI - Neuropathic pain features in patients with bone metastases referred for palliative radiotherapy. AB - PURPOSE: To estimate the prevalence of pain with neuropathic features among patients with metastatic bone pain and to assess differences between patients with and without neuropathic features by pain severity, functional interference, and quality-of-life (QOL) measures. PATIENTS AND METHODS: A prospective cross sectional survey of consecutive patients with symptomatic bone metastases was conducted between December 2006 and March 2008 at a comprehensive cancer center. Patients completed the Brief Pain Inventory (BPI), the Self-Reported Leeds Assessment of Neuropathic Symptoms and Signs (S-LANSS), and the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30). Statistical associations between pain with neuropathic features and other measures were explored. RESULTS: Ninety-eight patients were enrolled. Seventeen percent of patients (95% CI, 10% to 24%) had positive S-LANSS scores suggesting pain with neuropathic features. Mean worst pain and mean interference scores were 7.2 (standard deviation [SD], 2.0) and 5.8 (SD, 2.5), respectively. EORTC QLQ-C30 global QOL, function, and symptom scores were 42 (SD, 24), 52 (SD, 20), and 46 (SD, 17), respectively. Patients with neuropathic features had a higher BPI worst pain score than patients without neuropathic features (8.3 v 7.0, respectively; P = .016). Corticosteroid use, oral morphine equivalent dosing, and site of bone pain were not associated with neuropathic features. CONCLUSION: Some patients with bone metastases manifest bone pain with distinguishable neuropathic features, and these patients reported greater pain intensity. Additional work is required to validate the S-LANSS against clinical criteria for neuropathic pain in this context and to explore the unmet pain management needs in this population. PMID- 20921452 TI - Urinary obstructive problems exposed but hormonal health-related quality-of-life concerns eschewed in prostate cancer quality-of-life study. PMID- 20921453 TI - Optimizing collection of adverse event data in cancer clinical trials supporting supplemental indications. AB - PURPOSE: Although much is known about the safety of an anticancer agent at the time of initial marketing approval, sponsors customarily collect comprehensive safety data for studies that support supplemental indications. This adds significant cost and complexity to the study but may not provide useful new information. The main purpose of this analysis was to assess the amount of safety and concomitant medication data collected to determine a more optimal approach in the collection of these data when used in support of supplemental applications. METHODS: Following a prospectively developed statistical analysis plan, we reanalyzed safety data from eight previously completed prospective randomized trials. RESULTS: A total of 107,884 adverse events and 136,608 concomitant medication records were reviewed for the analysis. Of these, four grade 1 to 2 and nine grade 3 and higher events were identified as drug effects that were not included in the previously established safety profiles and could potentially have been missed using subsampling. These events were frequently detected in subsamples of 400 patients or larger. Furthermore, none of the concomitant medication records contributed to labeling changes for the supplemental indications. CONCLUSION: Our study found that applying the optimized methodologic approach, described herein, has a high probability of detecting new drug safety signals. Focusing data collection on signals that cause physicians to modify or discontinue treatment ensures that safety issues of the highest concern for patients and regulators are captured and has significant potential to relieve strain on the clinical trials system. PMID- 20921454 TI - Is zidovudine and interferon-alfa the gold standard for adult T-cell leukemia lymphoma? PMID- 20921455 TI - Clinical trials data collection: when less is more. PMID- 20921456 TI - Phase I study of vandetanib during and after radiotherapy in children with diffuse intrinsic pontine glioma. AB - PURPOSE: To evaluate the safety, maximum-tolerated dose, pharmacokinetics, and pharmacodynamics of vandetanib, an oral vascular endothelial growth factor receptor 2 (VEGFR2) and epidermal growth factor receptor inhibitor, administered once daily during and after radiotherapy in children with newly diagnosed diffuse intrinsic pontine glioma. PATIENTS AND METHODS: Radiotherapy was administered as 1.8-Gy fractions (total cumulative dose of 54 Gy). Vandetanib was administered concurrently with radiotherapy for a maximum of 2 years. Dose-limiting toxicities (DLTs) were evaluated during the first 6 weeks of therapy. Pharmacokinetic studies were obtained for all patients. Plasma angiogenic factors and VEGFR2 phosphorylation in mononuclear cells were analyzed before and during therapy. RESULTS: Twenty-one patients were administered 50 (n = 3), 65 (n = 3), 85 (n = 3), 110 (n = 6), and 145 mg/m(2) (n = 6) of vandetanib. Only one patient developed DLT (grade 3 diarrhea) at dosage level 5. An expanded cohort of patients were treated at dosage levels 4 (n = 10) and 5 (n = 4); two patients developed grade 4 hypertension and posterior reversible encephalopathy syndrome while also receiving high-dose dexamethasone. Despite significant interpatient variability, exposure to vandetanib increased with higher dosage levels. The bivariable analysis of vascular endothelial growth factor (VEGF) before and during therapy showed that patients with higher levels of VEGF before therapy had a longer progression-free survival (PFS; P = .022), whereas patients with increases in VEGF during treatment had a shorter PFS (P = .0015). VEGFR2 phosphorylation was inhibited on day 8 or 29 of therapy compared with baseline (P = .039). CONCLUSION: The recommended phase II dose of vandetanib in children is 145 mg/m(2) per day. Close monitoring and management of hypertension is required, particularly for patients receiving corticosteroids. PMID- 20921457 TI - EGFR antibodies in colorectal cancer: where do they belong? PMID- 20921458 TI - Definition of disease-risk stratification groups in childhood medulloblastoma using combined clinical, pathologic, and molecular variables. AB - PURPOSE: Medulloblastomas are heterogeneous and include relatively good-prognosis tumors characterized by Wnt pathway activation, as well as those that cannot be successfully treated with conventional therapy. Developing a practical therapeutic stratification that allows accurate identification of disease risk offers the potential to individualize adjuvant therapy and to minimize long-term adverse effects in a subgroup of survivors. METHODS: Using formalin-fixed paraffin-embedded (FFPE) tissue for immunohistochemistry, fluorescent in situ hybridization, and direct sequencing to identify tumors with a Wnt pathway signature and those harboring copy number abnormalities (CNAs) of potential prognostic significance (MYC/MYCN amplification, CNAs of chromosome 6 and 17), we evaluated clinical, pathologic, and molecular outcome indicators and stratification models in a cohort (n = 207) of patients with medulloblastoma 3 to 16 years of age from the International Society of Pediatric Oncology CNS9102 (PNET3) trial. RESULTS: Metastatic disease and large-cell/anaplastic (LC/A) phenotype were the clinicopathologic variables associated with poor progression free survival (PFS). Nuclear immunoreactivity for beta-catenin, CTNNB1 mutation, and monosomy 6 all identified a group of good-prognosis patients. MYC amplification was associated with poor outcome, but other CNAs were not. Low-risk medulloblastomas were defined as beta-catenin nucleopositive tumors without metastasis at presentation, LC/A phenotype, or MYC amplification. High-risk medulloblastomas were defined as tumors with metastatic disease, LC/A phenotype, or MYC amplification. Low-risk, standard-risk, and high-risk categories of medulloblastoma had significantly (P < .0001) different outcomes. CONCLUSION: Integrating assays of molecular biomarkers undertaken on routinely collected diagnostic FFPE tissue into stratification schemes for medulloblastoma alongside clinical and pathologic outcome indicators can refine current definition of disease risk and guide adjuvant therapy. PMID- 20921459 TI - Immunologic escape after prolonged progression-free survival with epidermal growth factor receptor variant III peptide vaccination in patients with newly diagnosed glioblastoma. AB - PURPOSE: Immunologic targeting of tumor-specific gene mutations may allow precise eradication of neoplastic cells without toxicity. Epidermal growth factor receptor variant III (EGFRvIII) is a constitutively activated and immunogenic mutation not expressed in normal tissues but widely expressed in glioblastoma multiforme (GBM) and other neoplasms. PATIENTS AND METHODS: A phase II, multicenter trial was undertaken to assess the immunogenicity of an EGFRvIII targeted peptide vaccine and to estimate the progression-free survival (PFS) and overall survival (OS) of vaccinated patients with newly diagnosed EGFRvIII expressing GBM with minimal residual disease. Intradermal vaccinations were given until toxicity or tumor progression was observed. Sample size was calculated to differentiate between PFS rates of 20% and 40% 6 months after vaccination. RESULTS: There were no symptomatic autoimmune reactions. The 6-month PFS rate after vaccination was 67% (95% CI, 40% to 83%) and after diagnosis was 94% (95% CI, 67% to 99%; n = 18). The median OS was 26.0 months (95% CI, 21.0 to 47.7 months). After adjustment for age and Karnofsky performance status, the OS of vaccinated patients was greater than that observed in a control group matched for eligibility criteria, prognostic factors, and temozolomide treatment (hazard ratio, 5.3; P = .0013; n = 17). The development of specific antibody (P = .025) or delayed-type hypersensitivity (P = .03) responses to EGFRvIII had a significant effect on OS. At recurrence, 82% (95% CI, 48% to 97%) of patients had lost EGFRvIII expression (P < .001). CONCLUSION: EGFRvIII-targeted vaccination in patients with GBM warrants investigation in a phase III, randomized trial. PMID- 20921460 TI - Cancer vaccines in glioma: how to balance the challenges of small trials, efficiency, and potential adverse events. PMID- 20921461 TI - Personalized medicine in non-small-cell lung cancer: is KRAS a useful marker in selecting patients for epidermal growth factor receptor-targeted therapy? AB - In patients with metastatic colorectal cancer, the predictive value of KRAS mutational status in the selection of patients for treatment with anti-epidermal growth factor (EGFR) monoclonal antibodies is established. In patients with non small-cell lung cancer (NSCLC), the utility of determining KRAS mutational status to predict clinical benefit to anti-EGFR therapies remains unclear. This review will provide a brief description of Ras biology, provide an overview of aberrant Ras signaling in NSCLC, and summarize the clinical data for using KRAS mutational status as a negative predictive biomarker to anti-EGFR therapies. Retrospective investigations of KRAS mutational status as a negative predictor of clinical benefit from anti-EGFR therapies in NSCLC have been performed; however, small samples sizes as a result of low prevalence of KRAS mutations and the low rate of tumor sample collection have limited the strength of these analyses. Although an association between the presence of KRAS mutation and lack of response to EGFR tyrosine kinase inhibitors (TKIs) has been observed, it remains unclear whether there is an association between KRAS mutation and EGFR TKI progression-free and overall survival. Unlike colorectal cancer, KRAS mutations do not seem to identify patients who do not benefit from anti-EGFR monoclonal antibodies in NSCLC. The future value of testing for KRAS mutational status may be to exclude the possibility of an EGFR mutation or anaplastic lymphoma kinase translocation or to identify a molecular subset of patients with NSCLC in whom to pursue a drug development strategy that targets the KRAS pathway. PMID- 20921462 TI - Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. AB - PURPOSE: Panitumumab is a fully human anti-epidermal growth factor receptor (EGFR) monoclonal antibody that improves progression-free survival (PFS) in chemotherapy-refractory metastatic colorectal cancer (mCRC). This trial evaluated the efficacy and safety of panitumumab plus fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone after failure of initial treatment for mCRC by tumor KRAS status. PATIENTS AND METHODS: Patients with mCRC, one prior chemotherapy regimen for mCRC, Eastern Cooperative Oncology Group performance status 0 to 2, and available tumor tissue for biomarker testing were randomly assigned 1:1 to panitumumab 6.0 mg/kg plus FOLFIRI versus FOLFIRI every 2 weeks. The coprimary end points of PFS and overall survival (OS) were independently tested and prospectively analyzed by KRAS status. RESULTS: From June 2006 to March 2008, 1,186 patients were randomly assigned 1:1 and received treatment. KRAS status was available for 91% of patients: 597 (55%) with wild type (WT) KRAS tumors, and 486 (45%) with mutant (MT) KRAS tumors. In the WT KRAS subpopulation, when panitumumab was added to chemotherapy, a significant improvement in PFS was observed (hazard ratio [HR] = 0.73; 95% CI, 0.59 to 0.90; P = .004); median PFS was 5.9 months for panitumumab-FOLFIRI versus 3.9 months for FOLFIRI. A nonsignificant trend toward increased OS was observed; median OS was 14.5 months versus 12.5 months, respectively (HR = 0.85, 95% CI, 0.70 to 1.04; P = .12); response rate was improved to 35% versus 10% with the addition of panitumumab. In patients with MT KRAS, there was no difference in efficacy. Adverse event rates were generally comparable across arms with the exception of known toxicities associated with anti-EGFR therapy. CONCLUSION: Panitumumab plus FOLFIRI significantly improved PFS and is well-tolerated as second-line treatment in patients with WT KRAS mCRC. PMID- 20921463 TI - Quality-of-life impact of primary treatments for localized prostate cancer in patients without hormonal treatment. AB - PURPOSE: Earlier studies evaluating the effect on quality of life (QoL) of localized prostate cancer interventions included patients receiving adjuvant hormone therapy, which could have affected their outcomes. Our objective was to compare the QoL impact of the three most common primary treatments on patients who were not receiving adjuvant hormonal treatment. PATIENTS AND METHODS: This was a prospective study of 435 patients treated with radical prostatectomy, external-beam radiotherapy, or brachytherapy. QoL was assessed before and after treatment with the Short Form-36 and the Expanded Prostate Cancer Index Composite. Differences between groups were tested by analysis of variance. Distribution of outcome at 3 years was examined by stratifying according to baseline status. Generalized estimating equation models were constructed to assess the effect of treatment over time. RESULTS: Compared with the brachytherapy group, the prostatectomy group showed greater deterioration on urinary incontinence and sexual scores but better urinary irritative-obstructive results (-18.22, -13.19, and +6.38, respectively, at 3 years; P < .001). In patients with urinary irritative-obstructive symptoms at baseline, improvement was observed in 64% of those treated with nerve-sparing radical prostatectomy. Higher bowel worsening (-2.87, P = .04) was observed in the external radiotherapy group, with 20% of patients reporting bowel symptoms. CONCLUSION: Radical prostatectomy caused urinary incontinence and sexual dysfunction but improved pre existing urinary irritative-obstructive symptoms. External radiotherapy and brachytherapy caused urinary irritative-obstructive adverse effects and some sexual dysfunction. External radiotherapy also caused bowel adverse effects. Relevant differences between treatment groups persisted for up to 3 years of follow-up, although the difference in sexual adverse effects between brachytherapy and prostatectomy tended to decline over long-term follow-up. These results provide valuable information for clinical decision making. PMID- 20921464 TI - Compliance with tamoxifen in women with breast cancer and a BRCA1 or BRCA2 mutation. PMID- 20921466 TI - Selecting systemic cancer therapy one patient at a time: is there a role for molecular profiling of individual patients with advanced solid tumors? PMID- 20921465 TI - Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. AB - PURPOSE: Panitumumab, a fully human anti-epidermal growth factor receptor (EGFR) monoclonal antibody that improves progression-free survival (PFS), is approved as monotherapy for patients with chemotherapy-refractory metastatic colorectal cancer (mCRC). The Panitumumab Randomized Trial in Combination With Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy (PRIME) was designed to evaluate the efficacy and safety of panitumumab plus infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as initial treatment for mCRC. PATIENTS AND METHODS: In this multicenter, phase III trial, patients with no prior chemotherapy for mCRC, Eastern Cooperative Oncology Group performance status of 0 to 2, and available tissue for biomarker testing were randomly assigned 1:1 to receive panitumumab-FOLFOX4 versus FOLFOX4. The primary end point was PFS; overall survival (OS) was a secondary end point. Results were prospectively analyzed on an intent-to-treat basis by tumor KRAS status. RESULTS: KRAS results were available for 93% of the 1,183 patients randomly assigned. In the wild-type (WT) KRAS stratum, panitumumab-FOLFOX4 significantly improved PFS compared with FOLFOX4 (median PFS, 9.6 v 8.0 months, respectively; hazard ratio [HR], 0.80; 95% CI, 0.66 to 0.97; P = .02). A nonsignificant increase in OS was also observed for panitumumab-FOLFOX4 versus FOLFOX4 (median OS, 23.9 v 19.7 months, respectively; HR, 0.83; 95% CI, 0.67 to 1.02; P = .072). In the mutant KRAS stratum, PFS was significantly reduced in the panitumumab-FOLFOX4 arm versus the FOLFOX4 arm (HR, 1.29; 95% CI, 1.04 to 1.62; P = .02), and median OS was 15.5 months versus 19.3 months, respectively (HR, 1.24; 95% CI, 0.98 to 1.57; P = .068). Adverse event rates were generally comparable across arms with the exception of toxicities known to be associated with anti-EGFR therapy. CONCLUSION: This study demonstrated that panitumumab-FOLFOX4 was well tolerated and significantly improved PFS in patients with WT KRAS tumors and underscores the importance of KRAS testing for patients with mCRC. PMID- 20921468 TI - Pilot study using molecular profiling of patients' tumors to find potential targets and select treatments for their refractory cancers. AB - PURPOSE: To compare the progression-free survival (PFS) using a treatment regimen selected by molecular profiling (MP) of a patient's tumor with the PFS for the most recent regimen on which the patient had experienced progression (ie, patient as his own control). PATIENTS AND METHODS: Patients with refractory metastatic cancer had tissue samples submitted for MP in two formats including formalin fixed tissue for immunohistochemistry and fluorescent in situ hybridization assays and immediately frozen tissue for oligonucleotide microarray (MA) gene expression assays (all performed in a Clinical Laboratory Improvement Amendments [CLIA]-certified laboratory). The MP approach was deemed of clinical benefit for the individual patient who had a PFS ratio (PFS on MP-selected therapy/PFS on prior therapy) of >= 1.3. RESULTS: In 86 patients who had MP attempted, there was a molecular target detected in 84 (98%). Sixty-six of the 84 patients were treated according to MP results. Eighteen (27%) of 66 patients had a PFS ratio of >= 1.3 (95% CI, 17% to 38%; one-sided, one-sample P = .007). Therefore, the null hypothesis (that <= 15% of this patient population would have a PFS ratio of >= 1.3) was rejected. CONCLUSION: It is possible to identify molecular targets in patients' tumors from nine different centers across the United States. In 27% of patients, the MP approach resulted in a longer PFS on an MP-suggested regimen than on the regimen on which the patient had just experienced progression. Issues to be considered in interpretation of this study include limited prior experience with patients as their own controls as a study end point and overall patient attrition. PMID- 20921467 TI - Phase II selection design trial of concurrent chemotherapy and cetuximab versus chemotherapy followed by cetuximab in advanced-stage non-small-cell lung cancer: Southwest Oncology Group study S0342. AB - PURPOSE: Randomized clinical trials failed to show a survival benefit for epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors plus concurrent chemotherapy in patients with metastatic non-small-cell lung cancer (NSCLC), with preclinical data suggesting potential negative interactions. In contrast, pilot trials of the EGFR-targeted antibody, cetuximab, plus chemotherapy suggested enhanced antitumor activity. This randomized phase II trial was designed to select a cetuximab plus chemotherapy regimen for phase III evaluation. PATIENTS AND METHODS: Treatment-naive patients with advanced-stage NSCLC were randomly assigned to receive paclitaxel (225 mg/m(2)) and carboplatin (area under the curve, 6) every 3 weeks plus concurrent cetuximab (400 mg/m(2) loading dose followed by 250 mg/m(2) weekly) for four cycles followed by maintenance cetuximab or sequential paclitaxel-carboplatin for four cycles followed by cetuximab. RESULTS: Of 242 patients enrolled, 224 were eligible and assessable for response (106 and 118 patients in the concurrent and sequential arms, respectively). With a median follow-up time of 32 months, the median overall survival was 10.9 months (95% CI, 9.2 to 13.0 months) for patients receiving concurrent therapy and 10.7 months (95% CI, 8.5 to 12.8 months) for patients receiving sequential therapy (P = .57); 1-year survival rates were 45% (95% CI, 36% to 54%) and 44% (95% CI, 35% to 53%), respectively. Response rates and progression-free survival times were similar in both arms, as was grade 3 rash, whereas sensory neuropathy was higher in the concurrent arm (15% v 5% in the sequential arm; P = .036). CONCLUSION: Although both regimens met the efficacy criterion for continued evaluation, the concurrent regimen of paclitaxel/carboplatin plus cetuximab was chosen. PMID- 20921470 TI - Stand and wait. PMID- 20921471 TI - Comparative effectiveness: coherent health care at last? PMID- 20921469 TI - Antitumor activity of hu14.18-IL2 in patients with relapsed/refractory neuroblastoma: a Children's Oncology Group (COG) phase II study. AB - PURPOSE: The hu14.18-IL2 fusion protein consists of interleukin-2 molecularly linked to a humanized monoclonal antibody that recognizes the GD2 disialoganglioside expressed on neuroblastoma cells. This phase II study assessed the antitumor activity of hu14.18-IL2 in two strata of patients with recurrent or refractory neuroblastoma. PATIENTS AND METHODS: Hu14.18-IL2 was given intravenously (12 mg/m(2)/daily) for 3 days every 4 weeks for patients with disease measurable by standard radiographic criteria (stratum 1) and for patients with disease evaluable only by [(123)I]metaiodobenzylguanidine (MIBG) scintigraphy and/or bone marrow (BM) histology (stratum 2). Response was established by independent radiology review as well as BM histology and immunocytology, and durability was assessed by repeat evaluation after more than 3 weeks. RESULTS: Thirty-nine patients were enrolled (36 evaluable). No responses were seen in stratum 1 (n = 13). Of 23 evaluable patients in stratum 2, five patients (21.7%) responded; all had a complete response (CR) of 9, 13, 20, 30, and 35+ months duration. Grade 3 and 4 nonhematologic toxicities included capillary leak, hypoxia, pain, rash, allergic reaction, elevated transaminases, and hyperbilirubinemia. Two patients required dopamine for hypotension, and one patient required ventilatory support for hypoxia. Most toxicities were reversible within a few days of completing a treatment course and were expected based on phase I results. CONCLUSION: Patients with disease evaluable only by MIBG and/or BM histology had a 21.7% CR rate to hu14.8-IL2, whereas patients with bulky disease did not respond. Hu14.18-IL2 warrants further testing in children with nonbulky high-risk neuroblastoma. PMID- 20921472 TI - The political fight over comparative effectiveness research. PMID- 20921474 TI - An evaluation of recent federal spending on comparative effectiveness research: priorities, gaps, and next steps. AB - The American Recovery and Reinvestment Act of 2009 included new funding for developing better evidence about health interventions, with a down payment of $1.1 billion for comparative effectiveness research. Our analysis of funds allocated in the legislation found that nearly 90 percent of the $1.1 billion will eventually be spent on two main types of activity: developing and synthesizing comparative effectiveness evidence, and improving the capacity to conduct comparative effectiveness research. Based on our analysis, priorities for the new funding should include greater emphasis on experimental research; evaluation of reforms at the health system level; identification of effects on subgroups of patients; inclusion of understudied groups of patients; and dissemination of results. PMID- 20921473 TI - Creating a high-performance system for comparative effectiveness research. AB - Enactment of the federal stimulus and health reform legislation heralds the beginning of a national comparative effectiveness research program. This article suggests how the Department of Health and Human Services (HHS) can, with collaborators, build a high-performing comparative effectiveness research system. New policies and investments should exploit the rapid-learning potential of electronic health records, computerized databases, data sharing, and research networks. A national database for effectiveness research studies should be established by presidential order. HHS will need to support all of these pieces and take the lead in creating a rapid-learning culture for the US health system. PMID- 20921475 TI - Health reform's tortuous route to the patient-centered outcomes research institute. AB - The Patient Protection and Affordable Care Act established a new public-private entity for comparative effectiveness research: the Patient-Centered Outcomes Research Institute. The institute is charged with identifying priorities, establishing an agenda, and carrying out comparative effectiveness research. The political process through which the institute was formalized greatly influenced its scope and charge, including the organization's goals, its unique private public composition, and its funding. In this paper I highlight key moments and offer background and insights into what did and did not end up in the final legislation. PMID- 20921476 TI - Comparative effectiveness and personalized medicine: evolving together or apart? AB - Comparative effectiveness research and personalized medicine can at first appear to be at odds with each other. This research initially compares the overall benefits of one therapeutic approach with those of another for the majority of patients, while personalized medicine identifies the subsets of patients who could benefit based on personal characteristics such as genetics. But because comparative effectiveness research typically enrolls heterogeneous patient populations, it can uncover subpopulations that might benefit most from particular treatments. Thus, comparative effectiveness research can help discern the appropriate role of personalized medicine in improving health care outcomes and rationalizing costs. PMID- 20921477 TI - Comparative effectiveness research: from clinical information to economic incentives. AB - Comparative effectiveness research has been promoted as a way to control health care costs, but there has been less discussion of the mechanisms through which new evidence actually will influence physician practice, patient preference, and manufacturer investment. Public and private insurers use conditional coverage, consumer cost sharing, provider contracting, and drug payment policies to manage and direct the flow of resources into the health care system. This paper examines how each of these approaches may be adapted to incorporate new evidence from comparative effectiveness research. PMID- 20921478 TI - How Medicare could use comparative effectiveness research in deciding on new coverage and reimbursement. AB - Medicare must find new ways to achieve cost control without limiting access to beneficial services. We propose a payment model incorporating comparative effectiveness research to encourage Medicare to pay equally for services that provide comparable patient outcomes. The model would include higher payments for services demonstrated by adequate evidence to provide superior health benefits compared to alternative options. New services without such evidence would receive usual reimbursement rates for a limited time but then be reevaluated as evidence emerged. In spite of the substantial political hurdles to changing Medicare reimbursement, efforts should be made to use comparative effectiveness research to reward superior services, improve incentives for cost-effective innovation, and place Medicare on a more sustainable financial footing. PMID- 20921479 TI - The role of costs in comparative effectiveness research. AB - The major expansion of federal comparative effectiveness research launched in 2009 held the potential to supply the information needed to help slow health spending growth while improving the outcomes of care. However, when Congress passed the Patient Protection and Affordable Care Act one year later, it limited the role of cost analysis in the work sponsored by the Patient-Centered Outcomes Research Institute. Despite this restriction, cost-effectiveness analysis meets important needs and is likely to play a larger role in the future. Under the terms of the Affordable Care Act, the institute can avoid commissioning cost effectiveness analyses and still provide information bearing on the use and costs of health care interventions. This information will enable others to investigate the comparative value of these interventions. We argue that doing so is necessary to decision makers who are attempting to raise the quality of care while reining in health spending. PMID- 20921480 TI - A flexible approach to evidentiary standards for comparative effectiveness research. AB - The Patient Protection and Affordable Care Act established a new Patient-Centered Outcomes Research Institute to identify and address research priorities for comparative effectiveness research. Among its many responsibilities, the institute has been charged with setting priorities, developing methodological standards, and communicating research results to decision makers. In this paper we consider how the institute can support the different standards for acceptable evidence used by various government agencies, providers, patients, and other decision makers. We argue that the public interest will best be served if the institute develops a balanced and flexible approach to deciding which types of studies to fund. PMID- 20921481 TI - Why observational studies should be among the tools used in comparative effectiveness research. AB - Doctors, patients, and other decision makers need access to the best available clinical evidence, which can come from systematic reviews, experimental trials, and observational research. Despite methodological challenges, high-quality observational studies have an important role in comparative effectiveness research because they can address issues that are otherwise difficult or impossible to study. In addition, many clinical and policy decisions do not require the very high levels of certainty provided by large, rigorous randomized trials. This paper provides insights and a framework to guide good decision making that involves the full range of high-quality comparative effectiveness research techniques, including observational research. PMID- 20921482 TI - The critical role of observational evidence in comparative effectiveness research. AB - Although not the gold standard of clinical research, observational studies can play a central role as the nation's health care system embraces comparative effectiveness research. Investigators generally prefer randomized trials to observational studies because the former are less subject to bias. Randomized studies, however, often don't represent real-world patient populations, while observational studies can offer quicker results and the opportunity to investigate large numbers of interventions and outcomes among diverse populations -sometimes at lower costs. But some decisions based on observational studies have turned out to be wrong. We recommend that researchers adopt a "body of evidence" approach that includes both randomized and observational evidence. PMID- 20921483 TI - How best to engage patients, doctors, and other stakeholders in designing comparative effectiveness studies. AB - Having patients, doctors, health plan managers, hospital executives, and other stakeholders participate in the design of comparative effectiveness studies can ensure that this vital research focuses on the evidence gaps most relevant to health care decision makers. Through a qualitative assessment of case studies, we identify five key principles for the effective engagement of a broad coalition of participants in research intended to improve health care and control costs. Those principles are to ensure balance among the participating stakeholders; get participants to "buy in" to the process and understand their roles; provide neutral and expert facilitators for research discussions; establish connections among the participants; and keep the participants engaged throughout the research process. PMID- 20921484 TI - Designing comparative effectiveness research on prescription drugs: lessons from the clinical trial literature. AB - As comparative effectiveness research becomes a more prominent feature of clinical medicine, investigators and policy makers would do well to seek lessons from prior examples of this type of research. Our analysis of previous examples reveals lessons in three key areas: choice of comparison treatments, time frame of study, and widespread applicability of study results. Based on our observations, we offer suggestions for increasing the clinical applicability of comparative effectiveness research, such as employing surrogate endpoints that meet a specific threshold of validity. Future trials that address these areas of concern hold the greatest promise for improving patients' outcomes. PMID- 20921485 TI - Special challenges in comparative effectiveness research on children's and adolescents' health. AB - The United States is undertaking a major expansion of comparative effectiveness research, with the potential to achieve systemwide improvements in health care quality, outcomes, and resource allocation. However, to achieve these improvements in children's health and health care, comparative effectiveness research needs to be targeted, designed, conducted, and reported in ways that are responsive to the unique circumstances of children and adolescents. These include clinically important differences in the type and course of disease in children; demographic differences between the overall child and adult population in the United States, such as racial and ethnic makeup; and methodological issues involving study design. Our overarching point is that the base of evidence in pediatrics must not fall even further behind that for the adult population in an era of rapid advancement and funding of comparative effectiveness research. PMID- 20921486 TI - Comparative effectiveness research in mental health: an advocate's perspective. AB - Comparative effectiveness research holds great promise for improving the care of people with mental health conditions and disorders related to substance abuse. But inappropriate application of such research can threaten the quality of that care. We examine the controversy surrounding a large real-world trial of schizophrenia treatments and conclude that the initial presentation of results led to overly simplistic policy suggestions that had the potential to harm patients. Patient advocacy groups helped illuminate these consequences and helped stimulate further discussion and analysis. Researchers must engage stakeholders, especially patients, in all aspects of comparative effectiveness research and translate the findings into sound mental health policy and practice. PMID- 20921487 TI - Adding the patient perspective to comparative effectiveness research. AB - Comparative effectiveness research generates evidence that helps consumers, clinicians, purchasers, and policy makers make better decisions about health care. Capturing the patient's perspective is central to this research because it provides a complete picture of treatment impact. This can be done with standardized questionnaires that ask patients to report on their functioning, well-being, symptoms, and satisfaction with care. These data, however, are not collected routinely in either clinical research or practice. Strategies and incentives to link patient-reported outcomes to data from conventional sources- including clinical research, electronic health records, and administrative data- will accelerate the development of useful evidence. PMID- 20921488 TI - The public wants information, not board mandates, from comparative effectiveness research. AB - We conducted two national surveys of public opinion about comparative effectiveness research and the integration of findings from the research into clinical practice. The first survey found broad support for using research results to provide information, but less support for using them to allocate government resources or mandate treatment decisions. In addition, the public is willing to consider the use of financial incentives to encourage patients to choose cheaper treatments, if research demonstrates that they work as well as more expensive ones. The second survey found that support for comparative effectiveness research dropped in response to general debates about its consequences but that arguments against the research could be effectively countered by specific, targeted rebuttals. PMID- 20921489 TI - A national survey reveals public skepticism about research-based treatment guidelines. AB - Using research to develop treatment guidelines is one way to lower medical costs and improve care. However, findings from a national survey show that the public is skeptical about this approach. Specifically, the public finds arguments against establishing research-based treatment guidelines more convincing than arguments in favor of it. Our findings suggest that for evidence-based treatment guidelines to win public acceptance, the public needs to be reassured that guidelines would not lead to the limiting of access to beneficial care. PMID- 20921490 TI - A patient advocate's perspective on patient-centered comparative effectiveness research. AB - The Patient Protection and Affordable Care Act created a new phrase and concept: patient-centered outcomes research. The author of this commentary, who served as a member of the US House of Representatives from California, is also a patient with epilepsy and a patient advocate. He consulted with lawmakers in the passage of the health reform law. Here he draws on his varied experiences to provide perspective on how the law will provide the necessary policy framework for patient-centered comparative effectiveness research. Elements of that framework include the meaningful engagement of multiple stakeholders, most especially patients; acknowledgment of individual differences among patients and the importance of advancing personalized medicine; transparency and opportunities to participate; a broad, clinically focused research agenda; and the need to communicate results appropriately. PMID- 20921491 TI - 'Bench to behavior': translating comparative effectiveness research into improved clinical practice. AB - The new national emphasis on comparative effectiveness research is likely to generate an unprecedented volume of new findings. It is essential to anticipate the obstacles that front-line health care professionals will face in translating these results into better clinical decision making. We review the current barriers to the dissemination of evidence-based clinical recommendations, including problems with continuing medical education, provider incentives, and quality assurance. We then propose solutions, including more effective educational outreach programs, requirements for practitioners to master important findings, and alignment of incentives to encourage evidence-based practice. Such strategies can lead to policies that could encourage the uptake of new comparative effectiveness data and encourage their translation into better clinical practice. PMID- 20921492 TI - Moving comparative effectiveness research into practice: implementation science and the role of academic medicine. AB - The success of the federal investment in comparative effectiveness research will hinge on using the power of science to guide reforms in health care delivery and improve patient-centered outcomes. Translating the results of comparative effectiveness research into practice calls for the rigors of implementation science to ensure the efficient and systematic uptake, dissemination, and endurance of these innovations. Academic medicine can help answer the call by thoroughly integrating its research and training missions with clinical care that is focused on patient-centered outcomes; building multidisciplinary teams that include a wide range of experts such as clinicians, clinical and implementation scientists, systems engineers, behavioral economists, and social scientists; and training future care providers, scientists, and educators to carry innovations forward. PMID- 20921493 TI - The Veterans Affairs experience: comparative effectiveness research in a large health system. AB - Comparative effectiveness research is a tool to use in achieving patient centered, high-value health care. However, applying the results to individual patients and health systems raises unique issues. Here, we review lessons learned by the Veterans Health Administration (VHA) in developing and implementing the research in a large integrated health system. Decision makers should examine whether individual studies apply to diverse populations, align tools and incentives to adopt evidence-based practices, and consider both the patient and population perspectives. A key challenge remains how to incorporate comparative evidence and patient values into busy clinical practices. PMID- 20921495 TI - The case for a national patient library. AB - A national patient library that stored and communicated findings from research on the comparative effectiveness of health services could be a valuable resource for patients and clinicians. It could assist in improving the quality of health care and help reduce inappropriate costs. Public confidence in a national patient library would require that its activities be insulated from government as well as from professional, provider, payer, and commercial groups and advocacy organizations. This article describes why such a library is possible and desirable, what it would do for whom, how it could be governed and financed, and how it could overcome initial challenges. PMID- 20921496 TI - Why I don't get mammograms. PMID- 20921497 TI - Helping nursing homes prepare for disasters. AB - Responding to the deaths and suffering of older adults in long-term care facilities following Hurricanes Katrina, Rita, and Wilma, the John A. Hartford Foundation funded an initiative called Hurricane and Disaster Preparedness for Long-Term Care Facilities. Long-term care providers are now acknowledged as health care providers by most federal and state emergency response centers. This paper describes the planning, research, and dissemination efforts of the Hartford grantees. It also provides insights into successful disaster grant making, noting foundations' unique flexibility, strategic and long-term view, and ability to be a neutral convener of stakeholders that can help grantees work toward achieving major policy change. PMID- 20921499 TI - Providers of anesthesia: does quality vary? PMID- 20921500 TI - Anesthesia training: another view. PMID- 20921502 TI - Communication goes two ways. PMID- 20921501 TI - The emotional work of dealing with patients. PMID- 20921504 TI - Continued education needed as reforms are implemented. PMID- 20921506 TI - Teaching NeuroImages: acquired Chiari malformation with syringohydromyelia caused by posterior fossa tumor. PMID- 20921507 TI - Teaching NeuroImages: vestibular schwannomas in neurofibromatosis type 2. PMID- 20921508 TI - MxA: a biomarker for predicting multiple sclerosis disease activity. PMID- 20921509 TI - Spontaneous MxA mRNA level predicts relapses in patients with recently diagnosed MS. AB - OBJECTIVE: To determine if myxovirus resistance protein A (MxA) mRNA is related to clinical disease activity in multiple sclerosis (MS). METHODS: Baseline MxA mRNA levels were measured in a prospective cohort of 116 untreated patients with early MS and were related to clinical relapses and MRI at baseline and at follow up. RESULTS: Low levels of MxA mRNA were associated with the occurrence of relapses (p = 0.002) and contrast-enhancing lesions (CELs) on baseline MRI (p = 0.045). In addition, high baseline MxA mRNA levels were related to a longer time to a first new relapse (hazard ratio [HR] 0.59; 95% confidence interval [CI] 0.35 1.00; p = 0.044). Adding the absence of CELs to high MxA mRNA, the predictive value increased (HR 0.35; 95% CI 0.17-0.74; p = 0.006), clearly showing a cumulative value for combining both factors. CONCLUSIONS: MxA mRNA is related to clinical exacerbations, the number of CELs on MRI, and is indicative for the time to a subsequent relapse. If confirmed, MxA mRNA has potential as a biomarker for clinical disease activity in MS. PMID- 20921510 TI - Cognitive compensation failure in multiple sclerosis. AB - OBJECTIVES: Compensatory processes involving the recruitment of additional cerebral areas can limit cognitive impairment caused by brain damage as revealed by fMRI. Multiple sclerosis (MS) is characterized by frequent cognitive deficiencies and diffuse brain damage. Understanding the missing or disturbed processes resulting in cognitive compensation failure is a major challenge in MS. METHODS: Fifteen patients with relapsing-remitting (RR) MS and 20 healthy controls underwent an fMRI paradigm based on Go/No-go task with increasing complexity and neuropsychological and morphologic MRI examinations. RESULTS: To perform all the Go/No-go conditions, patients with RRMS exhibited supplementary cerebral recruitment compared to controls. For the most complex condition, patients presented both collapse of additional cerebral recruitment and significant lower cognitive performance compared to controls. In patients, both response times and diffuse tissue damage were correlated with medial frontal activations. Functional connectivity analysis demonstrated strong correlation between dorsolateral prefrontal cortex and medial frontal region activations. CONCLUSIONS: High cognitive demand causes beneficial cerebral recruitment failure, leading to cognitive impairment in patients with RRMS. Functional compensatory mechanisms preserving good cognitive performances operate by a new cerebral strategy involving medial prefrontal regions recruitment, instead of cerebellar regions seen in controls. This new recruitment is diffuse tissue damage-dependent. Missing cerebellar involvement argues for an inability to generate proficient cognitive automation processes in patients, directly leading to recruitment of high-level decision-making areas. Recurrent mobilization of cortical regions could explain the limiting effect of the cognitive load on the cognitive compensatory phenomena in patients with MS. PMID- 20921511 TI - Assessment of potential measures in models of progression in Alzheimer disease. AB - BACKGROUND: In estimating the potential benefits of treatment, it is often necessary to extrapolate beyond clinical trial results using economic modeling. Previous attempts in Alzheimer disease (AD) were primarily based on the Mini Mental State Examination (MMSE) due to its widespread use. These models were criticized as not accurately reflecting the total impact of the disease, providing untrustworthy estimates of treatment benefit. We compared 3 alternatives to the MMSE with respect to bridging between clinical outcomes needed for regulatory approval and economic and quality of life (QOL) outcomes important to reimbursement agencies. METHODS: The MMSE, Disability Assessment in Dementia (DAD) scale, Clinical Dementia Rating (CDR) scale, and Dependence Scale (DS) were compared in their ability to explain variation in cognitive, functional, and behavioral measures as well as economic and QOL outcomes using univariate (Pearson correlations) and multivariate (linear regression) analyses of data from research sites in the United States and Europe. RESULTS: Subjects with mild to moderate AD (n = 196; mean 75.9 years; 56% female) were evaluated. The DS, DAD, and CDR were moderately correlated with the MMSE (Pearson correlations, range 0.54-0.58) but performed better (higher adjusted R(2)) than the MMSE in explaining variations in subject behavior, QOL, and health status. The DS and DAD performed better in explaining variation in medical costs, caregiver QOL, and caregiver time. CONCLUSIONS: Measures of function (DAD) or dependence on others (DS), or global measures (CDR), appear to be better candidates than the MMSE for modeling AD progression. PMID- 20921512 TI - What predicts mortality in Parkinson disease?: a prospective population-based long-term study. AB - OBJECTIVE: To identify independent risk factors of mortality in a community-based Parkinson disease (PD) cohort during prospective long-term follow-up. METHODS: A community-based prevalent sample of 230 patients with PD from southwestern Norway was followed prospectively with repetitive assessments of motor and nonmotor symptoms from 1993 to 2005. Information on vital status until October 20, 2009, was obtained from the National Population Register in Norway. Cox proportional hazards models were applied to identify independent predictors of mortality during follow-up. Chronological age, Unified Parkinson's Disease Rating Scale (UPDRS) motor score, levodopa equivalent dose, probable REM sleep behavior disorder, psychotic symptoms, dementia, and use of antipsychotics were included as time-dependent variables, and age at onset (AAO) and sex as time-independent variables. RESULTS: Of 230 patients, 211 (92%) died during the study period. Median survival time from motor onset was 15.8 years (range 2.2-36.6). Independent predictors of mortality during follow-up were AAO (hazard ratio [HR] 1.40 for 10-years increase, p = 0.029), chronological age (HR 1.51 for 10-years increase, p = 0.043), male sex (HR 1.63, p = 0.001), UPDRS motor score (HR 1.18 for 10-point increase, p < 0.001), psychotic symptoms (HR 1.45, p = 0.039), and dementia (HR 1.89, p = 0.001). CONCLUSIONS: This population-based long-term study demonstrates that in addition to AAO, chronological age, motor severity, and dementia, psychotic symptoms independently predict increased mortality in PD. In contrast, no significant impact of antipsychotic or antiparkinsonian drugs on survival was observed in our PD cohort. Early prevention of motor progression and development of psychosis and dementia may be the most promising strategies to increase life expectancy in PD. PMID- 20921513 TI - The Causative Classification of Stroke system: an international reliability and optimization study. AB - BACKGROUND: Valid and reliable ischemic stroke subtype determination is crucial for well-powered multicenter studies. The Causative Classification of Stroke System (CCS, available at http://ccs.mgh.harvard.edu) is a computerized, evidence based algorithm that provides both causative and phenotypic stroke subtypes in a rule-based manner. We determined whether CCS demonstrates high interrater reliability in order to be useful for international multicenter studies. METHODS: Twenty members of the International Stroke Genetics Consortium from 13 centers in 8 countries, who were not involved in the design and development of the CCS, independently assessed the same 50 consecutive patients with acute ischemic stroke through reviews of abstracted case summaries. Agreement among ratings was measured by kappa statistic. RESULTS: The kappa value for causative classification was 0.80 (95% confidence interval [CI] 0.78-0.81) for the 5 subtype, 0.79 (95% CI 0.77-0.80) for the 8-subtype, and 0.70 (95% CI 0.69-0.71) for the 16-subtype CCS. Correction of a software-related factor that generated ambiguity improved agreement: kappa = 0.81 (95% CI 0.79-0.82) for the 5-subtype, 0.79 (95% CI 0.77-0.80) for the 8-subtype, and 0.79 (95% CI 0.78-0.80) for the 16 subtype CCS. The kappa value for phenotypic classification was 0.79 (95% CI 0.77 0.82) for supra-aortic large artery atherosclerosis, 0.95 (95% CI 0.93-0.98) for cardioembolism, 0.88 (95% CI 0.85-0.91) for small artery occlusion, and 0.79 (0.76-0.82) for other uncommon causes. CONCLUSIONS: CCS allows classification of stroke subtypes by multiple investigators with high reliability, supporting its potential for improving stroke classification in multicenter studies and ensuring accurate means of communication among different researchers, institutions, and eras. PMID- 20921514 TI - Decreased serum BDNF levels in patients with epileptic and psychogenic nonepileptic seizures. AB - OBJECTIVE: Neurotrophins promote neurogenesis and help regulate synaptic reorganization. Their dysregulation has been implicated in a number of neurologic and psychiatric disorders. Previous studies have shown decreased levels of brain derived neurotrophic factor (BDNF) in the serum of patients with psychiatric disorders such as major depressive disorder (MDD) and conversion disorder (CD). In human patients with temporal lobe epilepsy, there is an increase in both BDNF mRNA and protein levels in surgically resected hippocampi compared to controls. One study of children with epilepsy has found normal to increased serum BDNF levels compared to controls. Plasma [corrected] BDNF levels have not been investigated in adult patients with epileptic seizures (ES). We hypothesized that BDNF would differentiate between ES and psychogenic nonepileptic seizures (PNES). METHODS: We assessed plasma [corrected] BDNF immunoreactivity in 15 patients with ES, 12 patients with PNES, and 17 healthy volunteers. Plasma [corrected] BDNF levels were measured using an enzyme-linked immunoassay. RESULTS: Healthy controls showed higher BDNF levels (4,289 +/- 1,810 pg/mL) compared to patients with PNES (1,033 +/- 435 pg/mL) (p < 0.001). However, unexpectedly, healthy controls also showed higher levels of BDNF compared to patients with ES without comorbid MDD (977 +/- 565 pg/mL) (p < 0.001). CONCLUSIONS: Unlike children, adults with epilepsy appear to have decreased levels of plasma [corrected] BDNF. Reduced plasma [corrected] BDNF levels can be used to differentiate adult patients with ES or PNES from healthy controls. Further human studies are needed to better understand the pathophysiology explaining the decreased plasma [corrected] BDNF levels found in epilepsy and in PNES. PMID- 20921515 TI - A meta-regression of the long-term effects of deep brain stimulation on balance and gait in PD. AB - OBJECTIVE: Deep brain stimulation (DBS) alleviates the cardinal Parkinson disease (PD) symptoms of tremor, rigidity, and bradykinesia. However, its effects on postural instability and gait disability (PIGD) are uncertain. Contradictory findings may be due to differences the in stimulation site and the length of time since DBS surgery. This prompted us to conduct the first meta-regression of long term studies of bilateral DBS in the subthalamic nucleus (STN) and globus pallidus interna (GPi). RESULTS: Eleven articles reported a breakdown of the Unified Parkinson's Disease Rating Scale score before and beyond 3 years postsurgery (mean 4.5 years). Random effects meta-regression revealed that DBS initially improved PIGD compared to the OFF medicated state before surgery, but performance declined over time and extrapolation showed subjects would reach presurgery levels 9 years postsurgery. ON medication, DBS improved PIGD over and above the effect of medication before surgery. Nevertheless, for the STN group, PIGD progressively declined and was worse than presurgery function within 2 years. In contrast, GPi patients showed no significant long-term decline in PIGD in the medicated state. Improvements in cardinal signs with DBS at both sites were maintained across 5 years in the OFF and ON medication states. CONCLUSIONS: DBS alone does not offer the same improvement to PIGD as it does to the cardinal symptoms, suggesting axial and distal control are differentially affected by DBS. GPi DBS in combination with levodopa seemed to preserve PIGD better than did STN DBS, although more studies of GPi DBS and randomized controls are needed. PMID- 20921516 TI - Relapsing rhabdomyolysis due to peroxisomal alpha-methylacyl-coa racemase deficiency. PMID- 20921517 TI - An unusual cause of isolated vomiting. PMID- 20921518 TI - Clinical and prognostic subforms of new daily-persistent headache. PMID- 20921519 TI - Distinct roles of vascular endothelial growth factor receptor-1- and receptor-2 mediated signaling in T cell priming and Th17 polarization to lipopolysaccharide containing allergens in the lung. AB - Vascular endothelial growth factor (VEGF) is a key mediator in the development of airway immune dysfunction to inhaled allergens. However, the exact role of its receptors-mediated signaling is controversial. In this study, we evaluated the role of VEGF receptor (VEGFR)-1- and VEGFR-2-mediated signaling in T cell priming and polarization in the context of inhalation of LPS-containing allergens. A murine asthma model of mixed Th1 and Th17 cell responses was generated using intranasal sensitization with LPS-containing allergens. Pharmacologic intervention was performed during sensitization. In vivo production of VEGF and Th1- and Th17-polarizing cytokines (IL-12p70 and IL-6, respectively) were upregulated by airway exposure to LPS. Pharmacological intervention with a VEGFR 2-neutralizing Ab (anti-Flk1 mAb) abolished the production of IL-6 (but not IL 12p70) and the subsequent development of allergen-specific Th17 cell response. On the other hand, blocking VEGFR-1 signaling with a VEGFR-1 antagonist (anti-Flt1 hexapeptide) did not affect the production of IL-12p70 and IL-6. However, blocking VEGFR-1 signaling resulted in T cell tolerance rather than priming, mainly by inhibiting the maturation of lung dendritic cells, and their migration into lung-draining lymph nodes. These results suggest that T cell priming to LPS containing allergens depends on VEGFR-1-mediated signaling, and the subsequent Th17 polarization depends on VEGFR-2 signaling. PMID- 20921520 TI - Error-prone DNA repair activity during somatic hypermutation in shark B lymphocytes. AB - Sharks are representatives of the earliest vertebrates that possess an immune system utilizing V(D)J recombination to generate Ag receptors. Their Ab repertoire diversity is based in part on a somatic hypermutation process that introduces adjacent nucleotide substitutions of 2-5 bp. We have isolated mutant nonfunctional Ig rearrangements and intronic flank sequences to characterize the nonselected, intrinsic properties of this phenomenon; changes unique to shark were observed. Duplications and deletions were associated with N additions, suggesting participation of a DNA polymerase with some degree of template independence during the repair of DNA breaks initiated by activation-induced cytidine deaminase. Other mutations were consistent with some in vitro activities of mammalian translesion DNA polymerase eta: tandem base substitutions, strand slippage, and small insertions/deletions. The nature of substitution patterns shows that DNA lesions at shark Ig genes recruit DNA repair factors with a species-specific repertoire of activities. We speculate that the tandem mutations are introduced by direct sequential misinsertions and that, in shark B cells, the mispairs tend to be extended rather than proofread. Despite extensive changes undergone by some mutants, the physical range of mutational activity remained restricted to VDJ and within the first 2-kb portion of the 6.8-kb J-C intron, perhaps a self-regulating aspect of activation-induced cytidine deaminase action that is conserved in evolution. PMID- 20921521 TI - Gender-associated differences of perforin polymorphisms in the susceptibility to multiple sclerosis. AB - The granule-dependent exocytosis pathway is an important mechanism to induce apoptosis by CD8(+) T cells and NK cells and involves lytic molecules such as perforin. In the current study, we investigated the perforin 1 gene (PRF1) as a candidate for multiple sclerosis (MS) susceptibility in the Spanish population. We genotyped three PRF1 single nucleotide polymorphisms (rs885822, rs10999426, and rs3758562) in 420 patients with MS and 512 controls. Associations of PRF1 polymorphisms with the disease were restricted to male patients with MS, and the finding was consistently observed at the allele, genotype, and haplotype levels. Gender-associated differences were validated in an additional replication cohort comprised of 292 MS cases and 300 controls. In addition, we identified minor risk haplotypes strongly associated with male patients having primary progressive MS (PPMS). Further characterization of male patients with PPMS carrying the risk haplotypes by means of gene expression microarrays revealed overrepresentation of the cell killing gene ontology category among downregulated genes in these patients compared with male patients with PPMS carrying protective haplotypes. Moreover, PRF1 mRNA expression levels were significantly lower in patients with risk haplotypes, and changes in perforin protein expression by CD8(+) T cells mirrored those observed in gene expression. These findings suggest a gender dimorphism in the PRF1 association with MS and point to the presence of a generalized defect in the expression of genes that code for proteins involved in cell killing in a subgroup of male patients with PPMS. PMID- 20921522 TI - Genetic susceptibility to the delayed sequelae of neonatal respiratory syncytial virus infection is MHC dependent. AB - Respiratory syncytial virus (RSV) is a major cause of respiratory morbidity, resulting in hospitalization for bronchiolitis in some infected infants that is associated with wheeze in later life. Genetic factors are known to affect the severity of the sequelae after RSV infection, but the complexity of the temporal and genetic effects makes it difficult to analyze this response in studies in man. Therefore, we developed a murine genetic model to analyze the sequelae occurring after RSV infection in early life. Haplotype-based genetic analysis of interstrain differences in severity identified the MHC as an important genetic determinant. This was confirmed by analysis of responses in congenic mice with different MHC haplotypes. We also found that susceptible strains had high CD8 levels during secondary infection. Analysis of first filial generation, second filial generation, and back-cross progeny produced by intercrossing resistant (H 2(k), C3H/HeN) and sensitive (H-2(b), BALB/c) strains indicated that susceptibility to sequelae after RSV infection was dominantly inherited but also segregated in a non-MHC-dependent manner. Thus, MHC haplotype and its effect on CD8 cell response is an important determinant of the outcome of neonatal RSV infection. PMID- 20921523 TI - Naive human T cells are activated and proliferate in response to the heme oxygenase-1 inhibitor tin mesoporphyrin. AB - Heme oxygenase-1 (HO-1) and its catabolic by-products have potent anti inflammatory activity in many models of disease. It is not known, however, if HO 1 also plays a role in the homeostatic control of T cell activation and proliferation. We demonstrate here that the HO-1 inhibitor tin mesoporphyrin (SnMP) induces activation, proliferation, and maturation of naive CD4(+) and CD8(+) T cells via interactions with CD14(+) monocytes in vitro. This response is dependent upon interactions of T cells with MHC class I and II on the surface of CD14(+) monocytes. Furthermore, CD4(+)CD25(+)FoxP3(+) regulatory T cells were able to suppress this proliferation, even though their suppressive activity was itself impaired by SnMP. Given the magnitude of the Ag-independent T cell response induced by SnMP, we speculate that HO-1 plays an important role in dampening nonspecific T cell activation. Based on these findings, we propose a potential role for HO-1 in the control of naive T cell homeostatic proliferation. PMID- 20921524 TI - Neutrophil elastase mediates pathogenic effects of anthrax lethal toxin in the murine intestinal tract. AB - Neutrophils isolated from BALB/c or C57BL/6 mice and treated in vitro with anthrax lethal toxin release bioactive neutrophil elastase, a proinflammatory mediator of tissue destruction. Similarly, neutrophils isolated from mice treated with anthrax lethal toxin in vivo and cultured ex vivo release greater amounts of elastase than neutrophils from vehicle-treated controls. Direct measurements from murine intestinal tissue samples demonstrate an anthrax lethal toxin-dependent increase in neutrophil elastase activity in vivo as well. These findings correlate with marked lethal toxin-induced intestinal ulceration and bleeding in neutrophil elastase(+/+) animals, but not in neutrophil elastase(-/-) animals. Moreover, neutrophil elastase(-/-) mice have a significant survival advantage over neutrophil elastase(+/+) animals following exposure to anthrax lethal toxin, thereby establishing a key role for neutrophil elastase in mediating the deleterious effects of anthrax lethal toxin. PMID- 20921525 TI - Differential localization of effector and memory CD8 T cell subsets in lymphoid organs during acute viral infection. AB - It is unclear where within tissues subsets of effector and memory CD8 T cells persist during viral infection and whether their localization affects function and long-term survival. Following lymphocytic choriomeningitis virus infection, we found most killer cell lectin-like receptor G1 (KLRG1)(lo)IL-7R(hi) effector and memory cells, which are long-lived and high proliferative capacity, in the T cell zone of the spleen. In contrast, KLRG1(hi)IL-7R(lo) cells, which appear terminally differentiated and have shorter life spans, were exclusively localized to the red pulp. KLRG1(lo)IL-7R(hi) T cells homed to the T cell zone using pertussis toxin-sensitive chemokine receptors and appeared to contact gp38(+) stromal cells, which produce the chemokines CCL19 and CCL21 and the T cell survival cytokine IL-7. The transcription factors T-bet and B lymphocyte-induced maturation protein-1 controlled effector CD8 T cell splenic migration. Effector CD8 T cells overexpressing T-bet homed to the red pulp, whereas those lacking B lymphocyte-induced maturation protein-1 homed to the T cell zone. Upon memory formation, CD62L(+) memory T cells were predominantly found in the T cell zone, whereas CD62L(-) cells were found in the red pulp. Thus, effector and memory CD8 T cell subset localization within tissues is linked to their differentiation states, and this may identify anatomical niches that regulate their longevity and homeostasis. PMID- 20921526 TI - Human plasma membrane-derived vesicles halt proliferation and induce differentiation of THP-1 acute monocytic leukemia cells. AB - Plasma membrane-derived vesicles (PMVs) are small intact vesicles released from the cell surface that play a role in intercellular communication. We have examined the role of PMVs in the terminal differentiation of monocytes. The myeloid-differentiating agents all-trans retinoic acid/PMA and histamine, the inflammatory mediator that inhibits promonocyte proliferation, induced an intracellular Ca(2+)-mediated PMV (as opposed to exosome) release from THP-1 promonocytes. These PMVs cause THP-1 cells to enter G(0)-G(1) cell cycle arrest and induce terminal monocyte-to-macrophage differentiation. Use of the TGF-beta receptor antagonist SB-431542 and anti-TGF-beta1 Ab showed that this was due to TGF-beta1 carried on PMVs. Although TGF-beta1 levels have been shown to increase in cell culture supernatants during macrophage differentiation and dendritic cell maturation, the presence of TGF-beta1 in PMVs is yet to be reported. In this study, to our knowledge we show for the first time that TGF-beta1 is carried on the surface of PMVs, and we confirm the presence within PMVs of certain leaderless proteins, with reported roles in myeloid cell differentiation. Our in vitro findings support a model in which TGF-beta1-bearing PMVs, released from promonocytic leukemia cells (THP-1) or primary peripheral blood monocytes on exposure to sublytic complement or after treatment with a differentiation therapy agent, such as all-trans retinoic acid, significantly reduce proliferation of THP 1 cells. Such PMVs also induce the terminal differentiation of primary peripheral blood monocytes as well as THP-1 monocytes. PMID- 20921527 TI - Deletion of ripA alleviates suppression of the inflammasome and MAPK by Francisella tularensis. AB - Francisella tularensis is a facultative intracellular pathogen and potential biothreat agent. Evasion of the immune response contributes to the extraordinary virulence of this organism although the mechanism is unclear. Whereas wild-type strains induced low levels of cytokines, an F. tularensis ripA deletion mutant (LVSDeltaripA) provoked significant release of IL-1beta, IL-18, and TNF-alpha by resting macrophages. IL-1beta and IL-18 secretion was dependent on inflammasome components pyrin-caspase recruitment domain/apoptotic speck-containing protein with a caspase recruitment domain and caspase-1, and the TLR/IL-1R signaling molecule MyD88 was required for inflammatory cytokine synthesis. Complementation of LVSDeltaripA with a plasmid encoding ripA restored immune evasion. Similar findings were observed in a human monocytic line. The presence of ripA nearly eliminated activation of MAPKs including ERK1/2, JNK, and p38, and pharmacologic inhibitors of these three MAPKs reduced cytokine induction by LVSDeltaripA. Animals infected with LVSDeltaripA mounted a stronger IL-1beta and TNF-alpha response than that of mice infected with wild-type live vaccine strain. This analysis revealed novel immune evasive mechanisms of F. tularensis. PMID- 20921528 TI - The early marginal zone B cell-initiated T-independent type 2 response resists the proteasome inhibitor bortezomib. AB - The proteasome inhibitor bortezomib is approved for the treatment of multiple myeloma and mantle cell lymphoma. We recently demonstrated that bortezomib eliminates autoreactive plasma cells in systemic lupus erythematosus mouse models, thereby representing a promising novel treatment for Ab-mediated diseases. In this study, we investigated the effects of bortezomib on the just developing and pre-existing T-dependent Ab response toward dinitrophenyl-keyhole limpet hemocyanin and the T-independent type 2 response toward (4-hydroxy-3-iodo 5-nitrophenyl)acetyl (NIP)-Ficoll in BALB/c mice. Bortezomib treatment strongly reduced T-dependent Ab titers mainly due to depletion of plasma cells. In contrast, the early T-independent type 2 response against i.v. administered NIP Ficoll, which is predominantly dependent on marginal zone (MZ) B cells, resisted bortezomib. Upon bortezomib treatment, immunoproteasome subunits and the antiapoptotic unfolded protein response including NF-kappaB were induced in NIP Ficoll-stimulated MZ B cells, but not in plasma cells and follicular B cells. In summary, bortezomib treatment decreases Ab titers arising from T-dependent immune responses predominantly by eliminating plasma cells. In contrast, the early T independent type 2 response protecting the organism against blood-borne pathogens remains largely intact due to a remarkable resistance of MZ B cells against proteasome inhibition. PMID- 20921530 TI - A cyclooxygenase-2/prostaglandin E2 pathway augments activation-induced cytosine deaminase expression within replicating human B cells. AB - Within inflammatory environments, B cells encountering foreign or self-Ag can develop tertiary lymphoid tissue expressing activation-induced cytosine deaminase (AID). Recently, this DNA-modifying enzyme was detected in nonlymphoid cells within several inflamed tissues and strongly implicated in malignant transformation. This study examines whether a cyclooxygenase 2 (COX-2) pathway, often linked to inflammation, influences AID expression in activated B lymphocytes. In this paper, we report that dividing human B cells responding to surrogate C3d-coated Ag, IL-4, and BAFF express AID, as well as COX-2. A progressive increase in AID with each division was paralleled by a division related increase in a COX-2-linked enzyme, microsomal PGE(2) synthase-1, and the PGE(2)R, EP2. Cells with the greatest expression of AID expressed the highest levels of EP2. Although COX-2 inhibitors diminished both AID expression and IgG class switching, exogenous PGE(2) and butaprost, a selective EP2 agonist, augmented AID mRNA/protein and increased the numbers of IgG(+) progeny. Despite the latter, the proportion of IgG(+) cells within viable progeny generally declined with PGE(2) supplementation. This was not due to PGE(2)-promoted differentiation to plasma cells or to greater downstream switching. Rather, because phosphorylated ataxia telangiectasia mutated levels were increased in progeny of PGE(2)-supplemented cultures, it appears more likely that PGE(2) facilitates AID-dependent DNA double-strand breaks that block B cell cycle progression or promote activation-induced cell death, or both. Taken together, the results suggest that a PGE(2) feed-forward mechanism for augmenting COX-2 pathway proteins promotes progressively increased levels of AID mRNA, protein, and function. PMID- 20921529 TI - IL-23 and IL-17A, but not IL-12 and IL-22, are required for optimal skin host defense against Candida albicans. AB - IL-23 and Th17 cells play important roles in host defense against systemic infections with extracellular bacteria and fungi, although their roles in immunity against localized skin infections are less well defined. Here, the contributions of IL-23 and Th17 cytokines in host defense against cutaneous Candida albicans infection were evaluated. Mice deficient in IL-23 or IL-17A demonstrated delayed healing and decreased IL-17A production after skin infection with C. albicans compared with wild-type mice or mice deficient in IL-12 or IL 22. Histologic examination revealed epidermal hyperplasia overlying infected dermis four days postinoculation in wild-type mice. In IL-23-deficient mice, fungal burden was greater in skin, neither IL-17A nor IL-22 mRNAs were expressed postinfection, and these mice demonstrated only minimal epidermal hyperplasia. Exogenous recombinant IL-17A injected at the site of skin infection promoted more rapid healing of candidiasis in both wild-type mice and mice deficient in IL-23 and IL-12. Taken together, these results demonstrate that IL-23 and IL-17A, but not IL-12 and IL-22, are required for optimal host defense against cutaneous candidiasis. In addition, recombinant IL-17A may serve as a potential therapy to enhance healing in individuals with chronic cutaneous candidiasis. PMID- 20921531 TI - Dual effects of TRAIL in suppression of autoimmunity: the inhibition of Th1 cells and the promotion of regulatory T cells. AB - TRAIL is known to play a pivotal role in the inhibition of autoimmune disease. We previously demonstrated that administration of dendritic cells engineered to express TRAIL and myelin-oligodendrocyte glycoprotein reduced the severity of experimental autoimmune encephalomyelitis and suggested that CD4(+)CD25(+) regulatory T cells (Tregs) were involved in mediating this preventive effect. In the current study, we investigated the effect of TRAIL on Tregs, as well as conventional T cells, using TRAIL-deficient mice. Upon induction of experimental autoimmune encephalomyelitis, TRAIL-deficient mice showed more severe clinical symptoms, a greater frequency of IFN-gamma-producing CD4(+) T (Th1) cells, and a lower frequency of CD4(+)Foxp3(+) Tregs than did wild-type mice. In vitro, conventional T cells stimulated by bone marrow-derived dendritic cells (BM-DCs) from TRAIL-deficient mice showed a greater magnitude of proliferation than did those stimulated by BM-DCs from wild-type mice. In contrast, TRAIL expressed on the stimulator BM-DCs enhanced the proliferative response of CD4(+)CD25(+) Tregs in the culture. The functional TRAILR, mouse death receptor 5 (mDR5), was expressed in conventional T cells and Tregs upon stimulation. In contrast, the decoy receptor, mDc-TRAILR1, was slightly expressed only on CD4(+)CD25(+) Tregs. Therefore, the distinct effects of TRAIL may be due to differences in the mDc TRAILR1 expression or the signaling pathways downstream of mouse death receptor 5 between the two T cell subsets. Our data suggest that TRAIL suppresses autoimmunity by two mechanisms: the inhibition of Th1 cells and the promotion of Tregs. PMID- 20921533 TI - Differential suppression of tumor-specific CD8+ T cells by regulatory T cells. AB - In the CT26 BALB/c murine model of colorectal carcinoma, depletion of regulatory T cells (Tregs) prior to tumor inoculation results in protective immunity to both CT26 and other BALB/c-derived tumors of diverse histological origin. In this paper, we show that cross-protection can be conferred by adoptively transferred CD8(+) CTLs. Other schedules for inducing immunity to CT26 have been described, but they do not lead to cross-protection. We show that Treg ablation facilitates the development of new CTL specificities that are normally cryptic, and have mapped the root epitope of one of these responses. This work has allowed us to demonstrate how the specificity of CTL responses to tumor Ags can be controlled via differential suppression of CTL specificities by Tregs, and how this can result in very different physiological outcomes. PMID- 20921532 TI - Identification of an autophagy defect in smokers' alveolar macrophages. AB - Alveolar macrophages are essential for clearing bacteria from the alveolar surface and preventing microbe-induced infections. It is well documented that smokers have an increased incidence of infections, in particular lung infections. Alveolar macrophages accumulate in smokers' lungs, but they have a functional immune deficit. In this study, we identify an autophagy defect in smokers' alveolar macrophages. Smokers' alveolar macrophages accumulate both autophagosomes and p62, a marker of autophagic flux. The decrease in the process of autophagy leads to impaired protein aggregate clearance, dysfunctional mitochondria, and defective delivery of bacteria to lysosomes. This study identifies the autophagy pathway as a potential target for interventions designed to decrease infection rates in smokers and possibly in individuals with high environmental particulate exposure. PMID- 20921535 TI - Zinc-induced copper deficiency in Wilson disease. PMID- 20921534 TI - LRRK2 is involved in the IFN-gamma response and host response to pathogens. AB - LRRK2 was previously identified as a defective gene in Parkinson's disease, and it is also located in a risk region for Crohn's disease. In this study, we aim to determine whether LRRK2 could be involved in immune responses. We show that LRRK2 expression is enriched in human immune cells. LRRK2 is an IFN-gamma target gene, and its expression increased in intestinal tissues upon Crohn's disease inflammation. In inflamed intestinal tissues, LRRK2 is detected in the lamina propria macrophages, B-lymphocytes, and CD103-positive dendritic cells. Furthermore, LRRK2 expression enhances NF-kappaB-dependent transcription, suggesting its role in immune response signaling. Endogenous LRRK2 rapidly translocates near bacterial membranes, and knockdown of LRRK2 interferes with reactive oxygen species production during phagocytosis and bacterial killing. These observations indicate that LRRK2 is an IFN-gamma target gene, and it might be involved in signaling pathways relevant to Crohn's disease pathogenesis. PMID- 20921536 TI - Summaries for patients: Using a gene test to better identify heart disease in patients with chest pain. PMID- 20921537 TI - Summaries for patients. Insufficient sleep, diet, and obesity. PMID- 20921538 TI - Summaries for patients. Cancer screening among adults who have survived childhood cancer. PMID- 20921539 TI - Summaries for patients. Do persons with AIDS develop common types of cancer at younger ages? PMID- 20921540 TI - In the clinic. Clostridium difficile Infection. AB - This issue provides a clinical overview of Clostridium difficile infection focusing on prevention, diagnosis, treatment, practice improvement, and patient information. Readers can complete the accompanying CME quiz for 1.5 credits. Only ACP members and individual subscribers can access the electronic features of In the Clinic. Non-subscribers who wish to access this issue of In the Clinic can elect "Pay for View." Subscribers can receive 1.5 category 1 CME credits by completing the CME quiz that accompanies this issue of In the Clinic. The content of In the Clinic is drawn from the clinical information and education resources of the American College of Physicians (ACP), including PIER (Physicians' Information and Education Resource) and MKSAP (Medical Knowledge and Self Assessment Program). Annals of Internal Medicine editors develop In the Clinic from these primary sources in collaboration with the ACP's Medical Education and Publishing division and with assistance of science writers and physician writers. Editorial consultants from PIER and MKSAP provide expert review of the content. Readers who are interested in these primary resources for more detail can consult www.acponline.org, http://pier.acponline.org, and other resources referenced within each issue of In the Clinic. PMID- 20921541 TI - Multicenter validation of the diagnostic accuracy of a blood-based gene expression test for assessing obstructive coronary artery disease in nondiabetic patients. AB - BACKGROUND: Diagnosing obstructive coronary artery disease (CAD) in at-risk patients can be challenging and typically requires both noninvasive imaging methods and coronary angiography, the gold standard. Previous studies have suggested that peripheral blood gene expression can indicate the presence of CAD. OBJECTIVE: To validate a previously developed 23-gene, expression-based classification test for diagnosis of obstructive CAD in nondiabetic patients. DESIGN: Multicenter prospective trial with blood samples obtained before coronary angiography. (ClinicalTrials.gov registration number: NCT00500617) SETTING: 39 centers in the United States. PATIENTS: An independent validation cohort of 526 nondiabetic patients with a clinical indication for coronary angiography. MEASUREMENTS: Receiver-operating characteristic (ROC) analysis of classifier score measured by real-time polymerase chain reaction, additivity to clinical factors, and reclassification of patient disease likelihood versus disease status defined by quantitative coronary angiography. Obstructive CAD was defined as 50% or greater stenosis in 1 or more major coronary arteries by quantitative coronary angiography. RESULTS: The area under the ROC curve (AUC) was 0.70 +/- 0.02 (P < 0.001); the test added to clinical variables (Diamond-Forrester method) (AUC, 0.72 with the test vs. 0.66 without; P = 0.003) and added somewhat to an expanded clinical model (AUC, 0.745 with the test vs. 0.732 without; P = 0.089). The test improved net reclassification over both the Diamond-Forrester method and the expanded clinical model (P < 0.001). At a score threshold that corresponded to a 20% likelihood of obstructive CAD (14.75), the sensitivity and specificity were 85% and 43% (yielding a negative predictive value of 83% and a positive predictive value of 46%), with 33% of patient scores below this threshold. LIMITATION: Patients with chronic inflammatory disorders, elevated levels of leukocytes or cardiac protein markers, or diabetes were excluded. CONCLUSION: A noninvasive whole-blood test based on gene expression and demographic characteristics may be useful for assessing obstructive CAD in nondiabetic patients without known CAD. PRIMARY FUNDING SOURCE: CardioDx. PMID- 20921542 TI - Insufficient sleep undermines dietary efforts to reduce adiposity. AB - BACKGROUND: Sleep loss can modify energy intake and expenditure. OBJECTIVE: To determine whether sleep restriction attenuates the effect of a reduced-calorie diet on excess adiposity. DESIGN: Randomized, 2-period, 2-condition crossover study. SETTING: University clinical research center and sleep laboratory. PATIENTS: 10 overweight nonsmoking adults (3 women and 7 men) with a mean age of 41 years (SD, 5) and a mean body mass index of 27.4 kg/m2 (SD, 2.0). INTERVENTION: 14 days of moderate caloric restriction with 8.5 or 5.5 hours of nighttime sleep opportunity. MEASUREMENTS: The primary measure was loss of fat and fat-free body mass. Secondary measures were changes in substrate utilization, energy expenditure, hunger, and 24-hour metabolic hormone concentrations. RESULTS: Sleep curtailment decreased the proportion of weight lost as fat by 55% (1.4 vs. 0.6 kg with 8.5 vs. 5.5 hours of sleep opportunity, respectively; P = 0.043) and increased the loss of fat-free body mass by 60% (1.5 vs. 2.4 kg; P = 0.002). This was accompanied by markers of enhanced neuroendocrine adaptation to caloric restriction, increased hunger, and a shift in relative substrate utilization toward oxidation of less fat. LIMITATION: The nature of the study limited its duration and sample size. CONCLUSION: The amount of human sleep contributes to the maintenance of fat-free body mass at times of decreased energy intake. Lack of sufficient sleep may compromise the efficacy of typical dietary interventions for weight loss and related metabolic risk reduction. PRIMARY FUNDING SOURCE: National Institutes of Health. PMID- 20921543 TI - Screening and surveillance for second malignant neoplasms in adult survivors of childhood cancer: a report from the childhood cancer survivor study. AB - BACKGROUND: Survivors of childhood cancer may develop a second malignant neoplasm during adulthood and therefore require regular surveillance. OBJECTIVE: To examine adherence to population cancer screening guidelines by survivors at average risk for a second malignant neoplasm and adherence to cancer surveillance guidelines by survivors at high risk for a second malignant neoplasm. DESIGN: Retrospective cohort study. SETTING: The Childhood Cancer Survivor Study (CCSS), a 26-center study of long-term survivors of childhood cancer that was diagnosed between 1970 and 1986. PATIENTS: 4329 male and 4018 female survivors of childhood cancer who completed a CCSS questionnaire assessing screening and surveillance for new cases of cancer. MEASUREMENTS: Patient-reported receipt and timing of mammography, Papanicolaou smear, colonoscopy, or skin examination was categorized as adherent to the U.S. Preventive Services Task Force guidelines for survivors at average risk for breast or cervical cancer or the Children's Oncology Group guidelines for survivors at high risk for breast, colorectal, or skin cancer as a result of cancer therapy. RESULTS: In average-risk female survivors, 2743 of 3392 (80.9%) reported having a Papanicolaou smear within the recommended period, and 140 of 209 (67.0%) reported mammography within the recommended period. In high risk survivors, rates of recommended mammography among women were only 241 of 522 (46.2%) and the rates of colonoscopy and complete skin examinations among both sexes were 91 of 794 (11.5%) and 1290 of 4850 (26.6%), respectively. LIMITATIONS: Data were self-reported. Participants in the CCSS are a selected group of survivors, and their adherence may not be representative of all survivors of childhood cancer. CONCLUSION: Female survivors at average risk for a second malignant neoplasm show reasonable rates of screening for cervical and breast cancer. However, surveillance for new cases of cancer is very low in survivors at the highest risk for colon, breast, or skin cancer, suggesting that survivors and their physicians need education about their risks and recommended surveillance. PRIMARY FUNDING SOURCE: The National Cancer Institute, National Institutes of Health, and the American Lebanese Syrian Associated Charities. PMID- 20921545 TI - Screening adults for bladder cancer: a review of the evidence for the U.S. preventive services task force. AB - BACKGROUND: Bladder cancer is 1 of the 10 most frequently diagnosed types of cancer. Screening could identify high-grade bladder cancer at earlier stages, when it may be more easily and effectively treated. PURPOSE: To update the 2004 U.S. Preventive Services Task Force evidence review on screening for bladder cancer in adults in primary care settings. DATA SOURCES: MEDLINE (2002 to December 2009), the Cochrane Database of Systematic Reviews, the Cochrane Central Register of Controlled Trials (through the fourth quarter of 2009), and the CancerLit subsection of PubMed (through March 2010) were searched for studies published in English. STUDY SELECTION: Randomized trials and controlled observational studies that directly evaluated screening for bladder cancer in adults, studies on the diagnostic accuracy of screening tests for bladder cancer, and randomized trials and controlled observational studies on clinical outcomes associated with treatment compared with no treatment of screen-detected or superficial bladder cancer. DATA EXTRACTION: Details were abstracted about the patient sample, study design, data analysis, follow-up, and results. Quality was assessed by using methods developed by the U.S. Preventive Services Task Force. DATA SYNTHESIS: No randomized trials or high-quality controlled observational studies evaluated clinical outcomes associated with screening compared with no screening or treatment of screen-detected bladder cancer compared with no treatment. No study evaluated the sensitivity or specificity of tests for hematuria, urinary cytology, or other urinary biomarkers for bladder cancer in asymptomatic persons without a history of bladder cancer. The positive predictive value of screening is less than 10% in asymptomatic persons, including higher risk populations. No study evaluated harms associated with treatment of screen detected bladder cancer compared with no treatment. LIMITATION: High-quality evidence was not available for any of the key questions. CONCLUSION: Additional research is needed to determine whether screening of adults for bladder cancer leads to better outcomes compared with no screening. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality. PMID- 20921544 TI - Age at cancer diagnosis among persons with AIDS in the United States. AB - BACKGROUND: Studies have reported young ages at cancer diagnosis in HIV-infected persons and have suggested that HIV accelerates carcinogenesis. However, these comparisons did not account for differences in population age structures. OBJECTIVE: To compare ages at diagnosis for non-AIDS-defining types of cancer that occur in both the AIDS and general populations, after adjustment for differences in age and other demographic characteristics between these populations. DESIGN: Registry linkage study. SETTING: 15 HIV/AIDS and cancer registry databases in the United States. PARTICIPANTS: 212 055 persons with AIDS enrolled in the U.S. HIV/AIDS Cancer Match Study from 1996 to 2007. MEASUREMENTS: Comparison of age-at-diagnosis distributions for various types of cancer in both the AIDS and general populations, after adjustment for age and other demographic characteristics. RESULTS: The proportion of person-time contributed by older persons (age >=65 years) was far smaller in the AIDS population (1.5%) than in the general population (12.5%). Reflecting this difference, the ages at diagnosis for most types of cancer were approximately 20 years younger among persons with AIDS. However, after adjustment for differences in the populations at risk, the median ages at diagnosis in the AIDS and general populations did not differ for most types of cancer (for example, colon, prostate, or breast cancer; all P > 0.100). In contrast, ages at diagnosis of lung (median, 50 vs. 54 years) and anal cancer (median, 42 vs. 45 years) were significantly younger in persons with AIDS than expected in the general population (P < 0.001), and the age at diagnosis of Hodgkin lymphoma was significantly older (median, 42 vs. 40 years; P < 0.001). LIMITATIONS: Information on other cancer risk factors, including cigarette smoking, was not available. Analysis was restricted to non-Hispanic white and black persons who had AIDS, which could limit the generalizability of the findings to other racial and ethnic groups or to persons with HIV but not AIDS. CONCLUSION: For most types of cancer, the age at diagnosis is similar in the AIDS and general populations, after adjustment for the ages of the populations at risk. Modest age differences remained for a few types of cancer, which may indicate either acceleration of carcinogenesis by HIV or earlier exposure to cancer risk factors. PRIMARY FUNDING SOURCE: National Cancer Institute. PMID- 20921546 TI - Gene expression algorithm for prevalent coronary artery disease: a first step in a long journey. PMID- 20921547 TI - Sleep well and stay slim: dream or reality? PMID- 20921548 TI - HIV and premature aging: A field still in its infancy. PMID- 20921549 TI - Whose funeral is it anyway? PMID- 20921550 TI - Attending rounds. PMID- 20921551 TI - Time of exposure and type of diabetes may determine treatment outcome of group clinics. PMID- 20921552 TI - The social mission of medical education. PMID- 20921553 TI - The social mission of medical education. PMID- 20921554 TI - The social mission of medical education. PMID- 20921555 TI - The social mission of medical education. PMID- 20921556 TI - The social mission of medical education. PMID- 20921557 TI - The social mission of medical education. PMID- 20921558 TI - The social mission of medical education. PMID- 20921559 TI - Successful extracorporeal membrane oxygenation for refractory cardiogenic shock due to the catastrophic antiphospholipid syndrome. PMID- 20921560 TI - Reducing alcohol-related harm and social disorder in a university community: a framework for evaluation. AB - BACKGROUND: In New Zealand and other middle to high income countries, university student are at high risk of alcohol-related injury and other problems due to their typical pattern of episodic heavy drinking. In 2007, one university implemented Campus Watch, a novel and extensive programme to reduce social disorder, including alcohol-related injury, in the university area. OBJECTIVES: To quantify the effects of this complex intervention. SETTING: A large public university campus and surrounding community in New Zealand. DESIGN: A health promotion evaluation model was used, examining: (1) how the programme was developed, introduced and received by the community? (process); (2) whether the programme affected behaviour? (impact); and (3) whether the programme reduced social disorder and alcohol-related harm in particular? (outcome). The outcome phase uses a non-equivalent control group design to measure changes occurring in the Campus Watch area compared with other universities, and with a same-city control site. PARTICIPANTS: Programme staff, university students and other community members. DATA: Interviews with university administrators and Campus Watch staff; surveys of local residents' views; Campus Watch incident data; national surveys of university students in 2005, 2007 and 2009; police data; fire department data. OUTCOME MEASURES: Prevalence of heavy episodic drinking; number of acute alcohol-related harms; incidence of antisocial behaviour, assault and street fires. ANALYSIS: Regression analyses will be used to examine changes in the intervention site relative to changes in the control areas. PMID- 20921561 TI - Cultural translation: acceptability and efficacy of a US-based injury prevention intervention in China. AB - BACKGROUND: Increased belt-positioning booster seat (BPB) awareness and access have led to increased use in the USA. Although transportation in Beijing is rapidly becoming 'motorised', Beijing's population has limited awareness of or access to BPBs. OBJECTIVE: To explore the efficacy and acceptability of using a US-developed BPB use promotion intervention in Beijing. DESIGN: Methods were adapted from a previously executed US-based study involving parents of 3-8-year old children. Focus groups (five groups, 71 participants) elicited behavioural antecedents to BPB use and reactions to video interventions promoting BPB use: a Chinese-produced instructional video and an English-language (dubbed into Mandarin) video that delivered concrete, theoretically driven messages through a personal story. Immediately after the focus groups, participants were provided with education and a free BPB. Participants were contacted 6 weeks later via telephone about use, knowledge and attitudes. RESULTS: Chinese parents saw safety as the most important benefit of BPB use; lack of accurate knowledge about and access to BPBs were parents' most prevalent barriers. Chinese participants described the videos as persuasive and instructional. At 6 weeks, participants remembered the messages of the English-language video, and reported BPB use increased from a baseline of 15.5% to 85.5%. CONCLUSIONS: This study shows the possibility of exporting US-designed prevention interventions dubbed into Mandarin without the need to alter their original context (in this case, an African American family in a US setting) into a Chinese context. Successful cultural translation involved ensuring that the behavioural antecedents targeted in the intervention (eg, barriers and benefits) were of relevance to the Chinese population. PMID- 20921562 TI - Advancing research in youth violence prevention to inform evidence-based policy and practice. PMID- 20921563 TI - Preventing intimate partner and sexual violence against women: taking action and generating evidence. PMID- 20921564 TI - Slow wave activity during sleep: functional and therapeutic implications. AB - Electroencephalographic slow-wave activity (EEG SWA) is an electrophysiological signature of slow (0.5 to 4.0 Hz), synchronized, oscillatory neocortical activity. In healthy individuals, EEG SWA is maximally expressed during non-rapid eye-movement (non-REM) sleep, and intensifies as a function of prior wake duration. Many of the cellular and network mechanisms generating EEG SWA have been identified, but a number of questions remain unanswered. For example, although EEG SWA is a marker of sleep need, its precise relationship with sleep homeostasis and its roles in the brain are unknown. In this review, the authors discuss their current understanding of the neural mechanisms and possible functions of EEG SWA. PMID- 20921565 TI - Longitudinal hand function in Rett syndrome. AB - Loss of hand function is a core feature of Rett syndrome. This article describes longitudinal hand function at 3 time points for 72 subjects participating in the Australian Rett Syndrome Database. Approximately 40% of subjects with some grasping abilities lost skill over the 3- to 4-year period between video assessments. In these subjects, a decrease in hand function was seen less frequently in girls 13 to 19 years old than in those younger than 8 years, in subjects with some mobility compared with those who were wheelchair bound, and in those who had previously been able to finger feed. Relationships with the magnitude of change reflected these findings. Change in hand function did not vary with clinical severity. The results for all subjects were similar to results obtained when analysis was restricted to those with a pathogenic mutation. Variability in the longitudinal course of hand function in Rett syndrome was observed. PMID- 20921566 TI - Congenital hypotonia in a child with a de novo 22q13 monosomy and 2pter duplication: a clinical and molecular genetic study. AB - The authors describe a 5-year-old girl with a neurological phenotype of 22q13 deletion syndrome (neonatal and persisting hypotonia, developmental delay, absence of language, decreased perception of pain) and minor dysmorphisms. Subtelomeric fluorescent in situ hybridization tests revealed de novo 22q13 monosomy and 2pter duplication. Numerous genetic and neurologic disorders of childhood are characterized by congenital hypotonia. This muscle tone disorder is often one of the symptoms that a neurologist is asked to evaluate. Recent advances in genetic testing can help provide a specific diagnosis for children with this symptom. Subtelomeric deletions are a category of disorders of which hypotonia can be a prominent feature. Deletions of chromosome 22q13 are some of the most commonly observed terminal deletions in humans, whereas duplications of chromosome 2p25.2 are very rare, and little is known about the phenotypic effect of these duplications. To the best of the authors' knowledge, this association has never been described before. PMID- 20921567 TI - Idiopathic intracranial hypertension and facial palsy: case report and review of the literature. AB - We present the case of an 11-year-old obese girl who presented with idiopathic intracranial hypertension affecting first the lateral abducens nerve. She received acetazolamide, but 5 days later she developed lateral, peripheral facial palsy. Imaging evaluation was normal, which primarily excluded cerebral venous thrombosis and sustained the initial diagnosis. Despite some complicating factors (obesity, elevated intracranial pressure), prednisolone was administered for a short-term period to counteract the facial palsy. Ophthalmological residuals resolved within almost 1.5 months, while facial palsy receded after 4 months. Peripheral facial palsy is an extremely rare, but not unknown condition in idiopathic intracranial hypertension. As a symptom, it should be investigated thoroughly, primarily to exclude cerebral venous sinus thrombosis, before it can be attributed to idiopathic intracranial hypertension. As far as treatment is concerned, corticosteroids can be added to the initial treatment with acetazolamide, without worsening already elevated intracranial hypertension or ophthalmologic findings. PMID- 20921568 TI - Inattention, hyperactivity, impulsivity--epidemiology and correlations: a nationwide greek study from birth to 18 years. AB - We examined the prevalence of inattention, hyperactivity, and impulsivity (attention-deficit hyperactivity disorder [ADHD]-like symptoms) at 7 and 18 years in a Greek birth cohort, and associated factors. Information was derived from a representative sample of 2695 Greek individuals followed-up from birth to18 years through 3 questionnaire surveys (1983, 1990, 2001). At 7 years, the prevalence of hyperactivity was 7%, inattention 9.5%, and impulsivity 7% for all children, while a significant decrease was observed at 18 years. Adverse perinatal factors, poor academic performance, fights or quarrels with peers, comorbidity, and a higher frequency of physical punishment and accidents during childhood were found to be associated with ADHD-like symptoms at 7 years. Factors identified to be related with these symptoms at 18 years included male gender, maternal stress, smoking during pregnancy, physical punishment, and psychological problems in childhood. These longitudinal findings provide significant information for health and educational planning in Greece and other countries. PMID- 20921570 TI - Blood ammonia levels in epileptic children on 2 dose ranges of valproic acid monotherapy: a cross-sectional study. AB - This cross-sectional study was planned to study the blood ammonia levels in epileptic children on 2 dose ranges of valproic acid monotherapy. A total of 60 epileptic children aged 3 months to 12 years, that were on valproic acid monotherapy for at least 3 months, were enrolled and divided into 2 groups, a low dose group (dose, 20-39 mg/kg/d [n = 32]) and a high-dose group (dose, 40-60 mg/kg/d [n=31]). Measurements of blood ammonia, serum valproic acid levels, and liver and renal function tests were performed. Blood ammonia levels were significantly higher in the high-dose group (median, 79.2 ug/dL; range, 55.23 114.29 ug/dL) as compared with the low-dose group (median, 47.2 ug/dL; range, 20.62-73.25 ug/dL). Blood ammonia levels significantly correlated with both the dose (r = .77, P < .001) and serum levels (r = .88, P < .001) of valproic acid. All the children with hyperammonemia were asymptomatic. There were no significant differences in the other biochemical parameters between the 2 groups. PMID- 20921569 TI - Clinical seizures in neonatal hypoxic-ischemic encephalopathy have no independent impact on neurodevelopmental outcome: secondary analyses of data from the neonatal research network hypothermia trial. AB - It remains controversial as to whether neonatal seizures have additional direct effects on the developing brain separate from the severity of the underlying encephalopathy. Using data collected from infants diagnosed with hypoxic-ischemic encephalopathy, and who were enrolled in an National Institute of Child Health and Human Development trial of hypothermia, we analyzed associations between neonatal clinical seizures and outcomes at 18 months of age. Of the 208 infants enrolled, 102 received whole body hypothermia and 106 were controls. Clinical seizures were generally noted during the first 4 days of life and rarely afterward. When adjustment was made for study treatment and severity of encephalopathy, seizures were not associated with death, or moderate or severe disability, or lower Bayley Mental Development Index scores at 18 months of life. Among infants diagnosed with hypoxic-ischemic encephalopathy, the mortality and morbidity often attributed to neonatal seizures can be better explained by the underlying severity of encephalopathy. PMID- 20921571 TI - Serial and free recall in children can be improved by training: evidence for the importance of phonological and semantic representations in immediate memory tasks. AB - Children were assigned to three groups given training on unfamiliar words- phoneme-awareness training, rhyme training, and vocabulary training--and an untrained control group. Before and after training, we assessed the children's performance on serial- and free-recall tasks with these words, as well as their ability to define the words, manipulate phonemes in them, and generate rhymes for them. We found that phoneme-awareness training improved serial recall substantially and improved free recall to a lesser extent. In contrast, vocabulary training produced a substantial increase in free recall and a lesser increase in serial recall. These effects on recall were specific and did not generalize to untrained words. Rhyme training produced increases in rhyming skills but no increase in either serial or free recall. We argue that serial and free recall depend on common memory mechanisms, but serial recall relies more on phonological codes and free recall relies more on semantic codes. PMID- 20921573 TI - Learned liking versus inborn delight: can sweetness give sensual pleasure or is it just motivating? AB - In this study, we separated for the first time the learned liking for a particular level of sweetness in a familiar drink from the infantile delight in sweetness as such ("the sweeter, the better"). It is widely assumed that sensing a liked food or drink evokes a pleasurable experience, but the only psychological evidence for this assumption has been tongue movements that are elicited specifically by sweet taste in animals and human neonates. We found that adults felt such movements in response to drinking juice at both their personally preferred level of sweetness and levels they deemed so sweet as to be undrinkable. Yet only the intolerably strong level of sweetness elicited enjoyment of the experienced movements, elevation of mood, and a sense of smiling. Hence, the pleasure that adults experience during ingestion could be exclusively linked with the congenital sweetness reflex that sends mother's milk down an infant's throat. PMID- 20921572 TI - The role of brain-derived neurotrophic factor genotype, parental depression, and relationship discord in predicting early-emerging negative emotionality. AB - The brain-derived neurotrophic factor (BDNF) gene is a plausible candidate for early-emerging negative emotionality (NE), and evidence suggests that the effects of this gene may be especially salient in the context of familial risk for child maladjustment. We therefore examined whether the single-nucleotide polymorphism producing a valine-to-methionine substitution at codon 66 (val66met) of the BDNF gene was associated with childhood NE, in the context of parental depression and relationship discord. A sample of 413 three-year-old children was assessed for NE using standardized laboratory measures. The children's parents completed clinical interviews as well as a measure of marital satisfaction. Children with at least one BDNF methionine (met) allele exhibited elevated NE when a parent had a history of depressive disorder or when relationship discord was reported by a parent. In contrast, this allele was associated with especially low NE when parental depression was absent and when the parental relationship was not discordant. Our findings suggest that the BDNF met allele confers increased child sensitivity to both positive and negative familial influences. PMID- 20921574 TI - Scene memory is more detailed than you think: the role of categories in visual long-term memory. AB - Observers can store thousands of object images in visual long-term memory with high fidelity, but the fidelity of scene representations in long-term memory is not known. Here, we probed scene-representation fidelity by varying the number of studied exemplars in different scene categories and testing memory using exemplar level foils. Observers viewed thousands of scenes over 5.5 hr and then completed a series of forced-choice tests. Memory performance was high, even with up to 64 scenes from the same category in memory. Moreover, there was only a 2% decrease in accuracy for each doubling of the number of studied scene exemplars. Surprisingly, this degree of categorical interference was similar to the degree previously demonstrated for object memory. Thus, although scenes have often been defined as a superset of objects, our results suggest that scenes and objects may be entities at a similar level of abstraction in visual long-term memory. PMID- 20921575 TI - What do we need to do to cure HIV infection. AB - Finding a cure for HIV infection requires methods to stop ongoing viral replication, to identify all reservoirs in which nonreplicating HIV persists, and to eliminate each of these reservoirs. Current antiretroviral therapy largely stops ongoing viral replication. This is a reflection of the extremely high antiviral activity of some classes of antiretroviral drugs as revealed in a novel index, the inhibitory potential, which incorporates the slope parameter of the dose-response curve. This index may aid in the rational selection of fully suppressive therapy. At least 2 stable reservoirs of latently infected cells have been identified, and attempts are under way to identify compounds that selectively reactivate latent HIV and allow elimination of these reservoirs. This article summarizes a presentation made by Robert F. Siliciano, MD, PhD, at the International AIDS Society-USA continuing medical education program held in Atlanta in March 2010. PMID- 20921576 TI - Cervical injection drug use: a pain in the neck. PMID- 20921578 TI - When to start antiretroviral therapy. AB - The question of when to initiate antiretroviral therapy has been a central controversy in HIV management for more than 15 years, yet there are limited data from randomized controlled trials addressing it. A major obstacle to performing such a study is the need for large numbers of asymptomatic, antiretroviral therapy-naive individuals observed over many years beginning from when their CD4+ cell counts are above 500/mm3. Observational cohort studies with substantial person-years of follow-up have informed this debate in the absence of randomized trials. Emerging evidence regarding the damage caused by untreated HIV infection related inflammation and immune activation at all stages of disease, and the benefits of modern antiretroviral therapy in preventing both AIDS- and non-AIDS related morbidity and mortality has supported a return to starting treatment early. The NA-ACCORD (North American AIDS Cohort Collaboration on Research and Design) study compared long-term outcomes of immediate versus deferred therapy at 2 CD4+ cell count thresholds. Results showed a 94% increased risk of all-cause mortality when antiretroviral therapy was deferred at CD4+ cell counts greater than 500/mm3. This article summarizes presentations made by Mari M. Kitahata, MD, MPH, at the International AIDS Society-USA continuing medical education programs held in November 2009 in New York City and May 2010 in San Francisco. The original presentations are available as Webcasts at www.iasusa.org. PMID- 20921577 TI - Dyslipidemia and its Treatment in HIV Infection. AB - HIV-infected patients have metabolic abnormalities that put them at increased risk of cardiovascular disease (CVD), including abnormalities associated with HIV infection itself, antiretroviral treatment, restoration to health, and body composition changes. The 2 major components of dyslipidemia in HIV-infected patients are hypertriglyceridemia and reduction in high-density lipoprotein (HDL) cholesterol (with likely altered function of HDL cholesterol); these abnormalities contribute to increased atherosclerotic risk. Adverse effects of antiretroviral drugs on lipids are not class specific but rather are associated with particular drugs. Thus, practitioners need to be cognizant of the risks of metabolic abnormalities posed by individual drugs. HIV infection increases CVD risk independent of the effects of traditional risk factors. The relative risk of CVD in HIV-infected patients has decreased in recent years with increasing use of lipid-lowering therapy. However, use of lipid-lowering therapy is complicated by numerous potential drug interactions with antiretroviral drugs that practitioners need to consider when prescribing lipid-lowering therapy. This article summarizes a presentation made by Carl Grunfeld, MD, PhD, at the International AIDS Society USA continuing medical education program in Los Angeles in March 2010. The original presentation is available as a Webcast at www.iasusa.org. PMID- 20921579 TI - Vehicle detection using partial least squares. AB - Detecting vehicles in aerial images has a wide range of applications, from urban planning to visual surveillance. We describe a vehicle detector that improves upon previous approaches by incorporating a very large and rich set of image descriptors. A new feature set called Color Probability Maps is used to capture the color statistics of vehicles and their surroundings, along with the Histograms of Oriented Gradients feature and a simple yet powerful image descriptor that captures the structural characteristics of objects named Pairs of Pixels. The combination of these features leads to an extremely high-dimensional feature set (approximately 70,000 elements). Partial Least Squares is first used to project the data onto a much lower dimensional sub-space. Then, a powerful feature selection analysis is employed to improve the performance while vastly reducing the number of features that must be calculated. We compare our system to previous approaches on two challenging data sets and show superior performance. PMID- 20921580 TI - Multiple kernel learning for dimensionality reduction. AB - In solving complex visual learning tasks, adopting multiple descriptors to more precisely characterize the data has been a feasible way for improving performance. The resulting data representations are typically high-dimensional and assume diverse forms. Hence, finding a way of transforming them into a unified space of lower dimension generally facilitates the underlying tasks such as object recognition or clustering. To this end, the proposed approach (termed MKL-DR) generalizes the framework of multiple kernel learning for dimensionality reduction, and distinguishes itself with the following three main contributions: first, our method provides the convenience of using diverse image descriptors to describe useful characteristics of various aspects about the underlying data. Second, it extends a broad set of existing dimensionality reduction techniques to consider multiple kernel learning, and consequently improves their effectiveness. Third, by focusing on the techniques pertaining to dimensionality reduction, the formulation introduces a new class of applications with the multiple kernel learning framework to address not only the supervised learning problems but also the unsupervised and semi-supervised ones. PMID- 20921581 TI - Shape Analysis of Elastic Curves in Euclidean Spaces. AB - This paper introduces a square-root velocity (SRV) representation for analyzing shapes of curves in euclidean spaces under an elastic metric. In this SRV representation, the elastic metric simplifies to the IL(2) metric, the reparameterization group acts by isometries, and the space of unit length curves becomes the unit sphere. The shape space of closed curves is the quotient space of (a submanifold of) the unit sphere, modulo rotation, and reparameterization groups, and we find geodesics in that space using a path straightening approach. These geodesics and geodesic distances provide a framework for optimally matching, deforming, and comparing shapes. These ideas are demonstrated using: 1) shape analysis of cylindrical helices for studying protein structure, 2) shape analysis of facial curves for recognizing faces, 3) a wrapped probability distribution for capturing shapes of planar closed curves, and 4) parallel transport of deformations for predicting shapes from novel poses. PMID- 20921582 TI - Overcoming shadows in 3-source photometric stereo. AB - Light occlusions are one of the most significant difficulties of photometric stereo methods. When three or more images are available without occlusion, the local surface orientation is overdetermined so that shape can be computed and the shadowed pixels can be discarded. In this paper, we look at the challenging case when only two images are available without occlusion, leading to a one degree of freedom ambiguity per pixel in the local orientation. We show that, in the presence of noise, integrability alone cannot resolve this ambiguity and reconstruct the geometry in the shadowed regions. As the problem is ill-posed in the presence of noise, we describe two regularization schemes that improve the numerical performance of the algorithm while preserving the data. Finally, the paper describes how this theory applies in the framework of color photometric stereo where one is restricted to only three images and light occlusions are common. Experiments on synthetic and real image sequences are presented. PMID- 20921584 TI - Accuracy of Pseudo-Inverse Covariance Learning--A Random Matrix Theory Analysis. AB - For many learning problems, estimates of the inverse population covariance are required and often obtained by inverting the sample covariance matrix. Increasingly for modern scientific data sets, the number of sample points is less than the number of features and so the sample covariance is not invertible. In such circumstances, the Moore-Penrose pseudo-inverse sample covariance matrix, constructed from the eigenvectors corresponding to nonzero sample covariance eigenvalues, is often used as an approximation to the inverse population covariance matrix. The reconstruction error of the pseudo-inverse sample covariance matrix in estimating the true inverse covariance can be quantified via the Frobenius norm of the difference between the two. The reconstruction error is dominated by the smallest nonzero sample covariance eigenvalues and diverges as the sample size becomes comparable to the number of features. For high dimensional data, we use random matrix theory techniques and results to study the reconstruction error for a wide class of population covariance matrices. We also show how bagging and random subspace methods can result in a reduction in the reconstruction error and can be combined to improve the accuracy of classifiers that utilize the pseudo-inverse sample covariance matrix. We test our analysis on both simulated and benchmark data sets. PMID- 20921583 TI - Force estimation and prediction from time-varying density images. AB - We present methods for estimating forces which drive motion observed in density image sequences. Using these forces, we also present methods for predicting velocity and density evolution. To do this, we formulate and apply a Minimum Energy Flow (MEF) method which is capable of estimating both incompressible and compressible flows from time-varying density images. Both the MEF and force estimation techniques are applied to experimentally obtained density images, spanning spatial scales from micrometers to several kilometers. Using density image sequences describing cell splitting, for example, we show that cell division is driven by gradients in apparent pressure within a cell. Using density image sequences of fish shoals, we also quantify 1) intershoal dynamics such as coalescence of fish groups over tens of kilometers, 2) fish mass flow between different parts of a large shoal, and 3) the stresses acting on large fish shoals. PMID- 20921585 TI - Matching forensic sketches to mug shot photos. AB - The problem of matching a forensic sketch to a gallery of mug shot images is addressed in this paper. Previous research in sketch matching only offered solutions to matching highly accurate sketches that were drawn while looking at the subject (viewed sketches). Forensic sketches differ from viewed sketches in that they are drawn by a police sketch artist using the description of the subject provided by an eyewitness. To identify forensic sketches, we present a framework called local feature-based discriminant analysis (LFDA). In LFDA, we individually represent both sketches and photos using SIFT feature descriptors and multiscale local binary patterns (MLBP). Multiple discriminant projections are then used on partitioned vectors of the feature-based representation for minimum distance matching. We apply this method to match a data set of 159 forensic sketches against a mug shot gallery containing 10,159 images. Compared to a leading commercial face recognition system, LFDA offers substantial improvements in matching forensic sketches to the corresponding face images. We were able to further improve the matching performance using race and gender information to reduce the target gallery size. Additional experiments demonstrate that the proposed framework leads to state-of-the-art accuracys when matching viewed sketches. PMID- 20921586 TI - Efficient edit propagation using hierarchical data structure. AB - This paper presents a novel unified hierarchical structure for scalable edit propagation. Our method is based on the key observation that in edit propagation, appearance varies very smoothly in those regions where the appearance is different from the user-specified pixels. Uniformly sampling in these regions leads to redundant computation. We propose to use a quadtree-based adaptive subdivision method such that more samples are selected in similar regions and less in those that are different from the user-specified regions. As a result, both the computation and the memory requirement are significantly reduced. In edit propagation, an edge-preserving propagation function is first built, and the full solution for all the pixels can be computed by interpolating from the solution obtained from the adaptively subdivided domain. Furthermore, our approach can be easily extended to accelerate video edit propagation using an adaptive octree structure. In order to improve user interaction, we introduce several new Gaussian Mixture Model (GMM) brushes to find pixels that are similar to the user-specified regions. Compared with previous methods, our approach requires significantly less time and memory, while achieving visually same results. Experimental results demonstrate the efficiency and effectiveness of our approach on high-resolution photographs and videos. PMID- 20921587 TI - Stochastic transparency. AB - Stochastic transparency provides a unified approach to order-independent transparency, antialiasing, and deep shadow maps. It augments screen-door transparency using a random sub-pixel stipple pattern, where each fragment of transparent geometry covers a random subset of pixel samples of size proportional to alpha. This results in correct alpha-blended colors on average, in a single render pass with fixed memory size and no sorting, but introduces noise. We reduce this noise by an alpha correction pass, and by an accumulation pass that uses a stochastic shadow map from the camera. At the pixel level, the algorithm does not branch and contains no read-modify-write loops, other than traditional z buffer blend operations. This makes it an excellent match for modern massively parallel GPU hardware. Stochastic transparency is very simple to implement and supports all types of transparent geometry, able without coding for special cases to mix hair, smoke, foliage, windows, and transparent cloth in a single scene. PMID- 20921588 TI - Hybrid, Multiresolution Wires with Massless Frictional Contacts. AB - We describe a method for the visual interactive simulation of wires contacting with rigid multibodies. The physical model used is a hybrid combining lumped elements and massless quasistatic representations. The latter is based on a kinematic constraint preserving the total length of the wire along a segmented path which can involve multiple bodies simultaneously and dry frictional contact nodes used for roping, lassoing, and fastening. These nodes provide stick and slide friction along the edges of the contacting geometries. The lumped element resolution is adapted dynamically based on local stability criteria, becoming coarser as the tension increases, and up to the purely kinematic representation. Kinematic segments and contact nodes are added, deleted, and propagated based on contact geometries and dry friction configurations. The method gives a dramatic increase in both performance and robustness because it quickly decimates superfluous nodes without loosing stability, yet adapts to complex configurations with many contacts and high curvature, keeping a fixed, large integration time step. Numerical results demonstrating the performance and stability of the adaptive multiresolution scheme are presented along with an array of representative simulation examples illustrating the versatility of the frictional contact model. PMID- 20921589 TI - Quantifying enzymatic lysis: estimating the combined effects of chemistry, physiology and physics. AB - The number of microbial pathogens resistant to antibiotics continues to increase even as the rate of discovery and approval of new antibiotic therapeutics steadily decreases. Many researchers have begun to investigate the therapeutic potential of naturally occurring lytic enzymes as an alternative to traditional antibiotics. However, direct characterization of lytic enzymes using techniques based on synthetic substrates is often difficult because lytic enzymes bind to the complex superstructure of intact cell walls. Here we present a new standard for the analysis of lytic enzymes based on turbidity assays which allow us to probe the dynamics of lysis without preparing a synthetic substrate. The challenge in the analysis of these assays is to infer the microscopic details of lysis from macroscopic turbidity data. We propose a model of enzymatic lysis that integrates the chemistry responsible for bond cleavage with the physical mechanisms leading to cell wall failure. We then present a solution to an inverse problem in which we estimate reaction rate constants and the heterogeneous susceptibility to lysis among target cells. We validate our model given simulated and experimental turbidity assays. The ability to estimate reaction rate constants for lytic enzymes will facilitate their biochemical characterization and development as antimicrobial therapeutics. PMID- 20921590 TI - Morphology and texture evolution of nanostructured CaF2 films on amorphous substrates under oblique incidence flux. AB - The morphology and biaxial texture of vacuum evaporated CaF(2) films on amorphous substrates as a function of vapour incident angle, substrate temperature and film thickness were investigated by scanning electron microscopy, x-ray pole figure and reflection high energy electron diffraction surface pole figure analyses. Results show that an anomalous [220] out-of-plane texture was preferred in CaF(2) films deposited on Si substrates at < 200 degrees C with normal vapour incidence. With an increase of the vapour incident angle, the out-of-plane orientation changed from [220] to [111] at a substrate temperature of 100 degrees C. In films deposited with normal vapour incidence, the out-of-plane orientation changed from [220] at 100 degrees C to [111] at 400 degrees C. In films deposited with an oblique vapour incidence at 100 degrees C, the texture changed from random at small thickness (5 nm) to biaxial at larger thickness (20 nm or more). Using first principles density functional theory calculation, it was shown that [220] texture formation is a consequence of energetically favourable adsorption of CaF(2) molecules onto the CaF(2)(110) facet. PMID- 20921591 TI - Magnetization reversal in Pt/Co(0.5 nm)/Pt nano-platelets patterned by focused ion beam lithography. AB - Arrays of ultrathin Pt/Co(0.5 nm)/Pt nano-platelets with lateral sizes ranging from 30 nm to 1 um have been patterned by focused ion beam (FIB) lithography under a weak Ga(+) ion fluence. From polar magneto-optical Kerr microscopy it is demonstrated that nano-platelets are ferromagnetic with perpendicular anisotropy down to a size of 50 nm. The irradiation process creates a magnetically soft ring at the nano-platelet periphery in which domain nucleation is initiated at a low field. The magnetization reversal in nano-platelets can be interpreted using a confined droplet model. All of the results prove that ultimate FIB patterning is suitable for preparing discrete magnetic recording media or small magnetic memory elements and nano-devices. PMID- 20921592 TI - Stress relaxation and creep on living cells with the atomic force microscope: a means to calculate elastic moduli and viscosities of cell components. AB - In this work we present a unified method to study the mechanical properties of cells using the atomic force microscope. Stress relaxation and creep compliance measurements permitted us to determine, the relaxation times, the Young moduli and the viscosity of breast cancer cells (MCF-7). The results show that the mechanical behaviour of MCF-7 cells responds to a two-layered model of similar elasticity but differing viscosity. Treatment of MCF-7 cells with an actin depolymerising agent results in an overall decrease in both cell elasticity and viscosity, however to a different extent for each layer. The layer that undergoes the smaller decrease (36-38%) is assigned to the cell membrane/cortex while the layer that experiences the larger decrease (70-80%) is attributed to the cell cytoplasm. The combination of the method presented in this work, together with the approach based on stress relaxation microscopy (Moreno-Flores et al 2010 J. Biomech. 43 349-54), constitutes a unique AFM-based experimental framework to study cell mechanics. This methodology can also be extended to study the mechanical properties of biomaterials in general. PMID- 20921593 TI - Phonon softening on the specific heat of nanocrystalline metals. AB - Specific heat enhancement in several common nanocrystalline metals is established by comparison with their bulk counterparts. Measurements were carried out in Fe, Cu, Ni and binary alloy LaAl(2). The excess specific heat is evidenced as a low temperature peak below 65 K and a high temperature slope above 150 K. The experimental data are in good agreement with a model which considers contributions from the grain boundary and core atoms in the nanoparticles. This model is supported by Raman spectroscopy measurements, showing a softening of the frequency phonon modes associated with a size reduction and increase of the atomic disorder. PMID- 20921594 TI - Step and repeat UV nanoimprint lithography on pre-spin coated resist film: a promising route for fabricating nanodevices. AB - A step and repeat UV nanoimprint lithography process on pre-spin coated resist film is demonstrated for patterning a large area with features sizes down to sub 15 nm. The high fidelity between the template and imprinted structures is verified with a difference in their line edge roughness of less than 0.5 nm (3sigma deviation value). The imprinted pattern's residual layer is well controlled to allow direct pattern transfer from the resist into functional materials with very high resolution. The process is suitable for fabricating numerous nanodevices. PMID- 20921595 TI - Tunable superconducting nanoinductors. AB - We characterize inductors fabricated from ultra-thin, approximately 100 nm wide strips of niobium (Nb) and niobium nitride (NbN). These nanowires have a large kinetic inductance in the superconducting state. The kinetic inductance scales linearly with the nanowire length, with a typical value of 1 nH um(-1) for NbN and 44 pH um(-1) for Nb at a temperature of 2.5 K. We measure the temperature and current dependence of the kinetic inductance and compare our results to theoretical predictions. We also simulate the self-resonant frequencies of these nanowires in a compact meander geometry. These nanowire inductive elements have applications in a variety of microwave frequency superconducting circuits. PMID- 20921596 TI - On the photoconduction properties of low resistivity TiO2 nanotubes. AB - TiO(2) nanotubes were synthesized by anodic oxidation of titanium foils using dimethyl sulfoxide and hydrofluoric acid as the electrolyte. The electrical properties of individual nanotube-based devices were evaluated and modeled after exposing some of them to different gas and illumination conditions. Resistivity values fully comparable to those of TiO(2) single crystal anatase (rho(SA) = 1.09 +/- 0.01Omega cm) were found, and their photoconductive characteristics, explained in terms of the Shockley-Read-Hall model for non-radiative recombination in semiconductors, were found to be strongly influenced by the applied experimental conditions such as the surrounding atmosphere. These devices may have potential applications in photocatalytic processes, such as CO(2) reduction or H(2)O splitting, avoiding the interfering effects typical of nanotube arrays. PMID- 20921597 TI - A versatile nanotechnology to connect individual nano-objects for the fabrication of hybrid single-electron devices. AB - We report on the high yield connection of single nano-objects as small as a few nanometres in diameter to separately elaborated metallic electrodes, using a 'table-top' nanotechnology. Single-electron transport measurements validate that transport occurs through a single nano-object. The vertical geometry of the device natively allows an independent choice of materials for each electrode and the nano-object. In addition ferromagnetic materials can be used without encountering oxidation problems. The possibility of elaborating such hybrid nanodevices opens new routes for the democratization of spintronic studies in low dimensions. PMID- 20921598 TI - K2[Hg(SO3)2].2.25H2O. AB - The characteristic feature of the structure of the title compound, dipotassium bis(sulfito-kappaS)mercurate(II) 2.25-hydrate, is a layered arrangement parallel to (001) where each of the two independent [Hg(SO(3))(2)](2-) anions are grouped into centrosymmetric pairs and are surrounded by two K(+) cations to give the overall layer composition {K(2)[Hg(SO(3))(2)](2)}(2-). The remaining cations and the uncoordinated water molecules are situated between these layers. Within the [Hg(SO(3))(2)](2-) anions, the central Hg atoms are twofold coordinated by S atoms, with a mean Hg-S bond length of 2.384 (2) A. The anions are slightly bent [174.26 (3) and 176.99 (3) degrees ] due to intermolecular O...Hg interactions greater than 2.8 A. All coordination polyhedra around the K(+) cations are considerably distorted, with coordination numbers ranging from six to nine. Although the H atoms of the five water molecules (one with symmetry 2) could not be located, O...O separations between 2.80 and 2.95 A suggest a system of medium to weak O-H...O hydrogen bonds which help to consolidate the structural set-up. Differences and similarities between the bis(sulfito-kappaS)mercurate(II) anions in the title compound and those in the related salts (NH(4))(2)[Hg(SO(3))(2)] and Na(2)[Hg(SO(3))(2)].H(2)O are discussed. PMID- 20921599 TI - Mg5TiO4(BO3)2. AB - Single crystals of pentamagnesium titanium(IV) tetraoxide bis(borate), Mg(5)TiO(4)(BO(3))(2), were prepared by slow cooling of the melt from 1623 K in air. The crystal is isostructural with the mineral ludwigite (Mg(2)FeO(2)BO(3)). The Mg and Ti atoms are coordinated by six O atoms and the B atom is coordinated by three O atoms. There are three Mg sites and one mixed site statistically occupied by Mg and Ti atoms. Atoms are at the following special positions: 2a (0, 0, 0) and 2d (0, 1/2, 1/2) for two Mg atoms, 4g (x, y, 0) for the mixed Ti/Mg site and the BO(3) group, and 4h (x, y, 1/2) for a third Mg and two oxide O atoms. MgO(6) and (Ti/Mg)O(6) octahedra are connected by sharing of edges to form zigzag folding layers along the c axis. Triangular prismatic tunnels are formed between the folding layers by sharing apical O atoms of the MgO(6) and (Ti/Mg)O(6) octahedra. PMID- 20921600 TI - The novel arsenate Na4Co(7-x)Al(2/3x)(AsO4)6 (x = 1.37): crystal structure, charge-distribution and bond-valence-sum investigations. AB - The title compound, tetrasodium cobalt aluminium hexaarsenate, Na(4)Co(7 x)Al(2/3x)(AsO(4))(6) (x = 1.37), is isostructural with K(4)Ni(7)(AsO(4))(6); however, in its crystal structure, some of the Co(2+) ions are substituted by Al(3+) in a fully occupied octahedral site (site symmetry 2/m) and a partially occupied tetrahedral site (site symmetry 2). A third octahedral site is fully occupied by Co(2+) ions only. One of the two independent tetrahedral As atoms and two of its attached O atoms reside on a mirror plane, as do two of the three independent Na(+) cations, all of which are present at half-occupancy. The proposed structural model based on a careful investigation of the crystal data is supported by charge-distribution (CHARDI) analysis and bond-valence-sum (BVS) calculations. The correlation between the X-ray refinement and the validation results is discussed. PMID- 20921601 TI - A new [(1R,2R)-1,2-diaminocyclohexane]platinum(II) complex: formation by nitrate acetonitrile ligand exchange. AB - The title compound, cis-diacetonitrile[(1R,2R)-1,2-diaminocyclohexane kappa(2)N,N']platinum(II) dinitrate monohydrate, [Pt(C(2)H(3)N)(2)(C(6)H(14)N(2))](NO(3))(2).H(2)O, is a molecular salt of the diaminocyclohexane-Pt complex cation. There are two formula units in the asymmetric unit. Apart from the two charge-balancing nitrate anions, one neutral molecule of water is present. The components interact via N-H...O and O-H...O hydrogen bonds, resulting in supramolecular chains. The title compound crystallizes only from acetonitrile with residual water, with the acetonitrile coordinating to the molecule of cis-[Pt(NO(3))(2)(DACH)] (DACH is 1,2 diaminocyclohexane) and the water forming a monohydrate. PMID- 20921602 TI - catena-Poly[thorium(IV)-tetrakis(MU(2)-3-carboxyadamantane-1-carboxylato)]: a quadruple helical strand driven by a synergy of coordination and hydrogen bonding. AB - The title compound, [Th(C(12)H(15)O(4))(4)](n), is the first homoleptic thorium carboxylate coordination polymer. It has a one-dimensional structure supported by the bidentate bridging coordination of the singly charged 3-carboxyadamantane-1 carboxylate (HADC(-)) anions. The metal ion is situated on a fourfold axis (site symmetry 4) and possesses a square-antiprismatic ThO(8) coordination, including four bonds to anionic carboxylate groups [Th-O = 2.359 (2) A] and four to neutral carboxyl groups [Th-O = 2.426 (2) A], while a strong hydrogen bond between these two kinds of O-atom donor [O...O = 2.494 (3) A] affords planar pseudo-chelated Th{CO(2)...HO(2)C} cycles. This combination of coordination and hydrogen bonding is responsible for the generation of quadruple helical strands of HADC(-) ligands, which are wrapped around a linear chain of Th(IV) ions [Th...Th = 7.5240 (4) A] defining the helical axis. PMID- 20921603 TI - Bis{MU-2-[(2-carbamoylhydrazin-1-ylidene)methyl]phenolato}bis[chloridozinc(II)] methanol disolvate, with non-aromatic-aromatic pi-pi stacking and N-H...Cl-Zn hydrogen bonding. AB - Centrosymmetric dimers of Zn(II) with singly deprotonated 2-[(2-carbamoylhydrazin 1-ylidene)methyl]phenolate, [Zn(2)(C(8)H(8)N(3)O(2))Cl(2)].2CH(3)OH, form an infinite one-dimensional hydrogen-bonded chain which is further aggregated by non aromatic-aromatic pi-pi stacking and nonclassical N-H...Cl hydrogen bonding. PMID- 20921604 TI - A two-dimensional Zn(II) coordination polymer constructed by benzotriazole-5 carboxylate and 1,4,8,9-tetraazatriphenylene. AB - Poly[[(MU(3)-benzotriazole-5-carboxylato-kappa(4)N(1):N(3):O,O')(1,4,8,9 tetraazatriphenylene-kappa(2)N(8),N(9))zinc(II)] 0.25-hydrate], {[Zn(C(7)H(3)N(3)O(2))(C(14)H(8)N(4))].0.25H(2)O}(n), exhibits a two-dimensional layer structure in which the asymmetric unit contains one Zn(II) centre, one 1,4,8,9-tetraazatriphenylene (TATP) ligand, one benzotriazole-5-carboxylate (btca) ligand and 0.25 solvent water molecules. Each Zn(II) ion is six coordinated and surrounded by four N atoms from two different btca ligands and one chelating TATP ligand, and by two O atoms from a third btca ligand, to furnish a distorted octahedral geometry. The infinite connection of the metal ions and ligands forms a two-dimensional wave-like (6,3) layer structure. Adjacent layers are connected by C-H...N hydrogen bonds. The solvent water molecules are located in partially occupied sites between parallel pairs of inversion-related TATP ligands that belong to two separate layers. PMID- 20921605 TI - A new coordination complex based on a polynitrile ligand: bis(4-amino-3,5-di-2 pyridyl-4H-1,2,4-triazole)diaquairon(II) bis(1,1,3,3-tetracyano-2 methylsulfanylpropenide). AB - The new high-spin iron(II) complex, [Fe(C(12)H(10)N(6))(2)(H(2)O)(2)](C(8)H(3)N(4)S)(2) or [Fe(abpt)(2)(H(2)O)(2)](tcnsme)(2) [where abpt is 4-amino-3,5-di-2-pyridyl-4H 1,2,4-triazole and tcnsme is the 1,1,3,3-tetracyano-2-methylthiopropenide anion], consists of discrete [Fe(abpt)(2)(H(2)O)(2)](2+) dications, where the Fe(II) ion is coordinated by two N,N'-bidentate chelating abpt ligands in the equatorial plane and two water molecules in trans positions, generating a distorted octahedral [FeN(4)O(2)] environment. The cationic unit is neutralized by two polynitrile tcnsme anions, in which the C-N, C-C and C-S bond lengths indicate extensive electronic delocalization. In the crystal structure, the dications and anions are linked through O-H...N and N-H...N hydrogen bonds involving the water H atoms and those of the NH(2) groups and the N atoms of the CN groups, leading to the formation of a three-dimensional network. PMID- 20921606 TI - An optically pure P-alkene-ligated Ir(I) complex. AB - The asymmetric unit of (P)-chloridobis[(S)-(+)-5-(3,5-dioxa-4 phosphacyclohepta[2,1-a:3,4-a']dinaphthalen-4-yl)dibenz[b,f]azepine]iridium(I) benzene-pentane (1/1/1), [IrCl(C(34)H(22)NO(2)P)(2)].C(6)H(6).C(5)H(12), contains two formula units. The two symmetry-independent molecules of the Ir complex have similar conformations and approximate C(2) symmetry, with small deviations arising from slightly different puckering of the seven-membered dioxaphosphacycloheptadiene rings. The Ir atoms have trigonal-bipyramidal coordination geometry, with the P atoms in axial positions. The steric strain of the bidentate coordination of the P-alkene ligand through its P and alkene C atoms causes the N atom to have pyramidal geometry, compared with the trigonal planar geometry observed in the free ligand. The coordination also results in an anti conformation of the binaphthyl and alkene groups within the P-alkene ligand. PMID- 20921607 TI - A urea adduct of bis(hinokitiolato)copper(II). AB - Bis(MU(2)-3-isopropyl-7-oxocyclohepta-1,3,5-trien-1-olato)bis[(3-isopropyl-7 oxocyclohepta-1,3,5-trien-1-olato)copper(II)]-urea-acetone (1/6/2), [Cu(2)(C(10)H(11)O(2))(4)].6CH(4)N(2)O.2C(3)H(6)O, where 3-isopropyl-7 oxocyclohepta-1,3,5-trien-1-olate is the systematic name for the hinokitiolate anion, contains three novel structural features. First, it contains a bis(hinokitiolato)copper(II) dimer, [Cu(hino)(2)](2), unlike any other, demonstrating that linkage isomerism is another avenue by which Cu(hino)(2) can transmute from one form to another. Second, [Cu(hino)(2)](2) is hydrogen bonded to two urea molecules, indicating that hydrogen bonding cannot yet be discounted from any proposed mechanism of action for the antimicrobial and antiviral properties of bis(hinokitiolato)copper(II). Finally, corrugated urea layers crosslinked by [Cu(hino)(2)](2) dimers are observed, suggesting that a new family of host-guest materials, i.e. metallo-urea clathrates, exists to challenge our understanding of crystal engineering and crystal growth and design. Selected details of the structure are that the [Cu(hino)(2)](2) dimers possess crystallographic inversion symmetry, the Cu atoms have square-pyramidal coordination geometries, the basal Cu-O bonds are in the range 1.916 (2)-1.931 (2) A, the apical Cu-O bond length is 2.582 (2) A, the hinokitiolate bite angles are in the range 83.41 (7)-83.96 (8) degrees , the urea-Cu(hino)(2) interactions have an R(2)(2)(8) motif, and the urea layers result from the close packing of R(8)(6)(28) 'butterflies' and R(8)(6)(24) 'strips of tape'. PMID- 20921608 TI - The first square-planar copper(II) 1:2 complex with differently coordinated 2 hydroxybenzaldehyde 4-allylthiosemicarbazone ligands. AB - The title compound, [(Z)-4-allyl-2-(2-hydroxybenzylidene)thiosemicarbazide kappaS][(E)-4-allyl-1-(2-oxidobenzylidene)thiosemicarbazidato kappa(3)O,N(1),S]copper(II) monohydrate, [Cu(C(11)H(11)N(3)OS)(C(11)H(13)N(3)OS)].H(2)O, crystallized as a rotational twin in the monoclinic crystal system (space group Cc) with two formula unit (Z' = 2) in the asymmetric unit, one of which contains an allyl substituent disordered over two positions. The Cu(II) atom exhibits a distorted square-planar geometry involving two differently coordinated thiosemicarbazone ligands. One ligand is bonded to the Cu(II) atom in a tridentate manner via the phenolate O, azomethine N and thioamide S atoms, while the other coordinates in a monodentate manner via the S atom only. The complex is stabilized by an intramolecular hydrogen bond, which creates a six-membered pseudo-chelate metalla-ring. The structure analysis indicates the presence of the E isomer for the tridentate ligand and the Z isomer for the monodentate ligand. The crystal structure contains a three-dimensional network built from intermolecular O-H...O, N-H...O, O-H...N and N-H...S hydrogen bonds. PMID- 20921609 TI - A low-temperature phase of bis(tetrabutylammonium) octa-MU(3)-chlorido hexachlorido-octahedro-hexatungstate. AB - The title compound, (C(16)H(36)N)(2)[W(6)Cl(14)], undergoes a reversible phase transition at 268 (1) K. The structure at 150 and 200 K has monoclinic (P2(1)/c) symmetry. Both crystallographically independent tungsten chloride cluster anions sit on crystallographic inversion centers [symmetry codes: (-x, -y + 1, -z) and ( x + 1, -y + 2, -z)]. Two previous studies at room temperature describe the structure in the space group P2(1)/n with a unit-cell volume approximately half the size of the low-temperature unit cell [Zietlow, Schaefer et al. (1986). Inorg. Chem. 25, 2195-2198; Venkataraman et al. (1999). Inorg. Chem. 38, 828 830]. The unit cells of the room- and low-temperature polymorphs are closely related. The hydrocarbon chain of one of the tetrabutylammonium cations is disordered at both 150 and 200 K. PMID- 20921610 TI - (Acetato-kappa2O,O')dihydroxidoytterbium(III) hemihydrate. AB - The title compound, [Yb(C(2)H(3)O(2))(OH)(2)].0.5H(2)O, was obtained via hydrothermal reaction of Yb(CH(3)COO)(3).H(2)O with NaOH at 443 K. The compound forms two-dimensional layers with six crystallographically independent Yb(III) atoms. Four of these form YbO(8) coordination polyhedra, while the coordination number of the remaining two Yb(III) atoms is 7. Five of these coordination polyhedra are interconnected mainly via hydroxide groups, as they build a narrow inner layer that extends infinitely within the ab plane. The sixth Yb(III) atom resides outside this inner layer and builds a terminal YbO(8) coordination polyhedron on the layer surface. Its coordination environment comprises four carboxylate O atoms belonging to three different acetate entities, three hydroxide groups and one water molecule. Adjacent layers experience weak interactions via hydrogen bonds. The Yb-O distances lie in the range 2.232 (4) 2.613 (5) A. PMID- 20921611 TI - Poly[(MU4-biphenyl-3,3',4,4'-tetracarboxylato)bis[MU2-1,4-bis(imidazol-1 ylmethyl)benzene]dicobalt(II)]. AB - The asymmetric unit of the title two-dimensional coordination polymer, [Co(2)(C(16)H(6)O(8))(C(14)H(14)N(4))(2)](n), contains one Co(2+) ion, half of a biphenyl-3,3',4,4'-tetracarboxylate (bptc) anion lying about an inversion centre and one 1,4-bis(imidazol-1-ylmethyl)benzene (bix) ligand. The Co(II) atom is coordinated by three carboxylate O atoms from two different bptc ligands and two N atoms from two bix ligands constructing a distorted square pyramid. Each Co(2+) ion is interlinked by two bptc anions, while each bptc anion coordinates to four Co atoms as a hexadentate ligand so that four Co(II) atoms and four bptc anions afford a larger 38-membered ring. These inorganic rings are further extended into a two-dimensional undulated network in the (101) plane. Two Co(II) atoms in adjacent 38-membered rings are joined together by pairs of bix ligands forming a 26-membered [Co(2)(bix)(2)] ring that is penetrated by a bptc anion; these components share a common inversion centre. PMID- 20921612 TI - Structural properties of trans-cyclohexane-1,2-diamine complexes of copper(II) and zinc(II) acesulfamates. AB - The title compounds, trans-bis(trans-cyclohexane-1,2-diamine)bis(6-methyl-2,2,4 trioxo-3,4-dihydro-1,2,3-oxathiazin-3-ido)copper(II), [Cu(C(4)H(4)NO(4)S)(2)(C(6)H(14)N(2))(2)], (I), and trans-diaquabis(cyclohexane 1,2-diamine)zinc(II) 6-methyl-2,2,4-trioxo-3,4-dihydro-1,2,3-oxathiazin-3-ide dihydrate, [Zn(C(6)H(14)N(2))(2)(H(2)O)(2)](C(4)H(4)NO(4)S)(2).2H(2)O, (II), are two-dimensional hydrogen-bonded supramolecular complexes. In (I), the Cu(II) ion resides on a centre of symmetry in a neutral complex, in a tetragonally distorted octahedral coordination environment comprising four amine N atoms from cyclohexane-1,2-diamine ligands and two N atoms of two acesulfamate ligands. Intermolecular N-H...O and C-H...O hydrogen bonds produce R(2)(2)(12) motif rings which lead to two-dimensional polymeric networks. In contrast, the Zn(II) ion in (II) resides on a centre of symmetry in a complex dication with a less distorted octahedral coordination environment comprising four amine N atoms from cyclohexane-1,2-diamine ligands and two O atoms from aqua ligands. In (II), an extensive two-dimensional network of N-H...O, O-H...O and C-H...O hydrogen bonds includes R(2)(1)(6) and R(4)(4)(16) motif rings. PMID- 20921613 TI - Two isomorphous azastilbene derivatives: 1-(2-chlorobenzyl)-4-[(E)-2-(4 hydroxyphenyl)ethenyl]pyridinium chloride and 1-(2-bromobenzyl)-4-[(E)-2-(4 hydroxyphenyl)ethenyl]pyridinium bromide. AB - The crystal structures of the two title (E)-stilbazolium halogenates, C(20)H(17)ClNO(+).Cl(-) and C(20)H(17)BrNO(+).Br(-), are isomorphous, with an isostructurality index of 0.985. The azastyryl fragments are almost planar, with dihedral angles between the benzene and pyridine rings of ca 4.5 degrees . The rings of the benzyl groups are, in turn, almost perpendicular to the azastyryl planes, with dihedral angles larger than 80 degrees . The cations and anions are connected by O-H...X(-) (X = halogen) hydrogen bonds. The halide anions are 'sandwiched' between the charged pyridinium rings of neighbouring molecules, and weak C-H...O hydrogen bonds and C-H...X and C-H...pi interactions also contribute to the crystal structures. PMID- 20921614 TI - 4-Deoxy-4-fluoro-beta-D-glucopyranose. AB - 4-Deoxy-4-fluoro-beta-D-glucopyranose, C(6)H(11)FO(5), (I), crystallizes from water at room temperature in a slightly distorted (4)C(1) chair conformation. The observed chair distortion differs from that observed in beta-D-glucopyranose [Kouwijzer, van Eijck, Kooijman & Kroon (1995). Acta Cryst. B51, 209-220], (II), with the former skewed toward a B(C3,O5) (boat) conformer and the latter toward an (O5)TB(C2) (twist-boat) conformer, based on Cremer-Pople analysis. The exocyclic hydroxymethyl group conformations in (I) and (II) are similar; in both cases, the O-C-C-O torsion angle is ~-60 degrees (gg conformer). Intermolecular hydrogen bonding in the crystal structures of (I) and (II) is conserved in that identical patterns of donors and acceptors are observed for the exocyclic substituents and the ring O atom of each monosaccharide. Inspection of the crystal packing structures of (I) and (II) reveals an essentially identical packing configuration. PMID- 20921615 TI - 6-[(4-Fluorophenyl)(1H-imidazol-1-yl)methyl]-1,3-benzodioxol-5-ol and 6-[(4 methoxyphenyl)(1H-imidazol-1-yl)methyl]-1,3-benzodioxol-5-ol. AB - The title compounds, C(17)H(13)FN(2)O(3) and C(18)H(16)N(2)O(4), are new potent aromatase inhibitors combining the common features of second- and third generation nonsteroid anti-aromatase compounds. The molecules have a propeller shape, with dihedral angles between adjacent planes in the range 49-86 degrees . A quantum mechanical ab initio Roothaan-Hartree-Fock calculation for the isolated molecules shows values for these angles close to the ideal value of 90 degrees . Docking studies of the molecules in the aromatase substrate show that their strong inhibitor potency can be attributed to molecular flexibility, hydrophobic interactions, heme Fe coordination and hydrogen bonding. PMID- 20921616 TI - 7-Amino-2-methylsulfanyl-1,2,4-triazolo[1,5-a]pyrimidine-6-carboxylic acid as the dimethylformamide and water monosolvates at 293 K. AB - The molecular structure of 7-amino-2-methylsulfanyl-1,2,4-triazolo[1,5 a]pyrimidine-6-carboxylic acid is reported in two crystal environments, viz. as the dimethylformamide (DMF) monosolvate, C(7)H(7)N(5)O(2)S.C(3)H(7)NO, (I), and as the monohydrate, C(7)H(7)N(5)O(2)S.H(2)O, (II), both at 293 (2) K. The triazolo[1,5-a]pyrimidine molecule is of interest with respect to the possible biological activity of its coordination compounds. While the DMF solvate exhibits a layered structural arrangement through N...O hydrogen-bonding interactions, the monohydrate displays a network of intermolecular O...O and N...O hydrogen bonds assisted by cocrystallized water molecules and weak pi-pi stacking interactions, leading to a different three-dimensional supramolecular architecture. Based on results from topological analyses of the electron-density distribution in X-H...O (X = O, N and C) regions, hydrogen-bonding energies have been estimated from structural information only, enabling the characterization of hydrogen-bond graph energies. PMID- 20921617 TI - Two three-dimensional networks in two polymorphs of biphenyl-4,4'-diaminium bis(3 carboxy-4-hydroxybenzenesulfonate) dihydrate. AB - Two polymorphs of biphenyl-4,4'-diaminium bis(3-carboxy-4 hydroxybenzenesulfonate) dihydrate, C(12)H(14)N(2)(2+).2C(7)H(5)O(6)S(-).2H(2)O, have been obtained and crystallographically characterized. Polymorph (I) crystallizes in the space group P2(1)/c with Z' = 2 and polymorph (II) in the space group P-1 with Z' = 0.5. The benzidinium cation in (II) is located on a crystallographic inversion centre. In both (I) and (II), the sulfonic acid H atoms are transferred to the benzidine N atoms, forming dihydrated 1:2 molecular adducts (base-acid). In the crystal packings of (I) and (II), the component ions are linked into three-dimensional networks by combinations of X-H...O (X = O, N and C) hydrogen bonds. In addition, pi-pi interactions are observed in (I) between inversion-related benzene rings [centroid-centroid distances = 3.632 (2) and 3.627 (2) A]. In order to simplify the complex three-dimensional networks in (I) and (II), we also give their rationalized topological analyses. PMID- 20921618 TI - Unconventional hydrogen bonding and pi-stacking in two substituted pyridine carboxamides. AB - The crystal structures of two para-substituted aryl derivatives of pyridine-2 carboxamide, namely N-(4-fluorophenyl)pyridine-2-carboxamide, C(12)H(9)FN(2)O, (I), and N-(4-nitrophenyl)pyridine-2-carboxamide, C(12)H(9)N(3)O(3), (II), have been studied. Compound (I) exhibits unconventional aryl-carbonyl C-H...O and pyridine-fluorine C-H...F hydrogen bonding in two dimensions and well defined pi stacking involving pyridine rings in the third dimension. The conformation of (II) is more nearly planar than that of (I) and the intermolecular interactions comprise one-dimensional aryl-carbonyl C-H...O hydrogen bonds leading to a stepped or staircase-like progression of loosely pi-stacked molecules. The close packed layers of planar pi-stacked molecules are related by inversion symmetry. Two alternating interplanar separations of 3.439 (1) and 3.476 (1) A are observed in the crystal lattice and are consistent with a repetitive packing sequence, ABA'B'AB..., for the pi-stacked inversion pairs of (II). PMID- 20921619 TI - 6,6'-Dimethoxygossypolone. AB - 6,6'-Dimethoxygossypolone (systematic name: 7,7'-dihydroxy-5,5'-diisopropyl-6,6' dimethoxy-3,3'-dimethyl-1,1',4,4'-tetraoxo-2,2'-binaphthalene-8,8' dicarbaldehyde), C(32)H(30)O(10), is a dimeric molecule formed by oxidation of 6,6'-dimethoxygossypol. When crystallized from acetone, 6,6'-dimethoxygossypolone has monoclinic (P2(1)/c) symmetry, and there are two molecules within the asymmetric unit. Of the four independent quinoid rings, three display flattened boat conformations and one displays a flattened chair/half-chair conformation. The angles between the planes of the two bridged naphthoquinone structures are fairly acute, with values of about 68 and 69 degrees . The structure has several intramolecular O-H...O and C-H...O hydrogen bonds and several weak intermolecular C-H...O hydrogen bonds, but no intermolecular O-H...O hydrogen bonds. PMID- 20921620 TI - 2-Cyano-N-(4,6-dimethoxypyrimidin-2-yl)acetamide: complex sheets built from N H...O and C-H...O hydrogen bonds. AB - Molecules of the title compound, C(9)H(10)N(4)O(3), (I), are linked into complex sheets by a combination of one N-H...O hydrogen bond and two C-H...O hydrogen bonds. Comparisons are drawn between (I) and some related compounds in respect of both their molecular conformations and their hydrogen-bonding arrangements. PMID- 20921621 TI - N,N-diphenylbenzamide. AB - In the title compound, C(19)H(15)NO, the neutral molecules are held together in the crystal structure by very weak C-H...O interactions, giving rise to a linear chain-like structure. The structure of the molecule has been optimized using density functional theory at the B3LYP/6-31G(d) level and this is compared with the molecular structure in the solid state. The two structures show significant differences in the relative orientations of the aromatic rings, which is interesting for further supramolecular study. Apart from the crystal structure analysis, powder X-ray diffraction, UV-visible and thermogravimetric analyses of the compound have been carried out. PMID- 20921622 TI - Molecular profiling of cytomegalovirus-induced human CD8+ T cell differentiation. AB - CD8+ T cells play a critical role in the immune response to viral pathogens. Persistent human cytomegalovirus (HCMV) infection results in a strong increase in the number of virus-specific, quiescent effector-type CD8+ T cells with constitutive cytolytic activity, but the molecular pathways involved in the induction and maintenance of these cells are unknown. We show here that HCMV infection induced acute and lasting changes in the transcriptomes of virus reactive T cells collected from HCMV-seropositive patients at distinct stages of infection. Enhanced cell cycle and metabolic activity was restricted to the acute phase of the response, but at all stages, HCMV-specific CD8+ T cells expressed the Th1-associated transcription factors T-bet (TBX21) and eomesodermin (EOMES), in parallel with continuous expression of IFNG mRNA and IFN-gamma-regulated genes. The cytolytic proteins granzyme B and perforin as well as the fractalkine binding chemokine receptor CX3CR1 were found in virus-reactive cells throughout the response. During HCMV latency, virus-specific CD8+ T cells lacked the typical features of exhausted cells found in other chronic infections. Persistent effector cell traits together with the permanent changes in chemokine receptor usage of virus-specific, nonexhausted, long-lived CD8+ T cells may be crucial to maintain lifelong protection from HCMV reactivation. PMID- 20921623 TI - Lipocalin 2 is essential for chronic kidney disease progression in mice and humans. AB - Mechanisms of progression of chronic kidney disease (CKD), a major health care burden, are poorly understood. EGFR stimulates CKD progression, but the molecular networks that mediate its biological effects remain unknown. We recently showed that the severity of renal lesions after nephron reduction varied substantially among mouse strains and required activation of EGFR. Here, we utilized two mouse strains that react differently to nephron reduction--FVB/N mice, which develop severe renal lesions, and B6D2F1 mice, which are resistant to early deterioration -coupled with genome-wide expression to elucidate the molecular nature of CKD progression. Our results showed that lipocalin 2 (Lcn2, also known as neutrophil gelatinase-associated lipocalin [NGAL]), the most highly upregulated gene in the FVB/N strain, was not simply a marker of renal lesions, but an active player in disease progression. In fact, the severity of renal lesions was dramatically reduced in Lcn2-/- mice. We discovered that Lcn2 expression increased upon EGFR activation and that Lcn2 mediated its mitogenic effect during renal deterioration. EGFR inhibition prevented Lcn2 upregulation and lesion development in mice expressing a dominant negative EGFR isoform, and hypoxia-inducible factor 1alpha (Hif-1alpha) was crucially required for EGFR-induced Lcn2 overexpression. Consistent with this, cell proliferation was dramatically reduced in Lcn2-/- mice. These data are relevant to human CKD, as we found that LCN2 was increased particularly in patients who rapidly progressed to end-stage renal failure. Together our results uncover what we believe to be a novel function for Lcn2 and a critical pathway leading to progressive renal failure and cystogenesis. PMID- 20921624 TI - Placental growth factor mediates aldosterone-dependent vascular injury in mice. AB - In clinical trials, aldosterone antagonists reduce cardiovascular ischemia and mortality by unknown mechanisms. Aldosterone is a steroid hormone that signals through renal mineralocorticoid receptors (MRs) to regulate blood pressure. MRs are expressed and regulate gene transcription in human vascular cells, suggesting that aldosterone might have direct vascular effects. Using gene expression profiling, we identify the pro-proliferative VEGF family member placental growth factor (PGF) as an aldosterone-regulated vascular MR target gene in mice and humans. Aldosterone-activated vascular MR stimulated Pgf gene transcription and increased PGF protein expression and secretion in the mouse vasculature. In mouse vessels with endothelial damage and human vessels from patients with atherosclerosis, aldosterone enhanced expression of PGF and its receptor, FMS like tyrosine kinase 1 (Flt1). In atherosclerotic human vessels, MR antagonists inhibited PGF expression. In vivo, aldosterone infusion augmented vascular remodeling in mouse carotids following wire injury, an effect that was lost in Pgf-/- mice. In summary, we have identified PGF as what we believe to be a novel downstream target of vascular MR that mediates aldosterone augmentation of vascular injury. These findings suggest a non-renal mechanism for the vascular protective effects of aldosterone antagonists in humans and support targeting the vascular aldosterone/MR/PGF/Flt1 pathway as a therapeutic strategy for ischemic cardiovascular disease. PMID- 20921625 TI - MAPK phosphatase-3 promotes hepatic gluconeogenesis through dephosphorylation of forkhead box O1 in mice. AB - Insulin resistance results in dysregulated hepatic gluconeogenesis that contributes to obesity-related hyperglycemia and progression of type 2 diabetes mellitus (T2DM). Recent studies show that MAPK phosphatase-3 (MKP-3) promotes gluconeogenic gene transcription in hepatoma cells, but little is known about the physiological role of MKP-3 in vivo. Here, we have shown that expression of MKP-3 is markedly increased in the liver of diet-induced obese mice. Consistent with this, adenovirus-mediated MKP-3 overexpression in lean mice promoted gluconeogenesis and increased fasting blood glucose levels. Conversely, shRNA knockdown of MKP-3 in both lean and obese mice resulted in decreased fasting blood glucose levels. In vitro experiments identified forkhead box O1 (FOXO1) as a substrate for MKP-3. MKP-3-mediated dephosphorylation of FOXO1 at Ser256 promoted its nuclear translocation and subsequent recruitment to the promoters of key gluconeogenic genes. In addition, we showed that PPARgamma coactivator-1alpha (PGC-1alpha) acted downstream of FOXO1 to mediate MKP-3-induced gluconeogenesis. These data indicate that MKP-3 is an important regulator of hepatic gluconeogenesis in vivo and suggest that inhibition of MKP-3 activity may provide new therapies for T2DM. PMID- 20921626 TI - Cytokinesis failure occurs in Fanconi anemia pathway-deficient murine and human bone marrow hematopoietic cells. AB - Fanconi anemia (FA) is a genomic instability disorder characterized by bone marrow failure and cancer predisposition. FA is caused by mutations in any one of several genes that encode proteins cooperating in a repair pathway and is required for cellular resistance to DNA crosslinking agents. Recent studies suggest that the FA pathway may also play a role in mitosis, since FANCD2 and FANCI, the 2 key FA proteins, are localized to the extremities of ultrafine DNA bridges (UFBs), which link sister chromatids during cell division. However, whether FA proteins regulate cell division remains unclear. Here we have shown that FA pathway-deficient cells display an increased number of UFBs compared with FA pathway-proficient cells. The UFBs were coated by BLM (the RecQ helicase mutated in Bloom syndrome) in early mitosis. In contrast, the FA protein FANCM was recruited to the UFBs at a later stage. The increased number of bridges in FA pathway-deficient cells correlated with a higher rate of cytokinesis failure resulting in binucleated cells. Binucleated cells were also detectable in primary murine FA pathway-deficient hematopoietic stem cells (HSCs) and bone marrow stromal cells from human patients with FA. Based on these observations, we suggest that cytokinesis failure followed by apoptosis may contribute to bone marrow failure in patients with FA. PMID- 20921629 TI - Autologous thin thiersch's grafts in vitiligo: experience of 8000 cases, 50000 grafts (1959-98) with modified technique in 198 cases in the year 1997-98. AB - The present study, spread over past four decades of experience gathered after operating 8000 stable vitiligo patients, reaffirms the value of thin Thiersch's grafts in treating this disfiguring disease. Under experienced hands, the success rate can be over 95%. However, selection of the patient, quality of the graft and the state of the donor and recipient sites can affect the final outcome. PMID- 20921627 TI - Distinct growth hormone receptor signaling modes regulate skeletal muscle development and insulin sensitivity in mice. AB - Skeletal muscle development, nutrient uptake, and nutrient utilization is largely coordinated by growth hormone (GH) and its downstream effectors, in particular, IGF-1. However, it is not clear which effects of GH on skeletal muscle are direct and which are secondary to GH-induced IGF-1 expression. Thus, we generated mice lacking either GH receptor (GHR) or IGF-1 receptor (IGF-1R) specifically in skeletal muscle. Both exhibited impaired skeletal muscle development characterized by reductions in myofiber number and area as well as accompanying deficiencies in functional performance. Defective skeletal muscle development, in both GHR and IGF-1R mutants, was attributable to diminished myoblast fusion and associated with compromised nuclear factor of activated T cells import and activity. Strikingly, mice lacking GHR developed metabolic features that were not observed in the IGF-1R mutants, including marked peripheral adiposity, insulin resistance, and glucose intolerance. Insulin resistance in GHR-deficient myotubes derived from reduced IR protein abundance and increased inhibitory phosphorylation of IRS-1 on Ser 1101. These results identify distinct signaling pathways through which GHR regulates skeletal muscle development and modulates nutrient metabolism. PMID- 20921630 TI - Short term treatment of pityrosporum folliculitis with itraconazole. AB - We compared the efficacy and safely of short-term itraconazole with that of placebo in 26 patients of pityrosporum folliculitis. Twenty-six patients of mycologically proven pityrosporum folliculitis entered a double-blind placebo controlled trial. Patients were randomly assigned to 7 days of treatment with either itraconazole, 200 mg once daily, or placebo. A global clinical assessment and mycological examination (KOH and smear examination) were performed at baseline and at 4 weeks after treatment. In this study, itraconazole in a dose of 200 mg for 7 days produced a distinct and statistically significant improvement over placebo (p<0.01). 84.6% of itraconazole treated patients were considered to be healed or markedly improved at the study's end point compared with 8.3% of placebo treated group (p<0.01). Eighty-four percent of patients receiving active treatment showed negative mycological examination as compared to 8.3% of placebo treated group (p<0.01). Short-term treatment with itraconazole is effective and well tolerated in the management of pityrosporum folliculitis. PMID- 20921631 TI - Dermatoses of the hand-an observation. AB - After going through 1000 case files of patients registered in the skin department of K.M.C. Hospital, it was found that 166 (16.6%) of them had dermatoses restricted to their hands. Based on the clinical findings and clinical diagnosis recorded, the various dermatoses were tabulated and evaluated. Ninety-two males and 74 females had dermatoses of hands. Warts and eczemas formed the major chunk of cases. Females out numbered males among patients with warts and eczemas. PMID- 20921632 TI - Prevalence of various dermatoses in school children. AB - In a school survey of 1161 children from 2 different schools studying in 1st to 5th standard between the age of 6 and 12 years, 890 (76.65%) students were found to have disorders of skin and its appendage. Most of the dermatoses were asymptomatic and were diagnosed in the routine examination. Nevoid conditions were seen in 255 (21.96%) students. Communicable dermatoses were noted in 221 (19%) students and nutritional deficiencies were seen in 78 (6.71%) students. Rest of the students had miscellaneous condition. Health education and good personal hygiene will definitely help to improve the health status of the school children. PMID- 20921633 TI - Assessment of the aetiological factors of non-specific (non gonococcal) urethritis, taking burning micturition as criteria. AB - Out of 90 cases of non-specific urethritis investigated, aetiological factors could be found in 58 cases. However, in 45 cases i.e. 50%, the causative factors turned out to be common factors like pyogenic, fungal, and trichomonal infections only. PMID- 20921634 TI - Hiv infection in patients of sexually transmitted disease. AB - A total of 1027 male patients suffering from sexually transmitted diseases (STD) during 1990 to 1996 were screened for HIV infection. All cases were in the age group 17 years to 48 years. One hundred and sixty-seven STD cases (16.3%) were found to have HIV infection. A rising trend in incidence of HIV infection in STD patients from 1990 (2.8%) to 1996 (27.8%) was noticed countrary to declining trend of STDs from 213 cases in 1990 to 79 cases in 1996. The incidence of HIV infection was 30.3% in lymphogranuloma venereum, 19.5% in chancroid, 13.5% in syphilis, 17.6% in herpes genitatis, 6.7% in gonorrhoea and 11.2% in other STD cases. PMID- 20921628 TI - Specialized roles for cysteine cathepsins in health and disease. AB - Cathepsins were originally identified as proteases that act in the lysosome. Recent work has uncovered nontraditional roles for cathepsins in the extracellular space as well as in the cytosol and nucleus. There is strong evidence that subspecialized and compartmentalized cathepsins participate in many physiologic and pathophysiologic cellular processes, in which they can act as both digestive and regulatory proteases. In this review, we discuss the transcriptional and translational control of cathepsin expression, the regulation of intracellular sorting of cathepsins, and the structural basis of cathepsin activation and inhibition. In particular, we highlight the emerging roles of various cathepsin forms in disease, particularly those of the cardiac and renal systems. PMID- 20921635 TI - Role of laser therapy in post herpetic neuralgia. AB - The efficacy of combi laser therpay was evaluated in fifty cases of post neuralgia (PHN) of different age groups (31 to 81 years) and with varying duration of illness from 2 months to 4 and a half years in the present study. The affected areas were irradiated from a distance of 5 cms. using the probe of 12x70 watts at a frequency of 1000 Hz. each area being exposed for a time period of 5 minutes and 6 seconds. In each case the combi laser therapy was given for 15 consecutive days and therapeutic effect of the therapy was evaluated after 5th, 10th and 15th laser application during the treatment with the help of visual analouge scale (VAS). Patients started responding to the therapy after an average of 3.28 laser applications and VAS steadily decreased as the therapy progressed. After completion of therapy, 43 (86%) out of 50 cases showed excellent relief (76 100%) and remaining 7 (14%) cases showed partial relief, 4(8%) cases with good relief (51-75%), 2 (4%) cases with fair relief (26-50%) and 1(2%) case with poor relief (1-25%). Partial relief in our 7 cases could be due to multiple factors like prolonged duration of illness, involvement of ophthalmic division of trigeminal nerve and formation of scarring and keloids. No side effects were observed during the treatment as well as duing the follow up period of 8 weeks. PMID- 20921636 TI - Cutaneous tuberculosis in children a clinico-microbiological study. AB - Twenty untreated patients of cutaneous tuberculosis varying from 2-12 years of age were included in the study. The incidence of cutaneous tuberculosis amongst the paediatric dermatological patients was 0.36%. Of these, 10 had lupus vulgaris, 8 had scrofuloderma, 3 had tuberculosis verrucosa cutis and 2 had lichen scrofulosorum. Three patients concomitantly had more than one type of skin tuberculosis. Systemic involvement in the form of pulmonary and osseous system was seen in 45% cases. The tuberculin test was uniformly positive. Affirmative clinico-histopathological correlation was observed in all the patients. However, acid fast bacilli could not be demonstrated in any of the sections. Only one patient (scrofuloderma) exhibited AFB on smear examination. In the same patient, M. tuberculosis could be cultured on L-J medium. However, Elisa for IgM antibodies in serum was positive in 12 (60%) cases. Need for newer techniques in the diagnosis is emphasised. PMID- 20921637 TI - Cutaneous leishmaniasis with unusual presentation. AB - Three cases of cutaneous leishmaniasis with unusual presentation seen at Central Hospital Tripoli, Libya are described. Case No. 1 and 2 had 102 and 109 noduloulcerative lesions with generalized almost bilaterally symmetrical distribution, suggestive of dissemination. Case No. 3 had large verrucous carcinoma but histopathology suggested lupoid (chronic cutaneous) leishmaniasis. Patient No. 2 developed hypersensitivity reaction to sodium stibogluconate after 10 days but responded well to the treatment. Case No. 2 did not tolerate the above treatment and was treated successfully with combination of rifampicin and INH. Case No. 3 was treated successfully with liquid nitrogen cryotherapy by Cryosurg-Frigitonics, using special open probes. PMID- 20921638 TI - Goldenhar syndrome with unusual features. AB - We report two cases of Goldenhar syndrome in whom bilateral ocular and auricular changes were observed. One patient also had hypertelorism, macrophthalmia and bulbous nose. PMID- 20921639 TI - De sanctis cacchione syndrome. AB - A case of de Sanctis Cacchine syndrome in a female infant is presented. PMID- 20921640 TI - Vulval varicosities in pregnancy. AB - Vulval varicosities reportedly occurs in pregnant women. We report a case of vulval varicosities with associated varicosities of the breast and saphenous veins, which regressed completely post partum with conservative management. PMID- 20921641 TI - Lepromatous leprosy presenting as a swelling in the neck. AB - A 25-year-old electrician presented with gradually, asymptomatic swelling on left of the neck since 2 years. The swelling which was initially diagnosed as cervical lymphadenitis by the internist represented the enlarged left great auricular nerve. Cutaneous examination revealed an ill-defined, hypoaesthetic macule with minimal atrophy on the pinna of the left ear. The histopathology of the nerve showed a lepromatous neuritis with bacteriological index (BI) of 5+. PMID- 20921642 TI - Single dose itraconazole therapy in tinea versicolor; a double blind, randomised placebo controlled study. PMID- 20921643 TI - Peyronies disease, scleroderma and diabetes mellitus. PMID- 20921644 TI - Nevus depigmentosus with segmental vitiligo. PMID- 20921645 TI - Etiopathogenesis of vitiligo : Are we dealing with an environmental disorder ? AB - The increasing incidence of vitiligo in this part of the world (4.25%), prompted us to study 5000 fresh vitiligo patients. Several triggering factors were elicitable. Malnutrition and intake of junk food were very common in childhood vitiligo. Intercurrent infections as well as intake of antibotics were also significant, immediately preceding the development of depigmented patches in younger age group. Genetic predisposition was uncommon. Autoimmune disorders were infrequent and usually accompanied late onset vitiligo. For management, vitiligo was classified into VI (active), V2 (quiescent) and V3 (improving) stages. The therapy administered varied in each stage. As a common denominator, all out efforts were made to eliminate possible trigger factors in individual cases throughout the period of treatment, and building the general health to prevent recurrence in future. The study strongly points out that vitiligo is a multifactorial disorder. It can be effectively managed after each patient is individually assessed. Elimination of possible triggering factors may form the mainstay of vitiligo therapy along with controlled pharmacological intervention. The improvement of general resistance of body may bring spontaneous repigmentation. PMID- 20921646 TI - A clinico-pathological study of 70 cases of pemphigus. AB - A clinicopalhological study of 70 cases of pemphigus observed over a span of four and a half years from January 1992 to June 1996 at the Sir J.J. Group of Hospitals and Grant Medical College, Mumbai is reported. Pemphigus vulgaris constituted the single largest group of 43 cases, followed by pemphigus foliaceus (25 cases) and pemphigus vegetans (2 cases). Majority of the cases were seen in the age group of 21-60 years, with a slight male predominance. The youngest patient was 14 years while the eldest was aged 75 years. Mucosal involvement was seen in 31 cases of pemphigus vulgaris, as opposed to only 5 cases of pemphigus foliaceus. Flaccid bullae were present in 100% cases. Pruritus was complained of in 14 cases, though it was more common in pemphigus vegetans and vulgaris. Salient histopathological features of pemphigus vulgaris observed were (I) intraepidermal suprabasal blisters (35 cases), (2) presence of acantholytic cells (40 cases), (3) "Row of tombstone appearance" (I8 cases) and (4) acantholysis involving follicular sheath (20 cases). Main histopathological features of pemphigus foliaceus were (1) subcorneal blister (15 case), (2) acantholysis (24 cases) and (3) bulla cavity containing inflammatory infiltrate (12 cases). Both cases of pemphigus vegetans showed hyperkeratosis, papillomatosis and irregular acanthosis with intra-epidermal eosinophilic abscesses besides suprabasal lacunae. PMID- 20921647 TI - A clinico - histopathological outcome of 4 weeks methotrexate pluse therapy in psoriasis. AB - A clinico-histopathological study was carried out In 50 patients of psoriasis to see clinical and histological outcome and/or correlation of weekly methotrexate pulse therapy. Clinically, results of therapy were evalutated by estimating the percentage of total body coverage with psoriasis. Prior to therapy, average involvement was 47.5% which after 4 weeks methotrexate therapy reduced to 8. 3%. A complete clearing of psoriasis occurred in 40% of patients after methotrexate therapy. The clinical response started as early as I week in most of patients. Only 2 patients failed to respond even after 4 weeks of therapy. Histopathologically in pretreatmenl biopsy, 34 showed classical psoriatic pathology while in 16 biopsy was suggestive of psoriasis but not confirmative. Histopathological examination after 4 weeks treatment showed that 41 still showed one or more histological evidence of psoriasis, although only two patients had classical, psoriatic pathology, in rest 9 patients there were complete regression. Thus, with methotrexate, clinical clearance was much faster than histopathological clearance. PMID- 20921648 TI - Prolong continuous versus weekly oral acyclovir in recurrent herpes genitalis. AB - Patients with frequent recurrences of genital herpes were treated with oral acyclovir tablet, 800 mg once daily or once a week for 2 years. Confirmed recurrences for all patients were treated with acyclovir, 200 mg orally 5 times per day, for five days. Of 58 patients enrolled, 12 of 26 daily acyclovir recipients and 22 of 32 weekly acyclovir recipients completed two years of study. Patients receiving daily acyclovir experienced a mean of 0.0991 recurrences / month compared with mean of 0.113 recurrences / month for patients receiving weekly acyclovir. A total of 33% of daily acyclovir recipients and 27% weekly acyclovir recipients were free of recurrences for two years. PMID- 20921649 TI - Bacteriological study of pyoderma with special reference to antibiotic susceptibility to newer antibiotics. AB - Five hundred and forty-two cases of pyoderma were investigated to study bacterial aetiology and their antibiotic susceptibility patterns. Of these 65.87% cases were of primary pyoderma and the rest were of secondary pyoderma. Maximum cases were of impetigo (38.78%) followed by folliculitis (12.92%), furunculosis (2.95%), ecthyma (3.5%), carbuncle (1.5%) and sycosis barbae (0.4%). Secondary pyoderma constituted infected trophic ulcer (18.82%), infected pemphigus (7.2%), infected contact dermatitis (6.27%), and infected scabies (1.8%). Single organism was isolated from 46.9% cases and more than one type of organisms in 65.46% of cases. No organism was isolated in 5% of cases. Staphylococcus (67.34%) was the predominant species isolated followed by beta-haemolytic streptococcus (21.77%). Maximum strains of Staph. aureus were susceptible to amikacin (75%), co trimoxazole (72%), cefotaxime (65%), chloramphenicol (62%), ciprofloxacin (61%) and clindamycin (61%). There was low susceptibility to cephaloridin (11%), gentamicin (12%) and penicillin (21%). Streptococcus betahaemolyticus was highly sensitive to most of the antibiotics and less sensitive to cefotaxime (7%), co trimoxazole (11%) and penicillin (27%). Most of the strains were found to be resistant to one or more antibiotics. PMID- 20921650 TI - Sexual behaviour and HIV prevalence in patients with sexually transmitted disease attending an STD clinic in north eastern state of India. AB - The study was done to determine the sexual risk behaviour and to monitor HIV seroprevalence among STD patients attending a STD clinic as a part of sentinel surveillance programme in North Eastern State of India. Face to face interviews, clinical and epidemiological investigations were carried out in all new patients. The frequency of condom use, and the number of sexual partners during the preceding 6 months were recorded. Out of 680 males, majority (66.4%) were aged 20 29 years. 89.2% men reported to have had sexual contacts with prostitutes. Being younger, single and staying away from home were independent risk factors for having sexual contact. 34.7% men used condom at all times, 27.2% reported inconsistent use and 38.1% did not use condoms. Eleven (1.6%) of the 680 STD patients tested were found to be HIV positive, did not use condom and had genitoulcerative disease. PMID- 20921651 TI - Angiolymphoid hyperplasia with eosinophilia (alhe) versus kimura's disease : Changing concepts. AB - The clinico-pathological differences between Kimura's angiolymphoid hyperplasia with eosinophilia are presented to emphasize that they are two separate disease entities which until now were considered as the same disease. PMID- 20921652 TI - Congenital erythropoietic porphyria associated with ventricular septal defect. AB - A case of congenital erythropoietic porphyria associated with ventricular septal defect in a 6-year-old girl is reported. PMID- 20921653 TI - Symmetrical progressive erythro-keratoderma. AB - A 13-year-old male child had gradually progressive, bilaterall, symmetrical, erythematous hyperkeratotic plaques over knees, elbows, natal cleft, dorsa of hands and feet with palmoplantar keratoderma. High arched palate, fissured tongue and sternal depression (pectus-excavatum) were unusual associations. PMID- 20921654 TI - Pyoderma gangrenosum associated with ulceratlve colitis-first case report from Nepal. AB - A case of pyoderma gangrenosum with ulcerative colitis from Nepal is reported. The patient responded well to a combination of oral steroids, clofazimine. dapsone and salazopyrine within a period of 3 months. PMID- 20921655 TI - Nail changes secondary to systemic drugs. PMID- 20921656 TI - Post kala azar dermal leishmaniasis. PMID- 20921657 TI - Foot wear dermatitis. PMID- 20921658 TI - Ichthyosis vulgaris involving the scalp area affected by androgenetic alopecia. PMID- 20921659 TI - Sexually transmitted diseases and infertility. PMID- 20921660 TI - Role of local NGOs as peer educators in slowing the slowing the spread of HIV in kasargod (1991-96). AB - The study reports the effective role of local NGOs in reaching traditional Indian community with information and education on HIV/AIDS. Target oriented IE programs with members of local NGOs as peer educators have resulted in significant slowing in the spread of HIV from the rate of 1.6% in 1992 to 0.4% in 1996. PMID- 20921661 TI - Incidence of HIV seropositivity in STD cases. AB - Two hundred patients comprising of 144 males and 56 females ranging in age from 10 years to 68 years were studied. The incidence of HIV positive cases in STD patients was 13.5%. Maximum incidence of STD cases were seen in the age group between 21-25 years (27%). Maximum incidence of HIV seropositivity was seen in 19 and 20 years age group (33.8%). In HIV positive cases, there was a male predominance (62.9%). Most of the patients were from low socio-economic status, CSW were the common source and GUD was the most common STD association. PMID- 20921662 TI - Fluconazole and itraconazole in pityriasis versicolor. AB - Pityriasis versicolor is a common superficial fungal infection caused by Malassezia species. It has a high incidence and prevalence in tropical climates. Although it responds well to treatment, relapses and recurrences are frequent. In the present study the therapeutic response of single dose fluconazole (400 mg) with itraconazole (100mg twice daily ? 7 days) was compared in sixty patients of pityriasis versicolor. No significant statistical difference (p>0.05%) was observed between efficacy of two drugs. Therapy with fluconazole is preferable in view of single dose administration and lesser cost as compared to itraconazole. PMID- 20921663 TI - Topical mometasone furoate for the treatment of childhood vltiligo. AB - Forty-five children with vitiligo were treated with topical applications of mometasone furoate for 2 to 6 months. The best results occurred in the facial vitiligo. Repigmentation of 90-100% was achieved in more than 80% of patients with vitiligo of the face and more than 60% of patients with vitiligo on other part of the body. Interestingly there was no single side effect noted even after six months application in children. PMID- 20921664 TI - Methicillin resistant staphylococcus aureus (MRSA) in skin isolates from hospital acquired infections. AB - Eighty-four isolates of Staphylococcus aureus (S.aureus) obtained from nosocomial infections were screened for methicillin resistance, which was found to be about 40.47%. This indicates a rising trend in the incidence of MRSA over the previous years. Early detection of resistant strains as well as prudent use of antibiotics can help to combat the global problem of resistance. PMID- 20921665 TI - Unilateral multiple linear lichen planus along the lines of blaschko : A report of two cases. AB - Two cases, a 54-yearl-old woman and a 48-year-old man developed papular lesions confined to the left side of their body. The lesions on the trunk were arranged in S-shaped manner. This arrangement was along Blaschko's lines and could be misinterpreted as that of zosteriform lichen planus. PMID- 20921666 TI - Glucagonoma syndrome. AB - Glucagonoma is a rare syndrome with pancreatic tumour, necrolytic migratory erythema, weight loss and diabetes mellitus. Two such cases are reported here to highlight the variety of presentation of this syndrome and also to stress the importance of early diagnosis of this condition. PMID- 20921667 TI - Disseminated malignant melanoma. AB - A 25-year-old man had multiple asymptomatic, nodular lesions on the trunk, extremities and the face for 3 months. He also had left facial palsy with severe headache and vomiting. There were no other systemic or constitutional symptoms. Skin biopsy from a nodular lesion showed features of malignant melanoma, confirmed by Fontana Masson and S-100 protein staining. A diagnosis of disseminated malignant melanoma was made and the patient was treated symptomatically. The patient died in 4 months. PMID- 20921668 TI - Lichenoid epidermal naevus. AB - A case of lichenoid epidermal naevus with unusual clinical presentation is reported. PMID- 20921669 TI - Hyperkeratotic oral lichen planus role of vitamin A. AB - Chronic tobacco chewing and smoking have been implicated as precipitating factors for the development of oral lichen planus (OLP). We here report a case of chronic cigarette smoker who developed OLP plaque, without any other clinical pattern of OLP and skin involvement, which did not respond to conventional corticosteroid treatment and dapsone, but responded when vitamin A was added. PMID- 20921670 TI - Acropigmentation of dohi. AB - Two cases of acropigmentation of Dohi are reported. First case was 9-year-old boy and the second was a 8-year-old girl. Hypopigmented macules with interspersed brownish macules were seen on dorsa of hands, feet and they became stationary after initial progression. PMID- 20921671 TI - Olmsted syndrome. AB - A 20-year-old Sikh man had palmoplantar keratoderma, flexion deformity of digits, universal alopecia, keratotic plaques at the angles of mouth, gluteal cleft, knees and dorsal aspects of the metacarpophalangeal joints of the hand; features of Olmsted syndrome. He had normal nails, teeth, oral mucosa and normal joint movements. Treatment with acitretin, 25mg/day for three and a half months, followed by 25mg once daily alternating with 50mg once daily for 3 months resulted in significant improvement. PMID- 20921672 TI - Angiokeratoma of fordyce on unusual site. AB - A 19-year-old married man presented with multiple, bright-red and reddish-blue papular lesions on glans and prepuce with intermittent bleeding on maceration since 6 months duration. Histopathological study revealed features of angiokeratoma. PMID- 20921673 TI - Jackson-lawler syndrome. AB - A 36-year-old woman presented with multiple yellowish cutaneous cysts of 5 years duration, over the scalp, trunk and upper limbs. She had pachyonychia, keratoderma of hands and feet, eyebrows which stood straight out and a single cafe-au-lait macule. PMID- 20921674 TI - Environmental influence, atopy and contact sensitivity in nummular dermatitis. PMID- 20921676 TI - Cryosurgery with liquid nitrogen in stable vitiligo. PMID- 20921675 TI - Skin diseases in the elderly. PMID- 20921677 TI - Multiple mucosal neuroma syndrome. PMID- 20921678 TI - Atopic dermatitis: Indian scenario. PMID- 20921679 TI - Pattern of skin diseases in Kashmir region of India. PMID- 20921681 TI - Airborne salicaceae allergy in Ladakh. PMID- 20921680 TI - Pattern of dermatological diseases in Trivandrum. PMID- 20921682 TI - Comparative study of ketoconazole and itraconazole in pityriasis versicolor. PMID- 20921683 TI - Topical methotrexate therapy in palmoplantar psoriasis. PMID- 20921684 TI - Lichen planus and liver disease. PMID- 20921685 TI - Allergic contact dermatitis to doxepin. PMID- 20921686 TI - Scar sarcoidosis - sparing post surgical scar. PMID- 20921687 TI - Focal dermal hypoplasia syndrome. PMID- 20921688 TI - Erythema annulare centrifugum due to candida infection. PMID- 20921689 TI - Hypopigmented mycosis fungoides treated successfully with puva. AB - Hypopigmented lesions are rarely encountered in mycosis fungoides. We here report a 22-year old female patient who presented with a 5-year history of asymptomatic progressively increasing discrete and confluent hypopigmented macules and a 1 year history of a few itchy erythematous, scaly, indurated plaques. The histological features were consistent with a clinical diagnosis of mycosis fungoides. She was successfully treated with PUVA therapy. PMID- 20921690 TI - Giant cell synovioma following physical trauma. PMID- 20921691 TI - Giant molluscum contagiosum in an infant. PMID- 20921692 TI - Cutaneous polyarteritis nodasa. PMID- 20921693 TI - Herpes zoster in a 9 - month - old infant. PMID- 20921694 TI - Epidermolysis bullosa acquisita in a young female. PMID- 20921695 TI - Tumour implantation on a donor site from malignant melanoma of the right arm: a rare clinical entity. PMID- 20921696 TI - Toxic epidermal necrolysis (le). PMID- 20921697 TI - Inflammatory linear verrucous epidermal nevus and spinal anomaly. PMID- 20921698 TI - Dapsone syndrome in pure neuritic hansen's disease. PMID- 20921699 TI - Generalised and bullous lichen planus treated successfully with oral mini-pulse therapy. PMID- 20921700 TI - Presidential address. PMID- 20921701 TI - Antiphospholipid syndrome-current status. PMID- 20921702 TI - A multicentric trial of loratadine and cetirizine in urticaria. AB - Two hundred and ten patients with chronic urticaria were divided into two groups; one group was treated with Loratadine 10mg daily while the other with cetirizine 10mg daily. The total duration of treatment was four weeks. Pretreatment and post treatment evaluations were made. It was noticed that loratadine was superior to cetirizine in terms of a rapid onset of actions, overall clinical efficacy and minimal side effects. PMID- 20921703 TI - The efficacy of flutamide, an antiandrogen in idiopathic hirsutism. AB - The efficacy of flutamide, an antiandrogen in idiopathic hirsutism was studied. The long term effects of. treatment with low doses of flutamide on clinical and hormonal parameters were investigated. Nine patients with idiopathic hirsutism were studied basally and during treatment with 125mg flutamide thrice daily for a period of 9 months. Safety parameters were assessed throughout the study. Hirsutism was graded by Ferriman and Gallwey score and hormones were evaluated basally and later quarterly. After three months of therapy, flutamide had caused a significant alleviation of hirsutism and this continued during the subsequent months. No clinical significant side effects were observed during the period of the study. Biochemical and hormonal parameters remained unchanged after 9 months of flutamide. PMID- 20921704 TI - Effect of minoxidil on hair transplantation in alopecia androgenetica. AB - Forty patients suffering from androgenetic alopecia were given 3 to 4 sittings of hair transplantation at an interval of 4 to 6 weeks each. Only patients of type III, type III(vertex) and type IV baldness were operated. Twenty patients, six of type III, six of type III(vertex) and eight of type IV baldness were advised to use minoxidil 2% locally at the recipient area in the dose of 1 ml applied twice daily. Twenty patients of similar types of baldness were advised to just shampoo their hair daily without using topical minoxidil. Percentage of response was compared between the two groups. Minoxidil did not play any role in the percentage of hair survival before and after transplantation in androgenetic alopecia. However in 60percent grafts of patients who had used topical minoxidil, there was no initial postoperative hair shedding. PMID- 20921705 TI - Cutaneous cryptococcosis and molluscum contagiosum occurring in the same lesion in a patient with AIDS. AB - Patients with acquired immunodeficiency syndrome (AIDS) are susceptible to a wide range of pathogens due to profound defect in cell-mediated immunity. The co existence of different diseases within the same lesion is a feature of human immunodeficiency virus (HIV) infection. We describe co-existent cutaneous cryptococcosis and molluscum contagiosum in the same lesion in a patient with the acquired immunodeficiency syndrome. PMID- 20921706 TI - Malignant acanthosis nigricans in a 2 year old child with Wilm's Tumour. AB - Case report of a 2-year-old male child who developed acanthosis nigricans lesions of sudden onset and rapid spread is described. The child was diagnosed as having Wilm's tumour and the lesions of acanthosis nigricans subsided with resection of the tumour. PMID- 20921707 TI - Werner's Syndrome. AB - A 41-year old unmarried man presented with erosions, ulcers and keratosis of tendoachilles. He was short statured and had features of premature aging, sclerosis of the skin of the limbs and hypogonadism. The head was small with a beak-like nose. Investigations revealed diabetes mellitus, generalised osteoporosis, calcification of blood vessel walls and microsplanchia of kidneys. All the features suggested a diagnosis of Werners's syndrome. PMID- 20921708 TI - Lichen nitidus of palms and soles. AB - Lichen nitidus occurs uncommonly on the palms and soles and has an unusual morphology at these sites. Two patients who presented with lesions on the palms and soles are reported. The first patient had rough papules with prominent keratotic plugs. In the second patient, the lesion was an irregular plaque with peripheral papules showing keratotic plugs. Both patients had typical lesions elsewhere on the body. Histopathology confirmed the diagnosis. Awareness of this variant will help in prompt recognition of the condition. PMID- 20921709 TI - Bowenoid papulosis turning to squamous cell carcinoma. AB - Bowenoid papulosis is clinically a benign appearing genital lesion that shows histologic features of squamous cell carcinoma-in-situ. Bowenoid papulosis of the scrotum turning to invasive squamous cell carcinoma is reported in an elderly male. PMID- 20921710 TI - Dracunculosis medinensis. PMID- 20921711 TI - Metastatic cutaneous adenocarcinoma. PMID- 20921712 TI - Koebner response in psoriasis. PMID- 20921713 TI - Allergic reaction to phorate : an organophosphorus compound. PMID- 20921714 TI - Photodynamic hyperpigmentation light- induced cumulative insult dermatitis - A new nomenclature. PMID- 20921715 TI - Transcutaneous electrical nerve stimulation in treatment of post herpetic neuralgia. PMID- 20921716 TI - Advances in laboratory diagnosis of systemic lupus erythematosus. PMID- 20921717 TI - Sexual behaviour of youths in Chandigarh. PMID- 20921718 TI - A study of 200 cases of genital lesions of non-venereal origin. PMID- 20921719 TI - Comparative evaluation of topical benzoyl peroxide, metronidazole and benzoyl peroxide - clindamycin combination in treatment of acne vulgaris. PMID- 20921720 TI - High risk behaviour and psychiatric morbidity in HIV positive intravenous drug users (report of two cases). PMID- 20921721 TI - Acquired digital fibrokeratoma. PMID- 20921722 TI - Metastatic Crohn's disease. AB - Crohn's disease is a granulomatous inflammatory disease of the gastrointestinal tract. It can involve other sites of the body also. When such lesion are separated from Crohn's lesion of the intestine by normal skin, they are referred to as metastatic Crohn's disease. Two such cases are reported. PMID- 20921723 TI - Multiple chondroid syringoma. PMID- 20921724 TI - Arciform purpura annularis telangiectoides. PMID- 20921725 TI - Familial woolly hair. PMID- 20921726 TI - Subcutaneous phycomycosis. PMID- 20921727 TI - Tinea nigra. PMID- 20921728 TI - Malignant atrophic papulosis. AB - Malignant atrophic papulosis (MAP) is a rare disorder and only a few cases have been reported in blacks and Asians. A 38-year old male with typical cutaneous lesions of MAP which were confirmed histopathologically is reported. PMID- 20921729 TI - Oral zinc in Job's syndrome. PMID- 20921731 TI - Azathioprine - hypersensitivity. PMID- 20921730 TI - Pulse steroid therapy in generalized lichen planus. PMID- 20921732 TI - Kerosene - Induced Acute Irritant Dermatitis (le). PMID- 20921734 TI - Toxic epidermal necrolysis. PMID- 20921733 TI - Photosensitve lichenoid papular sarcoidosis. PMID- 20921735 TI - Pattern of skin diseases in paediatric age group and adolescents. AB - A total of 300 patients from first day of life to 17 years of age were analysed for pattern of skin disorders. School going children formed majority (41.3%) of cases followed by preschool children (32%). Infections formed the commonest disorder (31 %) followed by eczemas (24%), papulosquamous disorders (12%), infestation (8.6%) and urticaria (5.3%) while vitiligo, acne vulgaris, alopecia areata and genodermatoses were seen in 2.7% cases each. PMID- 20921736 TI - Clinical profile of cutaneous leishmaniasis in Faifa-Gizan, South west province of Kingdom of Saudi Arabia (A study of 140 cases). AB - A preliminary study was conducted to know the age, sex distribution and clinical pattern of cutaneous leishmaniasis (CL) in a remote hilly area, Faifa, Gizan situated in the South West region of the Kingdom of Saudi Arabia. C L accounted for nearly 5% of the new outpatient attendance in the study period (1988-90) of 20 months. Out of the 140 new patients who formed the study group, 82 were males (58.57%) and 58 females (41.43%) in the age range of 9 months to 60 years. Ninety two patients were children (65.71%) below 15 years. including 58 boys and 34 girls and CL is a major public health problem in children of this area. The fact that out of 140 affected individuals, 134 were local Saudis and 6 non-Saudis reveals the autochthonous nature of the disease in this region. The clinical spectrum included dry crusted ulcers, erythematous indurated plaques, nodules, papules, and oozing shallow ulcers. The lesions were distributed mostly on face and extremities. Response to pentostam (Sodium stibogluconate) was highly satisfactory. PMID- 20921737 TI - Itraconazole pulse therapy in onychomycosis. AB - A prospective study of 30 clinically and mycologically diagnosed cases of onychomycosis was carried out for a period of twelve months from May 1996 to April 1997. Itraconazole pulse therapy was given for the 1st week followed by 3 week drug-free period, for 1st 3 months for the finger nail cases and 4 monthes for finger nail + toe nail and toe nail cases. Patients were evaluated at baseline, week 4, week 12, week 16, week 24, up to 12 months and assessed as cleared or markedly improved with clinical and mycological success. The result of our study is very much encouraging. It suggests that the use of itraconazole pulse therapy will maintain the continuous treatment efficacy and is cost effective than continuous therapy. PMID- 20921738 TI - Erythrokeratodermia progressivum symmetricum. AB - A case of progressive symmetric erythrokeratodermia (PSEK) in an Indian male is being reported. He presented with slowly progressive bilateral symmetrical plaques with peripheral rim of erythematous halo, which were limited only to the limbs. Koebner's phenomenon was positive. Family history was negative. Histopathology ruled out psoriasis and confirmed the diagnosis of PSEK. PMID- 20921739 TI - Acropigmentation of dohi. AB - A 9-year-old girl with multiple hyperpigmented and hypopigmented macules over the hands and neck since childhood is reported. PMID- 20921740 TI - Atypical multicentric reticulohistiocytosis. AB - A 38-year-old male had arthritis since 8 years and erythematous papules, plaques, cutaneous and subcutaneous nodules over face, ears, trunk, and extensors of arms since 2 years, Histopathologically, presence of multiple foreign body giant cells confirmed the clinical diagnosis of multicentric reticulohistiocytosis. Unusual associations were: tapered fingers with depressed scars on their tips, low ESR - (5mm 1st hour). Raynaud's phenomenon and exaggeration of lesions after methotrexate. PMID- 20921741 TI - Angiolymphoid hyperplasia with eosinophilia. AB - A 35-year old woman presented with asymptomatic dermal nodules over the scalp of 10- years duration. Histopathological study revealed proliferation of thick walled blood vessels lined by plump endothelium and lymphocyte and eosinophilic infiltrate with blood eosinophilia. PMID- 20921742 TI - Anhidrotic ectodermal dysplasia with pectus excavatum, mitral valve prolapse and palmo-plantar keratoderma. AB - Anhidrotic ectodermal dysplasia (AED) is a rare x-linked recessive disorder characterised by the triad of hypotrichosis, anodontia and anhidrosis. Here we report a case of AED with associated features of pectus excavatum, mitral valve prolapse and palmoplantar keratoderma. PMID- 20921743 TI - Hypopigmented pityriasis versicolor on Becker's naevus : Hope for new method of treatment ? AB - A case of hypopigmented pityriasis versicolor superimposed on pre existing Becker's naevus associated with congenital melanocytic naevus is being reported for its rarity. The possible role of dicarboxylic acid and other free radicles produced by Pityrosporum ovale in treating Becker's Naevus is also suggested. PMID- 20921744 TI - Pre-sezary To Sezary Erythroderma Syndrome. AB - A 50-year old woman was admitted with pre-Se'zary syndrome in May, 97 as she had intractable progressive erythroderma with intense pruritus since 15 months. She also had axillary, inguinal, hilar and para-aortic lymphadenopathy, hepatomegaly, alopecia, hypersensitivity to cefadroxyl, and abnormal Sezary cells in peripheral blood film. Histopathology confirmed the diagnosis. Initially she was given 20 mg of prednisolone which was later increased to 40 mg daily but she did not respond. She responded favourably to combination of 20 mg prednisolone and chlorambucil 2.5 mg daily. PMID- 20921745 TI - Necrotising fasciitis. AB - A case of necrotising fasciitis is being reported. Due to delay in diagnosis and treatment, patient developed contracture leading to flerxion deformity. PMID- 20921746 TI - Nail changes in systemic diseases : A clinical study of 435 cases. AB - Nail changes often are reflectors of an internal disease. Four hundred and thirty five patients admitted in the Medical, Surgical and Obstetric and Gynaecology wards were studied. Nail changes were seen in 134 which included clubbing (21.3%) longitudinal melanonychia (17.2%) and platonychia (14.2%). In patients with HIV associated pulmonary tuberculosis, clubbing was associated with an unique red "crescent sign". PMID- 20921747 TI - Effect of dialysis on psoriasis : A clinical study. AB - Twenty patients with extensive psoriasis of more than three years duration not responding to conventional medical treatment were studied to assess the effect of dialysis. Ten patients were subjected to haemodialysis and ten to peritoneal dialysis. Patients were periodically assessed regarding responses by standard critera. At the end of six months 4/8 (50%) in haemodialysis group and 6/10(60%) in peritoned dialysis group showed improvement. One patient in haemodialysis group developed exfoliative dermatitis eleven days after onset of dialysis. In this study though a beneficial effect in psoriasis was noted following dialysis, the effect was temporary. PMID- 20921748 TI - Direct immunofluorescence in lesional and uninvolved skin in dle. AB - Direct immunofluroscence was evaluated in 16 patients with DLE including 1 case of lupus profundus and 4 with disseminated DLE. A BMZ band with multiple immunoreactants was demonstrated in lesional skin in 14 patients (87.5%), while 2 had only single immunoreactants. C3 and lgM were the commonest reactants followed by lgG, lgA and fibrinogen. A perifollicular prominence was seen in several patients. Four patients showed a band in uninvolved skin. This may indicate a potential to develop SLE. ANA was also positive in 5 patients but ds DNS was negative. PMID- 20921749 TI - Clinical and bacteriological study of pyoderma in Jodhpur-Western Rajasthan (le). PMID- 20921750 TI - Kyrle's disease and vitamin D resistant rickets in chronic renal failure (le). PMID- 20921751 TI - Treatment of nodular scabies (le). PMID- 20921752 TI - Pediculosis palpebrarum (le). PMID- 20921753 TI - Vaccines in leprosy. PMID- 20921754 TI - Natural history of herpes zoster in the era of AIDS. AB - Seventy-four consecutive patients with herpes zoster (HZ) in Mumbai were recruited into the study to determine its natural history. Thirty-five (47.3%) with HZ were infected with HIV-1/2. HZ+HIV+ and HZ+HIV- were demographically similar but HZ+HIV+ were clinically different; the latter were characterised by multidermatomal involvement of thoracic dermatomes below T6 or that of trigeminal nerve, recurrent episodes, bullous lesions and 17/35 had associated illnesses such as severe weight loss, recurrent fever, chronic cough, active tuberculosis and oral candidiasis. Significant differences in the course of healing, incidence of secondary bacterial infection and scaring emerged between the two groups after day-10. HZ+HIV+ individuals had vesicles and ulcers persisting for significantly longer time with frequent sequelae of post inflammatory pigmentation and post herpetic neuralgia. In areas where resources are limited for health information, such clinical differences between HZ+HIV+ and HZ+HIV- will serve to identify individuals with HIV infection in dermatologic clinic. These findings will also be helpful for early diagnosis of HIV infection, associated opportunistic infections and prevent their secondary transmission through appropriate interventions. PMID- 20921755 TI - A regionwise comparative study of the extent of post punch graft surgical repigmentation in cutaneous achromia. AB - One hundred and ten cases of stable cutaneous achromia constituted the sample population, of which 67 were females and 43 males. Age ranged between 6 and 71 years. A total of 1742 grafts were placed over 177 lesions on 29 regions and the cases were followed up to a maximum period of 2 years. The extent of maximum pigment spread (MPS) was noted in different regions of the body. It was observed that exposed parts exhibited better outcome vis-a-vis covered and shadowed part. MPS ranged between 0 to 10 mm., with an overall average of approximately 5.5mm. PMID- 20921756 TI - A comparison of systemic photochemotherapy with 8-methoxypsoralen (8-MOP) and with trimethylpsoralen (TMP) in vitiligo. AB - Oral 8-MOP and TMP were compared in the PUVA therapy for vitiligo. Group A (25 cases) was initiated on 0.3 mg/kg of 8-MOP with 1/2 Joule/cm2 of UVA and weekly increments of 1/2 Joule/ cm2 and Group B was started on 0.6 mg/kg of TMP with 1 Joule/cm2 of UVA and weekly increments of 1 Joule/cm2. Therapy was given thrice a week. Repigmentation was evaluated by using a 0-6 scale. At the end of 60 sittings, on acceptable cosmetic response was seen over the face, neck and upper extremities in both groups, while trunk and lower extremities showed lesser response. 8-MOP gave earlier response, needing a lower cumulative UVA dose i.e. 75 J/cm2 as compared to TMP i.e. 106 J/cm2. Phototoxicity was seen more often with 8-MOP. In conclusion, in Indians, 8-MOP is the drug of choice in PUVA therapy of vitiligo provided precautions against phototoxicity are adequate. PMID- 20921757 TI - Antigen mapping in hereditary epidermolysis bullosa. AB - Standard immunofluorescence tests are not positive in the various inherited epidermolysis bullosa (EB). Using antibodies to known antigens present in the basement membrane zone, antigen mapping can be done by immuno fluorescence, to determine the level of blistering and establish the diagnosis. We report three cases of junctional EB and one case of dystrophic EB in whom the diagnosis was confirmed by antigen mapping. PMID- 20921758 TI - Varied forms of lupus vulgaris. AB - Two unusual forms of lupus vulgaris affecting the perinasal skin are reported. One presented with mutilating type of lupus vulgaris while the other had vegetative type. PMID- 20921759 TI - Pityriasis rosea with unsusual herald patch. AB - A case of pityriasis rosea is reported in a 15-year old boy. The herald patch was unusual being multiple and located in crural areas and armpit. The other features of the disease were however expressed classically. PMID- 20921760 TI - Ano-rectal involvement in lymphogranuloma venereum. PMID- 20921761 TI - Eruptive syringoma. PMID- 20921762 TI - A case of dermatomyositis responding to three weeks of treatment with methotrexate and steroid. AB - A case of dermatomyositis in a young girl of 18 years is reported. Though it is generally held that it is a very recalcitrant condition, we found that the patient improved by all parameters to treatment with methotrexate and steroids in three weeks. PMID- 20921763 TI - Multicentric reticulohistiocytosis. AB - A 54-year old male presented with multiple, itchy, reddish-brown coloured papules on the face, arms and trunk of 8 months duration. Histopathological study of the skin biopsy specimen revealed features typical of multicentric reticulohistiocytosis. PMID- 20921765 TI - Naevus comedonicus affecting the palms. PMID- 20921764 TI - Epidermodysplasia verruciformis with bowenoid changes. PMID- 20921766 TI - Poikilodermatous mycosis fungoides. PMID- 20921767 TI - Effect of parenteral vitamin D3 in skin diseases. PMID- 20921768 TI - Hand dermatitis in beauticians. PMID- 20921770 TI - Repigmentation of leukotrichia over vitiligo patches after punch grafting. PMID- 20921769 TI - Mupirocin in folliculitis cruris pustulosa et atrophicans. PMID- 20921771 TI - Clofazimine. PMID- 20921772 TI - A Clinico-epidermiological study of atopic dermatitis. PMID- 20921773 TI - A study of facial dermatosis-370 cases (Excluding pyoderma and acne vulgaris grade 1 and 2). PMID- 20921774 TI - A clinical trial of minocycline in uncomplicated gonococcal urethritis. PMID- 20921775 TI - Peripheral T-lymphocyte count in pityriasis rosea. PMID- 20921776 TI - Pattern of sexually transmitted diseases at VSS medical college. PMID- 20921777 TI - Cutaneous T-cell lymphoma, tumour d'emblee (THREE CASES). PMID- 20921778 TI - Siemens syndrome. PMID- 20921779 TI - Recurrent pityriasis rosea. AB - A case of recurrent pityriasis rosea in a 25-year old man is reported. He had his first attack 4 years ago and new outbreaks followed every year in winter with last 2 episodes occurring in the same year. All investigations were normal and no explanation for recurrences was found. PMID- 20921780 TI - Atypical fibroxanthoma. PMID- 20921781 TI - Spitz nevus. AB - A case of Spitz nevus is presented in view of the difficulties of differentiating it from malignant melanoma. Spitz nevus with predominantly epithelioid cell is uncommon. PMID- 20921783 TI - Battered child syndrome. AB - Primary genital herpes in a girl of 12 years age is reported as the condition is rare in this age group and sexual abuse was the direct cause for the Battered child syndrome. PMID- 20921782 TI - Post kala azar dermal leishmaniasis. AB - A 26 - year - old Muslim male patient of Bihar presented with multiple asymptomatic hypopigmented macules and nodules mainly over back, abdomen, extremities and scrotum. Clinical examination revealed hypopigmented macules on back, abdomen, extremities with nodular lesions on the scrotum. Common warts were present on dorsa of hands. Skin biopsy was helpful in diagnosis. PMID- 20921784 TI - Monilethrix. PMID- 20921785 TI - Mixed connective tissue disorder : A Clarification (le). PMID- 20921786 TI - Use of hydrogen peroxide in electrocautery procedures. PMID- 20921787 TI - Role of blood transfusion in the management of Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN). PMID- 20921788 TI - Effect of parenteral vitamin D3 in skin diseases. PMID- 20921789 TI - Repigmentation of leukotrichia over vitiligo patches after punch grafting. PMID- 20921790 TI - Chemokines in the skin. AB - In last few years, focus has shifted from cytokines which have pleiotropic biologic properties to chemokines with target cell selective activity. The separation has led frequently espoused proposition that chemokines are involved in the pathogenesis of disease having specific infiltrates and point to possible role in Chronic skin diseases. Depending upon the structure these chemokines are divided into three subfamilies, two major subfamilies: CXC and CC, and one putative subfamily C with only one member known as lymphotactin. A recent insight into chemokine physiology comes from demonstration of interaction between chemokines and their cloned receptors. These chemokine receptors are members of the transmembrane spanning (7-TMS), G-protein- coupled receptor family. So far CXC chemokine receptors and seven CC receptors have been cloned. Recently, the importance of selective chemoattractant activity of chemokines has been overshadowed by chemokine receptors emerging as new targets for anti-HIV therapy as the connection between chemokines and HIV-I had been established. Among the CXC chemokine receptors, CXCR4, and among the CC chemokines receptors, CCRI, CCR2b, CCR3, and CCR5 have been implicated as HIV-1 coreceptors. PMID- 20921791 TI - Knowledge, attitude, belief and practice (K.A.B.P) study on AIDS among senior secondary students. AB - A cross-sectional survey was done among students of four senior secondary schools including two boys and two girls schools of rural Delhi to know the knowledge, attitude, belief and practices regarding AIDS. A large majority (83.0%) of students though had heard about AIDS, yet majority of them did not know the possible methods for prevention of AIDS. There were only 27.1% girls who knew about regular condom usage. Half of them had permissible attitude for pre maritial sex, while sexual activity was observed in one-fourth students. Students were less reluctant to discuss about AIDS than sex, and teachers were preferred as compared to parents in this regard. School is an ideal setting to educate adolescents regarding HIV/AIDS transmission and safer sex behaviour. PMID- 20921792 TI - A study of dermatological disorders in geriatric age group. AB - A total of 320 patients of more than 60 years of age were studied for dermatological changes with aging. The male female ratio of patients was 3:1. Majority of cases (60.6%) were between 60-65 years of age. Pruritus was present in 37.5% cases, wrinkles in 82.1%, senile lentigenes in 57.8%, seborrhoeic keratosis in 48.8%, cherry angioma in 48.1%, idiopathic guttate hypomelanosis in 43%, skin tags in 37%, xerosis in 28%, comedones in 19%, infection and infestation in 40%, eczematous disorders in 36.9%, papulosquamous disorders in 10%, metabolic disorders in 16%, pigmentary disorders in 8.7%, keratinisation disorders in 4.1%, vesiculobullous disorders in 2.8% and associated systemic disorders in 49.7% cases. PMID- 20921793 TI - Heparin in psoriasis. AB - Ten patients with chronic stable psoriasis of more than three years duration were treated with injection heparin 2500 IU subcutaneously twice a day for 7 days. Six patients showed aggravation. Three showed no response and one patient improved and went into remission after 6 months. PMID- 20921794 TI - Trichomoniasis as sexually transmitted disease in sex partners. AB - Study of 30 male consorts of 30 cases of vaginal trichomoniasis with high levels of parasitic infection was undertaken to evaluate the sexually transmitted role of trichomoniasis in sex partners. There were 20 symptomatic and 10 asymptomatic male partners, who revealed T. vaginalis in 80.0% and 60.0 of the cases respectively and the overall prevalence was 73.3% (22 Of 30). T. vaginalis was detected in 83.3% male with urethritis and 50.0% males with prostatitis. Detection of trichomonas in urethral discharge, morning drop secretion, urine deposit and prostatic fluid was 80.0%, 50.0% 35.7% and 21.4% in that order. It is evident from these results that the sex consorts of all cases of trichomoniasis should be considered as harbouring T. vaginalis in their genito-urinary tract as carriers and be treated to break the chain of transmission. Fontanna smear was superior to culture and wet mount in the detection of T. vaginalis, the success rates being 73.3%, 63.3% and 53.3%. A good correlation was observed between smear and culture at high levels of parasitic infection. PMID- 20921795 TI - Trichomonas vaginalis - an indicator for other sexually transmitted infecting agents. AB - The present study is based on 350 women having sexually transmitted diseases and 68 men counterparts. Trichomonas vaginalis was a significant contributor in 216 (61.7%) out of 350 female SID cases' and in 56 (82.3%) out of 68 male counterparts. Further, out of 216 cases of T.vaginalis, 41 cases (32.5%) were associated with infection with Candida species; 29 (23%) with Neisseria gonorrhoea. 18 cases (14.3%) with Haemophilus ducreyi and 11 cases (8.7%), Chlamydia trachomatis. Treponema pallidum was observed in 8 cases (6.3%) which constituted a low percentage. Present study highlighted the importance of T. vaginalis by showing positivity in two-third cases which suggested that it can be an important indicator for other etiological STD agents in women. PMID- 20921796 TI - Relationship between lichen planus and hepatitis C virus. AB - The present study was conducted on 75 patients of lichen planus to observe the relationship of hepatitis C virus. Only 2 cases (2.66%) were positive for the hepatitis C virus antibody, which is almost parallel to the prevalence of hepatitis C virus in the general population in India (1.5 to 2.2%). PMID- 20921797 TI - Clinico-mycological profile of superficial mycoses. AB - Clinico-mycological study of 2743 clinically diagnosed cases of superficial mycoses attending skin and VD OPD of VSS Medical College during the year 1995 - 96 was conducted. Male predominance was observed. Highest incidence of tinea versicolor was found. T. rubrum was the commonest fungus isolated. PMID- 20921798 TI - Porokeratosis - report of three unsusual cases. AB - Three unusual cases of porokeratosis - linear, punctate and warty porokeratoses are reported with histopathological features. These three types are rarely seen in clinical practice. PMID- 20921799 TI - Lymphangioma circumscriptum of scrotum of late onset. AB - Lymphangioma circumscriptum is the commonest type of lymphangioma which is characterised by small, grouped vesicles resembling frog spawn. An interesting case of thin walled lymphangioma circumscriptum is reported which started at a late age of 45 years and limited to scrotum in a 70-year old man. PMID- 20921800 TI - Granuloma faciale. AB - A 40-year old woman presented with asymptomatic erythematous well-demarcated, infiltrated plaque of 8 cm x 7 cm in size on the right cheek for past four years. Histopathological study of skin biopsy revealed features of granuloma faciale. Oral dapsone and intralesional corticosteroid caused marked improvement. PMID- 20921801 TI - Fauntail naevus. AB - A case of fauntail naevus in a teenaged girl with radiological evidence of bifid vertebrae without any neurological, urological or orthopaedic complications is presented. PMID- 20921802 TI - Lichenoid epidermal naevus. AB - A case of lichenoid epidermal naevus with unusual clinical presentation is reported. PMID- 20921803 TI - Papulonecrotic tuberculid - relapse after treatment. AB - A 44-year old female suffered from boils on her elbows for the last 2 years. A diagnosis of papulonecrotic tuberculid was made based on clinical, laboratory parameters, histopathology and a prompt response to antituberculosis treatment. Ten months following the completion of multi-drug treatment her lesions relapsed. PMID- 20921804 TI - Linear focal elastosis. AB - A case of linear focal elastosis is reported. A 19-year old male presented with asymptomatic, palpable yellow lines over back along with striae distensae over axilla. Light microscopic examination demonstrated dermal thickening but no change in the epidermis. The elastic tissue stain revealed fragmented elastic fibres throughout the dermis. PMID- 20921805 TI - Eruptive mollusca contagiosa in an immunocompetent Indian adult. AB - A 35-year old Indian woman with eruptive onset of mollusca contagiosa with no underlying immunodeficiency who responded to etretinate therapy is reported. PMID- 20921806 TI - Papillon - lefevre syndrome with mental retardation. AB - A 9-year old boy, born of consanguineous parents, presented with keratoderma of palms and soles associated with severe enamel hypoplasia and mental retardation. A clinical diagnosis of Papillon - Lefevre was supported by histopathology. PMID- 20921807 TI - Generalized umbilicated granuloma annulare. AB - Generalised umbilicated granuloma annulare is reported in an elderly man. There was no association of diabetes or other systemic disease. PMID- 20921809 TI - Unstable vitiligo responding to methotrexate. PMID- 20921808 TI - Monomorphic cutaneous metastases with different primaries. AB - Telangiectatic type of secondary cutaneous metastases is described with primary malignancies in different organs in a female and in a male. The clinical and histopathological features of the secondary metastases are described along with the features of the primaries manifesting as adenocarcinoma of breast in the former and squamous cell carcinoma in the larynx in the latter. PMID- 20921810 TI - Shield as topical ointment in herpes zoster. PMID- 20921811 TI - Punch grafting in vitiligo. PMID- 20921813 TI - Effect of preoperative statin therapy on postoperative atrial fibrillation in cardiac surgery. PMID- 20921814 TI - Clinical characteristics of patients with kawasaki disease and levels of peripheral endothelial progenitor cells and blood monocyte subpopulations. AB - BACKGROUND: Coronary sequelae that persist after Kawasaki disease (KD) have been associated with coronary vascular events in adolescents and young adults. The aim of this study was to investigate the relationship between coronary sequelae late after KD and circulating endothelial progenitor cells (EPCs), as a marker of vascular repair, or monocyte subsets as a marker of inflammation. METHODS AND RESULTS: The 31 KD patients were divided into 3 groups according to the type of coronary artery lesion (CAL): group 1 consisted of 14 patients with persistent aneurysm; group 2 consisted of 9 patients with regressed aneurysms; group 3 included 8 KD patients with normal coronary arteries from disease onset. The control group (group 4) consisted of 10 healthy subjects. Flow cytometric analysis was used to quantify circulating EPCs defined as CD34(+)KDR(+) cells and 2 distinct monocyte subsets (CD14(+)CD16(+) and CD14(+)CD16(-)). The number of EPCs in group 1 and group 2 was significantly decreased compared with group 4. In contrast, neither the number of CD14(+)CD16(+) monocytes nor that of CD14(+)CD16( ) monocytes was significantly different among the 4 groups. Finally, there were not any significant relationship between the numbers of EPCs and the 2 monocyte subsets. CONCLUSIONS: There are lower numbers of EPCs in the chronic phase of KD, irrespective of both CAL formation and monocyte subsets. PMID- 20921815 TI - Tracking serum lipid levels and the association of cholesterol concentrations, blood pressure and cigarette smoking with carotid artery intima-media thickness in young adults born small for gestational age. AB - BACKGROUND: Small birth size is associated with increased cardiovascular disease risk, but the mediating factors are poorly understood. METHODS AND RESULTS: Serum lipids, blood pressure (BP), carotid artery intima-media thickness (CA-IMT), and brachial artery flow-mediated dilatation (BA-FMD) were studied in 70 20-year-old subjects [35 sex- and age-matched pairs born small (SGA) and appropriate for gestational age (AGA)]. The SGA subjects had higher serum levels of low-density lipoprotein (LDL) cholesterol, total/high-density lipoprotein (HDL) and LDL/HDL cholesterol ratios, and lower HDL cholesterol levels than the AGA subjects (2.71 vs 2.37 mmol/L, P<0.05; 3.12 vs 2.80, P<0.01; 1.98 vs 1.61, P=0.002; 1.43 vs 1.56 mmol/L, P<0.05, respectively). In the SGA group, total and LDL cholesterol levels correlated inversely with adult height SD score (r=0.463, P=0.006 and r=0.413, P=0.015, respectively). CA-IMT or BA-FMD did not differ between the groups, but cigarette smoking, higher diastolic BP, and shorter birth length associated with higher CA-IMT in the whole study population. A clear tracking of cholesterol levels was found from 12 to 20 years. CONCLUSIONS: SGA subjects had more unfavorable lipid profiles than the controls, the shortest having the highest LDL cholesterol. Cigarette smoking, higher diastolic BP, and shorter birth length associated with higher CA-IMT in the whole study population. A clear tracking of cholesterol levels through adolescence enables early targeting of lifestyle counseling for reducing cardiovascular disease risk. PMID- 20921816 TI - Preoperative indexed left ventricular dimensions to predict early recovery of left ventricular function after aortic valve replacement for chronic aortic regurgitation. AB - BACKGROUND: Aortic valve replacement (AVR) improves left ventricular (LV) systolic function in patients with chronic aortic regurgitation (AR). The objective of this study is to determine predictors for normalization of impaired LV systolic function after valve replacement for chronic AR. METHODS AND RESULTS: Between 1997 and 2007, 171 patients underwent AVR for severe chronic AR. Of these patients, 79 patients with LV systolic dysfunction or severe LV dilatation preoperatively, who were evaluated by echocardiography at predischarge and early follow up (mean, 6 months) were examined. The mean preoperative ejection fraction was 49%. The mean LV end-systolic and end-diastolic dimensions were 52.32 +/- 8.35 mm and 69.59 +/- 7.80 mm, respectively. In the early follow up, 62 of 79 patients exhibited restored normal LV function. LV end-systolic dimension and LV end-diastolic dimension were significantly decreased early after AVR (52.32 +/- 8.35 mm vs 37.82 +/- 6.88 mm, and 69.59 +/- 7.80 mm vs 51.55 +/- 6.40 mm, respectively). Operative mortality was 3.7%. Multivariate stepwise regression analysis revealed that preoperative indexed LV end-systolic and end-diastolic dimensions were independent predictors of restored LV systolic function. The sensitivity and specificity in predicting normalization of LV function were 88% and 92% for indexed LVESD <35.32 mm/m(2) and 71% and 86% for indexed LVEDD <44.42 mm/m(2). CONCLUSIONS: In patients who received a valve replacement for chronic AR, smaller indexed LV systolic and diastolic dimensions were associated with early restoration of LV systolic function. PMID- 20921817 TI - Plasma cystatin C concentration reflects the severity of coronary artery disease in patients without chronic kidney disease. AB - BACKGROUND: This study examines whether the serum concentration of cystatin C (Cys C) correlates with the severity of coronary artery disease (CAD) and whether it provides additional information on the risk for CAD in patients without chronic kidney disease (CKD) estimated by the creatinine-based glomerular filtration rate (GFR). METHODS AND RESULTS: The relationship between serum Cys C and the severity of CAD in 526 patients was investigated. Based on GFR, patients were divided into those with and without CKD. The relationship of serum Cys C with the severity of CAD was examined. Serum Cys C was closely correlated with GFR in all cases and in CKD patients, but not in non-CKD patients. The average number of stenotic coronary arteries was significantly higher in the quartiles of higher concentration of Cys C as well as in those of GFR. In 348 patients (66%) the GFR was >=60 ml . min(-1).1.73 m(-2). Those patients with increased Cys C (>0.90 mg/L, 143 patients) had a significantly larger number of stenotic coronary arteries than those patients with normal Cys C. CONCLUSIONS: Among patients considered to be at low risk based on the estimated GFR using serum creatinine, those with high concentrations of Cys C could have severe CAD. Besides CKD, Cys C might serve as a marker of CAD severity. PMID- 20921818 TI - Cardiac abnormalities in primary hyperoxaluria. AB - BACKGROUND: In patients with primary hyperoxaluria (PH), oxalate overproduction can result in recurrent urolithiasis and nephrocalcinosis, which in some cases results in a progressive decline in renal function, oxalate retention, and systemic oxalosis involving bone, retina, arterial media, peripheral nerves, skin, and heart. Oxalosis involving the myocardium or conduction system can potentially lead to heart failure and fatal arrhythmias. METHODS AND RESULTS: A retrospective review of our institution's database was conducted for all patients with a confirmed diagnosis of PH between 1/1948 and 1/2006 (n=103). Electrocardiogram (ECG) and echocardiography were used to identify cardiac abnormalities. Ninety-three patients fulfilled the inclusion criteria, 58% were male. Mean follow-up was 11.9 (median 8.8) years. In 38 patients who received an ECG or echocardiography, 31 were found to have any cardiac abnormalities. Cardiac findings correlated with decline in renal function. CONCLUSIONS: Our data suggests that physicians caring for patients with PH should pay close attention to cardiac status, especially if renal function is impaired. PMID- 20921819 TI - Activation of dopamine D4 receptors is protective against hypoxia/reoxygenation induced cell death in HT22 cells. AB - Several reports have shown that some dopamine receptor ligands modulate the ischemia-reperfusion injury in animal models; however, its underling mechanisms are still unclear. In this study, we sought to establish an in vitro experimental model of hypoxia/reoxygenation (H/R) using HT22 cells that originated from mouse hippocampal neurons and to examine protective the effect of dopamine-receptor ligands against H/R-induced cell injury. The treatment with hypoxia for 18 h followed by reoxygenation for 6 h induced the elevation of intracellular reactive oxygen species (ROS) and reduction of mitochondrial membrane potential; however, lactate dehydrogenase (LDH) release was not changed at this time point. LDH release was increased after reoxygenation for 18 h and longer, and this increase in LDH release was suppressed by dopamine receptor agonists such as apomorphine and apocodeine. The suppressive effects of these agonists were reversibly inhibited by L750667, a D(4)-receptor antagonist but not by D(2)- or D(3) receptor antagonists. In addition, PD168077, a selective dopamine D(4)-receptor agonist, also protected against H/R-induced cell death. These results suggest that H/R causes oxidative stress-induced cell death and that the activation of dopamine D(4) receptors protects against H/R-induced cell death in HT22 cells. PMID- 20921820 TI - Vascular homeostasis regulators, Edn1 and Agpt2, are upregulated as a protective effect of heat-treated zinc yeast in irradiated murine bone marrow. AB - PURPOSE: To elucidate the mechanism underlying the in vivo radioprotection activity by Zn-containing, heat-treated Saccharomyces cerevisiae yeast (Zn yeast). MATERIALS AND METHODS: Zn-yeast suspension was administered into C3H/He mice immediately after whole body irradiation (WBI) at 7.5 Gy. Bone marrow was extracted from the mice 6 hours after irradiation and analyzed on a microarray. Expression changes in the candidate responsive genes differentially expressed in treated mice were re-examined by qRT-PCR. The bone marrow was also examined pathologically at 6 h, 3, 7, and 14 days postirradiation. RESULTS: Thirty-six genes, including Edn1 and Agpt2, were identified as candidate responsive genes in irradiated mouse bone marrow treated with Zn-yeast by showing a greater than three-fold change compared with control (no irradiation and no Zn-yeast) mice. The expressions of Cdkn1a, Bax, and Ccng, which are well known as radioresponsive genes, were upregulated in WBI mice and Zn-yeast treated WBI mice. Pathological examination showed the newly formed microvessels lined with endothelial cells, and small round hematopoietic cells around vessels in bone marrow matrix of mice administered with Zn-yeast after WBI, while whole-body irradiated mice developed fatty bone marrow within 2 weeks after irradiation. CONCLUSION: This study identified a possible mechanism for the postirradiation protection conferred by Zn-yeast. The protective effect of Zn-yeast against WBI is related to maintaining the bone marrow microenvironment, including targeting endothelial cells and cytokine release. PMID- 20921821 TI - Protective effect of atorvastatin on radiation-induced vascular endothelial cell injury in vitro. AB - Vascular endothelial cells are very sensitive to ionizing radiation, and it is important to develop effective prevent agents and measures in radiation exposure protection. In the present study, the protective effects of atorvastatin on irradiated human umbilical vein endothelial cells (HUVEC) and the possible mechanisms were explored. Cultured HUVEC were treated by atorvastatin at a final concentration of 10 u mol/ml for 10 minutes, and then irradiated at a dose of 2 Gy or 25 Gy. Twenty-four hours after irradiation, apoptosis of HUVEC was monitored by flow cytometry, and the expression of thrombomodulin (TM) and protein C activation in HUVEC was respectively assessed by flow cytometry and spectrophotometry. After treatment with atorvastatin for 24 h, the rate of cell apoptosis decreased by 6% and 16% in cells irradiated with 2 Gy and 25 Gy, respectively. TM expression increased by 77%, 59%, and 61% in untreated cells, 2 Gy irradiation-treated cells, and 25 Gy irradiation-treated cells, respectively. The protein C levels in 2 Gy and 25 Gy irradiation-treated cells were reduced by 23% and 34% when compared with untreated cells, but up-regulated by 79% and 76% when compared with cells which were irradiated and treated with atorvastatin. In conclusion, these data indicate that atorvastatin exerts protective effects on irradiated HUVEC by reducing apoptosis by up-regulating TM expression and enhancing protein C activation in irradiated HUVEC. PMID- 20921822 TI - Evaluation of the dosimetric parameters for 125I brachytherapy determined in prostate medium using CT images. AB - In the present study, the prostate medium determined from the CT images of 149 patients was developed. The dosimetric parameters such as Lambda, g(L)(r) and F(r, theta) used in TG-43U1-based calculation for an iodine-125 ((125)I) brachytherapy-source were examined using Monte Carlo code Geant4. Clinical dosimetry parameters such as the D(90) were evaluated among a subgroup of 50 randomly selected patients who had been treated with permanent brachytherapy between January 2008 and December 2008 at the Tokyo Medical Center. The results show a slight difference in the dose rate constant Lambda (within 1.0%). The radial dose function g(L)(r) exhibits a prominent difference in the region over 3 cm, and this difference is maintained within 2.9% in the region close to the source. The calculated values of F(r, theta) for the prostate medium were similar to values for water (within 1%), except in the longitudinal axis. A comparison of D(90) values shows a systematic dose overestimation of 2.8 +/- 0.7 Gy in water, where the distribution of the differences can be seen with a spread of 1.8 +/- 0.3% compared to that in prostate medium. It was concluded that the introduction of any kind of tissue correction for the TG-43U1-based calculation was not necessary to allow for the differences in elemental compositions and densities between water and prostate medium. PACS number: 87.00.00; 87.55.dk; 87.55.K-; 87.56.B-. PMID- 20921823 TI - Quantitative structure activity relationship modeling for predicting radiosensitization effectiveness of nitroimidazole compounds. AB - This paper provides quantitative structure activity relationship (QSAR) models for predicting the radiosensitization effectiveness of nitroimidazole compounds. A new method, combining a heuristic method and projection pursuit regression, was used to build an advanced QSAR model. Compared to the conventional multi-linear regression model, this model showed better predictive ability and reliability, with the values of regression coefficient (R(2)) and root mean square error (RMSE) 0.92 and 0.18 for the training set and 0.90 and 0.17 for the test set, respectively. The provided models were useful tools to predict the radiosensitization effectiveness of nitroimidazole compounds. Also, the new finding descriptors derived from this study will help us to facilitate the design of new radiation sensitizers with better activities. PMID- 20921824 TI - Effect of hBD2 genetically modified dermal multipotent stem cells on repair of infected irradiated wounds. AB - Deficiencies in repair cells and infection are two of the main factors that can hinder the process of wound healing. In the present study, we investigated the ability of human beta-defensin-2 (hBD2) genetically modified dermal multipotent stem cells (dMSCs) to accelerate the healing irradiated wounds complicated by infections. An hBD2 adenovirus expression vector (Adv-hBD2) was firstly constructed and used to infect dMSCs. The antibacterial activity of the supernatant was determined by Kirby-Bauer method and macrodilution broth assay. Time to complete wound healing, residual percentage of wound area, and the number of bacteria under the scar were measured to assess the effects of Adv-hBD2 infected dMSC transplantation on the healing of irradiated wounds complicated by Pseudomonas aeruginosa infection. Results showed that the supernatant from Adv hBD2-infected dMSCs had obvious antibacterial effects. Transplantation of Adv hBD2-infected dMSCs killed bacteria in the wound. The complete wound healing time was 19.8 +/- 0.45 days, which was significantly shorter than in the control groups (P < 0.05). From 14 days after transplantation, the residual wound area was smaller in the experimental group than in the control groups (P < 0.05). In conclusion, we found that transplantation of hBD2 genetically modified dMSCs accelerated the healing of wounds complicated by P. aeruginosa infection in whole body irradiated rats. PMID- 20921825 TI - Dosimetric comparison of three-dimensional conformal radiotherapy in salvage radiotherapy for PSA relapse after radical prostatectomy. AB - The purpose of this study is to compare three-dimensional conformal radiotherapy (3D-CRT) plans in a setting of salvage radiotherapy after radical prostatectomy (RP) and to simulate whether dose escalation is possible with the most adequate 3D-CRT technique. This study included consecutive 10 patients underwent salvage radiotherapy (RT) for biochemical relapse of prostate cancer after RP. Normal structures included the rectum, bladder, and femoral head. For each patient, four different treatment plans including four fields RT (4F-RT), dynamic conformal arc radiotherapy (DCAT), six fields RT (6F-RT), and DCAT with rectum hollow-out technique (DCAT-HO), were created to entire the prostate bed. The parameters of the maximum and mean doses received by organs at risk (OAR), target coverage, dose homogeneity for the planning target volume (PTV) were compared. All plans were considered to be clinically tolerable for PTV coverage and dose homogeneity. The rectum sparing at the high dose area for DCAT-HO was considered to be the most superior to those for other three techniques by comparison of the dose delivered to a 1%, 5%, and 10% volume of the rectum. In the simulation of dose escalation to 70 Gy with DCAT-HO, OAR met a requirement of the dose-volume constraints. However, in the simulation of dose escalation to 72 Gy, the rectum that receives 60 to 65 Gy and bladder that receives 65 Gy exceeded the optimal dose-volume constraints. DCAT-HO was considered to be one of the most appropriate techniques in 3D-CRT if dose escalation to 70 Gy might be needed in a setting of salvage RT after RP in the future. PMID- 20921826 TI - Influence of histological subtype on survival after combined therapy of surgery and radiation in WHO grade 3 glioma. AB - World Health Organization (WHO) grade 3 glioma is one of the common brain tumors and has three main histological subtypes, including anaplastic astrocytoma (AA), anaplastic oligoastrocytoma (AOA) and anaplastic oligodendroglioma (AO). However, most previous studies have considered AOA and AO as one group because of the difficult differential diagnosis between AOA and AO. Therefore the prognostic difference among patients with these histological subtypes has been unclear. In this study, 68 patients with histologically proven WHO grade 3 glioma, consecutively received postoperative radiotherapy at the Gunma University Hospital, Japan, between 1983 and 2005, were investigated to assess the impact of histological subtype on the survival. The number of AA, AOA and AO patients was 41, 16 and 11, respectively. The mean and median follow-up periods were 72 and 48 months, respectively. The number of patients treated with gross total resection, partial resection and biopsy was 14, 38 and 16, respectively. The mean and median radiation doses were 58 +/- 5 Gy and 60 Gy, respectively. The 5-year overall survival rates of AA, AOA and AO were 21%, 38% and 80%, and median survival period were 16 months, 58 months and not reached, respectively. Univariate analysis showed that the histological subtype (P < 0.01) and extent of surgery (P < 0.01) were significant prognostic factors for survival. Selective comparison showed that overall survival of patients with AA was significantly worse than for those with AOA (P = 0.01) and AO (P < 0.01). The overall survival of patients with AO was better than for those with AOA; however, the difference was not statistically significant (P = 0.14). Multivariate analysis demonstrated that histological subtype, age and extent of surgery were the significant independent variable for survival (P < 0.01, P < 0.01 and P = 0.04). In our study, histological subtype was one of the most important prognostic factors of WHO grade 3 glioma. PMID- 20921827 TI - Therapeutic effects of recombinant human epidermal growth factor (rhEGF) in a murine model of concurrent chemo- and radiotherapy-induced oral mucositis. AB - Concurrent chemotherapy with radiotherapy (CCRT) has been applied for the treatment of advanced stage of head and neck cancer patients. However CCRT is associated with several complications including mucositis, dermatitis, stomatitis, etc. This study was conducted to evaluate the therapeutic effect of systemically administrated recombinant human epidermal growth factor (rhEGF) in CCRT-induced oral mucositis in a mouse model. Oral mucositis was induced in male BALB/c mice through combination treatment with cisplatin (11 mg/kg, i.p.) and irradiation (17 Gy) of the head and neck area. rhEGF (1.0 mg/kg/day for consecutive 3 days) was administered systemically, and the therapeutic effect was determined by histological evaluation of the oral mucosa. To elucidate optimal dose of rhEGF on CCRT-induced mucositis, various concentrations (0.04-3 mg/kg) of rhEGF were injected for 3 days. Systemic rhEGF administration accelerated the recovery of body weight. Histologically, rhEGF-treated mice showed significantly increased epithelial cell layer thickness, basal cell number, and expression of Ki-67 compared to control mice. Most effective dose was 1 mg/kg among other doses tested. Systemic administration of 1 mg/kg of rhEGF reduces the severity of oral mucositis induced by CCRT in a mouse model, suggesting that rhEGF can be used for treating CCRT-induced mucositis during the cancer treatment. PMID- 20921828 TI - A Study on the effects of 50 Hz magnetic fields on UV-induced radical reactions in murine fibroblasts. AB - The aim of this study was to test the hypothesis that the "radical pair mechanism" (magnetic field effect on recombination rate of radical pairs) explains our previous findings indicating that 50 Hz magnetic fields (MF) of about 100 uT modify biological responses to ultraviolet (UV) radiation. In the present study, the effects of 50 Hz MF on cellular oxidative processes induced by UV radiation were investigated. Murine L929 fibroblast cells were exposed to 50 Hz MF of 100 or 300 uT during a 1-h UV exposure or for 24 h before it. The decay kinetics of oxidative reactions were analysed by measuring ultraweak chemiluminescence (photon emissions) of the exposed cells by scintillation counter in the out-of-coincidence mode. No significant MF effects were found. The results do not support the hypothesis that 100-300 uT MF modify biological responses to UV radiation by causing an overall change in oxidative reactions at cellular level. PMID- 20921829 TI - G0 and G2 chromosomal assays in the evaluation of radiosensitivity in a cohort of Italian breast cancer patients. AB - Breast cancer (BC) is the most common type of malignancy in female patients and radio-treatment is the conventional therapy even if a great number of studies reported that enhanced sensitivity to ionizing radiation as measured as chromosome effects is present in a significant proportion of cancer patients, including breast cancer ones. In this study we analysed whether peripheral blood lymphocytes from sporadic BC patients and healthy subjects showed a different sensitivity to ionizing radiation and whether cytogenetic radiosensitivity may serve as a breast cancer risk biomarker. To test this hypothesis, the in vitro radiation sensitivity was measured by using both G(0) and G(2) chromosome radiosensitivity assays, on 46 subjects (23 BC patients and 23 healthy subjects). Results show that cancer patients are more radiosensitive than healthy controls and that G(2) assay could be more appropriate to define the individual radiosensitivity if compared to G(0) assay. PMID- 20921830 TI - A novel method of boron delivery using sodium iodide symporter for boron neutron capture therapy. AB - Boron Neutron Capture Therapy (BNCT) effectiveness depends on the preferential sequestration of boron in cancer cells relative to normal tissue cells. We present a novel strategy for sequestering boron using an adenovirus expressing the sodium iodide symporter (NIS). Human glioma grown subcutaneously in athymic mice and orthotopic rat brain tumors were transfected with NIS using a direct tumor injection of adenovirus. Boron bound as sodium tetrafluoroborate (NaBF(4)) was administered systemically several days after transfection. Tumors were excised hours later and assessed for boron concentration using inductively coupled plasma atomic emission spectroscopy. In the human glioma transfected with NIS, boron concentration was more than 10 fold higher with 100 mg/kg of NaBF(4), compared to tumor not transfected. In the orthotopic tumor model, the presence of NIS conferred almost 4 times the boron concentration in rat tumors transfected with human virus compared with contralateral normal brain not transfected. We conclude that adenovirus expressing NIS has the potential to be used as a novel boron delivery agent and should be explored for future clinical applications. PMID- 20921831 TI - Revisiting anatomic landmarks: lateral popliteal approach for sciatic nerve block based on magnetic resonance imaging. AB - BACKGROUND AND OBJECTIVES: When the conventional lateral popliteal sciatic nerve (SN) block is performed, the needle angle required to localize and the level of the SN bifurcation are highly variable. The aim of our magnetic resonance imaging (MRI) study was to determine the most common range of needle-insertion angles and the relationship between skin-to-femur distance and angle. We also evaluated the variability of the SN bifurcation level and the relationship between patient height and nerve bifurcation level. METHODS: Using 289 thigh MRIs to simulate a lateral approach in the supine position, we measured and analyzed with simple linear regressions the level of SN bifurcation, the skin-to-femur and SN-to-femur distances, and the angle at which the needle must be directed posteriorly to intersect the SN at 9 cm proximal to the lateral joint line. RESULTS: The mean insertion angle was 30 (SD, 8) degrees. In 95% of cases, angles ranged from 15 to 45 degrees, and the larger the thigh, the smaller the angle. The SN divided at a mean distance of 7.5 (SD, 1.6) cm (range, 1.5-12.8 cm) proximal to the lateral joint line. In 93% of cases, the bifurcation level was 10 cm or less. CONCLUSIONS: Our simulated lateral popliteal SN block on MRIs shows a 15- to 45 degree range of needle-insertion angles. As the skin-to-femur distance was greater than 4.5 cm, the angles were progressively smaller than 30 degrees. Although this was an MRI study, it does provide some evidence that indicates the conventional clinically recommended 25- to 30-degree-angle ranges may need to be reevaluated. Needle insertion of 10 cm or greater proximal to the popliteal crease may increase the chance of placement at or proximal to the SN bifurcation. PMID- 20921832 TI - Intrathecal infusion of pyrrolidine dithiocarbamate for the prevention and reversal of neuropathic pain in rats using a sciatic chronic constriction injury model. AB - BACKGROUND AND OBJECTIVES: Recent studies have suggested that nuclear factor kappaB (NF-kappaB) may play a role in mediating nerve injury-induced neuropathic pain. Here, we examined the effects of intrathecal pyrrolidine dithiocarbamate (PDTC), a NF-kappaB inhibitor, on the development of neuropathic pain, spinal microglial activation, and CX3CR1 expression induced by sciatic chronic constriction injury (CCI) model in rats. METHODS: Under chloral hydrate anesthesia, male Sprague-Dawley rats (300-350 g) fitted with intrathecal catheters underwent either sciatic CCI or sham surgery. Intrathecal saline or PDTC (100 or 1000 pmol/d) was infused 1 day before or 3 days after CCI (n = 8). The rat hind-paw withdrawal threshold to mechanical stimuli and withdrawal latency to radiant heat were determined before surgery and from days 1 to 7 after CCI. Spinal microglial activation was evaluated with OX-42 immunoreactivity, and spinal CX3CR1 expression was assessed by Western blotting. RESULTS: Chronic constriction injury induced mechanical allodynia and thermal hyperalgesia and microglial activation as demonstrated by OX-42 expression. Whereas it had no apparent effect on spinal cord histology, intrathecal administration of PDTC prevented the development of the mechanical and thermal hyperalgesia and inhibited nerve injury-induced microglial activation and spinal CX3CR1 expression. CONCLUSIONS: In this study, we have shown the protective effect of intrathecal PDTC on the development of nociceptive behaviors induced by CCI in rats. The activation of NF-kappaB pathway may contribute to spinal microglial activation and CX3CR1 up-regulation. PMID- 20921833 TI - A macromolecular tracer indicates that the spinal epidural space connects directly to the venous circulation in pigs. AB - BACKGROUND AND OBJECTIVES: Air injected into the epidural space of the spine reaches the heart within 15 secs, suggesting easy access to the bloodstream. We wished to quantify the washout of a macromolecular tracer (albumin labeled with Evans blue) from the thoracic epidural space. METHODS: Eleven juvenile pigs were anesthetized with isoflurane and positioned on their sides. We injected a bolus of the tracer into the thoracic epidural space followed by serial saline infusions (total, 50-70 mL). We measured plasma concentrations of the tracer during washout. Finally, we injected Microfil (a liquid rubber compound that hardens on standing) into the epidural space and later inspected with a dissecting microscope the nerve roots and veins draining the spine. RESULTS: More than half (60% +/- 12%; range, 31%-79%) of the tracer injected in the epidural space was detected in the bloodstream. Microfil was detected in the veins draining the cervical or high thoracic spine, but never in veins draining the lumbar spine or sacrum. CONCLUSIONS: Because the macromolecular tracer cannot enter the bloodstream by absorption, these results indicate that pathways capable of handling bulk flow connect the spinal epidural space to the venous circulation. These pathways are located in the cervical and high thoracic spine of the pig. PMID- 20921834 TI - Does "opening the perineural space" before stimulating catheter placement for continuous nerve block add value in clinical practice? AB - INTRODUCTION: A study using unblinded block performance and subjective outcome measurements suggested that "opening the space" surrounding the femoral nerve with 10 mL dextrose 5% in water (D5W) before catheter placement facilitated placement and improved the quality of the nerve block. We conducted a double blind, prospectively randomized study to evaluate this suggestion by adding objective measurements to the original subjective measurements. METHODS: A Tuohy needle was directed toward the femoral nerve under ultrasound and nerve stimulator guidance. A quadriceps femoris motor response was identified by cephalad patellar movements with a maximum nerve stimulator output of 0.5 mA. The primary anesthesiologist either injected D5W or made no injection through the needle, depending on patient randomization. A second anesthesiologist, unaware of randomization, placed the stimulating perineural catheter. The primary measurement was the procedure time (in seconds) for threading the catheter. Additional measurements included total nerve block time (in minutes), number of attempts passing the catheter, subjective ease of placement by the second anesthesiologist, depth of needle and catheter, minimum stimulating current through needle and catheter, and the quality of the nerve block. RESULTS: Two groups of 35 patients were enrolled. Statistically significant differences were found in the median (5th-95th confidence intervals) catheter threading time (21.0 [9.6-118] and 33.0 [13.4-193] secs in the control and D5W groups, respectively; P = 0.03). Significant difference was also found in the number of attempts at passing the catheter (1 [1-2] and 2 [1-4] in the control and D5W groups, respectively; P = 0.03). CONCLUSIONS: The findings of this study do not support the concept that opening the space surrounding the femoral nerve with D5W before femoral catheter placement adds value to perineural catheter placement. PMID- 20921835 TI - Intravenous lidocaine reduces ischemic pain in healthy volunteers. AB - BACKGROUND AND OBJECTIVES: Lidocaine, a local anesthetic and antiarrhythmic drug that alters depolarization in neurons by blocking the fast voltage-gated sodium (Na+) channels in the cell membrane, is used for regional anesthesia, as antiarrhythmic drug, and as analgesic for various painful conditions. It is unclear whether monotherapy with intravenous lidocaine has an analgesic effect in healthy individuals. To address this important question, we studied pain perception before, during, and after the administration of intravenous lidocaine in 16 human volunteers. Our hypothesis was that lidocaine, administered as a short intravenous infusion, does not have an analgesic effect in healthy volunteers. METHODS: Sixteen healthy human volunteers received systemic lidocaine at plasma concentration 2 mg/mL using a computer-assisted infusion. Participants underwent a series of sensory tests-thermal, electrical, and ischemic pain and normal pinprick sensation-at baseline, during, and 30 mins after administration of a 20-min lidocaine infusion at a 2 mg/mL effect site concentration. RESULTS: We found a sustained decrease in ischemic pain ratings and a limited analgesic effect for electrical pain, whereas thermal pain and normal sensation did not change. CONCLUSIONS: The observed sustained analgesic effect of systemic lidocaine in the ischemic pain model suggests that lidocaine may be used to treat acute pain. PMID- 20921836 TI - A double-blind, controlled, randomized trial to evaluate the efficacy of botulinum toxin for the treatment of lumbar myofascial pain in humans. AB - BACKGROUND: Among all the causes of chronic low back pain, myofascial pain syndrome of the spinal stabilizer muscles is one of the most frequent, yet underconsidered sources of pain. The purpose of this prospective, randomized, double-blind, controlled trial was to evaluate the efficacy of type-A botulinum toxin (BTX-A) in relieving myofascial pain in patients experiencing mechanical low back pain due to bilateral myofascial pain syndrome involving the iliopsoas and/or the quadratus lumborum muscles. METHODS: Each of the 27 enrolled patients received a bilateral, fluoroscopically guided injection in the affected muscle(s) to randomly deliver BTX-A in one side of the low back and a control drug (randomly constituted by NaCl 0.9% or bupivacaine 0.25%) in the opposite side. To evaluate the effects of treatment on daily life activities and psychologic status, 5 different questionnaires were administered (Hospital Anxiety and Depression scale [HAD-A and HAD-D], Lattinen, Oswestry, and Spielberger State Trait Anxiety Index). RESULTS: BTX-A injection did not significantly reduce visual analog scale scores more than treatment with NaCl or bupivacaine in the contralateral side; furthermore, the treatments administered did not result in a significant improvement of patients' daily life activities or psychologic status. Although a trend toward a decrease in postintervention visual analog scale scores could be recognized in all low back sides, this trend was significant only in the sides treated with BTX-A. CONCLUSIONS: BTX-A seems to provide significant postintervention pain relief. However, considering its high cost and the small differences compared with control treatments, its use should be reserved only for patients with pain refractory to other invasive treatments. PMID- 20921837 TI - Evaluation of the addition of bupivacaine to intrathecal morphine and fentanyl for postoperative pain management in laparascopic liver resection. AB - BACKGROUND: Optimal modality of pain management after liver resection has been controversial. Epidural analgesia is often avoided because of transient coagulopathy and the associated risk of epidural hematoma. Single-dose intrathecal morphine has been shown to be an effective alternative in open liver resection. The purpose of this trial was to compare the analgesic efficacy of intrathecal morphine and fentanyl versus intrathecal bupivacaine 0.5%, morphine, and fentanyl for patients undergoing laparoscopic liver resection. METHODS: This prospective randomized controlled double-blind trial compared morphine consumption between control (CTRL) group receiving a spinal injection of fentanyl 15 MUg and morphine 0.4 mg and bupivacaine (BUPI) group receiving the same medications in addition to bupivacaine 0.5% (15 mg). Forty patients scheduled for laparoscopic liver resection were enrolled. Primary outcome was intravenous patient-controlled analgesia morphine consumption measured at 6, 9, 12, 18, 24, 36, and 48 hrs after spinal injection. Secondary outcomes were pain scores at rest and with movement, sedation, nausea, pruritus, and respiratory rate. RESULTS: Cumulative doses of morphine were significantly lower for all time intervals in the BUPI group: 54 (30) versus 94 (47) mg (P = 0.01) at 48 hrs. Morphine consumption was significantly lower for each time interval up to 18 hrs. Pain scores with movement were significantly lower in the BUPI group up to 24 hrs after injection. Pain score at rest was significantly lower in the BUPI group 9 hrs after injection. There were no differences in adverse effects. CONCLUSIONS: The addition of bupivacaine to intrathecal morphine and fentanyl significantly reduced intravenous morphine consumption after laparoscopic liver resection. PMID- 20921838 TI - Ultrasound-guided popliteal block distal to sciatic nerve bifurcation shortens onset time: a prospective randomized double-blind study. AB - BACKGROUND AND OBJECTIVES: Popliteal sciatic nerve block (SNB) in combination with saphenous nerve block provides anesthesia and analgesia for foot and ankle surgeries. Landmark-based and image-guided techniques, to date, aim at blocking the sciatic nerve proximal to its bifurcation. Sciatic nerve block is usually associated with a long onset time (30-60 mins). We hypothesized that SNB distal to its bifurcation (blocking its 2 main branches tibial and common peroneal nerves separately) is associated with a shorter onset time than blockade proximal to its bifurcation. METHODS: Fifty patients scheduled for major elective foot or ankle surgery were randomly allocated to receive ultrasound-guided SNB 5 cm proximal to (group P) or 3 cm distal to (group D) its bifurcation in the popliteal fossa. Thirty milliliters of a standardized local anesthetic solution of equal volumes of 2% lidocaine and 0.5% bupivacaine with 1:200,000 epinephrine was used. Sensory and motor assessments were performed every 5 mins by a blinded observer until complete sensory and motor blockade developed in both tibial and common peroneal nerve territories. RESULTS: All patients in both groups developed a complete block. Patients in group D presented a 30% shorter onset of both sensory (21.4 [SD, 9.9] vs 31.4 [SD, 13.9] mins) (P = 0.005) and motor block (21.5 [SD, 11.3] vs 32.4 [SD, 14.9] mins) (P = 0.006) than patients in group P. Procedure time, procedure-related discomfort, and patient satisfaction were similar in both groups. CONCLUSIONS: Our data suggest that popliteal SNB distal to the bifurcation has a shorter onset time than SNB proximal to its bifurcation, and therefore, it may be a good option when a fast onset for a surgical block is required. PMID- 20921839 TI - Clinical sonopathology for the regional anesthesiologist: part 1: vascular and neural. AB - The use of ultrasound to facilitate regional anesthesia is an evolving area of clinical, education, and research interests. As our community's experience grows, it has become evident that anesthesiologists performing "routine" ultrasound guided blocks may very well be confronted with atypical or even pathologic anatomy. As an educational resource for anesthesiologists, the following articles present examples of common sonopathology that may be encountered during ultrasound-guided regional anesthesia. This present article describes sonopathology related to blood vessels and nerves. PMID- 20921840 TI - Clinical sonopathology for the regional anesthesiologist: part 2: bone, viscera, subcutaneous tissue, and foreign bodies. AB - The use of ultrasound to facilitate regional anesthesia is an evolving area of clinical, education, and research interests. As our community's experience grows, it has become evident that anesthesiologists performing "routine" ultrasound guided blocks may very well be confronted with atypical or even pathologic anatomy. As an educational resource for anesthesiologists, the following articles present examples of common sonopathology that may be encountered during ultrasound-guided regional anesthesia. This present article describes sonopathology related to bone, viscera, and subcutaneous tissue. PMID- 20921841 TI - A low-cost ultrasound phantom of the lumbosacral spine. AB - BACKGROUND AND OBJECTIVES: This report describes the production of a low-cost ultrasound phantom of the lumbosacral spine. The phantom should be a very useful tool to teach the basic skills for ultrasound-guided procedures of the lumbosacral spine. METHODS: A lumbosacral spine model is secured to the bottom of a microwave-safe container and is immersed in a concentrated gelatin solution. After the gelatin hardens, the model can be used for scanning practice as well as needle placement. The phantom can be recovered after use by melting the gelatin in a microwave to "erase" any needle track marks. RESULTS: A transparent and durable gelatin block is produced. This allows trainees to have direct visual access to the lumbosacral spine model to correlate with the ultrasound images as well as to confirm proper needle placement. Disadvantages of the model include lack of simulated soft tissue structures and an absence of simulated haptic feedback during needle placement. Metamucil can be added to the gelatin to simulate the appearance of soft tissue, although this increases the opacity and thus decreases the visual access of the gelatin. CONCLUSIONS: This teaching tool can provide trainees with an opportunity to familiarize themselves with sonoanatomy of the lumbosacral spine in addition to practicing probe handling techniques and needle placement. PMID- 20921851 TI - Optimal surgical staging in early stage epithelial ovarian cancer: a sorry state. PMID- 20921842 TI - Duloxetine: a review of its pharmacology and use in chronic pain management. AB - Duloxetine is a serotonin and norepinephrine reuptake inhibitor that possesses antidepressant and pain-relieving properties. Compared with other antidepressants, it has a high affinity for both norepinephrine and serotonin reuptake transporters, which are relatively balanced. Analgesic onset has been observed within the first week of administration in randomized controlled trials and is likely obtained by enhancing the tone of the descending pain inhibition pathways of the central nervous system. Randomized trials have documented significant analgesic effects for managing chronic pain associated with fibromyalgia and diabetic peripheral neuropathic pain. Studies have also suggested that pain associated with major depressive disorder can be reduced with this medication. Modest effects for headache, osteoarthritic pain, and pain secondary to Parkinson disease have also been documented, but data are obtained from single-blinded or open-label trials that require further corroboration with larger randomized studies. Duloxetine has not yet been directly compared with other antidepressants or anticonvulsants for the treatment of pain syndromes. PMID- 20921852 TI - What can the tongue tell you about Sjogren's syndrome? PMID- 20921853 TI - Ectopic calcification and weakness in an adult. PMID- 20921854 TI - Severe atlantoaxial subluxation in early ankylosing spondylitis. PMID- 20921856 TI - The impact of human papillomavirus and human papillomavirus vaccination among rheumatology patients. PMID- 20921857 TI - Serious concerns related to the article entitled "Tai Chi improves physical function in older Chinese women with knee osteoarthritis". PMID- 20921858 TI - Tai Chi improves physical function in older Chinese women with knee osteoarthritis: retraction. PMID- 20921859 TI - War zone veterans returning to treatment: effects of social functioning and psychopathology. AB - Patients with mental illness often return for further treatment after an initial episode of care. Two processes that may contribute to the return for further treatment are the severity of patients' initial social and clinical status; and/or deterioration in their status over time, regardless of their initial status. This study examined these processes in an administrative database of war zone veterans who had received outpatient treatment from a Veterans Affairs specialized posttraumatic stress disorder program. The results suggest that both initial severity and deterioration of status contribute to return to treatment and involve changes in both social functioning and psychopathology. Determination of the direction of effects between social functioning and psychopathology showed that psychopathology in the form of PTSD, other Axis I disorder or violent behavior generally affected subsequent social functioning, but not vice versa. Psychopathology in the form of alcohol or drug abuse/dependence, however, showed reciprocal effects with social functioning. These results point to the importance of emphasizing interventions that address social dysfunction and that address psychopathology, from the beginning of treatment as a way of maximizing the benefits and minimizing the need for recurrent care. PMID- 20921860 TI - Impact of traumatic and violent victimization experiences in individuals with schizophrenia and schizoaffective disorder. AB - Individuals with schizophrenia or schizoaffective disorder (SZ) experience more violent victimization and noninterpersonal traumatic experiences than the general population. Earlier studies, however, have generally excluded one or grouped together victimization and trauma experiences into single outcome variables, which may obscure their contributory role to SZ symptoms. This issue is important because there is some evidence that intentionally induced violence produces higher rates of psychopathology than nonintentional traumatic experiences. We examined the independent contribution of both types of victimization experiences on SZ patients' symptomatology. We were also interested in determining whether SZ patients' pattern of acute symptom presentation could discriminate between SZ patients with and without posttraumatic stress disorder (PTSD) comorbidity. SZ inpatients (n = 70) were assessed for the presence of comorbid PTSD diagnosis, violent victimization, and noninterpersonal traumatic experiences. Patients were also rated on SZ symptom severity and general psychopathology measures. Past violent victimization experiences predicted severity of dysphoria and anxiety in SZ. Past traumatic experiences, however, predicted severity of psychosis. Victimization predicted severity of patients' autistic/cognitive symptoms. SZ patients with comorbid PTSD presented with significantly more anxiety and dysphoria symptoms and SZ illness chronicity than their non-PTSD counterparts. Discriminant function analysis revealed that the severity of positive, dysphoric, autistic/cognitive, and anxiety symptoms differentiated comorbid PTSD patients from their non-PTSD counterparts, with an overall 72.9% classification rate. Past traumatic and victimization experiences are significantly associated with SZ patients' symptom severity and illness course in partially overlapping domains. Use of common assessment strategies may be employed to increase detection of PTSD in SZ patients presenting for acute treatment. PMID- 20921861 TI - Mobile interventions for severe mental illness: design and preliminary data from three approaches. AB - Mobile devices can be used to deliver psychosocial interventions, yet there is little prior application in severe mental illness. We provide the rationale, design, and preliminary data from 3 ongoing clinical trials of mobile interventions developed for bipolar disorder or schizophrenia. Project 1 used a personal digital assistant to prompt engagement in personalized self-management behaviors based on real-time data. Project 2 employed experience sampling through text messages to facilitate case management. Project 3 was built on group functional skills training for schizophrenia by incorporating between-session mobile phone contacts with therapists. Preliminary findings were of minimal participant attrition, and no broken devices; yet, several operational and technical barriers needed to be addressed. Adherence was similar to that reported in nonpsychiatric populations, with high participant satisfaction. Therefore, mobile devices seem feasible and acceptable in augmenting psychosocial interventions for severe mental illness, with future research in establishing efficacy, cost effectiveness, and ethical and safety protocols. PMID- 20921862 TI - Alexithymia, human relationships, and mobile phone use. AB - Alexithymia is a personality trait associated with difficulties in identifying feelings, difficulties in describing feelings to other people, constricted imaginal processes, and an externally oriented cognitive style. It has been found to be associated with personality features that may cause interpersonally avoidant behavior and other interpersonal problems. The present study explored, in a sample of primary care patients (N = 491), whether alexithymia is associated with mobile phone usage, and whether the perceived quality and quantity of human relationships mediate its effect. Even controlling for sociodemographic variables and symptoms of depression, mania and psychoses, alexithymia, measured by the 20 Item Toronto Alexithymia Scale, was associated with less frequent mobile phone use. Not having enough relationships or a close friend, and relationships being less satisfactory mediated the effect of alexithymia on less frequent mobile phone use. The results support the findings of earlier studies that have linked interpersonal problems with alexithymia. PMID- 20921863 TI - Is a history of school bullying victimization associated with adult suicidal ideation?: a South Australian population-based observational study. AB - The objective of this research was to determine whether a history of school bullying victimization is associated with suicidal ideation in adult life. A random and representative sample of 2907 South Australian adults was surveyed in Autumn, 2008. Respondents were asked "When you were at school, did you experience traumatic bullying by peers that was particularly severe, for example, being frequently targeted or routinely harassed in any way by 'bullies'?" Depression was determined by the mood module of the PRIME-MD which includes a suicidal ideation question; "In the last 2 weeks, have you had thoughts that you would be better off dead or hurting yourself in some way?" The overall prevalence of suicidal ideation in postschool age respondents was 3.4% (95% confidence interval: 2.8%-4.2%) in 2008. Bullying by peers was recalled by 18.7% (17.2% 20.3%). Respondents with a history of being bullied were approximately 3 times (odds ratio: 3.2) more likely to report suicidal ideation compared with those who did not. The association between being bullied and suicidal ideation remained after controlling for both depression and sociodemographic variables (odds ratio: 2.1). The results from the present research suggest that there is a strong association between a history of childhood bullying victimization and current suicidal ideation that persists across all ages. Bullying prevention programs in schools could hold the potential for longer lasting benefits in this important area of public health. PMID- 20921864 TI - Persistent insomnia in chronic hypnotic users presenting to a sleep medical center: a retrospective chart review of 137 consecutive patients. AB - Chronic insomnia patients may fail pharmacotherapy. We reviewed charts on 137 chronic insomnia patients new to our sleep medical center who reported persisting insomnia despite long-term usage of pharmacotherapy. We examined 4 areas: (1) patient views on encounters with prescribing physicians; (2) self-reported medication efficacy; (3) treatment-seeking goals; and (4) completion of a sleep medicine workup. Insomnia chronicity averaged 13 years; use of prescription medication for sleep averaged 3.81 years. Encounters with prescribing physicians yielded few options beyond drugs. Drug efficacy was not optimal for most of these patients. Sleeping better or drug-free were their chief goals. Subjective and objective sleep measures confirmed moderately severe residual insomnia as well as fair to poor waking impairment and quality of life. Sleep workup revealed high rates of maladaptive behavioral influences (96%), psychiatric complaints (89%), and obstructive sleep apnea (71%). In chronic insomnia patients who failed pharmacotherapy, comorbid mental and physical factors indicated a sleep disturbance complexity unlikely to respond fully to medication. PMID- 20921865 TI - Knowledge of and stigma associated with mental disorders in a South african community sample. AB - The aim of this study was to assess the awareness of, attitudes toward, and stigma associated with psychiatric disorders among South Africans. A convenience sample of 1081 members of the general public participated in the study. One of 10 vignettes portraying different psychiatric disorders with subtle or obvious symptoms was presented to each respondent. Schizophrenia was reported as being the most representative of a psychiatric disorder and post-traumatic stress disorder as the least representative. Psychosocial stress was reported more frequently than medical etiologies as a possible cause of mental disorders. Seeking help from a health professional in the form of psychotherapy was often endorsed as an effective treatment option, whereas taking medication was rarely endorsed. Respondents held more stigmatizing attitudes toward patients with substance abuse and schizophrenia, whereas post-traumatic stress disorder was stigmatized significantly less than the other conditions. Further effort is required to educate the public about the psychobiological underpinnings of psychiatric disorders and about the value of effective treatments. PMID- 20921866 TI - Clinical characteristics of depressed patients with a history of suicide attempts: results from the CRESCEND study in South Korea. AB - South Korea is a country with one of the highest suicide rates in the world, and the suicide rate is still on the rise. The purpose of this study was to determine the sociodemographic and clinical characteristics of suicide attempts and risk factors related to suicide attempts among depressed patients in South Korea. Among the 1183 participants, 21.4% had a history of a suicide attempt. When the severity of depression was controlled, the risk factors for patients who attempted suicide included younger age, experienced significant life events before 12 years of age, psychotic symptoms, and previous depressive episodes. The characteristics of attempted suicide in depressed patients in South Korea can be summarized as a high suicide attempt rate with no difference in the number of suicide attempts and lethality between males and females. This unique tendency is probably related to the sociodemographic and cultural characteristics of South Korea. PMID- 20921867 TI - Genetic and environmental influences on multiple dimensions of religiosity: a twin study. AB - In recent years there has been a renewed scientific interest in the study of religiosity, including research on genetic and environmental contributions to religiosity. In this article, we investigate genetic and environmental effects on 7 religiosity factors and explore how genetic and environmental effects covary across these factors. Seven religiosity factors estimated from 78 items were examined in a sample of adult male and female twins. The 7 religiosity factors were largely influenced by additive genetic and unique environmental effects, with relatively little influence from common environmental effects. Multivariate genetic analyses found the 7 religiosity factors were influenced by 1 common additive genetic factor, 3 common unique environmental factors, and unique environmental effects specific to each religiosity factor. The results suggest that for the population studied, additive genetic and unique environmental effects largely account for the variance across the religiosity construct. PMID- 20921868 TI - HADStress screen for posttraumatic stress: replication in ethiopian refugees. AB - Purpose was to assess whether a 4-symptom somatic screen, shown to correlate with current post-traumatic stress symptoms in 1 refugee group, could function as a screening instrument in another group of refugees. Sample consisted of 512 community-dwelling refugees from Ethiopia. Data collection included demography, types of torture and nontorture trauma experienced a decade earlier in Africa, and current posttraumatic stress symptoms. Somatic symptoms included headaches (H), appetite change (A), dizziness and faintness (D), and sleep problems (S), added with equal weighting into the HADStress Screen, ranging from 0 to 4. Results showed that age, gender, torture, and other trauma experiences from a decade ago, and current posttraumatic stress symptoms predicted current somatic symptoms on univariate analyses. On a negative binomial regression model, current posttraumatic stress symptoms, male gender, and number of torture types predicted a high HADStress score. Post hoc tests supported cut-off levels at 3 and at 4 symptoms. Conclusion is that the HADStress Screen can serve as an efficient, nonthreatening screen for posttraumatic stress symptoms among refugees. PMID- 20921869 TI - Evaluation of the linkoping youth life experience scale. AB - The objective of this study was to investigate the psychometric properties of a newly developed instrument for potentially traumatic life events, the Linkoping Youth Life Experience Scale (LYLES), and determine the benefits of including adverse childhood circumstances (ACCs) as factors in the evaluation. In addition, we wanted to investigate the difference between interpersonal and noninterpersonal traumatic events, the impact of ACCs, and the cumulative effects of these events on self-reported symptoms of dissociation, depression, and anxiety. Adolescents from the normative population (n = 188) answered the questionnaire LYLES and also the Dissociation-Questionnaire-Sweden and Hospital Anxiety and Depression Scale. The results showed that LYLES was stable, with test retest r = 0.79 and kappa item per item ranging between k = 0.44 and 1.0. ACCs contributed independently to the explanation of symptoms explaining them better than potentially traumatic events alone, particularly for boys where the impact of ACCs exceeded the impact of events. The conclusions are that LYLES displayed satisfactory psychometric properties and that ACCs seem to be a valuable addition to an instrument to evaluate potentially traumatic events. PMID- 20921870 TI - Traumatic events, posttraumatic stress disorder, attachment style, and working alliance in a sample of people with psychosis. AB - There is a high incidence of trauma and posttraumatic stress disorder (PTSD) in people with a diagnosis of psychosis. Sequelae of trauma may affect the ability to engage in both attachment and therapeutic relationships. This study investigated associations between trauma histories, PTSD, attachment styles, and working alliance in a sample of 110 individuals with psychosis and substance misuse. Anxious attachment was associated with number of interpersonal traumas and PTSD reported, but there were no associations between trauma and alliance. There were discrepancies in number of traumatic events reported by care coordinators and patients. The findings of this study highlight the potential use of attachment theory in working with trauma and PTSD in psychosis. PMID- 20921871 TI - Selective attention impairment in Schizophrenia: can it explain source monitoring failure? AB - Impairments in selective attention have been proposed as an explanation for the source monitoring deficits in schizophrenia. We tested this hypothesis by examining correlations between source monitoring variables and a measure of selective attention (from the Stroop Test) in 54 individuals with schizophrenia subjects and 42 normal controls. We did not find significant correlations between source monitoring measures and selective attention. Selective attention impairments do not explain source monitoring deficits observed in schizophrenia. Source monitoring deficits deserve continued efforts to elucidate their causes and consequences. PMID- 20921872 TI - Instrumented posterior lumbar fusion outcomes for lumbar degenerative disorders in a southern European, semirural population. AB - STUDY DESIGN: Prospective, clinical study. OBJECTIVE: This study compares the preoperative and postoperative status of patients with degenerative lumbar spine disorders, who underwent instrumented posterior lumbar fusion (IPLF), from the functional, economic and psychologic perspectives in a semirural population. SUMMARY OF BACKGROUND DATA: IPLF is a common procedure in the treatment of a more common disorder, lumbar spine degeneration. It has been postulated that both the disorder and the surgical procedure may affect many aspects of patients' life. METHODS: During a 2 years period, 46 patients underwent IPLF for degenerative disorders of the lumbar spine. The surgical procedure included posterior decompression of the affected segment(s) and stabilization by means of pedicle screws and rods in every case, and interbody implants in selected cases. The outcome measures included the Greek versions of (a) Visual Analogue Scale (VAS) for pain assessment, (b) Oswestry Disability Index (ODI) for back-related disability, (c) Prolo Scale for the functional and economic status and (d) Zung Depression Scale to screen for depression. Measurements were taken 1-week preoperatively, and 3 years after the procedure. The comparison of the preoperative and postoperative results was done using the paired-samples t test. RESULTS: Thirty-nine patients (25 females, 14 males) with a mean age of 59 years were eligible for our study. Half of them worked in the agricultural sector. All developed solid, lumbar fusions. Instrumented posterior lumbar fusion decreased patient's somatic pain, as shown by the VAS (P<0.001) and improved function as indicated by the ODI (P<0.001), and allowed return to work (P<0.001). Nevertheless, the Zung Depression Scale revealed that the incidence of depression increased postoperatively (P<0.001). CONCLUSIONS: IPLF in the treatment of degenerative disorders of the lumbar spine improves function and promotes the patients' complete or partial return to work. In contrast, degenerative lumbar spine disorders are chronic conditions and may negatively affect patients' psychology. PMID- 20921873 TI - Shortening osteotomy and sacro-sacral fixation for U-shaped sacral fractures. AB - STUDY DESIGN: Technical note and retrospective first cases study. OBJECTIVE: To present a novel surgical procedure for treating rare and challenging U-shaped fractures of the sacrum. SUMMARY OF BACKGROUND DATA: U-shaped fractures of the sacrum are not frequent and usually seen in the context of high energy trauma (high-fall injury). There is no consensus about the therapeutic strategy. When surgery is decided on selected patients, the technique raises several issues for the neural decompression, reduction, and fixation. The L5-S1 mobility has to be sacrificed for most authors. METHODS: Based on anatomic considerations, the authors present here the original surgical technique they have been using at their institution and a consecutive series of patients. The procedure associates a shortening osteotomy of the sacrum at the site of the fracture and a sacro sacral fixation. RESULTS: The proposed procedure was simple, safe, and effective. CONCLUSIONS: Performing the osteotomy helps in the reduction and allows a short fixation, which spares the mobility of the lumbo-sacral junction. PMID- 20921874 TI - Awareness of cognitive deficits in older adults with cognitive-impairment-no dementia (CIND): comparison with informant report. AB - Impaired awareness of cognitive deficits is a common symptom of dementia, but its prognostic importance in people with cognitive impairment-no dementia (CIND) is uncertain. In this study, we examined whether community volunteers with CIND and reduced awareness had worse cognitive performance and cognitive decline over 18 months than CIND participants with intact awareness or healthy controls. We recruited 92 participants with CIND and 91 healthy controls with their respective informants. We used discrepancy scores (informant minus participant) on the Anosognosia Questionnaire for Dementia and Dysexecutive Questionnaire to ascertain participants' awareness of their cognitive performance. The main cognitive outcome variable was the Alzheimer Disease Assessment Scale: Cognitive Section. Bivariate correlations showed no relationship between the awareness measures and cognitive performance or decline. Overall, CIND participants' ratings of cognitive deficits correlated significantly with their Alzheimer Disease Assessment Scale: Cognitive Section score after 18-months (for Anosognosia Questionnaire for Dementia, r=0.45, P <0.001) and showed a stronger relationship with cognitive performance than informant ratings. These results indicate that reduced awareness of deficit may be uncommon in community volunteer samples with CIND. In addition, self-report of cognitive complaints may be at least as useful as informant report when screening community-dwelling older adults at risk of cognitive decline and dementia. PMID- 20921875 TI - Could Toxoplasma gondii have any role in Alzheimer disease? AB - BACKGROUND: Alzheimer disease (AD), a chronic progressive neurodegenerative disorder, has a mainly unknown multifactorial etiology. Neuroinflammatory mechanisms might contribute to the cascade of events leading to neuronal degeneration. Central nervous system infections have been previously suggested as possible etiological agents in the development of sporadic AD. Toxoplasmosis can be associated with various neuropsychiatric disorders. In this study, we aimed to investigate the possible association between toxoplasma infection and AD. METHODS: This study evaluated the serum anti-Toxoplasma gondii IgG levels. It included an age-matched and sex-matched study and control groups that consisted of 34 patients with AD and 37 healthy individuals, respectively. There were no difference between the socio economic states of the patients and control subjects. serecm anti-I-gondi IgG levels were measured by using ELISA. RESULTS: According to the statistical analysis, there were no significant differences among the patients and the control participants with respect to age (68.05+/ 15.98, 62.91+/-5.89 y, P=0.072; respectively) and sex. The seropositivity rate for anti-T. gondii IgG antibodies among AD patients and control groups were 44.1% and 24.3%, respectively, and there was significant difference between the serum anti-T. gondii IgG levels (P=0.005). CONCLUSIONS: Our findings suggest that toxoplasma infection may be involved in the pathogenetic mechanisms of AD. If confirmed, a positive correlation between toxoplasmosis and AD may lead to new approaches for the management of AD. PMID- 20921876 TI - Adding delayed recall to the Alzheimer Disease Assessment Scale is useful in studies of mild cognitive impairment but not Alzheimer disease. AB - OBJECTIVE: To determine if the addition of delayed recall (DR) assessment adds sensitivity to the cognitive subscale of the Alzheimer Disease Assessment Scale (ADAS-cog) in clinical trials in mild cognitive impairment (MCI) and Alzheimer Disease (AD). BACKGROUND: Memory, particularly DR, is the most sensitive test for early detection of AD and MCI. However, it is not clear that assessment of DR adds benefit for measuring change over time after a diagnosis is made or in clinical trials. The ADAS-cog is the most commonly used tool to assess treatment efficacy in AD clinical trials. In an attempt to improve sensitivity to change, assessment of DR after the 3-trial, 10-word list was added to the standard 11 item ADAS-cog. We examined the added value of the DR in participants with MCI and AD followed for at least 1 year. DESIGN/METHODS: Data from 111 subjects with AD and 259 subjects with MCI who were randomly assigned to the placebo arm of 2 clinical trials were included. Participants with AD had Mini-Mental State Examination scores of 13 to 27 and those with MCI had 24 to 30. We calculated the ADAS-cog11 score based on the original 11 items (range: best to worse, 0 to 70), the DR item score (range: 0 to 10 words not recalled), and the ADAS-cog12 (range: 0 to 80). We assessed the rate of missing items for DR over time, the change scores, the association between scores and baseline performance, and used longitudinal mixed effects regression models to examine the rate of change. RESULTS: At baseline AD subjects were near floor on DR (8.93 +/- 1.6 SD) and showed little change over 1 year (0.12 +/- 1.34); the MCI subjects baseline DR was 6.2 +/- 2.2 with 1-year change of 0.20+/-1.7. We compared standardized change (change/SD) for ADAS-cog11, and 12 in MCI and found a 10% improvement with ADAS cog12; there was no improvement in the AD group. In a subset of MCI and AD cases with matching Mini-Mental State Examination (23 to 27), the ADAS-cog12 provided an 18% improvement in standardized change in MCI subjects, with no benefit in the AD cohort, primarily owing to increased variance. CONCLUSIONS/RELEVANCE: The addition of DR to the ADAS-cog score increased the ability to detect change in subjects with MCI over 1 year compared with the ADAS-cog11 but increased the variance in subjects with AD, even in those with mild impairment These findings speak to the need to tailor outcome measures to the specific study population and diagnosis for maximal efficiency and economy when conducting clinical trials. PMID- 20921877 TI - Nonfibrillar Abeta 1-42 inhibits glutamate uptake and phosphorylates p38 in human fibroblasts. AB - Alzheimer disease (AD) is the most prevalent neurodegenerative disease, characterized by an increased deposition of beta-amyloid (Abeta) within the central nervous system, leading to neuronal death. The availability of effective models, in which confirming novel pathogenic hypotheses and developing therapeutic targets, represents a very important goal for the field of AD. Fibroblasts from these patients may be relevant models in which addressing these issues, as they display biochemical alterations mirroring SNC ones. In this work, fibroblasts obtained from controls were studied after exposure to nonfibrillar Abeta 1-42, showing decreased glutamate uptake, similar to that observed in AD cells, in absence of transporters modifications. Nonfibrillar Abeta 1-42 was able to induce in control cells mitochondrial alterations and p38-phosphorylation, mirroring similar alterations found in AD fibroblasts. Under our experimental conditions, this treatment induced neither apoptosis nor necrosis. To investigate a putative role of p38-modulation in mediating nonfibrillar Abeta 1-42 toxicity, fibroblasts from controls were pretreated with retinoic-acid, and SB203580, a p38 inhibitor. These pretreatments prevented both p38-phosphorylation and glutamate uptake inhibition. Our results suggest that nonfibrillar Abeta 1-42 downregulates glutamate transporters activity interfering with p38-activation and mitochondrial stress. Thus, modulating complex kinase signaling pathway might represent a future therapeutic target in AD. PMID- 20921878 TI - The measurement of psychosis in dementia: a comparison of assessment tools. AB - The precise operational definition of psychosis in dementia lacks consensus, partially owing to incongruence in the various assessment tools used. This study compares assessments of psychotic symptoms in persons with dementia, specifically of hallucinations and delusions, through the 4 most frequently used assessments. Participants were 74 nursing home residents from 9 nursing homes in Israel, diagnosed with dementia. Assessment tools used included the Behavioral Pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD), the Neuropsychiatric Inventory Nursing Homes (NPI-NH), the Consortium to Establish a Registry for Alzheimer's Disease Behavior Rating Scale for Dementia (CERAD-BRSD), and the Columbia University Scale for Psychopathology in Alzheimer's Disease (CUSPAD). The highest prevalence rates of delusions were found through the CUSPAD, and the lowest through the CERAD-BRSD. Rates identified by the BEHAVE-AD were intermediate and similar to those of the NPI-NH. As for hallucinations, rates indicated by the BEHAVE-AD, the NPI-NH, and the CUSPAD were similar, with small sample-based differences, and higher than those found through the CERAD-BRSD. The CERAD-BRSD, soliciting reports of the fewest specific symptoms, detected the fewest psychotic symptoms. The CUSPAD, soliciting the most items, presented the highest prevalence rates. The BEHAVE-AD and the NPI-NH had similar rates and showed a high convergent validity. PMID- 20921880 TI - Development and validity of the Family Stigma in Alzheimer's disease Scale (FS ADS). AB - Although it is widely assumed that persons with Alzheimer disease (AD) and their family caregivers are victims of stigmatization, family stigma in the area of AD has received surprisingly limited attention. Reliable, valid, and user-friendly scales are a first step in expanding this body of knowledge. The aim of this study was to develop and examine the validity of the Family Stigma in Alzheimer's disease Scale. Interviews were conducted with 185 children of persons with AD. A pool of 100 items was identified from the literature and an earlier qualitative study including 3 dimensions (caregivers' stigma, lay persons' stigma, and structural stigma). Exploratory factor analyses, theoretical relevance, and internal reliability analyses allowed us to reduce the pull to 62 items. Regarding construct validity, statistically significant associations were found between family stigma and caregivers' burden and behavioral problems, in most of the scales. Although further testing is warranted, these findings indicate that the Family Stigma in Alzheimer's disease Scale is a reliable and valid instrument for assessing stigma in the context of AD. PMID- 20921879 TI - Undiagnosed illness and neuropsychiatric behaviors in community residing older adults with dementia. AB - The aim of this retrospective analysis was to examine prevalence of undiagnosed acute illness and characteristics including neuropsychiatric symptoms associated with illness in community residing older adults with Alzheimer disease or related disorders. Subjects included 265 community residing older adults with dementia who participated in 1 of 2 interventions being tested in randomized clinical trials. Measures included a brief nursing assessment and laboratory evaluations including complete blood count, blood chemistry (Chem 7), and thyroid function tests of serum samples and culture and sensitivity tests of urine samples. Undiagnosed illness was identified according to currently published criteria. Neuropsychiatric behaviors were assessed using 21 behaviors derived from standard measures. Thirty-six percent (N=96) of patients had clinical findings indicative of undetected illness. Conditions most prevalent were bacteriuria (15%), followed by hyperglycemia (6%) and anemia (5%). The behavior most often demonstrated among those with detected illness was resisting or refusing care (66% vs. 47% for those without detected illness). Individuals with detected illness had significantly lower functional status scores [3.8 vs. 4.4, t(275)=7.01, P=0.01], lower cognitive status scores [10.5 vs. 14.4, t(275)=12.1, P<0.01], and were more likely to be prescribed psychotropic medications for behavior (41% vs. 26%, chi=3.67, P<0.05) than those without illness. Findings suggest that challenges of diagnosing acute illness with atypical presentation must be addressed to promote quality of care and the specialized needs for this vulnerable population. PMID- 20921882 TI - General selection criteria of patients for radioembolization of liver tumors: an international working group report. AB - A combined treatment approach that incorporates surgical resection, ablation, chemotherapy, targeted agents, and radiotherapy has augmented the management of liver tumors (both primary and metastatic). The challenge that remains is how to reduce the burden of liver disease and thus enable greater patient eligibility for resection as well as lengthened survival for those who remain unsuitable for surgery. Radioembolization can deliver high doses of radiation preferentially to liver tumors and is a valuable treatment option that should be considered as part of a multimodal treatment approach for the management of patients in whom the liver is the sole or dominant site of disease. Essential in this consideration is a careful assessment by a multidisciplinary team of the individuals most likely to benefit from this treatment modality. Along with the clinical benefits, integration of radioembolization into the treatment paradigm can provide added options of using systemic chemotherapy synergistically as a radiosensitizer and to control extrahepatic metastases, permitting a reduction in hepatic disease and conserving remaining liver function. If successful, the possibility of improved patient survival and quality of life is increased. PMID- 20921881 TI - Incidence and risk factors for cognitive impairment no dementia and mild cognitive impairment in African Americans. AB - The aim of this study was to estimate the age-specific incidence of cognitive impairment, no dementia and mild cognitive impairment (CIND/MCI) in a large, community-based sample of older African Americans in Indianapolis, IN. A longitudinal, prospective, 2-stage design was used with follow-up assessments 2 and 5 years after the baseline. A total of 1668 participants completed the 2-year follow-up and a total of 1255 participants completed the 5-year follow-up. The person-years method was used to calculate incidence rates. The age-standardized, annual incidence of CIND/MCI was 4.95% (CI=3.39-6.52) and the subtype of medically unexplained memory loss (single-domain and multidomain amnestic MCI) was 3.67% (CI 2.75-4.48). Rates increased with age (3.43% for participants aged 65 to 74 y, 6.44% from age 75 to 84 y, and 9.62% from age 85+ y), history of head injury [OR 2.37 (CI 1.31-4.29)], and history of depression [OR 2.22 (CI 1.16 4.25)] while increased years of schooling was protective [OR 0.91 (CI 0.85 0.97)]. Rates did not vary substantially by sex. Almost 1 in 20 elderly community dwelling African Americans, and almost 1 in 10 of the oldest-old (85+ y) developed CIND/MCI each year in this cohort. Risk factors of age and education suggest exposures or mechanisms at both ends of the life span may be important variables in onset of CIND/MCI. PMID- 20921883 TI - Multidrug resistance gene (MDR-1) and risk of brain metastasis in epithelial ovarian, fallopian tube, and peritoneal cancer. AB - BACKGROUND: To evaluate risk factors that predict brain metastasis in epithelial ovarian, fallopian tube, and peritoneal cancer. METHODS: All patients with FIGO stage I to IV who underwent initial cytoreductive surgery between January 1995 and January 2009 were evaluated. The tumor samples were evaluated for 7 markers including multidrug resistance gene (MDR-1), DNA aneuploidity and S-phase fraction, human epidermal growth factor receptor 2, estrogen receptor, progesterone receptor, p53 mutation, epidermal growth factor receptor, and CD31. Biomarker expression was evaluated as a predictor of hematogenous metastasis to the following locations: (i) liver and spleen, (ii) lung, and (iii) brain. RESULTS: There were 309 cases identified during the period. Of those, 5 (1.6%, 95% CI: 0.2%-3.0%) women developed brain metastasis. Time to onset of brain metastasis was significantly longer than that for other recurrent sites (median time to recurrence after initial cytoreduction, brain vs. lung vs. liver, 21.4 vs. 12.6 vs. 11.0 months, P< 0.05). Significantly increased expression of MDR-1 was seen in tumors from women who developed brain metastasis (brain vs. nonbrain sites, 80% vs. 4.2%-24.3%, P= 0.004). In multivariate analysis, MDR-1 was the only significant variable associated with the risk of brain metastasis. MDR-1 expression predicted brain metastasis (receiver-operator-characteristic curve analysis, AUC 0.808, P= 0.018), and with a 10% positive expression of MDR-1 as the cutoff value, sensitivity, specificity, positive predictive value, negative predictive value, accuracy of prediction of brain metastasis were 80%, 86.1%, 15.4%, 99.3%, and 85.9%, respectively (odds ratio: 24.7, 95% CI: 2.64-232, P= 0.002). CONCLUSIONS: Increased expression of MDR-1 in the tumor tissue obtained at initial cytoreduction is associated with increased risk of developing brain metastases in women with epithelial ovarian, fallopian tube, or peritoneal cancer. PMID- 20921884 TI - "But I'm (became) different": cancer generates reprioritizations in masculine identity. AB - BACKGROUND: Cancer is a leading cause of death worldwide. The disease accounted for 7.4 million deaths (or around 13% of all deaths worldwide) in 2005. A sharp increase in new cases to 15 million is predicted to occur by 2020. Recently, the National Cancer Intelligence Network showed that men have 40% more risk of death related to cancer, and in Brazil, it is estimated by the National Cancer Institute that there were 466,730 new cases of cancer in 2009, 231,860 of which occurred in men. However, there is little literature describing how Brazilian men experience cancer treatment related to their sense of personal masculinity. OBJECTIVE: The purpose of this study was to describe the experience of cancer treatment from the perspective of Brazilian men receiving chemotherapy for various cancers. METHODS: This was a cross-sectional descriptive qualitative study using semistructured interviews with 12 men during a chemotherapy session at a major chemotherapy clinic in Brazil. Interviews were audiotaped and transcribed verbatim. Data were analyzed using thematic analysis. RESULTS: The analysis resulted in the identification of several major themes. These were the life before cancer, the cancer treatment, reprioritizations of values, and a glimpse of the postcancer life. CONCLUSIONS: Results illuminate changes in masculine identity among Brazilian men treated for cancer. Men are capable of reprioritizing and reestablishing a sense of order in their social worlds to maintain a sense of masculinity despite the challenges of cancer treatment. IMPLICATIONS FOR PRACTICE: Understanding the complex dynamics between masculine identity and health across cultures is necessary to develop interventions designed to promote effective coping with cancer treatment in ways that are consistent with the cultural context in which masculine identity is developed. PMID- 20921885 TI - Chinese nurses' attitudes and beliefs toward sexuality care in cancer patients. AB - BACKGROUND: The importance of having nurses address patients' sexuality concerns is emphasized by a growing body of literature. Most relevant studies were conducted in Western cultural settings. OBJECTIVE: The purpose of this study was to describe Chinese nurses' attitudes and beliefs regarding sexuality care in cancer patients. METHODS: A descriptive and correlation design was adopted. Data were collected by an inventory of Sexuality Attitudes and Beliefs Survey. RESULTS: Oncology nurses (n = 199) were recruited from a tumor hospital in China. The study results indicate that most Chinese nurses (76.4%) perceived sexuality as too private an issue to discuss with cancer patients, and 63.8% assumed that most cancer patients lacked interest in sexuality because of their illnesses. The results also show that most nurses (77.9%) did not make time to discuss sexuality issues with patients, and nearly 70% did not feel confident and comfortable discussing cancer patients' sexuality concerns. CONCLUSION: Helping nurses overcome barriers to addressing patients' sexuality concerns requires a careful assessment of their attitudes and beliefs. This study added insights into Chinese nurses' attitudes and beliefs surrounding the sexuality issues of cancer patients. IMPLICATIONS FOR PRACTICE: In this study, nurses reported that they were less likely to make time to discuss sexuality issues with cancer patients; thus, future research needs to identify specific factors keeping nurses from incorporating sexuality care into practice. Additionally, most nurses felt less confident and uncomfortable in addressing cancer patients' sexuality concerns. More training related to sexuality care is needed for Chinese nurses. PMID- 20921886 TI - Assessment of symptom distress in cancer patients before and after radiotherapy. AB - BACKGROUND: Previous literature revealed that cancer patients undergoing radiotherapy commonly experience physical and psychological symptom distress. Except lack of medical information, inadequate communication with physicians also affected patients' willingness and preparation toward radiotherapy. The prognosis consequently becomes worse. OBJECTIVE: This study aimed to evaluate the change in symptom distress in cancer patients after radiotherapy and its predisposing factors. METHODS: A longitudinal design was conducted on 164 cancer patients who underwent radiotherapy at a medical center in southern Taiwan. The structured questionnaire included sections on demographics, medical conditions, and a symptom distress scale. RESULTS: Of the cancer patients, 35.9% reported an increase in the overall figures of symptom distress after radiotherapy, whereas 32.2% experienced a decrease. Cancer patients 20 to 39 years old or who received radiotherapy on the head and neck reported the greatest increase in bleeding and the overall figure of symptom distress. Patients after radiotherapy on the head and neck experienced significant increase in bowel disturbance. CONCLUSIONS: Radiotherapy did not necessarily increase symptom distress in all patients. The development of bleeding and the overall figure of symptom distress were closely related to younger age and site of radiotherapy. IMPLICATIONS FOR PRACTICE: For those cancer patients 20 to 39 years old or who received radiotherapy on the head and neck, nurses may strengthen health education before radiotherapy and pay more attention after radiotherapy, especially in bleeding distress, and remind their families of the correct steps for nursing a wound after radiotherapy and the harmful effects of wound odor on patients' interpersonal relations. PMID- 20921887 TI - Left hanging in the air: experiences of living with cancer as expressed through E mail communications with oncology nurses. AB - BACKGROUND: Cancer patients experience many physical, psychosocial, and existential problems and worries during their illness. To support patients in managing their illness, we implemented an online patient-nurse communication (OPNC) service, where breast and prostate cancer patients could ask questions and receive advice from oncology nurses. OBJECTIVE: The aim of this study was to explore the use and content of patients' e-mail messages sent to oncology nurses and thus gain a "snapshot" of patients' experiences of living with cancer as expressed through these messages. METHODS: Using qualitative content analysis, 276 messages from 60 breast and prostate cancer patients were analyzed. Messages were coded into categories and major themes. Both manifest and latent content was coded. RESULTS: Four main themes emerged from patients' messages: (1) living with symptoms and side effects, (2) living with a fear of relapse, (3) concerns for everyday life, and (4) unmet information needs from health care providers. CONCLUSIONS: Patients used the OPNC service actively to pose questions and raise concerns related to symptom experiences, fear of relapses, and uncertainty in everyday life. However, patients also expressed experiences of being "left in a void" after being discharged from hospital and living with serious unmet informational needs. IMPLICATIONS FOR PRACTICE: The study demonstrated that online communication can provide patients with a space for otherwise unmet questions and worries and that they will seek support from nurses online when given the opportunity. Therefore, OPNC can be an important means and supplement to traditional health care in the effort to support patients to better manage their illness. PMID- 20921888 TI - The experiences and feelings of Chinese children living with leukemia: a qualitative study. AB - BACKGROUND: Leukemia is the most common pediatric malignancy. Many children with leukemia display behavioral and emotional problems. Promoting children's psychological development and quality of life during hospitalization is an important activity carried out by health professionals. OBJECTIVE: The objective of this study was to describe the experiences and feelings of Chinese children with leukemia in the hospital. METHOD: In-depth interviews were conducted with Chinese children with leukemia using a descriptive qualitative research method. The data were analyzed using content analysis. RESULTS: Twenty-nine children with leukemia were interviewed. Almost all children had negative experiences and feelings during the early stage of hospitalization, and there were 3 levels of adaptation that they displayed: inability to adapt to hospitalization, a sense of being compelled to accept hospitalization, and adaptation to hospitalization. CONCLUSIONS: Three factors are associated with children's psychological distress, including the duration of treatment, children's personality, and age. Children of a younger age, with more extrovert personalities and who were undergoing longer treatment courses, adapted to hospitalization more easily. IMPLICATIONS FOR PRACTICE: The findings provide information for health professionals to understand children's psychological status during hospitalization and help nurses to plan individualized psychological care for children. PMID- 20921889 TI - Advancing palliative care in Kenya. AB - BACKGROUND: Life-threatening illnesses such as HIV/AIDS, malaria, tuberculosis, and other disorders are prevalent in the developing world, including Kenya. OBJECTIVE: The aim of this project was to assist in the development of palliative care throughout Kenya by enhancing the knowledge and skill of faculty members in palliative care so they could integrate this content into existing nursing curricula. METHODS: In an effort to develop palliative care throughout the country, experts from the Kenya Hospices and Palliative Care Association and the Kenyatta National Hospital invited faculty from the End-of-Life Nursing Education Consortium with the United States to adopt the content of its training program to address the needs of nurses and other health care professionals in Kenya. This curriculum was delivered to nursing faculty from throughout Kenya during a 5-day training course that incorporated presentations, case studies, exercises, and other teaching methods. RESULTS: The course participants completed daily course evaluations in which they rated each session on a scale of 0 = not helpful to 5 = very helpful. All of the sessions were rated very favorably, with scores for all sessions across the 5 days ranging from 4.57 to 4.91. CONCLUSION: End-of-Life Nursing Education Consortium provided educational and other support to faculty teaching in nursing schools in Kenya so they could advance palliative care efforts in this country. IMPLICATIONS FOR PRACTICE: Nurses working in the United States can share their expertise and learn immense lessons from colleagues in developing worlds. PMID- 20921890 TI - An open-label tolerability study of BL-1020 antipsychotic: a novel gamma aminobutyric acid ester of perphenazine. AB - BACKGROUND: BL-1020, a novel gamma aminobutyric acid (GABA) ester of perphenazine, is a new oral antipsychotic with a strong affinity for dopamine and serotonin receptors. Unlike first- and second-generation antipsychotics, it has agonist activity at GABA(A). OBJECTIVE: This is the first study to examine tolerability and safety of BL-1020 in schizophrenia. METHODS: This was a phase II, open-label, multicenter, 6-week study treating patients (n = 36) with chronic schizophrenia. Dosing started at 20 mg/d and increased over 7 days to 40 mg/d. Weekly assessments were conducted. RESULTS: All but 1 patient was titrated to 30 mg/d at day 4; on day 7, 30 were titrated to 40 mg/d. Four patients discontinued the study prematurely. There was no clinically relevant increase in vital signs, sedation, dizziness, or other central nervous system effects or electrocardiogram or laboratory abnormalities and a small increase in weight. Ten patients experienced extrapyramidal symptoms (EPS) requiring treatment with an anticholinergic; 4 patients were unable to reach maximum dose because of EPS. Extrapyramidal Symptom Rating Scale did not indicate clinically significant changes in EPS. The most common adverse event was insomnia (6 patients); other frequent adverse effects (all n = 3) were extrapyramidal disorder, headache, parkinsonism, tremor, and hyperprolactinemia. There was improvement on Positive and Negative Syndrome Scale and Clinical Global Impression of Change with 22 patients showing at least 20% decrease by end point on Positive and Negative Syndrome Scale and 31 patients showing at least minimal improvement on Clinical Global Impression of Change. CONCLUSIONS: These data suggest that 20 to 40 mg/d of BL-1020 is associated with clinically relevant improvement of psychosis with no worsening of EPS and support further testing in randomized controlled trials. PMID- 20921891 TI - Effect of varying phase between frequency and amplitude modulation on bone conduction auditory steady state responses. AB - OBJECTIVES: Auditory steady state response (ASSR) testing provides a means to objectively estimate hearing levels in newborns and adults for whom behavioral tests prove difficult. When testing these patient groups, it is preferable that clear responses to both air and bone conduction stimuli are obtained in a short amount of time. Much of the literature addressing ASSRs, such as investigations of stimulus and recording parameters, have focused on air conduction ASSRs. The aim of this investigation was to study the amplitudes, latencies, and test times of bone conduction ASSRs elicited using amplitude- (AM), frequency- (FM), and mixed-modulated (MM) stimuli and provide suggestions for optimum recording parameters. DESIGN: Bone and air conduction multiple ASSRs were recorded from two groups of 20 normal-hearing adults using the Multiple Auditory Steady State Response research system. AM, FM, and MM sinusoidal tones were used (0.5-, 1-, 2 , and 4-kHz carrier frequencies), which were modulated between 78 and 92 Hz. AM depth was 100% and FM depth was 20%. ASSR amplitudes and latencies (calculated using the "preceding cycles" technique) were analyzed for MM phase settings across the cycle from 0 degrees at 45 degrees intervals and compared with AM responses. Optimum phase settings for bone and air conduction ASSRs were calculated using a sinusoidal model based on the amplitude data. RESULTS: Similar effects of stimulus type and carrier frequency were observed for bone and air conduction ASSRs. AM responses were larger in amplitude compared with FM responses. MM (at all phase settings tested) and AM response latencies increased with decreasing carrier frequency. MM phase setting had a significant (p < 0.01) sinusoidal effect on ASSR amplitudes, compared with AM responses, at 1, 2, and 4 kHz but not 0.5 kHz for air conduction and 1 and 2 kHz but not 0.5 and 4 kHz for bone conduction. Using a sinusoidal function to model this effect, MM phase settings (+/-95% confidence intervals) of 318 degrees (295 to 350 degrees ) and 295 degrees (290 to 310 degrees ) are predicted to evoke the largest responses for bone conduction ASSRs at 1 and 2 kHz, respectively. Phase settings of 293 degrees (285 to 310 degrees ), 300 degrees (280 to 310 degrees ), and 280 degrees (255 to 330 degrees ) are predicted for air conduction ASSRs at 1, 2, and 4 kHz, respectively. MM phase setting had little effect on estimated latency. Test times were significantly (p < 0.01) affected by phase setting with both increases and decreases being observed. Test times for ASSRs at 1, 2, and 4 kHz could be significantly reduced if the estimated optimum phase settings are used. CONCLUSIONS: Different stimuli can significantly affect the amplitudes of bone conduction ASSRs. These effects are similar to those observed for air conduction ASSRs. MM stimuli with specific phase settings evoke larger bone conduction ASSRs compared with AM and FM stimuli alone, and calculations show that the time taken to obtain these responses is reduced. Implementation of the suggested optimum settings will promote efficient collection of bone conduction, and indeed air conduction, ASSR data. PMID- 20921892 TI - Impact of communicating personalized genetic risk information on perceived control over the risk: a systematic review. AB - PURPOSE: Much concern has been expressed that feedback of personalized genetic risk information may lead to fatalism, i.e., a lack of perceived control over the risk. This review aimed to assess the strength of evidence for such a view. METHOD: Electronic databases were searched to find eligible studies, which comprised randomized, controlled trials and analog studies, in which participants in one arm received either real or imagined personalized genetic risk information and assessed perceived control in relation to the treatability or preventability of the health problem. RESULTS: Inspection of 1340 abstracts resulted in 5 studies meeting the inclusion criteria, involving the prediction of obesity, heart disease, depression, and diabetes. Meta-analyses of the clinical studies revealed no impact of personalized genetic risk information on perceived control in either the short term (pooled standardized mean difference 0.09, 95% confidence interval, -0.51 to 0.70) or longer term (pooled standardized mean difference 0.00, confidence interval, -0.20 to 0.21). Similarly, no impact on perceived control was evident in the three analog studies (pooled standardized mean difference 0.02, confidence interval, -0.17 to 0.20). CONCLUSION: Few studies have assessed empirically the impact of personalized genetic risk information on fatalism, assessed using perceptions of control over the risk. Limited evidence suggests feedback of genetic risk information may have little impact on such beliefs. PMID- 20921893 TI - Regulating direct-to-consumer genetic tests: what is all the fuss about? AB - The number of genetic tests available direct-to-consumer has burgeoned over the last few years, prompting numerous calls for tighter regulation of these services. However, there is a lack of consensus about the most appropriate and achievable level of regulation, particularly given the global nature of the market. By consideration of potential for direct and indirect harms caused by genetic susceptibility or genomic profiling tests, in this study we offer an overarching framework that we believe to be feasible for the regulation of direct to-consumer genetic tests and likely to be relevant to other forms of predictive testing. We suggest that just five key requirements would adequately protect the consumer: a proportionate set of consent procedures; formal laboratory accreditation; evidence of a valid gene-disease association; appropriately qualified staff to interpret the test result; and consumer protection legislation to prevent false or misleading claims. PMID- 20921895 TI - Research use of leftover newborn bloodspots: attitudes of Canadian geneticists regarding storage and informed consent requirements. AB - PURPOSE: Leftover newborn spots can provide a powerful research tool as a population-wide DNA bank. Some provinces/states store them for more than 20 years; however, parents are usually not informed of the retention of leftover newborn spots. To examine the opinions of Canadian geneticists regarding permission for leftover newborn spots storage for research purposes and the associated risks, a web-based survey was distributed to all members of the Canadian College of Medical Geneticists with a valid e-mail address (n = 209) and completed by 78 respondents (37%). RESULTS: The majority of respondents (73%) favored opt-out notification for retention of samples that would be held for longer than 2 years. For research on multifactorial conditions using leftover newborn spots originally banked without parental permission, geneticists favored different types of permission depending on the level of identifiable information attached to samples. Thirty-eight percent were concerned that information pamphlets that state that leftover newborn spots will be stored and may be "a source of DNA for research" would lead to a decreased participation in newborn screening. Twenty-eight percent believed that group stigma or family anxiety was likely to result from using nonidentified leftover newborn spots to study multifactorial conditions. CONCLUSION: The concerns of this knowledgeable cohort supports the critical importance of public engagement about both the potential risks and societal benefits associated with the use of leftover newborn spots in research as policy for leftover newborn spots is developed. PMID- 20921894 TI - Generation after generation: exploring the psychological impact of providing genetic services through a cascading approach. AB - PURPOSE: The provision of genetic services often occurs in a cascading fashion within families experiencing inherited diseases. This study examines whether previous family experiences with genetic services influences levels of psychological well-being of family members receiving services later. METHODS: Two hundred ninety-seven persons from 38 families with Lynch syndrome completed questionnaires before receiving genetic services. Baseline levels of test-related distress, depressive symptoms, and cancer worries were assessed in relationship to the (1) amount of time elapsed since services were provided to the index case and (2) generation of the family member relative to the index case. RESULTS: Family members in the same generation as the index case experienced significant increases in test-related distress (P = 0.003) and cancer worry (P = 0.001) with increasing time between receipt of genetic test results by the index case and provision of services to family members. Change in the number of depressive symptoms was not significant (P = 0.17). CONCLUSION: The provision of genetic services through a cascading approach significantly increases distress and worry among family members within the same generation as the index case who receive services at increasingly distant time intervals. Additional research is needed to explore social influences after the introduction of genetic services. PMID- 20921896 TI - Time to prophylactic surgery in BRCA1/2 carriers depends on psychological and other characteristics. AB - PURPOSE: To investigate the medical and psychosocial factors determining the time to prophylactic surgery of unaffected women carriers of a deleterious BRCA1/2 mutation. METHODS: Prospective study on a French national cohort of unaffected BRCA1/2 carriers (N = 244); multivariate Cox proportional hazard modeling. RESULTS: Median follow-up time was 2.33 years (range, 0.04-6.84 years). Time to surgery was shorter when the psychological impact of BRCA1/2 result disclosure was stated to be higher (P <= 0.01). Those who intended to opt for prophylactic surgery before being tested did so faster and more frequently after test disclosure than those who were undecided/opposed. The older the women were, the faster their uptake of risk-reducing salpingo-oophorectomy (adjusted hazard ratio >2.95; P < 0.001) was; the uptake of those with at least two children was also faster (adjusted hazard ratio = 2.51; [1.38-4.55]). Those who opted most quickly for risk-reducing mastectomy more frequently had a younger child at the time of testing (adjusted hazard ratio = 4.63 [1.56-13.74]). Time to surgery was shorter when there was a first-degree relative with ovarian/breast cancer (P <= 0.01). CONCLUSION: Time to prophylactic surgery depends on the stated psychological impact of disclosure and on women's cognitive anticipation of surgery after adjusting on sociodemographic characteristics. PMID- 20921897 TI - Population prevalence of familial cancer and common hereditary cancer syndromes. The 2005 California Health Interview Survey. AB - PURPOSE: Family history guides cancer prevention and genetic testing. We sought to estimate the population prevalence of increased familial risk for breast, ovarian, endometrial, prostate, and colorectal cancers and hereditary cancer syndromes that include these cancers. METHODS: Using the 2005 California Health Interview Survey data, a weak, moderate, or strong familial cancer risk was assigned to 33,187 respondents. Guidelines were applied to identify individuals with hereditary breast-ovarian cancer and hereditary nonpolyposis colon cancer. RESULTS: Among respondents without a personal history of cancer, familial breast cancer was most prevalent; 7% had a moderate and 5% a strong familial risk. Older individuals and women were more likely to report family history of cancer. Generally, whites had the highest prevalence, and Asians and Latinos had the lowest prevalence. Among women without a personal history of breast or ovarian cancer, 2.5% met criteria for hereditary breast-ovarian cancer, and among individuals without a personal history of colorectal, endometrial or ovarian cancer, 1.1% met criteria for hereditary nonpolyposis colon cancer. CONCLUSIONS: We provide population-based prevalence estimates for moderate and strong familial risk for five common cancers and hereditary breast-ovarian cancer and hereditary nonpolyposis colon cancer. Such estimates are helpful in planning and evaluation of genetic services and prevention programs, and assessment of cancer surveillance and prevention strategies. PMID- 20921900 TI - Macrophage activation syndrome: why and what should a gastroenterologist know. AB - We recently treated a patient with adult-onset Still's disease who developed macrophage activation syndrome (MAS) secondary to disseminated histoplasmosis while being treated with adalimumab. The gastroenterology service was consulted early, before diagnosis, as the patient presented with elevated liver enzymes and disseminated intravascular coagulation. MAS is an exaggerated immune response that can develop as a primary condition or secondary to infections, drugs and various diseases, resulting in liver dysfunction, encephalopathy, pancytopenia and disseminated intravascular coagulation. The development of MAS has also been reported in patients with inflammatory bowel disease and post-liver transplantation and has been triggered by medications used by gastroenterologists, particularly sulfasalazine and anti-tumor necrosis factor biologic modifiers. Therefore, we present a review on etiology, pathogenesis, clinical and laboratory features, and treatment of MAS with a focus on gastrointestinal aspects and presentations. MAS is a life threatening condition with a high mortality rate if untreated. Therefore it is important to recognize this condition early. As these patients may occasionally present to gastroenterologists we hope this review will increase awareness of this rare, but serious syndrome. PMID- 20921899 TI - Extreme genetic divergence is required for coreceptor switching in HIV-1 subtype C. AB - BACKGROUND: Coreceptor switching from CCR5 to CXCR4 is less common in subtype C HIV-1 infection than in subtype B for reasons that are unclear. We have examined sequential virus samples from a subtype C-infected child who had evidence of coreceptor switching. METHODS: To examine HIV-1 envelope evolution towards CXCR4 usage, env sequences were correlated with phenotypic characteristics determined by entry assays, as well as the ability to use alternative coreceptors such as FPRL1, CCR3, CCR8 and others. The value of a phenotype predictor based on V3 sequences was also assessed. RESULTS: Ninety-three sequences revealed 3 distinct coexistent virus lineages and only some members of one lineage evolved to use CXCR4. These lineages also had diverse alternative coreceptor patterns including the ability to use FPRL1, CCR3, CCR8, APJ, CMKLR1, RDC-1, CXCR6, CCR1, GPCR1, GPR15 and CCR6. Coreceptor switching was associated with extensive and rapid sequence divergence in the V1/V2 region in addition to V3 changes. Furthermore, interlineage recombination within the C2 region resulted in low predictability of a V3 sequence-based phenotype algorithm, and highlighted the importance of V1/V2 and V3 sequences in coreceptor usage. CONCLUSION: These results suggest that the evolution to coreceptor switching in subtype C infection requires more mutations than other subtypes, and this contributes to the reduced incidence of R5X4 viruses. PMID- 20921901 TI - Eosinophilic myenteric ganglionitis: a case of intestinal pseudo-obstruction in a 93-year-old female. AB - Eosinophilic myenteric ganglionitis is a disorder characterized by infiltration of the Auerbach plexus by eosinophils. It can be associated with a bowel dysmotility and a few cases of intestinal pseudo-obstructive syndrome have been described in children. In this case report, we present an elderly 93-year-old woman who presented with episodes of functional bowel obstruction of unknown etiology. After several admissions for recurrent obstipation requiring fecal disimpaction, she had a Hartmann procedure performed with a resection of the sigmoid colon. The sigmoid colon was markedly dilated and the only significant finding on histology was infiltration of the Auerbach plexus by eosinophils. The mucosa and the muscular layers appeared unremarkable. Her symptoms resolved after the resection and the patient is currently well after 5 months. Recurrent gastrointestinal pseudo-obstruction can arise secondary to eosinophilic myenteric ganglionitis even in adults. Clinical improvement is likely if this disease entity is promptly recognized and treated. PMID- 20921898 TI - Sustained long-term antiviral maintenance therapy in HCV/HIV-coinfected patients (SLAM-C). AB - BACKGROUND: Hepatitis C virus (HCV)/HIV coinfection treatment is suboptimal with low sustained viral response rates to standard therapies. A multicenter randomized clinical trial designed to assess the efficacy/safety of pegylated interferon maintenance therapy was performed by the National Institutes of Health funded AIDS Clinical Trials Group network. METHODS: HCV treatment-naive and nonresponding interferon-experienced subjects with confirmed HCV and HIV, CD4 >200 cells per cubic millimeter, and at least stage 1 fibrosis were enrolled and treated for 12 weeks with pegylated interferon alfa 2a 180 mcg per week (PEG) + weight-based ribavirin to determine response status. Nonresponder subjects (failure to clear HCV RNA or achieve 2-log drop) underwent liver biopsy and were randomized to receive full dose PEG or observation only for 72 weeks. Paired biopsies were evaluated by a central pathologist. RESULTS: Three hundred thirty subjects were enrolled; median age was 48 years; 43% white, 37% black, non Hispanic; 83% male; CD4+ 498 cells per cubic millimeter; 32% were interferon experienced; 74% had entry HIV RNA <50 copies per milliliter. early virologic responder was observed in 55.9% and 42.5% achieved complete Early Viral Response (cEVR). A planned interim analysis of occurred when 84 subjects were randomized. With data on 40 paired biopsies available, a safety monitoring board stopped the trial due to lack of fibrosis progression (median = 0 Metavir units/year) in the observation arm. CONCLUSIONS: Lack of fibrotic progression in the control arm was unexpected and may represent a short-term PEG/ribavirin therapy effect, high levels of HIV viral suppression, and use of antiretroviral regimens that may be less toxic than prior generations of therapy. PMID- 20921902 TI - Initial report of a variable stiffness duodenoscope for use during endoscopic retrograde cholangiopancreatography. AB - GOALS: To evaluate a new variable stiffness duodenoscope. BACKGROUND: Variable stiffness colonoscopies have been in use for nearly a decade. We report the initial experience with a new, variable stiffness duodenoscope for use during endoscopic retrograde cholangiopancreatography (ERCP). STUDY: Retrospective, single tertiary referral academic center. Among the first 50 patients to undergo ERCP with the variable stiffness cope, 3 patients in whom the variable stiffness duodenoscope was instrumental in procedural success are discussed in detail. RESULTS: In the first 50 patients in whom the variable stiffness duodenoscope was used, the variable stiffness function was critical to procedural success in 3 patients (6%). One patient had a gastric bypass with Roux-en-Y anatomy, 1 patient had a large J-shaped stomach that could not be traversed by a routine duodenoscope, and 1 patient had a duodenal stenosis that could not be traversed by a routine duodenoscope. In these 3 patients, the variable stiffness function allowed for procedure success. CONCLUSIONS: Although most ERCPs can be accomplished with standard duodenoscopes, in cases in which extra endoscope stiffness was felt to be required, the variable stiffness function was extremely helpful. PMID- 20921903 TI - Interobserver agreement for pancreatic endoscopic ultrasonography determined by same day back-to-back examinations. AB - GOALS: We aimed to determine interobserver agreement between endosonographers for pancreatic morphology by performing same day back-to-back endoscopic ultrasonography (EUS) examinations on patients without known hepatopancreaticobiliary disease. BACKGROUND: Morphologic EUS examination is often used to make the diagnosis of chronic pancreatitis, although perceived lack of interobserver agreement limits it accuracy. STUDY: A prospective clinical trial was performed in patients without known hepatopancreaticobiliary disease referred for EUS. All subjects underwent back-to-back same day EUS examinations at our institution performed by 2 blinded endosonographers. The main outcome measurement was the Cohen kappa scores between endosonographers calculated for each parenchymal and ductal EUS feature. RESULTS: Twenty-four patients were male and indications for EUS included staging of esophageal malignancy (10), submucosal mass (9), lymphadenopathy (7), gastrointestinal stromal tumor (4), and other (14). Both endosonographers agreed that 32% (14 of 44) had hyperechoic strands, 30% (13 of 44) had hyperechoic duct walls, 16% (7 of 44) had hyperechoic foci, 14% (6 of 44) had a dilated main pancreatic duct, 9% (4 of 44) had parenchymal lobularity, and 5% (2 of 44) had parenchymal cysts. Kappa scores showed "good" or better correlation only for the presence of hyperechoic strands and parenchymal cysts; the presence of parenchymal lobularity, a dilated main pancreatic duct, and hyperechoic foci had "moderate" correlation. The correlation for the presence of hyperechoic foci was "fair." CONCLUSIONS: Same day back-to back EUS examinations on patients without known hepatopancreaticobiliary disease showed a wide variation in interobserver agreement for standard pancreatic morphologic findings. These results suggest the need for improvements in the current EUS classification system of chronic pancreatitis. PMID- 20921904 TI - Role of ghrelin and insulin-like growth factor binding protein-3 in the development of osteoporosis in inflammatory bowel disease. AB - BACKGROUND: A high prevalence of bone loss is observed in patients with inflammatory bowel disease (IBD). Leptin, ghrelin, insulin-like growth factor (IGF)-1, and IGF binding protein (IGFBP)-3 have been suggested to interfere in the bone metabolism. The aim of this study was to investigate the role of these peptides in the development of osteoporosis in IBD. METHODS: One hundred and eighteen consecutive IBD patients were included. All patients underwent bone densitometry by dual energy x-ray absorptiometry at the femoral neck and lumbar spine levels. Serum samples were collected from all patients and analyzed for concentrations of the aforementioned peptides by radioimmunoassay. RESULTS: Forty (33.9%) patients were normal, 55 (46.6%) were osteopenic, and 23 (19.5%) were osteoporotic. Positive statistically significant correlations were found between body mass index (BMI), leptin, IGFBP-3 levels, and the bone mineral density (BMD) of the femoral neck and lumbar spine. Moreover, an inverse statistically significant correlation was found between BMD of the femoral neck and the lumbar spine, and age, duration of the disease, and ghrelin levels. Multivariate analysis revealed that the most significant factors associated with the BMD were age and BMI. A weak but statistically significant correlation was found between IGFBP-3 and femoral neck BMD (P=0.045) and between ghrelin and spine BMD (P=0.039). No correlation was observed between leptin and BMD. CONCLUSIONS: Low BMI is the most important independent risk factor for osteoporosis in IBD patients. There is no independent influence of leptin but ghrelin and IGFBP-3 may play a role in the bone metabolism in the IBD. PMID- 20921905 TI - Mixed variant multicentric Castleman disease treated with rituximab: case report. PMID- 20921906 TI - The safety, tolerability, and efficacy of a liquid formulation of deferiprone in young children with transfusional iron overload. AB - Limited data are available on the use of deferiprone in children younger than 10 years of age. This study evaluated the safety and efficacy of a new liquid formulation of deferiprone for the treatment of transfusional iron overload in children 1-10 years old. One hundred children (91 thalassemia major, 8 Hb E-beta thalassemia, and 1 sickle cell disease) were enrolled for a 6-month treatment with deferiprone (50 to 100 mg/kg/d). The safety profile was similar to or better than that reported in earlier studies with deferiprone tablets in older children and adults. No unexpected adverse reactions were observed. Gastrointestinal intolerance (GI) was observed in 11% and an increased serum ALT in 12% of the children. Both events were transient. Mild neutropenia, observed in 6% of patients, did not progress to agranulocytosis and resolved despite continuous deferiprone treatment. Two patients experienced agranulocytosis that resolved without complications upon discontinuation of therapy. Deferiprone use was associated with a significant decline in mean serum ferritin level from 2532+/ 1463 MUg/L at baseline to 2176+/-1144 MUg/L (P<0.0005). The results of this study show a favorable benefit/risk ratio of deferiprone oral solution for the treatment of young children with transfusional iron overload. PMID- 20921907 TI - Anaphylactic reaction owing to ondansetron administration in a child with neuroblastoma and safe use of granisetron: a case report. AB - A 1-year-old girl with stage-IV neuroblastoma developed ondansetron hydrochloride anaphylaxis. Safe use of granisetron as an antiemetic after skin prick, oral, and intravenous challenge tests is presented. We present this case to emphasize that ondansetron hydrochloride may cause a serious anaphylactic reaction. In such a case, granisetron may be given to patients as an antiemetic after some provocative tests performed. PMID- 20921908 TI - Reduced methotrexate clearance and renal impairment in a boy with osteosarcoma and earlier undetected autosomal dominant polycystic kidney disease (ADPKD). AB - We report a 12-year-old boy with osteoblastic osteosarcoma of the right femur. He was started on chemotherapy according to the EURAMOS/COSS 1 protocol. Chemotherapy with doxorubicin/cisplatin resulted in reversible acute renal failure and methotrexate levels were repeatedly elevated. Family history suggested an autosomal dominant polycystic kidney disease. Genetic testing revealed a novel mutation c.10707_10712del (p.Val3569_3570del) in exon 36 of the PKD1 gene. Patients with autosomal dominant polycystic kidney disease may be at risk for acute renal failure during chemotherapy without signs of renal impairment. A careful family history is important to exclude risk factors for renal impairment before introducing high-dose chemotherapy. PMID- 20921909 TI - A trial to assess the efficacy of glutamic acid in prevention of vincristine induced neurotoxicity in pediatric malignancies: a pilot study. AB - Vincristine is considered as a backbone of therapy in the induction and consolidation phases of pediatric malignancies. Neurotoxicity is a principal side effect of its use. This study is a randomized single-blinded placebo-controlled clinical trial to evaluate the role of glutamic acid in ameliorating neurotoxicity in pediatric patients with hematologic and solid tumors receiving vincristine during induction course. Fifty-four patients in the glutamic acid group received glutamic acid 1.5 grams daily orally in 3 divided doses during the 4-week induction with vincristine in a dose of 1.5 mg/m2 IV weekly. Placebo group (40 patients) received oral placebo 3 times daily in the same way as the glutamic acid group. The onset of neurotoxicity was significantly earlier in placebo group than in glutamic acid group regarding tendon Achilles reflex, Patellar reflex, parasthesia, and increased frequency of constipation. This was statistically significant mostly in third and fourth visits, no severe cases of strength and mental alteration side effects in both groups. Glutamic acid was well tolerated with no gastrointestinal side effects in patients. This study suggests that the coadministration of oral glutamic acid with repetitive intravenous bolus injections of vincristine resulted in a reduction of its neurotoxicity. PMID- 20921910 TI - Prevalence of valvular regurgitation in adolescent idiopathic scoliosis patients. AB - Sixty-seven adolescent scoliosis patients with thoracic curve (Lenke type 1, 3, and 6) and 16 nonthoracic curve patients (Lenke type 5) were evaluated with color Doppler echocardiography to identify and compare the prevalence and frequency of valvular regurgitation. Regurgitation of one or more valves was detected in 36 thoracic curve patients (53.73%) and seven nonthoracic curve patients (43.75%). Regurgitation with tricuspid valve involvement was statistically significant in patients with thoracic curve (P=0.0216). Frequency of tricuspid valve involvement was statistically significant (28.57 vs. 83.33%, P=0.0076) in patients with thoracic curve. Those without cardiac disease had a higher incidence of valvular regurgitation. PMID- 20921911 TI - Focal fatty areas in the myocardium of patients with tuberous sclerosis complex: a unique finding. AB - With this collection of computed tomography and magnetic resonance images, we illustrate a recently described novel finding in the myocardium of patients with tuberous sclerosis complex. PMID- 20921912 TI - Takotsubo cardiomyopathy: utility of cardiac computed tomography angiography for acute diagnosis. AB - Takotsubo (stress) cardiomyopathy may present as acute cardiovascular collapse, simulating an acute coronary syndrome or other emergencies such as pulmonary embolism or aortic dissection. The diagnosis relies on demonstration of characteristic wall motion abnormalities in the absence of obstructive coronary lesions and is typically diagnosed with cardiac catheterization. Cardiac computed tomography angiography is well suited to use in the emergency setting to diagnose or exclude thoracic cardiovascular events. We describe a case of Takotsubo cardiomyopathy that occurred during induction of anesthesia, in which emergent cardiac computed tomography angiography confirmed the diagnosis and excluded other potential etiologies of disease. PMID- 20921913 TI - Ovarian cancer: Listen for the disease that whispers. PMID- 20921914 TI - Fulminant valvulitis from acute rheumatic fever: successful use of extracorporeal support. AB - OBJECTIVE: To describe an unusual case of fulminant rheumatic fever presenting acutely as severe respiratory failure managed with extracorporeal membrane oxygenation and ultimately valve replacement while on extracorporeal membrane oxygenation. DESIGN: Case report. SETTING: Large quaternary care pediatric intensive care unit. PATIENT: A 6-yr-old female with profound respiratory failure found to be due to mitral valve dysfunction stemming from acute fulminant rheumatic fever. INTERVENTIONS AND MAIN RESULTS: The patient was originally maintained on venovenous extracorporeal membrane oxygenation but required conversion to venoarterial extracorporeal membrane oxygenation due to the progression of her mitral valve disease. Her condition did not improve with atrial septostomy, and she required valve replacement while anticoagulated. She was decannulated in the operating room and extubated 2 days later, and she survived to discharge. The institutional review board subsequently granted a waiver of consent for a report of this case. CONCLUSIONS: Manifestations of rheumatic fever can develop acutely even in the setting of an industrialized country. Valvulitis with severe, isolated mitral valve dysfunction may masquerade initially as respiratory failure. Multiple invasive procedures can be performed successfully while patients are fully anticoagulated and on extracorporeal membrane oxygenation support. PMID- 20921915 TI - Evaluation of a new pediatric continuous oximetry catheter. AB - PURPOSE: To evaluate the accuracy of central venous oxygen saturation recordings from a new in-line pediatric oximetry catheter. DESIGN: Prospective, observational study. STUDY POPULATION: Eighteen pediatric patients who needed central venous access for monitoring and/or treatment between January 2006 and June 2006 in the pediatric intensive care unit of the Hospital for Sick Children in Toronto, Canada. METHODS AND MAIN RESULTS: Measurements were done at the baseline and then every 4-8 hrs. The monitor was calibrated in vivo at the baseline and then daily. In vitro calibration of the monitor was also performed in the last five patients. The hemoglobin value was updated when there was a significant change. The maximum duration of sampling was 72 hrs (if indicated). There were 131 measurements in 17 patients; each subject had a different number of paired measurements (median 5). Three patients were excluded due to violation of the protocol, and 113 measurements were left in analysis. The mean difference of catheter value from the laboratory value was -1.01 (median 0). The interquartile range was 5. The difference of both methods was evenly distributed as per a Bland-Altman plot, with one patient's data lying outside of the comparable limits of +/- 1.96 sd from the mean differences. The relationship of the difference between the catheter data and the lab data to the independent variables (age, weight, gender, catheter tip, diagnosis, and signal quality index) was estimated by using the multiple regression analysis (version 9.1, SAS Institute, Cary, NC). All variables were eliminated. The Pearson correlation coefficient between lab-mixed venous oxygen saturation and oximetry catheter readings for measurements was 0.88. CONCLUSION: In this limited number of patients, use of the PediaSat venous oximetry catheter was safe and had good agreement with co-oximetry-measured values. PMID- 20921916 TI - U.S. attitudes and perceived practice for noninvasive ventilation in pediatric acute respiratory failure. AB - OBJECTIVE: Few pediatric studies exist regarding the use of noninvasive positive pressure ventilation for acute respiratory failure; however, those that do suggest a role. This study seeks to describe attitudes and perceived practices of pediatric intensivists regarding the use of noninvasive positive-pressure ventilation in children with acute respiratory failure. DESIGN: Electronic survey. SETTING: Medical institutions. PARTICIPANTS: Of the 932 physicians approached, 353 (38%) responded to the survey. Respondents included U.S. physicians practicing pediatric critical care (90%), pediatric anesthesia critical care (4%), pediatric pulmonary critical care (4%), and other disciplines (2%). INTERVENTIONS: Survey. MEASUREMENTS AND MAIN RESULTS: The survey contained questions regarding 1) practitioner demographics, 2) patient characteristics, and 3) clinical cases designed to assess noninvasive positive-pressure ventilation use in certain patient scenarios. Noninvasive positive-pressure ventilation was used by 99% of the respondents, with 60% using noninvasive positive-pressure ventilation as initial support >10% of the time. Respondents reported use of noninvasive positive-pressure ventilation for acute respiratory failure in lower airway disease (70%), asthma (51%), acute lung injury/acute respiratory distress syndrome (43%), and upper airway obstruction (31%). In clinical scenarios, respondents reported that the factors associated with nonuse of noninvasive positive-pressure ventilation as initial support were disease process (31%), oxygenation (19%), ventilation severity (15%), expectation that the patient was likely to worsen (12%), and age or inability to cooperate (11%). CONCLUSIONS: Noninvasive positive-pressure ventilation is widely used and most frequently utilized in patients with acute lower airway disease. Factors such as severe defects in oxygenation and ventilation, disease progression, and patient tolerability decreased the likelihood of use. These findings may help direct further studies of noninvasive positive-pressure ventilation in children with acute respiratory failure. PMID- 20921917 TI - Early blood exchange transfusion in malignant pertussis: a case report. AB - OBJECTIVE: To report early blood exchange transfusion in malignant pertussis and a favorable clinical outcome. SETTING: A pediatric intensive care unit in a tertiary hospital in Geneva, Switzerland. DESIGN: A descriptive case report. PATIENT: An 8-wk-old girl was diagnosed with malignant pertussis (extreme leukocytosis, seizures, pneumonia, and secondary severe hypoxic respiratory failure associated with pulmonary hypertension). After administration of a one volume blood exchange transfusion, a rapid decrease in white blood cell count (from 119,000/mm(3) to 36,500/mm(3)) was observed and followed by clinical improvement and favorable outcome despite the initial presence of all described risk factors associated with a high mortality. CONCLUSION: The use of exchange blood transfusion early in the course of the disease might help to prevent a fatal outcome of malignant pertussis. PMID- 20921918 TI - Toddlers requiring pediatric intensive care unit admission following at-home exposure to buprenorphine/naloxone. AB - BACKGROUND: Sublingual buprenorphine is an alternative to methadone for office based treatment of opioid dependence. Recent reports have examined a growing number of unintentional buprenorphine exposures in children resulting in significant toxicity, even after a single lick or taste of a sublingual tablet. Here, we report a series of unintentional buprenorphine exposures in toddlers over a 2.5-yr period that led to admission to the pediatric intensive care unit. OBJECTIVES: The goals of this study were to determine: 1) the prevalence of symptomatic buprenorphine exposure in children <3 yrs of age; 2) the severity of toxicity associated with such exposures; and 3) effective clinical interventions. METHODS AND MAIN RESULTS: A retrospective case review was performed on records from the pediatric intensive care unit at an academic medical center located in the northeastern United States. Unintentional buprenorphine/naloxone exposure (n = 9) accounted for the largest single fraction of toxic ingestions among patients younger than 3 yrs within the study period (9/33, 27%). All exposures occurred at the child's place of residence (n = 9, 100%). Clinical signs of opioid toxicity were evident in all nine cases, with the most common symptom being drowsiness or lethargy (n = 9, 100%), followed by miosis (n = 6, 67%) and respiratory depression (n = 5, 56%). Six patients were effectively treated with naloxone (n = 6, 67%). CONCLUSIONS: The increased use and similarity to candy of the current formulation of buprenorphine pose a special risk to children, especially toddlers. Buprenorphine exposure in children <3 yrs old can cause significant opioid toxidrome. Naloxone is an effective agent for reversal of symptoms; however, given buprenorphine's high affinity and long action, higher doses or continuous infusion may be required. Adults on buprenorphine should be educated on the risks posed to young children in their household and the appropriate storage of medication. PMID- 20921919 TI - Pediatric residents experience a significant decline in their response capabilities to simulated life-threatening events as their training frequency in cardiopulmonary resuscitation decreases. AB - OBJECTIVE: To determine the frequency of cardiopulmonary resuscitation education using high-fidelity patient simulators during pediatric residency training. DESIGN: Randomized controlled trial. SETTING: Suburban tertiary care children's hospital residency training program. SUBJECTS: Twenty-four second year pediatric residents. INTERVENTIONS: Twenty-four second year pediatric residents were randomized into two study groups, 12 residents in each. Both groups completed a formal resuscitation training course utilizing lectures, skill stations, and six scenarios on high-fidelity patient stimulators. Group A was retested on three scenarios 4 months after training and group B was similarly retested 8 months after training. MEASUREMENTS AND MAIN RESULTS: Time intervals from induction of a clinical problem to its definitive management were recorded for each resident. Residents were also asked to complete surveys following each episode of training and testing. The mean time intervals, for group A, to start effective bag mask ventilation and chest compressions in response to apnea and cardiac arrest were 17.75 secs (+/- 3.39 secs) and 23.42 secs (+/- 9.33 secs), respectively. These were significantly shorter than 32.7 secs (+/- 18.6 secs) and 81.2 secs (+/- 74.9 secs), for group B, respectively (p < .05). Residents in group A provided higher survey scores for their level of confidence in using cardiopulmonary resuscitation pharmacology than residents in group B did (p < .05). The two groups were no different in their response time to defibrillate or to start anti arrhythmia medications for life-threatening arrhythmias and in their endotracheal intubation skills. CONCLUSIONS: Pediatric residents show a significantly slower response time to effectively manage episodes of apnea and cardiac arrest 8 months after their initial resuscitation training, when compared to 4 months after training. These results may indicate that residents require more frequent training than currently recommended. PMID- 20921920 TI - Opportunities for antibiotic reduction in mechanically ventilated children. AB - OBJECTIVE: To identify opportunities to safely reduce antibiotic use in critically ill children with moderately severe respiratory failure. DESIGN: Prospective observational. SETTING: Four pediatric intensive care units at three American tertiary care children's hospitals. PATIENTS: Children aged 2 months to 18 yrs who were mechanically ventilated, had an abnormal chest radiograph, and for whom the attending physicians had initiated antibiotics for presumed bacterial pneumonia. INTERVENTION: Nonbronchoscopic bronchoalveolar lavage. METHODS AND MAIN RESULTS: Eligible children were subjected to nonbronchoscopic bronchoalveolar lavage within 12 hrs of initiating antibiotics. The concentration of bacteria in the lavage fluid was determined by quantitative assay, and the diagnosis of pneumonia was confirmed if >10 (4)pathogenic bacteria/mL were cultivated. Twenty-one subjects were enrolled, in whom 20 nonbronchoscopic bronchoalveolar lavage procedures were completed. Six of 20 subjects had nonbronchoscopic bronchoalveolar lavage results confirmatory of bacterial pneumonia, three additional subjects had bacteria isolated at concentrations below levels conventionally used to diagnose bacterial pneumonia, and the remaining 11 demonstrated no growth. Clinical parameters reflective of severity of disease and laboratory parameters reflective of systemic and local inflammation were tested for their association with a positive nonbronchoscopic bronchoalveolar lavage, but none was demonstrated. CONCLUSIONS: Eleven of 20 mechanically ventilated children treated with antibiotics for presumed infectious pneumonia had undetectable concentrations of bacteria in their lower respiratory tract, and three others had organisms present at low concentrations, suggesting that opportunities exist to reduce antibiotic exposure in this population. PMID- 20921921 TI - In the absence of a central venous catheter, risk of venous thromboembolism is low in critically injured children, adolescents, and young adults: evidence from the National Trauma Data Bank. AB - OBJECTIVE: To describe the incidence and risk factors of venous thromboembolism in a large sample of critical care pediatric, adolescent, and young adult trauma patients. DATA SOURCE: The National Trauma Data Bank-the largest and most complete aggregation of trauma registry data in the United States. SETTING: Seven hundred eighty-four level I to level IV trauma centers. PATIENTS: Patients <= 21 yrs of age who spent at least 1 day in a critical care unit during a trauma admission between 2001 and 2005. MEASUREMENTS AND MAIN RESULTS: To characterize differences between patients with and without venous thromboembolism, we extracted variables regarding patient demographics, injury pattern and severity, procedures, total length of stay, and intensive care unit and ventilator days. Odds ratios for predictors of venous thromboembolism were estimated with a logistic regression model. Among the 135,032 critical care patients analyzed, venous thromboembolism was uncommon (6 per 1,000 discharges). Placement of a central venous catheter was a significant predictor of venous thromboembolism (odds ratio = 2.24; p < .0001) when populations were analyzed collectively. When we narrowed our focus to injuries associated with venous thromboembolism, such as lower-extremity fractures, the effects of central venous catheter were of even greater magnitude, particularly in adolescents and young adults. The risk of venous thromboembolism in critical care patients without a central venous catheter was <1% even in adolescents/young adults. CONCLUSIONS: Venous thromboembolism is rare in young critical care trauma patients, even older adolescents. The absence of published data on both the baseline risk of venous thromboembolism in pediatric critical care patients and the efficacy and safety of venous thromboembolism prophylaxis preclude the ability to make definitive recommendations for the use of venous thromboembolism prophylaxis in this setting. Our results, however, suggest that venous thromboembolism prophylaxis may need to be considered only in critically injured adolescents and young adults with a continuing need for central venous access. PMID- 20921922 TI - Hemodynamic correlates of serum cortisol in neonates after cardiopulmonary bypass. AB - OBJECTIVES: To document preoperative and early postoperative serum cortisol levels among a group of neonates with complex congenital heart disease undergoing cardiopulmonary bypass surgery and to describe the relationship between serum cortisol and hemodynamic variables in the early postoperative period. DESIGN: Prospective observational substudy conducted within a randomized controlled trial. SETTING: Tertiary-care pediatric cardiac intensive care unit. PATIENTS: : We consecutively enrolled neonates undergoing a modified Norwood procedure or repair of interrupted aortic arch with ventricular septal defect in a randomized, placebo-controlled trial of triiodothyronine replacement. Methylprednisolone (30 mg/kg intravenously) was administered at anesthetic induction. MEASUREMENTS AND MAIN RESULTS: We measured serum cortisol preoperatively and at 24 and 48 hrs postoperatively. Atrial filling pressures were documented 24 and 48 hrs after surgery. Oxygen consumption was measured and cardiac index was calculated 48 hrs after surgery. Spearman's correlation and linear regression were used to examine the relationship between serum cortisol and postoperative variables. Thirty-eight patients met eligibility criteria. Median serum cortisol levels 24 and 48 hrs postoperatively were 5.0 MUg/dL (range 0.4-74.0) and 4.0 MUg/dL (range 0.3-17.0), respectively (p = not significant). Greater atrial filling pressures were correlated with higher serum cortisol levels 24 hrs (r = .42, p = .019) and 48 hrs (r = .46, p = .022) after surgery. A lower cardiac index was correlated with higher serum cortisol levels 48 hrs postoperatively (r = -.49, p = .039), and this relationship remained significant after controlling for inotrope score, treatment with triiodothyronine, and atrial filling pressure in bivariate models. Systolic and diastolic BP did not correlate with serum cortisol at 24 or 48 hrs. CONCLUSIONS: Serum cortisol levels were low in the majority of subjects, although a wide range was observed. Higher cortisol levels were associated with greater atrial filling pressures and a lower cardiac index. The relationship between serum cortisol and cardiovascular performance after cardiopulmonary bypass in infants warrants further evaluation. PMID- 20921923 TI - Continuous veno-venous single-pass albumin hemodiafiltration in children with acute liver failure. AB - OBJECTIVE: To investigate the applicability, efficacy, and safety of single-pass albumin dialysis in children. DESIGN: Retrospective data review of uncontrolled clinical data. SETTING: University-based pediatric intensive care unit collaborating with a local center for liver transplantation. PATIENTS: Nine children, aged 2 to 15 yrs, who were treated with single-pass albumin dialysis for acute liver failure of various origins under a compassionate-use protocol between 2000 and 2006. All patients met high-urgency liver transplantation criteria. INTERVENTIONS: Single-pass albumin dialysis was performed as rescue therapy for children with acute liver failure. MEASUREMENTS AND MAIN RESULTS: The decrease in hepatic encephalopathy (grades 1-4) and the serum levels of bilirubin, bile acids, and ammonium were measured to assess the efficacy of detoxification. As a measure of liver synthesis function, thromboplastin time and fibrinogen were analyzed. The safety of the procedure was assessed by documenting adverse effects on mean arterial blood pressure, platelet count, and clinical course. Seven out of nine patients were bridged successfully to either native organ recovery (n = 1) or liver transplantation (n = 6), one of them twice. Six out of nine patients undergoing single-pass albumin dialysis (ten treatments) survived. In six patients, hepatic encephalopathy could be reduced at least by one degree. Ammonium, bilirubin, and bile acid levels decreased in all patients. One patient had an allergic reaction to albumin. CONCLUSIONS: In childhood acute liver failure, treatment with single-pass albumin dialysis was generally well tolerated and seems to be effective in detoxification and in improving blood pressure, thus stabilizing the critical condition of children before liver transplantation and facilitating bridging to liver transplantation. It may be beneficial in avoiding severe neurologic sequelae after acute liver failure and thereby improve survival. Single-pass albumin dialysis is an inexpensive albumin based detoxification system that is easy to set up and requires little training. Whether and to what extent single-pass albumin dialysis can support children with acute liver failure until native liver recovery remains unclear. PMID- 20921924 TI - Relationship Between Neonatal Blood Protein Concentrations and Placenta Histologic Characteristics in Extremely Low GA Newborns. AB - Amniotic fluid infection with chorioamnionitis is associated with increased risks of morbidity and mortality in children born prematurely. These risks depend on the presence of a fetal inflammatory response. We measured the concentrations of 25 proteins in the blood of 871 infants born before the 28th wk of gestation and examined their placentas for acute inflammation. Newborns who had inflammatory lesions of the placenta were much more likely than their peers (p < 0.01) to have elevated blood concentrations of cytokines (IL-1beta, IL-6, and TNF-alpha), chemokines (IL-8, MIP-1beta, RANTES, and I-TAC), adhesion molecules (ICAM-1, ICAM 3, and E-selectin), matrix metalloproteinases (MMP-1 and MMP-9), the angiogenic inflammatory factor VEGF and its receptor VEGF-R2, and acute phase proteins (SAA and CRP) during the first 3 d after birth. In contrast, newborns with poor placental perfusion had lower levels of inflammatory proteins (p < 0.01; IL-6, RANTES, ICAM-1, ICAM-3, VCAM-1, E-selectin, MMP-1, MMP-9, MPO, and VEGF). An inverse pattern was found between newborn levels of VEGF and its competitive inhibitor VEGF-R1 in both the inflamed and poorly perfused placenta categories. These results confirm the predictive value of placental histology for the presence or absence of elevated inflammatory response in newborns. PMID- 20921925 TI - Effect of single nucleotide polymorphisms within the interleukin-4 promoter on aspirin intolerance in asthmatics and interleukin-4 promoter activity. AB - OBJECTIVE: Aspirin affects interleukin-4 (IL-4) synthesis; however, the genetic role of IL-4 has not been evaluated in asthmatics with aspirin hypersensitivity. The objective of the study was to examine the influence of single nucleotide polymorphisms (SNPs) in IL-4 gene on aspirin hypersensitivity in asthmatics at the genetic and molecular levels. METHODS: Aspirin-intolerant (AIA, n=103) and aspirin-tolerant asthmatics (n=270) were genotyped and functional promoter assays were performed. RESULTS: Of 15 SNPs tested, seven (-589T>C (rs2243250) in promoter, -33T>C (rs2070874) in the 5'-untranslated region, +4047A>G (rs2243266), +4144C>G (rs2243267), +4221C>A (rs2243268), +4367G>A (rs2243270), and +5090A>G (rs2243274) in introns) were significantly associated with AIA risk. The frequency of the rare allele (C) of -589T>C was higher in the AIA group than in the aspirin-tolerant asthmatic group (P=0.016), and a gene dose-dependent decline in forced expiratory volume in 1 s was noted after an aspirin challenge (P=0.0009). Aspirin unregulated IL-4 mRNA production in Jurkat T and K562 leukemia cells. A reporter plasmid assay revealed that aspirin augmented IL-4 promoter transactivation with the -589T>C C and -33T>C C alleles, compared with that bearing the -589T>C T and -33T>C T alleles. Further, electrophoretic mobility shift assay showed the formation of nuclear complexes with -33T>C and 589T>C allele-containing probes; this was augmented by aspirin. The complexes formed with the -33T>C and -589T>C probes were shifted by treatment with anti CCAAT-enhancer-binding proteins beta and anti-nuclear factor of activated T-cells antibodies, respectively, indicating the inclusion of these transcription factors. CONCLUSION: Aspirin may regulate IL4 expression in an allele-specific manner by altering the availability of transcription factors to the key regulatory elements in the IL4 promoter, leading to aspirin hypersensitivity. PMID- 20921926 TI - Residual triamcinolone acetonide sequestered in the fovea after macular hole repair. AB - PURPOSE: To report the macular hole closure rate and visual outcomes of patients with residual triamcinolone acetonide in the fovea after macular hole repair. METHODS: We reviewed the medical records of consecutive patients who underwent macular hole surgery at our institution between 2005 and 2008. Only patients with visible triamcinolone in the fovea in the first postoperative month were included. RESULTS: Six patients with Stage III or IV macular holes were included. All patients underwent pars plana vitrectomy, internal limiting membrane peeling, and gas tamponade. Triamcinolone acetonide was used to visualize the vitreous in every patient, and diluted indocyanine green was used to stain the internal limiting membrane in five patients. The median preoperative best-corrected visual acuity was 20/200, which improved to a median of 20/40 at the last follow-up. Five patients eventually developed retinal pigment epithelial alterations. Anatomic hole closure was achieved in every patient. The mean follow-up was 23 months (range, 3-36 months). CONCLUSION: Residual triamcinolone sequestered in the fovea after macular hole surgery did not affect hole closure or prevent improvement in visual acuity. It is unclear whether the retinal pigment epithelial alterations in our patients represent toxicity or are unrelated to the triamcinolone exposure. PMID- 20921927 TI - Nidek MP1 is able to detect subtle decline in function in inherited and age related atrophic macular disease with stable visual acuity. AB - PURPOSE: To investigate whether the Nidek MP1 microperimeter (NAVIS software Version 1.7; Nidek Technologies, Padua, Italy) can detect functional decline in progressive atrophic macular disease with stable visual acuity. METHODS: Nine eyes of nine patients with stable acuity but progressive inherited or age-related atrophic macular disease evident on fundus autofluorescence imaging were reviewed. Each patient underwent 3 consecutive microperimetry tests at baseline, 6 months, and 12 months. Acuity, fixation, and microperimetry tests were performed at each visit. Changes in acuity, fixation stability, and macular sensitivity were analyzed. To detect regional change in retinal sensitivity, the test grid was divided into clusters based on either topographical or functional features. The mean sensitivities within each zone were also compared across the three visits. RESULTS: In this cohort, there was no significant change in visual acuity, fixation stability, and macular sensitivity over 1 year. However, significant decline in mean sensitivity within the central macula and test loci adjacent to dense scotoma was found (P = 0.004 and 0.002, respectively). In contrast, mean sensitivity elsewhere remained stable. CONCLUSION: The MP1 can detect significant change in regional retinal sensitivity within 12 months in patients with progressive atrophic macular disease and stable acuity. Individualized analysis of regional sensitivity may be a useful method for quantifying microperimetry. PMID- 20921928 TI - Grading diabetic retinopathy severity from compressed digital retinal images compared with uncompressed images and film. AB - PURPOSE: To compare research grading of diabetic retinopathy (DR) severity level from compressed digital images versus uncompressed images and film. METHODS: Compressed (JPEG2000, 37:1) digital images (C) were compared with uncompressed digital (U) and film (F) stereoscopic photographs from a 152-eye cohort with full spectrum Early Treatment Diabetic Retinopathy Study severity levels for agreement on severity level, DR presence with ascending severity threshold, presence of DR index lesions, and repeatability of grading. RESULTS: Classification of Early Treatment Diabetic Retinopathy Study severity levels from C images agreed substantially with results from F images (kappa = 0.60, kappa(w) [linear weighted] = 0.86) and uncompressed digital images (kappa = 0.76, kappa(w) = 0.92). For agreement of uncompressed digital versus F images, kappa = 0.62 and kappa(w) = 0.86. Distribution of Early Treatment Diabetic Retinopathy Study levels was not significantly different between C and F images (P = 0.09, Bhapkar's test for marginal homogeneity). For presence/absence of DR at 8 ascending severity thresholds, agreement between C and F was "almost perfect" (kappa >= 0.8). Agreement on severity level between readers with C images was at least as good as that with uncompressed digital image or F. Repeatability of severity threshold grading between readers was similar using C or F images. For identifying individual DR lesions, agreement between C and F ranged from "moderate" to "perfect." Agreement of grading venous beading from C was slightly lower than from F. CONCLUSION: Full Early Treatment Diabetic Retinopathy Study scale DR severity level grading using C images is comparable to that using U images or film. PMID- 20921929 TI - Intravitreous injection of bevacizumab, tissue plasminogen activator, and gas in the treatment of submacular hemorrhage in age-related macular degeneration. AB - PURPOSE: To investigate the benefit of adding bevacizumab to intravitreal recombinant tissue plasminogen activator (rTPA) and gas as initial therapy in subretinal hemorrhage and choroidal neovascularization because of age-related macular degeneration. METHODS: Thirty-eight consecutive patients with recent (1 31 days) subretinal hemorrhage who were treated with intravitreal rTPA and gas (26 patients) or with intravitreal bevacizumab, rTPA, and gas (12 patients) were included in this retrospective analysis. In all patients, a standardized antivascular endothelial growth factor therapy was followed. Testing of best corrected visual acuity, biomicroscopy, and fundus examination were performed at 4 weeks and 7 months. RESULTS: The mean pretreatment best-corrected visual acuity in the rTPA/gas group was 0.08 +/- 0.09 and 0.12 +/- 0.13 in the bevacizumab/rTPA/gas group. After 4 weeks, it was significantly higher in the bevacizumab/rTPA/gas group (0.25 +/- 0.26) than in the rTPA/gas (0.08 +/- 0.1) group (P < 0.05). Also, after 7 months, best-corrected visual acuity was significantly higher in the bevacizumab/rTPA/gas group (0.07 +/- 0.07 vs. 0.24 +/ 0.35; P < 0.05). Reading vision could be restored in 0% (rTPA/gas) versus 50% (bevacizumab/rTPA/gas). Stabilization (0 +/- 2 lines) or improvement of best corrected visual acuity was obtained in 62% (rTPA/gas) versus 84% (bevacizumab/rTPA/gas). CONCLUSION: From our retrospective pilot study, there is a strong indication that the addition of intravitreal bevacizumab is safe and superior to the displacement of submacular hemorrhages alone with rTPA and gas. PMID- 20921930 TI - Changing patterns of sexual risk behavior among London gay men: 1998-2008. AB - OBJECTIVES: To examine changes in the sexual behavior of London gay men between 1998 and 2008. METHODS: Gay men using London gyms were surveyed annually between 1998 and 2005, and again in 2008 (n=6064; range, 482-834 per year). Information was collected on human immunodeficiency virus (HIV) status of the respondent, unprotected anal intercourse (UAI) in the previous 3 months, type (main or casual) and HIV status of partner for UAI. Nonconcordant UAI (ncUAI) was defined as UAI with a partner of unknown or discordant HIV status. Concordant UAI (cUAI) was defined as UAI with a partner of the same HIV status ("serosorting"). RESULTS: Between 1998 and 2008, the percentage of men reporting UAI increased from 24.3% to 36.6% (P=0.07). This overall increase concealed important differences between nonconcordant and concordant UAI. While the percentage of men engaging in cUAI increased steadily between 1998 and 2008 (9.8%, 20.8%; P=0.01), the percentage reporting ncUAI increased between 1998 and 2001 (14.5%, 23.7%; P<0.001), decreased between 2001 and 2005 (23.7%, 15.6%; P<0.001), and then leveled off between 2005 and 2008 (15.6%, 15.7%; P=0.2). However, the percentage of men reporting ncUAI with a main partner increased between 2005 and 2008 for HIV-positive men (2.5%, 8.1%; P<0.05) and HIV negative men (2.1%, 5.5%; P=0.06). While the percentage of HIV negative men who reported cUAI with a main partner (i.e., serosorting) increased between 1998 and 2008 (12.4%, 21.1%; P<0.05), less than half established seroconcordance by testing together. CONCLUSIONS: The patterns of sexual behavior among London's gay men between 1998 and 2008 were dynamic and complex. Our data suggest that HIV risk with a main partner and HIV testing among couples should be given greater priority by health promotion programmes. PMID- 20921931 TI - The short-term variability of bacterial vaginosis diagnosed by Nugent Gram stain criteria among sexually active women in Rakai, Uganda. AB - BACKGROUND: Studies evaluating clinical and behavioral factors related to short term fluctuations in vaginal microbiota are limited. We sought to describe changes in vaginal microbiota evaluated by Gram stain and assess factors associated with progression to and resolution of bacterial vaginosis (BV) at weekly intervals. METHODS: A cohort of 255 sexually experienced, postmenarcheal women provided self-collected vaginal swabs to assess vaginal microbiota by Nugent score criteria at weekly visits for up to 2 years contributing 16,757 sequential observations. Absolute differences in Nugent scores (0-10) and transition probabilities of vaginal microbiota states classified by Nugent score into normal (0-3), intermediate (4-6), and BV (7-10) between visits were estimated. Allowing each woman to serve as her own control, weekly time-varying factors associated with progression from normal microbiota to BV and resolution of BV to normal microbiota were estimated using conditional logistic regression. RESULTS: The distribution of absolute difference in Nugent scores was fairly symmetric with a mode of 0 (no change) and a standard deviation of 2.64. Transition probabilities showed weekly persistence, was highest for normal (76.1%) and BV (73.6%) states; whereas, intermediate states had similar probabilities of progression (36.6%), resolution (36.0%), and persistence (27.4%). Weekly fluctuation between normal and BV states was associated with menstrual cycle phase, recency of sex, treatment for vaginal symptoms, pregnancy, and prior Nugent score. CONCLUSIONS: Weekly changes in vaginal microbiota were common in this population. Clinical and behavioral characteristics were associated with vaginal microbiota transitioning, which may be used to inform future studies and clinical management of BV. PMID- 20921932 TI - Antimicrobial activity of flavonoids from Piper lanceaefolium and other Colombian medicinal plants against antibiotic susceptible and resistant strains of Neisseria gonorrhoeae. AB - BACKGROUND: The successful treatment of Neisseria gonorrhoeae (NG) infections is increasingly problematic because of the resistance of this pathogen to multiple antimicrobial agents. This development underscores the need for new antimicrobial sources. In the current study, 21 crude methanol extracts, from 19 plants used in Colombian traditional medicine for cutaneous infections, were screened for antimicrobial activity against NG. METHODS: Extracts were screened by disc susceptibility assay. In addition, the minimum inhibitory concentrations of active compounds from P. lanceaefolium were assayed using a panel of 26 NG strains comprising 12 antibiotic-resistant phenotypes. RESULTS: In all, 71% of the crude extracts exhibited antibacterial activity against the antibiotic susceptible NG strain WHO V, whereas 10% of the extracts inhibited penicillinase producing NG strain GC1-182. The crude extract of Piper lanceaefolium was the only extract to show significant activity without ultraviolet (UV) light activation. Preliminary screening identified 3 compounds in this plant possessing antimicrobial activity: the flavonoids 5,7-dihydroxyflavanone (pinocembrin), 2',4',6'-trihydroxychalcone (pinocembrin chalcone), and the prenylated benzoic acid derivative cyclolanceaefolic acid methyl ester. Pinocembrin and pinocembrin chalcone inhibited 100% of the NG panel at 64 MUg/mL and 128 MUg/mL, respectively, whereas cyclolanceaefolic acid methyl ester inhibited 44% of the strains at 128 MUg/mL. CONCLUSIONS: This is the first report of the antibacterial activity of Columbian plants against NG. The activity of the 2 flavonoids, pinocembrin, and pinocembrin chalcone, toward both susceptible and resistant NG strains makes them promising candidates for further research. PMID- 20921933 TI - Pandemic influenza A/H1N1 virus infection in solid organ transplant recipients: a multicenter study. AB - BACKGROUND: The 2009 novel influenza A/H1N1 virus pandemic did not spare solid organ transplant (SOT) recipients. We aimed to describe the behavior of pandemic influenza infection in a group of SOT recipients in Argentina. METHODS: Data from 10 transplant (Tx) centers were retrospectively collected for SOT that presented with a respiratory illness compatible with pandemic influenza A infection, between May and September 2009. Cases were defined as suspected, probable, or confirmed according to diagnostic method. RESULTS: Seventy-seven cases were included. No significant differences in presenting symptoms, pulmonary infiltrates, and graft involvement were found among 35 suspected, 19 probable, and 23 confirmed cases. The 33 ambulatory cases had significantly more sore throat and headache when compared with 34 cases admitted to medical ward (MW) and 10 admitted to intensive care unit (ICU), 9 of whom required ventilatory support. MW and ICU cases had significantly more dyspnea, hypoxemia, pulmonary infiltrates, and graft dysfunction. Time from onset of symptoms to first visit and to treatment was significantly longer in MW and ICU cases (P=0.008). Coinfections were found in six cases. Most cases received oseltamivir for 5 to 10 days. Six patients (7.8%) died from viral infection at a median of 15 days from admission. No differences in outcome were seen related to the transplanted organ, the immunosuppressive regimen, time from Tx, or confirmation of diagnosis. CONCLUSIONS: Mortality is higher in Tx recipients than in the general population. Poor outcome seems to be related to a delay in the beginning of treatment. PMID- 20921934 TI - Dual-kidney transplants as an alternative for very marginal donors: long-term follow-up in 63 patients. AB - BACKGROUND: Organ shortage has led to the use of dual-kidney transplant (DKT) of very marginal donors into a single recipient to increase the use of marginal organs. To date, few data are available about the long-term outcome of DKT and its usefulness to increase the pool of available organ. METHODS: We conducted a single-center cohort study of DKTs with longitudinal follow-up over an 8-year period. Between 1999 and 2007, 63 DKTs were performed. All kidneys from donors younger than 75 years refused by all centers for single transplantation, and kidneys from donors aged 75 years or older were routinely evaluated based on preimplantation glomerulosclerosis. Renal function, patient or graft survival, and perioperative complications were compared with 66 single kidneys from expanded criteria donors (ECD) and 63 ideal kidney donors. RESULTS: After a median follow-up of 56 months, patient or graft survival was similar between the three groups. Twelve-, 36-, and 84-month creatinine clearance were similar for DKT and ECD (12 months: 58 and 59 mL/min; 36 months: 54 and 60 mL/min; and 84 months: 62 and 51 mL/min, respectively). For the study period, the routine evaluation of very marginal kidneys for DKT in our center has led to an increase of 47% in the transplants from donors aged 50 years or older, which represent 12% at the level of our organ procurement organization. CONCLUSIONS: DKT patients can expect long-term results comparable with single kidney ECD. The implementation of a DKT program in our unit safely increased the pool of organs from marginal donors. PMID- 20921936 TI - Impaired bone geometry after heart and heart-lung transplantation in childhood. AB - BACKGROUND: Impaired bone health has been advocated after solid organ transplantation in adult and pediatric patients. Osteoporosis accompanied by fractures have been found also in heart transplantation recipients. METHODS: Parameters of bone mineral density (BMD) and bone geometry were measured in 34 patients (15 females, mean age: 14.6 +/- 5.5 years) 5.28 +/- 5.16 years after heart transplantation (n=30) and heart-lung transplantation (n=4) using peripheral quantitative computed tomography. Transplantation had been performed because of dilated cardiomyopathy in 25, congenital heart disease in five, idiopathic pulmonary hypertension in three patients, and arrhythmogenic right ventricular dysplasia in one patient at a mean age of 9.4 +/- 6.1 years. RESULTS: Trabecular BMD (z scores -0.82 +/- 0.50, P<0.01) was reduced and cortical BMD (0.62 +/- 1.17, P<0.05) increased in patients (n=11) on steroids, whereas patients on immunosuppression with tacrolimus showed normal trabecular BMD (-0.19 +/- 1.03). All patients had normal total cross-sectional area (CSA; -0.22 +/- 1.50) and relatively enlarged medullary CSA (0.44 +/- 1.37) resulting in smaller cortical CSA (-0.91 +/- 1.20, P<0.01). Mean muscle CSA was significantly reduced (-2.02 +/- 0.99, P<0.001) irrespective of glucocorticoid treatment and correlated significantly with cortical CSA (r=0.43, P=0.001). CONCLUSION: After heart transplantation and heart-lung transplantation in childhood, all our patients showed altered bone geometry and low muscle CSA. Patients on glucocorticoid treatment had additionally lower trabecular BMD. The clinical impact of these findings on increased risk for fractures has to be determined. PMID- 20921938 TI - Identification of p100 target promoters by chromatin immunoprecipitation-guided ligation and selection (ChIP-GLAS). AB - The multifunctional protein p100 is a vital transcriptional regulator that increases gene transcription by forming a physical bridge between promoter specific transcription factors and the basal transcription machinery. To identify potential signal transduction pathways in which human p100 acts as a coregulator and to find target promoter regions that may interact with p100, we performed a promoter microarray assay called chromatin immunoprecipitation-guided ligation and selection (ChIP-GLAS). From this assay, we determined that a set of promoter fragments, including several factors in the transforming growth factor beta (TGF beta) signaling pathway, exhibited interaction with p100. The ChIP-GLAS data were validated by RT-PCR assessing the mRNA expression of various factors in the TGF beta signaling pathway in cell lines. PMID- 20921939 TI - Enhancing the antihepatitis B virus immune response by adefovir dipivoxil and entecavir therapies. AB - Chronicity of hepatitis B (CHB) infection is characterized by a weak immune response to the virus. Entecavir (ETV) and adefovir dipivoxil (ADV) are effective in suppressing hepatitis B virus (HBV) replication. However, the underlying immune mechanism in the antiviral response of patients treated with nucleoside or nucleotide analogs is not clearly understood. In this study, regulatory T cells (Tregs) and intracellular cytokines, including IL-2, interferon (IFN)-gamma, tumor-necrosis factor (TNF)-alpha and IL-4, were measured prior to and at 12, 24, 36 and 48 weeks after treatment with ETV or ADV. The cytokines were increased from 24 to 48 weeks after treatment. Higher levels of Th1 cytokines were observed with ETV (n=29) versus ADV (n=28) treatment. By contrast, the numbers of Tregs in both groups were decreased. The altered cytokine profile and cellular component was accompanied by a decrease in HBV DNA levels in both groups, which may contribute to their therapeutic effect in CHB infection. Our findings suggest that the antiviral effect of the drugs may be attributed not only to their direct effect on virus suppression but also to their immunoregulatory capabilities. PMID- 20921940 TI - An instructive case of hypercalcemia preceding relapse of AML following allogeneic BMT. PMID- 20921941 TI - UVA (UVA-1) therapy for the treatment of acute GVHD of the skin. AB - Long-wavelength UVA (340-400 nm UVA-1) phototherapy has been reported to be effective in atopic dermatitis, localized scleroderma and T-cell-derived skin diseases. We retrospectively investigated 70 patients with acute cutaneous GVHD after allogeneic haematopoietic cell transplantation or donor lymphocyte infusion. Complete and partial responses with a median duration of 10 months were achieved in 49 (70%) and 17 (24.3%) patients, respectively. Overall, 47 (67.1%) patients were not treated with systemic steroids. Furthermore, immunosuppression could be tapered in 24 (34.3%) patients while they were receiving UVA-1 treatment. Responses were seen irrespective of age or type of conditioning. Treatment was very well tolerated. After a median follow-up of 18 (range 10-60) months, three patients developed epithelial skin neoplasia. We conclude that UVA 1 therapy is feasible, well tolerated and can be an effective treatment for acute GVHD of the skin, thereby avoiding the use of systemic steroids and/or allowing a more rapid tapering of systemic immunosuppression in a substantial number of patients. The results of this retrospective analysis warrant larger, prospective studies and the effectiveness of UVA-1 therapy should be compared with other established treatment modalities. PMID- 20921942 TI - Polyomavirus JC-targeted T-cell therapy for progressive multiple leukoencephalopathy in a hematopoietic cell transplantation recipient. AB - Progressive multifocal leukoencephalopathy (PML) associated with polyomavirus JC (JCV) infection has been reported to be usually fatal in allogeneic hematopoietic SCT (HSCT) recipients. We present the case of a 19-year-old HSCT patient diagnosed with JCV-associated PML after prolonged immunosuppression for severe GVHD. No short-term neurological improvement was observed after antiviral treatment and discontinuation of immunosuppressive therapy. Donor-derived JCV Ag specific CTLs were generated in vitro after stimulation with 15-mer peptides derived from VP1 and large T viral proteins. After adoptive CTL infusion, virus specific cytotoxic cells were shown in the peripheral blood, JCV-DNA was cleared in the cerebrospinal fluid and the patient showed remarkable improvement. Adoptive T-lymphocyte therapy with JCV-specific CTLs was feasible and had no side effects. This case suggests that adoptive transfer of JCV-targeted CTLs may contribute to restore JCV-specific immune competence and control PML in transplanted patients. PMID- 20921943 TI - Delayed platelet recovery after allogeneic transplantation: a predictor of increased treatment-related mortality and poorer survival. AB - Delayed platelet recovery (DPR) is common after allo-SCT. Insufficient data on risk factors and association with OS and TRM are available. We conducted a retrospective analysis of all allografts at the University of Minnesota between 2000 and 2005 to characterize the frequency of DPR (platelets <50 000/MUL by day 60), risk factors and related complications. A total of 850 patients with hematological malignancies and benign disorders were included. Myeloablative (MA) conditioning was used in 65% of the patients and 45% received umbilical cord blood (UCB) grafts. The 60-day cumulative incidence of platelet recovery was 40% in UCB, 57% in unrelated donor (URD) and 74% in sibling donor. Multivariate analysis confirmed that the variables associated with DPR were MA (versus reduced intensity) conditioning, graft source other than sibling donor, ABO major mismatch, recipient CMV-positive serostatus, the presence of grade II-IV acute GVHD and slower neutrophil recovery. These data demonstrate that DPR is frequent after allogeneic hematopoietic cell transplantation, especially after UCB. DPR is a significant independent risk factor for increased TRM and poorer OS along with HLA-mismatched URD, but not UCB, grade II-IV acute GVHD, old age and advanced disease stage. PMID- 20921944 TI - Plerixafor 'just in time' for stem cell mobilization in a normal donor. PMID- 20921945 TI - Retrospective analysis of common scoring systems and outcome in patients older than 60 years treated with reduced-intensity conditioning regimen and alloSCT. AB - In this retrospective study, 63 patients >60 years with hematological malignancies and treated with allo-SCT and with reduced-intensity conditioning (RIC) were reviewed. A total of 51% of patients suffered from AML or myelodysplastic syndromes. Disease status before transplantation was CR or PR 71 with 29% transplanted with active disease. Patients were classified according to three published prognostic indexes: (1) hematopoietic cell transplantation comorbidity index (HCT-CI); (2) European BMT (EBMT) score; and (3) Pretransplantation Assessment of Mortality (PAM) score. The 100-day and 1-year treatment-related mortality (TRM) were 6 and 22%, respectively, for the entire group. The 2-year OS and PFS were 60 and 58%, respectively. The incidence of grade II-IV acute GVHD (aGVHD) and extensive chronic GVHD was 46 and 48%, respectively. In a univariate analysis, neither the HCT-CI nor the EBMT score, nor the PAM score were predictive of TRM and OS. Only the occurrence of aGVHD affected the TRM and OS. ALLO-RIC is feasible in elderly patients. Even if those prognostic scores were not adapted to elderly patients, they did not predict for TRM and OS. aGVHD is the main cause of TRM and more efforts should be made to reduce its incidence without sacrificing graft vs tumor effect. PMID- 20921946 TI - Standardization of Aspergillus PCR is needed. PMID- 20921947 TI - beta-Adrenoceptor blockade in sclerosing cholangitis of Mdr2 knockout mice: antifibrotic effects in a model of nonsinusoidal fibrosis. AB - Primary sclerosing cholangitis (PSC) is a cholestatic liver disease with high propensity to develop into cholangiocarcinoma. The hepatobiliary disorder of PSC is due to progressive fibrosis surrounding the intra- and extrahepatic bile ducts. Until now, no effective medical therapy exists. To study the progression of sclerosing cholangitis after inhibition of the sympathetic nervous system by blockade of the beta-adrenoceptors, we used the Mdr2(-/-) mouse model, which develops periportal fibrosis similar to human PSC. Liver tissues of Mdr2(-/-) mice untreated or treated with the beta-adrenoceptor antagonist propranolol were analyzed for inflammation and fibrosis progression at different time points by histological scoring and immunostaining for alpha-smooth muscle actin (alpha SMA), CD45 and S100A4. Transaminases and hydroxyproline contents were determined. Expression of angiotensinogen, endothelin-1, TGF-beta, TNF-alpha, CTGF and procollagen 1A1 was studied by real-time PCR on laser-microdissected areas of acinar zones I and II-III. After 3 months, periportal fibrosis had developed in Mdr2(-/-) mice, but immunostaining revealed no sinusoidal and only minor periportal contribution of myofibroblasts with prominent fibroblasts. Propranolol treatment of Mdr2(-/-) mice improved liver architecture. Additionally, inflammation and fibrosis were significantly reduced. After 3 months of treatment, the antifibrotic effect of the beta-blockade was most obvious. The transcript levels of procollagen 1A1, TNF-alpha, TGF-beta, CTGF and endothelin-1 were markedly repressed in the portal areas of treated mice. Taken together, these data show that propranolol efficiently delays progression of sclerosing cholangitis. Therefore, the blockade of beta-adrenoceptors is a promising option to support future therapeutic strategies in the treatment of human PSC. PMID- 20921949 TI - Kupffer cells are associated with apoptosis, inflammation and fibrotic effects in hepatic fibrosis in rats. AB - Hepatocellular apoptosis, hepatic inflammation, and fibrosis are prominent features in chronic liver diseases. However, the linkage among these processes remains mechanistically unclear. In this study, we examined the apoptosis and activation of Kupffer cells (KCs) as well as their pathophysiological involvement in liver fibrosis process. Hepatic fibrosis was induced in rats by dimethylnitrosamine (DMN) or carbon tetrachloride (CCl4) treatment. KCs were isolated from normal rats and incubated with lipopolysaccharide (LPS) or from fibrotic rats. The KCs were stained immunohistochemically with anti-CD68 antibody, a biomarker for KC. The level of expression of CD68 was analyzed by western blot and real-time PCR methods. The apoptosis and pathophysiological involvement of KCs in the formation of liver fibrosis were studied using confocal microscopy. The mRNA and protein expression of CD68 were significantly increased in DMN- and CCL4-treated rats. Confocal microscopy analysis showed that CD68 positive KCs, but not alpha-smooth muscle actin (SMA)-positive cells, underwent apoptosis in the liver of DMN- and CCL4-treated rats. It was also revealed that the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling and CD68-double-positive apoptotic KCs located in the portal or fibrotic septa area were situated next to hepatic stellate cells (HSCs). Tumor necrosis factor-alpha (TNF-alpha) and KC co-localized in the liver in the neighbor of HSCs. The double alpha-SMA- and collagen type I-positive cells predominantly existed in fibrotic septa, and those cells were co-localized clearly with CD68-positive cells. Interestingly, some CD68 and Col (1) double positive, but completely negative for alpha-SMA, were found in the portal areas and hepatic sinusoids; this phenomenon was also validated in primary isolated KCs after 6 h LPS exposure or fibrotic rats in vitro. These results show that KCs are associated with hepatocellular apoptosis, inflammation, and fibrosis process in a liver fibrosis models. PMID- 20921948 TI - Dynamic control of the complement system by modulated expression of regulatory proteins. AB - The complement system serves many biological functions, including the eradication of invasive pathogens and the removal of damaged cells and immune-complexes. Uncontrolled complement activation causes injury to host cells, however, so adequate regulation of the system is essential. Control of the complement system is maintained by a group of cell surface and circulating proteins referred to as complement regulatory proteins. The expression of the cell surface complement regulatory proteins varies from tissue to tissue. Furthermore, specific cell types can upregulate or downregulate the expression of these proteins in response to a variety of signals or insults. Altered regulation of the complement regulatory proteins can have important effects on local complement activation. In some circumstances this can be beneficial, such as in the setting of certain infections. In other circumstances, however, this can be a cause of complement mediated injury of the tissue. A full understanding of the mechanisms by which the complement system is modulated at the local level can have important implications for how we diagnose and treat a wide range of inflammatory diseases. PMID- 20921950 TI - Hepatic and HSC-specific sorafenib effects in rats with established secondary biliary cirrhosis. AB - Portal hypertension in cirrhosis depends on increased intrahepatic vascular resistance, which is explained by fibrosis and intrahepatic hyperresponsiveness to vasoconstrictors. Both are caused by activation and proliferation of hepatic stellate cells (HSCs). Portal hypertension of cirrhotic rats can be reduced by the multikinase inhibitor sorafenib, due to a reduction of intrahepatic vascular resistance. Therefore, the hepatic effects of sorafenib require further understanding. Here, we investigated hepatic and HSC-specific sorafenib effects in cirrhotic rats. Animal models of bile duct ligation-induced secondary biliary cirrhosis in rats were studied. The rats were treated with sorafenib (60 mg/kg/day) for 1 week, starting after established cirrhosis. Histological evaluation was carried out using hemalaun and eosin (HE) staining. Apoptosis was studied by PARP cleavage, colorimetric caspase-3 assay, and electrophoretic DNA detection. HSC activation was studied by hepatic Sirius red and immunohistochemical alphaSMA (alpha-smooth muscle actin) staining, and by in vitro experiments with culture-activated primary HSCs. Biochemical serum parameters suggested the occurrence of sorafenib-induced liver damage. HE staining revealed histological changes in livers of sham-operated and bile duct ligated (BDL) rats in response to sorafenib, which were different in both groups. In BDL rats and isolated HSCs, the treatment with sorafenib reduced hepatic alphaSMA and procollagen-1alpha mRNA expression. As shown by immunohistochemical staining, perisinusoidal alphaSMA expression was reduced by sorafenib in BDL rats. This was associated with reduced perisinusoidal deposition of extracellular matrix, as revealed by Sirius red staining. Although no change in PARP cleavage and only a minor increase in hepatic caspase-3 activity were detected in BDL rats in response to sorafenib, livers of sorafenib-treated BDL rats contained small DNA fragments, which were not observed in untreated BDL rats. In conclusion, sorafenib treatment reduces the number of activated HSCs in cirrhotic livers. This leads to the decrease in intrahepatic vascular resistance, but also to liver damage in the dosage we used. Therefore, any translation to portal hypertensive patients who may profit from sorafenib should be done with particular care. PMID- 20921951 TI - Mitochondrial damage-induced impairment of angiogenesis in the aging rat kidney. AB - Decreased expression of vascular endothelial growth factor (VEGF) in the renal tubules is thought to cause progressive loss of the renal microvasculature with age. Mitochondrial dysfunction may be a principal phenomenon underlying the process of aging. The relation between VEGF expression and mitochondrial dysfunction in aging is not fully understood. We hypothesized that mitochondrial dysfunction blocks VEGF expression and contributes to impaired angiogenesis in the aging kidney. The aim of this study was to assess the role of mitochondria in VEGF expression in the aging rat kidney. We evaluated the accumulation of 8 hydroxy-2'-deoxyguanosine in mitochondrial DNA, as well as mitochondrial dysfunction, as assessed by electron microscopy of mitochondrial structure and histochemical staining for respiratory chain complex IV, in aging rat kidney. An increase in hypoxic area and a decrease in peritubular capillaries were detected in the cortex of aging rat kidneys; however, upregulation of VEGF expression was not observed. The expression of VEGF in proximal tubular epithelial cells in response to hypoxia was suppressed by the mitochondrial electron transfer inhibitor myxothiazol. Mitochondrial DNA-deficient cells also failed to upregulate VEGF expression under hypoxic conditions. These results indicate that impairment of VEGF upregulation, possibly as a result of mitochondrial dysfunction, contributes to impaired angiogenesis, which in turn leads to renal injury in the aging rat kidney. PMID- 20921952 TI - Adapting in vitro dual perfusion of the human placenta to soluble oxygen tensions associated with normal and pre-eclamptic pregnancy. AB - For decades, superoxic ex vivo dual perfusion of the human placental lobule has been used as a model to study the physiology and metabolism of the placenta. The aim of this study was to further develop the technique to enable perfusion at soluble oxygen concentrations similar to those in normal pregnancy (normoxia) and in pre-eclampsia (PE; hypoxia). Our design involved reducing the mean soluble oxygen tension in the maternal-side intervillous space (IVS) perfusate to 5-7% and <3% for normoxia and hypoxia, respectively, while providing a more ubiquitous delivery of perfusate into the IVS, using 22 maternal-side cannulae. We achieved quasi-steady states in [O2](fetal venous (soluble)), which were statistically different between the two adaptations at t=150 to t=240 min of dual perfusion (2.1, 1.2, 2.8 and 0.4, 0.0, 1.5%; median, 25th, 75th percentiles, n=20 and 24 readings in n=5 and n=6 lobules, normoxic and hypoxic perfusion, respectively; P<0.001, Mann-Whitney U-test). Lactate dehydrogenase (LDH) levels in fetal and maternal venous outflow perfusates were unaffected by the adaptations. There was also no difference in tissue lactate release between the two adaptations. Glucose consumption from the fetal circulation and maternal-side 'venous' pyruvate release were higher under normoxic conditions, indicative of a greater metabolic flux through glycolysis. Furthermore, there was greater release of the hypoxic sensitive marker, macrophage inflammatory protein-1alpha, into the maternal venous perfusate in the hypoxic model. Also, during hypoxic perfusion, we found that fetal-side venous placental growth factor (PlGF) levels were higher compared with normoxic perfusion. We conclude that these ex vivo adapted methods of placental perfusion provide a means of studying aspects of placental metabolism in relation to normal oxygenation and hypoxia-associated pregnancy disease. PMID- 20921953 TI - Frontiers of vascular biology and disease research. PMID- 20921955 TI - Evidence for disease and antipsychotic medication effects in post-mortem brain from schizophrenia patients. AB - Extensive research has been conducted on post-mortem brain tissue in schizophrenia (SCZ), particularly the dorsolateral prefrontal cortex (DLPFC). However, to what extent the reported changes are due to the disorder itself, and which are the cumulative effects of lifetime medication remains to be determined. In this study, we employed label-free liquid chromatography-mass spectrometry based proteomic and proton nuclear magnetic resonance-based metabonomic profiling approaches to investigate DLPFC tissue from two cohorts of SCZ patients grouped according to their lifetime antipsychotic dose, together with tissue from bipolar disorder (BPD) subjects, and normal controls (n=10 per group). Both techniques showed profound changes in tissue from low-cumulative-medication SCZ subjects, but few changes in tissue from medium-cumulative-medication subjects. Protein expression changes were validated by Western blot and investigated further in a third group of subjects who were subjected to high-cumulative-medication over the course of their lifetime. Furthermore, key protein expression and metabolite level changes correlated significantly with lifetime antipsychotic dose. This suggests that the detected changes are present before antipsychotic therapy and, moreover, may be normalized with treatment. Overall, our analyses revealed novel protein and metabolite changes in low-cumulative-medication subjects associated with synaptogenesis, neuritic dynamics, presynaptic vesicle cycling, amino acid and glutamine metabolism, and energy buffering systems. Most of these markers were altered specifically in SCZ as determined by analysis of the same brain region from BPD patients. PMID- 20921957 TI - Minimal invasive electrode implantation for conditional stimulation of the dorsal genital nerve in neurogenic detrusor overactivity. AB - STUDY DESIGN: Experimental. OBJECTIVES: Electrical stimulation of the dorsal genital nerves (DGN) suppresses involuntary detrusor contractions (IDCs) in patients with neurogenic detrusor overactivity (DO). The feasibility of minimal invasive electrode implantation near the DGN and the effectiveness of conditional stimulation to suppress IDCs at different amplitudes in spinal cord injury (SCI) patients with DO were studied. SETTING: Radboud University Nijmegen MC, The Netherlands. METHODS: In eight healthy volunteers, a needle electrode was inserted from both a medial and lateral-to-midline site at the level of the pubic bone. Electrode insertion was guided by the genito-anal reflex (GAR) evoked by electrical stimulation and by sensation to this stimulation. In eight SCI patients with DO, the bladder was repeatedly filled and emptied partially in between. Conditional stimulation using a needle electrode was applied when an IDC was observed at urodynamics. Different amplitudes were used during each filling. Control cystometry was carried out before electrode insertion and after stimulation. RESULTS: The lateral implant approach was preferred, as it was easier to manoeuvre the needle along the pubic bone and fixate the needle. In SCI patients, the electrode was positioned successfully, and IDCs were suppressed (range 1-6 IDC suppressions) with conditional stimulation at maximum tolerable amplitude, except for one patient. Stimulation was less effective at lower amplitudes. Stimulation lowered the intensity of bladder sensations concomitant with IDC. CONCLUSION: The lateral-to-midline implant approach, in combination with GAR and sensation to stimulation, is feasible for electrode implantation near the DGN in SCI patients. Conditional stimulation effectively suppresses IDCs. PMID- 20921958 TI - Epidemiology of traumatic spinal cord injury in Tianjin, China. AB - STUDY DESIGN: A retrospective epidemiological study. OBJECTIVES: To provide recent epidemiological characteristics of traumatic spinal cord injuries (TSCIs) in adults living in Tianjin. SETTING: Tianjin, China. METHODS: This study included all TSCI patients aged 15 years or older who were admitted to tertiary hospitals in Tianjin from 2004 to 2008. Epidemiological characteristics, such as age, sex, date of admission, causes of injury, level of injury, America Spinal Injury Association impairment scale and date of discharge were included. RESULTS: A total of 869 patients were included, with an estimated annual incidence was 23.7 per million populations. The male/female ratio was 5.63:1. Mean age of TSCI was 46.0+/-14.2 years (men 45.8+/-14.2 years, women 47.5+/-14.5 years), with a range of 16-90 years. Falls were regarded as the leading causes of injury, followed by motor vehicle collisions. The lesion level was cervical in 71.5%, thoracic in 13.3% and lumbar/sacral in 15.1%. The frequency of tetraplegia (71.5%) was higher than paraplegia (28.5%), and roughly four-fifth of tetraplegia cases were incomplete injury. CONCLUSION: To our knowledge, national or local epidemiological study of spinal cord injury (SCI) has not been carried out previously in China. The number of SCI patients in this country is large and would increase gradually. Similar to other developing countries, falls were the main causes of TSCI. Low falls were more common in those over 60 years old. As the ageing society coming, the number of low falls-induced TSCI would increase gradually, which poses a challenge to the society health system. PMID- 20921959 TI - Length of stay and medical stability for spinal cord-injured patients on admission to an inpatient rehabilitation hospital: a comparison between a model SCI trauma center and non-SCI trauma center. AB - STUDY DESIGN: Retrospective database review. OBJECTIVE: To compare lengths of stay (LOS), pressure ulcers and readmissions to the acute care hospital of patients admitted to the inpatient rehabilitation facility (IRF) from a model spinal cord injury (SCI) trauma center or from a non-SCI acute hospital. BACKGROUND: Only sparse data exist comparing the status of patients admitted to IRF from a model SCI trauma center or from a non-SCI acute hospital. METHODS: Acute care, IRF and total LOS were compared between patients transferred to IRF from the SCI center (n=78) and from non-SCI centers (n=131). The percentages of pressure ulcers on admission to IRF and transfer back to acute care were also compared. RESULTS: Patients admitted to IRF from the SCI trauma center (SCI TC) had significantly shorter (P=0.01) acute care LOS and total LOS compared with patients admitted from non-SCI TCs. By neurological category, acute-care LOS was less for all groups admitted from the SCI center, but statistically significant only for tetraplegia. There was no significant difference in the incidence of readmissions to acute care from IRF. More patients from non-SCI centers (34%) than SCI centers (12%) had pressure ulcers (P<0.001). CONCLUSION: Acute care in organized SCI TCs before transfer to IRF can significantly lower acute-care LOS or total LOS and incidence of pressure ulcers compared with non-SCI TCs. Patients admitted to IRF from SCI TCs are no more likely to be sent back to an acute hospital than those from non-SCI TCs. PMID- 20921960 TI - Epigenetics: Demethylation links cell fate and cancer. PMID- 20921962 TI - Gene expression: Genomic space-savers. PMID- 20921961 TI - Stress and the epigenetic landscape: a link to the pathobiology of human diseases? AB - Accumulating evidence points to a major role for chronic stress of cell renewal systems in the pathogenesis of important human diseases, including cancer, atherosclerosis and diabetes. Here we discuss emerging evidence that epigenetic abnormalities may make substantial contributions to these stress-induced pathologies. Although the mechanisms remain to be fully elucidated, we suggest that chronic stress can elicit heritable changes in the chromatin landscape that 'lock' cells in abnormal states, which then lead to disease. We emphasize the need to investigate epigenetic states in disease and links to stress and to consider how the knowledge gained through these studies may foster new means of disease prevention and management. PMID- 20921963 TI - The relationship between body size and mortality in the linked Scottish Health Surveys: cross-sectional surveys with follow-up. AB - OBJECTIVE: To investigate the relationship between body mass index (BMI), waist circumference (WC) or waist-hip ratio (WHR) and all-cause mortality or cause specific mortality. DESIGN: Cross-sectional surveys linked to hospital admissions and death records. SUBJECTS: In total, 20,117 adults (aged 18-86 years) from a nationally representative sample of the Scottish population. MEASUREMENTS: Cox proportional hazards models were used to estimate hazard ratios (HRs) for all cause, or cause-specific, mortality. The three anthropometric measurements BMI, WC and WHR were the main variables of interest. The following were adjustment variables: age, gender, smoking status, alcohol consumption, survey year, social class and area of deprivation. RESULTS: BMI-defined obesity (>= 30 kg m(-2)) was not associated with increased risk of mortality (HR = 0.93; 95% confidence interval = 0.80-1.08), whereas the overweight category (25-<30 kg m(-2)) was associated with a decreased risk (0.80; 0.70-0.91). In contrast, the HR for a high WC (men >= 102 cm, women >= 88 cm) was 1.17 (1.02-1.34) and a high WHR (men >= 1, women >= 0.85) was 1.34 (1.16-1.55). There was an increased risk of cardiovascular disease (CVD) mortality associated with BMI-defined obesity, a high WC and a high WHR categories; the HR estimates for these were 1.36 (1.05 1.77), 1.41 (1.11-1.79) and 1.44 (1.12-1.85), respectively. A low BMI (<18.5 kg m(-2)) was associated with elevated HR for all-cause mortality (2.66; 1.97-3.60), for chronic respiratory disease mortality (3.17; 1.39-7.21) and for acute respiratory disease mortality (11.68; 5.01-27.21). This pattern was repeated for WC but not for WHR. CONCLUSIONS: It might be prudent not to use BMI as the sole measure to summarize body size. The alternatives WC and WHR may more clearly define the health risks associated with excess body fat accumulation. The lack of association between elevated BMI and mortality may reflect the secular decline in CVD mortality. PMID- 20921965 TI - Gender differences in the association between maternal smoking during pregnancy and childhood growth trajectories: multilevel analysis. AB - OBJECTIVES: This study examines the gender differences in the association between maternal smoking during pregnancy and later growth in childhood. DESIGN: Ongoing prospective cohort study, which is called 'the Project Koshu', initiated in the foetal stage to the age of 9-10 years. SETTING: Koshu City which was in Japanese rural area. PARTICIPANTS: The study population comprised children born between 1 April 1991 and 31 March 1999 in Koshu City, Japan, and their mothers. Maternal smoking during early pregnancy was the exposure studied. MAIN OUTCOME MEASURES: Childhood body mass index (BMI) and BMI z-score trajectories of the children born to the smoking and non-smoking mothers by gender. Multilevel analysis that includes both individual and age as different-level variables was used for statistical analyses. RESULTS: The participating mothers delivered 1619 babies during the study period. Birth weight and anthropometric data were collected from 1603 (at birth, 99.0%), 1358 (at age 3, 83.9%), 1248 (at age 5, 77.1%), 1270 (at age 7-8, 78.4%) and 1274 (at age 9-10, 78.7%) of these children. The mean birth weight of both the male and female children whose mothers had smoked during pregnancy was significantly low compared with those born to non-smoking mothers (P < 0.01). However, the childhood BMI at each subsequent checkup age significantly increased only among the male children born to the smoking mothers. Moreover, this increase was continuously observed after 3 years of age. The results of BMI z-score analysis were also similar to these of BMI analysis. CONCLUSIONS: Smoking by pregnant women decreases the infant birth weight irrespective of gender but increases childhood weight gain especially by male children. The results might be valuable to explore the mechanism of fetal programming. PMID- 20921964 TI - The effects of intermittent or continuous energy restriction on weight loss and metabolic disease risk markers: a randomized trial in young overweight women. AB - BACKGROUND: The problems of adherence to energy restriction in humans are well known. OBJECTIVE: To compare the feasibility and effectiveness of intermittent continuous energy (IER) with continuous energy restriction (CER) for weight loss, insulin sensitivity and other metabolic disease risk markers. DESIGN: Randomized comparison of a 25% energy restriction as IER (~ 2710 kJ/day for 2 days/week) or CER (~ 6276 kJ/day for 7 days/week) in 107 overweight or obese (mean (+/- s.d.) body mass index 30.6 (+/- 5.1) kg m(-2)) premenopausal women observed over a period of 6 months. Weight, anthropometry, biomarkers for breast cancer, diabetes, cardiovascular disease and dementia risk; insulin resistance (HOMA), oxidative stress markers, leptin, adiponectin, insulin-like growth factor (IGF)-1 and IGF binding proteins 1 and 2, androgens, prolactin, inflammatory markers (high sensitivity C-reactive protein and sialic acid), lipids, blood pressure and brain-derived neurotrophic factor were assessed at baseline and after 1, 3 and 6 months. RESULTS: Last observation carried forward analysis showed that IER and CER are equally effective for weight loss: mean (95% confidence interval ) weight change for IER was -6.4 (-7.9 to -4.8) kg vs -5.6 (-6.9 to -4.4) kg for CER (P value for difference between groups = 0.4). Both groups experienced comparable reductions in leptin, free androgen index, high-sensitivity C-reactive protein, total and LDL cholesterol, triglycerides, blood pressure and increases in sex hormone binding globulin, IGF binding proteins 1 and 2. Reductions in fasting insulin and insulin resistance were modest in both groups, but greater with IER than with CER; difference between groups for fasting insulin was -1.2 (-1.4 to 1.0) MUU ml(-1) and for insulin resistance was -1.2 (-1.5 to -1.0) MUU mmol(-1) l(-1) (both P = 0.04). CONCLUSION: IER is as effective as CER with regard to weight loss, insulin sensitivity and other health biomarkers, and may be offered as an alternative equivalent to CER for weight loss and reducing disease risk. PMID- 20921966 TI - Heterogeneous expression of toll-like receptors in lymphatic endothelial cells derived from different tissues. AB - As lymphatic endothelial cells (LECs) express different lymphatic and vascular markers depending on the organ they are derived from, we analysed whether they also show a heterogeneity of response against pathogens. To this end we analysed, for the presence of mRNA encoding for all human toll-like receptor (TLR), LECs isolated from lymph nodes and thymuses. RNA for TLR1-6 and 9 was identified in thymus-derived cells, whereas cells derived from lymph nodes contained mRNA for TLR1-4, 6 and 9, but failed to express mRNA specific for TLR5. The differential expression of TLRs was confirmed by the phosphorylation of nuclear factor-kappaB p65 only when the two types of LECs were incubated with the appropriate TLR agonists. The stimulation with specific agonists gives rise to a heterogeneous pattern of cytokine and chemokine secretion: thymus-derived LECs produced preferentially interleukin-6, interferon-inducible protein (IP)-10 and tumour necrosis factor-alpha, whereas cells prepared from lymph nodes mainly released interleukin-8, monocyte chemotactic protein-1, RANTES and (IP)-10. Finally, cells purified from lymph nodes expressed a higher level of intercellular adhesion molecule-1 than did cells prepared from the thymus when stimulated with several TLR agonists. The expression of a large set of TLRs and the responsiveness to specific agonists suggest that LECs are able to respond to pathogens, and the observed differences reflect specialized functions, redundancy and/or roles of LECs of different origin. PMID- 20921967 TI - B cells do not take up bacterial DNA: an essential role for antigen in exposure of DNA to toll-like receptor-9. AB - Murine dendritic cells (DC) and macrophages respond to bacterial CpG DNA through toll-like receptor 9 (TLR9). Although it is frequently assumed that bacterial DNA is a direct stimulus for B cells, published work does not reliably show responses of purified B cells. Here we show that purified splenic B cells did not respond to Escherichia coli DNA with induction of CD86, despite readily responding to single-stranded (ss) phosphodiester CpG oligodeoxynucleotides (ODN). This was due to a combination of weak responses to both long and double-stranded (ds) DNA. B cell DNA uptake was greatly reduced with increasing DNA length. This contrasts with macrophages where DNA uptake and subsequent responses were enhanced with increasing DNA length. However, when DNA was physically linked to hen egg lysozyme (HEL), HEL-specific B cells showed efficient uptake of DNA, and limited proliferation in response to the HEL-DNA complex. We propose that, in the absence of other signals, B cells have poor uptake and responses to long dsDNA to prevent polyclonal activation. Conversely, when DNA is physically linked to a B-cell receptor (BCR) ligand, its uptake is increased, allowing TLR9-dependent B-cell activation in an antigen-specific manner. We could not generate fragments of E. coli DNA by limited DNaseI digestion that could mimic the stimulatory effect of ss CpG ODN on naive B cells. We suggest that the frequently studied polyclonal B cell responses to CpG ODN are relevant to therapeutic applications of phosphorothioate-modified CpG-containing ODN, but not to natural responses to foreign or host dsDNA. PMID- 20921968 TI - Effects of OCT1 polymorphisms on the cellular uptake, plasma concentrations and efficacy of the 5-HT(3) antagonists tropisetron and ondansetron. AB - After uptake into liver cells, the antiemetic drugs tropisetron and ondansetron undergo metabolic inactivation by cytochrome P450 2D6 (CYP2D6). We investigated whether the hepatic organic cation transporter 1 (OCT1; SLC22A1) mediates cellular uptake and whether common OCT1 loss-of-function polymorphisms affect pharmacokinetics and efficacy of both drugs. Both tropisetron and ondansetron inhibited ASP(+) uptake in OCT1-overexpressing HEK293 cells. Overexpression of wild-type, but not OCT1 loss-of-function variants, significantly increased tropisetron uptake. Correspondingly, patients with two loss-of-function OCT1 alleles had higher tropisetron plasma concentrations (n=59, P<0.04) and higher clinical efficacy (n=91, P=0.009) compared with carriers of fully active OCT1. Overexpression of OCT1 did not increase ondansetron uptake. Nevertheless, OCT1 genotypes correlated with pharmacokinetics (n=45, P<0.05) and clinical efficacy (n=222, P<0.02) of ondansetron, the effect size of OCT1 genotypes on pharmacokinetics and efficacy was greater for tropisetron than for ondansetron. In conclusion, in addition to the known effects of CYP2D6, OCT1 deficiency may increase efficacy of tropisetron and potentially of ondansetron by limiting their hepatic uptake. PMID- 20921969 TI - Genome-wide association study of antipsychotic-induced QTc interval prolongation. AB - QT prolongation is associated with increased risk of cardiac arrhythmias. Identifying the genetic variants that mediate antipsychotic-induced prolongation may help to minimize this risk, which might prevent the removal of efficacious drugs from the market. We performed candidate gene analysis and five drug specific genome-wide association studies (GWASs) with 492K single-nucleotide polymorphisms to search for genetic variation mediating antipsychotic-induced QT prolongation in 738 schizophrenia patients from the Clinical Antipsychotic Trial of Intervention Effectiveness study. Our candidate gene study suggests the involvement of NOS1AP and NUBPL (P-values=1.45 * 10(-05) and 2.66 * 10(-13), respectively). Furthermore, our top GWAS hit achieving genome-wide significance, defined as a Q-value <0.10 (P-value=1.54 * 10(-7), Q-value=0.07), located in SLC22A23, mediated the effects of quetiapine on prolongation. SLC22A23 belongs to a family of organic ion transporters that shuttle a variety of compounds, including drugs, environmental toxins and endogenous metabolites, across the cell membrane. This gene is expressed in the heart and is integral in mouse heart development. The genes mediating antipsychotic-induced QT prolongation partially overlap with the genes affecting normal QT interval variation. However, some genes may also be unique for drug-induced prolongation. This study demonstrates the potential of GWAS to discover genes and pathways that mediate antipsychotic induced QT prolongation. PMID- 20921970 TI - A genetic marker at the OLIG3/TNFAIP3 locus associates with methotrexate continuation in early inflammatory polyarthritis: results from the Norfolk Arthritis Register. AB - Whole-genome association studies in rheumatoid arthritis have identified single nucleotide polymorphisms (SNPs) predisposing to disease with moderate risk. We aimed to investigate the role of these markers in predicting methotrexate (MTX) response, measured by continuation on MTX monotherapy in patients with recent onset inflammatory polyarthritis (IP). In all, 19 SNPs were genotyped in 736 patients treated with MTX following registration, or not more than 3 months before registration, to the Norfolk Arthritis Register. The association of SNPs with MTX continuation by year 1 and by year 2 was investigated using Cox proportional hazard regression models. A SNP within the OLIG3/TNFAIP3 locus (rs6920220) was associated with being less likely to maintain MTX monotherapy at year 1, hazards ratio (HR) 1.73 (1.18, 2.52) and year 2, HR 1.49 (1.11, 2.00); correlating with an increased in adverse events. Weak evidence for an effect at the PTPN22 locus was also observed. These findings require replication in other large datasets. PMID- 20921972 TI - Scaffolds in tissue engineering of blood vessels. AB - Tissue engineering of small diameter (<5 mm) blood vessels is a promising approach for developing viable alternatives to autologous vascular grafts. It involves in vitro seeding of cells onto a scaffold on which the cells attach, proliferate, and differentiate while secreting the components of extracellular matrix that are required for creating the tissue. The scaffold should provide the initial requisite mechanical strength to withstand in vivo hemodynamic forces until vascular smooth muscle cells and fibroblasts reinforce the extracellular matrix of the vessel wall. Hence, the choice of scaffold is crucial for providing guidance cues to the cells to behave in the required manner to produce tissues and organs of the desired shape and size. Several types of scaffolds have been used for the reconstruction of blood vessels. They can be broadly classified as biological scaffolds, decellularized matrices, and polymeric biodegradable scaffolds. This review focuses on the different types of scaffolds that have been designed, developed, and tested for tissue engineering of blood vessels, including use of stem cells in vascular tissue engineering. PMID- 20921971 TI - Mapping genes that predict treatment outcome in admixed populations. AB - There is great interest in characterizing the genetic architecture underlying drug response. For many drugs, gene-based dosing models explain a considerable amount of the overall variation in treatment outcome. As such, prescription drug labels are increasingly being modified to contain pharmacogenetic information. Genetic data must, however, be interpreted within the context of relevant clinical covariates. Even the most predictive models improve with the addition of data related to biogeographical ancestry. The current review explores analytical strategies that leverage population structure to more fully characterize genetic determinants of outcome in large clinical practice-based cohorts. The success of this approach will depend upon several key factors: (1) the availability of outcome data from groups of admixed individuals (that is, populations recombined over multiple generations), (2) a measurable difference in treatment outcome (that is, efficacy and toxicity end points), and (3) a measurable difference in allele frequency between the ancestral populations. PMID- 20921973 TI - Effect of fasudil on growth, adhesion, invasion, and migration of 95D lung carcinoma cells in vitro. AB - The objective of the study was to investigate the effects of a Rho-kinase inhibitor on 95D lung carcinoma cell growth, adhesion, invasion, and migration and to explore the underlying molecular mechanisms involved in this process. After treatment of 95D lung carcinoma cells with fasudil, an inhibitor of Rho kinase, cell biological behaviors such as growth, adhesion, invasion, and migration were observed. Matrix metalloproteinase (MMP) activity and Western blot assay were used to evaluate underlying molecular mechanisms. The IC50 of fasudil to 95D lung carcinoma cells was approximately 0.79 mg/mL (95% confidence limits 0.58-1.11 mg/mL). After treatment with 0.75 mg/mL fasudil, the ability of 95D lung carcinoma cells for growth, adhesion, migration, and invasion was decreased significantly. Total active MMP2 was decreased approximately 22.7% (p < 0.05) and total MMP9 65.9% (p < 0.01). Myosin phosphatase target subunit 1 (MYPT1) was reduced by 29.4% (p < 0.05). We conclude that the Rho-kinase inhibitor prevents the growth, adhesion, invasion, and migration of 95D lung carcinoma cells by inhibiting the Rho/Rho-kinase pathway. Changes in MMP2, MMP9, and MYPT1 may be part of its molecular mechanisms. PMID- 20921974 TI - In vitro myometrial inhibition by the partitioned aqueous fraction of Anthocleista djalonensis leaves. AB - This study investigated the effect on the uterus of the aqueous fraction of the partitioned methanol crude extract of the leaves of Anthocleista djalonensis (AD) and the possible mechanism of AD activity. AD inhibited the concentration response curves induced by oxytocin and CaCl2 on the rat uterus in vitro and significantly reduced the EC50 in a concentration-dependent manner (p < 0.05). A similar effect was observed with salbutamol and verapamil on the concentration response curves obtained for oxytocin and CaCl2. The inhibitory effect of AD was not attenuated in the presence of propranolol. AD, salbutamol, and verapamil also produced a concentration-dependent relaxation on K+-induced sustained uterine contraction. In Ca2+-free medium, AD and salbutamol similarly inhibited oxytocin induced contraction, but verapamil failed to produce this effect. The present results suggest that AD, being a mixture of phytochemicals, probably exerts inhibitory activity on in vitro uterine contractions of the nonpregnant, diethylstilboestrol-treated rat by multiple mechanisms that do not involve interaction with β-adrenergic receptors and do not solely depend on inhibition of calcium influx. PMID- 20921975 TI - Effects of proanthocyanidins from grape seed on treatment of recurrent ulcerative colitis in rats. AB - The aim of the present study was to investigate the therapeutic effect and mechanism of proanthocyanidins from grape seed (GSPE) in the treatment of recurrent ulcerative colitis (UC) in rats. To induce recurrent colitis, rats were instilled with 2,4,6-trinitrobenzenesulfonic acid (TNBS) (80 mg/kg) into the colon through the cannula in the first induced phase, and then the rats were instilled a second time with TNBS (30 mg/kg) into the colon on the sixteenth day after the first induction UC. Rats were intragastrically administered GSPE (200 mg/kg) per day for 7 days after twice-induced colitis by TNBS. Sulfasalazine at 500 mg/kg was used as a positive control drug. Rats were killed 7 days after GSPE treatment. The colonic injury and inflammation were assessed by macroscopic and macroscopic damage scores, colon weight/length ratio (mg/cm), and myeloperoxidase activity. Then, superoxide dismutase, glutathione peroxidase, inducible nitric oxide synthase (iNOS) activities, and the levels of malonyldialdehyde, glutathione, and nitric oxide in serum and colonic tissues were measured. Compared with the recurrent UC group, GSPE treatment facilitated recovery of pathologic changes in the colon after induction of recurrent colitis, as demonstrated by reduced colonic weight/length ratio and macroscopic and microscopic damage scores. The myeloperoxidase and iNOS activities with malonyldialdehyde and nitric oxide levels in serum and colon tissues of colitis rats were significantly decreased in the GSPE group compared with those in the recurrent UC group. In addition, GSPE treatment was associated with notably increased superoxide dismutase, glutathione peroxidase activities, and glutathione levels of colon tissues and serum of rats. GSPE exerted a protective effect on recurrent colitis in rats by modifying the inflammatory response, inhibiting inflammatory cell infiltration and antioxidation damage, promoting damaged tissue repair to improve colonic oxidative stress, and inhibiting colonic iNOS activity to reduce the production of nitric oxide. PMID- 20921976 TI - Hyperosmolarity alters micturition: a comparison of urinary bladder motor activity in hyperosmolar and cyclophosphamide-induced models of overactive bladder. AB - Hyperosmolar factors induce the neurogenic inflammatory response, leading to bladder overactivity (OAB). The aim of the study was to compare the bladder motor activity in a hyperosmolar and acute cyclophosphamide (CYP)-induced model of OAB. Furthermore, we set our sights on defining the most physiological model of OAB in experimental practice. Forty-two female rats were divided randomly into 5 groups. All animals underwent cystometry with the usage of isotonic saline or saline of increasing concentration. Acute chemical cystitis was induced by CYP to elicit OAB. The following cystometric parameters were analyzed: basal pressure, threshold pressure, micturition voiding pressure, intercontraction interval, compliance, functional bladder capacity, motility index, and detrusor overactivity index. CYP and hypertonic saline solutions induced OAB. Having been compared with CYP OAB, none of the rats infused with hypertonic solution exhibited macroscopic signs of bladder inflammation. The comparison of CYP and hyperosmolar models of OAB revealed that the greatest similarity existed between the 2080 mOsm/L OAB model and the acute CYP-induced model. We postulate that the 2080 mOsm/L model of OAB can be established as being a less invasive and more physiological model when compared with the CYP-induced OAB model. Additionally, it may also be a more reliable experimental tool for evaluating novel therapeutics for OAB as compared with CYP-induced models. PMID- 20921977 TI - Apocynum venetum leaf extract protects rat cortical neurons from injury induced by oxygen and glucose deprivation in vitro. AB - This study aimed to investigate the protective effect of Apocynum venetum leaf extract (AVLE) on an in vitro model of ischemia-reperfusion induced by oxygen and glucose deprivation (OGD) and further explored the possible mechanisms underlying protection. Cell injury was assessed by morphological examination using phase contrast microscopy and quantified by measuring the amount of lactate dehydrogenase (LDH) leakage; cell viability was measured by XTT reduction. Neuronal apoptosis was determined by flow cytometry, and electron microscopy was used to study morphological changes of neurons. Caspase-3, -8, and -9 activation and Bcl-2/Bax protein expression were determined by Western blot analysis. We report that treatment with AVLE (5 and 50 ug/mL) effectively reduced neuronal cell death and relieved cell injury induced by OGD. Moreover, AVLE decreased the percentage of apoptotic neurons, relieved neuronal morphological damage, suppressed overexpression of active caspase-3 and -8 and Bax, and inhibited the reduction of Bcl-2 expression. These findings indicate that AVLE protects against OGD-induced injury by inhibiting apoptosis in rat cortical neurons by down regulating caspase-3 activation and modulating the Bcl-2/Bax ratio. PMID- 20921978 TI - Using blood pressure telemetry to assess acute changes in arterial stiffness in rats after nitric oxide synthase inhibition or environmental tobacco smoke exposure. AB - Although environmental tobacco smoke (ETS) exposure has been reported to acutely increase arterial stiffness in humans, understanding of the underlying mechanisms is unclear and few studies have measured these effects in experimental animals. One potential mechanism for the increased arterial stiffness is reduced nitric oxide (NO) bioactivity as a result of oxidative stress. Thus, the objective of this study was to determine whether acute changes in arterial stiffness could be detected using arterial pulse wave dP/dt in blood pressure telemetry implanted rats and to investigate the role of NO in regulating dP/dt. Intravenous injection of acetylcholine (0.91 ng/kg) decreased and norepinephrine (0.02 mg/kg) increased dP/dt compared to saline vehicle (0.5 mL/kg). Injection of the NO synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME; 30 mg/kg) decreased plasma nitrate/nitrite (NOx), but transiently increased dP/dt. ETS at low and high doses had no effect on dP/dt, but increased plasma NOx levels at high ETS exposure and increased plasma nitrotyrosine levels in both ETS groups. In conclusion, acute changes in NO production via acetylcholine or L-NAME alter the arterial pulse wave dP/dt consistently with the predicted changes in arterial stiffness. Although acute ETS appears to biologically inactivate NO, a concomitant increase in NO production at high ETS exposure may explain why dP/dt was not acutely altered by ETS in the current study. PMID- 20921979 TI - Extracellular glutamate alters mature osteoclast and osteoblast functions. AB - Glutamatergic intercellular communication is involved in many aspects of metabolic homeostasis in normal bone. In bone metastasis, the balance between bone formation and degradation is disrupted. Although the responsible mechanisms are not clear, we have previously identified that cancer cell lines used in bone tumour models secrete glutamate, suggesting that tumour-derived glutamate may disrupt sensitive signalling systems in bone. This study examines the role of glutamate in mature osteoclastic bone resorption, osteoblast differentiation, and bone nodule formation. Glutamate was found to have no effect on the survival or activity of mature osteoclasts, although glutamate transporter inhibition and receptor blockade increased the number of bone resorption pits. Furthermore, transporter inhibition increased the area of resorbed bone while significantly decreasing the number of osteoclasts. Alkaline phosphatase activity and extracellular matrix mineralization were used as measurements of osteoblast differentiation. Glutamate significantly increased osteoblast differentiation and mineralization, but transport inhibitors had no effect. These studies support earlier findings suggesting that glutamate may be more important for osteoclastogenesis than for osteoclast proliferation or functions. Since glutamate is capable of changing the differentiation and activities of both osteoclast and osteoblast cell types in bone, it is reasonable to postulate that tumour-derived glutamate may impact bone homeostasis in bone metastasis. PMID- 20921980 TI - Abstracts from the 2010 Canadian Society for Exercise Physiology (CSEP) General Meeting, 3-6 November, 2010, Toronto, Ontario, Canada. PMID- 20921981 TI - Occurrence and dominance of yeast species in naturally fermented milk from the Tibetan Plateau of China. AB - To determine which yeasts are present in the naturally fermented milks of China, 69 samples made by the nomads of Tibet were collected from the Tibetan Plateau in China. From these samples, 225 strains of yeast were isolated and identified using conventional microbiological analysis and gene sequencing analysis of the D1/D2 domain of the large subunit (26S) ribosomal DNA. The results showed that the total concentration of yeasts in these samples ranged from 5.01 to 8.97 log10 colony-forming units (CFU)/mL (6.91 +/- 1.02 log10 CFU/mL; mean +/- SD). The number of cultivable yeasts was higher in the samples from Qinghai (7.55 +/- 0.75 log10 CFU/mL) than those from Tibet (6.21 +/- 0.79 log10 CFU/mL, P < 0.05). Moreover, there were 15 phylotypes in these 69 samples. Among these phylotypes, Kluyveromyces marxianus (49.3%, frequency percentage), Saccharomyces cerevisiae (62.3%), and Pichia fermentans (46.4%) appeared frequently and can be considered the most common culturable species in naturally fermented milk products. Traditional fermented Mongolian cow milk featured a wide diversity of yeast species, including Issatchenkia orientalis, Kazachstania unisporus, Rhodotorula mucilaginosa, Candida pararugosa, Torulaspora delbrueckii, Geotrichum sp., Kazachstania unisporus, Geotrichum fragrans, Debaryomyces hansenii, Yarrowia lipolytica, Trichosporon gracile, and Pichia membranifaciens. This study provides new data on yeast composition in naturally fermented milk and shows the yeast biodiversity of fermented milk products from the Tibetan Plateau of China. PMID- 20921982 TI - Frequency of virulence genes and antibiotic resistances in Enterococcus spp. isolates from wastewater and feces of domesticated mammals and birds, and wildlife. AB - Enterococci are gastrointestinal tract residents and also an important cause of nosocomial infections. To understand which species, virulence determinants, and antibiotic resistances are prevalent in enterococci shed by various hosts groups, a total of 1460 strains isolated from 144 fecal samples obtained from wastewater, domesticated mammals and birds, and wildlife were characterized. Identification of isolates to the species level showed that Enterococcus faecalis was dominant in domesticated mammals and birds and wildlife feces, whereas Enterococcus faecium was dominant among wastewater isolates, and that no single Enterococcus species could be associated with a specific host group. The frequency of 12 virulence determinants was evaluated among isolates, but no single virulence determinant could be associated with a specific host group. Resistance to 12 antibiotics was evaluated among isolates, and it was shown that the highest frequency of resistance at breakpoint concentration was found in domesticated mammals and birds (P ≤ 0.05 for 4 antibiotics). Our results suggests that (1) species identification and virulence typing of Enterococcus spp. isolates are not useful for the identification of the host groups responsible for fecal contamination of water by microbial source tracking and that (2) antibiotic use for clinical, veterinary, or animal husbandry practices is promoting resistance. PMID- 20921983 TI - Development and pilot evaluation of a novel probiotic mixture for the management of seasonal allergic rhinitis. AB - Microbial exposure may direct the immune system away from allergic-type responses, but until now probiotic interventions have had limited success in the prevention and treatment of allergic diseases. In this study, a novel probiotic mixture was specifically created based on preliminary in vitro investigations on pollen-induced immune responses. A mixture with Lactobacillus rhamnosus GR-1 and a novel fecal Bifidobacterium adolescentis isolate was formulated into a yogurt and tested for its effects in 36 subjects with allergic rhinitis over 2 pollen seasons in a double-blind, placebo-controlled trial. The new formulation was well tolerated, but did not have significant effects on the quality of life scores, use of antihistamines, or eosinophil cationic protein concentration in nasal lavage. However, at the end of the grass pollen season, serum IL-10 and IL-12 levels were increased in the probiotic group compared to the controls. During the ragweed season, the serum TGF-β levels were significantly higher in the probiotic group than in the controls. In conclusion, the novel probiotic formulation had potentially desirable effects on the cytokine profile of patients with allergic rhinitis, but provided few clinical benefits. The study highlights the challenges in designing efficient immunomodulatory probiotic therapies based upon in vitro findings. PMID- 20921984 TI - The role of Tir, EspA, and NleB in the colonization of cattle by Shiga toxin producing Escherichia coli O26:H11. AB - Shiga toxin producing Escherichia coli (STEC) O26:H11 is an enteric pathogen capable of causing severe hemorrhagic colitis that can lead to hemolytic uremic syndrome. This organism is able to colonize cattle and human intestinal epithelial cells by secreting effectors via a type III secretion system (T3SS). In this investigation, we examined the role of 2 effectors, Tir and NleB, and the structural translocator component EspA in the adherence of STEC to epithelial cells and in the colonization of cattle. Isogenic deletion mutants were constructed and using microscopy and flow cytometry compared to the wild-type strain in their ability to adhere to HEp-2 cells. A competitive assay was also used to measure the capacity of the mutants to colonize the intestinal tract of cattle, where both the mutant and the parental strains were introduced orally at the same time. Genomic DNA was extracted from enriched fecal samples collected at various time points, and quantitative real-time PCR was used to quantify bacteria. A significant reduction in fecal shedding was observed, and adherence to HEp-2 cells was decreased for the tir and espA mutants. Deletion of the nleB gene did not have a significant effect on the adherence of HEp-2 cells; however, in an in vivo model, it strongly reduced the ability of STEC O26:H11 to colonize the bovine intestinal tract. PMID- 20921985 TI - Keratinolytic activity from new recombinant fusant AYA2000, derived from endophytic Micromonospora strains. AB - Two different endophytic strains, ESRAA1997 and ALAA2000, were isolated from the Egyptian herbal plant Anastatica hierochuntica. The 2 strains produced alkaline serine protease and were identified based on their phenotypic and chemotypic characteristics as different strains of Micromonospora spp. Both strains grew and produced keratinase, using different keratinous waste substances as the sole source of carbon and nitrogen. In our study, the activity and properties of keratinase enzymes of the wild strains ESRAA1997 and ALAA2000 were altered by genetic recombination through protoplast fusion between them, leading to a potent keratinolytic fusant Micromonospora strain AYA2000 with improved properties (activity, stability, specificity, and tolerance to inhibitors). Using a mixture of yeast extract, peptone, and malt extract as a supplement to the bovine hair medium increased keratinase production by 48%, and addition of 1% glucose suppressed enzyme production by Micromonospora strain AYA2000. The enzyme was purified by ammonium sulphate precipitation and DEAE-cellulose chromatography followed by gel filtration. The molecular weight, estimated using SDS-PAGE, was 39 kDa. The enzyme exhibited remarkable activity towards all keratinous wastes used and could also adapt to a broad range of pH and temperatures, with optima at pH 11 and 60 degrees C. The enzyme was not influenced by chelating reagents, metal ions, or alcohols. These properties make AYA2000 keratinase an ideal candidate for biotechnological application. PMID- 20921986 TI - Presence of antibiotic-resistant commensal bacteria in samples from agricultural, city, and national park environments evaluated by standard culture and real-time PCR methods. AB - This study examined the presence of antibiotic-resistant commensal bacteria among cattle operations representing areas heavily affected by agriculture, city locations representing areas affected by urban activities and indirectly affected by agriculture, and a national park representing an area not affected by agriculture. A total of 288 soil, fecal floor, and water samples were collected from cattle operations, from the city of Fort Collins, and from Rocky Mountain National Park (RMNP) in Colorado. In addition, a total of 42 new and unused feed, unused bedding, compost, and manure samples were obtained from the cattle operations. Total, tetracycline-resistant, and ceftiofur-resistant bacterial populations were enumerated by both standard culture plating and real-time PCR methods. Only wastewater samples from the cattle operations demonstrated both higher tetracycline-resistant bacterial counts (enumerated by the culture plating method) and tetracycline resistance gene copies (quantified by real-time PCR) compared to water samples collected from non-farm environments. The ceftiofur resistance gene, blaCMY-2, was not detectable in any of the samples, while the tetracycline resistance genes examined in this study, tet(B), tet(C), tet(W), and tet(O), were detected in all types of tested samples, except soil samples from RMNP. Tetracycline resistance gene pools quantified from the tet(O) and tet(W) genes were bigger than those from the tet(B) and tet(C) genes in fecal and water samples. Although only limited resistance genes, instead of a full set, were selected for real-time PCR quantification in this study, our results point to the need for further studies to determine natural and urban impacts on antibiotic resistance. PMID- 20921987 TI - Invasive aspergillosis promotes tumor growth and severity in a tumor-bearing mouse model. AB - Invasive aspergillosis increases in chronic immunosuppressive diseases such as cancer. There is little information about the mechanisms by which Aspergillus infection affects the immune regulation and microenvironment of cancer cells. Hence, this study was aimed at investigating the effect of invasive aspergillosis on immunosurveillance, metastasis, and prognosis of cancer in tumor-bearing mice. After implantation of mouse mammary tumor in BALB/c mice, they were infected with Aspergillus conidia intravenously. For comparison, groups of mice were experimentally infected with Aspergillus conidia or implanted with tumor cells separately. Seven days after Aspergillus infection, the serum levels of tissue inhibitor of metalloproteinase-1 (TIMP-1) were measured by ELISA, and subsequently regulatory T lymphocytes were analyzed by flow cytometry. The survival of animals and mean tumor size were then determined. Our results indicated that tumor sizes in mice increased significantly after infection with Aspergillus conidia. Moreover, invasive aspergillosis enhanced the population of regulatory lymphocytes and level of TIMP-1. This study supports the idea that massive Aspergillus infection could stimulate tumor growth and increases the possibility of a bad prognosis. As a result, treatment of Aspergillus infection could be considered an important issue for efficient cancer therapy. PMID- 20921988 TI - Responses of Staphylococcus aureus exposed to HCl and organic acid stress. AB - Staphylococcus aureus is an important food poisoning bacterium. In food preservation, acidification is a well-known method. Permeant weak organic acids, like lactic and acetic acids, are known to be more effective against bacteria than inorganic strong acids (e.g., HCl). Growth experiments and metabolic and transcriptional analyses were used to determine the responses of a food pathogenic S. aureus strain exposed to lactic acid, acetic acid, and HCl at pH 4.5. Lactic and acetic acid stress induced a slower transcriptional response and large variations in growth patterns compared with the responses induced by HCl. In cultures acidified with lactic acid, the pH of the medium gradually increased to 7.5 during growth, while no such increase was observed for bacteria exposed to acetic acid or HCl. Staphylococcus aureus increased the pH in the medium mainly through accumulation of ammonium and the removal of acid groups, resulting in increased production of diacetyl (2,3-butanedione) and pyrazines. The results showed flexible and versatile responses of S. aureus to different types of acid stress. As measured by growth inhibition, permeant organic acid stress introduced severe stress compared with the stress caused by HCl. Cells exposed to lactic acid showed specific mechanisms of action in addition to sharing many of the mechanisms induced by HCl stress. PMID- 20921989 TI - FTIR spectroscopic discrimination of Saccharomyces cerevisiae and Saccharomyces bayanus strains. AB - In this study, we tested the potential of Fourier-transform infrared absorption spectroscopy to screen, on the one hand, Saccharomyces cerevisiae and non-S. cerevisiae strains and, on the other hand, to discriminate between S. cerevisiae and Saccharomyces bayanus strains. Principal components analysis (PCA), used to compare 20 S. cerevisiae and 21 non-Saccharomyces strains, showed only 2 misclassifications. The PCA model was then used to classify spectra from 14 Samos strains. All 14 Samos strains clustered together with the S. cerevisiae group. This result was confirmed by a routinely used electrophoretic pattern obtained by pulsed-field gel electrophoresis. The method was then tested to compare S. cerevisiae and S. bayanus strains. Our results indicate that identification at the strain level is possible. This first result shows that yeast classification and S. bayanus identification can be feasible in a single measurement. PMID- 20921990 TI - ATP-type DNA ligase requires other proteins for its activity in vitro and its operon components for radiation resistance in Deinococcus radiodurans in vivo. AB - A multiprotein DNA processing complex isolated from Deinococcus radiodurans contains the DNA repair protein PprA, an ATP-type DNA repair ligase (LigB) encoded by the drB0100 gene, and protein kinase activity. An ATP-dependent DNA end-joining activity was detected in the complex. To elucidate the function of the drB0100 gene, we generated the deletion mutant for the DR_B0100 ORF. The mutant exhibited a nearly 2-log cycle reduction in growth rate when exposed to a 10,000 Gray dose of gamma-radiation, and a significant loss in mitomycin C and methylmethane sulphonate tolerance as compared with wild type. Functional complementation of these phenotypes required the wild-type copy of drB0100 along with other genes such as drb0099 and drb0098, organized downstream in the operon. The in vitro DNA ligase activity of LigB was stimulated severalfold by PprA in the presence of the recombinant DRB0098 protein. However, this activity did not improve when PprA was substituted with purified DRB0099 protein or when DRB0098 protein was substituted with the DRB0099 protein in the presence of PprA in solution. These results suggest that PprA and DRB0098 protein are required for LigB function. Furthermore, they also suggest that the LigB operon components contribute to radiation resistance and double-strand break (DSB) repair in D. radiodurans. PMID- 20921991 TI - Interactions of intrinsically disordered Thellungiella salsuginea dehydrins TsDHN 1 and TsDHN-2 with membranes - synergistic effects of lipid composition and temperature on secondary structure. AB - Dehydrins are intrinsically disordered (unstructured) proteins that are expressed in plants experiencing stressful conditions such as drought or low temperature. Dehydrins are typically found in the cytosol and nucleus, but also associate with chloroplasts, mitochondria, and the plasma membrane. Although their role is not completely understood, it has been suggested that they stabilize proteins or membrane structures during environmental stress, the latter association mediated by formation of amphipathic α-helices by conserved regions called the K segments. Thellungiella salsuginea is a crucifer that thrives in the Canadian sub Arctic (Yukon Territory) where it grows on saline-rich soils and experiences periods of both extreme cold and drought. We have cloned and expressed in Escherichia coli two dehydrins from this plant, denoted TsDHN-1 (acidic) and TsDHN-2 (basic). Here, we show using transmission-Fourier transform infrared (FTIR) spectroscopy that ordered secondary structure is induced and stabilized in these proteins by association with large unilamellar vesicles emulating the lipid compositions of plant plasma and organellar membranes. Moreover, this induced folding is enhanced at low temperatures, lending credence to the hypothesis that dehydrins stabilize plant outer and organellar membranes in conditions of cold. PMID- 20921992 TI - Prevention of cytokine withdrawal-induced apoptosis by Mcl-1 requires interaction between Mcl-1 and Bim. AB - Growth factor withdrawal from hemopoietic cells results in activation of the mitochondrial pathway of apoptosis. Members of the Bcl-2 family regulate this pathway, with anti-apoptotic members counteracting the effects of pro-apoptotic members. We investigated the effect on Mcl-1 function of mutation at a conserved threonine 163 residue (T163) in its proline, glutamate, serine, and threonine rich (PEST) region. Under normal growth conditions, Mcl-1 half-life increased with alteration of T163 to glutamic acid, but decreased with mutation to alanine. However, both T163 mutants exhibited greater pro-survival effects compared with the wild type, which can be explained by an increased stability of the T163A mutant in cytokine-starved conditions. Both the mutant forms exhibited prolonged binding to pro-apoptotic Bim in cytokine-deprived cells. The extent to which Mcl 1 mutants were able to exert their anti-apoptotic effects correlated with their ability to associate with Bim. We further observed that primary bone marrow derived macrophages survived following cytokine withdrawal as long as Bim and Mcl 1 remained associated. In our study, we were unable to detect a role for GSK-3 mediated regulation of Mcl-1 expression. Based on these results we propose that upon cytokine withdrawal, survival of hemopoietic cells depends on association between Mcl-1 and Bim. Furthermore, alteration of T163 of Mcl-1 may change the protein such that its association with Bim is affected, resulting in prolonged association and increased survival. PMID- 20921993 TI - Hepatoprotection by carotenoids in isoniazid-rifampicin induced hepatic injury in rats. AB - This study evaluates the hepatoprotective effect of carotenoids against isoniazid (INH) and rifampicin (RIF). Thirty-six adult rats were divided into the following 4 groups: (1) control group treated with normal saline; (2) INH + RIF group treated with 50 mg.(kg body mass)-1.day-1 of INH and RIF each; (3) INH + RIF+ carotenoids group treated with 50 mg.(kg body mass)-1.day-1 of INH and RIF each and 10 mg.(kg body mass)-1.day-1 of carotenoids; and (4) carotenoids group treated with 10 mg.(kg body mass)-1.day-1 of carotenoids for 28 days intragastrically. Oxidative stress and antioxidant levels in liver and blood, liver histology and change in transaminases were measured in all the above mentioned groups. There was an increase in lipid peroxidation with a reduction in thiols, catalase, and superoxide dismutase (SOD) in the liver and blood of rats accompanied by an increase in transaminases, bilirubin, and alkaline phosphatase. Treatment with carotenoids along with INH + RIF partially reversed lipid peroxidation, thiols, catalase, and SOD in the liver and blood of rats. Elevated levels of the enzymes in serum were also reversed partially by this treatment. The degree of necrosis, portal triaditis, and inflammation were also lowered in the carotenoids group. In conclusion, carotenoids supplementation in INH + RIF treated rats showed partial protection. PMID- 20921994 TI - Higher expression of ferritin protects Chlamydia trachomatis infected HeLa 229 cells from reactive oxygen species mediated cell death. AB - Apoptosis plays an important role in modulating the pathogenesis of a variety of infectious diseases. Chlamydial infection protects cells against different forms of apoptosis: extrinsic, intrinsic, and granzyme B mediated. Redox reactions are central to the life and death decision of cells and pathogens and an intimate relationship exists between oxidative stress and iron metabolism. The link between redox status and ferritin was largely unexplored in chlamydia-infected cells. In the present study, we showed that Chlamydia trachomatis (CT) infection induced FHC protein in HeLa cells. FHC induction by CT-infected cells stably expressing FHC blunted ROS production compared with mock infected cells, and the infected cells were relatively resistant to apoptosis induced by H2O2. We also demonstrated that endogenous FHC overexpression correlates well with the stabilization of the mitochondrial membrane potential in CT-infected cells. Increased expression of FHC is independent of iron supplementation (FAC) and depletion (DFO) in CT-infected cells. These data suggest that FHC up-regulation is an acute response of HeLa cells against CT infection and that FHC exerts anti apoptotic activity against oxidative stress. PMID- 20921995 TI - Trends in matrix metalloproteinase research from 1986-2007: a bibliometric study. AB - Using the SCI-expanded database, this study provides a quantitative description of the development of the research involving matrix metalloproteinase (MMP) over a period of 20 years. From 1986 to 2007 the scientific literature related to MMP increased sevenfold (397 papers in 1986-1987 and 2834 in 2006-2007). The number of countries participating in MMP-related research doubled during this period (33 in 1986-1987 to 67 in 2006-2007), and the USA continually remained the leader. Several industrialized nations (Japan, Germany, UK, Canada, and France) also continuously played important roles, with some emerging Asian countries joining the top 10 most productive countries in 2006-2007: China (ranked 5th), South Korea (6th), and Taiwan (10th). The MMP-related literature was distributed among a continuously growing number of journals (188 in 1986-1987, 527 in 1996-1997, and 913 in 2006-2007) and The Journal of Biological Chemistry remained the most prolific throughout the entire period. The development of the research involving MMPs during the past two decades was also characterized by a progressive transfer of interest from basic research to clinical medicine; cell biology and pharmacology were important routes of investigation generally pursued by researchers. Journals dedicated to oncology have progressively risen to the top 8 most prolific journals during the 20 year period analyzed. PMID- 20921996 TI - Rosiglitazone regulates IL-6-stimulated lipolysis in porcine adipocytes. AB - Interleukin (IL)-6, a proinflammatory cytokine, stimulates adipocyte lipolysis and induces insulin resistance in obese and diabetic subjects. However, the effects of the anti-diabetic drug rosiglitazone on IL-6-stimulated lipolysis and the underlying molecular mechanism are largely unknown. In this study, we demonstrated that rosiglitazone suppressed IL-6-stimulated lipolysis in differentiated porcine adipocytes by inactivation of extracellular signal-related kinase (ERK). Meanwhile, rosiglitazone enhanced the lipolysis response of adipocytes to isoprenaline. In addition, rosiglitazone significantly reversed IL 6-induced down-regulation of several genes such as perilipin A, peroxisome proliferators activated receptor gamma (PPARγ), and fatty acid synthetase, as well as the up-regulation of IL-6 mRNA. However, mRNA expression of PPARγ coactivator-1 alpha (PCG-1α) was enhanced by rosiglitazone in IL-6-stimulated adipocytes. These results indicate that rosiglitazone suppresses IL-6-stimulated lipolysis in porcine adipocytes through multiple molecular mechanisms. PMID- 20921997 TI - Role of Met-542 as a guide for the conformational changes of Phe-601 that occur during the reaction of β-galactosidase (Escherichia coli). AB - The Met-542 residue of beta-galactosidase is important for the enzyme's activity because it acts as a guide for the movement of the benzyl side chain of Phe-601 between two stable positions. This movement occurs in concert with an important conformational change (open vs. closed) of an active site loop (residues 794 803). Phe-601 and Arg-599, which interact with each other via the pi electrons of Phe-601 and the guanidium cation of Arg-599, move out of their normal positions and become disordered when Met-542 is replaced by an Ala residue because of the loss of the guide. Since the backbone carbonyl of Phe-601 is a ligand for Na(+), the Na(+) also moves out of its normal position and becomes disordered; the Na(+) binds about 120 times more poorly. In turn, two other Na(+) ligands, Asn-604 and Asp-201, become disordered. A substrate analog (IPTG) restored Arg-599, Phe-601, and Na(+) to their normal open-loop positions, whereas a transition state analog d-galactonolactone) restored them to their normal closed-loop positions. These compounds also restored order to Phe-601, Asn-604, Asp-201, and Na(+). Binding energy was, however, necessary to restore structure and order. The K(s) values of oNPG and pNPG and the competitive K(i) values of substrate analogs were 90-250 times higher than with native enzyme, whereas the competitive K(i) values of transition state analogs were ~3.5-10 times higher. Because of this, the E*S energy level is raised more than the E*transition state energy level and less activation energy is needed for galactosylation. The galactosylation rates (k2) of M542A-beta-galactosidase therefore increase. However, the rate of degalactosylation (k3) decreased because the E*transition state complex is less stable. PMID- 20921999 TI - Color constancy based on texture pyramid matching and regularized local regression. AB - Considering that no single algorithm available is universal in color constancy, we propose an effective combination approach using a texture-based matching strategy and a local regression with prior-knowledge regularization. To represent the images, we construct a texture pyramid using an integrated Weibull distribution. Then we define an image similarity measure to search for the K most similar images of the test image. To combine the single algorithms, we integrate prior knowledge into a regularized local regression in a decorrelated color space. Regression weights are obtained on these similar images, and the regularization is implemented by the frequency ratio of the best single algorithm. Experiments on two real world datasets show our approach outperforms the state-of-the-art single algorithms and popular combination approaches with a performance increase of at least 29% compared to the best-performing single algorithm w.r.t median angular error. PMID- 20922000 TI - Number of discernible colors for color-deficient observers estimated from the MacAdam limits. AB - We estimated the number of colors perceived by color normal and color-deficient observers when looking at the theoretic limits of object-color stimuli. These limits, the optimal color stimuli, were computed for a color normal observer and CIE standard illuminant D65, and the resultant colors were expressed in the CIELAB and DIN99d color spaces. The corresponding color volumes for abnormal color vision were computed using models simulating for normal trichromatic observers the appearance for dichromats and anomalous trichomats. The number of colors perceived in each case was then computed from the color volumes enclosed by the optimal colors also known as MacAdam limits. It was estimated that dichromats perceive less than 1% of the colors perceived by normal trichromats and that anomalous trichromats perceive 50%-60% for anomalies in the medium wavelength-sensitive and 60%-70% for anomalies in the long-wavelength-sensitive cones. Complementary estimates obtained similarly for the spectral locus of monochromatic stimuli suggest less impairment for color-deficient observers, a fact that is explained by the two-dimensional nature of the locus. PMID- 20922001 TI - Probabilistic spectral model of color halftone incorporating substrate fluorescence and interface reflections. AB - A spectral model incorporating three major physical phenomena, lateral light scattering, substrate fluorescence, and interface reflections governing light print interaction is presented. In the model, light scattering inside a paper substrate is described by probabilities applicable for any degree of light diffusion. The concept of fluorescence enhanced transmittance has been proven very useful for extending the probability approach to prints on fluorescent substrates. The contribution of multiple internal reflections is accounted for by series expansion of fast convergence. Previously developed models like the Neugebauer equation and the Clapper-Yule model can easily be obtained as special cases of the present model. PMID- 20922002 TI - Comparison of depth-of-focus-enhancing pupil masks based on a signal-to-noise ratio criterion after deconvolution. AB - We consider optimization of hybrid imaging systems including a pupil mask for enhancing the depth of field and a digital deconvolution step. In a previous paper [Opt. Lett. 34, 2970 (2009)] we proposed an optimization criterion based on the signal-to-noise ratio of the restored image. We use this criterion in order to optimize different families of phase or amplitude masks and to compare them, on an objective basis, for different desired defocus ranges. We show that increasing the number of parameters of the masks allows one to obtain better performance. PMID- 20922003 TI - Designing coupled free-form surfaces. AB - The problem of designing optical systems that contain free-form surfaces is a challenging one, even in the case of designing a single surface. Here we present a method for the coupled design of two free-form reflective surfaces that will have a prescribed distortion. On one hand, the method can be described using traditional vectors and matrices, which we do, but it is motivated by viewing the problem in the language of distributions from differential geometry and makes use of the exterior differential systems, which we relegate to an appendix. Example applications are given to the design of a mirror pair that increases the field of view of an observer, a similar mirror pair that also rotates the observer's view, and a pair of mirrors that give the observer a traditional panoramic strip view of the scene. PMID- 20922004 TI - Evolution of the scintillation index and the optical vortex density in speckle fields after removal of the least-squares phase. AB - Knowledge of the behavior of stochastic optical fields can aid the understanding of the scintillation of light propagating through a turbulent medium. For this purpose, we perform a numerical investigation of the evolution of the scintillation index and the optical vortex density in a speckle field after removing its continuous phase. We find that both the scintillation index and the vortex density initially drop and then increase again to reach an equilibrium level. It is also found that the initial rate of decrease in both cases is 1 order of magnitude faster than the eventual rate of increase. Their detail shapes are however different. Therefore different empirical functions are used to fit the shapes of these curves. PMID- 20922005 TI - Operational and convolution properties of three-dimensional Fourier transforms in spherical polar coordinates. AB - For functions that are best described with spherical coordinates, the three dimensional Fourier transform can be written in spherical coordinates as a combination of spherical Hankel transforms and spherical harmonic series. However, to be as useful as its Cartesian counterpart, a spherical version of the Fourier operational toolset is required for the standard operations of shift, multiplication, convolution, etc. This paper derives the spherical version of the standard Fourier operation toolset. In particular, convolution in various forms is discussed in detail as this has important consequences for filtering. It is shown that standard multiplication and convolution rules do apply as long as the correct definition of convolution is applied. PMID- 20922006 TI - Strategies for global optimization in photonics design. AB - This paper reports on two important issues that arise in the context of the global optimization of photonic components where large problem spaces must be investigated. The first is the implementation of a fast simulation method and associated matrix solver for assessing particular designs and the second, the strategies that a designer can adopt to control the size of the problem design space to reduce runtimes without compromising the convergence of the global optimization tool. For this study an analytical simulation method based on Mie scattering and a fast matrix solver exploiting the fast multipole method are combined with genetic algorithms (GAs). The impact of the approximations of the simulation method on the accuracy and runtime of individual design assessments and the consequent effects on the GA are also examined. An investigation of optimization strategies for controlling the design space size is conducted on two illustrative examples, namely, 60 degrees and 90 degrees waveguide bends based on photonic microstructures, and their effectiveness is analyzed in terms of a GA's ability to converge to the best solution within an acceptable timeframe. Finally, the paper describes some particular optimized solutions found in the course of this work. PMID- 20922007 TI - Beam scintillations for ground-to-space propagation. Part I: Path integrals and analytic techniques. AB - We extend our theory of on-axis beam scintillations [Waves Random Media 4, 243 (1994)] for the case of propagation on slant turbulent paths, where turbulence is concentrated in a relatively thin layer near the transmitter. Our technique is based on the parabolic equation for optical wave propagation and the Markov approximation for the calculation of statistical moments of beam intensity. This first of two companion papers presents the details of the path integral formulation of the solution for the fourth-order coherence function. We also discuss in detail two analytic techniques that can be used for the treatment of the path integrals. PMID- 20922008 TI - Beam scintillations for ground-to-space propagation. Part 2: Gaussian beam scintillation. AB - On the basis of the analytic techniques presented in the first of these two companion papers [J. Opt. Soc. Am. A27, 2169 (2010)] we present the complete asymptotic analysis of the axial beam scintillation index for coherent Gaussian beams on the ground-to-space propagation paths. The ratio of turbulence layer thickness to overall propagation path length contributes an additional small parameter to the analysis. We show that it is possible to use three dimensionless parameters to describe the problem and that the general arrangement of the asymptotic regions established in our earlier work [Waves Random Media 4, 243 (1994)]) is preserved. We find that on a slant propagation path, collimated beams can experience the unusual double-scattering-dominated scintillation found originally for focused beams. PMID- 20922009 TI - Controlling the contribution of the electric field components to the focus of a high-aperture lens using binary phase structures. AB - We show that the contribution of the electric field components into the focal region can be controlled using binary phase structures. We discuss differently polarized incident waves, for each case suggesting easily implemented binary phase distributions that ensure a maximum contribution of a definite electric field component on the optical axis. A decrease in the size of the central focal spot produced by a high numerical aperture (NA) focusing system comes as the result of the spatial redistribution of the contribution of different electric field components into the focal region. Using a polarization conversion matrix of a high NA lens and the numerical simulation of the focusing system in Debye's approximation, we demonstrate benefits of using asymmetric to polar angle phi binary phase distributions (such as arg[cos phi] or arg[sin 2phi]) for generating a subwavelength focal spot in separate electric field components. Additional binary structure variations with respect to the azimuthal angle also make possible controlling the longitudinal distribution of light. In particular, the contribution of the transverse components in the focal plane can be reduced by the use of a simple axicon-like structure that serves to enhance the NA of the lens central part, redirecting the energy from focal plane. As compared with the superimposition of a narrow annular aperture, this approach is more energy efficient, and as compared with the Toraldo filters, it is easier to control when applied to three-dimensional focal shaping. PMID- 20922010 TI - Optimum sensors for color constancy in scenes illuminated by daylight. AB - The apparent color of an object within a scene depends on the spectrum of the light illuminating the object. However, recording an object's color independent of the illuminant spectrum is important in many machine vision applications. In this paper the performance of a blackbody-model-based color constancy algorithm that requires four sensors with different spectral responses is investigated under daylight illumination. In this investigation sensor noise was modeled as gaussian noise, and the responses were quantized using different numbers of bits. A projection-based algorithm whose output is invariant to illuminant is investigated to improve the results that are obtained. The performance of both of these algorithms is then improved by optimizing the spectral sensitivities of the four sensors using freely available CIE standard daylight spectra and a set of lightness-normalized Munsell reflectance data. With the optimized sensors the performance of both algorithms is shown to be comparable to the human visual system. However, results obtained with measured daylight spectra show that the standard daylights may not be sufficiently representative of measured daylight for optimization with the standard daylight to lead to a reliable set of optimum sensor characteristics. PMID- 20922011 TI - Comparison among the variants of subspace-based optimization method for addressing inverse scattering problems: transverse electric case. AB - The subspace-based optimization method (SOM) is an efficient approach to addressing the inverse scattering problem. In this paper, a comparative study, on the basis of numerical experiments, is conducted to evaluate the performances of variants of SOM, so as to find the optimal method for the determination of the ambiguous portion, which has a dominant influence on the computational cost and the reconstruction capability of the algorithm. PMID- 20922012 TI - Image formation and tomogram reconstruction in optical coherence microscopy. AB - In this work we present a model for image formation in optical coherence microscopy. In the spectral domain detection, each wavenumber has a specific coherent transfer function that samples a different part of the object's spatial frequency spectrum. The reconstruction of the tomogram is usually accurate only in a short depth of field. Using numerical simulations based on the developed model, we identified two distinct mechanisms that influence the signal of out-of focus sample information. Besides the lateral blurring induced through defocusing, an additional axial envelope contributing equally to the signal degradation was found. PMID- 20922014 TI - Design of a one-dimensional electromagnetic transparent wall. AB - For a one-dimensional (1D) anisotropic slab, if its electromagnetic parameters satisfy certain conditions, an incident wave can be totally transmitted without any reflections. In this work, a classical method based on analytical results and a transformation optics method using an arbitrary piecewise continuous transformation function are applied to design a 1D electromagnetic transparent wall, whose presence does not disturb the field distribution in the ambient environment. Material parameters and the geometrical requirement of the layered structure using these two different methods are derived, and they agree well with each other. Full-wave simulations validate the transparency of the proposed wall. Because of the simple constitutive parameters and geometry, a transparent structure could be realized using anisotropic and homogeneous materials. The proposed structure has potential applications in radomes, anti-reflection films, and various sensor sectors. PMID- 20922013 TI - Investigation on an application of silver substrates for sensitive surface plasmon resonance imaging detection. AB - A surface plasmon resonance (SPR) imaging biosensor based on silver substrates was investigated to demonstrate that silver could be used as a substrate material for sensitive detection of biomolecular interactions, despite its poor chemical stability. The calculation results showed that oxidation of silver film may lead to a decrease in the sensitivity due to a variation in SPR characteristics such as a broader curve width and shallower minimum reflectance at resonance. The effect of a change in the refractive index of target analytes on the sensitivity was also explored. In particular, it is noteworthy that Ag/Au bimetallic substrates with a thin gold protection layer to prevent oxidation of a silver film can provide a significant amplification of SPR imaging signals in comparison with conventional gold substrates. PMID- 20922015 TI - Non-interferometric, non-iterative phase retrieval by Green's functions. AB - In this paper a non-interferometric, non-iterative method for phase retrieval by Green's functions is presented. The theory is based on the parabolic wave equation that describes propagation of light in the Fresnel approximation in homogeneous media. Green's first identity will be used to derive an algorithm for phase retrieval considering different boundary conditions. Finally it will be shown that a commonly used solution of the transport-of-intensity equation can be obtained as a special case of the more general Green's function formulation derived here. PMID- 20922016 TI - Properties of caustics produced by a positive lens: meridional rays. AB - We study the formation of the caustic surfaces formed in both convex-plane and plano-convex spherical lenses by considering a plane wave incident on the lens along the optical axis. Using the caustic formulas and a paraxial approximation we derive analytical expressions to evaluate the spherical aberration to third order. Furthermore, we apply the formulas to evaluate the circle of least confusion for a positive lens. PMID- 20922017 TI - Accurate and versatile modeling of electromagnetic scattering on periodic nanostructures with a surface integral approach. AB - A surface integral formulation for light scattering on periodic structures is presented. Electric and magnetic field equations are derived on the scatterers' surfaces in the unit cell with periodic boundary conditions. The solution is calculated with the method of moments and relies on the evaluation of the periodic Green's function performed with Ewald's method. The accuracy of this approach is assessed in detail. With this versatile boundary element formulation, a very large variety of geometries can be simulated, including doubly periodic structures on substrates and in multilayered media. The surface discretization shows a high flexibility, allowing the investigation of irregular shapes including fabrication accuracy. Deep insights into the extreme near-field of the scatterers as well as in the corresponding far-field are revealed. This method will find numerous applications for the design of realistic photonic nanostructures, in which light propagation is tailored to produce novel optical effects. PMID- 20922018 TI - Illumination artifacts in hyper-NA vector imaging. AB - Off-axis polarized monopole illumination is applied to a hyper-numerical-aperture (NA) (NA>1) microscopic system. Illumination artifacts due to vector effects are observed, which are asymmetric and depend on illumination conditions. A model based on rigorous coupled wave theory is used to simulate image profiles for dielectric, semiconductor, and metal gratings with different monopole locations and polarization states. A solid immersion lens microscope is used to image different types of samples including MoSi photomask, patterned silicon wafer, and chrome photomask. The experimental images are in good agreement with simulation results. PMID- 20922019 TI - Topography retrieval using different solutions of the transport intensity equation. AB - The topography of a phase plate is recovered from the phase reconstruction by solving the transport intensity equation (TIE). The TIE is solved using two different approaches: (a) the classical solution of solving the Poisson differential equation and (b) an algebraic approach with Zernike functions. In this paper we present and compare the topography reconstruction of a phase plate with these solution methods and justify why one solution is preferable over the other. PMID- 20922020 TI - Surface waves and atomic force microscope probe-particle near-field coupling: discrete dipole approximation with surface interaction. AB - Evanescent waves on a surface form due to the collective motion of charges within the medium. They do not carry any energy away from the surface and decay exponentially as a function of the distance. However, if there is any object within the evanescent field, electromagnetic energy within the medium is tunneled away and either absorbed or scattered. In this case, the absorption is localized, and potentially it can be used for selective diagnosis or nanopatterning applications. On the other hand, scattering of evanescent waves can be employed for characterization of nanoscale structures and particles on the surface. In this paper we present a numerical methodology to study the physics of such absorption and scattering mechanisms. We developed a MATLAB implementation of discrete dipole approximation with surface interaction (DDA-SI) in combination with evanescent wave illumination to investigate the near-field coupling between particles on the surface and a probe. This method can be used to explore the effects of a number of physical, geometrical, and material properties for problems involving nanostructures on or in the proximity of a substrate under arbitrary illumination. PMID- 20922021 TI - Upscaling image resolution of compact imaging systems using wavefront coding and a property of the point-spread function. AB - We propose an image-resolution upscaling method for compact imaging systems. The image resolution is calculated using the resolving power of the optics and the pixel size of a digital image sensor. The resolution limit of the compact imaging system comes from its size and the number of allowed lenses. To upscale the image resolution but maintain the small size, we apply wavefront coding and image restoration. Conventional image restoration could not enhance the image resolution of the sensor. Here, we use the upscaled image of a wavefront-coded optical system and apply an image-restoration algorithm using a more precisely calculated point-spread function (PSF) as the deconvolution filter. An example of a wavefront-coded optical system with a 5-megapixel image sensor is given. The final image had a resolution equivalent to that of a 10-megapixel image using only four plastic lenses. Moreover, image degradation caused by hand motion could also be reduced using the proposed method. PMID- 20922022 TI - Fisher information and surrogate figures of merit for the task-based assessment of image quality. AB - Fisher information can be used as a surrogate for task-based measures of image quality based on ideal observer performance. A new and improved derivation of the Fisher information approximation for ideal-observer detectability is provided. This approximation depends only on the presence of a weak signal and does not depend on Gaussian statistical assumptions. This is also not an asymptotic result and therefore applies to imaging, where there is typically only one dataset, albeit a large one. Applications to statistical mixture models for image data are presented. For Gaussian and Poisson mixture models the results are used to connect reconstruction error with ideal-observer detection performance. When the task is the estimation of signal parameters of a weak signal, the ensemble mean squared error of the posterior mean estimator can also be expanded in powers of the signal amplitude. There is no linear term in this expansion, and it is shown that the quadratic term involves a Fisher information kernel that generalizes the standard Fisher information. Applications to imaging mixture models reveal a close connection between ideal performance on these estimation tasks and detection tasks for the same signals. Finally, for tasks that combine detection and estimation, we may also define a detectability that measures performance on this combined task and an ideal observer that maximizes this detectability. This detectability may also be expanded in powers of the signal amplitude, and the quadratic term again involves the Fisher information kernel. Applications of this approximation to imaging mixture models show a relation with the pure detection and pure estimation tasks for the same signals. PMID- 20922023 TI - Region-based reconstruction method for fluorescent molecular tomography. AB - A common difficulty for the traditional methods of fluorescent molecular tomographic (FMT) reconstruction is that only a small amount of measurements can be used to recover the image comprised of a large number of pixels. This difficulty not only leads to expensive computational cost but also likely results in an unstable solution prone to be affected by the noise in the measurement data. In this paper, we propose a region-based method for reducing the unknowns, where the target areas are determined by searching for the nearest neighbor nodes. In this method, the Hessian matrix of the second-order derivatives is incorporated to speed up the optimization process. An iteration strategy of multi wavelength measurement is introduced to further improve the accuracy of inverse solutions. Simulation results demonstrate that the proposed approach can significantly speed up the reconstruction process and improve the image quality of FMT. PMID- 20922024 TI - Application of orbital angular momentum to simultaneous determination of tilt and lateral displacement of a misaligned laser beam. AB - We present an analysis of the combined effects of tilt and lateral displacement on the orbital angular momentum spectrum of a laser beam. Our theory explains the symmetries and properties of the spectrum under the influence of misalignments. We apply the theory to establish a reliable and efficient method for determining and subsequently eliminating tilt and lateral displacement. An improved technique for obtaining the orbital angular momentum spectrum employing Laguerre-Gaussian modes is proposed. Finally, a numerical experiment is carried out to verify the method. PMID- 20922025 TI - Optical element for generation of accelerating Airy beams. AB - We demonstrate an optical element for generation of accelerating Airy beams. The element is conveniently constructed by combination of positive and negative cylindrical lenses of matching radii of curvature. With proper choice of lens curvatures, the resulting surface profile closely follows a cubic polynomial. Passing a gaussian beam through this element and performing optical Fourier transform yields beam profiles close to the Airy function. Our experiments demonstrate parabolic propagation, or acceleration, of the resulting focal spots. PMID- 20922026 TI - Assessing Coping Responses within Specific Faith Traditions: Suffering in Silence, Stress, and Depressive Symptoms Among Older Catholics. AB - The purpose of this study is empirically evaluate a coping response that is thought to be unique among older Catholics - suffering in silence. Two hypotheses are examined. The first predicts that older Catholics will be more likely than older Protestants to suffer in silence when ongoing economic difficulty is encountered. The second hypothesis specifies that the potentially deleterious effects of financial problems on depressive symptoms will be offset for older adults who prefer to suffer in silence. Data from an ongoing nationwide survey of older people in the United States provide support for both hypotheses. PMID- 20922027 TI - Application of virtual microscopy in consultation practice of gastrointestinal and liver pathology. PMID- 20922028 TI - Digital pathology in clinical consultation practice. PMID- 20922029 TI - A decade of experience in the development and implementation of tissue banking informatics tools for intra and inter-institutional translational research. AB - CONTEXT: Tissue banking informatics deals with standardized annotation, collection and storage of biospecimens that can further be shared by researchers. Over the last decade, the Department of Biomedical Informatics (DBMI) at the University of Pittsburgh has developed various tissue banking informatics tools to expedite translational medicine research. In this review, we describe the technical approach and capabilities of these models. DESIGN: Clinical annotation of biospecimens requires data retrieval from various clinical information systems and the de-identification of the data by an honest broker. Based upon these requirements, DBMI, with its collaborators, has developed both Oracle-based organ specific data marts and a more generic, model-driven architecture for biorepositories. The organ-specific models are developed utilizing Oracle 9.2.0.1 server tools and software applications and the model-driven architecture is implemented in a J2EE framework. RESULT: The organ-specific biorepositories implemented by DBMI include the Cooperative Prostate Cancer Tissue Resource (http://www.cpctr.info/), Pennsylvania Cancer Alliance Bioinformatics Consortium (http://pcabc.upmc.edu/main.cfm), EDRN Colorectal and Pancreatic Neoplasm Database (http://edrn.nci.nih.gov/) and Specialized Programs of Research Excellence (SPORE) Head and Neck Neoplasm Database (http://spores.nci.nih.gov/current/hn/index.htm). The model-based architecture is represented by the National Mesothelioma Virtual Bank (http://mesotissue.org/). These biorepositories provide thousands of well annotated biospecimens for the researchers that are searchable through query interfaces available via the Internet. CONCLUSION: These systems, developed and supported by our institute, serve to form a common platform for cancer research to accelerate progress in clinical and translational research. In addition, they provide a tangible infrastructure and resource for exposing research resources and biospecimen services in collaboration with the clinical anatomic pathology laboratory information system (APLIS) and the cancer registry information systems. PMID- 20922030 TI - The state of telepathology in Japan. AB - Telepathology began in Japan in the early 1990s in response to advances in computing and telecommunications equipment development and a dearth of pathologists. Telepathology in Japan is most often used for rapid intraoperative pathological diagnosis using frozen section, followed by second opinions and consultation. Intraoperatively, telepathology is used to determine malignancy, metastasis of malignant tumors, and the extent of excision. Infrastructure and equipment has evolved from analog lines to digital lines like integrated services digital network (ISDN) and asymmetric digital subscriber line (ADSL), and recently to fiber optics. The use of communications satellites is also being considered. Image quality is being improved to Hi-Vision (HDTV), and from still images to real-time video. Digital microscopy has been introduced, and is used in education and consultation. PMID- 20922031 TI - Medical education in the digital age: Digital whole slide imaging as an e learning tool. PMID- 20922032 TI - Digital images and the future of digital pathology. PMID- 20922033 TI - Students' perception of the learning environment in a distributed medical programme. AB - BACKGROUND: The learning environment of a medical school has a significant impact on students' achievements and learning outcomes. The importance of equitable learning environments across programme sites is implicit in distributed undergraduate medical programmes being developed and implemented. PURPOSE: To study the learning environment and its equity across two classes and three geographically separate sites of a distributed medical programme at the University of British Columbia Medical School that commenced in 2004. METHOD: The validated Dundee Ready Educational Environment Survey was sent to all students in their 2nd and 3rd year (classes graduating in 2009 and 2008) of the programme. The domains of the learning environment surveyed were: students' perceptions of learning, students' perceptions of teachers, students' academic self-perceptions, students' perceptions of the atmosphere, and students' social self-perceptions. Mean scores, frequency distribution of responses, and inter- and intrasite differences were calculated. RESULTS: The perception of the global learning environment at all sites was more positive than negative. It was characterised by a strongly positive perception of teachers. The work load and emphasis on factual learning were perceived negatively. Intersite differences within domains of the learning environment were more evident in the pioneer class (2008) of the programme. Intersite differences consistent across classes were largely related to on-site support for students. CONCLUSIONS: Shared strengths and weaknesses in the learning environment at UBC sites were evident in areas that were managed by the parent institution, such as the attributes of shared faculty and curriculum. A greater divergence in the perception of the learning environment was found in domains dependent on local arrangements and social factors that are less amenable to central regulation. This study underlines the need for ongoing comparative evaluation of the learning environment at the distributed sites and interaction between leaders of these sites. PMID- 20922034 TI - Retinal nerve fiber layer evaluation in multiple sclerosis with spectral domain optical coherence tomography. AB - PURPOSE: Histopathologic studies have reported retinal nerve fiber layer (RNFL) thinning in various neurodegenerative diseases. Attempts to quantify this loss in vivo have relied on time-domain optical coherence tomography (TDOCT), which has low resolution and requires substantial interpolation of data for volume measurements. We hypothesized that the significantly higher resolution of spectral-domain optical coherence tomography (SDOCT) would better detect RNFL changes in patients with multiple sclerosis, and that RNFL thickness differences between eyes with and without optic neuritis might be identified more accurately. METHODS: In this retrospective case series, patients with multiple sclerosis were recruited from the Judith Jaffe Multiple Sclerosis Center at Weill Cornell Medical College in New York. Patients with a recent clinical diagnosis of optic neuritis (less than three months) were excluded. Eyes with a history of glaucoma, optic neuropathy (other than multiple sclerosis-related optic neuritis), age related macular degeneration, or other relevant retinal and/or optic nerve disease were excluded. Both eyes of each patient were imaged with the Heidelberg Spectralis((r)) HRA + OCT. RNFL and macular thickness were measured for each eye using the Heidelberg OCT software. These measurements were compared with validated published normal values, and were modeled as linear functions of duration of disease. The odds of an optic neuritis diagnosis as a function of RNFL and macular thickness were calculated. RESULTS: Ninety-four eyes were prospectively evaluated using OCT. Ages of patients ranged from 26 to 69 years, with an average age of 39 years. Peripapillary RNFL thinning was demonstrated in multiple sclerosis patients; mean RNFL thickness was 88.5 MUm for individuals with multiple sclerosis compared with a reported normal value of 97 MUm (P < 0.001). Eyes with a history of optic neuritis had more thinning compared with those without optic neuritis (83.0 MUm versus 90.5 MUm, respectively, P = 0.02). No significant differences were observed in macular thickness measurements between eyes with and without optic neuritis, nor were macular thickness measurements significantly different from normal values. As a function of multiple sclerosis duration and controlling for age, RNFL thickness was decreased in patients with a duration of multiple sclerosis greater than five years compared with those with a duration less than or equal to one year (P = 0.008). CONCLUSIONS: Patients with a history of multiple sclerosis had RNFL thinning that was detectable on SDOCT. Decreasing RNFL thickness in eyes with optic neuritis was found, and the odds of having optic neuritis were increased significantly with decreasing RNFL thickness. Average RNFL thinning with increasing duration of disease was an excellent predictor of a reported history of optic neuritis. SDOCT retinal imaging may represent a high-resolution, objective, noninvasive, and easily quantifiable in vivo biomarker of the presence of optic neuritis and severity of multiple sclerosis. PMID- 20922036 TI - Cytotoxicity of five fluoroquinolone and two nonsteroidal anti-inflammatory benzalkonium chloride-free ophthalmic solutions in four corneoconjunctival cell lines. AB - PURPOSE: Epithelial disorders after eye surgery can result in visual deterioration and patient discomfort. Such disorders may be caused by drug toxicity. In the present study, we evaluated the toxicity of ophthalmic solutions, with or without benzalkonium chloride (BAK) as the preservative, used for postoperative care. METHODS: A range of commercially available antibiotic and anti-inflammatory ophthalmic solutions used postoperatively (ie, levofloxacin, moxifloxacin, gatifloxacin, norfloxacin, tosufloxacin, dibekacin, cefmenoxime, diclofenac, bromfenac, pranoprofen, betamethasone, and fluoromethorone) were assessed in three corneal cell lines and one conjunctival cell line. All antibiotic solutions were BAK free. Cell viability was determined with the 3-(4,5 dimethyl-2 thiazoyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay after cells had been exposed to the drugs for 48 h. The effects of preservatives on cell viability were also determined. Toxicity was compared using the cell viability score (CVS). RESULTS: Based on results of the MTT assay and CVS, the order of cell viability after exposure to the antibiotic solutions was cefmenoxime >= tosufloxicin >= dibekacin >= levofloxacin >= norfloxacin = gatifloxacin = moxifloxacin. For the anti-inflammatory solutions, the order of cell viability was betamethasone >= betamethasone + fradiomycin > preservative-free diclofenac >= preservative-free bromfenac >> 0.02% fluoromethorone >= 0.1% fluoromethorone = diclofenac + preservative = bromfenac + preservative = pranoprofen. The anti inflammatory drugs were more toxic than the antibiotics. The toxicity of antibiotic drugs against ocular surface cells was dependent on the pharmaceutical components of the solution, whereas that of the anti-inflammatory drugs was dependent on both the pharmaceutical components and the preservatives. CONCLUSION: Postoperative drug-induced epitheliopathy may be caused primarily by anti-inflammatory drugs. CVS is useful in comparing the cytotoxicity of different drugs. PMID- 20922035 TI - Photorefractive keratectomy: measuring the matrix metalloproteinase activity and chondroitin sulfate concentration in tear fluid. AB - We herein report the case of a 20-year-old man who underwent a photorefractive keratectomy (PRK). We measured matrix metalloproteinase-9 (MMP-9) activity and chondroitin 4 sulfate and chondroitin 6 sulfate concentrations in tear fluid. Tear fluid was collected pre-operatively via microcapillary tube, and was collected postoperatively on the first and fourth days, and after one week, one month, three months, and six months. Samples were formulated by dilution with 200 MUL of saline. MMP-9 activity was analyzed by an enzyme immunocapture activity assay, and the concentrations of chondroitin sulfate were analyzed by enzyme linked immunosorbent assay. No complications were observed after surgery, except for a minimal subepithelial haze. Although MMP-9 activity changed on the fourth postoperative day, the activity changed only minimally at this time. Chondroitin 4 sulfate concentrations in tear fluid increased dramatically from one week to one month, decreased transiently at three months, and increased by six months. The chondroitin 6 sulfate concentration did not normalize within one week, and decreased from one week to three months compared with the preoperative score, and was close to the preoperative score at six months. We conclude that corneal wound healing was still incomplete six months after PRK, and chondroitin 4 sulfate appears to be critical in this process. PMID- 20922038 TI - A case of acute retinal pigment epithelitis: spectral domain optical coherence tomography time course and physiopathologic hypothesis. AB - PURPOSE: To report the time course of retinal morphologic changes in a patient with acute retinal pigment epithelitis (ARPE) using spectral domain optical coherence tomography (SD-OCT). METHODS: A 30-year old man was referred for blurred vision of his right eye after five days that appeared suddenly 15 days after recovery from a flu-like syndrome. SD-OCT was performed immediately, followed by fluorescein and infracyanine angiography at eight days and then at three weeks. RESULTS: At presentation, a bubble of sub-macular deposit was observed on the right macula with central golden micronodules in a honeycomb pattern. SD-OCT showed an "anterior dislocation" of all the retinal layers up to the inner/outer segment (IS/OS) line and irregular deposits at the OS level together with thickening of the retinal pigment epithelial (RPE) layer. As visual acuity increased, eight days later, the OCT showed reduction of the sub-retinal deposits and an abnormal hyperflectivity of the sub-retinal and RPE layers was observed. The patient showed a positive serology for picornavirus. DISCUSSION: The acute SD-OCT sections of this patient with ARPE were compared with histological sections of a 35 day old Royal College of Surgeons rat. Similar findings could be observed, with preservation of the IS/OS line and accumulation of debris at the OS level, suggesting that ARPE symptoms could result from a transient phagocytic dysfunction of the RPE at the fovea, inducing reversible accumulation of undigested OS. Picornaviruses comprising enterovirus and coxsachievirus described as being associated with acute chorioretinitis. In this case, it was responsible for ARPE. CONCLUSION: We hypothesize that ARPE syndrome results from a transient dysfunction of RPE, which can occur as a post viral reaction. PMID- 20922037 TI - Optic disc measurements using the Heidelberg Retina Tomograph in amblyopia. AB - PURPOSE: To investigate the characteristics of optic disc parameters in amblyopic eyes in which retinal involvement is uncertain. METHODS: A total of 44 patients with a history of unilateral amblyopia (27 patients with persistent amblyopia and 17 patients with resolved amblyopia) were examined using the Heidelberg Retina Tomograph (HRT) II. Parameters examined included disc area, cup area, cup volume, rim area, rim volume, cup-to-disc area ratio, and mean retinal nerve fiber layer thickness. RESULTS: In patients with persistent amblyopia, the amblyopic eyes were significantly more hyperopic than the fellow eyes. In the HRT parameters, there were no significant differences between the amblyopic and fellow eyes. In addition, after adjusting for refraction, the presence of strabismus, and the disc area, there was no significant difference in any HRT parameter between the amblyopic eyes of patients with persistent amblyopia and the previously amblyopic eyes of patients with resolved amblyopia. CONCLUSIONS: We did not find any strong evidence for the deformity of the optic disc of amblyopic eyes. PMID- 20922039 TI - Efficacy of two-month treatment with Xiloial eyedrops for discomfort from disposable soft contact lenses. AB - PURPOSE: To evaluate the efficacy and tolerability of Xiloial((r)) monodose eyedrops in the treatment of patients suffering from subjective symptoms of discomfort related to disposable soft contact lens (dSCL) wear. METHODS: Fifteen (12 female, three male, medium age 39 +/- 9 years) dSCL wearers were enrolled. Inclusion criteria were Ocular Surface Disease Index (ODSI) symptom questionnaire score >12, tear film break-up time (TFBUT) <10 sec, Schirmer test I >10 mm over five minutes, mild punctuate keratopathy, and conjunctival staining (Oxford grading <=4). Monodose Xiloial eyedrops were administered three times daily for a two-month period. Patients were evaluated at enrollment, after three days of washout (baseline), and after one and two months of treatment, by OSDI score, Schirmer test I, TFBUT, ferning test, ocular surface damage (Oxford grade), and serum albumin in tears (index of passive exudation related to serum leakage). RESULTS: At endpoint versus baseline, respectively, the mean +/- standard deviation of all variables improved as follows: OSDI (8.5 +/- 3 versus 20.2 +/- 1.6); TFBUT (9.6 +/- 1.1 versus 7.1 +/- 1.0); Oxford grading (0.5 +/- 0.1 versus 3.6 +/- 0.8); ferning test (2 +/- 1 versus 2.4 +/- 0.5); and Schirmer test I (14.6 +/- 1.1 versus 12 +/- 2.1), with P < 0.05 for all variables (Friedman and Wilcoxon tests). Tolerability was high, with no adverse events noted. CONCLUSIONS: A two-month treatment with Xiloial showed good tolerance and appeared to reduce ocular surface damage and symptoms of discomfort. PMID- 20922040 TI - Vitreous levels of vascular endothelial growth factor in eyes with anterior hyaloidal fibrovascular proliferation. AB - PURPOSE: To determine the intravitreal levels of vascular endothelial growth factor (VEGF) in eyes with anterior hyaloidal fibrovascular proliferation (AHFVP). METHODS: Three eyes of three patients who underwent vitrectomy for proliferative diabetic retinopathy (PDR) and subsequently developed an AHFVP (AHFVP group) were studied. We measured the level of VEGF in vitreous samples collected at the primary and following operations by enzyme-linked immunosorbent assay. The vitreous levels of VEGF in 25 eyes of 22 patients with PDR were also studied as controls (PDR group). RESULTS: The averaged VEGF level in the samples collected at the primary surgery was 1.98 +/- 2.23 ng/mL in the PDR group, and it was 9.07, 1.94, and 8.07 ng/mL in the AHFVP cases. After the primary surgery, the VEGF level rose up to 49.50, 15.60, and 50.60 ng/mL at the subsequent surgeries for respective cases of the AHFVP group. These levels of VEGF were more than five times higher than the baseline at the primary surgery. CONCLUSION: The subsequent increase of the VEGF level after the primary surgery in eyes with an AHFVP suggests that the vitreous levels of VEGF are associated with the development of the AHFVP although only three eyes were studied. PMID- 20922041 TI - Correlation between penile cavernosal artery blood flow and retinal vascular findings in arteriogenic erectile dysfunction. AB - OBJECTIVES: Arteriogenic erectile dysfunction (ED) is a target organ disease of atherosclerosis, and therefore might be a predictor of systemic atherosclerosis. Being systemic, it might be possible to evaluate the extent of atherosclerosis from retinal vascular findings. We investigated the possible correlation between penile cavernosal artery blood flow and retinal vascular findings in patients with arteriogenic ED. PATIENTS AND METHODS: Sixty patients with ED were divided according to the peak systolic velocity (PSV) in their penile cavernosal arteries into two groups; Group A included 30 patients with PSV less than 25 cm/sec, and Group B included 30 patients with PSV more than 35 cm/sec. Blood flow in the penile cavernosal artery was measured with color Doppler ultrasonography. All patients were assessed by ocular fundus examination under amydriatic conditions to evaluate retinal vascular atherosclerotic changes using Hyman's classification. RESULTS: Evidence of retinal vascular atherosclerotic changes was found in 19 patients (63.3%) in Group A and in 10 patients (33.3%) in Group B. CONCLUSIONS: Our study confirms the possibility of predicting penile arterial vascular status in patients with ED from their retinal vascular findings by using amydriatic simple, practical funduscopy. PMID- 20922042 TI - Swelling studies of camel and bovine corneal stroma. AB - In the present study we investigated the swelling characteristics of fresh camel and bovine cornea in sodium salt solutions. Swelling studies were carried out at 20 minutes, 14 hours, and 46 hours on five fresh camel and 5 five fresh bovine corneas. During the 20-minute hydration of fresh corneal stroma was investigated using sodium chloride (NaCl), sodium bicarbonate (NaHCO(3)), sodium acetate (CH(3)COONa), sodium thiocyanate (NaSCN), and sodium floride (NaF) at 2-minute time intervals. During a 46-hour time period, the hydration study was carried out using NaCl (150, 300 mM) and NaF (150 mM) at random intervals. The 14-hour study was carried out to assess the rehydration of corneal stroma after 6 hours of drying. During the 20-minute swelling studies in the first 2 minutes the rate of hydration in both camel and bovine corneas was high but gradually reduced in the 2-20-minute period. The rates and levels of hydration of camel and bovine cornea were not significantly different from each other in all the strengths of solutions. During the 46-hour swelling studies, the initial rate of hydration (0 2 hours) of camel and bovine stroma, in all solutions was significantly higher (Z = 0.056) compared to hydration during later hours (2-46 hours). Camel stromal hydration (high) in 150 mM NaCl was significantly higher compared to bovine stromal hydration in the same solution during the 10-24, and 24-46-hour time periods. Rehydration in camel stroma was significantly lower than bovine in 150 mM NaF. The 20-minute study showed that there was no selective affinity for particular ions in camel or bovine corneal stroma. Initial swelling in both corneal and bovine stroma is faster and more prominant compared to later swelling. The swelling in camel cornea is more prominant compared to bovine corneal stroma. This could be due to higher negatively charged keratin sulfate proteoglycans in the stroma. Lower rehydration in camel cornea suggests stronger leaching of proteoglycans from stroma in NaF. PMID- 20922043 TI - Retinal nerve fiber layer thickness in recovered and persistent amblyopia. AB - PURPOSE: To investigate, using optical coherence tomography (OCT), whether retinal nerve fiber layer thickness (RNFLT) is affected in amblyopic eyes. METHODS: Using OCT (Stratus OCTTM [Carl Zeiss, Dublin, CA]), the RNFLT was measured in 26 patients with persistent unilateral amblyopia and in 25 patients with recovered unilateral amblyopia. The RNFLT was compared between the affected and fellow eyes in patients with persistent amblyopia and in those with recovered amblyopia, and between the amblyopic eyes of patients with persistent amblyopia and the previously amblyopic eyes of patients with recovered amblyopia. RESULTS: In patients with persistent amblyopia and in those with recovered amblyopia, the affected eyes were significantly more hyperopic than the fellow eyes. The average (+/-standard deviation) RNFLT measured 105.5 +/- 14.0 MUm for the persistently amblyopic eyes; this value did not significantly differ from that of the fellow eyes (105.2 +/- 13.0 MUm) or the previously amblyopic eyes of recovered amblyopia (107.1 +/- 11.7 MUm). Also, logistic regression analysis adjusting for refraction showed no significant difference in the RNFLT between the persistently amblyopic eyes and the previously amblyopic eyes. CONCLUSIONS: Our results indicate that there is no significant change in the RNFLT in amblyopic eyes. PMID- 20922045 TI - Mind and language architecture. AB - A distinction is made between the brain and the mind. The architecture of the mind and language is then described within a neo-dualistic framework. A model for the origin of language based on emergence theory is presented. The complexity of hominid existence due to tool making, the control of fire and the social cooperation that fire required gave rise to a new level of order in mental activity and triggered the simultaneous emergence of language and conceptual thought. The mind is shown to have emerged as a bifurcation of the brain with the emergence of language. The role of language in the evolution of human culture is also described. PMID- 20922044 TI - Cell membrane modification for rapid display of bi-functional peptides: a novel approach to reduce complement activation. AB - Ischemia and reperfusion of organs is an unavoidable consequence of transplantation. Inflammatory events associated with reperfusion injury are in part attributed to excessive complement activation. Systemic administration of complement inhibitors reduces reperfusion injury but leaves patients vulnerable to infection. Here, we report a novel therapeutic strategy that decorates cells with an anti-complement peptide. An analog of the C3 convertase inhibitor Compstatin (C) was synthesized with a hexahistidine (His(6)) tag to create C His(6). To decorate cell membranes with C-His(6), fusogenic lipid vesicles (FLVs) were used to incorporate lipids with nickel (Ni(2+)) tethers into cell membranes, and these could then couple with C-His(6). Ni(2+) tether levels to display C His(6) were modulated by changing FLV formulation, FLV incubation time and FLV levels. SKOV-3 cells decorated with C-His(6) effectively reduced complement deposition in a classical complement activation assay. We conclude that our therapeutic approach appears promising for local ex vivo treatment of transplanted organs to reduce complement-mediated reperfusion injury. PMID- 20922047 TI - Brain, mind and language functional architectures. AB - The interaction between brain and language has been investigated by a vast amount of research and different approaches, which however do not offer a comprehensive and unified theoretical framework to analyze how brain functioning performs the mental processes we use in producing language and in understanding speech. This Special Issue addresses the need to develop such a general theoretical framework, by fostering an interaction among the various scientific disciplines and methodologies, which centres on investigating the functional architecture of brain, mind and language, and is articulated along the following main dimensions of research: (a) Language as a regulatory contour of brain and mental processes; (b) Language as a unique human phenomenon; (c) Language as a governor of human behaviour and brain operations; (d) Language as an organizational factor of ontogenesis of mentation and behaviour. PMID- 20922046 TI - The role of speech production system in audiovisual speech perception. AB - Seeing the articulatory gestures of the speaker significantly enhances speech perception. Findings from recent neuroimaging studies suggest that activation of the speech motor system during lipreading enhance speech perception by tuning, in a top-down fashion, speech-sound processing in the superior aspects of the posterior temporal lobe. Anatomically, the superior-posterior temporal lobe areas receive connections from the auditory, visual, and speech motor cortical areas. Thus, it is possible that neuronal receptive fields are shaped during development to respond to speech-sound features that coincide with visual and motor speech cues, in contrast with the anterior/lateral temporal lobe areas that might process speech sounds predominantly based on acoustic cues. The superior posterior temporal lobe areas have also been consistently associated with auditory spatial processing. Thus, the involvement of these areas in audiovisual speech perception might partly be explained by the spatial processing requirements when associating sounds, seen articulations, and one's own motor movements. Tentatively, it is possible that the anterior "what" and posterior "where / how" auditory cortical processing pathways are parts of an interacting network, the instantaneous state of which determines what one ultimately perceives, as potentially reflected in the dynamics of oscillatory activity. PMID- 20922048 TI - A diffusion tensor imaging study on the auditory system and tinnitus. AB - Tinnitus is an auditory percept in the absence of an external sound source. Mechanisms in the central nervous system are believed to be key in the pathophysiology of tinnitus. Diffusion tensor imaging (DTI) is an MR imaging technique that allows in vivo exploration of white matter tissue in the human brain. Using a probabilistic DTI approach, we determined the characteristics of fiber tracts from the inferior colliculus to the medial geniculate body up to the primary auditory cortex. We also investigated the connections between the auditory system and the amygdala, which may be involved in some forms of tinnitus. White matter tracts were characterized by three quantities: the mean fractional anisotropy, the weighted mean fractional anisotropy and the path strength. All these quantities are measures of the patency of white matter tracts. The most important finding is an increased patency of the white matter tracts between the auditory cortex and the amygdala in tinnitus patients as compared to healthy controls. PMID- 20922049 TI - GPIIb/IIIa Receptor Antagonism Using Small Molecules Provides no Additive Long Term Protection after Percutaneous Coronary Intervention as Compared to Clopidogrel Plus Aspirin. AB - BACKGROUND: There is some controversy as to whether tirofiban or eptifibatide, two small anti-aggregating drugs (AAD), may reduce the incidence of composite ischemic events within one year in patients undergoing percutaneous coronary intervention (PCI) in the real clinical world. METHODS: We compared consecutive patients on oral double AAD (with clopidogrel and aspirin) who underwent PCI (n=207) and patients who were on single AAD and received a second AAD, just prior to PCI, and either high-dose tirofiban or double-bolus eptifibatide (double AAD plus small molecules group, n=666). The primary end point (incidence of composite ischemic events within one year) included death, acute myocardial infarction, unstable angina, stent thrombosis or repeat PCI or coronary bypass surgery (related to the target vessel PCI failure) and was modelled by Cox's regression. RESULTS: There were 89 composite ischemic events: 24 (11.6%) in double AAD alone and 65 (9.8%) in double AAD plus small molecules groups (log-rank test: p=0.36). Incidences by type of ischemic events were similar between the 2 groups. Based on 21 potential covariates fitted simultaneously, adjusted hazard ratios (HR and 95% confidence intervals) showed that age (HR 1.03, 1.01-1.06, p=0.01), diabetes (HR 1.68, 1.01-2.79, p=0.05) and intra aortic balloon pump (HR 5.12, 2.36-11.10, p=0.0001) were significant risk factors whereas thrombolysis by tenecteplase (HR 0.35, 0.13-0.98, p=0.05) and having had hypertension or anti-hypertensive treatment (HR 0.58, 0.36-0.93, p=0.03) were significant protectors for events. Whether small molecules were present provided a non significant additional benefit as compared to double AAD alone (HR 0.83, 0.51-1.36, p=0.46). Pre-PCI CK MB were not useful to predict events (HR 1.01, 0.99-1.01, p=0.17). CONCLUSIONS: In clinical world patients undergoing PCI (rescue plus primary <13%) while on double AAD, based on clopidogrel plus aspirin, small molecules (tirofiban or eptifibatide) provided no additive long-term protection against the occurrence of composite ischemic events whereas thrombolysis by tenecteplase did. PMID- 20922050 TI - Acute myocardial infarction manifested with headache. AB - We report a very rare case of a patient who presented with headache as the sole symptom of an acute myocardial infarction (AMI). The patient underwent primary percutaneous coronary angioplasty followed by drug-eluting stent implantation and the headache was immediately relieved. The pathophysiologic explanation of the occurrence of headache as a sole manifestation of an AMI is discussed. PMID- 20922051 TI - DNA stretching as a probe for nucleic acid interactions: Reply to Comments on "Biophysical characterization of DNA binding from single molecule force measurements" by Kathy R. Chaurasiya, Thayaparan Paramanathan, Micah J. McCauley, Mark C. Williams. PMID- 20922052 TI - Severe anisocoria after oral surgery under general anesthesia. AB - INTRODUCTION: Anisocoria indicates a difference in pupil diameter. Etiologies of this clinical manifestation usually include systemic causes as neurological or vascular disorders, and local causes as congenital iris disorders and pharmacological effects. CASE REPORT: We present a case of a 47-year-old man, suffering from spastic tetraparesis. After the oral surgery under general anesthesia, the patient developed severe anisocoria: in particular, a ~4 mm diameter increase of the left pupil compared to the right pupil. We performed Computed Tomography (CT) in the emergency setting, Nuclear magnetic resonance (NMR) of the brain and Magnetic Resonance Angiography of intracranial vessels. These instrumental examinations did not show vascular or neurological diseases. The pupils returned to their physiological condition (isocoria) after about 180 minutes. DISCUSSION AND CONCLUSIONS: Literature shows that the cases of anisocoria reported during or after oral surgery are rare occurrences, especially in cases of simple tooth extraction. Anisocoria can manifest in more or less evident forms: therefore, it is clear that knowing this clinical condition is of crucial importance for a correct and timely resolution. PMID- 20922053 TI - Influenza vaccination: healthcare workers attitude in three Middle East countries. AB - BACKGROUND: Healthcare workers (HCWs) pose a potential risk of transmitting communicable diseases in the hospital settings where they usually work. This study aims to determine the current influenza vaccination rates among HCWs in three Middle East countries namely United Arab Emirates (UAE), Kuwait and Oman, and also to identify the different variables associated with the noncompliance of HCWs to the recommendations of the Advisory Committee on Immunization Practices (ACIP) set in those countries. METHODS: 1500 questionnaires were distributed to health care workers in the three countries during the period of July-October 2009. RESULTS: Among 993 respondents, the vaccination rate was 24.7%, 67.2% and 46.4% in UAE, Kuwait and Oman, respectively. The different motivating factors that influenced the health care workers to take the vaccine was assessed and found that the most common factor that influenced their decision to take the vaccine was for their self protection (59%). On the other hand, the most common reason that discouraged HCWs to take the vaccine was "lack of time" as reported by 31.8% of the respondents. Other reasons for not taking the vaccine were unawareness of vaccine availability (29.4%), unavailability of vaccine (25.4%), doubts about vaccine efficacy (24.9%), lack of information about importance (20.1%) and concerns about its side effects (17.3%). CONCLUSIONS: influenza immunization by healthcare workers in the studied countries was suboptimal which could be improved by setting different interventions and educational programs to increase vaccination acceptance among HCWs. PMID- 20922054 TI - Inhibition of Hypoxia-Induced Cell Motility by p16 in MDA-MB-231 Breast Cancer Cells. AB - Our previous studies indicated that p16 suppresses breast cancer angiogenesis and metastasis, and downregulates VEGF gene expression by neutralizing the transactivation of the VEGF transcriptional factor HIF-1alpha. Hypoxia stimulates tumor malignant progression and induces HIF-1alpha. Because p16 neutralizes effect of HIF-1alpha and attenuates tumor metastatic progression, we intended to investigate whether p16 directly affects one or more aspects of the malignant process such as adhesion and migration of breast cancer cells. To approach this aim, MDA-MB-231 and other breast cancer cells stably transfected with Tet-on inducible p16 were used to study the p16 effect on growth, adhesion and migration of the cancer cells. We found that p16 inhibits breast cancer cell proliferation and migration, but has no apparent effect on cell adhesion. Importantly, p16 inhibits hypoxia-induced cell migration in breast cancer in parallel with its inhibition of HIF-1alpha transactivation activity. This study suggests that p16's ability to suppress tumor metastasis may be partially resulted from p16's inhibition on cell migration, in addition to its known functions on inhibition of cell proliferation, angiogenesis and induction of apoptosis. PMID- 20922055 TI - Functional mechanisms for human tumor suppressors. AB - Tumor suppressors refer to a large group of molecules that are capable of controlling cell division, promoting apoptosis, and suppressing metastasis. The loss of function for a tumor suppressor may lead to cancer due to uncontrolled cell division. Because of their importance, extensive studies have been undertaken to understand the different functional mechanisms of tumor suppressors. Here, we briefly review the four major mechanisms, inhibition of cell division, induction of apoptosis, DNA damage repair, and inhibition of metastasis. It is noteworthy that some tumor suppressors, such as p53, may adopt more than one mechanism for their functions. PMID- 20922056 TI - Mesothelin as a potential therapeutic target in human cholangiocarcinoma. AB - BACKGROUND: Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) are the two most common primary liver cancers, yet there have been no significant advances in effective therapeutics. Mesothelin has been reported as a new therapeutic target in various types of cancer. Here, we investigated the expression of mesothelin in liver cancer and its potential role as a novel therapeutic target for immunotherapy. METHODS: HCC and CCA specimens were examined by immunohistochemistry for mesothelin expression. Protein expression was assessed by immunoblotting and flow cytometry. The SS1P immunotoxin targeting mesothelin was evaluated in the well-established CCA cell lines HuCCT1, HuH-28, KMBC, KMCH, Mz-ChA-1 and OZ. RESULTS: We showed strong immunochemical mesothelin staining in 33% of the surgically resected CCA specimens and 3 of 6 CCA cell lines (OZ, KMBC and KMCH). No mesothelin staining was found in HCC or normal liver tissue. Mesothelin was primarily localized to the cellular plasma membrane and the mature form (molecular weight, ~40 kDa) was expressed at a high level in CCA tissues. Moreover, 22% of CCA specimens had a high mesothelin expression level which was comparable to the CCA cell line models. Interestingly, SS1P showed very high and specific growth inhibition when added to mesothelin expressing CCA cells with IC(50) values ranging from 0.5 to 11 ng/mL. CONCLUSIONS: Mesothelin is overexpressed in one-third of CCA tissues. SS1P targeting mesothelin reveals a remarkable single agent activity against CCA in vitro. These findings indicate a potential for SS1P in the immunotherapeutic treatment of CCA. PMID- 20922058 TI - Is Analogical Reasoning just Another Measure of Executive Functioning? PMID- 20922057 TI - Astroglial Wiring is Adding Complexity to Neuroglial Networking. AB - Astrocytes are organized as networks of communicating cells due to their high expression level of connexins, the molecular constituents of gap junction channels. Based on their permeability properties for ions and small signaling molecules such astroglial wiring interferes with neuronal activity and survival. In this paper, I identify and discuss which future technical and conceptual progress or advances should be achieved in order to better understand how neuroglial networking contributes to brain functions and dysfunctions. PMID- 20922060 TI - Ambiguity aversion in rhesus macaques. AB - People generally prefer risky options, which have fully specified outcome probabilities, to ambiguous options, which have unspecified probabilities. This preference, formalized in economics, is strong enough that people will reliably prefer a risky option to an ambiguous option with a greater expected value. Explanations for ambiguity aversion often invoke uniquely human faculties like language, self-justification, or a desire to avoid public embarrassment. Challenging these ideas, here we demonstrate that a preference for unambiguous options is shared with rhesus macaques. We trained four monkeys to choose between pairs of options that both offered explicitly cued probabilities of large and small juice outcomes. We then introduced occasional trials where one of the options was obscured and examined their resulting preferences; we ran humans in a parallel experiment on a nearly identical task. We found that monkeys reliably preferred risky options to ambiguous ones, even when this bias was costly, closely matching the behavior of humans in the analogous task. Notably, ambiguity aversion varied parametrically with the extent of ambiguity. As expected, ambiguity aversion gradually declined as monkeys learned the underlying probability distribution of rewards. These data indicate that ambiguity aversion reflects fundamental cognitive biases shared with other animals rather than uniquely human factors guiding decisions. PMID- 20922059 TI - Ten challenges for decision neuroscience. AB - Decision neuroscience research, as currently practiced, employs the methods of neuroscience to investigate concepts drawn from the social sciences. A typical study selects one or more variables from psychological or economic models, manipulates or measures choices within a simplified choice task, and then identifies neural correlates. Using this "neuroeconomic" approach, researchers have described brain systems whose functioning shapes key economic variables, most notably aspects of subjective value. Yet, the standard approach has fundamental limitations. Important aspects of the mechanisms of decision making - from the sources of variability in decision making to the very computations supported by decision-related regions - remain incompletely understood. Here, I outline 10 outstanding challenges for future research in decision neuroscience. While some will be readily addressed using current methods, others will require new conceptual frameworks. Accordingly, a new strain of decision neuroscience will marry methods from economics and cognitive science to concepts from neurobiology and cognitive neuroscience. PMID- 20922061 TI - Year-round variability of ambient noise in temperate freshwater habitats and its implications for fishes. AB - Changes in habitat acoustics over the year can potentially affect fish hearing and orientation to sound, especially in temperate climates. This is the first study where year-round changes in ambient noise in aquatic habitats were assessed. Seven different European fresh-water habitats were chosen for this study. Sound pressure level (SPL) and spectral composition of the ambient noise varied in both quiet stagnant habitats (lakes, backwaters) and in flowing habitats (streams, rivers). Linear equivalent SPL (L(Leq, 60s)) tended to be lower in stagnant habitats (means: 91.6-111.7 dB) than in flowing habitats (means: 111.2-133.4 dB). The changes in SPL were smallest in the river (means: 4.2-4.4 dB, maxima: 8.5-10.1 dB), whereas significantly higher values were measured in stagnant habitats and the stream (means: 9.9-14.9 dB, maxima: 25.1 30.9 dB). The spectral compositions of the ambient noise determined at different times of the year were highly correlated to each other at the river sites (mean cross-correlation coefficients: 0.85 and 0.94) and were weaker or not correlated at the other study sites (means: 0.24-0.76). The changes in ambient noise spectra were negatively correlated to changes in SPL, indicating that large changes in SPLs were accompanied by large changes in spectral composition and vice versa. Comparison of these ecoacoustical data with a preceding study (Amoser and Ladich in J Exp Biol 208:3533-3542, 2005) indicates that the auditory sensitivity in hearing specialists is affected by changes in ambient noise levels and spectra throughout a year and that this effect tends to be more pronounced in stagnant waters and the stream than at river sites. On the other hand, absolute noise levels result in a higher degree of masking in flowing waters. PMID- 20922062 TI - Drug Discovery in Academia- the third way? AB - As the pharmaceutical industry continues to re-strategise and focus on low-risk, relatively short term gains for the sake of survival, we need to re-invigorate the early stages of drug discovery and rebalance efforts towards novel modes of action therapeutics and neglected genetic and tropical diseases. Academic drug discovery is one model which offers the promise of new approaches and an alternative organisational culture for drug discovery as it attempts to apply academic innovation and thought processes to the challenge of discovering drugs to address real unmet need. PMID- 20922063 TI - Collaborative working within UK NHS secondary care and across sectors for COPD and the impact of peer review: qualitative findings from the UK National COPD Resources and Outcomes Project. AB - INTRODUCTION: WE INVESTIGATED THE EFFECTS ON COLLABORATIVE WORK WITHIN THE UK NATIONAL HEALTH SERVICE (NHS) OF AN INTERVENTION FOR SERVICE QUALITY IMPROVEMENT: informal, structured, reciprocated, multidisciplinary peer review with feedback and action plans. The setting was care for chronic obstructive pulmonary disease (COPD). THEORY AND METHODS: We analysed semi-structured interviews with 43 hospital respiratory consultants, nurses and general managers at 24 intervention and 11 control sites, as part of a UK randomised controlled study, the National COPD Resources and Outcomes Project (NCROP), using Scott's conceptual framework for action (inter-organisational, intra-organisational, inter-professional and inter-individual). Three areas of care targeted by NCROP involved collaboration across primary and secondary care. RESULTS: Hospital respiratory department collaborations with commissioners and hospital managers varied. Analysis suggested that this is related to team responses to barriers. Clinicians in unsuccessful collaborations told 'atrocity stories' of organisational, structural and professional barriers to service improvement. The others removed barriers by working with government and commissioner agendas to ensure continued involvement in patients' care. Multidisciplinary peer review facilitated collaboration between participants, enabling them to meet, reconcile differences and exchange ideas across boundaries. CONCLUSIONS: The data come from the first randomised controlled trial of organisational peer review, adding to research into UK health service collaborative work, which has had a more restricted focus on inter professional relations. NCROP peer review may only modestly improve collaboration but these data suggest it might be more effective than top-down exhortations to change when collaboration both across and within organisations is required. PMID- 20922064 TI - Open Dialogues in social networks: professional identity and transdisciplinary collaboration. AB - AIM: The aim of this article is to explore the challenges connected to the transformation and emergence of professional identity in transdisciplinary multi agency network meetings and the use of Open Dialogue. INTRODUCTION: The empirical findings have been taken from a clinical project in southern Norway concerning multi-agency network meetings with persons between 14 and 25 years of age. The project explores how these meetings are perceived by professionals working in various sectors. METHODOLOGY: Data was collected through three interviews conducted with two focus groups, the first comprising health care professionals and the second professionals from the social and educational sectors. Content analysis was used to create categories through condensation and interpretation. The two main categories that emerged were 'professional role' and 'teamwork'. These were analysed and compared according to the two first meeting in the two focus groups. RESULTS AND DISCUSSION: The results indicate different levels of motivation and understanding regarding role transformation processes. The realization of transdisciplinary collaboration is dependent upon the professionals' mutual reliance. The professionals' participation is affected by stereotypes and differences in their sense of belonging to a certain network, and thus their identity transformation seems to be strongly affected. To encourage the use of integrated solutions in mental health care, the professionals' preference for teamwork, the importance of familiarity with each other and knowledge of cultural barriers should be addressed. PMID- 20922065 TI - Coordination in networks for improved mental health service. AB - INTRODUCTION: Well-organised clinical cooperation between health and social services has been difficult to achieve in Sweden as in other countries. This paper presents an empirical study of a mental health coordination network in one area in Stockholm. The aim was to describe the development and nature of coordination within a mental health and social care consortium and to assess the impact on care processes and client outcomes. METHOD: Data was gathered through interviews with 'joint coordinators' (n=6) from three rehabilitation units. The interviews focused on coordination activities aimed at supporting the clients' needs and investigated how the joint coordinators acted according to the consortium's holistic approach. Data on The Camberwell Assessment of Need (CAN-S) showing clients' satisfaction was used to assess on set of outcomes (n=1262). RESULTS: The findings revealed different coordination activities and factors both helping and hindering the network coordination activities. One helpful factor was the history of local and personal informal cooperation and shared responsibilities evident. Unclear roles and routines hindered cooperation. CONCLUSIONS: This contribution is an empirical example and a model for organisations establishing structures for network coordination. One lesson for current policy about integrated health care is to adapt and implement joint coordinators where full structural integration is not possible. Another lesson, based on the idea of patient quality by coordinated care, is specifically to adapt the work of the local addiction treatment and preventive team (ATPT)-an independent special team in the psychiatric outpatient care that provides consultation and support to the units and serves psychotic clients with addictive problems. PMID- 20922066 TI - Integrative treatment approaches: family satisfaction with a multidisciplinary paediatric Abdominal Pain Clinic. AB - OBJECTIVES: To assess patient and family satisfaction with evaluation received through a multidisciplinary paediatric Abdominal Pain Clinic (APC) staffed by a paediatric gastroenterologist and a paediatric psychologist as compared to a traditional gastroenterology clinic (GI) staffed by a paediatric gastroenterologist only. METHODS: Two hundred and ninety-eight families (145 APC, 153 GI) with a child or adolescent aged 8-17 years seen for initial evaluation of a chronic abdominal pain completed an anonymous survey to assess understanding of the treatment recommendations made, intent to follow through with various treatment recommendations, and the overall level of satisfaction with the evaluation service provided. Family perceptions of strengths and challenges of the APC evaluation process also were explored. RESULTS: APC families reported being prescribed adjunctive mental health and other therapies at significantly higher rates than GI families, while the rates of medication were comparable. APC families also reported significantly greater receptivity to beginning the treatments prescribed and higher levels of overall satisfaction with the evaluation process. The contribution of integrated medical and psychological perspectives frequently was identified as a strength of the APC evaluation process. Challenges identified for the APC evaluation were few and focused on issues related to paperwork and scheduling issues. CONCLUSIONS: Integrative care approaches to the evaluation of paediatric abdominal pain appear well accepted by families, yielding high levels of satisfaction, and enhance receptivity to treatment recommendations. Integrative care starting at the time of first evaluation may be particularly well-tailored to enhance outcomes, reduce health care utilization, and yield financial savings within this population. PMID- 20922067 TI - Looking back whilst moving forward: observations on the science and application of integrated care over the past 10 years and predictions for what the next 10 years may hold. PMID- 20922068 TI - Evaluation of UK Integrated Care Pilots: research protocol. AB - BACKGROUND: In response to concerns that the needs of the aging population for well-integrated care were increasing, the English National Health Service (NHS) appointed 16 Integrated Care Pilots following a national competition. The pilots have a range of aims including development of new organisational structures to support integration, changes in staff roles, reducing unscheduled emergency hospital admissions, reduced length of hospital stay, increasing patient satisfaction, and reducing cost. This paper describes the evaluation of the initiative which has been commissioned. STUDY DESIGN AND DATA COLLECTION METHODS: A mixed methods approach has been adopted including interviews with staff and patients, non-participant observation of meetings, structured written feedback from sites, questionnaires to patients and staff, and analysis of routinely collected hospital utilisation data for patients/service users. The qualitative analysis aims to identify the approaches taken to integration by the sites, the benefits which result, the context in which benefits have resulted, and the mechanisms by which they occur. METHODS OF ANALYSIS: The quantitative analysis adopts a 'difference in differences' approach comparing health care utilisation before and after the intervention with risk-matched controls. The qualitative data analysis adopts a 'theory of change' approach in which we triangulate data from the quantitative analysis with qualitative data in order to describe causal effects (what happens when an independent variable changes) and causal mechanisms (what connects causes to their effects). An economic analysis will identify what incremental resources are required to make integration succeed and how they can be combined efficiently to produce better outcomes for patients. CONCLUSION: This evaluation will produce a portfolio of evidence aimed at strengthening the evidence base for integrated care, and in particular identifying the context in which interventions are likely to be effective. These data will support a series of evaluation judgements aimed at reducing uncertainties about the role of integrated care in improving the efficient and effective delivery of healthcare. PMID- 20922069 TI - JISP is in PubMed. PMID- 20922070 TI - Rapidly progressing periodontology. PMID- 20922071 TI - Omega fatty acids and resolution of inflammation: A new twist in an old tale. AB - Identification of the factors that regulate immune tolerance and control the appearance of exacerbated inflammatory conditions is crucial for the development of new therapies of inflammatory and autoimmune diseases. Resolution of inflammation and the return of tissues to homeostasis protect us against excessive tissue injury and promote the restoration of function and structure. Resolution of inflammation, which was considered a passive event, is actually an active process where new families of endogenous lipid mediators from omega-3 polyunsaturated fatty acids play an important role in removing proinflammatory mediators generated from arachidonic acid. These chemical mediator families, termed Resolvins and Protectins, are potent stereoselective agonists that control the duration and magnitude of inflammation, along with the Lipoxins as signals in resolution. This review examines the mapping of these circuits and recent advances in our understanding of the biosynthesis and actions of these novel proresolving lipid mediators. A search in the electronical databases PubMed and the Cochrane Central Register of Controlled Trials was carried out. The search strategy applied was: "Omega fatty acid" AND "resolution of inflammation," including articles from January 1,1985 to October 2009. This resulted in the identification of a total of 52 articles, which were analyzed in full text leading to consideration of only nine full texts. PMID- 20922072 TI - Phagocytic activity of peripheral blood and crevicular phagocytes in health and periodontal disease. AB - BACKGROUND: Neutrophils constitute the main phagocytic cell system in mammalian host defense against an infecting agent. Abnormalities in leukocyte number and function are associated with increased susceptibility to periodontal diseases. The purpose of this study is to evaluate the in vitro phagocytic properties of crevicular and peripheral blood neutrophils in healthy and periodontitis subjects. PATIENTS AND METHODS: A total of 30 subjects, that is, 10 patients in each of the following three groups: healthy controls, chronic periodontitis (CP), and localized aggressive periodontitis (LAP), were included in the study. The neutrophils were isolated from the peripheral blood and gingival crevice and tested for phagocytosis of Candida albicans. The percentage of leukocytes with ingested C. albicans was determined by light microscopy. RESULTS: A significant reduction in the phagocytic activity of crevicular fluid polymorphonuclear neutrophils (CF-PMN) of LAP subjects (mean: 54.3+/-7)(P<0.001) was observed, compared to healthy controls (mean: 74.2+/-9) and chronic periodontitis subjects (mean: 69+/-9)(P=0.352). The mean percentage of peripheral blood polymorphonuclear neutrophils (PMNs) with phagocytosis of opsonized C. albicans in LAP patients was significantly reduced (mean: 74.9+/-5)(P<0.0068) compared to the phagocytic activity of neutrophils from controls (mean:82.1+/-3) and chronic periodontitis subjects (mean: 82.0+/-5)(P=0.970). There was no significant reduction in the phagocytic activity of CF PMNs (mean: 69+/-9) (P=0.35) and peripheral blood PMNs (mean: 82.5)(P=0.97) in the chronic periodontitis group when compared to the control group. CONCLUSION: The phagocytic activity of both crevicular and peripheral neutrophils in subjects with periodontitis is altered, increasing the susceptibility to periodontitis. Thus individual susceptibility may be an additional and important modifying factor in the pathogenesis of periodontal disease. PMID- 20922073 TI - Osteoplant acts on stem cells derived from peripheral blood. AB - OBJECTIVES: The osteoplant is an equine, flexible, heterologous, deantigenic, cortical, and spongy bone tissue, totally reabsorbable, used for implantation of bone tissue, to restore skeletal, even weight-bearing structures. However, how the osteoplant alters osteoblast activity to promote bone formation is poorly understood. MATERIALS AND METHODS: To study how the osteoplant induces osteoblast differentiation in mesenchymal stem cells, the expression levels of bone-related genes, and mesenchymal stem cell markers are analyzed, using real time Reverse Transcription-Polymerase Chain Reaction (RT-PCR). RESULTS: The osteoplant causes induction of osteoblast transcriptional factors such as osterix (RUNX2), and of bone-related genes such as osteopontin (SPP1) and osteocalcin (BGLAP). In contrast the expression of ENG (CD105) is significantly decreased in stem cells treated with osteoplant, with respect to untreated cells, indicating the differentiation effect of this biomaterial on stem cells. CONCLUSION: The obtained results can be relevant to better understand the molecular mechanism of bone regeneration and as a model for comparing other materials with similar clinical effects. PMID- 20922074 TI - Postoperative bacteremia in periodontal flap surgery, with and without prophylactic antibiotic administration: A comparative study. AB - OBJECTIVES: Many a times in clinical periodontology, the decision whether to prescribe prophylactic antibiotics or not, is perplexing.The present study was conducted to compare the bacteremias induced after periodontal flap surgeries with and without prophylactic antibiotics. MATERIALS AND METHODS: The occurrence of postoperative bacteremia following periodontal flap surgery was studied in 30 patients. On these patients, 30 quadrant wise flap surgeries were carried out without any preoperative prophylactic antibiotics and 30 surgeries carried out after prophylactic administration of amoxycillin preoperatively. A blood sample was taken from each patient at the time of maximum surgical trauma and was cultured for micro-organisms and antibiotic sensitivity. RESULTS: 18 out of 60 blood samples were positive for micro-organisms. There was a significant reduction in post operative bacteremia after amoxycillin prophylaxis (x(2) - 7.96 with P<0.01) as post operative bacteremia was found in 14 of the non medicated patients as compared to only 4 of the pre medicated patients. The micro-organisms encountered in the study are as follows:- 1) Staphylococcus albus coagulase negative, 2) Klebsiella, 3) Psedomonas aerugenosa, 4) Streptococcus viridans, 5) Alpha hemolytic streptococcus, 6) Neisseria catarrhalis CONCLUSION: On the basis of the study, it is concluded that the incidence of postoperative bacteremia following periodontal flap surgery is not as high as previously reported. The clinical results show that Amoxicillin is highly effective in reducing postoperative bacteremia in periodontal flap surgery and thus in preventing the possible sequelae (Infective Endocarditis and other systemic maladies) in susceptible patients. However, cefotaxime and cephalexin may prove to be more effective in preventing the same. PMID- 20922075 TI - Clinical evaluation of regenerative potential of type I collagen membrane along with xenogenic bone graft in the treatment of periodontal intrabony defects assessed with surgical re-entry and radiographic linear and densitometric analysis. AB - BACKGROUND AND OBJECTIVES: The primary goal of periodontal therapy is to restore the tooth supporting tissues lost due to periodontal disease. The aim of the present study was to compare the efficacy of combination of type I collagen (GTR membrane) and xenogenic bone graft with open flap debridement (OFD) in treatment of periodontal intrabony defects. MATERIALS AND METHODS: Twenty paired intrabony defects were surgically treated using split mouth design. The defects were randomly assigned to treatment with OFD + collagen membrane + bone graft (Test) or OFD alone (Control). The clinical efficacy of two treatment modalities was evaluated at 9 month postoperatively by clinical, radiographical, and intrasurgical (re-entry) parameters. The measurements included probing pocket depth (PD), clinical attachment level (CAL), gingival recession (GR), bone fill (BF), bone density (BD) and intra bony component (INTRA). RESULTS: The mean reduction in PD at 0-9 month was 3.3+/-0.82 mm and CAL gain of 3.40+/-1.51 mm occurred in the collagen membrane + bone graft (Test) group; corresponding values for OFD (Control) were 2.20+/-0.63 mm and 1.90+/-0.57 mm. Similar pattern of improvement was observed when radiographical and intra-surgical (re-entry) post operative evaluation was made. All improvement in different parameters was statistically significant (P< 0.01). INTERPRETATION AND CONCLUSION: Treatment with a combination of collagen membrane and bone graft led to a significantly more favorable clinical outcome in intrabony defects as compared to OFD alone. PMID- 20922076 TI - Periodontitis and bone mineral density among pre and post menopausal women: A comparative study. AB - AIM: The aim of the study was to assess the relationship between bone mineral density and periodontitis in premenopausal and postmenopausal women. MATERIALS AND METHODS: Twenty women between the age group of 45-55 years were selected for this study. Ten premenopausal women with healthy periodontium constituted the control group and 10 postmenopausal women with >=2mm of clinical attachment loss in >30% of sites constituted the study group. All patients were assessed for plaque index, probing depth and clinical attachment loss. Radiographs (six IOPA and two posterior bitewing) were taken and assessed for interproximal alveolar bone loss. The patients were scanned to assess the bone mineral density of lumbar spine (L2) and femur using dual energy X-ray absorptiometry (DEXA). RESULTS: The bone mineral densities of lumbar spine (L2) and femur were significantly lower in the study group than the control group. Osteopenia of the lumbar spine and femur was observed in 60% whereas osteoporosis of lumbar spine was observed in 30% of cases in study group. CONCLUSION: Increased proportion of osteopenia and osteoporosis cases of lumbar spine and femur in postmenopausal women with periodontitis suggests that there is association between bone mineral density and periodontitis. PMID- 20922077 TI - Effect of retraction materials on gingival health: A histopathological study. AB - BACKGROUND: Gingival retraction methods are used in dentistry for impressions of subgingival crown margins, such as, mechanical, chemical, chemicomechanical, and surgical. These methods may injure the gingival sulcular epithelium. Hence, the present study is carried out to evaluate the effect of different retraction materials, such as, Expasyl, Magic Foam Cord, and impregnated retraction cord on the gingival sulcular epithelium. MATERIALS AND METHODS: This study included 30 cases of bilateral premolar extraction patients with Loe and Silness gingival index zero. Retraction materials were kept in the dry, isolated labial gingival sulcus for the required time. The retraction materials were removed by rinsing with water. Retracted gingiva of 2 - 3 mm from the gingival margin along with the tooth was extracted and the decalcified sections were microscopically studied. DATA ANALYSIS: Data were analyzed by applying the chi-square test. RESULTS: This study showed better results with retraction paste as compared to the retraction cord, and there was a significant association between retraction materials and the relative degree of injury to the sulcular epithelium. CONCLUSION: There is a significant association between retraction materials and gingival sulcular epithelium. It can be stated that impregnated retraction cord, may be used commonly but it needs proper tissue manipulation and is technique sensitive. Newly advanced material in the form of retraction paste like Expasyl or Magic Foam Cord was found to be better than cord as assessed histologically, it respects periodontium. PMID- 20922078 TI - Evaluation of an aminobisphosphonate (alendronate) in the management of periodontal osseous defects. AB - BACKGROUND AND OBJECTIVES: Alendronate, an aminobisphosphonate, is capable of inhibiting periodontitis associated osteoclastic activity and hence is effective in protecting the alveolar bone in periodontitis. In the present study, we explored the efficacy of local delivery of alendronate on the alveolar bone following mucoperiosteal flap surgery. This is the first study to use polymer impregnated gel based delivery of alendronate. MATERIALS AND METHODS: A total of 15 patients with chronic periodontitis in the age group of 35 - 55 years, of both sexes, with pocket depth of >= 5mm and radiographic evidence of identical osseous defects in the mandibular molar region bilaterally were included in this prospective study. A gel based drug delivery system of Alendronate was formulated. Following surgical flap debridement, 0.1 ml alendronate gel and 0.1 ml placebo gel was placed at the experimental and control sites respectively. Clinical and radiographic parameters were recorded at baseline, three months and six months post surgery. RESULTS: Alendronate was more effective in improving clinical and radiographic parameters compared to placebo. INTERPRETATION AND CONCLUSION: Alendronate is effective in the management of periodontitis associated bone loss. Gel based local delivery of the drug addresses the critical concern of exposing the patient to adverse effects of systemic administration. PMID- 20922079 TI - Comparative evaluation of micronutrient status in the serum of diabetes mellitus patients and healthy individuals with periodontitis. AB - BACKGROUND: Periodontal diseases are microbial induced chronic inflammatory conditions characterized by infiltration of leukocytes, loss of connective tissue, alveolar bone resorption, and formation of periodontal pockets. In response to periodontal pathogens, the leukocytes (PMN) elaborate destructive oxidants, proteinases and other factors. The balance between these factors, the antioxidants and endogenously synthesized antiproteinases determine the extent of periodontal damage. Diabetes mellitus is a metabolic disorder. Most of the complications of diabetes are due to hyperglycemia. Persons with diabetes are at a greater risk for periodontal disease Malnutrition is characterized by marked tissue depletion of antioxidant nutrients and impaired acute phase protein response to infections resulting in impaired healing. Diabetes mellitus also alters the micronutrient levels. Malnutrition is characterized by marked tissue depletion of antioxidant nutrients and impaired acute phase protein response to infections resulting in impaired healing. Malnutrition, which usually involves concomitant deficiencies of several essential macro and micro nutrients, therefore, has the potential to adversely influence the prognosis of periodontal infections. OBJECTIVES: This study has been conducted to evaluate and compare the serum levels of vitamin C, zinc and copper in diabetic and healthy individuals with periodontitis. MATERIALS AND METHODS: In this case control study 60 subjects inclusive of both sexes were selected and divided into 3 groups of 20 each. Group 1 comprised of 20 subjects with type 2 diabetes mellitus and periodontal disease, Group 2 comprised of 20 healthy subjects with periodontal disease. And Group 3 comprised of 20 healthy subjects without periodontal disease. Venous blood samples were collected and centrifuged at 3000rpm for 15 minutes and the superanatant serum is collected to measure the vitamin C, zinc and copper levels. The vitamin C levels of clinical samples were measured using spectrophotometric quantitation (dinitrophenyl hydrazine method) and zinc and copper levels were measured using atomic absorption spectrophotometry. RESULTS: The results showed that the levels of vitamin C and zinc decreased and copper levels increased in diabetic patients with periodontits compared to healthy individuals with periodontitis. CONCLUSION: It may be reasonable to suggest vitamin and/or mineral supplements for patients whose nutrition might be inadequate. Future research should focus on an evaluation of which nutrients may help to prevent the onset and progression of periodontal disease. PMID- 20922080 TI - Treatment of protruding osseo integrated dental implant. AB - Titanium dental implants have been used in the treatment of partial or complete edentulism. The height and width of the residual alveolus and surrounding anatomical structures can determine the proper position and path of insertion of dental implants. The following case report describes the treatment of a malpositioned osseo integrated dental implant with an apex perforating the buccal cortex of alveolar bone. A 61-year-old male was referred by his local dentist for the chief complaint of a swelling at site of tooth 14 where an implant was present. Intraoral clinical examination revealed an implant supported porcelain fused to metal crown replacing the maxillary right first premolar. A peri-apical radiograph of the implant revealed no signs of peri-implant bone loss or radiolucency. Surgical exploration and modification of the protruding implant. The area healed uneventfully without the need of explantation of the implant in site of tooth 14. We felt that the conservative treatment provided was prudent and treatment of choice and anticipate that the implant will most likely continue to function for a lifetime. PMID- 20922081 TI - Management of infrabony defects in mandibular molars in a patient with generalized aggressive periodontitis using autogenous bone graft from maxillary tuberosity. AB - This clinical case report presents a technique utilizing autogenous cancellous bone from maxillary tuberosity to fill two infrabony defects distal to mandibular molars in a patient diagnosed with aggressive periodontitis. After debridement a 6 mm defect was present distal to mandibular right first molar and 6.5 mm defect was present distal to mandibular second molar of same side. Autogenous bone graft from maxillary tuberosity was placed in both the defects. There was a significant bony fill present six months post surgery and probing depth reduced by 7mm on both the sites. PMID- 20922082 TI - Retrograde peri-implantitis. AB - Retrograde peri-implantitis constitutes an important cause for implant failure. Retrograde peri-implantitis may sometimes prove difficult to identify and hence institution of early treatment may not be possible. This paper presents a report of four cases of (the implant placed developing to) retrograde peri-implantitis. Three of these implants were successfully restored to their fully functional state while one was lost due to extensive damage. The paper highlights the importance of recognizing the etiopathogenic mechanisms, preoperative assessment, and a strong postoperative maintenance protocol to avoid retrograde peri-implant inflammation. PMID- 20922083 TI - An update on periodontic-orthodontic interrelationships. AB - Talking about periodontic-orthodontic interrelationships is related primarily to the 1960s, where a generalized increase in salivary bacterial counts, especially Lactobacillus, had been shown after orthodontic band placement. The purpose of this article is to provide the dental practitioner with basic understanding of the interrelationship between periodontics and orthodontics by means of representing classical studies, and, to give an update on this topic by demonstrating the most recent opinions concerning periodontic-orthodontic interrelationships. Specific areas reviewed are the ability of orthodontic treatment to afford some degree of protection against periodontal breakdown, short-term and long-term effects of orthodontic treatment on the periodontium, and some mucogingival considerations. Topics considering orthodontic treatment in periodontally compromised patients were not included in this review. While past studies have shown that orthodontic treatment can positively affect the periodontal health, recent reviews indicate an absence of reliable evidence for the positive effects of orthodontic therapy on patients' periodontal status. Periodontic-orthodontic interrelationships are still controversial issues. However, a standard language between the periodontist and the orthodontist must always be established to eliminate the existing communications barrier, and to improve the outcomes of the whole treatment. PMID- 20922085 TI - Can we help? PMID- 20922084 TI - Nicotine and periodontal tissues. AB - Tobacco use has been recognized to be a significant risk factor for the development and progression of periodontal disease. Its use is associated with increased pocket depths, loss of periodontal attachment, alveolar bone and a higher rate of tooth loss. Nicotine, a major component and most pharmacologically active agent in tobacco is likely to be a significant contributing factor for the exacerbation of periodontal diseases. Available literature suggests that nicotine affects gingival blood flow, cytokine production, neutrophil and other immune cell function; connective tissue turnover, which can be the possible mechanisms responsible for overall effects of tobacco on periodontal tissues. Inclusion of tobacco cessation as a part of periodontal therapy encourages dental professionals to become more active in tobacco cessation counseling. This will have far reaching positive effects on our patients' oral and general health. PMID- 20922086 TI - New trends in regional anesthesia for shoulder surgery: Avoiding devastating complications. AB - Surgeons and patients are often reluctant to support regional anesthesia (RA) for shoulder and other orthopedic surgeries. This is because of the sometimes true but usually incorrectly perceived "slowing down" of operating room turnover time and the perceived potential for added morbidity. Recently, severe devastating and permanent nerve injury complications have surfaced, and this article attempts to clarify the modern place of RA for shoulder surgery and the prevention of these complications. A philosophical approach to anesthesiology and regional anesthesiology is offered, while a fresh appreciation for the well-described and often forgotten microanatomy of the brachial plexus is revisited to explain and avoid some of the devastating complications of RA for shoulder surgery. PMID- 20922087 TI - Variation of tension in the long head of the biceps tendon as a function of limb position with simulated biceps contraction. AB - PURPOSE: This study was designed to quantify tensile forces within the intra articular long head of the bicep tendon (LHBT) under conditions of passive limb positioning and physiologic load, which simulate contraction of the LHBT. MATERIALS AND METHODS: A force probe was inserted into the intra-articular LHBT, just distal to its supra-glenoid origin, in six fresh-frozen cadaveric specimens. Initially, specimens were manually manipulated through 30 glenohumeral joint positions, combining humeral rotation and elbow/forearm position. In the second phase, a 55 N tensile load was applied through the LHBT in 18 limb positions. Intra-tendinous tension was recorded in all positions under both conditions. RESULTS: External humeral rotation significantly increased tension with glenohumeral forward flexion (P<0.0001). Conversely, internal humeral rotation significantly increased tension with glenohumeral abduction and extension (P<0.0001). A position of glenohumeral extension and internal rotation, with the elbow extended and forearm pronated, produced the highest tension in the intra articular LHBT (P<0.0001). Under applied load conditions, observed LHTB tension was not statistically different in any glenohumeral position (P=0.1468, power = 88%). The greater tuberosity was noted to impinge on the force probe in forward flexion and internal rotation in two specimens. CONCLUSIONS: Variable tensile forces are seen in the intra-articular LHBT as a function of both limb position and simulated biceps contraction. Our findings provide a thorough data set that may be used to help substantiate or refute current or future hypotheses regarding LHBT function, pathology, and clinical tests. CLINICAL RELEVANCE: Identifying positions of glenohumeral motion, which affect LHBT tension will provide an anatomic basis for clinical tests proposed to be for diagnosing LHBT lesions, including superior labral anterior and posterior tears. PMID- 20922088 TI - A simple and safe technique for reconstruction of the acromioclavicular joint. AB - Surgical reconstruction of the dislocated acromioclavicular joint often requires exposure and instrumentation of the coracoid. This carries risks to the surrounding neurovascular structures. We present a safe and simple technique of primary fixation of the acromioclavicular joint, relying on mechanical principles and biological repair, without the need for metalwork. By avoiding the coracoid we hope this approach will appeal to the general orthopedic surgeon. We have found that this technique is suited to both acute and chronic acromioclavicular joint dislocation. PMID- 20922089 TI - Metastasis from scapular Ewing's sarcoma presenting as sutural diastasis: An unusual presentation. AB - Ewing's sarcoma is a malignant non-osteogenic primary tumor of the bone. It is one of the most common primary malignant tumors of bone. Peak incidence is noticed in second decade of life with male preponderance of 1.6:1. It occurs most frequently in long bones and flat bones of pelvic girdles. In 30% cases, Ewing's sarcoma is multicentric in origin. In 14-50%, multiple metastases are present at the time of diagnosis. CNS spread is rare and isolated CNS involvement is not seen. Skull metastasis of Ewing's sarcoma is not rare compared to primary Ewing's sarcoma of the skull, but the actual frequency is unknown. We wish to report a case of "Primary Ewing's sarcoma of scapula with metastasis to Skull Vault in a Child resulting in sutural diastasis" diagnosed by clinicoradiological examination and confirmed by histopathology. PMID- 20922090 TI - Streptococcus subpectoral abscess with shoulder pain: A rare emergency with a common symptom? PMID- 20922091 TI - Tackling diabetes through translation. PMID- 20922092 TI - Avian flu: examining role of ducks in Indian context. PMID- 20922093 TI - West nile virus: do we need its surveillance and control program in punjab state of India? PMID- 20922094 TI - Community-based monitoring: key to success of national health programs. PMID- 20922095 TI - Censoring in clinical trials: review of survival analysis techniques. PMID- 20922096 TI - HIV/AIDS Vaccine: An Update. PMID- 20922097 TI - Where and how breastfeeding promotion initiatives should focus its attention? A study from rural wardha. AB - BACKGROUND: In India, the practice of breastfeeding is almost universal, but initiation of breastfeeding is generally quite late and colostrum is discarded. Integrated Management of Neonatal and Childhood Illness (IMNCI) strategy recommended systematic assessment of breastfeeding and emphasized counseling of the mother on proper positioning and attachment of infant to the breast. OBJECTIVE: To assess breastfeeding among mothers of below six months children in rural Wardha. MATERIALS AND METHODS: The present cross-sectional study was undertaken in surrounding 23 villages of Kasturba Rural Health Training Center (KRHTC), Anji. Two Auxiliary Nurse Midwives (ANMs) trained in IMNCI paid house visits to 99 mothers during the study period and undertook the assessment of breastfeeding using IMNCI assessment form for young infants. Auxiliary Nurse Midwives observed and recorded the positioning and attachment of infant to the breast as per IMNCI guidelines. The data were entered and analyzed using Epi_Info (version 6.04d) software package. RESULTS: Most of the deliveries 94 (94.9%) took place in the healthcare facilities. Majority 61 (61.6%) newborn babies had received breastfeeding within half an hour. About half of the mothers had any of the feeding problems like feeding less than eight times in 24 h, giving any other food or drinks or is low weight for age. Significantly more mothers with feeding problems had problems in positioning and attachment of infant to the breast as compared with those mothers who did not have any feeding problems. CONCLUSIONS: In the settings, where practice of institutional delivery is high, the staff of healthcare facility should ensure education of the mothers regarding position and attachment of infant to the breast before discharge from the healthcare facility. At the village level, Village Health Nutrition Day (VHND) can be utilized for health education of future mothers and support for the breastfeeding mothers. The IMNCI assessment form for young infant should also include assessment of positioning of infant. PMID- 20922098 TI - A study of gender differentials in the prevalence of tuberculosis based on NFHS-2 and NFHS-3 data. AB - BACKGROUND: Worldwide, the case notification rate of tuberculosis has been reported to be higher for men than women. In India also, the prevalence of TB is higher among males as compared to females but it is important to study the trend of gender gap in the prevalence of tuberculosis over the years. OBJECTIVE: To examine the trend in gender gap in the prevalence of TB over the years. MATERIALS AND METHODS: The unit level data of NFHS-2 (1998-99) and NFHS-3 (2005-06) has been utilized. Gender gap in the prevalence of TB has been estimated for the two rounds of the surveys. The delta (Delta), the difference in gender gap in two surveys, has been estimated and decomposed by background characteristics such as place of residence(urban/rural), religion (Hindus/Muslims/others), caste(SC/ST/OBC/others) and standard of living(SLI) (low/medium/high) categories. MAIN FINDINGS: Overall, the prevalence of TB has remained almost same in the two surveys [432/lakh in NFHS-2 and 418/lakh in NFHJS-3; Z=1.19, P=0.275. The gender gap has increased to 217/lakh in NFHS-3 in comparison to 145 per lakh in NFHS-2. The increase in gender gap is significantly higher in rural areas [of 98 per lakh;167/ lakh in NFHS-2 vs 265/lakh in NFHS-3; P<0.05] as compared to corresponding increase in urban areas [of 30 per lakh; 88/ lakh in NFHS-2 vs118/ lakh in NFHS-3, P>0.05]. The increase in delta (D) (difference in gender gap in two surveys) is accounted for as 88% by the rural areas and 12% by the urban areas. CONCLUSION: The increase in gender gap in the prevalence of TB is more in rural areas as compared to urban areas. The increase in rural areas is mainly contributed by Hindus, SC and ST and low and medium SLI categories and in urban areas, the contribution is mainly by Hindus, other castes and high SLI categories. PMID- 20922099 TI - Alcohol use and implications for public health: patterns of use in four communities. AB - BACKGROUND: Alcohol is one of the leading causes of death and disability globally and in India. Information on quantum and pattern of consumption is crucial to formulate intervention programs. OBJECTIVES: To identify the extent and pattern of alcohol use in urban, rural, town and slum populations using a uniform methodology. MATERIALS AND METHODS: Door-to-door survey was undertaken and simple random sampling methodology was adopted; households were the primary sampling unit. One respondent in each alcohol-user household was randomly chosen for detailed interview. RESULTS: Overall, 13% of males and females consumed alcohol. Proportion of users was greater in town (15.7%) and among 26-45 years (67.4%). Whisky (49%) and arrack (35%) were the preferred types and the preferences differed between rural (arrack) and urban (beer) areas. Nearly half (45%) of rural population were very frequent users (consuming daily or every alternate days) as against users in town (23%) or slum (20%). Two-thirds were long-term users and the proportions were greater in the rural and town areas. While, overall 17% of the users were heavy-users, frequent-heavy-drinking was more in slum and rural areas. Nearly two-thirds consumed alcohol in liquor-shops, restaurants, bars and pubs. Habituation and peer-pressure were the key reasons for alcohol use. CONCLUSIONS: The study documented alcohol use and patterns of use in four different communities particularly in transitional areas using similar methodology. Many of the patterns identified are detrimental to health both immediate and over the long period of time. PMID- 20922100 TI - Patterns of tobacco use across rural, urban, and urban-slum populations in a north Indian community. AB - BACKGROUND: Tobacco is the leading cause of mortality globally and in India. The magnitude and the pattern of tobacco consumption are likely to be influenced by the geographical setting and with rapid urbanization in India there is a need to study this differential pattern. AIM: The aim was to study the rural, urban, and urban-slum differences in patterns of tobacco use. SETTINGS: The study was conducted in Ballabgarh block, Faridabad district, Haryana, and was a community based cross-sectional study. MATERIALS AND METHODS: The study was conducted in years 2003-2004 using the WHO STEPS approach with 7891 participants, approximately equal number of males and females, selected using multistage sampling from urban, urban-slum, and rural strata. STATISTICAL ANALYSIS: The analysis was done using the SPSS 12.0 statistical package (SPSS Inc., Chicago, IL, USA). Direct standardization to the WHO world standard population was done to and chi-square and ANOVA tests were used for comparison across three study settings. RESULTS: Self-reported tobacco use among males was as follows: urban 35.2%; urban-slums 48.3%; and rural 52.6% (P value <0.05). Self-reported tobacco use among females was as follows: Urban 3.5%; urban-slums 11.9%; and rural 17.7% (P value <0.05). More males reported daily bidi (tobacco wrapped in temburini leaf) smoking (urban 17.8%, urban-slums 36.7%, rural 44.6%) than cigarette use (urban 9.6%, urban-slums 6.3%, rural 2.9%). Females using smoked tobacco were almost exclusively using bidis (urban 1.7%, 7.9%, 11% in rural). Daily chewed tobacco use had urban, urban-slum, and rural gradients of 12%, 10.5%, and 6.8% in males respectively. Its use was low in females. CONCLUSION: The antitobacco policies of India need to focus on bidis in antitobacco campaigns. The program activities must find ways to reach the rural and urban-slum populations. PMID- 20922101 TI - Analysis of birth weights of a rural hospital. AB - BACKGROUND: Low birth weight remains a major reason behind childhood malnutrition. The NFHS findings show no dent in this problem. OBJECTIVE: This study was undertaken to explore change in birth weights in a period from 1989 to 2007 and any associations thereof. MATERIALS AND METHODS: All birth records of a private rural hospital spanning two decades (1989-2007) were analyzed for birth weight, age of mother, gender, birth order of the baby, proportion of pre-term babies and low birth weight babies. RESULTS: No change was observed in the average birth weights (average 2.71 kg) over the period. Although the birth weight shows some expected variance with the age of mother, it was found to have no relation with the baby's birth order and gender. The low birth weight proportion is about 24% and shows little difference before and after the series midpoint of year 1998. CONCLUSION: The birth weights have hardly changed in this population in the two decades. PMID- 20922102 TI - Patient's Utilization and Perception of the Quality of Curative Care in Community Health Centers of the Fifth Commune of Bsamako. AB - BACKGROUND: Community health centers are an important component of the health system in Mali. Despite the adhesion of the populations and the commitment of the authorities, many things must be done to improve the quality of care provided in those structures. OBJECTIVES: The study aimed to know the patients' utilization and perception of the curative care in the community health centers of Bamako and the physicians' satisfaction of their work condition and perspective in the community health sector. MATERIALS AND METHODS: A cross-sectional study was conducted in nine community health centers of Bamako in 2008. A total of 270 patients were interviewed through a face-to-face interview. Thirteen physicians took a self-administrated questionnaire relating to their material and financial conditions and their plan for the future. RESULTS: The sample was characterized by the low literacy (32.6%) and socio-economic level (15.9% of steady income).139 patients claimed the nearness as the reason of the choice of the health center whereas only 51 claimed the health staff skill. The women felt more satisfied than men (P=0.005) and illiterates felt more satisfied than bachelors and beyond (P=0.034). The patients claimed the reduction of waiting time, the improvement of information and the creation of news services. 30.80% of physicians were satisfied from their material and financial conditions, 38.46% were motivated and 76.92% planned to leave their health center. CONCLUSION: Although a high level of satisfaction regarding the provided service was observed, user reported some shortage in the quality of care and claimed a widening of CSCom capability. PMID- 20922103 TI - Risk Factor Scenario in an Industrial Set-up: Need for an Effective Screening Tool to Assess the High-Risk Group. AB - BACKGROUND: Industrial and technological revolution has resulted in nutrition transition. This calls for analyzing the risk factor scenario in the industrial population. OBJECTIVE: The objective was to map the prevalence and assess the risk factors of industrial employees. MATERIALS AND METHODS: The employees of a large petrochemical industry were enrolled (N=269) for the study. Risk factors were elicited through a structured questionnaire. Parameters monitored were fasting blood sugar and lipid profile. Relative risk was calculated to find out significant predictor variables. RESULTS: The employees had high prevalence of overweight (27%), obesity (22%), central obesity (48.7%), prehypertension (43.2%), hypertension (36.6%), and dyslipidemia (41.4%). They had erroneous dietary habits such as low intake of fruits and vegetables and high fat intake. Most of the employees had low physical activity levels. The prevalence of smoking (13.5%), tobacco (28.2%), and alcohol use (22.2%) were also high with 15.1% having multiple habits. One-fifth of the employees had metabolic syndrome (MS). Seven predictor variables, namely, family history, BMI, WHR, blood pressure, physical inactivity, TG, and TG/H were identified and used to develop the risk score card to identify people at high risk of CVD and DM. CONCLUSION: Multiple risk factor scenario among the industrial population studied calls for effective intervention strategies and policy changes to combat the burden of non communicable diseases. The risk score card can be used to screen the high-risk group in the industrial population. PMID- 20922104 TI - Increased prevalence of pulmonary tuberculosis in male adults of sahariya tribe of India: a revised survey. AB - BACKGROUND: A survey made in 1991-92, reported Sahariya, a primitive tribe of India (M. P.), having high prevalence of pulmonary tuberculosis. No follow-up study was undertaken thereafter. OBJECTIVE: The present study was aimed to know the current status of tuberculosis (TB) in Sahariya after more than a decade of the last survey of 1991-92, as compared to that in Bhil, another primitive tribe living in the same area but never investigated for TB incidence. MATERIALS AND METHODS: A total of 763 random sputum smears from Sahariya and 169 sputum smears from Bhil were screened for the presence of Mycobacterium tuberculosis (M..tb) in order to evaluate the prevalence of pulmonary tuberculosis in both the tribes. Chi square (chi(2)) statistics was performed to study the correlation between age, sex on the one hand and with the prevalence of smear-positive pulmonary TB on the other hand, if any. RESULTS: In Sahariya, the prevalence of smear-positive pulmonary TB was found increased significantly (P<0.005) to 0.454 as against 0.274 estimated in the earlier survey (1991-92). Males, particularly, appeared most affected (P<0.005; 0.382), especially adults (0.260). In contrast, among Bhil, the prevalence was very low. CONCLUSION: The observed increase in TB prevalence and its gender bias in Sahariya tribe indicate the high incidence rate and faster transmission of infection, especially in male sex. PMID- 20922105 TI - Tobacco use among adolescent students and the influence of role models. AB - BACKGROUND: Seventy per cent of premature deaths among adults are due to behavioral patterns that emerge in adolescence, including smoking. OBJECTIVE: The objective was to study the prevalence of tobacco use among adolescent students in South Delhi and its epidemiological correlates. MATERIALS AND METHODS: This was a cross-sectional study. SETTING: Three schools and two colleges of South Delhi were chosen. There were 550 adolescent students aged 14-19. STATISTICAL ANALYSIS: Statistical analysis was done using proportions, the chi-square test, and multivariate logistic regression. RESULTS: A total of 88 (16.0%) students reported having ever tried cigarette or bidi smoking. The prevalence of current smoking was 7.1%. Exactly 10% (55) of the students reported having ever used smokeless forms of tobacco. The prevalence of tobacco use overall was found to be 20.9%, and was significantly higher (P=0.016) among the males than the females. Tobacco use was found to be significantly associated with having seen a brother/sister smoke (OR 5.15), best friend smoke (OR 2.92), and belonging to a nuclear family (OR 1.96). CONCLUSIONS: Tobacco use is still an important risk behavior among adolescent students. This study found a strong association of tobacco use by the adolescents with their having seen various role models ever smoking. PMID- 20922106 TI - Assessment of Malnutrition Among Adolescents:Can BMI be Replaced by MUAC. AB - OBJECTIVES: To find out the magnitude of malnutrition among the adolescents of an urban slum of Kolkata study population. To compare the middle upper arm circumference (MUAC) with that of body mass index (BMI) for determination of nutritional status of the study population. MATERIALS AND METHODS: This was a school-based descriptive epidemiological study done among adolescent male students aged 10-19 years in the service area of Urban Health Centre, Chetla. The school is an all boy's government aided school and all the students reside in the Chetla slum, the largest slum of Kolkata. Anthropometric measurements of the students of one section selected from each class i.e. class V to XII were recorded. RESULTS: Results showed 47.93% of study population as per BMI and 60.30% as per MUAC were malnourished. Evaluation of screening test showed MUAC as a marker was 94.6% sensitive and 71.2% specific. A correlation between measurements of MUAC and BMI was demonstrated (r=0.822; SE=0.035; 95% CI; P=0.000000; r(2)=0.74). PMID- 20922107 TI - Relationship of personal hygiene with nutrition and morbidity profile: a study among primary school children in South kolkata. AB - BACKGROUND: Majority of the health problems affecting school children are preventable by promotion of hygienic practices through proper health education by the teachers, who are the first contacts. OBJECTIVES: The study was undertaken to find out the status of nutrition and personal hygiene among primary school children and their association with their varied morbidity profiles. MATERIALS AND METHODS: A descriptive, observational, cross-sectional study was conducted in a primary school situated in the largest slum of Kolkata. RESULTS: The participants included 103 boys and 81 girls, with a mean age of 6.2 years. The mean personal hygiene score of the girls (4.15 +/- 0.98) was significantly higher than that of boys (3.2 +/- 1.4) [P<0.05]. Most of the boys (54.37%) and girls (74.07%) were normally nourished as per the CDC growth chart. Over 70% of the children were suffering from one or more morbidities, the most common morbidity in both the sexes being pallor, followed by worm infestation. Personal hygiene scores were significantly higher (P<0.05) among those children who were normally nourished as well as those who did not suffer from any morbidity in the last 15 days. CONCLUSIONS: Care should be taken to improve the pitiable state of personal hygiene and poor sanitary practices of these school children through coordinated and concerted health education measures by teachers as well as parents. PMID- 20922108 TI - Estimation of the Incidence of Bacterial Vaginosis and other Vaginal Infections and its Consequences on Maternal/Fetal Outcome in Pregnant Women Attending an Antenatal Clinic in a Tertiary Care Hospital in North India. AB - AIMS: This study was undertaken to estimate the incidence of bacterial vaginosis (BV) and other vaginal infections during pregnancy and its association with urinary tract infections (UTI) and its consequences on pregnancy outcome, maternal and fetal morbidity and mortality. SETTINGS AND DESIGN: Prospective cohort study. MATERIALS AND METHODS: The present prospective cohort study was conducted on 200 women attending the antenatal clinic (ANC) of a tertiary hospital. All pertinent obstetric and neonatal data covering antenatal events during the course of pregnancy, delivery, puerperium and condition of each newborn at the time of birth were collected. BV was detected by both Gram stain and gold standard clinical criteria (Amsel's composite criteria). STATISTICAL ANALYSIS USED: Data were analyzed using SPSS version 9. Fischer's exact test, chi square tests and Student's' test has been used for analysis. The probability of 5% was considered as significant for continuous variables such as age, period of gestation and birth weight. Odds ratio (OR) and confidence interval (CI) with 95% probability were determined. RESULTS: The incidence of bacterial vaginosis was 41 in 200 patients. Adverse outcomes such as preterm labor, PROM and fetal complications were found more in pregnant women who had bacterial vaginosis (N=41), bacterial vaginosis with UTI (N=14) as compared to those without bacterial vaginosis (N=118). CONCLUSIONS: The incidence of poor pregnancy outcome was higher in bacterial vaginosis with UTI. Prevention of BV and UTI is cost effective to minimize the pregnancy-related complications and preterm labor to decrease in perinatal and maternal mortality and morbidity. We recommend all antenatal patients should be screened for the presence of bacterial vaginosis, other infections and UTI. PMID- 20922109 TI - Knowledge and Outcome Measure of HbA1c Testing in Asian Indian Patients with Type 2 Diabetes from a Tertiary Care Center. AB - AIM: HbA1c test is considered to be the reliable measure for evaluating long-term glycemic control in type 2 diabetes. The purpose of this study was to evaluate whether knowledge about HbA1c test is associated with a better glycemic control. MATERIALS AND METHODS: We conducted a cross-sectional survey of 480 (M:F; 287:193) adults with type 2 diabetes attending a tertiary care center during a period of four months. Baseline demographic and clinical data of all the subjects was obtained. Subject's knowledge about HbA1c test and their target goal was assessed using a questionnaire. Recent HbA1c results were obtained from medical records. RESULTS: Seventy four per cent of the subjects had awareness about HbA1c test and about 43% of those who knew HbA1c test also knew their target goal. 33% remember their last HbA1c result. The mean A1C of Group A was significantly lower when compared with Group B (8.1 +/- 1.7 vs 9.2 +/- 1.9, P<0.0001). Group C had lower A1C levels compared to Group D (7.7 +/- 1.4 vs 8.5 +/- 1.9, p<0.0001). Patients who kept their HbA1c less than 7% were significantly higher in Group C than in Group D. (37.8 vs 12.7%, p<0.00001). Subjects had good glycemic control with increasing levels of awareness about HbA1c. CONCLUSION: Majority of the diabetic patients who attended the tertiary care center for diabetes care knew HbA1c test and half of them were aware about their target goal. Awareness about HbA1c had a positive impact on maintenance of better glycemic control. PMID- 20922110 TI - Epidemic investigation of the jaundice outbreak in girdharnagar, ahmedabad, gujarat, India, 2008. AB - BACKGROUND: Since 1976, seven outbreaks of hepatitis E occurred in Ahmedabad. Clusters of jaundice cases were reported on June 19, 2008, by a civic center, Girdharnagar ward, Ahmedabad. OBJECTIVES: THE OBJECTIVES WERE AS FOLLOWS: (1) to identify the etiological agent, source of outbreak, and mode of transmission; (2) to propose a control measure based on the outbreak investigation. MATERIALS AND METHODS: We defined a case as an acute illness with (a) a discrete onset of symptoms and (b) jaundice or elevated serum aminotransferase levels, from March to September 2008 in the households of the Girdharnagar ward. We collected data through a door-to-door survey and hospital records. We described the outbreak in terms of time, place, and person. We collected laboratory investigation reports of case patients admitted to the civil hospital. To test our hypothesis we conducted a retrospective cohort study to find out the relative risk for hepatitis. We conducted environment investigation to find out the source of contamination of water supply. RESULTS: A total 233 case patients of hepatitis were identified with the attack rate of 10.9/1000 population. Cases were reported in all the age groups with a higher attack rate in the age group of 20-29 years (18.5/1000). Out of 17 case patients, 16 were positive for the hepatitis E IgM antibody. The attack rate was two times more among those who were exposed to the leaking pipeline than the non-exposed (RR=2.3, 95% CI 1.76, 2.98). Environmental investigation also confirmed the sewage contamination of drinking water in the distribution system. CONCLUSION: The outbreak was due to hepatitis E virus. We recommended a temporary alternative water supply, repair of the leakages, and water quality surveillance. PMID- 20922111 TI - Assessment of Skeletal and Non-skeletal Fluorosis in Endemic Fluoridated Areas of Vidharbha Region, India: A Survey. AB - OBJECTIVES: To evaluate skeletal and non-skeletal fluorosis in patients living at endemic fluoridated areas and also the morphological changes in red blood cells (R.B.C.'s). MATERIALS AND METHODS: The cross-sectional study was conducted at Vidharbha region of Maharashtra, India. An ethical clearance was obtained from the concerned authorities. Fifty families were screened and 204 subjects who had dental/skeletal fluorosis were included in the study. The aims and objectives were explained to the study subjects of the village and biochemical, hematological and radiological assessment was done. The main source of drinking water in this area was tube well. The concentrations of fluoride in two different areas of same village were 4 and 4.5 ppm. RESULTS: Prevalence of skeletal fluorosis and non-skeletal fluorosis in male patients was 56.87% (116) and in female patients (88) it was 43.13%. RBC count in male patients was 5.03 +/- 0.49 while in female patients it was 4.70 +/- 0.47. With significant difference between male and female patients, P value was 0.003. Hb% in male patients was 12.44 +/- 1.76 and in female patients it was 11.31+/- 1.34, showing significant difference between male and female patients P value 0.038. Alkaline phosphate level in male patients was 289.68 +/- 149.09 and in female patients it was 276.68 +/- 164.97. ESR count in male patients was found 11.41 +/- 8.75 and in female patients it was 13.29 +/-7.37. Radiological finding of fluorosis patients shows thickening of inner and outer tables of skull bone in 83.92% of patients and only 7.84% of the patients were suffering from barrowing of long bone. PMID- 20922112 TI - Awareness and Perceptions of School Children about Female Feticide in Urban Ludhiana. AB - BACKGROUND: Although the Indian girl child's position is precarious throughout the country, she remains the most vulnerable in Punjab. OBJECTIVES: To assess the awareness and perceptions of school children regarding female feticide. STUDY DESIGN: Crosssectional study. MATERIALS AND METHODS: The study involved collection of information regarding knowledge and perception of school students about female feticide using multiple choice questionnaire. A total of 527 students between the age group of 11-18 years of various schools of district Ludhiana, Punjab were the study subjects. They had come to participate in the poster competition on organ donation (SAARC Transplant games), organized by Department of Community Medicine, D.M.C and H, Ludhiana. RESULTS: Out of total 527 students, 97.9% were aware of female feticide. Main source of information was TV (56%), followed by newspaper (33%). Majority of the students (65.2 %) felt that discrimination between boys and girls is prevalent in the society. Regarding perception of school students for curbing this social evil, 37.8% school students were of the view that awareness among the masses is the solution to stop this practice, while 25% of the students responded that equal status to girls will stop this practice of female feticide. CONCLUSIONS: The school students had optimum level of awareness about female feticide and almost all of them strongly felt that this harmful practice should be stopped altogether. PMID- 20922113 TI - A Multi-sectoral Approach to Capture Information on Road Traffic Injuries. AB - BACKGROUND: Regularly available data is shown to be inadequate for developing, implementing, and evaluating injury prevention and control programs in India. The present study was undertaken in the hospitals of Bangalore and Pune, to examine the feasibility of gathering information on injuries using multiple sources. MATERIALS AND METHODS: Stakeholders meeting and training programs were held for the hospital staff, police personnel, and traffic and transport staff, to identify their roles and responsibilities. Prospective data on morbidity and mortality due to injuries were collected by trained staff from Emergency Departments on a pre-tested questionnaire. The information gathered was cross checked with the hospital and police records. RESULTS: The stakeholders meeting and training programs were able to motivate the departments to provide the correct data. Data on 32188 patients could be extracted from hospital and police records during the study period. Injuries accounted for 16% of the emergency cases. Unintentional injuries were 64%, and 32% were intentional. Road traffic injuries accounted for 44% of all the injuries. One-third of the injured were children and young adults below 25 years. Among the injured, two wheeler riders were 29% and pedestrians were 23%. CONCLUSION: It was possible to improve the data on injuries by adequate training and a data linking mechanism between the Police, Hospital, and Transport Departments. The problem of road traffic injuries could be highlighted and addressed by a good data capture mechanism. PMID- 20922114 TI - A study on domestic violence against adult and adolescent females in a rural area of west bengal. AB - BACKGROUND: Globally, domestic violence against females is common across culture, religion, class and ethnicity. There are various reasons for domestic violence and it might have serious health outcomes. OBJECTIVES: The study was undertaken to determine the prevalence, characteristics, reasons and the socio-demographic correlates of domestic violence, if any, and to find out the perceptions of the females to cope with the act of violence and to overcome the situation. MATERIALS AND METHODS: A cross-sectional observational study was undertaken by interviewing 141 adult and adolescent females residing in a village of West Bengal, with the help of a pre-designed and pre-tested questionnaire. Data were analyzed statistically by simple proportions and tests of significance (Chi-square test). RESULTS: Out of 141 respondents, 33 (23.4%) adult and adolescent females in this village were exposed to domestic violence in the past year. Among the demographic characteristics, statistically significant maximum prevalence was observed among 30-39 years age group, illiterate and unmarried females. For most of the females who were exposed to domestic violence, their husbands acted as the perpetrators (72.73%) and they reported slapping as the specific act of physical assault (72.73%). Majority of the respondents reported that opportunity of education (31.9%), being economically productive (31.9%) and better family income (23.4%) would help them to overcome the situation. CONCLUSION: This study emphasizes the need for justified female empowerment and this calls for multidisciplinary approach to develop public health measures, which would most effectively address the problem of domestic violence. PMID- 20922115 TI - Body Image Perception and Attempts to Change Weight among Female Medical Students at Mangalore. AB - BACKGROUND: Assessing body image self-perception has used BMI as an indicator of nutritional status. The visual analogue scale is a highly effective instrument for assessing people's level of dissatisfaction with their body weight while evaluating the perceptual component of body image. OBJECTIVE: By knowing body mass index of female medical students, to find out their pattern of body image perception and any attempts done to change their weight. MATERIALS AND METHODS: All the students residing in MBBS ladies hostel were included in this study and a questionnaire regarding body image perception, diet, physical activity and attempts to change weight was instituted. Their responses were collected, tabulated, analyzed and interpreted. RESULTS: Among 147 study subjects, according to BMI, 25(17%) were undernourished while 111(75.5%) and 11(7.5%) were normally nourished and overweight respectively. 35(23.8%) of the subjects felt they were lean, 95(64.6%) felt they were normal and 17(11.6%) felt they were overweight. Regarding image satisfaction, 98(66.7%) of them were satisfied with their image and out of 49 who were not satisfied 30 (20.4 %) wanted to reduce weight. Skipping meals was practiced by 42 (28.6%) of subjects. CONCLUSION: About 75.5% of the study group were having normal BMI. Most of them perceived their image correctly regarding to their weight. Most of the underweight and all overweight females were not satisfied. Underweight females preferred to gain weight and overweight females preferred to lose weight. PMID- 20922116 TI - Work-related Musculoskeletal Disorder: An Occupational Disorder of the Goldsmiths in India. AB - BACKGROUND: Gold ornament making industries are one of the widespread small-scale industries of India. These industries belong to the unorganized sector of the state. A large number of goldsmiths are working there for prolonged period in cross leg posture at semi-confined workstation. OBJECTIVES: The aim of this study is to identify Occupational Disorder of the Goldsmiths in India. MATERIALS AND METHODS: In the spresent study, 120 male goldsmiths were randomly selected from the Davangere district of Karnataka. A detailed questionnaire study on discomfort feeling was done by the modified Nordic questionnaire, which considering the information about work nature, job stress and discomfort feeling. The existing workstations were assessed by the measurement of work areas. Analysis of body posture by rapid upper limb assessment was done to evaluate the work stress during their job. RESULTS: From the analysis, it was revealed that MSDs were the major problem of the goldsmiths. The activities of the goldsmiths were also highly repetitive. Moreover, the questionnaire study revealed that most of the workers were affected by occupational disorder like pain at neck (80%), shoulder (20%), wrist (45%), and low back (75%) and also eye problem like irritation (30%) and burning sensation (70%). They also perform their job in hazardous postures. It was recorded that the workstations were poorly illuminated (19 Lux) in respect to precision work. Accidents like cut and burn occurred frequently due to the unsafe condition of the workstation. CONCLUSIONS: From the observation and analysis of the result it was concluded that health of the goldsmiths were highly affected improper body posture and workload. Twisting, bending, and over-reaching are the resultant of poorly designed workstation. These actions force them into a non-neutral position that increases the overall discomfort and pain at the lower back, neck, and shoulders. Moreover, lack of proper illumination at work site also exerts an additional adverse effect on the health of the goldsmiths. PMID- 20922117 TI - Putting people first: a primary health care success in rural India. AB - BACKGROUND: The World Health Report, 2008, contains a global review of primary health care on the 30th anniversary of the Declaration of Alma-Ata. The period covered by the study reported on here corresponds with that of the Report, allowing for a comparison of achievements and challenges in one primary health care centre vis-a-vis the WHO standards. MATERIALS AND METHODS: This study uses qualitative and quantitative data from a rural primary care facility in Western Maharashtra, collected over three decades. It analyzes the four groups of reforms defined by WHO in the context of the achievements and challenges of the study facility. RESULTS: According to the WHO Report, health systems in developing countries have not responded adequately to people's needs. However, our in-depth observations revealed substantial progress in several areas, including in family planning, safe deliveries, immunization and health promotion. Satisfaction with services in the study area was high. CONCLUSION: Adequate primary health care is possible, even when all recommended WHO reforms are not fully in place. PMID- 20922118 TI - Arsenic contamination of ground water and its health impact on population of district of nadia, west bengal, India. AB - BACKGROUND: The global health impact and disease burden due to chronic arsenic toxicity has not been well studied in West Bengal. OBJECTIVE: To ascertain these, a scientific epidemiological study was carried out in a district of the state. MATERIALS AND METHODS: Epidemiological study was carried out by house-to-house survey of arsenic affected villages in the district of Nadia. A stratified multi stage design has been adopted for this survey for the selection of the participants. A total number of 2297 households of 37 arsenic affected villages in all the 17 blocks were surveyed in the district. RESULT: Out of 10469 participants examined, prevalence rate of arsenicosis was found to be 15.43%. Out of 0.84 million people suspected to be exposed to arsenic, 0.14 million people are estimated to be suffering from arsenicosis in the district. Highest level of arsenic in drinking water sources was found to be 1362 MUg/l, and in 23% cases it was above 100 MUg/l. Majority of the population living in the arsenic affected villages were of low socio-economic condition, inadequate education and were farmers or doing physical labour. Chronic lung disease was found in 207 (12.81%) subjects among cases and 69 (0.78%) in controls. Peripheral neuropathy was found in 257 (15.9%) cases and 136 (1.5%) controls. CONCLUSION: Large number of people in the district of Nadia are showing arsenical skin lesion. However, insufficient education, poverty, lack of awareness and ineffective health care support are major factors causing immense plight to severely arsenic affected people. PMID- 20922119 TI - A study to evaluate mobile phone dependence among students of a medical college and associated hospital of central India. PMID- 20922120 TI - Red Tide Phenomenon Leading to Panic Attack and Mass Casualty among Children in Coastal Kerala. PMID- 20922121 TI - A study on the Perception of General Practitioners of a Locality in Kolkata Regarding RNTCP and DOTS. PMID- 20922122 TI - Proportion, pattern and need assessment of deformities among registered leprosy affected individuals in chamrajanagar district. PMID- 20922123 TI - Harassment among Women at Workplace: A Cross-Sectional Study in Coastal South India. PMID- 20922124 TI - Potentially Modifiable Micro-Environmental and Co-Morbid Factors Associated with Severe Wasting and Stunting in Children below 3 Years of Age in Aligarh District. PMID- 20922125 TI - Community ophthalmology: revisited. PMID- 20922126 TI - Clinical Course of Development of Alcohol and Opioid Dependence: What are the Implications in Prevention? PMID- 20922127 TI - Use of condoms: clarifying the message. PMID- 20922128 TI - Low birth weight of newborns: magnitude of the problem seen in a 100 bed hospital of a rural area in vellore district, Tamil Nadu (India). PMID- 20922129 TI - Risk factors among patients with acute coronary syndrome in rural kerala. PMID- 20922130 TI - Sharp disposal practices in urban dispensaries. PMID- 20922131 TI - Selecting the Right Toys for Your child is Not a Child's Play. PMID- 20922132 TI - Assessment of the Quality of Service Given by Health Care Provider about Tuberculosis in RNTCP. PMID- 20922133 TI - Study of Knowledge, Attitude and Practices Regarding Biomedical Waste among Paramedical Workers. PMID- 20922135 TI - Overview on the 1st international workshop on gynecologic oncology. PMID- 20922134 TI - A cyclic-RGD-BioShuttle functionalized with TMZ by DARinv "Click Chemistry" targeted to alphavbeta3 integrin for therapy. AB - Clinical experiences often document, that a successful tumor control requires high doses of drug applications. It is widely believed that unavoidable adverse reactions could be minimized by using gene-therapeutic strategies protecting the tumor-surrounding healthy tissue as well as the bone-marrow. One new approach in this direction is the use of "Targeted Therapies" realizing a selective drug targeting to gain effectual amounts at the target site, even with drastically reduced application doses. MCF-7 breast cancer cells expressing the alpha(v)beta(3) [alpha(v)beta(3)] integrin receptor are considered as appropriate candidates for such a targeted therapy. The modularly composed BioShuttle carrier consisting of different units designed to facilitate the passage across the cell membranes and for subcellular addressing of diagnostic and/or therapeutic molecules could be considered as an eligible delivery platform. Here we used the cyclic RGD-BioShuttle as a carrier for temozolomide (TMZ) at the alpha(v)beta(3) integrin receptor realizing local TMZ concentrations sufficient for cell killing. The IC50 values are 12 uMol/L in the case of cRGD-BioShuttle-TMZ and 100 uMol/L for underivatized TMZ, which confirms the advantage of TMZ reformulation to realize local concentrations sufficient for cell killing. Our paper focuses on the design, synthesis and application of the cRGD-BioShuttle conjugate composed of the cyclic RGD, a alpha(v)beta(3) integrin-ligand, ligated to the cytotoxic drug TMZ. The ligation was carried out by the Diels Alder Reaction with inverse electron demand (DAR(inv)). PMID- 20922136 TI - Asian society of gynecologic oncology workshop 2010. AB - This workshop was held on July 31-August 1, 2010 and was organized to promote the academic environment and to enhance the communication among Asian countries prior to the 2nd biennial meeting of Australian Society of Gynaecologic Oncologists (ASGO), which will be held on November 3-5, 2011. We summarized the whole contents presented at the workshop. Regarding cervical cancer screening in Asia, particularly in low resource settings, and an update on human papillomavirus (HPV) vaccination was described for prevention and radical surgery overview, fertility sparing and less radical surgery, nerve sparing radical surgery and primary chemoradiotherapy in locally advanced cervical cancer, were discussed for management. As to surgical techniques, nerve sparing radical hysterectomy, optimal staging in early ovarian cancer, laparoscopic radical hysterectomy, one port surgery and robotic surgery were introduced. After three topics of endometrial cancer, laparoscopic surgery versus open surgery, role of lymphadenectomy and fertility sparing treatment, there was a special additional time for clinical trials in Asia. Finally, chemotherapy including neo-adjuvant chemotherapy, optimal surgical management, and the basis of targeted therapy in ovarian cancer were presented. PMID- 20922138 TI - Survival benefit of laparoscopic surgical staging-guided radiation therapy in locally advanced cervical cancer. AB - OBJECTIVE: This study was designed to evaluate the survival benefit of laparoscopic surgical staging (LSS)-guided tailored radiation therapy (RT) in locally advanced cervical cancer (LACC). METHODS: We retrospectively reviewed 89 LACC patients' medical records who primarily received non-surgical treatment, of which pretreatment LSS was performed in 20 (LSS group) and primary chemoradiation therapy (CCRT) without LSS (CCRT group) was carried out in 69 from January 2000 to January 2006. We analyzed clinical characteristics, pretreatment imaging study results and survival outcomes including disease free survival (DFS) and overall survival (OS) to compare them between the two groups. RESULTS: There were as many as eight cases (40%) of LSS related complications. The mean time interval between LSS and RT or CCRT was 26.6 days (+/-18.8 days). Six out of twenty (30%) in LSS group and 10 out of 69 (14.5%) in CCRT group received extended field RT when paraaortic lymph nodes (LNs) were positive based on the pathologic findings after LSS and the results of imaging studies, respectively. Three-year DFS and OS were both better in 33 imaging-negative CCRT group patients than those in 4 imaging negative/pathology-positive (false negative) patients after LSS (3-year DFS, 50% vs. 87%, p=0.022; 3-year OS, 50% vs. 84%, p=0.033). The 5-year DFS rates were 52% and 55% in LSS group and in CCRT group, respectively (p=0.28). The 5-year OS rates were 68% in LSS group and 62% in CCRT group without significant difference between the two groups (p=0.79). CONCLUSION: We found that LSS-based RT tailoring did not show survival benefit in LACC despite inaccuracy of imaging-based RT tailoring. Further studies are required to find new method to overcome this inaccuracy and improve survival outcomes. PMID- 20922137 TI - Current status in the management of uterine corpus cancer in Korea. AB - Uterine corpus cancer has increased in prevalence in Korean women over the last decade. Recently, elegant studies have been reported from many institutes. To improve treatment strategies, a review of our own data is warranted. This work will discuss the risks and prognostic factors for uterine corpus cancer, and the radiologic evaluation, prediction of lymph node metastasis, systematic lymphadenectomy, minimally invasive surgery, ovarian-saving surgery, fertility sparing treatment, and adjuvant treatment in women with uterine cancer. PMID- 20922139 TI - GST (GSTM1, GSTT1, and GSTP1) polymorphisms in the genetic susceptibility of Turkish patients to cervical cancer. AB - OBJECTIVE: This work investigates the role of glutathione S-transferase M1 (GSTM1), glutathione S-transferase T1 (GSTT1), and glutathione S-transferase P1 (GSTP1) enzymes and polymorphisms, which are found in phase II detoxification reactions in the development of cervical cancer. METHODS: This study was conducted with 46 patients diagnosed with cervical cancer and 52 people with no cancer history. Multiplex PCR methods were used to evaluate the GSTM1 and GSTT1 gene polymorphism. However, the GSTP1 (Ile105Val) gene polymorphism was studied using a PCR-RFLP method. The patient and control groups were compared using a chi square test with p<0.05. RESULTS: In the patient group, statistical significance was determined for gravidity (p=0.03), parity (p=0.01), and the number of living children (p=0.01) compared to the control group. The gene frequency of GSTM1, GSTT1, and GSTP1 polymorphisms was evaluated. We observed that GSTM1 and GSTT1 null genotype frequencies were 54.3% and 32.6% respectively, while GSTP1 (Ile/Val), (Ile/Ile), (Val/Val) genotype frequencies were 52%, 44%, and 4%, respectively, in the cervical cancer patients. No statistical variation was determined between the control and patient groups in terms of GSTM1, GSTT1, and GSTP1 polymorphisms (p>0.05). CONCLUSION: Our results demonstrate that GSTT1, GSTM1, and GSTP1 polymorphisms are not associated with cervical cancer in Turkish patients. PMID- 20922141 TI - High expression of mTOR is associated with radiation resistance in cervical cancer. AB - OBJECTIVE: Mammalian target of rapamycin (mTOR) is known to promote cell proliferation, survival, and resistance to radiation. The aim of this study was to determine whether mTOR expression was associated with survival and the response to radiation in patients with cervical cancer. METHODS: After reviewing 119 patients treated by primary radiotherapy for stage IIB-IVA cervical cancer, a case-control study was performed. The cases (n=12) with local recurrence or radiation failure after primary radiation therapy were selected. For each case, two controls that had no recurrence were selected. Using pretreatment paraffin embedded tissues, the cytoplasmic expression of phosphorylated-mTOR (p-mTOR) was evaluated by immunohistochemistry. Staining was scored based on intensity (intensity score [IS] 0-3) and proportion (proportion score [PS] 0-100). The progression free survival (PFS) was defined from the end of treatment to the day of recurrence by imaging studies or biopsy. The staining distribution and PFS were compared between the two groups. The results were analyzed by the Student t test, Mann-Whitney U-test, Fisher's exact test, and Cox proportional hazards regression model. RESULTS: The p-mTOR cytoplasmic expression was significantly associated with a poor response to radiotherapy (p<0.01). With respect to survival, a higher cytoplasmic expression of p-mTOR was associated with a worse outcome (p=0.02). The hazard ratio for recurrence or radiation failure was 6.18 for mTOR IS and 1.04 for mTOR PS (p<0.05 for both), indicating that the degree of p-mTOR staining correlated with the recurrence risk. CONCLUSION: High expression of p-mTOR was associated with radiation resistance; therefore p-mTOR may be a prognostic marker for response to radiotherapy in patients with cervical cancer. PMID- 20922140 TI - Plasma levels of insulin-like growth factor-1 and insulin-like growth factor binding protein-3 in women with cervical neoplasia. AB - OBJECTIVE: The goal of this study was to investigate the relationship between plasma levels of insulin-like growth factors-1 (IGF-1) and IGF-binding protein-3 (IGFBP-3) and the risk for cervical intraepithelial neoplasia (CIN) and cervical cancer. METHODS: Plasma levels of IGF-1 and IGFBP-3 of 44 cervical cancer patients, 82 CIN patients and 40 neoplasm-free patients were investigated. Then the associations of the plasma levels of IGF-1 and IGFBP-3 with cervical neoplasm or its clinicopathologic parameters were analyzed. RESULTS: The mean IGF-1 concentrations were significantly different among the control, CIN, and cervical cancer groups; the levels were higher in the CIN group compared to the controls. According to the quartile category, the plasma IGF-1 level was significantly higher (p=0.0015) in the CIN group than in the controls. The IGFBP-3 level showed no association between the controls and CIN groups (p=0.842). Although the mean IGF-1/IGFBP-3 molar ratio had borderline significance (p=0.08) among the study population, the quartile comparison showed a significantly higher IGF-1/IGFBP-3 molar ratio in the CIN group compared to the control group (p=0.041). CONCLUSION: Plasma levels of IGF-1 and the IGF-1/IGFBP-3 molar ratio might be useful for the development early detection of cervical lesions and used as an adjuvant diagnostic tool for cervical neoplasia after more larger scale research. PMID- 20922142 TI - The type of metastasis is a prognostic factor in disseminated cervical cancer. AB - OBJECTIVE: THE OBJECTIVES OF THIS STUDY WERE TWOFOLD: to verify whether the type of metastasis (lymphatic vs. hematogenous) is a prognostic factor, and to identify molecular markers associated with survival in patients with disseminated cervical cancer. METHODS: Between April 1997 and May 2008, 30 patients with disseminated cervical cancer who had supraclavicular lymph node (N=13) or hematogenous metastases (N=17) were initially treated at our institute. We reviewed medical records to extract clinicopathologic variables. For 17 patients with available pathological specimens, we evaluated the association of immunohistochemical staining for metalloproteinase (MMP)-2, vascular endothelial growth factor (VEGF)-A, and laminin V gamma (LAMC)-2 with survival and clinicopathologic variables via a log-rank test and Cox regression analysis. RESULTS: Patients who had only lymphatic metastasis (odds ratio [OR], 5.3; 95% confidence interval [CI], 1.4 to 19.5) or completed initial treatment (OR, 3.2; 95% CI, 1.1 to 9.9) showed better survival than patients who did not, but none of the molecular markers were associated with survival. Out of 13 patients with only lymphatic metastasis, three patients who had received volume-directed radiation with concurrent chemotherapy had a long-term survival of over two years. However, patients with hematogenous metastasis showed extremely poor prognosis. CONCLUSION: The type of metastasis and completion of initial treatment were associated with prolonged survival in patients with disseminated cervical cancer, and over 20% of patients with lymphatic metastasis were salvaged with volume directed radiation with concurrent chemotherapy. None of the molecular markers were associated with survival in patients with disseminated cervical cancer. PMID- 20922143 TI - Uterine metastases in ovarian carcinoma: frequency and survival in women who underwent hysterectomy. AB - OBJECTIVE: Possible reasons for hysterectomy in the initial surgical management of advanced invasive epithelial ovarian carcinoma (EOC) might be a high frequency of uterine involvement and its impact on survival. The aim of the present study was to describe the frequency of uterine involvement and its association with survival in an unselected population of EOC patients who underwent hysterectomy. METHODS: All incident cases of EOC diagnosed in Israeli Jewish women between March 1994 to June 1999, were identified within the framework of a nationwide case-control epidemiological study. The target population of the present report includes all stage II-IV EOC patients who had a uterus at the time of diagnosis. Of the 822 such patients, 695 fulfilled the inclusion criterion. Excluded were 141 patients for various reasons. The present analysis is based on the remaining 554 patients. RESULTS: Uterine involvement was present in 291 (52.5%) of the patients and it was macroscopic in only 78 (14.1%). The serosa was the most common site of isolated metastases. Multivariate analysis showed that advanced stage significantly increased the risk for uterine involvement. The overall median survival with any uterine involvement was significantly lower compared to those with no involvement (38.9 months vs. 58.0 months; p<0.001). CONCLUSION: There is an association between uterine involvement, whether macro- or microscopic, and lower survival even after hysterectomy although residual tumor could not be included in the analysis. Further studies are required to establish whether uterine involvement itself is an unfavorable risk factor or merely a marker of other unfavorable prognostic factors. PMID- 20922144 TI - Skeletal muscle metastasis from carcinoma cervix: a case report. AB - Cervical cancer is the most common malignancy in Indian women. Cervical cancer usually spread by local extension and through the lymphatics to the retroperitoneal lymph nodes. Direct invasion of muscles by primary growth is more common than by metastatic involvement. We present a case of carcinoma of the cervix post radiotherapy to pelvis who on follow up presented with biceps muscle metastases as the initial sign of disseminated disease. PMID- 20922145 TI - Primary amelanotic melanoma of the cervix: case report with review of literature. AB - Primary malignant melanoma of the uterine cervix is a rare neoplasm with poor prognosis. It may be misdiagnosed especially when amelanotic, in which case immunohistochemistry is useful in reaching the diagnosis. We present one such case of a 65-year-old postmenopausal female patient presenting with bleeding per vaginum. Speculum examination revealed an ulcero-proliferative growth involving the cervix. On histopathological examination it was originally suspected to be a poorly differentiated carcinoma or a non-epithelial malignant tumor, but was subsequently correctly diagnosed by immunohistochemical staining with the HMB-45 antibody and S-100 protein. PMID- 20922146 TI - Co-occurrence of an adenoma malignum and an endocervical-type adenocarcinoma of the uterine cervix in a woman with Peutz-Jeghers syndrome. AB - We report a rare co-occurrence of an adenoma malignum and an adenocarcinoma in a 30-year-old woman with Peutz-Jeghers syndrome. The woman was diagnosed with Peutz Jeghers syndrome based on an endoscopic biopsy after vaginal bleeding. A pelvic examination and an MRI revealed the co-occurrence of a 4*5 cm protruding adenocarcinoma of FIGO stage Ib2 based on a punch biopsy and a 4.5*5.7 cm multilocular cystic mass above the solid cancer. The patient received two courses of neoadjuvant chemotherapy, followed by a laparoscopic radical hysterectomy with pelvic lymph node dissection. Pathologic findings were consistent with adenocarcinoma (40%) and adenoma malignum (60%) confined to the cervix. Three courses of adjuvant chemotherapy were performed and no clinical evidence of recurrence was seen during a 12 month follow-up period. This study will contribute to defining the best diagnosis and treatment for these rare complicating tumors. PMID- 20922147 TI - Diagnosing homicidal mania: forensic psychiatry and the purposeless murder. PMID- 20922148 TI - Specialization without the Hospital: The Case of British Sports Medicine. PMID- 20922149 TI - "Open the other eye": payment, civic duty and hospital contributory schemes in Bristol, c. 1927-1948. PMID- 20922150 TI - "Fascinating scalpel-wielders and fair dissectors": women's experience of Irish medical education, c. 1880s-1920s. PMID- 20922151 TI - The truth about our bones: William Cheselden's Osteographia. PMID- 20922152 TI - Clifford Dobell and the Making of Paul de Kruif's Microbe Hunters. PMID- 20922154 TI - Oral health status of disabled individuals attending special schools. AB - OBJECTIVES: The purpose of this study was to determine the prevalence of the dmft DMFT indexes and the oral hygiene status of 136 individuals attending a special school for the disabled. METHODS: Participants were grouped according to disability [Mental Retardation (MR), Cerebral Palsy (CP), Autistic Disorder (AD), Down Syndrome (DS), Other (OTH)] and age [2-6 years (n=24), 7-12 years (50 children) and 13+ years (62 children]. Caries examinations were carried out in accordance with WHO criteria and oral cleanliness was evaluated by visually assessing the presence of plaque on teeth. RESULTS: The age range of patients was 2-26 years (mean age: 11.89+/-5.19 years). Mean dmft and DMFT scores by age group were as follows: 2-6 years: dmft=2.04+/-2.24; 7-12 years: dmft=2.24+/-2.60, DMFT=0.98+/-2.58; 13+years: DMFT=2.68+/-2.91. Overall, 15.4% of children had no caries or fillings. While dmft and DMFT levels (P>.05) did not vary significantly by type of disability, oral cleanliness did. Children with autism were observed to maintain the best oral hygiene and those with mental retardation (MR), the poorest. CONCLUSIONS: It is important for the dentist to concentrate on a preventive approach and provide proper dental education to parents of disabled individuals. Among the children with disabilities, more attention should be paid to the oral hygiene of MR group. PMID- 20922155 TI - The effects of prophylactic ozone pretreatment of enamel on shear bond strength of orthodontic brackets bonded with total or self-etch adhesive systems. AB - OBJECTIVES: The aim of this in vitro study is to determine (1) shear bond strength (SBS) of brackets bonded with self-etch and total-etch adhesive after ozone treatment (2) bond failure interface using a modified Adhesive Remnant Index (ARI). METHODS: 52 premolars were randomly assigned into four groups (n=13) and received the following treatments: Group 1: 30 s Ozone (Biozonix, Ozonytron, Vehos Medikal, Ankara, Turkey) application + Transbond Plus Self-Etching Primer (SEP) (3M) + Transbond XT (3M), Group 2: Transbond Plus SEP + Transbond XT, Group 3: 30 s Ozone application + 37% orthophosphoric acid + Transbond XT Primer (3M) + Transbond XT, Group 4: 37% orthophosphoric acid + Transbond XT Primer + Transbond XT. All samples were stored in deionised water at 37 degrees C for 24 hours. Shear debonding test was performed by applying a vertical force to the base of the bracket at a cross-head speed of 1 mm/min. RESULTS: The mean SBS results were Group 1: 10.48 MPa; Group 2: 8.89 MPa; Group 3: 9.41 MPa; Group 4: 9.82 MPa. One Way Variance Test revealed that the difference between the groups was not statistically significant (P=0.267). Debonded brackets were examined by an optical microscope at X16 magnification to determine the bond failure interface using a modified ARI. The results were (mean) Group 1: 2.38; Group 2: 1.31; Group 3: 3.00; Group 4: 1.92. Multiple comparisons showed that Groups 1 and 2, 2 and 3, 3 and 4 were statistically different (P=0.014, P<.001 and P=0.025). CONCLUSIONS: Ozone treatment prior to bracket bonding does not affect the shear bond strength. PMID- 20922156 TI - The Effect of Framework Design on Stress Distribution in Implant-Supported FPDs: A 3-D FEM Study. AB - OBJECTIVES: The biomechanical behavior of the superstructure plays an important role in the functional longevity of dental implants. However, information about the influence of framework design on stresses transmitted to the implants and supporting tissues is limited. The purpose of this study was to evaluate the effects of framework designs on stress distribution at the supporting bone and supporting implants. METHODS: In this study, the three-dimensional (3D) finite element stress analysis method was used. Three types of 3D mathematical models simulating three different framework designs for implant-supported 3-unit posterior fixed partial dentures were prepared with supporting structures. Convex (1), concave (2), and conventional (3) pontic framework designs were simulated. A 300-N static vertical occlusal load was applied on the node at the center of occlusal surface of the pontic to calculate the stress distributions. As a second condition, frameworks were directly loaded to evaluate the effect of the framework design clearly. The Solidworks/Cosmosworks structural analysis programs were used for finite element modeling/analysis. RESULTS: The analysis of the von Mises stress values revealed that maximum stress concentrations were located at the loading areas for all models. The pontic side marginal edges of restorations and the necks of implants were other stress concentration regions. There was no clear difference among models when the restorations were loaded at occlusal surfaces. When the veneering porcelain was removed, and load was applied directly to the framework, there was a clear increase in stress concentration with a concave design on supporting implants and bone structure. CONCLUSIONS: The present study showed that the use of a concave design in the pontic frameworks of fixed partial dentures increases the von Mises stress levels on implant abutments and supporting bone structure. However, the veneering porcelain element reduces the effect of the framework and compensates for design weaknesses. PMID- 20922157 TI - Effects of Finger Pressure Applied By Dentists during Cementation of All-Ceramic Crowns. AB - OBJECTIVES: To compare the finger pressure applied by dentists during cementation and to examine the effect of gender and time of day on finger pressure. METHODS: Fifteen dentists (9 males, 6 females) formed a study group and 10 master dies in premolar shape and Turcom Cera all-ceramic crowns were prepared to measure the maximum finger pressure applied by dentists during cementation. The dentists performed a total of 300 cementation processes. One-way analysis of variance and independent t tests were used to evaluate the results. RESULTS: A statistically significant difference was found in the amount of pressure applied during cementation (P<.005). However, there was no significant difference for time of day or gender according to one-way analysis of variance. CONCLUSIONS: Our results show that finger pressure varies by dentist. For this reason, the optimum pressure should be determined exactly. Special equipment or an apparatus could be developed to apply that pressure. PMID- 20922158 TI - Age estimation for dental patients using orthopantomographs. AB - OBJECTIVES: The aim of this study was to conduct age estimates for dental patients using orthopantomographs (OPGs). The OPGs were selected by an independent author with respect to criteria and evaluated by two independent dentists. The results were compared to chronologic ages. The reliability of the estimates, concurrently made by the two independent dentists using OPGs, was also evaluated. METHODS: In this retrospective study, the OPGs of 238 Turkish individuals of known chronological age, ranging from 1 to 60 years, were measured. Patients were then classified. Radiographs were evaluated by two independent dentists and age estimation was achieved according to the decades. RESULTS: The truest age estimates made by the dentists were in the 1-10 years age range (89.6%), the most inaccurate age estimates were in the 41-50 years age range (41.7%). Results indicate that the accuracy of age estimation diminishes with age. CONCLUSIONS: Despite the variations related to the practitioners, in this study, there were no significant differences in age estimations between the two participant practitioners. Age estimation through evaluating OPGs was the most accurate in the first decade and the least in fourth decade. It can be concluded that OPGs are not adequate for accurate age estimation. PMID- 20922159 TI - Effectiveness of two methods for preparation of autologous platelet-rich plasma: an experimental study in rabbits. AB - OBJECTIVES: The purpose of this study was to compare the quantity and quality of platelets in platelet-rich plasma (PRP) samples prepared using either the single- or the double-centrifugation protocol. METHODS: Ten adult white New Zealand rabbits were used. Ten ml of blood were drawn from each animal via cardiac puncture. Each blood sample was divided into two equal parts for PRP preparation: 5 ml of blood were centrifuged according to a single-centrifugation protocol (Group I), and 5 ml were centrifuged according to a double-centrifugation protocol (Group II). Manual platelet counts were performed on the whole blood and PRP samples of each group. Smears were also done on all samples in order to see the morphology of the platelets. The data obtained in the manual platelet count were submitted to statistical analysis (repeated measures ANOVA, Tukey, P<.05). RESULTS: The average whole blood platelet count was 446,389/MUl. The PRP samples in Group II presented an average platelet amount significantly higher than that of Group I (1,986,875 +/- 685,020/MUl and 781,875 +/- 217,693/MUl, respectively). The PRP smears from Group II were the only one to present platelets with altered morphology (75% of the smears). A few lymphocytes with increased cytoplasm were observed in the PRP smears of both Groups I (25% of the smears) and II (62.5% of the smears). CONCLUSIONS: Within the limits of this study, it can be concluded that the double-centrifugation protocol resulted in higher platelet concentrations than did the single-centrifugation protocol. However, the double centrifugation protocol caused alterations in platelet morphology and was more sensitive to small processing errors. PMID- 20922160 TI - Effect of autogenous cortical bone grafting in conjunction with guided tissue regeneration in the treatment of intraosseous periodontal defects. AB - OBJECTIVES: The aim of this clinical trial was to evaluate the additional benefit of using guided tissue regeneration (GTR) with autogenous cortical bone (ACB) grafting versus ACB grafting alone for the regenerative treatment of intraosseous periodontal defects. METHODS: Via a split-mouth design, 12 patients with chronic periodontitis (five men, seven women; mean age, 45.3+/-4.6 years) who had probing pocket depths (PPDs) of >=6 mm following initial periodontal therapy were randomly assigned to two treatments in contralateral areas of the dentition: a combination of ACB grafting and GTR (with a absorbable membrane of polylactic acid) or ACB grafting alone. The compared parameters were preoperative and 6 month postoperative PPDs, clinical attachment levels (CALs), and radiographic alveolar bone heights. RESULTS: Both treatment modalities resulted in significant changes in the postoperative measurements from the preoperative values (P<.01). The reduction in the PPDs, gain in the CALs, and gain in the radiographic alveolar bone heights were 4.58+/-1.08, 4.25+/-1.06, and 5.50+/-2.24 mm in the patients treated with ACB grafting and GTR and 4.92+/-1.00, 4.50+/-0.80, and 5.92+/-1.83 mm in those treated with ACB grafting alone, respectively. The differences between the treatments were not statistically significant (P>.05). CONCLUSIONS: Within the study limitations, both ACB grafting with GTR and ACB grafting alone lead to significant improvements in clinical and radiographic parameters at 6 months postoperatively. The combined approach does not provide any additional benefit for treating intraosseous periodontal defects. PMID- 20922161 TI - Effect of acidic challenge preceded by food consumption on enamel erosion. AB - OBJECTIVES: This in vitro study aimed to evaluate the effect of food consumption followed by acidic challenge on enamel erosion. METHODS: Seventy-five enamel blocks obtained from bovine teeth were divided randomly into five groups (n=15 per group): GI - erosion with previous immersion in milk; GII - erosion with previous immersion in cheese extract; GIII - erosion with previous immersion in liver extract; GIV - erosion with previous immersion in broccoli extract; and GV erosive effect of cola drink (control). Over 24 h, the slabs were submitted to 3 pH-cycles, each consisting of immersion in the studied food (GI to GIV) for 5 min followed by immersion in a cola drink for 5 min, and subsequently, the slabs were stored in artificial saliva (110 min). At the end of the pH-cycles, the slabs were stored in artificial saliva for 18 h. Enamel alterations were assessed by profilometry (MUm). Data were tested using ANOVA and Scott-Knott's tests (P<.05). RESULTS: Mean erosion depths for enamel (MUm) were 0.46 in GI, 0.55 in GII, 0.64 in GIII, 0.54 in GIV, and 1.18 in GVI. Enamel loss by acidic challenge alone (GV) was significantly higher than when the acidic challenges were preceded by food extract immersion. CONCLUSIONS: The data suggest that all studied foods could minimize the erosive effect on enamel. PMID- 20922162 TI - Effect of EDTA and phosphoric Acid pretreatment on the bonding effectiveness of self-etch adhesives to ground enamel. AB - OBJECTIVES: This in vitro study determined the effect of enamel pretreatment with phosphoric acid and ethylenediaminetetraacetic acid (EDTA) on the bond strength of strong, intermediary strong, and mild self-etching adhesive systems. METHODS: Ninety sound human premolars were used. Resin composite cylinders were bonded to flat ground enamel surfaces using three self-etching adhesive systems: strong Adper Prompt L-Pop (pH=0.9-1.0), intermediary strong AdheSE (pH=1.6-1.7), and mild Frog (pH=2). Adhesive systems were applied either according to manufacturer instructions (control) or after pretreatment with either phosphoric acid or EDTA (n=10). After 24 hours, shear bond strength was tested using a universal testing machine at a cross-head speed of 0.5 mm/minute. Ultra-morphological characterization of the surface topography and resin/enamel interfaces as well as representative fractured enamel specimens were examined using scanning electron microscopy (SEM). RESULTS: Neither surface pretreatment statistically increased the mean shear bond strength values of either the strong or the intermediary strong self-etching adhesive systems. However, phosphoric acid pretreatment significantly increased the mean shear bond strength values of the mild self etching adhesive system. SEM examination of enamel surface topography showed that phosphoric acid pretreatment deepened the same etching pattern of the strong and intermediary strong adhesive systems but converted the irregular etching pattern of the mild self-etching adhesive system to a regular etching pattern. SEM examination of the resin/enamel interface revealed that deepening of the etching pattern was consistent with increase in the length of resin tags. EDTA pretreatment had a negligible effect on ultra-morphological features. CONCLUSIONS: Use of phosphoric acid pretreatment can be beneficial with mild self etching adhesive systems for bonding to enamel. PMID- 20922163 TI - Permeability of Dental Adhesives - A SEM Assessment. AB - OBJECTIVES: To morphologically evaluate the permeability of different commercial dental adhesives using scanning electron microscopy. METHODS: SEVEN ADHESIVE SYSTEMS WERE EVALUATED: one three-step system (Scotchbond Multi-Purpose - MP); one two-step self-etching primer system (Clearfil SE Bond - SE); three two-step etch-and-rinse systems (Single Bond 2 - SB; Excite - EX; One-Step - OS); and two single-step self-etching adhesives (Adper Prompt - AP; One-Up Bond F - OU). The mixture of primer and bond agents of the Clearfil SE Bond system (SE-PB) was also tested. The adhesives were poured into a brass mold (5.8 mm x 0.8 mm) and light cured for 80 s at 650 mW/cm2. After a 24 h desiccation process, the specimens were immersed in a 50% ammoniac silver nitrate solution for tracer permeation. Afterwards, they were sectioned in ultra-fine slices, carbon-coated, and analyzed under backscattered electrons in a scanning electron microscopy. RESULTS: MP and SE showed slight and superficial tracer permeation. In EX, SB, and OS, permeation extended beyond the inner superficies of the specimens. SE-PB did not mix well, and most of the tracer was precipitated into the primer agent. In AP and OU, "water-trees" were observed all over the specimens. CONCLUSIONS: Different materials showed distinct permeability in aqueous solution. The extent of tracer permeation varied according to the composition of each material and it was more evident in the more hydrophilic and solvated ones. PMID- 20922164 TI - The effect of irradiation distance on microhardness of resin composites cured with different light curing units. AB - OBJECTIVES: The aim of this study was to compare the microhardness of five different resin composites at different irradiation distances (2 mm and 9 mm) by using three light curing units (quartz tungsten halogen, light emitting diodes and plasma arc). METHODS: A total of 210 disc-shaped samples (2 mm height and 6 mm diameter) were prepared from different resin composites (Simile, Aelite Aesthetic Enamel, Clearfil AP-X, Grandio caps and Filtek Z250). Photoactivation was performed by using quartz tungsten halogen, light emitting diode and plasma arc curing units at two irradiation distances (2 mm and 9 mm). Then the samples (n=7/per group) were stored dry in dark at 37 degrees C for 24 h. The Vickers hardness test was performed on the resin composite layer with a microhardness tester (Shimadzu HMV). Data were statistically analyzed using nonparametric Kruskal Wallis and Mann-Whitney U tests. RESULTS: Statistical analysis revealed that the resin composite groups, the type of the light curing units and the irradiation distances have significant effects on the microhardness values (P<.05). CONCLUSIONS: Light curing unit and irradiation distance are important factors to be considered for obtaining adequate microhardness of different resin composite groups. PMID- 20922165 TI - The prevalence and treatment outcomes of primary tooth injuries. AB - OBJECTIVES: The aim of the present study was to evaluate the type and prevalence of primary tooth injuries, as well as their treatment and treatment outcomes, among children referred to the Department of Pedodontics at the Ankara University Faculty of Dentistry in Turkey. METHODS: The study population consisted of patients applying to the department with a primary tooth injury over a period of 21 months. Fifty-one patients presented with trauma to 99 primary teeth. Clinical and radiographic examinations were conducted on each patient. Age, sex, time, cause of injury, and number of teeth affected were recorded, and the type of trauma was identified according to Andreasen's classification. The teeth were treated by one of the authors. RESULTS: The majority of trauma occurred between the ages of 2 and 4. The most common type of injury was lateral luxation (33.3%). Most injuries (33.3%) presented during May. The most common form of treatment was follow-up only (39.4%), followed by extraction (29.3%) and root canal treatment (12.1%). The average follow-up period was 11 months. During the follow-up period, complications were observed in 4 teeth. CONCLUSIONS: The study results show that in the absence of acute symptoms, parents tend not to apply to a dental clinic for children's injuries. This finding highlights the importance of informing the public about primary tooth injuries and their consequences. PMID- 20922166 TI - Immunohistochemical and Stereologic Analysis of NF-kappaB Activation in Chronic Periodontitis. AB - OBJECTIVES: Nuclear factor kappa B (NF-kappaB) is a member of the transcription factor family, and it plays a key role in coordinating the expression of genes in many chronic inflammatory diseases. This study investigated the cytoplasmic and nuclear activation of (NF-kappaB) and the cytoplasmic expression of inhibitor kappa B (IkappaB) in gingival tissues of subjects who had chronic periodontitis. METHODS: Thirty-five patients were included in this study; 17 patients had chronic periodontitis, and 18 were healthy. Gingival tissues were obtained from each individual and then stained immunohistochemically. The obtained sections were examined under a stereomicroscope, and the numerical density values of the stained cells were computed using the stereologic method. A one-way analysis of variance (ANOVA) and a multiple range least significant difference (LSD) were used for intergroup comparisons (P=0.05). RESULTS: According to the immunohistochemical analysis of the cytoplasmic positive cells stained with IkappaB, statistically significant differences were found between the case and control groups. When comparing the cytoplasmic and nuclear positive immunoreactivity of p50 and p65, statistically significant differences were found between the diseased and control groups. Statistically significant correlations were also found between the clinical periodontal scores and the immunohistochemical results of the diseased subjects. CONCLUSIONS: It was shown that NF-kappaB was highly activated in subjects who had chronic periodontitis, compared to healthy controls. The findings of this study can be useful in planning new treatment strategies for periodontal diseases. Further investigations are needed to understand more about the signaling mechanisms of inflammatory mediators and their interactions with NF-kappaB in chronic periodontitis. PMID- 20922167 TI - An Assessment of the Relationship between the Maxillary Sinus Floor and the Maxillary Posterior Teeth Root Tips Using Dental Cone-beam Computerized Tomography. AB - OBJECTIVES: The aim of the present study was to assess the relationship between the maxillary sinus floor and the maxillary posterior teeth root tips using dental cone-beam CT. METHODS: A total of 87 right and 89 left maxillary sinus regions from 92 patients were examined using dental cone-beam CT. Images were analyzed by a specialist in oral and maxillofacial radiology. Perpendicular lines were drawn on the cross-sectional images between the deepest point of the maxillary sinus floor and the root tips of the maxillary first and second premolars and first, second and third molars, and the distances were measured using built-in measurement tools. Means, standard deviations and minimum and maximum values were calculated for all right and left premolars and molars. T tests were used to compare measurements between left and right sides and between female and male patients. RESULTS: The distance between sinus floor and root tip was longest for the first premolar root tip and shortest for the second molar buccodistal root tip for both right and left sides. No statistically significant differences were found between the right and left side measurements or between female and male patients (P>.05). CONCLUSIONS: Knowledge of the anatomical relationship between the maxillary sinus floor and the maxillary posterior teeth root tips is important for the preoperative treatment planning of maxillary posterior teeth. PMID- 20922168 TI - Use of mineral trioxide aggregate in the treatment of large periapical lesions: reports of three cases. AB - Pulpal and periradicular pathosis are the result of microbial, mechanical, or chemical invasion. Microorganisms are the main irritants of pulpal and periapical tissues. The goal of the obturation is to obtain a fluid-tight seal of the root canal system from its coronal aspect through its apical extent to preserve from the irritants.. Root apices have morphological irregularities in teeth with periapical lesions. Therefore, it is more difficult to produce hermetically apical stop with conventional guttapercha obturation techniques. This case report describes the treatment and six years follow-up of the teeth with large periapical lesion using MTA as apical filling material. PMID- 20922169 TI - Repair of Furcal Iatrogenic Perforation with Mineral Trioxide Aggregate: Two Years Follow-up of Two Cases. AB - Furcal perforation is usually an undesired complication that can occur during preparation of endodontic access cavities or exploring canal orifice of multirooted teeth. Inadequacy of the repair materials has been a contributing factor to the poor outcome of repair procedures. On the basis of the recent physical and biologic property studies of the relatively new introduced mineral trioxide aggregate, this material may be suitable for closing the communication between the pulp chamber and the underlying periodontal tissues. There are few reports on repair of furcal perforation with MTA in molar teeth. The purpose of this case report was to describe the treatment of two furcal perforation using MTA in molar teeth. The perforations were cleaned with NaOCl and saline solution and sealed with MTA without internal matrix. Finally, the teeth were endodontically treated and coronally restored with composite resin and ceramic veneer crown and bridge. After 2 years, the absence of periradicular radiolucent lesions, pain, and swelling along with functional tooth stability indicated a successful outcome of sealing perforations in two cases. PMID- 20922170 TI - Interim prosthetic rehabilitation of a patient following partial rhinectomy: a clinical report. AB - Surgical defects often have adverse effects on patient perception of esthetics and self-esteem. Rehabilitation of such surgical defects poses a challenge to the clinician. Presented here is a clinical report of an interim prosthetic rehabilitation of a patient who underwent partial rhinectomy for basal cell carcinoma. Nasal resection included part of the nasal septum, the entire cartilage, and the ala. An interim nasal prosthesis was fabricated for this patient 3 weeks after surgery, to provide early rehabilitation. This prosthesis provided a sociopsychological benefit to the patient, and the prosthesis was well tolerated. The spectacle glasses retained the prosthetic nose. PMID- 20922171 TI - Occlusal interferences: how can this concept influence the clinical practice? AB - This brief review discusses the role of occlusal interferences on the development and progression of temporomandibular dysfunction (TMD) and postural disorders. The eligible literature is described and critically presented to demonstrate that occlusal interferences are an important factor in the risk of TMD. Several studies have demonstrated through their findings that the use of occlusal adjustments, whether or not associated with restorative procedures, might avoid the development of articular problems in vulnerable patients. The occlusal interferences caused by restorative procedures or orthodontic treatment can cause TMDs in susceptible patients, and occlusal adjustments can be an alternative in the treatment of these TMDs. PMID- 20922172 TI - Is the thyroid to blame? AB - Treat the rare case of acute suppurative thyroiditis as a medical emergency, with attention to airway protection, intravenous antibiotics, and surgical drainage. Order a sedimentation rate if you suspect subacute thyroiditis. It is almost always elevated in patients with this disease. Treat subacute thyroiditis with prednisone 40 mg daily in patients refractory to treatment with nonsteroidal anti inflammatory drugs. PMID- 20922173 TI - Don't overlook the complications of tonsillectomy. PMID- 20922174 TI - A package worth paying for. PMID- 20922175 TI - What's causing your young patient's hip pain? AB - Diagnosing hip pain--which is increasingly common in children and adolescents- can be a daunting task, unless you know what to look for. These tips can help. PMID- 20922176 TI - Beneath the surface: derm clues to underlying disorders. AB - When evaluating patients with suspected cutaneous lupus erythematosus, use multiple criteria--including histologic and immunofluorescent biopsy findings and American College of Rheumatology criteria--to rule out systemic disease. PMID- 20922177 TI - Breast cancer prevention and Tx: an evidence-based guide. AB - When to begin screening mammography may be the latest controversy, but it's not the only uncertainty regarding breast health and cancer care. We've culled the latest evidence to help you do what's best. PMID- 20922178 TI - PURLs: Add a fibrate to a statin? AB - For most patients with diabetes and dyslipidemia, adding a fibrate does not improve cardiovascular outcomes. PMID- 20922179 TI - Erythematous rash on face. PMID- 20922180 TI - Clinical inquiries. Does office spirometry improve quit rates in smokers? AB - It depends. Simply performing spirometry and offering cessation advice doesn't improve quit rates in patients who smoke (strength of recommendation [SOR]: A, systematic review of randomized controlled trials [RCTs]). However, when the spirometry results are communicated in terms of "lung age", smokers are more likely to quit (SOR: B, large RCT). Patients with abnormal spirometry results may be more likely to quit than patients with normal results (SOR: B, cohort studies). PMID- 20922181 TI - Clinical inquiries. Which drugs are best when aggressive Alzheimer's patients need medication? AB - Atypical antipsychotics are effective; so are selective serotonin reuptake inhibitors (SSRIs), and they may be safer. Atypical antipsychotics are an effective short-term (6-12 weeks) treatment for aggressive behavior in patients with Alzheimer's disease because they consistently decrease aggression scores (strength of recommendation [SOR]: A, multiple randomized controlled trials [RCTs]). However, evidence of drug-related deaths in patients taking these drugs mandates weighing the benefits against the risks. SSRIs may be a safer, effective alternative (SOR: B, limited studies). PMID- 20922183 TI - JGLD has got its first impact factor. PMID- 20922184 TI - Is the future of Romanian gastroenterology training bright? PMID- 20922185 TI - Incarcerated umbilical hernia after large volume paracentesis for refractory ascites. PMID- 20922186 TI - Alkaline reflux esophagitis in patients with total gastrectomy and Roux en Y esojejunostomy. AB - BACKGROUND AND AIMS: Alkaline reflux esophagitis is a complication that might develop in patients with total gastrectomy. The aim of the study was to analyze the prevalence and severity of reflux esophagitis and the occurence of complications (Barrett's esophagus and esophageal stenosis) in patients with total gastrectomy and Roux en Y esojejunostomy. METHODS: 92 patients with total gastrectomy performed for gastric cancer were included in the study. None of the patients had esophagitis prior to gastrectomy. The patients were assessed clinically and endoscopically after a certain interval from surgery. RESULTS: An important number of patients (14 out of 92, 15.22%) had reflux esophagitis; 5.43% of the patients had also complications of reflux esophagitis (Barrett's esophagus and benign esophageal stenosis) and 6.52% had local tumor recurrence. Of the 14 patients with reflux esophagitis, the majority (9/14) had Los Angeles (LA) grade C esophagitis. The mean interval between surgery and the endoscopic evaluation was 4.43 years. Barrett's esophagus and benign stenosis were diagnosed after a longer period of time (10.33 and 8 years, respectively) as compared to reflux esophagitis (5.29 years). More than half of the esophagitis patients had reflux symptoms. CONCLUSIONS: Although Roux en Y esojejunostomy is a reconstructive technique which prevents the reflux, an important percentage of our patients developed alkaline reflux esophagitis. In most cases, the esophagitis was moderate or severe. Complications of alkaline reflux, i.e. benign stenosis and Barrett's esophagus, also occurred after longer periods of time (8 to 10 years) in a small percentage of patients. PMID- 20922187 TI - Association of gastroesophageal reflux disease symptoms with exacerbations of chronic obstructive pulmonary disease. AB - BACKGROUND: Symptoms of gastroesophageal reflux disease (GERD) are common in various chronic respiratory diseases, but little is known about GERD in the setting of chronic obstructive pulmonary disease (COPD). The aim of this study was to determine the effect of GERD symptoms on COPD exacerbations and subsequent hospitalization and drug usage. METHODS: This retrospective study was conducted from December 2008 to February 2009 in the Pulmonary Clinic of Dr. Shariati University Hospital, Isfahan, Iran. Consecutive patients who were diagnosed with COPD based on clinical features and pulmonary function tests were included. Patients were categorized in GERD positive and GERD negative groups based on the Mayo GERD questionnaire. Exacerbation of COPD, hospitalization, and drug usage were compared between the two groups. RESULTS: During the study period, 110 patients with COPD (mean age = 68.0 +/- 8.4 years, 87.3% male) were included; 59 (53.6%) patients were GERD positive. There was no significant difference between the GERD positive and GERD negative patients in age, gender, tobacco use, or body mass index. GERD positive patients experienced significantly more acute exacerbations of COPD than patients who were GERD negative (p < 0.001). The rate of hospitalization due to COPD exacerbations was significantly higher in GERD positive patients and they had a more severe COPD (p < 0.05) and more concurrent use of multiple therapies as compared with GERD negative patients (p < 0.05). CONCLUSION: Patients with GERD symptoms have more COPD exacerbations and subsequent hospitalizations and drug usage. Clinical trials and preventive strategies for GERD in patients with COPD are warranted. PMID- 20922188 TI - Faecal lactoferrin, capsule endoscopy and Crohn's disease. Is there a three way relationship? A pilot study. AB - BACKGROUND & AIMS: Capsule endoscopy has been shown to be useful in diagnosing small bowel Crohn's disease. Faecal lactoferrin has been shown to have a high sensitivity and specificity in discriminating between inflammatory bowel disease and irritable bowel syndrome. There have been no studies on the use of faecal lactoferrin in the setting of suspected Crohn's disease using capsule endoscopy. Our aim was to investigate the clinical utility of lactoferrin in patients with suspected Crohn's disease using capsule endoscopy. METHODS: Data was collected prospectively on patient symptoms, family history and blood parameters. Patients were requested to return a stool sample and quantitative analysis using sandwich ELISA was performed for faecal lactoferrin. RESULTS: Seventeen patients were recruited with all patients having had more than one criterion for referral. The diagnostic yield for capsule endoscopy was 41%, of which 71% of patients had an elevated faecal lactoferrin (correlation coefficient 0.56, p=0.01). The sensitivity, specificity, positive predictive value and negative predictive value of faecal lactoferrin were 71%, 100%, 100% and 83%, respectively. CONCLUSION: Faecal lactoferrin has a high positive and negative predictive value for the diagnosis of small bowel Crohn's disease, detected by capsule endoscopy. Faecal lactoferrin is a useful marker (in conjunction with clinical parameters) to determine which patients should be referred for capsule endoscopy. PMID- 20922189 TI - Outcome of antiviral treatment in patients with chronic genotype 1 HCV hepatitis. A retrospective study in 507 patients. AB - BACKGROUND AND AIM: The current standard of care in chronic HCV genotype 1 hepatitis is the combination of pegylated interferon (PegIFN) with ribavirin for 48 weeks. The aim of our paper was to verify if there are significant differences regarding the sustained virologic response (SVR) in patients treated with PegIFN alfa-2a vs. those treated PegIFN alpha-2b, both in combination with ribavirin. METHOD: We performed a retrospective study on 507 patients with chronic viral C hepatitis treated with PegIFN alpha-2a 180 microg/kg/week or PegIFN alpha-2b 1.5 microg/kg/week plus ribavirin in the recommended doses according to weight, following the current treatment guidelines. We evaluated the SVR defined as PCR RNA-HCV undetectable 24 weeks after the end of treatment. RESULTS: There were no differences regarding the baseline characteristics among the subgroups of patients treated with PegIFN alpha-2a or PegIFN alpha-2b concerning the pretreatment viral load (p=0.2445), the severity of fibrosis (p=0.2403), the mean age of the patients (p=0.9597) and the women/men ratio (p=0.2087). The SVR rates in patients treated with PegIFN alpha-2a were similar to those in patients treated with PegIFN alpha-2b: 208/338 (61.5%) vs. 94/169 (55.6%) (p=0.2129). CONCLUSION: Sustained virologic response rates were similar in HCV genotype 1 patients treated with PegIFN alpha-2a and with Peg-IFN alpha-2b. PMID- 20922190 TI - Effects of pro-inflammatory cytokines on the production of soluble fractalkine and ADAM17 by HepG2 cells. AB - BACKGROUND & AIMS: Soluble fractalkine is increased in the liver during times of injury; however the effect of pro-inflammatory cytokines in this process is currently unknown. The aim of this study was to determine whether pro inflammatory cytokines elevated in patients with hepatocellular carcinoma influence fractalkine shedding from HepG2 cells and whether ADAM17 was involved in this process. METHODS: In vitro experiments were performed in the human hepatocellular carcinoma cell line HepG2. Soluble fractalkine was detected using an ELISA. ADAM17 expression was investigated using quantitative real time (reverse transcription)-polymerase chain reaction and flow cytometry. Short interfering RNA transfection was used to down-regulate ADAM17 expression. RESULTS: Soluble fractalkine was present in supernatants of HepG2 cells, and was significantly increased by interleukin-1beta (p <= 0.005) and tumour necrosis factor-alpha (p <= 0.043), but not by interleukin-6 (p >= 0.316). This corresponded to minor increases in ADAM17 protein, but not ADAM17 mRNA, following the same treatments. However, the down-regulation of ADAM17 protein did not affect fractalkine shedding. CONCLUSIONS: This study showed that soluble fractalkine is up-regulated under inflammatory conditions associated with hepatocellular carcinoma development, but ADAM17 does not appear to be responsible for regulating this process. PMID- 20922191 TI - Analysis of the common vasoactive intestinal peptide receptor 1 polymorphism in gallstone patients. AB - BACKGROUND AND AIM: Cholesterol gallstone disease is caused by both genetic and environmental factors (e.g., deranged motility of the gallbladder wall). Recently, a single nucleotide polymorphism (SNP) of the vasoactive intestinal peptide receptor 1 (VIPR1) gene has been linked to late onset of achalasia, a lower esophagus dysmotility disorder. As VIPR1 is expressed in the gallbladder wall as well, and patients with achalasia exhibit extraesophageal motility disorders, the influence of VIPR1 SNP on cholelithiasis was investigated. METHODS: We analyzed 254 gallstone-free controls (confirmed by ultrasound, age 21 78 years, 88% women, BMI 16-43 kg/m2) and 226 individuals from 107 families with gallstones (age 24-80 years, 87% women, BMI 17-55 kg/m2). All individuals were genotyped for the VIPR1 rs437876 SNP (intron 4) with PCR-based 5'-nuclease and fluorescence detection assays (TaqMan). We performed nonparametric linkage (NPL) analysis in affected sib-pairs (ASP), association tests, and regression analyses. RESULTS: Controls were significantly younger (P < 0.01) and leaner than ASP and cases (P < 0.01), and both age as well as BMI significantly increased the risk of developing gallstones (P < 0.001). Allele frequencies were in line with database entries and no deviation from Hardy-Weinberg equilibrium was detected. Neither allele and genotype distributions nor NPL scores or the restriction of analysis to individuals older than 50 years provided evidence for association or linkage of the VIPR1 SNP and cholelithiasis. CONCLUSION: The VIPR1 polymorphism, previously linked to gastrointestinal dysmotility disorders, does not represent a common risk factor for gallstones in the general or in an elderly population. PMID- 20922192 TI - Prevalence of gastroparesis in type 1 diabetes mellitus and its relationship to dyspeptic symptoms. AB - BACKGROUND AND AIM: Gastroparesis and/or dyspeptic symptoms occur in around 50% of type 1 diabetic patients. The aim of our study was to evaluate the prevalence of gastroparesis in patients with type 1 diabetes using 13C-octanoic acid breath test (13C-OBT) and the relationship between dyspeptic symptoms and gastric emptying. METHODS: Gastric emptying of solids was evaluated prospectively in euglycemic conditions in 69 type 1 diabetic patients (male/female: 36/33; mean age 49.5 +/- 14.2 years; mean duration of diabetes 20.4 +/- 8.2 years) and 40 healthy volunteers (male/female 17/23; mean age 34.3 +/- 16 years) using 13C-OBT. Dyspeptic symptoms, autonomic nerve function and Helicobacter pylori (H. pylori) status were assessed. RESULTS: Solid gastric emptying was slower in diabetic patients (T1/2 = 125.36 +/- 31.5 min) than in healthy subjects (T1/2 = 88.5 +/- 27.3 min) (p < 0.05). Gastric emptying was slower in diabetic female compared to diabetic male patients (p < 0.05). Body mass index (BMI) was the only independent predictor for delayed solid gastric emptying in a logistic regression model testing HbA1c, BMI, age, diabetes duration, H. pylori status, peripheral neuropathy, retinopathy, nephropathy, and autonomic neuropathy. Abdominal bloating and upper abdominal pain were associated with delayed gastric emptying. CONCLUSIONS: We found that 33.7% of type 1 diabetic patients had delayed gastric emptying that correlated with female gender, increased BMI, abdominal bloating and upper abdominal pain. PMID- 20922193 TI - Survival and quality of life of cholangiocarcinoma patients: a prospective study over a 4 year period. AB - BACKGROUND AND AIMS: Cholangiocarcinomas (CCAs) are tumors with a poor prognosis and a lower quality of life (QoL). The aim of this study was to evaluate the survival rate and quality of life in CCA patients. METHOD: We prospectively enrolled 133 patients diagnosed with CCA in the 3rd Medical Clinic, Cluj Napoca, over a 4-year period (2005-2009). The QoL was evaluated by means of a QoL questionnaire (EORTC QLQ-C30). RESULTS: The mean age of the patients was 65 +/- 10.6 years: 55% were males. 71% of the patients had hilar tumor (Klatskin), 23% distal and 6% intrahepatic CCA (IH). Only 11.3% of the patients were eligible to receive curative treatment. The 1-year overall survival was 22.3 +/- 4.4% and the 2-year survival was 3.4 +/- 2.1%. The patients receiving metallic stents had better survival than those receiving plastic stents (40.4% vs 12.5% at 1 year, 9.1% vs 5.0% at 2 years, respectively). The 1-year survival was significantly improved for patients who underwent surgery plus adjuvant chemotherapy. The post therapy QoL demonstrated a less improvement in Klatskin tumor patients than in patients with other types of tumors. Endoscopic palliative therapy allowed a faster community reintegration, but with variable evolution. CONCLUSIONS: The highest 2-year survival rate was 5.5%. Slightly longer survival was recorded when chemotherapy was added and also after endoscopic placement of metallic stents. Endoscopic biliary decompression improved the QoL faster than surgery. PMID- 20922194 TI - Dosing 6-thioguanine in inflammatory bowel disease: expert-based guidelines for daily practice. AB - Conventional thiopurines are considered to be effective and safe in the treatment of inflammatory bowel disease (IBD) patients; unfortunately more than 50% of patients discontinue thiopurine therapy, mainly due to the development of intractable adverse events. In recent years, the use of 6-thioguanine has been proposed as an alternative thiopurine in IBD patients failing to tolerate or to respond to conventional thiopurine therapy. In this clinical review, we describe the rationale for 6-thioguanine therapy and discuss the reported hepatotoxicity of 6-thioguanine (especially nodular regenerative hyperplasia). We propose expert based guidelines for balanced treatment. PMID- 20922195 TI - Cyclic antibiotic therapy for diverticular disease: a critical reappraisal. AB - Different symptoms have been attributed to uncomplicated diverticular disease (DD). Poor absorbable antibiotics are largely used for uncomplicated DD, mainly for symptom treatment and prevention of diverticulitis onset. Controlled trials on cyclic administration of rifaximin in DD patients were evaluated. Four controlled, including 1 double-blind and 3 open-label, randomized studies were available. Following a long-term cyclic therapy, a significant difference emerged in the global symptoms score (range: 0-18) between rifaximin plus fibers (from 6 6.5 to 1-2) and fibers alone (from 6.7 to 2-3.8), although the actual clinically relevance of such a very small difference remains to be ascertained. Moreover, a similar global symptom score reduction (from 6 to 2.4) can be achieved by simply recommending an inexpensive high-fiber diet. Current data suggest that cyclic rifaximin plus fibers significantly reduce the incidence of the first episode of acute diverticulitis as compared to fibers alone (1.03% vs 2.75%), but a cost efficacy analysis is needed before this treatment can be routinely recommended. The available studies have been hampered by some limitations, and definite conclusions could not be drawn. The cost of a long-life, cyclic rifaximin therapy administered to all symptomatic DD patients would appear prohibitive. PMID- 20922196 TI - Clostridium difficile infection and liver disease. AB - The rates of the predominantly hospital acquired infection, Clostridium difficile, have increased throughout the world. Several risk factors and susceptible patient populations have been identified. Patients with pre-existing liver disease represent an important cohort; recent evidence suggests that Clostridium difficile infection (CDI) is associated with a worse outcome and increased health care costs. This review focuses on the epidemiology, risk factors, pathogenesis, treatment options and outcomes associated with CDI in patients with liver disease. PMID- 20922197 TI - World Gastroenterology Organisation Guideline. Hepatocellular carcinoma (HCC): a global perspective. PMID- 20922199 TI - An unusual cause of dysphagia: esophageal tuberculosis. AB - A 25-year old Indian exchange-student presented to our department with a three week history of dysphagia. Diagnostic evaluation by upper gastrointestinal endoscopy, endosonography and chest-CT revealed a tumor-suspect ulcerative lesion at the middle esophagus, and a mediastinal lymph node enlargement. Initial histopathological evaluation of multiple esophageal tissue biopsies showed an unspecific esophagitis without signs for malignancy. A positive T-spot (R) TB assay result, together with the bronchoscopic detection of a small exophytic lesion at the right main bronchus depicting caseating epitheloid cell granulomas, provided evidence for a tuberculous etiology of the esophageal tumor. Multiple further deep submucosal biopsies were needed to finally detect epitheloid cell granulomas in the esophageal lesion. Microbacteriological or molecular tests were negative for M. tuberculosis. Tuberculostatic treatment resulted in a good response with complete remission of the esophageal lesion and the mediastinal lymph node enlargement. Esophageal tuberculosis is rare in developed countries, and its possible presence deserves consideration particularly in patients at risk. PMID- 20922200 TI - Incomplete deployment of an expandable metallic stent in a patient with esophageal malignant stenosis. AB - The use of self expandable metallic stents (SEMS) in the palliation of dysphagia due to malignant esophageal stenosis is a gold standard. Covered stents are used in all cases with overt air-digestive fistula or high potential for fistula development. The procedure is associated with a low incidence of procedure related complications. We present a case with a major accident which developed during stent deployment. The delivery system became blocked and we found it impossible to fully deploy the stent, which remained attached to the introductory system. The stent was forcefully removed and replaced later on with a new stent. This is the first report of a SEMS related accident due to malfunction of the stent deployment system. Stent malfunction is unusual and unlikely to happen, but one should be aware and prepared for such unusual situations. PMID- 20922201 TI - Rapid recovery of a rectovaginal fistula with infliximab in a patient with Crohn's disease. AB - We present the case of a female patient diagnosed with colonic Crohn's disease, having a clinical evolution with many recurrences and in whom conventional therapy had failed. The patient was admitted in our department 4 years after the onset of the disease, with an altered general state, diarrhea, malnutrition, fever and fecaloid vaginal discharge. Investigations classified the patient in a severe activity flare of Crohn's disease (CDAI 329), complicated with a rectovaginal fistula. Infliximab therapy was initiated. The evolution was rapidly favorable and the fistula closed after 4 weeks of therapy. PMID- 20922202 TI - Acute spontaneous chylous peritonitis: report of a case. AB - Acute abdominal pain with peritonitis due to sudden extravasation of lymph into the peritoneal cavity is a rare condition that is often mistaken for other causes of acute abdomen. The diagnosis of spontaneous chylous peritonitis is rarely suspected preoperatively, usually misdiagnosed with diverse common surgical emergencies. We report the case of an 81 year old female who presented with typical symptoms of acute abdomen, presumed as acute mesenteric ischemia. The diagnosis of chylous peritonitis was established during laparoscopy and treatment consisted of low fat diet and octreotide. PMID- 20922203 TI - Ranitidine induced hepatitis. PMID- 20922204 TI - More on serum markers of liver fibrosis:are they still clinically limited? PMID- 20922205 TI - Is it untrue that ultrasonography guidance is superior to the blind method for liver biopsy? PMID- 20922208 TI - Primary neuroendocrine tumor of the extrahepatic biliary tree mimicking Klatskin tumor. PMID- 20922209 TI - Emergence of Crohn's disease in juvenile idiopathic arthritis during treatment with etanercept: a causal link or a mere coincidence? PMID- 20922210 TI - TiO2 and SnO2@TiO2 hollow spheres assembled from anatase TiO2 nanosheets with enhanced lithium storage properties. AB - TiO(2) and SnO(2)@TiO(2) hollow spheres assembled from anatase TiO(2) nanosheets with exposed (001) high-energy facets are constructed via a templating approach, and the as-prepared samples exhibit enhanced lithium storage properties. PMID- 20922211 TI - A versatile gold synthon for acetylene C-H bond activation. AB - The reaction of N,N'-bis(2,6-diisopropylphenyl)imidazol-2-ylidene gold hydroxide ([Au(OH)(IPr)]; 1) with acetylene and trimethylsilylacetylene derivatives cleanly leads to the formation of a gold-acetylide bond with the concomitant formation of water or trimethylsilanol. All compounds were isolated in high yield (>85%). The crystal structures of selected gold acetylides in conjunction with their UV-vis absorption/emission properties were investigated. Finally, DFT calculations were performed in an attempt to gain an insight into the mechanism of the general reaction. PMID- 20922212 TI - Genome-wide analysis of eukaryotic twin CX9C proteins. AB - Twin CX(9)C proteins are eukaryotic proteins that derive their name from their characteristic motif, consisting of two pairs of cysteines that form two disulfide bonds stabilizing a coiled coil-helix-coiled coil-helix (CHCH) fold. The best characterized of these proteins are Cox17, a copper chaperone acting in cytochrome c oxidase biogenesis, and Mia40, the central component of a system for protein import into the mitochondrial inter-membrane space (IMS). However, the range of possible functions for these proteins is unclear. Here, we performed a systematic search of twin CX(9)C proteins in eukaryotic organisms, and classified them into groups of putative homologues, by combining bioinformatics methods with literature analysis. Our results suggest that the functions of most twin CX(9)C proteins vary around the common theme of playing a scaffolding role, which can tie their observed roles in mitochondrial structure and function. This study will enhance the present annotation of eukaryotic proteomes, and will provide a rational basis for future experimental work aimed at a deeper understanding of this remarkable class of proteins. PMID- 20922214 TI - Preparation of large thermally stable platinum nanocubes by using solvent-thermal reaction. AB - We describe the synthesis of single-crystalline Pt nanocubes with a large diameter (around 35 nm) using a solvent-thermal reaction in a polarity-controlled mixture of 1-butanol, toluene, and N,N-dimethylformamide at 185 degrees C. PMID- 20922213 TI - Impact of linker length on the activity of PROTACs. AB - Conventional genetic approaches have provided a powerful tool in the study of proteins. However, these techniques often preclude selective manipulation of temporal and spatial protein functions, which is crucial for the investigation of dynamic cellular processes. To overcome these limitations, a small molecule-based novel technology termed "PROteolysis TArgeting ChimeraS (PROTACs)" has been developed, targeting proteins for degradation at the post-translational level. Despite the promising potential of PROTACs to serve as molecular probes of complex signaling pathways, their design has not been generalized for broad application. Here, we present the first generalized approach for PROTAC design by fine-tuning the distance between the two participating partner proteins, the E3 ubiquitin ligase and the target protein. As such, we took a chemical approach to create estrogen receptor (ER)-alpha targeting PROTACs with varying linker lengths and the loss of the ER in cultured cells was monitored via western blot and fluorometric analyses. We found a significant effect of chain length on PROTAC efficacy, and, in this case, the optimum distance between the E3 recognition motif and the ligand was a 16 atom chain length. The information gathered from this experiment may offer a generalizable PROTAC design strategy to further the expansion of the PROTAC toolbox, opening new possibilities for the broad application of the PROTAC strategy in the study of multiple signaling pathways. PMID- 20922215 TI - Towards preparative-scale, biocatalytic alkene reductions. AB - Simple strategies for using alkene reductase enzymes to produce gram-scale quantities of both (R)- and (S)-citronellal have been developed. The methodology is easily accessible to non-specialist laboratories, allowing alkene reductases to be added to the toolbox of routine synthetic transformations. PMID- 20922216 TI - Large scale lithography-free nano channel array on polystyrene. AB - This paper reports a new fabrication method of lithography-free nanochannel array. It is based on the cracking process on the surface of a polystyrene (PS) Petri-dish, one type of thermoplastic that is composed of uni-axial macromolecular chains. Under proper conditions, parallel nanochannels with equal interspaces are obtained. Control over the channel depth from 20 nm to 200 nm is achieved, with the channel length reaching tens of millimetres. The PDMS replication based on PS nanochannel array has been successfully carried out. In combination with the microstructure, both an ion enrichment device and a current rectification device are fabricated, and their quantified characters manifested the applicability of the channel array structure in nanofluidics. PMID- 20922217 TI - Natural sesquiterpenoids. PMID- 20922218 TI - Bioprospecting for antituberculosis leads from microbial metabolites. PMID- 20922219 TI - Energetic features of copper and lead sorption by innovative aminoalcohol functionalized cobalt phyllosilicates. AB - Inorganic-organic cobalt phyllosilicate hybrids were synthesized by the sol-gel procedure under mild non-hydrothermal conditions with a silicon precursor, formed through individual reactions between the silane 3-glycidoxypropyltriethoxysilane and the aminoalcohols ethanol- or diethanolamine. These procedures generated talc like phyllosilicates containing pendant organic chains with nitrogen and oxygen basic centres located in the interlamellar region. For organofunctionalized phyllosilicates the lamellar structure obtained through the sol-gel method was confirmed by X-ray powder diffraction, while elemental analysis indicated that the densities of the organic groups attached to the new matrices were 3.31 +/- 0.05 and 3.08 +/- 0.07 mmol g(-1) for hybrids functionalized with ethanol- and diethanolamines, respectively. Infrared spectroscopy and nuclear magnetic resonance in the solid state for (13)C and (29)Si showed that the organic groups are indeed covalently bonded to the inorganic structures and the process of functionalization did not affect the original structures of the silylating agents employed. The thermally stable hybrids presented well-formed particles with a homogeneous distribution of cobalt and nitrogen atoms. Their abilities for copper removal from aqueous solutions gave maximum capacities of sorption of 2.01 +/- 0.11 and 2.55 +/- 0.15 mmol g(-1) for phyllosilicates containing ethanol- and diethanolamine groups, respectively. For lead sorption the values of 2.59 +/- 0.11 and 2.43 +/- 0.12 mmol g(-1) were found for this same sequence. These sorption data were adjusted to the non-linear regression of the Langmuir equation. Energetic features related to the interactions between the cations and the pendant basic centres were determined through calorimetric titrations. The acid-basic interactions reflect the spontaneity of the reactions, which are also enthalpically and entropically favourable for these chelating processes at the solid-liquid interface. PMID- 20922225 TI - Cerium-based triple-stranded helicates as luminescent chemosensors for the selective sensing of magnesium ions. AB - Cerium-based triple-strand helicates Ce-CL(1) and Ce-CL(2) were achieved via self assembly from malonohydrazone derived bis-tridentate ligands H(2)CL(1) and H(2)CL(2), respectively. Structure analysis of Ce-CL(1) shows that six oxygen atoms of the beta-diketone groups on the ligands form a lantern-like cavity inside the helicate. Thus the helicates exhibit crown ether recognition behaviors and could work as luminescent magnesium chemosensors. The restricted geometry constraints of the internal cavities provide high selectivities of the helical probes towards Mg(2+) ion over other alkaline and alkaline-earth ions such as Li(+), Na(+), K(+), Ca(2+) and Ba(2+). PMID- 20922220 TI - Synthesis, DNA binding, photo-induced DNA cleavage and cytotoxicity studies of europium(III) complexes. AB - Two Eu(III) complexes, [Eu(acac)(3)(dpq)] (1) and [Eu(acac)(3)(dppz)] CH(3)OH (2) {viz. acetylacetonate (acac), dipyrido[3,2-d:20,30-f]quinoxaline (dpq), dipyrido[3,2-a:20,30-c] phenazine (dppz)}, have been synthesized and their DNA binding, photo-induced DNA cleavage activity and cell cytotoxicity are studied. The complexes display significant binding propensity to the calf thymus DNA in the order: 2(dppz) >1(dpq). Cleavage experiments using pBR322 supercoiled DNA suggest major groove binding for 2 and minor groove binding for 1. The mechanistic aspects on natural light (natural light in room during the day) and UV-A (365 nm) irradiation are via a mechanistic pathway involving formation of singlet oxygen and hydroxyl radical as the reactive species. The photo-induced DNA cleavage activity of 2 is also stronger than 1. The cytotoxicity of 1 and 2 against HeLa (cervical) cancer cells show that the IC(50) value of 19.11 +/- 3.56 MUM and 17.95 +/- 5.47 MUM, respectively. PMID- 20922226 TI - Enhanced mixing of droplets during coalescence on a surface with a wettability gradient. AB - We investigated the dynamics of head-on collisions between a moving droplet and a stationary droplet on a surface with a wettability gradient. The mixing of fluids is achieved passively through convective mass transfer caused by the release of surface energy during coalescence, and also through diffusive mass transfer. The coalescence dynamics were visualized with a high-speed camera; the internal flow patterns were resolved with measurement of micro-PIV (particle image velocimetry). The results show that the released surface energy creates a pair recirculation flow inside the merged droplet when the stationary droplet is placed near the gradient, whereas most released surface energy is converted into oscillation when the stationary droplet is far from the gradient. This distinction is attributed to the motion of the contact line during coalescence. The mixing of fluorescently labeled oligonucleotides in these two modes is revealed with confocal micro-laser induced fluorescence technique. The results of 3D scans demonstrate that the motion of the contact line during coalescence distributes the fluids in a complicated manner, thus beneficial for mixing. This mechanism of enhanced mixing is applicable also for platforms other than a surface with a wettability gradient; prospective applications include improving the mixing of biochemical fluids. PMID- 20922227 TI - Cu(I)-containing room temperature ionic liquids as selective and reversible absorbents for propyne. AB - A Cu(i)-containing room temperature ionic liquid (Cu-RTIL), prepared from CuCl and 1,3-dimethylimidazolium methylphosphite ([DMIM][MeHPO(3)]), was found to reversibly and selectively interact with propyne over propylene. Cu-RTIL exhibited 12 times higher propyne absorption capacity and 14 times higher ideal propyne/propylene selectivity than [DMIM][MeHPO(3)]. Fast atom bombardment (FAB) mass spectral and computational results with Cu-RTIL (CuCl/[DMIM][MeHPO(3)] = 1/2) strongly imply that the Cu-RTIL contains stable methylphosphite-coordinated anionic Cu(i) species such as CuCl(MeHPO(3))(-) and Cu(MeHPO(3))(2)(-). Computational studies on the optimized structures demonstrate that the preferential absorption of propyne over propylene in a Cu-RTIL originates from the difference in the interaction mode between the coordinated phosphite ligand and propyne or propylene. Strong pi-complexation of propylene and propyne with Cu in Cu-RTIL is not observed. PMID- 20922228 TI - Tandem driven dynamic self-inhibition of acetylcholinesterase. AB - A concept of tandem driven dynamic self-inhibition is demonstrated through dynamic inhibitors of acetylcholinesterase (AChE) using reversible transthiolesterification. PMID- 20922229 TI - Amplification of chirality in N,N'-1,2-ethanediylbisbenzamides: from planar sheets to twisted ribbons. AB - A remarkable sergeants-and-soldiers effect is observed in the coassembly of N,N' 1,2-ethanediylbisbenzamides onto surfaces that experience an amplification of chirality able to transform flat lamellae into twisted ribbons. PMID- 20922230 TI - Perylene bisimide macrocycles and their self-assembly on HOPG surfaces. AB - Acetylene-linked macrocycles incorporating multiple perylene tetracarboxylic acid bisimide (PBI) chromophores have been synthesised and separated by recycling GPC. The very first example of such macrocycles, i.e., cyclic trimer 5, containing three PBI dyes self-assembles into highly ordered donut-shaped unique hexagonal nanopatterns on HOPG surfaces as revealed by atomic force microscopy (AFM). PMID- 20922231 TI - Novel interstrand communication systems within DNA duplexes based on 1-, 2- and 4 (phenylethynyl)pyrenes attached to 2'-amino-LNA: high-affinity hybridization and fluorescence sensing. AB - Functionalisation of 2'-amino-LNA oligonucleotides with 1-, 2- and 4 (phenylethynyl)pyrene fluorophores via a carbonyl linker (PEPyc) resulted in efficient interstrand communication systems in nucleic acid duplexes, providing effective tools for stabilization of nanostructures and fluorescence monitoring of DNA self-assembly. PMID- 20922232 TI - On the route to mimic natural movements: synthesis and photophysical properties of a molecular arachnoid. AB - The synthesis, photoswitchability and NIR emitting properties of a novel pi extended pyrene derivative, peripherally decorated with four azobenzenyl-ethynyl legs, are reported. PMID- 20922233 TI - Dramatic lithium chloride effect on the reaction stereocontrol in Zn-mediated asymmetric cinnamylation: highly practical synthesis of beta-aryl homoallylic amines. AB - An extremely mild and practical approach for the preparation of enantiomerically enriched beta-aryl substituted homoallylic amines bearing two adjacent stereogenic centers was realized by room temperature zinc-mediated highly stereoselective cinnamylation of N-sulfinyl imines. PMID- 20922234 TI - Ultrafine tin nanocrystallites encapsulated in mesoporous carbon nanowires: scalable synthesis and excellent electrochemical properties for rechargeable lithium ion batteries. AB - A morphology-conserved transformation yields Sn@C nanowires (UTP@CW, ~21 wt% carbon and ~77 wt% tin) with a high encapsulation density of ultrafine tin nanoparticles in porous carbon nanowires, which exhibit excellent reversible capacities and cycling performance for lithium ion batteries, especially at high current rates. PMID- 20922235 TI - Bismuth- and lead-texaphyrin complexes: towards potential alpha-core emitters for radiotherapy. AB - Lead(II)-texaphyrins and the first discrete binuclear MU-oxo bismuth(III) texaphyrin are reported. The latter was characterized via single crystal X-ray diffraction analysis. Cell proliferation assays using the A2780 ovarian cancer cell line were used to determine the cytotoxicity of the complexes. PMID- 20922236 TI - NMR studies into colloidal stability and magnetic order in fatty acid stabilised aqueous magnetic fluids. AB - We report the physico-chemical characterisation of fatty acid stabilised aqueous magnetic fluids, which are ideal systems for studying the influence of nanoparticle aggregation on the emergent magnetic resonance properties of the suspensions. Stable colloids of superparamagnetic magnetite, Fe(3)O(4), nanoparticle clusters in the 80 to 100 nm size range were produced by in situ nanoparticle growth and stabilisation, and by suspending pre-formed nanoparticles. NMR relaxation analysis shows that the magnetic resonance properties of the two types of suspension differ substantially and provides new insights into how the relaxation mechanisms are determined by the organisation of the nanoparticles within the clusters. PMID- 20922237 TI - Conformational transitions of glycine induced by vibrational excitation of the O H stretch. AB - Vibrational energy flow and conformational transitions following excitation of the OH stretching mode of the most stable conformer of glycine are studied by classical trajectories. "On the fly" simulations with the PM3 semiempirical electronic structure method for the potential surface are used. Initial conditions are selected to correspond to the nu=1 excitation of the OH stretch. The main findings are: (1) An an equilibrium-like ratio is established between the populations of the 3 lowest-lying conformers after about 10 picoseconds. (2) There is a high probability throughout the 150 ps of the simulations for finding the molecule in geometries far from the equilibrium structures of the lowest energy conformers. (3) Energy from the initial excited OH (nu=1) stretch flows preferentially to 5 other vibrational modes, including the bending motion of the H atom. (4) RRK theory yields conformational transition rates that deviate substantially from the classical trajectory results. Possible implication of these results for vibrational energy flow and conformational transitions in small biological molecules are discussed. PMID- 20922238 TI - Synthesis, X-ray crystal structures, thermal and electrochemical properties of thiosemicarbazidatodioxouranium(VI) complexes. AB - The stable uranyl complexes, [UO(2)(L)C(9)H(19)OH], were obtained from 3,5 dichlorosalicyl-(L(I)) and salicyl-aldehyde-S-propyl-thiosemicarbazones (L(II)) with substituted-salicylaldehyde in nonyl alcohol. The structures of the complexes have been characterized by elemental analysis, IR, (1)H NMR, conductivity, magnetic moment measurements, cyclic voltammetry, thermal gravimetric analysis and single crystal X-ray diffraction technique. The U(VI) centre is seven-coordinated in a distorted pentagonal bipyramidal geometry. The relative orientations of the nonyl alcohol and S-propyl group in the title complexes are completely different due to different crystal packing. Electrochemical behaviors of the thiosemicarbazone ligands and the uranyl complexes were studied using cyclic voltammetry and square wave voltammetry. Redox processes of the compounds are significantly influenced by the central metal ions and the nature of substituents on the thiosemicarbazones, which are important factors in controlling the redox properties. In situ spectroelectrochemical studies were employed to determine the colors and spectra of electro-generated species of the complexes. PMID- 20922239 TI - Structural and electronic properties of luminescent copper(I) halide complexes of bis[2-(diphenylphosphano)phenyl] ether (DPEphos). Crystal structure of [CuCl(DPEphos)(dmpymtH]. AB - Heteroleptic copper(I) halide complexes containing the bis[2 (diphenylphosphano)phenyl]ether (DPEphos) ligand and the heterocyclic thioamides pyridine-2(1H)-thione (py2SH), pyrimidine-2(1H)-thione (pymtH) or 4,6 dimethylpyrimidine-2(1H)-thione (dmpymtH) have been synthesized and characterized by (1)H-NMR, IR spectroscopy, elemental analyses and melting point determinations. The complexes can be readily obtained by the addition of the thione ligand to a CuX-diphosphane adduct in dichloromethane-ethanol solution. The molecular structure of [CuCl(DPEphos)(dmpymtH)] complex has been established by single-crystal X-ray diffraction. The structure features a tetrahedral copper(I) center with two phosphorus atoms from the chelating diphos ligand, one halogen atom and the exocyclic sulfur atom of the heterocyclic thioamide unit. The complexes are strongly emissive in the solid state at ambient temperature. DFT and TD-DFT calculations were employed to study the structural, electronic and photophysical properties of the novel complexes. Electronic absorption spectra show two broad bands in the regions 275-290 and 380-398 nm of mixed MLCT/IL character. Intense blue-green emission is observed in the region 500-558 nm for complexes having py2SH or dmpymtH thione ligands. The emitting first triplet excited state, T(1) is mainly localized on the thione ligand. PMID- 20922240 TI - Hydride ion-carrier ability in Rh(I) complexes of a nicotinamide-functionalised N heterocyclic carbene ligand. AB - (Spectro-)electrochemical results demonstrate ligand-centred hydride ion-carrier capacity for a Rh(I) complex of a novel 'non-innocent' N-heterocyclic carbene ligand created by nicotinamide functionalisation. PMID- 20922241 TI - Improved dehydrogenation properties of Ca(BH4)2-LiNH2 combined system. AB - Ca(BH(4))(2)-LiNH(2) combined system is shown to release hydrogen at much lower temperature compared to the pure Ca(BH(4))(2). The improved dehydrogenation in this system can be ascribed to a combination reaction between [BH(4)] and [NH(2)] based on the reaction mechanism of positive H and negative H. PMID- 20922242 TI - Syntheses and structures of copper(I) complexes based on Cu(n)X(n) (X = Br and I; n = 1, 2 and 4) units and bis(pyridyl) ligands with longer flexible spacer. AB - Self-assembly of four bis(pyridyl) ligands with longer flexible spacer: 1,4-bis(3 pyridylaminomethyl)benzene (L1), 1,4-bis(2-pyridylaminomethyl)benzene (L2), 1,3 bis(3-pyridylaminomethyl)benzene (L3) and 1,3-bis(2-pyridylaminomethyl)benzene (L4), and CuX (X = Br and I) leads to the formation of eight [Cu(n)X(n)]-based (X = Br and I; n = 1, 2, and 4) complexes, [Cu(2)I(2)L1(PPh(3))(4)] (1), [Cu(4)Cl(2)Br(2)(L4)(2)(PPh(3))(6)].(CH(3)CN)(2) (2), [Cu(2)I(2)(L3)(2)] (3), {[Cu(2)Br(2)L2(PPh(3))(2)].(CH(2)Cl(2))(2)}(n) (4), [CuIL1](n).nCH(2)Cl(2) (5), [CuIL1](n) (6), [CuIL4](n) (7) and [Cu(2)I(2)L4](n) (8), which have been synthesized and characterized by elemental analysis, IR, TG, powder and single crystal X-ray diffraction. Structural analyses show that the eight complexes possess an increasing dimensionality from 0D (1-3) to 1D (4) to 2D (5-8), in which 1 and 2 contain a CuX unit, 2-7 contain a Cu(2)X(2) unit and 8 contains a Cu(4)X(4) unit. Such evolvement indicates that the conformation of flexible bis(pyridyl) ligands and the participation of triphenylphosphine (PPh(3)) as a second ligand take an essential role in the framework formation of the Cu(i) complexes. Moreover, a pair of symmetry-related L3 ligands in complex 3 coordinate to the rhomboid Cu(2)I(2) dimer to form "handcuff-shaped" dinuclear structures, which are further joined together through intermolecular N-HI hydrogen bonds to furnish a 2D (4,4) layer. Although complexes 5 and 6 exhibit a similar 2D (4,4) layer constructed from L1 ligand bridging [Cu(2)I(2)](n) units, the different packing fashion of the layers leads to the formation of 3D porous frameworks of 5 and dense 3D frameworks of 6. The "twisted-boat" conformation of the Cu(4)I(4) tetramer unit in complex 8 has not been reported so far. PMID- 20922243 TI - Insights into the control of magnetic coupling in the Mn4(III) complex: from ferromagnetic to antiferromagnetic. AB - Magnetic coupling interactions of a Mn(III)(4) system are investigated by calculations based on density functional theory combined with a broken-symmetry approach (DFT-BS). Three different interactions including ferromagnetic and antiferromagnetic coupling are concomitant in this complex. This magnetic phenomenon of the complex is due to the different bridging angles between the Mn(III) centers in the three different models and the orbital complementarity of the MU-pzbg and MU-OCH(3) bridging ligands, which is proven by the analyses of the molecular orbitals. According to the analyses of the magneto-structural correlation, it is revealed that the magnetic coupling interaction switches from ferromagnetic to antiferromagnetic at the point of the bridging angle Mn-(MU OCH(3))-Mn = 99 degrees , which is equal to the value in the origin crystal. Significant correlation between the magnetic properties and the component of the d orbitals in these systems shows that the larger contribution of the d(z(2)) orbital corresponds to the larger ferromagnetic coupling interaction. These results should provide a means to control the magnetic coupling of the polynuclear Mn systems, which is instructive for the design of new molecular magnetic materials. PMID- 20922244 TI - Complex formation between Ru(eta(6)-p-cym)(H2O)3]2+ and (O,O) donor ligands with biological relevance in aqueous solution. AB - The interaction between [Ru(eta(6)-p-cym)(H(2)O)(3)](2+) and (O,O) type chelators with different basicity of the donor atoms was studied using combined pH potentiometric, (1)H-NMR and ESI-TOF-MS techniques. The studied nine ligands are building blocks of reported complexes with antitumor activity or may model (O,O) donor serum components capable of interacting with the administered half-sandwich ruthenium(II) type drug. Composition and stability constants of the [Ru(eta(6)-p cym)(O,O)Y] type species (Y: H(2)O or OH(-)) were determined (T = 25.0 degrees C; I = 0.20 M (KCl)) and the metal ion binding strengths of the ligands are discussed. It was found that ligands with two low basicity O donors (oxalic and cyclobutane-1,1-dicarboxylic acid) bind the metal ion at acidic conditions but are not able to prevent the hydrolysis at physiologically relevant conditions. Ligands with one low and one high basicity O donor (lactic and salicylic acid) are weak binders for Ru(eta(6)-p-cym)(H(2)O)(3)](2+). Pyrone or pyridinone based ligands are capable of binding the metal ion over a wide pH range and no hydrolysis product is detectable at pH = 7.4. The obtained speciation models may help in the rationalization of the biological activity of such complexes and provide a deeper insight into the solution behaviour of half-sandwich Ru(II) complexes with potential anticancer activity. PMID- 20922245 TI - Sonochemical synthesis of Ce(1-x)Fe(x)O(2-delta) (0 <= x <= 0.45) and Ce(0.65)Fe(0.33)Pd(0.02)O(2-delta) nanocrystallites: oxygen storage material, CO oxidation and water gas shift catalyst. AB - Nanocrystalline Ce(1-x)Fe(x)O(2-delta) (0 <= x <= 0.45) and Ce(0.65)Fe(0.33)Pd(0.02)O(2-delta) of ~4 nm sizes were synthesized by a sonochemical method using diethyletriamine (DETA) as a complexing agent. Compounds were characterized by powder X-ray diffraction (XRD), X-ray photo electron spectroscopy (XPS) and transmission electron microscopy (TEM). Ce(1 x)Fe(x)O(2-delta) (0 <= x <= 0.45) and Ce(0.65)Fe(0.33)Pd(0.02)O(2-delta) crystallize in fluorite structure where Fe is in +3, Ce is in +4 and Pd is in +2 oxidation state. Due to substitution of smaller Fe(3+) ion in CeO(2), lattice oxygen is activated and 33% Fe substituted CeO(2)i.e. Ce(0.67)Fe(0.33)O(1.835) reversibly releases 0.31[O] up to 600 degrees C which is higher or comparable to the oxygen storage capacity of CeO(2)-ZrO(2) based solid solutions (Catal. Today 2002, 74, 225-234). Due to interaction of redox potentials of Pd(2+/0)(0.89 V) and Fe(3+/2+) (0.77 V) with Ce(4+/3+) (1.61 V), Pd ion accelerates the electron transfer from Fe(2+) to Ce(4+) in Ce(0.65)Fe(0.33)Pd(0.02)O(1.815), making it a high oxygen storage material as well as a highly active catalyst for CO oxidation and water gas shift reaction. The activation energy for CO oxidation with Ce(0.65)Fe(0.33)Pd(0.02)O(1.815) is found to be as low as 38 kJ mol(-1). Ce(0.67)Fe(0.33)O(1.835) and Ce(0.65)Fe(0.33)Pd(0.02)O(1.815) have also shown high activity for the water gas shift reaction. CO conversion to CO(2) is 100% H(2) specific with these catalysts and conversion rate was found to be as high 27.2 MUmoles g(-1) s(-1) and the activation energy was found to be 46.4 kJ mol( 1) for Ce(0.65)Fe(0.33)Pd(0.02)O(1.815). PMID- 20922246 TI - Binding of H+ and Zn(II) ions with a new fluorescent macrocyclic phenanthrolinophane. AB - The new macrocyclic ligand 1,9(4,7)-diphenanthroline-3,7,11,15 tetraazacyclohexadecaphane (L) was synthesized by a 2 : 2 reaction of 1,10 phenanthroline-4,7-dialdehyde with 1,3-diaminopropane, followed by reduction with NaBH(4). L contains two phenanthroline groups linked together by two 1,3 diaminopropane chains in such a way that the heteroaromatic nitrogen atoms point outside the ligand cavity. The ligand structure defines two pairs of identical compartments displaying a specific ability in the binding of protons (1,3 diaminopropane) and metal ions (phenanthroline). Protonation and Zn(II) coordination were studied by means of potentiometric and spectroscopic ((1)H NMR, UV-vis, fluorescence) techniques. Both protonation and Zn(II) coordination consistently affect the fluorescence emission properties of L, giving rise to enhancement or quenching of the emission, depending on the species involved. L becomes emissive upon protonation, but the formation of the highly protonated species, in particular the fully protonated [H(6)L](6+), quenches the emission. The mono- and dinuclear Zn(II) complexes of the unprotonated ligand are non emissive, like free L, while Zn(II) binding to [HL](+) activates the emission. The most interesting aspect, however, is the chelation enhancement of quenching (CHEQ) observed upon Zn(II) binding to [H(2)L](2+) and [H(4)L](4+), being among the few examples of CHEQ effect observed for Zn(II) complexes. Hydrogen bonding between a metal coordinated water molecule and a phenanthroline group seems to be responsible for the CHEQ observed for [ZnH(2)L](4+). PMID- 20922247 TI - Gold- and silver-based ionic liquids: modulation of luminescence depending on the physical state. AB - A series of gold- and silver-containing ionic liquids, [C(n)MIM][M(CN)(2)] (M = Au, Ag; n = 12, 14, 18), prepared by metathesis reactions, present luminescence depending on their physical state i.e. crystalline or smectic A phases. The photoluminescent measurements as well as DFT calculations suggest that the modulation of aurophilic intermolecular interactions are responsible for this phosphorescent behaviour. PMID- 20922248 TI - A unique single carboxylate-bridged spin-frustrated chiral Mn(II) metallatriangle. AB - The reaction between Hmbpymca ligand (prepared in situ from the hydrolysis of 5 methyl-4-cyano-bispyrimidine with NaOH and further neutralization with 2 M HCl) and Mn(ClO(4))(2).4H(2)O in 1:1 molar ratio afforded the triangulo trimanganese(II) complex [Mn(3)(bpymca)(3)(H(2)O)(6)]Cl(3).6H(2)O 1. The chloride anions in this complex come from the HCl used in the neutralization process. The molecular structure of 1 consists of cationic molecular triangles [Mn(3)(MU mbpymca)(3)(H(2)O)(6)](3+) with C(3) symmetry, chloride anions and crystallization water molecules, all of them involved in an extensive network of hydrogen bonds, leading to a chiral network. Within the [Mn(3)(MU mbpymca)(3)(H(2)O)(6)](3+) cations, seven-coordinated Mn(II) ions are bridged by both oxygen atoms of the carboxylate groups and exhibit a MnO(5)N(2) compressed pentagonal bipyramidal coordination environment. The temperature dependence of the magnetic susceptibility shows the presence of weak antiferromagnetic interactions between Mn(II) ions mediated by the carboxylate group of the mbpymca ligand and the existence of a 3D antiferromagnetic ordering below 4 K, which has its origin in the AF inter-trimer exchange interactions mediated by the strong hydrogen bonds present in the crystal of 1. The experimental magnetic susceptibility data above 7 K could be satisfactorily fitted to the theoretical analytical expression derived from the spin Hamiltonian H = -J(S(1)S(2) + S(1)S(3) + S(2)S(3)) with J = -0.782(3) cm(-1) and g = 2.092(3). The model predicts a degenerate ground state with an S = 1/2, which is typical of triangular trimetallic spin frustrated systems containing metal with non-integer spins. DFT calculations were performed on the molecular structure as found in the solid state to support the experimental J value and the Mn-O(carb)-Mn as the primarily exchange pathway. PMID- 20922249 TI - Rational synthesis of chiral layered magnets by functionalization of metal simple hydroxides with chiral and non-chiral Ni(II) Schiff base complexes. AB - Synthesis of new heterometallic layered magnets with controlled chirality have been achieved by insertion of chiral and non-chiral salen-type Ni(II) complexes into copper and cobalt layered simple hydroxides. PMID- 20922250 TI - On the nature of the transition metal-main group metal bond: synthesis and theoretical calculations on iridium gallyl complexes. AB - The iridum-gallyl complex MeIr(PCy(3))(2)(GaMe(2))(Cl*GaMe(3)) exhibits a short Ir-Ga bond length of 2.381(1)-2.389(2) A. Theoretical calculations (ZORA BP86/TZ2P) support the presence of a Ir-Ga single bond but highlight a pi orbital contribution. PMID- 20922251 TI - Blue light induced A2E oxidation in rat eyes--experimental animal model of dry AMD. AB - Previous studies have shown that short-wavelength blue visible light induces retinal injury and may be a risk factor for age related macular degeneration. A2E is a blue light absorbing retinal chromophore that accumulates with age. Our previous in vitro studies have determined that, although A2E itself has a low phototoxic efficiency, the oxidation products of A2E that are formed in the presence of visible light can contribute to observed retinal pigment epithelial photodamage. The purpose of this study was to investigate the effects of blue light on retinal phototoxicity and its relationship to A2E, oxidized A2E and its isomers. Sprague-Dawley albino rats were dark adapted for 24 h. Control rats remained in the dark while experimental rats were exposed to blue light (lambda = 450 nm, 3.1 mW cm(-2)) for 6 h. Isolated retinas were homogenized in Folch extraction mixture and then in chloroform. The dried extracts were reconstituted and divided for determination of organic soluble compound. Esters of fatty acids were determined with GC-MS, A2E and other chromophores using HPLC, and A2E oxidation products with LC-MS. Exposure of rat eyes to blue light did not significantly change the fatty acid composition of the retina. The A2E concentration (normalized to fatty acid content) in blue light exposed animals was found to be lower than the A2E concentration in control rats. The concentrations of all-trans-retinal-ethanolamine adduct and iso-A2E a precursor and an isomer of A2E respectively, were also lower after blue-light exposure than in the retinas of rats housed in the dark. On the other hand, the amount of oxidized forms of A2E was higher in the animals exposed to blue light. We conclude that in the rat eye, blue-light exposure promotes oxidation of A2E and iso-A2E to the products that are toxic to retinal tissue. Although high concentrations of A2E may be cytotoxic to the retina, the phototoxicity associated with blue light damage to the retina is in part a result of the formation of toxic A2E oxides. This effect may partially explain the association between blue light induced retinal injury and macular degeneration. PMID- 20922252 TI - Mechanism of photooxidation of folic acid sensitized by unconjugated pterins. AB - Folic acid, or pteroyl-l-glutamic acid (PteGlu), is a precursor of coenzymes involved in the metabolism of nucleotides and amino acids. PteGlu is composed of three moieties: a 6-methylpterin (Mep) residue, a p-aminobenzoic acid (PABA) residue, and a glutamic acid (Glu) residue. Accumulated evidence indicates that photolysis of PteGlu leads to increased risk of several pathologies. Thus, a study of PteGlu photodegradation can have significant ramifications. When an air equilibrated aqueous solution of PteGlu is exposed to UV-A radiation, the rate of the degradation increases with irradiation time. The mechanism involved in this "auto-photo-catalytic" effect was investigated in aqueous solutions using a variety of tools. Whereas PteGlu is photostable under anaerobic conditions, it is converted into 6-formylpterin (Fop) and p-aminobenzoyl-l-glutamic acid (PABA-Glu) in the presence of oxygen. As the reaction proceeds and enough Fop accumulates in the solution, a photosensitized electron-transfer process starts, where Fop photoinduces the oxidation of PteGlu to Fop, and H(2)O(2) is formed. This process also takes place with other pterins as photosensitizers. The results are discussed with the context of previous mechanisms for processes photosensitized by pterins, and their biological implications are evaluated. PMID- 20922253 TI - Selective hydrophobic pocket binding observed within the carbonic anhydrase II active site accommodate different 4-substituted-ureido-benzenesulfonamides and correlate to inhibitor potency. AB - 4-Substituted-ureido benzenesulfonamides showing inhibitory activity against carbonic anhydrase (CA, EC 4.2.1.1) II between 3.3-226 nM were crystallized in complex with the enzyme. Hydrophobic interactions between the scaffold of the inhibitors in different hydrophobic pockets of the enzyme were observed, explaining the diverse inhibitory range of these derivatives. PMID- 20922254 TI - Modular approach to functional hyaluronic acid hydrogels using orthogonal chemical reactions. AB - A modular approach for the synthesis of hyaluronic acid hydrogels using orthogonal chemoselective reactions for subsequent enzymatic decomposition to nanoparticles is described. PMID- 20922255 TI - The use of artificial neural networks to forecast biological atmospheric allergens or pathogens only as Alternaria spores. AB - The monitoring of atmospheric Alternaria spores is of major importance due to their adverse effects on crops and their role as human allergens. Most species act as plant pathogens, prompting considerable economic losses worldwide on important crops such as potato, tomato or wheat. Fungal spores can also have serious detrimental effects on human health, triggering respiratory diseases and allergenic processes. The aim of this study was not only to examine the relationship between the atmospheric Alternaria spore content and the prevailing meteorological parameters, but also to predict the atmospheric Alternaria spore content in the Northwest Spain using a novel data analysis technique, ANNs (Artificial Neural Networks). A Hirst-type LANZONI VPPS 2000 volumetric 7-day recording sampler was used to collect the airborne spores from 1997 to 2008. Neural networks provided us with a good tool for forecasting Alternaria airborne spore concentration, and thus could help the automation of the prediction system in the aerobiological information diffusion to the population suffering from allergic problems or the prevention of considerable economic worldwide losses on important crops. Our proposed model would be applied to different geographical areas; nevertheless, the adjustment of the model, by using the available and adequate variables, would be realised in each case. PMID- 20922256 TI - Vertebrate ancient opsin and melanopsin: divergent irradiance detectors. AB - Both vertebrates and invertebrates respond to light by utilising a wide-ranging array of photosensory systems, with diverse photoreceptor organs expressing a characteristic photopigment, itself consisting of an opsin apoprotein linked to a light-sensitive retinoid chromophore based on vitamin A. In the eye, the pigments expressed in both cone and rod photoreceptors have been studied in great depth and mediate contrast perception, measurement of the spectral composition of environmental light, and thus classical image forming vision. By contrast, the molecular basis for non-visual and extraocular photoreception is far less understood; however, two photopigment genes have become the focus of much study, the vertebrate ancient (va) opsin and melanopsin (opn4). In this review, we discuss the history of discovery for each gene, as well as focusing on the evolution, expression profile, functional role and broader physiological significance of each photopigment. Recently, it has been suggested independently by Arendt et al. and Lamb that an ancestral opsin bifurcated in early metazoans and evolved into two quite different photopigments, one expressed in rhabdomeric photoreceptors and the other in ciliary photoreceptors. This interpretation of the evolution of the metazoan eye has provided a powerful framework for understanding photobiological organization. Their proposal, however, does not encompass all current experimental observations that would be consistent with what we term a central "Evolution of Photosensory Opsins with Common Heredity (EPOCH)" hypothesis to explain the complexity of animal photosensory systems. Clearly, many opsin genes (e.g. va opsin) simply do not fit neatly within this scheme. Thus, the review concludes with a discussion of these anomalies and their context regarding the phylogeny of photoreceptor and photopigment development. PMID- 20922257 TI - Nanostructured materials for thermoelectric applications. AB - Recent studies indicate that nanostructuring can be an effective method for increasing the dimensionless thermoelectric figure of merit (ZT) in materials. Most of the enhancement in ZT can be attributed to large reductions in the lattice thermal conductivity due to increased phonon scattering at interfaces. Although significant gains have been reported, much higher ZTs in practical, cost effective and environmentally benign materials are needed in order for thermoelectrics to become effective for large-scale, wide-spread power and thermal management applications. This review discusses the various synthetic techniques that can be used in the production of bulk scale nanostructured materials. The advantages and disadvantages of each synthetic method are evaluated along with guidelines and goals presented for an ideal thermoelectric material. With proper optimization, some of these techniques hold promise for producing high efficiency devices. PMID- 20922258 TI - Diols and anions can control the formation of an exciplex between a pyridinium boronic acid with an aryl group connected via a propylene linker. AB - The exciplex formation between a pyridinium boronic acid and phenyl group connected via a propylene linker can be monitored using fluorescence. Addition of pinacol affords a cyclic boronate ester with enhanced Lewis acidity that increases the strength of its cation-pi stacking interaction causing a four-fold fluorescence enhancement. PMID- 20922259 TI - Arylation of unactivated arenes. AB - Transition metal-catalyzed and metal-free direct arylation of unactivated arenes is described. The transition metal-catalyzed direct arylation of unactivated arenes as a state-of-the-art method towards biaryl synthesis is highlighted in this Perspective. PMID- 20922260 TI - New reactions of anticancer-platinum complexes and their intriguing behaviour under various experimental conditions. AB - The anticancer platinum complexes here described react with organic substrates (such as acids, alkenes, alkynes) and catalyze transformations that can occur in biomolecules which contain unsaturated functions. We have analyzed the role of the platinum complexes in the observed reactions and studied the progress of the detected transformations upon variation of the reaction conditions. PMID- 20922261 TI - Synthesis and structural analysis of a novel iodinated cyclopentadienone via ring contraction iodination and its application in synthesis of alkyne-functionalized cyclopentadienones. AB - The first iodinated cyclopentadienone was isolated and its structure was confirmed by single crystal X-ray analysis. Based on this intermediate, the first direct C-C bond formation on cyclopentadienone ring was achieved. The photo induced intramolecular charge transfer of alkynylated cyclopentadienones was evaluated by solvent polarity effect on their electronic absorption spectra. PMID- 20922262 TI - Carving two adjacent holes on [60]fullerene through two consecutive epoxide to diol to dione transformations. AB - Repeated acid catalyzed epoxide opening and oxidation of the resulting diol with diacetoxyiodobenzene led to two 10-membered orifices on C(60) cage. PMID- 20922263 TI - Artificial hydrogenases: assembly of an H-cluster analogue within a functionalised poly(pyrrole) matrix. AB - We show that a redox active {Fe(4)S(4)}(2+)-cubane assembly covalently bound within a cysteinyl-alkylammonium functionalised polypyrrole can be modified with a diiron dithiolate carbonyl unit to give an artificial hydrogenase H-cluster framework confined within the polymer matrix. PMID- 20922264 TI - Gas pressure effects on the rates of catalytic H(2) oxidation by hydrogenases. AB - During catalysis by hydrogenases, entities no larger than H(2) or H(+) reach and leave a deeply buried active site, by as yet unidentified pathways. Novel experiments, conducted mainly with the membrane-bound [NiFe]-hydrogenase from Ralstonia eutropha, explore why small excess gas pressures (H(2) or He) attenuate the rate of H(2) oxidation. PMID- 20922265 TI - Decrease in blood pressure, body mass index and glycemia after aerobic training in elderly women with type 2 diabetes. AB - BACKGROUND: The aging process is associated with the development of several diseases, which can be attenuated by the practice of physical activities. Aerobic training is an effective method to maintain and improve cardiovascular function. Additionally, it has a crucial role in the prevention and treatment of several chronic-degenerative diseases, especially diabetes mellitus. } OBJECTIVE: To verify the effect of a 13-week aerobic training program on blood pressure (BP), body mass index (BMI) and glycemia levels in elderly women with type-2 diabetes mellitus (DM2). METHODS: Eleven sedentary elderly women with DM2, aged 61.0 +/- 9.1 years, were submitted a 13-week aerobic training program, constituting group G2. Eleven controlled elderly women (aged 60.2 +/- 6.8 years) were not submitted to the aerobic training, constituting the control group (G1). G1 attended educational lectures once a week, whereas G2 walked three times a week. RESULTS: Both groups presented a significant decrease in glycemia and diastolic blood pressure levels. No significant decreases in BMI were observed after the aerobic training in either group. CONCLUSION: The 13-week aerobic training program was enough to promote significant decrease in the diastolic blood pressure and glycemia levels; therefore, this type of exercise training decreases the risk factors for cardiovascular and metabolic diseases. PMID- 20922266 TI - Cost-effectiveness of implantable cardioverter defibrillators in Brazil in the public and private sectors. AB - BACKGROUND: Many randomized clinical trials have demonstrated the effectiveness of the implantable cardioverter-defibrillator (ICDs) in death reduction of chronic heart failure (CHF) patients. Some developed countries studies have evaluated its cost-effectiveness, but these data are not applicable to Brazil. OBJECTIVE: To evaluate the cost-effectiveness of ICD in CHF patients under two perspectives in Brazil: public and supplementary health systems. METHODS: A Markov model was developed to analyze the incremental cost-effectiveness ratio (ICER) of ICD compared to conventional therapy in patients with CHF. Effectiveness was measured in quality-adjusted life years (QALYs). We searched the literature for data regarding effectiveness and complications. Costs were retrieved from public and health insurances reimbursement codebooks and from mean cost of admissions from a public and a private hospital. One-way sensitivity analysis was performed in all variables of the model. RESULTS: ICER was R$ 68,318/QALY in the public and R$ 90,942/QALY in the private perspective. These values are much higher than the one suggested by the World Health Organization of 3 times the gross domestic product per head (R$ 40,545 in Brazil). The results were sensitive to the cost of the device, battery replacement interval and ICD effectiveness. In a simulation resembling MADIT-I population survival and ICD benefit, ICER was R$ R$ 23,739/QALY in the public and R$ 33,592/QALY in the private perspective. CONCLUSION: The ICER of ICD is elevated in the general ICC population, in either the public or private perspective. A more favorable result occurs in patients with a high sudden death risk. PMID- 20922267 TI - Quality of life of patients that had a heart transplant: application of Whoqol Bref scale. AB - BACKGROUND: The success of cardiac transplantation involves ensuring the survival of patients with heart disease and allowing them to carry out their daily activities. Heart transplant is the first option of treatment for heart failure and it represents an increase in the survival rate and quality of life of transplant patients. OBJECTIVE: To evaluate the quality of life of patients that had a heart transplant by using a standardized scale (Whoqol-Bref). METHODS: A quantitative descriptive exploratory study, conducted with 55 patients that had a heart transplant, in a period ranging between the third and 103(rd) months, who were monitored at the Transplant and Heart Failure Unit in a benchmark cardiology hospital in the city of Fortaleza, State of Ceara. The data were collected from February 2009 to April 2009, by administering a WHO-standardized questionnaire and by using data contained in medical records. RESULTS: With respect to the physical domain, 62.8% of male patients and 58.3% of female patients are satisfied. In the psychological domain, 65.1% of males are satisfied with the quality of life and, 58.3% of females are satisfied. In terms of social relations, it was observed that 53.5% of males are very satisfied and 100% of females are satisfied. With regard to the environment, 65.1% of male patients and 83.3% of female patients are satisfied. CONCLUSION: The heart transplant had a lot of influence on the quality of life of transplant patients, because the results have proven to be statistically significant after the transplant. PMID- 20922268 TI - Biopsychosocial variables and attitudes towards treatment influence complicated hypertension. AB - BACKGROUND: Complicated hypertension can be influenced by the characteristics of hypertensive patients. OBJECTIVE: To associate the condition of complicated hypertension with biosocial variables such as attitudes and beliefs about the disease and treatment and subjective well-being. METHODS: We studied 251 uncomplicated hypertensive patients (SBP > 140 mmHg and/or 90 < DBP < 110 mmHg for patients under no treatment and DBP <110mmHg for patients under treatment without target organ damage and other diseases) and 260 complicated hypertensive patients (DBP > 110 mmHg with or without treatment, with target organ damage or other diseases). RESULTS: Complicated hypertensive patients were significantly different from uncomplicated ones (p <0.05) in relation to: 1 - Prevalence of men, not white (53.0%), higher body mass index (29.5 +/- 4.6 vs 28.5 +/- 4.0 kg/m2), over 10 years of disease (54.0%), completion of previous treatment (53.0%) and reports of sadness about life as a whole (74.0%) 2 - Complicated hypertensive patients never bring the drugs when they travel (59.0%), nor do they buy them before running out the drugs (71.0%) and rarely follow eating guidelines (69.0%) 3 - Uncomplicated hypertensive patients showed no more migraines, joint pain and, among women, menopausal status and hormone replacement therapy, and 4 - Of those who had pressure control (< 140/90 mmHg), 61.9% were uncomplicated hypertensive patients; and 5 - Complicated hypertensive patients were not aware that treatment can prevent kidney problems and they thought that young people do not have high blood pressure. CONCLUSION: Complicated hypertensive patients showed more negative structural and psychosocial characteristics, more negative attitudes towards treatment and are unaware of the disease. PMID- 20922269 TI - Regulation of protein synthesis and the role of eIF3 in cancer. AB - Maintenance of cell homeostasis and regulation of cell proliferation depend importantly on regulating the process of protein synthesis. Many disease states arise when disregulation of protein synthesis occurs. This review focuses on mechanisms of translational control and how disregulation results in cell malignancy. Most translational controls occur during the initiation phase of protein synthesis, with the initiation factors being the major target of regulation through their phosphorylation. In particular, the recruitment of mRNAs through the m7G-cap structure and the binding of the initiator methionyl-tRNA(i) are frequent targets. However, translation, especially of specific mRNAs, may also be regulated by sequestration into processing bodies or stress granules, by trans-acting proteins or by microRNAs. When the process of protein synthesis is hyper-activated, weak mRNAs are translated relatively more efficiently, leading to an imbalance of cellular proteins that promotes cell proliferation and malignant transformation. This occurs, for example, when the cap-binding protein, eIF4E, is overexpressed, or when the methionyl-tRNA(i)-binding factor, eIF2, is too active. In addition, enhanced activity of eIF3 contributes to oncogenesis. The importance of the translation initiation factors as regulators of protein synthesis and cell proliferation makes them potential therapeutic targets for the treatment of cancer. PMID- 20922270 TI - Acute kidney injury in AIDS: frequency, RIFLE classification and outcome. AB - The objective of the present study was to evaluate the characteristics of acute kidney injury (AKI) in AIDS patients and the value of RIFLE classification for predicting outcome. The study was conducted on AIDS patients admitted to an infectious diseases hospital inBrazil. The patients with AKI were classified according to the RIFLE classification: R (risk), I (injury), F (failure), L (loss), and E (end-stage renal disease). Univariate and multivariate analyses were used to evaluate the factors associated with AKI. A total of 532 patients with a mean age of 35 +/- 8.5 years were included in this study. AKI was observed in 37% of the cases. Patients were classified as "R" (18%), "I" (7.7%) and "F" (11%). Independent risk factors for AKI were thrombocytopenia (OR = 2.9, 95%CI = 1.5-5.6, P < 0.001) and elevation of aspartate aminotransferase (AST) (OR = 3.5, 95%CI = 1.8-6.6, P < 0.001). General mortality was 25.7% and was higher among patients with AKI (40.2 vs17%, P < 0.001). AKI was associated with death and mortality increased according to RIFLE classification - "R" (OR 2.4), "I" (OR 3.0) and "F" (OR 5.1), P < 0.001. AKI is a frequent complication in AIDS patients, which is associated with increased mortality. RIFLE classification is an important indicator of poor outcome for AIDS patients. PMID- 20922271 TI - In vitro modulation of Bcl-2 levels in small cell lung cancer cells: effects on cell viability. AB - Small cell lung cancer (SCLC) is an aggressive disease, representing 15% of all cases of lung cancer, has high metastatic potential and low prognosis that urgently demands the development of novel therapeutic approaches. One of the proposed approaches has been the down-regulation of BCL2, with poorly clarified and controversial therapeutic value regarding SCLC. The use of anti-BCL2 small interfering RNA (siRNA) in SCLC has never been reported. The aim of the present study was to select and test the in vitro efficacy of anti-BCL2 siRNA sequences against the protein and mRNA levels of SCLC cells, and their effects on cytotoxicity and chemosensitization. Two anti-BCL2 siRNAs and the anti-BCL2 G3139 oligodeoxynucleotide (ODN) were evaluated in SCLC cells by the simultaneous determination of Bcl-2 and viability using a flow cytometry method recently developed by us in addition to Western blot, real-time reverse-transcription PCR, and cell growth after single and combined treatment with cisplatin. In contrast to previous reports about the use of ODN, a heterogeneous and up to 80% sequence specific Bcl-2 protein knockdown was observed in the SW2, H2171 and H69 SCLC cell lines, although without significant sequence-specific reduction of cell viability, cell growth, or sensitization to cisplatin. Our results question previous data generated with antisense ODN and supporting the present concept of the therapeutic interest in BCL2 silencing per se in SCLC, and support the growing notion of the necessity of a multitargeting molecular approach for the treatment of cancer. PMID- 20922272 TI - An improved strategy for evaluating the extent of chronic arterial baroreceptor denervation in conscious rats. AB - There is no index or criterion of aortic barodenervation, nor can we differentiate among rats that have suffered chronic sham, aortic or sino-aortic denervation. The objective of this study was to develop a procedure to generate at least one quantitative, reproducible and validated index that precisely evaluates the extent of chronic arterial barodenervation performed in conscious rats. Data from 79 conscious male Wistar rats of about 65-70 days of age with diverse extents of chronic arterial barodenervation and used in previous experiments were reanalyzed. The mean arterial pressure (MAP) and the heart rate (HR) of all rats were measured systematically before (over 1 h) and after three consecutive iv bolus injections of phenylephrine (PHE) and sodium nitroprusside (SNP). Four expressions of the effectiveness of barodenervation (MAP lability, PHE ratio, SNP ratio, and SNP-PHE slope) were assessed with linear fixed models, three-level average variance, average separation among levels, outlier box plot analysis, and overlapping graphic analysis. The analysis indicated that a) neither MAP lability nor SNP-PHE slope was affected by the level of chronic sodium intake; b) even though the Box-Cox transformations of both MAP lability [transformed lability index (TLI)] and SNP-PHE slope [transformed general sensitivity index (TGSI), {((3-(DeltaHR(SNP)-DeltaHR(PHE)/DeltaMAP(SNP) DeltaMAP(PHE)))(-0.4)-1)/-0.04597}] could be two promising indexes, TGSI proved to be the best index; c) TLI and TGSI were not freely interchangeable indexes for this purpose. TGSI ranges that permit differentiation between sham (10.09 to 11.46), aortic (8.40 to 9.94) and sino-aortic (7.68 to 8.24) barodenervated conscious rats were defined. PMID- 20922273 TI - [The insertion of the violence against elderly theme at health care public policies in Brazil]. AB - This article approaches the insertion of violence against elderly in the Brazilian health care public policies. It presents concepts of violence applied to this group of population, mortality data and number of elder interned by violence and accidents. Also, it compares and discusses some policies that are, direct or indirectly, about elder care, victims of violence, and the specific object of the text. Methodologically, it first aimed to identify if the theme of violence was contemplated in official documents, and if so, which are the guidelines that orient elder care, not only regarding attendance, but also regarding prevention actions. The conclusions are that official policies, with special emphasis to the Elder Statute and the National Policy to Elder Care, are very slowly incorporating this theme and offering support to the Protection Network, mainly in this first decade of the 21st century. PMID- 20922274 TI - [The construction of public polices in democratic spaces of civic participation: the violence against elder in the social movement agenda]. PMID- 20922275 TI - [Living a full life without violence at maturity: the contemporary search]. PMID- 20922276 TI - [Thinking on the violence origins]. PMID- 20922277 TI - [Health care for aged victims of accidents and violence: analysis of SUS health services in Recife (PE, Brazil)]. AB - A situational diagnosis of the health services regarding the care of aged victims of accidents and violence (AVAV) was carried out in Recife, Pernambuco, Brazil. The National Policy for Reducing Accident and Violence Related Morbidity and Mortality and the National Policy for the Aged People Health were used as references. The methodology was based on the triangulation method, with both quantitative and qualitative approaches. Questionnaires and interviews were answered by managers and health staff of hospital, prehospital and rehabilitation services; and local aged health policy managers. In 2006, only the Family Health Program reported prehospital care for AVAV, 31 cases were due to violence and 18 to accidents. The hospital care for aged people was 7.2% of the total care, 27% from accidents and 10% from violence. In the same year, there was no record of rehabilitation care of AVAV. The directives of the policies studied are only partially followed. The health care is deficient in several aspects, such as: clinical protocols; notification devices; support to the aged, caregivers and aggressors; and also continuous training. This analysis can be such a contribution to the reorganization of the local health system, recognizing the aged person as vulnerable to accidents and violence. PMID- 20922278 TI - [Analysis of hospital clinical services to elderly victims of accidents and violence]. AB - The increase of elderly population and more active life allow a greater exposure to accidents and violence in this population. A diagnostic analysis of hospital services for emergency and urgent care to victims of accidents and violence in the elderly population was carried out in five capitals of Brazil. The research was based on the principles of triangulation of methods, including quantitative approaches, through the application of questionnaires to managers and pre hospital, hospital and rehabilitation service professionals, as well as qualitative, in which interviews were made with managers and professionals and with those in charge of elderly health. Based on the guidelines of the policies studied, it was realized that none of the capitals has met all requirements, with a poor attendance characterized by lack of structure to keep a companion for the elderly, referrals to reference services, specific clinical protocols, reporting sheets, support to the elderly, job training and definition of the flow for this population. The outcome showed that the selected health services do not have the appropriate and integral profile to look after the elderly population, demonstrating the need for adequacy of these services aiming the accomplishment of the guidelines of the policies reviewed. PMID- 20922279 TI - [Perceptions of managers and health professionals about health care to elderly victims of violence in the city of Rio de Janeiro (RJ, Brazil)]. AB - This article presents the vision of managers and health professionals about the care of elderly victims of violence in Rio de Janeiro, showing the specificities of this attention in pre-hospital, hospital and rehabilitation areas, including mental health services. Based on a qualitative methodology, 20 semi-structured interviews with managers and health professionals were produced. The analysis considered the perceptions about violence against elderly, and the specificities of attention provided by SUS services to elderly victims. The State, the family and the social support organizations emerged as structuring categories of the network of care for elderly victims of violence. All attention areas presented insufficient care services or specific programs for the elderly victims of accidents and violence. Also there was a precarious network of social support for care of dependent elderly. With few exceptions elderly are treated as anyone else in public health services, without the priority set by the Statute of the Elderly. The family is called to participate in the care for the elderly in all areas of care. Abandonment, neglect, physical and psychological abuse against seniors cases were reported. PMID- 20922280 TI - [Systematic review of the Brazilian academic production about external causes and violence against the elderly]. AB - This article presents a review about violence against the elderly, covering the period of 2000 to 2009. The database used in this research was the collection of articles, books, book chapters, manuals and plans of action of the Virtual Library on Violence and Health. We analyzed 115 documents divided into the following categories: falls; external causes and violence in general; epidemiological and socio-epidemiological studies; prevention of violence; violence and accidents in the family; conceptual and methodological review; legal order and denunciation; violence from the elderly's point of view; health services, professionals and caretakers; and construction and validation of research instruments. The results show a relevant increase in production and methodological improvement in public health, social work, law, physiotherapy, nursing, psychology and otorhinolaryngology. However, there are issues that have not been sufficiently approached such as traffic accidents, homicides, suicides, drowning and suffocation. PMID- 20922281 TI - [Situational analysis of the pre-hospital health services for attending accidents and violence against the elderly in Curitiba (PR, Brazil)]. AB - This study is a situational analysis of the health care services for attending accidents and violence, in Curitiba, focusing the general conditions of infrastructure, planning and support at the pre-hospital assistance level, considering mobile and fixed emergency services dedicated to the victimized elderly. Positive points were evidenced as well as gaps and needs to meet the national guidelines. The investigation integrated quantitative and qualitative approaches and it was carried out on the grounds of the triangulation of methods. It is concluded that on the theme of accidents and violence against the elderly still there is room for important improvements in the actions developed by the researched services: (1) preventive actions are not part of the routine of the services; (2) most of the services does not develop specific services, addressed to the peculiar demands of the elderly; (3) the interviewees' experience reveals difficulties for obtaining hospital beds, either for referral or transfer/admission of patients. Facing the issue of accidents and violence against the elderly in Curitiba requires considering the organization of data, flows, training of professionals and planning in the development of prevention programs, attendance and rehabilitation to the elderly. PMID- 20922282 TI - [Rehabilitation service to the elder person victim of accidents and violence on different regions of Brazil]. AB - The purpose of this work is to describe the structure and characterize the services offered for rehabilitation of elder people, victims of accidents and violence, based on the main public policies of health for this population in Brazil. Following the principles of the triangulation method, a 27 question questionnaire was applied to 19 rehabilitation services (five in Manaus, seven in Recife, two in Brasilia, two in Rio de Janeiro and three in Curitiba) about structure and organization of the service besides data registration. Managers and health professionals were interviewed about the flow, characterization and specificities of the service to elder people, protection chains, services evaluation and suggestions. Services in Manaus and Brasilia are better prepared to attend elder victims of accidents and violence. The services in Brasilia surpass the specific issues of elderly care. The rehabilitation units in Recife are more unprepared, especially regarding laboratorial support, qualification of professionals to identify and attend the cases of violence, registration and analysis of data. It is concluded that the rehabilitation service presents great fragility on the implantation of public policies and in insertion of the violence theme. PMID- 20922283 TI - [Scenario of the service to damage provoked by accidents and violence against elderly at SUS in Manaus (AM, Brazil)]. AB - The aim of this article is to describe the public service of Manaus to elderly, either victims of accidents or violence, on three levels of service (32 pre hospital, 5 hospital and 5 rehabilitation). It is a descriptive study with a quantitative and qualitative approach, where 42 health units were investigated. The results reveal that the emergency services department presents a better physical structure. The organization concerning these matters is still incipient in Manaus. It was detected scarcity in the number of hospital beds and vacancies in the intensive care unit to offer the continuity of the treatment. There's a need for professional qualifications and medical specialties to attend elderly admitted due to injury. Very little has been done in the prevention area. Data entry and notification appear as one of the weakest points on the three levels of attention. The most critical point is related to hospitalization, being this level of attention largely mentioned by managers and health professionals as in great need for re-structuring. PMID- 20922284 TI - [Construction of indicators for assessing the policy of reducing accidents and violence for the elderly care]. AB - The follow article presents the methodology used to construct indicators to assess the implementation of the National Policy of Mortality Reduction by Accidents and Violence, of public health policies aimed at the elderly and the Mental Health Policy developed in the research entitled Diagnostic Analysis of Local Health Systems to Meet the Problems Caused by Accidents and Violence against Elderly. These indicators were applied in health services that meet elderly victims of accidents and violence in five Brazilian cities: Brasilia, Curitiba, Manaus, Recife and Rio de Janeiro. It started with 124 indicatives to assistance level pre-hospital, hospital, rehabilitation and CAPS. There was a selection phase where indicatives without discriminatory capability were eliminated. It was also decided by the relaxation of some criteria are creating new categories. After this step, a group of the experts validate the questionnaires created with these indicators by using Nominal Technical Group. We performed the Kruskal-Wallis test and a graphical analysis. In the final round, the indicators were grouped by similarity, building synthetic indices, 60 indicatives left. These methods can be used in other organizations to evaluate and adjust their health care based on public policies. PMID- 20922285 TI - [Violence against the elderly: analysis of aspects of mental health care in five Brazilian cities]. AB - This is a research on the aspects of mental health care offered to elderly victims of violence in the cities of Curitiba, Rio de Janeiro, Brasilia, Recife and Manaus. It was used the triangulation method that relied on the analysis of secondary data, information from questionnaires and individual and group interviews, defining itself as a target audience of this study, professionals and managers in mental health care. It was investigated the line of practices developed in services regarding policies governing mental health attention and addressed to the elderly who are victims of violence. Among the findings are: the disparity in records between elderly care hospitals (22.3%) and outpatient (0.4%), lack of information on the care of elderly victims of violence; and the incipient perception of professionals regarding the violence as a health intervention. In conclusion, there is a need for greater public investments: in improving the quality of information; the adequacy of the physical structure of services; the training/qualification of professionals to attend for specific elder health issues; under the aspect of violence, it was observed the need to adopt actions of prevention and attention of the most frequent disorders in the elderly. PMID- 20922286 TI - [Pre-hospital attendance to elders victims of violence in five Brazilian capitals]. AB - This article reviews the characteristics and operation in the daily routine of a pre-hospital care to the elderly victims of violence and accidents in five capitals (Manaus, Recife, Brasilia, Rio de Janeiro and Curitiba). Besides that, it analyses their abilities, and potential obstacles. It was based on the triangulation of quantitative and qualitative methods analyzing data from 80 departments of mobile and fixed pre-hospitals: 32 in Manaus, 18 in Recife, 10 in Brasilia, 12 in Rio de Janeiro and eight in Curitiba. Among the findings are the differences in size and diversity of occupational categories and difficulties of the teams to identify, serve and report cases for lack of training, limited preventive action, almost no involvement and guidance to the family, practically no attention to the perpetrator; incipient articulation and partnership network, especially regarding on pre-hospital services and the hospital. PMID- 20922287 TI - Endotoxin and cancer. AB - Exposure to endotoxin, a component of gram-negative bacterial cell walls, is widespread in many industrial settings and in the ambient environment. Heavy exposure environments include livestock farms, cotton textile facilities, and saw mills. In this article, we review epidemiologic, clinical trial, and experimental studies pertinent to the hypothesis that endotoxin prevents cancer. Since the 1970s, epidemiologic studies of cotton textile and other endotoxin-exposed occupational groups have consistently demonstrated reduced lung cancer risks. Experimental animal toxicology research and some limited therapeutic trials in cancer patients offer additional support for an anticarcinogenic potential. The underlying biological mechanisms of anticarcinogenesis are not entirely understood but are thought to involve the recruitment and activation of immune cells and proinflammatory mediators (e.g., tumor necrosis factor alpha and interleukin-1 and -6). In view of the current state of knowledge, it would be premature to recommend endotoxin as a cancer-chemopreventive agent. However, further epidemiologic and experimental investigations that can clarify further dose-effect and exposure-timing relations could have substantial public health and basic biomedical benefits. PMID- 20922288 TI - [Vocal care: question of prevention and health]. AB - Planned by Brazilian doctors, the National Week of the Voice (Semana Nacional da Voz) conquered the world due to the huge reached success. This study has the objective to demonstrate the results reached during the 9th National Week of the Voice (9a Semana Nacional da Voz) that took place in the Hospital das Clinicas of the Federal University of Goias. During the event, 125 patients had been selected by the phonoaudiology team and manually filled a questionnaire elaborated for the campaign in the validity of possible pharyngolaryngeal alterations. The patients had been examined by the otorhinolaryngologist using indirect laryngoscopy and, when necessary, submitted to videolaryngoscopy. After medical evaluation, it was observed that 52 people (41.6%) had presented alterations in the speech organs or in proximal regions, in one patient paralysis of left vocal fold was detected and one patient presented tumoral injury. Considering all the patients attended, only one presented malignant neoplasm (squamous cell carcinoma), confirmed later by biopsy. PMID- 20922289 TI - [Effect of vestibular rehabilitation in elder people: regarding balance, quality of life and perception]. AB - The current concerns with quality of life, population aging, limitations imposed by balance disturbance in the elder population and the alternative treatment through the vestibular rehabilitation had justified this study. The objective was to analyze in perspective the application of the Cawtome & Cooksey protocol for vestibular rehabilitation results in aged institutionalized people with complains of balance alterations and probability of fall, aiming the improvement of quality of life and that elders could perceive the limitations imposed by the balance disturbance. A hybrid methodology was used, searching an integration of quantitative and qualitative data associating the experimental to the phenomenological in a population of 30 elders with complains of balance alterations living in an asylum. The evaluation instruments had been the Berg Scale, Dizziness Handicap Inventory (DHI) and speech analysis. As conclusion, it was evidenced that, within the population studied, the vestibular rehabilitation was effective regarding the improvement of symptoms of balance alteration in relation to quality of life, probability of fall as well as the security and independence feelings of the elders. PMID- 20922290 TI - [Factors potentially associated to domestic negligence among elders assisted in home assistance program]. AB - The cases of abuse against elderly people have been growing significantly throughout the entire world. Among the various forms of abuse, one of the less known and denounced is the domestic negligence. As it occurs mostly inside family and nursing homes, it is hardly identified. This article presents the results of a cross-sectional descriptive/analytical study that pointed out the existing factors potentially associated to domestic negligence towards elderly patients attended by the Elderly Home Care Program as part of the discipline of Geriatrics of the Paulista Medical School, Federal University of Sao Paulo, Brazil. Interviews were made with 40 familiar caregivers of these patients who had functional disability. The profiles of those patients and their caregivers were identified by questionnaires and the impact on those familiars by the Caregiver Burden Scale. The results revealed the existence of the following factors potentially associated with domestic negligence among elderly people, in the study population: the dimensions general tension and isolation, as well as depression and stress on the caregiver's side, and the elder's functional ability, are the causes that impact the most on caregivers. PMID- 20922291 TI - [Constructivist evaluation, under an integrating and intersectoral approach, of actions of the Disque Idoso Project in Sobral (CE, Brazil)]. AB - The population aging in Brazil and in the world is a reason for an epidemic inquietude. So, the violence against senior people has been considered a problem of public health. This study takes as context the health need of seniors that suffer of violence, aiming to evaluate in a constructive way the Disque Idoso Project in Sobral (Ceara, Brazil). We used Furtado's Constructivist Method of Evaluation, which provides practices of participative evaluation. Trying to reach such perspective, we are guided by paths of the integrative approach (inter, multi and transdisciplinary) and intersectoral. We accomplished the focal groups with representatives of the sections of health, social assistance, justice and senior, the benefited by the project as well as others that contribute to its development. When interacting with the professionals that act in the project headquarters we understood that there is a fear in publishing their work, because there is not structure to enlarge the attendance. The group believes that the efficiency of its actions is limited due to the lack of transport and other professionals. For the professionals of the support social networks, the project should look for intersectoral performance, once it intends to reach a complete attendance. For the seniors, the project is quite valid and needs to be consolidated in the district. PMID- 20922292 TI - [Reflexions about aging and work]. AB - This qualitative research has the aim to know the meaning of the aging process in the work market referring to the aged people. Six aged persons have participated in this research. The data were collected through an interview and were analyzed using the technique of thematically analyze. Three analytical categories emerged: the meaning of aging/to be aged; the meaning of work; the meaning of aging in the work. Concluding, this paper reinforces the theory that the capitalist societies attach excessive value to the work in the human being life. When it isn't into the life--because of the retirement or the unemployment--it compromises the quality of aging/to be aged of the person, mainly if skills and (individual, social and economical) conditions will lack participation and priority to others activities and values in her/his life. PMID- 20922293 TI - [Biology of aging: theories, mechanisms, and perspectives]. AB - Abstract The article reviews the major biological theories of aging, and discusses the most relevant mechanisms to explain the aging process. It begins with the evolutionary theories, explores the molecular-cellular mechanisms, and presents the perspective of the systemic theories. The complex etiology of aging is a challenge to the researchers. The knowledge on that phenomenon develops towards an integrative approach. PMID- 20922294 TI - [Information on seniors' morbidity upon internments on the Brazilian Unified Health System]. AB - Considering the high hospital costs of the elderly, this study aimed to compare the seven highest frequencies of morbidity in the elderly using data from Hospital Information System. The methodology used was the evaluation of information obtained in the database Datasus/Ministry of Health on the morbidity of hospital admissions in the elderly, in 2005 and 1994. Additionally, it was performed the calculation of standard and adjusted rates by the direct standardization method using Epidat 3.1. The main results were the diseases of the circulatory system remained prevalent in 2005 (28%) and 1994 (32%), with a reduction of 4% between these years. The number of cases of neoplasms doubled from 1994 (4%) to 2005 (8%), and infectious and parasitic diseases were basically maintaining the same percentage of 7% in 1994 and 2005. It can be concluded that in Brazil, the hospital morbidity in elderly remains the prevalence of cardiovascular diseases. At the same time, there is a reduction of non-infectious and parasitic diseases, and also signs of recent and sharp increase of neoplasms. It is recommended the use of comparison studies between periods become as a tool used in management. PMID- 20922295 TI - [Epidemiological characteristics, functional capacity and factors associated with elders in a private health insurance]. AB - This cross-sectional study aimed to trace the epidemiological profile of elders associated to a private healthcare insurance and to check their functional capacity, through the Barthel index and associated factors. The population of the study included all associates of the insurance over 60 years old. The data was collected with two self-answered questionnaires: one about family socioeconomic factors and another related to individual health issues. Regarding the functional capacity among the 254 aged participants, four (1.6%) individuals presented total dependence, one (0.4%) was seriously dependent, one (0.4%) was moderately dependent, 29 (11.4%) were somewhat dependent, and 219 (86.2%) were classified as independent. Thus, the variable was added in such way that 86.2% had been classified as independents and 13.8% (CI 95%: 9.5 to 18.0) as dependents. The adjusted analysis showed that only age remained associated to the outcome. Results showed that the individuals over 80 years old presented greater probability of functional incapacity. It was also pointed that in populations with improved socioeconomic conditions there is the possibility of survival bias. PMID- 20922296 TI - [Influenza-vaccinated and non-vaccinated elderly: reported morbidity and sociodemographic aspects, Porto Alegre (RS, Brazil), 2004]. AB - This descriptive transversal epidemiological study had the objective of comparing the elderly population who took the influenza vaccine and who did not regarding the occurrence of events of diseases or hospital admittances within three months after the vaccination. It was not possible to work with probable sampling and the attempt of pairing the vaccinated and non-vaccinated elderly was not successful due to the high vaccine coverage observed (73% of the target population) and due to the short time available to make the interviews. The result of the descriptive analysis of the 1,130 elderly interviewed was quite interesting even not being possible to infer it regarding the universe of the elderly population from Porto Alegre. We found a higher proportion of vaccinated people in the age group of 70 to 79 years old (42%), and a prevalence of non-vaccinated among the age group of 60 to 64 years old (40%). The vaccinated elderly were mostly older; female, who have private health care insurance; with higher income; that perform physical activities and non-smokers. The non-vaccinated were mostly men; younger; with lower income; that do not perform physical exercises; and smoke. A lower percentage of pneumonias reports and hospital admittances was observed among the vaccinated in comparison to the non-vaccinated people. PMID- 20922297 TI - [Functional capacity, socioeconomic conditions and of health of elderly assisted by Family Health teams in Goiania (GO, Brazil)]. AB - The population ageing is a challenge for health professionals. This study seek to evaluate the functional capacity and to identify the factors associated to the dependence for the activities of daily life (ADL) and activities instrumental of daily life (AIDL), and also to describe the socioeconomic, demographic and health profile of the elderly. A transverse study was carried out with seniors assisted by Family Health teams of the District East Sanitary of Goiania (GO). A questionnaire was applied to obtain socioeconomic and demographic date, factors related to the health and scales of the functional evaluation. For analyses it was used Square-Qui Test considering the level of significance of 5%. The sample was composed by 388 elderly, 57.5% with age varying from 60 to 69 years, 58.5% female, 39.7% illiterate, 77.3% with income <= 2 minimum wages and 70.9% bearers of chronic diseases. It was verified that 34.8% needed help in one or more ADL and 60.6% in AIDL. The factors more frequently associated at dependence in both activities were: balance and mobility debilitated, depression, cognitive deficit and age >= 80 years. These results denote that the elderly are living aging characterized by comorbidities and dependence to accomplish daily activities. PMID- 20922298 TI - [Study of the use of medicine in elderly living in a city in the South of Santa Catarina (Brazil): a look at the polymedication]. AB - The objective was to evaluate the use of medicines in the elderly population living in a city in the South of Santa Catarina state. It was carried out a transverse study where 104 patients distributed in five Family Health Program covering area were interviewed. 68.3% of the interviewed people were women, 78.8% aged between 60 and 79 years old and most of them with low schooling. The number of medicines in use was 3.5 (DP=2.58) per elderly and the number of daily rate doses were 5.4 (DP=4.78). 64.4% of the elderly people reported to have used the health services two times or more last year. It was observed that 51.9% of the elderly were classified as smaller polymedication and 28.8% as larger polymedication. The classes of medicines that contributed the most to the polymedication were the ones acting in the cardiovascular and nervous system, eating treatment and metabolism mainly used for hypertension, heart and circulatory problems, diabetes, insomnia and depression. It was verified that 16.5% of the elderly people presented risk of having drug-related problems. It was identified the association between the polymedication and the gender, schooling and the frequency they searched for health services. It was noticed that in this population the polymedication may be related to the elderly profile. PMID- 20922299 TI - [Voice perception and quality of life of elder teachers and non teachers]. AB - The aim of this article is to compare elder teachers (GP) and non-teachers' (GNP) scores from the voice related quality of life (VR-QOL) protocol and verify the relation between these scores, chronological age and voice change perception. Data from the vocal change perception was collected in 47 subjects, 23 GP and 24 GNP, over 65 years old, both sexes, and the VR-QOL protocol has been applied. There was no significant difference between the score of the two groups or between these scores and the voice change perception. There was a positive correlation (p=0.039) between chronological age and the VR-QOL physical domain scores for the GP. There was significant difference between the two groups of subjects that realized the vocal change, for the VR-QOL answers to questions 2 (p=0.02), 4 (p=0.007), 5 (p=0.012) and 9 (p=0.002). In both groups, the impact of the voice changes was higher in the VR-QOL physical than in the socio-emotional domain. The self perception of vocal aging was related to the professional or non professional use of the voice. Teachers, apart from having this perception had more problems in the VR-QOL questions of the physical domain, related to the professional requests. Non-teachers that noticed the vocal aging had difficulties with the socio-emotional and physical aspects. PMID- 20922300 TI - [Medication leaflets used by elderly with hypertension: adequacy of information for sanitary regulation and possible implications for health]. AB - The medication leaflets represent the main source of written information supplied to the patients, in special to the elderly. This study aimed to analyze the content of the leaflets of drugs often prescribed for elderly people with hypertension, as well as their adequacy to the sanitary regulations and possible health implications. A descriptive study was conducted in two stages: A, in July 2002, and B, in July 2007. In each stage were analyzed 34 medication leaflets of seven antihypertensive drugs of the National Essential Drugs List (2006). Among the 68 leaflets analyzed, most did not contain all the information required by Portaria no 110/1997 (89.5%) in the stage A and the RDC no 140/2003 (100%) in B. In 100% of the leaflets, the legislation had not been fulfilled. Some important topics as way of administration, how to use and overdose had been absent in 76% of the leaflets, the lack of this information has an impact in the security of the antihypertensive users. Based on these data, it was possible to evidence inadequate contents of the medication leaflets. So, it is necessary greater surveillance by Anvisa, to ensure the rational use of medicines and the reduction of the risks to the elderly health. PMID- 20922301 TI - [Self-perception of oral health condition of the institutionalized and non institutionalized elders]. AB - This study evaluated the self-perception of oral health condition of institutionalized and non institutionalized elder population using a oral examination and a questionnaire divided in three parts: demographic data, general health and the GOHAI index. A total of 96 individuals above 60 years old living in Fortaleza, Brazil, were interviewed. They were divided in two groups, G1- institutionalized (n=48) and G2--non-institutionalized (n=48). The mean age of the study population was 69.8 years (SD 7.5) and 70.8% of the interviewed were woman. 62% had some type of medical treatment in the last year, and despite the fact that the majority (84.4%) of the elders thought that their general health was good or regular, the average number of teeth presented was 3.9 in both groups. Among them, 47.9% were using superior prosthesis and 26% inferior prosthesis. The GOHAI average was 17.53 qualifying as negative the self perception of oral health. There was no difference between the two groups regarding physical and psychological aspects. PMID- 20922302 TI - [Difficulties and rewards on aging: the elderly's self perception]. AB - The purpose of this study was to identify in the scientific literature, the self image and representations that elders have about themselves in different contexts. Frequently, the society considers aging as a "problem", creating stereotypes that could result in the exclusion of the aged. Through the analysis of researches that investigated the opinion of the elders about their difficulties and rewards in old age, it was evidenced how important are the choices people make through the life. The inner possibilities and the social participation were identified as important elements for the elderly self perception. PMID- 20922303 TI - [Aging by the perspective of elderly caregivers]. AB - This study reports elderly caregivers' perception in charge of giving assistance to three benefiting institutions in elderly care, in the city of Aracatuba, Sao Paulo, Brazil. Questions were approached regarding aging, caregivers' personal motivation in the search of working with this sector of population, relationship with elderly, most common difficulties found during work and caregivers' satisfaction. An interview was done with caregivers and the collected verbal material was analyzed through the Collective Subject Discursive Technique. It was possible to realize through the reports the emotional involvement of caregivers with their work as well as the emotional and physical overload which they are exposed to. Reports related to aging could also be collected as well as social questions which motivated caregivers to search for this kind of job. The several eyes of caregivers lead us to search for new strategies of theoretical capability and psychological support for this group, thinking of their well-being along with the elderly well-being. PMID- 20922304 TI - [Oral condition, habits and treatment necessity of institutionalized elders in Araras (SP, Brazil)]. AB - The aim of this study was to check the oral condition of the elderly citizens from the city of Araras (Sao Paulo, Brazil), and to evaluate treatment needs for this population. 118 volunteers were interviewed and 112 were examined, all of them with age above 60 years. The research was accomplished through a previous 14 question questionnaire that evaluated the patient general health, besides verified the self-knowledge of their oral health in addition to an intraoral physical exam, observing the oral conditions of the patients. In order to verify cavities prevalence, it was used an advocated criterion and index by WHO. It was observed that the systemic diseases that presented most prevalence were insomnia (40.67%), followed by visual disturbances (36.44%) and arthritis (33.05%). In relation to the self-knowledge of the volunteers as to their oral condition, it was noticed that 90.67% of the individuals thought that oral condition does not affect their quality of life. With the intraoral exam, it was obtained a DMF-T media equals to 30.6 with the lost component contributing to 93.9% of the cavities prevalence value (p = 28.7). This population requires special care focused on the oral health because besides having a high DMF-T, they also present inadequate oral health self-knowledge. PMID- 20922305 TI - [Impact of oral health in the daily life of institutionalized and non institutionalized elder in the city of Recife (PE, Brazil)]. AB - The objective of the study is to assess the influence of oral health in the daily routine of both institutionalized and non-institutionalized elders living in the city of Recife-PE, as well as to come to conclusions concerning the relevance level of oral health in both groups. In order to assess the perception of oral health, it was used the Geriatric Oral Health Assessment Index (GOHAI). The GOHAI levels, concerning the perception, were categorized in: low (<= 50), average (51 to 60) and high (57 to 60). Oral health conditions were represented by the DMFT index (with cavity, lost and repaired teeth). It was observed that the percentage of elderly with a GOHAI not higher than 50 (low perception of oral health) was rather higher in the non-institutionalized group than in the institutionalized (92.2% x 64.9%). The average DMFT and the number of lost teeth were higher in the institutionalized group (96.01% x 87.87%). The perception of oral health was lower for more than half of the examined elderly population, but there being a meaningful difference between the two groups concerning the GOHAI, with lower levels for the non-institutionalized group. The result of the perception of oral health was compatible with the high number of decayed and lost teeth. PMID- 20922306 TI - [Design, implementation and evaluation of a health education program for the elderly]. AB - The objective was to design, implement and evaluate a health education program, using the analysis of the habits that harm the health of people over 65 years old. An evaluative research was carried out from a multiple case study in the North-West area of Spain, combining both the quantitative and the qualitative approach. A questionnaire and interview were used as tools for data collection. The elderly take a lot of medicines and also treat themselves. A small group smoke and drink alcohol. Over 25% have sedentary habits and their average body mass rate was 30.55. The implementation of the programme has significantly influenced their quality of life. Elderly people have deep rooted unhealthy habits. The achievement of educational contents improved their quality of life. However, they are reluctant to assume new habits, even though they are healthy. PMID- 20922307 TI - Moving from reclusion to partial freedom: the experience of family caregivers for disabled elderly persons assisted in a day care center. AB - This study aimed at understanding the interactional experience between family caregivers and disabled elderly persons supported in a Day Care Center according to the caregiver's perspective. It also aimed at developing a representative theoretical model for the events experienced by such caregiver. The Grounded Theory was used as methodological framework whereas Interactional Symbolism served as the theoretical framework. Observation and interviews were used for data collection. The following phenomenon arose from the results: feeling of support by the Day Care Center, by the strength of the bond with the elderly and by spirituality in order to continue playing the challenging role of a family caregiver for a disabled elderly person. The study made possible to understand that, among these three supporting cornerstones for coping with the burden generated by the family caregiver role, the care model promoted by the Day Care Center was the intervenient variable in the process of improving the quality of life of the family caregiver-disabled elderly person binomial. This allowed the identification of the main category--moving from reclusion to partial freedom: the experience of family caregivers for disabled elderly persons assisted in a Day Care Center. PMID- 20922310 TI - Nursing taxonomy and studies of efficacy, efficiency and effectiveness: a challenge. PMID- 20922308 TI - [The domestic violence against the elderly within the Family Health Program of Niteroi (RJ, Brazil)]. AB - This article investigates the magnitude and characteristics of violence against the elderly by trusted people at Ilha da Conceicao, Niteroi--RJ registered at the Family Health Program. A domestic survey interviewed 343 individuals with 60 years or more, selected by a simple random sample. To identify the violence it was used the Conflict Tactics Scales. Information about identification, demographics and socio-economics characteristics were obtained using the National Health Interview Survey. The Mini-Mental State Examination was used to evaluate mental health. In order to evaluate the functional capacity, the Health Assessment Questionnaire was used. In cases of alcohol suspicion among men, it was used the instrument CAGE. To female elder or caregivers, the TWEAK instrument was used. 43% reported at least one episode of psychological violence. Physical violence was reported by 9.6% of the interviewed, 6.1% reported serious physical violence in this period. The prevalence of different modalities of violence was higher among the youngest individuals, with higher scholarity, among those who have one of the pathologies that characterize the elderly as having a vulnerability (depression and/or urinary incontinence/fecal and/or diabetes and/or rheumatism) and those living with the greatest number of individuals. PMID- 20922311 TI - The ISO 18.104: 2003 as integrative model of nursing terminologies. AB - This paper presents the ISO 18.104:2003 as an integrative model of nursing terminology. It describes the standard, studies and experiences with its use and discusses possibilities to develop knowledge in the field. The standard has been shown to be effective in developing reference terminologies, and as a standard method for interoperability and reuse. Studies have internal limitations such as language and notations unknown to nursing. Correspondence of the model with classifications used in health services and practice is incipient, which hinders its applicability and development due to the lack of examples to be analyzed and discussed. PMID- 20922312 TI - Self-care behaviors and health indicators in adults with type 2 diabetes. AB - This descriptive correlational study aimed to analyze self-care behaviors and their relationship with health indicators represented by glycemic control, lipid profile, Body Mass Index [BMI], waist circumference and body fat percentage in a sample of 98 adults with type 2 diabetes in an area of Nuevo Leon, Mexico (August 2005/May 2006). The results showed a low self-care behaviors index (X = 36.94, SD=15.14). A significant relationship was found between self-care behaviors and glycosilated hemoglobin [HbA1c] (r s=-.379, p<.001), triglycerides (r s=-.208, p=.040), BMI (r s=-.248, p=.014) and body fat percentage (r s=-.221, p=.029). Multivariate analysis revealed the influence of self-care behaviors on HbA1c, BMI and body fat percentage with explained variances of 9 to 41% (p < .05). From all self-care dimensions, diet was the most predictive for health indicators, moderated by gender and understanding of diabetes contents (p< .05). PMID- 20922313 TI - Dermatological toxicity in women with breast cancer undergoing chemotherapy treatment. AB - This study aimed to analyze the occurrence of skin toxicity caused by drugs used in the protocol of neoadjuvant and adjuvant chemotherapy among women with breast cancer. Patient records of 72 women who were subject to this therapy between 2003 and 2006 were assessed. Of the 558 cycles of chemotherapy, 152 adverse events were registered. There were 37 registrations of dermatological toxicity, of those, 20 were extravasations that affected 17 women. Nine reports of hardened local injury, local fibrosis, pain, and hyperemia were registered during neoadjuvancy. In adjuvancy, among the 11 extravasations registered there were reports of hardened local injury, fibrosis and local pain. Lack of follow-up records for both periods was observed. Registration of the events and reports by the nursing team are essential to monitor the sites of venous puncture during the chemotherapy treatment, besides measuring and making a photographic record of the site. PMID- 20922314 TI - Stressors in breast cancer post-treatment: a qualitative approach. AB - With the increasing effectiveness of breast cancer treatment, the scientific interest in investigating the quality of life of survivors has increased. However, research addressing the post-treatment period is still scarce. The aim of this study was to identify the stressors present in the lives of women in the one to five years post-diagnosis period. The sample was composed of 16 women assisted at a specialized mastectomy rehabilitation service. Data were collected through semi-structured interviews and analyzed using content analysis. The results indicate conflicts with self-image and alteration in the feeling of autonomy, fear in relation to the evolution of the condition, feelings of guilt about the disorder generated in the family, experience of disturbing social situations and a desire to return to their professional occupation. These results reveal the existence of stressors in this phase and the importance of support offered by psychosocial rehabilitation services for this population. PMID- 20922315 TI - Knowledge of patients with mechanical valve prostheses concerning chronic oral anticoagulant therapy. AB - Adherence to chronic Oral Anticoagulant Therapy (OAT) is directly related to patients' understanding of the therapy. This study verified the knowledge of patients with mechanical valve prostheses concerning OAT. This is a contemporary cross-sectional study, the sample is composed of patients with mechanical valve prostheses (MVP) in outpatient follow-up. A 10-question instrument was used; answers were 'know' (1 point), 'know partially' (half point), or 'do not know' (zero). Patients were grouped according to the result obtained: <= 4 points was considered insufficient knowledge; > 4 <= 8 equated to moderate knowledge; and > 8 was considered appropriate knowledge. Of the 110 patients, 61.8% presented moderate knowledge, 40.9% were not able to name at least one factor that may alter the INR (International Normalized Ratio) and 37.3% were not able to report their INR target range. The majority of patients presented moderate knowledge concerning the treatment. Strategies to improve knowledge on the topic should be implemented to minimize risks. PMID- 20922316 TI - Demographic factors and risk indicators of stroke: comparison between inhabitants of Fortaleza municipal district and the national profile. AB - The aim of this study was to compare the demographic factors and the risk indicators for the occurrence of the stroke in the city of Fortaleza with other cities, based on national studies. A transversal study developed with 180 patients who were diagnosed with stroke in nine different public institutions within the period from October 2007 to April 2008. For data collection, a questionnaire was applied by interviewing the patient and/or their companions. The following tests were used for the comparative analysis of epidemiological data: The Chi-Square Test for the adherence and the T-Test for the mean. The patients with stroke evaluated in Fortaleza were younger and had higher rates of hypertension than in the national profile, however, fewer were smokers or consumers of alcohol. It is necessary to increase knowledge about the health of the Brazilian population by region, since there are specific influential factors in the occurrence of stroke. PMID- 20922317 TI - Mothers' view on late postoperative pain management by the nursing team in children after cardiac surgery. AB - Postoperative pain management in children is a complex, multidimensional and subjective phenomenon. It represents a challenge for children, parents and health professionals. This study aimed to understand how mothers assess their children's pain management by the nursing team in the late postoperative phase of cardiac surgery. Empirical data collection was carried out through semistructured interviews with 17 mothers who accompanied their children. Data were subject to qualitative analysis, revealing that, for the mothers, taking good care results from the confidence they vest in the nursing team and from the observation of the medication interventions this team performs. Not taking good care of their children is a consequence of lack of information or inadequate communication between the team and the mothers. The results of this study permit identifying aspects that strengthen and weaken nursing care for these clients, contributing to the improvement of the delivered care. PMID- 20922318 TI - Infusion of hematopoietic stem cells: types, characteristics, adverse and transfusion reactions and the implications for nursing. AB - Hematopoietic stem cell infusion is an important procedure in Hematopoietic Stem Cell Transplantation (HSCT). This study identifies transfusion and other adverse reactions that can occur during infusion and the nursing care related to the procedure. This epidemiologic study used transplantations performed between 2006 and 2008. A total of 166 transplantations were performed: 114 were autologous, 47 allogeneic and five haploidentical. Three transfusion reactions and 96 adverse reactions were observed. Adverse reactions were related to the presence of cryoprotectant, though the infusion rate and quantity of infused cryoprotectant were not related to the occurrence of reactions. The products were fresh and infused within the recommended time when transfusion reactions occurred. In regard to cell source, lower engraftment time was found in peripheral blood. Nursing documentation is relevant for patients' safety as well to planning an infusion in order to minimize the occurrence of reactions. PMID- 20922319 TI - Factors related to the quality of the dying process in cancer patients. AB - This correlational and descriptive research examined the Quality of the Dying Process (QDP) in cancer patients. Data were collected from one significant person for each of the 78 patients who had died, using QDP and communication quality questionnaires. The highest QDP scores were found for social experiences related to: the moment of death, family company and their concern with the person. The lowest score was for symptoms. A statistically significant association (p<0.001) was found between a better QDP and: preparation for death, spending time with the family, concern and care for the patient, communication quality. CONCLUSIONS: patient care needs to be focused on the aspects fostering closeness and dialogue with the patient's close relatives, promoting communication in order to detect and handle the real problems, along with efficient pain management, in which humanized care is essential. PMID- 20922320 TI - Body and sexuality: puerperas' experiences. AB - The aim of this study was to determine how women deal with sexuality and bodily changes during the puerperium. A qualitative methodology was used and a semi structured interview with a leading question script was chosen as the research tool. Six puerperas from the west area of Sao Paulo (Brazil) took part in this study. The interviews were accomplished at their homes. In analysis, the responses were grouped into three main categories: "Changes", Sexuality" and "Social Support". The study results revealed that during this period there are important changes. Sexuality has been shown to evolve many difficulties, fears and worries. The relationships with the person's partner and support network have revealed themselves as being of great importance. It can be concluded that the puerperal period evolves in terms of many transformations in the emotional and psychosocial areas. Thus it is necessary for health professionals who deal with women's care to value this period. PMID- 20922321 TI - Nursing care of women who suffered sexual violence. AB - The aim of this study was to characterize the nursing care, provided to women who suffered sexual violence, treated at The Women's Hospital-CAISM/UNICAMP. A retrospective, descriptive study performed using 146 nursing care records of women attended from June 2006 to May 2007. The results showed that the majority of attendances occurred during the day period, that there was consistency between the interventions and the nursing diagnoses identified, and that women reported having received guidance in accordance with the protocol of the program. The nursing consultation time was greater at night (p=0.0227) and the women frequently understood the health risks resulting from sexual violence (p=0.0072), the use of antiretrovirals according to their daily activities (p=0.0397) and they were more focused on the purpose of the serology (p=0.0351). We concluded that the care provided was shown to be appropriate and of a better quality in the nightshift period. PMID- 20922322 TI - Representations of primary care professionals about the occupational risk of HIV infection. AB - This was a qualitative study, based on the Social Representations Theory, with professionals that work in primary care, about the risk of HIV infection to which they are exposed in their quotidian work routine. Twelve physicians and nurses who work in two Health Centers in the city of Belo Horizonte, MG, Brazil, were interviewed. The final analysis, carried out using the saturation of information criterion, was based on the method proposed by Structural Analysis of Narrative. The results show that the health professionals interviewed knew the infection risk in their work routine, representing it as very low in primary care, because they relate it to technological complexity which they consider does not exist in the level of assistance in which they work. They believed that the use of personal protection equipment may minimize the risks and that, nowadays, no primary care professional refuses to attend a patient due to fear of infection, even if not using all the recommended precautions. PMID- 20922323 TI - Social representations of the wheelchair for people with spinal cord injury. AB - In seeking to understand the social representation of the use of the wheelchair through the analysis of interviews with ten people who have suffered spinal cord injury, the construction of five representations was elaborated. The phenomenon experienced regarding the wheelchair provided a route of meanings and symbologies: essential equipment, after the person perceive the inability to walk; a symbol of disability when the person experienced functional dependence; means of locomotion and transport after the rescue of their potential functional; becoming an integral part or all of their body and, finally, the concept of autonomy on four wheels by adjusting to their new ability to walk emerges. The wheelchair as an extension of the modified body for spinal cord injury, returns them the right of locomotion, presents them not only with autonomy for various acts of life, but also restores their dignity, so essential to human life. PMID- 20922324 TI - Humanization of care from the perspective of the family health strategy teams in a city in the interior of Sao Paulo, Brazil. AB - This study analyzes the understanding of professionals composing teams of the Family Health Strategy concerning humanization of care. This qualitative survey was carried out in a city in the interior of Sao Paulo through interviews with 20 professionals. The data analysis method used was Interpretation of Meanings based on the hermeneutic-dialectic perspective. The meaning of humanization according to the interviewed professionals includes an enlarged view, respect for ethical principles and facilitated access. The difficulties refer to the lack of prepared professionals, excessive demand and deficiencies in service organization. The professionals propose to educate and qualify professionals, make activities adequate given the professionals' roles and improve the organization of services. The professionals demonstrate understanding of the meaning of humanization and acknowledge the need to cope with difficulties. PMID- 20922325 TI - Analysis of the organizational aspects of a clinical emergency department: a study in a General Hospital in Ribeirao Preto, SP, Brazil. AB - Demand for the Emergency Department (ED) has increased, making the organization of work difficult. This quantitative, descriptive and documental study identifies and analyzes the characteristics of clinical care in the ED of a General Hospital in Ribeirao Preto, SP, in 2007, according to organizational variables. The study population included all clinical care consultations registered in the Hospital Management Information System. Data were analyzed through descriptive statistics and discussed considering the theoretical framework of the Single Health System (SUS). A total of 5,285 consultations were registered in the period, which were more frequent in patients from the city itself, in January (10%), on Mondays (16%), from 12pm to 12am (67.1%). The main reason for discharge from the unit was hospitalization (63.8%) and the predominant length of stay in the unit was less than six hours (39.8%). The results support the management of human resources, materials and equipment, indicating the desirability of reorganizing emergency care in the hospital. PMID- 20922326 TI - Attention demands in the workplace and the capacity to direct attention of nurses. AB - This was a descriptive, correlational study designed to evaluate the capacity to direct attention (CDA) of the nurse and to verify an association between the CDA and attention demand situations. For data collection the instruments used were: the Attentional Function Index and the Directed Attention Demands. The participants were 169 nurses of a teaching hospital in the State of Sao Paulo. The mean perception of performance or CDA was 60.4 which differed between the variables: unit of work (p=0.013), work hours (p=0.044), presence of health problems (p=0.026) and problems of a psychological nature (p=0.005). There was a negative association between the situations of demand and CDA (r = - 0.294, p<0.0001). It was concluded that nurses showed good CDA, which was related to some professional and demographic variables, and the higher the attentional demands, the lower the CDA. PMID- 20922327 TI - Sterility maintenance assessment of moist/wet material after steam sterilization and 30-day storage. AB - Moist/wet materials stored after autoclaving are considered contaminated and not recommended for use. This study evaluates the maintenance of sterility in moist/wet material after being submitted to steam sterilization and stored for a period of 30 days. Aiming to support decision-making in emergency situations, 40 surgical boxes packed in nonwoven cloth covering Spunbound, Metblouwn, Spunbound (SMS): half (the experimental group) were placed in an autoclave but the drying phase was interrupted, yielding moist/wet materials and the other half (the negative control group) underwent the complete cycle. The external parts of each surgical box were deliberately contaminated with Serratia marcescens and subsequently stored for 30 days. After this period, the boxes' contents were submitted to sterility tests and no growth was observed. The presence of moisture inside the surgical boxes did not interfere with maintaining their sterility. PMID- 20922328 TI - Prevalence of anemia in children three to 12 months old in a health service in Ribeirao Preto, SP, Brazil. AB - Iron deficiency anemia is the most common nutritional deficiency among children. This cross-sectional, descriptive and quantitative study is part of a multicenter project, which verified the prevalence of anemia in children aged three to 12 months, treated by a health service unit in Ribeirao Preto, SP, Brazil. Interviews with mothers and determining hemoglobin dosage were carried out with 121 children who participated in the study. Two international criteria were adopted as parameters of anemia according to the children's age. Descriptive statistics, measures of central tendency and associations were used for data analysis. The prevalence of anemia among 69 children aged three to 5 months was 20.2% and 48.0% among 52 children aged six to 12 months. The total prevalence of anemia was 32.2%. There was significant association between anemia and children's age, and anemia and the consumption of liquid cow's milk. PMID- 20922329 TI - Sociodemographic and clinical characteristics of psychiatric re-hospitalizations. AB - Segregated individuals with mental disorders, families without support or guidance concerning disease and treatment, and unprepared professionals are some of the factors that can contribute to re-hospitalizations. This study identifies sociodemographic variables, clinical conditions, diagnoses and treatments in order to identify their relationship with psychiatric re-hospitalizations. This is an exploratory and descriptive study. A form was used to search data in patients' files from 2006 and 2007 in a regional psychiatric facility. A total of 681 re-hospitalizations were identified, the majority due to treatment abandonment. Length of hospitalization was higher for women between 40 and 49 years of age. Positive associations of sociodemographic data with previous hospitalizations were found, such as type of discharge, and physical and mental condition, which is in accordance with the literature. Readmissions are associated with sociodemographic and clinical indicators. These findings can guide care and public policies regarding mental health. PMID- 20922330 TI - Factors associated with smoking in pregnancy. AB - The aim of this cross-sectional study was to identify factors related to smoking during pregnancy. The sample included 267 puerperae hospitalized in the maternity unit of a university hospital in Porto Alegre/RS. The data were collected through a self-applied instrument and statistically analyzed. The majority of the puerperae (51.3%) were between 18 and 25 years old, 55.4% were nonsmokers, 25.5% were smokers, 19.1% had recently ceased smoking (in abstinence). The nonsmokers had more consultations than the smokers and the abstinent smokers (p=0.025). The number of women who had more than one child was higher among smokers than among nonsmokers and abstinent smokers (p=0.002). Women were more likely to stop smoking before pregnancy when they had a partner who was a nonsmoker (p=0.007). Several factors influence smoking and smoking cessation and these are important in prenatal interventions aimed at pregnant women and their partners. PMID- 20922331 TI - Social model: a new approach of the disability theme. AB - The experience of disability is part of the daily lives of people who have a disease, lesion or corporal limitation. Disability is still understood as personal bad luck; moreover, from the social and political points of view, the disabled are seen as a minority. The aim of this study is to contribute to the knowledge about the experience of disability. The research presents a new approach on the theme: the social model. This approach appeared as an alternative to the medical model of disability, which sees the lesion as the primary cause of social inequality and of the disadvantages experienced by the disabled, ignoring the role of social structures in their oppression and marginalization. The study permits reflecting on how the difficulties and barriers society imposed on people considered different make disability a reality and portray social injustice and the vulnerability situation lived by excluded groups. PMID- 20922332 TI - Systematic review and its relationship with evidence-based practice in health. AB - Systematic reviews (SR) have gained relevance in the world and Latin America because of their credibility in the search, compilation, arranging and analysis of the information obtained from research about health interventions, during a period of time. Consequently, evidence-based practice uses SR as a way to capture the best evidence of clinical effectiveness. This article reviews SR methodology, process, and its usefulness in health professions like nursing and medicine. PMID- 20922335 TI - Can self-reported height and weight be used to calculate 10 year risk of osteoporotic fracture? AB - OBJECTIVES: 1) To determine the magnitude of error between self reported height and weight and measured height and weight, 2) To measure what affect this has on calculating 10 year probability of osteoporotic fracture using the World Health Organisation Fracture Risk Assessment Tool (FRAX(r)). DESIGN: Data collection from a nurse led community osteoporosis clinic. PARTICIPANTS: 214 post-menopausal women with at least one risk factor for osteoporosis. MEASUREMENTS: Self reported and measured height and weight, risk factors for osteoporosis, demographic details, and 10 year probability of hip fracture or any major osteoporotic fracture as measured by FRAX(r). RESULTS: Patients over-reported their height by a mean (95% confidence interval) of 2.8 (2.3-3.2) cm and under reported their weight by a mean of 2.1 (1.3-2.6) Kg. The resulting underestimation of body mass index was 1.8 (1.3-2.0) units. Using self reported height and weight resulted in a significant over-estimation of 10 year risk of hip fracture and any major osteoporotic fracture when compared to measured height and weight; Median 10 probability of hip fracture 3.75% Vs 3.25% (p < 0.001 ), median 10 year probability of any major osteoporotic fracture 15% Vs. 14% (p < 0.001). CONCLUSION: When calculating 10 year risk of fracture using the FRAX on line assessment tool, measured height and weight should be used instead of self reported height and weight. PMID- 20922336 TI - Influence of the consumption of fruits and vegetables on the nutritional status of a group of institutionalized elderly persons in the Madrid region. AB - AIM: To determine the nutritional status in a group of institutionalized elderly people in the Madrid region of Spain, with respect to their consumption of fruits and vegetables. SETTING: The Madrid region, Spain. PARTICIPANTS: Men and women 65 years of age (n=180). MEASUREMENTS: A dietetic study undertaken using the precise weighing method (7 consecutive days). Anthropometric and blood analysis data were also recorded. The study subjects were grouped according to whether or not they consumed the WHO/FAO-recommended amount of 400 g/day of fruits and vegetables. RESULTS: Mean fruit and vegetable consumption was 446.77 +/- 168.80 g/day. The subjects who consumed at least 400 g/day of these foods also took in the largest total weight of food, and had the largest macronutrient, fiber, vitamin and mineral intakes. They also had higher serum and erythrocyte folate concentrations and lower plasma homocysteine concentrations than those who consumed less than the recommended 400 g/day of fruits and vegetables. CONCLUSIONS: The subjects who consumed at least 400 g/day of fruits and vegetables generally showed a better nutritional status. It would be advisable that the consumption of such foods be relatively increased, especially by those who currently consume less than 400 g/day. PMID- 20922337 TI - Older rehabilitation patients are at high risk of malnutrition: evidence from a large Australian database. AB - BACKGROUND/OBJECTIVES: Routine nutrition screening is recommended for all older patients admitted to hospital however data on the prevalence of malnutrition in rehabilitation settings is sparse. This study assessed the nutritional status of older patients admitted to rehabilitation hospitals over a 5 year period and described the association between nutritional status and length of hospital stay (LOS) in this context. The usefulness of a recently revised version of the shortened MNA (MNA-SF) was also investigated. METHODS: A retrospective analysis was conducted of patients aged 65 + y admitted to two rehabilitation hospitals in New South Wales, Australia between 1st March 2003-30th June 2004, and 11th January 2005-10th December 2008. Nutritional status was determined on admission by trained dietitians using the full MNA instrument and the MNA-SF. Information on diagnosis-related grouping and length of stay (LOS) was obtained. RESULTS: Data was available for 2076 patients with a mean age of 80.6 (27.7) y. Thirty three percent and 51.5% of patients were classified as malnourished and at nutritional risk, respectively. Controlling for date of admission and diagnosis related grouping, LOS was higher in malnourished and at risk groups compared to their well nourished peers (P < 0.001) by 18.5 and 12.4 days, respectively. MNA SF demonstrated high sensitivity but relatively low specificity against the full MNA. CONCLUSION: The majority of older patients in the rehabilitation setting are nutritionally compromised which adversely influences LOS. In order to encourage more widespread screening, the MNA-SF may be able to replace the full MNA. PMID- 20922338 TI - Health economics and health policy issues in Alzheimer's disease. PMID- 20922339 TI - Costs of dementia in Hungary. AB - OBJECTIVE: The main aim of this paper is to give an overview on the quality of life, health care utilisation and costs of dementia in Hungary. METHOD: A cross sectional non-population based study of 88 consecutive dementia patients and their caregivers was conducted in three GP practices and one outpatient setting in 2008. Resource Utilization in Dementia (RUD), Mini Mental State Examination (MMSE) and quality of life (EQ-5D) were surveyed and cost calculations were performed. Costs of patients living at home were estimated by the current bottom up cost-of-illness calculations, while costs of nursing home patients were considered by official reimbursement to determine the disease burden from a societal viewpoint. RESULTS: The mean age of the patients was 77.4 years (SD=9.2), 59% of them were female. The mean MMSE score was 16.70 (SD=7.24), and the mean EQ-5D score was 0.40 (SD=0.34). The average annual cost of dementia was 6,432 Euros per patient living at home and 6,086 Euros per patient living in nursing homes. For the whole demented population (based on EuroCoDe data) we estimated total annual costs of 846.8 million Euros; of which 55% are direct costs, 9% indirect costs and 36% informal care cost. Compared to acute myocardial infarction the total disease burden of dementia is 26.3 times greater. CONCLUSIONS: This is the first study investigating resource utilisation, costs, and quality of life of dementia patients in the Central and Eastern European region. Compared to the general population of Hungary EQ-5D values of the demented patients are lower in all age groups. Dementia related costs are much lower in Hungary compared to Western European countries. There is no remarkable difference between the costs of demented patients living at home and in nursing homes, from the societal point of view. PMID- 20922340 TI - Novel approaches to incorporating pharmacoeconomic studies into phase III clinical trials for Alzheimer's disease. AB - The societal and individual costs of Alzheimer's disease are significant, worldwide. As the world ages, these costs are increasing rapidly, while health systems face finite budgets. As a result, many regulators and payers will require or at least consider phase III cost-effectiveness data (in addition to safety and efficacy data) for drug approval and reimbursement, increasing the risks and costs of drug development. Incorporating pharmacoeconomic studies in phase III clinical trials for Alzheimer's disease presents a number of challenges. We propose several specific suggestions to improve the design of pharmacoeconomic studies in phase III clinical trials. We propose that acute episodes of care are key outcome measures for pharmacoeconomic studies. To improve the possibility of detecting a pharmacoeconomic impact in phase III, we suggest several strategies including; study designs for enrichment of pharmacoeconomic outcomes that include co-morbidity of patients; reducing variability of care that can affect pharmacoeconomic outcomes through standardized care management; employing administrative claims data to better capture meaningful pharmacoeconomic data; and extending clinical trials in open label follow-up periods in which pharmacoeconomic data are captured electronically by administrative claims. Specific aspects of power analysis for pharmacoeconomic studies are presented. The particular pharmacoeconomic challenges caused by the use of biomarkers in clinical trials, the increasing use of multinational studies, and the pharmacoeconomic challenges presented by biologicals in development for Alzheimer's disease are discussed. In summary, since we are entering an era in which pharmacoeconomic studies will be essential in drug development for supporting regulatory approval, payor reimbursement and integration of new therapies into clinical care, we must consider the design and incorporation of pharmacoeconomic studies in phase III clinical trials more seriously and more creatively. PMID- 20922341 TI - Differences in resource use and costs of dementia care between European countries: baseline data from the ICTUS study. AB - OBJECTIVES: This study aimed to estimate the costs of formal and informal care of patients with Alzheimer's disease, to compare care costs across European countries and identify potential differences in cost patterns between countries and regions. SETTING: The ICTUS study is a prospective, naturalistic observational study conducted in specialised memory clinics in 12 European countries. In total, 1385 patients diagnosed with Alzheimer's disease were enrolled at baseline. All subjects had a reliable informant (primary caregiver) and informed consent was obtained from patients or their primary caregiver. MAIN OUTCOME MEASURES: Resource utilization data was captured with the RUD Lite (Resource Utilization in Dementia) instrument and caregiver burden with the Zarit Burden Interview (ZBI). Patient disease severity was measured with the Mini Mental State Examination (MMSE), Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-cog), Katz' index (PADL), Instrumental activities of daily living (IADL) scale and Neuropsychiatric inventory (NPI). RESULTS: The mean annual cost of care per patient was estimated to ?7,820 (95% CI: ?7,194-?8,446), whereof 54% were costs of informal care, 16% direct medical costs and 30% community care costs. There were substantial differences in total resource utilization and also in the balance between formal and informal care between Northern, Western and Southern Europe. PADL scores were strongly associated with formal care costs while IADL scores correlated strongly with informal care costs. CONCLUSIONS: Costs of Alzheimer's disease are high across European countries. Activities of daily living is an important determinant of care costs. Formal care service use is lower and informal care higher in Southern Europe compared to Western and Northern Europe. Differences in resource utilization patterns are important to consider in international studies of dementia care costs as well as in economic evaluations of new treatments for dementia. PMID- 20922342 TI - Alzheimer's disease: the strength of association of costs with different measures of disease severity. AB - OBJECTIVE: To identify Alzheimer's disease (AD) severity measures for use in cost effectiveness models that effectively capture the impact of AD on costs. METHODS: A review of the literature and data abstraction from papers that present 1) mean AD costs (direct, indirect, or total) by disease severity, defined using measure of cognition, functional status, and behavior; and/or 2) the results of regression analyses that estimate the strength of the association between AD costs and disease severity. RESULTS: All papers reviewed showed that mean total costs increase with disease severity regardless of severity-measurement method. The relative difference in mean total costs between patients with severe disease compared to those with moderate disease, or moderate disease compared to mild disease, was fairly consistent across studies, suggesting that any of the disease severity measures may be used to broadly categorize patients by cost. However, when regression analysis included multiple disease-severity measures, independent associations with costs were noted for the different measures. Cognitive and functional status measures were consistently associated with direct costs, whereas functional status and behavioral measures were consistently associated with indirect costs and caregiver hours. CONCLUSIONS: Either multidimensional disease-severity measures, or a single disease-severity measure, that capture the impact of cognition, functional status, and behavior on costs are needed for cost effectiveness models. PMID- 20922343 TI - Savings from sub-groups?: Policy guidance and Alzheimer's disease treatments. AB - BACKGROUND: A range of new therapeutic agents are now available for the management of Alzheimer's disease. With limited resources available however, policy-makers and other health care professionals have to prioritise and judge competing treatments on criteria such as the magnitude of clinical effectiveness and cost-effectiveness. Policy guidance that restricts treatments to defined patient sub-groups can improve the cost-effectiveness of treatments, and can help limit rises in health care expenditures. Budget impact models that estimate the amount of additional costs and potential savings are being increasingly used by policy-makers. However, the amount of savings estimated in such models depends on the effectiveness of treatment in changing morbidity, and the association between morbidity and costs. AIM: To examine the magnitude of cost savings arising from provision of treatment to different patient sub-groups, using policy guidance decisions made by the National Institute for Health and Clinical Excellence (NICE) for cholinesterase inhibitor therapies in Alzheimer's Disease (AD) in the United Kingdom National Health Service (NHS). METHOD: Cohort simulation modelling. RESULTS: Policy guidance decisions that restricted treatment to smaller patient sub-groups were associated with lower overall care costs, but did not reduce drug costs. CONCLUSIONS: Given increasing recognition by health policy makers of the importance of affordability of new treatments, greater attention should be paid to measurement of cost impacts by sub-groups within health economic modelling. PMID- 20922344 TI - Dementia case management effectiveness on health care costs and resource utilization: a systematic review of randomized controlled trials. AB - The growing number of dementia patients leads to both policy, economic and health organization constraints. Many healthcare systems have developed case management programs in order to optimize dementia patients and caregivers care and services delivery. Nevertheless, to what extend case management programs can lead to an improvement of care and expenditures savings is not known. Thus, the objective of this paper was to analyse the efficacy of case management programs on health care cost, institutionalization and hospitalization. A systematic review of randomized controlled trials was therefore conducted of the databases MEDLINE and SCOPUS up to September 2009. Included were English language randomized controlled trials of case management for community dwelling dementia patients and their caregivers evaluating costs, institutionalization and hospitalization. An evaluation of the methodological quality was performed. Thirteen relevant studies concerning 12 trials were identified and included. None of the 7 low quality studies reported positive impact of case management on the outcomes of interest. Among the 6 good quality studies, 4 reported positive impact on institutionalization delay, institutionalization length or nursing home admission rate. In none of the good quality studies was evidence found for savings in health care expenditures or reduction in hospitalization recourse. The weak convincing evidences from randomized trials do not allow any conclusion about the efficacy of case management for dementia patient and caregivers on costs and resource utilization. Further research should focus on determining subgroups of caregivers who could benefit the most from case management. PMID- 20922345 TI - Clinic visits and prescribing patterns among Veterans Affairs Maryland Health Care System dementia patients. AB - OBJECTIVE: Our objective was to determine how patient demographics and outpatient referrals to specialized dementia (DEM) or mental health (MH) clinics influence receipt of anti-dementia (AD), antidepressant (ADEP), antipsychotic (APSY) and sedative-hypnotic (SEDH) medications among veterans with dementia. DESIGN: Retrospective, cross-sectional observational study. SETTING: Veterans Affairs Maryland Health Care System (VAMHCS). PARTICIPANTS: Veterans aged >= 60 years with Alzheimer's or related dementia diagnosis after 1999 with minimum of one year follow-up or death were included. MEASUREMENTS: Retrospective analysis of VAMHCS electronic medical records were used to determine predictors of AD, ADEP, APSY, and SEDH prescribing using logistic regression models that examined visits to DEM or MH clinics, patient age, follow-up time, race/ethnicity and marital status. RESULTS: Among 1209 veterans with average follow-up of 3.2 (SD 1.9) years, 36% percent had MH visits, 38% had DEM visits and 19% visited both clinics. DEM visits were associated with AD and ADEP but not APSY medication receipt (OR(AD:DEM) = 1.47, 95% CI = (1.052, 2.051); OR(ADEP:DEM) = 1.66, 95% CI = (1.193, 2.302); OR(APSY:DEM) = 1.35, 95% CI = (0.941, 1.929)). MH visit was associated with ADEP and APSY medication receipt (OR(AD:MH)? = 1.16, 95% CI = (0.821, 1.631); OR(ADEP:MH) = 2.83, 95% CI = (2.005, 4.005); OR (APSY:MH) = 4.41, 95% CI = (3.109, 6.255)). CONCLUSION: In the VAMHCS dementia population, visits to DEM or MH specialty clinics increase the odds of receiving AD, ADEP, and APSY medications. PMID- 20922346 TI - The Resource Utilization in Dementia (RUD) instrument is valid for assessing informal care time in community-living patients with dementia. AB - OBJECTIVE: Informal care is a significant component of the societal resource use and costs in dementia care. Thus it is fundamental that assessments of informal care are valid. Thus the aim was to analyse the validity of time estimates with the Resource Utilization in Dementia (RUD) instrument. DESIGN: Prospective observational study. SETTING: Community sample. PARTICIPANTS: Fourteen married and cohabiting patient-caregiver pairs. MEASUREMENTS: Comparisons of estimates of caregiver time by recall with the RUD instrument, by diaries and by direct observation, with calculation of agreement statistics for recall vs. diary and recall vs. direct observation to assess accuracy of the time estimates derived from recall. RESULTS: The patients and their caregivers participated in 47 diaries and 30 observation sessions. The agreement between diaries and recall estimates was high for personal ADL (intra-class correlation (ICC) 0.93), supervision (ICC 0.87) and total time (ICC 0.91) and lower but acceptable for instrumental ADL (ICC 0.75). Regarding observation vs recall estimates, the corresponding figures were for personal ADL (ICC 0.81), for instrumental ADL (ICC 0.74), for supervision (ICC 0.78) and for total time (ICC 0.80). CONCLUSION: The RUD instrument appears to accurately estimate the amount of informal care provided by caregivers to dementia patients. PMID- 20922347 TI - Effects of swimming on eye hand coordination and balance in the elderly. AB - OBJECTIVE: To evaluate the effects of swimming on upper extremity motor control, and balance in elderly population. DESIGN: Cross-sectional study. SETTING: The biomechanical laboratory in a tertiary hospital. PARTICIPANTS: The swimming group consisted of 20 swimmers (n_20, 65.4 +/- 5.5 years) who received regular swimming exercise for more than 2 years. The control group consisted of 34 healthy active subjects (n_34, 67.4 +/- 5.7 years) who have regular exercises other than swimming. MEASUREMENTS: The eye hand coordination was evaluated by calculating the mean reaction time required in accurately pointing onto the center of the target sensors that come in three different sizes (1 cm, 1.5 cm, and 2 cm in diameter). The SMART Balance Master device was used to measure posture balance. The maximal stability, center of pressure (COP) velocity, and percentage ankle strategy were obtained under six different balance conditions. RESULTS: In the testing of upper extremity motor control, the swimming group had significant shorter mean reaction time as compared with the control group in all three target sensor sizes (p < 0.05). In balance testing, the swimming group had significant greater percentage of ankle strategy during eyes closed and fixed support (EC), and sway-referenced vision and support (SVSS) conditions as compared with the control group (p < 0.05). CONCLUSION: Regular swimming exercise may result in improved eye hand coordination as faster and more accurate repetitive movements. Swimming may also result in improved balance function under few complicated balance conditions. PMID- 20922348 TI - Do general practitioners recognize mild cognitive impairment in their patients? AB - OBJECTIVES: The need for recognition of mild cognitive impairment (MCI) in primary care is increasingly discussed because MCI is a risk factor for dementia. General Practitioners (GPs) could play an important role in the detection of MCI since they have regular and long-term contact with the majority of the elderly population. Thus the objective of this study is to find out how well GPs recognize persons with MCI in their practice population. DESIGN: Cross-sectional study. SETTING: Primary care chart registry sample. PARTICIPANTS: 3,242 non demented GP patients aged 75-89 years. MEASUREMENTS: GPs assessed the cognitive status of their patients on the Global Deterioration Scale (GDS). Thereafter, trained interviewers collected psychometric data by interviewing the patients at home. The interview data constitute the basis for the definition of MCI cases (gold standard). RESULTS: The sensitivity of GPs to detect MCI was very low (11 12%) whereas their specificity amounts to 93-94%. Patients with MCI with a middle or high level of education more often got a false negative assignment than patients with a low educational level. The risk of a false positive assignment rose with the patients' degree of comorbidity. GPs were better at detecting MCI when memory or two and more MCI-domains were impaired. CONCLUSION: The results show that GPs recognise MCI in a very limited number of cases when based on clinical impression only. A further development of the MCI concept and its operationalisation is necessary. Emphasis should be placed on validated, reliable and standardised tests for routine use in primary care encompassing other than only cognitive domains and on case finding approaches rather than on screening. Then a better attention and qualification of GPs with regard to the recognition of MCI might be achievable. PMID- 20922349 TI - Functional evaluation distinguishes MCI patients from healthy elderly people--the ADCS/MCI/ADL scale. AB - Patients with MCI may present minor impairments in activities of daily living (ADL). The main objective of this work was to evaluate the ability of two versions of the Alzheimer's Disease Cooperative Study/Activities of Daily Living scale adapted for MCI patients (ADCS/MCI/ADL18 and ADCS/MCI/ADL24) to distinguish patients with MCI from healthy control subjects. Participants were 60 years or older and community dwelling: 31 control subjects, 30 aMCI patients and 33 AD patients. A protocol of neuropsychological tests, global evaluation scales, functional scales, and depressive symptoms assessment was used. Activities of balancing the cheque book, using a telephone, going shopping, taking medication regularly, finding objects, talking about current events, watching television, initiating complex activities, keeping appointments or meetings, reading, getting around outside the home and driving a car were impaired in aMCI patients. The ADCS/MCI/ADL24 scale was better than the ADCS/MCI/ADL18 scale in distinguishing aMCI patients from healthy controls (sensitivity=0.87, specificity=0.87, ROC c=0.887, cut-off point=52/53). The detection of initial functional changes with appropriate scales may contribute to the early diagnosis of MCI and the development of targeted interventions to improve everyday function or prolong independence. PMID- 20922350 TI - An urgent need to improve life conditions of seniors. AB - In the fall of 2007, the Government of Quebec set up a Public Consultation on Living Conditions of Seniors. Fifty sessions were held in 26 cities across all 17 regions of the province. More than 4000 seniors attended the sessions and 275 briefs were received from scientists and associations. Three themes were identified in the report published in 2008: supporting seniors and their caregivers, reinforcing the place of seniors in society, and preventing problems associated with aging (suicide, abuse, addictions). The main actions that I recommended included: Increasing the Guaranteed Income Supplement to prevent poverty; Modifying pension plans and working conditions to allow for progressive retirement; Making a major investment in home care to provide access to services regardless of place of residence; Introducing an Autonomy Support Benefit and autonomy insurance program for financing services to support people with disabilities; Generalizing an Integrated Service Delivery Network providing services to frail older people; Better training for professionals in gerontology. I also recommended setting up a National Policy on Seniors to align all government departments and agencies, municipalities and the private sector around a vision, objectives and a set of actions for improving the integration of seniors in an aging society. This would contribute to a more equitable, interdependent and wiser society. Unfortunately, the Government did not support these recommendations. It is now time for scientists to get involved in leading policy on seniors and in the political arena. PMID- 20922351 TI - Circulating TNF alpha receptor levels identify older adults who fail to regain weight after acute weight loss. AB - OBJECTIVE: Some healthy older adults have difficulty regaining weight after acute weight loss, and the reason for this failure to regain weight is unknown. The objective of this study was to determine if elevated leptin or pro-inflammatory cytokine levels are associated with failure to regain weight over two years after an acute weight loss intervention. DESIGN: Two year prospective study after an acute weight loss intervention. SETTING: University of Washington Medical Center from 2001-2006. PARTICIPANTS: Nineteen older (>= 70 years old) men and women. MEASUREMENTS: Body weights, health status questionnaire, body composition data, serum leptin, glucose, insulin, C- reactive protein and pro-inflammatory cytokine levels were measured every six months for two years. RESULTS: Five subjects out of 19 failed to regain weight after two years. The subjects who failed to regain weight after 2 years had higher circulating levels of tumor necrosis factor receptor particle 55 (TNFRp55) at baseline and at 6, 12, 18 and 24 months of follow up compared to subjects who regained weight after 2 years (P = 0.02 ). CONCLUSION: Five out of 19 older subjects had difficulty regaining weight for up to 2 years following an acute weight loss intervention, and their TNFRp55 levels were persistently higher than in subjects who regained weight. Greater TNF alpha action, as reflected by higher circulating levels of TNFRp55, could be contributing towards inability of some older persons to regain weight after acute weight loss. PMID- 20922352 TI - [Angiotensin-converting enzyme inhibitor induced angioedema : new therapy options]. AB - Angiotensin-converting enzyme (ACE) inhibitors block the catalysis of angiotensin I to angiotensin II and also the breakdown of bradykinin. ACE inhibitor-induced angioedema is mediated by inhibited bradykinin degradation leading to enhanced bradykinin plasma levels. The efficacy of currently used standard treatments with antiallergic drugs is questionable. A patient with acute ACE inhibitor-induced angioedema was treated with icatibant, a specific bradykinin B2 receptor antagonist approved for the treatment of hereditary angioedema. A single subcutaneous injection of 30 mg icatibant resulted in a rapid onset of symptom relief and a remarkable shortening of duration of the attack. PMID- 20922353 TI - [Management of complex thrombocytopenia with thrombelastometry : a case of simultaneous posttransfusion purpura and heparin-induced thrombocytopenia]. AB - The case presented describes the combined onset of heparin-induced thrombocytopenia II (HIT) and post-transfusion purpura (PTP) 5-10 days following exposure to heparin and blood transfusion during aortic dissection repair. On day 4 the platelet count decreased by 40% and D-dimers started to increase again. Despite a low clinical probability for HIT-II at this time (4T score of 3) serological testing was done the next day and yielded a negative test result. Following a transient rise after platelet transfusion another 40% decrease in platelet count occurred on day 8. To increase precision of the 4T score, screening ultrasonography was performed and identified a clinically unapparent jugular vein thrombosis. As this increased the 4T score to 6 points, serological testing was repeated and now showed the presence of HIT-II antibodies. Despite switching from heparin to argatroban the platelet count continued to decrease to <5*10(3)/ul. Conventional clotting tests showed a prolonged prothrombin time and severe hypofibrinogenemia. Because of the female sex, age >50 years, history of pregnancy and transfusion 8 days before, PTP was suspected. The alteration of the plasmatic coagulation, however, could not be explained by PTP. Therefore, disseminated intravascular coagulation (DIC) and interference of argatroban with conventional clotting tests were considered as alternative diagnoses. In order to differentiate between the two alternatives rotational thrombelastometry (ROTEM(r)) was performed and revealed an increased functional fibrinogen level without signs of hyperfibrinolysis. This argued for an interference of argatroban with the Clauss method of fibrinogen measurement and rendered DIC unlikely. Under suspicion of PTP, treatment with immunoglobulin was initiated and blood transfusions were avoided. Detection of PTP antibodies 1 day later confirmed the combined presence of PTP and HIT-II. As hyperfibrinogenemia compensated for the effects of thrombocytopenia on clot firmness in ROTEM(r), anticoagulation with lepirudin was started at 9*10(3) platelets/ul only. The next day the platelet count increased to 32*10(3)/ul and clot firmness returned to normal. No thromboembolic complications and no relevant bleeding were observed. In summary, this case shows for the first time that HIT-II and PTP can occur in parallel in patients with simultaneous exposure to heparin and blood transfusions. Confounding effects of argatroban on conventional clotting tests may mimic DIC under these circumstances and make diagnosis difficult. Careful evaluation of the time-related magnitude in platelet decrease, patient history, course of D-dimers, screening ultrasonography and ROTEM(r) seem to be helpful to initiate early appropriate therapy before serological test results become available. In contrast to the Clauss method of fibrinogen measurement, assessment of clot firmness in ROTEM(r) is not influenced by argatroban. Moreover, ROTEM(r) reveals the compensatory effects of increased functional fibrinogen on clot firmness during severe thrombocytopenia as an important variable for anticoagulation therapy during thrombocytopenia with increased thromboembolic risk. PMID- 20922354 TI - [Anesthesia with neuromuscular diseases]. AB - Among the neuromuscular diseases (NMDs) over 800 individual entities have been identified. The vast majority of these diseases occur very seldom but all NMDs together add up to a prevalence of 1:1,500. Accordingly the conclusion "seldom diseases are common" seems to be appropriate. The scope of NMDs is very wide varying from the affection of single muscle groups to the complete musculature, from slowly progressive to fulminant progressive forms, from perinatal to the adult manifestation as well as number, course and character of associated comorbidities. Due to the wide heterogeneity concerning NMDs it is of great importance for anesthesiologists to be knowledgeable on relevant comorbidities as well as indications and contraindications for the various anesthetics. PMID- 20922355 TI - [Emergency rescue XXL. Morbidly obese patient in the emergency medical service]. AB - Obesity in Germany is becoming more and more prevalent. Significantly overweight patients (>200 kg) pose an increasing and difficult challenge for emergency medical services, emergency doctors and the hospitals responsible for further treatment. The anatomic and physiological characteristics of patients with extreme obesity must be taken into consideration, particularly the airway, breathing, circulation, disability, exposure and environment of the patient. Furthermore special preparations for medical supplies, concepts and strategies for transport and further treatment in hospital are required. Suitable equipment and coordinated processes are essential for both the safety of the persons involved and the patient's dignity. It is, however, a fact that many organizations and hospitals are poorly prepared for this challenge as the complete infrastructure of a hospital has to be adapted. Emergency transport in a bed should be avoided. Neighboring rescue services must be alarmed at an early stage if the commune concerned does not have adequate means of its own. Politics should guarantee cost-covering remuneration for hospitals and rescue services. PMID- 20922356 TI - [Xenon revisited]. PMID- 20922357 TI - [Diagnostic and interventional operations in childhood: anesthesiology management]. AB - Diagnostic and interventional procedures in children often need to be performed under sedation. This prevents pain and stress in children and provides optimal examination conditions. For complete immobilization and stress shielding the depth of sedation often corresponds with general anesthesia. Therefore, established safety standards need to be observed and a fundamental precondition is implementation by a skilled anesthesiologist who can handle the anesthesiology procedure and its possible complications. Organization, schedule, medication, equipment, monitoring and post-anesthesiology care should be institutionally defined. A professional anesthesiology management of pediatric patients is an important factor to increase the quality of care, patient safety and patient satisfaction. PMID- 20922358 TI - [Improved survival by guideline compliant cardiopulmonary resuscitation: analysis of primary survival rates in the Hamburg emergency medical service]. AB - BACKGROUND: In 2005 revised guidelines for cardiopulmonary resuscitation (CPR) were published by the European Resuscitation Council replacing the guidelines implemented in the year 2000. The aim of this study was to test the compliance with valid guidelines and to establish the quality of pre-hospital CPR provided by paramedics over a period of 38 months. PATIENTS AND METHODS: A total of 299 CPRs performed by paramedics of the emergency medical services of Hamburg, Germany between 1(st) November 2004 and 31(st) December 2007 were analyzed. Digital recordings of automated external defibrillators and emergency protocol data were analyzed in detail. CPR was judged as incorrect if the defibrillation energy level did not correspond to the valid guidelines or if the interval between defibrillations exceeded a tolerance range of more than 30% compared to the valid guidelines. RESULTS: All CPRs (299) were included in the analysis of which 197 (65.9%) were intended to follow the 2000 guidelines and 102 (34.1%) the 2005 guidelines. Return of spontaneous circulation (ROSC) was achieved in 164 cases (54.8%) and survival to hospital admission in 125 cases (41.8%). CPR was performed accurately according to guidelines in only 26 cases (8.7%). In 273 cases (91.3%) the guidelines were not followed completely. Concerning the translation of guidelines into practice most faults occurred due to wrong intervals (89.3%), wrong defibrillation energy (33.4%) and medical errors, such as defibrillating an asystolic patient (7.0%). Primary survival rates were not significantly different when CPR accurately followed the 2000 or 2005 guidelines (40.1% versus 45.1%). Comparing primary survival rates of cases in which the guidelines were followed completely, there was no significant difference between the 2000 guidelines (15 out of 21 cases 71.4%) and 2005 guidelines (4 out of 5 cases 80.0%). However, compliance with valid guidelines significantly increased primary survival rates compared to non-compliance with valid guidelines (19 out of 26 cases 73.1% versus 106 out of 273 cases 38.8%; p=0.007). This effect was independent of the duration of CPR. Comparing CPR with monophasic defibrillation (189 cases) or biphasic defibrillation (58 cases), there was a significantly higher rate of ROSC (56.1% versus 72.4%) and a significantly higher rate of primary survival (41.3% versus 56.9%) in favour of biphasic defibrillation. CONCLUSION: The results of our study show that compliance with valid guidelines is low and furthermore suggest that compliance with guidelines significantly reduces mortality. Future research may be warranted into the question of how to increase compliance with current CPR guidelines in pre-hospital emergency care. PMID- 20922360 TI - [Importance of mammography, sonography and MRI for surveillance of neoadjuvant chemotherapy for locally advanced breast cancer]. AB - PURPOSE: The aim of this study is to give an overview on the surveillance of response to neoadjuvant chemotherapy in locally advanced breast cancer with mammography, ultrasound and breast MRI. MATERIAL AND METHODS: The results of a recently presented study on surveillance in the course of chemotherapy with contrast-enhanced MRI are compared with ratings based on mammography and ultrasound. RESULTS: Contrast-enhanced MRI correlates best with the histological tumor size when compared with mammography and ultrasound. Tumors with a high HER2 score (2+ with positive FISH test or 3+) show a significantly higher response compared to tumors with a lower HER2 score: size p <0.01, maximum enhancement p <0.01 and area under the curve (AUC) p <0.05. Reduction of tumor size and enhancement are complementary parameters and are not correlated to each other (r=0.22). DISCUSSION: Contrast-enhanced MRI of the breast is a reliable method for quantification of the response to neoadjuvant chemotherapy. The reductions of tumor size and of tumor enhancement are not correlated. Therefore, it may be reasonable to take both aspects for quantification of therapy response into account. Further studies are needed for evaluation of the value of breast MRI as a prognostic factor. PMID- 20922361 TI - Roles of the alpha1A-adrenergic receptor carboxyl tail in protein kinase C induced phosphorylation and desensitization. AB - Noradrenaline- and tetradecanoyl phorbol acetate (TPA)-induced phosphorylation and functional desensitization of the following receptors were studied: (1) wild type bovine alpha(1A)- and hamster alpha(1B)-adrenergic receptors (ARs), (2) chimeric ARs in which the carboxyl terminus tails were exchanged (alpha(1AB)- and alpha(1BA)-ARs), and (3) carboxyl terminus-truncated alpha(1A)-ARs fussed to enhanced green fluorescent protein. Noradrenaline and TPA pronouncedly increased alpha(1B)-AR phosphorylation while TPA markedly desensitized these receptors. In contrast, TPA-induced desensitization and TPA- and noradrenaline-induced phosphorylation of alpha(1A)-ARs were clearly of lesser magnitude. Chimeric ARs with exchanged carboxyl terminus tails showed that the extent of phosphorylation reflected the carboxyl domain rather than the receptor core. Surprisingly, there was no correlation between phosphorylation and functional desensitization, i.e., activation of protein kinase C clearly desensitized both chimeric receptors to a similar extent. Interestingly, TPA and noradrenaline increased carboxyl terminus truncated alpha(1A)-AR phosphorylation and TPA also induced receptor desensitization. We were unable to detect carboxyl terminus-truncated alpha(1A) AR internalization after 5-min stimulations with noradrenaline or TPA. Our results suggest the following: (a) the alpha(1A)-AR carboxyl terminus tail was not essential for signaling or desensitization; (b) carboxyl terminus tail exchange "transplanted" the phosphorylation pattern of the receptors, but the functional consequences of such a transplant were very limited; (c) alpha(1A)-AR desensitization was not associated to receptor internalization. PMID- 20922362 TI - Reduction of fear-potentiated startle by benzodiazepines in C57BL/6J mice. AB - RATIONALE: Anxiety disorders affect 18% of the United States adult population annually. Recent surges in the diagnosis of posttraumatic stress disorder (PTSD) from combat-exposed veterans have prompted an urgent need to understand the pathophysiology underlying this debilitating condition. OBJECTIVES: Anxiety and fear responses are partly modulated by gamma aminobutyric acid type A (GABA(A)) receptor-mediated synaptic inhibition; benzodiazepines potentiate GABAergic inhibition and are effective anxiolytics. Many genetically modified mouse lines are generated and/or maintained on the C57BL/6J background, a strain where manipulation of anxiety-like behavior using benzodiazepines is difficult. Fear potentiated startle (FPS), a test of conditioned fear, is a useful preclinical tool to study PTSD-like responses but has been difficult to establish in C57BL/6J mice. METHODS: We modified several FPS experimental parameters and developed a paradigm to assess conditioned fear in C57BL/6J mice. The 6-day protocol consisted of three startle Acclimation days, a Pre-Test day followed by Training and Testing for FPS. Subject responses to the effects of three benzodiazepines were also examined. RESULTS: C57BL/6J mice had low levels of unconditioned fear assessed during Pre-Test (15-18%) but showed robust FPS (80-120%) during the Test session. Conditioned fear responses extinguished over repeated test sessions. Administration of the benzodiazepines alprazolam (0.5 and 1 mg/kg, i.p.), chlordiazepoxide (5 and 10 mg/kg, i.p.), and diazepam (1, 2, and 4 mg/kg, i.p.) significantly reduced FPS to Pre-Test levels. CONCLUSIONS: We used a modified and pharmacologically-validated paradigm to assess FPS in mice thereby providing a powerful tool to examine the neurobiology of PTSD in genetic models of anxiety generated on the C57BL/6J background. PMID- 20922364 TI - An assessment of serum sodium within 48 h after percutaneous nephrolithotomy with half-strength saline solution. AB - The aim of this study was to evaluate the postoperative serum sodium changes after percutaneous nephrolithotomy (PCNL) with half-strength saline irrigation. PCNL operations from June to August 2008 were included. PCNL was performed according to the standard prone position with fluoroscopic guidance. Patients received 0.3% saline-3.3% dextrose by intravenous infusion in the first 24 h after operation. Serum sodium was measured before the operation and at 6, 24 and 48 h after the operation. 96 patients were included. Serum sodium slightly decreased from preoperative 140.3 +/- 2.8 mEq/l to 140.1 +/- 3.6, 139.1 +/- 3.4 (p < 0.01) and 139.3 +/- 2.7 (p < 0.05) at 6, 24 and 48 h after the operation, respectively. Half-strength saline irrigation does not result in considerable change in the postoperative serum sodium in simple PCNL operations. The use of intravenous solutions with hypotonic sodium is discouraged in PCNL patients with the possibility of high volume absorption of hypotonic irrigation fluid. PMID- 20922363 TI - Revisiting the thermodynamic theory of optimal ATP stoichiometries by analysis of various ATP-producing metabolic pathways. AB - The stoichiometry of ATP-producing metabolic pathways had been analysed theoretically by several authors by using evolutionary arguments and optimality principles. Waddell et al. (Biochem Educ 27:12-13, 1999) analysed (lactate producing) glycolysis and used linear irreversible thermodynamics. The result was that half of the free-energy difference should be converted into free-energy of ATP and the remaining half should be used to drive the pathway. The calculated stoichiometry is in agreement with the observed yield of two moles of ATP per mole of glucose. Using the same approach, we here analyse eight other metabolic pathways. Although the deviation is not very large, the calculated values do not fit as nicely as for glycolysis as leading to lactate. For example, for O2 respiration, the theoretical ATP yield equals 27.9. The real value varies among organisms between 26 and 38. For mixed-acid fermentation in Escherichia coli, the theoretical and experimental values are 2.24 and 2, respectively. For arginine degradation in M. pneumoniae, the calculated value is 2.43 mol of ATP, while in vivo only one mole is produced. During evolution, some pathways may not have reached their optimal ATP net production because energy yield is not their only function. Moreover, it should be acknowledged that the approach by linear irreversible thermodynamics is a rough approximation. PMID- 20922366 TI - Progressive noninfectious anterior vertebral fusion. PMID- 20922367 TI - Nasopharyngeal carcinoma with splenic and cystic liver metastases in a pediatric patient: 18F-FDG PET-CT findings. AB - Pediatric nasopharyngeal carcinoma (NPC) is rare and usually poorly differentiated. We report a 14-year-old boy with NPC with metastases to liver, spleen, lymph nodes and bone marrow. The liver metastases closely resembled benign cystic liver disease on imaging; however, they showed intense uptake similar to other metastatic sites on positron emission tomography (PET) scan. A liver biopsy could not be performed on the boy. The boy responded clinically to platinum-based chemotherapy, and all the baseline PET-positive lesions became negative. This case highlights the rarity of splenic and cystic liver metastases in pediatric NPC and demonstrates the potential use of PET/CT in diagnosis, staging and response assessment in metastatic pediatric NPC. PMID- 20922368 TI - Temporomandibular joint injections: interventional MR imaging demonstrates anatomical landmark approach to be inaccurate when compared to direct visualization of the injectant. PMID- 20922369 TI - Nasogastric tubes and videofluoroscopic swallowing studies in children. AB - BACKGROUND: Videofluoroscopic swallowing study (VFSS) is considered to be the gold standard method in assessing the risk of aspiration. Not infrequently, children who undergo VFSS are on tube feeds. OBJECTIVE: To investigate the reliability of the findings of VFSS when a nasogastric tube is in place at the time of the study. MATERIALS AND METHODS: A retrospective review of VFSS covered a 6.5-year period. This review included only patients who had studies performed both with and without a nasogastric tube in place. Ninety-two studies (46 with and 46 without a nasogastric tube) were assessed in 46 children (30 boys, 16 girls) with a mean age of 6.7 months. The VFSS checklist of findings included weak sucking, incoordination, nasopharyngeal reflux, valecular and pyriform sinus pooling, penetration, aspiration and associated cough or respiratory compromise. We compared the occurrence rates of these events between studies with and without a nasogastric tube. RESULTS: No significant statistical difference was found in the occurrence of the different swallowing events during VFSS in the two groups. The presence of a nasogastric tube does not significantly alter the association of cough; however, it shows a moderately significant (P=0.06) higher incidence of clinical respiratory compromise if aspiration does occur (8.5% of aspiration events). CONCLUSION: The presence of a nasogastric tube does not alter the findings of VFSS; however, it might increase the incidence of respiratory compromise when aspiration is present. PMID- 20922370 TI - Membrane protein dynamics in different environments: simulation study of the outer membrane protein X in a lipid bilayer and in a micelle. AB - The bacterial outer membrane protein OmpX from Escherichia coli has been investigated by molecular dynamics simulations when embedded in a phospholipid bilayer and as a protein-micelle aggregate. The resulting simulation trajectories were analysed in terms of structural and dynamic properties of the membrane protein. In agreement with experimental observations, highest relative stability was found for the beta-barrel region that is embedded in the lipophilic phase, whereas an extracellular protruding beta-sheet, which is a unique structural feature of OmpX that supposedly plays an important role in cell adhesion and invasion, shows larger structure fluctuations. Additionally, we investigated water permeation into the core of the beta-barrel protein, which contains a tight salt-bridge and hydrogen-bond network, so that extensive water flux is unlikely. Differences between the bilayer and the micellar system were observed in the length of the barrel and its position inside the lipid environment, and in the protein interactions with the hydrophilic part of the lipids near the lipid/water interface. Those variations suggest that micelles and other detergent environments might not offer a wholly membrane-like milieu to promote adoption of the physiological conformational state by OmpX. PMID- 20922371 TI - Engineering of nitrogen metabolism and its regulation in Corynebacterium glutamicum: influence on amino acid pools and production. AB - Nitrogen is one of the macronutrients necessary for living cells, and consequently, assimilation of nitrogen is a crucial step for metabolism. To satisfy their nitrogen demand and to ensure a sufficient nitrogen supply even in situations of nitrogen limitation, microorganisms have evolved sophisticated uptake and assimilation mechanisms for different nitrogen sources. This mini review focuses on nitrogen metabolism and its control in the biotechnology workhorse Corynebacterium glutamicum, which is used for the industrial production of more than 2 million tons of L: -amino acids annually. Ammonium assimilation and connected control mechanisms on activity and transcription level are summarized, and the influence of mutations on amino acid pools and production is described with emphasis on L: -glutamate, L: -glutamine, and L: -lysine. PMID- 20922372 TI - Identification and quantification of mycothiol in Actinobacteria by a novel enzymatic method. AB - Mycothiol (MSH) was reported to be the dominant low molecular weight thiol in members of the Actinobacteria. In this study, a simple, fast, and sensitive method for qualitative and quantitative determination of MSH molecules was developed based on maleylpyruvate isomerase (MPI) from Corynebacterium glutamicum. The principle of this method is that the activity of MPI from C. glutamicum was dependent on MSH molecules. It was found that this MPI activity displayed a linear response (R (2) = 0.9928) at MSH amounts ranging from 0.12 to 3.98 pmol in the defined assay system. This observation was applied to calculate the MSH levels, and the newly developed method was compared with thiol-specific fluorescent-labeling high-performance liquid chromatography method. Forty-eight genera of Actinobacteria were screened for MSH and 43 genera were reported for MSH occurrence, and the MSH levels in Actinobacteria were determined to be 0.01 to 9.69 MUmol/g of residual dry cell weight. PMID- 20922373 TI - Identification of chitinases Is-chiA and Is-chiB from Isoptericola jiangsuensis CLG and their characterization. AB - A 274-bp conserved fragment of chiA (chiA-CF) was amplified from the genomic DNA of Isoptericola jiangsuensis CLG (DSM 21863, CCTCC AB208287) using the specific PCR primers. Based on chiA-CF sequences, a 5233-bp DNA fragment was obtained by self-formed adaptor PCR. DNA sequencing analysis revealed there were two contiguous open reading frames coding for the precursors of Is-chiA [871 amino acids (aa)] and Is-chiB (561 aa) in the 5233-bp DNA fragment. The Is-chiA and Is chiB exhibited 58% and 62% identity with ArChiA and ArChiB chitinase from Arthrobacter sp. TAD20, respectively. The Is-chiA and Is-chiB genes were cloned into expression vector pET28a (+) and expressed in Escherichia coli BL21 (DE3) with isopropyl-beta-D-thiogalactopyranoside induction. Is-chiA and Is-chiB were 92 kDa and 60 kDa by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and showed chitobiosidase and endochitinase activity, respectively. Is-chiA and Is-chiB were purified by Ni-nitrilotriacetic acid affinity chromatography and the characteristics of both Is-chiA and Is-chiB were studied. PMID- 20922374 TI - Effects of a defective ERAD pathway on growth and heterologous protein production in Aspergillus niger. AB - Endoplasmic reticulum associated degradation (ERAD) is a conserved mechanism to remove misfolded proteins from the ER by targeting them to the proteasome for degradation. To assess the role of ERAD in filamentous fungi, we have examined the consequences of disrupting putative ERAD components in the filamentous fungus Aspergillus niger. Deletion of derA, doaA, hrdC, mifA, or mnsA in A. niger yields viable strains, and with the exception of doaA, no significant growth phenotype is observed when compared to the parental strain. The gene deletion mutants were also made in A. niger strains containing single- or multicopies of a glucoamylase glucuronidase (GlaGus) gene fusion. The induction of the unfolded protein response (UPR) target genes (bipA and pdiA) was dependent on the copy number of the heterologous gene and the ERAD gene deleted. The highest induction of UPR target genes was observed in ERAD mutants containing multiple copies of the GlaGus gene. Western blot analysis revealed that deletion of the derA gene in the multicopy GlaGus overexpressing strain resulted in a 6-fold increase in the intracellular amount of GlaGus protein detected. Our results suggest that impairing some components of the ERAD pathway in combination with high expression levels of the heterologous protein results in higher intracellular protein levels, indicating a delay in protein degradation. PMID- 20922375 TI - Cloning and characterisation of a cystathionine beta/gamma-lyase from two Oenococcus oeni oenological strains. AB - Sulphur-containing compounds in wine have been extensively studied because of their effect on wine flavour and quality. In this study, an enzyme that degrades sulphur-containing amino acids was cloned and characterised from two Oenococcus oeni strains of oenological origins. The enzyme has features of a cystathionine gamma-lyase (EC 4.4.1.1), a pyridoxal-5-phosphate-dependent enzyme catalysing an alpha,gamma-elimination reaction of L: -cystathionine to produce L: -cysteine, alpha-ketobutyrate and ammonia. Moreover, it was able to catalyse an alpha,beta elimination reaction producing homocysteine, pyruvate and ammonia from L: cystathionine. An elimination reaction of L: -cysteine and DL: -homocysteine was also efficiently catalysed by the enzyme, resulting in the formation of hydrogen sulphide. Furthermore, the ability to demethiolate methionine into methanethiol, an unfavourable volatile sulphur compound in terms of wine aroma, was observed. The findings of this work suggest that O. oeni seems to play a minor role in the production of volatile sulphur compounds during the vinification process as the optimal conditions were far from the harsh wine environment. PMID- 20922376 TI - Interaction of SCO2127 with BldKB and its possible connection to carbon catabolite regulation of morphological differentiation in Streptomyces coelicolor. AB - In Streptomyces coelicolor, the sco2127 gene is located upstream of the gene encoding for glucose kinase. This region restores sensitivity to carbon catabolite repression (CCR) of Streptomyces peucetius var. caesius mutants, resistant to 2-deoxyglucose (Dog(R)). In order to search for the possible mechanisms behind this effect, sco2127 was overexpressed and purified for protein protein interaction studies. SCO2127 was detected during the late growth phase of S. coelicolor grown in a complex media supplemented with 100 mM glucose. Pull down assays using crude extracts from S. coelicolor grown in the same media, followed by far-western blotting, allowed detection of two proteins bound to SCO2127. The proteins were identified by MALDI-TOF mass spectrometry as SCO5113 and SCO2582. SCO5113 (BldKB) is a lipoprotein ABC-type permease (~66 kDa) involved in mycelium differentiation by allowing the transport of the morphogenic oligopeptide Bld261. SCO2582, is a putative membrane metalloendopeptidase (~44 kDa) of unknown function. In agreement with the possible role of SCO2127 in mycelium differentiation, delayed aerial mycelium septation and sporulation was observed when S. coelicolor A3(2) was grown in the presence of elevated glucose concentrations (100 mM), an effect not seen in a Delta-sco2127 mutant derived from it. We speculate that SCO2127 might represent a key factor in CCR of mycelium differentiation by interacting with BldKB. PMID- 20922377 TI - Microbial community differences between propionate-fed microbial fuel cell systems under open and closed circuit conditions. AB - We report the electrochemical characterization and microbial community analysis of closed circuit microbial fuel cells (CC-MFCs) and open circuit (OC) cells continuously fed with propionate as substrate. Differences in power output between MFCs correlated with their polarization behavior, which is related to the maturation of the anodophilic communities. The microbial communities residing in the biofilm growing on the electrode, biofouled cation-exchange membrane and anodic chamber liquor of OC-and CC-MFCs were characterized by restriction fragment length polymorphism screening of 16S rRNA gene clone libraries. The results show that the CC-MFC anode was enriched in several microorganisms related to known electrochemically active and dissimilatory Fe(III) reducing bacteria, mostly from the Geobacter spp., to the detriment of Bacteroidetes abundant in the OC-MFC anode. The results also evidenced the lack of a specific pelagic community in the liquor sample. The biofilm growing on the cation-exchange membrane of the CC-MFC was found to be composed of a low-diversity community dominated by two microaerophilic species of the Achromobacter and Azovibrio genus. PMID- 20922378 TI - Change in ammonia-oxidizing microorganisms in enriched nitrifying activated sludge. AB - In this study, sludge was taken from a municipal wastewater treatment plant that contained a nearly equal number of archaeal amoA genes (5.70 * 106 +/- 3.30 * 105 copies mg sludge-1) to bacterial amoA genes (8.60 * 106 +/- 7.64 * 105 copies mg sludge-1) and enriched in three continuous-flow reactors receiving an inorganic medium containing different ammonium concentrations: 2, 10, and 30 mM NH (4) (+) N (28, 140, and 420 mg N l-1). The abundance and communities of ammonia-oxidizing archaea (AOA) and ammonia-oxidizing bacteria (AOB) in enriched nitrifying activated sludge (NAS) were monitored at days 60 and 360 of the operation. Early on, between day 0 and day 60 of reactor operation, comparative abundance of AOA amoA genes to AOB amoA genes varied among the reactors depending on the ammonium levels found in the reactors. As compared to the seed sludge, the number of AOA amoA genes was unchanged in the reactor with lower ammonium level (0.06 +/- 0.04 mgN l-1), while in the reactors with higher ammonium levels (0.51 +/- 0.33 and 0.25 +/- 0.10 mgN l-1), the numbers of AOA amoA genes were deteriorated. By day 360, AOA disappeared from the ammonia-oxidizing consortiums in all reactors. The majority of the AOA sequences from all NASs at each sampling period fell into a single AOA cluster, however, suggesting that the ammonium did not affect the AOA communities under this operational condition. This result is contradictory to the case of AOB, where the communities varied significantly among the NASs. AOB with a high affinity for ammonia were present in the reactors with lower ammonium levels, whereas AOB with a low affinity to ammonia existed in the reactors with higher ammonium levels. PMID- 20922379 TI - Proteomics of industrial fungi: trends and insights for biotechnology. AB - Filamentous fungi are widely known for their industrial applications, namely, the production of food-processing enzymes and metabolites such as antibiotics and organic acids. In the past decade, the full genome sequencing of filamentous fungi increased the potential to predict encoded proteins enormously, namely, hydrolytic enzymes or proteins involved in the biosynthesis of metabolites of interest. The integration of genome sequence information with possible phenotypes requires, however, the knowledge of all the proteins in the cell in a system-wise manner, given by proteomics. This review summarises the progress of proteomics and its importance for the study of biotechnological processes in filamentous fungi. A major step forward in proteomics was to couple protein separation with high-resolution mass spectrometry, allowing accurate protein quantification. Despite the fact that most fungal proteomic studies have been focused on proteins from mycelial extracts, many proteins are related to processes which are compartmentalised in the fungal cell, e.g. beta-lactam antibiotic production in the microbody. For the study of such processes, a targeted approach is required, e.g. by organelle proteomics. Typical workflows for sample preparation in fungal organelle proteomics are discussed, including homogenisation and sub-cellular fractionation. Finally, examples are presented of fungal organelle proteomic studies, which have enlarged the knowledge on areas of interest to biotechnology, such as protein secretion, energy production or antibiotic biosynthesis. PMID- 20922380 TI - A novel plasmid addiction system for large-scale production of cyanophycin in Escherichia coli using mineral salts medium. AB - INTRODUCTION: Hitherto the production of the biopolymer cyanophycin (CGP) using recombinant Escherichia coli strains and cheap mineral salts medium yielded only trace amounts of CGP (<0.5%, w/w) of the cell dry matter (CDM). This was probably due to the instability of the plasmids encoding the cyanophycin synthetase. MATERIAL AND METHODS: In this study, we developed an anabolism-based media dependent plasmid addiction system (PAS) to enhance plasmid stability, and we established a process based on a modified mineral salts medium yielding a CGP content of 42% (w/w) at the maximum without the addition of amino acids to the medium for the first time. This PAS is based on different lysine biosynthesis pathways and consists of two components: (1) a knockout of the chromosomal dapE disrupts the native succinylase pathway in E. coli and (2) the complementation by the plasmid-encoded artificial aminotransferase pathway mediated by the dapL gene from Synechocystis sp. PCC 6308, which allows the synthesis of the essential lysine precursor L,L-2,6-diaminopimelate. In addition, this plasmid also harbors cphAC595S, an engineered cyanophycin synthetase gene responsible for CGP production. RESULTS: Cultivation experiments in Erlenmeyer flask and also in bioreactors in mineral salts medium without antibiotics revealed an at least 4.5 fold enhanced production of CGP in comparison to control cultivations without PAS. DISCUSSION: Fermentation experiments with culture volume of up to 400 l yielded a maximum of 18% CGP (w/w) and a final cell density of 15.2 g CDM/l. Lactose was used constantly as an effective inducer and carbon source. Thus, we present a convenient option to produce CGP with E. coli at a technical scale without the need to add antibiotics or amino acids using the mineral salts medium designed in this study. PMID- 20922381 TI - Citrus peel influences the production of an extracellular naringinase by Staphylococcus xylosus MAK2 in a stirred tank reactor. AB - Staphylococcus xylosus MAK2, Gram-positive coccus, a nonpathogenic member of the coagulase-negative Staphylococcus family was isolated from soil and used to produce naringinase in a stirred tank reactor. An initial medium at pH 5.5 and a cultivation temperature of 30 degrees C was found to be optimal for enzyme production. The addition of Ca(+)2 caused stimulation of enzyme activity. The effect of various physico-chemical parameters, such as pH, temperature, agitation, and inducer concentration was studied. The enzyme production was enhanced by the addition of citrus peel powder (CPP) in the optimized medium. A twofold increase in naringinase production was achieved using different technological combinations. The process optimization using technological combinations allowed rapid optimization of large number of variables, which significantly improved enzyme production in a 5-l reactor in 34 h. An increase in sugar concentration (15 g l-1) in the fermentation medium further increased naringinase production (8.9 IU ml-1) in the bioreactor. Thus, availability of naringinase renders it attractive for potential biotechnological applications in citrus processing industry. PMID- 20922382 TI - Bacterial community analysis of swine manure treated with autothermal thermophilic aerobic digestion. AB - Due to the environmental problems associated with disposal of livestock sludge, many stabilization studies emphasizing on the sludge volume reduction were performed. However, little is known about the microbial risk present in sludge and its stabilized products. This study microbiologically explored the effects of anaerobic lagoon fermentation (ALF) and autothermal thermophilic aerobic digestion (ATAD) on pathogen-related risk of raw swine manure by using culture independent 16S rDNA cloning and sequencing methods. In raw swine manure, clones closely related to pathogens such as Dialister pneumosintes, Erysipelothrix rhusiopathiae, Succinivibrioan dextrinosolvens, and Schineria sp. were detected. Meanwhile, in the mesophilic ALF-treated swine manure, bacterial community clones closely related to pathogens such as Schineria sp. and Succinivibrio dextrinosolvens were still detected. Interestingly, the ATAD treatment resulted in no detection of clones closely related to pathogens in the stabilized thermophilic bacterial community, with the predominance of novel Clostridia class populations. These findings support the superiority of ATAD in selectively reducing potential human and animal pathogens compared to ALF, which is a typical manure stabilization method used in livestock farms. PMID- 20922383 TI - Optimization of cold-active chitinase production from the Antarctic bacterium, Sanguibacter antarcticus KOPRI 21702. AB - In the present study, cultivation conditions and medium components were optimized using statistical design and analysis to enhance the production of Chi21702, a cold-active extracellular chitinase from the Antarctic bacterium Sanguibacter antarcticus KOPRI 21702. Identification of significant carbon sources and other key elements was performed using a statistical design technique. Chitin and glycerol were selected as main carbon sources, and the ratio of complex nitrogen sources to carbon sources was determined to be 0.5. Among 15 mineral components included in basal medium, NaCl, Fe(C6H5O7), and MgCl2 were found to have the most influence on Chi21702 production. The optimal parameters of temperature, initial pH, and dissolved oxygen level were found to be 25 degrees C, 6.5, and above 30% of air saturation, respectively. The maximum Chi21702 activity obtained under the optimized conditions was 90 U/L. Through statistical optimization methods, a 7.5 fold increase in Chi21702 production was achieved over unoptimized conditions. Chi21702 showed relatively high activity, even at low temperatures close to 0 degrees C. The information obtained in the present study could be applied to the production of cold-active endochitinase on a large scale, suitable for a process at low temperature in industry. PMID- 20922384 TI - Increased bioclogging and corrosion risk by sulfate addition during iodine recovery at a natural gas production plant. AB - Iodine recovery at a natural gas production plant in Japan involved the addition of sulfuric acid for pH adjustment, resulting in an additional about 200 mg/L of sulfate in the waste brine after iodine recovery. Bioclogging occurred at the waste brine injection well, causing a decrease in well injectivity. To examine the factors that contribute to bioclogging, an on-site experiment was conducted by amending 10 L of brine with different conditions and then incubating the brine for 5 months under open air. The control case was exposed to open air but did not receive additional chemicals. When sulfate addition was coupled with low iodine, there was a drastic increase in the total amount of accumulated biomass (and subsequently the risk of bioclogging) that was nearly six times higher than the control. The bioclogging-associated corrosion rate of carbon steel was 84.5 MUm/year, which is four times higher than that observed under other conditions. Analysis of the microbial communities by denaturing gradient gel electrophoresis revealed that the additional sulfate established a sulfur cycle and induced the growth of phototrophic bacteria, including cyanobacteria and purple bacteria. In the presence of sulfate and low iodine levels, cyanobacteria and purple bacteria bloomed, and the accumulation of abundant biomass may have created a more conducive environment for anaerobic sulfate-reducing bacteria. It is believed that the higher corrosion rate was caused by a differential aeration cell that was established by the heterogeneous distribution of the biomass that covered the surface of the test coupons. PMID- 20922385 TI - Organisation, data evaluation, interpretation and effect of arthroplasty register data on the outcome in terms of revision rate in total hip arthroplasty. AB - Originally developed in Scandinavia, national arthroplasty registers have spread worldwide during the last decade. The value of registers for quality improvement in arthroplasty has frequently been documented. However, for the development of a successful register a few key points should be taken into account. Uncontrolled loss of patients from the registry area should be avoided. Registers should form an integral part of a country's medical system. To realise the potential for improvement, it is crucial that physicians deal with the results in detail. Thus it is absolutely essential to involve the specialty societies in the interpretation and dissemination of results. With respect to revision rates, register data are usually more valid than meta-analyses of clinical studies. For every physician the most valuable data are those coming from a register in his own country; the development of national arthroplasty registers should therefore be continued. PMID- 20922387 TI - A prognostic model and treatment strategy for intrahepatic recurrence of hepatocellular carcinoma after curative resection. AB - BACKGROUND: The aim of this study was to evaluate the prognostic factors for intrahepatic recurrence of hepatocellular carcinoma (HCC) after curative resection. METHODS: Of 297 patients with HCC who underwent curative resection between 1998 and 2007, 145 had intrahepatic recurrence, and 125 of these were enrolled in this study. We analyzed the relationships between overall survival after HCC recurrence and 20 variables at initial hepatectomy and recurrence. RESULTS: Recurrent HCC was treated by repeat hepatectomy (Re-Hr, n = 29), radiofrequency ablation (RFA, n = 58), or transarterial chemoembolization (TAE, n = 38). Complete tumor control (CTC) by Re-He and RFA was selected for 70% of patients. RFA-treated patients had more tumors, smaller tumors, and poorer liver function at recurrence than the Re-Hr group. The overall 1-, 3-, and 5-year post recurrence survival rates (SR) were 93.1, 66.8, 58.1%; 94.7, 75.1, 48.3%; and 80.1, 22.5, 0%, respectively, in the Re-Hr, RFA, and TAE groups. The SR was better for Re-Hr and RFA than for TAE (p < 0.0001). Outcomes were similar in Re Hr and RFA, regardless of recurrent tumor size. Multivariate analysis identified Child-Pugh grade B, AFP >=100 ng/ml at recurrence, recurrent tumor size >=3 cm, tumor number >=3, and CTC as significant prognostic factors for overall post recurrence survival. A scoring system using 1 point for each patient-background factor provided a well-categorized predictive model. The overall 3-/5-year post recurrence SRs were 83.1/59.3%, 64.1/41.9%, 42.0/18.0%, and 13.6/0% at risk number (R) R0, R1, R2, and R3/4, respectively (p < 0.05). CONCLUSIONS: Significant prognostic factors for intrahepatic recurrent HCC are poor hepatic reserve, AFP, recurrent tumor size and number, and CTC. Selection of treatment modality for intrahepatic recurrence requires the clinician to be mindful of the predictive factors and to control tumors aggressively by adequate treatment, selected by balancing various conditions. PMID- 20922388 TI - Managing BRCA mutation carriers in China. PMID- 20922389 TI - Salvage treatment in metastatic breast cancer with weekly paclitaxel and bevacizumab. AB - BACKGROUND: Weekly paclitaxel (P) in combination with bevacizumab (B) is an effective regimen as initial treatment of metastatic breast cancer (MBC). We investigated in a phase II study the activity of the same regimen as salvage therapy in MBC. METHODS: Pretreated women with MBC received weekly P (90 mg/m(2) days 1, 8, 15) and B (10 mg/kg days 1, 15) every 28 days. B could continue after discontinuing P until disease progression. This was second-line chemotherapy for 30% and third-line or more for 70% of patients. RESULTS: A total of 40 patients were enrolled. Median age: 61 (range 32-80) years; postmenopausal: 80%; baseline ECOG performance status <2 in 80% of patients. Two patients (5%) achieved complete response, 10 (25%) partial response (overall response rate 30%; 95% CI 15.8-44.2), and 10 (25%) stable disease. The response rate was 28% for the patients who had previously received taxanes. After a median follow-up of 20.6 months, the median time to progression was 4.8 months (95% CI 1.7-7.8), median survival 13.0 months (95% CI 10.3-15.7), and the probability of 1-year survival 55.5%. Main grade 3-4 toxicities were neutropenia 42.5%, febrile neutropenia 5%, and asthenia 10%. There was one toxic death due to sepsis. CONCLUSION: The PB regimen is well tolerated and active as salvage therapy in pretreated women with MBC. It could be an effective option even for patients exposed to taxanes during prior treatments. PMID- 20922390 TI - Sandostatin desensitization--a strategy useful for patients with carcinoid tumors, intolerant to sandostatin. AB - Sandostatin immediate release (IR) is frequently used to treat patients with carcinoid tumors. However, some patients are unable to tolerate the immediate side effects of sandostatin IR leading to discontinuation of the drug. There is no literature available to guide the management of patients' sensitivity/intolerance to sandostatin IR. We report a 49-year-old male with carcinoid tumor who was intolerant to sandostatin IR initially but was able to tolerate the drug after we employed a desensitization strategy. PMID- 20922391 TI - MR enterography versus capsule endoscopy in paediatric patients with suspected Crohn's disease. AB - OBJECTIVE: The aim of this prospective study was to compare the diagnostic yield of MR enterography (MRE) with small-bowel capsule endoscopy (SBCE) in paediatric patients with suspected Crohn's disease (CD). METHODS: Paediatric patients with suspected CD were considered eligible to be enrolled in the study. All patients underwent diagnostic work-up including 1.5-T MRE, ileo-colonoscopy and oesophagogastroduodenoscopy. SBCE was not performed if MRE showed SB stricture or extra-intestinal findings consistent with symptoms. RESULTS: Sixty consecutive paediatric patients (36 male; average age 14) were enrolled into the study. A positive diagnosis for CD was made in 19 patients, 29 had a negative result and 12 were affected by other gastro-intestinal conditions. SBCE was performed in 37 patients (61.7%); 23 patients were excluded (strictures in five, extra-intestinal findings in 11 and parents' refusal in seven cases). The accuracy, sensitivity, and specificity of MRE and SBCE were 98.3%, 100%, 97.6%, and 91.9%, 90.9%, 92.3%, respectively. CONCLUSION: Both MRE and SBCE are accurate methods for patients with suspected CD. MRE can be used as a primary imaging technique in suspected CD, in that it allows access to the ileal stricture, which forms a contra indication for SBCE and provides extra-intestinal information. PMID- 20922392 TI - Commercial software upgrades may significantly alter Perfusion CT parameter values in colorectal cancer. AB - OBJECTIVE: To determine how commercial software platform upgrades impact on derived parameters for colorectal cancer. MATERIALS AND METHODS: Following ethical approval, 30 patients with suspected colorectal cancer underwent Perfusion CT using integrated 64 detector PET/CT before surgery. Analysis was performed using software based on modified distributed parameter analysis (Perfusion software version 4; Perfusion 4.0), then repeated using the previous version (Perfusion software version 3; Perfusion 3.0). Tumour blood flow (BF), blood volume (BV), mean transit time (MTT) and permeability surface area product (PS) were determined for identical regions-of-interest. Slice-by-slice and 'whole tumour' variance was assessed by Bland-Altman analysis. RESULTS: Mean BF, BV and PS was 20.4%, 59.5%, and 106% higher, and MTT 14.3% shorter for Perfusion 4.0 than Perfusion 3.0. The mean difference (95% limits of agreement) were +13.5 ( 44.9 to 72.0), +2.61 (-0.06 to 5.28), -1.23 (-6.83 to 4.36), and +14.2 (-4.43 to 32.8) for BF, BV, MTT and PS respectively. Within subject coefficient of variation was 36.6%, 38.0%, 27.4% and 60.6% for BF, BV, MTT and PS respectively indicating moderate to poor agreement. CONCLUSION: Software version upgrades of the same software platform may result in significantly different parameter values, requiring adjustments for cross-version comparison. PMID- 20922393 TI - Transperitoneal in situ intraarterial cooling in laparoscopic partial nephrectomy. AB - INTRODUCTION: Aiming the principles of open partial nephrectomy, warm ischemia time is the limiting factor especially in case of central or complex tumors in laparoscopy. We demonstrate a novel solely laparoscopic technique for in situ cold perfusion of kidneys with direct catheterization of the renal artery to increase the tolerance of renal parenchyma for ischemia. MATERIALS AND METHODS: In two patients with hilus compromising tumors, renal artery was clamped; a small incision in the artery was used to place a 5Fr centrally open angiographic balloon catheter and blocked with 1 ml NaCl. The kidney was perfused with 4 degrees C Ringer solution. After tumor excision, the kidney was subsequently reconstructed by mattress bolster sutures and fibrin glue. The arterial incision was closed by a 4/0 Prolene suture. RESULTS: Both patients had an uneventful follow-up without neither intraoperative nor postoperative complications. No intraoperative body temperature drop occurred. Cold ischemia time was 66 (men, 65a) and 60 min (women, 43a), respectively. Hemoglobin drop was 4.1 and 1.9 g/dl; no transfusion was necessary. Preoperative and postoperative creatinine levels were 0.90 and 0.76 mg/dl, and 1.3 and 0.9 mg/dl, respectively. Patients were discharged on day 12 and day 8. Histology revealed clear cell RCC (pT1b pNx pMx G2 R0) in the first patient and oncocytoma in the second patient. Postoperative CT angiograpy demonstrated no sign of arterial insufficiency. DISCUSSION: Intraarterial renal cooling could expand the ischemia time and therefore the indication of laparoscopic partial nephrectomy in complex exposition. Furthermore, the identification of tumor borders and injured vessels is facilitated by the outflow of the cooling solution. Further investigations into this promising method could proof its feasibility in everyday clinical routine. PMID- 20922394 TI - Toothy craniopharyngioma: a literature review and case report of craniopharyngioma with extensive odontogenic differentiation and tooth formation. PMID- 20922395 TI - Impact of tethered cord release on symptoms of Chiari II malformation in children born with a myelomeningocele. AB - PURPOSE: The role of distal traction in the form of a tethered spinal cord in exacerbating anatomical findings or symptoms of Chiari II malformation (CIIM) has been debated for decades. Despite the association of Chiari II malformation with myelomeningocele, the impact of tethered cord release on CIIM symptoms in patients has not been explored. METHODS: A retrospective review of 59 patients born with a myelomeningocele was performed. A total of 92 untethering procedures were performed in which symptoms of CIIM were present in 29 cases. In 57 out of 92 cases, the patients did not have symptoms of CIIM prior to untethering. Six cases were excluded because cervicomedullary decompression was performed prior to untethering. The response of CIIM symptoms, syrinx size, and cerebellar tonsil position were examined before and after spinal cord untethering. RESULTS: Forty four characteristic signs and symptoms of CIIM were present prior to 29 untetherings. Thirty-three of 44 (75%) symptoms improved following spinal cord untethering, though no symptom resolved completely. Syrinx size and cerebellar tonsil position were unchanged following untethering. CONCLUSION: The authors conclude that mild to moderate symptoms of CIIM may respond positively to spinal cord untethering, potentially by normalization cerebrospinal fluid flow dynamics. Symptom improvement occurs despite the lack of radiographic evidence of CIIM resolution. PMID- 20922396 TI - Pediatric stroke: clinical characteristics, acute care utilization patterns, and mortality. AB - PURPOSE: Acute care utilization patterns are not well described but may help inform care coordination and treatment for pediatric stroke. The Kids Inpatient Database was queried to describe demographics and clinical characteristics of children with stroke, compare acute care utilization for hemorrhagic vs. ischemic stroke and Children's vs. non-Children's Hospitals, and identify factors associated with aggressive care and in-hospital mortality. METHODS: Using a retrospective cohort of children hospitalized with stroke, demographics, predisposing conditions, and intensive (mechanical ventilation, advanced monitoring, and blood product administration) or aggressive (pharmacological therapy and/or invasive interventions) care were compared by stroke and hospital types. Factors associated with aggressive care or in-hospital mortality were explored using logistic regression. RESULTS: Hemorrhagic stroke comprised 43% of stroke discharges, was more common in younger children, and carried greater mortality. Ischemic stroke was more common in older children and more frequently associated with a predisposing condition. Rates of intensive and aggressive care were low (30% and 15%), similar by stroke type, and greater at Children's Hospitals. Older age, hemorrhagic stroke, predisposing condition, and treatment at a Children's Hospital were associated with aggressive care. Hemorrhagic stroke and aggressive care were associated with in-hospital mortality. CONCLUSIONS: Acute care utilization is similar by stroke type but both intensive and aggressive care are more common at Children's Hospitals. Mortality remains relatively high after pediatric stroke. Widespread implementation of treatment guidelines improved outcomes in adult stroke. Adoption of recently published treatment recommendations for pediatric stroke may help standardize care and improve outcomes. PMID- 20922398 TI - Neuropathology in Parkinson's disease with mild cognitive impairment. PMID- 20922397 TI - Outcome of hepatoblastomas treated using the Japanese Study Group for Pediatric Liver Tumor (JPLT) protocol-2: report from the JPLT. AB - BACKGROUND: In the recent years, surgical resection with pre- and/or postoperative chemotherapy has markedly improved the survival rate of hepatoblastoma patients. We herein report the results of patients treated with the current protocol of the Japanese Study Group for Pediatric Liver Tumor, JPLT 2. METHODS: A total of 279 patients with malignant liver tumor were enrolled in JPLT-2. Data from 212 hepatoblastoma cases were analyzed. PRETEXT I patients were treated with primary resection followed by low doses of cisplatin-pirarubicin (tetrahydropyranyl-adriamycin). Otherwise, patients received preoperative cisplatin-pirarubicin (CITA), followed by surgery and postoperative chemotherapy. Ifosfamide, pirarubicin, etoposide, and carboplatin (ITEC) were given as a salvage treatment. High-dose chemotherapy with hematopoietic stem cell transplantation (SCT) was reserved for patients with metastatic diseases. RESULTS: The 5-year overall survival rate (OS) in non-metastatic cases was 100% for PRETEXT I, 87.1% for PRETEXT II, 89.7% for PRETEXT III, and 78.3% for PRETEXT IV. The 5-year OS in metastatic cases was 43.9%. The outcome in non-metastatic PRETEXT IV cases was markedly improved, while the results of metastatic tumors remained poor. CONCLUSIONS: JPLT-2 protocol achieved satisfactory survival among children with non-metastatic hepatoblastoma. New approaches are needed for patients with metastatic diseases. PMID- 20922399 TI - Management and outcomes of adnexal torsion: a 5-year experience. AB - PURPOSE: To discuss the surgical results of patients with diagnosis of adnexal torsion. METHODS: One hundred and fifty patients with diagnosis of adnexal torsion who presented to our clinic between January 2005 and December 2009 were included in this retrospective analysis. Data regarding age, gravidity, parity, size of mass, operation time, and duration of hospitalization were recorded and compared between the patients who had laparoscopy to those who had laparotomy. The pathological results of patients were also recorded. RESULTS: Fifty-eight patients were treated laparoscopically while 92 patients had laparotomy. The most frequent presenting symptom was pelvic pain (96%). Laparoscopy group consisted of young patients with low parity; operation and hospital stay time was shorter in laparoscopy group. Velocity loss in Doppler ultrasonography was noted in 81.3% of the patients. Of the laparotomy group 35 postmenopausal patients had hysterectomy and bilateral salpingo-oopherectomy, and staging surgery was done for 16 of them. The pathological finding was found to be malignant in four and borderline serous tumor in four patients. CONCLUSION: Laparoscopy is preferred for young patients who want to preserve their fertility. Because of high risk of malignancy in postmenopausal ovarian masses presenting with torsion; frozen section should be used. If not possible or not conclusive, staging surgery is more appropriate especially if there is suspicion of malignancy. PMID- 20922400 TI - Secondary malignant fibrous histiocytoma of thigh with surface ulceration following radiotherapy for carcinoma cervix. AB - INTRODUCTION: Radiotherapy is known to cause rarely various malignancies including leukemia, sarcoma, and thyroid and lung carcinoma. Post-radiation sarcomas account for 0.5-5.5% of all sarcomas; and include extra skeletal osteosarcoma, fibrosarcoma leiomyosarcoma, and malignant fibrous histiocytoma. Reports on post radiotherapy malignant fibrous histiocytoma in cervical cancer patients are rare. CASE REPORT: We present a case of 45-years-old female diagnosed with squamous cell carcinoma of the uterine cervix stage IIB; she underwent a radical hysterectomy with pelvic lymphadenectomy and postoperative radiotherapy and chemotherapy. Five years later, she presented with ulcerated nodular masses in right and left medial aspect of thigh. Cytological and histological diagnosis of the masses was malignant fibrous histiocytoma which was further confirmed by immunohistochemistry. CONCLUSION: Post-irradiation sarcoma must be considered in patients of carcinoma cervix treated with radiotherapy, when soft tissue mass is seen in the previously irradiated area. It should be differentiated from metastasis from primary tumor with the help of appropriate markers as it has a grave prognosis. PMID- 20922401 TI - Perception of intimate pelvic examination by gynaecological clinic attendees in rural Southeast Nigeria. AB - CONTEXT: Intimate gynaecological examinations are part of the necessary retinue in gynaecological consultation and management. OBJECTIVE: To evaluate women's perception of digital and speculum vaginal examinations in rural Southeast Nigeria. METHODS: This was a prospective descriptive study. Gynaecologic clinic attendees in a Mission hospital in rural Nigeria were interviewed using a pre tested questionnaire over a 3-year period. RESULTS: Four hundred and eighty-six women with a mean age of 35.2 +/- 8.1 years were interviewed. They presented mainly for infertility (36.8%), menstrual abnormalities (31.1%) and early pregnancy complications (10.7%). Over a quarter of the women felt embarrassed at vaginal examination and 37.2% found it a bit painful or felt discomfort. In spite of the discomfort, 73.7% believed vaginal examination was necessary and over 95% indicated readiness to undergo such examination in future if necessary. CONCLUSION: Performing intimate gynaecological examination should be a carefully planned procedure with patient's consent, and performed conscientiously taking patient's feelings and emotions into consideration, to engender confidence. PMID- 20922402 TI - Endoscope assisted submandibular sialadenectomy: the face-lift approach. AB - This study evaluated the benefits of a new approach, endoscopic resection of a submandibular gland through the face-lift approach. The study comprised the clinical trial of new procedure. Six submandibular sialadenectomies were carried out (4 women, 2 men; mean age 28 years) via the face-lift approach by endoscopy. All six submandibular gland resections were successfully performed endoscopically, and no conversion to conventional open resection was necessary. Five patients had a mixed tumor and one patient had sialadenitis. The procedures lasted 55-115 min (mean 74 min). No complications associated with the operation occurred, and the scar was almost invisible. Endoscope assisted submandibular sialadenectomy via the face-lift approach was safe and effective treatment of benign lesions. The main advantage of this procedure is that the operative scar is concealed by the hairline. PMID- 20922404 TI - Usefulness of triglyceride levels in pleural fluid. AB - The determination of pleural fluid triglycerides (PF-TRIG) is useful in the diagnosis of chylothorax, but its diagnostic value for other causes of pleural effusions is unknown. The aim of this study was to evaluate the usefulness of PF TRIG in the diagnosis of other pleural effusions and investigate the origin of their increase in these fluids. We studied 390 pleural effusions (75 tuberculous, 107 neoplastic, 39 parapneumonic, 30 miscellaneous, 42 idiopathic, and 97 transudates). The correlation was analyzed with the PF-TRIG values as the dependent variable and serum triglycerides (S-TRIG) and the pleural fluid/serum protein ratio (PF/S PROT ratio) as independent variables. The PF-TRIG was significantly higher in exudates. The sensitivity of PF-TRIG for identifying exudates was 84.3%, specificity 61.9%. The correlation between PF-TRIG and S-TRIG was significant in the exudates and in the total pleural effusions. There was a significant correlation between PF-TRIG and S-TRIG and capillary permeability, which worsened when looking at the transudates and exudates separately. No correlations were found between the PF-TRIG and the number of red cells and white cells in any of the groups. Except for diagnosing a chylothorax, the determination of triglycerides in pleural fluid does not appear to be justified. The cause of the increase in PF-TRIG in exudates could not be established because the correlations obtained were insufficient to be able to predict PF-TRIG values from their serum values and the measurement of capillary permeability. PMID- 20922405 TI - A multicenter study of the predictors of adherence to self-injected glatiramer acetate for treatment of relapsing-remitting multiple sclerosis. AB - Treatment with disease-modifying immunomodulators is recommended for patients with relapsing-remitting MS (RRMS). However, continuous adherence to treatment with these injected therapies can be challenging. The main objective was to examine the predictors of adherence to glatiramer acetate using a study model derived from Prochaska's transtheoretical model of change. We conducted a 12 week, prospective, observational study. Potential predictors included readiness stage, MS self-efficacy, decisional balance (pros and cons of self-injection), and injection competence. Adults with RRMS, either treatment-naive (TN) or treatment-experienced (TE), taking glatiramer acetate for the first time were studied. Interventions (including injection training) were implemented to promote adherence. The evaluable population included 146 TN patients and 88 TE patients who had previously discontinued beta-interferons. Adherence rates did not differ between TN and TE groups (86% for both at week 12); however, predictors of adherence did. For TN patients, greater functional self-efficacy, higher self injection competence at baseline, and improvement in self-injection competence over the first month of therapy predicted adherence. For TE patients, lower body mass index and longer duration of MS predicted adherence. Interventions to improve self-efficacy and self-injection competence should be a priority when treating TN patients. Behavioral predictors of adherence in TE patients warrant further study. PMID- 20922406 TI - A novel primary KIT exon 9 single nucleotide substitution c.1427G>T (p.Ser476Ile) in a gastrointestinal stromal tumor. PMID- 20922407 TI - Glucagon expression in cystic pancreatic neuroendocrine neoplasms: an immunohistochemical analysis. AB - Pancreatic neuroendocrine neoplasms (P-NENs) are usually solid and only rarely cystic. Glucagon expression and the association with multiple endocrine neoplasia type 1 (MEN1) seem to be common in cystic P-NENs. In this study, we analyzed 404 P-NENs to gain information about the relative frequency of grossly cystic P-NENs and their association with glucagon production by the tumor cells. Three hundred forty-six solitary P-NENs and 58 P-NENs (>1 cm in diameter) from 35 patients with an MEN1 syndrome were studied. Immunostaining was performed for the four pancreatic hormones; 5.5% (19/346) of the sporadic P-NENs showed unilocular or multilocular cystic changes that were macroscopically detectable. Sixty-three percent of the solitary cystic P-NENs (versus 7% of the solitary non-cystic P NENs) expressed predominantly glucagon. In MEN1-associated P-NENs, the relative frequency of cystic tumors was 10.3%, and all of them expressed glucagon. None of the glucagon-positive cystic P-NENs were associated with a glucagonoma syndrome. Solitary non-MEN1-associated and MEN1-associated cystic P-NENs are predominantly non-syndromic glucagon-expressing tumors. However, cystic insulinomas may also occur. Cyst formation seems to be related to hormone production. PMID- 20922408 TI - Nasal seromucinous hamartoma (microglandular adenosis of the nose): a morphological and molecular study of five cases. AB - Five cases of nasal seromucinous hamartoma were studied and their clinical, morphological, immunohistochemical and molecular data are reported. The patients, three females and two males, ranged in age from 49 to 66 years (mean 56 year, SD +/- 7.91). All lesions were located in the nasal cavity. In four cases where follow-up was obtained, no recurrence was evident. In all cases, numerous small seromucinous tubules, embedded in a cellular stroma, were present in the lamina propria. Tubules were lined by one layer of cuboidal cells which displayed luminal phenotype positive for lysozyme and EMA in four, and S100 protein in all cases. Collagen IV and laminin positive basal lamina outlined the tubules which lacked basal cells. Stromal spindle cells present among tubules were immunoreactive for calponin in all cases and for alpha-smooth muscle actin in four cases. DNA mutation analysis of mitochondrial D-loop region was performed by direct sequencing in order to verify the mutation rate of these lesions. The tubules of the five seromucinous hamartomas showed a higher mutation rate especially in heteroplasmy (0.52% homoplasmy, 2.02% heteroplasmy) in comparison to normal seromucinous glands which exhibited a lower mutation frequency (0.83%). This is considered a sign of a low cellular proliferation rate consistent with a benign process. It is concluded that nasal seromucinous hamartomas are benign glandular proliferations that may resemble microglandular adenosis of the breast. Their distinction from benign and malignant mimics is discussed. PMID- 20922409 TI - A moulage museum is not just a museum : Wax models as teaching instruments. AB - The technique of making moulages (wax models) for the teaching of anatomy was introduced in Florence from the late 1600s. Studying the moulages was a much more pleasant way of learning anatomy than the alternative of dissecting dead bodies, when the tissues were undergoing postmortem decay. The technique spread to other medical schools in Europe as well as to England, Russia, North and South America, and Japan. The introduction of photography in the late 1800s made the moulageurs redundant. However, all of these countries now have historical museums that exhibit the specimens that remain from this period. A few moulageurs did continue to make specimens, mainly of dermatological conditions, right into the late 1900s. In 2005, the University of Zurich opened a new museum to showcase some such moulages made by local artists. PMID- 20922410 TI - Warfarin embryopathy: fetal manifestations. AB - During the period 1991-2007, autopsy was undertaken in 13 fetuses with warfarin embryopathy. Pregnancy data and radiographic babygrams were available in each instance. Gestational age ranged from 17 to 37 weeks. Eleven of the fetuses had the characteristic nasal hypoplasia, but only three had radiological epiphyseal stippling. Cerebral hemorrhage was a major feature of autopsy in 8 of the fetuses, and it is evident that bleeding is a significant factor in the pathogenesis of warfarin embryopathy. A wide variety of additional visceral manifestations which were observed at autopsy have been tabulated. There was no obvious correlation between maternal or gestational age and the presence and severity of any specific embryopathic feature. No information was available concerning the dose and timing of warfarin administration in this series. PMID- 20922411 TI - Protein change of intestinal epithelial cells induced in vitro by Trichinella spiralis infective larvae. AB - The aim of this study was to observe the protein changes of intestinal epithelial cells induced in vitro by Trichinella spiralis infective larvae and their excretory-secretory (ES) or surface antigens and identity the proteins related with invasion. HCT-8 cells were incubated for 2 h in the culture medium contained ES or surface antigens of infective larvae, and observed by Immunofluorescent test (IFT). The infective larvae were inoculated into culture of HCT-8 cells to incubate for 18 h, and the lysates of HCT-8 cells were analyzed by SDS-PAGE and Western blot. IFA showed that normal HCT-8 cells had positively reactions with sera of the infected mice and mice immunized with ES or surface antigens. However, after incubating with ES or surface antigens, HCT-8 cells had stronger positively reaction with the above sera. On Western blot, after cultured with infective larvae, additional seven protein bands (66, 61, 57, 45, 34, 21, and 17 kDa) of HCT-8 cells were recognized by sera of the infected or immunized mice, but three protein bands (48, 43, and 23 kDa) of HCT-8 cells were not recognized by the above sera, compared with normal HCT-8 cells. Our results showed that after cultured with infective larvae the protein components of HCT-8 cell changed, suggesting that additional seven proteins recognized by sera of the infected or immunized mice may be related with invasion of intestinal epithelial cells by infective larvae, these proteins might mediate or facilitate entry into the cells, while the three proteins not recognized by the above sera may be the specific mediators released from the cells which permit invasion. PMID- 20922412 TI - Larvicidal activity of metabolites from the endophytic Podospora sp. against the malaria vector Anopheles gambiae. AB - In a screening for natural products with mosquito larvicidal activities, the endophytic fungus Podospora sp. isolated from the plant Laggera alata (Asteraceae) was conspicuous. Two xanthones, sterigmatocystin (1) and secosterigmatocystin (2), and an anthraquinone derivative (3) 13 hydroxyversicolorin B were isolated after fermentation on M(2) medium. These compounds were characterised using spectroscopic and X-ray analysis and examined against third instar larvae of Anopheles gambiae. The results demonstrated that compound 1 was the most potent one with LC(50) and LC(90) values of 13.3 and 73.5 ppm, respectively. Over 95% mortality was observed at a concentration 100 ppm after 24 h. These results compared farvorably with the commercial larvicide pylarvex(r) that showed 100% mortality at the same concentration. Compound 3 was less potent and had an LC(50) of 294.5 ppm and over 95% mortality was achieved at a concentration of 1,000 ppm. Secosterigmatocystin (2) revealed relatively weak activity and therefore LC values were not determined. PMID- 20922413 TI - Association of Blastocystis hominis genetic subtypes with urticaria. AB - Although intestinal parasites are a possible cause of skin disorders, there are few case reports concerning the role of Blastocystis hominis in urticaria. To clarify this association, we determined the frequency of B. hominis genetic subtype in urticarial patients by stool culture and polymerase chain reaction (PCR) and evaluated the clinical and parasitological recovery of urticarial patients after treatment with metronidazole. Of 54 urticarial patients (group I), 18 (33.3%) were diagnosed as acute urticaria (group IA) and 36 (66.7%) were diagnosed as chronic (group IB). Thirty-three (61.1%) out of 54 urticarial (group I) patients were Blastocystis positive by stool culture and PCR. Out of these 33 patients, 21 were symptomatic and 12 were asymptomatic. The amoeboid form was found in 20 (95.2%) out of 21 symptomatic Blastocystis urticarial patients assuring their pathogenic potential. Of 50 normal control group (group II), four (8%) Blastocystis isolates were found with no amoeboid form. B. hominis subtype 3 was the only detected genotype in both groups. Of 20 symptomatic Blastocystis urticarial patients, 12 (60%) patients recovered symptomatically and parasitologically after one course of metronidazole. Recovery reached 100% on repeating the treatment for a second course with disappearance of the amoeboid form. It was concluded that acute urticaria of unknown etiology and chronic idiopathic urticaria patients who are resistant to the ordinary regimen of urticaria treatment might be examined for infection with B. hominis, in order to prescribe the proper specific anti-protozoan treatment. PMID- 20922414 TI - Morphological alterations and growth inhibition of Leishmania (L.)amazonensis promastigotes exposed to zidovudine (AZT). AB - Leishmania parasites cause a worldwide public health disease and its treatment is still based on pentavalent antimonials which present financial and toxicologic limitations. Some nucleosidic derivatives have demonstrated anti-leishmanial properties and this study aims to evaluate the in vitro morphologic alterations and growth inhibition of Leishmania (L.) amazonensis promastigotes exposed to zidovudine at several concentrations. The citotoxicity of zidovudine (AZT) to macrophages was determined by an MTT assay. After which the promastigotes were exposed to concentrations of AZT, ranging from 1 to 50 MUM. The evaluation of survival and morphometry alterations were performed in two distinct phases of in vitro growth, on the third and sixth days, representing the logarithmic and stationary phases, respectively. Slides with the promastigotes were photographed and analyzed using Image J. A significant reduction of parasite number in the logarithmic phase of in vitro growth was observed when the parasites were submitted to 20, 30, 40, and 50 MUM of AZT. Morphometric alterations were observed such as an increase in width of the body, cytoplasmic granulations and vacuolizations. These data indicate the toxicity of AZT which prevents the parasite's multiplication, indicating a promising use of AZT as an anti leishmania drug. PMID- 20922415 TI - Clinical efficacy of Saccharomyces boulardii or metronidazole in symptomatic children with Blastocystis hominis infection. AB - Although many Blastocystis infections remain asymptomatic, recent data suggest it also causes frequent symptoms. Therapy should be limited to patients with persistent symptoms and a complete workup for alternative etiologies. The goal of this study was to compare the natural evolution (no treatment) to the efficacy of Saccharomyces boulardii (S. boulardii) or metronidazole for the duration of diarrhea and the duration of colonization in children with gastrointestinal symptoms and positive stool examination for Blastocystis hominis. This randomized single-blinded clinical trial included children presenting with gastrointestinal symptoms (abdominal pain, diarrhea, nausea-vomiting, flatulence) more than 2 weeks and confirmed B. hominis by stool examination (B. hominis cysts in the stool with microscopic examination of the fresh stool). The primary end points were clinical evaluation and result of microscopic stool examination at day 15. Secondary end points were the same end points at day 30. Randomization was performed by alternating inclusion: group A, S. boulardii (250 mg twice a day, Reflor(r)) during 10 days; group B, metronidazole (30 mg/kg twice daily) for 10 days; group C, no treatment. At day 15 and 30 after inclusion, the patients were re-evaluated, and stool samples were examined microscopically. On day 15, children that were still symptomatic and/or were still B. hominis-infected in group C were treated with metronidazole for 10 days. There was no statistically significant difference between the three study groups for age, gender, and the presence of diarrhea and abdominal pain. On day 15, clinical cure was observed in 77.7% in group A (n, 18); in 66.6% in group B (n, 15); and 40% in group C (n:15) (p < 0.031, between groups A and C). Disappearance of the cysts from the stools on day 15 was 80% in group B, 72.2% in group A, and 26.6% in group C (p = 0.011, between group B and group C; p = 0.013, between group A and group C). At the end of the first month after inclusion, clinical cure rate was 94.4% in group A and 73.3% in group B (p = 0.11). Parasitological cure rate for B. hominis was very comparable between both groups (94.4% vs. 93.3%, p = 0.43). Metronidazole or S. boulardii has potential beneficial effects in B. hominis infection (symptoms, presence of parasites). These findings challenge the actual guidelines. PMID- 20922416 TI - Elimination of Angiostrongylus costaricensis larvae in feces from experimentally infected Swiss mice: circadian rhythm and correlation with survival. AB - Angiostrongylus costaricensis is a nematode which harbors mesentery arteries of rodents. In these animals, a circadian rhythm of elimination of first-stage larvae (L1) and a relation between the amount of L1 in feces and survival are unknown. We assessed fecal elimination of A. costaricensis L1 from experimentally infected Swiss mice and tried to correlate L1 elimination with survival. Thirteen Swiss mice were infected by gavage with ten A. costaricensis L3 larvae obtained from Phyllocaulis slugs. Feces were weighed at 7 A.M: . and 7 P.M: . starting from the 24th day post-infection until animal death. Feces sediment was examined in microscope for L1 counting. The mice were dead after a period ranging 19-61 days post-infection. Compared to diurnal samples, both feces' weight (2.3 +/- 0.7 vs. 1.8 +/- 0.5 g; P < 0.0001) and L1 total count [median 1,950 vs. 1,250; P = 0.015] were higher in feces eliminated at night. No difference was observed between diurnal and nocturnal elimination when counting L1 by gram of feces (725 vs. 650 L1/g; P = 0.821). A significant correlation was observed between survival and total number of L1 in feces (r = 0.84; P = 0.0007). This study suggests that mice experimentally infected with A. costaricensis eliminate more L1 at night due to higher fecal volume at this period. The correlation between number of L1 in feces and survival suggests a phenomenon of tolerance to A. costaricensis infection in mice with longer survival. PMID- 20922417 TI - Cutaneus myxosporidiasis in the Australian green tree frog (Litoria caerulea). AB - This case is reported with the intention of highlighting the presentation of cutaneous myxosporidiasis in Australian tree frog (Litoria caerulea) caused by genus Myxobolus. The morphology and morphometric characteristic of the spores were determined using light microscopy and differential interference contrast microscopy. Spores were pyriform in shape in frontal view and oval in lateral view, and the average size was respectively 11.4 * 6.0 * 4.5 MUm (12.1 - 9.5 * 6.3 - 5.4 * 5.0 - 4.1 MUm). To the best of our knowledge, this is the second case of skin invasion caused by myxosporeans in amphibians. PMID- 20922418 TI - Sequence analysis of cox1 and nad1 genes in Echinococcus granulosus G3 genotype in camels (Camelus dromedarius) from central Iran. AB - Nineteen hydatid cyst isolates collected from camels in central Iran were subjected to sequences analysis of mitochondrial cytochrome c oxidase subunit 1 (cox1) and NADH dehydrogenase subunit 1 (nad1) genes. A consensus sequence obtained containing 366 nucleotides for cox1 and 471 nucleotides for nad1 genes. Overall, the camel isolates indicated five different sequences in cox1 and nine in nad1 genes. The sequences analysis indicated that 26.3%, 42.1%, and 31.6% of isolates belonging to G1, G3, and G6 genotypes of Echinococcus granulosus, respectively. The isolates with G3 genotype indicated one cox1 sequence having 100% homology with reference G3 sequence (AN: M84663) and two different nad1 sequences, one having 100% homology with reference G3 sequence (AN: AJ237634) and the other with a silent mutation (G to A) in position 279. The presence of G3 genotype (buffalo strain) of E. granulosus as dominant genotype in camels is emphasized. As G3 genotype has formerly been reported in human, the epidemiological role of camels is warranted in future surveys. PMID- 20922419 TI - Evaluation of medicinal plant extracts against ticks and fluke. AB - The present study was based on assessments of the antiparasitic activities to determine the efficacies of leaf hexane, chloroform, ethyl acetate, acetone and methanol extracts of Aegle marmelos (Linn.) Correa ex Roxb, Andrographis lineata Wallich ex Nees., Andrographis paniculata (Burm.f.) Wallich ex Nees., Cocculus hirsutus (L.) Diels, Eclipta prostrata L., and Tagetes erecta L. against the adult cattle tick Haemaphysalis bispinosa Neumann 1897 (Acarina: Ixodidae), the larvae of Rhipicephalus (Boophilus) microplus Canestrini 1887 (Acari: Ixodidae) and sheep fluke Paramphistomum cervi Zeder 1790 (Digenea: Paramphistomatidae). All plant extracts showed moderate toxic effect on parasites after 24 h of exposure; however, the highest parasitic activity was found in leaf ethyl acetate extract of A. lineata, methanol extract of A. marmelos, A. paniculata, and C. hirsutus against H. bispinosa (LC(50) = 395.27, 358.45, 327.21 and 420.50 ppm); ethyl acetate extract of A. paniculata, C. hirsutus, methanol extracts of A. marmelos, A. lineata, and E. prostrata against the larvae of R. microplus (LC(50) = 207.70, 258.61, 134.09, 206.00, and 274.33 ppm); hexane extract of A. lineata, ethyl acetate extract of A. paniculata, E. prostrata, acetone extracts of T. erecta, methanol extracts of A. marmelos and C. hirsutus against P. cervi (LC(50) = 254.23, 451.17, 425.73, 253.60, 542.71, and 360.17 ppm), respectively. The present study is the first report on the veterinary parasitic activity of plant extracts from Southern India. PMID- 20922420 TI - Structure of capsule surrounding acanthocephalans Corynosoma strumosum in paratenic hosts of three species. AB - Morphology of capsules surrounding acanthocephalan Corynosoma strumosum in paratenic hosts (sea fishes of three species from the northern part of the Sea of Okhotsk) was studied. A thick layer of glycocalyx is formed on the surface of acanthocephalan's tegument in smelts Osmerus mordax dentex and Hypomesus olidus; the surrounding capsule is formed by fibroblasts and collagen fibers and do not include inflammatory cells. Besides fibroblasts, capsule of the sole Limanda aspera consists also of macrophages, granulocytes, "dark" cells, and once of erythrocytes that indicate obvious inflammatory response of the host's organism to invasion; glycocalyx on the surface of acanthocephalans from the sole is weakly developed. The obtained results allow considering the smelts as the most suitable paratenic hosts and the yellow-finned sole as unsuitable paratenic host for the studied acanthocephalans. PMID- 20922421 TI - Entamoeba histolytica calreticulin: an endoplasmic reticulum protein expressed by trophozoites into experimentally induced amoebic liver abscesses. AB - Entamoeba histolytica calreticulin (EhCRT) is remarkably immunogenic in humans (90-100% of invasive amoebiasis patients). Nevertheless, the study of calreticulin in this protozoan is still in its early stages. The exact location, biological functions, and its role in pathogenesis are yet to be fully understood. The aim of the present work is to determine the location of EhCRT in virulent trophozoites in vivo and the expression of the Ehcrt gene during the development of experimentally induced amoebic liver abscesses (ALA) in hamsters. Antibodies against recombinant EhCRT were used for the immunolocalization of EhCRT in trophozoites through confocal microscopy; immunohistochemical assays were also performed on tissue sections of ALAs at different times after intrahepatic inoculation. The expression of the Ehcrt gene during the development of ALA was estimated through both in situ RT-PCR and real-time RT-PCR. Confocal assays of virulent trophozoites showed a distribution of EhCRT in the cytoplasmic vesicles of different sizes. Apparently, EhCRT is not exported into the hepatic tissue. Real-time RT-PCR demonstrated an over-expression of the Ehcrt gene at 30 min after trophozoite inoculation, reaching a peak at 1-2 h; thereafter, the expression fell sharply to its original levels. These results demonstrate for the first time in an in vivo model of ALA, the expression of Ehcrt gene in E. histolytica trophozoites and add evidence that support CRT as a resident protein of the ER in E. histolytica species. The in vivo experiments suggest that CRT may play an important role during the early stages of the host-parasite relationship, when the parasite is adapting to a new environment, although the protein seems to be constitutively synthesized. Moreover, trophozoites apparently do not export EhCRT into the hepatic tissue in ALA. PMID- 20922422 TI - Schistosoma japonicum-infected hamsters (Mesocricetus auratus) used as a model in experimental chemotherapy with praziquantel, artemether, and OZ compounds. AB - The purpose of the study is to better understand the antischistosomal properties of artemether, praziquantel, and ozonide (OZ) compounds (synthetic trioxolanes, secondary ozonides) in hamster (Mesocricetus auratus) model. A total of 230 male hamsters infected each with 100 Schistosoma japonicum cercariae were used in the study. Groups of five to ten hamsters were treated orally with artemether, praziquantel, and OZ78 or OZ277 7-35 days post-infection at single doses of 50, 100, 150, or 200 mg/kg. Untreated but infected hamsters in each batch of test served as the control. All treated hamsters were sacrificed 4 weeks post treatment for collection of residual worms using perfusion technique. Nonparametric method (Mann-Whitney test) was used to analyze the data. In groups of five hamsters treated with artemether 7, 14, 21, 28, and 35 days post infection at single doses of 150 and 200 mg/kg, the difference of mean worm burden between each treated group and control group was statistically significant (P<0.01). Apart from individual group, no difference in mean worm burden between each two groups of them was seen (P>0.05). Further test with various single doses of 50-200 mg/kg confirmed the similar susceptibility of 7-day-old juvenile and 35 day-old adult schistosomes to artemether. After administration of praziquantel 100 mg/kg to groups of five hamsters 7, 21, and 35 days post-infection, higher worm burden reduction of 95.5% was seen in the group with 35-day-old adult schistosomes while in the groups with 7- and 21-day-old juvenile schistosomes, poor efficacy was seen with mean worm burden reductions of 36.6% and 35.6%. In the same batch of hamster treated with praziquantel 200 mg/kg, the moderate effect of the drug against 7- and 21-day-old worms was seen, but their mean worm burden was significantly higher than that of the group with adult schistosomes. In comparison of artemether and praziquantel against various stages of schistosomes, the results further demonstrated that artemether possessed similar effect against juvenile and adult schistosomes in hamsters, while praziquantel was more effective against adult schistosomes than the juvenile ones in the same host. Finally, after administration of OZ78 and OZ277 to the groups of four to six hamsters with 14- and 35-day-old schistosomes at a single dose of 200 mg/kg, promising effect against juvenile and adult schistosome was observed with the mean worm burden and female worm burden reductions of 69.6-94.2% and 64.2-100% as well as 73.3-80.7% and 68.3-81.1%, respectively. The results indicate that in hamster model, praziquantel exhibits higher effect against adult schistosomes than the juvenile ones, while artemether and OZ compound display similar effect against both juvenile and adult schistosomes. PMID- 20922423 TI - Comparison of protein-free defined media, and effect of L-cysteine and ascorbic acid supplementation on viability of axenic Entamoeba histolytica. AB - Entamoeba histolytica is the etiologic agent for amoebiasis. The excretory secretory (ES) products of the trophozoites contain virulence factors and antigens useful for diagnostic applications. Contaminants from serum supplements and dead trophozoites impede analysis of ES. Therefore, a protein-free medium that can sustain maximum viability of E. histolytica trophozoites for the longest time duration will enable collection of contaminant-free and higher yield of ES products. In the present study, we compared the efficacy of four types of media in maintaining >= 95% trophozoite viability namely Roswell Memorial Park Institute (RPMI-1640), Dulbecco's Modified Eagle Medium (DMEM), phosphate buffered saline for amoeba (PBS-A), and Hank's balanced salt solution (HBSS). Concurrently, the effect of adding L: -cysteine and ascorbic acid (C&A) to each medium on the parasite viability was also compared. DMEM and RPMI 1640 showed higher viabilities as compared to PBS-A and HBSS. Only RPMI 1640 showed no statistical difference with the control medium for the first 4 h, however the >= 95% viability was only maintained for the first 2 h. The other protein-free media showed differences from the serum- and vitamin-free TYI-S-33 control media even after 1 h of incubation. When supplemented with C&A, all media were found to sustain higher trophozoite viabilities than those without the supplements. HBSS C&A, DMEM-C&A, and RPMI 1640-C&A demonstrated no difference (P>0.05) in parasite viabilities when compared with the control medium throughout the 8-h incubation period. DMEM-C&A showed an eightfold increment in time duration of sustaining >= 95% parasite viability, i.e. 8 h, as compared to DMEM alone. Both RPMI 1640-C&A and HBSS-C&A revealed fourfold and threefold increments (i.e., 8 and 6 h, respectively), whereas PBS-A-C&A showed only one fold improvement (i.e., 2 h) as compared to the respective media without C&A. Thus, C&A-supplemented DMEM or RPMI are recommended for collection of ES products. PMID- 20922424 TI - prag01, a novel deltamethrin-resistance-associated gene from Culex pipiens pallens. AB - The prag01 gene (GenBank accession no. EU073017) was cloned from Culex pipiens pallens. An open reading frame of 270 bp was found to encode a putative 89-amino acid protein which has the highest homology with Culex quinquefasciatus and Anopheles funestus. Real-time quantitative PCR analysis demonstrated that the transcription level of prag01 gene in deltamethrin-resistant strain was 1.65-fold higher than in deltamethrin-susceptible strain of C. pipiens pallens. Overexpression of prag01 gene in the mosquito C6/36 cells showed better prolification than the cells with empty vector when treated by deltamethrin. Our data for the first time approved that prag01 gene might play some role in the development of deltamethrin resistance in C. pipiens pallens. PMID- 20922425 TI - Effect of mefloquine administered orally at single, multiple, or combined with artemether, artesunate, or praziquantel in treatment of mice infected with Schistosoma japonicum. AB - The purpose of the study is to explore the efficacy of mefloquine administered orally at single, multiple doses, or in combination with artesuante, artemether, or praziquantel in mouse--Schistosoma japonicum model. A total of 205 mice were divided into 4 batches and each batch of mice was infected percutaneously with 40 S. japonicum cercariae for 35 days. The infected mice were treated orally with mefloquine at single doses, multiple daily doses, or combined with artesunate, artemether, or praziquantel, while infected but untreated mice served as control. All treated animals were killed 4 weeks post-treatment for assessment of effect. When infected mice were treated orally with mefloquine at single or multiple daily doses under the same total dose levels, the tendency to decrease the efficacy was seen. Particularly, when a lower single dose of 100 mg/kg was divided equally into five daily doses of 20 mg/kg, the efficacy decreased statistically significant (P<0.05), i.e., the total worm and female worm reductions of 67.9% and 73.4% decreased to 31.3% and 30.3%, respectively. In infected mice treated with mefloquine or artesuante at a single dose of 100 mg/kg, a moderate effect against schistosomes was observed. No further significant reduction of total and female worm burdens was seen, when the two drugs combined together at the same dose level. On the other hand, administration of mefloquine combined with artesunate at single dose of 50 mg/kg, which exhibited no effect against schistosomes, resulted in significant reduction of total and female worm burdens in comparison with the groups treated with mefloquine and artesunate alone at the same dose level. Similar results were observed in treatment of infected mice with mefloquine in combination with artemether at the smaller dose of 50 mg/kg. The total worm burden was significantly lower than that of control and the female worm burden was also significant lower than that of groups treated with mefloquine and artemether alone. Interestingly, in administration of mefloquine 100 mg/kg combined with artemether 100 mg/kg to the infected mice, all female worms were killed and the total worm burden was also statistically significant lower than that of groups treated with either drug alone. Finally, when infected mice were treated with mefloquine combined with prazqiuatel at single dose of 50 mg/kg, no apparent improvement in efficacy was seen. Administration of mefloquine 100 mg/kg combined with praziquantel 100 mg/kg, only the difference of female worm burdens between praziquantel group and combined treatment group was statistically significant. The results indicate that under the same dose level of mefloquine, the efficacy of single dose is superior to that of multiple daily doses; mefloquine combined with artesunate or artemether at an invalid or moderate effective dose may show synergistic effect, especially the effect against female worms; no prominent synergistic effect is observed, when the similar dose level of mefloquine in combination with praziquantel. PMID- 20922426 TI - Up-regulation of lipophorin (Lp) and lipophorin receptor (LpR) gene in the mosquito, Culex quinquefasciatus (Diptera: Culicidae), infected with the filarial parasite, Wuchereria bancrofti (Spirurida: Onchocercidae). AB - In mosquitoes, including Culex quinquefasciatus, immune molecules are known to be upregulated or produced de novo upon exposure to parasites or pathogens. These molecules are regulatory in nature acting against parasite or pathogen infection and development. Similarly, there are molecules that are upregulated to facilitate parasite development in the vector mosquitoes. Lipophorin, a major lipid transporting lipoprotein in the hemolymph of insects, is implicated as a helper molecule in the clotting mechanism and facilitator of parasite and pathogen development in mosquitoes. In the present study, upregulation of a 240 kDa protein was detected in C. quinquefasciatus infected with the human lymphatic filarial parasite, Wuchereria bancrofti. It was identified as a lipophorin through nano-Lc-MS/MS analysis. Transcription of the lipophorin receptor gene also was identified through RACE-PCR. C. quinquefasciatus is the vector of W. bancrofti, and it allows successful development of the parasite. The role of upregulated lipophorin and transcription of its receptor gene in this mosquito could be implicated as a facilitator for the parasite development. PMID- 20922427 TI - Comparative analysis of the diagnostic performance of crude sheep hydatid cyst fluid, purified antigen B and its subunit (12 Kda), assessed by ELISA, in the diagnosis of human cystic echinococcosis. AB - The diagnosis of patients with cystic echinococcosis (CE) by means of serology has a limited support in clinical practice due to cross-reactivity with other helminthes leading to overestimation of the parasite's true prevalence. A wealth of reports on the diagnostic performance of antigen B (AgB) has been produced. This study was designed to comparatively assess the diagnostic efficacy of crude sheep hydatid cyst fluid (HCF), AgB and its subunit (12 KDa) to detect IgG or IgG4 antibodies in CE patients' sera using enzyme-linked immunosorbent assay (ELISA).The best diagnostic performance was obtained with anti-HCF IgG ELISA which gave 92.4% sensitivity and 92.6% specificity. Despite the low sensitivity of anti AgB IgG ELISA (84%), it gave the best specificity (94.4%) with less cross reaction with sera of subjects infected with other parasites. In conclusion, it is recommended to use anti-HCF IgG ELISA for initial screening in large seroprevalence studies. Further analysis of positive serum samples with anti AgB IgG ELISA would allow the confirmation of true positives. Specific IgG4 ELISA may represent a complementary assay, useful as secondary confirmatory tests for patients with suspected CE and negative for total IgG ELISA. PMID- 20922428 TI - Antileishmanial activity of imidothiocarbamates and imidoselenocarbamates. AB - In the present study, a family of 15 imidothio- and imidoselenocarbamates (1-15) analogs have been synthesized and screened for their in vitro antileishmanial potential against Leishmania infantum promastigotes. The six most active ones (2, 4, 7, 13, 14, and 15) were also tested in an axenic amastigote model. In order to establish their selectivity indexes (SI) the cytotoxic effect of each compound was also assayed against Jurkat and THP-1 cell lines. Compounds 2 and 4, both with a pyridine moiety, showed a moderate antileishmanial activity with an IC(50) value of 4.68 +/- 0.46 and 3.03 +/- 0.24 MUM, respectively, in the amastigote model. The activity was compared with that of standard drugs, edelfosine (IC50 = 0.82 +/- 0.13 MUM) and miltefosine (IC50 = 2.84 +/- 0.10 MUM). Related to selectivity, the SI of both compounds are similar to those of the standard drugs when compared against the THP-1 cell line. Moreover, compound 4 was able to reduce the number of amastigote-infected THP-1 cells to 40% of that observed in untreated controls after a 96-h period of treatment. These derivatives thus represent two new leads for further studies aimed at establishing their mechanism of action. PMID- 20922429 TI - What is the evidence for the existence of Plasmodium ovale hypnozoites? AB - Relapsing human malaria is regarded to be caused by Plasmodium vivax and Plasmodium ovale. P. vivax relapses originate from dormant liver stages: "hypnozoites". Also, P. ovale, a species considered as closely related to P. vivax, is in analogy assumed to display hypnozoites. A close biologic relationship is, however, not supported by molecular genetic studies. Therefore, original literature published since the description of P. ovale in 1922 was systematically screened for the demonstration of hypnozoites or circumstantial evidence for their existence, i.e. the occurrence of true relapses. In P. ovale infection, hypnozoites have never been demonstrated by biological experiments, and the few reports published on relapses have conflicting results. PMID- 20922430 TI - Seasonal prevalence of gastrointestinal nematode parasites of sheep in Northern region of Nile Delta, Egypt. AB - Over 1 year, from January to December 1999, a total of 173 slaughtered sheep at Al-Mahala abattoir were examined for presence of nematode parasites. Eighteen sheep (10.4%) were infected with eight different species of nematodes. The prevalence rates of detected nematode parasites were; Haemonchus contortus (3.5%), Haemonchus placei (1.7%), Trichuris ovis (5.8%), Parabronema skrjabini (2.9%), Ostertagia trifurcata (1.2%), Chabertia ovina (0.6%) and Strongyloides papillosus (0.6%), and Graphidiops species (2.9%). The seasonal prevalence of the infection with the nematode parasites was studied and the highest rate was during autumn (15.2%) followed by summer (11.1%) and winter (9.4%) while the lowest rate was during spring (5.6%). PMID- 20922431 TI - Long-term changes in a population of an invasive bivalve and its effects. AB - Although the ecological and economic effects of non-native species probably often change through time, few studies have documented such effects. The zebra mussel (Dreissena polymorpha) is an important invader that has had large ecological and economic effects on the ecosystems it has invaded in North America and western Europe. Our 20-year study of the Hudson River, New York, showed that the characteristics of a zebra mussel population and its effects on other benthic animals both changed substantially through time. Over the period of study, annual survivorship of adult zebra mussels fell >100-fold, which caused the aggregate filtration rate of the population to fall by 82%. Population size and body size of zebra mussels may also have fallen. In the early years of the invasion, densities of nearly all benthic animals in deepwater sites fell steeply (by 80 99%). After about 8 years of decline, these populations began to recover, and are approaching pre-invasion densities. The littoral zoobenthos showed neither the initial decline nor the subsequent recovery. Although the mechanisms behind these changes are not fully clear, our study shows that the effects of an invader may change considerably over time. PMID- 20922432 TI - Risperidone-induced bulbar palsy-like syndrome. AB - There have been several case reports of risperidone-associated dysphagia. Risperidone-induced bulbar palsy-like syndrome has not been previously described. We report on a 58-year-old gentleman with prior history of schizophrenia and remote chlorpromazine use with no history of extrapyramidal symptoms who experienced acute onset of dysphagia and facial diplegia with hyperprolactinemia while being treated with risperidone. To date there have been five reported cases of dysphagia associated with risperidone, occurring by such mechanisms as isolated pharyngeal dysfunction from pharyngeal constrictor palsy and dystonia, drug-induced parkinsonism, and acute dystonic reaction. These cases were associated either with initiation or up-titration of risperidone, with complete resolution of dysphagia after medication discontinuation or dose change. Our patient developed dysphagia within 2 weeks of taking risperidone and completely resolved 1 month after the medication was stopped. Unlike other reported cases, our patient also experienced symptomatic hyperprolactinemia, another known side effect of risperidone. Physicians should also be aware that risperidone can be associated with oropharyngeal dysphagia secondary to an acute bulbar palsy-like syndrome that places patients at increased risk of aspiration events and its associated morbidity and mortality. PMID- 20922434 TI - Arbuscular mycorrhizal inoculum potential: a mechanism promoting positive diversity-invasibility relationships in mountain beech forests in New Zealand? AB - Mycorrhizal fungi are important symbionts for the majority of plant species, but their role in determining the susceptibility of habitat to plant invasion is poorly understood. Hieracium lepidulum is an arbuscular mycorrhizal herb, currently invading the understorey of ectomycorrhizal Nothofagus solandri var. cliffortioides (mountain beech) forest in New Zealand. Mountain beech is solely ectomycorrhizal, and other plant species within the understorey occur sporadically. Hieracium has been shown to establish preferentially in microsites with higher plant species richness at a scale of less than 1 m(2) within mountain beech forest, and we tested the hypothesis that more diverse microsites (<1 m(2)) are associated with higher levels of arbuscular mycorrhizal fungal (AMF) inoculum. We found low levels of AMF inoculum across all microsites, and over a third of samples contained no inoculum at all. Higher vascular-plant species richness (but not biomass) was associated with higher AMF spore densities in field soil, and greater AMF colonization of H. lepidulum seedlings in a bioassay. Absence of AMF inoculum from much of the soil and the positive association of inoculum potential with species richness provide a potential mechanism for the establishment of a positive diversity-invasibility relationship in the mountain beech forest. PMID- 20922433 TI - Vertebral fractures despite normal spine bone mineral density in a boy with nephrotic syndrome. AB - Glucocorticoids (GCs) are associated with fragility fractures in children with various chronic illnesses. The impact of GCs on bone health in children with nephrotic syndrome (NS) is less well understood. Here we report skeletal findings in a 10-year-old boy with steroid-sensitive NS who presented with back pain due to vertebral fractures 5 years after NS diagnosis. Spine radiographs showed a Genant grade 2 fracture at T7 and a grade 1 fracture at T8. Dual-energy X-ray absorptiometry (DXA) revealed a lumbar spine areal bone mineral density (BMD) Z score of -0.5 and a total body areal BMD Z-score of -0.4. Quantitative transiliac bone histomorphometry revealed low trabecular bone volume and cortical width but no osteomalacia. Our findings show the potential for significant bone morbidity due to osteoporosis in steroid-sensitive NS treated with intermittent GC therapy and emphasize that vertebral fractures may be an underrecognized complication. Furthermore, our report highlights that vertebral fractures can be associated with normal spine areal BMD in this context, suggesting that DXA-based, anteroposterior areal BMD should not be relied upon exclusively for assessing bone health and disease in children with steroid-sensitive NS. PMID- 20922435 TI - Fungal root symbionts and their relationship with fine root proportion in native plants from the Bolivian Andean highlands above 3,700 m elevation. AB - Here, we examined the colonization by fungal root symbionts in the cultivated Andean grain Chenopodium quinoa and in 12 species that dominate plant communities in the Bolivian Altiplano above 3,700 m elevation and explore for the possible relationships between fungal colonization and fine root proportion. The 12 most abundant species in the study area were consistently colonized by AMF and DSE. In contrast, the annual Andean grain C. quinoa showed negligible or absence of mycorrhizal fungi colonizing roots. On the other hand, C. quinoa, Junelia seriphioides and Chersodoma jodopappa were infected to a varying degree by the root pathogen Olpidium sp. We observed no relationship between AMF and DSE colonization and proportion of fine roots in the root system, but instead, the ratio between DSE and AMF colonization (ratio DSE/AMF) negatively related with proportion of fine roots. Our findings support the hypothesis regarding the importance of DSE at high altitudes and suggest a functional relationship between the rate of DSE/AMF and proportion of fine roots. The colonization by the root pathogen Olpidium sp. in C. quinoa deserves further study since this Andean grain is increasingly important for the local economy in these marginal areas. PMID- 20922436 TI - Description of a new putative virus infecting the conifer pathogenic fungus Heterobasidion parviporum with resemblance to Heterobasidion annosum P-type partitivirus. AB - The complete sequences of two double-stranded RNA segments from the fungus Heterobasidion parviporum were characterized. The larger segment (2,290 bp) contained an open reading frame encoding a putative RNA-dependent RNA polymerase (RdRp, 722 aa), while the smaller one (2,238 bp) encoded a putative coat protein of 659 aa. Based on phylogenetic analysis, the dsRNA segments constitute the genome of a new virus assigned to the family Partitiviridae and named Heterobasidion RNA virus 2 (HetRV2). The RdRp segment was clearly related to H. annosum P-type partitivirus (aa similarity of 59%) but was only distantly related to previously described viruses of H. parviporum (aa similarity 26-35%). The dsRNA could be experimentally transmitted to all five species of the Heterobasidion annosum sensu lato complex and two species of the H. insulare complex, indicating that horizontal transfer between these intersterile fungal species is possible. PMID- 20922437 TI - Characterization of an isolate of Sowbane mosaic virus. PMID- 20922438 TI - The effects of intravenous zoledronic acid in Chinese women with postmenopausal osteoporosis. AB - The aim of this study was to assess the efficacy and safety of a once-yearly zoledronic acid treatment for Chinese women with postmenopausal osteoporosis in Taiwan and Hong Kong. This post hoc subpopulation analysis, from the Health Outcome and Reduced Incidence with Zoledronic Acid One Yearly Pivotal Fracture Trial, enrolled 323 Chinese women with osteoporosis who were randomly given either annual infusions of zoledronic acid or placebo for 3 consecutive years. The incidence of fractures and changes in bone mineral density (BMD) were measured; adverse events (AEs) and tolerability were recorded and assessed. The results of this study at 36 months demonstrate that there was a significantly reduced risk of morphometric vertebral fracture and clinical vertebral fracture in subjects treated with zoledronic acid (P < 0.05). In addition, there were significant increases of BMD by 4.9%, 4.3%, and 7.0% in the total hip, femoral neck, and trochanter, respectively, in the zoledronic acid group compared with the placebo group (P < 0.001 for all comparisons). The incidences of AEs were comparable between the two groups. Thus, once-yearly zoledronic acid treatment showed bone protection effects by reducing the risk of vertebral fracture and increasing BMD in Chinese women with postmenopausal osteoporosis. PMID- 20922439 TI - Influence of the fabrication process on the in vitro performance of fixed dental prostheses with zirconia substructures. AB - Chipping of the applied veneering ceramic is reported to be a main clinical failure type of computer-aided design/computer-aided manufacturing- or manually copy-milled zirconia restorations. The aim of this in vitro study was to investigate whether different substructure designs and veneering processes done by different dental technicians do significantly influence chipping in zirconia based all-ceramic fixed dental prostheses during simulated oral service. Five groups (n = 8 per group) of three-unit zirconia substructures were fabricated in three different laboratories using copy-milling technique. Three series were veneered with identical porcelain (groups 1-3) and one with a second different porcelain (group 4). The fifth group was milled to final contour design without veneering. Dimensions of the connector areas were determined. All fixed partial dentures (FPDs) were adhesively boned on human teeth and thermally cycled and mechanically loaded (1.2 * 10(6) * 50 N; 6,000 * 5 degrees C/55 degrees C) using human antagonists. Restorations were monitored during thermal cycling and mechanical loading (TCML). FPDs which survived were loaded to fracture. FPDs which failed during TCML were investigated with fractographic means. During TCML, chipping took place in groups 1 (two times), 2 (four times) and 3 (five times) (Table 1). Chipping areas varied between 2.3 mm(2) (group 3) and 58.7 mm(2) (group 2). Groups 4 and 5 provided no failures during TCML. Failure in all cases started from contact points, where superficial wear and disruption of the porcelain were found. No significant correlation could be determined between connector thickness and number of failures. Median fracture results varied between 1,011 N (group 3) and 2,126 N (group 2). The results show the necessity of considering individual design and manufacturing of restorations as well as contact situation. Advanced technical training on zirconia-based restorations is recommended. PMID- 20922440 TI - Abatacept: a potential therapy in refractory cases of juvenile idiopathic arthritis-associated uveitis. AB - BACKGROUND: Juvenile idiopathic arthritis (JIA) is the most common of all systemic conditions associated with childhood uveitis. Visual impairment has been shown to be as high as 40% of which 10% being blind (6/60 or worse). Due to the lack of well-designed randomized control trials for paediatric uveitis and arthritis there are limited comparative data regarding the efficacy of single or combination treatments. Recently, abatacept was shown to control ocular inflammation in a case of psoriatic arthritis- associated uveitis, seven cases of JIA- associated uveitis and in JIA. We present two cases with JIA-associated uveitis who have responded dramatically to abatacept therapy following unsuccessful therapy with other immunosuppressants. Control of arthritis still represents a challenge with this treatment. METHODS: Prospective review of two patients with refractory JIA- associated uveitis not responding to maximum conventional treatment. Patients were regularly reviewed in the ophthalmology and rheumatology clinics. Assessment of their ocular condition was characterized according to the Standardization of Uveitis Nomenclature (SUN) group. RESULTS: In case 1, ocular inflammation was brought under control after repeated abatacept infusions. Case 2 showed complete resolution of cystoids macular edema CME and improvement of 5 Snellen's lines in best corrected visual acuity. After 9 months, the ocular condition of both patients remains in remission with steroid sparing. Joint disease was brought to clinical remission in case 2, but not in case 1. CONCLUSIONS: Abatacept is a promising alternative treatment in refractory cases of JIA uveitis but may not be as successful in controlling joint disease. Larger series with long term follow up of biological therapies in paediatric uveitis are essential to assess the efficacy and cost effectiveness. PMID- 20922441 TI - Green tea extract given before regional myocardial ischemia-reperfusion in rats improves myocardial contractility by attenuating calcium overload. AB - There is evidence for a negative correlation between green tea consumption and cardiovascular diseases. The aim of the present study was to examine whether green tea extract (GTE) given before regional myocardial ischemia could improve depression of myocardial contractility by preventing cytosolic Ca(2+) overload. Regional ischemia-reperfusion (IR) was induced in rats by ligating the left anterior descending branch for 20 min, then releasing the ligature. Ligation induced ventricular arrhythmias in rats without GTE pretreatment, but decreased arrhythmogenesis was seen in rats pretreated 30 min earlier with GTE (400 mg/kg). During reperfusion, arrhythmias only occurred during the initial 5 min, and GTE pretreatment had no effect. After overnight recovery, serum cTnI levels were greatly increased in control post-IR rats but only slightly elevated in GTE pretreated post-IR rats. Myocardial contractility measured by echocardiography was still depressed after 3 days in control post-IR rats, but not in GTE pretreated post-IR rats. No myocardial ischemic injury was seen in post-IR rats with or without GTE pretreatment. Using freshly isolated single heart myocytes, GTE was found to attenuate the post-IR injury-associated cytosolic Ca(2+) overload and modulate changes in the levels and distribution of myofibril, adherens junction, and gap junction proteins. In summary, GTE pretreatment protects cardiomyocytes from IR injury by preventing cytosolic Ca(2+) overload, myofibril disruption, and alterations in adherens and gap junction protein expression and distribution. PMID- 20922442 TI - CCK mediated the inhibitory effect of oxytocin on the contraction of longitudinal muscle strips of duodenum in male rats. AB - The aim of the present study was to investigate the effect of oxytocin (OT) on duodenum motility in rats and the possibility that cholecystokinin (CCK) was involved in this process. The isometric contraction of longitudinal muscle strips of duodenum was monitored by polygraph. ELISA was used to measure the concentration of CCK and OT in duodenum. CCK mRNA was assayed by RT-PCR. Oxytocin receptor (OTR) and CCK in duodenum were located by immunohistochemistry and immunofluorescence staining. OT (10-5 and 10-6 M) inhibited the spontaneous contraction of the muscle strips. On the contrary, atosiban (OT receptor antagonist), lorglumide (CCK1 receptor antagonist), and tetrodotoxin (TTX, blocker of voltage-dependent Na(+) channel on nerve fiber) excited the contraction. The inhibitory effect of OT on duodenal motility was reversed by pretreatment of atosiban, lorglumide, or TTX. Exogenous OT did not influence the expression of OT mRNA in duodenum but increased the concentration of CCK in the culture medium of the cells isolated from longitudinal muscle myenteric plexus. The OTR and CCK were co-expressed in the neurons of the myenteric plexus in duodenum. We concluded that OT inhibited the contraction of the LD spontaneous contraction of rats in vitro. This effect was mediated by the CCK released from the neurons of the myenteric plexus in duodenum. PMID- 20922443 TI - 3,4,5-Trisubstituted-1,2,4-4H-triazoles as WT and Y188L mutant HIV-1 non nucleoside reverse transcriptase inhibitors: docking-based CoMFA and CoMSIA analyses. AB - 3,4,5-Trisubstituted-1,2,4-4H-triazoles (TTs) have recently been identified as a new class of potent non-nucleoside HIV-1 reverse transcriptase (RT) inhibitors. Two series of triazoles have been studied, one of which was also screened against the Y188L mutant. A computational strategy based on molecular docking studies followed by comparative molecular fields analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) has been used to elucidate the atomic details of the RT/TT interactions and to identify the most important features impacting the TT antiretroviral activity. Two 3D-QSAR CoMFA and CoMSIA models were derived, using the TT pEC50 values measured against wild-type (WT) HIV-1 (model A) and the Y188L mutant form (model B), respectively, as the dependent variable. The final model A CoMSIA (r(ncv)2 = 0.97, r(cv)2 = 0.89, SEE = 0.314, and r(pred)2 = 0.82) and model B CoMSIA (r(ncv)2 = 0.91, r(cv)2 = 0.61, SEE = 0.236, and r(pred)2 = 0.73) analyses were more predictive. The results allowed us to obtain useful information for the design of new compounds with improved potency towards WT HIV-1 or that are potentially active against the Y188L mutant. PMID- 20922444 TI - Third-order nonlinear optical materials: practical issues and theoretical challenges. AB - The renewed interest in all-optical switching has led to more detailed experimental investigations of nonlinear optical properties of materials within wide wavelength ranges. The objectives of these studies are discussed here in the context of the availability of suitable computational data that might be compared with the results of the experimental research. It is concluded that the currently available data are insufficient and should be augmented to provide better guidance for experimental work. PMID- 20922445 TI - Computational investigation of the histidine ammonia-lyase reaction: a modified loop conformation and the role of the zinc(II) ion. AB - Possible reaction intermediates of the histidine ammonia-lyase (HAL) reaction were investigated within the tightly closed active site of HAL from Pseudomonas putida (PpHAL). The closed structure of PpHAL was derived from the crystal structure of PpHAL inhibited with L-cysteine, in which the 39-80 loop including the catalytically essential Tyr53 was replaced. This modified loop with closed conformation was modeled using the structure of phenylalanine ammonia-lyase from Anabaena variabilis (AvPAL) with a tightly closed active site as a template. Three hypothetical structures of the covalently bound intermediate in the PpHAL active site were investigated by conformational analysis. The distances between the acidic pro-S beta-hydrogen of the ligand and the appropriate oxygen atoms of Tyr53, Ty280 and Glu414--which may act as enzymic bases--in the conformations of the three hypothetical intermediate structures were analyzed together with the substrate and product arrangements. The calculations indicated that the most plausible HAL reaction pathway involves the N-MIO intermediate structure in which the L-histidine substrate is covalently bound to the N-3,5-dihydro-5-methylidene 4H-imidazol-4-one (MIO) prosthetic group of the apoenzyme via the amino group. Density functional theory (DFT) calculations--on a truncated model of the N-MIO intermediate containing a Zn2+ ion coordinated to the imidazole ring of the ligand and to His83, Met382 and a water molecule--indicated that Zn-complex formation plays a role in the reactivity and substrate specificity of HAL. PMID- 20922446 TI - Gas gangrene of the abdominal wall due to late-onset enteric fistula after polyester mesh repair of an incisional hernia. AB - The occurrence of enteric fistulae after wall repair using a prosthetic mesh is a serious but, fortunately, rare complication. We report the case of a 66-year-old diabetic man who presented with gas gangrene of the abdominal wall due to an intra-abdominal abscess caused by intestinal erosion six years after an incisional hernia repair using a polyester mesh. The aim of this case report is to illustrate the seriousness of enteric fistula after parietal repair using a synthetic material. PMID- 20922449 TI - Impact of double-balloon rectal catheter use in external-beam radiotherapy for prostate cancer. AB - BACKGROUNDS: Prostate motion and rectal sparing are important treatment strategy issues in external-beam radiotherapy for localized prostate cancer. To address these issues, we prospectively investigated the feasibility of using a double balloon rectal catheter. METHODS: The rectal catheter has inner and outer balloons that wedge the anus between them. Computed tomography (CT) examinations with and without the catheter were conducted in seven patients with localized prostate cancer treated by external-beam radiotherapy. The rectal wall sparing effect was evaluated using virtual three-dimensional conformal radiotherapy plans in each arm. To evaluate interfractional prostate motion, each patient underwent a series of four CT examinations consisting of a planning CT followed by three additional series of CT with and without a catheter during the course of radiotherapy. RESULTS: Virtual plans demonstrated the reduction of the dose to the rectum by expanding the posterior wall to lie outside the high- to intermediate-dose area when a catheter was applied. Interfractional prostate motion in the anteroposterior direction was effectively reduced by catheter usage; the mean +/- standard deviation (SD) of the displacement was 1.3 +/- 0.9 mm with a catheter as compared to 2.8 +/- 1.8 mm without a catheter (P = 0.014), and the maximum displacement was successfully suppressed to 3 mm with a catheter compared to 6 mm without a catheter. Systematic and random components were also reduced with the catheter. CONCLUSION: These results suggest the feasibility and clinical applicability of the double-balloon rectal catheter. PMID- 20922448 TI - Pathologic complete response with neoadjuvant imatinib for locally advanced pelvic GIST. AB - There are few data that show pathologic complete response (pCR) to imatinib treatment in gastrointestinal stromal tumors (GISTs). We describe a case of a patient with pCR of a pelvic, locally advanced, high-risk GIST who was treated with neoadjuvant imatinib and ultimately underwent a conservative procedure. A 48 year-old male presented with a pelvic mass 10 cm in diameter. Biopsy revealed a gastrointestinal stromal tumor of rectal origin. Although it was considered initially resectable, an extensive procedure would have been necessary for complete resection. Treatment with imatinib was initiated, resulting in partial response. The patient remained on imatinib for over 15 months, maintaining stable disease. Radical prostatectomy with anal sphincter preservation was performed. Pathological report revealed no viable neoplastic cells. The use of imatinib was held for 6 months after the surgery. At a follow-up 15 months after surgery, the patient had no evidence of disease. Our report may help to guide future studies of neoadjuvant imatinib for large pelvic or rectum GISTs that are initially considered unresectable. PMID- 20922447 TI - Upregulation of transcription factor NRF2-mediated oxidative stress response pathway in rat brain under short-term chronic hypobaric hypoxia. AB - Exposure to high altitude (and thus hypobaric hypoxia) induces electrophysiological, metabolic, and morphological modifications in the brain leading to several neurological clinical syndromes. Despite the known fact that hypoxia episodes in brain are a common factor for many neuropathologies, limited information is available on the underlying cellular and molecular mechanisms. In this study, we investigated the temporal effect of short-term (0-12 h) chronic hypobaric hypoxia on global gene expression of rat brain followed by detailed canonical pathway analysis and regulatory network identification. Our analysis revealed significant alteration of 33, 17, 53, 81, and 296 genes (p < 0.05, <1.5 fold) after 0.5, 1, 3, 6, and 12 h of hypoxia, respectively. Biological processes like regulation, metabolic, and transport pathways are temporally activated along with anti- and proinflammatory signaling networks like PI3K/AKT, NF-kappaB, ERK/MAPK, IL-6 and IL-8 signaling. Irrespective of exposure durations, nuclear factor (erythroid-derived 2)-like 2 (NRF2)-mediated oxidative stress response pathway and genes were detected at all time points suggesting activation of NRF2 ARE antioxidant defense system. The results were further validated by assessing the expression levels of selected genes in temporal as well as brain regions with quantitative RT-PCR and western blot. In conclusion, our whole brain approach with temporal monitoring of gene expression patterns during hypobaric hypoxia has resulted in (1) deciphering sequence of pathways and signaling networks activated during onset of hypoxia, and (2) elucidation of NRF2-orchestrated antioxidant response as a major intrinsic defense mechanism. The results of this study will aid in better understanding and management of hypoxia-induced brain pathologies. PMID- 20922450 TI - The importance of pharmacokinetic consultation of cefepime treatment for Pseudomonas aeruginosa bacteremia: a case report of severe thermal burn injury. AB - The patient is a 54-year-old man with severe thermal burn injury involving 45.5% of the total body-surface area, complicated with bacteremia caused by Pseudomonas aeruginosa with a cefepime MIC of 8 ug/ml. The plasma concentrations of cefepime 1 g every 6 h measured by validated high performance liquid chromatography were 25.8 ug/ml at 1 h and 6.28 ug/ml at 5 h after infusion, and 3.9 ug/ml before the infusion, when creatinine clearance was increased to 136 ml/min by vigorous fluid replacement. The pharmacokinetic-pharmacodynamic analyses in the one-compartment model with use of the Sawchuk-Zaske method revealed marked increase in the volume of distribution (28.9 l), total clearance (10.7 l/h), and shortening of plasma half- life (1.79 h) of cefepime, with time >MIC and 24-h area under the concentration-time-curve being 58% and 358, respectively. These pharmacokinetic parameters of cefepime quantified in the patient estimated a time >MIC of 87% if administered every 4 h. P. aeruginosa, however, was successfully eradicated without revision of the dosing regimen of cefepime. Decrease in creatinine clearance by correction of the fluid imbalance and wound closure by skin graft surgery likely contributed to the restoration of fluid shift, resulting in normal disposition of cefepime and favorable clinical outcome of the patient. PMID- 20922451 TI - Different cellular and genetic basis of noise-related endocochlear potential reduction in CBA/J and BALB/cJ mice. AB - The acute and permanent effects of noise exposure on the endocochlear potential (EP) and cochlear lateral wall were evaluated in BALB/cJ (BALB) inbred mice, and compared with CBA/J (CBA) and C57BL/6 (B6) mice. Two-hour exposure to broadband noise (4-45 kHz) at 110 dB SPL leads to a approximately 50 mV reduction in the EP in BALB and CBA, but not B6. EP reduction in BALB and CBA is reliably associated with characteristic acute cellular pathology in stria vascularis and spiral ligament. By 8 weeks after exposure, the EP in CBA mice has returned to normal. In BALBs, however, the EP remains depressed by an average approximately 10 mV, so that permanent EP reduction contributes to permanent threshold shifts in these mice. We recently showed that the CBA noise phenotype in part reflects the influence of a large effect quantitative trait locus on Chr. 18, termed Nirep (Ohlemiller et al., Hear Res 260:47-53, 2010b). While CBA "EP susceptibility" alleles are dominant to those in B6, examination of (B6 * BALB) F1 hybrid mice and (F1 * BALB) N2 backcross mice revealed that noise-related EP reduction and associated cell pathology in BALBs are inherited in an autosomal recessive manner, and are dependent on multiple genes. Moreover, while N2 mice formed from B6 and CBA retain strong correspondence between acute EP reduction, ligament pathology, and strial pathology, N2s formed from B6 and BALB include subsets that dissociate pathology of ligament and stria. We conclude that the genes and cascades that govern the very similar EP susceptibility phenotypes in BALB and CBA mice need not be the same. BALBs appear to carry alleles that promote more pronounced long term effects of noise on the lateral wall. Separate loci in BALBs may preferentially impact stria versus ligament. PMID- 20922452 TI - Weber-Christian disease associated with granulomatous mastitis: a variant type of Weber-Christian disease? PMID- 20922453 TI - Incidence and predictive factors for malignancies in 136 Japanese patients with dermatomyositis, polymyositis and clinically amyopathic dermatomyositis. AB - The aim of this study was to define the standardized incidence ratio (SIR) of malignancy and the potential risk factors of concomitant malignancies in patients with inflammatory myopathies, including clinically amyopathic dermatomyositis (CADM). A total of 145 patients diagnosed with either dermatomyositis/polymyositis (DM/PM) or CADM at our institute between 1984 and 2002 were enrolled in the study. The demographic, clinical and laboratory features of the patients at the time of DM/PM or CADM diagnosis were compared between patients with and without malignancies, respectively. Multivariate analysis by logistic regression was used to determine the independent risk factors for the development of malignancies in DM/PM patients. Malignancy was found in 17 of 70 patients with DM (24%), three of 15 patients with CADM (20%), and three of 51 patients with PM (6%). Gastric cancer (8/23) was the most common malignancy. Compared with general population, the SIR of malignancies was 13.8 (range 9.0-21.1). The patients who developed malignancies were older (61.5 vs. 51.1 years; P < 0.005), presented more often with dysphagia (61 vs. 15%; P < 0.0001) and were less likely to have the complication of interstitial lung disease (30 vs. 60%; P < 0.05). These features were independent predictive factors for developing malignancies in multiple logistic regression analysis. The results of our study confirm that CADM in addition to DM was associated with high rates of malignancy among our patient cohort. PMID- 20922454 TI - Posterior interosseous nerve palsy caused by synovial chondromatosis arising in the annular periradial recesses of the elbow. AB - We present a rare case report of a patient who presented with posterior interosseous nerve palsy caused by synovial chondromatosis. Synovial chondromatosis arising in the annular periradial recesses of the elbow joint was detected, and the mass developed two major portions constricted with the annular ligament. After surgical resection, posterior interosseous nerve palsy fully recovered and there was no recurrence of the lesion of synovial chondromatosis. PMID- 20922455 TI - Molecular mechanisms of centrosome and cytoskeleton anchorage at the nuclear envelope. AB - Cell polarization is a fundamental process underpinning organismal development, and tissue homeostasis, which requires an orchestrated interplay of nuclear, cytoskeletal, and centrosomal structures. The underlying molecular mechanisms, however, still remain elusive. Here we report that kinesin-1/nesprin-2/SUN-domain macromolecular assemblies, spanning the entire nuclear envelope (NE), function in cell polarization by anchoring cytoskeletal structures to the nuclear lamina. Nesprin-2 forms complexes with the kinesin-1 motor protein apparatus by associating with and recruiting kinesin light chain 1 (KLC1) to the outer nuclear membrane. Similar to nesprin-2, KLC1 requires lamin A/C for proper NE localization. The depletion of nesprin-2 or KLC1, or the uncoupling of nesprin 2/SUN-domain protein associations impairs cell polarization during wounding and dislodges the centrosome from the NE. In addition nesprin-2 loss has profound effects on KLC1 levels, the cytoskeleton, and Golgi apparatus organization. Collectively these data show that NE-associated proteins are pivotal determinants of cell architecture and polarization. PMID- 20922456 TI - Interleukin-10 repletion suppresses pro-inflammatory cytokines and decreases liver pathology without altering viral replication in murine cytomegalovirus (MCMV)-infected IL-10 knockout mice. AB - OBJECTIVE AND DESIGN: To determine the role of interleukin-10 (IL-10) in protecting against the deleterious pro-inflammatory cytokine response to murine cytomegalovirus (MCMV), we studied the impact of IL-10 repletion in MCMV-infected IL-10 knockout (KO) mice. MATERIALS AND METHODS: IL-10 KO mice were infected with a sub-lethal dose of MCMV and treated daily with 5 MUg of mouse recombinant IL-10 (mrIL-10). Cytokine transcription, viral load, cytokine expression and liver histopathology were assessed in IL-10 treated and untreated mice. RESULTS: mrIL 10 repletion suppressed the exaggerated pro-inflammatory cytokine response observed in IL-10 KO mice (vs. control) both systemically and at the organ level, without affecting viral load. Levels of IFN-gamma and TNF-alpha mRNA in livers of treated mice were ~50-70-fold lower than in untreated mice at day 5 post infection (p <= 0.05). In spleens and sera, levels of IFN-gamma and IL-6 were significantly lower in treated mice than in untreated mice at day 5-7 post infection (p <= 0.05). IL-10 blunting of cytokine responses was accompanied by attenuation of inflammation in livers of treated mice. CONCLUSIONS: Repletion of IL-10 modulates the exaggerated pro-inflammatory cytokine responses that characterize IL-10 KO mice and protects against liver damage without altering viral load. IL-10 may be useful to control dysregulated pro-inflammatory cytokines responses during CMV infection. PMID- 20922457 TI - Multipoint covalent immobilization of lipase on chitosan hybrid hydrogels: influence of the polyelectrolyte complex type and chemical modification on the catalytic properties of the biocatalysts. AB - This work aimed at the production of stabilized derivatives of Thermomyces lanuginosus lipase (TLL) by multipoint covalent immobilization of the enzyme on chitosan-based matrices. The resulting biocatalysts were tested for synthesis of biodiesel by ethanolysis of palm oil. Different hydrogels were prepared: chitosan alone and in polyelectrolyte complexes (PEC) with kappa-carrageenan, gelatin, alginate, and polyvinyl alcohol (PVA). The obtained supports were chemically modified with 2,4,6-trinitrobenzene sulfonic acid (TNBS) to increase support hydrophobicity, followed by activation with different agents such as glycidol (GLY), epichlorohydrin (EPI), and glutaraldehyde (GLU). The chitosan-alginate hydrogel, chemically modified with TNBS, provided derivatives with higher apparent hydrolytic activity (HA(app)) and thermal stability, being up to 45-fold more stable than soluble lipase. The maximum load of immobilized enzyme was 17.5 mg g(-1) of gel for GLU, 7.76 mg g(-1) of gel for GLY, and 7.65 mg g(-1) of gel for EPI derivatives, the latter presenting the maximum apparent hydrolytic activity (364.8 IU g(-1) of gel). The three derivatives catalyzed conversion of palm oil to biodiesel, but chitosan-alginate-TNBS activated via GLY and EPI led to higher recovered activities of the enzyme. Thus, this is a more attractive option for both hydrolysis and transesterification of vegetable oils using immobilized TLL, although industrial application of this biocatalyst still demands further improvements in its half-life to make the enzymatic process economically attractive. PMID- 20922458 TI - On the reliability of fungal materials used in studies on Ophiocordyceps sinensis. AB - Ophiocordyceps sinensis (=Cordyceps sinensis) is one of the best known traditional Chinese medicines, with great benefits to human health and huge economic value. The reliability of fungal materials used in studies of the species is particularly important because contradictory results have been found in various studies in the past decades. Examination of fungal materials specified in reports on O. sinensis showed great variation in both sources and culture conditions of living strains. To test the reliability of the materials used, experiments were carried out to study the effect of culture conditions on the growth of living strains of O. sinensis by using six reliable strains representing the major production regions of the fungus on the Tibetan Plateau. The results showed that O. sinensis is a slow-growing fungus at comparatively low temperature, and that temperature and growth period are crucial factors which can be verified by experiment. Analyses of fungal materials used in 152 papers on O. sinensis from PubMed since 1998 showed that 41 papers lacked detailed information on the fungal materials; 26 used natural products, 11 used artificially cultivated fruit bodies, and 80 used fermentation products from living strains. Of the latter category (using fermentation products), 64 of the papers were found to use unreliable (45) or uncertain (19) strains for fermentation products based on the temperature and growth period for O. sinensis strains verified in this study. Apart from the natural products of O. sinensis, which require scientific identification, a total of at least 116 papers (over three-quarters) used unreliable, uncertain or unspecified materials, including so-called cultivated fruit bodies which were apparently from other species. The reliability of materials or living strains used in studies on O. sinensis is discussed in this paper, and suggestions are made for use of reliable fungal materials in further studies of this fungus. PMID- 20922459 TI - Favorable outcome in the elderly cohort treated by concomitant temozolomide radiochemotherapy in a multicentric phase II safety study of 5-ALA. AB - The primary objective of this augmental, prospective, uncontrolled phase II multicentre trial was to assess adverse events (AE) associated with malignant glioma resection using 5-aminolevulinic (5-ALA). During accrual, the standard of adjuvant therapy changed to concomitant radiochemotherapy with adjuvant temozolomide (RT/TMZ). Thus, this study also provided a platform for investigating the influence of RT/TMZ on survival in patients with fluorescence guided resections. Malignant glioma patients, aged 18-75 years and with a Karnofsky performance score (KPS) >=70%, were eligible. Data were collected on adverse events, KPS, survival and adjuvant therapies. In 243 patients evaluable for safety, 6-week AE incidence was 51.9% (nervous system disorders: 30.0%). Three patients experienced four possibly drug-related AEs. Grade III/IV incidence was 18.9% (nervous system disorders: 10.7%). About 48 h after surgery, AE incidence was 26.3% (9.9% grade III/IV), which was related to overall survival. A total of 219 patients (glioblastoma 206; anaplastic astrocytoma: 13) qualified for efficacy analysis. Median overall survival was 14.1 months (95% CI: 12.0 16.6), but 16.3 (13-19.2) months in 122 glioblastoma patients receiving RT/TMZ compared to 11.9 (9.6-14.1) months in the remaining 84 patients (P = 0.0194). Older patients (>=60 years) had less adjuvant therapies than younger patients. Median survival of older glioblastoma patients with RT/TMZ was also significantly prolonged (16.3; 12.0-17.2 months vs. 11.2; 7.4-14.1, hazard ratio = 0.55; 0.32 0.92). Risks of surgery were similar to past experiences with 5-ALA. Ancillary analyses demonstrated surgical glioblastoma patients, including the elderly, to have derived benefit from RT/TMZ. Thus, older patients should not generally be excluded from accepted therapies (fluorescence-guided resection plus RT/TMZ). PMID- 20922460 TI - Congenital retinal macrovessel: atypical presentation using optical coherence tomography. AB - To describe a congenital retinal macrovessel with macular thickening. This case was investigated using fundus photography, fluorescein angiography, Spectralis optical coherence tomography and a 10-2 visual field test. A 23-year-old man was referred to our clinic with decreased vision in the right eye. Fundus examination of the right eye revealed a congenital retinal macrovessel that originated inferior to the superotemporal branch of the central retinal vein. Using fluorescein angiography, early filling and delayed emptying of the aberrant vein were observed. Spectralis optical coherence tomography demonstrated macular thickening and was supported by a 10-2 visual field test that revealed a relative scotoma corresponding to the same location. At the 18-month follow-up, visual acuity remained stable. Although rare, this case demonstrated that macular thickening can cause decreased visual acuity in the presence of a congenital retinal macrovessel. PMID- 20922461 TI - The phosphatidyl inositol 3-kinase/AKT signaling pathway in breast cancer. AB - The phosphatidyl inositol 3-kinase (PI3K)/Akt pathway mediates the effects of a variety of extracellular signals in a number of cellular processes including cell growth, proliferation, and survival. The alteration of integrants of this pathway through mutation of its coding genes increases the activation status of the signaling and can thus lead to cellular transformation. The frequent dysregulation of the PI3K/Akt pathway in breast cancer (BC) and the mediation of this pathway in different processes characteristically implicated in tumorigenesis have attracted the interest of this pathway in BC; however, a more comprehensive understanding of the signaling intricacies is necessary to develop clinical applications of the modulation of this pathway in this pathology. We review a series of experiments examining the contribution of alteration of integrants of this signaling network to human BC and we make an update of the information about the effect of the modulation of this pathway in this cancer. PMID- 20922462 TI - The guardians of the genome (p53, TA-p73, and TA-p63) are regulators of tumor suppressor miRNAs network. AB - The tumor suppressor p53 homologues, TA-p73, and p63 have been shown to function as tumor suppressors. However, how they function as tumor suppressors remains elusive. Here, I propose a number of tumor suppressor pathways that illustrate how the TA-p73 and p63 could function as negative regulators of invasion, metastasis, and cancer stem cells (CSCs) proliferation. Furthermore, I provide molecular insights into how TA-p73 and p63 could function as tumor suppressors. Remarkably, the guardians--p53, p73, and p63--of the genome are in control of most of the known tumor suppressor miRNAs, tumor suppressor genes, and metastasis suppressors by suppressing c-myc through miR-145/let-7/miR-34/TRIM32/PTEN/FBXW7. In particular, p53 and TA-p73/p63 appear to upregulate the expression of (1) tumor suppressor miRNAs, such as let-7, miR-34, miR-15/16a, miR-145, miR-29, miR 26, miR-30, and miR-146a; (2) tumor suppressor genes, such as PTEN, RBs, CDKN1a/b/c, and CDKN2a/b/c/d; (3) metastasis suppressors, such as Raf kinase inhibitory protein, CycG2, and DEC2, and thereby they enlarge their tumor suppressor network to inhibit tumorigenesis, invasion, angiogenesis, migration, metastasis, and CSCs proliferation. PMID- 20922463 TI - Chemical and microbiological changes during vermicomposting of coffee pulp using exotic (Eudrilus eugeniae) and native earthworm (Perionyx ceylanesis) species. AB - Coffee pulp is the main solid residue from the wet processing of coffee berries. Due to presence of anti-physiological and anti-nutritional factors, coffee pulp is not considered as adequate substrate for bioconversion process by coffee farmers. Recent stringent measures by Pollution Control authorities, made it mandatory to treat all the solid and liquid waste emanating from the coffee farms. A study was conducted to evaluate the efficiency of an exotic (Eudrilus eugeniae) and a native earthworm (Perionyx ceylanesis) from coffee farm for decomposition of coffee pulp into valuable vermicompost. Exotic earthworms were found to degrade the coffee pulp faster (112 days) as compared to the native worms (165 days) and the vermicomposting efficiency (77.9%) and vermicompost yield (389 kg) were found to significantly higher with native worms. The multiplication rate of earthworms (280%) and worm yield (3.78 kg) recorded significantly higher with the exotic earthworms. The percentage of nitrogen, phosphorous, potassium, calcium and magnesium in vermicompost was found to increase while C:N ratio, pH and total organic carbon declined as a function of the vermicomposting. The plant nutrients, nitrogen (80.6%), phosphorus (292%) and potassium (550%) content found to increase significantly in the vermicompost produced using native earthworms as compared to the initial values, while the calcium (85.7%) and magnesium (210%) content found to increase significantly in compost produced utilizing exotic worms. Vermicompost and vermicasts from native earthworms recorded significantly higher functional microbial group's population as compared to the exotic worms. The study reveals that coffee pulp can be very well used as substrate for vermicomposting using exotic (Eudrilus eugeniae) and native earthworm (Perionyx ceylanesis). PMID- 20922464 TI - Reprogrammed fibrocytes induce a mixed Th1/Th2 cytokine response of naive CD4(+) T cells. AB - Naive CD4(+) T cells develop different effector T cells and cytokine profiles after antigenic stimulation. It has been previously documented that fibrocytes function as antigen presenting cells inducing proliferation as well as Th2 cytokine response in naive CD4(+) T cells. Our group has reported that several circulating cell types recruited to the wound site can be transformed into anti fibrotic profile cells, which subsequently induce MMP-1 stimulation in dermal fibroblasts. Here, we report how similar reprogramming pathway of fibrocytes could modify the CD4(+) T cell response. Our findings confirmed that reprogrammed fibrocytes induce CD4(+) T cell activation with a mixed Th1/Th2 cytokine response. Since a reciprocal positive feedback between Th2 cells and fibrocytes exist to amplify and perpetuate the pro-fibrotic stimulation in dermal fibroblasts, the novel transdifferentiation of regular mature fibrocytes into reprogrammed fibrocytes appears to be a promising strategy to reverse the Th2 cytokine overproduction, and subsequently control the local fibrogenesis. PMID- 20922466 TI - Population pharmacokinetic analysis of blood and joint synovial fluid concentrations of robenacoxib from healthy dogs and dogs with osteoarthritis. AB - PURPOSE: The purpose of this population analysis was to characterize the pharmacokinetic properties of robenacoxib in blood and stifle joint synovial fluid of dogs. METHODS: Data were obtained from two studies: 1) 8 healthy Beagle dogs in which an acute inflammation was induced by injection of urate crystals into one joint; 2) 95 dogs from various breeds diagnosed with osteoarthritis (OA). Robenacoxib concentrations in blood and synovial fluid were measured using a validated HPLC-UV and LC-MS method. Non-linear mixed effects modeling was performed using NONMEM6. RESULTS: A two-compartment pharmacokinetic model with linear elimination was developed to describe blood concentrations of robenacoxib. Blood clearance in healthy animals was found to be 75% higher than in OA dogs. Synovial fluid concentrations were modeled using an effect-compartment-type model predicting longer residence times in OA dogs compared to healthy Beagles (e.g. concentrations above the IC(50) for COX-2, respectively, 16 h vs. 10 h at 1.5 mg/kg). CONCLUSIONS: Robenacoxib was found to reside longer at the effect site (inflamed joint) compared to blood in both healthy and OA dogs. These results may explain the good efficacy observed with once-daily dosing in clinical trials and the high safety index of robenacoxib in dogs. PMID- 20922465 TI - Reciprocal regulation of 11beta-hydroxysteroid dehydrogenase 1 and glucocorticoid receptor expression by dexamethasone inhibits human coronary artery smooth muscle cell proliferation in vitro. AB - The actions of glucocorticoids are mediated, in part, by 11beta-hydroxysteroid dehydrogenase 1 (11beta-HSD1), which amplifies their effects at the pre-receptor level by converting cortisone to cortisol. Glucocorticoids, such as dexamethasone, inhibit vascular smooth muscle cell proliferation; however, the role of 11beta-HSD1 in this response remains unknown. Accordingly, we treated human coronary artery smooth muscle cells (HCSMC) with dexamethasone (10(-9)-10( 6) mol/l) and found that after 72 h dexamethasone increased 11beta-HSD1 expression (14.16 +/- 1.6-fold, P < 0.001) and activity (6.21 +/- 1.2-fold, P < 0.001) in a dose- and time-dependent manner, which was dependent upon glucocorticoid receptor (GR) activation and C/EBPbeta and C/EBPdelta signaling. As glucocorticoids are known to negatively regulate GR expression, we examined the effect of decreasing 11beta-HSD1 expression on GR expression. In HCSMC transfected with 11beta-HSD1 siRNA, GR expression was increased; this effect was associated with protein kinase A activation and CREB phosphorylation. To examine the role of 11beta-HSD1 in HCSMC proliferation, we decreased 11beta-HSD1 expression and stimulated cells with platelet-derived growth factor (PDGF) (10 ng/ml). Decreased 11beta-HSD1 expression was associated with increased cell proliferation in the absence of PDGF compared to scrambled control-transfected cells (236.10 +/- 13.11%, n = 4, P < 0.001) and this effect was augmented by PDGF. Furthermore, the inhibitory effect of dexamethasone on cellular proliferation was abrogated in 11beta-HSD1 siRNA-transfected HCSMC. Downregulation of 11beta-HSD1 was associated with decreased p27(kip1) expression and increased phosphorylated retinoblastoma protein, consistent with a proliferative response. These findings suggest that 11beta-HSD1 plays a role in the effects of glucocorticoids on vascular smooth muscle cell phenotype. PMID- 20922467 TI - Design and evaluation of a service oriented architecture for paperless ICU tarification. AB - The computerization of Intensive Care Units provides an overwhelming amount of electronic data for both medical and financial analysis. However, the current tarification, which is the process to tick and count patients' procedures, is still a repetitive, time-consuming process on paper. Nurses and secretaries keep track manually of the patients' medical procedures. This paper describes the design methodology and implementation of automated tarification services. In this study we investigate if the tarification can be modeled in service oriented architecture as a composition of interacting services. Services are responsible for data collection, automatic assignment of records to physicians and application of rules. Performance is evaluated in terms of execution time, cost evaluation and return on investment based on tracking of real procedures. The services provide high flexibility in terms of maintenance, integration and rules support. It is shown that services offer a more accurate, less time-consuming and cost-effective tarification. PMID- 20922468 TI - Fluorescent probing of protein bovine serum albumin stability and denaturation using polarity sensitive spectral response of a charge transfer probe. AB - The polarity sensitive photo-induced intra-molecular charge transfer (ICT) fluorescence probe (E)-3-(4-methylamino-phenyl)-acrylic acid ethyl ester (MAPAEE) has been used to study the model protein Bovine Serum Albumin (BSA) in its native and thermal and urea induced denatured states. The interaction between BSA and the regular surfactant Sodium Dodecyl Sulphate (SDS) as well as the biologically relevant steroid-based amphiphile Sodium Deoxycholate (NaDC) has also been very keenly followed using this ICT probe. The variation of micellar properties of both SDS and NaDC with increasing ionic strengths and in presence of the chaotrope urea has also been well documemted by the same probe. Steady-state spectroscopy, FRET, and fluorescence anisotropy measurements have been used to gain better insight into these processes and the molecule MAPAEE to be a full bodied fluorescent probe for studying such intricate biological systems, their properties and interactions. PMID- 20922469 TI - Simultaneous pH and temperature measurements using pyranine as a molecular probe. AB - Steep variations in concentration and temperature frequently occur in small fluid compartments such as those found in cells or microfluidic devices. A quantitative characterization of concentration and temperature gradients is therefore required before these systems can be fully understood. Although different spatially resolved fluorescence methods have been developed to measure either the temperature or the concentration of ions such as proton or calcium, often concentration measurements depend on temperature and vice versa. Here, we describe a method allowing simultaneous measurement of pH and temperature. This method is based on the detection of the blinking of the fluorescent pH indicator pyranine, a process due to its alternating between a basic form and an acidic form. Fluorescence correlation spectroscopy allows measuring both the protonation and deprotonation rates of pyranine, and each pair of rates can be uniquely related to a pair of pH and temperature values. We show, however, that the relationship between rates, pH and temperature, is very sensitive to the presence of other acid-base molecules in solution. We also show that it is influenced by the overall ionic strength of the solution, in a manner that depends on buffer composition. PMID- 20922470 TI - Synthesis, characterization and photoluminescence study of novel sulfobetaine polyelectrolytes. AB - A novel sulfobetaine copolymer is developed via polycondensation approach. The comonomers, melamine, condenses with a diketone, 5,5-dimethyl-1,3-cyclohexane (dimedone) to produce polyimine chain based on Schiff base chemistry. Dimedone [N,N' melaminium] propane sulfonate copolymer crystals were obtained on treatment of the polyimine with sulfopropylating agent, 1,3-propane sultone with a crosslinker, di(ethylene glycol diacrylate) (DEGDA). This crosslinked sulfobetaine polymer yielded fine needle like single crystals and shows strong blue fluorescence and a week green phosphorescence. Multi-exponential fluorescence decay function indicates the presence of different conformers both in solution and crystalline phase. This easy straightforward protocol for synthesis of crystalline, soluble, and luminescent polymer could prove to be a landmark in development of next generation smart functional materials. PMID- 20922471 TI - Essential role of copper in the activity and regular periodicity of a recombinant, tumor-associated, cell surface, growth-related and time-keeping hydroquinone (NADH) oxidase with protein disulfide-thiol interchange activity (ENOX2). AB - ECTO-NOX proteins are growth-related cell surface proteins that catalyze both hydroquinone or NADH oxidation and protein disulfide interchange and exhibit time keeping and prion-like properties. A bacterially expressed truncated recombinant 46 kDa ENOX2 with full ENOX2 activity bound ca 2 moles copper and 2 moles of zinc per mole of protein. Unfolding of the protein in trifluoroacetic acid in the presence of the copper chelator bathocuproine resulted in reversible loss of both enzymatic activities and of a characteristic pattern in the Amide I to Amide II ratios determined by FTIR with restoration by added copper. The H546-V-H together with His 562 form one copper binding site and H582 represents a second copper site as determined from site-directed mutagenesis. Bound copper emerges as having an essential role in ENOX2 both for enzymatic activity and for the structural changes that underly the periodic alternations in activity that define the time keeping cycle of the protein. PMID- 20922472 TI - Pulmonary vein isolation with Mesh Ablator versus cryoballoon catheters: 6-month outcomes. AB - INTRODUCTION: We sought to compare the results of pulmonary vein (PV) ablation using the high-density Mesh Ablator catheter (MESH) versus the cryoballoon (CRYO). METHODS AND RESULTS: From August 2007 to November 2009, all patients with paroxysmal atrial fibrillation scheduled for a first procedure of PV isolation were screened by cardiac computed tomography for anatomical suitability to undergo ablation with a circumferential ostial ablation catheter. The procedure was finally performed in 79 out of 120 patients matching the criteria of four clearly separated PVs with an ostial diameter of 15-25 mm. The first consecutive 43 patients were treated with the MESH; the following 36 consecutive patients were treated with the CRYO. The procedures were performed with up to 900 s of either pulsed radiofrequency energy delivered by the MESH or cryoenergy applied with the CRYO. The clinical success rate was evaluated 6 months after a single procedure. Isolation of all PVs could be achieved in 40 patients (93%) in the MESH group compared to 31 patients (89%) in the CRYO group (p = ns). Major complications consisted of one tamponade in the MESH group and one reversible phrenic nerve palsy in the CRYO group. After 6 months, the clinical success rate was 44% (19/43 P) in the MESH versus 69% (25/36 P) in the CRYO group (p < 0.05). CONCLUSION: Both methods of simplified circumferential PV ablation reveal a high acute success rate. The clinical 6-month results of the MESH are statistically significant inferior compared to the CRYO. PMID- 20922473 TI - The role of prenatal, obstetric and neonatal factors in the development of autism. AB - We conducted a linked database cohort study of infants born between 1990 and 2002 in Nova Scotia, Canada. Diagnoses of autism were identified from administrative databases with relevant diagnostic information to 2005. A factor representing genetic susceptibility was defined as having an affected sibling or a mother with a history of a psychiatric or neurologic condition. Among 129,733 children, there were 924 children with an autism diagnosis. The results suggest that among those with low genetic susceptibility, some maternal and obstetric factors may have an independent role in autism etiology whereas among genetically susceptible children, these factors appear to play a lesser role. The role of pre-pregnancy obesity and excessive weight gain during pregnancy on autism risk require further investigation. PMID- 20922474 TI - Association between genetic polymorphisms in androgen receptor gene and the risk of preeclampsia in Korean women. AB - PURPOSE: To investigate associations between the androgen receptor (AR) polymorphisms as CAG repeats, GGC repeats and c.211G>A polymorphism and the risk of preeclampsia. METHODS: The AR polymorphisms were experienced in 184 preeclamptic patients and 190 normal pregnancies and analyzed by multiple logistic regression. RESULTS: Women with GGC repeats>16 were more frequently observed in preeclampsia, compared to those with GGC repeats<=16 [adjOR (95% CI): 3.64 (1.71-6.23)]. However, no significant differences were observed between the two groups with respect to CAG repeats. The genotypic and allelic frequencies of c.211G>A variant were significantly higher in cases than in controls (P < 0.05 for both). In the combined distribution of these polymorphisms, the highest risk of preeclampsia was found among women with the haplotype as CAG > 20/GA/GGC >16 [adjOR (95% CI): 4.26 (1.92-12.23)]. CONCLUSIONS: Our findings suggest that longer GGC repeats and c.211G>A variant in the AR gene are associated with increased susceptibility to the risk of preeclampsia. PMID- 20922475 TI - Social withdrawal subtypes during early adolescence in India. AB - The overarching goal of this study was to examine the associations between three social withdrawal subtypes (shyness, unsociability, avoidance), peer isolation, peer difficulties (victimization, rejection, exclusion, low acceptance), and loneliness in India during early adolescence. Participants were 194 adolescents in Surat, India (M age = 13.35 years). Peer nominations of peer relations and socioemotional behaviors were gathered, along with self-reports of reasons for being alone and loneliness. Preliminary evidence of validity for the self-report measure of withdrawal subtypes and isolation was found, and factor analyses indicated that shyness, unsociability, and avoidance represent related, but distinct forms of withdrawal that are distinct from isolation. Shyness and avoidance were uniquely associated with loneliness and exclusion, but unsociability was not. The association between avoidance and loneliness was mediated by exclusion. Findings suggest that social withdrawal may be best conceptualized as a multifaceted construct during childhood and adolescence, in Western and non-Western societies. PMID- 20922477 TI - Evidence-based practice: a review of theoretical assumptions and effectiveness of teaching and assessment interventions in health professions. AB - Health care professionals are expected to use a systematic approach based on evidence, professional reasoning and client preferences in order to improve client outcomes. In other words, they are expected to work within an evidence based practice (EBP) context. This expectation has had an impact on occupational therapy academic programs' mandates to prepare entry-level clinicians who demonstrate competence in the knowledge, skills and behaviors for the practice of evidence-based occupational therapy. If the EBP approach is to be entrenched in the day to day practice of future clinicians, a pedagogically sound approach would be to incorporate EBP in every aspect of the curriculum. This, however, would require a comprehensive understanding of EBP: its basis, the principles that underpin it and its effectiveness in promoting core professional competencies. The existing literature does not elucidate these details nor does it shed light on how requisite competencies for EBP are acquired in professional education in general and in occupational therapy education in particular. Drawing from educational psychology and EBP in the health professions, this paper provides a critical review of the evidence that supports EBP and the effectiveness of EBP teaching and assessment interventions in professional heath sciences programs and offers suggestions for the design of EBP instruction, grounding recommendations in educational theory for the health professions. PMID- 20922476 TI - Investigating the candidacy of LPS-based glycoconjugates to prevent invasive meningococcal disease: immunology of glycoconjugates with high carbohydrate loading. AB - We investigated the immune responses of rabbits that were immunised with lipopolysaccharide (LPS)-based glycoconjugates by measuring the reactivity of the derived sera to a panel of selected wild-type and mutant strains of Neisseria meningitidis. In all cases, high titers of antibodies capable of recognising LPS elaborating the identical structure as presented on the immunising glycoconjugate were obtained, and in most cases the derived sera also recognised heterologous strains including wild-type, but at lower titers. However, although serum bactericidal antibodies were consistently obtained against strains elaborating the same LPS structure as the immunising antigen, this functional response was not observed against wild-type strains. We identified several potentially competing neo-epitopes that had been introduced via our conjugation strategies, which might compete with the conserved inner core oligosaccharide target region, thus reducing the antibody titers to epitopes which could facilitate bactericidal killing. This study has therefore identified key factors that are crucial to control in order to increase the likelihood of obtaining bactericidal antibodies to wild-type meningococcal cells with LPS-derived glycoconjugates. Glycoconjugates utilised in this study, have been found to contain epitopes that do not contribute to the derivation of antibodies that may facilitate bactericidal killing of wild-type strains and must be avoided in future LPS-based glycoconjugate preparations. PMID- 20922478 TI - Antifungal effects of Ellagitannin isolated from leaves of Ocotea odorifera (Lauraceae). AB - Ocotea odorifera is a medicinal plant that is popularly known in Brazil as "canela-sassafras" and is used to treat dermatosis. This study investigated the antifungal properties of O. odorifera. The methanol extract of O. odorifera was submitted to successive chromatographic separation and yielded Tellimagrandin II (TEL). Candida parapsilosis strain ATCC 22019 was used to determine the minimum inhibitory (MIC) and fungicidal concentrations, and to study the synergistic action with nystatin (NYS), amphotericin (AMP), and fluconazole (FLU). After treatment, the morphology of the yeast was analysed by scanning electron microscopy. Cytotoxicity was assessed in Vero cells, and genotoxicity by the micronucleus test. The TEL structure was proposed based on NMR and comparison with literature data and ESI-MSMS analysis. The compound showed potent inhibitory activity against C. parapsilosis, with a MIC of 1.6 MUM. TEL acted synergistically with NYS, AMP, and FLU, and caused morphological alterations in the yeast cells. The methanolic extract showed low cytotoxicity in vitro and in vivo, and was not mutagenic in mice (P < 0.05). The use of O. odorifera in traditional medicine seems to have a valid basis, in view of the antifungal activity of TEL demonstrated in this study, and may contribute to potential drug development. PMID- 20922479 TI - The incidence of potential drug-drug interactions in elderly patients with arterial hypertension. AB - OBJECTIVE: To assess the incidence and type of potential, clinically significant drug-drug interactions in elderly outpatients with arterial hypertension. SETTING: Three community pharmacies in Croatia. METHOD: Eligible patients were aged 65 or older, treated for arterial hypertension and received 2 or more drugs. Potential interactions were identified by Lexi-Interact software. The software categorized each potential interaction according to clinical significance in five groups: (A) No known interaction; (B) Specified agents may interact, but there is little to no evidence of clinical concern; (C) Specified agents may interact in a clinically significant manner. Monitoring therapy is suggested; (D) The two medications may interact in a clinically significant manner. Modification of therapy is suggested; (X) Contraindicated combination. Interactions of level C, D and X were considered clinically significant. MAIN OUTCOME MEASURE: The incidence and type of potential drug-drug interactions. RESULTS: There were 265 patients included in the study. Potential, clinically significant drug interactions were identified in 240 (90.6%) patients, out of which 97.9% had interactions with clinical significance C, 20.4% D, and 0.8% X. The median number of drug interactions per patient was 4. We identified 215 drug combinations with the potential to cause clinically significant interaction, out of which 83.3% had clinical significance C, 16.3% clinical significance D, and 0.4% clinical significance X. CONCLUSION: Drug-drug interactions are common in elderly hypertensive patients. Computer-based screening could help pharmacists and physicians to recognize potential, clinically significant interactions. PMID- 20922480 TI - Which factors predict the time spent answering queries to a drug information centre? AB - OBJECTIVE: To develop a model based upon factors able to predict the time spent answering drug-related queries to Norwegian drug information centres (DICs). SETTING AND METHOD: Drug-related queries received at 5 DICs in Norway from March to May 2007 were randomly assigned to 20 employees until each of them had answered a minimum of five queries. The employees reported the number of drugs involved, the type of literature search performed, and whether the queries were considered judgmental or not, using a specifically developed scoring system. MAIN OUTCOME MEASURES: The scores of these three factors were added together to define a workload score for each query. Workload and its individual factors were subsequently related to the measured time spent answering the queries by simple or multiple linear regression analyses. RESULTS: Ninety-six query/answer pairs were analyzed. Workload significantly predicted the time spent answering the queries (adjusted R (2) = 0.22, P < 0.001). Literature search was the individual factor best predicting the time spent answering the queries (adjusted R(2) = 0.17, P < 0.001), and this variable also contributed the most in the multiple regression analyses. CONCLUSION: The most important workload factor predicting the time spent handling the queries in this study was the type of literature search that had to be performed. The categorisation of queries as judgmental or not, also affected the time spent answering the queries. The number of drugs involved did not significantly influence the time spent answering drug information queries. PMID- 20922481 TI - Oral health attitudes and practices among a German Mexican Mennonite farmworker community. AB - The oral health needs of migrant farm laborers are greater and more immediate than those of comparable populations. However, little is known about the conditions of oral health care among German-speaking Mexican Mennonites, a distinctive cultural subgroup of migrant farm laborers. The purpose of this study was to examine the oral health practices, perceived oral health status, and barriers to obtaining dental care among a community of Low German-speaking Mexican Mennonites residing in Southwest Kansas. Interviews were conducted with a sample of 25 individuals, with questions addressing access/barriers to care, oral health practices, and perceived oral health status. The most frequently identified barriers to dental care were limited finances, lack of adequate health/dental insurance, and limited awareness of available dental services. Although the majority of participants reported experiencing no problems related to language or scheduling dental appointments, the results also indicated low utilization levels of oral care services. Findings suggest that: (1) this population is at-risk for periodontal disease, (2) culturally appropriate programs are needed for preventive oral care education, (3) community and statewide support may help improve access to affordable oral health care. PMID- 20922482 TI - The complete mitochondrial genomes of three cestode species of Taenia infecting animals and humans. AB - Mitochondrial (mt) genome sequences provide useful markers for investigating population genetic structures, systematics and phylogenetics of organisms. Although Taenia multiceps, T. hydatigena, and T. taeniaeformis are common taeniid tapeworms of ruminants, pigs, dogs, or cats, causing significant economic losses, no published study on their mt genomes is available. The complete mt genomes of T. multiceps, T. hydatigena, and T. taeniaeformis were amplified in two overlapping fragments and then sequenced. The sizes of the entire mt genome were 13700 bp for T. multiceps, 13489 bp for T. hydatigena, and 13647 bp for T. taeniaeformis. Each of the three genomes contains 36 genes, consisting of 12 genes for proteins, 2 genes for rRNA, and 22 genes for tRNA, which are the same as the mt genomes of all other cestode species studied to date. All genes are transcribed in the same direction and have a nucleotide composition high in A and T. The contents of A+T of the complete genomes are 71.3% for T. multiceps, 70.8% for T. hydatigena, and 73.0% for T. taeniaeformis. The AT bias had a significant effect on both the codon usage pattern and amino acid composition of proteins. T. multiceps and T. hydatigena had two noncoding regions, but T. taeniaeformis had only one. Phylogenetic analyses based on concatenated amino acid sequences of 12 protein-coding genes revealed that T. multiceps, T. hydatigena, and T. taeniaeformis were more closely related to the other members of the Taenia genus, consistent with results of previous morphological and molecular studies. The present study determined the complete mt genome sequences for three Taenia species of animal and human health significance, providing useful markers for studying the systematics, population genetics, and molecular epidemiology of these cestode parasites of animals and humans. PMID- 20922483 TI - Efficiency and quality of care in nursing homes: an Italian case study. AB - This study investigates efficiency and quality of care in nursing homes. By means of Data Envelopment Analysis (DEA), the efficiency of 40 nursing homes that deliver their services in the north-western area of the Lombardy Region was assessed over a 3-year period (2005-2007). Lombardy is a very peculiar setting, since it is the only Region in Italy where the healthcare industry is organised as a quasi-market, in which the public authority buys health and nursing services from independent providers-establishing a reimbursement system for this purpose. The analysis is conducted by generating bootstrapped DEA efficiency scores for each nursing home (stage one), then regressing those scores on explanatory variables (stage two). Our DEA model employed two input (i.e. costs for health and nursing services and costs for residential services) and three output variables (case mix, extra nursing hours and residential charges). In the second stage analysis, Tobit regressions and the Kruskall-Wallis tests of hypothesis to the efficiency scores were applied to define what are the factors that affect efficiency: (a) the ownership (private nursing houses outperform their public counterparts); and (b) the capability to implement strategies for labour cost and nursing costs containment, since the efficiency heavily depends upon the alignment of the costs to the public reimbursement system. Lastly, even though the public institutions are less efficient than the private ones, the results suggest that public nursing homes are moving towards their private counterparts, and thus competition is benefiting efficiency. PMID- 20922484 TI - Probability model for estimating colorectal polyp progression rates. AB - According to the American Cancer Society, colorectal cancer (CRC) is the third most common cause of cancer related deaths in the United States. Experts estimate that about 85% of CRCs begin as precancerous polyps, early detection and treatment of which can significantly reduce the risk of CRC. Hence, it is imperative to develop population-wide intervention strategies for early detection of polyps. Development of such strategies requires precise values of population specific rates of incidence of polyp and its progression to cancerous stage. There has been a considerable amount of research in recent years on developing screening based CRC intervention strategies. However, these are not supported by population-specific mathematical estimates of progression rates. This paper addresses this need by developing a probability model that estimates polyp progression rates considering race and family history of CRC; note that, it is ethically infeasible to obtain polyp progression rates through clinical trials. We use the estimated rates to simulate the progression of polyps in the population of the State of Indiana, and also the population of a clinical trial conducted in the State of Minnesota, which was obtained from literature. The results from the simulations are used to validate the probability model. PMID- 20922485 TI - The RSM-scale: a pilot study on a new specific scale for self- and observer-rated quality of life in patients with schizophrenia. AB - PURPOSE: To develop and evaluate a self- and observer-rating scale on quality of life in patients suffering from schizophrenia with regard to the efficacy of atypical antipsychotics based on different dimensions and to apply within a pilot study. METHODS: Following review of existing scales and a prevalidation phase, the Riedel-Spellmann-Musil (RSM) scale was developed comprising 36 items assigned to different subscales. As reference scales, the Quality of Life Scale (QLS) and the Subjective Well-being Under Neuroleptic Treatment Scale-short version (SWN-K) were performed, psychopathology and adverse events were measured at all visits. Reliability was assessed using Cronbach's alpha, Pearson's correlation coefficients were used to assess construct validity, and Intraclass Correlation Coefficients (ICCs) were used for test-retest reliability. T tests were performed in normal distributed samples; otherwise Wilcoxon tests were used. RESULTS: One hundred and thirty-six patients were included in the study. Cronbach's alpha was 0.917 for the self-rating and 0.915 for the interviewer-rating part. ICCs were >0.70 for all subscales. The self-rating part correlated strongly with the SWN-K and the observer part with the QLS. Changes in psychopathology over the study period and different levels of functioning were detected. CONCLUSION: The RSM scale is a new scale to assess the quality of life in different dimensions of patients with schizophrenia treated with antipsychotics and shows good internal consistency, test-retest reliability, construct and discriminant validity. PMID- 20922486 TI - NMR and X-ray structures of the putative sterol carrier protein 2 from Thermus thermophilus HB8 show conformational changes. AB - Sterol carrier protein 2 (SCP-2), also known as nonspecific lipid transfer protein, is a ubiquitous intracellular ~13 kDa protein found in mammals, insects, plants, archaea, and bacteria. Vertebrate SCP-2 has been implicated in a wide range of lipid-related functions in vitro, although its actual physiological role is still unknown. Tunnels in the protein serve as fatty acid binding vehicles. Here we report the first putative SCP-2 structure from a bacterium: specifically, the NMR and X-ray structures of the TTHA0401 protein (also designated as TT1886) from the extremely thermophilic bacterium Thermus thermophilus. The NMR structure and the two chain structures (chain A and chain B) of the asymmetric crystallographic unit (space group (P2(1)2(1)2(1))) revealed an internal cavity. However, this cavity is open to the outside, forming a tunnel, in only one of those structures (chain A, X-ray). The location of this tunnel is different from the one found in other SCP-2 proteins, and inaccessible cavities have not been seen before in SCP structures. We present evidence that at physiological concentrations, TTHA0401 likely exists as a monomer in equilibrium between open and closed conformations. This equilibrium is influenced by temperature-dependent dynamics, and is likely to be very different at the high temperatures preferred by this hyperthermophilic bacterium. Alternatively, another protein binding to TTHA0401 may induce a conformational change, which would constitute an intriguing metabolic regulation method in bacteria. PMID- 20922487 TI - Caloric restriction does not alter effects of aging in cardiac side population cells. AB - The aged heart displays a loss of cardiomyocyte number and function, possibly due to the senescence and decreased regenerative potential that has been observed in some cardiac progenitor cells. An important cardiac progenitor that has not been studied in the context of aging is the cardiac side population (CSP) cell. To address this, flow cytometry-assisted cell sorting was used to isolate CSP cells from adult (6-10 months old) and aged (24-32 months old) C57Bl/6 mice that were fed either a control diet or an anti-aging diet (caloric restriction, CR). Aging caused a 2.3-fold increase in the total number of CSP cells and a 3.2-fold increase in the cardiomyogenic sca1(+)/CD31(-) subpopulation. Aging did not affect markers of proliferation or senescence, including telomerase activity and expression of cell cycle genes, in sca1(+)/CD31(-) CSP cells. In contrast, the aged cells had reduced expression of genes associated with differentiation, including smooth muscle actin and cardiac muscle actin (5.1- and 3.2-fold, respectively). None of these age effects were altered by CR diet. Therefore, it appears that the manner in which CSP cells age is distinct from the aging of post mitotic tissue (and perhaps other progenitor cells) that can often be attenuated by CR. PMID- 20922488 TI - Carotid body function in aged rats: responses to hypoxia, ischemia, dopamine, and adenosine. AB - The carotid body (CB) is the main arterial chemoreceptor with a low threshold to hypoxia. CB activity is augmented by A(2)-adenosine receptors stimulation and attenuated by D(2)-dopamine receptors. The effect of aging on ventilatory responses mediated by the CB to hypoxia, ischemia, and to adenosine and dopamine administration is almost unknown. This study aims to investigate the ventilatory response to ischemia and to adenosine, dopamine, and their antagonists in old rats, as well as the effect of hypoxia on adenosine 3',5'-cyclic monophosphate (cAMP) accumulation in the aged CB. In vivo experiments were performed on young and aged rats anesthetized with pentobarbitone and breathing spontaneously. CB ischemia was induced by bilateral common carotid occlusions. cAMP content was measured in CB incubated with different oxygen concentrations. Hyperoxia caused a decrease in cAMP in the CB at all ages, but no differences were found between normoxia and hypoxia or between young and old animals. The endogenous dopaminergic inhibitory tonus is slightly reduced. However, both the ventilation decrease caused by exogenous dopamine and the increase mediated by A(2A) adenosine receptors are not impaired in aged animals. The bradycardia induced by adenosine is attenuated in old rats. The CB's peripheral control of ventilation is preserved during aging. Concerns have also arisen regarding the clinical usage of adenosine to revert supraventricular tachycardia and the use of dopamine in critical care situations involving elderly people. PMID- 20922489 TI - Polychlorinated biphenyls and organochlorinated pesticides in birds from a contaminated region in South China: association with trophic level, tissue distribution and risk assessment. AB - PURPOSE: Birds have been used successfully for biomonitoring of the levels and effects of persistent organic pollutants (POPs) in the environments; however, there is exceedingly little data on organochlorinated pesticide (OCPs) and polychlorinated biphenyls (PCBs) residues in bird inhabiting in China. In the present study, we detected the concentrations of PCBs, dichlorodiphenyltrichloroethane and its metabolites (DDTs) and hexachlorocyclohexanes (HCHs) in muscle, liver and kidney of birds that inhabit in an e-waste recycling site. Associated with the stable isotope ratio (delta (15)N), we investigated the effect of trophic level on the body burdens of persistent contaminants in birds. The tissue distributions of contaminants in these birds were examined, and a preliminary risk assessment was also conducted. MATERIALS AND METHODS: Specimens from eight bird species were collected from Qingyuan County, Guangdong Province, South China. Pectoral muscle, liver and kidney tissues were Soxhlet-extracted and finally dissolved in isooctane. Both PCBs and OCPs were analyzed by gas chromatography-mass spectrometry. The subsamples for nitrogen stable isotope analysis were lyophilized, ground and analyzed by a flash EA 112 series elemental analyzer interfaced with an isotope ration mass spectrometer. RESULTS AND DISCUSSION: PCBs exhibited the highest concentrations among all target compounds, and a preliminary risk assessment suggested that adverse effects might occur in some birds for its high level. Generally, the concentrations of pollutants in liver and kidney were higher than those in muscle, which was mainly driven by passive diffusion to the 'lipid compartment'. Significant differences in level of contaminants were obtained among species due to the varieties in dietary composition and habitat. An increasing trend was obtained between concentrations of PCBs and DDTs with trophic levels; however, HCHs exhibited the same level among species. RECOMMENDATIONS AND PERSPECTIVES: Because of the e-waste recycling activities, the study area has been heavily polluted by PCBs. Studies on the species-specific hazard assessment associated with exposure to PCBs are urgently needed in the study of birds in the area. PMID- 20922490 TI - The role of 64-slice multi-detector computed tomography in the detection of subclinical atherosclerosis of the coronary artery. AB - Multi-detector computed tomography (MDCT) has been used for detecting or excluding coronary atherosclerotic stenosis in symptomatic patients. However, the role of MDCT for routine medical examination in asymptomatic, high-risk patients has not been established. We therefore conducted the present study to test the hypothesis that MDCT could be a valuable method for detecting subclinical coronary artery stenosis in asymptomatic patients. An observational, retrospective, single-centre study was conducted with a cohort of 1,529 patients (mean age, 56.4 +/- 8.3 years; 1,353 males) who had undergone MDCT as part of their general medical checkups from November 2005 to April 2008. The patients who had a past history of coronary artery disease, typical chest pain, or evidence of myocardial ischemia were excluded. During clinical follow up of these patients, the incidence of subclinical coronary stenosis and the usefulness of MDCT for routine medical examination in asymptomatic patients were investigated. Of the 1,529 enrolled patients, 42.3% had hypertension, 13.5% had diabetes mellitus, 7.7% had hyperlipidemia, and 40.4% were current smokers. Abnormal MDCT findings were noted in 560 (36.6%) patients, who were classified into two groups. One group had the presence coronary calcium with a luminal diameter stenosis of the coronary artery of <50% (n = 508, 33.2%). These patients were treated with medication or clinical follow-up. The other group had a luminal diameter stenosis of the coronary artery of >=50% with the presence or absence of coronary calcium (n = 52, 3.4%). These patients underwent a conventional coronary angiogram and intravascular ultrasound. A total of 29 of the 1,529 patients (1.9%) presented with insignificant stenosis or myocardial bridge, and 23 patients (1.5%) presented with significant stenosis. The patients with significant stenosis underwent percutaneous coronary intervention (PCI) with stent implantation. Major adverse cardiac events occurred in only 2 patients who had been treated with PCI during a mean follow-up period of 387 +/- 253 days. The incidence of significant subclinical coronary stenosis as detected by MDCT in a general medical check-up was 3.4%, and the false-positive rate of MDCT for detecting significant coronary artery stenosis was 55.8% (29/52). 64-Slice MDCT can be a useful tool for noninvasive evaluation of coronary arteries in asymptomatic patients. Further study is needed to clarify the clinical implications of MDCT in general medical check-ups. PMID- 20922491 TI - Complex coronary artery fistulas in adults: evaluation with multidetector computed tomography. AB - Coronary artery fistulas (CAFs) are rare congenital or acquired abnormalities that have anomalous terminations of the coronary arteries. Although many patients with CAFs are asymptomatic, they can display various clinical features associated with ischemic heart disease or heart failure. Making an early diagnosis is important for the proper management and prevention of late symptoms and complications. Conventional coronary angiography and cardiac CT have been commonly performed to diagnose CAFs, but multi-detector computed tomography (MDCT) is now being widely applied for diagnosing cardiovascular anomalies, and the number of incidentally detected CAFs on MDCT has been increasing. Therefore, we have to be familiar with the image findings of CAFs, and especially the image findings of MDCT for making the correct diagnosis of CAFs. In this article, we illustrate the MDCT findings of various types of CAFs in adults and we review the pathophysiology and clinical features of CAFs. PMID- 20922492 TI - Physical therapy and chiropractic use among childhood cancer survivors with chronic disease: impact on health-related quality of life. AB - INTRODUCTION: The use of rehabilitation services to address musculoskeletal, neurological and cardiovascular late effects among childhood cancer survivors could improve physical function and health-related quality-of-life (HRQL). We describe physical therapy (PT) and chiropractic utilization among childhood cancer survivors and their association with HRQL. METHODS: The sample included 5+ year survivors from the Childhood Cancer Survivor Study (N = 9,289). Questions addressing use of PT or chiropractic services and HRQL (Medical Outcomes Survey Short Form (SF-36)) were evaluated. Multivariable regression models compared PT and/or chiropractic utilization between survivors and siblings, and by diagnosis, treatment and demographic characteristics; associations between chronic disease, PT/chiropractic use, and HRQL were similarly evaluated. RESULTS: Survivors were not more likely to use PT (OR 1.0; 95% CI 0.8-1.2) or chiropractic (OR 0.8; 95% CI 0.7-1.0) services than siblings. More survivors reported using chiropractic (12.4%) than PT (9.2%) services. Older age and having health insurance were associated with utilization of either PT or chiropractic services. Grade 3-4 chronic conditions and a CNS tumor or sarcoma history were associated with PT but not with chiropractic service utilization. Survivors with musculoskeletal (OR 1.8; 95% CI 1.1-2.9), neurological (OR 3.4; 95% CI 1.6-6.9), or cardiovascular (OR 3.3; 95% CI 1.6-6.9) chronic conditions who used PT/chiropractic services were more likely to report poor physical health than survivors who did not use services. CONCLUSIONS: The reported prevalence of PT/chiropractic among survivors is consistent with that reported by siblings. Severity of late effects is associated with service use and with reporting poor physical health. IMPLICATIONS FOR CANCER SURVIVORS: Long-term childhood cancer survivors do not appear to utilize rehabilitation services to optimize physical function and support increased HRQL. PMID- 20922493 TI - Adolescent cancer survivors' smoking intentions are associated with aggression, attention, and smoking history. AB - INTRODUCTION: The present study examines behavioral and psychosocial factors associated with smoking intentions and experimentation among adolescent survivors of pediatric cancer. METHODS: Adolescent survivors of brain tumor and acute lymphoblastic leukemia (n = 99) provided information about their smoking histories and their intentions to smoke in the future. Behavior rating scales were completed by survivors, parents, and teachers. RESULTS: Past experimentation with smoking and higher levels of self-reported aggression were associated with intentions to smoke in the future (OR = 4.18, 95% CI 1.02-17.04, and OR = 1.08, 95% CI 1.01-1.15, respectively), while teacher-ratings of inattention in the classroom were negatively associated with intentions to smoke (OR = 0.94, 95% CI.88-.99), all p < .05. Experimentation with smoking was more likely among older survivors (OR = 1.76, 95% CI 1.16-2.66, p < .01) and those whose parents had divorced (OR = 4.40, 95% CI 1.21-16.06, p < .05). DISCUSSION: A concerning minority of adolescent survivors have clear intentions to smoke, a behavior that adds to their overall health risk. Smoking intentions and experimentation are important precursors to regular smoking. Prevention efforts are needed to interrupt the progression from intentions and experimentation to established smoking and nicotine dependence in this medically vulnerable population. IMPLICATIONS FOR CANCER SURVIVORS: Assessment of an adolescent's history of parental divorce, past experimentation with smoking, and aggressive behavior will identify those survivors who are likely to consider smoking in the future. Screening for these characteristics will allow clinicians to be more vigilant in health promotion. PMID- 20922495 TI - Control of health care-associated infections (HAI): winning both the battles and the war. AB - At present, the United States (US) experiences its greatest life expectancy due mainly to improvements in mortality from cardiovascular diseases, which include coronary heart disease and stroke. These, in turn, are due largely to decreases in cigarette smoking as well as earlier and more aggressive diagnoses and treatments. These advances in health care delivery are, not surprisingly, accompanied by increasing numbers of complicating health care-associated infections (HAI). HAIs are a major and increasing cause of morbidity and mortality in the US as well as around the world. To win both the battles and the war against HAI requires a multidisciplinary approach to the vigorous implementation and maintenance of proper infection control procedures. This should include continuous surveillance and reinforcement of guidelines to enhance evidence-based practices to prevent and control HAI. It will also be necessary to implement a new paradigm of early and formal education of future health care providers into the biology of infection as well as the principles of infection control in the classroom and subsequently, with translation into their clinical training. Finally, there must also be the incorporation and expansion of continuing medical education for established health care providers about prevention and control of HAI. PMID- 20922494 TI - Primary care management of chronic kidney disease. AB - BACKGROUND: Chronic kidney disease (CKD) causes substantial morbidity and mortality; however, there are limited data to comprehensively assess quality of care in this area. OBJECTIVE: To assess quality of care for CKD according to patient risk and identify correlates of improved care delivery. DESIGN: Retrospective cohort. SETTING: Fifteen health centers within a multi-site group practice in eastern Massachusetts. PARTICIPANTS: 166 primary care physicians caring for 11,774 patients with stages 3 or 4 CKD defined as two estimated glomerular filtration rates (eGFR) between 15 and 60. MAIN MEASURES: Two measures of kidney disease monitoring, five measures of cardiovascular disease management, four measures of metabolic bone disease and anemia management, and one measure of drug safety were extracted from the electronic health record. Primary care recognition of CKD was assessed as a problem list diagnosis, and nephrology co management was assessed as at least one visit with a nephrologist in the prior 12 months. KEY RESULTS: Overall, 46% of patients were high risk for death based on the presence of diabetes, proteinuria, or an eGFR <45. Seventy percent of patients lacked annual urine protein testing, 46% had a blood pressure >=130/80 mmHg and 25% were not receiving appropriate angiotensin blockade. Appropriate screening for anemia was common (76%), while screening rates for metabolic bone disease were low. Use of potentially harmful drugs was common (26%). Primary care physician recognition and nephrology co-management were both associated with improved quality of care, though rates of both were low (24% and 10%, respectively). CONCLUSIONS: Significant deficiencies in the quality of CKD care exist. Opportunities for improvement include increasing physician recognition of CKD and improving collaborative care with nephrology. PMID- 20922497 TI - Junior tutor programme--benefits and risks. PMID- 20922496 TI - Alterations in medical interpretation during routine primary care. AB - BACKGROUND: Increasing numbers of patients require medical interpretation, yet few studies have examined its accuracy or effect on health outcomes. OBJECTIVE: To understand how alterations in medical interpretation affect health care delivery to patients with limited English proficiency (LEP), we aimed to determine the frequency, type, and clinical significance of alterations. We focused on best-case encounters that involved trained, experienced interpreters interacting with established patients. DESIGN: We audio-recorded routine outpatient clinic visits in which a medical interpreter participated. Audiotapes were transcribed and translated into English. We identified and characterized alterations in interpretation and calculated their prevalence. PARTICIPANTS: In total, 38 patients, 16 interpreters, and 5 providers took part. Patients spoke Cantonese, Mandarin, Somali, Spanish, and Vietnamese, and received care for common chronic health conditions. MEASURES: Unlike previous methods that report numbers of alterations per interpreted encounter, we focused on alterations per utterance, which we defined as the unit of spoken content given to the interpreter to interpret. All alteration rates were calculated by dividing the number of alterations made during the encounter by the number of utterances for that encounter. We defined clinically significant changes as those with potential consequences for evaluation and treatment. KEY RESULTS: We found that 31% of all utterances during a routine clinical encounter contained an alteration. Only 5% of alterations were clinically significant, with 1% having a positive effect and 4% having a negative effect on the clinical encounter. CONCLUSION: Even in a best case scenario, the rate of alteration remains substantial. Training interpreters and clinicians to address common patterns of alteration will markedly improve the quality of communication between providers and LEP patients. PMID- 20922499 TI - Whole blood thallium determination by GFAAS with high-frequency modulation polarization Zeeman effect background correction. AB - A new technique of blood thallium direct determination based on graphite furnace atomic absorption spectrometry with Zeeman background absorption correction system was designed. The developed technique does not require sample digestion. Sample treatment includes only a fivefold per volume dilution of blood sample with 0.1% (m/v) Triton X-100. L'vov integrated platform was modified with 400 MUg of Rh. Matrix modifier (200 MUg NH(4)NO(3) and 160 MUg Pd(NO(3))(2)) was suggested for coping chloride and blood organic matter interferences. Standard reference material (Clincheck(r) Plasma Control for trace elements) analysis was used for validation. Additional validation was performed by analyzing spiked blood samples in the whole dynamic range. The dynamic range was 2-50 MUg/L. Precision (RSD) was found <12%. Blood thallium limit of detection was 0.2 MUg/L. PMID- 20922498 TI - NAFLD and insulin resistance do not increase the risk of postoperative complications among patients undergoing bariatric surgery--a prospective analysis. AB - BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) and insulin resistance are common consequences of obesity and are highly prevalent among patients undergoing bariatric surgery. Insulin resistance and NAFLD have been reported to be associated with postoperative complications following major surgery. METHODS: We prospectively evaluated complications in a cohort of 437 consecutive patients undergoing bariatric surgery. Detailed metabolic profile was obtained prior to surgery, and liver biopsies were taken routinely during surgery. RESULTS: Mean age was 47.8 years (20-77), and mean body mass index (BMI) was 48.5 kg/m(2) (32 94). Common co-morbid conditions were metabolic syndrome (79%), obstructive sleep apnea (73%), and hypertension (60%). Seventy-seven percent underwent Roux-en-Y gastric bypass, 15% biliopancreatic diversion with duodenal switch, and 8% adjustable gastric banding. The operative approach was laparoscopic in 81% of patients. Liver histology was normal in 22% of patients. Seventy-eight percent of patients had NAFLD. Nonalcoholic steatohepatitis (NASH) was present in 18%. Advanced fibrosis (stage 3-4) was present in 5%. Complications were observed in 25% of the cohort, the most frequent being infection, occurring in 14%. The wound was the most frequent site of infection (9%). There were no cases of postoperative hepatic decompensation. Reoperation was necessary in 7%. In univariate analysis, the factors associated with complications were male gender (p = 0.009), type and approach of surgery (p = 0.023 and p = 0.0001, respectively), BMI (p = 0.000), serum creatinine (p = 0.023), and serum albumin (p = 0.0001). In multivariate analysis, the independent factors associated with complications in bariatric surgery were BMI (OR 1.039, 95% CI 1.010-1.068; p = 0.008), surgical approach (OR 2.696, 95% CI 1.547-4.698; p = 0.000), and serum albumin (OR 0.416, 95% CI 0.176-0.978; p = 0.044). NASH was not predictive of complications. CONCLUSIONS: Bariatric surgery is a safe and efficient treatment for obesity. The occurrence of NAFLD or NASH without portal hypertension should not preclude the procedure. PMID- 20922500 TI - Ensemble modeling coupled with six element concentrations in human blood for cancer diagnosis. AB - Six important metal contents (i.e., zinc, barium, magnesium, calcium, copper, and selenium) in blood samples coupled with an ensemble classification algorithm have been used for the classification of normal people and cancer patients. A dataset containing 42 healthy samples and 32 cancer samples was used for experiment. The prediction results from this method outperformed those from the newly developed support vector machine, i.e., a sensitivity of 100%, a specificity of 95.2%, and an overall accuracy of 98.6%. It seems that ELDA coupled with blood element analysis can serve as a valuable tool for diagnosing cancer in clinical practice. PMID- 20922501 TI - VIP-PACAP 2010: my own perspective on modulation of cognitive and emotional behavior. PMID- 20922502 TI - Depletion of intranuclear rodlets in mouse models of diabetes. AB - Intranuclear rodlets (INRs) are structures present within the nuclei of human insulin-secreting beta cells of the endocrine pancreas. Their physiological significance, and whether they are altered in disease, is unknown. In the present study, the proportion of pancreatic beta cells containing INRs was examined in mouse models of type II diabetes and in a model with improved beta cell function. To gain insights into the molecular regulators of INR formation, mice with a conditional adult beta cell-specific knockout of the serine/threonine protein kinase Lkb1 (Lkb1 adult beta cell knockout (LABKO) mice) were studied. To investigate INR changes in a pathophysiological context, beta cell INRs were examined in two models of human metabolic syndrome: (1) mice maintained on a high fat diet and (2) leptin-deficient ob/ob mice. The proportion of beta cells containing INRs was significantly reduced in LABKO mice. This reduction was not mediated by two key downstream effectors of Lkb1, mTor and Mark2. High-fat diet regimen reduced beta cell INR frequency by more than 40%, and leptin-deficient ob/ob mice exhibited a dramatically (19-fold) reduced INR frequency relative to wild-type mice. Taken together, our results support the view that INR formation in pancreatic beta cells is a dynamic and regulated process. The substantial depletion of beta cell INRs in LABKO and diabetic mice suggests their relationship to beta cell function and potential involvement in diabetes pathogenesis. PMID- 20922503 TI - The increase in the expression and hypomethylation of MUC4 gene with the progression of pancreatic ductal adenocarcinoma. AB - The MUC4 gene could have a key role in the progression of pancreatic cancer, but the quantitative measurement of its expression in clinical tissue samples remains a challenge. The correlations between MUC4 promoter methylation status in vivo and either pancreatic cancer progression or MUC4 mRNA expression need to be demonstrated. We used the techniques of quantitative real-time PCR and DNA methylation-specific PCR combined microdissection to precisely detect MUC4 expression and promoter methylation status in 116 microdissected foci from 57 patients with pancreatic ductal adenocarcinoma. Both mRNA expression and hypomethylation frequency increased from normal to precancerous lesions to pancreatic cancer. Multivariate Cox regression analysis showed that high-level MUC4 expression (P = 0.008) and tumor-node-metastasis staging (P = 0.038) were significant independent risk factors for predicting the prognosis of 57 patients. The MUC4 mRNA expression was not significantly correlated with promoter methylation status in 30 foci of pancreatic ductal adenocarcinoma. These results suggest that high mRNA expression and hypomethylation of the MUC4 gene could be involved in carcinogenesis and in the malignant development of pancreatic ductal adenocarcinoma. The MUC4 mRNA expression may become a new prognostic marker for pancreatic cancer. Microdissection-based quantitative real-time PCR and methylation-specific PCR contribute to the quantitative detection of MUC4 expression in clinical samples and reflect the epigenetic regulatory mechanisms of MUC4 in vivo. PMID- 20922504 TI - Update on surgical management for asymptomatic carotid stenosis. AB - The management of asymptomatic carotid stenosis has been a topic of considerable debate. In this article, we aim to critically review the recent literature as it pertains to surgical management of asymptomatic carotid stenosis. We will explore the most recent trials looking at advancements in best medical therapy, as well as trials that compare traditional carotid endarterectomy to carotid stenting. In addition, we will review the current literature on surgical technique and perioperative risk management. Overall, our current recommendation is for surgical management of asymptomatic carotid disease for stenoses >= 80% in patients who are of reasonable perioperative risk. PMID- 20922505 TI - Telemedicine or telephone consultation in patients with acute stroke. AB - The advantages of telephone consultations for patients with acute stroke syndromes are history of use, simplicity, availability, portability, short consultation time, and facile implementation. The favorable aspects of telemedicine consultations are high accuracy, reliability, efficacy, and effectiveness, the growing technological sophistication of the offerings and features, and the high grade of recommendation. Between the two modalities, telemedicine is optimal for assessing patients with acute stroke and superior to telephone-only evaluations. Telephone consultations can serve as an adequate ancillary, adjunctive, supplemental, or back-up modality for a telestroke network. With recent advances in one-way/two-way video and teleradiology features adapted to Smartphones, the dividing line between "telephone" and "telemedicine" consultations for acute stroke is indistinct. Telestroke providers prefer a figurative "tool belt" of technologies available to adapt to individual consultation requirements. PMID- 20922506 TI - Effects of early intervention on the course of bipolar disorder: theories and realities. AB - Given the severity and early onset of pediatric bipolar disorder, early intervention is important to bring about recovery and alter the course of the illness. There is a new and burgeoning body of literature on the biological basis of early signs of the illness and the mechanistic understanding of treatment interventions. Biological findings based on multimodal imaging, genomic studies of cellular proteins, and performance-based findings of neurocognitive studies are beginning to assemble a cohesive and interlinked model of systems neuroscience. This offers the promise of identifying biomarkers, predictors of illness, and treatment outcomes. In complement, at the tier of clinical application is a multitude of efficacy trials, yet neither a single medication nor a combination of choices seems to suffice in reality. The current review develops a point of view bridging scientific developments to where comprehensive, multipronged treatment strategies find their clinical application-a model that is similarly applicable in adult bipolar disorder. PMID- 20922507 TI - The role of vitamin D in asthmatic children. PMID- 20922508 TI - Exercise-induced anaphylaxis: an update on diagnosis and treatment. AB - Exercise-induced anaphylaxis (EIA) and food-dependent, exercise-induced anaphylaxis (FDEIA) are rare but potentially life-threatening clinical syndromes in which association with exercise is crucial. The range of triggering physical activities is broad, including as mild an effort as a stroll. EIA is not fully repeatable (ie, the same exercise may not always result in anaphylaxis in a given patient). In FDEIA, the combined ingestion of sensitizing food and exercise is necessary to precipitate symptoms. Clinical features and management do not differ significantly from other types of anaphylaxis. The pathophysiology of EIA and FDEIA is not fully understood. Different hypotheses concerning the possible influence of exercise on the development of anaphylactic symptoms are taken into consideration. These include increased gastrointestinal permeability, blood flow redistribution, and most likely increased osmolality. This article also describes current diagnostic and therapeutic possibilities, including changes in lifestyle and preventive properties of antiallergic drugs as well as acute treatment of these dangerous syndromes. PMID- 20922509 TI - Diagnosis of food allergy: epicutaneous skin tests, in vitro tests, and oral food challenge. AB - Food allergy is becoming an increasingly common diagnosis. Because of this increase in prevalence, it is imperative that physicians evaluating patients with possible adverse reactions to foods understand the currently available assays and how they should best be used to accurately diagnose the disease. Simple tests such as skin prick testing (SPT) and serum food-specific IgE testing are the most commonly used diagnostic tests to evaluate for IgE-mediated food reactions. However, these tests, which measure sensitization and not clinical allergy, are not without pitfalls, and their utility must be appreciated to avoid over- and underdiagnosis. Although the physician-supervised oral food challenge remains the gold standard for food allergy diagnosis, a careful medical history paired with SPT and serum food-specific IgE testing often can provide a reliable diagnosis. In this review, we examine the usefulness and pitfalls of SPT and serum food specific IgE levels, as well as examine atopy patch testing and other emerging tests, such as component-resolved diagnostics and the basophil activation test. Finally, we describe the use of the double-blind, placebo-controlled oral food challenge as the current gold standard for food allergy diagnosis. PMID- 20922510 TI - Improving coping skills for self-management of treatment side effects can reduce antiretroviral medication nonadherence among people living with HIV. AB - BACKGROUND: Human immunodeficiency virus (HIV) treatment side effects have a deleterious impact on treatment adherence, which is necessary to optimize treatment outcomes including morbidity and mortality. PURPOSE: To examine the effect of the Balance Project intervention, a five-session, individually delivered HIV treatment side effects coping skills intervention on antiretroviral medication adherence. METHODS: HIV+ men and women (N = 249) on antiretroviral therapy (ART) with self-reported high levels of ART side effect distress were randomized to intervention or treatment as usual. The primary outcome was self reported ART adherence as measured by a combined 3-day and 30-day adherence assessment. RESULTS: Intent-to-treat analyses revealed a significant difference in rates of nonadherence between intervention and control participants across the follow-up time points such that those in the intervention condition were less likely to report nonadherence. Secondary analyses revealed that intervention participants were more likely to seek information about side effects and social support in efforts to cope with side effects. CONCLUSIONS: Interventions focusing on skills related to ART side-effects management show promise for improving ART adherence among persons experiencing high levels of perceived ART side effects. PMID- 20922511 TI - Impact of seropositivity to Chlamydia pneumoniae and anti-hHSP60 on cardiovascular events in hemodialysis patients. AB - Autoimmunity to heat shock protein 60 (HSP60) has been related to atherosclerosis. Chlamydia pneumoniae (CP), the most studied infectious agent implicated in promoting atherosclerosis, produces a form of HSP60, which can induce an autoimmune response, due to high antigenic homology with human HSP60 (hHSP60). In this study, we evaluated the correlations among anti-hHSP60 antibodies, CP infection, and cardiovascular disease (CVD) in a high-risk population, such as patients undergoing hemodialysis (HD). Thirty-two patients (67.9 +/- 13.9 years; male/female, 23:9) on regular HD were enrolled. Global absolute cardiovascular risk (GCR) was assessed using the Italian CUORE Project's risk charts, which evaluate age, gender, smoking habits, diabetes, systolic blood pressure, and serum cholesterol. The occurrence of cardiovascular events during a 24-month follow-up was recorded. Seropositivity to CP and the presence of anti hHSP60 antibodies were tested by specific enzyme-linked immunosorbent assays. Inflammation was assessed by measurement of C-reactive protein (CRP) serum levels. Fifteen healthy sex and age-matched (61.9 +/- 9.5 years; male/female, 11:4) subjects were the control group. Fifteen of 32 patients resulted seropositive for CP. CP + patients were older than CP-, while they did not differ for GCR, CRP, and dialytic parameters. CVD incidence was significantly higher in CP+ (9 CP+ vs 2 CP-, p < 0.05). Cox analysis recognized that the incidence of CVD was independently correlated with seropositivity to CP (HR, 7.59; p = 0.01; 95% CI = 1.63-35.4). On the other hand, there were no significant differences in anti hHSP60 levels among CP+, CP- and healthy subjects: 18.11 MUg/mL (14.8-47.8), 31.4 MUg/mL (23.2-75.3), and 24.72 MUg/mL (17.7-41.1), respectively. Anti-hHSP60 did not correlate to GCR, CRP, and incidence of CVD. In conclusion, our data suggest that anti-hHSP60 autoimmune response is not related to CP infection and CP related CVD risk in HD patients. PMID- 20922513 TI - The impact of a medical toxicology fellowship on the training of future emergency medicine residents. PMID- 20922514 TI - Knowledge and health care-seeking behavior in relation to gynecological malignancies in India: a study of the patients with gynecological malignancies in a tertiary care hospital of Kolkata. AB - This cross-sectional observational study was undertaken to find out the knowledge about gynecological malignancies and health care-seeking behavior of patients with gynecological malignancies. In a gynecology out-patient clinic in Kolkata, India, the patients with the suggestive symptoms of gynecological malignancies were screened out. Their diagnoses were confirmed by histopathology. One hundred thirteen patients with histopathologically confirmed gynecological malignancies were interviewed. Eleven patients (9.7%) knew that white discharge or bleeding per vagina was the early symptom and 38 (33.6%) patients knew that gynecological malignancies were treatable. Fifty-six patients (49.5%) had discussed about their symptoms first with their husbands. Most of the patients (91 patients or 80.5%) had visited a private health facility first for their symptoms. Educational level of the patients was found to be inversely associated with the time of presentation at this hospital. This study highlights the need to increase the awareness about gynecological malignancies among women and the community. PMID- 20922515 TI - [Patients with bladder cancer in clinical stage T2 : survival benefit of downstaging in comparison to patients with confirmed muscle invasion in cystectomy specimens]. AB - BACKGROUND: Few and partially contradictory data are available regarding the prognostic signature of downstaging of muscle-invasive clinical tumour stages in patients treated with radical cystectomy. MATERIALS AND METHODS: Clinicopathological parameters of 1,643 patients (study group, SG) treated with radical cystectomy due to muscle-invasive urothelial bladder cancer were summarized in a multi-institutional database. Patients of the SG fulfilled the following conditions: clinical tumour stage T2 N0 M0 and no administration of neoadjuvant radiation or chemotherapy. Cancer-specific survival (CSS) rates were calculated referring to pathological tumour stages in cystectomy specimens (pT2) (mean follow-up: 51 months). Furthermore, a multivariable model integrating clinical information was developed in order to predict the probability of downstaging. RESULTS: A total of 173 patients (10.5%) of the SG presented with downstaging in pathological tumour stages (pT0: 4.8%, pTa: 0.4%, pTis: 1.3%, pT1: 4.1%); 12 of these patients had positive lymph nodes (7%, in comparison with 21% pN+ of pT2 tumours and 43% of >pT2 tumours). Patients with tumour stages pT2 had CSS rates after 5 years of 89, 69 and 46%, respectively (p<0.001). In a multivariable Cox model the presence of pathological downstaging resulted in a significant reduction of cancer-specific mortality (HR 0.30; 95% CI 0.18-0.50). By logistic regression analysis the date of TURB (benefit for more recent operations) was identified as the only independent predictor for downstaging of muscle-invasive clinical tumour stages. Age, gender, grading and associated Tis in the TURB did not reveal any significant influence. CONCLUSION: Patients with muscle-invasive clinical tumour stages and downstaging in cystectomy specimens represent a subgroup with significantly enhanced CSS rates. Further trials that integrate the parameters tumour size, stages cT2a vs cT2b and focality are required in order to define the independent prognostic signature of downstaging of tumour stages more precisely. PMID- 20922516 TI - Analysis and aging of unsaturated polyester resins in contemporary art installations by NMR spectroscopy. AB - Two original art installations constructed from unsaturated polyester resins (UPR) and four different reference UPR products (before and after UVB aging) were analyzed by high-resolution 1D and 2D nuclear magnetic resonance (NMR) spectroscopy. Breaking strain studies were also conducted for the four UPR model products before and after different aging procedures (moisture, UVB exposure, melt/freeze). NMR analysis of the chemical composition of the UPR resin extracts showed they contain several low MW organic compounds and oligomers rich in polar OH groups that play a significant role in the degradation behavior of the composite UPR materials. Statistical analysis of the NMR compositional data showed that styrene and benzaldehyde contents can be used to differentiate between fresh and aged UPR samples. The phthalate and propylene glycol unit speciation (esterified, primary or secondary -OH) of the extracts provided evidence that UPR resin C was used in the construction of the two art installations, and direct comparison of (1)H and (13)C NMR spectra verified this compositional similarity. UPR resin C was shown by both NMR and breaking strain studies to be the reference UPR most susceptible to degradation by different aging procedures, a characteristic attributed to the lower styrene content of resin C. PMID- 20922517 TI - Comparison of different chemometric and analytical methods for the prediction of particle size distribution in pharmaceutical powders. AB - This work compares the estimation of the particle size distribution of a pharmaceutical powder using near-infrared spectroscopy (NIRS), powder flowability properties, and components concentration. The estimations were made by considering the former data blocks separately and together using a multi-block approach. The powders were based on a formulation of paracetamol as the pharmaceutical active ingredient. The reference method used to determine particle size distribution was sieving. Partial least squares methods were used to estimate the multivariate regression models, and the results were compared in terms of figures of merit. It was shown that the partial least squares methods gave similar prediction errors. Regarding the data blocks used, the NIRS block was proven the most advantageous to estimate the particle size distribution. The prediction error of the NIRS block was similar to the other data blocks with additional advantages such as less generalization problems and the possibility of its use to predict additional physical and chemical properties with an improvement to analysis time. The multi-block approach produced the worst results but nevertheless allowed a deeper understanding of the individual contributions of the data blocks in the prediction of the particle size distribution. PMID- 20922512 TI - Models of calcium dynamics in cerebellar granule cells. AB - Intracellular calcium dynamics is critical for many functions of cerebellar granule cells (GrCs) including membrane excitability, synaptic plasticity, apoptosis, and regulation of gene transcription. Recent measurements of calcium responses in GrCs to depolarization and synaptic stimulation reveal spatial compartmentalization and heterogeneity within dendrites of these cells. However, the main determinants of local calcium dynamics in GrCs are still poorly understood. One reason is that there have been few published studies of calcium dynamics in intact GrCs in their native environment. In the absence of complete information, biophysically realistic models are useful for testing whether specific Ca(2+) handling mechanisms may account for existing experimental observations. Simulation results can be used to identify critical measurements that would discriminate between different models. In this review, we briefly describe experimental studies and phenomenological models of Ca(2+) signaling in GrC, and then discuss a particular biophysical model, with a special emphasis on an approach for obtaining information regarding the distribution of Ca(2+) handling systems under conditions of incomplete experimental data. Use of this approach suggests that Ca(2+) channels and fixed endogenous Ca(2+) buffers are highly heterogeneously distributed in GrCs. Research avenues for investigating calcium dynamics in GrCs by a combination of experimental and modeling studies are proposed. PMID- 20922518 TI - Protamine neutralisation of low molecular weight heparins and their oligosaccharide components. AB - Protamine sulphate is an effective inhibitor of heparin and is used clinically to neutralise both low molecular weight heparins (LMWH) and unfractionated heparin (UFH). However, protamine sulphate does not fully counter the anti-Xa effect of LMWH, even in excess (>40 MUg to 1 IU/ml). To investigate the molecular basis for this observation, the residual potencies in the presence and absence of plasma as well as the molecular weight profiles of commercial LMWH neutralised with increasing amounts of protamine were measured. Materials over 5000 Da are preferentially neutralised by protamine. To further investigate this molecular weight dependence, monodisperse oligosaccharides were prepared from three commercial LMWHs. The specific anti-Xa activity for the fractions increased with molecular weight, and was found to vary between the three preparations for oligosaccharides of the same molecular weight. Our results indicate that protamine sulphate neutralisation is largely dependent on molecular weight, leading to the implication that LMWHs containing a larger proportion of small oligosaccharides will not be as effectively neutralised. Protamine sulphate neutralisation of any given LMWH is also affected by the specific anticoagulant activities of its low molecular weight components, which varies between LMWH products, presumably with the method of manufacture. PMID- 20922519 TI - Analytical methods in DNA and protein adduct analysis. AB - DNA or protein adducts are reaction products of endogenous or exogenous chemicals and cellular macromolecules. Adducts are useful in toxicological studies and/or human biomonitoring exercises. In particular, DNA damage provides invaluable information for risk analysis. Second, metabolites or conjugates can be regarded as markers of phase II reactions though they may not give accurate information about the levels of reactive and damage-provoking reactive compounds or intermediates. Electrophiles are often short-lived molecules and therefore difficult to monitor. In contrast, adducts are often chemically stable, though their levels in biological samples are low, which makes their detection challenging. The assay of adducts is similar to the analysis of any other trace organic molecule, i.e. problems with the matrix and small amounts of analytes in samples. The (32)P-postlabelling assay is a specific method for DNA adducts but immunochemical and fluorescence-based methods have been developed which can detect adducts linked to both DNA and protein. Tandem mass spectrometry, particularly if combined with ultrahigh-performance liquid chromatography, is currently the recommended detection technique; however investigators are striving to develop novel ways to achieve greater sensitivity. Standards are a prerequisite in adduct analysis, but unfortunately they are seldom commercially available. PMID- 20922521 TI - Methods for conducting bioassays using embryos and larvae of Pacific herring, Clupea pallasi. AB - The rapid decrease of several stocks of Pacific herring, Clupea pallasi, in Puget Sound, Washington, has led to concerns about the effects of industrial and nonpoint source contamination on the embryo and larval stages of this and related forage fish species. To address these concerns, the state of Washington and several industries have funded efforts to develop embryo and larval bioassay protocols that can be used by commercial laboratories for routine effluent testing. This article presents the results of research to develop herring embryo and larval bioassay protocols. Factors evaluated during protocol development included temperature, salinity, dissolved oxygen (DO), light intensity, photoperiod, larval feeding regimes, use of brine and artificial sea salts, gonad sources, collection methods, and egg quality. PMID- 20922523 TI - Autoimmune hemolytic anemia and autoimmune neutropenia in a child with erythroblastopenia of childhood (TEC) caused by human herpesvirus-6 (HHV-6). PMID- 20922522 TI - Automatic, three-segment, MR-based attenuation correction for whole-body PET/MR data. AB - PURPOSE: The combination of positron emission tomography (PET) and magnetic resonance (MR) tomography in a single device is anticipated to be the next step following PET/CT for future molecular imaging application. Compared to CT, the main advantages of MR are versatile soft tissue contrast and its capability to acquire functional information without ionizing radiation. However, MR is not capable of measuring a physical quantity that would allow a direct derivation of the attenuation values for high-energy photons. METHODS: To overcome this problem, we propose a fully automated approach that uses a dedicated T1-weighted MR sequence in combination with a customized image processing technique to derive attenuation maps for whole-body PET. The algorithm automatically identifies the outer contour of the body and the lungs using region-growing techniques in combination with an intensity analysis for automatic threshold estimation. No user interaction is required to generate the attenuation map. RESULTS: The accuracy of the proposed MR-based attenuation correction (AC) approach was evaluated in a clinical study using whole-body PET/CT and MR images of the same patients (n = 15). The segmentation of the body and lung contour (L-R directions) was evaluated via a four-point scale in comparison to the original MR image (mean values >3.8). PET images were reconstructed using elastically registered MR-based and CT-based (segmented and non-segmented) attenuation maps. The MR-based AC showed similar behaviour as CT-based AC and similar accuracy as offered by segmented CT-based AC. Standardized uptake value (SUV) comparisons with reference to CT-based AC using predefined attenuation coefficients showed the largest difference for bone lesions (mean value +/- standard variation of SUV(max): -3.0% +/- 3.9% for MR; -6.5% +/- 4.1% for segmented CT). A blind comparison of PET images corrected with segmented MR-based, CT-based and segmented CT-based AC afforded identical lesion detectability, but slight differences in image quality were found. CONCLUSION: Our MR-based attenuation correction method offers similar correction accuracy as offered by segmented CT. According to the specialists involved in the blind study, these differences do not affect the diagnostic value of the PET images. PMID- 20922524 TI - Long-term follow-up of patients with chronic myeloid leukemia having received autologous stem cell transplantation. AB - Prior to introduction of imatinib mesylate, the median survival of chronic myeloid leukemia (CML) patients was approximately 60 months and the standard treatment with interferon-alpha (IFN-alpha) resulted in major cytogenetic responses of 20-25%. As an alternative treatment approach besides allogeneic transplantation, intensive chemotherapy followed by autologous hematopoietic stem cell transplantation (autoHSCT) was investigated at that time with the rationale of debulking disease burden and mobilization and transplantation of Philadelphia chromosome-negative (Ph-) stem cells. In the era of tyrosine kinase inhibitors as state-of-the-art therapy for CML, the concept of autoHSCT has attracted only little interest and long-term follow-up and outcome data after autoHSCT in CML patients is scarce. In this long-term analysis, we report on 21 CML patients, mobilized in early chronic phase and transplanted with largely Ph- grafts, who received IFNalpha as maintenance therapy. Imatinib mesylate was administered upon cytogenetic relapse or disease progression while on IFN-alpha. The 10-year survival was 61% and 11 patients (52%) were alive at a median follow-up of 12.5 years (range 0.3-13.8) with eight patients in complete hematologic remission (CHR) and three of eight in major molecular remission (MMR). While all patients in MMR and two of five patients in CHR received imatinib, it is noteworthy that three patients remaining in CHR only received IFN-alpha maintenance after autoHSCT. With the limitations of a small patient population, this is the longest follow-up analysis demonstrating that autoHSCT in CML is very efficient to debulk the disease, restore Ph-negative hematopoiesis, and is able to induce major and sustained molecular responses in the majority of patients with substantial long term survival rates. PMID- 20922525 TI - Hydralazine and magnesium valproate as epigenetic treatment for myelodysplastic syndrome. Preliminary results of a phase-II trial. AB - Decitabine and azacitidine, two DNA methyltransferase (DNMT) inhibitors, are the current standard of treatment for myelodysplastic syndrome (MDS). Histone deacetylase (HDAC) inhibitors are also being tested against MDS. Both drug classes synergize in their gene reactivating and anticancer activities. The combination of hydralazine and valproate (Transkrip(r)), a DNMT and HDAC inhibitor, respectively), has been developed as epigenetic therapy under the drug repositioning concept. To evaluate the clinical efficacy and safety of hydralazine and valproate against MDS, an open phase-II study for previously treated patients with MDS was conducted. The hydralazine dose was given according with the acetylator phenotype, and valproate was dosed at 30 mg/kg/day. Response was graded with International Working Group criteria. Toxicity was evaluated by the Common Toxemia Criteria-National Cancer Institute version 3 scale. From November 2007 to January 2010, 12 patients were included. Median age+/-SD was 53+/-19.78 years (range, 23-79 years); median time from diagnosis to inclusion in the study was 7.9 months (range 2.6-36.1 months). Median of previous treatment was 2 (range, 1-6). Refractory cytopenia with multilineage dysplasia was diagnosed in ten cases, and refractory anemia with excess of blasts in two. Overall response was documented in six (50%) of 12 cases, including one CR, one PR, and four hematological improvements of the erythroid series. Two patients (16.6%) progressed to acute myeloid leukemia. Hemoglobin increased from 7.4 to 10.3 g/dL (in 13 weeks), neutrophils, from 1.1 to 2.0 (in 3 weeks), and platelets, from 66*10(9) to 72*10(9)/L (in 2 weeks). Transfusional requirements decreased from 2.3 to 0 U bi-monthly for red blood cells and from 0.5 to 0 U bi monthly for platelets in responding patients. Main toxicities were mild, including somnolence and nausea. Preliminary results of this phase-II study suggest that the combination of hydralazine and valproate is a promising non toxic and effective therapy for MDS. PMID- 20922526 TI - The role of zinc protoporphyrin measurement in the differentiation between primary myelofibrosis and essential thrombocythaemia. AB - The differentiation between primary myelofibrosis (PMF) and essential thrombocythaemia (ET) may be difficult especially in early-stage disease. In PMF, increased levels of inflammatory cytokines induce impaired iron utilisation and disturbed erythropoiesis. In conditions with impaired iron support to erythropoiesis, zinc protoporphyrin (ZPP) is produced instead of heme. Here, we investigate whether ZPP concentration can be useful in the differentiation between PMF and ET. Seventy newly diagnosed patients (PMF, n=24; ET, n=46) were analysed. Intraerythrocytic ZPP concentration (normal<=40 MUmol/mol heme) was measured by an Aviv front-face haematofluorometer. In PMF, ZPP concentrations were significantly increased when compared to ET (99+/-37 MUmol/mol heme vs. 36+/ 13 MUmol/mol heme, p<0.0001). There was also a significant difference between early-stage PMF and advanced disease (77+/-30 MUmol/mol heme vs. 122+/-31 MUmol/mol heme, p=0.003). ZPP>76 MUmol/mol heme as observed in 71% of PMF patients were not seen in ET. In PMF patients responding to immunosuppressive treatment (n=4), the increase in haemoglobin was accompanied by declining ZPP. In summary, by detecting the disturbed iron metabolism common in PMF, ZPP may assist in the differentiation between PMF and ET. Concentrations>60 MUmol/mol heme are unlikely in ET if iron deficiency is excluded. ZPP determination is also useful for monitoring the effect of therapy in PMF. PMID- 20922527 TI - Long-term outcome of hemizygous and heterozygous carriers of a germline GATA1 (G208R) mutation. AB - The transcriptional regulator GATA1 is crucially involved in megakaryocytopoiesis and erythropoiesis. Mutations of the gene which is located on the X chromosome have been associated with platelet and red blood cell abnormalities. We identified a family with a GATA1 (G208R) mutation in whom a low male birth rate and frequent miscarriages among heterozygous females suggested increased fetal death in male hemizygotes. Female mutation carriers had normal or near normal hemoglobin levels and platelet counts ranging from normal to severely reduced, probably reflecting skewed X chromosome inactivation. Platelets were dimorphous, and thrombocytopenia was associated with erythroblastosis. The only living male mutation carrier had severe macrothrombocytopenia with life-threatening bleeding episodes, moderate to severe anemia, eosinopenia, skeletal abnormalities, and abundant extramedullary hematopoiesis. Long-term sequelae in the 50-year-old patient included unilateral nephrectomy following misinterpretation of paraspinal hematopoiesis as renal cancer, spinal stenosis which was possibly favored by progressive bone marrow expansion, and severe secondary gout. PMID- 20922528 TI - Costs of managing severe immune thrombocytopenia in adults: a retrospective analysis. AB - This study aims to report resource utilisation and annual cost for chronic immune thrombocytopenia (ITP) patients enrolled consecutively and followed for 1 year. A single-centre, single-arm, retrospective 1-year observational cohort study of adult patients with chronic ITP from a French hospital was conducted. Healthcare resource utilisation and mean cost per patient (with 95% confidence intervals) were estimated for the whole group. Patients requiring at least one hospitalisation formed subgroup 1. Patients with the most severe category of disease formed subgroup 2 [defined as hospitalised patients with >=1 immunoglobulin (IVIg) infusion (usually reserved for those with bleeding score>8)]. Fifty-seven patients (42F/15M) with a mean age of 48 years (SD=19) at ITP diagnosis were studied. Mean platelet count at diagnosis was 28+/-26*109/L. Mean duration of ITP was 3.1 years (SD=2); eight patients had undergone splenectomy at baseline. Subgroup 1 included 27 patients who were hospitalised (full hospitalisation, n=23; and/or day hospitalisation, n=8). Of those, 12 patients received at least one IVIg infusion during hospitalisation (subgroup 2). Total mean cost per patient for the 1-year study period was ?7,293 (95% CI=3,369 13,584) for the whole group, ?15,334 (95% CI=7,876-27,459) for subgroup 1 and ?26,581 (95% CI=12,241-50,578) for subgroup 2. IVIg accounted for 33% of costs for subgroup 1 and up to 43% of costs for patients with more severe disease (subgroup 2). Management of adults with chronic ITP is costly in France, especially for patients with severe disease. IVIg use was a major cost driver. PMID- 20922529 TI - [Effect of applanation tonometry on precision of biometry measurements]. AB - BACKGROUND: The aim of this study was to investigate the effect of applanation tonometry on the accuracy of biometric measurements and the reproducibility of keratometric measurements. PATIENTS AND METHODS: In this clinical prospective study a total of 16 patients were enrolled who presented for cataract surgery on 30 eyes. Biometry measurements were made using an IOLMaster optical biometer before and 10 min after standard Goldmann applanation tonometry. Local anesthesia was achieved by administering one drop of fluorescein-stained oxybuprocaine 0.4%. RESULTS: The mean absolute difference of intraocular lens power for emmetropia was 0.31 +/- 0.33 D (range -1.56 to +1.12 D) and the mean standard deviation for R1 and R2 (n=28 eyes) was 0.014 +/- 0.013 mm before and 0.024 +/- 0.021 mm after tonometry. This difference was statistically significant (t-test, p<0.01). Moderate to severe irregular corneal surfaces were noted in some cases after tonometry. CONCLUSIONS: Local anesthesia and applanation tonometry reduced the accuracy of IOL power calculations with differences exceeding +/- 1 D and the reliability of consecutive keratometry measurements decreased significantly. Therefore, it is advisable to perform biometry measurements at the very beginning of the preoperative examination. PMID- 20922530 TI - [Astigmatic keratotomy with the femtosecond laser: correction of high astigmatisms after keratoplasty]. AB - OBJECTIVE: The purpose of this study was to evaluate a novel technique for the correction of postoperative astigmatism after penetrating keratoplasty with the use of the femtosecond laser creating astigmatic keratotomies (femto-AK) in the scope of a retrospective case series. METHODS: Clinical data of ten eyes of nine patients with high residual astigmatism after penetrating keratoplasty undergoing paired femto-AK using a 60-kHz femtosecond laser (IntraLaseTM, AMO) were analyzed. A new software algorithm was used to create paired arcuate cuts deep into the donor corneal button with different cut angles. Target values were refraction, uncorrected visual acuity, best corrected visual acuity, topographic data (Orbscan(r), Bausch & Lomb, Rochester, NY, USA), and corneal wavefront analysis using Visual Optics Lab (VOL)-Pro 7.14 Software (Sarver and Associates). Vector analysis was performed using the Holladay, Cravy and Koch formula. Statistical analysis was performed to detect significances between visits using Student's t test. RESULTS: All procedures were performed without any major complications. The mean follow-up was 13 months. The mean patient age was 48.7 years. The preoperative mean uncorrected visual acuity (logMAR) was 1.27, best corrected visual acuity 0.55, mean subjective cylinder -7.4 D, and mean topometric astigmatism 9.3 D. The postoperative mean uncorrected visual acuity (logMAR) was 1.12, best corrected visual acuity 0.47, mean subjective cylinder 4.1 D, and mean topometric astigmatism 6.5 D. Differences between corneal higher order aberrations showed a high standard deviation and were therefore not statistically significant. CONCLUSIONS: Astigmatic keratotomy using the femtosecond laser seems to be a safe and effective tool for the correction of higher corneal astigmatisms. Due to the biomechanical properties of the cornea and missing empirical data for the novel femto-AK technology, higher numbers of patients are necessary to develop optimal treatment nomograms. PMID- 20922531 TI - [A topodiagnostically characteristic visual field defect]. AB - A 69-year-old female patient presented with unilateral optic nerve atrophy and visual loss. The visual field examination showed not only a subtotal visual field loss in the affected eye but also a visual field defect in the other eye which was classified as an anterior junction syndrome. Cranial MRI revealed a tuberculum sellae meningioma which was treated surgically. PMID- 20922532 TI - The N-type and L-type calcium channel blocker cilnidipine suppresses renal injury in Dahl rats fed a high-salt diet. AB - The aims of the present study were to compare the effects of cilnidipine [L type/N-type calcium channel blocker (CCB)] and amlodipine (L-type CCB) alone or in combination with the angiotensin II receptor blocker (ARB), valsartan, on blood pressure (BP), kidney function in Dahl salt-sensitive (DS) rats. DS rats fed a high-salt diet were divided into six groups; control (n = 13), two CCB (cilnidipine or amlodipine) groups at 1 mg/kg/day (n = 10), ARB (valsartan) at 10 mg/kg/day (n = 12), cilnidipine + valsartan (CV, n = 12), and amlodipine + valsartan (AV, n = 12). BPs were lower in the combination therapy groups than in those given either drug alone, but only CV inhibited the increase in urinary albumin excretion (UAE) and lowered the glomerular sclerosis score. In addition, AV elevated plasma renin activity and the angiotensin II concentration, and thus failed to inhibit increases in UAE and to lower glomerular sclerosis score. In conclusion, combination therapy with CCB and ARB decreases BP more effectively than either drug alone. When used in combination with valsartan, cilnidipine is more effective than amlodipine for preventing kidney injury. PMID- 20922533 TI - Association between clinical characteristics and AL amyloid deposition in the kidney. AB - Renal involvement is very common in AL amyloidosis. Our aim was to investigate associations between the clinical characteristics and renal pathology of patients with AL amyloidosis. The data of 11 adult Japanese patients with AL amyloidosis and renal involvement were analyzed retrospectively. To assess the difference based on the pattern of distribution of amyloid deposition, we divided the patients into a group with the capillary form and a group with the small vessel form, and compared the clinical characteristics of the two groups. Concerning AL amyloidosis, the small vessel form group was associated with cardiac involvement and left ventricular thickening compared with the capillary form group (p = 0.03). There were no significant differences between the groups in the rates of patient survival and renal survival. There was a negative correlation between grade of amyloid deposition and renal survival duration (p = 0.04, r2 = 0.66). The degree of amyloid deposition was not correlated with the extent of proteinuria or renal function. These findings suggest that the vascular deposition pattern of amyloid in the kidney is important for determining patient survival and renal outcome. PMID- 20922534 TI - A novel phenylpyridazinone, T-3999, reduces the progression of autoimmune myocarditis to dilated cardiomyopathy. AB - Regardless of the origin, injury to the heart can result in cardiomyocyte hypertrophy, fibrosis, and cell death. Myocarditis often progresses to dilated cardiomyopathy (DCM), a major cause of heart failure. In our study, we used a rat model of myosin-induced experimental autoimmune myocarditis (EAM), in which the heart transits from an acute phase (inflammatory myocarditis) to a chronic phase (remodeling and DCM). Our objective was to investigate whether T-3999, a novel phenylpyridazinone, can reduce this progression. Four weeks after myosin injection, T-3999 was administered daily to male Lewis rats in two doses (3 and 10 mg/kg, orally). Four weeks later, treatment was terminated; hemodynamic and echocardiographic measurements were performed; hearts were excised for histopathology and estimation of histamine, mRNA, and protein levels. Mortality rate was reduced by drug treatment. T-3999 reduced % fibrosis and tissue collagen III. Profibrotic markers-transforming growth factor-beta(1), tumor necrosis factor-alpha, and galectin-3--were attenuated by treatment. Mast cell density and degranulation, and tissue histamine concentration were also reduced. This indicates an anti-inflammatory effect of the drug in reducing fibrosis. Hypertrophy was reduced as reflected by reduced myocyte diameter and natriuretic peptide expression. T-3999 treatment increased the sarcoendoplasmic reticulum Ca(2+) ATPase 2 protein level and improved several cardiac function parameters. The reduction of the remodeling process and improvement in myocardial function suggest an effect of T-3999 in attenuating ventricular remodeling in post myocarditis DCM. PMID- 20922535 TI - Effect of diet-induced weight loss on endothelial dysfunction: early improvement after the first week of dieting. AB - Obesity is associated with impaired endothelial function, and this may lead to increased cardiovascular risk. To gain insight into the beneficial effects of diet-induced weight loss on endothelial function, endothelium-dependent, flow mediated dilation (FMD) of the brachial artery and several metabolic and inflammatory markers were assessed in 40 obese women (BMI 34.9 +/- 4.88 kg/m(2)) at baseline, after the 1st week and after 5 months on a low-calorie diet of 5.0 MJ/day. Twenty lean women served as controls. At entry, the obese women had a lower FMD than the lean women (7.7 +/- 1.8 vs. 11.5 +/- 4.2%, p < 0.001). After 1 week of the intervention and 4% reduction of BMI, FMD improved by 22% (p = 0.005), and a decrease in circulating triglycerides, insulin, leptin, tissue type plasminogen activator and its inhibitor, von Willebrand factor, C-reactive protein and tumor necrosis factor receptor 1 was observed. Improvement of FMD was associated only with a decrease in BMI (r = 0.39, p = 0.03). Twenty-two women completed the weight reduction program and reduced their BMI by 16%. FMD was further improved by 64% (to 12.4 +/- 5.3%, p = 0.001) and became comparable to that of lean women. None of the significant changes in the observed parameters was associated with improvement of FMD at the end of the program. Improvements in obesity-related endothelial dysfunction began in the 1st week of dieting and continued during the following months of this simple non-pharmacological lifestyle modification to reach normalisation of endothelial function. The favourable effect of dieting on endothelial function is independent of the accompanying improvement of classical risk factors. PMID- 20922536 TI - Effect of graft adaptation of the internal mammary artery on longitudinal phasic blood flow velocity characteristics after surgery. AB - Left internal mammary artery (LIMA) bypass conduits undergo gradual longitudinal flow transition from the proximal to distal segments, and the diastolic/systolic (D/S) ratios of the flow indices can diagnose graft patency. However, the influence of graft adaptation on this has not been studied. We examined 46 patients with LIMA graft to the left anterior descending artery using a Doppler tipped guidewire in the proximal, middle, and distal segments; 34 had patent LIMAs (group A: new LIMAs; <1 month postoperatively; n = 22 and group B: old LIMAs; >=1 month postoperatively; n = 12), and 12 had new LIMAs with distal stenosis (group C). In diastole, the time-averaged peak velocities, maximum peak velocities, and velocity-time integrals in each segment were significantly greater in group A than in groups B or C; however, in systole, they did not differ significantly among the three groups. The D/S ratios of the indices in all segments in group A were significantly greater than those in groups B or C; however, they did not differ between groups B and C in any of the segments. Graft adaptation of a patent LIMA, itself, affects the longitudinal flow transition pattern. The D/S ratio of the three indices in the patent old LIMAs did not differ from those in the LIMAs with distal stenosis early after surgery. The timing of LIMA flow assessment must be considered during assessment of the graft patency from the flow velocity patterns. PMID- 20922538 TI - Treatment effects of renin-angiotensin system inhibitor and calcium channel blocker in patients with coronary artery narrowing (from the Japanese Coronary Artery Disease Study). AB - Low-dose antihypertensive drugs in combination are prescribed frequently in clinical practice. Combination treatment is superior to monotherapy with higher doses of each drug in terms of blood pressure reduction and side effects. However, it is unclear whether combination treatment provides additional prognostic benefit beyond the blood pressure lowering effects. We assessed the usefulness of the combined treatment of a renin-angiotensin system inhibitor (RASI) and a calcium channel blocker (CCB) for all cardiovascular events in the Japanese Coronary Artery Disease (JCAD) Study population. In the JCAD Study, which is an observational and non-randomized trial, 13,812 patients with angiographically shown narrowing >50% in >=1 of 3 major coronary arteries were followed up for a mean of 2.7 years. The primary endpoint of the study was all cardiovascular events. In the present study, baseline covariates possibly influencing the event rate were adjusted between the different treatment groups. There was no statistically significant difference in the event rate between the RASI monotherapy and combined treatment groups, although Kaplan-Meier analysis showed a 23% (p = 0.0003) relative risk reduction with an RASI monotherapy compared with the control group. In conclusion, there may be no additional benefit beyond blood pressure lowering effects in the combination of an RASI and a CCB in patients with angiographically documented CAD. PMID- 20922537 TI - Effects of telmisartan on markers of ventricular remodeling in patients with acute myocardial infarction: comparison with enalapril. AB - Enalapril is effective in the suppression of left ventricular remodeling after acute myocardial infarction (AMI), but the effect of telmisartan is unclear. The consecutive 163 AMI patients underwent primary percutaneous coronary intervention and were randomized to telmisartan (n = 82) or enalapril (n = 81). Left ventriculography was performed in the acute and chronic (6 months) phases. Matrix metalloproteinase (MMP)-2 and MMP-9 activities were measured by zymography in the acute (days 1, 7, and 14) and chronic (6 months) phases. Plasma pentraxin3 (PTX3), a marker of vascular inflammation, was also measured. There were no adverse effects in the telmisartan group. The analysis of the left ventriculograms in the acute and chronic phases revealed no difference between the two groups. MMP-9 activities at days 7 and 14 and in the chronic phase were decreased compared to that at day 1 in both groups. MMP-2 activity was also decreased in the acute phase, but increased in the chronic phase in both groups. There was no difference in the plasma PTX3 level in the acute phase, but in the chronic phase, PTX3 was significantly lower in telmisartan than in enalapril group (2.6 +/- 1.4 vs. 3.2 +/- 1.6 ng/ml, p = 0.04). Telmisartan is well tolerated, shows similar effects on the markers of left ventricular remodeling to those of enalapril, and suppresses vascular inflammation more effectively than enalapril in AMI patients. Telmisartan can be an alternative to angiotensin converting enzyme inhibitor in patients with AMI. PMID- 20922539 TI - Predictive value of the relative lymphocyte count in coronary heart disease. AB - The physiological stress suffered by patients with coronary heart disease (CHD) may result in a shift in leukocyte differential toward a decreased percentage of lymphocytes (L%). The purpose of this study was to determine the prognostic value of a low L% in CHD. One hundred forty patients evaluated in our department between 2007 and 2008 were retrospectively reviewed. Thirty-eight patients had primary percutaneous coronary intervention (PCI), and 102 patients had elective PCI. Various statistical analyses were used to examine the association between a low L% or other clinical characteristics and CHD. Univariate analysis showed that low L% was significantly related to ACS compared with stable CHD or control. White blood cell (WBC) count, C-reactive protein (CRP) and left ventricular systolic dysfunction (LVSD) were also correlated with CHD. Multivariate analysis and logistic regression analysis revealed that L%, CRP, WBC count and LVSD were all independently significant risk factors to have predictive value for CHD and 1 year major adverse cardiac events (MACE). A low L% could be used as an independent predictor for ACS on admission and is associated with MACE during clinical follow-up in CHD patients. PMID- 20922540 TI - Laparoscopic adult colorectal surgeon and adolescents with inflammatory bowel disease: a safe combination? AB - INTRODUCTION: A multidisciplinary tertiary service for adolescents with inflammatory bowel disease (IBD) was commenced in April 2008, aiming to provide specialist treatment for adolescent patients and bridge the gap between existing paediatric and adult surgical services. A single laparoscopic colorectal surgeon who normally treats adult patients has been part of the multidisciplinary team since its inception. AIM: To analyse outcomes for those patients requiring surgical resection during the first 2 years of service. METHODS: In this service evaluation study, all data for patients undergoing surgery from 1 April 2008 to 31 March 2010 were prospectively collected on a dedicated electronic database. RESULTS: Nineteen patients underwent surgical resection (15 laparoscopic and four open) over the 2-year period. Median patient age was 15 years (range 11-16), and 14 patients were female. Of the 15 laparoscopic resections, eight were subtotal colectomy and ileostomy and seven ileocaecal resection/right hemicolectomy. There was one (6.7%) conversion due to a pericolic abscess. There were four planned open cases, including two subtotal colectomy and ileostomy and two small bowel resections. Median operating time was 150 and 172.5 min in the open and laparoscopic groups respectively. Median length of stay was 6 days (range 3-16) in the laparoscopic group, and 8 days (range 5-13) in the open group. There were three (15.8%) post-operative complications, one (5.3%) readmission within 30 days and no mortality. CONCLUSION: This study suggests that an adult colorectal surgeon can provide a safe and effective service for adolescents with IBD, including the provision of laparoscopic resection in this challenging patient group. PMID- 20922541 TI - Right colon, left colon, and rectal surgeries are not similar for surgical site infection development. Analysis of 277 elective and urgent colorectal resections. AB - PURPOSE: Surgical site infections (SSIs) are the most common infections in colorectal surgery. Although some studies suggest that rectal surgery differs from colon surgery for SSI incidence and risk factors, the National Nosocomial Infection Surveillance system categorizes all colorectal surgeries into only one group. The aim of this study was to determine incidence, characteristics, and risk factors of SSIs according to the subclassification of colorectal surgery into right colon surgery (RCS), left colon surgery (LCS), and rectum surgery (RS). METHODS: From November 2005 to July 2009, all patients requiring colorectal resectioning were enrolled into our program. The outcome of interest was an SSI diagnosis. Univariate and multivariate analyses were performed to determine SSI predictors in each group. RESULTS: Two hundred seventy-seven consecutive colorectal resections were analyzed. SSI rates were 8% in RCS, 18.4% in LCS, and 17.6% in RS. LCS and RS showed significantly higher SSI incidences (p = 0.022) and greater rates of organ/space infections compared to RCS (p = 0.029). Predictors of SSI were steroid use among RCS, age greater than 70 years, multiple comorbidities, steroid use, non-neoplastic colonic disease, urgent operation, ostomy creation, postoperative intensive care among LCS, preoperative chemoradiation, heart disease, and prolonged operation among RS patients. On multivariate analysis, the coupled LCS and RS groups showed an increased risk for SSI compared to RCS (OR, 2.57). CONCLUSIONS: SSI incidences, characteristics, and risk factors seem to be different among RCS, LCS, and RS. A tailored SSI surveillance program should be applied for each of the three groups, leading to a more competent SSI recognition and reduction of SSI incidence and related costs. PMID- 20922542 TI - The surgical stress response and postoperative immune function after laparoscopic or conventional total mesorectal excision in rectal cancer: a randomized trial. AB - PURPOSE: This study evaluated differences in stress response and immunological function following laparoscopic and conventional total mesorectal excision (TME) for rectal cancer. METHODS: Patients with non-metastasized rectal cancer were prospectively randomized to open (n = 18) or laparoscopic (n = 22) TME. Blood samples were taken preoperatively (baseline), 2, 24, and 72 h following surgery. Systemic white blood cell and monocyte count, C-reactive protein, interleukin-6 (IL-6), interleukin-8 (IL-8), HLA-DR expression on monocytes, growth hormone, prolactin, and cortisol were measured. RESULTS: Forty patients with a median age of 66 years (interquartile range, 60-74 years) were included. Eighteen patients (45%) were randomized to open surgery and 22 patients (55%) to laparoscopic surgery. Patient demographics in terms of gender, age, BMI, ASA classification, localization of the tumor, and type of neoadjuvant therapy were comparable for both groups. Laparoscopic surgery resulted in a significantly better short-term preservation of postoperative immune function. HLA-DR expression on monocytes was significantly higher (64% vs 50%, P = 0.014) and IL-6 level increase was significantly lower (4.6 vs 10.8, P = 0.003) 2 h after laparoscopic surgery. No differences between the open and laparoscopic technique were observed in postoperative white blood cell count, monocyte count, C-reactive protein, IL-8, growth hormone, prolactin, and cortisol levels. CONCLUSION: Short-term postoperative immune and inflammatory functions tended to be better after laparoscopic rectal surgery. However, the differences were not consistent at all time intervals, making a definitive conclusion difficult. Better preserved inflammatory function 2 h after surgery may reflect a reduction in operative trauma when the laparoscopic technique is compared with open rectal procedures. PMID- 20922543 TI - Biomarkers, population-based studies and a proof of principle investigation in pharmacotherapy. PMID- 20922544 TI - Chlamydomonas reinhardtii: duration of its cell cycle and phases at growth rates affected by light intensity. AB - In the cultures of the alga Chlamydomonas reinhardtii, division rhythms of any length from 12 to 75 h were found at a range of different growth rates that were set by the intensity of light as the sole source of energy. The responses to light intensity differed in terms of altered duration of the phase from the beginning of the cell cycle to the commitment to divide, and of the phase after commitment to cell division. The duration of the pre-commitment phase was determined by the time required to attain critical cell size and sufficient energy reserves (starch), and thus was inversely proportional to growth rate. If growth was stopped by interposing a period of darkness, the pre-commitment phase was prolonged corresponding to the duration of the dark interval. The duration of the post-commitment phase, during which the processes leading to cell division occurred, was constant and independent of growth rate (light intensity) in the cells of the same division number, or prolonged with increasing division number. It appeared that different regulatory mechanisms operated through these two phases, both of which were inconsistent with gating of cell division at any constant time interval. No evidence was found to support any hypothetical timer, suggested to be triggered at the time of daughter cell release. PMID- 20922545 TI - Distinct roles for Arabidopsis SUMO protease ESD4 and its closest homolog ELS1. AB - SUMO conjugation affects a broad range of processes in Arabidopsis thaliana, including flower initiation, pathogen defense, and responses to cold, drought and salt stress. We investigated two sequence-related SUMO-specific proteases that are both widely expressed and show that they differ significantly in their properties. The closest homolog of SUMO protease ESD4, ESD4-LIKE SUMO PROTEASE 1 (ELS1, alternatively called AtULP1a) has SUMO-specific proteolytic activity, but is functionally distinct from ESD4, as shown by intracellular localization, mutant phenotype and heterologous expression in yeast mutants. Furthermore, we show that the growth defects caused by loss of ESD4 function are not due to increased synthesis of the stress signal salicylic acid, as was previously shown for a SUMO ligase, indicating that impairment of the SUMO system affects plant growth in different ways. Our results demonstrate that two A. thaliana SUMO proteases showing close sequence similarity have distinct in vivo functions. PMID- 20922547 TI - [Pain and fear of movement in the elderly : the need for an interdisciplinary approach]. AB - According to evidence-based guidelines a physically activating therapy approach in older chronic pain patients is necessary for the preservation of autonomy. Often the elderly are not easy to motivate for this because of inappropriate attitudes, low self-efficacy, fear of pain and fear of falling. The latter might be more important for self-induced restriction of activity in older pain patients than fear avoidance beliefs known from pain research. The fear of caregivers concerning pain and falls can also lead to physical restrictions in the elderly. The underlying diseases and drug effects have to be borne in mind in exercise oriented therapy. It seems necessary to design special therapy elements for all national care sectors using age-specific motivation strategies and to assure an interdisciplinary cooperation. PMID- 20922546 TI - Identification, phylogeny, and transcript profiling of ERF family genes during development and abiotic stress treatments in tomato. AB - Ethylene responsive transcription factors have been shown to be intimately connected to plant development, defense responses and stress signaling pathways and in order to use them for plant improvement, we need to have better understanding of these proteins. In this study, 85 ERF genes have been identified from tomato using raw EST data in various public repositories. Phylogenetic analysis with tomato ERF domains revealed their distribution in all the groups, previously identified in model systems. MEME motif analysis resulted in identification of conserved domains, characteristic to member of each clade, in addition to ERF domain. Expression analysis during vegetative and reproductive stages of development using QPCR and tomato GeneChip arrays, revealed their tissue-specific/preferential accumulation. In total, 57 genes were found to be differentially expressed during temporal stages of tomato fruit development. The expression analysis of 23 ERF family genes representing each clade in response to seven abiotic stress treatments revealed their differential expression in response to more than one abiotic stress treatments. Results suggest that ERF genes play diverse roles in plant's life and comprehensive data generated will be helpful in conducting functional genomics studies to understand their precise role during plant development and stress response. PMID- 20922548 TI - Microtubule motors and pollen tube growth--still an open question. AB - The growth of pollen tubes is supported by the continuous supply of secretory vesicles in the tip area. Movement and accumulation of vesicles is driven by the dynamic interplay between the actin cytoskeleton and motor proteins of the myosin family. A combination of the two protein systems is also responsible for the bidirectional movement of larger organelle classes. In contrast, the role of microtubules and microtubule-based motors is less clear and often ambiguous. Nevertheless, there is evidence which shows that the pollen tube contains a number of microtubule-based motors of the kinesin family. These motor proteins are likely to be associated with pollen tube organelles and, consequently, they have been hypothesized to participate in the distribution of organelles during pollen tube growth. Whether microtubule motor proteins take part in either the transport or positioning of organelles is not known for sure, but there is evidence for this second possibility. This review will discuss the current knowledge of microtubule-based motor proteins (including kinesins and hypothetical dyneins) and will make some hypothesis about their role in the pollen tube. PMID- 20922549 TI - Opportunities and successes in the search for plasmodesmal proteins. AB - The proteinaceous composition of plasmodesmata (PDs) is a puzzle for which pieces have proven particularly difficult to find. This review describes the numerous approaches that have been undertaken in the search for PD-associated proteins and what each has contributed to our understanding of PD structure and function. These approaches include immunolocalisation of known proteins, proteomic characterisation of PD-enriched tissue fractions, high-throughput screens of random cDNAs and mutant screens. In addition to components of the cytoskeleton, novel proteins with predicted or unknown functions have been identified. Many of these have properties that relate to the symplastic and/or apoplastic faces of the plasma membrane. Mutant screens have identified proteins involved in previously unconnected cell pathways such as ROS signalling, implicating ROS in PD formation and regulation. Proteins associated with callose synthesis and degradation have also been identified and characterised, providing considerable weight to the hypothesis that callose deposition around the neck of the PD pore is one mechanism by which the PD aperture is regulated. The techniques described in this review have been developed such that it is to be expected that a considerable number of new PD proteins will be identified in coming years to fill in further detail of the structure and functional mechanisms of these dynamic pores. PMID- 20922550 TI - Familial risk factors in social anxiety disorder: calling for a family-oriented approach for targeted prevention and early intervention. AB - Within the last decade, social anxiety disorder (SAD) has been identified as a highly prevalent and burdensome disorder. Both the characterization of its symptomatology and effective treatment options are widely documented. Studies particularly indicate that SAD aggregates in families and has its onset in early adolescence. Given the family as an important context for children's cognitive, emotional and behavioural development, familial risk factors could be expected to significantly contribute to the reliable detection of populations at risk for SAD. Reviewing studies on familial risk factors for SAD argues for the importance of parental psychopathology and unfavourable family environment, but also denotes to several shortcomings such as cross-sectional designs, short follow-up periods, diverging methodologies and the focus on isolated factors. Using a prospective longitudinal study that covers the high-risk period for SAD, including a broader spectrum of putative risk factors may help to overcome many of the methodological limitations. This review sets out to develop a more family-oriented approach for predicting the onset and maintenance of SAD that may be fruitful to derive targeted prevention and early intervention in SAD. PMID- 20922551 TI - Isolation of a CK2alpha subunit and the holoenzyme from the mussel Mytilus galloprovincialis and construction of the CK2alpha and CK2beta cDNAs. AB - Protein kinase CK2 is a ubiquitous, highly pleiotropic, and constitutively active phosphotransferase that phosphorylates mainly serine and threonine residues. CK2 has been studied and characterized in many organisms, from yeast to mammals. The holoenzyme is generally composed of two catalytic (alpha and/or alpha') and two regulatory (beta) subunits, forming a differently assembled tetramer. The free and catalytically active alpha/alpha' subunits can be present in cells under some circumstances. We present here the isolation of a putative catalytic CK2alpha subunit and holoenzyme from gills of the mussel Mytilus galloprovincialis capable of phosphorylating the purified recombinant ribosomal protein rMgP1. For further analysis of M. galloprovincialis protein kinase CK2, the cDNA molecules of CK2alpha and CK2beta subunits were constructed and cloned into expression vectors, and the recombinant proteins were purified after expression in Escherichia coli. The recombinant MgCK2beta subunit and MgP1 were phosphorylated by the purified recombinant MgCK2alpha subunit. The mussel enzyme presented features typical for CK2: affinity for GTP, inhibition by both heparin and ATP competitive inhibitors (TBBt, TBBz), and sensitivity towards NaCl. Predicted amino acid sequence comparison showed that the M. galloprovincialis MgCK2alpha and MgCK2beta subunits have similar features to their mammalian orthologs. PMID- 20922552 TI - The protective effect of ENA Actimineral resource A on CCl4-induced liver injury in rats. AB - ENA Actimineral Resource A (ENA-A) is alkaline water that is composed of refined edible cuttlefish bone and two different species of seaweed, Phymatolithon calcareum and Lithothamnion corallioides. In the present study, ENA-A was investigated as an antioxidant to protect against CCl(4)-induced oxidative stress and hepatotoxicity in rats. Liver injury was induced by either subacute or chronic CCl(4) administration, and the rats had free access to tap water mixed with 0% (control group) or 10% (v/v) ENA-A for 5 or 8 weeks. The results of histological examination and measurement of antioxidant activity showed that the reactive oxygen species production, lipid peroxidation, induction of CYP2E1 were decreased and the antioxidant activity, including glutathione and catalase production, was increased in the ENA-A groups as compared with the control group. On 2-DE gel analysis of the proteomes, 13 differentially expressed proteins were obtained in the ENA-A groups as compared with the control group. Antioxidant proteins, including glutathione S-transferase, kelch-like ECH-associated protein 1, and peroxiredoxin 1, were increased with hepatocyte nuclear factor 3-beta and serum albumin precursor, and kininogen precursor decreased more in the ENA-A groups than compared to the control group. In conclusion, our results suggest that ENA-A does indeed have some protective capabilities against CCl(4)-induced liver injury through its antioxidant function. PMID- 20922553 TI - Isolation and identification of a novel antioxidant with antitumour activity from Serratia ureilytica using squid pen as fermentation substrate. AB - The antioxidant activity of the culture supernatant of Serratia ureilytica TKU013 with squid pen as the sole carbon/nitrogen source was assessed by three methods, and the phenolic contents were assayed. The supernatant with the highest antioxidant activity was further purified by liquid-liquid partition, revealing the ethyl acetate extract exhibited the strongest antioxidant activity and the highest total phenolic content. Eight fractions were retrieved from silica gel column chromatography of this extract, designated F1-F8. F4 was found to possess the strong antioxidative activity and the highest total phenolic content and also exhibited strong cytotoxic activities against two different tumoural cell lines. A new compound (Serranticin) with antioxidant and antitumor activity was obtained from F4. The structure of Serranticin is analogous to that of siderophores (hexacoordinated catecholamine), which are iron chelators. As such, Serranticin has the potential for use as a deferration agent in various iron overload diseases. PMID- 20922555 TI - Aggravation of diabetic nephropathy in OLETF rats by Thy-1.1 nephritis. AB - OBJECTIVE: To clarify whether the induction of Thy-1.1 nephritis aggravates diabetic nephropathy in the Otsuka Long-Evans Tokushima Fatty (OLETF) rat, which is a model of diabetes mellitus. METHOD: Forty-week-old OLETF rats were divided into 2 groups according to treatment: (1) 1 mg/kg body weight of OX7, an anti Thy1.1 antibody (administered intravenously) (Group T, n = 14); (2) 0.9% saline (Group C, n = 14). The histological findings for the kidneys and the index of glomerulosclerosis (IGS) were determined 20 weeks after administration, and urine and serum chemistry were also assessed. The same procedure was performed as a control in 2 groups of Long-Evans Tokushima Otsuka (LETO) rats (i.e., nondiabetic OLETF rats). RESULTS: The urinary protein excretion values and the levels of serum albumin in the OX7-treated OLETF rats were significantly higher and lower than those in the untreated OLETF rats, respectively. Total cholesterol was significantly increased in the OX7-treated OLETF rats compared with the untreated OLETF rats. In the histological analysis, IGS was significantly higher in the OX7 treated OLETF rats than in the untreated OLETF rats. Neither deteriorations in the laboratory assessment values nor histological alterations were seen in the LETO rats. CONCLUSION: These findings indicate that an anti-Thy-1.1 antibody irreversibly aggravates diabetic nephropathy in the OLETF rat. PMID- 20922556 TI - Growth of the chorioallantoic membrane into a rapid-prototyped model pore system: experiments and mathematical model. AB - This paper presents a mathematical model to describe the growth of tissue into a rapid-prototyped porous scaffold when it is implanted onto the chorioallantoic membrane (CAM). The scaffold was designed to study the effects of the size and shape of pores on tissue growth into conventional tissue engineering scaffolds, and consists of an array of pores each having a pre-specified shape. The experimental observations revealed that the CAM grows through each pore as an intact layer of tissue, provided the width of the pore exceeds a threshold value. Based on these results a mathematical model is described to simulate the growth of the membrane, assuming that the growth is a function of the local isotropic membrane tension. The model predictions are compared against measurements of the extent of membrane growth through the pores as a function of time for pores with different dimensions. PMID- 20922558 TI - Collaboration, competition, validation and plans for the future : an interview with Gerard Kleywegt, Head of the Protein Data Bank in Europe. Interviewed by Wendy A Warr. PMID- 20922557 TI - Predictive factors of pathologic complete response and clinical tumor progression after preoperative chemotherapy in patients with stage II and III breast cancer. AB - BACKGROUND: This study aimed to define predictive factors of pathologic complete response (pCR) and disease progression in stage II and III breast cancer patients. PATIENTS AND METHODS: Three hundred thirty-eight patients were included in the study. Patients had received preoperative chemotherapy as follows: 101 had doxorubicin plus cyclophosphamide (AC); 91 had doxorubicin plus docetaxel; 103 had docetaxel plus capecitabine; and 43 had paclitaxel plus gemcitabine. A pCR was defined as the absence of residual invasive carcinoma in the breast. RESULTS: The majority of patients (73%) were premenopausal with a median age of 44 (range, 21-76) years. Fifty-four patients (16%) achieved pCR and were distributed among the 4 breast cancer subtypes as follows: 10% of patients with -ER or PR+/HER2-, 13% with ER or PR+/HER2+, 33% with ER-/PR-/HER2+, and 19% with ER-/PR-/HER2-(p = 0.001). Taxane-containing regimen (p = 0.042) and Breast cancer subtype (p = 0.005) were significant predictive variables for pCR. On the other hand, significantly more patients who received non-taxane-containing regimen (AC) experienced no response (p = 0.001) or progression (p = 0.006). CONCLUSIONS: Patients with ER-/PR-/HER2+ tumors and those who received taxane-containing regimen achieved a higher pCR rate, while significantly more patients developed tumor progression by preoperative non-taxane-containing regimen (AC) compared to those who received taxane-containing chemotherapy. PMID- 20922559 TI - Magnesium-based composites with improved in vitro surface biocompatibility. AB - In this study, bioactive glass (BG, 45S5) particles were added to a biodegradable magnesium alloy (ZK30) through a semi-solid high-pressure casting process in order to improve the surface biocompatibility of the biomaterial and potentially its bioactivity. The observation of the as-cast microstructures of ZK30-BG composites indicated homogeneous dispersion of BG particles in the matrix. SEM, EDX and EPMA showed the retention of the morphological characteristics and composition of BG particles in the as-cast composite materials. In vitro tests in a cell culture medium confirmed that the composites indeed possessed an enhanced ability to induce the deposition of a bone-like apatite layer on the surface, indicating an improved surface biocompatibility as compared with the matrix alloy. PMID- 20922560 TI - Image processing and fractal box counting: user-assisted method for multi-scale porous scaffold characterization. AB - Image analysis has gained new effort in the scientific community due to the chance of investigating morphological properties of three dimensional structures starting from their bi-dimensional gray-scale representation. Such ability makes it particularly interesting for tissue engineering (TE) purposes. Indeed, the capability of obtaining and interpreting images of tissue scaffolds, extracting morphological and structural information, is essential to the characterization and design of engineered porous systems. In this work, the traditional image analysis approach has been coupled with a probabilistic based percolation method to outline a general procedure for analysing tissue scaffold SEM micrographs. To this aim a case study constituted by PCL multi-scaled porous scaffolds was adopted. Moreover, the resulting data were compared with the outputs of conventionally used techniques, such as mercury intrusion porosimetry. Results indicate that image processing methods well fit the porosity features of PCL scaffolds, overcoming the limits of the more invasive porosimetry techniques. Also the cut off resolution of such IP methods was discussed. Moreover, the fractal dimension of percolating clusters, within the pore populations, was addressed as a good indication of the interconnection degree of PCL bi-modal scaffolds. Such findings represent (i) the bases for a novel approach complementary to the conventional experimental procedure used for the morphological analysis of TE scaffolds, in particular offering a valid method for the analysis of soft materials (i.e., gels); also (ii) providing a new perspective for further studies integrating to the structural and morphological data, fluid-dynamics and transport properties modelling. PMID- 20922561 TI - IVIg attenuates TLR-9 activation in B cells from SLE patients. AB - INTRODUCTION: Toll-like receptor-9 (TLR-9) plays an important role in the pathogenesis of systemic lupus erythematosus (SLE). The aim of this study was to evaluate the influence of intravenous immunoglobulin (IVIg) on CpG oligodeoxynucleotides (ODN-CpG) activated B cells from SLE patients. METHODS: Peripheral blood B cells were isolated from 16 SLE patients and 21 healthy age matched controls. B cells were cultured with ODN-CpG 1MUM alone or IVIg (10mg/ml) together with ODN-CpG. After 24-h incubation, B cells and supernatants were collected and analyzed for interleukin (IL)-10, IL-6 secretion, and TLR-9 expression. RESULTS: IVIg decreased the secretion of IL-10 from ODN-CpG-activated B cells isolated from both SLE patients and healthy controls (194 +/- 46.2 to 103.2 +/- 27.13 pg/ml, p < 0.016, 153.2 +/- 19 vs 84.6 +/- 7.5, p < 0.0001, respectively). Similarly, IVIg decreased the secretion of IL-6 from ODN-CpG activated B cell isolated from both SLE patients and healthy controls (431.2 +/- 83 to 307.6 +/- 94.3 pg/ml, p < 0.0008, 319.5 +/- 31 vs 193.3 +/- 22.8, p < 0.0001, respectively). The decrement of IL-10 and IL-6 secretion was associated with a significant decrease in TLR-9 expression in memory B cells from SLE patients and healthy controls (11.47 +/- 1.2 vs 13.29 +/- 1.2, p = 0.005, 11 +/- 0.8 vs 12.8 +/- 0.98, p = 0.0016, respectively). CONCLUSIONS: IVIg attenuates the activation of TLR-9 in B cells from SLE patients, suggesting a novel additional mechanism of IVIg mode of action in these patients. PMID- 20922562 TI - KIF3A, a cilia structural gene on chromosome 5q31, and its polymorphisms show an association with aspirin hypersensitivity in asthma. AB - INTRODUCTION: The kinesin family number 3A (KIF3A) gene on the human chromosomal 5q31-33 region, which is known as a susceptibility locus for immune diseases including asthma, plays a crucial role in generation of cilia. RESULTS: A treatment with aspirin in the human bronchial epithelial cells increased the mRNA expression level of KIF3A compared to that of the untreated control (P <= 0.01), and nasal polyp epithelia from aspirin-intolerant asthma (AIA) patients also showed a higher expression of KIF3A protein than aspirin-tolerant asthma controls. Further logistic analyses revealed that most polymorphisms of KIF3A were significantly associated with AIA (P = 0.0004-0.02; P(corr) = 0.004-0.04) and the decline of forced expiratory volume at 1 s (FEV(1))% by aspirin provocation (P = 0.004-0.04; P(corr) = 0.03). DISCUSSION: Our findings suggest that the KIF3A gene and/or its polymorphisms might have a susceptibility effect on AIA, providing a new step toward controlling aspirin intolerance in asthmatics. PMID- 20922563 TI - Heterogeneous postprandial lipoprotein responses in the metabolic syndrome, and response to fenofibrate therapy. AB - BACKGROUND: Hypertriglyceridemia subjects with metabolic syndrome exhibit variable postprandial triglyceride responses. We investigate the effects of fenofibrate therapy on postprandial triglyceride-containing lipoproteins in subjects with early (3.5 h) versus late (8 h) postprandial triglyceride responses. METHODS: Fifty-five subjects with fasting hypertriglyceridemia (>=1.7 mmol/L (150 mg/ dL) and <5.8 mmol/L (500 mg/dL)) and >=2 Adult Treatment Panel III criteria of the metabolic syndrome were randomized to daily fenofibrate (160 mg/d) or placebo for 12 weeks in a double-blind controlled clinical trial. A standardized fat load (50 g/m(2)) was given orally after a 12 h fast. Blood specimens were obtained at 0 h (fasting), 3.5 h, and 8 h after the test meal. Analysis is confined to the 53 subjects with clearly identifiable early or late triglyceride peaks prior to therapy. RESULTS: Fenofibrate was more effective in late peakers (n = 8) when compared to early peakers (n = 15) with respect to reducing postprandial triglyceride concentrations (-67% vs. -34%, p = 0.0024) and large VLDL (-76% vs. -31%, p = 0.0016), and increasing total HDL particles (20% vs. 11%, p = 0.008) and large HDL particles (185% vs. 88%, p = 0.003). On fenofibrate therapy, 100% of those initially designated as late peakers were reclassified as early peakers; 47% of late peakers assigned to placebo were reclassified as early peakers. CONCLUSIONS: Late postprandial triglyceride responders have attenuated clearance of large VLDL particles, but they were more responsive to fenofibrate. PMID- 20922564 TI - Zoledronic acid prevents bone loss in premenopausal women with early breast cancer undergoing adjuvant chemotherapy: a phase III trial of the Korean Cancer Study Group (KCSG-BR06-01). AB - To determine whether zoledronic acid (ZA) can prevent bone loss in premenopausal women undergoing adjuvant chemotherapy for breast cancer. In this randomized, open-label, phase III multicenter trial, premenopausal women >40 years were randomly assigned to ZA treatment (4 mg IV, every 6 months) or observation after surgery. All patients were treated with four cycles of AC followed by four cycles of taxane. Between March 2007 and May 2008, we assessed a total of 112 premenopausal women, all of whom developed amenorrhea at 1 year after chemotherapy. The mean percent change of BMD in the lumbar spine (LS) was -1.1% in the ZA group versus -7.5% in observation group at 12 months. Differences in percent change of BMD from baseline between the two groups were 6.4% for the LS, and 3.6% for the femoral neck. The mean levels of bone turnover at 12 months were significantly lower in the ZA group. ZA was generally well tolerated. Infusion of ZA 4 mg every 6 months effectively prevented bone loss within the first year in premenopausal women receiving adjuvant chemotherapy for early breast cancer. Regular BMD measurements and early bisphosphonate therapy should be considered in these patients. PMID- 20922565 TI - Cloning and expression pattern of alkaline phosphatase during the development of Paralichthys olivaceus. AB - Alkaline phosphatases are ubiquitous enzymes involved in many important biological processes. Mammalian tissue-nonspecific alkaline phosphatase has long been thought to feature in embryonic development and bone formation. In this study, an alkaline phosphatase (ALP) gene from Paralichthys olivaceus was identified by rapid amplification of cDNA ends and genome-walking PCR. The ALP gene extends 10,141 bp and contains 11 exons and 10 introns. The open reading frame of the ALP transcript consists of 1,431 bp, which encodes 476 amino acids products named as POALP. An analysis of its secondary and tertiary structure revealed that the POALP was conserved in different species, but one disulfide linkage made it possible to adapt to low-temperature environment. The ALP activity was found to be first detectable in the embryo before hatching. The POALP was distributed ubiquitously in the body of P. olivaceus and was particularly high in the digestive tract. These findings suggest the potential role of POALP in nutrient absorption and transportation. During the pre metamorphosis (F stage), ALP gene expression is 2.5-folds of that in the pro metamorphosis (E stage); but in the post-metamorphosis (I stage), it was 1.8 folds of that of pro-metamorphosis. Exogenetic thyroxine (T4) and thiourea (TU) influenced the ALP gene expression significantly during the metamorphosis. Bioinformatics analysis showed that Japanese flounder ALP promoter region contained promoter sequence and putative recognition site for several transcriptional factors, including SREBP-1, SYR, and CdxA. In vitro promoter assays employing EGFP reporter system demonstrated that the promoter of ALP was active. PMID- 20922566 TI - The physiological tolerance of the grey carpet shark (Chiloscyllium punctatum) and the epaulette shark (Hemiscyllium ocellatum) to anoxic exposure at three seasonal temperatures. AB - The epaulette shark (Hemiscyllium ocellatum) and the grey carpet shark (Chiloscyllium punctatum) are commonly found in periodically hypoxic environments. The ecophysiological time available for these animals to safely exploit these niches during different seasonal temperatures was examined. The time to loss of righting reflex (T (LRR)) was examined in response to an open ended anoxic challenge at three seasonal temperatures (23, 25 and 27 degrees C). Ventilation rates were measured in an open ended anoxic challenge at 23 degrees C and during 1.5 h of anoxia followed by 2 h of re-oxygenation at 23 and 25 degrees C. The mean T (LRR) of epaulette and grey carpet sharks was inversely proportional to temperature. The T (LRR) was similar between species at 23 degrees C; however, grey carpet sharks had significantly reduced T (LRR) at higher temperatures. During the standardised anoxic challenge, epaulette sharks entered into ventilatory depression significantly earlier at 25 degrees C. During re-oxygenation, epaulette sharks exposed to anoxia at 23 degrees C had no significant increase in ventilation rates. However, after anoxic challenge and re oxygenation at 25 degrees C, epaulette sharks showed a significant increase in ventilation rates during re-oxygenation. Grey carpet sharks displayed no evidence of ventilatory depression during anoxia. However, during re-oxygenation, grey carpet sharks had significantly elevated ventilation rates above pre-experimental levels and control animals. These data demonstrate that the anoxia tolerance times of both species were temperature dependent, with a significant reduction in the T (LRR) occurring at higher temperatures. Epaulette sharks had a significantly greater T (LRR) at higher temperatures than grey carpet sharks, which did not enter into a ventilatory depression. PMID- 20922567 TI - Galleria mellonella are resistant to Pneumocystis murina infection. AB - Studying Pneumocystis has proven to be a challenge from the perspective of propagating a significant amount of the pathogen in a facile manner. The study of several fungal pathogens has been aided by the use of invertebrate model hosts. Our efforts to infect the invertebrate larvae Galleria mellonella with Pneumocystis proved futile since P. murina neither caused disease nor was able to proliferate within G. mellonella. It did, however, show that the pathogen could be rapidly cleared from the host. PMID- 20922568 TI - Filial obligations to elderly parents: a duty to care? AB - A continuing need for care for elderly, combined with looser family structures prompt the question what filial obligations are. Do adult children of elderly have a duty to care? Several theories of filial obligation are reviewed. The reciprocity argument is not sensitive to the parent-child relationship after childhood. A theory of friendship does not offer a correct parallel for the relationship between adult child and elderly parent. Arguments based on need or vulnerability run the risk of being unjust to those on whom a needs-based claim is laid. To compare filial obligations with promises makes too much of parents' expectations, however reasonable they may be. The good of being in an unchosen relationship seems the best basis for filial obligations, with an according duty to maintain the relationship when possible. We suggest this relationship should be maintained even if one of the parties is no longer capable of consciously contributing to it. We argue that this entails a duty to care about one's parents, not for one's parents. This implies that care for the elderly is not in the first place a task for adult children. PMID- 20922569 TI - 6q24 transient neonatal diabetes. AB - Transient Neonatal Diabetes (type 1) is the commonest cause of diabetes presenting in the first week of life. The majority of infants recover by 3 months of age but are predisposed to developing type 2 diabetes in later life. It is associated with low birth weight but rapid catch up by 1 year of life. The condition is usually due to genetic or epigenetic aberrations at an imprinted locus on chromosome 6q24 and can be sporadic or inherited. Early diagnosis alters medical treatment strategies and differentiates it from other types of early onset diabetes. In some individuals, diabetes may be the initial presentation of a more complex imprinting disorder due to recessive mutations in the gene ZFP57 and may be associated with other developmental problems. PMID- 20922570 TI - Permanent neonatal diabetes due to activating mutations in ABCC8 and KCNJ11. AB - The ATP-sensitive potassium (K(ATP)) channel is composed of two subunits SUR1 and Kir6.2. The channel is key for glucose stimulated insulin release from the pancreatic beta cell. Activating mutations have been identified in the genes encoding these subunits, ABCC8 and KCNJ11, and account for approximately 40% of permanent neonatal diabetes cases. The majority of patients with a K(ATP) mutation present with isolated diabetes however some have presented with the Developmental delay, Epilepsy and Neonatal Diabetes syndrome. This review focuses on mutations in the K(ATP) channel which result in permanent neonatal diabetes, we review the clinical and functional effects as well as the implications for treatment. PMID- 20922571 TI - In vivo monitoring of stem cells in Drosophila pupae using the radiative transfer equation-based fluorescence molecular tomography. AB - PURPOSE: The aim of this study is to realize in vivo monitoring of DSRed expressing cell distribution in Drosophila pupae using fluorescence molecular tomography (FMT). PROCEDURES: The radiative transfer equation (RTE)-based FMT reconstruction algorithm is implemented using finite element method for mesoscopic- or millimeter-scale imaging. The RTE algorithm is validated using both simulated and phantom experimental data. For the in vivo experiments, DsRed fluorescent reporter was inserted into the middle of irradiation-responsive enhancer region (IRER) of Drosophila pupae and expressed only in IRER-open cells. RESULTS: Quantitatively accurate fluorescence images can be reconstructed from both simulated and phantom data. The in vivo images obtained agree well with the in vitro images obtained from confocal microscopy both qualitatively and semi quantitatively. CONCLUSION: DsRed-bearing stem cells in Drosophila pupae can be markedly imaged using our FMT approach. This study suggests that the technique described can be used for dynamic in vivo monitoring of biological events in mesoscopic-scale animals and facilitates basic biologic research such as genetics, epigenetics, and stem cells. PMID- 20922572 TI - How do tumors actively escape from host immunosurveillance? AB - The immunological background for the process of tumor growth is still obscure. However, our understanding of what happens could have important consequences, namely in the context of cancer immunotherapy. A tumor is able to grow in the host environment either because it is recognizable as normal tissue and tolerated by host immune cells, or because it can "escape" from host immunosurveillance. According to the second option the mechanisms of tumor recognition and consequent destruction are actively disturbed by such processes as: change of tumor immunogenicity, production of tumor-derived regulatory molecules, and interaction of cancer cells with tumor-infiltrating immune cells. The results of studies devoted to the problem of immunoregulation in the tumor environment seem to support the "escape" hypothesis. PMID- 20922573 TI - Functional polymorphisms associated with disease-free survival in resected carcinoma of the esophagus. AB - PURPOSE: The aim of this study was to determine whether clinical outcome after surgical resection of esophageal adenocarcinoma (EAC) or esophageal squamous cell carcinoma (ESCC) could be predicted by functional polymorphisms in different proto-oncogenes and tumor suppressor genes. EXPERIMENTAL DESIGN: Six single nucleotide polymorphisms (SNPs) in the AURKA (rs2273535), ERBB2 (rs1136201), MDM2 (rs2279744), CDH1 (rs5030625), CDKN2A (rs11515), and TP73 (rs2273953) genes were genotyped in a consecutive cohort of 346 esophageal cancer patients, who had underwent surgical resection with curative intent. Associations with disease-free survival (DFS) were analyzed with Kaplan-Meier curves and Cox regression, adjusting for potential confounders. RESULTS: Univariate analysis showed no significant associations between the tested polymorphisms and DFS in patients with EAC or ESCC. However, in a multivariate analysis, patients with EAC carrying the heterozygous MDM2 (rs2279744) T/G genotype had significantly improved DFS compared with patients carrying the wild-type genotype (adjusted hazard ratio (AHR), 0.63; 95% confidence interval (CI) [0.45-0.88]). Patients with EAC harboring the homozygous CDH1 (rs5030625) GA/GA genotype had a significantly reduced survival as compared with patients carrying the wild-type genotype AHR 4.0, 95% CI [1.4-11]. CONCLUSIONS: In a large cohort of esophageal cancer patients, the MDM2 T/G and CDH1 GA/GA genotype confer risk of death in patients with EAC. These data suggest that inter-individual differences in germ-line DNA have an impact on DFS in patients with EAC. PMID- 20922574 TI - Treatment of colorectal cancer with unresectable synchronous liver-only metastases with combined therapeutic modalities. AB - BACKGROUND: Resection + radiofrequency ablation (RFA) + hepatic artery infusion (HAI) + systemic chemotherapy for patients with unresectable synchronous liver only metastases from colorectal cancer was rarely used previously. METHODS: We compared the outcomes of 42 patients underwent resection + RFA + HAI + systemic chemotherapy (RRHS) with that of 43 patients underwent resection + RFA + systemic chemotherapy (RRS). RESULTS: The overall survival, the survival free of hepatic recurrence and the median survival in the RRHS group were all significantly higher than those in RRS group at 4 years. While the rates of adverse effects were similar in the two groups. CONCLUSION: For patients with unresectable synchronous liver-only metastases from colorectal cancer, RRHS not only decreases but also postpones hepatic recurrence and therefore improves overall survival at 4 years, as compared with RRS. PMID- 20922575 TI - Minimally invasive total gastrectomy for gastric cancer: a pilot series. AB - BACKGROUND: Minimally invasive surgery for select gastrointestinal disease has gained worldwide acceptance. However, laparoscopic total gastrectomy for cancer remains controversial. The purpose of this study was to examine an initial experience with laparoscopic total gastrectomy. METHODS: Medical records of 16 consecutive patients who underwent laparoscopic total gastrectomy between September 2007 and December 2009 were reviewed in a retrospective manner. Esophagojejunostomy was completed using a transorally delivered anvil, with double-stapled esophageal anastomosis. RESULTS: There were no conversions to open procedures. Two patients (12.5%) required extended resections with en bloc distal pancreatectomy and splenectomy, one of whom also underwent transverse colectomy. The median lymph node count for patients who underwent D2 lymphadenectomy (n = 12) for gastric adenocarcinoma was 31. There were no perioperative deaths and the median length of stay was 8 days. There were no anastomotic leaks, but three patients developed anastomotic strictures amenable to dilatation. CONCLUSIONS: Minimally invasive total gastrectomy can be performed safely and with adequate lymphadenectomy. The procedure provides an excellent short-term outcome with potential for improved patient outcome. PMID- 20922576 TI - Single-incision versus hand-assisted laparoscopic colectomy: a case-matched series. AB - BACKGROUND: Single-incision laparoscopic colorectal surgery is an emerging modality. We incorporated this technique as an alternative to hand-assisted laparoscopic surgery. We investigated intraoperative and short-term outcomes following single-incision laparoscopic colectomy compared with hand-assisted laparoscopic colectomy. METHODS: Between July and November 2009, single-incision colorectal procedures were performed and matched to hand-assisted procedures based on five criteria: gender, age, body mass index, pathology, and type of procedure. Demographic, intraoperative, and postoperative data were assessed. RESULTS: Twenty-four pairs of patients with a mean age of 55.1 years and mean body mass index of 28.5 kg/m(2) were matched. The majority of cases (79.2%) were right hemicolectomies. The ranges of incision length were 2-6 cm (single incision) and 5-11 cm (hand-assisted). Mean operating time was significantly longer for single-incision procedures (143.2 min) compared with hand-assisted procedures (112.8 min), p < 0.0004. There was no significant difference in the groups regarding conversions or intraoperative complications (p < 0.083 and p < 1.0, respectively). Mean length of stay for the single-incision approach (2.7 days) was significantly shorter compared with the hand-assisted approach (3.3 days), p < 0.02. CONCLUSION: Single-incision laparoscopic colectomy is a safe and feasible alternative to hand-assisted laparoscopic surgery. Although the technique required longer operative time, it resulted in smaller incision size and significantly shorter length of hospitalization. PMID- 20922577 TI - Depth of tumor invasion independently predicts lymph node metastasis in T2 rectal cancer. AB - OBJECTIVE: The aim of this study was to identify risk factors of lymph node metastasis (LNM) for T2 rectal cancer. METHODS: From a prospectively maintained single-institution database, we identified 346 consecutive pT2 rectal cancers treated with total mesorectal excision from 1998 to 2009. Univariate and multivariate analyses were performed to identify risk factors associated with overall and intermediate/apical LNM. The incidence of overall and intermediate/apical LNM was analyzed by tree analysis. RESULTS: Age, tumor location, pathological features, and depth of invasion were independent predictors for overall LNM. Tumor location, pathological features, and depth of invasion were independent predictors for intermediate/apical LNM. Tree analysis showed that the incidence of LNM was 7.7% for upper rectal cancer with favorable pathological features, and 3.4% for mid/lower rectal cancer without other identified risk factors. The incidence of intermediate/apical LNM was 5.7% for superficial T2 rectal cancer with favorable pathological features, and 3.1% for deep T2 rectal cancer locating in upper rectum with favorable pathological features. CONCLUSIONS: Depth of invasion is an independent predictor for LNM in T2 rectal cancer. Using tree analysis, we identified a subset of patients with low risk of LNM who may be candidates of local excision. PMID- 20922578 TI - A robust model to describe the differentiation of T-helper cells. AB - There is a wealth of information regarding the differentiation of T-helper cells. Nevertheless, there is no general agreement on the topology and dynamical properties of the molecular network controlling the differentiation of these cells. This paper presents a continuous dynamical system to model the signaling network that controls the differentiation process of T-helper cells. The model is able to represent the differentiation from the precursor Th0 cell to any of the four effectors types (Th1, Th2, Th17, and Treg), as well as the phenotype of single null mutants. We present the first sensitivity analysis of the equations defining the Th model, showing that the qualitative dynamical behavior of the model is very robust against changes in three out of four tested parameters. The robustness of the model is in agreement with our claim that the qualitative behavior of the system is to a large extent independent of the methodological framework used for modeling. PMID- 20922579 TI - Colonic perforation following polypectomy of a gastrointestinal follicular lymphoma masquerading as a colon polyp. AB - INTRODUCTION: The gastrointestinal (GI) tract is the predominant site for primary extranodal non-Hodgkin lymphomas (NHL), accounting for 5-10% of all extranodal disease. CASE: A 74-year-old man underwent colonoscopy for a positive fecal occult blood test. Colonoscopy revealed a 3.5-cm polyp in the descending colon and was removed by snare cautery polypectomy. Post-polypectomy site showed a 0.3 0.5-cm mucosal defect. Five endoclips were applied to close the mucosal defect. The patient remained stable during subsequent intensive monitoring and never required surgical intervention. Pathology of the polyp revealed follicular lymphoma (FL) involving the lamina propria of the mucosa with extension into the submucosa. The patient had no systemic symptoms, and staging for NHL with contrast computerized tomography of the chest, abdomen, and pelvis revealed no evidence suggestive of lymphoma. DISCUSSION: Approximately 6-20% of all primary GI-NHL are in the colon. The frequency of GI-FL accounts for 1-3.6% of all GI NHL. After a search of the current literature, there have been no cases of a follicular lymphoma presenting solely as an isolated colon polyp. Likewise, bowel perforation due to polypectomy of such polyps has never been cited. Retrospectively, the diagnosis and extent of the polyp could have been established using endoscopic end-to-end forceps biopsy and/or endoscopic ultrasound with a radial scanning catheter probe and fine-needle aspiration of the lesion. Such a diagnosis could have changed the strategy for endoscopic removal of the polyp. Our case is interesting because it is the first report of a follicular lymphoma presenting as a single isolated colon polyp involving all layers of the colonic mucosa. PMID- 20922580 TI - Clinicopathological significance of macrophage migration inhibitory factor and its relation with p53 in gastric cancer. AB - AIM: Based on previous investigations, the progress of gastritis may lead to gastric carcinomas. In some epithelial tumors, macrophage migration inhibitory factor (MIF), which is an inflammatory cytokine may inactivate p53 and play a role in tumorigenesis process. We decided to evaluate clinicopathological significance of MIF expression and the relation between p53 and MIF expressions in gastric adenocarcinomas. METHODS: Seventy-three consecutive cases of gastric adenocarcinomas, the tissue samples of which were available, were included in this study. Tissue sections were stained for MIF and p53 expression by immunohistochemistry and the expression was defined as positive (for more than 10%) and negative (for less than 10%) groups. Location of the tumor, histological subtypes, and grade of the tumor were determined by using routine H&E staining. Distant metastasis, lymph node involvement, and consequently the stage of tumor were specified. The patients' age and gender were obtained from their medical records. The relationship between expression of MIF and these variables was determined. RESULTS: Overexpression of MIF was observed in the cytoplasm of cancer cells in 46.6% (34/73) of cases and nuclear immunostaining of p53 was observed in 37% (27/73) of cases. Expression of MIF was significantly correlated with the location of tumor, but this expression has no statistically significant correlation with variables including: age, gender histological subtypes, distant metastasis, and lymph node involvement, stage and grade of the tumor, and p53 tumor suppressor gene expression. CONCLUSIONS: Our study suggests that MIF in gastric adenocarcinomas versus many other epithelial tumors cannot have a prominent role in tumor progress and inactivation of p53 tumor suppressor gene. PMID- 20922581 TI - Response to nilotinib as a first-line treatment for metastatic gastrointestinal stromal tumors. AB - PURPOSE: Effective and safe treatment options are needed for patients with advanced gastrointestinal stromal tumors (GIST) who are initially unresponsive to the tyrosine kinase inhibitor (TKI) imatinib, or develop acquired secondary imatinib resistance. CASE REPORT: We report a 39-year-old woman with primary rectal GIST who underwent abdominoperineal resection in December 2004, achieving R0 margins. In August 2009, the patient was referred to our clinic, and we detected metastatic GIST of the liver, as well as peritoneal and gluteal lesions. The patient was treated with imatinib 400 mg/day for 3 weeks and subsequently switched to nilotinib (400 mg bid) after enrolling in a clinical trial. After 8 weeks of nilotinib treatment, a response was observed in the liver metastasis, and metabolic activity was no longer detected. Also, the gluteal and peritoneal lesions were no longer detected. After 16 weeks of nilotinib treatment, a cystic mass was identified in the liver metastasis. Tumor rupture was considered a strong possibility, prompting resection of the liver metastasis. Greater than 80% of the resected tumor mass was necrotic, consistent with the lack of metabolism observed 8 weeks prior. The patient resumed nilotinib treatment (400 mg bid) shortly after surgery and continues treatment while remaining disease-free for more than 9 months with normal liver function. CONCLUSION: This is the first report demonstrating the feasibility of nilotinib (400 mg bid) for the first-line treatment of metastatic GIST. Furthermore, these results underscore that responses to TKIs may be underestimated by Response Evaluation Criteria in Solid Tumors. PMID- 20922582 TI - Measures of glycemic variability and links with psychological functioning. AB - The goal of this article is to review the recent literature on measures of glycemic variability, links between glycemic variability and psychological functioning, and methods for examining these links. A number of commonly used measures of glycemic variability are reviewed and compared, including recently proposed methods. Frequently used measures of glycemic variability are also discussed in the context of research that uses continuous glucose monitoring for the collection of blood glucose data. The results of previous studies that have examined the link between psychological functioning and glycemic variability within relatively short-term time frames are reviewed. Methods for examining glycemic variability and its link with psychological functioning are discussed so that important research questions can be addressed to aid in understanding the effect of changes in psychological functioning on glycemic variability and vice versa in future research. PMID- 20922583 TI - 100 most cited articles in orthopaedic surgery. AB - BACKGROUND: Citation analysis reflects the recognition a work has received in the scientific community by its peers, and is a common method to determine 'classic' works in medical specialties. QUESTIONS/PURPOSES: We determined which published articles in orthopaedic journals have been most cited by other authors by ranking the 100 top-cited works. By analyzing characteristics of these articles, we intended to determine what qualities make an orthopaedic article important to the specialty. Finally, we determined if there was a change in level of evidence of studies on this list with time. METHODS: Science Citation Index Expanded was searched for citations to articles published in any of the 49 journals in the subject category "ORTHOPEDICS." Each of the 49 journals was searched separately using the "cited reference search" to determine the 100 most often cited articles. Each article was reviewed for basic information including year of publication, country of origin, source journal of the article, article type, and level of evidence. We categorized the journal article by field of research where possible. RESULTS: The number of citations ranged from 1748 to 353. The 100 most often cited articles in orthopaedic surgery were published in 11 of the 49 journals, spanning from general to more specific subspecialty journals. The majority of the papers (76) were clinical, with the remaining representing some type of basic science research. The most common level of evidence was IV (42 of the 76 studies). Of the 76 clinical articles, 27 introduced or tested classification systems or outcome measurement tools. CONCLUSIONS: Authors aiming to write a highly cited article in an orthopaedic surgery journal will be favored by language of publication, source journal, country of origin, and introduction of a classification scheme or outcome tool. PMID- 20922584 TI - Is intraoperative CT of posterior cervical spine instrumentation cost-effective and does it reduce complications? AB - BACKGROUND: Symptomatic multilevel cervical myelopathy is often addressed using posterior decompression using two-dimensional fluoroscopy. Intraoperative three dimensional fluoroscopy provides more accurate information on the position of instrumentation to prevent screw-related complications. QUESTIONS/PURPOSES: We documented the incidence of hardware-related complications and evaluate cost effectiveness when using intraoperative three-dimensional fluoroscopy (ISO-C CT) in posterior cervical spine surgery. METHODS: Records from 87 patients who underwent posterior cervical decompression and instrumented fusion for multilevel cervical spondylosis with myelopathy were retrospectively reviewed. Patients in whom a lateral mass, pars, or pedicle screw was removed or revised based on intraoperative ISO-C CT was recorded. Cost analysis was performed using 2008 Medicare reimbursements and was compared against cost estimates for ISO-C CT. RESULTS: Seven patients (8%) had screws changed based on the results of the three dimensional fluoroscopy: 0.5% of lateral mass screws, 3.1% of thoracic pedicle screws, and 15% of C2 pars screws. No patients who had evaluation of hardware with the ISO-C CT required a return to surgery for complications secondary to hardware failure, malposition, or cutout. CONCLUSIONS: Cost savings are achieved if use of intraoperative ISO-C CT prevents eight patients from requiring a return to the operating room. If every malpositioned screw has the potential to be symptomatic, then 240 patients must have screws placed to be cost-effective. ISO C CT can safely replace postoperative CT as the standard of care in patients undergoing posterior cervical spinal fusion. LEVEL OF EVIDENCE: Level III, economic and decision analyses. See Guidelines for Authors for a complete description of levels of evidence. PMID- 20922585 TI - Large acetabular defects can be managed with cementless revision components. AB - BACKGROUND: Optimal techniques for acetabular revision in the setting of major pelvic osteolysis have not been established. Bilobed components, structural grafts, and reinforcement cages have demonstrated 10-24% midterm failure rates. While cementless hemispherical components have been utilized to treat large acetabular defects, most reports have not focused specifically on patients with extensive deficiencies. QUESTIONS/PURPOSES: We report midterm clinical scores, component revisions, and complications following focal bone grafting and cementless acetabular revision in cases with major periacetabular osteolysis. METHODS: We identified 30 patients (32 hips) who underwent cementless acetabular revision to treat massive acetabular bone loss at an average followup of 53 months. We excluded three patients lost to followup and two patients who died prior to minimum 24 month followup. Harris Hip Scores were assessed before and after surgery. Postoperative radiographs were evaluated for graft incorporation and component migration. Component revision and component migration are reported as failures. RESULTS: Mean Harris Hip Score improved from 52.5 (range, 17.7-90.7) to 87.3 (range, 25.3-100) points. Three hips (9%) were revised for aseptic loosening. Three components (10.7%) demonstrated radiographic migration, but were not revised. Complete graft incorporation was seen in 17 cases (68%). There were five major complications (14%). CONCLUSIONS: Cementless acetabular fixation and bone grafting result in clinical scores and survivorship comparable to other options at midterm followup, with potential for biological fixation. LEVEL OF EVIDENCE: Level IV, clinical research study. See the Guidelines for Authors for a complete description of levels of evidence. PMID- 20922586 TI - Ringer's lactate is compatible with saline-adenine-glucose-mannitol preserved packed red blood cells for rapid transfusion. AB - PURPOSE: Guidelines state that Ringer's lactate (RL) should not be co administered with packed red blood cells (PRBC) due to a potential risk of clotting. The purpose of this study was to determine whether RL causes clotting in PRBC with the currently used preservative, saline-adenine-glucose-mannitol (SAGM). METHODS: Phase 1: Samples from 12 units of SAGM-PRBC were diluted from 0 97.5% with RL and normal saline (NS), incubated for 30 min, and passed through 40 MUm filters. Additional samples were frozen and batch analyzed using an enzyme linked immunosorbent assay (ELISA) to measure prothrombin activation fragment 1 + 2 (F1 + 2), indicative of thrombin generation. Packed red blood cells were also diluted, flushed with crystalloid using a rapid transfusion model, and filtered. Phase 2: Eight further units were serially diluted with RL and incubated for 30, 60, 120, 180, and 240 min. Fresh samples were analyzed by filtration and ELISA. RESULTS: Phase 1: No clotting was seen during filtration or using the transfusion model with NS or RL. The F1 + 2 ranged from 2.28 to 154.37 pmol.L-1 in NS dilutions and from 2.80 to 1675.93 pmol.L-1 in RL dilutions, indicating coagulation in some samples. Phase 2: No clotting was observed within 60 min by filtration or ELISA. However, 4 of the 8 units showed clots in the filters of some dilutions between 120 and 240 min. CONCLUSIONS: No clotting was detected at any dilution of RL with SAGM- preserved PRBC within 60 min, but clotting was detected with extended incubation. The results indicate RL can be safely co administered with PRBC during rapid transfusion (< 60 min). PMID- 20922587 TI - The prevalence of undiagnosed diabetes in non-cardiac surgery patients, an observational study. AB - PURPOSE: Given that preoperative hyperglycemia is associated with poor outcomes and many non-diabetic patients have high plasma glucose (PG) levels, the purpose of our study was to estimate the prevalence of undiagnosed diabetes among non cardiac surgery patients and to identify predictors of hyperglycemia in non diabetics. METHODS: We included all non-cardiac surgery patients with complete records in the Clinical Database of the Anesthesiology Institute at the Cleveland Clinic during January 2007 to April 2009, and we estimated the prevalence of undiagnosed diabetes and impaired fasting glucose (IFG) among the non-diabetic patients. The mean glucose levels for known diabetics and undiagnosed diabetics were compared using two-tailed Student's t tests, and we assessed the association between PG levels and demographic variables within the non-diabetics. RESULTS: Of the 39,434 patients analyzed, 5,511 (14%) were known diabetics. Of the 33,923 known non-diabetics, 3,426 (10 %) were undiagnosed diabetics and another 3,549 (11%) had IFG. Thus, 6,975 patients (21%) of the non-diabetic patients presented with abnormally high glucose. Previously undiagnosed diabetics had higher preoperative glucose levels compared with known diabetics, with a mean +/- standard deviation (SD) of 161 +/- 48 vs 146 +/- 67 mg.dL-1 (8.9 +/- 2.7 vs 8.1 +/- 3.7 mmoL.L-1), respectively. The difference remained highly significant after adjusting for body mass index, age, sex, and American Society of Anesthesiologists (ASA) physical status (P < 0.001). Among non-diabetics, older age, obesity, male sex, and a higher ASA physical status were collectively significant predictors of hyperglycemia, with a c-statistic (95% confidence interval) of 0.67 (0.66-0.68). CONCLUSION: A significant proportion of non cardiac surgery patients have previously undiagnosed diabetes and pre-diabetes. Previously undiagnosed patients have higher fasting glucose levels compared with diabetic patients. Further studies should be conducted to identify the implications of these findings on patient outcomes. PMID- 20922597 TI - [Retirement of Professor Dr. med. Ulrich Modder]. PMID- 20922598 TI - [On the 100th birthday of Lothar Diethelms]. PMID- 20922599 TI - [In memory of Prof. Dr. Helga Schmidt]. PMID- 20922603 TI - [Minimum equipment of a medical university professor in the health care field]. PMID- 20922604 TI - Targeted depiction of the fetal corpus callosum with 3D-ultrasound. PMID- 20922605 TI - The genetic diagnostics law--help or confusion in prenatal diagnostics? PMID- 20922606 TI - Sonographic diagnosis of cerebral malformations in infancy. Part 1: Chiari and Dandy-Walker malformations. PMID- 20922607 TI - New trends in elasticity imaging. PMID- 20922611 TI - [Certification guideline of the Austrian Physician Chamber in the home stretch]. PMID- 20922616 TI - [Combined diagnosis and therapy]. PMID- 20922617 TI - [Ultrasonography]. PMID- 20922619 TI - Cardiac surgery in Germany during 2009. A report on behalf of the German Society for Thoracic and Cardiovascular Surgery. AB - All cardiac surgical procedures performed in 80 German cardiac surgical units throughout the year 2009 are presented in this report, based on a voluntary registry which is organized by the German Society for Thoracic and Cardiovascular Surgery. In 2009 a total of 96 129 cardiac surgical procedures (excluding ICD and pacemaker procedures) were collected in this registry. More than 11.8 % of the patients were older than 80 years compared to 10.3 % in 2008. Hospital mortality in 45 171 isolated CABG procedures (13.1 % off-pump) was 2.8 %. In 23 556 isolated valve procedures (including 2216 catheter-based procedures) a mortality of 4.7 % was observed. This voluntary registry of the German Society for Thoracic and Cardiovascular Surgery continues to be an important tool for quality control and illustrates the development of cardiac surgery in Germany. PMID- 20922620 TI - Mild-to-moderate COPD as a risk factor for increased 30-day mortality in cardiac surgery. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is still a serious comorbidity in surgical procedures. We assessed the impact of mild to moderate COPD in a modern cardiac surgery unit. METHODS: An age-, gender- and operation matched cohort analysis of 242 patients treated between 01/2006 and 12/2008 was performed. COPD was defined as a FEV1 < 80 % and a FEV1/FVC ratio < 0.7 in preoperative spirometry. Primary end point was 30-day mortality. RESULTS: Preoperative beta-agonist treatment of COPD patients was noted for 43 % of patients and not in the control group. After comparable surgery, postoperative respiratory failure was more frequent in COPD patients (10.4 % vs. 2.5 %, P = 0.02), whereas median ventilation time (12 h) and rate of reintubation (2.5 % vs. 3.5 %) did not significantly differ between both groups. Intensive care and hospital stay were significantly longer in the COPD group ( P = 0.02 and P = 0.04), and 30-day mortality was significantly higher in COPD patients (0.8 % vs. 6.1 %, P = 0.03). CONCLUSIONS: COPD increases 30-day mortality, postoperative pulmonary complications, ICU stay and hospital stay. Proper identification and therapy may help to improve outcome in this high-risk population. PMID- 20922621 TI - Prognostic value of daily cardiac surgery score (CASUS) and its derivatives in cardiac surgery patients. AB - BACKGROUND: We aimed to validate the usefulness of CASUS derivatives for cardiac surgery patients and their reliability for daily decision making. METHODS: We included, prospectively, the data of all adult cardiac surgery patients who had an ICU stay of at least 12 hours between 20 January 2003 and 14 October 2005 in the Department of Cardiothoracic Surgery of the University of Cologne, Germany. Data were collected until ICU discharge and included initial, maximum, mean, and total CASUS values. delta CASUS (difference from initial value) was calculated at 48 and 96 hours postoperatively. The predictive efficacy of the derivatives was tested with calibration and discrimination statistics. RESULTS: 2372 patients were included with a mean age of 66.2 +/- 11.2 years. ICU mortality was 3.6 % (n =85). Mean ICU stay was 3.0 +/- 6.1 days. The discrimination was very good for all derivatives (area under the curve ranged between 0.988 and 0.926). The calibration was also good except for the total CASUS, which showed a significant difference between the expected and observed mortality. Increased delta CASUS at 48 hours (1038 patients) and 96 hours (435 patients) correlated with an increase in mortality (23.1 % and 42.9 %, respectively), and conversely a decreased mortality rate was observed with decreasing values (1.9 % and 3.8 %, respectively). CONCLUSION: CASUS derivatives including delta CASUS have a good prognostic value for cardiac surgery patients with regard to the prediction of mortality and survival during ICU stay, with the exception of total CASUS which was not informative. PMID- 20922622 TI - Early reintubation after cardiac operations: impact of nasal continuous positive airway pressure (nCPAP) and noninvasive positive pressure ventilation (NPPV). AB - BACKGROUND: Due to an increasing number of comorbidities there is still a significant incidence of respiratory failure after primary postoperative extubation in patients who undergo cardiosurgery. We wanted to study whether nCPAP could improve pulmonary oxygen transfer and avoid the necessity for reintubation after cardiac surgery. Additionally, we compared this protocol to noninvasive positive pressure ventilation (NPPV). PATIENTS AND METHODS: Over a period of 3 years we analyzed all patients who were extubated within 12 hours after cardiac surgery, and in whom pulmonary oxygen transfer (PaO2/FIO2) deteriorated without hypercapnia so that all these patients met predefined criteria for reintubation. There were three groups of patients: A = patients required immediate reintubation (n = 125); B = patients had nCPAP with intermittent mask CPAP (n = 264); and C = patients had NPPV (n = 36). RESULTS: 25.8 % of patients in Group B and 22.2 % of patients in Group C were also intubated after a period of CPAP or NPPV. All other patients of Groups B and C could be weaned from these devices (B: 33.4 +/- 5.8 hours, C: 26.2 +/- 4.2 h; P < 0.05) and were well oxygenated using a face mask at ambient pressures (PaO2/FIO2: B: 136 +/- 12, C: 141 +/- 12). In Group A, we found a higher mortality (8.8 %) than in Group B (4.2 %) and Group C (5.6 %). The ICU stay and in-hospital stay were significantly prolonged in Group A. The incidence of pulmonary infections (A: 24 %, B: 10.6 %, C: 13.8 %; P < 0.05) and the need for catecholamines were significantly increased in Group A, whereas nCPAP patients suffered significantly more often from impaired sternal wound healing (A: 4.8 %, B: 8.3 %; P < 0.05). CONCLUSIONS: We conclude that reintubation after cardiac operations should be avoided since nCPAP and NPPV are safe and effectively improve arterial oxygenation in the majority of patients with nonhypercapnic oxygenation failure. However, it is of great importance to pay special care to sternal wound complications in these patients. PMID- 20922623 TI - Female gender does not increase perioperative risk in coronary bypass surgery. AB - INTRODUCTION: Female gender has been identified as an independent risk factor for perioperative mortality in several risk scores for cardiac surgery. Since no explanation has been given for this, this study aimed to evaluate potential differences in the distribution of other risk factors between the genders. PATIENTS AND METHODS: 10 714 consecutive coronary bypass patients were analyzed retrospectively. The distribution of the risk factors as used in the EuroSCORE was evaluated. Diabetes mellitus was added to the analysis as an additional risk factor. Patients aged between 60 and 70 years without any additional risk factors were directly compared in a subgroup analysis. Statistical analysis was done using the T-test or chi-square test where appropriate. RESULTS: Female patients were significantly older compared to male ones (69.1 +/- 8.5 vs. 65.4 +/- 4 years, P < 0.05). The distribution of the analyzed risk factors did not differ except for diabetes mellitus: female patients were more likely to present with diabetes (42 % vs. 29 %, P < 0.05) and in diabetic patients, the incidence of insulin dependency was higher in female patients (50 % vs. 33 %, P < 0.05). Overall perioperative mortality was higher in female patients (2.7 % vs. 1.8 %, P < 0.05). This difference increased when diabetes was present (3.9 % vs. 1.8 %, P < 0.05) and was even higher in insulin-dependent patients (4.9 % vs. 1.9 %, P < 0.05). However, when adjusting for age and diabetes, the differences were reduced. This was most evident when subgroups of age-adjusted patients without any additional risk factors were analyzed: no gender-specific difference in perioperative mortality was observed. CONCLUSIONS: Female gender itself did not present as an independent risk factor. The presence of diabetes mellitus increased the risk in female patients significantly more than in male patients. The higher prevalence of diabetes in female patients in combination with the older age at presentation might result in the higher overall mortality observed in female patients compared to men. PMID- 20922624 TI - "Anaortic" off-pump coronary artery bypass grafting significantly reduces neurological complications compared to off-pump and conventional on-pump surgery with aortic manipulation. AB - OBJECTIVE: Most studies comparing off-pump coronary artery bypass grafting (OPCAB) with conventional on-pump coronary artery bypass grafting (ONCAB) include patients with aortic manipulation in the OPCAB group. Performing OPCAB without aortic manipulation, i.e., "anaortic" OPCAB (anOPCAB), may improve neurological outcome. METHODS: We reviewed the perioperative data of all isolated CABG patients at two metropolitan hospitals for the period from January 2002 to December 2007. Multiple logistic regression analysis was performed to determine whether the type of procedure was an independent predictor of adverse neurological outcome. RESULTS: Out of a total of 3699 consecutive patients, 1346 were anOPCAB, 600 OPCAB and 1753 ONCAB cases. Neurological complications occurred in 0.9 % of all patients. Compared to the anOPCAB group, there was a statistically significant higher odds for neurological complications in the OPCAB group [odds ratio (OR) 7.01, 95 % confidence interval (CI) 1.4-35.0, P = 0.0175] and in the ONCAB group (OR 12.33, 95 % CI 2.9-52.2, P = 0.0007). CONCLUSIONS: In this series "anaortic" OPCAB surgery significantly decreases the risk of neurological complications compared to both ONCAB and OPCAB with aortic manipulation. If possible, we advocate avoiding aortic manipulation in OPCAB surgery. PMID- 20922625 TI - Long-term outcomes following repair or replacement in degenerative mitral valve disease. AB - BACKGROUND: We studied whether mitral valvuloplasty (MVP) was superior to mitral valve replacement (MVR) in patients with degenerative mitral regurgitation (MR), and analyzed the independent risk factors for survival and reoperation. METHODS: 326 patients with degenerative MR underwent MVP (n = 241), mitral valve replacement (MVR) (n = 78) or emergent MVR due to failure of repair (EMVR). Clinical data were analyzed retrospectively. RESULTS: Thirty-day mortality was lower after MVP (2.5 %) compared to MVR (9.0 %) ( P < 0.05). Late survival at 1 and 5 years in the MVP group was 94.4 % and 84.3 % versus 80.4 % and 64.6 % in the MVR group ( P < 0.05), respectively. After adjusting the baseline characteristics by the propensity score method, a significant survival benefit was found for patients who underwent MVP. Multivariable analysis showed that MVR was an independent predictor of thirty-day mortality and survival. There was no significant difference in thirty-day mortality and survival between the EMVR and MVR groups. The need for reoperation was not significantly different between the MVP and MVR groups. In the MVP group, the risk factors for survival and reoperation were identified. CONCLUSIONS: MVP is superior to MVR for the treatment of degenerative MR despite the impact of repair failure. Age less than 60 years, ring size to body surface area greater than 19.0, absence of a prosthetic ring and residual MR at the end of surgery (>= 1/4) reduce the durability of MVP. PMID- 20922626 TI - 18-fluorine fluorodeoxyglucose positron emission tomography with computerized tomography versus computerized tomography alone for the management of solitary lung nodules with diameters inferior to 1.5 cm. AB - OBJECTIVE: Aim of the study was to establish a noninvasive method for the preoperative characterisation of a pulmonary nodule when biopsy of the small mass is impossible. METHODS: From 1 January 2006 to 31 December 2008, we observed 124 asymptomatic patients with a noncalcified single lung nodule highlighted by computerised tomography (CT) of the thorax. Patients were divided into 2 groups: Group A consisted of 57 patients with lesion diameters between 0.5 cm and 0.99 cm; Group B consisted of 67 patients with lesion diameters between 1.0 cm and 1.5 cm. Fibreoptic bronchoscopy was negative for endobronchial neoformation in all patients. The topographic distribution of the lesions advised against CT-guided transthoracic needle biopsy or video-assisted thoracoscopy. All patients had preoperative 18-fluorine fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) associated with CT of the thorax, which was compared with CT for evaluation of the mass. RESULTS: Postoperative histological diagnosis revealed 54 primary lung cancers, 47 lung metastases and 23 benign lesions. In Group A the sensitivity of 18F-FDG PET/CT and CT was 95 % and 73 % and the specificity was 72 % and 64 %, respectively ( P = 0.000001 for 18F-FDG PET/CT; P = 0.000177 for CT). In Group B the sensitivity of 18F-FDG PET/CT and CT was 95 % and 97 %, and the specificity was 80 % and 87 %, respectively ( P = 0.000001). CONCLUSIONS: Our study shows that 18F-FDG PET/CT improves the identification and characterisation of potentially malignant pulmonary nodules with a diameter < 1 cm. This technique could be a valid alternative to a surgical approach, currently the main method to investigate indeterminate lung nodules. PMID- 20922627 TI - A novel technique of tracheal reconstruction with autologous bronchial pedicle flap. AB - We describe a technique used in 2 patients for resection of a bronchogenic carcinoma arising from the right main bronchus and extending along the lateral wall of the lower trachea without carinal invasion. A right pneumonectomy was performed in the first case, and lower and middle lobes were preserved in the second case after extended upper lobe resection. A flap was mobilized from the non-involved left lateral wall of the right main bronchus, which was left attached to the carina. This was used to close the defect in the lower trachea. An autologous bronchial pedicle flap provides reliable material to repair and reconstruct a massive central airway defect. PMID- 20922628 TI - Thoracoscopic treatment of recurrent pneumothorax in a pregnant woman: a case of ectopic deciduosis. AB - We report here on a case of recurrent pneumothorax during pregnancy, which was successfully treated with thoracoscopic surgery. This report describes the intraoperative and histopathological findings of diaphragmatic and pulmonary ectopic deciduosis. Our case highlights the need for all surgeons to explore the diaphragm when performing surgery to treat pneumothorax in a woman, even if she is pregnant. PMID- 20922629 TI - Pacemaker-associated thrombotic occlusion of the inferior vena cava causing liver failure. AB - Pacemaker implantation using endocardial leads can give rise to thrombotic venous occlusion. We report the case of a 23-year-old male with transposition of the great arteries, who had previously undergone a Senning repair at the age of one year. A sick sinus syndrome required pacemaker implantation with subsequent multiple lead revisions. Following the implantation of the last lead, the patient developed complete occlusion of the inferior vena cava (IVC) with stenosis of the superior vena cava (SVC) with pacemaker leads in both lesions. Liver failure, ascites and esophageal varices developed. Thrombolytic treatment was ineffective; finally the patient was listed for liver transplantation. We explanted the lead embedding the thrombosis, together with some lead remnants. The stenosis of the SVC and the occlusion of the IVC were dilatated and stabilized with four stents. Over a follow-up period of 4 months, NYHA class improved from NYHA III to NYHA I II, the hepatic function showed complete remission, and a liver transplantation was not necessary. PMID- 20922630 TI - Successful treatment of acute fulminant myocarditis with double sets of extracorporeal membrane oxygenation: report of a case and review of the literature. AB - We report a case of acute fulminant myocarditis (AFM) with cardiogenic shock and hemodynamic collapse. We performed emergency extracorporeal life support (ECLS) with right femoral venoarterial cannulation by Seldinger procedure. Because of poor systemic perfusion over the upper trunk with low O2 saturation due to inadequate venous return, a second ECLS was applied 16 hours after the first ECLS with right subclavian venoarterial cannulation by cut-down procedure. Total flow of both ECLS sets can achieve a flow of up to 6-8 l/min without massive destruction of blood cells. Combined with supportive intravenous immunoglobulin (IVIG) treatment, cardiac function recovered well and the ECLS sets were removed one-by-one. Follow-up studies one year after admission showed good cardiac systolic function and no sequelae of AFM. PMID- 20922631 TI - Cavitating lymph node metastasis demonstrated by endobronchial ultrasound. AB - Cavitation of primary non-small cell lung carcinoma (NSCLC) occurs in a small number of patients. We report a case of cavitation of lymph node metastases in NSCLC. CT chest showed central low attenuation of the subcarinal lymph node, suggestive of necrosis, and endobronchial ultrasound (EBUS) imaging demonstrated two cystic spaces within the lymph node. Transbronchial needle aspiration of the cystic space confirmed the presence of metastatic NSCLC. Cystic necrosis was only demonstrable by EBUS. The incidence of such findings is unknown, however with the increasing use of EBUS for evaluation of the mediastinum such images may be more commonly encountered in the future. PMID- 20922633 TI - Cardiac defect with diaphragmatic hernia and left lung agenesis--heart disease and other anomalies. AB - This report describes a rare case of left pulmonary agenesis associated with congenital diaphragmatic hernia and congenital heart disease in a 2-year-old child with pulmonary hypertension. We performed direct radical correction of the congenital heart defect. The postoperative course was challenging but without major complications. PMID- 20922632 TI - Pulmonary Palacos embolism: a case report. AB - Instrumentation with cement-augmented pedicle screws has expanded the therapeutic spectrum. This technique is useful for the palliation of bone metastases and in generalized osteoporosis. Serious complications such as pulmonary embolism have been described following percutaneous vertebroplasty, a frequently used technique. We report the case of a 55-year-old patient with a large central Palacos embolism of the right pulmonary artery after corporectomy of the lumbar vertebrae 3 and 4 and reconstruction using autologous pelvic bone. The large Palacos embolism was removed successfully from the right pulmonary artery with extracorporeal circulation. PMID- 20922635 TI - [Lung transplantation for pulmonary emphysema--who, when, how?]. AB - End stage pulmonary emphysema is the most common indication for lung transplantation worldwide. The shortness of donor organs and the better natural prognosis compared to other diseases leading to transplantation such as pulmonary fibrosis and cystic fibrosis demands careful patient selection.Lung transplantation is considered in patients with declining lung function after receiving all conservative treatment options including smoking cessation and rehabilitation programmes. Preoperative evaluation using consensus criteria needs to be performed by a multidisciplinary team in specialized centres. Assessment of co-morbidities is crucial, as they may significantly increase transplant-related mortality. The largest survival advantage from lung transplantation has been shown for the subgroup of patients below 60 years of age presenting with end stage obstructive lung disease (FEV1 < 20% predicted) and respiratory failure. Similarly, high risk patients with secondary pulmonary hypertension or cachexia (BMI < 20) will likely benefit from transplantation.The 5-year-survival rate averages 60 percent, with superior outcome following double versus single lung transplantation. A clear survival benefit can only be achieved in a subgroup of patients, whereas the impact on quality of life seems to be even more important in patients suffering from chronic obstructive pulmonary disease. PMID- 20922636 TI - [Epidemiology of severe Clostridium difficile infections in Hesse, Germany in 2008-2009]. AB - BACKGROUND AND OBJECTIVE: Clostridium difficile is a major cause of health care associated infections in industrialized countries. During the past decade, the incidence and clinical severity of C. difficile infections (CDI) have increased markedly. This increase has been associated with the emergence of a possibly highly virulent strain, the C. difficile PCR ribotype 027. We investigated the emergence of severe CDI and the associated PCR ribotypes in Hesse, Germany. PATIENTS AND METHODS: We conducted a retrospective analysis of clinical information and ribotyping results of all cases of severe CDI that were reported to the Hesse State Health Office or sent to our microbiologic diagnostic laboratory for detection and molecular typing of C. difficile in severe cases of CDI from 01/2008 to 12/2009. The data of a of 88 patients and 50 isolates were analysed. RESULTS: 89% of patients were at least 65 years old; the mean age was 77 years. The clinical outcome was known in 85 patients. 27% had died within 30 days of the diagnosis of CDI. Ribotyping results were available in 39 and 11 patients from 2008 and 2009, respectively. The isolates were assigned to nine different ribotypes. RT 027 and RT 001 were the most frequent ribotypes with 31 and 10 isolates, respectively. All other ribotypes were isolated once or twice. CONCLUSION: Our data indicate that C. difficile RT 027 and RT 001 are prevalent in Hesse and are often associated with severe or notifiable CDI. The high prevalence of RT 027 among the reported CDI cases does not indicate a generally high prevalence of the latter strain in Hesse, because detection of RT 027 was a case definition criterion, a fact that may cause a bias in the reported data. Further investigation would help to improve our understanding of the molecular epidemiology of severe CDI and to improve the prevention strategies. PMID- 20922637 TI - [Urinary bladder tuberculosis and Bacillus Calmette-Guerin instillation: reduced efficacy of bisoprolol in hypertension]. AB - HISTORY AND ADMISSION FINDINGS: A 71-year-old patient with a superficial carcinoma of the urinary bladder and high risk of recurrence was treated with intravesical instillation of Bacillus Calmette-Guerin (BCG) after transurethral resection. As a complication of the catheterization during BCG-instillation therapy the patient suffered from tuberculosis. The patient received a tuberculosis triple-therapy including rifampicin 600 mg once daily, isoniazid 300 mg once daily and ethambutol 400 mg thrice daily. The existing arterial hypertension had successfully been controlled by 3.75 mg bisoprolol medication once daily for the last 15 years. An increase of blood pressure and cardiac arrhythmia were seen after combining the beta1-receptor blocker treatment with the triple-therapy. INVESTIGATIONS AND DIAGNOSIS: The blood pressure was 160/90 mm Hg. The heart rate reflected a value of 98 beats per minute. In the resting ECG monotopic ventricular extrasystoles could be diagnosed. TREATMENT AND COURSE: The dosage of bisoprolol was changed to 3.75 mg in the morning and additional 1.875 mg in the evening. Due to this increase of dosage the blood pressure could be controlled sufficiently. CONCLUSION: Rifampicin is one of the best known potent enzyme inducing drugs. It strongly induces the expression of cytochrome P450 3A4 in the liver. The enzyme induction enhance the hepatic bisoprolol metabolism, hence the metabolic clearance of the drug increased. The maximal plasma level of bisoprolol decrease and in our use the arterial hypertension could not be treated sufficiently. It is well known that half the dose of bisoprolol undergoes oxidative metabolism in the liver and the rest eliminated unchanged in the kidney. A dosage adjustment of bisoprolol is necessary if the clinical status of the patient requires treatment with the antituberculosis drug rifampicin. PMID- 20922638 TI - [74-year-old patient with shortness of breath: a bullet in the heart? V. a. thrombus in early myocardial infarct]. PMID- 20922640 TI - [Nutrition in acute pancreatitis]. AB - Nutritional concepts in acute pancreatitis have changed. Early enteral nutrition widely replaced parenteral nutrition alone in severe acute pancreatitis. First trials suggest early oral refeeding as nutritional treatment of choice in patients with mild acute pancreatitis. In this review, we summarise the current knowledge on nutrition in acute pancreatitis and discuss future developments. PMID- 20922639 TI - [Combined liver-kidney and kidney after liver transplantation: indications and experiences from a nephrological perspective at a single center]. AB - Combined liver-kidney transplantations (CLKT) and kidney after liver transplantations (KALT) are established treatments for patients with end-stage hepatic and renal disease and the number of transplantations has continuously increased over the past few years. The most frequent indications for CLKT in adults are polycystic kidney disease with severe liver involvement and liver cirrhosis of different origins with concomitant chronic kidney failure due to chronic glomerulonephritis or diabetic nephropathy. In children, CLKT is most frequently required due to primary oxalosis type I. At present the main indication for KALT still is calcineurin inhibitor-induced chronic nephrotoxicity, emphasizing the need for a nephron-sparing long-term immunosuppression in liver transplant recipients. Compared to KALT, the indications for CLKT are not as well defined and the decision must therefore be made on a case-by-case basis by a multidisciplinary team of experienced clinicians to avoid unnecessary transplantations of both organs in patients with reversible kidney failure, given the scarcity of organs for transplantation worldwide. In hepatorenal syndrome CLKT should only be considered if the GFR is lower than 20 ml/min for more than three months or if the patient has been on renal replacement treatment for more than one month. In CLKT, there appears to be a certain immunological protection for the kidney transplant by the liver transplant. PMID- 20922642 TI - [Thrombolysis during cardio-pulmonary resuscitation]. AB - Sudden cardiac death is a leading cause of death in Europe. In the vast majority, myocardial infarction or pulmonary embolism is the underlying cause. Lethality is still high, especially if the arrest occurs out of hospital. For these two severe conditions, thrombolysis has proven to be an established therapy. Coronary perfusion is restored or the occlusion in the pulmonary arteries is removed, restoring normal circulation and normalising right-ventricular afterload. Nevertheless, thrombolysis was contraindicated during cardio-pulmonary resuscitation (CPR) for many years due to the fear of severe bleeding complications. Case reports and series using thrombolysis as successful ultima ratio therapy during prolonged CPR were soon followed by retrospective and interventional studies. These trials showed significantly improved survival for patients after thrombolysis during CPR. Nevertheless, none of these trials was randomised. Other trials showed that bleeding complications do not occur more frequently after thrombolysis during CPR. Experimental investigations demonstrated that thrombolysis during CPR improves cerebral microcirculation. The results of the randomised, multicenter trial TROICA show that tenecteplase alone, does not significantly improve survival. Further studies on thrombolysis during CPR with additional administration of heparin and acetylsalicylic acid must follow to ascertain the role of thrombolysis during CPR. Although thrombolysis during CPR is not a standard therapy, it should not be withheld from patients in whom pulmonary embolism is the suspected cause of cardiac arrest, as well as in selected other patients on the physician's individual decision according to recent guidelines. PMID- 20922641 TI - [79-year-old patient with pulmorenal syndrome]. AB - HISTORY AND ADMISSION FINDINGS: A 79-year-old female patient was referred with acute renal failure requiring haemodialysis and haemoptysis. INVESTIGATIONS: Kidney biopsy showed extracapillary proliferative glomerulonephritis with crescents in 7 from 15 glomeruli and sclerosis in the remaining. A computed tomography scan of the chest showed evidence of alveolar haemorrhage. Serologic testing revealed autoantibodies against the glomerular basement membrane (anti GBM antibodies) and myeloperoxidase antineutrophil cytoplasmic antibodies (MPO ANCA). DIAGNOSIS, TREATMENT AND COURSE: The patient was diagnosed with goodpasture's disease and underwent immunosuppressive therapy including prednisolone, cyclophosphamide pulses and plasmapheresis, resulting in clearance of anti-GBM antibodies and discontinuation of haemoptysis. Renal function, however, did not recover and the patient remained on dialysis. CONCLUSIONS: Aggressive treatment including cyclophosphamide and plasma separation often ensures patient survival in goodpasture's disease, in most cases, however, renal function does not recover. PMID- 20922643 TI - [Physicians' responsibility to remind patients after failure to keep their follow up appointments]. PMID- 20922644 TI - Continuously moving table MRI in oncology. AB - Magnetic resonance imaging (MRI) with a continuously moving table (CMT) represents a novel method allowing for the seamless acquisition of an extended field-of-view in the z-direction. One option to realize CMT MRI from a technical point of view is based on very fast sequences like echo planar imaging (EPI). Consequently, table translation for signal sampling and image reconstruction can be neglected. The acquisition of different contrasts, however, necessitates table motion correction, either during acquisition or via post-processing. First clinical studies applying fast steady-state imaging already yielded promising results with respect to metastasis detection. Nevertheless, additional equipment has to be installed for table motion and position tracking. In contrast, the subsequently developed sliding multislice (SMS) technique can be implemented without any additional hardware. In clinical studies, the achievable image quality corresponds to stationary sequences. Additionally, the use of SMS for the detection of pulmonary and abdominal metastases appears to be comparable to computed tomography (CT). Due to the relatively short examination times, CMT MRI can be integrated into highly specialized stationary imaging protocols, thus increasing the possibility to combine local staging with thoracoabdominal metastasis screening within one examination. New contrasts like diffusion weighted imaging (DWI) or Dixon techniques as well as improved workflow including breathing motion compensation and intuitive scout acquisition have already been proposed and will further expand the clinical applications of this technique. PMID- 20922645 TI - [Digital volume tomography (DVT) and multislice spiral CT (MSCT): an objective examination of dose and image quality]. AB - PURPOSE: In the last five years digital volume tomographs (DVT) have found their way into the diagnostic imaging of the facial skull. In this study both the image quality and dose of DVT and multislice spiral CT (MSCT) in this field of application were investigated using established physical methods for CT. MATERIALS AND METHODS: Measurements on DVT scanners of various manufacturers and on a modern MSCT scanner were performed. The investigation was based on equivalent dose levels for both modalities (CT dose index, CTDI). For this purpose, the dose was measured with an ionization chamber in a cylindrical PMMA phantom. For the evaluation of image quality, the spatial resolution, contrast and noise were investigated with phantoms established for CT. RESULTS: MSCT exhibited spatial resolution values of 1.0 to 1.6 lp/mm, while DVT provided resolution between 0.6 and 1.0 lp/mm only. Thus, MSCT offered similar or better resolution at an equivalent dose. For soft tissue resolution, DVT showed significant image artifacts. MSCT yielded higher homogeneity and no significant artifacts, and the contrast steps of the phantom were more verifiable. The different DVT devices, from image intensifiers to modern flat-detector (FD) devices, showed significant differences in favor of the FD devices. CONCLUSION: For medium and high contrast applications (teeth/bones), DVT scanners can be an alternative to MSCT at comparable radiation exposure. However, MSCT offers advantages in terms of constantly good and controlled image quality with significantly more flexible scan parameters at a constant or lower dose and should therefore be given preference. PMID- 20922646 TI - Gadofosveset-enhanced MR imaging for the preoperative evaluation of potential living kidney donors: correlation with intraoperative findings. AB - PURPOSE: The purpose of this study was to evaluate the blood pool contrast agent gadofosveset for MR angiography (MRA) of the renal vasculature in living kidney donors (LKD). MATERIALS AND METHODS: Of the 28 consecutive potential LKDs (13 men, 15 women; mean age 55.14 years +/- 11.97) initially included in this prospective study, 20 patients underwent surgery and were considered for further evaluation. 7 acquisitions of a 3D T 1-weighted FLASH sequence were performed following administration of gadofosveset for the assessment of the vascular anatomy and collecting system at predefined time points at 1.5 T. All MR exams were prospectively analyzed by 2 radiologists in consensus mode prior to surgery. In addition, ROI-based relative SNR measurements were performed in the vena cava inferior and abdominal aorta. RESULTS: MR image acquisition was completed in all 20 potential living donors. In 8 donors an additional CT scan was available for further comparison with the collateral anatomy, resulting in a total of 28 analyzed kidneys. MRA disclosed 36 renal arteries, since 8 accessory arteries were found in 8 subjects. One accessory artery and one case of fibromuscular dysplasia were missed by MRA. The venous anatomy and the collecting system were assessed correctly with MRI. In addition, MRI diagnosed two renal cell carcinomas. The overall sensitivity and positive predictive value of gadofosveset enhanced MRI on a per kidney basis were 92.9 % and 100 %, respectively. CONCLUSION: Gadofosveset enables accurate evaluation of potential LKDs. PMID- 20922647 TI - [Quality of diagnostic accuracy studies: QUADAS (Quality Assessment of Diagnostic Accuracy Studies Included in Systematic Reviews)]. PMID- 20922648 TI - Treatment of biliary leakage by an adjoined antegrade and retrograde percutaneous transhepatic cholangio drainage approach: a case report. PMID- 20922649 TI - [A patient with an event recorder in MRI]. PMID- 20922650 TI - [Inferior nasal transposition of the lateral rectus muscle for third nerve palsy]. AB - OBJECTIVE: The choice and extent of extraocular muscle surgery in N.III palsy are based on the specific pattern and degree of the palsy. In severe paralysis the eye has to be shifted from an exotropic to a straight ahead position. Additionally, a change in vertical position may be desirable. To reach this aim, transposition of the integral lateral rectus muscle to the nasal hemisphere of the eye was performed in 3 patients. PATIENTS AND METHOD: Patient #1 (50 y, m) had vertical gaze palsy and N.III palsy RE with 35 degrees exo-, 25 degrees hyper- and 9 degrees incyclotropia. Patient #2 (41 y, m) had vertical gaze palsy and asymmetric bilateral N.III palsy. The RE was 35 degrees exo-, 8 degrees hyper- and 8 degrees incyclotropic. Adduction was limited to the sagittal plane in both patients. Patient #3 (61 y, f) had vertical gaze palsy together with bilateral N.III paralysis. The eyes were immobile. The RE was 40 degrees abducted and blind. The LE was in 40 degrees abduction. The patient could hardly use this eye for everyday demands. In all 3 patients, the lateral rectus muscle was transposed between the inferior rectus muscle and the globe to the lower margin of the medial rectus muscle, passing behind the inferior oblique muscle. During general anaesthesia, the location of the attachment site from the corneal limbus was determined such that the eye was moved into the desired position. RESULTS: In all patients, the resulting eye position was slightly below primary position. As expected, incyclotropia had increased. Patient #1 had a residual deviation of 2 degrees exo-, 9 degrees hypo-, and 17 degrees incyclotropia. Horizontal motility of the RE ranged from 5 degrees adduction to 5 degrees abduction. As a second side effect, depression occurred on attempted abduction. Patient #2 had no horizontal deviation, but 10 degrees hypo- and 25 degrees incyclotropia. Horizontal motility of the RE ranged from 0 degrees to 5 degrees adduction. Patient #3 could use her eye in a nearly straight ahead position in slight down gaze. Her RE was still 15 degrees exotropic. These results remained stable after 18, 12 and 10 months, respectively. None of the patients was disturbed any more by either confusion or diplopia or image tilt. CONCLUSIONS: Transposition of the entire lateral rectus muscle to the nasal hemisphere is an efficient method to correct for exotropia associated with vertical deviation in specific cases of N.III palsy. The cyclotorsional effect of the procedure has to be considered. The vertical effect is useful to correct for hypertropia and induce a durable, slightly depressed eye position which is profitable for monocular visual demands and aesthetically appealing. PMID- 20922651 TI - Protective, antioxidative and antiapoptotic effects of 2-methoxy-6-acetyl-7 methyljuglone from Polygonum cuspidatum in PC12 cells. AB - Much correlative evidence indicates that the oxidative modification of protein by reactive oxygen species (ROS) is involved in normal aging as well as the pathogenesis of neurodegenerative diseases such as Alzheimer's disease. In this study, we explored the antioxidative and neuroprotective effects of a naphthoquinone, 2-methoxy-6-acetyl-7-methyljuglone (MAM), purified from the dried rhizome of POLYGONUM CUSPIDATUM (Chinese name Hu-Zhang). Pretreatments with MAM (24 h) were investigated for their protective effects against apoptosis induced by the oxidizing agent TERT-butyl hydroperoxide ( T-BHP) in PC12 cells. The results indicated that MAM pretreatments could effectively protect PC12 cells against cytotoxicity induced by T-BHP in a dose-dependent manner. Cell viability was determined by both MTT and LDH assays. Increasing concentrations of MAM enhanced cell viability significantly and completely prevented cell death induced by T-BHP at 2.5 uM. The corresponding extracellular lactate dehydrogenase (LDH) levels were also attenuated significantly by various concentrations of MAM. In addition, it was found that the antioxidative effect of MAM was stronger than those of resveratrol and lipoic acid. The antiapoptotic property of MAM was further investigated with Hoechst 33342 nuclear staining and TUNEL assay. Pretreatments of MAM were able to prevent the T-BHP-induced nucleus fragmentation and accumulation of apoptotic bodies (commonly accepted as markers of apoptosis) inside the cells in a dose-dependent manner. T-BHP induced the phosphorylation of ERK 1/2, JNK and p38 MAPK, which were all impeded by pretreatments with MAM, indicating that MAM may act as a potent antioxidant which significantly interferes with the MAPK apoptotic cascades, probably rescuing cells by inhibiting the death pathways. PMID- 20922652 TI - Constituents from Cistus salvifolius (Cistaceae) activate peroxisome proliferator activated receptor-gamma but not -delta and stimulate glucose uptake by adipocytes. AB - A number of medicinal/culinary herbs have been reported to improve glucose metabolism and to yield hypoglycemic effects in patients with diabetes. Since stimulation of insulin sensitivity appears to be a potential mechanism, peroxisome proliferator-activated receptor (PPAR) gamma is a likely target molecule for small lipophilic compounds derived from endogenous metabolism and nutrition. Functionally, PPAR gamma integrates the control of energy, lipid, and glucose homeostasis. In addition, PPAR delta activity is involved in energy expenditure. Therefore the aim of this study was to investigate whether PPAR gamma and PPAR delta as well as the stimulation of glucose uptake is activated by botanical products. CISTUS SALVIFOLIUS (Cistaceae) has been identified as a candidate botanical in a preliminary screening of extracts from medicinal plants of Greek flora. In a bioguided approach, crude extracts, fractions and in the end purified compounds have been evaluated for PPAR gamma and PPAR delta specific activities using cell-based transactivation assays. Glucose uptake was measured by nonradioactive 2-[ N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxyglucose (2-NBDG) uptake. Concerning PPAR gamma several extracts induced reporter gene activity, and clear dose-response patterns (0.1-100 ug/mL) could be established in the case of the cyclohexane and dichloromethane extracts. Isolation of individual compounds from the cyclohexane extract revealed that at least 6 out of 7 compounds isolated were active with TRANS-cinnamic acid showing a clear dose response pattern. In contrast, they were found to be inactive on PPAR delta. The same compounds, however, were also active in stimulating glucose uptake into 3T3 L1 adipocytes. In summary, the bioguided fractionation of CISTUS SALVIFOLIUS yields PPAR gamma stimulating metabolites with differing chemical natures. In conclusion, PPAR gamma represents a candidate molecule for the mediation of improvement of glucose metabolism by botanical/nutritional products. PMID- 20922653 TI - Cytotoxic aporphine alkaloids from Ocotea acutifolia. AB - Two new aporphinoid alkaloids, (+)-6 S-ocoteine N-oxide and (+)-norocoxylonine, were isolated from the leaves and trunk bark of OCOTEA ACUTIFOLIA (Lauraceae) along with thirteen aporphine analogues, one morphinan alkaloid, and one flavonoid. The aporphine alkaloids (+)-thalicsimidine and (+)-neolitsine are reported for the first time for the genus OCOTEA. The structures of all compounds were established on the basis of 1D- and 2D-NMR spectroscopic techniques, optical rotation and/or mass spectrometry data. The cytotoxic potential of eight of the aporphine alkaloids against four human cancer cell lines (Hep-2, MCF-7, B16-F10 and 786-0) was also evaluated. PMID- 20922654 TI - Free transverse rectus abdominis myocutaneous flap for breast reconstruction in patients with prior abdominal contouring procedures. AB - With an increasing number of women undergoing abdominal liposuction and abdominoplasties, patients who have a history of an abdominal-contouring procedure are now presenting to plastic surgeons with breast cancer and are interested in autologous breast reconstruction. Based on the principle of vascular ingrowth and experience of seeing intact perforators arise from the rectus abdominis muscle in repeat abdominoplasty patients, it was hypothesized that these new perforators could adequately and safely supply the abdominal skin island as a flap in this patient population. A retrospective chart review was performed searching for cases of free transverse rectus abdominis myocutaneous (TRAM) or deep inferior epigastric perforator (DIEP) flap breast reconstruction in patients with a prior history of either abdominal liposuction, abdominoplasty, or both. Three successful cases of free TRAM flap breast reconstruction were performed in patients who had undergone previous full abdominoplasties. Additionally, three successful cases of free TRAM or DIEP flaps were performed in patients after abdominal liposuction. Major complications included one anterial thrombosis in which the flap was salvaged. This study demonstrates the feasibility and viability of free TRAM flaps after previous abdominoplasty and DIEP flaps following prior abdominal liposuction. This is an important advance in the potential uses of the free TRAM flap. PMID- 20922655 TI - Replantation of above-knee amputation: a surviving but dysfunctional case needing secondary amputation. AB - Above-knee amputations are rare injuries that need emergent replantation or primary amputation. Although survival could be achieved in selective cases, postoperative function of the affected limb is usually unsatisfactory and a late amputation has to be performed for poor prognosis or severe complications. Experience of the surgical team may play an important role in primary decision making, which leads us to report one case of above-knee replantation with poor postoperative function and needing a late amputation. Scoring systems, expected results based on our case, and a brief review of literature concerning above-knee replantations are discussed. PMID- 20922656 TI - The use of the vacuum-assisted closure in microsurgical reconstruction revisited: application in the reconstruction of the posttraumatic lower extremity. AB - Introduction of vacuum-assisted closure (VAC) system into clinical practice has revolutionized wound care. Despite its multiple advantages, however, the VAC is only rarely used in the setting of microsurgical reconstruction. Concerns have been the inability to clinically monitor the flap as well the possibility of flap compression by the device. The authors put their postoperative treatment concept of applying the VAC to free flaps to the test by reviewing their experience with this concept in patients undergoing microsurgical reconstruction of posttraumatic lower-extremity soft tissue defects. Twenty-six patients (22 male, 4 female) were included in this study. Use of the implantable Doppler probe allowed for postoperative flap monitoring. Two flap failures were observed, both in patients with peripheral vascular disease. In conclusion, using the VAC device in the setting of microsurgical reconstruction is safe and allows for increased patient comfort. PMID- 20922657 TI - [Medication prices in Germany--how are they determined?]. PMID- 20922666 TI - NEMO: Extraction and normalization of organization names from PubMed affiliations. AB - BACKGROUND: Today, there are more than 18 million articles related to biomedical research indexed in MEDLINE, and information derived from them could be used effectively to save the great amount of time and resources spent by government agencies in understanding the scientific landscape, including key opinion leaders and centers of excellence. Associating biomedical articles with organization names could significantly benefit the pharmaceutical marketing industry, health care funding agencies and public health officials and be useful for other scientists in normalizing author names, automatically creating citations, indexing articles and identifying potential resources or collaborators. Large amount of extracted information helps in disambiguating organization names using machine-learning algorithms. RESULTS: We propose NEMO, a system for extracting organization names in the affiliation and normalizing them to a canonical organization name. Our parsing process involves multi-layered rule matching with multiple dictionaries. The system achieves more than 98% f-score in extracting organization names. Our process of normalization that involves clustering based on local sequence alignment metrics and local learning based on finding connected components. A high precision was also observed in normalization. CONCLUSION: NEMO is the missing link in associating each biomedical paper and its authors to an organization name in its canonical form and the Geopolitical location of the organization. This research could potentially help in analyzing large social networks of organizations for landscaping a particular topic, improving performance of author disambiguation, adding weak links in the co-author network of authors, augmenting NLM's MARS system for correcting errors in OCR output of affiliation field, and automatically indexing the PubMed citations with the normalized organization name and country. Our system is available as a graphical user interface available for download along with this paper. PMID- 20922667 TI - Addition of hydroxyapatite improves stiffness, interconnectivity and osteogenic potential of a highly porous collagen-based scaffold for bone tissue regeneration. AB - There is an enduring and unmet need for a bioactive, load-bearing tissue engineering scaffold, which is biocompatible, biodegradable and capable of facilitating and promoting osteogenesis when implanted in vivo. This study set out to develop a biomimetic scaffold by incorporating osteoinductive hydroxyapatite (HA) particles into a highly porous and extremely biocompatible collagen-based scaffold developed within our laboratory over the last number of years to improve osteogenic performance. Specifically we investigated how the addition of discrete quantities of HA affected scaffold porosity, interconnectivity, mechanical properties, in vitro mineralisation and in vivo bone healing potential. The results show that the addition of HA up to a 200 weight percentage (wt%) relative to collagen content led to significantly increased scaffold stiffness and pore interconnectivity (approximately 10 fold) while achieving a scaffold porosity of 99%. In addition, this biomimetic collagen HA scaffold exhibited significantly improved bioactivity, in vitro mineralisation after 28 days in culture, and in vivo healing of a critical-sized bone defect. These findings demonstrate the regenerative potential of these biodegradable scaffolds as viable bone graft substitute materials, comprised only of bone's natural constituent materials, and capable of promoting osteogenesis in vitro and in vivo repair of critical-sized bone defects. PMID- 20922669 TI - [Stem cells and endothelial repair in kidney patients: hope or illusion?]. PMID- 20922670 TI - [Dialysis, transplant and donation: three contraindications to pregnancy?]. PMID- 20922671 TI - [Fibrogenesis and epigenetics: a ''dangerous liaison'']. PMID- 20922672 TI - [Pregnancy in women with renal disease: consolidated evidence and open issues]. PMID- 20922673 TI - [Are we ready to screen for albuminuria in the general population?]. PMID- 20922674 TI - [PPAR-gamma agonists: a role in the prevention of chronic allograft nephropathy?]. PMID- 20922675 TI - [Peritoneal dialysis: a time-limited therapy because of encapsulating peritoneal sclerosis? No, but due attention is warranted]. AB - Encapsulating peritoneal sclerosis (EPS) is a rare complication that occurs mainly in patients on long-term peritoneal dialysis (PD). It is characterized by marked thickening of the peritoneal membrane with signs of inflammation. Vascular occlusions and microscopic and macroscopic calcifications are frequent. Signs of acute and chronic inflammation are always present with leukocyte infiltration, microabscesses and giant cells of macrophage origin. The triggering factor in patients on PD may be an acute inflammatory process such as an episode of severe peritonitis. After discontinuation of PD for kidney transplant, immunosuppressive therapy with calcineurin inhibitors, which have profibrotic properties, may lead to EPS. After a switch from PD to hemodialysis, EPS may be induced by the inability to remove proinflammatory factors, cytokines, coagulation factors and fibrin from the peritoneal cavity. These considerations are not meant to imply a PD ''expiry date'' but should prompt nephrologists to be more careful in treating PD patients, using more biocompatible solutions and monitoring (through clinical observation and diagnostic evaluation) patients on long-term PD to avoid the appearance of this rare but dreaded complication. PMID- 20922676 TI - [Peritoneal dialysis: a time-limited therapy because of encapsulating peritoneal sclerosis? No, but better approaches are available]. AB - In recent years the fear of encapsulating peritoneal sclerosis (EPS) prompted some nephrologists to consider peritoneal dialysis a time-limited therapy. Such an expiry date is devoid of a rational basis because peritoneal dialysis is a mere risk factor for EPS, not an etiological cause. This disease is in fact triggered by a second stimulus different from peritoneal dialysis and often even consisting of its withdrawal. Epidemiological studies have confirmed that interrupting peritoneal dialysis at a fixed time not only is useless in preventing EPS but might be counterproductive. Moreover, the quality of life of the patient should also be taken into account. Evidence obtained in recent years strongly suggests the effectiveness of other approaches in the prevention of EPS: 1) routine use of biocompatible peritoneal dialysis solutions; 2) inhibition of the renin-angiotensin-aldosterone axis as an elective therapy for hypertension in peritoneal dialysis; 3) prophylaxis with low-dose tamoxifen (10 mg per day) in high-risk patients (peritoneal dialysis >5 years, development of ultrafiltration failure and/or transport alterations); 4) a specific immunosuppressive protocol for former peritoneal dialysis patients undergoing transplantation: a sirolimus- or everolimus-based regimen with mycophenolate, avoidance or at least minimization of cyclosporine and tacrolimus, and use of steroids in the first 6 12 months. All of us should seriously consider the efficacy of these approaches in controlled clinical trials. PMID- 20922677 TI - [Peritoneal dialysis: a time-limited therapy because of encapsulating peritoneal sclerosis?]. AB - Encapsulating peritoneal sclerosis (EPS) is a rare but severe disease with a mortality rate of 24%-54%, whose main risk factor is peritoneal dialysis (PD) (cumulative incidence 0.5%-7.3%). Although the role of the time spent on peritoneal dialysis is not completely clear, the available evidence suggests that peritoneal dialysis should not be discontinued early for the sake of reducing the EPS risk. We proposed a ''pro-con'' debate which confirmed that PD is not a time limited technique. Nevertheless, in patients on long-term PD, surveillance of the peritoneal membrane is crucial. The development of EPS requires two ''hits'': first a chronic, inflammatory stimulus, which is typical of peritoneal dialysis, then a second event like PD interruption or kidney transplant. The main pharmacological and dialysis strategies that have been used as primary prevention did not show any significant results, and benefits are more likely to be achieved by reducing the peritoneal inflammation and better preservation of the membrane integrity, for example by means of more biocompatible PD solutions. Among the main surveillance and early diagnosis procedures other than the peritoneal equilibration test, the Ca-125 appearance rate and new tests that evaluate the peritoneal water transport seem to be promising. PMID- 20922678 TI - [The role of terlipressin in hepatorenal syndrome]. AB - Hepatorenal syndrome (HRS) is a severe complication in patients with endstage liver disease. It consists of functional renal vasoconstriction leading to severe reduction of the glomerular filtration rate. In some patients the renal failure shows a rapidly progressive course, a clinical pattern known as type 1 HRS. In other cases the renal failure is less severe and remains stable for months, a condition known as type 2 HRS. HRS is pathogenically related to disturbances in circulatory function, mainly characterized by marked arterial vasodilation of the splanchnic circulation, triggered by portal hypertension. This vasodilation may result in effective arterial underfilling, with subsequent activation of vasoconstrictor systems including the renin-angiotensin system and the sympathetic nervous system, as well as hypersecretion of arginine vasopressin. These compensatory mechanisms may lead to renal failure due to the increase in intrarenal resistance and hypoperfusion. Although the available data are derived from studies including a limited number of patients mainly affected by type 1 HRS, vasoconstrictor drugs, in particular the vasopressin analog terlipressin, seem to be the most effective approach for the management of HRS. Associated with albumin infusion, these drugs have been shown to lead to reduced mortality and improved renal function in type 1 HRS. This is particularly true in HRS patients awaiting liver transplantation in whom the vasoconstrictor drugs appear to be the ''bridging'' therapy of choice. Finally, their use has been shown to be safe, and side effects usually disappear after dose reduction. PMID- 20922679 TI - [Lights and shadows on single and dual RAAS blockade]. AB - Angiotensin-converting enzyme inhibitors (ACE-i) and angiotensin II receptor blockers (ARBs) are of paramount importance in everyday clinical practice. Developed as antihypertensive drugs, they soon acquired another important indication as a result of their antiproteinuric activity and capacity to delay the progression of chronic kidney disease. ACE-i and ARBs started out being used as single drugs and were subsequently combined to obtain more complete blocking of the renin-angiotensin-aldosterone system (RAAS). The most evident advantages derived from the administration of these drugs - alone or in combination - have been obtained in proteinuric nephropathies, such as chronic glomerulonephritis and diabetic nephropathy, where they have become the treatment choice. Dual RAAS blockade has been recently evaluated in a large trial of high-risk cardiovascular patients, in whom no related benefits were shown. To the contrary, a higher risk of worsening renal function emerged. It is now quite clear that patients with high proteinuria levels are the ones that benefit most from RAAS inhibition, also with combined ACE-i and ARB. It is very important to pay the utmost attention when these drugs are used in patients in whom no benefit is obtained by RAAS inhibition, such as patients with chronic kidney disease and atherosclerosis, elderly patients, and those without any significant proteinuria. PMID- 20922680 TI - [Use of oral anticoagulants to prevent central venous catheter-related thrombosis in hemodialysis]. AB - Central venous catheters (CVCs) are fundamental in the management of hemodialysis. Despite major efforts to provide arteriovenous access, their use is increasing in dialysis units worldwide. The presence of a catheter inside a vein increases the risk of thrombosis, both within the catheter and in the vein. Thrombosis is a serious complication because it can lead to inefficient dialysis, alter the venous circulation, and facilitate infections. In this article, questions regarding anticoagulant treatment in dialysis patients with CVCs are explored and specific suggestions offered for clinical practice, based on the evidence available and the personal experience of the authors. Should CVC-induced thrombosis be treated? The duration, site and extension of the thrombotic complication should be assessed. If thrombosis is recent and symptomatic, heparin treatment followed by oral anticoagulant therapy is suggested. Is oral anticoagulant therapy useful for primary prevention of thrombosis, both within the CVC and the vein where the catheter is inserted? The available evidence favoring the use of oral anticoagulant therapy is not entirely convincing. At any rate, before such treatment is started the balance between the antithrombotic efficacy and the possible side effects should be carefully weighed. Is oral anticoagulant therapy useful for secondary prevention of CVC thrombosis? If a permanent CVC is in place and its position is correct and the blood flow < 250 mL/min, we recommend - before replacing the CVC - thrombolytic treatment followed by oral anticoagulants, aiming at an INR target between 2 and 3. Are the side effects of oral anticoagulant therapy an issue? The use of anticoagulants in renal failure carries an increased risk of complications, in particular bleeding and vascular calcifications, which could annul the advantages derived from reduced thrombotic events. Before starting oral anticoagulant therapy we suggest to carefully evaluate if there are potential overall benefits and to pay attention to concomitant antiplatelet therapy. PMID- 20922681 TI - [Uremic toxins: the case of protein-bound compounds]. AB - Uremic retention solutes, if biologically or biochemically active, are called ''uremic toxins''. The retention of these solutes has a negative impact on many functions of the organism, particularly the cardiovascular system. The classification which is applied today is based on the kinetic behavior of the uremic retention solutes during dialysis: 1) small water-soluble molecules (< 500 Daltons); 2) middle molecules (> 500 Daltons); 3) protein-bound compounds. The latter are the object of the present review. The most important among them are p cresol, p-cresyl sulfate, homocysteine, phenols, and indoles. No interventional studies are currently available that show the effect of an improvement in the removal of protein-bound compounds on patient outcomes, simply because most of the alternative dialysis strategies proposed so far are not superior to standard dialysis in removing protein-bound compounds. The question as to how to improve the removal of these solutes therefore remains unanswered. Alternative strategies might include adsorption therapies, either administered orally or during the extracorporeal treatment. In conclusion, the uremic syndrome is a complex clinical entity which involves a large number of retention solutes, many more than the small water-soluble molecules. Dialysis strategies should therefore aim to remove not only urea but also retention solutes, mainly because middle and protein-bound molecules appear to be correlated more frequently with deleterious biological, biochemical and clinical effects. PMID- 20922682 TI - [Vascular access for hemodialysis: recommendations of the Vascular Access Study Group of the Italian Society of Nephrology]. AB - The Vascular Access Study Group of the Italian Society of Nephrology has scheduled four national studies regarding the choice, implantation and use of vascular access. Study topics will include 1) utilization of vascular grafts for hemodialysis; 2) indications and use of venous catheters; 3) tunneled central venous catheter infection; 4) organization of the implantation and repair of vascular access. After examining the difficulties in implementing international guidelines on vascular access in Italy and the differences in practice patterns between our and other countries (where the most important studies were published), the Study Group set out to prepare four position papers based on discussion of controversial aspects of the international guidelines by nephrologists and surgeons experienced in the Italian practice. An innovative operative method for verifying the consensus on vascular access practice patterns was used. The final aim was to write a document addressed to vascular access operators (surgeons and nephrologists) based on the consensus of experts on controversial vascular-access- related issues. The project will include yearly updates of the documents. PMID- 20922684 TI - [Native vascular access for hemodialysis in patients with diabetes: a single center experience]. AB - With 135 million cases the prevalence of diabetes mellitus (DM) is very high worldwide. Diabetic nephropathy is a major complication of DM. In many countries diabetic nephropathy has become the most frequent cause of endstage renal disease. It is believed that in diabetic patients the creation of a native vascular access (NVA) might be difficult. We evaluated 274 occurrences of NVA creation during the period January 2003 to December 2008: 68 in diabetic patients (group 1) and 206 in nondiabetics (group 2). We compared the type of NVA, primary failure, and primary patency in these groups. Age was significantly higher in diabetic patients (68 vs 64 years; p < 0.05). No statistical differences in primary failure between groups were found for any NAV. Wrist vascular access survival rates were higher in diabetic versus nondiabetic patients (56.9% vs 20.7% at 72 months). No statistical differences were observed between groups in primary patency rates for middle- and upper-arm vascular access. According to our experience diabetes does not lead to additional difficulties in the creation of permanent vascular access, provided proper physical and instrumental examination is performed. Despite the advanced age of the diabetic patients in our study, wrist vascular access showed better results in this group than in nondiabetic patients on long-term follow-up. PMID- 20922683 TI - [Indications for vascular grafts as dialysis access; consensus from the Italian experience]. AB - In Italy, the use of arteriovenous grafts (AVGs) is limited (1-4%) due to different approaches to vascular access management compared to other countries, where guidelines that may not apply to the Italian setting have been produced. Therefore, the Vascular Access Study Group of the Italian Society of Nephrology produced this position paper, providing a list of 8 recommendations built upon current guidelines. The most controversial and innovative issues of the existing guidelines have been summed up in 12 different topics. We selected 60 Italian dialysis graft experts, nephrologists and vascular surgeons (PP1SIN Study Investigators). They were asked to express their approval or disapproval on each issue, thus creating a new method to share and exchange information. Almost all agreed on specific criteria for the choice of AVG over native arteriovenous fistulas (AVF) and tunneled venous catheters (tVC) and on the necessary conditions to implant them. They did not fully agree on the use of AVG in obese patients and patients at risk of developing ischemia, as an alternative to brachiobasilic fistula with vein transposition, and in case of a poorly organized setting. When AVF is feasible, it should be preferred. AVGs are indicated when superficial veins are unavailable or to repair an AVF (bridge graft). An AVG is an alternative to tVC if the expected patient survival is long enough to allow clinical benefits. The ultimate choice of the graft type is made by the physician in charge of the surgical intervention. Antithrombotic prophylaxis may be justified in some cases. PMID- 20922685 TI - [Ultrasound parameter-based response to treatment with new drugs for secondary hyperparathyroidism: a retrospective analysis in a single dialysis center]. AB - In hemodialysis patients with secondary hyperparathyroidism (SHPT) ultrasonography of the parathyroid glands allows to assess the glandular growth and to define the limits of medical treatment. The present retrospective study evaluated the relationship between parathyroid gland hyperplasia and the effectiveness of new drugs. Fifty-three patients with SHPT (iPTH > 400 pg/mL) after treatment with oral calcitriol were included in the study. These patients underwent parathyroid ultrasonography and sequential therapy with intravenous calcitriol (first step), paracalcitol (second step), and paracalcitol + cinacalcet (third step). Patients with median PTH < 300 pg/mL during the period of therapy and follow-up were considered responders. The therapeutic response was correlated with ultrasound parameters (number of parathyroid glands, maximum longitudinal diameter, structural score, and vascular score). Four (10%) of 41 patients treated with IV calcitriol, 7 (27%) of 26 patients treated with paracalcitol, 7 (41%) of 17 patients treated with cinacalcet and paracalcitol, and 1 (20%) of 5 patients treated with cinacalcet alone were responders. ROC curve analysis showed that maximum longitudinal diameter (< 9 mm), number of parathyroid glands (< -1), structural score (< 2), and vascular score (< 2) predicted response to any treatment. New drugs (paracalcitol, cinacalcet) are more effective in SHPT than conventional ones. However, the traditional ultrasonographic cutoff for the efficacy of medical therapy remained unchanged. Thus parathyroid gland ultrasonography predicts the therapeutic response also to the new drugs. PMID- 20922686 TI - [Clinical trials (Part II)]. PMID- 20922687 TI - [Erythrocytosis, renal artery stenosis and arterial hypertension in a kidney transplant recipient]. AB - A 53-year-old man with end-stage renal disease received a cadaver kidney after 15 months of peritoneal dialysis. Within one year of transplantation he developed hypertension and erythrocytosis. Percutaneous transluminal angioplasty was performed but 13 months later magnetic resonance angiography showed an anastomotic stenosis of the renal artery in the graft. In the meantime, he was submitted to venesections while the hypertension proved resistant to a multiple drug combination. After two years, color Doppler sonography performed at our unit showed a noncritical stenosis, so we decided to start the patient on ACE inhibitors followed by angiotensin receptor blockers. A reduction of hematocrit to < 50% and partial control of blood pressure with stable renal function was obtained. Later we added minoxidil at low dosage, which resulted in excellent blood pressure control. The diagnosis of hemodynamically significant stenosis is not always easy to make; in this case a correct diagnosis was helpful for the treatment of erythrocytosis. PMID- 20922688 TI - [Caroli's syndrome in a patient on hemodialysis: diagnostic and therapeutic difficulties]. AB - We present the case of a 65-year-old male patient without any family history of renal or hepatic disease. He had been on maintenance hemodialysis for 4 months because of autosomal recessive polycystic kidney disease. At the start of the hemodialysis session he reported general malaise, abdominal pain, fever and diarrhea occurring in the last two days. Laboratory workup showed neutrophilic leukocytosis and increased serum amylase and C-reactive protein. Abdominal contrast-enhanced CT scan and MRI cholangiography showed hepatic cysts with marked dilatation of the intra- and extrahepatic bile ducts. The patient underwent cholecystectomy with hepaticojejunal Rouxen- Y anastomosis and was discharged with oral ciprofloxacin. Histology confirmed marked cystic dilatation of the bile ducts. Because of persistent episodes of septic fever, administration of ciprofloxacin was continued. After 4 months retrograde endoscopic pancreatography was performed which led to a diagnosis of Caroli's syndrome associated with polycystic kidneys. Given the rarity of the disease and its difficult diagnosis, when patients with polycystic kidneys and liver cysts experience recurrent episodes of septic fever of unknown origin, Caroli's disease should be taken into account and the appropriate tests should be carried out to confirm the diagnosis. PMID- 20922690 TI - [Genetics and oncogenesis of renal cancer]. AB - The development and progression of cancer requires several genetic modifications. Multiple transformation and progression events such as point mutations, deletions/insertions, chromosomal abnormalities, and epigenetic deregulation contribute to renal oncogenesis. Three types of genes are involved in this multistep process: oncogenes, tumor suppressor genes, and DNA repair genes. About 4% of renal tumors are hereditary, i.e., the first mutation is present at the constitutive level in all cells of an individual, leading to an increased lifetime risk of cancer. Sporadic tumors are mainly single and of late onset, while hereditary tumors are usually multiple and of early onset in the presence of a positive family history for kidney cancer. Moreover, hereditary tumors are often associated with specific syndromic signs. The main hereditary syndromes that include renal tumors are Von Hippel- Lindau disease, hereditary papillary renal clear cell carcinoma, hereditary leiomyomatosis renal cell carcinoma, and the Birt-Hogg-Dube' syndrome. Other rarer conditions are chromosome 3 translocation, tuberous sclerosis, and the Lynch syndrome. Study of these diseases and identification of the responsible genes have been extremely useful in understanding several molecular issues of renal oncogenesis. Genetic testing makes it possible to diagnose hereditary cancer and confirm a clinical suspicion, as well as to identify at-risk individuals within a family. It is extremely important for nephrologists to be aware of these hereditary conditions, as this will allow early recognition and improved clinical management. PMID- 20922691 TI - [Immunogical surveillance and oncogenesis: role of proliferation signal inhibitors]. AB - The authors review the antineoplastic effect of mTOR inhibitors and their biological basis. In normal cells mTOR is an intracellular serine/threonine kinase that is a central controller of cell growth and proliferation. mTOR integrates signals from a variety of sources as nutrients and growth factors. mTOR regulation can affect angiogenesis, cell growth, nutrient uptake and utilization, and metabolism. Growth factors such as insulin growth factor (IGF), epidermal growth factor (EGF), platelet-derived growth factor (PDGF), and vascular endothelial growth factor (VEGF) bind to and activate receptors located on the cell surface. Receptors activate intracellular signaling cascades through PI3K-AKT-mTOR (phosphatidylinositol 3-kinase/serine-threonine kinase-mTOR), leading to protein synthesis. As a consequence, activation of the mTOR pathway is linked to increased protein synthesis by modulating elements that are important in a number of cellular processes, including growth, proliferation, angiogenesis, and nutrient uptake. Deregulation of mTOR-linked pathways increases the risk of developing cancer and has been identified in many human cancer types. Such deregulation includes overexpression of growth factors, overexpression or mutations of growth factor receptors, loss of tumor suppressor genes, and gain-of function mutations in mTOR-linked pathways. These changes permit the survival, growth, proliferation, and migration of cancer cells and promote tumor angiogenesis. Targeting them has been a successful anticancer strategy. Targeting mTOR as well as these deregulated pathways could provide enhanced anticancer activity. The efficacy of mTOR inhibitors in preventing several types of cancer in transplanted patients, or making them regress once developed, has been documented in clinical trials and case reports. PMID- 20922692 TI - [Renal involvement in monoclonal gammopathy and multiple myeloma]. AB - Lymphoproliferative disorders often involve the kidney either by direct cell infiltration (lymphoma) or by deposition of paraproteins (monoclonal gammopathy, multiple myeloma, LCDD, amyloidosis). Nowadays the latter phenomenon seems to be the most common as a result of the growing number of elderly people affected by monoclonal gammopathies. The nephrotoxic potential of monoclonal immunoglobulins and amyloidogenic proteins make monoclonal gammopathies clinical entities of considerable interest in nephrology. Renal involvement presents different clinicomorphological patterns depending on the qualitative and quantitative characteristics of the paraproteins. Tubulointerstitial toxicity is frequent, while vascular and glomerular lesions resulting from non-inflammatory reactions due to immunoglobulin deposition are less common. Acute kidney failure may complicate the clinical course; this could be due to tubular obstruction by paraproteins or to hypovolemia induced by chemotherapy in association with diuretics. Early diagnosis of renal involvement will allow prophylactic interventions to prevent renal complications. At the same time, the increased number of therapeutic tools has enabled better management of kidney complications in lymphoproliferative disorders. PMID- 20922693 TI - [Lymphomatous renal involvement]. AB - The incidence of lymphomas, especially non-Hodgkin's lymphoma (NHL), has shown a steady increase over the last decades. At the same time, the prognosis has improved. Given the longer survival of lymphoma patients, pathological manifestations related to malignancy might become more frequent. In this setting, the kidney is one of the most important solid organs affected by direct or indirect lymphomatous involvement. Kidney involvement can be related to obstruction or treatment-induced toxicity, but more intriguing are 1) direct infiltration (NHL); 2) renal malignancies in patients affected by Hodgkin's disease or NHL; 3) associated glomerular diseases. Primary infiltration is rarely seen, while secondary infiltration is described most frequently in autopsy series, even in the absence of renal failure. These alterations may mimic glomerular and/or interstitial disease. The association with kidney malignancies, mostly renal cell carcinoma but also urothelial tumors in Hodgkin''s disease, is higher in lymphoma patients than in the general population: the relative risk at 10 years is about 1.5. Glomerulonephritis is described in patients with Hodgkin's disease or NHL; in the former minimal change disease is most frequent, in the latter the glomerular pattern varies widely. Glomerulonephritis can precede, be concurrent with, or follow lymphoma manifestations. Renal biopsy is often needed in this setting. PMID- 20922694 TI - [Kidney damage caused by treatment for hematological malignancies: from tumor lysis syndrome to post-transplant kidney failure]. AB - In the wide spectrum of therapies for hematological malignancies, hematopoietic stem cell transplantation, whether autologous or allogeneic, is a common procedure. In addition to other transplant-related organ toxicities, renal failure is a common complication following transplantation. This paper discusses the incidence, timing, etiologies, risk factors and prognosis of renal failure associated with three commonly used transplantation procedures: myeloablative autologous, myeloablative allogeneic, and non-myeloablative allogeneic transplantation. The epidemiology and prognosis of renal failure are different after these three procedures. Severe renal failure occurs with all three varieties, but the frequency increases from myeloablative autologous to non myeloablative allogeneic to myeloablative allogeneic. In all three types of transplantation, the mortality is clearly associated with the severity of renal injury, and it is greater than 80% when dialysis is required. Strategies to improve renal failure following transplantation may have a beneficial impact on these patients. Reduction of acute renal failure will likely reduce the severity of non-renal organ dysfunction, the incidence and severity of chronic kidney disease, and the mortality. PMID- 20922695 TI - [Kidney transplantation and lymphomas]. AB - Post-transplant lymphoproliferative disease (PTLD) accounts for 30% of nonskin cancers after kidney transplants. Diffuse large B-cell lymphoma is the most frequent form of PTLD. The incidence of PTLD increases over time: from 1.2% at 5 years to 6.8% at 20 years. Its late occurrence is therefore not unusual. Moreover, not only is it more frequent but also more serious than the early type because of the lower responsiveness to therapy. Epstein-Barr virus (EVB) infection is one of the most important risk factors for this disease, along with the use of antilymphocyte agents, which should be avoided in EVB-negative patients. During the first year after transplant, EBV-PCR monitoring can be helpful for the early diagnosis of EBV-associated PTLD, especially in children. No effective strategy has yet been reported for the prevention of late PTLD. Interruption of immunosuppression is the first step of therapy, but it is rarely effective by itself. Rituximab (4-8 doses) is widely used and is successful in about 50% of cases. Chemotherapy becomes essential in relapsed or refractory disease, but it significantly increases the risk of life-threatening infections. The mortality rate is around 50% 12 months after diagnosis, often due to the side effects of chemotherapy. PMID- 20922696 TI - [Solid tumors and paraneoplastic glomerulonephritis]. AB - Neoplastic diseases can cause renal damage directly or indirectly. Also their treatment can provoke renal damage. The incidence and prevalence of paraneoplastic glomerulonephritis, especially associated with solid tumors, are a matter of debate and the causal link between cancer and glomerular diseases remains unclear. Paraneoplastic glomerulonephritis is a rare occurrence, with a slightly higher prevalence in the elderly. The most common cancer types associated with paraneoplastic glomerular disease are carcinoma of the lung and the gastrointestinal tract. Membranous nephropathy is the most frequent but not the only presentation of paraneoplastic glomerulonephritis. Patients with unexplained nephrotic syndrome, especially if older than 60 years, with membranous nephropathy and/or with their own risk factors for malignancies should be screened for occult cancer at diagnosis and be followed up carefully after the diagnosis. The primary treatment of paraneoplastic glomerulopathy must be aimed at the cancer and immunosuppressive treatment must obviously be avoided. PMID- 20922697 TI - [Renal and upper urinary tract tumors: what the nephrologist should know]. AB - Urinary tract carcinomas are among the most common malignancies and are derived from neoplastic transformation of the urothelium. They can be located in the lower (bladder, urethra) or upper (pyelocaliceal cavities, ureter) urinary tract. Urothelial carcinomas are the fourth most common cancer type after prostate or breast cancer, lung cancer, and colorectal cancer. Bladder cancer accounts for 90 95% of urothelial carcinomas and it is the most common malignancy of the urinary tract. Renal cancer also belongs to the urothelial carcinomas and is a relatively uncommon solid tumor, accounting for about 3% of all adult malignancies, although its incidence is on the rise. The most common histological subtype, renal cell carcinoma (RCC), is a clear cell carcinoma that makes up approximately 70-80% of all renal neoplasms and appears to be the only histological subtype that is partially responsive to immunotherapeutic approaches. The current review gives an overview of upper urinary tract tumors and renal cancer, in particular RCC, highlighting issues related to its molecular pathogenesis and the new immunotherapeutic approaches. PMID- 20922698 TI - [Genetics and nosological classification of renal cystic diseases]. AB - Renal cystic diseases are the major group of inherited renal disorders in humans and a leading cause of end-stage renal disease. Dominant and recessive polycystic kidney disease (ADPKD and ARPKD, respectively) account for most of the clinical conditions. However, nephronophthisis (NPHP), medullary cystic kidney disease (MCKD), and dominant glomerulocystic kidney disease (GCKD) still have a relevant clinical impact, particularly in children. The discovery that the proteins that are defective in ADPKD and ARPKD localize to the primary cilium and the recognition of the role of this organelle in cystogenesis have led to the term ''ciliopathies''. In the last decade, the list of ciliopathies has continued to grow. Analysis of the protein products of the nine NPHP genes (NPHP 1-9) evinced a strong relation between ciliary function and pathogenesis of NPHP. The oral facial-digital syndrome (OFD) type I, characterized by congenital malformations and cystic kidney disease, was found to result from mutations in the OFD1 gene, which encodes a protein located to the primary cilium. Parallel to these advances, mutations in UMOD, the gene encoding uromodulin, were identified in pedigrees with MCKD2, familial juvenile hyperuricemic nephropathy, and autosomal dominant GCKD. In all these disorders, uromodulin was found to be accumulating in intracellular aggregates, suggesting a common pathogenesis. Taken together, these findings suggest the need for the separation of renal cystic diseases due to UMOD mutations (uromodulin-associated diseases) from renal cystic diseases related to mutation of genes encoding for proteins expressed in the primary cilium (ciliopathies). PMID- 20922700 TI - [Skin cancer in renal transplant recipients]. AB - Kidney transplant is the best treatment option for renal failure. Over the years the 1-year patient survival has gradually increased, along with a reduction in acute rejection. The main causes of death in the late post-transplant period are cardiovascular disease, infections and malignancies. It is known that the incidence of cancer increases with the duration of post-transplant follow-up. Twenty years after transplantation, approximately 70% of patients on continuous immunosuppressive therapy present one or more tumor types. Some of the tumors that occur with a significantly higher frequency in transplant recipients compared with the general population are often associated with the reactivation of oncogenic viruses. Examples are herpes virus 8 (HHV8), implicated in Kaposi's sarcoma (KS), human papillomavirus (HPV), involved in squamous cell cancer of the skin, vulva, vagina and cervix, and Epstein-Barr virus (EBV), responsible for post-transplant lymphoproliferative disorder (PTLD). The type of drug used for the induction and maintenance of immunosuppression and the duration of treatment influence both the incidence and the type of cancer. For this reason, post transplant malignancies often show a more aggressive behavior than tumors in the normal population. It is estimated that sarcomas occur 40 to 250 times more frequently in transplant recipients and are the leading cause of death from skin cancer after transplantation. The classic form of KS occurs in males and homosexuals. In the population of the Mediterranean area, KS is often associated with HHV8 infection that is reactivated by immunosuppression. The reduction or suspension of immunosuppressive therapy is the first step in the treatment of post-transplant KS. The second approach is chemotherapy. Since m-TOR, the target of sirolimus, is altered in many tumors, sirolimus may be an effective tool. Sirolimus inhibits not only cell proliferation but also tumor neovascularization by reducing VEGF production and inhibiting VEGF receptor signaling in endothelial cells. In conclusion, new strategies must be developed to reduce cancer mortality in transplant recipients while ensuring adequate immunosuppression to preserve the transplanted organ. One such strategy is the adoption of immunosuppressive regimens tailored to individual patients' medical history. PMID- 20922699 TI - [Cancer treatment-induced nephrotoxicity: BCR-Abl and VEGF inhibitors]. AB - The nephrotoxicity of some cancer drugs is well known. Given the rapid development of cancer research, careful assessment of patients treated with new drugs, which may have new toxicity profiles, is mandatory. The nephrotoxicity of cisplatin is likely due to inhibition of autophagy priming, while that of methotrexate is related to direct tubular toxicity and intratubular precipitation. Both can be prevented by adequate hydration. The mechanism of radiation nephropathy development is unclear, but chronic oxidative stress and inflammation seem to play a key role. Mesangiolysis is a characteristic feature, followed by vascular alterations, atrophy, fibrosis, and necrosis. Inhibitors of vascular endothelial growth factor (VEGF), such as bevacizumab, sunitinib, and sorafenib, interfere with angiogenesis. Bevacizumab is a humanized monoclonal antibody which binds to circulating VEGF. Sunitinib and sorafenib are small molecules inhibiting tyrosine kinase of the intracellular domain of the VEGF receptor. Treatment with anti-VEGF drugs is frequently complicated by proteinuria, acute renal failure, and hypertension. The most frequent histological lesion is thrombotic microangiopathy. Inhibitors of the BCR-Abl tyrosine kinase domain on the Philadelphia chromosome (imatinib, nilotinib and dasatinib) may cause acute renal failure. PMID- 20922701 TI - [Minimizing the risk of cancer in transplant patients]. AB - Recent improvements in immunosuppressive therapies have reduced the incidence of acute rejection and increased patient survival. These agents may however contribute to higher rates of mortality due to an increased risk of cardiovascular disease or malignancy. Transplant patients are in an immunocompromised state, and have a reduced ability to combat the development of malignancy. The higher risk for the activity of oncoviruses may also contribute to the higher incidence and the specific tumor types seen. Some immunosuppressants may have a direct oncogenic effect. In vitro data have demonstrated that calcineurin inhibitors (CNIs) may have a direct effect on tumor growth and the development of metastases. In contrast, mTOR inhibitors have demonstrated in vitro antitumoral properties, perhaps via a potent antiangiogenic effect. Recent studies and registry analyses have confirmed that mTOR inhibitors are associated with a reduced incidence of malignancies. UNOS data demonstrated that an mTOR inhibitor, with or without a CNI, is associated with a reduced incidence of cancer compared to regimens without mTOR inhibitors. The Rapamune Maintenance Regimen study demonstrated that patients receiving sirolimus-based, CNI-free therapy after CsA withdrawal at 3 months had a reduced incidence of malignancy at 5 years post-transplant compared with those who continued a regimen including CsA. In the CONVERT study, patients converted to sirolimus had significantly lower malignancy rates (3.1%) at 24 months compared with those who continued CNI-based therapy (9.8%, p<0.001). The elimination of CNIs and the introduction of sirolimus may therefore have a role in reducing the risk of cancer in post-transplant patients. PMID- 20922702 TI - [Adrenal tumors as a cause of hypertension]. AB - Hypertension is one of the main risk factors for cardiovascular diseases, which today are the primary cause of mortality in developed countries. To decrease the mortality and morbidity due to cardiovascular disease, it is necessary to treat hypertension correctly on the basis of an accurate diagnosis. A secondary cause of hypertension must be suspected if it is severe or resistant to treatment, if there is a sudden increase in blood pressure in a patient hitherto well controlled, or if it develops in childhood or in a person under 30 years of age, especially if not obese and without a family history of hypertension. In these instances the frequency of hypertension varies from 1-5% for mild to moderate to 10-20% for severe or refractory hypertension. One of the principal causes of secondary hypertension is related to adrenal gland tumors or dysfunctions such as Cushing's syndrome, primary aldosteronism (Conn's syndrome) and pheochromocytoma. This paper will discuss the clinical presentation and diagnostic tests pertinent to these neoplasms, organ damage assessment, utilization of imaging techniques, and the medical and surgical options. PMID- 20922703 TI - [Renal function in primary hyperparathyroidism]. AB - The kidney is one of the classical target organs of PTH action. Symptomatic primary hyperparathyroidism (PHPT) is nowadays less frequent but mostly occurs with renal symptoms, in particular kidney stones. Nephrocalcinosis and polyuria, the latter closely related to the severity of hypercalcemia, are uncommon. Parathyroidectomy leads to a marked and long-lasting improvement of nephrolithiasis, whereas it has a limited effect on nephrocalcinosis. Kidney failure is one of the long-term complications of PHPT and is associated with a more severe clinical expression of the disease and a higher risk of morbidity and mortality. Current guidelines on the management of asymptomatic PHPT, the most common presentation of PHPT today, recommend surgical treatment if renal function is decreased. However, in this particular clinical setting it is unclear whether PHPT is really associated with a more rapid decline of renal function or whether successful parathyroidectomy could protect renal function. PMID- 20922704 TI - [Neoplastic polyendocrine syndromes and the kidney]. AB - Some neoplastic polyendocrine syndromes may affect the kidney. These include multiple endocrine neoplasia type 1 and 2 (MEN 1, MEN 2) as well as mixed syndromes characterized by endocrine and non-endocrine diseases. Kidney involvement may be related to secondary systemic hypertension or diabetes mellitus, direct hormonal effects, and benign or malignant kidney tumors or kidney malformations (very rare). Neoplastic polyendocrine syndromes are rare and it is important that the endocrinologist knows the possible renal complications or associated diseases for correct screening, and that the nephrologist is aware of the need for endocrinological assessment in young hypertensive patients who are resistant to therapy, hypertensive patients with adrenal lesions, and patients with hypercalciuria or renal calculi, especially at a young age. PMID- 20922705 TI - Ultrasound-guided tandem placement for low-dose-rate brachytherapy in advanced cervical cancer minimizes risk of intraoperative uterine perforation. AB - OBJECTIVES: Tandem placement as part of low-dose-rate (LDR) brachytherapy boost for cervical cancer may be complicated by uterine perforation. The objective of this study was to describe a 10-year experience of using intraoperative ultrasound guidance in an attempt to minimize the risk of uterine perforation. METHODS: Operative and inpatient records were reviewed to identify cases in which intraoperative ultrasound guidance was employed in order to assist tandem placement, and to determine whether clinical or radiographic findings subsequently suggested uterine perforation. Demographic factors were collected in order to determine the baseline risk of perforation within this population. RESULTS: Between 1998 and 2008, 71 patients underwent 110 ultrasound-guided placements of tandem applicators. The median age was 48 (range, 26-88) years, and 20% were older than 60 years. Disease stage was FIGO IB1 (n = 10), IB2 (n = 13), IIA (n = 4), IIB (n = 19), IIIA (n = 2), IIIB (n = 16), IVA (n = 5) and IVB (n = 2). The median gravidity was 3 (range 1-10) and median parity was 3 (range 0-10). Seven patients had a preimplant history of pelvic infection, four had a history of intrauterine contraceptive device use, and 10 had a prior history of Cesarean section delivery. Only one patient experienced infection that may have been attributable to tandem placement-associated uterine perforation. At median survivor follow-up of 34 months, 19 patients had died. The estimated 3-year disease-free and overall survival rates for the entire population were 60% and 66%, respectively. CONCLUSIONS: Within the present population, intraoperative ultrasound guidance of tandem placement was associated with no confirmed cases of uterine perforation. PMID- 20922706 TI - Effects of the use of phytosterol/-stanol-enriched margarines on adherence to statin therapy. AB - PURPOSE: The use of margarines enriched with phytosterols or phytostanols is recommended as an appropriate adjunctive therapy for patients with certain lipid profiles, but may result in a behavioral modification leading to a change in person's adherence to lipid-lowering drug treatment. This study aimed to examine the influence of the use of margarines enriched with phytosterols/-stanols on adherence to statin therapy. METHODS: Retrospective data from food frequency questionnaires were used to assess phytosterol/-stanol-enriched margarine intake from a population based, longitudinal cohort between 1998 and 2007. Intake data were linked to pharmacy-dispensing records. Multivariate Cox proportional-hazards models were used to calculate hazard ratios for discontinuation of statin therapy. Drug-taking compliance was compared between users and non-users of enriched margarine using the Mann-Whitney U-test. Pre-defined subgroup analyses were performed to evaluate differences in adherence between prevalent statin users and starters of statins. RESULTS: Among 4848 subjects, 522 used statins only and 60 combined these drugs with phytosterol/-stanol-enriched margarine. Overall statin discontinuation rates were not significantly different between the users and non-users of enriched margarine, but more combination users discontinued statin therapy within 12 months in the subgroup of starters (HR(adj) : 2.52 [95%CI: 1.06-6.00]). Drug-taking compliance was high in both users and non users of enriched margarine and was slightly lower in combination users (P<0.10). CONCLUSIONS: These results imply that persons who combine enriched margarines with statins may neglect taking their drug according to the prescription. Further investigations in larger populations are important, especially among patients susceptible to a low adherence to drug therapy. PMID- 20922707 TI - Use of multiple international healthcare databases for the detection of rare drug associated outcomes: a pharmacoepidemiological programme comparing rosuvastatin with other marketed statins. AB - BACKGROUND: Statins (inhibitors of 3-hydroxy-3-methyl-glutaryl-CoA reductase) are associated with rare but serious adverse events involving the muscle, kidney and liver. To compare the safety profile of rosuvastatin with other marketed statins, four pharmacoepidemiological studies were conducted using different national healthcare databases. These studies used a coordinated methodology to facilitate future meta-analysis. OBJECTIVE: To achieve enhanced estimates of rosuvastatin safety relative to other statins, by performing a meta-analysis of four rosuvastatin safety studies. METHODS: Outcomes were identified using computerised codes, and validated using hospital records or questionnaires. Incidence estimates were based on current statin exposure. Incidence estimates for hospitalised myopathy, rhabdomyolysis, acute renal failure and acute liver injury among users of rosuvastatin and users of other statins were pooled across studies using a weighted average corresponding to the Mantel-Haenszel estimate of the common relative risk. RESULTS: More than 29,900 person-years were accrued for rosuvastatin use and more than 166,900 person-years were accrued for other statin use. Relative to other statins, rosuvastatin was not associated with significant differences in the incidence of hospitalised myopathy (+0.5 cases per 10,000 person-years; 95%CI: -0.6 to 1.6), rhabdomyolysis (+0.7 cases per 10,000 person years; 95%CI: -0.3 to 1.6), acute renal failure (-0.2 cases per 10,000 person years; 95%CI: -2.9 to 2.5) or acute liver injury (-0.8 cases per 10,000 person years; 95%CI: -1.8 to 0.2). CONCLUSION: In this large sample (~ 200,000 person years), no significant difference in the risk of myopathy, rhabdomyolysis, acute liver injury or acute renal failure was seen between rosuvastatin and other statins. PMID- 20922708 TI - Gabapentin and suicide attempts. AB - PURPOSE: On 16 December 2008, FDA issued a class warning for antiepileptic drugs and suicidal thoughts and behavior. The purpose of this study was to determine if the antiepileptic drug gabapentin increases risk of suicide attempt in patients to which it was prescribed for various indications. METHODS: We conducted a pharmacoepidemiologic study in which suicide attempt rates were compared before and after gabapentin was prescribed. We used the PharMetrics medical claims database to study the relationship between gabapentin and suicide attempts in a cohort of 131,178 patients with a 1-year window of information before and after initial prescription. Patients had diagnoses of epilepsy, pain disorders, bipolar illness, major depressive disorder, schizophrenia, and other psychiatric disorders. RESULTS: Overall, there was no significant difference in suicide attempt rates before (3.48/1000 patient years--PY) versus after (3.45/1000 PY) gabapentin prescription. Pre-prescription suicide attempt rates were five times higher in psychiatric populations compared with non-psychiatric populations leading us to analyze the two groups separately. No drug effect was detected in the non-psychiatric populations. Significant reductions in suicide attempt rates were seen for bipolar disorder (47.85/1000 PY versus 31.46/1000 PY), major depressive disorder (17.30/1000 PY versus 12.66/1000 PY), and other psychiatric disorders (12.84/1000 PY versus 10.14/1000 PY). Person-time analysis revealed an overall significant reduction in suicide attempt rates (2.01/1000 PY on drug versus 2.30/1000 PY off drug). CONCLUSIONS: This study finds that gabapentin does not increase risk of suicide attempts in non-psychiatric populations and is associated with a reduction in suicide attempt risk in patients with psychiatric disorders. PMID- 20922709 TI - Identification of hospitalizations for intentional self-harm when E-codes are incompletely recorded. AB - CONTEXT: Suicidal behavior has gained attention as an adverse outcome of prescription drug use. Hospitalizations for intentional self-harm, including suicide, can be identified in administrative claims databases using external cause of injury codes (E-codes). However, rates of E-code completeness in US government and commercial claims databases are low due to issues with hospital billing software. OBJECTIVE: To develop an algorithm to identify intentional self harm hospitalizations using recorded injury and psychiatric diagnosis codes in the absence of E-code reporting. METHODS: We sampled hospitalizations with an injury diagnosis (ICD-9 800-995) from two databases with high rates of E-coding completeness: 1999-2001 British Columbia, Canada data and the 2004 US Nationwide Inpatient Sample. Our gold standard for intentional self-harm was a diagnosis of E950-E958. We constructed algorithms to identify these hospitalizations using information on type of injury and presence of specific psychiatric diagnoses. RESULTS: The algorithm that identified intentional self-harm hospitalizations with high sensitivity and specificity was a diagnosis of poisoning, toxic effects, open wound to elbow, wrist, or forearm, or asphyxiation; plus a diagnosis of depression, mania, personality disorder, psychotic disorder, or adjustment reaction. This had a sensitivity of 63%, specificity of 99% and positive predictive value (PPV) of 86% in the Canadian database. Values in the US data were 74, 98, and 73%. PPV was highest (80%) in patients under 25 and lowest those over 65 (44%). CONCLUSIONS: The proposed algorithm may be useful for researchers attempting to study intentional self-harm in claims databases with incomplete E-code reporting, especially among younger populations. PMID- 20922710 TI - Current trends in robot assisted surgery: a survey of gynecologic oncologists. AB - BACKGROUND: To evaluate the perceptions of the importance and utility of robot assisted surgery in gynecologic oncology. METHODS: A 39 question web-based survey was sent to members of the Society of Gynecologic Oncologists. RESULTS: The survey response rate was 28%, with 277 surveys completed. Nearly 40% of respondents felt robotic surgical training was required as a part of their career goals, and 73% of respondents have performed a robotic hysterectomy. Among respondents, 39% felt that robotic surgery was as good as laparoscopic surgery but 23% thought robot assisted surgery should be the gold standard for the treatment of endometrial cancer. CONCLUSIONS: Robot assisted surgery is gaining widespread acceptance and is perceived to be as good as laparoscopic surgery for the treatment of early stage endometrial and cervical cancers. Among respondents the greatest benefit of robot assisted surgery was its ease of use and perceived improvement in a patient's quality of life. PMID- 20922711 TI - Lack of KISS1R expression is associated with rapid progression of conventional renal cell carcinomas. AB - The mortality of patients with conventional renal cell carcinomas (RCC) correlates directly with the development of metastasis, which cannot be reliably predicted simply by TNM classification. The aim of this study was to identify genes associated with the tumour progression. We have analysed the global gene expression in conventional RCCs, including those with and without progression by Affymetrix GeneChip and selected the genes by gene set enrichment analysis. The expression and function of KISS1R was validated by RT-PCR, western blotting and immunohistochemistry and by in vitro experiments. An immunohistochemical and clinical follow-up study showed that lack of KISS1R expression is associated with rapid progression of tumours. In vitro studies showed that activation of KISS1/KISS1R signalling by kisspeptin treatment decreases the motility and invasive capacity of tumour cells. The kisspeptin treatment also induces the expression of KISS1R in tumour cells in vitro and activates signalling in cases without constitutional expression of the receptor. Expression of the KISS1R protein can be used for estimating the prognosis of conventional RCCs. Confirming the activation of KISS1R signalling in vivo may open a way for kisspeptin treatment of patients with conventional RCCs. PMID- 20922712 TI - Pin1 acts as a modulator of cell proliferation through alteration in NF-kappaB but not beta-catenin/TCF4 signalling in a subset of endometrial carcinoma cells. AB - Prolyl isomerase Pin1 is frequently up-regulated in a variety of human malignancies, modulating signalling in several oncogenic pathways, including those involving NF-kappaB and beta-catenin. Our previous study provided evidence that alterations in these signal pathways are essential events during trans differentiation of endometrial carcinoma (Em Ca) cells. Here we focused on the functional roles of Pin1. In normal endometrium, Pin1 expression showed a stepwise decrease from proliferative to secretory phases during the menstrual cycle, correlating positively with cell proliferation and expression of several cell cycle-related molecules including E2F1 and pRb. Transfection of E2F1 caused transactivation of Pin1, indicating control by E2F1/Rb pathways. In Em Cas with morules, Pin1 expression was found to be significantly increased in glandular but not in morular components, correlating inversely with nuclear accumulation of beta-catenin. Overexpression also caused an increase in the stability of nuclear p65, leading to enhancement of NF-kappaB-mediated transactivation of the cyclin D1 gene, in contrast to minimal inhibition of beta-catenin/TCF4 transcription activity. These findings indicate that Pin1 may play an important role in preserving cell proliferative activity in glandular carcinoma components through enhancement of NF-kappaB signalling, but its down-regulation may be a key signal for induction of trans-differentiation of Em Ca cells, contributing to a shift from NF-kappaB to beta-catenin/TCF signalling pathways. PMID- 20922713 TI - Proposal for a modified grading system based on mitotic index and Bcl2 provides objective determination of clinical outcome for patients with breast cancer. AB - We hypothesized that the interaction between mitotic index (M) and Bcl2 could accurately discriminate between low- and high-grade breast cancer (BC) and provide a more objective measure of clinical outcome than histological grade, especially for patients with intermediate histological grade (G2), small size or oestrogen receptor (ER)-negative cancers. A well-characterized series of 1650 BCs with long-term follow-up was subjected to immunohistochemical analysis for Bcl2. Mitotic index (M) was assessed according to Nottingham Grading System (NGS) guidelines: M1: < 10 mitoses; M2: 10-18 mitoses; M3: > 18 mitoses. Results were validated in an independent series of patients (n = 245) uniformly treated with adjuvant anthracycline-based chemotherapy. Subsequently, BCs were classified according to the combined M/Bcl2 profile and compared with NGS. Multivariate Cox regression models using validated prognostic factors demonstrated that the subgroups defined by M/Bcl2 profile remained significantly associated with patients' outcome but also performed better than lymph node status and tumour size. Incorporation of the M/Bcl2 profile into the Nottingham Prognostic Index (NPI) reclassified twice as many patients into the excellent prognosis group, potentially improving decision-making and sparing patients unneeded systemic adjuvant therapy. Patients with M2-3/Bcl2- and M3/Bcl2+ (high risk) had a two- to three-fold increased risk of recurrence when treated with either adjuvant hormone therapy or anthracycline-based chemotherapy compared with those with M1/Bcl2 +/- and M2/Bcl2+ (low risk) [HR = 3.4 (2.8-5.6); p < 0.0001 and HR = 2.3 (1.2-4.3); p = 0.0009]. In conclusion, a grading system defined by mitotic counting and Bcl2 expression accurately reclassified patients with NGS-G2, small tumour size or ER negative cancers into two groups: low risk (NGS-G1-like) versus high risk (NGS-G3 like) of BC mortality and recurrence, improving prognosis and therapeutic planning. PMID- 20922714 TI - AMP-activated protein kinase: 'a cup of tea' against cholesterol-induced neurotoxicity. AB - Disturbances in brain cholesterol metabolism have been linked to Alzheimer's disease (AD) pathology. A high-cholesterol diet increases fibrillar amyloid beta peptide (Abeta) deposition, inflammation, and apoptosis that eventually results in neurodegeneration and learning and memory impairments. In the October 2010 issue of The Journal of Pathology, Lu and colleagues provided a novel and interesting mechanism that explains how quercetin, a flavonoid found at high concentrations in green and black teas, may help to protect against cholesterol induced neurotoxicity through activation of AMP-activated protein kinase (AMPK), a metabolic energy gauge. Further work will be necessary to address whether AMPK may be a potential target to combat neurodegenerative diseases. PMID- 20922716 TI - Tuning the HOMO energy levels of organic dyes for dye-sensitized solar cells based on Br-/Br3- electrolytes. AB - A series of novel metal-free organic dyes TC301-TC310 with relatively high HOMO levels were synthesized and applied in dye-sensitized solar cells (DSCs) based on electrolytes that contain Br(-)/Br(3)(-) and I(-)/I(3)(-). The effects of additive Li(+) ions and the HOMO levels of the dyes have an important influence on properties of the dyes and performance of DSCs. The addition of Li(+) ions in electrolytes can broaden the absorption spectra of the dyes on TiO(2) films and shift both the LUMO levels of the dyes and the conduction band of TiO(2), thus leading to the increase of J(sc) and the decrease of V(oc). Upon using Br( )/Br(3)(-) instead of I(-)/I(3)(-), a large increase of V(oc) is attributed to the enlarged energy difference between the redox potentials of electrolyte and the Fermi level of TiO(2), as well as the suppressed electron recombination. Incident photon to current efficiency (IPCE) action spectra, electrochemical impedance spectra, and nanosecond laser transient absorption reveal that both the electron collection yields and the dye regeneration yields (Phi(r)) depend on the potential difference (the driving forces) between the oxidized dyes and the Br( )/Br(3)(-) redox couple. For the dyes for which the HOMO levels are more positive than the redox potential of Br(-)/Br(3)(-) sufficient driving forces lead to the longer effective electron-diffusion lengths and almost the same efficient dye regenerations, whereas for the dyes for which the HOMO levels are similar to the redox potential of Br(-)/Br(3)(-), insufficient driving forces lead to shorter effective electron-diffusion lengths and inefficient dye regenerations. PMID- 20922717 TI - Fluorescence spectroscopic evidence for hydrogen bonding and deprotonation equilibrium between fluoride and a thiourea derivative. AB - Interaction of anions with thiourea-linked acridinedione fluorophore was studied by absorption, (1)H NMR, steady-state and time-resolved fluorescence techniques. Addition of AcO(-) and H(2)PO(4)(-) shows a genuine H-bonded complex with thiourea receptor; whereas, F(-) shows stepwise H-bonding and deprotonation of thiourea NH as confirmed by (1)H NMR titration. Free receptor 1 shows emission maximum at 418 nm; whereas, H-bonded complex of 1.F(-) shows a new redshifted emission maximum at 473 nm and the deprotonated 1 exhibits an emission peak at 502 nm. Presence of these three different emitting species was probed by 3D emission spectroscopic studies. Equilibrium between the free receptor 1, 1.F(-) H bonded complex and deprotonated 1 was confirmed by time-resolved fluorescence studies. Time-resolved area normalised emission spectra (TRANES) of 1 in the presence of F(-) shows two isoemissive points at 456 and 479 nm between time delays of 0-0.5 ns and 1-20 ns, respectively, due to the existence of three emitting species in equilibrium. Observation of such an equilibrium based on fluorescence spectroscopic studies further proves the earlier reported absorption and (1)H NMR spectroscopic studies of H-bonding and deprotonation processes and also illustrates the dynamics of anion-receptor interactions. PMID- 20922715 TI - Diabetes as a disease of endoplasmic reticulum stress. AB - Endoplasmic reticulum (ER) stress is an integral part of life for all professional secretory cells, but it has been studied to greatest depth in the pancreatic beta-cell. This reflects both the crucial role played by ER stress in the pathogenesis of diabetes and also the exquisite vulnerability of these cells to ER dysfunction. The adaptive cellular response to ER stress, the unfolded protein response, comprises mechanisms to both regulate new protein translation and a transcriptional program to allow adaptation to the stress. The core of this response is a triad of stress-sensing proteins: protein kinase R-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1 (IRE1) and activating transcription factor 6. All three regulate portions of the transcriptional unfolded protein response, while PERK also attenuates protein synthesis during ER stress and IRE1 interacts directly with the c-Jun amino-terminal kinase stress kinase pathway. In this review we shall discuss these processes in detail, with emphasis given to their impact on diabetes and how recent findings indicate that ER stress may be responsible for the loss of beta-cell mass in the disease. PMID- 20922718 TI - Electron attachment to a hydrated DNA duplex: the dinucleoside phosphate deoxyguanylyl-3',5'-deoxycytidine. AB - The minimal essential section of DNA helices, the dinucleoside phosphate deoxyguanylyl-3',5'-deoxycytidine dimer octahydrate, [dGpdC](2), has been constructed, fully optimized, and analyzed by using quantum chemical methods at the B3LYP/6-31+G(d,p) level of theory. Study of the electrons attached to [dGpdC](2) reveals that DNA double strands are capable of capturing low-energy electrons and forming electronically stable radical anions. The relatively large vertical electron affinity (VEA) predicted for [dGpdC](2) (0.38 eV) indicates that the cytosine bases are good electron captors in DNA double strands. The structure, charge distribution, and molecular orbital analysis for the fully optimized radical anion [dGpdC](2)(.-) suggest that the extra electron tends to be redistributed to one of the cytosine base moieties, in an electronically stable structure (with adiabatic electron affinity (AEA) 1.14 eV and vertical detachment energy (VDE) 2.20 eV). The structural features of the optimized radical anion [dGpdC](2)(.-) also suggest the probability of interstrand proton transfer. The interstrand proton transfer leads to a distonic radical anion [d(G H)pdC:d(C+H)pdG](.-), which contains one deprotonated guanine anion and one protonated cytosine radical. This distonic radical anion is predicted to be more stable than [dGpdC](2)(.-). Therefore, experimental evidence for electron attachment to the DNA double helices should be related to [d(G-H)pdC:d(C+H)pdG](. ) complexes, for which the VDE might be as high as 2.7 eV (in dry conditions) to 3.3 eV (in fully hydrated conditions). Effects of the polarizable medium have been found to be important for increasing the electron capture ability of the dGpdC dimer. The ultimate AEA value for cytosine in DNA duplexes is predicted to be 2.03 eV in aqueous solution. PMID- 20922719 TI - Syntheses and photochromic studies of dithienylethene-containing imidazolium derivatives and their reactivity towards nucleophiles. AB - A series of dithienylethene-containing imidazolium salts with various substituents on the 2-position of the imidazolium ring has been synthesized. The photochromic properties of these compounds have been studied, and the closed forms are found to be solvatochromic due to the donor-acceptor interaction with the solvent molecules. The closed form of the imidazolium salt shows a much higher affinity towards nucleophiles over the open form of the salt. A reaction pathway has been proposed to account for this reactivity difference based on the structure-property relationship, and the possible structure of the reaction product is discussed. PMID- 20922720 TI - A series of vanadogermanates from 1D chain to 3D framework built by Ge-V-O clusters and transition-metal-complex bridges. AB - Three novel extended vanadogermanates, {[(en)(2)Cd(2)Ge(8)V(12)O(40)(OH)(8)(H(2)O)][Cd(en)(2)](2)}.6H(2)O (1), {[Zn(2)(dap)(3)][Zn(dap)](2)Ge(6)V(15)O(48)(H(2)O)}[Zn(dap)(2)(H(2)O)](2).3H(2)O (2), and {[Cd(3)(MU dien)(2)(Hdien)(2)(H(2)O)(2)]Ge(4)V(16)O(42)(OH)(4)(H(2)O)}.2H(2)O (3; en=ethylenediamine, dap=1,2-diaminopropane, dien=diethylenetriamine), have been hydrothermally synthesized and structurally characterized by elemental analysis, IR spectroscopy, powder XRD, thermogravimetric analysis, and single-crystal XRD. Their Ge-V-O cluster anions are derived from the V(18)O(42) cluster shell by replacing VO(5) square pyramids with Ge(2)O(7) groups. Compound 1 exhibits a 1D sinusoidal chain built up from rare inorganic-organic hybrid dicadmium substituted vanadogermanate {[Cd(en)](2)V(12)O(40)(GeOH)(8)(H(2)O)} clusters and [Cd(en)(2)] complexes. Compound 2 is the first example of a 2D network based on linkage of the unusual {Ge(6)V(15)O(48)(H(2)O)} clusters and two types of Zn complex fragments. Compound 3 is an unprecedented 3D framework built by {Ge(4)V(16)O(42)(OH)(4)(H(2)O)} clusters and rare trinuclear bridging complex cations [Cd(3)(MU-dien)(2)(Hdien)(2)(H(2)O)(2)](8+). Magnetic measurements illustrate that both 1 and 2 have antiferromagnetic exchange interactions between metal centers, whereas 3 exhibits ferrimagnetic behavior, which is rare in polyoxovanadate complexes. PMID- 20922721 TI - Synthesis and structural aspects of N-triflylphosphoramides and their calcium salts--highly acidic and effective Bronsted acids. AB - Recently, 1,1'-bi-2-naphthol (BINOL)-based N-triflylphosphoramides emerged as a new class of potent Bronsted acid catalysts. In this paper we describe the efficient synthesis of various BINOL-based N-triflylphosphoramides and their calcium salts. Furthermore, X-ray crystal structure analysis combined with energy dispersive X-ray spectroscopy (EDX) measurements confirmed that the synthesised chiral N-triflylphosphoramides are highly acidic metal-free catalysts. PMID- 20922722 TI - Metal-complex/DNA conjugates: a versatile building block for DNA nanoarrays. AB - The use of DNA networks as templates for forming nanoarrays of metallic centres shows an exciting potential to generate addressable nanostructures. Inorganic units can be photoactive, electroactive and/or can possess magnetic and catalytic properties and can adopt different spatial arrangements due to their varied coordination nature. All these properties influence both the structure and function of passive DNA scaffolds and provide DNA nanostructures as a new platform for new materials in emerging technologies, such as nanotechnology, biosensing or biocomputing. PMID- 20922723 TI - Switchable selectivity during oxidation of anilines in a ball mill. AB - A solvent-free method for the direct oxidation of anilines to the corresponding azo and azoxy homocoupling products by using a planetary ball mill was developed. Various oxidants and grinding auxiliaries were tested and a variety of substituted anilines were investigated. It was possible to form chemoselectively either azo, azoxy, or the nitro compounds from reaction of aromatic anilines. The selectivity of the solvent-free reaction is switchable by applying a combination of oxidant and grinding auxiliary. Furthermore, a comparison with other methods of energy input (microwave, classical heating, and ultrasound) highlighted the advantages of the ball mill approach and its high energy efficiency. PMID- 20922724 TI - Complexation and extraction of PAHs to the aqueous phase with a dinuclear Pt(II) diazapyrenium-based metallacycle. AB - New palladium and platinum metallacycles have been synthesized by reaction between a 2,7-diazapyrenium-based ligand and Pd(II) and Pt(II) complexes. The inclusion complexes between the metallacycles and polycyclic aromatic hydrocarbons (PAHs) in CD(3)NO(2) and D(2)O were studied by NMR spectroscopy. The structures of the inclusion complexes of the Pt metallacycle as host with pyrene, phenanthrene, and triphenylene were confirmed by single crystal X-ray crystallography. The association constants between the Pt metallacycle and the selected PAHs were determined in CH(3)CN following the characteristic charge transfer band displayed in their UV/Vis absorption spectrum. Although in aqueous solution all the complexes showed a 1:1 stoichiometry, in CH(3)CN the Job plot indicated a 2:1 stoichiometry for complexes with triphenylene and benzo[a]pyrene. The estimated association constants in water correlate with the hydrophobicity of the PAH, indicating that hydrophobic forces play an important role in the complexation process. PMID- 20922725 TI - Enzyme mimics based upon supramolecular coordination chemistry. AB - Recent advances in supramolecular coordination chemistry have allowed chemists to synthesize macromolecular complexes that exhibit various properties intrinsic to enzymes. This Review focuses on structures inspired by properties and functions observed in enzymes rather than precise models of enzyme active sites. These structures are synthesized using convergent, modular, and high-yielding coordination-chemistry-based methods, which allow one to tailor the size, shape, and properties of the resulting complexes. Many of the structures discussed exhibit reactivity and specificity reminiscent of natural systems, and some of them have functions that exceed the natural systems which provided the inspiration for initially making them. PMID- 20922726 TI - Reductive dehydroxylation of allyl alcohols by IspH protein. AB - The biosynthesis of natural products is a treasure trove of unusual reaction mechanisms. This Minireview summarizes recent work on the structure and mechanism of IspH protein, which catalyzes the reductive dehydroxylation of an allyl alcohol in a biosynthetic pathway leading to isoprenoid precursors. PMID- 20922727 TI - Climate change and atmospheric chemistry: how will the stratospheric ozone layer develop? AB - The discovery of the ozone hole over Antarctica in 1985 was a surprise for science. For a few years the reasons of the ozone hole was speculated about. Soon it was obvious that predominant meteorological conditions led to a specific situation developing in this part of the atmosphere: Very low temperatures initiate chemical processes that at the end cause extreme ozone depletion at altitudes of between about 15 and 30 km. So-called polar stratospheric clouds play a key role. Such clouds develop at temperatures below about 195 K. Heterogeneous chemical reactions on cloud particles initiate the destruction of ozone molecules. The future evolution of the ozone layer will not only depend on the further development of concentrations of ozone-depleting substances, but also significantly on climate change. PMID- 20922728 TI - Facile two-step synthesis of porous antigen-loaded degradable polyelectrolyte microspheres. PMID- 20922729 TI - Introducing quadrupole interactions into the peptide design toolkit. PMID- 20922730 TI - Water-switching of spin transitions induced by metal-to-metal charge transfer in a microporous framework. PMID- 20922731 TI - Catalytic solvolysis of ammonia borane. PMID- 20922732 TI - Controlled colloidal growth of ultrathin single-crystal ZnS nanowires with a magic-size diameter. PMID- 20922733 TI - Copper-catalyzed direct carboxylation of C-H bonds with carbon dioxide. PMID- 20922734 TI - Fabrication of a structure-specific RNA binder for array detection of label-free microRNA. PMID- 20922735 TI - Combining independent drug classes into superior, synergistically acting hybrid molecules. PMID- 20922736 TI - Unusual E-selective ring-closing metathesis to form eight-membered rings. PMID- 20922737 TI - Design of a highly sensitive fluorescent probe for interfacial electron transfer on a TiO2 surface. PMID- 20922738 TI - FtsK DNA translocase: the fast motor that knows where it's going. AB - FtsK is a double-stranded DNA translocase, a motor that converts the chemical energy of binding and hydrolysing ATP into movement of a DNA substrate. It moves DNA at an amazing rate->5000 bp per second-and is powerful enough to remove other proteins from the DNA. In bacteria it is localised to the site of cell division, the septum, where it functions as a DNA pump at the late stages of the cell cycle, to expedite cytokinesis and chromosome segregation. The N terminus of the protein is involved in the cell-cycle-specific localisation and assembly of the cell-division machinery, whereas the C terminus forms the motor. The motor portion of FtsK has been studied by a combination of biochemistry, genetics, X ray crystallography and single-molecule mechanical assays, and these will be the focus here. The motor can be divided into three subdomains: alpha, beta and gamma. The alpha and beta domains multimerise to produce a hexameric ring with a central channel for dsDNA, and contain a RecA-like nucleotide-binding/hydrolysis fold. The motor is given directionality by the regulatory gamma domain, which binds to polarised chromosomal sequences-5'-GGGNAGGG-3', known as KOPS-to ensure that the motor is loaded onto DNA in a specific orientation such that subsequent translocation is always towards the region of the chromosome where replication usually terminates (the terminus), and specifically to the 28 bp dif site, located in this region. Once the FtsK translocase has located the dif site it then interacts with the XerCD site-specific recombinases to activate recombination. PMID- 20922739 TI - G protein-coupled receptor activation: amino acid movements caught infra-red handed. PMID- 20922740 TI - Synthesis and crystal structure of a phosphorylated estrogen receptor ligand binding domain. PMID- 20922741 TI - An autocatalytic cycle model of asymmetric amplification and mirror-symmetry breaking in the Soai reaction. PMID- 20922743 TI - Entangled photons from a light-emitting diode. PMID- 20922742 TI - Single-molecule fluorescence coincidence spectroscopy and its application to resonance energy transfer. AB - The use of Forster resonance energy transfer (FRET) as a tool to study biomolecules has been greatly enhanced by new advances in single-molecule fluorescence (SMF) techniques. This has allowed new insights into the structure and dynamics of complex biomolecular machinery. However, there are still technical drawbacks in the application of conventional SMF-FRET. Herein, we review the use of single-molecule coincidence spectroscopy to study FRET systems, an analytical variation of the conventional scheme, using one or two confocal lasers of different colours. We highlight the advantages of the coincidence spectroscopy and illustrate this with examples of its application to some biological systems of interest. PMID- 20922744 TI - Towards the discovery of new hypnotic agents: synthesis and preliminary pharmacological evaluation of a novel class of dibenzo[a,d]cycloheptene derivatives. PMID- 20922745 TI - Fusion intermediates of HIV-1 gp41 as targets for antibody production: design, synthesis, and HR1-HR2 complex purification and characterization of generated antibodies. AB - The objective of this project was to study the interaction between HR1 and HR2, the stability of the complex formed, and to characterize the antibodies produced against monomeric HR1 and HR2 peptides as well as the HR1-HR2 complex. In this work, HR1 was mimicked by peptide N36, and HR2 was mimicked by peptide C34L and its analogues C34M2, C34M3, and C34D. Whereas C34M2 and C34M3 are partially composed of D-amino acids, C34D has same sequence as C34L, but is assembled entirely of D-amino acids. Using CD analysis, SPR assays, and gel filtration chromatography, we demonstrate the physical interaction between N36 and C34L and its analogues C34M2 and C34M3, but not C34D. We show that the HR1-HR2 complex is formed rapidly (<1 min) and remains stable, as demonstrated by its inability, in contrast to each free peptide, to inhibit the formation of syncytia. To generate antibodies with predetermined specificity against the transiently exposed intermediate that corresponds to the six-helix bundle structure, purified preformed HR1-HR2 complex was used, in parallel with monomeric HR1 and HR2 peptides, as immunogens in mice. Although the produced antibodies recognize total HIV-1 envelope glycoproteins in ELISA, they are unable to neutralize HIV-1 mediated fusion at 37 degrees C. However, if the incubation with these antibodies is carried out at 27 degrees C, a temperature that allows stabilization of the transient intermediate complex, anti-peptide antibodies are able to bind their corresponding domains in HeLa cells expressing HIV-1 gp41 in co-culture with HeLa CD4-CCR5/CXCR4 during the dynamic mechanism of membrane fusion. In agreement with the latter results, these antibodies, if previously incubated for 2 h at 27 degrees C, are able to strongly neutralize HIV-1 entry by membrane fusion, as shown by their ability to block the formation of syncytia. PMID- 20922746 TI - Feeding the antimalarial pipeline. PMID- 20922747 TI - Molecular assembly of multifunctional 99(m)Tc radiopharmaceuticals using "clickable" amino acid derivatives. AB - Synthetic strategies that enable the efficient and selective combination of different biologically active entities hold great promise for the development of multifunctional hybrid conjugates useful for biochemical and medical applications. Starting from side-chain-functionalized N(alpha)-propargyl lysine derivatives, conjugates containing a 99(m)Tc-based imaging probe for SPECT and two different moieties (e.g., tumor-targeting vectors, pharmacological modifiers, affinity tags, or second imaging probes) can be assembled using the Cu(I) catalyzed alkyne-azide cycloaddition in efficient one-pot protocols. This strategy was successfully applied to the preparation of a 99(m)Tc-labeled conjugate comprising a tumor-targeting peptide sequence (bombesin(7-14)) and a low-molecular-weight albumin binder, a pharmacological modifier that prolongs the blood circulation time of the conjugate. Evaluation of the conjugate in vitro and in vivo provided promising results for its use as an imaging agent for the visualization of tumors positive for the gastrin-releasing peptide receptor. The methodology presented herein provides an attractive synthetic tool for the preparation of multifunctional 99(m)Tc-based radiopharmaceuticals with significant potential for a multitude of applications. PMID- 20922748 TI - Multicomponent reactions for the synthesis of heterocycles. AB - Multicomponent domino reactions (MDRs) serve as a rapid and efficient tool for the synthesis of versatile heterocycles, particularly those containing structural diversity and complexity, by a one-pot operation. These reactions can dramatically reduce the generation of chemical wastes, costs of starting materials, and the use of energy and manpower. Moreover, the reaction period can be substantially shortened. This Review covers recent advances on multicomponent domino reactions for the construction of five-, six-, and seven-membered heterocyclic skeletons and their multicyclic derivatives. PMID- 20922749 TI - Hydrosilylation of ketones: from metal-organic frameworks to simple base catalysts. PMID- 20922750 TI - The design of alpha/beta-peptides: study on three-residue turn motifs and the influence of achiral glycine on helix and turn. AB - Novel three-residue helix-turn secondary structures, nucleated by a helix at the N terminus, were generated in peptides that have 'beta-Caa-L-Ala-L-Ala,' 'beta Caa-L-Ala-gamma-Caa,' and 'beta-Caa-L-Ala-delta-Caa' (in which beta-Caa is C linked carbo-beta-amino acid, gamma-Caa is C-linked carbo-gamma-amino acid, and delta-Caa is C-linked carbo-delta-amino acid) at the C terminus. These turn structures are stabilized by 12-, 14-, and 15-membered (mr) hydrogen bonding between NH(i)/CO(i+2) (i+2 is the last residue in the peptide) along with a 7-mr hydrogen bond between CO(i)/NH(i+2). In addition, a series of alpha/beta-peptides were designed and synthesized with alternating glycine (Gly) and (S)-beta-Caa to study the influence of an achiral alpha-residue on the helix and helix-turn structures. In contrast to previous results, the three 'beta-alpha-beta' residues at the C terminus (alpha-residue being Gly) are stabilized by only a 13-mr forward hydrogen bond, which resembles an alpha-turn. Extensive NMR spectroscopic and molecular dynamics (MD) studies were performed to support these observations. The influence of chirality and side chain is also discussed. PMID- 20922751 TI - Supramolecular porphyrin-DABCO array in single- and double-stranded polynorbornenes. AB - Zinc-porphyrin-appended norbornene derivative 6, the corresponding dimer 7, coherently aligned single-stranded polynorbornene 5, and zinc-porphyrin-linked double-stranded polymeric ladderphane 3 have been used for complexation with 1,4 diazabicyclo[2.2.2]octane (DABCO) to generate an array of porphyrin-DABCO supramolecular scaffolds. The stoichiometries of the complex formation are analyzed in detail by (1)H NMR spectroscopy as well as absorption and emission spectroscopic methods. Bidentate ligand DABCO is found to form with 7, 5, and 3 to give 2-to-1 porphyrin-DABCO sandwich structures. Monomer 6, on the other hand, forms a 2-to-1 porphyrin-DABCO sandwich structure at high concentration (20 mM), but a 1-to-1 porphyrin-DABCO complex at low concentration (10(-6) M). Time resolved fluorescence decays revealed a similar behavior for the 2-to-1 porphyrin DABCO sandwich structures that are formed from 3, 5, and 7. PMID- 20922752 TI - Aryl azide based, photochemical patterning of cyclic olefin copolymer surfaces with non-biofouling poly[(3-(methacryloylamino)propyl)dimethyl(3 sulfopropyl)ammonium hydroxide]. PMID- 20922753 TI - Highly effective Pd-catalyzed ortho olefination of acetanilides: broad substrate scope and high tolerability. PMID- 20922754 TI - Next-generation biofuels: Survey of emerging technologies and sustainability issues. AB - Next-generation biofuels, such as cellulosic bioethanol, biomethane from waste, synthetic biofuels obtained via gasification of biomass, biohydrogen, and others, are currently at the center of the attention of technologists and policy makers in search of the more sustainable biofuel of tomorrow. To set realistic targets for future biofuel options, it is important to assess their sustainability according to technical, economical, and environmental measures. With this aim, the review presents a comprehensive overview of the chemistry basis and of the technology related aspects of next generation biofuel production, as well as it addresses related economic issues and environmental implications. Opportunities and limits are discussed in terms of technical applicability of existing and emerging technology options to bio-waste feedstock, and further development forecasts are made based on the existing social-economic and market situation, feedstock potentials, and other global aspects. As the latter ones are concerned, the emphasis is placed on the opportunities and challenges of developing countries in adoption of this new industry. PMID- 20922755 TI - Use of medaka in toxicity testing. AB - Small aquarium fishes are increasingly used as animal models, and one of these, the Japanese Medaka (Oryzias latipes), is frequently utilized for toxicity testing. While these vertebrates have many similarities with their terrestrial counterparts, there are differences that must be considered if these organisms are to be used to their highest potential. Commonly, testing may employ either the developing embryo or adults; both are easy to use and work with. To illustrate the utility and breadth of toxicity testing possible using medaka fish, we present protocols for assessing neurotoxicity in developing embryos, evaluating toxicant effects on sexual phenotype after treatment with endocrine disrupting chemicals by sexual genotyping, and measuring hepatotoxicity in adult fish after treatment with a model hepatotoxicant. The methods run the gamut from immunohistology through PCR to basic histological techniques. PMID- 20922756 TI - The nematode C. elegans as an animal model to explore toxicology in vivo: solid and axenic growth culture conditions and compound exposure parameters. AB - Significant limitations in vertebrate animal model systems include the time involved, the expense, the fact that in vitro results may not reflect live animal pathology, difficulties in transporting the toxin past the blood brain barrier, and the inability to identify the mechanism of action without some a priori knowledge of the toxin's target. The availability of the complete genome sequence of the nematode C. elegans, coupled with the worm's size, growth rate, ease of culturing, and the realization that basic biological mechanisms and disease processes between worms and humans are highly conserved, makes this genetically tractable model a remarkable opportunity to dissect and identify in vivo the cellular processes involved in toxin-induced cell dysregulation and death. This unit includes protocols for culturing worms on solid and axenic media and acute and chronic exposure parameters for Parkinson's disease-associated toxins and hemin chloride. These methods provide the groundwork for using this powerful model system to further elucidate and understand the molecular mechanisms involved in nutrition as well as toxicological responses relevant to human diseases. PMID- 20922757 TI - Optimization of cyclical electrical field flow fractionation. AB - Cyclical electrical field flow fractionation (CyElFFF) is a variation on electrical field flow fractionation (ElFFF) where cyclical electrical fields are used instead of steady DC fields to increase the effective field experienced by particles in the flow channel. Even though the effective field increases more than 20-fold compared to normal ElFFF, the retention and resolution in CyElFFF has not been shown to be better than in ElFFF. In this paper we report how one can optimize operational parameters in CyElFFF to obtain good retention and resolution in CyElFFF. The effects of offset voltage, frequency, flowrate, concentration of particles and sample size on retention, resolution and retained peak/void peak ratio have been observed. The results obtained from these experiments were analyzed and suggestions have been made to improve both retention and resolution. A 4-fold improvement in retention without a significant increase in band broadening is reported. PMID- 20922758 TI - Online immunoaffinity assay-CE using magnetic nanobeads for the determination of anti-Helicobacter pylori IgG in human serum. AB - About two-thirds of the world's population is infected with Helicobacter pylori (H. pylori). This Gram-negative bacterium is the most important etiological agent of chronic active type B gastritis and peptic ulcer diseases. Conventional methods such as gastric biopsy, ELISA and culture, require a long time for the determination of H. pylori infections. Moreover, the antibodies in human serum sample are capable to react immunologically with the purified H. pylori antigens immobilized on different kinds of support like magnetic nanobeads. In this study, we have developed an online immunoaffinity assay-CE to determine the concentration of anti-H. pylori IgG using magnetic nanobeads as a support of the immunological affinity ligands and an LIF as a detector. The separation was performed in 0.1 M glycine-HCl, pH 2, as the background electrolyte. The linear calibration curve to predict the concentration of H. pylori-specific immunoglobulin G antibodies in serum was produced within the range of 0.12-100 U/mL. The linear regression equation was i = 492.86+96.03 * C(anti-H. pylori), with the linear regression coefficient r(2) = 0.999. The LOD calculated by fluorescence detection procedure was of 0.06 U/mL. The whole assay was done in no more than 35 min and it was entirely automatized. The development of immunoaffinity assay-CE in this study demonstrates that there is a large possibility to introduce nanotechnology in several fields with significant advantages over the classic methodologies. Our proposition comprises the diagnosis and screening field. PMID- 20922759 TI - The use of novel ionic liquid-in-water microemulsion without the addition of organic solvents in a capillary electrophoretic system. AB - In this work, a new ionic liquid-in-water (IL/W) microemulsion without requiring toxic organic solvents was investigated as a pseudostationary phase (PSP) in CE. As observed during the IL/W microemulsion system, a fast and an efficient separation of eight phenolic acids was achieved using 1-butyl-3 methylimidazolivmhexa fluorophosphate (bmimPF(6)) as oil drops, Tween 20 as the surfactant, and borate as the BGE. The effects of oil phase, surfactant, buffer and pH on the separation were explored in detail to evaluate the novel PSP. In contrast, the detection efficiency of these same analytes was markedly decreased using oil-in-water (O/W) MEEKC. We have also validated the practicality of the IL/W microemulsion method by quantitative determination of acidic compounds in pharmaceutical injection. The results obtained indicated that an additional association between the IL cations and analytes tested seemed to play a prominent role in the separation mechanism exhibited by this novel PSP compared with the conventional O/W MEEKC. PMID- 20922760 TI - Determination of inorganic ions in mineral water by gradient elution moving boundary electrophoresis. AB - A sensitive method was developed for the determination of the major inorganic ions in commercial mineral waters using gradient elution moving boundary electrophoresis with capacitively coupled contactless conductivity detection. This application was the first to demonstrate the separation of cations and anions simultaneously using gradient elution moving boundary electrophoresis. Seven ionic analytes (calcium, chloride, magnesium, nitrate, potassium, sodium, and sulfate) were separated in less than 7 min with detection values in the low MUmol/L to sub-MUmol/L range. Calculated values of the major ions in three commercial mineral waters were compared to reported values with good correlation. In another application, phosphate and arsenate were separated in less than 2 min with limits of detection of 300 and 140 nmol/L, respectively. For all standard analyses, the RSD for migration times and peak areas were under 3%. PMID- 20922761 TI - Physical interpretation of the L(r) parameter in the theory for the gel electrophoresis of partially denatured DNA. AB - Partial strand melting of dsDNA during gel electrophoresis typically results in an abrupt reduction of mobility. Several DNA analysis technologies are based on this phenomenon. Inspired by the de Gennes' theory for the reptation of branched polymers in gels, Lerman et al. (Ann. Rev. Biophys. Bioeng. 1984, 13, 399-423) proposed a mathematical expression to predict this reduced mobility. The latter contains only two parameters: the average number of denatured bases p (which can be obtained using a theory for DNA melting) and a constant L(r). However, there is confusion in the literature regarding the physical interpretation of L(r) and little is known about its dependence upon experimental parameters. The purpose of this short communication is to derive an explicit equation for the parameter L(r) from the de Gennes theory of reptation. Our derivation shines light on the meaning of L(r), clarifies the scope of the underlying approximations, and makes predictions about the dependence of L(r) upon the gel pore size and the persistence length of ssDNA. PMID- 20922762 TI - Interaction of uranyl with Se(IV) and Se(VI) in aqueous acid solutions by means of capillary electrophoresis. AB - The uranyl-selenium(IV) and uranyl-selenium(VI) interactions were studied by CE in aqueous acid solutions, containing U(VI) and Se(IV) or Se(VI) at different concentrations, at pH 1.5, 2.0 and 2.5. The method proposed in this paper allows one with the use of CE data on metal ion mobilities at different pHs to establish the ligand species interacting with metal ion and complex species formed. In the case of Se(VI) a selenate, as demonstrated, interacts with uranyl ions, in the case of Se(IV) this is a hydroselenite. It was also shown that the equilibria for the U(VI)-Se(VI) and U(VI)-Se(IV) systems can be established from CE data. The formation of UO(2)SeO(4), UO(2)(SeO(4))(2) (2-), UO(2)HSeO(3) (+) and UO(2)(HSeO(3))(2) species is demonstrated. The stability constant values were measured at different ionic strengths (from 0.02 to 0.2 mol/L). The logarithms of the stability constant values (beta degrees ) extrapolated to ionic strength 0 by the specific ion interaction theory (SIT) are found to be log beta degrees (1) = 2.93 +/- 0.06 for UO(2)SeO(4) formation, log beta degrees (2) = 4.030.18 for UO(2)(SeO(4))(2) (2-) formation, log beta degrees (1) = 3.270.15 for UO(2)HSeO(3) (+) formation and log beta degrees (2) = 5.510.11 for UO(2)(HSeO(3))(2) at 25 degrees C. The results for the first constant values for each of systems are consistent with the published values. For UO(2)(SeO(4))(2) (2-) formation, a new constant stability value is given. The existence of UO(2)(HSeO(3))(2) complex species is demonstrated and its constant stability value is given for the first time. PMID- 20922764 TI - Assessing the impact of paediatric oncology publications using three citation databases. AB - Despite some reported limitations, Web of Science has been the standard source to assess the impact of individual articles, and consequently journals. By analysing the citations to articles published in the field of paediatric oncology, we demonstrate that Scopus and Google Scholar, the two new citation databases, retrieve more citations than Web of Science. The strength of Scopus lies in identifying non-English literature from Western and Eastern Europe, while Google Scholar is proficient at identifying English and non-English literature from Africa, Asia and Central and South America. These findings have implications for researchers, journals and health libraries. PMID- 20922763 TI - National Cancer Institute pediatric preclinical testing program: model description for in vitro cytotoxicity testing. AB - BACKGROUND: The National Cancer Institute (NCI) has established the Pediatric Preclinical Testing Program (PPTP) for testing drugs against in vitro and in vivo childhood cancer models to aid in the prioritization of drugs considered for early phase pediatric clinical trials. PROCEDURES: In vitro cytotoxicity testing employs a semi-automated fluorescence-based digital imaging cytotoxicity assay (DIMSCAN) that has a 4-log dynamic range of detection. Curve fitting of the fractional survival data of the cell lines in response to various concentrations of the agents was used to calculate relative IC(50) , absolute IC(50) , and Y(min) values. The panel of 23 pediatric cancer cell lines included leukemia (n = 6), lymphoma (n = 2), rhabdomyosarcoma (n = 4), brain tumors (n = 3), Ewing family of tumors (EFT, n = 4), and neuroblastoma (n = 4). The doubling times obtained using DIMSCAN were incorporated into data analyses to estimate the relationship between input cell numbers and final cell number. RESULTS: We report in vitro activity data for three drugs (vincristine, melphalan, and etoposide) that are commonly used for pediatric cancer and for the mTOR inhibitor rapamycin, an agent that is currently under preclinical investigation for cancer. To date, the PPTP has completed in vitro testing of 39 investigational and approved agents for single drug activity and two investigational agents in combination with various "standard" chemotherapy drugs. CONCLUSIONS: This robust in vitro cytotoxicity testing system for pediatric cancers will enable comparisons to response data for novel agents obtained from xenograft studies and from clinical trials. PMID- 20922765 TI - Clinical complications in severe pediatric sickle cell disease and the impact of hydroxyurea. AB - BACKGROUND: More evidence of the safety and effectiveness of hydroxyurea (HU) in community-based cohorts of pediatric patients with sickle cell disease (SCD) are needed. The association of HU with organ-specific clinical complications and adverse events is examined herein. METHODS: Medicaid medical and pharmacy claims for the calendar years January 1996 through December 2006 were used to identify a cohort of children and adolescent patients (ages 17 and under) with a diagnosis of SCD (homozygous) who were treated with HU and developed disparate complications or adverse side effects. Of the 2,194 pediatric SCD patients identified, 175 (8%) were treated with HU. Incidence density matching (1 case: 2 controls) was used to select the control group on age, gender, ethnicity, time in the Medicaid data set, and baseline severity resulting in a total study cohort of 523 cases. RESULTS: Organ-specific complications were more likely in the HU treated group compared to non-HU-treated group: cardiovascular complications (odds ratio [OR] = 3.15; confidence interval [CI] = 1.97-5.03); hepatic complications (OR 5.41; CI = 3.54-8.27); renal complications (OR 5.09; CI 3.37 7.67); and pulmonary complications (OR 4.07; CI 1.88-8.79). Many of these conditions began developing before HU was prescribed. Developing three or more complications was also more likely in the HU group (27.4% vs. 7.0%, P < 0.0001). CONCLUSIONS: Extending previous findings to routine practice settings, HU is being administered to the most severely ill children with SCD, many of whom had already started to develop organ-specific complications, but it is not associated with development of serious adverse events. PMID- 20922766 TI - Do symptoms of anxiety in the terminally ill child affect long-term psychological well-being in bereaved parents? PMID- 20922767 TI - Large-scale immunohistochemical examination for lymphoreticular prion protein in tonsil specimens collected in Britain. AB - There have been 173 cases of variant Creutzfeldt-Jakob disease (vCJD) in the UK, as of 5 July 2010, as a result of the bovine spongiform encephalopathy epidemic. The number of individuals subclinically infected with vCJD, and thus the eventual number of cases, remains, however, uncertain. In an attempt to address this problem, 63,007 tonsil tissue specimens were previously tested by enzyme immunoassay (EIA) for the presence of disease-related prion protein (PrP(res)) and found to be negative. To confirm the reliability of this result, all those in the birth cohort most at risk (1961-1985) and a few others, including controls, have now been tested by immunohistochemistry (IHC). Histological slides were prepared from 10,075 anonymized formalin-fixed, paraffin-embedded tissues and examined for PrP(res) with two anti-prion protein antibodies, ICMS35 and KG9. One specimen showed a single strongly positive follicle with both antibodies, on two slides from adjacent sections. As this specimen was negative when it was further investigated by EIA, IHC, and immunoblotting, it is unclear whether the patient from whom the tonsil came will go on to develop vCJD. If, however, this is the case, then a finding of 1 out of 9160 gives a prevalence of disease-related prion protein in the British population of 109 per million, with a 95% confidence interval (CI) of 3-608 per million, which is not statistically different (exact p = 0.63) from population prevalence estimates based on finding three positives out of 10 278 in a previous IHC study of appendix tissue. If this is not the case, a finding of 0 out of 9160 gives a prevalence of 0-403 per million (95% CI) for the 1961-1985 cohort, which is also not different (exact p = 0.25) from previous population prevalence estimates. Therefore, the results of this work could be summarized as finding, by IHC, no or one vCJD-positive individual. PMID- 20922768 TI - High frequency of cognitive dysfunction before stroke among older people. AB - OBJECTIVES: We examined cognitive functions before and in acute phase of stroke studying frequency and profile of cognitive impairment and relationships between cognitive status. METHODS: Seventy-four patients with early phase after stroke and 49 healthy controls were included and examined using the Mini-Mental State Examination (MMSE) and a battery of neuropsychological tests. Cognitive status before stroke-onset was investigated using Cognitive Impairment Questionnaire. RESULTS: Cognitive impairments were present in 96% of patients after stroke onset using the battery of neuropsychological tests and in 39% of patients using the MMSE, but in only 9% of controls. Seventy-six percent exhibited reduced executive function and 75% reduced psychomotor tempo. Cognitive dysfunction was present in 52% before stroke onset without any impact on the frequency of impairment in the various cognitive areas in early phase after stroke. CONCLUSIONS: Cognitive impairment is frequent before the onset of stroke among older people and may partially explain the very high frequency of cognitive impairment observed after stroke onset. PMID- 20922769 TI - The three latent classes of adolescent delinquency and the risk factors for membership in each class. AB - This study used latent class analysis to examine subpopulation membership based on self-reports of delinquent behaviors obtained from Australian youth. Three discrete identifiable classes were derived based on 51 indicators of physical violence, property damage, minor infractions, drug use, and social delinquency. One class of youth engaged in primarily rule breaking and norm violations including underage alcohol use, typical of this age period. A second class was more actively delinquent emphasizing drug use, trespassing, and various forms of disobedience. A third class of highly delinquent youth differed from their counterparts by endorsing drug use, thievery that involved stealing money, goods, and cars, property damage, gambling, precocious sexual experiences, involvement with pornographic materials, and fighting. Multinomial logistic regression predicting class membership indicated highly delinquent youth were more likely to be older males, use venting coping strategies, and be fun or novelty seeking compared with rule breakers. Findings are discussed in terms of refining current taxonomic arguments regarding the structure of delinquency and implications for prevention of early-stage antisocial behavior. PMID- 20922771 TI - Can epigenetics solve the case of the midwife toad?--a comment on Vargas. AB - In a recent article in this journal, A. O. Vargas (2009. J Exp Zool B (Mol Dev Evol) 312:667-678) suggests to interpret the controversial midwife toad experiments of the early 20th century zoologist Paul Kammerer in the context of epigenetic inheritance. For information on Kammerer's work he resorts to a popular science book (Kammerer, '24. The Inheritance of Acquired Characteristics). However, the study of Kammerer's original publications reveals that there are substantial misunderstandings in Vargas' treatment of the subject. While Vargas' general idea-invoking epigenetic effects as an explanation of Kammerer's findings-remains attractive, at least two key aspects of his model need to be revised. Clarification of these issues is an important prerequisite for any experimental design with the aim to (dis)prove Kammerer and to establish a (potential) epigenetic basis of his observations about the mating behavior in midwife toads. PMID- 20922770 TI - Identifying early signs of aggression: psychometric properties of the Cardiff infant contentiousness scale. AB - Our aim was to develop an age-appropriate measure of early manifestations of aggression. We constructed a questionnaire about normative developmental milestones into which a set of items measuring infants' use of physical force against people and expressed anger were included. These items comprise the Cardiff Infant Contentiousness Scale (CICS). Evidence for the reliability and validity of the CICS is provided from analyses of a sample of N=310 British infants, assessed at a mean age of 6 months as part of a larger longitudinal study of the development of aggression. The informants' CICS ratings demonstrated reasonable levels of internal consistency and interrater agreement. Informants' ratings were validated by observations of infants' distress in response to restraint in a car seat. Longitudinal analyses revealed that contentiousness was stable over time and that contentiousness at 6 months predicted infants' later use of force with peers. When used in the company of other methods, the simple four-item CICS scale could serve as a useful screen for early manifestations of aggressiveness in human infants. PMID- 20922772 TI - Do patients diagnosed with Alzheimer's disease benefit from a psycho-educational programme for family caregivers? A randomised controlled study. AB - OBJECTIVE: The Aide dans la Maladie d'Alzheimer (AIDMA) study was conducted to determine whether a psycho-educational programme (PEP) for primary caregivers in addition to standard anti-dementia drugs for patients improves caregivers' psychological condition and patients' activities of daily life. METHOD: Multicentre randomised controlled intervention trial. One hundred and sixty-seven dyads 'patient-caregiver' were recruited from 15 French memory clinics and randomised in two parallel groups. The intervention group was offered the PEP in 12 group sessions for 3 months. The control group had usual care. Patients in both groups with mild to moderate Alzheimer's disease (AD) were diagnosed and treated with pharmacotherapy. Patients' primary efficacy variable was functional status assessed with the Disability Assessment Scale for Dementia (DAD) scale. Alzheimer Disease Assessment Scale (ADAS-Cog) and Neuropsychiatric Inventory (NPI) were secondary criteria. Caregivers' first outcome measure was depressive symptoms assessed with the Montgomery and Asberg Depression Rating Scale (MADRS) scale. Zarit scale, Sense of Competence Questionnaire (SCQ) and Visual Analogue Scales (VAS) were secondary criteria. Assessment was done at baseline, 3 months (M3, end of intervention) and 6 months (M6). RESULTS: Patients' stabilisation was observed in both groups. In caregivers, significant improvement in disease understanding at M3 (p = 0.007) and M6 (p = 0.0001) and in ability to cope with care-recipients' disease at M6 (0.02) was evidenced. CONCLUSION: The PEP had no additional impact on patients but carers developed more effective disease understanding and ability of coping. Results support the idea that the PEP although improving caregivers' condition is not sufficient to improve patients' activities in daily life which requires additional individually tailored interventions provided by professionals. PMID- 20922773 TI - Birth of the first ESS: George Price, John Maynard Smith, and the discovery of the lost "Antlers" paper. AB - The application of game theory to evolutionary problems is so commonplace today, that few stop to consider how it all began. John Maynard Smith and George R. Price's 1973 Nature article, "The Logic of Animal Conflict," is often referred to as the first description in the literature of the concept of an evolutionary stable strategy (ESS), but what was the "behind the scenes" of the writing of that seminal paper? This article tracks the little known story of the curious American polymath, George Price. As will be shown, it was an earlier paper, the lost "Antlers, Intraspecific Combat, and Altruism," sent by Price to Nature in August 1968 (Unpublished), and refereed by Maynard Smith, which instigated the birth of the first ESS. Recently, the "Antlers" paper has been re-discovered by the author, shedding new light, together with letters and journals from the personal papers of George Price and John Maynard Smith, on their historical paper. PMID- 20922774 TI - Same but different: ontogeny and evolution of the Musculus adductor mandibulae in the Tetraodontiformes. AB - The morphological diversity of fishes provides a rich source to address questions regarding the evolution of complex and novel forms. The Tetraodontiformes represent an order of highly derived teleosts including fishes, such as the pelagic ocean sunfishes, triggerfishes, and pufferfishes. This makes the order attractive for comparative analyses to understand the role of development in generating new forms during evolution. The adductor mandibulae complex, the main muscle associated with jaw closure, represents an ideal model system within the Tetraodontiformes. The adductor mandibulae differs in terms of partitions and their attachment sites between members of the different tetraodontiform families. In order to understand the evolution of the jaws among the Tetraodontiformes, we investigate the development of the adductor mandibulae in pufferfishes and triggerfishes as representatives of two different suborders (Balistoidei and Tetraodontoidei) that follows two different adaptations to a durophagous feeding mode. We show that the varied patterns of the adductor mandibulae derive from similar developmental sequence of subdivision of the partitions. We propose a conserved developmental program for partitioning of the adductor mandibulae as a foundation for the evolution of different patterns of subdivisions in Tetraodontiformes. Furthermore, we argue that derived conditions in the higher taxa are realized by supplementary subdivisions and altered attachment sites. These findings support a reinterpretation of homology of different muscle partitions among the Tetraodontiformes, as muscle partitions previously thought to be disparate, are now clearly related. PMID- 20922776 TI - Uterine myomas during pregnancy: a longitudinal sonographic study. AB - OBJECTIVE: To evaluate volumetric changes of uterine myomas (fibroids) during pregnancy. METHODS: This was an observational, longitudinal and prospective study of 38 consecutive Caucasian women with singleton pregnancies and a total of 42 uterine myomas, enrolled from a cohort of 1492 women who took part in our first trimester Down syndrome screening program. Myoma volume was evaluated by ultrasound at 11-14, 20-22 and 32-34 weeks of gestation. RESULTS: Mean myoma volume increased significantly throughout pregnancy. Taking a volumetric change of > 10% between gestational periods to be an increase in size, 71.4% of uterine myomas increased in size between the first and second gestational periods, while this percentage was slightly lower (66.6%) between the second and third periods. Logistic regression analysis revealed that greater maternal age was correlated with a reduction/no change in overall myoma size and multiparity was correlated with a decrease/no change between the first and second trimesters, while a higher prepregnancy maternal body mass index (BMI) was correlated with a volumetric increase between the first and second trimesters and a decrease/no change between the second and third trimesters. CONCLUSIONS: Fibroids enlarge during pregnancy regardless of their initial size or local factors, and maternal age, prepregnancy BMI and parity are apparently correlated with these changes. PMID- 20922775 TI - Modularity in the mammalian dentition: mice and monkeys share a common dental genetic architecture. AB - The concept of modularity provides a useful tool for exploring the relationship between genotype and phenotype. Here, we use quantitative genetics to identify modularity within the mammalian dentition, connecting the genetics of organogenesis to the genetics of population-level variation for a phenotype well represented in the fossil record. We estimated the correlations between dental traits owing to the shared additive effects of genes (pleiotropy) and compared the pleiotropic relationships among homologous traits in two evolutionary distant taxa-mice and baboons. We find that in both mice and baboons, who shared a common ancestor >65 Ma, incisor size variation is genetically independent of molar size variation. Furthermore, baboon premolars show independent genetic variation from incisors, suggesting that a modular genetic architecture separates incisors from these posterior teeth as well. Such genetic independence between modules provides an explanation for the extensive diversity of incisor size variation seen throughout mammalian evolution-variation uncorrelated with equivalent levels of postcanine tooth size variation. The modularity identified here is supported by the odontogenic homeobox code proposed for the patterning of the rodent dentition. The baboon postcanine pattern of incomplete pleiotropy is also consistent with predictions from the morphogenetic field model. PMID- 20922777 TI - Maxilla-nasion-mandible angle: a new method to assess profile anomalies in pregnancy. AB - OBJECTIVES: To collect normative data and test the feasibility and reproducibility of measurement of the maxilla-nasion-mandible (MNM) angle between 16 and 36 weeks' gestation and its diagnostic ability in a group of pathological cases. METHODS: The MNM angle is defined as the angle between the intersection of the maxilla-nasion and mandible-nasion lines in the exact mid-sagittal plane. After assessing reproducibility, the MNM angle was measured in 3D volumes in 241 fetuses cross-sectionally and in 11 fetuses longitudinally. The MNM angle was then tested in 18 pathological cases with facial malformations or syndromes with specific facial features. RESULTS: The MNM angle could be measured in 92.3% of normal fetuses. Intra- and interobserver intraclass correlation coefficient (ICC) variability was 0.92 and 0.81, respectively. The difference between paired measurements performed by one or two observers was less than 2.5 degrees and 3.6 degrees , respectively in 95% of the cases. The mean MNM angle was 13.5 degrees and did not change significantly during pregnancy (r = - 0.08, P = 0.25). The MNM angle was above the 95(th) centile in all cases of retrognathia and maxillary alveolar ridge interruption. The MNM angle was below the 5(th) centile in Apert syndrome, thanatophoric dysplasia and in two of the three Down syndrome cases. CONCLUSIONS: The feasibility and reproducibility of measurement of the MNM angle is good. The MNM angle can be used to evaluate the convexity of the fetal profile by enabling an objective assessment of the anteroposterior relationship of the jaws and it may therefore be of help in the diagnosis of retrognathia, maxillary alveolar ridge interruption and flat profile. PMID- 20922778 TI - Fetal umbilical artery Doppler to predict compromise of fetal/neonatal wellbeing in a high-risk population: systematic review and bivariate meta-analysis. AB - OBJECTIVE: We investigated the accuracy of fetal umbilical artery Doppler to predict the risk of compromise of fetal/neonatal wellbeing in a high-risk population. METHODS: Searches in MEDLINE, Embase, The Cochrane Library and Medion (from inception to March 2009) were carried out, together with hand searching of relevant journals, reference list checking of included articles and contact with experts. Criteria for selection were observational studies with umbilical artery Doppler used in a high-risk pregnant population with an outcome measure for compromise of fetal/neonatal wellbeing. Data on study design, quality and results were extracted to construct 2 * 2 tables. Bivariate meta-analysis was performed. Likelihood ratios (LRs) were used as the summary measure of accuracy. RESULTS: One-hundred and four studies met the selection criteria (19 191 fetuses). In a high-risk population, umbilical artery Doppler predicted small-for-gestational age with a pooled LR+ of 3.76 (2.96, 4.76) and pooled LR- of 0.52 (0.45, 0.61), and compromise of fetal/neonatal wellbeing with a pooled LR+ of 3.41 (2.68, 4.34) and pooled LR- of 0.55 (0.48, 0.62). In this group it was also possible to predict, with accuracy, intrauterine death (pooled LR+ = 4.37 (0.88, 21.8); pooled LR- = 0.25 (0.07, 0.91)) and acidosis (pooled LR+ = 2.75 (1.48, 5.11); pooled LR- = 0.58 (0.36, 0.94)). CONCLUSIONS: In a high-risk population, fetal umbilical artery Doppler is a moderately useful test with which to predict mortality and risk of compromise. PMID- 20922779 TI - Low-resistance hepatic artery flow in first-trimester fetuses: an ominous sign. AB - OBJECTIVE: Low-resistance hepatic artery (HA) flow has been reported in severely growth-restricted fetuses. The same finding has been incidentally observed in first-trimester fetuses with enlarged nuchal translucency (NT). The aim of this study was to investigate HA flow in first-trimester fetuses. METHODS: Crown-rump length (CRL), NT, ductus venosus (DV) pulsatility index for veins (PIV) and HA pulsatility index (PI) were measured prospectively in fetuses at increased risk on first-trimester assessment for aneuploidy and in a control group of low-risk fetuses. Outcome of pregnancy was known in all cases. Independent sample t-test was used for intergroup comparison. RESULTS: NT, DV-PIV and HA-PI were measured prospectively in 59 fetuses. Thirty-four had an enlarged NT and underwent karyotyping, which was abnormal in 16 cases (trisomy 21, n = 12; trisomy 18, n = 3; 47,XXY, n = 1). Two pregnancies were terminated in view of fetal anomalies. In three other infants an abnormality was confirmed after birth (Noonan syndrome, unspecified genetic syndrome and cardiac defect). The remaining 13 fetuses with enlarged NT and the 25 with normal NT had an uneventful pregnancy outcome. HA-PI was significantly and inversely correlated with NT and DV-PIV. Mean HA-PI was significantly lower in fetuses with adverse outcome (chromosomal anomalies 1.60; chromosomally normal fetuses with adverse outcome 1.66) than in controls (2.03). CONCLUSIONS: Low-resistance HA flow can be observed in first-trimester fetuses and, based on its association with adverse outcome, it can be regarded as an ominous sign. PMID- 20922780 TI - Learning curve for Doppler measurement of fetal modified myocardial performance index. AB - OBJECTIVE: To assess the learning curve for measurement of the fetal modified myocardial performance index (MPI). METHODS: Three trainees with the theoretical knowledge of but without prior experience in performing MPI measurement were selected. Each trainee and one experienced examiner measured MPI in a cohort of 90 consecutive fetuses. The average difference between the three trainees and the expert in the MPI measurements was calculated; a difference below 10% was considered to indicate an accurate measurement. Individual and averaged learning curves were delineated using cumulative sum analysis (CUSUM). RESULTS: The gestational age at evaluation ranged from 20 + 4 to 41 + 4 (mean, 33 + 3) weeks. The CUSUM plots demonstrated that, on average, competence in performing fetal MPI measurement was achieved by 65 cases. The average number of attempts to achieve competence were 42, 77 and 83 for the ejection time, isovolumetric contraction time and isovolumetric relaxation time, respectively. CONCLUSIONS: Evaluation of fetal MPI by an inexperienced trainee requires on average 65 measurements to achieve competence. PMID- 20922781 TI - Persistent right umbilical vein: a prenatal condition worth mentioning? AB - OBJECTIVES: To investigate the incidence and clinical impact of prenatally diagnosed persistent right umbilical vein (PRUV) in a referral population and to evaluate the findings together with those from previous publications. METHODS: This was a retrospective analysis of 39 cases with PRUV diagnosed in three tertiary referral centers for prenatal medicine between 1996 and 2009. Fetuses with situs inversus, situs ambiguous and heterotaxy (left and right isomerism) were excluded. During the study period 46 653 consecutive high- and low-risk pregnancies were examined. The prenatal sonograms and neonatal outcome data of affected individuals were reviewed. Our findings were analyzed together with findings retrieved from the scientific literature. RESULTS: Twenty-nine fetuses had an isolated PRUV as a single anomaly, whereas 10/39 (25.6%) were found to have PRUV accompanied by additional minor and major abnormalities. These anomalies comprised mainly cardiovascular, genitourinary and gastrointestinal malformations. In common with our series, previously published cases of isolated PRUV (n = 197) displayed an uneventful course of pregnancy and a favorable postnatal outcome. Sixty-six previously reported cases of PRUV with additional anomalies were identified in the literature. Intrahepatic umbilical drainage is the most frequent type of PRUV. Including our cases, there were 16 cases (5.3%) with extrahepatic drainage of PRUV, all of which had additional anomalies. CONCLUSIONS: Consistent with previous reports, in the majority of cases (74.8%) PRUV is an isolated finding. While these cases carry an excellent prognosis, PRUV can be associated with severe congenital anomalies, so this finding should prompt detailed prenatal assessment of the fetus. PMID- 20922782 TI - Review of open and minimal access approaches to oesophagectomy for cancer. AB - BACKGROUND: Minimally invasive approaches to oesophagectomy are being used increasingly, but there remain concerns regarding safety and oncological acceptability. This study reviewed the outcomes of totally minimally invasive oesophagectomy (MIO; 41 patients), hybrid procedures (partially minimally invasive; 34) and open oesophagectomy (46) for oesophageal cancer from a single unit. METHODS: Demographic and clinical data were entered into a prospective database. MIO was thoracoscopic-laparoscopic-cervical anastomosis, hybrid surgery was thoracoscopic-laparotomy or laparoscopic gastric mobilization-thoracotomy, and open resections were left thoracoabdominal (LTA), Ivor Lewis (IL) or transhiatal oesophagectomy (THO). RESULTS: There were 118 resections for carcinoma (23 squamous cell carcinoma, 95 adenocarcinoma) and three for high grade dysplasia. MIO took longer than open surgery (median 6.5 h versus 4.8 h for THO, 4.7 h for IL and LTA). MIO required less epidural time (P < 0.001 versus IL and LTA, P = 0.009 versus thorascopic hybrid, P = 0.014 versus laparoscopic IL). Despite a shorter duration of single-lung ventilation with MIO compared with IL and LTA (median 90 versus 150 min; P = 0.013), respiratory complication rates and duration of hospital stay were similar. There were seven anastomotic leaks after MIO, four after hybrid procedures and one following open surgery. Mortality rates were 2, 6 and 2 per cent respectively. Lymph node harvests were similar between all groups, as were rates of complete (R0) resection in patients with locally advanced tumours. CONCLUSION: MIO is technically feasible. It does not reduce pulmonary complications or length of stay. Oncological outcomes appear equivalent. PMID- 20922783 TI - Cost-effectiveness of traditional and endovenous treatments for varicose veins. AB - BACKGROUND: The aim of this study was to evaluate the cost-effectiveness of traditional and endovenous treatments for patients with primary great saphenous varicose veins. METHODS: A Markov model was constructed to compare costs and quality-adjusted life years (QALYs) for great saphenous vein (GSV) reflux. Eight popular treatment strategies were compared up to 5 years. Estimates for the effectiveness of treatments were obtained from published randomized studies and cost values were obtained from published National Health Service (NHS) healthcare resource group tariffs and device manufacturers. Parameter uncertainty was tested using sensitivity analysis and Monte Carlo simulation. RESULTS: Ultrasound-guided foam sclerotherapy (UGFS) had the lowest initial cost, but a higher requirement for further interventions. Day-case surgery (with concomitant treatment of varicosities), endovenous laser ablation (EVLA) and radiofrequency ablation (RFA) performed in an outpatient or office setting (with staged treatment of varicosities) were likely to be cost-effective treatment strategies. The incremental cost-effectiveness ratio (ICER) for UGFS (versus conservative care), EVLA (versus UGFS) and RFA (versus EVLA) were L1366, L5799 and L17 350 per QALY respectively. The ICER for traditional surgery (performed on a day-case basis) was L19 012 compared with RFA. Other strategies were not cost-effective using the NHS threshold of L20 000 per QALY. CONCLUSION: Day-case surgery or endovenous ablation using EVLA or RFA performed as an outpatient are likely to be cost effective treatment strategies for patients with primary unilateral GSV reflux requiring treatment. PMID- 20922784 TI - Phase 1 dose-escalation trial of tremelimumab plus sunitinib in patients with metastatic renal cell carcinoma. AB - BACKGROUND: On the basis of potential additive or synergistic immunostimulatory antitumor effects, in this phase 1 study, the authors evaluated the combination of sunitinib and tremelimumab (CP-675206; an antibody against cytotoxic T lymphocyte-associated antigen 4 [CTLA4]) in patients with metastatic renal cell carcinoma (mRCC) was evaluated. METHODS: Adult patients with mRCC who had received <= 1 previous systemic treatment received tremelimumab (6 mg/kg, 10 mg/kg, or 15 mg/kg) intravenously once every 12 weeks and oral sunitinib (50 mg daily for 4 weeks then 2 weeks off or 37.5 mg daily as a continuous dose). The primary objective was to determine the maximum tolerated dose (MTD). Secondary objectives were to assess antitumor activity, safety, and pharmacokinetics. RESULTS: Twenty-eight patients were enrolled. Two of 5 patients who received 50 mg sunitinib plus tremelimumab 6 mg/kg experienced dose-limiting toxicities (DLTs), and no further enrollment to the combination with sunitinib 50 mg dosing was pursued. Among patients who received continuous sunitinib 37.5 mg daily, 1 of 7 patients who received tremelimumab 10 mg/kg plus sunitinib suffered a sudden death, and 3 of 6 patients who received tremelimumab 15 mg/kg plus sunitinib experienced DLTs. An expansion cohort (n = 7) was enrolled at tremelimumab 10 mg/kg plus sunitinib 37.5 mg daily; 3 of those patients experienced DLTs. Overall, rapid-onset renal failure was the most common DLT. Nine of 21 patients who were evaluable for response achieved partial responses (43%; 95% confidence interval, 22%-66%), and 4 of those responses were ongoing at the time of the current report. CONCLUSIONS: In this study of tremelimumab plus sunitinib, rapid onset acute renal failure was observed unexpectedly, and further investigation of tremelimumab doses > 6 mg/kg plus sunitinib 37.5 mg daily is not recommended. Preclinical investigation may be warranted to understand the mechanism of renal toxicity. PMID- 20922785 TI - A phase 2 study of pemetrexed plus gemcitabine every 2 weeks for patients with recurrent or metastatic head and neck squamous cell cancer. AB - BACKGROUND: Preclinical studies suggest that additive or synergistic effects are achieved with the combination of pemetrexed plus gemcitabine. A phase 1 study of pemetrexed plus gemcitabine given every 2 weeks demonstrated encouraging preliminary efficacy against head and neck squamous cell cancer (HNSCC). METHODS: This was an open-label, single-institution, single-arm, phase 2 study for patients who had received no more than 2 cytotoxic regimens for recurrent and/or metastatic HNSCC. All patients received pemetrexed 500 mg/m2 intravenously plus gemcitabine 1250 mg/m2 intravenously every 2 weeks with vitamin B12 and folate support. The primary endpoint was the objective response rate according to Response Evaluation Criteria in Solid Tumors (RECIST); secondary endpoints were to estimate overall survival and to evaluate safety and tolerability. RESULTS: Twenty-five patients received therapy. All patients had received prior radiotherapy, and half had received prior cytotoxic chemotherapy for recurrent and/or metastatic disease. Neutropenia (grade >= 3) occurred in 24% of patients. Four patients (16%) had a partial response (PR) according to RECIST, and 5 additional patients (20%) had objective tumor reductions of > 20 but < 30% did not meet RECIST criteria for a PR. The median overall survival for all treated patients was 8.8 months. CONCLUSIONS: Treatment with pemetrexed plus gemcitabine every 2 weeks with vitamin support generally was well tolerated. The results of this study provided further evidence that pemetrexed may have significant palliative activity against advanced HNSCC. PMID- 20922786 TI - Intolerance to tyrosine kinase inhibitors in chronic myeloid leukemia: Definitions and clinical implications. AB - Tyrosine kinase inhibitor (TKI) treatment targeting breakpoint cluster region Abelson murine leukemia virus, the cause of chronic myeloid leukemia (CML), has revolutionized therapy for patients with this disease. The majority of patients with CML maintain favorable responses with long-term imatinib therapy; however, the availability of the second-generation TKIs nilotinib and dasatinib limits the need for patients intolerant to imatinib to continue with therapy. Unfortunately, there is currently no standard definition of intolerance to imatinib. Common Toxicity Criteria for grading adverse events, designed to identify acute toxicities, are often used to determine intolerance. However, because CML therapies are long-term, patient quality of life may provide a better measure of true intolerance. Several general methods of quantifying patient quality of life are in use for patients with CML, and a CML-specific variant of the M. D. Anderson Symptom Inventory is in development. An appropriate and consistent definition of intolerance will provide clinicians with an algorithm for managing their patients with severe or chronic adverse events during treatment with imatinib. As more long-term data become available for newer TKIs, the definition of intolerance in the context of CML treatment will continue to evolve to maximize the likelihood of durable responses and superior quality of life for patients. PMID- 20922787 TI - Twenty years of follow-up of survivors of childhood osteosarcoma: a report from the Childhood Cancer Survivor Study. AB - BACKGROUND: Osteosarcoma survivors have received significant chemotherapy and have undergone substantial surgeries. Their very long-term outcomes (20 year) are reported here. METHODS: The authors assessed the long-term outcomes of 733 5-year survivors of childhood osteosarcoma diagnosed from 1970 to 1986 to provide a comprehensive evaluation of medical and psychosocial outcomes for survivors enrolled in the Childhood Cancer Survivor Study (CCSS). Outcomes evaluated included overall survival, second malignant neoplasms (SMNs), recurrent osteosarcoma, chronic health conditions, health status (general and mental health and functional limitations), and psychosocial factors. Outcomes of osteosarcoma survivors were compared with general-population statistics, other CCSS survivors, and CCSS siblings. RESULTS: Survivors had a mean follow-up of 21.6 years. The overall survival of children diagnosed with osteosarcoma who survived 5 years at 20 years from original diagnosis was 88.6% (95% confidence interval [CI], 86.6% 90.5%). The cumulative incidence of SMNs at 25 years was 5.4%, with a standardized incidence ratio of 4.79 (95% CI, 3.54-6.33; P<.01). Overall, 86.9% of osteosarcoma survivors experienced at least 1 chronic medical condition, and >50% experienced >=2 conditions. Compared with survivors of other cancers, osteosarcoma survivors did not differ in their reported general health status (odds ratio [OR], 0.9; 95% CI, 0.7-1.2), but were more likely to report an adverse health status in at least 1 domain (OR, 1.9; 95% CI, 1.6-2.2), with activity limitations (29.1%) being the most common. CONCLUSIONS: Childhood osteosarcoma survivors in this cohort did relatively well, considering their extensive treatment, but are at risk of experiencing chronic medical conditions and adverse health status. Survivors warrant life-long follow-up. PMID- 20922788 TI - Primary cardiac lymphoma: an analysis of presentation, treatment, and outcome patterns. AB - BACKGROUND: Primary cardiac lymphoma (PCL) represents a rare subset of non Hodgkin lymphoma, characterized by poor outcomes. The authors aimed to construct a framework of known clinical presentations, diagnostic features, disease complications, treatment, and outcomes to improve prognostication. METHODS: Individual patient data were obtained from defined cases of PCL (1949-2009) and systematically analyzed. RESULTS: The authors report results of a review of 197 cases of PCL, with half of all cases reported since 1995. Survival was affected by 4 factors: immune status, left ventricular involvement, presence of extra cardiac disease, and arrhythmia. Median overall survival (OS) for immunocompromised and immunocompetent was 3.5 months (m) and not reached, respectively (HR 0.29, 95% CI, 0.13-0.68; P = .004). LV involvement was uncommon (26%) and associated with an OS of only 1 m, whereas patients free of LV involvement had a median OS of 22 m (HR 0.28, 95% CI, 0.12-0.64; P = .002). Patients with extracardiac disease had shorter median OS compared with those without (6 m vs 22 m, HR 0.49, 95% CI, 0.26-0.91; P = .02). Those patients with an arrhythmia of any type had a median OS that was not reached (n = 55), whereas those without rhythm disturbances (n = 41) had median OS of 6 m (HR 0.51, 95% CI, 0.29-0.91; P = .024). Overall response rate to therapy was 84%, with long-term OS over 40%. CONCLUSIONS: The current study presents the largest analysis of PCL to date. The data demonstrate that PCL is now more frequently diagnosed premortem and appears to have reasonable response rates. Lack of LV involvement and the presence of arrhythmias are associated with improved survival. PMID- 20922790 TI - Intra-arterial chemotherapy for head and neck cancer: is there a verdict? PMID- 20922793 TI - Impact of postoperative prostate-specific antigen disease recurrence and the use of salvage therapy on the risk of death. PMID- 20922792 TI - Genetic inactivation of ERK1 and ERK2 in chondrocytes promotes bone growth and enlarges the spinal canal. AB - Activating mutations in FGFR3 cause the most common forms of human dwarfism: achondroplasia and thanatophoric dysplasia. In mouse models of achondroplasia, recent studies have implicated the ERK MAPK pathway, a pathway activated by FGFR3, in creating reduced bone growth. Our recent studies have indicated that increased Fgfr3 and ERK MAPK signaling in chondrocytes also causes premature synchondrosis closure in the cranial base and vertebrae, accounting for the sometimes fatal stenosis of the foramen magnum and spinal canal in achondroplasia. Conversely, whether the decrease--or inactivation--of ERK1 and ERK2 promotes bone growth and delays synchondrosis closure remains to be investigated. In this study, we inactivated ERK2 in the chondrocytes of ERK1-null mice using the Col2a1-Cre and Col2a1-CreER transgenes. We found that the genetic inactivation of ERK1 and ERK2 in chondrocytes enhances the growth of cartilaginous skeletal elements. We also found that the postnatal inactivation of ERK1 and ERK2 in chondrocytes delays synchondrosis closure and enlarges the spinal canal. These observations make ERK1 and ERK2 an attractive target for the treatment of achondroplasia and other FGFR3-related skeletal syndromes. PMID- 20922795 TI - Experimental therapeutics for patients with myeloproliferative neoplasias. AB - Philadelphia chromosome (Ph)-negative myeloproliferative neoplasms (MPNs) are characterized by stem cell-derived, unrestrained clonal myeloproliferation. The World Health Organization classification system, proposed in 2008, identifies 7 distinct categories of Ph-negative MPNs including essential thrombocythemia (ET); polycythemia vera (PV); primary myelofibrosis (PMF); mastocytosis; chronic eosinophilic leukemia; chronic neutrophilic leukemia; and MPN, unclassifiable. For many years, the treatment of ET, PV, and PMF, the most frequently diagnosed Ph-negative MPNs, has been largely supportive. In recent years, that paradigm has been challenged because of the discovery of a recurrent point mutation in the Janus kinase 2 (JAK2) gene (JAK2(V617F)). This mutation can be detected in the vast majority of patients with PV and approximately half of patients with ET or PMF and serves as both a diagnostic marker as well as representing a putative molecular target for drug development. Several putative targeted agents with significant in vitro JAK2 inhibitory activity and various degrees of JAK2 specificity are currently undergoing clinical evaluation. Furthermore, other investigational non-tyrosine kinase inhibitor approaches such as immunomodulatory agents and pegylated interferon- have also shown promising results in MPNs. PMID- 20922797 TI - Platelet-rich plasma (PRP) impairs the craniofacial bone repair associated with its elevated TGF-beta levels and modulates the co-expression between collagen III and alpha-smooth muscle actin. AB - Transforming growth factor-beta (TGF-beta) is considered the main inducer of both the alpha-smooth muscle actin (alpha-SMA) phenotype and collagen synthesis and deposition and plays a significant role in the tissue repair and the development of fibrosis. Since the PRP constitutes an important source of TGF-beta and its efficacy on the craniofacial bone repair remains controversy, the aim of this study was to evaluate the effect of PRP in the presence of levels of TGF-beta on PRP samples, as well as in the presence of collagen III and alpha-SMA+ cells, while comparing these results by means of a histomorphometric analysis of the bone matrix and fibrous deposition on the bone repair. Four bone defects of 16 mm(2) were created on the calvarium of 21 rabbits. The surgical defects were treated with either particulate autograft, particulate autograft mixed with PRP and PRP alone. Animals were euthanized at 15, 30, and 45 days postoperative. Histomorphometric and immunohistochemical analyses were performed to assess repair time, as well as the expression of collagen III, and alpha-SMA. The histomorphometric results demonstrated intensive deposition of fibrous tissue while hinder bone deposition occurred in PRP groups. These results coincided with higher values of the TGF-beta on the PRP sample, also larger occurrence of diffuse collagen III deposition and higher presence of alpha-SMA+ cells spread among the fibrous tissue. Thus, the higher levels of TGF-beta associated with the both expression of collagen III and alpha-SMA on defect treated with PRP suggest that its biomaterial induce an effect that can be considered similarly to a fibroproliferative disorder. PMID- 20922798 TI - Bladder cancer and BCG response prediction: what we must know? PMID- 20922799 TI - Association of multi-drug resistance gene polymorphisms with pancreatic cancer outcome. AB - BACKGROUND: The purpose of this study was to identify single nucleotide polymorphisms (SNPs) of multidrug resistance genes that are associated with clinical outcome in patients with potentially resectable pancreatic adenocarcinoma who were treated with preoperative gemcitabine-based chemoradiotherapy at M. D. Anderson Cancer Center. METHODS: We selected 8 SNPs of 7 drug resistance genes, including MDR1 (ABCB1), MRP1-5 (ABCC1-5), and BCRP (ABCG2), reported to be important in mediating drug resistance. Genotype was determined by the Taqman method. The associations of genotype with tumor response to therapy and overall survival (OS) were evaluated using log-rank test, Cox regression, and logistic regression models. RESULTS: MRP5 A-2G AA genotype showed significant association with OS (log-rank P = .010). The hazard ratio (95% confidence interval) was 1.65 (1.11-2.45) after adjusting for clinical predictors. The MRP2 G40A GG genotype had a weak association with reduced OS (log rank P = .097). A combined effect of the two genotypes on OS was observed. Patients with none of the adverse genotypes had a median survival time (MST) of 34.0 months, and those with 1-2 deleterious alleles had a significantly lower MST of 20.7 months (log-rank P = .006). MRP2 G40A GG genotype was also significantly associated with poor histological response to chemoradiotherapy (P = .028). CONCLUSIONS: These observations suggest a potential role of polymorphic variants of drug resistance genes in predicting therapeutic efficacy and survival of patients with potentially resectable pancreatic cancer. PMID- 20922800 TI - Biomarker-based phase I dose-escalation, pharmacokinetic, and pharmacodynamic study of oral apricoxib in combination with erlotinib in advanced nonsmall cell lung cancer. AB - BACKGROUND: Apricoxib, a novel once-daily selective cyclooxygenase-2 inhibitor, was investigated in combination with erlotinib for recurrent stage IIIB/IV nonsmall cell lung cancer to determine the maximum tolerated dose, dose-limiting toxicity, and recommended phase II dose (RP2D) based on changes in urinary prostaglandin E2 metabolite (PGE-M). METHODS: Patients received escalating doses of apricoxib (100, 200, and 400 mg/day) in combination with erlotinib 150 mg/day until disease progression or unacceptable toxicity. Urinary PGE-M was used to assess biologic activity and inform the optimal biologic dose. RESULTS: Twenty patients were treated (3 at 100 mg; 3 at 200 mg; 14 at 400 mg apricoxib) with a median of 4 cycles (range, 2-14 cycles); 8 patients (40%) received prior EGFR directed therapies. No dose-limiting toxicity was observed. Study drug-related adverse events (AEs) included diarrhea, rash, dry skin, anemia, fatigue, and increased serum creatinine; 4 patients had grade >= 3 drug-related AEs (diarrhea, perforated duodenal ulcer, hypophosphatemia, and deep vein thrombosis). The RP2D was 400 mg/day based on safety, biologic activity based on decreases in urinary PGE-M, and pharmacokinetics. One patient had a partial response, and 11 had stable disease. Stable disease was observed in patients who had received prior EGFR inhibitor therapy but was greater in patients not previously treated with an EGFR inhibitor. Seventeen patients had elevated urinary PGE-M at baseline, and 14 (70%) had a decrease from baseline, which was associated with disease control. CONCLUSIONS: Apricoxib plus erlotinib was well tolerated and yielded a 60% disease control rate. A phase II trial is currently investigating 400 mg/day apricoxib plus 150 mg/day erlotinib in patients selected based on change in urinary PGE-M. PMID- 20922801 TI - Prognostic model for survival in patients with early stage cervical cancer. AB - BACKGROUND: In the management of early stage cervical cancer, knowledge about the prognosis is critical. Although many factors have an impact on survival, their relative importance remains controversial. This study aims to develop a prognostic model for survival in early stage cervical cancer patients and to reconsider grounds for adjuvant treatment. METHODS: A multivariate Cox regression model was used to identify the prognostic weight of clinical and histological factors for disease-specific survival (DSS) in 710 consecutive patients who had surgery for early stage cervical cancer (FIGO [International Federation of Gynecology and Obstetrics] stage IA2-IIA). Prognostic scores were derived by converting the regression coefficients for each prognostic marker and used in a score chart. The discriminative capacity was expressed as the area under the curve (AUC) of the receiver operating characteristic. RESULTS: The 5-year DSS was 92%. Tumor diameter, histological type, lymph node metastasis, depth of stromal invasion, lymph vascular space invasion, and parametrial extension were independently associated with DSS and were included in a Cox regression model. This prognostic model, corrected for the 9% overfit shown by internal validation, showed a fair discriminative capacity (AUC, 0.73). The derived score chart predicting 5-year DSS showed a good discriminative capacity (AUC, 0.85). CONCLUSIONS: In patients with early stage cervical cancer, DSS can be predicted with a statistical model. Models, such as that presented here, should be used in clinical trials on the effects of adjuvant treatments in high-risk early cervical cancer patients, both to stratify and to include patients. PMID- 20922802 TI - Structural and reliability analysis of a patient satisfaction with cancer-related care measure: a multisite patient navigation research program study. AB - BACKGROUND: Patient satisfaction is an important outcome measure of quality of cancer care and 1 of the 4 core study outcomes of the National Cancer Institute (NCI)-sponsored Patient Navigation Research Program to reduce race/ethnicity based disparities in cancer care. There is no existing patient satisfaction measure that spans the spectrum of cancer-related care. The objective of this study was to develop a Patient Satisfaction With Cancer Care measure that is relevant to patients receiving diagnostic/therapeutic cancer-related care. METHODS: The authors developed a conceptual framework, an operational definition of Patient Satisfaction With Cancer Care, and an item pool based on literature review, expert feedback, group discussion, and consensus. The 35-item Patient Satisfaction With Cancer Care measure was administered to 891 participants from the multisite NCI-sponsored Patient Navigation Research Program. Principal components analysis (PCA) was conducted for latent structure analysis. Internal consistency was assessed using Cronbach coefficient alpha (alpha). Divergent analysis was performed using correlation analyses between the Patient Satisfaction With Cancer Care, the Communication and Attitudinal Self-Efficacy Cancer, and demographic variables. RESULTS: The PCA revealed a 1-dimensional measure with items forming a coherent set explaining 62% of the variance in patient satisfaction. Reliability assessment revealed high internal consistency (alpha ranging from 0.95 to 0.96). The Patient Satisfaction With Cancer Care demonstrated good face validity, convergent validity, and divergent validity, as indicated by moderate correlations with subscales of the Communication and Attitudinal Self-Efficacy-Cancer (all P < .01) and nonsignificant correlations with age, primary language, marital status, and scores on the Rapid Estimate of Adult Literacy in Medicine Long Form (all P > .05). CONCLUSIONS: The Patient Satisfaction With Cancer Care is a valid tool for assessing satisfaction with cancer-related care for this sample. PMID- 20922803 TI - Gemcitabine and docetaxel in metastatic, castrate-resistant prostate cancer: results from a phase 2 trial. AB - BACKGROUND: Docetaxel is the standard of care for patients with metastatic, castrate-resistant prostate cancer (CRPC). Gemcitabine is a nucleoside analogue with broad antitumor activity. In a phase 2 study of combined docetaxel and gemcitabine, the authors assessed its safety and activity in patients with chemotherapy-naive, metastatic CRPC. METHODS: Eligible patients had untreated, metastatic CRPC with radiologic and/or biochemical evidence of progression after antiandrogen withdrawal with castrate testosterone levels, an Eastern Cooperative Oncology performance status (ECOG PS) of 0 to 2, and adequate organ function; no previous chemotherapy was permitted. Patients received gemcitabine (800 mg/m2) Days 1 and 8 and docetaxel (75 mg/m2) on Day 8 every 21 days for a maximum of 6 cycles. Response was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) for measurable disease. A prostate-specific antigen (PSA) response was defined as a decline >= 50% in baseline PSA level. RESULTS: Thirty-five patients with chemotherapy-naive, metastatic CRPC were enrolled. The median age was 67 years, and 60% of patients had an ECOG PS of 0. PSA responses were observed in 49% of patients. Among the patients who had measurable disease (n = 25), 3 patients (12%) had a confirmed, RECIST-defined partial response (PR); 4 patients (16%) had an unconfirmed PR; and 15 patients (60%) achieved stable disease. The most common adverse events included grade 1 and 2 fatigue (69%), alopecia (80%), and nausea/vomiting (54%). No treatment-related deaths were noted, but an unusually high incidence of grade 3 and 4 neutropenia was observed. CONCLUSIONS: The efficacy of combined gemcitabine and docetaxel in metastatic CRPC was similar to that observed with single-agent docetaxel. In contrast to single-agent docetaxel, the combination was moderately toxic and had an impact primarily on bone marrow reserve. PMID- 20922804 TI - Ovarian cancer care for the underserved: are surgical patterns of care different in a public hospital setting? AB - BACKGROUND: The New York City (NYC) public hospital system includes subspecialty care for gynecologic cancers, providing care to patients regardless of insurance status. The authors sought to determine the surgical patterns of care for ovarian cancer patients in the NYC public hospital system. METHODS: Ovarian cancer cases were identified in the New York State Department of Health Statewide Planning and Research Cooperative System database for years 2001 to 2006. Cases from NYC hospitals were separated into 2 cohorts: public and other NYC hospitals. Surgeons associated with each case were identified using the database and were stratified by volume of cases and presence of subspecialty training. RESULTS: A total of 12,202 admissions for ovarian cancer were identified. Of these, 3639 involved major surgery, and 187 were performed at public hospitals. There were more African American and Asian patients in the public cohort (P < .001). The primary insurer was more likely to be Medicaid or a self-payer in the public cohort (P < 0.001). Urgent or emergent admissions comprised 55% of all admissions in public hospitals, compared with 29% of admissions in other NYC hospitals (P < .001). Patients in public hospitals were less likely to have their surgery performed by a gynecologic oncologist (57% vs 74%, P < .001) and less likely to have their surgery performed by a high-volume surgeon (21% vs 47%; P < .001) compared with patients in other NYC hospitals. CONCLUSIONS: Ovarian cancer patients treated in public hospitals are less likely to have gynecologic oncologists and high-volume surgeons involved in their care. This is a preliminary finding that warrants further investigation. PMID- 20922805 TI - Bulk metallic glass: the smaller the better. AB - Bulk metallic glasses (BMGs) are strong, highly elastic, and resistant to wear but still find limited utility due to their macroscopic brittle nature, high costs, and difficulty of processing, particularly when complex shapes are desired. These drawbacks can be mitigated when BMGs are used in miniature parts (< 1 cm), an application which takes advantage of BMGs' enhanced plasticity at small length scales as well the insignificant material cost associated with such parts. As an alternative to traditional metal processing techniques, thermoplastic forming (TPF)-based microfabrication methods have been developed which can process some BMGs like plastics. In this article, we discuss the properties and fabrication of BMGs on minuscule length scales to explore their prospective application in small-scale devices. PMID- 20922807 TI - What are the most important nonmotor symptoms in patients with Parkinson's disease and are we missing them? AB - Nonmotor symptoms (NMS) are increasingly recognized as important and neglected aspects of Parkinson's disease (PD). We evaluated their relative frequency and comparative impact on health-related quality of life (Hr-QoL) using validated questionnaires. In addition, we assessed the rate of reporting of NMS in neurology clinics compared with their subjective impact on patients. We used a range of validated clinimetric scales of motor and nonmotor symptoms and Hr-QoL to assess consecutive patients with PD. Reporting of NMS was assessed by comparison with case note documentation. A mean of 11 of 30 NMS per patient were elicited on the NMS questionnaire of which on average 4.8 were reported in the clinical notes (44%). The most common NMS were autonomic (particularly urinary). The Hr-QoL scores correlated most strongly with autonomic dysfunction (r = 0.84; particularly urinary and gastrointestinal symptoms), mood (r = 0.74), fatigue (r = 0.74), sleep problems (nocturnal r = 0.55; daytime somnolence r = 0.65), pain (r = 0.56), and psychosis (r = 0.55, all p < 0.0001) followed by UPDRS motor score (r = 0.48, p < 0.0001). Greater motor fluctuations (r = 0.57) and dyskinesia (r = 0.43, both p < 0.0001) were also associated with worse Hr-QoL. In multivariate analysis, depression had the strongest association with Hr-QoL (adjusted R(2) = 0.53, p = 0.005) followed by fatigue, thermoregulatory, gastrointestinal, and cardiovascular autonomic function (especially orthostatic hypotension), daytime somnolence, and urinary problems. This study demonstrates that a autonomic dysfunction, psychiatric complications, pain, fatigue, and sleep problems are major correlates of poor Hr-QoL. However, whilst psychiatric problems are increasingly documented, many symptoms (particularly those possibly perceived as embarrassing or unrelated) remain under-reported. PMID- 20922806 TI - Overexpression of receptor tyrosine kinase Axl promotes tumor cell invasion and survival in pancreatic ductal adenocarcinoma. AB - BACKGROUND: The receptor tyrosine kinase Axl has been reported to be overexpressed in a variety of human cancers. Although previous studies have identified the role of Axl in the transformation, proliferation, survival, and invasion in cancers, the expression and functions of Axl in pancreatic cancer have not been studied in detail. METHODS: The expression of Axl protein in 12 pancreatic cancer cell lines and 54 patient samples of stage II pancreatic ductal adenocarcinoma (PDA) and their paired non-neoplastic pancreatic tissue samples were examined. Using univariate and multivariate analysis, Axl expression was correlated with survival and other clinicopathologic features. To examine Axl functions in PDA, the effects of Axl knockdown on the invasion ability and radiation-induced apoptosis in PDA cell lines were measured. RESULTS: Axl was overexpressed in 38 of 54 (70%) stage II PDA samples and 9 of 12 (75%) PDA cell lines. Axl overexpression was associated with higher frequencies of distant metastasis and poor overall and recurrence-free survivals (P = .03 and P = .04, respectively) independent of tumor size and stage or lymph node status in patients with stage II PDA. Knockdown of Axl expression in PDA cells abolished Gas6-mediated Akt activation, decreased invasion, and increased radiation-induced PARP cleavage and the percentage of apoptosis. CONCLUSIONS: This study showed that Gas6 and Axl are frequently overexpressed in PDA cells and are associated with a poor prognosis in patients with stage II PDA. Axl promotes the invasion and survival of PDA cells. Therefore, targeting the Axl signaling pathway may represent a new approach to the treatment of PDA. PMID- 20922809 TI - Regional cortical grey matter loss in Parkinson's disease without dementia is independent from visual hallucinations. AB - In our previous functional magnetic resonance imaging study, Parkinson's disease (PD) patients with visual hallucinations (VH) showed reduced activations in ventral/lateral visual association cortices preceding image recognition, compared with both PD patients without VH and healthy controls. The primary aim of the current study was to investigate whether functional deficits are associated with grey matter volume changes. In addition, possible grey matter differences between all PD patients and healthy controls were assessed. By using 3-Tesla magnetic resonance imaging (MRI) and voxel-based morphometry (VBM), we found no differences between PD patients with (n = 11) and without VH (n = 13). However, grey matter decreases of the bilateral prefrontal and parietal cortex, left anterior superior temporal, and left middle occipital gyrus were found in the total group of PD patients, compared with controls (n = 14). This indicates that previously demonstrated functional deficits in PD patients with VH are not associated with grey matter loss. The strong left parietal reduction in both nondemented patient groups was hemisphere specific and independent of the side of PD symptoms. PMID- 20922808 TI - Amyloid imaging of Lewy body-associated disorders. AB - Clinicopathologic studies of Parkinson disease dementia (PDD) and dementia with Lewy bodies (DLB) commonly reveal abnormal beta-amyloid deposition in addition to diffuse Lewy bodies (alpha-synuclein aggregates), but the relationship among these neuropathologic features and the development of dementia in these disorders remains uncertain. The purpose of this study was to determine whether amyloid beta deposition detected by PET imaging with Pittsburgh Compound B (PIB) distinguishes clinical subtypes of Lewy body-associated disorders. Nine healthy controls, 8 PD with no cognitive impairment, 9 PD with mild cognitive impairment, 6 DLB, and 15 PDD patients underwent [(11)C]-PIB positron emission tomography imaging, clinical examination, and cognitive testing. The binding potential (BP) of PIB for predefined regions and the mean cortical BP (MCBP) were calculated for each participant. Annual longitudinal follow-up and postmortem examinations were performed on a subset of participants. Regional PIB BPs and the proportion of individuals with abnormally elevated MCBP were not significantly different across participant groups. Elevated PIB binding was associated with worse global cognitive impairment in participants with Lewy body disorders but was not associated with any other clinical or neuropsychological features, including earlier onset or faster rate of progression of cognitive impairment. These results suggest that the presence of fibrillar amyloid-beta does not distinguish between clinical subtypes of Lewy body-associated disorders, although larger numbers are needed to more definitively rule out this association. Amyloid-beta may modify the severity of global cognitive impairment in individuals with Lewy body-associated dementia. PMID- 20922810 TI - Presentation, diagnosis, and management of multiple system atrophy in Europe: final analysis of the European multiple system atrophy registry. AB - Multiple system atrophy (MSA) is a Parkinson's Disease (PD)-like alpha synucleinopathy clinically characterized by dysautonomia, parkinsonism, cerebellar ataxia, and pyramidal signs in any combination. We aimed to determine whether the clinical presentation of MSA as well as diagnostic and therapeutic strategies differ across Europe and Israel. In 19 European MSA Study Group centres all consecutive patients with a clinical diagnosis of MSA were recruited from 2001 to 2005. A standardized minimal data set was obtained from all patients. Four-hundred thirty-seven MSA patients from 19 centres in 10 countries were included. Mean age at onset was 57.8 years; mean disease duration at inclusion was 5.8 years. According to the consensus criteria 68% were classified as parkinsonian type (MSA-P) and 32% as cerebellar type (MSA-C) (probable MSA: 72%, possible MSA: 28%). Symptomatic dysautonomia was present in almost all patients, and urinary dysfunction (83%) more common than symptomatic orthostatic hypotension (75%). Cerebellar ataxia was present in 64%, and parkinsonism in 87%, of all cases. No significant differences in the clinical presentation were observed between the participating countries. In contrast, diagnostic work up and therapeutic strategies were heterogeneous. Less than a third of patients with documented orthostatic hypotension or neurogenic bladder disturbance were receiving treatment. This largest clinical series of MSA patients reported so far shows that the disease presents uniformly across Europe. The observed differences in diagnostic and therapeutic management including lack of therapy for dysautonomia emphasize the need for future guidelines in these areas. PMID- 20922811 TI - Toxic effect of gestational exposure to nonylphenol on F1 male rats. AB - OBJECTIVE: The purpose of this study was to examine whether gestational exposure to major environmental endocrine-disrupting chemicals, nonylphenol (NP), would lead to nerve behavioral and learning and memory capacity alterations in the male offspring of rats, and reproductive development alterations in the male offspring of rats. METHODS: Dams were gavaged with NP at a dose level of 50 mg/kg/day, 100 mg/kg/day or 200 mg/kg/day daily from gestational day 9 to 15, and at a dose level of 40 mg/kg/day, 80 mg/kg/day or 200 mg/kg/day daily from gestational day 14 to 19 (transplacental exposures). RESULTS: Exposure to 200 mg/kg/day NP produced a significant decrease in learning and memory functions in offspring rats (P<0.05) in Morris water maze task, as demonstrated by the increased escape latency and number of error. In Step-down Avoidance Test, offspring rats exposed to NP spent more reaction time (RT) and presented lower latency to first step down than the control offspring (P<0.01). In utero exposure to 80 and 200 mg/kg/day NP produced a significant decrease in the number of live pups per litter and ratio of anogenital distance to body length on PND 0 (P<0.05), and also testes and prostate weight, activities of ALP, plasma testosterone concentration, cauda epididymis sperm counts, daily sperm production et al. respectively on PND 90 (P<0.05). Histopathological examination of the brain biopsy illustrates that exposure to NP at high dose induces the presence of abnormal distribution of spermatozoa showed in lumina of the seminiferous tubules, and absence of spermatogenesis and spermiogenesis. CONCLUSION: Gestational exposure to nonylphenol might induce neurotoxic and reproductive toxic effects on F1 male rats. PMID- 20922813 TI - Controlling ligand surface density optimizes nanoparticle binding to ICAM-1. AB - During infection, pathogens utilize surface receptors to gain entry into intracellular compartments. Multiple receptor-ligand interactions that lead to pathogen internalization have been identified and the importance of multivalent ligand binding as a means to facilitate internalization has emerged. The effect of ligand density, however, is less well known. In this study, ligand density was examined using poly(DL-lactic-co-glycolic acid) nanoparticles (PLGA NPs). A cyclic peptide, cLABL, was used as a targeting moiety, as it is a known ligand for intercellular cell adhesion molecule-1 (ICAM-1). To modulate the number of reactive sites on the surface of PLGA NPs, modified Pluronic with carboxyl groups and Pluronic with hydroxyl groups were combined in different ratios and the particle properties were examined. Utilizing a surfactant mixture directly affected the particle charge and the number of reactive sites for cLABL conjugation. The surface density of cLABL peptide increased as the relative amount of reactive Pluronic was increased. Studies using carcinomic human alveolar basal epithelial cells (A549) showed that cLABL density might be optimized to improve cellular uptake. These results complement other studies, suggesting that surface density of the targeting moiety on the NP surface should be considered to enhance the effect of ligands used for cell targeting. PMID- 20922814 TI - Hydroxypropyl-beta-cyclodextrin copolymers and their nanoparticles as doxorubicin delivery system. AB - A novel biodegradable amphiphilic copolymer composed of hydroxypropyl-beta cyclodextrin, polylactide, and 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine, was successfully synthesized. The chemical structures of copolymers were determined by FT-IR, (1)H nuclear magnetic resonance (NMR) spectroscopy, (13)C NMR, (31)P NMR, thermogravimetric analysis ,and differential scanning calorimetry. Doxorubicin (DOX)-loaded copolymer nanoparticles (NPs) were prepared by double emulsion and nanoprecipitation methods. The factors of copolymer composition and fabrication methods, which influence size and encapsulation efficiency (EE) were investigated. Their EE to DOX could reach 90.6% at an available condition. In vitro release behavior of NPs showed a continuous release after a burst release. The antitumor activity of the DOX-loaded NPs against cancer HepG2 and A549 cells was evaluated by 3-(4, 5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide method. The DOX-loaded copolymer NPs showed comparable anticancer efficacy with the free drug. PMID- 20922815 TI - Retraction: spatial and temporal distribution of laminins in permanent focal ischemic brain damage of the adult rat. PMID- 20922818 TI - Bile acid-binding ability of kaki-tannin from young fruits of persimmon (Diospyros kaki) in vitro and in vivo. AB - The bile acid-binding ability of a highly polymerized tannin (kaki-tannin) extracted from dried-young fruits of persimmon (Diospyros kaki) was examined. The kaki-tannin was composed mainly of epicatechin, epigallocatechin, epicatechin-3-O gallate and epigallocatechin-3-O-gallate. Bile acid-binding ability of kaki tannin was examined against cholic acid, glycocholic acid, taurocholic acid and deoxycholic acid in vitro, and its effect on fecal bile acid excretion in mice was also examined. Although the bile acid-binding ability of kaki-tannin was weaker than that of cholestyramine, kaki-tannin adsorbed all the bile acids tested and significantly promoted fecal bile acid excretion in mice when supplied at 1% (w/w) in the diet. PMID- 20922817 TI - Planning a Bayesian early-phase phase I/II study for human vaccines in HER2 carcinomas. AB - Recent innovative statistical approaches for phase I/II clinical trials allow one to jointly model the toxicity and efficacy of a new treatment, taking into account the information gathered during the trial. Prior probabilities are then updated with interim data and thus predictive probabilities become more accurate as the trial progresses. In this study, prior distribution elicited from a physician's opinion on the available dose levels planned for a vaccination dose finding trial, with human DNA in patients with HER2-positive tumours in terms of toxicity and therapeutic response is presented and discussed. A simulation study was conducted in order to quantify the impact of the choice of prior on study results, i.e. the recommended dose level at the end of the trial. PMID- 20922819 TI - Evolution and predictors of morphological and functional arterial changes in the course of type 1 diabetes mellitus. AB - BACKGROUND: Diabetes mellitus results in accelerated atherosclerosis. We evaluated preclinical, morphological and functional vascular changes in type 1 diabetes mellitus. METHODS: Diameter, intima-media thickness, intima-media cross section area, and elasticity features (compliance, distensibility coefficient, circumferential strain, stiffness index, incremental elastic modulus) of the common carotid arteries and carotid-femoral pulse wave velocity were studied in 42 patients with type 1 diabetes mellitus without macroangiopathy, and 41 control subjects matched for sex, age and body mass index using an ultrasonographic vessel wall-movement tracking system and applanation tonometry. RESULTS: Significantly larger intima-media thickness (523 +/- 55 versus 567 +/- 89 um, p < 0.01), intima-media cross-section area (11.60 +/- 1.81 versus 13.08 +/- 3.02 mm(2) , p < 0.01), SI (5.58 +/- 1.24 versus 7.08 +/- 2.69, p < 0.01) and pulse wave velocity (6.00 +/- 0.82 versus 6.61 +/- 1.56 m/s, p < 0.05) were found in type 1 diabetes mellitus patients compared to controls. When type 1 diabetes mellitus patients with short and long disease duration (<= or > 10 years) were compared, diameter (6450 +/- 433 versus 6847 +/- 750 um, p < 0.05), intima-media cross-section area (11.97 +/- 1.98 versus 14.01 +/- 3.43 mm, p < 0.05) and pulse wave velocity (5.90 +/- 0.92 versus 7.20 +/- 1.74 m/s, p < 0.01) differed significantly. When multivariate analyses were restricted to type 1 diabetes mellitus patients, age was an independent predictor of stiffness index and pulse wave velocity, the duration of diabetes mellitus of intima-media cross-section area and pulse wave velocity, systolic blood pressure of diameter and pulse wave velocity, and low-density lipoprotein-cholesterol of intima-media thickness, intima-media cross-section area and stiffness index. CONCLUSIONS: There are differences in the time course of evolution and in predictors of morphological and functional changes in arteries in type 1 diabetes mellitus. PMID- 20922820 TI - Issues for stratified randomization based on a factor derived from a continuous baseline variable. AB - Stratified randomization based on the baseline value of the primary analysis variable is common in clinical trial design. We illustrate from a theoretical viewpoint the advantage of such a stratified randomization to achieve balance of the baseline covariate. We also conclude that the estimator for the treatment effect is consistent when including both the continuous baseline covariate and the stratification factor derived from the baseline covariate. In addition, the analysis of covariance model including both the continuous covariate and the stratification factor is asymptotically no less efficient than including either only the continuous baseline value or only the stratification factor. We recommend that the continuous baseline covariate should generally be included in the analysis model. The corresponding stratification factor may also be included in the analysis model if one is not confident that the relationship between the baseline covariate and the response variable is linear. In spite of the above recommendation, one should always carefully examine relevant historical data to pre-specify the most appropriate analysis model for a perspective study. PMID- 20922821 TI - [Surgical treatment of the complicated echinococcosis of the thyroid gland]. PMID- 20922822 TI - [Diffusion weighted whole-body MRI]. PMID- 20922823 TI - Cancer linked to Alzheimer disease but not vascular dementia. PMID- 20922824 TI - Measles in the unvaccinated. PMID- 20922825 TI - Nanofilm developed to rejuvenate dental tissue could advance root canal treatment. PMID- 20922826 TI - Study suggests nanoparticles may assist early detection of melanoma. PMID- 20922827 TI - Targeted therapies: PARP inhibitor olaparib is safe and effective in patients with BRCA1 and BRCA2 mutations. PMID- 20922828 TI - Surgery: Laparoscopy versus laparotomy in early-stage endometrial cancer. PMID- 20922829 TI - Prostate cancer from basal cells. PMID- 20922830 TI - Tumor genotyping to predict response. PMID- 20922831 TI - Genetics: A new method for predicting metastasis in sarcomas. PMID- 20922832 TI - Imaging: PET is prognostic of survival in pancreatic cancer patients. PMID- 20922833 TI - Pediatric oncology: Pulsed treatment in continuation therapy improves disease free survival in children with hematologic malignancies. PMID- 20922834 TI - Health services, economics and outcomes research: Questionnaire developed specifically for older people with cancer. PMID- 20922835 TI - Germany: victory of democracy over tobacco. PMID- 20922836 TI - USA: AMA backs commemorative stamp. PMID- 20922837 TI - Drug crime and criminalisation threaten progress on MDGs. PMID- 20922838 TI - Taking on malaria in the Amazon. PMID- 20922839 TI - It's the eyes that are important"--stories about artificial eyes. PMID- 20922840 TI - History and philosophy. Current world literature. PMID- 20922841 TI - Clinical therapeutics. Current world literature. PMID- 20922842 TI - [Autoimmunity and autoimmune syndrome: norm and pathology]. AB - Multicomponent analysis of variations of serum marker antibodies is an efficacious tool for preventive (pre-clinical) diagnosis of immune disorders causing serious diseases. Successful development of this method may lead to revision of the approaches accepted in modern medicine and facilitate practical transition to the prognosis-prevention paradigm. The study of antibody spectra reflecting individual genetic and epigenetic features provides a basis for prognostication of health and pathological conditions. We believe that in most cases early diagnosis of reversible pathologic processes their further development can be arrested which provides a real opportunity to preserve health. PMID- 20922843 TI - [Endemic and biogeochemical characteristics of the territory of Chuvash Republic]. AB - The study of endemic and biogeochemical features of the territory of Chuvash Republic showed that dietary patterns of the local population reflect specific environmental factors including selenium, manganese, and iron deficiency. Calcium deficit is mainly due to poorly balanced nutrition. PMID- 20922844 TI - [Intracranial pressure. Intracranial pressure monitoring]. AB - Based on the data on the current literature, the authors present the basic physiological and pathophysiological aspects of measurement of intracranial pressure and discuss indications for its monitoring and clinical value. PMID- 20922845 TI - [Comparative evaluation of preventive analgesia with xefocam, ropivacaine, and transdermal drug delivery system of durogesic in patients after craniotomy]. AB - The goal of this study was to comparatively evaluate the efficacy of pre-emptive analgesia in patients after supra- and infratentorial craniotomy. Three hundred and sixty-two postcraniotomy patients aged 16 to 72 years were recruited in the study. The patients were divided into 5 groups. The first two groups received traditional analgesia on demand with metamizole sodium and ketoprofen (Group 1) or xefocam (Group 2). Groups 3-5 had different preemptive analgesia modes. Scheduled dosing of xefocam (8 mg i.v. 30 min prior to surgery and then 8 mg every 8 hours within 48 hours) was used in Group 3. Group 4 underwent scalp nerve block and skin infiltration with ropivacaine. Group 5 had a scheduled dosing of fentanyl (12-18 hours before surgery, Durogesic was applied to the patient's skin in a dose 25 microg per hour for 3 days). Postoperative pain was assessed using the visual analogue scale (VAS) at 6, 18, 30, 42, and 54 hours after surgery. The patients who received pre-emptive analgesia showed significantly lower VAS scores than those who had traditional analgesia (p < 0.05). PMID- 20922846 TI - [Prognostic evaluation of sleep in patients in a vegetative state]. AB - Coma in the genuine sense is a dreamlike state that lasts not more than 3 weeks, thereafter it progresses to a vegetative stage of consciousness recovery, except when a patient has died or regained conscious wakefulness. Among those who have achieved the vegetative state progress to the following stage of recovery: mal consciousness or completely return to the initial cognitive level. Others remain in a persistent vegetative state. The registered cases of the vegetative state is as high as 100 per million population (S. Ashwal et al., 1996). This patient category remains terra incognita even for interdisciplinary analysis by neurologists and reanimatologists. Nonetheless, the emotional and financial support to manage this patient category is high. In searching for prognostic criteria for the outcome of a vegetative state, the authors attempted to analyze sleep, one of the earliest phylogenetic autonomic functions. Based on the hypothesis that the cognitive status cannot be regained if sleep is not recovered, the authors conducted a polysomnographic study in 64 patients. Preserved sleep patterns were observed in 27 (96%) of 28 patients with a good outcome versus 11 (31%) of 36 patients with a poor outcome. It is concluded that it is expedient to incorporate polysomnographic monitoring into the examination protocol for patients in a vegetative state. PMID- 20922847 TI - [A respiratory failure rating scale in neurosurgical patients]. AB - A respiratory failure (RF) rating scale has been developed to objectify indications for artificial ventilation (AV). The scale consists of three blocks gauging the level of consciousness, the degree of swallowing problems, cough, airway patency, and lung parenchymatous injury. The scale was tested in the period December 2009 to March 2010. Selection of patients in accordance with the chosen study inclusion and exclusion criteria allowed 15 patients to be enrolled in the study. Of them there were 8 (53%) women and 7 (47%) men. The patients' age was 25 to 68 years; median age was 42 years. There were cerebrovascular aneurysms and brain tumors of various locations and histology in 7 and 8 cases, respectively. Three groups of patients were identified. The first two groups included patients with successful extubation, but Group 2 patients were further reintubated because of neurological deterioration. In Group 3 patients, extubation was unsuccessful, i.e. these required reintubation within 48 hours after extubation. Groups 2 and 3 patients developed inflammatory complications, such as nosocomial pneumonia and sepsis; there were worse outcomes. If the tactics of AV initiation were determined from scale scores, it should not differ in Groups 1 and 2. Based on the scale scores, AV should be regained much more early than was practised. The developed scale allows one to optimize the time of AV initiation. Single patient assessment can ascertain a direct cause of respiratory failure (RF) while dynamic assessment can determine the sequence of changes in the magnitude of individual determinants of RF. In patients with unsuccessful tracheal intubation, the scale will optimize the time of reintubation, thereby reducing the incidence of nosocomial and aspiration pneumonia. PMID- 20922848 TI - [Hemostatic disorders caused by chronic use of valproic acid in neurosurgical patients. Thromboelastographic monitoring]. AB - The paper gives the results of analyzing the hemostatic system in 26 patients with various neurosurgical diseases on the basis of routine laboratory biochemical tests and thromboelastographic indicators. In all the patients, the pattern of the disease contained an epilepsy syndrome that required mono- or combination therapy with valproic acid. Laboratory indicators of clinical hypocoagulation were found to develop during the use of valproic acid, and its monotherapy in particular. Hemorrhagic complications were also analyzed in not only the immediate, but also late postoperative period (for as long as 6 months after surgery). Two cases of severe late complications, such as formation of chronic subdural hematomas requiring surgical intervention, were diagnosed in the valproate monotherapy group. A tactic using a thromboelastographic technique is proposed to prepare these patients for further neurosurgical intervention. PMID- 20922849 TI - The effective management of out of hours treatment in primary care using telephone clinical assessment software (TeleAssess). PMID- 20922850 TI - Cancer linked to Alzheimer disease but not vascular dementia. PMID- 20922851 TI - Is there a link between cancer and Alzheimer disease? PMID- 20922852 TI - Modeling relationships in clinical research using path analysis part I: an overview of the process. AB - Scientific Inquiry provides a forum to facilitate the ongoing process of questioning and evaluating practice, presents informed practice based on available data, and innovates new practices through research and experimental learning. PMID- 20922853 TI - The seven lamps of bioengineering. PMID- 20922854 TI - Two historic events-a first in Washington [conference report]. PMID- 20922856 TI - Radiation oncology. PMID- 20922855 TI - Pre-Existing Condition Insurance Plans created by the Affordable Care Act of 2010. AB - The Patient Protection and Affordable Care Act includes a provision for the establishment of a temporary high-risk pool, also called the Pre-Existing Condition Insurance Plan (PCIP), to quickly make health insurance available to uninsured individuals with preexisting conditions, many of whom previously had been denied coverage. Twenty-seven states elected to administer the PCIPs for their citizens, while the remaining states and the District of Columbia chose to let their PCIPs be federally administered. This issue brief examines eligibility, benefits, premiums, cost-sharing, and oversight of the PCIP programs, as well as variation of the plans from state to state. The PCIPs will run through December 31, 2013, at which time participants will be transitioned to exchange coverage. PMID- 20922857 TI - Dermatology. PMID- 20922858 TI - [On the 80th birthday of Dr. Jaroslav Blahos, President of the J.E. Purkinje Czech Medical Society]. PMID- 20922859 TI - [Compression therapy for lymphedema: our experience]. AB - The term lymphedema refers to a chronic, progressive edema, usually of a limb, due to insufficient lymphatic flow. It may appear as a primary disturbance or secondary to other causes, e.g., after infections or surgery. The most common cause of lymphedema in the Western world is cancer surgery and/or radiotherapy. The authors summarize the etiology, pathophysiology and clinical staging of lymphedema. The diagnosis of lymphedema is usually based on history and clinical appearance. However, lymphoscintigraphy is the gold standard of imaging in doubtful cases. Adequate and early compression therapy and good patient compliance are the cornerstones of management of lymphedema. The authors present their experience with compression therapy for lymphedema. While no differences were found in the efficiency of compression therapy between oncologic and non oncologic patients, compression stockings of class III seemed to be efficient in the majority of secondary lower limb lymphedemas but not as maintenance therapy for primary lower limb lymphedema. PMID- 20922860 TI - [Hypertension and age of the donor in living-related kidney transplantation]. AB - INTRODUCTION: Post-transplantation hypertension is one of the most important factors with negative influence on survival of a graft and a patient. The objective of this study was to evaluate the influence of donor's age on hypertension and the outcome in living-related transplantation of the kidney. METHODS: The research included 52 recipients of the graft, 30 women and 22 men who received living-related kidney graft in the time period of 1999 to 2004. In the while control group consisted of recipients of graft who's donors were younger than 55. Age and sex of the donor, glomerular filtration rate of the donated kidney, dialysis treatment, kidney disease and number of months after transplantation were monitored. Blood pressure was measured once a day and average monthly value was assessed. Creatinine clearance was evaluated once in six months period. Functional kidney graft after 60 months was considered the one with serum creatinine < or = micromol/l. Statistical analysis included t test, Fisher's exact test, chi-square test, Kaplan - Meier curve and multivariate logistic regression. RESULTS: Experimental group included 23 examinees who received grafts from donors 55 years old and above (18 men and 5 women, average age 34.86 +/- 6.54, who have been treated for 35.33 +/- 37.59 months) while control group included 29 examinees (16 men and 13 women, average age 31.69 +/- 10.5, who have been treated for 21.03 +/- 25.59 months). Average age of the donors in the experimental group was 62.43 +/- 4.10 and 45.31 +/- 5.24 in control group. Mean creatinine clearance of the donated kidneys was 47.87 +/- 10.5 ml/min in experimental group and 51.19 +/- 10.1 ml/min in the control (p = 0.005). Sixty months after transplantation graft was functional in 32.69% recipients of the experimental group and in 82.75% recipients of the control group. The average systolic blood pressure in test group was 146 +/- 20 mm Hg, and in the control 129 +/- 16 mm Hg (p < 0.001). Average diastolic blood pressure was 90 +/- 11 mm Hg in experimental group, and 83 +/- 10 mm Hg in the control (p < 0.03). CONCLUSIONS: Age of the donor has significant influence on long-term survival of the kidney graft in the living-related transplantation. Survival of the graft in examinees without hypertension is significantly longer. Treatment of post transplantation hypertension is one of the most important tasks in the treatment of patients with transplanted kidney. PMID- 20922861 TI - [Diagnostic and therapeutic algorithm for the treatment of premenstrual dysphoric disorder]. AB - Many women experience psychological and physical symptoms associated with menstrual cycle. In 3% to 5% of women that meet the criteria for premenstrual dysphoric disorder, the symptoms are severe and impair their social and occupational functioning. Although the etiology of premenstrual dysphoric disorder is unknown, the symptoms of dysphoria, including depression and anxiety, have been associated with serotonergic dysregulation. Selective serotonin reuptake inhibitors, taken only during the symptomatic luteal phase, are considered as first-line therapy for premenstrual dysphoric disorder. PMID- 20922862 TI - [Osteogenesis imperfecta and achievements in cell and gene therapy]. AB - Osteogenesis imperfecta (OI) or "brittle bone" disease is characterized by fragile bones, skeletal deformity, and growth retardation. Depending on the mutation and related phenotype, O1 is classified into types I-IV, which are caused by different mutations in collagen genes, and types V-VIII, which are indirectly but not directly collagen related. The most common cause of this inheritable disorder of connective tissue are mutations affecting the COL1A1 and COL1A2 genes of type I collagen. There is no cure for OI and current treatments include surgical intervention, use of prostheses and physical therapy. Pharmacological agents have also been tried with limited success, with the exception of recent use of bisphosphonates, which have been shown to have some effect in bone mass acquisition. Since OI is a genetic disease, these agents are not expected to alter the course of collagen mutations. Recent technology in molecular biology has led to the development of transgenic models of OI, which are necessary for development of cell and gene therapies as potential treatments for OI and are currently being actively investigated. However, the design of gene therapies for OI is complicated by genetic heterogeneity of the disease and by the fact that most of OI mutations are dominant negative where the mutant allele product interferes with the function of the normal allele. Therefore, therapy needs to include suppression of the mutant allele and introduction of the wild type allele. The present review will discuss the classification of OI and molecular changes seen in different types of OI and transgenic murine models that mimic different types of OI. Cell therapy, gene therapy, and a combination of both represent new approaches in OI therapy development that are being investigated as potential future treatments for OI. Modest success of cell therapy, encouraging results of gene therapy in vitro and in animal models as well as their problems and limitations for use in humans will be presented. PMID- 20922863 TI - [Lumbosacral spine herniation--computed tomography diagnostics]. AB - The aim of this retrospective study was to establish the incidence of particular types of disk radicular conflicts of the lumbar region. The study showed no patient sex or age differences. Disk radicular conflicts were most commonly diagnosed at L5-S1 and L4-L5 levels. Study results pointed to dorsomedial protrusion of the intervertebral disk to be most common in the study region, followed by dorsolateral one, whereas foraminal protrusion of the intervertebral disk was the rarest one. Study results suggested that there was no significant age or sex difference in the incidence of disk radicular conflicts of the lumbar region. PMID- 20922864 TI - [Endoscopically assisted lipectomy]. AB - The aim of the study was to compare lipectomy and endoscopically assisted lipectomy. In a group of 32 patients with cytologically verified lipoma, 16 patients underwent classic lipectomy and endoscopically assisted lipectomy each. At 12-month follow up, there was no difference in the number of lipoma recurrences between the two techniques. Endoscopically assisted lipectomy proved to be a safe method with excellent cosmetic result and shorter recovery period for patients at the same risk of recurrent lipomas. PMID- 20922865 TI - [Factors affecting blood loss in total knee arthroplasty patients]. AB - The aim of the study was to identify the factors affecting major blood loss in patients undergoing total knee arthroplasty (TKA), in order to reduce blood loss and requirements for blood transfusion. This prospective randomized study included 80/184 patients treated by TKA at University Hospital of Traumatology, Zagreb, Croatia, from January 2005 till December 2007. The following parameters were analyzed: patient age, sex, body mass index (BMI), arterial blood pressure, preoperative hemoglobin level and hemoglobin level preceding blood transfusion, length of surgery, blood loss and volume of blood transfused. According to patient age, there were no differences in the length of surgery, blood loss volume, hemoglobin level before blood transfusion and use of blood transfusion. Older patients had lower hemoglobin level before blood transfusion and received greater volumes of blood transfusion, but the difference was not statistically significant. Male patients had a significantly higher preoperative hemoglobin level as compared to female patients (P = 0.012). The mean volume of blood loss and of transfused blood was larger in male than female patients, however, the difference did not reach statistical significance. According to BMI, there were no differences in the length of surgery, blood loss, volume of transfused blood and hemoglobin level before transfusion. Patients with a lower preoperative hemoglobin level did not lose more blood during and after surgery, but the requirement for blood transfusion was significantly higher (P = 0.014). Hypertensive patients had a statistically greater perioperative blood loss (P = 0.038), but did not receive more transfused blood (P = 0.494). Preoperative hemoglobin level was higher in patients with elevated arterial blood pressure than in those with normal blood pressure, but the difference was not statistically significant (P = 0.595). Hemoglobin level before blood transfusion was also higher in hypertensive patients than in those with normal blood pressure, but it was not statistically significant (P = 0.288). In patients with longer duration of surgery, blood loss and volume of blood transfused blood were statistically significantly greater (P = 0.003 and P = 0.015, respectively). Study results yielded a significant positive correlation between the length of surgery and the volume of blood loss (r = 0.282; P = 0.011) as well as between the length of surgery and the volume of blood transfused (r = 0.362; P = 0.001). A significant negative correlation was established between the preoperative hemoglobin level and application of blood transfusion (r = -0.250; P = 0.025). Patients with hypertension had a significantly larger blood loss volume as compared to patients with normal arterial pressure (P = 0.038) and received more blood transfusions than patients with normal blood pressure, but the difference was not statistically significant (P = 0.494). Age, sex and BMI had no statistically significant effect on blood loss volume and application of blood transfusion. Male patients had a significantly higher preoperative hemoglobin level (P=0.012), larger mean blood loss volume (P = 0.057) and received more blood transfusions than female patients, however, the difference did not reach statistical significance (P = 0.562). Based on study results, it is concluded that requirements for blood transfusion will be greater in patients with hypertension and lower preoperative hemoglobin level as well as in all cases with longer duration of surgery. To reduce the use of allogeneic blood transfusion, it is necessary to correct arterial blood pressure before surgery in hypertensive patients and also to magnify preoperative hemoglobin level if it is lower. PMID- 20922866 TI - [Pregnancies and deliveries in patients with Charcot-Marie-Tooth disease]. AB - Hereditary motor sensory neuropathy (HMSN), also known as Charcot-Marie-Tooth (CMT) disease, is a spectrum of disorders caused by a specific mutation in one of several myelin genes, which results in defects in myelin structure, maintenance and formation. Affected individuals show progressive distal limb atrophy and weakness, often with gait disturbance and deformity of feet and hands. There have been few studies on how CMT disease can affect pregnancy, birth and the newborn. CMT is an independent risk factor for complications during pregnancy and delivery. Patients with CMT have more operative deliveries, malpresentations and postpartum bleeding than the general obstetric population. It is not clear whether the increased prevalence of malpresentation is related to fetal disease, although the disorder typically does not present until later in childhood. Postpartum bleeding from atony may be related to the disease effect on uterine adrenergic nerves. Exacerbation of CMT disease can occur in pregnancy, an effect that may be mediated by increased plasma progesterone level. Observations in an animal model were consistent with these findings as the administration of progesterone resulted in a more progressive neuropathy, while a progesterone antagonist slowed the disease progression. We treated two patients with CMT (type 5 and type X1) at our Department. Both of them had normal course of pregnancy until delivery. Emergency cesarean section was performed in both cases; in one because of malpresentation, contracted pelvis and signs of impending fetal asphyxiation during the second stage of delivery, and in the other one based on neurologist indication. In the latter, uterine atony with profuse postpartum bleeding occurred immediately after cesarean section and emergency hysterectomy was performed according to clinical status. PMID- 20922867 TI - [Bilateral choroidal metastases of kidney carcinoma]. AB - Metastatic tumors are among the most common intraocular malignancies, and are exclusively localized in the uvea, 88% in the choroids. A 54-year-old male patient was admitted to Urology Department for macrohematuria. A tumor of the left kidney was found. Upon nephrectomy, histopathology indicated papillary carcinoma of the kidney with some focal sarcomatous differentiation. The left suprarenal gland was normal, but one of the regional lymph nodes was invaded. Three years later, the patient was hospitalized again for tumor of the right suprarenal gland and para-aortic tumor. At the same time, the patient complained of visual acuity worsening on the left eye. Fundus examination and fundus photography revealed yellowish subretinal lesions with serous retinal detachment. Metastatic eye lesions may anticipate or follow the diagnosis of kidney carcinoma. All tumors with a tendency of hematogenous metastasizing have a high affinity of metastasizing into the uvea because of its abundant blood flow. Posterior pole is the most common localization; over 40% of lesions are found in macular region, which is attributed to the higher posterior choroidal blood flow and easy macular symptom detection. That is why kidney carcinoma has to be ruled out in all patients with such yellowish subretinal lesions. PMID- 20922868 TI - [Relationship between phacoemulsification and extracapsular cataract extraction at University Department of Ophthalmology, Split University Hospital Center, during the 1997-2009 period]. AB - The aim of the study was to show the relationship between phacoemulsification and extracapsular cataract extraction at University Department of Ophthalmology, Split University Hospital Center (assessing the length of postoperative hospital stay and postoperative visual acuity), during the 1997-2009 period. We also wanted to explore the tendency of using different types of intraocular lenses. The study was designed as a retrospective analysis of operative records. Data were collected on all patients operated for cataract at our Department during the study period. We compared the mean duration of postoperative hospital stay and mean postoperative visual acuity between 1997/1998 (more than 90% were treated with ECCE technique) and 2007/2008 (more than 90% were treated with PHACO technique). Information was also collected on the type of lenses implanted. The rate of cataract extraction by phacoemulsification was less than 10% in 1997/1998, then progressively rising to reach 99.2% in 2009. The mean hospital stay was 5.73 (range 2-19) days in 1997/1998 as compared with 1.99 (range 0.02-1) days in 2007/2008. The mean uncorrected postoperative visual acuity was 0.71 (range 0.01-1.0) in 2007/2008. In conclusion, the number of cataract patients operated on by the phacoemulsification technique progressively and significantly increased during the 1997-2009 period, confirming the method as the most acceptable and less traumatic technique that is applicable in most of cataract patients. PMID- 20922869 TI - [The AURORA study]. PMID- 20922870 TI - [Pathophysiological links between obstructive sleep apnea syndrome and metabolic syndrome]. AB - Obstructive sleep apnea (OSA) is a chronic disease characterized by repetitive partial or complete closure of the upper airway during sleep. OSA tends to be associated with components of metabolic syndrome sharing a common ground of metabolic changes with metabolic syndrome itself. Recent studies showed that subjects with OSA were 6-9 times more likely to have metabolic syndrome than subjects without OSA. Intermittent hypoxia and sleep fragmentation in OSA can initiate intermediary mechanisms (oxidative stress, neurohumoral changes, inflammation) leading to the components of metabolic syndrome. OSA has been suggested to be a novel risk factor, inside the metabolic syndrome, contributing to increased cardiovascular risk. Several studies report that continuous positive airway pressure (CPAP) treatment can reverse pathophysiological changes in OSA, increasing insulin sensitivity and reducing blood pressure. Recent evidences show that CPAP treatment reduces the risk of cardiovascular events and mortality in subjects with OSA. Some subjects with metabolic syndrome can be affected by undiagnosed OSA: CPAP treatment could significantly reduce cardiovascular risk in this subgroup of patients. PMID- 20922871 TI - [Hypoglycemic therapy in heart disease patients with type 2 diabetes mellitus]. AB - In type 1 diabetes, insulin treatment reduces complications related to microvascular disease and atherosclerosis. The same holds true in patients with short duration of type 2 diabetes, treated either with oral antidiabetic drugs or with insulin. Conversely, in patients with long-standing type 2 diabetes, advanced age or history of cardiovascular disease, treatment with oral diabetic drugs or insulin must be given with caution because of the unfavorable risk benefit profile when these drugs are used with too aggressive aims. In the last year, several studies have clearly demonstrated that an excessive reduction of glycated hemoglobin exposes the patient at risk of hypoglycemia and fattening, with neutral results about clinical events or even with a paradoxical increase of cardiovascular events (hospitalization and mortality). The glycemic goal in heart disease and diabetic patients should be settled on higher values (probably 7-8%). There are no significant differences among drugs that reduce insulin resistance and drugs that stimulate its secretion. The only drug that proved to be effective in reducing cardiovascular events is metformin, which increases AMP-activated protein kinase activity and has a potent cardioprotective effect against ischemia reperfusion injury. These findings should be confirmed in larger longitudinal studies in heart disease patients. Patients in intensive care units should be treated with intravenous insulin with a glycemic target <180 mg/dl (mean 142 mg/dl) because more aggressive goals may lead to increased mortality. These results demand important considerations about the management of heart disease patients with type 2 diabetes, also because self-monitoring of blood glucose concentration seems to induce an increase in depression. Conversely, an aggressive multifactorial intervention (improvement of lifestyle, blood pressure and dyslipidemia control, platelet aggregation inhibitors in secondary prevention) reduces effectively cardiovascular events and mortality. PMID- 20922873 TI - [The Valsalva maneuver in the diagnosis of patent foramen ovale]. PMID- 20922872 TI - [Atherothrombosis in patients with type 2 diabetes mellitus: an overview of pathophysiology]. AB - Type 2 diabetes mellitus is a well known condition characterized by a functional and metabolic milieu that promotes the development of the atherosclerotic process and its macrovascular complications (e.g., acute myocardial infarction, stroke, peripheral arterial disease). In diabetic patients, several negative alterations lead to the progression of the atherosclerotic disease. These alterations involve the coagulation cascade, the endothelial function, platelet and monocyte adhesiveness, macrophage function, and fibrinolysis: all these processes are adversely affected by hyperglycemia and insulin resistance. In diabetic patients, the fluid and the cellular phases are modified to generate a prothrombotic phenotype. In this review we will discuss about the main pathophysiological mechanisms involved in diabetic atherotrombosis in order to look beyond the usual "hydraulic-rheologic" picture of macrovascular diabetic disease, and to better understand the importance of the adverse interactions that occur between the endothelial wall and the circulating cells. PMID- 20922874 TI - [Does dual antiplatelet therapy always require gastroprotection? Tailored medical therapy should prevail over the generalized prescription of proton pump inhibitors in patients on dual antiplatelet therapy]. PMID- 20922875 TI - [Does dual antiplatelet therapy always require gastroprotection? Gastroprotection with proton pump inhibitors is advisable for all patients who need dual antiplatelet therapy]. PMID- 20922876 TI - [Pericardial cyst with intracystic hemorrhage. A case report and review of the literature]. AB - Pericardial cysts are rare benign intrathoracic lesions, more often located in the right rather than in the left cardiophrenic angle. At echocardiography, they appear as echolucent unilocular structures, which are in contact with the pericardium. They contain a clear water-like fluid and, thus, are referred to as "spring water cysts". They are usually discovered incidentally in asymptomatic patients. Sometimes they can cause symptoms (dyspnea, chest pain, dysphagia, cough), depending on their dimensions and location, or severe complications such as cardiac tamponade. Asymptomatic cases are managed conservatively with a close follow-up, being surgical excision recommended only in symptomatic patients. Actually, the treatment options include excision via thoracotomy, video-assisted thoracoscopic surgery, and percutaneous echo-guided aspiration. We describe the case of a patient for whom the echocardiographic follow-up allowed to disclose intracystic hemorrhage, leading to surgical treatment before the patient became symptomatic. PMID- 20922877 TI - [Atrial myxoma presenting during pregnancy]. AB - We report a case of left atrial myxoma presenting as acute respiratory failure following surgical intervention for voluntary interruption of pregnancy. After cardiac surgery T-wave changes were observed on the ECG, most likely due to coronary embolism. PMID- 20922878 TI - [Persistent left-sided superior vena cava associated with prominent Chiari network prolapsing into the right ventricle in an asymptomatic young subject]. PMID- 20922879 TI - [Appropriateness in echocardiography and clinical priority classification criteria: a proposal from the Italian Society of Cardiovascular Echography]. AB - One of the main tasks of a scientific society is to define the theoretical bases and appropriate management strategies with the aim to maintain a high-quality diagnostic and therapeutic standard. As far as echocardiography is concerned, the task of the Italian Society of Cardiovascular Echography is to provide appropriate, complete, and useful echocardiographic tests for clinical application, as well as procedural, technological, organizational and economic indications to be adopted in clinical practice. In addition, there is an increasing need for regulating access to echocardiographic assessment according to clinical priority, because of the huge proportion of patients who should undergo a first or follow-up echocardiographic evaluation. The aim of this document is to implement appropriateness in echocardiography for the study and follow-up of cardiovascular diseases, and to optimize demand on the basis of clinical priority classification criteria outlined by the scientific societies and used by the National Health Service. Besides cardiovascular diseases, this document also addresses other diseases that often require echocardiographic investigation, such as liver diseases, connective tissue diseases, endocrine diseases, peripheral vascular and oncological diseases. Although not included in the previous guidelines, clinical priority and followup criteria are defined also for these groups of diseases according to the available literature. In conclusion, this document aims at guaranteeing access to the diagnostic echocardiographic procedures provided by the National Health Service to the general population, with practical indications on how to solve the problem of waiting lists. PMID- 20922880 TI - [Sustainability of cardiological imaging]. PMID- 20922881 TI - Probability of spacesuit-induced fingernail trauma is associated with hand circumference. AB - A significant number of astronauts sustain hand injuries during extravehicular activity training and operations. These hand injuries have been known to cause fingernail delamination (onycholysis) that requires medical intervention. This study investigated correlations between the anthropometrics of the hand and susceptibility to injury. METHODS: The analysis explored the hypothesis that crewmembers with a high finger-to-hand size ratio are more likely to experience injuries. A database of 232 crewmembers' injury records and anthropometrics was sourced from NASA Johnson Space Center. RESULTS: No significant effect of finger to-hand size was found on the probability of injury, but circumference and width of the metacarpophalangeal (MCP) joint were found to be significantly associated with injuries by the Kruskal-Wallis test. A multivariate logistic regression showed that hand circumference is the dominant effect on the likelihood of onycholysis. DISCUSSION: Male crewmembers with a hand circumference > 22.86 cm (9") have a 19.6% probability of finger injury, but those with hand circumferences < or = 22.86 cm (9") only have a 5.6% chance of injury. Findings were similar for female crewmembers. This increased probability may be due to constriction at large MCP joints by the current NASA Phase VI glove. Constriction may lead to occlusion of vascular flow to the fingers that may increase the chances of onycholysis. Injury rates are lower on gloves such as the superseded series 4000 and the Russian Orlan that provide more volume for the MCP joint. This suggests that we can reduce onycholysis by modifying the design of the current gloves at the MCP joint. PMID- 20922882 TI - Laser acupuncture and prevention of bone loss in tail-suspended rats. AB - BACKGROUND: Skeletal unloading during spaceflight results in bone loss. This study investigated whether laser acupuncture could be an effective countermeasure to prevent unloading-induced bone loss in rats. METHODS: There were 18 rats that were randomly assigned into three groups: a control group, a tail-suspended group (TS), and a tail-suspended with laser acupuncture treatment group (TSA). The rats in the TSA group were treated with laser acupuncture at the KI1 (Yong Quan) and ST36 (Zu San Li) acupoints of the left leg for 3 min per day. Bone mineral density (BMD), biomechanical properties, and histomorphometry of both tibiae were determined after the animals were euthanized at the end of week 4. RESULTS: Compared with the control group, BMD in the TS group significantly decreased by 12.3% in cortical bone and 15.1% in cancellous bone, whereas BMD in the TSA group decreased by only 3.1% in cortical bone and 9.0% in cancellous bone. The hardness of cortical bone dropped 44.1% in the TS group and 22.3% in the TSA group compared with the control group. The histomorphometry data were in accordance with BMD measurements. Although acupuncture treatment was applied only to the left side, we observed similar changes between the measurements of both the left and right tibiae. CONCLUSION: Laser acupuncture on KI1 and ST36 can inhibit bone loss in rats subjected to unloading. The fact that similar changes between the right and left sides when only the left limbs were treated suggests that the preventive effect of laser acupuncture occurs via a systemic regulation. PMID- 20922883 TI - Changes in toe clearance during treadmill walking after long-duration spaceflight. AB - INTRODUCTION: Astronauts exhibit sensorimotor changes upon return from long duration spaceflight that can result in altered gait kinematics and possibly an increased risk of tripping. Toe trajectory during locomotion is a precise motor control task involving both legs, thus providing a composite metric of locomotor control. The purpose of this study was to determine whether astronauts are at an increased risk of tripping after their return from long-duration spaceflight. This was accomplished by assessing the pre- to postflight changes in toe clearance during treadmill walking. METHODS: Ten crewmembers walked on a treadmill while performing a visual-acuity task pre- and postflight. RESULTS: In the three subjects on whom landing day data were available, each exhibited a characteristic of increased tripping risk on landing day: either a decreased median toe clearance or an increased interquartile range (a measure of variance). For all crewmembers, toe clearance median and interquartile range were not significantly different from preflight for the other postflight sessions (the earliest being 1 d after landing). A follow-up analysis showed that changes in foot pitch, ankle dorsiflexion, and pelvis roll angles were significant predictors of changes in toe clearance. DISCUSSION: The landing-day observations indicated an increased risk of tripping, which may pose a hazard during locomotion immediately upon return to Earth, especially in an emergency scenario. However, tripping risk on subsequent days was not different than preflight. The joint angle analysis suggested that the crewmembers tried to reestablish their normal walking pattern postflight, instead of developing a new motor control strategy. PMID- 20922884 TI - Head movements and simulator sickness generated by a virtual environment. AB - BACKGROUND: For virtual environments (VEs) to be useful in training it is important to understand the negative effects of VE exposure. The purpose of this study was to observe head movements in virtual and real environments and the relation between those movements and simulator sickness. METHOD: There were 48 men who were trained in 4-person teams in either a head-mounted display (HMD) based VE or in a real world environment. Head position data were collected in both systems and simulator sickness scores were collected in the VE. The relationship of head movements and sickness scores in theVE was examined and the degree of head movements in the real world and VE compared. RESULTS: Differences were found in the length of time subjects spent moving their heads; subjects with the highest sickness scores moved their heads less often than other subjects in the VE. Also, subjects moved their heads significantly less and less often in the VE (means: 3 degrees x 50 ms(-1), 71% of trial time not moving head), compared to the real world (means: 10 degrees 50 ms(-1), 59% of trial time not moving head). CONCLUSIONS: This study observed that when head movements are quantified, past assumptions of the link between increased sickness scores and decreased head movements may not hold. Though not linked to simulator sickness, head movements were reduced in the VE compared to the real world. Though observational in nature, this study is one of the first to quantify head movements and how they may relate to simulator sickness. PMID- 20922885 TI - Individual and team susceptibility to change blindness. AB - BACKGROUND: Individual operators in command and control environments are susceptible to change blindness. Change blindness by teams of operators, which is typical in military command and control, has not been extensively studied. This experiment investigated change blindness in individuals and teams in a simulated military command and control situation display. METHODS: Subjects completed a change-detection task individually or in three-person teams. In one team condition team members could actively communicate with each other, but in another condition they could not. The change-detection task involved monitoring flicker sequences of displays containing 6, 12, 24, or 48 icons for changes in icon position. RESULTS: Results revealed a team advantage that was more pronounced when teams communicated. Communicating teams had higher overall correct detection rates (mean = 95%) than both non-communicating triads (mean = 80%) and individuals (mean = 79%). Teams were susceptible to change blindness just as individuals were, but teamwork and communication were beneficial in reducing change blindness susceptibility. Communicating teams also experienced lower global workload (mean = 24.08) than non-communicating triads (mean = 38.44) and individuals (mean = 47.18). DISCUSSION: This research highlights the importance of teamwork and communication in reducing change blindness and workload in a command and control environment. The findings can be used to facilitate development of methods and tools for reducing individual and team change blindness susceptibility. PMID- 20922886 TI - Air break during preoxygenation and risk of altitude decompression sickness. AB - INTRODUCTION: To reduce the risk of decompression sickness (DCS), current USAF U 2 operations require a 1-h preoxygenation (PreOx). An interruption of oxygen breathing with air breathing currently requires significant extension of the PreOx time. The purpose of this study was to evaluate the relationship between air breaks during PreOx and subsequent DCS and venous gas emboli (VGE) incidence, and to determine safe air break limits for operational activities. METHODS: Volunteers performed 30 min of PreOx, followed by either a 10-min, 20-min, or 60 min air break, then completed another 30 min of PreOx, and began a 4-h altitude chamber exposure to 9144 m (30,000 ft). Subjects were monitored for VGE using echocardiography. Altitude exposure was terminated if DCS symptoms developed. Control data (uninterrupted 60-min PreOx) to compare against air break data were taken from the AFRL DCS database. RESULTS: At 1 h of altitude exposure, DCS rates were significantly higher in all three break in prebreathe (BiP) profiles compared to control (40%, 45%, and 47% vs. 24%). At 2 h, the 20-min and 60-min BiP DCS rates remained higher than control (70% and 69% vs. 52%), but no differences were found at 4 h. No differences in VGE rates were found between the BiP profiles and control. DISCUSSION: Increased DCS risk in the BiP profiles is likely due to tissue renitrogenation during air breaks not totally compensated for by the remaining PreOx following the air breaks. Air breaks of 10 min or more occurring in the middle of 1 h of PreOx may significantly increase DCS risk during the first 2 h of exposure to 9144 m when compared to uninterrupted PreOx exposures. PMID- 20922887 TI - A software-based solution for research in space ethology. AB - INTRODUCTION: In this paper we present details of new applications of a software based system for human ethological investigations in space missions and analogous settings. The studies address astronauts' motor adaptation to microgravity during short-term stays and the crews' social behavior in isolation and confinement over extended time periods. The current working hypotheses are based on differences observed in multicultural and mixed-gender crews for future interplanetary missions. METHODS: In our approach, we use The Observer XT computer application to facilitate the observation, description, and quantification of behavioral data collected in parabolic flights, isolation and confinement campaigns, and polar missions. We implemented video recording protocols based on a goal-directed orientation task and daily life activities. RESULTS: The software integrates several steps: project management, definition of a coding scheme, annotation of videos linked to external data, data selection, and analysis. Numerical outcomes are presented. We show differences in motor skills between male (resting: 22%) and female (flexing/stretching: 22%) subjects in parabolic flights. We did not observe significant differences in social behavior by nationality during the isolation and confinement campaign. Notable findings include cultural grouping (20% of place preferences) and gender-based individuality (15%) during wintering at the polar base. DISCUSSION: The Observer XT may be a valuable tool to synchronize behavioral events with video files and bring forth visual representations and statistical analysis. It will be used for the next interdisciplinary project on the Mars 500 experiment to study physical ability, psychological capabilities, and behavioral performance over a 520-d stay in a simulated ground-based environment. PMID- 20922888 TI - Evaluation of a human factors analysis and classification system used by trained raters. AB - BACKGROUND: The U.S. Department of Defense (DoD) has used the DoD Human Factors Analysis and Classification System (DoD-HFACS) to help identify and classify human factors that may have caused or contributed to aircraft mishaps since 2005. METHOD: In this study 22 military officers used DoD-HFACS to classify information obtained from an interview with an individual who had been involved in an aviation incident in which the potential for serious injury had been high. RESULTS: It was found that although the overall interrater reliability was generally acceptable (as reflected by a mean Fleiss' kappa of 0.75) and there were high levels of agreement regarding the factors that did not contribute to the incident (there was agreement of 50% or greater between raters for 84.4% of unselected nanocodes); the level of agreement on the factors that did cause the incident as classified using DoD-HFACS were lower than desirable (agreement of 50% or greater between raters that a particular nanocode was causal was found only for a mean of 22.5% of selected nanocodes). DISCUSSION: The findings from this study are consistent with the small number of other studies reporting an evaluation of the reliability of DoD-HFACS. It is recommended that organizations must evaluate the reliability and validity of mishap coding systems, as applied by the proposed end-users, prior to the widespread adoption of a system. It is only through the accurate identification of mishap causal factors that informed decisions can be made to prevent future mishaps. PMID- 20922889 TI - Vestibular schwannoma and fitness to fly. AB - INTRODUCTION: When a pilot is referred for vestibular schwannoma (VS), his or her fitness to fly may be questioned. The objective of this retrospective study was to describe a series of VS cases in a pilot population and to discuss their fitness to fly options. METHODS: Between September 2002 and March 2010, the ENT/Head and Neck Surgery Department of the National Pilot Expertise Center conducted nearly 120,000 expert consultations for 40,000 pilots. We examined the files of 10 pilots who were referred to our 2 national experts for VS. RESULTS: At the time of the expert consultation, hypoacusis was present in nine cases (four with total deafness), tinnitus in one case, and vertigo in nine cases. In our series, only 2 of the 10 pilots experienced a negative impact on their fitness to fly. DISCUSSION: Decisions on fitness to fly were based on several factors: minimally disturbed audition, i.e., less than a 35-dB hearing loss with a good speech discrimination score; good balance, i.e., no reported difficulties; no spontaneous nystagmus recorded on videonystagmography (VNG); no postural deviation; and a normal head-shaking test. The delay and the VS's evolution between diagnosis and expert consultation are important because the selection of a treatment to control VS is critical in minimizing the possible associated complications. When a pilot is referred for VS, his or her fitness to fly is determined by the size of the tumor, balance, auditory status, and the follow-up results of these findings. The complications that may arise from VS treatments must also be considered. PMID- 20922890 TI - Abdominal sonography in the medical evaluation of aviation aspirants. AB - BACKGROUND: Ultrasonography is increasingly used in elderly individuals for screening of occult malignancy and abdominal aortic aneurysm. Its utility as a screening tool in healthy asymptomatic individuals is not yet established. The current study was undertaken to evaluate the utility of abdominal and pelvic ultrasonographic screening as an adjunct to routine physical examination among young adults undergoing initial medical examination for aviation duties. METHODS: Abdominal ultrasound findings of 2598 candidates (2339 men, 259 women, mean age 20.3 +/- 1.8 yr) reporting for initial aircrew medical examination between January 2004 and December 2006 at two established medical evaluation centers were analyzed. RESULTS: Of the candidates, 90% (N=2339) screened were for cockpit aircrew duties. Sonographic abnormalities were noted in 6.0% of candidates. These included fatty infiltration of the liver in 2.9%, renal abnormalities in 1.57%, gallstones in 0.34%, and splenomegaly in 0.30%. Of the 259 female candidates, 7 were noted to have pelvic abnormalities which included ovarian cyst in 5, and uterine agenesis and fibroid uterus in 1 each. Of the aircrew who had abnormal findings on the initial ultrasonography, 71% required further testing. Based on the ultrasound findings 10 candidates were declared permanently unfit, 39 candidates were declared temporarily unfit, and the remaining were found fit for aviation duties. DISCUSSION: Abdominal sonographic screening in young healthy asymptomatic aircrew may be a valuable extension of the initial medical evaluation. It is particularly important in the high-risk subgroup of military aviators for determining long-term career prospects. PMID- 20922891 TI - An artificial pancreas. PMID- 20922892 TI - You're the flight surgeon. H. pylori positive peptic ulcer disease. PMID- 20922893 TI - Classics in space medicine. An account of experiments in which two monkeys were recovered unharmed after ballistic space flight. PMID- 20922894 TI - Right subclavian artery aneurysm: report of a case. AB - A subclavian artery aneurysm is relatively rare in comparison with other peripheral aneurysms. Surgical repair should be considered regardless of size and location, because thromboembolism or rupture can occur when a small aneurysm is untreated. We describe the management and surgical treatment in a patient with a right subclavian artery aneurysm. Surgical repair included the ligation of the right vertebral artery and reconstruction of the subclavian artery through an upper partial median sternotomy with right supraclavicular extension. Successful repair of the aneurysm was accomplished and the patient's postoperative course was uneventful with no medication. PMID- 20922895 TI - Sentinel lymph node biopsy in conjunctival malignant melanoma at the lacrimal caruncle: a case report. AB - BACKGROUND: Conjunctival malignant melanoma (CMM) is so rare that there are no certain guidelines for its treatment. Factors influencing its prognosis include region of onset, tumor thickness, lymph node metastasis, and distant metastasis. Whether regional lymph node metastasis is present or not is one of the most powerful factors for predicting recurrence in and survival of patients with CMM. METHODS: A 72-year-old man with conjunctival malignant melanoma at the lacrimal caruncle was underwent sentinel lymph node (SLN) biopsy by preoperative lymphoscintigraphy and intraoperative vital blue mapping. RESULTS: A blue-dyed node could be identified in the superficial lobe of the parotid gland. A split half of the cropped SLN was immediately submitted to rapid pathological examination. After confirming no metastasis, it was decided not to perform lymph node dissection. The final diagnosis was pT3N0M0. Neither recurrence nor distant metastasis has been observed for 7 years after the operation. CONCLUSIONS: We were able to evaluate N (lymph node metastasis) in the TNM classification accurately. SLN may facilitate N classification and decisions regarding employment of appropriate lymph node dissection as well as combined therapy after operation. PMID- 20922896 TI - Baylor's Frederick Savelsbergh on capital financing strategy. PMID- 20922897 TI - Payment reform, accountable care, and risk: early lessons for providers. AB - Several organizations have begun to design and even implement accountable care organization (ACO), payment reform, and risk sharing pilots. Here are some early lessons: Providers should not design and implement ACOs, payment pilots, and risk models in a vacuum. Providers should tackle five core decision areas that underlie all ACOs, payment pilots, and risk arrangements. Providers should invest in analytics to inform tactical and strategic decisions simultaneously. Successful organizations implement pilot programs before going into full production mode. PMID- 20922898 TI - The cost of confusion: healthcare reform and value-based purchasing. AB - Title III of the Affordable Care Act presents two types of opportunities: those whose outcomes pose some uncertainties and those whose outcomes are well known. Accountable care organizations (ACOs) represent an uncertain opportunity, and although they may prove to be a worthwhile pursuit, focus on ACOs should generally not take precedence over more pressing concerns, such as impending loss of Medicare revenue. Value-based purchasing represents an opportunity that, if missed, would likely result in a revenue loss. PMID- 20922899 TI - The intended-and unintended-consequences of healthcare reform. AB - Healthcare reform will affect providers by: Changing employer-sponsored health plans. Cutting Medicare payment. Expanding Medicaid coverage. Penalizing excessive avoidable readmissions. Increasing Medicaid payment to primary care physicians. Increasing payment to community health centers. Changing patient provider relationships. PMID- 20922900 TI - HFMA's reform resources. PMID- 20922901 TI - Understanding variation in Medicare inpatient payment. AB - Average Medicare payments vary widely from state to state. Average Medicare costs vary widely too but often not in concert with payment variation. As a result, many states have negative Medicare margins, and some are surprising. PMID- 20922903 TI - Hospitals join forces to transform the revenue cycle. AB - Standardization across hospitals fosters accountability and productivity, facilitates the dissemination of best practices, and provides for comparable measurement. Managin by metrics allows leaders to drive targeted projects, achieve desired results, and sustain the projects, achieve desired results, and sustain the improvements made. Strong sponsorship is key to successfully deploying Six Sigma black belts to partner with process owners and drive process improvement. PMID- 20922902 TI - Using the medicare cost report to improve financial performance. AB - The Medicare cost report can help you understand your organization's financial performance by providing a means to: Analyze costs. Assess departmental and payer margins. Compare performance with the competition. PMID- 20922904 TI - From acquisition to integration: transforming a hospital into an ACO. AB - Five steps are essential to the process of hospitals acquiring physician groups to develop truly integrated delivery systems: Securing internal and external approvals. Integrating physicians into leadership and governance. Developing physician employment terms and compensation. Exploiting reimbursement improvement opportunities. Streamlining operations PMID- 20922905 TI - Automating the OR supply chain at Memorial Hermann Healthcare System. AB - Implementing point-of-use automation for the operating room supply chain involved automating and standardizing supply chain processes. Each supply item was identified and assigned a unique code as part of the automated chargemaster catalog. The pilot generated additional net revenue and yielded operational efficiencies. PMID- 20922906 TI - Reducing clinical costs with an EHR. AB - Steps that hospitals should take to ensure they are gaining optimal value from their electronic health record (EHR) systems include: Creating a value framework for EHR implementation a value framework or EHR implementation. Creating and build executive understanding of the framework. Quantifying each of the expected benefits of EHR implementation. Creating a cross-functional executive team to lead investments in performance management related to the EHR system. Aligning incentives through a formal physician engagement strategy. PMID- 20922907 TI - Road trip to organizational success. PMID- 20922908 TI - Major capital projects and hospital cost position. PMID- 20922909 TI - Inhibitory effect of arsenic on aerobic gut flora in rat. AB - An in vivo study was carried on rats to see the influence of arsenic on aerobic gut flora. A significant inhibition of gut flora was observed after 2 weeks of administration of arsenic (1 mg/L) ad libitum with a decrease in stool arsenic level and increase in liver arsenic level. However, this inhibitory effect of arsenic on gut flora was not observed in presence of vitamin E (1 mg/day) or selenium (0.4 microg/day). Pretreatment with streptomycin (500 mg twice daily) showed similar results. Rats that received folic acid (200 microg/day) showed inhibition of gut floral count but there were decreased liver arsenic level. PMID- 20922910 TI - Ethnobotanical, phytochemical and toxicological studies of Xanthium strumarium L. AB - The present study describes the ethnobotanical, phytochemical, and toxicological evaluations of Xanthium strumarium L. growing in Bangladesh. In toxicity evaluation on rats, the methanol extract of seedlings showed mortality, while both seedling and mature plant extracts raised the serum alanine transaminase and aspartate transaminase values and produced significant abnormalities in the histopathology of liver and kidney of rats. On the other hand, the aqueous soluble fraction of methanol extract of mature plant (LC50 = 0.352 microg/mL) and methanol crude extract of seedlings (LC50 = 0.656 microg/mL) demonstrated significant toxicity in the brine shrimp lethality bioassay. A total of four compounds were purified and characterized as stigmasterol (1), 11-hydroxy-11 carboxy-4-oxo-1(5),2(Z)-xanthadien-12,8-olide (2), daucosterol (3) and lasidiol 10-anisate (4). The present study suggests that X. strumarium is toxic to animal. PMID- 20922911 TI - Levofloxacin prophylaxis to prevent bacterial infection in chemotherapy-induced neutropenia in acute leukemia. AB - Infection in chemotherapy-induced neutropenia (neutrophils < 500/mm3) is the main cause of death during the treatment of acute leukemia. Antibiotic prophylaxis is a controversial issue to prevent or delay this infection. This study assessed the efficacy of prophylaxis with oral levofloxacin in chemotherapy-induced febrile neutropenic patients. Eighty patients of acute leukemia was randomly assigned to had levofoxacin (500 mg/daily) or placebo from the starting of chemotherapy. Out of 80 patients 53 developed neutropenia and fever. The number of patients with fever (78% vs. 68%), isolation of the pathogenic bacteria (30.43% vs. 16%) was higher and mean starting day of the fever (11.1 vs. 13.2) was shorter in the placebo group than the levofloxacin group. Levofloxacin reduced the bacterial infections and delays the onset of fever in chemotherapy-induced neutropenia especially in short duration (< 7 days). PMID- 20922912 TI - Free radicals and antioxidant status in acute myocardial infarction patients with and without diabetes mellitus. AB - In this study we investigated the oxidative stress, antioxidants and inflammatory molecules in patients of acute myocardial infarction (AMI) with diabetes (n = 50) and non-diabetes (n = 50). Fifty healthy subjects were taken as control. The levels of plasma TBARS and ceruloplasmin levels were significantly high in diabetic and non-diabetic AMI patients as compared with control. On the other hand, the activities of both enzymatic and non-enzymatic antioxidants were significantly decreased in diabetic and non-diabetic AMI patients as compared with control. Inflammatory markers showed significant rise in diabetic patients as compared with controls. Our results show increased inflammation and oxidative stress in patients with AMI, and magnitude of imbalance is greater in diabetic AMI patients, possibly because of greater inflammation in diabetic patients. PMID- 20922913 TI - Determining infants' age for measles vaccination based on persistence of protective level of maternal measles antibody. AB - The present study was conducted over a period of one year to find the right time for measles vaccination when maternal antibody titer in infants was decayed rendering them susceptible to wild virus infection. Blood samples were collected from the cord of new born (147), 2-5 months (47) and 5 to 7.5 months (24) of age. The mean measles IgG antibody titer detected in cord blood at birth (0 months) was 348.8 mlU/mL which steeply decreased to 155.6 mlU/mL by the age of 2-3 months. After that the fall in antibody becomes relatively slower and decreased to 101.6 mIU/mL by the age of 3-5 months and 38.8 mlU/mL by the age of 5-6 months and to 19.2 mIU/mL between the age of 6 to 7.5 months. The fall in antibody level with the advance of age was statistically significant (p < 0.001 ). Majority of the subjects (97.6%) exhibited protective level of antibody at birth. But only a little above one-quarter (25.5%) of them persisted the protective level between the age of 2-5 months and none had protective level from 5 months onwards. PMID- 20922914 TI - Effect of carvedilol on adrenaline-induced changes in serum electrolytes in rat. AB - Circulating catecholamine that is increased in early phase of myocardial infarction alters serum electrolyte levels which might predispose to serious ventricular arrhythmias. In this study the effect of pretreatment of carvedilol on adrenaline-induced changes in the serum electrolytes (Mg2+, K+, Ca2+, Na+) was evaluated in rats. Adrenaline was administered at a dose of 2 mg/kg body weight subcutaneously 2 injections 24 hours apart and serum electrolytes were estimated at 12 hours, 24 hours and 7 days after the 2nd injection of adrenaline. Adrenaline administration initially caused hypomagnesemia, hypokalemia, hypocalcemia and hyponatremia, which were restored to normal spontaneously within 7 days. Pretreatment of carvedilol orally at a dose of 1 mg/kg body weight for 2 weeks significantly prevented initial reduction in serum electrolyte levels induced by adrenaline. It was concluded that prophylactic use of carvedilol might prevent the serious consequences of myocardial infarction as sudden cardiac death due to arrhythmia caused by electrolyte changes. PMID- 20922915 TI - Seroprevalence of cytomegalovirus antibody in antenatal population in Bangladesh. PMID- 20922916 TI - [Current population-based public health workforces in Bangladesh]. PMID- 20922917 TI - Safety and efficacy of atrial septal defect closure on normothermic on-pump beating heart. PMID- 20922918 TI - Evaluation of a new cultural competency training program: CARE Columbus. AB - PURPOSE: This article reports the educational outcomes of the newly developed CARE (Cultural Awareness and Respect Through Education) Columbus cultural competency training program. METHODS: Questionnaires were administered to course participants, who completed the 3-hour CARE Columbus cultural competency training program from March 17, 2006, to April 18, 2008. A pilot work site implementation questionnaire was also sent to a smaller sample of participants who completed the course. RESULTS: The CARE Columbus cultural competency training received an overall program rating of 4.5 on a 5-point scale. Sixty-three percent (379 of 601) of the participants completed the program questionnaires. In addition, 55% (33 of 60) of the pilot work site implementation questionnaires were completed. CONCLUSION: Initial evaluation of the CARE Columbus cultural competency training program appears to demonstrate its effectiveness in improving attitudes, knowledge, and skills. Expanded evaluation to include determination of how best to overcome work site implementation barriers is warranted. Future challenges include development of an optimal business plan to maintain sustainability and improve outreach of CARE Columbus and similar classroom style training programs. PMID- 20922919 TI - First-year medical students' perceptions of physicians' responsibilities toward the underserved: an analysis of reflective essays. AB - OBJECTIVE: To explore medical students' perceptions of their future role as physicians as it relates to personal and professional responsibilities toward the underserved. METHODS: The authors conducted a qualitative content analysis of 53 first-year medical students' reflective essays focusing on the question: "Access to health care is a societal problem. Do physicians have a professional obligation to help by participating in free clinics, or otherwise doing some service-type activity? What are your personal feelings about how you might balance service to other people with personal issues like income, family, and career choice?" RESULTS: The student essays revealed students' awareness of the distinct expertise that enables physicians to offset limited access to health care. Although the majority of respondents supported physicians' responsibility to provide uncompensated care, a minority believed that there was no such responsibility attached to being a physician. Students also recognized the competing demands physicians often encounter that conflict with personal desires for service. CONCLUSION: The use of reflective essays in medical school curricula seems promising, in that they elicited students' beliefs on a complex topic with direct implications for professional identity and career decisions. PMID- 20922920 TI - Barriers to collecting patient race, ethnicity, and primary language data in physician practices: an exploratory study. AB - BACKGROUND: Experts recommend that physician practices collect and use patient race, ethnicity, and primary language data to document and address health care disparities and improve health care quality for diverse populations. Little is known about demographic data collection in small practice settings. OBJECTIVE: To conduct an exploratory study to examine demographic data collection in physician practices to reduce disparities and provide qualitative descriptions of facilitators and barriers to data collection. DESIGN: Semistructured telephone interviews. SETTING: Medical practices with 5 or fewer physicians. PARTICIPANTS: Practice managers, nurse managers, and physicians from 20 practices nationwide. RESULTS: Of the 20 practices interviewed, 9 reported collecting demographic data. Only 1 practice feature facilitated demographic data collection: use of an electronic medical record (EMR) system (7 of 10 practices with an EMR collected data). Participation in pay-for-performance programs, cultural competency training, and measuring clinical quality did not facilitate data collection. One practice linked demographic and quality data. A few used the data to track language service needs. The main perceived barriers to demographic data collection included concerns about privacy, the legality of collecting the information, possible resistance from patients and staff, difficulty recording the data, and uncertainty about whether the data would be useful. CONCLUSIONS: Few small practices use data to track or address disparities in health care. Most perceived barriers to data collection can be surmounted. There is hope for improved collection and use of data through the spread of information technology with comprehensive national health reform. PMID- 20922921 TI - Utilization of health care services and willingness to participate in future medical research: the role of race and social support. AB - OBJECTIVES: Utilization of health care services and participation in medical research are 2 distinct yet closely related areas. The goal of this study was to investigate the similarities and differences in factors that are associated with health care service utilization and future participation in medical research, and the influence of race and social support. METHOD: We used data from the Greater Pittsburgh Randomized Household Health Survey, which consisted of a weighted sample of 741 white and 277 black respondents from Allegheny County, Pennsylvania. RESULTS: Logistic regression analyses revealed that utilization of health care services was associated with being younger (OR, 0.98; p < .001), being female (OR, 1.55; p < .05), high self-rated health (OR poor health, 2.29; OR average health, 2.18; p < .001; both in comparison to high self-rated health group) and high perceived quality of health care (OR poor quality, 3.63; OR average quality, 1.79; p < .001; both in Comparison to high perceived quality group), while future participation in medical research was associated with greater awareness of the Tuskegee Syphilis Study (none OR, 0.07; p < .01; only a little OR, 0.13; p < .01), more favorable opinions toward medical research (unfavorable OR; p < .001; neutral OR, 0.35; p < .05), and increased research incentives (free medical care OR, 1.27; p < .05; free transportation OR, 1.29; p < .05; money OR, 1.25; p < .05; free medication OR, 1.50; p < .001). CONCLUSIONS: While utilization of health care services and willingness to participate in future research are related, the factors associated with each vary greatly. Implications for health research and policy are discussed. PMID- 20922922 TI - Factors affecting whites' and blacks' attitudes toward race concordance with doctors. AB - This paper assesses whether 2 dimensions of whites' and blacks' attitudes toward race concordance with doctors are associated with past unfair treatment in health care and general racial attitudes, and whether the association varies by race. Using telephone survey data, we find that among blacks, but not whites, more positive attitudes toward race-concordant doctors are associated with past unfair treatment in health care related to doctor race. In addition, we find that among whites, but not blacks, more positive attitudes toward race concordance are associated with negative attitudes toward interracial contact in general. We conclude that these dimensions of blacks' and whites' attitudes toward health care are associated with distinct factors. The findings encourage research on how attitudes formed outside health care, as well as how health care experiences influence attitudes toward health care and how these factors may vary by location in the system of racial inequality. PMID- 20922923 TI - Addressing obesity and diabetes among African American men: examination of a community-based model of prevention. AB - The Save Our Sons study is a community-based, culturally responsive, and gender specific intervention aimed at reducing obesity and diabetes among a small sample (n = 42) of African American men. The goals of the study were to: (1) test the feasibility of implementing a group health education and intervention model to reduce the incidence of diabetes and obesity among African American men; (2) improve regular access to and utilization of health care services and community supportive resources to promote healthy lifestyles among African American men; and (3) build community networks and capacity for advocacy and addressing some of the health needs of African American men residing in Lorain County, Ohio. Trained community health workers facilitated activities to achieve program aims. Following the 6-week intervention, results indicated that participant's had greater knowledge about strategies for prevention and management of obesity and diabetes; increased engagement in exercise and fitness activities; decreased blood pressure, weight, and body mass index levels; and visited a primary care doctor more frequently. Also, local residents elevated African American men's health and identified it as a priority in their community. This model of prevention appears to be a substantial, robust, and replicable approach for improving the health and wellbeing of African American men. PMID- 20922924 TI - Racial/ethnic disparities in the utilization of high-technology hospitals. AB - INTRODUCTION: Hospitals with high-technology services may have better outcomes. However, access to high-technology hospitals might not be uniform across racial/ethnic groups. This study examined if racial/ethnic minorities, compared to whites, are less likely to utilize hospitals that have the availability of technology services and infrastructure items such as computed tomography, positron emission tomography, magnetic resonance imaging, diagnostics radiation facility, and a level 1 trauma unit. METHODS: Data were obtained from the 2003 Healthcare Cost & Utilization Project's Nationwide Inpatient Sample and the 2003 American Hospital Association's annual survey data. The sample consisted of 3381 324 patients admitted to and discharged from 368 hospitals in 18 states in the United States. RESULTS: Logistic regression results suggest that Hispanic patients are less likely than whites to utilize high-technology hospitals when controlling for other factors (odds ratio[OR], 0.47; 95% confidence interval [CI], 0.28-0.79). CONCLUSIONS: Our study adds empirical evidence that significant gaps persist in access to care between minorities and whites. Particularly, access to high-technology hospitals for Hispanics appears to be a major problem. PMID- 20922925 TI - Head and neck cancer screening in homeless communities: HEAL (Health Education, Assessment, and Leadership). AB - Homeless persons are at high risk for medical illness, particularly for head and neck cancers, but they face several barriers to receiving adequate health care. We conducted cancer screening and education about head and neck cancer risk factors in one such population (n = 325). Although 41.4% of the participants reported at least 1 otolaryngologic sign or symptom, and 8.6% reported having 2 or more symptoms, most of them (72.3%) had received no medical care. The symptom reported most often was a change in voice (17.2%). In all, 11% of the participants were referred for head or neck cancer evaluation, and 9% of those undergoing biopsy had a malignancy that was later treated. Nearly 75% of participants had at least a ninth-grade education. However, although 71.2% knew that the use of tobacco can lead to lung cancer, 78.9% did not recognize that it can also lead to head or neck cancer. In this population, cigarette smoking was associated with more than doubled odds of follow-up medical care (odds ratio, 2.31). Head and neck cancers cause substantial morbidity and mortality. Community outreach programs can be an excellent starting point to improving early detection and health education for underserved communities. PMID- 20922926 TI - Racial/ethnic disparities in poststroke outpatient rehabilitation among veterans. AB - OBJECTIVE: To examine racial/ethnic differences in the use of poststroke outpatient rehabilitation in veterans. METHODS: We examined data from 4115 veterans with a diagnosis of stroke who were seen at a VA Medical Center in the southeastern United States. We compared the receipt of physical therapy (PT) and occupational therapy (OT) evaluations, visits, and procedures among 3 racial/ethnic groups. Multiple logistic regression was used to assess the independent effect of race/ethnicity on the receipt of a PT or OT evaluation and Poisson regression to estimate the effect of race/ethnicity on treatment visits and procedures received. RESULTS: In univariate comparisons, a higher proportion of blacks received PT and OT evaluations than whites and others. Similarly, blacks received a higher mean number of PT/ OT treatments than whites and others. In multivariate logistic models with whites as reference, blacks were more likely to receive PT evaluations (odds ratio [OR], 1.47; 95% confidence interval [CI], 1.24-1.74) and OT evaluations (OR, 1.23; 95% CI, 1.01-1.51). In multivariate Poisson models with whites as reference, blacks received more PT/OT visits (OR, 7.22; 95% CI, 5.95-8.76) than non-Hispanic whites (OR, 5.28; 95% CI, 4.41-6.33), while others received fewer visits (OR, 4.39; 95% CI, 3.58-5.39) than the reference group. No significant differences were observed across groups in the number of procedures completed during each treatment visit. CONCLUSIONS: In an equal-access system, blacks were more likely to receive outpatient PT/OT evaluations and higher mean number of PT/OT treatments. Future studies need to examine sociodemographic and disease-specific factors that account for these differences. PMID- 20922928 TI - Unusual case of dysphagia in a male. AB - Plummer Vinson Syndrome, a triad of dysphagia, esophageal web, and iron deficiency anemia, is a rarely reported diagnosis in current literature. The exact etiology of the syndrome remains controversial, but it has been linked to complicated nutritional deficiencies, autoimmune disorders, and hereditary factors, and has a remarkably high female to male ratio. This paper describes an atypical case presentation in a 53-year-old male with a remote history of peptic ulcer disease surgery. PMID- 20922927 TI - Partnerships in health disparities research and the roles of pastors of black churches: potential conflict, synergy, and expectations. AB - BACKGROUND: The black church is a promising site to engage in health disparities research; however, little is understood about the pastors' perspectives. We used role theory to explore their expectations, potential conflicts, and synergy with research. METHODS: Four focus groups (n = 30) were conducted with pastors and analyzed using principles of grounded theory and content analysis. RESULTS: Pastors identified a variety of potential roles in research. They noted potential conflicts due to perceptions of research, the process, and pace of research. Areas of synergy included perceptions of health disparities research as consistent with the healthy mind, body, and spirit ideology, and clear benefits to congregations and communities. Pastors' research expectations included long term commitments, honest and clear communication, investigator visibility, respect for church traditions/practices, and support in forming collaborations. CONCLUSIONS: Understanding pastors' roles, potential areas of synergy and conflict, and collaboration expectations offers insight in support of successful church-academic partnerships. PMID- 20922929 TI - Who owns your genes. PMID- 20922930 TI - In the Journal of the National Medical Association 100 years ago: the JNMA fights back. PMID- 20922931 TI - A successful combination. AB - In 1967, the American Board of Pediatrics and the American Board of Internal Medicine uniformly recognized the 4-year combined medicine and pediatrics training program. Since that time, the number of combined internal medicine and pediatrics programs has increased. Today, there are more than 78 combined residency programs with more than 354 first-year residency positions throughout the United States. Medicine/pediatrics residency programs give the resident the opportunity to rotate 24 months in each specialty. Graduates of combined medicine/pediatrics residency programs have several career options available to them. In 2007, a total of 55% of medicine/pediatrics residents went into primary care practice, 18% went into subspecialty training, 17% went into hospital medicine, and 10% chose other careers. PMID- 20922932 TI - Danny O. Jacobs, MD, MPH. PMID- 20922933 TI - New instruments for electron, fluorescence, and helium ion microscopy. PMID- 20922934 TI - New and improved HPLC methods for drug formulations and clinical analysis. PMID- 20922935 TI - Determination of carbamazepine and its impurities iminostilbene and iminodibenzyl in solid dosage form by column high-performance liquid chromatography. AB - An accurate and precise RP-HPLC method was developed and validated for the determination of carbamazepine and its impurities iminostilbene and iminodibenzyl in a tablet formulation with fluphenazine as an internal standard. Buffer methanol (50 + 50, v/v) was used as the mobile phase. During validation, specificity, linearity, precision, accuracy, LOD, LOQ, and robustness of the method were tested. The method was proven to be specific against placebo interference. Linearity was evaluated over the concentration range of 100-500, 0.05-0.25, and 0.1-0.5 microg/mL, and the r values were 0.9994, 0.9997, and 0.9979 for carbamazepine, iminostilbene, and iminodibenzyl, respectively. Intraday precision of the method was good, and RSD was below 2% for all analytes. The accuracy of the method ranged from 100.69 to 102.10, 99.76 to 102.66, and 99.26 to 100.08% for carbamazepine, iminostilbene, and iminodibenzyl, respectively. LOD was 0.0125, 0.025, and 0.05 microg/mL and LOQ was 0.05, 0.05, and 0.1 microg/mL for carbamazepine, iminostilbene, and iminodibenzyl, respectiviely. Robustness of the method was proven by using a chemometric approach. The method was successfully applied to the analysis of commercially available carbamazepine tablets and showed good repeatability, with RSD below 2%. PMID- 20922936 TI - Rapid high-performance liquid chromatography method for determination of pregabalin in a pharmaceutical dosage form following derivatization with fluorescamine. AB - A simple, fast, and sensitive HPLC method was developed and validated for the evaluation of pregabalin in a pharmaceutical dosage form using fluorescamine as a derivatization agent for the first time. After a precolumn derivatization (5 min, room temperature), the reaction mixture was chromatographed on a C18 column with isocratic elution using 0.2% of triethylamine in a mixture of methanol and water (10 + 90, v/v). 3-Aminopentanoic acid was used as the internal standard. Using fluorescent detection (lamdaex 395 nm, lamdaem 476 nm), a low detection limit of 0.02 microg/mL was reached. The method was linear (r > 0.999) over the lower (0.125-25 microg/mL) and higher (1.25-250 microg/mL) concentration range. The intraday and interday precision of the QC samples was < 4.3%, and the accuracy was 94.2-102.5%. The samples were stable for 24 h at 4 degrees C. The robustness study showed that the derivatization is more robust than the chromatography method. The method was applied for the analysis of pregabalin content in 25, 75, and 300 mg capsules, and a good agreement was found with the declared amount of pregabalin (the relative error did not exceed 3.2%). Finally, the method was successfully used for dissolution studies of pregabalin capsules. PMID- 20922937 TI - Reversed-phase HPLC analysis of levetiracetam in tablets using monolithic and conventional C18 silica columns. AB - Development and validation of an RP-HPLC method for determination of levetiracetam in pharmaceutical tablets is described. The separation and quantification of levetiracetam and caffeine (internal standard) were performed using a single analytical procedure with two different types of stationary phases, conventional Phenomenex Gemini C18 (100 x 4.6 mm, 5 microm) and Merck Chromolith Performance RP18e (100 x 4.6 mm, macropore size 2 mm, micropore size 13 nm) monolithic silica. Five-microliter aliquots of samples were injected into the system and eluted using water-acetonitrile (90 + 10, v/v) mobile phase pumped at the rate of 1 mL/min. The analyte peaks were detected at 200 nm using a diode array detector with adequate resolution. Validation studies were performed using the method recommended by the International Conference on Harmonization, the U.S. Pharmacopeia, and AOAC INTERNATIONAL, which includes accuracy, precision, range, limits, robustness, and system suitability parameters. Levetiracetam and caffeine were detected in about 7 min using the conventional column, whereas less than 5 min was required when the monolithic column was used. Calibration plots had r values close to unity in the range of 0.8-8.0 microg/mL. Assay of levetiracetam in a tablet formulation was demonstrated as an application to real samples. PMID- 20922938 TI - Stability-indicating validated HPLC method for simultaneous determination of oral antidiabetic drugs from thiazolidinedione and sulfonylurea groups in combined dosage forms. AB - For type 2 diabetes treatment, combinations of drugs from the thiazolidinedione and sulfonylurea groups are now available in the same tablet or capsule. Therefore, a stability-indicating and validated HPLC method was developed for simultaneous determination of pioglitazone, rosiglitazone, and glipizide in combined dosage forms. The examined drugs were subjected to different conditions such as acid and base, temperature, and UV light, and degradation of pioglitazone and glipizide was observed under thermal and acidic stress. However, selectivity of the presented method for pioglitazone, rosiglitazone, and glipizide assay against their degradation products was confirmed. It was also demonstrated to be robust, resisting small deliberate changes in pH of the buffer, flow rate, and percentage of acetonitrile in the mobile phase. The presented method utilizes a LiChrospher RP18 column (125 x 4.0 mm), acetonitrile in phosphate buffer at pH 4.3 (40 + 60, v/v) as the mobile phase, and UV detection at 225 nm for pioglitazonel glipizide or 245 nm for rosiglitazone/glipizide. The method was validated with respect to linearity, precision, and accuracy. Finally, the elaborated procedure was applied for the QC of pioglitazone/glipizide and rosiglitazone/glipizide mixtures. PMID- 20922939 TI - A porous graphitized carbon column HPLC method for the quantification of paracetamol, pseudoephedrine, and chlorpheniramine in a pharmaceutical formulation. AB - A simple, rapid, and stability-indicating HPLC method has been developed, fully validated, and applied to the quantification of paracetamol, pseudoephedrine hydrochloride, and chlorpheniramine maleate in a pharmaceutical formulation, using hydrochlorothiazide as an internal standard. Chromatographic separation was achieved isocratically on an RP porous graphitized carbon analytical column (125 x 2.1 mm id, particle size 5 microm) using 5.0 mM ammonium acetate-acetonitrile (35 + 65, v/v) mobile phase at a flow rate of 0.50 mL/min. UV spectrophotometric detection at 220 nm was used. The method had linear calibration curves over the range of 30-70 microg/mL for paracetamol, 1.8-4.2 microg/mL for pseudoephedrine hydrochloride, and 120-280 ng/mL for chlorpheniramine maleate. The intraday and interday RSD values were less than 3.2% for all compounds, while the relative error was less than 2.9%. Accelerated stability studies performed under various stress conditions proved the selectivity of the method. The developed method was applied successfully to QC and content uniformity tests of commercial tablets. PMID- 20922940 TI - Validation of a column liquid chromatographic method for the analysis of pramipexole and its five impurities. AB - In this paper, a previously optimized method for HPLC analysis of pramipexole and its impurities was subjected to method validation in accordance with official regulations. The optimized chromatographic conditions were as follows: mobile phase acetonitrile-water phase [15 + 85, v/v, water phase contained 1% triethylamine (TEA), pH adjusted to 7.0 with orthophosphoric acid]; detection at 262 nm for pramipexole, BI-II 751 xx, BI-I 786 BS, BI-II 820 BS, and 2 aminobenzothiazole and at 326 nm for BI-II 546 CL; column temperature, 25 degrees C; and flow rate, 1 ml/min. Acetonitrile and TEA content, pH of the water phase, flow rate, column temperature, and column type were factors studied in robustness testing. According to the experimental plan defined by a Plackett-Burman design, five dummy variables were added in order to have 12 factors. As output, resolution factor was chosen. Robustness was assessed by graphical (half-normal probability plots and Pareto charts) and statistical (t-test) methods. Also, nonsignificance intervals for significant factors were estimated, and limits for the system suitability test were determined. Finally, linearity, accuracy, and precision of the proposed HPLC method were defined. LOD and LOQ values for analyzed impurities were determined. The method was completely defined by these experiments. PMID- 20922941 TI - Development of an ion-pair reversed-phase HPLC method with indirect UV detection for determination of phosphates and phosphites as impurities in sodium risedronate. AB - A method based on RP-HPLC with indirect UV detection was developed for the determination of phosphates and phosphites as impurities in sodium risedronate. RP separation of the phosphates and phosphites was achieved by adding tetrabutylammonium hydroxide as an ion-pairing agent in the mobile phase. Potassium hydrogen phthalate was added to the mobile phase as an ionic chromophore in order to obtain high background absorption of the mobile phase. Separation was performed on a C18 column using a mixture of pH 8.2 buffer (containing 0.5 mM tetrabutylammonium hydroxide and 1 mM phthalate) and acetonitrile (95 + 5, v/v) as the mobile phase, with indirect UV detection at 248 nm. The validation of the method included determination of specificity/selectivity, linearity, LOD, LOQ, accuracy, precision, and robustness. The LOD was 0.86 microg/mL for phosphates and 0.76 microg/mL for phosphites. The LOQ was 2.60 microg/mL for phosphates and 2.29 microg/mL for phosphites. The developed method is suitable for quantitative determination of phosphates and phosphites as impurities in QC of sodium risedronate. PMID- 20922942 TI - High-performance liquid chromatographic determination of pantoprazole and its main impurities in pharmaceuticals. AB - An RP-HPLC method for simultaneous separation and quantification of pantoprazole and its five main impurities in pharmaceutical formulations was developed and validated. The separation was accomplished on a Zorbax Eclipse XDB C18 column (5 microm particle size, 150 x 4.6 mm id) using a gradient with mobile phase A [buffer-acetonitrile (70 + 30, v/v)], and mobile phase B [buffer-acetonitrile (30 + 70, v/v)]. The buffer was 0.01 M ammonium acetate solution with addition of 1 mL triethylamine/L of the solution, adjusted to pH 4.5 with orthophosphoric acid. The eluent flow rate was 1 mL/min, the temperature of the column was 30 degrees C, and the eluate was monitored at 290 nm. Linearity (r = 0.999), recovery (97.6 105.8%), RSD (0.55-1.90%), and LOQ (0.099-1.48 microg/mL) were evaluated and found to be satisfactory. The proposed method can be used for simultaneous identification and quantification of the analyzed compounds in pharmaceutical formulations. PMID- 20922943 TI - Validation of a novel, fully automated high throughput high-performance liquid chromatographic/tandem mass Spectrometric method for quantification of pantoprazole in human plasma. AB - An automated high-throughput HPLC/MS/MS method was developed for the quantitative determination of pantoprazole in human plasma. Only 100 microL plasma was placed in 2.2 mL 96 deep-well plates, and both pantoprazole and omeprazole (IS) were extracted from human plasma by liquid-liquid extraction, using diethyl ether dichloromethane (70:30, v/v) as the organic solvent. Robotic liquid-handling workstations were used for all liquid transfer and solution preparation steps and resulted in a short sample preparation time. After vortexing, centrifugation, and freezing, the supernatant organic solvent was evaporated and reconstituted in a small volume of reconstitution solution. Sample analysis was performed by utilizing the combination of RP-HPLC/MS/MS, with positive-ion electrospray ionization and multiple reaction monitoring detection. The chromatographic run time was set at 1.8 min with a flow rate of 0.6 mL/min on a Nucleosil octylsilyl (C8) analytical column. The method was proven to be sensitive, specific, accurate, and precise for the determination of pantoprazole in human plasma. The method was applied to a bioequivalence study after per os administration of a 40 mg pantoprazole gastric retentive tablet. PMID- 20922944 TI - Analysis of salazinic, norstictic, and usnic acids in Xanthoparmelia chlorochroa by ultra-performance liquid chromatography/tandem mass spectrometry. AB - The lichen species Xanthoparmelia chlorochroa is toxic when consumed by domestic sheep, cattle, and Rocky Mountain elk. Clinical signs exhibited by poisoned animals include red urine, ataxia, and muscular weakness that rapidly progresses to recumbency. Elk are unable to recover once becoming recumbent; however, most affected cattle can recover if offered suitable feed shortly following the onset of signs. At present, the pathogenesis and specific toxin(s) are unknown. As part of an effort to elucidate the proximate toxin, a method using ultra-performance LC coupled to MS/MS with negative-ion electrospray ionization has been developed to compare salazinic, norstictic, and usnic acid concentrations in X. chlorochroa collected from locales associated with lichen poisonings. Compounds were extracted from lichen samples with acetone and sonication. The stationary phase was a Waters Acquity UPLCTM BEH Ca18 (50 x 2.1 mm; 1.7 microm particle size) column. The mobile phase consisted of an acetonitrile-water gradient. The precision of the method was confirmed by an SD below 0.4% (n=9) for triplicate samples. LOD values were 200, 100, and 50 ng/mL for salazinic, norstictic, and usnic acids, respectively. PMID- 20922945 TI - Determination of molecular weight of silk fibroin by non-gel sieving capillary electrophoresis. AB - A simple non-gel sieving capillary electrophoresis (NGSCE) method was established to determine the MW of silk fibroin using CE. The background electrolyte with a pH of 8.8 was based on three components: polyethylene glycol, tris(hydroxymethyl)aminomethane, and sodium dodecyl sulfate (SDS). NGSCE showed a good linear relationship with satisfactory reproducibility between the migration time and the MW of standard proteins. It was found that the regenerated silk fibroin had an MW around 83 kDa with a wide MW distribution (MWD). This absolute value is lower than the result obtained from SDS-polyacrylamide gel electrophoresis due to the different principles of the methods, but their similar MWD shapes indicated that NGSCE could be a feasible, highly sensitive, rapid method for determination of the MW of silk fibroin. PMID- 20922946 TI - Mass spectroscopic fingerprinting method for differentiation between Scutellaria lateriflora and the germander (Teucrium canadense and T. chamaedrys) species. AB - Scutellaria lateriflora, commonly known as skullcap, is used as an ingredient in numerous herbal products. However, it has been occasionally adulterated/contaminated with Teucrium canadense and T. chamaedrys, commonly known as germander, which contain hepatotoxic diterpenes. Due to the morphological similarities between the two genera, analytical methodologies to distinguish authentic S. lateriflora from the Teucrium species are needed to ensure public safety. In this study, a direct-injection electrospray ionization/MS method was used to generate spectral fingerprints of extracts from 21 skullcap and germander samples at a rate of 90 s/sample. MS fingerprints were analyzed by principal component analysis. The newly developed method offers a rapid and easy way to differentiate between skullcap and germander samples. PMID- 20922947 TI - Determination of fumonisin B1 in botanical roots by liquid chromatography with fluorescence detection: single-laboratory validation. AB - The accuracy, repeatability, and reproducibility characteristics of a published method for measuring levels of fumonisin B1 (FB1) in botanical root products were determined by an AOAC single-laboratory validation procedure. Replicates of 10 test portions of each powdered root product (black cohosh, echinacea, ginger, ginseng, valerian, dong quai, and turmeric) at each spiking level (FB1 at 0, 50, 100, and 200 ng/g) were analyzed on 3 separate days. Test samples were extracted with methanol-acetonitrile-water (25 + 25 + 100, v/v/v). The extracts were centrifuged, the supernatants diluted with phosphate-buffered saline (PBS) containing 1% Tween 20 and filtered, and the filtrates applied to an immunoaffinity column containing antibodies specific for fumonisins. After the column was washed sequentially with PBS and water, the toxin was eluted from the column with 80% methanol, and the eluate dried by lyophilization. The residue was reconstituted with 50% acetonitrile. FB1 was derivatized with a mixture of o phthaldialdehyde and mercaptoethanol by using an LC autoinjector. Separations were performed with an RP-LC column, and the FB1 derivative was quantified by fluorescence detection. All root products were found to contain FB1 at <10 ng/g. Average within- and between-day recoveries of FB1 from the botanical roots ranged from 67 to 95% and from 68 to 100%, respectively. Total RSD values for within- and between-day repeatability ranged from 5.5 to 26.4%. HorRat values were <1.3 for all of the matrixes examined. The method meets the AOAC method performance criteria at levels of >50 ng/g for the seven botanical roots tested. PMID- 20922948 TI - Development and validation of an HPLC-DAD analytical procedure for quality control of damiana (Turnera diffusa), using an antioxidant marker isolated from the plant. AB - Damiana is a shrub used as a dietary supplement and as an additive in several foods. This report presents the first validated analytical method for QC of products made from damiana. Through bioassay-guided fractionation, the compound showing the best antioxidant activity, determined using 2,2-diphenyl-1-picryl hydrazyl assay in TLC, was purified and identified as 8-C-beta-[6-deoxy-2-O (alpha-1-rhamnopyranosyl)-xylo- hexopyranos-3-uloside] (Cl50 5.56 g/mL). This is the only natural source from which this compound has been reported, and has been found in all native damiana samples analyzed. Therefore, it was used as a biomarker to develop an HPLC-diode-array detection analytical procedure using the first-order derivative of the chromatograms. Separation was achieved using an AccQ Tag C18 150 x 3.9 mm (4 microm) column, with a gradient of methanol and 0.1% trifluoroacetic acid in water. The method was shown to be accurate, sensitive, and reproducible, providing a useful quantitative means to apply QC to damiana products. PMID- 20922949 TI - Determination of multiresidue pesticides in green tea by using a modified QuEChERS extraction and ion-trap gas chromatography/mass spectrometry. AB - The pesticide residues in exported and imported tea products must not exceed the maximum residue limits (MRLs) regulated by the import countries. Tea is a complex matrix that obfuscates the determination of pesticide residues. Many available methods for multiresidue pesticide analysis of tea are time-consuming and require many cleanup steps. The objective of this study was to develop a simple multiresidue method by using a modified quick, easy, cheap, effective, rugged, and safe (QuEChERS) extraction and ion-trap GC/MS/MS, which can identify, confirm, and quantify pesticides in complex matrixes. A tea product was homogenized with water, and the pesticides were extracted with acetonitrile containing 1% acetic acid. The extract was subjected to centrifugation, initial cleanup with dispersive SPE (dSPE), solvent exchange, and final cleanup with dSPE. Diethyl-d10-parathion and triphenyl phosphate were used as the internal standard and surrogate, respectively. The final extract was injected into an ITQ 700 gas chromatograph/mass spectrometer. Quantitation of individual pesticides was based on matrix-matched calibration curves with a correlation coefficient of > 0.9930 for the 22 pesticides selected for the study. The recoveries of the 22 pesticides ranged from 78 to 115%, except those for diazinon (130%) and malathion (122%), with an average RSD of 8.7%. The LOD values of all of the pesticides, except for terbufos, were below the MRLs set by the European Union and Japan. PMID- 20922950 TI - HPLC, TLC, and first-derivative spectrophotometry stability-indicating methods for the determination of tropisetron in the presence of its acid degradates. AB - Three stability-indicating assay methods were developed for the determination of tropisetron in a pharmaceutical dosage form in the presence of its degradation products. The proposed techniques are HPLC, TLC, and first-derivative spectrophotometry (1D). Acid degradation was carried out, and the degradation products were separated by TLC and identified by IR, NMR, and MS techniques. The HPLC method was based on determination of tropisetron in the presence of its acid induced degradation product on an RP Nucleosil C18 column using methanol-water acetonitrile-trimethylamine (65 + 20 + 15 + 0.2, v/v/v/v) mobile phase and UV detection at 285 nm. The TLC method was based on the separation of tropisetron and its acid-induced degradation products, followed by densitometric measurement of the intact spot at 285 nm. The separation was carried out on silica gel 60 F254 aluminum sheets using methanol-glacial acetic acid (22 + 3, v/v) mobile phase. The 1D method was based on the measurement of first-derivative amplitudes of tropisetron in H2O at the zero-crossing point of its acid-induced degradation product at 271.9 nm. Linearity, accuracy, and precision were found to be acceptable over concentration ranges of 40-240 microg/mL, 1-10 microg/spot, and 6 36 micro/mL for the HPLC, TLC, and 1D methods, respectively. The suggested methods were successfully applied for the determination of the drug in bulk powder, laboratory-prepared mixtures, and a commercial sample. PMID- 20922951 TI - Validated HPLC determination of the two fixed dose combinations (chlordiazepoxide hydrochloride and mebeverine hydrochloride; carvedilol and hydrochlorothiazide) in their tablets. AB - Simple, rapid, and selective RP-HPLC methods with UV detection were developed for simultaneous determination of chlordiazepoxide hydrochloride and mebeverine hydrochloride (Mixture I) and carvedilol and hydrochlorothiazide (Mixture II). The chromatographic separation in both mixtures was achieved by using an RP-C8 (octylsilyl) analytical column. For Mixture I, a mobile phase composed of acetonitrile-0.05 M disodium hydrogen phosphate-triethylamine (50 + 50 + 0.2, v/v/v), pH 2.5, was used; the detector wavelength was 247 nm. For Mixture II, the mobile phase consisted of acetonitrile-0.05 M disodium hydrogen phosphate (50 + 50, v/v), pH 4.0, and the detector was set at 220 nm. Quantification of the analytes was based on measuring their peak areas. Both mixtures were resolved in less than 6 min. The reliability and analytical performance of the proposed HPLC procedures were statistically validated with respect to linearity, range, precision, accuracy, selectivity, robustness, LOD, and LOQ. The linear dynamic ranges were 2.5-150 and 2.5-500 microg/mL for chlordiazepoxide HCI and mebeverine HCI, respectively, and 0.25-200 and 0.25-150 microg/mL for carvedilol and hydrochlorothiazide, respectively. The validated HPLC methods were successfully applied to the analysis of their commercial tablet dosage forms, for which no interfering peaks were encountered from common pharmaceutical adjuvants. PMID- 20922952 TI - Analysis of quinapril by two solvent-saving methods: application of capillary column high-performance liquid chromatography with ultraviolet absorbance detection and LDI-TOF-MS. AB - A capillary column high-performance liquid chromatography (CapLC) method and a laser desorption ionization-time of flight (LDI-TOF)-MS method are described for the determination of quinapril, an angiotensin-converting enzyme inhibitor. Effective separation was achieved by using a C18 capillary column at a flow rate of 10 microL/min. For CapLC, quinapril and 7-hydroxycoumarin (internal standard) were detected at 210 and 320 nm, respectively. Phenformin replaced 7 hydroxycoumarin as the internal standard for the LDI-TOF-MS method successfully developed to detect quinapril. The calibration curves showed good linearity in the range of 1-100 micro/mL in these two methods. For high throughput purposes, the LDI-TOF-MS method was simpler and faster than the CapLC method. Both green methods were suitably validated and successfully applied to determine quinapril in commercial tablets. PMID- 20922953 TI - Development and validation of a stability-indicating RP-HPLC method for determination of atomoxetine hydrochloride in tablets. AB - This paper describes the development of a stability-indicating RP-HPLC method for the determination of atomoxetine hydrochloride (ATX) in the presence of its degradation products generated from forced decomposition studies. The drug substance was subjected to stress conditions of acid, base, oxidation, wet heat, dry heat, and photodegradation. In stability tests, the drug was susceptible to acid, base, oxidation, and dry and wet heat degradation. It was found to be stable under the photolytic conditions tested. The drug was successfully separated from the degradation products formed under stress conditions on a Phenomenex C18 column (250 x 4.6 mm id, 5 microm particle size) by using acetonitrile-methanol-0.032 M ammonium acetate (55 + 05 + 40, v/v/v) as the mobile phase at 1.0 mL/min and 40 degrees C. Photodiode array detection at 275 nm was used for quantitation after RP-HPLC over the concentration range of 0.5-5 microg/mL with a mean recovery of 100.8 +/- 0.4% for ATX. Statistical analysis demonstrated that the method is repeatable, specific, and accurate for the estimation of ATX. Because the method effectively separates the drug from its degradation products, it can be used as a stability-indicating method. PMID- 20922954 TI - Development and validation of an HPLC/MS/MS method for determining the thiazolidinone PG15 in rat plasma. AB - A rapid, sensitive, and simple HPLC/MS/MS method was developed and validated for the determination of (5Z,E)-3-[2-(4-chlorophenyl)-2-oxoethyl]-5-(1H-indol-3 ylmethylene)-thiazolidine-2, 4-dione (PG15) in rat plasma using chlortalidone as an internal standard (IS). Analyses were performed using a C18 column and isocratic elution with acetonitrile-water (90 + 10, v/v) containing 10 mM ammonium hydroxide (pH 8.0) as the mobile phase pumped at 0.3 mL/min. Detection was performed by MS with negative ion mode electrospray ionization. Rat plasma samples were prepared by deproteinizing with acetonitrile. Detected fragments were 395.1 > 171.9 for PG15 and 337.3 > 189.9 for the IS. Calibration curves were linear from 10 to 1000 ng/mL, with the determination coefficient > 0.99. The intraday and interday precisions were less than 12.2 and 11.3%, respectively. The applicability of the HPLC/MS/MS method for pharmacokinetic studies was tested using plasma samples obtained after oral administration of PG15 to rats, and it provided the necessary sensitivity, linearity, precision, accuracy, and specificity. PMID- 20922955 TI - Determination of rosuvastatin and ezetimibe in a combined tablet dosage form using high-performance column liquid chromatography and high-performance thin layer chromatography. AB - This paper describes validated HPLC and HPTLC methods for the simultaneous determination of rosuvastatin (ROS) and ezetimibe (EZE) in a combined tablet dosage form. The isocratic RP-HPLC analysis was performed on a Chromolith C18 column (100 x 6 mm id) using 0.1% (v/v) orthophosphoric acid solution (pH 3.5) acetonitrile (63 + 37, v/v) mobile phase at a flow rate of 1 mL/min at ambient temperature. Quantification was carried out using a photodiode array UV detector at 245 nm over the concentration range of 0.5-10 microg/mL for ROS and EZE. The HPTLC separation was carried out on an aluminum-backed sheet of silica gel 60F(254) layers using n-butyl acetate-chloroform-glacial acetic acid (1 + 8 + 1, v/v/v) mobile phase. Quantification was achieved with UV densitometry at 245 nm over a concentration range of 0.1-0.9 micro/spot for ROS and EZE. The analytical methods were validated according to International Conference on Harmonization guidelines. Low RSD values indicated good precision. Both methods were successfully applied for the analysis of the drugs in laboratory-prepared mixtures and commercial tablets. No chromatographic interference from the tablet excipients was found. These methods are simple, precise, and sensitive, and are applicable for simultaneous determination of ROS and EZE in pure powder and tablets. PMID- 20922956 TI - Development and validation of a micellar high-performance liquid chromatographic method for determination of risedronate in raw material and in a pharmaceutical formulation: application to stability studies. AB - A micellar HPLC method was developed for analysis of the antiosteoporosis drug risedronate. The analysis was carried out using a 250 x 4.6 mm id, 5 microm particle size C18 Waters Symmetry column. The mobile phase consisted of 0.02 M sodium dodecyl sulfate + 0.3% triethylamine + 10% n-propanol, prepared in 0.02 M orthophosphoric acid. The pH of the mobile phase was adjusted to pH 6.0, and it was pumped at a flow rate of 0.7 mL/min with UV detection at 262 nm. The method showed good linearity in the range of 2-80 microg/mL, with an LOD of 0.40 microg/mL (1.31 x 10(-6) M) and an LOQ of 1.21 microg/mL. The suggested method was successfully applied for the analysis of risedronate in raw material and a tablet formulation, with average recoveries of 99.91 +/- 1.30 and 101.52 +/- 0.30%, respectively. The stability-indicating capability of the proposed method was proved using forced degradation. By changing the pH of the mobile phase to 4.0, the oxidative degradation product could be separated from risedronate. PMID- 20922957 TI - Determination of deoxynivalenol in processed foods. AB - Deoxynivalenol (DON), commonly referred to as vomitoxin, belongs to a class of naturally occurring mycotoxins produced by Fusarium fungi. The presence of DON in foods is a human health concern. The frequency of occurrence of DON in wheat is high, although cleaning prior to milling can reduce DON concentration in final products, and food processing can partially degrade the toxin. This paper describes a method for the determination of DON in some major wheat food products, including bread, breakfast cereals, pasta, pretzels, and crackers. Test samples containing 5% polyethylene glycol were extracted with water. After blending and centrifuging, the supernatant was diluted with water and filtered through glass microfiber filter paper. The filtrate was then passed through an immunoaffinity column and the toxins eluted with methanol. The toxins were then subjected to RPLC separation and UV detection. The accuracy and repeatability characteristics of the method were determined. Recoveries of DON spiked at levels from 0.5 to 1.5 microg/g in the five processed foods were >70%. SD and RSD values ranged from 2.0 to 23.5% and from 2.0 to 23.2%, respectively. HorRat values were <2 for all of the matrixes examined. The method was found to be acceptable for the matrixes examined. LC/MS/MS with multiple-reaction monitoring was used to confirm the identity of DON in naturally contaminated test samples. PMID- 20922958 TI - Evaluation of different machines used to quantify genetic modification by real time PCR. AB - Quantification of genetic modification (GM) is often undertaken to test for compliance with the European Union GM labeling threshold in food. Different control laboratories will often use common validated methods, but with different models of real-time PCR machines. We performed two separate ring trials to evaluate the relative precision and accuracy of different types of real-time PCR machines used to quantify the concentration of GM maize. Both trials used dual labeled fluorogenic probes for quantification. The first ring trial used separate GM and reference assays (a single fluorescence channel), and the second used a combined duplex assay (two simultaneous fluorescence channels). Five manufacturers and seven models--including a 96-well microtiter-plate, rotary, and portable machines--were examined. In one trial, the machine used had a significant effect on precision, but in the other it did not. Overall, the degree of variation due to the machine model was lower than other factors. No significant repeatable difference in accuracy was observed between machine models. It was not possible to use sufficient replication of machine type in each laboratory to examine all sources of variation in this study, but the results strongly indicate that factors other than machine type or manufacturer (e.g., method or laboratory) contribute more to variation in a GM quantification result. PMID- 20922959 TI - Simple gas chromatographic method for the quantification of total cholesterol in fish meats. AB - Six fish species-Cirrhinus mrigala (Morakhi), Labeo rohita (Danbhro), Catla catla (Thalli), Wallago attu (Jarko), Ctenopharyngodon idella (Grass), and Cyprimus carpio (Gulfam)--commonly found in the Pakistani Indus river, were selected for fat and cholesterol evaluation. Fat content was quantified by the Folch method and cholesterol content was determined by a simple GC method. The application of the proposed method to quantify cholesterol content revealed variations among the six breeds evaluated. The breeds studied contained 0.80-1.95% fat, indicating that all investigated fishes were lean; significant variation was found in cholesterol content, and ranged between 72 and 392 mg/100 g. Standard addition analyses showed that the method was accurate, as the recovery of cholesterol varied from 95 to 103%, with a coefficient of variance not more than 5.6%. The results showed that, after the development of suitable calibration, within 11 min, the cholesterol could be accurately determined by GC. PMID- 20922960 TI - Determination of walnut protein in processed foods by enzyme-linked immunosorbent assay: interlaboratory study. AB - Because food allergens from tree nuts, including walnuts, are a frequent cause of adverse food reactions for allergic patients, the labeling of foods containing ingredients derived from tree nuts is required in numerous countries. According to Japanese regulations, the labeling of food products containing walnuts is recommended. To ensure proper labeling, a novel sandwich ELISA kit for the determination of walnut protein in processed foods (Walnut Protein [2S-Albumin] Kit; Morinaga Institute of Biological Science, Inc.; "walnut kit") has been developed. We prepared seven types of incurred samples (model processed foods: biscuits, bread, sponge cake, orange juice, jelly, chicken meatballs, and rice gruel) containing 10 microg walnut soluble protein/g of food for use in interlaboratory evaluations of the walnut kit. The walnut kit displayed sufficient reproducibility relative standard deviations (interlaboratory precision: 5.8-9.9% RSDR) and a high level of recovery (81-119%) for all the incurred samples. All the repeatability relative standard deviation (RSDr) values for the incurred samples that were examined were less than 6.0%. The results of this interlaboratory evaluation suggested that the walnut kit could be used as a precise and reliable tool for determination of walnut protein in processed foods. PMID- 20922961 TI - Preparation and characterization of standard reference material 1849 infant/adult nutritional formula. AB - Standard Reference Material (SRM) 1849 Infant/Adult Nutritional Formula has been issued by the National Institute of Standards and Technology (NIST) as a replacement for SRM 1846 Infant Formula, issued in 1996. Extraction characteristics of SRM 1846 have changed over time, as have NIST's analytical capabilities. While certified mass fraction values were provided for five constituents in SRM 1846 (four vitamins plus iodine), certified mass fraction values for 43 constituents are provided in SRM 1849 (fatty acids, elements, and vitamins) and reference mass fraction values are provided for an additional 43 constituents including amino acids and nucleotides, making it the most extensively characterized food-matrix SRM available from NIST. PMID- 20922962 TI - Listeria monocytogenes: knowledge gained through DNA sequence-based subtyping, implications, and future considerations. AB - The purpose of subtyping is to differentiate bacterial isolates beyond the classification of species or subspecies. Subtyping methods can be grouped into two broad categories based on the cellular components targeted: (1) phenotypic subtyping methods that differentiate isolates by the enzymes, proteins, or other metabolites expressed by the cell, and (2) molecular subtyping methods that discriminate isolates based on interrogation of nucleic acid sequences. The two major types of molecular subtyping methods include band-based methods based on fragment pattern data or DNA fingerprints, and methods that generate DNA sequence data. Molecular subtyping methods have shown that Listeria monocytogenes isolates can be classified into four genetic lineages or divisions. Although band-based molecular subtyping methods continue to serve as the gold standard for routine molecular subtyping of most clinically important foodborne pathogens, including L. monocytogenes, the explosion of recently completed and ongoing DNA sequencing projects, and thus available DNA sequence data, have stimulated efforts to develop highly discriminatory and high-throughput DNA sequence-based subtyping methods for L. monocytogenes. L. monocytogenes represents one of the most highly sequenced human pathogens; more than 20 genome sequences are currently available for this organism. This review provides an overview of the concepts behind subtyping and discusses the application of molecular subtyping methods, with an emphasis on DNA sequence-based subtyping methods to characterize L. monocytogenes. PMID- 20922963 TI - Separation and preconcentration of trace amounts of gold(III) ions using modified multiwalled carbon nanotube sorbent prior to flame atomic absorption spectrometry determination. AB - Multiwalled carbon nanotubes are attractive as sorbents for SPE because they can be used for enrichment of organic compounds and metal ions at trace levels. In this study, multiwalled carbon nanotubes were oxidized with concentrated HNO3, and then the oxidized multiwalled carbon nanotubes were modified with 5-(4' dimethylamino-benzyliden)-rhodanine. The modified multiwalled carbon nanotubes were used as a solid sorbent for separation and preconcentration of trace amounts of Au(III) ions. The sorption of Au(III) ions was quantitative in the pH range of 2.0-5.0, whereas quantitative desorption occurred instantaneously with 5.0 mL 2.0 M Na2S2O3. The eluted solution was aspirated directly into the flame for atomic absorption spectrometry. The proposed method resulted in an enrichment factor of 94. The RSD of the method was +/- 1.11% (n=10, 2.0 microg/mL) and the LOD was 0.15 ng/mL. The calibration curve for Au(III) was linear between 0.53 ng/mL and 36.0 microg/mL in the initial solution, with an R2 value of 0.9999. The sorbent capacity of the modified multiwalled carbon nanotubes was 7.3 mg Au(III)/g sorbent. The influences of the experimental parameters, including sample pH, sample flow rate, eluent volume and flow rate, sample volume, and interference of some ions on the recoveries of the Au ions, were investigated. The proposed method was applied for preconcentration and determination of Au in different samples. PMID- 20922964 TI - Determination of chlorantraniliprole residues in crops by liquid chromatography coupled with atmospheric pressure chemical ionization mass spectrometry/mass spectrometry. AB - An analytical method is presented for the determination of chlorantraniliprole residues in crops. Chlorantraniliprole residues were extracted from crop matrixes with acetonitrile after a water soak. The extracts were passed through a strong anion-exchange (SAX) SPE cartridge stacked on top of a reversed-phase (RP) polymer cartridge. After both cartridges were rinsed and vacuum-dried, the SAX cartridge was removed, and chlorantraniliprole was eluted from the RP polymer cartridge with acetonitrile. The acetonitrile eluate was evaporated to dryness, reconstituted, and analyzed using an LC/MS/MS instrument equipped with an atmospheric pressure chemical ionization source. The method was successfully validated at 0.010, 0.10, and 10 mg/kg for the following crop matrixes: potatoes, sugar beets (tops), lettuce, broccoli, soybeans, soybean forage, tomatoes, cucumbers, oranges, apples, pears, peaches, almonds (nutmeat), rice grain, wheat grain, wheat hay, corn stover, alfalfa forage, cottonseed, grapes, and corn grain. The average recoveries from all crop samples fortified at the method LOQ ranged from 91 to 108%, with an overall average recovery of 97%. The average recoveries from all crop samples fortified at 10 times the method LOQ ranged from 89 to 115%, with an overall average recovery of 101%. For all of the fortified control samples analyzed in this study, the overall average recovery was 99%. PMID- 20922965 TI - Solid-phase extraction of antimony using chemically modified SiO2-PAN nanoparticles. AB - A new analytical method using 1-(2-pyridylazo)-2-naphthol (PAN)-modified SiO2 nanoparticles as solid-phase extractant has been developed for the preconcentration of trace amounts of Sb(III) in different water samples. Conditions of the analysis such as preconcentration factor, effect of pH, sample volume, shaking time, elution conditions, and effects of interfering ions for the recovery of the analyte were investigated. The adsorption capacity of nanometer SiO2-PAN was found to be 186.25 micromol/g at optimum pH and the LOD (3sigma) was 0.60 microg/L. The extractant showed rapid kinetic sorption. The adsorption equilibrium of Sb(III) on nanometer SiO2-PAN was achieved in 10 min. Adsorbed Sb(III) was easily eluted with 4 mL 2 M hydrochloric acid. The maximum preconcentration factor was 62.20. The method was applied for the determination of trace amounts of Sb(III) in various water samples (tap, mineral water, and industrial effluents). PMID- 20922966 TI - Fast analysis of polybrominated diphenyl ethers in eggs using selective pressurized liquid extraction coupled with online GPC-GC/MS. AB - This article reports the applicability of online gel permeation chromatography (GPC)-GC/MS for the determination of seven predominant polybrominated diphenyl ethers (PBDEs) in eggs to effectively eliminate matrix interference. Selective pressurized liquid extraction using acidic alumina as a fat retainer was used for cleanup of the PBDEs in eggs. It was selected because of its advantages: simpler operation, minimum time spent on sample handing to get fat-free extracts, and low volume of solvent consumption. After concentration, the extract was directly injected for online GC/MS operated in the negative ion chemical ionization mode with a 15 m capillary column. Recoveries of spiked samples were between 75.1 and 102.0%, with RSDs (n=3) ranging from 3.69-11.47% when spiked at levels of 2 and 20 ng/g, dry mass. The LOD varied from 0.25-34 ng/g, dry mass. The proposed method was proven to be rapid, efficient, and reliable for the trace determination of PBDEs in eggs. PMID- 20922967 TI - Analysis of triclosan and triclocarban in soil and biosolids using molecularly imprinted solid phase extraction coupled with HPLC-UV. AB - A molecularly imprinted polymer (MIP) able to selectively bind triclosan (TCS) and triclocarban (TCC), commonly used antibacterial agents in many consumer products, was prepared using noncovalent molecular imprinting methods. The prepared MIP was evaluated as a selective sorbent in SPE for sample cleanup before HPLC-UV analysis of TCS and TCC in soil and biosolid samples. The MIP was also compared with commercially available C18 SPE sorbent. The molecularly imprinted SPE (MISPE) developed in this study was more efficient than C18 SPE for the cleanup of extracts of soil and biosolid samples prior to the analysis of TCC and TCS using HPLC-UV. The LOQ values for both TCC and TCS in the soil samples were determined to be 40 microg/kg; in the biosolid samples, the LOQ values were 100 and 300 microg/kg for TCC and TCS, respectively. Compared to C18 SPE, using MISPE for sample cleanup may result in a significant reduction of analytical cost, because one MIP can be reused up to 35 times and HPLC-UV instead of HPLC/MS can be used for instrumental analysis following sample cleanup by MISPE. PMID- 20922968 TI - A practical approach for linearity assessment of calibration curves under the International Union of Pure and Applied Chemistry (IUPAC) guidelines for an in house validation of method of analysis. AB - Linearity assessment as required in method validation has always been subject to different interpretations and definitions by various guidelines and protocols. However, there are very limited applicable implementation procedures that can be followed by a laboratory chemist in assessing linearity. Thus, this work proposes a simple method for linearity assessment in method validation by a regression analysis that covers experimental design, estimation of the parameters, outlier treatment, and evaluation of the assumptions according to the International Union of Pure and Applied Chemistry guidelines. The suitability of this procedure was demonstrated by its application to an in-house validation for the determination of plasticizers in plastic food packaging by GC. PMID- 20922969 TI - Rapid determination of fluoroquinolone residues in honey by a microbiological screening method and liquid chromatography. AB - A rapid and efficient method was developed for the simultaneous determination of seven fluoroquinolone (FQ) residues: norfloxacin, ciprofloxacin, danofloxacin, enrofloxacin, orbifloxacin, sarafloxacin, and difloxacin in honey. The samples were first screened with a microbiological method by using test plates made from metal-free purified agar seeded with Bacillus subtilis BGA. When a sample was found to contain FQ residues by using the microbiological method, it was analyzed by LC with fluorescence detection (LC/FL). FQs were extracted with Na2EDTA McIlvaine buffer and purified by a dual SPE method in which a cation-exchange cartridge was connected to an anion-exchange cartridge. The overall recoveries of the seven FQs ranged from 70.0 to 92.1%. The intra-assay and interassay CVs were < or = 7.8 and < or = 5.1%, respectively. For the microbiological method, the LOD values ranged from 2 to 9 microg/kg. For LC/FL, the LOQ values ranged from 2 to 7 microg/kg. The developed method was used to analyze 70 honey samples. In 14 samples in which the microbiological method detected the presence of FQ residues, norfloxacin, ciprofloxacin, and enrofloxacin were identified by LC/FL. PMID- 20922970 TI - Determination of bithionol, bromophen, nitroxynil, oxyclozanide, and tribromsalan in milk with liquid chromatography coupled with tandem mass spectrometry. AB - LC/MS/MS was developed to determine the residues of bithionol (BTN), bromofen (BMF), nitroxynil (NTX), oxyclozanide (OCZ), and tribromsalan (TBS) in milk. Samples were extracted with ethyl acetate and cleaned up by liquid-liquid separation with acetonitrile and n-hexane. The compounds were determined by RP-LC using a C18 column with 0.1% formic acid-methanol. Mass spectral acquisition was performed in the negative mode by applying selected-reaction monitoring. The method was validated in milk spiked with these compounds at 5-600 microg/kg; average recoveries were in the range 83.8-97.1%, with RSD values of 1.4-8.0%. The interassay RSDs were less than 11%. The LODs of these compounds in milk were 0.1 microg/kg. The method was applied to 24 raw milk samples. The concentration of these compounds in all samples was lower than the Japanese maximum residue limits. The method is rapid, sensitive, and specific for monitoring residues of BTN, BMF, NTX, OCZ, and TBS in milk. PMID- 20922971 TI - [A time for changes]. PMID- 20922972 TI - [Voluntary social year: orientation for adolescents and young adults: creating positive experiences with openness and trust ]. PMID- 20922973 TI - [Nursing in the USA--experiences from a study excursion: "I'm proud to be a nurse"]. PMID- 20922974 TI - [Creating relationships in geriatric nursing: cannot be documented but are nonetheless important]. PMID- 20922975 TI - [Personal challenges for the near future: inpatient geriatric nursing in transition]. PMID- 20922976 TI - [Conflict laden communication in the team: mobbing--violence toward colleagues]. PMID- 20922977 TI - [Methods of conflict resolution and role finding in the team: psychodrama - a useful method in geriatric nursing]. PMID- 20922978 TI - [Moderating techniques and coaching competences: how are station meetings conducted?]. PMID- 20922979 TI - [Flow of information in shift and part time team: who is informed?]. PMID- 20922980 TI - [Networking nursing in the national and international context: requirements under economic factors]. PMID- 20922981 TI - [Defining the internship from employment status: when does the internship become employment?]. PMID- 20922982 TI - [Survey in hospitals. Nursing errors, error culture and error management]. AB - Knowledge on errors is important to design safe nursing practice and its framework. This article presents results of a survey on this topic, including data of a representative sample of 724 nurses from 30 German hospitals. Participants predominantly remembered medication errors. Structural and organizational factors were rated as most important causes of errors. Reporting rates were considered low; this was explained by organizational barriers. Nurses in large part expressed having suffered from mental problems after error events. Nurses' perception focussing on medication errors seems to be influenced by current discussions which are mainly medication-related. This priority should be revised. Hospitals' risk management should concentrate on organizational deficits and positive error cultures. Decision makers are requested to tackle structural problems such as staff shortage. PMID- 20922983 TI - [Planning a practical instruction situation - 10: Activation in day nursing]. PMID- 20922984 TI - [Coding specialists ensure reimbursement in the inpatient and ambulatory domain: not giving money away]. PMID- 20922985 TI - [From case to case: team work means being prepared for further learning]. PMID- 20922986 TI - [Recognizing and understanding illnesses: oliguria as the primary complaint]. PMID- 20922987 TI - Microbial transformation of (-)-nopol benzyl ether: direct dihydroxylation of benzene ring. AB - The biotransformation of (-)-nopol benzyl ether (5) by Aspergillus niger TBUYN-2 and A. niger Tiegh CBSYN was investigated. A. niger biotransformed 5 to afford ( )-4-oxonopol-2',4'-dihydroxybenzyl ether (6), and (-)-4-oxonopol (7) as main products. Compound 6 showed strong antioxidant activity (IC50 30.2 microM), which was very similar to that of butyl hydroxyl anisol (BHA). PMID- 20922988 TI - Structure-activity relationships of sandalwood odorants: synthesis of a new campholene derivative. AB - Structural modifications of natural (-)-(Z)-beta-santalol have shown that the sandalwood odor impression is highly sensitive, even to small structural changes. Particularly, the substitution of the quaternary carbon is of great influence on the scent. Epi-compounds with side chains in the endo-position possess sandalwood odor in only a few derivatives, whereas modifications at this side chain, as well as modification at the bicyclic ring systems mostly lead to a complete loss of sandalwood fragrance. PMID- 20922989 TI - Chemical composition, olfactory evaluation and antimicrobial activity of selected essential oils and absolutes from Morocco. AB - The chemical compositions of selected essential oils from North Africa, especially Morocco, of geranium, wild Moroccan chamomile and rosemary as well as absolutes of rose and geranium were determined using GC/FID and GC/MS. These oils and absolutes were tested concerning their antimicrobial activity against some food spoilage strains obtained from fresh milk and minced meat products, like sausages and pork fillet, in accordance with ISO testing procedures. Gram positive (Bacillus cereus and Staphylococcus aureus) and Gram-negative (Escherichia coli, Salmonella abony and Pseudomonas aeruginosa) strains were used, as well as the yeast Candida albicans. Using a serial broth dilution method, all samples demonstrated weak antimicrobial activity against the Gram negative bacteria and the yeast, compared with the activity towards the Gram positive bacteria. PMID- 20922990 TI - Chemical composition and antimicrobial activity of cumin oil (Cuminum cyminum, Apiaceae). AB - Cumin oil samples (Cuminum cyminum L.) from four different geographical origins were analyzed using GC-MS and GC-FID for their qualitative and quantitative composition. The major compounds in all cumin oils were the monoterpenes beta pinene, p-cymene and gamma-terpinene and the terpenoid aldehydes cuminic aldehyde and the isomeric menthadien carboxaldehydes. All essential oils, and cuminic aldehyde, were tested, using agar diffusion and serial dilution methods, against different Gram-positive and Gram-negative bacteria isolated from different sources of food (pork fillet, minced meat and sausages) and clinical isolates, as well as three different Candida albicans isolates. All cumin oils and cuminic aldehyde exhibited a considerable inhibitory effect against all the organisms tested, except Pseudomonas spp. PMID- 20922991 TI - Chemical composition and antibacterial activity of selected essential oils and some of their main compounds. AB - The chemical composition of essential oils of cabreuva (Myrocarpus fastigiatus Allemao, Fabaceae) from Brazil, cedarwood (Juniperus ashei, Cupressaceae) from Texas, Juniper berries (Juniperus communis L., Cupressaceae) and myrrh (Commiphora myrrha (Nees) Engl., Burseraceae) were analyzed using GC/FID and GC/MS. The antimicrobial activity of these essential oils and some of their main compounds were tested against eleven different strains of Gram-positive and Gram negative bacteria by using agar diffusion and agar serial dilution methods. Animal and plant pathogens, food poisoning and spoilage bacteria were selected. The volatile oils exhibited considerable inhibitory effects against all tested organisms, except Pseudomonas, using both test methods. Higher activity was observed against Gram-positive strains in comparison with Gram-negative bacteria. Cabreuva oil from Brazil showed similar results, but in comparison with the other oils tested, only when higher concentrations of oil were used. PMID- 20922992 TI - Antimicrobial activities of single aroma compounds. AB - Commercially available aroma samples were evaluated for their olfactory quality by professional perfumers and tested for their antimicrobial activity. Agar diffusion and agar-dilution were used as test methods and a set of two Gram positive (Staphylococcus aureus and Enterococcus faecalis) and four Gram-negative bacterial strains (Escherichia coli, Pseudomonas aeruginosa, Proteus vulgaris G, Klebsiella pneumoniae and Salmonella abony) and a yeast, Candida albicans, were the test microorganisms. All the investigated compounds were active against Gram positive bacteria, especially beta-caryophyllene against Enterococcus faecalis (MIC 6 ppm), but only few substances showed activity towards Gram-negative bacteria, except for cinnamic acid, which was active against all (MIC 60 ppm) and Candida albicans, against which cinnamic acid and caryophyllene oxide showed high activity (MIC < 60 ppm). PMID- 20922993 TI - Essential oil composition, antimicrobial and cytotoxic activities of two endemic Stachys cretica subspecies (Lamiaceae) from Turkey. AB - The chemical compositions of the water-distilled essential oil of Stachys cretica ssp. lesbiaca Rech. fil. and S. cretica ssp. trapezuntica Rech. fil. were determined by GC and GC-MS. Altogether 63 compounds were identified. The sesquiterpene hydrocarbon, germacrene D (20.3% and 12.9% respectively) was the main component identified in both oils. Furthermore, ethanol, light petroleum, dichloromethane, ethyl acetate and n-butanol extracts prepared from the aerial parts of the plants were tested for their antimicrobial activities against six bacterial strains and the yeast Candida albicans. The extracts exhibited no antibacterial activity, but the light petroleum and n-butanolic fractions showed low antifungal activities. Crude ethanolic extracts of the two subspecies were tested for their ability to inhibit the growth of HL-60 and Ishikawa human tumor cell lines. The IC50 values were 100 microg/mL for the HL-60 cell line and 200 microg/mL for the Ishikawa cell line. PMID- 20922994 TI - Volatile components of selected liverworts, and cytotoxic, radical scavenging and antimicrobial activities of their crude extracts. AB - Crude extracts of the Tahitian liverworts Mastigophora diclados and Frullania sp., the Indonesian Frullania sp., Dumortiera hirsuta and Marchantia sp., and the Japanese Porella perrottetiana were investigated chemically by using gas chromatography-mass spectrometry (GC-MS). All extracts contained various volatile sesqui- and diterpenoids and a few aromatic compounds. The Tahitian M. diclados and Frullania sp., and the Indonesian Frullania sp. exhibited cytotoxic activity against HL-60 and KB cell lines. The extracts of the Tahitian M. diclados and the Indonesian Marchantia sp. showed radical scavenging activity, whereas the crude extracts of the Tahitian M. diclados and Frullania sp., and the Indonesian Frullania and Marchantia sp. showed antimicrobial activity against Staphylococcus aureus and Bacillus subtilis. PMID- 20922995 TI - Pharmacological interactions of essential oil constituents on the viability of micro-organisms. AB - Complex interactions between numerous components of essential oils often contribute to the pharmacological effect and therapeutic outcome. To further elucidate these interactions, several essential oil constituents (EOCs) were combined in different ratios and their inhibitory effects on the growth of bacteria and yeast determined using the minimum inhibitory concentration (MIC) microplate assay. When combined and tested against Candida albicans, (+)-beta pinene interacted antagonistically with (-)-menthone (sigmaFIC(T) = 9.80), but synergistically with 1,8-cineole (sigmaFIC(T) = 0.35). Against Escherichia coli, the combination of E- and Z-(+/-)-nerolidol and geranyl acetate displayed an additive interaction (sigmaFIC(T) = 1.04); while a variable interaction was observed between E- and Z-(+/-)-nerolidol and eugenol with antagonism and synergy being observed at different ratios of each EOC. The combination of either carvacrol or eugenol with an antimicrobial agent (ciprofloxacin or amphotericin B) resulted in synergistic interactions against all microorganisms tested. These favourable results further support the use of essential oil constituents as adjuvants in the development of a new generation of phytopharmaceuticals that can be used in combination with synthetic drugs against drug-resistant microorganisms. PMID- 20922996 TI - Antimicrobial properties of volatile phenylpropanes. AB - The examination of antimicrobial structure-activity relationships of 93 volatile phenylpropanes (VPs) and 21 related aromatic compounds revealed a dependence of antimicrobial activity from the kind and number of substituents on the aromatic ring, their substitution pattern and microbial characteristics, such as Gram coloring and strain specific factors. Eugenol isomers were predominantly inhibitory in a concentration range from 25 to 2000 mg/L against all microorganisms tested, which were three strains of Escherichia coli and Klebsiella pneumoniae, Pseudomonas aeruginosa, Staphylococcus aureus, Bacillus subtilis, Listeria monocytogenes, and Candida albicans. Etherified VPs were either less active or inactive depending on the type of side chain and/or substitution pattern. Differences in the antimicrobial activity of cis- and trans isomers were observed. Species specific structure-activity relationships exist as was demonstrated with the Gram-negative bacteria (inactivity of E-ortho-eugenol) C. albicans (activity of di- and threefold methoxylated 1-propenylbenzenes), S. aureus and B. subtilis (activity of di-ortho methoxylated phenolic allylbenzenes and hydroquinone derivatives). With regard to the variety of observed specific effects and natural variation of susceptibility towards VPs according to literature reference data, the chances for successful prediction by computational analysis (QSAR) appear to be limited. PMID- 20922997 TI - Potential interaction between the volatile and non-volatile fractions on the in vitro antimicrobial activity of three South African Pelargonium (Geraniaceae) species. AB - Previous studies have reported promising antimicrobial efficacy for the essential oils and solvent extracts of several indigenous Pelargonium species. This study aimed to determine if any pharmacological interaction (e.g. synergism or antagonism) exists between the volatile and non-volatile components when the different fractions were investigated. The antimicrobial activity of the following fractions were tested; the essential oil prepared by hydrodistillation (EO), non-volatile fraction (NV), prepared by extraction of plant material remaining in the distilling apparatus (having no or negligible volatile constituents) and solvent extracts prepared from fresh (FC) and dried (DC) plant material containing both volatile and non-volatile constituents. Pelargonium quercifolium oil was dominated by p-cymene (42.1%) and viridiflorol (16.9%), while P. graveolens and P. tomentosum oil had high levels of isomenthone (84.0 and 58.8%, respectively). Menthone was noted as a major constituent in the P. tomentosum EO sample. It was evident from the results that the presence of volatile constituents in the three species; P. graveolens, P. quercifolium and P. tomentosum is generally not a pre-requisite for antimicrobial activity. The most significant variations of antimicrobial activity were noted for P. tomentosum where poorer activity was noted for the FC and EO fractions against Bacillus cereus and Candida albicans. Studies on Staphylococcus aureus, however, showed the converse, where best activity was noted for the FC fraction (3.0 mg/mL). For P. quercifolium, the DC fraction indicated a notable increase in anti staphylococcal activity (2.0 mg/mL) when compared with the FC (8.0 mg/mL) and EO (16.0 mg/mL) fractions. For P. tomentosum, the FC fraction indicated much lower antimicrobial activity (against both B. cereus and C. albicans) when compared with all other fractions, suggesting that the essential oils may impact negatively on the antimicrobial activity when tested against these two pathogens. PMID- 20922998 TI - Encapsulation of essential oils within a polymeric liposomal formulation for enhancement of antimicrobial efficacy. AB - Essential oils and their constituents are known to possess antimicrobial activity; however, their inherent volatility is a limiting factor. In order to exploit the antimicrobial efficacy of essential oils, encapsulation within polymeric liposomal systems was undertaken. The liposomes were subsequently polymer-coated in order to further enhance the stability of the formulations. Essential oils distilled from Artemisia afra, Eucalyptus globulus and Melaleuca alternifolia were encapsulated into diastearoyl phosphatidylcholine and diastearoyl phosphatidylethanolamine liposomes employing a reverse phase evaporation methodology. A polyelectrolyte coating was then applied via the layer by-layer self-deposition technique. A batch of the liposomes was polymer-coated with a 0.15%w/v chitosan solution. Using the minimum inhibitory concentration assay, the liposome-encapsulated, unencapsulated and polymer-coated liposome encapsulated essential oils were compared in order to observe whether the antimicrobial efficacy was improved with encapsulation and polymer coating. Fractional inhibitory concentrations (FICs) were calculated in order to determine the antimicrobial interactions amongst the lipoid components, polymer coating and essential oils (synergistic, additive, indifferent and antagonistic interactions). With the exception of A. afra, microbial growth was inhibited at lower concentrations for the encapsulated formulations in comparison with the nonencapsulated oils. Synergistic to additive interactions were noted for encapsulated E. globulus (sigmaFIC values 0.25-0.45) and M alternifolia (sigmaFIC values 0.26-0.52) formulations. The addition of the polymer coating did not enhance antimicrobial activity, but owing to their positive effects on membrane stability, its presence is important as a means of extending the shelf life of these formulations. Additionally, the presence of the polymeric coating availed the essential oil at a slower rate. This investigation is a stepping stone towards the promotion of the antimicrobial use of essential oils. The added benefits are that essential oils not only provide effective antimicrobial efficacy, but also promote a "greener" consumerism. Within liposomes, they will enhance dermato-cosmetic properties and increase the marketing image of the final product. PMID- 20922999 TI - Eupatorium capillifolium essential oil: chemical composition, antifungal activity, and insecticidal activity. AB - Natural plant extracts often contain compounds that are useful in pest management applications. The essential oil of Eupatorium capillifolium (dog-fennel) was investigated for antifungal and insecticidal activities. Essential oil obtained by hydrodistillation of aerial parts was analyzed by gas chromatography (GC) and gas chromatography-mass spectrometry (GC/MS). The major components were determined to be thymol methyl ether (=methyl thymol) (36.3%), 2,5-dimethoxy-p cymene (20.8%) and myrcene (15.7%). Antifungal activity of the essential oil was weak against the plant pathogens Colletotrichum acutatum, C. fragariae, and C. gloeosporioides in direct bioautography assay. The E. capillifolium oil showed promising repellent activity against the yellow fever mosquito Aedes aegypti, whereas the oil exhibited moderate activity against the mosquito's first instar larvae in a high throughput bioassay. Topical applications of the oil showed no activity against the blood-feeding female adults of A. aegypti. Eupatorium capillifolium essential oil showed a linear dose response between adult lace bug (Stephanitis pyrioides) mortality and increasing oil concentration in an adulticidal activity bioassay. The dog-fennel oil was more potent than the conventional insecticide malathion. In conclusion, these combined results showed Eupatorium capillifolium oil is a promising novel source of a biological insecticide with multiple modes of action. PMID- 20923000 TI - Raman optical activity: a powerful technique to investigate essential oil components. AB - The theory and some applications of Raman Optical Activity (ROA) towards terpene analysis are presented. With this technique, vibrational optical activity from chiral molecules can be measured providing their absolute configuration. This short review provides data obtained for pinene, verbenone, menthol, camphor, carenes and related molecules. The ROA technique seems to be a powerful tool which permits correlation between the properties of biocompounds and their structure. PMID- 20923001 TI - Microdistillation and analysis of volatiles from eight ornamental Salvia taxa. AB - Volatile compounds from seven Salvia species and one interspecific hybrid growing at the Dallas Arboretum and Botanical Garden, Texas, US. Salvia coccinea, S. farinacea, S. greggii, S. leucantha, S. longispicata x farinacea, S. madrensis, S. roemeriana and S. splendens were investigated for their chemical compositions using a microdistillation technique. Volatiles were analyzed by gas chromatography (GC) and gas chromatography-mass spectrometry (GC/MS). One hundred and twenty seven compounds were identified representing 94.3-99.7% of the oils. The major components in each of the seven species were as follows: S. coccinea (Z)-3-hexenal (31%), viridiflorol (19%); S. farinacea 1-octen-3-ol (30%) and (Z) 3-hexenal (23%); S. greggii 1,8-cineole (22%), borneol (17%), camphene (11%) and alpha-pinene (10%); S. leucantha limonene (35%) and alpha-pinene (17%); S. longispicata x farinacea 1-octen-3-ol (50%) and (Z)-3-hexenal (24%); S. madrensis (Z)-3-hexenal (53%); S. roemeriana limonene (49%) and alpha-pinene (20%); and S. splendens (Z)-3-hexenal (36%), 2,5-dimethoxy-p-cymene (19%) and linalool (11%). The microdistillation method was fast, practical and a useful technique that enabled the isolation of the volatiles in samples when only limited quantities were available. PMID- 20923002 TI - Comparison of hydrodistillation and headspace solid-phase microextraction techniques for antibacterial volatile compounds from the fruits of Seseli libanotis. AB - The volatile compounds from the fruits of Seseli libanotis, wild-growing in Poland, were obtained by hydrodistillation (HD) and headspace solid-phase microextraction techniques (HS-SPME) and analyzed using GC-MS. A total of 58 components were identified. The most abundant compounds were sabinen and beta phellandrene. MIC (minimal inhibitory concentration) and MBC (minimal bactericidal concentration) values for the essential oil against reference bacterial strains and clinical S. aureus isolates were determined. The essential oil showed better antibacterial activity against the Gram-positive bacteria (MICs between 0.15 to 1.25 mg/mL) when compared with Gram-negative bacteria (MICs between 1.25 to 2.5 mg/mL). The low values of the MBC/MIC ratio suggest that the examined oil behaved as a bactericidal agent. PMID- 20923003 TI - Volatile fraction of lavender and bitter fennel infusion extracts. AB - The relative proportions of chemical classes (hydrocarbons, oxides, alcohols/ethers, aldehydes/ketones, acids/esters/lactones) in the essential oil of lavender (Lavendula angustifolia Mill., family Lamiaceae) and bitter fennel (Foeniculum vulgare Mill. subsp. vulgare var. vulgare (Mill.) Thellung, family Apiaceae) and in the volatile fraction of infusion extracts were examined and showed remarkable differences. The volatile compounds of infusions were isolated by hydrodistillation and solid phase extraction (SPE). Their qualitative and semiquantitative compositions were compared with the essential oil isolated by hydrodistillation directly from the plant material and analyzed by GC-MS. Furthermore, quantification of the major constituents of lavender oil and of the volatile fraction obtained by hydrodistillation of the infusion was performed. Comparison of the total essential oil yield quantified by hydrodistillation of the lavender infusion (0.7% v/w, corresponding to plant material) with the essential oil yield of the blossoms (5.1% v/w) revealed that only 13.9% of the initial oil could be extracted by infusion. The main constituents of the volatile fraction of the lavender infusion were (hydrodistillation/SPE): linalool (39.3%/28.2%), 1,8 cineole (24.8%/18.9%), cis-linalool oxide (furanoid) (5.8%/8.0%), trans-linalool oxide (furanoid) (4.1%/7.1%), camphor (5.3%/4.0%) and alpha-terpineol (4.0%/3.0%). The major constituents of lavender essential oil were linalool (28.8%), 1,8-cineole (18.05%), linalyl acetate (13.9%) and alpha terpineol (4.0%). Most intriguing, in the volatile fraction of lavender infusion a significant proportional decrease of linalyl acetate and an increase of linalool oxides was recognized. The essential oil yield of fennel fruits was 12.5% v/w, whereas 1.8% v/w volatile fraction (corresponding to plant material) was obtained by hydrodistillation of the fennel infusion, which is equivalent to 14.5% of the initial fennel essential oil. The main constituents of the volatile fraction of the fennel infusion were (hydrodistillation/SPE): trans-anethole (56.4%/54.8%), fenchone (36.2%/39.5%) and estragole (2.5%/2.2%), which were also the major compounds of the genuine bitter fennel essential oil. In infusions, the proportion of ethers vs. ketones was shifted significantly towards a higher proportion of the latter compared with the essential oil obtained from the fruits. PMID- 20923004 TI - Can glandular hair density be a breeding marker for Origanum vulgare subsp. hirtum with high essential oil content? AB - Origanum vulgare subsp. hirtum (Link) Ietswaart is an essential oil rich plant traditionally used as oregano. Based on the interest of the essential oil producing sector, in 2000 we have started a breeding program of O. vulgare subsp. hirtum. Plant material for our breeding work consists of 6 progeny. Individual evaluation of the plant material was carried out in 2008-2009 with the primary aim of finding mother plants with appropriate morphological features, high essential oil content (> 7%) and with carvacrol as the main essential oil component. Among the survey of morphological characteristics special attention was given to glandular hair density in order to test the usability of it as a morphological marker for screening progeny for high essential oil content. The characteristics of the progeny can be described with high variability ensuring the possibility of a good selection base. Evaluating the morphology, essential oil content and constitution of the individuals, 20 plants were selected on the grounds of their high (7-8.6%) essential oil content, high ratio (70-93%) of carvacrol in the essential oil and typical morphological features of O. vulgare subsp. hirtum. From the results of glandular hair density it can be stated that the correlation between glandular hair density of the upper, middle and lower leaves either on vegetative or generative shoots and essential oil content was never strong enough (correlation coefficient < or = 0.5) to use it exclusively as a morphological marker for individual selection. PMID- 20923005 TI - The influence of essential oils on human vigilance. AB - Olfactory stimuli are used in aromatherapy to enhance mood, well-being and work efficiency. Nevertheless, the impact of fragrances on cognitive performance in humans is not well understood. The present investigation aimed to evaluate the effects of 1,8-cineol, jasmine absolute ether, linalyl acetate and peppermint essential oil on human vigilance performance. The odorants were administered by means of inhalation and, except for peppermint essential oil, were tested at 2 different dosages. Performance in a standard visual vigilance task was measured in terms of speed and accuracy and subjective ratings of the odorants were assessed in terms of pleasantness, intensity, arousal and stress. We hypothesized that 1,8-cineol, jasmine absolute ether and peppermint essential oil would improve vigilance performance, whereas linalyl acetate would impair such performance. Comparison of the performances of the seven independent experimental groups with that of a control group did not show any of the expected effects. In contrast, inhalation of linalyl acetate decreased reaction times. Within-group analyses, however, revealed significant interactions between subjective ratings of the odorants and task performance. The results of the present investigation emphasize the high impact of subjective factors on the modulation of attentional functions by olfactory stimuli in humans. PMID- 20923006 TI - Comparison of liquid-liquid partition, HS-SPME and static HS GC/MS analysis for the quantification of (-)-linalool in human whole blood samples. AB - The aim of this investigation was to develop a fast and convenient method for the determination of (-)-linalool in human whole blood to facilitate pharmacokinetic studies. Analytical protocols were elaborated for three different GC/MS sampling techniques, i.e., static headspace (s-HS), headspace solid phase micro extraction (HS-SPME), and liquid-liquid partition. In principle, all tested methods were feasible, but s-HS had the greatest benefit because of the easy handling of the blood samples and its short analysis time. For s-HS two different incubation temperatures were tested (40 degrees C and 60 degrees C). The limit of detection was slightly lower when samples were incubated at 60 degrees C, but the same quantitative results were achieved using alpha-terpineol as internal standard. An accurate and sensitive method for the quantification of (-)-linalool in blood samples after either inhalation or percutaneous application, as well as pharmacokinetic data are presented. PMID- 20923007 TI - Salvia officinalis L.: composition and antioxidant-related activities of a crude extract and selected sub-fractions. AB - The composition and antioxidant properties of a methanol: acetic acid (99:1, v/v) soluble crude extract isolated from S. officinalis L. leaves through maceration and selected fractions isolated thereof are presented in this study. The total phenol content was estimated as gallic acid equivalents, whilst qualitative quantitative phenolic content was determined using high performance liquid chromatography with photodiode array detection. Antioxidant evaluation consisted of ferric reductive capacity and 1,1-diphenyl-2-picrylhydrazyl and hydroxyl free radical scavenging determinations. The crude extract contained hydroxybenzoic acids, hydroxycinnamic acids, flavonoids and diterpenoids, whilst caffeic acid, carnosic acid, luteolin, luteolin-7-O-glucoside and rosmarinic acid were identified from their chromatographic and spectral characteristics and quantified from their respective calibration curves. The crude extract and sub-fractions demonstrated varying degrees of efficacy in the antioxidant-related assays used, except the n-hexane fraction, which was unable to reduce iron(III) at reasonable concentrations. Although the positive controls, ascorbic acid, BHA and BHT, were more potent than the S. officinalis samples, two fractions were significantly (p < 0.05) more potent iron(III) reducing agents than pycnogenol, a proanthocyanidin rich commercial preparation. PMID- 20923008 TI - Developing and characterizing a mouse model of hepatotoxicity using oral pyrrolizidine alkaloid (monocrotaline) administration, with potentiation of the liver injury by co-administration of LPS. AB - Oral administration of xenobiotics is preferable for research in in vivo models because it mimics the real life situation of human subjects. Therefore, oral (po) monocrotaline (MCT) (a common contaminant of dietary supplements)/intraperitoneal (ip) lipopolysaccharides (LPS)-induced liver injury possibly imitates idiosyncratic hepatotoxicity in humans. Cytokines, for example interleukin-1beta (IL-1beta) and transforming growth factor beta (TGF-beta) are known to play a role in the development of toxicity and repair processes, respectively. The purpose of this study was to develop and characterize a model of po MCT/ip LPS hepatotoxicity which may elucidate the mechanisms of injury. ND4 male mice were given MCT (200 mg/kg) followed 4 h later by LPS (6 mg/kg). Blood samples were drawn for plasma chemistry and IL-1beta. Animals were euthanized and livers were harvested at different time points. We have shown that MCT/LPS cotreatment results in significant elevation of plasma alanine aminotransferase (ALT), CRP, IL-1beta and TGF-1beta. Histopathological evaluation revealed diffuse degenerative injury. In summary, we have established a reproducible in vivo model of hepatotoxicity by po MCT/ip LPS cotreatment that may closely mimic real life idiosyncratic hepatotoxicity. PMID- 20923009 TI - Xenobiotic biotransformation of 4-methoxy-N-methyl-2-quinolone, isolated from Zanthoxylum monophyllum. AB - Phytochemical evaluation of Zanthoxylum monophyllum has led to the isolation of the alkaloid 4-methoxy-N-methyl-2-quinolone (1) with a significant activity against methicillin-resistant Staphylococcus aureus (MRSA), with an IC50 value of 1.5 microg/mL. Xenobiotic biotransformation of 1 has been conducted with the general goal of increasing the bioactivity of the compound and contributing new leads for further pharmacological research. Twenty-nine microorganisms were used for screening and two (Aspergillus flavus and Cunninghamella echinulata var. echinulata) were able to transform compound 1 to 4-methoxy-2-quinolone (2). Structural identification of the compounds was based on NMR, IR, and MS data. PMID- 20923010 TI - Volatiles from Thymbra and Thymus species of the western Mediterranean basin, Portugal and Macaronesia. AB - Thyme is the common name of many taxa belonging to the Thymbra and Thymus genera. Given the economic importance of thyme oils, many thyme species have been studied and their essential oils and other volatile-containing extracts chemically characterized. Thymbra and Thymus species are frequent in the west Mediterranean region, considered to be the centre of origin of the genus Thymus, and extend further westwards in the Iberian Peninsula and northwest Africa, to the Macaronesian region in the Atlantic Ocean. The present work gives an overview of the chemical composition of the volatiles from the taxa of these two genera occurring in the above geographic area. PMID- 20923011 TI - Essential oil composition of wild growing Apiaceae from Europe and the Mediterranean. AB - In this overview, the essential oil composition of more than 150 species from about 50 genera of the Apiaceae is reviewed. Essential oil components encountered in Apiaceae proved to be very diverse; they include monoterpenes, sesquiterpenes, rarely diterpenes, phenylpropanoids, phthalides, octanol and octyl esters, trimethylbenzaldehydes and aliphatic aldehydes. In assessing the data one has to keep in mind that the essential oil amount and composition is influenced by many factors, including geographic and genetic variation, physiological aspects and environmental conditions. In some species the occurrence of chemotypes could be demonstrated, but in many cases the data available do not allow the evaluation of infraspecific variability. PMID- 20923013 TI - Terpene bioconversion--how does its future look? AB - The usage of essential oils as such or of volatile fractions thereof is widespread in the flavor and fragrance industry to aromatize perfumery and cosmetic products, foodstuffs, and many household and pharmaceutical products. The increased market share of convenience food together with consumers' request for constant high quality and natural products have established a lasting increase in the demand for natural flavorings that cannot be satisfied by the traditional plant materials. This review summarizes selected work on terpene bioconversion/transformation and focuses on recently published papers dealing with novel strains and products, high product yields, intriguing genetic engineering approaches, and integrated bioprocesses. The future perspectives of an industrial realization of a biotechnological production of terpene-derived natural flavors are critically evaluated. PMID- 20923012 TI - Essential oil and volatile components of the genus Hypericum (Hypericaceae). AB - The flowering plant genus Hypericum (Hypericaceae) contains the well-known medicinally valuable species Hypericum perforatum (common St. John's wort). Species of Hypericum contain many bioactive constituents, including proanthocyanins, flavonoids, biflavonoids, xanthones, phenylpropanes and naphthodianthrones that are characterized by their relative hydrophilicity, as well as acylphloroglucinols and essential oil components that are more hydrophobic in nature. A concise review of the scientific literature pertaining to constituents of Hypericum essential oils and volatile fractions is presented. PMID- 20923014 TI - [Dyspnea. A reliable symptom]. PMID- 20923015 TI - [Astellas Pharma backs on innovations."Our claim is to compete with the best products on the market"]. PMID- 20923016 TI - [When women complain about lacking libido. The problem with the desire]. PMID- 20923017 TI - [Depression during and after pregnancy' "Will I be a good mother?"]. PMID- 20923018 TI - [Testosterone deficiency syndrome. Imaginary disease or true complaint picture?]. PMID- 20923019 TI - [Www.SpringerMedizin.de. The Internet of physicians]. PMID- 20923020 TI - [Chronic urinary tract infection]. PMID- 20923021 TI - [Iron deficiency. To be treated before anemia comes!]. PMID- 20923022 TI - [Alternative therapy methods in chronic inflammatory bowel diseases. Possibly acupuncture helps a little]. PMID- 20923023 TI - [Injuries, blood alcohol level and state of health. The GP as witness and expert]. PMID- 20923024 TI - [Documentation requirements and descriptions of injuries]. PMID- 20923025 TI - [Taking medical samples under forensic aspects]. PMID- 20923026 TI - [Medical certificate]. PMID- 20923027 TI - [Palmar hyperhidrosis]. PMID- 20923028 TI - [Stress and primary headache in children and adolescents]. PMID- 20923029 TI - [Management of chronic wounds]. PMID- 20923030 TI - [Isolated systolic hypertension threatens the heart and the brain. Fixed combination optimizes blood pressure control and offers clear prognostic advantage]. PMID- 20923031 TI - Androgen deprivation therapy: a survival benefit or detriment in men with high risk prostate cancer? AB - Androgen deprivation therapy (ADT) has been used in the management of prostate cancer for more than four decades. Initially, hormone therapy was given largely for palliation of symptomatic metastases. Following several randomized trials of patients with intermediate- to high-risk prostate cancer that demonstrated improvements in biochemical control and survival with the addition of ADT to external beam radiotherapy, there was a dramatic increase in the use of hormone therapy in the definitive setting. More recently, the safety of ADT has been questioned, as some studies have suggested an association of hormone therapy with increased cardiovascular morbidity and mortality. This is particularly worrisome in light of practice patterns that show ADT use extrapolated to situations for which there has been no proven benefit. In the setting of dose escalation with modern radiotherapy, in conjunction with the latest concerns about cardiovascular morbidity with ADT, the magnitude of expected benefit along with potential risks of ADT use must be carefully considered for each patient. PMID- 20923032 TI - Cardiovascular risk associated with androgen deprivation therapy. PMID- 20923033 TI - Androgen deprivation therapy in high-risk prostate cancer. PMID- 20923034 TI - The role, timing, and clinical use of ADT in prostate cancer. PMID- 20923035 TI - Intensity-modulated radiation therapy for anal cancer: toxicity versus outcomes. AB - The treatment of cancer of the anal canal has changed significantly over the past several decades. Although the abdominoperineal resection (APR) was the historical standard of care, a therapeutic paradigm shift occurred with the seminal work of Nigro, who reported that anal canal cancer could be treated with definitive chemoradiation, with APR reserved for salvage therapy only. This remains an attractive approach for patients and physicians alike and the standard of care in this disease. Now, nearly four decades later, a similar approach continues to be utilized, albeit with higher radiation doses; however, this strategy remains fraught with considerable treatment-related morbidities. With the advent of intensity-modulated radiation therapy (IMRT), many oncologists are beginning to utilize this technology in the treatment of anal cancer in order to decrease these toxicities while maintaining similar treatment efficacy. This article reviews the relevant literature leading up to the modern treatment of anal canal cancer, and discusses IMRT-related toxicity and disease-related outcomes in the context of outcomes of conventionally treated anal cancer. PMID- 20923036 TI - Intensity-modulated radiation therapy for anal cancer: an obvious yet complicated transition. PMID- 20923037 TI - Solitary extramedullary plasmacytoma of the bladder: a case report and literature. AB - Plasmacytoma is a rare B-lymphocyte neoplastic disorder that usually presents as the generalized disease multiple myeloma. Less than 5% of the cases present as a solitary mass of monoclonal plasma cells in the bone or soft tissue. Although solitary extramedullary plasmacytoma (SEP) may arise in any organ, it rarely involves the urinary bladder. A 67-year-old male without a history of multiple myeloma presented with urinary frequency and nocturia; he was later diagnosed with SEP of the bladder. The patient was initially treated with a course of radiation therapy without symptomatic improvement; therefore a chemotherapy regimen consisting of lenalidomide and dexamethasone was subsequently given for six cycles. SEP usually carries a better prognosis and higher cure rate than solitary plasmacytoma of bone, as SEP is radiation sensitive. The role of adjuvant chemotherapy in the treatment of SEP that is resistant to radiation therapy is not clear, since most of the recommendations have been derived from the experience of head and neck SEP. The literature also lacks recommendations for choice of a chemotherapy regimen and surveillance of isolated bladder plasmacytoma. Here we present the first case of a radiation-resistant solitary plasmacytoma of the bladder that was successfully treated with lenalidomide and dexamethasone with successful clinical remission. PMID- 20923038 TI - Solitary extramedullary and bone plasmacytomas versus multiple myeloma with extramedullary manifestation. PMID- 20923039 TI - Rare bladder tumors: caveat emptor. PMID- 20923040 TI - Metabolic syndrome after hormone-modifying therapy: risks associated with antineoplastic therapy. AB - The incidence of metabolic syndrome is rapidly increasing. Metabolic syndrome is associated with elevated morbidity and mortality secondary to cardiovascular disease, insulin resistance, and hepatic dysfunction. A body of evidence has already implicated metabolic syndrome as a cancer risk factor; emerging evidence now suggests that cancer survivors themselves may be at risk for developing metabolic syndrome as a result of their anti-cancer therapy. Treatment of both breast cancer and prostate cancer often involves hormone-modifying agents that have been linked to features of metabolic syndrome. Androgen suppression in men with prostate cancer is associated with dyslipidemia, increasing risk of cardiovascular disease, and insulin resistance. Anti-estrogen therapy in women with breast cancer can affect lipid profiles, cardiovascular risk, and liver function. Similar findings have been noted in men with testicular cancer treated with chemotherapy. In addition, several emerging therapies, including mammalian target of rapamycin (mTOR) inhibitors and targeted kinase inhibitors, are increasingly associated with some features of metabolic syndrome. As the number of cancer survivors continues to grow, consideration of these factors and of the risk of metabolic syndrome will become increasingly important when choosing between therapy options and managing long-term follow-up. PMID- 20923041 TI - Considering metabolic effects when making breast cancer treatment decisions. PMID- 20923042 TI - Metabolic effects of hormone deprivation therapy: weighing the evidence. PMID- 20923043 TI - Complementary therapies, herbs, and other OTC agents. PMID- 20923044 TI - Health, supervisory support, and workplace culture in relation to work-family conflict and synergy. AB - This research examined health, supervisory support, and workplace culture as predictors of work interfering with family, family interfering with work, and work-family synergy. The analysis of data from 2,796 respondents from the 2002 National Study of the Changing Workforce yielded significant relations among measures of mental health, self-rated health, supervisory support, and work family culture with a focus on career concerns. Support was found for a measure of work-family synergy. Implications and directions for research are discussed. PMID- 20923045 TI - Cognitive biases and decision making in gambling. AB - Heuristics and cognitive biases can occur in reasoning and decision making. Some of them are very common in gamblers (illusion of control, representativeness, availability, etc.). Structural characteristics and functioning of games of chance favor the appearance of these biases. Two experiments were conducted with nonpathological gamblers. The first experiment was a game of dice with wagers. In the second experiment, the participants played two bingo games. Specific rules of the games favored the appearance of cognitive bias (illusion of control) and heuristics (representativeness and availability) and influence on the bets. Results and implications for gambling are discussed. PMID- 20923046 TI - Body height and occupational success for actors and actresses. AB - The association of body height with occupational success has been frequently studied, with previous research mainly finding a positive effect among men and positive or null effects among women. Occupational success has almost exclusively been measured so far by short-term success variables (e.g., annual income). In the present study, the relationship of success and height was examined in a group of actors and actresses using a large online database about movies (Internet Movie Database) where heights of actors and actresses are stated. The number of roles played in movies and television series during each actor's lifetime was used as a measure of long-term occupational success. No height effect was found for male actors but a significant negative effect was found for actresses, even after controlling for possible confounding influences (age and birth year). Compared to the general population, actors and actresses were significantly taller; however, actresses who were shorter than average were more likely to achieve greater occupational success, in terms of being featured in more movies. PMID- 20923047 TI - Hurlbert Index of Sexual Assertiveness: a study of psychometric properties in a Spanish sample. AB - The study analyzed psychometric properties of a Spanish version of the Hurlbert Index of Sexual Assertiveness in a Spanish sample of 400 men and 453 women who had had a partner for the last 6 mo. or longer at the time of the study. Exploratory and confirmatory factor analyses suggested a two-factor solution with the factors Initiation and No shyness/Refusal. Internal consistency values for total scores were .87 and .83 for the factors, respectively. Convergent validity tests were also satisfactory. It is therefore reasonable to conclude that the Spanish version of the scale has appropriate psychometric properties. PMID- 20923048 TI - Effects of anchoring and adjustment in the evaluation of product pricing. AB - Anchoring and adjustment comprise a heuristic that creates expectations. Two types of anchors were applied on participants' evaluation of products: the price reference of the product (maximum, minimum, or no price reference) and the context in which the products were evaluated (the prestige of the shopping center). Results showed that both factors anchored evaluations of products' value. Context effects were explained by the different expectations of visitors in prestigious (looking for quality) and less prestigious (seeking a bargain) centers. PMID- 20923049 TI - Psychometric properties of the Purdue Pharmacist Directive Guidance (PPDG) Scale in a sample of diabetes patients in the Southwestern United States. AB - Despite the fairly widespread adoption of the 10-item Purdue Pharmacist Directive Guidance Scale (PPDG) over the last decade, only one study has assessed its psychometric properties. The present study examined the validity and reliability of the scale in a sample of 99 diabetic patients in the Southwestern United States. Principal axis factor analysis with Varimax rotation yielded two factors, "Instruction" and "Feedback and Goal Setting," similar to those found when the scale was originally developed. Cronbach's alphas for the total scale and the two factors were 0.95, 0.95, and 0.92, respectively. The scale and the two factors correlated significantly and positively with number of visits by patients to the pharmacist in the past 3 mo. These results provide further evidence for the internal consistency, and construct and criterion-related validities of the scale. PMID- 20923050 TI - Language and cognitive shifting: evidence from young monolingual and bilingual children. AB - The relationship between language and cognitive shifting in young children was examined. Specifically, second language experiences from infancy as well as individual differences in monolingual language experience may affect performances on the Dimensional Change Card Sort Task. 54 Japanese-French bilingual children and two groups of Japanese monolingual children participated (ns = 18). One monolingual group was matched to the bilingual group on verbal ability and chronological age (VC monolingual group) and the other group was matched by chronological age but had higher verbal ability (C monolingual group). The results showed that the groups of children who were bilingual and monolingual with higher verbal ability performed the task significantly better than matched monolingual children. Language experiences may affect cognitive set shifting in young children. PMID- 20923051 TI - Psychosexual fixation and defense mechanisms in a sample of young Japanese women: a preliminary study. AB - The present pilot study examined psychosexual fixations and defense mechanisms in a sample of young Japanese women. The Lexical Rorschach count and the Defense Mechanisms Inventory were administered to 24 female college students. Sadism on the Lexical Rorschach count was positively correlated with Reversal of Affect. Phallic fixation on the Lexical Rorschach count was positively correlated with Projection. Psychoanalytic hypotheses about the associations between psychosexual fixations and defense mechanisms were partially confirmed. PMID- 20923052 TI - Depression-related distress in Mauritian and South African adolescent girls: an exploratory investigation. AB - Self-reports of depression-related distress were obtained from girls of 14 to 17 years of age living in communities of low socioeconomic status in Mauritius (n = 198) and South Africa (n = 275). Of the girls in the two samples, 26.3 and 21.5%, respectively, had thought about self-harm during the past 5 yr., while between 14.6 and 16.7% had made self-harm attempts. Also, 39.9% of the Mauritian girls and 31.0% of the South Africans reported being sad and tearful every day for more than 2 wk. over the past year. Of the girls, Mauritians (54.0%) and South Africans (32.1%) felt their problems were too much to cope with, while 20.4% of the South African girls and 44.4% of the Mauritians knew of no place to go for help when feeling sad or depressed. The findings highlight the extent of depression-related symptoms and issues related to access to mental health services. Increasing mental health services and awareness programmes are indicated. PMID- 20923053 TI - A reliability generalization study of the Frost Multidimensional Perfectionism Scale (F-MPS). AB - Perfectionism has been identified as a common concern among clients who seek counseling services. For more than 20 years, the Frost Multidimensional Perfectionism Scale (F-MPS) has been used extensively to measure the construct of individuals' perfectionism. The current study used reliability generalization to identify the average score reliability as well as variables explaining the variability of score reliability. Typical reliability across subscale scores ranged from .71 to.86 with the Doubt about Action subscale showing the least variability and the Organization subscale showing the most. In addition, sex, language, and standard deviation of the scale had statistically significant relations to reliability estimates. PMID- 20923054 TI - Differential effect of lesion side on intra-individual variability in children with focal lateralized epilepsy. AB - A differential impact of hemispheric side (left vs right) on cognitive measures, specifically Verbal and Performance IQ, has been described previously for both focal onset seizures and lateralized brain lesions. This study revealed a differential effect on intra-individual variability, measured as subtest scaled score range, on the Dutch WISC-R and WISC-III, in children with epilepsy. The presence of documented brain lesion was associated with elevated variability on the Verbal Scale for the left hemisphere seizure group and with decreased variability on the Verbal and Full Scales for the right hemisphere seizure group. PMID- 20923055 TI - Exploratory factor analysis and psychometric properties of the General Health Questionnaire in Spanish adolescents. AB - The aim of this study was to assess the homogeneity of items, reliability as a metric indicator of global quality (internal consistency and temporal stability), and the exploratory factor structure of the General Health Questionnaire-28 (GHQ 28) in a sample of 2,010 Spanish adolescents. Mean age was 15.9 yr. (range 14-19, SD = 2.1). The test was administered twice with 20 days between responses, Answers were scored on a Likert-type scale. The internal consistency and test retest reliabilities obtained were .93 and .94. In exploratory factor analysis, four factors explained 52.7% of the variance. These results indicated that the GHQ-28 is a psychometrically sound mental health measure in Spanish adolescents. PMID- 20923056 TI - Testing rival measurement models of the Personal Report of Communication Apprehension in two Taiwanese samples. AB - Some previous research has questioned the appropriateness of using McCroskey's Personal Report of Communication Apprehension with participants of non-Western countries. Rival measurement models of the scale were examined on two samples of 216 and 177 college students in Taiwan. Confirmatory factor analysis of the data showed that although a four-factor model was more representative of the data than the models with one, two, or three factors, this model did not generate an acceptable fit to the data. Further testing of discriminant validity suggested that Taiwanese college students do not differentiate a meeting setting from group, dyadic, and public speaking settings. Findings of this study suggest a re examination of the conceptualization of communication apprehension before evaluating the relative importance of biological and environmental causes. PMID- 20923057 TI - Gender label and perceived infant emotionality: a partial replication of a classic study. AB - In a study often referred to as "classic," Condry and Condry (1976) showed a videotaped infant to participants, telling half of them the infant was a boy and half it was a girl. Participants who thought they were viewing a boy rated the infant's reaction to a jack-in-the-box as anger; those who thought they were viewing a girl rated the reaction as fear. Participants in the present partial replication of the Condrys' study did not rate the infant differently based on the infant's gender label, although there was evidence that participants' own sex affects their perception of an infant's emotionality. Results were discussed in light of inconsistent results among other gender-labeling studies and relevant methodological, historical, and theoretical issues. PMID- 20923058 TI - Men's sense of humor and women's responses to courtship solicitations: an experimental field study. AB - Producing humor might function as a fitness indicator associated with greater desirability during dating selection. A male confederate in a bar was instructed to tell (or not tell) funny jokes to two other male confederates. A few minutes later, when the second of two male confederates left, the first male confederate asked a female who was near his table and who had heard the funny jokes for her phone number. The previous expression of humor was associated with greater compliance with the male confederate's request and with a higher positive evaluation. The possible effects of humor are discussed from an evolutionary perspective. PMID- 20923059 TI - Sweden: income and suicide. AB - Previous publications have reported two conflicting patterns describing the relationship between income and suicide in Sweden; positive and negative. Methodologically the studies have differed, and the analysis has been limited to a few areas. To better understand the relationship, a nationwide, cross sectional, ecological study of the 290 municipalities in Sweden was planned. OLS regression analyses showed the overall and female suicide rates were negatively related to income, while the effect on male suicide rates was not statistically significant. The results confirm earlier findings of a negative relationship between income and suicide. PMID- 20923060 TI - The personality correlates of adults who had imaginary companions in childhood. AB - Two studies showed that adults who reported having an imaginary companion as a child differed from adults who did not on certain personality dimensions. The first yielded a higher mean on the Gough Creative Personality Scale for the group who had imaginary companions. Study 2 showed that such adults scored higher on the Achievement and Absorption subscales of Tellegen's Multidimensional Personality Questionnaire. The results suggest that some differences reported in the developmental literature may be observed in adults. PMID- 20923061 TI - Financial stress, attitudes toward money, and scores on a Dream Inventory. AB - During stock market losses in 2009 and high unemployment, ratings on the KJP Dream Inventory were correlated with factors of the Money Attitude Scale and items on the Contemporary Financial Stress Inventory for 71 graduate students in Counseling Psychology and Education. Correlations were significant for Retention on the Money Attitude Scale with Dissociative Avoidance (-.31), Dreams of falling (.26), Risk-taking in dreams (.24), and Dreaming of being chased (.28). Also, ratings for the Money Attitude Scale of Distrust correlated with Discontentedness in dreams (.33) and Dreams of being chased (.26), Repetitive trauma (.33), Nightmares (.30), and Recurring nightmares (.35). Concern about retention in graduate school due to finances correlated with recalled frequencies of nightmares (.27) and dreams of flying (.25). PMID- 20923062 TI - Relation of success and nontraditional career choice to selection for dating and friendship. AB - Women who succeed in traditionally male-dominated fields have previously been found to experience lower social acceptance, both from men in romantic contexts and from women in platonic contexts. The present study examined whether such preferences continue to exist. Participants were 256 university students (110 men, 146 women) with an average age of 21.4 yr. (SD = 3.6). They answered the Bem Sex Role Inventory and the Modern Sexism Scale and also responded to four descriptions of stimulus persons which represented the variables of traditional versus nontraditional field and successful versus nondescribed academic performance. Results indicated that men preferred to date women in traditional careers (independent of their success). This finding was unrelated to men's scores on sex role orientation or egalitarianism and sexism. However, in platonic relationships, women favored women in nontraditional careers as friends. PMID- 20923063 TI - Association between alexithymia, neuroticism, and social desirability scores among Italian graduate students. AB - An inverse correlation between social desirability and alexithymia has been observed in undergraduate students in Japan and Australia. It is not clear how this association is influenced by the personality dimension of neuroticism. This study examined the association of scores on social desirability with those on alexithymia controlled for neuroticism, in a sample of 111 Italian graduate students, with age range of 24 to 58 years. Students completed the Eysenck Personality Questionnaire (short form) and the Toronto Alexithymia Scale-20 (TAS 20). Social desirability scores inversely correlated with TAS-20 total scores, neuroticism scores, and the TAS-20 subscale, Difficulty identifying feelings. Neuroticism directly correlated with TAS-20 total score, Difficulty identifying feelings, and Difficulty describing feelings. Students with higher alexithymia and neuroticism scores seem to present themselves in less socially desirable ways. The correlation of social desirability with alexithymia was moderated by higher neuroticism scores. PMID- 20923064 TI - Job burnout: toward an integration of two dominant resource-based models. AB - The goal of this study was to integrate the job demands-resources model and the conservation of resources model of job burnout into a unified theoretical framework. The data were collected through a mail questionnaire survey among nurses holding managerial positions in the Hospital Authority of Hong Kong. From a computer-generated random sample of nurses, 543 (84.3% women) returned usable surveys, amounting to a response rate of 24.2%. Structural equation modeling was used to test the proposed paths originating from job demands and job resources to the core job burnout dimensions, namely, emotional exhaustion and depersonalization. Results supported the integrated model, indicating that job demands and job resources had differing effects on the burnout dimensions. The effect of job demands was stronger and partially mediated the effect of job resources. Implications of the results from this study on management practices were discussed. PMID- 20923065 TI - Survey return rates for multiple-authored versus single-authored covering letters. AB - Differences in response rates to a three-wave mail survey were assessed when the covering letters were signed by three versus one researcher. 375 surveys including covering letters signed by three researchers and 375 surveys including covering letters signed by one researcher were sent. A follow-up mailing was used to increase the response rate. 199 surveys were returned (53.5%) in which the covering letter had three researchers, and 218 when the covering letter had one researcher (58.7%), not a significantly different distribution. PMID- 20923066 TI - Perceived psychosocial benefits associated with perceived restorative potential of wilderness river-rafting trips. AB - Analysis of the restorative experiences and psychosocial benefits of wilderness river rafting trips of varying difficulty with 186 Canadian participants of different ages supported the restorative potential of natural settings for all age groups as measured by the Perceived Restorativeness Scale. The two-factor structure (General Restorativeness and Coherence) was confirmed. Significant associations were found between scores on the General Restorative subscale and perceived psychosocial benefits (relaxation, nature appreciation or kinship, and physical fitness or achievement) and positive affect. However, the findings associated with the Coherence subscale were not conclusive. PMID- 20923067 TI - Educational level signals unobserved abilities of people with high functioning autism spectrum disorders. AB - The effect of educational level on employment of people with high functioning autism spectrum disorders (HFASD) was examined. If education augments natural abilities to accomplish tasks in people with HFASD, then those with more education would have comparative advantages in both obtaining and retaining jobs. In contrast, if education did not augment natural abilities and only signaled unobservable abilities, one would expect an advantage only in obtaining a job, but not in retention. 22 people with HFASD replied to questionnaires regarding their history of education and employment. Those with job experience had higher educational levels than those with no job experience, but educational level was not significantly different between groups with and without more than one year of job experience. Educational level seems to be associated with abilities, but probably the unobserved abilities underlie both educational attainment and employment history. PMID- 20923068 TI - A hierarchical linear modeling assessment of dual-addiction status and change in sexual compulsivity over time. AB - This study examined the association between dual-addiction status and sexual compulsivity over time in a sample of self-identified sexually compulsive males. Hierarchical linear modeling was utilized to address the study's research questions. Dually addicted sexually compulsive males exhibited lower rates of sexual compulsivity than their singularly addicted counterparts initially but displayed less precipitous declines in sexual compulsiveness over time. Implications for treatment providers are discussed. PMID- 20923069 TI - Asymmetrical clustering by sex in free-forming groups: an observational field study. AB - 464 observations were carried out in public places of 3- or 4-person, mixed sex, free-forming groups who spontaneously divided into subgroups. An analysis of sex composition of the subgroups showed that significantly more single-sex subgroups were formed than expected by chance. This was significantly more pronounced among women than among men. Several explanations were considered. PMID- 20923070 TI - Associations between climate and IQ in the United States of America. AB - Relations between average temperature of each of the 48 contiguous states and estimates of state IQ were inspected. Additional state variables were controlled in the correlational analyses, namely gross state product, percent Hispanic, Black, and Asian in the state population, and the pupil-to-teacher ratio for each state. A significant correlation between average temperature and state IQ was found (r = -.70, p < .001). Possible explanations are discussed. PMID- 20923071 TI - Workers' personal initiative as a moderator of the relations between job characteristics and well-being. AB - Having personal initiative means that workers are self-starting, pro-active, and persistent in pursuing their goals. This study examined whether personal initiative contributed to the prediction of two aspects of well-being (emotional exhaustion and learning motivation). Personal initiative was expected to have direct effects on well-being as well as moderate the effects of relevant work characteristics such as job demands and control. As expected, stepwise hierarchical regression using data from 834 Dutch telecommunications workers yielded positive main effects of personal initiative on both aspects of well being. Moreover, personal initiative moderated the relationship between control and learning motivation: the positive effect of control on learning motivation was stronger for workers with high initiative. These findings support the hypothesis that personal initiative is a predictor of well-being. PMID- 20923072 TI - Measuring well-being among Spanish older adults: development of a simplified version of Ryff's Scales of Psychological Well-being. AB - Two studies were designed to develop and obtain information about the psychometric properties of a shortened 54-item, Spanish version of Ryff's Scales of Psychological Well-being adapted to older people. In Study 1, 267 older people completed the scales, and data were submitted to a principal components analysis. Then, 22 items were selected and grouped into four components (Self-confidence, Orientation to present, Stress, and Social tension) to form the Simplified Ryff's Well-being Scales. In Study 2, the new scales were administered to 107 older people. While internal consistency estimates were similar to those generally obtained for the 54-item scale, results extracted from a confirmatory factor analysis did not support any factorial model. Although the simplified scales can distinguish between conceptually different approaches to well-being, further studies are needed to obtain estimates of reliability and validity. PMID- 20923073 TI - Influence of the interests of children with autism on everyday learning opportunities. AB - Findings from a pilot study investigating the influence of the interests of young children with autism on parents' provision of everyday informal child learning opportunities are described. 17 children (13 boys, 4 girls) were divided into two groups that received everyday learning opportunities of Low interest and High interest, based on parents' bi-weekly ratings of the interestingness of the opportunities to the children, using an investigator-developed measure. A brief intervention of 12 to 14 weeks showed that the children in the High interest based group were provided more learning opportunities than were the Low interest based group, and that the parents indicated that their children benefited more from the learning opportunities. Implications for future research are described. PMID- 20923074 TI - Metamemory beliefs and episodic memory in obstructive sleep apnea syndrome. AB - This study assessed metamemory and its role in actual episodic memory performance in 26 patients with obstructive sleep apnea syndrome and 27 healthy controls. Metamemory knowledge and memory beliefs were assessed using the Metamemory Inventory in Adulthood. Episodic memory performance was investigated with the Remember/Know paradigm. Subjective sleepiness was evaluated. Patients underwent a polysomnographic assessment. In contrast to the control group's more stable memory beliefs, patients self-assessed their memory as declining across time, and felt more anxious about their memory. There was only a modest difference between patients' self-perceptions of their memory capacities and those of the control group, but patients' actual memory performance was strongly disturbed. While the latter was significantly correlated with severity of obstructive sleep apnea, scores on the Metamemory Inventory in Adulthood scales were not correlated with physiological measures, subjective sleepiness, or episodic memory performance. Obstructive sleep apnea may affect prefrontal cortex functioning and hence the ability to assess one's own memory impairment. PMID- 20923075 TI - Self-regulated learning: the role of environmental perceptions and motivational beliefs. AB - To examine the correlations among environmental perceptions, motivational beliefs, and self-regulated learning of Tehran third-year high school boys based on a proposed model, multistage cluster-sampling method gave a sample of 685 students. The Motivated Strategies for Learning Questionnaire (Pintrich & De Groot, 1990), Students' Achievement Goal Orientations (Midgley, Kaplan, Middleton, Maehr, Urdan, Anderman, et al., 1998), Students' Perceptions of Classroom Activities (Gentry, Gable, & Rizza, 2002), and Perceptions of Parents Scales (Grolnick, Deci, & Ryan, 1997) were administered. Analysis showed relations among components of self-regulated learning, family environmental perceptions, perceptions of classroom activities, and motivational beliefs. Structural equation modeling indicated the proposed model had an acceptable fit to the data. All paths or structural coefficients of the proposed model were statistically significant. PMID- 20923076 TI - Self-awareness training associated with personality traits and sex: a pilot study. AB - 107 volunteers learning Reiki-Do self-awareness techniques participated in this study. Results indicate that personality traits in healthy participants might be affected by specific self-awareness training, such as Reiki-Do, with participants' sex playing an independent role. PMID- 20923077 TI - Poet interrupted: differences in the emotionality and imagery of Byron's poetry associated with his turbulent mid-career years in England. AB - The Dictionary of Affect in Language was employed to compare two parts of Byron's Childe Harold's Pilgrimage, written before and after an interruption of several turbulent years in England. The post-interruption part of the poem employed fewer extreme emotional words and more abstract words than the pre-interruption part. In a second analysis, poems written during the interruption and poems written before and after Childe Harold were examined, along with it, in terms of emotion, imagery, and linguistic richness. Two variables--year and an interruption dummy coded as 1 for publications between 1812.5 and 1816.17--predicted observed differences accurately. Byron's poetry became linguistically richer, more abstract, and less passionate across time, and it was emotionally more negative and linguistically simpler during the turbulent years. Differences between the two parts of Childe Harold were best explained on the basis of time-dependent growth curves rather than the interruption. PMID- 20923078 TI - Cultural differences in drawing movements between right-handed Japanese and German participants. AB - Differences in drawing movements with the dominant and nondominant hands by 41 right-handed students from Japan (9 men, 12 women; M age = 20.3 yr., SD = 1.4) and Germany (13 men, 7 women; M age = 23.4 yr., SD = 3.0) were investigated. Participants were asked to use each hand to draw a circle, a pentagon, and a rhombus in one stroke. Analysis showed that Japanese participants drew a circle clockwise with the dominant right hand, starting from 6 or 7 o'clock on the face of a clock, while the German participants drew the circle counterclockwise, starting from 11 or 12 o'clock. Moreover, when drawing a pentagon and a rhombus with the right hand, Japanese participants drew counterclockwise from the top center vertex, whereas almost half of German participants drew clockwise from the left side and others drew counterclockwise from the top-center vertex. Using the left hand, no significant difference was found in starting positions or directionality. Cultural differences in the starting positions and directionality when using the dominant right hand probably reflect the influence of writing habits on the drawing movement of the dominant hand. PMID- 20923079 TI - Human left-sided cradling preferences for dogs. AB - Photographs of men and women holding dogs were analyzed for side-holding preferences. A significant majority of women in dog-themed magazines held dogs on their left sides, similar to reports of women holding infants. Men did not show the same left-sided preference, which is also consistent with other studies. The implications of these results for various hypotheses about infant cradling behavior were discussed. PMID- 20923080 TI - Characterizing perceptual learning using regression statistics: development of a perceptual calibration index. AB - Perceptual learning, improvement in perceptual skill with practice, can improve both accuracy and consistency of perceptual reports. Regression statistics can quantify ongoing calibration of perceptible scalar properties (i.e., improvements in accuracy and consistency) because, ideally, actual and perceived values are linearly related. Changes in variance accounted for (r2) track changes in consistency, and changes in both slope and intercept track changes in accuracy. Conjoint changes in all three regression statistics, obscured in separate plots, can be seen simultaneously in a perceptual calibration state space diagram, with the regression statistics as axes, in which an attractor (r2 = 1.00, slope = 1.00, intercept = 0.00) represents optimal performance. Decreases in the distance between the attractor and successive points in the state space, each representing perceptual performance, quantify perceptual learning; that distance is a perceptual calibration index. To show the utility of the perceptual calibration index, we illustrate its use in an experiment on wielding hand-held objects. PMID- 20923081 TI - Does exposure to ambient odors influence the emotional content of memories? AB - This study examined the effects of implicitly presented odors on the emotional content of memory narratives. Participants were exposed to low levels of perfumes or no odors while they reconstructed a memory from childhood and a recurrent dream. Narratives were analyzed for emotional content using the Linguistic and Inquiry Word Count program. Exposure to perfumes increased the percentage of positive emotion words used by participants in recalling both dreams and childhood memories. In addition, exposure to odors decreased the percentage of negative emotion words that men used in their narratives, whereas the opposite effect was found for women. Discussion focuses on gender differences in written emotional expression, possible ways by which perfumes may exert their effects, and the usefulness of using ambient odors and objective content analysis when studying emotions in memories. PMID- 20923082 TI - Recognizing odors associated with meaningful places. AB - Thirty-two undergraduates inhaled odors while outlining episodes, set in 8 living rooms, involving either themselves or the actual inhabitants. They rated odors, rooms, and episodes on 7-point scales and were tested for odor recognition. Episodes were content analyzed, and the frequency of categories was assessed. Separate factor analyses determined relationships between rating scales and content analysis categories. Regression analysis showed greater odor recognition when participants judged the odor to fit the imagined episode but less recognition when an unpleasant odor was incongruously paired with a warm episode. Odor recognition also was greater when the narrative outlines described familiar characters figuring out the scenes. Results supported the congruity hypothesis, whereby odors become markers for meaningful scenes with which they fit. PMID- 20923083 TI - The impact of domain and subject specialization on knowledge organization. AB - Thematic organization is the association of information that is observed within a given time frame or event, and taxonomic organization is characterized by class membership based on featural overlap. Research in cognitive psychology has suggested a developmental progression in preference from thematic organization to taxonomic organization, with a preference for taxonomic organization seen as cognitively more advanced. However, recent research has found thematic preferences in adults and shown that organizational preference can be influenced by context and experience. This study expanded on previous findings of individual differences and explored preferences across different domains. Specifically, preferences for knowledge organization were measured between student type (history and psychology) and across content type (general and history). The results indicated that history material was more likely to be organized thematically than general material. PMID- 20923084 TI - Memes and their themata. AB - When it is instantiated as a neuronal state, a meme is characterized as a phenotype in a novel neuronal sense. A thema is an instantiation of a meme as a conscious experience (a thought-meme). It is a primitive to which no location may be attributed, and it serves as a canonical representative of a class of memes. Memes in such a class may have physical or ideal (Platonic) instantiations. Pairing of this memetic phenotype characterization with the ideal thematic primitive is an example of other pairings in nature that are identified, and in particular it informs a description of the pairing of the unconscious mind and manifestations of consciousness. Interrelationship of these pairings is what illuminates aspects of each of them. These constructs support introduction of a consciousness thesis and then a notion of a dynamic self-referential grammar that generates a growing repertoire of consciousness manifestations. A method showing how a neuronal state generates a specific concept (thema) is introduced, and a sample of a class of examples is given. Pointers to experiments relevant to development of the thesis are given. PMID- 20923085 TI - Credibility judgments of narratives: language, plausibility, and absorption. AB - Two experiments were conducted in order to find out whether textual features of narratives differentially affect credibility judgments made by judges having different levels of absorption (a disposition associated with rich visual imagination). Participants in both experiments were exposed to a textual narrative and requested to judge whether the narrator actually experienced the event he described in his story. In Experiment 1, the narrative varied in terms of language (literal, figurative) and plausibility (ordinary, anomalous). In Experiment 2, the narrative varied in terms of language only. The participants' perceptions of the plausibility of the story described and the extent to which they were absorbed in reading were measured. The data from both experiments together suggest that the groups applied entirely different criteria in credibility judgments. For high-absorption individuals, their credibility judgment depends on the degree to which the text can be assimilated into their own vivid imagination, whereas for low-absorption individuals it depends mainly on plausibility. That is, high-absorption individuals applied an experiential mental set while judging the credibility of the narrator, whereas low-absorption individuals applied an instrumental mental set. Possible cognitive mechanisms and implications for credibility judgments are discussed. PMID- 20923086 TI - Testing the attention shift hypothesis as an account for the flanker sequence based congruency modulation in spatial flanker tasks. AB - Smaller Simon effects when stimulus locations are repeated on successive trials rather than alternated have been explained by the attention shift hypothesis, suggesting that shifts of attention result in interfering response codes. We investigated whether the attention shift hypothesis can also explain smaller flanker effects for repeated flankers than for alternated flankers, which occur only with directional information. In 3 peripheral letter identification tasks, target locations were cued by partial or complete flanker stimuli. Experiments 1 and 2 showed that directional flankers elicit shifts of attention. However, Experiment 3 revealed that directional flankers induced inverted cuing effects when reacting to the central target arrow was additionally required. These results are difficult to reconcile with the attention shift hypothesis as an explanation for the congruency reduction with repetitions of directional flankers. PMID- 20923087 TI - How the behavioral approach system predicts everyday life outcomes. AB - This study tested crucial components of Gray's reinforcement sensitivity theory that have generally been overlooked in the literature. We tested whether the perceived amount of reward moderates the behavioral approach system (BAS) and the importance of reward mediates BAS in the prediction of job satisfaction and organizational commitment. Results from 514 participants employed in part-time and full-time jobs provided support for our model, such that the indirect effect of BAS through the importance of reward was strongest when reward was provided. This model advances our understanding of reinforcement sensitivity theory and offers a solid foundation for predicting outcomes in everyday life. PMID- 20923088 TI - Monitoring of non-point source pollutants load from a mixed forest land use. AB - The aim of this study was to determine the unit load of NPS (non-point source) pollutants including organic variables such as BOD (biochemical oxygen demand), COD (chemical oxygen demand) and DOC (dissolved organic carbon), nitrogen and phosphorus constituents, and suspended solids (SS) and their event mean concentration (EMC) of runoff flows from a water-shed of mixed forest land use by intensive field experiments. Field monitoring for continuous measurements of rainfall, flow, and water quality was conducted over 12 storm events during 2008 2009 using automated and manual sampling methods. The EMCs of individual runoff event were estimated for each water quality constituent based on the flow rate and concentration data of runoff discharge. The average EMCs of BOD, COD, DOC, SS, TN (total nitrogen), NH4(+)-N, NO3(-)-N, TP (total phosphorus), PO4(3-)-P from the mixed forest land were 1.794, 3.498, 1.462, 10.269, 0.862, 0.044, 0.634, 0.034, and 0.005 mg/L, respectively. The annual unit loads of BOD, COD, DOC, SS, TN, NH4(+)-N, NO3(-)-N, TP and PO4(3-)-P were estimated as 66.9, 133.2, 55.5, 429.8, 36.5, 1.6, 26.9, 1.3 and 0.1 kg/(ha x yr), respectively. In addition, affecting parameters on the EMCs were investigated by statistic analysis of the field data. As a result, significant correlations with precipitation, rainfall intensity, and total runoff flows were found in most constituents. PMID- 20923089 TI - Understanding nutrient build-up on urban road surfaces. AB - This article discusses the outcomes of a research project on nutrients build-up on urban road surfaces. Nutrient build-up was investigated on road sites belonging to residential, industrial and commercial land use. Collected build-up samples were separated into five particle size ranges and were tested for total nitrogen (TN), total phosphorus (TP) and sub species of nutrients, namely, NO2-, NO3-, TKN and PO4(3-). Multivariate analytical techniques were used to analyse the data and to develop detailed understanding on buildup. Data analysis revealed that the solids loads on urban road surfaces are highly influenced by factors such as land use, antecedent dry period and traffic volume. However, the nutrient build-up process was found to be independent of the type of land use. It was solely dependent on the particle size of solids build-up. Most of the nutrients were associated with the particle size range < 150 microm. Therefore, the removal of particles below 150 microm from road surfaces is of importance for the removal of nitrogen and phosphorus from road surface solids build-up. It is also important to consider the difference in the composition of nitrogen and phosphorus build-up in the context of designing effective stormwater quality mitigation strategies. PMID- 20923090 TI - Restoration of Koggala lagoon: modelling approach in evaluating lagoon water budget and flow characteristics. AB - Groyne system modification is described related to restoration efforts to Koggala lagoon, Sri Lanka.The large-scale unplanned sand removal at the lagoon mouth shifted the formation of sand bar towards the lagoon and made adverse effects on its ecosystem. After the removal of the natural sand bar, groyne system was constructed to avoid sand deposition in the lagoon and to protect the highway bridge (across the lagoon outlet channel) from the wave attack. The existing groyne system resulted the lagoon mouth being permanently open to sea which in turn led to many environmental problems. Groyne system modification is proposed in this study to reduce the sea water intrusion. Water budget and two-dimensional depth averaged hydrodynamic model were developed for understanding the hydrologic and flow characteristics of the lagoon. Numerical experiments was performed at lagoon mouth area for two cases: (1) existing condition and (2) proposed rubble mound groyne system condition. Comparison of results was obtained for both cases to describe flow pattern at lagoon mouth. Results further showed, the width should be reduced to a maximum of 40 m. Proposed mouth width (40 m) pushed the salting factor towards 0.5 from 0.68. Salting factor reduction with the groyne modification may result a predominant influence of fresh water which may in turn lead lagoon to a fresh water ecosystem. PMID- 20923091 TI - Evaluation of the effectiveness of horizontal subsurface flow constructed wetlands for different media. AB - Two media bed (gravel and Filtralite NR) were tested in a mesocosm to evaluate the removal of organic matter (as chemical oxygen demand (COD)), ammonia (NH4-N), nitrite, nitrate and solid matter (as total suspended solids (TSS)) for a synthetic wastewater (acetate-based) and a domestic wastewater. The use of Filtralite allowed average removal rates (6-16.8 g COD/(m2 x day), 0.8-1.1 g NH4 N/(m2 x day) and 3.1 g TSS/(m2 x day)) and removal efficiencies (65%-93%, 57%-85% and 78% for COD, NH4-N and TSS, respectively), higher than that observed in the experiments with gravel. The applied loads of COD, ammonia, nitrate and TSS seem to influence the respective removal rates but only for the treatment of domestic wastewater with higher correlation coefficients for Filtralite. Regardless the type of media bed and the type of wastewater, nitrate was completely removed for nitrogen loading rates up to 1.3 g NO3-N/(m2 x day). There was no evidence of the influence of nitrate loads on the removal of organic matter. PMID- 20923092 TI - Evaluation of non-point source pollution reduction by applying best management practices using a SWAT model and QuickBird high resolution satellite imagery. AB - This study evaluated the reduction effect of non-point source pollution by applying best management practices (BMPs) to a 1.21 km2 small agricultural watershed using a SWAT (Soil and Water Assessment Tool) model. Two meter QuickBird land use data were prepared for the watershed. The SWAT was calibrated and validated using daily streamflow and monthly water quality (total phosphorus (TP), total nitrogen (TN), and suspended solids (SS)) records from 1999 to 2000 and from 2001 to 2002. The average Nash and Sutcliffe model efficiency was 0.63 for the streamflow and the coefficients of determination were 0.88, 0.72, and 0.68 for SS, TN, and TP, respectively. Four BMP scenarios viz. the application of vegetation filter strip and riparian buffer system, the regulation of Universal Soil Loss Equation P factor, and the fertilizing control amount for crops were applied and analyzed. PMID- 20923093 TI - Modeling the effects of constructed wetland on nonpoint source pollution control and reservoir water quality improvement. AB - This article describes the integrated modeling approach for planning the size and the operation of constructed wetlands for maximizing retention of nonpoint source pollutant loads and reservoir water-quality improvement at a catchment scale. The experimental field-scale wetland systems (four sets, 0.88 ha each) have been in operation since 2002, where water depth was maintained at 30-50 cm and hydraulic loading rate was at 6.3-18.8 cm/day. The wetland system was found to be adequate for treating polluted stream water with stable removal efficiency even during the winter. The integrated modeling system (modified-BASINS) was applied to the Seokmoon estuarine reservoir watershed and calibrated with monitoring data from constructed wetland, stream, and reservoir. The calibrated integrated modeling system estimated that constructing wetlands on 0.5% (about 114 ha) of the watershed area at the mouth of reservoir could reduce 11.61% and 13.49% of total external nitrogen and phosphorus loads, respectively. It also might improve the nitrogen and phosphorus concentration of the reservoir by 9.69% and 16.48%, respectively. The study suggested that about 0.1%-1.0% of the watershed area should be allocated for constructed wetland to meet specified water-quality standards for the estuarine reservoir at the polder area where land use planning is relatively less complicated. PMID- 20923094 TI - Predicting the impacts of climate change on nonpoint source pollutant loads from agricultural small watershed using artificial neural network. AB - This study described the development and validation of an artificial neural network (ANN) for the purpose of analyzing the effects of climate change on nonpoint source (NPS) pollutant loads from agricultural small watershed. The runoff discharge was estimated using ANN algorithm. The performance of ANN modelwas examined using observed data from s tudy watershed. The simulationresults agreed well with observed values during calibration and validation periods. NPS pollutant loads were calculated from load-discharge relationship driven by long-term monitoring data. LARS-WG (Long Ashton Research Station-Weather Generator) model was used to generate rainfall data. The calibrated ANN model and load-discharge relationship with the generated data from LARS-WGwere applied to analyze the effects of climate change on NPS pollutant loads from the agricultural small watershed. The results showed that the ANN model provided valuable approach i n estimating future runof f discharge, and the NPS pollutantloads. PMID- 20923095 TI - Evaluation of the relationship between two different methods for enumeration fecal indicator bacteria: colony-forming unit and most probable number. AB - Most probable number (MPN) and colony-forming unit (CFU) estimates of fecal indicator bacteria (FIB) concentration are common measures of water quality in aquatic environments. Thus, FIB intensively monitored in Yeongsan Watershed in an attempt to compare two different methods and to develop a statistical model to convert from CFU to MPN estimates or vice versa. As a result, the significant difference was found in the MPN and CFU estimates. The enumerated Escherichia coli concentrations in MPN are greater than those in CFU, except for the measurement in winter. Especially in fall, E. coli concentrations in MPN are one order of magnitude greater than that in CFU. Contrarily, enterococci bacteria in MPN are lower than those in CFU. However, in general, a strongly positive relationship are found between MPN and CFU estimates. Therefore, the statistical models were developed, and showed the reasonable converting FIB concentrations from CFU estimates to MPN estimates. We expect this study will provide preliminary information towards future research on whether different analysis methods may result in different water quality standard violation frequencies for the same water sample. PMID- 20923096 TI - Assessment of physically-based and data-driven models to predict microbial water quality in open channels. AB - In the present study, a physically-based hydraulic modeling tool and a data driven approach using artificial neural networks (ANNs) were evaluated for their ability to simulate the fate and transport of microorganisms in a water system. To produce reliable data, a pipe network was constructed and a series of experiments using a fecal coliform indicator (Escherichia coli 15597) was conducted. For the physically-based model, morphological (pipe size, link length, slope, etc.) and hydraulic (flow rate) conditions were used as input variables, and for ANNs, water quality parameters (conductivity, pH, and turbidity) were used. Both approaches accurately described the fate and transport of microorganisms (physically-based model: correlation coefficient (R) in the range of 0.914-0.977 and ANNs: R in the range of 0.949 - 0.980), with the exception of one case at a low flow rate (q = 31.56 cm3/sec). This study also indicated that these approaches could be complementarily utilized to assess the vulnerability of water facilities and to establish emergency plans based on hypothetical scenarios. PMID- 20923097 TI - Ecotoxicological assessment of diffuse pollution using biomonitoring tool for sustainable land use in Thailand. AB - As a developing country, Thailand has a significant issue with diffuse pollution of the soil ecosystem due to an indiscriminate use of agrichemicals and poorly regulated disposal of a wide variety of hazardous wastes. Practical risk assessment tools based on locally-occurring species are needed to assess the effects of diffuse pollutants on the soil ecosystem in Thailand because reliance on soil criteria developed for overseas conditions may provide inadequate protection. Native soil organisms in Thailand may be more or less sensitive to contaminants compared to overseas test species. This article described a biological indicator approach for ecological risk assessment of diffuse pollution in the soil ecosystem of Thailand from pesticide application with the aim of developing standardized protocols using native species and locally generated data to better evaluate the ecological risks of non-point source soil pollution. It was found that ecotoxicological assessment provided a better understanding of the ecological impacts that diffuse pollution induced on Thai environmental conditions. Thai soil biota species were more sensitive to soil contaminants than similar species overseas. Soil series also had an influence on the ecotoxicology of contaminants to soil biota. Collembolan, Cyphoderus sp., was demonstrated as a useful alternative test species to Folsomia candida (international test species) for terrestrial ecotoxicological testing of Thai soils. In addition, the soil biota activities such as soil respiration and earthworm avoidance including soil biodiversity and the litter bag decomposition technique are also good tools to assess the effects of diffuse pollution by pesticides on the soil ecosystem of Thailand. PMID- 20923098 TI - Control of petroleum-hydrocarbon contaminated groundwater by intrinsic and enhanced bioremediation. AB - In the first phase of this study, the effectiveness of intrinsic bioremediation on the containment of petroleum hydrocarbons was evaluated at a gasoline spill site. Evidences of the occurrence of intrinsic bioremediation within the BTEX (benzene, toluene, ethylbenzene, and xylenes) plume included (1) decreased BTEX concentrations; (2) depletion of dissolved oxygen (DO), nitrate, and sulfate; (3) production of dissolved ferrous iron, methane, and CO2; (4) deceased pH and redox potential; and (5) increased methanogens, total heterotrophs, and total anaerobes, especially within the highly contaminated areas. In the second phase of this study, enhanced aerobic bioremediation process was applied at site to enhance the BTEX decay rates. Air was injected into the subsurface near the mid plume area to biostimulate the naturally occurring microorganisms for BTEX biodegradation. Field results showed that enhanced bioremediation process caused the change of BTEX removal mechanisms from anaerobic biodegradation inside the plume to aerobic biodegradation. This variation could be confirmed by the following field observations inside the plume due to the enhanced aerobic bioremediation process: (1) increased in DO, CO2, redox potential, nitrate, and sulfate, (2) decreased in dissolved ferrous iron, sulfide, and methane, (3) increased total heterotrophs and decreased total anaerobes. Field results also showed that the percentage of total BTEX removal increased from 92% to 99%, and the calculated total BTEX first-order natural attenuation rates increased from 0.0092% to 0.0188% per day, respectively, after the application of enhanced bioremediation system from the spill area to the downgradient area (located approximately 300 m from the source area). PMID- 20923099 TI - Forecasting the effects of EU policy measures on the nitrate pollution of groundwater and surface waters. AB - We used the interdisciplinary model network AGRUM [corrected] to predict the actual mean nitrate concentration in percolation water at the scale of the Weser river basin (Germany) using an area differentiated (100 m x 100 m) approach. AGRUM [corrected] combines the agro-economic model RAUMIS for estimating nitrogen surpluses and the hydrological models GROWA/DENUZ for assessing the nitrate leaching from the soil. For areas showing predicted nitrate concentrations in percolation water above the European Union (EU) groundwater quality standard of 50 mg NO3-N/L, effective agri-environmental reduction measures need to be derived and implemented to improve groundwater and surface water quality by 2015. The effects of already implemented agricultural policy are quantified by a baseline scenario projecting the N-surpluses from agricultural sector to 2015. The AGRUM [corrected] model is used to estimate the effects of this scenario concerning groundwater and surface water pollution by nitrate. From the results of the model analysis the needs for additional measures can be derived in terms of required additional N-surplus reduction and in terms of regional prioritization of measures. Research work will therefore directly support the implementation of the Water Framework Directive of the European Union in the Weser basin. PMID- 20923100 TI - Scenario analysis for reduction of pollutant load discharged from a watershed by recycling of treated water for irrigation. AB - A model in which a river model was layered on a distributed model (double-layered model) was developed to analyse the transport of water and pollutants (nitrogen, phosphorus, and BOD as organic matter) in watersheds and rivers. The model was applied to the watershed of Abragafuchi Lake, Japan, where serious water pollution has occurred over three decades, and the applicability of the model was demonstrated. Scenarios of recycling of sewage treated-water into agriculture to reduce pollutant load discharged into the lake were analysed. The results showed that irrigating paddy fields with the sewage-treated water could contribute to conserving water and reducing pollutant load, with reduction rate in BOD, nitrogen, and phosphorus ranging from 6%-36%, 16%-46%, and 18%-51%, respectively. Particularly, the results indicated that, irrigating paddy fields with the treated water during non-cropping periods and the accompanying reduction in withdrawn water from the river were more effective in reducing pollutant loads discharged into the lake. Further study is required on the effect of recycled water on crop cultivation and soil conditions for safe implementation. PMID- 20923101 TI - Water-saving irrigation of paddy field to reduce nutrient runoff. AB - The purpose of this work is to study the effect of a type of water-saving irrigation (WSI) on nutrient runoff of paddy field. The volume of surface drainage was maintained low by WSI. In particular, WSI effectively reduced surface drainage in rain events. Model simulation indicated that net runoff load of total nitrogen (TN) from the paddy field was increased by WSI. Meanwhile, net runoff loads of total phosphorus (TP) and total organic carbon (TOC) from the paddy field was decreased by WSI. Because ponding waters of the study fields were enriched with TP and TOC, WSI reduced runoff of these nutrients by controlling the volume of surface drainage. WSI could be considered an efficient method for reducing runoff loads and could conserve water quality in an agricultural watershed. PMID- 20923102 TI - Natural purification effects in the river in consideration with domestic wastewater pollutant discharge reduction effects. AB - The first social experiment program in Japan to reduce domestic wastewater pollutant discharge by "soft interventions" in households has been conducted in the Yamato-gawa River drainage area since 2005. The Yamato-gawa River has been listed as one of the worst water quality rivers in Japan because of the larger annual average BOD. "Hard interventions" including deployment of wastewater treatment facilities and artificial installation of natural purification facilities in the river has been conducted in these years to improve river water quality. At the first Yamato-gawa River social experiment program (YR-SEP) in March 2005, BOD at the monitoring point near the river mouth decreased about 6% during the Program. Natural purification effect along the river was evaluated in this article with one-dimensional water quality model for the six river sections. Larger biological oxygen consumption rate, kb, was estimated in the sections with artificially installed natural purification facilities. The effect of "soft interventions" in households in the YR-SEP was estimated as 25% BOD decrease in the nearest monitoring point to the river mouth, when all the households participate in the Program and BOD discharge reduction rate with "soft interventions" in households was 40%. PMID- 20923103 TI - Classification of different sustainable flood retention basin types. AB - Using a revised version of a previously published expert classification system, a database of potential Sustainable Flood Retention Basins has been developed for Scotland. The research shows that the majority of small and former (often old) drinking water reservoirs are kept full and their spillways are continuously in operation. Utilising some of the available capacity to contribute to flood control could significantly reduce the costs of complying with the European Union Flood Directive. Furthermore, the application of a previously developed classification model for Baden in Germany for the Scottish data set showed a lower diversity for basins in Scotland due to less developed infrastructure. The classification system appears to be robust and has the potential, with minor modifications, to be applied across Europe. The principle value of this approach is a clear and unambiguous categorisation, based on standard variables, which can help to promote communication and understanding between stakeholders. PMID- 20923104 TI - Parameter determination to calculate water environmental capacity in Zhangweinan canal sub-basin in China. AB - Zhangweinan canal sub-basin (ZWN) has the most serious water resource shortage and water pollution problems in north of China. To calculate the water environmental capacity in ZWN, determination methods for design flow rates and degradation coefficients were discussed in this study. Results showed that 90% and 50% hydrological guarantee flow rates were suitable to be the design flow rates for rainy and dry seasons, respectively. Degradation coefficients of COD(Mn) and NH3-N were 0.25 day(-1) and 0.15 day(-1) for branch streams and 0.5 day(-1) and 0.25 day(-1) for mainstreams, respectively in ZWN. With one dimensional water quality simulation model, water environmental capacities were calculated to be 82,139 tons/yr for COD(Mn) and 2394 tons/yr for NH3-N in ZWN. PMID- 20923105 TI - Effect of a seasonal diffuse pollution migration on natural organic matter behavior in a stratified dam reservoir. AB - This article aims to describe the influence of diffuse pollution on the temporal and spatial characteristics of natural organic matter (NOM) in a stratified dam reservoir, the Daecheong Dam, on the basis of intensive observation results and the dynamic water quality simulation using CE-QUAL-W2. Turbidity is regarded as a comprehensive representation of allochothonous organic matter from diffuse sources in storm season because the turbidity concentration showed reasonable significance in a statistical correlation with the UV absorbance at 254 nm and total phosphorus. CE-QUAL-W2 simulation results showed good consistency with the observed data in terms of dissolved organic matter (DOM) including refractory dissolved organic carbon (RDOC) and labile DOC and also well explained the internal movement of constituents and stratification phenomenon in the reservoir. Instead turbidity and NOM were related well in the upper region of the reservoir according to flow distance, gradually as changing to dissolved form of organic matter, RDOM affected organic matter concentration of reservoir water quality compared to turbidity. To control the increase of soluble organic matters in the dam reservoir, appropriate dam water discharge gate operation provided effective measurement. Because of the gate operation let avoid the accumulation of organic matter within a dam reservoir by shorten of turbid regime retention time. PMID- 20923106 TI - Probability mass first flush evaluation for combined sewer discharges. AB - The Korea government has put in a lot of effort to construct sanitation facilities for controlling non-point source pollution. The first flush phenomenon is a prime example of such pollution. However, to date, several serious problems have arisen in the operation and treatment effectiveness of these facilities due to unsuitable design flow volumes and pollution loads. It is difficult to assess the optimal flow volume and pollution mass when considering both monetary and temporal limitations. The objective of this article was to characterize the discharge of storm runoff pollution from urban catchments in Korea and to estimate the probability of mass first flush (MFFn) using the storm water management model and probability density functions. As a result of the review of gauged storms for the representative using probability density function with rainfall volumes during the last two years, all the gauged storms were found to be valid representative precipitation. Both the observed MFFn and probability MFFn in BE-1 denoted similarly large magnitudes of first flush with roughly 40% of the total pollution mass contained in the first 20% of the runoff. In the case of BE-2, however, there were significant difference between the observed MFFn and probability MFFn. PMID- 20923107 TI - Effects of land use change and water reuse options on urban water cycle. AB - The aim of this article was to study the effects of land use change and water reuse options on an urban water cycle. A water cycle analysis was performed on the Goonja drainage basin, located in metropolitan Seoul, using the Aquacycle model. The chronological effects of urbanization were first assessed for the land uses of the Goonja drainage basin from 1975 to 2005, where the ratio of impervious areas ranged from 43% to 84%. Progressive urbanization was identified as leading to a decrease in evapotranspiration (29%), an increase in surface runoff (41%) and a decrease in groundwater recharge (74%), indicating a serious distortion of the water cycle. From a subsequent analysis of the water reuse options, such as rainwater use and wastewater reuse, it is concluded that wastewater reuse seemed to have an advantage over rainwater use for providing a consistent water supply throughout the year for a country like Korea, where the rainy season is concentrated during the summer monsoon. PMID- 20923108 TI - Mortality rates of pathogen indicator microorganisms discharged from point and non-point sources in an urban area. AB - This research measured the mortality rates of pathogen indicator microorganisms discharged from various point and non-point sources in an urban area. Water samples were collected from a domestic sewer, a combined sewer overflow, the effluent of a wastewater treatment plant, and an urban river. Mortality rates of indicator microorganisms in sediment of an urban river were also measured. Mortality rates of indicator microorganisms in domestic sewage, estimated by assuming first order kinetics at 20 degrees C were 0.197 day(-1), 0.234 day(-1), 0.258 day(-1) and 0.276 day(-1) for total coliform, fecal coliform, Escherichia coli, and fecal streptococci, respectively. Effects of temperature, sunlight irradiation and settlement on the mortality rate were measured. Results of this research can be used as input data for water quality modeling or can be used as design factors for treatment facilities. PMID- 20923109 TI - Salinity intrusion characteristics analysis using EFDC model in the downstream of Geum River. AB - As social interest in the environmental conservation and ecological restoration has recently increased, more research works have been done to resolve problems concerning environmental management of estuaries. In this study, a three dimensional numerical model, Environmental Fluid Dynamics Code (EFDC) was used in the analysis of the salinity intrusion characteristics in the downstream of Geum River. The numerical simulation was performed to investigate the influence range for salinity intrusion when the gates were fully opened. The conditions used for simulation were the four flow regimes in Geum River Basin, Korea. Results indicated that the ranges of salinity intrusion from the barrage were 50.72 km (drought flow), 48.87 km (low flow), 46.56 km (normal flow) and 42.10 km (flood flow). These results indicated that the EFDC model used for numerical simulation has high accuracy. The result concluded in this study can be used as a basis in understanding the extent of salinity intrusion effects at different flow rates. PMID- 20923110 TI - Characteristics of contaminants in water and sediment of a constructed wetland treating piggery wastewater effluent. AB - Constructed wetland (CW) is the preferred means of controlling water quality because of its natural treatment mechanisms and function as a secondary or tertiary treatment unit. CW is increasingly applied in Korea for secondary effluent of livestock wastewater treatment. This study was conducted to recognize the characteristics of contaminants in the accumulated sediment at the bottom soil layer and to reduce the phosphorus release from sediments of the free water surface CW for the treatment of secondary piggery wastewater effluent from a livestock wastewater treatment facility. The results revealed that the dominant phosphorus existence types at near the inlet of the CW were non-apatite phosphorus (59%) and residual phosphorus (32%) suggesting that most of the particles of the influent are made up of inorganic materials and dead cells. Sediment accumulation is important when determining the long-term maintenance requirements over the lifetime of CW. Continuous monitoring will be performed for a further assessment of the CW system and design. PMID- 20923111 TI - Multiple linear regression models of urban runoff pollutant load and event mean concentration considering rainfall variables. AB - Rainfall is an important factor in estimating the event mean concentration (EMC) which is used to quantify the washed-off pollutant concentrations from non-point sources (NPSs). Pollutant loads could also be calculated using rainfall, catchment area and runoff coefficient. In this study, runoff quantity and quality data gathered from a 28-month monitoring conducted on the road and parking lot sites in Korea were evaluated using multiple linear regression (MLR) to develop equations for estimating pollutant loads and EMCs as a function of rainfall variables. The results revealed that total event rainfall and average rainfall intensity are possible predictors of pollutant loads. Overall, the models are indicators of the high uncertainties of NPSs; perhaps estimation of EMCs and loads could be accurately obtained by means of water quality sampling or a long term monitoring is needed to gather more data that can be used for the development of estimation models. PMID- 20923112 TI - A review of probabilistic analysis in orthopaedic biomechanics. AB - Probabilistic analysis methods are being increasingly applied in the orthopaedics and biomechanics literature to account for uncertainty and variability in subject geometries, properties of various structures, kinematics and joint loading, as well as uncertainty in implant alignment. As a complement to experiments, finite element modelling, and statistical analysis, probabilistic analysis provides a method of characterizing the potential impact of variability in parameters on performance. This paper presents an overview of probabilistic analysis and a review of biomechanics literature utilizing probabilistic methods in structural reliability, kinematics, joint mechanics, musculoskeletal modelling, and patient specific representations. The aim of this review paper is to demonstrate the wide range of applications of probabilistic methods and to aid researchers and clinicians in better understanding probabilistic analyses. PMID- 20923113 TI - An in vitro investigation of image-guided steerable catheter navigation. AB - The objective of this study is to provide catheterization with a three dimensional (3D) guiding image and reduce the collision probability between the catheter tip and vascular wall. A bidirectional steerable catheter was integrated with two magnetic position-tracking sensors on both sides of its bending segment. The tracking information was displayed on the guiding image, which helped the surgeons to determine the relative position between the catheter tip and surrounding vessels. The navigation path was generated on the basis of the vascular skeleton. Moreover, along the path, a series of guiding circular planes were set as the guidance for the catheter. Three operations (bending, advancing, and twisting) were jointly conducted to get the catheter through these guiding planes in turn and eventually into the target vessel. The effectiveness of the proposed navigation method was verified by experiments implemented in an aorta vascular phantom. The navigation system has a mean error of 0.19 mm, a root mean square of 0.49 mm, and a standard deviation of 0.46 mm. PMID- 20923114 TI - A two-system, single-analysis, fluid-structure interaction technique for modelling abdominal aortic aneurysms. AB - This work reports on the implementation and validation of a two-system, single analysis, fluid-structure interaction (FSI) technique that uses the finite volume (FV) method for performing simulations on abdominal aortic aneurysm (AAA) geometries. This FSI technique, which was implemented in OpenFOAM, included fluid and solid mesh motion and incorporated a non-linear material model to represent AAA tissue. Fully implicit coupling was implemented, ensuring that both the fluid and solid domains reached convergence within each time step. The fluid and solid parts of the FSI code were validated independently through comparison with experimental data, before performing a complete FSI simulation on an idealized AAA geometry. Results from the FSI simulation showed that a vortex formed at the proximal end of the aneurysm during systolic acceleration, and moved towards the distal end of the aneurysm during diastole. Wall shear stress (WSS) values were found to peak at both the proximal and distal ends of the aneurysm and remain low along the centre of the aneurysm. The maximum von Mises stress in the aneurysm wall was found to be 408kPa, and this occurred at the proximal end of the aneurysm, while the maximum displacement of 2.31 mm occurred in the centre of the aneurysm. These results were found to be consistent with results from other FSI studies in the literature. PMID- 20923115 TI - An investigation of the flow field within patient-specific models of an abdominal aortic aneurysm under steady inflow conditions. AB - The flow fields within three patient-specific models of an abdominal aortic aneurysm (AAA) were investigated under steady laminar inflow conditions over a range of Reynolds numbers. Each model extended from the renal arteries to downstream of the iliac bifurcation. The aneurysms (referred to as models A, B, and C) are mature, with D/d ratios of 1.83, 1.57, and 1.95 respectively. The mass flowrates in each of the iliac arteries were equal. Using flow visualization it was observed that the flow proximally in the aneurysm was characterized by a primary jet that separated from either the posterior wall or the lateral wall or both, producing large recirculating zones. The primary jet impinged either normally or obliquely upon the anterior or right lateral wall in the distal half of the aneurysm, the flow distally in the aneurysm having been greatly disturbed. Measurements of the turbulence intensity along the median lumen centre-line showed that in each model the onset of transition and full turbulence occurred at Reynolds numbers much lower than those previously measured in idealized models. Computational fluid dynamics showed substantial differences in the velocity and stress fields when using the shear stress transport turbulence model as opposed to a laminar viscous model. It was also observed that turbulence was largely produced along the shear layers surrounding the primary jet and, in particular, at interfaces between the jet and the recirculating zones. In conclusion, turbulence may be expected to exist at Reynolds numbers typically encountered within an AAA, and it must be taken account of in an analysis of the flow field. PMID- 20923116 TI - Coupling of dynamics and contact mechanics of artificial hip joints in a pendulum model. AB - To date, fully coupled dynamics and contact mechanics analysis is still limited by expensive computational cost and long computing time and has not been addressed comprehensively, particularly in the hip joint. To understand the influence of different parameters on the biomechanics of the total hip replacement (THR) and improve its design, two numerical approaches were developed and implemented in finite element models to investigate the coupling between the dynamics response and the contact mechanics for three different THR configurations, metal-on-polyethylene (MOP), metal-on-metal (MOM), and ceramic-on ceramic (COC). The dynamic force and the contact pressure distribution at the bearing surfaces from the two methods were predicted and compared. The influences of various parameters (motion angle, load applied in the pendulum, friction coefficient, geometry, and material properties) were subsequently investigated. From the comparisons, the decoupled method, based on the rigid-body dynamics and the quasi-static elastic contact mechanics, was adequate to predict the performance of the THRs efficiently. The load had the greatest influence on the dynamics/contact mechanics among other factors. PMID- 20923117 TI - A Galerkin-type finite element solution for simulation of mass diffusion in the application of tissue engineering: heterogeneous and non-porous media. AB - This study is an effort to produce a generic and comprehensive solution to the simulation of mass diffusion through a multiphasic and heterogeneous material model. A Galerkin-type finite element formulation is developed to solve Fick's equation for steady-state and time-dependent analysis. The effect of the interface in modelling of a liquid-solid medium is presented in this work. To show the robustness of the proposed approach, the gas exchange (oxygen and carbon dioxide) process through the capillary network between the alveolar membrane and red blood cells has been analysed and then validated with experimental data. The current work is a significant asset to modelling the diffusion of oxygen between cells and scaffolds in tissue engineering or tissue regeneration/repair studies. It is one step towards the development of high-order elements for application of the simulation of mass transfer through a multiphasic and porous model with varying degrees of interconnectivity and pore size for tissue engineering applications. PMID- 20923118 TI - [Pathogenesis of Pseudomonas aeruginosa infections]. PMID- 20923119 TI - [Implication of quorum sensing phenomenon in the expression of genes that code for bacteriocines in lactic bacteria]. AB - Bacterial Quorum sensing and response or simply quorum sensing (QS) is an ubiquitous regulatory mechanism that allows a continuous monitoring of the cell density in bacterial communities and adequate responses/behaviour to the cellular density. Each cell in these communities produces and responds to a signalling molecule that belongs to some different compounds family: acyl-homoserine lactones (Gram negative bacteria), oligopeptides (Gram positive bacteria), A12 family (present in both Gram positive and Gram negative bacteria). For an efficient colonization and adaptation to different environmental conditions, lactic acid bacteria require complex sensor systems for the specific detection of the external signals. This function is mediated by the two component regulatory system composed of a histidine protein kinase (HK) with cell-membrane localisation that senses external signals, and a cytoplasmic response regulator (RR), that directly modulates the genome expression. Lactic acid bacteria synthesize bacteriocins depending on the cell density and thus implicating a QS regulatory mechanism. Bacteriocin production is an inducible mechanism that require an extracellular accumulation of some peptides, called peptide inductors, that function as an chemical messenger that activate the bacteriocin synthesis following the QS regulatory pathway. PMID- 20923120 TI - [Origin and evolution of human immunodeficiency viruses]. AB - After the diagnosis of the AIDS symptoms, in 1981, and after the discovery of the virus that causes AIDS, in 1983, the virologists have formulated different theories about its origin. Some of them involved natural causes, e.g., HIV origin from SIV strains. Other theories go further to the possibility of a deadly man made virus escaped from laboratories or voluntary spread by some conspirative organisations. At this moment, the scientists limits themselves to search proofs to sustain the zoonotic origin of HIV from SIV and its accomodation to human body conditions. PMID- 20923121 TI - [Rickettsia conorii infection in Romania, 2000-2008]. AB - OBJECTIVES: presenting the epidemiological aspects of Rickettsia conorii infection in Romania between 2000-2008. METHODS: A descriptive epidemiology study of Rickettsia conorii infection cases noticed in Romania between 2000-2008, which provide data regarding: time, place a4d person. The study also presents some risk factors. RESULTS: All cases were sporadic and were noticed in southern Romania. The highest incidence was registered in 2001 in Constanta district (44.2% per ten thousand inhabitants). The majority of cases were registred between April November with a maximum of cases in August (38%) The patients were mainly from urban areas (80%); The more affected age group was 45-54 year (25%). The most predominant clinical expression was the medium one (58% of cases). In 99% of the cases, the release status from the hospital was cured and the evolution of the illness was favorable. In this period were just 2 deceased In 96% of the confirmed cases the tick exposure has appeared within the contact with parasited animals and took place in 60% of cases at home. 4% of the cases recognaised a professional contact with parasitated animals. In 93% of the cases the reservoir was represented by the parasitated dog. CONCLUSION: The sporadic evolution of the cases demonstrated that the natural focality of the disease in Romania persists, the distribution of cases matches with that of Rickettsia conorii and its tick vectors and also with the period of greatest activity of the vector (Rhipicephalus sanguineous, specific for dogs). The disease clearly represents a public health problem whose magnitude is not known. PMID- 20923122 TI - Competition and the internet. PMID- 20923123 TI - Power hackers. PMID- 20923124 TI - The biggest bang theory. PMID- 20923125 TI - Closing the health gap. PMID- 20923126 TI - Question time. PMID- 20923127 TI - How we are evolving. PMID- 20923128 TI - Origami observatory. PMID- 20923129 TI - In science we trust. PMID- 20923130 TI - Revolution postponed. PMID- 20923131 TI - The (elusive) theory of everything. PMID- 20923132 TI - Robot be good. PMID- 20923133 TI - Sensational sucker. PMID- 20923134 TI - Desperate for an autism cure. PMID- 20923135 TI - Reinventing the leaf. PMID- 20923136 TI - Digitizer in chief. Interview by Michael Moyer. PMID- 20923137 TI - Can you hear me now? PMID- 20923138 TI - Dying to eat. PMID- 20923140 TI - Paper disk on screen printed electrode for one-step sensing with an internal standard. AB - A point-of-care device, an ideal application is to provide a direct answer for an analysis with only a simple sample introduction. In order to meet the requirements, reagents storage, and self-calibration must be integrated on the portable device. This study describes a device with a paper disk impregnated with reagents including an internal standard and buffer on a screen printed electrode leading to accurate result in a single-step assay. We demonstrated on the applicability of this device by detection of trace lead (ppb level) in 10 MUL solution based on the simultaneous (in situ) plating of bismuth and heavy metals onto electrode, which formed alloys followed by anodic stripping, Zn(II) was employed as an internal standard. We believe this approach is attractive for use in field based portable devices. PMID- 20923139 TI - The aging-associated enzyme CLK-1 is a member of the carboxylate-bridged diiron family of proteins. AB - The aging-associated enzyme CLK-1 is proposed to be a member of the carboxylate bridged diiron family of proteins. To evaluate this hypothesis and characterize the protein, we expressed soluble mouse CLK-1 (MCLK1) in Escherichia coli as a heterologous host. Using Mossbauer and EPR spectroscopy, we established that MCLK1 indeed belongs to this protein family. Biochemical analyses of the in vitro activity of MCLK1 with quinone substrates revealed that NADH can serve directly as a reductant for catalytic activation of dioxygen and substrate oxidation by the enzyme, with no requirement for an additional reductase protein component. The direct reaction of NADH with a diiron-containing oxidase enzyme has not previously been encountered for any member of the protein superfamily. PMID- 20923141 TI - Determination of intermediates and mechanism for soot combustion with NOx/O2 on potassium-supported Mg-Al hydrotalcite mixed oxides by in situ FTIR. AB - The soot combustion with NO(x) and/or O(2) on potassium-supported Mg-Al hydrotalcite mixed oxides under tight contact condition was studied using temperature-programmed oxidation (TPO), isothermal reaction and in situ FTIR techniques. The presence of NO(x) in O(2) favors the soot combustion at lower temperatures (<300 degrees C). However, a little suppression was observed at higher temperatures (>300 degrees C), which was accompanied by a substantial NO(x) reduction. The ketene (C?C?O) and isocyanate (NCO(-)) species were determined as the reaction intermediates. In NO(x) + O(2), NO(2) directly interacts with the free carbon sites (C?C*) through two parallel reactions: (1) NO(2) + C?C* -> C?C?O + NO; (2) NO(2) + C?C* -> NCO(-) + CO(2). The two reactions can proceed easily, which accounts for the promotion effect of NO(x) on soot combustion at lower temperatures. The further oxidation of NCO(-) by NO(2) or O(2) is responsible for the simultaneous reduction of NO(x). However, the reactions between NO(2) and C?C* are limited by the amount of free carbon sites, which can be provided by the oxidation of soot by O(2) at higher temperatures. The interaction of NO(x) and catalyst results in the formation of nitrates and nitrites, which poisoned the active K sites. PMID- 20923143 TI - Comment on "Submicrometer plate heights for capillaries packed with silica colloidal crystals". PMID- 20923142 TI - Investigation of sialylation aberration in N-linked glycopeptides by lectin and tandem labeling (LTL) quantitative proteomics. AB - The accuracy in quantitative analysis of N-linked glycopeptides and glycosylation site mapping in cancer is critical to the fundamental question of whether the aberration is due to changes in the total concentration of glycoproteins or variations in the type of glycosylation of proteins. Toward this goal, we developed a lectin-directed tandem labeling (LTL) quantitative proteomics strategy in which we enriched sialylated glycopeptides by SNA, labeled them at the N-terminus by acetic anhydride ((1)H(6)/(2)D(6)) reagents, enzymatically deglycosylated the differentially labeled peptides in the presence of heavy water (H(2)(18)O), and performed LC/MS/MS analysis to identify glycopeptides. We successfully used fetuin as a model protein to test the feasibility of this LTL strategy not only to find true positive glycosylation sites but also to obtain accurate quantitative results on the glycosylation changes. Further, we implemented this method to investigate the sialylation changes in prostate cancer serum samples as compared to healthy controls. Herein, we report a total of 45 sialylated glycopeptides and an increase of sialylation in most of the glycoproteins identified in prostate cancer serum samples. Further quantitation of nonglycosylated peptides revealed that sialylation is increased in most of the glycoproteins, whereas the protein concentrations remain unchanged. Thus, LTL quantitative technique is potentially an useful method for obtaining simultaneous unambiguous identification and reliable quantification of N-linked glycopeptides. PMID- 20923144 TI - Selective etching of graphene edges by hydrogen plasma. AB - We devised a controlled hydrogen plasma reaction at 300 degrees C to etch graphene and graphene nanoribbons (GNRs) selectively at the edges over the basal plane. Atomic force microscope imaging showed that the etching rates for single layer and few-layer (>=2 layers) graphene are 0.27 +/- 0.05 nm/min and 0.10 +/- 0.03 nm/min, respectively. Meanwhile, Raman spectroscopic mapping revealed no D band in the planes of single-layer or few-layer graphene after the plasma reaction, suggesting selective etching at the graphene edges without introducing defects in the basal plane. We found that hydrogen plasma at lower temperature (room temperature) or a higher temperature (500 degrees C) could hydrogenate the basal plane or introduce defects in the basal plane. Using the hydrogen plasma reaction at the intermediate temperature (300 degrees C), we obtained narrow, presumably hydrogen terminated GNRs (sub-5 nm) by etching of wide GNRs derived from unzipping of multiwalled carbon nanotubes. Such GNRs exhibited semiconducting characteristics with high on/off ratios (~1000) in GNR field effect transistor devices at room temperature. PMID- 20923145 TI - Fisetin inhibits lipopolysaccharide-induced macrophage activation and dendritic cell maturation. AB - Macrophages and dendritic cells are required for initiating innate immunity and adaptive immunity. Aberrant activation of macrophages and dendritic cells can cause detrimental immune responses; thus, agents effectively modulating their functions are of great clinical value. We herein investigated whether fisetin, a flavonoid prevalently present in fruits and vegetables, could inhibit macrophage activation and dendritic cell maturation. Fisetin suppressed LPS-induced NF kappaB activation, expression of pro-inflammatory proteins (TNF-alpha and iNOS), MMP-9 activity, and phagocytic activity in macrophages. Furthermore, upon LPS induced dendritic cell maturation, fisetin at nontoxic concentrations suppressed the expression of costimulatory molecules (CD80 and CD86), the production of cytokines (IL-12, IL-6, and TNF-alpha), and the endocytic activity of dendritic cells. Fisetin treatment significantly attenuated migration of dendritic cells into spleens and dendritic cell-mediated T cell activation in LPS-treated mice. Collectively, our data reveal that fisetin inhibits macrophage activation and impairs functional maturation of dendritic cells. PMID- 20923146 TI - Automated protein hydrolysis delivering sample to a solid acid catalyst for amino acid analysis. AB - In this study, we developed an automatic protein hydrolysis system using strong cation-exchange resins as solid acid catalysts. Examining several kinds of inorganic solid acids and cation-exchange resins, we found that a few cation exchange resins worked as acid catalysts for protein hydrolysis when heated in the presence of water. The most efficient resin yielded amounts of amino acids that were over 70% of those recovered after conventional hydrolysis with hydrochloric acid and resulted in amino acid compositions matching the theoretical values. The solid-acid hydrolysis was automated by packing the resin into columns, combining the columns with a high-performance liquid chromatography system, and heating them. The amino acids that constitute a protein can thereby be determined, minimizing contamination from the environment. PMID- 20923147 TI - Amyloid fibril polymorphism is under kinetic control. AB - Self-assembly of proteins into amyloid aggregates displays a broad diversity of morphologies, both at the protofibrillar and final fibrillar species. These polymorphic species can coexist at fixed experimental conditions, and their relative abundance can be controlled by changing the solvent composition, or stirring the solution. However, the extent to which external conditions regulate the equilibrium of morphologically distinct species is still unknown. Here we investigate the nucleation of distinct fibril morphologies using computer simulations of a simplified model of an amyloid polypeptide. Counterintuitively, the energetically less favorable fibril morphologies nucleate more frequently than the morphologies of higher stability for models with low aggregation propensity. The free-energy profiles of the aggregation process indicate that the nucleation barrier determines the population fractions of different fibril morphologies, i.e., amyloid polymorphism is under kinetic control. PMID- 20923148 TI - Effects of nitrate supply site on selenite uptake by rice roots. AB - Selenite uptake by rice roots is regulated by many factors. The goal of this paper was to study the effects of the nitrate supply site on selenite uptake by rice roots. Using the excised-root experiment system, we found that, due to anion anion interactions, nitrate can partly block the selenite uptake by rice roots by local action (a corporate supply of nitrate and selenite in the same portion). Using a split-root experiment system (whole-plant level), we found that (1) nitrate can also partly block selenite uptake by rice (roots and shoots) by local action; and that (2) under long-distance action (separate supply of nitrate and selenite in two different portions of the root), nitrate can partly facilitate selenite uptake by rice (roots and shoots), probably by regulating root glutathione content. Thus, our results suggest that nitrate can inhibit or facilitate selenite uptake by rice roots depending on the nitrate supply site. PMID- 20923149 TI - Synthesis, radical scavenging activity, protection during storage, and frying by novel antioxidants. AB - Novel antioxidants, derivatives of trolox, and selected phenolic acids have been prepared in good yields and fully characterized by (1)H NMR, (13)C NMR, and MS. Their antioxidant activities have been assessed by DPPH and ORAC assays, and during frying and accelerated storage tests. Novel phenolic compounds exhibited higher radical scavenging activities than both trolox and alpha-tocopherol. Trolox hydroxybenzoate showed a significantly higher protection than alpha tocopherol under storage conditions. All new antioxidants performed better than alpha-tocopherol under frying conditions. Moreover, their outstanding thermal stability makes them more valuable than alpha-tocopherol for frying applications. PMID- 20923150 TI - Identification of (E,E)-2,4-undecadienal from coriander (Coriandrum sativum L.) as a highly effective deodorant compound against the offensive odor of porcine large intestine. AB - The leaves of coriander ( Coriandrum sativum L.) exhibited a strong deodorizing effect against porcine internal organs (large intestine). The effective deodorizing compounds of coriander were identified by separating the volatile component of coriander, testing the effectiveness of each fraction against the offensive odor of porcine large intestine, and then identifying the compounds by GC-MS. The volatile component of coriander was first separated into six fractions (A-F) by preparative gas chromatography, and the deodorizing activity of each of these fractions against the offensive odor was measured. Fraction D, which showed the strongest deodorizing effect, was then separated into 12 subfractions by preparative GC. The deodorant activity of each subfraction was evaluated, and the deodorant compounds were identified by GC-MS. It was discovered that (E,E)-2,4 undecadienal was the most effective deodorizing compound. The deodorizing activity of (E,E)-2,4-undecadienal on the porcine large intestine increased as with concentration, reaching almost complete deodorizing ability at 10 ppb. PMID- 20923151 TI - Glycosylation of smoke-derived volatile phenols in grapes as a consequence of grapevine exposure to bushfire smoke. AB - The presence of glycosides of smoke-derived volatile phenols in smoke-affected grapes and the resulting wines of Chardonnay and Cabernet Sauvignon was investigated with the aid of high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). All volatile phenols studied (phenol, p-, m-, and o cresols, methylguaiacol, syringol, and methylsyringol) could be detected as glycosylated metabolites in smoke-affected grapes in a similar fashion to that previously reported for guaiacol. These phenolic glycosides were found in smoke affected grapes and wines at significantly elevated levels compared to those in non-smoked control grapes and wines. The extraction of these glycosides from grapes into wine was estimated to be 78% for Chardonnay and 67% for Cabernet Sauvignon. After acid hydrolysis, a large proportion of these phenolic glycosides in grapes (50%) and wine (92%) disappeared but the concentrations of volatile phenols determined by gas chromatography-mass spectrometry (GC-MS) were lower than expected. In the case of wine, the majority of the glycosides of phenol, cresols, guaiacol, and methylguaiacol were decomposed upon acid hydrolysis without releasing their respective aglycones, while syringol and methylsyringol were more effectively released. PMID- 20923152 TI - Measurement of protein-ligand binding constants from reaction-diffusion concentration profiles. AB - Protein-ligand dissociation constants, K(d), are determined precisely and down to the picomolar range from reaction-diffusion (RD) concentration profiles created by proteins diffusing through hydrogels functionalized with protein ligands. The RD process effectively amplifies the molecular-scale binding events into macroscopic patterns visible to the naked eye. The method is applicable to various protein-ligand pairs and does not require any prior knowledge about the protein structure. PMID- 20923153 TI - Orthogonality of SFC versus HPLC for small molecule library separation. AB - Preparative HPLC and HPLC-MS are well established as the methods of choice for purification of pharmaceutical library compounds. Recent advances in supercritical fluid chromatography (SFC) have now made SFC a viable alternative to HPLC for this application. One of the potential arguments for using SFC in place of, or in addition to, HPLC is that it may offer different selectivity and thus has the potential for improved separation success rates. In this paper, we examine relative success rates for SFC and HPLC in obtaining adequate selectivity for successful separation. Our results suggest that use of SFC in addition to HPLC may result in a slight (1-2%) improvement in success rate compared to use of HPLC alone. PMID- 20923154 TI - Debromination of polybrominated diphenyl ethers by nanoscale zerovalent iron: pathways, kinetics, and reactivity. AB - The debromination of selected polybrominated diphenyl ethers (PBDEs) by nanoscale zerovalent iron particles (nZVI) was studied to investigate the degradation pathways and the reaction kinetics of the PBDEs. The primary PBDE investigated was 2,3,4-tribromodiphenyl ether (BDE 21) to assess degradation pathways. nZVI could effectively debrominate the selected PBDEs into lower brominated compounds and diphenyl ether, a completely debrominated form of PBDEs. The susceptibility of the meta-bromine by nZVI was observed from the debromination tests for PBDEs with single-flanked (2,3-diBDE and 3,4-diBDE) and unflanked (three mono-BDEs) bromines. The stepwise debromination from n-bromo- to (n-1)-bromodiphenyl ether was observed as the dominant reaction process, although simultaneous multistep debromination seemed to be plausible for di-BDEs having two bromines adjacent on the same phenyl ring. The reaction rate constants were estimated by assuming the reaction between PBDEs and nZVI was a pseudo-first-order reaction and the rates decreased with fewer bromine substituents. The reaction rate constants were correlated with the heat of formation and the energy of the lowest unoccupied molecular orbital of the corresponding compounds, and these appear to be useful descriptors of relative reaction rates among PBDE homologue groups. PMID- 20923155 TI - Long-lasting hydrophilicity on nanostructured Si-incorporated diamond-like carbon films. AB - We investigated the long-lasting hydrophilic behavior of a Si-incorporated diamond-like carbon (Si-DLC) film by varying the Si fraction in DLC matrix through oxygen and nitrogen plasma surface treatments. The wetting behavior of the water droplets on the pure DLC and Si-DLC with the nitrogen or oxygen plasma treatment revealed that the Si element in the oxygen-plasma-treated Si-DLC films played a major role in maintaining a hydrophilic wetting angle of <10 degrees for 20 days in ambient air. The nanostructured patterns with a roughness of ~10 nm evolved because of the selective etching of the carbon matrix by the oxygen plasma in the Si-DLC film, where the chemical component of the Si-Ox bond was enriched on the top of the nanopatterns and remained for over 20 days. PMID- 20923156 TI - Oxygen precursor to the reactive intermediate in methanol synthesis by Cu-ZSM-5. AB - The reactive oxidizing species in the selective oxidation of methane to methanol in oxygen activated Cu-ZSM-5 was recently defined to be a bent mono(MU oxo)dicopper(II) species, [Cu(2)O](2+). In this communication we report the formation of an O(2)-precursor of this reactive site with an associated absorption band at 29,000 cm(-1). Laser excitation into this absorption feature yields a resonance Raman (rR) spectrum characterized by (18)O(2) isotope sensitive and insensitive vibrations, nuO-O and nuCu-Cu, at 736 (Delta(18)O(2) = 41 cm(-1)) and 269 cm(-1), respectively. These define the precursor to be a MU (eta(2):eta(2)) peroxo dicopper(II) species, [Cu(2)(O(2))](2+). rR experiments in combination with UV-vis absorption data show that this [Cu(2)(O(2))](2+) species transforms directly into the [Cu(2)O](2+) reactive site. Spectator Cu(+) sites in the zeolite ion-exchange sites provide the two electrons required to break the peroxo bond in the precursor. O(2)-TPD experiments with (18)O(2) show the incorporation of the second (18)O atom into the zeolite lattice in the transformation of [Cu(2)(O(2))](2+) into [Cu(2)O](2+). This study defines the mechanism of oxo-active site formation in Cu-ZSM-5. PMID- 20923158 TI - Ketene functionalized polyethylene: control of cross-link density and material properties. AB - The functionalization and cross-linking of polyethylene is synthetically challenging, commonly relying on highly optimized radical based postpolymerization strategies. To address these difficulties, a norbornene monomer containing Meldrum's acid is shown to be effectively copolymerized with polyethylene using a nickel alpha-iminocarbaxamidato complex, providing high melting, semicrystalline polymers with a tunable incorporation of the functional comonomer. Upon heating the copolymer to common polyethylene processing temperatures, the thermolysis of Meldrum's acid to ketene provides the desired reactive group. This simple and versatile methodology does not require small molecule radical sources or catalysts, and the dimerization of the in situ generated ketenes is shown to provide tunable cross-linking densities in polyethylene. Subsequent rheological and tensile experiments illustrate the ability to tune cross-linked polyethylene properties by comonomer incorporation and elucidate valuable structure/property relationships in these materials. This study illustrates the power of well-defined and synthetically accessible functional groups in polyolefin synthesis and functionalization. PMID- 20923159 TI - Glycopolypeptides via living polymerization of glycosylated-L-lysine N carboxyanhydrides. AB - The preparation of new glycosylated-L-lysine-N-carboxyanhydride (glyco-K NCA) monomers is described. These monomers employ C-linked sugars and amide linkages to lysine for improved stability without sacrificing biochemical properties. Three glyco-K NCAs were synthesized, purified, and found to undergo living polymerization using transition metal initiation. These are the first living polymerizations of glycosylated NCAs and were used to prepare well-defined, high molecular weight glycopolypeptides and block and statistical glycocopolypeptides. This methodology solves many long-standing problems in the direct synthesis of glycopolypeptides from N-carboxyanhydrides relating to monomer synthesis, purification, and polymerization and gives polypeptides with 100% glycosylation. These long chain glycopolypeptides have potential to be good mimics of natural high molecular weight glycoproteins. PMID- 20923160 TI - Self-patterned mixed phospholipid monolayers for the spatially selective deposition of metals. AB - Metal-reactive organosulfur groups were patterned onto mica and silicon surfaces by dewetting instabilities during the Langmuir-Blodgett (LB) deposition of phase separated mixed phospholipid monolayers. Monolayers were formed from binary mixtures of dipalmitoylphosphatidylcholine (DPPC), dilauroylphosphatidylcholine (DLPC), and their omega-methyldisulfide-dialkylphosphatidylcholine analogues, DSDPPC and DSDLPC. Patterns of highly parallel stripes of condensed DPPC or DSDPPC, protruding by 0.7-0.9 nm from a fluid matrix of DLPC or DSDLPC, were observed over areas extending at least 30 * 30 MUm(2) in the LB films. The average stripe width varied from ca. 150 to 500 nm, depending on the lipid composition and deposition pressure. X-ray photoelectron spectroscopy confirmed that the phospholipid-monolayer-bound methydisulfides react with Au vapor to form a gold-thiolate species. The adsorption of thermally evaporated Au, Ag, and Cu onto DSDPPC/DLPC and DPPC/DSDLPC patterns was investigated by field emission gun scanning electron microscopy (FEGSEM) and atomic force microscopy (AFM). A change in phase contrast is observed in FEGSEM and AFM over the methyldisulfide functionalized areas following metal deposition due to metal-thiolate bond formation. An increase in step height between the DSDPPC stripes and nonfunctionalized DLPC background following metal deposition, as well as the resistance of the metal-coated DSDPPC or DSDLPC regions to detergent extraction from the surface, attest to a selective metallization of the pattern. Our results indicate that the preferential adsorption of vapor-deposited metal onto the omega methyldisulfide-terminated phase occurs at submonolayer coverages. The chemical reactivity exhibited by the organosulfur-modified phospholipid LB films make these templates potentially interesting for the fabrication of solid-supported patterns of metal nanostructures. PMID- 20923161 TI - Autogenic synthesis of green- and red-emitting single-phase Pr(2)O(2)CO(3) and PrO(1.833) luminescent nanopowders. AB - This Article reveals a rare synthesis of pure Pr(2)O(2)CO(3) (POC) nanopowder by thermolysis (700 degrees C) of a single chemical precursor in an autogenic reaction. The autogenic thermolysis of praseodymium acetate is a solvent-free, efficient, and straightforward approach yielding luminescent POC nanoparticles. The as-prepared POC nanopowder converted to PrO(1.833) (PO) powder via combustion. Methodical morphological, structural, and compositional characterizations of POC and PO powders are carried out, supported by mechanistic elucidation and the photoluminescent properties. PMID- 20923162 TI - Electrically defined ferromagnetic nanodots. AB - While ferromagnetic nanodots are being widely studied from fundamental as well as application points of views, so far all the dots have been physically defined; once made, one cannot change their dimension or size. We show that ferromagnetic nanodots can be electrically defined. To realize this, we utilize an electric field to modulate the in-plane distribution of carriers in a ferromagnetic semiconductor (Ga,Mn)As film with a meshed gate structure having a large number of nanoscaled windows. PMID- 20923163 TI - Effect of different anchoring groups on the adsorption of photoactive compounds on the anatase (101) surface. AB - The effect of replacing the anchoring carboxylate groups in the Ru(H(2)dcbpy)(2)(NCS)(2) (H(2)dcbpy = 4,4'-dicarboxylic acid-2,2'- bipyridine) photoactive dye was studied by computational density functional theory (DFT) and time-dependent DFT (TD-DFT) methods. The main emphasis in the study was to compare a series of attaching groups, including COOH, B(OH)(2), PO(OH)(2), SO(2)(OH), OH, NO(2), and SiCl(3), by the relative adsorption strength and geometry of the sensitizer molecules on the anatase (101) surface. Additionally, the substituent effect on the absorption signals in simulated UV-vis spectra was calculated with isolated dye molecules. Most of the selected substituents produced only small changes in the absorption characteristics of the dyes. However, OH groups were found to show a quite large blue-shift compared to traditional COOH anchor groups in the simulated UV-vis spectra, while NO(2) groups had an opposite effect of red-shifting the signals. On the other hand, although the NO(2) substituents on the bipyridine ligands led to favorable absorption characteristics, the calculated adsorption strength of the NO(2) substituted bipyridine models on the surface of anatase (101) was much smaller than that of the COOH-substituted one, indicating that larger modifications are necessary for both attaching the dye molecules on the surface and for tuning the absorption properties of photoactive compounds in the DSSC applications. The computational methods utilized here proved to be an efficient tool to study the effect of subtle structural changes on the properties of the dye molecules. PMID- 20923164 TI - Evidence of solvent-gelator interaction in sugar-based organogel studied by field cycling NMR relaxometry. AB - The dynamics of bulk toluene and toluene confined in the 1,2-O-(1 ethylpropylidene)-alpha-D-glucofuranose gel was studied using (1)H field-cycling nuclear magnetic resonance relaxometry. The proton spin-lattice relaxation time T(1) was measured as a function of the magnetic field strength and temperature. The observed dispersion in the frequency range 10(4)-10(6) Hz for the relaxation rate of toluene in the gel system give evidence of the interaction between the toluene and the gelator aggregates. The data were interpreted in terms of the two fraction fast-exchange model. Additionally it was also shown that a cooling rate during gel preparation process influences the gel microstructure and leads to different gelator-solvent interactions as reflected in a different behavior of the proton spin-lattice relaxation rate of toluene within the gel observed at the low frequency range. PMID- 20923165 TI - Asymmetric Brownian motor driven by bubble formation in a hydrophobic channel. AB - The "asymmetric brownian ratchet model" is a variation of Feynman's ratchet and pawl system proposed. In this model, a system consisting of a motor and a rail has two binding states. One is the random brownian state, and the other is the asymmetric potential state. When the system is alternatively switched between these states, the motor can be driven in one direction. This model is believed to explain nanomotor behavior in biological systems. The feasibility of the model has been demonstrated using electrical and magnetic forces; however, switching of these forces is unlikely to be found in biological systems. In this paper, we propose an original mechanism of transition between states by bubble formation in a nanosized channel surrounded by hydrophobic atoms. This amounts to a nanoscale motor system using bubble propulsion. The motor system consists of a hydrophobic motor and a rail on which hydrophobic patterns are printed. Potential asymmetry can be produced by using a left-right asymmetric pattern shape. Hydrophobic interactions are believed to play an important role in the binding of biomolecules and molecular recognition. The bubble formation is controlled by changing the width of the channel by an atomic distance (~0.1 nm). Therefore, the motor is potentially more efficient than systems controlled by other forces, in which a much larger change in the motor position is necessary. We have simulated the bubble-powered motor using dissipative particle dynamics and found behavior in good agreement with that of motor proteins. Energy efficiency is as high as 60%. PMID- 20923166 TI - New synthesis of 3-trifluoromethylpyrroles by condensation of mesoionic 4 trifluoroacetyl-1,3-oxazolium-5-olates with phosphorus ylides. AB - Mesoionic 4-trifluoroacetyl-1,3-oxazolium-5-olates (1), obtained from the reaction of N-acyl-N-alkylglycines with trifluoroacetic anhydride, react with phosphorus ylides to give beta-trifluoromethylpyrroles (2) in good yields. The novel ring transformations of 1 into 2 occur via an initial attack of the ylide anions on the C-2 position of the ring. PMID- 20923167 TI - Acetyl radical production by the methylglyoxal-peroxynitrite system: a possible route for L-lysine acetylation. AB - Methylglyoxal is an alpha-oxoaldehyde putatively produced in excess from triose phosphates, aminoacetone, and acetone in some disorders, particularly in diabetes. Here, we investigate the nucleophilic addition of ONOO(-), known as a potent oxidant and nucleophile, to methylglyoxal, yielding an acetyl radical intermediate and ultimately formate and acetate ions. The rate of ONOO(-) decay in the presence of methylglyoxal [k(2,app) = (1.0 +/- 0.1) * 10(3) M(-1) s(-1); k(2) ~ 1.0 * 10(5) M(-1) s(-1)] at pH 7.2 and 25 degrees C was found to be faster than that reported with monocarbonyl substrates (k(2) < 10(3) M(-1) s( 1)), diacetyl (k(2) = 1.0 * 10(4) M(-1) s(-1)), or CO(2) (k(2) = 3-6 * 10(4) M( 1) s(-1)). The pH profile of the methylglyoxal-peroxynitrite reaction describes an ascendant curve with an inflection around pH 7.2, which roughly coincides with the pK(a) values of both ONOOH and H(2)PO(4)(-) ion. Electron paramagnetic resonance spin trapping experiments with 2-methyl-2-nitrosopropane revealed concentration-dependent formation of an adduct that can be attributed to 2-methyl 2-nitrosopropane-CH(3)CO(*) (a(N) = 0.83 mT). Spin trapping with 3,5-dibromo-4 nitrosobenzene sulfonate gave a signal that could be assigned to a methyl radical adduct [a(N) = 1.41 mT; a(H) = 1.35 mT; a(H(m)) = 0.08 mT]. The 2-methyl-2 nitrosopropane-CH(3)CO(*) adduct could also be observed by replacement of ONOO(-) with H(2)O(2), although at much lower yields. Acetyl radicals could be also trapped by added L-lysine as indicated by the presence of (epsilon)N-acetyl-L lysine in the spent reaction mixture. This raises the hypothesis that ONOO( )/H(2)O(2) in the presence of methylglyoxal is endowed with the potential to acetylate proteins in post-translational processes. PMID- 20923168 TI - Inflicting controlled nonthermal damage to subcellular structures by laser activated gold nanoparticles. AB - We show that low-intensity laser irradiation of cancer cells containing endosomal gold nanoparticles leads to endosome rupture and escape of the nanoparticles into the cytosol without affecting the cells' viability. The low light intensity of our experiments allows us to rule out photothermal effects as the underlying mechanism, and we present results that suggest photoinduced radicals as the photogenerated active species. This nonthermal mechanism may also be important in the context of cell death at higher laser intensities, which had been reported previously. PMID- 20923169 TI - High-throughput aided synthesis of the porous metal-organic framework-type aluminum pyromellitate, MIL-121, with extra carboxylic acid functionalization. AB - A new porous metal-organic framework (MOF)-type aluminum pyromellitate (MIL-121 or Al(OH)[H(2)btec].(guest), (guest = H(2)O, H(4)btec = pyromellitic acid) has been isolated by using a high-throughput synthesis method under hydrothermal conditions. Its structure was determined from powder X-ray diffraction analysis using synchrotron radiation (Soleil, France) and exhibits a network closely related to that of the MIL-53 series. It is a three-dimensional (3D) framework containing one-dimensional (1D) channels delimited by infinite trans-connected aluminum-centered octahedra AlO(4)(OH)(2) linked through the pyromellitate ligand. Here the organic ligand acts as tetradendate linker via two of the carboxylate groups. The two others remain non-bonded in their protonated form, and this constitutes a rare case of the occurrence of both bonding and non bonding organic functionalities of the MOF family. The non-coordinated -COOH groups points toward the channels to get them an open form configuration. Within the tunnels are located unreacted pyromellitic acid and water species, which are evacuated upon heating, and a porous MIL-121 phase is obtained with a Brunauer Emmett-Teller (BET) surface area of 162 m(2) g(-1). MIL-121 has been characterized by IR, thermogravimetry (TG) analyses, and solid state NMR spectroscopy employing a couple of two-dimensional (2D) techniques such as (1)H (1)H SQ-DQ BABA, (1)H-(1)H SQ-SQ RFDR, (27)Al{(1)H} CPHETCOR and (27)Al MQMAS. PMID- 20923157 TI - Comprehensive survey of chemical libraries for drug discovery and chemical biology: 2009. PMID- 20923170 TI - Trimethylsilyldiazomethane as a versatile stitching agent for the introduction of aziridines into functionalized organic molecules. AB - A highly enantioselective route for the introduction of aziridines into functionalized organic molecules was developed via a tandem acylation and aziridination of TMSCHN(2). PMID- 20923171 TI - Asymmetric synthesis of 2,3-dihydro-4-pyranones by reaction of chiral 3 alkoxycyclobutanone and aldehydes. AB - Chiral cyclobutanone which had ethyl l-lactate as a chiral auxiliary at the 3 position reacted with aldehydes to give 2,3-dihydro-4-pyranones in up to 93% ee by combined use of titanium(IV) chloride and tin(II) chloride. PMID- 20923172 TI - Dual sensing of hairpin and quadruplex DNA structures using multicolored peptide nucleic acid fluorescent probes. AB - Synthesis of water-soluble 5-mer peptide nucleic acids (PNAs) functionalized at their 5'- and 3'-ends with two original precursors of pentamethine cyanine dye synthesis is reported. The successful use of these PNA probes for sensing DNA hairpin structures in vitro was also demonstrated where specific hairpin formation was associated with the appearance of a characteristic fluorescence signal at 660 nm. A comparative study between three different strategies where PNAs were targeting either the stem or the loop of the hairpin was carried out. Best sensitivity was obtained using PNA sequences complementary to the loop sequence and directing both functional moieties toward the base of loop. Unprecedented proof-of-concept for the simultaneous sensing of hairpin and quadruplex DNAs with a nonoverlapping two-color system (C3 and C5) is also demonstrated. PMID- 20923174 TI - The quest for tetracoordinated halonium ions: a theoretical investigation. AB - Di-, tri-, and tetravalent halonium ions have been investigated by theoretical means with respect to their geometries and their electronic structure using DFT as well as MP2 calculations. Even tricationic species where halides (F, Cl, Br, and I) are surrounded by an appropriate tetracationic hydrocarbon cage are calculated to be stable species. All halides show bonding interactions with all four cationic carbon centers. PMID- 20923173 TI - Finding a needle in the haystack: computational modeling of Mg2+ binding in the active site of protein farnesyltransferase. AB - Studies aimed at elucidating the unknown Mg2+ binding site in protein farnesyltransferase (FTase) are reported. FTase catalyzes the transfer of a farnesyl group to a conserved cysteine residue (Cys1p) on a target protein, an important step for proteins in the signal transduction pathways (e.g., Ras). Mg2+ ions accelerate the protein farnesylation reaction by up to 700-fold. The exact function of Mg2+ in catalysis and the structural characteristics of its binding remain unresolved to date. Molecular dynamics (MD) simulations addressing the role of magnesium ions in FTase are presented, and relevant octahedral binding motifs for Mg2+ in wild-type (WT) FTase and the Dbeta352A mutant are explored. Our simulations suggest that the addition of Mg2+ ions causes a conformational change to occur in the FTase active site, breaking interactions known to keep FPP in its inactive conformation. Two relevant Mg2+ ion binding motifs were determined in WT FTase. In the first binding motif, WT1, the Mg2+ ion is coordinated to D352beta, zinc-bound D297beta, two water molecules, and one oxygen atom from the alpha- and beta-phosphates of farnesyl diphosphate (FPP). The second binding motif, WT2, is identical with the exception of the zinc-bound D297beta being replaced by a water molecule in the Mg2+ coordination complex. In the Dbeta352A mutant Mg2+ binding motif, D297beta, three water molecules, and one oxygen atom from the alpha- and beta-phosphates of FPP complete the octahedral coordination sphere of Mg2+. Simulations of WT FTase, in which Mg2+ was replaced by water in the active site, recreated the salt bridges and hydrogen-bonding patterns around FPP, validating these simulations. In all Mg2+ binding motifs, a key hydrogen bond was identified between a magnesium-bound water and Cys1p, bridging the two metallic binding sites and, thereby, reducing the equilibrium distance between the reacting atoms of FPP Cys1p. The free energy profiles calculated for these systems provide a qualitative understanding of experimental results. They demonstrate that the two reactive atoms approach each other more readily in the presence of Mg2+ in WT FTase and mutant. The flexible WT2 model was found to possess the lowest barrier toward the conformational change, suggesting it is the preferred Mg2+ binding motif in WT FTase. In the mutant, the absence of D352beta makes the transition toward a conformational change harder. Our calculations find support for the proposal that D352beta performs a critical role in Mg2+ binding and Mg2+ plays an important role in the conformational transition step. PMID- 20923175 TI - Improved description of the structure of molecular and layered crystals: ab initio DFT calculations with van der Waals corrections. AB - The implementation of technique for full structural optimizations of complex periodic systems in the DFT-PAW package VASP, including the volume and shape of the unit cell and the internal coordinates of the atoms, together with a correction that allows an appropriate modeling of London dispersion forces, as given by the DFT-D2 approach of Grimme [Grimme, S. J. Comp. Chem. 2006, 27, 1787], is reported. Dispersion corrections are calculated not only for the forces acting on the atoms, but also for the stresses on the unit cell. This permits a simultaneous optimization of all degrees of freedom. Benchmark results on a series of prototype systems are presented and compared to results obtained by other methods and experimental data. It is demonstrated that the computationally inexpensive DFT-D2 scheme yields reasonable predictions for the structure, bulk moduli, and cohesive energies of weakly bonded materials. PMID- 20923176 TI - Decorating poly(alkyl aryl-ether) dendrimers with metallacarboranes. AB - A new family of polyanionic poly(alkyl aryl-ether) metallodendrimers decorated with four and eight cobaltabisdicarbollide units have been obtained in high yield by the ring-opening reaction of cyclic oxonium [3,3'-Co(8-(C(2)H(4)O)(2)-1,2 C(2)B(9)H(10))(1',2'-C(2)B(9)H(11))] with alkoxides formed by deprotonation of terminal alcohols in the alpha,alpha'-bis[3,5-bis(hydroxymehyl)phenoxy]-p-xylene, alpha,alpha'-bis[3,5-bis(hydroxymehyl)phenoxy]-m-xylene, alpha,alpha'-bis[3,5-bis [3,5-bis(hydroxymethyl)phenoxy]methylen]phenoxy]-p-xylene, and alpha,alpha,' bis[3,5-bis-[3,5-bis(hydroxymethyl)phenoxy]methylen]phenoxy]-m-xylene dendrimers. The crystal structure of the precursor alpha,alpha'-bis[3,5 bis(chloromethyl)phenoxy]-p-xylene is also described. Final products are fully characterized by FTIR, NMR, UV-vis spectroscopies and elemental analysis. For metallodendrimers, the UV-vis absorptions have been a good tool for estimating the experimental number of cobaltabisdicarbollide units peripherally attached to the dendrimeric structure and consequently to corroborate the complete functionalization of the dendrimers. PMID- 20923178 TI - Water-processable polymer-nanocrystal hybrids for thermoelectrics. AB - We report the synthesis and thermoelectric characterization of composite nanocrystals composed of a tellurium core functionalized with the conducting polymer poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS). Solution processed nanocrystal films electronically out perform both PEDOT:PSS and unfunctionalized Te nanorods while retaining a polymeric thermal conductivity, resulting in a room temperature ZT ~ 0.1. This combination of electronic and thermal transport indicates the potential for tailored transport in nanoscale organic/inorganic heterostructures. PMID- 20923179 TI - Fano-like interference in self-assembled plasmonic quadrumer clusters. AB - Assemblies of strongly interacting metallic nanoparticles are the basis for plasmonic nanostructure engineering. We demonstrate that clusters of four identical spherical particles self-assembled into a close-packed asymmetric quadrumer support strong Fano-like interference. This feature is highly sensitive to the polarization of the incident electric field due to orientation-dependent coupling between particles in the cluster. This structure demonstrates how careful design of self-assembled colloidal systems can lead to the creation of new plasmonic modes and the enabling of interference effects in plasmonic systems. PMID- 20923180 TI - Bioactive Cycloperoxides Isolated from the Puerto Rican Sponge Plakortis halichondrioides. AB - Two new five-membered-ring polyketide endoperoxides, epiplakinic acid F methyl ester (1) and epiplakinidioic acid (3), and a peroxide-lactone, plakortolide J (2), were isolated from the Puerto Rican sponge Plakortis halichondrioides, along with two previously reported cyclic peroxides, 4 and 5. The structures of the new metabolites were determined by spectroscopic and chemical analyses. The absolute stereostructures of 1, 2, and 5 were determined by degradation reactions followed by application of Kishi's method for the assignment of absolute configuration of alcohols. Biological screening of cycloperoxides 1-5 and semisynthetic analogues 7-12 for cytotoxic activity against various human tumor cell lines revealed that compounds 3, 4, and 11 are very active. Upon assaying for antimalarial and antitubercular activity, some of the compounds tested showed strong activity against the pathogenic microbes Plasmodium falciparum and Mycobacterium tuberculosis. PMID- 20923182 TI - Dissociating excitons photogenerated in semiconducting carbon nanotubes at polymeric photovoltaic heterojunction interfaces. AB - Semiconducting single-walled carbon nanotubes (s-SWCNTs) have strong near infrared and visible absorptivity and exceptional charge transport characteristics, rendering them highly attractive semiconductor absorbers for photovoltaic and photodetector technologies. However, these applications are limited by a poor understanding of how photogenerated charges, which are bound as excitons in s-SWCNTs, can be dissociated in large-area solid-state devices. Here, we measure the dissociation of excitons in s-SWCNT thin films that form planar heterojunction interfaces with polymeric photovoltaic materials using an exciton dissociation-sensitive photocapacitor measurement technique that is advantageously insensitive to optically induced thermal photoconductive effects. We find that fullerene and polythiophene derivatives induce exciton dissociation, resulting in electron and hole transfer, respectively, away from optically excited s-SWCNTs. Significantly weaker or no charge transfer is observed using wider gap polymers due to insufficient energy offsets. These results are expected to critically guide the development of thin film s-SWCNT-based photosensitive devices. PMID- 20923181 TI - Sizing nanomatter in biological fluids by fluorescence single particle tracking. AB - Accurate sizing of nanoparticles in biological media is important for drug delivery and biomedical imaging applications since size directly influences the nanoparticle processing and nanotoxicity in vivo. Using fluorescence single particle tracking we have succeeded for the first time in following the aggregation of drug delivery nanoparticles in real time in undiluted whole blood. We demonstrate that, by using a suitable surface functionalization, nanoparticle aggregation in the blood circulation is prevented to a large extent. PMID- 20923184 TI - Role of Marangoni instability in fabrication of axially and internally grooved hollow fiber membranes. AB - Hollow fiber membranes (HFMs) are extensively used in different industrial applications. Under some controlled fabrication conditions, axially aligned grooves can be formed on the HFM inner surface during typical immersion precipitation-based phase inversion fabrication processes. Such grooved HFMs are found to be promising for nerve repair and regeneration. The axially aligned grooves appearing on the inner surface of the membrane are considered as hydrodynamic instability patterns. During the immersion precipitation process, a transfer of solvent takes place across the interface between a polymer solution and a nonsolvent. This solvent transfer induces gradients of interfacial tension that are considered to be the driving mechanism for Marangoni instability. The onset of the stationary instability is studied by means of a linear instability theory, and the critical and maximum wavenumbers are determined and discussed in terms of the dimensionless groups characterizing the system: viscosity ratio, diffusivity ratio, Schmidt number, crispation number, adsorption number, Marangoni number, and the polymer bulk concentration. A good agreement is found between the predicted wavelength of the most dangerous wave and the experimental groove width. Consequently, solutal Marangoni instability can explain the groove formation mechanism in HFM fabrication. PMID- 20923183 TI - Peptide nucleic acids as tools for single-molecule sequence detection and manipulation. AB - The ability to strongly and sequence-specifically attach modifications such as fluorophores and haptens to individual double-stranded (ds) DNA molecules is critical to a variety of single-molecule experiments. We propose using modified peptide nucleic acids (PNAs) for this purpose and implement them in two model single-molecule experiments where individual DNA molecules are manipulated via microfluidic flow and optical tweezers, respectively. We demonstrate that PNAs are versatile and robust sequence-specific tethers. PMID- 20923185 TI - The effect of Alzheimer's Abeta aggregation state on the permeation of biomimetic lipid vesicles. AB - Alzheimer's disease is characterized by the aggregation and deposition of the Abeta peptide. This 40 or 42 residue peptide is the product of the proteolysis of the amyloid precursor protein membrane protein and is able to assemble to form ordered, stable amyloid fibrils as well as small, soluble, and potentially cytotoxic oligomers. The toxicity of the oligomers may be associated with the ability to bind to and affect the integrity of lipid membranes. In this novel work, we have monitored and compared the ability of the potent Abeta42 peptide, the less amyloidogenic Abeta40 peptide, and a variant with reduced amyloidogenicity to bind to and affect the integrity of membranes using dye filled synthetic vesicles. We reveal that the potency of the assemblies reduces with incubation time of the peptide and that maximal effect occurs when a particular species is apparent by electron microscopy. We have investigated the effect of lipid vesicle composition, and our results suggest that charge on the vesicles is important and that binding may partly be mediated by the GM1 ganglioside receptors expressed in the outer leaflet of vertebrate membranes. PMID- 20923186 TI - Persistent metal bis(hexafluoroacetylacetonato) complexes featuring a 2,2' bipyridine substituted triarylamminium radical cation. AB - Herein, we describe the preparation of a 2,2'-bipyridine derivative containing a redox-active N,N'-(4,4'-dimethoxydiphenylamino) substituent (1), which readily coordinates M(hfac)(2) salts [M = Mn (2), Ni (3), Cu (4)] to generate stable, neutral, and pseudo-octahedral coordination complexes, which have been fully characterized. Cyclic voltammetry and spectroelectrochemical measurements on complexes 2-4 indicate stable one-electron oxidation processes, and the formation of persistent radical cation complexes. The neutral complexes (M = Mn or Ni) were subject to one-electron oxidation with NOPF(6) in acetonitrile, and magnetic moments of the resulting solutions were obtained using the Evans method at different temperatures. Our experimental results suggest that the first reported ferromagnetically coupled metal-triarylamminum radical cation complex is obtained when M = Mn(2+), and antiferromagnetic coupling results when M = Ni(2+). These results are supported by results from density functional theory calculations, which indicate that a pi spin polarization mechanism for magnetic exchange coupling is operative in singly oxidized complexes, 2-4. PMID- 20923187 TI - Effect of morphology on ultrafast free carrier generation in polythiophene:fullerene organic solar cells. AB - Despite significant study, the precise mechanisms that dictate the efficiency of organic photovoltaic cells, such as charge separation and recombination, are still debated. Here, we directly observe efficient ultrafast free charge generation in the absence of field in annealed poly(3 hexylthiophene):methanofullerene (P3HT:PCBM). However, we find this process is much less efficient in unannealed and amorphous regiorandom blends, explaining the superior short-circuit current and fill-factor of annealed RR-P3HT:PCBM solar cells. We use transient optical spectroscopy in the visible and near-infrared spectral region covering, but not limited to, the previously unobserved and highly relevant time scale spanning 1 to 100 ns, to directly observe both geminate and nongeminate charge recombination. We find that exciton quenching leads directly (time scale less than 100 fs) to two populations: bound charges and free charges. The former do not lead to photocurrent in a photovoltaic cell; they recombine geminately within 2 ns and are a loss channel. However, the latter can be efficiently extracted in photovoltaic cells. Therefore, we find that the probability of ultrafast free charge formation after exciton quenching directly limits solar cell efficiency. This probability is low in disordered P3HT:PCBM blends but approaches unity in annealed blends. PMID- 20923188 TI - Soyasaponin I attenuates TNBS-Induced colitis in mice by inhibiting NF-kappaB pathway. AB - Soybean, which contains soyasaponins and isoflavones as representative constituents, exhibits anti-inflammatory and antioxidant effects. To understand the anti-inflammatory effects of soyasaponins, we isolated soyasaponin I, a major constituent of soybean, and investigated the inhibitory effects on inflammatory markers in LPS-stimulated mouse peritoneal macrophages and 3,4,5 trinitrobenzenosulfonic acid (TNBS)-induced colitic mice. Soyasaponin I, which exhibited lipid peroxidation-inhibitory effects in vitro, inhibited the production of proinflammatory cytokines (TNF-alpha and IL-1beta), inflammatory mediators (NO and PGE2), and inflammatory enzymes (COX-2 and iNOS) in LPS stimulated peritoneal macrophages. Soyasaponin I also suppressed the phosphorylation of IkappaB-alpha and the nuclear translocation of NF-kappaB. However, these soyasaponins barely inhibited mitogen-activated protein kinases. Oral administration of soyasaponin I (10 and 20 mg/kg) to TNBS-treated colitic mice significantly reduced inflammatory markers, colon length, myeloperoxidase, lipid peroxide (malondialdehyde and 4-hydroxy-2-nonenal), proinflammatory cytokines and NF-kappaB activation in the colon, as well as increased glutathione content, superoxide dismutase, and catalase activity. Based on these findings, soyasaponin I may attenuate colitis by inhibiting the NF-kappaB pathway. PMID- 20923190 TI - Embedded high density metal nanoparticles with extraordinary thermal stability derived from guest-host mediated layered double hydroxides. AB - A chemical precursor mediated process was used to form catalyst nanoparticles (NPs) with an extremely high density (10(14) to 10(16) m(-2)), controllable size distribution (3-20 nm), and good thermal stability at high temperature (900 degrees C). This used metal cations deposited in layered double hydroxides (LDHs) to give metal catalyst NPs by reduction. The key was that the LDHs had their intercalated anions selected and exchanged by guest-host chemistry to prevent sintering of the metal NPs, and there was minimal sintering even at 900 degrees C. Metal NPs on MoO(4)(2-) intercalated Fe/Mg/Al LDH flakes were successfully used as the catalyst for the double helix growth of single-walled carbon nanotube arrays. The process provides a general method to fabricate thermally stable metal NPs catalysts with the desired size and density for catalysis and materials science. PMID- 20923189 TI - The flavonol isorhamnetin exhibits cytotoxic effects on human colon cancer cells. AB - The aim of this study was to determine whether isorhamnetin, an immediate 3'-O methylated metabolite of quercetin, affects proliferation, cell death, and the cell cycle of human colon carcinoma (HCT-116) cells. Isorhamnetin was found to be a potent antiproliferative agent in a dose- and time-dependent manner, with an IC50 of 72 MUM after 48 h of incubation as estimated by MTT assay. Flow cytometry and fluorescence microscopy analysis showed that isorhamnetin exerted a stimulatory effect on apoptosis and necrosis. Isorhamnetin also increased the number of cells in G2/M phase. Serum deprivation appeared to potentiate the effects of isorhamnetin on cell death and facilitated cell cycle progression to G0/G1 phase. These results suggest that isorhamnetin might mediate inhibition of HCT-116 cell growth through the perturbation of cell cycle progression and are consistent with the notion that G2/M checkpoints could be a conserved target for flavonoids in human colon cancer cells, leading to apoptotic and necrotic death. These antiproliferative, apoptotic, necrotic, and cell cycle effects suggest that isorhamnetin may have clinically significant therapeutic and chemopreventive capabilities. To our knowledge, this is the first report of the effect of isorhamnetin on human colon cancer cells. PMID- 20923191 TI - Cubic polyoxometalate-organic molecular cage. AB - Tris(hydroxymethyl)aminomethane (Tris) was successfully grafted onto the surface of a Ni(6)-substituted polyoxotungstate formed in situ to further generate a three-connected polyoxometalate building block. The cooperative assembly of Tris functionalized three-connected building blocks and rigid 1,3,5 benzenetricarboxylate gave rise to an unprecedented cubic polyoxometalate-organic molecular cage with high thermal and hydrothermal stability. PMID- 20923192 TI - Influence of harvest method and period on olive oil composition: an NMR and statistical study. AB - The influence of harvest period and harvest method on olive oil composition was investigated by nuclear magnetic resonance (NMR) spectroscopy and by some quality parameters such as free acidity, peroxide value, and UV spectrophotometric indices. This work focuses on two secondary factors (harvest period and harvest method) and investigated their interactions with primary (genetic and pedoclimatic) and secondary (agronomic practices and technological procedures) factors. To avoid misinterpretation, the general linear model analysis (GLM) was used to adjust the result obtained from the analysis of variance (ANOVA). In this way, the effect of the factor of interest was corrected for the effects of the other factors that might influence the variable under investigation. The weight of each factor was evaluated by the variance component analysis (VCA). Finally, multivariate statistical analyses, namely, principal component analysis (PCA) and linear discriminant analysis (LDA), were applied. Samples were grouped according to the harvest period and harvest method. Volatile compounds, that is, hexanal and trans-2-hexenal, as well as the sn-1,3-diglycerides and squalene, significantly decreased during the ripening. The relative value of the DeltaK parameter and the hexanal amount were higher in the olive oils obtained from olives harvested by one type of hand-held machine (shaker), whereas the unsaturated fatty chains in the olive oils were higher when another type (comb) was used. PMID- 20923193 TI - Use of green rooibos (Aspalathus linearis) extract and water-soluble nanomicelles of green rooibos extract encapsulated with ascorbic acid for enhanced aspalathin content in ready-to-drink iced teas. AB - Heat-induced changes in aspalathin, iso-orientin, and orientin content of ready to-drink (RTD) green rooibos iced tea formulations were investigated. An organic solvent-based aspalathin-enriched extract prepared from green rooibos was used "as-is" or encapsulated with ascorbic acid in a water-soluble nanomicelle-based carrier system. The common iced tea ingredients, ascorbic acid, and/or citric acid were added to the iced tea containing green rooibos extract. Only citric acid was added to the iced tea containing the nanomicelles. Heat treatments consisted of pasteurization (93 degrees C/5 min and 93 degrees C/30 min), normal-temperature sterilization (NTS; 121 degrees C/15 min), and high temperature sterilization (HTS; 135 degrees C/4 min). Pasteurization had little or no effect on the flavonoid content. NTS and HTS induced significant losses in the flavonoids. The addition of citric and ascorbic acids improved the stability of the flavonoids, but encapsulation of green rooibos extract with ascorbic acid in nanomicelles did not offer additional stability. The only benefit of using the water-soluble nanomicelles was the improved clarity of the RTD product. Iso orientin and orientin contents were substantially less affected than aspalathin by the heat treatments, partially because of conversion of aspalathin to these flavones, which countered losses. 5-Hydroxymethylfurfural (HMF), a known dehydration product of hexoses under mild acidic conditions and also a degradation product of ascorbic acid, was observed in formulations containing citric and/or ascorbic acids. PMID- 20923194 TI - Enhancing the open-circuit voltage of molecular photovoltaics using oxidized Au nanocrystals. AB - For organic photovoltaics (OPV) to realize applications effective strategies to maximize the open-circuit voltage must be developed. Herein we show that solution processed surface-oxidized Au nanocrystals (o-AuNC) dramatically increase the open-circuit voltage (V(oc)) of OPV cells based on boron-subphthalocyanine chloride (SubPc)/C(60) and chloro-aluminum phthalocyanine (ClAlPc)/C(60) heterojunctions when incorporated at the interface between the hole-extracting electrode and the phthalocyanine donor layer. In addition, the cell-to-cell variation in V(oc) is reduced by up to 10-fold combined with a large reduction in the light intensity dependence of V(oc), both of which are important advantages for practical application. The largest increase in V(oc) is achieved for SubPc/C(60)-based cells which exhibit a 45% increase to 1.09 +/- 0.01 V--an exceptionally high value for a single junction small molecule OPV. Remarkably these improvements are achieved using submonolayers of o-AuNC, which can be rationalized in terms of the exceptionally high work function of o-AuNC (~5.9 eV) and geometric electric field enhancement effects. PMID- 20923195 TI - Guest recognition in a partially bridged deep cavitand. AB - The synthesis of a new deep cavitand partially bridged via disulfide bonds is described. Its thermodynamic and kinetic complexation parameters are compared with those of an unbridged analogue. The disulfide bridges cause deviations in DeltaH and DeltaS but result in only small differences in DeltaG of complexation. The bridges increase the activation barrier for guest dissociation and lead to complexes with enhanced kinetic stability. PMID- 20923196 TI - Copper-mediated oxidative trifluoromethylation of boronic acids. AB - A copper-mediated oxidative cross-coupling of aryl- and alkenylboronic acids with (trifluoromethyl)trimethylsilane (Me(3)SiCF(3)) under mild conditions has been developed. This method allows a wide range of functional group tolerant trifluoromethylated arenes and alkenes to be easily prepared. This oxidative trifluoromethylation has the potential to introduce trifluoromethyl groups into advanced, highly functionalized organic molecules. PMID- 20923197 TI - Desiccation tolerance mechanism in resurrection fern-ally Selaginella tamariscina revealed by physiological and proteomic analysis. AB - Drought is one of the most severe limitations to plant growth and productivity. Resurrection plants have evolved a unique capability to tolerate desiccation in vegetative tissues. Fern-ally Selaginella tamariscina (Beauv.) is one of the most primitive vascular resurrection plants, which can survive a desiccated state and recover when water becomes available. To better understand the mechanism of desiccation tolerance, we have applied physiological and proteomic analysis. Samples of S. tamariscina were water-deprived for up to seven days followed by 12 h of rewatering. Our results showed that endogenous abscisic acid (ABA) increased to regulate dehydration-responsive genes/proteins and physiological processes. In the course of dehydration, the contents of osmolytes represented by soluble sugars and proline were increased to maintain cell structure integrity. The activities of four antioxidant enzymes (superoxide dismutase (SOD), peroxidase (POD), catalase (CAT), and glutathione reductase (GR)) also increased. In contrast, both the rate of photosynthesis and the chlorophyll content decreased, and plasma membrane integrity was lost. We identified 138 desiccation-responsive two-dimensional electrophoresis (2-DE) spots, representing 103 unique proteins. Hierarchical clustering analysis revealed that 83% of the proteins were down regulated upon dehydration. They were mainly involved in photosynthesis, carbohydrate and energy metabolism, stress and defense, protein metabolism, signaling, membrane/transport, cell structure, and cell division. The dynamic expression changes of the desiccation-responsive proteins provide strong evidence that cell structure modification, photosynthesis reduction, antioxidant system activation, and protein post-transcriptional/translational modifications are essential to the poikilochlorophyllous fern-ally S. tamariscina in response to dehydration. In addition, our comparative analysis of dehydration-responsive proteins in vegetative tissues from 19 desiccation tolerant and nontolerant plant species suggests that resurrection S. tamariscina has developed a specific desiccation tolerant mechanism. To our knowledge, this study constitutes the first detailed investigation of the protein complement in fern/fern-allies. PMID- 20923198 TI - Synthesis of statistical copolymers containing multiple functional peptides for nucleic Acid delivery. AB - Our report describes RAFT copolymerization of multiple species of active peptide monomers with N-(2-hydroxypropyl(methacrylamide) (HPMA) under aqueous conditions. Resulting statistical copolymers are narrowly disperse with highly controlled molecular weight and composition. Side-chain peptide copolymers were synthesized using a DNA condensing peptide (K12), and an endosomal escape peptide (K6H5) that had been modified with an aminohexanoic linker and capped with methacrylamide vinyl on the NH2-terminus. Copolymers of HMPA-co-K12 and HPMA-co-K12-co-K6H5 efficiently condensed DNA into small particles that maintain size stability even in 150 mM salt solutions. With increasing peptide content, the peptide-based polymers demonstrated gene delivery efficiencies to HeLa cells that were comparable to branched polyethylenimine. PMID- 20923199 TI - Cell proliferation on stereoregular isotactic-poly(propylene oxide) as a bulk substrate. AB - Stereoregular isotactic-poly(propylene oxide) (it-PPO) was investigated for use as a biomaterial surface. The conventional characteristic of nonstereoregular atactic PPO was altered to a hydrophobic solid nature (contact angle: 95.6 +/- 3.8 degrees ), which resulted in the potential solid surface applications. The high crystallinity of it-PPO created both smooth and microsized, random crater shaped surfaces using the spin coating and dip coating approaches, respectively. The results of protein adsorption with bovine serum albumin (BSA), bovine gamma globulin (BgammaG), and bovine plasma fibrinogen (BPF) showed multilayered adsorption onto it-PPO. Mouse fibroblast L929 cells adhered onto the it-PPO surfaces, and cultured well as compared with commercially available Cell Desk LF1 as a control surface. These unique physical characteristics of it-PPO were due to the configuration of the polymer chain backbone structure, which maintained the polyether chemical structure. PMID- 20923201 TI - Unusual molecular conformations in fluorinated, contorted hexabenzocoronenes. AB - Fluorinated, contorted hexabenzocoronenes (HBCs) have been synthesized in a facile manner via Suzuki-Miyaura coupling of fluorinated phenyl boronic acids followed by photocyclization and Scholl cyclization. In addition to the molecular conformation observed in previous HBC derivatives, close-contact fluorine fluorine intramolecular interactions result in a metastable conformation not previously observed. Heating the metastable HBCs above 100 degrees C irreversibly converts them to the stable conformation, suggesting that the metastable conformation arises from a kinetically arrested state during cyclization. PMID- 20923200 TI - A biosynthetic strategy for re-engineering the Staphylococcus aureus cell wall with non-native small molecules. AB - Staphylococcus aureus (S. aureus) is a Gram-positive bacterial pathogen that has emerged as a major public health threat. Here we report that the cell wall of S. aureus can be covalently re-engineered to contain non-native small molecules. This process makes use of endogenous levels of the bacterial enzyme sortase A (SrtA), which ordinarily functions to incorporate proteins into the bacterial cell wall. Thus, incubation of wild-type bacteria with rationally designed SrtA substrates results in covalent incorporation of functional molecular handles (fluorescein, biotin, and azide) into cell wall peptidoglycan. These conclusions are supported by data obtained through a variety of experimental techniques (epifluorescence and electron microscopy, biochemical extraction, and mass spectrometry), and cell-wall-incorporated azide was exploited as a chemical handle to perform an azide-alkyne cycloaddition reaction on the bacterial cell surface. This report represents the first example of cell wall engineering of S. aureus or any other pathogenic Gram-positive bacteria and has the potential for widespread utility. PMID- 20923202 TI - Influence of cellulose on ion diffusivity in 1-ethyl-3-methyl-imidazolium acetate cellulose solutions. AB - Solutions of microcrystalline cellulose in 1-ethyl-3-methyl-imidazolium acetate have been investigated using pulsed-field gradient (1)H NMR. In all cases the geometrically larger cation was found to diffuse faster than the smaller anion. Arrhenius temperature analysis has been applied to the ion diffusivities giving activation energies. The diffusion and published viscosity data for these solutions were shown to follow the Stokes-Einstein relationship, giving hydrodynamic radii of 1.6 A (cation) and 1.8 A (anion). Theories for obstruction, free-volume and hydrodynamic effects on solvent diffusion have been applied. The Mackie-Meares and Maxwell-Fricke obstruction models provided a correct trend only when assuming a certain fraction of ions are bound to the polymer. From this fraction it was shown that the maximum dissolvable cellulose concentration is ~27% w/w, which is consistent with the highest known prepared concentration of cellulose in this ionic liquid. The Phillies' hydrodynamic model is found to give the best description for the cellulose concentration dependence of the ion diffusivities. PMID- 20923203 TI - Using the rotaxane mechanical bond to enhance chemical reactivity. AB - Rates of cycloreversion for squaraine rotaxane mono(endoperoxides) were enhanced by structural modifications that increased cross-component steric destabilization of the inward directed 9,10-anthracene endoperoxide group. The largest rate enhancements were obtained when the surrounding macrocycle contained two 2,6 pyridine dicarboxamide bridging units, which induced a cavity contraction effect. The precursor fluorescent, near-IR, squaraine rotaxanes are effectively photostable because the mono(endoperoxide) products, formed by reaction with photogenerated singlet oxygen, rapidly cyclorevert back to the original squaraine rotaxane. PMID- 20923204 TI - High-efficiency dye-sensitized solar cells: the influence of lithium ions on exciton dissociation, charge recombination, and surface states. AB - We present a time-saving staining protocol based upon the low-toxicity and nonvolatile solvent dimethyl sulfoxide for a high-efficiency dye-sensitized solar cell, which is very critical for the roll-to-roll flexible cell production. Power conversion efficiencies of 11.7-12.1% were achieved under AM1.5G simulated sunlights. The intrinsic roles of lithium cations on efficiency enhancement were scrutinized by measuring transient absorption and electrical impedance spectroscopies. Our studies have revealed that lithium ions can enhance exciton dissociation at the energy-offset dye/titania interface effectively. Charge collection is not found to be a crucial current loss channel in our high efficiency dye-sensitized solar cell. PMID- 20923205 TI - Ab initio chemical kinetic study on Cl + ClO and related reverse processes. AB - The reaction of ClO with Cl and its related reverse processes have been studied theoretically by ab initio quantum chemical and statistical mechanical calculations. The geometric parameters of the reactants, products, and transition states are optimized by both UMPW1PW91 and unrestricted coupled-cluster single and double excitation (UCCSD) methods with the 6-311+G(3df) basis set. The potential energy surface has been further refined (with triple excitations, T) at the UCCSD(T)/6-311+G(3df) level of theory. The results show that Cl(2) and O ((3)P) can be produced by chlorine atom abstraction via a tight transition state, while ClOCl ((1)A(1)) and ClClO ((1)A') can be formed by barrierless association processes with exothermicities of 31.8 and 16.0 kcal/mol, respectively. In principle the O ((1)D) atom can be generated with a large endothermicity of 56.9 kcal/mol; on the other hand, its barrierless reaction with Cl(2) can readily form ClClO ((1)A'), which fragments rapidly to give ClO + Cl. The rate constants of both forward and reverse processes have been predicted at 150-2000 K by the microcanonical variational transition state theory (VTST)/Rice-Ramsperger-Kassel Marcus (RRKM) theory. The predicted rate constants are in good agreement with available experimental data within reported errors. PMID- 20923206 TI - A fused donor-acceptor system based on an extended tetrathiafulvalene and a ruthenium complex of dipyridoquinoxaline. AB - An application of the Horner-Wadsworth-Emmons reaction carried out on a ruthenium compound as the electrophilic precursor is described for the synthesis of fused donor-acceptor system 1 based on an extended tetrathiafulvalene and a ruthenium complex of dipyridoquinoxaline units. PMID- 20923207 TI - Reactivity of 2,6-lutidine/BR3 and pyridine/BR3 Lewis pairs (R = F, Me, C6F5): a density functional study. AB - The reactivity of 2,6-lutidine/BR3 and pyridine/BR3 Lewis pairs (R = F, Me, C6F5) is investigated in detail by quantum chemical calculations. The observed reactivity difference of these pairs is interpreted in terms of the existence of a "frustrated complex" on the potential energy curve for coordination of Lewis acid and base, the profiles of local reactivity descriptors with respect to the bond distance between acid and base centers, and the thermodynamic/kinetic properties of the heterolytic dihydrogen cleavage reaction. The calculated results are shown to account well for the observed reactivity of these Lewis pairs. PMID- 20923208 TI - Shock tube/laser absorption measurements of the reaction rates of OH with ethylene and propene. AB - Reaction rates of hydroxyl (OH) radicals with ethylene (C2H4) and propene (C3H6) were studied behind reflected shock waves. OH + ethylene -> products (rxn 1) rate measurements were conducted in the temperature range 973-1438 K, for pressures from 2 to 10 atm, and for initial concentrations of ethylene of 500, 751, and 1000 ppm. OH + propene -> products (rxn 2) rate measurements spanned temperatures of 890-1366 K, pressures near 2.3 atm, and initial propene concentrations near 300 ppm. OH radicals were produced by shock-heating tert-butyl hydroperoxide, (CH3)3-CO-OH, and monitored by laser absorption near 306.7 nm. Rate constants for the reactions of OH with ethylene and propene were extracted by matching modeled and measured OH concentration time-histories in the reflected shock region. Current data are in excellent agreement with previous studies and extend the temperature range of OH + propene data. Transition state theory calculations using recent ab initio results give excellent agreement with our measurements and other data outside our temperature range. Fits (in units of cm3/mol/s) to the abstraction channels of OH + ethylene and OH + propene are k1 = 2.23 * 104 (T)(2.745) exp(-1115 K/T) for 600-2000 K and k2 = 1.94 * 106 (T)(2.229) exp(-540 K/T) for 700-1500 K, respectively. A rate constant determination for the reaction TBHP -> products (rxn 3) was also obtained in the range 745-1014 K using OH data from behind both incident and reflected shock waves. These high-temperature measurements were fit with previous low-temperature data, and the following rate expression (0.6-2.6 atm), applicable over the temperature range 400-1050 K, was obtained: k3 (1/s) = 8.13 * 10-12 (T)(7.83) exp(-14598 K/T). PMID- 20923209 TI - First-principles thermochemistry for gas phase species in an industrial rutile chlorinator. AB - This work presents thermochemical data for possible gas phase intermediate species in an industrial rutile chlorinator. An algorithm developed for previous work is employed to ensure that all possible species are considered, reducing the number of important species neglected. Thermochemical data and enthalpies of formation are calculated for 22 new species using density functional theory, post Hartree-Fock coupled cluster calculations, and statistical mechanics. Equilibrium calculations are performed to identify whether any Ti/C intermediates are likely to be important to the high temperature industrial process. These new species are not present at high concentration in the exit stream. It is therefore likely that the two chemical processes do not interact. Rather, the Cl2 rapidly reacts with the solid TiO2 to form TiCl4 and O2. The latter then reacts with the solid C to form CO and CO2 and provide the heat. Data for all the new species is provided as Supporting Information. Finally, a new methodology for data collaboration is investigated in which the data is made openly accessible using the resource description framework. Example scripts are provided to demonstrate how to query and retrieve the data automatically. PMID- 20923210 TI - Theoretical studies on Myers-Saito and Schmittel cyclization mechanisms of hepta 1,2,4-triene-6-yne. AB - The mechanisms of the Myers-Saito cyclization and the Schmittel cyclization of hepta-1,2,4-triene-6-yne are studied by ab initio multireference MO methods (CASSCF and MRMP2 methods). For the Myers-Saito cyclization, two transition states with C(s) and C1 symmetries are located. The transition state with C1 symmetry is only 1.5 kcal/mol lower in energy than that with C(s) symmetry at the MRMP2 calculation level. The obtained activation energy at the transition state with C1 symmetry and the reaction energy are 16.6 and 16.2 kcal/mol exothermic, respectively. For the Schmittel cyclization, two transition states with C(s) and C1 symmetry are also obtained. The transition state with C1 symmetry is 7.9 kcal/mol lower in energy than that with C(s) symmetry. The transition state with C1 symmetry for Schmittel cyclization is 6.7 kcal/mol higher in energy than that for the Myers-Saito cyclization. The reaction mechanisms are analyzed by a CiLC IRC method. The interactions of orbitals for the Myers-Saito and Schmittel cyclizations can be distinguished. PMID- 20923211 TI - Noncovalent binding between fullerenes and protonated porphyrins in the gas phase. AB - Noncovalent interactions between protonated porphyrin and fullerenes (C60 and C70) were studied with five different meso-substituted porphyrins in the gas phase. The protonated porphyrin-fullerene complexes were generated by electrospray ionization of the porphyrin-fullerene mixture in 3:1 dichloromethane/methanol containing formic acid. All singly protonated porphyrins formed the 1:1 complexes, whereas porphyrins doubly protonated on the porphine center yielded no complexes. The complex ion was mass-selected and then characterized by collision-induced dissociation with Xe. Collisional activation exclusively led to a loss of neutral fullerene, indicating noncovalent binding of fullerene to protonated porphyrin. In addition, the dissociation yield was measured as a function of collision energy, and the energy inducing 50% dissociation was determined as a measure of binding energy. Experimental results show that C70 binds to the protonated porphyrins more strongly than C60, and electron-donating substituents at the meso positions increase the fullerene binding energy, whereas electron-withdrawing substituents decrease it. To gain insight into pi-pi interactions between protonated porphyrin and fullerene, we calculated the proton affinity and HOMO and LUMO energies of porphyrin using Hartree-Fock and configuration interaction singles theory and obtained the binding energy of the protonated porphyrin-fullerene complex using density functional theory. Theory suggests that the protonated porphyrin-fullerene complex is stabilized by pi-pi interactions where the protonated porphyrin accepts pi-electrons from fullerene, and porphyrins carrying bulky substituents prefer the end-on binding of C70 due to the steric hindrance, whereas those carrying less-bulky substituents favor the side-on binding of C70. PMID- 20923212 TI - A DFT study on the magnetostructural property of ferromagnetic heteroverdazyl diradicals with phenylene coupler. AB - We have theoretically designed five different m-phenylene coupled high-spin bis heteroverdazyl diradicals and their analogous p-phenylene coupled low-spin positional isomers. The geometry-based aromaticity index, harmonic oscillator model of aromaticity (HOMA) values for both the couplers (local HOMA), and the whole diradicals (global HOMA) have been calculated for all the diradicals. We also qualitatively relate these HOMA values with the intramolecular magnetic exchange coupling constants (J), calculated using a broken symmetry approach within unrestricted density functional theory framework. Structural aromaticity index HOMA of linkage specific benzene rings in our designed diradical systems shows that the aromatic character depends on the planarity of the molecule and it controls the sign and magnitude of J. The predicted J values are explained on the basis of spin polarization maps, average dihedral angles, and magnetic orbitals. The effect of the spin leakage phenomenon on magnetic exchange coupling constant and that on HOMA values of certain phosphaverdazyl systems has been explicitly discussed. In addition, a similar comparison is made between the calculated exchange coupling constants and corresponding HOMA values. The main novelty of this work stands on the consideration of the aromatic behavior by means of the geometrical index HOMA. We also estimate another aromaticity index, nucleus independent chemical shift (NICS) values for the phenylene coupler in each diradical to measure aromaticity and compare its value with that of HOMA. The ground state stabilities of these diradicals have also been compared. PMID- 20923213 TI - Effect of multiple ionic species on the electrophoretic behavior of a charge regulated particle. AB - It is often assumed in the conventional electrophoresis analysis that the liquid phase contains only one kind of each cation and anion. That analysis is extended to the case where the liquid phase contains multiple ionic species in this study so that the conditions considered are closer to reality. Using a dispersion of SiO(2) particles, which is of a charge-regulated nature, as an example, where the dispersion pH is adjusted by HCl and NaOH, numerical simulation is conducted to examine the electrophoretic behaviors of the particle under various conditions. We show that the presence of multiple ionic species is capable of yielding profound and interesting electrophoretic behaviors, which are justified by the experimental data in the literature. In addition, we show that two types of double-layer polarization (DLP) are present that have not been reported previously in the electrophoresis analyses. Type I DLP, which reduces the mobility of a particle, occurs inside the double layer, and type II DLP, which raises that mobility, occurs immediately outside the double layer. PMID- 20923214 TI - Effect of an encapsulated bubble in inhibiting droplet sliding. AB - The transport of liquid droplets on surfaces carrying reactants offers advantages in the creation of fluidic devices crucial for life science applications. In a majority of situations, a selection of these droplets on a surface, rather than all of them, will need to be moved at any one time. It is a formidable challenge to deliver the motive energy source only to specific droplets while leaving the others unmoved. Here, we describe an alternative novel solution of momentarily pinning specific droplets to the surface while allowing the rest to be moved. We demonstrate this concept via the injection of a sizable bubble that is attached to a PTFE surface within a droplet. This then affects the contact line of the droplet, pinning it despite the introduction of an incline that will normally result in sliding. The use of bubbles offers easy release of pinning at will by simple rupture using mechanical means. PMID- 20923215 TI - Thiol reactivity and its impact on the ciliate toxicity of alpha,beta-unsaturated aldehydes, ketones, and esters. AB - A recently introduced chemoassay has been used to determine second-order rate constants of the electrophile-nucleophile reaction of 15 alpha,beta-unsaturated aldehydes with glutathione. The respective kGSH values vary for more than 3 orders of magnitude, and are within the range determined previously for 31 alpha,beta-unsaturated ketones and esters. Structure-reactivity analyses yield distinct relationships between kGSH and structural features of the compounds. Moreover, increasing kGSH increases the aldehyde toxicity toward ciliates in terms of 48 h-EC50 values (effective concentration yielding 50% growth inhibition of Tetrahymena pyriformis within 48 h). A respective log-log regression equation including both kGSH and the octanol/water partition coefficient, Kow, yields a squared correlation coefficient of 0.96. Comparative analysis with corresponding data for 15 ketones and 16 esters reveals systematic differences between the three compound classes with regard to the individual contributions of hydrophobicity and electrophilic reactivity to aquatic toxicity. The former is particularly pronounced for aldehydes, while the ester toxicity is largely governed by reactivity, with ketones showing an intermediate pattern that is more similar to the one of esters than of aldehydes. It follows that within the Michael acceptor domain of alpha,beta-unsaturated carbonyls, a distinction between aldehydes and nonaldehydic derivatives appears necessary when employing electrophilic reactivity as a component for the quantitative prediction of their reactive toxicity toward aquatic organisms. PMID- 20923216 TI - Water stability of microporous coordination polymers and the adsorption of pharmaceuticals from water. AB - The stability of a variety of microporous coordination polymers (MCPs) to water containing solutions was studied using powder X-ray diffraction. It was determined that the stability of the MCP is related to the metal cluster present in the structure with trinuclear chromium clusters more stable than copper paddlewheel clusters which are more stable than basic zinc acetate clusters. Zn(2 methylimidizolate)(2) was found to be more water stable than zinc MCPs with carboxylate linkers; however, extended exposure to water led to decomposition of all zinc-based MCPs. Materiaux de l'Institut Lavoisier (MIL)-100 was also found to be completely water stable and was used to adsorb the pharmaceuticals furosemide and sulfasalazine from water with large uptakes achievable at low concentrations, indicating that the adsorption of wastewater contaminants may be a feasible application for these materials. PMID- 20923217 TI - Gelation behavior by the lanthanoid adsorption of the cyanobacterial extracellular polysaccharide. AB - The self-organization behavior of an extracellular polysaccharide (sacran) extracted from the cyanobacterium Aphanothece sacrum in response to lanthanoid ion adsorption was investigated. Consequently, cryogenic TEM images revealed that sacran could be cross-linked by Nd(3+) trivalent ions and formed a fibrous nanostructural network containing water. Furthermore, sacran adsorbed trivalent metal ions at a 3:1 ratio, which was the theoretical ionic adsorption and showed more efficient adsorption than alginate based on electric conductivity titration. The critical gelation concentrations, Cg, where sacran formed tough gels upon metal ion binding were estimated. The Cg for trivalent metal ions was lower than that for divalent ions, and the Cg for lanthanoid ions was particularly low at 10(-3) to 10(-4) M, changing every four elemental numbers. The extracellular matrix of Aphanothece sacrum, sacran, may adsorb metal ions to create fibrous nanostructures that reinforce the jelly matrix. PMID- 20923218 TI - Unified theory of the exciplex formation/dissipation. AB - The natural extension and reformulation of the unified theory (UT) proposed here makes it integro-differential and capable of describing the distant quenching of excitation by electron transfer, accompanied with contact but reversible exciplex formation. The numerical solution of the new UT equations allows specifying the kinetics of the fluorescence quenching and exciplex association/dissociation as well as those reactions' quantum yields. It was demonstrated that the distant electron transfer in either the normal or inverted Marcus regions screens the contact reaction of exciplex formation, especially at slow diffusion. PMID- 20923219 TI - Rh-catalyzed oxidative coupling between primary and secondary benzamides and alkynes: synthesis of polycyclic amides. AB - A methodology for the high yield and facile synthesis of isoquinolones from benzamides and alkynes via the oxidative ortho C-H activation of benzamides has been developed. Ag(2)CO(3) proved to be an optimal oxidant when MeCN was used as a solvent, and [RhCp*Cl(2)](2) was utilized as an efficient catalyst. Both N alkyl and N-aryl secondary benzamides can be applied as effective substrates. Furthermore, primary benzamides react with two alkyne units, leading to tricyclic products via double C-H activation and oxidative coupling. The reactivity of the structurally related 1-hydroxyisoquinoline was also demonstrated, where both N- and O-containing rhodacyclic intermediates can be generated, leading to the construction of different O- or N-containing heterocycles. PMID- 20923220 TI - Quantifying the perturbations of persistent organic pollutants induced by climate change. AB - A perturbed air-surface coupled model has been developed to simulate and predict perturbations of POPs concentrations in various environmental media under given climate change scenarios. By introducing the perturbations in air temperature and precipitation induced by climate change in the model, we have examined the corresponding perturbations in the concentration of POPs in the closed air-soil and air-water systems. Numerical experiments for several POPs have been conducted based on the possible future climate change scenarios. It was found that hexachlorobenzene (HCB), hexachlorocyclohexanes (HCHs), and a polychlorinated biphenyl (PCBs) congener, PCB-153, exhibit strong response to specified climate change scenarios as shown by their high concentrations perturbations in air. In the air-soil system the coupled model predicts 4-50% increases in the air concentrations of these chemicals corresponding to an increase of 0.05-0.1 K yr( 1) in the air temperature. Based on our simulations, a 20% increase/decrease in precipitation can result in a 53% and 4% decrease/increase in perturbed air concentration of gamma-HCH and alpha-HCH, respectively. Also, the model can be used to determine the direction of air-surface exchange of POP perturbations induced by climate change. PMID- 20923221 TI - Further insight into the latex metabolite profile of Ficus carica. AB - Latex is a sticky emulsion that exudes upon damage from specialized canals from several plants. It contains several biologically active compounds, such as phytosterols, fatty acids, and amino acids. In plants, these compounds are involved in the interaction between plants, insects, and the environment. Despite its chemical, biological, and ecological importance, Ficus carica latex is still poorly studied. To improve the knowledge on the metabolite profile of this matrix, a targeted metabolite analysis was performed in a representative sample from F. carica latex. Seven phytosterols were determined by gas chromatography ion trap mass spectrometry (GC-ITMS) and high-performance liquid chromatography coupled to diode array detection (HPLC-DAD), with beta-sitosterol and lupeol being the compounds present in higher concentrations (ca. 54 and 14%, respectively). A total of 18 fatty acids were characterized by GC-ITMS, being essentially represented by saturated fatty acids (ca. 86.4% of total fatty acids). A total of 13 free amino acids were also identified by high-performance liquid chromatography coupled to ultraviolet-visible spectroscopy (HPLC/UV-vis), and cysteine and tyrosine were the major ones (ca. 38.7 and 31.4%, respectively). In humans, phytosterols and some polyunsaturated fatty acids, such as linoleic acid, are known for their anticarcinogenic properties. With regard to amino acids, some of them, such as glycine, are neurotransmitters. Our results reveal the presence of a wide diversity of compounds, from distinct classes, in F. carica latex, possessing various potential pharmacological activities; thus, its biological potential appears to be worth further exploring. PMID- 20923222 TI - Effects of the design of environmental disclosure regulation on information provision: the case of Israeli securities regulation. AB - Focusing on the potential of information regulations, this article aims to contribute to ongoing efforts of policymakers to improve policy tools, in light of the increasing complexity of assessing the environmental impacts of new technologies and industrial corporations. Using the annual reports of corporations and performance data from the Ministry of Environmental Protection, the study analyzed the quality of responses to the amendments of Israel's Securities Regulations by major, publicly traded, polluting industrial corporations in Israel. The main theoretical claim of this paper is that within mandatory regulations there may be a large variability in the degree of specification of requirements. When considerable discretion is left to corporations, the result is a mixed mandatory-voluntary regulation regime. Our findings suggest that such variability impacts the implementation outcomes, as responses to environmental requirements depend on the level of discretion. Facilities increased their reported information, including the negative aspects, when specific mandatory prescriptions were stipulated. However, voluntary motivations did not result in the provision of information when corporations were allowed a high level of discretion. The authors recommend the delineation of exact stipulations of prescriptive requirements for the provision of comparative environmental information in order to obtain the environmental information deemed necessary. PMID- 20923223 TI - Molecular dynamics study of secretory phospholipase A2 of Russell's viper and bovine pancreatic sources. AB - A comparative molecular dynamics simulation of free and inhibitor-bound form of secretory phospholipase A(2) (sPLA(2)) of Russell's viper discloses the sort of restrictions in active site for inhibitor binding and implies suitable sites for further design of inhibitors based on active site scaffold. This enzyme belongs to group II PLA(2)s and dimerize asymmetrically with difference in orientation of W31 at the gateway of the active site of both the subunits. Hence, the active site of subunit A is open and that of subunit B is inaccessible to monodispersed inhibitors. PLA(2) enzymes are active at solvent-lipid interface and their action could be inhibited at the solvent environment before it reacts with aggregated substrates. Some sPLA(2)s, especially of different venom sources, undergo aggregation in a concentration-dependent manner, associate symmetrically into dimeric or trimeric form, and attain functional monomeric form during their interaction with the aggregated substrate. All sPLA(2)s exhibit catalysis with similar mechanism and show considerable differences in its way of inhibition. This necessitates conformational analysis on asymmetric dimer viper PLA(2) and its comparison with bovine pancreatic sPLA(2) (BPsPLA(2)) which belongs to group IB. BPsPLA(2) exists in monomeric form and does not have W31 at the gateway of hydrophobic pocket. In general, both monomeric and dimeric forms possess conserved active site with six subsites including the residues H48 and D49, and calcium-binding and surface loops. In the PLA(2) inhibitor complexes, the presence of calcium in monomer and W31 in dimer form is the unique feature and it makes the difference only in inhibitory mechanism without altering the catalytic mechanism. With this context, molecular dynamics simulation is performed for monomer and dimer form of sPLA(2)s in both native and complex forms. Comparison of trajectories with respect to fluctuation and deviation discloses the dynamics of surface and calcium-binding loops as well as the difference in dynamics of active site residues of group IB and II sPLA(2). Further, principal component and conformational cluster analyses are performed to substantiate the results. PMID- 20923224 TI - Novel pyridinium dyes that enable investigations of peptoids at the single molecule level. AB - Single-molecule microscopy is a powerful tool for investigating various uptake mechanisms of cell-penetrating biomolecules. A particularly interesting class of potential transporter molecules are peptoids. Fluorescence labels for such experiments need to comply with several physical, chemical, and biological requirements. Herein, we report the synthesis and photophysical investigation of new fluorescent pyridinium derived dyes. These fluorescent labels have advantageous structural variations and spacer units in order to avoid undesirable interactions with the labeled molecule and are able to easily functionalize biomolecules. In our case, cell-penetrating peptoids are successfully labeled on solid supports, and in ensemble measurements the photophysical properties of the dyes and the fluorescently labeled peptoids are investigated. Both fluorophores and peptoids are imaged at the single-molecule level in thin polymer gels. With respect to bleaching times and fluorescence lifetimes the dye molecules and the peptoids show only slightly perturbed optical behaviors. These investigations indicate that the new fluorophores fulfill well single-molecule microscopy and solid-phase synthesis requirements. PMID- 20923225 TI - Optimization of transversal relaxation of nitroxides for pulsed electron-electron double resonance spectroscopy in phospholipid membranes. AB - Pulsed electron-electron double resonance (PELDOR) spectroscopy is increasingly applied to spin-labeled membrane proteins. However, after reconstitution into liposomes, spin labels often exhibit a much faster transversal relaxation (T(m)) than in detergent micelles, thus limiting application of the method in lipid bilayers. In this study, the main reasons for enhanced transversal relaxation in phospholipid membranes were investigated systematically by use of spin-labeled derivatives of stearic acid and phosphatidylcholine as well as spin-labeled derivatives of the channel-forming peptide gramicidin A under the conditions typically employed for PELDOR distance measurements. Our results clearly show that dephasing due to instantaneous diffusion that depends on dipolar interaction among electron spins is an important contributor to the fast echo decay in cases of high local concentrations of spin labels in membranes. The main difference between spin labels in detergent micelles and membranes is their local concentration. Consequently, avoiding spin clustering and suppressing instantaneous diffusion is the key step for maximizing PELDOR sensitivity in lipid membranes. Even though proton spin diffusion is an important relaxation mechanism, only in samples of low local concentrations does deuteration of acyl chains and buffer significantly prolong T(m). In these cases, values of up to 7 MUs have been achieved. Furthermore, our study revealed that membrane composition and labeling position in the membrane can also affect T(m), either by promoting the segregation of spin-labeled species or by altering their exposure to matrix protons. Effects of other experimental parameters including temperature (<50 K), presence of oxygen, and cryoprotectant type are negligible under our experimental conditions. PMID- 20923226 TI - Exploring the changes in the structure of alpha-helical peptides adsorbed onto a single walled carbon nanotube using classical molecular dynamics simulation. AB - Classical molecular dynamics (MD) simulation has been carried out in an explicit solvent environment to understand the interaction between the single walled carbon nanotube (SWCNT) and alpha-helix. A polyalanine peptide consisting of 40 alanine residues has been chosen as the model for the alpha-helix (PA(40)). Results reveal that the SWCNT induces conformational changes in PA(40). Furthermore, breakage of hydrogen bonds in the chosen model peptides has been observed, which leads to conformational transitions (alpha -> turns) in different parts of the PA(40). Owing to these transitions, regions of different structural and energetic stability are generated in PA(40) which enable the PA(40) to curl around the surface of the SWCNT. The overall observations obtained from the MD simulations are not significantly influenced by the starting geometry and the choice of the force field. Although the qualities of structural information obtained from the MD simulation using ff03 and OPLS are different, the overall observation derived from the ff03 is similar to that of OPLS. Results from the MD simulation on the interaction of the alpha-helical fragment of the SNARES protein with the SWCNT elicit that the amino acid composition influences the interaction pattern. The wrapping of the alpha-helical fragment of the SNARES onto the SWCNT is similar to that of PA(40). Overall, there is a considerable decrease in the helical content of peptides upon interaction with SWCNTs, in agreement with the experimental findings. PMID- 20923227 TI - Cholesterol flip-flop: insights from free energy simulation studies. AB - The mechanism of lipid flip-flop motion is important for maintaining the asymmetric distribution of lipids in a biological membrane. To explore the energetics and mechanism of passive cholesterol flip-flop and its dependence on chain saturation, we performed two-dimensional umbrella sampling simulations in DPPC, POPC, and DAPC (dipalmitoyl-, palmitoyloleoyl-, and diarachidonylphosphatidylcholine) and used the string method to identify the most probable flip-flop paths based on the two-dimensional free energy maps. The resulting paths indicate that cholesterol prefers to tilt first and then move to the bilayer center where the free energy barrier exists. The barrier is lower in DAPC than in DPPC or POPC, and the calculated flip-flop rates show that cholesterol flip-flop in a poly-unsaturated bilayer is faster than in more saturated bilayers. The free energy barrier results from the unfavorable enthalpic contribution arising from cholesterol-water/lipid interactions and the favorable entropic contribution due to increased lipid dynamics. While the cholesterol-water interaction has similar contributions to the barrier due to desolvation of the cholesterol hydroxyl group in all lipids, the cholesterol lipid interaction has a much lower barrier in DAPC than in DPPC or POPC, resulting in the lower free energy barrier in DAPC. PMID- 20923228 TI - Optimization of the electrodeposition process of high-performance bismuth antimony telluride compounds for thermoelectric applications. AB - High-quality films of bismuth antimony telluride were synthesized by electrodeposition from nitric acid electroplating baths. The influence of a surfactant, sodium ligninsulfonate, on the structure, morphology, stoichiometry, and homogeneity of the deposited films has been investigated. It was found that addition of this particular surfactant significantly improved the microstructural properties as well as homogeneity of the films with a significant improvement in the thermoelectric properties over those deposited in the absence of surfactant. A detailed microprobe analysis of the deposited films yielded a stoichiometric composition of Bi(0.35)Sb(1.33)Te(3) for the films electrodeposited in the absence of surfactant and a stoichiometry of Bi(0.32)Sb(1.33)Te(3) for films deposited in the presence of surfactant. PMID- 20923229 TI - Sustainability: the art of the possible. PMID- 20923230 TI - One-step sample concentration, purification, and albumin depletion method for urinary proteomics. AB - Workflows in urinary proteomics studies are often complex and require many steps to enrich, purify, deplete, and separate the complex mixture. Many of these methods are laborious, are time-consuming, and have the potential for error. Although individual steps of these methods have been previously studied, their downstream compatibilities with fractionation technologies such as off-gel electrophoresis have not been investigated. We developed a one-step sample preparation workflow that simultaneously (i) concentrates proteins, (ii) purifies by removing salts and other low molecular weight compounds, and (iii) depletes (albumin) from urine samples. This simple and robust workflow can be multiplexed and is compatible with a diverse range of downstream multidimensional separation technologies. Additionally, because of its high reproducibility and flexibility in processing samples with different volumes and concentrations, it has the potential to be used for standardization of urinary proteomics studies, as well as for studying other body fluids of similar complexity. PMID- 20923232 TI - Tunable SERS in gold nanorod dimers through strain control on an elastomeric substrate. AB - In this Letter we provide experimental verification of the interparticle distance dependence of the SERS enhancement factor in 1 MUm gold gapped nanorods. Au dimers are fabricated from electrochemically grown heterogeneous Au-Ag-Au nanorods and deposited on a stretchable elastomer film which allows active and reversible tuning of the interparticle gap on the sub-5-nm level. Significantly, this technique allows the distance dependence to be tracked using a single dimer, thereby avoiding enhancement factor reproducibility issues arising from morphological differences in disparate nanoparticle pairs. PMID- 20923231 TI - The association-dissociation behavior of the ApoE proteins: kinetic and equilibrium studies. AB - The apolipoprotein E family consists of three major protein isoforms: apolipoprotein E4 (ApoE4), ApoE3, and ApoE2. The isoforms, which contain 299 residues, differ only by single-amino acid changes, but of the three, only ApoE4 is a risk factor for Alzheimer's disease. At micromolar concentrations, lipid free ApoE exists predominantly as tetramers. In more dilute solutions, lower molecular mass species predominate. Using fluorescence correlation spectroscopy (FCS), intermolecular fluorescence resonance energy transfer (FRET), and sedimentation methods, we found that the association-dissociation reaction of ApoE can be modeled with a monomer-dimer-tetramer process. Equilibrium constants have been determined from the sedimentation data, while the individual rate constants for association and dissociation were determined by measurement of the kinetics of dissociation of ApoE and are in agreement with the equilibrium constants. Dissociation kinetics as measured by intermolecular FRET show two phases reflecting the dissociation of tetramer to dimer and of dimer to monomer, with dissociation from tetramer to dimer being more rapid than the dissociation from dimer to monomer. The rate constants differ for the different ApoE isoforms, showing that the association-dissociation process is isoform specific. Strikingly, the association rate constants are almost 2 orders of magnitude slower than expected for a diffusion-controlled process. Dissociation kinetics were also monitored by tryptophan fluorescence in the presence of acrylamide and the data found to be consistent with the monomer-dimer-tetramer model. The approach combining multiple methods establishes the reaction scheme of ApoE self association. PMID- 20923233 TI - Synthesis, characterization, and in vitro evaluation of long-chain hyperbranched poly(ethylene glycol) as drug carrier. AB - A series of novel long-chain hyperbranched poly(ethylene glycol)s (LHPEGs) with biodegradable connections were designed and synthesized in one pot through proton transfer polymerization using PEG and commercial glycidyl methacrylate as monomers and potassium hydride as catalyst. The LHPEGs were hydrolyzed at neutral pH resulting in the decrease of molecular weights. In vitro evaluation demonstrated that LHPEGs were biocompatible and displayed negligible hemolytic activity. The efficient cellular uptake of LHPEGs was confirmed by flow cytometry and confocal laser scanning microscopy. Moreover, conjugation of a model hydrophobic anticancer drug methotrexate to LHPEGs inhibited the proliferation of a human cervical carcinoma Hela cell line. MTT assay indicated that the conjugated methotrexate dose required for 50% cellular growth inhibition against Hela cells was 20 MUg/mL. By combining the advantages of long-chain hyperbranched structure and PEG, LHPEG provides a promising drug carrier for therapeutic fields. PMID- 20923234 TI - Heat conduction across monolayer and few-layer graphenes. AB - We report the thermal conductance G of Au/Ti/graphene/SiO(2) interfaces (graphene layers 1 <= n <= 10) typical of graphene transistor contacts. We find G ~ 25 MW m(-2) K(-1) at room temperature, four times smaller than the thermal conductance of a Au/Ti/SiO(2) interface, even when n = 1. We attribute this reduction to the thermal resistance of Au/Ti/graphene and graphene/SiO(2) interfaces acting in series. The temperature dependence of G from 50 <= T <= 500 K also indicates that heat is predominantly carried by phonons through these interfaces. Our findings suggest that metal contacts can limit not only electrical transport but also thermal dissipation from submicrometer graphene devices. PMID- 20923235 TI - Differential immunogenicity and clinical relevance of kidney compartment specific antigens after renal transplantation. AB - To evaluate the pathogenic role of non-HLA antibodies after organ transplantation, 81 unique serum samples from renal transplant patients were analyzed by protein array technology on integrative genomics approach (Li, L.; et al. Proc. Natl. Acad. Sci. U.S.A. 2009, 106 (11), 4148-53; Higgins, J. P.; et al. Mol. Biol. Cell 2004, 15 (2), 649-56), validated by ELISA, and the results correlated with clinical relevance with time post-transplantation or post transplant graft function. There was a significant association of de novo non-HLA antibodies with time post-transplantation (n = 1,785) and decline in graft function over the subsequent year (n = 105). There was an enrichment of immunogenic antigens in the renal cortex (p = 0.01) with post-transplant time, and for glomerular specific targets (p = 0.02) with decline in graft function. Two targets with very strong correlation in each category (AGT and SPDYA) were validated by customized ELISA assays in independent patient sera and their localization confirmed by immunohistochemistry. In conclusion, defined profiles of these non-HLA antibodies to renal cortical proteins develop with increasing length of engraftment, and may reflect the increasing recognition of altered localization or exposure of renal tubular and interstitial proteins, affected by advancing chronic nonimmune graft injury. The panel of non-HLA antibodies to glomerular targets is most interesting, as these corresponding antigenic targets may be important pathways in functional graft injury and could provide novel targets for drug design. PMID- 20923236 TI - Alternative sigma factors in the free state are equilibrium mixtures of open and compact conformations. AB - Conformational switching upon core RNA polymerase binding is an integral part of functioning of bacterial sigma factors. Here, we have studied dynamical features of two alternative sigma factors. A study of fluorescence resonance energy transfer and hydrodynamic measurements in Escherichia coli sigma(32) suggest a compact shape like those found in complex with anti-sigma factors. On the other hand, the fluorescence anisotropy of probes attached to different regions of the protein and previous hydrogen exchange measurements suggest significant internal flexibility, particularly in the C-terminal half and region 1. In a homologous sigma factor, sigma(F) of Mycobacterium tuberculosis, emission spectra and fluorescence resonance energy transfer between the single tryptophan (W112) and probes placed in different regions suggest a compact conformation for a major part of the N-terminal half encompassing region 2 and the flexible C-terminal half. Fluorescence anisotropy measurements suggest significant flexibility in the C-terminal half and region 1, as well. Thus, free alternative sigma factors may be in equilibrium between two conformations: a compact one in which the promoter interacting motifs are trapped in the wrong conformation and another less abundant one with a more open and flexible conformation. Such flexibility may be important for promoter recognition and interaction with many partner proteins. PMID- 20923237 TI - Glycoproteomic profile in wine: a 'sweet' molecular renaissance. AB - Glycoproteins are believed to be important in several technological, oenological and allergological processes due to their physicochemical properties. The knowledge of the protein glycosylation status in wine will aid in the understanding of these processes. A multiplexed glycopeptide enrichment strategy in combination with tandem mass spectrometry was performed in order to analyze the glycoproteome of white wine. A total of 28 glycoproteins and 44 glycosylation sites were identified. The identified glycoproteins were from grape and yeast origin. In particular, several glycoproteins derived from grape, like invertase and pathogenesis-related (PR) proteins, and from the yeast, were found after the vinification process. Bioinformatic analysis revealed sequence similarity between the identified grape glycoproteins and known plant allergens. This study is an important step forward in order to investigate the implication of glycoproteins in several processes, like protein stabilization and potential allergenic cross reactivity in wine. PMID- 20923238 TI - The interface of inorganic chemistry and biology. PMID- 20923239 TI - Functional compromises among pH tolerance, site specificity, and sequence tolerance for a DNA-hydrolyzing deoxyribozyme. AB - We recently reported the identification by in vitro selection of 10MD5, a deoxyribozyme that requires both Mn2+ and Zn2+ to hydrolyze a single-stranded DNA substrate with formation of 5'-phosphate and 3'-hydroxyl termini. DNA cleavage by 10MD5 proceeds with kobs=2.7 h(-1) and rate enhancement of 10(12) over the uncatalyzed P-O hydrolysis reaction. 10MD5 has a very sharp pH optimum near 7.5, with greatly reduced DNA cleavage rate and yield when the pH is changed by only 0.1 unit in either direction. Here we have optimized 10MD5 by reselection (in vitro evolution), leading to variants with broader pH tolerance, which is important for practical DNA cleavage applications. Because of the extensive Watson-Crick complementarity between deoxyribozyme and substrate, the parent 10MD5 is inherently sequence-specific; i.e., it is able to cleave one DNA substrate sequence in preference to other sequences. 10MD5 is also site-specific because only one phosphodiester bond within the DNA substrate is cleaved, although here we show that intentionally creating Watson-Crick mismatches near the cleavage site relaxes the site specificity. Newly evolved 10MD5 variants such as 9NL27 are also sequence-specific. However, the 9NL27 site specificity is relaxed for some substrate sequences even when full Watson-Crick complementarity is maintained, corresponding to a functional compromise between pH tolerance and site specificity. The site specificity of 9NL27 may be restored by expanding its "recognition site" from ATGT (as for 10MD5) to ATGTT or larger, i.e., by considering 9NL27 to have reduced substrate sequence tolerance relative to 10MD5. These findings provide fundamental insights into the interplay among key deoxyribozyme characteristics of tolerance and selectivity, with implications for ongoing development of practical DNA-catalyzed DNA hydrolysis. PMID- 20923241 TI - Targeted oral therapies in the treatment of pulmonary arterial hypertension. AB - Recent advances in our understanding of the pathophysiology of pulmonary arterial hypertension (PAH) have led to the US FDA's approval of eight drugs for its treatment. Although guidelines for the use of PAH therapies are available and regularly updated, there is a lack of information on how these agents differ and what characteristics may enable one agent to be of greater relative clinical utility than another. Oral agents may be compared across a variety of measures, including clinical efficacy, safety and tolerability, dosing and pharmacology, potential for drug interactions, treatment adherence and suitability for use in combination regimens. Although no large, prospective, head-to-head trial has been conducted with oral agents for PAH, data from placebo-controlled studies indicate that the enrolled patient populations were remarkably homogeneous with respect to demographic and disease severity parameters. In general, data suggest that these agents improve functional capacity, delay disease progression and improve haemodynamics. Additionally, long-term sustainability of response has been demonstrated. However, there was no consistently superior agent across the primary and secondary endpoints assessed in these trials, and the magnitudes of improvements were in a fairly defined range across agents. Consequently, treatment choice may shift to other aspects such as drug safety and tolerability, potential for drug interactions, dosing convenience, treatment adherence, effect on quality of life and access to medication. In this review, the four targeted oral agents approved for the treatment of PAH in the US are reviewed, and clinical results are placed into context. PMID- 20923242 TI - Aripiprazole in acute mania and long-term treatment of bipolar disorder: a critical review by an Italian working group. AB - Bipolar disorder (BD) is a chronic illness that is characterized by recurrent episodes of mania, depression or mixed symptoms. BD has a prevalence of approximately 2-4% in the general population and is associated with a substantial burden in terms of morbidity and mortality. Mania is one of the most difficult to treat manifestations of BD and antipsychotic drugs play a major therapeutic role in this respect. Acting mainly at dopamine receptors, first-generation antipsychotics are effective in controlling symptoms of BD; however, these drugs cause troublesome extrapyramidal symptoms (EPS) and hyperprolactinaemia. The more recently developed second-generation antipsychotics, which act at other receptors, provide a broader spectrum of clinical efficacy and have a more favourable tolerability profile than first-generation antipsychotics. Some second generation antipsychotics are, however, associated with adverse effects such as weight gain and metabolic disorders, which may be cause for concern. Aripiprazole, a recently introduced second-generation antipsychotic, has a unique receptor-binding profile and mechanism of action, which are thought to account for its low propensity for weight gain, metabolic disturbances and sedation. Aripiprazole is approved in the US and in Europe for the acute management and maintenance of manic and mixed episodes associated with bipolar I disorder. In both the acute and long-term maintenance settings, clinical trials have shown aripiprazole to be clinically effective in terms of response rates, remission rates and prevention of relapse. The lack of a sedative effect does not affect the efficacy of aripiprazole in controlling mania and agitation. With both short- and long-term aripiprazole treatment, adverse event rates were similar to placebo and significantly lower than seen with comparators; one exception to this is the occurrence of EPS, which was observed more frequently in aripiprazole recipients than in patients receiving placebo, but less frequently than in patients treated with haloperidol. Aripiprazole is likely to promote treatment adherence because of its favourable tolerability profile, but more specifically focused studies are required to confirm this hypothesis. The efficacy and favourable metabolic profile of aripiprazole make it a good option in the management of acute mania and maintenance treatment, especially in an outpatient setting. Thus, aripiprazole provides clinicians with a valuable additional therapeutic option for BD. Cognizant of the lack of standardized strategies for aripiprazole dosing, switching, and prevention and management of adverse effects, an expert consensus meeting was held in Italy with the aim of producing guidelines for the use of aripiprazole in acute and long-term management of BD mania. The resulting dosage, administration and switching recommendations outlined in this report are based on empirical results from well designed aripiprazole clinical trials and clinical experience, and are in accord with the manufacturer's prescribing information. However, careful evaluation of the individual patient and a thorough risk/benefit assessment should be made prior to initiating any treatment plan. PMID- 20923244 TI - Bioequivalence of sitagliptin/metformin fixed-dose combination tablets and concomitant administration of sitagliptin and metformin in healthy adult subjects: a randomized, open-label, crossover study. AB - BACKGROUND: Treatment with an oral antihyperglycaemic agent administered as monotherapy is often unsuccessful at achieving or maintaining glycaemic control in patients with type 2 diabetes mellitus. The combined use of sitagliptin and metformin is an effective treatment for type 2 diabetes mellitus, consistent with the complementary mechanisms of action by which these two agents improve glucose control. OBJECTIVES: To establish bioequivalence between sitagliptin/metformin fixed-dose combination (FDC) tablets (Janumet(r)) and co-administration of corresponding doses of sitagliptin and metformin as individual tablets. METHODS: This was an randomized, open-label, two-part, two-period crossover study, which included a total of 48 healthy subjects, 24 subjects per part (parts I and II). Within each part, subjects were assigned to receive treatments in random order; treatment periods were separated by a washout interval of at least 7 days. Eligible study participants included healthy, non-smoking (within previous 6 months), male and female subjects aged between 18 and 45 years with a body mass index <=32 kg/m2. Part I consisted of treatments A (co-administration of sitagliptin 50 mg and metformin 500 mg) and B (sitagliptin/metformin 50 mg/500 mg FDC tablet); part II consisted of treatments C (co-administration of sitagliptin 50 mg and metformin 1000 mg) and D (sitagliptin 50 mg/metformin 1000 mg FDC tablet). Blood samples were collected pre-dose and up to 72 hours post-dose in each treatment period for determination of plasma sitagliptin and metformin concentrations and calculation of the respective pharmacokinetic parameters. The area under the plasma concentration-time curve from time zero to infinity (AUC(infinity)) and the maximum plasma concentration (C(max)) for both sitagliptin and metformin were designated as the primary and secondary study endpoints, respectively, and analysed using an ANOVA model after logarithmic transformation of the data. Bioequivalence was established if the 90% confidence intervals (CIs) for the geometric mean ratios (GMRs; FDC tablet/co administration) of the AUC(infinity) and C(max) for both sitagliptin and metformin fell within pre-specified bounds of (0.80, 1.25). RESULTS: The GMRs (90% CI) for the AUC(infinity) of sitagliptin 50 mg and metformin 500 mg were 0.98 (0.96, 1.00) and 1.0 (0.95, 1.04), respectively, and for C(max) of sitagliptin and metformin were 1.00 (0.94, 1.06) and 1.00 (0.94, 1.06), respectively. The GMRs (90% CI) for the AUC(infinity) of sitagliptin 50 mg and metformin 1000 mg (part II) were 0.97 (0.95, 0.99) and 1.00 (0.94, 1.07), respectively, and for the C(max) of sitagliptin and metformin were 0.94 (0.88, 1.01) and 1.01 (0.93, 1.10), respectively. In both part I and part II, the 90% CIs of the GMRs of the AUC(infinity) and C(max) for both sitagliptin and metformin all fell within the pre-specified bioequivalence bounds of (0.80, 1.25). Administration of single doses of sitagliptin/metformin 50 mg/500 mg (part I) and 50 mg/1000 mg FDC tablets (part II) and co-administration of corresponding doses of sitagliptin and metformin as individual tablets were generally well tolerated. CONCLUSION: The sitagliptin/metformin 50 mg/500 mg and 50 mg/1000 mg FDC tablets are bioequivalent to co-administration of corresponding doses of sitagliptin and metformin as individual tablets and support bioequivalence to the sitagliptin/metformin 50 mg/850 mg tablet strength. These results indicate that the safety and efficacy profile of co-administration of sitagliptin and metformin can be extended to the sitagliptin/metformin FDC tablets. PMID- 20923243 TI - Rationale for the use of a fixed-dose combination in the management of hypertension: efficacy and tolerability of lercanidipine/enalapril. AB - Hypertension, a significant factor in the development of cerebrovascular disorders, heart disease and renal failure, is a common disorder worldwide. Despite the availability of a wide range of antihypertensive agents, almost two thirds of hypertensive patients have poorly controlled blood pressure (BP). Numerous clinical trials have shown that most patients require at least two antihypertensive agents to achieve adequate BP control and associated significant reductions in cardiovascular morbidity and mortality. Combination therapy using two drugs with different, complementary mechanisms of action achieves better efficacy and tolerability outcomes than treatment with either component drug alone. When such a combination is administered as a fixed-dose formulation, other benefits, such as improved compliance and potentially lower costs, are also likely. The good efficacy and tolerability of the combination of a calcium channel antagonist and an angiotensin-converting enzyme inhibitor is well established, and this combination is recommended by European Society of Hypertension/European Society of Cardiology guidelines as a first choice in high risk hypertensive patients, including those with type 2 diabetes mellitus. Lercanidipine/enalapril is a promising example of a fixed-dose combination of these drug classes. In clinical trials in hypertensive patients, including those with type 2 diabetes, lercanidipine/enalapril improved BP to a greater extent than either drug as monotherapy (in patients who were previous non-responders to lercanidipine or enalapril) or the combination of lercanidipine/hydrochlorothiazide, and was equally well tolerated. Further studies are required to evaluate the cardiovascular protective effects of lercanidipine/enalapril. PMID- 20923245 TI - Effects of rifampicin (rifampin) on the pharmacokinetics and safety of ambrisentan in healthy subjects: a single-sequence, open-label study. AB - BACKGROUND: Ambrisentan is a once-daily, endothelin (ET) type A receptor selective antagonist approved for the treatment of pulmonary arterial hypertension. Ambrisentan is primarily metabolized by glucuronidation and undergoes cytochrome P450 (CYP)-mediated oxidation to a lesser extent. OBJECTIVE: To assess the effects of rifampicin (rifampin), a potent inducer of CYP3A4 and inhibitor of organic anion transporter polypeptides (OATPs), on the steady-state pharmacokinetics, safety and tolerability of ambrisentan. METHODS: This was a 14 day, single-sequence, open-label study that was conducted in 24 healthy adults. Subjects were administered oral doses of ambrisentan (10 mg) once daily on days 1 through 5 and were then co-administered ambrisentan (10 mg) plus rifampicin (600 mg) once daily on days 6 through 13. The steady-state pharmacokinetics of ambrisentan and its oxidative metabolite 4-hydroxymethyl ambrisentan were determined in the absence and presence of repeated administration of rifampicin. The main outcome measure was the analysis of ambrisentan pharmacokinetics (area under the plasma concentration-time curve during a dosage interval [AUC(tau)], maximum plasma drug concentration [C(max)] and minimum plasma drug concentration [C(min)]) for steady-state ambrisentan alone (day 5) as compared with steady state ambrisentan plus steady-state rifampicin (day 13). Adverse events (AEs), ECG recordings, vital signs and clinical laboratory parameters were monitored throughout the study and at follow-up. RESULTS: A transient increase (+87% [95% CI 79, 95]) in ambrisentan steady-state systemic exposure (AUC(tau)) was observed during the first 2 days of rifampicin co-administration. However, in the presence of steady-state rifampicin, ambrisentan C(max) and AUC(tau) values were similar (+2% [95% CI -7, 12] and -4% [-9, 2], respectively) to those observed for ambrisentan alone. Relative systemic exposure of 4-hydroxymethyl ambrisentan was unaffected by either acute or steady-state rifampicin. No serious AEs or AEs leading to withdrawal were reported and there were no clinically significant changes in vital signs, ECG recordings or clinical laboratory parameters with co administration of ambrisentan and rifampicin. CONCLUSION: Steady-state rifampicin had no clinically relevant effects on the steady-state pharmacokinetics of ambrisentan. The overall safety profile of ambrisentan was similar in the presence and absence of rifampicin. No dose adjustment of ambrisentan should be required when it is co-administered with rifampicin, a strong inducer of CYP3A4 activity and inhibitor of OATPs. PMID- 20923246 TI - A quantitative framework and strategies for management and evaluation of metabolic drug-drug interactions in oncology drug development: new molecular entities as object drugs. AB - This article outlines general strategies for the management and evaluation of pharmacokinetic drug-drug interactions (DDIs) resulting from perturbation of clearance of investigational anticancer drug candidates by concomitantly administered agents in a drug development setting, with a focus on drug candidates that cannot be evaluated in first-in-human studies in healthy subjects. A risk level classification is proposed, based on quantitative integration of knowledge derived from preclinical drug-metabolism studies evaluating the projected percentage contribution [f(i)(%)] of individual molecular determinants (e.g. cytochrome P450 isoenzymes) to the overall human clearance of the investigational agent. The following classification is proposed with respect to susceptibility to DDIs with metabolic inhibitors: a projected maximum DDI expected to result in a <=1.33-fold increase in exposure, representing a low level of risk; a projected maximum DDI expected to result in a >1.33-fold but <2-fold increase in exposure, representing a moderate level of risk; and a projected maximum DDI expected to result in a >=2-fold increase in exposure, representing a potentially high level of risk. For DDIs with metabolic inducers, the following operational classification is proposed, based on the sum of the percentage contributions of enzymes that are inducible via a common mechanism to the overall clearance of the investigational drug: <<25%, representing a low level of risk; <50%, representing a moderate level of risk; and >=50%, representing a potentially high level of risk. To ensure patient safety and to minimize bias in determination of the recommended phase II dose (RP2D), it is recommended that strong and moderate inhibitors and inducers of the major contributing enzyme are excluded in phase I dose-escalation studies of high risk compounds, whereas exclusion of strong inhibitors and inducers of the contributing enzyme(s) is recommended as being sufficient for moderate-risk compounds. For drugs that will be investigated in diseases such as glioblastoma, where there may be relatively frequent use of enzyme-inducing antiepileptic agents (EIAEDs), a separate dose-escalation study in this subpopulation is recommended to define the RP2D. For compounds in the high-risk category, if genetic deficiencies in the activity of the major drug-metabolizing enzyme are known, it is recommended that poor metabolizers be studied separately to define the RP2D for this subpopulation. Whereas concomitant medication exclusion criteria that are utilized in the phase I dose-escalation studies will probably also need to be maintained for high-risk compounds in phase II studies unless the results of a clinical DDI study indicate the absence of a clinically relevant interaction, these exclusion criteria can potentially be relaxed beyond phase I for moderate-risk compounds, if supported by the nature of clinical toxicities and the understanding of the therapeutic index in phase I. Adequately designed clinical DDI studies will not only inform potential relaxation of concomitant medication exclusion criteria in later-phase studies but, importantly, will also inform the development of pharmacokinetically derived dose-modification guidelines for use in clinical practice when coupled with adequate safety monitoring, as illustrated in the prescribing guidance for many recently approved oncology therapeutics. PMID- 20923247 TI - Pharmacokinetic and pharmacodynamic perspectives on the clinical drug development of panitumumab. AB - Panitumumab is a recombinant, fully human IgG2 monoclonal antibody directed against the epidermal growth factor receptor (EGFR). It is indicated for use as monotherapy in the treatment of patients with EGFR-expressing metastatic colorectal cancer after disease progression with standard chemotherapy. The currently indicated dose is 6 mg/kg given every 2 weeks. Panitumumab is mainly distributed into the vascular space and exhibits nonlinear pharmacokinetics that are consistent with target-mediated drug disposition, involving saturable binding to EGFR and subsequent internalization and degradation inside the cells. Panitumumab is also cleared in a linear fashion by the reticuloendothelial system, similarly to other endogenous immunoglobulins. After single-dose administration of panitumumab as a 1-hour intravenous infusion, the area under the serum concentration-time curve increases in a greater-than-dose-proportional manner as the dose increases from 0.75 to 5 mg/kg; however, at doses above 2 mg/kg, the exposure to panitumumab increases in a dose-proportional manner. Panitumumab pharmacokinetics are not meaningfully affected by the tumour type, EGFR membrane expression, tumour KRAS mutation, sex, age, race or renal or hepatic dysfunction. In addition, irinotecan-containing and paclitaxel/carboplatin-containing chemotherapeutic regimens do not appear to affect panitumumab pharmacokinetics. The results of population pharmacokinetic analyses have shown that bodyweight is the most influential covariate on panitumumab exposure, supporting the current use of bodyweight-adjusted doses (mg/kg). The relationship between the weekly dose of panitumumab and skin rash, an on-target pharmacodynamic effect of EGFR inhibition, reaches a plateau at 2.5 mg/kg, indicating that this is the optimal weekly dose. Two less-frequent dosing regimens (6 mg/kg given every 2 weeks and 9 mg/kg given every 3 weeks) achieve steady-state serum trough concentrations similar to those achieved by 2.5 mg/kg given every week, ensuring maximal EGFR coverage. Anti-panitumumab antibody production is uncommon and does not appear to have an impact on the pharmacokinetics of panitumumab. PMID- 20923249 TI - Fluoxetine disposition in patients with chronic hepatitis C treated with interferon-alpha. AB - BACKGROUND AND OBJECTIVES: Combination therapy with interferon-alpha and ribavirin is considered the treatment of choice for chronic hepatitis C. However, interferon-alpha may induce severe depression. It has been suggested that interferon-alpha is able to modify cytochrome P450 (CYP) 1A2 and 2D6 activity. We therefore decided to study the effects of the interferon-alpha-2b pegylated derivative on fluoxetine disposition in patients receiving combination chemotherapy for chronic hepatitis C. METHODS: After approval by the institutional ethics committee, 20 adult patients with chronic hepatitis C, but with no history of other liver diseases, were prospectively admitted to the study, which included phenotyping by means of a dextromethorphan test and evaluation of fluoxetine and norfluoxetine pharmacokinetic parameters (the area under the serum concentration-time curve, maximum serum concentration, time to reach the maximum serum concentration and terminal elimination half-life) before and after 2 months of continuous peginterferon-alpha-2b therapy. RESULTS: The only statistically significant difference we observed was a significant reduction in the terminal elimination half-life of fluoxetine (from 47.30 to 33.23 hours; p = 0.014) after peginterferon-alpha-2b treatment. CONCLUSION: These data suggest that interferon-alpha may induce, rather than inhibit, the biotransformation of fluoxetine. PMID- 20923250 TI - Plasma anti-Xa monitoring for low-molecular-weight heparins in patients with chronic kidney disease. PMID- 20923248 TI - Oseltamivir in seasonal, avian H5N1 and pandemic 2009 A/H1N1 influenza: pharmacokinetic and pharmacodynamic characteristics. AB - Oseltamivir is the ester-type prodrug of the neuraminidase inhibitor oseltamivir carboxylate. It has been shown to be an effective treatment for both seasonal influenza and the recent pandemic 2009 A/H1N1 influenza, reducing both the duration and severity of the illness. It is also effective when used preventively. This review aims to describe the current knowledge of the pharmacokinetic and pharmacodynamic characteristics of this agent, and to address the issue of possible therapeutic drug monitoring. According to the currently available literature, the pharmacokinetics of oseltamivir carboxylate after oral administration of oseltamivir are characterized by mean +/- SD bioavailability of 79 +/- 12%, apparent clearance of 25.3 +/- 7.0 L/h, an elimination half-life of 7.4 +/- 2.5 hours and an apparent terminal volume of distribution of 267 +/- 122 L. A maximum plasma concentration of 342 +/- 83 MUg/L, a time to reach the maximum plasma concentration of 4.2 +/- 1.1 hours, a trough plasma concentration of 168 +/- 32 MUg/L and an area under the plasma concentration-time curve from 0 to 24 hours of 6110 +/- 1330 MUg . h/L for a 75 mg twice-daily regimen were derived from literature data. The apparent clearance is highly correlated with renal function, hence the dosage needs to be adjusted in proportion to the glomerular filtration rate. Interpatient variability is moderate (28% in apparent clearance and 46% in the apparent central volume of distribution); there is no indication of significant erratic or limited absorption in given patient subgroups. The in vitro pharmacodynamics of oseltamivir carboxylate reveal wide variation in the concentration producing 50% inhibition of influenza A and B strains (range 0.17-44 MUg/L). A formal correlation between systemic exposure to oseltamivir carboxylate and clinical antiviral activity or tolerance in influenza patients has not yet been demonstrated; thus no formal therapeutic or toxic range can be proposed. The pharmacokinetic parameters of oseltamivir carboxylate after oseltamivir administration (bioavailability, apparent clearance and the volume of distribution) are fairly predictable in healthy subjects, with little interpatient variability outside the effect of renal function in all patients and bodyweight in children. Thus oseltamivir carboxylate exposure can probably be controlled with sufficient accuracy by thorough dosage adjustment according to patient characteristics. However, there is a lack of clinical study data on naturally infected patients. In addition, the therapeutic margin of oseltamivir carboxylate is poorly defined. The usefulness of systematic therapeutic drug monitoring in patients therefore appears to be questionable; however, studies are still needed to extend the knowledge to particular subgroups of patients or dosage regimens. PMID- 20923251 TI - Diclofenac epolamine plus heparin plaster versus diclofenac epolamine plaster in mild to moderate ankle sprain: a randomized, double-blind, parallel-group, placebo-controlled, multicentre, phase III trial. AB - BACKGROUND: In general sports, ankle sprain is the most frequently reported ankle injury and can cause chronic lateral ankle pain and tenderness. Treatment with NSAIDs is preferred, and several topical NSAID formulations are now available, helping to avoid the systemic adverse events typically associated with oral preparations. OBJECTIVE: To compare the efficacy and tolerability of a newly developed fixed-dose diclofenac epolamine (diclofenac hydroxyethylpyrrolidine, DHEP)/heparin plaster (Flectoparin(r) Tissugel) with that of a DHEP (Flector EP Tissugel(r)) or placebo plaster in the treatment of mild to moderate ankle sprain in adults. METHODS: This was a randomized, double-blind, parallel-group, placebo controlled, multicentre, phase III study conducted in the emergency medical centres of hospitals or private clinics in Europe. Outpatients aged 18-65 years who had suffered an acute ankle sprain (O'Donoghue grade I or II in severity, with external lateral ligament involvement) within the previous 48 hours and had peri-malleolar oedema were eligible for inclusion. A total of 430 patients were randomized to receive a DHEP/heparin 1.3%/5600 IU (n = 142), DHEP 1.3% (n = 146) or placebo (n = 142) plaster, applied once daily to the injured ankle for a total of 7 days. The primary endpoint was the mean change from baseline in pain on movement on day 3, as measured by a visual analogue scale (VAS). RESULTS: The DHEP/heparin plaster was associated with a significantly (p = 0.002) greater mean reduction from baseline in pain on movement after 3 days of treatment than the DHEP plaster (-24.2 vs -18.8 mm VAS), with each active treatment providing significantly (p <= 0.005) greater pain relief than placebo (-13.7 mm VAS). Both DHEP/heparin and DHEP were also effective in relieving other measures of pain, with DHEP/heparin recipients experiencing significantly less daily pain while leaning on the injured limb than DHEP recipients (p < 0.001). In addition, oedema was reduced to a significantly greater extent with DHEP/heparin than with placebo (day 7 only; p = 0.012). The DHEP/heparin plaster and DHEP plaster were both well tolerated, with adverse event profiles similar to that of placebo. Local adverse events were infrequent and generally mild in severity and there were no systemic adverse effects. CONCLUSION: The fixed-dose DHEP/heparin plaster is effective and has advantages over the DHEP plaster in relieving pain, and possibly also swelling, associated with mild to moderate acute ankle sprains with oedema in adults. PMID- 20923252 TI - Thermodynamic descriptors, profiles and driving forces in membrane receptor ligand interactions. AB - Extension of the (isothermal) Gibbs-Helmholtz equation for the heat capacity terms (DeltaC(p)) allows formulating a temperature function of the free (Gibbs) energy change (DeltaG). An approximation of the virtually unknown DeltaC(p) temperature function enables then to determine and numerically solve temperature functions of thermodynamic parameters DeltaH and DeltaS (enthalpy and entropy change, respectively). Analytical solutions and respective numeric procedures for several such approximation formulas are suggested in the presented paper. Agreement between results obtained by this analysis with direct microcalorimetric measurements of DeltaH (and DeltaC(p) derived from them) was approved on selected cases of biochemical interactions presented in the literature. Analysis of several ligand-membrane receptor systems indicates that temperature profiles of DeltaH and DeltaS are parallel, largely not monotonic, and frequently attain both positive and negative values within the current temperature range of biochemical reactions. Their course is determined by the reaction change of heat capacity: temperature extremes (maximum or minimum) of both DeltaH and DeltaS occur at DeltaC(p)=0, for most of these systems at roughly 285-305 K. Thus, the driving forces of these interactions may change from enthalpy-, entropy-, or enthalpy entropy-driven in a narrow temperature interval. In contrast, thermodynamic parameters of ligand-macromolecule interactions in solutions (not bound to a membrane) mostly display a monotonic course. In the case of membrane receptors, thermodynamic discrimination between pharmacologically defined groups-agonists, partial agonists, antagonists-is in general not specified and can be achieved, in the best, solely within single receptor groups. PMID- 20923253 TI - Pitrakinra for asthma. AB - IMPORTANCE OF THE FIELD: In asthma IL-4 and IL-13 have been demonstrated to play major pathogenic roles and therefore their blockade would potentially represent a plausible therapeutic approach. AREAS COVERED IN THIS REVIEW: Pitrakinra is a dual IL-4/IL-13 inhibitor currently under development for asthma and the existing preclinical and clinical data are discussed. WHAT THE READER WILL GAIN: Inhaled pitrakinra demonstrated a good anti-inflammatory potential and a good safety profile on a short-term basis but its place in asthma therapy is still to be found. TAKE HOME MESSAGE: Specific anticytokine therapies might in the near future reshape asthma therapy. PMID- 20923254 TI - Novel mesalamine-loaded beads in tablets for delayed release of drug to the colon. AB - Novel 'beads-in-a-tablet' formulations (total weight ~740-780 mg) have been prepared that meet USP 31 requirements for Delayed Release of mesalamine. Several methods are presented that overcome breakage of beads during tablet compaction were explored. Bead formulations comprise a combination of extrusion and spheronization to produce a relatively high drug load (80%), followed by coating (25%) with a colonic-targeted drug release polymer (polymethacrylates, Eudragit((r)) S100), overcoated (3%) with hydroxypropyl methylcellulose (Opadry((r))) to improve bead binding and compactability, and using 20% coat of lactose/sodium starch glycolate (Explotab((r))) as binder/disintegrant/cushioning agent, thus allowing a sufficiently thick coating to be uniform and without being broken during tablet compaction. Then, the aforementioned beads were compressed into tablets at 1500 pounds of pressure containing 400 mg of mesalamine, and finally coating the compressed tablets with Surelease((r)) (ethylcellulose):Opadry((r)) = 1:0.5 ranging from 1.5-2.5% weight gain; the resulting tablets met USP 31 dissolution requirements for delayed release tablets. PMID- 20923255 TI - Potential value of repeat stool testing for Clostridium difficile stool toxin using enzyme immunoassay? AB - OBJECTIVE: The aim of this brief review is to summarize the literature as it relates to the potential value of repeat stool testing for Clostridium difficile (C. difficile) toxin using an enzyme immunoassay (EIA) for toxin A&B and also propose a potential newer algorithm for diagnosing C. difficile. RESEARCH DESIGN AND METHODS: Two investigators conducted independent literature searches using PubMed, Web of Science, and Scopus until May 1st, 2010. All databases were searched using the terms Clostridium difficile, CDAD, antibiotic associated diarrhea, C. difficile in combination with enzyme immunoassay, enzyme linked immunosorbent assay, Clostridium difficile toxin A, Clostridium difficile toxin B, Clostridium difficile toxin and repeat stool testing. Articles which discussed EIA in C. difficile infection (CDI) patients were reviewed and relevant cross references also read and evaluated for inclusion. Selection bias could be a possible limitation of the approach used in selecting or finding articles for this article. FINDINGS: The evidence for repeat stool testing for C. difficile toxin detection using toxin EIA is becoming weaker. Most recent published practice guidelines recommend a two- or three-step testing algorithm for the detection of C. difficile. CONCLUSIONS: EIA for C. difficile stool toxin has a limited sensitivity, but, it does not warrant repeat stool testing. The data for this are suggestive but not conclusive. More studies and better tests are needed to have clear guidelines which can specify the number of tests needed in a diagnostic workup of suspected C. difficile infection. A two-step or three-step method in the diagnosis of C. difficile-associated diarrhea offered a marked increase in sensitivity compared to that of toxin A&B EIA alone. PMID- 20923256 TI - Treatment of postmenopausal women with osteoporosis with PTH(1-84) for 36 months: treatment extension study. AB - OBJECTIVE: To determine the safety and efficacy of full-length parathyroid hormone, PTH(1-84), treatment for up to 36 months by evaluating bone mineral density (BMD) changes, bone histomorphometric indices, and clinical fracture incidence in postmenopausal women with osteoporosis. BACKGROUND: The TOP trial demonstrated increased lumbar spine BMD (6.9%) versus placebo after 18 months of PTH(1-84) treatment and reduced the incidence of new vertebral fractures (61%; p = 0.001). The therapeutic benefits of long-term treatment of postmenopausal women with PTH(1-84) are unknown. METHODS: The safety and efficacy of 36 months of once daily dosing with 100 ug PTH(1-84) in postmenopausal women with osteoporosis were assessed. Women receiving placebo during the TOP trial were eligible for PTH(1 84) in the extension study. CLINICAL TRIAL REGISTRATION: NCT00172120. RESULTS: Lumbar spine BMD increased by 8.5% above baseline (p < 0.001) at 36 months of PTH(1-84) treatment, remaining stable during the last 12 months of treatment. Increases in total hip and femoral neck BMD occurred more slowly, reaching 3.2% and 3.4%, respectively above baseline at 36 months (p < 0.001). The total hip BMD showed no signs of reaching a limiting value although the femoral neck plateaued from months 24 to 36. Seven patients had vertebral fractures during the placebo phase of the TOP trial and before entering the extension study, but this rate decreased with the introduction of PTH(1-84) therapy, resulting in a single worsened vertebral fracture in the first 6 months and no further vertebral fractures from months 6 to 36. Treatment over 36 months with PTH(1-84) was well tolerated and iliac crest biopsies showed no adverse effects on bone. LIMITATIONS: There was no placebo group for BMD comparisons. The number of patients assessed for fracture incidence was small. CONCLUSIONS: PTH(1-84) treatment for 36 months resulted in significant increases in BMD at the lumbar spine and hip, was associated with a lower incidence of vertebral fracture when compared to before therapy initiation, and was well-tolerated. The continuous increases in total hip BMD suggest that prolonged PTH(1-84) treatment may be beneficial for postmenopausal osteoporosis. Increased BMD at the femoral neck and lumbar spine also showed favourable changes but plateaued between 24 and 36 months. Long-term treatment was not associated with abnormalities in bone biopsies. PMID- 20923257 TI - Incidence and characteristics of sexually transmitted acute hepatitis C virus infection among HIV-positive men who have sex with men in Copenhagen, Denmark during four years (2006-2009): a retrospective cohort study. AB - We determined the incidence of hepatitis C virus among Danish human immunodeficiency virus (HIV)-positive men who have sex with men (MSM) and described their characteristics. We included 871 HIV-positive MSM seen from 1 January 2006 to 31 December 2009 at Rigshospitalet in Copenhagen; drug users were excluded. We found 13 incident infections, i.e. a yearly incidence of 0.4%. PMID- 20923258 TI - Association between orthodontic treatment need and caries experience. AB - OBJECTIVE: To investigate the association between orthodontic treatment need (OTN) and caries experience (CE). SUBJECTS AND METHODS: Using a stratified sampling method, 748 subjects (355 females, 393 males; mean +/- standard deviation age 15.11 +/- 2.23 years) were examined. The Dental Aesthetic Index (DAI), DMFT, simple (DMFT > 0) and severe CE (DMFT > 8) were recorded. Socio economic status (SES) was assessed by recording parental education, mother's employment status, and household size. RESULTS: Higher (but not statistically significant) CE was observed in subjects with OTN (DAI > 30). The association between DAI and DMFT scores was not significant (rho = 0.05). Mean DMFT score did not vary significantly between the SES and OTN subgroups. In children with a household size >6 persons (n = 85), OTN was associated with higher CE and a higher prevalence of severe CE compared with those without OTN. In this group, when DAI treatment need grade increased, severe CE prevalence also increased from 10.8% to 50%. Similarly, in those with OTN and household size >6 persons, the odds of observing subjects with severe CE was 4.6 times higher (95% confidence interval 1.45-14.55) compared to those without OTN. CONCLUSIONS: Associations were observed between OTN and CE and also between the prevalence of severe CE and the severity of malocclusion in children with a household size >6 persons. The current findings suggest that the relationship between caries experience and malocclusion should be assessed in a wider context of SES and background factors. PMID- 20923259 TI - Anastrozole. AB - IMPORTANCE OF THE FIELD: Anastrozole is a third-generation aromatase inhibitor used in the adjuvant setting for the treatment of hormone receptor-positive breast cancer. Several adjuvant randomized trials have reported greater efficacy for anastrozole when compared to tamoxifen. AREAS COVERED IN THIS REVIEW: This review discusses the mechanism of action of anastrozole; pharmacokinetic and pharmacodynamic characteristics; results of randomized controlled trials of anastrozole compared to tamoxifen in the adjuvant treatment of postmenopausal women with hormone receptor-positive breast cancer and the safety profile of anastrozole compared to tamoxifen. WHAT THE READER WILL GAIN: The reader will gain an understanding of the basic pharmacology of anastrozole, efficacy data from clinical trials comparing anastrozole to tamoxifen, safety profile of anastrozole and ongoing areas of research. TAKE HOME MESSAGE: The adverse effects of anastrozole. PMID- 20923260 TI - Novel therapeutic strategies targeting vascular endothelium in essential hypertension. AB - IMPORTANCE OF THE FIELD: Several studies have demonstrated the high prevalence of hypertension and the crucial role of the association between endothelial function and hypertension. Thus, in depth investigation of the pathophysiological mechanisms linking endothelial dysfunction and hypertension, as well as evaluation of the efficacy of therapeutic approaches targeting vascular endothelium in states of essential hypertension seems to be of great interest. AREAS COVERED IN THIS REVIEW: The association of essential hypertension and endothelial function are discussed in depth. In addition to the classical anti hypertensive agents, agents such as statins, tetrahydrobiopterin, l-arginine, antioxidants, sildenafil, third generation beta blockers and NO-release related agents have been found to be beneficial by improving endothelial dysfunction in essential hypertension. WHAT THE READER WILL GAIN: Important aspects regarding the association of hypertension and endothelial dysfunction will be highlighted. In addition, classical and novel agents especially, will be reported thoroughly according to their effects on endothelial function in hypertension. TAKE HOME MESSAGE: There is a strong bidirectional association between essential hypertension and endothelial dysfunction. Moreover, novel agents appear to be beneficial and promising in improving endothelial function in states of hypertension. However, more studies are required to evaluate their role, as the literature lacks large scale studies. PMID- 20923261 TI - Vaccination against Toxoplasma gondii: an increasing priority for collaborative research? PMID- 20923262 TI - Tuberculosis vaccines for cattle: the way forward. PMID- 20923264 TI - Advances in the vaccination of the elderly against influenza: role of a high-dose vaccine. AB - On 23 December 2009, the US FDA approved Fluzone® High Dose, a high-dose formulation of the trivalent inactivated influenza vaccine, for prevention of influenza in people 65 years of age and older. As it was approved via an accelerated process designed to allow expeditious availability of safe and effective products with promise to treat or prevent serious or life-threatening diseases, the manufacturer is required to conduct further studies to demonstrate effectiveness. Although these studies are underway, a recently completed randomized, controlled trial demonstrated that this vaccine, containing four times more hemagglutinin than standard-dose inactivated influenza vaccines, can produce an enhanced immunologic response in subjects of 65 years of age and older, while maintaining a favorable safety profile. This article introduces the vaccine, presents currently available safety and immunogenicity data, discusses current recommendations for use, and proposes what we can expect in the coming years. PMID- 20923265 TI - MF59™ as a vaccine adjuvant: a review of safety and immunogenicity. AB - Approximately 70 years passed between the licensing of alum salts as vaccine adjuvants and that of MF59TM MF59, an oil-in-water emulsion, is currently licensed for use in the elderly as an adjuvant in seasonal influenza vaccines. Its mechanism of action is not fully understood, but enhancement of the interaction between the antigen and the dendritic cell seems to be involved. When used with seasonal influenza vaccines, an increase occurs in the hemagglutination inhibition antibody titers against some, but not all, seasonal vaccine influenza strains. The adjuvant effect is more pronounced when MF59 is combined with novel influenza antigens such as H9 and H5. The use of the adjuvant is associated with an increase in the frequency of local and systemic early post-vaccine adverse events (3-7 days), but no increase in adverse events was observed thereafter. Currently, MF59 is under evaluation as an adjuvant with other antigens such as pandemic influenza antigens and cytomegalovirus antigens. PMID- 20923266 TI - Effective control of viral infections by the adaptive immune system requires assistance from innate immunity. AB - Evaluation of: Nakayama Y, Plisch EH, Sullivan JM et al. Role of PKR and type I IFNs in viral control during primary and secondary infection. PLoS Pathog. 6(6), e1000966 (2010). During acute viral infections, innate antiviral immunity has been extensively studied for its ability to inhibit and/or control viral replication while priming the adaptive immune system. Recently, these processes have been studied for their role in assisting adaptive immunity to effectively clear or control viral rechallenge. The paper under evaluation introduces the concept that functional innate immune mechanisms such as dsRNA-activated protein kinase (PKR) and type I interferons are critical in controlling viral replication during secondary lymphocyte choriomeningitis virus infection. Elegant adoptive transfer studies revealed that during lymphocyte choriomeningitis virus secondary infections, dependence of viral control relied on expression of these innate factors in virally infected cells and not in adaptive immune T cells. Such findings illustrate that functional adaptive responses are less effective in providing protection against reinfections in the absence of innate mechanisms. This demonstrates the importance of intact innate mechanisms when considering effective vaccine strategies. PMID- 20923267 TI - Virus-like particles in vaccine development. AB - Virus-like particles (VLPs) are multiprotein structures that mimic the organization and conformation of authentic native viruses but lack the viral genome, potentially yielding safer and cheaper vaccine candidates. A handful of prophylactic VLP-based vaccines is currently commercialized worldwide: GlaxoSmithKline's Engerix (hepatitis B virus) and Cervarix (human papillomavirus), and Merck and Co., Inc.'s Recombivax HB (hepatitis B virus) and Gardasil (human papillomavirus) are some examples. Other VLP-based vaccine candidates are in clinical trials or undergoing preclinical evaluation, such as, influenza virus, parvovirus, Norwalk and various chimeric VLPs. Many others are still restricted to small-scale fundamental research, despite their success in preclinical tests. This article focuses on the essential role of VLP technology in new-generation vaccines against prevalent and emergent diseases. The implications of large-scale VLP production are discussed in the context of process control, monitorization and optimization. The main up- and down-stream technical challenges are identified and discussed accordingly. Successful VLP based vaccine blockbusters are briefly presented concomitantly with the latest results from clinical trials and the recent developments in chimeric VLP-based technology for either therapeutic or prophylactic vaccination. PMID- 20923269 TI - Cost–effectiveness of catch-up programs in human papillomavirus vaccination. AB - We reviewed cost–effectiveness models that combine routine vaccination with the human papillomavirus (HPV) vaccine with temporary catch-up programs. Cost–effectiveness results of catch-up programs are variable, and we reviewed methods and underlying assumptions to get more insight into any factor with a potential impact on cost-effectiveness. Results were dependent on differences between models used, their design and input data. Modeling aspects and assumptions were not always sufficiently described, making comparison difficult. Despite this, several differences between models likely to impact results were identified. All models used dynamic transmission modeling techniques except for one, which did not incorporate the effect of herd immunity. Catch-up strategies varied between models and comparator strategies were not necessarily the same. Cervical diseases outcomes were considered in all base cases, but the impact of genital warts was not always considered. Our article suggests that a conclusion on cost–effectiveness should be based on a fully transparent model including all possible benefits of vaccination. PMID- 20923268 TI - Experimental rabies vaccines for humans. AB - Rabies remains a global public health threat that kills more than 55,000 people per year. Rabies disproportionately affects children and, therefore, is ranked the seventh most important infectious disease due to years lost. Prevention of human rabies is accomplished by controlling rabies in domestic and wild animals, including the use of vaccination programs. The usefulness of human rabies vaccines is hampered by high cost, complicated vaccination regimens and lack of compliance, especially in areas of Africa and Asia where human rabies infections are endemic. A single-dose vaccine would greatly benefit efforts to combat this global health threat. However, a single-dose vaccine based on current inactivated vaccines does not appear feasible and other approaches are needed. Technology has advanced since modern human rabies vaccines were developed over 40 years ago. In addition, our understanding of immunological principles that influence the outcome of vaccination has increased. This article describes the current status of inactivated rabies virus vaccines and recent developments arising from the use of reverse genetics technologies designed to develop replication-deficient or single-cycle live rabies virus-based vectors for use as a single-dose rabies vaccine for humans. PMID- 20923270 TI - Genetic shifts of Neisseria meningitidis serogroup B antigens and the quest for a broadly cross-protective vaccine. AB - Serogroup B Neisseria meningitidis is the leading cause of meningococcal disease in developed countries. There is currently no vaccine offering wide-ranging protection. Development of a serogroup B polysaccharide-based vaccine has been hindered by potential risks of autoantibodies that cross-react with glycosylated host antigens. A number of subcapsular vaccine candidates, including outer membrane proteins (OMPs), are therefore being investigated. The availability of several meningococcal genome sequences has allowed for a comprehensive analysis of genetic differences occurring within the species. Novel vaccine candidates have been identified by means of reverse vaccinology utilizing the serogroup B meningococcal genome and show promising results for safe and effective vaccines against serogroup B N. meningitidis. The design of protein-based meningococcal vaccines is, however, complicated by the high level of genetic and antigenic diversity exhibited by the meningococcus. N. meningitidis has the capability to change its genome and adapt surface structures to changing environments by a variety of genetic mechanisms. Knowledge of the extent and structuring of this diversity has implications for the use of particular proteins as potential vaccine candidates. In this article, we describe the high degree of genomic variability in N. meningitidis and several of the mechanisms involved. An overview of the implications of antigenic variation of several surface-exposed proteins on their potential vaccine candidacy is provided. The outlook for the quest for broadly cross-protective meningococcal serogroup B vaccine components in the postgenomic era will be discussed. PMID- 20923271 TI - Potency testing for the experimental Na-GST-1 hookworm vaccine. AB - Over the next decade, a new generation of vaccines will target the neglected tropical diseases (NTDs). The goal of most NTD vaccines will be to reduce the morbidity and decrease the chronic debilitating nature of these often-forgotten infections – outcomes that are hard to measure in the traditional potency testing paradigm. The absence of measurable correlates of protection, a lack of permissive animal models for lethal infection, and a lack of clinical indications that do not include the induction of sterilizing immunity required us to reconsider the traditional bioassay methods for determining vaccine potency. Owing to these limitations, potency assay design for NTD vaccines will increasingly rely on a paradigm where potency testing is one among many tools to ensure that a manufacturing process yields a product of consistent quality. Herein, we discuss the evolution of our thinking regarding the design of a potency assay along these newly defined lines and its application to the release of the experimental Necator americanus-glutathione-S- transferase-1 (Na-GST-1) vaccine to prevent human hookworm infection. We discuss the necessary steps to accomplish the design and implementation of such a new potency assay as a resource for the burgeoning NTD vaccine community. Our experience is that much of the existing information is proprietary and needs to be pulled together in a single source to aid in our overall understanding of potency testing. PMID- 20923272 TI - Multiplex cytokine analysis technologies. AB - Multiplex technologies at both the mRNA and protein level have given researchers the ability to determine the co-ordinated cellular response to any given stimuli, in both biological and laboratory-derived fluids. This article examines some of the different mRNA and protein multiplex platforms available and how they may be used in assessing vaccine immunity. PMID- 20923274 TI - Proteomic biomarkers for diagnosis in acute myocardial infarction. AB - Acute myocardial infarction (AMI) is considered the leading cause of morbidity and mortality in many industrialized nations. AMI is defined currently by detection of a rise and/or fall of cardiac biomarkers at least above the 99th percentile of the upper limit. Early detection of AMI could conceivably provide important information for understanding the molecular functions of heart disease, and would enable more effective diagnosis and treatment of patients. However, diagnostic approaches currently in use for the evaluation of patients, associated with chest pain or other symptoms suggestive of AMI are acceptable, but they are time-consuming, high-cost and labour-intensive in most cases. Thus, much work is needed in the development of biomarkers for accurate and cost-effective diagnosis of AMI and for effective management of patients. In this article, we give an overview of proteomic biomarkers for rapid and reliable diagnosis of AMI, focusing on biochemical characteristics and their clinical applications for point of-care of AMI. We also postulate the future directions in the pursuit of integrated multiplex assay systems for multifunctional diagnosis in AMI. PMID- 20923275 TI - Turner's syndrome and pregnancy: has the 45,X/47,XXX mosaicism a different prognosis? Own clinical experience and literature review. AB - Turner's syndrome is characterized by an ovarian failure which occurs in most cases before puberty and leads to infertility. In less than 10% of women with Turner syndrome, puberty may occur and spontaneous pregnancies is possible but with a high risk of fetal loss, chromosomal and congenital abnormalities. We present the case of a 33-year-old woman with a mosaic Turner's syndrome karyotype 45,X/47,XXX who conceived spontaneously and had two successful pregnancies. Short stature was the only manifestation of Turner's syndrome. In the present report, we reviewed the available literature on the fertility of women with Turner's syndrome and the phenotypic effects of mosaicism for a 47,XXX cell line in Turner's syndrome. PMID- 20923276 TI - Is there any association between periodontitis and preterm low birth weight? AB - OBJECTIVE: To estimate the association between periodontitis (PD) and preterm low birth weight (LBW). STUDY DESIGN: Observational study in a University clinical setting on a population of 120 pregnant women. RESULTS: One specialist in periodontics examined all the patients. Two thresholds for definition of PD were used, which detected respectively 29 women (24%) and 4 (3%) as affected by the pathology. Six patients were lost to follow-up. Out of the remaining 114, 1 had an abortion, while 20 (17%) delivered pre-term. Eleven per cent of all women delivered low-weight babies. Ten women (9%) delivered preterm LBW babies. No association was detected between any of the two definitions of PD and any of the adverse pregnancy outcomes. CONCLUSION: This study was unable to provide evidence of association between PD and preterm LBW. PMID- 20923277 TI - A rapid, simple, and reproducible method for the isolation of mesenchymal stromal cells from Wharton's jelly without enzymatic treatment. AB - The co-infusion of mesenchymal stromal cells (MSCs) with hematopoietic stem cells could improve the hematopoietic engraftment after cord blood transplant. Adult bone marrow is the major source of MSCs for cell therapy. However, bone marrow aspiration involves an invasive procedure and, in the case of a cord blood transplant, requires the use of a third party. The umbilical cord matrix, called Wharton's jelly (WJ), was previously shown to be a valuable source of MSCs. However, the process of cell separation is not standardized and needs to be optimized. In this study, we focused on the efficiency of the isolation procedure and expansion of cells from WJ MSCs isolated from human full-term umbilical cords. MSCs were isolated from the WJ without enzyme digestion or dissection. The procedure was based only on the plastic adhesion capacities of MSCs. Briefly, umbilical cord segments of 5-10 cm were cut longitudinally and plated with the WJ onto a plastic surface for 5 days in an appropriate culture medium. After removing the cord segment, the culture was pursued until subconfluency. The number of cells and their phenotypes, clonogenic capacities, differentiation capacities, immunomodulation, and hematopoietic supportive functions were evaluated. Using this method, we were able to isolate MSCs from all human umbilical cords analyzed (n = 50). We obtained a mean of 1.4 * 10(8) cells at the second passage and >7 * 10(9) cells at the third. The expanded cells expressed characteristic markers and presented typical functional properties of MSCs such as differentiation capacities, immunologic properties, and hematopoietic supportive functions. In conclusion, we have established a simple, rapid, and reproducible protocol to isolate abundant MSCs from short segments of umbilical cords. PMID- 20923278 TI - Metabolic and reproductive characteristics of first-degree relatives of women with self-reported oligo-amenorrhoea and hirsutism. AB - OBJECTIVE: To investigate the occurrence of oligo-amenorrhoea and hirsutism, infertility and metabolic morbidity among first-degree relatives of women with and without self-reported oligo-amenorrhoea and hirsutism. DESIGN: Nested case control study. SETTING, POPULATION AND METHODS: A postal questionnaire about symptoms of oligo-amenorrhoea and hirsutism was sent to all women of the Northern Finland Birth Cohort 1966 (n = 5889). From this population were randomly selected 98 women with both symptoms and 163 without symptoms. A further questionnaire on the occurrence of oligo-amenorrhoea, hirsutism, infertility, early balding and metabolic morbidity in their relatives was sent to this subpopulation. MAIN FINDINGS: We obtained data on 183 relatives of 43 women with symptoms and 412 relatives of 86 symptomless women. Compared with relatives of symptomless women, mothers of women with symptoms suffered significantly more often from hirsutism and menstrual disorders, and sisters more often from hirsutism and infertility, and had fewer children and were more often childless. There was an increased prevalence of diabetes in the sisters and of hypertension in the fathers of women with symptoms. CONCLUSIONS: These results strengthen earlier findings of significantly increased metabolic and reproductive morbidity in the relatives of women with symptoms of PCOS. PMID- 20923279 TI - Dynamic endocrine test of inhibin B and anti-Mullerian hormone in men with non obstructive azoospermia. AB - Although both serum inhibin B (Inh-B) and anti-Mullerian hormone (AMH) concentrations have been proposed as markers of spermatogenesis in men with subfertility, there are wide overlaps with fertile controls. The main aim of this study was to evaluate stimulated serum Inh-B and AMH concentrations in men with non-obstructive azoospermia (NOA). Thirty-seven men with NOA confirmed by testicular fine-needle aspiration and 17 fertile controls participated at this prospective, case-control study. All subjects underwent the Exogenous FSH SErtoli Reserve Test (EFSERT): estimation of serum Inh-B and AMH concentrations before, 24 and 48 hours after administration of 300 IU human recombinant FSH (hrFSH). Basal serum Inh-B and AMH concentrations, as well as Inh-B concentrations at 24 and 48 h were lower in men with NOA as compared to controls. No changes in Inh-B or AMH concentrations were recorded throughout the EFSERT in either men with NOA or controls nor when men with NOA were classified according to their clinical, hormonal and cytological diagnosis. Thus, stimulated serum concentrations of Inh B and AMH, as obtained by an EFSERT, do not contribute to the diagnostic evaluation of the men with NOA, as the same information can be acquired by the basal serum concentrations of these hormones. PMID- 20923280 TI - Successful outcome of pregnancy in a patient with Cushing's disease under treatment with ketoconazole during the first trimester of gestation. AB - BACKGROUND: Ketoconazole is the most widely used medical treatment for Cushing's syndrome, but, because of its potential to cause birth defects, it is not recommended during pregnancy. Specifically, due to its antiandrogenic effects, ketoconazole entails theoretical risks of interfering with the development of external genitalia in male fetuses. CASE: A pregnancy was diagnosed at 13 weeks of gestation in a 26-year-old woman with Cushing's disease under treatment with ketoconazole. The drug was withdrawn and the patient underwent transsphenoidal surgery at 16 weeks of pregnancy. She did not develop postsurgical adrenal insufficiency and was treated with metyrapone during the second and third trimesters of gestation. Partum was induced at 34 weeks of pregnancy. The patient delivered a healthy male infant with normal external genitalia. CONCLUSION: Treatment with ketoconazole during the critical period of organogenesis did not cause congenital birth defects to the male fetus of a woman with Cushing's disease. This report should be taken into account for future cases of unplanned pregnancies in women with Cushing's syndrome treated with ketoconazole, as well in those cases in which other therapeutic options are not feasible. PMID- 20923282 TI - Microbiologic and clinical epidemiologic characteristics of the Chicago subset of a multistate outbreak of Serratia marcescens bacteremia. AB - We describe 22 patients from a multistate outbreak of Serratia marcescens bacteremia that was linked to contaminated prefilled syringes of heparin and saline supplied by 1 manufacturer. Contents of unused syringes were cultured in pools; samples from 25 (5.3%) of 472 syringes grew S. marcescens. Despite good clinical outcomes overall, patients had substantial morbidity. PMID- 20923281 TI - Patient-associated risk factors for acquisition of methicillin-resistant Staphylococcus aureus in a tertiary care hospital. AB - BACKGROUND: Determining risk factors for acquisition of methicillin-resistant Staphylococcus aureus (MRSA) in hospitals is important for defining infection control measures that may lead to fewer hospital-acquired infections. OBJECTIVE: To determine patient-associated risk factors for acquisition of MRSA in a tertiary care hospital with the goal of identifying modifiable risk factors. METHODS: A retrospective matched case-control study was performed. Case patients who acquired MRSA during hospitalization and 2 matched control patients were selected among inpatients admitted to target units during the period from 2001 through 2008. The odds of exposure to potential risk factors were compared between case patients and control patients, using matched univariate conditional logistic regression. A single multivariate conditional logistic regression model identifying independent patient-specific risk factors was generated. RESULTS: A total of 451 case patients and 866 control patients were analyzed. Factors positively associated with MRSA acquisition were as follows: target unit stay before index culture; primary diagnosis of respiratory disease, digestive tract disease, injury or trauma, or other diagnosis compared with cardiocirculatory disease; peripheral vascular disease; mechanical ventilation with pneumonia; ventricular shunting or ventriculostomy; and ciprofloxacin use. Factors associated with decreased risk were receipt of a solid-organ transplant and use of penicillins, cephalosporins, rifamycins, daptomycin or linezolid, and proton pump inhibitors. CONCLUSION: Among the factors associated with increased risk, few are modifiable. Patients with at-risk conditions could be targeted for intensive surveillance to detect acquisition sooner. The association of MRSA acquisition with target unit exposure argues for rigorous application of hand hygiene, appropriate barriers, environmental control, and strict aseptic technique for all procedures performed on such patients. Our findings support focusing efforts to prevent MRSA transmission and restriction of ciprofloxacin use. PMID- 20923283 TI - Estimating excess length of stay due to central line-associated bloodstream infection: separating the wheat from the chaff. PMID- 20923284 TI - The use of antimicrobial agents after diagnosis of viral respiratory tract infections in hospitalized adults: antibiotics or anxiolytics? AB - OBJECTIVE: Because extensive antibiotic use by inpatients has been associated with the development of multidrug-resistant organisms, we aimed to determine which variables were associated with the use of antibiotics after viral respiratory tract infection diagnosis among adult patients admitted to the hospital with respiratory symptoms. METHODS: A retrospective cohort study was conducted at 2 affiliated urban hospitals in Pennsylvania. We identified all adult patients admitted to the hospital during the period from November 1, 2005, through August 1, 2007, with a viral assay positive for influenza A or B, parainfluenza, adenovirus, or respiratory syncytial virus. Among these patients, we identified those who received antibiotics after the diagnosis of viral RTI. Data on demographics; comorbidities; and physical examination, laboratory, and radiographic findings were ascertained to identify risk factors for antimicrobial use among these patients. RESULTS: A total of 196 hospitalized patients with positive viral assay results were included; 125 of 131 patients administered antibiotics continued to receive them after viral RTI diagnosis. Among 52 patients with an abnormal chest radiograph, 46 continued antibiotic therapy. An abnormal chest radiograph was independently associated with continued antibiotic use (adjusted odds ratio, 4.28 [95% confidence interval, 1.71-10.77]; P = .002). However, the majority of patients (79 of 125 [63%]) who continued antibiotic therapy had normal chest imaging findings. Eight patients (6%) who continued antibiotic therapy and no patients who stopped developed C. difficile infection (95% CI, 1.5-infinity; P = .05), but there was no significant difference in length of stay or mortality. CONCLUSIONS: Antibiotics are commonly used to treat hospitalized patients with known acute viral RTIs. Continued use is strongly associated with abnormal radiograph findings at admission. However, the reasons for continuation of antibiotics in the treatment of the majority of patients with normal radiographs are unclear and may represent inappropriate use. PMID- 20923286 TI - Acquisition of multidrug-resistant gram-negative bacteria: incidence and risk factors within a long-term care population. AB - BACKGROUND AND OBJECTIVE: An improved understanding of the transmission dynamics of multidrug-resistant (MDR) gram-negative bacteria and the mechanism of acquisition in long-term care facilities (LTCFs) could aid in the development of prevention strategies specific to LTCFs. We thus investigated the incidence of acquisition of these pathogens among an LTCF population. DESIGN: Prospective cohort study. SETTING: Three separate wards at a 600-bed LTCF in metropolitan Boston, Massachusetts, during the period October 31, 2006, through October 22, 2007. PARTICIPANTS: One hundred seventy-two LTCF residents. METHODS: A series of rectal samples were cultured to determine acquisition of MDR gram-negative bacteria, defined as absence of MDR gram-negative bacterial colonization at baseline and de novo recovery of MDR gram-negative bacteria from a follow-up culture. Molecular typing was performed to identify genetically linked strains. A nested matched case-control study was performed to identify risk factors associated with acquisition. RESULTS: Among 135 residents for whom at least 1 follow-up culture was performed, 52 (39%) acquired at least 1 MDR gram-negative organism during the study period. Thirty-two residents (62%) had not been colonized at baseline and had acquired at least 1 MDR gram-negative species at follow-up culture, and 20 residents (38%) were colonized at baseline and had acquired at least 1 MDR gram-negative species at follow-up culture. The most common coresistance pattern was resistance to extended-spectrum penicillins, ciprofloxacin, and gentamicin (57 isolates [42.5%]). Genetically related strains of MDR gram-negative bacteria were identified among multiple residents and between roommates. On conditional logistic regression analysis, antibiotic exposure during the study period was significantly associated with acquisition of MDR gram-negative bacteria (odds ratio, 5.6 [95% confidence interval, 1.1-28.7]; P = .04). CONCLUSIONS: Acquisition of MDR gram-negative bacteria occurred frequently through resident-to-resident transmission. Existing infection control interventions need to be reevaluated. PMID- 20923287 TI - Excess length of stay due to central line-associated bloodstream infection in intensive care units in Argentina, Brazil, and Mexico. AB - OBJECTIVE: To estimate the excess length of stay in an intensive care unit (ICU) due to a central line-associated bloodstream infection (CLABSI), using a multistate model that accounts for the timing of infection. DESIGN: A cohort of 3,560 patients followed up for 36,806 days in ICUs. SETTING: Eleven ICUs in 3 Latin American countries: Argentina, Brazil, and Mexico. PATIENTS: All patients admitted to the ICU during a defined time period with a central line in place for more than 24 hours. RESULTS: The average excess length of stay due to a CLABSI increased in 10 of 11 ICUs and varied from -1.23 days to 4.69 days. A reduction in length of stay in Mexico was probably caused by an increased risk of death due to CLABSI, leading to shorter times to death. Adjusting for patient age and Average Severity of Illness Score tended to increase the estimated excess length of stays due to CLABSI. CONCLUSIONS: CLABSIs are associated with an excess length of ICU stay. The average excess length of stay varies between ICUs, most likely because of the case-mix of admissions and differences in the ways that hospitals deal with infections. PMID- 20923285 TI - The economic effect of screening orthopedic surgery patients preoperatively for methicillin-resistant Staphylococcus aureus. AB - BACKGROUND AND OBJECTIVE: Patients undergoing orthopedic surgery are susceptible to methicillin-resistant Staphylococcus aureus (MRSA) infections, which can result in increased morbidity, hospital lengths of stay, and medical costs. We sought to estimate the economic value of routine preoperative MRSA screening and decolonization of orthopedic surgery patients. METHODS: A stochastic decision analytic computer simulation model was used to evaluate the economic value of implementing this strategy (compared with no preoperative screening or decolonization) among orthopedic surgery patients from both the third-party payer and hospital perspectives. Sensitivity analyses explored the effects of varying MRSA colonization prevalence, the cost of screening and decolonization, and the probability of decolonization success. RESULTS: Preoperative MRSA screening and decolonization was strongly cost-effective (incremental cost-effectiveness ratio less than $6,000 per quality-adjusted life year) from the third-party payer perspective even when MRSA prevalence was as low as 1%, decolonization success was as low as 25%, and decolonization costs were as high as $300 per patient. In most scenarios this strategy was economically dominant (ie, less costly and more effective than no screening). From the hospital perspective, preoperative MRSA screening and decolonization was the economically dominant strategy for all scenarios explored. CONCLUSIONS: Routine preoperative screening and decolonization of orthopedic surgery patients may under many circumstances save hospitals and third-party payers money while providing health benefits. PMID- 20923288 TI - Effect of a multifaceted intervention on adherence to hand hygiene among healthcare workers: a cluster-randomized trial. AB - OBJECTIVES: Adherence to hand hygiene among healthcare workers (HCWs) is widely believed to be a key factor in reducing the spread of healthcare-associated infection. The objective of this study was to evaluate the impact of a multifaceted intervention to increase rates of adherence to hand hygiene among HCWs and to assess the effect on the incidence of hospital-acquired methicillin resistant Staphylococcus aureus (MRSA) colonization. DESIGN: Cluster-randomized controlled trial. SETTING: Thirty hospital units in 3 tertiary care hospitals in Hamilton, Ontario, Canada. INTERVENTION: After a 3-month baseline period of data collection, 15 units were randomly assigned to the intervention arm (with performance feedback, small-group teaching seminars, and posters) and 15 units to usual practice. Hand hygiene was observed during randomly selected 15-minute periods on each unit, and the incidence of MRSA colonization was measured using weekly surveillance specimens from June 2007 through May 2008. RESULTS: We found that 3,812 (48.2%) of 7,901 opportunities for hand hygiene in the intervention group resulted in adherence, compared with 3,205 (42.6%) of 7,526 opportunities in the control group (P < .001; independent t test). There was no reduction in the incidence of hospital-acquired MRSA colonization in the intervention group. CONCLUSION: Among HCWs in Ontario tertiary care hospitals, the rate of adherence to hand hygiene had a statistically significant increase of 6% with a multifaceted intervention, but the incidence of MRSA colonization was not reduced. PMID- 20923289 TI - Testosterone levels and psychological health status in men from a general population: the Tromso study. AB - AIMS: To investigate the association between endogenous testosterone levels and psychological health symptoms in men from a general population. METHODS: Total testosterone and sex hormone-binding globulin levels were analysed and free testosterone levels was calculated in 3413 men participating in the fifth Tromso study in 2001. Self-administered questionnaires including information about education, marital status, smoking habits and the Hopkins Symptom Checklist-10 (SCL-10, a 10-item psychological health questionnaire) were completed. The cross sectional data were analysed with partial association and analysis of variance and covariance. RESULTS: The complete SCL-10 was not associated with total or free testosterone, but symptoms of anxiety were negatively associated with both total and free testosterone (p<0.05). Men presumed to be testosterone deficient, with testosterone levels in the lowest 10th percentile, had increased SCL-10 score compared to men with higher testosterone levels (p=0.021), before and after adjusting for age, waist circumference, marital status, education and smoking. There was an even stronger association between men presumed to be testosterone deficient and symptoms of anxiety (p<0.001). However, men with more pronounced symptoms indicating mental disorder did not have lower testosterone levels. CONCLUSIONS: Men presumed being testosterone deficient had a higher symptom score, in particularly regarding anxiety, but they did not have pathological symptoms. Thus, lower testosterone levels was only associated with subthreshold symptoms of anxiety and depression. PMID- 20923292 TI - Demonstration of Charcot-Leyden crystals in eosinophilic cystitis. PMID- 20923293 TI - The rise of the social pathologist: the importance of social media to pathology. PMID- 20923294 TI - What are we anyway? The role of pathologists in the 21st century. PMID- 20923295 TI - Acute myeloid leukemia diagnosis in the 21st century. AB - CONTEXT: Rapid advances in understanding the molecular biology of acute myeloid leukemia are transforming the approach to diagnosis, prognostication, and treatment of these cases. OBJECTIVE: To briefly review the current state of AML classification with a particular emphasis on the role of molecular studies and their impact on the management of acute myeloid leukemia and other malignancies. DATA SOURCES: Current literature and experience of the authors. CONCLUSIONS: While morphology, immunophenotyping, cytogenetics, and clinical history continue to play an important role, an increasing number of molecular tests are now required to properly classify these cases. PMID- 20923296 TI - Nodular lymphocyte predominant Hodgkin lymphoma: diagnostic pearls and pitfalls. AB - CONTEXT: The diagnosis of nodular lymphocyte predominant Hodgkin lymphoma involves key histopathologic and immunophenotypic findings. Appropriate classification is essential owing to the unique therapeutic and prognostic implications of this diagnosis. OBJECTIVE: To define the histologic and immunophenotypic features useful in diagnosing nodular lymphocyte predominant Hodgkin lymphoma and to identify the important differential diagnostic considerations. Diagnostic difficulty can arise in differentiating nodular lymphocyte predominant Hodgkin lymphoma from classical Hodgkin lymphoma, T cell/histiocyte-rich large B-cell lymphoma, follicular lymphoma (floral variant), and follicular hyperplasia with progressive transformation of germinal centers. DESIGN: Discussion of illustrative cases including morphologic and immunophenotypic findings. RESULTS: With the morphologic and immunophenotypic methods described, a diagnosis of nodular lymphocyte predominant Hodgkin lymphoma can be made on excisional biopsies. CONCLUSION: Clinical, histologic, and immunophenotypic features are invaluable in reaching an accurate diagnosis. PMID- 20923297 TI - Adrenocortical tumors: an integrated clinical, pathologic, and molecular approach at the University of Michigan. AB - CONTEXT: The University of Michigan Health System has a rich tradition in the study and treatment of endocrine neoplasia. Recently, an integrated clinical and research program focused on primary cancer of the adrenal gland has been developed. OBJECTIVE: To discuss the foundation of the University of Michigan Adrenal Cancer Program that consists of 3 components: (1) advancement of excellent clinical care, (2) dissemination of resources and knowledge, and (3) scientific discovery. DATA SOURCES: Recent programmatic activity includes genome wide transcriptomic evaluation of human adrenocortical tumors for diagnostic and prognostic evaluation; interrogation of the Wnt signaling pathway in adrenocortical carcinoma, using mouse models and transcriptome profiling; and clinical trials with targeted therapy focused on inhibition of insulin-like growth factor signaling pathway. CONCLUSIONS: This review article presents an overview of this program and its recent activity. PMID- 20923298 TI - Sinonasal glomangiopericytoma: case report with emphasis on the differential diagnosis. AB - Glomangiopericytoma (sinonasal-type hemangiopericytoma) is an uncommon sinonasal neoplasm with a perivascular myoid phenotype. This tumor differs from conventional soft tissue hemangiopericytoma in location, biologic behavior, and histologic features. The proposed cell of origin is a modified perivascular glomuslike myoid cell. Glomangiopericytoma is an indolent tumor that tends to arise in the sinonasal tract of older adults and has a low malignant potential with excellent prognosis after surgical resection. Histologically, this lesion is composed of a diffuse, subepithelial proliferation of bland, uniform, closely packed spindled cells growing in a variety of patterns. A distinctive vascular network composed of variably sized vascular channels, the smaller of which demonstrate perivascular hyalinization, is often present. We report the case of a 48-year-old woman with epistaxis and nasal obstruction who was diagnosed with glomangiopericytoma and discuss the histologic differential diagnosis. PMID- 20923299 TI - Bronchioloalveolar carcinoma and the significance of invasion: predicting biologic behavior. AB - A resected adenocarcinoma illustrates challenges in diagnosing bronchioloalveolar carcinoma (BAC). Bronchioloalveolar carcinoma is defined by lack of invasion, something that may be difficult to assess in scars. Small (<=0.5 cm) invasive foci have little impact on the good prognosis associated with low-stage tumors. The term microinvasive adenocarcinoma or minimally invasive adenocarcinoma has been proposed for otherwise typical BACs and small invasive foci measuring 0.5 cm or less. Larger areas of invasion are associated with a more aggressive course and more reliably distinguish BAC from other variants of adenocarcinoma. Separating BAC from other forms of adenocarcinoma is important owing to differences in prognosis and emerging therapeutic strategies. PMID- 20923300 TI - Nephrogenic adenoma: report of a case and review of morphologic mimics. AB - Nephrogenic adenoma, also referred to as nephrogenic metaplasia, is an uncommon benign lesion of the urothelial tract, characterized by a circumscribed proliferation of tubules, cysts, and papillae lined by cells with low cuboidal to columnar epithelium. The diagnostic features that are useful in the recognition of this benign entity are the characteristic mixture of various architectural patterns, associated stromal edema and inflammation, hyaline sheath around tubules, eosinophilic colloidlike secretion within tubules, and lack of mitotic activity. Nephrogenic adenoma can be a significant diagnostic pitfall as certain histologic features, such as the presence of enlarged nuclei with prominent nucleoli, degenerative nuclear atypia, tiny tubules with blue mucin simulating signet ring cells, and focal invasion into superficial muscle, when taken out of context, can mimic malignancy. Herein, I report a case of nephrogenic adenoma with some worrisome histologic features and review the diagnostic criteria as well as pertinent morphologic malignant mimics of nephrogenic adenoma. PMID- 20923301 TI - Osteoblastoma. AB - Osteoblastoma is a rare benign bone tumor. Although the histologic features in most cases are distinctive, there are various permutations that make the diagnosis challenging. It can mimic a variety of other benign bone tumors, but more importantly, distinguishing it from osteoblastoma-like osteosarcoma can be difficult. In this case report, I describe the clinicopathologic findings for a 13-year-old adolescent boy with T7 spinal osteoblastoma and review salient clinical, radiographic, and pathologic features of osteoblastoma, as well as the differential diagnoses. PMID- 20923302 TI - Total colonic aganglionosis: case report, practical diagnostic approach and pitfalls. AB - Hirschsprung disease remains a challenging diagnosis for many pathologists. The disease is characterized by a lack of ganglion cells in the myenteric and submucosal plexus, associated with increased numbers of acetylcholinesterase positive nerve fibers. Hypertrophic nerve fibers are present in most but not all patients. Total colonic aganglionosis (TCA) is an uncommon form of Hirschsprung disease with clinical, histologic, and genetic differences and is even more difficult to diagnose and manage. This case illustrates some of the difficulties frequently faced by the pathologists dealing with total colonic aganglionosis. Suction rectal biopsy specimens often lack significant nerve hypertrophy and positive acetylcholinesterase staining, which aid in the diagnosis. Pathologists have to depend mainly on the lack of ganglion cells in adequate submucosa to establish the diagnosis. Transition zone is often long in total colonic aganglionosis and interpretation of frozen sections can be difficult. The presence of several uniformly distributed clusters of mature ganglion cells and lack of nerve hypertrophy are required to avoid connections at the transition zone. PMID- 20923303 TI - Fine-needle aspiration of intrapancreatic accessory spleen, mimic of pancreatic neoplasms. AB - Intrapancreatic accessory spleen (IPAS) is a congenital abnormality, which mimics neoplasm. Distinguishing IPAS from pancreatic neoplasm/malignancy is extremely important from a treatment perspective. We report the case of a 67-year-old asymptomatic man who had a 1.3-cm, incidentally detected, pancreatic tail mass. The mass was round, well-circumscribed, and hypervascular with uniform enhancement. The image findings were highly suggestive of a pancreatic endocrine neoplasm. An endoscopic ultrasound-guided fine-needle aspiration was performed. Conventional smears revealed a polymorphous population of lymphocytes admixed with a subset of other inflammatory cells. Hematoxylin-eosin-stained cell block sections showed conspicuous thin-walled blood vessels in addition to inflammatory cells. Immunostaining for CD8 demonstrated strong positivity in endothelial cells of the thin-walled vessels. By correlating the cytologic findings with the result of immunostaining, we rendered the diagnosis of IPAS. Our experience supports the view that endoscopic ultrasound-guided fine-needle aspiration may enable a reliable, preoperative diagnosis of IPAS and thus prevent unnecessary surgery. PMID- 20923304 TI - Controversies in the diagnosis of Barrett esophagus and Barrett-related dysplasia: one pathologist's perspective. AB - CONTEXT: athologists frequently assess esophageal biopsy specimens to "rule out Barrett esophagus," as well as to assess for the presence or absence of dysplasia. OBJECTIVE: To review some of the recent controversies in the diagnosis of Barrett esophagus and Barrett-related dysplasia. DATA SOURCES: Sources were the author's experience and review of the English literature from 1978 to 2009. CONCLUSIONS: Although goblet cells are required by the American College of Gastroenterology to confirm a diagnosis of Barrett esophagus, this definition might expand to include columnar-lined esophagus without goblet cells. The recognition of dysplasia in Barrett esophagus remains a difficult task for the surgical pathologist, with difficulties in distinguishing reactive epithelium from dysplasia, low-grade dysplasia from high-grade dysplasia, and even high grade dysplasia from intramucosal adenocarcinoma. PMID- 20923305 TI - The collagenous gastroenteritides: similarities and differences. AB - Collagenous gastritis, collagenous sprue, and collagenous colitis share striking histologic similarities and occur together in some patients. They also share some drug and disease associations. Pediatric cases of collagenous gastritis, however, lack most of these associations. The etiologies of the collagenous gastroenteritides are not known, so it is not clear whether they are similar because they share pathogeneses, or because they indicate a common histologic response to varying injuries. The features, disease and drug associations, and the inquiries into the pathogenesis of these disorders are reviewed. PMID- 20923306 TI - A review of sentinel laboratory performance: identification and notification of bioterrorism agents. AB - CONTEXT: The anthrax incident of 2001 in the United States prompted the College of American Pathologists (CAP), the Association of Public Health Laboratories, and the Centers for Disease Control and Prevention to develop exercises for Laboratory Response Network (LRN) sentinel laboratories. OBJECTIVE: To provide an overview of the results of the CAP bioterrorism Laboratory Preparedness Survey (LPS, 2007) and Laboratory Preparedness Exercise (LPX, 2008) and assist LRN sentinel laboratories and public health agencies in planning for bioterrorism events. DESIGN: Bioterrorism agents and nonbiothreat mimic organisms were provided in 2 mailings per year (2007 and 2008, 20 total challenges). Within each mailing, 2 to 3 agents were category A or category B bioterrorism agents (total of 10 categoric challenges). Some category A/B isolates were modified/vaccine strains. The total number of laboratories participating in these exercises ranged from 1316 to 1381. Isolate characteristics used to identify the organisms were compiled along with the participants' reporting actions. Educational commentary was provided with each exercise. RESULTS: Acceptable identification responses were as follows: Bacillus anthracis, 90% (2007) and 99.9% (2008); Yersinia pestis, 83.8% (2007) and 87.6% (2008); and Francisella tularensis subsp Holarctica, 86.6% (2007) and 91.6% (2008). The time interval between specimen receipt and notification of results to an LRN reference laboratory decreased from more than 10 days in 2007 to 3 or 4 days in 2008 for some challenges. CONCLUSIONS: The bioterrorism challenge program (LPS, LPX) provides important comparative data from more than 1300 sentinel laboratories that can be used by individual laboratories to evaluate their identification and LRN reporting performance. PMID- 20923307 TI - Diagnostic concordance of histologic lung cancer type between bronchial biopsy and cytology specimens taken during the same bronchoscopic procedure. AB - CONTEXT: The diagnosis of lung cancer is often confirmed by cytology and biopsy specimens obtained during a bronchoscopic procedure. At our institution, these specimens are read by different pathologists, and the rate of concordance was not known. OBJECTIVES: To evaluate the concordance rate in the diagnosis of lung cancer types between cytology and biopsy specimens and to correlate discordance with patient outcome. DESIGN: Specimens obtained during the same procedure, between January 1, 2000, and December 31, 2005, were identified. Cases with cytology and biopsy specimens positive for cancer were evaluated for concordance of histologic type, small cell versus non-small cell lung carcinoma. Cases with different types were considered discordant, and slides were reviewed. RESULTS: Of 231 cases, 225 (97.4%) had concordant diagnoses. Discordance was the result of misinterpretation of undifferentiated carcinoma, overinterpretation of squamous dysplasia, interpretation of suboptimal specimens with necrosis and crush artifact, and sampling error. CONCLUSIONS: Even though the cytology and biopsy specimens were reviewed by different pathologists, the concordance rate for histologic type at our institution was high, emphasizing that this is a safe practice. The few discordant cases did not affect the patient's outcome. PMID- 20923308 TI - Modified Alcian blue enhances the intraoperative diagnosis of sentinel lymph node metastasis in invasive lobular carcinoma: a prospective study. AB - CONTEXT: The sensitivity of an intraoperative diagnosis of sentinel lymph node metastasis of invasive lobular carcinoma using conventional staining is low. OBJECTIVE: To develop a fast, modified, Alcian blue stain to decrease the intraoperative false-negative results in testing for metastatic invasive lobular carcinoma. DESIGN: Modified Alcian blue was optimized. Patients who had invasive lobular carcinoma on needle biopsy were candidates for this study. Touch preparations from every sentinel lymph node were prospectively prepared in the same manner, one stained with modified Alcian blue and one with conventional staining. These slides were independently interpreted. RESULTS: A total of 121 sentinel lymph nodes from 31 patients with invasive lobular carcinoma were studied. There were 11 patients (35.5%) who had at least one positive lymph node test result. There were a total of 18 positive lymph node results (14.9%). Although 10 sentinel lymph nodes with abnormalities were detected in 7 patients with conventional staining, modified Alcian blue detected 15 sentinel lymph node abnormalities in 10 patients. Modified Alcian blue increased the sensitivity compared with conventional staining from 63.6% to 90.9% (calculated based on the number of patients) and from 55.6% to 83.3% (calculated based on number of sentinel lymph nodes). The staining process takes approximately 11 minutes. CONCLUSIONS: Modified Alcian blue stain is a relatively rapid, cheap, highly sensitive, and specific method of detecting metastatic invasive lobular carcinoma. This method can be used in conjunction with conventional staining methods used intraoperatively. PMID- 20923309 TI - Podoplanin expression in cancerous stroma induces lymphangiogenesis and predicts lymphatic spread and patient survival. AB - CONTEXT: Podoplanin is a mucin-type glycoprotein and a lymphatic endothelial marker. Immunohistochemical staining for podoplanin is currently used as a routine pathologic diagnosis tool in Japan to identify lymphatic invasion of cancer cells. Recent reports suggest that podoplanin and other proangiogenic molecules are expressed in stromal fibroblasts and myofibroblasts. OBJECTIVE: To analyze the distribution of podoplanin expression in tumor stroma and its clinical and biologic significance. DESIGN: We performed immunohistochemistry for podoplanin on tissue microarrays from 1350 cases of 14 common cancer types. RESULTS: Two hundred eighty-seven of 662 cases (43%) showed podoplanin expression in the stromal cells within cancer nests. Stromal podoplanin expression in 14 common cancer types was significantly associated with tumor stage (P < .001), lymph node metastases (P < .001), lymphatic invasion (P = .02), and venous invasion (P < .001). The stromal cells positive for podoplanin were also positive for alpha-smooth muscle actin but negative for desmin, confirming a myofibroblasts phenotype. In contrast, myofibroblasts in inflammatory fibrotic lung diseases were podoplanin negative. Lymphatic vessel density was greater in the stromas with podoplanin expression than in the stroma lacking podoplanin expressing stromal cells (P = .01). Survival data were available for non-small cell lung cancer. Stromal podoplanin expression was associated with poorer prognosis in adenocarcinoma (P < .001) and remains statistically significant after adjustment for sex, age, and stage (P = .01). CONCLUSION: Our data indicate that podoplanin expression in stromal myofibroblasts may function as a proangiogenic biomarker and may serve as a predictive marker of lymphatic/vascular spread of cancer cells and a prognostic marker of patient survival. PMID- 20923310 TI - A method for optimizing and validating institution-specific flagging criteria for automated cell counters. AB - CONTEXT: Automated cell counters use alerts (flags) to indicate which differential white blood cell counts can be released directly from the instrument and which samples require labor-intensive slide reviews. The thresholds at which many of these flags are triggered can be adjusted by individual laboratories. Many users, however, use factory-default settings or adjust the thresholds through a process of trial and error. OBJECTIVE: To develop a systematic method, combining statistical analysis and clinical judgment, to optimize the flagging thresholds on automated cell counters. DESIGN: Data from 502 samples flagged by Sysmex XE-2100/5000 (Sysmex, Kobe, Japan) instruments, with at least 1 of 5 user adjustable, white blood cell count flags, were used to change the flagging thresholds for maximal diagnostic effectiveness by optimizing the Youden index for each flag (the optimization set). The optimized thresholds were then validated with a second set of 378 samples (the validation set). RESULTS: Use of the new thresholds reduced the review rate caused by the 5 flags from 6.5% to 2.9% and improved the positive predictive value of the flagging system for any abnormality from 27% to 37%. CONCLUSIONS: This method can be used to optimize thresholds for flag alerts on automated cell counters of any type and to improve the overall positive predictive value of the flagging system at the expense of a reduction in the negative predictive value. A reduced manual review rate helps to focus resources on differential white blood cell counts that are of clinical significance and may improve turnaround time. PMID- 20923311 TI - Antihuman leukocyte antigen-specific antibody strength determined by complement dependent or solid-phase assays can predict positive donor-specific crossmatches. AB - CONTEXT: The association of circulating donor-specific antibody (DSA) strength with crossmatch results is of potential interest to predict allograft outcome. OBJECTIVES: To systematically investigate the aforementioned association and to attempt to define a cutoff value for DSA strength that can predict a positive crossmatch result. DESIGN: We analyzed DSA strength and crossmatch results from the 2006 to 2008 proficiency testing samples of the American Society of Histocompatibility and Immunogenetics (n = 50). We further validated our findings in candidates for potential kidney transplant (n = 19). RESULTS: Proficiency test samples with positive antihuman globulin T-cell crossmatch results had significantly higher DSA strength, as assessed by Luminex (Austin, Texas) mean fluorescent intensity (MFI; MFI [SD], 7860 [4770]), compared with samples with negative crossmatch results (MFI [SD], 2900 [1820]; P = .001). Similarly, higher Luminex values were observed in samples from candidates for transplant with positive antihuman globulin T-cell crossmatch results (MFI [SD], 7910 [2370] versus 2840 [1960]; P < .001). The MFI value of 6540 had 61% and 75% sensitivity and 92% and 94% specificity for predicting positive antihuman globulin T-cell crossmatches in proficiency test samples and in candidates for transplant, respectively. CONCLUSIONS: The DSA strength correlates well with crossmatch results. An MFI of 6540 predicted a positive antihuman globulin T-cell crossmatch. PMID- 20923312 TI - Ultrasound physics and instrumentation for pathologists. AB - CONTEXT: Interest in pathologist-performed ultrasound-guided fine-needle aspiration is increasing. Educational courses discuss clinical ultrasound and biopsy techniques but not ultrasound physics and instrumentation. OBJECTIVE: To review modern ultrasound physics and instrumentation to help pathologists understand the basis of modern ultrasound. DATA SOURCES: A review of recent literature and textbooks was performed. CONCLUSIONS: Ultrasound physics and instrumentation are the foundations of clinical ultrasound. The key physical principle is the piezoelectric effect. When stimulated by an electric current, certain crystals vibrate and produce ultrasound. A hand-held transducer converts electricity into ultrasound, transmits it into tissue, and listens for reflected ultrasound to return. The returning echoes are converted into electrical signals and used to create a 2-dimensional gray-scale image. Scanning at a high frequency improves axial resolution but has low tissue penetration. Electronic focusing moves the long-axis focus to depth of the object of interest and improves lateral resolution. The short-axis focus in 1-dimensional transducers is fixed, which results in poor elevational resolution away from the focal zone. Using multiple foci improves lateral resolution but degrades temporal resolution. The sonographer can adjust the dynamic range to change contrast and bring out subtle masses. Contrast resolution is limited by processing speed, monitor resolution, and gray-scale perception of the human eye. Ultrasound is an evolving field. New technologies include miniaturization, spatial compound imaging, tissue harmonics, and multidimensional transducers. Clinical cytopathologists who understand ultrasound physics, instrumentation, and clinical ultrasound are ready for the challenges of cytopathologist-performed ultrasound-guided fine-needle aspiration and core-needle biopsy in the 21st century. PMID- 20923313 TI - A cribriform urothelial neoplasm of the renal pelvis: an adenoid cysticlike variant of inverted urothelial papilloma or florid ureteritis cystica? AB - Tumors with cribriform appearance, similar to that of salivary gland adenoid cystic carcinoma, have been described at various anatomic sites. We present an unusual polypoid tumor, discovered incidentally, in the renal pelvis of an elderly man. The mass displayed a prominent cribriform architecture, akin to adenoid cystic carcinoma with an immunophenotype that supported a urothelial origin. Because of its lack of significant invasive growth and other adverse morphologic features, this lesion will likely behave in a banal fashion. This cribriform urothelial neoplasm of the renal pelvis may, in fact, represent a variant of an inverted urothelial neoplasm with a prominent cystic component or florid ureteritis cystica. It is important for pathologists to recognize this growth pattern as a possible variant of urothelial tumors. PMID- 20923314 TI - Neurocysticercosis. AB - Neurocysticercosis is a significant public health issue within the United States. Although cysticercosis was once thought to have been eradicated in the United States, the number of documented cases is rising and immigrants from endemic areas are at the highest risk for acquiring and developing this disease. The clinical presentation of neurocysticercosis is variable and vague neurologic symptoms or sudden unexplained death in individuals with risk factors may be the only available information warranting a consideration of neurocysticercosis. Radiologic and laboratory findings can help guide medical and surgical interventions, while histologic confirmation establishes a more definitive diagnosis. Encysted larvae can be found throughout the central nervous system and undergo progressive stages of decay. Degenerating vesicles elicit an inflammatory response, involving surrounding structures, and cause the major clinical symptomatology. PMID- 20923316 TI - Understanding physical factors associated with participation in community ambulation following stroke. AB - PURPOSE: This study examined the association between impaired physical function and participation in community ambulation following stroke. We hypothesised that participation would be significantly less following stroke, and that physical impairments would be associated with participation. METHOD: Using a case-control design 30 survivors of stroke aged 45 and older and 30 controls provided health status information and a self-report of participation in community ambulation (number of trips and walking-related activities (WRA) reported prospectively over a 12-day period). The association of physical impairments (strength, range of motion, sensation, muscle tone, vision, and activity limitations (gait speed and performance on complex walking tasks)) with level of participation was analysed using negative binomial regression and goodness of fit. RESULTS: Participants included 30 individuals with and 30 without stroke, average age 68 years, majority were Caucasian women. Average time since stroke was 40 months. Participation in survivors of stroke was characterised by fewer trips and WRA and lower satisfaction (p < 0.001). Usual gait speed, balance, muscle strength and muscle length were impaired (p < 0.001) in stroke vs. controls, and associated with number of trips and WRA (p < 0.05). However, these factors explained less than very little of the variance in participation. CONCLUSIONS: While individual factors were associated with level of participation, results failed to accurately predict participation in community ambulation following stroke. Other factors, such as depression, cognition and self-efficacy may be stronger determinants of participation. PMID- 20923317 TI - The impact of storage effects in biobanks on biomarker discovery in systems biology studies. AB - Sample handling and storage conditions in specimens frozen over long periods of time can severely impact marker levels. If laboratory technologies, practices and related protocols change over time, biomarker studies are potentially biased and report erroneous results. These issues and pitfalls are often overlooked in system biology studies using previously collected and stored materials, and are likely to be one notable cause for biomarker candidates failing to be validated. We present results from simulation studies quantifying the loss in statistical power to detect true biomarkers, due to diminishing concentration of analytes in samples subject to poor handling and storage conditions. PMID- 20923319 TI - Evaluation of sit-to-stand motion using a pressure distribution measurement system--effect of differences in seat hardness on sit-to-stand motion. AB - PURPOSE: This study examined differences between standing from an ordinary seat and standing from a low-repulsion mat using a pressure distribution measurement system (BIG-MAT) and identified parameters to determine sit-to-stand (STS) motion difficulty. METHOD: Ten healthy male volunteers (aged 30-38 years) participated. During STS motion from an ordinary seat and from a low-repulsion urethane mat, plantar surface pressure changes of both feet and the centre of pressure (COP) trajectory were recorded for 7 s. This series of tests was performed four times in each subject. Left and right pressure changes and COP changes were evaluated. Differences in the measurements between the low-repulsion mat and the ordinary seat were compared using the paired t-test. RESULTS: COP changes were similar to those previously reported. Time from hindfoot peak to forefoot peak was significantly shorter with the ordinary chair than with the mat (p < 0.05). Percent change in forefoot pressure at forefoot peak and hindfoot peak (p < 0.01) and percent change in forefoot pressure at forefoot peak and stabilisation (p < 0.05) were significantly different. CONCLUSIONS: Time from hindfoot peak to forefoot peak and percent change in forefoot pressure at forefoot peak and hindfoot peak were the best indicators of STS motion difficulty. PMID- 20923321 TI - Film coated tablets (ColoPulse technology) for targeted delivery in the lower intestinal tract: influence of the core composition on release characteristics. AB - The design of a film coating technology which allows a tablet to deliver the drug in the ileocolonic segment would offer new treatment possibilities. The objective is to develop a platform technology that is suitable for a broad range of drug compounds. We developed a coated tablet with a delayed, pulsatile release profile based on a pH-sensitive coating technology (ColoPulse). The production process was validated, and the effect of core composition on the in vitro release and water uptake investigated. The release profile of the standard tablet core composition, based on the use of cellulose as a filler, was independent of the coat thickness in a range of 9.0-13.2 mg/cm(2). The release profile of a coated tablet was strongly influenced when cellulose was partly replaced by the model substance glucose (loss of sigmoidal release), citric acid (stabilization), sodium bicarbonate (destabilization) or sodium benzoate (destabilization). The film coating takes up water when below the pH-threshold. However, this did not cause early disintegration of the coating. The ColoPulse technology is successfully applied on tablets. The in vitro release characteristics of the coated tablets are influenced by the composition of the core. PMID- 20923322 TI - The use and application of assistive technology to promote literacy in early childhood: a systematic review. AB - The Individuals with Disabilities Act was implemented in 1975 to assure that all children aged 0-21 years old have access and the right to an equal education. However, young children with disabilities continue to need additional support to meet the reading readiness standards as outlined in The No Child Left Behind legislation (2004). Although all children benefit from readiness skills, it is essential for children with special needs. With the technology boom of the past decade, assistive technology (AT) has been used increasingly to enhance emerging literacy skills. In order to identify current trends in the use of AT as a means to enhance emergent literacy skills in young children with disabilities, a systematic review of the literature was undertaken. The findings from this review support the scarcity of empirical research demonstrating the benefit of AT to promote emergent literacy with young children with disabilities. We also found a need for evidence supporting education approaches for the proper use of AT in early childhood literacy as well as little family knowledge regarding the implementation and instructional use of AT. PMID- 20923323 TI - Effects of extremely low-frequency magnetic field on growth and differentiation of human mesenchymal stem cells. AB - Human Mesenchymal Stem Cells (hMSCs) were exposed to a developed extremely low frequency (ELF) magnetic fields (50 Hz ,20 mT ELF) system to evaluate whether exposure to (ELF) magnetic fields affects growth, metabolism, and differentiation of hMSCs. MTT method was used to determine the growth and metabolism of hMSCs following exposure to ELF magnetic fields. Na(+)/K(+) concentration and osmolality of extracellular were measured after exposured culture. Alkaline phosphatase (ALP) assay and Calcium assay, ALP staining, and Alizarin red staining were performed to evaluate the osteogenic differentiation of hMSCs under the ELF magnetic field exposure. In these experiments, the cells were exposed to ELF for up to 23 days. The results showed that exposure to ELF magnetic field could inhibit the growth and metabolism of hMSC, but have no significant effect on differentiation of hMSCs. These results suggested that ELF magnetic field may influence the early development of hMSCs related adult cells. PMID- 20923325 TI - Evaluation of non ionizing radiation around the dielectric heaters and sealers: a case report. AB - Dielectric heaters and sealers present the most common source of occupational exposure to excessive radio frequency (RF) fields. These systems are used industrially to heat or melt dielectric materials. Nowadays, the effects of high frequency electromagnetic (EM) fields on the health have been discussed frequently but there are few health studies done for workers around dielectric heaters and sealers. In this study, the leakage fields around dielectric heaters and sealers (27.12 MHz) were measured in MKE--Mechanical and Chemical Industry Corporation, Gazi Rocket Factory and evaluated in terms of standards. It has been observed that operators exposed to same RF fields with occupational exposure limits. Many workers have health complaints, such as elevated body temperatures in the factory. Safe distances or areas for workers should be recommended in these systems. Protective measures could be implemented to minimize these exposures. Further measurements and occupational exposure studies of RF exposed women and men are needed to demonstrate the levels of exposed Radio Frequency Radiation (RFR). Precautions should therefore be taken either to reduce the leakage fields or minimise the exposed fields. PMID- 20923326 TI - HLA-class II genes in Mexican Amerindian Mayas: relatedness with Guatemalan Mayans and other populations. AB - We analyzed the HLA class II allele frequencies in 50 healthy unrelated Mayan individuals. The relationship with other worldwide populations was studied by using HLA data from 71 different populations. The most frequent alleles were HLA DRB1*04, HLA-DRB1*01, HLA-DQB1*0302 and HLA-DQB1*0501. When comparisons with other Mexican Amerindian groups were made, some differences were observed. Mayans showed an increased frequency of HLA-DRB1*01 when compared to Nahuas, Mayos, Teenek and Mazatecans (p < 0.05), whereas the HLA-DRB1*04 was increased in Mayans when compared to Nahuas (p < 0.05). The analysis of HLA-DQB1 alleles showed an increased frequency of DQB1*0302 in Mayans when compared to Nahuas and Mazatecans (p < 0.05), whereas the frequency of HLA-DQB1*0301 was decreased in Mayans when compared to Nahuas, Mayos, Teenek and Mazatecans (p < 0.05). Decreased frequency of HLA-DQB1*0501 in Mayans when compared to Nahuas was found. Neighbour Joining dendrogram shows that Mexican Mayans are genetically close to some of the most ancient groups living in Mexico and some South American Amerindians. However, Guatemalan Mayans do not cluster together with Mexican Mayas showing that languages do not correlate with genes, particularly in Amerindians. The data corroborate the restricted polymorphism of HLA-DRB1 and DQB1 alleles and the high frequency of HLA-DRB1*04 and HLA-DQB1*0302 in Mayans from Mexico. PMID- 20923324 TI - Matrix metalloproteinase-9 and plasminogen activator inhibitor-1 are associated with right ventricular structure and function: the MESA-RV Study. AB - Elevated resistance and reduced compliance of the pulmonary vasculature increase right ventricular (RV) afterload. Local and systemic inflammation and haemostatic abnormalities are prominent in pulmonary vascular diseases. We hypothesized that plasma biomarker levels indicating greater inflammation and coagulability associated with pulmonary vascular disease would be associated with RV structure and function measured by cardiac magnetic resonance imaging (MRI). The Multi Ethnic Study of Atherosclerosis (MESA) performed cardiac MRI among participants aged 45-84 years without clinical cardiovascular disease. We assessed the associations of RV mass, RV end-diastolic volume (RVEDV), RV stroke volume (RVSV) and RV ejection fraction (RVEF) with plasma measures of inflammation (matrix metalloproteinase (MMP)-3 and -9, intercellular adhesion molecule (ICAM)-1, tumour necrosis factor receptor (TNF-R1), and E-selectin) and thrombosis (plasminogen activator inhibitor (PAI)-1, tissue factor, tissue factor pathway inhibitor and CD40 ligand).The study sample included 731 subjects. Higher MMP-9 levels were associated with lower RV mass before and after adjustment for left ventricular (LV) mass (p=0.008 and p=0.044, respectively). Higher levels of MMP-9 and PAI-1 were also associated with smaller RVEDV (p<0.05). Higher PAI-1 levels were associated with lower RVEF even after adjustment for LV ejection fraction (p=0.017). In conclusion, MMP-9 and PAI-1 are associated with changes in RV structure and function which could be potentially related to a subclinical increase in pulmonary vascular resistance. PMID- 20923327 TI - HLA genes in Wayu Amerindians from Colombia. AB - Amerindians origins and prehistory are still debated. HLA profile is different to all other World populations, although they have particular alleles in common with Asians, Australians and Pacific Islanders. In the present work, HLA-A, -B, -DRB1, -DQB1 alleles have been studied in Wayu Amerindians from Colombia. HLA alleles haplotypes, genetic distances and NJ dendrograms were calculated by Arlequin and DISPAN software. Only a few both class I and class II alleles have been observed. Most common extended haplotypes include: A*24-B*51-DRB1*0403-DQB1*0302, A*2-B*15 DRB1*1602-DQB1*0301, A*2-B*35-DRB1*0407-DQB1*0302, but also A*68-B*15-DRB1*0403 DQB1*0302. No trace of Caucasoid or Negroid admixture is detected. The Wayu HLA profile is typical from Amerindians and shows how languages and genes do not correlated particularly in this case (i.e., Wayu closest HLA genetic group is North Argentinian Guarani group). Results obtained in this work may be useful for future transplant programs and also for HLA linked diseases and individualized pharmacogenetics. PMID- 20923328 TI - Anti-inflammatory effect of glycoprotein isolated from Cudrania tricuspidata Bureau: involvement of MAPK/NF-kappaB signaling. AB - The aim of this study was to evaluate inhibitory effect of glycoprotein isolated from Cudrania tricuspidata Bureau (CTB glycoprotein) on allergic responses. We evaluated the activities of mitogen-activated protein kinase (MAPK), transcriptional factor, and production of immunoglobulin (Ig)E and interleukin (IL)-4 in RBL-2H3 cells and BALB/c mice. Our results showed that CTB glycoprotein inhibited the production of IgE and IL-4 in serum from ovalbumin (OVA)-treated BALB/c mice. We also found that CTB glycoprotein inhibited the phosphorylation of p38 MAPK, and transcriptional activation of nuclear factor (NF)-kappaB in RBL-2H3 cells. The activation of NF-kappaB was effectively blocked by treatment with p38 MAPK inhibitor (SKF86002). The results from these experiments indicate that the CTB glycoprotein inhibits release of beta-hexosaminidase, and production of IgE and IL-4 via down regulation of MAPK/ NF-kappaB on the stage of mast cell degranulation. In conclusion, we suggest that the CTB glycoprotein might be a potent preventive agent in allergic responses. PMID- 20923329 TI - No evidence of cellular alterations by MilliTesla-level static and 50 Hz magnetic fields on S. cerevisiae. AB - In an attempt to determine whether magnetic field (MF) exposures might induce cellular alterations, S. cerevisiae yeast cells were exposed to static or sinusoidal 50 Hz homogeneous MF (0.35 mT, 1.4 mT, and 2.45 mT) for 1 h and 72 h. Unsynchronized cells grown exponentially while exposed to MF, containing cells in all stages of the mitotic cell cycle. MF was generated by a pair of Helmholtz coils (40 cm in diameter, coaxial, separated by 20 cm). Survival, cell cycle distribution, colony forming ability, and mutation frequency were assayed. No differences in the above-mentioned parameters were observed in MF exposed samples in relation to unexposed controls, suggesting that homogeneous MF at these intensities do not produce appreciable cellular alterations in this organism under typical in vitro growth conditions. PMID- 20923330 TI - Extremely-low frequency magnetic field effects on sulfate reducing bacteria viability. AB - 50 Hz magnetic fields effects on Sulfate Reducing Bacteria (SRB) viability were studied by colony forming units (CFU) counting. We found a 15% decrease of CFU number after magnetic field exposure (B=7.1 mT, f=50 Hz, t=24 min) compared to the control samples. These results are in good agreement with our previous work on other bacterial strains. The magnetic field effects on SRB are relatively large for small magnetic fields. The data correlations have been subjected to a simple physical chemical analysis, yielding surprisingly large estimates for the characteristic magnetic reaction susceptibility, even when the entire bacterium is assumed to be the direct target of interaction of the magnetic ac fields for the exposures in the time range from 3-24 min. PMID- 20923332 TI - Influenza virus RNA structure: unique and common features. AB - The influenza A virus genome consists of eight negative-sense RNA segments. Here we review the currently available data on structure-function relationships in influenza virus RNAs. Various ideas and hypotheses about the roles of influenza virus RNA folding in the virus replication are also discussed in relation to other viruses. PMID- 20923331 TI - Antitumor activity of glycosylated molluscan hemocyanins via Guerin ascites tumor. AB - As observed in most molluscan hemocyanins, high-mannose type glycans were identified in hemocyanins from Rapana venosa (RvH), Helix lucorum (HlH) and keyhole limpet (Megatura crenulata). In addition, a glycan with a branching structure containing xylose, fucose and terminal methyl hexose was identified in beta-HlH. We have examined the immuno-adjuvant properties of hemocyanins, their derivatives and conjugates associated with the cell mediated immunity in experimental tumor-bearing animals with ascites tumor of Guerin. After immunization of the animals with the experimental vaccine preparations, the highest values of splenic lymphocytes were observed in groups immunized with the conjugates RvH-TAg, beta-HlH-TAg and KLH-TAg (42.3%; 40.8% and 40.58%, respectively) than with the native hemocyanins (36.5%; 35.1% and 32.4%, respectively). The immunization of rats with the hemocyanins beta-HlH, RvH and KLH and their conjugates, prolonged the median survival time of tumor-bearing animals compared with non-immunized animals (39, 33, 31 and 7 days, respectively). Both hemocyanins beta-HlH and RvH activate the immune system of the experimental animals and therefore could be a good alternative for KLH. For this reason they could be included into the composition of non-specific anti tumor vaccines to enhance their effectiveness. PMID- 20923333 TI - Should lung ultrasonography be more widely used in the assessment of acute respiratory disease? PMID- 20923336 TI - Probiotics for the prevention of ventilator-associated pneumonia. PMID- 20923335 TI - Budesonide/formoterol in the treatment of asthma. AB - Budesonide and formoterol are available in a combined inhaler that offers therapeutic advantages in the treatment of asthma. The rapid onset of bronchodilation seen with formoterol means that budesonide/formoterol can be used as both maintenance and relief therapy. This approach has been shown to reduce exacerbations and overcome the problem of patients who overuse short-acting β-agonists at the expense of inhaled corticosteroids. Concerns regarding safety of long-acting β-agonists have not been confirmed in studies of the budesonide/formoterol combination inhaler, and we believe the benefits of this medication clearly outweigh any possible small increased risk. PMID- 20923338 TI - Should atopy be assessed in elderly patients with respiratory symptoms suggestive of asthma? AB - Aging is associated with modifications of the immune system and this could contribute to a reduced prevalence of allergic disease in the elderly. Atopy has rarely been considered in the clinical assessment of the geriatric respiratory patient. This article is a review of the available literature assessing the impact of age on atopy in the asthmatic patient. In the majority of papers, we found a lower prevalence of atopy in the most advanced ages, both in healthy subjects and in individuals affected by allergic respiratory diseases. No large, longitudinal studies performed in the general population have been conducted to confirm this observation. Although available data seem to favor the decline of allergen sensitization with age, the prevalence of allergic sensitizations in the elderly population with respiratory symptoms is substantial enough to warrant evaluation of the atopic condition. For this reason, the evaluation of the atopic condition in the geriatric patient is recommended. The role of atopy as regards diagnosis, therapy and prognosis of asthma in the elderly is addressed. PMID- 20923339 TI - Preterm birth and respiratory disease in later life. AB - Chronic respiratory diseases are a common complication of preterm birth, particularly among very immature infants or those suffering from bronchopulmonary dysplasia. Major progress in the treatment of preterm newborns has changed the pattern of late respiratory complications. The major respiratory problem in infancy and early childhood is respiratory exacerbations caused by infections (particularly viral ones), which need hospitalization. The symptoms become mild in school-age children; however, a group of children still present with chronic airway obstruction defined by recurrent episodes of wheezing and decreased lung function tests (decreased forced expiratory volume). For some preterm infants, particularly those with bronchopulmonary dysplasia, obstructive lung disease persists into adulthood. They are very likely to develop chronic obstructive pulmonary disease or similar disease later in life. In these patients, a program of lung function monitoring and pulmonary prophylaxis by means of elimination of specific risk factors in adulthood is advisable. PMID- 20923337 TI - Autophagy in cigarette smoke-induced chronic obstructive pulmonary disease. AB - The molecular and cellular mechanisms underlying the pathogenesis of chronic obstructive pulmonary disease (COPD) remain incompletely understood. We have investigated the potential role of macro-autophagy, a cellular homeostatic mechanism, in COPD and cigarette smoke-induced lung-cell injury. Autophagy is a dynamic process for the turnover of organelles and proteins, which regenerates metabolic precursors through the lysosomal-dependent catabolism of cellular macromolecules. It is typically associated with survival pathways, especially in nutrient deficiency states. The role of autophagy in human diseases is less clear, and has been associated with both protective and detrimental consequences, depending on the disease model. While autophagy is considered cytoprotective, this process is often found in association with cell death, and the relationships between autophagy and cell death remain ambiguous. We have found elevated autophagy in COPD lung specimens, as well as in response to cigarette smoke exposure in vitro and in vivo. In our studies, the activation of autophagic proteins was associated with epithelial cell apoptosis in response to cigarette smoke, with pathogenic implications in COPD. Further studies are needed to determine the functional significance of autophagy in COPD and other diseases of the lung. PMID- 20923340 TI - What's new in asthma pathophysiology and immunopathology? AB - Research on asthma pathophysiology over the past decade has expanded the complex repertoire involved in the pathophysiology of asthma to include inflammatory, immune and structural cells, as well as a wide range of mediators. Studies have identified a role for connective and other mesenchymal tissues involved in airway remodeling. Recent findings have implicated the innate immune response in asthma and have revealed interesting patterns of interaction between the innate and adaptive immune response and the associated complex chronic inflammatory reaction. New immune cell populations have also been added to this repertoire, including Tregs, natural killer T cells and Th17 cells. The role of the eosinophil, a prominent pathological feature in most asthma phenotypes, has also been expanding to include roles such as tissue modifiers and immune regulators via a number of fascinating and hitherto unexplored mechanistic pathways. In addition, new and significant roles have been proposed for airway smooth muscle cells, fibroblasts, epithelial and endothelial cells. Tissue remodeling is now considered an integral element of asthma pathophysiology. Finally, an intricate network of mediators, released from both immune and inflammatory cells, including thymus stromal lymphopoietin and matrix metalloproteinases, have added to the complex milieu of asthma immunity and inflammation. These findings have implications for therapy and the search for novel strategies towards better disease management. Sadly, and perhaps due to the complex nature of asthma, advances in therapeutic discoveries and developments have been limited. Thus, understanding the precise roles played by the numerous dramatis personae in this odyssey, both individually and collectively within the context of asthma pathophysiology, continues to pose new challenges. It is clear that the next stage in this saga is to embark on studies that transcend reductionist approaches to involve system analysis of the complex and multiple variables involved in asthma, including the need to narrow down the phenotypes of this condition based on careful analysis of the organs (lung and airways), cells, mediators and other factors involved in bronchial asthma. PMID- 20923342 TI - Lung epithelial wound healing in health and disease. AB - Physiological lung epithelial wound repair is a complex, highly orchestrated process presenting numerous points where dysregulation may occur, leading to the development of several pulmonary disorders. Current studies are limited by a lack of relevant lung injury models, with much work relying on other organ models such as the skin or in vitro cultures. However, much promising investigative work is being undertaken, some of which is described in this article. This article attempts to describe the processes required to heal a severe wound to the airway epithelium, characteristic of several chronic pulmonary disorders, highlighting areas where dysregulation may occur, which in turn leads to the development or continuation of a disease state. PMID- 20923343 TI - Short-course fluoroquinolones in acute exacerbations of chronic bronchitis. AB - It is estimated that 50-70% of acute exacerbations of chronic bronchitis (AECB) are caused by bacterial infections. Appropriate selection of antimicrobials may lead to better outcomes and reduced healthcare costs. Respiratory fluoroquinolones (moxifloxacin, levofloxacin and gemifloxacin) have a broad spectrum of activity against most AECB-causing pathogens and are used as first line treatment in patients with comorbidity, severe airway obstruction or recurrent exacerbations. We review studies, identified through a MEDLINE search, that compared clinical efficacy and speed of recovery for short-course (<= 5 days) fluoroquinolone therapy with commonly prescribed standard therapy (>= 7 days). Among 177 studies reporting the use of fluoroquinolones for AECB treatment, 23 used a short-course regimen, shown to be at least as effective as standard therapy of 7 or more days duration. Furthermore, evidence suggests that short-course therapy offers faster resolution of symptoms, faster rate of recovery, fewer relapses, fewer and shorter hospitalizations, and longer time between recurrences. PMID- 20923344 TI - Monitoring chronic cough: current and future techniques. AB - Coughing produces a characteristic sound that is readily recognized by the human ear and provides the opportunity to objectively quantify coughing through acoustic recordings. The development of digital recording technologies has facilitated such recordings over the extended time periods needed to capture symptom episodes. However, the manual counting of coughs by listening to long recordings is time-consuming, laborious and restricts usage to research studies. This article outlines the challenges in recording, analyzing and quantifying cough sounds and describes the systems under development. Progress is being made towards automated algorithms to identify and count cough sounds; however, current systems have only been tested over short time periods and in limited patient groups. Further work is required to achieve broadly applicable accurate cough monitoring systems. PMID- 20923341 TI - Lung cancer therapeutics that target signaling pathways: an update. AB - Claiming more than 150,000 lives each year, lung cancer is the deadliest cancer in the USA. First-line treatments in lung cancer include surgical resection and chemotherapy, the latter of which offers only modest survival benefits at the expense of often severe and debilitating side effects. Recent advances in elucidating the molecular biology of lung carcinogenesis have elucidated novel drug targets, and treatments are rapidly evolving into specialized agents that hone in on specific aspects of the disease. Of particular interest is blocking tumor growth by targeting the physiological processes surrounding angiogenesis, pro-tumorigenic growth factor activation, anti-apoptotic cascades and other cancer-promoting signal transduction events. This article looks at several areas of interest to lung cancer therapeutics and considers the current state of affairs surrounding the development of these therapies. PMID- 20923345 TI - The difficult-to-wean patient. AB - Up to 20% of patients requiring mechanical ventilation will suffer from difficult weaning (the need of more than 7 days of weaning after the first spontaneous breathing trial), which may depend on several reversible causes: respiratory and/or cardiac load, neuromuscular and neuropsychological factors, and metabolic and endocrine disorders. Clinical consequences (and/or often causes) of prolonged mechanical ventilation comprise features such as myopathy, neuropathy, and body composition alterations and depression, which increase the costs, morbidity and mortality of this. These difficult-to-wean patients may be managed in two type of units: respiratory intermediate-care units and specialized regional weaning centers. Two weaning protocols are normally used: progressive reduction of ventilator support (which we usually use), or progressively longer periods of spontaneous breathing trials. Physiotherapy is an important component of weaning protocols. Weaning success depends strongly on patients’ complexity and comorbidities, hospital organization and personnel expertise, availability of early physiotherapy, use of weaning protocols, patients’ autonomy and families’ preparation for home discharge with mechanical ventilation. PMID- 20923348 TI - All hands on deck-the role of chloroplasts, endoplasmic reticulum, and the nucleus in driving plant innate immunity. AB - Plant innate immunity is mediated by cell membrane and intracellular immune receptors that function in distinct and overlapping cell-signaling pathways to activate defense responses. It is becoming increasingly evident that immune receptors rely on components from multiple organelles for the generation of appropriate defense responses. This review analyzes the defense-related functions of the chloroplast, nucleus, and endoplasmic reticulum (ER) during plant innate immunity. It details the role of the chloroplasts in synthesizing defense specific second messengers and discusses the retrograde signal transduction pathways that exist between the chloroplast and nucleus. Because the activities of immune modulators are regulated, in part, by their subcellular localization, the review places special emphasis on the dynamics and nuclear–cytoplasmic transport of immune receptors and regulators and highlights the importance of this process in generating orderly events during an innate immune response. The review also covers the recently discovered contributions of the ER quality control pathways in ensuring the signaling competency of cell surface immune receptors or immune regulators. PMID- 20923349 TI - A four-partner plant-virus interaction: enemies can also come from within. AB - Plant viruses are disseminated by either vertical (vegetative multiplication or sexual reproduction) or horizontal (vector-mediated) propagation. Plant pararetroviruses—members of the Caulimoviridae family—have developed an alternative strategy for vertical propagation via integration within the host plant genome, although integration is not required for viral replication. Integrated endogenous pararetrovirus (EPRV) sequences have undergone extensive viral genome rearrangements and contain more than one copy of the viral genome. Furthermore, EPRV can become infectious upon spontaneous escape of active virus following stresses such as wounding, tissue culture, or interspecific crosses. Such infectious EPRV are of great importance, not only in terms of their ability to precipitate epidemic outbreaks but also because of their effect on breeding of numerous plant genomes in temperate and tropical crops. This is especially true for banana, a crop susceptible to banana streak viruses, the causative agents of banana streak disease. Thus, the classical three-component banana–Banana streak virus (BSV)–mealybug pathosystem can be expanded to include endogenous BSV as an alternative source of active virions. The BSV-banana pathosystem is one of only three pathosystems known to date to harbor this remarkable feature, and the present review focuses exclusively on it to illustrate this four-partner interaction. PMID- 20923350 TI - A host-factor interaction and localization map for a plant-adapted rhabdovirus implicates cytoplasm-tethered transcription activators in cell-to-cell movement. AB - To identify host factors that play critical roles in processes, including cell-to cell movement of plant-adapted rhabdoviruses, we constructed and validated a high resolution Nicotiana benthamiana yeast two-hybrid library. The library was screened with the putative movement protein (sc4), nucleocapsid (N), and matrix (M) proteins of Sonchus yellow net virus (SYNV). This resulted in identification of 31 potential host factors. Steady-state localization studies using autofluorescent protein fusions to full-length clones of interactors were conducted in transgenic N. benthamiana marker lines. Bimolecular fluorescence complementation assays were used to validate two-hybrid interactions. The sc4 interactor, sc4i21, localized to microtubules. The N interactor, Ni67, localized to punctuate loci on the endoplasmic reticulum. These two proteins are 84% identical homologues of the Arabidopsis phloem-associated transcription activator AtVOZ1, and contain functional nuclear localization signals. Sc4i17 is a microtubule-associated motor protein. The M interactor, Mi7, is a nuclear localized transcription factor. Combined with a binary interaction map for SYNV proteins, our data support a model in which the SYNV nucleocapsids are exported from the nucleus and moved cell-to-cell by transcription activators tethered in the cytoplasm. PMID- 20923351 TI - Effects of amino-acid substitutions in the Brome mosaic virus capsid protein on RNA encapsidation. AB - Brome mosaic virus (BMV) packages its genomic RNAs (RNA1, RNA2, and RNA3) and subgenomic RNA4 into three different particles. However, since the RNAs in the virions have distinct lengths and electrostatic charges, we hypothesize that subsets of the virions should have distinct properties. A glutamine to cysteine substitution at position 120 of the capsid protein (CP) was found to result in a mutant virus named QC that exhibited a dramatically altered ratio of the RNAs in virions. RNA2 was far more abundant than the other RNAs, although the ratios could be affected by the host plant species. RNAs with the QC mutation were competent for replication early in the infection, suggesting that they were either selectively packaged or degraded after packaging. In support of the latter idea, low concentrations of truncated RNA1 that co-migrated with RNA2 were found in the QC virions. Spectroscopic analysis and peptide fingerprinting experiments showed that the QC virus capsid interacted with the encapsidated RNAs differently than did the wild type. Furthermore, wild-type BMV RNA1 was found to be more susceptible to nuclease digestion relative to RNA2 as a function of the buffer pH. Other BMV capsid mutants also had altered ratios of packaged RNAs. PMID- 20923352 TI - Enhanced glutathione metabolism is correlated with sulfur-induced resistance in Tobacco mosaic virus-infected genetically susceptible Nicotiana tabacum plants. AB - Sulfur-induced resistance, also known as sulfur-enhanced defense (SIR/SED) was investigated in Nicotiana tabacum cv. Samsun nn during compatible interaction with Tobacco mosaic virus (TMV) in correlation with glutathione metabolism. To evaluate the influence of sulfur nutritional status on virus infection, tobacco plants were treated with nutrient solutions containing either sufficient sulfate (+S) or no sulfate (-S). Sufficient sulfate supply resulted in a suppressed and delayed symptom development and diminished virus accumulation over a period of 14 days after inoculation as compared with -S conditions. Expression of the defense marker gene PR-1a was markedly upregulated in sulfate-treated plants during the first day after TMV inoculation. The occurrence of SIR/SED correlated with a higher level of activity of sulfate assimilation, cysteine, and glutathione metabolism in plants treated with sulfate. Additionally, two key genes involved in cysteine and glutathione biosynthesis (encoding adenosine 5'-phosphosulfate reductase and gamma-glutamylcysteine synthetase, respectively) were upregulated within the first day after TMV inoculation under +S conditions. Sulfate withdrawal from the soil was accelerated at the beginning of the infection, whereas it declined in the long term, leading to an accumulation of sulfur in the soil of plants grown with sulfate. This observation could be correlated with a decrease in sulfur contents in TMV-infected leaves in the long term. In summary, this is the first study that demonstrates a link between the activation of cysteine and glutathione metabolism and the induction of SIR/SED during a compatible plant-virus interaction in tobacco plants, indicating a general mechanism behind SIR/SED. PMID- 20923353 TI - An h-type thioredoxin functions in tobacco defense responses to two species of viruses and an abiotic oxidative stress. AB - Various thioredoxin (Trx) proteins have been identified in plants. However, many of the physiological roles played by these proteins remain to be elucidated. We cloned a TRXh-like gene predicted to encode an h-type Trx in tobacco (Nicotiana tabacum) and designated it NtTRXh3, based on the biochemical activity of the NtTRXh3 protein. Overexpression of NtTRXh3 conferred resistance to Tobacco mosaic virus and Cucumber mosaic virus, both of which showed reduced multiplication and pathogenicity in NtTRXh3-overexpressing plants compared with controls. NtTRXh3 overexpression also enhanced tobacco resistance to oxidative stress induced by paraquat, an herbicide that inhibits the production of reducing equivalents by chloroplasts. The NtTRXh3 protein localized exclusively to chloroplasts in coordination with the maintenance of cellular reducing conditions, which accompanied an elevation in the glutathione/glutathione disulfide couple ratio. NtTRXh3 gene expression and NtTRXh3 protein production were necessary for these defensive responses, because they were all arrested when NtTRXh3 was silenced and the production of NtTRXh3 protein was abrogated. These results suggest that NtTRXh3 is involved in the resistance of tobacco to virus infection and abiotic oxidative stress. PMID- 20923354 TI - The N-terminal domain of PMTV TGB1 movement protein is required for nucleolar localization, microtubule association, and long-distance movement. AB - The triple-gene-block (TGB)1 protein of Potato mop-top virus (PMTV) was fused to fluorescent proteins and expressed in epidermal cells of Nicotiana benthamiana under the control of the 35S promoter. TGB1 fluorescence was observed in the cytoplasm, nucleus, and nucleolus and occasionally associated with microtubules. When expressed from a modified virus (PMTV.YFP-TGB1) which formed local lesions but was not competent for systemic movement, yellow fluorescent protein (YFP) TGB1 labeled plasmodesmata in cells at the leading edge of the lesion and plasmodesmata, microtubules, nuclei, and nucleoli in cells immediately behind the leading edge. Deletion of 84 amino acids from the N-terminus of unlabeled TGB1 within the PMTV genome abolished movement of viral RNA to noninoculated leaves. When the same deletion was introduced into PMTV.YFP-TGB1, labeling of microtubules and nucleoli was abolished. The N-terminal 84 amino acids of TGB1 were fused to green fluorescent protein (GFP) and expressed in epidermal cells where GFP localized strongly to the nucleolus (not seen with unfused GFP), indicating that these amino acids contain a nucleolar localization signal; the fusion protein did not label microtubules. This is the first report of nucleolar and microtubule association of a TGB movement protein. The results suggest that PMTV TGB1 requires interaction with nuclear components and, possibly, microtubules for long-distance movement of viral RNA. PMID- 20923355 TI - Characterization of the interactions between Cucumber mosaic virus and Potato virus Y in mixed infections in tomato. AB - Mixed infection with the SON41 strain of Potato virus Y (PVY-SON41) in tomato increased accumulation of RNAs of strains Fny and LS of Cucumber mosaic virus (CMV-Fny and CMV-LS, respectively) and enhanced disease symptoms. By contrast, replication of PVY-SON41 was downregulated by CMV-Fny and this was due to the CMV Fny 2b protein. The CMV-FnyDelta2b mutant was unable to systemically invade the tomato plant because its movement was blocked at the bundle sheath of the phloem. The function needed for invading the phloem was complemented by PVY-SON41 in plants grown at 22 degrees C whereas this complementation was not necessary in plants grown at 15 degrees C. Mutations in the 2b protein coding sequence of CMV Fny as well as inhibition of translation of the 2a/2b overlapping region of the 2a protein lessened both the accumulation of viral RNAs and the severity of symptoms. Both of these functions were complemented by PVY-SON41. Infection of CMV-Fny supporting replication of the Tfn-satellite RNA reduced the accumulation of CMV RNA and suppressed symptom expression also in plants mixed-infected with PVY-SON41. The interaction between CMV and PVY-SON41 in tomato exhibited different features from that documented in other hosts. The results of this work are relevant from an ecological and epidemiological perspective due to the frequency of natural mixed infection of CMV and PVY in tomato. PMID- 20923364 TI - BAK1 is not a target of the Pseudomonas syringae effector AvrPto. AB - Plant cell surface-localized receptor kinases such as FLS2, EFR, and CERK1 play a crucial role in detecting invading pathogenic bacteria. Upon stimulation by bacterium-derived ligands, FLS2 and EFR interact with BAK1, a receptor-like kinase, to activate immune responses. A number of Pseudomonas syringae effector proteins are known to block immune responses mediated by these receptors. Previous reports suggested that both FLS2 and BAK1 could be targeted by the P. syringae effector AvrPto to inhibit plant defenses. Here, we provide new evidence further supporting that FLS2 but not BAK1 is targeted by AvrPto in plants. The AvrPto-FLS2 interaction prevented the phosphorylation of BIK1, a downstream component of the FLS2 pathway. PMID- 20923365 TI - Characterization of Geminivirus resistance in an accession of Capsicum chinense Jacq. AB - Pepper golden mosaic virus (PepGMV) and Pepper huasteco yellow vein virus (PHYVV), members of the Geminiviridae family, are important pathogens of pepper (Capsicum annuum L.) and other solanaceous crops. Accession BG-3821 of C. chinense Jacq. was reported earlier as resistant to mixed infection with PepGMV and PHYVV. In this work, we characterized the Geminivirus resistance trait present in BG-3821. Segregation analysis suggested that resistance depends on two genes. Our data showed that PepGMV replication in protoplast of resistant plants is approximately 70% lower when compared with the levels observed in protoplasts from susceptible plants. Additionally, viral movement is less efficient in resistant plants. We also evaluated several characteristics commonly associated with systemic acquired resistance (SAR), which is a conserved defensive mechanism. The concentration of salicylic acid was higher in resistant plants inoculated with PepGMV than in susceptible plants. Marker genes for SAR were induced after inoculation with PepGMV in resistant leaves. Similarly, we found a higher accumulation of reactive oxygen species on resistant leaves compared with susceptible ones. A model for the mechanism acting in the Geminivirus resistance detected in BG-3821 is proposed. Finally, the importance of BG-3821 in Geminivirus resistance breeding programs is discussed. PMID- 20923366 TI - Phenotypic characterization of potato late blight resistance mediated by the broad-spectrum resistance gene RB. AB - The potato gene RB, cloned from the wild potato species Solanum bulbocastanum, confers partial resistance to late blight, caused by the oomycete pathogen Phytophthora infestans. In order to better characterize this partial resistance phenotype, we have compared host resistance responses mediated by RB with those mediated by the S. demissum-derived R gene R9, which confers immunity to P. infestans carrying the corresponding avirulence gene avrR9. We found that both RB and R9 genes were capable of eliciting a hypersensitive cell death response (HR). However, in RB plants, the pathogen escaped HR lesions and continued to grow beyond the inoculation sites. We also found that callose deposition was negatively correlated with resistance levels in tested plants. Transcription patterns of pathogenesis-related (PR) genes PR-1 basic, PR-2 acidic, and PR-5 indicated that P. infestans inoculation induced transcription of these defense related genes regardless of the host genotype; however, transcription was reduced in both the susceptible and partially resistant plants later in the infection process but remained elevated in the immune host. Most interestingly, transcription of the HR-associated gene Hin1 was suppressed in both Katahdin and RB-transgenic Katahdin but not in R9 4 days after inoculation. Together, this suggests that suppression of certain defense-related genes may allow P. infestans to spread beyond the site of infection in the partially resistant host despite elicitation of hypersensitive cell death. PMID- 20923368 TI - Impact of Swiss needle-cast on growth of Douglas-fir. AB - Phaeocryptopus gaeumannii, the cause of Swiss needle-cast, is widely distributed in plantations of Douglas-fir in many parts of the world. Nevertheless, information remains limited on its precise effect on stand growth, particularly in relation to regional climate, and on its consequent economic cost. In New Zealand, the spread of P. gaeumannii over a period of ~30 years following its discovery in 1959 was closely monitored, and the timing of its arrival in different forests is known. This information was coupled with data from permanent sample plots in order to quantify the associated historical growth increment loss. Analyses revealed a steady decline in growth rate over the period from the first appearance of P. gaeumannii to a point when it stabilized at a lower increment level 14 to 20 years later. The cumulative mean reduction was 25% for mean top height, 27% for basal area, and 32% for stem volume. Volume growth rate decline was greater in the North Island (35%) than the South Island (23%) of New Zealand. These reductions in volume growth are estimated to equate to a loss in net present value of $NZ2,620 ha(-1) and $NZ1,470 ha(-1) for the North and South Islands, respectively, using a discount rate of 6%. Mortality did not increase as a result of infection by P. gaeumannii. The disease had less effect on cooler sites, especially those with low spring minimum temperatures (P < 0.001). Negligible growth decline occurred on sites with daily minimum October temperatures averaging <3.2 degrees C. PMID- 20923367 TI - Genetic analysis of streptomycin-resistant (Sm(R)) strains of Erwinia amylovora suggests that dissemination of two genotypes is responsible for the current distribution of Sm(R) E. amylovora in Michigan. AB - Streptomycin-resistant (Sm(R)) strains of the fire blight pathogen Erwinia amylovora were first isolated in southwest Michigan in 1991. Since that time, resistant strains have progressed northward to other apple-producing regions in the state. A total of 98.7% of Sm(R) strains isolated between 2003 and 2009 in Michigan harbored the strA-strB genes on transposon Tn5393. strA and strB encode phosphotransferase enzymes that modify streptomycin to a nonbactericidal form. Mutational resistance to streptomycin, caused by a point mutation-mediated target site alteration of the ribosomal S12 protein, occurred in 1.3% of E. amylovora strains from Michigan. Tn5393 was originally introduced to E. amylovora on the plasmid pEa34; thus, the first Sm(R) strains isolated contained both pEa34 and the ubiquitous nonconjugative plasmid pEA29. More recently, we have observed Sm(R) strains in which Tn5393 is present on pEA29, suggesting that the transposon has moved via transposition from pEa34 to pEA29. Almost all of the strains containing Tn5393 on pEA29 had lost pEa34. Of 210 pEA29::Tn5393 plasmids examined, the transposon was inserted at either nucleotide position 1,515 or 17,527. Both of these positions were in noncoding regions of pEA29. Comparative sequencing of the housekeeping genes groEL and potentially variable sequences on pEA29 was done in an attempt to genetically distinguish Sm(R) strains from streptomycin-sensitive (Sm(S)) strains isolated in Michigan. Only 1 nucleotide difference within the total 2,660 bp sequenced from each strain was observed in 2 of 29 strains; multiple sequence differences were observed between the Michigan strains and E. amylovora control strains isolated in the western United States or from Rubus spp. Alterations in virulence observable using an immature pear fruit assay were detected in three of eight Sm(R) strains examined. Our current genetic data indicate that only two Sm(R) strain genotypes (strains containing pEA29::Tn5393 with Tn5393 inserted at either nucleotide position 1,515 or 17,527 on the plasmid) are responsible for the dissemination of Tn5393-encoded streptomycin resistance in Michigan, and that the Sm(R) and Sm(S) strains in Michigan compose a homogenous group. PMID- 20923369 TI - Evaluation of kasugamycin for fire blight management, effect on nontarget bacteria, and assessment of kasugamycin resistance potential in Erwinia amylovora. AB - The emergence and spread of streptomycin-resistant strains of Erwinia amylovora in Michigan has necessitated the evaluation of new compounds effective for fire blight control. The aminoglycoside antibiotic kasugamycin (Ks) targets the bacterial ribosome and is particularly active against E. amylovora. The efficacy of Ks formulated as Kasumin 2L for control of fire blight was evaluated in six experiments conducted over four field seasons in our experimental orchards in East Lansing, MI. Blossom blight control was statistically equivalent to the industry standard streptomycin in all experiments. E. amylovora populations remained constant on apple flower stigmas pretreated with Kasumin and were ~100 fold lower than on stigmas treated with water. Kasumin applied to apple trees in the field also resulted in a 100-fold reduced total culturable bacterial population compared with trees treated with water. We performed a prospective analysis of the potential for kasugamycin resistance (Ks(R)) development in E. amylovora which focused on spontaneous resistance development and acquisition of a transferrable Ks(R) gene. In replicated lab experiments, the development of spontaneous resistance in E. amylovora to Ks at 250 or 500 ppm was not observed when cells were directly plated on medium containing high concentrations of the antibiotic. However, exposure to increasing concentrations of Ks in media (initial concentration 25 MUg ml(-1)) resulted in the selection of Ks resistance (at 150 MUg ml(-1)) in the E. amylovora strains Ea110, Ea273, and Ea1189. Analysis of mutants indicated that they harbored mutations in the kasugamycin target ksgA gene and that all mutants were impacted in relative fitness observable through a reduced growth rate in vitro and decreased virulence in immature pear fruit. The possible occurrence of a reservoir of Ks(R) genes in orchard environments was also examined. Culturable gram-negative bacteria were surveyed from six experimental apple orchards that had received at least one Kasumin application. In total, 401 Ks(R) isolates (42 different species) were recovered from apple flowers and leaves and orchard soil samples. Although we have not established the presence of a transferrable Ks(R) gene in orchard bacteria, the frequency, number of species, and presence of Ks(R) enterobacterial species in orchard samples suggests the possible role of nontarget bacteria in the future transfer of a Ks(R) gene to E. amylovora. Our data confirm the importance of kasugamycin as an alternate antibiotic for fire blight management and lay the groundwork for the development and incorporation of resistance management strategies. PMID- 20923370 TI - Ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: a meta-analysis. AB - OBJECTIVE: To assess the efficacy and safety of ustekinumab for psoriasis. METHODS: In this meta-analysis study, we searched The Cochrane Library (2009, 1 issue), MEDLINE (1966 to March 2009), EMBASE (1974 to March 2009), and China Academic Journal Full-text Database (CNKI, 1994-2009/3), China Biomedical Literature Database (CBM, 1978-2009/3), Chinese Scientific Journals Database (VIP, 1989-2008/3), and Wan fang Database (1999-2009). The quality of included studies was critically evaluated. Data analyses were performed with the Cochrane Collaboration's RevMan 5.0 software. RESULTS: Three randomized controlled trials (RCTs) with a total of 2316 patients were included in the inclusion criteria. The meta-analysis showed significant improvement of the psoriasis area and severity index (PASI), dermatology life quality index (DLQI) score or physician's global assessment when receiving ustekinumab compared with patients receiving placebo, while significant differences were noted between the ustekinumab 45 mg group and the ustekinumab 90 mg group in these indexes. There was no statistical significance with regard to adverse effects. CONCLUSIONS: The present study showed ustekinumab to be safe and effective for patients with psoriasis. Future high-quality, long-treatment, placebo-controlled, double-blind trials are needed. PMID- 20923371 TI - Placental perivascular cells for human muscle regeneration. AB - Perivascular multipotent mesenchymal progenitors exist in a variety of tissues, including the placenta. Here, we suggest that the abundant vasculature present in the human placenta can serve as a source of myogenic cells to regenerate skeletal muscle. Chorionic villi dissected from the mid-gestation human placenta were first transplanted intact into the gastrocnemius muscles of SCID/mdx mice, where they participated in muscle regeneration by producing myofibers expressing human dystrophin and spectrin. In vitro-cultured placental villi released rapidly adhering and migratory CD146+CD34-CD45-CD56- cells of putative perivascular origin that expressed mesenchymal stem cell markers. CD146+CD34-CD45-CD56- perivascular cells isolated and purified from the placental villi by flow cytometry were indeed highly myogenic in culture, and generated dystrophin positive myofibers, and they promoted angiogenesis after transplantation into SCID/mdx mouse muscles. These observations confirm the existence of mesenchymal progenitor cells within the walls of human blood vessels, and suggest that the richly vascularized human placenta is an abundant source of perivascular myogenic cells able to migrate within dystrophic muscle and regenerate myofibers. PMID- 20923372 TI - Class I HLA-A*7401 is associated with protection from HIV-1 acquisition and disease progression in Mbeya, Tanzania. AB - Here we explore associations between HLA variation and human immunodeficiency virus type 1 (HIV-1) acquisition and disease progression in a community cohort in Mbeya, Tanzania, a region that, despite harboring high rates of HIV-1 infection, remains understudied. African-specific allele HLA-A*74:01 was associated with decreased risk of infection (odds ratio [OR], 0.37; 95% confidence interval [CI], 0.14-0.80; P = .011) and with protection from CD4(+) cell counts <200 cells/uL in women (OR, 0.31; 95% CI, 0.07-0.91; P = .032) and men (OR, 0.15; 95% CI, 0.01 0.78; P = .020). These associations remained significant after adjustment for linkage disequilibrium with HLA-B and HLA-C alleles. This observation calls for additional investigation of mechanisms by which HLA-A*74:01 may influence HIV-1 acquisition and control of the infection. PMID- 20923373 TI - Antiretroviral adherence and development of drug resistance are the strongest predictors of genital HIV-1 shedding among women initiating treatment. AB - Persistent genital human immunodeficiency virus type 1 (HIV-1) shedding among women receiving antiretroviral therapy (ART) may present a transmission risk. We investigated the associations between genital HIV-1 suppression after ART initiation and adherence, resistance, pretreatment CD4 cell count, and hormonal contraceptive use. First-line ART was initiated in 102 women. Plasma and genital HIV-1 RNA levels were measured at months 0, 3, and 6. Adherence was a strong and consistent predictor of genital HIV-1 suppression (P < .001), whereas genotypic resistance was associated with higher vaginal HIV-1 RNA level at month 6 (P = .04). These results emphasize the importance of adherence to optimize the potential benefits of ART for reducing HIV-1 transmission risk. PMID- 20923374 TI - Efficacy of CMX001 against herpes simplex virus infections in mice and correlations with drug distribution studies. AB - CMX001, an orally active lipid conjugate of cidofovir, is 50 times more active in vitro against herpes simplex virus (HSV) replication than acyclovir or cidofovir. These studies compared the efficacy of CMX001 to acyclovir in BALB/c mice inoculated intranasally with HSV types 1 or 2. CMX001 was effective in reducing mortality using doses of 5 to 1.25 mg/kg administered orally once daily, even when treatments were delayed 48-72 h post viral inoculation. Organ samples obtained from mice treated with CMX001 had titers 3-5 log(10) plaque-forming units per gram of tissue lower than samples obtained from mice treated with acyclovir, including 5 different regions of the brain. Detectable concentrations of drug-related radioactivity were documented in the central nervous system of mice after oral administration of (14)C-CMX001. These studies indicate that CMX001 penetrates the blood-brain barrier, is a potent inhibitor of HSV replication in disseminated infections and central nervous system infections, and is superior to acyclovir. PMID- 20923375 TI - Interrater reliability of the Physical Ability Scale for patients after stroke: a pilot study. AB - This study aimed to evaluate the interrater reliability of the Physical Ability Scale (PAS) and secondly to test the statistical methods to analyse the scoring. Williamson ( 1993a ) stated that the PAS measures the degree of compatibility of the trunk with gravity and the supporting surface through investigation of limb, head, and posture in five different positions, each with six levels of ability. Four experienced physiotherapists observed a video of 10 inpatients from a general hospital stroke unit being assessed with the PAS up to 5 months after a stroke. The intraclass coefficient (ICC) for the total scores was 0.7 (95% CI 0.35-0.91) with the highest individual position scores in standing 0.86 (95% CI 0.68-0.96) and long sitting 0.74 (95% CI 0.46-0.92). The ICC for the levels of ability indicated good agreement in standing 0.79 (95% CI 0.55-0.93) and long sitting 0.77 (95% CI 0.52-0.93). Kappa values for each body part yielded the highest values in long sitting (0.62) and standing (0.56). Interrater reliability is variable, with the greatest level of agreement in long sitting and standing but with poor to fair agreement in sitting, prone, and supine. The study has also shown that the scoring can be analysed to yield meaningful repeatable results. Further investigation is needed to examine validity and reliability with a larger sample of diverse ability, therapists with varying clinical experience, and with direct observation of the assessment. PMID- 20923377 TI - Wire-guided selective cannulation of the bile duct with a sphincterotome: a prospective randomized comparative study with the standard method. AB - OBJECTIVE: Wire-guided cannulation (WGC) is expected to reduce the incidence of post-ERCP pancreatitis (PEP). Our aim was to compare the incidence of PEP and the success rate of deep biliary cannulation using WGC or the standard cannulation method with contrast injection (STD). MATERIAL AND METHODS: A total of 172 cases with an intact papilla were randomized into the STD group (n = 86) and the WGC group (n = 86). First a trainee endoscopist attempted the cannulation and if it was not successful, an expert endoscopist tried. When the cannulation was not successful within 10 min, the other method was conducted as a second attempt. The primary endpoint was the incidence of PEP and the secondary endpoint was the success rate of selective cannulation. RESULTS: In successful cases, PEP occurred in 6.5% in the STD group and 3.0% in the WGC group in the first attempt. Overall rate of PEP was 6.0% (3, mild; 1, moderate and 1, severe) in the STD group and 2.3% (2, mild) in the WGC group, which were not significantly different. Selective cannulation rate in the first attempt was 73.8% in the STD group and 77.9% in the WGC group. After a crossover, the cannulation was successful in the second attempt in 36.4% and 42.1% and finally in 95.2% and 100% by the STD and WGC method, respectively. CONCLUSIONS: The incidence of PEP tended to be lower in the WGC method compared to the STD method. In addition, all cases of pancreatitis in the WGC group were mild. The success rate of cannulation was comparable between two groups. PMID- 20923378 TI - Colonoscope with a sub-distal hyper-flaccid segment for improved insertion at colonoscopy: a randomized study. AB - BACKGROUND: In sharp bends, particularly in the colonic flexures, the axial pushing force conveyed to the distal actively bending tip of the endoscope may cause impaction rather than progression. It is hypothesized that colonoscopes with a very flaccid segment immediately proximal to the distal bending tip might reduce this problem. MATERIAL AND METHODS: Two prototype colonoscopes with a flaccid passively bending segment (either progressively graded or ungraded flaccidity) positioned immediately proximal to the distal actively bending tip was evaluated in a single-blinded randomized study. The primary end-point was patients' evaluation of pain. RESULTS: Altogether, 400 patients were randomized 1:1 to examination with a prototype (60 patients to endoscope with graded flaccidity; 141 to the endoscope with ungraded flaccidity) or a standard colonoscope. The groups were similar regarding age, sex and previous abdominal surgery. Severe pain was reported by 7% of patients in the prototype and 18% in the standard group (p = 0.001). There was a trend toward shorter cecal intubation time in the prototype group (mean 14.1 min, 95% CI 12.8-15.3) compared to the standard group (mean 15.5 min, 95% CI 14.3-16.7) (p = 0.12) and similar intubation rates (89% and 85%, respectively). Results for first (ungraded flaccidity) and second (graded flaccidity) generation prototypes collectively were similar to the second generation separately. CONCLUSIONS: The concept of an endoscope with a hyper-flaccid segment may facilitate negotiation of sharp bends and reduce pain without compromising cecal intubation rate or intubation time. PMID- 20923379 TI - Retrograde double balloon enteroscopy: comparing performance of solely retrograde versus combined same-day anterograde and retrograde procedure. AB - OBJECTIVE: Retrograde double balloon enteroscopy (DBE) is important for evaluating the distal small bowel, but it is more challenging compared to the oral route. Optimizing small bowel insertion may enhance the diagnostic utility of the examination. We sought to determine if insertion depths achieved with retrograde DBE when performed as an isolated procedure differed significantly from when performed immediately following anterograde DBE. MATERIAL AND METHODS: A retrospective analysis was conducted of all retrograde DBE procedures performed at our center with comparisons made between "distal-only" DBE without preceding anterograde DBE and "combined" DBE after a prior same-day anterograde DBE. RESULTS: Two hundred ninety retrograde DBE procedures were performed in 264 patients over 5 years. Success of terminal ileal intubation exceeded 95%. The mean insertion depth into the distal small bowel differed significantly with 112 cm (95% CI 95-129) in the "distal-only" group and 92 cm (95% CI 85-98) in the "combined" group (p = 0.01), with a trend toward a corresponding increased diagnostic yield of 48% versus 37%, respectively (p = 0.15). Multivariate regression analysis identified both insertion route strategy (distal-only > combined; p = 0.01) and type of DBE endoscope (diagnostic > therapeutic; p = 0.02) as significant predictors of retrograde insertion depth. CONCLUSIONS: The insertion depth of retrograde DBE is significantly greater when carried out as a separate distal procedure and not in combination with a preceding anterograde DBE, and when performed using a diagnostic as opposed to the therapeutic DBE endoscope. This increased retrograde depth of insertion may be associated with an increased diagnostic yield. PMID- 20923380 TI - The relationship between p27(kip1) expression and the change of radiosensitivity of esophageal carcinoma cells. AB - OBJECTIVE: Radioresistance is considered the main reason for therapeutic failure in radiotherapy of esophageal carcinoma. However, the underlying mechanisms of radioresistance remain elusive. The purpose of this study was to investigate the relationship between p27(kip1) expression and the change of radiosensitivity of esophageal carcinoma cells. MATERIAL AND METHODS: Radioresistant cells were gradually isolated by means of repeated gamma-ray irradiation upon esophageal carcinoma cells. The radiosensitivity of established radioresistant cells and parental cells was measured by standard colony-forming assay. Cell cycle was detected by flow cytometry. Western blot method was performed to identify the expression of p27(kip1). RESULTS: Colony-forming assay showed that the radioresistant cells had obvious radioresistance. Percentage of the radioresistant cells at G(0)/G(1) and G(2)/M phase was significantly decreased, and the percentage of S phase cells was significantly increased compared with the parent cells (p < 0.05). Western blotting revealed that p27(kip1) expression of the radioresistant cells was lower than that of parent cells. CONCLUSIONS: Our results suggest that cell phase change due to the decrease of p27(kip1) expression is one of the mechanisms of radioresistance in esophageal carcinoma cells. PMID- 20923381 TI - Phlebotomy in the treatment of primary biliary cirrhosis. PMID- 20923382 TI - Long-term outcome of infliximab therapy is highly comparable in a Danish and in a Hungarian tertiary center. PMID- 20923383 TI - Comparison of radical and partial nephrectomy in terms of renal function: a retrospective cohort study. AB - OBJECTIVE: This study aimed to evaluate kidney function following radical or partial nephrectomy and to evaluate the role of two common chronic diseases, hypertension (HT) and diabetes mellitus (DM), on glomerular filtration rate (GFR) in the long term. MATERIAL AND METHODS: Data on 488 patients who underwent surgery for renal tumours between 1994 and 2008 were investigated. Patient characteristics and estimated GFR, history of DM or HT, tumour size and new-onset decrease in GFR were recorded. Multivariable Cox proportional hazards regression was used to investigate whether the two types of operation were associated with chronic kidney failure after surgery, and the outcome was adjusted for age, gender, HT, DM and tumour size. p Values less than 0.05 was regarded as significant. RESULTS: Seventeen patients (18.9%) in group 1 and 176 (68%) in group 2 developed new onset of GFR < 60 ml/min/1.73 m(2). Three patients (2.9%) in group 1 and 137 (37.2%) in group 2 developed new onset of GFR < 45 ml/min/1.73 m(2) (p < 0.05). HT was associated with new-onset chronic renal failure in the radical nephrectomy group (hazard ratio 1.39, 95% confidence interval 1.028 1.890). CONCLUSION: After surgical treatment of renal masses, patients are at risk for development of chronic renal failure. A decrease in GFR was detected in both partial and radical nephrectomy, the latter associated with increased risk, especially in hypertensive patients. Routine praxis of radical nephrectomy should be overviewed. PMID- 20923384 TI - Impaired nerve growth factor homeostasis in patients with bipolar disorder. AB - OBJECTIVE: Neuro-trophins are critically involved in neuro-plasticity, the impairment of which is a major role-player in bipolar disorder (BD), and their altered levels have been recently advocated in the patho-physiology of this affective malady. The aim of this study, therefore, was to evaluate the plasma levels of nerve growth factor (NGF) in BD patients in comparison with control subjects. METHODS: Forty-nine BD type-I individuals (30 in mania and 19 in euthymia) and 36 healthy controls were assessed by Mini-plus, Young mania and Hamilton depression rating scales. NGF levels were detected by ELISA. RESULTS: Plasma NGF concentrations were decreased in BD patients when compared to that seen with controls. BD individuals in mania had lower NGF levels than euthymic patients or controls. NGF levels were negatively correlated with the severity of mania. CONCLUSIONS: This is the first study to evaluate NGF levels in BD patients, providing further support to the hypothesis of impaired neuro plasticity in BD. These data also suggest that NGF measurement could be used for the biological marker for manic state. PMID- 20923385 TI - Levalbuterol versuss levalbuterol plus ipratropium in the treatment of severe acute asthma. AB - BACKGROUND: The National Asthma Education and Prevention Program (NAEPP) Expert Panel Report 3 guidelines advise the addition of ipratropium bromide to short acting beta-agonist therapy for the treatment of patients with severe acute asthma exacerbation. METHODS: This was a prospective, double-blind, randomized, controlled study involving 141 adults, presenting to two EDs with acute severe asthma exacerbation. Patients were treated using a standardized pathway with levalbuterol plus ipratropium or levalbuterol alone. Primary outcomes were changes from baseline in the percentage of predicted forced expiratory volume in 1 second (FEV1) at 30 minutes and 60 minutes after completion of treatment. Secondary outcomes included hospitalization and relapse rates. Occurrence of adverse events was recorded. RESULTS: Sixty-seven patients in the levalbuterol plus ipratropium group and 74 patients in the levalbuterol group completed the study. Overall, there was no significant difference in the improvement in percent predicted FEV1 between the two groups at 30 minutes [difference in change between study groups at 30 minutes: 1% (95% CI: ?3 to 2%) or at 60 minutes: 3% (95% CI: 1 6%)] No difference was noted in hospitalization rates between the treatment groups [combination therapy group, 33%; single therapy group, 47%, difference: 14% (95% CI: -30 to 20%)]. Post-hoc analysis revealed that patients receiving ipratropium in addition to levalbuterol were 1.5 times more likely to experience side effects (palpitations) than patients treated with levalbuterol alone (RR 1.5; 95% CI: 1.2-1.9) No differences in relapse rates were noted between the groups. Post-hoc analysis revealed more side effects in patients receiving levalbuterol plus ipratropium. CONCLUSION: We were unable to demonstrate superiority of adding ipratropium to levalbuterol in alleviating obstruction as measured by FEV1 or in decreasing the need for hospitalization among adult patients presenting to the ED with acute severe asthma exacerbation. PMID- 20923387 TI - Synthesis and in vitro characterization of a novel PAA-ATP conjugate. AB - The objective of this study was to improve the multifunctional properties of poly(acrylic acid) (PAA) by covalent attachment of 4-aminothiophenol (ATP) to its backbone. The permeation enhancing effect of PAA-ATP together with glutathione was evaluated in Ussing-type chambers using fluorescein isothiocyanate dextran as model compound. The mucoadhesive properties were evaluated in vitro on freshly excised porcine intestinal mucosa through the rotating cylinder method. The resulting conjugates PAA-ATP1 and PAA-ATP2 displayed 168 +/- 35 and 426 +/- 55 MUmol immobilized free thiol groups per gram polymer, respectively. In addition, 279 +/- 28 and 139 +/- 22 MUmol disulfide bonds per gram polymer, respectively, were identified on PAA-ATP1 and PAA-ATP2. Within disintegration studies in aqueous buffer solution, the modified polymers showed improved cohesive properties. Because of the immobilization of ATP, the swelling of PAA-ATP1 and PAA-ATP2 improved 12.0- and 17.8-fold, respectively. The adhesion times of the conjugates PAA-ATP1 and PAA-ATP2 were more than 20- and 30-fold increased in comparison to unmodified PAA. Furthermore, conjugates PAA-ATP1 and PAA-ATP2 exhibited a 1.86- and 2.07-fold higher permeation enhancing effect, respectively, over unmodified PAA. According to these results, PAA-ATP conjugates represent a very promising novel type of thiomer for the development of various mucoadhesive drug delivery systems. PMID- 20923388 TI - Formulation development and in vitro evaluation of didanosine-loaded nanostructured lipid carriers for the potential treatment of AIDS dementia complex. AB - The purpose of this article was to investigate the feasibility of incorporating didanosine (DDI) into nanostructured lipid carriers (NLC) for potential treatment of AIDS dementia complex. Aqueous DDI-free and DDI-loaded NLC were manufactured using hot high-pressure homogenization. The lipid matrix contained a mixture of Precirol(r) ATO 5 and Transcutol(r) HP. Photon correlation spectroscopy revealed that the mean particle size for all formulations was below 250 nm with narrow polydispersity indices. In addition, the d99% values for all formulations determined using laser diffractometry were below 400 nm with the span values ranging from 0.84 to 1.0. The zeta potential values ranged from -18.4 to -11.4 mV and the encapsulation efficiency of NLC for DDI ranged from 33.02% to 78.34%. These parameters remained relatively constant for all formulations tested following storage for 2 months at 25 degrees C indicating that all the formulations were relatively stable. Differential scanning calorimetry revealed a decrease in the degree of crystallinity of NLC in all formulations developed relative to the bulk lipid material. In addition, wide-angle X-ray scattering showed that NLC in all formulations tested existed in a single beta-modification form and that DDI that had been incorporated into the NLC appeared to be molecularly dispersed in the lipid matrices. Images of the NLC formulations obtained using transmission electron microscopy revealed that all formulations contained a mixture of spherical and nonspherical particles irrespective of the amount of DDI that was added during the manufacture of the formulations. PMID- 20923389 TI - In vitro and in vivo evaluation of hydrophilic and hydrophobic polymers-based nicorandil-loaded peroral tablet compared with its once-daily commercial sustained-release tablet. AB - CONTEXT: Hydrophilic and hydrophobic polymer-based nicorandil (10 mg)-loaded peroral tablets were prepared using the wet granulation technique. The influence of varying amounts of hydroxypropyl methylcellulose (HPMC) (30-50 mg), ethylcellulose (2-4 mg), microcrystalline cellulose (5-20 mg) and Aerosil(r) (5 12 mg) in conjunction with the constant amounts (3 mg) of glidant and lubricant (magnesium stearate and talc) on the in vitro performances of the tablets (hardness, friability, weight variation, thickness uniformity, drug content, and drug release behavior) were investigated. OBJECTIVE: The objectives of this study were (i) to select a nicorandil-loaded peroral tablet that matched the in vitro dissolution profile of once-daily commercial sustained-release tablet, and (ii) to compare the in vivo sustaining/controlling efficacy of the selected peroral tablet with that of its commercial counterparts. RESULTS AND DISCUSSION: Because the nicorandil (10 mg)-loaded tablet prepared based on F-IX composition (50 mg HPMC, 4 mg ethylcellulose, 10 mg MCC and 3 mg glidant and lubricant) showed a release profile comparable to that of the Nikoran(r) OD SR tablet release profile, the tablet with this composition was considered to be the optimized/selected formulation and, therefore, was subjected to stability study and in vivo study in rabbits. Despite of the higher C(max) and AUC values obtained with the optimized tablet, there was no sign of difference between the optimized- and Nikoran(r) OD SR- tablets following a single-dose crossover oral administration into rabbit. CONCLUSION: The optimized tablet could be used as an alternative to the commercial once-daily tablet. PMID- 20923390 TI - The application of atomic absorption spectrometry for the determination of residual active pharmaceutical ingredients in cleaning validation samples. AB - The objective of this work was the development and validation of atomic absorption spectrometric (AAS) methods for the determination of residual active pharmaceutical ingredients (API) in rinse samples for cleaning validation. AAS as an indirect method for the determination of API in rinse samples can be applied when it is in the form of salt with metal ions or when the metal ion is a part of the API's structure. The electrothermal AAS methods (aqueous and ethanol medium) for the determination of magnesium in esomeprazole magnesium and the flame AAS method for the determination of lithium in lithium carbonate in rinse samples were developed. Various combinations of solvents were tested and a combination of 1% aqueous or ethanol solution of nitric acid for esomeprazole magnesium and 0.1% aqueous solution of nitric acid for lithium carbonate were found to be the most suitable. The atomization conditions in the graphite furnace and in the flame were carefully studied to avoid losses of analyte and to achieve suitable sensitivity. The cleaning verification methods were validated with respect to accuracy, precision, linearity, limit of detection, and quantification. In all the cases, the limits of detection were at the microgram level. The methods were successfully applied for the determination of esomeprazole magnesium and lithium carbonate in rinse samples from cleaning procedures. PMID- 20923391 TI - Automated actuation of nasal spray products: determination and comparison of adult and pediatric settings. AB - OBJECTIVE: To determine and compare patient-relevant settings for automated nasal spray actuation stations from adult and pediatric hand data. METHODS: Twenty adults and 20 pediatric participants were asked to spray Flonase((r)) Nasal Spray six times in a Hand Actuation Monitor, which records force and displacement data in 5-ms increments. Settings for force- and velocity-controlled actuation stations were determined from the data using a predefined set of calculations. RESULTS: For force-controlled settings, hand spraying by children resulted in lower actuation forces, and longer force rise, hold and fall times. Pediatric velocity-controlled actuator settings were lower for travel, compression velocity, and release velocity compared with adults. The pediatric spray weight recorded during hand spraying was significantly lower than the spray weight generated by adult participants. Adult participants were able to generate full sprays with each attempt, whereas 11 out of 120 actuations performed by pediatric participants resulted in partial and 'no spray' events. No differences in spray weight were detected in participants who chose to actuate the nasal spray using both hands. CONCLUSIONS: A predefined set of calculations was used to determine patient-relevant settings from force and displacement hand data for force- and velocity-controlled automated actuation stations. This study determined and quantified, for the first time, the differences in hand spraying between adults and children. PMID- 20923392 TI - Bioscavenger therapy for organophosphate poisoning - an open-labeled pilot randomized trial comparing fresh frozen plasma or albumin with saline in acute organophosphate poisoning in humans. AB - INTRODUCTION: Traditional treatment of organophosphate poisoning (OP) with oximes has had limited success. Fresh frozen plasma (FFP) or albumin, acting as bioscavengers to mop up free organophosphate, has been recently proposed as a treatment modality. In this pilot open-label, three-arm, randomized controlled study exploring proof of concept, we evaluated if bioscavenger therapy had a role in OP. PATIENTS AND METHODS: Sixty patients with significant poisoning presenting within 12 hours, with suppression of pseudocholinesterase activity to < 1,000 U/L, were randomized to receive FFP (8 bags, 250 mL each over 3 days), 20% human albumin (4 * 100 mL over 3 days), or saline (2,000 mL over 3 days) in addition to atropine and supportive care. Pseudocholinesterase and organophosphate levels were measured pretreatment, post-infusion (Day 2, Day 3), and predischarge and expressed as mean +/- standard error. The incidence of intermediate syndrome, need for mechanical ventilation, atropine requirement, and mortality were assessed. RESULTS: Twenty patients received albumin and 19 patients each FFP or saline. FFP increased pseudocholinesterase levels (250 +/- 44-1,241 +/- 364 U/L) significantly (p = 0.007). Small, nonsignificant increases were observed with saline (160 +/- 30-259 +/- 78) and albumin (146 +/- 18-220 +/- 61). Organophosphate levels reduced in all 3 arms; no clear-cut trends were observed. We observed more cases of intermediate syndrome with FFP [10/19 (53%) vs. 5/20 (25%) vs. 5/19 (26%), FFP, albumin, and saline arms (p = 0.15)]. The interventions did not affect ventilatory requirements (14/19 vs. 15/20 vs. 14/19) or prevent delayed intubation. There were no differences in mean (+/-standard error) atropine requirement (in milligrams) in the first 3 days (536 +/- 132 vs. 361 +/- 125 vs. 789 +/- 334) and duration (in days) of ventilation (10.0 +/- 2.1 vs. 7.1 +/- 1.5 vs. 7.5 +/- 1.5) or hospital stay (12.4 +/- 2.2 vs. 9.8 +/- 1.4 vs. 9.8 +/- 1.6). Two patients developed adverse effects with FFP. Mortality was similar (4/19 vs. 5/20 vs. 2/19, p = 0.6). CONCLUSIONS: Despite significant increase in pseudocholinesterase levels with FFP, this pilot study did not demonstrate favorable trends in clinical outcomes with FFP or albumin. PMID- 20923393 TI - Should phenytoin or barbiturates be used as second-line anticonvulsant therapy for toxicological seizures? AB - INTRODUCTION: Seizures are a common sequela of self-poisoning. However, their mechanism differs from seizures of other etiologies. Toxicological seizures result from alterations in the excitatory and inhibitory balance of otherwise normal neurons. In contrast, idiopathic or trauma related seizures usually start with a focus of abnormal neurons. For both forms of seizures, benzodiazepines are recommended as first-line therapy; however, there is debate about the use of phenytoin or barbiturates for second-line therapy. METHODS AND RESULTS: In this article, we systematically review the evidence for the use of these drugs as second-line therapy for toxicological seizures. Barbiturates complement the anticonvulsant effect of benzodiazepines at the GABAA receptor by increasing the duration of chloride channel opening; phenytoin blocks voltage-dependent sodium channels to inhibit propagation from active electrical foci, an effect more useful for nontoxicological seizures. We found no randomized controlled trial comparing phenytoin and barbiturates in toxicological seizures refractory to benzodiazepines; similarly no trial was found comparing the use of these drugs in nonpoisoned patients. Animal studies indicate that phenobarbital has greater effectiveness than phenytoin for many poisons; a few case reports suggest a better response in patients. CONCLUSION: Despite the lack of high-quality clinical trial data, pharmacological knowledge and animal studies suggest that phenobarbital or thiopentone should be second-line agents for controlling toxicological seizures. The role of newer agents such as propofol and levetiracetam in toxicological seizures is currently unclear because of a lack of clinical or animal studies. PMID- 20923394 TI - Methomyl-alphamethrin poisoning presented with cholinergic crisis, cortical blindness, and delayed peripheral neuropathy. AB - OBJECTIVE: Methomyl-alphamethrin is a mixture of carbamate and pyrethroid insecticides. Carbamate insecticides function as reversible cholinesterase inhibitors, which may produce life-threatening cholinergic syndrome. Cortical blindness and delayed neuropathy were rarely reported complications of carbamate insecticide exposures. Here we reported a case of intentional methomyl alphamethrin ingestion. CASE REPORT: A 41-year-old woman attempted suicide by drinking 200 mL of methomyl-alphamethrin insecticide and soon presented with unconsciousness, hypothermia, and shock. She developed pulseless electrical activity and regained spontaneous circulation after resuscitation. Diagnosis of carbamate poisoning was made by her clinical features, decreased levels of cholinesterases and the presence of methomyl in her urine. She complained of blurred vision and blindness 4 days post-exposure. Visual evoked potential and brain magnetic resonance imaging study confirmed the diagnosis of cortical blindness. On day 21, she had low limbs numbness, progressive weakness, and right foot drop. Electophysiological tests performed on day 27 revealed neuropathy of bilateral peroneal nerves. CONCLUSION: We reported a patient who manifested severe carbamate insecticide poisoning and developed cortical blindness and delayed neuropathy. Physicians should be aware of these rare toxicities among patients with severe carbamate insecticide poisoning. PMID- 20923395 TI - Health impact of unicellular algae of the Ostreopsis genus blooms in the Mediterranean Sea: experience of the French Mediterranean coast surveillance network from 2006 to 2009. AB - OBJECTIVE: Ostreopsis ovata and Ostreopsis siamensis are tropical unicellular algae that have been found recently in the Mediterranean. Both of these dinoflagellates produce palytoxin (PTX)-like toxins that are powerful vasoconstrictors in mammals. Since 2003, Ostreopsis blooms in Italy and Spain have been accompanied by reports of respiratory problems and skin/mucosa irritation in persons in contact with toxic microalgal cells (epiphytes, plankton, or sea spray) or associated toxins. METHODS: In France, a surveillance network has been set up to monitor water conditions and to protect swimmers from contamination due to Ostreopsis. RESULTS: Between 2006 and 2009, a total of nine blooms were observed on the French Mediterranean coast including five that led to manifestations in divers, swimmers, and shoreline inhabitants. A total of 47 patients presented symptoms of involving benign or mild skin, mucosal, and/or respiratory irritation that regressed spontaneously without treatment within 12 72 h (4-12 h with nonsteroidal anti-inflammatory drugs). During the study period, five beaches were temporarily closed. DISCUSSION: In the Mediterranean, Ostreopsis blooms induce skin and respiratory disorders when human beings are exposed to saltwater with a high concentration of algal cells. However, palytoxin dosages carried out on the food chain (urchins, mussels) indicate that this risk of toxins accumulation in seafood must be taken into account and that the surveillance network should be upgraded accordingly. PMID- 20923396 TI - A case of black urine and dark skin - cresol poisoning. AB - INTRODUCTION: Cresol is a phenol derivative used as a disinfectant worldwide. Acute cresol poisoning is potentially fatal as it may cause multiple organ failure. We present a case of acute cresol intoxication in a male patient to illustrate the effects of cresol poisoning. CASE: A 42-year-old male presented with black urine, painless brownish dermal burns, and a strong carbolic acid odor. The patient was immediately resuscitated with adequate oxygenation and aggressive fluid resuscitation. He was subsequently admitted to the intensive care unit, where his treatment course was complicated by pneumonia, gastrointestinal bleeding, hepatic dysfunction, and acute renal failure. After receiving supportive intensive care, the patient recovered and was discharged with no sequelae. CONCLUSION: The distinctive clinical features of this case may be useful in diagnosis, because laboratory analytical methods for cresols are not routinely available at most hospitals. PMID- 20923398 TI - Solid lipid nanoparticles (SLNs) derived from para-acyl-calix[9]-arene: preparation and stability. AB - A study of the parameters relating to the preparation of para-acyl-calix[9]arene based solid lipid nanoparticles (SLNs) has been undertaken. Dynamic light scattering and electron microscopy have shown that the particle size varies between 85 and 215 nm depending on the acyl chain length. Parameters, including the organic solvent, amphiphile concentration and the presence of a co-surfactant affect the size of the SLNs obtained significantly. In contrast, stirring speed and solution viscosity have no effect. The ionic strength of the suspension has been shown to affect SLN stability in a salt-dependent manner. Ultrasonic and ultraviolet and 80°C treatment of the SLN suspensions have no effect on the SLN stability. The SLNs are unstable with respect to freezing–defreezing cycles, but can be reconstituted using mono- or disaccharides as cryoprotectants. Importantly, the temporal stability of these suspensions in water has been shown to be superior to 6 months. With regard to protein interactions, no SLN aggregation was observed in the presence of human serum albumin, with formation of a monolayer of albumin on the surface of the SLNs. Encapsulation was shown using acridine as a fluorescent probe. PMID- 20923399 TI - Incorporation of obidoxime into human serum albumin nanoparticles: optimisation of preparation parameters for the development of a stable formulation. AB - Intoxication with organophosphorous nerve agents such as paraoxon requires immediate administration of antidotes such as oximes. However, the oximes lack sufficient activity in the central nervous system as they are unable to rapidly penetrate the blood-brain barrier (BBB) in therapeutically relevant concentrations. Human serum albumin (HSA) nanoparticles represent a promising drug carrier system for the transport of drugs across the BBB. This study focussed on the development of an obidoxime-loaded nanoparticles prepared by desolvation using an incorporation technique. The nanoparticle preparation parameters, i.e. drug amount, pH value, ethanol volume and crosslinking degree, were optimised. The in vitro release study showed a sustained release profile, indicating the suitability of the developed formulation for the transport of oximes across the BBB. PMID- 20923397 TI - Keeping it in the family: diverse histone recognition by conserved structural folds. AB - Epigenetic regulation of gene transcription relies on an array of recurring structural domains that have evolved to recognize post-translational modifications on histones. The roles of bromodomains, PHD fingers, and the Royal family domains in the recognition of histone modifications to direct transcription have been well characterized. However, only through recent structural studies has it been realized that these basic folds are capable of interacting with increasingly more complex histone modification landscapes, illuminating how nature has concocted a way to accomplish more with less. Here we review the recent biochemical and structural studies of several conserved folds that recognize modified as well as unmodified histone sequences, and discuss their implications on gene expression. PMID- 20923400 TI - Liposomes and lipopolymeric carriers for gene delivery. AB - In this work we have examined the ability of various lipopolyplexes to deliver genes into liver cancer cells. We evaluated different parameters such as the protocol of preparation, the lipid/DNA molar ratio, and the molecular weight and type of PEI, to optimize the formulation to achieve high transfection activity. Our hypothesis was that the association of PEI with cationic liposomes (lipopolyplexes) would increase luciferase expression compared to lipoplexes (cationic lipid and DNA) and polyplexes (cationic polymer and DNA) alone. PMID- 20923403 TI - The leptin system: a potential target for sepsis induced immune suppression. AB - Sepsis, which is defined as a systemic inflammatory response syndrome that occurs during infection, is associated with several clinical conditions and high mortality rates. As sepsis progresses immune paralysis can become severe, leaving an already vulnerable patient ill equipped to eradicate primary or secondary infections. At present the predominant treatments for sepsis have not demonstrated convincing efficacy of decreased mortality. During sepsis, it has been observed that leptin levels initially increase but subsequently decline. A body of evidence has demonstrated that central or systemic leptin can beneficially regulate immune function. In this report expression of leptin and its receptor, signaling, and function on leukocytes will be reviewed. Furthermore, the effects mediated by central and systemic leptin during sepsis will be reviewed. Altogether, the ability of leptin to beneficially enhance inflammation and the host response during sepsis supports its use as a therapeutic agent, particularly during the latter phases of the syndrome. PMID- 20923402 TI - PKC-theta is a drug target for prevention of T cell-mediated autoimmunity and allograft rejection. AB - Protein kinase C theta (PKC-theta) is a key kinase in mediating T cell receptor (TCR) signals. PKC-theta activated by T cell receptor (TCR) engagement translocates to immunological synapses and regulates the activation of transcriptional factors NFkappaB, AP-1, and NFAT. These transcription factors then activate target genes such as IL-2. T cells deficient in PKC-theta display defects in T cell activation, survival, activation-induced cell death, and the differentiation into inflammatory T cells, such as Th2 and Th17 cells both in vitro and in vivo. Since these effector T helper cells are responsible for mediating autoimmunity, selective inhibition of PKC-theta is considered a treatment for prevention of autoimmune diseases and allograft rejection. PMID- 20923401 TI - Isoforms of vitamin E differentially regulate inflammation. AB - Vitamin E regulation of disease has been extensively studied in humans, animal models and cell systems. Most of these studies focus on the alpha-tocopherol isoform of vitamin E. These reports indicate contradictory outcomes for anti inflammatory functions of the alpha-tocopherol isoform of vitamin E, especially with regards to clinical studies of asthma and atherosclerosis. These seemingly disparate clinical results are consistent with recently reported unrecognized properties of isoforms of vitamin E. Recently, it has been reported that physiological levels of purified natural forms of vitamin E have opposing regulatory functions during inflammation. These opposing regulatory functions by physiological levels of vitamin E isoforms impact interpretations of previous studies on vitamin E. Moreover, additional recent studies also indicate that the effects of vitamin E isoforms on inflammation are only partially reversible using physiological levels of a vitamin E isoform with opposing immunoregulatory function. Thus, this further influences interpretations of previous studies with vitamin E in which there was inflammation and substantial vitamin E isoforms present before the initiation of the study. In summary, this review will discuss regulation of inflammation by vitamin E, including alternative interpretations of previous studies in the literature with regards to vitamin E isoforms. PMID- 20923404 TI - Wound-associated skin fibrosis: mechanisms and treatments based on modulating the inflammatory response. AB - Skin fibrosis, in its mildest form, may present only a minor aesthetic problem, but in the most severe cases it can lead to debilitating pathologies of the skin, for example keloid and hypertrophic scars, and systemic sclerosis. In recent years, extensive basic research aimed at understanding the molecular mechanisms underlying fibrosis has revealed an impressive but baffling number of genes, molecules, and cell types that may contribute to this problem. However, one recurring and consistent theme in these studies is that inflammatory cells and their secreted mediators appear to be leading culprits in activating dermal fibroblasts to become fibrotic. This review will first describe the histology of normal versus fibrotic skin, and will also describe the process of wound repair, a primary cause of skin fibrosis. We will then focus on what is currently known about the molecular mechanisms underlying skin fibrosis, with particular attention paid to how inflammation contributes. Finally, current treatment strategies and emerging therapeutic targets will be discussed. PMID- 20923407 TI - Sensorial strabismus due to congenital toxoplasmosis. Is it an eso- or exotropia? AB - OBJECTIVE: To examine sensorial strabismus due to congenital toxoplasmosis to elucidate differences and similarities between cases with esotropia (ET) and with exotropia (XT). METHODS: Restrospective analysis of 49 patients treated between 2002 and 2007. Visual acuity, cycloplegic refraction, strabismus patterns, presence of nystagmus, site of scar, surgery performed and strabismus surgical outcome obtained were evaluated. RESULTS: Mean age: 5 years old. 25 patients had bilateral involvement: 10 had ET, 10 XT and 4 were aligned. 15/24 unilateral cases presented with XT, 7 ET and other 2 orthotropia. 6/8 patients with the right eye affected, manifest ET and 14/16 patients with their OS affected had XT. (P=0.01) CONCLUSION: In bilateral cases of ocular toxoplasmosis ET and XT are found in similar proportions; in unilateral cases, XT is more frequent and the left eye is affected in most cases by both the toxoplasmosis and the strabismus. Esotropia appears more frequently in cases where the right eye is so affected, whereas XT predominates in cases where the left eye is affected. PMID- 20923408 TI - Lateral rectus resection strabismus surgery in unilateral duane syndrome with esotropia and limited abduction. AB - BACKGROUND: Resection of the lateral rectus in Duane retraction syndrome (DRS) with esotropia (ET) and limited abduction can be a useful component of surgical planning in specific circumstances, when combined with medial rectus (MR) recession. This article reports the results of a prospective series of patients for whom this approach was used successfully. METHODS: Seven patients were treated, aged 3 to 52 years, with uniltaeral DRS with the following features: 1) ET at least 25 PD; 2) "mild" retraction on adduction; 3) clinically normal adduction; 4) significantly limited abduction; 5) no or mild upshoots/downshoots; and 6) positive forced duction to abduction at surgery. surgery involved MR recession up to 5.0 mm and LR resection of maximum 3.5 mm. Postoperative followup was at least 6 months in all cases. RESULTS: ET angles ranged from 25 to 32 PD; abduction limitations ranged from -3.5 to -4. All patients had face turn postures preoperatively. Postoperatively, the binoclar alignment in primary position was orthotropia and head postures wre eliminated in all patients. Abduction postoperatively ranged from -1 to -2.5; adduction ranged from -0.5 to -1. Two patients had minimal worsening of upshoots and downshoots after surgery. CONCLUSION: In treating DRS with ET and limited abduction, a small LR resection can be a safe and effective component of surgery. It has a low risk of worsening retraction or "crippling" adduction when done in appropriate cases. PMID- 20923409 TI - Case report: Duane Retraction Syndrome associated with hand anomaly. AB - Duane Retraction Syndrome is a congenital eye movement disorder characterized by a failure of cranial nerve VI to develop normally, resulting in restriction or absence of abduction, restricted adduction and narrowing of the palpebral fissure and retraction of the globe on attempted adduction. Patients with Duane Retraction Syndrome appear to have a significant increase in the number of associated congenital malformations. In the present paper, the authors report a case of Duane Retraction Syndrome with a unique hand abnormality not reported previously. PMID- 20923405 TI - Molecular and vascular targets in the pathogenesis and management of the hypertension associated with preeclampsia. AB - Normal pregnancy is associated with significant hemodynamic changes and vasodilation of the uterine and systemic circulation in order to meet the metabolic demands of the mother and developing fetus. Preeclampsia (PE) is one of the foremost complications of pregnancy and a major cause of maternal and fetal mortality. The pathophysiological mechanisms of PE have been elusive, but some parts of the puzzle have begun to unravel. Genetic factors such as leptin gene polymorphism, environmental and dietary factors such as Ca(2+) and vitamin D deficiency, and co-morbidities such as obesity and diabetes may increase the susceptibility of pregnant women to develop PE. An altered maternal immune response may also play a role in the development of PE. Although the pathophysiology of PE is unclear, most studies have implicated inadequate invasion of cytotrophoblasts into the uterine artery, leading to reduced uteroplacental perfusion pressure (RUPP) and placental ischemia/hypoxia. Placental ischemia induces the release of biologically active factors such as growth factor inhibitors, anti-angiogenic factors, inflammatory cytokines, reactive oxygen species, hypoxia-inducible factors, and antibodies to vascular angiotensin II (AngII) receptor. These bioactive factors could cause vascular endotheliosis and consequent increase in vascular resistance and blood pressure, as well as glomerular endotheliosis with consequent proteinuria. The PE associated vascular endotheliosis could be manifested as decreased vasodilator mediators such as nitric oxide, prostacyclin and hyperpolarizing factor and increased vasoconstrictor mediators such as endothelin-1, AngII and thromboxane A2. PE could also involve enhanced mechanisms of vascular smooth muscle contraction including intracellular Ca(2+), and Ca(2+) sensitization pathways such as protein kinase C and Rho-kinase. PE-associated changes in the extracellular matrix composition and matrix metalloproteinases activity also promote vascular remodeling and further vasoconstriction in the uterine and systemic circulation. Some of these biologically active factors and vascular mediators have been proposed as biomarkers for early prediction or diagnosis of PE, and as potential targets for prevention or treatment of the disease. PMID- 20923411 TI - Erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) blocks differentiation and maintains the expression of pluripotency markers in human embryonic stem cells. AB - hESCs (human embryonic stem cells) have enormous potential for use in pharmaceutical development and therapeutics; however, to realize this potential, there is a requirement for simple and reproducible cell culture methods that provide adequate numbers of cells of suitable quality. We have discovered a novel way of blocking the spontaneous differentiation of hESCs in the absence of exogenous cytokines by supplementing feeder-free conditions with EHNA [erythro-9 (2-hydroxy-3-nonyl)adenine], an established inhibitor of ADA (adenosine deaminase) and cyclic nucleotide PDE2 (phosphodiesterase 2). hESCs maintained in feeder-free conditions with EHNA for more than ten passages showed no reduction in hESC-associated markers including NANOG, POU5F1 (POU domain class 5 transcription factor 1, also known as Oct-4) and SSEA4 (stage-specific embryonic antigen 4) compared with cells maintained in feeder-free conditions containing bFGF (basic fibroblast growth factor). Spontaneous differentiation was reversibly suppressed by the addition of EHNA, but, upon removing EHNA, hESC populations underwent efficient spontaneous, multi-lineage and directed differentiation. EHNA also acts as a strong blocker of directed neuronal differentiation. Chemically distinct inhibitors of ADA and PDE2 lacked the capacity of EHNA to suppress hESC differentiation, suggesting that the effect is not driven by inhibition of either ADA or PDE2. Preliminary structure-activity relationship analysis found the differentiation-blocking properties of EHNA to reside in a pharmacophore comprising a close adenine mimetic with an extended hydrophobic substituent in the 8- or 9-position. We conclude that EHNA and simple 9-alkyladenines can block directed neuronal and spontaneous differentiation in the absence of exogenous cytokine addition, and may provide a useful replacement for bFGF in large-scale or cGMP-compliant processes. PMID- 20923412 TI - Green synthesis of gold nanoparticles by the marine microalga Tetraselmis suecica. AB - The application of green-synthesis principles is one of the most impressive research fields for the production of nanoparticles. Different kinds of biological systems have been used for this purpose. In the present study, AuNPs (gold nanoparticles) were prepared within a short time period using a fresh cell extract of the marine microalga Tetraselmis suecica as a reducing agent of HAuCl4 (chloroauric acid) solution. The UV-visible spectrum of the aqueous medium containing AuNPs indicated a peak at 530 nm, corresponding to the surface plasmon absorbance of AuNPs. The X-ray diffraction pattern also showed a Bragg reflection related to AuNPs. Fourier-transform infrared spectroscopy was performed for analysis of surface functional groups of AuNPs. Transmission electron microscopy and particle-size-distribution patterns determined by the laser-light-scattering method confirmed the formation of well-dispersed AuNPs. The most frequent size of particles was 79 nm. PMID- 20923413 TI - Osteoblast mineralization with composite nanofibrous substrate for bone tissue regeneration. AB - Several studies are currently ongoing to construct synthetic bone-like materials with composites of natural and polymeric materials with HA (hydroxyapatite). The present study aims to fabricate composite nanofibrous substrate of Chit/HA (chitosan/HA - 80:25) prepared by dissolving in TFA/DCM (trifluoroacetic acid/dichloromethane) (70:30, w/w) for 5 days and electrospun to fabricate a scaffold for bone tissue engineering. HA (25 wt %) was sonicated for 30 min to obtain a homogenous dispersion of nanoparticles within the Chit (80 wt %) matrix for fabricating composite nanofibrous scaffold (Chit/HA). The nanofibres of Chit and Chit/HA were obtained with fibre diameters of 274 +/- 75 and 510 +/- 198 nm, respectively, and characterized by FESEM (field emission scanning electron microscopy) and FTIR (Fourier transform infrared). The interaction of hFOBs (human fetal osteoblasts) and nanofibrous substrates were analysed for cell morphology (FESEM), mineralization [ARS (Alizarin Red-S) staining], quantification of minerals and finally identified the elements present in Chit/HA/osteoblasts by EDX (energy-dispersive X-ray) analysis. EDX analysis confirmed that the spherulites contain calcium and phosphorus, the major constituents in calcium phosphate apatite, the mineral phase of the bone. Mineralization was increased significantly (P<0.001) up to 108% in Chit/HA compared with Chit nanofibres. These results confirmed that the electrospun composite Chit/HA nanofibrous substrate is a potential biocomposite material for the proliferation and mineralization of hFOBs required for enhanced bone tissue regeneration. PMID- 20923414 TI - Production of scFv-displaying BmNPV in silkworm larvae and its efficient purification. AB - Baculovirus-display technology utilizing the gp64 envelope protein has been developed. A simple and efficient process to separate the virus from the majority of the protein contaminants may be needed for the future demand of pure and functional baculovirus vectors ideal for vaccine- and gene-delivery applications. In the present study, using Bombyx mori (silkworm) larvae as a host, scFv (single chain variable fragment)-surface displaying recombinant baculovirus production and its purification from silkworm larval haemolymph by SEC (size-exclusion chromatography) were demonstrated. The amounts of scFv were 4-8 MUg/ml in the haemolymph. The scFv-gp64 fusion protein was confirmed to be incorporated into the cell membrane and the BmNPV (B. mori nucleopolyhedrovirus) surface by immunofluorescence microscopy and Western blotting. rBmNPV (recombinant BmNPV) was purified to higher purity by SEC using Sephacryl S-1000 column chromatography than by sucrose-density-gradient centrifugation. The recovery of purified rBmNPV was 22.2%, and the virus purity in the SEC fraction was increased 269-fold compared with its purity in haemolymph. Judging from the results of ELISA, approx. 0.9% of the total baculovirus-particle proteins were occupied by scFv on their surface. A BmNPV-based silkworm-larval system is suitable for large-scale production of baculovirus-surface-displayed proteins or peptides in comparison with a cell-culture system. The present study will be useful for future BmNPV application studies for gene delivery and vaccine trials. PMID- 20923415 TI - A simple method for large-scale purification of plasma-derived apo-transferrin. AB - We investigated and optimized a purification process, suitable for industrial scale, to obtain pharmaceutical grade apo-Tf (apo-transferrin), preserving its physiological properties and functions. Apo-Tf was obtained from fraction IV subfraction 1 and IV subfraction 4 (fraction IV-1,4), a waste product of the Cohn fractionation process, performing a single chromatographic run and two viral inactivation/removal steps. The structural integrity and the biological activity of the final product were extensively tested. The yield of apo-Tf produced was 80% on laboratory scale and 90% in scale-up lots, and the purity was higher than 95%. The purified protein preserves iron- and receptor-binding activities and shows a normal glycosylation pattern. The single chromatographic step process presented here provides an efficient means to prepare commercial quantities of the protein. The final product is sterile and two viral inactivation/removal steps were introduced into the process. PMID- 20923416 TI - The BCCT family of carriers: from physiology to crystal structure. AB - Increases in the environmental osmolarity are key determinants for the growth of microorganisms. To ensure a physiologically acceptable level of cellular hydration and turgor at high osmolarity, many bacteria accumulate compatible solutes. Osmotically controlled uptake systems allow the scavenging of these compounds from scarce environmental sources as effective osmoprotectants. A number of these systems belong to the BCCT family (betaine-choline-carnitine transporter), sodium- or proton-coupled transporters (e.g. BetP and BetT respectively) that are ubiquitous in microorganisms. The BCCT family also contains CaiT, an L-carnitine/gamma-butyrobetaine antiporter that is not involved in osmotic stress responses. The glycine betaine transporter BetP from Corynebacterium glutamicum is a representative for osmoregulated symporters of the BCCT family and functions both as an osmosensor and osmoregulator. The crystal structure of BetP in an occluded conformation in complex with its substrate glycine betaine and two crystal structures of CaiT in an inward-facing open conformation in complex with L-carnitine and gamma-butyrobetaine were reported recently. These structures and the wealth of biochemical data on the activity control of BetP in response to osmotic stress enable a correlation between the sensing of osmotic stress by a transporter protein with the ensuing regulation of transport activity. Molecular determinants governing the high affinity binding of the compatible solutes by BetP and CaiT, the coupling in symporters and antiporters, and the osmoregulatory properties are discussed in detail for BetP and various BCCT carriers. PMID- 20923417 TI - Adaptive responses to purine starvation in Leishmania donovani. AB - Starvation of Leishmania donovani parasites for purines leads to a rapid amplification in purine nucleobase and nucleoside transport. Studies with nucleoside transport-deficient L. donovani indicate that this phenomenon is mediated by the nucleoside transporters LdNT1 and LdNT2, as well as by the purine nucleobase transporter LdNT3. The escalation in nucleoside transport cannot be ascribed to an increase in either LdNT1 or LdNT2 mRNA. However, Western analyses on parasites expressing epitope-tagged LdNT2 revealed a marked upregulation in transporter protein at the cell surface. Kinetic investigations of LdNT1 and LdNT2 activities from purine-replete and purine-starved cells indicated that both transporters exhibited significant increases in V(max) for their ligands under conditions of purine-depletion, although neither transporter displayed an altered affinity for its respective ligands. Concomitant with the increase in purine nucleoside and nucleobase transport, the purine salvage enzymes HGPRT, XPRT and APRT were also upregulated, suggesting that under conditions where purines are limiting, Leishmania parasites remodel their purine metabolic pathway to maximize salvage. Moreover, qRT-PCR analyses coupled with cycloheximide inhibition studies suggest that the underlying molecular mechanism for this augmentation in purine salvage occurs post-transcriptionally and is reliant on de novo protein synthesis. PMID- 20923418 TI - Proteobactin and a yersiniabactin-related siderophore mediate iron acquisition in Proteus mirabilis. AB - Proteus mirabilis causes complicated urinary tract infections (UTIs). While the urinary tract is an iron-limiting environment, iron acquisition remains poorly characterized for this uropathogen. Microarray analysis of P. mirabilis HI4320 cultured under iron limitation identified 45 significantly upregulated genes (P <= 0.05) that represent 21 putative iron-regulated systems. Two gene clusters, PMI0229-0239 and PMI2596-2605, encode putative siderophore systems. PMI0229-0239 encodes a non-ribosomal peptide synthetase-independent siderophore system for producing a novel siderophore, proteobactin. PMI2596-2605 are contained within the high-pathogenicity island, originally described in Yersinia pestis, and encodes proteins with apparent homology and organization to those involved in yersiniabactin production and uptake. Cross-feeding and biochemical analysis shows that P. mirabilis is unable to utilize or produce yersiniabactin, suggesting that this yersiniabactin-related locus is functionally distinct. Only disruption of both systems resulted in an in vitro iron-chelating defect; demonstrating production and iron-chelating activity for both siderophores. These findings clearly show that proteobactin and the yersiniabactin-related siderophore function as iron acquisition systems. Despite the activity of both siderophores, only mutants lacking the yersiniabactin-related siderophore have reduced fitness in vivo. The fitness requirement for the yersiniabactin-related siderophore during UTI shows, for the first time, the importance of siderophore production in vivo for P. mirabilis. PMID- 20923419 TI - Biochemical analysis of PIFTC3, the Trypanosoma brucei orthologue of nematode DYF 13, reveals interactions with established and putative intraflagellar transport components. AB - DYF-13, originally identified in Caenorhabditis elegans within a collection of dye-filling chemosensory mutants, is one of several proteins that have been classified as putatively involved in intraflagellar transport (IFT), the bidirectional movement of protein complexes along cilia and flagella and specifically in anterograde IFT. Although genetic studies have highlighted a fundamental role of DYF-13 in nematode sensory cilium and trypanosome flagellum biogenesis, biochemical studies on DYF-13 have lagged behind. Here, we show that in Trypanosoma brucei the orthologue to DYF-13, PIFTC3, participates in a macromolecular complex of approximately 660 kDa. Mass spectroscopy of affinity purified PIFTC3 revealed several components of IFT complex B as well as orthologues of putative IFT factors DYF-1, DYF-3, DYF-11/Elipsa and IFTA-2. DYF 11 was further analysed and shown to be concentrated near the basal bodies and in the flagellum, and to be required for flagellum elongation. In addition, by coimmunoprecipitation we detected an interaction between DYF-13 and IFT122, a component of IFT complex A, which is required for retrograde transport. Thus, our biochemical analysis supports the model, proposed by genetic analysis in C. elegans, that the trypanosome orthologue of DYF-13 plays a central role in the IFT mechanism. PMID- 20923420 TI - Reversal of an epigenetic switch governing cell chaining in Bacillus subtilis by protein instability. AB - Bacillus subtilis forms long chains of cells during growth and biofilm formation. Cell separation is mediated by autolysins, whose genes are under the negative control of a heteromeric complex composed of the proteins SinR and SlrR. Formation of the SinR-SlrR complex is governed by a self-reinforcing, double negative feedback loop in which SinR represses the gene for SlrR and SlrR, by forming the SinR-SlrR complex, titrates SinR and prevents it from repressing slrR. The loop is a bistable switch and exists in a SlrR(LOW) state in which autolysin genes are on, and a SlrR(HIGH) state in which autolysin genes are repressed by SinR-SlrR. Cells in the SlrR(LOW) state are driven into the SlrR(HIGH) state by SinI, an antirepressor that binds to and inhibits SinR. However, the mechanism by which cells in the SlrR(HIGH) state revert back to the SlrR(LOW) state is unknown. We report that SlrR is proteolytically unstable and present evidence that self-cleavage via a LexA-like autopeptidase and ClpC contribute to its degradation. Cells producing a self-cleavage-resistant mutant of SlrR exhibited more persistent chaining during growth and yielded biofilms with enhanced structural complexity. We propose that degradation of SlrR allows cells to switch from the SlrR(HIGH) to the SlrR(LOW) state. PMID- 20923421 TI - Ether cleaving methyltransferases of the strict anaerobe Acetobacterium dehalogenans: controlling the substrate spectrum by genetic engineering of the N terminus. AB - The anaerobic cleavage of ether bonds of methoxylated substrates such as vanillate or veratrol in acetogenic bacteria is mediated by multi-component enzyme systems, the O-demethylases. Acetobacterium dehalogenans harbours different inducible O-demethylases with various substrate spectra. Two of these enzyme systems, the vanillate- and the veratrol-O-demethylases, have been characterized so far. One component of this enzyme system, the methyltransferase I (MT I), catalyses the cleavage of the substrate ether bond and the subsequent transfer of the methyl group to a corrinoid protein. For the C-termini of the methyltransferases I of the vanillate- and the veratrol-O-demethylases, a TIM barrel structure of the enzymes was predicted, whereas the N-termini are not part of this conserved structure. The deletion of the N-terminal regions led to a significant increase of activity (up to 20-fold) and an extended substrate spectrum of the mutants, which also comprised non-aromatic compounds such as the thioether methionine and diethylether. The exchange of the N-termini of the two methyltransferases I resulted in chimeric enzymes whose substrate specificities were those of the enzymes from which the N-termini were derived. This demonstrated the crucial role of the N-termini for the substrate specificity of the methyltransferases. PMID- 20923423 TI - The TetR-type transcriptional regulator FasR of Corynebacterium glutamicum controls genes of lipid synthesis during growth on acetate. AB - The addition of fatty acids to either Escherichia coli or Bacillus subtilis elicits an elaborate cellular response of the lipid metabolism. We found that in Corynebacterium glutamicum the expression of accD1 encoding the beta-subunit of the essential acetyl-CoA carboxylase is repressed in acetate-grown cells without the addition of fatty acids. The TetR-type transcriptional regulator NCgl2404, termed FasR, was identified and deleted. During growth on acetate, but not on glucose, 17 genes are differentially expressed in the deletion mutant, among them accD1, and fasA and fasB both encoding fatty acid synthases, which were upregulated. Determination of the 5' ends of accD1, fasA, fasB and accBC together with the use of isolated FasR protein identified the FasR binding site, fasO, which is located within the accD1 and fasA transcript initiation site thus blocking transcription by RNA polymerase binding directly. The identified fasO motif is present in C. efficiens or C. diphtheriae, too, and it is actually similarly positioned in these bacteria within the 5' ends of the accD1 and fasA transcripts, and a fasR orthologue is also present. The identification of the FasR-fasO system in Corynebacteriaceae might indicate a conserved transcriptional control of the unique lipid synthesis in these mycolic acid-containing bacteria. PMID- 20923422 TI - ABI domain-containing proteins contribute to surface protein display and cell division in Staphylococcus aureus. AB - The human pathogen Staphylococcus aureus requires cell wall anchored surface proteins to cause disease. During cell division, surface proteins with YSIRK signal peptides are secreted into the cross-wall, a layer of newly synthesized peptidoglycan between separating daughter cells. The molecular determinants for the trafficking of surface proteins are, however, still unknown. We screened mutants with non-redundant transposon insertions by fluorescence-activated cell sorting for reduced deposition of protein A (SpA) into the staphylococcal envelope. Three mutants, each of which harboured transposon insertions in genes for transmembrane proteins, displayed greatly reduced envelope abundance of SpA and surface proteins with YSIRK signal peptides. Characterization of the corresponding mutations identified three transmembrane proteins with abortive infectivity (ABI) domains, elements first described in lactococci for their role in phage exclusion. Mutations in genes for ABI domain proteins, designated spdA, spdB and spdC (surface protein display), diminish the expression of surface proteins with YSIRK signal peptides, but not of precursor proteins with conventional signal peptides. spdA, spdB and spdC mutants display an increase in the thickness of cross-walls and in the relative abundance of staphylococci with cross-walls, suggesting that spd mutations may represent a possible link between staphylococcal cell division and protein secretion. PMID- 20923424 TI - Interface between hypothalamic-pituitary-adrenal axis and brain-derived neurotrophic factor in depression. AB - Although the pathophysiology of depressive disorder remains elusive, two hypothetical frameworks seem to be promising: the involvement of hypothalamic pituitary-adrenal (HPA) axis abnormalities and brain-derived neurotrophic factor (BDNF) in the pathogenesis and in the mechanism of action of antidepressant treatments. In this review, we focused on research based on these two frameworks in relation to depression and related conditions and tried to formulate an integrated theory of the disorder. Hormonal challenge tests, such as the dexamethasone/corticotropin-releasing hormone test, have revealed elevated HPA activity (hypercortisolism) in at least a portion of patients with depression, although growing evidence has suggested that abnormally low HPA axis (hypocortisolism) has also been implicated in a variety of stress-related conditions. Several lines of evidence from postmortem studies, animal studies, blood levels, and genetic studies have suggested that BDNF is involved in the pathogenesis of depression and in the mechanism of action of biological treatments for depression. Considerable evidence has suggested that stress reduces the expression of BDNF and that antidepressant treatments increase it. Moreover, the glucocorticoid receptor interacts with the specific receptor of BDNF, TrkB, and excessive glucocorticoid interferes with BDNF signaling. Altered BDNF function is involved in the structural changes and possibly impaired neurogenesis in the brain of depressed patients. Based on these findings, an integrated schema of the pathological and recovery processes of depression is illustrated. PMID- 20923425 TI - Is breast-feeding of infants advisable for epileptic mothers taking antiepileptic drugs? AB - Epilepsy is a relatively common maternal complication affecting 0.3-0.5% of pregnant women. For most mothers with epilepsy, the use of antiepileptic drugs (AED) is unavoidable, even during pregnancy and lactation. Therefore, the fetus is indirectly exposed to AED via the placenta and breast milk. AED are also prescribed for female patients with other diseases, such as bipolar disorders. In clinical settings, physicians are frequently questioned whether or not women patients taking AED should breast-feed their offspring. Thus, it is necessary to establish an optimum AED regimen for women taking AED, in particular for those with epilepsy during pregnancy and lactation. In this article, we critically review the effects of AED on infants via breast milk and attempt to provide suggestions for clinicians regarding these effects during breast-feeding, based on the data of transplacental passage of AED, breast milk concentration/maternal serum concentration ratios, AED metabolism in infants and the effects of AED in breast milk on infants. PMID- 20923426 TI - Lipid peroxidation in patients with schizophrenia. AB - AIMS: There is evidence that dysregulation of free radicals metabolism associated with abnormal activities of antioxidative enzymes in schizophrenia can lead to lipid peroxidation in plasma, erythrocytes, blood platelets and cerebrospinal fluid. Injury to neurons in schizophrenia may affect their function, i.e. membrane transport, impairment of energy production in mitochondria, changes in membrane phospholipid composition, alteration of receptors and transporters as well as neurotransmission. The purpose of the present study was to assess the total antioxidant capacity (TAC) and lipid peroxidation (expressed as the level of thiobarbituric acid reactive substances [TBARS]) in plasma from schizophrenic patients taking olanzapine or risperidone. The level of TBARS estimated according to the Rice-Evans method and TAC ([ABTS; 2,2'-azinobis-(3-ethylbenzothiazoline-6 sulfonic acid) radical cation decolorization assay]) in plasma from schizophrenic patients (DSM-IV criteria for schizophrenia, n = 30, age 18-36) taking olanzapine or risperidone and from healthy volunteers (n = 30) were measured. METHODS: The level of TBARS in plasma from healthy volunteers after incubation with olanzapine or risperidone was also estimated. RESULTS: Significantly lower plasma TAC (P < 0.05) and significantly increased level of TBARS (P < 0.001) in schizophrenic patients were observed. The in vitro study showed that after olanzapine or risperidone (at final concentrations corresponding to doses used in acute episodes of schizophrenia treatment) no changes of plasma lipid peroxidation were found (P > 0.05). The obtained results indicate that the pro-oxidant disturbances occur in schizophrenic patients (acute episode) taking stable doses of olanzapine or risperidone. CONCLUSION: It seems that second-generation antipsychotics (olanzapine and risperidone) are not responsible for increase of plasma lipid peroxidation. PMID- 20923427 TI - Increased N-Acetylaspartate/creatine ratio in the medial prefrontal cortex among unmedicated obsessive-compulsive disorder patients. AB - AIMS: Changes in the fronto-striato-thalamo-cortical-circuit loop have been suggested in the pathogenesis of obsessive-compulsive disorder (OCD), and have been studied using (1)H magnetic resonance spectroscopy ((1)H MRS) with interesting findings. However, whether neural metabolites are abnormal in the medial prefrontal cortex in patients with OCD is unknown. The purpose of the present study was to investigate neural metabolites in this brain region in a sample of patients with OCD. METHODS: Subjects were 21 unmedicated OCD patients, including 10 who were drug-naive, and 19 healthy controls. Single-voxel (1)H MRS was used to study the medial prefrontal cortex for each subject. Levels of N acetylaspartate (NAA), choline-containing compounds and myoinositol were measured in terms of their ratios with creatine (Cr). RESULTS: The NAA/Cr ratio was significantly higher among OCD patients than among healthy controls (F = 4.76, P = 0.037). However, it did not correlate with patients' symptoms or with their illness durations. The NAA/Cr ratio also did not differ between drug-naive and previously medicated patients. No significant group differences were found between OCD patients and normal controls for the choline-containing compounds/Cr or myoinositol/Cr ratios. In addition, a significant correlation between the NAA/Cr ratio and trait anxiety scores on the State-Trait Anxiety Inventory was found among the controls (r = 0.639, P = 0.010). CONCLUSIONS: The N Acetylaspartate level relative to creatine in the medial prefrontal cortex was increased among unmedicated OCD patients. This cannot be attributed to the effect of medications. The possible significance of this finding in the pathophysiology of OCD is discussed. PMID- 20923428 TI - Effects of osmotic-release methylphenidate in attention-deficit/hyperactivity disorder as measured by event-related potentials. AB - AIM: Attention-deficit/hyperactivity disorder (ADHD) is a relatively common central nervous system disorder in school-age children, which may involve a specific disorder in cognition and/or information processing. Event-related potentials (ERP) are commonly used as physiological measures of cognitive function as they are easily measured and non-invasive. Thus, in the present study, we examined the effects of osmotic-release methylphenidate (MPH) (Concerta), a common treatment for childhood attention-deficit/hyperactivity disorder (ADHD), in ADHD children as measured by ERP. METHODS: Ten ADHD children participated after giving consent. Based on the guidelines for evoked potential measurement, mismatch negativity (MMN) and P300 were obtained by auditory odd ball tasks. We measured both MMN and P300 in the drug-naive condition and after intake of osmotic-release MPH. RESULTS: The MMN amplitudes after intake of osmotic-release MPH were significantly greater than those in the drug-naive situation at Pz and C4. The P300 amplitudes after intake of osmotic-release MPH were significantly greater than those in the drug-naive situation at Cz and Pz. CONCLUSION: MMN and P300 are sensitive tools for measuring the pharmacological effects of osmotic-release MPH in ADHD children. PMID- 20923429 TI - Psychometric properties of the 10-item Connor-Davidson Resilience Scale in Chinese earthquake victims. AB - AIM: Resilience refers to positive adaption in the face of stress or trauma. Assessing resilience is crucial in trauma-related research and practice. The 10 item Connor-Davidson Resilience Scale (CD-RISC) has been demonstrated to be a valid and reliable tool to achieve this goal. This study was designed to examine the psychometric properties of the 10-item CD-RISC in a sample of Chinese earthquake victims. METHODS: A total of 341 participants (185 women, 156 men) aged 20-63 years were recruited from a psychological relief program supported by the Institute of Psychology, Chinese Academy of Sciences following the 'Wenchuan' earthquake. The participants were given the 10-item CD-RISC and the 17-item post traumatic stress disorder (PTSD) subscale of the Los Angeles Symptom Checklist (LASC) 4 months after the earthquake. RESULTS: The results of exploratory factor analysis indicated that a single-factor model consistent with the original design of the 10-item CD-RISC was support. The scale was also demonstrated to have good internal consistency (Cronbach's alpha = 0.91) and test-retest reliability (r = 0.90 for a two-week interval). Scores on the scale could reflect different levels of resilience in populations that are thought to be differentiated (probable PTSD vs healthy controls, t(339) = -7.60, P < 0.01, Cohen's d = 0.84). Moreover, the total resilience scores were significantly negatively correlated with scores on total PTSD scale and its three subscales for all participants. CONCLUSION: The Chinese version of the 10-item CD-RISC has excellent psychometric properties, and is applicable for Chinese people. PMID- 20923430 TI - Quality of life and related factors among cancer caregivers in China. AB - AIMS: The present study was designed to investigate quality of life (QOL) among caregivers of cancer inpatients, and to explore the related factors with the long term goal to improve QOL of cancer caregivers in China. METHODS: A cross sectional study was performed during the period January-March 2008. Subjects comprised 358 caregivers of cancer inpatients. The questionnaires pertaining to QOL, sociodemographic characteristics, caregiving demands, available social resources, caregiving situation, and caregiver's health status were used. Data were collected by nurses through interviews. RESULTS: The average QOL score of these subjects was 5.26. General linear model analysis showed that caregiver's QOL was significantly associated with, in standardized estimate sequence, spousal relationship, patient's activities of daily living, and chronic disease (no). Overall spousal relationship to patient had the strongest association with caregiver's QOL. CONCLUSIONS: Psychological well-being and social concerns of cancer caregivers were disrupted more seriously than spiritual well-being and physical well-being. In addition, spousal relationship, patient's disability, and caregiver's health status could affect the caregiver's QOL. PMID- 20923431 TI - Impact of biopsychosocial factors on psychiatric training in Japan and overseas: are psychiatrists oriented to mind, brain, or sociocultural issues? AB - AIM: To clarify the impact of biopsychosocial factors on psychiatric training under the new and traditional postgraduate medical education system in Japan and to compare them with young psychiatrists from other countries. METHODS: Psychiatric residents and early-career psychiatrists were recruited in Japan and other countries. Using mail-based and web-based self-administered questionnaires, we evaluated participants' demographic information, motivation to become psychiatrists, interest and commitment to various aspects of psychiatry, and reactions to a case vignette, focusing on biopsychosocial factors. RESULTS: A total of 137 responses, 81 from Japan and 56 from other countries, were collected. Before starting psychiatric training, Japanese participants showed a strong interest in 'mind' and less interest in 'brain' and 'environmental factors', while the interest in 'brain' and 'environmental factors' is presently as high as that in 'mind.' Japanese participants reported less commitment to their training toward ICD/DSM-based diagnosis, interview, pharmacotherapy, psychosocial treatment and epidemiology, compared with participants from other countries. In particular, Japanese participants showed less commitment to their training in suicide prevention, despite their perception of its high importance due to a high suicide rate in Japan. Suicide risk of a case vignette proved to be differently assessed according to participants' commitment levels to each aspect of psychiatry. CONCLUSION: Our results suggest that young psychiatrists' attitudes concerning the biopsychosocial model generally become well-balanced with psychiatric training, however sociocultural factors do not seem to be well represented in the Japanese psychiatric training system. Additional training on sociocultural issues, such as suicide in Japan, should be considered. PMID- 20923432 TI - Reduced gray matter volume of dorsal cingulate cortex in patients with obsessive compulsive disorder: a voxel-based morphometric study. AB - AIMS: Previous morphometric studies using magnetic resonance imaging (MRI) have revealed structural brain abnormalities in obsessive-compulsive disorder (OCD). The aim of the present study was to investigate the alterations in brain structure of patients with OCD using a voxel-based morphometry (VBM) method. METHODS: Sixteen patients with OCD free of comorbid major depression, and 32 sex- and age-matched healthy subjects underwent MRI using a 1.5-T MR scanner. OCD severity was assessed with the Yale-Brown Obsessive-Compulsive Scale (mean +/- SD: 22 +/- 7.6; range: 7-32). MR images were spatially normalized and segmented using the VBM5 package (http://dbm.neuro.uni-jena.de/vbm/). Statistical analysis was performed using statistical parametric mapping software. RESULTS: Significant reductions in regional gray matter volume were detected in the left caudal anterior cingulate cortex and right dorsal posterior cingulate cortex in the patients with OCD as compared to healthy controls (uncorrected, P < 0.001). No significant differences in white matter volumes were observed in any brain regions of the patients. No significant correlation between Yale-Brown Obsessive Compulsive Scale score and regional gray matter or white matter volume was observed. CONCLUSIONS: Regional gray matter alteration in the dorsal cingulate cortex, which is suggested to play a role in non-emotional cognitive processes, may be related to the pathophysiology in OCD. PMID- 20923433 TI - Diurnal cortisol patterns of young male patients with schizophrenia. AB - AIMS: It has been suggested that schizophrenic patients are more vulnerable to stress than healthy persons, and that stressors can trigger a psychotic episode or worsen symptoms. The biological system often studied in relation to stress is the hypothalamic-pituitary-adrenal (HPA) axis, which controls the release of cortisol. We investigated whether the diurnal basal activity of the HPA axis differed between young male patients with schizophrenia and healthy controls. METHODS: Twenty-seven male patients (mean age 22 +/- 5 years) and 38 healthy male control subjects (mean age 22 +/- 3 years) were included in the present study. Saliva was sampled at five time points during the day: directly after awakening, 30 min thereafter, and at 12.00 hours, 16.00 hours and 22.00 hours. RESULTS: The cortisol concentration decreased significantly more during the day in the patient group thanin the control group. Patients also showed a significantly decreased area under the curve with respect to the increase, again indicating that the cortisol concentrations decreased more during the day in patients than in controls. Both the morning increase and the area under the curve with respect to the increase were significantly negatively correlated with negative symptom severity. CONCLUSIONS: Patients with schizophrenia showed a different daytime sensitivity of the HPA axis. Our findings further suggest that an increase in negative symptom severity is related to a decreased HPA axis sensitivity. PMID- 20923434 TI - Association between FOXP2 gene and speech sound disorder in Chinese population. AB - AIM: FOXP2 was described as the first gene relevant to human speech and language disorders. The main objective of this study was to compare the distribution of FOXP2 gene polymorphisms between patients with speech sound disorder and healthy controls. METHODS: Five FOXP2 polymorphisms, rs923875, rs2396722, rs1852469, rs17137124 and rs1456031, were analyzed in 150 patients with speech sound disorder according to DSM-IV, as well as in 140 healthy controls. Coding exons for key domains of FOXP2 were also sequenced in all the patients. RESULTS: Significant differences in the genotype (P = 0.001) and allele (P = 0.0025) frequencies of rs1852469 (located 5' upstream of the ATG initiator codon) were found between patients and controls. The excess of the T allele in the patients group remained significant after Bonferroni correction (P = 0.0126). Further investigations revealed a risk haplotype: rs2396722T/+rs1852469T. Our screening of key domains did not detect any point mutations in this sample. But we detected heterozygous triplet deletion of the glutamine-encoding region of exon 5 that alter FOXP2 protein sequence in five probands. These changes are predicted to yield a polyglutamine tract reduction from 40 to 39 consecutive glutamines. CONCLUSIONS: Our data support a possible role of FOXP2 in the vulnerability to speech sound disorder, which adds further evidence to implicate this gene in speech and language functions. PMID- 20923435 TI - Case of organic mania associated with stroke and open heart surgery. PMID- 20923436 TI - Lack of association between chemokine (C-C motif) receptor 3 (CCR3) gene and schizophrenia in the Korean population. PMID- 20923437 TI - Case of delirium complicated with pneumonia that improved with blonanserin administration. PMID- 20923438 TI - DNA paternity test resolving refractory Capgras syndrome. PMID- 20923439 TI - Bacterial growth response to photoactive quinones. AB - Quinones are known producers of reactive oxygen species (ROS) that may be toxic in natural aquatic environments. In this study, the effects of parent quinones and their photodegradation products on bacterial growth were determined, and photochemical ROS formation rates were measured. Using (3)H-leucine incorporation to measure growth of the bacterium Pseudomonas aeruginosa and natural seawater bacterioplankton, growth inhibition was observed when samples were exposed to dichlone, chloranil and sodium anthraquinone-2-sulfonate (AQ2S). For seawater, compared with other quinones tested, dichlone showed the greatest toxicity in the dark, and AQ2S toxicity was greatest during simultaneous exposure to sunlight. Photodegraded chloranil and dichlone showed decreased toxicity compared with nonirradiated samples. For P. aeruginosa, AQ2S and its photodegradation products showed the greatest toxicity during simultaneous exposure to sunlight. Chloranil photodegradation products showed reduced toxicity compared with the parent compound during simultaneous exposure to sunlight. Dichlone was the only compound to show any toxicity to P. aeruginosa in the dark, and its photodegradation products were more toxic than the parent compound. Based on the results of dark and light controlled experiments measuring bacterial growth and estimated ROS production rates, ROS alone does not account for relative differences in toxicity between these quinones. PMID- 20923440 TI - Epidemiology of oral yeast colonization and infection in patients with hematological malignancies, head neck and solid tumors. AB - BACKGROUND: The aim of this study was to investigate the epidemiology of oral yeast colonization and infection amongst cancer patients. METHODS: Patients with solid tumor, head-neck cancer or hematological malignancy were recruited into the study. Demographic data on age, gender, type of cancer, preceding treatment with antibiotics, anti-fungal agents, chemotherapy, radiation or surgery and presence of dentures were recorded on admission. Oral examination and microbial swabs were obtained and yeast culture, identification and antifungal susceptibility performed. RESULTS: Oral yeast colonization was prevalent in 56.8% (227/400) of all cancer patients and 18.9% (43/227) of those had clinical and microbiological evidence of infection. The incidence of oral candidiasis in yeast colonized patients was highest in head neck cancer (29.2%) followed by hematological malignancies (20.5%) and solid tumor (17%) patients. Age and dentures were identified as independent risk factors associated with yeast carriage. Candida albicans was the dominant (74%) species (497.5 per 1000 cancer admissions) followed by C. glabrata (11.5%), C. tropicalis (2.6%), C. krusei (2.6%) and C. parapsilosis (1.9%). The overall resistance to azoles was 28.2% (75/266). Resistance to specific drugs was seen for fluconazole (4.5%), itraconazole (11.7%), ketoconazole (11.3%), voriconazole (0.75%) and caspofungin (41.1%) but none to amphotericin B or nystatin. CONCLUSIONS: The highest incidence of oral candidiasis amongst cancer patients was seen in head neck cancers. The majority of infections were caused by C. albicans but almost one third of patients harbored non-C. albicans strains such as C. glabrata which were often more resistant to anti-fungal agents. PMID- 20923442 TI - Effects of ethanol and extract of cigarette smoke on the rabbit buccal mucosa. AB - AIM: The combination of smoking and drinking alcohol has a high association with diseases of squamous epithelium within the human oral cavity. Therefore, a study was done to assess the impact of these agents alone or in combination on the squamous epithelium using as model the buccal epithelium from rabbit oral cavity. METHODS: Buccal epithelium was mounted in Ussing chambers to monitor electrical parameters during exposure to ethanol (5-40%) or to Ringer extract of cigarette smoke (EOCS) from one to six cigarettes dissolved in 10 ml Ringer either alone or with combination. RESULTS: Exposure to EOCS reduced in a dose dependent manner above 2 cigarettes/10 ml transmural electrical potential difference (PD), short circuit current (I(sc)), increased transmural electrical resistance (R). Morphology showed from generalize tissue edema to patchy necrosis with the increasing concentrations. Ethanol alone raised PD, I(sc) and R at lower concentrations (5%) and lowered PD, I(sc) and R at higher concentrations (40%). The combination of 5% ethanol, EOCS-1cigarette/10 ml reduced PD, I(sc) by 58% and increased R by 29%. Unlike exposure to 5% EtOH and EOCS-1, 10% EtOH combined with EOCS-1 produces a harmful effect by dropping PD and I(sc). CONCLUSION: Both, simultaneous, and sequential, use of these agents enhanced their negative impact on these parameters. The enhancement of these effects are not due to solubulization of additional tobacco products by EtOH or by or by EtOH enhancing smoking noxious effect. Histopathologic damage needs higher concentrations of ethanol and EOCS combination and changes were more profound compared to the sum of the isolated effects of both agents. PMID- 20923441 TI - An amelogenin mutation leads to disruption of the odontogenic apparatus and aberrant expression of Notch1. AB - BACKGROUND: Amelogenins are highly conserved proteins secreted by ameloblasts in the dental organ of developing teeth. These proteins regulate dental enamel thickness and structure in humans and mice. Mice that express an amelogenin transgene with a P70T mutation (TgP70T) develop abnormal epithelial proliferation in an amelogenin null (KO) background. Some of these cellular masses have the appearance of proliferating stratum intermedium, which is the layer adjacent to the ameloblasts in unerupted teeth. As Notch proteins are thought to constitute the developmental switch that separates ameloblasts from stratum intermedium, these signaling proteins were evaluated in normal and proliferating tissues. METHODS: Mandibles were dissected for histology and immunohistochemistry using Notch1 antibodies. Molar teeth were dissected for western blotting and RT-PCR for evaluation of Notch levels through imaging and statistical analyses. RESULTS: Notch1 was immunolocalized to ameloblasts of TgP70TKO mice, KO ameloblasts stained, but less strongly, and wild-type teeth had minimal staining. Cells within the proliferating epithelial cell masses were positive for Notch1 and had an appearance reminiscent of calcifying epithelial odontogenic tumor with amyloid like deposits. Notch1 protein and mRNA were elevated in molar teeth from TgP70TKO mice. CONCLUSION: Expression of TgP70T leads to abnormal structures in mandibles and maxillae of mice with the KO genetic background and these mice have elevated levels of Notch 1 in developing molars. As cells within the masses also express transgenic amelogenins, development of the abnormal proliferations suggests communication between amelogenin producing cells and the proliferating cells, dependent on the presence of the mutated amelogenin protein. PMID- 20923443 TI - Angiogenin expression in head and neck basaloid and conventional squamous cell carcinoma: a site- and stage-matched comparison. AB - BACKGROUND: Basaloid squamous cell carcinoma is an uncommon variant of squamous cell carcinoma (SCC). Angiogenin (ANG), a member of the ribonuclease super family, is essential to tumor angiogenesis, but has also been implicated in tumor consolidation and proliferation. METHODS: ANG expression was first investigated in 12 head and neck basaloid squamous cell carcinomas (HNBSCCs) and compared with a control group of 24 site- and stage-matched conventional SCCs to establish whether the supposedly more aggressive biological behavior of HNBSCCs might be ANG-related. RESULTS: No significant differences were found between HNBSCCs, and SCCs in terms of recurrence, disease-free survival (DFS), or overall survival rates. In HNBSCC, we identified a trend toward a significant inverse correlation between endothelial ANG expression and DFS (statistical trend, P = 0.08). Endothelial ANG expression did not differ significantly in HNBSCCs and SCCs. A high ANG expression in carcinoma cells was directly associated with pT in both the HNBSCC (P = 0.04) and the SCC (statistical trend, P = 0.07) groups. ANG expression in carcinoma cells was significantly lower in HNBSCCs than in SCCs (P = 0.005). CONCLUSIONS: All the biological mechanisms investigated to date, including ANG-mediated angiogenesis or cell proliferation, have failed to confirm that HNBSCCs have a more aggressive behavior than matched SCC. PMID- 20923444 TI - Influence of methylenetetrahydrofolate reductase polymorphisms in oral cancer patients. AB - BACKGROUND: Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in folate metabolism. Two common polymorphisms associated with MTHFR gene - C677T and A1298C - influence the thermolabile nature and activity of the enzyme. This study aimed to investigate the role of MTHFR polymorphisms on oral cancer susceptibility and its potential impact on the prognostic outcome. METHODS: Oral cancer cases and controls were genotyped using PCR-RFLP technique for MTHFR C677T and A1298C polymorphisms. Disease susceptibility analysed using regression analysis. The association between clinical outcomes and the polymorphisms were analysed using univariate and multivariate model. RESULTS: The 677CT+TT genotype showed a significant three-fold reduction in oral cancer risk (RR-0.35, p-0.009). 1298CC genotype showed decreased cancer risk when compared to AA+AC genotype (RR 0.55, p-0.062). When prognostic significance of MTHFR polymorphism was evaluated, 677CT+TT patients showed improved survival than the CC individuals (RR = 0.56, P = 0.378). The 1298 CC and AC+CC showed an increased risk for treatment failure and poor survival when compared with the wild AA genotype (HR = 4.27, P = 0.001). CONCLUSION: Here we observed MTHFR C677T to influence oral cancer susceptibility, while A1298C polymorphism associated with patient prognosis. Our data support MTHFR polymorphism to be an independent prognostic marker in oral carcinoma. PMID- 20923445 TI - Pathogenesis of oral lichen planus--a review. AB - Oral lichen planus (OLP) is a T-cell-mediated chronic inflammatory oral mucosal disease of unknown etiology. OLP presents as white striations, white papules, white plaques, erythema, erosions, or blisters affecting predominantly the buccal mucosa, tongue and gingiva. Both antigen-specific and non-specific mechanisms are hypothesized to be involved in the pathogenesis of oral lichen planus (OLP). Antigen-specific mechanisms in OLP include antigen presentation by basal keratinocytes and antigen-specific keratinocyte killing by CD8(+) cytotoxic T cells. Non-specific mechanisms include mast cell degranulation and matrix metalloproteinase activation in OLP lesions. These mechanisms may combine to cause T cell accumulation in the superficial lamina propria, basement membrane disruption, intra-epithelial T cell migration and keratinocyte apoptosis in OLP. The various hypotheses proposed for pathogenesis of oral lichen planus are discussed in this review. PMID- 20923446 TI - Efficacy of topical Aloe vera in patients with oral lichen planus: a randomized double-blind study. AB - BACKGROUND: Different treatments have been used in application to symptomatic oral lichen planus (OLP), with variable results, perhaps caused by the refractory nature of the disease. The objective of this study was to evaluate the efficacy of the topical application of aloe vera (AV) in OLP compared with placebo. METHODS: A total of 64 patients with OLP were randomized in a double-blind study to either AV (32 patients) or placebo (32 patients), at a dose of 0.4 ml (70% concentration) three times a day. A Visual Analog Scale was used for rating pain, with the application of a clinical scale for scoring the lesions, the Oral Health Impact Profile 49 (OHIP-49), and the Hospital Anxiety-Depression (HAD) scale. The patients were evaluated after 6 and 12 weeks. RESULTS: No statistically significant differences were recorded between both groups in relation to pain after 6 and 12 weeks. In the AV group, complete pain remission was achieved in 31.2% of the cases after 6 weeks, and in 61% after 12 weeks. In the placebo group, these percentages were 17.2% and 41.6%, respectively. There were no adverse effects in any of the groups. In relation to quality of life, significant differences were observed between the two groups in the psychological disability domain and total OHIP-49 score. CONCLUSION: The topical application of AV improves the total quality of life score in patients with OLP. PMID- 20923447 TI - Psychiatric morbidity among patients with oral sub-mucous fibrosis: a preliminary study. AB - BACKGROUND: Oral submucous fibrosis (OSF) is a chronic oral mucosal condition with pre-malignant potential. The association between psychiatric morbidity and OSF has been sparsely studied. METHODS: This cross-sectional study included 33 consecutive subjects clinically diagnosed with OSF who attended an academic tertiary care dental centre. General Health Questionnaire-28 was administered to assess the psychological morbidity. Dependence to areca products was assessed using the ICD-10 criteria. Patient group was compared with an age and gender matched control group (n=33) from the same hospital that comprised patients who had dental diseases other than OSF and had no areca/tobacco habit. RESULTS: Total mean scores (SD) of GHQ-28 for study group and control group respectively were 48.2 (18.1) vs. 24.2 (6.5) (P<0.001). Among the patient group, the mean total GHQ scores were significantly higher in those with functional stage C (those with worst functional staging) of OSF 63.4 (15.2) when compared with those with stage B 54 (14.2) and stage A 38.7 (17) (d.f.=2; P=0.005). 22 (66.7%) of patients met ICD-10 criteria for dependence to areca products. CONCLUSIONS: OSF may be associated with considerable psychological morbidity. This morbidity may be significantly more in patients with worst functional staging. It is difficult to determine whether this is the cause or effect of the disease. Further systematic studies are urgently needed to address this issue. PMID- 20923448 TI - Nicotine modulates gelatinase B (MMP-9) and epilysin (MMP-28) expression in reconstituted human oral epithelium. AB - Oral epithelial keratinocytes express nicotinic cholinergic receptors which activation modulates keratinocytes differentiation and migration through different metabolic pathways. Matrix metalloproteinases (MMPs) are Zn-dependent enzyme involved in cell migration. Among them, gelatinase B (MMP-9) and epilysin (MMP-28) are two MMPs expressed by human keratinocytes during both wound healing and proliferation. Their expression has been investigated in a reconstituted human oral epithelium (HOE) exposed to nicotine (Nic, 1-50 MUM) for 72 h both in the absence and presence of the nicotinic antagonist mecamylamine (Mec), H7, a PKC inhibitor and PD98059, a MAPK inhibitor (PD). At the end of treatment, MMP-28 expression has been analyzed in epithelium sections using an anti-MMP-28 antibody, whereas MMP-9 presence and activity has been measured in cell conditioned medium analyzed by gelatine zymography. The expression of MMP-9 was reduced by Nic in a dose-dependent fashion and this effect was antagonized by Mec, H7 and PD. On the other hand, Nic increased the expression of MMP-28, and this effect was blocked both by H7 and PD, whereas Mec even enforced it. Nic effects on MMP-9 and MMP-28 expression by oral keratinocytes were not previously reported and these data suggest MMPs expression mediated by PKC and MAPK as a possible target for Nic toxicity in oral epithelium. PMID- 20923449 TI - Establishment of human dental epithelial cell lines expressing ameloblastin and enamelin by transfection of hTERT and cdk4 cDNAs. AB - BACKGROUND: An in vitro cell culture system of dental epithelium is useful for the investigations of cellular differentiation and function of ameloblast in amelogenesis and of regenerative therapy in human tooth. However, there have been no immortalized human dental epithelial ameloblastic-lineage cell lines, which proliferate indefinitely and additionally produce enamel matrix proteins. METHODS: We transfected two retroviral constructs of human telomerase reverse transcriptase (hTERT) cDNA and mouse cyclin-dependent kinase 4 (cdk4) cDNA into the primary ameloblastoma cells and isolated immortalized human dental epithelial cell lines of HAM1, HAM2 and HAM3. The three cell lines were examined by electron microscopy, assay of senescence-associated beta-galactosidase activity, mRNA expression and immuno-reactivity of dental epithelial marker cell molecules and enamel matrix proteins. RESULTS: They showed undifferentiated phenotypes in monolayer culture and did not have any beta-galactosidase activity. The transcripts of dental epithelial cell markers of Msx2, Jagged1, Notch1, Sp3, Sp6, keratin 14 and keratin 18 were confirmed. In addition, mRNA and protein expression of ameloblastin and enamelin were also detected in three cell lines. All cells in the three cell lines were keratin 14- and 18-positive and some elongated cells were Jagged1-positive. Msx2-positive nuclei were noted in only HAM2 cells. CONCLUSION: We established three cell lines by transfection of hTERT and cdk4 cDNAs, which were characterized as dental epithelial progenitor cells containing ameloblast-lineage cell phenotype. PMID- 20923450 TI - Classic neurothekeoma (nerve sheath myxoma) and cellular neurothekeoma of the oral mucosa: immunohistochemical profiles. AB - BACKGROUND: Classic neurothekeoma (nerve sheath myxoma) is regarded as being a true benign cutaneous tumor of nerve sheath origin. Cellular neurothekeoma was separated from the classic type by histogenesis, morphology and immunophenotype. Whether cellular neurothekeoma represents a continuum within the spectrum of classic neurothekeoma or is an independent entity is controversial. Only a small number of classic neurothekeomas of the oral mucosa have been reported and there are even fewer publications on cellular neurothekeoma. We analyzed a series of oral neurothekeomas (classic and cellular) with a panel of neural and other mesenchymal markers to enhance their diagnosis and classification. METHODS: One cellular and three classic neurothekeomas were submitted to a panel of immunohistochemical stains with antibodies against S100, S100A6, NSE, NKI/C3, PGP9.5, alpha-SMA, HHF-35, CD68 and vimentin. Two cases of neurofibroma (plexiform type), representing a true lesion of neural origin, served as control. RESULTS: The cellular neurothekeoma yielded a positive immunoreaction for S100A6 and NKI/C3 and a negative immunoreaction for S-100. The classic neurothekeomas demonstrated a positive reaction for S-100 and S100A6, but a negative one for NKI/C3. Other markers were non-contributory to distinguishing between these types of lesions. CONCLUSIONS: The small number of reported oral neurothekeomas (classic and cellular) could be due, in part, to the lack of recognition of their particular morphologic and immunohistochemical features. Our results indicate that testing for NKI/C3 immunoreactivity may be of value in distinguishing between cellular and classic neurothekeoma. PMID- 20923451 TI - A molecular study of desmosomes identifies a desmoglein isoform switch in head and neck squamous cell carcinoma. AB - Desmosomes, the intercellular junctions that confer strong adhesion between epithelial cells, are frequently altered in malignancy. However, a comprehensive analysis of these structures has not been carried out in oral neoplasia. Oral squamous cell carcinomas (SCCs) and pre-malignant dysplasia can be sub-classified according to their in vitro replicative lifespan, where the immortal dysplasia (ID) and carcinoma (IC) subsets have p16(ink4a) and p53 dysfunction, telomerase deregulation and genetic instability and the mortal subset (MD and MC) do not. We found that the desmosomal proteins exhibit a distinct expression pattern in oral mucosa when compared with epidermis in vivo. Microarray data from a large panel of lines revealed that the transcript levels of DSG3, DSC2/3, DP, PG and PKP1 were reduced in ID and IC. Interestingly, DSG2 was up-regulated in MC. Reduction of DSG3 and up-regulation of DSG2 were found in two independent microarray datasets. Significantly, we demonstrated that reduction of DSG3 and up-regulation of DSG2 was reversible in vitro by using RNAi-mediated knockdown of DSG2 in IC cells. The remaining desmosomal proteins were largely disrupted or internalized and associated with retraction of keratin intermediate filaments in oral SCC lines. These findings suggest dysfunction and loss of desmosomal components are common events in the immortal class of oral SCC and that these events may precede overt malignancy. PMID- 20923452 TI - Strain-specific spleen remodelling in Plasmodium yoelii infections in Balb/c mice facilitates adherence and spleen macrophage-clearance escape. AB - Knowledge of the dynamic features of the processes driven by malaria parasites in the spleen is lacking. To gain insight into the function and structure of the spleen in malaria, we have implemented intravital microscopy and magnetic resonance imaging of the mouse spleen in experimental infections with non-lethal (17X) and lethal (17XL) Plasmodium yoelii strains. Noticeably, there was higher parasite accumulation, reduced motility, loss of directionality, increased residence time and altered magnetic resonance only in the spleens of mice infected with 17X. Moreover, these differences were associated with the formation of a strain-specific induced spleen tissue barrier of fibroblastic origin, with red pulp macrophage-clearance evasion and with adherence of infected red blood cells to this barrier. Our data suggest that in this reticulocyte-prone non lethal rodent malaria model, passage through the spleen is different from what is known in other Plasmodium species and open new avenues for functional/structural studies of this lymphoid organ in malaria. PMID- 20923453 TI - Electrodermal activity by DC potential and AC conductance measured simultaneously at the same skin site. AB - BACKGROUND: For a long time, DC conductance has been the most important parameter in electrodermal routine measurements. However, DC current flow polarizes the electrodes, electrolyzes the skin, disturbs the measurement of conductance by possible varying electromotive forces (EMFs) in the circuit, and impedes the registration of the skin endosomatic DC potential. METHODS: We therefore present a measuring system where DC current was replaced by a small AC current in a monopolar system, enabling the DC potential and AC conductance to be measured simultaneously at the same skin site. RESULTS: We have also found examples of skin potential (SP) response waveforms with diphasic sharp edges not appearing in the conductance waveforms. The potential responses were found to be more robust with respect to movement artifacts, and the instrumentation could discern whether the indifferent electrode actually was on an inactive skin site. CONCLUSION: In order to study the generating mechanisms of EDA in detail, the SP must be measured without DC current flow and compared with AC conductance results. PMID- 20923454 TI - Weighted performance index for objective evaluation of border detection methods in dermoscopy images. AB - PURPOSE: This paper presents a novel approach for objective evaluation of border detection in dermoscopy images of melanoma. BACKGROUND: In melanoma studies, border detection is a fundamental step toward the development of a computer-aided diagnosis system. Therefore, its accuracy is essential for accurate implementation of the subsequent parts of the diagnostic system. METHOD: An objective evaluation procedure of border detection methods is presented. The evaluation procedure uses the weighted performance index, which is composed of weighted metrics of sensitivity, specificity, accuracy, precision, border error and similarity. This index can also be used to optimize the parameters of a border detection method. RESULT AND CONCLUSION: Experiments are performed on 55 high-resolution dermoscopy images. Using the union of four sets of dermatologist drawn borders as the ground truth, weighted metrics of sensitivity, specificity, accuracy, precision, border error and similarity are evaluated. Then, the weighted performance index is constructed and used to optimize the parameters of the hybrid border detection method. The outcome of the optimization process, verified through statistical analysis, yields a higher degree of agreement between automatic borders and the ground truth, compared with using standard metrics only. Finally, the weighted performance index is used to evaluate five recently reported border detection methods. PMID- 20923455 TI - Spatial variations in forearm skin tissue dielectric constant. AB - BACKGROUND: Tissue dielectric constant (TDC) values measured at 300MHz via the open-ended coaxial line reflection method depend on the effective measurement depth and the anatomical site being evaluated. Measurements on the forearm have shown that the TDC values decrease with increasing measurement depth but the spatial variability of the TDC values among forearm anatomical positions is unknown. Our goal was to characterize the extent of such spatial variations. METHODS: In 30 healthy seated women (27.4+/-6.5 years), TDC was measured on the forearm midline and 1.2cm medial and lateral to the midline at sites 4, 8 and 12cm distal to the antecubital crease. RESULTS: The midline and medial TDC values increased progressively from 4 to 8 to 12cm sites (P<0.001), with the largest spatial gradient along the midline. At a depth of 2.5mm, the TDC values increased from 26.3+/-2.8 to 27.4+/-3.4 to 28.4+/-3.7, with a maximum difference of 8.2+/ 10.6%. For all sites, the TDC values were significantly (P<0.001) less for increasing depths. CONCLUSION: The findings reveal increased TDC values along the forearm from proximal to distal, most prominent at the midline and medial positions. Because many skin-related dermatological and biophysical studies utilize the forearm as a test target, such differences may be important to consider because TDC values in part are reflective of local tissue water (LTW). Although the variation in the TDC values among sites was less than 10%, such differences are of importance when evaluating LTW changes using the TDC method in patients with arm lymphedema that is present in variable arm anatomical locations. PMID- 20923456 TI - Unsupervised segmentation for digital dermoscopic images. AB - BACKGROUND: Skin cancer is among the most common types of cancer. Melanoma is the most fatal of all skin cancer types. The only effective treatment is early excision. Recognising melanoma is challenging both for general physicians and for expert dermatologists. A computer-aided diagnostic system improving diagnostic accuracy would be of great importance. Segmenting the lesion from the skin is the first step in this process. METHODS: The present segmentation algorithm uses a multiscale approach for density analysis. Only the skin mode is found by density analysis and then the location of the lesion mode is estimated. The density estimates are attained by Gaussian kernel smoothing with several bandwidths. A new algorithm for hair recognition based on morphological operations on binary images is incorporated into the segmentation algorithm. RESULTS: The algorithm provides correct segmentation for both unimodal and multimodal densities. The segmentation is totally unsupervised, with a digital image as the only input. The algorithm has been tested on an independent set of images collected in dermatological practice, and the segmentation is verified by three dermatologists. CONCLUSION: The present segmentation algorithm is fast and intuitive. It gives correct segmentation for most types of skin lesions, but fails when the lesion is brighter than the surrounding skin. PMID- 20923457 TI - Colour change in the human histamine wheal made visible by LYYN: a technique to enhance colour differences. AB - BACKGROUND: Colour differences in photographs can be enhanced using a digital image-processing technique called LYYN. OBJECTIVE: To investigate colour changes in the histamine wheal after skin prick tests (SPTs). METHODS: Histamine SPTs were performed on the forearm of six medical students, and the reactions of the skin were photographed every 2min for 30min. Colour differences in the photographs were then enhanced using the LYYN technique. These images were processed using ImageJ to yield numerical values. RESULTS: In the LYYN-processed images, there was a rapid colour change in the histamine wheals between the 18th and the 20th minute (P<0.01). Histamine perfusion in isolated rabbit ears indicated vasodilatation in post-capillary vessels and desensitized histamine 1 (H1) receptors after a mean of 17min. It is possible that a similar desensitization takes place in the human histamine wheal, and a study of two histamine SPTs 90 min apart at the same site supports this hypothesis. CONCLUSION: The LYYN technique was sensitive enough to discover a rapid colour change in the histamine wheal, a change that has not been described before. PMID- 20923458 TI - Efficacy of anti-wrinkle products in skin surface appearance: a comparative study using non-invasive methods. AB - BACKGROUND/PURPOSE: Age has a huge influence on skin roughness; with increasing age, the number of collagen and elastine fibers is reduced and elasticity decreases significantly. Pharmaceutical and cosmetics, environmental factors and lifestyle have an important effect on skin. In this study, the efficacy of 12 commercial anti-wrinkle products was evaluated using a direct non-invasive method to measure the skin surface morphology. Four clinical parameters surface evaluation of the living skin (SELS) (Ser, Sesc, Sesm, and Sew) were evaluate using Visioscan((r)) VC98. METHODS: Two hundred and forty-eight healthy female volunteers, aged between 30 and 70 years, were chosen for this study. The duration of treatment was 28 days. Skin microrelief parameters were evaluated using the Visioscan((r)) VC98 - SELS 2000 from Courage+Khazaka. Measurements were made in the crow's feet area and the differences were evaluated for statistical significance. RESULTS: Significant differences were found for some of the SELS parameters. According to the results obtained for SELS Sew, products that showed to be more effective against aging were V, M, N, T, P, R and L. We think this methodology may be considered very useful for the direct study of the skin surface and may be suitable as a routine method in wrinkle evaluation. PMID- 20923459 TI - Improved quantitative evaluation of atopic dermatitis by camera calibration and rectification of a stereo image. AB - BACKGROUND/PURPOSE: The aim of this study was to establish a scientific assessment method to evaluate the severity of atopic dermatitis (AD) by calibrating part of a previously described stereo-image optical topometer (SOT). METHODS: The old SOT was created using a non-convergence model. However, this study utilizes a convergence model. Camera calibration and rectification were performed using images obtained from stereo cameras. We attempted to verify the efficacy of AD treatment by objectively measuring the improvement in a group of subjects. Twenty AD patients with a variety of disease types were divided into a control group and a treatment group. RESULTS: The scoring of the AD (SCORAD) index did not show any improvements in the treated patients. However, when comparing the advanced SOT and the old SOT, we observed a decreased variation for five parameters, indicating that the treated patients experienced improved outcomes compared with controls. Most notably, we found that the coefficient of variation of the advanced SOT was lower than that of the old SOT. CONCLUSION: We conclude that the advanced SOT may be useful for evaluating AD. The use of an advanced stereo image system may yield more reliable results than the old SOT system. PMID- 20923460 TI - Appearance benefits of skin moisturization. AB - BACKGROUND/PURPOSE: Skin hydration is essential for skin health. Moisturized skin is generally regarded as healthy and healthy looking. It is thus speculated that there may be appearance benefits of skin moisturization. This means that there are corresponding changes in the optical properties when skin is moisturized. METHODS: The appearance of the skin is the result of light reflection, scattering and absorption at various skin layers of the stratum corneum, epidermis, dermis and beyond. The appearance benefits of skin moisturization are likely primarily due to the changes in the optical properties of the stratum corneum. We hypothesize that the major optical effect of skin moisturization is the decrease of light scattering at the skin surface, i.e., the stratum corneum. This decrease of surface scattering corresponds to an increase of light penetration into the deeper layers of the skin. An experiment was conducted to measure the corresponding change in skin spectral reflectance, the skin scattering coefficient and skin translucency with a change in skin hydration. In the experiment, skin hydration was decreased with the topical application of acetone and alcohol and increased with the topical application of known moisturizers and occlusives such as PJ. RESULT AND CONCLUSION: It was found that both the skin spectral reflectance and the skin scattering coefficient increased when the skin was dehydrated and decreased when the skin was hydrated. Skin translucency increased as the skin became moisturized. The results agree with the hypothesis that there is less light scattering at the skin surface and more light penetration into the deeper skin layers when the skin is moisturized. As a result, the skin appears darker, more pinkish and more translucent. PMID- 20923461 TI - Use of Raman spectroscopy for the early detection of filaggrin-related atopic dermatitis. AB - BACKGROUND: Filaggrin (FLG) gene mutations, which result in complete or incomplete loss of proFLG/FLG peptides, have been reported as an important predisposing factor for atopic dermatitis (AD) and secondary atopic phenotypes such as atopic asthma. METHOD: The presence of the protein FLG in the skin was evaluated at birth on 12 infants using Raman spectroscopy; these 12 infants were monitored for 1 year to see whether they developed AD. Three different statistical analysis procedures, two of which involved principal component analysis (PCA), were performed on the Raman spectra in order to determine the FLG content. RESULTS: The infants who had a lower FLG content, determined using any of the three statistical analysis procedures proposed, were also the ones that clinically developed AD. CONCLUSION: The results suggest that Raman spectroscopy and statistical analysis such as PCA could be used as an early detection procedure for FLG -related AD and as a possible quantitative marker for FLG gene mutations. PMID- 20923463 TI - Applicability of an exaggerated forearm wash test for efficacy testing of two corticosteroids, tacrolimus and glycerol, in topical formulations against skin irritation induced by two different irritants. AB - BACKGROUND/PURPOSE: Alternatives to corticosteroids in the treatment of irritant contact dermatitis (ICD) are needed and may include glycerol and topical immunomodulators like tacrolimus. Because the efficacy of different treatments in experimentally induced ICD may vary depending on the irritant applied, we tested the efficacy of four anti-irritant compounds using the two different irritants sodium lauryl sulfate (SLS) and nonanoic acid (NON). METHODS: In a randomized, double-blind, controlled trial, healthy volunteers were exposed to 5% SLS and 50% NON (the right and the left forearm, respectively) in a cumulative wash test. Induction of ICD was obtained by three daily washings for 7 days, followed by a maintenance phase with two daily washings for 12 days. Treatment (triamcinolone acetonide, clobetasol propionate, tacrolimus and glycerol ointment) was started at day 7 and applied immediately after washing. Vehicle and no treatment served as the control. Reactions were evaluated clinically and instrumentally. RESULTS: No treatments were significantly better than the other treatments and controls. There was a tendency toward a dose-dependent response to corticoid treatment, and a trend toward worsened irritancy by tacrolimus on SLS-irritated skin. Explained variance in the experiment by anova revealed a very small effect of treatments compared with an immense and significant subject effect. CONCLUSION: No claims of effective anti-irritant properties for any of the ointments can be maintained. Application of the present wash test as a tool for anti-irritant efficacy testing may be complicated by the small observed variance explained by treatment. PMID- 20923462 TI - Dermatological feasibility of multimodal facial color imaging modality for cross evaluation of facial actinic keratosis. AB - BACKGROUND/PURPOSE: Digital color image analysis is currently considered as a routine procedure in dermatology. In our previous study, a multimodal facial color imaging modality (MFCIM), which provides a conventional, parallel- and cross-polarization, and a fluorescent color image, was introduced for objective evaluation of various facial skin lesions. This study introduces a commercial version of MFCIM, DermaVision-PRO, for routine clinical use in dermatology and demonstrates its dermatological feasibility for cross-evaluation of skin lesions. METHODS/RESULTS: Sample images of subjects with actinic keratosis or non-melanoma skin cancers were obtained at four different imaging modes. Various image analysis methods were applied to cross-evaluate the skin lesion and, finally, to extract valuable diagnostic information. DermaVision-PRO is potentially a useful tool as an objective macroscopic imaging modality for quick prescreening and cross-evaluation of facial skin lesions. CONCLUSION: DermaVision-PRO may be utilized as a useful tool for the cross-evaluation of widely distributed facial skin lesions and as an efficient database management of patient information. PMID- 20923464 TI - Investigation of aging effects in human hair using atomic force microscopy. AB - BACKGROUND: A thorough characterization of the morphological structure and physical properties is essential for an understanding of human hair. A number of techniques such as scanning electron microscopy, transmission electron microscopy and confocal microscopy have been used to study hair surfaces. Recently, atomic force microscopy (AFM) has emerged as an ideal method for the non-invasive examination of hair surfaces. PURPOSE: To investigate the effects of aging on normal Korean hair diameter and surface features using AFM. METHODS: We enrolled 60 Korean volunteers of various ages who had no hair diseases. We analyzed hair diameter, AFM images of the hair surface, cuticular descriptors and micro-scale mechanical properties for their associations with aging. RESULTS: Hair diameter was found to increase for the first 20-30 years of life, after which it began to decrease. AFM images of most of the younger subjects showed typical step-like topographic properties with clear scale edges. The AFM images of most of the older subjects revealed dilapidated structures, poorly demarcated scale edges and undulated surfaces. Among the cuticular descriptors, surface roughness increased significantly with age. Force to distance analysis demonstrated a dependence on age. CONCLUSION: These results suggest that aging causes changes in hair diameter and surface structure. PMID- 20923465 TI - Skin application of urea-containing cream affected cutaneous arterial sympathetic nerve activity, blood flow, and water evaporation. AB - BACKGROUND/PURPOSE: We observed that olfactory stimulation with scent of grapefruit oil elevated the activities of sympathetic nerves, and increased the plasma glycerol concentration and blood pressure. In contrast, olfactory stimulation with scent of lavender oil had opposite effects in rats. These suggest that changes in autonomic activities cause physiological functions via histaminergic H1 and H3 receptor. Moreover, it has been reported that somatic sensory stimulation affected autonomic neurotransmission. To examine effects of skin application of urea-containing cream on cutaneous arterial sympathetic nerve activity (CASNA), blood flow, and transepidermal water loss (TEWL). METHOD: The activity of CASNA was determined by electrophysiological method, and cutaneous blood flow was determined using laser flowmeter in urethane-anesthetized rats, TEWL was measured using VapoMeter in the back skin of HWY hairless rats. RESULTS: CASNA was markedly and significantly inhibited by skin application of 10% urea containing cream, whereas cutaneous blood flow was significantly elevated via histaminergic H3-receptor. In conscious hairless rats, TEWL was significantly decreased 24 h after application of 10% urea-containing cream to the back skin. CONCLUSION: These findings suggest that skin application of 10% urea-containing cream increases the cutaneous blood flow and water retaining ability, and that histaminergic H3-receptors may mediate these effects. PMID- 20923466 TI - Capsaicin-induced neurogenic inflammation in the skin in patients with symptoms induced by odorous chemicals. AB - BACKGROUND: Intradermal injection of capsaicin induces the axonal release of neuropeptides, vasodilatation and flare, e.g. neurogenic inflammation. The spatial profile of neurogenic inflammation in the skin has been studied in various experimental models. Polarization spectroscopy imaging introduced recently may be used for the quantitative assessment of the temporal profile of neurogenic inflammation expressed as erythema intensity. PURPOSE: In the present study, we aimed to compare capsaicin-induced erythema intensity with the flare area in patients with symptoms induced by odorous chemicals, thereby comparing the temporal and spatial profiles of neurogenic inflammation. METHODS: Sixteen patients fulfilling Cullen's criteria for multiple chemical sensitivity (MCS) and 15 eczema (EC) patients with airway symptoms elicited by odorous chemicals were compared with 29 age-matched, healthy controls. Participants were administered two intradermal injections of capsaicin 3.3 and 33MUM. Erythema intensity was measured by polarization spectroscopy imaging and flare response was quantified by visual inspection. RESULTS: Erythema intensity and flare area did not differ between patients and controls, and they were not correlated. Erythema intensity and flare area showed a dose-dependent increase (P<0.05). Erythema intensity increased with age at 3.3MUM but not at 33MUM capsaicin, whereas the flare area increased with age at both concentrations (P<0.05). CONCLUSION: Capsaicin-induced erythema intensity and visual flare were normal in patients with MCS and EC patients with airway symptoms from odorous chemicals. Polarized light spectroscopy was a useful method for the measurement of the rapid temporal changes in erythema of experimental reactions. PMID- 20923467 TI - Better understanding of digital photography for skin color measurement: With a special emphasis on light characteristics. AB - BACKGROUND/AIM: Digital photography can be used to measure skin color colorimetrically when combined with proper techniques. To better understand the settings of digital photography for the evaluation and measurement of skin colors, we used a tungsten lamp with filters and the custom white balance (WB) function of a digital camera. MATERIALS AND METHODS: All colored squares on a color chart were photographed with each original and filtered light, analyzed into CIELAB coordinates to produce the calibration method for each given light setting, and compared statistically with reference coordinates obtained using a reflectance spectrophotometer. They were summarized as to the typical color groups, such as skin colors. We compared these results according to the fixed vs. custom WB of a digital camera. RESULTS: The accuracy of color measurement was improved when using light with a proper color temperature conversion filter. The skin colors from color charts could be measured more accurately using a fixed WB. In vivo measurement of skin color was easy and possible with our method and settings. CONCLUSION: The color temperature conversion filter that produced daylight-like light from the tungsten lamp was the best choice when combined with fixed WB for the measurement of colors and acceptable photographs. PMID- 20923468 TI - Objective melanoma progression. AB - BACKGROUND/PURPOSE: Many aspects of the natural history of malignant melanoma (MM) are still unclear, specifically its appearance at onset and particularly how it changes in time. The purpose of our study was to retrospectively determine objective changes in melanoma over a 3-24-month observation period. MATERIALS AND METHODS: Our study was carried out in two Italian dermatology centers. Digital dermoscopy analyzers (DB-Mips System) were used to retrospectively evaluate dermoscopic images of 59 MM (with no initial clinical aspects suggesting melanoma) under observation for 3-24 months. The analyzer evaluates 49 parameters grouped into four categories: geometries, colors, textures and islands of color. Multivariate analysis of variance for repeated measures was used to evaluate the statistical significance of the changes in the digital dermoscopy variables of melanomas. RESULTS: Within-lesion analysis indicated that melanomas increased in dimension (Area, Minimum, and Maximum Diameter), manifested greater disorganization of the internal components (Red, Green and Blue Multicomponent, Contrast, and Entropy) and increased in clusters of milky pink color (Light Red Area). CONCLUSION: Analysis of the parameters of our model and statistical analysis enabled us to interpret/identify the most significant factors of melanoma modification, providing quantitative insights into the natural history of this cutaneous malignancy. PMID- 20923469 TI - Troubling ethical questions from gestational diabetes trial. PMID- 20923470 TI - Islet cell transplantation for Type 1 diabetes. AB - Islet transplantation is an attractive concept for the treatment of Type 1 diabetes because of its potential high efficacy and minimal invasion to patients. The treatment may effectively control blood glucose for brittle Type 1 diabetes, resulting in a marked reduction in hypoglycemic episodes and improvements in HbA1c. In addition, approximately 70% of transplanted Type 1 diabetic patients have achieved insulin independence. However, there are still important issues to be addressed before this treatment is widely applicable, including difficulty in maintaining insulin independence, low islet isolation success rate, multiple donor requirements, and side effects associated with the use of immunosuppressants. Donor shortage is another dilemma. To address the issue of donor shortage, living donor islet transplantation and bioartificial islet transplantation using pig islets are being evaluated. Bioartificial islet transplantation could be the ultimate solution of the donor shortage. Currently, overcoming immunological hurdles, establishing reliable islet isolation methods, and controlling porcine endogenous retrovirus are the primary obstacles to the implementation of this treatment. If bioartificial islet transplant becomes a clinical reality, it may even be applicable in the treatment of select Type 2 diabetic patients. beta-Cell regeneration from naive pancreas and beta-cell generation from embryonic stem cells or induced pluripotent stem cells are the next-generation treatments for Type 1 diabetes. PMID- 20923471 TI - Television watching and incident diabetes: Findings from the European Prospective Investigation into Cancer and Nutrition-Potsdam Study. AB - BACKGROUND: The aim of the present study was to examine whether the amount of time spent watching television is a potential risk factor for incident diabetes and to what extent this association may be explained by obesity. METHODS: We used data for 23,855 men and women from the European Prospective Investigation into Cancer and Nutrition-Potsdam Study. During an average of 7.8 years of follow-up, 927 participants developed diabetes. Incident diabetes was identified on the basis of self-report and was verified by contacting the patient's attending physician. The amount of time spent watching television was self-reported. RESULTS: The mean time that the participants who developed diabetes watched television was 2.4 h/week, compared with 2.0 h/week for those who did not develop diabetes (P<0.001). After adjusting for age, sex, educational status, smoking status, alcohol use, occupational activity, physical activity, the intake of various foods, and systolic blood pressure, the adjusted hazard ratio for diabetes among participants who watched >=4 h/day of television compared with those who watched <1 h/day was 1.63 [95% confidence interval (CI): 1.17-2.27]. After additional adjustment for waist circumference and body mass index, the hazard ratio was reduced to 1.14 (95% CI: 0.81-1.61). CONCLUSIONS: In the present study, the amount of time spent watching television was an independent predictor of incident diabetes only in models that adjusted for sociodemographic characteristics, lifestyle behaviors, and systolic blood pressure. The attenuation of the association after adjusting for anthropometric measures may represent an explanatory mechanism for our findings. PMID- 20923472 TI - Facile fingerstick insulin analysis: Application to monitoring postprandial insulin responses to snack foods. AB - BACKGROUND: Energy intake from snacks has been increasing in the American diet, but insulin and glucose responses to foods are generally reported for meal-sized portions (800-1200 kJ). Established methods for insulin determination routinely use indwelling catheters and radioimmunoassay (RIA). The aim of the present study was to develop a more facile method, collecting fingerstick blood samples and measuring insulin with precise ELISA, and then applying this method to determine responses to snack-sized food portions. METHODS: Six healthy, fasting adult volunteers consumed seven different snack foods on separate days, containing approximately 400 kJ/portion. Insulin was measured by ELISA and glucose was measured with the hexokinase procedure in samples collected by fingerstick at 0, 30, and 60 min after consumption of the snack food. RESULTS: A portion of doughnut (half a glazed doughnut) led to marked changes in insulin and glucose; skim milk, an apple, and oatmeal changed insulin significantly; wrinkled peas resulted in a lower glucose response than smooth peas; and walnuts led to non significant changes in both insulin and glucose over a 60-min period. CONCLUSIONS: The fingerstick sampling and insulin measurement procedure is simple, economical, and more precise than established RIA. The method can be applied to children and adults to monitor insulin responses following food consumption, as well as during therapeutic assessments or intervention trials. Public health advisories regarding snacks that minimize increases in insulin are desirable for individuals trying to reduce or maintain their weight, because elevated insulin stimulates carbohydrate conversion to fat and suppresses the mobilization of stored triglycerides for energy generation. PMID- 20923473 TI - Lack of effect of subtherapeutic vitamin D treatment on glycemic and lipid parameters in Type 2 diabetes: A pilot prospective randomized trial. AB - BACKGROUND: Epidemiological studies suggest a higher prevalence of metabolic syndrome and its components among individuals with vitamin D deficiency. The aim of the present study was to determine whether vitamin D treatment improves glucose control and insulin sensitivity in Type 2 diabetes mellitus (T2DM). METHODS: Subjects with T2DM and serum 25-hydroxyvitamin D (25(OH)D) concentrations <25 ng/mL were randomized to receive 400 IU (Group 1) or 1200 IU (Group 2) cholecalciferol for 4 months. Fasting plasma glucose, glycosylated hemoglobin (HbA1c), Quantitative Insulin Sensitivity Check Index (QUICKI), serum lipid levels and serum adiponectin were measured at baseline and at 4 months. RESULTS: Mean 25(OH)D levels increased in both groups (from 17.6+/-1.5 to 25.5+/ 1.8 ng/mL in Group 1 and from 15.6+/-1.4 to 27.4+/-2.4 ng/mL in Group 2; P<=0.001 vs baseline for each group). No significant differences were noted in fasting plasma glucose, HbA1c, QUICKI, serum adiponectin, and lipid levels compared with baseline within groups or between the two groups. CONCLUSIONS: In the present pilot study, conventional vitamin D treatment at a level improving, but not optimizing, serum 25(OH)D did not improve glycemia, insulin sensitivity, or lipid profile. However, diabetes and lipids were relatively well controlled at baseline. Future studies should be designed to achieve optimal concentrations of serum 25(OH)D (at least >32 ng/mL) and should include subjects showing more abnormal parameters of glycemia, lipid, and insulin sensitivity at baseline. PMID- 20923474 TI - Enhanced healing of diabetic foot ulcers using local heat and electrical stimulation for 30 min three times per week. AB - BACKGROUND: Electrical stimulation (ES) with heating is effective in healing chronic wounds. However, it this effect due to ES alone or both heating and ES? The aim of the present study was to deduce the individual roles of heat and ES in the healing of chronic wounds. METHODS: The study was performed on 20 patients (mean age 48.4 +/- 14.6 years) with non-healing diabetic foot ulcers (mean duration 38.9 +/- 23.7 months) who received local dry heat (37 degrees C; n = 10) or local dry heat + ES (n = 10) three times a week for 4 weeks. Patients were given ES using biphasic sine wave stimulation (30 Hz, pulse width 250 MUs, current approximately 20 mA). RESULTS: Skin blood flow in and around the wound was measured with a laser Doppler flow imager. In the ES + heat group, the average wound area and volume decreased significantly by 68.4 +/- 28.6% and 69.3 +/- 27.1%, respectively (both P < 0.05), over the 1-month period. During the average session, blood flow increased to 102.3 +/- 25.3% with local heat and to 152.3 +/- 23.4% with ES + heat. In the group receiving treatment with local heat only, wounds that had not healed for at least 2 months showed 30.1 +/- 22.6% healing (i.e. a decrease in wound area) after 1 month. Although this level of healing was significant, it was less than that observed in the ES + heat group (P<0.05). CONCLUSIONS: Local dry heat and ES work well together to heal chronic diabetic foot wounds; however, local heat would appear to be a relevant part of this therapy because ES alone has produced little healing in previous studies. PMID- 20923475 TI - Prehypertension is associated with atherosclerosis in Type 2 diabetes. AB - BACKGROUND: Prehypertension is a risk factor for hypertension, diabetes, and cardiovascular diseases. However, the association between prehypertension and atherosclerosis in Type 2 diabetes mellitus (T2DM) has not been evaluated. In the present study, we investigated the impact of prehypertension on atherosclerosis in T2DM. METHODS: Patients (n=930) with T2DM were recruited for the present study from the outpatient clinic of Shanghai Ruijin Hospital. The intima-media thickness (IMT) of the common carotid artery (CCA) was determined using ultrasound and brachial-ankle pulse wave velocity (baPWV) was determined by volume plethysmography to assess atherosclerosis. RESULTS: Of the 930 patients with T2DM (mean age of 59 years), 167 were categorized as normotensive, 213 were prehypertensive, and 550 were hypertensive. Diabetic subjects with prehypertension had significantly higher CCA-IMT and baPWV than those with normal blood pressure after adjustment for age and gender. Multiple logistic regression analysis revealed that, compared with normotension, prehypertension was a significant independent determinant of atherosclerosis (for maximum IMT >=1.1 mm, odds ratio (OR) 2.10 and 95% confidence interval (CI) 1.28-3.44; for baPWV >=1400 cm/s, OR 3.09 and 95% CI 1.78-5.36). CONCLUSION: Prehypertension is associated with atherosclerosis independent of conventional cardiovascular risk factors in T2DM patients. We speculate that maintenance of systolic blood pressure <120 mmHg and diastolic blood pressure <80 mmHg may reduce the risk of atherosclerosis in T2DM. PMID- 20923476 TI - Good news! PMID- 20923477 TI - Hypertension in patients with diabetes: questions. PMID- 20923478 TI - Response to Bloomgarden et al. Insulin treatment of type 2 diabetes: a clinical perspective. PMID- 20923479 TI - Gut hormones and the brain. AB - The dialogue between gut hormone, bile acids, and the brain plays an important role in energy homeostasis and the onset of Type 2 diabetes mellitus (T2DM). The present review focuses on: (i) bile acid metabolism and the role of bile acids in the regulation of both glucose homeostasis and the control of hypercholesterolemia; (ii) the role of gut hormones in energy homeostasis; and (iii) translation of the pathophysiology of bile acids and gut hormones into clinical practice. Although definitive mechanisms of action of gut hormones and bile acids have not been elucidated completely, these concepts allow us to understand several pharmacological interventions in the treatment of T2DM. Results from further clinical studies with related therapies will help us determine the role of these treatments in the management of energy homeostasis. PMID- 20923480 TI - Effects of testosterone on Type 2 diabetes and components of the metabolic syndrome. AB - Observations from clinical studies suggest that low serum levels of testosterone in men are often associated with obesity, insulin resistance, and metabolic compromise. Indeed, the clinical symptoms of late-onset hypogonadism are markedly similar to those of Type 2 diabetes mellitus (T2DM) and metabolic syndrome, and may share a similar pathophysiology. Observational and experimental data suggest that testosterone treatment improves a number of hallmark features of T2DM and metabolic syndrome, namely insulin resistance, obesity, dyslipidemia, and sexual dysfunction. Consequently, clinical studies have been undertaken to assess the impact of testosterone-replacement therapy in this patient group. The present article reviews the observational clinical data suggesting an association between low serum testosterone and metabolic impairment, the clinical data relating to the effects of testosterone treatment on components of the metabolic syndrome, and the randomized clinical trails that have formally investigated whether testosterone-replacement therapy provides clinical benefit to hypogonadal men with T2DM and/or metabolic syndrome. PMID- 20923481 TI - Short-chain 3-hydroxyacyl-CoA dehydrogenase is a negative regulator of insulin secretion in response to fuel and non-fuel stimuli in INS832/13 beta-cells. AB - BACKGROUND: Hyperinsulinemia associated with non-ketotic hypoglycemia is observed in patients with mutated beta-oxidation enzyme short-chain 3-hydroxyacyl-CoA dehydrogenase (HADHSC). In the present study, we investigated the mechanism underlying HADHSC-mediated regulation of insulin secretion. METHODS: Knockdown of HADHSC expression by RNA interference in INS832/13 beta-cells was achieved using short hairpin RNA and short interference RNA. RESULTS: Knockdown of HADHSC increased both fuel- (glucose or leucine plus glutamine) and non-fuel (high KCl) induced insulin secretion. Enhanced glucose-stimulated insulin secretion (GSIS) induced by HADHSC knockdown was independent of changes in cytosolic Ca(2+) and also occurred in the presence of fatty acids. L-Carnitine, used in the formation of acyl-carnitine compounds, increased GSIS in control cells, but was unable to further increase the augmented GSIS in HADHSC-knockdown cells. The pan transaminase inhibitor amino-oxyacetate reversed HADHSC knockdown-mediated increases in GSIS. Oxidation of [1-(14) C]-palmitate and -octanoate was not reduced in HADHSC-knockdown cells. L-3-Hydroxybutyryl-carnitine (tested using its precursor L-3-hydroxybutyrate) and L-3-hydroxyglutarate, which accumulate in blood and urine, respectively, of HADHSC-deficient patients, did not change insulin secretion. CONCLUSIONS: Insulin secretion promoted by both fuel and non fuel stimuli is negatively regulated by HADHSC. Enhanced secretion after HADHSC knockdown is not due to inhibition of fatty acid oxidation causing an accumulation of long-chain fatty acids or their CoA derivatives. L-3 Hydroxybutyrate and L-3-hydroxyglutarate do not mediate enhanced secretion caused by reduced HADHSC activity. Transamination reaction(s) and the formation of short chain acylcarnitines and CoAs may be implicated in the mechanism whereby HADHSC deficiency results in enhanced insulin secretion and hyperinsulinemia. PMID- 20923482 TI - Results and analysis of the 2008-2009 Insulin Injection Technique Questionnaire survey. AB - BACKGROUND: The efficacy of injection therapy in diabetes depends on correct injection technique and, to provide patients with guidance in this area, we must understand how they currently inject. METHODS: From September 2008 to June 2009, 4352 insulin-injecting Type 1 and Type 2 diabetic patients from 171 centers in 16 countries were surveyed regarding their injection practices. RESULTS: Overall, 3.6% of patients use the 12.7-mm needle, 1.8% use the 12-mm needle, 1.6% use the 10-mm needle, 48.6% use the 8-mm needle, 15.8% use the 6-mm needle, and 21.6% use the 5-mm needle; 7% of patients do not know what length of needle they use. Twenty-one percent of patients admitted injecting into the same site for an entire day, or even a few days, a practice associated with lipohypertrophy. Approximately 50% of patients have or have had symptoms suggestive of lipohypertrophy. Abdominal lipohypertrophy seems to be more frequent in those using the two smaller injection size areas, and less frequent in those using larger areas. Nearly 3% of patients reported always injecting into lipohypertrophic lesions and 26% inject into them sometimes. Of the 65% of patients using cloudy insulins (e.g. NPH), 35% do not remix it before use. CONCLUSIONS: It is clear from the latest survey that we have improved in certain areas, but that, in others, we have either not moved at all or our efforts have not yielded the results we expected. The results of the present survey are available online on a country-by-country and question-by-question basis at http://www.titan-workshop.org. PMID- 20923483 TI - Prevalence and correlates of metabolic syndrome based on a harmonious definition among adults in the US. AB - BACKGROUND: Recently, a Joint Scientific Statement bridged differences between previous definitions of metabolic syndrome. Our objective was to estimate the prevalence of metabolic syndrome in a representative sample of US adults and to examine its correlates. METHODS: We analyzed data for up to 3461 participants aged >= 20 years of the 2003-2006 National Health and Nutrition Examination Survey. RESULTS: Using waist circumference thresholds of >= 102 cm for men and >= 88 cm for women, the age-adjusted prevalence of metabolic syndrome was 34.3% among all adults, 36.1% among men, and 32.4% among women. Using racial- or ethnic specific International Diabetes Federation criteria for waist circumference, the age-adjusted prevalence of metabolic syndrome was 38.5% for all participants, 41.9% for men, and 35.0% for women. Prevalence increased with age, peaking among those aged 60-69 years. Prevalence was lower among African American men than White or Mexican American men, and lower among White women than among African American or Mexican American women. In a multivariate regression model, significant independent associations were noted for age (positive), gender (men higher than women), race or ethnicity (African Americans and participants of another race lower than Whites), educational status (inverse), hypercholesterolemia (positive), concentrations of C-reactive protein (positive), leisure time physical activity (inverse), microalbuminuria (positive), and hyperinsulinemia (positive). Additional adjustment for body mass index weakened many of the associations, with educational status and microalbuminuria no longer significant contributors to the model. CONCLUSION: Metabolic syndrome continues to be highly prevalent among adults in the US. PMID- 20923484 TI - Many patients with Type 1 diabetes estimate their prandial insulin need inappropriately. AB - BACKGROUND: Many factors contribute to the need for prandial insulin in Type 1 diabetes. However, patients' success in achieving normal postprandial glucose concentration is understudied. The aim of the present study was to determine how often patients with Type 1 diabetes achieve normal postprandial glucose concentrations and to evaluate factors associated with postprandial hypo- and hyperglycemia. METHODS: Data on food intake, physical activity, insulin administration, and blood glucose concentration were collected using a self administered questionnaire from 331 patients with Type 1 diabetes (43% men; mean age 49 +/- 12 years; mean diabetes duration 32 +/- 13 years). Of these, 179 provided data on blood glucose concentrations measured 110-150 min postprandially. One such meal per patient was randomized for analyses. RESULTS: Hypoglycemia (< 4.0 mmol/L), normoglycemia (4.0-7.9 mmol/L), and hyperglycemia (>= 8.0 mmol/L) were observed after 23%, 36%, and 41% of meals, respectively. The three postprandial glycemia groups did not differ with respect to the meal composition or the timing of the postprandial blood glucose measurement. In women, postprandial hyperglycemia was associated with shorter diabetes duration and higher preprandial blood glucose concentration, whereas postprandial hypoglycemia was associated with higher physical activity. No single factor explained the postprandial glycemic state in men. CONCLUSIONS: A total of 64% of patients estimated their prandial insulin need inappropriately, suggesting that estimation of the optimal prandial insulin dose is not easy, even after a long duration of diabetes. PMID- 20923485 TI - Benefits of self-monitoring blood glucose in the management of new-onset Type 2 diabetes mellitus: the St Carlos Study, a prospective randomized clinic-based interventional study with parallel groups. AB - BACKGROUND: Intensive treatment of patients with Type 2 diabetes mellitus (T2DM) from the moment of diagnosis facilitates beta-cell recovery. Self-monitoring of blood glucose (SMBG)-based educational and pharmacological intervention may be better than conventional HbA1c algorithms in the treatment of newly diagnosed T2DM. METHODS: Newly diagnosed T2DM patients were randomized to either an SMBG based intervention or an HbA1c-based control group (n = 99 and 62, respectively) and were followed for 1 year. RESULTS: Higher rates of diabetes regression (HbA1c < 6% on metformin alone) and remission (HbA1c between 6.0% and 6.4%) were achieved in the intervention compared with the control group (39% vs 5% (P < 0.001) and 37% vs 30% (P < 0.01), respectively). Furthermore, significantly greater reductions in median HbA1c (6.6% to 6.1%; P < 0.05) and body mass index (29.6-27.9 kg/m(2) ; P < 0.001) were seen in the intervention over the 1 year of therapy. The percentage of patients achieving a lifestyle score >12 was significantly greater in the SMBG compared with the control group (38.4% vs 9.7% respectively; P < 0.001). An inverse correlation was observed between SMBG and HbA1c levels (P < 0.04). CONCLUSIONS: The results indicate that SMBG-based structured educational and pharmacological programs empower patients to achieve nutritional and physical activity goals, and encourage physicians and patients to use SMBG to optimize therapy. We believe that the concept of intensive treatment of T2DM patients should be modified; instead of referring to the type of treatment (insulin use), the term should reflect the intensity with which we work to reach glucose objectives. PMID- 20923486 TI - Pioglitazone and the risk of cardiovascular events in patients with Type 2 diabetes receiving concomitant treatment with nitrates, renin-angiotensin system blockers, or insulin: results from the PROactive study (PROactive 20). AB - BACKGROUND: Patients with Type 2 diabetes mellitus (T2DM) are often treated with multiple glucose-lowering and cardiovascular agents. The concomitant use of nitrates, renin-angiotensin system (RAS) blockers, or insulin has been linked to a potential increase in myocardial ischemic risk with rosiglitazone. The PROactive database provides an opportunity to investigate the effects of these medications on the potential macrovascular benefits reported with pioglitazone. METHODS: The PROactive study was a randomized double-blind prospective trial that evaluated mortality and cardiovascular morbidity in 5238 patients with T2DM and macrovascular disease. Patients received pioglitazone or placebo in addition to their baseline glucose-lowering and cardiovascular medications. The effect of pioglitazone on composite endpoints was evaluated, including all-cause death, myocardial infarction (MI), and stroke, as well as safety events of edema and serious heart failure, in subgroups using nitrates, RAS blockers, or insulin at baseline. RESULTS: The risk of all-cause death, MI, and stroke for pioglitazone versus placebo was similar regardless of the baseline use of nitrates, RAS blockers, or insulin, with hazard ratios ranging from 0.81 to 0.87. Similar results were obtained for the other composite endpoints analyzed. There were no significant interactions between baseline medication subgroups and treatment. The increased risk of edema and serious heart failure was consistent across the baseline medication subgroups. CONCLUSIONS: This post hoc analysis did not reveal an increased risk of macrovascular events with pioglitazone in patients receiving nitrates, RAS blockers, or insulin. Rather, all patients realized the same trend towards benefit with pioglitazone, and adverse events of edema and heart failure were predictable. PMID- 20923487 TI - Insulin treatment of Type 2 diabetes: a clinical perspective. PMID- 20923488 TI - Distinctions between islet neogenesis and beta-cell replication: implications for reversal of Type 1 and 2 diabetes. AB - The terms "islet" and "beta-cell" are often used interchangeably, yet islets are highly complex multicellular organelles that contain the insulin-producing beta cells and four other cells types, all of which play a role in maintaining glucose homeostasis within a very narrow range. Although the formation of new islets in adults is rare, occurring primarily in response to pancreatic injury and major stress to the pancreas, beta-cell replication from existing cells occurs throughout adulthood. An understanding of the regulatory factors controlling pancreatic development has more clearly defined the differences between new islet formation from progenitor cells located throughout the adult pancreas and beta cell replication occurring within existing islets. The present review sets forth to more clearly distinguish the differences between the postnatal pathways of islet neogenesis and beta-cell replication with a discussion of the potential implications for reversal of Type 1 and 2 diabetic patients using islet neogenesis agents that are now in development. For Type 1 diabetic patients, an immune tolerance agent in conjunction with an islet neogenesis agent may allow achievement of adequate islet mass, perhaps with subsequent potential to withdraw medications. For Type 2 diabetic patients, lifestyle changes and/or medications may sustain the production of new islets and limit the accelerated beta-cell apoptosis characteristic of the condition. PMID- 20923489 TI - Epidemiology of Type 2 diabetes mellitus in Aleppo, Syria. AB - BACKGROUND: Type 2 diabetes mellitus (T2DM) is considerable public health problem, but data on the prevalence and correlates of T2DM in Syria are scarce. The aim of the present study was to establish reliable estimates of the prevalence of T2DM in Syria. METHODS: A cross-sectional, population-based survey was conducted in Aleppo, Syria (population 2.5 million), in 2006. The study was conducted on a random sample of 1168 subjects >=25 years of age (47.7% men; mean age 44.7 +/- 12.7 years). Information regarding a personal history of diabetes and other risk factors was collected, followed by measurement of weight, height, and the waist:hip ratio (WHR). Of the 1168 participants, 806 provided fasting blood samples that were analyzed for fasting plasma glucose (FPG) and HbA1c. RESULTS: The prevalence of T2DM based on FPG >=126 mg/dL and HbA1c >=6.5% was 15.6% (11.2% self-reported; 5.0% diagnosed) and 14.8%, respectively. The prevalence of impaired fasting glucose (FPG >=110 and <126 mg/dL) was 8.6%. There was a significant positive association between T2DM and age, WHR, a family history of T2DM, and body mass index (BMI) and an inverse association between T2DM and physical activity (P < 0.01 for all). Multivariate analysis showed that age, BMI, WHR, and a family history of T2DM were the most important factors associated with T2DM. Only 16.7% of treated cases of T2DM were under control (i.e. HbA1c <7%). CONCLUSIONS: Based on the results obtained in our sample, T2DM is widespread in Syria. Many of those with T2DM are unaware of their disease and most have unsatisfactory control of their disease. PMID- 20923490 TI - Does A1c consistently reflect mean plasma glucose? AB - BACKGROUND: A1c, a surrogate measure of glycemic control, is known to have a strong linear correlation with mean plasma glucose (MPG) when analyzed in populations of patients. However, clinically significant intersubject variability in this relationship exists, which suggests that A1c measurements may not reflect actual glycemic control in some patients. In the present study we explored the extent to which A1c accurately represents glycemic control, as measured by MPG, for individual patients. METHODS: Data were pooled from randomized clinical trials in which A1c and self-monitored plasma glucose (SMPG) profiles were collected by patients with Type 2 diabetes treated with insulin analog regimens. MPG levels were calculated from SMPG profiles. Distributions of MPG were analyzed for patients within similar ranges of A1c (<6.5%, 6.5%-<7.5%, 7.5%-<8.5%, 8.5% <9.5%, and >=9.5%) and distributions of A1c were analyzed in patients within similar ranges of MPG (<6.1, 6.1-<7.8, 7.8-<9.4, 9.4-<11.1, and >=11.1 mmol/L). RESULTS: Substantial proportions of patients had clinically significant differences between A1c and MPG. For example, among 260 patients with A1c between 6.5% and 7.5%, 10% had MPG levels <6.4 mmol/L, whereas 10% had MPG >9.5 mmol/L. Among the 224 patients with MPG levels >=6.1 mmol/L and <7.8 mmol/L, 10% had A1c <6% and 10% had A1c >8.1%. CONCLUSIONS: In the absence of SMPG, A1c may inadequately represent glycemic control for many diabetic patients. PMID- 20923491 TI - Antidiabetic activity of the mangrove species Ceriops decandra in alloxan-induced diabetic rats. AB - BACKGROUND: Diabetes is a series of disorders characterized by increased fasting and postprandial glucose concentration and insulin deficiency and/or decreased insulin action. Although there are a number of commercially available drugs for the treatment of diabetes, their long-term use may cause unwanted side effects. Consequently, many studies are underway to find natural remedies that can effectively reduce the intensity of diabetes. The aim of the present study was to evaluate the antidiabetic activity of the mangrove species Ceriops decandra. METHODS: The effects of daily oral administration of an ethanolic extract from the leaves of C. decandra (30, 60, 120 mg/kg) for 30 days on blood glucose, hemoglobin (Hb), HbA1c, liver glycogen and some carbohydrate metabolic enzymes were evaluated in normal and alloxan-induced diabetic rats. The effects of these extracts were compared with the effect of 30-days treatment with 0.1 mg/kg, p.o., glibenclamide, a commercially available drug commonly used in the treatment of diabetes. RESULTS: Oral administration of 120 mg/kg extract modulated all the parameters evaluated to levels seen in control rats. The effects of 120 mg/kg extract were comparable to those of glibenclamide. CONCLUSION: The extract of the mangrove plant C. decandra exhibited promising antidiabetic activity and could be considered for further evaluation in clinical studies and drug development. PMID- 20923492 TI - Assessment of self-reported self-esteem in healthy and diabetic children and adolescents in Greece. AB - BACKGROUND: The aim of the present study was to evaluate any possible negative effect of diabetes on the self-esteem of children and adolescents with diabetes. METHODS: Self-esteem was evaluated using the Culture-Free Self-Esteem Inventory (CFSEI-2) in 144 patients with Type 1 diabetes mellitus (T1DM; 7-18 years of age) treated in a diabetes center and compared against that of 136 healthy children and adolescents. RESULTS: Self-esteem was correlated with age (P = 0.017), but not with diabetes (P = 0.886). The median CFSEI-2 score for both healthy and diabetic children was 22. There was no significant correlation between self esteem and sex, body mass index (BMI), physical exercise, HbA1c or parental educational level. According to Spearman's rank correlation coefficient (r(s)), there was a significant association between age and self-esteem (r(s) = -0.15). Conversely, although BMI (r(s) = -0.09) and treatment duration (r(s) = -0.107) had a slight negative effect on self-esteem and the duration of physical exercise (r(s) = 0.11) and parental education (r(s) = 0.07) seemed to have a positive effect, the associations did not reach statistical significance. CONCLUSIONS: Self-esteem in diabetic children is mainly affected by their age, level of physical activity and level of family support. These findings emphasize the need to discriminate between glycemic control and diabetic adjustment. PMID- 20923493 TI - Lifestyle factors and mortality among adults with diabetes: findings from the European Prospective Investigation into Cancer and Nutrition-Potsdam study*. AB - BACKGROUND: Healthy lifestyle behaviors are among the cornerstones of diabetes self-management, but the extent to which healthy lifestyle factors could potentially prevent premature mortality among people with diabetes remains unknown. The aim of the present study was to estimate the reduction in mortality that could be achieved if people with diabetes did not smoke, had a body mass index <30 kg/m(2) , performed physical activity for >=3.5 h/week, reported better dietary habits, and consumed alcohol moderately. METHODS: A prospective cohort study of 1263 German men and women with diabetes aged 35-65 years who were followed for an average of 7.8 years was used and multivariate Cox regression models for all-cause and cause-specific mortality were calculated. RESULTS: Approximately 7% of study participants had no favorable factors, 24% had one, 35% had two, and 34% had three or more. Compared with participants who had no favorable factors, the reduction in risk was 34% [95% confidence interval (CI) 19%, 63%] for those with one favorable factor, 49% (95% CI 9%, 71%) for those with two, and 63% (95% CI 31%, 80%) for those with three or more. Furthermore, a competing risk analysis did not show any difference in the inverse associations with mortality due to cardiovascular disease, cancer, or other causes. CONCLUSIONS: Favorable lifestyle factors can potentially achieve substantial reductions in premature mortality among people with diabetes. Our results emphasize the importance of helping people with diabetes optimize their lifestyle behaviors. PMID- 20923495 TI - Asymmetric diabetic retinopathy. PMID- 20923494 TI - Measurement of HbA1c from stored whole blood samples in the Atherosclerosis Risk in Communities study. AB - BACKGROUND: The aims of the present study were to demonstrate the reliability of HbA1c measurements during two time periods and to compare these measurements with HbA1c distribution in the general US population. METHODS: HbA1c was measured in 14,069 whole blood samples in the Atherosclerosis Risk in Communities (ARIC) study using different HPLC instruments across two time periods, namely 2003-2004 and 2007-2008. At the time of measurement, samples had been in storage at -70 degrees C for up to 18 years. To assess differences in values, HbA1c measurements were repeated in 383 samples at both periods. Indirect comparisons were made by comparing our measurements against those from a nationally representative study. RESULTS: The coefficients of variation for quality control samples were 1.8% (n = 89) in 2003-2004 and 1.4% (n = 259) in 2007-2008. The correlation between measurements at the two time points was high (r = 0.99), but with a slight bias: 0.29% points higher in 2007-2008 vs 2003-2004 (n = 383; P < 0.0001). The comparison yielded the following Deming regression equation: y((2007-2008)) = 0.073 + 1.034x((2003-2004)) . After alignment using this equation, the distribution of HbA1c in the ARIC study was similar to that in the national study using fresh samples. CONCLUSIONS: Measurements of HbA1c from samples stored for up to 18 years are highly reliable when using state-of-the-art HPLC instruments, but with some bias introduced over time. The HbA1c data now available in the ARIC study should be invaluable for investigations into the clinical utility of HbA1c as a diagnostic test for diabetes. PMID- 20923496 TI - Effect of diabetes on enzymes involved in rat hepatic corticosterone production. AB - BACKGROUND: Numerous studies have explored the etiologic or permissive role of 11beta-hydroxysteroid dehydrogenase (11beta-HSD1) in obesity and Type 2 diabetes, biochemical conditions often with concurrent hyperinsulinism. In contrast, there are limited data on the effect of insulin deficiency (i.e. Type 1 diabetes) on 11beta-HSD1 or endoplasmic reticulum enzymes that generate the reduced pyridine cofactor NADPH. Thus, the aim of the present study was to examine the effect of insulin-deficient, streptozotozin diabetes on key microsomal enzymes involved in rat hepatic corticosterone production. METHODS: After rats had been rendered diabetic with streptozotocin and some had been treated with insulin (2-6 units, s.c., long-acting insulin once daily) for 7 days, hepatic microsomes were isolated. Serum corticosterone and fructosamine were obtained premortem. Intact microsomes were incubated in vitro and 11beta-HSD1, hexose-6-phosphate dehydrogenase (H6PDH), and isocitrate dehydrogenase (IDH) measured. RESULTS: Although diabetes markedly altered body weight gain and serum protein glycosylation (assessed by fructosamine), there was no significant change in hepatic 11beta-HSD1 reductase activity, with or without insulin treatment. However, serum corticosterone levels were significantly correlated with 11beta HSD1 reductase activity when all groups were analyzed together (P < 0.05). Untreated diabetes modified (P < 0.01) two hepatic microsomal NADPH-generating enzymes, namely H6PDH and IDH, resulting in a 37% decrease and 14% increase in enzyme levels, respectively. CONCLUSIONS: Consistent with most in vivo studies, chronic insulin deficiency with attendant hyperglycemia does not significantly modify hepatic 11beta-HSD1 reductase activity, but does alter the activity of two microsomal enzymes coupled with pyridine cofactors. PMID- 20923497 TI - Macrophage migration inhibitory factor deficiency augments cardiac dysfunction in Type 1 diabetic murine cardiomyocytes. AB - BACKGROUND: It has become evident that macrophage migration inhibitory factor (MIF) is associated with the development of Type 1 diabetes mellitus. The aim of the present study was to determine whether MIF plays a role in cardiac contractile dysfunction in T1DM mice. METHODS: Mechanical and intracellular Ca(2+) properties were measured in cardiomyocytes isolated from wild-type (WT) and MIF-knockout (MIF-KO) mice administrated or not streptozotocin (200 mg/kg, i.p.). Relative stress signaling was evaluated using western blot analysis. RESULTS: Peak shortening (PS) and maximal velocity of shortening/relengthening (+/-dL/dt) were reduced and the duration of relengthening (TR90) was prolonged in both WT and MIF-KO cardiomyocytes treated with STZ (P < 0.01 vs control), which may be associated with reduced intracellular Ca(2+) decay in both groups. However, STZ-treated WT cardiomyocytes demonstrated significantly better contractile function and intracellular Ca(2+) properties compared with STZ treated MIF-KO cardiomyocytes (all P < 0.05). Interestingly, the physiological data clearly showed that blood glucose levels were significantly higher in STZ treated MIF-KO mice than STZ-treated WT mice (P < 0.01). Moreover, phosphorylation of AMP-activated protein kinase (AMPK) and its direct downstream target acetyl-CoA carboxylase (ACC) was markedly lower in hearts from STZ-treated MIF-KO mice than STZ-treated WT mice (P < 0.05). There were no significant differences between untreated WT and MIF-KO control groups. CONCLUSIONS: There is a beneficial action of MIF in the management of cardiac dysfunction in T1DM. The cardioprotective effect of MIF may be associated with AMPK signaling. PMID- 20923498 TI - Evaluation of the weight-increasing effects of biphasic analog and regular NPH insulin mixtures in patients with Type 2 diabetes mellitus. AB - BACKGROUND: Weight gain is a significant problem in diabetic patients in terms of worsening glycemic control, increasing diabetic and cardiovascular morbidity and mortality, and contributing to social and psychological problems. In the present study, we evaluated the effects of a biphasic analog and regular NPH insulin mixtures on weight gain in patients with Type 2 diabetes mellitus (T2DM) over 1 year. METHODS: Group I consisted of 71 patients (29 men and 42 women) being treated with analog mixtures (insulin lispro 75/25 mix and biphasic insulin aspart 70/30 mix) twice daily; Group II consisted of 69 patients (23 men and 46 women) being treated with a regular insulin mixture (70/30) twice daily. Starting weight, body mass index, HbA1c, and hypoglycemic episodes were evaluated after 6 and 12 months. RESULTS: Weight gain in Group I at 6 and 12 months was 1.41 +/- 2.70 and 2.08 +/- 3.74 kg, respectively. In Group II, weight gain at 6 and 12 months was 1.5 +/- 3.0 and 2.29 +/- 3.85 kg, respectively. Intragroup comparisons indicated that, for both groups, weight gain at 6 and 12 months differed significantly from the starting weight. However, no significant differences in weight gain were found between the two groups (P > 0.05). CONCLUSIONS: The weight increasing effects of an analog mixture of insulin and the NPH regular mixture of insulin appear to be similar. This should be taken into account when determining the type of insulin to use in treating T2DM patients. PMID- 20923499 TI - Transforming growth factor-beta regulation of proteoglycan synthesis in vascular smooth muscle: contribution to lipid binding and accelerated atherosclerosis in diabetes. AB - Atherosclerosis is accelerated in the setting of diabetes, but the factors driving this phenomenon remain elusive. Hyperglycemia leads to elevated levels of transforming growth factor (TGF)-beta and TGF-beta has been implicated as a factor in atherosclerosis. Given the established association between hyperglycemia and elevated TGF-beta, it is plausible that elevated TGF-beta levels in diabetes play a pathogenic role in the development of accelerated atherosclerosis. TGF-beta is a potent regulator of extracellular matrix synthesis, including many actions on proteoglycan synthesis that lead to increased binding to low-density lipoprotein and therefore potentially increased lipid retention in the vessel wall and accelerated atherosclerosis. TGF-beta signals through the canonical TGF-beta receptor I-mediated phosphorylation of Smad transcription factors and TGF-beta signaling is also known to involve, positively and negatively, interactions with the mitogen-activated protein kinase pathways. The focus of the present review is on the effects of TGF-beta on proteoglycan synthesis in vascular smooth muscle and particularly the signaling pathways through which TGF-beta exerts its effects, because those pathways may be therapeutic targets for the prevention of pathological modifications in the proteoglycan component of the vessel wall in the vascular diseases of diabetes. PMID- 20923500 TI - Targeting metabolic syndrome: candidate natural agents. AB - Following on from impressive economic development and urbanization, China is currently experiencing a high prevalence of metabolic syndrome. Patients with metabolic syndrome suffer from the "The Deadly Quartet" of hyperglycemia, hypertriglyceridemia, hypertension, and central (or upper body) obesity. Current treatment strategies directed towards metabolic syndrome tend to be limited to just one of these four conditions, so developing novel drugs to target multiple metabolic abnormalities could be preferable to current approaches. New insights suggest benefits of natural agents as treatments for metabolic syndrome. Herein, we review the evidence for using nine such agents developed on the basis of traditional medicine or herbal preparations. PMID- 20923501 TI - Effects of Nigella sativa and thymoquinone on biochemical and subcellular changes in pancreatic beta-cells of streptozotocin-induced diabetic rats. AB - BACKGROUND: The present study investigated the effects of Nigella sativa aqueous extract and oil, as well as thymoquinone, on serum insulin and glucose concentrations in streptozotocin (STZ) diabetic rats. METHODS: Rats were divided into five experimental groups (control, untreated STZ-diabetic, and aqueous extract-, oil-, or thymoquinone-treated diabetic rats). Treated rats received 2 mL/kg, i.p., 5%N. sativa extract, 0.2 mL/kg, i.p., N. sativa oil, or 3 mg/mL, i.p., thymoquinone 6 days/week for 30 days. Serum insulin and glucose concentrations, superoxide dismutase (SOD) levels, and pancreatic tissue malondialdehyde (MDA) were determined. Electron microscopy was used to identify any subcellular changes. RESULTS: Diabetes increased tissue MDA and serum glucose levels and decreased insulin and SOD levels. Treatment of rats with N. sativa extract and oil, as well as thymoquinone, significantly decreased the diabetes induced increases in tissue MDA and serum glucose and significantly increased serum insulin and tissue SOD. Ultrastructurally, thymoquinone ameliorated most of the toxic effects of STZ, including segregated nucleoli, heterochromatin aggregates (indicating DNA damage), and mitochondrial vacuolization and fragmentation. The aqueous extract of N. sativa also reversed these effects of STZ, but to a lesser extent. The N. sativa oil restored normal insulin levels, but failed to decrease serum glucose concentrations to normal. CONCLUSIONS: The biochemical and ultrastructural findings suggest that N. sativa extract and thymoquinone have therapeutic and protect against STZ-diabetes by decreasing oxidative stress, thus preserving pancreatic beta-cell integrity. The hypoglycemic effect observed could be due to amelioration of beta-cell ultrastructure, thus leading to increased insulin levels. Consequently, N. sativa and thymoquinone may prove clinically useful in the treatment of diabetics and in the protection of beta-cells against oxidative stress. PMID- 20923502 TI - Novel biphenyl compound, VMNS2e, ameliorates streptozotocin-induced diabetic nephropathy in rats. AB - AIM: To study the effect of a new biphenyl synthetic compound showing interactions with the active site of protein tyrosine phosphatase 1B by docking and molecular dynamics, VMNS2e in streptozotocin-induced diabetic nephropathy in rats with various renal function parameters and renal ultrastructure. METHODS: Streptozotocin (55 mg/kg)-induced diabetic rats were orally treated once daily with VMNS2e (30, 60, and 120 mg/kg) for 8 weeks. The body weight and blood glucose levels of the rats were recorded during the study period. After 8 weeks of treatment creatinine clearance, urinary protein, blood urea nitrogen, urinary albumin excretion rate, and insulin levels were measured. An ultrastructure study of the kidney tissue was performed and the glomerular basement membrane thickness was measured. RESULTS: Eight weeks of VMNS2e treatment significantly reduced the fasting blood glucose level, attenuated elevating blood urea nitrogen levels, and reduced glomerular basement membrane thickness. CONCLUSION: It is concluded that VMNS2e treatment at 30 and 60 mg/kg, when given for 8 weeks, partly ameliorated early diabetic nephropathy in diabetic rats. PMID- 20923503 TI - Periodontitis and risk of diabetes mellitus. AB - Diabetes mellitus (DM) is a complex disease with varying degrees of systemic and oral complications. The periodontium is also a target for diabetic damage. Diabetes is a pandemic in both developed and developing countries. In recent years, a link between periodontitis and diabetes mellitus has been postulated. The oral cavity serves as a continuous source of infectious agents that could further worsen the diabetic status of the patient and serve as an important risk factor deterioration of diabetes mellitus. The present review highlights the relationship between diabetes mellitus and periodontitis. The potential mechanisms involved in the deterioration of diabetic status and periodontal disease are also discussed. PMID- 20923504 TI - Diabetes News. PMID- 20923505 TI - The Avandia debate: an unhappy conclusion. PMID- 20923506 TI - Knowing is not enough! PMID- 20923507 TI - Cognitive leisure activities and their role in preventing dementia: a systematic review. AB - BACKGROUND: Dementia inflicts a tremendous burden on the healthcare system. Identifying protective factors or effective prevention strategies may lead to considerable benefits. One possible strategy mentioned in the literature relates to participation in cognitive leisure activities. AIM: To determine the effectiveness of cognitive leisure activities in preventing Alzheimer's and other dementias among older adults. INCLUSION CRITERIA: Types of participants. Adults aged at least 60 years of age with or without a clinical diagnosis of dementia that resided in the community or care setting. Types of interventions. Cognitive leisure activities, defined as activities that required a mental response from the individual taking part in the activity (e.g. reading). Types of outcomes. The presence or absence of dementia was the outcome of interest. Types of studies. Any randomised controlled trials, other experimental studies, as well as cohort, case-control and cross-sectional studies were considered for inclusion. Search strategy. A search for published and unpublished studies in the English language was undertaken with no publication date restriction. METHODOLOGICAL QUALITY: Each study was appraised independently by two reviewers using the standard Joanna Briggs Institute instruments. DATA COLLECTION AND ANALYSIS: Information was extracted from studies meeting quality criteria using the standard Joanna Briggs Institute tools. Because of the heterogeneity of populations and interventions, meta-analyses were not possible and results are presented in narrative form. RESULTS: There were no randomised controlled trials located that met inclusion criteria. Thirteen observational studies were included in the review; the majority were cohort design. Because of the heterogeneity of interventions, the study design, the way in which they were grouped and the different stages of life they were measured at, statistical pooling was not appropriate. Studies were grouped by stage of adult life participation when interventions were undertaken, that is, early adulthood, middle adulthood and late life. Five out of six studies showed a positive association between participating in activities and a reduced risk of developing Alzheimer's disease and other dementias when interventions were undertaken in middle adulthood and six out of seven studies produced a positive association for late life participation. Results indicated that some activities might be more beneficial than others; however, results should be interpreted with caution because of the subjective nature of activity inclusion. CONCLUSION: * Actively participating in cognitive leisure activities during mid- or late life may be beneficial in preventing the risk of Alzheimer's disease and other dementias in the elderly; however, the evidence is currently not strong enough to infer a direct causal relationship. * Participating in selected cognitive leisure activities may be more favourable than others but currently there is no strong evidence to recommend one over the other. PMID- 20923508 TI - Ethical conduct of research in developing countries. PMID- 20923509 TI - Recent evidence on the development and maintenance of constructive staff-family relationships in the care of older people--a report on a systematic review update. AB - AIM: This paper is an update to a systematic review that presents the best available evidence on the factors that are most effective in promoting constructive staff-family relationships in the care of older people in the institutional healthcare setting. METHODS: Systematic review. RESULTS: The updated review supports findings from the earlier review. Additional evidence points to the importance of monitoring care, family involvement in decision making, staff upholding the uniqueness of the older person, trust, the involvement of the multidisciplinary care team and family dynamics as factors underpinning effective staff-family relationships. CONCLUSION: A number of factors critical to the development and maintenance of positive staff-family relationships in the institutional setting have been identified. The delivery of quality care is predicated on staff having an understanding of these factors. PMID- 20923510 TI - Review of studies and guidelines on fasting and procedural sedation at the emergency department. AB - AIM: Procedural sedation and analgesia allows urgent procedures to be performed safely by preserving patients' airway reflexes. Fasting, which is required before deeper levels of sedation, and where the airway reflexes are not preserved, is difficult to impose in emergencies. This paper aims to synthesise evidence on the need for pre-procedure fasting to minimise aspiration among adults undergoing procedural sedation and analgesia for emergency procedures. METHODS: Overviews, guidelines with graded recommendations and primary studies on aspiration and pre procedure fasting in procedural sedation and analgesia were retrieved from Medline, Cochrane, and Center for Reviews and Dissemination Databases. Terms searched were procedural sedation, fasting, emergency and sedation. RESULTS: One primary study and one guideline were included. The American College of Emergency Physicians Clinical Policies Subcommittee on Procedural Sedation and Analgesia issued a recommendation based on 'preliminary, inconclusive or conflicting evidence, or on panel consensus'. The recommendation states: 'recent food intake is not a contraindication for administering procedural sedation and analgesia...'. The primary study conducted by Bell in an emergency department in Australia compared patients who last ate or drank more than 6 and 2 h from induction, respectively, with those who last ate or drank within 6 and 2 h. There were no cases of aspiration in both groups. Out of 118 patients who fasted, 1 (0.8%) vomited, as did one of 282 patients (0.4%) who did not fast. CONCLUSIONS: Aspiration risk is expected to be lower in procedural sedation and analgesia than in general anaesthesia. Current guidelines rely on expert consensus due to the lack of primary studies. Contextualisation of existing guidelines are quick and efficient strategies for developing locally relevant tools. PMID- 20923511 TI - Systematic review of practice guideline dissemination and implementation strategies for healthcare teams and team-based practice. AB - AIM: To synthesis the literature relevant to guideline dissemination and implementation strategies for healthcare teams and team-based practice. METHODS: Systematic approach utilising Joanna Briggs Institute methods. Two reviewers screened all articles and where there was disagreement, a third reviewer determined inclusion. RESULTS: Initial search revealed 12,083 of which 88 met the inclusion criteria. Ten dissemination and implementation strategies identified with distribution of educational materials the most common. Studies were assessed for patient or practitioner outcomes and changes in practice, knowledge and economic outcomes. A descriptive analysis revealed multiple approaches using teams of healthcare providers were reported to have statistically significant results in knowledge, practice and/or outcomes for 72.7% of the studies. CONCLUSION: Team-based care using practice guidelines locally adapted can affect positively patient and provider outcomes. PMID- 20923512 TI - General pain assessment among patients with cancer in an acute care setting: a best practice implementation project. AB - AIMS: This project sought to determine improve local practice in managing patients with cancer. It involved by: educating Registered Nurses on the importance of pain assessment, and ensuring this practice is done according to the current best available evidence and monitoring compliance with the audit criteria. METHODS: This project utilised a pre- and post-implementation audit strategy using the Joanna Briggs Institute Practical Application of Clinical Evidence System and Getting Research Into Practice programs. It was implemented in three phases over a 6-month period, from September 2009 to February 2010. The audits utilised three out of 10 criteria recommended by The National Health Service Quality Improvement Scotland. The audits took place in a 24-bed oncology ward in a large acute care setting in Singapore involving a sample size of 24 patients and Registered Nurses. It involved going through the clinical charts and medical records of the cases, and educating Registered Nurses on pain assessment for patients with cancer. RESULTS: The post-implementation audit findings indicated a modest to significant improvement in all the three criteria: first, an improvement of 33% through using a pain assessment tool to assess pain in patients with cancer; second, a 75% increase in the number of Registered Nurses who received education on pain assessment; and third, a 46% increase in accuracy in the assessment and documentation of pain. CONCLUSION: The project had shown that pre- and post-implementation audits represent a useful method for translating evidence into practice. The conduct of this project showed that achieving change in clinical practice was challenging. It also showed that positive audit results were achieved through the enthusiasm, commitment and dedication of every member of the project team, the use of champions who were involved in direct patient care and performance feedback. PMID- 20923513 TI - The Journal of Diabetes. PMID- 20923515 TI - Review of hemoglobin A(1c) in the management of diabetes. AB - Hemoglobin HbA(1c) (A(1c)) has been used clinically since the 1980s as a test of glycemic control in individuals with diabetes. The Diabetes Control and Complications Trial (DCCT) demonstrated that tight glycemic control, quantified by lower blood glucose and A(1c) levels, reduced the risk of the development of complications from diabetes. Subsequently, standardization of A(1c) measurement was introduced in different countries to ensure accuracy in A(1c) results. Recently, the International Federation of Clinical Chemists (IFCC) introduced a more precise measurement of A(1c) , which has gained international acceptance. However, if the IFCC A(1c) result is expressed as a percentage, it is lower than the current DCCT-aligned A(1c) result, which may lead to confusion and deterioration in diabetic control. Alternative methods of reporting have been proposed, including A(1c) -derived average glucose (ADAG), which derives an average glucose from the A(1c) result. Herein, we review A(1c) , the components involved in A(1c) formation, and the interindividual and assay variations that can lead to differences in A(1c) results, despite comparable glycemic control. We discuss the proposed introduction of ADAG as a surrogate for A(1c) reporting, review imprecisions that may result, and suggest alternative clinical approaches. PMID- 20923516 TI - Current scenario of diabetes in India. AB - India, a country experiencing rapid socioeconomic progress and urbanization, carries a considerable share of the global diabetes burden. Studies in different parts of India have demonstrated an escalating prevalence of diabetes not only in urban populations, but also in rural populations as a result of the urbanization of lifestyle parameters. The prevalence of prediabetes is also high. Recent studies have shown a rapid conversion of impaired glucose tolerance to diabetes in the southern states of India, where the prevalence of diabetes among adults has reached approximately 20% in urban populations and approximately 10% in rural populations. Because of the considerable disparity in the availability and affordability of diabetes care, as well as low awareness of the disease, the glycemic outcome in treated patients is far from ideal. Lower age at onset and a lack of good glycemic control are likely to increase the occurrence of vascular complications. The economic burden of treating diabetes and its complications is considerable. It is appropriate that the Indian Government has initiated a national program for the management and prevention of diabetes and related metabolic disorders. Lifestyle modification is an effective tool for the primary prevention of diabetes in Asian Indians. The primary prevention of diabetes is urgently needed in India to curb the rising burden of diabetes. PMID- 20923517 TI - Repaglinide-loaded long-circulating biodegradable nanoparticles: rational approach for the management of type 2 diabetes mellitus. AB - BACKGROUND: Repaglinide (RPG) is an oral hypoglycemic agent with excellent bioavailability (90-98%) and a short plasma half-life (2-6 h). A full dose of RPG is required before each meal; hence, therapy may become inconvenient. Thus, the aim of the present study was to design a novel delivery system to maintain peak plasma levels of RPG for the long-term management of diabetes mellitus. METHODS: Two nanoparticle formulations were prepared by combining RPG with poly (lactic-co glycolic) acid alone or as a copolymer with methoxypolyethylene glycol (RPGNP1 and RPGNP2, respectively); both formulations were subjected to in vitro and in vivo characterization. In vivo characterization was performed in a streptozotocin (STZ)-induced diabetic male albino rats. RESULTS: The mean particle size of the RPGNP1 and RPGNP2 formulations was 387.8 +/- 11.9 and 310.2 +/- 12.4 nm, respectively, with a zeta potential of -27.4 +/- 0.7 and -15.7 +/- 0.5 mV, respectively. The entrapment efficiency and drug content of RPGNP1 (58.7 +/- 1.3% and 27.4 +/- 2.3%, respectively) was better than that of RPGNP2 (45.8 +/- 1.2% and 24.3 +/- 1.1%, respectively). Blood glucose levels of RPGNP1- and RPGNP2 treated STZ-diabetic rats were reduced significantly (to normal levels) compared with untreated STZ-diabetic rats (P < 0.05), but there was no difference between the two treatment groups (P > 0.05). However, whereas RPGNP1 was effective for a period of only 24 h, RPGNP2 was effective for up to 1 week. CONCLUSIONS: The results of the present study show that RPGNP2 effectively manages type 2 diabetes mellitus for up to 1 week. Surface-modified NPs could be used to improve patient compliance with drug treatment as a result of decreased dosing frequency. PMID- 20923518 TI - A preliminary case-control study on nutritional status, body composition, and glycemic control of Greek children and adolescents with type 1 diabetes. AB - BACKGROUND: Because scientific data on the diet of diabetic Greek youngsters are scarce, diabetic experts use findings from international studies. However, because of diet variations between countries, this may result in problems in diabetes control. The aim of the present pilot study was to assess body composition, nutritional status, and diabetes control in Greek youngsters with type 1 diabetes mellitus (T1DM). METHODS: Twenty-four children and adolescents with diabetes, aged 4-16 years, and the same number of age- and sex-matched controls participated in the study. Anthropometry included stature, weight, and body fat determined by bioelectrical impedance analysis. Body mass index (BMI), fat mass index (FMI), fat-free mass index (FFMI), and z-scores were calculated. Diabetes control was evaluated through glycosylated hemoglobin (HbA1c) and dietary intake was recorded for 3 days. RESULTS: The FFMI, BMI z-score and weight for-age z-score were lower in controls compared with diabetic youngsters (P <= 0.001, P <= 0.02, and P <= 0.01, respectively). Three diabetic participants were overweight (12.5%) and two controls were underweight (8.3%). The energy and nutrient intake was similar between the two groups, and all participants consumed a diet high in fats and proteins at the expense of carbohydrates. Dietary fat was highly correlated with BMI in both groups. The consumption of vitamin D was inadequate in the diabetic participants, but they had a higher intake of antioxidant vitamins, vitamin B(6) , and folate compared with the control group. CONCLUSIONS: In conclusion, youngsters with T1DM failed to adhere to the macronutrient recommendations for diabetes, but dietary patterns were similar in both the diabetic and control groups. The control of diabetes was not associated with any nutrient or anthropometric variable. PMID- 20923519 TI - Rate of peripheral glucose change during cognitive testing predicts performance in diabetes mellitus. AB - BACKGROUND: The reason for cognitive deterioration in diabetes mellitus (DM) remains unknown. One suggestion is that despite elevated glucose levels, patients with DM generally have difficulty utilizing glucose during cognitive tasks. This assumption was tested in the present study. METHODS: Male outpatients with DM (n = 46; age 52-85 years) were administered a series of standard neuropsychological and cognitive tests. In addition to assessing the time to complete the series of tests, peripheral blood glucose levels were measured prior to and following testing. RESULTS: The rate at which peripheral blood glucose levels changed was examined in relation to cognitive performance. Multiple linear regression analyses revealed significant relationships between the rate of glucose change and performance on tests measuring psychomotor skills, attention, visuoperceptual abilities, sequencing skills, mental flexibility, and planning. Higher rates of decline in peripheral blood glucose levels were associated with better performance on all cognitive measures, except verbal fluency. CONCLUSIONS: During cognitive testing, higher rates of decline in peripheral blood glucose levels may reflect stronger glucose utilization by the brain, thereby facilitating higher levels of cognitive performance. This non-invasive measure may be useful in primary care settings to provide a link between blood glucose changes and cognitive status. PMID- 20923520 TI - Index of myocardial performance in patients with type 2 diabetes without hypertension and its relationship with clinical and echocardiographic parameters. AB - BACKGROUND: Diabetes mellitus affects the systolic and diastolic function of the left ventricle (LV). The aim of the present study was to evaluate the index of myocardial performance (IMP), a new Doppler index, in asymptomatic, normotensive patients with type 2 diabetes mellitus (T2DM). METHODS: The study population consisted of 40 asymptomatic normotensive patients with T2DM (22 women, 18 men; mean [+/-SD] age 49 +/- 7 years) and 20 healthy controls (13 women, seven men; mean age 45 +/- 4 years). M-Mode and two-dimensional Doppler echocardiography was performed in all subjects to calculate IMP. Venous blood samples were collected for analysis and body mass index (BMI) was calculated. RESULTS: In normotensive T2DM patients, the mitral E wave was decreased, whereas mitral A wave, mitral E/A ratio, and septal wall thickening were increased compared with values obtained for the control group. The IMP was higher in normotensive T2DM patients than in the control group (P = 0.004). There was a significant correlation between IMP and triglyceride (TG) levels (P < 0.001), mitral E wave (P < 0.001), mitral E/A ratio (P < 0.001), ejection fraction (P = 0.001), fasting blood glucose (P =0.007), LV systolic dimension (P < 0.001), duration of diabetes (P = 0.017), and BMI (P = 0.029). Stepwise multiple regression analysis demonstrated that only TG levels (beta = 0.355, t = 2.487, P = 0.017) and the mitral E/A ratio (beta = 0.384, t = -2.690, P = 0.011) had an independent effect on IMP. CONCLUSION: The results of the present study indicate that IMP is increased in normotensive T2DM patients. The findings suggest that increased IMP may be an early sign of diabetic cardiomyopathy in normotensive diabetic patients with preserved LV function. PMID- 20923521 TI - Prevalence of metabolic syndrome and its association with obesity indices in a Chinese population. AB - BACKGROUND: To investigate the prevalence of metabolic syndrome in an urbanizing community in Qingpu, a suburb of Shanghai, and to determine which obesity indices, including body mass index, waist circumference (WC), and waist:hip (WHpR), and waist:height (WHtR) ratios, are most closely associated with metabolic syndrome. METHODS: We conducted a cross-sectional health survey of 1634 individuals (age 15-87 years) in the Jinhulu community located in Qingpu. The National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (NCEP ATP III) criteria were used to define metabolic syndrome, with central obesity defined according to Asia Pacific (APC) region criteria. RESULTS: The age-standardized prevalence of metabolic syndrome was 3.6% in men and 7.2% in women. Using the criterion of central obesity in the APC, the age-standardized prevalence of metabolic syndrome increased to 8.3% in men and 10.9% in women. Regardless of age, WHtR consistently showed a higher odd ratios (OR) after adjustment for confounding factors of 2.17 (95% confidence interval [CI] 1.12-4.20; P = 0.022) in subjects<52 years of age and 1.92 (95% CI 1.18-3.11; P = 0.008) in those >=52 years of age. In men, the WHtR was the only significant predictor (OR 2.42; 95% CI 1.15-5.08; P = 0.02) of metabolic syndrome after adjustment, whereas in women WHtR (OR 1.87; 95% CI 1.37 2.85; P =0.0088) was slightly inferior to WHpR and WC. CONCLUSION: Metabolic syndrome is prevalent in an urbanizing rural area in Qingpu. Of the anthropometric parameters commonly used to identify metabolic syndrome, WHtR may be the best. PMID- 20923522 TI - Exercise test and glucose homeostasis in rats treated with alloxan during the neonatal period or fed a high calorie diet. AB - BACKGROUND: Animal models appear well-suited for studies into the role of exercise in the prevention of non-insulin-dependent diabetes mellitus (NIDDM). The aim of the present study was to analyze glucose homeostasis and blood lactate during an exercise swimming test in rats treated with alloxan during the neonatal period and/or fed a high calorie diet from weaning onwards. METHODS: Rats were injected with alloxan (200 mg/kg, i.p.) or vehicle (citrate buffer) at 6 days of age. After weaning, rats were divided into four groups and fed either a balanced diet or a high-caloric diet as follows: C, control group (vehicle + normal diet); A, alloxan-treated rats fed the normal diet; H, vehicle-treated rats fed the high caloric diet; and HA, alloxan-treated rats fed the high-caloric diet. RESULTS: Fasting serum glucose levels were higher in groups A and AH compared with the control group. The Homeostatic Model Assessment index varied in the groups as follows: H>A>HA = C. There were no differences in free fatty acids or blood lactate concentrations during the swim test. CONCLUSIONS: Alloxan-treated rats fed a normal or high-caloric diet have the potential to be used in studies analyzing the role physical exercise plays in the prevention of NIDDM. PMID- 20923523 TI - Recent cardiovascular trials: what are the drivers of benefit and adverse effect? PMID- 20923524 TI - Metabolic syndrome and chronic kidney disease. AB - The prevalence of metabolic syndrome (MetS) is increasing worldwide in both developing and developed countries. Experimental and clinical studies have revealed that MetS plays an important role in the development of chronic kidney disease (CKD), which leads to end-stage renal disease. Emerging evidence also suggests that CKD may actually cause MetS since the kidney is an important organ of glucose and lipid homeostasis. Although multiple mechanisms have been shown to be involved in the pathogenesis of MetS, insulin resistance appears to be a central pathophysiological factor contributing to MetS. In this review we will discuss the association of MetS with insulin resistance and CKD, and the renal pathophysiological changes associated with MetS. PMID- 20923525 TI - Diabetes and skeletal health. AB - Osteoporosis and diabetes affect a large proportion of the elderly population. The prevalence of diabetes and osteoporosis is increasing. Compared with individuals without diabetes, both men and women with diabetes have a higher risk of fractures, particularly at the hip, with consequent significant morbidity and mortality. Type 1 diabetes is associated with decreased bone mass and although bone mass data for Type 2 diabetes may or may not be decreased, there is evidence of altered bone quality in diabetes. The mechanisms involved include effects of insulin, insulin-like growth factor 1, cytokines, advanced glycation end products, and altered calcium homeostasis. In addition, a drug-induced increase in the incidence of fractures has been noted with the use of thiazolidinediones (TZDs). TZDs improve insulin sensitivity and have multitude other beneficial effects. Osteoblasts and adipocytes are derived from a common multipotential mesenchymal stem cell progenitor, with activation of peroxisome proliferator activated receptor gamma2 by both currently available TZDs (i.e. rosiglitazone and pioglitazone) stimulating adipogenesis and inhibiting osteoblastogenesis. The use of both rosiglitazone and pioglitazone is associated with an increased fracture risk, with changes in bone turnover markers and decreased bone mineral density. PMID- 20923526 TI - Ethnic difference in patients with type 2 diabetes mellitus in inter-East Asian populations: a systematic review and meta-analysis focusing on gene polymorphism. AB - BACKGROUND: We previously reported that the fasting serum insulin level was significantly lower in Japanese patients than in Korean and Chinese patients, and showed evidence that a difference in the dietary component would be one of the most influential factors for the ethnic difference. However, it is well known that type 2 diabetes mellitus (T2DM) results from the interaction between genetic predispositions and environmental risk factors. Therefore, we investigated ethnic differences by focusing on gene polymorphism, possibly related to T2DM in Japanese, Korean, and Chinese subjects. METHODS: Data sources included MEDLINE and EMBASE between January 2001 and October 2008. We conducted a search for articles containing minor allele frequency (MAF) in the gene polymorphisms of peroxisome proliferator-activated receptor-gamma (PPARG), inward-rectifying potassium channel Kir6.2 (KCNJ11), Calpain 10 (CAPN10), and transcription factor 7-like 2 (TCF7L2). The pooled odds ratio was calculated by using a fixed-effects model with the Mantel-Haenszel method after confirming statistical evidence of homogeneity across the ethnicities using the Breslow-Day test. RESULTS: The Breslow-Day test revealed that there were no statistically significant differences between ethnicities in pooled odds ratios for the gene polymorphisms in PPARG (P = 0.828), KCNJ11 (P = 0.194), CAPN10 (P = 0.090), and TCF7L2 (P = 0.376). Also, pooled odds ratios of each gene polymorphism in East Asians were 0.645 for PPARG (P = 0.000), 1.168 for KCNJ11 (P = 0.000), 0.967 for CAPN10 (P = 0.759), and 1.386 for TCF7L2 (P = 0.000). CONCLUSION: The results of this study and our previous studies suggest that behavioral and environmental risk factors have a more significant impact on ethnic difference in East Asian patients with T2DM compared with genetic predispositions. PMID- 20923527 TI - Glucose represses PPARalpha gene expression via AMP-activated protein kinase but not via p38 mitogen-activated protein kinase in the pancreatic beta-cell. AB - BACKGROUND: Peroxisome proliferator-activated receptor alpha (PPARalpha) regulates the expression of fatty acid metabolism genes and is thought to play a role in the regulation of insulin secretion and lipid detoxification. We have examined the mechanism whereby glucose decreases PPARalpha gene expression in the pancreatic beta-cell. METHODS: INS832/13 beta-cell and isolated rat islets were incubated at 3 and 20 mM glucose for 18 h in the absence or presence of adenosine monophosphate (AMP)-activated protein kinase (AMPK) activators and inhibitors, as well as p38 mitogen-activated protein kinase (p38 MAPK) inhibitors. In another set of experiments, INS832/13 were infected with an adenovirus expressing a dominant-negative form of AMPK. PPARalpha expression levels were measured by reverse transcription polymerase chain reaction and Western blot. RESULTS: Elevated glucose reduced the abundance of the PPARalpha transcript and protein, and its target genes acyl-coenzyme A (CoA) oxidase (ACO) and uncoupling protein 2 (UCP-2) in INS832/13 beta-cell and isolated rat islets. Glucose reduced AMPK activity, while the AMPK activators 5-amino-4-imidazolecarboxamide riboside and metformin increased PPARalpha expression and suppressed the action of glucose. By contrast, the AMPK inhibitor compound C mimicked the glucose effect. A dominant negative form of AMPKalpha reduced the PPARalpha, ACO and UCP-2 transcripts to the same extent as elevated glucose. Pharmacological evidence indicated that glucose-regulated PPARalpha expression does not involve p38 MAPK, a target of AMPK in several cell types. CONCLUSIONS: The results indicate that glucose represses PPARalpha gene expression via AMPK, but not via p38 MAPK in the beta cell. PMID- 20923528 TI - Genistein improves liver function and attenuates non-alcoholic fatty liver disease in a rat model of insulin resistance. AB - BACKGROUND: The high fructose-fed rat is widely used as a model of insulin resistance. Genistein, a soy isoflavone, has been shown to improve insulin sensitivity in this model. The present study investigated whether genistein could prevent fatty liver disease in this model. METHODS: Male Wistar rats were fed a diet containing starch (control) or 60% fructose (insulin-resistant model). Fifteen days later, rats in each dietary group were divided into two groups and were treated with either genistein (1 mg/kg per day) in dimethylsulfoxide (DMSO) or 30% DMSO alone. After 60 days, markers of liver injury, oxidative stress, interleukin (IL)-6, tumor necrosis factor (TNF)-alpha, lipids, lipoprotein profile, nitrite, and nitrosothiol in the plasma and liver were quantified. Liver sections were examined for 3-nitrotyrosine (3-NT) expression and pathological lesions. RESULTS: Fructose-fed rats displayed hyperlipidemia, significant changes in plasma lipoprotein profile, and increases in IL-6 and TNF-alpha levels compared with control. In addition, the accumulation of lipids, liver injury, a decline in liver function, inactivation of the glyoxalase system, depletion of antioxidants, and increased 3-NT expression were observed in the fructose-fed group. Administration of genistein to fructose-fed rats significantly reduced these biochemical and histological abnormalities. CONCLUSIONS: Genistein activates the antioxidant profile, decreases IL-6 and TNF-alpha concentrations, prevents oxidative damage, and ameliorates fatty liver in insulin-resistant rats. PMID- 20923529 TI - Long-term effects of a carbohydrate-rich diet on fasting blood sugar, lipid profile, and serum insulin values in rural Bengalis. AB - BACKGROUND: The prevalence of Type 2 diabetes is increasing in rural areas of India, where there is also often a lack of health infrastructure. Thus, a proper dietary study with the view of combating diabetes is essential. The aim of the present study was to determine the long-term effect of a carbohydrate-rich diet in rural Bengal. METHODS: Volunteers (n = 320) were selected from three villages in Kharagpur and were randomly divided into a control and experimental group (n = 160 in each). The design of the study was such that non-significant differences in any of the dependent variables were maintainted prior to the application of control or treatment modes. In the control group, volunteers consumed <70% carbohydrate as part of their diet, whereas in the experimental group carbohydrate consumption was >70%. Blood samples from both groups were collected on yearly basis for 5 years and fasting blood sugar (FBS), lipid profile and serum insulin values were analyzed. RESULTS: The blood biochemistry profiles were monitored before the start and at the end of the study. The results indicate that increased intake of carbohydrate causes significant increases in FBS (P < 0.05) and serum insulin (P < 0.05), as well as changes in the lipid profile, particularly triglycerides (P < 0.05) and very low-density lipoprotein cholesterol (VLDL-C; P < 0.05). CONCLUSIONS: The effects of increased carbohydrate on FBS, serum insulin, triglycerides and VLDL-C indicate that a proper nutritional policy needs to be implemented for this population of rural, low-income Bengalis. PMID- 20923530 TI - Serum concentrations of vitamin D and parathyroid hormone and prevalent metabolic syndrome among adults in the United States. AB - BACKGROUND: Some reports suggest that concentrations of vitamin D are inversely, whereas concentrations of parathyroid hormone (PTH) are directly, associated with prevalent metabolic syndrome. Because of lingering uncertainty about these associations, we examined the cross-sectional associations between serum concentrations of 25-hydroxyvitamin D(3) and PTH with metabolic syndrome in a representative sample of adults in the US. METHODS: We used data from 1705 participants in the 2005-2006 National Health and Nutrition Examination Survey. Vitamin D was measured by radioimmunoassay, whereas PTH was measured using an electrochemiluminescent process. RESULTS: The mean concentration of vitamin D for participants with and without metabolic syndrome was 20.3 and 22.9 ng/mL, respectively (P = 0.001). The mean concentration of PTH for participants with and without metabolic syndrome was 44.5 and 41.0 pg/mL, respectively (P = 0.002). The age-adjusted mean concentrations of vitamin D (P for linear trend <0.001) decreased linearly, whereas PTH (P for linear trend = 0.002) increased linearly, as the number of components of metabolic syndrome increased. After adjusting for age, gender, physical activity, urinary albumin creatinine ratio, and concentrations of C-reactive protein and calcium, concentrations in the highest quintile of vitamin D [prevalence ratio (PR) = 0.59; 95% confidence interval (CI) 0.44-0.79], but not PTH (PR = 1.18; 95% CI 0.97-1.43), was significantly associated with prevalent metabolic syndrome. CONCLUSION: Concentrations of vitamin D, but not PTH, were significantly associated with prevalent metabolic syndrome among US adults. PMID- 20923531 TI - Cancer mortality and insulin glargine. PMID- 20923532 TI - Indian diabetes risk score according to menopausal status in Asian Indian women: The Santiniketan Women study. PMID- 20923533 TI - Insulin secretory function in type 2 diabetes: Does it matter how you measure it? AB - The following estimates of insulin secretory function have been used widely to evaluate the role of pancreatic beta-cells in the pathogenesis and treatment of patients with type 2 diabetes (2DM): (i) Homeostatic Model Assessment (HOMA) beta, a calculation based on fasting plasma glucose and insulin concentrations; (ii) post-glucose acute insulin response (AIRg), the increment in insulin concentration measured in the 5 min after intravenous glucose; and (iii) DeltaI/DeltaG, the ratio of the increment in plasma insulin concentration (I)/increment in plasma glucose concentration (G) 30 min after the oral administration of 75 g glucose. Experiments based on these approaches have led to a widely held point of view that that the natural history of 2DM is characterized by a progressive increase in the magnitude of hyperglycemia, secondary to an inexorable decline in pancreatic beta-cell function: the greater the increase in plasma glucose concentration, the greater the impairment of the ability of the pancreas to secrete insulin. In the present review, theoretical questions are raised as to the physiological validity of these estimates of insulin secretory function and experimental data are presented demonstrating that hourly measurements of plasma insulin and glucose concentrations in response to mixed meals throughout an 8-h day lead to a very different point of view. Studies are also reviewed that question the 'inexorability' of the changes in insulin secretory function that have been reported. It is concluded that it may be time to challenge current conventional wisdom as to the role of the beta-cell in the natural history of 2DM. PMID- 20923534 TI - Reactive oxygen-derived free radicals are key to the endothelial dysfunction of diabetes. AB - Vascular complications are an important pathological issue in diabetes that lead to the further functional deterioration of several organs. The balance between endothelium-dependent relaxing factors and endothelium-dependent contracting factors (EDCFs) is crucial in controlling local vascular tone and function under normal conditions. Diabetic endothelial dysfunction is characterized by reduced endothelium-dependent relaxations and/or enhanced endothelium-dependent contractions. Elevated levels of oxygen-derived free radicals are the initial source of endothelial dysfunction in diabetes. Oxygen-derived free radicals not only reduce nitric oxide bioavailability, but also facilitate the production and/or action of EDCFs. Thus, the endothelial balance tips towards vasoconstrictor responses over the course of diabetes. PMID- 20923535 TI - Progress in diabetes research in China. AB - The prevalence of diabetes, especially Type 2 diabetes mellitus (T2DM), is increasing markedly throughout the world, including in China. Because T2DM and its complications are associated with considerable socioeconomic burden and mortality, there is increasing interest in developing strategies to prevent or delay progression of the disease. In recent decades, many researchers have focused on the mechanism of onset of diabetes, as well as examining the benefits of various interventions in subjects with different glucose tolerance status to prevent or delay development of the disease. In the present article, we focus on five areas (epidemiology, early intervention, insulin sensitivity and beta-cell function, adipocytokines, and traditional Chinese medicine) to review the progress of research into diabetes in China today. The prevalence of diabetes in China is one of the highest in the world. However, with lifestyle interventions and appropriate pharmacological therapies (including traditional Chinese medicine), T2DM may be prevented, well controlled, or even put into remission. Accurate estimation of insulin secretion and insulin sensitivity, as well as better characterization of the physiological function of adipocytokines, could give us a better understanding of the basic mechanisms underlying the onset of diabetes and could lead to better interventions in people with impaired glucose tolerance and T2DM. PMID- 20923537 TI - Diabetic foot ulcer burden may be modified by high-dose atorvastatin: A 6-month randomized controlled pilot trial. AB - BACKGROUND: Diabetic foot ulcers (DFUs) are common complications of diabetes mellitus (DM), with a complex pathogenesis. Treatment is difficult and no single treatment with measurable clinical impact is available. In the present clinical pilot trial, we investigated whether statins could be of use against some of the pathogenic factors in DFUs. METHODS: Thirteen diabetic patients (10 men; 11 with Type 2 DM; mean age 64 years; mean duration of DM 18 years) with neuropathic DFUs <4 months were randomized to treatment with either 10 mg (six patients; six ulcers) or 80 mg (seven patients; nine ulcers) atorvastatin for 6 months in addition to conventional DFU care (i.e. prompt debridement, DFU pressure relief, and management of any underlying infection). RESULTS: There were no significant differences in background factors (i.e. HbA1c 8.9%, micro- and macrovascular complications, concomitant medications) or DFU characteristics (duration, surface area, grading) between the two groups. All ulcers in the group receiving 10 mg atorvastatin healed, compared with six of nine ulcers in the group receiving 80 mg atorvastatin (NS). However, two previously healed DFUs recurred and six new DFUs developed in the low-dose group compared with none and one, respectively, in the high-dose group (P = 0.048). There was a significant decrease in C-reactive protein (-1.5 mg/L; P = 0.044) and a non-significant trend towards beneficial effects on lipids and the ankle-arm blood pressure index in the high-dose compared with the low-dose group. CONCLUSIONS: We observed a possible beneficial effect of 6-months high-dose atorvastatin on DFUs, which should be tested in appropriately sized prospective studies. PMID- 20923536 TI - Smoking, diabetes and cardiovascular diseases in men in the Asia Pacific region. AB - BACKGROUND: To assess whether there is a statistical interaction between smoking and diabetes that is related to the risk of cardiovascular disease (CVD) in men in the Asia Pacific region. METHODS: An individual participant data meta-analysis was conducted on 34 cohort studies, involving 16 492 participants with diabetes (47.4% smokers) and 188 897 without (47.6% smokers). Hazard ratios (HR) and 95% confidence intervals (CI) were calculated for smoking (stratified by study and adjusted for age) for those with and without diabetes. RESULTS: In men with diabetes, the HR (95% CI) comparing current smokers with non-smokers was 1.42 (1.10-1.83) for coronary heart disease, 1.10 (0.88-1.37) for total stroke and 1.15 (0.98-1.35) for total CVD. The corresponding figures for men without diabetes were 1.47 (1.33-1.61), 1.27 (1.16-1.39) and 1.35 (1.27-1.44), respectively. There was no evidence of a statistical interaction between diabetes and current smoking, the number of cigarettes smoked per day or quitting smoking. Smoking cessation was associated with a 19% reduction in CVD risk, irrespective of diabetes status. CONCLUSIONS: The effects of cigarette smoking and smoking cessation are broadly similar in men with and without diabetes. In Asia, where there are high rates of smoking and a rapidly increasing prevalence of diabetes, strategies that encourage smokers to quit are likely to have huge benefits in terms of reducing the burden of CVD in men with diabetes. PMID- 20923538 TI - Additional value of carotid artery intima-media thickness in cardiovascular risk assessment by Framingham risk-score in Type 2 diabetes: a retrospective cohort study. AB - BACKGROUND: The intima-media thickness (IMT) of the carotid artery is highly correlated with cardiovascular events in Type 2 diabetes mellitus (T2DM). The aim of the present study was to undertake a cardiovascular risk assessment in a group of patients (n = 102) who had been followed-up for 10 years. METHODS: Framingham risk score (FRS), IMT, and various other clinical parameters were evaluated retrospectively using Student's t-test, regression analysis, and chi2 tests. Primary endpoints were defined as cardiovascular death, non-fatal myocardial infarction, angina, and ischemic stroke. RESULTS: The IMT (1.09 +/- 0.32 vs 0.89 +/- 0.25; P < 0.001) and percentage coronary risk as determined by the FRS (24.33 +/- 11.07 vs 16.54 +/- 8.35; P = 0.001) were significantly higher in patients presenting with any of the primary endpoints compared with patients in whom no cardiovascular morbidity or mortality was recorded. Other factors that significantly predicted cardiovascular mortality and morbidity included diastolic blood pressure and urinary albumin excretion (UAE; P < 0.001). The likelihood of primary endpoints could be predicted by UAE >30 mg/day, carotid artery IMT >=0.9 mm, and FRS >=20 (odds ratios 8.800, 3.377, and 2.807, respectively). CONCLUSION: Although FRS predicts 10-year risk for cardiovascular mortality and morbidity in T2DM, we suggest that UAE and carotid artery IMT should also be considered in risk assessments. PMID- 20923539 TI - Dietary fiber improves lipid homeostasis and modulates adipocytokines in hamsters. AB - BACKGROUND: The hypocholesterolemic and hypoglycemic effects of various natural and semisynthetic dietary fibers have been studied for their potential use in the prevention and improvement of metabolic syndrome. Of these dietary fibers, hydroxypropyl methylcellulose (HPMC) has been shown to lower plasma cholesterol and reduce weight gain. However, the underlying mechanisms are not known. In the present study, we examined associations between plasma adipocytokine levels and both lipid metabolism and insulin sensitivity after HPMC intake in golden Syrian hamsters. In addition, endogenous adiponectin from hamster plasma was purified and characterized. METHODS: Hamsters were treated with HPMC (2% and 4% in a high fat diet) or 2% or 4% microcrystalline cellulose (MCC; control diet) for 8 weeks. Plasma glucose, insulin, lipids, adiponectin, leptin, and hepatic lipid levels were assessed using standard techniques. RESULTS: After 8 weeks of feeding, plasma total cholesterol and triglyceride levels in hamsters fed the 4% HPMC supplemented diet were significantly lower than in hamsters fed the control diet. Moreover, a significant increase in adiponectin levels and a decrease in leptin levels were observed in hamsters fed the 4% HPMC-supplemented diet. Hamster adiponectin was found to be comprised of 244 amino acid residues with an apparent molecular weight of 30 kDa, consistent with the adiponectin reported in other species. CONCLUSIONS: Reductions in plasma cholesterol and triglyceride levels were correlated with a decrease in plasma leptin and an increase in adiponectin. These results suggest that adipocytokines are regulated by HPMC and may play a pivotal role in the hypocholesterolemic effect. PMID- 20923540 TI - Randomized clinical trial of standard dietary treatment versus a low carbohydrate/high-protein diet or the LighterLife Programme in the management of obesity*. AB - BACKGROUND: With the current obesity epidemic, the search for effective weight loss approaches is required. In the present study, changes in weight, body composition and cardiovascular (CV) risk in response to a low-fat, reduced-energy diet (LFRE), a low-carbohydrate/high-protein diet (LCHP), or a commercially available very low-calorie diet (LighterLife; LL) were assessed. METHODS: One hundred and twenty obese patients (body mass index >=35 kg/m2 ) underwent a screening period of 3 months on the LFRE. Those who lost >5% of their body weight were maintained on this approach for an additional 3 months, whereas those who lost >10% at this time were maintained for 1 year. Patients failing to achieve these targets were randomly allocated to either the LCHP (n = 38) or LL (n = 34) for a period of 9 months. RESULTS: Significantly greater weight loss was seen for patients on the LL than the LCHP at 3 (mean (+/- SD) -11.6 +/- 12.9 vs -2.8 +/- 4.5 kg, respectively; P < 0.0001) and 9 months (-15.1 +/- 21.1 vs -1.9 +/- 5.0 kg, respectively; P < 0.0001) after screening. Significantly greater improvement in total cholesterol, low-density lipoprotein-cholesterol, fasting glucose, and diastolic blood pressure was seen at 3 months in patients on the LL compared with the LCHP (P < 0.05). These differences were no longer significant at 9 months, with the exception of fasting glucose. The attrition rate was elevated in the LCHP group, but did not differ significantly from the LL group. CONCLUSION: Greater weight loss and improved CV risk were achieved with the LL, which mostly reflects the patient support provided for each dietary treatment. PMID- 20923541 TI - Early life factors and type 2 diabetes in south India: Do the associations change with age? AB - BACKGROUND: Studies since the early 1990s have shown that birth size can be a predictor of the development of Type 2 diabetes mellitus (T2DM). In the present study, we evaluated changes in the strength of associations between T2DM and birth size and maternal weight with age. METHODS: In 1993-1994 (t0), 509 men and women (mean age 46 years) who had been born in Holdsworth Memorial Hospital were screened for diabetes, with increased diabetes risk identified in those who were shorter at birth and those born to heavier mothers. Ten years later (t10), the screening was repeated in 266 subjects who were non-diabetic at t0 (70% of survivors). RESULTS: At t10, 56 new cases of diabetes were found. The incidence of diabetes decreased with increasing birth length (odds ratio (OR) = 0.90, 95% confidence interval (CI) 0.84-0.97/cm birth length; P = 0.006) after adjustment for sex, age, socioeconomic status, family history, and current body mass index. Overall, there were no significant differences in OR for the association between birth length and diabetes at t0 compared with t10, but limiting analysis to subjects with normal glucose tolerance at t0 resulted in a stronger association at t10 (OR = 0.71, 95% CI 0.58-0.87) than at t0 (OR = 0.95, 95% CI 0.86-1.05; P = 0.015 for the difference). There was a positive correlation between maternal weight and incident disease at t0 (OR = 1.08, 95% CI 1.03-1.14; P = 0.001), but not at t10 (OR = 0.98/kg, 95% CI 0.92-1.05; P = 0.6; P = 0.02 for the difference). CONCLUSIONS: Short birth length remains a risk factor for diabetes. Changes in the effects of birth length and maternal weight on diabetes risk with age may indicate different causal pathways. These findings require replication in studies with more accurate dating of the onset of diabetes. PMID- 20923542 TI - Metabolic syndrome in menopausal transition: Isfahan Healthy Heart Program, a population based study. AB - INTRODUCTION: There is a remarkable increase in cardiovascular disease after menopause. On the other hand, metabolic syndrome as a collection of risk factors has a known effect on cardiovascular diseases. Hormone changes are considered as one of the main relevant factor regarding cardiovascular disease as well as some recognized relationship with metabolic syndrome's components. This study was carried out in order to search for prevalence of metabolic syndrome during menopausal transition. METHOD: In a cross sectional study in urban and rural areas of Isfahan, Najafabad and Arak cities, 1596 women aged more than 45 years were investigated using Isfahan Healthy Heart Program's (IHHP) samples. Participants were categorized into three groups of pre-menopause, menopause and post-menopause. Leisure time physical activity and global dietary index were included as life style factors. The association of metabolic syndrome and its components with menopausal transition considering other factors such as age and life style was analyzed. RESULTS: there were 303, 233 and 987 women in premenopausal, early menopausal and postmenopausal groups respectively. Metabolic syndrome was found in 136(44.9%) premenopausal participants and significantly increased to 135(57.9%) and 634(64.3%) in early menopausal and postmenopausal participants respectively, when age was considered (P = 0.010). Except for hypertension and hypertriglyceridemia, there was no significant difference between three groups of menopausal transition when metabolic syndrome's components were considered. CONCLUSION: In contrary to the claims regarding the role of waist circumference and blood glucose in increasing of metabolic syndrome during the menopausal transition, this study showed this phenomenon could be independence of them. PMID- 20923543 TI - The frequency of CD25+CD4+ and FOXP3+ regulatory T cells in ectopic endometrium and ectopic decidua. AB - BACKGROUND: The presence of regulatory T (Treg) cells in human endometrium is crucial for maintaining immunological homeostasis within the uterus. For this study we decided to evaluate the subpopulations of Treg cells in conditions where a disturbance in the immunological equilibrium in ectopic endometrium and decidua has been observed, such as in cases of ovarian endometriosis (involving local immune cell suppression) and ectopic pregnancy (involving an increase in local immune system activity). We then compared these findings to what we observed in the normal eutopic endometrium of women during the secretory phase of the menstrual cycle (with immune cells under individual control). METHODS: The endometrium tissue samples evaluated in our study were obtained from 47 women during one of two kinds of laparoscopic procedures. 16 of the women underwent laparoscopies due to Fallopian tube pregnancies (EP), and 16 due to ovarian endometrioma, while 15 women made up a control group. The presence of regulatory T cells in these tissue samples was evaluated by FACS. RESULTS: In our study, the percentages of FOXP3+ cells within the subpopulation of CD4+ T lymphocytes found in the decidua of the patients treated for Fallopian tube pregnancies were statistically significantly lower than both those observed in the ovarian endometriosis tissue samples and those found in the secretory eutopic endometrium samples of the control group. CONCLUSION: The disturbance in the immunological equilibrium observed in ectopic endometrium and decidua would seem to be related to the alteration in the Treg cell population that occurs in these ectopic tissues. PMID- 20923544 TI - Safety and pharmacokinetics of novel selective vascular endothelial growth factor receptor-2 inhibitor YN968D1 in patients with advanced malignancies. AB - BACKGROUND: YN968D1 (Apatinib) selectively inhibits phosphorylation of VEGFR-2 and tumor angiogenesis in mice model. The study was conducted to determine the maximum tolerated dose (MTD), safety profile, pharmacokinetic variables, and antitumor activity in advanced solid malignancies. METHODS: This dose-escalation study was conducted according to the Chinese State Food and Drug Administration (SFDA) recommendations in patients with advanced solid tumors to determine the MTD for orally administered apatinib. Doses of continuously administered apatinib were escalated from 250 mg. Treatment continued after dose-escalation phase until withdrawal of consent, intolerable toxicities, disease progression or death. RESULTS: Forty-six patients were enrolled. Hypertension and hand-foot syndrome were the two dose-limiting toxicities noted at dose level of 1000 mg. MTD was determined to be 850 mg once daily. Pharmacokinetic analysis showed early absorption with a half-life of 9 hours. The mean half-life was constant over all dose groups. Steady-state conditions analysis suggested no accumulation during 56 days of once-daily administration. The most frequently observed drug-related adverse events were hypertension (69.5%, 29 grade 1-2 and 3 grade 3-4), proteinuria (47.8%, 16 grade 1-2 and 6 grade 3-4), and hand-foot syndrome (45.6%, 15 grade 1-2 and 6 grade 3-4). Among the thirty-seven evaluable patients, PR was noted in seven patients (18.9%), SD 24 (64.9%), with a disease control rate of 83.8% at 8 weeks. CONCLUSIONS: The recommended dose of 750 mg once daily was well tolerated. Encouraging antitumor activity across a broad range of malignancies warrants further evaluation in selected populations. TRIAL REGISTRATION: ClinicalTrials.gov unique identifier: NCT00633490. PMID- 20923545 TI - Sudeck's disease stage 1, or diabetic Charcot's foot stage 0? Case report and assessment of the diagnostic value of MRI. AB - BACKGROUND: The diagnosis of Sudeck's syndrome stage 1 (nowadays termed complex regional pain syndrome I, abbreviated CRPS I) is based on clinical features, namely swelling and pain in a limb. Plain X-ray may be normal. In the absence of pain sensitivity, e.g. in diabetic neuropathy, CRPS I of the foot can be mistaken for Charcot's foot stage 0 (so-called neuro-osteoarthropathy). CASE PRESENTATION: The case of a type-1 diabetic woman is reported, in whom CRPS I following a calcaneal fracture was mistaken for Charcot's osteoarthropathy (because of bone marrow edema displayed by conventional MR imaging). In addition, a review is presented on 6 consecutive cases with CRPS I of the foot, and on 20 cases with Charcot's foot stage 0, with particular emphasis on MR imaging findings. The number of bones per foot affected with marrow edema was similar in either condition, with a tendency towards a more patchy, diffuse distribution of bone marrow edema in CRPS I. Bone marrow edema apparently regressed more promptly in response to treatment in Charcot's foot stage 0. CONCLUSION: Differentiation of CRPS I from Charcot's foot stage 0 remains a diagnostic dilemma in patients with pain insensitivity. Conventional MRI may be helpful, when repeated for monitoring the treatment response. PMID- 20923546 TI - Intravenous lipid emulsion in clinical toxicology. AB - Intravenous lipid emulsion is an established, effective treatment for local anesthetic-induced cardiovascular collapse. The predominant theory for its mechanism of action is that by creating an expanded, intravascular lipid phase, equilibria are established that drive the offending drug from target tissues into the newly formed 'lipid sink'. Based on this hypothesis, lipid emulsion has been considered a candidate for generic reversal of toxicity caused by overdose of any lipophilic drug. Recent case reports of successful resuscitation suggest the efficacy of lipid emulsion infusion for treating non-local anesthetic overdoses across a wide spectrum of drugs: beta blockers, calcium channel blockers, parasiticides, herbicides and several varieties of psychotropic agents. Lipid emulsion therapy is gaining acceptance in emergency rooms and other critical care settings as a possible treatment for lipophilic drug toxicity. While protocols exist for administration of lipid emulsion in the setting of local anesthetic toxicity, no optimal regimen has been established for treatment of acute non local anesthetic poisonings. Future studies will shape the evolving recommendations for lipid emulsion in the setting of non-local anesthetic drug overdose. PMID- 20923547 TI - Head and neck cancer in the elderly: a retrospective study over 10 years (1999 - 2008). AB - INTRODUCTION: Treatment of elderly patients is in many ways different from that for younger ones. The aim of the present study was to identify the particular characteristics and needs of elderly patients suffering from head and neck cancer. From these patterns, considerations for this special group can be deduced. PATIENTS AND MATERIAL: The subjects for this study consisted of 376 patients suffering from head and neck cancer that were treated between 1999 and 2008, 99 (26.3.%) of whom were older than 70 years and were evaluated retrospectively concerning smoking/alcohol abuse, ASA status, kind of malignant neoplasm, localization and treatment. RESULTS: The male-female ratio was 53:46, and mean age, 79 years (71 - 98). Out of 95 patients with a squamous cell carcinoma, 4 patients had a verrucous form. Out of 99 patients, 26 had a maxillary carcinoma and 12 patients had experienced previous non-head-and-neck cancer. An ASA score of 2 or 3 was found in 86 of the patients. CONCLUSION: The group of patients with head and neck cancer who were older than 70 years was characterized by a higher portion of female patients, a higher number of maxillary carcinomas, and a higher prevalence of previous second cancer. Making decisions in cancer therapy for elderly patients is challenging. Patients suffering from operable head and neck cancer should be treated with curative intent and with regard to quality of life if a careful assessment of comorbidities is performed preoperatively. PMID- 20923548 TI - The humoral response to Plasmodium falciparum VarO rosetting variant and its association with protection against malaria in Beninese children. AB - BACKGROUND: The capacity of Plasmodium falciparum-infected erythrocytes to bind uninfected erythrocytes (rosetting) is associated with severe malaria in African children. Rosetting is mediated by a subset of the variant surface antigens PfEMP1 targeted by protective antibody responses. Analysis of the response to rosette-forming parasites and their PfEMP1 adhesive domains is essential for understanding the acquisition of protection against severe malaria. To this end, the antibody response to a rosetting variant was analysed in children recruited with severe or uncomplicated malaria or asymptomatic P. falciparum infection. METHODS: Serum was collected from Beninese children with severe malaria, uncomplicated malaria or P. falciparum asymptomatic infection (N = 65, 37 and 52, respectively) and from immune adults (N = 30) living in the area. Infected erythrocyte surface-reactive IgG, rosette disrupting antibodies and IgG to the parasite crude extract were analysed using the single variant Palo Alto VarO infected line. IgG, IgG1 and IgG3 to PfEMP1-varO-derived NTS-DBL1alpha1, CIDRgamma and DBL2betaC2 recombinant domains were analysed by ELISA. Antibody responses were compared in the clinical groups. Stability of the response was studied using a blood sampling collected 14 months later from asymptomatic children. RESULTS: Seroprevalence of erythrocyte surface-reactive IgG was high in adults (100%) and asymptomatic children (92.3%) but low in children with severe or uncomplicated malaria (26.1% and 37.8%, respectively). The IgG, IgG1 and IgG3 antibody responses to the varO-derived PfEMP1 domains were significantly higher in asymptomatic children than in children with clinical malaria in a multivariate analysis correcting for age and parasite density at enrolment. They were essentially stable, although levels tended to decrease with time. VarO-surface reactivity correlated positively with IgG reactivity to the rosetting domain varO NTS-DBL1alpha1. None of the children sera, including those with surface-reactive antibodies possessed anti-VarO-rosetting activity, and few adults had rosette disrupting antibodies. CONCLUSIONS: Children with severe and uncomplicated malaria had similar responses. The higher prevalence and level of VarO-reactive antibodies in asymptomatic children compared to children with malaria is consistent with a protective role for anti-VarO antibodies against clinical falciparum malaria. The mechanism of such protection seems independent of rosette disruption, suggesting that the cytophilic properties of antibodies come into play. PMID- 20923549 TI - Identification of the Rage-dependent gene regulatory network in a mouse model of skin inflammation. AB - BACKGROUND: In the past, molecular mechanisms that drive the initiation of an inflammatory response have been studied intensively. However, corresponding mechanisms that sustain the expression of inflammatory response genes and hence contribute to the establishment of chronic disorders remain poorly understood. Recently, we provided genetic evidence that signaling via the receptor for advanced glycation end products (Rage) drives the strength and maintenance of an inflammatory reaction. In order to decipher the mode of Rage function on gene transcription levels during inflammation, we applied global gene expression profiling on time-resolved samples of mouse back skin, which had been treated with the phorbol ester TPA, a potent inducer of skin inflammation. RESULTS: Ranking of TPA-regulated genes according to their time average mean and peak expression and superimposition of data sets from wild-type (wt) and Rage deficient mice revealed that Rage signaling is not essential for initial changes in TPA-induced transcription, but absolutely required for sustained alterations in transcript levels. Next, we used a data set of differentially expressed genes between TPA-treated wt and Rage-deficient skin and performed computational analysis of their proximal promoter regions. We found a highly significant enrichment for several transcription factor binding sites (TFBS) leading to the prediction that corresponding transcription factors, such as Sp1, Tcfap2, E2f, Myc and Egr, are regulated by Rage signaling. Accordingly, we could confirm aberrant expression and regulation of members of the E2f protein family in epidermal keratinocytes of Rage-deficient mice. CONCLUSIONS: In summary, our data support the model that engagement of Rage converts a transient cellular stimulation into sustained cellular dysfunction and highlight a novel role of the Rb-E2f pathway in Rage-dependent inflammation during pathological conditions. PMID- 20923550 TI - Sensitive detection of Abeta protofibrils by proximity ligation--relevance for Alzheimer's disease. AB - BACKGROUND: Protein aggregation plays important roles in several neurodegenerative disorders. For instance, insoluble aggregates of phosphorylated tau and of Abeta peptides are cornerstones in the pathology of Alzheimer's disease. Soluble protein aggregates are therefore potential diagnostic and prognostic biomarkers for their cognate disorders. Detection of the aggregated species requires sensitive tools that efficiently discriminate them from monomers of the same proteins. Here we have established a proximity ligation assay (PLA) for specific and sensitive detection of Abeta protofibrils via simultaneous recognition of three identical determinants present in the aggregates. PLA is a versatile technology in which the requirement for multiple target recognitions is combined with the ability to translate signals from detected target molecules to amplifiable DNA strands, providing very high specificity and sensitivity. RESULTS: For specific detection of Abeta protofibrils we have used a monoclonal antibody, mAb158, selective for Abeta protofibrils in a modified PLA, where the same monoclonal antibody was used for the three classes of affinity reagents required in the assay. These reagents were used for detection of soluble Abeta aggregates in solid-phase reactions, allowing detection of just 0.1 pg/ml Abeta protofibrils, and with a dynamic range greater than six orders of magnitude. Compared to a sandwich ELISA setup of the same antibody the PLA increases the sensitivity of the Abeta protofibril detection by up to 25-fold. The assay was used to measure soluble Abeta aggregates in brain homogenates from mice transgenic for a human allele predisposing to Abeta aggregation. CONCLUSIONS: The proximity ligation assay is a versatile analytical technology for proteins, which can provide highly sensitive and specific detection of Abeta aggregates - and by implication other protein aggregates of relevance in Alzheimer's disease and other neurodegenerative disorders. PMID- 20923551 TI - AnnoTrack--a tracking system for genome annotation. AB - BACKGROUND: As genome sequences are determined for increasing numbers of model organisms, demand has grown for better tools to facilitate unified genome annotation efforts by communities of biologists. Typically this process involves numerous experts from the field and the use of data from dispersed sources as evidence. This kind of collaborative annotation project requires specialized software solutions for efficient data tracking and processing. RESULTS: As part of the scale-up phase of the ENCODE project (Encyclopedia of DNA Elements), the aim of the GENCODE project is to produce a highly accurate evidence-based reference gene annotation for the human genome. The AnnoTrack software system was developed to aid this effort. It integrates data from multiple distributed sources, highlights conflicts and facilitates the quick identification, prioritisation and resolution of problems during the process of genome annotation. CONCLUSIONS: AnnoTrack has been in use for the last year and has proven a very valuable tool for large-scale genome annotation. Designed to interface with standard bioinformatics components, such as DAS servers and Ensembl databases, it is easy to setup and configure for different genome projects. The source code is available at http://annotrack.sanger.ac.uk. PMID- 20923552 TI - Variation and inheritance of iron reductase activity in the roots of common bean (Phaseolus vulgaris L.) and association with seed iron accumulation QTL. AB - BACKGROUND: Iron deficiency anemia is a global problem which often affects women and children of developing countries. Strategy I plants, such as common bean (Phaseolus vulgaris L.) take up iron through a process that involves an iron reduction mechanism in their roots; this reduction is required to convert ferric iron to ferrous iron. Root absorbed iron is critical for the iron nutrition of the plant, and for the delivery of iron to the shoot and ultimately the seeds. The objectives of this study were to determine the variability and inheritance for iron reductase activity in a range of genotypes and in a low * high seed iron cross (DOR364 x G19833), to identify quantitative trait loci (QTL) for this trait, and to assess possible associations with seed iron levels. RESULTS: The experiments were carried out with hydroponically grown plants provided different amounts of iron varying between 0 and 20 MUM Fe(III)-EDDHA. The parents, DOR364 and G19833, plus 13 other cultivated or wild beans, were found to differ in iron reductase activity. Based on these initial experiments, two growth conditions (iron limited and iron sufficient) were selected as treatments for evaluating the DOR364 * G19833 recombinant inbred lines. A single major QTL was found for iron reductase activity under iron-limited conditions (1 MUM Fe) on linkage group b02 and another major QTL was found under iron sufficient conditions (15 MUM Fe) on linkage group b11. Associations between the b11 QTL were found with several QTL for seed iron. CONCLUSIONS: Genes conditioning iron reductase activity in iron sufficient bean plants appear to be associated with genes contributing to seed iron accumulation. Markers for bean iron reductase (FRO) homologues were found with in silico mapping based on common bean synteny with soybean and Medicago truncatula on b06 and b07; however, neither locus aligned with the QTL for iron reductase activity. In summary, the QTL for iron reductase activity under iron limited conditions may be useful in environments where beans are grown in alkaline soils, while the QTL for iron reductase under sufficiency conditions may be useful for selecting for enhanced seed nutritional quality. PMID- 20923553 TI - Relating the shape of protein binding sites to binding affinity profiles: is there an association? AB - BACKGROUND: Various pattern-based methods exist that use in vitro or in silico affinity profiles for classification and functional examination of proteins. Nevertheless, the connection between the protein affinity profiles and the structural characteristics of the binding sites is still unclear. Our aim was to investigate the association between virtual drug screening results (calculated binding free energy values) and the geometry of protein binding sites. Molecular Affinity Fingerprints (MAFs) were determined for 154 proteins based on their molecular docking energy results for 1,255 FDA-approved drugs. Protein binding site geometries were characterized by 420 PocketPicker descriptors. The basic underlying component structure of MAFs and binding site geometries, respectively, were examined by principal component analysis; association between principal components extracted from these two sets of variables was then investigated by canonical correlation and redundancy analyses. RESULTS: PCA analysis of the MAF variables provided 30 factors which explained 71.4% of the total variance of the energy values while 13 factors were obtained from the PocketPicker descriptors which cumulatively explained 94.1% of the total variance. Canonical correlation analysis resulted in 3 statistically significant canonical factor pairs with correlation values of 0.87, 0.84 and 0.77, respectively. Redundancy analysis indicated that PocketPicker descriptor factors explain 6.9% of the variance of the MAF factor set while MAF factors explain 15.9% of the total variance of PocketPicker descriptor factors. Based on the salient structures of the factor pairs, we identified a clear-cut association between the shape and bulkiness of the drug molecules and the protein binding site descriptors. CONCLUSIONS: This is the first study to investigate complex multivariate associations between affinity profiles and the geometric properties of protein binding sites. We found that, except for few specific cases, the shapes of the binding pockets have relatively low weights in the determination of the affinity profiles of proteins. Since the MAF profile is closely related to the target specificity of ligand binding sites we can conclude that the shape of the binding site is not a pivotal factor in selecting drug targets. Nonetheless, based on strong specific associations between certain MAF profiles and specific geometric descriptors we identified, the shapes of the binding sites do have a crucial role in virtual drug design for certain drug categories, including morphine derivatives, benzodiazepines, barbiturates and antihistamines. PMID- 20923555 TI - Basic primitives for molecular diagram sketching. AB - A collection of primitive operations for molecular diagram sketching has been developed. These primitives compose a concise set of operations which can be used to construct publication-quality 2 D coordinates for molecular structures using a bare minimum of input bandwidth. The input requirements for each primitive consist of a small number of discrete choices, which means that these primitives can be used to form the basis of a user interface which does not require an accurate pointing device. This is particularly relevant to software designed for contemporary mobile platforms. The reduction of input bandwidth is accomplished by using algorithmic methods for anticipating probable geometries during the sketching process, and by intelligent use of template grafting. The algorithms and their uses are described in detail. PMID- 20923554 TI - RARalpha1 control of mammary gland ductal morphogenesis and wnt1-tumorigenesis. AB - INTRODUCTION: Retinoic acid signaling pathways are disabled in human breast cancer suggesting a controlling role in normal mammary growth that might be lost in tumorigenesis. We tested a single receptor isotype, RARalpha1, for its role in mouse mammary gland morphogenesis and MMTV-wnt1-induced oncogenesis. METHODS: The role of RARalpha1 in mammary morphogenesis was tested in RARalpha1-knockout (KO) mice and in mammary tumorigenesis in bi-genic (RARalpha1/KO crossed with MMTV wnt1) mice. We used whole mounts analysis, stem cells/progenitor quantification, mammary gland repopulation, Q-PCR, test of tumor-free survival, tumor fragments and cell transplantation. RESULTS: In 2 genetic backgrounds (129/Bl-6 and FVB) the neo-natal RARalpha1/KO-mammary epithelial tree was 2-fold larger and the pubertal tree had 2-fold more branch points and 5-fold more mature end buds, a phenotype that was predominantly epithelial cell autonomous. The stem/progenitor compartment of the RARalpha1/KO mammary, defined as CD24(low)/ALDH(high activity) was increased by a median 1.7 fold, but the mammary stem cell (MaSC)-containing compartment, (CD24(low)/CD29(high)), was larger (~1.5 fold) in the wt-glands, and the mammary repopulating ability of the wt-gland epithelium was ~2-fold greater. In MMTV-wnt1 transgenic glands the progenitor (CD24(low)/ALDH(high activity)) content was 2.6-fold greater than in the wt and was further increased in the RARalpha1/KO-wnt1 glands. The tumor-free survival of RARalpha1/KO-wnt1 mice was significantly (p=0.0002, Kaplan Meier) longer, the in vivo growth of RARalpha1/KO wnt1 transplanted tumor fragments was significantly (p=0.01) slower and RARalpha1/KO-wnt1 tumors cell suspension produced tumors after much longer latency. CONCLUSIONS: In vitamin A-replete mice, RARalpha1 is required to maintain normal mammary morphogenesis, but paradoxically, also efficient tumorigenesis. While its loss increases the density of the mammary epithelial tree and the content of luminal mammary progenitors, it appears to reduce the size of the MaSC-containing compartment, the mammary repopulating activity, and to delay significantly the MMTV-wnt1-mammary tumorigenesis. Whether the delay in tumorigenesis is solely due to a reduction in wnt1 target cells or due to additional mechanisms remains to be determined. These results reveal the intricate nature of the retinoid signaling pathways in mammary development and carcinogenesis and suggest that a better understanding will be needed before retinoids can join the armament of effective anti- breast cancer therapies. PMID- 20923556 TI - A novel mutation of the ACADM gene (c.145C>G) associated with the common c.985A>G mutation on the other ACADM allele causes mild MCAD deficiency: a case report. AB - A female patient, with normal familial history, developed at the age of 30 months an episode of diarrhoea, vomiting and lethargy which resolved spontaneously. At the age of 3 years, the patient re-iterated vomiting, was sub-febrile and hypoglycemic, fell into coma, developed seizures and sequels involving right hemi body. Urinary excretion of hexanoylglycine and suberylglycine was low during this metabolic decompensation. A study of pre- and post-prandial blood glucose and ketones over a period of 24 hours showed a normal glycaemic cycle but a failure to form ketones after 12 hours fasting, suggesting a mitochondrial beta-oxidation defect. Total blood carnitine was lowered with unesterified carnitine being half of the lowest control value. A diagnosis of mild MCAD deficiency (MCADD) was based on rates of 1-14C-octanoate and 9, 10-3H-myristate oxidation and of octanoyl-CoA dehydrogenase being reduced to 25% of control values. Other mitochondrial fatty acid oxidation proteins were functionally normal. De novo acylcarnitine synthesis in whole blood samples incubated with deuterated palmitate was also typical of MCADD. Genetic studies showed that the patient was compound heterozygous with a sequence variation in both of the two ACADM alleles; one had the common c.985A>G mutation and the other had a novel c.145C>G mutation. This is the first report for the ACADM gene c.145C>G mutation: it is located in exon 3 and causes a replacement of glutamine to glutamate at position 24 of the mature protein (Q24E). Associated with heterozygosity for c.985A>G mutation, this mutation is responsible for a mild MCADD phenotype along with a clinical story corroborating the emerging literature view that patients with genotypes representing mild MCADD (high residual enzyme activity and low urinary levels of glycine conjugates), similar to some of the mild MCADDs detected by MS/MS newborn screening, may be at risk for disease presentation. PMID- 20923557 TI - Design of the Prevention of Adult Caries Study (PACS): a randomized clinical trial assessing the effect of a chlorhexidine dental coating for the prevention of adult caries. AB - BACKGROUND: Dental caries is one of the primary causes of tooth loss among adults. It is estimated to affect a majority of Americans aged 55 and older, with a disproportionately higher burden in disadvantaged populations. Although a number of treatments are currently in use for caries prevention in adults, evidence for their efficacy and effectiveness is limited. METHODS/DESIGN: The Prevention of Adult Caries Study (PACS) is a multicenter, placebo-controlled, double-blind, randomized clinical trial of the efficacy of a chlorhexidine (10% w/v) dental coating in preventing adult caries. Participants (n = 983) were recruited from four different dental delivery systems serving four diverse communities, including one American Indian population, and were randomized to receive either chlorhexidine or a placebo treatment. The primary outcome is the net caries increment (including non-cavitated lesions) from baseline to 13 months of follow-up. A cost-effectiveness analysis also will be considered. DISCUSSION: This new dental treatment, if efficacious and approved for use by the Food and Drug Administration (FDA), would become a new in-office, anti-microbial agent for the prevention of adult caries in the United States. TRIAL REGISTRATION NUMBER: NCT00357877. PMID- 20923559 TI - Characterization of chaotic dynamics in the human menstrual cycle. AB - BACKGROUND: The human menstrual cycle is known to exhibit a significant amount of unexplained variability. This variation is typically dismissed as random fluctuations in an otherwise periodic and predictable system. Given the many delayed nonlinear feedbacks in the multiple levels of the reproductive endocrine system, however, the menstrual cycle can properly be construed as the output of a nonlinear dynamical system, and such a system has the possibility of being in a chaotic trajectory. We hypothesize that this is in fact the case and that it accounts for the observed variability. RESULTS: Here, we test this hypothesis by performing time series analyses on data for 7749 menstrual cycles from 40 women in the 20-40 year age range, using the database maintained by the Tremin Research Program on Women's Health. Both raw menstrual cycle length data and a formal time series constructed from this data are utilized in these analyses. Employing phase space reconstruction techniques with a maximum embedding dimension of 12, we find appropriate scaling behavior in the correlation sums for these data, indicating low dimensional deterministic dynamics. A correlation dimension of Dc ~ 5.2 is measured in the scaling regime. This result is confirmed by recalculation using the Takens estimator and by surrogate data tests. We interpret this result as an approximation to the fractal dimension of a strange attractor governing chaotic dynamics in the menstrual cycle. We also use the time series to calculate the correlation entropy (K2 ~ 0.008/tau) and the maximal Lyapunov exponent (lambda ~ 0.005/tau) for the system, where tau is the sampling time of the series. CONCLUSIONS: Taken collectively, these results constitute significant evidence that the menstrual cycle is the result of chaos in a nonlinear dynamical system. This view of the menstrual cycle has potential implications for clinical practice, modelling of the endocrine system, and the interpretation of the perimenopausal transition. PMID- 20923558 TI - Genomic organization and evolution of the Atlantic salmon hemoglobin repertoire. AB - BACKGROUND: The genomes of salmonids are considered pseudo-tetraploid undergoing reversion to a stable diploid state. Given the genome duplication and extensive biological data available for salmonids, they are excellent model organisms for studying comparative genomics, evolutionary processes, fates of duplicated genes and the genetic and physiological processes associated with complex behavioral phenotypes. The evolution of the tetrapod hemoglobin genes is well studied; however, little is known about the genomic organization and evolution of teleost hemoglobin genes, particularly those of salmonids. The Atlantic salmon serves as a representative salmonid species for genomics studies. Given the well documented role of hemoglobin in adaptation to varied environmental conditions as well as its use as a model protein for evolutionary analyses, an understanding of the genomic structure and organization of the Atlantic salmon alpha and beta hemoglobin genes is of great interest. RESULTS: We identified four bacterial artificial chromosomes (BACs) comprising two hemoglobin gene clusters spanning the entire alpha and beta hemoglobin gene repertoire of the Atlantic salmon genome. Their chromosomal locations were established using fluorescence in situ hybridization (FISH) analysis and linkage mapping, demonstrating that the two clusters are located on separate chromosomes. The BACs were sequenced and assembled into scaffolds, which were annotated for putatively functional and pseudogenized hemoglobin-like genes. This revealed that the tail-to-tail organization and alternating pattern of the alpha and beta hemoglobin genes are well conserved in both clusters, as well as that the Atlantic salmon genome houses substantially more hemoglobin genes, including non-Bohr beta globin genes, than the genomes of other teleosts that have been sequenced. CONCLUSIONS: We suggest that the most parsimonious evolutionary path leading to the present organization of the Atlantic salmon hemoglobin genes involves the loss of a single hemoglobin gene cluster after the whole genome duplication (WGD) at the base of the teleost radiation but prior to the salmonid-specific WGD, which then produced the duplicated copies seen today. We also propose that the relatively high number of hemoglobin genes as well as the presence of non-Bohr beta hemoglobin genes may be due to the dynamic life history of salmon and the diverse environmental conditions that the species encounters.Data deposition: BACs S0155C07 and S0079J05 (fps135): GenBank GQ898924; BACs S0055H05 and S0014B03 (fps1046): GenBank GQ898925. PMID- 20923560 TI - Intraperitoneal injection of thalidomide attenuates bone cancer pain and decreases spinal tumor necrosis factor-alpha expression in a mouse model. AB - BACKGROUND: Tumor necrosis factor alpha (TNF-alpha) may have a pivotal role in the genesis of mechanical allodynia and thermal hyperalgesia during inflammatory and neuropathic pain. Thalidomide has been shown to selectively inhibit TNF-alpha production. Previous studies have suggested that thalidomide exerts anti nociceptive effects in various pain models, but its effects on bone cancer pain have not previously been studied. Therefore, in the present study, we investigated the effect of thalidomide on bone cancer-induced hyperalgesia and up regulated expression of spinal TNF-alpha in a mouse model. RESULTS: Osteosarcoma NCTC 2472 cells were implanted into the intramedullary space of the right femurs of C3H/HeJ mice to induce ongoing bone cancer related pain behaviors. At day 5, 7, 10 and 14 after operation, the expression of TNF-alpha in the spinal cord was higher in tumor-bearing mice compared to the sham mice. Intraperitoneal injection of thalidomide (50 mg/kg), started at day 1 after surgery and once daily thereafter until day 7, attenuated bone cancer-evoked mechanical allodynia and thermal hyperalgesia as well as the up-regulation of TNF-alpha in the spinal cord. CONCLUSIONS: These results suggest that thalidomide can efficiently alleviate bone cancer pain and it may be a useful alternative or adjunct therapy for bone cancer pain. Our data also suggest a role of spinal TNF-alpha in the development of bone cancer pain. PMID- 20923561 TI - Abnormal function of the vasopressin-cyclic-AMP-aquaporin2 axis during urine concentrating and diluting in patients with reduced renal function. A case control study. AB - BACKGROUND: The kidneys ability to concentrate and dilute urine is deteriorated during progressive renal insufficiency. We wanted to test the hypothesis that these phenomena could be attributed to an abnormal function of the principal cells in the distal part of the nephron. METHODS: Healthy control subjects and patients with chronic kidney diseases were studied. Group 1 comprised healthy subjects, n = 10. Groups 2-4 comprised patients with chronic kidney disease (Group 2, n = 14, e-GFR <= 90 m1/min; Group 3, n = 11, 60 m1/min <= e-GFR < 90 ml/min; and Group 4, n = 16, 15 ml/min <= e-GFR < 60 ml/min). The subjects collected urine during 24 hours. A urine concentrating test was done by thirsting during the following 12 hours. Thereafter, a urine diluting test was performed with a water load of 20 ml/kg body weight. The effect variables were urinary excretions of aquaporin2 (u-AQP2), cyclic-AMP (u-c-AMP), urine volume (UV), free water clearance (CH2O), urine osmolarity (u-Osm), and plasma arginine vasopressin (p-AVP). RESULTS: After fluid deprivation, u-Osm increased. In all groups, UV and CH2O decreased and u-AQP2 and u-c-AMP increased in Groups 1 and 2, but were unchanged in Group 3 and 4. P-AVP was significantly higher in Group 4 than in the other groups. During urine diluting, UV and CH2O reached significantly higher levels in Groups 1-3 than Group 4. Both before and after water loading, u-AQP2 and p-AVP were significantly higher and u-c-AMP was significantly lower in Group 4 than the other groups. Estimated-GFR was correlated negatively to p-AVP and positively to u-c-AMP. CONCLUSIONS: Patients with moderately severe chronic kidney disease have a reduced renal concentrating and diluting capacity compared to both patients with milder chronic kidney disease and healthy control subjects. These phenomena can be attributed, at least partly, to an abnormally decreased response in the AVP-c-AMP-AQP2 axis.ClinicalTrials.Gov Identifier: NCT00313430. PMID- 20923562 TI - Lipid and lipoprotein profiles among middle aged male smokers: a study from southern India. AB - OBJECTIVES: The objectives were to investigate into the relationship between lipid profile including Apolipoprotein-A1 (Apo-A1) and Apolipoprotein-B (Apo-B) and smokers and to relate them with smoking pack years. MATERIALS AND METHODS: A total of 274 active male smokers without any other illnesses and age matched male healthy control subjects (78) with similar socio-cultural background were assessed for clinical details, dietary habits, physical activities, smoking and alcohol consumption. Standard methods were adopted to check the lipid levels. The data were analyzed statistically. RESULTS: Their ages ranged from 40 to 59 years, systolic BP from 110 to 130 mmHg, and diastolic BP from 76 to 88 mmHg. All of them had similar pattern of diet (vegetarianism with occasional meat). None was on any medication influences lipid level. Their physical activity was moderate. Number of pack years varied from 10 to 14 (mild), 15 to 19 (moderate) and 20 and above (heavy) among 69, 90 and 115 cases, whose mean ages were 43, 44 and 49 respectively. The mean (+SD) values in mg/dl of total cholesterol (TC), Triglyceride (TGL), Apo-B, low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol and Apo-A1 in mg/dl among mild/ moderate/ heavy smokers and control subjects were 198 (30.6)/ 224 (27.2)/ 240 (24.3) and 160 (20.4); 164(42.6)/ 199 (39.5)/ 223(41.7) and 124 (31.6); 119 (24.9)/ 121 (27)/ 127 (28.3) and 116 (21.4); 94 (19.7)/ 104 (21.8)/ 120 (20.5) and 82 (17.6); 42 (5.9)/ 39 (3.1)/ 35(4.4) and 48 (5.3); and 120 (17)/ 119 (21)/ 115 (25) and 126 (19), respectively. In smokers, there was a rise in TC, TGL, LDL, Apo-B and fall in HDL and Apo-A; these changes were significant (P < 0.05). CONCLUSION: Number of pack years was directly proportional to abnormal lipid profile. It is also concluded that changes in Apo-A1 and Apo-B were more significant when compared to HDL and LDL cholesterol among smokers. In the view of double risk for smokers (smoking and altered lipid profile) efforts may be made to introduce smoking cessation program. PMID- 20923563 TI - Interethnic diversity of NAT2 polymorphisms in Brazilian admixed populations. AB - BACKGROUND: N-acetyltransferase type 2 (Nat2) is a phase II drug- metabolizing enzyme that plays a key role in the bioactivation of aromatic and heterocyclic amines. Its relevance in drug metabolism and disease susceptibility remains a central theme for pharmacogenetic research, mainly because of its genetic variability among human populations. In fact, the evolutionary and ethnic specific SNPs on the NAT2 gene remain a focus for the potential discoveries in personalized drug therapy and genetic markers of diseases. Despite the wide characterization of NAT2 SNPs frequency in established ethnic groups, little data are available for highly admixed populations. In this context, five common NAT2 SNPs (G191A, C481T, G590A, A803G and G857A) were investigated in a highly admixed population comprised of Afro-Brazilians, Whites, and Amerindians in northeastern Brazil. Thus, we sought to determine whether the distribution of NAT2 polymorphism is different among these three ethnic groups. RESULTS: Overall, there were no statistically significant differences in the distribution of NAT2 polymorphism when Afro-Brazilian and White groups were compared. Even the allele frequency of 191A, relatively common in African descendents, was not different between the Afro-Brazilian and White groups. However, allele and genotype frequencies of G590A were significantly higher in the Amerindian group than either in the Afro-Brazilian or White groups. Interestingly, a haplotype block between G590A and A803G was verified exclusively among Amerindians. CONCLUSIONS: Our results indicate that ethnic admixture might contribute to a particular pattern of genetic diversity in the NAT2 gene and also offer new insights for the investigation of possible new NAT2 gene-environment effects in admixed populations. PMID- 20923564 TI - Accurate and efficient gp120 V3 loop structure based models for the determination of HIV-1 co-receptor usage. AB - BACKGROUND: HIV-1 targets human cells expressing both the CD4 receptor, which binds the viral envelope glycoprotein gp120, as well as either the CCR5 (R5) or CXCR4 (X4) co-receptors, which interact primarily with the third hypervariable loop (V3 loop) of gp120. Determination of HIV-1 affinity for either the R5 or X4 co-receptor on host cells facilitates the inclusion of co-receptor antagonists as a part of patient treatment strategies. A dataset of 1193 distinct gp120 V3 loop peptide sequences (989 R5-utilizing, 204 X4-capable) is utilized to train predictive classifiers based on implementations of random forest, support vector machine, boosted decision tree, and neural network machine learning algorithms. An in silico mutagenesis procedure employing multibody statistical potentials, computational geometry, and threading of variant V3 sequences onto an experimental structure, is used to generate a feature vector representation for each variant whose components measure environmental perturbations at corresponding structural positions. RESULTS: Classifier performance is evaluated based on stratified 10-fold cross-validation, stratified dataset splits (2/3 training, 1/3 validation), and leave-one-out cross-validation. Best reported values of sensitivity (85%), specificity (100%), and precision (98%) for predicting X4-capable HIV-1 virus, overall accuracy (97%), Matthew's correlation coefficient (89%), balanced error rate (0.08), and ROC area (0.97) all reach critical thresholds, suggesting that the models outperform six other state-of-the art methods and come closer to competing with phenotype assays. CONCLUSIONS: The trained classifiers provide instantaneous and reliable predictions regarding HIV 1 co-receptor usage, requiring only translated V3 loop genotypes as input. Furthermore, the novelty of these computational mutagenesis based predictor attributes distinguishes the models as orthogonal and complementary to previous methods that utilize sequence, structure, and/or evolutionary information. The classifiers are available online at http://proteins.gmu.edu/automute. PMID- 20923565 TI - Deaths of infants subject to forensic autopsy in Estonia from 2001 to 2005: what can we learn from additional information? AB - BACKGROUND: Deaths from childhood injury are a public health problem worldwide. A relatively high proportion of child deaths of undetermined manner in Estonia raises concerns about potential underestimation of intentional deaths, especially in infants. This suggests that more information on the circumstances surrounding death is needed to establish the manner of death correctly and, more importantly, to prevent these deaths. The objective of this study was to detect, describe, and analyze the circumstances around deaths of infants subject to forensic autopsy in Estonia to reveal hidden cases of child abuse and more accurately determine causes of death. METHODS: Study cases included all infant deaths in Estonia from 2001 to 2005 subject to forensic autopsy at the Estonian Bureau of Forensic Medicine. Additional information was obtained from a series of visits to general practitioners, including characteristics of infant health, family composition, parents' education and employment, living conditions, and circumstances around death as perceived by medical staff in charge of outpatient services for these families. RESULTS: The total number of infant deaths in Estonia between 2001 and 2005 subject to forensic autopsy was 98, with 40 (40.8%) deaths attributed to a disease and 58 deaths (59.2%) resulting from injury. Elements of child abuse were involved in as many as 57.7% (95% CI 46.9-68.1) of the deaths for which medical records were available (n = 90). At death, the majority of these cases were registered as diseases or deaths from unintentional injury. Average annual mortality from external causes in Estonian infants, 2001-2005, previously reported by us as 88.1 per 100,000 (95% CI 68.1-113.6) would decrease to 41.0 (95% CI 26.9-57.8).Many infants in the studied group had faced multiple threats and were living in poor hygienic conditions. In a number of cases, they were left alone or looked after by older siblings. Parents' alcohol abuse played an important role in a considerable number of cases. CONCLUSIONS: Using additional sources of information revealed new information about child abuse not reflected in the cause of death diagnosis. Effective interventions aimed at parent education and improved follow-up of children by medical staff may reduce mortality from external causes among Estonian infants by more than half. PMID- 20923566 TI - Oestrogen is important for maintenance of cartilage and subchondral bone in a murine model of knee osteoarthritis. AB - INTRODUCTION: Oestrogen depletion may influence onset and/or progression of osteoarthritis. We investigated in an ovariectomized mouse model the impact of oestrogen loss and oestrogen supplementation on articular cartilage and subchondral bone in tibia and patella, and assessed bone changes in osteoarthritis development. METHODS: C3H/HeJ mice were divided into four groups: sham-operated, oestrogen depletion by ovariectomy (OVX), OVX with estradiol supplementation (OVX+E) and OVX with bisphosphonate (OVX+BP). Each mouse had one knee injected with low-dose iodoacetate (IA), and the contralateral knee was injected with saline. Cartilage was analysed histologically 12 weeks postsurgery; bone changes were monitored over time using in vivo micro-computed tomography. RESULTS: In tibiae, OVX alone failed to induce cartilage damage, but OVX and IA combination significantly induced cartilage damage. In patellae, OVX alone induced significant cartilage damage, which was enhanced by IA. In both tibiae and patellae, OVX in combination with IA significantly decreased subchondral cortical thickness in an additive manner. OVX+E and OVX+BP inhibited tibial and patellar subchondral cortical thinning, inhibited patellar and tended to diminish tibial cartilage damage. In patellae, IA interacted with BP, leading to increased subchondral cortical and trabecular bone. CONCLUSIONS: This study demonstrates the significance of oestrogen for articular cartilage and subchondral bone and maintenance of healthy joints, supporting an etiological role for altered oestrogen signaling in osteoarthritis either by directly affecting cartilage or increasing susceptibility for an osteoarthritis trigger. The data strongly support the concept of involvement of subchondral bone plate in osteoarthritis. PMID- 20923567 TI - Raman spectroscopy in head and neck cancer. AB - In recent years there has been much interest in the use of optical diagnostics in cancer detection. Early diagnosis of cancer affords early intervention and greatest chance of cure. Raman spectroscopy is based on the interaction of photons with the target material producing a highly detailed biochemical 'fingerprint' of the sample. It can be appreciated that such a sensitive biochemical detection system could confer diagnostic benefit in a clinical setting. Raman has been used successfully in key health areas such as cardiovascular diseases, and dental care but there is a paucity of literature on Raman spectroscopy in Head and Neck cancer. Following the introduction of health care targets for cancer, and with an ever-aging population the need for rapid cancer detection has never been greater. Raman spectroscopy could confer great patient benefit with early, rapid and accurate diagnosis. This technique is almost labour free without the need for sample preparation. It could reduce the need for whole pathological specimen examination, in theatre it could help to determine margin status, and finally peripheral blood diagnosis may be an achievable target. PMID- 20923568 TI - Neuroprotective effect of peroxiredoxin 6 against hypoxia-induced retinal ganglion cell damage. AB - BACKGROUND: The ability to respond to changes in the extra-intracellular environment is prerequisite for cell survival. Cellular responses to the environment include elevating defense systems, such as the antioxidant defense system. Hypoxia-evoked reactive oxygen species (ROS)-driven oxidative stress is an underlying mechanism of retinal ganglion cell (RGC) death that leads to blinding disorders. The protein peroxiredoxin 6 (PRDX6) plays a pleiotropic role in negatively regulating death signaling in response to stressors, and thereby stabilizes cellular homeostasis. RESULTS: We have shown that RGCs exposed to hypoxia (1%) or hypoxia mimetic cobalt chloride display reduced expression of PRDX6 with higher ROS expression and activation of NF-kappaB. These cells undergo apoptosis, while cells with over-expression of PRDX6 demonstrate resistance against hypoxia-driven RGC death. The RGCs exposed to hypoxia either with 1% oxygen or cobalt chloride (0-400 MUM), revealed ~30%-70% apoptotic cell death after 48 and 72 h of exposure. Western analysis and real-time PCR showed elevated expression of PRDX6 during hypoxia at 24 h, while PRDX6 protein and mRNA expression declined from 48 h onwards following hypoxia exposure. Concomitant with this, RGCs showed increased ROS expression and activation of NF-kappaB with IkB phosphorylation/degradation, as examined with H2DCF-DA and transactivation assays. These hypoxia-induced adverse reactions could be reversed by over expression of PRDX6. CONCLUSION: Because an abundance of PRDX6 in cells was able to attenuate hypoxia-induced RGC death, the protein could possibly be developed as a novel therapeutic agent acting to postpone RGC injury and delay the progression of glaucoma and other disorders caused by the increased-ROS-generated death signaling related to hypoxia. PMID- 20923569 TI - Associations between SNPs in candidate immune-relevant genes and rubella antibody levels: a multigenic assessment. AB - BACKGROUND: The mechanisms of immune response are structured within a highly complex regulatory system. Genetic associations with variation in the immune response to rubella vaccine have typically been assessed one locus at a time. We simultaneously assessed the associations between 726 SNPs tagging 84 candidate immune response genes and rubella-specific antibody levels. Blood samples were obtained from 714 school-aged children who had received two doses of MMR vaccine. Associations between rubella-specific antibody levels and 726 candidate tagSNPs were assessed both one SNP at a time and in a variety of multigenic analyses. RESULTS: Single-SNP assessments identified 4 SNPs that appeared to be univariately associated with rubella antibody levels: rs2844482 (p = 0.0002) and rs2857708 (p = 0.001) in the 5'UTR of the LTA gene, rs7801617 in the 5'UTR of the IL6 gene (p = 0.0005), and rs4787947 in the 5'UTR of the IL4R gene (p = 0.002). While there was not significant evidence in favor of epistatic genetic associations among the candidate SNPs, multigenic analyses identified 29 SNPs significantly associated with rubella antibody levels when selected as a group (p = 0.017). This collection of SNPs included not only those that were significant univariately, but others that would not have been identified if only considered in isolation from the other SNPs. CONCLUSIONS: For the first time, multigenic assessment of associations between candidate SNPs and rubella antibody levels identified a broad number of genetic associations that would not have been deemed important univariately. It is important to consider approaches like those applied here in order to better understand the full genetic complexity of response to vaccination. PMID- 20923570 TI - Expression of inwardly rectifying potassium channels by an inducible adenoviral vector reduced the neuronal hyperexcitability and hyperalgesia produced by chronic compression of the spinal ganglion. AB - BACKGROUND: A chronic compressed dorsal root ganglion (CCD) in rat produces pain behavior and an enhanced excitability of neurons within the compressed ganglion. Kir2.1 is an inwardly rectifying potassium channel that acts to stabilize the resting potential of certain cell types. We hypothesized that an inducible expression of Kir2.1 channels in CCD neurons might suppress neuronal excitability in the dorsal root ganglion (DRG) and reduce the associated pain behavior. RESULTS: We delivered, by microinjection into the fourth lumbar (L4) DRG, an adenoviral vector containing a reporter gene encoding the enhanced green fluorescent protein (GFP) and a Kir2.1 channel (AdKir). At the same time the ganglion was compressed by implantation of a rod through the intervertebral foramen (CCD). The in vivo expression of the transferred gene was controlled by an ecdysone analog via an ecdysone-inducible promoter in the viral vector. In comparison with the effects of vehicle or a control vector containing only the GFP gene, AdKir significantly reduced the neuronal hyperexcitability after CCD. Electrophysiological recordings, in vivo, from nociceptive and non-nociceptive DRG neurons expressing the virally produced Kir2.1 channels revealed a hyperpolarized resting membrane potential, an increased rheobase, and lack of spontaneous activity. Inducing the Kir2.1 gene at the beginning of CCD surgery partially prevented the development of mechanical hyperalgesia. However, a delayed induction of the Kir2.1 gene (3 days after CCD surgery) produced no significant effect on the pain behavior. CONCLUSIONS: We found that an inducible expression of Kir2.1 channels in chronically compressed DRG neurons can effectively suppress the neuronal excitability and, if induced at the beginning of CCD injury, prevent the development of hyperalgesia. We hypothesize that a higher level of neuronal hyperexcitability in the DRG is required to initiate than to maintain the hyperalgesia and that the hyperexcitability contributing to neuropathic pain is best inhibited as soon as possible after injury. PMID- 20923571 TI - Evaluation of endogenous references for gene expression profiling in different tissues of the oriental fruit fly Bactrocera dorsalis (Diptera: Tephritidae). AB - BACKGROUND: quantitative real-time reverse transcriptase PCR (RT-qPCR) has been widely used for quantification of mRNA as a way to determine key genes involved in different biological processes. For accurate gene quantification analysis, normalization of RT-qPCR data is absolutely essential. To date, normalization is most frequently achieved by the use of internal controls, often referred to as reference genes. However, several studies have shown that the reference genes used for the quantification of mRNA expression can be affected by the experimental set-up or cell type resulting in variation of the expression level of these key genes. Therefore, the evaluation of reference genes is critical for gene expression profiling, which is often neglected in gene expression studies of insects. For this purpose, ten candidate reference genes were investigated in three different tissues (midgut, Malpighian tubules, and fat body) of the oriental fruit fly, Bactrocera dorsalis (Hendel). RESULTS: two different programs, geNorm and Normfinder, were used to analyze the data. According to geNorm, alpha-TUB + ACT5 are the most appropriate reference genes for gene expression profiling across the three different tissues in the female flies, while ACT3 + alpha-TUB are considered as the best for males. Furthermore, we evaluated the stability of the candidate reference genes to determine the sexual differences in the same tissue. In the midgut and Malpighian tubules, ACT2 + alpha-TUB are the best choice for both males and females. However, alpha-TUB + ACT1 are the best pair for fat body. Meanwhile, the results calculated by Normfinder are quite the same as the results with geNorm; alpha-TUB is always one of the most stable genes in each sample validated by the two programs. CONCLUSIONS: in this study, we validated the suitable reference genes for gene expression profiling in different tissues of B. dorsalis. Moreover, appropriate reference genes were selected out for gene expression profiling of the same tissues taking the sexual differences into consideration. This work not only formed a solid basis for future gene expression study in B. dorsalis, but also will serve as a resource to screen reference genes for gene expression studies in any other insects. PMID- 20923572 TI - Novel concept microarray enabling PCR and multistep reactions through pipette free aperture-to-aperture parallel transfer. AB - BACKGROUND: The microarray has contributed to developing the omic analysis. However, as it depends basically on the surface reaction, it is hard to perform bulk reactions and sequential multistep reactions. On the other hand, the popular microplate technology, which has a great merit of being able to perform parallel multistep reactions, has come to its limit in increasing the number of wells (currently, up to 9600) and reducing the volume to deal with due to the difficulty in operations. RESULTS: Here, we report a novel microarray technology which enables us to explore advanced applications, termed microarray-with manageable volumes (MMV). The technical essence is in the pipette-free direct parallel transfer from well to well performed by centrifugation, evading the evaporation and adsorption-losses during handling. By developing the MMV plate, accompanying devices and techniques, generation of multiple conditions (256 kinds) and performance of parallel multistep reactions, including PCR and in vitro translation reactions, have been made possible. These were demonstrated by applying the MMV technology to searching lysozyme-crystallizing conditions and selecting peptides aimed for Abeta-binding or cathepsin E-inhibition. CONCLUSIONS: With the introduction of a novel concept microarray (MMV) technology, parallel and multistep reactions in sub-MUL scale have become possible. PMID- 20923573 TI - Genetic and epigenetic characteristics of human multiple hepatocellular carcinoma. AB - BACKGROUND: Multiple carcinogenesis is one of the major characteristics of human hepatocellular carcinoma (HCC). The history of multiple tumors, that is, whether they derive from a common precancerous or cancerous ancestor or individually from hepatocytes, is a major clinical issue. Multiple HCC is clinically classified as either intratumor metastasis (IM) or multicentric carcinogenesis (MC). Molecular markers that differentiate IM and MC are of interest to clinical practitioners because the clinical diagnoses of IM and MC often lead to different therapies. METHODS: We analyzed 30 multiple tumors from 15 patients for somatic mutations of cancer-related genes, chromosomal aberrations, and promoter methylation of tumor suppressor genes using techniques such as high-resolution melting, array comparative genomic hybridization (CGH), and quantitative methylation-specific PCR. RESULTS: Somatic mutations were found in TP53 and CTNNB1 but not in CDKN2A or KRAS. Tumors from the same patient did not share the same mutations. Array-CGH analysis revealed variations in the number of chromosomal aberrations, and the detection of common aberrations in tumors from the same patient was found to depend on the total number of chromosomal aberrations. A promoter methylation analysis of genes revealed dense methylation in HCC but not in the adjacent non tumor tissue. The correlation coefficients (r) of methylation patterns between tumors from the same patient were more similar than those between tumors from different patients. In total, 47% of tumor samples from the same patients had an r >= 0.8, whereas, in contrast, only 18% of tumor samples from different patients had an r >= 0.8 (p = 0.01). All IM cases were highly similar; that is, r >= 0.8 (p = 0.025). CONCLUSIONS: The overall scarcity of common somatic mutations and chromosomal aberrations suggests that biological IM is likely to be rare. Tumors from the same patient had a methylation pattern that was more similar than those from different patients. As all clinical IM cases exhibited high similarity, the methylation pattern may be applicable to support the clinical diagnosis of IM and MC. PMID- 20923575 TI - Levels of (1->3)-beta-D-glucan, Candida mannan and Candida DNA in serum samples of pediatric cancer patients colonized with Candida species. AB - BACKGROUND: Surveillance cultures may be helpful in identifying patients at increased risk of developing invasive candidiasis. However, only scant information exists on the effect of Candida colonization on serum levels of diagnostic biomarkers. This prospective surveillance study determined the extent of Candida colonization among pediatric cancer patients and its possible impact on serum levels of (1-3)-beta-D-glucan (BDG), Candida mannan and Candida DNA. METHODS: A total of 1075 swabs originating from oropharynx (n = 294), nostrils (n = 600), rectum (n = 28), groin (n = 50), ear (n = 54), and axilla (n = 49) of 63 pediatric cancer patients were cultured for the isolation of Candida spp. Patients yielding Candida spp. from any sites were considered as colonized. Serum samples were collected from patients at the time of first surveillance culture for detection of BDG by Fungitell kit and Candida mannan by Platelia Candida Ag. Candida DNA was detected by using panfungal primers and identification was carried out by using species-specific primers and DNA sequencing. RESULTS: Seventy-five (7.6%) swab cultures from 35 (55.5%) patients yielded Candida spp. These isolates included C. albicans (n = 62), C. dubliniensis (n = 8), C. glabrata and C. tropicalis (n = 2 each) and C. krusei (n = 1). Eleven patients were colonized at three or more sites. Eight of 36 serum samples from 6 colonized patients yielded BDG values higher than the currently recommended cut-off value of >=80 pg/ml. However, none of the serum samples yielded Candida mannan levels >=0.5 ng/ml and PCR test for Candida DNA was also negative in all the serum samples of colonized patients. During the study period, only two colonized patients subsequently developed candidemia due to C. tropicalis. Besides positive blood cultures, C. tropicalis DNA, BDG and Candida mannan were also detected in serum samples of both the patients. CONCLUSIONS: The present study demonstrates that while mucosal colonization with Candida species in pediatric cancer patients is common, it does not give rise to diagnostically significant levels of Candida mannan or Candida DNA in serum specimens. However, BDG values may be higher than the cut-off value in some pediatric patients without clinical evidence of invasive Candida infection. The study suggests the utility of Candida mannan or Candida DNA in the diagnosis of invasive candidiasis, however, the BDG levels in pediatric cancer subjects should be interpreted with caution. PMID- 20923574 TI - GPI-anchored single chain Fv--an effective way to capture transiently-exposed neutralization epitopes on HIV-1 envelope spike. AB - BACKGROUND: Identification of broad neutralization epitopes in HIV-1 envelope spikes is paramount for HIV-1 vaccine development. A few broad neutralization epitopes identified so far are present on the surface of native HIV-1 envelope spikes whose recognition by antibodies does not depend on conformational changes of the envelope spikes. However, HIV-1 envelope spikes also contain transiently exposed neutralization epitopes, which are more difficult to identify. RESULTS: In this study, we constructed single chain Fvs (scFvs) derived from seven human monoclonal antibodies and genetically linked them with or without a glycosyl phosphatidylinositol (GPI) attachment signal. We show that with a GPI attachment signal the scFvs are targeted to lipid rafts of plasma membranes. In addition, we demonstrate that four of the GPI-anchored scFvs, but not their secreted counterparts, neutralize HIV-1 with various degrees of breadth and potency. Among them, GPI-anchored scFv (X5) exhibits extremely potent and broad neutralization activity against multiple clades of HIV-1 strains tested. Moreover, we show that GPI-anchored scFv (4E10) also exhibited more potent neutralization activity than its secretory counterpart. Finally, we demonstrate that expression of GPI anchored scFv (X5) in the lipid raft of plasma membrane of human CD4+ T cells confers long-term resistance to HIV-1 infection, HIV-1 envelope-mediated cell cell fusion, and the infection of HIV-1 captured and transferred by human DCs. CONCLUSIONS: Thus GPI-anchored scFv could be used as a general and effective way to identify antibodies that react with transiently-exposed neutralization epitopes in envelope proteins of HIV-1 and other enveloped viruses. The GPI anchored scFv (X5), because of its breadth and potency, should have a great potential to be developed into anti-viral agent for HIV-1 prevention and therapy. PMID- 20923576 TI - Association of the LIPG 584C > T polymorphism and serum lipid levels in the Guangxi Bai Ku Yao and Han populations. AB - BACKGROUND: Endothelial lipase (EL) is a major determinant of high-density lipoprotein-cholesterol (HDL-C) metabolism, but the association of endothelial lipase gene (LIPG) polymorphism and serum HDL-C levels is scarce and conflicting in diverse populations. Bai Ku Yao is an isolated subgroup of the Yao minority in China. This study was designed to detect the association of LIPG 584C > T (rs2000813) polymorphism and several environmental factors with serum lipid levels in the Guangxi Bai Ku Yao and Han populations. METHODS: A total of 645 subjects of Bai Ku Yao and 638 participants of Han Chinese were randomly selected from our previous stratified randomized cluster samples. Genotyping of the LIPG 584C > T was performed by polymerase chain reaction and restriction fragment length polymorphism combined with gel electrophoresis, and then confirmed by direct sequencing. RESULTS: The levels of serum total cholesterol (TC), HDL-C, low-density lipoprotein cholesterol (LDL-C) and apolipoprotein (Apo) AI and ApoB were lower in Bai Ku Yao than in Han (P < 0.05 - 0.001). The frequency of C and T alleles was 73.5% and 26.5% in Bai Ku Yao, and 67.9% and 32.1% in Han (P < 0.01); respectively. The frequency of CC, CT and TT genotypes was 50.4%, 46.2% and 3.4% in Bai Ku Yao, and 41.4%, 53.1% and 5.5% in Han (P < 0.01); respectively. Serum HDL-C levels in both ethnic groups were different among the three genotypes (P < 0.05 for each). Serum TC levels in both ethnic groups were also different between the CC and CT/TT genotypes (P < 0.05 for each). The T allele carriers had higher serum HDL-C and TC levels than the T allele noncarriers. Multivariate logistic regression analysis showed that the levels of HDL-C and ApoB were correlated with genotypes in Bai Ku Yao (P < 0.05 for each), whereas the levels of TC and HDL-C were associated with genotypes in Han Chinese (P < 0.05 and P < 0.01). Serum lipid parameters were also correlated with several environmental factors in the both ethnic groups. CONCLUSIONS: The frequency of LIPG 584T allele is lower in Bai Ku Yao than in Han Chinese. The LIPG 584T allele is associated with increased serum HDL-C, TC and ApoB levels. The differences in serum HDL-C, TC and ApoB levels between the two ethnic groups might partly result from different genotypic and allelic frequencies of LIPG 584C > T or different LIPG-enviromental interactions. PMID- 20923577 TI - Phase II trial of isotonic fluid resuscitation in Kenyan children with severe malnutrition and hypovolaemia. AB - BACKGROUND: Children with severe malnutrition who develop shock have a high mortality. Contrary to contemporaneous paediatric practice, current guidelines recommend use of low dose hypotonic fluid resuscitation (half-strength Darrows/5% dextrose (HSD/5D). We evaluated the safety and efficacy of this guideline compared to resuscitation with a standard isotonic solution. METHODS: A Phase II randomised controlled, safety and efficacy trial in Kenyan children aged over 6 months with severe malnutrition and shock including children with severe dehydration/shock and presumptive septic shock (non-diarrhoeal shock). Eligible children were randomised to HSD/5D or Ringer's Lactate (RL). A maximum of two boluses of 15 ml/kg of HSD/5D were given over two hours (as recommended by guidelines) while those randomised to RL received 10 ml/kg aliquots half hourly (maximum 40 ml/kg). Primary endpoint was resolution of shock at 8 and 24 hours. Secondary outcomes included resolution of acidosis, adverse events and mortality. RESULTS: 61 children were enrolled: 41 had shock and severe dehydrating diarrhoea, 20 had presumptive septic shock; 69% had decompensated shock. By 8 hours response to volume resuscitation was poor with shock persisting in most children:-HSD/5D 15/22 (68%) and RL14/25 (52%), p = 0.39. Oliguria was more prevalent at 8 hours in the HSD/5D group, 9/22 (41%), compared to RL-3/25 (12%), p = 0.02. Mortality was high, HSD/5D-15/26(58%) and RL 13/29(45%); p = 0.42. Most deaths occurred within 48 hours of admission. Neither pulmonary oedema nor cardiogenic failure was detected. CONCLUSIONS: Outcome was universally poor characterised by persistence of shock, oliguria and high case fatality. Isotonic fluid was associated with modest improvement in shock and survival when compared to HSD/5D but inconclusive due to the limitations of design and effectiveness of either resuscitation strategy. Although isotonic fluid resuscitation did not result in cardiogenic heart failure, as previously feared, we conclude that the modest volumes used and rate of infusion were insufficient to promptly correct shock. The adverse performance of the recommended fluid resuscitation guideline for severe malnutrition should prompt clinical investigation of isotonic fluids for resuscitation of compensated shock, defining rate and volumes required to inform future guidelines. TRIAL REGISTRATION: The trial is registered as ISCRTN: 61146418. PMID- 20923579 TI - Current standards for the storage of human samples in biobanks. AB - Biobanks are diverse in their design and purpose; the idea of fully harmonizing historical and future biobanks is unaffordable and unfeasible. Biobanks should focus their efforts instead on developing and maintaining high-quality collections of samples capable of providing a wide range of biological information using processes that minimize introduced variability. A full data audit trail on sample processing, archiving, and quality control procedures should also be provided. This should enable the data derived from biobanks to contribute as part of wider collaborative efforts with other similar resources. PMID- 20923578 TI - Genetically complex epilepsies, copy number variants and syndrome constellations. AB - Epilepsy is one of the most common neurological disorders, with a prevalence of 1% and lifetime incidence of 3%. There are numerous epilepsy syndromes, most of which are considered to be genetic epilepsies. Despite the discovery of more than 20 genes for epilepsy to date, much of the genetic contribution to epilepsy is not yet known. Copy number variants have been established as an important source of mutation in other complex brain disorders, including intellectual disability, autism and schizophrenia. Recent advances in technology now facilitate genome wide searches for copy number variants and are beginning to be applied to epilepsy. Here, we discuss what is currently known about the contribution of copy number variants to epilepsy, and how that knowledge is redefining classification of clinical and genetic syndromes. PMID- 20923580 TI - Stem cell banking: between traceability and identifiability. AB - Stem cell banks are increasingly seen as an essential resource of biological materials for both basic and translational research. Stem cell banks support transnational access to quality-controlled and ethically sourced stem cell lines from different origins and of varying grades. According to the Organisation for Economic Co-operation and Development, advances in regenerative medicine are leading to the development of a bioeconomy, 'a world where biotechnology contributes to a significant share of economic output'. Consequently, stem cell banks are destined to constitute a pillar of the bioeconomy in many countries. While certain ethical and legal concerns are specific to the nature of stem cells, stem cell banking could do well to examine the approaches fostered by tissue banking generally. Indeed, the past decade has seen a move to simplify and harmonize biological tissue and data banking so as to foster international interoperability. In particular, the issues of consent and of traceability illustrate not only commonalities but the opportunity for stem cell banking to appreciate the lessons learned in biobanking generally. This paper analyzes convergence and divergence in issues surrounding policy harmonization, transnational sharing, informed consent, traceability and return of results in the context of stem cell banks. PMID- 20923581 TI - Products deriving from microbial fermentation are linked to insulinaemic response in pigs fed breads prepared from whole-wheat grain and wheat and rye ingredients. AB - The effects of wheat and rye breads made from whole-wheat grain (WWG), wheat aleurone flour (WAF) or rye aleurone flour (RAF) on net portal absorption of carbohydrate-derived nutrients (glucose, SCFA and lactate) and apparent insulin secretion were studied in a model experiment with catheterised pigs. The breads were similar in dietary fibre (DF, 120-125 g/kg DM) but differed in arabinoxylans (50-62 g/kg), beta-glucans (4-9 g/kg) and content of soluble DF (13-29 g/kg). Six pigs in a repeated 3 * 3 crossover design were fitted with catheters in the portal vein and the mesenteric artery and a portal flow probe. Pigs were fed three meals daily (at 09.00, 14.00 and 19.00 hours), and blood profiles were collected repeatedly from 08.30 until 19.00 hours once weekly. Net portal absorption of glucose was similar among breads and between meals. In contrast, insulin secretion was lowest (P < 0.05) in pigs fed RAF bread (3.9 nmol/h), intermediate in pigs fed WAF bread (5.4 nmol/h) and highest in pigs fed WWG bread (5.9 nmol/h), indicating that RAF bread improved insulin economy. Portal concentrations of propionate, butyrate and valerate were high, intermediate and low (P < 0.05) when pigs were fed RAF, WAF and WWG breads, respectively. Insulin secretion was higher (P < 0.001), and portal absorption of SCFA was lower (P < 0.05) after the first daily meal than after the second daily meal (8.8 v. 4.4 nmol/h). A low insulin response was associated with high portal absorption of SCFA. In conclusion, RAF bread was able to improve insulin economy compared to WWG bread. PMID- 20923582 TI - Hypocholesterolaemic effect of dietary inclusion of two putative probiotic bile salt hydrolase-producing Lactobacillus plantarum strains in Sprague-Dawley rats. AB - The purpose of the present study was to evaluate the anti-hypercholesterolaemic effects of two putative probiotic bile salt hydrolase (Bsh)-producing Lactobacillus plantarum strains, i.e. Lp91 and Lp21, in rats. L. plantarum Lp91 exhibited excellent tolerance to low pH and high bile salt concentrations as well as showed potential Bsh activity, cholesterol assimilation and cholesterol co precipitation ability along with L. plantarum Lp21 and NCDO82 strains. Furthermore, the potential effect of L. plantarum Lp91 on plasma cholesterol level was evaluated in Sprague-Dawley rats. Five treatment groups of rats (n 6) were fed experimental diets: normal diet, hypercholesterolaemic diet (HD), HD plus L. plantarum Lp91 (HD91) at >= 1.0 * 108 colony-forming units (cfu)/g, HD plus microencapsulated L. plantarum Lp91 (HDCap91) at >= 1.0 * 108 cfu/g and HD plus L. plantarum Lp21 (HD21) at >= 1.0 * 108 cfu/g for 3 weeks. Feed intake and feed efficiency differed significantly among the five groups. After 21 d of dietary treatment, comparative analysis revealed 23.26, 15.71 and 15.01 % reduction in total cholesterol, 21.09, 18.77 and 18.17 % reduction in TAG, 38.13, 23.22 and 21.42 % reduction in LDL-cholesterol, and the corresponding HDL cholesterol values increased at the rate of 18.94, 10.30 and 7.78 % in treated groups HD91, HDCap91 and HD21, respectively. Faecal excretion of cholic acid and faecal lactobacilli counts were significantly higher in the probiotic treatment groups than in the control groups. In conclusion, these results suggest that the indigenous L. plantarum Lp91 strain has the potential to be explored as a probiotic in the management of hypercholesterolaemia. PMID- 20923583 TI - Elaphostrongylus cervi in a population of red deer (Cervus elaphus) and evidence of cerebrospinal nematodiasis in small ruminants in the province of Varese, Italy. AB - Thirty-one faecal samples were collected from red deer in the northern area of Varese, in the Italian region of Lombardy, between August and October 2008. The animals had either been hunted or accidently killed. Examination for internal parasites showed a prevalence of 45.2% for Elaphostrongylus cervi larvae and species identification was confirmed by polymerase chain reaction (PCR). Ninety seven faecal samples were also collected from two goat flocks grazing in the same area between December 2007 and May 2008. These showed a prevalence of 74.7% for lungworms. Furthermore, the central nervous systems from five goats and one sheep from this area with a history of neurologically related lameness were examined. Histopathology confirmed E. cervi cerebro-spinal nematodiasis in five cases out of six. This study demonstrates E. cervi transmission from wild to domestic ruminants when the animals graze in the same area, and the possible occurrence of clinical disease in infected goats and sheep associated with high prevalence in deer. PMID- 20923584 TI - Information needs of health technology assessment units and agencies in Spain. AB - OBJECTIVES: The aim of this study was to analyze the information needs of Spanish health technology assessment (HTA) agencies and units to facilitate access to the resources they require to substantiate their reports. METHODS: A questionnaire was designed and distributed among HTA bodies to ascertain the actual situation of subscriptions to information resources and what information specialists from these bodies considered would be the ideal subscription situation. Their information needs were then studied, and the resources that best met these needs were put forward. Following this definition, a subscriptions policy was adopted with suppliers and publishers. RESULTS: The survey showed that HTA bodies share a minimum of core subscriptions that includes open sources (MEDLINE, DARE) and sources that the government subscribes to for the health community (ISI Web of Science, Cochrane Library Plus). There was no common approach to determining which databases to subscribe to (UpToDate, EMBASE, Ovid EBMR, CINAHL, or ECRI). After identifying the information needs, a list of resources was proposed that would best cover these needs and, of these, subscription to the following was proposed: Scopus, Ovid EBMR, Clinical Evidence, DynaMed, ECRI, and Hayes. CONCLUSIONS: There are differences in the way that HTA agencies and units access the different resources of biomedical information. Combined subscription to several resources for documentation services was suggested as a way of resolving these differences. PMID- 20923585 TI - Information on ethical issues in health technology assessment: how and where to find them. AB - BACKGROUND: Comprehensive health technology assessments (HTAs) include thorough reflections on ethical issues associated with health technologies, their use, and value-based decisions in the assessment process. As methods of information retrieval for effectiveness assessments are not applicable to information retrieval on ethical issues, a specific methodological approach is necessary. OBJECTIVES: In the absence of existing adapted methods, our objective was to develop a methodological approach for the systematic retrieval of information on ethical issues related to health technologies. METHOD AND RESULTS: A literature search was conducted to verify the non-existence of published comprehensive methodological approaches for the information retrieval on ethical issues for HTAs, and resulted in no hits. We, therefore, developed a step-by-step workflow following the workflow of information retrieval for effectiveness assessments: Step 1: Translation of the search question using the PICO scheme and additional components. Step 2: Concept building by modeling and linking search components. Step 3: Identification of synonyms in all relevant languages. Step 4: Selection of relevant information sources. Step 5: Design of search strategies for bibliographic databases. Step 6: Execution of search strategies and information seeking, including hand-searching. Step 7: Saving of retrieval results and standardized reporting of the process and results. Step 8: Final quality check and calculation of precision and recall. CONCLUSIONS: Systematic searching for information on ethical issues related to health technologies can be performed following the common retrieval workflow for effectiveness assessments, but should be performed separately applying adapted procedures and search terms on ethical issues relevant to the research question. PMID- 20923586 TI - How much searching is enough? Comprehensive versus optimal retrieval for technology assessments. AB - OBJECTIVES: The aim of this study is to review briefly different methods for determining the optimal retrieval of studies for inclusion in a health technology assessment (HTA) report. METHODS: This study reviews the methodology literature related to specific methods for evaluating yield from literature searching strategies and for deciding whether to continue or desist in the searching process. RESULTS: Eight different methods were identified. These include using the Capture-recapture technique; obtaining Feedback from the commissioner of the HTA report; seeking the Disconfirming case; undertaking comparison against a known Gold standard; evaluating retrieval of Known items; recognizing the Law of diminishing returns, specifying a priori Stopping rules, and identifying a point of Theoretical saturation. CONCLUSIONS: While this study identified a variety of possible methods, there has been very little formal evaluation of the specific strengths and weaknesses of the different techniques. The author proposes an evaluation agenda drawing on an examination of existing data together with exploration of the specific impact of missing relevant studies. PMID- 20923587 TI - Centre for Reviews and Dissemination databases: value, content, and developments. AB - BACKGROUND: The Centre for Reviews and Dissemination (CRD) funded through the United Kingdom National Institute for Health Research undertakes systematic reviews evaluating the research evidence on health and public health questions of national and international importance. CRD is involved in methods research and produces internationally accepted guidelines for undertaking systematic reviews. A core product of the Centre are the CRD databases; a key resource for health professionals, policy makers, and researchers around the world. Research evidence evaluating the effects and cost-effectiveness of healthcare interventions is growing year on year, and can be difficult and time consuming to identify and appraise. The databases assist decision makers by systematically identifying and critically describing systematic reviews and economic evaluations, appraising their quality and highlighting their relative strengths and weaknesses; and providing a comprehensive listing of ongoing and published health technology assessments. METHODS AND RESULTS: This article briefly outlines the processes behind each of the three databases, gives details of the records, the information they contain and the value added by CRD. An overview of the new public interface for the CRD databases to be launched later this year is given. Improvements and innovations to supplement existing functions are listed, including enhanced and new search options, the addition of quick links to relevant material from within individual records, an integrated PubMed search and the ability to select personal preferences. CONCLUSIONS: CRD's databases provide free access to an important knowledge base and are used widely to underpin evidence informed healthcare decisions in the United Kingdom and internationally. PMID- 20923588 TI - Classification of evidence in decision-analytic models of cost-effectiveness: a content analysis of published reports. AB - OBJECTIVES: The aim of this study was to assess systematically the scope of evidence and purposes for which evidence is used in decision-analytic models of cost-effectiveness and to assess the implications for search methods. METHODS: A content analysis of published reports of models was undertaken. Details of cited sources were extracted and categorized according to three dimensions; type of information provided by the evidence, type of source from which the evidence was drawn and type of modeling activity supported by the evidence. The analysis was used to generate a classification of evidence. Relationships within and between the categories within the classification were sought and the implications for searching considered. RESULTS: The classification generated fourteen types of information, seven types of sources of evidence and five modeling activities supported by evidence. A broad range of evidence was identified drawn from a diverse range of sources including both research-based and non-research-based sources. The use of evidence was not restricted to the population of model parameters but was used to inform the development of the modeling framework and to justify the analytical and methodological approach. CONCLUSIONS: Decision analytic models use evidence to support all aspects of model development. The classification of evidence defines in depth the role of evidence in modeling. It can be used to inform the systematic identification of evidence. PMID- 20923589 TI - Information retrieval for health technology assessment: standardization of search methods. PMID- 20923590 TI - Percutaneous radiofrequency ablation for the treatment of early stage hepatocellular carcinoma: a health technology assessment. AB - OBJECTIVES: The aim of this study was to compare the clinical effectiveness and cost of percutaneous radiofrequency ablation (PRFA) and surgical resection (SRS) for the management of early stage Hepatocellular Carcinoma. METHODS: A systematic literature search of articles in English, French, and Chinese was performed using online databases. Only articles with patients classified as Child-Pugh Class A or B, with tumor size <5 cm were included. A meta-analysis was carried out to estimate the survival rate and disease-free survival rate following PRFA or SRS treatments. The cost of each treatment was estimated from the third party perspective. Univariate sensitivity analyses were used to study the relative importance of each component cost. RESULTS: We identified six studies (one randomized controlled trial (RCT) and five comparative cohort studies) meeting our inclusion criteria. There is good evidence that among Child-Pugh A patients for whom both SRS and PRFA are available options, survival rates following either procedure are comparable, while complications are more frequent and hospitalization longer following SRS. The evidence concerning recurrence rates and disease-free survival is less clear. Whereas the RCT indicates comparable outcomes with either procedure up to 3 years, the results of five cohort studies (with possible selection bias), particularly those with a mix of Child-Pugh A and B patients, favor the surgical option. SRS, costs approximately Canadian $8,275 more per case than PRFA. CONCLUSIONS: Continuing doubts on this issue can only be resolved by a substantial RCT. Meanwhile, for early stage HCC patients classified as Child-Pugh A, who despite a possibly higher recurrence rate, prefer the less invasive PRFA to open surgery with its attendant risks, there is sufficient evidence to justify such a choice. For those classified as Child-Pugh (B) it is possible that overall survival is equally good with PRFA, but the evidence is less certain. PMID- 20923591 TI - Perceptions and attitudes of hospital staff toward paging system and the use of mobile phones. AB - OBJECTIVES: Our objective was to document the pattern of mobile phone usage by medical staff in a hospital setting, and to explore any perceived benefits (such as improved communications) associated with mobile phones. METHODS: This cross sectional survey was conducted in Waterford Regional Hospital, Ireland, where bleep is the official system of communication. All non-consultant hospital doctors, of medical disciplines only, were asked to participate. The questionnaire was designed to explore the pattern and different aspects of mobile phone usage. RESULTS: At the time of study, there were sixty medical junior doctors, and the response rate was 100 percent. All participants used mobile phones while at work, and also for hospital-related work. For 98.3 percent the mobile phone was their main mode of communication while in the hospital. Sixty two percent (n = 37) made 6-10 calls daily purely for work-related business, and this comprised of >= 80 percent of their daily usage of mobile phones. For 98 percent of participants, most phone calls were work-related. Regarding reasons for using mobile phones, all reported that using mobile phone is quicker for communication. CONCLUSIONS: Mobile phone usage is very common among the medical personnel, and this is regarded as a more efficient means of communication for mobile staff than the hospital paging system. PMID- 20923592 TI - Supporting the use of health technology assessments in policy making about health systems. AB - OBJECTIVES: The objective of this study is to profile the health technology assessments (HTAs) produced in Canada and other selected countries and assess their potential to inform policy making about health systems in jurisdictions other than the ones for which they were produced, and to develop and pilot test prototypes for packaging and assessing the relevance of HTAs for health system managers and policy makers. METHODS: We compiled an inventory of all HTAs that were produced by nine HTA agencies between September 2003 and August 2006; coded the title and abstract of each HTA according to the technologies assessed, methods used, and whether or not context-specific actionable messages were provided; developed a prototype for a structured, decision-relevant HTA summary and for a relevance-assessment form; and pilot-tested the prototypes using semistructured telephone interviews with a purposive sample of Canadian healthcare managers and policy makers. RESULTS: Our review of the 223 HTAs identified that: (i) 44 HTAs addressed health system arrangements (20 percent); (ii) 205 incorporated a systematic review (92 percent), whereas only 12 incorporated a sociopolitical assessment using explicit methods (5 percent); and (iii) 50 contained context-specific actionable messages (22 percent). Our interviews identified significant support for both the general idea of an HTA summary and the prototype's specific elements, but mixed views about using peer assessments of relevance. CONCLUSIONS: Those involved in supporting the use of HTAs in policy making about health systems may wish to produce structured decision-relevant summaries for their systematic review-containing HTAs to increase the prospects for their HTAs being used outside the jurisdiction for which they were produced. PMID- 20923593 TI - Implanting inequality: empirical evidence of social and ethical risks of implantable radio-frequency identification (RFID) devices. AB - OBJECTIVES: The aim of this study was to assess empirically the social and ethical risks associated with implantable radio-frequency identification (RFID) devices. METHODS: Qualitative research included observational studies in twenty three U.S. hospitals that have implemented new patient identification systems and eighty semi-structured interviews about the social and ethical implications of new patient identification systems, including RFID implants. RESULTS: The study identified three primary social and ethical risks associated with RFID implants: (i) unfair prioritization of patients based on their participation in the system, (ii) diminished trust of patients by care providers, and (iii) endangerment of patients who misunderstand the capabilities of the systems. CONCLUSIONS: RFID implants may aggravate inequalities in access to care without any clear health benefits. This research underscores the importance of critically evaluating new healthcare technologies from the perspective of both normative ethics and empirical ethics. PMID- 20923594 TI - Longitudinal strain and strain rate by tissue Doppler are more sensitive indices than fractional shortening for assessing the reduced myocardial function in asphyxiated neonates. AB - The function of the heart was studied in 20 asphyxiated term neonates by measuring the longitudinal peak systolic strain and peak systolic strain rate by tissue Doppler in 18 segments of the heart on days 1, 2, and 3 of life. The fractional shortening was assessed at each examination as well. Measurements were compared against measurements in 48 healthy term neonates examined by the same protocol. The function of the heart was lower in the asphyxiated neonates - peak systolic strain (mean (95% confidence interval) -19.4% (-20.4, -18.5), peak systolic strain rate -1.65 (-1.74, -1.56) per second) than in the healthy term neonates (peak systolic strain -21.7% (-22.3, -21.0), peak systolic strain rate 1.78 (-1.84, -1.74) per second; p < 0.001). Fractional shortening was similar in the asphyxiated (29.2% (26.8, 31.5)) and healthy term neonates (29.0% (27.9, 30.1); p = 0.874). The peak systolic strain differed significantly between the asphyxiated and healthy term neonates for the left basal and right basal groups of segments (p < 0.05) but not for the left apical, right apical, septum apical, or septum basal groups of segments. The peak systolic strain rate differed significantly only for the septum apical group of segments. The differences were largest on the second day of life. Measurements were similar in asphyxiated neonates with elevated and normal cardiac troponin T levels. The peak systolic strain and strain rate were in this study more sensitive indices than fractional shortening for assessing the reduced myocardial function in asphyxiated term neonates. PMID- 20923595 TI - Ten-year experience with surgical treatment of adults with congenital cardiac disease. AB - The number of adults with congenital cardiac disease continues to increase, and adult patients are now more numerous than paediatric patients. We sought to identify risk factors for perioperative death and report our results with surgical management of adult patients with congenital cardiac disease. We retrospectively analysed in-hospital data for 244 consecutive adult patients who underwent surgical treatment of congenital cardiac disease in our centre between January, 1998 and December, 2007. The mean patient age was 27.2 plus or minus 11.9 years, 29% were in functional class III or IV, and 25% were cyanosed. Of the patients, half were operated on for the first time. A total of 61% of patients underwent curative operations, 36% a reoperation after curative treatment, and 3% a palliative operation. Overall mortality was 4.9%. Predictive factors for hospital death were functional class, cyanosis, non-sinus rhythm, a history of only palliative previous operation(s), and an indication for palliative treatment. Functional class, cyanosis, type of initial congenital cardiac disease (single ventricle and double-outlet right ventricle), and only palliative previous operation were risk factors for prolonged intensive care stay (more than 48 hours). The surgical management of adult patients with congenital cardiac disease has improved during recent decades. These generally young patients, with a complex pathology, today present a low post-operative morbidity and mortality. Patients having undergone palliative surgery and reaching adulthood without curative treatment present with an increased risk of morbidity and mortality. Univentricular hearts and double-outlet right ventricles were associated with the highest morbidity. PMID- 20923596 TI - Pepsi and Coca Cola in Delhi, India: availability, price and sales. AB - OBJECTIVE: India is experiencing increased consumption of sugar-sweetened carbonated drinks, consumption that may be associated with increased risk of type 2 diabetes and obesity. The aim of the study was to determine the availability, price and quantity sold of 'Pepsi' and 'Coca Cola' in their 'regular' and 'diet' forms in Delhi and London. DESIGN: A questionnaire about the availability, price and quantity sold per day of both regular and diet Pepsi and Coca Cola was devised and piloted. Using this, a survey of food and drink outlets within a 100 m radius of randomly selected Metro stations was conducted in both cities. SUBJECTS: Store vendors, owners and staff of food and drink outlets. SETTING: Delhi, India; London, United Kingdom. RESULTS: In Delhi, of the outlets stocking regular Pepsi and Coca Cola, only 34% sold diet versions and these were more readily available in the most affluent areas than in the poorest areas (34% v. 6%, Z=3.67, P<0.001). This social patterning was not observed in London. Little price differential between regular and diet versions of Pepsi and Coca Cola was observed in Delhi; however, profit margins were better for regular, relative to diet, Coca Cola. Sales of regular products were significantly greater than those of diet products (P<0.002). CONCLUSIONS: Low availability of diet versions of Pepsi and Coca Cola in less affluent areas of Delhi is likely to exacerbate the obesity and diabetes trends. Price differentials to promote diet versions and other healthier or traditional low-energy drinks may be beneficial. PMID- 20923597 TI - Consumption of whole grains is associated with improved diet quality and nutrient intake in children and adolescents: the National Health and Nutrition Examination Survey 1999-2004. AB - OBJECTIVE: To examine the association of consumption of whole grains (WG) with diet quality and nutrient intake in children and adolescents. DESIGN: Secondary analysis of cross-sectional data. SETTING: The 1999-2004 National Health and Nutrition Examination Survey. SUBJECTS: Children aged 2-5 years (n 2278) and 6-12 years (n 3868) and adolescents aged 13-18 years (n 4931). The participants were divided into four WG consumption groups: >= 0 to < 0.6, >= 0.6 to < 1.5, >= 1.5 to < 3.0 and >= 3.0 servings/d. Nutrient intake and diet quality, using the Healthy Eating Index (HEI)-2005, were determined for each group from a single 24 h dietary recall. RESULTS: The mean number of servings of WG consumed was 0.45, 0.59 and 0.63 for children/adolescents at the age of 2-5, 6-12 and 13-18 years, respectively. In all groups, HEI and intakes of energy, fibre, vitamin B6, folate, magnesium, phosphorus and iron were significantly higher in those consuming >= 3.0 servings of WG/d; intakes of protein, total fat, SFA and MUFA and cholesterol levels were lower. Intakes of PUFA (6-12 years), vitamins B1 (2-5 and 13-18 years), B2 (13-18 years), A (2-5 and 13-18 years) and E (13-18 years) were higher in those groups consuming >= 3.0 servings of WG/d; intakes of added sugars (2-5 years), vitamin C (2-5 and 6-12 years), potassium and sodium (6-12 years) were lower. CONCLUSIONS: Overall consumption of WG was low. Children and adolescents who consumed the most servings of WG had better diet quality and nutrient intake. PMID- 20923598 TI - Ready-meal consumption: associations with weight status and cooking skills. AB - OBJECTIVE: The ready-meal market has grown considerably in recent years. At the same time, a degradation of traditional cooking skills has been observed. Ready meals are often rich in energy, fat and sugar and lack vegetables; however, studies investigating associations between ready-meal consumption, overweight and cooking skills are lacking. The present study examines whether demographic factors, overweight, beliefs about the nutritional value and taste of ready meals and cooking skills are associated with ready-meal consumption. DESIGN: Cross sectional survey. SETTING: Ready-meal consumption, weight status, cooking skills, beliefs about the taste and nutritional value of ready meals and demographic variables were assessed with self-administered questionnaires. Data were analysed with one-way ANOVA and multiple regression analysis. SUBJECTS: A total of 1017 adults from the German-speaking part of Switzerland. RESULTS: Men reported being more positive about ready meals and having fewer cooking skills compared with women. Overweight adults (BMI > 25 kg/m2) were more positive about nutrients and vitamins in ready meals compared with normal-weight adults. Ready-meal consumption was associated with cooking skills (beta = -0.192), age (beta =- 0.228), overweight (beta = 0.129), nutritional value (beta = -0.131), taste (beta = -0.126), working status (beta = 0.096) and gender (beta = 0.084). CONCLUSIONS: Cooking skills were identified as a strong predictor of ready-meal consumption. The importance of cooking skills as a barrier to healthy eating should be explored, as it is plausible that cooking skills will further decrease in the future. Next, the study provided evidence for an association between ready-meal consumption and overweight. Further research should examine the importance of ready meals for the overweight epidemic. PMID- 20923599 TI - Long-lasting recovery of psychotic-like symptoms in isolation-reared rats after chronic but not acute treatment with the cannabinoid antagonist AM251. AB - In this work we investigated the ability of AM251 to reverse schizophrenia-like symptoms produced by a neurodevelopmental animal model based on a social isolation procedure. First, we assessed the validity of our isolation-rearing protocol and, as expected, isolation-reared rats showed hyperlocomotion in a novel environment, cognitive impairment in the novel object recognition (NOR) test and a significant increase in the number of aggressive behaviours in the social interaction test compared to group-housed controls. This behavioural picture was associated with a reduction in CB1 receptor/G protein coupling in specific brain areas as well as reduced c-Fos immunoreactivity in the prefrontal cortex and caudate putamen. In this model, chronic but not acute treatment with the CB1 receptor antagonist AM251 counteracted isolation-induced cognitive impairment in the NOR test and aggressive behaviours in the social interaction test. This behavioural recovery was accompanied by the rescue of CB1 receptor functionality and c-Fos levels in all brain regions altered in isolation-reared rats. Moreover, chronic AM251 also increased c-Fos immunoreactivity in the nucleus accumbens, as previously demonstrated for antipsychotic drugs. Interestingly, the behavioural recovery due to chronic AM251 administration persisted until 10 d after discontinuing the treatment, indicating a long-lasting effect of the cannabinoid antagonist on psychotic-like symptoms. PMID- 20923600 TI - Avoiding skin burns with transcranial direct current stimulation: preliminary considerations. PMID- 20923602 TI - Imaging not imagination: towards a revision of the role of neuroimaging in the diagnosis of dementia. PMID- 20923603 TI - An update on the potential role of excitotoxicity in the pathogenesis of Parkinson's disease. AB - The primary cause of the neurodegenerative process that underlies Parkinson's disease (PD) is still unknown. Different mechanisms probably contribute to triggering neuronal death in the nigrostriatal pathway, including mitochondrial defects, oxidative stress and proteolytic stress. Glutamate-mediated excitotoxicity may be a further contributor. Glutamate is the predominant fast excitatory neurotransmitter in the central nervous system and, in the presence of specific conditions, a potential neurotoxin. Although excitotoxicity per se is unlikely to act as a major causative agent in PD pathogenesis, glutamate-mediated intracellular changes may contribute, in a more subtle way, to the mechanisms that trigger the neurodegenerative process in the substantia nigra pars compacta (SNc). It is, therefore, likely that synergistic interactions between mitochondrial defects, oxidative stress and glutamatergic stimulation take place at the SNc level. These interactions may create the conditions for the development of the nigrostriatal damage that characterizes PD. PMID- 20923604 TI - Spinal muscular atrophy: from animal model to clinical trial. AB - Spinal muscular atrophy (SMA) is an autosomal recessive disease characterized by degeneration and loss of lower motor neurons in the spinal cord and brainstem. Clinically, SMA has been classified into four types, according to the maximum function attained. The disease is caused by deletion or mutation of the telomeric copy of the SMN gene (SMN1), and the clinical severity is in part determined by the copy number of the centromeric SMN gene (SMN2). The SMN2 mRNA lacks exon 7, resulting in reduced production of the full-length SMN protein. Treatment of SMA consists of supportive care, although many drugs have been demonstrated to improve muscle strength and motor function of patients. The development of animal models of SMA has led to better interpretation of the physiopathology of the disease and testing of potential drug targets. Several mechanisms have been targeted in SMA drug trials, including neuroprotection, neurogenesis, energy metabolism improvement, anabolic stimulation and increment of SMN2 transcripts. Gene therapy and cell transplantation have also been tested in murine SMA. PMID- 20923605 TI - Evaluation of neuropsychological functions in patients with Friedreich ataxia before and after cognitive therapy. AB - Friedreich ataxia (FA) is a neurodegenerative disease characterized by progressive nervous system damage resulting in severe disability. Cognitive functions and mood disorders in FA have been studied little and with conflicting results. The aim of this study was to investigate cognitive functions and mood disorders in FA subjects and the role of cognitive rehabilitation therapy (sequential treatments) performed during a scheduled study period. The executive functions of 24 subjects with FA were evaluated over one year during three separate periods of in-hospital rehabilitation. The neuropsychological evaluations performed before and after cognitive therapy did not reveal differences in the mean test scores of the MMSE, the Rey 15-item Memorization Test for long-term memory, Raven's Colored Progressive Matrices, the Phonemic Verbal Fluency Test, the Symbol Digit Modalities Test, or the Zung scale. The mean scores of the Stroop color-word interference task and of the Rey 15-item Memorization Test for short-term memory were increased at the final evaluation. This finding of long-lasting stability of neuropsychological test scores is noteworthy, as it suggests that one-year cognitive rehabilitation therapy (sequential treatments) may at least contribute to reducing cognitive decline. A cognitive rehabilitation therapy in addition to the conventional neuromotor rehabilitation treatment may improve the management of subjects with FA. PMID- 20923606 TI - Event-related potentials study in attention deficit hyperactivity disorder. AB - Attention deficit hyperactivity disorder (ADHD) is a childhood disorder characterized by lack of sustained attention, hyperactivity and impulsivity. Children with ADHD have functional impairment occurring at multiple levels. In the present study, cognitive status was assessed using auditory event-related potentials (ERPs). Twenty ADHD children and 20 controls were recruited for the study and ERPs were recorded on a computerized evoked potential recorder, using the international 10-20 system of electrode placement. The ADHD children showed a statistically significant N200 latency prolongation and amplitude decrease compared with the controls; the latencies of the other waves, i.e. N100, P200, P300, were prolonged in the ADHD children but the difference versus the controls was statistically insignificant. Reaction time was significantly longer in the ADHD subjects as compared with the controls. The above findings are suggestive of dysfunctions in the discrimination of task-relevant stimuli and a slower motor response in ADHD children. PMID- 20923607 TI - Characterisation of the sympathetic skin response evoked by own-face recognition in healthy subjects. AB - The ability to recognise one's own face is crucial for self-identity formation and it plays a key role in the development of social interactions. Our starting hypothesis was that own-face recognition may be a psychophysiological phenomenon capable of activating the vegetative system in a peculiar manner, via sympathetic pathways. To test this hypothesis we studied the sympathetic skin responses (SSRs) evoked in 18 healthy subjects by the image of their own faces and by six other different visual stimuli. The SSRs were enhanced when participants were shown their own faces. Both SSR area and SSR amplitude contributed to this phenomenon. This work may offer new insights into the psycho- physiological processes involved in own-face recognition; moreover, the SSR could be a useful tool for future studies of patients affected by neuropsychiatric disorders presenting impairment of own-face recognition or representation of self-identity. PMID- 20923608 TI - Use of surface EMG for evaluation of upper limb spasticity during botulinum toxin therapy in stroke patients. AB - The clinical assessment of spasticity in stroke patients generally includes descriptive scales, such as the Modified Ashworth Scale (MAS) and the Global Pain Scale (GPS), however these may not be sufficiently sensitive to accurately detect improvements, especially at upper limb level; electromyography (EMG) may be the answer to this clinical requirement. The aim of this study was to quantify the effects of botulinum toxin type A (BTX) in treating upper extremity spasticity in stroke patients, using clinical evaluation (MAS and GPS) and EMG. Ten patients were assessed before, 30 days and 180 days after BTX injection using clinical evaluations and EMG. At 30 days all clinical measures improved significantly. Whereas MAS scores, after recording an improvement at the first evaluation session, were worse at the second assessment, GPS scores improved over time, both at the first and at the second evaluation session. A reduction of EMG activity was found 30 days after injections, in particular at baseline and during passive flexion movement. Our results demonstrated that measurement of EMG activity may be an effective means of detecting functional improvements and of monitoring the effects of treatment in post-stroke patients. PMID- 20923609 TI - 3 Tesla is twice as sensitive as 1.5 Tesla magnetic resonance imaging in the assessment of diffuse axonal injury in traumatic brain injury patients. AB - Diffuse axonal injury (DAI), associated with deafferentation and functional rearrangement, probably plays a role in the chronic phase of traumatic brain injury (TBI). DAI with a haemorrhagic component can be quantified using magnetic resonance imaging (MRI) thanks to the iron-based susceptibility effect of haemosiderin, which increases with magnetic field strength. The aim of this work was to compare conventional 1.5 Tesla and 3 Tesla MRI in the assessment of DAI in TBI patients. Eighteen TBI patients were submitted, in random order, to a 1.5T and a 3T MRI examination using standard gradient echo sequences. Both scans were always performed on the same day. DAI lesions with a haemorrhagic component were manually segmented and classified by anatomical location. The Wilcoxon and ANOVA tests were used for statistical analysis, significance being set at p<0.05. The results of this study showed that 3T MRI is almost twice as sensitive as 1.5T MRI in assessing DAI in terms of lesion number and volume. Differences between the two scanners were not significant in the posterior cranial fossa. High-field MRI enhances the assessment of DAI and may help to increase understanding of the mechanisms underlying subacute and chronic clinical, cognitive and behavioural changes in TBI patients. PMID- 20923610 TI - Open-label, randomised, parallel-group, multicentre study to evaluate the safety, tolerability and immunogenicity of an AS03(B)/oil-in-water emulsion-adjuvanted (AS03(B)) split-virion versus non-adjuvanted whole-virion H1N1 influenza vaccine in UK children 6 months to 12 years of age. AB - OBJECTIVE: To evaluate the safety, tolerability and immunogenicity of an AS03(B)/oil-in-water emulsion-adjuvanted (AS03(B)) split-virion versus non adjuvanted whole-virion H1N1 influenza vaccine in UK children aged 6 months to 12 years. DESIGN: Multicentre, randomised, head-to-head, open-label trial. SETTING: Five UK sites (Oxford, Bristol, Southampton, Exeter and London). PARTICIPANTS: Children aged 6 months to < 13 years, for whom a parent or guardian had provided written informed consent and who were able to comply with study procedures, were eligible for inclusion. INTERVENTIONS: A tocopherol/oil-in-water emulsion adjuvanted (AS03(B)) egg culture-derived split-virion H1N1 vaccine and a non adjuvanted cell culture-derived whole-virion vaccine, given as a two-dose schedule, 21 days apart, were compared. Participants were grouped into those aged 6 months to < 3 years (younger group) and 3 years to < 13 years of age (older group) and were randomised by study investigators (1 : 1 ratio) to receive one of the two vaccines. Vaccines were administered by intramuscular injection (deltoid or anterior-lateral thigh, depending on age and muscle bulk). Local reactions and systemic symptoms were collected for 1 week post immunisation, and serum was collected at baseline and after the second dose. To assess safety and tolerability, parents or guardians recorded the following information in diary cards from days 0-7 post vaccination: axillary temperature, injection site reactions, solicited and unsolicited systemic symptoms, and medications. MAIN OUTCOME MEASURE: Comparison between vaccines of the percentage of participants demonstrating seroconversion by microneutralisation assay. RESULTS: Among 937 children receiving vaccine, per-protocol seroconversion rates were higher after the AS03(B)-adjuvanted vaccine than after the whole-virion vaccine (98.2% vs 80.1% in children < 3 years, 99.1% vs 95.9% among those aged 3-12 years), as were severe local reactions (3.6% vs 0.0% in those under 5 years, 7.8% vs 1.1% in those aged 5-12 years), irritability in children < 5 years (46.7% vs 32.0%), and muscle pain in older children (28.9% vs 13.2%). The second dose of the adjuvanted vaccine was more reactogenic than the first, especially for fever > 38.0 degrees C in those under 5 years of age (8.9% vs 22.4%). CONCLUSION: The adjuvanted vaccine, although reactogenic, was more immunogenic, especially in younger children, indicating the potential for improved immunogenicity of influenza vaccines in this age group. TRIAL REGISTRATION NUMBER: ISRCTN89141709. PMID- 20923611 TI - Evaluation of droplet dispersion during non-invasive ventilation, oxygen therapy, nebuliser treatment and chest physiotherapy in clinical practice: implications for management of pandemic influenza and other airborne infections. AB - BACKGROUND: Influenza viruses are thought to be spread by droplets, but the role of aerosol dissemination is unclear and has not been assessed by previous studies. Oxygen therapy, nebulised medication and ventilatory support are treatments used in clinical practice to treat influenzal infection are thought to generate droplets or aerosols. OBJECTIVES: Evaluation of the characteristics of droplet/aerosol dispersion around delivery systems during non-invasive ventilation (NIV), oxygen therapy, nebuliser treatment and chest physiotherapy by measuring droplet size, geographical distribution of droplets, decay in droplets over time after the interventions were discontinued. METHODS: Three groups were studied: (1) normal controls, (2) subjects with coryzal symptoms and (3) adult patients with chronic lung disease who were admitted to hospital with an infective exacerbation. Each group received oxygen therapy, NIV using a vented mask system and a modified circuit with non-vented mask and exhalation filter, and nebulised saline. The patient group had a period of standardised chest physiotherapy treatment. Droplet counts in mean diameter size ranges from 0.3 to > 10 um were measured with an counter placed adjacent to the face and at a 1-m distance from the subject/patient, at the height of the nose/mouth of an average health-care worker. RESULTS: NIV using a vented mask produced droplets in the large size range (> 10 um) in patients (p = 0.042) and coryzal subjects (p = 0.044) compared with baseline values, but not in normal controls (p = 0.379), but this increase in large droplets was not seen using the NIV circuit modification. Chest physiotherapy produced droplets predominantly of > 10 um (p = 0.003), which, as with NIV droplet count in the patients, had fallen significantly by 1 m. Oxygen therapy did not increase droplet count in any size range. Nebulised saline delivered droplets in the small- and medium-size aerosol/droplet range, but did not increase large-size droplet count. CONCLUSIONS: NIV and chest physiotherapy are droplet (not aerosol)-generating procedures, producing droplets of > 10 um in size. Due to their large mass, most fall out on to local surfaces within 1 m. The only device producing an aerosol was the nebuliser and the output profile is consistent with nebuliser characteristics rather than dissemination of large droplets from patients. These findings suggest that health-care workers providing NIV and chest physiotherapy, working within 1 m of an infected patient should have a higher level of respiratory protection, but that infection control measures designed to limit aerosol spread may have less relevance for these procedures. These results may have infection control implications for other airborne infections, such as severe acute respiratory syndrome and tuberculosis, as well as for pandemic influenza infection. PMID- 20923612 TI - Evaluation of triage methods used to select patients with suspected pandemic influenza for hospital admission: cohort study. AB - BACKGROUND: Triage methods are necessary in emergency departments to provide clinicians with a reliable method for determining each patient's risk of adverse outcome. Prior to the 2009 H1N1 influenza pandemic the CURB-65 (a risk prediction score for pneumonia, based on confusion, urea level, respiratory rate, blood pressure and age over 65 years) pneumonia score and the Pandemic Modified Early Warning Score (PMEWS) were used to assess adults. In response to the emergence of the pandemic, national guidance produced a new swine flu hospital pathway for use adults and children. However, none of these methods had been widely validated or tested in the setting of pandemic influenza. OBJECTIVES: To use the initial waves of the 2009 H1N1 pandemic to evaluate existing triage methods in patients presenting with suspected pandemic influenza, and to determine whether an improved triage method could be developed. METHODS: A prospective cohort study was undertaken of patients with suspected swine flu presenting to four hospitals during the second wave of the 2009 H1N1 pandemic. Staff completed a standardised assessment form that included the CURB-65 score, PMEWS and the swine flu hospital pathway. Patients who died or required respiratory, cardiovascular or renal support during the 30-day follow-up were defined as having a poor outcome. Patients who survived to 30 days without requiring respiratory, cardiovascular or renal support were defined as having a good outcome. RESULTS: Data were collected and analysed from 481 cases across three hospitals. Most of the cases were children, with 347 out of 481 (72%) aged 16 years or less. There were five poor outcomes: two deaths and three survivors who required respiratory support. The five patients with poor outcomes had CURB-65 scores of zero, one (three cases) and two, and PMEWS scores of one, five, six, seven and eight. The swine flu hospital pathway was positive in three out of five cases. The C-statistic for each method was CURB-65 0.78 [95% confidence interval (CI) 0.58 to 0.99], PMEWS 0.77 (95% CI 0.55 to 0.99) and the swine flu hospital pathway 0.70 (95% CI 0.45 to 0.96). Patients with a higher CURB-65 score were more likely to be admitted (p < 0.001): 25 out of 101 (25%) with a score of zero, 11 out of 24 (46%) with a score of one, 7 out of 8 (88%) with a score of two, and the patient with a score of three were admitted. Admitted patients had a higher mean PMEWS score (4.6 vs 2.0, p < 0.001). The C-statistics for CURB-65, PMEWS and the swine flu hospital pathway in adults in terms of discriminating between those admitted and discharged were 0.65 (95% CI 0.54 to 0.76), 0.76 (95% CI 0.66 to 0.86) and 0.62 (95% CI 0.51 to 0.72) respectively. LIMITATIONS: The 2009 H1N1 pandemic was much smaller and less severe than predicted and resulted in a lack of sufficient data. CONCLUSIONS: Potential concerns were raised about the use of existing triage methods for patients with suspected pandemic influenza, as these methods may fail to discriminate between patients who will have an adverse outcome and those with a benign course. Clinicians in the study did not generally appear to admit or discharge on the basis of these methods, despite their recommended use. Further research is required to evaluate existing triage methods and develop new triage tools for suspected pandemic influenza. PMID- 20923613 TI - Virus shedding and environmental deposition of novel A (H1N1) pandemic influenza virus: interim findings. AB - BACKGROUND: The relative importance of different routes of influenza transmission, including the role of bioaerosols, and ability of masks and/or hand hygiene to prevent transmission, remains poorly understood. Current evidence suggests that infectious virus is not typically released from adults after 5 days of illness, however, little is known about the extent to which virus is deposited by infected individuals into the environment and whether deposited virus has the ability to infect new hosts. Further information about the deposition of viable influenza virus in the immediate vicinity of patients with pandemic influenza is fundamental to our understanding of the routes and mechanisms of transmission. OBJECTIVES: To collect data on patients infected with pandemic H1N1 2009 (swine flu). Primary objectives were to correlate the amount of virus detected in a patient's nose with that recovered from his/her immediate environment, and with symptom duration and severity. Secondary objectives were to describe virus shedding and duration according to major patient characteristics: adults versus children, and those with mild illness (community patients) versus those with more severe disease (hospitalised patients). METHODS: Adults and children, both in hospital and from the community, who had symptoms of pandemic H1N1 infection, were enrolled and visited every day during follow-up for a maximum of 12 days. Symptom data was collected and samples were taken, including nose swabs and swabs from surfaces and objects around patients. Samples of air were obtained using validated sampling equipment. The samples were tested for the presence of pandemic H1N1 virus, using polymerase chain reaction (PCR) to detect virus genome and an immunofluorescence technique to detect viable virus. RESULTS: Forty-three subjects were followed up, and 19 of them were subsequently proven to be infected with pandemic H1N1 virus. The median duration of virus shedding from the 19 infected cases was 6 days when detection was performed by PCR, and 3 days when detection was performed by a culture technique. Over 30% of cases remained potentially infectious for at least 5 days. Only 0.5% of all community and none of the hospital swabs taken revealed virus on surfaces. Five subjects had samples of the air around them collected and virus was detected by PCR from four; some of the air particles in which virus was detected were small enough to be inhaled and deposited deep in the lungs. LIMITATION: Small number of subjects recruited. CONCLUSIONS: The finding that over 30% of infected individuals have infectious virus in their noses for 5 days or more has infection control implications. The data suggest that contact transmission of pandemic influenza via fomites may be less important than previously thought, but transmission via bioaerosols at short range may be possible, meaning that high-level personal protective equipment may be needed by health-care workers when attending patients with pandemic influenza. Further work is being undertaken to consolidate these findings, as they have important potential implications for the protection of health-care workers and the formulation of advice to households, nationally and internationally. PMID- 20923614 TI - Role of antidepressants in bipolar depression. AB - A gap exists between the standard of care for bipolar depression and actual clinical practice. Although practice guidelines advise against treating bipolar depression with antidepressant monotherapy, this is the most frequently prescribed initial treatment. To provide quality care and improve patient outcomes, clinicians must be aware of the benefits and dangers of antidepressant use in bipolar disorder. Further, they must be informed about alternative, more efficacious treatment options for patients with depressive symptoms. PMID- 20923615 TI - Optimizing depression treatment to increase the likelihood of remission. AB - Depression is one of the highest ranking causes of disease burden worldwide but remains underrecognized and undertreated in clinical settings. Measurement-based care is the standard of care strived for by leading psychiatric researchers and is considered treatment as usual in other areas of medicine. However, routine measurement has yet to be implemented in all clinical practices for the detection and treatment of mental disorders such as depression. Physicians may help to improve illness outcomes and reduce illness burdens of patients with depression by using measurement-based care, including standardized measurement instruments and treatment algorithms in all phases of the treatment process. PMID- 20923616 TI - Long-term treatment of bipolar disorder in children. AB - Bipolar disorder has been shown to have a chronic course of illness, and children with this disorder are likely to need long-term treatment. Although limited data exist on the efficacy of long-term pharmacotherapy for pediatric bipolar disorder, 5 medications are approved as monotherapy for mixed or manic episodes and 2 are approved as adjunctive treatment. Clinicians should be vigilant in monitoring adverse events in children and adolescents taking psychotropic medications and should consider implementing psychotherapeutic interventions, which can improve youths' symptomatic and functional outcomes. PMID- 20923617 TI - Using complementary and alternative medicines for depression. AB - The use of complementary and alternative medicines (CAM) has increased among patients with psychiatric disorders over recent decades. Therefore, clinicians must inquire and be knowledgeable about the use of CAM therapies, not only to give their patients accurate and up-to-date information but also to know when to appropriately prescribe CAM therapies to patients. Of the available CAMs, omega-3 fatty acids, folate, SAM-e, and St John's wort are reviewed. PMID- 20923618 TI - Evaluating the patient with fibromyalgia. AB - Once the physician has identified fibromyalgia as a potential diagnosis, further evaluation is warranted, both to understand the full dimensions of fibromyalgia and to evaluate other potential causes of the patient's symptoms. For example, mood disorders, sleep disorders, and daytime fatigue are often present in patients with fibromyalgia and often are closely related to pain. In addition, a number of physical conditions can mimic fibromyalgia and must be considered in the patient's evaluation. These include endocrine conditions, neurologic disorders, musculoskeletal diseases, and medication-related side effects. Taking a complete medical history and performing a thorough physical examination, including a complete laboratory assessment, can be very helpful in confirming the diagnosis or establishing an alternate diagnosis. PMID- 20923619 TI - Illustrating the circuits of sexual desire. PMID- 20923621 TI - A clinician's guide to monitoring kidney function in lithium-treated patients. AB - OBJECTIVE: Bipolar disorder treatment guidelines recommend kidney-function monitoring at regular intervals for patients taking lithium, but they tend not to provide specifics with regard to what to measure and how to ensure that the results most accurately reflect true kidney function. This overview clarifies those practical aspects of monitoring that are often overlooked or misunderstood. DATA SOURCES: Utilized English language materials were obtained by PubMed searches (1970-2009), from the Lithium Information Center database, and from books. Search terms included lithium, kidney function, creatinine, creatinine clearance, GFR, GFR prediction equations, albuminuria, and urine concentration. DATA SYNTHESIS: Urine osmolality most accurately reflects urine concentrating ability, although specific gravity is usually adequate for clinical purposes. Serum creatinine concentration can be influenced by extrarenal factors, but even when these are controlled, it remains a less than ideal measure of glomerular filtration rate (GFR). Prediction equations are used commonly to estimate GFR and are an advance over serum creatinine alone, but even they are not as useful when GFR is only mildly impaired. Urine albumin measurement is important, but it requires greater standardization and sensitivity to maximize its potential. CONCLUSIONS: The safe and effective use of lithium requires regular monitoring of kidney function. Doing so effectively requires knowledge of what to measure, how to ensure accurate results, and how to properly interpret them. PMID- 20923620 TI - Past and present progress in the pharmacologic treatment of schizophrenia. AB - Despite treatment advances over the past decades, schizophrenia remains one of the most severe psychiatric disorders that is associated with a chronic relapsing course and marked functional impairment in a substantial proportion of patients. In this article, a historical overview of the pharmacologic advances in the treatment of schizophrenia over the past 50 years is presented. This is followed by a review of the current developments in optimizing the treatment and outcomes in patients with schizophrenia. Methodological challenges, potential solutions, and areas of particular need for further research are highlighted. Although treatment goals of response, remission, and recovery have been defined more uniformly, a good "effectiveness" measure mapping onto functional outcomes is still lacking. Moreover, the field must advance in transferring measurement-based approaches from research to clinical practice. There is an ongoing debate regarding whether and which first- or second-generation antipsychotics should be used. However, especially when considering individual adverse effect profiles, the differentiation into first- and second-generation antipsychotics as unified classes cannot be upheld, and a more differentiated view and treatment selection are required. The desired, individualized treatment approach needs to consider current symptoms, comorbid conditions, past therapeutic response, and adverse effects, as well as patient choice and expectations. Acute and long-term goals and effects of medication treatment should be balanced. To date, clozapine is the only evidence-based treatment for refractory patients, and the role of antipsychotic polypharmacy and other augmentation strategies remains unclear, at best. To discover novel treatments with enhanced/broader efficacy and improved tolerability, and to enable personalized treatment, the mechanisms underlying illness development and progression, symptomatic improvement, and side effect development need to be elucidated. PMID- 20923622 TI - Complexity of pharmacologic treatment required for sustained improvement in outpatients with bipolar disorder. AB - OBJECTIVE: To evaluate the clinical correlates of and types of naturalistic treatments associated with sustained improvement/remission for at least 6 months in outpatients with bipolar disorder. METHOD: Five hundred twenty-five outpatients with bipolar disorder (77.7% bipolar I) gave informed consent, had their mood rated daily on the National Institute of Mental Health Life Chart Method for a minimum of at least 1 year, and recorded all medications. Demographics and clinical characteristics of patients with a "sustained response" (ratings of "improved" or "very much improved" on the Clinical Global Impressions Bipolar Version for a period of at least 6 months) versus nonresponders were compared. The study was conducted from 1996 to 2002. RESULTS: Of the 429 patients who were ill at study entry, 195 (45.5%) showed a sustained response; 54.5% showed no or insufficient response. A mean of 2.98 medications was given at time of improvement, which occurred after a mean of 18 months of participation in the study. Lithium and valproate were the medications most frequently prescribed at the time of improvement and had among the highest overall success rates. Equally complex regimens were employed in the nonresponders who, however, had a more adverse clinical course prior to network entry. Nonresponders were ultimately exposed to more antidepressants and antipsychotics than the sustained responders. CONCLUSIONS: A mean of 1.5 years and at times highly complex medication regimens were required to achieve a sustained response for 6 months during naturalistic outpatient treatment of bipolar disorder. Delineating the clinical and biologic correlates of individual response to combination treatment is a very high clinical research priority, as is developing new treatment strategies for the large proportion of patients who fail to respond in a sustained fashion. PMID- 20923624 TI - What's next after 50 years of psychiatric drug development: an FDA perspective. AB - This article discusses changes in psychiatric drug development from a US Food and Drug Administration (FDA) standpoint. It first looks back at changes that have been influenced by regulatory process and then looks forward at FDA initiatives that are likely to affect psychiatric drug development in the future. FDA protects the public health by ensuring the safety and efficacy of drug products introduced into the US market. FDA works with drug sponsors during development, and, when applications are submitted, reviews the safety and efficacy data and the proposed labeling. Drug advertising and promotion and postmarketing surveillance also fall within FDA's responsibility. Among the many changes in psychiatric drug development over the past 50 years, several have been particularly influenced by FDA. Populations studied have expanded diagnostically and demographically, and approved psychiatric indications have become more focused on the clinical entities actually studied, including in some cases specific symptom domains of recognized syndromes. Trial designs have become increasingly complex and informative, and approaches to data analysis have evolved to better model the reality of clinical trials. This article addresses 2 general areas of innovation at FDA that will affect psychiatric drug development in years to come. Several programs falling under the general heading of the Critical Path Initiative, ie, biomarkers, adaptive design, end-of-phase 2A meetings, and data standards, are described. In addition, a number of important safety initiatives, including Safety First, the Sentinel Initiative, the Safe Use Initiative, and meta-analysis for safety, are discussed. PMID- 20923623 TI - Comorbidity of generalized anxiety disorder and substance use disorders: results from the National Epidemiologic Survey on Alcohol and Related Conditions. AB - OBJECTIVE: Prior research has consistently documented a strong association between generalized anxiety disorder (GAD) and substance use disorder (SUD). Comorbidity of GAD and SUD (GAD-SUD) represents clinical challenges, as the patients' symptoms are often more severe and are frequently prolonged, making their management more complex when compared with individuals with GAD only. The purpose of this study was to examine whether individuals with GAD-SUD differ meaningfully from individuals with GAD and no SUD comorbidity (GAD-NSUD) in terms of demographic characteristics, risk factors, psychiatric comorbidity, and clinical correlates. METHOD: Data were derived from the 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions (N = 43,093). Diagnoses were made using the Alcohol Use Disorder and Associated Disabilities Interview Schedule-DSM-IV Version. RESULTS: We found that the lifetime prevalence rate of GAD-SUD is about 2.04%, while that of GAD-NSUD is 2.10%. Individuals with GAD-SUD showed higher psychiatric comorbidity rates than those with GAD-NSUD. Treatment seeking rates for GAD are equally low in individuals with GAD-SUD and GAD-NSUD. Both groups were as likely to receive pharmacologic treatment for anxiety. CONCLUSIONS: The findings of our study indicate that individuals with GAD-SUD constitute half of the lifetime prevalence of GAD and that GAD-SUD is associated with high overall vulnerability for additional psychopathology, particularly in the externalizing spectrum; higher disability; and higher use of alcohol and drugs to relieve anxiety symptoms. PMID- 20923625 TI - New antipsychotic drugs: how do their receptor-binding profiles compare? PMID- 20923626 TI - Gambling on acamprosate: a case report. PMID- 20923627 TI - What do internet users seek to know about depression from web searches? A descriptive study of 21 million web queries. PMID- 20923628 TI - Comparing psychotherapy and pharmacotherapy for adult depression: adjusting for differential dropout rates. PMID- 20923629 TI - Minocycline augmentation of pharmacotherapy in obsessive-compulsive disorder: an open-label trial. PMID- 20923630 TI - Experimental evidence for membrane-mediated protein-protein interaction. AB - Membrane proteins diffuse within the membrane, form oligomers and supramolecular assemblies. Using high-speed atomic force microscopy, we present direct experimental measure of an in-membrane-plane interaction potential between membrane proteins. In purple membranes, ATP-synthase c-rings formed dimers that temporarily dissociated. C-ring dimers revealed subdiffusive motion, while dissociated monomers diffused freely. C-rings center-to-center distance probability distribution allowed the calculation and modeling of an in-membrane plane energy landscape that presented repulsion at 80 A, most stable dimer association at 103 A (-3.5 k(B)T strength), and dissociation at 125 A (-1 k(B)T strength). This first experimental data of nonlabeled membrane protein diffusion and the corresponding in-membrane-plane interaction energy landscape characterized membrane protein interaction with an attractive range of several k(B)T that reaches to a radius of ~50 A within the membrane plane. PMID- 20923631 TI - Real-time nanoscopy by using blinking enhanced quantum dots. AB - Superresolution optical microscopy (nanoscopy) is of current interest in many biological fields. Superresolution optical fluctuation imaging, which utilizes higher-order cumulant of fluorescence temporal fluctuations, is an excellent method for nanoscopy, as it requires neither complicated optics nor illuminations. However, it does need an impractical number of images for real time observation. Here, we achieved real-time nanoscopy by modifying superresolution optical fluctuation imaging and enhancing the fluctuation of quantum dots. Our developed quantum dots have higher blinking than commercially available ones. The fluctuation of the blinking improved the resolution when using a variance calculation for each pixel instead of a cumulant calculation. This enabled us to obtain microscopic images with 90-nm and 80-ms spatial temporal resolution by using a conventional fluorescence microscope without any optics or devices. PMID- 20923632 TI - On the question of hydronium binding to ATP-synthase membrane rotors. AB - A recently determined atomic structure of an H(+)-coupled ATP-synthase membrane rotor has revived the long-standing question of whether protons may be bound to these structures in the form of a hydronium ion. Using both classical and quantum mechanical simulations, we show that this notion is implausible. Ab initio molecular dynamics simulations of the binding site demonstrate that the putative H(3)O(+) deprotonates within femtoseconds. The bound proton is thus transferred irreversibly to the carboxylate side chain found in the ion-binding sites of all ATP-synthase rotors. This result is consistent with classical simulations of the rotor in a phospholipid membrane, on the 100-nanosecond timescale. These simulations show that the hydrogen-bond network seen in the crystal structure is incompatible with a bound hydronium. The observed coordination geometry is shown to correspond instead to a protonated carboxylate and a bound water molecule. In conclusion, this study underscores the notion that binding and transient storage of protons in the membrane rotors of ATP synthases occur through a common chemical mechanism, namely carboxylate protonation. PMID- 20923633 TI - Water permeation through the sodium-dependent galactose cotransporter vSGLT. AB - It is well accepted that cotransporters facilitate water movement by two independent mechanisms: osmotic flow through a water channel in the protein and flow driven by ion/substrate cotransport. However, the molecular mechanism of transport-linked water flow is controversial. Some researchers believe that it occurs via cotransport, in which water is pumped along with the transported cargo, while others believe that flow is osmotic in response to an increase in intracellular osmolarity. In this letter, we report the results of a 200-ns molecular dynamics simulation of the sodium-dependent galactose cotransporter vSGLT. Our simulation shows that a significant number of water molecules cross the protein through the sugar-binding site in the presence as well as the absence of galactose, and 70-80 water molecules accompany galactose as it moves from the binding site into the intracellular space. During this event, the majority of water molecules in the pathway are unable to diffuse around the galactose, resulting in water in the inner half of the transporter being pushed into the intracellular space and replaced by extracellular water. Thus, our simulation supports the notion that cotransporters act as both passive water channels and active water pumps with the transported substrate acting as a piston to rectify the motion of water. PMID- 20923634 TI - High speed bio-AFM reveals motion of membrane proteins driven by hydrophobic mismatch with nm precision in label-free fashion. PMID- 20923635 TI - Nanostructure of the fibrin clot. AB - The nanostructure of the fibrin fibers in fibrin clots is investigated by using spectrometry and small angle x-ray scattering measurements. First, an autocoherent analysis of the visible light spectra transmitted through formed clots is demonstrated to provide robust measurements of both the radius and density of the fibrin fibers. This method is validated via comparison with existing small-angle and dynamic light-scattering data. The complementary use of small angle x-ray scattering spectra and light spectrometry unambiguously shows the disjointed nature of the fibrin fibers. Indeed, under quasiphysiological conditions, the fibers are approximately one-half as dense as their crystalline fiber counterparts. Further, although the fibers are locally crystalline, they appear to possess a lateral fractal structure. PMID- 20923636 TI - Activation or tolerance of natural killer cells is modulated by ligand quality in a nonmonotonic manner. AB - Natural killer (NK) cells extend important immune resistance in vertebrates by lysing infected and tumor cells. A fine balance between opposing signals generated by a diverse set of stimulatory and inhibitory NK-cell receptors determines the fate of target cells interacting with the NK cells. We have developed a mathematical model involving membrane proximal initial signaling events that provides novel mechanistic insights into how activation of NK cells is modulated by the half-life of receptor-ligand interaction and ligand concentrations. We show that strong stimulatory ligands produce digital activation, whereas weaker stimulatory ligands can mediate inhibition by strengthening the signals generated by inhibitory ligands, as indicated in experiments in knockout mice. We find under certain conditions, counterintuitively, inhibitory receptors can help mediate activation instead of inhibition. Mechanistic insights gained from NK-cell signaling can facilitate understanding of complex signaling responses that occur due to cross talk between dueling signaling pathways in other cell types. PMID- 20923638 TI - Cancer cell stiffness: integrated roles of three-dimensional matrix stiffness and transforming potential. AB - While significant advances have been made toward revealing the molecular mechanisms that influence breast cancer progression, much less is known about the associated cellular mechanical properties. To this end, we use particle-tracking microrheology to investigate the interplay among intracellular mechanics, three dimensional matrix stiffness, and transforming potential in a mammary epithelial cell (MEC) cancer progression series. We use a well-characterized model system where human-derived MCF10A MECs overexpress either ErbB2, 14-3-3zeta, or both ErbB2 and 14-3-3zeta, with empty vector as a control. Our results show that MECs possessing ErbB2 transforming potential stiffen in response to elevated matrix stiffness, whereas non-transformed MECs or those overexpressing only 14-3-3zeta do no exhibit this response. We further observe that overexpression of ErbB2 alone is associated with the highest degree of intracellular sensitivity to matrix stiffness, and that the effect of transforming potential on intracellular stiffness is matrix-stiffness-dependent. Moreover, our intracellular stiffness measurements parallel cell migration behavior that has been previously reported for these MEC sublines. Given the current knowledge base of breast cancer mechanobiology, these findings suggest that there may be a positive relationship among intracellular stiffness sensitivity, cell motility, and perturbed mechanotransduction in breast cancer. PMID- 20923637 TI - Synergy between CaMKII substrates and beta-adrenergic signaling in regulation of cardiac myocyte Ca(2+) handling. AB - Cardiac excitation-contraction coupling is a highly coordinated process that is controlled by protein kinase signaling pathways, including Ca(2+)/calmodulin dependent protein kinase II (CaMKII) and protein kinase A (PKA). Increased CaMKII expression and activity (as occurs during heart failure) destabilizes EC coupling and may lead to sudden cardiac death. To better understand mechanisms of cardiac CaMKII function, we integrated dynamic CaMKII-dependent regulation of key Ca(2+) handling targets with previously validated models of cardiac EC coupling, Ca(2+)/calmodulin-dependent activation of CaMKII, and beta-adrenergic activation of PKA. Model predictions are validated against CaMKII-overexpression data from rabbit ventricular myocytes. The model demonstrates how overall changes to Ca(2+) handling during CaMKII overexpression are explained by interactions between individual CaMKII substrates. CaMKII and PKA activities during beta-adrenergic stimulation may synergistically facilitate inotropic responses and contribute to a CaMKII-Ca(2+)-CaMKII feedback loop. CaMKII regulated early frequency-dependent acceleration of relaxation and EC coupling gain (which was highly sarcoplasmic reticulum Ca(2+) load-dependent). Additionally, the model identifies CaMKII dependent ryanodine receptor hyperphosphorylation as a proarrhythmogenic trigger. In summary, we developed a detailed computational model of CaMKII and PKA signaling in cardiac myocytes that provides unique insights into their regulation of normal and pathological Ca(2+) handling. PMID- 20923639 TI - Probing field-induced tissue polarization using transillumination fluorescent imaging. AB - Despite major successes of biophysical theories in predicting the effects of electrical shocks within the heart, recent optical mapping studies have revealed two major discrepancies between theory and experiment: 1), the presence of negative bulk polarization recorded during strong shocks; and 2), the unexpectedly small surface polarization under shock electrodes. There is little consensus as to whether these differences result from deficiencies of experimental techniques, artifacts of tissue damage, or deficiencies of existing theories. Here, we take advantage of recently developed near-infrared voltage sensitive dyes and transillumination optical imaging to perform, for the first time that we know of, noninvasive probing of field effects deep inside the intact ventricular wall. This technique removes some of the limitations encountered in previous experimental studies. We explicitly demonstrate that deep inside intact myocardial tissue preparations, strong electrical shocks do produce considerable negative bulk polarization previously inferred from surface recordings. We also demonstrate that near-threshold diastolic field stimulation produces activation of deep myocardial layers 2-6 mm away from the cathodal surface, contrary to theory. Using bidomain simulations we explore factors that may improve the agreement between theory and experiment. We show that the inclusion of negative asymmetric current can qualitatively explain negative bulk polarization in a discontinuous bidomain model. PMID- 20923640 TI - Pivotal role of actin depolymerization in the regulation of cochlear outer hair cell motility. AB - Cochlear outer hair cells undergo reversible changes in shape when externally stimulated. This response, known as OHC motility, is a central component of the cochlear amplifier, the mechanism responsible for the high sensitivity of mammalian hearing. We report that actin depolymerization, as regulated by activation/inhibition of LIMK/cofilin-mediated pathways, has a pivotal role in OHC motility. LIMK-mediated cofilin phosphorylation, which inhibits the actin depolymerizing activity of this protein, increases both electromotile amplitude and total length of guinea pig OHCs. In contrast, a decrease in cofilin phosphorylation reduces both OHC electromotile amplitude and OHC length. Experiments with acetylcholine and lysophosphatidic acid indicate that the effects of these agents on OHC motility are associated with regulation of cofilin phosphorylation via different signaling cascades. On the other hand, nonlinear capacitance measurements confirmed that all observed changes in OHC motile response were independent of the performance of the motor protein prestin. Altogether, these results strongly support the hypothesis that the cytoskeleton has a major role in the regulation of OHC motility, and identify actin depolymerization as a key process for modulating cochlear amplification. PMID- 20923641 TI - The role of amino terminus of mouse Cx50 in determining transjunctional voltage dependent gating and unitary conductance. AB - Amino-terminus and carboxyl-terminus of connexins have been proposed to be responsible for the transjunctional voltage-dependent gating (V(j)-gating) and the unitary gap junction channel conductance (gamma(j)). To better understand the molecular structure(s) determining the V(j)-gating properties and the gamma(j) of Cx50, we have replaced part of the amino-terminus of mCx50 by the corresponding domain of mCx36 to engineer a chimera Cx50-Cx36N, and attached GFP at the carboxyl-terminus of mCx50 to construct Cx50-GFP. The dual whole-cell patch-clamp technique was used to test the resulting gap junction channel properties in N2A cells. The Cx50-Cx36N gap junction channel lowered the sensitivity of steady state junctional conductance to V(j) (G(j)/V(j) relationship), slowed V(j)-gating kinetics, and reduced gamma(j) as compared to Cx50 channel. Cx50-GFP gap junction channel showed similar V(j)-gating properties and gamma(j) to Cx50 channel. We further characterized a mutation, Cx50N9R, where the Asn (N) at the ninth position of Cx50 was replaced by the corresponding Arg (R) at Cx36. The G(j)/V(j) relationship of Cx50N9R channel was significantly changed; most strikingly, the macroscopic residual conductance (G(min)) was near zero. Moreover, the single Cx50N9R channel only displayed one open state (gamma(j) = 132 +/- 4 pS), and no substate could be detected. Our data suggest that the NT of Cx50 is critical for both the V(j)-gating and the gamma(j), and the introduction of a positively charged Arg at the ninth position reduced the G(min) with a correlated disappearance of the substate at the single channel level. PMID- 20923642 TI - Confining the sodium pump in a phosphoenzyme form: the effect of lead(II) ions. AB - The effect of Pb(2+) ions on the Na(+),K(+)-ATPase was investigated in detail by means of steady-state fluorescence spectroscopy. Experiments were performed by using the electrochromic styryl dye RH421. It is shown that Pb(2+) ions can bind reversibly to the protein and do not affect the Na(+) and K(+) binding affinities in the E(1) and P-E(2) conformations of the enzyme. The pH titrations indicate that lead(II) favors binding of one H(+) to the P-E(2) conformation in the absence of K(+). A model scheme is proposed that accounts for the experimental results obtained for backdoor phosphorylation of the enzyme in the presence of Pb(2+) ions. Taken together, our results clearly indicate that Pb(2+) bound to the enzyme stabilizes an E(2)-type conformation. In particular, under conditions that promote enzyme phosphorylation, Pb(2+) ions are able to confine the Na(+),K(+)-ATPase into a phosphorylated E(2) state. PMID- 20923643 TI - Modulation of plant mitochondrial VDAC by phytosterols. AB - We have investigated the effect of cholesterol and two abundant phytosterols (sitosterol and stigmasterol) on the voltage-dependent anion-selective channel (VDAC) purified from mitochondria of bean seeds (Phaseolus coccineus). These sterols differ by the degree of freedom of their lateral chain. We show that VDAC displays sensitivity to the lipid-sterol ratio and to the type of sterol found in the membrane. The main findings of this study are: 1), cholesterol and phytosterols modulate the selectivity but only stigmasterol alters the voltage dependence of the plant VDAC in the range of sterol fraction found in the plant mitochondrial membrane; 2), VDAC unitary conductance is not affected by the addition of sterols; 3), the effect of sterols on the VDAC is reversible upon sterol depletion with 10 MUM methyl-beta-cyclodextrins; and 4), phytosterols are essential for the channel gating at salt concentration prevailing in vivo. A quantitative analysis of the voltage-dependence indicates that stigmasterol inhibits the transition of the VDAC in the lowest subconductance states. PMID- 20923644 TI - Ionic partition and transport in multi-ionic channels: a molecular dynamics simulation study of the OmpF bacterial porin. AB - We performed all-atom molecular dynamics simulations studying the partition of ions and the ionic current through the bacterial porin OmpF and two selected mutants. The study is motivated by new, interesting experimental findings concerning their selectivity and conductance behavior at neutral pH. The mutations considered here are designed to study the effect of removal of negative charges present in the constriction zone of the wild-type OmpF channel (which contains, on one side, a cluster with three positive residues, and on the other side, two negatively charged residues). Our results show that these mutations induce an exclusion of cations from the constriction zone of the channel, substantially reducing the flow of cations. In fact, the partition of ions inside the mutant channels is strongly inhomogeneous, with regions containing an excess of cations and regions containing an excess of anions. Interestingly, the overall number of cations inside the channel is larger than the number of anions, this excess being different for each protein channel. We found that the differences in ionic charge inside these channels are justified by the differences in electric charge between the wild-type OmpF and the mutants, following an electroneutral balance. PMID- 20923645 TI - The N-terminus of the intrinsically disordered protein alpha-synuclein triggers membrane binding and helix folding. AB - Alpha-synuclein (alphaS) is a 140-amino-acid protein that is involved in a number of neurodegenerative diseases. In Parkinson's disease, the protein is typically encountered in intracellular, high-molecular-weight aggregates. Although alphaS is abundant in the presynaptic terminals of the central nervous system, its physiological function is still unknown. There is strong evidence for the membrane affinity of the protein. One hypothesis is that lipid-induced binding and helix folding may modulate the fusion of synaptic vesicles with the presynaptic membrane and the ensuing transmitter release. Here we show that membrane recognition of the N-terminus is essential for the cooperative formation of helical domains in the protein. We used circular dichroism spectroscopy and isothermal titration calorimetry to investigate synthetic peptide fragments from different domains of the full-length alphaS protein. Site-specific truncation and partial cleavage of the full-length protein were employed to further characterize the structural motifs responsible for helix formation and lipid-protein interaction. Unilamellar vesicles of varying net charge and lipid compositions undergoing lateral phase separation or chain melting phase transitions in the vicinity of physiological temperatures served as model membranes. The results suggest that the membrane-induced helical folding of the first 25 residues may be driven simultaneously by electrostatic attraction and by a change in lipid ordering. Our findings highlight the significance of the alphaS N-terminus for folding nucleation, and provide a framework for elucidating the role of lipid induced conformational transitions of the protein within its intracellular milieu. PMID- 20923646 TI - Quantitative experimental assessment of macromolecular crowding effects at membrane surfaces. AB - We examined how crowding of the surfaces of lipid vesicles with either grafted polyethyleneglycol (PEG) chains or bilayer-anchored protein molecules affects the binding of soluble proteins to the vesicle surface. Escherichia coli dihydrofolate reductase (DHFR, 18 kDa) or a larger fusion protein, NusA-DHFR (72 kDa), binds reversibly but with high affinity to a methotrexate-modified lipid (MTX-PE) incorporated into large unilamellar vesicles. Incorporation of phosphatidylethanolamine-PEG5000 into the vesicles strongly decreases the affinity of binding of both proteins, to a degree that varies roughly exponentially with the lateral density of the PEG chains. Covalently coupling maltose-binding protein (MBP) to the vesicle surfaces also strongly decreases the affinity of binding of NusDHFR or DHFR, to a degree that likewise varies roughly exponentially with the surface density of anchored MBP. Surface-coupled MBP strongly decreases the rate of binding of NusDHFR to MTX-PE-incorporating vesicles but does not affect the rate of NusDHFR dissociation. The large magnitudes of these effects (easily exceeding an order of magnitude for moderate degrees of surface crowding) support previous theoretical analyses and suggest that surface-crowding effects can markedly influence a variety of important aspects of protein behavior in membranes. PMID- 20923647 TI - Direct simulation of protein-mediated vesicle fusion: lung surfactant protein B. AB - We simulated spontaneous fusion of small unilamellar vesicles mediated by lung surfactant protein B (SP-B) using the MARTINI force field. An SP-B monomer triggers fusion events by anchoring two vesicles and facilitating the formation of a lipid bridge between the proximal leaflets. Once a lipid bridge is formed, fusion proceeds via a previously described stalk - hemifusion diaphragm - pore opening pathway. In the absence of protein, fusion of vesicles was not observed in either unbiased simulations or upon application of a restraining potential to maintain the vesicles in close proximity. The shape of SP-B appears to enable it to bind to two vesicles at once, forcing their proximity, and to facilitate the initial transfer of lipids to form a high-energy hemifusion intermediate. Our results may provide insight into more general mechanisms of protein-mediated membrane fusion, and a possible role of SP-B in the secretory pathway and transfer of lung surfactant to the gas exchange interface. PMID- 20923648 TI - Probing intracellular motor protein activity using an inducible cargo trafficking assay. AB - Although purified cytoskeletal motor proteins have been studied extensively with the use of in vitro approaches, a generic approach to selectively probe actin and microtubule-based motor protein activity inside living cells is lacking. To examine specific motor activity inside living cells, we utilized the FKBP-rapalog FRB heterodimerization system to develop an in vivo peroxisomal trafficking assay that allows inducible recruitment of exogenous and endogenous kinesin, dynein, and myosin motors to drive specific cargo transport. We demonstrate that cargo rapidly redistributes with distinct dynamics for each respective motor, and that combined (antagonistic) actions of more complex motor combinations can also be probed. Of importance, robust cargo redistribution is readily achieved by one type of motor protein and does not require the presence of opposite-polarity motors. Simultaneous live-cell imaging of microtubules and kinesin or dynein propelled peroxisomes, combined with high-resolution particle tracking, revealed that peroxisomes frequently pause at microtubule intersections. Titration and washout experiments furthermore revealed that motor recruitment by rapalog induced heterodimerization is dose-dependent but irreversible. Our assay directly demonstrates that robust cargo motility does not require the presence of opposite polarity motors, and can therefore be used to characterize the motile properties of specific types of motor proteins. PMID- 20923649 TI - Quantitative analysis of actin turnover in Listeria comet tails: evidence for catastrophic filament turnover. AB - Rapid assembly and disassembly (turnover) of actin filaments in cytoplasm drives cell motility and shape remodeling. While many biochemical processes that facilitate filament turnover are understood in isolation, it remains unclear how they work together to promote filament turnover in cells. Here, we studied cellular mechanisms of actin filament turnover by combining quantitative microscopy with mathematical modeling. Using live cell imaging, we found that actin polymer mass decay in Listeria comet tails is very well fit by a simple exponential. By analyzing candidate filament turnover pathways using stochastic modeling, we found that exponential polymer mass decay is consistent with either slow treadmilling, slow Arp2/3-dissociation, or catastrophic bursts of disassembly, but is inconsistent with acceleration of filament turnover by severing. Imaging of single filaments in Xenopus egg extract provided evidence that disassembly by bursting dominates isolated filament turnover in a cytoplasmic context. Taken together, our results point to a pathway where filaments grow transiently from barbed ends, rapidly terminate growth to enter a long-lived stable state, and then undergo a catastrophic burst of disassembly. By keeping filament lengths largely constant over time, such catastrophic filament turnover may enable cellular actin assemblies to maintain their mechanical integrity as they are turning over. PMID- 20923650 TI - Fluorescence lifetime imaging reveals that the environment of the ATP binding site of myosin in muscle senses force. AB - Fluorescence lifetime imaging microscopy is used to demonstrate that different loads applied to a muscle fiber change the microenvironment of the nucleotide binding pocket of myosin. Permeabilized skeletal muscle fibers in rigor were labeled with a fluorescent ATP analog, 3'-DEAC-propylenediamine (pda)-ATP (3'-O {N-[3-(7-diethylaminocoumarin-3-carboxamido)propyl]carbamoyl}ATP), which was hydrolyzed to the diphosphate. Cycles of small-amplitude stretches and releases (<1% of muscle segment length) were synchronized with fluorescence lifetime imaging and force measurements to correlate the effect of force on the lifetime of the ATP analog bound to the actomyosin complex. Analysis of the fluorescence decay resolved two lifetimes, corresponding to the free nucleotide DEAC-pda-ATP (tau(1) = 0.47 +/- 0.03 ns; mean +/- SD) and nucleotide bound to the actomyosin complex (tau(2) = 2.21 +/- 0.06 ns at low strain). Whereas tau(1) did not change with force, tau(2) showed a linear dependence with the force applied to the muscle of 0.43 +/- 0.05 ps/kPa. Hence, the molecular environment of the nucleotide binding pocket of myosin is directly affected by a change of length applied at the ends of the fiber segments. These changes may help explain how force modulates the actomyosin ATPase cycle and thus the physiology and energetics of contraction. PMID- 20923651 TI - DnaB helicase activity is modulated by DNA geometry and force. AB - The replicative helicase for Escherichia coli is DnaB, a hexameric, ring-shaped motor protein that encircles and translocates along ssDNA, unwinding dsDNA in advance of its motion. The microscopic mechanisms of DnaB are unknown; further, prior work has found that DnaB's activity is modified by other replication proteins, indicating some mechanistic flexibility. To investigate these issues, we quantified translocation and unwinding by single DnaB molecules in three tethered DNA geometries held under tension. Our data support the following conclusions: 1), Unwinding by DnaB is enhanced by force-induced destabilization of dsDNA. 2), The magnitude of this stimulation varies with the geometry of the tension applied to the DNA substrate, possibly due to interactions between the helicase and the occluded ssDNA strand. 3), DnaB unwinding and (to a lesser extent) translocation are interrupted by pauses, which are also dependent on force and DNA geometry. 4), DnaB moves slower when a large tension is applied to the helicase-bound strand, indicating that it must perform mechanical work to compact the strand against the applied force. Our results have implications for the molecular mechanisms of translocation and unwinding by DnaB and for the means of modulating DnaB activity. PMID- 20923652 TI - A nucleotide-independent nitroxide probe reports on site-specific stereomeric environment in DNA. AB - In this report, stereospecific structural and dynamic features in DNA are studied using the site-directed spin labeling technique. A stable nitroxide radical, 1 oxyl-4-bromo-2,2,5,5-tetramethylpyrroline (R5a), was attached postsynthetically to phosphorothioates that were chemically introduced, one at a time, at five sites of a DNA duplex. The two phosphorothioate diastereomers (R(p) or S(p)) were separated, and nitroxide rotational motions were monitored using electron paramagnetic resonance spectroscopy. The resulting spectra vary according to diastereomer identity and location of the labeling site, with R(p)-R5a spectra effectively reporting on local DNA structural features and S(p)-R5a spectra sensing variations in local DNA motions. This establishes R(p)- and S(p)-R5a as unique probes for investigating nucleic acids in a site- and stereospecific manner, which may aid studies of stereospecific DNA/protein interactions. In addition, weighted averages of individual R(p) and S(p) spectra match those of R5a attached to mixed diastereomers. This suggests that R5a linked to mixed diastereomers reports on the composite behaviors of R(p)- and S(p)-R5a and is useful in initial probing of the DNA local environment. This work advances understanding of R5a/DNA coupling, and is a key step forward in developing a nucleotide-independent spectroscopic probe for studying nucleic acids. PMID- 20923653 TI - Anisotropic elastic network modeling of entire microtubules. AB - Microtubules are supramolecular structures that make up the cytoskeleton and strongly affect the mechanical properties of the cell. Within the cytoskeleton filaments, the microtubule (MT) exhibits by far the highest bending stiffness. Bending stiffness depends on the mechanical properties and intermolecular interactions of the tubulin dimers (the MT building blocks). Computational molecular modeling has the potential for obtaining quantitative insights into this area. However, to our knowledge, standard molecular modeling techniques, such as molecular dynamics (MD) and normal mode analysis (NMA), are not yet able to simulate large molecular structures like the MTs; in fact, their possibilities are normally limited to much smaller protein complexes. In this work, we developed a multiscale approach by merging the modeling contribution from MD and NMA. In particular, MD simulations were used to refine the molecular conformation and arrangement of the tubulin dimers inside the MT lattice. Subsequently, NMA was used to investigate the vibrational properties of MTs modeled as an elastic network. The coarse-grain model here developed can describe systems of hundreds of interacting tubulin monomers (corresponding to up to 1,000,000 atoms). In particular, we were able to simulate coarse-grain models of entire MTs, with lengths up to 350 nm. A quantitative mechanical investigation was performed; from the bending and stretching modes, we estimated MT macroscopic properties such as bending stiffness, Young modulus, and persistence length, thus allowing a direct comparison with experimental data. PMID- 20923654 TI - Coupling of retinal, protein, and water dynamics in squid rhodopsin. AB - The light-induced isomerization of the retinal from 11-cis to all-trans triggers changes in the conformation of visual rhodopsins that lead to the formation of the activated state, which is ready to interact with the G protein. To begin to understand how changes in the structure and dynamics of the retinal are transmitted to the protein, we performed molecular dynamics simulations of squid rhodopsin with 11-cis and all-trans retinal, and with two different force fields for describing the retinal molecule. The results indicate that structural rearrangements in the binding pocket, albeit small, propagate toward the cytoplasmic side of the protein, and affect the dynamics of internal water molecules. The sensitivity of the active-site interactions on the retinal force field parameters highlights the coupling between the retinal molecule and its immediate protein environment. PMID- 20923655 TI - Stable and metastable states of human amylin in solution. AB - Patients with type II diabetes exhibit fibrillar deposits of human amylin protein in the pancreas. It has been proposed that amylin oligomers arising along the aggregation or fibril-formation pathways are important in the genesis of the disease. In a step toward understanding these aggregation pathways, in this work we report the conformational preferences of human amylin monomer in solution using molecular simulations and infrared experiments. In particular, we identify a stable conformer that could play a key role in aggregation. We find that amylin adopts three stable conformations: one with an alpha-helical segment comprising residues 9-17 and a short antiparallel beta-sheet comprising residues 24-28 and 31-35; one with an extended antiparallel beta-hairpin with the turn region comprising residues 20-23; and one with no particular structure. Using detailed calculations, we determine the relative stability of these various conformations, finding that the beta-hairpin conformation is the most stable, followed by the alpha-helical conformation, and then the unstructured coil. To test our predicted structure, we calculate its infrared spectrum in the amide I stretch regime, which is sensitive to secondary structure through vibrational couplings and linewidths, and compare it to experiment. We find that theoretically predicted spectra are in good agreement with the experimental line shapes presented herein. The implications of the monomer secondary structures on its aggregation pathway and on its interaction with cell membranes are discussed. PMID- 20923656 TI - Statistical mechanics of integral membrane protein assembly. AB - During the synthesis of integral membrane proteins (IMPs), the hydrophobic amino acids of the polypeptide sequence are partitioned mostly into the membrane interior and hydrophilic amino acids mostly into the aqueous exterior. Using a many-body statistical mechanics model, we analyze the minimum free energy state of polypeptide sequences partitioned into alpha-helical transmembrane (TM) segments and the role of thermal fluctuations. Results suggest that IMP TM segment partitioning shares important features with general theories of protein folding. For random polypeptide sequences, the minimum free energy state at room temperature is characterized by fluctuations in the number of TM segments with very long relaxation times. Moreover, simple assembly scenarios do not produce a unique number of TM segments due to jamming phenomena. On the other hand, for polypeptide sequences corresponding to actual IMPs, the minimum free energy structure with the wild-type number of segments is free of number fluctuations due to an anomalously large gap in the energy spectrum. Now, simple assembly scenarios do reproduce the minimum free energy state without jamming. Finally, we find a threshold number of random point mutations where the size of the anomalous gap is reduced to the point that the wild-type ground state is destabilized and number fluctuations reappear. PMID- 20923657 TI - Exploring the conformational states and rearrangements of Yarrowia lipolytica Lipase. AB - We report the 1.7 A resolution crystal structure of the Lip2 lipase from Yarrowia lipolytica in its closed conformation. The Lip2 structure is highly homologous to known structures of the fungal lipase family (Thermomyces lanuginosa, Rhizopus niveus, and Rhizomucor miehei lipases). However, it also presents some unique features that are described and discussed here in detail. Structural differences, in particular in the conformation adopted by the so-called lid subdomain, suggest that the opening mechanism of Lip2 may differ from that of other fungal lipases. Because the catalytic activity of lipases is strongly dependent on structural rearrangement of this mobile subdomain, we focused on elucidating the molecular mechanism of lid motion. Using the x-ray structure of Lip2, we carried out extensive molecular-dynamics simulations in explicit solvent environments (water and water/octane interface) to characterize the major structural rearrangements that the lid undergoes under the influence of solvent or upon substrate binding. Overall, our results suggest a two-step opening mechanism that gives rise first to a semi-open conformation upon adsorption of the protein at the water/organic solvent interface, followed by a further opening of the lid upon substrate binding. PMID- 20923658 TI - Dimerization and its role in GMP formation by human guanylate binding proteins. AB - The mechanism of oligomerization and its role in the regulation of activity in large GTPases are not clearly understood. Human guanylate binding proteins (hGBP 1 and 2) belonging to large GTPases have the unique feature of hydrolyzing GTP to a mixture of GDP and GMP with unequal ratios. Using a series of truncated and mutant proteins of hGBP-1, we identified a hydrophobic helix in the connecting region between the two domains that plays a critical role in dimerization and regulation of the GTPase activity. The fluorescence with 1-8-anilinonaphthalene sulfonate and circular dichroism measurements together suggest that in the absence of the substrate analog, the helix is masked inside the protein but becomes exposed through a substrate-induced conformational switch, and thus mediates dimerization. This is further supported by the intrinsic fluorescence experiment, where Leu(298) of this helix is replaced by a tryptophan. Remarkably, the enzyme exhibits differential GTPase activities depending on dimerization; a monomer produces only GDP, but a dimer gives both GDP and GMP with stimulation of the activity. An absolute dependence of GMP formation with dimerization demonstrates a cross talk between the monomers during the second hydrolysis. Similar to hGBP-1, hGBP-2 showed dimerization-related GTPase activity for GMP formation, indicating that this family of proteins follows a broadly similar mechanism for GTP hydrolysis. PMID- 20923659 TI - Allosteric response is both conserved and variable across three CheY orthologs. AB - A computational method to identify residues likely to initiate allosteric signals has been developed. The method is based on differences within stability and flexibility profiles between wild-type and perturbed structures as computed by a distance constraint model. Application of the approach to three bacterial chemotaxis protein Y (CheY) orthologs provides a comparison of allosteric response across protein family divergence. Interestingly, we observe a rich mixture of both conservation and variability within the identified allosteric sites. While similarity within the overall response parallels the evolutionary relationships, >50% of the best scoring putative sites are only identified in a single ortholog. These results suggest that detailed descriptions of intraprotein communication are substantially more variable than structure and function, yet do maintain some evolutionary relationships. Finally, structural clusters of large response identify four allosteric hotspots, including the beta4/alpha4 loop known to be critical to relaying the CheY phosphorylation signal. PMID- 20923660 TI - Consistent picture of the reversible thermal unfolding of hen egg-white lysozyme from experiment and molecular dynamics. AB - Synchrotron radiation circular dichroism, Fourier transform infrared, and nuclear magnetic resonance spectroscopies, and small-angle x-ray scattering were used to monitor the reversible thermal unfolding of hen egg white lysozyme. The results were compared with crystal structures and high- and low-temperature structures derived from molecular-dynamics calculations. The results of both experimental and computational methods indicate that the unfolding process starts with the loss of beta-structures followed by the reversible loss of helix content from ~40% at 20 degrees C to 27% at 70 degrees C and ~20% at 77 degrees C, beyond which unfolding becomes irreversible. Concomitantly there is a reversible increase in the radius of gyration of the protein from 15 A to 18 A. The reversible decrease in forward x-ray scattering demonstrates a lack of aggregation upon unfolding, suggesting the change is due to a larger dilation of hydration water than of bulk water. Molecular-dynamics simulations suggest a similar sequence of events and are in good agreement with the (1)H(N) chemical shift differences in nuclear magnetic resonance. This study demonstrates the power of complementary methods for elucidating unfolding/refolding processes and the nature of both the unfolded structure, for which there is no crystallographic data, and the partially unfolded forms of the protein that can lead to fibril formation and disease. PMID- 20923661 TI - Activation of the edema factor of Bacillus anthracis by calmodulin: evidence of an interplay between the EF-calmodulin interaction and calcium binding. AB - Calmodulin (CaM) is a remarkably flexible protein which can bind multiple targets in response to changes in intracellular calcium concentration. It contains four calcium-binding sites, arranged in two globular domains. The calcium affinity of CaM N-terminal domain (N-CaM) is dramatically reduced when the complex with the edema factor (EF) of Bacillus anthracis is formed. Here, an atomic explanation for this reduced affinity is proposed through molecular dynamics simulations and free energy perturbation calculations of the EF-CaM complex starting from different crystallographic models. The simulations show that electrostatic interactions between CaM and EF disfavor the opening of N-CaM domains usually induced by calcium binding. Relative calcium affinities of the N-CaM binding sites are probed by free energy perturbation, and dissociation probabilities are evaluated with locally enhanced sampling simulations. We show that EF impairs calcium binding on N-CaM through a direct conformational restraint on Site 1, by an indirect destabilization of Site 2, and by reducing the cooperativity between the two sites. PMID- 20923662 TI - Role of the conformational versatility of the neurotrophin N-terminal regions in their recognition by Trk receptors. AB - Neurotrophins (NTs) represent a family of proteins that play an important role in the survival, development, and function of neurons. Extensive efforts are currently being made to develop small molecules endowed with agonist or antagonist NT activity. The structurally versatile N-termini of these proteins are considered regions of interest for the design of new molecules. By combining experimental and computational approaches, we analyzed the intrinsic conformational preferences of the N-termini of two of the most important NTs: NGF (NGF-Nter) and NT4 (NT4-Nter). Circular dichroism spectra clearly indicate that both peptides show a preference for random coil states. Because this finding does not preclude the possibility that structured forms may occur in solution as minor conformational states, we performed molecular-dynamics simulations to gain insights into the structural features of populated species. In line with the circular dichroism analysis, the simulations show a preference for unstructured states for both peptides. However, the simulations also show that for NT4-Nter, and to a lesser extent for NGF-Nter, helical conformations, which are required for binding to the Trk receptor, are present in the repertoire of structures that are intrinsically accessible to these peptides. Accordingly, molecular recognition of NTs by the Trk receptor is accomplished by the general mechanism known as population shift. These findings provide a structural rationale for the observed activity of synthetic peptides based on these NT regions. They also suggest strategies for the development of biologically active peptide-based compounds. PMID- 20923663 TI - Effects of curvature and composition on alpha-synuclein binding to lipid vesicles. AB - Parkinson's disease is characterized by the presence of intracellular aggregates composed primarily of the neuronal protein alpha-synuclein (alphaS). Interactions between alphaS and various cellular membranes are thought to be important to its native function as well as relevant to its role in disease. We use fluorescence correlation spectroscopy to investigate binding of alphaS to lipid vesicles as a function of the lipid composition and membrane curvature. We determine how these parameters affect the molar partition coefficient of alphaS, providing a quantitative measure of the binding energy, and calculate the number of lipids required to bind a single protein. Specific anionic lipids have a large effect on the free energy of binding. Lipid chain saturation influences the binding interaction to a lesser extent, with larger partition coefficients measured for gel-phase vesicles than for fluid-phase vesicles, even in the absence of anionic lipid components. Although we observe variability in the binding of the mutant proteins, differences in the free energies of partitioning are less dramatic than with varied lipid compositions. Vesicle curvature has a strong effect on the binding affinity, with a >15-fold increase in affinity for small unilamellar vesicles over large unilamellar vesicles, suggesting that alphaS may be a curvature-sensing protein. Our findings provide insight into how physical properties of the membrane may modulate interactions of alphaS with cellular membranes. PMID- 20923664 TI - Influence of pH on the human prion protein: insights into the early steps of misfolding. AB - Transmissible spongiform encephalopathies, or prion diseases, are caused by misfolding and aggregation of the prion protein PrP. Conversion from the normal cellular form (PrP(C)) or recombinant PrP (recPrP) to a misfolded form is pH sensitive, in that misfolding and aggregation occur more readily at lower pH. To gain more insight into the influence of pH on the dynamics of PrP and its potential to misfold, we performed extensive molecular-dynamics simulations of the recombinant PrP protein (residues 90-230) in water at three different pH regimes: neutral (or cytoplasmic) pH (~7.4), middle (or endosomal) pH (~5), and low pH (<4). We present five different simulations of 50 ns each for each pH regime, amounting to a total of 750 ns of simulation time. A detailed analysis and comparison with experiment validate the simulations and lead to new insights into the mechanism of pH-induced misfolding. The mobility of the globular domain increases with decreasing pH, through displacement of the first helix and instability of the hydrophobic core. At middle pH, conversion to a misfolded (PrP(Sc)-like) conformation is observed. The observed changes in conformation and stability are consistent with experimental data and thus provide a molecular basis for the initial steps in the misfolding process. PMID- 20923665 TI - The effects of pK(a) tuning on the thermodynamics and kinetics of folding: design of a solvent-shielded carboxylate pair at the a-position of a coiled-coil. AB - The tuning of the pK(a) of ionizable residues plays a critical role in various protein functions, such as ligand-binding, catalysis, and allostery. Proteins harness the free energy of folding to position ionizable groups in highly specific environments that strongly affect their pK(a) values. To investigate the interplay among protein folding kinetics, thermodynamics, and pK(a) modulation, we introduced a pair of Asp residues at neighboring interior positions of a coiled-coil. A single Asp residue was replaced for an Asn side chain at the a position of the coiled-coil from GCN4, which was also crosslinked at the C terminus via a flexible disulfide bond. The thermodynamic and kinetic stability of the system was measured by circular dichroism and stopped-flow fluorescence as a function of pH and concentration of guanidine HCl. Both sets of data are consistent with a two-state equilibrium between fully folded and unfolded forms. Distinct pK(a) values of 6.3 and 5.35 are assigned to the first and second protonation of the Asp pair; together they represent an energetic difference of 5 kcal/mol relative to the protonation of two Asp residues with unperturbed pK(a) values. Analysis of the rate data as a function of pH and denaturant concentration allowed calculation of the kinetic constants for the conformational transitions of the peptide with the Asp residues in the doubly protonated, singly protonated, and unprotonated forms. The doubly and singly protonated forms fold rapidly, and a phi-value analysis shows that their contribution to folding occurs subsequent to the transition state ensemble for folding. By contrast, the doubly charged state shows a reduced rate of folding and a phi-value near 0.5 indicative of a repulsive interaction, and possibly also heterogeneity in the transition state ensemble. PMID- 20923666 TI - Large domain fluctuations on 50-ns timescale enable catalytic activity in phosphoglycerate kinase. AB - Large-scale domain motions of enzymes are often essential for their biological function. Phosphoglycerate kinase has a wide open domain structure with a hinge near the active center between the two domains. Applying neutron spin echo spectroscopy and small-angle neutron scattering we have investigated the internal domain dynamics. Structural analysis reveals that the holoprotein in solution seems to be more compact compared to the crystal structure but would not allow the functionally important phosphoryl transfer between the substrates if the protein were static. Brownian large-scale domain fluctuation dynamics on a timescale of 50 ns was revealed by neutron spin echo spectroscopy. The dynamics observed was compared to the displacement patterns of low-frequency normal modes. The displacements along the normal-mode coordinates describe our experimental results reasonably well. In particular, the domain movements facilitate a close encounter of the key residues in the active center to build the active configuration. The observed dynamics shows that the protein has the flexibility to allow fluctuations and displacements that seem to enable the function of the protein. Moreover, the presence of the substrates increases the rigidity, which is deduced from a faster dynamics with smaller amplitude. PMID- 20923667 TI - Time-resolved NMR: extracting the topology of complex enzyme networks. AB - The use of nondestructive NMR spectroscopy for enzymatic studies offers unique opportunities to identify nearly all enzymatic byproducts and detect unstable short-lived products or intermediates at the molecular level; however, numerous challenges must be overcome before it can become a widely used tool. The biosynthesis of acetyl-coenzyme A (acetyl-CoA) by acetyl-CoA synthetase is used here as a case study for the development of an analytical NMR-based time-course assay platform. We describe an algorithm to deconvolve superimposed spectra into spectra for individual molecules, and further develop a model to simulate the acetyl-CoA synthetase enzyme reaction network using the data derived from time course NMR. Simulation shows indirectly that synthesis of acetyl-CoA is mediated via an enzyme-bound intermediate (possibly acetyl-AMP) and is accompanied by a nonproductive loss from an intermediate. The ability to predict enzyme function based on partial knowledge of the enzymatic pathway topology is also discussed. PMID- 20923669 TI - NMR separation of intra- and extracellular compounds based on intermolecular coherences. AB - NMR spectroscopy is a powerful tool for detection and characterization of chemical compounds in biological systems. Its application in pharmaceutical studies in cell cultures, however, has been hampered by the enormous technical challenges in separating intra- from extracellular amounts of one substance. We introduce a novel approach to separate intra- from extracellular NMR signal based on the detection of intermolecular zero-quantum coherences in presence of a chemical shift agent. In a sample of large cells in culture, the investigation of cellular uptake of pharmacological substances becomes feasible. The addition of 10 mM Tm-DOTP to a suspension of 100 Xenopus laevis oocytes resulted in sufficient separation of resonance frequencies between intra- and extracellular water. Upon selective excitation of either intra- or extracellular water signal, only intra- or extracellular components were observed, respectively. The presented localization technique provides intrinsic averaging over a large number of cells, resulting in a significant signal gain. The method works on standard NMR spectrometers, which are available at most scientific research institutions today. On a high-resolution NMR system with a cryoprobe, a 20-fold sensitivity gain was observed as compared to conventionally localized NMR spectroscopy of a single X. laevis oocyte on dedicated NMR microscopes. PMID- 20923668 TI - SEIRA spectroscopy on a membrane receptor monolayer using lipoprotein particles as carriers. AB - Surface-enhanced infrared absorption (SEIRA) difference spectroscopy can probe reactions in a protein monolayer tethered to a nanostructured gold surface. SEIRA studies of membrane proteins, however, remain challenging due to sample stability, effects of the metal surface on function, and the need for a membrane mimicking environment. Here we demonstrate and characterize a model system for membrane receptor investigations using SEIRA spectroscopy. The system employs nanoscale apolipoprotein bound bilayer (NABB) particles, similar to discoidal high-density lipoprotein particles, as soluble carriers for the G-protein-coupled receptor rhodopsin. The His-tag of the engineered apolipoprotein allows for selective binding of the NABBs to a Ni-NTA modified surface, while the lipid environment of the particle ensures stability and protection of the embedded receptor. Using SEIRA spectroscopy, we followed specific binding of rhodopsin loaded NABB particles to the surface and formation of a membrane protein monolayer. Functionality of the photoreceptor in the immobilized NABBs was probed by SEIRA difference spectroscopy confirming protein conformational changes associated with photoactivation. Orientation of the immobilized NABB particles was assessed by comparing SEIRA data with polarized attenuated total reflection Fourier-transform infrared spectroscopy. Thus, SEIRA difference spectroscopy supported by the NABB technology provides a promising approach for further functional studies of transmembrane receptors. PMID- 20923670 TI - Signal/noise analysis of FRET-based sensors. AB - Molecular sensors based on intramolecular Forster resonance energy transfer (FRET) have become versatile tools to monitor regulatory molecules in living tissue. However, their use is often compromised by low signal strength and excessive noise. We analyzed signal/noise (SNR) aspects of spectral FRET analysis methods, with the following conclusions: The most commonly used method (measurement of the emission ratio after a single short wavelength excitation) is optimal in terms of signal/noise, if only relative changes of this uncalibrated ratio are of interest. In the case that quantitative data on FRET efficiencies are required, these can be calculated from the emission ratio and some calibration parameters, but at reduced SNR. Lux-FRET, a recently described method for spectral analysis of FRET data, allows one to do so in three different ways, each based on a ratio of two out of three measured fluorescence signals (the donor and acceptor signal during a short-wavelength excitation and the acceptor signal during long wavelength excitation). Lux-FRET also allows for calculation of the total abundance of donor and acceptor fluorophores. The SNR for all these quantities is lower than that of the plain emission ratio due to unfavorable error propagation. However, if ligand concentration is calculated either from lux FRET values or else, after its calibration, from the emission ratio, SNR for both analysis modes is very similar. Likewise, SNR values are similar, if the noise of these quantities is related to the expected dynamic range. We demonstrate these relationships based on data from an Epac-based cAMP sensor and discuss how the SNR changes with the FRET efficiency and the number of photons collected. PMID- 20923671 TI - Improved probes for hybrid voltage sensor imaging. AB - Hybrid voltage sensors (hVoS) probe membrane potential by coupling the fluorescence of membrane-anchored proteins to the movement of a membrane-embedded hydrophobic anion dipicrylamine. Fluorescence resonance energy transfer between these two components transduces voltage changes into fluorescence changes, providing a signal for imaging electrical activity in genetically targeted cells. To improve hVoS signals, we systematically varied the optical properties, membrane targeting motifs, and linkages of fluorescent proteins to optimize the normalized fluorescence change (DeltaF/F) and signal/noise ratio. The best results were obtained with cerulean fluorescent protein tagged N-terminally with a GAP43 motif and C-terminally with a truncated h-ras motif. With 100 mV steps in PC12 cells, this probe produced DeltaF/F = 26% (4 MUM dipicrylamine), which was threefold greater than that obtained with the original farnesylated EGFP construct. We also obtained a fivefold greater signal/noise ratio, which was 70% of a theoretical optimum. We designate this GAP43-CerFP-t-h-ras construct as hVoS 2.0. With the aid of a theoretical analysis, we estimated that hVoS 2.0 places its fluorophore ~40 A from the bilayer midplane. hVoS 2.0 performed well in cultured hippocampal neurons, where single action potentials produced clear fluorescence changes in a single trial. This improved probe should help investigators image voltage in genetically targeted neurons. PMID- 20923672 TI - Binding of more than one retinoid to visual opsins. AB - Visual opsins bind 11-cis retinal at an orthosteric site to form rhodopsins but increasing evidence suggests that at least some are capable of binding an additional retinoid(s) at a separate, allosteric site(s). Microspectrophotometric measurements on isolated, dark-adapted, salamander photoreceptors indicated that the truncated retinal analog, beta-ionone, partitioned into the membranes of green-sensitive rods; however, in blue-sensitive rod outer segments, there was an enhanced uptake of four or more beta-ionones per rhodopsin. X-ray crystallography revealed binding of one beta-ionone to bovine green-sensitive rod rhodopsin. Cocrystallization only succeeded with extremely high concentrations of beta ionone and binding did not alter the structure of rhodopsin from the inactive state. Salamander green-sensitive rod rhodopsin is also expected to bind beta ionone at sufficiently high concentrations because the binding site is present on its surface. Therefore, both blue- and green-sensitive rod rhodopsins have at least one allosteric binding site for retinoid, but beta-ionone binds to the latter type of rhodopsin with low affinity and low efficacy. PMID- 20923674 TI - Mass spectrometry in laboratory medicine: When "high-tech" meets routine needs. PMID- 20923673 TI - Magnetic and contrast properties of labeled platelets for magnetomotive optical coherence tomography. AB - This article introduces a new functional imaging paradigm that uses optical coherence tomography (OCT) to detect rehydrated, lyophilized platelets (RL platelets) that are in the preclinical trial stage and contain superparamagnetic iron oxides (SPIOs) approved by the U.S. Food and Drug Administration. Platelets are highly functional blood cells that detect and adhere to sites of vascular endothelial damage by forming primary hemostatic plugs. By applying magnetic gradient forces, induced nanoscale displacements (magnetomotion) of the SPIO-RL platelets are detected as optical phase shifts in OCT. In this article, we characterize the iron content and magnetic properties of SPIO-RL platelets, construct a model to predict their magnetomotion in a tissue medium, and demonstrate OCT imaging in tissue phantoms and ex vivo pig arteries. Tissue phantoms containing SPIO-RL platelets exhibited >3 dB contrast/noise ratio at >=1.5 * 10(9) platelets/cm(3). OCT imaging was performed on ex vivo porcine arteries after infusion of SPIO-RL platelets, and specific contrast was obtained on an artery that was surface-damaged (P < 10(-6)). This may enable new technologies for in vivo monitoring of the adherence of SPIO-RL platelets to sites of bleeding and vascular damage, which is broadly applicable for assessing trauma and cardiovascular diseases. PMID- 20923675 TI - Modification of the EMIT immunoassay for the measurement of unbound mycophenolic acid in plasma. AB - OBJECTIVES: Evaluation of the performance of a modified Enzyme Multiplied Immunoassay Technique for therapeutic drug monitoring of plasma free mycophenolic acid (fMPA) concentrations. DESIGN AND METHODS: A fMPA assay was developed on a Viva-E analyzer. A study of prior ultrafiltration conditions and analytical validation of the EMIT assay were performed. RESULTS: The method was reliable and reproducible. CONCLUSIONS: fMPA levels can be monitored using this EMIT assay with the advantage of being an automated method. PMID- 20923676 TI - Validation of an automated intact N-terminal propeptide of type I procollagen (PINP) assay. AB - OBJECTIVES: N-terminal propeptide of type I procollagen assay (PINP) reflects the rate of type I collagen synthesis DESIGN AND METHODS: Different sera were fractioned by gel filtration and analyzed with intact and total PINP assays. The sizes of the antigens were determined by western blotting. The thermal stability was tested at +37 degrees C, +4 degrees C and room temperature (RT). RESULTS: Automated intact PINP assay hardly measured monomeric form. In haemodialysis patients intact and total PINP assays gave significantly different results. The monomeric PINP antigen in serum was larger than the trimeric PINP antigen. PINP were thermally stable at least 7 days at +4 degrees C and at RT but the results of both assays were decreased similarly at +37 degrees C. CONCLUSIONS: The IDS iSYS intact PINP assay is precise and sensitive. It seems that monomeric form is not derived from the thermal instability of the trimers but acts as a confounding factor. PMID- 20923677 TI - Multicenter evaluation of a new automated electrochemiluminescence immunoassay for the quantification of testosterone compared to liquid chromatography tandem mass spectrometry. AB - OBJECTIVES: A new electrochemiluminescence testosterone immunoassay (Elecsys(r) Testo II) was evaluated. DESIGN AND METHODS: Within-run precision, total precision, and method comparisons to the former immunoassay and LC-MS/MS were investigated. Reference intervals were established for adults and children. RESULTS: Imprecision ranged from 0.9% to 8.5%. Method comparisons revealed slopes from 0.68 to 1.32 and coefficients of correlation from 0.893 to 0.991. CONCLUSIONS: Improved agreement with LC-MS/MS was demonstrated, especially for female patients. The assay may be a suitable alternative for laboratories with no access to MS techniques. PMID- 20923678 TI - Type of CFTR mutation determines risk of pancreatitis in patients with cystic fibrosis. AB - BACKGROUND & AIMS: Different mutations in the cystic fibrosis gene (CFTR) are associated with different functional status of the exocrine pancreas. We investigated whether CFTR genotypes determine the risk of pancreatitis in patients with cystic fibrosis (CF). METHODS: Patients with pancreatic-sufficient CF were identified from 2 CF population-based databases (N = 277; 62 with pancreatitis and 215 without pancreatitis); patients' genotypes and clinical characteristics were analyzed. The loss of pancreatic function associated with each CFTR genotype was determined based on the pancreatic insufficiency prevalence (PIP) score. RESULTS: Patients with pancreatitis were more likely to have genotypes associated with mild (70%) than moderate-severe (30%) PIP scores (P = .004). The cumulative proportion of patients who developed pancreatitis through to the age of 50 years was significantly greater for genotypes associated with mild (50%) than moderate-severe (27%) PIP scores (P = .006). The genotype associated with mild PIP scores had a hazard ratio of 2.4 for pancreatitis (95% confidence interval, 1.3-4.5; P = .006). Patients with pancreatitis were diagnosed with CF at an older median age than those without pancreatitis (14.9 years [interquartile range, 9.5-27.7] vs 9.3 years [interquartile range, 1.5 21.4]; P = .003) and had lower mean levels of sweat chloride than patients without pancreatitis (74.5 +/- 26.2 mmol/L vs 82.8 +/- 25.2 mmol/L; P = .03). CONCLUSIONS: Specific CFTR genotypes are significantly associated with pancreatitis. Patients with genotypes associated with mild phenotypic effects have a greater risk of developing pancreatitis than patients with genotypes associated with moderate-severe phenotypes. This observation provides further insight into the complex pathogenesis of pancreatitis. PMID- 20923679 TI - Acute venous occlusion enhances matrix metalloprotease activity: Implications on endothelial dysfunction. AB - Venous hypertension is associated with microvascular inflammation, restructuring, and apoptosis, but the cellular and molecular mechanisms underlying these events remain uncertain. In the present study, we tested the hypothesis that elevated venous pressure and reduction of shear stress induce elevated enzymatic activity. This activity in turn may affect endothelial surface receptors and promote their dysfunction. Using a rodent model for venous hypertension using acute venular occlusion, microzymographic techniques for enzyme detection, and immunohistochemistry for receptor labeling, we found increased activity of the matrix metalloproteases (MMPs) -1, -8, and -9 and tissue inhibitors of metalloproteases (TIMPs) -1 and -2 in both high- and low-pressure regions. In this short time frame, we also observed that elevated venule pressure led to two different fates for the vascular endothelial growth factor receptor-2 (VEGFR2); in higher-pressure upstream regions, some animals exhibited higher VEGFR2 expression, while others displayed lower levels upstream compared to their downstream counterparts with lower pressure. VEGFR2 expression was, on average, more pronounced upon application of MMP inhibitor, suggesting possible cleavage of the receptor by activated enzymes in this model. We conclude that venous pressure elevation increases enzymatic activity which may contribute to inflammation and endothelial dysfunction associated with this disease by influencing critical surface receptors. PMID- 20923680 TI - Comparison of the binding affinity of chlorogenic acid with two serum albumins. AB - Chlorogenic acid (CA) is a well-known ester of caffeic acid present in some food. It is also an active component in traditional Chinese medicines which are used to treat various diseases, but the molecular basis of CA is not clear. In the present work, the proton selective relaxation rate and the affinity index were used to investigate the interaction of CA with human serum albumin and bovine serum albumin under the same buffer conditions. The results indicated that the binding affinity of chlorogenic acid to BSA was stronger than that to HSA. The binding site of the ligand-protein complex was elucidated by molecular docking, and the specific interaction was observed from those hydrogen bonds formed by the ligand and active residues. Using a combination of TR-NOE detection, the optimal ligand conformation was illustrated. Further conformational analysis of the complex revealed that the ability of hydrogen bond formation by polar side chain residues in the binding site of BSA might contribute to the greater binding affinity. The results provide a better understanding of CA binding and should contribute towards the design of modifications of CA for therapeutic purposes. PMID- 20923681 TI - Generation of the oxidized form protects human brain type creatine kinase against cystine-induced inactivation. AB - Cystine accumulation in cystinotic patients has been reported to inhibit brain type creatine kinase (BBCK), an important thiol-containing enzyme in energy homeostasis. In this research, we found that the oxidized form of BBCK (O-BBCK) was induced by cystine, and the intramolecular disulfide bond of O-BBCK was formed between Cys74 and Cys254. The wild type BBCK was found to be more resistant to the inactivation induced by cystine when compared to the single point mutant C74S or C254S. Meanwhile, the existence of GSH could protect the wild type BBCK more efficiently than the mutants. These observations suggested that the ability to generate the oxidized form could protect BBCK against the intracellular oxidative stress. PMID- 20923683 TI - Comparison of the protective efficacy of recombinant adenoviruses against classical swine fever. AB - Classical swine fever (CSF), which is caused by classical swine fever virus (CSFV), is a highly contagious and often fatal swine disease that is responsible for significant losses to the swine industry worldwide. Previously, we demonstrated that pigs immunized with a recombinant adenovirus (rAdV-E2) expressing the E2 glycoprotein of CSFV were protected against virulent CSFV; however, a few pigs showed a short-term fever and occasional pathological changes. To enhance the efficacy of the vaccine, we constructed two recombinant adenoviruses, namely, rAdV-E2UL49, which encodes the CSFV E2 gene fused with the UL49 gene from pseudorabies virus (PRV), and rAdV-optiE2, which expresses the codon-optimized CSFV E2 gene. With these viruses, we performed a comparative immunogenicity trial in rabbits and pigs and compared these recombinant adenovirus vaccines (rAdV-E2UL49 and rAdV-optiE2) with the one containing the wild-type E2 gene (rAdV-E2). In terms of antibody titers, IFN-gamma production, lymphocyte proliferation, viral loads and clinical protection from the disease, rAdV-E2UL49 was more immunogenic and protective against C-strain CSFV in rabbits and Shimen strain CSFV in pigs than rAdV-optiE2 and rAdV-E2. Data from this study could assist in making decisions for further development of recombinant adenoviruses as vaccine candidates against CSF. PMID- 20923684 TI - Differential expression of SLAMS and other modulatory molecules by human plasma cells during normal maturation. AB - Plasma cells (PCs) are specialized in antibody (Ab) production and they are, therefore, responsible for maintaining humoral immune responses. The human PC compartment is heterogeneous. PCs from inductive secondary lymphoid organs and from peripheral blood (PB) show less capability for prolonged survival and Ab production than bone marrow (BM) PCs, a pool consisting of fully mature cells. The HLDA9 workshop has allowed the use of labeled-monoclonal Abs (moAbs) recognizing a variety of recently identified lymphocyte modulatory surface receptors. In this study, flow cytometry analysis has been used to define the presence of these receptors on human PCs obtained from human tonsil (as an example of inductive organ), from PB and from BM. It was found that human PCs commonly expressed SLAMF1 (CD150), SLAMF2 (CD48), SLAMF3 (CD229), SLAMF6 (CD352) and SLAMF7 (CD319), but not SLAMF4 (CD244). In addition, PCs distinctively showed a low level of SLAMF5 (CD84) and a very high level of SLAMF7 expression in comparison with earlier stages of B cell maturation. All PC subsets exhibited a similar pattern of expression of SLAMF receptors suggesting a stage-dependent role for these proteins. In addition, most circulating PCs clearly expressed TNFRSF14 (CD270), BTLA (CD272), B7-1 (CD80) and B7-2 (CD86), and a substantial fraction of them were also positive for TNFRSF18 (CD357), FCRL1 (CD307a) and LAIR 1 (CD305). In contrast, tonsil and BM PCs only exhibited partial expression of TNFRSF14 and B7-2, a pattern of molecular expression similar to that detected on germinal center (GC) B cells. Present results indicate that human PCs exhibit a common pattern of SLAMF proteins, but differ in the rest of the receptors examined; this difference might be associated with their distinctive homing and functional requirements. PMID- 20923685 TI - Cluster analysis of immunophenotypic data: the example of chronic lymphocytic leukemia. AB - Studies of gene expression profiling have been successfully used for the identification of molecules to be employed as potential prognosticators. In analogy with gene expression profiling, we have previously proposed an original method to identify the immunophenotypic signature of chronic lymphocytic leukemia (CLL) subsets with different prognosis, named surface-antigen expression profiling. According to this method, expression data for surface markers can be successfully analyzed by data mining tools identical to those employed in gene expression profiling studies, including unsupervised and supervised algorithms, with the aim to identify the immunophenotypic signature of CLL subsets with different prognosis. By employing an identical approach for investigating the reactivity of a wide panel of monoclonal antibodies provided by the "Ninth International Workshop on Leukocyte Differentiation Antigens", we were able to identify some of them (i.e. TCL1, CCR7, FCRL2, FCRL3, and CD150) as additional potential markers with prognostic relevance in CLL. These suggestions need to be confirmed: (i) in a new set of clinically characterized CLL cases; (ii) in combination with other prognostic markers in the context of comprehensive scoring systems for clinical outcome prediction. PMID- 20923682 TI - Serotonin 5-HT7 receptor agents: Structure-activity relationships and potential therapeutic applications in central nervous system disorders. AB - Since its discovery in the 1940s in serum, the mammalian intestinal mucosa, and in the central nervous system, serotonin (5-HT) has been shown to be involved in virtually all cognitive and behavioral human functions, and alterations in its neurochemistry have been implicated in the etiology of a plethora of neuropsychiatric disorders. The cloning of 5-HT receptor subtypes has been of importance in enabling them to be classified as specific protein molecules encoded by specific genes. The 5-HT(7) receptor is the most recently classified member of the serotonin receptor family. Since its identification, it has been the subject of intense research efforts driven by its presence in functionally relevant regions of the brain. The availability of some selective antagonists and agonists, in combination with genetically modified mice lacking the 5-HT(7) receptor, has allowed for a better understanding of the pathophysiological role of this receptor. This paper reviews data on localization and pharmacological properties of the 5-HT(7) receptor, and summarizes the results of structure activity relationship studies aimed at the discovery of selective 5-HT(7) receptor ligands. Additionally, an overview of the potential therapeutic applications of 5-HT(7) receptor agonists and antagonists in central nervous system disorders is presented. PMID- 20923686 TI - Serologic cross-reactivity among humans and birds infected with highly pathogenic avian influenza A subtype H5N1 viruses in China. AB - To study immunogenicity and serologic cross-reactivity of hemagglutinins (HAs) among humans and birds infected with highly pathogenic avian influenza (HPAI) H5N1, four representative H5N1 HA genes from humans and birds infected with distinct genetic clusters of H5N1 viruses in China were cloned, and several H5N1 infected human serum and H5N1 positive bird serum samples were used. Recombinant HA proteins were generated for ELISA assays and pseudotype viruses containing HAs were produced for neutralization assays and hemagglutination inhibition (HI) tests. We found significant differences among clades compared to species in binding, neutralization and HI activity of H5N1 strains isolated from birds. While significant differences were observed among species in H5N1 isolated from humans, investigation of H5N1 infected human and avian sera provided evidence that the pressure from nAb may be a driving force for positive selection. Therefore, improved anti-viral nAb therapies could block avian influenza transmission in humans. PMID- 20923687 TI - Invariant natural killer T (iNKT) cell deficiency in chronic mucocutaneous candidiasis--a consequence or a cause? AB - Chronic mucocutaneous candidiasis (CMC) is a group of heterogeneous disorders characterised by primary selective susceptibility to chronic, recurrent Candida infections. The genetic defect of one subgroup of CMC patients have been identified as mutations of the autoimmune regulator (AIRE) gene. Recent data implicated the AIRE gene in iNKT cell development, raising the possibility that iNKT cells may be important in defending against Candida infections. In this study, we enumerated the circulating iNKT frequency in 22 CMC patients (9 with AIRE gene mutations) and 25 healthy controls. We also examined the effect of Candida stimulation on iNKT cells in vitro. Our data demonstrated that peripheral iNKT cell frequency is significantly reduced in CMC patients compared to healthy controls, regardless of their AIRE gene mutation status. Direct stimulation with heat-inactivated whole Candida did not induce iNKT cell proliferation. Furthermore, circulating iNKT cell frequencies in some healthy controls were comparable to CMC patients. These observations suggest that iNKT cell deficiency is part of the CMC disease phenotype irrespective of the presence of AIRE gene mutations but does not appear to confer susceptibility to chronic Candida infections. We postulate that the reduced circulating iNKT cell frequency in CMC is a consequence rather than a cause of chronic Candida infections. PMID- 20923688 TI - Universal primers for rapid detection of hytrosaviruses. AB - Hytrosaviridae is a proposed virus family encompassing viruses that cause salivary gland hypertrophy (SGH) syndrome in infected insects and reduce the fertility in their dipteran insect hosts. They contain a large, double stranded DNA genome of 120-190 kbp. To date, these viruses have been detected only in adult Diptera. These include hytrosaviruses detected in various tsetse fly species (Glossina spp.), the narcissus bulb fly Merodon equestris and the house fly Musca domestica. The limited number of hytrosaviruses reported to date may be a reflection of the frequent absence of external symptoms in infected adult flies and the fact that the virus does not cause rapid mortality. Based on the complete genome sequence of Glossinia pallidipes (GpSGHV) and Musca domestica (MdSGHV) salivary gland hypertrophy viruses, a PCR based methodology was developed to detect the viruses in these species. To be able to detect hytrosaviruses in other Diptera, five degenerate primer pairs were designed and tested on GpSGHV and MdSGHV DNA using gradient PCR with annealing temperatures from 37 to 61 degrees C. Two pairs of primers were selected from p74, two pairs from PIF-1 and one pair from ODV-e66 homologous proteins. Four primer pairs generated a virus specific PCR product on both MdSGHV and GpSGHV at all tested annealing temperatures, while the ODV-e66 based primers did not generate a virus specific product with annealing temperatures higher that 47 degrees C. No non-specific PCR product was found when using genomic DNA of infected flies as template DNA. These results offer new sets of primers that could be used to detect hytrosaviruses in other insects. PMID- 20923689 TI - Simultaneous virus-specific detection of the two cassava brown streak-associated viruses by RT-PCR reveals wide distribution in East Africa, mixed infections, and infections in Manihot glaziovii. AB - The expanding cassava brown streak disease (CBSD) epidemic in East Africa is caused by two ipomoviruses (genus Ipomovirus; Potyviridae), namely, Cassava brown streak virus (CBSV), and Ugandan cassava brown streak virus (UCBSV) that was described recently. A reverse transcription polymerase chain reaction (RT-PCR) based diagnostic method was developed in this study for simultaneous virus specific detection of the two viruses. Results showed that CBSV and UCBSV are distributed widely in the highlands (> 1000 m above the sea level) of the Lake Victoria zone in Uganda and Tanzania and also in the Indian Ocean costal lowlands of Tanzania. Isolates of UCBSV from the Lake Victoria zone were placed to two phylogenetic clusters in accordance with their origin in Uganda or Tanzania, respectively. Mixed infections with CBSV and UCBSV were detected in many cassava plants in the areas surveyed. CBSV was also detected in the perennial species Manihot glaziovii (DNA-barcoded in this study) in Tanzania, which revealed the first virus reservoir other than cassava. The method for detection of CBSV and UCBSV described in this study has important applications for plant quarantine, resistance breeding of cassava, and studies on epidemiology and control of CBSD in East Africa. PMID- 20923690 TI - Development of a blocking ELISA for detection of serum neutralizing antibodies against porcine circovirus type 2. AB - A monoclonal antibody (Mab)-based blocking ELISA was developed for the detection of serum neutralizing antibodies to porcine circovirus type 2 (PCV2). The Mab with neutralizing activity, which was produced by immunizing a recombinant capsid protein of PCV2 expressed in insect cells, was used as the detector antibody. The assay was evaluated in comparison with a serum neutralization assay, and its sensitivity and specificity were determined to be 98.8% and 88.5%, respectively. A significant positive correlation was found between results of the blocking ELISA and the serum neutralization assay (r=0.9381). The assay was verified by testing experimental and commercial pig sera. A longitudinal antibody profile showed that serum neutralizing antibodies were detected 2 weeks after vaccination and that the detection rate reached 100% at 4 weeks. The serum neutralizing antibody profile showed a decrease from the age of 4 to 13 weeks, and seroconversion after 13 weeks in pigs from a commercial pig farm. Additionally, the positive detection rate in 703 sera collected from nine commercial pig farms was 73%. This report demonstrates that the assay is a simple, specific, sensitive and convenient method for epidemiological surveys and evaluations of serum neutralizing antibodies against PCV2. PMID- 20923691 TI - A fish bradykinin (Arg0, Trp5, Leu8-bradykinin) from the defensive skin secretion of the European edible frog, Pelophylax kl. esculentus: structural characterization; molecular cloning of skin kininogen cDNA and pharmacological effects on mammalian smooth muscle. AB - Extensive studies on bradykinin-related peptides (BRPs) generated from plasma kininogens in representative species of various vertebrate taxa, have confirmed that many amphibian skin BRPs reflect those present in putative vertebrate predators. For example, the (Val(1), Thr(6))-bradykinin, present in the defensive skin secretions of many ranids and phyllomedusines, can be generated from plasma kininogens in colubrid snakes-common predators of these frogs. Here, we report the presence of (Arg(0), Trp(5), Leu(8))-bradykinin in the skin secretion of the European edible frog, Pelophylax kl. esculentus, and have found it to be encoded in single copy by a kininogen with an open-reading frame of 68 amino acid residues. This peptide is the archetypal bony fish bradykinin that has been generated from plasma kininogens of the bowfin (Amia calva), the long-nosed gar (Lepisosteus oseus) and the rainbow trout (Onchorhynchus mykiss). More recently, this peptide has been shown to be encoded within cloned kininogens of the Atlantic cod (Gadus morhua) spotted wolf-fish (Anarichas minor), zebrafish (Danio rerio), pufferfish (Tetraodon nigroviridis) and Northern pike (Esox lucius). The latter species is regarded as a major predator of P. kl. esculentus. Synthetic (Arg(0), Trp(5), Leu(8))-bradykinin was previously reported as having multiphasic effects on arterial blood pressure in conscious trout and here we have demonstrated that it can antagonize the relaxation in rat arterial smooth muscle induced by canonical mammalian bradykinin. The discovery of (Arg(0), Trp(5), Leu(8))-bradykinin in the defensive skin secretion of this amphibian completes the spectrum of vertebrate taxon-specific BRPs identified from this source. PMID- 20923692 TI - The absence of VPAC2 leads to aberrant antibody production in Aspergillus fumigatus sensitized and challenged mice. AB - Vasoactive intestinal peptide (VIP) facilitates a "pro-allergy" phenotype when signaling through its G protein-coupled receptor, VPAC(2). We have shown that VPAC(2) knock-out (KO) mice developed an allergic phenotype marked by eosinophilia and elevated serum IgE. Therefore, we hypothesized that the humoral response to allergen challenge in these mice was T(H)2 dominant similar to wild type (WT) C57BL/6 mice. Antibody responses in WT and KO mice were measured after Aspergillus fumigatus conidia inhalation. In contrast to previous reports, basal levels of serum IgG(2a) and IgA were significantly higher in naive VPAC(2) KO animals. Antibody availability in the serum as well as the bronchoalveolar lavage fluid after fungal challenge was dominated by the pro-inflammatory isotype IgG(2a) and the mucosal isotype, IgA. IgA localizing cells dominated in the peribronchovascular areas of allergic KO mice while IgE immune complexes were found in WT allergic lungs. This research shows for the first time that VPAC(2) has a significant effect on antibody regulation, in the context of allergy. PMID- 20923693 TI - Perillyl alcohol protects against ethanol induced acute liver injury in Wistar rats by inhibiting oxidative stress, NFkappa-B activation and proinflammatory cytokine production. AB - Oxidative stress and inflammation are two major etiological factors that are suggested to play key roles in the development of ethanol induced liver injury. Release of proinflammatory cytokine like tumor necrosis factor alpha (TNF-alpha) and activation of nuclear factor kappa-B (NFkappa-B) may strongly intensify inflammation and cell damage. Additionally, reactive oxygen species (ROS) also exerts significant effect in this whole cell signaling machinery. The present study was designed to investigate the protective effects of perillyl alcohol (POH) on ethanol-induced acute liver injury in Wistar rats and its probable mechanism. We have successfully demonstrated that pre-treatment with POH, besides exerting antioxidant activity might be able to modulate TNF-alpha release and NFkappa-B activation. Rats were divided into five groups and treated with ethanol or POH via an intragastric tube for one week. Control group was treated with vehicle, and ethanol treated group was given ethanol (5 g/kg body wt). Animal of treatment groups were pretreated with POH (50 & 100 mg/kg body wt) and have been given ethanol. Serum aspartate aminotransferase, alanine aminotransferase and lactate dehydrogenase and hepatic malondialdehyde were increased significantly by ethanol treatment. Ethanol administration decreased hepatic reduced glutathione content and various antioxidant enzymes activity. TNF-alpha production and NFkappa-B activation was also found to be increased after ethanol administration. POH pre-treatment significantly ameliorates ethanol induced acute liver injury possibly by inhibition of lipid peroxidation, replenishment of endogenous enzymatic and non-enzymatic defense system, downregulation of TNF-alpha as well as NFkappa-B. PMID- 20923694 TI - Neurocognitive effects of HF-rTMS over the dorsolateral prefrontal cortex on the attentional processing of emotional information in healthy women: an event related fMRI study. AB - Current evidence concerning the neurocircuitry underlying the interplay between attention and emotion is mainly correlational. We used high-frequency repetitive Transcranial Magnetic Stimulation (HF-rTMS) to experimentally manipulate activity within the right or left dorsolateral prefrontal cortex (DLPFC) of healthy women and examined changes in attentional processing of emotional information using an emotional modification of the exogenous cueing task during event-related fMRI. Right prefrontal HF-rTMS resulted in impaired disengagement from angry faces, associated with decreased activation within the right DLPFC, dorsal anterior cingulate cortex (dACC) and left superior parietal gyrus, combined with increased activity within the right amygdala. Left prefrontal HF-rTMS resulted in diminished attentional engagement by angry faces and was associated with increased activity within the right DLPFC, dACC, right superior parietal gyrus and left orbitofrontal cortex. The present observations are in line with reports of a functionally interactive network of cortical-limbic pathways that play a central role in emotion regulation. PMID- 20923695 TI - Aggressive behavior during social interaction in mice is controlled by the modulation of tyrosine hydroxylase expression in the prefrontal cortex. AB - The Balb/c strain and the C57BL/6 strain show constitutive differences for tyrosine hydroxylase expression, and noradrenaline (NA) prefrontal transmission. Male mice of these strains also show striking differences in social interaction behaviors, with an increased aggressiveness for the Balb/c strain. To test a potential link between these neurobiological and behavioral parameters, we evaluated the behavioral effects of chronic treatment of mice with BC19, a noreburnamine compound previously known as RU24722, found to modify cell organisation, tyrosine hydoxylase (TH) expression, and its activity into the locus coeruleus (LC). We compared the pharmacological effects between the two strains in social behaviors. Our results show that the emergence of additional TH expressing (TH+) neurons in the rostral part of the LC of Balb/c mice was associated with an increase in the density of TH+ and noradrenergic (NA+) fibers in the molecular layer in the cingular (Cg1) and prelimbic (PrL) parts of the prefrontal cortex (PFC). BC19 treatment resulted in the near-equalization of the LC number of TH+ neurons and of the density of TH+ and NA+ fibers between both strains. The aggressiveness in Balb/c mice was considerably diminished by BC19 treatment, while the originally non aggressive behavior of C57Bl/6 mice was much less affected by BC19 treatment, despite a moderate increase in some offensive behaviors. In additional control experiments, we checked the effect of BC19 on a separate test for anxiety and assessed the effect of noradrenergic N-(2 chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP-4) mediated lesions in C57BL/6 mice on social behaviors. In the present study we show that the BC19 effect in Balb/c mice was independent of anxiety as measured in the light/dark test and that DSP-4 lesions in C57BL/6 mice produced a robust increase in aggressive social interaction. Altogether, these results show that the noradrenergic system, and particularly its projections to the PFC, strongly modulates aggressive behaviors. PMID- 20923696 TI - Enhanced anorexigenic signaling in lean obesity resistant syndecan-3 null mice. AB - Obesity is associated with increased risk of diabetes, cardiovascular disease and several types of cancers. The hypothalamus is a region of the brain critical in the regulation of body weight. One of the critical and best studied hypothalamic circuits is comprised of the melanocortinergic orexigenic agouti-related protein (AgRP) and anorexigenic alpha-melanocyte stimulating hormone (alpha-MSH) neurons. These neurons project axons to the same hypothalamic target neurons and balance each other's activity leading to body weight regulation. We previously showed that the brain proteoglycan syndecan-3 regulates feeding behavior and body weight, and syndecan-3 null (SDC-3(-/-)) mice are lean and obesity resistant. Here we show that the melanocortin agonist Melanotan II (MTII) potently suppresses food intake and activates the hypothalamic paraventricular nuclei (PVN) in SDC-3(-/-) mice based on c-fos immunoreactivity. Interestingly, we determined that the AgRP neuropeptide is reduced in the PVN of SDC-3(-/-) mice compared to wild type mice. In contrast, neuropeptide Y, coexpressed in the AgRP neuron, is not differentially expressed nor is the counteracting neuropeptide alpha-MSH. These findings are unprecedented and indicate that AgRP protein localization can be selectively regulated within the hypothalamus resulting in altered neuropeptide response and tone. PMID- 20923697 TI - Role of the NR2A/2B subunits of the N-methyl-D-aspartate receptor in glutamate induced glutamic acid decarboxylase alteration in cortical GABAergic neurons in vitro. AB - The vulnerability of brain neuronal cell subpopulations to neurologic insults varies greatly. Among cells that survive a pathological insult, for example ischemia or brain trauma, some may undergo morphological and/or biochemical changes that may compromise brain function. The present study is a follow-up of our previous studies that investigated the effect of glutamate-induced excitotoxicity on the GABA synthesizing enzyme glutamic acid decarboxylase (GAD65/67)'s expression in surviving DIV 11 cortical GABAergic neurons in vitro [Monnerie and Le Roux, (2007) Exp Neurol 205:367-382, (2008) Exp Neurol 213:145 153]. An N-methyl-D-aspartate receptor (NMDAR)-mediated decrease in GAD expression was found following glutamate exposure. Here we examined which NMDAR subtype(s) mediated the glutamate-induced change in GAD protein levels. Western blotting techniques on cortical neuron cultures showed that glutamate's effect on GAD proteins was not altered by NR2B-containing diheteromeric (NR1/NR2B) receptor blockade. By contrast, blockade of triheteromeric (NR1/NR2A/NR2B) receptors fully protected against a decrease in GAD protein levels following glutamate exposure. When receptor location on the postsynaptic membrane was examined, extrasynaptic NMDAR stimulation was observed to be sufficient to decrease GAD protein levels similar to that observed after glutamate bath application. Blocking diheteromeric receptors prevented glutamate's effect on GAD proteins after extrasynaptic NMDAR stimulation. Finally, NR2B subunit examination with site-specific antibodies demonstrated a glutamate-induced, calpain-mediated alteration in NR2B expression. These results suggest that glutamate-induced excitotoxic NMDAR stimulation in cultured GABAergic cortical neurons depends upon subunit composition and receptor location (synaptic vs. extrasynaptic) on the neuronal membrane. Biochemical alterations in surviving cortical GABAergic neurons in various disease states may contribute to the altered balance between excitation and inhibition that is often observed after injury. PMID- 20923698 TI - Isolation of a novel catechin from Bergenia rhizomes that has pronounced lipase inhibiting and antioxidative properties. AB - An aqueous ethanol extract of Bergenia crassifolia rhizomes strongly inhibited human pancreatic lipase activity and increased scavenging of DPPH free radicals in vitro. Chromatographic separation of this extract led to isolation of the hydrolysable tannins (+)-catechin 3,5-di-O-gallate (1) and (+)-catechin 3-O gallate (2). This is the first report of the isolation of compound 1 from plant material. This compound strongly inhibited human pancreatic lipase (with an IC(50) value of 0.42 MUg/ml) and exhibited a remarkable free radical-scavenging ability (with an SC(50) value of 1.04 MUg/ml). The chemical structures of 1 and 2 were elucidated using MS, NMR and chemical approaches. PMID- 20923700 TI - A nonsense mutation in the optic atrophy 3 gene (OPA3) causes dilated cardiomyopathy in Red Holstein cattle. AB - Cardiomyopathies are severe degenerative disorders of the myocardium that lead to heart failure. During the last three decades bovine dilated cardiomyopathy (BDCMP) was observed worldwide in cattle of Holstein-Friesian origin. In the Swiss cattle population BDCMP affects Fleckvieh and Red Holstein breeds. The heart of affected animals is enlarged due to dilation of both ventricles. Clinical signs are caused by systolic dysfunction and affected individuals die as a result of severe heart insufficiency. BDCMP follows an autosomal recessive pattern of inheritance and the disease-causing locus was mapped to bovine chromosome 18 (BTA18). In the present study we describe the successful identification of the causative mutation in the OPA3 gene located on BTA18 that was previously reported to cause 3-methylglutaconic aciduria type III in Iraqi Jewish patients. We demonstrated conclusive genetic and functional evidence that the nonsense mutation c.343C>T in the bovine OPA3 gene causes the late-onset dilated cardiomyopathy in Red Holstein cattle. PMID- 20923699 TI - Obesity-mediated inflammatory microenvironment stimulates osteoclastogenesis and bone loss in mice. AB - Clinical evidence indicates that fat is inversely proportional to bone mass in elderly obese women. However, it remains unclear whether obesity accelerates bone loss. In this report we present evidence that increased visceral fat leads to inflammation and subsequent bone loss in 12-month-old C57BL/6J mice that were fed 10% corn oil (CO)-based diet and a control lab chow (LC) for 6 months. As expected from our previous work, CO-fed mice demonstrated increased visceral fat and enhanced total body fat mass compared to LC. The adipocyte-specific PPARgamma and bone marrow (BM) adiposity were increased in CO-fed mice. In correlation with those modifications, inflammatory cytokines (IL-1beta, IL-6, TNF-alpha) were significantly elevated in CO-fed mice compared to LC-fed mice. This inflammatory BM microenvironment resulted in increased superoxide production in osteoclasts and undifferentiated BM cells. In CO-fed mice, the increased number of osteoclasts per trabecular bone length and the increased osteoclastogenesis assessed ex-vivo suggest that CO diet induces bone resorption. Additionally, the up-regulation of osteoclast-specific cathepsin k and RANKL expression and down regulation of osteoblast-specific RUNX2/Cbfa1 supports this bone resorption in CO fed mice. Also, CO-fed mice exhibited lower trabecular bone volume in the distal femoral metaphysis and had reduced OPG expression. Collectively, our results suggest that increased bone resorption in mice fed a CO-enriched diet is possibly due to increased inflammation mediated by the accumulation of adipocytes in the BM microenvironment. This inflammation may consequently increase osteoclastogenesis, while reducing osteoblast development in CO-fed mice. PMID- 20923701 TI - The hydroxyl functional group of N-(4-hydroxyphenyl)retinamide mediates cellular uptake and cytotoxicity in premalignant and malignant human epithelial cells. AB - In a previous study, we demonstrated that the anticancer synthetic retinoid N-(4 hydroxyphenyl)retinamide (4HPR) redox cycles at the mitochondrial enzyme dihydroorotate dehydrogenase to trigger anomalous reactive oxygen species (ROS) production and attendant apoptosis in transformed human epithelial cells. Furthermore, we speculated that the hydroxyl functional group of 4HPR was required for this pro-oxidant property. In this study, we investigated the role of the hydroxyl functional group in the in vitro cytotoxicity of 4HPR. Using 4HPR, its primary in vivo metabolite N-(4-methoxyphenyl)retinamide (4MPR), and the synthetic derivative N-(4-trifluoromethylphenyl)retinamide (4TPR), we examined the pro-oxidant and apoptotic effects, as well as the cellular uptake, of these three N-(4-substituted-phenyl)retinamides in premalignant and malignant human skin, prostate, and breast epithelial cells. Compared to 4HPR, both 4MPR and 4TPR were ineffective in promoting conspicuous cellular ROS production, mitochondrial disruption, or DNA fragmentation in these transformed cells. Interestingly, both 4MPR and 4TPR were not particularly cell permeative relative to 4HPR in skin or breast epithelial cells, which implied an additional role for the hydroxyl functional group in the cellular uptake of 4HPR. Moreover, the short term uptake of 4HPR was directly proportional to cell size, but this characteristic, in obvious contrast to cellular bioenergetic status and/or dihydroorotate dehydrogenase expression, was not fundamentally influential in the overall sensitivity to the promotion of cellular ROS production and apoptosis induction by this agent. Together, these results strongly implicate the hydroxyl functional group in the cytotoxic effects of 4HPR. PMID- 20923702 TI - Proinflammatory effect of cholesterol and its oxidation products on CaCo-2 human enterocyte-like cells: effective protection by epigallocatechin-3-gallate. AB - Cholesterol and its oxidation products, namely oxysterols, have very recently been shown to potentially interfere with homeostasis of the human digestive tract, by promoting and sustaining irreversible damage of the colonic epithelial layer. This report concerns the strong proinflammatory action that a dietary oxysterol mixture and, to a lesser extent, an identical concentration of unoxidized cholesterol exert on CaCo-2 colonic epithelial cells by up-regulating both expression and synthesis of interleukin 8. The oxysterol mixture and its most effective component, 7beta-hydroxycholesterol, are also shown to markedly enhance the expression of key inflammatory and chemotactic cytokines in colonic epithelial cells, more efficiently than unoxidized cholesterol. The sterols' proinflammatory effect seems to be mediated by enhanced activation of NOX1, because it is prevented by pretreatment of the cells with DPI, a selective inhibitor of this oxidase. Importantly, NOX1 hyperactivation by the oxysterol mixture or cholesterol was fully prevented by CaCo-2 cell preincubation with epigallocatechin-3-gallate. Consistently, supplementation with this compound fully protected colonic epithelial cells against overexpression of inflammatory and chemotactic genes induced by the sterols investigated. PMID- 20923703 TI - The effects of nitric oxide-oxidase and putative glutathione-peroxidase activities of ceruloplasmin on the viability of cardiomyocytes exposed to hydrogen peroxide. AB - Ceruloplasmin (CP), a ferroxidase (EC 1.16.3.1) and a scavenger of reactive oxygen species, is an important extracellular antioxidant. Bovine CP indeed protects the isolated heart under ischemia-reperfusion conditions. Human CP has been shown to also exhibit, in vitro, glutathione (GSH)-peroxidase and nitric oxide (NO)-oxidase/S-nitrosating activities. This work tested, using bovine CP, the hypothesis that both activities could provide cytoprotection during oxidative stress induced by hydrogen peroxide (H(2)O(2)), the former activity by consuming H(2)O(2) and the latter by shielding thiols from irreversible oxidation. In acellular assays, bovine CP stimulated the generation of the nitrosating NO(+) species from the NO donors propylaminepropylamine-NONOate (PAPA/NO), S-nitroso-N acetylpenicillamine, and S-nitrosoglutathione. This NO-oxidase activity S nitrosated GSH as well as CP itself and was not affected by H(2)O(2). In contrast to human CP, bovine CP consumed H(2)O(2) in an additive rather than synergistic manner in the presence of GSH. A nonenzymatic scavenging of H(2)O(2) could have masked the GSH-peroxidase activity. Cytoprotection was evaluated using neonatal rat cardiomyocytes. CP and PAPA/NO were not protective against the H(2)O(2) induced loss of viability. In contrast, GSH provided a slight protection that increased more than additively in the presence of CP. This increase was canceled by PAPA/NO. CP's putative GSH-peroxidase activity can thus provide cytoprotection but is possibly affected by the S-nitrosation of a catalytically important cysteine residue. PMID- 20923704 TI - Modulation of gene expression by alpha-tocopherol and alpha-tocopheryl phosphate in THP-1 monocytes. AB - The natural vitamin E analog alpha-tocopheryl phosphate (alphaTP) modulates atherosclerotic and inflammatory events more efficiently than the unphosphorylated alpha-tocopherol (alphaT). To investigate the molecular mechanisms involved, we have measured plasma levels of alphaTP and compared the cellular effects of alphaT and alphaTP in THP-1 monocytes. THP-1 cell proliferation is slightly increased by alphaT, whereas it is inhibited by alphaTP. CD36 surface expression is inhibited by alphaTP within hours without requiring transport of alphaTP into cells, suggesting that alphaTP may bind to CD36 and/or trigger its internalization. As assessed by gene expression microarrays, more genes are regulated by alphaTP than by alphaT. Among a set of confirmed genes, the expression of vascular endothelial growth factor is induced by alphaTP as a result of activating protein kinase B (PKB/Akt) and is associated with increased levels of reactive oxygen species (ROS). Increased Akt(Ser473) phosphorylation and induction of ROS by alphaTP occur in a wortmannin-sensitive manner, indicating the involvement of phosphatidylinositol kinases. The induction of Akt(Ser473) phosphorylation and ROS production by alphaTP can be attenuated by alphaT. It is concluded that alphaTP and alphaT influence cell proliferation, ROS production, and Akt(Ser473) phosphorylation in an antagonistic manner, most probably by modulating phosphatidylinositol kinases. PMID- 20923705 TI - Expression of multiple copies of mitochondrially targeted catalase or genomic Mn superoxide dismutase transgenes does not extend the life span of Drosophila melanogaster. AB - The simultaneous overexpression of multiple copies of Mn superoxide dismutase (SOD) and ectopic catalase (mtCat) transgenes in the mitochondria of the fruit fly, Drosophila melanogaster, was shown previously to diminish the life span. The hypothesis tested in this study was that this effect was due primarily to the presence of one or the other transgene. An alternative hypothesis was that both transgenes have additive, negative effects. Crosses were performed between five pairs of transgenic lines containing single-copy insertions of mtCat, Mn SOD, or P element vector control transgenes at unique loci, and the life spans of progeny containing two mtCat, Mn SOD, or vector insertions were determined. Increasing amounts of mitochondrial catalase activity tended to be associated with decreases in mean life span. Overexpression of two copies of the genomic Mn SOD transgene had no effect on life span. The results do not support the hypothesis that enhanced mitochondrial SOD or catalase activity promotes longevity in flies. PMID- 20923706 TI - A web-based brain atlas of the vervet monkey, Chlorocebus aethiops. AB - Vervet monkeys are a frequently studied animal model in neuroscience research. Although equally distantly related to humans, the ancestors of vervets diverged from those of macaques and baboons more than 11 million years ago, antedating the divergence of the ancestors of humans, chimpanzees and gorillas. To facilitate anatomic localization in the vervet brain, two linked on-line electronic atlases are described, one based on registered MRI scans from hundreds of vervets (http://www.loni.ucla.edu/Research/Atlases/Data/vervet/vervetmratlas/vervetmratla .html) and the other based on a high-resolution cryomacrotome study of a single vervet (http://www.loni.ucla.edu/Research/Atlases/Data/vervet/vervetatlas/vervetatlas.ht l). The averaged MRI atlas is also available as a volume in Neuroimaging Informatics Technology Initiative format. In the cryomacrotome atlas, various sulcal and subcortical structures have been anatomically labeled and surface rendered views are provided along the primary planes of section. Both atlases simultaneously provide views in all three primary planes of section, rapid navigation by clicking on the displayed images, and stereotaxic coordinates in the averaged MRI atlas space. Despite the extended time period since their divergence, the major sulcal and subcortical landmarks in vervets are highly conserved relative to those described in macaques. PMID- 20923708 TI - Developmental influences on the neural bases of responses to social rejection: implications of social neuroscience for education. AB - Relational aggression such as social rejection is common within school peer groups. Converging evidence suggests that adolescent females are particularly sensitive to social rejection. We used a novel fMRI adaptation of the Cyberball social rejection paradigm to investigate the neural response to social rejection in 19 mid-adolescent (aged 14-16) and 16 adult female participants. Across all participants, social exclusion (relative to inclusion) elicited a response in bilateral medial prefrontal cortex (mPFC) extending into ventral and subgenual anterior cingulate cortex and medial orbitofrontal cortex; and the left ventrolateral PFC (vlPFC); regions that have been associated in previous studies with social evaluation, negative affective processing, and affect regulation respectively. However, the exclusion-related response in right vlPFC, a region associated in previous studies with the regulation of rejection-related distress, was attenuated in adolescents. Within mPFC, greater activation during exclusion vs. inclusion was associated with greater self-reported susceptibility to peer influence in adolescents but not in adults. This suggests that the brain's response to experimentally-induced social rejection relates to adolescent behaviour in real-world social interactions. We speculate about the potential implications of these findings for educational settings. In particular, functional development of affective circuitry during adolescence may influence social interaction within the school peer group. PMID- 20923707 TI - Differential effects of age and history of hypertension on regional brain volumes and iron. AB - Aging affects various structural and metabolic properties of the brain. However, associations among various aspects of brain aging are unclear. Moreover, those properties and associations among them may be modified by age-associated increase in vascular risk. In this study, we measured volume of brain regions that vary in their vulnerability to aging and estimated local iron content via T2* relaxometry. In 113 healthy adults (19-83 years old), we examined prefrontal cortex (PFC), primary visual cortex (VC), hippocampus (HC), entorhinal cortex (EC), caudate nucleus (Cd), and putamen (Pt). In some regions (PFC, VC, Cd, and Pt) age-related differences in iron and volume followed similar patterns. However, in the medial-temporal structures, volume and iron content exhibited different age trajectories. Whereas age-related volume reduction was mild in HC and absent in EC, iron content evidenced significant age-related declines. In hypertensive participants significantly greater iron content was noted in all examined regions. Thus, iron content as measured by T2* may be a sensitive index of regional brain aging and may reveal declines that are more prominent than gross anatomical shrinkage. PMID- 20923709 TI - Toxicity equivalence range design (TEQR): a practical Phase I design. AB - PURPOSE: This paper introduces the target equivalence range (TEQR) design, a frequentist implementation of the modified toxicity probability interval (mTPI) design, as a competitor to the standard 3+3 design (3+3). The 3+3 is the work horse design in Phase I. It is good at determining if a safe dose exits, but provides poor accuracy and precision in estimating the level of toxicity at the maximum tolerated dose (MTD). Its main competitor, the continual reassessment method (CRM) has not found a true niche in the Phase I armamentarium resulting from statistical and implementation complexities. METHODS: We describe the four competing designs (3+3, mTPI, CRM, and TEQR), comparing them based on i) operating characteristics from simulated trials, and ii) ease of implementation. RESULTS: The TEQR is better than the 3+3 when compared on; 1) number of times the dose at or nearest the target toxicity level was selected as the MTD, 2) number of patients assigned to dose levels at or nearest the MTD, 3) overall trial dose limiting toxicity rate and 4) accuracy and precision of estimates for the rate of toxicity at the MTD. Further it is reasonably comparable to the CRM and mTPI on 1 3. CONCLUSION: The TEQR offers trial designers a competitor to the 3+3 for ease of implementation with better operating characteristics and the added attraction of a glimpse of activity at the MTD. The R package TEQR, freely available from the comprehensive R archive network, includes functions to calculate dose escalation guidelines and operating characteristics. PMID- 20923710 TI - Mechanotransduction and epigenetic control in autoimmune diseases. AB - Differentiation of epithelial cells is required to define tissue architecture and appropriate function of these cells is associated with a specific pattern of gene expression. DNA methylation, post-translational modification of histones and chromatin remodeling are nuclear mechanisms implicated in epigenetic control of gene expression. All factors relevant to tissue differentiation, including cell adhesion and shape, extracellular stimuli and transcriptional control, modulate gene expression and, thus, some of them are likely to impact on nuclear mechanisms of epigenetic control. The epithelial cells of salivary glands from Sjogren's syndrome patients display alterations in cell adhesion and shape. In this review, we summarize how these alterations are thought to lead to chromatin remodeling and, in doing so, bring about changes in transcriptional patterns. Additionally, we discuss how mechanotransduction in cells with impaired structural organization is implicated in modifying gene expression in these patients. PMID- 20923711 TI - Forecasting the economic value of an Enterovirus 71 (EV71) vaccine. AB - Enterovirus 71 (EV71) is a growing public health concern, especially in Asia. A surge of EV71 cases in 2008 prompted authorities in China to go on national alert. While there is currently no treatment for EV71 infections, vaccines are under development. We developed a computer simulation model to determine the potential economic value of an EV71 vaccine for children (<5 years old) in China. Our results suggest that routine vaccination in China (EV71 infection incidence ~0.04%) may be cost-effective when vaccine cost is $25 and efficacy >=70% or cost is $10 and efficacy >=50%. For populations with higher infection risk (>=0.4%), a $50 or $75 vaccine would be highly cost-effective even when vaccine efficacy is as low as 50%. PMID- 20923712 TI - Persistence of the effects of Cerebrolysin on cognition and qEEG slowing in vascular dementia patients: results of a 3-month extension study. AB - The maintenance of the effects of Cerebrolysin, a peptidergic compound with neurotrophic activity, on cognitive performance and qEEG activity was investigated through a 12-week, open-label extension of a 4-week, randomised, placebo-controlled pilot study. Thirty-three out of 41 patients with mild-to moderate severe probable vascular dementia (VaD) according to NINDS-AIREN participating in the double-blind phase of the study were also assessed at the follow-up visit at week 16. Patients received i.v. infusions of Cerebrolysin (10 or 30 mL) or placebo (saline) 5 days/week for 4 weeks. Neuropsychological evaluations and qEEG recordings were done at baseline, week 4 and week 16. The mean change in score from baseline in the ADAS-cog+ and the slow-to-fast qEEG power ratio (PR), used as an index of qEEG slowing, were the two primary endpoints. Correlations between changes in cognition and qEEG induced by the treatment were also assessed. At the week 16 follow-up visit, Cerebrolysin improved (p<0.05) cognitive performance at the 10-mL and 30-mL doses and reduced qEEG slowing significantly (p<0.05) at the 30-mL dose with respect to the placebo. In addition, a significant (p<0.05) positive correlation between the change from the baseline qEEG PR and ADAS-cog+ variables was observed at week 16. These results indicate a persistence of the beneficial effects of Cerebrolysin on cognition and qEEG activity in VaD patients for at least 12 weeks after treatment cessation, and they suggest the potential utility of qEEG parameters as biomarkers for VaD clinical trials. PMID- 20923713 TI - Pre-operative heparin reduces pulmonary microvascular fibrin deposition following cardiac surgery. PMID- 20923714 TI - Active case-finding for TB in the community: time to act. PMID- 20923716 TI - The persistence of low expectations in special education law viewed through the lens of therapeutic jurisprudence. AB - For more than thirty-five years a paradigm of low expectations has infected efforts to educate children with disabilities and has been a persistent and stubborn obstacle to the successful implementation of the Individuals with Disabilities Education Act (IDEA), and its predecessor, the Education of All Handicapped Children Act (EAHCA). This dilemma raises questions addressed in this paper: What is meant by low expectations in the context of Special Education Law? What are the root causes of this phenomenon, and what makes it so resistant to change? How does it impede implementation of the IDEA? And lastly, in what ways does the paradigm of low expectations impact children with disabilities socially, emotionally, and psychologically? The primary purpose of this paper is to consider these questions, particularly the last, utilizing therapeutic jurisprudence (TJ), a theoretical lens through which the emotional and psychological impact of the law and its processes upon those who interact in its context may be viewed and analyzed. PMID- 20923715 TI - Comparison of two active case-finding strategies for community-based diagnosis of symptomatic smear-positive tuberculosis and control of infectious tuberculosis in Harare, Zimbabwe (DETECTB): a cluster-randomised trial. AB - BACKGROUND: Control of tuberculosis in settings with high HIV prevalence is a pressing public health priority. We tested two active case-finding strategies to target long periods of infectiousness before diagnosis, which is typical of HIV negative tuberculosis and is a key driver of transmission. METHODS: Clusters of neighbourhoods in the high-density residential suburbs of Harare, Zimbabwe, were randomised to receive six rounds of active case finding at 6-monthly intervals by either mobile van or door-to-door visits. Randomisation was done by selection of discs of two colours from an opaque bag, with one disc to represent every cluster, and one colour allocated to each intervention group before selection began. In both groups, adult (>=16 years) residents volunteering chronic cough (>=2 weeks) had two sputum specimens collected for fluorescence microscopy. Community health workers and cluster residents were not masked to intervention allocation, but investigators and laboratory staff were masked to allocation until final analysis. The primary outcome was the cumulative yield of smear positive tuberculosis per 1000 adult residents, compared between intervention groups; analysis was by intention to treat. The secondary outcome was change in prevalence of culture-positive tuberculosis from before intervention to before round six of intervention in 12% of randomly selected households from the two intervention groups combined; analysis was based on participants who provided sputum in the two prevalence surveys. This trial is registered, number ISRCTN84352452. FINDINGS: 46 study clusters were identified and randomly allocated equally between intervention groups, with 55 741 adults in the mobile van group and 54,691 in the door-to-door group at baseline. HIV prevalence was 21% (1916/9060) and in the 6 months before intervention the smear-positive case notification rate was 2.8 per 1000 adults per year. The trial was completed as planned with no adverse events. The mobile van detected 255 smear-positive patients from 5466 participants submitting sputum compared with 137 of 4711 participants identified through door-to-door visits (adjusted risk ratio 1.48, 95% CI 1.11-1.96, p=0.0087). The overall prevalence of culture-positive tuberculosis declined from 6.5 per 1000 adults (95% CI 5.1-8.3) to 3.7 per 1000 adults (2.6-5.0; adjusted risk ratio 0.59, 95% CI 0.40-0.89, p=0.0112). INTERPRETATION: Wide implementation of active case finding, particularly with a mobile van approach, could have rapid effects on tuberculosis transmission and disease. FUNDING: Wellcome Trust. PMID- 20923717 TI - Establishing a compulsory drug treatment prison: Therapeutic policy, principles, and practices in addressing offender rights and rehabilitation. AB - A Compulsory Drug Treatment Correctional Center (CDTCC) was established in Australia in 2006 for repeat drug-related male offenders. Compulsory treatment law is inconsistent with a therapeutic jurisprudence approach. Despite the compulsory law, a normative offender rehabilitation framework has been established based on offender moral rights. Within moral rights, the offender rehabilitation framework addresses the core values of freedom (supporting autonomous decision-making) and well-being (supporting support physical, social, and psychological needs). Moral rights are underpinned by a theory or principle which, in this instance, is a humane approach to offender rehabilitation. While a law that permits offenders to choose drug treatment and rehabilitation is preferable, the article discusses the establishment of a prison based on therapeutic policy, principles, and practices that respond to participants as both rights-violators and rights-holders. The opportunity for accelerated community access and a therapeutic alliance with staff has resulted in offenders actively seeking to be ordered into compulsory drug treatment and rehabilitation. PMID- 20923718 TI - Neonatal neuroblastoma. PMID- 20923719 TI - Preventing parenteral nutrition liver disease. AB - Parenteral nutrition liver disease (PNLD) develops in 40-60% of infants who require long-term PN for intestinal failure. The clinical spectrum includes hepatic steatosis, cholestasis, cholelithiasis, and hepatic fibrosis. Progression to biliary cirrhosis and the development of portal hypertension and liver failure occurs in a minority who require combined liver and intestinal transplantation. The pathogenesis is multifactorial and is related to prematurity, low birth weight, duration of PN, short bowel syndrome requiring multiple laparotomies and recurrent sepsis. Other important mechanisms include lack of enteral feeding which leads to reduced gut hormone secretion, reduction of bile flow and biliary stasis which leads to the development of cholestasis, biliary sludge and gallstones, which exacerbate hepatic dysfunction, especially in premature neonates with immature hepatic function. The use of lipid emulsions, particularly soy bean emulsions have been associated with hepatic cholestasis in children, although there are little data now to support toxicity from other PN components. Management strategies for the prevention of parenteral nutrition liver disease include consideration of early enteral feeding, a multidisciplinary approach to the management of parenteral nutrition with a specialized nutritional care team and aseptic catheter techniques to reduce sepsis. The use of specialized lipid emulsions such as fish oil emulsions and or SMOF (Soy bean/Medium Chain Triglyceride/Olive Oil/Fish oil) improves established cholestasis and may prevent the onset. Oral administration of ursodeoxycholic acid may improve bile flow and reduce gall bladder stasis, although there is little data to suggest that prophylactic use prevents the onset of PNLD. Survival following either isolated small bowel or combined liver and small bowel transplantation is approximately 50% at 5 years making this an acceptable therapeutic option in children with irreversible liver and intestinal failure. PMID- 20923720 TI - Personality disorders improved after arachnoid cyst neurosurgery, then rediagnosed as 'minor' organic personality disorders. AB - The prevalence of arachnoid cysts (AC) is considerably increased in psychiatric patients, suggesting a possible causal relationship between AC and certain psychiatric disorders. Neurosurgery of AC in psychiatric disorders is, however, not recommended if no accompanying neurological symptoms or signs of increased intracranial pressure are present. In two cases of slow onset personality disorder in persons suffering from so-called asymptomatic AC, we performed AC neurosurgery beyond established rules. Both comparisons before and after neurosurgery of psychopathology and the following long-term course support in retrospect that both cases might be re-diagnosed as having suffered from 'minor' organic personality disorders before AC neurosurgery, which improved thereafter. The two cases did not initially appear to fulfill the established criteria for organic personality disorders either according to ICD-10 or DSM-IV, but in retrospect satisfied most criteria. In themselves, the personality disorders appeared not very severe, but had considerable relevance for the patients' lives. The established rules for AC neurosurgery should be reconsidered at least when therapy-resistant psychiatric disorders are observed in AC sufferers. PMID- 20923721 TI - Electrically induced quantitative sudomotor axon reflex test in human volunteers. AB - Chemically-induced quantitative sudomotor axon reflex test (QSART) and quantitative sensory testing (QST) are established clinical tools to assess thin fiber function in humans. We investigated stimulus-response functions to transcutaneous electrical stimuli of different current intensity (3.75 to 10mA) and pulse frequency (5 to 100Hz) comparing sweat output (ml/h/m(2)) and pain intensity (numeric rating scale [NRS], 0-10). Efferent sudomotor and afferent nociceptive responses were recorded after a 30s electrical stimulation period of distal (hand and foot) and proximal (forearm and thorax) body sites with 3 repetitive measures per body site. Sweat responses increased intensity dependently and peaked (~100ml/h/m(2)) at highest currents (10mA) that had been administered. Similarly, pain ratings increased with an escalating current intensity. At a constant stimulus intensity of 7.5mA, sudomotor activity was highest (~75ml/h/m(2)) at a stimulus frequency of 20Hz without further increase at 50 or 100Hz. In contrast, pain ratings increased frequency dependently and reached NRS 7 at 100Hz. Sudomotor activity, but not pain ratings, was significantly different between the body sites (p<0.05, ANOVA) with maximum sweat responses obtained at the ventral forearm. Varying response patterns for higher stimulation frequencies between sweating (peak maximum at 20Hz) and pain (maximum at 100Hz) might indicate differential axonal properties of sympathetic efferent and nociceptive afferent fibers. Electrically induced QSART could be a useful explorative and clinical method to indirectly study characteristics of frequency dependent axonal excitability changes of sudomotor fibers. PMID- 20923722 TI - Effect of formation of biofilms and chemical scale on the cathode electrode on the performance of a continuous two-chamber microbial fuel cell. AB - A two-chamber MFC system was operated continuously for more than 500 days to evaluate effects of biofilm and chemical scale formation on the cathode electrode on power generation. A stable power density of 0.57 W/m(2) was attained after 200 days operation. However, the power density decreased drastically to 0.2 W/m(2) after the cathodic biofilm and chemical scale were removed. As the cathodic biofilm and chemical scale partially accumulated on the cathode, the power density gradually recovered with time. Microbial community structure of the cathodic biofilm was analyzed based on 16S rRNA clone libraries. The clones closely related to Xanthomonadaceae bacterium and Xanthomonas sp. in the Gammaproteobacteria subdivision were most frequently retrieved from the cathodic biofilm. Results of the SEM-EDX analysis revealed that the cation species (Na(+) and Ca(2+)) were main constituents of chemical scale, indicating that these cations diffused from the anode chamber through the Nafion membrane. However, an excess accumulation of the biofilm and chemical scale on the cathode exhibited adverse effects on the power generation due to a decrease in the active cathode surface area and an increase in diffusion resistance for oxygen. Thus, it is important to properly control the formation of chemical scale and biofilm on the cathode during long-term operation. PMID- 20923724 TI - Measuring social desirability amongst men with intellectual disabilities: the psychometric properties of the Self- and Other-Deception Questionnaire Intellectual Disabilities. AB - BACKGROUND: Social desirability has been construed as either inaccurately attributing positive characteristics to oneself (self-deception), or inaccurately denying that one possesses undesirable characteristics to others (other-deception or impression management). These conceptualisations of social desirability have not been considered in relation to people with intellectual disabilities (IDs), but they are important constructs to consider when undertaking a psychological assessment of an individual, especially within forensic contexts. Therefore, we revised two existing measures of self- and other-deception and considered their psychometric properties. METHODS: Thirty-two men with mild IDs and 28 men without IDs completed the Self- and Other-Deception Questionnaires-Intellectual Disabilities (SDQ-ID and ODQ-ID) on two occasions, two weeks apart. RESULTS: Men with IDs scored significantly higher on the SDQ-ID and the ODQ-ID than men without IDs. However, these differences disappeared when Full Scale IQ, Verbal IQ and Performance IQ were controlled in relation to the SDQ-ID, and partially disappeared in relation to the ODQ-ID. The SDQ-ID and the ODQ-ID had substantial internal consistency in relation to men with IDs (k=0.82 and 0.84 respectively). The test-retest reliability of the SDQ-ID was good (r(i)=0.68), while the test retest reliability of the ODQ-ID was moderate (r(i)=0.56), for men with IDs. The SDQ-ID had moderate (k=0.60) and the ODQ-ID had substantial (k=0.70) internal consistency in relation to men without IDs, while the test-retest reliability of the SDQ-ID was excellent (r(i)=0.87) as was the case for the ODQ-ID (r(i)=0.85). CONCLUSIONS: The SDQ-ID and the ODQ-ID have satisfactory psychometric properties in relation to men with and without IDs. Future research using these instruments is proposed. PMID- 20923725 TI - Psychometric evaluation of the Dutch version of the Mood, Interest and Pleasure Questionnaire (MIPQ). AB - Recently, several instruments have been developed to measure the subjective component of the quality of life (QOL) of people with profound intellectual and multiple disabilities (PIMD). A next step, however, must be the further validation of these instruments. The present study aimed at evaluating the psychometric properties of one of these instruments, the Dutch version of the Mood, Interest and Pleasure Questionnaire (MIPQ). The MIPQ is a 25-item Likert scale questionnaire with two subscales (Mood and Interest and Pleasure). The MIPQ and the Aberrant Behavior Checklist were completed on 360 participants with severe or profound intellectual disabilities. About 27% of these participants were included in an examination of test-retest of and the inter-rater reliability of the MIPQ. The results suggest that the proposed two-factor structure did not show an adequate fit to our data. An exploratory factor analysis revealed a three factor structure with positive mood, negative mood and interest as three correlated but distinct subscales. These results are in concurrence with the literature on positive emotions. High internal consistency (alpha >= .80), high inter-rater (r >= .69) and high test-retest reliability (r >= .86) were found, which indicates the reliable use of the MIPQ in the population of people with PIMD. Strong negative correlations between the MIPQ total score and the Aberant Behavior Checklist's 'lethargy, social withdrawal' subscale provides some evidence of the construct validity of the MIPQ. However, further validation of the MIPQ including other measures of subjective well-being is warranted. PMID- 20923726 TI - Arterial stiffness using radial arterial waveforms measured at the wrist as an indicator of diabetic control in the elderly. AB - Although current technique of photoplethysmography (PPG) is a popular noninvasive method of waveform contour analysis in assessing arterial stiffness, data obtained are frequently affected by various environmental and physiological factors. We proposed an easily operable air pressure sensing system (APSS) for radial arterial signal capturing. Totally, 108 subjects (young, the aged with or without diabetes) were recruited from July 2009 to May 2010. Arterial waveform signals from the wrist were obtained and analyzed using Hilbert-Huang transformation (HHT). Through ensemble empirical mode decomposition (EEMD), the signals were decomposed into eight intrinsic mode functions (IMF1-8) of which IMF5 was found to be the desired signal with a discernible diastolic peak. The results showed significant differences in reflection index (RI) and stiffness index (SI) from the young subjects and those from the aged participants with or without diabetes. Significant differences in RI and SI were also noted between subjects with well-controlled diabetes and those without. Good reproducibility and correlation were demonstrated. In conclusion, the present study proposed the application of radial arterial signal capturing subsystem and HHT in acquiring more reliable data on RI and SI compared with the conventional PPG method. PMID- 20923727 TI - Temporal sequence parameters in isodistributional surrogate data: model and exact expressions. AB - In this paper, a set of formulae for the temporal spontaneous baroreceptor reflex (sBRR) sequence parameters in isodistributional (ID) surrogate data is derived. This is facilitated by representing successive positive or negative amplitude changes as a Markov chain model. The obtained analytical tool measures the effect of random fluctuations on the overall number of sequences, estimated from the original biomedical time series. The formulae are tested using ID surrogates of systolic blood pressure and pulse-interval signals recorded from 13 healthy male Wistar rats at baseline conditions. PMID- 20923728 TI - A new spatiotemporal filtering method for single-trial estimation of correlated ERP subcomponents. AB - A novel spatiotemporal filtering method for single trial estimation of event related potential (ERP) subcomponents is proposed here. Unlike some previous works in ERP estimation [1], , the proposed method is able to estimate temporally correlated ERP subcomponents such as P3a and P3b. A new cost function is, therefore, defined which can deflate one of the correlated subcomponents. The method is applied to both simulated and real data and has shown to perform very well even in low signal-to-noise ratio situations. In addition, the method is compared to spatial principal component analysis and its superiority has been confirmed by using simulated signals. The approach can be especially useful in mental fatigue analysis where the relative variability of P300 subcomponents is the key factor in detecting the level of fatigue. PMID- 20923729 TI - Quantitative falls risk assessment using the timed up and go test. AB - Falls are a major problem in older adults worldwide with an estimated 30% of elderly adults over 65 years of age falling each year. The direct and indirect societal costs associated with falls are enormous. A system that could provide an accurate automated assessment of falls risk prior to falling would allow timely intervention and ease the burden on overstretched healthcare systems worldwide. An objective method for assessing falls risk using body-worn kinematic sensors is reported. The gait and balance of 349 community-dwelling elderly adults was assessed using body-worn sensors while each patient performed the "timed up and go" (TUG) test. Patients were also evaluated using the Berg balance scale (BBS). Of the 44 reported parameters derived from body-worn kinematic sensors, 29 provided significant discrimination between patients with a history of falls and those without. Cross-validated estimates of retrospective falls prediction performance using logistic regression models yielded a mean sensitivity of 77.3% and a mean specificity of 75.9%. This compares favorably to the cross-validated performance of logistic regression models based on the time taken to complete the TUG test (manually timed TUG) and the Berg balance score. These models yielded mean sensitivities of 58.0% and 57.8%, respectively, and mean specificities of 64.8% and 64.2%, respectively. Results suggest that this method offers an improvement over two standard falls risk assessments (TUG and BBS) and may have potential for use in supervised assessment of falls risk as part of a longitudinal monitoring protocol. PMID- 20923730 TI - Computing and analyzing the sensitivity of MLP due to the errors of the i.i.d. inputs and weights based on CLT. AB - In this paper, we propose an algorithm based on the central limit theorem to compute the sensitivity of the multilayer perceptron (MLP) due to the errors of the inputs and weights. For simplicity and practicality, all inputs and weights studied here are independently identically distributed (i.i.d.). The theoretical results derived from the proposed algorithm show that the sensitivity of the MLP is affected by the number of layers and the number of neurons adopted in each layer. To prove the reliability of the proposed algorithm, some experimental results of the sensitivity are also presented, and they match the theoretical ones. The good agreement between the theoretical results and the experimental results verifies the reliability and feasibility of the proposed algorithm. Furthermore, the proposed algorithm can also be applied to compute precisely the sensitivity of the MLP with any available activation functions and any types of i.i.d. inputs and weights. PMID- 20923731 TI - Stability analysis of multiplicative update algorithms and application to nonnegative matrix factorization. AB - Multiplicative update algorithms have proved to be a great success in solving optimization problems with nonnegativity constraints, such as the famous nonnegative matrix factorization (NMF) and its many variants. However, despite several years of research on the topic, the understanding of their convergence properties is still to be improved. In this paper, we show that Lyapunov's stability theory provides a very enlightening viewpoint on the problem. We prove the exponential or asymptotic stability of the solutions to general optimization problems with nonnegative constraints, including the particular case of supervised NMF, and finally study the more difficult case of unsupervised NMF. The theoretical results presented in this paper are confirmed by numerical simulations involving both supervised and unsupervised NMF, and the convergence speed of NMF multiplicative updates is investigated. PMID- 20923732 TI - Neuro-adaptive force/position control with prescribed performance and guaranteed contact maintenance. AB - In this paper, we address unresolved issues in robot force/position tracking including the concurrent satisfaction of contact maintenance, lack of overshoot, desired speed of response, as well as accuracy level. The control objective is satisfied under uncertainties in the force deformation model and disturbances acting at the joints. The unknown nonlinearities that arise owing to the uncertainties in the force deformation model are approximated by a neural network linear in the weights and it is proven that the neural network approximation holds for all time irrespective of the magnitude of the modeling error, the disturbances, and the controller gains. Thus, the controller gains are easily selected, and potentially large neural network approximation errors as well as disturbances can be tolerated. Simulation results on a 6-DOF robot confirm the theoretical findings. PMID- 20923733 TI - Semisupervised kernel matrix learning by kernel propagation. AB - The goal of semisupervised kernel matrix learning (SS-KML) is to learn a kernel matrix on all the given samples on which just a little supervised information, such as class label or pairwise constraint, is provided. Despite extensive research, the performance of SS-KML still leaves some space for improvement in terms of effectiveness and efficiency. For example, a recent pairwise constraints propagation (PCP) algorithm has formulated SS-KML into a semidefinite programming (SDP) problem, but its computation is very expensive, which undoubtedly restricts PCPs scalability in practice. In this paper, a novel algorithm, called kernel propagation (KP), is proposed to improve the comprehensive performance in SS-KML. The main idea of KP is first to learn a small-sized sub-kernel matrix (named seed kernel matrix) and then propagate it into a larger-sized full-kernel matrix. Specifically, the implementation of KP consists of three stages: 1) separate the supervised sample (sub)set X(l) from the full sample set X; 2) learn a seed kernel matrix on X(l) through solving a small-scale SDP problem; and 3) propagate the learnt seed-kernel matrix into a full-kernel matrix on X . Furthermore, following the idea in KP, we naturally develop two conveniently realizable out-of sample extensions for KML: one is batch-style extension, and the other is online style extension. The experiments demonstrate that KP is encouraging in both effectiveness and efficiency compared with three state-of-the-art algorithms and its related out-of-sample extensions are promising too. PMID- 20923734 TI - New passivity analysis for neural networks with discrete and distributed delays. AB - In this brief, the problem of passivity analysis is investigated for a class of uncertain neural networks (NNs) with both discrete and distributed time-varying delays. By constructing a novel Lyapunov functional and utilizing some advanced techniques, new delay-dependent passivity criteria are established to guarantee the passivity performance of NNs. Essentially different from the available results, when estimating the upper bound of the derivative of Lyapunov functionals, we consider and best utilize the additional useful terms about the distributed delays, which leads to less conservative results. These criteria are expressed in the form of convex optimization problems, which can be efficiently solved via standard numerical software. Numerical examples are provided to illustrate the effectiveness and less conservatism of the proposed results. PMID- 20923735 TI - Discretization error analysis and adaptive meshing algorithms for fluorescence diffuse optical tomography in the presence of measurement noise. AB - Quantitatively accurate fluorescence diffuse optical tomographic (FDOT) image reconstruction is a computationally demanding problem that requires repeated numerical solutions of two coupled partial differential equations and an associated inverse problem. Recently, adaptive finite element methods have been explored to reduce the computation requirements of the FDOT image reconstruction. However, existing approaches ignore the ubiquitous presence of noise in boundary measurements. In this paper, we analyze the effect of finite element discretization on the FDOT forward and inverse problems in the presence of measurement noise and develop novel adaptive meshing algorithms for FDOT that take into account noise statistics. We formulate the FDOT inverse problem as an optimization problem in the maximum a posteriori framework to estimate the fluorophore concentration in a bounded domain. We use the mean-square-error (MSE) between the exact solution and the discretized solution as a figure of merit to evaluate the image reconstruction accuracy, and derive an upper bound on the MSE which depends upon the forward and inverse problem discretization parameters, noise statistics, a priori information of fluorophore concentration, source and detector geometry, as well as background optical properties. Next, we use this error bound to develop adaptive meshing algorithms for the FDOT forward and inverse problems to reduce the MSE due to discretization in the reconstructed images. Finally, we present a set of numerical simulations to illustrate the practical advantages of our adaptive meshing algorithms for FDOT image reconstruction. PMID- 20923736 TI - Automatic exact histogram specification for contrast enhancement and visual system based quantitative evaluation. AB - Histogram equalization, which aims at information maximization, is widely used in different ways to perform contrast enhancement in images. In this paper, an automatic exact histogram specification technique is proposed and used for global and local contrast enhancement of images. The desired histogram is obtained by first subjecting the image histogram to a modification process and then by maximizing a measure that represents increase in information and decrease in ambiguity. A new method of measuring image contrast based upon local band-limited approach and center-surround retinal receptive field model is also devised in this paper. This method works at multiple scales (frequency bands) and combines the contrast measures obtained at different scales using L(p)-norm. In comparison to a few existing methods, the effectiveness of the proposed automatic exact histogram specification technique in enhancing contrasts of images is demonstrated through qualitative analysis and the proposed image contrast measure based quantitative analysis. PMID- 20923737 TI - 1-D transforms for the motion compensation residual. AB - Transforms used in image coding are also commonly used to compress prediction residuals in video coding. Prediction residuals have different spatial characteristics from images, and it is useful to develop transforms that are adapted to prediction residuals. In this paper, we explore the differences between the characteristics of images and motion compensated prediction residuals by analyzing their local anisotropic characteristics and develop transforms adapted to the local anisotropic characteristics of these residuals. The analysis indicates that many regions of motion compensated prediction residuals have 1-D anisotropic characteristics and we propose to use 1-D directional transforms for these regions. We present experimental results with one example set of such transforms within the H.264/AVC codec and the results indicate that the proposed transforms can improve the compression efficiency of motion compensated prediction residuals over conventional transforms. PMID- 20923739 TI - Spatial sparsity-induced prediction (SIP) for images and video: a simple way to reject structured interference. AB - We propose a prediction technique that is geared toward forming successful estimates of a signal based on a correlated anchor signal that is contaminated with complex interference. The corruption in the anchor signal involves intensity modulations, linear distortions, structured interference, clutter, and noise just to name a few. The proposed setup reflects nontrivial prediction scenarios involving images and video frames where statistically related data is rendered ineffective for traditional methods due to cross-fades, blends, clutter, brightness variations, focus changes, and other complex transitions. Rather than trying to solve a difficult estimation problem involving nonstationary signal statistics, we obtain simple predictors in linear transform domain where the underlying signals are assumed to be sparse. We show that these simple predictors achieve surprisingly good performance and seamlessly allow successful predictions even under complicated cases. None of the interference parameters are estimated as our algorithm provides completely blind and automated operation. We provide a general formulation that allows for nonlinearities in the prediction loop and we consider prediction optimal decompositions. Beyond an extensive set of results on prediction and registration, the proposed method is also implemented to operate inside a state-of-the-art compression codec and results show significant improvements on scenes that are difficult to encode using traditional prediction techniques. PMID- 20923738 TI - Face recognition system using multiple face model of hybrid Fourier feature under uncontrolled illumination variation. AB - The authors present a robust face recognition system for large-scale data sets taken under uncontrolled illumination variations. The proposed face recognition system consists of a novel illumination-insensitive preprocessing method, a hybrid Fourier-based facial feature extraction, and a score fusion scheme. First, in the preprocessing stage, a face image is transformed into an illumination insensitive image, called an "integral normalized gradient image," by normalizing and integrating the smoothed gradients of a facial image. Then, for feature extraction of complementary classifiers, multiple face models based upon hybrid Fourier features are applied. The hybrid Fourier features are extracted from different Fourier domains in different frequency bandwidths, and then each feature is individually classified by linear discriminant analysis. In addition, multiple face models are generated by plural normalized face images that have different eye distances. Finally, to combine scores from multiple complementary classifiers, a log likelihood ratio-based score fusion scheme is applied. The proposed system using the face recognition grand challenge (FRGC) experimental protocols is evaluated; FRGC is a large available data set. Experimental results on the FRGC version 2.0 data sets have shown that the proposed method shows an average of 81.49% verification rate on 2-D face images under various environmental variations such as illumination changes, expression changes, and time elapses. PMID- 20923740 TI - Methods to window data to differentiate between Markov models. AB - In this paper, we consider how we can detect patterns in data streams that are serial Markovian, where target behaviors are Markovian, but targets may switch from one Markovian behavior to another. We want to reliably and promptly detect behavior changes. Traditional Markov-model-based pattern detection approaches, such as hidden Markov models, use maximum likelihood techniques over the entire data stream to detect behaviors. To detect changes between behaviors, we use statistical pattern matching calculations performed on a sliding window of data samples. If the window size is very small, the system will suffer from excessive false-positive rates. If the window is very large, change-point detection is delayed. This paper finds both necessary and sufficient bounds on the window size. We present two methods of calculating window sizes based on the state and transition structures of the Markov models. Two application examples are presented to verify our results. Our first example problem uses simulations to illustrate the utility of the proposed approaches. The second example uses models extracted from a database of consumer purchases to illustrate their use in a real application. PMID- 20923741 TI - Comprehensive joint feedback control for standing by functional neuromuscular stimulation-a simulation study. AB - Previous investigations of feedback control of standing after spinal cord injury (SCI) using functional neuromuscular stimulation (FNS) have primarily targeted individual joints. This study assesses the potential efficacy of comprehensive (trunk, hips, knees, and ankles) joint feedback control against postural disturbances using a bipedal, 3-D computer model of SCI stance. Proportional derivative feedback drove an artificial neural network trained to produce muscle excitation patterns consistent with maximal joint stiffness values achievable about neutral stance given typical SCI muscle properties. Feedback gains were optimized to minimize upper extremity (UE) loading required to stabilize against disturbances. Compared to the baseline case of maximum constant muscle excitations used clinically, the controller reduced UE loading by 55% in resisting external force perturbations and by 84% during simulated one-arm functional tasks. Performance was most sensitive to inaccurate measurements of ankle plantar/dorsiflexion position and hip ab/adduction velocity feedback. In conclusion, comprehensive joint feedback demonstrates potential to markedly improve FNS standing function. However, alternative control structures capable of effective performance with fewer sensor-based feedback parameters may better facilitate clinical usage. PMID- 20923742 TI - Maternal exposure to ambient levels of benzene and neural tube defects among offspring: Texas, 1999-2004. AB - BACKGROUND: Previous studies have reported positive associations between maternal exposure to air pollutants and several adverse birth outcomes. However, there have been no studies assessing the association between environmental levels of hazardous air pollutants, such as benzene, and neural tube defects (NTDs), a common and serious group of congenital malformations. OBJECTIVE: Our goal was to conduct a case-control study assessing the association between ambient air levels of benzene, toluene, ethylbenzene, and xylene (BTEX) and the prevalence of NTDs among offspring. METHODS: The Texas Birth Defects Registry provided data on NTD cases (spina bifida and anencephaly) delivered between 1999 and 2004. The control group was a random sample of unaffected live births, frequency matched to cases on year of birth. Census tract-level estimates of annual BTEX levels were obtained from the U.S. Environmental Protection Agency 1999 Assessment System for Population Exposure Nationwide. Restricted cubic splines were used in mixed effects logistic regression models to determine associations between each pollutant and NTD phenotype. RESULTS: Mothers living in census tracts with the highest benzene levels were more likely to have offspring with spina bifida than were women living in census tracts with the lowest levels (odds ratio = 2.30; 95% confidence interval, 1.22-4.33). No significant associations were observed between anencephaly and benzene or between any of the NTD phenotypes and toluene, ethylbenzene, or xylene. CONCLUSION: In the first study to assess the relationship between environmental levels of BTEX and NTDs, we found an association between benzene and spina bifida. Our results contribute to the growing body of evidence regarding air pollutant exposure and adverse birth outcomes. PMID- 20923743 TI - Population-based inorganic mercury biomonitoring and the identification of skin care products as a source of exposure in New York City. AB - BACKGROUND: Mercury is a toxic metal that has been used for centuries as a constituent of medicines and other items. OBJECTIVE: We assessed exposure to inorganic mercury in the adult population of New York City (NYC). METHODS: We measured mercury concentrations in spot urine specimens from a representative sample of 1,840 adult New Yorkers in the 2004 NYC Health and Nutrition Examination Survey. Cases with urine concentrations >= 20 ug/L were followed up with a telephone or in-person interview that asked about potential sources of exposure, including ritualistic/cultural practices, skin care products, mercury spills, herbal medicine products, and fish. RESULTS: Geometric mean urine mercury concentration in NYC was higher for Caribbean-born blacks [1.39 ug/L; 95% confidence interval (CI), 1.14-1.70] and Dominicans (1.04 ug/L; 95% CI, 0.82 1.33) than for non-Hispanic whites (0.67 ug/L; 95% CI, 0.60-0.75) or other racial/ethnic groups. It was also higher among those who reported at least 20 fish meals in the past 30 days (1.02 ug/L; 95% CI, 0.83-1.25) than among those who reported no fish meals (0.50 ug/L; 95% CI, 0.41-0.61). We observed the highest 95th percentile of exposure (21.18 ug/L; 95% CI, 7.25-51.29) among Dominican women. Mercury-containing skin-lightening creams were a source of exposure among those most highly exposed, and we subsequently identified 12 imported products containing illegal levels of mercury in NYC stores. CONCLUSION: Population-based biomonitoring identified a previously unrecognized source of exposure to inorganic mercury among NYC residents. In response, the NYC Health Department embargoed products and notified store owners and the public that skin lightening creams and other skin care products that contain mercury are dangerous and illegal. Although exposure to inorganic mercury is not a widespread problem in NYC, users of these products may be at risk of health effects from exposure. PMID- 20923744 TI - Genetic, biochemical, and environmental factors associated with pregnancy outcomes in newborns from the Czech Republic. AB - BACKGROUND: Oxidative damage to placental DNA can result in negative pregnancy outcomes, including intrauterine growth restriction (IUGR) and low birth weight (LBW). OBJECTIVE: We investigated associations between the levels of 8-oxo-7,8 dihydro-2'-deoxyguanosine (8-oxodG), a marker of oxidative DNA damage, in placental DNA, exposure to air pollutants during pregnancy, genetic polymorphisms in 94 selected genes, and pregnancy outcomes. METHODS: We studied 891 newborns who were IUGR- or LBW-affected or normal weight and were born between 1994 and 1999 in the Czech Republic in two districts with different levels of air pollution. RESULTS: We found nonsignificantly elevated 8-oxodG levels in the IUGR affected group compared with the non-IUGR group (p = 0.055). Similarly, slightly elevated 8-oxodG levels were found in the LBW-affected group compared with the non-LBW group (p < 0.050). In univariate analyses, we identified single nucleotide polymorphisms associated with 8-oxodG levels, IUGR, and LBW. Exposure to particulate matter < 2.5 um was associated with increased 8-oxodG levels in placental DNA and LBW. However, multivariate-adjusted logistic regression revealed that above-median 8-oxodG levels were the only factor significantly associated with IUGR [OR = 1.56; 95% confidence interval (CI), 1.07-2.37; p = 0.022]. Above-median levels of 8-oxodG were associated with LBW (OR = 1.88; 95% CI, 1.15-3.06; p = 0.011). Other variables associated with LBW included sex and gestational age of the newborn, maternal smoking, and haplotypes in the promoter region of the gene encoding mannose-binding lectin 2 (MBL2). The role of air pollutants in the risk of adverse pregnancy outcomes seemed to be less important. CONCLUSIONS: Levels of 8-oxodG in placental DNA were associated with the risk of IUGR as well as LBW. Newborn's sex, gestational age, maternal smoking, and genetic polymorphisms in the promoter region of the MBL2 gene were associated with LBW incidence. PMID- 20923745 TI - Prenatal organochlorine compound exposure, rapid weight gain, and overweight in infancy. AB - BACKGROUND: Although it has been hypothesized that fetal exposure to endocrine disrupting chemicals may increase obesity risk, empirical data are limited, and it is uncertain how early in life any effects may begin. OBJECTIVES: We explored whether prenatal exposure to several organochlorine compounds (OCs) is associated with rapid growth in the first 6 months of life and body mass index (BMI) later in infancy. METHODS: Data come from the INMA (Infancia y Medio-Ambiente) Child and Environment birth cohort in Spain, which recruited 657 women in early pregnancy. Rapid growth during the first 6 months was defined as a change in weight-for-age z-scores > 0.67, and elevated BMI at 14 months, as a z-score >= the 85th percentile. Generalized linear models were used to estimate the risk of rapid growth or elevated BMI associated with 2,2-bis(p-chlorophenyl)-1,1 dichloroethylene (DDE), hexachlorobenzene, beta-hexachlorohexane, and polychlorinated biphenyls in first-trimester maternal serum. RESULTS: After multivariable adjustment including other OCs, DDE exposure above the first quartile was associated with doubling of the risk of rapid growth among children of normal-weight (BMI < 25 kg/m2), but not overweight, mothers. DDE was also associated with elevated BMI at 14 months (relative risk per unit increase in log DDE = 1.50; 95% confidence interval, 1.11-2.03). Other OCs were not associated with rapid growth or elevated BMI after adjustment. CONCLUSIONS: In this study we found prenatal DDE exposure to be associated with rapid weight gain in the first 6 months and elevated BMI later in infancy, among infants of normal-weight mothers. More research exploring the potential role of chemical exposures in early-onset obesity is needed. PMID- 20923746 TI - Postmenopausal breast cancer is associated with exposure to traffic-related air pollution in Montreal, Canada: a case-control study. AB - BACKGROUND: Only about 30% of cases of breast cancer can be explained by accepted risk factors. Occupational studies have shown associations between the incidence of breast cancer and exposure to contaminants that are found in ambient air. OBJECTIVES: We sought to determine whether the incidence of postmenopausal breast cancer is associated with exposure to urban air pollution. METHODS: We used data from a case-control study conducted in Montreal, Quebec, in 1996-1997. Cases were 383 women with incident invasive breast cancer, and controls were 416 women with other incident, malignant cancers, excluding those potentially associated with selected occupational exposures. Concentrations of nitrogen dioxide (NO2) were measured across Montreal in 2005-2006. We developed a land-use regression model to predict concentrations of NO2 across Montreal for 2006, and developed two methods to extrapolate the estimates to 1985 and 1996. We linked these estimates to addresses of residences of subjects at time of interview. We used unconditional logistic regression to adjust for accepted and suspected risk factors and occupational exposures. RESULTS: For each increase of 5 ppb NO2 estimated in 1996, the adjusted odds ratio was 1.31 (95% confidence interval, 1.00-1.71). Although the size of effect varied somewhat across periods, we found an increased risk of approximately 25% for every increase of 5 ppb in exposure. CONCLUSIONS: We found evidence of an association between the incidence of postmenopausal breast cancer and exposure to ambient concentrations of NO2. Further studies are needed to confirm whether NO2 or other components of traffic related pollution are indeed associated with increased risks. PMID- 20923747 TI - Transient paresis of the right recurrent laryngeal nerve after treatment with etanercept for plaque-type psoriasis. PMID- 20923748 TI - Primary mucinous carcinoma of the skin. PMID- 20923749 TI - Efficacy and safety of etanercept in patients with psoriasis and hepatitis C. PMID- 20923750 TI - Epidermolysis bullosa simplex with mottled pigmentation - mutation analysis proved the diagnosis in a four-generation pedigree. AB - Epidermolysis bullosa simplex with mottled pigmentation (EBS-MP) is a rare variant of the basal form of EBS, characterized by mild intraepidermal blistering due to lysis of basal keratinocytes and with a progressive reticular hyperpigmentation on the trunk and extremities. A limited number of cases - to date twenty unrelated families - have been published from all over the world, including thirteen reports from Europe. We here report the first Hungarian case in a four generation pedigree with EBS-MP symptoms and prove the diagnosis by mutation analysis. A heterozygous p.Pro25Leu mutation in the first exon of KRT5, together with the heterozygous polymorphism p.Gly138Glu, was identified in all the five affected family members studied. Our report extends the limited number of EBS-MP cases and gives further evidence that KRT5 mutations are responsible for this rare phenotype. PMID- 20923751 TI - Bullous systemic lupus erythematosus responding to mycophenolate mofetil. PMID- 20923752 TI - Ultrasound detection of a PET/CT negative lymph node metastasis in cutaneous melanoma. PMID- 20923753 TI - Expression of estrogen-related receptor beta (ERRbeta) in human skin. AB - Skin is a non classical target tissue for estrogens, whose biological and mechanical properties are affected by the hormonal deprivation occurring at the menopause. Estrogen-related receptors (ERR), closely related to the estrogen receptors (ER), constitute a subfamily of orphan receptors, interfering with ER mediated signalling pathways. The expression of ERRbeta has been detected in only a few adult tissues so far, such as the prostate and the inner ear. Here, we demonstrate the expression of ERRbeta in normal human skin. ERRbeta was detected in human epidermis, in both keratinocytes and Langerhans cells, by immunohistochemistry. These results were validated on freshly extracted epidermal cells and on monolayer-cultured keratinocytes by RT-PCR and western blotting (WB), suggesting the implication of ERRbeta in skin immunity and endocrine effects. PMID- 20923754 TI - Primary cutaneous cribriform apocrine carcinoma on a typical location. PMID- 20923755 TI - Biomedical informatics techniques for processing and analyzing web blogs of military service members. AB - INTRODUCTION: Web logs ("blogs") have become a popular mechanism for people to express their daily thoughts, feelings, and emotions. Many of these expressions contain health care-related themes, both physical and mental, similar to information discussed during a clinical interview or medical consultation. Thus, some of the information contained in blogs might be important for health care research, especially in mental health where stress-related conditions may be difficult and expensive to diagnose and where early recognition is often key to successful treatment. In the field of biomedical informatics, techniques such as information retrieval (IR) and natural language processing (NLP) are often used to unlock information contained in free-text notes. These methods might assist the clinical research community to better understand feelings and emotions post deployment and the burden of symptoms of stress among US military service members. METHODS: In total, 90 military blog posts describing deployment situations and 60 control posts of Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) were collected. After "stop" word exclusion and stemming, a "bag-of-words" representation and term weighting was performed, and the most relevant words were manually selected out of the high-weight words. A pilot ontology was created using Collaborative Protege, a knowledge management application. The word lists and the ontology were then used within General Architecture for Text Engineering (GATE), an NLP framework, to create an automated pipeline for recognition and analysis of blogs related to combat exposure. An independent expert opinion was used to create a reference standard and evaluate the results of the GATE pipeline. RESULTS: The 2 dimensions of combat exposure descriptors identified were: words dealing with physical exposure and the soldiers' emotional reactions to it. GATE pipeline was able to retrieve blog texts describing combat exposure with precision 0.9, recall 0.75, and F score 0.82. DISCUSSION: Natural language processing and automated information retrieval might potentially provide valuable tools for retrieving and analyzing military blog posts and uncovering military service members' emotions and experiences of combat exposure. PMID- 20923756 TI - Updates on the genetics of neurodegenerative disorders. AB - Since the publication in 1998 of the last special issue of JGPN on the genetics of dementia, we have witnessed the completion of the Human Genome Project and an exponential increase in the identification of causative genes in human diseases. This special issue revisits the 6 neurodegenerative disorders described in that issue, offering important updates to the genetic findings for these disorders that together comprise the most common causes of dementia among elderly people. It is critical for practicing neurologists, psychiatrists, and geriatricians to keep abreast of these advances as they will impact the clinical diagnosis and management of these disorders. The reviews in this issue have been written by an outstanding group of international experts who provide a clear and insightful update on the molecular genetic advances and genetic counseling principles for each disorder. PMID- 20923757 TI - The clinical and genetic features of Huntington disease. AB - Huntington disease (HD) is a dominantly inherited neurodegenerative disorder that usually presents in adulthood with characteristic motor and cognitive features and with variable and diverse psychiatric disturbances. Following the discovery of the causative defect in the HTT gene in 1993, great advances in understanding the pathogenesis of HD have been made, yet no effective disease-modifying therapy has been identified. In this new era of HD research, we have seen the emergence of a number of large clinical trials, the systematic search for novel biomarkers and the recent initiation of the first pre-manifest HD clinical studies. In this review, we seek to provide an overview of the clinical and genetic features of HD together with a summary of clinical research at this time. PMID- 20923758 TI - Identification of residue-to-residue contact between a peptide ligand and its G protein-coupled receptor using periodate-mediated dihydroxyphenylalanine cross linking and mass spectrometry. AB - Fundamental knowledge about how G protein-coupled receptors and their ligands interact is important for understanding receptor-ligand binding and the development of new drug discovery strategies. We have used cross-linking and tandem mass spectrometry analyses to investigate the interaction of the N terminus of the Saccharomyces cerevisiae tridecapeptide pheromone, alpha-factor (WHWLQLKPGQPMY), and Ste2p, its cognate G protein-coupled receptor. The Trp(1) residue of alpha-factor was replaced by 3,4-dihydroxyphenylalanine (DOPA) for periodate-mediated chemical cross-linking, and biotin was conjugated to Lys(7) for detection purposes to create the peptide [DOPA(1),Lys(7)(BioACA),Nle(12)]alpha-factor, called Bio-DOPA(1)-alpha-factor. This ligand analog was a potent agonist and bound to Ste2p with ~65 nanomolar affinity. Immunoblot analysis of purified Ste2p samples that were treated with Bio-DOPA(1)-alpha-factor showed that the peptide analog cross-linked efficiently to Ste2p. The cross-linking was inhibited by the presence of either native alpha factor or an alpha-factor antagonist. MALDI-TOF and immunoblot analyses revealed that Bio-DOPA(1)-alpha-factor cross-linked to a fragment of Ste2p encompassing residues Ser(251)-Met(294). Fragmentation of the cross-linked fragment and Ste2p using tandem mass spectrometry pinpointed the cross-link point of the DOPA(1) of the alpha-factor analog to the Ste2p Lys(269) side chain near the extracellular surface of the TM6-TM7 bundle. This conclusion was confirmed by a greatly diminished cross-linking of Bio-DOPA(1)-alpha-factor into a Ste2p(K269A) mutant. Based on these and previously obtained binding contact data, a mechanism of alpha factor binding to Ste2p is proposed. The model for bound alpha-factor shows how ligand binding leads to conformational changes resulting in receptor activation of the signal transduction pathway. PMID- 20923759 TI - Channel domain of colicin A modifies the dimeric organization of its immunity protein. AB - Proteins conferring immunity against pore-forming colicins are localized in the Escherichia coli inner membrane. Their protective effects are mediated by direct interaction with the C-terminal domain of their cognate colicins. Cai, the immunity protein protecting E. coli against colicin A, contains four cysteine residues. We report cysteine cross-linking experiments showing that Cai forms homodimers. Cai contains four transmembrane segments (TMSs), and dimerization occurs via the third TMS. Furthermore, we observe the formation of intramolecular disulfide bonds that connect TMS2 with either TMS1 or TMS3. Co-expression of Cai with its target, the colicin A pore-forming domain (pfColA), in the inner membrane prevents the formation of intermolecular and intramolecular disulfide bonds, indicating that pfColA interacts with the dimer of Cai and modifies its conformation. Finally, we show that when Cai is locked by disulfide bonds, it is no longer able to protect cells against exogenous added colicin A. PMID- 20923760 TI - MicroRNA (miRNA)-mediated interaction between leukemia/lymphoma-related factor (LRF) and alternative splicing factor/splicing factor 2 (ASF/SF2) affects mouse embryonic fibroblast senescence and apoptosis. AB - Leukemia/lymphoma-related factor (LRF) is a transcriptional repressor, which by recruiting histone deacetylases specifically represses p19/ARF expression, thus behaving as an oncogene. Conversely, in mouse embryonic fibroblasts (MEF), LRF inhibition causes aberrant p19ARF up-regulation resulting in proliferative defects and premature senescence. We have recently shown that LRF is controlled by microRNAs. Here we show that LRF acts on MEF proliferation and senescence/apoptosis by repressing miR-28 and miR-505, revealing a regulatory circuit where microRNAs (miRNAs) work both upstream and downstream of LRF. By analyzing miRNA expression profiles of MEF transfected with LRF-specific short interfering RNAs, we found that miR-28 and miR-505 are modulated by LRF. Both miRNAs are predicted to target alternative splicing factor/splicing factor 2 (ASF/SF2), a serine/arginine protein essential for cell viability. In vertebrates, loss or inactivation of ASF/SF2 may result in genomic instability and induce G(2) cell cycle arrest and apoptosis. We showed that miR-28 and miR 505 modulate ASF/SF2 by directly binding ASF/SF2 3'-UTR. Decrease in LRF causes a decrease in ASF/SF2, which depends on up-regulation of miR-28 and miR-505. Alteration of each of the members of the LRF/miR-28/miR-505/ASF/SF2 axis affects MEF proliferation and the number of senescent and apoptotic cells. Consistently, the axis is coordinately modulated as cell senescence increases with passages in MEF culture. In conclusion, we show that LRF-dependent miRNAs miR-28 and miR-505 control MEF proliferation and survival by targeting ASF/SF2 and suggest a central role of LRF-related miRNAs, in addition to the role of LRF-dependent p53 control, in cellular homeostasis. PMID- 20923761 TI - Classical NF-kappaB activation negatively regulates noncanonical NF-kappaB dependent CXCL12 expression. AB - Ligation of the lymphotoxin-beta receptor (LTbetaR) by LIGHT (lymphotoxin-related inducible ligand that competes for glycoprotein D binding to herpes virus entry mediator on T cells (TNFSF14)) activates the noncanonical (NC) NF-kappaB (nuclear factor-kappaB) pathway and up-regulates CXCL12 gene expression by human umbilical vein endothelial cells (HUVEC). In contrast, TNF only activates classical NF kappaB signaling and does not up-regulate CXCL12. To determine whether cross-talk between the classical and NC pathways affects CXCL12 expression, we investigated the effects of TNF on LIGHT signaling in HUVEC. We show here that TNF inhibits both basal and LIGHT-induced CXCL12 expression. Negative regulation by TNF requires the classical NF-kappaB pathway as inhibition of basal and induced CXCL12 was reversed in HUVEC-expressing dominant negative IkappaB (inhibitor of NF-kappaB) kinase (IKK)beta (IKKbeta(K44M)). TNF did not inhibit the NC NF-kappaB pathway activation as LIGHT-induced p100 processing to p52 was intact; however, TNF either alone or together with LIGHT up-regulated p100 and RelB expression and induced the nuclear localization of p100-RelB complexes. Enhanced p100 and RelB expression was inhibited by IKKbeta(K44M), which led us to question whether the IkappaB function of elevated p100 mediates the inhibition of CXCL12 expression by TNF. We retrovirally transduced HUVEC to express p100 at a level similar to that up-regulated by TNF; however, basal and LIGHT-induced CXCL12 expression was normal in the transduced cells. In contrast, ectopic RelB expression recapitulated the effects of TNF on NC signaling and inhibited basal and LIGHT induced CXCL12 expression by HUVEC. Our findings therefore demonstrate that TNF induced classical NF-kappaB signaling up-regulates RelB expression that inhibits both basal and NC NF-kappaB-dependent CXCL12 expression. PMID- 20923762 TI - The first type III repeat in fibronectin activates an inflammatory pathway in dermal fibroblasts. AB - Remodeling of the fibronectin matrix occurs during a variety of pathological and regenerative processes. Cellular generated tensional forces can alter the secondary and tertiary structure of the fibronectin matrix and regulate the exposure of cryptic activities that directly impact cell behavior. In the present study, we evaluated the effect of the partially unfolded Type III fibronectin module, FnIII-1c, on gene expression in dermal fibroblasts. Microarray and PCR analysis indicated that the addition of FnIII-1c to human dermal fibroblasts induced the expression of several inflammatory genes including the cytokines, IL 8 and TNF-alpha. ELISA analysis indicated that the increased gene expression was accompanied by the secretion of IL-8 and TNF-alpha protein. FnIII-1c-induced gene expression was preceded by increased phosphorylation of IkappaB kinase (IKK) and IkappaBalpha as well as the nuclear translocation of NFkappaB. PCR and ELISA analysis showed that inhibition of the NFkappaB signaling pathway completely blocked the induction of IL-8 and TNF-alpha. Blocking antibodies to Toll-like receptor 4 inhibited both the activation of the NFkappaB signaling pathway as well as cytokine expression in response to FnIII-1c. These data suggest that fibronectin matrix remodeling can induce the expression of cytokines by stromal cells present in the tissue microenvironment. PMID- 20923763 TI - Hemin binds to human cytoplasmic arginyl-tRNA synthetase and inhibits its catalytic activity. AB - The free form of human cytoplasmic arginyl-tRNA synthetase (hcArgRS) is hypothesized to participate in ubiquitin-dependent protein degradation by offering arginyl-tRNA(Arg) to arginyl-tRNA transferase (ATE1). We investigated the effect of hemin on hcArgRS based on the fact that hemin regulates several critical proteins in the "N-end rule" protein degradation pathway. Extensive biochemical evidence has established that hemin could bind to both forms of hcArgRS in vitro. Based on the spectral changes of the Soret band on site directed protein mutants, we identified Cys-115 as a specific axial ligand of hemin binding that is located in the Add1 domain. Hemin inhibited the catalytic activity of full-length and N-terminal 72-amino acid-truncated hcArgRSs by blocking amino acid activation. Kinetic analysis demonstrated that the K(m) values for tRNA(Arg), arginine, and ATP in the presence of hemin were not altered, but k(cat) values dramatically decreased compared with those in the absence of hemin. By comparison, the activity of prokaryotic ArgRS was not affected obviously by hemin. Gel filtration chromatography suggested that hemin induced oligomerization of both the isolated Add1 domain and the wild type enzyme, which could account for the inhibition of catalytic activity. However, the catalytic activity of an hcArgRS mutant with Cys-115 replaced by alanine (hcArgRS-C115A) was also inhibited by hemin, suggesting that hemin binding to Cys 115 is not responsible for the inhibition of enzymatic activity and that the specific binding may participate in other biological functions. PMID- 20923764 TI - Timing of gene transcription in the galactose utilization system of Escherichia coli. AB - In the natural environment, bacterial cells have to adjust their metabolism to alterations in the availability of food sources. The order and timing of gene expression are crucial in these situations to produce an appropriate response. We used the galactose regulation in Escherichia coli as a model system for understanding how cells integrate information about food availability and cAMP levels to adjust the timing and intensity of gene expression. We simulated the feast-famine cycle of bacterial growth by diluting stationary phase cells in fresh medium containing galactose as the sole carbon source. We followed the activities of six promoters of the galactose system as cells grew on and ran out of galactose. We found that the cell responds to a decreasing external galactose level by increasing the internal galactose level, which is achieved by limiting galactose metabolism and increasing the expression of transporters. We show that the cell alters gene expression based primarily on the current state of the cell and not on monitoring the level of extracellular galactose in real time. Some decisions have longer term effects; therefore, the current state does subtly encode the history of food availability. In summary, our measurements of timing of gene expression in the galactose system suggest that the system has evolved to respond to environments where future galactose levels are unpredictable rather than regular feast and famine cycles. PMID- 20923765 TI - PTPD1 supports receptor stability and mitogenic signaling in bladder cancer cells. AB - PTPD1, a cytosolic non-receptor protein-tyrosine phosphatase, stimulates the Src EGF transduction pathway. Localization of PTPD1 at actin cytoskeleton and adhesion sites is required for cell scattering and migration. Here, we show that during EGF stimulation, PTPD1 is rapidly recruited to endocytic vesicles containing the EGF receptor. Endosomal localization of PTPD1 is mediated by interaction with KIF16B, an endosomal kinesin that modulates receptor recycling at the plasma membrane. Silencing of PTPD1 promotes degradation of EGF receptor and inhibits downstream ERK signaling. We also found that PTPD1 is markedly increased in bladder cancer tissue samples. PTPD1 levels positively correlated with the grading and invasiveness potential of these tumors. Transgenic expression of an inactive PTPD1 mutant or genetic knockdown of the endogenous PTPD1 severely inhibited both growth and motility of human bladder cancer cells. These findings identify PTPD1 as a novel component of the endocytic machinery that impacts on EGF receptor stability and on growth and motility of bladder cancer cells. PMID- 20923766 TI - Functional hypervariability and gene diversity of cardioactive neuropeptides. AB - Crustacean cardioactive peptide (CCAP) and related peptides are multifunctional regulatory neurohormones found in invertebrates. We isolated a CCAP-related peptide (conoCAP-a, for cone snail CardioActive Peptide) and cloned the cDNA of its precursor from venom of Conus villepinii. The precursor of conoCAP-a encodes for two additional CCAP-like peptides: conoCAP-b and conoCAP-c. This multi peptide precursor organization is analogous to recently predicted molluscan CCAP like preprohormones, and suggests a mechanism for the generation of biological diversification without gene amplification. While arthropod CCAP is a cardio accelerator, we found that conoCAP-a decreases the heart frequency in Drosophila larvae, demonstrating that conoCAP-a and CCAP have opposite effects. Intravenous injection of conoCAP-a in rats caused decreased heart frequency and blood pressure in contrast to the injection of CCAP, which did not elicit any cardiac effect. Perfusion of rat ventricular cardiac myocytes with conoCAP-a decreased systolic calcium, indicating that conoCAP-a cardiac negative inotropic effects might be mediated via impairment of intracellular calcium trafficking. The contrasting cardiac effects of conoCAP-a and CCAP indicate that molluscan CCAP like peptides have functions that differ from those of their arthropod counterparts. Molluscan CCAP-like peptides sequences, while homologous, differ between taxa and have unique sequences within a species. This relates to the functional hypervariability of these peptides as structure activity relationship studies demonstrate that single amino acids variations strongly affect cardiac activity. The discovery of conoCAPs in cone snail venom emphasizes the significance of their gene plasticity to have mutations as an adaptive evolution in terms of structure, cellular site of expression, and physiological functions. PMID- 20923767 TI - On the role of molecular oxygen in lipoxygenase activation: comparison and contrast of epidermal lipoxygenase-3 with soybean lipoxygenase-1. AB - The oxygenation of polyunsaturated fatty acids by lipoxygenases (LOX) is associated with a lag phase during which the resting ferrous enzyme is converted to the active ferric form by reaction with fatty acid hydroperoxide. Epidermal lipoxygenase-3 (eLOX3) is atypical in displaying hydroperoxide isomerase activity with fatty acid hydroperoxides through cycling of the ferrous enzyme. Yet eLOX3 is capable of dioxygenase activity, albeit with a long lag phase and need for high concentrations of hydroperoxide activator. Here, we show that higher O(2) concentration shortens the lag phase in eLOX3, although it reduces the rate of hydroperoxide consumption, effects also associated with an A451G mutation known to affect the disposition of molecular oxygen in the LOX active site. These observations are consistent with a role of O(2) in interrupting hydroperoxide isomerase cycling. Activation of eLOX3, A451G eLOX3, and soybean LOX-1 with 13 hydroperoxy-linoleic acid forms oxygenated end products, which we identified as 9R- and 9S-hydroperoxy-12S,13S-trans-epoxyoctadec-10E-enoic acids. We deduce that activation partly depends on reaction of O(2) with the intermediate of hydroperoxide cleavage, the epoxyallylic radical, giving an epoxyallylic peroxyl radical that does not further react with Fe(III)-OH; instead, it dissociates and leaves the enzyme in the activated free ferric state. eLOX3 differs from soybean LOX-1 in more tightly binding the epoxyallylic radical and having limited access to O(2) within the active site, leading to a deficiency in activation and a dominant hydroperoxide isomerase activity. PMID- 20923768 TI - Endocannabinoids prevent beta-amyloid-mediated lysosomal destabilization in cultured neurons. AB - Neuronal cell loss underlies the pathological decline in cognition and memory associated with Alzheimer disease (AD). Recently, targeting the endocannabinoid system in AD has emerged as a promising new approach to treatment. Studies have identified neuroprotective roles for endocannabinoids against key pathological events in the AD brain, including cell death by apoptosis. Elucidation of the apoptotic pathway evoked by beta-amyloid (Abeta) is thus important for the development of therapeutic strategies that can thwart Abeta toxicity and preserve cell viability. We have previously reported that lysosomal membrane permeabilization plays a distinct role in the apoptotic pathway initiated by Abeta. In the present study, we provide evidence that the endocannabinoid system can stabilize lysosomes against Abeta-induced permeabilization and in turn sustain cell survival. We report that endocannabinoids stabilize lysosomes by preventing the Abeta-induced up-regulation of the tumor suppressor protein, p53, and its interaction with the lysosomal membrane. We also provide evidence that intracellular cannabinoid type 1 receptors play a role in stabilizing lysosomes against Abeta toxicity and thus highlight the functionality of these receptors. Given the deleterious effect of lysosomal membrane permeabilization on cell viability, stabilization of lysosomes with endocannabinoids may represent a novel mechanism by which these lipid modulators confer neuroprotection. PMID- 20923769 TI - A conserved aromatic residue in the autochaperone domain of the autotransporter Hbp is critical for initiation of outer membrane translocation. AB - Autotransporters are bacterial virulence factors that share a common mechanism by which they are transported to the cell surface. They consist of an N-terminal passenger domain and a C-terminal beta-barrel, which has been implicated in translocation of the passenger across the outer membrane (OM). The mechanism of passenger translocation and folding is still unclear but involves a conserved region at the C terminus of the passenger domain, the so-called autochaperone domain. This domain functions in the stepwise translocation process and in the folding of the passenger domain after translocation. In the autotransporter hemoglobin protease (Hbp), the autochaperone domain consists of the last rung of the beta-helix and a capping domain. To examine the role of this region, we have mutated several conserved aromatic residues that are oriented toward the core of the beta-helix. We found that non-conservative mutations affected secretion with Trp(1015) in the cap region as the most critical residue. Substitution at this position yielded a DegP-sensitive intermediate that is located at the periplasmic side of the OM. Further analysis revealed that Trp(1015) is most likely required for initiation of processive folding of the beta-helix at the cell surface, which drives sequential translocation of the Hbp passenger across the OM. PMID- 20923770 TI - Phosphatidylserine is involved in the ferrichrome-induced plasma membrane trafficking of Arn1 in Saccharomyces cerevisiae. AB - Arn1 is an integral membrane protein that mediates the uptake of ferrichrome, an important nutritional source of iron, in Saccharomyces cerevisiae. In the absence of ferrichrome, Arn1p is sorted directly from the trans-Golgi network to the vacuolar lumen for degradation. In the presence of low levels of ferrichrome, the siderophore binds to a receptor domain on Arn1, triggering the redistribution of Arn1 to the plasma membrane. When extracellular ferrichrome levels are high, Arn1 cycles between the plasma membrane and intracellular vesicles. To further understand the mechanisms of trafficking of Arn1p, we screened 4580 viable yeast deletion mutants for mislocalization of Arn1-GFP using synthetic genetic array technology. We identified over 100 genes required for trans-Golgi network-to vacuole trafficking of Arn1-GFP and only two genes, SER1 and SER2, required for the ferrichrome-induced plasma membrane trafficking of Arn1-GFP. SER1 and SER2 encode two enzymes of the major serine biosynthetic pathway, and the Arn1 trafficking defect in the ser1Delta strain was corrected with supplemental serine or glycine. Plasma membrane trafficking of Hxt3, a structurally related glucose transporter, was unaffected by SER1 deletion. Serine is required for the synthesis of multiple cellular components, including purines, sphingolipids, and phospholipids, but of these only phosphatidylserine corrected the Arn1 trafficking defects of the ser1Delta strain. Strains with defects in phospholipid synthesis also exhibited alterations in Arn1p trafficking, indicating that the intracellular trafficking of some transporters is dependent on the phospholipid composition of the cellular membranes. PMID- 20923771 TI - A mouse macrophage lipidome. AB - We report the lipidomic response of the murine macrophage RAW cell line to Kdo(2) lipid A, the active component of an inflammatory lipopolysaccharide functioning as a selective TLR4 agonist and compactin, a statin inhibitor of cholesterol biosynthesis. Analyses of lipid molecular species by dynamic quantitative mass spectrometry and concomitant transcriptomic measurements define the lipidome and demonstrate immediate responses in fatty acid metabolism represented by increases in eicosanoid synthesis and delayed responses characterized by sphingolipid and sterol biosynthesis. Lipid remodeling of glycerolipids, glycerophospholipids, and prenols also take place, indicating that activation of the innate immune system by inflammatory mediators leads to alterations in a majority of mammalian lipid categories, including unanticipated effects of a statin drug. Our studies provide a systems-level view of lipid metabolism and reveal significant connections between lipid and cell signaling and biochemical pathways that contribute to innate immune responses and to pharmacological perturbations. PMID- 20923772 TI - Consequences of depletion of the signal recognition particle in Escherichia coli. AB - Thus far, the role of the Escherichia coli signal recognition particle (SRP) has only been studied using targeted approaches. It has been shown for a handful of cytoplasmic membrane proteins that their insertion into the cytoplasmic membrane is at least partially SRP-dependent. Furthermore, it has been proposed that the SRP plays a role in preventing toxic accumulation of mistargeted cytoplasmic membrane proteins in the cytoplasm. To complement the targeted studies on SRP, we have studied the consequences of the depletion of the SRP component Fifty-four homologue (Ffh) in E. coli using a global approach. The steady-state proteomes and the proteome dynamics were evaluated using one- and two-dimensional gel analysis, followed by mass spectrometry-based protein identification and immunoblotting. Our analysis showed that depletion of Ffh led to the following: (i) impaired kinetics of the biogenesis of the cytoplasmic membrane proteome; (ii) lowered steady-state levels of the respiratory complexes NADH dehydrogenase, succinate dehydrogenase, and cytochrome bo(3) oxidase and lowered oxygen consumption rates; (iii) increased levels of the chaperones DnaK and GroEL at the cytoplasmic membrane; (iv) a sigma(32) stress response and protein aggregation in the cytoplasm; and (v) impaired protein synthesis. Our study shows that in E. coli SRP-mediated protein targeting is directly linked to maintaining protein homeostasis and the general fitness of the cell. PMID- 20923773 TI - Regulation of lung cancer cell migration and invasion by reactive oxygen species and caveolin-1. AB - The acquired capability of tumor cells to migrate and invade neighboring tissues is associated with high metastatic potential and advanced stage of cancers. Recently, signaling molecules such as reactive oxygen species (ROS) and caveolin 1 (Cav-1) have been implicated in the aggressive behavior of cancer cells. However, the roles of specific ROS in cancer cell migration and Cav-1 regulation are unclear. We demonstrate here that Cav-1 plays an important role in the migration and invasion of human lung carcinoma H460 cells and that these effects are differentially regulated by cellular ROS. Using various known inhibitors and donors of ROS, we found that different ROS have different effects on Cav-1 expression and cell migration and invasion. Superoxide anion and hydrogen peroxide down-regulated Cav-1 expression and inhibited cell migration and invasion, whereas hydroxyl radical up-regulated the Cav-1 expression and promoted cell migration and invasion. The down-regulating effect of superoxide anion and hydrogen peroxide on Cav-1 is mediated through a transcription-independent mechanism that involves protein degradation via the ubiquitin-proteasome pathway. These results indicate the essential role of different ROS in cancer cell motility and through Cav-1 expression, which may provide a key mechanism controlling tumor progression and metastasis. The up-regulation of Cav-1 and cell motility by hydroxyl free radical suggests an important role of this ROS as a positive regulator of tumor progression. PMID- 20923774 TI - Tay1 protein, a novel telomere binding factor from Yarrowia lipolytica. AB - Inspection of the complete genome of the yeast Yarrowia lipolytica for the presence of genes encoding homologues of known telomere-binding proteins surprisingly revealed no counterparts of typical yeast Myb domain-containing telomeric factors including Rap1 or Taz1. Instead, we identified a gene, YALIOD10923g, encoding a protein containing two Myb domains, exhibiting a high degree of similarity to the Myb domain of human telomeric proteins TRF1 and TRF2 and homologous to an essential fission yeast protein Mug152 whose expression is elevated during meiosis. The protein, which we named Tay1p (telomere-associated in Yarrowia lipolytica 1), was purified for biochemical studies. Using a model Y. lipolytica telomere, we demonstrate that the protein preferentially binds to Y. lipolytica telomeric tracts. Tay1p binds along the telomeric tract as dimers and larger oligomers, and it is able to remodel the telomeric DNA into both looped structures and synaptic complexes of two model telomere DNAs. The ability of Tay1p to induce dimerization of telomeres in vitro goes in line with its oligomeric nature, where each oligomer can employ several Myb domains to form intermolecular telomere clusters. We also provide experimental evidence that Tay1p may be associated with Y. lipolytica telomeres in vivo. Together with its homologues from Schizosaccharomyces pombe and several basidiomycetous fungi (Sanchez-Alonso, P., and Guzman, P. (2008) Fungal Genet. Biol. 45, S54-S62), Tay1p constitutes a novel family of putative telomeric factors whose analysis may be instrumental in understanding the function and evolution of double-stranded DNA telomeric proteins. PMID- 20923775 TI - Rsf-1, a chromatin remodeling protein, induces DNA damage and promotes genomic instability. AB - Rsf-1 (HBXAP) has been reported as an amplified gene in human cancer, including the highly aggressive ovarian serous carcinoma. Rsf-1 protein interacts with SNF2H to form an ISWI chromatin remodeling complex, RSF. In this study, we investigated the functional role of Rsf-1 by observing phenotypes after expressing it in nontransformed cells. Acute expression of Rsf-1 resulted in DNA damage as evidenced by DNA strand breaks, nuclear gammaH2AX foci, and activation of the ATM-CHK2-p53-p21 pathway, leading to growth arrest and apoptosis. Deletion mutation and gene knockdown assays revealed that formation of a functional RSF complex with SNF2H was required for Rsf-1 to trigger DNA damage response (DDR). Gene knock-out of TP53 alleles, TP53 mutation, or treatment with an ATM inhibitor abolished up-regulation of p53 and p21 and prevented Rsf-1-induced growth arrest. Chronic induction of Rsf-1 expression resulted in chromosomal aberration and clonal selection for cells with c-myc amplification and CDKN2A/B deletion. Co culture assays indicated Rsf-1-induced DDR as a selecting barrier that favored outgrowth of cell clones with a TP53 mutation. The above findings suggest that increased Rsf-1 expression and thus excessive RSF activity, which occurs in tumors harboring Rsf-1 amplification, can induce chromosomal instability likely through DDR. PMID- 20923776 TI - Metabolome analysis revealed increase in S-methylcysteine and phosphatidylisopropanolamine synthesis upon L-cysteine deprivation in the anaerobic protozoan parasite Entamoeba histolytica. AB - L-cysteine is ubiquitous in all living organisms and is involved in a variety of functions, including the synthesis of iron-sulfur clusters and glutathione and the regulation of the structure, stability, and catalysis of proteins. In the protozoan parasite Entamoeba histolytica, the causative agent of amebiasis, L cysteine plays an essential role in proliferation, adherence, and defense against oxidative stress; however, the essentiality of this amino acid in the pathways it regulates is not well understood. In the present study, we applied capillary electrophoresis time-of-flight mass spectrometry to quantitate charged metabolites modulated in response to L-cysteine deprivation in E. histolytica, which was selected as a model for examining the biological roles of L-cysteine. L cysteine deprivation had profound effects on glycolysis, amino acid, and phospholipid metabolism, with sharp decreases in the levels of L-cysteine, L cystine, and S-adenosylmethionine and a dramatic accumulation of O-acetylserine and S-methylcysteine. We further demonstrated that S-methylcysteine is synthesized from methanethiol and O-acetylserine by cysteine synthase, which was previously considered to be involved in sulfur-assimilatory L-cysteine biosynthesis. In addition, L-cysteine depletion repressed glycolysis and energy generation, as it reduced acetyl-CoA, ethanol, and the major nucleotide di- and triphosphates, and led to the accumulation of glycolytic intermediates. Interestingly, L-cysteine depletion increased the synthesis of isopropanolamine and phosphatidylisopropanolamine, and it was confirmed that their increment was not a result of oxidative stress but was a specific response to L-cysteine depletion. We also identified a pathway in which isopropanolamine is synthesized from methylglyoxal via aminoacetone. To date, this study represents the first case where L-cysteine deprivation leads to drastic changes in core metabolic pathways, including energy, amino acid, and phospholipid metabolism. PMID- 20923777 TI - Microglial Toll-like receptor 2 contributes to kainic acid-induced glial activation and hippocampal neuronal cell death. AB - Recent studies indicate that Toll-like receptors (TLRs), originally identified as infectious agent receptors, also mediate sterile inflammatory responses during tissue damage. In this study, we investigated the role of TLR2 in excitotoxic hippocampal cell death using TLR2 knock-out (KO) mice. TLR2 expression was up regulated in microglia in the ipsilateral hippocampus of kainic acid (KA) injected mice. KA-mediated hippocampal cell death was significantly reduced in TLR2 KO mice compared with wild-type (WT) mice. Similarly, KA-induced glial activation and proinflammatory gene expression in the hippocampus were compromised in TLR2 KO mice. In addition, neurons in organotypic hippocampal slice cultures (OHSCs) from TLR2 KO mouse brains were less susceptible to KA excitotoxicity than WT OHSCs. This protection is partly attributed to decreased expression of proinflammatory genes, such as TNF-alpha and IL-1beta in TLR2 KO mice OHSCs. These data demonstrate conclusively that TLR2 signaling in microglia contributes to KA-mediated innate immune responses and hippocampal excitotoxicity. PMID- 20923778 TI - Inhibitors of catalase-amyloid interactions protect cells from beta-amyloid induced oxidative stress and toxicity. AB - Compelling evidence shows a strong correlation between accumulation of neurotoxic beta-amyloid (Abeta) peptides and oxidative stress in the brains of patients afflicted with Alzheimer disease (AD). One hypothesis for this correlation involves the direct and harmful interaction of aggregated Abeta peptides with enzymes responsible for maintaining normal, cellular levels of reactive oxygen species (ROS). Identification of specific, destructive interactions of Abeta peptides with cellular anti-oxidant enzymes would represent an important step toward understanding the pathogenicity of Abeta peptides in AD. This report demonstrates that exposure of human neuroblastoma cells to cytotoxic preparations of aggregated Abeta peptides results in significant intracellular co-localization of Abeta with catalase, an anti-oxidant enzyme responsible for catalyzing the degradation of the ROS intermediate hydrogen peroxide (H(2)O(2)). These catalase Abeta interactions deactivate catalase, resulting in increased cellular levels of H(2)O(2). Furthermore, small molecule inhibitors of catalase-amyloid interactions protect the hydrogen peroxide-degrading activity of catalase in Abeta-rich environments, leading to reduction of the co-localization of catalase and Abeta in cells, inhibition of Abeta-induced increases in cellular levels of H(2)O(2), and reduction of the toxicity of Abeta peptides. These studies, thus, provide evidence for the important role of intracellular catalase-amyloid interactions in Abeta-induced oxidative stress and propose a novel molecular strategy to inhibit such harmful interactions in AD. PMID- 20923779 TI - MAP/ERK kinase kinase 1 (MEKK1) mediates transcriptional repression by interacting with polycystic kidney disease-1 (PKD1) promoter-bound p53 tumor suppressor protein. AB - Mitogen-activated protein kinase (MAPK) cascades regulate a wide variety of cellular processes that ultimately depend on changes in gene expression. We have found a novel mechanism whereby one of the key MAP3 kinases, Mekk1, regulates transcriptional activity through an interaction with p53. The tumor suppressor protein p53 down-regulates a number of genes, including the gene most frequently mutated in autosomal dominant polycystic kidney disease (PKD1). We have discovered that Mekk1 translocates to the nucleus and acts as a co-repressor with p53 to down-regulate PKD1 transcriptional activity. This repression does not require Mekk1 kinase activity, excluding the need for an Mekk1 phosphorylation cascade. However, this PKD1 repression can also be induced by the stress-pathway stimuli, including TNFalpha, suggesting that Mekk1 activation induces both JNK dependent and JNK-independent pathways that target the PKD1 gene. An Mekk1-p53 interaction at the PKD1 promoter suggests a new mechanism by which abnormally elevated stress-pathway stimuli might directly down-regulate the PKD1 gene, possibly causing haploinsufficiency and cyst formation. PMID- 20923780 TI - Thrombospondin-1 inhibits VEGF receptor-2 signaling by disrupting its association with CD47. AB - Thrombospondin-1 (TSP1) can inhibit angiogenic responses directly by interacting with VEGF and indirectly by engaging several endothelial cell TSP1 receptors. We now describe a more potent mechanism by which TSP1 inhibits VEGF receptor-2 (VEGFR2) activation through engaging its receptor CD47. CD47 ligation is known to inhibit downstream signaling targets of VEGFR2, including endothelial nitric oxide synthase and soluble guanylate cyclase, but direct effects on VEGFR2 have not been examined. Based on FRET and co-immunoprecipitation, CD47 constitutively associated with VEGFR2. Ligation of CD47 by TSP1 abolished resonance energy transfer with VEGFR2 and inhibited phosphorylation of VEGFR2 and its downstream target Akt without inhibiting VEGF binding to VEGFR2. The inhibitory activity of TSP1 in large vessel and microvascular endothelial cells was replicated by a recombinant domain of the protein containing its CD47-binding site and by a CD47 binding peptide derived from this domain but not by the CD36-binding domain of TSP1. Inhibition of VEGFR2 phosphorylation was lost when CD47 expression was suppressed in human endothelial cells and in murine CD47-null cells. These results reveal that anti-angiogenic signaling through CD47 is highly redundant and extends beyond inhibition of nitric oxide signaling to global inhibition of VEGFR2 signaling. PMID- 20923781 TI - Identification of species by multiplex analysis of variable-length sequences. AB - The quest for a universal and efficient method of identifying species has been a longstanding challenge in biology. Here, we show that accurate identification of species in all domains of life can be accomplished by multiplex analysis of variable-length sequences containing multiple insertion/deletion variants. The new method, called SPInDel, is able to discriminate 93.3% of eukaryotic species from 18 taxonomic groups. We also demonstrate that the identification of prokaryotic and viral species with numeric profiles of fragment lengths is generally straightforward. A computational platform is presented to facilitate the planning of projects and includes a large data set with nearly 1800 numeric profiles for species in all domains of life (1556 for eukaryotes, 105 for prokaryotes and 130 for viruses). Finally, a SPInDel profiling kit for discrimination of 10 mammalian species was successfully validated on highly processed food products with species mixtures and proved to be easily adaptable to multiple screening procedures routinely used in molecular biology laboratories. These results suggest that SPInDel is a reliable and cost-effective method for broad-spectrum species identification that is appropriate for use in suboptimal samples and is amenable to different high-throughput genotyping platforms without the need for DNA sequencing. PMID- 20923782 TI - Conserved small RNAs govern replication and incompatibility of a diverse new plasmid family from marine bacteria. AB - Plasmids are autonomously replicating extrachromosomal DNA molecules that often impart key phenotypes to their bacterial hosts. Plasmids are abundant in marine bacteria, but there is scant knowledge of the mechanisms that control their replication in these hosts. Here, we identified and characterized the factors governing replication of a new family of plasmids from marine bacteria, typified by the virulence-linked plasmid pB1067 of Vibrio nigripulchritudo. Members of this family are prevalent among, yet restricted to, the Vibrionaceae. Unlike almost all plasmid families characterized to date, the ori regions of these plasmids do not encode a Rep protein to initiate DNA replication; instead, the ori regions encode two partially complementary RNAs. The smaller, termed RNA I, is ~68-nt long and functions as a negative regulator and the key determinant of plasmid incompatibility. This Marine RNA-based (MRB) plasmid family is the first characterized family of replicons derived from marine bacteria. Only one other plasmid family (the ColE1 family) has previously been reported to rely on RNA mediated replication initiation. However, since the sequences and structures of MRB RNA I transcripts are not related to those of ColE1 replicons, these two families of RNA-dependent replicons likely arose by convergent evolution. PMID- 20923783 TI - Theoretical and empirical quality assessment of transcription factor-binding motifs. AB - Position-specific scoring matrices (PSSMs) are routinely used to predict transcription factor (TF)-binding sites in genome sequences. However, their reliability to predict novel binding sites can be far from optimum, due to the use of a small number of training sites or the inappropriate choice of parameters when building the matrix or when scanning sequences with it. Measures of matrix quality such as E-value and information content rely on theoretical models, and may fail in the context of full genome sequences. We propose a method, implemented in the program 'matrix-quality', that combines theoretical and empirical score distributions to assess reliability of PSSMs for predicting TF binding sites. We applied 'matrix-quality' to estimate the predictive capacity of matrices for bacterial, yeast and mouse TFs. The evaluation of matrices from RegulonDB revealed some poorly predictive motifs, and allowed us to quantify the improvements obtained by applying multi-genome motif discovery. Interestingly, the method reveals differences between global and specific regulators. It also highlights the enrichment of binding sites in sequence sets obtained from high throughput ChIP-chip (bacterial and yeast TFs), and ChIP-seq and experiments (mouse TFs). The method presented here has many applications, including: selecting reliable motifs before scanning sequences; improving motif collections in TFs databases; evaluating motifs discovered using high-throughput data sets. PMID- 20923784 TI - DNA methyltransferase 3b preferentially associates with condensed chromatin. AB - In mammals, DNA methylation is catalyzed by DNA methyltransferases (DNMTs) encoded by Dnmt1, Dnmt3a and Dnmt3b. Since, the mechanisms of regulation of Dnmts are still largely unknown, the physical interaction between Dnmt3b and chromatin was investigated in vivo and in vitro. In embryonic stem cell nuclei, Dnmt3b preferentially associated with histone H1-containing heterochromatin without any significant enrichment of silent-specific histone methylation. Recombinant Dnmt3b preferentially associated with nucleosomal DNA rather than naked DNA. Incorporation of histone H1 into nucleosomal arrays promoted the association of Dnmt3b with chromatin, whereas histone acetylation reduced Dnmt3b binding in vitro. In addition, Dnmt3b associated with histone deacetylase SirT1 in the nuclease resistant chromatin. These findings suggest that Dnmt3b is preferentially recruited into hypoacetylated and condensed chromatin. We propose that Dnmt3b is a 'reader' of higher-order chromatin structure leading to gene silencing through DNA methylation. PMID- 20923785 TI - Analysis of DNA double-strand break response and chromatin structure in mitosis using laser microirradiation. AB - In this study the femtosecond near-IR and nanosecond green lasers are used to induce alterations in mitotic chromosomes. The subsequent double-strand break responses are studied. We show that both lasers are capable of creating comparable chromosomal alterations and that a phase paling observed within 1-2 s of laser exposure is associated with an alteration of chromatin as confirmed by serial section electron microscopy, DAPI, gammaH2AX and phospho-H3 staining. Additionally, the accumulation of dark material observed using phase contrast light microscopy (indicative of a change in refractive index of the chromatin) ~ 34 s post-laser exposure corresponds spatially to the accumulation of Nbs1, Ku and ubiquitin. This study demonstrates that chromosomes selectively altered in mitosis initiate the DNA damage response within 30 s and that the accumulation of proteins are visually represented by phase-dark material at the irradiation site, allowing us to determine the fate of the damage as cells enter G1. These results occur with two widely different laser systems, making this approach to study DNA damage responses in the mitotic phase generally available to many different labs. Additionally, we present a summary of most of the published laser studies on chromosomes in order to provide a general guide of the lasers and operating parameters used by other laboratories. PMID- 20923786 TI - Localization of an accessory helicase at the replisome is critical in sustaining efficient genome duplication. AB - Genome duplication requires accessory helicases to displace proteins ahead of advancing replication forks. Escherichia coli contains three helicases, Rep, UvrD and DinG, that might promote replication of protein-bound DNA. One of these helicases, Rep, also interacts with the replicative helicase DnaB. We demonstrate that Rep is the only putative accessory helicase whose absence results in an increased chromosome duplication time. We show also that the interaction between Rep and DnaB is required for Rep to maintain rapid genome duplication. Furthermore, this Rep-DnaB interaction is critical in minimizing the need for both recombinational processing of blocked replication forks and replisome reassembly, indicating that colocalization of Rep and DnaB minimizes stalling and subsequent inactivation of replication forks. These data indicate that E. coli contains only one helicase that acts as an accessory motor at the fork in wild type cells, that such an activity is critical for the maintenance of rapid genome duplication and that colocalization with the replisome is crucial for this function. Given that the only other characterized accessory motor, Saccharomyces cerevisiae Rrm3p, associates physically with the replisome, our demonstration of the functional importance of such an association indicates that colocalization may be a conserved feature of accessory replicative motors. PMID- 20923787 TI - Therapeutic modulation of cerebral L-lysine metabolism in a mouse model for glutaric aciduria type I. AB - Glutaric aciduria type I, an inherited deficiency of glutaryl-coenzyme A dehydrogenase localized in the final common catabolic pathway of L-lysine, L hydroxylysine and L-tryptophan, leads to accumulation of neurotoxic glutaric and 3-hydroxyglutaric acid, as well as non-toxic glutarylcarnitine. Most untreated patients develop irreversible brain damage during infancy that can be prevented in the majority of cases if metabolic treatment with a low L-lysine diet and L carnitine supplementation is started in the newborn period. The biochemical effect of this treatment remains uncertain, since cerebral concentrations of neurotoxic metabolites can only be determined by invasive techniques. Therefore, we studied the biochemical effect and mechanism of metabolic treatment in glutaryl-coenzyme A dehydrogenase-deficient mice, an animal model with complete loss of glutaryl-coenzyme A dehydrogenase activity, focusing on the tissue specific changes of neurotoxic metabolites and key enzymes of L-lysine metabolism. Here, we demonstrate that low L-lysine diet, but not L-carnitine supplementation, lowered the concentration of glutaric acid in brain, liver, kidney and serum. L-carnitine supplementation restored the free L-carnitine pool and enhanced the formation of glutarylcarnitine. The effect of low L-lysine diet was amplified by add-on therapy with L-arginine, which we propose to result from competition with L-lysine at system y(+) of the blood-brain barrier and the mitochondrial L-ornithine carriers. L-lysine can be catabolized in the mitochondrial saccharopine or the peroxisomal pipecolate pathway. We detected high activity of mitochondrial 2-aminoadipate semialdehyde synthase, the rate limiting enzyme of the saccharopine pathway, in the liver, whereas it was absent in the brain. Since we found activity of the subsequent enzymes of L-lysine oxidation, 2-aminoadipate semialdehyde dehydrogenase, 2-aminoadipate aminotransferase and 2-oxoglutarate dehydrogenase complex as well as peroxisomal pipecolic acid oxidase in brain tissue, we postulate that the pipecolate pathway is the major route of L-lysine degradation in the brain and the saccharopine pathway is the major route in the liver. Interestingly, treatment with clofibrate decreased cerebral and hepatic concentrations of glutaric acid in glutaryl coenzyme A dehydrogenase-deficient mice. This finding opens new therapeutic perspectives such as pharmacological stimulation of alternative L-lysine oxidation in peroxisomes. In conclusion, this study gives insight into the discrepancies between cerebral and hepatic L-lysine metabolism, provides for the first time a biochemical proof of principle for metabolic treatment in glutaric aciduria type I and suggests that further optimization of treatment could be achieved by exploitation of competition between L-lysine and L-arginine at physiological barriers and enhancement of peroxisomal L-lysine oxidation and glutaric acid breakdown. PMID- 20923789 TI - Too many platelets to cause compartment syndrome. PMID- 20923788 TI - Smaller intracranial volume in prodromal Huntington's disease: evidence for abnormal neurodevelopment. AB - Huntington's disease is an autosomal dominant brain disease. Although conceptualized as a neurodegenerative disease of the striatum, a growing number of studies challenge this classic concept of Huntington's disease aetiology. Intracranial volume is the tissue and fluid within the calvarium and is a representation of the maximal brain growth obtained during development. The current study reports intracranial volume obtained from an magnetic resonance imaging brain scan in a sample of subjects (n = 707) who have undergone presymptomatic gene testing. Participants who are gene-expanded but not yet manifesting the disease (prodromal Huntington's disease) are compared with subjects who are non-gene expanded. The prodromal males had significantly smaller intracranial volume measures with a mean volume that was 4% lower compared with controls. Although the prodromal females had smaller intracranial volume measures compared with their controls, this was not significant. The current findings suggest that mutant huntingtin can cause abnormal development, which may contribute to the pathogenesis of Huntington's disease. PMID- 20923790 TI - A comparison of magnesium sulphate and sildenafil in the treatment of the newborns with persistent pulmonary hypertension: a randomized controlled trial. AB - The aim of this prospective, randomized and controlled study was to compare the clinical efficacy of intravenous magnesium sulfate (MgSO4) and oral sildenafil therapies with persistent pulmonary hypertension of the newborn. A total of 34 infants in the MgSO4 group and 31 infants in the sildenafil group completed the study. The time to reach the adequate clinical response [defined as oxygen index (OI) level of <15, a pulmonary artery pressure of < 20 mmHg) was significantly shorter in the sildenafil group (p = 0.002). Duration of mechanical ventilation was longer and the number of the patients requiring inotropic support was higher in the MgSO4 group (p = 0.001 and p = 0.002, respectively). Although among two groups the difference in OI > 5 as speculated in our hypothesis could only be found at 36 h of the treatment, sildenafil was more effective than MgSO4 in the treatment of persistent pulmonary hypertension of the newborns with regard to time to adequate clinical response, duration of mechanical ventilation and support requirement with inotropic agents. PMID- 20923791 TI - Omphalocele management using goal-oriented classification in African centre with limited resources. AB - In 2000-09, 96 children comprising 57 males and 39 females who were presented between 2 h and 1 week of birth with omphalocele were prospectively managed using goal-oriented classification at the University of Benin Teaching Hospital, Nigeria. All were born through spontaneous vaginal delivery, out of which 9 (9.4%) were preterm. Eighty-two (85.4%) mothers in villages with no supervised antenatal care/delivery and/or prenatal diagnosis presented their babies late. Thirty-three (34.4%) babies in group A, with defect size <= 4.5 cm and intact sac, were managed conservatively and had fascial closure after neonatal period, resulting in 32 (97%) survivors. Forty-two (43.8%) babies in group B, with defect size > 4.5 cm and intact sac, were managed conservatively and had fascial closures for 9 months to 5 years, resulting in 40 (95.2%) survivors. Group C comprised of 21 (21.9%) babies with defect of any size/ruptured sac and who had immediate repair, resulting in two (9.5%) survivors owing to lack of facilities (p < 0.0001). Hospital delivery and provision of facilities are advocated. PMID- 20923792 TI - Endosonography for lung cancer staging: one scope fits all? PMID- 20923793 TI - Viral community-acquired pneumonia: if we do not diagnose it and do not treat it, can it still hurt us? PMID- 20923794 TI - Role of contrast echocardiography in screening for pulmonary arteriovenous malformation in patients with hereditary hemorrhagic telangiectasia. PMID- 20923795 TI - Percutaneous coronary intervention in anticoagulated patients and balancing the risk of stroke and bleeding: to interrupt or not to interrupt? PMID- 20923796 TI - Point: Efficacy of extracorporeal membrane oxygenation in 2009 influenza A(H1N1): sufficient evidence? PMID- 20923797 TI - Counterpoint: Efficacy of extracorporeal membrane oxygenation in 2009 influenza A(H1N1): sufficient evidence? PMID- 20923798 TI - Use it or lose it: Medicare's new paradigm for durable medical equipment coverage? AB - The 2008 National Coverage Determination by the US Centers for Medicare and Medicaid Services (CMS) authorizing coverage of positive airway pressure (PAP) treatment of obstructive sleep apnea on the basis of diagnosis by portable monitoring was seen by some as a major advance in reimbursement policy for sleep medicine services. However, along with the national coverage decision came additional rules (local coverage determinations) setting forth the conditions that would apply in order for reimbursement to continue beyond 90 days. These rules specified the means by which adherence must be measured, a rigid threshold for the acceptable degree of adherence, and a requirement for face-to-face evaluation by the clinician to document clinical response, all of which must take place within a specific timeframe. Whether CMS or the local carriers anticipated the difficulties that would be experienced by clinicians, durable medical equipment (DME) companies, and patients in complying with these rules is unknown. What has become abundantly clear to many is the burden that these rules impose on clinicians and DME providers and, more importantly, that indiscriminate enforcement may well result in adverse consequences for some patients. The latter include not only the inconvenience and added expense for patients of complying with the rules, but those resulting from failure by CMS to recognize that a dose response relationship exists with respect to the degree of PAP adherence and clinical outcome. Moreover, there is reason to believe that patients of low socioeconomic class, or who are unmarried, or who have psychiatric disease will have more difficulty achieving the required adherence and therefore will, in effect, be victims of government-mandated discrimination in the provision of a vital healthcare service. PMID- 20923799 TI - Risk of symptomatic DVT associated with peripherally inserted central catheters. AB - BACKGROUND: Previous studies undertaken to identify risk factors for peripherally inserted central catheter (PICC)-associated DVT have yielded conflicting results. PICC insertion teams and other health-care providers need to understand the risk factors so that they can develop methods to prevent DVT. METHODS: A 1-year prospective observational study of PICC insertions was conducted at a 456-bed, level I trauma center and tertiary referral hospital affiliated with a medical school. All patients with one or more PICC insertions were included to identify the incidence and risk factors for symptomatic DVT associated with catheters inserted by a facility-certified PICC team using a consistent and replicated approach for vein selection and insertion. RESULTS: A total of 2,014 PICCs were inserted during 1,879 distinct hospitalizations in 1,728 distinct patients for a total of 15,115 days of PICC placement. Most PICCs were placed in the right arm (76.9%) and basilic vein (74%) and were double-lumen 5F (75.3%). Of the 2,014 PICC insertions, 60 (3.0%) in 57 distinct patients developed DVT in the cannulated or adjacent veins. The best-performing predictive model for DVT (area under the curve, 0.83) was prior DVT (odds ratio [OR], 9.92; P < .001), use of double-lumen 5F (OR, 7.54; P < .05) or triple-lumen 6F (OR, 19.50; P < .01) PICCs, and prior surgery duration of > 1 h (OR, 1.66; P = .10). CONCLUSIONS: Prior DVT and surgery lasting > 1 h identify patients at increased risk for PICC associated DVT. More importantly, increasing catheter size also is significantly associated with increased risk. Rates of PICC-associated DVT may be reduced by improved selection of patients and catheter size. PMID- 20923801 TI - Pulmonary complications of hemoglobinopathies. AB - Hemoglobinopathies are diseases caused by genetic mutations that result in abnormal, dysfunctional hemoglobin molecules or lower levels of normal hemoglobin molecules. The most common hemoglobinopathies are sickle cell disease (SCD) and the thalassemias. In SCD, an abnormal hemoglobin alters the erythrocyte, causing a chronic hemolytic anemia, which can lead to pulmonary parenchymal damage and impaired vascular function. Pulmonary complications of SCD include the acute chest syndrome (ACS), reactive airways disease, pulmonary hypertension (PH), and pulmonary fibrosis. Episodes of ACS and the development of PH both increase the risk of death in patients with SCD. Both alpha and beta thalassemia are characterized by impaired production of hemoglobin subunits, and severity of disease varies widely. Although screening studies suggest that PH is a common complication for patients with thalassemia, its impact on survival is unknown. Understanding the pathogenesis, diagnostic options, and prevention and treatment strategies for such complications is critical for clinicians who care for these patients. In this review, we discuss the mechanisms and clinical presentation of pulmonary complications associated with hemoglobinopathies, with a focus on recent advances in pathogenesis and treatment. PMID- 20923800 TI - Therapeutic potential of mesenchymal stem cells for severe acute lung injury. AB - Preclinical studies indicate that allogeneic human mesenchymal stem cells (MSC) may be useful for the treatment of several clinical disorders, including sepsis, acute renal failure, acute myocardial infarction, and more recently, acute lung injury (ALI). This article provides a brief review of the biologic qualities of MSC that make them suitable for the treatment of human diseases, as well as the experimental data that provide support for their potential efficacy for critically ill patients with acute respiratory failure from ALI. The article then discusses which patients with ALI might be the best candidates for cell-based therapy and provides a template for the regulatory and practical steps that will be required to test allogeneic human MSC in patients with severe ALI. There is a dual focus on how to design trials for testing both safety and efficacy. PMID- 20923802 TI - Legionnaires disease in cannabis smokers. AB - Tobacco smoking is a well-recognized risk factor for Legionnaires disease. However, it may be potentiated by cannabis use, as there is strong evidence that Delta(9)-tetrahydrocannabinol impairs immune functions in vitro and in vivo. We report herein two out of three cases of severe Legionnaires disease in three men with no overt comorbid illnesses, aged 38, 28, and 48 years, respectively. All of them were heavy cigarette and cannabis smokers. PMID- 20923803 TI - Dramatic improvement in pulmonary hypertension with rapamycin. AB - This is a report of a 61-year-old woman with improved pulmonary arterial hypertension following treatment with rapamycin for an islet cell tumor of the pancreas with liver metastases. PMID- 20923805 TI - A 53-year-old woman with recurrent transient ischemic attacks. PMID- 20923804 TI - Alcohol-use disorders in the critically ill patient. AB - Alcohol abuse and dependence, referred to as alcohol-use disorders (AUDs), affect 76.3 million people worldwide and account for 1.8 million deaths per year. AUDs affect 18.3 million Americans (7.3% of the population), and up to 40% of hospitalized patients have AUDs. This review discusses the development and progression of critical illness in patients with AUDs. In contrast to acute intoxication, AUDs have been linked to increased severity of illness in a number of studies. In particular, surgical patients with AUDs experience higher rates of postoperative hemorrhage, cardiac complications, sepsis, and need for repeat surgery. Outcomes from trauma are worse for patients with chronic alcohol abuse, whereas burn patients who are acutely intoxicated may not have worse outcomes. AUDs are linked to not only a higher likelihood of community-acquired pneumonia and sepsis but also a higher severity of illness and higher rates of nosocomial pneumonia and sepsis. The management of sedation in patients with AUDs may be particularly challenging because of the increased need for sedatives and opioids and the difficulty in diagnosing withdrawal syndrome. The health-care provider also must be watchful for the development of dangerous agitation and violence, as these problems are not uncommonly seen in hospital ICUs. Despite studies showing that up to 40% of hospitalized patients have AUDs, relatively few guidelines exist on the specific management of the critically ill patient with AUDs. AUDs are underdiagnosed, and a first step to improving patient outcomes may lie in systematically and accurately identifying AUDs. PMID- 20923806 TI - A 41-year-old man with fluorodeoxyglucose-avid thickening on PET scan. PMID- 20923807 TI - A 19-year-old woman with intracranial hemorrhage and diffuse pulmonary infiltrates. PMID- 20923808 TI - CHA2DS2-VASc risk scheme: not ready for clinical use. PMID- 20923809 TI - Patients'-best-interests standard trumps autonomous health-care decisions: paternalism vs self-determination. PMID- 20923810 TI - Could decortication become necessary in cases of pseudochylothorax? PMID- 20923811 TI - Less-obvious predictors of post-ICU informal caregiver burden. PMID- 20923813 TI - The potential impact of comparative effectiveness research on the health of minority populations. AB - Minorities suffer more frequently and more severely from many diseases than do non-Hispanic whites, and they often receive lower-quality care, which leads to poorer health outcomes. Given the diversity of the US population, comparative effectiveness research should capture the health outcomes of racial and ethnic minority groups and investigate whether disparities reflect variations in care or different responses to treatment. We recommend a number of measures to ensure that this research addresses the needs of minorities, including greater attention to subgroup analysis. We also recommend the increased recruitment of minorities for clinical trials, and such measures as using community health workers to translate research results in ways that will increase their relevance to minority patients. PMID- 20923812 TI - Extubation of patients with neuromuscular weakness: a routine step or a challenging procedure? PMID- 20923814 TI - How the Recovery Act's Federal Coordinating Council paved the way for the Patient Centered Outcomes Research Institute. AB - The American Recovery and Reinvestment Act of 2009 provided $1.1 billion for comparative effectiveness research and established the Federal Coordinating Council for Comparative Effectiveness Research to direct that investment. The council laid a critical foundation for comparative effectiveness research in the steps it took to gather information, invite public input, set priorities, coordinate project solicitations, and stress the importance of evaluating research investments. Although the council has been superseded by a successor- the Patient-Centered Outcomes Research Institute--the experiences of the council can and should inform the work of the new institute as it begins its operations. PMID- 20923815 TI - The day of the triffids? AB - This is a case report of two children who presented with a widespread bullous erythematous rash secondary to exposure to the hogweed plant. PMID- 20923816 TI - Emergency department presentation following falls: development of a routine falls surveillance system. AB - INTRODUCTION: Falls are recognised as a major public health issue, particularly among older people, and have been targeted for attention by national service frameworks and National Institute for Health and Clinical Excellence guidelines in the UK. However, reliable epidemiological data are not easily available, and it remains difficult to monitor the effect of interventions that seek to reduce the public health impact of falls. METHOD: In a 1-year study based in the emergency department (ED) of the University Hospital of Wales all Cardiff residents who described their presentation as following a fall were identified. From a catchment population of 305,353 people a total of 86,031 such ED presentations were recorded, 20,154 (23.4%) of which followed a fall. RESULTS: This gives an overall falls incidence of 66/1000 population per year, meaning that in just a year one resident in 15 attended the ED following a fall. The impact of falls was greatest in the oldest age groups, and in women aged over 75 years the falls incidence of 139/1000 per year was significantly higher than the figure of 99/1000 per year observed in men of the same age. CONCLUSIONS: This study describes a simple way for ED to establish routine falls surveillance. It offers the first estimate of the impact of falls on ED in the UK, suggesting that such services are dealing with 4 million falls-related attendances every year. PMID- 20923817 TI - 'To treat or not to treat'. Kerrie Wooltorton, lessons to learn. AB - One of the main reasons for contact of psychiatric patients with Accident and Emergency (A&E) departments is deliberate self-harm. The situation is often complicated by the patient's ambivalence about treatment. Kerrie Wooltorton was one such patient who presented to an A&E department after having self-harmed by taking a fatal dose of antifreeze. She had an Advance Decision forbidding any treatment for her overdose, and continued to refuse the treatment. Her wishes were honoured and she died 3 days later. The case raises many ethical and practice issues, and this review aims to clarify the medico legal position in such a situation. It draws on the Mental Capacity Act and case law, which clearly favour preservation of life, to argue that there are many lessons to learn from this case. There are enough safeguards for treating clinicians if they are not satisfied of the validity and applicability of the Advance Decision and decide to override it. Alternatively, any decision to follow the Advance Decision has to be objectively supported by evidence. The Mental Capacity Act itself allows for overriding the patient's wishes if certain criteria under the Mental Health Act are met. This route was not explored in the Wooltorton case and this is the main lesson to learn. PMID- 20923818 TI - Analysis of amitriptyline overdose in emergency medicine. AB - INTRODUCTION: Amitriptyline is a tricyclic antidepressant. In general, toxicity effects develop within 30 min of overdose and peak from 2 h to 6 h. Anticholinergic effects predominate in cases of low dose ingestion. In cases of high dose ingestion, marked depression of the central nervous system is coupled with cardiotoxicity, seizures and hypotension. PATIENTS AND METHODS: Amitriptyline-intoxicated patients admitted to the emergency department (ED) of Dicle University Hospital were evaluated between January 2005 and April 2007. Social and demographic status, clinical and laboratory findings, treatments and outcomes were recorded. Age, sex, marital status, time of hospital admission, consciousness levels, ECG findings, requirement for respiratory support, follow up periods and antidepressant overdose risk assessment (ADORA) criteria were analysed using SPSS software. RESULTS: A total of 110 cases of overdose by amitriptyline was evaluated. Suicide attempts by amitriptyline overdose in adult single women were the commonest finding. The commonest symptoms seen during initial examinations were sinus tachycardia (66.3%), altered mental state (78.1%) and hypotension (7.3%). Mechanical ventilatory support was required in 9.1% of cases. Most patients (n=76, 69.1%) were treated in the ED (p=0.001). 60 (54.5%) patients were discharged from the ED within 24 h after admission (p<0.0001). CONCLUSION: Most of the patients were young single women. Altered mental state and tachycardia were the commonest symptoms. The initial symptoms of amytriptyline overdose patients may be life threatening, but effective supportive treatments were helpful. There was high correlation between ADORA criteria and the dose ingested. PMID- 20923819 TI - Effect of nail polish and henna on oxygen saturation determined by pulse oximetry in healthy young adult females. AB - OBJECTIVE: The purpose of this study was to determine the effect of different colour nail polishes and henna on the measurement of oxygen saturation and the differences among the measurements of three pulse oximetry devices. MATERIAL AND METHODS: 33 healthy females with a mean age of 19+/-1.0 years and no complaints or known disease were included into the study. All the participants applied henna to one of their fingers a day before the study. Just before the study, one finger was left empty as control and the other fingers were dyed using various colours of nail polish (red, blue, beige, purple, brown, white, pink, green, colourless polish, light blue, light green and yellow). There were more than eight colour nail polishes and some fingers were used for the other colours after being completely cleaned. The same brand nail polishes were used for the study. Oxygen saturation measurements were done using three different pulse oximetry devices (device I, II, III) from the control, different colour nail polished and henna applied fingers. The measurements of different devices, different colour nail polishes, henna and control were statistically compared. RESULTS: The mean saturations obtained from blue, beige, purple and white nail polished fingers were significantly lower than those of control and the other coloured fingers. In addition, the mean measurement of device II was significantly lower than those of other devices. CONCLUSION: The results suggest that blue, beige, purple and white nail polished fingers might cause pulse oximetry devices to make incorrect measurements. PMID- 20923820 TI - An iatrogenic burn from the use of a topical haemostatic agent. PMID- 20923821 TI - Rare procedures. PMID- 20923823 TI - Hexosamines stimulate apoptosis by altering SIRT1 action and levels in rodent pancreatic beta-cells. AB - The activity and levels of SIRT1, which promotes cell survival in several models, are linked to glucose concentrations and cellular energy metabolism. The present study aimed to determine whether impaired Sirt1 activity is involved in the induction of apoptosis by the nutrient-sensing hexosamine biosynthesis pathway (HBP). Pancreatic Nit-1, Rin-m5F, and Min6 beta-cells were acutely treated at different doses and times with glucosamine, which enters and stimulates the HBP. Sirt1 levels were genetically modulated by retroviral infection. Expression levels, cellular localization, and activity of apoptosis-related markers were determined by qPCR, immunoblotting, and co-immunoprecipitation. Glucosamine treatment dose- and time dependently induced cell apoptosis in all cell lines studied. HBP stimulation time dependently modified SIRT1 protein levels, notably in the cytoplasm. This was concomitant with increased E2F1 binding to the c-myc promoter. In both NIT-1 and min6 beta-cells, genetic knockdown of Sirt1 expression resulted in higher susceptibility to HBP-stimulated apoptosis, whereas overexpression of Sirt1 had the opposite impact. These findings indicate that reduction of SIRT1 levels by hexosamines contributes to beta-cell apoptosis. Methods to increase SIRT1 levels or activity could thus prevent the decrease in beta-cell mass, notably that observed in type 2 diabetes. PMID- 20923822 TI - Radiation pharmacogenomics: a genome-wide association approach to identify radiation response biomarkers using human lymphoblastoid cell lines. AB - Radiation therapy is used to treat half of all cancer patients. Response to radiation therapy varies widely among patients. Therefore, we performed a genome wide association study (GWAS) to identify biomarkers to help predict radiation response using 277 ethnically defined human lymphoblastoid cell lines (LCLs). Basal gene expression levels and 1.3 million genome-wide single nucleotide polymorphism (SNP) markers from both Affymetrix and Illumina platforms were assayed for all 277 human LCLs. MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3 carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] assays for radiation cytotoxicity were also performed to obtain area under the curve (AUC) as a radiation response phenotype for use in the association studies. Functional validation of candidate genes, selected from an integrated analysis that used SNP, expression, and AUC data, was performed with multiple cancer cell lines using specific siRNA knockdown, followed by MTS and colony-forming assays. A total of 27 loci, each containing at least two SNPs within 50 kb with P-values less than 10(-4) were associated with radiation AUC. A total of 270 expression probe sets were associated with radiation AUC with P < 10(-3). The integrated analysis identified 50 SNPs in 14 of the 27 loci that were associated with both AUC and the expression of 39 genes, which were also associated with radiation AUC (P < 10(-3)). Functional validation using siRNA knockdown in multiple tumor cell lines showed that C13orf34, MAD2L1, PLK4, TPD52, and DEPDC1B each significantly altered radiation sensitivity in at least two cancer cell lines. Studies performed with LCLs can help to identify novel biomarkers that might contribute to variation in response to radiation therapy and enhance our understanding of mechanisms underlying that variation. PMID- 20923824 TI - Six-month survival benefits and clinical guideline recommendations in ACS. PMID- 20923825 TI - Diagnosis and prevention of iron deficiency and iron-deficiency anemia in infants and young children (0-3 years of age). AB - This clinical report covers diagnosis and prevention of iron deficiency and iron deficiency anemia in infants (both breastfed and formula fed) and toddlers from birth through 3 years of age. Results of recent basic research support the concerns that iron-deficiency anemia and iron deficiency without anemia during infancy and childhood can have long-lasting detrimental effects on neurodevelopment. Therefore, pediatricians and other health care providers should strive to eliminate iron deficiency and iron-deficiency anemia. Appropriate iron intakes for infants and toddlers as well as methods for screening for iron deficiency and iron-deficiency anemia are presented. PMID- 20923826 TI - Changes in the patterns, presentation and management of penetrating chest trauma patients at a level II trauma centre in southern Pakistan over the last two decades. AB - Penetrating chest trauma can be used as an indicator of violence in the country. We aimed to look at the changes in its incidence and management at a major trauma centre in the country. We also wanted to look at any effect of prehospital time on surgical intervention and outcome of the victim. In this retrospective descriptive study, we observed the presentation and management of 191 penetrating chest injury patients at a level II trauma hospital in Pakistan in the last 20 years. The study sample was divided into two groups: Group 1, 1988-1998 and Group 2, 1999-2009. No significant change in incidence of trauma was observed between the two groups. The delay in the time between event and arrival showed an increase in the number of surgical procedures performed. Also the number of thoracotomies performed went up significantly in the second decade from 5.7 to 16.5% with a P<0.05. Six (3.1%) mortality cases were observed in 20 years. It was seen that the greater the prehospital time, the greater the chances of surgery. Also seen was the increase in mortality as critical cases could make it to the hospital alive in recent times due to improved transportation services. PMID- 20923827 TI - Cardiac resynchronization therapy for management of congestive heart failure after repair of tetralogy of Fallot in an elderly patient. AB - A 65-year-old woman underwent total correction of tetralogy of Fallot with closure of ventricular septal defect, right ventricular outflow patch, pulmonary valve replacement and tricuspid valve repair. Pacemaker implantation using epicardial electrodes was simultaneously needed because she had complete atrioventricular block. The postoperative course was excellent. Eighteen months postoperatively, she was admitted with severe congestive heart failure and frequent ventricular arrhythmia. Echocardiography and cardiac catheterization revealed depressed left ventricular function caused by conduction delay. Cardiac resynchronization therapy with a defibrillation system was effective for improvement of left ventricular function. Ventricular contractility rapidly recovered to normal, and the patient has been asymptomatic for two years since implantation. PMID- 20923828 TI - A remnant left aortic arch and a right aortic arch as well as Kommerell's diverticulum with an aberrant left subclavian artery. AB - We report the case of a 63-year-old woman who had dysphagia and dyspnea for one year. Enhanced computed tomography revealed that she had an ascending aortic dorsal projection and a right aortic arch as well as Kommerell's diverticulum (KD) with an aberrant left subclavian artery (LSA). Her KD compressed her trachea and esophagus. We cut her aorta just distal to the KD and performed an ascending and total arch replacement through a midsternotomy. The LSA was reconstructed in front of her trachea. Her dysphagia and dyspnea disappeared following the operation and her postoperative course was uneventful. PMID- 20923829 TI - Remote muscle salvage by regional substrate enhancement during on-bypass beating heart treatment of cardiogenic shock. AB - Surgical revascularization for postinfarction cardiogenic shock carries 20-50% mortality. Beating-heart techniques have been favoured, but their impact on the avoidance of additional myocardial injury is unknown. Ten consecutive patients with postinfarction cardiogenic shock, unsuitable anatomy for percutaneous coronary intervention (Syntax score 34.0+/-7.5; triple-vessel disease, 10/10; left main stenosis, 5/10), and no associated cardiac procedure, were selected for salvage/emergent on-pump beating-heart coronary bypass surgery. Remote muscle was sequentially substrate-enhanced reperfused through the grafts after construction of distal anastomoses. Early/late mortality, preoperative/peak postoperative enzyme release, and baseline/pre-discharge ventricular function were analysed. One early death occurred. Patients received 2.9+/-0.6 grafts, always employing the left internal mammary artery. Cardiopulmonary bypass duration was 140+/-62 min. Left ventricular ejection fraction (29.4+/-5.8 vs. 37.5+/-8.3%), wall motion score index (2.10+/-0.29 vs. 1.86+/-0.28), and end-systolic volume index (42.1+/ 11.5 vs. 33.1+/-14.0 ml/m(2)) acutely improved (P<=0.001), whereas functional mitral regurgitation decreased from 1.4+/-0.8 to 0.8+/-0.4 (P=0.051). Total creatine kinase levels significantly increased (P=0.017), but myocardial band isoenzyme did not (P=0.18). After 3.1+/-1.4 years, eight patients are alive and seven are free of recurrent heart failure. Satisfactory functional outcome can be achieved with beating-heart on-pump revascularization for postinfarction cardiogenic shock. Perioperative enzyme releases and ventricular functional variables may suggest reduced perioperative myocardial injury. PMID- 20923833 TI - First antiretroviral patent in global drug pool puts pressure on companies to follow suit. PMID- 20923834 TI - Do drugs have a role in turning indifference into passion? PMID- 20923835 TI - IVF pioneer Robert Edwards wins Nobel prize. PMID- 20923836 TI - Regulation of Hip1r by epsin controls the temporal and spatial coupling of actin filaments to clathrin-coated pits. AB - Recently, it has become clear that the actin cytoskeleton is involved in clathrin mediated endocytosis. During clathrin-mediated endocytosis, clathrin triskelions and adaptor proteins assemble into lattices, forming clathrin-coated pits. These coated pits invaginate and detach from the membrane, a process that requires dynamic actin polymerization. We found an unexpected role for the clathrin adaptor epsin in regulating actin dynamics during this late stage of coated vesicle formation. In Dictyostelium cells, epsin is required for both the membrane recruitment and phosphorylation of the actin- and clathrin-binding protein Hip1r. Epsin-null and Hip1r-null cells exhibit deficiencies in the timing and organization of actin filaments at clathrin-coated pits. Consequently, clathrin structures persist on the membranes of epsin and Hip1r mutants and the internalization of clathrin structures is delayed. We conclude that epsin works with Hip1r to regulate actin dynamics by controlling the spatial and temporal coupling of actin filaments to clathrin-coated pits. Specific residues in the ENTH domain of epsin that are required for the membrane recruitment and phosphorylation of Hip1r are also required for normal actin and clathrin dynamics at the plasma membrane. We propose that epsin promotes the membrane recruitment and phosphorylation of Hip1r, which in turn regulates actin polymerization at clathrin-coated pits. PMID- 20923837 TI - The cargo-selective retromer complex is a recruiting hub for protein complexes that regulate endosomal tubule dynamics. AB - The retromer complex is required for the efficient endosome-to-Golgi retrieval of the CIMPR, sortilin, SORL1, wntless and other physiologically important membrane proteins. Retromer comprises two protein complexes that act together in endosome to-Golgi retrieval; the cargo-selective complex is a trimer of VPS35, VPS29 and VPS26 that sorts cargo into tubules for retrieval to the Golgi. Tubules are produced by the oligomerization of sorting nexin dimers. Here, we report the identification of five endosomally-localised proteins that modulate tubule formation and are recruited to the membrane via interactions with the cargo selective retromer complex. One of the retromer-interacting proteins, strumpellin, is mutated in hereditary spastic paraplegia, a progressive length dependent axonopathy. Here, we show that strumpellin regulates endosomal tubules as part of a protein complex with three other proteins that include WASH1, an actin-nucleating promoting factor. Therefore, in addition to a direct role in endosome-to-Golgi retrieval, the cargo-selective retromer complex also acts as a platform for recruiting physiologically important proteins to endosomal membranes that regulate membrane tubule dynamics. PMID- 20923838 TI - Clathrin recruits phosphorylated TACC3 to spindle poles for bipolar spindle assembly and chromosome alignment. AB - Transforming acidic coiled-coil-containing protein 3 (TACC3) has been implicated in mitotic spindle assembly, although the mechanisms involved are largely unknown. Here we identify that clathrin heavy chain (CHC) binds specifically to phosphorylated TACC3 and recruits it to spindle poles for proper spindle assembly and chromosome alignment. Phosphorylation of Xenopus TACC3 at serine 620 (S620) and S626, but not S33, is required for its binding with CHC. Knockdown of CHC by RNA interference (RNAi) abolishes the targeting of TACC3 to spindle poles and results in abnormal spindle assembly and chromosome misalignment, similar to the defects caused by TACC3 knockdown. Furthermore, the binding of CHC with phosphorylated TACC3 is inhibited by importin beta and this inhibition is reversed by the presence of the GTP-binding nuclear protein Ran in the GTP-bound state. Together, these results indicate that the recruitment of phosphorylated TACC3 to spindle poles by CHC ensures proper spindle assembly and chromosome alignment, and is regulated by Ran. PMID- 20923839 TI - Facilitative glucose transporter Glut1 is actively excluded from rod outer segments. AB - Photoreceptors are among the most metabolically active cells in the body, relying on both oxidative phosphorylation and glycolysis to satisfy their high energy needs. Local glycolysis is thought to be particularly crucial in supporting the function of the photoreceptor's light-sensitive outer segment compartment, which is devoid of mitochondria. Accordingly, it has been commonly accepted that the facilitative glucose transporter Glut1 responsible for glucose entry into photoreceptors is localized in part to the outer segment plasma membrane. However, we now demonstrate that Glut1 is entirely absent from the rod outer segment and is actively excluded from this compartment by targeting information present in its cytosolic C-terminal tail. Our data indicate that glucose metabolized in the outer segment must first enter through other parts of the photoreceptor cell. Consequently, the entire energy supply of the outer segment is dependent on diffusion of energy-rich substrates through the thin connecting cilium that links this compartment to the rest of the cell. PMID- 20923840 TI - Chronic pelvic pain in women. PMID- 20923841 TI - Effectiveness of earlier antenatal screening for sickle cell disease and thalassaemia in primary care: cluster randomised trial. AB - OBJECTIVE: To evaluate the effectiveness of offering antenatal screening for sickle cell disease and thalassaemia in primary care as a way of facilitating earlier uptake of screening. DESIGN: Partial factorial cluster randomised controlled trial. SETTING: 25 UK general practices from deprived inner city areas. PARTICIPANTS: Anonymised data on all pregnant women attending participating practices during a six month period before randomisation and a seven month period after randomisation. This included 1708 eligible women. INTERVENTION: Practices were randomised to three groups for seven months: parallel testing in general practice (tests for sickle cell disease and thalassaemia offered to both parents when pregnancy was first reported); sequential testing in general practice (tests offered to mothers when pregnancy was first reported, and subsequently to the partners of women who were found to be carriers); and midwife care (tests offered to mothers at first consultation with a midwife). MAIN OUTCOME MEASURES: The primary outcome (available for all women) was the proportion of eligible women screened before 10 weeks' (70 days') gestation. Secondary outcomes were an offer of screening to women before 10 weeks' gestation, gestational age at testing, mean interval from first visit to the general practice visit to screening, and women's knowledge of the carrier status of their baby's father before 77 days' (11 weeks') gestation. The study was designed to detect a 20% absolute increase in screening uptake. Cluster level analyses were adjusted for age group, parity, ethnic group, primary care organisation, and number of general practitioners per practice. RESULTS: Data were analysed for 1708 eligible women. In the midwife care arm, 2% (9/441) of women were screened before 10 weeks' gestation compared with 24% (161/677) in the GP parallel testing arm and 28% (167/590) in the GP sequential testing arm. The estimated adjusted difference between the midwife care and GP parallel testing arms was 16.5% (95% confidence interval 7.1% to 25.8%; P=0.002) and between the midwife care and GP sequential testing arms was 27.8% (14.8% to 40.7%; P<0.001). By 26 weeks' gestation the proportion of women screened across the three trial arms was similar (81%). The proportion of women who knew the carrier status of the baby's father by 11 weeks' gestation was 0% (0/441) in the midwife care arm, 2% (13/677) in the GP parallel testing arm (P=0.003), and 1% (3/590) in the GP sequential testing arm (P=0.374). CONCLUSION: Offering antenatal screening for sickle cell disease and thalassaemia as part of consultations for pregnancy confirmation in primary care increases the proportion of women screened before 10 weeks' gestation. Even with intervention, however, only a minority of women were screened before 10 weeks. Additional interventions should be considered to achieve testing early in pregnancy for most women wanting such tests so that couples with affected pregnancies have less time pressure to choose options, which may include termination of the pregnancy. TRIAL REGISTRATION: Current Controlled Trials ISRCTN00677850. PMID- 20923842 TI - Reporting of euthanasia in medical practice in Flanders, Belgium: cross sectional analysis of reported and unreported cases. AB - OBJECTIVES: To estimate the rate of reporting of euthanasia cases to the Federal Control and Evaluation Committee and to compare the characteristics of reported and unreported cases of euthanasia. Design Cross sectional analysis. Setting Flanders, Belgium. PARTICIPANTS: A stratified at random sample was drawn of people who died between 1 June 2007 and 30 November 2007. The certifying physician of each death was sent a questionnaire on end of life decision making in the death concerned. MAIN OUTCOME MEASURES: The rate of euthanasia cases reported to the Federal Control and Evaluation Committee; physicians' reasons for not reporting cases of euthanasia; the relation between reporting and non reporting and the characteristics of the physician and patient; the time by which life was shortened according to the physician; the labelling of the end of life decision by the physician involved; and differences in characteristics of due care between reported and unreported euthanasia cases. RESULTS: The survey response rate was 58.4% (3623/6202 eligible cases). The estimated total number of cases of euthanasia in Flanders in 2007 was 1040 (95% CI 970 to 1109), thus the incidence of euthanasia was estimated as 1.9% of all deaths (95% CI 1.6% to 2.3%). Approximately half (549/1040 (52.8%, 95% CI 43.9% to 60.5%)) of all estimated cases of euthanasia were reported to the Federal Control and Evaluation Committee. Physicians who perceived their case as euthanasia reported it in 93.1% (67/72) of cases. Cases of euthanasia were reported less often when the time by which life was shortened was less than one week compared with when the perceived life shortening was greater (37.3% v 74.1%; P<0.001). Unreported cases were generally dealt with less carefully than reported cases: a written request for euthanasia was more often absent (87.7% v 17.6% verbal request only; P<0.001), other physicians and caregivers specialised in palliative care were consulted less often (54.6% v 97.5%; 33.0% v 63.9%; P<0.001 for both), the life ending act was more often performed with opioids or sedatives (92.1% v 4.4%; P<0.001), and the drugs were more often administered by a nurse (41.3% v 0.0%; P<0.001). CONCLUSIONS: One out of two euthanasia cases is reported to the Federal Control and Evaluation Committee. Most non-reporting physicians do not perceive their act as euthanasia. Countries debating legalisation of euthanasia should simultaneously consider developing a policy facilitating the due care and reporting obligations of physicians. PMID- 20923843 TI - FDA on PROMs. Two important points. PMID- 20923844 TI - Government readmission proposals. Improved data collection is needed to support these proposals. PMID- 20923845 TI - Millennium development goals. Listen to the needs of existing healthcare workers. PMID- 20923846 TI - Millennium development goals. Focus on the needs of the existing health workforce. PMID- 20923847 TI - Advanced directives and suicidal behaviour. What to do about treatment refusal at 3 am? PMID- 20923848 TI - Advanced directives and suicidal behaviour. "If in doubt treat" is not as easy as it sounds. PMID- 20923849 TI - New doctors' group challenges medical bodies' opposition to assisted dying. PMID- 20923851 TI - CGP-37157 inhibits the sarcoplasmic reticulum Ca2+ ATPase and activates ryanodine receptor channels in striated muscle. AB - 7-Chloro-5-(2-chlorophenyl)-1,5-dihydro-4,1-benzothiazepin-2(3H)-one [CGP-37157 (CGP)], a benzothiazepine derivative of clonazepam, is commonly used as a blocker of the mitochondrial Na+/Ca2+ exchanger. However, evidence suggests that CGP could also affect other targets, such as L-type Ca2+ channels and plasmalemma Na+/Ca2+ exchanger. Here, we tested the possibility of a direct modulation of ryanodine receptor channels (RyRs) and/or sarco/endoplasmic reticulum Ca2+ stimulated ATPase (SERCA) by CGP. In the presence of ruthenium red (inhibitor of RyRs), CGP decreased SERCA-mediated Ca2+ uptake of cardiac and skeletal sarcoplasmic reticulum (SR) microsomes (IC50 values of 6.6 and 9.9 MUM, respectively). The CGP effects on SERCA activity correlated with a decreased V(max) of ATPase activity of SERCA-enriched skeletal SR fractions. CGP (>= 5 MUM) also increased RyR-mediated Ca2+ leak from skeletal SR microsomes. Planar bilayer studies confirmed that both cardiac and skeletal RyRs are directly activated by CGP (EC(50) values of 9.4 and 12.0 MUM, respectively). In summary, we found that CGP inhibits SERCA and activates RyR channels. Hence, the action of CGP on cellular Ca2+ homeostasis reported in the literature of cardiac, skeletal muscle, and other nonmuscle systems requires further analysis to take into account the contribution of all CGP-sensitive Ca2+ transporters. PMID- 20923852 TI - Expression of functional human alpha6beta2beta3* acetylcholine receptors in Xenopus laevis oocytes achieved through subunit chimeras and concatamers. AB - alpha6beta2beta3* acetylcholine receptors (AChRs) on dopaminergic neurons are important targets for drugs to treat nicotine addiction and Parkinson's disease. However, it has not been possible to efficiently express functional alpha6beta2beta3* AChRs in oocytes or transfected cells. alpha6/alpha3 subunit chimeras permit expression of functional AChRs and reveal that parts of the alpha6 M1 transmembrane domain and large cytoplasmic domain impair assembly. Concatameric subunits permit assembly of functional alpha6beta2beta3* AChRs with defined subunit compositions and subunit orders. Assembly of accessory subunits is limiting in formation of mature AChRs. A single linker between the beta3 accessory subunit and an alpha4 or alpha6 subunit is sufficient to permit assembly of complex beta3-(alpha4beta2)(alpha6beta2) or beta3 (alpha6beta2)(alpha4beta2) AChRs. Concatameric pentamers such as beta3-alpha6 beta2-alpha4-beta2 have been functionally characterized. alpha6beta2beta3* AChRs are sensitive to activation by drugs used for smoking cessation therapy (nicotine, varenicline, and cytisine) and by sazetidine. All these are partial agonists. (alpha6beta2)(alpha4beta2)beta3 AChRs are most sensitive to agonists. (alpha6beta2)2beta3 AChRs have the greatest Ca2+ permeability. (alpha4beta2)(alpha6beta2)beta3 AChRs are most efficiently transported to the cell surface, whereas (alpha6beta2)2beta3 AChRs are the least efficiently transported. Dopaminergic neurons may have special chaperones for assembling accessory subunits with alpha6 subunits and for transporting (alpha6beta2)2beta3 AChRs to the cell surface. Concatameric pentamers and pentamers formed from combinations of trimers, dimers, and monomers exhibit similar properties, indicating that the linkers between subunits do not alter their functional properties. For the first time, these concatamers allow analysis of functional properties of alpha6beta2beta3* AChRs. These concatamers should enable selection of drugs specific for alpha6beta2beta3* AChRs. PMID- 20923854 TI - The role of asymmetric dimethylarginine and arginine in the failing heart and its vasculature. AB - Nitric oxide (NO) is formed from arginine by the enzyme nitric oxide synthase (NOS). Asymmetric dimethylarginine (ADMA) can inhibit NO production by competing with arginine for NOS binding. Therefore, the net amount of NO might be indicated by the arginine/ADMA ratio. In turn, arginine can be metabolized by the enzyme arginase, and ADMA by the enzyme dimethylarginine dimethylaminohydrolase (DDAH). While ADMA has been implicated as a cardiovascular risk factor, arginine supplementation has been indicated as a treatment in cardiac diseases. This review discusses the roles of ADMA and arginine in the failing heart and its vasculature. Furthermore, it proposes nutritional therapies to improve NO availability. PMID- 20923853 TI - Discovery of novel allosteric modulators of metabotropic glutamate receptor subtype 5 reveals chemical and functional diversity and in vivo activity in rat behavioral models of anxiolytic and antipsychotic activity. AB - Modulators of metabotropic glutamate receptor subtype 5 (mGluR5) may provide novel treatments for multiple central nervous system (CNS) disorders, including anxiety and schizophrenia. Although compounds have been developed to better understand the physiological roles of mGluR5 and potential usefulness for the treatment of these disorders, there are limitations in the tools available, including poor selectivity, low potency, and limited solubility. To address these issues, we developed an innovative assay that allows simultaneous screening for mGluR5 agonists, antagonists, and potentiators. We identified multiple scaffolds that possess diverse modes of activity at mGluR5, including both positive and negative allosteric modulators (PAMs and NAMs, respectively). 3-Fluoro-5-(3 (pyridine-2-yl)-1,2,4-oxadiazol-5-yl)benzonitrile (VU0285683) was developed as a novel selective mGluR5 NAM with high affinity for the 2-methyl-6-(phenylethynyl) pyridine (MPEP) binding site. VU0285683 had anxiolytic-like activity in two rodent models for anxiety but did not potentiate phencyclidine-induced hyperlocomotor activity. (4-Hydroxypiperidin-1-yl)(4 phenylethynyl)phenyl)methanone (VU0092273) was identified as a novel mGluR5 PAM that also binds to the MPEP site. VU0092273 was chemically optimized to an orally active analog, N-cyclobutyl-6-((3-fluorophenyl)ethynyl)nicotinamide hydrochloride (VU0360172), which is selective for mGluR5. This novel mGluR5 PAM produced a dose dependent reversal of amphetamine-induced hyperlocomotion, a rodent model predictive of antipsychotic activity. Discovery of structurally and functionally diverse allosteric modulators of mGluR5 that demonstrate in vivo efficacy in rodent models of anxiety and antipsychotic activity provide further support for the tremendous diversity of chemical scaffolds and modes of efficacy of mGluR5 ligands. In addition, these studies provide strong support for the hypothesis that multiple structurally distinct mGluR5 modulators have robust activity in animal models that predict efficacy in the treatment of CNS disorders. PMID- 20923855 TI - The growth hormone/insulin-like growth factor-I system in chronic heart failure and its interaction with adiponectin. PMID- 20923856 TI - Close connection between improvement in left ventricular function by cardiac resynchronization therapy and the incidence of arrhythmias in cardiac resynchronization therapy-defibrillator patients. AB - AIMS: The aim of this study was to determine the relationship between improved ejection fraction (EF) and occurrence of arrhythmias in patients with cardiac resynchronization therapy devices with defibrillator function (CRT-D). The hypothesis was that patients who experienced a marked improvement in EF also had fewer appropriate defibrillator interventions. METHODS AND RESULTS: We analysed data of 270 patients from 2 prospective registries with follow-up of >=12 months and echocardiography performed >=8 months after CRT-D implantation. The discriminator was whether left ventricular ejection fraction (LVEF) improved to >35% [cut-off for primary prevention implantable cardioverter-defibrillator (ICD) implantation]. Mean age was 61+/-11 years, LVEF 22+/-5%, and follow-up 40+/-22 months. Ischaemic cardiomyopathy was present in 48%, and secondary prevention indication was present in 25%. Implantable cardioverter-defibrillator interventions were delivered to 35% of patients. Echocardiography (20+/-15 months after implantation) showed an improvement in LVEF from 22% (SD 5.4%) to 30% (SD 9.8%). Improvement to >35% was seen in 21% of patients. Those who improved to >35% had fewer ICD interventions than those who did not (23 vs.38%; P-value 0.03). Analysing only patients with a primary prevention indication and stratifying again in patients with and without improvement of LVEF to >35%, the latter had highly significant more ICD-therapies (6 vs. 31%; P-value 0.0008). CONCLUSION: Patients with CRT-D for primary prevention, whose LVEF improved to >35% during mid-term follow-up, are at low risk of first ICD therapies beyond year 1. If similar findings are reported in other patient cohorts, this might impact on decision-making at the time of battery depletion. PMID- 20923857 TI - Identification of predictive markers of response to the MEK1/2 inhibitor selumetinib (AZD6244) in K-ras-mutated colorectal cancer. AB - Mutant K-ras activity leads to the activation of the RAS/RAF/MEK/ERK pathway in approximately 44% of colorectal cancer (CRC) tumors. Accordingly, several inhibitors of the MEK pathway are under clinical evaluation in several malignancies including CRC. The aim of this study was to develop and characterize predictive biomarkers of response to the MEK1/2 inhibitor AZD6244 in CRC in order to maximize the clinical utility of this agent. Twenty-seven human CRC cell lines were exposed to AZD6244 and classified according to the IC(50) value as sensitive (<= 0.1 MUmol/L) or resistant (>1 MUmol/L). All cell lines were subjected to immunoblotting for effector proteins, K-ras/BRAF mutation status, and baseline gene array analysis. Further testing was done in cell line xenografts and K-ras mutant CRC human explants models to develop a predictive genomic classifier for AZD6244. The most sensitive and resistant cell lines were subjected to differential gene array and pathway analyses. Members of the Wnt signaling pathway were highly overexpressed in cell lines resistant to AZD6244 and seem to be functionally involved in mediating resistance by shRNA knockdown studies. Baseline gene array data from CRC cell lines and xenografts were used to develop a k-top scoring pair (k-TSP) classifier, which predicted with 71% accuracy which of a test set of patient-derived K-ras mutant CRC explants would respond to AZD6244, providing the basis for a patient-selective clinical trial. These results also indicate that resistance to AZD6244 may be mediated, in part, by the upregulation of the Wnt pathway, suggesting potential rational combination partners for AZD6244 in CRC. PMID- 20923858 TI - cDNA cloning and expression pattern of two enolase genes from the Chinese oak silkworm, Antheraea pernyi. AB - In this study, two enolase genes were isolated and characterized from the Chinese oak silkworm, Antheraea perny, which were designated as enolase I and II, respectively. The enolase I cDNA sequence was 1712 bp with an open reading frame (ORF) of 1302 bp encoding 433 amino acids. The enolase II cDNA sequence was 1549 bp with an ORF of 1296 bp encoding 431 amino acids. The amino acid sequences of the two genes share several conserved features/sites of enolase. Antheraea pernyi enolase I shows 93%-97% sequence identity to enolases of lepidopterans available to date, 75%-82% identity to enolases of other invertebrates, 60%-72% identity to enolases of other organisms including vertebrates, plants, and fungi. Antheraea pernyi enolase II shows 84% identity to Bombyx mori enolase II, but 60% identity to A. pernyi enolase I. In the phylogenetic tree, enolase II sequences from A. pernyi and B. mori were clearly separated from the majority of enolase sequences of higher organisms including A. pernyi and B. mori enolase I sequences. By sequence comparisons and phylogenetic analysis, we suggest that enolase II from A. pernyi and B. mori may be a new member of the enolase superfamily. Antheraea pernyi enolase I mRNA was found in all tested tissues whereas enolase II mRNA was expressed specifically in the spermaries and ovaries, suggesting that the product of enolase II gene may be related to reproduction. The transcript abundance of A. pernyi enolase I gene was significantly down-regulated after cold shock and significantly up-regulated after heat shock, suggesting that A. pernyi enolase I gene may be inducible by temperature stress. PMID- 20923859 TI - Identification of immunodominant linear B-cell epitopes within the major outer membrane protein of Chlamydia trachomatis. AB - Chlamydia trachomatis is one of the most prevalent sexually transmitted pathogens. Chlamydial major outer membrane protein (MOMP) can induce strong cellular and humoral immune responses in murine models and has been regarded as a potential vaccine candidate. In this report, the amino acid sequence of MOMP was analyzed using computer-assisted techniques to scan B-cell epitopes, and three possible linear B-cell epitopes peptides (VLKTDVNKE, TKDASIDYHE, TRLIDERAAH) with high predicted antigenicity and high conservation were investigated. The DNA coding region for each potential epitope was cloned into pET32a(+) and expressed as Trx-His-tag fusion proteins in Escherichia coli. The fusion proteins were purified by Ni-NTA agarose beads and followed by SDS-PAGE and western blot analysis. We immunized mice with these three fusion proteins. The sera containing anti-epitope antibodies from the immunized mice could recognize C. trachomatis serovars D and E in ELISA. Antisera of these fusion proteins displayed an inhibitory effect on invasion of serovar E by in vitro neutralization assays. In addition, serum samples from convalescent C. trachomatis-infected patients were reactive with the epitope fusion proteins by western blot assay. Our results showed that the epitope sequences selected by bioinformatic analysis are highly conserved C. trachomatis MOMP B-cell epitopes, and could be good candidates for the development of subunit vaccines, which can be used in clinical diagnosis. PMID- 20923860 TI - Evaluation context impacts neuropsychological performance of OEF/OIF veterans with reported combat-related concussion. AB - Although soldiers of Operations Iraqi Freedom (OIF) and Enduring Freedom (OEF) encounter combat-related concussion at an unprecedented rate, relatively few studies have examined how evaluation context, insufficient effort, and concussion history impact neuropsychological performances in the years following injury. The current study explores these issues in a sample of 119 U.S. veterans (OEF/OIF forensic concussion, n = 24; non-OEF/OIF forensic concussion, n = 20; OEF/OIF research concussion, n = 38; OEF/OIF research without concussion, n = 37). The OEF/OIF forensic concussion group exhibited significantly higher rates of insufficient effort relative to the OEF/OIF research concussion group, but a comparable rate of insufficient effort relative to the non-OEF/OIF forensic concussion group. After controlling for effort, the research concussion and the research non-concussion groups demonstrated comparable neuropsychological performance. Results highlight the importance of effort assessment among OEF/OIF and other veterans with concussion history, particularly in forensic contexts. PMID- 20923861 TI - AVR/NAVR deficiency lowers blood pressure and differentially affects urinary concentrating ability, cognition, and anxiety-like behavior in male and female mice. AB - Arginine vasopressin (AVP) and angiotensin II (ANG II) are distinct peptide hormones involved in multiple organs modulating renal, cardiovascular, and brain functions. They achieve these functions via specific G protein-coupled receptors, respectively. The AVR/NAVR locus encodes two overlapping V2-type vasopressin isoreceptors: angiotensin-vasopressin receptor (AVR) responding to ANG II and AVP equivalently, and nonangiotensin vasopressin receptor (NAVR), which binds vasopressin exclusively. AVR and NAVR are expressed from a single gene by alternative promoter usage that is synergistically upregulated by testosterone and estrogen. This study tested the hypothesis that AVR/NAVR modulates urinary concentrating ability, blood pressure, and cognitive performance in vivo in a sex specific manner. We developed a C57BL/6 inbred AVR/NAVR(-/-) knockout mouse that showed lower blood pressure in both male and female subjects and a urinary concentrating defect restricted to male mice. We also detected sex-specific effects on cognitive and anxiety-like behaviors. AVR/NAVR(-/-) male mice exhibited impaired visuospatial and associative learning, while female mice showed improved performance in both type of cognition. AVR/NAVR deficiency produced an anxiolytic-like effect in female mice, while males were unaffected. Analysis of AVR- and NAVR-mediated phosphorylation/dephosphorylation of signaling proteins revealed activation/deactivation of known modulators of cognitive function. Our studies identify AVR/NAVR as key receptors involved in blood pressure regulation and sex-specific modulation of renal water homeostasis, cognitive function, and anxiety-like behavior. As such, the AVR/NAVR receptor system provides a molecular mechanism for sexually diergic traits and a putative common pathway for the emerging association of hypertension and cognitive decline and dementia. PMID- 20923862 TI - Temporal genomewide expression profiling of DSS colitis reveals novel inflammatory and angiogenesis genes similar to ulcerative colitis. AB - Dextran sodium sulfate (DSS)-induced colitis is widely used to study pathological mechanisms and potential treatments of inflammatory bowel disease. Because temporal changes in genome expression profiles remain unknown in this model, we performed whole genome expression profile analysis during the development of DSS colitis in comparison with ulcerative colitis (UC) specimens to identify novel and common responses during disease. Colon tissue from DSS-treated mice was collected at days 0, 2, 4, and 6. Half of each specimen was used for histopathological analysis and half for Affymetrix whole genome expression profiling and qRT-PCR validation. Genesifter and Ingenuity software analysis was used to identify differentially expressed genes and perform interactive network analysis. Identified DSS-associated genes in mice were also compared with UC patient data. We identified 1,609 genes that were significantly altered during DSS colitis; the majority were functionally related to inflammation, angiogenesis, metabolism, biological adhesion, cellular growth and proliferation, and cell-to-cell signaling responses. Five hundred and one genes were progressively upregulated, while one hundred seventy-three genes were progressively downregulated. Changes in gene expression were validated in a subset of 33 genes by qRT-PCR, with r(2) = 0.925. Ingenuity gene interaction network analysis revealed novel relationships among antigen presentation, cell morphology, and other biological functions in the DSS mouse. Finally, DSS colitis gene array data were compared with UC patient array data: 152 genes were similarly upregulated, and 22 genes were downregulated. Temporal genomewide expression profile analysis of DSS-induced colitis revealed novel associations with various immune responses and tissue remodeling events such as angiogenesis similar to those in UC patients. This study provides a comprehensive view of DSS colitis changes in colon gene expression and identifies common molecules with clinical specimens that are interesting targets for further investigation. PMID- 20923863 TI - mRNA expression of genes regulating oxidative phosphorylation in the muscle of beef cattle divergently ranked on residual feed intake. AB - Our objective was to evaluate the effects of phenotypic ranking on residual feed intake (RFI) on the transcription of genes 1) involved in the respiratory chain complex and 2) coding for transcriptional factors regulating mitochondrial biogenesis, across two contrasting diet types. Beef heifers (n = 86) fed a diet comprising 70:30 concentrate-corn silage [low forage (LF)] over a 82-day period were ranked on RFI. The 10 highest (feed inefficient, high-RFI) and 10 lowest (feed efficient, low-RFI) ranking animals were selected for the current study. Biopsies of the M. longissimus dorsi were harvested following initial selection (LF diet) and again following a 6 wk period while the animals were offered a high forage (HF) grass silage-only diet. Real-time PCR was used to quantify mRNA transcripts of 17 genes associated with cellular energetic efficiency. The mRNA expression of UCP3 tended to be upregulated (2.2-fold, P = 0.06) for the high-RFI compared with the low-RFI animals. mRNA transcripts coding for the transcription factor PGC-1alpha was 1.7-fold higher (P = 0.01) in low compared with high-RFI animals. A phenotype * diet interaction was evident for the abundance of ANT1 mRNA transcript, with greater (P = 0.04) expression levels detected in the low RFI phenotype during the HF period, but no difference (P = 0.50) between phenotypes during the LF period. A phenotype * diet interaction was also evident for COX II with greater expression levels detected (P = 0.04) in the low compared with the high RFI phenotype while on LF but not the HF diet (P = 0.22). These data suggest an association between cellular energetic efficiency and RFI in cattle. PMID- 20923864 TI - A novel TMEM127 mutation in a patient with familial bilateral pheochromocytoma. AB - OBJECTIVE: In this report, we describe a new patient with unexplained familial bilateral pheochromocytoma. Following the recent description of TMEM127 as a new pheochromocytoma susceptibility gene, the aim of this study was to test the hypothesis of a causative TMEM127 gene mutation in this patient. DESIGN: Pheochromocytoma susceptibility genes were analyzed in germline DNA and losses of heterozygosity (LOH) assessed by BAC array comparative genomic hybridization in tumor DNA. SDHB expression and S6 kinase (S6K) phosphorylation were analyzed by immunohistochemistry. Genome-wide expression microarray studies were performed, and vascular density was quantified after CD34 immunohistochemistry. RESULTS: A first germline variant was identified in the SDHB gene (c.158G>A; p.Gly53Glu). However, a positive SDHB immunostaining in the tumor indicated that this SDHB variant was a non-functional polymorphism. A novel TMEM127 germline mutation (c.140C>A, p.Ala47Asp) associated with a 2q11 LOH was found. Transcriptome and immunohistochemical analyses showed that TMEM127-related pheochromocytoma clusterized with NF1-related and RET-related tumors in a large series of pheochromocytomas and paragangliomas, exhibited a reduced TMEM127 mRNA expression and displayed a low vascularization. The phosphorylation of S6K observed in this tumor was suggestive of an activation of the MTOR pathway. CONCLUSIONS: Pathological and genomic data demonstrated that a TMEM127 gene mutation not previously described was causative of a new case of familial bilateral pheochromocytoma. This report highlights the importance of supplementary analyses on tumor tissue to provide an accurate pheochromocytoma/paraganglioma genetic testing result to affected patients. PMID- 20923865 TI - Measures of learning, memory and processing speed accurately predict smoking status in short-term abstinent treatment-seeking alcohol-dependent individuals. AB - AIM: Chronic cigarette smoking appears to adversely affect several domains of neurocognition in those with alcohol use disorders (AUDs). The primary goal of this study was to identify which measures commonly used to assess neurocognition in AUDs accurately predict smoking status of individuals seeking treatment of alcohol dependence. METHODS: Treatment-seeking alcohol-dependent participants (ALC; n = 92) completed a comprehensive neuropsychological battery after 33 +/- 9 days of abstinence. Measures significantly different between smoking and non smoking ALC were entered as predictors in binary logistic regression and discriminant analysis models, with smoking status as the dependent variable. RESULTS: Smoking ALC performed significantly worse than non-smoking ALC on measures assessing processing speed, auditory-verbal and visuospatial learning and memory. Using these measures as predictors, a logistic regression model accurately classified 91% of smokers and non-smokers into their respective groups overall and accounted for 68% of the variance in smoking status. The discriminant analysis confirmed the findings from the logistic regression. In smoking ALC, smoking chronicity was inversely related to performance on multiple measures after controlling for lifetime alcohol consumption. CONCLUSIONS: Measures of processing speed, learning and memory robustly predicted the smoking status of ALC with high sensitivity and specificity during early abstinence. The results identified specific measures within a comprehensive neurocognitive battery that discriminated smoking and non-smoking alcohol-dependent individuals with a high sensitivity and specificity. The association of greater smoking chronicity and poorer performance on multiple measures after control for alcohol consumption suggests that chronic smoking adds an additional burden to neurocognitive function in those with alcohol dependence. PMID- 20923866 TI - Among-individual variation in pollen limitation and inbreeding depression in a mixed-mating shrub. AB - BACKGROUND AND AIMS: Variation in inbreeding depression (delta) among individual plants is considered to play a central role in mating system evolution and population genetics. Moreover, such variation could be linked to individual susceptibility to pollen limitation (PL) because those individuals strongly affected by delta for seed production will require more outcross pollen for setting a given number of fruits or seeds. However, no study has tested explicitly for associations between PL and delta at the individual plant level. This study assesses the extent of among-individual variation in PL and delta, the consistency of delta across life stages, and the relationships between individual PL and delta in the mixed-mating shrub Myrtus communis. METHODS: Controlled hand pollinations were performed in a natural M. communis population. Marked flowers were monitored until fruit production and a greenhouse experiment was conducted with the seeds produced. KEY RESULTS: Compared with selfing, outcross-pollination enhanced seed number per fruit, germination rate and seedling growth, but did not enhance fruit-set. Only seed number per fruit was pollen limited and, thus, cumulative pollen limitation depended more on pollen quality (outcross pollen) than on quantity. The effects of delta varied considerably across life stages and individual plants. Cumulative delta was high across individuals (mean delta = 0.65), although there were no positive correlations between delta values at different life stages. Interestingly, maternal plants showing stronger delta for seed production were more pollen limited, but they were also less affected by delta for seedling growth because of a seed size/number trade-off. CONCLUSIONS: Results show a general inconsistency in delta across life stages and individuals, suggesting that different deleterious loci are acting at different stages. The association between delta and PL at the individual level corroborates the idea that pollen limitation may be 'genotype-dependent' regardless of other factors. PMID- 20923867 TI - Chronic suppression of phosphodiesterase 10A alters striatal expression of genes responsible for neurotransmitter synthesis, neurotransmission, and signaling pathways implicated in Huntington's disease. AB - Inhibition of phosphodiesterase 10A (PDE10A) promotes cyclic nucleotide signaling, increases striatal activation, and decreases behavioral activity. Enhanced cyclic nucleotide signaling is a well established route to producing changes in gene expression. We hypothesized that chronic suppression of PDE10A activity would have significant effects on gene expression in the striatum. A comparison of the expression profile of PDE10A knockout (KO) mice and wild-type mice after chronic PDE10A inhibition revealed altered expression of 19 overlapping genes with few significant changes outside the striatum or after administration of a PDE10A inhibitor to KO animals. Chronic inhibition of PDE10A produced up-regulation of mRNAs encoding genes that included prodynorphin, synaptotagmin10, phosphodiesterase 1C, glutamate decarboxylase 1, and diacylglycerol O-acyltransferase and a down-regulation of mRNAs encoding choline acetyltransferase and Kv1.6, suggesting long-term suppression of the PDE10A enzyme is consistent with altered striatal excitability and potential utility as a antipsychotic therapy. In addition, up-regulation of mRNAs encoding histone 3 (H3) and down-regulation of histone deacetylase 4, follistatin, and claspin mRNAs suggests activation of molecular cascades capable of neuroprotection. We used lentiviral delivery of cAMP response element (CRE)-luciferase reporter constructs into the striatum and live animal imaging of 2-{4-[-pyridin-4-yl-1-(2,2,2 trifluoro-ethyl)-1H-pyrazol-3-yl]-phenoxymethyl}-quinoline succinic acid (TP-10) induced luciferase activity to further demonstrate PDE10 inhibition results in CRE-mediated transcription. Consistent with potential neuroprotective cascades, we also demonstrate phosphorylation of mitogen- and stress-activated kinase 1 and H3 in vivo after TP-10 treatment. The observed changes in signaling and gene expression are predicted to provide neuroprotective effects in models of Huntington's disease. PMID- 20923869 TI - Altered cardiovascular responses to tracheal intubation in patients with complete spinal cord injury: relation to time course and affected level. AB - BACKGROUND: We determined cardiovascular responses to tracheal intubation in relation to the time since injury in patients with different levels of spinal cord injury. METHODS: Two hundred and fourteen patients with complete cord injury were studied. They were either quadriplegics (>C7, n=71) or paraplegics (20 yr. Twenty patients with no cord injury served as controls. Systolic arterial pressure (SAP), heart rate (HR), and plasma catecholamine concentrations were determined. RESULTS: Intubation did not affect SAP in the quadriplegics regardless of the time post-injury, but it significantly increased SAP in all paraplegics. Moreover, the pressor response was enhanced in the paraplegics who were 10 yr or more since injury (P<0.05). HR increased significantly in all groups; the magnitude of the increase was less only in acute quadriplegics compared with controls. Plasma concentrations of norepinephrine increased in every group except for the quadriplegics within 4 weeks of injury. The maximum increases in SAP, HR, and norepinephrine from awake baseline values were smaller in the quadriplegics than in the paraplegics (P<0.01). CONCLUSIONS: The cardiovascular and catecholamine responses to intubation change as a function of the time elapsed and the level of the cord injury. In this study, the pressor response to tracheal intubation was abolished in the quadriplegics but not in paraplegics; indeed, it was enhanced at 10 yr or more since injury in this group. PMID- 20923868 TI - Functional plasticity of group II metabotropic glutamate receptors in regulating spinal excitatory and inhibitory synaptic input in neuropathic pain. AB - Metabotropic glutamate receptors (mGluRs) are involved in the modulation of synaptic transmission and plasticity. Group II mGluRs in the spinal cord regulate glutamatergic input, but their functional changes in neuropathic pain are not clear. In this study, we determined the plasticity of spinal group II mGluRs in controlling excitatory and inhibitory synaptic transmission and nociception in neuropathic pain. Neuropathic pain was induced by spinal nerve ligation in rats, and whole-cell voltage-clamp recordings of glutamatergic excitatory postsynaptic currents (EPSCs) and spontaneous and miniature GABAergic and glycinergic inhibitory postsynaptic currents (sIPSCs and mIPSCs, respectively) were performed in spinal cord slices. The specific group II mGluR agonist (2S,2'R,3'R)-2-(2',3' dicarboxycyclopropyl)glycine (DCG-IV) had a similar inhibitory effect on monosynaptic EPSCs evoked from the dorsal root in sham and nerve-injured rats. However, DCG-IV produced a greater inhibitory effect on evoked polysynaptic EPSCs and the frequency of spontaneous EPSCs in nerve-injured rats than in control rats. Although DCG-IV similarly reduced the frequency of GABAergic sIPSCs and mIPSCs in both groups, it distinctly inhibited the frequency of glycinergic sIPSCs and mIPSCs only in nerve-injured rats. The DCG-IV effect was blocked by the group II mGluR antagonist but not by the N-methyl-D-aspartate receptor antagonist. Strikingly, intrathecal injection of DCG-IV dose-dependently attenuated allodynia and hyperalgesia in nerve-injured rats but produced hyperalgesia in control rats. Our study provides new information that nerve injury up-regulates group II mGluRs present on glutamatergic and glycinergic interneurons in the spinal cord. Activation of group II mGluRs reduces neuropathic pain probably by attenuating glutamatergic and glycinergic input to spinal dorsal horn neurons. PMID- 20923870 TI - Cerebral microhemorrhage and iron deposition in mild cognitive impairment: susceptibility-weighted MR imaging assessment. AB - PURPOSE: To test whether susceptibility-weighted magnetic resonance imaging at baseline may help predict cognitive decline. MATERIALS AND METHODS: This prospective study was approved by the institutional review board, and written informed consent was obtained from all participants. Thirty-five healthy control subjects and 69 patients with mild cognitive impairment were included. Patients with mild cognitive impairment underwent neuropsychologic follow-up after 1 year (40 patients with stable mild cognitive impairment, 27 with progressive mild cognitive impairment, and two lost to follow-up). Cerebral microhemorrhages were visually analyzed by two experienced neuroradiologists in consensus. Iron deposition in deep gray matter was assessed with voxel-wise and region-of interest analysis after nonlinear spatial registration. In addition, individual classification of mild cognitive impairment was analyzed by using a support vector machine (SVM). RESULTS: At baseline, the number of cerebral microhemorrhages was significantly higher in the mild cognitive impairment group than in the control group (P < .01) but did not differ between the patients with stable and those with progressive mild cognitive impairment. Compared with the control group, patients with mild cognitive impairment had increased iron concentration in the right pallidum (P < .01) and right substantia nigra (P < .01) but decreased concentration in the right red nucleus (P < .05). The classification based on the SVM successfully helped discriminate patients with mild cognitive impairment from the healthy control subjects (accuracy, 84%; sensitivity, 89%; specificity, 85%) and those with stable from those with progressive mild cognitive impairment (accuracy, 85%; sensitivity, 84%; specificity, 83%). CONCLUSION: The findings reveal an accumulation of cerebral microhemorrhage in patients with mild cognitive impairment that is present at baseline, independent of subsequent cognitive decline, as well as an altered iron distribution in subcortical nuclei between the healthy control subjects and patients with mild cognitive impairment. Analysis of iron deposition at baseline performed with an SVM might help identify individual patients with mild cognitive impairment at risk for cognitive decline. SUPPLEMENTAL MATERIAL: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.10100612/-/DC1. PMID- 20923871 TI - Specimen preparation of porous Au for transmission electron microscopy using cryo ion-milling. AB - Porous Au specimens suitable for transmission electron microscopic investigations were prepared by the Ar ion-milling equipped with a cryo-system. The cryo technique enabled the preparation of an artifact-free specimen, avoiding the deposition of Au particles induced by ion-milling. This result demonstrates that cooling is necessary for defect-free preparation of the specimens. PMID- 20923872 TI - Development of an active targeting liposome encapsulated with high-density colloidal gold for transmission electron microscopy. AB - Active targeting of the liposome is an attractive strategy for drug delivery and in vivo bio-imaging. We previously reported the specific accumulation of Sialyl Lewis X (SLX) liposome to inflamed tissue in arthritic model mice or tumor bearing mice. SLX-liposome encapsulation with fluorescent substances allows for the visualization of these liposomes by the time-dependent transvascular accumulation of fluorescent signals in the histological sections. In the present study, we developed a new SLX-liposome encapsulated with colloidal gold for transmission electron microscopic observation. We herein describe the characterization of the colloidal gold-loaded SLX-liposomes and demonstrate its specific targeting to the endothelial cells of tumor blood vessels in tumor bearing mice. PMID- 20923873 TI - Types of ovarian activity in women and their significance: the continuum (a reinterpretation of early findings). AB - BACKGROUND: There are many types of ovarian activity that occur in women. This review provides information on the relationship between the hormone values and the degree of biological response to the hormones including the frequency and degree of uterine bleeding. The continuous process is termed the 'Continuum' and is thus similar to other processes in the body. METHODS: This review draws on information already published from monitoring ovarian activity by urinary oestrogen and pregnanediol measurements using timed 24-h specimens of urine. Much of the rationalization was derived from 5 to 6 year studies of girls progressing from childhood to adulthood, women progressing through menopause, and the return of fertility post-partum. During these times, all the reported types of ovarian activity were encountered. RESULTS: All cycle types can be understood in terms of steps in the normal maturation of fertility at the beginning of reproductive life, its return post-partum and its demise at menopause. Each step merges into the next and therefore the sequence is termed the 'Continuum'. Unpredictable movement from fertile to infertile types and back can occur at any time during reproductive life. Stress is a major causative factor. Hormonal definitions for each step, the relevance of the various cycle types in determining fertility and in the initiation of uterine bleeding and the roles of the pituitary hormones in causing them, are presented. CONCLUSIONS: The findings explain the erratic fertility of women and why ovulation is not always associated with fertility. They provide an understanding of the various types of ovarian activity and their relation to pituitary function, fertility and uterine bleeding. PMID- 20923875 TI - James Boyer Brown, 1919-2009. PMID- 20923876 TI - Local statistics in natural scenes predict the saliency of synthetic textures. AB - The visual system is challenged with extracting and representing behaviorally relevant information contained in natural inputs of great complexity and detail. This task begins in the sensory periphery: retinal receptive fields and circuits are matched to the first and second-order statistical structure of natural inputs. This matching enables the retina to remove stimulus components that are predictable (and therefore uninformative), and primarily transmit what is unpredictable (and therefore informative). Here we show that this design principle applies to more complex aspects of natural scenes, and to central visual processing. We do this by classifying high-order statistics of natural scenes according to whether they are uninformative vs. informative. We find that the uninformative ones are perceptually nonsalient, while the informative ones are highly salient, and correspond to previously identified perceptual mechanisms whose neural basis is likely central. Our results suggest that the principle of efficient coding not only accounts for filtering operations in the sensory periphery, but also shapes subsequent stages of sensory processing that are sensitive to high-order image statistics. PMID- 20923874 TI - Cell-free fetal nucleic acids in amniotic fluid. AB - BACKGROUND: Research into cell-free fetal (cff) nucleic acids has primarily focused on maternal plasma; however, cff DNA and RNA are also detectable in other body fluids such as amniotic fluid (AF). In AF, cff DNA is present in much greater concentrations than in maternal plasma and represents a pure fetal sample uncontaminated by maternal- and trophoblast-derived nucleic acids. The aim of this review was to summarize the current knowledge on cff nucleic acids in AF and to outline future research directions. METHODS: MEDLINE and PREMEDLINE were searched up to August 2010 for original investigations of cell-free RNA or DNA in AF. Sixteen studies were included in the review. RESULTS: AF cff DNA represents a physiologically separate pool from cff DNA in maternal plasma. The placenta is not a major source of nucleic acids in AF. It is feasible to isolate cff nucleic acids from small volumes of discarded AF supernatant in sufficient quality and quantity to perform microarray studies and downstream applications such as pathway analysis. This 'discovery-driven approach' has resulted in new information on the pathogenesis of Down syndrome and polyhydramnios. There is otherwise a paucity of information relating to the basic biology and clinical applications of cff nucleic acids in AF. CONCLUSIONS: AF supernatant is a valuable and widely available but under-utilized biological resource. Further studies of cff nucleic acids in AF may lead to new insights into human fetal development and ultimately new approaches to antenatal treatment of human disease. PMID- 20923877 TI - Epstein-Barr latent membrane protein 1 transformation site 2 activates NF-kappaB in the absence of NF-kappaB essential modifier residues 133-224 or 373-419. AB - Epstein Barr virus latent membrane protein 1 (LMP1) induces NF-kappaB activation through transformation effector sites (TES) 1 and 2, both of which are critical for B-lymphocyte transformation. TES2 principally activates canonical NF-kappaB, which we confirm is NF-kappaB essential modifier (NEMO)-dependent and requires an intact ubiquitin binding in A20 binding inhibitor of NF-kappaB and NEMO (UBAN) domain. LMP1 TES2 activated NF-kappaB in Jurkat cell lines harboring NEMO truncated at 372 (A45) or NEMO with an in-frame deletion of 133-224 (2C), whereas TNFalpha, 12-O-Tetradecanoylphorbol-13-acetate, human T-cell leukemia virus 1 Tax, and CD40 did not. In both A45 and 2C Jurkat cell lines, LMP1 TES2-mediated NF-kappaB activation was blocked by siRNAs to TNFalpha receptor-associated factor 6 and NEMO, by IkappaB kinase inhibitors, and by the IkappaBalpha superrepressor, indicating that the NEMO mutants function to support canonical NF-kappaB activation. Expression of A45 or 2C mutants in NEMO-deficient murine embryonic fibroblasts reproduced the Jurkat phenotypes: LMP1 TES2 activated NF-kappaB in fibroblasts lacking NEMO amino acids 133-224 or 373-419, but TNFalpha and Tax did not. Further analysis indicated that TES2 did not activate NF-kappaB in cells expressing the double deletion mutant Delta133-224/Delta372-419. These data provide further evidence of the essential role for NEMO in LMP1 TES2 NF-kappaB activation and highlight the importance of unique domains within NEMO for sensing distinct NF-kappaB stimuli. PMID- 20923878 TI - Memory T cells persisting within the brain after local infection show functional adaptations to their tissue of residence. AB - The brain is not routinely surveyed by lymphocytes and is defined as an immuno privileged site. However, viral infection of the brain results in the infiltration and long-term persistence of pathogen-specific CD8(+) T cells. These cells survive without replenishment from the circulation and are referred to as resident memory T cells (Trm). Brain Trm selectively express the integrin CD103, the expression of which is dependent on antigen recognition within the tissue. After clearance of virus, CD8(+) T cells persist in tight clusters, presumably at prior infection hot spots. Antigen persistence is not a prerequisite for T-cell retention, as suggested by the failure to detect viral genomes in the T-cell clusters. Furthermore, we show that an intracranial dendritic cell immunization regimen, which allows the transient introduction of antigen, also results in the generation of memory T cells that persist long term in the brain. Brain Trm die rapidly on isolation from the tissue and fail to undergo recall expansion after adoptive transfer into the bloodstream of antigen-challenged recipients. These ex vivo defects imply a dependency on the local milieu for function and survival. Cumulatively, this work shows that Trm are a specialized population of memory T cells that can be deposited in tissues previously thought to be beyond routine immune surveillance. PMID- 20923879 TI - Heterogeneous myocyte enhancer factor-2 (Mef2) activation in myocytes predicts focal scarring in hypertrophic cardiomyopathy. AB - Unknown molecular responses to sarcomere protein gene mutations account for pathologic remodeling in hypertrophic cardiomyopathy (HCM), producing myocyte growth and increased cardiac fibrosis. To determine if hypertrophic signals activated myocyte enhancer factor-2 (Mef2), we studied mice carrying the HCM mutation, myosin heavy-chain Arg403Gln, (MHC(403/+)) and an Mef2-dependent beta galactosidase reporter transgene. In young, prehypertrophic MHC(403/+) mice the reporter was not activated. In hypertrophic hearts, activation of the Mef2 dependent reporter was remarkably heterogeneous and was observed consistently in myocytes that bordered fibrotic foci with necrotic cells, MHC(403/+) myocytes with Mef2-dependent reporter activation reexpressed the fetal myosin isoform (betaMHC), a molecular marker of hypertrophy, although MHC(403/+) myocytes with or without betaMHC expression were comparably enlarged over WT myocytes. To consider Mef2 roles in severe HCM, we studied homozygous MHC(403/403) mice, which have accelerated remodeling, widespread myocyte necrosis, and neonatal lethality. Levels of phosphorylated class II histone deacetylases that activate Mef2 were substantially increased in MHC(403/403) hearts, but Mef2-dependent reporter activation was patchy. Sequential analyses showed myocytes increased Mef2 dependent reporter activity before death. Our data dissociate myocyte hypertrophy, a consistent response in HCM, from heterogeneous Mef2 activation and reexpression of a fetal gene program. The temporal and spatial relationship of Mef2-dependent gene activation with myocyte necrosis and fibrosis in MHC(403/+) and MHC(403/403) hearts defines Mef2 activation as a molecular signature of stressed HCM myocytes that are poised to die. PMID- 20923881 TI - Virus engineering: functionalization and stabilization. AB - Chemically and/or genetically engineered viruses, viral capsids and viral-like particles carry the promise of important and diverse applications in biomedicine, biotechnology and nanotechnology. Potential uses include new vaccines, vectors for gene therapy and targeted drug delivery, contrast agents for molecular imaging and building blocks for the construction of nanostructured materials and electronic nanodevices. For many of the contemplated applications, the improvement of the physical stability of viral particles may be critical to adequately meet the demanding physicochemical conditions they may encounter during production, storage and/or medical or industrial use. The first part of this review attempts to provide an updated general overview of the fast-moving, interdisciplinary virus engineering field; the second part focuses specifically on the modification of the physical stability of viral particles by protein engineering, an emerging subject that has not been reviewed before. PMID- 20923880 TI - In vivo two-photon imaging reveals monocyte-dependent neutrophil extravasation during pulmonary inflammation. AB - Immune-mediated pulmonary diseases are a significant public health concern. Analysis of leukocyte behavior in the lung is essential for understanding cellular mechanisms that contribute to normal and diseased states. Here, we used two-photon imaging to study neutrophil extravasation from pulmonary vessels and subsequent interstitial migration. We found that the lungs contained a significant pool of tissue-resident neutrophils in the steady state. In response to inflammation produced by bacterial challenge or transplant-mediated, ischemia reperfusion injury, neutrophils were rapidly recruited from the circulation and patrolled the interstitium and airspaces of the lung. Motile neutrophils often aggregated in dynamic clusters that formed and dispersed over tens of minutes. These clusters were associated with CD115(+) F4/80(+) Ly6C(+) cells that had recently entered the lung. The depletion of blood monocytes with clodronate liposomes reduced neutrophil clustering in the lung, but acted by inhibiting neutrophil transendothelial migration upstream of interstitial migration. Our results suggest that a subset of monocytes serve as key regulators of neutrophil extravasation in the lung and may be an attractive target for the treatment of inflammatory pulmonary diseases. PMID- 20923885 TI - The prospect of using cyanobacterial bicarbonate transporters to improve leaf photosynthesis in C3 crop plants. PMID- 20923887 TI - Risk factors for autism and Asperger syndrome. Perinatal factors and migration. AB - Using the Swedish Medical Birth Registry (MBR), obstetrical and demographic information was retrieved for 250 children with autism or Asperger syndrome who were born in Malmoe, Sweden, and enrolled at the local Child and Youth Habilitation Center. The reference group consisted of all children born in Malmoe during 1980-2005. Obstetric sub-optimality (prematurity, low Apgar scores, growth restriction, or macrosomia) was positively associated with autism but not with Asperger syndrome. Maternal birth outside the Nordic countries was positively associated with autism (adjusted OR: 2.2; 95%CI: 1.6-3.1) and negatively associated with Asperger syndrome (OR: 0.6; 95%CI: 0.3-0.97). The highest risk estimate for autism was found among children to women who were born in sub Saharan Africa (OR: 7.3), or in East Asia (OR: 3.4). PMID- 20923886 TI - Increased phloem transport of S-methylmethionine positively affects sulfur and nitrogen metabolism and seed development in pea plants. AB - Seeds of grain legumes are important energy and food sources for humans and animals. However, the yield and quality of legume seeds are limited by the amount of sulfur (S) partitioned to the seeds. The amino acid S-methylmethionine (SMM), a methionine derivative, has been proposed to be an important long-distance transport form of reduced S, and we analyzed whether SMM phloem loading and source-sink translocation are important for the metabolism and growth of pea (Pisum sativum) plants. Transgenic plants were produced in which the expression of a yeast SMM transporter, S-Methylmethionine Permease1 (MMP1, YLL061W), was targeted to the phloem and seeds. Phloem exudate analysis showed that concentrations of SMM are elevated in MMP1 plants, suggesting increased phloem loading. Furthermore, expression studies of genes involved in S transport and metabolism in source organs, as well as xylem sap analyses, support that S uptake and assimilation are positively affected in MMP1 roots. Concomitantly, nitrogen (N) assimilation in root and leaf and xylem amino acid profiles were changed, resulting in increased phloem loading of amino acids. When investigating the effects of increased S and N phloem transport on seed metabolism, we found that protein levels were improved in MMP1 seeds. In addition, changes in SMM phloem loading affected plant growth and seed number, leading to an overall increase in seed S, N, and protein content in MMP1 plants. Together, these results suggest that phloem loading and source-sink partitioning of SMM are important for plant S and N metabolism and transport as well as seed set. PMID- 20923888 TI - Aspects of quality of life in adults diagnosed with autism in childhood: a population-based study. AB - The present study is a long-term prospective follow-up study of a population based cohort of 120 individuals diagnosed with autism in childhood, followed into late adolescence/early adulthood. Specific aims of the study were to attempt to measure and study social aspects/quality of life in those 108 individuals with autism alive and available for study at the time of follow-up (13-22 years after original diagnosis). A newly constructed scale for rating 'autism-friendly environment'/quality of life was used alongside a structured parent/carer interview assessing current occupation, educational history, services provided, accommodation type, and recreational activities. The majority of the group with autism remained dependent on parents/caregivers for support in education, accommodation and occupational situations. In spite of this, the estimation of the study group's general quality of life was encouragingly positive. Nevertheless, there was an obvious need for improvements in the areas of occupation and recreational activities. Future studies need to look in more depth at the concept of an autism-friendly environment and develop more detailed quality of life assessment tools relevant for people in the autism spectrum. PMID- 20923889 TI - The social interactive behaviour of young children with autism spectrum disorder and their mothers: is there an effect of familiarity of the interaction partner? AB - In this study the social behaviour of young children with autism spectrum disorder (ASD) and their mothers is compared within two different dyads: a dyad consisting of a mother and her own child and a dyad consisting of a mother and an unfamiliar child. Mothers did not change the frequency of their social initiatives and responsiveness with an unfamiliar child, but they became less directive than with their own child. Children with ASD did not show significantly better social behaviour with their own mother than with an unfamiliar mother. The results suggest that the social behaviour of a child with autism is not significantly enhanced by the familiarity of the social partner, but rather by the partner's autism-adapted interaction style. Clinical implications of these findings have been discussed. PMID- 20923890 TI - Socio-dramatic affective-relational intervention for adolescents with asperger syndrome & high functioning autism: pilot study. AB - This study examined the effectiveness of a novel intervention called 'socio dramatic affective-relational intervention' (SDARI), intended to improve social skills among adolescents with Asperger syndrome and high functioning autism diagnoses. SDARI adapts dramatic training activities to focus on in vivo practice of areas of social skill deficit among this population. SDARI was administered as a six-week summer program in a community human service agency. Nine SDARI participants and eight age- and diagnosis-group matched adolescents not receiving SDARI were compared on child- and parent-report of social functioning at three week intervals beginning six weeks prior to intervention and ending six weeks post-intervention. Hierarchical Linear Modeling (HLM) was used to estimate growth trends between groups to assess treatment outcomes and post-treatment maintenance. Results indicated significant improvement and post-treatment maintenance among SDARI participants on several measures of child social functioning. Implications for practice and research are discussed. PMID- 20923892 TI - Recognizing faces based on inferred traits in autism spectrum disorders. AB - Recent findings indicate that individuals with autism spectrum disorders (ASD) could, surprisingly, infer traits from behavioural descriptions. Now we need to know whether or not individuals with ASD are able to use trait information to identify people by their faces. In this study participants with and without ASD were presented with pairs of faces each accompanied by a sentence. One sentence allowed a trait to be inferred (e.g. 'This is Ross who smiled and said hello to everyone at the party.') and one allowed a fact to be inferred (e.g. 'This is Ben who has to bend down to enter most doors.'). Subsequently, the same face stimuli were presented with a single descriptive trait, fact or name cue (e.g. friendly or tall and Ross or Ben respectively in the above examples). Participants had to choose which of the faces best related to the cue word. Participants with ASD performed surprisingly well in associating traits, facts, and names to the appropriate person significantly above what would be expected by chance. Indeed, they performed as well as participants without ASD. PMID- 20923891 TI - Narrowing the broader autism phenotype: a study using the Communication Checklist Adult Version (CC-A). AB - This study investigated whether the Communication Checklist - Adult (CC-A) could identify subtypes of social and communication dysfunction in autism probands and their parents. The CC-A is divided into subscales measuring linguistic ability as well as two aspects of social communication: the Pragmatic Skills subscale assesses the level of pragmatic oddities (e.g. excessive talking), while the Social Engagement subscale picks up on those behaviours that reflect a more passive communication style (e.g. failure to engage in social interactions). CC-A data were collected for 69 autism probands, 238 parents of autism probands and 187 typical participants. The CC-A proved sensitive to the communication difficulties of autism probands and a proportion of their parents. The majority of parents who demonstrated the broader phenotype scored poorly on either the Pragmatic Skills or Social Engagement scale only. The Social Engagement scale was particularly sensitive to the difficulties of the parents, indicating that social communicative passivity may be an important part of the broader autism phenotype. The findings provide evidence for the existence of more constrained pragmatic phenotypes in autism. Molecular genetic studies in this area may benefit from stratifying samples according to these phenotypes. PMID- 20923893 TI - A comparison of a specialist autism spectrum disorder assessment team with local assessment teams. AB - BACKGROUND: Early diagnosis of autism spectrum disorders (ASD) is of crucial importance, but lengthy delays are common. We examined whether this issue could be reliably addressed by local teams trained by a specialist ASD assessment team. METHOD: Four local teams were trained in diagnostic assessment. Their assessments of 38 children and young people using the Autism Diagnostic Observation Schedule Generic (ADOS-G) were video recorded and independently assessed by the specialist team. RESULTS: There was a high level of correspondence between the diagnoses of the local teams and of the specialist team. The number of assessments carried out increased and there was a considerable reduction in waiting times. CONCLUSION: This study has demonstrated the potential feasibility of creating local, multi agency ASD assessment teams, which will serve to reduce waiting times, improve clinical skills at a lower level of specialism and thereby improve the overall quality of ASD services. PMID- 20923894 TI - Early symptoms and recognition of pervasive developmental disorders in Germany. AB - Pervasive developmental disorders are characterised by the presence of abnormalities in social interaction and communication as well as repetitive patterns of behaviours. Although early symptoms of the disorder often appear during the first two years of life, its diagnosis is often delayed. The purpose of this study is to analyse the delay between age at first symptoms and age at diagnosis as well as the characteristics of the first symptoms for the different subcategories of pervasive developmental disorders. The sample consists of 601 children with a diagnosis of a pervasive developmental disorder. Age at first symptoms, age at diagnosis and the type of the first problems are registered. The results show that children with autism show first symptoms at a mean age of 15 months whereas diagnosis is made at a mean age of 76 months. Children with Asperger's syndrome show first symptoms at a mean age of 26 months, while diagnosis is made at the mean age of 110 months. There is still a large delay between the age at which parents first report first symptoms and age at diagnosis. To improve early detection, systematic screening and training of primary care paediatricians should be implemented. PMID- 20923895 TI - Understanding emotional transfer in children with autism spectrum disorders. AB - The present study examined the understanding of emotional transfer in 11 children with autism, 20 children with PDD-NOS and 31 typically developing children, aged 6 to 12 years. Children were asked about their emotional responses to successive, conflicting emotional situations. All children reported that preceding emotional situations would influence their emotional response towards a successive situation. Children from the typically developing group reported a stronger influence of preceding negative versus positive emotions. However, children with autism reported equal effects of preceding positive and negative emotions, and children with PDD-NOS were relatively unaffected by the preceding emotions. These findings may indicate a scripted understanding of emotions in children with autism in contrast to a more personalized understanding of typically developing children. PMID- 20923896 TI - Social Stories TM to improve social skills in children with autism spectrum disorder: a systematic review. AB - Over the past 20 years a variety of treatments have been developed to remediate deficits associated with autism. Since the early 1990 s, Social Stories TM have been suggested to positively affect the social development of children with autism spectrum disorder (ASD). Despite much research, there remains uncertainty regarding the effectiveness of this modality. We conducted a systematic review of the literature using pre-defined, rigorous methods. Studies were considered eligible if they were controlled trials evaluating Social Stories TM among persons with ASD. Two reviewers independently screened articles for inclusion, applied eligibility criteria, extracted data, and assessed methodological quality. A qualitative analysis was conducted on six eligible controlled trials. Five of the six trials showed statistically significant benefits for a variety of outcomes related to social interaction. This review underscores the need for further rigorous research and highlights some outstanding questions regarding maintenance and generalization of the benefits of Social Stories TM. PMID- 20923898 TI - Concordance of mental health impairment and service utilization among children in care. AB - This paper describes caregiver-reported patterns of mental health service use for 347 pre-adolescent children in foster and kinship care in New South Wales (NSW), Australia. Children's mean time in care and mean time with their present caregivers were 4.3 and 3.3 years respectively. Forty-four percent of children received individual therapy or counselling, 45% received interventions in the form of clinical guidance for their caregivers, and 31% received both forms of service. Among children scoring in the clinical range on any CBCL sub-scale (N = 191), equivalent rates of mental health service use were 60%, 55% and 41% respectively. Although not directly comparable, these findings describe a higher rate of service use than that reported for children in care elsewhere. While children with more complex and severe difficulties had higher rates of service use, there was no evidence of variable access for treatment of different types of disorder. Predictors of service use are reported and contrasted with previous findings. The paper considers several features of the NSW child welfare, health and education systems that may account for the relatively high rate of service use. PMID- 20923897 TI - A national study of the impact of outpatient mental health services for children in long-term foster care. AB - Despite the tremendous mental health need evidenced by children in foster care and high rates of use of mental health services among children in foster care, little is known about the impact of outpatient mental health services on the behavioral health of this population. This study utilizes data from the National Survey of Child and Adolescent Well-being (NSCAW), the first nationally representative study of child welfare in the United States. A subsample of 439 children who have experienced long-term foster care were included in this study. These data were used to estimate the impact of outpatient mental health services on the externalizing and internalizing behavior problems of children in long-term foster care. A propensity score matching model was employed to produce a robust estimate of the treatment effect. Results indicate that children who have experienced long-term foster care do not benefit from the receipt of outpatient mental health services. Study results are discussed in the context of earlier research on the quality of mental health services for children in foster care. PMID- 20923899 TI - The "Spirit of New Orleans": translating a model of intervention with maltreated children and their families for the Glasgow context. AB - Children in care have higher rates of mental health problems than the general population and placement instability contributes to this. Children are both most vulnerable to the effects of poor quality care and most responsive to treatment in the early weeks and months of life yet, in the UK, permanency decisions are generally not in place until around the age of four. We aimed to understand the components of an innovative system for assessing and intervening with maltreated children and their families developed in New Orleans and to consider how it might be implemented in Glasgow, UK. During and after a visit to New Orleans by a team of Glasgow practitioners, eight key interviews and meetings with New Orleans and Glasgow staff were audio-recorded. Qualitative analysis of verbatim transcripts identified key themes. Themes highlighted shared aspects of the context and attitudes of the two teams, identified gaps in the Glasgow service and steps that would be needed to implement a version of the New Orleans model in Glasgow. Our discussions with the New Orleans team have highlighted concrete steps we can take, in Glasgow, to make better decision-making for vulnerable children a reality. PMID- 20923900 TI - Assessment of children coming into care: processes, pitfalls and partnerships. AB - Children in out-of-home care (OOHC) present with high levels of physical, developmental and emotional and behavioural difficulties, yet often fail to receive appropriate services. This article describes a joint health and welfare service specifically developed to provide comprehensive physical, developmental and mental health assessments to a cohort of children entering long-term care in one region of Sydney, New South Wales (NSW), Australia. Paediatric, allied health, dental and psychosocial assessments were co-ordinated from a single referral from the child's welfare case manager. Follow-up appointments were held 6-12 months later to assess the outcomes of recommendations. Physical, mental health and developmental difficulties in the children are reported, the implications for service requirements are presented and process blocks described. There is a need for a specific co-ordinating service to overcome the inherent fragmentation of this group (related both to transience and change in the welfare sector, and levels of comorbidity and chronicity in health presentations). Health and Welfare services must operate together, with an awareness of the processes and resource constraints in each sector, if they are to deliver sustainable and reliable health care to this vulnerable group. PMID- 20923901 TI - Enhancing adoptive parenting: a randomized controlled trial. AB - The aim was to conduct a pragmatic randomized controlled trial (RCT) to evaluate two parenting programmes designed for adopters of children late placed from care. Adoptive parents, with children between 3 and 8 years who were screened to have serious behavioural problems early in the placement, participated in home-based, manualized, parenting programmes delivered by trained and supervised family social workers. The adopters who agreed to join the study were randomly allocated to one of two parenting interventions or to a "services as usual" group. Baseline, immediate post-intervention and six-month follow-ups were assessed using questionnaires and adopter interviews. No cases were lost to follow-up at any point and satisfaction was high with both parenting interventions. At the six month follow-up, a significant difference (p < 0.007) was found for "satisfaction with parenting" in favour of the intervention group (Effect Size d = 0.7). Negative parenting approaches were reduced in the intervention group. However, no significant differences in child problems were found between the intervention groups and control group, adjusting for baseline scores. Costs analysis showed that a relatively modest investment in post-adoption support would be well spent in improving adopters' satisfaction with parenting in the intervention group compared to the routine service group. PMID- 20923902 TI - A "real-world" evaluation of an adoptive parenting programme: reflections after conducting a randomized trial. PMID- 20923903 TI - Mental health services for children in public care and other vulnerable groups: implications for international collaboration. AB - Children in public care and other vulnerable young groups (homeless, adopted, refugees) are increasingly becoming the focus of policy and service planning. There is strong evidence that all these client populations have high rates of mental health problems which are closely associated with other needs. We also have good knowledge on the factors that predispose individuals to and maintain mental health problems, as well as on the reasons for their not easily accessing and engaging with services. There is less evidence on the effectiveness of interventions or service models, although some interesting patterns are beginning to emerge. These include the need for inter-agency commissioning, clear care pathways, designated provision, applied therapeutic interventions, training for carers and frontline practitioners, and multi modal programmes. This paper discusses these issues, as well as ways forward, both for systems with relatively well developed child mental health services and for low-income countries. Service quality can be greatly strengthened by international collaboration on policy, practice and research networks, training and research. PMID- 20923904 TI - Multi-agency and specialist working to meet the mental health needs of children in care and adopted. AB - Many of the children and young people who are looked after in foster and residential care or are adopted have complex mental health needs that are not well met by traditional mental health services. These vulnerabilities stem from an interaction between pre- and post-care experience, and often include trauma, attachment and developmental difficulties. It is now widely recognized that these children are best served by dedicated services provided by professionals with expertise in meeting the needs of looked after and adopted children. This involves effective joint working between health, education and social care services and requires supportive policies and structures at all levels of the organizations. This paper will explore the strengths, challenges and barriers of multi-agency and specialist working to meet the needs of these vulnerable children and young people.This will be illustrated with case examples drawn from a multi-agency service in Worcestershire, UK. PMID- 20923905 TI - Some reflections on the use of psychiatric diagnosis in the looked after or "in care" child population. AB - The current classification system, DSM-IV, inadequately captures the range and type of psychopathology seen in the "in care" population of children. A combination of pre-natal influences, early interpersonal trauma involving the primary caregiving relationship, disturbed and disrupted attachment relationships and other significant losses and adverse environmental effects produce a complex constellation of symptoms and a pervasive impact on development that is difficult to categorize. The challenges facing DSM-V are illustrated, highlighting unresolved topics such as quasi-autism, reactive attachment disorder and complex trauma. PMID- 20923906 TI - The making and breaking of relationships: organizational and clinical questions in providing services for looked after children? AB - The mental health of children in public care has received considerable attention in recent years. There are significant differences in the prevalence rates compared to children living at home and not in public care and these are added to by other adverse lifestyle issues. Considerable attention has been focused on the importance of stable and secure placements supported by access to a range of services including education, health and mental health. Identifying and classifying mental health needs proves to be challenging as the child's genetic inheritance, pre- and post-birth experiences, including maltreatment, interact with the uncertainty and delays commonly associated with child protection processes, action in the legal system and the difficulty in establishing secure and permanent placements. Clinical need is also related to the age of the child and the reasons they came into care and the length of time they remain. A case illustrating many of these issues, publicly reported in the court's judgement, is used as the basis for exploring the complexity for the identified child in understanding and making sense of their experiences as placement plans are made for them. These are used to explore the difficulties in establishing clinical protocols such as those recently published in the USA. Particular emphasis is given to the issues faced by children and their carers in establishing new family relationships which address the child's inheritance from their family of origin especially where these are traumatic and conflicted in origin. PMID- 20923907 TI - It's time to re-think mental health services for children in care, and those adopted from care. AB - Much of what is written in this special issue points to the need for a clinical workforce that has much greater knowledge and skills for working with children with a history of alternate care, including those who are subsequently adopted. Standard child clinical conceptualization, assessment methods, and formulations miss the mark for these vulnerable populations in a number of critical ways. The present paper proposes 10 principles to guide the design of mental health services for children in care, and those adopted from care. Effective specialization in child welfare work by clinical child psychologists, psychotherapists and psychiatrists, requires: (i) specialized knowledge and skills; (ii) a shift from traditional clinical practice to a clinical psychosocial-developmental scope of practice; and (iii) a strong advocacy role. To support such specialized practice, service design should be guided by: (iv) a primary-specialist care nexus, that includes universal, comprehensive assessments; (v) a shift from acute care to preventative, long-term engagement and monitoring; (vi) integration within the social care milieu; (vii) a shift from exclusion to active ownership of these client groups; (viii) normalization strategies; and (ix) alignment of services for these client groups. Finally, it is argued that mental health service provision for these children is strengthened by policy that promotes (x) "whole of government" accountability for their mental health needs. PMID- 20923908 TI - Test of time: children who wait (1973) by Jane Rowe and Lydia Lambert. PMID- 20923910 TI - Validation of a measure of smoothness of walking. AB - BACKGROUND: Altered biomechanics and/or neural control disrupt the timing of postures and muscle patterns necessary for smooth and regular stepping. Harmonic ratio of trunk accelerations has been proposed as a measure of smoothness of walking. We sought to validate this measure of smoothness by examining the measure in groups expected to differ in smoothness (ie, young and old) and across walking conditions expected to affect smoothness (ie, straight path, curved path, and dual task). METHODS: Thirty young (mean age = 24.4 +/- 4.3 years) and 30 older adults (mean age = 77.5 +/- 5.1 years) who could ambulate independently participated. We measured linear acceleration of the body along vertical, anterior-posterior, and medial-lateral axes using a triaxial accelerometer firmly attached to the skin over the L3 segment of the lumbar spine during straight path, curved path, and dual task (reciting every other letter of the alphabet) walking. RESULTS: Older adults had lower harmonic ratio anterior-posterior (HR(AP)), that is, were less smooth in the direction of motion and walked more slowly than young adults for all walking conditions. Once the analyses were adjusted for walking speed, only HR(AP) differed between young and old participants for all walking conditions. For the most part, both young and old participants were less smooth for slow pace walking, curved path walking, and dual task walking compared with usual pace straight path walking. CONCLUSIONS: The harmonic ratio, calculated from trunk acceleration, is a valid measure of smoothness of walking, which may be thought of as a measure of the motor control of walking. PMID- 20923911 TI - Impact of the high-definition multileaf collimator on linear accelerator-based intracranial stereotactic radiosurgery. AB - OBJECTIVES: The impact of two multileaf collimator (MLC) systems for linear accelerator-based intracranial stereotactic radiosurgery (SRS) was assessed. METHODS: 68 lesions formed the basis of this study. 2.5 mm leaf width plans served as reference. Comparative plans, with identical planning parameters, were based on a 5 mm leaf width MLC system. Two collimation strategies, with collimation fixed at 0 degrees or 90 degrees and optimised per arc or beam, were also assessed. Dose computation was based on the pencil beam algorithm with allowance for tissue heterogeneity. Plan normalisation was such that 100% of the prescription dose covered 95% of the planning target volume. Plan evaluation was based on target coverage and normal tissue avoidance criteria. RESULTS: The median conformity index difference between the MLC systems ranged between 0.8% and 14.2%; the 2.5 mm MLC exhibited better dose conformation. The median reduction of normal tissue exposed to >=100%, >=50% and >=25% of the prescription dose ranged from 13.4% to 29.7%, favouring the 2.5 mm MLC system. Dose fall-off was steeper for the 2.5 mm MLC system with an overall median absolute difference ranging from 0.4 to 1.2 mm. The use of collimation optimisation resulted in a decrease in differences between the MLC systems. The results demonstrated the dosimetric merit of the 2.5 mm leaf width MLC system over the 5 mm leaf width system, albeit small, for the investigated range of intracranial SRS targets. CONCLUSION: The clinical significance of these results warrants further investigation to determine whether the observed dosimetric advantages translate into outcome improvements. PMID- 20923913 TI - Content analysis of antismoking videos on YouTube: message sensation value, message appeals, and their relationships with viewer responses. AB - Focusing on several message features that are prominent in antismoking campaign literature, this content-analytic study examines 934 antismoking video clips on YouTube for the following characteristics: message sensation value (MSV) and three types of message appeal (threat, social and humor). These four characteristics are then linked to YouTube's interactive audience response mechanisms (number of viewers, viewer ratings and number of comments) to capture message reach, viewer preference and viewer engagement. The findings suggest the following: (i) antismoking messages are prevalent on YouTube, (ii) MSV levels of online antismoking videos are relatively low compared with MSV levels of televised antismoking messages, (iii) threat appeals are the videos' predominant message strategy and (iv) message characteristics are related to viewer reach and viewer preference. PMID- 20923912 TI - MRI findings of uncommon non-hepatocyte origin primary liver tumours with pathological correlation. AB - The objective of this article was to illustrate the MRI findings of uncommon non hepatocyte origin primary liver tumours, correlate them with the pathological features and discuss differential diagnoses. In conclusion, the MRI findings of uncommon benign and malignant non-hepatocyte-origin primary liver tumours vary. Awareness of characteristic MRI features can aid differential diagnosis and prevent unnecessary surgery. PMID- 20923909 TI - Design and conduct of the CALERIE study: comprehensive assessment of the long term effects of reducing intake of energy. AB - BACKGROUND: In a robust and consistent manner, sustained caloric restriction (CR) has been shown to retard the aging process in a variety of animal species. Nonhuman primate studies suggest that CR may have similar effects in longer-lived species. The CALERIE (Comprehensive Assessment of the Long-term Effects of Reducing Intake of Energy) research program is the first systematic investigation of CR in nonobese human beings. In the phase 2 study, it is hypothesized that 2 years of sustained CR, involving a 25% reduction of ad libitum energy intake, results in beneficial effects similar to those observed in animal studies. This article presents the design and implementation of this study. METHODS: The study is a multicenter, parallel-group, randomized controlled trial. A sample of 225 participants (22.0 <= body mass index [BMI] < 28.0 kg/m(2)) is being enrolled with 2:1 allocation to CR. RESULTS: An intensive dietary and behavioral intervention was developed to achieve 25% CR and sustain it over the 2 years. Adherence is monitored using a doubly labeled water technique. Primary outcomes are resting metabolic rate and core temperature, and are assessed at baseline and at 6-month intervals. Secondary outcomes address oxyradical formation, cardiovascular risk markers, insulin sensitivity and secretion, immune function, neuroendocrine function, quality of life and cognitive function. Biologic materials are stored in a central repository. CONCLUSIONS: An intricate protocol has been developed to conduct this study. Procedures have been implemented to safeguard the integrity of the data and the conclusions drawn. The results will provide insight into the detrimental changes associated with the human aging process and how CR mitigates these effects. PMID- 20923915 TI - Schizophrenia: a multisystem disease? PMID- 20923916 TI - The paradox of premature mortality in schizophrenia: new research questions. AB - The life expectancy of patients with schizophrenia is reduced by between 15 and 25 years. Those patients dying of natural causes die of the same diseases as in the general population. In 2009 the World Health Organization (WHO) identified underlying global risk factors for mortality in the general population. However, there is little evidence in the literature assessing their validity in those with schizophrenia. The WHO report on global health risks (2009) identifies hypertension, smoking, raised glucose, physical inactivity, overweight and obesity, and high cholesterol as the six leading global mortality risk factors. Currently, there are minimal data on the contribution to mortality that these risk factors make in schizophrenia, and their optimum management. Both short and long-term studies are needed to address these gaps. New research has raised important questions about risk balance with regards to ideal body mass, with some studies showing that being overweight is associated with lower all-cause mortality and lower suicide rates. Cardiorespiratory fitness is being recognized as a more powerful predictor of mortality than smoking, hypertension or diabetes in men. However, there are virtually no published data on assessment of fitness levels in schizophrenia. New studies have raised concerns about the quality of physical care for patients with schizophrenia, which is another important avenue of future research. A greater biological understanding of the relationship between these disorders and schizophrenia would inform clinical practice. Low birth weight has been associated with increased risk for schizophrenia, and it will be important to explore this risk factor for both physical and mental health outcomes. PMID- 20923917 TI - Mortality in schizophrenia: a measurable clinical endpoint. AB - Over the last five years, large data sets on mortality in schizophrenia have been published which have established mortality as a measurable clinical endpoint. Four issues need clarification: whether mortality rates are declining, what the causes of death are, the effects antipsychotic treatments have on mortality and whether these data inform as to how mortality may be reduced in the future. A PubMed search was carried out to identify relevant publications. The search strategy was conducted as a review focusing predominantly on data since 2006. A large number of retrospective epidemiological and prospective studies have been published on mortality rates and causation in schizophrenia, predominantly from 2006-2009. Data suggest that the mortality gap with the general population increased from the 1970s but may have peaked in the mid-1990s. The main causes of mortality are suicide, cancer and cardiovascular disease, with evidence that cancer mortality rates are similar to cardiovascular mortality rates. Mortality causation is dependent upon age of the cohort, length of follow up and type of study. Antipsychotic treatments reduce mortality when compared with no treatment and atypical antipsychotics do not appear to increase cardiovascular mortality and morbidity compared with conventionals; further research is required for any definitive conclusion. PMID- 20923918 TI - Mortality trends in the general population: the importance of cardiorespiratory fitness. AB - Cardiorespiratory fitness (CRF) is not only an objective measure of habitual physical activity, but also a useful diagnostic and prognostic health indicator for patients in clinical settings. Although compelling evidence has shown that CRF is a strong and independent predictor of all-cause and cardiovascular disease mortality, the importance of CRF is often overlooked from a clinical perspective compared with other risk factors such as hypertension, diabetes, smoking, or obesity. Several prospective studies indicate that CRF is at least as important as the traditional risk factors, and is often more strongly associated with mortality. In addition, previous studies report that CRF appears to attenuate the increased risk of death associated with obesity. Most individuals can improve their CRF through regular physical activity. Several biological mechanisms suggest that CRF improves insulin sensitivity, blood lipid profile, body composition, inflammation, and blood pressure. Based on the evidence, health professionals should encourage their patients to improve CRF through regular physical activity. PMID- 20923919 TI - Are there modifiable risk factors which will reduce the excess mortality in schizophrenia? AB - The 2009 World Health Organization report on global health risks identifies hypertension, smoking, raised glucose, physical inactivity, obesity and dyslipidaemia, in that order, as being the top six modifiable global mortality risk factors. Patients with schizophrenia have high levels of all these risk factors. There are a small number of studies showing that interventions can improve these, but prospective long-term studies are not available to show their impact on mortality. A number of studies are now supporting the view that patients with schizophrenia may be dying prematurely as they are not gaining access to or receiving the same medical care as the general population. The literature now suggests that low cardiorespiratory fitness and muscle strength are among the strongest predictors of all-cause mortality in the general population. Smoking is still one of the largest risk factors for premature all cause mortality. The literature supports the thesis that lifestyle intervention programmes addressing exercise, smoking cessation and compliance with medication are likely to have significant impact on mortality in schizophrenia. It will be important to ensure that all patients with schizophrenia have advocates to ensure appropriate treatment and avoid prejudice, and to establish fitness standards in schizophrenia. PMID- 20923920 TI - Cancer and schizophrenia: is there a paradox? AB - People with schizophrenia are more likely to die prematurely than the general population from both suicide and physical ill health. Published studies examining the incidence of cancer in schizophrenia patients report increased, reduced or similar incidence compared with the general population. Older studies tended to report lower incidence rates which fuelled speculation as to the biological and other mechanisms for this protective effect. Furthermore, mortality rates in patients with schizophrenia appear higher than expected. We undertook a non systematic review of published data to give an overview for these variable findings and illustrate methodological confounders by highlighting a systematic review of breast cancer studies. PMID- 20923921 TI - Inequalities in healthcare provision for people with severe mental illness. AB - There are many factors that contribute to the poor physical health of people with severe mental illness (SMI), including lifestyle factors and medication side effects. However, there is increasing evidence that disparities in healthcare provision contribute to poor physical health outcomes. These inequalities have been attributed to a combination of factors including systemic issues, such as the separation of mental health services from other medical services, healthcare provider issues including the pervasive stigma associated with mental illness, and consequences of mental illness and side effects of its treatment. A number of solutions have been proposed. To tackle systemic barriers to healthcare provision integrated care models could be employed including co-location of physical and mental health services or the use of case managers or other staff to undertake a co-ordination or liaison role between services. The health care sector could be targeted for programmes aimed at reducing the stigma of mental illness. The cognitive deficits and other consequences of SMI could be addressed through the provision of healthcare skills training to people with SMI or by the use of peer supporters. Population health and health promotion approaches could be developed and targeted at this population, by integrating health promotion activities across domains of interest. To date there have only been small-scale trials to evaluate these ideas suggesting that a range of models may have benefit. More work is needed to build the evidence base in this area. PMID- 20923922 TI - Do deficits in cardiac care influence high mortality rates in schizophrenia? A systematic review and pooled analysis. AB - We have previously documented inequalities in the quality of medical care provided to those with mental ill health but the implications for mortality are unclear. We aimed to test whether disparities in medical treatment of cardiovascular conditions, specifically receipt of medical procedures and receipt of prescribed medication, are linked with elevated rates of mortality in people with schizophrenia and severe mental illness. We undertook a systematic review of studies that examined medical procedures and a pooled analysis of prescribed medication in those with and without comorbid mental illness, focusing on those which recruited individuals with schizophrenia and measured mortality as an outcome. From 17 studies of treatment adequacy in cardiovascular conditions, eight examined cardiac procedures and nine examined adequacy of prescribed cardiac medication. Six of eight studies examining the adequacy of cardiac procedures found lower than average provision of medical care and two studies found no difference. Meta-analytic pooling of nine medication studies showed lower than average rates of prescribing evident for the following individual classes of medication; angiotensin converting enzyme inhibitors (n = 6, aOR = 0.779, 95% CI = 0.638-0.950, p = 0.0137), beta-blockers (n = 9, aOR = 0.844, 95% CI = 0.690-1.03, p = 0.1036) and statins (n = 5, aOR = 0.604, 95% CI = 0.408 0.89, p = 0.0117). No inequality was evident for aspirin (n = 7, aOR = 0.986, 95% CI = 0.7955-1.02, p = 0.382). Interestingly higher than expected prescribing was found for older non-statin cholesterol-lowering agents (n = 4, aOR = 1.55, 95% CI = 1.04-2.32, p = 0.0312). A search for outcomes in this sample revealed ten studies linking poor quality of care and possible effects on mortality in specialist settings. In half of the studies there was significantly higher mortality in those with mental ill health compared with controls but there was inadequate data to confirm a causative link. Nevertheless, indirect evidence supports the observation that deficits in quality of care are contributing to higher than expected mortality in those with severe mental illness (SMI) and schizophrenia. The quality of medical treatment provided to those with cardiac conditions and comorbid schizophrenia is often suboptimal and may be linked with avoidable excess mortality. Every effort should be made to deliver high-quality medical care to people with severe mental illness. PMID- 20923924 TI - A systematic review of hypothalamic-pituitary-adrenal axis function in schizophrenia: implications for mortality. AB - There is convincing evidence that environmental stress plays a significant role in modifying both mental and physical health. The biological mechanisms linking stress to ill health are not fully understood, but significant evidence points to a central role of the stress axes; the hypothalamic- pituitary-adrenal (HPA) axis and the sympathetic nervous system. Together these two systems link the brain and the body and are crucial in maintaining homeostasis as well as improving an organism's survival chances in the face of environmental challenge. There is evidence of altered HPA axis function in people with a range of mental disorders, and this may in part explain the poor physical health of people with psychotic, mood and anxiety disorders. This paper systematically reviews HPA axis function in people with schizophrenia and relates this to the pattern of physical health seen in this disease. In summary, the evidence suggests people with schizophrenia can experience both hyper- and hypo-function of the HPA axis. It is likely that this contributes to the pattern of poor physical health and premature mortality suffered by people with schizophrenia, in particular the high rates of cardiovascular and metabolic disturbance. PMID- 20923923 TI - Suicide and schizophrenia: a systematic review of rates and risk factors. AB - Risk assessment is a core skill in psychiatry. Risk prediction for suicide in schizophrenia is known to be complex. We undertook a systematic review of all original studies concerning suicide in schizophrenia published since 2004. We found 51 data-containing studies (from 1281 studies screened) that met our inclusion criteria, and ranked these by standardized quality criteria. Estimates of rates of suicide and risk factors associated with later suicide were identified, and the risk factors were grouped according to type and strength of association with suicide. Consensus on the lifetime risk of suicide was a rate of approximately 5%. Risk factors with a strong association with later suicide included being young, male, and with a high level of education. Illness-related risk factors were important predictors, with number of prior suicide attempts, depressive symptoms, active hallucinations and delusions, and the presence of insight all having a strong evidential basis. A family history of suicide, and comorbid substance misuse were also positively associated with later suicide. The only consistent protective factor for suicide was delivery of and adherence to effective treatment. Prevention of suicide in schizophrenia will rely on identifying those individuals at risk, and treating comorbid depression and substance misuse, as well as providing best available treatment for psychotic symptoms. PMID- 20923925 TI - Conventional, but not high-purity, dialysate-induced monocyte apoptosis is mediated by activation of PKC-delta and inflammatory factors release. AB - BACKGROUND: Use of conventional dialysate (CD) (powdered sodium bicarbonate dissolved manually with reverse osmosis water before dialysis) is common in Chinese haemodialysis (HD) centres. However, this preparation carries the risk of degradation and contamination, potentially negatively impacting host defense. Commercially available high-purity dialysate (HPD) may decrease inflammation and improve nutritional status in HD patients. However, whether HPD affects immune cells is unclear. The purpose of this study was to investigate the in vitro effect of these dialysates on apoptosis in U937 monocytes and its possible mechanism. METHODS: Following incubation with two different types of dialysate, U937 cell apoptosis was measured by flow cytometry. Cell morphological changes were observed by Hoechst 33258 fluorescence staining. The expression of protein kinase C-delta (PKC-delta) was assayed by RT-polymerase chain reaction and western blot. Cytokine levels in U937 cells after exposure to CD or HPD for an indicated time were assayed by commercial enzyme-linked immunosorbent assay. RESULTS: CD contained more bacteria (66 +/- 6 CFU/mL) than HPD (7 +/- 3 CFU/mL) while there was no difference in endotoxin levels. Compared with cells exposed to HPD and phosphate-buffered saline (PBS), U937 monocytes experienced more apoptosis when exposed to CD for 24 and 48 h, while there was no significant difference between HPD and PBS. Expressions of PKC-delta mRNA and protein in U937 cells were enhanced following exposure to CD for 24 and 48 h, with increased proteolytic cleavage of PKC-delta which could be inhibited by rottlerin, a specific inhibitor of PKC-delta. Moreover, the cultured supernatant in CD-exposed cells contained significantly higher levels of interleukin-6 (4.09 +/- 0.36 vs 2.73 +/- 0.38 pg/mL, P < 0.01, 24 h; 4.28 +/- 0.32 vs 2.83 +/- 0.32 pg/mL, P < 0.01, 48 h) and tumour necrosis factor alpha (3.45 +/- 0.79 vs 2.44 +/- 0.39 pg/mL, P < 0.05, 24 h; 4.60 +/- 0.57 vs 2.50 +/- 0.37 pg/mL, P < 0.01, 48 h) than those of HPD. CONCLUSION: CD, but not HPD, contained more bacterial contamination, increased monocyte apoptosis in a PKC-delta-dependent manner and induced more cell inflammation. These findings suggest that impurity of dialysis fluid may be an important determinant of the elevated inflammation seen in CD treated patients. PMID- 20923926 TI - ADAMTS13--marker of contractile phenotype of arterial smooth muscle cells lost in benign nephrosclerosis. AB - BACKGROUND: Hypertensive nephrosclerosis alone and in combination with other renal diseases is a leading cause of terminal renal insufficiency. Histologic lesions manifest as benign nephrosclerosis (bN) with arteriolar hyalinosis and later fibrosis. Procoagulant micromilieus have been implicated in fibrosis. Hyalinosis is considered to consist of plasma insudation possibly containing procoagulant factors like von Willebrand factor (VWF). Therefore, it is hypothesized that VWF cleaving protease ADAMTS13 (a disintegrin-like and metalloprotease with thrombospondin type-1 motif, 13) is normally expressed by arteriolar vascular smooth muscle cells (VSMCs) and diminished in bN and that this reduction contributes to fibrosis in bN. METHODS: ADAMTS13 expression was examined by immunohistochemistry and quantitative real-time polymerase chain reaction in VSMCs of various human organs. Fifty-four specimens with and seven without bN were immunostained for ADAMTS13, VWF, CD61 and VSMC differentiation markers in arteriolar walls. RESULTS: Expression of ADAMTS13 is confirmed in VSMCs. In bN, ADAMTS13 immunostaining of arterial VSMCs correlated inversely with fibrotic but not hyalinotic lesions. Smooth muscle myosin heavy chain showed an inverse correlation with hyalinotic, as opposed to fibrotic lesions of bN. Smoothelin showed an inverse correlation with both hyalinotic and fibrotic lesions of bN. VWF was absent in normal controls and hyalinotic lesions, but present exclusively in fibrotic lesions in 7/54 (13%) bN cases. CD61 was absent in all arteriolar walls. CONCLUSIONS: The present results establish ADAMTS13 as a novel marker of contractile VSMCs that is retained in early hyalinotic bN but partially lost later in fibrotic bN. Loss of ADAMTS13 and accumulation of VWF in fibrotic but not hyalinotic arteriolar walls could further propagate fibrosis in bN. PMID- 20923927 TI - Proto-dialytic cardiac function relates to intra-dialytic morbid events. AB - BACKGROUND: Intra-dialytic morbid events (IDME) such as intra-dialytic hypotension (IDH) and muscle cramps frequently complicate haemodialysis (HD). Cardiac dysfunction is highly prevalent in HD patients. We investigated the relationship between proto-dialytic (i.e. early intra-dialytic) cardiac function and IDME in HD patients. METHODS: Heart rate, beat-to-beat blood pressure (BP) and cardiac output were continuously measured during the first 30 min of dialysis treatment using the Task ForceTM Monitor. Total peripheral resistance index (TPRI) was calculated from cardiac index (CI) and BP. Univariate, multivariate and logistic regression analyses were employed to relate IDME to haemodynamic predictors; Kaplan-Meier method was employed for time-to-event analysis. RESULTS: Fourteen HD patients (age 67 +/- 15 years; 7 females) were studied. Dialysis treatment was complicated by IDH and muscle cramps in 4 and 8 out of 30 sessions, respectively. CI was higher in patients without IDME (2.6 +/- 0.5 L/min/m(2)) as compared to those with muscle cramps (2.0 +/- 0.3 L/min/m(2)) or IDH (1.8 +/- 0.2 L/min/m(2); all P < 0.05). CI and TPRI at baseline independently predicted IDME in a multivariate regression analysis (odds ratio: 0.043 per unit of CI, 95% confidence interval: 0.003-0.611; odds ratio: 1.124 per unit of TPRI, 95% confidence interval: 1.25-1.01). Patients were stratified by tertiles of CI. IDME occurred in the two lower tertiles, whereas patients in the upper tertile were event free (log-rank test, P < 0.002). CONCLUSIONS: Low CI and high TPRI in the first 30 min of HD are associated with an increased risk of IDME. PMID- 20923928 TI - Infants get five stars on iconic memory tests: a partial-report test of 6-month old infants' iconic memory capacity. PMID- 20923929 TI - Beyond the best interests of children: four views of the family and of foundational disagreements regarding pediatric decision making. AB - This paper presents four different understandings of the family and their concomitant views of the authority of the family in pediatric medical decision making. These different views are grounded in robustly developed, and conflicting, worldviews supported by disparate basic premises about the nature of morality. The traditional worldviews are often found within religious communities that embrace foundational metaphysical premises at odds with the commitments of the liberal account of the family dominant in the secular culture of the West. These disputes are substantial and ultimately irresolvable by sound rational argument because of the failure to share common foundational premises and rules of evidence. It is in light of these fundamental disagreements that there is a need to evaluate critically the claims and agenda advanced by the Convention on the Rights of the Child. PMID- 20923930 TI - Should the Confucian family-determination model be rejected? A case study. AB - This essay explores a tragic event that happened in China, which garnered much attention, the Li case: a young woman who was nine months pregnant and her baby died as a result of the failure to receive a medically necessary c-section due to the hospital having failed to secure her family's consent for the c-section. Differing from some critiques, this essay argues that the Li case should not be used to blame the Confucian family-determination model that has been applied in Chinese society for thousands of years. Based on summarizing the reasons supporting the model, this essay indicates that it is an integral part of the model that, in emergency or special cases, the physician must take medical action to save the patient, without the need to secure the consent of a family member. In order to prevent tragic cases like the Li case from happening, we recommend that relevant Chinese laws be further developed and specified and that, most importantly, Chinese physicians must cultivate the Confucian virtue of benevolence in their practice of taking care of patients in a virtuous way, along with patients' families. PMID- 20923931 TI - Odor identification and mortality in old age. AB - The association of olfactory dysfunction with mortality was examined in 1162 older persons without dementia or Parkinson's disease. They completed a standard 12-item test of odor identification and then were followed for a mean of 4.2 years (standard deviation [SD] = 2.6, range: 0-9) during which 321 individuals died (27.6%). The relation of olfactory score to risk of death was assessed in a series of proportional hazards models adjusted for age, sex, education, and other covariates. Olfactory scores ranged from 0 to 12 correct (mean = 9.0, SD = 2.2). In an initial analysis, risk of death decreased by about 6% for each additional odor correctly identified (hazard ratio = 0.94; 95% confidence interval: 0.90, 0.98). Thus, mortality risk was about 36% higher with a low score (6, 10th percentile) compared with a high score (11, 90th percentile). The association persisted in subsequent analyses that controlled for naming ability, disability, cerebrovascular disease, characteristic patterns of leisure activity, depressive symptoms, and apolipoprotein E genotype. The results indicate that difficulty identifying familiar odors in old age is associated with increased risk of death. PMID- 20923932 TI - Mechanisms of sperm-egg interactions: between sugars and broken bonds. AB - A model of the early events of mammalian fertilization has emerged during the past 30 years. However, studies during the past decade have used newly available mouse models to readdress these processes. Here, we will consider these new data in light of the existing model and point to areas of reconciliation and of controversy. PMID- 20923933 TI - Apolipoprotein E controls ATP-binding cassette transporters in the ischemic brain. AB - The adenosine triphosphate-binding cassette transporters ABCB1 and ABCC1 show coordinated changes in abundance at the luminal and abluminal membranes of ischemic cerebral capillaries that impede the brain access of pharmacological compounds. We found that apolipoprotein E (ApoE) was present on ischemic microvessels but not contralateral controls. ApoE signaled through ApoE receptor 2 (ApoER2), which was constitutively expressed on brain microvessels, to decrease c-Jun amino-terminal kinase 1 and 2 and c-Jun activities. ApoE regulated the postischemic abundance of ABCB1 and ABCC1, thereby controlling drug accumulation in the ischemic brain. Our data suggest that inhibition of ApoE signaling may enable improved delivery of drugs to the brain. PMID- 20923935 TI - A comparison of cephalometric measurements: a picture archiving and communication system versus the hand-tracing method--a preliminary study. AB - Traditionally, cephalometric analysis has been carried out using a hand-tracing manual method. In imaging, picture archiving and communication systems (PACS) are information management systems used for the capture and measurement of medical and dental radiographs. Although not customized for lateral cephalometry, this study aimed to evaluate the cephalometric measurements made on screen using PACS compared with the conventional hand-tracing method. Six angular and four liner parameters were measured on five radiographs of four females and one male with an age range of 14-20 years. Analysis was completed using the Wilcoxon rank-sum test. For the electronic method, SNB (P=0.04) and lower incisor angle (P=0.05) were the only parameters found to be significantly different between the two operators. There was no significant difference between operators 1 and 2 for the hand-tracing method for any measurement. All measurements were comparable between the two methods. This preliminary study would suggest that using PACS may be an acceptable method for obtaining cephalometric measurements for treatment planning; however, further evaluation is necessary with a larger sample size. PMID- 20923934 TI - Nonsynaptic communication through ATP release from volume-activated anion channels in axons. AB - The release of neuronal messengers outside synapses has broad biological implications, particularly with regard to communication between axons and glia. We identify a mechanism for nonsynaptic, nonvesicular release of adenosine triphosphate (ATP) from axons through volume-activated anion channels (VAACs) activated by microscopic axon swelling during action potential firing. We used a combination of single-photon imaging of ATP release, together with imaging for intrinsic optical signals, intracellular calcium ions (Ca(2+)), time-lapse video, and confocal microscopy, to investigate action potential-induced nonsynaptic release of this neurotransmitter. ATP release from cultured embryonic dorsal root ganglion axons persisted when bafilomycin or botulinum toxin was used to block vesicular release, whereas pharmacological inhibition of VAACs or prevention of action potential-induced axon swelling inhibited ATP release and disrupted activity-dependent signaling between axons and astrocytes. This nonvesicular, nonsynaptic communication could mediate various activity-dependent interactions between axons and nervous system cells in normal conditions, development, and disease. PMID- 20923936 TI - The masticatory system under varying functional load. Part 2: Effect of reduced masticatory load on the degree and distribution of mineralization in the rabbit mandible. AB - A reduction in mechanical loading of the mandible brought about by mastication of soft food is assumed to decrease the remodelling rate of bone, which, in turn, might increase the degree of bone mineralization. The effect of a reduction in masticatory functional load on the degree and distribution of mineralization of mandibular bone was investigated in male juvenile New Zealand White rabbits. The experimental animals (n=8) had been raised on a diet of soft pellets from 8 to 20 weeks of age, while the controls (n=8) had been fed pellets of normal hardness. The degree of mineralization of bone (DMB) was assessed at the attachment sites of various jaw muscles, the condylar head, and the alveolar process. Differences between groups and among sites were tested for statistical significance using a Student's t-test and one-way analysis of variance, respectively. The DMB did not differ significantly between the experimental and control animals at any of the sites assessed. However, in the rabbits that had been fed soft pellets, both cortical bone at the attachment sites of the temporalis and digastric muscles and cortical bone in the alveolar process had a significantly higher DMB than cortical bone at the attachment site of the masseter muscle, while there were no significant differences among these sites in the control animals. The results suggest that a moderate reduction in masticatory functional load does not significantly affect the remodelling rate and the DMB in areas of the mandible that are loaded during mastication but might induce a more heterogeneous mineral distribution. PMID- 20923937 TI - The masticatory system under varying functional load. Part 1: Structural adaptation of rabbit jaw muscles to reduced masticatory load. AB - Skeletal muscle fibres can change their myosin heavy-chain (MyHC) isoform and cross-sectional area, which determine their contraction velocity and maximum force generation, respectively, to adapt to varying functional loads. In general, reduced muscle activity induces transition towards faster fibres and a decrease in fibre cross-sectional area. In order to investigate the effect of a reduction in masticatory load on three functionally different jaw muscles, the MyHC composition and the corresponding cross-sectional area of fibres were determined in the superficial masseter, superficial temporalis, and digastric muscles of male juvenile New Zealand White rabbits that had been raised on a soft diet (n=8) from 8 to 20 weeks of age and in those of normal diet controls (n=8). Differences between groups were tested for statistical significance using a Mann-Whitney rank sum test. The proportion and cross-sectional area of fibres co-expressing MyHC-I and MyHC-cardiac alpha were significantly smaller in the masseter muscles of the animals that had been fed soft food than in those of the controls. In contrast, the proportions and cross-sectional areas of the various fibre types in the temporalis and digastric muscles did not differ significantly between the groups. The results suggest that reducing the masticatory load during development affects the contraction velocity and maximum force generation of the jaw-closing muscles that are primarily responsible for force generation during chewing. These muscles adapt structurally to the reduced functional load with changes in the MyHC composition and cross-sectional area mainly within their slow fibre compartment. PMID- 20923939 TI - Acupuncture for a patient with whiplash-type injury. AB - A 69 year-old woman presented in the surgery because of a whiplash-type injury. Because of progressive headache and dizziness since the accident, and because she had developed rhinitis and intermittent flashes of the left visual field, she was admitted to the neurological department on suspicion of subdural haematoma and possible fracture of the skull. Neurological examination and a CT scan were normal and she was discharged. Because of persisting headaches, and dizziness, her own general practitioner decided to use acupuncture treatment. Acupuncture was given at points GB20 GB21 and SI16 bilaterally and directly over the site in the forehead, where she fell. After 6 weeks treatment, the dizziness disappeared, and after two additional treatments the rhinitis and headache disappeared. At follow-up 6 months after cessation of treatment, the patient had only intermittent dizziness, with no headaches, visual disturbances or rhinitis. PMID- 20923938 TI - The Arabidopsis thylakoid protein PAM68 is required for efficient D1 biogenesis and photosystem II assembly. AB - Photosystem II (PSII) is a multiprotein complex that functions as a light-driven water:plastoquinone oxidoreductase in photosynthesis. Assembly of PSII proceeds through a number of distinct intermediate states and requires auxiliary proteins. The photosynthesis affected mutant 68 (pam68) of Arabidopsis thaliana displays drastically altered chlorophyll fluorescence and abnormally low levels of the PSII core subunits D1, D2, CP43, and CP47. We show that these phenotypes result from a specific decrease in the stability and maturation of D1. This is associated with a marked increase in the synthesis of RC (the PSII reaction center-like assembly complex) at the expense of PSII dimers and supercomplexes. PAM68 is a conserved integral membrane protein found in cyanobacterial and eukaryotic thylakoids and interacts in split-ubiquitin assays with several PSII core proteins and known PSII assembly factors. Biochemical analyses of thylakoids from Arabidopsis and Synechocystis sp PCC 6803 suggest that, during PSII assembly, PAM68 proteins associate with an early intermediate complex that might contain D1 and the assembly factor LPA1. Inactivation of cyanobacterial PAM68 destabilizes RC but does not affect larger PSII assembly complexes. Our data imply that PAM68 proteins promote early steps in PSII biogenesis in cyanobacteria and plants, but their inactivation is differently compensated for in the two classes of organisms. PMID- 20923940 TI - Ear acupoint detection before and after hysteroscopy: is it possible to clarify the representation of the uterus on the outer ear? AB - BACKGROUND: In the auricular maps introduced over the past 50 years by the French and Chinese schools, most organs and systems overlap consistently. One exception is the reproductive system, which shows a markedly different somatotopic representation-for example, for the uterus and the ovary. OBJECTIVE: To identify the distribution of points with increased tenderness to pressure or with reduced electrical resistance, on the outer ear of a group of women undergoing hysteroscopy. METHODS: For diagnostic purposes the auricles of 78 women were examined before and after hysteroscopy using a pain-pressure test and electrical skin resistance test. The points identified were transcribed onto a graphic system called Sectogram. Spatial cluster analysis was used to identify the statistically significant clusters of sectors with a higher concentration of points appearing after hysteroscopy. RESULTS: The points identified after hysteroscopy tend to be concentrated in specific areas not previously recognised and which only partially overlap with the French and Chinese representation of the uterus. CONCLUSION: When auricular acupuncture is applied to reduce discomfort during hysteroscopy, particular attention must be paid when choosing the points/areas to be stimulated, which are not only those indicated in the Chinese or French maps. PMID- 20923941 TI - Cortical activation by Yamamoto new scalp acupuncture in the treatment of patients with a stroke: a sham-controlled study using functional MRI. PMID- 20923942 TI - Association between cancer and immunosuppressive therapy--analysis of selected studies in pemphigus and pemphigoid. AB - OBJECTIVE: To determine whether there is an association between the use of immunosuppressive agents (ISAs) and cancer in patients with pemphigus and pemphigoid-rare, potentially fatal diseases of the skin and mucous membranes, often requiring long-term use of ISAs. DATA SOURCE: Literature was accessed through PubMed (all years available), using the search terms cancer, immunosuppressive agents, pemphigoid, and pemphigus. STUDY SELECTION AND DATA EXTRACTION: A retrospective review of the literature was conducted. Inclusion criteria for studies were: (1) English language, (2) diagnosis of pemphigus and/or pemphigoid based on histology and immunopathology, (3) more than 10 patients evaluated, (4) investigators had a high index of suspicion of cancer and patients were monitored for it, (5) follow-up information was provided for at least 1 year after initiation of therapy, and (6) absence of diagnosis of cancer before initiation of an ISA. Case reports were not included in the analysis. DATA SYNTHESIS: A total of 929 patients diagnosed with either pemphigus or pemphigoid in 17 studies were identified. Patients were divided into 2 groups. Group A comprised patients treated with azathioprine, cyclophosphamide, cyclosporine, or mycophenolate mofetil in combination with prednisone. In Group A, 22 cases of cancer were reported in 21 of the 218 patients (9.6%). Group B comprised patients treated with systemic corticosteroids only. In this group, cancer was reported in 11 of the 711 patients (1.5%). In this study there was no control group (untreated patients) and the sample sizes were small. CONCLUSIONS: Preliminary data suggest a possible association between the use of azathioprine, cyclophosphamide, and cyclosporine and increased susceptibility to cancer in patients with pemphigus and pemphigoid. PMID- 20923943 TI - The mandatory residency dilemma: parallels to historical transitions in pharmacy education. AB - OBJECTIVE: To review recent literature regarding mandatory residencies in the perspective of the historical entry-level degree debate. DATA SOURCES: Articles were identified through searches of MEDLINE/PubMed, national pharmacy association Web sites, and a review of the references of related literature. STUDY SELECTION AND DATA EXTRACTION: Several studies, commentaries, and reviews are examined to discuss viewpoints from both the entry-level degree and mandatory residency debates. Similarities were observed between the 2 debates in regard to objectives and rationale for change, educational issues, pharmaceutical care issues, and economic issues. DATA SYNTHESIS: Fewer than 10 years ago, after many years of debate, colleges of pharmacy made the transition to offering the PharmD degree as the sole entry-level degree for licensure as a pharmacist. Similar debates have taken place over the past several years and continue to take place regarding the necessity for residency training. One key 2006 document by the American College of Clinical Pharmacy calls for mandatory residency training for entry into pharmacy practice by 2020. CONCLUSIONS: In parallel with the entry-level degree debate, consensus has yet to be reached among pharmacists and pharmacy organizations, but several have shown support for mandatory residency training for all pharmacists involved in direct patient care. Many questions have yet to be answered regarding the timeline, economics, and feasibility of such a mandate. PMID- 20923944 TI - Education...A must in all levels of pharmacy practice. AB - Public perception of a profession is extremely important, but even more vital is the actual worth the profession provides to those who partake of its services. As pharmacy recreates itself as a consultative profession, many changes are occurring in the college of pharmacy students' education. The onset of the Introductory Pharmacy Practice Experience (IPPE), the continued rotations in the Advanced Pharmacy Practice Experience (APPE), and the proposal to have mandatory residencies occurring by 2020 show the steps that pharmacy will take to move forward. But pharmacy continues to miss the first rung of the ladder as the profession climbs to its future success by not addressing the mandatory education of the primary workforce in day-to-day activities: that of standardized education and training of pharmacy technicians. While IPPE, APPE, and residencies will strengthen the pharmacy "dwelling," its foundation does not have solid ground. A deadline needs to be established for mandatory education, training, and certification for all technicians entering the profession today and, only after achieving these goals, should the pharmacy technicians be licensed to practice. With even more forethought, pharmacy might require that potential college of pharmacy students, as well as those not fortunate enough to be admitted to a college of pharmacy, become pharmacy technicians first. Only then can the pharmacy profession conquer the top rung of the ladder in a strong, upright fashion. PMID- 20923945 TI - Low-molecular-weight heparin overdose: management by observation. AB - OBJECTIVE: To describe 3 episodes of low-molecular-weight heparin (LMWH) overdose in 2 patients and discuss the clinical presentations, outcomes, and therapeutic options. CASE SUMMARIES: The first patient, a 35-year-old female, presented after an intentional overdose of 72,000 units of dalteparin. The peak measured anti-Xa activity was 6.2 U/mL at 7.5 hours postinjection. No interventions were performed and there were no bleeding complications. The patient presented 20 days later following another overdose of 72,000 units. Anti-Xa activity was 4.5 U/mL 2 hours postinjection. No treatment was given and the patient was discharged with plans for follow-up the next day. There was no evidence of bleeding complications on follow-up. The second patient, a 29-year-old male, presented after an intentional overdose of 480 mg of enoxaparin. The anti-Xa activity was 1.9 U/mL measured 2 hours postinjection. The patient was observed without intervention. There were no bleeding complications. DISCUSSION: To our knowledge, there is only one previous report of an LMWH overdose in the literature, an iatrogenic overdose in an infant treated with protamine. In our 3 presented episodes of LMWH overdose, no therapeutic interventions were performed and there were no bleeding complications. Review of the literature regarding the efficacy of protamine and recombinant factor VIIa for reversal of LMWH coagulopathy revealed that protamine is only partially effective and recombinant factor VIIa is effective in in vitro studies and case reports. CONCLUSIONS: In cases of LMWH overdose, observation seems to be appropriate in the absence of clinically significant bleeding. Prolonged monitoring may be necessary for patients with renal failure. Use of protamine or recombinant factor VIIa is not supported by this case series in patients without significant bleeding. There is a lack of data regarding how to treat patients with significant bleeding. PMID- 20923946 TI - Potential risk of medication discrepancies and reconciliation errors at admission and discharge from an inpatient medical service. AB - BACKGROUND: Medication discrepancies, defined as unexplained variations among drug regimens at care transitions, are common. Some are unintended and cause reconciliation errors that are potentially detrimental for patients. OBJECTIVE: To determine the prevalence of medication discrepancies and reconciliation errors at admission and discharge in hospitalized patients and explore risk factors for reconciliation errors and their potential clinical impact. METHODS: An observational prospective study was conducted at a general teaching hospital. Patients who were admitted to the internal medicine service and were receiving chronic preadmission treatment were included in the study. Preadmission treatment was compared with the treatment prescribed on admission (first 48 hours) and at hospital discharge, and discrepancies and reconciliation errors were identified. The primary endpoint was the presence of reconciliation errors at admission and/or discharge. Potential risk factors (patient-, medication-, and system related) for reconciliation errors were analyzed using a multivariate logistic regression model. RESULTS: Of the 120 patients enrolled in the study between April and August 2009, 109 (90.8%) showed 513 discrepancies. The prevalence of patients with reconciliation errors was 20.8% (95% CI 13.6 to 28.1). Intended medication discrepancies were more frequent at admission (96.6%) than at discharge (75.5%), while reconciliation errors were more frequent at discharge (24.5%) than at admission (3.4%). The prevalence ratio (admission vs discharge) was 2.4 (95% CI 1.9 to 3.0) for discrepancies and 0.65 (95% CI 0.32 to 1.32) for reconciliation errors. The logistic regression analysis revealed an association between the number of discrepancies at admission (OR 1.21; 95% CI 1.01 to 1.44) and age (OR 1.05; 95% CI 0.99 to 1.10) and an increased risk of reconciliation errors. CONCLUSIONS: Medication reconciliation strategies should focus primarily on avoiding errors at discharge. Since medication discrepancies at admission may predispose patients to reconciliation errors, early detection of such discrepancies would logically reduce the risk of reconciliation errors. Medication reconciliation programs must implement a process for gathering accurate preadmission drug histories and must submit this information to a critical assessment of patients' needs. PMID- 20923947 TI - Treatment of civilian and combat-related posttraumatic stress disorder with topiramate. AB - OBJECTIVE: To evaluate the use of topiramate for the treatment of posttraumatic stress disorder (PTSD). DATA SOURCES: Ovid MEDLINE (1950 to June week 4, 2010), International Pharmaceutical Abstracts (1970 to May 2010), ISI Web of Science (1945 to July 3, 2010), and Iowa Drug Information Service (searched July 6, 2010) were searched using the terms posttraumatic stress disorder and topiramate. Guidelines and other sources were identified from bibliography searches. STUDY SELECTION AND DATA EXTRACTION: All English-language human studies and case reports that evaluated the use of topiramate for treatment of PTSD were evaluated. DATA SYNTHESIS: One case report, 1 case series, 2 open-label trials, and 1 placebo-controlled trial that used topiramate (monotherapy or adjunct) to treat civilian PTSD were identified and evaluated. The case report and case series reported subjective reduction of symptoms, and the open-label trials reported a significant reduction in PTSD Checklist-Civilian score. The placebo controlled trial found no significant difference in Clinician-Administered PTSD Scale (CAPS) score. One open-label trial and 2 placebo-controlled trials that used topiramate in combat-related PTSD were identified and evaluated. The open label trial reported a significant reduction in CAPS score, and 1 placebo controlled trial reported a statistically significant difference in CAPS score. However, the other placebo-controlled trial found no significant differences. In some of the trials evaluated, the clinical significance of outcomes reported is difficult to determine. Adverse effects were reported throughout the trials but generally were not considered serious. CONCLUSIONS: Based on the limited evidence available, topiramate is a possible alternative or adjunct option for patients with PTSD that is refractory to standard treatments. PMID- 20923948 TI - Residency requirement for pharmacists providing direct patient care. AB - A residency requirement has been proposed as a prerequisite for all pharmacists providing direct patient care. This editorial explores the basis for requiring a residency, direct patient care offered by pharmacists with or without a residency, needs to increase interprofessional team-based health care, importance of distinguishing levels of pharmacy practice, role of pharmacy technicians, availability of residency positions, and future of pharmacy residencies. All PharmD graduates should be able to provide a certain level of direct patient care, including medication therapy management services, without completing a residency, and residency programs should be offered for complex levels of direct patient care in all practice settings. PMID- 20923949 TI - Exposure to in utero lipopolysaccharide induces inflammation in the fetal ovine skin. AB - Inflammation is a defensive process by which the body responds to both localized and systemic tissue damage by the induction of innate and adaptive immunity. Literature from human and animal studies links inappropriate in utero inflammation to preterm parturition and fetal injury. The pathways by which such inflammation may cause labor, however, are not fully understood. Any proinflammatory agonist in the amniotic fluid will contact the fetal skin, in its entirety, but a potential role of the fetal skin in the pathways to labor have not previously been explored. We hypothesized that the fetal skin would respond robustly to the presence of intra-amniotic lipopolysaccharide (LPS) in our ovine model of in utero inflammation. In vitro and in utero exposure of fetal ovine keratinocytes or fetal skin to Escherichia coli LPS reliably induced significant increases in interleukin 1beta (IL-1beta), IL-6, tumor necrosis factor alpha (TNF alpha), and IL-8 expression. We demonstrate that, in utero, this expression requires direct exposure with LPS suggesting that the inflammation is triggered directly in the skin itself, rather than as a secondary response to a systemic stimuli and that inflammation involves Toll-like receptor (TLR) regulation and neutrophil chemotaxis in concordance with an acute inflammatory reaction. We show that this response involves multiple inflammatory mediators, TLR regulation, and localized inflammatory cell influx characteristic of an acute inflammatory reaction. These novel data strongly suggests that the fetal skin acts as an important mediator of the fetal inflammatory response and as such may contribute to preterm birth. PMID- 20923950 TI - Generalized hyperalgesia in women with endometriosis and its resolution following a successful surgery. AB - Although pains of various kinds top the list of complaints from women with endometriosis and are the most debilitating of the disease, little is known about the mechanism/mechanisms of endometriosis-associated pains. To test the hypothesis that women with endometriosis have generalized hyperalgesia which may be alleviated by a successful surgery, we recruited 100 patients with surgically and histologically confirmed endometriosis and 70 women without, and tested their responses to pain stimulations. Before the surgery, all patients rated their dysmenorrhea severity by Visual Analog scale (VAS) and went through an ischemic pain test (IPT) and an electrical pain test (EPT). The controls were also administrated with IPT/EPT. Three and 6 months after surgery, all patients were administrated with IPT/EPT and rated their severity of dysmenorrhea. We found that patients with endometriosis had significantly higher IPT VAS scores and lower EPT pain threshold than controls, but after surgery their IPT scores and EPT pain threshold were significantly and progressively improved, along with their dysmenorrhea severity. Thus, we conclude that women with endometriosis have generalized hyperalgesia, which was alleviated by surgery. Consequently, central sensitization may be a possible mechanism underlying various forms of pain associated with endometriosis, and its recognition should have important implications for the development of novel therapeutics and better clinical management of endometriosis. PMID- 20923951 TI - Is Kawasaki disease incidence rising in Chandigarh, North India? AB - OBJECTIVE: To estimate incidence of Kawasaki disease (KD) over time among children in the city of Chandigarh, North India. PATIENTS AND METHODS: We analysed records of all children with KD below 15 years of age at the Pediatric Allergy Immunology Unit, Advanced Pediatrics Centre, Post Graduate Institute of Medical Education and Research, Chandigarh, from January 1994 to December 2008. Diagnosis and treatment of KD were based on American Heart Association criteria. Among these cases, children residing in Chandigarh were identified. Yearly incidence was calculated and compared from 1994 to 2008. RESULTS: During this period, 196 children were diagnosed as KD. Of these, 80 (40.8%; 48 boys, 32 girls) resided in Chandigarh. Four among these had coronary artery abnormalities (CAA) on echocardiography, while two had mitral regurgitation. Comparison of yearly data revealed increasing incidence of disease from 0.51 cases in 1994 to 4.54 cases per 100,000 children below 15 years of age in 2007. Majority (93.7%) of cases occurred in children <=10 years of age with the highest incidence reported in the seventh year of life. Monthly distribution of disease showed two peaks with a maximum number of cases presenting in October followed by a second peak in May with a nadir in the month of February. CONCLUSION: Increasing incidence of KD in Chandigarh could be due to increasing clinical recognition as a result of greater awareness among paediatricians in the city, or may represent an actual increase in numbers. Striking differences from KD series reported from other countries include the older median age of our patients, low rate of CAA and a different bimodal seasonality, which may be epidemiologic clues to the nature of this vasculitis. PMID- 20923952 TI - Simultaneous quantification of apolipoprotein A-I and apolipoprotein B by liquid chromatography-multiple- reaction-monitoring mass spectrometry. AB - BACKGROUND: If liquid-chromatography-multiple-reaction-monitoring mass spectrometry (LC-MRM/MS) could be used in the large-scale preclinical verification of putative biomarkers, it would obviate the need for the development of expensive immunoassays. In addition, the translation of novel biomarkers to clinical use would be accelerated if the assays used in preclinical studies were the same as those used in the clinical laboratory. To validate this approach, we developed a multiplexed assay for the quantification of 2 clinically well-known biomarkers in human plasma, apolipoprotein A-I and apolipoprotein B (apoA-I and apoB). METHODS: We used PeptideAtlas to identify candidate peptides. Human samples were denatured with urea or trifluoroethanol, reduced and alkylated, and digested with trypsin. We compared reversed-phase chromatographic separation of peptides with normal flow and microflow, and we normalized endogenous peptide peak areas to internal standard peptides. We evaluated different methods of calibration and compared the final method with a nephelometric immunoassay. RESULTS: We developed a final method using trifluoroethanol denaturation, 21-h digestion, normal flow chromatography electrospray ionization, and calibration with a single normal human plasma sample. For samples injected in duplicate, the method had intraassay CVs <6% and interassay CVs <12% for both proteins, and compared well with immunoassay (n = 47; Deming regression, LC-MRM/MS = 1.17 * immunoassay - 36.6; S(x|y) = 10.3 for apoA-I and LC-MRM/MS = 1.21 * immunoassay + 7.0; S(x|y) = 7.9 for apoB). CONCLUSIONS: Multiplexed quantification of proteins in human plasma/serum by LC MRM/MS is possible and compares well with clinically useful immunoassays. The potential application of single-point calibration to large clinical studies could simplify efforts to reduce day-to-day digestion variability. PMID- 20923953 TI - Characterization of the new serum protein reference material ERM-DA470k/IFCC: value assignment by immunoassay. AB - BACKGROUND: The availability of a suitable matrix reference material is essential for standardization of the immunoassays used to measure serum proteins. The earlier serum protein reference material ERM-DA470 (previously called CRM470), certified in 1993, has led to a high degree of harmonization of the measurement results. A new serum protein material has now been prepared and its suitability in term of homogeneity and stability has been verified; after characterization, the material has been certified as ERM-DA470k/IFCC. METHODS: We characterized the candidate reference material for 14 proteins by applying a protocol that is considered to be a reference measurement procedure, by use of optimized immunoassays. ERM-DA470 was used as a calibrant. RESULTS: For 12 proteins [alpha(2) macroglobulin (A2M), alpha(1) acid glycoprotein (orosomucoid, AAG), alpha(1) antitrypsin (alpha(1)-protease inhibitor, AAT), albumin (ALB), complement 3c (C3c), complement 4 (C4), haptoglobin (HPT), IgA, IgG, IgM, transferrin (TRF), and transthyretin (TTR)], the results allowed assignment of certified values in ERM-DA470k/IFCC. For CRP, we observed a bias between the lyophilized and liquid frozen materials, and for CER, the distribution of values was too broad. Therefore, these 2 proteins were not certified in the ERM DA470k/IFCC. Different value transfer procedures were tested (open and closed procedures) and found to provide equivalent results. CONCLUSIONS: A new serum protein reference material has been produced, and values have been successfully assigned for 12 proteins. PMID- 20923954 TI - Use of total lymphocyte count to predict absolute CD4 count in HIV-seropositive cases. AB - We conducted an observational study to assess the use of total lymphocyte counts (TLC) alone and along with hemoglobin (Hb) as a predictor of CD4 count. A total of 103 antiretroviral therapy (ART)-naive HIV-1-infected patients were enrolled and divided in 2 groups (with CD4 count <200 cells/mm(3) and CD4 count >=200 cells/mm(3)). The TLC and Hb were performed by automatic full digital cell counter. CD4 count was determined by flow cytometry. Among the World Health Organization (WHO) clinical stages 2 and 3, in the cases with CD4 count <200 cells/mm(3), 70.4% cases had TLC <=1200 cells/mm( 3), whereas 63% cases had TLC <=1200 cells/mm(3) + Hb <=12 g/dL. In the cases with CD4 count >200 cells/mm(3), 2% cases had TLC <=1200 cells/mm(3), whereas adding Hb <=12 g/dL with TLC <=1200 cells/mm(3), none of the cases would require initiation of ART. TLC + Hb can be used to treat all HIV-infected patients with WHO stages 2 and 3 who have a TLC <1200 cells/mm(3) + Hb <=12 g/dL and to limit CD4 counts to patients who are symptomatic but have TLC + Hb values other than TLC <1200 cells/mm(3) + Hb <=12 g/dL. PMID- 20923955 TI - Nevirapine-associated toxicity in clinical practice in Buenos Aires, Argentina. AB - OBJECTIVES: to determine the incidence and risk factors for nevirapine (NVP) associated toxicity in a cohort of HIV-infected people in Buenos Aires, Argentina. DESIGN: retrospective study. METHODS: HIV-infected adults who received NVP-based highly active antiretroviral therapy (HAART) at least for 2 weeks between May 1997 and March 2008 were included in this study. We analyzed patients' age, gender, HIV transmission route, HIV disease stage, pregnancy, alcohol intake, adverse events, coinfection with hepatitis B or C virus, time until toxicity, and withdrawal rates. RESULTS: a total of 1110 patients (631 men) were included. Rash was the most frequently observed adverse event; it was more frequent in women. The incidence of severe rash and hepatotoxicity was similar in women and men. Female sex was the only variable significantly associated with mild-to-moderate rash. High CD4 count, pregnancy, and chronic hepatitis were not associated with NVP-related toxicity. An undetectable viral load at the time of starting NVP treatment resulted in a lower risk of NVP-related rash. PMID- 20923956 TI - Outcomes of antiretroviral treatment: a comparison between hospitals and health centers in Ethiopia. AB - OBJECTIVE: the objective of this study was to compare the outcomes of antiretroviral therapy (ART) between hospital and health center levels in Ethiopia. METHODS: medical records of 1709 ART patients followed for 24 months at 2 hospitals and 3 health centers in the Oromia region of Ethiopia were reviewed. Noted outcomes of ART were currently alive and on treatment; lost to follow-up (LTFU); transferred out (TO); and died (D). RESULTS: of 1709 HIV-positive patients started on ART between September 2006 and February 2007, 1044 (61%) remained alive and were on treatment after 24-month follow-up. In all, 835 (57%) of ART patients at hospitals and 209 (83%) at health centers were retained in the program. Of those who were alive and receiving ART, 79% of patients at health centers and 72% at hospitals were clinically or immunologically improving. In addition, 331 (23%) patients at hospitals were LFTU as compared to 24 (10%) of patients at health centers (relative risk [RR] at 95% confidence interval [CI]: .358 [.231-.555]). While 11% was the mortality rate at hospitals, 5% of patients at health centers also died (RR at 95% CI: .360 [.192-.673]). CONCLUSION: antiretroviral therapy at health centers was associated with more favorable outcomes than at hospitals. PMID- 20923957 TI - Tenofovir-associated severe bone pain: I cannot walk! AB - Two adult patients living with AIDS presented with severe bone pain associated with tenofovir (TDF) use. Both were unable to walk without assistance and were severely restricted in their movement due to the bone pain. Both had mild renal impairment, Fanconi syndrome, and bone mineral density (BMD) loss. Bone pain and inability to walk were reversible with the cessation of TDF and supplementation with Vitamin D(3), calcium, and phosphate. These cases appear to be examples of the severity of BMD loss associated with TDF use and suggest not only attention to renal function with TDF use, but also monitoring of alkaline phosphatase (bone fraction) and plasma phosphorus as indicators of BMD loss. PMID- 20923958 TI - Exenatide does not evoke pancreatitis and attenuates chemically induced pancreatitis in normal and diabetic rodents. AB - The risk of developing pancreatitis is elevated in type 2 diabetes and obesity. Cases of pancreatitis have been reported in type 2 diabetes patients treated with GLP-1 (GLP-1R) receptor agonists. To examine whether the GLP-1R agonist exenatide potentially induces or modulates pancreatitis, the effect of exenatide was evaluated in normal or diabetic rodents. Normal and diabetic rats received a single exenatide dose (0.072, 0.24, and 0.72 nmol/kg) or vehicle. Diabetic ob/ob or HF-STZ mice were infused with exenatide (1.2 and 7.2 nmol.kg(-1).day(-1)) or vehicle for 4 wk. Post-exenatide treatment, pancreatitis was induced with caerulein (CRN) or sodium taurocholate (ST), and changes in plasma amylase and lipase were measured. In ob/ob mice, plasma cytokines (IL-1beta, IL-2, IL-6, MCP 1, IFNgamma, and TNFalpha) and pancreatitis-associated genes were assessed. Pancreata were weighed and examined histologically. Exenatide treatment alone did not modify plasma amylase or lipase in any models tested. Exenatide attenuated CRN-induced release of amylase and lipase in normal rats and ob/ob mice but did not modify the response to ST infusion. Plasma cytokines and pancreatic weight were unaffected by exenatide. Exenatide upregulated Reg3b but not Il6, Ccl2, Nfkb1, or Vamp8 expression. Histological analysis revealed that the highest doses of exenatide decreased CRN- or ST-induced acute inflammation, vacuolation, and acinar single cell necrosis in mice and rats, respectively. Ductal cell proliferation rates were low and similar across all groups of ob/ob mice. In conclusion, exenatide did not modify plasma amylase and lipase concentrations in rodents without pancreatitis and improved chemically induced pancreatitis in normal and diabetic rodents. PMID- 20923959 TI - GLUT4 in murine bone growth: from uptake and translocation to proliferation and differentiation. AB - Skeletal growth, taking place in the cartilaginous growth plates of long bones, consumes high levels of glucose for both metabolic and anabolic purposes. We previously showed that Glut4 is present in growing bone and is decreased in diabetes. In the present study, we examined the hypothesis that in bone, GLUT4 gene expression and function are regulated via the IGF-I receptor (IGF-IR) and that Glut4 plays an important role in bone growth. Insulin and IGF-I actions on skeletal growth and glucose uptake were determined using mandibular condyle (MC) organ cultures and MC-derived primary cell cultures (MCDC). Chondrogenesis was determined by following proliferation and differentiation activities using immunohistochemical (IHC) analysis of proliferating cell nuclear antigen and type II collagen expression, respectively. Overall condylar growth was assessed morphometrically. GLUT4 mRNA and protein levels were determined using in situ hybridization and IHC, respectively. Glut4 translocation to the cell membrane was assessed using confocal microscopy analysis of GFP-Glut4 fusion-transfected cells and immunogold and electron microscopy on MC sections; glucose uptake was assayed by 2-deoxyglucose (2-DOG) uptake. Both IGF-I and insulin-stimulated glucose uptake in MCDC, with IGF-I being tenfold more potent than insulin. Blockage of IGF-IR abrogated both IGF-I- and insulin-induced chondrogenesis and glucose metabolism. IGF-I, but not insulin, induced Glut4 translocation to the plasma membrane. Additionally, insulin induced both GLUT4 and IGF-IR gene expression and improved condylar growth in insulin receptor knockout mice-derived MC. Moreover, silencing of GLUT4 gene in MCDC culture abolished both IGF-I-induced glucose uptake and chondrocytic proliferation and differentiation. In growing bone, the IGF-IR pathway stimulates Glut4 translocation and enhances glucose uptake. Moreover, intact Glut4 cellular levels and translocation machinery are essential for early skeletal growth. PMID- 20923961 TI - Generalized impairment of vasodilator reactivity during hyperinsulinemia in patients with obesity-related metabolic syndrome. AB - Defective insulin-dependent vasodilation might contribute importantly to metabolic and vascular abnormalities of the metabolic syndrome (MetS). However, despite extensive investigation, the precise mechanisms involved in insulin's vasoactive effects have not been fully elucidated. Therefore, this study sought to better characterize insulin's physiological actions on vascular reactivity and their potential derangement in the MetS. Forearm blood flow responses to graded doses of acetylcholine, sodium nitroprusside, and verapamil were assessed by strain-gauge plethysmography in patients with obesity-related MetS (n = 20) and in matched controls (n = 18) before and after intra-arterial infusion of insulin (0.2 mU.kg(-1).min(-1)). Possible involvement of increased oxidative stress in the impaired insulin-stimulated vasodilator responsiveness of patients with MetS (n = 12) was also investigated using vitamin C (25 mg/min). In control subjects, significant potentiation of the vasodilator responses to acetylcholine, nitroprusside, and verapamil was observed after insulin infusion (all P < 0.05). However, no significant change in vasodilator reactivity to either of these drugs was observed following hyperinsulinemia in patients with MetS (all P > 0.05). Interestingly, administration of vitamin C to patients with MetS during hyperinsulinemia significantly enhanced the vasodilator responsiveness to acetylcholine, nitroprusside, and verapamil (all P < 0.05 vs. hyperinsulinemia alone). In conclusion, insulin exerts a generalized facilitatory action on vasodilator reactivity, and this effect is impaired in patients with MetS likely because of increased oxidative stress. Given the importance of vasodilator reactivity in affecting glucose disposal and vascular homeostasis, this defect may then contribute to the development of metabolic and vascular complications in insulin-resistant states. PMID- 20923960 TI - Effects of oral and intravenous fat load on blood pressure, endothelial function, sympathetic activity, and oxidative stress in obese healthy subjects. AB - We compared the effects of high and low oral and intravenous (iv) fat load on blood pressure (BP), endothelial function, autonomic nervous system, and oxidative stress in obese healthy subjects. Thirteen obese subjects randomly received five 8-h infusions of iv saline, 20 (32 g, low iv fat) or 40 ml/h intralipid (64 g, high iv fat), and oral fat load at 32 (low oral) or 64 g (high oral). Systolic BP increased by 14 +/- 10 (P = 0.007) and 12 +/- 9 mmHg (P = 0.007) after low and high iv lipid infusions and by 13 +/- 17 (P = 0.045) and 11 +/- 11 mmHg (P = 0.040) after low and high oral fat loads, respectively. The baseline flow-mediated dilation was 9.4%, and it decreased by 3.8 +/- 2.1 (P = 0.002) and 4.1 +/- 3.1% (P < 0.001) after low and high iv lipid infusion and by 3.8 +/- 1.8 (P = 0.002) and 5.0 +/- 2.5% (P < 0.001) after low and high oral fat load, respectively. Oral and iv fat load stimulated oxidative stress, increased heart rate, and decreased R-R interval variability. Acute iv fat load decreased blood glucose by 6-10 mg/dl (P < 0.05) without changes in insulin concentration, whereas oral fat increased plasma insulin by 3.7-4.0 MUU/ml (P < 0.01) without glycemic variations. Intravenous saline and both oral and iv fat load reduced leptin concentration from baseline (P < 0.01). In conclusion, acute fat load administered orally or intravenously significantly increased blood pressure, altered endothelial function, and activated sympathetic nervous system by mechanisms not likely depending on changes in leptin, glucose, and insulin levels in obese healthy subjects. Thus, fat load, independent of its source, has deleterious hemodynamic effects in obese subjects. PMID- 20923962 TI - Loss of stearoyl-CoA desaturase activity leads to free cholesterol synthesis through increased Xbp-1 splicing. AB - Stearoyl-CoA desaturase-1 (SCD-1) is the rate-limiting enzyme in the biosynthesis of monounsaturated fatty acids (MUFA), which are required for efficient neutral lipid esterification. In the present investigation, we demonstrate that loss of SCD-1 activity increases free cholesterol (FC) content and induces Xbp-1 splicing. We assessed the small molecule SCD-1 inhibitor A939572 on [(14)C]stearate incorporation into neutral lipids and found its incorporation into triglyceride was unaffected, whereas labeled cholesteryl ester (CE) content was notably diminished. Using either A939572 or liver knockout mice (LKO), we show that loss of SCD-1 activity increases FC levels and activates the liver X receptor (LXR) pathway. Using adenoviral delivery of an active form of X-box binding protein-1 (Xbp-1; Xbp-1s), we show increased sterol synthesis only when cells lack the ability to generate MUFA. The results of the cell-based model were confirmed in LKO mice where fasting-refeeding decreased CE, increased FC, and increased Xbp-1s. On the basis of the present data, we conclude that SCD-1 activity is required for efficient cholesterol esterification to MUFA and that loss of its activity increases Xbp-1s-mediated FC synthesis. It is likely that the accumulation of FC enhances Xbp-1 splicing, induces LXR transcriptional activity, and increases ABCA1 (ATP-binding cassette transporter A1) expression to maintain cholesterol homeostasis. PMID- 20923963 TI - Dissociating inhibition, attention, and response control in the frontoparietal network using functional magnetic resonance imaging. AB - Evidence suggests that the right inferior frontal cortex (IFC) plays a specialized role in response inhibition. However, more recent findings indicate a broader role for this region in attentional control. Here, we used functional magnetic resonance imaging to examine the functional role of the right IFC in attention, inhibition, and response control in 2 experiments that employed novel variations of the go/no-go task. Across the 2 experiments, we observed a graded response in the right insula/IFC, whereby increasing response control demands led to an increase in activation. The results are consistent with the hypothesis that this region plays a key role in the integration of bottom-up, sensory information with top-down, response-related information to facilitate flexible, goal-directed behavior. PMID- 20923964 TI - Prenatal hypoxia independent of undernutrition promotes molecular markers of insulin resistance in adult offspring. AB - Molecular mechanisms predisposing people to insulin resistance are starting to emerge. Altered insulin signaling for hepatic gluconeogenesis and muscle glucose uptake is thought to play a central role. Development under suboptimal conditions is also known to increase the risk of insulin resistance in adulthood. However, the partial contributions of reduced oxygen vs. nutrient delivery to the fetus, two common adverse conditions in utero, to developmental programming of insulin resistance remain unknown. The aim of this study was to determine the effects of developmental hypoxia or undernutrition on the expression of insulin-signaling proteins in liver and skeletal muscle in adult rat offspring. We show that the expression of hepatic phospho-Akt and muscle Akt2 were significantly reduced in offspring of hypoxic, relative to offspring from normoxic or undernourished, pregnancies. Hepatic Akt-1, Akt-2, and PKCzeta protein expression was reduced in offspring from both hypoxic and undernourished pregnancies. Muscle GLUT4 expression was decreased in undernourished, and further decreased in hypoxic, offspring. These findings link prenatal hypoxia to down-regulation of components of hepatic and muscle Akt expression in adult offspring. Akt may represent a pharmaceutical target for clinical intervention against the developmental programming of metabolic disease resulting from prenatal hypoxia. PMID- 20923965 TI - Conversion of D-ribulose 5-phosphate to D-xylulose 5-phosphate: new insights from structural and biochemical studies on human RPE. AB - The pentose phosphate pathway (PPP) confers protection against oxidative stress by supplying NADPH necessary for the regeneration of glutathione, which detoxifies H(2)O(2) into H(2)O and O(2). RPE functions in the PPP, catalyzing the reversible conversion of D-ribulose 5-phosphate to D-xylulose 5-phosphate and is an important enzyme for cellular response against oxidative stress. Here, using structural, biochemical, and functional studies, we show that human D-ribulose 5 phosphate 3-epimerase (hRPE) uses Fe(2+) for catalysis. Structures of the binary complexes of hRPE with D-ribulose 5-phosphate and D-xylulose 5-phosphate provide the first detailed molecular insights into the binding mode of physiological ligands and reveal an octahedrally coordinated Fe(2+) ion buried deep inside the active site. Human RPE folds into a typical (beta/alpha)(8) triosephosphate isomerase (TIM) barrel with a loop regulating access to the active site. Two aspartic acids are well positioned to carry out the proton transfers in an acid base type of reaction mechanism. Interestingly, mutating Ser-10 to alanine almost abolished the enzymatic activity, while L12A and M72A mutations resulted in an almost 50% decrease in the activity. The binary complexes of hRPE reported here will aid in the design of small molecules for modulating the activity of the enzyme and altering flux through the PPP. PMID- 20923966 TI - Simulation tests to assess occupational exposure to airborne asbestos from artificially weathered asphalt-based roofing products. AB - Historically, asbestos-containing roof cements and coatings were widely used for patching and repairing leaks. Although fiber releases from these materials when newly applied have been studied, there are virtually no useful data on airborne asbestos fiber concentrations associated with the repair or removal of weathered roof coatings and cements, as most studies involve complete tear-out of old roofs, rather than only limited removal of the roof coating or cement during a repair job. This study was undertaken to estimate potential chrysotile asbestos fiber exposures specific to these types of roofing products following artificially enhanced weathering. Roof panels coated with plastic roof cement and fibered roof coating were subjected to intense solar radiation and daily simulated precipitation events for 1 year and then scraped to remove the weathered materials to assess chrysotile fiber release and potential worker exposures. Analysis of measured fiber concentrations for hand scraping of the weathered products showed 8-h time-weighted average concentrations that were well below the current Occupational Safety and Health Administration permissible exposure limit for asbestos. There was, however, visibly more dust and a few more fibers collected during the hand scraping of weathered products compared to the cured products previously tested. There was a notable difference between fibers released from weathered and cured roofing products. In weathered samples, a large fraction of chrysotile fibers contained low concentrations of or essentially no magnesium and did not meet the spectral, mineralogical, or morphological definitions of chrysotile asbestos. The extent of magnesium leaching from chrysotile fibers is of interest because several researchers have reported that magnesium-depleted chrysotile fibers are less toxic and produce fewer mesothelial tumors in animal studies than normal chrysotile fibers. PMID- 20923967 TI - Sports-related injuries in primary health care. AB - INTRODUCTION: Sports activities play an important role in today's society. However, as more people become involved in these activities, the number of sports related injuries also increases. In the Netherlands, 3.5 million sports injuries occur annually. Twenty per cent of these injuries are first seen by a GP. Little is known about the epidemiology of these injuries in general practice. This study has been conducted to determine the incidence and prevalence of sports-related injuries in general practice and to provide information about the nature and treatment of these injuries. METHODS: Survey study conducted in 612 patients with sports-related injuries by 21 GP trainees in as many GP practices. Inclusion of study subjects took place between September 2007 and April 2009. RESULTS: In total, 694 sports-related injuries were registered. The incidence of sports related injuries was 23.7 in 1000 patients and prevalence 27.8 in 1000 patients. Soccer-related injuries are most prominent in this population, lower extremities being three times more often involved than upper extremities. GPs often (60.9%) used a symptom-based diagnosis. In 80% of the cases, no additional diagnostic testing took place, while in 36.5% of the cases, only explanation and advice sufficed. Few patients were referred to the hospital (6.6%). DISCUSSION: Patients with sports-related injuries regularly consult GPs (on average one to two times per week). GPs tend to use non-specific diagnoses in sports-related injuries. In part, this may be due to the lack of specific diagnoses available in the current registration system (International Classification of Primary Care). Most often these injuries require only explanation and medical advice from the GP. Usually, additional tests or hospital referrals are not necessary. Presumably, mostly patients with mild sports-related injuries consult the GP. PMID- 20923968 TI - Characteristics and outcome of patients with acute myeloid leukemia refractory to 1 cycle of high-dose cytarabine-based induction chemotherapy. AB - Pretreatment characteristics and outcome of patients treated with induction regimens containing high-dose ara-C (HiDAC) at M. D. Anderson Cancer Center refractory to 1 cycle of induction were compared with similar patients achieving a complete response (CR). Among 1597 patients treated with HiDAC-based induction from 1995 to 2009, 285 were refractory to 1 cycle. Median age was 59 years (range, 18-85 years). Induction regimens included HiDAC with anthracyclines (n = 181; 64%) or HiDAC with nonanthracycline chemotherapy (n = 104; 36%). Refractory patients were older (median age, 59 vs 56 years; P < .001), more likely with unfavorable cytogenetics (P < .001) and antecedent hematologic disorder (P < .001), and had a higher presentation white blood cell count (P = .04), but not a higher incidence of FLT3 mutations (P = .85), than those achieving CR. Forty three patients (22%) responded to salvage (35 CR and 8 CR without platelet recovery). With a median follow-up of 72 months (range, 27-118 months) in responders, 11 are alive. Nineteen patients (7%) were alive and in CR for at least 6 months, including 9 who underwent allogeneic stem cell transplantation. On multivariate analysis, severe thrombocytopenia, leukocytosis, increasing marrow blast percentage, unfavorable cytogenetics, and salvage not including allogeneic stem cell transplantation were associated with a worse survival. Alternative strategies are needed for these patients. PMID- 20923969 TI - Talin1 is required for integrin-dependent B lymphocyte homing to lymph nodes and the bone marrow but not for follicular B-cell maturation in the spleen. AB - Talin1 is a key integrin coactivator. We investigated the roles of this cytoskeletal adaptor and its target integrins in B-cell lymphogenesis, differentiation, migration, and function. Using CD19 Cre-mediated depletion of talin1 selectively in B cells, we found that talin1 was not required for B-cell generation in the bone marrow or for the entry of immature B cells to the white pulp of the spleen. Loss of talin1 also did not affect B-cell maturation into follicular B cells but compromised differentiation of marginal zone B cells. Nevertheless, serum IgM and IgG levels remained normal. Ex vivo analysis of talin1-deficient spleen B cells indicated a necessary role for talin1 in LFA-1 and VLA-4 activation stimulated by canonical agonists, but not in B-cell chemotaxis. Consequently, talin1 null B splenocytes could not enter lymph nodes nor return to the bone marrow. Talin1 deficiency in B cells was also impaired in the humoral response to a T cell-dependent antigen. Collectively, these results indicate that talin1 is not required for follicular B-cell maturation in the spleen or homeostatic humoral immunity but is critical for integrin-dependent B lymphocyte emigration to lymph nodes and optimal immunity against T-dependent antigens. PMID- 20923970 TI - Bayesian epistasis association mapping via SNP imputation. AB - Genetic mutations may interact to increase the risk of human complex diseases. Mapping of multiple interacting disease loci in the human genome has recently shown promise in detecting genes with little main effects. The power of interaction association mapping, however, can be greatly influenced by the set of single nucleotide polymorphism (SNP) genotyped in a case-control study. Previous imputation methods only focus on imputation of individual SNPs without considering their joint distribution of possible interactions. We present a new method that simultaneously detects multilocus interaction associations and imputes missing SNPs from a full Bayesian model. Our method treats both the case control sample and the reference data as random observations. The output of our method is the posterior probabilities of SNPs for their marginal and interacting associations with the disease. Using simulations, we show that the method produces accurate and robust imputation with little overfitting problems. We further show that, with the type I error rate maintained at a common level, SNP imputation can consistently and sometimes substantially improve the power of detecting disease interaction associations. We use a data set of inflammatory bowel disease to demonstrate the application of our method. PMID- 20923971 TI - eEF1A phosphorylation in the nucleus of insulin-stimulated C2C12 myoblasts: Ser53 is a novel substrate for protein kinase C betaI. AB - Recent data indicate that some PKC isoforms are translocated to the nucleus, in response to certain stimuli, where they play an important role in nuclear signaling events. To identify novel interacting proteins of conventional PKC (cPKC) at the nuclear level during myogenesis and to find new PKC isozyme specific phosphosubstrates, we performed a proteomics analysis of immunoprecipitated nuclear samples from mouse myoblast C2C12 cells following insulin administration. Using a phospho(Ser)-PKC substrate antibody, specific interacting proteins were identified by LC-MS/MS spectrometry. A total of 16 proteins with the exact and complete motif recognized by the phospho-cPKC substrate antibody were identified; among these, particular interest was given to eukaryotic elongation factor 1alpha (eEF1A). Nuclear eEF1A was focalized in the nucleoli, and its expression was observed to increase following insulin treatment. Of the cPKC isoforms, only PKCbetaI was demonstrated to be expressed in the nucleus of C2C12 myocytes and to co-immunoprecipitate with eEF1A. In-depth analysis using site-directed mutagenesis revealed that PKCbetaI could phosphorylate Ser53 of the eEF1A2 isoform and that the association between eEF1A2 and PKCbetaI was dependent on the phosphorylation status of eEF1A2. PMID- 20923973 TI - Maintenance of neuronal laterality in Caenorhabditis elegans through MYST histone acetyltransferase complex components LSY-12, LSY-13 and LIN-49. AB - Left/right asymmetrically expressed genes permit an animal to perform distinct tasks with the right vs. left side of its brain. Once established during development, lateralized gene expression patterns need to be maintained during the life of the animal. We show here that a histone modifying complex, composed of the LSY-12 MYST-type histone acetyltransferase, the ING-family PHD domain protein LSY-13, and PHD/bromodomain protein LIN-49, is required to first initiate and then actively maintain lateralized gene expression in the gustatory system of the nematode Caenorhabditis elegans. Similar defects are observed upon postembryonic removal of two C2H2 zinc finger transcription factors, die-1 and che-1, demonstrating that a combination of transcription factors, which recognize DNA in a sequence-specific manner, and a histone modifying enzyme complex are responsible for inducing and maintaining neuronal laterality. PMID- 20923972 TI - Phosphodiesterases catalyze hydrolysis of cAMP-bound to regulatory subunit of protein kinase A and mediate signal termination. AB - Although extensive structural and biochemical studies have provided molecular insights into the mechanism of cAMP-dependent activation of protein kinase A (PKA), little is known about signal termination and the role of phosphodiesterases (PDEs) in regulatory feedback. In this study we describe a novel mode of protein kinase A-anchoring protein (AKAP)-independent feedback regulation between a specific PDE, RegA and the PKA regulatory (RIalpha) subunit, where RIalpha functions as an activator of PDE catalysis. Our results indicate that RegA, in addition to its well-known role as a PDE for bulk cAMP in solution, is also capable of hydrolyzing cAMP-bound to RIalpha. Furthermore our results indicate that binding of RIalpha activates PDE catalysis several fold demonstrating a dual function of RIalpha, both as an inhibitor of the PKA catalytic (C) subunit and as an activator for PDEs. Deletion mutagenesis has localized the sites of interaction to one of the cAMP-binding domains of RIalpha and the catalytic PDE domain of RegA whereas amide hydrogen/deuterium exchange mass spectrometry has revealed that the cAMP-binding site (phosphate binding cassette) along with proximal regions important for relaying allosteric changes mediated by cAMP, are important for interactions with the PDE catalytic domain of RegA. These sites of interactions together with measurements of cAMP dissociation rates demonstrate that binding of RegA facilitates dissociation of cAMP followed by hydrolysis of the released cAMP to 5'AMP. cAMP-free RIalpha generated as an end product remains bound to RegA. The PKA C-subunit then displaces RegA and reassociates with cAMP-free RIalpha to regenerate the inactive PKA holoenzyme thereby completing the termination step of cAMP signaling. These results reveal a novel mode of regulatory feedback between PDEs and RIalpha that has important consequences for PKA regulation and cAMP signal termination. PMID- 20923974 TI - Cdc14-dependent dephosphorylation of a kinetochore protein prior to anaphase in Saccharomyces cerevisiae. AB - The budding yeast Cdc14 phosphatase reverses Cdk1 phosphorylation to promote mitotic exit. Although Cdc14 activity is thought to be restricted to anaphase, we found that dephosphorylation of the Dsn1 kinetochore protein in metaphase requires Cdc14. These data suggest that there is a nonnucleolar pool of active Cdc14 prior to anaphase. PMID- 20923976 TI - The rate of fitness-valley crossing in sexual populations. AB - Biological traits result in part from interactions between different genetic loci. This can lead to sign epistasis, in which a beneficial adaptation involves a combination of individually deleterious or neutral mutations; in this case, a population must cross a "fitness valley" to adapt. Recombination can assist this process by combining mutations from different individuals or retard it by breaking up the adaptive combination. Here, we analyze the simplest fitness valley, in which an adaptation requires one mutation at each of two loci to provide a fitness benefit. We present a theoretical analysis of the effect of recombination on the valley-crossing process across the full spectrum of possible parameter regimes. We find that low recombination rates can speed up valley crossing relative to the asexual case, while higher recombination rates slow down valley crossing, with the transition between the two regimes occurring when the recombination rate between the loci is approximately equal to the selective advantage provided by the adaptation. In large populations, if the recombination rate is high and selection against single mutants is substantial, the time to cross the valley grows exponentially with population size, effectively meaning that the population cannot acquire the adaptation. Recombination at the optimal (low) rate can reduce the valley-crossing time by up to several orders of magnitude relative to that in an asexual population. PMID- 20923975 TI - Slk19p of Saccharomyces cerevisiae regulates anaphase spindle dynamics through two independent mechanisms. AB - Slk19p is a member of the Cdc-14 early anaphase release (FEAR) pathway, a signaling network that is responsible for activation of the cell-cycle regulator Cdc14p in Saccharomyces cerevisiae. Disruption of the FEAR pathway results in defects in anaphase, including alterations in the assembly and behavior of the anaphase spindle. Many phenotypes of slk19Delta mutants are consistent with a loss of FEAR signaling, but other phenotypes suggest that Slk19p may have FEAR independent roles in modulating the behavior of microtubules in anaphase. Here, a series of SLK19 in-frame deletion mutations were used to test whether Slk19p has distinct roles in anaphase that can be ascribed to specific regions of the protein. Separation-of-function alleles were identified that are defective for either FEAR signaling or aspects of anaphase spindle function. The data suggest that in early anaphase one region of Slk19p is essential for FEAR signaling, while later in anaphase another region is critical for maintaining the coordination between spindle elongation and the growth of interpolar microtubules. PMID- 20923977 TI - Discovery of mutations in Saccharomyces cerevisiae by pooled linkage analysis and whole-genome sequencing. AB - Many novel and important mutations arise in model organisms and human patients that can be difficult or impossible to identify using standard genetic approaches, especially for complex traits. Working with a previously uncharacterized dominant Saccharomyces cerevisiae mutant with impaired vacuole inheritance, we developed a pooled linkage strategy based on next-generation DNA sequencing to specifically identify functional mutations from among a large excess of polymorphisms, incidental mutations, and sequencing errors. The VAC6-1 mutation was verified to correspond to PHO81-R701S, the highest priority candidate reported by VAMP, the new software platform developed for these studies. Sequence data further revealed the large extent of strain background polymorphisms and structural alterations present in the host strain, which occurred by several mechanisms including a novel Ty insertion. The results provide a snapshot of the ongoing genomic changes that ultimately result in strain divergence and evolution, as well as a general model for the discovery of functional mutations in many organisms. PMID- 20923978 TI - Comparative genetic mapping points to different sex chromosomes in sibling species of wild strawberry (Fragaria). AB - Separate sexes have evolved repeatedly from hermaphroditic ancestors in flowering plants, and thus select taxa can provide unparalleled insight into the evolutionary dynamics of sex chromosomes that are thought to be shared by plants and animals alike. Here we ask whether two octoploid sibling species of wild strawberry--one almost exclusively dioecious (males and females), Fragaria chiloensis, and one subdioecious (males, females, and hermaphrodites), F. virginiana--share the same sex-determining chromosome. We created a genetic map of the sex chromosome and its homeologs in F. chiloensis and assessed macrosynteny between it and published maps of the proto-sex chromosome of F. virginiana and the homeologous autosome of hermaphroditic diploid species. Segregation of male and female function in our F. chiloensis mapping population confirmed that linkage and dominance relations are similar to those in F. virginiana. However, identification of the molecular markers most tightly linked to the sex-determining locus in the two octoploid species shows that, in both, this region maps to homeologues of chromosome 6 in diploid congeners, but is located at opposite ends of their respective chromosomes. PMID- 20923979 TI - Functional specialization of sensory cilia by an RFX transcription factor isoform. AB - In animals, RFX transcription factors govern ciliogenesis by binding to an X-box motif in the promoters of ciliogenic genes. In Caenorhabditis elegans, the sole RFX transcription factor (TF) daf-19 null mutant lacks all sensory cilia, fails to express many ciliogenic genes, and is defective in many sensory behaviors, including male mating. The daf-19c isoform is expressed in all ciliated sensory neurons and is necessary and sufficient for activating X-box containing ciliogenesis genes. Here, we describe the daf-19(n4132) mutant that is defective in expression of the sensory polycystic kidney disease (PKD) gene battery and male mating behavior, without affecting expression of ciliogenic genes or ciliogenesis. daf-19(n4132) disrupts expression of a new isoform, daf-19m (for function in male mating). daf-19m is expressed in male-specific PKD and core IL2 neurons via internal promoters and remote enhancer elements located in introns of the daf-19 genomic locus. daf-19m genetically programs the sensory functions of a subset of ciliated neurons, independent of daf-19c. In the male-specific HOB neuron, DAF-19(M) acts downstream of the zinc finger TF EGL-46, indicating that a TF cascade controls the PKD gene battery in this cell-type specific context. We conclude that the RFX TF DAF-19 regulates ciliogenesis via X-box containing ciliogenic genes and controls ciliary specialization by regulating non-X-box containing sensory genes. This study reveals a more extensive role for RFX TFs in generating fully functional cilia. PMID- 20923980 TI - The effects of demography and linkage on the estimation of selection and mutation parameters. AB - We explore the effects of demography and linkage on a maximum-likelihood (ML) method for estimating selection and mutation parameters in a reversible mutation model. This method assumes free recombination between sites and a randomly mating population of constant size and uses information from both polymorphic and monomorphic sites in the sample. Two likelihood-ratio test statistics were constructed under this ML framework: LRTgamma for detecting selection and LRTkappa for detecting mutational bias. By carrying out extensive simulations, we obtain the following results. When mutations are neutral and population size is constant, LRTgamma and LRTkappa follow a chi-square distribution with 1 d.f. regardless of the level of linkage, as long as the mutation rate is not very high. In addition, LRTgamma and LRTkappa are relatively insensitive to demographic effects and selection at linked sites. We find that the ML estimators of the selection and mutation parameters are usually approximately unbiased and that LRTkappa usually has good power to detect mutational bias. Finally, with a recombination rate that is typical for Drosophila, LRTgamma has good power to detect weak selection acting on synonymous sites. These results suggest that the method should be useful under many different circumstances. PMID- 20923981 TI - Unbiased estimation of gene diversity in samples containing related individuals: exact variance and arbitrary ploidy. AB - Gene diversity, a commonly used measure of genetic variation, evaluates the proportion of heterozygous individuals expected at a locus in a population, under the assumption of Hardy-Weinberg equilibrium. When using the standard estimator of gene diversity, the inclusion of related or inbred individuals in a sample produces a downward bias. Here, we extend a recently developed estimator shown to be unbiased in a diploid autosomal sample that includes known related or inbred individuals to the general case of arbitrary ploidy. We derive an exact formula for the variance of the new estimator, H, and present an approximation to facilitate evaluation of the variance when each individual is related to at most one other individual in a sample. When examining samples from the human X chromosome, which represent a mixture of haploid and diploid individuals, we find that H performs favorably compared to the standard estimator, both in theoretical computations of mean squared error and in data analysis. We thus propose that H is a useful tool in characterizing gene diversity in samples of arbitrary ploidy that contain related or inbred individuals. PMID- 20923982 TI - Bulk segregation mapping of mutations in closely related strains of mice. AB - Phenovariance may be obscured when genetic mapping is performed using highly divergent strains, and closely similar strains are preferred if adequate marker density can be established. We sequenced the C57BL/10J mouse genome using the Applied Biosystems SOLiD platform and here describe a genome-wide panel of informative markers that permits the mapping of mutations induced on the closely related C57BL/6J background by outcrossing to C57BL/10J, and backcrossing or intercrossing. The panel consists of 127 single nucleotide polymorphisms validated by capillary sequencing: 124 spaced at ~20-Mb intervals across the 19 autosomes, and three markers on the X chromosome. We determined the genetic relationship between four C57BL-derived substrains and used the panel to map two N-ethyl-N-nitrosourea (ENU)-induced mutations responsible for visible phenotypes in C57BL/6J mice through bulk segregation analysis. Capillary sequencing, with computation of relative chromatogram peak heights, was used to determine the proportion of alleles from each strain at each marker. PMID- 20923984 TI - Accounting for vehicle, crash, and occupant characteristics in traffic crash studies. PMID- 20923983 TI - Inference of homologous recombination in bacteria using whole-genome sequences. AB - Bacteria and archaea reproduce clonally, but sporadically import DNA into their chromosomes from other organisms. In many of these events, the imported DNA replaces an homologous segment in the recipient genome. Here we present a new method to reconstruct the history of recombination events that affected a given sample of bacterial genomes. We introduce a mathematical model that represents both the donor and the recipient of each DNA import as an ancestor of the genomes in the sample. The model represents a simplification of the previously described coalescent with gene conversion. We implement a Monte Carlo Markov chain algorithm to perform inference under this model from sequence data alignments and show that inference is feasible for whole-genome alignments through parallelization. Using simulated data, we demonstrate accurate and reliable identification of individual recombination events and global recombination rate parameters. We applied our approach to an alignment of 13 whole genomes from the Bacillus cereus group. We find, as expected from laboratory experiments, that the recombination rate is higher between closely related organisms and also that the genome contains several broad regions of elevated levels of recombination. Application of the method to the genomic data sets that are becoming available should reveal the evolutionary history and private lives of populations of bacteria and archaea. The methods described in this article have been implemented in a computer software package, ClonalOrigin, which is freely available from http://code.google.com/p/clonalorigin/. PMID- 20923985 TI - Predictors of unintentional poisoning among children under 5 years of age in Karachi: a matched case-control study. AB - OBJECTIVE: Poisoning is the fourth leading cause of unintentional injury and a common paediatric emergency in children under 5 years of age. The objective of this study was to determine the factors associated with unintentional poisoning among children under 5 years of age presenting to emergency rooms at tertiary care hospitals in Karachi, Pakistan. SETTING: Children were recruited from the emergency rooms of the three biggest tertiary care hospitals in Karachi. DESIGN: A matched case-control study was conducted on 120 cases and 360 controls, with matching done on gender and age. Parents were interviewed using a structured questionnaire containing information on sociodemographic factors, the child's behaviour, and the storage practices of hazardous substances of caregivers in the homes. Conditional logistic regression was performed to analyse the data. RESULTS: Accessibility to hazardous chemicals and medicines due to unsafe storage (adj mOR=5.6, 95% CI 1.9 to 16.7), child's behaviour reported as usually aggressive (adj mOR=8.2, 95% CI 4.6 to 16.1), storage of kerosene oil and petrol in soft drink bottles (adj mOR=3.8, 95% CI 2.0 to 7.3), low socioeconomic status (adj mOR=9.2, 95% CI 2.8 to 30.1), low level of mother's education (adj mOR=4.2, 95% CI 1.8 to 9.6), and history of previous poisoning (adj mOR=8.6, 95% CI 1.7 to 43.5) were independently related to unintentional poisoning. CONCLUSION: The practice of storing kerosene and petroleum in soft drink bottles and the easy accessibility of chemicals and medicines are potentially modifiable. Health messages focusing on the safe storage of chemicals and medicines and the use of child resistant containers may play a key role in decreasing the burden of childhood poisoning in Karachi, Pakistan. PMID- 20923986 TI - Mehran contrast-induced nephropathy risk score predicts short- and long-term clinical outcomes in patients with ST-elevation-myocardial infarction. AB - BACKGROUND: The Mehran Risk Score (MRS) has been demonstrated to be clinically useful for prediction of contrast-induced nephropathy (CIN) after nonurgent percutaneous coronary intervention. We aim to validate the MRS in the setting of Primary percutaneous coronary intervention for prediction of both CIN and short- and long-term clinical outcomes. METHODS AND RESULTS: We assigned 891 consecutive patients with ST-elevation-myocardial infarction undergoing primary percutaneous coronary intervention to 4 groups of risk of CIN (RC) according to MRS (low, medium, high, and very high risk). We evaluated CIN, death, and major cardiovascular and cerebrovascular events after 25 months' mean follow-up. At multivariable analysis, mortality in very high-risk group was more than 10-fold higher (hazard ratio [HR], 10.11; 95% confidence interval [CI], 4.83 to 21.1; P<0.001) when compared with the low-risk group and was also increased in the high risk group (HR, 6.31; 95% CI, 3.28 to 12.14; P<0.001) and medium-risk group (HR, 3.18; 95% CI, 1.83 to 5.51; P<0.001). Similarly, an increasing effect was seen across MRS strata for major cardiovascular and cerebrovascular events both in the very high-risk group (HR, 3.79; 95% CI, 2.27 to 6.6.32; P<0.001), high-risk group (HR, 1.90; 95% CI, 1.31 to 2.75; P=0.001), and medium-risk group (HR, 1.42; 95% CI, 1.10 to 1.85; P=0.007). In addition, the HR for rehospitalization increased with the increasing RC groups (HR, 3.32; 95%CI, 1.96 to 5.63; P<0.001; HR, 3.11; 95% CI, 1.35 to 7.20; P=0.008; HR, 7.73; 95% CI, 2.97 to 20.10; P<0.001, respectively). The odds ratio for CIN was 2.84 (95% CI, 1.16 to 6.92; P=0.021) in the very high RC group, 1.33 (95% CI, 0.68 to 2.61; P=0.398) in the high RC group, and 1.10 (95% CI, 0.67 to 1.79; P=0.699) in the medium RC group, as compared with the lower one. CONCLUSIONS: The MRS may be applied in the primary angioplasty setting population and is able to predict CIN and to stratify patients for poor clinical outcomes both in the short- and long-term follow-up. PMID- 20923987 TI - Prognostic value of isolated troponin I elevation after percutaneous coronary intervention. AB - BACKGROUND: Mild elevations of cardiac troponin are frequent after percutaneous coronary intervention (PCI). Their prognostic value is uncertain in the absence of changes in creatine kinase-MB (CK-MB). METHODS AND RESULTS: We evaluated the relation between isolated elevations of cardiac troponin I (cTnI) and all-cause mortality. We studied 3494 consecutive patients who underwent PCI in 16 Italian tertiary cardiology centers. CK-MB and cTnI were analyzed in a central laboratory. Duration of follow-up was 2 years. The present analysis was restricted to 2362 patients with normal CK-MB and cTnI values at baseline and no CK-MB elevation after PCI. A rise in cTnI after PCI >0.15 ng/mL, the upper reference limit, was found in 932 patients (39.4%). A rise >0.45 ng/mL (>3*upper reference limit) was found in 467 patients (19.7%). Compared with patients with normal cTnI, those with cTnI elevation >0.15 ng/mL showed a slightly increased mortality (3.8% versus 2.6%; hazard ratio, 1.53; 95% confidence interval, 0.97 to 2.42; P=0.069). A cTnI elevation >0.45 ng/mL was associated with a higher risk of mortality (4.5% versus 2.7%; hazard ratio, 1.68; 95% confidence interval, 1.01 to 2.80; P=0.044), which, however, did not remain significant after adjustment for concomitant risk factors (hazard ratio, 1.45; 95% confidence interval, 0.86 to 2.46; P=0.162). Postprocedural cTnI elevation was associated with coronary and clinical features consistent with a worse risk profile. CONCLUSIONS: In the absence of a rise in CK-MB, elevated cTnI levels after PCI are associated with a modest increased risk of death. However, this is not independent of the concomitant adverse baseline clinical characteristics of these patients. PMID- 20923988 TI - Development and validation of risk adjustment models for long-term mortality and myocardial infarction following percutaneous coronary interventions. AB - BACKGROUND: Existing models for outcome after percutaneous coronary interventions (PCIs) lack assessment of long-term prognosis. Our goal was to derive 1- and 5 year mortality and mortality/myocardial infarction (MI) risk models for PCI outcomes from simple, easily obtainable clinical and laboratory variables. METHODS AND RESULTS: Using the Mayo Clinic registry, we analyzed long-term mortality and mortality/MI following PCIs on 9165 unique patients from January 1, 2001, through December 31, 2007. Cox proportional hazards regression was used to model the calculated risk score and major procedural complications. A total of 1243 patients died, and 696 had MI. Separate risk models derived from clinical, procedural, and laboratory characteristics were made for mortality and mortality/MI. Older age, comorbid conditions, low ejection fraction, acute MI, history of smoking, heart failure, hyperlipidemia, 3-vessel disease, procedural failure, ventricular arrhythmia during PCI, and low medication score were predictors of long-term mortality and mortality/MI. Simple integer scores stratified patients into low, moderate, high, and very high risk for subsequent events. Models had adequate goodness of fit, and areas under the receiver operating characteristic curve were 0.786 and 0.728 for mortality and mortality/MI, respectively, indicating good overall discrimination. Bootstrap analysis indicated that the model was not overfit to the available data set. CONCLUSIONS: Easily obtainable variables can be combined into a convenient risk scoring system at the time of patient dismissal following PCI to accurately predict long-term mortality and mortality/MI. This model may be useful for providing patients with individualized, evidence-based estimates of long-term risk. PMID- 20923990 TI - Population impact of heart failure and the most common forms of cancer: a study of 1 162 309 hospital cases in Sweden (1988 to 2004). AB - BACKGROUND: The contemporary impact of heart failure (HF) versus the most common forms of cancer as reflected by related first-ever hospitalizations and subsequent case-fatality rates is unknown. METHODS AND RESULTS: Using a national registry in Sweden, we compared the rate of first-ever hospitalization and associated short- and long-term survival for HF, acute myocardial infarction (AMI), and the most common forms of cancer on an age and sex-specific basis during 1988 to 2004 in 949 733 Swedish patients (1 162 309 hospital admissions in total). Annual incidence of first-ever hospitalization for HF, AMI, and cancer in Sweden were 484, 424, and 373 (lung, colorectal, prostate, and bladder cancer combined) per 100 000 men and 470, 280, and 350 (lung, colorectal, bladder, breast, and ovarian cancer combined) per 100 000 women age >20 years. The ratio of individual cases of HF to cancer was 1.37:1 (465 998 versus 340 738). Despite improvements in 30-day and 5-year survival (adjusted 7% and 6% increase per calendar year for men and women, respectively), HF was associated with unadjusted case-fatality rate of 59% within 5 years and 196 400 deaths versus 58% and 131 000 deaths in patients with cancer. During 10-year follow-up, HF was associated with 66 318 versus 55 364 premature life-years lost than all common forms of cancer in men. In women, the equivalent figures were 59 535 versus 64 533 premature life-years lost. CONCLUSIONS: These data confirm that, like most common forms of cancer combined, HF exerts a major health burden in respect to age adjusted rates of first hospitalization, poor overall survival, and premature life-years lost. PMID- 20923989 TI - Design of the Coronary ARtery DIsease Genome-Wide Replication And Meta-Analysis (CARDIoGRAM) Study: A Genome-wide association meta-analysis involving more than 22 000 cases and 60 000 controls. AB - BACKGROUND: Recent genome-wide association studies (GWAS) of myocardial infarction (MI) and other forms of coronary artery disease (CAD) have led to the discovery of at least 13 genetic loci. In addition to the effect size, power to detect associations is largely driven by sample size. Therefore, to maximize the chance of finding novel susceptibility loci for CAD and MI, the Coronary ARtery DIsease Genome-wide Replication And Meta-analysis (CARDIoGRAM) consortium was formed. METHODS AND RESULTS: CARDIoGRAM combines data from all published and several unpublished GWAS in individuals with European ancestry; includes >22 000 cases with CAD, MI, or both and >60 000 controls; and unifies samples from the Atherosclerotic Disease VAscular functioN and genetiC Epidemiology study, CADomics, Cohorts for Heart and Aging Research in Genomic Epidemiology, deCODE, the German Myocardial Infarction Family Studies I, II, and III, Ludwigshafen Risk and Cardiovascular Heath Study/AtheroRemo, MedStar, Myocardial Infarction Genetics Consortium, Ottawa Heart Genomics Study, PennCath, and the Wellcome Trust Case Control Consortium. Genotyping was carried out on Affymetrix or Illumina platforms followed by imputation of genotypes in most studies. On average, 2.2 million single nucleotide polymorphisms were generated per study. The results from each study are combined using meta-analysis. As proof of principle, we meta-analyzed risk variants at 9p21 and found that rs1333049 confers a 29% increase in risk for MI per copy (P=2*10-20). CONCLUSION: CARDIoGRAM is poised to contribute to our understanding of the role of common genetic variation on risk for CAD and MI. PMID- 20923991 TI - Low hemoglobin A1c and risk of all-cause mortality among US adults without diabetes. AB - BACKGROUND: Among individuals without diabetes, elevated hemoglobin A1c (HbA1c) has been associated with increased morbidity and mortality, but the literature is sparse regarding the prognostic importance of low HbA1c. METHODS AND RESULTS: National Health and Nutrition Examination Survey III (NHANES III) participants, 20 years and older, were followed up to 12 years (median follow-up, 8.8 years) for all-cause mortality. Cox proportional hazards regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CI) for the association between HbA1c levels and all-cause mortality for 14 099 participants without diabetes. There were 1825 deaths during the follow-up period. Participants with a low HbA1c (<4.0%) had the highest levels of mean red blood cell volume, ferritin, and liver enzymes and the lowest levels of mean total cholesterol and diastolic blood pressure compared with their counterparts with HbA1c levels between 4.0% and 6.4%. An HbA1c <4.0% versus 5.0% to 5.4% was associated with an increased risk of all-cause mortality (HR, 3.73; 95% CI, 1.45 to 9.63) after adjustment for age, race-ethnicity, and sex. This association was attenuated but remained statistically significant after further multivariable adjustment for lifestyle, cardiovascular factors, metabolic factors, red blood cell indices, iron storage indices, and liver function indices (HR, 2.90; 95% CI, 1.25 to 6.76). CONCLUSIONS: In this nationally representative cohort, low HbA1c was associated with increased all-cause mortality among US adults without diabetes. Additional research is needed to confirm these results and identify potential mechanisms that may be underlying this association. PMID- 20923992 TI - Patients' perspectives of a multifaceted intervention with a focus on technology: a qualitative analysis. AB - BACKGROUND: Few studies have investigated the effectiveness of multifaceted interventions from the study participants' perspective. We conducted qualitative interviews to understand patients' experiences with a multifaceted blood pressure (BP) control intervention involving interactive voice response technology, home BP monitoring, and pharmacist-led BP management. In the randomized study, the intervention resulted in clinically significant decreases in BP. METHODS AND RESULTS: We used insights generated from in-depth interviews from all study participants randomly assigned to the multifaceted intervention or usual care (n=146) to create a model explaining the observed improvements in health behavior and clinical outcomes. The data were analyzed using qualitative content analysis methods and consultative and reflexive team analysis. Six explanatory factors emerged from the patients' interviews: (1) improved relationships with medical personnel; (2) increased knowledge of hypertension; (3) increased participation in their health care and personal empowerment; (4) greater understanding of the impact of health behavior on BP; (5) high satisfaction with technology used in the intervention; and, for some patients, (6) increased health care utilization. Eighty-six percent of the intervention patients and 62% of the usual care patients stated that study participation had a positive effect on them. Of those expressing a positive effect, 68% (intervention) and 55% (usual care) reached their systolic BP goal. CONCLUSIONS: Establishing bidirectional conversations between patients and providers is a key element of successful hypertension management. Home BP monitoring coupled with interactive voice response technology reporting facilitates such conversations. PMID- 20923993 TI - The impact of hospital cardiac specialization on outcomes after coronary artery bypass graft surgery: analysis of medicare claims data. AB - BACKGROUND: Hospital volume has been widely embraced as a proxy measure for hospital quality; little attention has been focused on an alternative quality measure-hospital specialization. Even though specialization occurs on a continuum, previous studies have only focused on a small number of highly specialized hospitals (single-specialty hospitals). Studies on the broad relationship between hospital specialization and outcomes after coronary artery bypass grafting (CABG) are limited. METHODS AND RESULTS: We conducted a retrospective cohort study of 705 084 Medicare patients (1130 hospitals) who underwent CABG during 2001 to 2005. We stratified hospitals into quintiles, based on their degree of cardiac specialization (proportion of a hospital's Medicare discharges classified as Major Diagnostic Category 5-cardiovascular diseases). We compared patient and hospital characteristics and outcomes across quintiles of cardiac specialization. Patient characteristics were generally similar across quintiles, but mean annual CABG volume increased progressively from quintile 1 (least specialized) to quintile 5 (most specialized). Unadjusted 30-day mortality was similar at hospitals in quintiles 1 to 4 (4.8%), except quintile 5, where mortality was lower (4.3%). A strong inverse association was seen between hospital cardiac specialization and 30-day mortality after adjustment for patient characteristics (P(trend)=0.001). However, this was no longer significant after additional adjustment for CABG volume (P(trend)=0.65). Results were similar for other mortality outcomes and length of stay. CONCLUSIONS: After accounting for patient characteristics and CABG volume, greater cardiac specialization was not associated with clinically significant improvement in patient outcomes. This study calls into question the benefit of cardiac specialization for the vast majority of CABG-performing US hospitals. PMID- 20923994 TI - Impact of elevated cystatin C level on cardiovascular disease risk in predominantly high cardiovascular risk populations: a meta-analysis. AB - BACKGROUND: Chronic kidney disease is a growing public health problem that carries substantial risk for cardiovascular disease (CVD). Single studies have differentially examined the role of cystatin C, a novel renal index, with varying cut-point use. We undertook a meta-analysis of prospective studies to properly assess the link between cystatin C (dichotomized and continuous) versus CVD. METHODS AND RESULTS: Systematic literature search for studies reporting a multivariate-adjusted estimate, represented as relative risk (RR) with 95% confidence interval (CI), of the association between cystatin C and subsequent risk of (1) any CVD event and (2) specific CVD events. Data were collated from 14 studies, with 13 high cardiovascular risk population cohorts and 1 general population cohort, involving 22 509 subjects with 2321 CVD events, 741 coronary heart disease events, and 828 stroke events. Highest cystatin C category versus lowest was associated with greater risk of CVD (RR, 2.62; 95% CI, 2.05 to 3.37, P<0.001), coronary heart disease (RR, 1.72; 95% CI, 1.27 to 2.34; P<0.001), and stroke (RR, 1.83; 95% CI, 1.12 to 3.00; P=0.02) after adjustment for established cardiovascular risk factors. Each standard deviation rise in cystatin C concentration boosted CVD risk (RR, 1.34; 95% CI, 1.18 to 1.51; P<0.001). Highest cystatin C category was also independently linked to greater risk of all-cause mortality and heart failure. CONCLUSIONS: The meta-analysis, mostly derived from high cardiovascular populations, showed that cystatin C is strongly and independently associated with subsequent CVD risk. Further investigation is warranted to clarify whether measurement of cystatin C can usefully enhance CVD stratification beyond established predictors already in clinical use. PMID- 20923995 TI - Trends in mortality of acute myocardial infarction after discharge from the hospital. AB - BACKGROUND: We assessed trends in the prognosis of patients with acute myocardial infarction hospitalized in New Jersey hospitals. In recent decades, in-hospital mortality has declined markedly but the decline in longer-term mortality is less pronounced, implying that mortality after discharge has worsened. METHODS AND RESULTS: Using the Myocardial Infarction Data Acquisition System (MIDAS), we examined the outcomes of 285 397 patients hospitalized for a first acute myocardial infarction between 1986 and 2007. Mortality at discharge decreased by 9.4% from 16.9% to 7.5% (annual change, -0.44; 95% confidence interval, -0.49 to 0.40), but the decrease at 1 year was less pronounced (6.4%) because of an increase in mortality from discharge to 1 year after discharge (from 12.1% to 13.9%; annual change, +0.15; 95% confidence interval, +0.10 to +0.20). Mortality from 30 days after discharge to 1 year, a measure not affected by length of stay, increased by 1.2% (annual change, +0.10; 95% confidence interval, +0.06 to +0.23). The effect was more evident in the older age groups and was due to noncardiovascular mortality, especially from respiratory and renal diseases, septicemia, and cancer. All effects remained statistically significant (P<0.0001) after adjustment for demographics, comorbidities, infarction type, complications, and interventions. Piecewise linear regressions confirmed these trends. CONCLUSIONS: Postdischarge mortality of patients with acute myocardial infarction is increasing, primarily because of higher noncardiovascular mortality in the older age groups. PMID- 20923996 TI - Enoxaparin versus dabigatran or rivaroxaban for thromboprophylaxis after hip or knee arthroplasty: Results of separate pooled analyses of phase III multicenter randomized trials. AB - BACKGROUND: Dabigatran and rivaroxaban are novel oral anticoagulants approved for prevention of venous thromboembolism after hip or knee arthroplasty. However, information assessing clinically important efficacy and bleeding outcomes of these 2 new agents versus low-molecular-weight heparin (enoxaparin) is lacking. METHODS AND RESULTS: We separately pooled efficacy and safety data from 6 phase III randomized trials (18 405 participants) comparing equivalent durations of treatment with enoxaparin (40 mg once daily [od] or 30 mg twice daily) versus dabigatran (220 mg od) or versus rivaroxaban (10 mg od) after hip or knee arthroplasty. Odds ratios (OR) for individual outcomes were calculated for each trial and were pooled using the Mantel-Haenszel method. Compared with dabigatran, enoxaparin had a similar risk of symptomatic venous thromboembolism plus all cause mortality (0.9% versus 1.1%; OR, 0.76; 95% confidence interval [CI], 0.44 to 1.31; I2=76%) and bleeding (5.0% versus 5.6%; OR, 0.90; 95% CI, 0.71 to 1.15; I2=0%). Compared with rivaroxaban, enoxaparin had a 2-fold higher risk of symptomatic venous thromboembolism plus all-cause mortality (1.2% versus 0.6%; OR, 2.04; 95% CI, 1.32 to 3.17; P<0.001; number needed to treat, 167; I2=0%) but demonstrated a significant lower risk of bleeding (2.5% versus 3.1%; OR, 0.79; 95% CI, 0.62 to 0.99; P=0.049; number needed to harm, 167; I2=0%). CONCLUSIONS: In patients undergoing hip or knee arthroplasty, enoxaparin and dabigatran showed similar rates of efficacy and bleeding. Enoxaparin was less effective than rivaroxaban but had a lower risk of bleeding. These results may have important implications for the choice of prophylactic agent in major joint arthroplasty. PMID- 20923997 TI - Utilization of secondary prevention therapies in patients with nonobstructive coronary artery disease identified during cardiac catheterization: insights from the National Cardiovascular Data Registry Cath-PCI Registry. AB - BACKGROUND: Secondary prevention therapies are indicated for patients with coronary artery disease (CAD). However, patients with nonobstructive CAD may be less likely to receive these therapies compared with patients with obstructive CAD. Therefore, we compared rates of secondary prevention medication prescription between patients with nonobstructive and obstructive CAD. METHODS AND RESULTS: We conducted a retrospective cohort study of 1 489 745 CAD patients undergoing cardiac catheterization in 786 US centers between 2004 and 2007. We measured rates of aspirin, statin, beta-blocker, and angiotensin-converting enzyme inhibitor (ACEI)/angiotensin II receptor blocker (ARB) prescription at hospital discharge among eligible patients; 237 167 (15.9%) patients had nonobstructive CAD and 1 252 578 (84.1%) had obstructive CAD. Compared with obstructive CAD patients, nonobstructive CAD patients had significantly lower rates of rates of aspirin (72.7% versus 90.9%), statin (60.0% versus 80.3%), beta-blocker (57.9% versus 79.4%), and ACEI/ARB (45.9% versus 58.6%; all probability values <0.0001) prescription at hospital discharge. After multivariable adjustment, nonobstructive CAD patients remained significantly less likely to receive prescriptions for aspirin (odds ratio, 0.37; 95% confidence interval, 0.35 to 0.39), statins (odds ratio, 0.45; 95% confidence interval, 0.43 to 0.48), beta blockers (odds ratio, 0.46; 95% CI, 0.44 to 0.47), or ACEI/ARBs (odds ratio, 0.83; 95% confidence interval, 0.8 to 0.86) compared with obstructive CAD patients. Secondary analyses of selected subgroups supported the primary findings. CONCLUSIONS: Patients with nonobstructive CAD were significantly less likely to receive secondary prevention medication prescription at hospital discharge, as compared with patients with obstructive CAD. These findings highlight an opportunity to improve the quality of care for CAD patients with nonobstructive disease. PMID- 20923998 TI - Azathioprine-induced carcinogenesis in mice according to Msh2 genotype. AB - BACKGROUND: The thiopurine prodrug azathioprine is used extensively in cancer therapy. Exposure to this drug results in the selection of DNA mismatch repair deficient cell clones in vitro. It has also been suggested that thiopurine drugs might constitute a risk factor for the emergence of human neoplasms displaying microsatellite instability (MSI) because of deficient DNA mismatch repair. METHODS: Azathioprine was administered via drinking water (6-20 mg/kg body weight per day) to mice that were null (Msh2-(/)-; n = 27), heterozygous (Msh2(+/)-; n = 22), or wild type (Msh2(WT); n = 18) for the DNA mismatch repair gene Msh2. Control mice (45 Msh2-(/)-, 38 Msh2(+/)-, and 12 Msh2(WT)) received drinking water lacking azathioprine. The effect of azathioprine on tumorigenesis and survival of the mice was evaluated by Kaplan-Meier curves using log-rank and Gehan-Breslow-Wilcoxon tests. Mouse tumor samples were characterized by histology and immunophenotyping, and their MSI status was determined by polymerase chain reaction analysis of three noncoding microsatellite markers and by immunohistochemistry. Msh2 status of tumor samples was assessed by loss of heterozygosity analyses and sequencing after reverse transcription-polymerase chain reaction of the entire Msh2 coding sequence. All statistical tests were two sided. RESULTS: Most untreated Msh2(WT) and Msh2(+/)- mice remained asymptomatic and alive at 250 days of age, whereas azathioprine-treated Msh2(WT) and Msh2(+/)- mice developed lymphomas and died prematurely (median survival of 71 and 165 days of age, respectively). Azathioprine-treated Msh2(+/)- mice developed diffuse lymphomas lacking Msh2 expression and displaying MSI due to somatic inactivation of the functional Msh2 allele by loss of heterozygosity or mutation. By contrast, azathioprine-treated Msh2(WT) mice displayed no obvious tumor phenotype, but histological examination showed microscopic splenic foci of neoplastic lymphoid cells that retained Msh2 expression and did not display MSI. Both untreated and azathioprine-treated Msh2-(/)- mice had a reduced lifespan compared with untreated Msh2(WT) mice (median survival of 127 and 107 days of age, respectively) and developed lymphomas with MSI. CONCLUSION: Azathioprine-induced carcinogenesis in mice depends on the number of functional copies of the Msh2 gene. PMID- 20923999 TI - The cover. Vuillard's room at the Chateau des Clayes. PMID- 20924000 TI - A piece of my mind. Anticipatory guidance. PMID- 20924001 TI - Military probes epidemic of suicide: mental health issues remain prevalent. PMID- 20924002 TI - Race is on for effective dengue vaccine. PMID- 20924003 TI - New plaque-boosting protein a possible Alzheimer target. PMID- 20924004 TI - Arterial hyperoxia and in-hospital mortality after resuscitation from cardiac arrest. PMID- 20924005 TI - Arterial hyperoxia and in-hospital mortality after resuscitation from cardiac arrest. PMID- 20924006 TI - Critically ill patients and long-term acute care hospitals. PMID- 20924007 TI - Critically ill patients and long-term acute care hospitals. PMID- 20924008 TI - Changes in Idaho primary care physician clinical work hours, 1996-2009. PMID- 20924010 TI - Chest compression-only CPR by lay rescuers and survival from out-of-hospital cardiac arrest. AB - CONTEXT: Chest compression-only bystander cardiopulmonary resuscitation (CPR) may be as effective as conventional CPR with rescue breathing for out-of-hospital cardiac arrest. OBJECTIVE: To investigate the survival of patients with out-of hospital cardiac arrest using compression-only CPR (COCPR) compared with conventional CPR. DESIGN, SETTING, AND PATIENTS: A 5-year prospective observational cohort study of survival in patients at least 18 years old with out of-hospital cardiac arrest between January 1, 2005, and December 31, 2009, in Arizona. The relationship between layperson bystander CPR and survival to hospital discharge was evaluated using multivariable logistic regression. MAIN OUTCOME MEASURE: Survival to hospital discharge. RESULTS: Among 5272 adults with out-of-hospital cardiac arrest of cardiac etiology not observed by responding emergency medical personnel, 779 were excluded because bystander CPR was provided by a health care professional or the arrest occurred in a medical facility. A total of 4415 met all inclusion criteria for analysis, including 2900 who received no bystander CPR, 666 who received conventional CPR, and 849 who received COCPR. Rates of survival to hospital discharge were 5.2% (95% confidence interval [CI], 4.4%-6.0%) for the no bystander CPR group, 7.8% (95% CI, 5.8% 9.8%) for conventional CPR, and 13.3% (95% CI, 11.0%-15.6%) for COCPR. The adjusted odds ratio (AOR) for survival for conventional CPR vs no CPR was 0.99 (95% CI, 0.69-1.43), for COCPR vs no CPR, 1.59 (95% CI, 1.18-2.13), and for COCPR vs conventional CPR, 1.60 (95% CI, 1.08-2.35). From 2005 to 2009, lay rescuer CPR increased from 28.2% (95% CI, 24.6%-31.8%) to 39.9% (95% CI, 36.8%-42.9%; P < .001); the proportion of CPR that was COCPR increased from 19.6% (95% CI, 13.6% 25.7%) to 75.9% (95% CI, 71.7%-80.1%; P < .001). Overall survival increased from 3.7% (95% CI, 2.2%-5.2%) to 9.8% (95% CI, 8.0%-11.6%; P < .001). CONCLUSION: Among patients with out-of-hospital cardiac arrest, layperson compression-only CPR was associated with increased survival compared with conventional CPR and no bystander CPR in this setting with public endorsement of chest compression-only CPR. PMID- 20924012 TI - Use of advanced radiology during visits to US emergency departments for injury related conditions, 1998-2007. AB - CONTEXT: Excessive use of medical imaging increases health care costs and exposure to ionizing radiation (a potential carcinogen) without yielding significant benefits to all patients. OBJECTIVE: To determine whether there has been a change in the prevalence of emergency department visits for injury-related conditions for which computed tomography (CT) or magnetic resonance imaging (MRI) was obtained and whether there has been a change in the diagnosis of life threatening conditions and patient disposition. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cross-sectional analysis of emergency department visits using data from the National Hospital Ambulatory Medical Care Survey (1998 2007). Sampled visits were weighted to produce estimates for the United States. MAIN OUTCOMES MEASURES: Proportion of visits for injury-related conditions during which a CT or MRI was obtained, a life-threatening condition was diagnosed (eg, cervical spine fracture, skull fracture, intracranial bleeding, liver and spleen laceration), and which resulted in hospital and intensive care unit admission. RESULTS: The prevalence of CT or MRI use during emergency department visits for injury-related conditions increased from 6% (95% confidence interval [CI], 5%-7%) (257 of 5237 visits) in 1998 to 15% (95% CI, 14%-17%) (981 of 6567 visits) in 2007 (P < .001 for trend). There was a small increase in the prevalence of life threatening conditions (1.7% [95% CI, 1.2%-2.2%; 89 of 5237 visits] in 1998 and 2.0% [95% CI, 1.6%-2.5%; 142 of 6567 visits] in 2007; P=.04 for trend) [corrected].There was no change in prevalence of visits during which patients were either admitted to the hospital (5.9% [95% CI, 4.9%-6.9%] in 1998 and 5.5% [95% CI, 4.7%-6.5%] in 2007; P = .50 for trend) or to an intensive care unit (0.62% [95% CI, 0.40%-1.00%] in 1998 and 0.80% [95% CI, 0.53%-1.21%] in 2007; P = .14 for trend). Visits during which CT or MRI was obtained lasted 126 minutes (95% CI, 123-131 minutes) longer than those for which CT or MRI was not obtained. CONCLUSION: From 1998 to 2007, the prevalence of CT or MRI use during emergency department visits for injury-related conditions increased significantly, without an equal increase in the prevalence of life-threatening conditions. PMID- 20924013 TI - Evaluating the risks of clinical research. AB - The ethical appropriateness of clinical research depends on protecting participants from excessive risks. Yet no systematic framework has been developed to assess research risks, and as a result, investigators, funders, and review boards rely only on their intuitive judgments. Because intuitive judgments of risk are subject to well-documented cognitive biases, this approach raises concern that research participants are not being adequately protected. To address this situation, we delineate a method called the systematic evaluation of research risks (SERR), which evaluates the risks of research interventions by comparing these interventions with the risks of comparator activities that have been deemed acceptable. This method involves a 4-step process: (1) identify the potential harms posed by the proposed research intervention; (2) categorize the magnitude of the potential harms into 1 of 7 harm levels on a harm scale; (3) quantify or estimate the likelihood of each potential harm; and (4) compare the likelihood of each potential harm from the research intervention with the likelihood of harms of the same magnitude occurring as a result of an appropriate comparator activity. By explicitly delineating, quantifying, and comparing the risks of research interventions with the risks posed by appropriate comparator activities, SERR offers a way to minimize the influence of cognitive biases on the evaluation of research risks and thereby better protect research participants from excessive risks. PMID- 20924014 TI - Atypical fractures as a potential complication of long-term bisphosphonate therapy. AB - The development of bisphosphonate therapy represented an important advance in the treatment of low bone mass and osteoporosis, conditions that affect more than half of individuals older than 50 years. Currently available bisphosphonates have been shown to reduce spine, nonspine, and hip fractures in individuals at increased risk of fracture. Case reports and limited clinical series over the past 5 years have raised concern that prolonged bisphosphonate therapy may suppress bone remodeling to the extent that normal bone repair is impaired, resulting in increased fracture risk. Fractures potentially resulting from suppressed bone turnover have been described as "atypical," affecting sites such as the subtrochanteric femur that are infrequently affected by osteoporotic fractures. A prodrome of thigh pain, lack of trauma prior to the fracture, and specific radiological characteristics have also been reported. Data are limited on the prevalence of, risk factors for, and treatment of this potential problem. Current strategies include fracture risk assessment, targeting bisphosphonate therapy appropriately to individuals at increased risk of fracture, considering a 12-month interruption in therapy after 5 years in patients who are clinically stable, and considering teriparatide treatment in individuals who experience an atypical fracture while receiving bisphosphonate therapy. PMID- 20924015 TI - The right to bear arms: a uniquely American entitlement. PMID- 20924016 TI - Response of the food and beverage industry to the obesity threat. PMID- 20924017 TI - What if physicians actually had to control medical costs? PMID- 20924018 TI - What physician-investigators owe patients who participate in research. PMID- 20924019 TI - Compression-only CPR: pushing the science forward. PMID- 20924020 TI - Implementation of the ICMJE form for reporting potential conflicts of interest. PMID- 20924011 TI - Out-of-hospital hypertonic resuscitation following severe traumatic brain injury: a randomized controlled trial. AB - CONTEXT: Hypertonic fluids restore cerebral perfusion with reduced cerebral edema and modulate inflammatory response to reduce subsequent neuronal injury and thus have potential benefit in resuscitation of patients with traumatic brain injury (TBI). OBJECTIVE: To determine whether out-of-hospital administration of hypertonic fluids improves neurologic outcome following severe TBI. DESIGN, SETTING, AND PARTICIPANTS: Multicenter, double-blind, randomized, placebo controlled clinical trial involving 114 North American emergency medical services agencies within the Resuscitation Outcomes Consortium, conducted between May 2006 and May 2009 among patients 15 years or older with blunt trauma and a prehospital Glasgow Coma Scale score of 8 or less who did not meet criteria for hypovolemic shock. Planned enrollment was 2122 patients. INTERVENTION: A single 250-mL bolus of 7.5% saline/6% dextran 70 (hypertonic saline/dextran), 7.5% saline (hypertonic saline), or 0.9% saline (normal saline) initiated in the out-of-hospital setting. MAIN OUTCOME MEASURE: Six-month neurologic outcome based on the Extended Glasgow Outcome Scale (GOSE) (dichotomized as >4 or <=4). RESULTS: The study was terminated by the data and safety monitoring board after randomization of 1331 patients, having met prespecified futility criteria. Among the 1282 patients enrolled, 6-month outcomes data were available for 1087 (85%). Baseline characteristics of the groups were equivalent. There was no difference in 6-month neurologic outcome among groups with regard to proportions of patients with severe TBI (GOSE <=4) (hypertonic saline/dextran vs normal saline: 53.7% vs 51.5%; difference, 2.2% [95% CI, -4.5% to 9.0%]; hypertonic saline vs normal saline: 54.3% vs 51.5%; difference, 2.9% [95% CI, -4.0% to 9.7%]; P = .67). There were no statistically significant differences in distribution of GOSE category or Disability Rating Score by treatment group. Survival at 28 days was 74.3% with hypertonic saline/dextran, 75.7% with hypertonic saline, and 75.1% with normal saline (P = .88). CONCLUSION: Among patients with severe TBI not in hypovolemic shock, initial resuscitation with either hypertonic saline or hypertonic saline/dextran, compared with normal saline, did not result in superior 6-month neurologic outcome or survival. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00316004. PMID- 20924022 TI - JAMA patient page . Cardiopulmonary resuscitation. PMID- 20924021 TI - Calling Dr Kildare: the literary lives of Frederick Schiller Faust, aka Max Brand. PMID- 20924024 TI - Prevention of long-term sickness absence and major depression in high-risk employees: a randomised controlled trial. AB - OBJECTIVES: To examine the efficacy of early intervention on the prevention of long-term sickness absence and major depression among employees at high risk of future sickness absence and with mild to severe depressive complaints. METHODS: Randomised controlled trial conducted among employees working in an office environment. 139 employees were identified both at high risk of future sickness absence and with mild to severe depressive complaints through screening. Subsequently, they were randomly assigned to the intervention group (n = 69) or the control group (n = 70). Objective sickness absence was analysed at 12 and 18 months of follow-up. Depressive complaints were assessed by the Beck Depression Inventory (BDI-II) at baseline, and at 6 and 12 months of follow-up. RESULTS: Intention-to-treat analyses showed a significant difference in total sickness absence duration between the intervention (27.5 calendar days (SD 44.7)) and control group (50.8 days (SD 75.8)) over 12 months of follow-up, a reduction of 46% (p = 0.017). The intervention group showed a non-significantly lower proportion of long-term sickness absence spells compared with the control group (p = 0.127). Statistically significant and clinically relevant differences in depressive complaints were found after both 6 months (p = 0.001) and 12 months (p = 0.005) of follow-up, in favour of the intervention group. Relative risk reductions (RRR) were 19.2% and 19.8% respectively. Sickness absence data were available for all participants over 18 months of follow-up. Questionnaire data were available for 99 (at 6 months) and 90 participants (at 12 months). No adverse events or side effects occurred. CONCLUSIONS: Early intervention in employees with mild to severe depressive complaints and high risk of future long term sickness absence proved to be effective in preventing/reducing both sickness absence and depressive complaints. PMID- 20924023 TI - Exposure to occupational noise and cardiovascular disease in the United States: the National Health and Nutrition Examination Survey 1999-2004. AB - BACKGROUND: Chronic exposure to occupational noise may be associated with increased risk of coronary heart disease (CHD) and hypertension. However, findings are inconsistent and many previous studies are limited by small sample size and inappropriate control for potential confounders. We used a nationally representative US sample to examine associations of self-reported exposure to occupational noise with CHD and hypertension. METHODS: This cross-sectional study included 6307 participants of the National Health and Nutrition Examination Survey 1999-2004, aged >= 20 years and employed at the time of interview. Noise exposure assessment was based on self-reported exposure to loud noise in the workplace. RESULTS: Compared with never exposed participants, subjects chronically exposed to occupational noise had a 2-3-fold increased prevalence of angina pectoris, myocardial infarction, CHD and isolated diastolic hypertension. After adjustment for various covariates, the odds ratios (95% CIs) for angina pectoris, CHD and isolated diastolic hypertension were 2.91 (1.35 to 6.26), 2.04 (1.16 to 3.58) and 2.23 (1.21 to 4.12), respectively. There were clear exposure response relationships for the observed associations. Associations of noise exposure with angina pectoris, myocardial infarction and CHD were particularly strong for participants aged < 50 years, men and current smokers. There was no significant increase in levels of cardiovascular biomarkers including blood lipids and circulating inflammatory mediators associated with noise exposure. CONCLUSIONS: Chronic exposure to occupational noise is strongly associated with prevalence of CHD, especially for young male current smokers. This study suggests that excess noise exposure in the workplace is an important occupational health issue and deserves special attention. PMID- 20924025 TI - Prenatal and concurrent exposure to halogenated organic compounds and gene expression of CYP17A1, CYP19A1, and oestrogen receptor alpha and beta genes. AB - OBJECTIVE: To determine whether prenatal exposure to dichlorodiphenyl ethylene (DDE) and polychlorinated biphenyls (PCBs) and concurrent exposure to DDE, PCBs and polybrominated diphenylethers (PBDEs) affect gene expression of aromatase (CYP19A1), 17-alpha-hydroxylase (CYP17A1), and oestrogen receptors alpha and beta (ESR 1 and ESR2). METHODS: Based on maternal PCB and DDE levels in the parent generation of the Michigan Fisheater Cohort determined between 1973 and 1991, individual prenatal exposures were estimated and have been published. In 2007, female adult offspring of this cohort were examined. Gene expression and concurrent lipid-adjusted exposures to DDE, PCBs and PBDEs were measured in blood and serum, respectively. Using mixed models and path analyses, gene-expression data were regressed on prenatal and concurrent exposures controlling for confounders. RESULTS: 139 daughters of Michigan fisheaters (65.3%) participated in the investigation. While prenatal PCB levels were statistically significantly associated with decreased expression of the aromatase and 17-alpha-hydroxylase genes, prenatal DDE levels were significantly related to increased gene expression of aromatase but not of 17-alpha-hydroxylase. The DDE association seems to be mediated by concurrent lipid-adjusted p,p'-DDE serum levels. Prenatal and concurrent exposure of both PCBs and DDE had comparable effects. No association was found for PBDEs or for the gene expression of ESR 1 and ESR2. CONCLUSIONS: A 40-year antecedent prenatal exposure and concurrent levels of PCBs and DDE are associated with the expression of aromatase and 17-alpha-hydroxylase genes. Prenatal exposures to organochlorines may instigate long-term alterations of gene expression. Mechanisms of prenatal induction of persistent gene expression alterations are speculated to be epigenetic in nature. PMID- 20924026 TI - Sugar-hormone cross-talk in seed development: two redundant pathways of IAA biosynthesis are regulated differentially in the invertase-deficient miniature1 (mn1) seed mutant in maize. AB - The miniature1 (mn1) seed phenotype is a loss-of-function mutation at the Mn1 locus that encodes a cell wall invertase; its deficiency leads to pleiotropic changes including altered sugar levels and decreased levels of IAA throughout seed development. To understand the molecular details of such a sugar-hormone relationship, we have initiated studies on IAA biosynthesis genes in developing seeds of maize. Two tryptophan-dependent pathways of IAA biosynthesis, tryptamine (TAM) and indole-3-pyruvic acid (IPA), are of particular interest. We report on molecular isolation and characterization of an endosperm-specific ZmTARelated1 (ZmTar1) gene of the IPA branch; we have also reported recently on ZmYuc1 gene in the TAM branch. Comparative gene expression analyses here have shown that (1) the ZmTar1 transcripts were approximately 10-fold higher levels than the ZmYuc1; (2) although both genes showed the highest level of expression at 8-12 d after pollination (DAP) coincident with an early peak in IAA levels, the two showed highly divergent (antagonistic) response at 12 and 16 DAP but similar patterns at 20 and 28 DAP in the Mn1 and mn1 endosperm. The Western blot analyses for the ZmTAR1 protein, however, displayed disconcordant protein/transcript expression patterns. Overall, these data report novel observations on redundant trp dependent pathways of auxin biosynthesis in developing seeds of maize, and suggest that homeostatic control of IAA in this important sink is highly complex and may be regulated by both sucrose metabolism and developmental signals. PMID- 20924027 TI - Transcriptome analysis of high-temperature stress in developing barley caryopses: early stress responses and effects on storage compound biosynthesis. AB - High-temperature stress, like any abiotic stress, impairs the physiology and development of plants, including the stages of seed setting and ripening. We used the Affymetrix 22K Barley1 GeneChip microarray to investigate the response of developing barley (Hordeum vulgare) seeds, termed caryopses, after 0.5, 3, and 6 h of heat stress exposure; 958 induced and 1122 repressed genes exhibited spatial and temporal expression patterns that provide a detailed insight into the caryopses' early heat stress responses. Down-regulation of genes related to storage compound biosynthesis and cell growth provides evidence for a rapid impairment of the caryopsis' development. Increased levels of sugars and amino acids were indicative for both production of compatible solutes and feedback induced accumulation of substrates for storage compound biosynthesis. Metadata analysis identified embryo and endosperm as primary locations of heat stress responses, indicating a strong impact of short-term heat stress on central developmental functions of the caryopsis. A comparison with heat stress responses in Arabidopsis shoots and drought stress responses in barley caryopses identified both conserved and presumably heat- and caryopsis-specific stress-responsive genes. Summarized, our data provide an important basis for further investigation of gene functions in order to aid an improved heat tolerance and reduced losses of yield in barley as a model for cereal crops. PMID- 20924028 TI - Root-specific transcript profiling of contrasting rice genotypes in response to salinity stress. AB - Elevated salinity imposes osmotic and ion toxicity stresses on living cells and requires a multitude of responses in order to enable plant survival. Building on earlier work profiling transcript levels in rice (Oryza sativa) shoots of FL478, a salt-tolerant indica recombinant inbred line, and IR29, a salt-sensitive cultivar, transcript levels were compared in roots of these two accessions as well as in the roots of two additional salt-tolerant indica genotypes, the landrace Pokkali and the recombinant inbred line IR63731. The aim of this study was to compare transcripts in the sensitive and the tolerant lines in order to identify genes likely to be involved in plant salinity tolerance, rather than in responses to salinity per se. Transcript profiles of several gene families with known links to salinity tolerance are described (e.g. HKTs, NHXs). The putative function of a set of genes identified through their salt responsiveness, transcript levels, and/or chromosomal location (i.e. underneath QTLs for salinity tolerance) is also discussed. Finally, the parental origin of the Saltol region in FL478 is further investigated. Overall, the dataset presented appears to be robust and it seems likely that this system could provide a reliable strategy for the discovery of novel genes involved in salinity tolerance. PMID- 20924029 TI - Recycling of Solanum sucrose transporters expressed in yeast, tobacco, and in mature phloem sieve elements. AB - The plant sucrose transporter SUT1 (from Solanum tuberosum, S. lycopersicum, or Zea mays) exhibits redox-dependent dimerization and targeting if heterologously expressed in S. cerevisiae (Krugel et al., 2008). It was also shown that SUT1 is present in motile vesicles when expressed in tobacco cells and that its targeting to the plasma membrane is reversible. StSUT1 is internalized in the presence of brefeldin A (BFA) in yeast, plant cells, and in mature sieve elements as confirmed by immunolocalization. These results were confirmed here and the dynamics of intracellular SUT1 localization were further elucidated. Inhibitor studies revealed that vesicle movement of SUT1 is actin-dependent. BFA-mediated effects might indicate that anterograde vesicle movement is possible even in mature sieve elements, and could involve components of the cytoskeleton that were previously thought to be absent in SEs. Our results are in contradiction to this old dogma of plant physiology and the potential of mature sieve elements should therefore be re-evaluated. In addition, SUT1 internalization was found to be dependent on the plasma membrane lipid composition. SUT1 belongs to the detergent resistant membrane (DRM) fraction in planta and is targeted to membrane raft-like microdomains when expressed in yeast (Krugel et al., 2008). Here, SUT1-GFP expression in different yeast mutants, which were unable to perform endocytosis and/or raft formation, revealed a strong link between SUT1 raft localization, the sterol composition and membrane potential of the yeast plasma membrane, and the capacity of the SUT1 protein to be internalized by endocytosis. The results provide new insight into the regulation of sucrose transport and the mechanism of endocytosis in plant cells. PMID- 20924030 TI - Update on chloroplast research: new tools, new topics, and new trends. AB - Chloroplasts, the green differentiation form of plastids, are the sites of photosynthesis and other important plant functions. Genetic and genomic technologies have greatly boosted the rate of discovery and functional characterization of chloroplast proteins during the past decade. Indeed, data obtained using high-throughput methodologies, in particular proteomics and transcriptomics, are now routinely used to assign functions to chloroplast proteins. Our knowledge of many chloroplast processes, notably photosynthesis and photorespiration, has reached such an advanced state that biotechnological approaches to crop improvement now seem feasible. Meanwhile, efforts to identify the entire complement of chloroplast proteins and their interactions are progressing rapidly, making the organelle a prime target for systems biology research in plants. PMID- 20924031 TI - Significant increase in IgG4+ plasma cells in gastric biopsy specimens from patients with pernicious anaemia. AB - AIM: To investigate the presence of IgG4+ plasma cells in gastric mucosal biopsy samples from patients with atrophic gastritis (AG) and a history of pernicious anaemia (PA) (AG+PA+). METHODS: Gastric mucosal biopsy specimens from 46 patients with AG+PA+ were investigated. As controls, we evaluated specimens from patients with AG but no history of PA (AG+ PA-) (n=25), normal histology (n=25), mild chronic inactive gastritis (MCIG) (n=25) or Helicobacter pylori gastritis (HP) (n=25). IgG4+ plasma cells were detected by two immunohistochemical methods: (1) using a monoclonal antibody, the average of the three most cellular high-power fields was counted in areas with the highest density of IgG4+ plasma cells; (2) using a dual-chromagen stain for both IgG4 and CD138 (plasma cell marker), the number of IgG4+ cells per 200 CD138+ plasma cells was counted. The latter was used to ensure that the number of IgG4+ cells was not simply related to the degree of inflammation (density of plasma cells). RESULTS: Identical results were obtained with the two staining methods. Increased numbers of IgG4+ plasma cells were present in 37% of patients with AG+PA+, but in none with AG+PA-, MCIG, HP or normal gastric biopsy results (100% specific, p=0.0001). CONCLUSION: IgG4+ plasma cells may play a role in the pathogenesis of PA and may be a useful marker for its diagnosis. PMID- 20924032 TI - Expression of class I histone deacetylases (HDAC1 and HDAC2) in oesophageal adenocarcinomas: an immunohistochemical study. AB - BACKGROUND: Histone deacetylases (HDACs) are enzymes which play a central role in post-translational histone and non-histone protein modification. Deregulation of HDACs has been detected in various human malignancies and may also influence response to chemotherapy. AIMS: To investigate the expression of class I histone deacetylase (HDAC) isoforms 1 and 2 in oesophageal adenocarcinomas. METHODS: 132 primary resected tumours and 48 tumours treated by chemotherapy were analysed. Expression of HDAC1 and HDAC2 was determined by immunohistochemistry, applied on a tissue microarray and on pretherapeutic biopsies, and correlated with pathological features and prognosis. RESULTS: There was negative or low expression of HDAC1 in 54% of tumours, moderate expression in 41% and high expression in 5%. HDAC2 expression was negative or low in 30% of tumours, moderate in 47% and high in 21%. In primary resected tumours, high HDAC2 levels were associated with lymphatic tumour spread and lower tumour differentiation grade. HDAC1 levels were not associated with pT, pN category or tumour differentiation grade. For neoadjuvant treated tumours, there was only a trend for an association with high pretherapeutic HDAC2 expression and tumour regression after chemotherapy. Pretherapeutic HDAC1 levels were not associated with regression after chemotherapy. Survival analysis failed to show any prognostic impact of HDAC1 or HDAC2 expression. CONCLUSIONS: High HDAC2 expression is associated with aggressive tumour behaviour in oesophageal adenocarcinomas. No significant prognostic value could be found with respect to overall survival or an association with response to conventional chemotherapy for HDAC expression. Immunohistochemical determination of HDACs may be useful for prediction of response to specific HDAC inhibitors. PMID- 20924033 TI - Exploring the feasibility of establishing a disease-specific post-mortem tissue bank in the UK: a case study in ME/CFS. AB - BACKGROUND: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a condition, the aetiology of which remains controversial, and there is still no consensus on its nature and determination. It has rarely been studied in post mortem examinations, despite increasing evidence of abnormalities from neuroimaging studies. AIM: To ascertain the feasibility of developing a national post-mortem ME/CFS tissue bank in the UK, to enhance studies on aetiology and pathogenesis, including cell and tissue abnormalities associated with the condition. METHODS: The case study was carried out combining qualitative methods, ie, key informant interviews, focus group discussions with people with ME/CFS, and a workshop with experts in ME/CFS or in tissue banking. RESULTS AND CONCLUSIONS: The study results suggest that the establishment of the post-mortem ME/CFS tissue bank is both desirable and feasible, and would be acceptable to the possible tissue donors, provided that some issues were explicitly addressed. PMID- 20924034 TI - Hepatitis C virus and lymphoma: which is useful--serum or tissue? PMID- 20924035 TI - p16(INK4a) immunostaining as an alternative to histology review for reliable grading of cervical intraepithelial lesions. AB - BACKGROUND: Histomorphological grading of cervical intraepithelial neoplasia (CIN) is crucial for clinical management. CIN grading is however subjective and affected by substantial rates of discordance among pathologists, which may lead to overtreatment. To minimise this problem, a histology review of CIN lesions by a consensus panel of pathologists is often used. Diffuse strong p16(INK4a) immunostaining has been proposed to aid the identification of true high-grade cervical lesions (ie, CIN2/3). AIM: To assess the value of additional interpretation of p16(INK4a) immunostains for making a more reproducible diagnosis of CIN2/3 lesions. METHODS: The authors used a series of 406 biopsies of cervical lesions, with known HPV status, stained for both H&E- and p16(INK4a). First, in a randomly selected set of 49 biopsies, we examined the effect of additional interpretation of p16(INK4a) immunostained slides, on the agreement of CIN diagnosis among three pathologists. Second, the full series of samples was used to assess the accuracy of p16(INK4a)-supported lesion grading by a single pathologist, by evaluating the degree of diagnostic agreement with the consensus diagnosis of expert pathologists based on H&E-stained sections only. RESULTS: The study shows that the interobserver agreement between three pathologists for the routine H&E-based diagnosis ranged from fair (weighted kappa 0.44 (95% CI 0.19 to 0.64)) to moderate (weighted kappa 0.66 (95% CI 0.47 to 0.79)). The concordance increased substantially for p16(INK4a)-supported grading (mean weighted kappa 0.80 (95% CI 0.66 to 0.89)). Furthermore, an almost perfect agreement was found between the p16(INK4a)-supported diagnosis of a single pathologist and the consensus diagnosis of an expert pathology panel (kappa 0.88 (95% CI 0.85 to 0.89)). CONCLUSIONS: These data demonstrate that additive use of p16(INK4a) immunohistochemistry significantly improves the accuracy of grading CIN lesions by a single pathologist, equalling an expert consensus diagnosis. Hence, the authors advocate the combined use of p16(INK4a)-stained slides and conventional H&E sections in routine histopathology to improve accuracy of diagnosis. PMID- 20924036 TI - Absence of NPM1 promoter hypermethylation in human myelodysplastic syndrome. AB - Npm1(+/-) heterozygous mice develop a haematological disorder with features resembling human myelodysplastic syndrome (MDS). Promoter hypermethylation of the NPM1 gene may lead to suppressed gene transcription and hence functional haploinsufficiency, which contributes to the development of MDS. Thirty-one patients with MDS and eight normal individuals were studied for promoter methylation and mRNA expression of NPM1. Methylation-specific PCR (MSP), COBRA and bisulfite sequencing were used to examine the NPM1 methylation status. Quantitative PCR was used to assess the expression of NPM1. NPM1 DNA methylation was rare, occurring in one of 31 cases as determined by MSP. There was no significant difference in NPM1 mRNA expression between MDS and normal blood samples. In conclusion, the finding suggests that NPM1 methylation is rare in MDS and does not play a major role in its pathogenesis. PMID- 20924037 TI - Strong cytoplasmic expression of COX2 at the invasive fronts of gallbladder cancer is associated with a poor prognosis. AB - AIM: The significance of cell cycle proteins, p21 and p53, and cyclo-oxygenase-2 (COX2) is still controversial in gallbladder adenocarcinoma. Conflicting results exist with regard to the prognostic significance of p21 and p53 expression, and the strong association of gallbladder cancer with chronic inflammation makes it only natural that COX2 negativity is rarely encountered, even in non-neoplastic biliary epithelia. METHODS: The authors explored whether the p21 and p53 labelling indices (LI) and strong cytoplasmic COX2 expression differ in the central parts (TC) and invasive fronts (IF) of gallbladder cancer. Paraffin embedded whole tissue sections of 67 gallbladder cancers were immunohistochemically analysed for p21, p53 and COX2-LI at the IF and TC, and results were correlated with the clinicopathological features. RESULTS: Significantly higher LI was seen in IF compared with TC for p21, p53 and COX2. COX2-LI-IF showed significant positive correlations with perineural and lymphatic invasion, higher T and N stages, and non-papillary gross morphology. Gall-bladder cancers with COX2-LI-IF>=30% showed decreased overall and disease-free survival, and COX2-LI-IF>=30% was an independent poor prognostic factor on multivariable analysis. Gall-bladder cancers with high COX2 and p21-LI-IF showed decreased overall and disease-free survival. CONCLUSIONS: The IF of gallbladder cancer is characterised by significantly increased expression of p21, p53 and strong COX2 expression, and strong cytoplasmic COX2 expression at IF is associated with a poorer prognosis. Heterogeneity between TC and IF should be considered in in situ molecular studies, especially during interpretation of immunohistochemical stain results and tissue microarray construction. PMID- 20924038 TI - Selective testing of beta-galactosidase activity in the laboratory identification of Salmonella and Shigella species. AB - BACKGROUND: Salmonella and Shigella species are pathogens of great medical and public health importance. However, laboratory identification of these organisms is time consuming. Using current standard laboratory algorithms, the vast majority of organisms submitted for serological typing with Salmonella-specific and Shigella-specific antisera are not clinically significant. AIMS: To assess the addition of the O-nitrophenyl-beta-d-galactopyranoside (ONPG) test to the standard screening protocol for identification of Salmonella and Shigella species, and to describe a revised algorithm for the identification of these pathogens. METHODS: 71 non-lactose-fermenting isolates that were urease negative, indole negative, and produced acid and gas in triple sugar iron agar, with no H(2)S production in the agar, were tested for beta-galactosidase activity using the ONPG test. The test results were read at half-hourly intervals over a 4 h incubation period in O(2) at 37 degrees C. RESULTS: 42 isolates (59.2%) were found to be Hafnia alvei, of which 36 strains (85.7%) were ONPG positive. All 18 of the Enterobacter species (25.4%) were ONPG positive. Overall, about 79% of the ONPG-positive isolates were positive at the end of the first half-hour of incubation. The two pathogenic isolates obtained during this study were both identified as Salmonella enterica serovar Paratyphi A, and they were ONPG negative. CONCLUSIONS: Incorporation of a 30 min ONPG test for non-lactose fermenting organisms that are indole negative, urease negative, producers of acid and gas from glucose, oxidase negative and non-H(2)S gas producers eliminates the need for further serological testing of 79% of isolates, substantially improving the efficiency of the identification protocol. PMID- 20924039 TI - DNA methylation and genome evolution in honeybee: gene length, expression, functional enrichment covary with the evolutionary signature of DNA methylation. AB - A growing body of evidence suggests that DNA methylation is functionally divergent among different taxa. The recently discovered functional methylation system in the honeybee Apis mellifera presents an attractive invertebrate model system to study evolution and function of DNA methylation. In the honeybee, DNA methylation is mostly targeted toward transcription units (gene bodies) of a subset of genes. Here, we report an intriguing covariation of length and epigenetic status of honeybee genes. Hypermethylated and hypomethylated genes in honeybee are dramatically different in their lengths for both exons and introns. By analyzing orthologs in Drosophila melanogaster, Acyrthosiphon pisum, and Ciona intestinalis, we show genes that were short and long in the past are now preferentially situated in hyper- and hypomethylated classes respectively, in the honeybee. Moreover, we demonstrate that a subset of high-CpG genes are conspicuously longer than expected under the evolutionary relationship alone and that they are enriched in specific functional categories. We suggest that gene length evolution in the honeybee is partially driven by evolutionary forces related to regulation of gene expression, which in turn is associated with DNA methylation. However, lineage-specific patterns of gene length evolution suggest that there may exist additional forces underlying the observed interaction between DNA methylation and gene lengths in the honeybee. PMID- 20924040 TI - Applying toxicological risk assessment principles to constituents of smokeless tobacco products: implications for product regulation. AB - OBJECTIVE: To determine how information on chemical constituents of different smokeless tobacco products (STPs) may be used in cancer risk assessment for regulatory purposes. METHODS: This study investigated select STP constituents potentially associated with significant cancer risk by applying a known toxicological risk assessment framework. Cancer risk estimates were obtained for selected constituents of STPs and a medicinal nicotine gum formulation with comparable toxicity information and also median concentration data on the GothiaTek analytes. The calculated cancer risk was considered 'unacceptable' if it exceeded the US Environmental Protection Agency's (USEPA's) benchmark of an 'acceptable' cancer risk of 10E-6. RESULTS: The cancer risk estimates derived from daily use of 10 g of STPs meeting the industry-set GothiaTek limits exceed the levels generally considered 'acceptable' by the USEPA at least 8000 times. Except for the medicinal nicotine tested, all the STP types, including the relatively lower tobacco specific nitrosamine (TSNA)-containing snus, were found to carry an 'unacceptable' cancer risk. The calculated cancer risks associated with the snus and the US moist snuff products were, respectively, at least 1000 times and 6000 times greater than the minimum acceptable. TSNA and cadmium are associated with the largest estimated cancer risks for all the STPs evaluated. CONCLUSIONS: This study's findings provide an empirical risk assessment that could guide STP regulation using an existing toxicological assessment framework. The study findings question the scientific rationale of the industry-set standards and highlight the need for regulatory actions to reduce specific toxicants in all STPs. PMID- 20924041 TI - Definition of a quit attempt: a replication test. AB - INTRODUCTION: The incidence of quit attempts is often used to measure the effects of tobacco control interventions. Many surveys of quit attempts require that the attempt last >=24 hr, presumably to provide a more objective definition and to eliminate less serious attempts; however, this criterion may bias outcomes by excluding the more dependent quitters who cannot stop for 1 day despite a serious quit attempt. METHODS: We examined the 2003 and the 2006-2007 Tobacco Use Supplements to the Current Population Survey to determine the prevalence of quit attempts that did and did not last 24 hr, both in the last 12 months and in one's lifetime among current daily smokers. We also tested the hypothesis that those unable to quit for 24 hr were the more dependent smokers. RESULTS: Requiring quit attempts to last 24 hr excluded 6%-17% of smokers who stated they made a quit attempt. Whether smokers who could not quit for more than 24 hr were more dependent varied across survey, recall duration, and measure. CONCLUSIONS: We conclude restricting quit attempts to those who have quit for 24 hr underestimates the prevalence of attempts. Whether those unable to quit for 24 hr are the more dependent smokers is unclear. Empirical tests of whether the addition of a 24-hr criterion increases reliability or validity are needed. PMID- 20924042 TI - Smoking on both sides of the pacific: home smoking restrictions and secondhand smoke exposure among Korean adults and children in Seoul and California. AB - INTRODUCTION: This study, informed by ecological frameworks, compared the prevalence, predictors, and association of home smoking restrictions with secondhand smoke exposure (SHSe) between Koreans in Seoul, South Korea, and Korean Americans in California, United States. METHODS: A cross-sectional survey was drawn from telephone interviews with Korean adults in Seoul (N = 500) and California (N = 2,830) during 2001-02. Multivariable regressions were used for analyses. RESULTS: Koreans, compared with Korean Americans, had significantly fewer complete home smoking bans, 19% (95% CI: 16-23) versus 66% (95% CI: 64-68), and were more likely to not have a home smoking restriction, 64% (95% CI: 60-69) versus 5% (95% CI: 4-6). Home smoking restrictions were associated with lower home SHSe; however, the impact was consistently larger among Korean Americans. Households with more SHSe sources were less likely to have the strongest home smoking restrictions, where the difference in complete bans among Korean Americans versus Koreans was largely among those at low risk of SHSe, 82% (95% CI: 76-86) versus 36% (95% CI: 17-57), while high-risk Korean American and Koreans had similar low probabilities, 10% (95% CI: 7-13) versus 7% (95% CI: 3 13). CONCLUSIONS: Consistent with ecological frameworks, exposure to California's antismoking policy and culture was associated with stronger home smoking restrictions and improved effectiveness. Interventions tailored to Korean and Korean American SHSe profiles are needed. Behavioral interventions specifically for high-risk Korean Americans and stronger policy controls for Koreans may be effective at rapidly expanding home smoking restrictions. PMID- 20924043 TI - Stimulatory effects of propylthiouracil on pregnenolone production through upregulation of steroidogenic acute regulatory protein expression in rat granulosa cells. AB - Propylthiouracil (PTU) is a common and effective clinical medicine for the treatment of hyperthyroidism. Our previous study demonstrated that short-term treatment with PTU inhibits progesterone production in rat granulosa cells. However, our present results indicate that a 16-h treatment with PTU was able to stimulate pregnenolone production in rat granulosa cells, although progesterone production was diminished by PTU through inhibition of 3beta-hydroxysteroid dehydrogenase. Notably, we found that PTU treatment enhanced the conversion of cholesterol into pregnenolone, whereas the protein level of the cytochrome P450 side-chain cleavage enzyme (P450scc, which is the enzyme responding to this conversion) was not affected. Interestingly, the levels of steroidogenic acute regulatory protein (StAR) in both total cell lysate and the mitochondrial fraction were significantly increased by PTU treatment. Furthermore, the binding of steroidogenic factor-1 (SF-1) to the StAR promoter region was also enhanced by PTU treatment, which suggests that PTU could upregulate StAR gene expression. In addition to SF-1 regulation, we found that mitogen-activated protein (MAP) kinase kinase activation is an important regulator of PTU-stimulated StAR protein expression, based on the effects of the MEK inhibitor PD98059. In conclusion, these results indicate that PTU plays opposite roles in the production of progesterone and its precursor, pregnenolone. The regulation of negative feedback on speeding the cholesterol transportation and pregnenolone conversion after a 16 h PTU treatment may be the mechanism explaining PTU's inhibition of progesterone production in rat granulosa cells. PMID- 20924044 TI - Estimation of a preference-based carer experience scale. AB - BACKGROUND: There is growing interest in incorporating the effects of interventions on unpaid carers in economic evaluation. Current methods focus on using health measures (which neglect important aspects of care-related quality of life) or using carer-specific sum score measures (which are not preference based). OBJECTIVE: To estimate preference-based index values for a profile measure of the caring experience (the Carer Experience Scale). METHODS: Eighteen profiles from the Carer Experience Scale were included in a best-worst scaling experiment. In each profile, respondents were asked to pick the best and worst attribute level from the profiles. The choice task was completed in a postal questionnaire by 162 unpaid carers of older people from 5 geographical locations in the United Kingdom. Logistic regression was used to estimate utility weights for the attribute levels of the Carer Experience Scale. Alternative modeling assumptions were employed to determine the stability of the parameter estimates. These parameter estimates were rescaled so that the profile index values for the Carer Experience Scale lay on a 0-to-100 scale. RESULTS: The results indicate that low levels of "activities" and "getting on" result in larger decrements to utility than other attributes of the caring experience. In general, greater value is placed on differences between the bottom and middle levels of attributes than between the middle and top levels. Alternative modeling approaches had a negligible effect on the index values. CONCLUSION: The index values reported in this study offer a new preference-based approach to incorporating the effects on carers in economic evaluation, focusing on care (rather than health)-related quality of life. PMID- 20924045 TI - Estimating a preference-based index for a 5-dimensional health state classification for asthma derived from the asthma quality of life questionnaire. AB - BACKGROUND: This article presents a valuation study to estimate a preference based index for a 5-dimensional health state classification for asthma (AQL-5D) derived from the Asthma Quality of Life Questionnaire (AQLQ). METHODS: A sample of 307 members of the UK general population valued 99 asthma health states selected from the AQL-5D using the time tradeoff technique. Models were estimated to predict all possible 3125 health states defined by the AQL-5D, and the models were compared in terms of their ability to predict mean values for the 99 states. RESULTS: Mean health state values ranged from 0.39 to 0.94 based on an average of 22 valuations per state. A main effects model estimated on mean health state values and adjusted for consistency had the best predictive ability (mean absolute error of 0.047 and only 9/98 states with errors >0.1) and the most logical consistency with levels of the AQL-5D. The low number of valuations per state may have resulted in unreliable estimates for the models. Preference-based condition specific measures are limited in their ability to make cross-disease comparisons. CONCLUSION: This is the first study to derive a condition-specific preference-based measure from an existing measure of health-related quality of life in asthma for use in economic evaluation. PMID- 20924046 TI - Frequency of VDRL seropositivity among clinically healthy adult men from districts of Punjab province in Pakistan. PMID- 20924047 TI - Non-monogamy: risk factor for STI transmission and acquisition and determinant of STI spread in populations. AB - BACKGROUND: The concept of concurrent partnerships, while theoretically appealing, has been challenged at many levels. However, non-monogamy may be an important risk factor for the acquisition and transmission of sexually transmitted infections (STI). One's own non-monogamy is a risk factor for transmitting STI to others, partners' non-monogamy is a risk factor for acquiring STI and, most importantly, mutual non-monogamy is a population level determinant of increased STI spread. This study describes the levels, distribution and correlates of non-monogamy, partners' non-monogamy and mutual non-monogamy among adult men and women in the USA. METHODS: Data from the National Survey of Family Growth (NSFG) Cycle 6 were used. NSFG is a national household survey of subjects aged 15-44 years in the USA. Cochran-Mantel-Haenszel tests and chi(2) tests were used in the analysis. RESULTS: Among sexually active adults, 17.6% of women and 23.0% of men (an estimated 19 million) reported non-monogamy over the past 12 months in 2002. An estimated 11 million Americans (1 in 10) reported partners' non-monogamy and an estimated 8.4 million (7% of women and 10.5% of men) reported mutual non-monogamy. All three types of non-monogamy were reported more frequently by men than women. Younger age, lower education, formerly or never married status, living below the poverty level and having spent time in jail were associated with all three types of non-monogamy in general. CONCLUSIONS: The three types of non-monogamy may be helpful in tailoring prevention messages and targeting prevention efforts to subgroups most likely to spread infection. PMID- 20924048 TI - Treatment of syphilis in HIV-infected subjects: a systematic review of the literature. AB - BACKGROUND: The optimal antimicrobial regimen to treat syphilis in HIV-infected subjects remains controversial. OBJECTIVE: To systematically assess the literature for studies evaluating syphilis treatment regimens in this population. METHODS: Two reviewers independently assessed studies published between 1980 and June 2008 in electronic databases, trial registries and bibliographies (with no language restrictions) for content and quality. Studies that included 10 or more people, with documented HIV status, type and duration of syphilis treatment and at least 6 months of follow-up were included. The primary outcome was syphilis serological or clinical failure stratified by syphilis stage. RESULTS: Of 1380 unique citations, 23 studies (22 published papers and 1 conference abstract) were included in the systematic review. Owing to the significant heterogeneity among studies, pooled summary statistics could not be generated. The range of probabilities for serological failure with 2.4 million units (MU) of intramuscular benzathine penicillin G (BPG) was 6.9% (95% CI 2.6% to 14.4%) to 22.4% (11.7% to 36.6%); that of 7.2 MU of BPG in late latent syphilis was 19.4% (11.9% to 28.9%) to 31.1% (22.3% to 40.9%) and failure estimates with 18-24 MU of aqueous penicillin for the treatment of neurosyphilis were 27.3% (6.0% to 61.0%) to 27.8% (14.2% to 45.2%). CONCLUSIONS: The optimal antimicrobial regimen to treat syphilis in HIV-infected subjects is unknown; guideline recommendations in this population are based on little objective data. PMID- 20924049 TI - Different population-level vaccination effectiveness for HPV types 16, 18, 6 and 11. AB - BACKGROUND: Given that the human papillomavirus (HPV) vaccine types have different durations of infectiousness and infectivity, the population-level vaccine effectiveness of these types may differ even if vaccine efficacy is identical. OBJECTIVE: To compare the type-specific effectiveness of vaccination against HPV types 16, 18, 6 and 11. METHODS: An individual-based stochastic model of HPV transmission (18 HPV-types) in a population stratified by age, gender and sexual activity was developed. Multiple parameter sets were identified by fitting the model to sexual behaviour data and age- and type-specific HPV prevalence. RESULTS: Under base case assumptions (70% coverage, 99% vaccine efficacy per act and 20 years' duration of protection), vaccinating 12-year-old girls is predicted to reduce HPV-16, HPV-18 and HPV-6/11 prevalence by 61% (80% uncertainty interval (UI) 53-77), 92% (80% UI 65-100) and 100% (80% UI 97-100), respectively, 50 years after the start of the vaccination programme. Differences in type-specific vaccine effectiveness increased over time, and decreased with improved vaccine efficacy characteristics. CONCLUSIONS: For the same vaccine efficacy, the population-level impact of HPV vaccination will most likely be different, with HPV-16, the most oncogenic type, having the lowest effectiveness. These results should be taken into account when designing and interpreting post-vaccination surveillance studies. PMID- 20924050 TI - The concentration of sexual behaviours in the USA: a closer examination of subpopulations. AB - OBJECTIVE: To examine the frequency of three sexual behaviours from the most active to the least active members of the population in various subpopulations using measures of inequality. METHODS: Data from a US national probability sample of the population aged 15-44 years (National Survey of Family Growth) were used. Gini coefficients and Lorenz curves were calculated in order to examine the concentration of three sexual behaviours: vaginal sex acts (past 4 weeks) and number of opposite-sex partners (past 12 months; lifetime). Analyses were conducted separately for men and women and subpopulations of interest (by age, race/ethnicity, educational level and poverty level). RESULTS: The sexual behaviours examined were concentrated within the most active members of the population. This concentration was most pronounced for vaginal sex acts in the past 4 weeks and lifetime opposite-sex partners, with the top 5% of each population accounting for more of the sexual behaviour than the bottom 50% of the population. Sexual behaviours were most concentrated among adolescents, the least educated and the most impoverished. Some subpopulations had similar mean or median numbers of sex acts (or sex partners), but had different degrees of concentration of these behaviours. Finally, the most impoverished men and women had the highest concentration levels for two of the three sexual behaviours (vaginal sex acts, opposite-sex partners in past 12 months). CONCLUSION: Given that sexual behaviours tended to be highly concentrated in subpopulations that are often at the highest risk of sexually transmitted infections, targeted interventions may be the most efficient method to reduce risk in these groups while minimising potential unintended consequences. PMID- 20924051 TI - Light drinking during pregnancy: still no increased risk for socioemotional difficulties or cognitive deficits at 5 years of age? AB - BACKGROUND: This study examines the relationship between light drinking during pregnancy and the risk of socioemotional problems and cognitive deficits at age 5 years. METHODS: Data from the nationally representative prospective UK Millennium Cohort Study (N=11,513) were used. Participants were grouped according to mothers' reported alcohol consumption during pregnancy: never drinker; not in pregnancy; light; moderate; heavy/binge. At age 5 years the strengths and difficulties questionnaire (SDQ) and British ability scales (BAS) tests were administered during home interviews. Defined clinically relevant cut-offs on the SDQ and standardised scores for the BAS subscales were used. RESULTS: Boys and girls born to light drinkers were less likely to have high total difficulties (for boys 6.6% vs 9.6%, OR=0.67, for girls 4.3% vs 6.2%, OR=0.69) and hyperactivity (for boys 10.1% vs 13.4%, OR=0.73, for girls 5.5% vs 7.6%, OR=0.71) scores compared with those born to mothers in the not-in-pregnancy group. These differences were attenuated on adjustment for confounding and mediating factors. Boys and girls born to light drinkers had higher mean cognitive test scores compared with those born to mothers in the not-in-pregnancy group: for boys, naming vocabulary (58 vs 55), picture similarities (56 vs 55) and pattern construction (52 vs 50), for girls naming vocabulary (58 vs 56) and pattern construction (53 vs 52). Differences remained statistically significant for boys in naming vocabulary and picture similarities. CONCLUSIONS: At age 5 years cohort members born to mothers who drank up to 1-2 drinks per week or per occasion during pregnancy were not at increased risk of clinically relevant behavioural difficulties or cognitive deficits compared with children of mothers in the not in-pregnancy group. PMID- 20924052 TI - Marital history 1971-91 and mortality 1991-2004 in England & Wales and Finland. AB - BACKGROUND: Little is known about the effects of long-term marital history on mortality, and the relative importance of using marital history instead of baseline marital status in mortality analyses. No previous comparative studies on the associations of marital history and mortality exist. METHODS: Longitudinal data from England & Wales and from Finland were used to assess the effects of marital history, constructed from census records from years 1971, 1981 and 1991, on all-cause mortality in 1991-2004 among men and women aged >= 50 years. Data from England & Wales include 57,492 deaths; data from Finland include 424,602 deaths. Poisson regression analysis was applied. RESULTS: Adding marital history into models including baseline marital status was statistically significant when explaining male mortality, while it was generally not important for female mortality. Adjusted for socio-demographic covariates, those consistently married with no record of marital break-up had the lowest mortality rates among both men and women aged 50-74 in both countries. Those never married, those divorced with a history of divorce and those widowed with a history of widowhood showed the highest mortality risks. Associations between marital history and mortality were weaker among those aged 75+. CONCLUSIONS: Consistent evidence in favour of both protective effects of long-lasting marriage and detrimental effects of marital dissolution were found. Studies would benefit from including marital history in the models instead of baseline marital status whenever possible, especially when studying male mortality. PMID- 20924053 TI - A comparative study of educational inequality in the risk of stillbirth in Denmark, Finland, Norway and Sweden 1981-2000. AB - BACKGROUND: The stillbirth rates in Denmark, Finland, Norway and Sweden are among the lowest in the world, but socioeconomic disparities in stillbirth still exist. This study examined the educational patterns in the risk of stillbirth in Denmark, Finland, Norway and Sweden from 1981 to 2000. METHODS: From the national birth registries, all singleton live births and stillbirths with a gestational age of at least 28 weeks were selected in Denmark (n=1 182 888), Finland (n=419 729), Norway (n=1 006 767) and Sweden (n=1 974 101). The births were linked with individual data on parental socioeconomic factors from various national registers. Linear and logistic regression were used to calculate RR and risk differences for stillbirth according to maternal educational attainment. RESULTS: The risk of stillbirth was lowest in Finland and highest in Denmark. The risk decreased over time in Denmark, Norway and Finland, but remained stable in Sweden. Educational gradients were found in all countries in all time periods under study. In Denmark, the gradient remained stable over time. In Norway the gradient decreased slightly during the 1990s, whereas the gradient increased in Sweden. The gradient in Finland was relatively stable. CONCLUSIONS: There were persisting educational inequalities in stillbirth in Denmark, Finland, Norway and Sweden in the 1980s and 1990s. Inequalities were stable or decreasing except in Sweden, where an increase in inequality was observed. This increase was not solely attributable to a decreasing absolute risk of stillbirth as both the relative and absolute measures of inequality increased. PMID- 20924054 TI - Exposure to parental mortality and markers of morbidity, and the risks of attempted and completed suicide in offspring: an analysis of sensitive life periods. AB - BACKGROUND: There is evidence of parental risk factors for suicidal behaviour in offspring, but research on variations in their effects with offspring's age at first exposure is sparse. AIMS: To explore the effects of age at exposure to parental mortality and markers of morbidity on the risks of suicide and attempted suicide in offspring. METHODS: This was a case-control study effected through record linkage between Swedish registers. Individuals born 1973-83 who committed suicide (n=1407) or were hospitalised due to an attempted suicide (n=17 159) were matched to <=10 controls by sex, month and county of birth. ORs were measured in time windows representing age at first exposure. RESULTS: A general pattern of increasing risks of suicide and attempted suicide in offspring with decreasing age at exposure to parental risk factors emerged. Adjusted suicide risk (OR (95% CI)) was most pronounced in the youngest exposure window for parental psychiatric disability pension (3.1 (1.6 to 5.8)), somatic disability pension (1.9 (1.0 to 3.4)), psychiatric inpatient care (2.5 (2.0 to 3.1)), parental attempted suicide (2.9 (2.0 to 4.1)) and suicide (2.9 (1.7 to 5.2)). For parental non-suicidal deaths, the general pattern was the opposite. Patterns in offspring attempted suicide were similar to completed suicide for parental disability pension, psychiatric inpatient care and non-suicidal death. Attempted suicide risk after parental suicide showed an increasing trend with increasing age at exposure. CONCLUSION: Parental morbidity and parental suicidal behaviour show the most detrimental effects on completed suicide among offspring when they appear early in life. Early interventions in families at risk are necessary to prevent suicide in offspring. PMID- 20924055 TI - Changes of occupational class differences in physical functioning: a panel study among employees (2000-2007). AB - BACKGROUND: Panel studies on changes of occupational class differences in health have given varying results. The aim of this study was to examine changes of occupational class differences in physical functioning and the factors that explain these changes. METHODS: A cohort of middle-aged employees of the City of Helsinki was followed up for an average of 6 years in two surveys from 2000-2002 and 2007. Hierarchical linear random effects models were fitted to analyse the changes of occupational class differences in SF-36 physical functioning, as well as the contribution of physical and psychosocial working conditions, material conditions, health behaviours and employment status to these changes. RESULTS: Lower occupational classes had worse physical functioning at baseline: among women, the SF-36 scores ranged from 50.5 in the highest class to 47.1 in the lowest one, and among men from 52.2 to 48.9, with higher scores indicating better health. Occupational class differences widened during the follow-up due to stronger decline of physical functioning in the lower occupational classes than in the higher occupational classes. The largest difference in the decline of functioning between classes was 1.2 scores among women and 1.5 scores among men. Among women the widening of the class differences could be explained partly by health behaviours and employment status and among men by material conditions. CONCLUSION: Occupational class differences in physical functioning widened due to a faster decline of physical functioning in the lower occupational classes. Health behaviours, employment status and material conditions explained the widening class differences in physical functioning. PMID- 20924056 TI - 'No admittance to obese persons'. PMID- 20924057 TI - Propensity score matching approach to test the association of income inequality and mortality in Sao Paulo, Brazil. AB - BACKGROUND: Support for the adverse effect of high income inequality on population health has come from studies that focus on larger areas, such as the US states, while studies at smaller geographical areas (eg, neighbourhoods) have found mixed results. METHODS: We used propensity score matching to examine the relationship between income inequality and mortality rates across 96 neighbourhoods (distritos) of the municipality of Sao Paulo, Brazil. RESULTS: Prior to matching, higher income inequality distritos (Gini >= 0.25) had slightly lower overall mortality rates (2.23 per 10,000, 95% CI -23.92 to 19.46) compared to lower income inequality areas (Gini <0.25). After propensity score matching, higher inequality was associated with a statistically significant higher mortality rate (41.58 per 10,000, 95% CI 8.85 to 73.3). CONCLUSION: In Sao Paulo, the more egalitarian communities are among some of the poorest, with the worst health profiles. Propensity score matching was used to avoid inappropriate comparisons between the health status of unequal (but wealthy) neighbourhoods versus equal (but poor) neighbourhoods. Our methods suggest that, with proper accounting of heterogeneity between areas, income inequality is associated with worse population health in Sao Paulo. PMID- 20924058 TI - Data and safety monitoring plans and boards. PMID- 20924059 TI - Kenji Soda--researching enzymes with the spirit of an alpinist. AB - Like an alpinist continuously seeking virgin peaks to climb, Kenji Soda has investigated a variety of unique enzymes for which there was little or no information available; and by doing so he opened up a variety of new fields in enzyme science and technology. In particular, he has promoted the study of enzymes requiring vitamin B-derived cofactors such as FAD, NAD(P) and pyridoxal 5'-phosphate, shedding light on their reaction mechanisms, enzymological properties, crystal structures and potential practical applications. Highlighted in this review are the studies of enzymes acting on d-amino acids and sulphur/selenium-containing amino acids and those from thermophilic and psychrophilic bacteria. PMID- 20924060 TI - Transfer function analysis of cerebral autoregulation dynamics during jaw movements. AB - Mastication as a mild but life-long exercise has been examined as a possibility for maintaining brain function in the elderly. Little is known, however, about the cerebral circulatory response during masticatory movement. The aim of this study was to develop a monitoring system for circulation dynamics during masticatory movement and to apply this system to the study of cerebral autoregulation. Cerebral blood flow, heart rate, and arterial blood pressure were simultaneously recorded, and changes in these circulatory systems were quantitatively evaluated in 38 young healthy volunteers. Transfer function analysis was also performed on blood pressure and cerebral blood flow for investigation of cerebral autoregulation during gum chewing. Although increases in cerebral blood flow, mean blood pressure, and heart rate suggested the activation of cerebral and systemic circulation during gum chewing, increased cerebral circulation was independent of systemic circulation. Our results suggest that cerebral autoregulation is well maintained during jaw movements. PMID- 20924061 TI - The role of bacteria in the caries process: ecological perspectives. AB - Dental biofilms produce acids from carbohydrates that result in caries. According to the extended caries ecological hypothesis, the caries process consists of 3 reversible stages. The microflora on clinically sound enamel surfaces contains mainly non-mutans streptococci and Actinomyces, in which acidification is mild and infrequent. This is compatible with equilibrium of the demineralization/remineralization balance or shifts the mineral balance toward net mineral gain (dynamic stability stage). When sugar is supplied frequently, acidification becomes moderate and frequent. This may enhance the acidogenicity and acidurance of the non-mutans bacteria adaptively. In addition, more aciduric strains, such as 'low-pH' non-mutans streptococci, may increase selectively. These microbial acid-induced adaptation and selection processes may, over time, shift the demineralization/remineralization balance toward net mineral loss, leading to initiation/progression of dental caries (acidogenic stage). Under severe and prolonged acidic conditions, more aciduric bacteria become dominant through acid-induced selection by temporary acid-impairment and acid-inhibition of growth (aciduric stage). At this stage, mutans streptococci and lactobacilli as well as aciduric strains of non-mutans streptococci, Actinomyces, bifidobacteria, and yeasts may become dominant. Many acidogenic and aciduric bacteria are involved in caries. Environmental acidification is the main determinant of the phenotypic and genotypic changes that occur in the microflora during caries. PMID- 20924062 TI - Loaded microplasma-sprayed CaP-coated implants in vivo. AB - Microplasma spray equipment to deposit calcium phosphate ceramic (CaP) coatings has been developed. Fifty-six titanium implants were inserted into the mandibles of 7 adult beagle dogs. The implants were either acid-etched (NC), conventionally plasma-sprayed (PS), micro-plasma-sprayed (MPS), or micro-plasma-sprayed (aMPS) only at the apical part. After 6 weeks, implants in one half of the mandible were subjected to load. Fifty-two weeks thereafter, the animals were killed. Regardless of load, bone healing was comparable for all surfaces tested. It was concluded that loading of MPS CaP-coated implants evokes a favorable bone response, and that the bone response does not differ from that of PS CaP-coated implants. However, functional loading of PS as well as MPS CaP-coated implants might be associated with increased crestal bone maintenance as compared with non coated implants. PMID- 20924064 TI - Genetic etiology and dental pulp cell deficiency of hypophosphatasia. AB - Hypophosphatasia is caused by mutations of the tissue-non-specific alkaline phosphatase (TNSALP) gene with deficiency of dentin structure. The aim of this study was to examine whether TNSALP mutation in dental pulp cells contributes to dentin dysplasia in hypophosphatasia. Mutation analysis showed that compound heterozygous mutations of TNSALP were identified in three hypophosphatasia patients, including 3 novel mutation sites. Exfoliated teeth from the patients showed abnormal dentin mineralization and loss of cementum, as assessed by ground sections and scanning electron microscope analysis. Dental pulp cells isolated from one of the patients showed a significantly reduced TNSALP activity and mineralization capacity when compared with those in dental pulp cells from the unaffected individuals. Our results suggested that dentin dysplasia in hypophosphatasia may be associated with the decreased mineralization ability of dental pulp cells. PMID- 20924065 TI - Crystallization of high-strength fine-sized leucite glass-ceramics. AB - Manufacturing of leucite glass-ceramics often leads to materials with inhomogeneous microstructures. Crystal-glass thermal mismatches which produce microcracking around larger crystals-agglomerates are associated with reduced mechanical properties. The hypotheses were that fine (< 1 um) crystal size and uniform microstructure in a thermally matched glass would increase the biaxial flexural strength (BFS). Glass was synthesized, attritor-milled, and heat treated. Glasses and glass-ceramics were characterized by XRD, SEM, and Dilatometry. Experimental (A, M1A and M2A) and commercial glass-ceramics were tested by the BFS test. Experimental glass-ceramics showed an increased leucite crystal number and decreased crystal size with glass particle size reduction. Leucite glass-ceramics (< 1 um) showed minimal matrix microcracking and BFS values of [mean (SD) MPa]: M1A = 253.8 (53.3); and M2A = 219.5 (54.1). Glass ceramics M1A and M2A had higher mean BFS and characteristic strength than the IPS Empress Esthetic glass-ceramic (p < 0.05). Fine-grained, translucent leucite glass-ceramics were synthesized and produced high mean BFS. PMID- 20924063 TI - Recent advances and developments in composite dental restorative materials. AB - Composite dental restorations represent a unique class of biomaterials with severe restrictions on biocompatibility, curing behavior, esthetics, and ultimate material properties. These materials are presently limited by shrinkage and polymerization-induced shrinkage stress, limited toughness, the presence of unreacted monomer that remains following the polymerization, and several other factors. Fortunately, these materials have been the focus of a great deal of research in recent years with the goal of improving restoration performance by changing the initiation system, monomers, and fillers and their coupling agents, and by developing novel polymerization strategies. Here, we review the general characteristics of the polymerization reaction and recent approaches that have been taken to improve composite restorative performance. PMID- 20924066 TI - ALK5 inhibition blocks TGFbeta-induced CCN2 expression in gingival fibroblasts. AB - Connective tissue growth factor (CCN2/CTGF) is not normally expressed in gingival fibroblasts, but is induced by the potent profibrotic cytokine TGFbeta and is overexpressed in gingival fibrosis. Since CCN2 is a marker and mediator of fibrosis, targeting CCN2 expression in gingival fibroblasts may provide new insights into the future development of novel therapeutic opportunities to treat oral fibrosis. Herein we used real-time polymerase chain-reaction, Western blot, and indirect immunofluorescence analysis to evaluate whether SB-431542, a specific pharmacological inhibitor of TGFbeta type I receptor (ALK5), blocks the ability of TGFbeta to induce CCN2 mRNA and protein expression in human gingival fibroblasts. Our results indicate that CCN2 mRNA and protein are induced by TGFbeta in gingival fibroblasts in a SB-431542-sensitive fashion. These results suggest that blocking ALK5 may be useful in blocking the profibrotic effects of TGFbeta in gingival fibroblasts. PMID- 20924067 TI - Oral health literacy among female caregivers: impact on oral health outcomes in early childhood. AB - The aim of this study was to investigate the association of female caregivers' oral health literacy with their knowledge, behaviors, and the reported oral health status of their young children. Data on caregivers' literacy, knowledge, behaviors, and children's oral health status were used from structured interviews with 1158 caregiver/child dyads from a low-income population. Literacy was measured with REALD-30. Caregivers' and children's median ages were 25 yrs (range = 17-65) and 15 mos (range = 1-59), respectively. The mean literacy score was 15.8 (SD = 5.3; range = 1-30). Adjusted for age, education, and number of children, low literacy scores (< 13 REALD-30) were associated with decreased knowledge (OR = 1.86; 95% CI = 1.41, 2.45) and poorer reported oral health status (OR = 1.44; 95% CI = 1.02, 2.05). Lower caregiver literacy was associated with deleterious oral health behaviors, including nighttime bottle use and no daily brushing/cleaning. Caregiver oral health literacy has a multidimensional impact on reported oral health outcomes in infants and young children. PMID- 20924068 TI - Biofilms inducing ultra-low friction on titanium. AB - Biofilm formation is widely reported in the literature as a problem in the healthcare, environmental, and industrial sectors. However, the role of biofilms in sliding contacts remains unclear. Friction during sliding was analyzed for titanium covered with mixed biofilms consisting of Streptococcus mutans and Candida albicans. The morphology of biofilms on titanium surfaces was evaluated before, during, and after sliding tests. Very low friction was recorded on titanium immersed in artificial saliva and sliding against alumina in the presence of biofilms. The complex structure of biofilms, which consist of microbial cells and their hydrated exopolymeric matrix, acts like a lubricant. A low friction in sliding contacts may have major significance in the medical field. The composition and structure of biofilms are shown to be key factors for an understanding of friction behavior of dental implant connections and prosthetic joints. For instance, a loss of mechanical integrity of dental implant internal connections may occur as a consequence of the decrease in friction caused by biofilm formation. Consequently, the study of the exopolymeric matrix can be important for the development of high-performance novel joint-based systems for medical and other engineering applications. PMID- 20924070 TI - Metabolomics of supragingival plaque and oral bacteria. AB - Dental caries is initiated by demineralization of the tooth surface through acid production by sugar metabolism of supragingival plaque microflora. To elucidate the sugar metabolic system, we used CE-MS to perform metabolomics of the central carbon metabolism, the EMP pathway, the pentose-phosphate pathway, and the TCA cycle in supra- gingival plaque and representative oral bacteria, Streptococcus and Actinomyces. Supragingival plaque contained all the targeted metabolites in the central carbon metabolism, except erythrose 4-phosphate in the pentose phosphate pathway. After glucose rinse, glucose 6-phosphate, fructose 6 phosphate, fructose 1,6-bisphosphate, dihydroxyacetone phosphate, and pyruvate in the EMP pathway and 6-phosphogluconate, ribulose 5-phosphate, and sedoheptulose 7 phosphate in the pentose-phosphate pathway, and acetyl CoA were increased. Meanwhile, 3-phosphoglycerate and phosphoenolpyruvate in the EMP pathway and succinate, fumarate, and malate in the TCA cycle were decreased. These pathways and changes in metabolites observed in supragingival plaque were similar to the integration of metabolite profiles in Streptococcus and Actinomyces. PMID- 20924071 TI - FAK pathway regulates PGE2 production in compressed periodontal ligament cells. AB - This study examined the role of focal adhesion kinase (FAK) as a mechanoreceptor in human periodontal ligament (hPDL) cells. hPDL cells were obtained from premolars extracted for orthodontic purposes. Mechanical stress was applied in a compressive manner (2 g/cm(2)) for various time durations (0.5, 2, 6, 24, 48 hrs) with or without a knockdown treatment for FAK. Compressive stimulation increased the level of phosphorylated FAK and prostaglandin E(2) production. The FAK knockdown cells showed significantly lower prostaglandin E(2) levels than the control cells. Furthermore, compressive stress up-regulated cyclo-oxygenase-2 mRNA, whereas there were no changes observed in the FAK-knockdown cells. These results suggest that FAK regulates the production of prostaglandin E(2) via the transcriptional regulation of COX-2 mRNA in compressive stimulated PDL cells. The FAK-integrin complex plays a role in mechanoreception and mechanotransduction in hPDL cells. PMID- 20924069 TI - Aging and bone. AB - Bones provide mechanical and protective function, while also serving as housing for marrow and a site for regulation of calcium ion homeostasis. The properties of bones do not remain constant with age; rather, they change throughout life, in some cases improving in function, but in others, function deteriorates. Here we review the modifications in the mechanical function and shape of bones, the bone cells, the matrix they produce, and the mineral that is deposited on this matrix, while presenting recent theories about the factors leading to these changes. PMID- 20924072 TI - Clinical and genetic characterization of classical forms of familial adenomatous polyposis: a Spanish population study. AB - BACKGROUND: Classical familial adenomatous polyposis (FAP) is characterized by the appearance of >100 colorectal adenomas. PATIENTS AND METHODS: We screened the APC and MUTYH genes for mutations and evaluated the genotype-phenotype correlation in 136 Spanish classical FAP families. RESULTS: APC/MUTYH mutations were detected in 107 families. Sixty-four distinct APC point mutations were detected in 95 families of which all were truncating mutations. A significant proportion (39.6%) had not been previously reported. Mutations were spread over the entire coding region and great rearrangements were identified in six families. Another six families exhibited biallelic MUTYH mutations. No APC or MUTYH mutations were detected in 29 families. These APC/MUTYH-negative families showed clinical differences with the APC-positive families. A poor correlation between phenotype and mutation site was observed. CONCLUSIONS: Our results highlight that a broad approach in the genetic study must be considered for classical FAP due to involvement of both APC and MUTYH and the heterogeneous spectrum of APC mutations observed in this Spanish population. The scarcely consistent genotype-phenotype correlation does not allow making specific recommendations regarding screening and management. Differences observed in APC/MUTYH-negative families may reflect a genetic basis other than mutations in APC and MUTYH genes for FAP predisposition. PMID- 20924073 TI - Breast cancer screening case-control study design: impact on breast cancer mortality. AB - BACKGROUND: Recent case-control studies on the effectiveness of population-based breast cancer screening show differences in the magnitude of breast cancer mortality reduction. We investigated the role played by aspects of the case control study design on these differences, e.g. the definition of cases and exposure to screening. MATERIAL AND METHODS: We investigated six case-control studies conducted in East Anglia (UK), Wales, Iceland, central and northern Italy, South Australia and The Netherlands. RESULTS: The breast cancer mortality reduction in the different case-control studies ranged from 38% to 70% in the screened versus the nonscreened women. We identified differences in design, e.g. the inclusion or exclusion of the first years of screening, and the correction factor for self-selection bias. CONCLUSIONS: Overall, the design of the case control studies was similar. The differences in the magnitude of breast cancer mortality reductions are therefore unlikely to be caused by variations in the design of the case-control studies. These differences must be due to other factors, like the organisation of the service screening programme and the attendance rate. The reduction in breast cancer mortality estimated in these case control studies indicates that the impact of current mammographic screening is at least consistent with the effect reported by the former randomised screening trials. PMID- 20924074 TI - Serum levels of selenium in patients with breast cancer before and after treatment of external beam radiotherapy. AB - BACKGROUND: To evaluate the influence of radiotherapy on the selenium serum levels of breast cancer patients. PATIENTS AND METHODS: This prospective study includes 209 breast cancer patients treated by external beam radiotherapy from December 2007 until August 2008. Plasma selenium concentrations were determined before and at the end of the radiotherapeutic treatment. Age, clinical stage, prior chemotherapy, body mass index (BMI) and personal habits (smoking and alcoholism) were recorded for each patient. RESULTS: The mean age was 61 years; the mean BMI was 28.7. One hundred and seventy-four patients (83.3%) were nonsmokers. One hundred and eighty-nine patients (90.4%) showed no drinking habits and 110 (52.6%) have no prior chemotherapy. Sixty patients (28.7%) were in clinical stage I, 141 (67.5%) in clinical stage II and 8 (3.8%) in clinical stage III. At the beginning of radiotherapy, the mean selenium value for all patients was 86.4 MUg/l and after radiation this value dropped to 47.8 MUg/l. Multivariate analysis showed statistically significant difference in the plasma selenium concentration before and after radiotherapy for age (P > 0.001), BMI (P > 0.001), smoking (P > 0.001), alcoholism (P > 0.001), chemotherapy (P > 0.001) and clinical stage (P > 0.001). CONCLUSIONS: Significant reduction in plasma levels of selenium is recorded in patients undergoing radiotherapy, suggesting attention to the nutritional status of this micronutrient and other antioxidant agents. PMID- 20924075 TI - Double heterozygosity in the BRCA1 and BRCA2 genes in the Jewish population. AB - BACKGROUND: The frequency and characteristics of disease in individuals who concomitantly harbor pathogenic mutations in both BRCA1 and BRCA2 genes are not established. MATERIALS AND METHODS: Data were collected from the database of Clalit Health Services National Familial Cancer Consultation Service. Probands referred to this clinical service and their family members are routinely tested for the three Jewish founder mutations (BRCA1: 185delAG, 5382insC, BRCA2: 6174delT). In addition, carriers identified in a population-based cohort of all cases diagnosed with breast cancer in Israel in 1987-1988 allowed the estimation of the population frequency of this phenomenon. RESULTS: In the clinic-based series of 1191 carriers of mutations in BRCA1 or BRCA2 belonging to 567 families, 22 males and females (1.85%) from 17 different families (3.0%) were found to harbor two different mutations. These included 18 individuals (1.51%) who concomitantly carried the 185delAG BRCA1 and the 6174delT BRCA2 mutations and four individuals (0.34%) who carried the 5382insC BRCA1 and the 6174delT mutations. All individuals were heterozygote carriers and none had a double mutation of both founder mutations in the BRCA1 gene itself. Seven of the 16 double carrier women (46.7%) had a personal history of breast carcinoma, diagnosed at a mean age of 44.6, compared with 372/926 (40.2%) carriers of a single mutation diagnosed with a mean age at diagnosis of 48.1 [odds ratio (OR)=1.3, 95% confidence interval (CI) 0.4-4.0]. One case (6.7%) had a personal history of ovarian carcinoma diagnosed at the age of 53 compared with 55/926 (5.9%) of the women with single mutation (OR=1.1, CI=0.2-7.6). The frequency of double mutations in the population-based national breast cancer cohort was 2.2% of all carriers, and 0.3% of all breast cancer cases in the Ashkenazi population in the cohort. The mean age at diagnosis of breast cancer was younger in the carriers of two mutations. CONCLUSION: Double carriers of mutations in the BRCA genes are rare and seem to be carrying a similar probability of developing breast and ovarian cancers as carriers of single mutations. PMID- 20924076 TI - Platinum-based chemotherapy in metastatic triple-negative breast cancer: the Institut Curie experience. AB - BACKGROUND: Although recent experimental data strongly suggest that platinum based chemotherapy (PBCT) could improve the outcome of triple-negative breast cancer (TNBC), clinical data are lacking. Here, the authors reviewed clinical outcome in patients with metastatic TNBC treated with PBCT. PATIENTS AND METHODS: We conducted a retrospective analysis of all patients (N=143) treated for metastatic breast cancer with PBCT between 2000 and 2008, at Institut Curie, Paris, France. Ninety-three of them (63.7%) had TNBC. One-hundred twenty patients received cisplatin (CDDP). The main combination used was CDDP-ifosfamide, in 101 patients (70.2%). RESULTS: Median follow-up was 44 months. For the overall population (N=143), median overall survival (OS) and median progression-free survival (PFS) were 11 and 5 months, respectively. Objective response rate was 33.3% in the TNBC group versus 22% in non-TNBC, P=0.1. We observed no difference of OS, PFS and response duration. Other prognostic factors for poor OS were visceral metastasis sites (P<0.001). One patient died from sepsis during aplasia, 15 had to switch from CDDP to carboplatin because of CDDP-related toxicity. CONCLUSIONS: Metastatic TNBC patients treated with PBCT tended to have a higher response rate, without a significant improvement of PFS or OS, compared with other subtypes. Toxicity was acceptable. Longer observation and further analysis are warranted. PMID- 20924077 TI - Impact of expression differences of kallikrein-related peptidases and of uPA and PAI-1 between primary tumor and omentum metastasis in advanced ovarian cancer. AB - BACKGROUND: Primary tumor levels of serine proteases of the kallikrein-related peptidases (KLK) family as well as urokinase-type plasminogen activator (uPA) and its inhibitor PAI-1 impact disease course in ovarian cancer. The changes in levels of these factors from primary tumor to omentum metastasis ('level differentials') could thus be associated with metastastic processes. PATIENTS AND METHODS: Protein levels of seven tissue KLK (KLK5-8, 10, 11, 13), uPA, and PAI-1 were determined in extracts of primary tumor tissue and corresponding omentum metastasis of 54 ovarian cancer patients. RESULTS: Higher level differentials of KLK5-8, 10-11, and uPA were associated with residual tumor >10 mm. Residual tumor and larger level differentials of KLK5-7, 10, and uPA were associated with disease progression in the whole cohort. Remarkably, level differentials of KLK5 8 and 10-11 strongly impacted disease progression even in patients with residual tumor mass <=10 mm; hence, the observed impact of level differentials in KLK5-7 and 10 on disease progression was not simply attributable to their association with surgical success. CONCLUSION: Since they impact both surgical outcome and survival in advanced ovarian cancer, measurement of level differentials could support clinical decisions on surgical and systemic therapy or help in patient selection for novel targeted therapies. PMID- 20924078 TI - Clinical evaluation of AZD1152, an i.v. inhibitor of Aurora B kinase, in patients with solid malignant tumors. AB - BACKGROUND: To determine, for each of two dosing schedules, the dose-limiting toxicity (DLT) and maximum-tolerated dose (MTD) of AZD1152, an Aurora B kinase inhibitor, and to evaluate its safety, biologic activity and pharmacokinetics (PK). PATIENTS AND METHODS: Patients with advanced solid malignancies were treated with escalating doses (100-650 mg) of AZD1152, administered as a 2-h infusion every 7 days (A) or 14 days (B). Adverse events (AEs), PK variables and tumor response were assessed. RESULTS: Fifty-nine patients were treated; 19 in schedule A and 40 in schedule B. The MTDs were 200 and 450 mg, respectively. Neutropenia (with/without fever) was the most frequent AE and DLT in each schedule. Common Terminology Criteria of Adverse Events version 3.0 grade >=3 neutropenia and leukopenia occurred in 58% and 11% of patients, respectively, in schedule A and 43% and 20%, respectively, in schedule B. No objective tumor responses were observed at any dose or schedule, although stable disease, as defined by RECIST, was achieved in 15 patients (25%) overall. Systemic exposure to AZD1152-hQPA (active drug) was observed by 1 h into the infusion and exhibited linear PK. CONCLUSIONS: AZD1152 was generally well tolerated with neutropenia being the most frequently reported AE and DLT. Exposure to AZD1152-hQPA, the active drug of AZD1152, was linear. PMID- 20924079 TI - Quality of life during the course of cancer treatment in older newly diagnosed patients. Results of a prospective pilot study. AB - BACKGROUND: The aim of this prospective study was to report the quality of life (QoL) of older cancer patients during the first year after diagnosis and factors influencing QoL. PATIENTS AND METHODS: Newly diagnosed patients aged >=65 years were recruited for a pilot prospective cohort study at the Jewish General Hospital, Montreal, Canada. Participants were interviewed at baseline, and at 1.5, 3, 4.5, 6, and 12 months. QoL was assessed at each interview using the European Organization for the Research and Treatment of Cancer Quality of Life Core Questionnaire with 30 items. Logistic regression was conducted to determine which sociodemographic, health, and functional status characteristics were associated with decline in global health status/QoL between baseline and 12-month follow-up. RESULTS: There were 112 participants at baseline (response rate 72%), median age of 74.1, and 70% were women. Between baseline and 12-month follow-up (n=78), 18 participants (23.1%) declined >=10 points in global health status/QoL, while 34 participants (43.6%) remained stable and 23 participants (33.3%) improved >=10 points. None of the sociodemographic, health, and functional status variables were associated with decline in logistic regression analyses. CONCLUSION: Almost 25% of older adults experienced clinically relevant decline in their QoL. Further research is needed on which factors influence decline in QoL in older adults. PMID- 20924080 TI - Indoor air pollution from biomass burning activates Akt in airway cells and peripheral blood lymphocytes: a study among premenopausal women in rural India. AB - Biomass burning is a major source of indoor air pollution in rural India. The authors investigated in this study whether cumulative exposures to biomass smoke cause activation of the serine/threonine kinase Akt in airway cells and peripheral blood lymphocytes (PBL). For this, the authors enrolled 87 premenopausal (median age 34 years), nonsmoking women who used to cook with biomass (wood, dung, crop wastes) and 85 age-matched control women who cooked with cleaner fuel liquefied petroleum gas. Immunocytochemical and immunoblotting assays revealed significantly higher levels of phosphorylated forms of Akt protein (p-Akt(ser473) and p-Akt(thr308)) in PBL, airway epithelial cells, alveolar macrophages, and neutrophils in sputum of biomass-using women than control. Akt activation in biomass users was associated with marked rise in generation of reactive oxygen species and concomitant depletion of superoxide dismutase. Measurement of particulate matter having a diameter of less than 10 and 2.5 um in indoor air by real-time aerosol monitor showed 2 to 4 times more particulate pollution in biomass-using households, and Akt activation was positively associated with particulate pollution after controlling potential confounders. The findings suggest that chronic exposure to biomass smoke activates Akt, possibly via generation of oxidative stress. PMID- 20924081 TI - Thyroid follicular lesions induced by oral treatment for 2 years with 2,3,7,8 tetrachlorodibenzo-p-dioxin and dioxin-like compounds in female Harlan Sprague Dawley rats. AB - 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and structurally-similar dioxin-like compounds affect thyroid function and morphology and thyroid hormone metabolism in animals and humans. The National Toxicology Program conducted eight 2-year gavage studies in female Harlan Sprague-Dawley rats to determine the relative potency of chronic toxicity and carcinogenicity of TCDD, 3,3',4,4',5 pentachlorobiphenyl (PCB126), 2,3,4,7,8-pentachlorodibenzofuran (PeCDF), 2,3',4,4',5-pentachlorobiphenyl (PCB118), 2,2',4,4',5,5'-hexachloro-biphenyl (PCB153), a tertiary mixture of TCDD/PCB126/PeCDF, and two binary mixtures (PCB126/PCB153 and PCB126/PCB118). Administration of these compounds was associated with increased incidences of thyroid follicular cell hypertrophy, variably observed in the 14-, 31-, and 53-week interim and 2-year sacrifice groups. In all studies, the incidences of follicular cell adenoma and carcinoma were not increased. Decreased levels of serum thyroxine were primarily noted in the 14-or-later -week interim groups of all chemicals. Serum triiodothyronine (T3) levels were increased in the TCDD, PCB126, PeCDF, TCDD/PCB126/PeCDF, and PCB126/PCB153 studies, while decreased levels were noted in the PCB153 and PCB126/PCB118 studies. TCDD, PCB126, PCB126/PCB153, and PCB126/PCB118 increased levels of serum thyroid-stimulating hormone almost in a dose-dependent manner in the 14-week groups. These data suggest that although dioxin-like compounds alter thyroid hormones and increase follicular cell hyperplasia, there is not an increase in thyroid adenoma or carcinoma in female Sprague-Dawley rats. PMID- 20924082 TI - Recommendations for pathology peer review. AB - Pathology peer review verifies and improves the accuracy and quality of pathology diagnoses and interpretations. Pathology peer review is recommended when important risk assessment or business decisions are based on nonclinical studies. For pathology peer review conducted before study completion, the peer-review pathologist reviews sufficient slides and pathology data to assist the study pathologist in refining pathology diagnoses and interpretations. Materials to be reviewed are selected by the peer-review pathologist. Consultations with additional experts or a formal (documented) pathology working group may be used to resolve discrepancies. The study pathologist is solely responsible for the content of the final pathology data and report, makes changes resulting from peer review discussions, initiates the audit trail for microscopic observations after all changes resulting from peer-review have been made, and signs the final pathologist's report. The peer-review pathologist creates a signed peer-review memo describing the peer-review process and confirming that the study pathologist's report accurately and appropriately reflects the pathology data. The study pathologist also may sign a statement of consensus. It is not necessary to archive working notes created during the peer-review process. PMID- 20924083 TI - Evaluating the roles of energetic functional constraints on teleost mitochondrial encoded protein evolution. AB - Mitochondria are the power plant of cells, which play critical roles not only in energy metabolism but also in thermoregulation. These two roles have been individually suggested to influence mitochondrial DNA (mtDNA) evolution, however their relative importance is still rarely considered. Here, we conduct a comparative genomic analysis of 401 teleost complete mitochondrial genomes and test the roles of these dual functional constraints on mitochondria to provide a more complete view of mtDNA evolution. We found that mitochondrial protein-coding genes of migratory fishes have significantly smaller Ka/Ks than nonmigratory fishes. The same data set showed that the genes of fishes living in cold climates have significantly smaller Ka/Ks than tropical fishes. In contrast, these trends were not observed for two nuclear genes that are not involved in energy metabolism. The differences in selection patterns observed between mitochondrial and nuclear genes suggest that the functional constraints acting on mitochondria, due to energy metabolism and/or thermoregulation, influence the evolution of mitochondrial-encoded proteins in teleosts. PMID- 20924084 TI - Differential evolution of voltage-gated sodium channels in tetrapods and teleost fishes. AB - The voltage-gated sodium channel (SCN) alpha subunits are large proteins with central roles in the generation of action potentials. They consist of approximately 2,000 amino acids encoded by 24-27 exons. Previous evolutionary studies have been unable to reconcile the proposed gene duplication schemes with the species distribution and molecular phylogeny of the genes. We have carefully annotated the complete SCN gene sequences, correcting numerous database errors, for a broad range of vertebrate species and analyzed their phylogenetic relationships. We have also compared the chromosomal positions of the SCN genes relative to adjacent gene families. Our studies show that the ancestor of the vertebrates probably had a single sodium channel gene with two characteristic AT AC introns, the second of which is unique to vertebrate SCN genes. This ancestral gene, located close to a HOX gene cluster, was quadrupled along with HOX in the two rounds of basal vertebrate tetraploidizations to generate the ancestors of the four channels SCN1A, SCN4A, SCN5A, and SCN8A. The third tetraploidization in the teleost fish ancestor doubled this set of genes and all eight are still present in at least three of four investigated teleost fish genomes. In tetrapods, the gene family expanded by local duplications before the radiation of amniotes, generating the cluster SCN5A, SCN10A, and SCN11A on one chromosome and the cluster SCN1A, SCN2A, SCN3A, and SCN9A on a different chromosome. In eutherian mammals, a tenth gene, SCN7A, arose in a local duplication in the SCN1A gene cluster. The SCN7A gene has undergone rapid evolution and has lost the ability to cause action potentials-instead, it functions as a sodium sensor. The three genes in the SCN5A cluster were translocated from the HOX-bearing chromosome in a mammalian ancestor along with several adjacent genes. This evolutionary scenario is supported by the adjacent TGF-beta receptor superfamily (comprised of five distinct families) and the cysteine-serine-rich nuclear protein gene family as well as the HOX clusters. The independent expansions of the SCN repertoires in tetrapods and teleosts suggest that the functional diversification may differ between the two lineages. PMID- 20924085 TI - Molecular evolution and network-level analysis of the N-glycosylation metabolic pathway across primates. AB - N-glycosylation is one of the most important forms of protein modification, serving key biological functions in multicellular organisms. N-glycans at the cell surface mediate the interaction between cells and the surrounding matrix and may act as pathogen receptors, making the genes responsible for their synthesis good candidates to show signatures of adaptation to different pathogen environments. Here, we study the forces that shaped the evolution of the genes involved in the synthesis of the N-glycans during the divergence of primates within the framework of their functional network. We have found that, despite their function of producing glycan repertoires capable of evading rapidly evolving pathogens, genes involved in the synthesis of the glycans are highly conserved, and no signals of positive selection have been detected within the time of divergence of primates. This suggests strong functional constraints as the main force driving their evolution. We studied the strength of the purifying selection acting on the genes in relation to the network structure considering the position of each gene along the pathway, its connectivity, and the rates of evolution in neighboring genes. We found a strong and highly significant negative correlation between the strength of purifying selection and the connectivity of each gene, indicating that genes encoding for highly connected enzymes evolve slower and thus are subject to stronger selective constraints. This result confirms that network topology does shape the evolution of the genes and that the connectivity within metabolic pathways and networks plays a major role in constraining evolutionary rates. PMID- 20924086 TI - Methylation-associated silencing of microRNA-34b/c in gastric cancer and its involvement in an epigenetic field defect. AB - Altered expression of microRNA (miRNA) is strongly implicated in cancer, and recent studies have shown that the silencing of some miRNAs is associated with CpG island hypermethylation. To identify epigenetically silenced miRNAs in gastric cancer (GC), we screened for miRNAs induced by treatment with 5-aza-2' deoxycytidine and 4-phenylbutyrate. We found that miR-34b and miR-34c are epigenetically silenced in GC and that their downregulation is associated with hypermethylation of the neighboring CpG island. Methylation of the miR-34b/c CpG island was frequently observed in GC cell lines (13/13, 100%) but not in normal gastric mucosa from Helicobacter pylori-negative healthy individuals. Transfection of a precursor of miR-34b and miR-34c into GC cells induced growth suppression and dramatically changed the gene expression profile. Methylation of miR-34b/c was found in a majority of primary GC specimens (83/118, 70%). Notably, analysis of non-cancerous gastric mucosae from GC patients (n = 109) and healthy individuals (n = 85) revealed that methylation levels are higher in gastric mucosae from patients with multiple GC than in mucosae from patients with single GC (27.3 versus 20.8%; P < 0.001) or mucosae from H. pylori-positive healthy individuals (27.3 versus 20.7%; P < 0.001). These results suggest that miR-34b and miR-34c are novel tumor suppressors frequently silenced by DNA methylation in GC, that methylation of miR-34b/c is involved in an epigenetic field defect and that the methylation might be a predictive marker of GC risk. PMID- 20924087 TI - Putative role of TNF-alpha, interleukin-8 and ICAM-1 as indicators of an early inflammatory reaction after burn: a morphological and immunohistochemical study of lung tissue of fire victims. AB - AIMS: To investigate incipient inflammatory changes as first steps in the development of a systematic inflammatory response syndrome in the lungs of burn victims. METHODS: At the Institute of Legal Medicine of the University Hospital of Freiburg a collection of 40 forensic autopsy cases of burn victims was established that had died within 1 h after fire exposure. This group was compared with a total of 48 autopsy cases in three control groups (postmortem burns vs deaths from haemorrhagic shock vs railway suicide deaths). In all cases, immunohistochemical studies of lung tissue probes were performed to detect the presence of pro-inflammatory mediators using antibodies against tumour necrosis factor alpha (TNF-alpha), interleukin-8 (IL-8) and inter-cellular adhesion molecule 1 (ICAM-1). RESULTS: The lungs of burn victims showed a significantly higher extent of intra-alveolar oedema than the other groups. Immunohistochemically, macrophages in all groups mostly showed a distinct expression of TNF-alpha, but not of IL-8 or ICAM-1. Interestingly, intravascular erythrocytes often showed a positivity of TNF-alpha that was strongest in the group of burn victims and differed significantly from all the control groups. CONCLUSIONS: In burn victims with short survival times of <=1 h after fire exposure, the immunohistochemical expression profiles of TNF-alpha, IL-8 and ICAM 1 in the lungs were not altered enough to prove an instant inflammatory reaction in these cases. Nevertheless, the positive reaction of TNF-alpha in erythrocytes of burn victims may indicate the beginning of a non-specific immune response to fire-induced inhalation trauma. PMID- 20924088 TI - Chromosomal integration of the HHV-6 genome as a possible cause of HHV-6 detection in cardiac tissues. PMID- 20924089 TI - Xerostomia, hyposalivation and sialadenitis in patients with chronic hepatitis C are not associated with the detection of HCV RNA in saliva or salivary glands. AB - OBJECTIVE: Salivary gland disorders in patients with chronic hepatitis C (CHC) have been considered oral extrahepatic manifestations, reinforcing the hepatitis C virus (HCV) as a sialotropic virus. Hence, the authors investigated the prevalence of HCV RNA in saliva and salivary glands and its possible association with xerostomia, hyposalivation and sialadenitis in patients with CHC. PATIENTS AND METHODS: In 65 patients with confirmed CHC, the HCV RNA was investigated by nested RT-PCR in saliva samples and minor salivary glands. Xerostomia, hyposalivation, clinical and histopathological evidence of sialadenitis were also evaluated. Univariate and multivariate analyses were employed to verify associations. RESULTS: HCV RNA was detected in the saliva of 26/65 (40.0%) patients and in 12/65 (18.5%) salivary glands. Xerostomia was reported by 23/65 (35.4%) patients, and hyposalivation was diagnosed in 13/65 (20.0%) patients. Sialadenitis was confirmed by histopathological features in 31/65 (47.7%) patients. Twelve (38.7%) of the 31 patients with sialadenitis presented HCV RNA in saliva and 2/31 (6.5%) in salivary glands. No associations were found between xerostomia, hyposalivation or sialadenitis and the detection of HCV RNA in saliva or in salivary glands. CONCLUSIONS: Although xerostomia, hyposalivation and sialadenitis are frequent findings in CHC patients, our study did not confirm the association between the detection of HCV RNA in saliva or salivary glands with these salivary gland disorders. However, an indirect role of HCV by immune mediated virus mechanisms in the pathogenesis of salivary gland disorders in this group of patients cannot be ruled out. PMID- 20924090 TI - MTOC-MT is a major target antigen of autoantibody detected by autoimmune target tests in patients with hepatitis A virus infection. PMID- 20924091 TI - When is the practice of pathology malpractice? AB - Because of its complex nature, surgical pathology diagnosis has an appreciable degree of fallibility and is increasingly subject to legal scrutiny. In litigation, the first practical step is to explain why and how this adversity could happen, and the second is the question of apportionment of responsibility and its legal consequences. As pathologists, we have to provide a methodology of investigation allowing a clear distinction between reasonable and unacceptable pathology practice without the twist of hindsight. For that we need to examine the different steps from test ordering to the final report. The most critical aspect of the enquiry is the act of diagnosis itself. What can reasonably be expected and what precautions have normally to be taken? Experts are often requested to re-examine the slides. For that we need a well-devised protocol enabling blinded review. Tort law has two important interconnected goals: compensation for damages and prevention of the same slip ever being made again. We can only properly learn from our mistakes if we carry out an unbiased investigation. Poor normative judgement of diagnostic failures will backfire on the profession. PMID- 20924092 TI - Haemogenic endothelium in infantile haemangioma. AB - BACKGROUND: Proliferating infantile haemangioma (IH) is a tumour of the microvasculature composed predominantly of immature endothelial cells. The origin of IH is unclear, but it has been shown to express markers of both endothelial and haematopoietic lineages, and a role for endothelial progenitor cells in the aetiology of IH has been suggested. Haemangioblasts are precursors of both endothelial and haematopoietic cells, and their characterisation has identified the expression of cell surface and intracellular proteins that collectively can be used for assigning a haemangioblast phenotype. METHODS: The authors used immunohistochemical staining to characterise the expression of primitive haematopoietic-associated proteins in proliferating IHs. RESULTS AND DISCUSSION: The authors show that the cells forming the capillary endothelium express markers associated with primitive haematopoietic cells. Additionally, many of these cells express the transcription factors brachyury and GATA-2, indicating a primitive mesodermal origin. They hypothesise that the immature capillaries in IH are derived from primitive mesodermal cells with haemangioblastic differentiation capabilities. The expression of primitive mesodermal, endothelial and haematopoietic markers by the cells forming the endothelium suggests that the immature capillaries that predominate in proliferating IH are a haemogenic endothelium phenotype, derived from haemangioblasts. PMID- 20924093 TI - Colorectal duplication in adults: report of seven cases and review of the literature. AB - BACKGROUND: Gastrointestinal duplications are uncommon congenital abnormalities, usually recognised before the age of 2 (80%). Colorectal duplications (CDDs) occur in only 6.8% of cases, rarely in adults, and are revealed by abdominal pain and intestinal obstruction. Malignant changes are uncommon, but are most often found in the colon. METHODS AND RESULTS: During the last 7 years, the authors have observed seven cases of CDD (three men) with mean age 50.7 years (range 32 73). Four cases were revealed by abdominal pain, and three by intestinal obstruction. Five duplications were located in the caecum, one in the transverse colon, and one in the sigmoid colon. All CDDs were of the cystic type (4.42 cm, range 2-7.5), and three had a communication with the intestinal lumen. All patients except one underwent 'en bloc' resection of the cyst with the adjacent colon. On microscopic examination, CDDs contained multiple layers of the bowel wall, including colonic or small intestinal mucosa. Heterotopic gastric mucosa was observed in only one case, high-grade dysplasia in one case, and low-grade dysplasia in another. No invasive carcinoma was found. CONCLUSION: Although uncommon, CDDs should be included in the differential diagnosis of all abdominal masses. The treatment approach is excision, in order to avoid any complication. En bloc resection of the colon with CDD may be necessary, because of the intimate attachments of the common wall. Thorough sampling of the specimen is mandatory in order to detect any malignant changes. PMID- 20924094 TI - The molecular basis of the chemosensitivity of metastatic cutaneous melanoma to chemotherapy. AB - BACKGROUND: Chemotherapy benefits relatively few patients with cutaneous melanoma. The assessment of tumour chemosensitivity by the ATP-based tumour chemosensitivity assay (ATP-TCA) has shown strong correlation with outcome in cutaneous melanoma, but requires fresh tissue and dedicated laboratory facilities. AIM: To examine whether the results of the ATP-TCA correlate with the expression of genes known to be involved in resistance to chemotherapy, based on the hypothesis that the molecular basis of chemosensitivity lies within known drug resistance mechanisms. METHOD: The chemosensitivity of 47 cutaneous melanomas was assessed using the ATP-TCA and correlated with quantitative expression of 93 resistance genes measured by quantitative reverse transcriptase PCR (qRT-PCR) in a Taqman Array after extraction of total RNA from formalin-fixed paraffin-embedded tissue. RESULTS: Drugs susceptible to particular resistance mechanisms showed good correlation with genes linked to these mechanisms using signatures of up to 17 genes. Comparison of these signatures for DTIC, treosulfan and cisplatin showed several genes in common. HSP70, at least one human epidermal growth factor receptor, genes involved in apoptosis (IAP2, PTEN) and DNA repair (ERCC1, XPA, XRCC1, XRCC6) were present for these agents, as well as genes involved in the regulation of proliferation (Ki67, p21, p27). The combinations tested included genes represented in the single agent signatures. CONCLUSIONS: These data suggest that melanoma chemosensitivity is influenced by known resistance mechanisms, including susceptibility to apoptosis. Use of a candidate gene approach may increase understanding of the mechanisms underlying chemosensitivity to drugs active against melanoma and provide signatures with predictive value. PMID- 20924096 TI - Effects of zofenopril and ramipril on cough reflex responses in anesthetized and awake rabbits. AB - Cough is the most common symptom reported by patients in a primary care setting and is one of the most frequent secondary effects recorded during treatment with angiotensin-converting enzyme (ACE) inhibitors. The aim of the current study was to analyze potential differences in cough induction between 2 structurally different ACE inhibitors, namely zofenopril, which has a sulphydryl moiety, and ramipril, which has a carboxyl moiety. The cough reflex was induced by chemical (citric acid) and/or mechanical stimulation of the tracheobronchial tree in awake and anesthetized rabbits. Intravenous injection of the active compounds of the 2 ACE inhibitors, zofenoprilat (288 nmol/kg) and ramiprilat (129 nmol/kg), caused similar hypotensive effects in anesthetized rabbits. None of the studied cough related variables changed in response to ACE inhibitor administration, with the exception of the number of coughs. Ramiprilat, but not zofenoprilat, increased the cough response induced by both mechanical and chemical stimulation (1 mol/L citric acid aerosol) of the tracheobronchial tree. In awake animals, zofenoprilat or vehicle-treated rabbits did not show any significant changes in the number of coughs induced by 1 mol/L citric acid aerosol compared to their respective basal values (from 15.2 +/- 2.3 to 13.1 +/- 1.3 and from 16.1 +/- 4.9 to 15.8 +/- 4.3, respectively). Conversely, ramiprilat resulted in a significant increase in the number of coughs (from 21.1 +/- 2.6 to 34.9 +/- 3.5; P < .01). These findings confirm that there are differences in the cough potentiation effect induced by different ACE inhibitors. The low rate of cough seen with zofenoprilat may be related to its ability to induce a lower accumulation of bradykinin and prostaglandins at the lung level. PMID- 20924095 TI - Clinical and economic impact of clinical pharmacy service on hyperlipidemic management in Hong Kong. AB - OBJECTIVE: To assess the clinical and economic outcomes of a clinical pharmacy service (CPS) in dyslipidemic management. METHOD: This was a 24-month prospective controlled trial conducted at the lipid clinic of a public hospital in Hong Kong. In the intervention group, a clinical pharmacist assessed low-density lipoprotein cholesterol (LDL-C) levels and provided recommendations in accordance to the Adult Treatment Panel III (ATP III) guidelines. Medication compliance and the proper use of drugs were assessed. Education on healthy lifestyles was reinforced. Monthly telephone follow-ups were made to check on the progress of patients. In the control group, patients received usual medical care with no pharmacist intervention. Primary outcome was the percentage of patients achieving the ATP III LDL-C goal at the end of study. The estimated cost of such service was also evaluated. RESULTS: A total of 300 patients were recruited into the study (150 in intervention group and 150 in control group). In the intervention group, 58.7% patients achieved LDL-C goals compared with 45.3% in the control group (P < .05). The intervention group achieved 26.4%, 17.4%, and 30.0% mean reduction in LDL-C, total cholesterol (TC), and triglycerides (TG) levels, respectively, compared with 12.6%, 6.6%, and 11.5% in the control group (P < .05). The estimated cost for this clinical service was US$385/month for a total of 600 dyslipidemic patients seen per year. CONCLUSION: The results of this study demonstrate the positive impact CPS can have on achieving treatment goals in lipid management. Similar services for other problematic conditions such as hypertension and diabetes mellitus may also be benefited by similar CPSs. PMID- 20924097 TI - Improvement in left ventricular systolic and diastolic performance during ranolazine treatment in patients with stable angina. AB - PURPOSE: Ranolazine is a novel antianginal medication that acts by ameliorating disturbed sodium and calcium homeostasis. By preventing myocyte sodium and calcium overload, ranolazine also have potential beneficial effects on myocardial function. Experimental models support this concept, as do 2 small studies in human participants receiving ranolazine intravenously. We evaluated changes in parameters of left ventricular function in stable angina patients treated with oral ranolazine. METHODS: Twenty-two participants were enrolled with Doppler echocardiography performed at baseline and a mean of 2 months after initiation of treatment. RESULTS: Global left ventricular function, as assessed by the myocardial performance index, was significantly improved on drug therapy (P < .0001). This was due to improvement in both diastolic and systolic parameters. Of 21 patients, 17 reported less angina and 8 patients reported an increase in activity level. CONCLUSIONS: We report improved parameters of left ventricular function in response to ranolazine as used in the clinical setting. PMID- 20924098 TI - Antiplatelet therapy in acute coronary syndromes. AB - Antiplatelet therapy is integral to the acute and long-term management of acute coronary syndromes (ACSs) and for minimizing the thrombotic complications of percutaneous coronary intervention (PCI). This article reviews the most commonly used antiplatelet agents in ACS therapy--aspirin, adenosine diphosphate (ADP) receptor blockers, and glycoprotein IIb/IIIa inhibitors. More recent data are also reviewed on novel ADP-receptor blockers and thrombin inhibitors before addressing issues of adherence to antiplatelet regimens. PMID- 20924099 TI - Dietary insulin load, dietary insulin index, and colorectal cancer. AB - BACKGROUND: Circulating insulin levels have been positively associated with risk of colorectal cancer; however, it remains unclear whether a diet inducing an elevated insulin response influences colorectal cancer risk. On the basis of a novel insulin index for individual foods, we estimated insulin demand for overall diets and assessed its association with colorectal cancer in the Nurses' Health Study and Health Professionals Follow-up Study. METHODS: We followed 86,740 women and 46,146 men who were free of cancer and diabetes at baseline and identified a total of 2,481 colorectal cancer cases during up to 26 years of follow-up. Dietary insulin load was calculated as a function of food insulin index and the energy content of individual foods was reported on food frequency questionnaires. Average dietary insulin index was calculated by dividing the dietary insulin load by the total energy intake. RESULTS: Dietary insulin load and dietary insulin index were not associated with risk of colorectal cancer. Comparing the highest with the lowest quintiles, the pooled multivariate relative risks of colorectal cancer were 0.91 (95% CI = 0.79-1.05) for dietary insulin load and 0.93 (95% CI = 0.81-1.08) for dietary insulin index. Body mass index and physical activity did not modify the association of dietary insulin load or index with colorectal cancer. CONCLUSION: A diet high in foods that increase postprandial insulin levels did not increase the risk of colorectal cancer in this large prospective study. IMPACT: This study is the first to investigate insulin index and load in relation to colorectal cancer. PMID- 20924100 TI - In silico modeling and in vivo efficacy of cancer-preventive vaccinations. AB - Cancer vaccine feasibility would benefit from reducing the number and duration of vaccinations without diminishing efficacy. However, the duration of in vivo studies and the huge number of possible variations in vaccination protocols have discouraged their optimization. In this study, we employed an established mouse model of preventive vaccination using HER-2/neu transgenic mice (BALB-neuT) to validate in silico-designed protocols that reduce the number of vaccinations and optimize efficacy. With biological training, the in silico model captured the overall in vivo behavior and highlighted certain critical issues. First, although vaccinations could be reduced in number without sacrificing efficacy, the intensity of early vaccinations was a key determinant of long-term tumor prevention needed for predictive utility in the model. Second, after vaccinations ended, older mice exhibited more rapid tumor onset and sharper decline in antibody levels than young mice, emphasizing immune aging as a key variable in models of vaccine protocols for elderly individuals. Long-term studies confirmed predictions of in silico modeling in which an immune plateau phase, once reached, could be maintained with a reduced number of vaccinations. Furthermore, that rapid priming in young mice is required for long-term antitumor protection, and that the accuracy of mathematical modeling of early immune responses is critical. Finally, that the design and modeling of cancer vaccines and vaccination protocols must take into account the progressive aging of the immune system, by striving to boost immune responses in elderly hosts. Our results show that an integrated in vivo-in silico approach could improve both mathematical and biological models of cancer immunoprevention. PMID- 20924101 TI - Mesenchymal stromal cells expressing ErbB-2/neu elicit protective antibreast tumor immunity in vivo, which is paradoxically suppressed by IFN-gamma and tumor necrosis factor-alpha priming. AB - It is unknown whether mesenchymal stromal cells (MSC) can regulate immune responses targeting tumor autoantigens of low immunogenicity. We tested here whether immunization with MSC could break immune tolerance towards the ErbB-2/HER 2/neu tumor antigen and the effects of priming with IFN-gamma and tumor necrosis factor-alpha (TNF-alpha) on this process. BALB/c- and C57BL/6-derived MSC were lentivirally transduced to express a kinase-inactive rat neu mutant (MSC/Neu). Immunization of BALB/c mice with nontreated or IFN-gamma-primed allogeneic or syngeneic MSC/Neu induced similar levels of anti-neu antibody titers; however, only syngeneic MSC/Neu induced protective neu-specific CD8(+) T cell responses. Compared to immunization with nontreated or IFN-gamma-primed syngeneic MSC/Neu, the number of circulating neu-specific CD8(+) T cells and titers of anti-neu antibodies were observed to be decreased after immunizations with IFN-gamma- plus TNF-alpha-primed MSC/Neu. In addition, syngeneic MSC/Neu seemed more efficient than IFN-gamma-primed MSC/Neu at inducing a protective therapeutic antitumor immune response resulting in the regression of transplanted neu-expressing mammary tumor cells. In vitro antigen-presenting cell assays performed with paraformaldehyde-fixed or live MSC showed that priming with IFN-gamma plus TNF alpha, compared to priming with IFN-gamma alone, increased antigen presentation as well as the production of immunosuppressive factors. These data suggest that whereas MSC could effectively serve as antigen-presenting cells to induce immune responses aimed at tumor autoantigens, these functions are critically regulated by IFN-gamma and TNF-alpha. PMID- 20924102 TI - Selective depletion of Foxp3+ regulatory T cells improves effective therapeutic vaccination against established melanoma. AB - Tumor-bearing individuals have been reported to harbor increased numbers of Foxp3(+) regulatory T cells (Treg), which prevent the development of efficient antitumor immune responses. Thus, Treg depletion has already been tested as a promising therapeutic approach in various animal models and entered clinical trials. However, the use of nonspecific Treg targeting agents such as CD25 depleting antibodies, which in addition to CD25(+) Tregs also deplete recently activated CD25(+) effector T cells, potentially masked the tremendous potential of this therapeutic strategy. To avoid such nonspecific effects, we used transgenic DEREG (depletion of regulatory T cells) mice, which express a diphtheria toxin receptor under control of the Foxp3 locus, allowing selective depletion of Foxp3(+) Tregs even during ongoing immune responses. We showed that Foxp3(+) Treg depletion induced partial regression of established ovalbumin (OVA) expressing B16 melanoma, which was associated with an increased intratumoral accumulation of activated CD8(+) cytotoxic T cells. The antitumor effect could be significantly enhanced when Treg depletion was combined with vaccination against OVA. To further assess whether this therapeutic approach would break self tolerance, we crossed DEREG mice with RipOVA(low) mice, expressing OVA as neo self-antigen under control of the rat insulin promoter. In these mice, combined Treg depletion and vaccination also induced tumor regression without the onset of diabetes. Together, our data suggest that selective Treg targeting strategies combined with vaccinations against tumor-associated (self) antigens have the potential to evoke efficient antitumor responses without inducing overt autoimmunity. These findings might have implications for future therapeutic interventions in cancer patients. PMID- 20924103 TI - Epithelial-to-mesenchymal transition promotes tubulin detyrosination and microtentacles that enhance endothelial engagement. AB - Epithelial-to-mesenchymal transition (EMT) is associated with increased breast tumor metastasis; however, the specific mechanisms by which EMT promotes metastasis remain somewhat unclear. Despite the importance of cytoskeletal dynamics during both EMT and metastasis, very few current studies examine the cytoskeleton of detached and circulating tumor cells. Specific posttranslational alpha-tubulin modifications are critical for adherent cell motility and implicated in numerous pathologies, but also remain understudied in detached cells. We report here that EMT induced through ectopic expression of Twist or Snail promotes alpha-tubulin detyrosination and the formation of tubulin-based microtentacles in detached HMLEs. Mechanistically, EMT downregulates the tubulin tyrosine ligase enzyme, resulting in an accumulation of detyrosinated alpha tubulin (Glu-tubulin), and increases microtentacles that penetrate endothelial layers to facilitate tumor cell reattachment. Confocal microscopy shows that microtentacles are capable of penetrating the junctions between endothelial cells. Suppression of endogenous Twist in metastatic human breast tumor cells is capable of reducing both tubulin detyrosination and microtentacles. Clinical breast tumor samples display high concordance between Glu-tubulin and Twist expression levels, emphasizing the coupling between EMT and tubulin detyrosination in vivo. Coordinated elevation of Twist and Glu-tubulin at invasive tumor fronts, particularly within ductal carcinoma in situ samples, establishes that EMT-induced tubulin detyrosination occurs at the earliest stages of tumor invasion. These data support a novel model where the EMT that occurs during tumor invasion downregulates tubulin tyrosine ligase, increasing alpha tubulin detyrosination and promoting microtentacles that could enhance the reattachment of circulating tumor cells to the vascular endothelium during metastasis. PMID- 20924104 TI - Receptor tyrosine kinase signaling favors a protumorigenic state in breast cancer cells by inhibiting the adaptive immune response. AB - Using transgenic mouse models of breast cancer that ablate Src homology and collagen A (ShcA) expression or oncogene-coupled ShcA signaling, we previously showed that this adaptor is critical for mammary tumor onset and progression. We now provide the first evidence that ShcA regulates mammary tumorigenesis, in part, through its ability to regulate the adaptive immune response. Inactivation of ShcA signaling within tumor cells results in extensive CD4(+) T-cell infiltration and induction of a humoral immune response in mammary tumors. This is associated with a robust CTL response in preneoplastic lesions that are deficient in ShcA signaling. Moreover, mammary tumor progression of ShcA deficient hyperplasias is accelerated in a T cell-deficient background. We also uncover a clinically relevant correlation between high ShcA expression and low CTL infiltration in human breast cancers. Finally, we define a novel ShcA regulated immune signature that functions as an independent prognostic marker of survival in human epidermal growth factor receptor 2(+) and basal breast cancers. We reveal a novel role for tumor cell-derived ShcA in the establishment and maintenance of an immunosuppressive state. PMID- 20924106 TI - Vascular endothelial growth factor receptor-1 signaling promotes mobilization of macrophage lineage cells from bone marrow and stimulates solid tumor growth. AB - Vascular endothelial growth factor and its receptors, including Flt-1 and Flk-1, are involved in angiogenesis under physiologic and pathologic conditions. Recently, Flt-1-expressing cells were reported to contribute to the intracranial growth of glioma cells. However, the role of Flt-1 signaling in solid tumor growth in s.c. tissue has not been elucidated. To investigate how Flt-1 signaling is involved in the proliferation of solid tumors, we implanted tumor cells into wild-type (Wt) and Flt-1 tyrosine kinase (TK)-deficient (Flt-1 TK(-/-)) mice. Growth of HSML and B16 but not Lewis lung carcinoma cell in s.c. tissue was significantly decreased in Flt-1 TK(-/-) mice. Angiogenesis in HSML and B16 tumors was remarkably reduced in Flt-1 TK(-/-) mice. Moreover, the infiltration of macrophage lineage cells into HSML and B16 tumors was clearly suppressed in Flt-1 TK(-/-) mice. Pericyte marker(+) cells were also reduced in Flt-1 TK(-/-) mice. However, in the border area of tumor, angiogenesis and the infiltration of macrophage lineage cell were basically similar between Wt and Flt-1 TK(-/-) mice. In bone marrow (BM) transplantation experiments, tumor angiogenesis, infiltration of macrophage lineage cells, and tumor growth were significantly suppressed in Wt/Flt-1 TK(-/-) mice implanted with Flt-1 TK(-/-) BM cells compared with those implanted with Wt BM cells. We conclude that Flt-1 signaling is involved in the function of BM-derived cell, such as the migration of macrophages into cancerous tissues, and significantly contributes to angiogenesis and tumor progression. PMID- 20924105 TI - Impact of stromal sensitivity on radiation response of tumors implanted in SCID hosts revisited. AB - Severe combined immunodeficient (SCID) mice carry a germ-line mutation in DNA-PK, associated with deficiency in recognition and repair DNA double-strand breaks. Thus, SCID cells and tissues display increased sensitivity to radiation-induced postmitotic (clonogenic) cell death. Nonetheless, the single-radiation doses required for 50% permanent local control (TCD(50)) of tumors implanted in SCID mice are not significantly different from the TCD(50) values of the same tumors in wild-type hosts. Whereas the tumor stroma is derived from the host, the observation that tumors implanted in SCID mice do not exhibit hypersensitivity to radiation might imply that stromal endothelial elements do not contribute substantially to tumor cure by ionizing radiation. Here, we challenge this notion, testing the hypothesis that ASMase-mediated endothelial apoptosis, which results from plasma membrane alterations, not DNA damage, is a crucial element in the cure of tumors in SCID mice by single-dose radiotherapy (SDRT). We show that the endothelium in MCA/129 fibrosarcomas and B16 melanomas exhibits a wild-type apoptotic phenotype in SCID hosts, abrogated in tumors in SCID(asmase-/-) littermates, which also acquire resistance to SDRT. Conversion into a radioresistant tumor phenotype when implanted in SCID(asmase-/-) hosts provides compelling evidence that cell membrane ASMase-mediated microvascular dysfunction, rather than DNA damage-mediated endothelial clonogenic lethality, plays a mandatory role in the complex pathophysiologic mechanism of tumor cure by SDRT, and provides an explanation for the wild-type SDRT responses reported in tumors implanted in SCID mice. PMID- 20924107 TI - Expression of the transcriptional repressor Gfi-1 is regulated by C/EBP{alpha} and is involved in its proliferation and colony formation-inhibitory effects in p210BCR/ABL-expressing cells. AB - Ectopic expression of CAAT/enhancer binding protein alpha (C/EBPalpha) in p210BCR/ABL-expressing cells induces granulocytic differentiation, inhibits proliferation, and suppresses leukemogenesis. To dissect the molecular mechanisms underlying these biological effects, C/EBPalpha-regulated genes were identified by microarray analysis in 32D-p210BCR/ABL cells. One of the genes whose expression was activated by C/EBPalpha in a DNA binding-dependent manner in BCR/ABL-expressing cells is the transcriptional repressor Gfi-1. We show here that C/EBPalpha interacts with a functional C/EBP binding site in the Gfi-1 5' flanking region and enhances the promoter activity of Gfi-1. Moreover, in K562 cells, RNA interference-mediated downregulation of Gfi-1 expression partially rescued the proliferation-inhibitory but not the differentiation-inducing effect of C/EBPalpha. Ectopic expression of wild-type Gfi-1, but not of a transcriptional repressor mutant (Gfi-1P2A), inhibited proliferation and markedly suppressed colony formation but did not induce granulocytic differentiation of BCR/ABL-expressing cells. By contrast, Gfi-1 short hairpin RNA-tranduced CD34(+) chronic myeloid leukemia cells were markedly more clonogenic than the scramble transduced counterpart. Together, these studies indicate that Gfi-1 is a direct target of C/EBPalpha required for its proliferation and survival-inhibitory effects in BCR/ABL-expressing cells. PMID- 20924108 TI - hsa-miR-191 is a candidate oncogene target for hepatocellular carcinoma therapy. AB - Hepatocellular carcinoma (HCC) is generally a fatal disease due to a paucity of effective treatment options. The identification of oncogenic microRNAs that exert pleiotropic effects in HCC cells may offer new therapeutic targets. In this study, we have identified the human microRNA miR-191 as a potential target for HCC therapy. Inhibition of miR-191 decreased cell proliferation and induced apoptosis in vitro and significantly reduced tumor masses in vivo in an orthotopic xenograft mouse model of HCC. Additionally, miR-191 was found to be upregulated by a dioxin, a known liver carcinogen, and was found to be a regulator of a variety of cancer-related pathways. Our findings offer a preclinical proof of concept for miR-191 targeting as a rational strategy to pursue for improving HCC treatment. PMID- 20924109 TI - Microtentacles tip the balance of cytoskeletal forces in circulating tumor cells. AB - Detection of circulating tumor cells (CTC) is advancing as an effective predictor of patient outcome and therapeutic response. Unfortunately, our knowledge of CTC biology remains limited, and the impact of drug treatments on CTC metastatic potential is currently unclear. Improved CTC imaging in vivo and analysis of free floating tumor cells now show that cytoskeletal regulation in CTCs contrasts starkly with tumor cells attached to extracellular matrix. In this review, we examine how persistent microtubule stabilization promotes the formation of microtentacles on the surface of detached breast tumor cells and enhances metastatic potential. PMID- 20924110 TI - Role of LIM and SH3 protein 1 (LASP1) in the metastatic dissemination of medulloblastoma. AB - Medulloblastoma is the most common malignant pediatric brain tumor and is one of the leading causes of cancer-related mortality in children. Treatment failure mainly occurs in children harboring metastatic tumors, which typically carry an isochromosome 17 or gain of 17q, a common hallmark of intermediate and high-risk medulloblastoma. Through mRNA expression profiling, we identified LIM and SH3 protein 1 (LASP1) as one of the most upregulated genes on chromosome 17q in tumors with 17q gain. In an independent validation cohort of 101 medulloblastoma samples, the abundance of LASP1 mRNA was significantly associated with 17q gain, metastatic dissemination, and unfavorable outcome. LASP1 protein expression was analyzed by immunohistochemistry in a large cohort of patients (n = 207), and high protein expression levels were found to be strongly correlated with 17q gain, metastatic dissemination, and inferior overall and progression-free survival. In vitro experiments in medulloblastoma cell lines showed a strong reduction of cell migration, increased adhesion, and decreased proliferation upon LASP1 knockdown by small interfering RNA-mediated silencing, further indicating a functional role for LASP1 in the progression and metastatic dissemination of medulloblastoma. PMID- 20924111 TI - Conditional regulatory T-cell depletion releases adaptive immunity preventing carcinogenesis and suppressing established tumor growth. AB - Foxp3 is a central control element in the development and function of regulatory T cells (Treg), and mice expressing a diphtheria toxin (DT) receptor-enhanced green fluorescent protein fusion protein under the control of the foxp3 gene locus (DEREG mice) allow conditional and efficient depletion of Foxp3(+) Treg by DT injection. Herein, we use DEREG mice and a mouse model of carcinogenesis to show that conditional and effective Treg depletion can both protect mice from carcinogenesis by innate control, yet permanently eradicate a proportion of de novo-established tumors in mice in a largely CD8(+) T-cell- and IFN-gamma dependent manner. Tumors displayed a heterogeneous response to Treg depletion, and suppression of established tumors was accompanied by an increase in the tumor infiltrating CD8(+) T-cell/B-cell ratio. Tumor rejection occurred in the absence of overt autoimmunity, suggesting that effective transient Treg depletion strategies may be therapeutic in at least a proportion of spontaneous tumors developing in the host. PMID- 20924112 TI - Contextual synthetic lethality of cancer cell kill based on the tumor microenvironment. AB - Acute and chronic hypoxia exists within the three-dimensional microenvironment of solid tumors and drives therapy resistance, genetic instability, and metastasis. Replicating cells exposed to either severe acute hypoxia (16 hours with 0.02% O(2)) followed by reoxygenation or moderate chronic hypoxia (72 hours with 0.2% O(2)) treatments have decreased homologous recombination (HR) protein expression and function. As HR defects are synthetically lethal with poly(ADP-ribose) polymerase 1 (PARP1) inhibition, we evaluated the sensitivity of repair-defective hypoxic cells to PARP inhibition. Although PARP inhibition itself did not affect HR expression or function, we observed increased clonogenic killing in HR deficient hypoxic cells following chemical inhibition of PARP1. This effect was partially reversible by RAD51 overexpression. PARP1(-/-) murine embryonic fibroblasts (MEF) showed a proliferative disadvantage under hypoxic gassing when compared with PARP1(+/+) MEFs. PARP-inhibited hypoxic cells accumulated gammaH2AX and 53BP1 foci as a consequence of altered DNA replication firing during S phase specific cell killing. In support of this proposed mode of action, PARP inhibitor treated xenografts displayed increased gammaH2AX and cleaved caspase-3 expression in RAD51-deficient hypoxic subregions in vivo, which was associated with decreased ex vivo clonogenic survival following experimental radiotherapy. This is the first report of selective cell killing of HR-defective hypoxic cells in vivo as a consequence of microenvironment-mediated "contextual synthetic lethality." As all solid tumors contain aggressive hypoxic cells, this may broaden the clinical utility of PARP and DNA repair inhibition, either alone or in combination with radiotherapy and chemotherapy, even in tumor cells lacking synthetically lethal, genetic mutations. PMID- 20924113 TI - eIF2{alpha} Kinase PKR modulates the hypoxic response by Stat3-dependent transcriptional suppression of HIF-1{alpha}. AB - Hypoxia within the tumor microenvironment promotes angiogenesis, metabolic reprogramming, and tumor progression. In addition to activating hypoxia-inducible factor-1alpha (HIF-1alpha), cells also respond to hypoxia by globally inhibiting protein synthesis via serine 51 phosphorylation of translation eukaryotic initiation factor 2alpha (eIF2alpha). In this study, we investigated potential roles for stress-activated eIF2alpha kinases in regulation of HIF-1alpha. Our investigations revealed that the double-stranded RNA-dependent protein kinase R (PKR) plays a significant role in suppressing HIF-1alpha expression, acting specifically at the level of transcription. HIF-1alpha transcriptional repression by PKR was sufficient to impair the hypoxia-induced accumulation of HIF-1alpha and transcriptional induction of HIF-1alpha-dependent target genes. Inhibition of HIF-1A transcription by PKR was independent of eIF2alpha phosphorylation but dependent on inhibition of the signal transducer and activator of transcription 3 (Stat3). Furthermore, HIF-1A repression required the T-cell protein tyrosine phosphatase, which acts downstream of PKR, to suppress Stat3. Our findings reveal a novel tumor suppressor function for PKR, which inhibits HIF-1alpha expression through Stat3 but is independent of eIF2alpha phosphorylation. PMID- 20924114 TI - Optical detection of buccal epithelial nanoarchitectural alterations in patients harboring lung cancer: implications for screening. AB - We have recently developed a novel optical technology, partial wave spectroscopic (PWS) microscopy, which is exquisitely sensitive to the nanoarchitectural manifestation of the genetic/epigenetic alterations of field carcinogenesis. Our approach was to screen for lung cancer by assessing the cheek cells based on emerging genetic/epigenetic data which suggests that the buccal epithelium is altered in lung field carcinogenesis. We performed PWS analysis from microscopically normal buccal epithelial brushings from smokers with and without lung cancer (n = 135). The PWS parameter, disorder strength of cell nanoarchitecture (L(d)), was markedly (>50%) elevated in patients harboring lung cancer compared with neoplasia-free smokers. The performance characteristic was excellent with an area under the receiver operator characteristic curve of >0.80 and was equivalent for both disease stage (early versus late) and histologies (small cell versus non-small cell lung cancers). An independent data set validated the findings with only a minimal degradation of performance characteristics. Our results offer proof of concept that buccal PWS may potentially herald a minimally intrusive prescreening test that could be integral to the success of lung cancer population screening programs. PMID- 20924115 TI - Oncogene-driven intrinsic inflammation induces leukocyte production of tumor necrosis factor that critically contributes to mammary carcinogenesis. AB - Oncogene activation promotes an intrinsic inflammatory pathway that is crucial for cancer development. Here, we have investigated the actual effect of the inflammatory cytokine tumor necrosis factor (TNF) on the natural history of spontaneous mammary cancer in the HER2/neuT (NeuT) transgenic mouse model. Bone marrow transplantation from TNF knockout mice into NeuT recipients significantly impaired tumor growth, indicating that the source of TNF fostering tumor development was of bone marrow origin. We show that the absence of leukocyte derived TNF disarranged the tumor vasculature, which lacked pericyte coverage and structural integrity, leading to diffuse vascular hemorrhage and stromal necrosis. In addition, tumor-associated Tie2-expressing monocytes were reduced and cytokine expression skewed from Th2 to Th1 type. Treatment of NeuT mice with anti-TNF antibody partially phenocopied the antitumor effect of TNF-deficient bone marrow cell transplantation, providing a strong preclinical background and rationale for the introduction of TNF antagonists in the treatment of human breast cancer, including basal-like samples for which consolidated targeted therapies do not exist. PMID- 20924116 TI - Fission yeast Swi1-Swi3 complex facilitates DNA binding of Mrc1. AB - Replication fork protection complex Swi1-Swi3 and replication checkpoint mediator Mrc1 are required for maintenance of replication fork integrity during the course of DNA replication in the fission yeast Schizosaccharomyces pombe. These proteins play crucial roles in stabilizing stalled forks and activating replication checkpoint signaling pathways. Although they are conserved replication fork components, precise biochemical roles of these proteins are not known. Here we purified Mrc1 and Swi1-Swi3 proteins and show that these proteins bind to DNA independently but synergistically in vitro. Mrc1 binds preferentially to arrested fork or D-loop-like structures, although the affinity is relatively low, whereas the Swi1-Swi3 complex binds to double-stranded DNA with higher affinity. In the presence of a low concentration of Swi1-Swi3, Mrc1 generates a novel ternary complex and binds to various types of DNA with higher affinity. Moreover, purified Mrc1 and Swi1-Swi3 physically interact with each other, and this interaction is lost by mutations in the known DNA binding domain of Mrc1 (K235E,K236E). The interaction is also lost in a mutant form of Swi1 (E662K) that is specifically defective in polar fork arrest at a site called RTS1 and causes sensitivity to genotoxic agents, although the DNA binding affinity of Swi1-Swi3 is not affected by this mutation. As expected, the synergistic effect of the Swi1 Swi3 on DNA binding of Mrc1 is also lost by these mutations affecting the interaction between Mrc1 and Swi1-Swi3. Our results reveal an aspect of molecular interactions that may play an important role in replication pausing and fork stabilization. PMID- 20924118 TI - Health-related quality of life and classroom participation of deaf and hard-of hearing students in general schools. AB - A group of deaf and hard-of-hearing (D/HH) students at mainstream schools (N = 212) was investigated in a questionnaire-based survey using the Inventory of Life Quality of Children and Youth (ILC) and the Classroom Participation Questionnaire. The ILC data for the D/HH sample are for the most part comparable with the data from a normative hearing sample. Item-total correlations showed that the domains of school and social activities with peers were more important for the Health-Related Quality of Life (HRQoL) of the D/HH students than for that of the hearing students. The results also reveal differences in the HRQoL levels of the two samples, with the D/HH sample having higher scores for school experiences, physical and mental health, and overall HRQoL, though the effect sizes for the differences are small to moderate. Specific characteristics of the D/HH sample may be responsible for this result. There are also relationships between quality of life and perceived classroom participation in certain domains: Students who perceive classroom participation as satisfying have higher scores for quality of life in school, social contact with peers, and mental health. This also applied to the scores for global assessment and a summarized quality of life indicator. PMID- 20924117 TI - Ribonucleoside triphosphates as substrate of human immunodeficiency virus type 1 reverse transcriptase in human macrophages. AB - We biochemically simulated HIV-1 DNA polymerization in physiological nucleotide pools found in two HIV-1 target cell types: terminally differentiated/non dividing macrophages and activated/dividing CD4(+) T cells. Quantitative tandem mass spectrometry shows that macrophages harbor 22-320-fold lower dNTP concentrations and a greater disparity between ribonucleoside triphosphate (rNTP) and dNTP concentrations than dividing target cells. A biochemical simulation of HIV-1 reverse transcription revealed that rNTPs are efficiently incorporated into DNA in the macrophage but not in the T cell environment. This implies that HIV-1 incorporates rNTPs during viral replication in macrophages and also predicts that rNTP chain terminators lacking a 3'-OH should inhibit HIV-1 reverse transcription in macrophages. Indeed, 3'-deoxyadenosine inhibits HIV-1 proviral DNA synthesis in human macrophages more efficiently than in CD4(+) T cells. This study reveals that the biochemical landscape of HIV-1 replication in macrophages is unique and that ribonucleoside chain terminators may be a new class of anti-HIV-1 agents specifically targeting viral macrophage infection. PMID- 20924119 TI - Combined hardware--software considerations for triage of internally contaminated personnel. AB - Medical response to a radiological emergency involves first assessing, triaging and treating trauma, followed by determining potential hazard from radiological intake. A combined hardware-software strategy is required for this mission. The hardware strategy should consist of a dedicated detector suite capable of alpha, beta and gamma radiation detection, identification and quantification suitable for order of magnitude dose assessment. The hardware platform should provide a simple user interface suitable for field deployment. The software should provide first-on-the-scene responders with the ability to perform radiological triage in a mass casualty type event, physicians with the ability to assign treatment regimes, and long-term care medical personnel with information to provide continual risk reassessment of the patient taking into account toxicology of the decorporation therapy and dose aversion. The software should be rich in data, yet accessible through a simple user interface. Practicing in a radiological emergency exercise environment with the equipment is crucial to its efficacy in a real emergency. PMID- 20924120 TI - Spot measurements of intermediate frequency electric fields in the vicinity of compact fluorescent lamps. AB - Starting in 2009, certain types of incandescent light bulbs will be withdrawn from the market in the European Union and elsewhere. However, compact fluorescent lamps that are among the candidates to replace them produce intermediate frequency electric fields (EFs) much higher than any other device or appliance previously available to the general public. Measurement results of these EFs showed that the maximum recorded EF strength in the 1.2-100 kHz frequency range in close proximity to the lamps was > 42 V m(-1) for all tested lamps. In nine cases, the field strength exceeded 87 V m(-1) and the highest measured value was 216 V m(-1). PMID- 20924121 TI - Children as vulnerable populations in radiological/nuclear events: discussion scenarios. AB - A workshop to discuss Canada's preparedness to properly manage and treat children during radiological/nuclear (R/N) events was held in Ottawa, Canada, on 1-2 June 2010. This workshop provided a platform for participants of varied backgrounds including medicine, radiological and nuclear physics as well as child care, to discuss the strength and shortcoming of the currently implemented practices and procedures in Canada for the treatment and management of contaminated and/or exposed children during R/N events. To aid this discussion, scenarios (vignettes) involving the malicious use of radiological material were presented and discussed from the perspective of the emergency response focusing specifically on children. From these discussions, it was concluded that the management of children during R/N events is vastly different from the management of adults, and requires a specific set of protocols and procedures, not yet outlined in Canadian documentation. This paper is not meant to discuss existing response protocols during R/N events, but rather to discuss the deficiencies in planning and suggested improvements/revisions raised through discussion at the workshop on how to better manage children during an R/N event. PMID- 20924122 TI - Psychosocial considerations for mass decontamination. AB - Mass exposure to explosions, infectious agents, foodborne illnesses, chemicals or radiological materials may require mass decontamination that have critical psychosocial implications for the public and for both traditional and non traditional responders in terms of impact and of response. Five main issues are common to mass decontamination events: (i) perception, (ii) somatisation, (iii) media role and communication, (iv) information sharing, (v) behavioural guidance and (vi) organisational issues. Empirical evidence is drawn from a number of cases, including Chernobyl; Goiania, Brazil; the sarin gas attack in Tokyo; the anthrax attacks in the USA; Three Mile Island; and by features of the 2003 severe acute respiratory syndrome pandemic. In this paper, a common platform for mass casualty management is explored and suggestions for mass interventions are proposed across the complete event timeline, from pre-event threat and warning stages through to the impact and reconstruction phases. Implication for responders, healthcare and emergency infrastructure, public behaviour, screening processes, risk communication and media management are described. PMID- 20924123 TI - Monte Carlo simulations of the photon calibration fields at the underground laboratory of PTB. AB - A unique photon calibration facility operated by Physikalisch-Technische Bundesanstalt (PTB) provides photon fields with area dose rates in the order of the natural environmental radiation and even below. This facility is located in an underground laboratory in the Asse salt mine at a depth of 490 m below ground, where the ambient dose equivalent rate is only 2 nSv h(-1). Radioactive sources of the nuclides (241)Am, (57)Co, (137)Cs, (60)Co and (226)Ra are used to generate photon fields with different characteristics. In the past, the basic properties of the photon field, especially the area dose rate at the reference point and the mean energy of the photon spectra, were calculated by using analytic methods. However, information about scattered photons is only accessible through an investigation of spectra by performing Monte Carlos simulations. Therefore, the photon spectra at the reference point of the calibration facility were calculated using the Monte Carlo transport code MCNP. The results obtained by using this method are of relevance for the traceability of the reference dose rate values to PTB's primary standards, as well as for the determination of the mean photon energy of the spectra. The latter was calculated with respect to the different quantities 'photon fluence', 'air kerma' and 'ambient dose equivalent'. The origin of the scattered component in the photon spectrum is investigated in detail by studying the photon field produced by the quasi-monoenergetic gamma emitter (137)Cs (E(gamma) = 662 keV) under various geometrical conditions. Implications of the Monte Carlo simulations on the traceability of the dose rate reference values as well as on the assessment of uncertainties will be described. PMID- 20924124 TI - Aflibercept exerts antivascular effects and enhances levels of anthracycline chemotherapy in vivo in human acute myeloid leukemia models. AB - We examined whether potent vascular endothelial growth factor (VEGF) blockade mediated by aflibercept, a decoy VEGF receptor (VEGFR) 1/2 moiety with stronger affinity for VEGF than bevacizumab, resulted in antileukemia effects and enhanced the efficacy of systemic chemotherapy. The efficacy of aflibercept alone and in combination with doxorubicin was evaluated in human VEGF-expressing acute myeloid leukemia (AML) cell lines and primary cells xenotransplanted into immunodeficient mice. Aflibercept reduced primary VEGF/VEGFR-positive AML colony formation growth in vitro and inhibited AML xenograft growth up to 93% in association with antiangiogenic and antiproliferative effects, hypoxia, and VEGF sequestration in multiple models. High VEGF-A expression by AML cells promoted in vivo xenograft growth and aflibercept sensitivity. Aflibercept therapy slowed disease progression in two systemic human AML xenograft models and reduced peripheral leukemia disease in a primary relapsed AML model in NOD/SCID/IL2Rgammanull mice. Combination aflibercept and doxorubicin enhanced antitumor effects in local xenograft models. Sequential aflibercept followed by doxorubicin resulted in progressive anthracycline accumulation in marrow and extramedullary AML sites and resulted in 2-fold higher drug levels 24 hours after administration. In contrast, tissues (tumor, plasma, marrow) treated with chemotherapy only showed progressive drug clearance over time. Combination aflibercept and doxorubicin also resulted in vascular narrowing, decreased vessel number, and perivascular apoptosis. These data suggest that inefficient drug delivery by leukemia-associated vasculature may mediate chemoresistance and support further clinical evaluation of combination aflibercept and anthracycline therapy in refractory/relapsed AML patients. PMID- 20924126 TI - Small interfering RNA targeting 14-3-3zeta increases efficacy of chemotherapeutic agents in head and neck cancer cells. AB - Patients diagnosed in advanced stages of head and neck squamous cell carcinoma often show limited response to chemotherapeutic agents. Recently, we reported the overexpression of 14-3-3zeta protein in head and neck premalignant and cancer tissues using liquid chromatography-tandem mass spectrometry with isotopic labeling and revealed its significance as a prognostic marker using immunohistochemical analysis. In this study, we determined the potential of 14-3 3zeta as a therapeutic target for head and neck cancer. Small interfering RNA (siRNA) targeting 14-3-3zeta was used to downregulate its expression in head and neck cancer cells in culture. Cell cycle analysis showed that head and neck cancer cells transfected with siRNA targeting 14-3-3zeta showed G(2)-M arrest. These siRNA transfectants also showed increased cell death on treatment with any one of the following chemotherapeutic agents: cisplatin, 5-fluorouracil, paclitaxel, or doxorubicin in comparison with the no transfection controls. Flow cytometric analysis using propidium iodide staining showed increased sub-G(0) fraction in siRNA-transfected cells treated with any of these chemotherapeutic agents, suggesting cell death; in addition, Annexin V staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay revealed increased apoptosis. Taken together, our results strongly showed that downregulation of 14-3-3zeta expression may serve to improve the sensitivity of head and neck cancer cells to chemotherapeutic agents. PMID- 20924127 TI - A better TRAIL variant for tumor cell-specific targeting? - letter. PMID- 20924128 TI - Compensatory insulin receptor (IR) activation on inhibition of insulin-like growth factor-1 receptor (IGF-1R): rationale for cotargeting IGF-1R and IR in cancer. AB - Insulin-like growth factor-1 receptor (IGF-1R) is a receptor tyrosine kinase (RTK) and critical activator of the phosphatidylinositol 3-kinase-AKT pathway. IGF-1R is required for oncogenic transformation and tumorigenesis. These observations have spurred anticancer drug discovery and development efforts for both biological and small-molecule IGF-1R inhibitors. The ability for one RTK to compensate for another to maintain tumor cell viability is emerging as a common resistance mechanism to antitumor agents targeting individual RTKs. As IGF-1R is structurally and functionally related to the insulin receptor (IR), we asked whether IR is tumorigenic and whether IR-AKT signaling contributes to resistance to IGF-1R inhibition. Both IGF-1R and IR(A) are tumorigenic in a mouse mammary tumor model. In human tumor cells coexpressing IGF-1R and IR, bidirectional cross talk was observed following either knockdown of IR expression or treatment with a selective anti-IGF-1R antibody, MAB391. MAB391 treatment resulted in a compensatory increase in phospho-IR, which was associated with resistance to inhibition of IRS1 and AKT. In contrast, treatment with OSI-906, a small-molecule dual inhibitor of IGF-1R/IR, resulted in enhanced reduction in phospho IRS1/phospho-AKT relative to MAB391. Insulin or IGF-2 activated the IR-AKT pathway and decreased sensitivity to MAB391 but not to OSI-906. In tumor cells with an autocrine IGF-2 loop, both OSI-906 and an anti-IGF-2 antibody reduced phospho-IR/phospho-AKT, whereas MAB391 was ineffective. Finally, OSI-906 showed superior efficacy compared with MAB391 in human tumor xenograft models in which both IGF-1R and IR were phosphorylated. Collectively, these data indicate that cotargeting IGF-1R and IR may provide superior antitumor efficacy compared with targeting IGF-1R alone. PMID- 20924129 TI - MSH6 and MUTYH deficiency is a frequent event in early-onset colorectal cancer. AB - PURPOSE: Early-onset colorectal cancer (CRC) is suggestive of a hereditary predisposition. Lynch syndrome is the most frequent CRC hereditary cause. The MUTYH gene has also been related to hereditary CRC. A systematic characterization of these two diseases has not been reported previously in this population. EXPERIMENTAL DESIGN: We studied a retrospectively collected series of 140 patients <=50 years old diagnosed with nonpolyposis CRC. Demographic, clinical, and familial features were obtained. Mismatch repair (MMR) deficiency was determined by microsatellite instability (MSI) analysis, and immunostaining for MLH1, MSH2, MSH6, and PMS2 proteins. Germline MMR mutations were evaluated in all MMR-deficient cases. Tumor samples with loss of MLH1 or MSH2 protein expression were analyzed for somatic methylation. Germline MUTYH mutations were evaluated in all cases. BRAF V600E and KRAS somatic mutational status was also determined. RESULTS: Fifteen tumors (11.4%) were MSI, and 20 (14.3%) showed loss of protein expression (7 for MLH1/PMS2, 2 for isolated MLH1, 3 for MSH2/MSH6, 7 for isolated MSH6, and 1 for MSH6/PMS2). We identified 11 (7.8%) germline MMR mutations, 4 in MLH1, 1 in MSH2, and 6 in MSH6. Methylation analysis revealed one case with somatic MLH1 methylation. Biallelic MUTYH mutations were detected in four (2.8%) cases. KRAS and BRAF V600E mutations were present in 39 (27.9%) and 5 (3.6%) cases, respectively. CONCLUSIONS: Loss of MSH6 expression is the predominant cause of MMR deficiency in early-onset CRC. Our findings prompt the inclusion of MSH6 and MUTYH screening as part of the genetic counseling of these patients and their relatives. PMID- 20924130 TI - Simultaneous blockade of multiple immune system inhibitory checkpoints enhances antitumor activity mediated by interleukin-15 in a murine metastatic colon carcinoma model. AB - PURPOSE: Interleukin 15 (IL-15) is a promising cytokine for immunotherapy of cancer due to its ability to stimulate the immunity of natural killer, B, and T cells. Its effectiveness, however, may be limited by inhibitory checkpoints and pathways that can attenuate immune responses. Finding strategies to abrogate these negative regulators and enhance the efficacy of IL-15 is a critical challenge. EXPERIMENTAL DESIGN: In a preclinical study, we evaluated IL-15 combined with antibodies to block the negative immune regulators cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed death ligand 1 (PD-L1) in a metastatic murine CT26 colon carcinoma model. RESULTS: IL-15 treatment resulted in a significant prolongation of survival in mice with metastatic tumor. Administration of IL-15, however, also increased expression of PD-1 on the surface of CD8(+) T cells including CD8(+)CD44(high) memory phenotype T cells. Moreover, IL-15 also increased the secretion of the immunosuppressive cytokine, IL-10. Combining IL-15 with anti-PD-L1 and anti-CTLA-4 (multiple immune checkpoint blockade) exhibited greater CTL killing and IFNgamma secretion. Moreover, this combination resulted in a significant reduction in surface expression of PD-1 on CD8(+) T cells, a decrease in IL-10 secretion, and led to significantly longer survival of tumor-bearing animals compared with mice treated with IL-15 alone or combined singularly with anti-PD-L1 or anti-CTLA-4. CONCLUSIONS: Combining the immune stimulatory properties of IL-15 with the simultaneous removal of 2 critical immune system inhibitory checkpoints, we showed enhancement of immune responses leading to increased antitumor activity. PMID- 20924132 TI - Using an external gating signal to estimate noise in PET with an emphasis on tracer avid tumors. AB - The purpose of this study is to establish and validate a methodology for estimating the standard deviation of voxels with large activity concentrations within a PET image using replicate imaging that is immediately available for use in the clinic. To do this, ensembles of voxels in the averaged replicate images were compared to the corresponding ensembles in images derived from summed sinograms. In addition, the replicate imaging noise estimate was compared to a noise estimate based on an ensemble of voxels within a region. To make this comparison two phantoms were used. The first phantom was a seven-chamber phantom constructed of 1 liter plastic bottles. Each chamber of this phantom was filled with a different activity concentration relative to the lowest activity concentration with ratios of 1:1, 1:1, 2:1, 2:1, 4:1, 8:1 and 16:1. The second phantom was a GE Well-Counter phantom. These phantoms were imaged and reconstructed on a GE DSTE PET/CT scanner with 2D and 3D reprojection filtered backprojection (FBP), and with 2D- and 3D-ordered subset expectation maximization (OSEM). A series of tests were applied to the resulting images that showed that the region and replicate imaging methods for estimating standard deviation were equivalent for backprojection reconstructions. Furthermore, the noise properties of the FBP algorithms allowed scaling the replicate estimates of the standard deviation by a factor of 1/square root N, where N is the number of replicate images, to obtain the standard deviation of the full data image. This was not the case for OSEM image reconstruction. Due to nonlinearity of the OSEM algorithm, the noise is shown to be both position and activity concentration dependent in such a way that no simple scaling factor can be used to extrapolate noise as a function of counts. The use of the Well-Counter phantom contributed to the development of a heuristic extrapolation of the noise as a function of radius in FBP. In addition, the signal-to-noise ratio for high uptake objects was confirmed to be higher with backprojection image reconstruction methods. These techniques were applied to several patient data sets acquired in either 2D or 3D mode, with (18)F (FLT and FDG). Images of the standard deviation and signal-to-noise ratios were constructed and the standard deviations of the tumors' uptake were determined. Finally, a radial noise extrapolation relationship deduced in this paper was applied to patient data. PMID- 20924131 TI - Development of a validated immunofluorescence assay for gammaH2AX as a pharmacodynamic marker of topoisomerase I inhibitor activity. AB - PURPOSE: Phosphorylated histone H2AX (gammaH2AX) serves as a biomarker for formation of DNA double-strand break repair complexes. A quantitative pharmacodynamic immunofluorescence assay for gammaH2AX was developed, validated, and tested in human tumor xenograft models with the use of clinically relevant procedures. EXPERIMENTAL DESIGN: The gammaH2AX immunofluorescence assay uses a novel data quantitation and image processing algorithm to determine the extent of nuclear-specific gammaH2AX staining in tumor needle biopsies and hair follicles collected from mice bearing topotecan-responsive A375 xenografts. After method validation with the topoisomerase I (Top1) inhibitor topotecan, the assay was used to compare pharmacodynamic properties of three structurally related indenoisoquinoline Top1 inhibitors. RESULTS: gammaH2AX response to topotecan was quantified over a 60-fold dose range (0.016-1.0 times the murine single-dose maximum tolerated dose), and significant pharmacodynamic response was measured at the mouse equivalent of the 1.5 mg/m(2) clinical dose as well as the lowest dose tested. Responses were within a time window amenable for biopsy collection in clinical trials. These studies enabled characterization of dose and time responses for three indenoisoquinolines, resulting in selection of two for clinical evaluation. gammaH2AX response to Top1 inhibitors in hair follicles was also observable above a minimal dose threshold. CONCLUSIONS: Our gammaH2AX assay is sufficiently accurate and sensitive to quantify gammaH2AX in tumor samples and will be used in correlative studies of two indenoisoquinolines in a phase I clinical trial at the National Cancer Institute. Data suggest that hair follicles may potentially serve as a surrogate tissue to evaluate tumor gammaH2AX response to Top1 inhibitors. PMID- 20924133 TI - Generating arbitrary one-dimensional dose profiles using rotational therapy. AB - Conformal radiation therapy can be delivered using several methods: intensity modulated radiotherapy (IMRT) at fixed gantry angles, through the continuous gantry rotation of linac (rotational arc therapy), or by a dedicated treatment unit such as tomotherapy. The recently developed volumetric modulated arc therapy (VMAT), a form of rotational arc therapy, has attracted lots of attention from investigators to explore its capability of generating highly conformal dose to the target. The main advanced features of VMAT are the variable dose rate and gantry rotation speed. In this paper, we present a theoretical framework of generating arbitrary one-dimensional dose profiles using rotational arc therapy to further explore the new degree of freedom of the VMAT technique. This framework was applied to design a novel technique for total body irradiation (TBI) treatment, where the desired dose distribution can be simplified by a one dimensional profile. The technique was validated using simulations and experimental measurements. The preliminary results demonstrated that the new TBI technique using either dynamic MLC only, variable dose rate only, or a combination of dynamic MLC and variable dose rate can achieve arbitrary dose distribution in one dimension, such as uniform dose to target and lower dose to critical organ. This technique does not require the use of customized compensators, nor large treatment rooms as in the conventional extended SSD technique. PMID- 20924134 TI - Multifractal analysis of heart rate variability and laser Doppler flowmetry fluctuations:comparison of results from different numerical methods. AB - To contribute to the understanding of the complex dynamics in the cardiovascular system (CVS), the central CVS has previously been analyzed through multifractal analyses of heart rate variability (HRV) signals that were shown to bring useful contributions. Similar approaches for the peripheral CVS through the analysis of laser Doppler flowmetry (LDF) signals are comparatively very recent. In this direction, we propose here a study of the peripheral CVS through a multifractal analysis of LDF fluctuations, together with a comparison of the results with those obtained on HRV fluctuations simultaneously recorded. To perform these investigations concerning the biophysics of the CVS, first we have to address the problem of selecting a suitable methodology for multifractal analysis, allowing us to extract meaningful interpretations on biophysical signals. For this purpose, we test four existing methodologies of multifractal analysis. We also present a comparison of their applicability and interpretability when implemented on both simulated multifractal signals of reference and on experimental signals from the CVS. One essential outcome of the study is that the multifractal properties observed from both the LDF fluctuations (peripheral CVS) and the HRV fluctuations (central CVS) appear very close and similar over the studied range of scales relevant to physiology. PMID- 20924135 TI - Improving bone marrow stromal cell attachment on chitosan/hydroxyapatite scaffolds by an immobilized RGD peptide. AB - Ample cell adhesion to scaffolds is essential for effective bone tissue engineering. Chitosan/hydroxyapatite (CS/HA) scaffolds with channel-shaped and spherically shaped pore morphologies were prepared via in situ compositing hybridization in combination with lyophilization. The sizes of channel-shaped and spherically shaped pores of the CS/HA scaffolds were 150-650 um and 3-15 um, respectively. The RGD peptide (Arg-Gly-Asp) was bound to the surface of CS/HA scaffolds via physical adsorption. More than 63% of RGD present in a PBS solution spontaneously adsorbed onto CS/HA scaffolds. High numbers of viable bone marrow stromal cells (BMSCs) were observed by confocal and fluorescence microscopy for cells cultured on CS/HA scaffolds with and without RGD for 3 days. BMSCs on CS/HA scaffolds with RGD (RGD-CS/HA) were incubated for 4 h under standard culture conditions, and the degree of cell adhesion was calculated. Cell adhesion to RGD CS/HA scaffolds with different RGD concentrations was 71.6% and 80.7%, respectively. This was 30.9% and 47.5% higher than adhesion to the CS/HA scaffold without RGD, respectively. BMSCs cultured on the scaffolds for 14 days with osteogenic supplements expressed 103% higher alkaline phosphatase on the RGD CS/HA scaffold (0.001 97 +/- 0.000 31 U/L/ng), than on the unmodified scaffold (0.000 97 +/- 0.000 25 U/L/ng) (p < 0.01), indicating that a RGD peptide significantly promotes osteogenic differentiation of BMSCs on CS/HA scaffolds. The results of this study indicate that RGD-CS/HA scaffolds promote initial cell adhesion, spread and differentiation toward an osteogenic phenotype. PMID- 20924136 TI - Comparative analysis of adherence, viability, proliferation and morphology of umbilical cord tissue-derived mesenchymal stem cells seeded on different titanium coated expanded polytetrafluoroethylene scaffolds. AB - Umbilical cord tissue comprises an attractive new source for mesenchymal stem cells. Umbilical cord tissue-derived mesenchymal stem cells (UCMSC) exhibit self renewal, multipotency and immunological naivity, and they can be obtained without medical intervention. The transfer of UCMSC to the ischemic region of the heart may have a favorable impact on tissue regeneration. Benefit from typical cell delivery by injection to the infarcted area is often limited due to poor cell retention and survival. Another route of administration is to use populated scaffolds implanted into the infarcted zone. In this paper, the seeding efficiency of UCMSC on uncoated and titanium-coated expanded polytetrafluoroethylene (ePTFE) scaffolds with different surface structures was determined. Dualmesh (DM) offers a corduroy-like surface in contrast to the comparatively planar surface of cardiovascular patch (CVP). The investigation of adherence, viability and proliferation of UCMSC demonstrates that titanium-coated scaffolds are superior to uncoated scaffolds, independent of the surface structure. Microscopic images reveal spherical UCMSC seeded on uncoated scaffolds. In contrast, UCMSC on titanium-coated scaffolds display their characteristic spindle-shaped morphology and a homogeneous coverage of CVP. In summary, titanium coating of clinically approved CVP enhances the retention of UCMSC and thus offers a potential cell delivery system for the repair of the damaged myocardium. PMID- 20924137 TI - Effect of a porous tantalum rod on early and intermediate stages of necrosis of the femoral head. AB - The aim of this study was to evaluate the effect of a porous tantalum rod implant for the treatment of early femoral head necrosis. From April 2007 to June 2009, a total of 35 femoral head necrosis patients (with 49 hips) were treated with core decompression in combination with the insertion of a porous tantalum rod. The mean age was 38.2 years (22-50 years) and the mean follow-up period was 15.2 months (12-36 months). The surgical time and blood loss were recorded. The Harris hip scores and radiological results were adopted for evaluation. The mean surgical time was 35 min, and the mean blood loss was 50 ml. The mean Harris score improved from 48.3 +/- 3.2 preoperative to 83.7 +/- 4.1 at the last follow up (p < 0.05). Eight affected hips exhibited progressive pain including three hips that progressed to femoral collapse, and one revision followed by total hip arthroplasty (THA). For the patient who underwent revision and THA, the articular cartilage surface was seen to be damaged and fragmented. High-density metal particle residuals were observed on radiograph in the bone channel and femoral marrow cavity. We conclude that the selection criteria for porous tantalum implants should be early and intermediate stages of femoral head necrosis. Further study is warranted to reveal whether the metal particles released play a role in the progression of pain and failure. PMID- 20924138 TI - A modified double-emulsion method for the preparation of daunorubicin-loaded polymeric nanoparticle with enhanced in vitro anti-tumor activity. AB - The encapsulation of hydrophilic drug in polymeric nanoparticles with high loading remains a challenge due to the rapid penetration of the drug to the external aqueous phase. In order to improve the encapsulation efficiency of daunorubicin (DNR) in poly(D,L-lactic-co-glycolic acid (PLGA) and poly(D,L-lactic acid) (PDLLA) nanoparticles, we fabricated a series of DNR-loaded nanoparticles using a modified double-emulsion solvent evaporation/diffusion method, which introduced a partially water-soluble organic solvent into the particle formation. The influence of various preparation parameters was investigated systematically, such as the ratio of organic solvent, the type of surfactant, the type of polymers and the molecular weight. Results showed that regular spherical PLGA nanoparticles with diameters of 200-300 nm could be produced with a remarkably high DNR encapsulation efficiency (>80%) and loading (6.5% (w/w)). Upon encapsulation, the sustained release of DNR could be controlled over 2 weeks. The results of FT-IR and DSC analysis indicated that the encapsulated DNR in polymeric nanoparticles was inclusion, not absorption. Furthermore, optimized DNR/PLGA nanoparticles showed a significant enhancement of cellular uptake, higher cytotoxicity against HL-60 cells compared with free DNR. These results were potentially useful for the nanoparticle formulation of hydrophilic chemotherapeutic drugs that require efficient delivery to cancer cells as well as sustained release at the specific site. PMID- 20924139 TI - Stem cells in bone tissue engineering. AB - Bone tissue engineering has been one of the most promising areas of research, providing a potential clinical application to cure bone defects. Recently, various stem cells including embryonic stem cells (ESCs), bone marrow-derived mesenchymal stem cells (BM-MSCs), umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs), adipose tissue-derived stem cells (ADSCs), muscle-derived stem cells (MDSCs) and dental pulp stem cells (DPSCs) have received extensive attention in the field of bone tissue engineering due to their distinct biological capability to differentiate into osteogenic lineages. The application of these stem cells to bone tissue engineering requires inducing in vitro differentiation of these cells into bone forming cells, osteoblasts. For this purpose, efficient in vitro differentiation towards osteogenic lineage requires the development of well-defined and proficient protocols. This would reduce the likelihood of spontaneous differentiation into divergent lineages and increase the available cell source for application to bone tissue engineering therapies. This review provides a critical examination of the various experimental strategies that could be used to direct the differentiation of ESC, BM-MSC, UCB MSC, ADSC, MDSC and DPSC towards osteogenic lineages and their potential applications in tissue engineering, particularly in the regeneration of bone. PMID- 20924140 TI - Lack of a primary physicochemical determinant in the direct transport of drugs to the brain after nasal administration in rats: potential involvement of transporters in the pathway. AB - The objectives of this study were to evaluate the relative contribution of the direct pathway in overall brain transport for 17 model drugs with different physicochemical properties after nasal administrations and to identify factors that govern the fraction of the dose transported to the brain via the direct pathway (F(a, direct)). When the model drugs were nasally administered to rats, 5 of the 17 model drugs were delivered to a significant extent to the brain via the direct pathway. Multiple linear regression analyses showed that the correlation between various physicochemical properties and F(a, direct) was not statistically significant, indicative of a lack of primary physicochemical determinants in the direct transport pathway. Transporters such as rOAT3 and rOCT2 were expressed at significant levels in rat olfactory epithelia, and uptakes of standard substrates were significantly decreased in HEK293 cells expressing rOAT3 and rOCT2 in the presence of the five model drugs that were delivered to appreciable extents to the brain via the direct pathway. Therefore, these observations indicate that carrier-mediated transport may play a role in the brain delivery of drugs from the nose via the direct transport pathway. PMID- 20924141 TI - Pharmacokinetic/pharmacodynamic modeling of glucose clamp effects of inhaled and subcutaneous insulin in healthy volunteers and diabetic patients. AB - The pharmacokinetics and pharmacodynamics (PK/PD) of inhaled insulin in humans have not been modeled previously. We rationalized a model for the effects of inhaled insulin on glucose infusion rate during a euglycemic clamp study based on the mechanism of insulin action and compared parameter estimates between subcutaneous and inhaled insulin in healthy and diabetic subjects. Published data from two studies in 11 healthy volunteers and 18 type 1 diabetes patients were digitized. The subjects received four different doses of inhaled insulin and one or three different doses subcutaneously at the start of a 10 h glucose clamp. All data were modeled simultaneously using NONMEM VI. Insulin pharmacokinetics were described by a one-compartment model with one (inhaled) or two (subcutaneous insulin) first-order absorption processes and first-order elimination. Insulin effects on glucose were described by an indirect response model. A biophase direct effect equation for the glucose infusion rate was implemented. Pharmacodynamic parameter estimates were 15.1 mg/min/kg for maximal glucose infusion rate (GIR(max)) and 88.0 mIU/L for SC(50) for diabetic patients and 62.9 mIU/L for healthy subjects. A PK/PD model based on fundamental principles of insulin action and glucose turnover suggests comparable potencies of inhaled and subcutaneous insulin. PMID- 20924142 TI - Vitamin C nutriture in newly diagnosed diabetes. AB - This study was performed to investigate the relationship between serum L-ascorbic acid, vitamin C intake, and diabetes in a nested case-control study. A cross sectional survey of diet and health was conducted in 2,048 adults with an age of 30 y or older in Yonchon County, Korea. An oral glucose tolerance test was administered to all participants. One hundred cases of newly diagnosed diabetes were identified. Two healthy controls for each case matched with age, gender, drinking status, and smoking status were selected among the survey participants. L-Ascorbic acid levels were analyzed in fasting serum samples and one 24-h dietary recall was performed. Dietary vitamin C intake of persons with diabetes was 50.1+/-47.6 mg/d and that of controls was 55.1+/-41.1 mg/d. People with diabetes (22.3+/-16.8 umol/L) have lower serum ascorbic acid levels than their controls (26.3+/-17.0 umol/L) and the difference was significant by paired t-test (p<0.01). The association between diabetes and serum ascorbic acid level was still significant in non-smokers (24.2+/-17.8 umol/L for the diabetes group and 29.5+/-16.7 umol/L for the control group, p<0.01) but not in smokers (19.4+/-15.7 umol/L for the diabetes group and 21.2+/-16.0 umol/L for the control group). Our results suggest that diabetes and smoking interactively affect serum ascorbic acid levels. Since this population had poor nutritional status of vitamin C, further investigation of association between serum ascorbic acid level and diabetes and smoking by the level of vitamin C consumption is warranted. PMID- 20924143 TI - Serum retinol, alpha-tocopherol and systemic inflammatory response in metastatic colorectal carcinoma patients treated with combination chemotherapy and cetuximab. AB - Cetuximab is a chimeric antibody registered for the therapy of advanced colorectal carcinoma. Cancer and anticancer therapy are associated with oxidative stress, and disorders of antioxidant balance may be involved in the toxicity associated with anticancer treatment. The aim of the present study was to investigate the changes of serum retinol, alpha-tocopherol and C-reactive protein during the first month of treatment with cetuximab and chemotherapy. Twenty-five consecutive patients with metastatic colorectal carcinoma treated with a combination of chemotherapy and cetuximab were included in the present study. Serum retinol and alpha-tocopherol were determined by high-performance liquid chromatography and serum C-reactive protein was determined using commercial kits. Significant correlation was observed between baseline concentrations of retinol and C-reactive protein (r(s)=-0.54, p<0.01). Median survival of patients who had baseline serum retinol below 1.25 umol/L was 10 mo compared to 18 mo for patients who had serum retinol equal or above 1.25 umol/L (p<0.05); median survival of patients who had serum C-reactive protein below 24 mg/L was significantly longer compared to patients with C-reactive protein levels equal or above 24 mg/L (18 vs. 7 mo, p<0.05), but no difference in survival was observed based on alpha tocopherol levels. Twenty-two patients had evaluation of retinol, alpha tocopherol and C-reactive protein at least once during the follow up. Serum concentration of alpha-tocopherol decreased significantly during the therapy, but retinol and C-reactive protein concentrations remained unchanged. In conclusion, a significant correlation was observed between serum retinol and C-reactive protein. Serum alpha-tocopherol decreased significantly during the first month of combination therapy with cetuximab. Low retinol and high C-reactive protein concentrations were predictive of poor prognosis in this patient population. PMID- 20924144 TI - Impact of ethnic conflict on the nutritional status and quality of life of suburban villagers in the Solomon Islands. AB - This paper describes the health and nutritional status and quality of life (QOL) of suburban villagers in the Solomon Islands 3 y after the 1998-2003 ethnic conflict. Cross-sectional data were obtained from a small community located 50 km east of the capital city (n=206, 87 adults and 119 children). A health survey involving urine analysis, anthropometry, and blood pressure measurements was conducted to assess health and nutritional status and child growth. Simultaneously, 57 non-randomly selected adults participated in the QOL questionnaire survey. Results of anthropometry show that participants had good health and nutritional status (mean BMIs: 22.8 and 21.7 for men and women, respectively) and 73% of boys and 83% of girls were judged 'normal body size' based on their BMI values. Urinalysis revealed that 88% of the participants were healthy and indicated that they consumed considerable amounts of purchased food such as rice and tinned meat. These findings suggest that the population's lifestyle had essentially recovered from the ethnic conflict. However, possible consequences of the ethnic conflict on the QOL scores were observed in the environmental domain. This study found a positive association between body fat and QOL. This could be interpreted in terms of the traditionally positive view of large bodies in the South Pacific and as resulting from unstable social conditions prevailing after the ethnic conflict. PMID- 20924145 TI - Effects of dietary protein levels on body composition of zinc-deficient rats. AB - This study examined why decreased protein intake retards zinc deficiency in zinc deficient rats. Rats were freely provided zinc-deficient diets with either 10 or 20% protein. Experimental groups consisted of five rats that were fed experimental diets for 0, 3, 4, 12 and 25 d in Experiment 1. The body protein content in rats fed the 10% protein diet was similar to those fed the 20% protein diet for the duration of the experiment. The body zinc content in both dietary groups slowly decreased in a similar manner. Eventually, the body zinc/protein ratio in the 10% protein diet group decreased more slowly than that in the 20% protein diet group. Ingestion of the 10% protein diet also reduced the zinc/protein ratio in bone more slowly compared with that of the 20% protein diet, under zinc-deficient conditions, at 12 d in Experiment 2. However, there was no difference in the zinc/protein ratio of carcass total soft tissue between the two zinc-deficient groups. Decreased protein intake eventually slowed the reduction in both the body and bone zinc/protein ratios in zinc-deficient rats, resulting in retardation of zinc deficiency. PMID- 20924146 TI - Studies on the mechanism of antihypertensive action by nicotianamine. AB - Nicotianamine (NA), which is obtained from vegetables, lowers blood pressure through the renin-angiotensin system, and we clarified that NA preferentially inhibits the activity of angiotensin I-converting enzyme (ACE)-a zinc-containing enzyme. In this study, we elucidated the mechanism of antihypertensive action of NA through the Magnus method by using rat aortic blood vessels. Angiotensin I induced contractions were inhibited by NA in a concentration-dependant manner. Because NA did not inhibit angiotensin II-induced contractions, it was believed that NA inhibited ACE activity in vascular smooth muscles. NA did not affect KCl induced contractions, but it affected norepinephrine-induced contractions to a small extent. NA exerted similar effects on endothelium-denuded and endothelium intact blood vessels. Therefore, the antihypertensive action of NA did not play a role in the opening of voltage-dependent calcium channels, but this effect influenced vasoconstriction by the activation of alpha-adrenergic receptors. These results suggest that after absorption from the intestinal tract, NA may exert antihypertensive effects via 2 mechanisms: direct inhibition of ACE in vascular smooth muscle and activation of alpha-adrenergic receptors. PMID- 20924147 TI - Effects of simultaneous dietary fish oil ingestion and sulfur amino acid supplementation on the lipid metabolism in hepatoma-bearing rats with hyperlipidemia. AB - The effects of simultaneous dietary fish oil ingestion and sulfur amino acid (L methionine and L-cystine) supplementation on serum lipid concentrations and various parameters related to the lipid metabolism were studied in Donryu rats subcutaneously implanted with an ascites hepatoma cell line, AH109A. A diet containing 10% fish oil was found to reduce serum triglyceride, total cholesterol, (very-low-density lipoprotein plus low-density lipoprotein) cholesterol, phospholipid and nonesterified fatty acid (NEFA) concentrations in these animals, and dietary supplementation of 1.2% L-methionine and L-cystine also suppressed these serum lipid concentrations. Hepatic fatty acid synthesis and the availability of serum NEFA were decreased, and epididymal adipose tissue lipoprotein lipase (LPL) activity was elevated by dietary fish oil, while LPL activity in various tissues and hepatic fatty acid oxidation were increased by dietary sulfur amino acids, resulting in a reduction in the serum triglyceride concentration by dietary fish oil and sulfur amino acids, respectively. Dietary fish oil suppressed the hepatoma-induced increase in cholesterogenesis in the host liver, and dietary methionine and cystine enhanced bile acid excretion into feces, which were the causes of the hypocholesterolemic effect. In these serum lipid concentrations, there were significant effects of fish oil ingestion and sulfur amino acid supplementation, but no significant interaction between these two factors was seen. These results indicate that dietary fish oil and sulfur amino acid, L-methionine and L-cystine, have hypolipidemic effects in cancer related hyperlipidemia, and that the effects of these two factors on the decrease in these serum lipid concentrations are additive; these two factors may affect the lipid metabolism via different pathways and mechanisms. PMID- 20924148 TI - Effect of intermittent blood volume fluctuation of light resistance exercise after ingestion of the high-protein snacks on plasma branched-chain amino acid concentrations in young adults. AB - The study investigated exercise patterns resulting in the more efficient promotion of amino acid utilization. High-protein snacks (HPS; 15 g protein, 18 g sugar) were ingested by 8 young adult subjects 3 h after the basal meal ingestion. Sixty minutes after the HPS ingestion, the subjects performed arm flex/extend exercises for 15 min. The difference between 2 exercise patterns was compared. Pattern 1: High-number long-interval (HL) arm flex/extend (3+3 s) exercise; the HL group performed 9 sets of 15 exercises with a 10 s interval between sets. Pattern 2: Low-number short-interval (LS) arm flex/extend (3+3 s) exercise; the LS group performed 27 sets of 5 exercises with a 3-4 s interval between sets (135 exercises during 15 min, respectively). The plasma branched chain amino acid (BCAA) concentrations were measured before the HPS ingestion, before the exercise, and 60 and 90 min after the HPS ingestion. The plasma BCAA concentrations increased significantly after the HPS ingestion. In the HL group, BCAA concentration increased consistently during the period and 60 to 90 min after the HPS ingestion. During the same period in the LS group the BCAA concentration stopped increasing. After HPS ingestion, a significantly greater suppressive effect on plasma BCAA concentration was seen in the LS group compared to the HL group. Results confirmed that the intermittent blood volume fluctuation in muscle tissue during the exercise pattern performed by the LS group had an effect on the utilization of nutritional components (BCAA, glucose) from the blood, and showed the possibility that the group where the blood volume in the muscle tissue increased/lowered with higher frequency was a more effective exercise pattern for nutrient utilization. PMID- 20924149 TI - 2,4-Dinitrofluorobenzene-induced contact hypersensitivity response in NC/Nga mice fed fructo-oligosaccharide. AB - Strategies to manipulate gut microbiota in infancy have been considered to prevent the development of allergic diseases later in life. We previously demonstrated that maternal dietary supplementation with fructo-oligosaccharide (FOS) during pregnancy and lactation modulated the composition of gut microbiota and diminished the severity of spontaneously developing atopic dermatitis-like skin lesions in the offspring of NC/Nga mice. The present study tested whether dietary FOS affects contact hypersensitivity (CHS), another model for allergic skin disease, in NC/Nga mice. In experiment 1, 5-wk-old female NC/Nga mice were fed diets either with or without FOS supplementation for 3 wk and then received 2,4-dinitrofluorobenzene (DNFB) on the ear auricle 5 times at 7-d intervals. FOS supplementation reduced CHS response as demonstrated by ear swelling. Quantitative RT-PCR analysis showed that mRNA levels for interleukin (IL)-10, IL 12p40, and IL-17 in the lesional ear skin were significantly lower in mice fed FOS. In experiment 2, female NC/Nga mice were fed diets either with or without FOS during pregnancy and lactation. After weaning, offspring were fed the diets supplemented with or without FOS. Three weeks after weaning, offspring received DNFB on the ear auricle 4 times at 7-d intervals. Although FOS supplementation after weaning reduced ear swelling, maternal FOS consumption was ineffective in offspring. The present data suggest that dietary FOS reduces CHS while maternal FOS consumption is ineffective in offspring of DNFB-treated NC/Nga mice. PMID- 20924150 TI - Bioavailability of acetate from two vinegar supplements: capsule and drink. AB - The bioavailability of acetate in various vinegar supplements, e.g. as capsules and drinks, remains unclear. Thus, we conducted a cross-over clinical study in 30 healthy subjects. After an overnight fast, subjects received each test sample in a randomised sequence: 9 vinegar capsules (containing 750 mg acetic acid in total) with 150 mL of water, 100 mL of vinegar drink (containing 750 mg acetic acid), and 150 mL of water as reference. Blood samples were collected before (defined as 0 min), at 15, 30, 45, 60, 90, 120 and 180 min after each test sample intake. In the vinegar drink group, serum acetate concentration increased immediately after intake, peaked at 15 min and returned to baseline at 90 min. That in the vinegar capsule group rose slowly, peaked at 30 min and returned to baseline at 120 min. The peak values in both groups exceeded 200 umol/L, the physiologically active concentration confirmed by in vitro experiment. In the reference group, levels remained constant throughout the 180-min period. The amount of absorbed acetate from the vinegar capsule group and the drink group was evaluated by the difference value of the area under the serum acetate concentration-time curve (AUC) between in each vinegar group and in the reference group (expressed as AUC(capsule-ref) and AUC(drink-ref ), respectively). AUC(capsule-ref) was about 80% of AUC(drink-ref ), but there was no significant difference between them. PMID- 20924151 TI - Work-family spillover among Japanese dual-earner couples: a large community-based study. AB - OBJECTIVES: To examine the effects of multiple types of work-family spillover (work-to-family negative spillover, WFNS; family-to-work negative spillover, FWNS; and work-family positive spillover, WFPS) on psychological distress among Japanese dual-earner couples with preschool children. METHODS: 2,346 parents completed questionnaires measuring work-family spillover, work- and family specific variables (i.e., job demands and resources, family demands and resources), and psychological distress. A hierarchical multiple regression analysis was conducted by entering demographic characteristics (gender, age, age of the youngest child, and job contract) in step 1, job demands and resources in step 2, family demands and resources in step 3, work-family spillover in step 4, and three two-way interactions between types of work-family spillover and gender in the final step. RESULTS: Both WFNS and FWNS were positively related to psychological distress after controlling for demographic characteristics and domain specific variables (i.e. job and family demands/resources), and FWNS (beta=0.26) had a stronger relation with psychological distress than WFNS (beta=0.16). Although WFPS was significantly and negatively related to psychological distress, the relationship was weak (beta=-0.05). In addition, two way interactions of WFNS and FWNS with gender were found; the impact of both WFNS and FWNS on psychological distress is stronger for females than for males. No significant interaction effect was observed between WFPS and gender. CONCLUSIONS: In this study of Japanese dual-earner couples with preschool children, work family negative spillover had a stronger relationship with psychological distress than positive spillover. Gender had a moderating effect on the relationship between negative spillover and psychological distress. PMID- 20924152 TI - A cross-sectional survey of voice disorders among primary school teachers in Hong Kong. AB - OBJECTIVE: The purpose of the study was to investigate the prevalence of voice disorders and associated risk factors among primary school teachers in Hong Kong. METHODS: A cross-sectional survey was conducted based on a random sample of 20 primary schools in Hong Kong. A total of 714 full-time primary school teachers were invited to participate in the survey. Data were collected through a self administered questionnaire addressing the prevalence of voice disorders and potential risk factors. Stepwise logistic regression was used to assess the associations between voice disorders and the different risk factors. RESULTS: The response rate for the questionnaire was 69.7% (498/714). Among the teachers who responded, 348 (69.9%) had suffered from a voice disorder in the past 12 mo. Thirty-one teachers (8.9%) rated their voice disorders as minimal, 124 (35.6%) as mild, 151 (43.4%) as moderate, and 42 (12.1%) as severe. Of the 348 teachers reporting voice disorders, 215 (61.8%) had sought professional help for their voice problems. The univariate analyses showed that the factors significantly associated with voice disorders included talking quietly (p=0.018), using a microphone (p=0.002), speaking against background noise (p<0.001), consuming alcohol (p=0.027), and having a history of asthma (p=0.001), colds (p=0.012), sinusitis (p=0.039), or laryngitis (p<0.001). After adjusting for potential confounds, the significant risk factors included speaking against background noise (adjusted OR=1.8), alcohol consumption (adjusted OR=0.40), history of asthma (adjusted OR=3.3), or laryngitis (adjusted OR=4.2). CONCLUSIONS: Approximately 70% of the sampled primary school teachers were affected by voice disorders. A substantial proportion of the effected teachers suffered both functional and psychological adverse effects. The findings indicate an urgent need for further investigation to identify the risk factors for voice disorders and to develop preventive strategies for primary school teachers. PMID- 20924153 TI - Effects of pesticide use on semen quality among farmers in rural areas of Sabah, Malaysia. AB - OBJECTIVES: To determine the relationship between semen quality and exposure to pesticide residues. METHODS: A cross-sectional study was conducted among male farmers from 3 different communities in Sabah, Malaysia. A total of 152 farmers participated in this study of whom 62 farmers had been exposed to either paraquat or malathion or both to varying extents. Questionnaires were designed to record a history of pesticides exposure and other potential risk factors among farmers. All semen samples were collected, processed and analyzed by qualified personnel based on WHO guidelines. Volume, pH, sperm concentration, motility, morphology and WBC count were examined and recorded. The association between pesticide exposure and semen parameters was highly significant. RESULTS: The mean values of volume, pH, sperm concentration, motility, and WBC count were significantly less in the exposed group than in compared with the non-exposed group, with p<0.005. Those who were exposed to pesticides had greater risk of having abnormal semen parameters than those in with the non exposed group, with p values of less than 0.05. The comparison between semen qualities such as lower sperm count, motility and higher percentage of sperm abnormality of those exposed to different types of pesticides (paraquat and malathion) showed no significant differences. CONCLUSION: The results showed a significant decline in semen quality with a decline in sperm count, motility and higher percent of teratospermia among subjects with pesticide exposure, and those who were exposed to pesticides had significantly 3 to 9 times greater risk of having abnormal semen parameters. PMID- 20924154 TI - Effects of growth hormone therapy on cardiac dimensions in children and adolescents with Prader-Willi syndrome. AB - OBJECTIVES: Growth hormone (GH) secretory status and GH therapy influence cardiac muscle mass and function. Most patients with Prader-Willi syndrome (PWS) are GH deficient (GHD), and are at risk to develop obesity-related cardiac problems. Few data exist on the development of cardiac dimensions under GH treatment in PWS. STUDY DESIGN: in a retrospective study, cardiac dimensions measured echocardiographically in 26 children with PWS before and after 22.9 +/- 11.0 months of GH therapy (0.035 mg/kg/day) were compared to those of 13 GHD children treated with GH (0.025-0.035 mg/kg/day) over 13.5 +/- 4.2 months. RESULTS: low normal left ventricular end-systolic [diastolic] diameter SDS increased in PWS patients (1.41, p < 0.0001 [1.23, p < 0.0001]) and in controls (0.61, p = 0.04 [0.78, p = 0.013]), becoming elevated above normal in 2/26 PWS patients. There was a trend for a higher GH effect on left ventricular end-systolic diameter in PWS (p = 0.071). Mean values of all echocardiographic dimensions remained in the normal range in both PWS patients and controls, before and under GH therapy. CONCLUSION: the response of cardiac dimensions to GH treatment is similar in PWS patients and GHD controls, with a trend towards more elevated left ventricular parameters in PWS. Therefore, regular echocardiographic assessment may be considered in PWS children with longer treatment duration. PMID- 20924156 TI - Lipschutz genital ulceration associated with mumps. AB - Lipschutz ulcers are characterised by a first flare of non-sexually related acute genital ulcers (AGU) occurring in adolescent girls. Epstein-Barr primary infection is the most frequently reported aetiology but other infectious agents are probably implicated. We report the first case of mumps associated with an AGU in a 21-year-old girl. She presented a bilateral parotitis with genital ulcers, and serology confirmed she had mumps. As in our case, most Lipschutz ulcers heal spontaneously within a couple of weeks and the diagnosis should be reconsidered in case of recurrence. PMID- 20924157 TI - Prevalence of chronic pruritus in Germany: results of a cross-sectional study in a sample working population of 11,730. AB - BACKGROUND: Pruritus is a frequent symptom in many diseases; its prevalence in German adults is unknown. OBJECTIVE: Our purpose was to assess the prevalence, severity and health care of chronic pruritus in the German working population. METHODS: A cross-sectional observational study was conducted in employees of 144 German companies. Pruritus-specific data were obtained by standardized questions. RESULTS: 11,730 people (53.2% male, 16-70 years, mean = 43.7 years) were suitable for analysis. The point prevalence of chronic pruritus (at least 6 weeks prior to data collection) was 16.8%. The prevalence increased with age from 12.3% (16-30 years) to 20.3% (61-70 years). A quarter of the affected persons had suffered from pruritus for >5 years, 47% had never sought medical advice, and 94% had not undergone any treatment. CONCLUSIONS: Chronic pruritus is a prevalent symptom in the working age population. A high proportion of people affected are not medically treated. PMID- 20924158 TI - Pediatric Graves' disease: controversies in management. AB - BACKGROUND/AIMS: Graves' disease (GD) is the most common cause of thyrotoxicosis in children and adolescents. Caused by immunologic stimulation of the thyroid stimulating hormone receptor, lasting remission occurs in only a minority of pediatric patients with GD, including children treated with antithyroid drugs (ATDs) for many years. Thus the majority of pediatric patients with GD will need thyroidectomy or treatment with radioactive iodine (RAI; (131)I). RESULTS: When ATDs are used in children, only methimazole should be used. Propylthiouracil is associated with an unacceptable risk of severe liver injury in children and should never be used as first-line therapy. If remission (defined as normal thyroid function off ATDs) is not achieved after 1 or 2 years of ATD therapy, (131)I or surgery may be considered, with the choice influenced by the age of the individual. When (131)I is used, administered doses should be >150 MUCi/g of thyroid tissue. When surgery is performed, near total or total thyroidectomy is recommended. CONCLUSION: Choosing a treatment approach for childhood GD is often a difficult and highly personal decision. Discussion of the advantages and risks of each therapeutic option is essential to help the patient and family select a treatment option. PMID- 20924155 TI - Maternal immune activation and autism spectrum disorder: interleukin-6 signaling as a key mechanistic pathway. AB - An emerging area of research in autism spectrum disorder (ASD) is the role of prenatal exposure to inflammatory mediators during critical developmental periods. Epidemiological data has highlighted this relationship showing significant correlations between prenatal exposure to pathogens, including influenza, and the occurrence of ASD. Although there has not been a definitive molecular mechanism established, researchers have begun to investigate this relationship as animal models of maternal infection have support- ed epidemiological findings. Several groups utilizing these animal models have found that activation of the maternal immune system, termed maternal immune activation (MIA), and more specifically the exposure of the developing fetus to maternal cytokines precipitate the neurological, immunological and behavioral abnormalities observed in the offspring of these animals. These abnormalities have correlated with clinical findings of immune dysregulation, neurological and behavioral abnormalities in some autistic individuals. Additionally, researchers have observed genetic variations in these models in genes which regulate neurological and immunological development, similar to what is observed clinically in ASD. Altogether, the role of MIA and cytokine dysregulation, as a key mediator in the neuropathological, behavioral and possibly genetic irregularities observed clinically in autism are important factors that warrant further investigation. PMID- 20924159 TI - Cost-effectiveness of biological therapy in remission induction of moderate to severe plaque psoriasis. AB - BACKGROUND: The introduction of biological agents has considerably changed the treatment of moderate to severe psoriasis. So far only limited data on their cost effectiveness exist. OBJECTIVE: Determination of the cost-effectiveness of biologicals from a German third payer's perspective, assessed over a 12-week period. METHODS: Efficacies of the biologicals were determined by a literature review. Treatment modalities were taken from the European S3 psoriasis guideline. Costs were calculated on the basis of the German physicians' fee schedule. Cost effectiveness was determined and a sensitivity analysis performed. RESULTS: Infliximab at a dose of 3 mg/kg was the most cost-effective agent, directly followed by adalimumab, infliximab 5 mg/kg and ustekinumab. The least cost effective agent was etanercept 2 * 50 mg/week. Sensitivity analysis showed considerable overlap of the cost-effectiveness ratios. CONCLUSION: Under the conditions of the German health care system, biological agents for psoriasis differ in their cost-effectiveness ratios. Differences are small, however. A major limitation of the study is the short time horizon of 12 weeks. PMID- 20924160 TI - Recurrence of basosquamous carcinoma after Mohs micrographic surgery. AB - BACKGROUND: The recurrence rate of basal cell carcinoma (BCC) after Mohs micrographic surgery (MMS) is well documented. Only little is published concerning the recurrence rate in relation to the different histologic subgroups. OBJECTIVE: To analyze the recurrence rate of the different histologic groups and subgroups after MMS. SUBJECTS AND METHODS: We investigated 1,000 cases of epidermal tumors in a private center of MMS including BCC, squamous cell carcinoma and basosquamous carcinoma (BSC) treated by MMS from 1998 to 2007 in a retrospective study. The cases where analyzed regarding the histologic groups and subgroups. The mean follow-up time was 59.55 months. RESULTS: The recurrence rate of epidermal tumors in this study was about 2.5% and comparable to that in the literature. Interestingly we observed a relatively high incidence and recurrence rate of BSC compared to other studies. CONCLUSION: BSC seems to be highly aggressive and subject to recurrence even after MMS. The classical approach to stop further excision once the excision is total should be reevaluated. PMID- 20924161 TI - Neocortical-like organization of avian auditory 'cortex'. Commentary on Wang Y, Brzozowska-Prechtl A, Karten HJ (2010): Laminar and columnar auditory cortex in avian brain. Proc Natl Acad Sci USA 107:12676-12681. PMID- 20924162 TI - Cutaneous Malassezia microbiota in atopic dermatitis patients differ by gender and body part. AB - BACKGROUND: Malassezia is a particularly important factor in the occurrence of atopic dermatitis (AD). AIM: The aim of this study was to quantitatively clarify the Malassezia species isolated from AD patients by gender, body part and analytical method in detail. METHODS: The subjects were 20 AD males and 47 AD females. Samples were collected from lesion and nonlesion areas on the face and upper trunk of AD patients. Malassezia DNA was analyzed using a real-time PCR system. RESULTS: The cutaneous Malassezia microbiota in AD patients differed by gender, body part and analytical method. CONCLUSIONS: The present results indicate the possibility that the influence of Malassezia antigens is different according to gender and body part. PMID- 20924163 TI - Meiotic studies in infertile domestic pig-babirusa hybrids. AB - Mating of a babirusa (Babyrousa babyrussa) boar and a domestic sow (Sus scrofa) resulted in the birth of 5 live domestic pig-babirusa hybrid piglets. Chromosome analysis of one of the surviving males confirmed that they were domestic pig babirusa hybrids by revealing the presence of a complete haploid set of 19 porcine chromosomes as well as a complete haploid set of 19 babirusa chromosomes in the karyotype. None of the surviving piglets, two males and one female, had shown signs of sexual maturity at age 27 months. Histological examination of gonadal biopsies from the 2 males revealed that both were azoospermatic. Immunostaining revealed SCP3-positive axial elements in the nuclei of primary spermatocytes, indicating that they were progressing through leptotene and zygotene of meiotic prophase. However, the presence of multiple short stretches of axial elements in pachytene nuclei indicated that this phase was blocked, probably due to aberrant chromosome pairing. Histological examination of the ovaries revealed follicular structures, but oocytes within them were generally degenerated. We conclude that both male and female pig-babirusa hybrids were infertile, most likely due to germ cell death resulting from abnormalities of chromosome pairing during meiotic prophase. PMID- 20924164 TI - B chromosomes in Nierembergia aristata (Solanaceae): nucleolar activity and competition with the A chromosomes. AB - B chromosomes are additional dispensable chromosomes that may be present in some individuals, populations, or species, which have probably arisen from the A chromosomes but follow their own evolutionary pathway. Supposedly, B chromosomes do not contain major genes except for ribosomal DNA (rDNA) sequences that have been mapped on the supernumerary chromosomes of many plants and animals. This paper is a new report of B chromosome occurrence in plants. B chromosomes with nucleolar organizing regions (NORs) were found in a diploid sample of Nierembergiaaristata D. Don (sub nom. N. stricta Miers) (2n = 2x = 16). This is an extreme case in which B chromosomes possess not only strong nucleolar activity, as revealed by conventional staining methods, AgNOR and fluorescence banding, and fluorescent in situ hybridization (FISH), but also show nucleolar competition with the A chromosomes. The observed phenomenon could be analogous to the nucleolar dominance or 'differential amphiplasty' phenomenon that occurs in interspecific hybrids. PMID- 20924165 TI - Comparative cytogenetics of giant trahiras Hoplias aimara and H. intermedius (Characiformes, Erythrinidae): chromosomal characteristics of minor and major ribosomal DNA and cross-species repetitive centromeric sequences mapping differ among morphologically identical karyotypes. AB - Karyotype and cytogenetic characteristics of 2 species of giant trahiras, Hopliasintermedius, Sao Francisco river basin, and Hopliasaimara, Arinos river (Amazon basin), were examined by conventional (C-banding, Ag-NOR, DAPI/CMA(3) double-staining) and fluorescent in situ hybridization (FISH) with 5S, 18S rDNA probes and cross-species Cot-1 DNA probing. Both species invariably had diploid chromosome number 2n = 50 and identical karyotypes composed of 10 pairs of metacentric and 15 pairs of submetacentric chromosomes. On the other hand, staining with base-specific fluorochromes (CMA(3), DAPI) and FISH mapping of repetitive DNA sequences showed extensive interspecific differences: while the genome of H. aimara had one submetacentric pair bearing CMA(3)-positive (DAPI negative) sites, that of H. intermedius had 4 such pairs; while FISH with a 5S rDNA probe showed one (likely homologous) signal-bearing pair, that with 18S rDNA displayed one signal-bearing pair in H. intermedius and 2 such pairs in H. aimara. Cross-species FISH probing with Cot-1 DNA prepared from total DNA of both species showed no signals of Cot-1 DNA from H. aimara on chromosomes of H. intermedius but reciprocally (Cot-1 DNA from H. intermedius on chromosomes of H. aimara) displayed signals on at least 4 chromosome pairs. Present findings indicate (i) different composition of repetitive sequences around centromeres, (ii) different NOR phenotypes and (iii) distinct taxonomic status of both giant trahira species. PMID- 20924166 TI - Primary hyperparathyroidism in patients with gastric carcinoid tumors type 1: an unusual coexistence. AB - OBJECTIVE: Although a number of familiar syndromes are associated with primary hyperparathyroidism (PHP), there is no information regarding the prevalence of PHP in other sporadic neuroendocrine diseases. The aim of this study is to investigate the prevalence of PHP in our group of patients with gastric carcinoid (GC) type 1 tumors. METHODS: Twenty-six patients with biopsy-proven GC type 1 tumors were retrospectively studied. The diagnosis of PHP was suspected following elevated or high-normal serum calcium levels and elevated or inappropriate normal parathyroid hormone levels. Further tests for the localization of the hyperfunctioning parathyroid glands included neck ultrasound, (99m)Tc-SESTAMIBI scanning, and cervical or upper mediastinal MR imaging studies. Four control groups were also studied: two age- and sex-matched groups of individuals with (n = 49) and without (n = 34) thyroid autoimmunity and normal endoscopy of the stomach, a third group with nongastric neuroendocrine tumors (n = 68), and a fourth group with atrophic gastritis and hypergastrinemia, without gastric endocrine tumors (n = 30). RESULTS: PHP was diagnosed in 4 (15.38%) patients with GC type 1 tumors compared to none of the 4 control groups. Three of the 4 patients with PHP were operated and proved to have a parathyroid adenoma. No statistically significant differences were observed between patients with or without PHP in mean gastrin and chromogranin A levels, number of lesions, ki-67 labeling index expression, and maximum GC type 1 tumor diameter. CONCLUSION: PHP seems to be relatively common, approximately 15% in the present cohort, in patients with GC type 1 tumors. PHP should be actively looked for in such patients and treated accordingly. PMID- 20924167 TI - A novel target of mizoribine inhibiting mesangial cell proliferation: S phase kinase-associated protein 2. AB - BACKGROUND/AIMS: Mizoribine (MZR) can inhibit mesangial cell (MC) proliferation, but the mechanism remains unknown. In this study, we investigated the inhibitory effect of MZR on MC proliferation via a cell cycle regulatory protein-dependent mechanism. METHODS: We investigated the effect of MZR on MC proliferation and expression of cell cycle regulatory proteins such as cyclin D1, cyclin-dependent kinase 2 and p27(kip1) in primary cultured rat MCs. We further focused on analyzing the effects of MZR on S phase kinase-associated protein 2 (Skp2), which played a crucial role in p27(kip1) degradation. RESULTS: MZR effectively inhibited MC proliferation in primary cultured rat MCs, reduced the expression of cyclin D1 and cyclin-dependent kinase 2, while it dramatically increased the protein level of p27(kip1), maintained the nucleus location of p27(kip1) and induced G1/S arrest. In contrast to the protein level, MZR produced no changes in p27(kip1) mRNA abundance. MZR impaired p27(kip1) degradation through downregulating the expression of Skp2 and this effect was not dependent on its inhibition on DNA synthesis. Skp2 overexpression abolished MZR-induced p27(kip1) accumulation. CONCLUSION: These results suggested that MZR-induced p27(kip1) accumulation was at least partly mediated by Skp2, and that Skp2 might be a novel target of MZR inhibiting MC proliferation. PMID- 20924168 TI - Effect of kidney disease stage on pregnancy and delivery outcomes among patients with immunoglobulin A nephropathy. AB - BACKGROUND: Immunoglobulin A nephropathy (IgAN) has a peak onset that coincides with the reproductive age. Therefore, many young women who are affected become pregnant. The effects and outcome of pregnancy in women with renal diseases remain controversial, and the characteristics and outcome of pregnancy in IgAN patients must be further evaluated. METHODS: A prospective follow-up study of 29 pregnant women with IgAN was performed by analyzing laboratory data, histology and prognosis. To clarify the influence of renal insufficiency, we compared these patients according to the chronic kidney disease (CKD) stage. RESULTS: We found that pregnancy and delivery did not produce any significant changes of the renal function in any of the patients at 3 years after delivery, although the proteinuria was elevated at 30 weeks of pregnancy and at 3 months after delivery. Finally, the data of pregnant women with IgAN were compared with those of 45 nonpregnant women who had similar clinical and demographic characteristics. CONCLUSION: The pregnant patients with IgAN did not exhibit any significant reduction of renal function at 3 years after delivery as compared with the baseline, which is similar to the findings in nonpregnant patients. Furthermore, pregnancy with stage 2 or 3 CKD was not a risk factor for renal dysfunction or delivery. PMID- 20924169 TI - Trans-10,cis-12-CLA-caused lipodystrophy is associated with profound changes of fatty acid profiles of liver, white adipose tissue and erythrocytes in mice: possible link to tissue-specific alterations of fatty acid desaturation. AB - Dietary supplementation with conjugated linoleic acid (CLA) has been shown to reduce body fat mass. To investigate the effects of individual CLA isomers on the fatty acid profiles of lipogenic (liver and white adipose) and lipid sensitive (erythrocyte) tissues, BALB/c mice were fed with 1 of 2 diets supplemented with either a c9,t11-CLA-enriched and t10,c12-CLA-free or a CLA-mixture containing both isomers in equal amounts (1% w/w of the diet) for 5 weeks. A control group was fed with a diet enriched in sunflower oil to energy balance the CLA. Compared to the t10,c12-CLA-free and the control diets, we observed a significant reduction of adipose tissue accompanied by fatty livers in the CLA-mix-fed group. These alterations in body fat distribution entailed a conspicuous shift of the fatty acid profiles of adipose tissue and livers. Liver enlargement was mainly caused by accumulation of C18 monoenes that accounted for 67 +/- 1% of total fatty acid methyl esters. The significant reduction of the 18:0/18:1 desaturation index in the liver upon CLA-mix diet indicated high stearoyl-CoA desaturase activity. In contrast, reduction in white adipose tissue was largely driven by percental reduction of monounsaturated fatty acids (p <= 0.001). 16:0/ 16:1 and 18:0/18:1 desaturation indices for white adipose tissue significantly increased, suggesting an inhibition of stearoyl-CoA desaturase upon CLA-mix diet. The fatty acid profile of the erythrocytes widely reflected that of livers, depending on the supplemented diet. These profound changes in fatty acid composition of lipogenic organs due to t10,c12-CLA intake may be the consequence of functional alterations of lipid metabolism. PMID- 20924170 TI - Intradialytic changes of plasma amino acid levels: effect of hemodiafiltration with endogenous reinfusion versus acetate-free biofiltration. AB - During hemodialysis, amino acids (AA) are lost in the ultrafiltrate with consequent modification of their plasma profile. The aim of this cross-sectional study was to evaluate intradialytic changes of plasma AA levels during a single session of hemodiafiltration with endogenous reinfusion (HFR) versus acetate-free biofiltration (AFB). 48 patients chronically treated with HFR or AFB were matched 1:1 for age, gender, Kt/V and diabetes. Blood samples were collected at the beginning and the end of dialysis. Baseline plasma levels (MUmol/l) of total AA (3,176 +/- 722), essential AA (889 +/- 221), and branched chain AA (459 +/- 140) levels in HFR were similar to those in AFB (3,399 +/- 621, 938 +/- 277, and 463 +/- 71, respectively). Plasma intradialytic AA levels did not change in HFR, while in AFB there was a reduction by about 25%. In conclusion, as compared with AFB, HFR has a sparing effect on AA loss due to the lack of adsorption by cartridge and to their complete reinfusion in blood. PMID- 20924171 TI - Clinical features of 2009 pandemic influenza A (H1N1) virus infection in chronic hemodialysis patients. AB - BACKGROUND/AIMS: Infection is one of the most common complications and is considered the second leading cause of death in dialysis patients with end-stage renal disease. After the first cases of 2009 pandemic influenza A (H1N1) virus in China became public, persons with suspected infection and those who were in contact with persons with suspected infection were tested. Whether the presentation and clinical course of H1N1 influenza is similar in the dialysis population to the general population is currently unknown. Hemodialysis patients in whom an infection was confirmed were hospitalized and quarantined, and patients on chronic hemodialysis were closely observed for the purpose of investigating the nature and duration of the disease. METHODS: From May 2009 to February 2010, we observed 15 hemodialysis patients infected with the 2009 pandemic influenza A (H1N1) virus who were quarantined in Beijing Chao-Yang Hospital, Capital Medical University. Real-time reverse transcriptase polymerase chain reaction (RT-PCR) testing was used to confirm infection, the clinical features of the disease were closely monitored. RESULTS: The mean age of the 15 patients was 47.6 years, and 9 of the 15 patients were male. The diagnoses were all made in the hospital. All of the 15 patients had fluid overload. The median incubation period of the virus in hemodialysis patients was 4 days (range: 1-7 days). The most common symptoms were dyspnea (in all of the 15 patients) and productive cough (in all of the 15 patients). One of the 15 patients had low grade fever, and the other 14 patients were afebrile. Lymphopenia, which was common in 12 of the patients, typically occurred on day 2 (range: days 1-3) and resolved by day 9 (range: days 7-11). Hypoxemia was observed in all of the patients. Six of the 15 patients developed respiratory failure requiring mechanical ventilation on days 7-9 because they were complicated by Escherichia coli nosocomial pneumonia. All the patients were placed in respiratory isolation and were treated with oseltamivir. The median length of time during which patients had positive real-time RT-PCR test results was 12 days (range: 7-19 days), which was longer than that in general population. CONCLUSIONS: The presentation and clinical course of H1N1 influenza A in the hemodialysis patients was atypical and relatively serious, which differed from the general population in China. Furthermore, these patients may have an extended period of viral shedding. PMID- 20924172 TI - Recurrent transient loss of consciousness induced by acute massive gastrointestinal hemorrhage during hemodialysis: a case report. AB - A 67-year-old man with chronic hemodialysis (HD), who had end-stage renal disease secondary to diabetic nephropathy and had been on HD for 9 years with ultrapure dialysis solution, is presented with recurrent transient loss of consciousness during HD. PMID- 20924173 TI - Water conservation: an emerging but vital issue in hemodialysis therapy. AB - Water conservation refers to reducing the usage of water and recycling of wastewater for different purposes such as irrigation, laundry and sanitation. As water scarcity increases worldwide, dialysis facilities should be focused on salvaging water. However, most of them still ignorantly discard to the sewer huge volumes of this reusable resource. This article reviews the current water conservation techniques in hemodialysis and the potential benefits drawn when using this technology. PMID- 20924174 TI - Conversion of darbepoetin to low doses of CERA maintains hemoglobin levels in non dialysis chronic kidney disease patients. AB - BACKGROUND/AIMS: Finding the lowest effective dose of erythropoietin-stimulating agents is critical in the management of renal anemia. We evaluated the efficacy of converting darbepoetin to CERA at doses lower than those usually recommended. METHODS: We selected consecutive non-dialysis chronic kidney disease patients treated with darbepoetin doses <=40 MUg/week in absence of iron deficiency, recent blood transfusion, bleeding, neoplasia, myocardial infarction/stroke in the last 3 months. Darbepoetin <=20 MUg/week was shifted to CERA 75 MUg/month, while darbepoetin 21-40 MUg/week to CERA 100 MUg/month. Primary endpoint was the change in hemoglobin (Hb goal, 11-13 g/dl) at month 3, 6, 9 and 12. RESULTS: Studied patients (n = 37) were aged 70 +/- 13 years and GFR was 30 +/- 12 ml/min/1.73 m(2); prevalence of males, diabetes and prior cardiovascular disease was 43, 45 and 40%, respectively. Before switching, efficacy population received darbepoetin 18 +/- 10 MUg/week with 28 patients receiving <=20 MUg/week. Prevalence of Hb goal at baseline was 75.7% and did not change at months 3 (70.3%), 6 (70.3%), 9 (72.2%), and 12 (80.0%). CERA dose remained unchanged during the study (81 +/- 11, 82 +/- 16, 91 +/- 30, 90 +/- 54 and 88 +/- 61 MUg/month). Out of the 438 visits performed, CERA dose was increased in 52 (11.9%) and reduced in 36 (8.2%) visits. Blood pressure, Hb, GFR, transferrin saturation and ferritin did not change. CONCLUSIONS: In chronic kidney disease patients treated with darbepoetin doses <=40 MUg/week, CERA can be efficaciously used at doses lower than those recommended. PMID- 20924176 TI - An unusual case of encapsulating peritoneal sclerosis. PMID- 20924175 TI - Principles of antibacterial dosing in continuous renal replacement therapy. AB - BACKGROUND: Appropriate antibacterial therapy is important to maximize patient survival in sepsis. Acute renal failure complicates optimal antibiotic administration. METHODS: MEDLINE search from 1986 to 2010 using the terms 'acute renal failure', 'pharmacokinetics', 'clearance', 'dosage', 'h(a)emofiltration', 'h(a)emodialysis', 'h(a)emodiafiltration', 'continuous renal replacement therapy', 'antibiotics', 'intensive care' and 'critically ill'. RESULTS: Maximal bacterial killing and minimization of side effects depend on achieving pharmacokinetic targets appropriate to the selected antibacterial agent. Volume of distribution and clearance may be altered by critical illness and/or acute kidney injury. Clearance is determined by nonrenal clearance, residual renal clearance and continuous renal replacement therapy dose. Sieving and saturation coefficients are membrane specific, but may be altered by changes in protein binding induced by critical illness. A significant proportion of studies failed to report the essential dataset required for adequate antibacterial dosage calculation. CONCLUSIONS: Individualized dosing based on first principles may be the most appropriate method of dosing, particularly when enhanced by therapeutic drug monitoring. PMID- 20924177 TI - Systemic evaluation of platelet and leukocyte activation and interaction in a rat model of pulmonary arterial hypertension. AB - OBJECTIVES: Thrombosis and inflammation are associated with the pathogenesis of pulmonary arterial hypertension (PAH). However, there are no solid data supporting the involvement of platelet and leukocyte activation and interaction in PAH. The present study thus investigated the activation and interaction of circulating platelets and leukocytes in a rat model of monocrotaline (MCT) induced pulmonary hypertension. METHODS: Mean pulmonary arterial pressure (mPAP) was monitored in rats (n = 24) before and 2, 3 and 7 weeks after MCT (60 mg/kg)injection. In parallel, activation of circulating platelets and leukocytes and platelet-leukocyte aggregates were measured by whole-blood flow cytometry. RESULTS: Two weeks after MCT injection, mPAP had increased significantly, i.e. from 11.25 +/- 0.92 mm Hg at baseline to 15.71 +/- 1.66 mm Hg (p < 0.05), and it had increased even further at week 7 (26.83 +/- 3.29 mm Hg; p < 0.01). Fibrinogen binding of circulating platelets had increased from the basal level of 1.45 +/- 0.61 to 4.08 +/- 1.59% 3 weeks after MCT injection (p < 0.01). Platelet responsiveness to ADP was also significantly enhanced. CD11b expression of circulating neutrophils was elevated; i.e. mean fluorescence intensity increased from 1.67 +/- 0.38 before MCT injection to 2.37 +/- 0.31 3 weeks after MCT injection (p < 0.01), and N-formyl-methionyl-leucyl-phenylalanine (1 * 10-7M) stimulation induced more marked elevation of neutrophil CD11b expression in MCT treated animals. Circulating platelet-neutrophil aggregates were already increased 2 weeks after MCT treatment (14.93 +/- 4.22%; p < 0.01) compared to baseline (6.01 +/- 2.91%) and remained elevated at 3 weeks (15.19 +/- 4.78%; p < 0.01). CONCLUSIONS: MCT-induced PAH in rats is associated with increased platelet and leukocyte activation and platelet-leukocyte interaction in vivo, which may play an important role in the pathogenesis of PAH. PMID- 20924178 TI - Angiogenesis, magnetic fields and 'window effects'. PMID- 20924180 TI - Risk-factor medicine: an industry out of control? PMID- 20924179 TI - Pulsed magnetic field induces angiogenesis and improves cardiac function of surgically induced infarcted myocardium in Sprague-Dawley rats. AB - OBJECTIVE: It was the aim of this study to investigate the impact of pulsed magnetic field (PMF) on ischemic myocardium, though it has been reported that PMF treatment is a safe and effective method to facilitate bone and cutaneous wound healing. METHODS: In this report, we describe a study in which 10 Hz 4 mT PMF and 15 Hz 6 mT PMF was used to treat rats with myocardial infarction (MI). RESULTS: After 28 days of treatment, the rats treated with 15 Hz 6 mT PMF exhibited decreased left ventricular end-diastolic pressure and accelerated maximum dp/dt of left ventricular pressure when compared with the untreated MI and the MI + 10 Hz 4 mT groups. Additionally, capillary density was increased and infarction area size was decreased in the MI + 15 Hz 6 mT group. Furthermore, the plasma vascular endothelial growth factor concentration and the protein expression of vascular endothelial growth factor receptor 2 in myocardial tissue were increased in rats of the MI + 15 Hz 6 mT group. CONCLUSION: This study shows that 15 Hz 6 mT PMF promotes myocardial angiogenesis and improves cardiac function after MI in rats. This suggests that there is a potential use for some PMF signal strengths in ischemic myocardial disease. PMID- 20924181 TI - Coronary microcirculation changes during myocardial stunning in dogs. AB - OBJECTIVE: To investigate changes in the coronary microcirculation during myocardial stunning in dogs. METHODS: Male mongrel dogs underwent a 15- or 60-min occlusion of the left anterior descending coronary artery, followed by a 120-min reperfusion. Myocardial contrast echocardiography was performed before and after treatment with acetylcholine (ACH) or nitroglycerin (NG). Peak videointensity (PVI) in the myocardial zone was measured, and myocardial samples were examined using transmission electron microscopy. RESULTS: In the 15-min group, the ratio of the PVI between the stunned and intact myocardial zone (PVIR) before and after treatment with NG (NG-PVIR) or ACH (ACH-PVIR) declined markedly in the early period of reperfusion and then returned to preligation levels. In the 60-min group, NG-PVIR was reduced in the early period of reperfusion and then returned to its preligation level. A low level of ACH-PVIR lasted during the entire 120 min reperfusion. Similar changes in the ratio of the PVIR before and after treatment with NG or ACH were observed. In the 60-min group, capillary endothelial edema and widening of intercellular linking gaps were observed. CONCLUSIONS: We observed microvascular endothelial damage and endothelium dependent dilatation impairments in stunned myocardium, and their severity and recovery rate are affected by the duration of ischemia. PMID- 20924182 TI - Intra-aortic balloon pump improves clinical prognosis and attenuates C-reactive protein level in acute STEMI complicated by cardiogenic shock. AB - OBJECTIVES: Intra-aortic balloon pump (IABP) plays a pivotal role in the treatment of cardiogenic shock (CS) complicating acute ST-segment elevation myocardial infarction (STEMI). However, the influence of IABP on the inflammatory response has not been well evaluated. We sought to assess the effects of IABP support upon C-reactive protein (CRP) levels in patients with STEMI complicated by CS undergoing percutaneous coronary intervention (PCI). METHODS: This was a prospective study and a total of 91 patients with STEMI complicated by CS receiving emergency PCI were enrolled, 43 cases of which received IABP support, and the remaining cases without IABP therapy were the control group. CRP levels were determined at admission, and on days 3 and 7. Troponin I peak, left ventricular function and major adverse cardiovascular events were compared following PCI. RESULTS: The IABP group had lower CRP levels at days 3 and 7, greater improvement in left ventricular function and lower troponin peak following PCI. Significant differences were also observed in the incidence of mortality at 6-month follow-up, both in hospital and after 30 days. CONCLUSIONS: IABP support improves clinical prognosis and attenuates the CRP level in patients with CS complicating STEMI after PCI. PMID- 20924183 TI - Cytochrome P450 2C19 polymorphism, suboptimal reperfusion and all-cause mortality in patients with acute myocardial infarction. AB - OBJECTIVES: To determine whether the 681 G>A (*2) polymorphism of cytochrome P450 (CYP2C19) is related to suboptimal reperfusion and mortality in patients with acute myocardial infarction (AMI) pretreated with clopidogrel. METHODS: The study included 276 consecutive patients with AMI in whom percutaneous coronary intervention (PCI) with stenting was attempted. Four-year follow-up for all-cause mortality was obtained. RESULTS: There were 15 failed procedures (5.4%). In the remaining 261 patients, suboptimal reperfusion (post-PCI TIMI flow <3) was observed in 12.6% of the cases. There were 56 carriers (50 heterozygous and 6 homozygous) of CYP2C19*2. The prevalence of carriers in patients with suboptimal flow was 39.4% in comparison to 18.9% in the other patients (p = 0.01). Independent predictors of suboptimal reperfusion were initial TIMI flow <=1 (OR = 5.9, 95% CI 2.2-16.2, p = 0.001) and CYP2C19*2 (OR = 2.9, 95% CI 1.3-6.6, p = 0.01). Thirty patients died during follow-up (11.5%). Four-year mortality tended to be higher in carriers of CYP2C19*2 (17.9%) versus non-carriers (9.8%; p = 0.09), but the only independent predictors of death were age (HR = 2.0, 95% CI = 1.4-2.8, p = 0.0001) and suboptimal reperfusion (HR = 3.6, 95% CI 1.5-8.8, p = 0.004). CONCLUSIONS: The CYP2C19*2 allele is an independent predictor of suboptimal reperfusion in patients with AMI undergoing PCI with stenting after pretreatment with clopidogrel and may increase the risk of all-cause mortality. PMID- 20924184 TI - Behavior of Ebstein's anomaly. PMID- 20924185 TI - Behavior of Ebstein's anomaly: single-center experience and midterm follow-up. AB - OBJECTIVES: Ebstein's anomaly, characterized by an apical displacement of the tricuspid valve into the right ventricle, occurs in approximately 1/200,000 live births. Because long-term follow-up data of adults with Ebstein's anomaly are scarce, we evaluated the outcome of our Ebstein's anomaly patients. METHODS: All patients >16 years and registered in the congenital heart disease database of our hospital with isolated Ebstein's anomaly were selected for the study. Records were reviewed for outcome. RESULTS: Forty-nine patients (21 males, mean age at diagnosis 29.1 +/- 20.7 years) were followed for a mean time of 11.4 years (range 1.1-32.4). Twenty-five patients (51%) underwent tricuspid valve surgery (16 valvuloplasty and 9 valve replacement). Eight patients (32%) required redo tricuspid valve surgery. Twenty-six patients (52.1%) exhibited supraventricular arrhythmia, and the typical Wolff-Parkinson-White syndrome occurred in 15 patients (31.2%). Seventeen patients (34.7%) underwent ablation therapy and 5 patients (10.4%) required pacemaker implantation. CONCLUSIONS: Half of the patients with Ebstein's anomaly needed tricuspid valve surgery and redo surgery was not uncommon. Supraventricular arrhythmia occurred frequently and ablation therapy was often indicated. Careful follow-up is obligate, as some complications occur for the first time in adulthood. PMID- 20924186 TI - Generic and disease-specific measures of quality of life in patients with mild Alzheimer's disease. AB - BACKGROUND/AIM: The aim of the study was to investigate the pattern of association of generic and disease-specific quality of life (QoL) scales with standard clinical outcome variables in Alzheimer's disease (AD). METHODS: The participants were 321 home-living patients with mild AD and their primary caregivers from the Danish Alzheimer Intervention Study. QoL was assessed using the generic EuroQol-5D with visual analogue scale (VAS) and the disease-specific Quality of Life in Alzheimer's Disease (QOL-AD) scales (both caregiver and patient rated). Depression, activities of daily living, cognitive performance and neuropsychiatric symptom severity were also assessed. RESULTS: All 3 caregiver rated QoL scales correlated significantly with each other (p < 0.001) and with clinical measures. Patient-rated QoL versions correlated inversely with depression (p < 0.001) but not significantly with any other clinical variables. CONCLUSION: The caregiver-rated QoL scales showed stronger interscale correlation as well as a similar correlation pattern with standard clinical outcome variables compared to the patient-rated versions. There is some indication that the EQ-5D + VAS could be a suitable alternative to the QOL-AD scale in specific research designs. PMID- 20924187 TI - Ventilator-associated lung injury superposed to oleic acid infusion or surfactant depletion: histopathological characteristics of two porcine models of acute lung injury. AB - BACKGROUND: The pathophysiological concept of acute lung injury (ALI) in combination with ventilator-associated lung injury (VALI) is still unclear. We characterized the histopathological features of intravenous injection of oleic acid (OAI) and lung lavage (LAV) combined with VALI. METHODS: Pigs were randomized to the control, LAV or OAI group and ventilated by pressure-controlled ventilation. MEASUREMENTS INCLUDED: haemodynamics, spirometry, blood gas analysis, lung wet-to-dry weight ratio (W/D), total protein content in broncho alveolar lavage fluid (BALF), and lung pathological description and scoring. RESULTS: Five hours after lung injury induction, gas exchange was significantly impaired in both the OAI and the LAV groups. Compared to controls, we found an increase in W/D and histopathological total injury scores in both the LAV and OAI groups and an increase in BALF total protein content in the OAI group. In contrast to the LAV group, the OAI group showed septal necrosis and alveolar oedema. Both groups exhibited dorsal and caudal atelectasis and interstitial oedema. In addition, the OAI group demonstrated a propensity to dorsal necrosis and congestion whereas the LAV group tended to develop ventral overdistension and barotrauma. CONCLUSIONS: This study presents a comparison of porcine OAI and LAV models combined with VALI, providing information for study design in research on ALI. PMID- 20924188 TI - Pancreatic cancer cells expressing hypoxia-inducible factor-1alpha tend to be adjacent to intratumoral blood vessels. AB - We investigated whether cells expressing hypoxia-inducible factor-1alpha (HIF 1alpha) are specially related to blood vessels in human pancreatic tumors. HIF 1alpha and blood vessels were stained in 7 pancreatic ductal adenocarcinomas (PDAC) and 3 nonmalignant tumors. HIF-1alpha(+) cells accounted for 37 +/- 5% of the total PDAC cells and increased to 52 +/- 4% in perivascular PDAC cells and to 67 +/- 4% in PDAC cells found in intratumoral blood vessels. In nonmalignant tumors, 12 +/- 3% of the total tumoral cells examined were HIF-1alpha(+), and HIF 1alpha(+) cells decreased to 2 +/- 0.3% in perivascular cells examined in the tumors. In conclusion, HIF-1alpha(+) cells in PDAC and nonmalignant pancreatic tumors differ not only in their amounts but also in their relation to intratumoral blood vessels. HIF-1alpha(+) cells usually are adjacent to intratumoral blood vessels in PDAC tumors, but are farther away from the vessels in nonmalignant pancreatic tumors. PMID- 20924189 TI - Functional and radiological evaluations of unstable displaced proximal humeral fractures treated with closed reduction and percutaneous pinning fixation. AB - OBJECTIVE: The purpose of this study is to evaluate the functional and radiological outcomes of patients with unstable displaced proximal humeral fractures treated with closed reduction and percutaneous pinning (CRPP) fixation. METHODS: We retrospectively reviewed 87 cases of displaced (2-, 3- or 4-part fractures according to Neer classification) proximal humeral fractures treated with CRPP fixation in our center from September 2003 to September 2008. Sixty four patients were followed up for a period ranging from 12 to 48 months (averaging 16.2 months) and evaluated for the functional and radiological outcomes by a series of standard questionnaire and measurement. RESULTS: The fractures in all 64 patients were healed with an average time of 15.4 weeks (ranging from 12 to 43 weeks), and the mean interval between the operation and full functional exercise was 17.3 weeks (ranging from 14 to 38 weeks). At the final follow-up visit, no patients showed shoulder instability; the mean range of abduction motion was 157.1 degrees (ranging from 70 to 180 degrees ). For all patients, no statistically significant difference in the functional outcomes was observed between their 6-month and final follow-up visits, nor in the radiological findings between their immediately postoperative and fi- nal follow up examinations. CONCLUSION: CRPP fixation is a feasible treatment option for unstable displaced proximal humeral fractures, especially for 2- and 3-part fractures in elderly patients. Although technically demanding, it offers reliable stability without extensive soft tissue dissection, allowing the early painless range of motion. This technique could also promote bone healing, prevent ischemic osteonecrosis of the head of humerus and lead to few complications. PMID- 20924190 TI - Effect of mycophenolate mofetil on cerulein-induced acute pancreatitis. AB - AIM: The aim of this study was to determine the effects of mycophenolate mofetil (MMF) on acute pancreatitis with evaluation of biochemical and histopathological findings. MATERIALS AND METHODS: Cerulein was administered to induce acute pancreatitis in rats. Three groups of 10 rats each were formed. Animals in group 1 received physiologic saline solution. In group 2 animals received MMF at a dose of 14 mg/kg and group 3 had double doses of MMF. Alanine aminostransferase, aspartate aminotransferase (AST), amylase and bilirubin levels were assessed. Pancreatic tissues were evaluated under light microscopy for the presence of edema, acinar necrosis, hemorrhage, inflammation and perivascular infiltration. RESULTS: Amylase, serum AST, edema and inflammatory infiltration levels differed between groups (amylase: p = 0.0001, serum AST: p = 0.001, edema: p = 0.0001 and inflammatory infiltration: p = 0.002), group 1 showing the highest amylase, serum AST and edema levels. The lowest levels of edema were found in group 3. CONCLUSION: In an experimental pancreatitis model in rats, MMF proved to exert a beneficial effect on biochemical and histopathological parameters. PMID- 20924191 TI - Annexin-1 downregulation is associated with clinical outcome in Chinese patients with hilar cholangiocarcinoma. AB - AIMS: Annexin A1 (ANXA1) is a calcium- and phospholipid-binding protein and has been implicated in regulating inflammatory responses, cell proliferation and apoptosis. The evidence of its importance in carcinogenesis increased rapidly. However, the status of ANXA1 in hilar cholangiocarcinoma remains unclear. Here, we detected ANXA1 expression and determined its clinical significance in Chinese patients with hilar cholangiocarcinoma. METHODS: Tissue microarray blocks containing tumor specimens obtained from 61 patients were constructed. Expression of ANXA1 in these specimens was analyzed using immunohistochemical studies. RESULTS: ANXA1 expression was observed in 27 cases (44.3%). Loss of ANXA1 expression was significantly associated with lymph node metastases and histopathologic grade. ANXA1 expression has a significant inverse correlation with recurrence and poor survival in univariate analyses.Multivariate analyses revealed that loss of ANXA1 expression was an independent predictor for future recurrence and overall survival in patients with cholangiocarcinoma. CONCLUSIONS: Decreased expression of ANXA1 is a common event in human hilar cholangiocarcinoma and is significantly correlated with the poor outcome of patients with cholangiocarcinoma, suggesting a potential role of ANXA1 in cancer development and progression. PMID- 20924192 TI - Voice activity and participation profile presenting coordinates for readjustment of preventive action of educators. AB - PURPOSE: To investigate the perception of voice impairment in professional and social contexts, to correlate these data with existing data in the literature, and to explore the perception of voice problems and the adherence to vocal health programs. METHOD: 502 Brazilian educators working in municipal public schools responded to the Voice Activity and Participation Profile (VAPP) questionnaire. Then a correlation was made with previous results in the literature dealing with a dysphonic and a nondysphonic group. RESULTS: The VAPP data showed that self perception of voice problems had a higher vocal impact on daily communication and lower scores for activity limitation and participation restriction. The educators' scores were closer to those of the nondysphonic group with regard to daily and social communication, and emotional and activity limitation, but perception of the voice problem was closest to that of the dysphonic group. Nevertheless, the opposite was the case for participation restriction. CONCLUSIONS: The educators perceive vocal problems but do not perceive participation restriction to the same extent. This may explain the decreasing participation in the Vocal Health Program. It probably occurs because adults voluntarily apply for training when they feel that their work performance needs to improve so that they can carry out their job properly. PMID- 20924193 TI - A simple and computationally efficient sampling approach to covariate adjustment for multifactor dimensionality reduction analysis of epistasis. AB - Epistasis or gene-gene interaction is a fundamental component of the genetic architecture of complex traits such as disease susceptibility. Multifactor dimensionality reduction (MDR) was developed as a nonparametric and model-free method to detect epistasis when there are no significant marginal genetic effects. However, in many studies of complex disease, other covariates like age of onset and smoking status could have a strong main effect and may potentially interfere with MDR's ability to achieve its goal. In this paper, we present a simple and computationally efficient sampling method to adjust for covariate effects in MDR. We use simulation to show that after adjustment, MDR has sufficient power to detect true gene-gene interactions. We also compare our method with the state-of-art technique in covariate adjustment. The results suggest that our proposed method performs similarly, but is more computationally efficient. We then apply this new method to an analysis of a population-based bladder cancer study in New Hampshire. PMID- 20924194 TI - Systematic removal of outliers to reduce heterogeneity in case-control association studies. AB - BACKGROUND/AIMS: In human case-control association studies, population heterogeneity is often present and can lead to increased false-positive results. Various methods have been proposed and are in current use to remedy this situation. METHODS: We assume that heterogeneity is due to a relatively small number of individuals whose allele frequencies differ from those of the remainder of the sample. For this situation, we propose a new method of handling heterogeneity by removing outliers in a controlled manner. In a coordinate system of the c largest principal components in multidimensional scaling (MDS), we systematically remove one after another of the most extreme outlying individuals and each time recompute the largest association test statistic. The smallest p value obtained within M removals serves as our test statistic whose significance level is assessed in randomization samples. RESULTS: In power simulations of our method and three methods in current use, averaged over several different scenarios, the best method turned out to be logistic regression analysis (based on all individuals) with MDS components as covariates. CONCLUSION: Our proposed method ranked closely behind logistic regression analysis with MDS components but ahead of other commonly used approaches. In analyses of real datasets our method performed best. PMID- 20924195 TI - Biomarkers of acute kidney injury in different clinical settings: a time to change the paradigm? AB - Acute kidney injury (AKI) is diagnosed in 5% of all hospitalized patients and in up to 50% of all ICU patients. In the last years a dramatic rise in the prevalence of AKI has been observed with virtually no change in mortality, reaching up to 50-80% in all dialyzed ICU patients. AKI may progress to end-stage renal disease, and even subclinical episodes of AKI, which are common, may also progress to end-stage renal disease. The early detection of AKI may enable timely intervention and prevention of progression; however, in animal models and in human studies the 'window of therapeutic intervention' is narrow. Different urinary and serum proteins have been intensively investigated as possible biomarkers for the early diagnosis of AKI. There are promising candidate biomarkers with the ability to detect an early and graded increase in tubular epithelial cell injury and distinguish pre-renal disease from acute tubular necrosis. In this review, new emerging biomarkers of AKI are presented and described in some clinical settings, such as cardiac surgery, contrast-induced nephropathy, delayed graft function and ICU/emergency departments, where biomarkers are urgently needed to diagnose, make prognoses and differentiate. PMID- 20924196 TI - Characterization of methyltransferase properties of Escherichia coli YabC protein with an enzyme-coupled colorimetric assay. AB - An enzyme-coupled colorimetric assay for S-adenosylmethionine-dependent methyltransferase (MT) was established to characterize the enzymatic identity of YabC protein from Escherichia coli. Results showed that the MT activity of YabC is able to be effectively detected with this coupling assay system when filamentous cell lysates from an S-adenosylmethionine synthetase mutant, MEW402metK84, were employed as the source of methylation target, whereas no activity exhibited under same conditions from lysates from E. coli normal shape cells. Moreover, YabB, whose gene always clustered together with yabC, was demonstrated to be an inhibitor, but not a substrate of YabC protein. Analysis of each component's effect on methylation process further confirms that increase of MT's common product - S-adenosylhomocysteine - shows a methylation pattern depending on the protein concentration of cell lysates, which indicates that methylation target of YabC is the rate-limiting factor under current coupling assay conditions. Characterization of YabC's MT properties with the coupling assay system is consistent with the similar results identified with LC/MS and knockout strains by Kimura and Suzuki [Nucleic Acids Res 2010;38:1341-1352]. PMID- 20924197 TI - High efficiency of a sequential recombinase-mediated cassette exchange reaction in Escherichia coli. AB - A comparison between the efficiency of recombinase-mediated cassette exchange (RMCE) reactions catalyzed in Escherichia coli by the site-specific recombinases Flp of yeast and Int of coliphage HK022 has revealed that an Flp-catalyzed RMCE reaction is more efficient than an Int-HK022 catalyzed reaction. In contrast, an RMCE reaction with 1 pair of frt sites and 1 pair of att sites catalyzed in the presence of both recombinases is very inefficient. However, the same reaction catalyzed by each recombinase individually supplied in a sequential order is very efficient, regardless of the order. Atomic force microscopy images of Flp with its DNA substrates show that only 1 pair of recombination sites forms a synaptic complex with the recombinase. The results suggest that the RMCE reaction is sequential. PMID- 20924198 TI - Identification and overexpression of a bifunctional aldehyde/alcohol dehydrogenase responsible for ethanol production in Thermoanaerobacter mathranii. AB - Thermoanaerobacter mathranii contains four genes, adhA, adhB, bdhA and adhE, predicted to code for alcohol dehydrogenases involved in ethanol metabolism. These alcohol dehydrogenases were characterized as NADP(H)-dependent primary alcohol dehydrogenase (AdhA), secondary alcohol dehydrogenase (AdhB), butanol dehydrogenase (BdhA) and NAD(H)-dependent bifunctional aldehyde/alcohol dehydrogenase (AdhE), respectively. Here we observed that AdhE is an important enzyme responsible for ethanol production in T. mathranii based on the constructed adh knockout strains. An adhE knockout strain fails to produce ethanol as a fermentation product, while other adh knockout strains showed no significant difference from the wild type. Further analysis revealed that the DeltaadhE strain was defective in aldehyde dehydrogenase activity, but still maintained alcohol dehydrogenase activity. This showed that AdhE is the major aldehyde dehydrogenase in the cell and functions predominantly in the acetyl-CoA reduction to acetaldehyde in the ethanol formation pathway. Finally, AdhE was conditionally expressed from a xylose-induced promoter in a recombinant strain (BG1E1) with a concomitant deletion of a lactate dehydrogenase. Overexpressions of AdhE in strain BG1E1 with xylose as a substrate facilitate the production of ethanol at an increased yield. PMID- 20924199 TI - Interactions between glycolytic enzymes of Mycoplasma pneumoniae. AB - With only 688 protein-coding genes, Mycoplasma pneumoniae is one of the smallest self-replicating organisms. These bacteria use glycolysis as the major pathway for ATP production by substrate-level phosphorylation, suggesting that this pathway must be optimized to high efficiency. In this study, we have investigated the interactions between glycolytic enzymes using the bacterial adenylate cyclase based two-hybrid system. We demonstrate that most of the glycolytic enzymes perform self-interactions, suggesting that they form dimers or other oligomeric forms. In addition, enolase was identified as the central glycolytic enzyme of M. pneumoniae due to its ability to directly interact with all other glycolytic enzymes. Our results support the idea of the formation of a glycolytic complex in M. pneumoniae and we suggest that the formation of this complex might ensure higher fluxes through the glycolytic pathway than would be possible with isolated non-interacting enzymes. PMID- 20924200 TI - Stress tolerance of the Saccharomyces cerevisiae adenylate cyclase fil1 (CYR1) mutant depends on Hsp26. AB - Fermentation-induced loss of stress resistance in yeast is an important phenotype from an industrial point of view. It hampers optimal use of frozen dough applications as well as high gravity brewing fermentations because these applications require stress-tolerant yeast strains during active fermentation. Different mutants (e.g. fil1, an adenylate cyclase mutant CYR1(lys1682)) that are affected in this loss of stress resistance have been isolated, but so far the identification of the target genes important for the increased tolerance has failed. Previously we have shown that neither trehalose nor Hsp104 nor STRE controlled genes are involved in the higher stress tolerance of the fil1 mutant. The contribution of other putative downstream factors of the PKA pathway was investigated and here we show that the small heat-shock protein Hsp26 is required for the high heat stress tolerance of the fil1 mutant, both in stationary phase cells as well as during active fermentation. PMID- 20924201 TI - Streptomyces coelicolor A3(2) produces a new yellow pigment associated with the polyketide synthase Cpk. AB - Streptomyces coelicolor A3(2) is an extensively studied model organism for the genetic studies of Streptomycetes - a genus known for the production of a vast number of bioactive compounds and complex regulatory networks controlling morphological differentiation and secondary metabolites production. We present the discovery of a presumptive product of the Cpk polyketide synthase. We have found that on the rich medium without glucose S. coelicolor A3(2) produces a yellow compound secreted into the medium. We have proved by complementation that production of the observed yellow pigment is dependent on cpk gene cluster previously described as cryptic type I polyketide synthase cluster. The pigment production depends on the medium composition, does not occur in the presence of glucose, and requires high density of spore suspension used for inoculation. PMID- 20924202 TI - Multicopy proC in Streptomyces coelicolor A3(2) elicits a transient production of prodiginines, while proC deletion does not yield a proline auxotroph. AB - The last step of proline biosynthesis is typically catalysed by the enzyme Delta(1)-pyrroline-5-carboxylate reductase, encoded by the proC gene. Complete genome sequencing of Streptomyces coelicolor, a soil-dwelling Gram-positive bacterium that uses proline as a precursor for synthesis of prodiginine, revealed a single copy of this gene. Unexpectedly, disruption of this proC homologue (Sco3337) in S. coelicolor M145 yielded a prototrophic strain, yet the reductase activity of Sco3337 was confirmed by complementation of an Escherichia coli proC mutant. Multicopy proC within different genetic contexts elicited a transient production of prodiginines, which showed differential production kinetics of the two most common forms of this natural product produced by S. coelicolor, i.e. streptorubin B (cyclic) and undecylprodigiosin (linear). The metabolic and evolutionary implications of these observations are discussed. PMID- 20924203 TI - Early cyst growth is associated with the increased nuclear expression of cyclin D1/Rb protein in an autosomal-recessive polycystic kidney disease rat model. AB - BACKGROUND: In this study we hypothesised that proliferation, and the increased expression of G(1)-phase cyclins (D1, E) and phosphorylated retinoblastoma protein (p-Rb) is restricted to the early period of synchronized cyst growth in autosomal-recessive polycystic kidney disease (ARPKD). METHODS: Lewis polycystic kidney disease (lpk) rats (model of ARPKD; postnatal weeks 1, 3, 6, 12 and 24; n = 6 each) as well as human juvenile cystic renal disease tissue (n = 2) were examined. RESULTS: Between weeks 1 and 3, the percentage cyst area increased 6 fold in lpk rats, followed by a more progressive rise (1.5-fold increase) until week 24. The number of Ki-67-, cyclin D1- and p-Rb-positive cells increased in lpk rats and peaked at week 3, declining thereafter. By serial sections, cysts co expressed Ki-67, cyclin D1 and p-Rb. The expression of cyclin E was variable, and peaked at week 24. In human tissue, small cysts had a higher expression of p-Rb. CONCLUSION: Proliferation and the increased nuclear expression of cyclin D1 and p Rb coincide with the early phase of cyst growth in rats and humans, suggesting that there might be a therapeutic window in which cyclin-dependent kinase inhibitors are most effective in preventing kidney enlargement in ARPKD. PMID- 20924204 TI - Expression of SM22alpha (transgelin) in glomerular and interstitial renal injury. AB - BACKGROUND/AIMS: SM22alpha, transgelin, is abundantly expressed in smooth muscle tissues and our previous work demonstrated that it is a novel marker of injured glomerular epithelial cells in rat antiglomerular basement membrane nephritis. In this study, we investigated SM22alpha expression in models of glomerular and interstitial renal injury. METHODS: The 5/6 nephrectomy (Nx) model, ischemia reperfusion (I/R) model and puromycin aminonucleoside (PAN) nephrosis of rats were studied. Immunohistochemical analyses and immunoelectron microscopic studies of SM22alpha expression were performed. RESULTS: In the 5/6 Nx model, SM22alpha was first expressed in peritubular interstitial cells and was also expressed in injured glomerular epithelial cells at 8 weeks. In the I/R model, SM22alpha expression was induced in peritubular interstitial cells as early as 12 h after I/R with expression sustained at 7 days. However, SM22alpha was not detected in any glomerular cells or tubular epithelial cells. In PAN nephrosis, SM22alpha was only expressed in glomerular epithelial cells after 1 week, but expression was transient. CONCLUSION: SM22alpha was expressed in glomerular epithelial cells and interstitial cells in renal injury. SM22alpha is differentially upregulated in various models of renal injury and merits further study. PMID- 20924205 TI - Proinflammatory/profibrotic effects of interleukin-17A on human proximal tubule epithelium. AB - BACKGROUND/AIMS: Interleukin-17A (IL-17A) is a T cell-derived inflammatory cytokine that is upregulated during renal allograft rejection. The present study sought to further describe the IL-17A-mediated proinflammatory/profibrotic activity of proximal tubule epithelium that may contribute to allograft rejection. METHODS: Immortalized (HK-2) and primary (HRPTEpiC) human proximal tubule epithelial cells were utilized for this study. Profibrotic gene alterations were examined by real-time quantitative PCR. Inflammatory mediator secretion was examined by multiplex bead-based detection of secreted proteins. Immunofluorescence microscopy and immunoblotting were utilized to examine alterations in junctional protein expression and cell morphology. RESULTS: In HK 2 cells IL-17A significantly downregulated the expression of the proepithelial gene CDH1 (E-cadherin) while the proinflammatory/profibrotic genes CTGF, CD44 and TGFBR1 were significantly increased. IL-17A also increased the secretion of fractalkine, G-CSF, GM-CSF, VEGF, IL-6 and IL-8. In HRPTEpiC 100 ng/ml IL-17A upregulated the proinflammatory/profibrotic genes ACTA2, CCL2, CHMP1A, CTGF, FN1, IL6, FSP1, SMAD1, SMAD5, TGFB1 and TGFBR2 while treatment with a reduced concentration of IL-17A (0.1 ng/ml) decreased SMAD5, TGFB1 and PDGFRB expression. Changes in ZO-1 and E-cadherin protein expression and cell morphology were examined following IL-17A treatment as indicators of epithelial-to-mesenchymal transition. IL-17A decreased ZO-1 expression in HK-2 and HRPTEpiC; however, E cadherin was only reduced in HK-2 cells. Neither HK-2 nor HRPTEpiC assumed an elongated, fibroblast-like morphology following IL-17A treatment. CONCLUSIONS: IL 17A directly mediates proximal tubule epithelial cell proinflammatory/profibrotic activity as demonstrated by the alteration in genes associated with extracellular matrix remodeling and cell-cell interaction, and stimulation of inflammatory mediator and immune cell chemoattractant secretion. Additionally, IL-17A may have a negative impact on barrier integrity as indicated by ZO-1 downregulation. PMID- 20924206 TI - Transoral robotic surgery for parapharyngeal space tumors. AB - PURPOSE: To evaluate the outcomes of patients with parapharyngeal space (PPS) tumors treated with a transoral robotic surgery (TORS) approach. MATERIALS AND METHODS: We prospectively enrolled well-defined benign PPS tumors accessible from the oropharynx with no carotid encasement or bone erosion. We designated outcome measures that included technical feasibility of the approach, local tumor control and complication rates. Descriptive statistics were used to summarize the outcome data. RESULTS: With a mean follow-up of 29.9 months (range 12-40 months), a total of 10 patients have been enrolled. TORS was completed in 9 of 10 patients with acceptable operative time and blood loss and no significant complications including hemorrhage, infection, trismus or tumor spillage. Local control has been 100% for 7 patients with pleomorphic adenomas. CONCLUSIONS: We confirm the safety and feasibility of the TORS approach for PPS tumors that achieves a high local control and low surgical complication rate. TORS is a viable approach for removing benign tumors and lesions of the PPS. PMID- 20924207 TI - EIF2C is overexpressed and amplified in head and neck squamous cell carcinoma. AB - AIM: To discover putative oncogenes in head and neck squamous cell carcinoma (HNSCC) by integrating data from whole-genome comparison of array-based comparative genomic hybridization (CGH) and expression microarray analysis of HNSCC. METHODS: We integrated published data defining regions of loss/gain identified from the profiling of 21 HNSCC using high-resolution (<1 Mb) CGH arrays and data from an mRNA expression microarray (approx. 12,000 genes) comparing 6 normal tissues and 8 HNSCC tumor tissues. Eukaryotic translation initiation factor 2C subunit 2 (EIF2C2) was found to be the most significantly overexpressed gene by mRNA expression array, and corresponded to the most common region of amplification found by the CGH array described by Sparano et al. We validated EIF2C2 overexpression in primary tissue, overexpression and amplification in HNSCC lines (JHU-011, JHU-012, FADU) relative to a minimally transformed oral keratinocyte cell line (OKF6) and performed knockdown experiments. RESULTS: The tumor tissues had an average mRNA expression level of 123 (SD = 49) compared to the normal tissues (18.6, SD = 10) (p = 0.0005) by expression array. Quantitative RT-PCR validation of our expression arrays found that normal tissues had an average expression of 0.76 (SE = 0.08) and tumor tissues of 2.1 (SE = 0.35) (p = 0.0008). EIF2C2 was found to be amplified and overexpressed in 3 HNSCC cell lines. Knockdown of EIF2C2 in cell lines (JHU-012 and JHU-011) inhibited proliferation. CONCLUSION: EIF2C2 is amplified and overexpressed in HNSCC cell lines and primary tumors and functionally significant in cell lines. PMID- 20924208 TI - New treatments for chronic hepatitis C. AB - Treatments for chronic hepatitis C has evolved significantly in the past 15 years. The standard of care (SOC) is peginterferon alfa-2a/-2b with ribavirin for 48 weeks or 24 weeks in patients infected with HCV genotype 1 or 2/3, respectively. The treatment duration can be individualized based on the baseline viral load and the speed of the virologic response during treatment. However, current therapies are associated with side effects, complications, and poor patient tolerability. Therefore, there is an urgent need to identify better strategies for treating this disease. An improved sustained virologic response (SVR) can be achieved with new HCV-specific inhibitors against NS3/4A and NS5B polymerases. Recent trials have found SVR rates in patients with HCV genotype 1 infection of 61~68% and 67~75% for combining the SOC with the protease inhibitors telaprevir and boceprevir, respectively. Several new HCV-specific inhibitors such as protease inhibitors and nucleoside and non-nucleoside polymerase inhibitors as well as non-HCV-specific compounds with anti-HCV activity are currently in clinical evaluation. In this review we discuss these new treatments for chronic hepatitis C. PMID- 20924209 TI - Hypoxia-inducible factor 1, hepatocellular carcinoma and angiogenesis. PMID- 20924210 TI - Effects of the knockdown of hypoxia inducible factor-1alpha expression by adenovirus-mediated shRNA on angiogenesis and tumor growth in hepatocellular carcinoma cell lines. AB - BACKGROUND/AIMS: Hypoxia-inducible factor-1alpha (HIF-1alpha) is a central transcriptional factor involved in the cellular responses related to various aspects of cancer biology, including proliferation, survival, and angiogenesis, and the metabolism of the extracellular matrix in hypoxia. This study evaluated whether adenovirus-mediated small hairpin RNA (shRNA) against HIF-1alpha (shHIF 1alpha) inhibits cell proliferation and angiogenesis in hepatocellular carcinoma (HCC) cell lines. METHODS: Knockdown of HIF-1alpha expression was constructed by adenovirus-mediated RNA interference tools, and HCC cell lines infected with shHIF-1alpha coding virus were cultured under a hypoxia condition (1% O2) for 24 hours. Following infection, the expression levels of HIF-1alpha, angiogenesis factors, and matrix metalloproteinase (MMP) were examined using Western blotting. Cell proliferation and angiogenesis were measured by a cell proliferation assay (MTT assay) and an angiogenesis-related assay (invasion and tube-formation assay), respectively. RESULTS: Adenovirus mediated inhibition of HIF-1alpha induced suppression of tumor growth in HCC cell lines. It also down-regulated the expression of angiogenesis factor and MMP proteins. Angiogenesis as well as mobility of vascular cells to tumor was suppressed by adenovirus-mediated shHIF 1alpha-infected groups in human umbilical vein endothelial cells (HUVECs). CONCLUSIONS: These data suggest that adenovirus-mediated inhibition of HIF-1alpha inhibits the invasion, tube formation, and cell growth in HUVECs and HCC cells. PMID- 20924211 TI - Serum prohepcidin levels in chronic hepatitis C, alcoholic liver disease, and nonalcoholic fatty liver disease. AB - BACKGROUND/AIMS: Patients with various chronic liver diseases frequently have increased body iron stores. Prohepcidin is an easily measurable precursor of hepcidin, which is a key regulator of iron homeostasis. This study investigated the serum prohepcidin levels in patients with various chronic liver diseases with various etiologies. METHODS: Serum prohepcidin levels were measured in patients with chronic hepatitis C (CH-C) (n=28), nonalcoholic fatty liver disease (NAFLD) (n=24), and alcoholic liver disease (ALD) (n=22), and in healthy controls (n=25) using commercial ELISA. Serum interleukin 6 (IL-6) levels and blood iron indices were also measured. RESULTS: The serum levels of both prohepcidin and IL-6 were significantly higher in CH-C patients than in healthy controls, and there was a positive correlation between the IL-6 and prohepcidin levels (r=0.505, p=0.020). The prohepcidin levels in ALD patients did not differ from those in controls, despite their significantly elevated IL-6 levels. There was a tendency for a negative correlation between serum prohepcidin levels and transferrin saturation in ALD patients (r=-0.420, p=0.051). Neither prohepcidin nor IL-6 was significantly elevated in the NAFLD group, despite the presence of elevated serum iron and ferritin levels. CONCLUSIONS: The role of prohepcidin may differ in different human liver diseases. In the setting of CH-C, both the serum prohepcidin and IL-6 levels were significantly elevated and were positively correlated with each other. PMID- 20924212 TI - Factors influencing the severity of acute viral hepatitis A. AB - BACKGROUND/AIMS: Most patients with acute viral hepatitis A have a favorable course, but a few of them suffer from severe forms of hepatitis such as fulminant hepatitis. This study was carried out to identify the factors influencing the severity of acute viral hepatitis A. METHODS: We retrospectively reviewed the medical records of 713 patients with acute hepatitis A, who were divided into two groups: severe hepatitis A (N=87) and non-severe hepatitis A (N=626). Severe hepatitis was defined as fulminant hepatitis or prolongation of prothrombin time (INR>=1.5). Clinical variables were compared between the two groups. RESULTS: The incidence of fulminant hepatitis was 1.4 % (10/713) in patients with acute hepatitis A. Thirty-three (4.6 %) cases exhibited HBsAg positivity. In multivariate analyses, significant alcohol intake and the presence of HBsAg were significant predictive factors of fulminant hepatitis A, and significant alcohol intake and age were significant predictive factors of severe hepatitis A. HBeAg and HBV-DNA status did not affect the clinical course of hepatitis A in chronic hepatitis B carriers. CONCLUSIONS: While most patients with acute hepatitis A have an uncomplicated clinical course, our data suggest that a more-severe clinical course is correlated with being older, significant alcohol intake, and chronic hepatitis-B-virus infection. PMID- 20924213 TI - Diagnostic value of cystatin C for predicting acute kidney injury in patients with liver cirrhosis. AB - BACKGROUND/AIMS: The present study aimed to determine the role of cystatin C as a prognostic factor for acute kidney injury and survival in cirrhotic patients. METHODS: The study investigated 53 liver cirrhosis patients. The renal function was evaluated by serum creatinine, serum and urine cystatin C, and 24-hour creatinine clearance on admission. Acute kidney injury was defined as a serum creatinine level exceeding the normal range (>1.2 mg/dl) and an increase of at least 50% from the baseline value. Multivariate analysis, receiver operating characteristic curve, and survival analysis were used to investigate prognostic factors for acute kidney injury and survival. RESULTS: Nine of the 53 cirrhotic patients (17.0%) developed acute kidney injury within 3 months. Both serum creatinine and cystatin C were predictive factors for acute kidney injury in univariate analysis, with a diagnostic accuracy of 0.735 (95% confidence interval (CI), 0.525-0.945; p=0.028) for serum cystatin C and 0.698 (95% CI, 0.495-0.901, p=0.063) for creatinine. In multivariate analysis, only serum cystatin C was an independent risk factor for acute kidney injury. The sensitivity and specificity of a serum cystatin C level of >1.23 mg/L to acute kidney injury were 66% and 86%, respectively. Serum cystatin C was positively correlated with the Model for End-Stage Liver Disease (MELD) and MELD-Na scores (r=0.346 and p=0.011, and r=0.427 and p=0.001, respectively). Comparison of the survival rates over the observation period revealed that a serum cystatin C level of >1.23 mg/L was a useful marker for short-term mortality (p<0.001). CONCLUSIONS: The accuracy in predicting acute kidney injury and short-term mortality was higher for a serum cystatin C level of >1.23 mg/L than for the serum creatinine concentration in patients with cirrhosis. PMID- 20924214 TI - Effect of alcohol on the development of hepatocellular carcinoma in patients with hepatitis B virus-related cirrhosis: a cross-sectional case-control study. AB - BACKGROUND/AIMS: Whether alcohol intake increases the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B virus (HBV) infection remains controversial. The aim of this study was to determine the effect of alcohol intake on the development of HCC. METHODS: Between January 2006 and August 2008, 146 patients with an initial diagnosis of HCC who were hospitalized in 3 major hospitals in the Incheon area were enrolled as cases. Another 146 cirrhotic patients, who matched the cases by age and sex, were enrolled as controls. All cases and controls were HBsAg positive, and had a history of lifetime alcohol intake. RESULTS: The cases and controls were aged 53+/-8 and 53+/-9 years (mean+/-SD), respectively, with each group comprising 118 males and 28 females. The basal laboratory data, distribution of Child-Pugh class, HBeAg positivity (31.5% vs. 37.7%), HBV DNA level (5.74+/-2.35 vs. 5.98+/-2.29 log10 copies/mL), and proportion with a lifetime alcohol intake of more than 292 kg (30.8% vs. 34.9%) did not differ between cases and controls. The cumulative alcohol intake and the proportion of heavy drinkers did not differ between the two groups in male patients. CONCLUSIONS: Alcohol intake might not increase the risk of HCC in patients with HBV infection. PMID- 20924215 TI - Forty-eight weeks treatment with clevudine 30 mg qd versus lamivudine 100 mg qd for chronic hepatitis B infection: a double-blind randomized study. AB - BACKGROUND/AIMS: Clevudine is a pyrimidine analogue with potent activity against hepatitis B virus (HBV) replication in vitro. In a previous pivotal phase III clinical study, 24 weeks treatment with clevudine 30 mg has been shown to profoundly suppress HBV replication and normalize serum alanine aminotransferase level. METHODS: In this study, we compare the efficacy and safety of clevudine (30 mg daily) versus lamivudine (100 mg daily) for 48 weeks in treatment-naive chronic hepatitis B e antigen (HBeAg) positive patients. RESULTS: Ninety-two chronic HBeAg positive patients were randomized to receive clevudine 30 mg daily or lamivudine 100 mg daily in a 1:1 ratio. The clevudine group demonstrated greater viral suppression at week 48 when compared with the lamivudine group (median reduction: 4.27 vs. 3.17 log(10) copies/ml at week 48, p<0.0001). At week 48, serum HBV DNA level was below 300 copies/mL in 73% and 40% in the clevudine and lamivudine groups, respectively (p=0.001). HBeAg seroconversion occurred in 18% of patients in the clevudine group versus 12% in the lamivudine group at week 48. Lamivudine-resistant mutations were detected in 11 (24%) patients in the lamivudine group, who showed viral rebound during lamivudine therapy but no resistance was found in the clevudine group during 48-week treatment period. CONCLUSIONS: A 48-week dosing with clevudine 30 mg daily was superior to lamivudine 100 mg daily in suppressing HBV replication, with no emergence of viral breakthrough in patients with HBeAg positive chronic hepatits B. PMID- 20924216 TI - A case of concomitant Gilbert's syndrome and hereditary spherocytosis. AB - We describe moderate hyperbilirubinemia in a 28-year-old man who suffered from gallstones and splenomegaly, with combined disorders of hereditary spherocytosis (HS) and Gilbert's syndrome (GS). Since it is difficult to diagnose HS in the absence of signs of anemia, we evaluated both the genetic mutation in the UGT1A1 gene and abnormalities in the erythrocyte membrane protein; the former was heterozygous for a UGT1A1 allele with three mutations and the latter was partially deficient in ankyrin expression. This is the first report of the concomitance of HS and GS with three heterozygous mutations [T-3279G, A (TA)7TAA, and G211A] in the UGT1A1 gene. PMID- 20924217 TI - Detection of distant metastasis to skeletal muscle by 18F-FDG-PET in a case of intrahepatic cholangiocarcinoma. AB - Intrahepatic cholangiocarcinoma is a rare malignancy that originates from the epithelial cells of the intrahepatic bile ducts. Intrahepatic cholangiocarcinoma can metastasize in lymphatic chains, including the hepatoduodenal ligament, and it often invades adjacent organs or metastasizes to other visceral organs such as the lungs, bones, adrenal glands, and brain. However, distant skeletal muscle metastasis is very rare. Moreover, a metastatic skeletal muscle tumor rarely shows specific symptoms, making it difficult to identify in a routine examination. A 45-year-old man with a chief complaint of right upper quadrant abdominal pain was admitted to our hospital. Abdominal ultrasound and computed tomography with contrast enhancement showed a malignant mass in the right hepatic lobe, and 2-[18F] fluoro-2-deoxy-D-glucose positron-emission tomography revealed distant skeletal muscle metastases in the thorax and buttock. The patient underwent an ultrasound-guided percutaneous needle biopsy for the metastatic low echo masses in the skeletal muscle. PMID- 20924219 TI - Massive hepatic necrosis with large regenerative nodules. PMID- 20924218 TI - Clinical courses after administration of oral corticosteroids in patients with severely cholestatic acute hepatitis A; three cases. AB - Acute hepatitis A is currently outbreaking in Korea. Although prognosis of acute hepatitis A is generally favorable, a minority of patients are accompanied by fatal complications. Severe cholestasis is one of the important causes of prolonged hospitalization in patients with acute hepatitis A. In such cases, higher chances of additional complications and increased medical costs are inevitable. We report three cases of severely cholestatic hepatitis A, who showed favorable responses to oral corticosteroids. Thirty milligram of prednisolone was initiated and tapered according to the responses. Rapid improvement was observed in all cases without side effects. We suggest that corticosteroid administration can be useful in hepatitis A patients with severe cholestasis who do not show improvement by conservative managements. Clinical trial will be needed to evaluate effectiveness of corticosteroids in these patients. PMID- 20924220 TI - Hepatic adrenal rest tumor mimicking hepatocellular carcinoma. PMID- 20924222 TI - Bisphenol A effect on glutathione synthesis and recycling in testicular Sertoli cells. AB - BACKGROUND AND OBJECTIVE: Controversial effects of bisphenol A (BPA) have been reported on testicular function. These differences might reflect dissimilar exposure conditions. Dose responses to toxicants may be non-linear, e.g. U shaped, with effects at low and at high levels of exposure and lower or inexistent effects at intermediate levels. Sertoli cells produce high levels of glutathione (GSH) as a cell defense mechanism. In this study, we addressed the question whether the exposure to different doses of BPA could influence Sertoli cell GSH synthesis and recycling. MATERIALS AND METHODS: Primary Sertoli cell cultures were exposed to various doses of BPA (0.5 nM-100 MUM). Cell viability was measured as an outcome of toxic effect. GSH cell content was determined to evaluate cell response to toxicant exposure. Glutamate-cysteine ligase catalytic (GCLC) and modulatory (GCLM) subunit expression were assessed to estimate GSH synthesis, and GSH reductase (GR) expression to estimate GSH recycling. RESULTS: BPA 100 MUM, but not lower doses, decreased cell viability. BPA 10 and 50 MUM, but not lower doses, induced an increment in Sertoli cell GSH levels, due to a rapid upregulation of GCLC and GR and a slower upregulation of GCLM. CONCLUSIONS: High doses of BPA are deleterious for Sertoli cells. Intermediate doses do not affect Sertoli cell viability and increase cell content of GSH owing to increased GSH synthesis and recycling enzyme expression. Lower doses of BPA are not capable of eliciting a cell defense response. These observations may explain a non-linear dose response of Sertoli cells to BPA. PMID- 20924225 TI - Breast conservation therapy in patients with stage T1-T2 breast cancer: current challenges and opportunities. AB - OBJECTIVES: Despite the fact that breast conservation therapy has been established as an effective treatment, a number of issues and controversies currently surround the application of this treatment for patients with stage T1 and T2 breast cancer. METHODS: Records of patients with histologically confirmed stage T1 (n = 1172) and stage T2 (n = 349) breast cancer, treated with wide local tumor excision and whole breast irradiation between January 1970 and December 2000, were prospectively registered on our database. Median follow-up was 6.6 years. Numerous publications addressing issues to be reviewed were collected, and data and prevailing controversies are discussed. RESULTS: The 10-year actuarial incidence of ipsilateral breast relapse was 7% for T1 and 11% for T2 tumors. Results with breast conservation therapy were equivalent in white or black women with T1 or T2 tumors. In patients younger than 40 years, incidence of failures was 10% for T1 (in contrast to 4% for other age groups) and 15% for T2 lesions (in contrast to 6% in other groups). The incidence of ipsilateral recurrences in women younger than 40 years was, for T1 tumors, 9% with negative surgical margins and 12% with close or positive margins and for T2 tumors 12% and 22%, respectively (difference not statistically significant). CONCLUSIONS: Use of breast-conserving surgical therapy should be optimized to enhance therapeutic outcome. Many developments in the oncological field and refinements in treatment planning and delivery of radiation therapy provide unique opportunities for the radiation oncologist to continue to play an integral role in the management of patients with breast cancer. PMID- 20924223 TI - Zona fasciculata 21-hydroxysteroids and precursor-to-product ratios in 21 hydroxylase deficiency: further characterization of classic and non-classic patients and heterozygote carriers. AB - INTRODUCTION: Although much is known about the increased levels of the 21 hydroxylase substrates 17-hydroxyprogesterone (17OHP) and 21-deoxycortisol (21DF) - the biochemical markers of all forms of 21-hydroxylase deficiency (21OHD), only limited information is available on the zona fasciculata (ZF) products distal to the enzymatic block: 11-deoxycortisol (S), 11-deoxycorticosterone (DOC), and corticosterone (B). OBJECTIVE: To investigate whether basal and post-ACTH levels of S, DOC, and B and the 21-hydroxylase precursor-to-product ratios determined by tandem mass spectrometry preceded by high-performance liquid chromatography separation (liquid chromatography-tandem mass spectrometry) could disclose distinct profiles in genotypically confirmed classic (no.=14) and non-classic (NC) (no.=18) patients, heterozygote carriers (no.=61) and wildtypes (WT) (no.=27) for 21OHD. RESULTS: Salt wasting (SW) and simple virilizing (SV) had higher basal levels of DOC with no further increase in response to ACTH. Stimulated DOC was similar in 21OHD patients and carriers but was reduced as compared to WT. ACTH-stimulated B increased gradually from SW and SV through WT. The post-ACTH 21DF/B ratio was able to detect 92% of the carriers among WT. All NC patients could be detected by post-ACTH 17OHP/DOC and 21DF/B, with no overlap with 21OHD carriers. CONCLUSION: Although 21-hydroxylase is a key enzymatic step in both 17-hydroxy and 17-deoxy pathways of ZF, the reaction is mostly affected in the latter pathway, leading to a significant impairment of B production, which may further characterize the 21OHD subtypes. Also, the precursor-to-product ratios, particularly 21DF/B, can demonstrate the distinctive outline of 21OHD subtypes, including carriers and normal subjects. PMID- 20924224 TI - Differential action of two prolactin isoforms on ischemia and re-perfusion induced arrhythmias in rats in vivo. AB - BACKGROUND: The different influences of one of the PRL isoforms (PRL I) on the cardiovascular system have been described in the past. AIM: Our goal was to establish an appropriate iv dose of 2 PRL isoforms (PRL I and PRL II) in intact rats. After establishing this dose, PRL I (0.01 mg/kg) or PRL II (0.001 mg/kg) was administered in bolus 10 min before left anterior descending coronary artery occlusion (7 min) followed by re-perfusion (15 min). We then aimed to study and compare the effects of these isoforms on ischemia- and re-perfusion-induced arrhythmias in the ischemia and re-perfusion-induced arrhythmias model in rats. MATERIALS AND METHODS: Mortality index, ventricular fibrillation and tachycardia (VF, VT) incidence and duration, systolic, diastolic, and mean arterial blood pressure, heart rate and myocardial index of oxygen consumption [pressure rate product (PRP)] were measured and calculated. RESULTS: Both PRL isoforms reduced animal mortality (from 50 to 18.75 and 25%, respectively). PRL II significantly reduced VF incidence (to 25%) as well as VT duration (18.21 +/- 3.09) and these effects were markedly different from PRL I and from the control group (p<0.05). Both PRL reduced PRP in the recovery phase (p<0.05). CONCLUSIONS: We proved that supraphysiological doses of PRL isoforms administered in bolus could protect against sudden cardiac death as well as severe arrhythmias episodes during re perfusion. Because of PRL's positive influence on the cardiovascular system and as an endogenous, well-tolerated substance, it might be of potential clinical use. PMID- 20924226 TI - The end of chemotherapy in renal cell carcinoma: for much but not for all. PMID- 20924227 TI - Bibliography-Editors' selection of current world literature. PMID- 20924228 TI - Why the human microbiome project should motivate epidemiologists to learn ecology. PMID- 20924229 TI - Epidemiologic research and Web 2.0--the user-driven Web. PMID- 20924230 TI - At the intersection of public-health informatics and bioinformatics: using advanced Web technologies for phylogeography. PMID- 20924231 TI - Tracking the Global Express: new tools addressing disease threats across the world. PMID- 20924232 TI - The color of smoke. PMID- 20924234 TI - Accounting for center effects in multicenter trials. PMID- 20924235 TI - Parental celiac disease and offspring sex ratio. PMID- 20924236 TI - Cyclical variation in type 1 childhood diabetes. PMID- 20924237 TI - Oseltamivir and abnormal behavior. PMID- 20924238 TI - US National Children's Study. PMID- 20924241 TI - Smoking and miscarriage risk. PMID- 20924243 TI - Patient adherence and efficacy of quetiapine treatment in schizophrenia: results of a multicentre, naturalistic 6-month follow-up study. AB - The aim of the study was to evaluate the adherence and efficacy of quetiapine treatment in a 6-month, multicentre, noninterventional naturalistic design. Overall, 710 schizophrenia patients using quetiapine or who had switched to quetiapine were included. The continuation rate for quetiapine treatment during 6 month follow-up period was 69%. Adherence improved with each subsequent visit for continued patients, 92.9% at the second visit to 96.1% at the last. Treatment adherence was correlated to improvement of symptoms, though not significantly. Patients having lower clinical global impression severity scores at the beginning were twice as likely to improve compared with patients with higher clinical global impression scores. Schizophrenia patients with antisocial behaviour problems had two and a half times higher drop-out rates. In conclusion, this naturalistic study showed that adherence to quetiapine treatment was high, and treatment was effective in schizophrenia patients during long-term treatment. Remission of symptoms in schizophrenia is much related to severity of symptoms at baseline, treatment adherence and characteristics of patients such as antisocial behavioural patterns. PMID- 20924244 TI - "He is just a little shy like me": screening for autism in a young child. AB - CASE: Jacob is a 22-month-old wonderful boy, who is being seen a few months late for his 18-month-old visit because of scheduling snafus, as both parents work outside the home. At this visit, it is routine in our practice to administer the Modified Checklist for Autism in Toddlers (MCHAT) and the Parents' Evaluation of Developmental Status (PEDS). On the PEDS, in response to the question, "Do you have any concerns about how your child talks or makes speech sounds?" the parents respond "He only says 2 words in Hebrew and none in English." On the MCHAT, they reply "no" to 3 items: (1) "Does your child ever pretend, for example, to talk on the phone or take care of a doll or pretend other things?" (2) "Does your child respond to his/her name when you call?" and (3) "Does your child sometimes stare at nothing or wander with no purpose?" This results in failing 1 critical and 3 total items. Our practice protocol recommends a referral for a diagnostic evaluation. Jacob has been a healthy child, and this is the first time that his parents have fallen behind in routine health care maintenance visits. His medical history is unremarkable. He was born at term, weighing 3.2 kg, without any perinatal complications. His parents had emigrated from the Poland in their teenage years and have been married for 8 years. They also have a 5-year-old daughter. They both report that, in Poland, there are some relatives who were "very late talkers," but they do not know about any definitive family history of autism. At the 15-month visit, the parents reported that Jacob had expressive jargoning but no recognizable words. They stated then that he was not interested in toys but liked to play with the television remote control. He is in full-time child care--initially with a nanny in their home, but at 15 months started 3 days a week in a center-based childcare with many families from their community, where children speak Polish, English, and Hebrew at home. His mother works full time as an accountant and father as a physicist in a commercial laboratory. Both have graduate degrees and are trilingual. The parents are conflicted in their interpretation of Jacob's behavior. His father is concerned that he is autistic and his mother feels that "he is just a little shy like me." His physical examination is normal. He is somewhat inhibited and anxious but will sit still on the examination table and alone during the examination. You update his immunizations and then struggle with where to head next. PMID- 20924246 TI - Autism spectrum disorder in Down syndrome: definition of the cutoff point for the autism screening questionnaire screening instrument. PMID- 20924247 TI - From the editor. Patient safety and protection as components of the quality of care. PMID- 20924248 TI - Culture counts--sustainable inpatient computerized surveillance across Duke University Health System. AB - PURPOSE: The authors report on the managerial and logistical details of deploying a computerized adverse drug event surveillance system that was at first a grant funded research project and ultimately was changed to a sustained safety monitoring application serving 3 different hospitals. METHODS: Surveillance was deployed in 3 phases to 2 community-based hospitals and an academic medical center. A logic-based rules engine surveyed electronic records for laboratory, medication, and demographic information indicative of safety concerns. Potential adverse events triggered manual chart review by pharmacists to verify patient harm. RESULTS: During Phase 1, the research team created trigger rules for each hospital. In Phase 2, the trigger review was transitioned to hospital personnel and rule sets were reshaped for specific hospital needs. In Phase 3, surveillance was integrated into daily work flows and organizational balanced scorecards where it was accepted as a quantitative measure of medication safety performance. DISCUSSION AND CONCLUSION: Computerized surveillance helps detect potentially harmful events regardless of hospital size. Active leadership, change-tolerant culture, and hospital pharmacy practice models significantly impact successful adoption. Entrenched cultural issues impeded sustainability at the academic center but not at the 2 community hospitals. Tailoring surveillance to the needs of different inpatient settings is crucial to developing a sustainable model. PMID- 20924249 TI - Attributes of an independently self-sustaining implementation: nurse-administered HIV rapid testing in VA primary care. AB - BACKGROUND: Human immunodeficiency virus (HIV) oral rapid testing (RT) has the potential to facilitate the expansion of such diagnostics to front line providers, specifically clinical nursing staff. Training, policy requirements, and implementation methods used to launch such services have not been widely explored. OBJECTIVES: To evaluate the sustainability of a nurse-initiated HIV-RT intervention at 1 veterans affairs primary care clinic for 1 year. METHODS: Policies were implemented, enabling nurses to carry out HIV RTs. Willing RNs voluntarily enrolled in a 2-part in-service designed to teach pre- and posttest counseling techniques, administering, interpreting, and entering results in the patient's medical records. RESULTS: RNs administered a steady rate of HIV RTs (monthly mean = 25, SD = 3) along with an unexpected increase in HIV blood testing among other clinical staff, leading to a 70% (P < .0001) site-wide increase in HIV testing, with RNs accounting for one-third of these tests. CONCLUSION: In light of the researchers' 1-shot launch efforts, the steady rate of HIV RTs among RNs over the course of a year, combined with the concurrent progressive increase in HIV (blood) testing administered by MDs, PAs, and NPs stands as an anomaly in light of existing implementation science literature. PMID- 20924250 TI - A new approach to tracking the harmfulness of medical errors in health care systems. AB - A variety of approaches are available to monitor and quantify the frequency of medical errors and the harm associated with them. The University HealthSystem Consortium Patient Safety Net provides a categorical, rank-ordered approach for designating harm associated with medical errors but does not lend itself to routine monitoring of change over time. A brief questionnaire was developed and given to hospital administrators to collect ratings about the harmfulness of events occurring in each of the 10 University HealthSystem Consortium harm-score categories. Results revealed a high degree of agreement among raters for harmfulness ratings for each category. A cubic model fit the data best and provided weights for each of the harm-score categories. This preliminary study proposes a methodology for quantifying harm scores. PMID- 20924251 TI - Risks in the application of medical devices: human factors in the medical environment. AB - OBJECTIVE: The more complex a medical device is, the more difficult it is to control the hazards associated with its use. A substantial percentage of harm or injuries to patients resulting from treatment can be attributed to errors. No one knows exactly how many victims have been claimed by medical errors. Studies from the United States and other countries show that 3% to 4% of all hospital patients suffer harm or injuries. This text is intended to provide a practice-oriented approach to the discussion of targeted improvement opportunities in connection with a superficial consideration of the sociotechnical system comprising the manufacturers, the medical devices, and the users in the health facilities. METHOD: Analysis of the risk reports received by the Federal Institute for Drugs and Medical Devices (Bundesinstitut fur Arzneimittel und Medizinprodukte) in connection with undesirable events involving the use of medical devices. Supplementary consideration of additional data from previous human factors research in the field of medicine. The evaluation period for the primary data focuses on the years 2005 to 2008. A differentiation is made between the error causal factors, man, and device. RESULTS: A substantial percentage of the incidents that occurred can be attributed to human blunders. Within the scope of an evaluation of more than 16 000 risk reports in connection with medical devices, 5000 risk reports could not be directly attributed to the failure of a medical device. The lack of an error culture seems to be a considerable problem. CONCLUSION: The safe and reliable development and use of medical devices requires efficient and consistent risk management. Until now, human factors are not sufficiently considered when identifying sources of errors in sociotechnical systems. The useful data required for an extensive risk assessment are missing. An interface-overlapping method of solution is required which permits system analytical and unbiased error handling and integrates all stakeholders. PMID- 20924252 TI - Lean Six Sigma in health care and the challenge of implementation of Six Sigma methodologies at a Veterans Affairs Medical Center. AB - Six Sigma and Lean Thinking are quality initiatives initially deployed in industry to improve operational efficiency leading to better quality and subsequent cost savings. The financial rationale for embarking on this quality journey is clear; applying it to today's health care remains challenging. The cost of medical care is increasing at an alarming rate; most of these cost increases are attributed to an aging population and technological advances; therefore, largely beyond control. Furthermore, health care cost increases are caused by unnecessary operational inefficiency associated with the direct medical service delivery process. This article describes the challenging journey of implementing Six Sigma methodology at a tertiary care medical center. Many lessons were learned; however, of utmost importance were team approach, "buy in" of the stakeholders, and the willingness of team members to change daily practice and to adapt new and innovative ways how health care can be delivered. Six Sigma incorporated as part of the "company's or hospital's culture" would be most desirable but the learning curve will be steep. PMID- 20924253 TI - The current state of Lean implementation in health care: literature review. AB - PURPOSE: The purpose of this article is to discuss the current state of implementation of Lean production in health care. The study focuses on the definition of Lean in health care and implementation process, barriers, challenges, enablers, and outcomes of implementing Lean production methods in health care. DESIGN/METHODOLOGY/APPROACH: A comprehensive search of the literature concerning the implementation of Lean production in health care was used to generate a synthesis of the literature around the chosen research questions. FINDINGS: Lean production in health care is mostly used as a process improvement approach and focuses on 3 main areas: (1) defining value from the patient point of view, (2) mapping value streams, and (3) eliminating waste in an attempt to create continuous flow. Value stream mapping is the most frequently applied Lean tool in health care. The usual implementation steps include conducting Lean training, initiating pilot projects, and implementing improvements using interdisciplinary teams. One of the barriers is lack of educators and consultants who have their roots in the health care sector and can provide support by sharing experience and giving examples from real-life applications of Lean in health care. The enablers of Lean in health care seem not to be different from the enablers of any other change initiative. The outcomes can be divided into 2 broad areas: the performance of the health care system and the development of employees and work environment. PMID- 20924254 TI - A baseline study of communication networks related to evidence-based infection prevention practices in an intensive care unit. AB - This study seeks to gain a baseline understanding of the communication network structure, content of communication, and outcomes in a medical intensive care unit experiencing higher-than-expected central line blood stream infection (CLBSI) rates. The communication network structure refers to the direction and frequency of communication on evidence-based CLBSI prevention practices across various professional subgroups and hierarchical levels in the unit, including medical faculty, nurses, residents, students, unit managers, and hospital administrators. The content of communication refers to the type of knowledge (ie, tacit vs explicit knowledge) exchanged on CLBSI prevention practices. Outcomes include (1) compliance with CLBSI prevention practices and (2) hospital-acquired CLBSI rates in the unit. Data on communication network structure and content of communication are collected using communication logs completed weekly for 4 weeks, by individual participants in each professional subgroup and hierarchical level. Outcomes are collected weekly through chart (medical record) review. Study results indicate a sparse communication network structure with minimal interaction across professional subgroups and hierarchical levels. They also indicate that primarily explicit knowledge on general infection topics is being exchanged as against tacit knowledge on specific infection prevention practices. Unit outcomes are poor, with the central line bundle score at zero during all 4 weeks. The study represents an original attempt at developing methods for measuring the communication network structure related to evidence-based infection prevention practices at the unit level. It lays a foundation for testing hypotheses related to effective communication network structures for hospital infection prevention in a larger study. More significantly, the study lays a foundation for generating concrete and context-sensitive strategies for organizational learning and improvement in the context of evidence-based practices. Such insight is critical from the perspective of evidence-based health care management. PMID- 20924255 TI - Survey-assessed quality and organizational factors related to quality in Pursuing Perfection hospitals. AB - BACKGROUND: The goal of the Pursuing Perfection (P2) program was to encourage organizations to push quality improvement to new levels of excellence. As part of an evaluation of P2, we surveyed employees at the 7 participating P2 organizations to (1) assess their perceptions of patient care quality and improvement progress and (2) examine perceived performance on organizational and workgroup characteristics associated with quality. METHODS: Many survey questions were drawn from existing conceptual models and survey instruments. We used factor analysis to create new scales from questions that were not part of established scales. We used correlation coefficients and multivariable models to examine relationships among variables. RESULTS AND CONCLUSIONS: Variables most strongly associated with perceived quality included standardized and simplified care processes resulting in coordinated care and smooth handoffs, a clear sense of organizational direction and clear action plans, and communication with staff about reasons for change and improvement progress made. Of those variables with a strong relationship to quality, ones with relatively low mean ratings included workgroup coordination; sufficient resources and support for improvement; training; and efficient use of people, time, and energy. These are important areas on which management should focus to improve employee ratings of quality. PMID- 20924258 TI - Do we need a new classification for choroidal neovascularization in age-related macular degeneration? PMID- 20924259 TI - Pathway-based therapies for age-related macular degeneration: an integrated survey of emerging treatment alternatives. AB - PURPOSE: To review treatments under development for age-related macular degeneration (AMD) in the context of current knowledge of AMD pathogenesis. METHODS: Review of the scientific literature published in English. RESULTS: Steps in AMD pathogenesis that appear to be good targets for drug development include 1) oxidative damage; 2) lipofuscin accumulation; 3) chronic inflammation; 4) mutations in the complement pathway; and 5) noncomplement mutations that influence chronic inflammation and/or oxidative damage (e.g., mitochondria and extracellular matrix structure). Steps in neovascularization that can be targeted for drug development and combination therapy include 1) angiogenic factor production; 2) factor release; 3) binding of factors to extracellular receptors (and activation of intracellular signaling after receptor binding); 4) endothelial cell activation (and basement membrane degradation); 5) endothelial cell proliferation; 6) directed endothelial cell migration; 7) extracellular matrix remodeling; 8) tube formation; and 9) vascular stabilization. CONCLUSION: The era of pathway-based therapy for the early and late stages of AMD has begun. At each step in the pathway, a new treatment could be developed, but complete inhibition of disease progression will likely require a combination of the various treatments. Combination therapy will likely supplant monotherapy as the treatment of choice because the clinical benefits (visual acuity and frequency of treatment) will likely be superior to monotherapy in preventing the late-stage complications of AMD. PMID- 20924260 TI - Incidence of hemorrhagic complications after intravitreal bevacizumab (avastin) or ranibizumab (lucentis) injections on systemically anticoagulated patients. AB - PURPOSE: To assess the risk of hemorrhagic complications when performing intravitreal injections on systemically anticoagulated patients. METHODS: A single-center retrospective case series of 520 consecutive patients (675 eyes) receiving 3,106 antivascular endothelial growth factor injections. Patients on the systemic anticoagulants Coumadin (warfarin sodium) or Plavix (clopidogrel bisulfate) were identified, as well as patients on aspirin. Demographic parameters were recorded, as well as relevant anticoagulant medications, preoperative/postoperative best-corrected visual acuities and intraocular pressures, previous ocular surgery, relative ocular diagnoses, and injection complications. RESULTS: Of all patients, 104 were on Coumadin (134 eyes; 548 injections), 90 were on Plavix (123 eyes; 523 injections), 7 were on both Coumadin and Plavix (8 eyes; 33 injections), and 319 were not anticoagulated (400 eyes; 2002 injections). Also, 1,254 injections were on patients taking aspirin. There were no hemorrhagic complications (choroidal hemorrhage, vitreous hemorrhage, or increased submacular hemorrhage) noted in the Plavix (P = 1.0000; 95% confidence interval = 0.0000-0.0088), Coumadin (P = 1.0000; 95% confidence interval = 0.0000-0.0084), or aspirin (P = 1.0000; 95% confidence interval = 0.0000-0.0037) groups. CONCLUSION: The risk of hemorrhagic complications in systemically anticoagulated patients receiving intravitreal injections is extremely low. Because of the demonstrated thromboembolic risk of stopping anticoagulant therapy, we recommend that patients continue their current regiment without cessation. PMID- 20924261 TI - Anatomical benefit from ranibizumab treatment of predominantly classic neovascular age-related macular degeneration in the 2-year anchor study. AB - PURPOSE: To compare lesion anatomical responses to ranibizumab versus verteporfin photodynamic therapy (PDT) in the ANCHOR (Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization [CNV] in Age-Related Macular Degeneration) study. METHODS: In this 2-year, Phase III, randomized, multicenter, double-masked trial, 423 patients received ranibizumab (0.3 or 0.5 mg) monthly + sham PDT or PDT + monthly sham injection. Photodynamic therapy (or sham PDT) was administered at Day 0 and then quarterly as needed. A central reading center assessed fundus photography and fluorescein angiography images. A subset (n = 61) had optical coherence tomography assessments. Main outcome measures included mean change from baseline at Months 12 and 24 for area of classic CNV and total area of leakage from CNV. RESULTS: At Months 12 and 24, ranibizumab was superior to PDT (P < 0.0001) for mean changes from baseline in total area of lesion, CNV area, and total area CNV leakage. Month 12 optical coherence tomographies showed greater center point thickness decrease from baseline with ranibizumab than with PDT (P = 0.0003). Ranibizumab benefits over PDT were evident by 3 months (fluorescein angiography) and 7 days (optical coherence tomography). CONCLUSION: Differences between the PDT and the ranibizumab groups in lesion anatomical outcomes were early, sustained, and favored ranibizumab. PMID- 20924262 TI - Intravitreal bevacizumab during pregnancy. AB - PURPOSE: To report the clinical course of four women treated with intravitreal bevacizumab during pregnancy. METHODS: Observational case series. RESULTS: Four pregnant women were treated with intravitreal bevacizumab for choroidal neovascularization (CNV) because of presumed ocular histoplasmosis syndrome punctate inner choroidopathy, or sarcoid uveitis. Patients received a mean of 2.6 +/- 2.3 injections (range, 1-6 injections) while pregnant. One patient was treated with five additional injections while breastfeeding. The mean follow-up duration after the most recent injection was 14 +/- 2.9 months (range, 11-18 months). Snellen visual acuity improved in all 4 patients with a mean of 5.75 +/- 2.2 lines (range, 3-8 lines). At the most recent follow-up, all patients had involuted CNV that did not require additional treatment. All patients had an uneventful prenatal course and delivered healthy full-term infants. All children have remained healthy, exhibiting normal development and growth during infancy. CONCLUSION: Offering pregnant patients intravitreal bevacizumab therapy during pregnancy for off-label ocular indications can result in significant visual improvement. No adverse events related to treatment occurred in any patient included in this study. Additional studies with more patients and longer follow up duration are required to identify any risks associated with treatment. PMID- 20924264 TI - Factors associated with visual acuity outcomes after vitrectomy for diabetic macular edema: diabetic retinopathy clinical research network. AB - PURPOSE: To evaluate factors associated with favorable outcomes after vitrectomy for diabetic macular edema. METHODS: Data were collected prospectively on 241 eyes undergoing vitrectomy for diabetic macular edema. Multivariate models were used to evaluate associations of 20 preoperative and intraoperative factors with 6-month outcomes of visual acuity and retinal thickness. RESULTS: Median central subfield thickness decreased from 412 MUm to 278 MUm at 6 months, but median visual acuity remained unchanged (20/80, Snellen equivalent). Greater visual acuity improvement occurred in eyes with worse baseline acuity (P < 0.001) and in eyes in which an epiretinal membrane was removed (P = 0.006). Greater reduction in central subfield thickness occurred with worse baseline visual acuity (P < 0.001), greater preoperative retinal thickness (P = 0.001), removal of internal limiting membrane (P = 0.003), and optical coherence tomography evidence of vitreoretinal abnormalities (P = 0.006). No associations with clinician's preoperative assessments of the posterior vitreous were identified. CONCLUSION: These results suggest that the removal of epiretinal membranes may favorably affect visual outcome after vitrectomy. Preoperative presence of vitreoretinal abnormalities appeared to be associated with somewhat greater reductions in retinal thickness but not with visual acuity outcome. These results may be useful for future studies evaluating vitrectomy for diabetic macular edema. PMID- 20924263 TI - Drusen characterization with multimodal imaging. AB - PURPOSE: To characterize the known appearance of cuticular drusen, subretinal drusenoid deposits (reticular pseudodrusen), and soft drusen as revealed by multimodal fundus imaging and to create an explanatory model that accounts for these observations. METHODS: Reported color, fluorescein angiographic, autofluorescence, and spectral domain optical coherence tomography images of patients with cuticular drusen, soft drusen, and subretinal drusenoid deposits were reviewed, as were actual images from affected eyes. Representative histological sections were examined. The geometry, location, and imaging characteristics of these lesions were evaluated. A hypothesis based on the Beer Lambert law of light absorption was generated to fit these observations. RESULTS: Cuticular drusen appear as numerous, uniform, round, yellow-white punctate accumulations under the retinal pigment epithelium (RPE). Soft drusen are larger, yellow-white dome-shaped mounds of deposit under the RPE. Subretinal drusenoid deposits are polymorphous light-gray interconnected accumulations above the RPE. Based on the model, both cuticular and soft drusen appear yellow because of the removal of shorter wavelength light by a double pass through the RPE. Subretinal drusenoid deposits, which are located on the RPE, are not subjected to short wavelength attenuation and therefore are more prominent when viewed with blue light. The location and morphology of extracellular material in relationship to the RPE, and associated changes to RPE morphology and pigmentation, appeared to be the primary determinants of druse appearance in different imaging modalities. CONCLUSION: Although cuticular drusen, subretinal drusenoid deposits, and soft drusen are composed of common components, they are distinguishable by multimodal imaging because of differences in location, morphology, and optical filtering effects by drusenoid material and the RPE. PMID- 20924265 TI - A new dual port cutter system for vitrectomy surgery. AB - PURPOSE: To evaluate and compare the performance of several designs of 20-gauge dual port (DP) vitreous cutter tips with a standard 20-gauge single port tip. METHODS: Custom 20-gauge pneumatic vitreous DP cutter tips with different sizes and port positions were evaluated through porcine vitreous and water flow rates. Five designed and fabricated DP cutter tips were compared with a normal single port control tip and evaluated by the measurement of water and porcine vitreous flow rates, and surgical examination in enucleated porcine eyes. RESULTS: Some DP tips approached a maximum vitreous and water flow rates, removing water and vitreous faster than the normal control tip. With reference to surgical evaluation, some DP tips performed better than the single port tip for bulk vitrectomy, but none shaved the vitreous base more effectively. CONCLUSION: The DP cutter system has the potential to increase the flow rates depending on the size and position of the extra port. In the future, the DP cutter may allow the surgeon to perform bulk vitrectomy more efficiently. PMID- 20924266 TI - Young patients with branch retinal vein occlusion: a review of 60 cases. AB - PURPOSE: To investigate the risk factors for branch retinal vein occlusion (BRVO) in young patients. METHODS: Observational case series with retrospective comparative controls. The medical records of 60 consecutive patients (aged <= 49 years) with BRVO were reviewed to note patients' age, sex, body mass index, history of smoking, diabetes, hypertension, hyperlipidemia, and hormonal replacement therapy in women. Results were compared with those of a control group of 123 individuals. RESULTS: An increased risk of BRVO was found in patients with a history of systemic hypertension, hyperlipidemia, and increased body mass index but not with diabetes, smoking, or hormone replacement therapy. CONCLUSION: Systemic hypertension, hyperlipidemia, and increased body mass index are important risk factors for BRVO in young patients, just as in the older population. We recommend obtaining a complete blood count, reviewing the medical history, and evaluating the patient for systemic hypertension, obesity, and hyperlipidemia as part of the initial workup of young patients with BRVO. If no clear risk factors are found, a more extensive workup should be considered. PMID- 20924267 TI - Intravitreal infliximab for the treatment of sight-threatening chronic noninfectious uveitis. AB - PURPOSE: Tumor necrosis factor-alpha is known to play an important role in various immune-mediated ocular diseases. Infliximab, a chimeric monoclonal antibody against tumor necrosis factor-alpha, has been used for the treatment of various chronic systemic and ocular inflammatory diseases. The purpose of this study was to evaluate the effect of intravitreal injection of infliximab on the visual acuity and central macular thickness in patients with chronic noninfectious uveitis. METHODS: Ten eyes of 7 patients with chronic persistent noninfectious uveitis who were nonresponsive to conventional previous medications during the previous 3 months were included in this study. The patients received intravitreal injection of 1.5 mg/0.15 mL infliximab. Mean best-corrected visual acuity and mean central macular thickness 1 day before and 4 weeks after the injection were evaluated and compared. RESULTS: Mean logarithm of the minimum angle of resolution before and after injection was 1.37 +/- 0.43 and 0.67 +/- 0.56, respectively, with statistically significant improvement after injection (P = 0.005). The mean central macular thickness before and after injection was 673.20 +/- 338.39 MUm and 456.40 +/- 317.46 MUm, respectively, with a significant decrease in the central macular thickness after the injection (P = 0.005). CONCLUSION: Intravitreal injection of infliximab may improve the visual acuity and decrease the central macular thickness in patients with chronic noninfectious uveitis and significant visual loss and central macular edema. PMID- 20924268 TI - New eye speculum for pars plana vitrectomy. PMID- 20924269 TI - Evaluation of ultra wide angle "ora-ora" high refractive index self-stabilizing contact lens for vitreous surgery. PMID- 20924271 TI - Vitreoretinal surgery in pediatric cases. PMID- 20924272 TI - Use processed human retina samples to assay for RNA. PMID- 20924273 TI - Novel method used for assessing the size of the neovascularization. PMID- 20924276 TI - Clear cell tubulopapillary renal cell carcinoma: a study of 36 distinctive low grade epithelial tumors of the kidney. AB - Recently several low-grade renal cell tumors, distinct from those recognized by the 2004 World Health Organization classification of renal tumors, have been described. These tumors had similar clinicopathologic features, being low-stage tumors with cystic, tubuloacinar, and/or papillary architecture. The tumor cells were low grade with variable amounts of clear cytoplasm that was positive for cytokeratin 7 (CK7), but negative for CD10. Genetic changes characteristic of clear cell or papillary renal cell carcinoma were not seen in these tumors. We investigated the morphologic, immunohistochemical, and genetic features of 36 additional tumors. Immunohistochemistry was carried out for CK7, carbonic anhydrase 9, alpha-methylacyl-CoA racemase, CD10, TFE-3, and desmin. Interphase fluorescence in situ hybridization was carried out with centromeric probes for chromosomes 3, 7, 17, and a subtelomeric probe for 3p25. Sequencing of von Hippel Lindau gene and analysis of the methylation status of the promoter region was also carried out in 2 tumors. Thirty-six tumors from 33 patients (mean age: 60.4 , range: 26 to 88; 17 men and 16 women) were studied. Three patients had bilateral tumors and 1 patient had von Hippel-Lindau disease. Follow-up was available in 60% (20/33) of the patients for a mean of 27.4 (range 1 to 85) months. No patient had evidence of the disease after surgery except for the patient with von Hippel-Lindau disease, who was alive with stable disease in the contralateral kidney. All 36 tumors were small (mean size 2.4 cm; range 0.9 to 4.5 cm) and low stage (pT1). The majority was cystic and had prominent fibrous capsule and stroma. The tumors were composed of variable amount of cysts, papillae, tubules, acini, and solid nests. The most characteristic histologic features were branching tubules and acini and anastomosing clear cell ribbons with low-grade nuclei. All tumors were strongly positive for CK7 and variably positive for CA9, but largely negative for CD10, and negative for alpha methylacyl-CoA racemase and TFE-3. All but 1 tumor had no gains of chromosomes 7 and 17 and deletion of 3p. Only 1 tumor had low copy number gains of chromosomes 7 and 17. VHL gene mutation and promoter methylation were negative in 2 tumors analyzed. We show that these tumors, which we term as "clear cell tubulopapillary renal cell carcinoma," constitute a unique subtype in the spectrum of renal epithelial neoplasia based on their characteristic morphologic and immunohistochemical features. PMID- 20924279 TI - The FAQ initiative. PMID- 20924277 TI - Sporadic hemangioblastoma of the kidney: an underrecognized pseudomalignant tumor? AB - Hemangioblastoma is a benign tumor that can occur sporadically, or in association with von Hippel-Lindau disease in approximately one-quarter of the cases. Only exceptionally does it occur outside the central nervous system. This report describes 2 cases of sporadic renal hemangioblastoma, with 1 patient presenting with hematuria and polycythemia, and the other low back pain. Histologically, the tumors were circumscribed, and composed of sheets of large polygonal cells traversed by arborizing thin-walled blood vessels. Many of the tumor cells showed pleomorphic nuclei, but the mitotic figures were rare. The cytoplasm was eosinophilic, and occasionally finely vacuolated indicating the presence of lipid. The diagnosis of hemangioblastoma was confirmed by negative immunostaining for cytokeratin, and positive staining for alpha-inhibin, S100, and neuron specific enolase. This benign neoplasm which can be mistaken for various malignancies such as renal cell carcinoma, epithelioid angiomyolipoma, adrenal cortical carcinoma, and paraganglioma, deserves wider recognition for its occurrence as a primary renal tumor. PMID- 20924280 TI - Encapsulated papillary oncocytic neoplasms of the thyroid: morphologic, immunohistochemical, and molecular analysis of 18 cases. AB - Encapsulated papillary oncocytic neoplasms (EPONs) of the thyroid are rare tumors, whose relationship to other thyroid tumors has not been thoroughly elucidated. Earlier, they have been regarded as variants of papillary thyroid carcinoma (PTC), hyperplastic lesions, and follicular neoplasms. Eighteen EPONs were retrieved from our surgical pathology files and reviewed for defining morphologic features. Cases having the typical nuclear features of PTC were excluded. Immunohistochemistry (IHC) for CK19, HBME1, and CD56 was carried out. Microdissection, polymerase chain reaction, and sequencing of exon 15 of the BRAF gene were completed. Cases were evaluated for rearranged in transformation/papillary thyroid carcinoma RET/PTC rearrangement by fluorescent in situ hybridization (FISH). The majority of the tumors exhibited a distinctive histologic appearance. They were composed of true papillae lined by a single layer of predominantly cuboidal cells with oncocytic cytoplasm; hobnailing was typically prominent. Three tumors showed taller cells with uniformly apical nuclei and no hobnailing. Ten of 18 cases showed vascular and/or capsular invasion; hence, if the diagnostic criteria used to evaluate follicular neoplasms are applied, more than half of the tumors would be considered minimally invasive carcinomas. No cases were immunoreactive with antibodies to HBME1, whereas only 1 of 13 was immunoreactive for CK19. Six of 7 interpretable cases were immunoreactive for CD56. No BRAF point mutations or RET/PTC rearrangements were identified in the examined cases. All patients were alive at the time of last follow-up and no locally recurrent disease had been reported; however, 1 case was remarkable for a lymph node metastasis. Our results confirm that EPONs are histologically, immunohistochemically, and molecularly distinct from papillary thyroid carcinoma and seem to be most related to follicular neoplasms. PMID- 20924281 TI - Morphologic characterization of syndromic gastric polyps. AB - The morphology of gastric hamartomatous polyps from patients with juvenile polyposis syndrome (JuvPS) and Peutz-Jeghers' Syndrome (PJS) is poorly characterized. We investigated the histologic features of gastric polyps in patients with established JuvPS or PJS to develop improved histologic criteria to distinguish these from gastric hyperplastic (HP) polyps. The patients with clinically confirmed hamartomatous polyposis syndromes were identified, including 26 patients with JuvPS (both familial and sporadic) and 17 patients with PJS. All gastric polyps (n=30) from these patients were intermixed with gastric HP polyps from nonsyndromic patients (n=26) and subsequently blindly reviewed by a panel of gastrointestinal pathologists. A consensus diagnosis was rendered. The panel then reviewed the slides in the context of clinical data and identified histologic features for distinguishing JuvPS, PJS, and HP gastric polyps based on epithelial changes, pit architecture, lamina propria features, and smooth muscle qualities. A sleeping period of 6 months lapsed before the same cases were renumbered and blindly rereviewed independently. Diagnoses were then rendered while adhering to the suggested criteria. Cases that the reviewers recalled were discarded from the study (n=8). On initial review, accuracy in diagnosis of gastric polyps in JuvPS was 50% and was 18% in PJS compared with 92% for HP gastric polyps. Adherence to the recommended histologic criteria resulted in diagnostic accuracy of 41% for JuvPS and 54% for PJS, compared with 73% for HP gastric polyps. Accuracy in diagnosis in antral mucosa was 66%, oxyntic mucosa 71%, and transitional-type mucosa (mixed antral and oxyntic) 32%. The diagnostic accuracy based on polyp size was 59% for polyps which were less than equal to 3 mm, 56% for those 4 to 9 mm, and 81% for polyps which were more than equal to 10 mm. The identification of gastric polyps from JuvPS and PJS patients without the context of clinical history of these syndromes remains poor, even with adherence to a set of morphologic criteria. Abiding by such criteria improved recognition of PJS polyps by more than double (P<0.19), but yielded an accuracy of only 54%. The accuracy did not improve when results were stratified for polyp location but did with biopsy size which were more than equal to10 mm. Whereas these syndromic polyps are readily diagnosed in the small bowel and colon, histologic features to distinguish gastric JuvPS and PJS from gastric HP polyps are unreliable. PMID- 20924282 TI - Environmental tobacco smoke furthers progression of diabetic nephropathy. AB - Clinical studies suggest that smoking is a risk factor in the progression of chronic kidney disease, including diabetic nephropathy. The mechanisms involved are not completely understood. We have previously demonstrated that nicotine, one of the compounds present in large amounts in tobacco, promotes mesangial cell proliferation and fibronectin production. In this study, we hypothesized that exposure to environmental tobacco smoke (ETS) promotes the progression of diabetic nephropathy by increasing the expression of profibrotic cytokines such as transforming growth factor-beta (TGF-beta) and the extracellular matrix proteins fibronectin and collagen IV. Six-week-old diabetic (db/db) mice were divided into 2 groups. The experimental group (n = 12) was exposed to ETS at a concentration of 30 mg/m for 6 hr/d, 5 d/wk for 8 weeks. The control group (n = 8) was exposed to room air. Urine was collected before euthanasia for albumin (enzyme-linked immunosorbent assay) and creatinine measurements (mass spectrometry). After euthanasia, the kidneys were harvested for morphometric analysis and Western blot analysis. Serum was saved for cotinine measurements by enzyme-linked immunosorbent assay. ETS exposure resulted in serum levels of cotinine similar to those found in human smokers. ETS exposure for 8 weeks induced significant mesangial expansion (approximately 50% increase) that was accompanied by concomitant increases in TGF-beta and fibronectin expression (approximately 20%). However, ETS did not modify results in significant changes in urinary albumin excretion. These studies demonstrate that ETS exposure worsens the progression of diabetic nephropathy by increasing the amount of mesangial expansion and that these effects are likely mediated by increased expression of profibrotic cytokines such as TGF-beta. PMID- 20924283 TI - Significance of authorship position: an open-ended international assessment. AB - INTRODUCTION: The International Committee of Medical Journal Editors (ICMJE) does not recommend guidelines on authorship position, despite its important role in academic promotion. To identify perceptions of authorship position, the authors performed the first study of authorship position using only open-ended questioning. METHODS: Articles with at least 3 authors were selected from the top 10 cited and 20 other medical journals. The first, last, and 1 author in-between were selected and asked to identify contributions of first and last authors listed in medical journal articles. The responses were analyzed for differences between perceptions of first versus last authorship. RESULTS: Respondents were more likely to report ICMJE criteria being fulfilled by first authors; however, only 1.1% identified all 3 ICMJE conditions of authorship for either author. ICMJE criteria were no more likely identified by authors of high-impact versus low-impact journals. Significant differences existed between the understandings of appropriate roles for first- versus last-listed authors. First-listed authors were viewed at least 7 times more likely to be involved in study conduct, manuscript writing, have a major study contribution and perform the majority of the work involved. Last-listed authors were at least 7 times more likely to be viewed as having a minor or no contribution to the study, provide funding, be a laboratory head/mentor, hold a senior position and supervise/oversee the study. CONCLUSIONS: ICMJE authorship criteria were poorly identified by respondents in this open-ended, international sampling of medical journal authors. Although ICMJE criteria are ideally met by all authors, this does not seem to be well understood or accepted. PMID- 20924285 TI - Diversity of hepatitis C virus genotypes among intravenous heroin users in Taiwan. AB - INTRODUCTION: Limited information is available about genotypes of hepatitis C virus (HCV) in intravenous heroin users in Taiwan. The purpose of this study was to examine the concordance of the detection of antibody to HCV and HCV-RNA and to determine the distribution of HCV genotypes in male intravenous heroin users. METHODS: This was a cross-sectional study. The study population included 274 intravenous heroin drug users newly sentenced in a male prison in central Taiwan from November 2004 to February 2005, whose antibodies to HCV were positive, and antibodies to human immunodeficiency virus were negative. The mean age was 33.9 years (standard deviation, 7.8). The molecular diagnosis used to identify HCV-RNA was PCR. RESULTS: Among 274 subjects, 214 subjects were found to contain HCV-RNA. Positive predictive value of HCV infection using antibody to HCV as an indicator was 78.1%. Among 214 subjects, HCV genotype 2a was the most predominant (58.9%, n = 126), followed by 1a (17.3%, n = 37), 1b (14.5%, n = 31), 2b (8.9%, n = 19) and 1a + 2b (0.4%, n = 1). Age-specific analysis also showed genotype 2a was the most prominent genotype among the 4 age groups, with the highest prevalence in groups aged 20 to 29 years and 30 to 39 years (53.3% and 67.6%, respectively). CONCLUSIONS: The concordance of antibody to HCV and HCV-RNA is remarkable in selected high-risk groups. HCV genotype 2a is the most prevalent in male intravenous heroin users in central Taiwan, especially in aged 20 to 29 years and aged 30 to 39 years. PMID- 20924284 TI - Selective cyclooxygenase-2 inhibitor suppresses renal thromboxane production but not proliferative lesions in the MRL/lpr murine model of lupus nephritis. AB - INTRODUCTION: Proliferative lupus nephritis (LN) is marked by increased renal thromboxane (TX) A2 production. Targeting the TXA2 receptor or TXA2 synthase effectively improves renal function in humans with LN and improves glomerular pathology in murine LN. This study was designed to address the following hypotheses: (1) TXA2 production in the MRL/MpJ-Tnfrsf6(lpr)/J (MRL/lpr) model of proliferative LN is cyclooxygenase (COX)-2 dependent and (2) COX2 inhibitor therapy improves glomerular filtration rate (GFR), proteinuria, markers of innate immune response and glomerular pathology. METHODS: Twenty female MRL/lpr and 20 BALB/cJ mice were divided into 2 equal treatment groups: (1) SC-236, a moderately selective COX2 inhibitor or (2) vehicle. After treatment from the age of 10 to 20 weeks, the effectiveness of inhibition of TXA2 was determined by measuring urine TXB2. Response endpoints measured at the age of 20 weeks were renal function (GFR), proteinuria, urine nitrate + nitrite (NO(x)) and glomerular histopathology. RESULTS: SC-236 therapy reduced surrogate markers of renal TXA2 production during early, active glomerulonephritis. When this pharmacodynamic endpoint was reached, therapy improved GFR. Parallel reductions in markers of the innate immune response (urine NO(x)) during therapy were observed. However, the beneficial effect of SC-236 therapy on GFR was only transient, and renal histopathology was not improved in late disease. CONCLUSIONS: These data demonstrate that renal TXA2 production is COX2 dependent in murine LN and suggest that NO production is directly or indirectly COX2 dependent. However, COX2 inhibitor therapy in this model failed to improve renal pathology, making COX2 inhibition a less attractive approach for treating LN. PMID- 20924286 TI - A patient with diabetes and breast cancer in whom virilization was caused by a testosterone-producing mature cystic teratoma containing a Brenner tumor. AB - A 74-year-old woman with impaired glucose tolerance exhibited virilization. An examination of various hormone levels showed normal pituitary hormone and adrenal hormone levels. However, the patient's blood testosterone level was remarkably high and was suspected of having caused the virilization. An abdominal computed tomography revealed a multilocular cystoma in the left ovary with the features of a mature cystic teratoma. In addition, a chest computed tomography revealed the presence of a mass in the left breast that was subsequently diagnosed as breast cancer based on the results of a biopsy. After the simultaneous surgical resection of the ovarian and breast tumors, her blood testosterone level decreased. The mature cystic teratoma containing a Brenner tumor was considered to be responsible for the high testosterone level because of the presence of androgenic enzymes. This case is extremely rare, but the case was accurately diagnosed through a comprehensive analysis. PMID- 20924287 TI - Role of thymic stromal lymphopoietin in the pathogenesis of nasal polyposis. AB - INTRODUCTION: Polyposis is an end form of chronic mucosal inflammation in a number of disorders and has an important impact on patient's life quality. Thymic stromal lymphopoietin (TSLP) is involved in many inflammatory processes such as asthma and allergic rhinitis (AR). The aim of this study is to elucidate the role of TSLP in the pathogenesis of polyposis. METHODS: Ninety-four patients with nasal polyposis (NP) and/or allergic rhinitis (AR) were treated with inferior turbinectomy and polyp resection. Levels of TSLP in the nasal epithelial layer were measured; expression of TSLP receptor and OX40 ligand (OX40L) was assessed in isolated nasal mucosal dendritic cells (DC); tumor necrosis factor (TNF), interleukin (IL)-4 and interferon (IFN)-gamma expressions were determined in isolated nasal mucosal CD4(+) T cells. RESULTS: The levels of TSLP in nasal epithelial layer were higher in the NP group than in the non-NP group. Higher expression of TSLP receptor and OX40L were detected in DCs of NP nasal mucosa. TNF-alpha(+) IL-4(+)CD4(+) T cells were detected in NP/AR nasal mucosa; TNF(+) IFN-gamma(+) CD4(+) T cells were identified in NP/non-AR nasal mucosa. TSLP primed DCs drove naive CD4(+) T cells to become TNF(+) IL-4(+) CD4(+) T cells, whereas TSLP/lipopolysaccharide-primed DCs induced naive CD4(+) T cells to become TNF(+) IFN-gamma(+) T cells. CONCLUSIONS: The data indicate that TSLP is involved in the pathogenesis of polyposis. PMID- 20924288 TI - Adaptation status and related factors at 2 time points after surgery in patients with gastrointestinal tract cancer. AB - BACKGROUND: The diagnosis of cancer and subsequent surgery represent a life threatening and stressful experience with several factors relating to the patient's process of adaptation. OBJECTIVE: The purpose of this longitudinal study was to examine adaptation status and related factors in patients who have been diagnosed with and undergone surgery for gastrointestinal tract cancer. METHODS: The survey was administered twice (2 weeks after discharge from the hospital and 6 months after surgery). Twenty-five patients responded to both questionnaires about quality of life (QOL), which was regarded as an index of adaptation status, and illness-related demands, the "why me?" question, sense of coherence (SOC), perceived social support, and disease data. RESULTS: On the second survey, scores about illness-related demands, the "why me?" question, SOC, and QOL, other than the QOL social relationships domain, improved, but scores about perceived social support decreased. A correlation between the "why me?" question and the SOC and the difference in the overall QOL by cancer site were found only on the second survey. Low demands of illness and high SOC predicted high QOL on both surveys. CONCLUSIONS: Except for social relationships, adaptation status 6 months after surgery improved compared with after discharge. The relationships between some variables took on a significant meaning at 6 months after surgery. IMPLICATIONS FOR PRACTICE: Comparisons between 2 time points suggested that most cancer patients had dispositional resilience. Meanwhile, the findings related to social relationships and the relationships between some variables suggested the necessity for professional interventions targeting these factors. PMID- 20924290 TI - Abducens neuromyotonia as the presenting sign of an intracranial tumor. AB - In this case series and review of the literature, we describe 2 cases of abducens neuromyotonia (ANM) as the presenting sign of an intracranial tumor (meningioma). Review of the literature suggests that the pathophysiology of ocular neuromyotonia is incompletely understood. Most patients with ANM have a history of radiation therapy. The diagnosis of ANM is made on the basis of clinical findings and can be supported by electrophysiological studies. A complete neurologic examination is mandatory for patients with ANM. Treatment consists of eliminating the underlying cause; carbamazepine is effective in alleviating the symptoms of ANM. Neuroimaging should be performed if patients with ANM lack the typical history of radiation therapy, as ANM may be the presenting sign of an intracranial mass. PMID- 20924289 TI - CD4 intragenic SNPs associate with HIV-2 plasma viral load and CD4 count in a community-based study from Guinea-Bissau, West Africa. AB - OBJECTIVES: The human genetics of HIV-2 infection and disease progression is understudied. Therefore, we studied the effect of variation in 2 genes that encode products critical to HIV pathogenesis and disease progression: CD4 and CD209. DESIGN: This cross-sectional study consisted of 143 HIV-2, 30 HIV-1 + HIV 2 and 29 HIV-1-infected subjects and 194 uninfected controls recruited from rural Guinea-Bissau. METHODS: We genotyped 14 CD4 and 4 CD209 single nucleotide polymorphisms (SNPs) that were tested for association with HIV infection, HIV-2 plasma viral load (high vs. low), and CD4 T-cell count (high vs. low). RESULTS: The most significant association was between a CD4 haplotype rs11575097 rs10849523 and high viral load [odds ratio (OR): = 2.37, 95% confidence interval (CI): 1.35 to 4.19, P = 0.001, corrected for multiple testing], suggesting increased genetic susceptibility to HIV-2 disease progression for individuals carrying the high-risk haplotype. Significant associations were also observed at a CD4 SNP (rs2255301) with HIV-2 infection (OR: = 2.36, 95% CI: 1.19 to 4.65, P = 0.01) and any HIV infection (OR: = 2.50, 95% CI: 1.34 to 4.69, P = 0.004). CONCLUSIONS: Our results support a role of CD4 polymorphisms in HIV-2 infection, in agreement with recent data showing that CD4 gene variants increase risk to HIV 1 in Kenyan female sex workers. These findings indicate at least some commonality in HIV-1 and HIV-2 susceptibility. PMID- 20924292 TI - Exploring the role of 3-dimensional simulation in surgical training: feedback from a pilot study. AB - STUDY DESIGN: Randomized control study assessing the efficacy of a pedicle screw insertion simulator. OBJECTIVES: To evaluate the efficacy of an in-house developed 3-dimensional software simulation tool for teaching pedicle screw insertion, to gather feedback about the utility of the simulator, and to help identify the context and role such simulation has in surgical education. SUMMARY OF BACKGROUND DATA: Traditional instruction for pedicle screw insertion technique consists of didactic teaching and limited hands-on training on artificial or cadaveric models before guided supervision within the operating room. Three dimensional computer simulation can provide a valuable tool for practicing challenging surgical procedures; however, its potential lies in its effective integration into student learning. METHODS: Surgical residents were recruited from 2 sequential years of a spine surgery course. Patient and control groups both received standard training on pedicle screw insertion. The patient group received an additional 1-hour session of training on the simulator using a CT based 3-dimensional model of their assigned cadaver's spine. Qualitative feedback about the simulator was gathered from the trainees, fellows, and staff surgeons, and all pedicles screws physically inserted into the cadavers during the courses were evaluated through CT. RESULTS: A total of 185 thoracic and lumbar pedicle screws were inserted by 37 trainees. Eighty-two percent of the 28 trainees who responded to the questionnaire and all fellows and staff surgeons felt the simulator to be a beneficial educational tool. However, the 1-hour training session did not yield improved performance in screw placement. CONCLUSIONS: A 3 dimensional computer-based simulation for pedicle screw insertion was integrated into a cadaveric spine surgery instructional course. Overall, the tool was positively regarded by the trainees, fellows, and staff surgeons. However, the limited training with the simulator did not translate into widespread comfort with its operation or into improvement in physical screw placement. PMID- 20924291 TI - Moyamoya disease: a review of the disease and anesthetic management. AB - Moyamoya disease is a rare chronic cerebrovascular disease seen both in children and adults. It has a progressive course, but may have a variable clinical presentation. The disease causes ischemic stroke, intracranial hemorrhage, headache, seizures, and transient ischemia attack in children and in adults. Although the pathogenesis of the disease remains unknown, research suggests a genetic predisposition. There are also undefined systemic processes involved in this vasculopathy. Better noninvasive diagnostic techniques for diagnosis of the Moyamoya disease have been developed, but medical treatment can still be challenging. However, various surgical revascularization procedures have shown to provide symptomatic benefit in a majority of these patients. In addition, the anesthetic management of these patients has evolved over the years with an increased understanding of the disease. These have specifically resulted from the identification of risk factors for perioperative complications and outcomes related to the use of anesthetic agents. Finally, research in the last 3 decades has led to the recognition of the importance of pain control, the increased use of regional anesthesia, and better monitoring techniques in providing high quality and safe patient care to patients with Moyamoya disease. This article will provide a comprehensive review of the disease and its anesthetic management. PMID- 20924293 TI - A new 3-dimensional computed tomography imaging method to diagnose extraforaminal stenosis at the lumbosacral junction. AB - STUDY DESIGN: A prospective study using a newly developed imaging diagnosis method to examine the patients with L5 radiculopathy. OBJECTIVE: To confirm the efficacy of a new 3-dimensional computed tomography (3D CT) imaging method to diagnose extraforaminal stenosis at the lumbosacral junction. SUMMARY OF BACKGROUND DATA: The lack of recognition of extraforaminal stenosis at the lumbosacral junction is a cause of failed back surgery syndrome. A clear method to diagnose this condition is essential. METHODS: The participants were 75 consecutive patients (mean age 69.5 y) with or without cauda equina symptoms who were treated by microendoscopic spinal surgery for L5 radiculopathy. The lesion responsible for the symptoms was identified by a combination of neurologic findings, selective radiculography, (3D MRI), and intraoperative neurophysiological findings. Multislice CT scanning was carried out preoperatively from the L1 vertebral body to the sacrum in all patients. The CT scan images were transferred to a remote computer workstation, and the reconstructed images were examined after surgery by an investigator blinded to the clinical diagnoses. In the reconstructed plane, we measured the minimum cross sectional area of the de novo bony tunnel formed by the L5 transverse process, sacral ala, and L5 vertebral body, that is, lumbosacral bony tunnel (LSBT) and determined a cutoff value to diagnose extraforaminal stenosis. The shape of the LSBT was also evaluated in relation to the diagnosis. RESULTS: In 3D CT analysis, the LSBT was found on the ipsilateral side in 51 of the 75 patients. The bony tunnel was outside the foramen in all patients diagnosed clinically with extraforaminal stenosis, but in only 60% of the patients without extraforaminal stenosis. The minimum cross-sectional area of the bony tunnel was significantly smaller in patients with an extraforaminal stenosis than in those without extraforaminal stenosis. The cutoff value was set at 0.8 cm2. The cross-sectional area was <0.8 cm2 in all patients with extraforaminal stenosis. The specificity of this diagnostic procedure was 89.6%, and the sensitivity was 100%. All true positive cases had the spur-type shape of the bony tunnel, and all false-positive cases had the round-type shape. CONCLUSIONS: All patients with extraforaminal stenosis had an LSBT. The minimum cross-sectional area of the bony tunnel was significantly smaller in patients with an extraforaminal lesion than in those without an extraforaminal lesion. 3D CT is a useful tool for diagnosing extraforaminal stenosis at the lumbosacral junction. PMID- 20924294 TI - A prospective randomized trial comparing epidural morphine through intraoperatively placed epidural catheter and intravenous morphine in major lumbar spinal surgery. AB - STUDY DESIGN: A randomized, controlled trial. OBJECTIVE: To compare the efficacy of pain control and complications between patients utilizing continuous infusion epidural morphine versus intravenous morphine in posterior spinal surgery. SUMMARY OF BACKGROUND DATA: Recently, there has been increased interest in the use of epidural infusion analgesia for spinal surgery. By simply placing the tip of catheter at the level of operation before the wound closure, a continuous infusion of local anesthetics is directly delivered into the epidural space. Techniques used in the literature vary as per analgesic agents, number of catheters, and the infusion method. Few are the randomized control studies. METHODS: A total of 120 patients, who had posterior spinal operations, were randomly assigned to receive either continuous epidural infusion morphine, continuous epidural infusion morphine with Bupivacaine, or intravenous morphine as a postoperative analgesia. Visual analogue Pain scale (Pain VAS) was evaluated every 4 hours the first day, and at 36 and 48 hours postoperatively. Additional doses of intravenous Nalbuphine hydrochloride, complications, and the satisfaction score were recorded. RESULTS: Baseline characteristics of the 3 groups were similar. The mean Pain VAS in the epidural morphine group (groups 1 and 2) were less than that of group 3 at all times up to 48 hours postoperatively (P<0.05). Pain VAS for group 1 was more than that of group 2 at the 16- and 24 hour marks (P<0.05). Pruritus was a common complication in the epidural morphine group. There was no respiratory depression in this study. Patients in groups 1 and 2 had a high proportion of excellent and very good satisfaction (70% to 80%). CONCLUSION: Epidural infusion analgesia is safe and effective for posterior spinal surgery. PMID- 20924295 TI - Surgical strategy for multilevel severe ossification of posterior longitudinal ligament in the cervical spine. AB - STUDY DESIGN: A retrospective clinical study was conducted. OBJECTIVE: To compare surgical outcome of anterior approach (corpectomy and fusion) with that of posterior approach (laminoplasty or laminectomy and instrumented fusion) for the treatment of multilevel severe ossification of the posterior longitudinal ligament (OPLL) in the cervical spine, and simultaneously to investigate the potential benefits of instrumented fusion after laminectomy by comparing it with laminoplasty. SUMMARY OF BACKGROUND DATA: Surgical strategy for multilevel severe OPLL in the cervical spine still remains controversial. Although the advantages of anterior decompression and fusion have been reported earlier, it becomes more technically demanding and risky with the increasing narrowing rate and extent of ossification. Laminoplasty has been used to relieve cord decompression posteriorly, but results are not always good. It also has potential risks of ossification progression and kyphotic deformity after operation. METHODS: A total of 75 cervical patients with multilevel severe OPLL were included in this study. Twenty-two patients underwent anterior corpectomy and fusion. Among the patients undergoing posterior approach, laminectomy and instrumented fusion was performed on 28 patients and laminoplasty on 25 patients. The radiologic findings including plain radiographs, computed tomography scan, and magnetic resonance images were reviewed, and surgical outcome was assessed using the Japanese Orthopedic Association scoring system. The radiologic and clinical data were compared between 3 groups of different surgical processes. RESULTS: Radiologic studies showed preoperative cervical lordosis, occupying rate and extent of OPLL were comparable between 3 groups in this study, but the postoperative cervical lordosis after anterior corpectomy or laminectomy and instrumented fusion was significantly larger than that of after laminoplasty. Postoperative Japanese Orthopedic Association score and improvement rate of neurologic function after anterior corpectomy were significantly higher than those after laminoplasty, and the results after laminectomy and instrumented fusion were in the middle of results of above 2 processes. The main complication after anterior decompression was cerebrospinal fluid leakage, whereas posterior approach was complicated with a high incidence of C5 palsy and axial pain. CONCLUSIONS: Anterior corpectomy and fusion was significantly more effective for multilevel severe OPLL when compared with posterior laminoplasty in the cervical spine. If having technical difficulties and posterior decompression was alternatively performed, instrumented fusion was recommended to help to restore cervical lordosis and produce better results according to this study. PMID- 20924296 TI - Risk factor analysis for motor deficit and delayed recovery associated with L4/5 lumbar disc herniation. AB - STUDY DESIGN: Retrospective study of multivariable analysis for the risk factors of motor deficit associated with lumbar disc herniation (LDH). OBJECTIVES: To identify the risk factors for motor deficit and delayed recovery after surgery in patients with LDH. SUMMARY OF BACKGROUND DATA: LDH can cause motor deficit as well as pain and sensory disturbance. Even though motor deficit can lead to disabilities and affect treatment plans, few studies have described motor deficit and its risk factors in LDH patients. METHODS: Seventy-six consecutive patients who underwent microsurgical or microendoscopic discectomy for LDH at the L4/5 level were retrospectively reviewed. Motor deficit was defined as tibialis anterior muscle strength of lower than grade 4 by the manual muscle test, and delayed recovery was defined as cases requiring longer than 3 months to achieve complete recovery. The possible risk factors including sex, age, symptom duration, preoperative radiographic parameters, and type of herniation were evaluated by multivariate logistic regression analysis. RESULTS: Forty-three patients (56.6%) suffered from motor deficit before surgery. Forty cases (93%) completely recovered within a mean duration of 4 months. Multivariate logistic regression analysis revealed that noncontained-type (P=0.012, odds ratio=13.7) and migrated herniated nucleus pulposus (P=0.033, odds ratio=9.8) were important risk factors for motor deficit. Furthermore, severe motor deficit (preoperative manual muscle test<=3; P=0.019, odds ratio=19.6) and noncontained type (P=0.049, odds ratio=5.17) were identified as important risk factors for delayed recovery. CONCLUSIONS: Noncontained-type or migrated herniated nucleus pulposus seem to be the most important risk factors for motor deficit in LDH, whereas severe motor deficit and noncontained type seem to be associated with delayed recovery. The treatment options for patients with these factors at first visit should be carefully chosen during the follow-up period. PMID- 20924297 TI - Isolated pedicle screw instrumented correction for the treatment of thoracic congenital scoliosis. AB - STUDY DESIGN: Retrospective study. OBJECTIVE: To evaluate the radiologic results of fusion with segmental pedicle screw fixation in neglected thoracic congenital curves with a mean follow-up of 51.3 months (range: 24 to 108 mo). SUMMARY OF BACKGROUND DATA: Segmental pedicle screw fixation has been shown to be effective both in correcting and controlling the idiopathic spinal deformities. However, the choice of treatment modality is more controversial in neglected thoracic congenital curves of the aged. METHODS: Fourteen patients with thoracic congenital curves treated by segmental pedicle screw fixation and fusion were analyzed. The average age of the patients was 14.9 years (range: 10 to 25 y) at surgery. Deformity correction was achieved by compression of the convex deformity side with resection of apical 3 ribs. Radiologic analyses of coronal and sagittal plane included Cobb angles of the major compensatory curves, apical vertebrae translation, and sagittal Cobb angles, respectively. RESULTS: In the coronal plane, the preoperative mean major curve Cobb angle of 52.3 degree (range: 32.6 to 66.7 degrees) was corrected to 25.3 degree (range: 7.2 to 44.8 degree) and the mean compensatory curve Cobb angle of 23.6 degree (range: 10.3 to 34.8 degrees) was corrected to 15.9 degree (range: 5.7 to 30.6 degrees). The mean translation of apical vertebrae was 28.8 mm (range: 4.7 to 53.6 mm) before surgery and 15.5 mm (range: 2.4 to 41.3 mm) after surgery. In the sagittal plane, the mean preoperative and postoperative sagittal T5 to T12 angles were 34.8 degree (range: 16.5 to 44.7 degrees) and 27.3 degree (range: 10.4 to 43.5 degrees), respectively. The mean preoperative and postoperative sagittal T12 to S1 angles were 47.2 degree (range: 23.4 to 65.1 degrees) and 41.3 degree (range: 23.8 to 62.7 degrees), respectively. CONCLUSION: In the neglected thoracic congenital deformities of the aged, with posterior pedicle instrumented fusion, an acceptable correction can be achieved with relatively low morbidity. PMID- 20924298 TI - Bone invasion by adenoid cystic carcinoma of the lacrimal gland: preoperative imaging assessment and surgical considerations. AB - PURPOSE: To identify the incidence of radiologically and histologically documented bony invasion of the lacrimal gland fossa by adenoid cystic carcinoma. PATIENTS AND METHODS: The authors reviewed the records of all 18 patients with lacrimal gland adenoid cystic carcinoma surgically treated at their institution from 1997 to 2009 for imaging findings (blinded review) and histologic findings on evaluation of the lacrimal gland fossa. Preoperative CT and/or MRI findings were available for 17 patients. RESULTS: The 8 men and 10 women ranged in age from 9 to 69 years. American Joint Committee on Cancer tumor stages after preoperative imaging were as follows: T1N0M0, 2 patients; T2N0M0, 5 patients; T3aN0M0, 2 patients; T3bN0M0, 5 patients; T3bN0M1, 2 patients; T4bN0M0, one patient; and TxN0M0, one patient. Preoperative imaging suggested bony involvement of the lacrimal gland fossa in 13 patients (76.5%); this was histologically confirmed in 11 of the 13. Preoperative imaging suggested no bone involvement in 4 patients, 3 of whom had bone involvement by histology. Overall, 14 of 17 histologically evaluable cases (82.3%) had invasion of the lacrimal gland fossa. Histologic findings of bone/periosteal involvement led to upstaging of 3 tumors. Metastases developed in 8 of 18 patients and trended with basaloid histology (p = 0.066). CONCLUSIONS: Adenoid cystic carcinoma of the lacrimal gland is associated with bone invasion in essentially all but the smallest of tumors (T1). This high rate of bone involvement may warrant addressing the bony walls during surgery for adenoid cystic carcinoma of the lacrimal gland. PMID- 20924299 TI - Barbed suture suspension technique for prevention of lower eyelid ectropion after Mohs micrographic surgery. AB - Mohs micrographic surgery of the lower eyelid poses a risk of ectropion. Even though the lower eyelid is a very frequent location for basal cell carcinoma, prevention techniques for ectropion after Mohs micrographic surgery have rarely been introduced. After Mohs micrographic surgery of the lower eyelid, the authors applied a barbed suture suspension technique for the prevention of lower eyelid ectropion. Following primary wound closure, barbed sutures were prepared by cutting one side of a 4-0 Prolene suture and applied around the lower eyelid. Sutures were maintained for 7 days and then removed. Evaluation 10 weeks after surgery found that ectropion had been minimized or prevented entirely. PMID- 20924300 TI - Mucoepidermoid carcinoma of the lacrimal sac after dacryocystectomy for squamous papilloma. AB - A mass that recurred after dacryocystectomy for benign squamous papilloma of the lacrimal sac was diagnosed as a high-grade mucoepidermoid carcinoma in a 53-year old man on histopathology. Local excision to the orbital periosteum was performed and gave a margin free of invasion. Neither local recurrence nor systemic metastasis was found 3 years after local excision. Mucoepidermoid carcinoma of the lacrimal sac is extremely rare and spreads locally in an aggressive manner; a cure typically requires exenteration, radical resection, or adjuvant radiotherapy. In this rare case, despite the high malignancy, the patient underwent successful local excision, achieved an aesthetically satisfying result, and has had a long-term cancer-free period. PMID- 20924301 TI - Aneurysmal bone cyst secondary to ossifying fibroma in the orbit. AB - A 28-year-old man presented with proptosis and medial displacement of the right eye, intermittent pain, and diplopia of 1 month's duration. Radiologic examination demonstrated a mass in the right lateral orbit resembling an aneurysmal bone cyst (ABC). Histopathologic evaluation of the surgically excised lesion via orbitotomy confirmed the radiologic diagnosis. Two months later, the patient presented again with a mass at the same location as the previous one, with a major component that was solid. The recurrent lesion was excised via frontal craniotomy. Histopathologic examination of the surgical specimen led to a diagnosis of ABC secondary to trabecular ossifying fibroma. During the follow up of 13 months, the lesion did not recur. To the best of the authors' knowledge, this is the first case of ABC secondary to ossifying fibroma in the orbit. ABC can dominate the radiologic appearance of the lesion and veil the primary neoplasm. PMID- 20924302 TI - Osseous metaplasia with formation of hematopoietic bone marrow in a blind, painful eye. AB - A 31-year-old woman underwent an evisceration of her blind, painful right eye with placement of an aluminum oxide orbital implant. Histopathologic assessment revealed functional hematopoietic bone marrow, confirmed by immunohistochemistry, within osseous metaplasia of the retinal pigment epithelium. This finding is exceedingly rare, with few cases reported in the English literature. This report raises numerous questions, including the association between pain and hematopoietic bone marrow formation, the potential benefits of hematopoietic bone marrow in the eye, and the molecular biologic basis for this rare phenomenon. PMID- 20924303 TI - Muller's muscle tendon: microscopic anatomy in Asians. AB - PURPOSE: To describe the anatomic characteristics of Muller's muscle tendon. MATERIALS AND METHODS: Twelve postmortem, buffered formalin (10%)-fixed eyelids (6 right, 6 left) of 10 Asians (aged 62 to 92 years at death; mean age: 77.1 years) were used. Full-thickness sagittal sections of the upper eyelid specimens were dehydrated and embedded in paraffin and cut in 7-MUm-thickness sagittal sections. Sliced sections were stained with elastica van Gieson. The concentration of the elastic fibers in Muller's muscle tendon was analyzed and compared with the concentration in the levator aponeurosis. Fat deposition and the dimensions of Muller's muscle tendon were also analyzed. RESULTS: Both Muller's muscle tendon and the levator aponeurosis contained elastic fibers, which were more abundant in Muller's muscle tendon. Fat deposition in Muller's muscle tendon was demonstrated only in one specimen from an 84-year-old male. The average length of Muller's muscle tendon was 2.56 mm (range: 1.40-5.64 mm), and the average thickness of the tendon was 0.27 mm (range: 0.08-0.88 mm). There was no correlation between cadaver age and muscle length or thickness. CONCLUSIONS: Muller's muscle tendon is rich in elastic fibers with minimal age-related fat deposition. PMID- 20924304 TI - Patient experience with blepharoplasty. AB - PURPOSE: To prospectively study patients' postoperative experience with blepharoplasty and to determine how closely patients' expectations compare with their actual experience. METHODS: A prospective observational study of 51 consecutive patients undergoing bilateral upper eyelid blepharoplasty by a single surgeon (J.A.L.) between October 2008 and May 2009 was performed. Prior to surgery, patients were asked to rate, on a scale of 1 to 10, their expectations of pain, swelling, bruising, blurred vision, impairment of ability to function in daily activities, and itching. Patients were then asked to rate these 6 elements at 7 time points: 30 minutes, 4 hours, 24 hours, 2 days, 3 days, 1 week, and 2 months. The number of pain pills utilized was also assessed. An analysis of the data was performed to determine our patients' experience with blepharoplasty surgery. The paired t test was used to determine the statistical significance of patients' expectations compared with their actual reported experience. RESULTS: In this cohort of patients, the authors found the following: blurred vision and impairment in ability to function peaked in the immediate postoperative period, pain peaked at 4 hours, swelling and bruising peaked at 24 hours, and itching peaked at 3 days. The mean number of narcotic pain pills used by patients in the postoperative period was 2.45. Patients underestimated the degree of swelling, blurred vision, and impairment in ability to function experienced following surgery. CONCLUSIONS: Postoperative patient experience with blepharoplasty is based largely on anecdotal evidence; the data from this study will facilitate more objectively based preoperative counseling. PMID- 20924305 TI - Reply re: "Sinus opacification associated with exacerbation of thyroid eye disease". PMID- 20924306 TI - Atypical presentation of a periocular neurofibroma. AB - Neurofibromas of the eyelid are a well-recognized manifestation of neurofibromatosis. Several different presentations have been described. The authors present a case of a 52-year-old man with an unusual eyelid neurofibroma that presented as sudden vision loss from obstruction secondary to prolapse of the palpebral conjunctiva. PMID- 20924308 TI - Simultaneous upper and lower eyelid reconstruction using a first web space free flap. AB - The authors present a case of near-total upper and lower eyelid defects treated with a first web space free flap after a chemical burn injury. A first web space free flap was raised from the ipsilateral foot and transferred to the defect with its base turned toward the medial canthal area. The first dorsal metatarsal artery and veins were anastomosed to the superficial temporal artery and veins, respectively. The inner layer of the flap was sutured to the advanced upper and lower palpebral conjunctival flap from conjunctival cul-de-sacs, and the outer layer of the flap was sutured to the defected skin. Flap-debulking procedures were carried out 3 times after the microsurgical procedure. Postoperative aesthetic results were good, except for minor problems that included focal symblepharon and sebum formation. The described method could be used as an alternative for total eyelid reconstruction, especially in patients without available local facial tissue because of burns or trauma. PMID- 20924309 TI - Clinicopathological features and prognosis of mucinous cystic neoplasm with ovarian-type stroma: a multi-institutional study of the Japan pancreas society. AB - OBJECTIVE: The aim of this study was to elucidate the clinicopathological features and prognosis of mucinous cystic neoplasms (MCNs). MATERIALS AND METHODS: We performed a multi-institutional, retrospective study on a collected series of patients with MCN pathologically defined by ovarian-type stroma. Clinicopathological features and prognosis were investigated. RESULT: Mucinous cystic neoplasm was confirmed in 156 cases, including 129 adenomas (82.7%) and 21 noninvasive (13.4%) and 6 invasive carcinomas (3.9%). Patients with MCN were exclusively women (98.1%) with the mean age of 48.1 years. All but 1 MCN were in the pancreatic body/tail region with a mean size of 65.3 mm. Communication between the cyst and the pancreatic duct was found in 18.1%. The 3-, 5-, and 10 year survival rates were 97.6%, 96.6%, and 96.6%, respectively. A significant difference in the survival rates was observed between adenomas and carcinomas and between minimally invasive carcinomas and invasive carcinomas. Cyst diameter and presence of mural nodule were predictive of malignant MCN. CONCLUSIONS: Mucinous cystic neoplasm is a rare but distinctive pancreatic cystic neoplasm with a favorable overall prognosis. All MCNs should be resected to prevent malignant changes but can be observed for an appropriate time when the lesion is small without the presence of mural nodules. PMID- 20924310 TI - Standardized peptidome profiling of human serum for the detection of pancreatic cancer. AB - OBJECTIVE: To establish new biomarkers for accurate diagnosis of pancreatic cancer (PC) using a standardized serum peptidome profiling and compare the results with those from the tumor marker, CA 19-9. METHODS: Serum samples from 102 patients (55 with chronic pancreatitis and 47 with PC) and 56 healthy controls were collected and analyzed following a protocol that was rigorously designed to prevent preanalytical variation. Serum peptides were extracted using immobilized copper ion chromatography on a robotic platform. Mass spectra were acquired by matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry on an Autoflex II spectrometer (Bruker Daltonics, Bremen, Germany). Statistical analysis was performed using the Clinprotools 2.2 software (Bruker Daltonics) and the SPSS 15.0 software (SPSS Inc, Chicago, Ill). RESULTS: Standardized peptidome profiling showed a median coefficient of variation of 11.6% calculated using all the extracted peptides and negligible influence of sex and age on peptidome profiles. The diagnostic sensitivity was 89.9%, and the diagnostic specificity was 92.7%, using 2 serum features and CA 19-9 serum concentration. Healthy controls were differentiated from patients with PC and chronic pancreatitis, with the use of 3 features of the peptidome (diagnostic sensitivity, 98.2%; diagnostic specificity, 97.1%). CONCLUSIONS: Standardized serum peptidome profiling could be a useful tool to improve biochemical diagnosis of PC in combination with the classic tumor marker, CA 19-9. PMID- 20924311 TI - Lessons learned from a measles outbreak in Antwerp, Belgium 2007-2008. AB - A 2007 to 2008 measles outbreak in Antwerp, Belgium, identified the orthodox Jewish communities as a new risk group. This study analyzes vaccination data of 949 school children of 4 belief systems to assess the completeness and timeliness of their measles-mumps-rubella vaccination. Orthodox Jewish children show a 4 fold lower chance of complete vaccination, a delayed start, and increased temporal spacing of childhood vaccinations. Not only belief issues but difficulties to access the regular vaccination program also seem to be the main reason. PMID- 20924312 TI - Nijmegen breakage syndrome complicated with primary cutaneous tuberculosis. AB - Nijmegen breakage syndrome (NBS) is a rare autosomal recessive chromosomal instability syndrome characterized by severe immunodeficiency, growth retardation, microcephaly, a distinct facial appearance, and a high predisposition to lymphoid malignancy. We report a 7-year-old white girl with NBS associated with cutaneous tuberculosis. The patient presented with multiple red brown, centrally scaring plaques on the leg and had neither pulmonary nor systemic manifestation of tuberculosis. Polymerase chain reaction testing using Mycobacterium genus- and Mycobacterium tuberculosis species-specific primers confirmed the clinical diagnosis of cutaneous tuberculosis. This is the first report describing the simultaneous presentation of NBS and cutaneous tuberculosis. PMID- 20924313 TI - Effects of synchronization during nasal ventilation in clinically stable preterm infants. AB - Nasal ventilation is increasingly used to reduce invasive ventilation in preterm infants. The effects of nasal ventilation and the advantages of synchronized nasal ventilation have not been fully evaluated. The objective was to compare the short-term effects of nasal intermittent mandatory ventilation (NIMV) and synchronized NIMV (S-NIMV) with nasal continuous positive airway pressure (NCPAP) on ventilation, gas exchange, and infant-ventilator interaction. Sixteen clinically stable preterm infants requiring NCPAP (GA, 27.6 +/- 2.3 wk; birthweight (BW), 993 +/- 248 g; and age, 15 +/- 14 d) were exposed to NCPAP, NIMV at 20/min, NIMV at 40/min, S-NIMV at 20/min, and S-NIMV at 40/min for 1 h each (Infant-Star ventilator), in random order. Tidal volume, minute ventilation, and gas exchange did not differ significantly between NCPAP, NIMV, and S-NIMV. Inspiratory effort decreased during S-NIMV compared with NCPAP and NIMV, whereas inspiratory effort during NIMV did not differ from NCPAP. Active expiratory effort and expiratory duration increased during NIMV. Chest wall distortion, apnea and hypoxemia spells, abdominal girth, and comfort did not differ. In conclusion, there were no short-term benefits on ventilation and gas exchange of nasal ventilation compared with NCPAP in clinically stable preterm infants. However, synchronized nasal ventilation reduced breathing effort and resulted in better infant-ventilator interaction than nonsynchronized nasal ventilation. PMID- 20924314 TI - Polar Effects on Ion Transport and Cell Proliferation Induced by GC-C Ligands in Intestinal Epithelial Cells. AB - Guanylin receptor guanylate cyclase (GC-C) peaks in neonatal intestine and is involved in either enterocyte proliferation or chloride secretion. The latter is more potent when GC-C activator guanylin, or its analog Escherichia coli heat stable enterotoxin (ST), is added to the mucosal rather than serosal side of intestinal monolayers. By using Ussing chambers, we investigated transepithelial ion transport and enterocyte proliferation and their mechanisms in response to the addition of guanylin or ST to the mucosal or serosal side of Caco-2 monolayers and in ileal specimens from neonates. GC-C activation showed a polar pattern of the effects. GC-C mucosal activation resulted in a potent cGMP chloride secretion activation and in a marginal enterocyte proliferation. Conversely, serosal GC-C activation induced a potent enterocyte proliferation, through MAP kinase ERK 1/2. Finally, the inhibition of ERK1/2 enhanced the Isc increase in response to serosal but not to mucosal ST stimulation, indicating that ERK1/2 also acts as a brake of chloride secretion. These data suggest that the guanylin/GC-C system plays a key role in early postnatal intestinal adaptation exploiting the polar structure of enterocyte. PMID- 20924316 TI - The cerebellar development in chinese children-a study by voxel-based volume measurement of reconstructed 3D MRI scan. AB - Cerebellar disorder was frequently reported to have relation with structural brain volume alteration and/or morphology change. In dealing with such clinical situations, we need a convenient and noninvasive imaging tool to provide clinicians with a means of tracing developmental changes in the cerebellum. Herein, we present a new daily practice method for cerebellum imaging that uses a work station and a software program to process reconstructed 3D neuroimages after MRI scanning. In a 3-y period, 3D neuroimages reconstructed from MRI scans of 50 children aged 0.2-12.7 y were taken. The resulting images were then statistically analyzed against a growth curve. We observed a remarkable increase in the size of the cerebellum in the first 2 y of life. Furthermore, the unmyelinated cerebellum grew mainly between birth and 2 y of age in the postnatal stage. In contrast, the postnatal development of the brain mainly depended on the growth of myelinated cerebellum from birth through adolescence. This study presents basic data from a study of ethnic Chinese children's cerebellums using reconstructed 3D brain images. Based on the technique we introduce here, clinicians can evaluate the growth of the brain. PMID- 20924315 TI - Potential neuronal repair in cerebral white matter injury in the human neonate. AB - Periventricular leukomalacia (PVL) in the premature infant represents the major substrate underlying cognitive deficits and cerebral palsy and is characterized as focal periventricular necrosis and diffuse gliosis in the immature cerebral white matter. We have recently shown a significant decrease in the density of neurons in PVL relative to controls throughout the white matter, including the subventricular, periventricular, and subcortical regions. These neurons are likely to be remnants of the subplate and/or GABAergic neurons in late migration to the cerebral cortex, both of which are important for proper cortical circuitry in development and throughout adulthood. Here, we tested the hypothesis that intrinsic repair occurs in PVL to attempt to compensate for the deficits in white matter neurons. By using doublecortin (DCX) immunopositivity as a marker of postmitotic migrating neurons, we found significantly increased densities (p < 0.05) of DCX-immunopositive cells in PVL cases (n = 9) compared with controls (n = 7) in the subventricular zone (their presumed site of origin), necrotic foci, and subcortical white matter in the perinatal time-window, i.e. 35-42 postconceptional weeks. These data provide the first evidence suggestive of an attempt at neuronal repair or regeneration in human neonatal white matter injury. PMID- 20924317 TI - Preterm birth and necrotizing enterocolitis alter gut colonization in pigs. AB - Necrotizing enterocolitis (NEC) in preterm neonates is dependent on bacterial colonization, but it remains unclear whether a particular microbiota or specific pathogens are involved. We hypothesized that gut colonization differs between preterm and term neonates and that overgrowth of Clostridium perfringens predisposes to NEC. By using terminal-RFLP and FISH, we characterized the gut microbiota of preterm, caesarean-delivered, formula-fed pigs (n = 44) with or without NEC and of formula- or colostrum-fed term, and vaginally born pigs (n = 13). A different microbiota with high C. perfringens abundance was observed in preterm pigs with NEC compared with healthy individuals. However, immunization against C. perfringens toxins did not prevent NEC, and C. perfringens inoculation (3.6 * 10 cfu/d) failed to induce NEC (n = 16), whereas prophylactic broad spectrum antibiotics treatment prevented NEC (n = 24). Colonization in both groups of term pigs differed from preterm pigs and was dominated by Lactobacilli spp. In conclusion, gestational age (GA) and NEC influence neonatal gut colonization, whereas diet has minor effects. C. perfringens is more abundant in pigs with NEC but rather as a consequence than a cause of disease. The general bacterial load and underdeveloped gut immune responses in preterm neonates seem more important for NEC development than specific pathogens. PMID- 20924318 TI - Biomarkers of neutrophil-mediated glutathione and protein oxidation in tracheal aspirates from preterm infants: association with bacterial infection. AB - Bronchopulmonary dysplasia is associated with neutrophil infiltration into the lungs and oxidative injury. However, the pathological importance of neutrophil oxidants is still not clear. Nosocomial pneumonia is also implicated, but the evidence is limited, in part because of the difficulty of distinguishing genuine infection from bacterial colonization. Good biomarkers of neutrophil oxidant activity and lung infection are needed. We tested whether glutathione sulfonamide, a product of glutathione oxidation by myeloperoxidase-derived hypochlorous acid (HOCl) and a potential new neutrophil oxidant biomarker, is detectable in endotracheal aspirates from ventilated preterm infants. As infectious organisms stimulate neutrophils to generate HOCl, we determined whether levels of HOCl-specific biomarkers were increased in samples that were bacterial culture positive. Glutathione sulfonamide was detected in 66 of 87 endotracheal aspirate samples. Levels correlated with myeloperoxidase activity and another HOCl-specific marker, chlorotyrosine. Median levels of glutathione sulfonamide (4-fold) and other biomarkers (2-fold) were significantly higher in culture positive aspirates. Staphylococcus epidermidis, a frequent colonizer, was associated with glutathione sulfonamide levels no different from those in negative samples. Glutathione sulfonamide showed good sensitivity and specificity for detecting bacterial growth and has promise for detecting lung infection. PMID- 20924319 TI - Trauma mechanisms, patterns of injury, and outcomes in a retrospective study of 71 burns from civil gas explosions. AB - BACKGROUND: Although explosion injuries caused by terror attacks or in war are evaluated in many studies, limited information about civil explosion injuries can be found in the literature. METHODS: In a retrospective study of 71 civil gas explosion injuries treated in a single burn center during a 16-year period, we evaluated trauma mechanisms, patterns of injury, and clinical outcome. RESULTS: More than 50% of all gas explosions injuries occurred in private households. The mortality correlated significantly with higher burned total body surface area (TBSA), higher abbreviated burn severity index (ABSI) score, accompanying inhalation injuries, and lung contusions. Although mean ABSI score and burned TBSA were similar in men and women (6 vs. 7 and 22% vs. 21%), the female mortality from gas explosions was noticeably higher, albeit not statistically significant due to small patient numbers (32% vs. 17%). Although mean burned TBSA, ABSI scores, and intensive care unit lengths of stay in patients with burns from gas explosions were comparable and not significantly different compared with all burn patients treated in our burn center (TBSA: 22% vs. 17%; ABSI: 6 vs. 6; and intensive care unit lengths of stay: 12 vs. 11 days), the mortality from gas explosions was significantly higher (21% vs. 12%, p = 0.04). CONCLUSIONS: The mortality from gas explosion-related burns correlated significantly with burned TBSA, ABSI score, accompanying inhalation injuries, and lung contusions. Despite comparable ABSI scores, the mortality from gas explosion-related burns was significantly higher than the mortality for all burn victims. PMID- 20924321 TI - The mystery of aortic dissection: a 250-year evolution. PMID- 20924322 TI - Recent advances in the management of thoracic dissection. PMID- 20924320 TI - The roles of phytochemicals in bronchial asthma. AB - Despite gaps in our knowledge of how phytochemicals interfere with cellular functions, several natural plant products are utilized to prevent or treat a wide range of diseases. Identification of an agent with therapeutic potential requires multiple steps involving in vitro studies, efficacy and toxicity studies in animal models, and then human clinical trials. This review provides a brief introduction on natural products that may help to treat and/or prevent bronchial asthma and describes our current understanding of their molecular mechanisms based on various in vitro, in vivo, and clinical studies. We focus on the anti inflammatory and anti-vascular actions of the plant products and other roles beyond the anti-oxidative effects. PMID- 20924323 TI - Outcome of patients with open and endovascular repair in acute complicated type B aortic dissection: a systematic review and meta-analysis of case series and comparative studies. AB - AIM: Acute complicated type B aortic dissection is a life-threatening condition. We summarized all published studies for TEVAR among patients with acute complicated typ B aortic dissection (TBAD) with respect to clinical success, complications, and outcomes. Furthermore, we determined whether TEVAR reduces death and morbidity compared with open repair for TBAD. METHODS: Studies were identified from a literature search using various databases, and included studies when three or more patients were reported and at least in-hospital mortality was reported. Data from comparative studies of TEVAR versus open repair of the descending aorta in TBAD were combined through meta-analysis. RESULTS: Seventy six observational studies involving 1951 patients were included in the present meta-analysis. In-hospital mortality was 11.5% and other major complications (i.e., stroke (6.3%), paraplegia (4.9%), retrograde type A aortic dissection (7%), renal impairment including dialysis (6.9%), bowel infarction (4.1%), vascular problems including major amputation (2.5%)) occurred less frequently. Long-term follow-up was limited to a mean of 24 months. During this time, endovascular reintervention was required in 11.3%, surgical reintervention in 7.7%, and late aortic rupture was calculated for 3.2% of cases. A complete false lumen thrombosis was estimated to occur in 76.1% of cases. In comparative studies, 30-day/in-hospital mortality (OR=0.256, P=0.001) and paraplegia/paraparesis (OR=0.256, P=0.001) were significantly reduced for TEVAR versus open repair. In addition to that, the rate of vascular complications was reduced for TEVAR (OR=0.373, P=0.036). There was no significant difference between TEVAR and open repair in patients with acute complicated TBAD for the following outcomes: late mortality, reintervention rate, renal dysfunction (including dialysis), and stroke rate. CONCLUSION: This summary analysis suggests that endovascular treatment of complicated acute type B aortic dissection produces favourable initial outcomes and would seem to be a great addition to the treatment options for this condition. Further study of long-term outcomes is required. PMID- 20924324 TI - DeBakey type I dissection: when hybrid stent-grafting is indicated? AB - AIM: For avoidance of late downstream complications after classic DeBakey type I aortic dissection repair, replacement of the arch with simultaneous antegrade descending stent-grafting using a hybrid prosthesis was applied in acute and chronic aortic dissection. Indication and results were studied. METHODS: Between January 2001 and January 2010, 168 patients were operated for acute and chronic aortic dissection (AD). Forty-five patients received an E-vita open stent-graft prosthesis, 29 for acute aortic dissection (AAD) (28 for DeBakey type I, 1 for type III) and 16 for chronic aortic dissection (CAD) (13 type I, 3 type III). Indication was full circular arch dissection, an entry or re-entry tear distal to the left subclavian artery in AAD, and new abdominal malperfusion, rapid growth of the false lumen (FL), impending or contained rupture in CAD. RESULTS: Hospital mortality was 10% in AAD and 0 in CAD. Complications like new stroke occurred in 7% versus 6%, temporary dialysis in 55% versus 19%, and false lumen obliteration was observed in 93% versus 63% in AAD versus CAD, respectively. Follow-up was 100% at a mean of 19 months. Overall survival at four years was 72% in AAD versus 94% in CAD. FL thrombosis was stable in AAD (92%) and increased to 93% in CAD over time. Freedom from secondary aortic intervention was 90% in AAD and 75% in CAD. CONCLUSION: This hybrid approach in patients with AAD and CAD type I is safe when indicated and renders stable results over time down to the stent-graft end. Secondary TEVAR can be easily performed downstream when necessary. The international E-vita open registry data supports this single center results. PMID- 20924325 TI - Acute aortic dissection: natural history and classification. AB - Acute aortic dissection is an uncommon but potentially catastrophic pathology with high mortality and morbidity. Significant advances in the understanding, diagnosis and management of aortic dissection have been made since the first case was reported 3 centuries ago. This article aims to review our current understanding of the natural history and classification of acute aortic dissection. PMID- 20924326 TI - Arterial elastic fiber structure. Function and potential roles in acute aortic dissection. AB - The lethality of acute aortic dissection is well recognized. Successful treatment and prevention of aortic dissection is going to be dependent upon an improved understanding of the molecular and physiologic events which predispose to dissection development and propagation. In this review, we will focus on the elastic fiber, one of the critical elements of the aortic wall matrix. Mechanical or functional failure of the elastin in the wall of the aorta likely predisposes to dissection as well as the post-dissection aortic degeneration with aneurysm formation. Insight into the role of the elastin and the elastic fiber in aortic dissection has recently been accelerated by research into the molecular mechanisms associated with hereditary propensity for aortic dissection, such as Marfan syndrome. These studies have implicated both structural and metabolic contributions of alterations in the scaffolding proteins in matrix elastic fibers. In particular, increased transforming growth factor-beta (TGF-beta) activity may play a prominent role in predisposing the aortic wall to dissection. The events which predispose to post-dissection aortic degeneration are somewhat less well defined. However, the loss of the structural integrity of the remaining elastic fibers leaves the wall weaker and prone to dilatation and rupture. It appears likely that the upregulation of several potent proteases, particularly those of the matrix metalloproteinase (MMP) family such as MMP-9, are participating in the subsequent matrix damage. Novel medical treatments based on this pathologic data have been proposed and in some cases have made it to clinical trials. The ongoing study evaluating whether therapeutic inhibition of TGF-beta may be useful in reducing the risk of aortic dissection in patients at high risk represents one promising new strategy in the treatment of this deadly disease. PMID- 20924327 TI - Decision-making in type-B dissection: current evidence and future perspectives. AB - Aortic dissection is a devastating cardiovascular condition with an incidence of 3,5:100 000. It is classified according to anatomic extent, mechanism of lesion, duration from index event and course (uncomplicated vs. complicated). Intramural hematoma and penetrating aortic ulcers share many of the features of classic dissections, but tend to occur in older patients with advanced atherosclerosis. In uncomplicated type-B dissection, conservative treatment with tight blood pressure and heart rate control is safe and effective. Early stent-graft implantation may, however, result in more favorable aortic remodeling and reduced late complications. For acute complicated cases intervention is usually required. Stent-graft coverage of the entry tear frequently resolves malperfusion, but the role of the false lumen in organ perfusion must be assessed and endovascular revascularization performed if necessary. In chronic type-B dissections, coverage of the entry tear likely results in continued pressurization of the false lumen due to rigidity of the dissecting membrane and distal fenestrations. Better understanding of the different disease mechanisms involved, imaging advances and introduction of dedicated stent-grafts are expected to further improve patient outcomes in the future. Primary and secondary pharmacological prevention, stricter follow-up protocols and screening of family members may also prove valuable. Better patient selection will allow preventive treatment with low morbidity for those at higher risk of complications. PMID- 20924328 TI - Aortic dissection and sport: physiologic and clinical understanding provide an opportunity to save young lives. AB - Understanding the relationship between acute type A aortic dissection and sport is crucial to prevent sudden cardiac death in seemingly healthy young individuals. Aerobic exercise produces only a modest rise in arterial blood pressure (140-160 mmHg) except at the highest levels of exertion, at which pressures between 180-220 mmHg are reached. Weight training, on the other hand, routinely produces acute rises in blood pressure to over 300 mmHg. This presents a danger for individuals with an unknown aortic aneurysm; the deteriorated mechanical properties of the aortic wall resulting from aneurysmal enlargement increase the susceptibility to aortic rupture when the high wall coincident with exertion exceeds the tensile strength of the aortic wall. Investigations by our group into the inciting events leading up to dissection have demonstrated a causal link between extreme exertion, severe emotional stress, and acute type A aortic dissection. Since aortic enlargement is often unknown to persons participating in weight training, especially in the youth population, a iSnapShot Echocardiogrami screening program is been proposed; such a pilot program will raise awareness of the importance of pre-participation cardiac screening and allow for early detection of aneurysms as a means of preventing this isilent killeri from striking. As strong supporters of the numerous benefits of weight training, we encourage this activity in individuals without aneurysm; without aneurysm, wall tension does not reach dangerous levels, even at extremes of exertion. For individuals with known aortic dilatation, we recommend a program that limits their lifting to 50% of body weight in the bench press or equivalent level of perceived exertion for other specific strength exercises. PMID- 20924329 TI - Stent-graft in dissected aorta: aspects on seal and risk for disrupture of the dissection membrane. PMID- 20924330 TI - Marfan Syndrome: when to operate TAA(A)s? AB - Marfan Syndrome is a heritable disorder of connective tissue leading to aortic aneurysms and other cardiovascular complications associated with reduced life expectancy. Marfan patients with thoracic aortic aneurysms (TAAs) or with thoracoabdominal aortic aneurysms (TAAAs) should be treated by means of open surgery, requiring an extensive protocol, including extracorporeal circulation, neuromonitoring and adjunctive modalities to provide organ protection. Then, open surgical repair of TAA(A)s are associated with excellent results. However, in the last time a gradual change to endovascular treatment in Marfan patients is observable. Particularly in patients with an increased surgical risk due to redo sternotomy or thoracotomy, endovascular treatment might be an alternative due to its less invasive approach. Consequently, thoracic endovascular aortic repair comprises a therapeutic alternative in individual situations even in Marfan patients, when the landing zones are safe and appropriate. In cases of failed endovascular therapy, however, conversion to open surgery remains still an option with acceptable results, although the distal and proximal clamping positions change inappropriate with larger extensions due to the aortic stent. PMID- 20924331 TI - Renal angioplasty and stenting: is it still indicated after ASTRAL and STAR studies? AB - A renal artery stenosis (RAS) is common among patients with atherosclerosis, up to a third of patients undergoing cardiac catheterization. Fibromuscular dysplasia is the next cause of RAS, commonly found in young women. Atherosclerosis RAS generally progresses overtime and is often associated with loss of renal mass and worsening renal function (RF). Percutaneous renal artery stent placement is the preferred method of revascularization for hemodynamically significant RAS according to ACC and AHA guidelines. Several randomized trials have shown the superiority of endovascular procedures to medical therapy alone. However, two studies ASTRAL and STAR studies were recently published and did not find any difference between renal stenting and medical therapy. But these studies have a lot of limitations and flaws as we will discuss (poor indications, poor results, numerous complications, failures, poor technique, inexperienced operators, ecc.). Despite these questionable studies, renal stenting keeps indications in patients with: uncontrolled hypertension; ischemic nephropathy; cardiac disturbance syndrome (e.g. "flash" pulmonary edema, uncontrolled heart failure or uncontrolled angina pectoris); solitary kidney. To improve the clinical response rates, a better selection of the patients and lesions is mandatory with: good non-invasive or invasive imaging; physiologic lesion assessment using transluminal pressure gradients; measurements of biomarkers (e.g., BNP); fractional flow reserve study. A problem remains after renal angioplasty stenting, the deterioration of the RF in 20-30% of the patients. Atheroembolism seems to play an important role and is probably the main cause of this R.F deterioration. The use of protection devices alone or in combination with IIb IIa inhibitors has been proposed and seems promising as shown in different recent reports. Renal angioplasty and stenting is still indicated but we need: a better patient and lesion selection; improvements in techniques and maybe the use of protection devices to reduce the risk of RF deterioration after renal stenting. PMID- 20924332 TI - Catheter-based renal sympathectomy. AB - The sympathetic nervous system via its effect on the kidney maintains a key role in blood pressure regulation and in the pathogenesis of hypertension. In turn, the kidney receives a dense innervation of afferent sympathetic fibers allowing it to effectively modulate the sympathetic tone. Hence, the kidney can be both culprit and victim of increased sympathetic activity. In addition, conditions such as congestive heart failure, chronic renal failure or the metabolic syndrome are associated with an increased sympathetic activity whether or not hypertension is present. On this account, both the sympathetic nervous system and the kidney were identified as potential therapeutic targets in the treatment of hypertension and other conditions associated with a high sympathetic tone. Initial investigations focused on surgical removal of the sympathetic trunk, unfortunately accompanied by operative mortality and major side effects. More specific methods of disrupting interactions between the sympathetic nervous system and the kidneys were subsequently explored including the removal of diseased kidneys and, more recently, minimally invasive severance of the renal sympathetic nerves. Currently, most hypertensive patients can be treated by effective antihypertensive drugs. Notwithstanding, a small group of hypertensive patients remains suboptimally controlled despite identification of potential causes and appropriate treatment. In this group an elevated sympathetic tone may be a significant contributor to treatment resistance and selective renal sympathectomy may be beneficial. The role of the sympathetic nervous system in blood pressure control and the effect of selective sympathectomy are discussed in this review. PMID- 20924333 TI - Upper extremity access for renal artery stenting: radial, brachial and axillary access: how to do them safely and pitfalls to avoid. AB - This manuscript traces the history of changes in preferred upper extremity puncture sites for renal artery stenting as our understanding of anatomy, techniques, technology and pharmacology, each separately and their confluence, has improved. A very detailed description of each technique is beyond the scope of this review; the references should allow the reader to readily access this information. PMID- 20924334 TI - Efficacy of embolic protection devices in renal artery stenting. AB - The efficacy of embolic protection devices (EPDs) have been studied extensively in coronary saphenous vein grafts and extra cranial cerebrovascular disease. Recent ex-vivo and in-vivo renal artery stenting studies suggest atheroembolism is not unique to the coronary and cerebrovascular domain and it seems intuitive, renal EPDs may be beneficial. In an attempt to better understand the current objective evidence regarding renal protection efficacy we systematically reviewed the contemporary literature and summarize the findings herein. There is increasing observational data suggesting the use of embolic protection devices decrease the risk of continued decline in renal function after renal artery stenting. There is also prospective randomized data to suggest that the use of adjuvant IIb/IIIa glycoprotein inhibitor and embolic protection has synergistic benefit, but this is a very small series. However, there are currently no well controlled prospective trials to conclude the added risk and expense of renal protection is countered by proven clinical benefit. Based on the literature compiled in this manuscript we do believe EPDs should be considered in some high risk patients. PMID- 20924335 TI - Evidence-based medicine in renal artery stenting. AB - Atherosclerotic renovascular disease is an increasingly recognized cause of severe hypertension and declining kidney function. Patients with atherosclerotic renovascular disease have been demonstrated to have an increased risk of adverse cardiovascular events. Over the course of the last two decades renal artery revascularization for treatment of atherosclerotic renal artery stenosis (RAS) has gained great increase via percutaneous techniques. However the efficacy of contemporary revascularization therapies in the treatment of renal artery stenosis is unproven and controversial. The indication for renal artery stenting is widely questioned due to a not yet proven benefit of renal revascularization compared to best medical therapy. Many authors question the efficacy of percutaneous renal revascularization on clinical outcome parameters, such as preservation of renal function and blood pressure control. None of the so far published randomized controlled trials could prove a beneficial outcome of RAS revascularization compared with medical management. Currently accepted indications for revascularization are significant RAS with progressive or acute deterioration of renal function and/or severe uncontrollable hypertension, renal function decline with the use of agents blocking the renin-angiotensin system and recurrent flash pulmonary edema. The key point for success is the correct selection of the patient. This article summarizes the background and the limitations of the so far published and still ongoing controlled trials. PMID- 20924336 TI - Postoperative mediastinitis in open heart surgery patients. Treatment with unilateral or bilateral pectoralis major muscle flap? AB - AIM: the treatment of mediastinitis, after median sternotomy, in open heart surgery operated patients, remains an important and challenging problem in cardiac surgery. The management of this severe complication by means of surgical debridement of the sternum followed by mediastinal closure with pectoralis major muscle flaps, represents one of the best effective and most common modalities of treatment. The aim of the present publication is to demonstrate the good and comparable result in the mediastinal closure by using a single pectoralis muscle flap instead of two pectoralis muscle flaps. METHODS: in our hospital, between July 1998 and December 2004, 32 patients with mediastinitis were treated after adult open heart surgery with sternal debridement and pectoralis major muscle flaps. In 19 cases the sternal closure was performed with a single pectoralis muscle (group U) and in 13 cases with both pectoralis muscles (Group B). RESULTS: comparing the group U and group B, we did not found statistical differences in the variables of age, sex, associated diseases, previous myocardial infarction, kind of cardiac surgery undertaken, quality of the sternum, type of germen, number of previous sternal debridement performed and time of hospitalization. Patients in group U showed a statistically significant (P=0.001) shorted plastic reconstructive surgery time, an earlier extubation time (non statistically significant) and less need of blood transfusion (non statistically significant). The morbidity and hospital mortality in group U and B did not show any statistical differences. There were three cases of flap related complications in group B and two in group U. One death was recorded in group U (7.69%) and another in group B (5.26%). CONCLUSION: mediastinal infection after cardiac surgery can be effectively managed by surgical debridement followed by plastic coverage with a single pectoralis muscle flap. In our experience, this unilateral pectoralis muscle flap technique showed similar results to the classic closure with both pectoralis muscle flaps. The unilateral technique represents a relative low aggressive operation and preserves intact the contralateral pectoralis muscle. Comparing the single pectoralis muscle flap technique with the bilateral pectoralis musle technique, the former is faster, the extubation is earlier and there is less need of postoperative blood transfusions. PMID- 20924338 TI - Compression therapy. PMID- 20924337 TI - Patient's home care management in persistent air leaks and chronic pneumothorax using a new drainage system. AB - The management of persistent air leaks (PALs) is one of the most common problems in general thoracic surgery, especially after elective pulmonary resections. The statistically most frequent air leak is caused by alveolar-pleural fistula (APF), which is defined as a link between the pulmonary parenchyma distal to a segmental bronchus, and the pleural space. Prolonged air leaks result in an increase in patient's hospital length of stay with possible infectious complications, aside from an overall hospitalization cost increase. The ability to discharge a patient who would otherwise depend on continuous aspiration, because chronic PALs represent a very important clinical and technological improvement. We describe the case of a patient with chronic PALs and pneumothorax due to pulmonary fibrosis secondary to rheumatoid arthritis, with diffuse pulmonary nodules, in which surgical attempts to manage air leaks were ineffective. He was successfully home-assisted with a new chest drainage system with automatic constant negative suction pressure. PMID- 20924339 TI - Limb volume measurement: from the past methods to optoelectronic technologies, bioimpedance analysis and laser based devices. AB - Accurate measurement of limb volume is considered crucial to lymphedema management. Various non-invasive methods may be used and have been validated in recent years, though suboptimal standardisation has been highlighted in different publications. PMID- 20924340 TI - Optoelectric volume measurements to demonstrate volume changes in the lower extremities during orthostasis. AB - AIM: Although an increase in volume of the legs during prolonged standing is a well-known phenomenon, there is little information on the initial phase in orthostasis. The aim of this study is to measure the increase in volume and its distribution in the lower extremities during orthostatic stress in healthy and varicose patients. METHODS: In this prospective study volume changes of the legs in 16 healthy individuals and 24 patients with varicose veins were investigated using an optoelectric volume measurement system (Perometer(r)) during 10 minutes in a standing position. RESULTS: We could show that during a 10 minute standing experiment, a significant increase in volume of the entire leg, in both the healthy vein group (2.48%) and the varicose group (2.1%) occurred. Significant volume increase appeared in the upper and lower leg respectively. No significant differences could be demonstrated between right and left leg or between healthy and varicose legs. CONCLUSION: These results in accordance with other published data indicate that changing position from lying or sitting to standing initially leads to a rapid increase in volume of the leg. These changes take place very quickly and with respect to their volume changes, are significant. The volume increase is following a bi-exponential function fitting to a fast filling compartment (venous pooling) and a slow filling compartment reflecting extravasation. Over the course of the day additional edema formation may occur. PMID- 20924341 TI - A new device to measure upper limb circumferences: validity and reliability. AB - AIM: The aim of this paper was to examine the reliability and validity of a new measurement device that counters the disadvantages of the traditional method of arm circumference measurements. METHODS: We measured the arm on the non-operated side of breast cancer patients. Sixty-four patients were measured twice by the same assessor and 48 patients were measured twice by two different assessors. The arm circumferences were measured at the olecranon and each 4 cm proximal and distal of the olecranon. The measurements were performed with a self-developed device consisting of a stainless steel bar on which a tapeline was fixed at every 4 cm distance. The arm volume was calculated from the circumference measurements with the frustrum formula and was also measured directly with the water displacement method. RESULTS: For the circumference measurements, intrarater and interrater ICCs ranged between 0.942 and 0.998. ICCs for the calculated arm volume were also very high. No systematic changes between the first to the second assessment could be found. The standard error of measurement for the circumference measurements as well as for the calculated arm volume was low (between 0.8% and 2.0%). An increase of 1.0 cm or more of the arm circumference at any measurement side and of 55 ml or more of the calculated arm volume was clinically significant. CONCLUSION: Arm circumferences and also the calculated arm volume can be measured quickly and accurately with a simple and inexpensive device. PMID- 20924342 TI - Narrowing of leg veins under compression demonstrated by magnetic resonance imaging (MRI). AB - AIM: The aim of this paper was to demonstrate the usefulness of magnetic resonance imaging (MRI) for detecting the ability of compression material in narrowing superficial and deep veins in the lower extremity. METHODS: MRI of the legs was performed in one healthy volunteer and in 11 patients with CEAP C2-C4 without and with different kinds of compression devices. The cross section area of superficial and deep veins was measured by planimetry in mid-calf and mid thigh slices. The interface pressure of compression was measured at the same level. RESULTS: Examples are presented showing that the narrowing of veins does not only depend on the exerted pressure but also on the body position and the resulting distortion of the tissue. In the prone and the standing position deep veins may show a greater reduction of the cross section area than in superficial veins. CONCLUSION: MRI is a powerful method to assess venous narrowing by external compression. Especially in the standing position new insights regarding the effects of different compression devices may be expected. PMID- 20924343 TI - 3D multislice CT to demonstrate the effects of compression therapy. AB - The aim of this paper was to show the value of the 3D modelling of the leg by multislice computed tomography (MSCT) in demonstrating the effects of compression therapy on both the superficial veins and on the limb's volume. The spiral CT with 3D reconstruction of the lower limbs (with or without injection of contrast) is an accurate method to assess the 3D shape of the leg and the diameter of the superficial/deep veins. It is possible to obtain a realistic 3D model of the leg and its anatomical structures. This makes the evaluation of the interface pressure and effects due to the compression stocking possible. The real interface pressure in vivo between the skin and compression material is verified during the CT and recorded by a probe. It is measured by using the Kikuhime device at the B1 and B points of the calf. Technical limits: are exposure to X rays, a venous injection is usually not advisable, and this exam is strictly limited to the lying position. To assess the limb's volume by MSCT, we use metallic landmarks and dedicated modeling software. According to the Laplace's law, the variations of the shape of the leg i.e. cross sections at different levels, give a radius for each location, and so different interface pressures all around the limb, can be measured. The results of these theoretical values of the interface pressure are close to the real values measured at the same location by a probe: the compression of the saphenous veins in the lying position is observed below the knee providing the pressure at the ankle (B point) is at least 25 mmHg. It is not possible to make a compression of the veins at the thigh level without a pad. Regarding the assessment of the limb's volume, it it possible to localize a limb's edema and to quantify it with a precision of less than 1%. The multislice CT is a great research tool to provide a 3D model of the limb, making the assessment of the interface pressure of stockings and the evaluation of the effects on the superficial veins possible, but its main possible limitations are the lying position, and the use of X-rays. It is also possible to make an accurate measurement of the limb's volume, and to assess the specific location of edema int he soft tissues (fat, sub-cutaneous, muscle). PMID- 20924344 TI - Duplex scanning to evaluate the effect of compression on venous reflux. AB - AIM: The aim of this study was to demonstrate the usefulness of Duplex in measuring venous reflux and changes in reflux caused by leg compression. METHODS: Twelve patients with severe incompetence of the great saphenous vein (GSV) were investigated. A special Duplex probe was fixed by tapes on the mid-thigh portion of the incompetent GSV and reflux elicited by tip toeing was measured. Elastic and inelastic compression material with an interface supine pressure around 20, 40 and 60 mmHg was applied on the lower leg and the reflux measurement was repeated. RESULTS: Increasing compression of the leg led to a progressive reduction of the reflux in the GSV. Ultimately reflux was completely abolished by inelastic compression with a median pressure of 86 mm Hg in the standing position. Elastic material exerting this pressure can achieve similar results but is not tolerated by patients. CONCLUSION: Duplex is able to demonstrate a reduction of GSV reflux caused by compression of the lower leg, which explains one major beneficial effect of compression on the disturbed haemodynamics in venous incompetence. PMID- 20924345 TI - Measuring venous pumping function by strain-gauge plethysmography. AB - AIM: Hemodynamic effects of compression devices in patients with venous insufficiency are still under dispute. The aim of this paper was to describe a method which is able to give quantitative results concerning an improvement of the venous pumping function by using compression devices in patients with venous insufficiency. METHODS: The ejection fraction (EF) of the calf pump can be measured using strain gauge plethysmography proximal to a compression device on the leg and the degree of improvement depending on the exerted pressure and the elastic property of the material can be assessed. Experiments were carried out in 15 normal volunteers and in a total of 68 patients with severe superficial venous incompetence and who were investigated without compression and with various compression devices measuring interface pressure in different body positions. RESULTS: Examples demonstrating the usefulness of the plethysmographic method are given. The median values of EF were 64.6 (IQR 63.4-68.6) in normal subjects and about half in the venous patients. Statistically significant improvement was achieved using inelastic bandages, resulting in further improvements with increasing pressures between 20 and 60 mmHg. Elastic stockings led only to a moderate improvement of the deficient venous pumping function. Significant correlations were found between EF and standing and walking pressure. CONCLUSION: The described plethysmographic method is very useful to assess haemodynamic effects of different compression devices in patients with venous insufficiency. PMID- 20924346 TI - Comparison of three portable instruments to measure compression pressure. AB - AIM: Measurement of interface pressure between the skin and a compression device has gained practical importance not only for characterizing the efficacy of different compression products in physiological and clinical studies but also for the training of medical staff. METHODS: A newly developed portable pneumatic pressure transducer (Picopress(r)) was compared with two established systems (Kikuhime(r) and SIGaT tester(r)) measuring linearity, variability and accuracy on a cylindrical model using a stepwise inflated sphygmomanometer as the reference. In addition the variation coefficients were measured by applying the transducers repeatedly under a blood pressure cuff on the distal lower leg of a healthy human subject with stepwise inflation. RESULTS: In the pressure range between 10 and 80 mmHg all three devices showed a linear association compared with the sphygmomanometer values (Pearson r>0.99). The best reproducibility (variation coefficients between 1.05-7.4%) and the highest degree of accuracy demonstrated by Bland-Altman plots was achieved with the Picopress(r) transducer. Repeated measurements of pressure in a human leg revealed average variation coefficients for the three devices of 4.17% (Kikuhime(r)), 8.52% (SIGaT(r)) and 2.79% (Picopress(r)). CONCLUSION: The results suggest that the Picopress(r) transducer, which also allows dynamic pressure tracing in connection with a software program and which may be left under a bandage for several days, is a reliable instrument for measuring the pressure under a compression device. PMID- 20924347 TI - Pascal's law and the dynamics of compression therapy: a study on healthy volunteers. AB - AIM: The aim of this paper was to determine whether Pascal's law can be used to explain the dynamics of compression therapy. METHODS: Sub-bandage pressures were recorded at three different levels to investigate the transmission of applied pressure on the legs of 12 healthy volunteers and 216 applications. RESULTS: The experimental model revealed that when pressure is increased at a certain area in a compressed leg, the pressure is transmitted within the compressed area. CONCLUSION: The dynamics of effective compression therapy are explained by Pascal's Law, which states that when pressure is applied on a fluid (a muscle or muscle group) in a closed container (fascia muscularis and compression bandage), there is an equal increase at every other point in the container. PMID- 20924348 TI - Medical compression: effects on pulsatile leg blood flow. AB - AIM: Leg compression bandaging is the mainstay of venous ulcer treatment, yet little is known about the impact of therapeutic compression levels on arterial haemodynamics. In this study, the effect of foot-to-knee, four-layer compression bandaging on below-knee arterial pulsatile blood flow was assessed by nuclear magnetic resonance flowmetry. METHODS: In 14 healthy supine subjects, bilateral pulsatile blood flow measured at five below-knee sites without compression; and during compression of one leg to an average malleolar sub-bandage pressure of 40.7+/-4.0 mmHg. RESULTS: The forefoot-to-knee compression bandaging caused a highly significant (P<0.001) increase in the bandaged leg pulsatile blood flow due to increases in both peak flow and pulse width. CONCLUSION: It is hypothesized that arteriolar vasodilatation, induced either myogenically by reduced transmural pressure or by vasodilatory substance release triggered by increased venous shear stress and veno-arterial interactions, possibly combined with altered vascular compliance, produce the observed compression-related phenomenon. Whatever the mechanism(s), the finding of a compression-associated pulsatile flow increase suggests an arterial linkage, which may play a role in the well-documented beneficial effects of compression bandaging in venous ulcer and lymphedema treatment. Possible beneficial effects of the arterial flow-pulse increase on venous ulcer outcome may be related to a decrease in leukocyte effects in the distal microvasculature. PMID- 20924349 TI - Clinical trials needed to evaluate compression therapy in breast cancer related lymphedema (BCRL). Proposals from an expert group. AB - AIM: A mainstay of lymphedema management involves the use of compression therapy. Compression therapy application is variable at different levels of disease severity. Evidence is scant to direct clinicians in best practice regarding compression therapy use. Further, compression clinical trials are fragmented and poorly extrapolable to the greater population. An ideal construct for conducting clinical trials in regards to compression therapy will promote parallel global initiatives based on a standard research agenda. The purpose of this article is to review current evidence in practice regarding compression therapy for BCRL management and based on this evidence, offer an expert consensus recommendation for a research agenda and prescriptive trials. Recommendations herein focus solely on compression interventions. METHODS: This document represents the proceedings of a session organized by the International Compression Club (ICC) in June 2009 in Ponzano (Veneto, Italy). The purpose of the meeting was to enable a group of experts to discuss the existing evidence for compression treatment in breast cancer related lymphedema (BCRL) concentrating on areas where randomized controlled trials (RCTs) are lacking. RESULTS: The current body of research suggests efficacy of compression interventions in the treatment and management of lymphedema. However, studies to date have failed to adequately address various forms of compression therapy and their optimal application in BCRL. We offer recommendations for standardized compression research trials for prophylaxis of arm lymphedema and for the management of chronic BCRL. Suggestions are also made regarding; inclusion and exclusion criteria, measurement methodology and additional variables of interest for researchers to capture. CONCLUSION: This document should inform future research trials in compression therapy and serve as a guide to clinical researchers, industry researchers and lymphologists regarding the strengths, weaknesses and shortcomings of the current literature. By providing this construct for research trials, the authors aim to support evidence based therapy interventions, promote a cohesive, standardized and informative body of literature to enhance clinical outcomes, improve the quality of future research trials, inform industry innovation and guide policy related to BCRL. PMID- 20924350 TI - Diagnosis and treatment of primary lymphedema. Consensus document of the International Union of Phlebology (IUP)-2009. AB - Primary lymphedema can be managed safely as one of the chronic lymphedemas by a proper combination of DLT with compression therapy. Treatment in the maintenance phase should include compression garments, self management including the compression therapy, self massage and meticulous personal hygiene and skin care in addition to lymph-transport promoting excercises. The management of primary lymphedema can be further improved with proper addition of surgical therapy either reconstructive or ablative. These two surgical therapies can be effective only when fully integrated with MLD-based DLT postoperatively. Compliance with a long-term commitment of DLT postoperatively is the most critical factor determining the success of any new treatment strategy with either reconstructive or palliative surgery. The future of management of primary lymphedema caused by truncular lymphatic malformation has never been brighter with the new prospect of gene-oriented management. PMID- 20924351 TI - Internal jugular vein morphology and hemodynamics in patients with multiple sclerosis. PMID- 20924352 TI - Dynamic interaction networks in a hierarchically organized tissue. AB - Intercellular (between cell) communication networks maintain homeostasis and coordinate regenerative and developmental cues in multicellular organisms. Despite the importance of intercellular networks in stem cell biology, their rules, structure and molecular components are poorly understood. Herein, we describe the structure and dynamics of intercellular and intracellular networks in a stem cell derived, hierarchically organized tissue using experimental and theoretical analyses of cultured human umbilical cord blood progenitors. By integrating high-throughput molecular profiling, database and literature mining, mechanistic modeling, and cell culture experiments, we show that secreted factor mediated intercellular communication networks regulate blood stem cell fate decisions. In particular, self-renewal is modulated by a coupled positive negative intercellular feedback circuit composed of megakaryocyte-derived stimulatory growth factors (VEGF, PDGF, EGF, and serotonin) versus monocyte derived inhibitory factors (CCL3, CCL4, CXCL10, TGFB2, and TNFSF9). We reconstruct a stem cell intracellular network, and identify PI3K, Raf, Akt, and PLC as functionally distinct signal integration nodes, linking extracellular, and intracellular signaling. This represents the first systematic characterization of how stem cell fate decisions are regulated non-autonomously through lineage specific interactions with differentiated progeny. PMID- 20924353 TI - Connecting cell fate decision networks in hematopoeisis from the outside in. PMID- 20924354 TI - Cell-type specific analysis of translating RNAs in developing flowers reveals new levels of control. AB - Determining both the expression levels of mRNA and the regulation of its translation is important in understanding specialized cell functions. In this study, we describe both the expression profiles of cells within spatiotemporal domains of the Arabidopsis thaliana flower and the post-transcriptional regulation of these mRNAs, at nucleotide resolution. We express a tagged ribosomal protein under the promoters of three master regulators of flower development. By precipitating tagged polysomes, we isolated cell type-specific mRNAs that are probably translating, and quantified those mRNAs through deep sequencing. Cell type comparisons identified known cell-specific transcripts and uncovered many new ones, from which we inferred cell type-specific hormone responses, promoter motifs and coexpressed cognate binding factor candidates, and splicing isoforms. By comparing translating mRNAs with steady-state overall transcripts, we found evidence for widespread post-transcriptional regulation at both the intron splicing and translational stages. Sequence analyses identified structural features associated with each step. Finally, we identified a new class of noncoding RNAs associated with polysomes. Findings from our profiling lead to new hypotheses in the understanding of flower development. PMID- 20924355 TI - Intra-arterial brachytherapy of hepatic malignancies: watch the flow. AB - Although the liver possesses a dual blood supply, arterial vessels deliver only a small proportion of blood to normal parenchyma, but they deliver the vast majority of blood to primary and secondary cancers of the liver. This anatomical discrepancy is the basis for intra-arterial brachytherapy of liver cancers using radioactive microspheres, termed radio-embolization (RE). Radioactive microspheres implant preferentially in the terminal arterioles of tumors. Although biological models of the flow dynamics and distribution of microspheres are currently in development, there is a need to improve the imaging biomarkers of flow dynamics used to plan RE. Since a direct consequence of RE is vascular disruption and necrosis, we suggest that imaging protocols sensitive to changes in vasculature are highly likely to represent useful early biomarkers for treatment efficacy. We propose dynamic contrast-enhanced CT as the most appropriate imaging modality for studying vascular parameters in clinical trials of RE treatment. PMID- 20924356 TI - The APC/C subunit Cdc16/Cut9 is a contiguous tetratricopeptide repeat superhelix with a homo-dimer interface similar to Cdc27. AB - The anaphase-promoting complex/cyclosome (APC/C), an E3 ubiquitin ligase responsible for controlling cell cycle transitions, is a multisubunit complex assembled from 13 different proteins. Numerous APC/C subunits incorporate multiple copies of the tetratricopeptide repeat (TPR). Here, we report the crystal structure of Schizosaccharomyces pombe Cut9 (Cdc16/Apc6) in complex with Hcn1 (Cdc26), showing that Cdc16/Cut9 is a contiguous TPR superhelix of 14 TPR units. A C-terminal block of TPR motifs interacts with Hcn1, whereas an N terminal TPR block mediates Cdc16/Cut9 self-association through a homotypic interface. This dimer interface is structurally related to the N-terminal dimerization domain of Cdc27, demonstrating that both Cdc16/Cut9 and Cdc27 form homo-dimers through a conserved mechanism. The acetylated N-terminal Met residue of Hcn1 is enclosed within a chamber created from the Cut9 TPR superhelix. Thus, in complex with Cdc16/Cut9, the N-acetyl-Met residue of Hcn1, a putative degron for the Doa10 E3 ubiquitin ligase, is inaccessible for Doa10 recognition, protecting Hcn1/Cdc26 from ubiquitin-dependent degradation. This finding may provide a structural explanation for a mechanism to control the stoichiometry of proteins participating in multisubunit complexes. PMID- 20924358 TI - Redox regulation of the stability of the SUMO protease SENP3 via interactions with CHIP and Hsp90. AB - The molecular chaperone heat shock protein 90 (Hsp90) and the co chaperone/ubiquitin ligase carboxyl terminus of Hsc70-interacting protein (CHIP) control the turnover of client proteins. How this system decides to stabilize or degrade the client proteins under particular physiological or pathological conditions is unclear. We report here a novel client protein, the SUMO2/3 protease SENP3, that is sophisticatedly regulated by CHIP and Hsp90. SENP3 is maintained at a low basal level under non-stress condition due to Hsp90 independent CHIP-mediated ubiquitination. Upon mild oxidative stress, SENP3 undergoes thiol modification, which recruits Hsp90. Hsp90/SENP3 association protects SENP3 from CHIP-mediated ubiquitination and subsequent degradation, but this effect of Hsp90 requires the presence of CHIP. Our data demonstrate for the first time that CHIP and Hsp90 interplay with a client alternately under non stress and stress conditions, and the choice between stabilization and degradation is made by the redox state of the client. In addition, enhanced SENP3/Hsp90 association is found in cancer. These findings provide new mechanistic insight into how cells regulate the SUMO protease in response to oxidative stress. PMID- 20924357 TI - Spatial and temporal organization of the E. coli PTS components. AB - The phosphotransferase system (PTS) controls preferential use of sugars in bacteria. It comprises of two general proteins, enzyme I (EI) and HPr, and various sugar-specific permeases. Using fluorescence microscopy, we show here that EI and HPr localize near the Escherichia coli cell poles. Polar localization of each protein occurs independently, but HPr is released from the poles in an EI and sugar-dependent manner. Conversely, the beta-glucoside-specific permease, BglF, localizes to the cell membrane. EI, HPr and BglF control the beta-glucoside utilization (bgl) operon by modulating the activity of the BglG transcription factor; BglF inactivates BglG by membrane sequestration and phosphorylation, whereas EI and HPr activate it by an unknown mechanism in response to beta glucosides availability. Using biochemical, genetic and imaging methodologies, we show that EI and HPr interact with BglG and affect its subcellular localization in a phosphorylation-independent manner. Upon sugar stimulation, BglG migrates from the cell periphery to the cytoplasm through the poles. Hence, the PTS components appear to control bgl operon expression by ushering BglG between the cellular compartments. Our results reinforce the notion that signal transduction in bacteria involves dynamic localization of proteins. PMID- 20924359 TI - Ubiquitination and deubiquitination of NP protein regulates influenza A virus RNA replication. AB - Influenza A virus RNA replication requires an intricate regulatory network involving viral and cellular proteins. In this study, we examined the roles of cellular ubiquitinating/deubiquitinating enzymes (DUBs). We observed that downregulation of a cellular deubiquitinating enzyme USP11 resulted in enhanced virus production, suggesting that USP11 could inhibit influenza virus replication. Conversely, overexpression of USP11 specifically inhibited viral genomic RNA replication, and this inhibition required the deubiquitinase activity. Furthermore, we showed that USP11 interacted with PB2, PA, and NP of viral RNA replication complex, and that NP is a monoubiquitinated protein and can be deubiquitinated by USP11 in vivo. Finally, we identified K184 as the ubiquitination site on NP and this residue is crucial for virus RNA replication. We propose that ubiquitination/deubiquitination of NP can be manipulated for antiviral therapeutic purposes. PMID- 20924360 TI - Pulmonary hypertension with left-sided heart disease. AB - Pulmonary hypertension (PH) with left-sided heart disease is defined, according to the latest Venice classification, as a Group 2 PH, which includes left-sided ventricular or atrial disease, and left-sided valvular diseases. These conditions are all associated with increased left ventricular filling pressure. Although PH with left-sided heart disease is a common entity, and long-term follow-up trials have provided firm recognition that development of left-sided PH carries a poor outcome, available data on incidence, pathophysiology, and therapy are sparse. Mitral stenosis was reported as the most frequent cause of PH several decades ago, but PH with left-sided heart disease is now usually caused by systemic hypertension and ischemic heart disease. In patients with these conditions, PH develops as a consequence of impaired left ventricular relaxation and distensibility. Chronic sustained elevation of cardiogenic blood pressure in pulmonary capillaries leads to a cascade of untoward retrograde anatomical and functional effects that represent specific targets for therapeutic intervention. The pathophysiological and clinical importance of the hemodynamic consequences of left-sided heart disease, starting with lung capillary injury and leading to right ventricular overload and failure, are discussed in this Review, focusing on PH as an evolving contributor to heart failure that may be amenable to novel interventions. PMID- 20924361 TI - Prevention of diabetic neuropathy by regulatable expression of HSV-mediated erythropoietin. AB - Previous studies have demonstrated that gene transfer of genes coding for neurotrophic factors to the dorsal root ganglion (DRG) using nonreplicating herpes simplex virus (HSV)-based vectors injected subcutaneously can prevent the progression of diabetic neuropathy. Because prolonged expression of neurotrophic factors could potentially have unwanted adverse effects, we constructed a nonreplicating HSV vector, vHrtEPO, to express erythropoietin (EPO) under the control of a tetracycline response element (TRE)-minimal cytomegalovirus (CMV) fusion promoter. Primary DRG neurons in culture infected with vHrtEPO express and release EPO in response to exposure to doxycycline (DOX). Animals infected with vHrtEPO by footpad inoculation demonstrated regulated expression of EPO in DRG under the control of DOX administered by gavage. Mice rendered diabetic by injection of streptozotocin (STZ), inoculated with vHrtEPO, and treated with DOX 4 days out of 7 each week for 4 weeks were protected against the development of diabetic neuropathy as assessed by electrophysiologic and behavioral measures. These studies indicate that intermittent expression of EPO in DRG achieved from a regulatable vector is sufficient to protect against the progression of neuropathy in diabetic animals, and provides proof-of-principle preclinical evidence for the development of such vectors for clinical trial. PMID- 20924362 TI - Bispecific adapter-mediated retargeting of a receptor-restricted HSV-1 vector to CEA-bearing tumor cells. AB - The safety and efficacy of viral therapies for solid tumors can be enhanced by redirecting the virus infection to tumor-specific cell-surface markers. Successful retargeting of herpes simplex virus type 1 (HSV-1) has been achieved using vectors that carry a modified envelope glycoprotein D (gD) engineered to interact directly with novel receptors. In addition, soluble bridging molecules (adapters) have been used to link gD indirectly to cell-specific receptors. Here, we describe the development of an adapter connecting gD to the common tumor antigen carcinoembryonic antigen (CEA). The adapter consisted of a CEA-specific single-chain antibody fused to the gD-binding region of the gD receptor, herpes virus entry mediator (HVEM). We used this adapter in combination with a vector that is detargeted for recognition of the widely expressed gD receptor nectin-1, but retains an intact binding region for the less common HVEM. We show that the adapter enabled infection of HSV-resistant Chinese hamster ovary (CHO) cells expressing ectopic CEA and nectin-1/CEA-bearing human gastric carcinoma cells that are resistant to the vector alone. We observed cell-to-cell spread following adapter-mediated infection in vitro and reduced tumor growth in vivo, indicating that this method of vector retargeting may provide a novel strategy for tumor specific delivery of tumoricidal HSV. PMID- 20924363 TI - Physiological characterization of muscle strength with variable levels of dystrophin restoration in mdx mice following local antisense therapy. AB - Antisense-induced exon skipping can restore the open reading frame, and thus correct the dystrophin deficiency that causes Duchenne muscular dystrophy (DMD), a lethal muscle wasting condition. Successful proof-of-principle in preclinical models has led to human clinical trials. However, it is still not known what percentage of dystrophin-positive fibers and what level of expression is necessary for functional improvement. This study directly address these key questions in the mdx mouse model of DMD. To achieve a significant variation in dystrophin expression, we locally administered into tibialis anterior muscles various doses of a phosphorodiamidate morpholino oligomer (PMO) designed to skip the mutated exon 23 from the mRNA of murine dystrophin. We found a highly significant correlation between the number of dystrophin-positive fibers and resistance to contraction-induced injury, with a minimum of 20% of dystrophin positive fibers required for meaningful improvement. Furthermore, our results also indicate that a relatively low level of dystrophin expression in muscle fibers may have significant clinical benefits. In contrast, improvements in muscle force were not correlated with either the number of positive fibers or total dystrophin levels, which highlight the need to conduct appropriate functional assessments in preclinical testing using the mdx mouse. PMID- 20924364 TI - The FGF-2-derived peptide FREG inhibits melanoma growth in vitro and in vivo. AB - Previous data report that fibroblast growth factor-2 (FGF-2)-derived peptide FREG potently inhibits FGF-2-dependent angiogenesis in vitro and in vivo. Here, we show that FREG inhibits up to 70% in vitro growth and invasion/migration of smooth muscle and melanoma cells. Such inhibition is mediated by platelet-derived growth factor-receptor-alpha (PDGF-Ralpha); in fact, proliferation and migration were restored upon PDGF-Ralpha neutralization. Further experiments demonstrated that FREG interacts with PDGF-Ralpha both in vitro and in vivo and stimulates its phosphorylation. We have previously shown that overexpressing PDGF-Ralpha strongly inhibits melanoma growth in vivo; we, therefore, hypothesized that PDGF Ralpha agonists may represent a novel tool to inhibit melanoma growth in vivo. To support this hypothesis, FREG was inoculated intravenously (i.v.) in a mouse melanoma model and markedly inhibited pulmonary metastases formation. Immunohistochemical analyses showed less proliferation, less angiogenesis, and more apoptosis in metastasized lungs upon FREG treatment, as compared to untreated controls. Finally, in preliminary acute toxicity studies, FREG showed no toxicity signs in healthy animals, and neither microscopic nor macroscopic toxicity at the liver, kidney, and lungs level. Altogether, these data indicate that FREG systemic treatment strongly inhibits melanoma metastases development and indicate for the first time that agonists of PDGF-Ralpha may control melanoma both in vitro and in vivo. PMID- 20924365 TI - Antisense-induced myostatin exon skipping leads to muscle hypertrophy in mice following octa-guanidine morpholino oligomer treatment. AB - Myostatin is a negative regulator of muscle mass, and several strategies are being developed to knockdown its expression to improve muscle-wasting conditions. Strategies using antimyostatin-blocking antibodies, inhibitory-binding partners, signal transduction blockers, and RNA interference system (RNAi)-based knockdown have yielded promising results and increased muscle mass in experimental animals. These approaches have, however, a number of disadvantages such as transient effects or adverse immune complications. We report here the use of antisense oligonucleotides (AOs) to manipulate myostatin pre-mRNA splicing and knockdown myostatin expression. Both 2'O-methyl phosphorothioate RNA (2'OMePS) and phosphorodiamidate morpholino oligomers (PMO) led to efficient exon skipping in vitro and in vivo and knockdown of myostatin at the transcript level. The substantial myostatin exon skipping observed after systemic injection of Vivo-PMO into normal mice led to a significant increase in soleus muscle mass as compared to the controls injected with normal saline suggesting that this approach could be feasible to ameliorate muscle-wasting pathologies. PMID- 20924366 TI - Biomarkers and molecular diagnosis of gastrointestinal and pancreatic neoplasms. AB - Standard protocols for the diagnosis of neoplasms in the gastrointestinal tract are based on histopathologic analysis in combination with clinical information. With the completion of the Human Genome Project in 2003, our understanding of the contribution of genetics to human disease has increased exponentially. This knowledge is gradually being incorporated into clinical decision-making. However, the rate at which molecular biomarkers are validated for use in mainstream clinical applications has lagged far behind that of biomarker discovery. Nevertheless, a number of molecular biomarkers are available for use in the diagnosis and management of gastrointestinal tract neoplasms. This article reviews the most common molecular biomarkers currently available for neoplasms of the luminal gastrointestinal tract and pancreas. In neoplasms of the esophagus, for which no biomarkers are currently used in routine clinical practice, those that have shown the most promise in early clinical validation studies are discussed. PMID- 20924367 TI - Diagnosis and management of iron deficiency anemia in patients with IBD. AB - Anemia is the most prevalent extraintestinal complication of IBD. It can affect quality of life and ability to work, and can also increase the hospitalization rate in patients with IBD. Although the causes of anemia in IBD are multifactorial, iron deficiency anemia (IDA) is the most common. Assessment of the iron status of patients who have a condition associated with inflammation, such as IBD, by using common biochemical values is insufficient. However, new indices of iron metabolism (for instance ferritin:transferrin receptor ratio, reticulocyte hemoglobin content or percentage of hypochromic red blood cells) may help to improve the assessment of iron status in patients with IBD. The treatment of IDA traditionally involves oral iron supplementation. However, because of extensive gastrointestinal adverse effects, and data showing that the use of oral iron in IBD may be associated with disease exacerbation, current guidelines suggest that iron supplementation in IBD should be administered intravenously. This Review provides an overview of iron homeostasis in health before discussing diagnostic and therapeutic strategies for IDA in patients with IBD. PMID- 20924368 TI - Weak peristalsis in esophageal pressure topography: classification and association with Dysphagia. AB - OBJECTIVES: Esophageal manometry is frequently used to assess for weak peristalsis. Although commonly used clinically, there are currently no validated metrics of weak peristalsis in high-resolution esophageal pressure topography (EPT). This study aimed to develop a classification of weak peristalsis in EPT based on a comparative analysis of control subjects and patients with unexplained non-obstructive dysphagia. METHODS: High-resolution esophageal pressure topography (high-resolution impedance manometry) studies were carried out in 16 control subjects to verify EPT features associated with incomplete bolus transit (IBT). The technique of superimposing EPT plots in a computer simulation was used to derive normal limits of peristaltic integrity in EPT in another 75 control subjects. The occurrence of critical EPT defects was then compared between control subjects and 113 patients with non-obstructive dysphagia identified from a large clinical series. RESULTS: IBT occurred with failed peristalsis or with breaks in the 20 mm Hg isobaric contour occurring at the proximal or distal pressure troughs in EPT plots. The normal range for isobaric contour breaks was 0 20% for large (>5 cm) and 0-30% for small (2-5 cm) breaks, with both occurring significantly more frequently in dysphagic patients. Failed peristalsis was not more frequent in dysphagic patients. CONCLUSIONS: A classification of weak peristalsis adapted to EPT is proposed based on the occurrence of breaks in the 20 mm Hg isobaric contour wherein weak peristalsis with large breaks is defined by those occurring with >20% of swallows and weak peristalsis with small breaks defined by those occurring with >30% of swallows. PMID- 20924369 TI - IL28B genomic-based treatment paradigms for patients with chronic hepatitis C infection: the future of personalized HCV therapies. AB - Genome-wide association studies (GWAS) have recently identified host genetic variation to be critical for predicting treatment response and spontaneous clearance in patients infected with hepatitis C virus (HCV). These important new studies are reviewed and their future clinical implications discussed. Single nucleotide polymorphisms in the region of the IL28B gene on chromosome 19, coding for the interferon (IFN)-lambda-3 or IL28B gene, are strongly associated with treatment response to pegylated IFN and ribavirin in patients infected with genotype 1 HCV. The good response variant is associated with a twofold increase in the rate of cure. Allele frequencies differ between ethnic groups, largely explaining the observed differences in response rates between Caucasians, African Americans and Asians. IL28B polymorphism is also strongly associated with spontaneous clearance of HCV. The biological mechanisms responsible for these genetic associations remain unknown and are the focus of ongoing research. Knowledge of a patient's IL28B genotype is likely to aid in clinical decision making with standard of care regimens. Future studies will investigate the possibility of individualizing treatment duration and novel regimens according to IL28B type. PMID- 20924370 TI - Coupling of receptor conformation and ligand orientation determine graded activity. AB - Small molecules stabilize specific protein conformations from a larger ensemble, enabling molecular switches that control diverse cellular functions. We show here that the converse also holds true: the conformational state of the estrogen receptor can direct distinct orientations of the bound ligand. 'Gain-of allostery' mutations that mimic the effects of ligand in driving protein conformation allowed crystallization of the partial agonist ligand WAY-169916 with both the canonical active and inactive conformations of the estrogen receptor. The intermediate transcriptional activity induced by WAY-169916 is associated with the ligand binding differently to the active and inactive conformations of the receptor. Analyses of a series of chemical derivatives demonstrated that altering the ensemble of ligand binding orientations changes signaling output. The coupling of different ligand binding orientations to distinct active and inactive protein conformations defines a new mechanism for titrating allosteric signaling activity. PMID- 20924371 TI - Fit-for-purpose biomarker method validation for application in clinical trials of anticancer drugs. AB - Clinical development of new anticancer drugs can be compromised by a lack of qualified biomarkers. An indispensable component to successful biomarker qualification is assay validation, which is also a regulatory requirement. In order to foster flexible yet rigorous biomarker method validation, the fit-for purpose approach has recently been developed. This minireview focuses on many of the basic issues surrounding validation of biomarker assays utilised in clinical trials. It also provides an overview on strategies to validate each of the five categories that define the majority of biomarker assays. PMID- 20924373 TI - A pilot study on the immunogenicity of dendritic cell vaccination during adjuvant oxaliplatin/capecitabine chemotherapy in colon cancer patients. AB - BACKGROUND: Dendritic cell (DC) vaccination has been shown to induce anti-tumour immune responses in cancer patients, but so far its clinical efficacy is limited. Recent evidence supports an immunogenic effect of cytotoxic chemotherapy. Pre clinical data indicate that the combination of chemotherapy and immunotherapy may result in an enhanced anti-cancer activity. Most studies have focused on the immunogenic aspect of chemotherapy-induced cell death, but only few studies have investigated the effect of chemotherapeutic agents on the effector lymphocytes of the immune system. METHODS: Here we investigated the effect of treatment with oxaliplatin and capecitabine on non-specific and specific DC vaccine-induced adaptive immune responses. Stage III colon cancer patients receiving standard adjuvant oxaliplatin/capecitabine chemotherapy were vaccinated at the same time with keyhole limpet haemocyanin (KLH) and carcinoembryonic antigen (CEA)-peptide pulsed DCs. RESULTS: In 4 out of 7 patients, functional CEA-specific T-cell responses were found at delayed type hypersensitivity (DTH) skin testing. In addition, we observed an enhanced non-specific T-cell reactivity upon oxaliplatin administration. KLH-specific T-cell responses remained unaffected by the chemotherapy, whereas B-cell responses were diminished. CONCLUSION: The results strongly support further testing of the combined use of specific anti-tumour vaccination with oxaliplatin-based chemotherapy. PMID- 20924372 TI - Identification of serum angiopoietin-2 as a biomarker for clinical outcome of colorectal cancer patients treated with bevacizumab-containing therapy. AB - BACKGROUND: The combination of chemotherapy with the vascular endothelial growth factor (VEGF) antibody bevacizumab is a standard of care in advanced colorectal cancer (CRC). However, biomarkers predicting outcome of bevacizumab-containing treatment are lacking. As angiopoietin-2 (Ang-2) is a key regulator of vascular remodelling in concert with VEGF, we investigated its role as a biomarker in metastatic CRC. METHODS: Serum Ang-2 levels were measured in 33 healthy volunteers and 90 patients with CRC. Of these, 34 had metastatic disease and received bevacizumab-containing therapy. To determine the tissue of origin of Ang 2, quantitative real-time PCR was performed on microdissected cryosections of human CRC and in a murine xenograft model of CRC using species-specific amplification. RESULTS: Ang-2 originated from the stromal compartment of CRC tissues. Serum Ang-2 levels were significantly elevated in patients with metastatic CRC compared with healthy controls. Amongst patients receiving bevacizumab-containing treatment, low pre-therapeutic serum Ang-2 levels were associated with a significant better response rate (82 vs 31%; P<0.01), a prolonged median progression-free survival (14.1 vs 8.5 months; P<0.01) and a reduction of 91% in the hazard of death (P<0.05). CONCLUSION: Serum Ang-2 is a candidate biomarker for outcome of patients with metastatic CRC treated with bevacizumab-containing therapy, and it should be further validated to customise combined chemotherapeutic and anti-angiogenic treatment. PMID- 20924374 TI - Serum cytokine concentrations, flavonol intake and colorectal adenoma recurrence in the Polyp Prevention Trial. AB - BACKGROUND: Serum cytokine concentrations may reflect inflammatory processes occurring during the development of colorectal neoplasms. Flavonols, bioactive compounds found in plant-based foods and beverages, may inhibit colorectal neoplasms partly by attenuating inflammation. METHODS: Using logistic regression, we estimated odds ratios (ORs) and 95% confidence intervals (CIs) to investigate the association between serum concentrations of interleukin (IL) beta, 2, 8, 10, 12p70, granulocyte macrophage colony stimulating factor, interferon-gamma, and tumour necrosis factor-alpha, measured over time, flavonol intake, estimated from a flavonol database used in conjunction with a food frequency questionnaire, and adenoma recurrence in 872 participants from the intervention arm of the Polyp Prevention Trial. RESULTS: Decreased IL-2 concentration during the trial increased the risk of any adenoma recurrence (4th vs 1st quartile, OR=1.68, 95% CI=1.13-2.49), whereas decreased IL-1beta or IL-10 reduced the risk of advanced adenoma recurrence (OR=0.37, 95% CI=0.15-0.94; OR=0.39, 95% CI=0.15-0.98, respectively). Individuals with flavonol intake above the median (29.7 mg per day) and decreased cytokine concentrations had the lowest risk of advanced adenoma recurrence. CONCLUSION: Overall, no consistent associations were observed between serum cytokine profile and colorectal adenoma recurrence; however, decreased cytokine concentrations during high flavonol consumption may indicate prevention of colorectal neoplasms. PMID- 20924375 TI - Activity of irinotecan and temozolomide in the presence of O6-methylguanine-DNA methyltransferase inhibition in neuroblastoma pre-clinical models. AB - BACKGROUND: The combination of temozolomide (TMZ) and irinotecan is a regimen used in neuroblastoma patients with recurrent disease. O(6)-methylguanine-DNA methyltransferase (MGMT) may have a function in resistance to TMZ. Using neuroblastoma pre-clinical models, we determined whether the inhibition of MGMT by O(6)-benzylguanine (O6-BG) could enhance the anti-tumour activity of TMZ and irinotecan. METHODS: The cytotoxicity of TMZ and irinotecan, either alone or in combination, was measured in five neuroblastoma cell lines in the presence or absence of O6-BG with a fluorescence-based cell viability assay (DIMSCAN). Anti tumour activity was measured in three neuroblastoma xenograft models. RESULTS: MGMT mRNA and protein were expressed in 9 out of 10 examined cell lines. Pretreatment of cells with 25 MUM O6-BG decreased MGMT protein expression and enhanced The TMZ cytotoxicity by up to 0.3-1.4 logs in four out of five tested cell lines. TMZ (25 mg kg(-1) per day for 5 days every 3 weeks for four cycles) did not significantly improve mice survival, whereas the same schedule of irinotecan (7.5 mg kg(-1) per day) significantly improved survival (P<0.0001) in all three xenograft models. Combining O6-BG and/or TMZ with irinotecan further enhanced survival. CONCLUSION: Our in vitro and in vivo findings suggest that irinotecan drives the activity of irinotecan and TMZ in recurrent neuroblastoma. Inhibitors of MGMT warrant further investigation for enhancing the activity of regimens that include TMZ. PMID- 20924376 TI - Phase II trial of sagopilone, a novel epothilone analog in metastatic melanoma. AB - BACKGROUND: Sagopilone is a novel fully synthetic epothilone with promising preclinical activity and a favourable toxicity profile in phase I testing. METHODS: A phase II pharmacokinetic and efficacy trial was conducted in patients with metastatic melanoma. Patients had measurable disease, Eastern Cooperative Oncology Group performance status 0-2, adequate haematological, and organ function, with up to 2 previous chemotherapy and any previous immunotherapy regimens. Sagopilone, 16 mg m-2, was administered intravenously over 3 h every 21 days until progression or unacceptable toxicity. RESULTS: Thirty-five patients were treated. Sagopilone showed multi-exponential kinetics with a mean terminal half-life of 64 h and a volume of distribution of 4361 l m-2 indicating extensive tissue/tubulin binding. Only grade 2 or lower toxicity was observed: these included sensory neuropathy (66%), leukopenia (46%), fatigue (34%), and neutropenia (31%). The objective response rate was 11.4% (one confirmed complete response, two confirmed partial responses, and one unconfirmed partial response). Stable disease for at least 12 weeks was seen in an additional eight patients (clinical benefit rate 36.4%). CONCLUSION: Sagopilone was well tolerated with mild haematological toxicity and sensory neuropathy. Unlike other epothilones, it shows activity against melanoma even in pretreated patients. Further clinical testing is warranted. PMID- 20924377 TI - Insulin-like growth factors and insulin control a multifunctional signalling network of significant importance in cancer. AB - Insulin-like growth factor (IGF) and insulin (INS) proteins regulate key cellular functions through a complex interacting multi-component molecular network, known as the IGF/INS axis. We describe how dynamic and multilayer interactions give rise to the multifunctional role of the IGF/INS axis. Furthermore, we summarise the importance of the regulatory IGF/INS network in cancer, and discuss the possibilities and limitations of therapies targeting the IGF/INS axis with reference to ongoing clinical trials concerning the blockage of IGF1R in several types of cancer. PMID- 20924378 TI - A phase II study of weekly docetaxel and cisplatin plus oral tegafur/uracil and leucovorin as first-line chemotherapy in patients with locally advanced or metastatic gastric cancer. AB - BACKGROUND: Docetaxel plus cisplatin and 5-fluorouracil has become a new standard for treating advanced gastric cancer. However, high rates of severe neutropenia limit its application. Modification of the regimen could be the solution to get similar activity but less myelosuppression. METHODS: Patients with histologically confirmed, locally advanced, or recurrent/metastatic gastric adenocarcinoma without previous chemotherapy were enrolled. This regimen consisted of docetaxel (Tyxan, TTY, Taipei, Taiwan) 30-min infusion at a dose of 36 mg m(-2), followed by cisplatin 30 mg m(-2) infusion over 1 h on days 1 and 8, and oral tegafur/uracil 300 mg m(-2) per day plus leucovorin 90 mg per day on days 1-14, every 3 weeks. Tumour response was evaluated after every 2 cycles of treatment. RESULTS: From August 2007 to March 2009, 45 patients were enrolled. The median age was 56 years (range: 22-75). Among the 40 patients evaluable for tumour response, one achieved a complete response, 22 had partial responses and 11 had stable disease. The overall response rates of the evaluable and intent-to-treat (ITT) populations were 58% (95% CI: 41-74%) and 53% (95% CI: 38-68%), respectively. The disease control rates in these populations were 85% (95% CI: 70 94%) and 82% (95% CI: 68-92%), respectively. In the ITT analysis, the median time to progression and overall survival were 6.8 and 13.9 months, respectively. Major grade 3-4 toxicities were neutropenia (51%), anaemia (22%), diarrhoea (16%), and infections (20%). No patient died of treatment-related toxicities. CONCLUSION: Concurrent weekly docetaxel and cisplatin plus oral tegafur/uracil and leucovorin are effective and well tolerated in the treatment of advanced gastric cancer. PMID- 20924379 TI - Detecting treatment response in a model of human breast adenocarcinoma using hyperpolarised [1-13C]pyruvate and [1,4-13C2]fumarate. AB - BACKGROUND: The recent introduction of a dynamic nuclear polarisation technique has permitted noninvasive imaging of tumour cell metabolism in vivo following intravenous administration of (13)C-labelled cell substrates. METHODS: Changes in hyperpolarised [1-(13)C]pyruvate and [1,4-(13)C(2)]fumarate metabolism were evaluated in both MDA-MB-231 cells and in implanted MDA-MB-231 tumours following doxorubicin treatment. RESULTS: Treatment of MDA-MB-231 cells resulted in the induction of apoptosis, which was accompanied by a decrease in hyperpolarised (13)C label flux between [1-(13)C]pyruvate and lactate, which was correlated with a decrease in the cellular NAD(H) coenzyme pool. There was also an increase in the rate of fumarate conversion to malate, which accompanied the onset of cellular necrosis. In vivo, the decrease in (13)C label exchange between pyruvate and lactate and the increased flux between fumarate and malate, following drug treatment, were shown to occur in the absence of any detectable change in tumour size. CONCLUSION: We show here that the early responses of a human breast adenocarcinoma tumour model to drug treatment can be followed by administration of both hyperpolarised [1-(13)C]pyruvate and [1,4-(13)C(2)]fumarate. These techniques could be used, therefore, in the clinic to detect the early responses of breast tumours to treatment. PMID- 20924380 TI - Combination of sapacitabine and HDAC inhibitors stimulates cell death in AML and other tumour types. AB - BACKGROUND: Alternative treatments are needed for elderly patients with acute myeloid leukaemia, as the disease prognosis is poor and the current treatment is unsuitable for many patients. METHODS: In this study, we investigated whether combining the nucleoside analogue sapacitabine with histone deacetylase (HDAC) inhibitors could be an effective treatment. Synergy and mode-of-action analysis were studied in cultured cell lines and the efficacy of the combination was confirmed in a xenograft model. RESULTS: CNDAC (1-(2-C-cyano-2-deoxy-beta-D arabino-pentofuranosyl)-cytosine), the active component of sapacitabine, synergised with vorinostat in cell lines derived from a range of tumour types. Synergy was not dependent on a specific sequence of drug administration and was also observed when CNDAC was combined with an alternative HDAC inhibitor, valproate. Flow cytometry and western blot analysis confirmed that the combination induced a significant increase in apoptosis. Mode-of-action analysis detected changes in Bcl-xl, Mcl-1, Noxa, Bid and Bim, which are all regulators of the apoptotic process. The sapacitabine/vorinostat combination demonstrated significant benefit compared with the single-agent treatments in an MV4-11 xenograft, in the absence of any observed toxicity. CONCLUSION: Sapacitabine and HDAC inhibitors are an effective drug combination that is worthy of clinical exploration. PMID- 20924381 TI - Antibacterial to antifungal conversion of neamine aminoglycosides through alkyl modification. Strategy for reviving old drugs into agrofungicides. AB - Many Actinomycetes aminoglycosides are widely used antibiotics. Although mainly antibacterials, a few known aminoglycosides also inhibit yeasts, protozoans and important crop pathogenic fungal oomycetes. Here we show that attachment of a C8 alkyl chain to ring III of a neamine-based aminoglycoside specifically at the 4" o position yields a broad-spectrum fungicide (FG08) without the antibacterial properties typical for aminoglycosides. Leaf infection assays and greenhouse studies show that FG08 is capable of suppressing wheat fungal infections by Fusarium graminearum-the causative agent of Fusarium head blight-at concentrations that are minimally phytotoxic. Unlike typical aminoglycoside action of ribosomal protein translation miscoding, FG08's antifungal action involves perturbation of the plasma membrane. This antibacterial to antifungal transformation could pave the way for the development of a new class of aminoglycoside-based fungicides suitable for use in crop disease applications. In addition, this strategy is an example of reviving a clinically obsolete drug by simple chemical modification to yield a new application. PMID- 20924382 TI - Cytotoxic aromatic compounds from Hericium erinaceum. PMID- 20924383 TI - The psychotrimine natural products have antibacterial activity against Gram positive bacteria and act via membrane disruption. PMID- 20924384 TI - Bioconversion of AS1387392: bioconversion studies involving Amycolatopsis azurea JCM 3275. AB - We screened actinomycetes capable of converting AS1387392 to AS1429716 and identified those strains capable of hydroxylation. Amycolatopsis azurea JCM 3275 was found to be a particularly efficient strain, capable of converting AS1387392 to AS1429716, with a yield of 44% after 9 h. This strain can metabolize not only the hydroxylation of phenylalanine at the meta and para positions but also the reduction of hydroxyketones, as shown by the isolation of bioconversion products. Examination of more suitable conversion conditions showed that pH 7.8 and 25 degrees C were the optimum pH and temperature for bioconversion, respectively. We also demonstrated the effect of carbon and nitrogen sources in the culture media on hydroxylation. Using this strain, we were able to efficiently produce AS1429716 as a chemical template. Further derivatization studies may provide more effective, safer immunosuppressants than those that are currently on-market. PMID- 20924385 TI - Cloning and heterologous expression of P450Um-1, a novel bacterial P450 gene, for hydroxylation of immunosuppressive agent AS1387392. AB - Biotransformation technology involving enzymatic modification of original substrates by organisms such as microbes is a valuable tool in improving pharmacokinetics or physicochemical properties of the base compounds. The fungal metabolite AS1387392 is a histone deacetylase inhibitor with potential as a therapeutic immunosuppressant. However, its paucity of functional groups, essential to synthesizing derivatives, is a drawback. Amycolatopsis azurea JCM 3275 catalyzed hydroxylation of AS1387392 to AS1429716, which may facilitate the synthesis of more derivatives by the additional hydroxyl moiety present in AS1429716. This reaction was inhibited by cytochrome P450 inhibitor metyrapone, indicating that cytochrome P450 may be responsible for the transformation. Degenerate PCR primers were subsequently constructed and used to clone genes encoding cytochrome P450 from the genomic DNA of A. azurea JCM-3275. We cloned an entire novel P450 gene (1209 bp) and named it P450Um-1. Its deduced amino acid sequence was homologous with that of the CYP105 subfamily. Further cloning of the upstream region, which may contain the native promoter site, was followed by insertion of the open reading frame with the upstream area into Streptomycetes high copy vector pIJ702, giving the expression plasmid pNUm-1. P450Um-1 was specifically expressed in Streptomyces lividans TK24, and this recombinant strain converted AS1387392 to AS1429716 without any redox partners. These results show that P450Um-1, a novel bacterial P450, catalyzed hydroxylation of AS1387392 to AS1429716. This resultant recombinant strain is expected to be an efficient biocatalyst with application to more suitable redox systems than those tested here. PMID- 20924386 TI - 25 years of C60. AB - The discovery of buckminsterfullerene has had a widespread impact throughout science. PMID- 20924388 TI - Nanopores: Graphene opens up to DNA. PMID- 20924389 TI - Nanoelectronics: Nanoribbons on the edge. PMID- 20924390 TI - Nanomaterials: Graphene rests easy. PMID- 20924391 TI - Thermoelectric materials: Silicon stops heat in its tracks. PMID- 20924392 TI - beta-glucan from barley and its lipid-lowering capacity: a meta-analysis of randomized, controlled trials. AB - BACKGROUND/OBJECTIVES: To more precisely quantify the effect of barley beta glucan on blood lipid concentrations in humans and to examine the factors that could affect its efficacy. SUBJECTS/METHODS: Eleven eligible randomized clinical trials published from 1989 to 2008 were identified from nine databases. Weighted mean effect sizes were calculated for net differences in lipid profile using a random effect model (RevMan 4.2). RESULTS: Overall, barley and beta-glucan isolated from barley lowered total and low-density lipoprotein (LDL) cholesterol concentrations by 0.30 mmol/l (95% confidence interval (CI): -0.39 to -0.21, P<0.00001) and 0.27 mmol/l (95% CI: -0.34 to -0.20, P<0.00001), respectively, compared with control. The pattern of cholesterol-lowering action of barley in this analysis could not be viewed as a dose-dependent response. There were no significant subgroup differences by type of intervention and food matrix. CONCLUSIONS: Increased consumption of barely products should be considered as a dietary approach to reduce LDL cholesterol concentrations. PMID- 20924393 TI - Effects of PGX, a novel functional fibre, on acute and delayed postprandial glycaemia. AB - BACKGROUND: Viscous fibre in food has established health benefits, but few functional fibre preparations are both effective and palatable. Our objective was to determine the most effective dose, formulation and timing of consumption of a novel fibre supplement (PolyGlycopleX (PGX)) in reducing postprandial glycaemia. SUBJECTS/METHODS: Three trials were undertaken, each with 10 subjects (8M and 8F; age 24.4 +/- 2.6 years). Granular supplement was tested at four doses (0, 2.5, 5.0 and 7.5 g) with breakfast (study 1). Granular and capsule forms of the supplement were given in a single dose (5 g for granules and 4.5 g in capsules) at -60, -45, -30, -15 and 0 before, and +15 min after a bread meal (study 2). Capsules at increasing doses (1.5, 3, 4.5 and 6 g) were consumed with the evening meal to determine effects on glucose tolerance at breakfast (study 3). Incremental area under the blood glucose curve was determined. RESULTS: Granular PGX at breakfast time at doses of 2.5, 5 and 7.5 g reduced the incremental area under the curve by up to 50% in a linear dose-response fashion (P<0.001). The granular form of PGX (5 g), but not the capsules, reduced glycaemia by up to 28% when consumed from -45 to +15 min (P<0.001). Capsules containing 3, 4.5 and 6 g PGX consumed with the evening meal reduced glycaemia at breakfast by up to 28% (P<0.001). CONCLUSIONS: PGX has biologically important, dose-related effects on acute and delayed (second meal) postprandial glycaemia. PMID- 20924394 TI - Soy consumption is not protective against diabetes in Hawaii: the Multiethnic Cohort. AB - Based on the hypothesis that soy consumption may improve glucose tolerance, we examined the association of soy intake with diabetes risk in the Hawaii component of the Multiethnic Cohort. Among 29 719 Caucasian, 35 141 Japanese American and 10 484 Native Hawaiian men and women, 8564 incident diabetes cases were identified during 14 years of follow-up. Cox regression was used to calculate hazard ratios while adjusting for known confounders with stratifications by sex, ethnicity and weight status. We observed no protective effect of soy food consumption on diabetes risk in this population, which has a wide range of soy intakes though lower than in Asian populations. Indeed, higher soy food intake was associated with a weakly elevated diabetes risk across ethnic groups; the higher risk was limited to overweight and obese individuals. The current findings do not support a protective effect of modest levels of soy food consumption against diabetes. PMID- 20924395 TI - A splicing mastermind for EMT. PMID- 20924396 TI - Somatic piRNA biogenesis. PMID- 20924397 TI - Autophagy: in the hands of HMGB1. PMID- 20924398 TI - Crossing the great divide: telomeres and ecology. PMID- 20924399 TI - Fusion-fission experiments in Aphidius: evolutionary split without isolation in response to environmental bimodality. AB - Studying host-based divergence naturally maintained by a balance between selection and gene flow can provide valuable insights into genetic underpinnings of host adaptation and ecological speciation in parasites. Selection-gene flow balance is often postulated in sympatric host races, but direct experimental evidence is scarce. In this study, we present such evidence obtained in host races of Aphidius ervi, an important hymenopteran agent of biological control of aphids in agriculture, using a novel fusion-fission method of gene flow perturbation. In our study, between-race genetic divergence was obliterated by means of advanced hybridisation, followed by a multi-generation exposure of the resulting genetically uniform hybrid swarm to a two-host environment. This fusion fission procedure was implemented under two contrasting regimes of between-host gene flow in two replicated experiments involving different racial pairs. Host based genetic fission in response to environmental bimodality occurred in both experiments in as little as six generations of divergent adaptation despite continuous gene flow. We demonstrate that fission recovery of host-based divergence evolved faster and hybridisation-induced linkage disequilibrium decayed slower under restricted (6.7%) compared with unrestricted gene flow, directly pointing at a balance between gene flow and divergent selection. We also show, in four separate tests, that random drift had no or little role in the observed genetic split. Rates and patterns of fission divergence differed between racial pairs. Comparative linkage analysis of these differences is currently under way to test for the role of genomic architecture of adaptation in ecology driven divergent evolution. PMID- 20924401 TI - Go figure. AB - A picture may be worth a thousand words, but ensuring that those words make sense is important, especially in the context of a scientific figure. Here are some tips for making your figures count. PMID- 20924402 TI - The molecular principles of N-end rule recognition. AB - The N-end rule pathway is a proteolytic system in which recognition components (N recognins) recognize a set of N-terminal residues as part of degradation signals (N-degrons). Two studies in this issue report the structures of Ubr boxes, a substrate recognition domain of eukaryotic N-recognins. We discuss how eukaryotic and prokaryotic N-recognins use a similar molecular principle to recognize a different set of N-degrons. PMID- 20924400 TI - Hereditary disorders of renal phosphate wasting. AB - Inherited diseases of renal phosphate handling lead to urinary phosphate wasting and depletion of total body phosphorus stores. Clinical sequelae of inherited disorders that are associated with increased urinary phosphate excretion are deleterious and can lead to abnormal skeletal growth and deformities. This Review describes hereditary disorders of renal phosphate wasting taking into account developments in our understanding of renal phosphate handling from the last decade. The cloning of genes involved in these disorders and further studies on their pathophysiological mechanisms have given important insights in to how phosphatonins, such as FGF-23, regulate renal phosphate reabsorption in health and disease. X-linked dominant hypophosphatemic rickets results from mutation of a metalloprotease (PHEX) that has an unidentified role in FGF-23 degradation. Mutation of an RXXR proteolytic cleavage site in FGF-23 prevents degradation and increases circulating levels of FGF-23 in autosomal dominant hypophosphatemic rickets. FGF-23 acts to remove sodium phosphate co-transporters from the luminal membrane of proximal tubular cells with resultant renal phosphate wasting. Loss of function mutations in genes encoding the transporters NaPi-IIc and NaPi-IIa also result in renal phosphate wasting and rickets. PMID- 20924403 TI - One motor driving two translocases. AB - In this issue, Wu et al. show that the RecBC helicase, which is involved in repairing double-strand DNA breaks,uses one ATPase motor to drive two translocases along opposite strands of DNA-much as an all-wheel drive engine controls movement of both front and back wheels. This mechanism may allow RecBC to load onto blunt-end DNA more efficiently and to move through obstacles such as gaps and DNA damage. PMID- 20924406 TI - Gene-based interaction analysis by incorporating external linkage disequilibrium information. AB - Gene-gene interactions have an important role in complex human diseases. Detection of gene-gene interactions has long been a challenge due to their complexity. The standard method aiming at detecting SNP-SNP interactions may be inadequate as it does not model linkage disequilibrium (LD) among SNPs in each gene and may lose power due to a large number of comparisons. To improve power, we propose a principal component (PC)-based framework for gene-based interaction analysis. We analytically derive the optimal weight for both quantitative and binary traits based on pairwise LD information. We then use PCs to summarize the information in each gene and test for interactions between the PCs. We further extend this gene-based interaction analysis procedure to allow the use of imputation dosage scores obtained from a popular imputation software package, MACH, which incorporates multilocus LD information. To evaluate the performance of the gene-based interaction tests, we conducted extensive simulations under various settings. We demonstrate that gene-based interaction tests are more powerful than SNP-based tests when more than two variants interact with each other; moreover, tests that incorporate external LD information are generally more powerful than those that use genotyped markers only. We also apply the proposed gene-based interaction tests to a candidate gene study on high-density lipoprotein. As our method operates at the gene level, it can be applied to a genome-wide association setting and used as a screening tool to detect gene-gene interactions. PMID- 20924405 TI - Desperately seeking microRNA targets. AB - MicroRNAs (miRNAs) suppress gene expression by inhibiting translation, promoting mRNA decay or both. Each miRNA may regulate hundreds of genes to control the cell's response to developmental and other environmental cues. The best way to understand the function of a miRNA is to identify the genes that it regulates. Target gene identification is challenging because miRNAs bind to their target mRNAs by partial complementarity over a short sequence, suppression of an individual target gene is often small, and the rules of targeting are not completely understood. Here we review computational and experimental approaches to the identification of miRNA-regulated genes. The examination of changes in gene expression that occur when miRNA expression is altered and biochemical isolation of miRNA-associated transcripts complement target prediction algorithms. Bioinformatic analysis of over-represented pathways and nodes in protein-DNA interactomes formed from experimental candidate miRNA gene target lists can focus attention on biologically significant target genes. PMID- 20924407 TI - Empowerment: qualitative underpinning of a new clinical genetics-specific patient reported outcome. AB - Recent qualitative research developed a new construct labelled Empowerment describing a new patient outcome from using clinical genetics services that included four dimensions: Knowledge and Understanding, Decision-Making, Instrumentality and Future-Orientation. The aim of this study was to explore the validity, relevance and importance of the Empowerment construct for use as a patient-reported outcome (PRO) for clinical genetics services, and to refine the construct if necessary. Qualitative research (interviews and focus groups) was conducted in the UK with 12 patients, 15 representatives from patient support groups, 10 genetics clinicians and 4 service commissioners. Participants were asked to (1) describe what they think are the patient benefits from using clinical genetics services and (2) critique the Empowerment construct as a PRO. Interviews and focus groups were transcribed in full and analyzed using grounded theory. Findings confirmed the relevance and importance of the Empowerment construct, and identified Emotional Regulation as a further dimension of Empowerment. Data analysis also resulted in refinement of the construct, by renaming the other four dimensions to be Cognitive Control, Decisional Control, Behavioural Control and Hope. Empowerment has the potential to be a useful PRO to evaluate interventions in clinical genetics, and for use in clinical practice to generate data for continuous quality improvement. A study is underway to operationalise Empowerment by developing a psychometrically sound PRO measure that will take the form of a short questionnaire. PMID- 20924408 TI - Does heritability hide in epistasis between linked SNPs? PMID- 20924409 TI - Estimating penetrance from multiple case families with predisposing mutations: extension of the 'genotype-restricted likelihood' (GRL) method. AB - Some diseases are due to germline mutations in predisposing genes, such as cancer family syndromes. Precise estimation of the age-specific cumulative risk (penetrance) for mutation carriers is essential for defining prevention strategies. The genotype-restricted likelihood (GRL) method is aimed at estimating penetrance from multiple case families with such a mutation. In this paper, we proposed an extension of the GRL to account for multiple trait disease and to allow for a parent-of-origin effect. Using simulations of pedigrees, we studied the properties of this method and the effect of departures from underlying hypotheses, misspecification of disease incidence in the general population or misspecification of the index case, and penetrance heterogeneity. In contrast with the previous version of the GRL, accounting for multiple trait disease allowed unbiased estimation of penetrance. We also showed that accounting for a parent-of-origin effect allowed a powerful test for detecting this effect. We found that the GRL method was robust to misspecification of disease incidence in the population, but that misspecification of the index case induced a bias in some situations for which we proposed efficient corrections. When ignoring heterogeneity, the penetrance estimate was biased toward that of the highest risk individuals. A homogeneity test performed by stratifying the families according to the number of affected members was shown to have low power and seems useless for detecting such heterogeneity. These extensions are essential to better estimate the risk of diseases and to provide valid recommendations for the management of patients. PMID- 20924411 TI - Justification for including MRI as a tool in the diagnosis of axial SpA. AB - New classification criteria for axial spondyloarthritis (SpA) have been developed and validated. MRI of the sacroiliac joints is an important feature in these criteria. This is rightfully so, as MRI can identify active lesions in the subchondral bone marrow that are thought to be related to the underlying pathophysiological process at the cartilage-bone junction. Follow-up studies using various imaging techniques, including MRI, in unselected patients with undiagnosed back pain of short symptom duration will provide more information on the differential diagnostic capacity of MRI and its predictive value for long term outcomes. Even longer-term follow-up (>10 years) is necessary to provide reliable data; however, the validity of MRI in the diagnostic process can only be approximated, as it will never cover the entire gestalt of SpA. PMID- 20924410 TI - The role of synovitis in pathophysiology and clinical symptoms of osteoarthritis. AB - Osteoarthritis (OA), one of the most common rheumatic disorders, is characterized by cartilage breakdown and by synovial inflammation that is directly linked to clinical symptoms such as joint swelling, synovitis and inflammatory pain. The gold-standard method for detecting synovitis is histological analysis of samples obtained by biopsy, but the noninvasive imaging techniques MRI and ultrasonography might also perform well. The inflammation of the synovial membrane that occurs in both the early and late phases of OA is associated with alterations in the adjacent cartilage that are similar to those seen in rheumatoid arthritis. Catabolic and proinflammatory mediators such as cytokines, nitric oxide, prostaglandin E(2) and neuropeptides are produced by the inflamed synovium and alter the balance of cartilage matrix degradation and repair, leading to excess production of the proteolytic enzymes responsible for cartilage breakdown. Cartilage alteration in turn amplifies synovial inflammation, creating a vicious circle. As synovitis is associated with clinical symptoms and also reflects joint degradation in OA, synovium-targeted therapy could help alleviate the symptoms of the disease and perhaps also prevent structural progression. PMID- 20924412 TI - 'MRI-tis' in the early diagnosis of axial SpA: issues and limitations. AB - Sacroiliitis on conventional radiography, a key diagnostic feature of axial spondyloarthritis (SpA), often appears only late in the disease course. With the introduction of potent biologic agents that may also be effective in early disease, diagnostic techniques that can identify SpA early in the disease course would be highly beneficial to patients. MRI has been proposed as a novel diagnostic tool for early axial SpA based on the visualization of active inflammatory lesions in established axial SpA, as well as in pre-radiographic axial SpA. Accordingly, MRI is already widely used in clinical practice and has been included in new classification criteria. However, the specificity and predictive value of MRI lesions for the development of axial SpA remain to be fully defined and validated. Most data come from cross-sectional analyses and have not been validated in prospective studies, and the few available prospective studies were performed in highly selected patient populations and have assessed the value of MRI for the prediction of sacroiliitis rather than axial SpA. Also, some studies have indicated considerable diversity in the pattern and extent of MRI lesions, and suggest that many lesions are not specific for SpA. Prospective, longitudinal studies are needed to validate the utility of this new imaging modality for the diagnosis of axial SpA. PMID- 20924414 TI - Coptotermes gestroi (Isoptera: Rhinotermitidae) in Brazil: possible origins inferred by mitochondrial cytochrome oxidase II gene sequences. AB - The Asian subterranean termite, Coptotermes gestroi, originally from northeast India through Burma, Thailand, Malaysia, and the Indonesian archipelago, is a major termite pest introduced in several countries around the world, including Brazil. We sequenced the mitochondrial COII gene from individuals representing 23 populations. Phylogenetic analysis of COII gene sequences from this and other studies resulted in two main groups: (1) populations of Cleveland (USA) and four populations of Malaysia and (2) populations of Brazil, four populations of Malaysia, and one population from each of Thailand, Puerto Rico, and Key West (USA). Three new localities are reported here, considerably enlarging the distribution of C. gestroi in Brazil: Campo Grande (state of Mato Grosso do Sul), Itajai (state of Santa Catarina), and Porto Alegre (state of Rio Grande do Sul). PMID- 20924413 TI - ANCA-associated vasculitides--advances in pathogenesis and treatment. AB - Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) include Wegener granulomatosis, microscopic polyangiitis, Churg-Strauss syndrome and renal-limited vasculitis. This Review highlights the progress that has been made in our understanding of AAV pathogenesis and discusses new developments in the treatment of these diseases. Evidence from clinical studies, and both in vitro and in vivo experiments, supports a pathogenic role for ANCAs in the development of AAV; evidence is stronger for myeloperoxidase-ANCAs than for proteinase-3 ANCAs. Neutrophils, complement and effector T cells are also involved in AAV pathogenesis. With respect to treatment of AAV, glucocorticoids, cyclophosphamide and other conventional therapies are commonly used to induce remission in generalized disease. Pulse intravenous cyclophosphamide is equivalent in efficacy to oral cyclophosphamide but seems to be associated with less adverse effects. Nevertheless, alternatives to cyclophosphamide therapy have been investigated, such as the use of methotrexate as a less-toxic alternative to cyclophosphamide to induce remission in non-organ-threatening or non-life-threatening AAV. Furthermore, rituximab is equally as effective as cyclophosphamide for induction of remission in AAV and might become the standard of therapy in the near future. Controlled trials in which specific immune effector cells and molecules are being therapeutically targeted have been initiated or are currently being planned. PMID- 20924415 TI - Comparative genomic analysis of the false killer whale (Pseudorca crassidens) LMBR1 locus. AB - The sequencing and comparative genomic analysis of LMBR1 loci in mammals or other species, including human, would be very important in understanding evolutionary genetic changes underlying the evolution of limb development. In this regard, comparative genomic annotation of the false killer whale LMBR1 locus could shed new light on the evolution of limb development. We sequenced two false killer whale BAC clones, corresponding to 156 kb and 144 kb, respectively, harboring the tightly linked RNF32, LMBR1, and NOM1 genes. Our annotation of the false killer whale LMBR1 gene showed that it consists of 17 exons (1473 bp), in contrast to 18 exons (1596 bp) in human, and it displays 93.1% and 95.6% nucleotide and amino acid sequence similarity, respectively, compared with the human gene. In particular, we discovered that exon 10, deleted in the false killer whale LMBR1 gene, is present only in primates, and this fact strongly implies that exon 10 might be crucial in determining primate-specific limb development. ZRS and TFBS sequences have been well conserved across 11 species, suggesting that these regions could be involved in an important function of limb development and limb patterning. The neighboring gene RNF32 showed several lineage-conserved exons, such as exons 2 through 9 conserved in eutherian mammals, exons 3 through 9 conserved in mammals, and exons 5 through 9 conserved in vertebrates. The other neighboring gene, NOM1, had undergone a substitution (ATG→GTA) at the start codon, giving rise to a 36 bp shorter N-terminal sequence compared with the human sequence. Our comparative analysis of the false killer whale LMBR1 genomic locus provides important clues regarding the genetic regions that may play crucial roles in limb development and patterning. PMID- 20924416 TI - Construction of a Coix BAC library and isolation of the 22 kDa α-coixin gene cluster. AB - Coix lacryma-jobi L. (Coix) is a close relative of maize and is considered a valuable genetic resource for crop improvement. Here we report the construction of the first Coix bacterial artificial chromosome (BAC) library using accession PI 324059. This BAC library contains about 230 400 clones with an average insert size of 113 kb, has low organellar DNA contamination, and provides 16.3-fold coverage of the genome. The library was stored in 12 * 96 pools that could be screened with a PCR protocol. Library screening was performed for the 22 kDa α-coixin gene family. A total of 57 positive pools were identified, and single clones were isolated from 19 of these pools. Based on DNA fingerprinting and Southern blot analysis, these 19 BAC clones form a single contig of about 340 kb in length, indicating that the 22 kDa α-coixin genes occur in a cluster. These results demonstrated the suitability of this BAC library for gene isolation and comparative genomics studies of the Coix genome. PMID- 20924417 TI - Complex prokaryotic genome structure: rapid evolution of chromosome II. AB - Although many bacteria with two chromosomes have been sequenced, the roles of such complex genome structuring are still unclear. To uncover levels of chromosome I (CI) and chromosome II (CII) sequence divergence, Mauve 2.2.0 was used to align the CI- and CII-specific sequences of bacteria with complex genome structuring in two sets of comparisons: the first set was conducted among the CI and CII of bacterial strains of the same species, while the second set was conducted among the CI and CII of species in Alphaproteobacteria that possess two chromosomes. The analyses revealed a rapid evolution of CII-specific DNA sequences compared with CI-specific sequences in a majority of organisms. In addition, levels of protein divergence between CI-specific and CII-specific genes were determined using phylogenetic analyses and confirmed the DNA alignment findings. Analysis of synonymous and nonsynonymous substitutions revealed that the structural and functional constraints on CI and CII genes are not significantly different. Also, horizontal gene transfer estimates in selected organisms demonstrated that CII in many species has acquired higher levels of horizontally transferred segments than CI. In summary, rapid evolution of CII may perform particular roles for organisms such as aiding in adapting to specialized niches. PMID- 20924418 TI - The ionotropic γ-aminobutyric acid receptor gene family of the silkworm, Bombyx mori. AB - γ-Aminobutyric acid (GABA) is a very important inhibitory neurotransmitter in both vertebrate and invertebrate nervous systems. GABA receptors (GABARs) are known to be the molecular targets of a class of insecticides. Members of the GABAR gene family of the silkworm, Bombyx mori, a model insect of Lepidoptera, have been identified and characterized in this study. All putative silkworm GABAR cDNAs were cloned using the reverse transcriptase polymerase chain reaction (RT PCR) and rapid amplification of cDNA ends (RACE). Bombyx mori appears to have the largest insect GABAR gene family known to date, including three RDL, one LCCH3, and one GRD subunit. The silkworm RDL1 gene has RNA-editing sites, and the RDL1 and RDL3 genes possess alternative splicing. These mRNA modifications enhance the diversity of the silkworm's GABAR gene family. In addition, truncated transcripts were found for the RDL1 and LCCH3 genes. In particular, the three RDL subunits may have arisen from two duplication events. PMID- 20924419 TI - Genetic diversity and population structure analysis of the tropical pasture grass Brachiaria humidicola based on microsatellites, cytogenetics, morphological traits, and geographical origin. AB - Brachiaria humidicola (Rendle) Schweick. is a warm-season grass commonly used as forage in the tropics. Accessions of this species were collected in eastern Africa and massively introduced into South America in the 1980s. Several of these accessions form a germplasm collection at the Brazilian Agricultural Research Corporation. However, apomixis, ploidy, and limited knowledge of the genetic basis of this germplasm collection have constrained breeding activities. The objectives of this work were to identify genetic variability in the Brazilian B. humidicola germplasm collection using microsatellite markers and to compare the results with information on the following: (1) collection sites of the accessions; (2) reproductive mode and ploidy levels; and (3) genetic diversity revealed by morphological traits. The evaluated germplasm population is highly structured into four major groups. The sole sexual accession did not group with any of the clusters. Genetic dissimilarities did not correlate with either geographic distances or genetic distances inferred from morphological descriptors. Additionally, the genetic structure identified in this collection did not correspond to differences in ploidy level. Alleles exclusive to either sexual or apomictic accessions were identified, suggesting that further evaluation of the association of these loci with apospory should be carried out. PMID- 20924420 TI - Mapping of quantitative trait loci for fire blight resistance in the apple cultivars 'Florina' and 'Nova Easygro'. AB - Fire blight is a devastating bacterial disease of rosaceous plants. Its damage to apple production is a major concern, since no existing control option has proven to be completely effective. Some commercial apple varieties, such as 'Florina' and 'Nova Easygro', exhibit a consistent level of resistance to fire blight. In this study, we used an F1 progeny of 'Florina' * 'Nova Easygro' to build parental genetic maps and identify quantitative trait loci (QTLs) related to fire blight resistance. Linkage maps were constructed using a set of microsatellites and enriched with amplified fragment length polymorphism (AFLP) markers. In parallel, progeny plants were artificially inoculated with Erwinia amylovora strain CFBP 1430 in a quarantine glasshouse. Shoot length measured 7 days after inoculation (DAI) and lesion length measured 7 and 14 DAI were used to calculate the lesion length as a percentage of the shoot length (PLL1 and PLL2, respectively). Percent lesion length data were log10-transformed (log10(PLL)) and used to perform the Kruskal-Wallis test, interval mapping (IM), and multiple QTL mapping (MQM). Two significant fire blight resistance QTLs were detected in 'Florina'. One QTL was mapped on linkage group 10 by IM and MQM; it explained 17.9% and 15.3% of the phenotypic variation by MQM with log10(PLL1) and log10(PLL2) data, respectively. A second QTL was identified on linkage group 5 by MQM with log10(PLL2) data; it explained 10.1% of the phenotypic variation. Genotyping the plants of 'Florina' pedigree with the microsatellites flanking the QTLs showed that the QTLs on linkage groups 5 and 10 were inherited from 'Jonathan' and 'Starking' (a 'Red Delicious' sport mutation), respectively. Other putative QTLs (defined as QTLs with LOD scores above the chromosomal threshold and below the genome-wide threshold) were detected by IM on linkage groups 5 and 9 of 'Nova Easygro'. PMID- 20924421 TI - Sequence characterization and phylogenetic analysis of the 5S ribosomal DNA in species of the family Batrachoididae. AB - 5S ribosomal DNA (rDNA) sequences were analyzed in four species belonging to different genera of the fish family Batrachoididae. Several 5S rDNA variants differing in their non-transcribed spacers (NTSs) were found and were grouped into two main types. Two species showed both types of 5S rDNA, whereas the other two species showed only one type. One type of NTS of Amphichthys cryptocentrus showed a high polymorphism due to several deletions and insertions, and phylogenetic analysis showed a between-species clustering of this type of NTS in Amphichthys cryptocentrus. These results suggest a clear differentiation in the model of 5S rDNA evolution of these four species of Batrachoididae, which appear to have been subject to processes of concerted evolution and birth-and-death evolution with purifying selection. PMID- 20924422 TI - The evolution of chloroplast genome structure in ferns. AB - The plastid genome (plastome) is a rich source of phylogenetic and other comparative data in plants. Most land plants possess a plastome of similar structure. However, in a major group of plants, the ferns, a unique plastome structure has evolved. The gene order in ferns has been explained by a series of genomic inversions relative to the plastome organization of seed plants. Here, we examine for the first time the structure of the plastome across fern phylogeny. We used a PCR-based strategy to map and partially sequence plastomes. We found that a pair of partially overlapping inversions in the region of the inverted repeat occurred in the common ancestor of most ferns. However, the ancestral (seed plant) structure is still found in early diverging branches leading to the osmundoid and filmy fern lineages. We found that a second pair of overlapping inversions occurred on a branch leading to the core leptosporangiates. We also found that the unique placement of the gene matK in ferns (lacking a flanking intron) is not a result of a large-scale inversion, as previously thought. This is because the intron loss maps to an earlier point on the phylogeny than the nearby inversion. We speculate on why inversions may occur in pairs and what this may mean for the dynamics of plastome evolution. PMID- 20924423 TI - Improved detection of motifs with preferential location in promoters. AB - Many transcription factor binding sites (TFBSs) involved in gene expression regulation are preferentially located relative to the transcription start site. This property is exploited in in silico prediction approaches, one of which involves studying the local overrepresentation of motifs using a sliding window to scan promoters with considerable accuracy. Nevertheless, the consequences of the choice of the sliding window size have never before been analysed. We propose an automatic adaptation of this size to each motif distribution profile. This approach allows a better characterization of the topological constraints of the motifs and the lists of genes containing them. Moreover, our approach allowed us to highlight a nonconstant frequency of occurrence of spurious motifs that could be counter-selected close to their functional area. Therefore, to improve the accuracy of in silico prediction of TFBSs and the sensitivity of the promoter cartography, we propose, in addition to automatic adaptation of window size, consideration of the nonconstant frequency of motifs in promoters. PMID- 20924424 TI - [XXX anniversary of the "Revista Gastroenterologia del Peru"]. PMID- 20924425 TI - [Acute pancreatitis: a non silent epidemic]. PMID- 20924426 TI - [Necrotic acute pancreatitis in the intensive care unit: a comparison between conservative and surgical medical treatment]. AB - OBJECTIVE: To determine the prognosis of patients with necrotic acute pancreatitis receiving medical and surgical treatments. SUMMARY: The severe acute pancreatitis treatment is multidisciplinary and requires a daily evaluation of the patient that will allow to observe changes and apply therapy in due time. The treatment includes: Admission in the ICU, fluids, nutrition and antibiotics, as well as other life supports for high-risk patients. Thus, patients undergo conservative treatment or, if it is necessary, surgery. METHODS: A retrospective study of patients with necrotic acute pancreatitis admitted to the ICU between January 2004 and August 2006. The patients with necrotic acute pancreatitis without signs of sepsis underwent a conservative medical treatment, while fine needle punction-aspiration was performed in all patients who were suffering from necrotic acute pancreatitis and persistent sepsis four weeks after their admission and after discarding and eradicating every non-pancreatic focus of infection. All Gram stain or culture positive patients underwent surgery immediately. RESULTS: Seventy patients with necrotic acute pancreatitis were included in the study. Thirty-six patients (51%) suffered acute pancreatitis with sterile necrosis and underwent a conservative treatment, while 34 patients (49%) developed acute pancreatic with infected necrosis and underwent surgery. The average age was 55.19 vs. 57.65 (p=0.57). The average amylase was 1421.74 vs. 1402.45. (p=0.96). The tomography severity index was 8.47 vs. 8.79 (p=0.36). The Apache II was 8.22 vs. 9 (p=0.46). The average number of failed organs was 0.39 vs. 0.68. (p=0.19). The ICU stay was 10.75 vs. 26.5 days (p<0.05) while the total hospital stay was 46.47 vs. 57.26 days (p<0.05). The mortality rate was (3/36) 8.3% vs. (9/34) 26.5% (p<0.05) for conservative medical treatment vs. surgical treatment, respectively. Between the first and the twelfth month the evaluated patients who attended consultation, after discharge, showed: pancreatic pseudocyst 9/36 (25%) vs. 8/34(23.5%); recurring abdominal pain 3/36 (8.3%) vs. 4/34 (11.8%); and relapsing acute pancreatitis 3/36 (8.3%) vs. 2/34 (5.8%); while 4/36 (11.1%) vs. 3/34 (8.8%) did not show any problem. There were not significant differences between the conservative and the surgical medical treatment, respectively. CONCLUSIONS: Patients suffering acute pancreatitis with sterile necrosis can undergo conservative medical treatment which will result in a lower mortality rate, while the hospital stay, in comparison with acute pancreatitis with infected necrosis, will not be affected. PMID- 20924428 TI - [Predictive mortality value of the peritonitis index of Mannheim]. AB - OBJECTIVE: To determine the predictive value of the index of peritonitis of Mannheim in patients with peritonitis in the Hospital Nacional Cayetano Heredia. PATIENTS AND METHODS: A prospective study appears, of 103 patients, greater of 14 years, with I diagnose of peritonitis, between November 2004 to April 2005. For its analysis I am used the square test of chi with coefficient of Pearson, and the test of T of student. For the analysis of the data two modalities were used, the first patients were divided in 3 groups, according to the value of the index of Mannheim, < 21, of 21 to 29, and > 29, and in 2 groups, d 26 and > 26 points. I am made considered of survival of Kaplan the Meier, using statistical program STATA 8.0 RESULTS: a mortality of 50% in patients with greater index of 26 points was obtained. One was a sensitivity 95.9%, a specificity of 80%, with positive a predictive value 98.9% and a negative predictive value of 50%. When considering 3 groups, < 21, 21-29 and > 29 points, was a mortality of 60% in patients with greater index of 29. I am made a survival curve obtaining itself a significant difference with a p=0, 0098. Figure 2. CONCLUSIONS: We found that the classification in 3 groups presents statistically significant difference, reason why recommended its use for the evaluation and beginning of aggressive measures. PMID- 20924427 TI - [Clinical, endoscopic and histologic profile of the Gastrointestinal Stromal Tumours in the Rebagliati Hospital]. AB - INTRODUCTION: Gastrointestinal Stromal Tumors (GIST) are lesions which origin from Intersticial Cells of Cajal that may be asymptomatic or cause complications like digestive bleeding or malignant transformation. AIM: To determine the clinical, endoscopic and histological profile, as well as the main demographic features of patients with GIST in Hospital Edgardo Rebagliati (Lima-Peru) from January 2002 to December 2004. METHODS: Descriptive, transversal and retrospective study in which we reviewed clinical and anatomopathological archives from 34 patients with GIST during the above mentioned period. The collected data were placed on a sheet of recollection. RESULTS: There was male predominance (58.82%).The most affected age group was 71-80 years old (26.47%). The average age was 64.7 years old. The most frequent clinical presentation was abdominal pain (47.06%) followed by melena (44.12%). Diagnosis was made by endoscopic method in 58.82%. The main histological type was spindle (47.06%). There was high risk of malignancy in 50% and the most often involved site was stomach (61.77%). Endoscopicall the characteristic image was a submucosal tumor with ulceration, the average size was 6.44 cm. There was significant statistical relation (p<0.05) between endoscopic method and melena. CONCLUSION: Patients with GIST in HNERM are mostly men, older than 60 years that come with abdominal pain and melena, being endoscopy the best method to diagnose if patients present melena. Predominating histology was fusiform. PMID- 20924429 TI - [Acute necrotizing pancreatitis by a foreign body. First worldwide report secondary to a match impactation]. AB - Pancreatitis caused by foreign bodies is exceptionally rare. It has been described: needles, surgical clips, sutures, belt buckles, toothpicks, spines of fish, chicken feathers and bezoars. This is the first case reported in world literature caused by a match ("cerillo"). A 73-year-old women, admitted with the diagnostic of severe necrotizing pancreatitis, APACHE score 12, during 36 hours following the admission she developed refractory hypotension, acute renal failure and finally died. The necropsy showed: extensive necrosis that compromise the whole pancreas and a match impacted in the duct of Wirsung. Microscopic evaluation revealed coagulative parenchymal necrosis, micro abscesses and a dense accumulation of acute inflammatory cells surrounding the match. PMID- 20924430 TI - [Duodenal involvement in Henoch-Schonlein purpura. Report of a case]. AB - Henoch-Schonlein purpura (HSP) is a systemic vasculitis of the small vessels of the skin, joints, gastrointestinal tract and kidneys. It is the most common cause of nonthrombocytopenic purpura in children, but may also occur in adults. Gastrointestinal symptoms and disease occurs in up to 85% of patients and can be of varying intensity. We report a 12 year old boy with gastrointestinal bleeding due to duodenal involvement associated with this condition evidenced by endoscopy. PMID- 20924431 TI - [Primary hydatid cyst of the spleen]. AB - We present the case of a 63 year male patient, natural from Lima. He has been in a cattle zone seven years ago. His illness had an insidious start and a progressive course; from a month ago he had malaise associated with nausea, abdominal distention and occasional vomiting; denies weight loss. In the clinical examination was lucid and stable, and without jaundice. The abdomen was soft without signs of peritoneal irritation; in the left flank there was a large mass with defined limits, painless, attached to deeper layers. Auxiliary tests: CBC: eosinophils 5.74%; the levels coagulation, biochemistry and electrolytes were normal. Total protein, albumin, bilirubin levels, aminotransferasas (ALT an AST) and alkaline phosphatase were normals. Arco V: 248 (N<22) and positive Inmunoblot to Echinococcus granulosus. Abdominal ultrasound showed two cystic formations of 161 x 95 mm and 146 x 130 mm, that moving the left kidney and spleen. Axial tomography was interpreted as a large ovoid formation (12 x 18 x 27 cm) dependent on spleen, lobed, hypodense, with rounded focal areas with less attenuation in the peripheral area; without contrast enhancement, compatible with hydatid cyst Gharbi III. The surgical intervention was a partial cystectomy plus external drainage; the surgeon found a giant splenic hydatid cyst, occupied the left hypochondrium and the left flank; had thick walls, daughter vesicles and clear liquid inside. The cystic lesion was attached to the descending colon, stomach, and left diaphargm. We present this case because the splenic hydatid cyst is rare, even less as a single site, and their prevalence does not exceed 1 %. PMID- 20924432 TI - [Appendiceal orifice inflammation in distal ulcerative colitis. Report of a case and review of the literature]. AB - We report the case of a 45-year-old female patient with an 18 month diagnosis of distal ulcerative colitis (proctosigmoiditis) of 18 months, who presented initially with allergy to salicylates, for which the disease was managed with corticosteroids and azathioprine and subsequently with Infliximab infusions, entering in remission. When she was about to receive her fifth Infliximab infusion she presented an exacerbation of her underlying disease with frequent stools with mucus, blood and tenesmus. Given that her initial diagnosis was made with a sigmoidoscopy we scheduled a total colonoscopy showing marked inflammation, erythema and friability limited to the recto-sigmoid mucosa, like at the disease onset, and when we reached the cecum an erythematous area circumscribed to the appendiceal orifice was observed, with a mucosal aspect identical to the described for the recto-sigmoid mucosa. The biopsies taken from that area were compatible with ulcerative colitis. We herein describe the details of the case and review the literature. PMID- 20924433 TI - [Spontaneous rupture of choriocarcinoma hepatic metastases: Report of a Case]. AB - Choriocarcinoma is a highly vascularized gestational trophoblastic neoplasia, and has a propensity to metastasize hematogenously. Hepatic metastases are less common and spontaneous rupture of them results in a hemoperitoneum. We present a case of a young female with liver metastases from choriocarcinoma, who had severe haemorrhage and died after the second laparotomy. The possibility of choriocarcinoma should be suspected in women of child bearing age who present liver metastases. Because of the high risk oh haemorrhage, liver biopsy should be deferred until HCG has been measured. PMID- 20924434 TI - [Lumbar abscess secundary to retained gallstones]. AB - Lost gallstones after accidental opening of the gallbladder during cholecystectomy usually under laparoscopy, can cause late complications. Intra abdominal abscess is the most frequent and the diagnosis is based on imaging techniques (abdominal ultrasound or computed tomography scan). Surgical drainage with gallstones removal seems to be the best approach, due to the fact that a simple percutaneous drainage has a high failure rate. However, a posterior abdominal wall abscess as the initial manifestation of intra-abdominal abscess due to retained gallstones is uncommon, and this prompted us to report this case. PMID- 20924435 TI - [Gastrointestinal stromal tumor (GIST) of Duodenum: Case report]. AB - Female of 64 years old, who two years ago was hospitalized in another institution for treatment of an abscess in the right liver lobe. During that hospitalization, it was found a duodenal tumor by tomography; however, no further studies or follow up on this finding was done. Prior to actual hospitalization, she was seen in a private clinic and treated with antibiotics for a suggestive"organized abscess" in the pancreatic head diagnosed by tomography. She presented with fever, abdominal pain and a palpable abdominal tumor in the right upper quadrant for a month. We realized a three-phase multislice spiral tomography with pancreatic curved reconstruction, which allowed to identified an ovoid tumor of 80 x 60 mm, with an area of central necrosis and intense contrast enhancement (arterial phase), located between the second and third duodenal portion, near the head of the pancreas. An upper endoscopy showed an extrinsic compression of the third duodenal portion. The patient underwent tumor resection without complication and the histologic diagnosis of the surgical specimen revealed a duodenal stromal tumor (GIST) with extraluminal transmural growth. We presented this case because of its unusual presentation of this tumor. PMID- 20924436 TI - Assessment of cumulative exposure to UVA through the study of asymmetrical facial skin aging. AB - BACKGROUND: Published studies assessing whether asymmetrical facial ultraviolet light exposure leads to underlying differences in skin physiology and morphology report only clinical observations. The aim of this study was to assess the visual impact on the skin of repeated ultraviolet-A (UVA) exposure through a window. METHODS: Eight women and two men presenting with asymmetrical signs of photoaging due to overexposure of one side of their face to the sun through a window over a long period of time were enrolled in the study. Split-face biometrologic assessments were performed (clinical scoring, hydration with Corneometer, mechanical properties with Cutometer, transepidermal water loss with AquaFlux, skin relief with fringe projection, photography, stripping, and then lipid peroxidation analysis). RESULTS: Significant differences were observed in clinical scores for wrinkles, skin roughness assessed by fringe projection on the cheek, and skin heterogeneity assessed with spectrocolorimetry on the cheekbone. Other differences were observed for skin hydration, as well as skin laxity, which tended towards significance. DISCUSSION: This study suggests the potential benefit of daily UVA protection during nondeliberate exposure indoors as well as outside. PMID- 20924437 TI - Aging, human immunodeficiency virus, and bone health. AB - Highly active antiretroviral therapy (HAART) has had a profound impact on improving the long-term prognosis for individuals infected with human immunodeficiency virus (HIV). HAART has been available for close to two decades, and now a significant number of patients with access to HAART are over the age of 50 years. Many clinical studies have indicated that HIV infection, as well as components of HAART, can increase the risk in these individuals to a variety of noninfectious complications, including a risk to bone health. There is a significant need for detailed mechanistic analysis of the aging, HIV-infected population regarding the risk of HIV infection and therapy in order to maintain bone health. Insights from basic mechanistic studies will help to shed light on the role of HIV infection and the components of HAART that impact bone health, and will help in identifying preventative countermeasures, particularly for individuals 50 years of age and older. PMID- 20924440 TI - The question of authorship: Whose research is it anyway? PMID- 20924438 TI - Facial rejuvenation for middle-aged women: a combined approach with minimally invasive procedures. AB - Facial rejuvenation is a significant process involved in restoring youthfulness. The introduction of less invasive procedures has increased acceptance of such procedures. Often a combination of different techniques allows individualized treatment with optimal outcomes. Furthermore, this leads to a natural look without a significant downtime. We report herein the use of such a combined approach in middle-aged women with particular emphasis on botulinum toxin type A, dermal fillers, and chemical peels. PMID- 20924439 TI - What is the job of the editor of a plastic surgery journal? PMID- 20924441 TI - Prof. M. M. Mukherjee. PMID- 20924442 TI - Tensor Facia Lata-iliac crest osteocutaneous flap for orbitomaxillary reconstruction: A preliminary report. AB - Tensor Fascia Lata muscle and musculocutaneous flap has been used in the past for reconstruction of trunk defects and also as a free flap for soft tissue reconstruction elsewhere in the body. Transferring the iliac crest along with the muscle as a free flap has been described earlier, reported for bridging calcaneal defect and small mandibular defects. The use of this flap as a source of free vascularised bone has not been widely practised since these initial few reports. Anatomical studies were carried out to assess the feasibility of using this flap for reconstructing maxillary and other head and neck defects, following which it was successfully used for these indications. The preliminary report describes the flap anatomy, method of harvest and its potential uses in head and neck reconstruction. PMID- 20924443 TI - Two-stage reconstruction for flexor tendon injuries in zone II using a silicone rod and pedicled sublimis tendon graft. AB - We report the results of staged flexor tendon reconstruction in 12 patients (12 fingers) with neglected or failed primary repair of flexor tendon injuries in zone II. Injuries involved both flexor digitorum profundus (FDP) and flexor digitorum sublimis (FDS), with poor prognosis (Boyes grades II-IV). The procedure included placing a silicone rod and creating a loop between the FDP and FDS in the first stage and reflecting the latter as a pedicled graft through the pseudosheath created around the silicone rod in the second stage. At a mean follow-up of 18 months (range 12-30 months), results were assessed by clinical examination and questionnaire. The mean total active motion of these fingers was 188 degrees . The mean power grip was 80.0% and pinch grip was 76% of the contralateral hand. The rate of excellent and good results was 75% according to the Buck-Gramcko scale. These results were better than the subjective scores given by the patients. Complications included postoperative hematoma in two, infection in one, silicone synovitis in one (after stage I) and three flexion contractures after stage II. This study confirmed the usefulness of two-stage flexor tendon reconstruction using the combined technique as a salvage procedure to restore flexor tendon function with a few complications. PMID- 20924444 TI - A modified tubularised incised plate urethroplasty technique and a revised hypospadias algorithm. AB - To simplify and standardize surgical management of hypospadias, a modified tubularised incised plate (TIP) urethroplasty (Snodgrass) technique has been described and a revised hypospadias management algorithm has been formulated. The study aims to evaluate the viability of the described procedure in different types of hypospadias and tests the validity of the algorithm. The modification described is recruitment of penile and glandular skin lateral to the urethral plate to facilitate tubularisation. The algorithm starts with penile degloving with preservation of urethral plate. Snodgrass repair was done in cases with no chordee and where skin chordee resolved by skin take down. Modified Snodgrass repair was done in cases where urethral plate was narrow. Another modification proposed by us is single layer penile skin closure instead of an added dartos flap, which was done in both classical and modified Snodgrass repair. Cases of severe chordee not resolved by skin take down were repaired by transverse preputial island flap (TPIF) and Bracka's technique. Dorsal plication was not used as an orthoplasty modality. It was possible to repair 68.89% of the cases by Snodgrass repair. These patients either had no chordee or had superficial skin tethering (skin chordee) which resolved on degolving. All these cases were coronal, distal and mid penile hypospadias. Remaining cases were mid, proximal and penoscrotal with true fibrous chordee and were repaired by TPIF or Bracka's technique. The Snodgrass technique had a fistula rate of 9.67%. Acceptably, low fistula rate and simple execution make the proposed modification of classical Snodgrass repair a viable option. The proposed algorithm proves to be a useful tool for standardised and logical preoperative decision making. It also defines indications of the three techniques vis-a-vis the type of hypospadias. PMID- 20924445 TI - Hypospadias algorithm: The way to propose. PMID- 20924446 TI - The acute management of acid assault burns: A pragmatic approach. AB - This case series comprises 31 patients who were victims of acid assault burns. They were admitted for acute or reconstructive care to a regional burns unit. Ten patients were admitted late with suboptimal acute care and needed a total of 50 reconstructive procedures. Of 13 patients admitted acutely, 7 had surgery performed after 48 hours of constant lavage while seven had urgent surgical debridement within 48 hours, followed by lavage. Although the number of reconstructive procedures performed in these two groups was similar, i.e., 20 and 19, respectively, the magnitude of the deformity in the urgent surgery group was significantly less than in the conventional surgery group. As in many cases of acute burns care, determining the evidence for best practice using a prospective, randomised, controlled comparison of conventional versus urgent surgery is difficult in view of the small number of cases involved. However, basing surgical practice on ethical principles, and in particular 'primum non nocere,' we propose that the urgent reduction of the chemical load on the skin by surgical debridement is appropriate in selected cases and should be considered in the acute management of these devastating injuries. PMID- 20924447 TI - Long-term results of high-density porous polyethylene implants in facial skeletal augmentation: An Indian perspective. AB - CONTEXT: With the increasing emphasis on well-sculpted facial features, today there is a growing need for tools to augment the facial skeleton; either for cosmetic reasons or to re-contour deformities-congenital, post-traumatic and post ablative. The limitations of autogenous materials has lead to evolution of numerous 'alloplasts', of which, high-density porous polyethylene (HDPE) seems to be a promising alternative. AIMS: To evaluate the long term results of HDPE in facial skeletal augmentation in terms of achieving desired facial contour, patient satisfaction and complications. SETTINGS: A tertiary care referral centre in a metropolitan set-up. DESIGN: Case Series MATERIALS AND METHODS: All patients undergoing HDPE implant insertion for facial skeletal augmentation between July 2001 and November 2009 were included in the study. A total of 70 HDPE implants were inserted in 44 patients. All procedures were performed by a single surgeon following standardized pre, intra and post-operative protocols. The results were evaluated with respect to improvement in facial contour desired and achieved, overall patient satisfaction and complications encountered. RESULTS: The study included 44 patients with a male:female ratio of 1:1, a mean age of 25.09 years (14 to 58 years) and a mean follow-up of 45.34 months (0.5 to 100 months). HDPE implants were used to augment the nasal dorsum, maxilla, malar eminence, chin, mandibular body and angle, orbital rim and frontal region. The overall recontouring afforded by the HDPE implants was good, with most patients reporting satisfactory results. There were seven complications (10%), including three cases of deviation (4.29%), three cases of exposure (4.29%) and one case of sub clinical infection (1.43%). None however necessitated implant removal. Nasal dorsal HDPE implants, especially those involving secondary surgery, suffered a much higher complication rate compared to other implants. CONCLUSIONS: HDPE is an alternative to autogenous grafts for facial skeletal augmentation with good long term results and a low incidence of complications, provided there is adequate vascular soft tissue cover. PMID- 20924448 TI - Use of HDPE implants in facial skeletal augmentation: Should we rush for it? PMID- 20924449 TI - Analysis of facial bone fractures: An 11-year study of 2,094 patients. AB - PURPOSE: The medical records of these patients were reviewed and analysed to determine the clinical characteristics and treatment of facial bone fractures. PATIENTS AND METHODS: This is a retrospective study of 2,094 patients with facial bone fractures from various accidents that were treated at the Inha University Hospital from 1996 to 2007. RESULTS: The most common age group was the third decade of life (29%). Males were more common than females (3.98:1). The most common aetiology was violent assault or nonviolent traumatic injury (49.4%). The most common isolated fracture site was the nasal bone (37.7%), followed by the mandible (30%), orbital bones (7.6%), zygoma (5.7%), maxilla (1.3%) and the frontal bone (0.3%). The largest group with complex fractures included the inferior region of the orbital floor and zygomaticomaxilla (14%). Closed reduction was performed in 46.3% of the cases while 39.7% of the cases required open reduction. For open reductions, the most commonly used soft-tissue approach was the intraoral approach (32.3%). The complication rate was 6.4% and the most common complication was hypoesthesia (68.4%) followed by diplopia (25.6%). CONCLUSION: Long-term collection of epidemiological data regarding facial fractures and concomitant injuries is important for the evaluation of existing preventive measures and useful in the development of new methods of injury prevention and treatment. PMID- 20924450 TI - Determination of hand and palm area as a ratio of body surface area in Indian population. AB - BACKGROUND: Accurate estimation of body surface area (BSA) burn is important. In small and patchy burns, the patient's hand is used to estimate percentage of burn which is traditionally considered as 1%. There is discrepancy about what percentage of TBSA is constituted by the palm and hand. Therefore, this study was designed to determine correctly the TBSA represented by the palmar surface of the entire hand and palm in the Indian population. MATERIAL AND METHODS: 300 healthy adult (male and female) and 300 healthy children (male and female) were included in the study. TBSA was calculated using DuBois formula and hand and palm surface area was calculated using hand tracing on plain paper. The hand/palm percentage of BSA (ratio) was determined by dividing hand/palm surface area by total BSA. RESULTS: The mean hand and palm ratio for adults was 0.92% and 0.50%, respectively. The mean hand and palm ratio in children was 1.06% and 0.632%, respectively. CONCLUSION: The hand area (palm plus digits) is more closely represented to 1% of TBSA in Indian population. PMID- 20924451 TI - Frequency of homologous blood transfusion in patients undergoing cleft lip and palate surgery. AB - AIM: The study aims to determine the frequency of homologous blood transfusion in patientsundergoing cleft lip and palate surgery at the Lagos University Teaching Hospital, Nigeria. SETTING AND DESIGN: A prospective study of transfusion rate in cleft surgery conducted at the Lagos University Teaching Hospital, Nigeria. MATERIAL AND METHODS: One hundred consecutive patients who required cleft lip and palate surgery were recruited into the study. Data collected included age, sex and weight of patients, type of cleft defects, type of surgery done, preoperative haematocrit, duration of surgery, amount of blood loss during surgery, the number of units of blood cross-matched and those used. Each patient was made to donate a unit of homologous blood prior to surgery. RESULTS: There were 52 females and 48 males with a mean age of 64.4 +/- 101.1 months (range, 3-420 months). The most common cleft defect was isolated cleft palate (45%) followed by unilateral cleft lip (28%). Cleft palate repair was the most common procedure (45%) followed by unilateral cleft lip repair (41%). The mean estimated blood loss was 95.8 +/- 144.9 ml (range, 2-800ml). Ten (10%) patients (CL=2; CP=5, BCL=1; CLP=2) were transfused but only two of these were deemed appropriate based on percentage blood volume loss. The mean blood transfused was 131.5 +/- 135.4ml (range, 35 500ml). Six (60%) of those transfused had a preoperative PCV of < 30%. Only 4.9% of patients who had unilateral cleft lip surgery were transfused as compared with 50% for CLP surgery, 11% for CP surgery, and 10% for bilateral cleft lip surgery. CONCLUSIONS: The frequency of blood transfusion in cleft lip and palate surgery was 10% with a cross-match: transfusion ratio of 10 and transfusion index of 0.1. A "type and screen" policy is advocated for cleft lip and palate surgery. PMID- 20924452 TI - Marginal mandibular branch of the facial nerve: An anatomical study. AB - Smile is one of the most natural and important expressions of human emotion. Man uses his lips mainly to register his emotions. Thus, the slightest asymmetry or weakness around the lips and mouth may transform this pleasant expression into embarrassment and distortion. The circumoral musculature, the major part of which is supplied by the marginal mandibular branch of the facial nerve, is the main factor in this expression. Therefore, an injury to this nerve during a surgical procedure can distort the expression of the smile as well as other facial expressions. This nerve often gets injured by surgeons in operative procedures in the submandibular region, like excision of the submandibular gland due to lack of accurate knowledge of variations in the course, branches and relations. In the present study, 50 facial halves were dissected to study the origin, entire course, termination, branches, muscles supplied by it, its anastomoses with other branches of facial nerve on the same as well as on the opposite side and its relations with the surrounding structures. The marginal mandibular branch of the facial nerve was found superficial to the facial artery and (anterior) facial vein in all the cases (100%). Thus the facial artery can be used as an important landmark in locating the marginal mandibular nerve during surgical procedures. Such a study can help in planning precise and accurate incisions and in preventing the unrecognized severance of this nerve during surgical procedures. PMID- 20924453 TI - Marginal mandibular nerve - Interpolation from anatomy: A flaw? PMID- 20924454 TI - A status report on management of cleft lip and palate in India. AB - INTRODUCTION: This national survey on the management of cleft lip and palate (CLP) in India is the first of its kind. OBJECTIVE: To collect basic data on the management of patients with CLP in India for further evaluation. MATERIALS AND METHODS: A proforma was designed and sent to all the surgeons treating CLP in India. It was publicized through internet, emails, post and through personal communication. SUBJECTS: 293 cleft surgeons representing 112 centers responded to the questionnaire. Most of the forms were filled up by personal interview. RESULTS: The cleft workload of the participating centers is between 10 and 2000 surgeries annually. These centers collectively perform 32,500-34,700 primary and secondary cleft surgeries every year. The responses were analyzed using Microsoft excel and 112 as the sample size. Most surgeons are repairing cleft lip between 3 6 months and cleft palate between 6 months to 1 year. Millard and Tennison repairs form the mainstay of lip repair. Multiple techniques are used for palate repair. Presurgical orthopedics, lip adhesion, nasendoscopy, speech therapy, video-fluoroscopy and orthognathic surgery were not always available and in some cases not availed of even when available. CONCLUSION: Management of CLP differs in India. Primary surgical practices are almost similar to other studies. There is a lack of interdisciplinary approach in majority of the centers, and hence, there is a need for better interaction amongst the specialists. A more comprehensive study with an improved questionnaire would be desirable. PMID- 20924455 TI - A new and simplified functional tendon transfer for a dropped hallux. AB - A case of fracture of the right tibia proximal 1/3rd extending up to diaphysis after a road traffic accident along with a dropped hallux is being reported. The extensor digitorum longus (EDL) was intact. Patient was taken up for surgery for the fracture tibia with conservative management for his dropped hallux for initial six weeks. After six weeks when no improvement was seen surgical intervention was planned for the dropped hallux. The subsequent management of this patient is being described. PMID- 20924456 TI - Pedicle transfer in oral cavity reconstruction. AB - In head and neck reconstructions when a free flap is used intra orally to provide the lining its vascular pedicle has to be transferred to the neck for anastomosis. This has to be performed in such a way that the pedicle does not get kinked or twisted. The pedicle is enrolled in a split open glove from its point of entry into the flap till its proximal most part. In order to prevent twisting of the vessels and to maintain orientation, the glove is wrapped in such a way that the imprint on the glove is on the visualized surface. The glove wrapped pedicle is passed from inside the oral cavity while an artery clamp passed from the neck wound through the submandibular or subcutaneous tunnel holds the tip of the glove component and guides it safely to the neck without exerting any traction on the flap or the pedicle vessels. PMID- 20924457 TI - Mammoth orbitofrontal neurofibromatosis with herniating meningo-encephalocele. AB - We are presenting a mammoth orbito-frontal neurofibroma with a herniating meningo encephalocele in a 23 year old African male. The tumour measured 87cm x 54cm and occupied the right orbito-temporo-facial region and had destroyed the right orbit. A pre operative embolization of the feeding vessels was followed by a one stage near total excision of the tumour and repair of the meningo-encephalocele in hypotensive anaesthesia. The excised tumour weighed 8 Kg and, to the best of our knowledge, is the largest orbito-facial neurofibroma reported in literature. PMID- 20924458 TI - Parotid lipoblastoma in a child: Rare presentation as huge infratemporal mass with cervical extension. AB - Lipoblastomas arising within the parotid gland and extending into the infratemporal fossa are very rare. They are common in children <3 years of age. Access to the tumour requires careful planning and interpretation of imaging studies. Lipoblastomas tend to recur. Meticulous dissection of the tumour is needed to prevent recurrence. By adopting the appropriate approach, complete removal is possible with minimal morbidity. PMID- 20924459 TI - Chest wall reconstruction using a combined musculocutaneous anterolateral anteromedial thigh flap. AB - We present a massive 25 cm * 20 cm chest wall defect resulting from resection of recurrent cystosarcoma phyllodes of the breast along with six ribs exposing pleura. The chest wall was reconstructed with a Prolene mesh-methylmethacrylate cement sandwich while soft tissue reconstruction was carried out using a combined free anterolateral-anteromedial thigh musculocutaneous flap with two separate pedicles, anastomosed to the thoracodorsal and thoracoacromial vessels respectively. We explain our rationale for and the advantages of combining the musculocutaneous anterolateral thigh flap with the anteromedial-rectus femoris thigh flap. PMID- 20924460 TI - Ectodermal dysplasia - Maxillary and mandibular alveolar reconstruction with dental rehabilitation: A case report and review of the literature. AB - Ectodermal dysplasia is a rare group of inherited disorders characterized by aplasia or dysplasia of tissues of ectodermal origin, such as hair, nails, teeth and skin. Dental manifestations include hypodontia, complete anodontia or malformed teeth. Oral rehabilitation is the major surgical challenge in such patients. It frequently requires alveolar reconstruction followed by dental implants. We report a case of hypohidrotic ectodermal dysplasia, which was managed with reconstruction of both the upper and the lower alveolus using free fibula flaps with dental rehabilitation using osseointegrated implants. PMID- 20924462 TI - Causation and complications. PMID- 20924461 TI - Hazards of steroid injection: Suppurative extensor tendon rupture. AB - Local steroid injections are often administered in the office setting for treatment of trigger finger, carpal tunnel syndrome, de Quervain's tenosynovitis, and basal joint arthritis. If attention is paid to sterile technique, infectious complications are rare. We present a case of suppurative extensor tenosynovitis arising after local steroid injection for vague symptoms of dorsal hand and wrist pain. The progression of signs and symptoms following injection suggests a natural history involving bacterial superinfection leading to tendon rupture. We discuss the pitfalls of local steroid injection and the appropriate management of infectious extensor tenosynovitis arising in such situations. PMID- 20924463 TI - Pedicled anterolateral thigh flap for contralateral groin composite defect. AB - Pedicled anterolateral thigh flap has been well described for ipsilateral groin defects. Its versatility depends on the intact femoral vessels. When the external iliac and the femoral vessels are absent, especially secondary to wide surgical tumour ablations in the groin region, ipsilateral ALT flap is not an option. Free flaps also are difficult because of lack of recipient vessels. We report a case of composite groin defect following wide resection of recurrent liposarcoma along with encased vessels which was covered with a pedicled anterolateral thigh flap from the opposite thigh. The technique of lengthening the vascular pedicle and medializing the pedicle, to effectively increase its reach to the contralateral anterior superior iliac spine without vascular compromise, is described. PMID- 20924464 TI - A foregoing thenar muscular branch of the median nerve. AB - We present a 62-year-old female patient who had an anatomic variation in the median nerve of the left hand. During surgery for releasing the left carpal tunnel, an abnormally high level of origin of the thenar muscular branch of the median nerve was detected, at 2.5 cm above the proximal border of transverse carpal ligament. It traveled between the medial side of the flexor carpi radialis tendon and median nerve and entered the carpal tunnel. After exiting the carpal tunnel distally, the nerve, was noted to course towards the thenar area. Such variations in the median nerve should be kept in mind while performing carpal tunnel release. PMID- 20924465 TI - Secondary reconstruction of below knee amputation stump with free anterolateral thigh flap. AB - Below knee stump preservation reduces ambulatory energy expenditure and improves the quality of life. Reconstruction of soft tissue loss around the stump is a challenging task. Below knee stump reconstruction demands stable skin with sufficient soft tissue to allow weigh bearing. Microsurgical tissue transfer is increasingly being used as a salvage option. Anterolateral thigh flap with additional vastus lateralis muscle provides extra cushioning effect. We report two cases of amputation below knee successfully salvaged. The anterolteral flap with abundant tissue and stable skin offers a reliable option for cover. Two patients with below knee amputation were reconstructed secondarily. After 6 to 20 months of follow -up, stumps showed no signs of pressure effects. Patients are able to bear 50-70 hours of weight per week. PMID- 20924466 TI - Median cleft lip: A new method of surgical repair. AB - The aim is to discuss a new method of muscle repair in midline cleft lip. Three patients with midline cleft lip were repaired with our technique of muscle repair and the results evaluated. Our new method of muscle repair in the form of 'Z' helps in forming the philtral dimple. PMID- 20924467 TI - Considerations in the choice of side in a free Latissimus Dorsi flap to determine expendability in extensive lower extremity defects. PMID- 20924468 TI - Variant formation and distribution of the superficial palmar arch. PMID- 20924469 TI - Managing the cut end of a K wire. PMID- 20924470 TI - Splinting of penis after micro vascular reconstruction: A simple inexpensive method. PMID- 20924471 TI - Remember S.E.P.A. flap? PMID- 20924472 TI - Honey vs. silver sulphadiazine. PMID- 20924473 TI - Better patient care: Need of the hour. PMID- 20924474 TI - Oncogenic osteomalacia: A reversible metabolic bone disorder. PMID- 20924475 TI - Pathology of Ewing's sarcoma/PNET: Current opinion and emerging concepts. AB - Ewing's sarcoma/PNET are small round cell tumors showing a varying degree of neuroectodermal differentiation. They are one of the commonest tumors of childhood and occur in bone and within soft tissues. Traditionally, light microscopy with the aid of immunohistochemical stains was suitable for diagnosis. But now translocation analyses are being used not only for the diagnosis and classification of small round cell tumors, but to ascertain their prognostic significance, detect micrometastasis, and monitor minimal residual disease, with potential for targeted therapy. This article analyzes the pathology, biology, and molecular aspects of Ewing's sarcoma/PNET and discusses their clinical and therapeutic implications. PMID- 20924476 TI - Chemotherapy in Ewing's sarcoma. AB - Ewing's sarcoma constitutes three per cent of all pediatric malignancies. Ewing's sarcoma has generally been more responsive to chemotherapy than adult-type sarcomas, and chemotherapy is now recommended for all patients with this disease. It is essential to integrate local control measures in the form of surgery and/or radiotherapy at the appropriate time, along with chemotherapy to eradicate the disease. This approach has improved the survival substantially to the tune of 70% in localized disease, although outcome for metastatic disease remains dismal. Newer therapeutic approaches are required to improve outcome for metastatic and recurrent or refractory Ewing's sarcoma in organized co-operative group trials. PMID- 20924477 TI - Outcome of multimodality treatment of Ewing's sarcoma of the extremities. AB - BACKGROUND: The management of Ewing's sarcoma family of tumors (ESFT, Ewing's sarcoma/primitive neuroectodermal tumor) has been established as a multimodality treatment. Advances in imaging and diagnostics, chemotherapy, surgical techniques, radiotherapy and prosthetic technology have resulted in drastic changes in the outcome of this disease, with most of the recent studies having 5 year survival rates of more than 60%. The Indian patients present at a more advanced stage and the compliance of treatment is suboptimal. While there is plenty of data in the world literature on the outcome of Ewing's sarcoma, there is paucity of data in Indian patients. Therefore, we conducted the present study to analyze the outcome of multimodality treatment of ESFT of the extremities at a tertiary nonprofit institute over a decade. MATERIALS AND METHODS: 34 patients who had histopathologically proven diagnosis of Ewing's sarcoma of the extremities and had received treatment at our institute from 1997 through 2007 were included for analysis. The majority of patients had involvement of the femur (35%), followed by tibia (17%), fibula and foot (15% each), humerus (12%) and soft tissue of thigh (6%). Twenty-nine patients presented with localized disease (Enneking stage II B) while five patients presented with metastases (Enneking stage III). All patients received Vincristine, Actinomycin D, Cyclofosfamide + Ifosfamide and Etoposide (VAC+IE)-based chemotherapy and local treatment was offered to all but three patients having multicentric disease. The local treatment offered were, radiation (n= 15), surgery (n= 12) both surgery and radiation (n=4). All patients were analyzed for oncological outcome (event-free and overall survival, local and systemic relapses) by clinical and imaging evaluation and functional outcome by using the musculoskeletal tumor society (MSTS) score. These outcomes were correlated with age, sex, size of tumor, stage at presentation, modality of local treatment and site of relapse. RESULTS: At the final follow-up (mean, 26 months; median, 17 months; range, 3-97 months), the overall and event-free survivals were 47 +/- 12% and 34 +/- 9%, respectively. Sixty-two percent of the patients presented with a tumor size more than 8 cm. On correlation with age, sex, size of tumor, stage at presentation, modality of local treatment and site of relapse, no correlation of survival was seen with any of the variables except event-free survival with size of the tumor. The functional outcome of all the patients was satisfactory (MSTS score >16 out of 30). No patient underwent amputation. CONCLUSION: Although the demographic profile, stage at presentation and the local and systemic treatment regimen followed in our study was similar to the world literature, the outcome of Ewing's sarcoma in Indian patients were found to be inferior to that reported in the western literature. Larger multicentric studies with longer follow-up are required to exactly determine the key areas crucial in improving this outcome. PMID- 20924478 TI - Short-term followup after surgical treatment of Ewing's sarcoma. AB - BACKGROUND: Results of surgical treatment in Indian patients of Ewing's sarcoma managed with multimodality treatment with chemotherapy and/or radiotherapy are insufficient. We report a retrospective evaluation of a series of cases of Ewing's sarcoma managed with chemotherapy, surgery with or without radiotherapy. MATERIALS AND METHODS: 54 patients of biopsy-proven Ewing's sarcoma of the bone, except craniofacial and vertebral bones were included. The patients having recurrence or having previous treatment were excluded from the study. Local and systemic extent of the sarcoma was defined, staged, and patients were subjected to the chemotherapy, surgery, and in some cases radiotherapy. Patients were evaluated for results of surgery with respect to complications, recurrence, and metastases at 3, 6, 9, 12, 18 and 24 months of follow-up RESULTS: Average age of patients was 15.6 years (range 7-26 years); average delay in treatment was 4.1 months (1-7 months); follow-up ranged from 2 to 5 years (median 3.1 years); 14 patients (25.9%) had pulmonary metastases at their initial presentation. Twenty one patients (38.9%) underwent resection and intercalary reconstruction with bone grafting, fixed with locking plates. Allograft was also used in 11 of these. Sixteen patients underwent resection and reconstruction with endoprosthesis, while seven patients (13.0%) underwent resection and arthrodesis. An above-knee amputation was required in 7.4% (four patients). Mesh was used for containing the graft longitudinally in five patients (femoral and tibial intercalary reconstructions) and for soft tissue attachment in two patients (hip and shoulder endoprostheses). Two patients had deep wound infection. One patient presented 1 year later with implant failure. The disease-free survival at 2 years from the time of diagnosis was 57.5% (23 out of 40) for patients without preoperative metastases and 42.9% (6 out of 14) for those with preoperative metastases. Overall, the disease-free survival at 2 years was 53.7% (29 out of 54 patients). Overall survival rate at 2 years was 61.1% (33 out of 54 patients). CONCLUSION: Results of surgical treatment in this study are comparable with the current literature in spite of involvement of long bony segment and large soft tissue component. Intramedullary fibular autograft with morcellized cancellous autograft and allograft contained longitudinally in a mesh appears to be a good alternative with such large bone tumors. PMID- 20924479 TI - Extracorporeal irradiated tumor bone: A reconstruction option in diaphyseal Ewing's sarcomas. AB - BACKGROUND: Limb salvage in extremity tumors is now established as an oncologically safe option without compromising long-term survival. En bloc resection followed by extracorporeal radiation and reimplantation is a biological reconstruction option in diaphyseal Ewing's sarcomas. We analyzed the results of 12 cases of diaphyseal Ewing's sarcomas treated using this modality. MATERIALS AND METHODS: Between March 2006 and March 2008, 12 patients with Ewing's sarcoma underwent enbloc resection and reconstruction, with reimplantation of the sterilized tumor bone, after extracorporeal irradiation. There were eight males and four females, with a mean age of 14 years (range 2 to 22 years). The femur was the most common bone involved (n=8) followed by the tibia and the humerus (two cases each). All these patients were non-metastatic at presentation and received chemotherapy as per the existing hospital protocol. The mean length of the bone resected was 20 cm (range 11 to 25 cm). The specimen was irradiated with 50 Gy prior to reimplantation and stabilized with the host bone, using suitable internal fixation. Standard biplanar radiographs were assessed for evidence of union on the follow-up visits. The functional status was assessed using the Musculoskeletal Tumor Society Scoring system at the time of the last follow up. The mean follow up duration was 29 months (range 12 to 57 months). RESULTS: Two patients (17%) had early infection with graft removal, hence are excluded from any analysis of union, however they are included when analysing complications such as infection. Rest 10 cases were analyzed for bony union at the osteotomy sites. Sixteen (84%) of the 19 osteotomy sites united primarily, without any intervention. Implant failure and non-union was seen at three diaphyseal osteotomy sites. The average time for union of all osteotomy sites was 7.2 months (range 3 to 13 months).The average time for union of the metaphyseal osteotomy sites was 5.9 months (range 3 to 12 months) and of diaphyseal osteotomy sites was 8.3 months (range 4 to 13 months). The mean Musculoskeletal Tumor Society Score was 27 (range 19 to 30) with a mean of 27. Nine of the ten patients with lower limb involvement were independent ambulators without additional aids. At the time of the last review, six patients were free of disease and six patients had died from the disease. There were two recurrences around the operative site. Both were associated with disseminated disease and in both the recurrences were in the soft tissue, away from the irradiated graft. CONCLUSION: Extracorporeal irradiation is a useful, convenient technique for limb salvage in diaphyseal Ewing's sarcomas when there is reasonable residual bone stock. It is oncologically safe and has good functional results. A radiation dose of 50 Gy for sterilizing the bone ensures adequate tumor kill, while minimizing the deleterious effects on the biomechanical and biological properties of the bone. The use of appropriate implants for adequate internal fixation and supplementary bone grafting at the index surgery may help reduce the need for subsequent additional interventions to achieve union. The limitations of this procedure are that it is not applicable in tumor bones that are structurally weak and in bones with pathological fractures. PMID- 20924480 TI - Surgical management of pelvic Ewing's sarcoma. AB - BACKGROUND: Despite advances in adjuvant therapy, Ewing's sarcoma of the pelvis remains an anatomic site with a poor prognosis due to its relative inaccessibility, complex anatomy, and limited reconstructive options available. This study evaluates the role of surgery in the management of patients with pelvic Ewing's sarcoma who also have received conventional radiation therapy and chemotherapy. MATERIALS AND METHODS: From July 1990 to July 2006, we received 10 patients with Ewing's sarcoma of pelvis at our center. Nine patients were in stage II B and one in Stage III at the time of presentation to us. All patients underwent surgical resection after preoperative chemotherapy with or without radiotherapy, which was given at the discretion of the referral center. Reconstruction was attempted using plate osteosynthesis in four patients, SS wires and screws in three patients, free fibular strut graft in one patient, and none was done in two patients. RESULTS: Functional outcome assessed by Enneking's criteria revealed excellent outcome in two patients, good outcome in five patients, and poor outcome in two patients. At a mean followup of 10.3 years, seven patients remained free from the disease, and three patients died. The 5- and 10-year cumulative survival (Kaplan Meier method) was 63% and 34%, respectively. CONCLUSION: This study demonstrates that surgery plus chemotherapy and radiation therapy is helpful for treating patients with pelvic Ewing's sarcoma, particularly in achieving local control. PMID- 20924481 TI - Experimental posterolateral spinal fusion with beta tricalcium phosphate ceramic and bone marrow aspirate composite graft. AB - BACKGROUND: Beta tricalcium phosphate is commonly used in metaphyseal defects but its use in posterolateral spinal fusion remains controversial. There are very few published animal studies in which use of beta tricalcium phosphate has been evaluated in the posterolateral lumbar arthrodesis model. Hence we conducted a study to evaluate the potential of composite graft of beta tricalcium phosphate and bone marrow aspirate in comparison to autologous bone graft, when used for posterolateral spinal fusion. MATERIALS AND METHODS: Single level posterolateral lumbar fusion was performed in 40 adult male Indian rabbits, which were assigned randomly into one of the four groups based on graft materials implanted; a) 3 gm beta tricalcium phosphate plus 3 ml bone marrow aspirate (Group I); b) 3 ml bone marrow aspirate alone (Group II); c) 3 gm beta tricalcium phosphate (Group III) and d) 3 gm autologous bone graft (Group IV). Each group had 10 rabbits. Half of the rabbits were sacrificed by injecting Phenobarbitone intraperitoneally after eight weeks and the remaining after 24 weeks, and were evaluated for fusion by X rays, computed tomography (CT) scans, manual palpation test and histology. RESULTS: Beta tricalcium phosphate used with bone marrow aspirate produced best results when compared to other groups (P =.0001). When beta tricalcium phosphate was used alone, fusion rates were better as compared to fusion achieved with autologous iliac crest bone graft though statistically not significant (P =0.07). Autologous bone graft showed signs of new bone formation. However, the rate of new bone formation was comparatively slow. CONCLUSION: Composite graft of beta tricalcium phosphate and bone marrow aspirate can be used as an alternative to autologous iliac crest bone graft. PMID- 20924482 TI - Simultaneously anterior decompression and posterior instrumentation by extrapleural retroperitoneal approach in thoracolumbar lesions. AB - BACKGROUND: Anterior decompression with posterior instrumentation when indicated in thoracolumbar spinal lesions if performed simultaneously in single-stage expedites rehabilitation and recovery. Transthoracic, transdiaphragmatic approach to access the thoracolumbar junction is associated with significant morbidity, as it violates thoracic cavity; requires cutting of diaphragm and a separate approach, for posterior instrumentation. We evaluated the clinical outcome morbidity and feasibility of extrapleural retroperitoneal approach to perform anterior decompression and posterior instrumentation simultaneously by single "T" incision outcome in thoracolumbar spinal trauma and tuberculosis. PATIENTS AND METHODS: Forty-eight cases of tubercular spine (n = 25) and fracture of the spine (n = 23) were included in the study of which 29 were male and 19 female. The mean age of patients was 29.1 years. All patients underwent single-stage anterior decompression, fusion, and posterior instrumentation (except two old traumatic cases) via extrapleural retroperitoneal approach by single "T" incision. Tuberculosis cases were operated in lateral position as they were stabilized with Hartshill instrumentation. For traumatic spine initially posterior pedicle screw fixation was performed in prone position and then turned to right lateral position for anterior decompression by same incision and approach. They were evaluated for blood loss, duration of surgery, superficial and deep infection of incision site, flap necrosis, correction of the kyphotic deformity, and restoration of anterior and posterior vertebral body height. RESULTS: In traumatic spine group the mean duration of surgery was 269 minutes (range 215-315 minutes) including the change over time from prone to lateral position. The mean intraoperative blood loss was 918 ml (range 550-1100 ml). The preoperative mean ASIA motor, pin prick and light touch score improved from 63.3 to 74.4, 86 to 94.4 and 86 to 96 at 6 month of follow-up respectively. The mean preoperative loss of the anterior vertebral height improved from 44.7% to 18.4% immediate postoperatively and was 17.5% at final follow-up at 1 year. The means preoperative kyphus angle also improved from 23.3 degrees to 9.3 degrees immediately after surgery, which deteriorated to 11.5 degrees at final follow up. One patient developed deep wound infection at the operative site as well as flap necrosis, which needed debridement and removal of hardware. Five patients had bed sore in the sacral region, which healed uneventfully. In tubercular spine (n=25) group, mean operating time was approximately 45 minutes less than traumatic group. The mean intraoperative blood loss was 1100 ml (750-2200 ml). The mean preoperative kyphosis was corrected from 55 degrees to 23 degrees . Wound healing occurred uneventful in 23 cases and wound dehiscence occurred in only 2 cases. Nine out of 11 cases with paraplegia showed excellent neural recovery while 2 with panvertebral disease showed partial neural recovery. None of the patients in both groups required intensive unit care. CONCLUSIONS: Simultaneous exposure of both posterior and anterior column of the spine for posterior instrumentation and anterior decompression and fusion in single stage by extra pleural retroperitoneal approach by "T" incision in thoracolumbar spinal lesions is safe, an easy alternative with reduced morbidity as chest and abdominal cavities are not violated, ICU care is not required and diaphragm is not cut. PMID- 20924483 TI - Os odontoideum with "free-floating" atlantal arch causing C1-2 anterolisthesis and retrolisthesis with cervicomedullary compression. AB - BACKGROUND: Os odontoideum (OO) with C1-2 anterolisthesis and retrolisthesis may cause cervicomedullary injury both from anterior and posterior aspects. We analyzed fourteen such patients for biomechanical issues, radiological features and management of OO with free-floating atlantal arch and review pertinent literature. MATERIALS AND METHODS: Fourteen patients having nonsyndromic, reducible atlantoaxial dislocation (AAD) with orthotopic OO were analyzed. During neck flexion, their C1 anterior arch-os complex displaced anteriorly relative to remnant odontoid-C2 body. The posteriorly directed hypoplastic remnant odontoid sliding below the atlas and forward translation of the C1 posterior arch caused concomitant cervicomedullary compression. During neck extension, there was retrolisthesis of the "free-floating" C1 arch-os complex into spinal canal. Spinal stenosis and lateral C1-2 facet dislocation; Klippel-Feil anomaly; and posterior circulation infarcts were also present in one patient each, respectively. Posterior C1-2 (n=10) or occipitocervical fusion (n=3) was performed in neutral position to stabilize atlantoaxial movements. RESULTS: Follow-up (mean, 3.9 years) assessment revealed improvement in spasticity and weakness in 13 patients. One patient had neurological deterioration following C1 2 posterior sublaminar fusion, requiring its conversion to occipitocervical contoured rod fusion. One patient with posterior circulation stroke died prior to any operative intervention. Follow-up lateral view radiographs showed a bony union or a stable construct in these 13 patients. CONCLUSIONS: OO with free floating atlantal arch may precipitate cord injury both during neck flexion and extension. This condition may be overlooked unless lateral radiographs of craniovertebral junction are undertaken in neck extension, along with the usual ones in neutral and flexed positions. Etiological factors include C1 ring-OO unrestrained movements above the hypoplastic odontoid; upward pull on OO by alar and apical ligaments; lax C1-2 facet joint ligaments; and congenital presence of horizontal facet joint surfaces that facilitates C1-2 translation. PMID- 20924484 TI - The impact of chronic obstructive pulmonary disease and obesity on length of stay and cost of spine surgery. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) and obesity may be more common among spine surgery patients than in the general population and may affect hospital cost. MATERIALS AND METHODS: We retrospectively studied the prevalence of COPD and obesity among 605 randomly selected spine surgery inpatients operated between 2005 and 2008, including lumbar microdiskectomy, anterior cervical decompression and fusion and lumbar decompression and fusion patients. The length of hospital stay and hospital charges for patients with and without COPD and obesity (body mass index [BMI]>=30 kg/m(2)) were compared. RESULTS: Among 605 spine surgery patients, 9.6% had a history of COPD. There were no statistical difference in the prevalence of COPD between the three spine surgery groups. Obesity was common, with 47.4% of the patients having a BMI>=30 kg/m(2). There were no significant differences in obesity rates or BMI values between the three types of spine surgery patients. Obesity rates between patients with and without COPD were 62.1% vs. 45.9%, and were statistically different (P<0.05). Similarly, significant difference (P<0.01) in BMI values between COPD and non-COPD groups, 32.66+/-7.19 vs. 29.57+/-6.048 (mean +/- std. deviation), was noted. There was significant difference (P<0.01) in cost between nonobese female patients without COPD and those with obesity and COPD in the anterior cervical decompression and fusion (ACDF) group. No association with increased hospital length of stay or cost was found in the other two types of spine surgery or in male ACDF patients. CONCLUSION: COPD and obesity seem to additively increase the length of hospital stay and hospital charges in ACDF female patients, an important finding that requires further investigation. PMID- 20924486 TI - Clinical signs and anatomical correlation of patellar tendinitis. AB - BACKGROUND: Patellar tendinitis is one of the several differential diagnosis of anterior knee pain. The clinical diagnosis of patellar tendinitis is based on tenderness to palpation at the inferior pole of the patella. The tenderness has been noted to be maximal when the knee is extended and the quadriceps relaxed, but a definite clinical sign for diagnosis is lacking. The accuracy of two clinical signs was assesed by a two-stage study which included physical examination, MRI and a cadaveric study. MATERIALS AND METHODS: Two clinical signs, the "passive flexion-extension sign" and the "standing active quadriceps sign" were assessed in 10 consecutive patients with presumed patellar tendinitis. Five patients had an MRI, showed focal abnormality in the tendon. The location of the MRI finding corresponded, to the region of maximal tenderness. A cadaveric dissection was undertaken to describe the anatomy of the patella and the patellar tendon during these tests. RESULTS: Both tests showed a significant decrease in tenderness at the area of inflammation when the patellar tendon was under tension. The cadaveric dissection showed that when the knee is flexed to 90 degrees or when the quadriceps is tensioned the deep fibers of the tendon do not deform to anteriorly applied pressure. CONCLUSION: We suggest using these studies routinely in the evaluation of patients with anterior knee pain. PMID- 20924485 TI - Primary hemiarthroplasty for unstable osteoporotic intertrochanteric fractures in the elderly: A retrospective case series. AB - BACKGROUND: The management of unstable osteoporotic intertrochantric fractures in elderly is challenging because of difficult anatomical reduction, poor bone quality, and sometimes a need to protect the fracture from stresses of weight bearing. Internal fixation in these cases usually involves prolonged bed rest or limited ambulation, to prevent implant failure secondary to osteoporosis. This might result in higher chances of complications like pulmonary embolism, deep vein thrombosis, pneumonia, and decubitus ulcer. The purpose of this study is to analyze the role of primary hemiarthroplasty in cases of unstable osteoporotic intertrochanteric femur fractures. MATERIALS AND METHODS: We retrospectively analyzed 37 cases of primary hemiarthroplasty performed for osteoporotic unstable intertrochanteric fractures (AO/OTA type 31-A2.2 and 31-A2.3 and Evans type III or IV fractures). There were 27 females and 10 males with a mean age of 77.1 years (range, 62-89 years). RESULTS: Two patients died due to unrelated cause (myocardial infarction) within 6 months of surgery and remaining 35 patients were followed up to an average of 24.5 months (range,18-39 months). The average surgery time was 71 min (range, 55-88 min) with an average intraoperative blood loss of 350 ml (range, 175-500 ml). Six patients needed blood transfusion postoperatively. The patients walked on an average 3.2 days after surgery (range, 2-8 days). One patient had superficial skin infection and one had bed sore with no other significant postoperative complications. One patient of Alzheimer's disease refused to walk and had a poor result. A total of 32 out of 35 patients (91%) had excellent to fair functional results and 2 had poor result with respect to the Harris hip score (mean 84.8+/-9.72, range 58-97). One patient who had neurological comorbidity refused to walk post operatively and was labeled as failed result. CONCLUSION: Hemiarthroplasty for unstable osteoporotic intertrochanteric fractures in elderly results in early ambulation and good functional results although further prospective randomized trials are required before reaching to conclusion. PMID- 20924487 TI - Dislocation following total knee arthroplasty: A report of six cases. AB - BACKGROUND: Dislocation following total knee arthroplasty (TKA) is the worst form of instability. The incidence is from 0.15 to 0.5%. We report six cases of TKA dislocation and analyze the patterns of dislocation and the factors related to each of them. MATERIALS AND METHODS: Six patients with dislocation of knee following TKA are reported. The causes for the dislocations were an imbalance of the flexion gap (n=4), an inadequate selection of implants (n=1), malrotation of components (n=1) leading to incompetence of the extensor mechanism, or rupture of the medial collateral ligament (MCC). The patients presented complained of pain, giving way episodes, joint effusion and difficulty in climbing stairs. Five patients suffered posterior dislocation while one anterior dislocation. An urgent closed reduction of dislocation was performed under general anaesthesia in all patients. All patients were operated for residual instability by revision arthroplasty after a period of conservative treatment. RESULTS: One patient had deep infection and knee was arthrodesed. Two patients have a minimal residual lag for active extension, including a patient with a previous patellectomy. Result was considered excellent or good in four cases and fair in one, without residual instability. Five out of six patients in our series had a cruciate retaining (CR) TKA designs: four were revised to a posterior stabilized (PS) TKA and one to a rotating hinge design because of the presence of a ruptured MCL. CONCLUSION: Further episodes of dislocation or instability will be prevented by identifying and treating major causes of instability. The increase in the level of constraint and correction of previous technical mistakes is mandatory. PMID- 20924488 TI - Ilizarov's method for treatment of nonunion of diaphyseal fractures of the humerus. AB - BACKGROUND: Nonunion in diaphyseal fractures of the humerus can be treated by various modalities like plating and bone grafting, exchange nailing, fibular strut grafting and Ilizarov's method of ring fixation. To achieve union in infected nonunion in which multiple surgeries have already been done is further challenging. We conducted a prospective study wherein the outcome of the treatment of nonunion of diaphyseal fractures of the humerus by Ilizarov's method was analyzed. MATERIALS AND METHODS: Nineteen patients with diaphyseal nonunion of the humerus were treated by Ilizarov's external fixator. These included nonunion after plating (n=11), intramedullary nailing (n=1) or conservative methods (n=7). In post-surgical infected nonunion (n=6), the implants were removed, debridement done, bone fragments were docked followed by application of ring fixator and compression. In aseptic nonunion (n=13), distraction for three weeks followed by compression was the protocol. Early shoulder and elbow physiotherapy was instituted. The apparatus was removed after clinical and radiological union and the results were assessed for bone healing and functional status. RESULTS: Fracture union was achieved in all the 19 cases. Pin site infection was seen in 2 cases (10.52%). The bone healing results were excellent in eighteen cases (94.73%) and good in one case (5.26%).The functional results were found to be excellent in fourteen cases (73.68%), good in four (21.05%) and fair in one case (5.26%). CONCLUSION: Ilizarov's method is an excellent option for treatment of septic and aseptic non union of diaphyseal fractures of the humerus as it addresses all the problems associated with non union of the humerus like infection, deformity and joint stiffness. PMID- 20924489 TI - Percutaneous osteosynthesis of Galeazzi fracture-dislocation. AB - BACKGROUND: A Galeazzi fracture is defined as a fracture of the radius associated with dislocation of the distal radio-ulnar joint (DRUJ). The conventional surgical technique of nailing does not give enough stability and open reduction, internal fixation with the plate is associated with numerous complications. The stacked nailing for the management of these injuries provides adequate stability, maintains the relationship of the DRUJ and promotes uneventful union by closed technique. The purpose of this study is to evaluate the results of simple, user friendly, low cost elastic stacked nailing for the management of Galeazzi fracture dislocation. MATERIALS AND METHODS: We treated 22 young adults with fresh Galeazzi fracture-dislocation of the forearm, from January 2004 to January 2008, by percutaneous fixation of fracture by stacked elastic nailing at our institute. There were 19 males and three females and the age group ranged from 20 56 years (average 35 years). Surgery was performed within 48 to 72 hours under the guidance of image intensifier. Medullary cavity was filled with two elastic titanium nails having unequal lengths and diameter. One nail acts as a reduction nail and the other acts as a stabilizing nail. The results were evaluated using Mikic criteria based on union, alignment, relationship of the DRUJ, and movements at the inferior radio ulnar joint, elbow and wrist. RESULTS: In six cases, following radiological union, nails in the radius were extracted between six to nine months after operation because of discomfort complained by the patient at site of insertion. After one year follow-up, 18 patients had excellent, four had fair results. CONCLUSION: Closed reduction and internal fixation of Galeazzi fracture by two elastic rods re-establishes the normal relationship of the fractured fragments and the DRUJ without repair of the ligaments. The stability is achieved by the flexibility and elasticity of the nails, crowding of the medullary canal and anchorage they gain in the radial diaphysis. Elastic nailing can produce excellent clinical results for Galeazzi fracture-dislocation. It has the advantages of technical simplicity, minimal cost, user-friendly instrumentation, and a short learning curve. PMID- 20924490 TI - Oncogenic osteomalacia: Problems in diagnosis and long-term management. AB - Oncogenic osteomalacia is a rare association between mesenchymal tumors and hypophosphatemic rickets. It is more of a biochemical entity than a clinical one. The pathophysiology of the tumor is not clear. However, it has been seen that the clinical and biochemical parameters become normal if the lesion responsible for producing the osteomalacia is excised. For a clinical diagnosis a high index of suspicion is necessary. We present three such cases where in one the oncogenic osteomalacia reversed while in rest it did not. We present this case report to sensitize about the entity. PMID- 20924491 TI - Subchondral stress fracture of femoral head in a healthy adult. AB - Subchondral fracture of the femoral head is an uncommon entity and usually occurs as an insufficiency fracture associated with poor bone quality or as a fatigue fracture in young military recruits. This condition should be considered in the differential diagnosis of acute hip pain in young patients along with transient osteoporosis and avascular necrosis of the hip. We report a case of acute onset hip pain in an asymptomatic healthy adult in which the diagnosis was made by magnetic resonance imaging and the patient responded well to conservative treatment. PMID- 20924492 TI - Early lateral migration of head after bipolar hemiarthoplasty in a cerebral palsy patient. AB - Migration of the outer head after bipolar hemiarthroplasty within several years after surgery is not a rare complication. We present a patient with cerebral palsy who showed lateral migration of the outer head seven months after bipolar hemiarthroplasty for femoral neck fracture. The patient had no acetabular pathology prior to the fracture, and lacked ambulatory ability in a community setting. She underwent conversion to a total hip arthroplasty and returned to her previous lifestyle. PMID- 20924493 TI - A new mode of clinical failure of porous tantalum rod. AB - The area of osteonecrosis of the head of femur affected by the disease process varies from a small localized lesion to a global lesion. Without specific treatment 80% of the clinically diagnosed cases will progress, and most will eventually require arthroplasty. Therefore the goal is to diagnose and treat the condition in the earliest stage. A number of surgical procedures have been described to retard or prevent progression of the disease and to preserve the femoral head. An implant made of porous tantalum has been developed to function as a structural graft to provide mechanical support to the subchondral plate of the necrotic femoral head, and possibly allow bone growth into the avascular region. Porous tantalum implant failure with associated radiological progression of the disease is reported in the literature; however, there is no report of clinical failure of the implant without radiological progression of the disease. We report a case of clinical failure of porous tantalum implant, seven months after surgery without any radiological progression of the disease, and with histopathological evidence of new bone formation around the porous tantalum implant. The patient was succesfully treated by total hip arthroplasty. PMID- 20924494 TI - Neglected irreducible posterolateral knee dislocation. AB - Knee dislocations are rare injuries. Posterolateral knee dislocations are only a small subset of them. There is a paucity of literature regarding the management of such neglected cases. We report here, a case of neglected irreducible posterolateral knee dislocation treated with open reduction and isolated posterior cruciate ligament reconstruction followed by gradual rehabilitation with good outcome at 3 years followup. PMID- 20924495 TI - Internal jugular phlebectasia as an incidental finding in cervical spine surgery. AB - Idiopathic internal jugular phlebectasia, occurs either unilaterally or bilaterally affecting the internal jugular vein is a rare congenital variation often diagnosed during childhood. It usually presents with a benign swelling over the lateral side of neck on the affected side, seen on exertion. A-30-year old male was operated for anterior cervical dissectomy from right lateral approach and was diagnosed per-operatively as internal jugular phlebectasia. The surgery was abandoned at this stage on the advice of cardiothoracic surgeon to investigate the patient for the secondary etiological factors for internal jugular vein dilatation. The patient was reassured without any active intervention for the phlebectasia and cervical dissectomy was performed in the second surgery through the lateral approach from left side. This case is presented in view of rarity and suggested that during preoperative workup the nearby structures like carotid sheath should be evaluated by magnetic resonance imaging to avoid such per-operative surprises. PMID- 20924496 TI - Protective Mechanism of KIOM-4 in Streptozotocin-Induced Pancreatic beta-Cells Damage Is Involved in the Inhibition of Endoplasmic Reticulum Stress. AB - Endoplasmic reticulum stress-mediated apoptosis plays an important role in the destruction of pancreatic beta-cells and contributes to the development of type 1 diabetes. The present study examined the effect of KIOM-4, a mixture of four plant extracts, on streptozotocin- (STZ-) induced endoplasmic reticulum (ER) stress in rat pancreatic beta-cells (RINm5F). KIOM-4 was found to inhibit STZ induced apoptotic cell death, confirmed by formation of apoptotic bodies and DNA fragmentation. STZ was found to induce the characteristics of ER stress; mitochondrial Ca(2+) overloading, enhanced ER staining, release of glucose regulated protein 78 (GRP78), phosphorylation of RNA-dependent protein kinase (PKR) like ER kinase (PERK) and eukaryotic initiation factor-2alpha (eIF-2alpha), cleavage of activating transcription factor 6 (ATF6) and caspase 12, and upregulation of CCAAT/enhancer-binding protein-homologous protein (CHOP). However, KIOM-4 attenuated these changes induced by STZ. Furthermore, KIOM-4 suppressed apoptosis induced by STZ in CHOP downregulated cells using CHOP siRNA. These results suggest that KIOM-4 exhibits protective effects in STZ-induced pancreatic beta-cell damage, by interrupting the ER stress-mediated pathway. PMID- 20924497 TI - Red ginseng extract facilitates the early differentiation of human embryonic stem cells into mesendoderm lineage. AB - Human embryonic stem cells (hESCs) have capacities to self-renew and differentiate into all cell types in vitro. Red ginseng (RG) is known to have a wide range of pharmacological effects in vivo; however, the reports on its effects on hESCs are few. In this paper, we tried to demonstrate the effects of RG on the proliferation and differentiation of hESCs. Undifferentiated hESCs, embryoid bodies (EBs), and hESC-derived cardiac progenitors (CPs) were treated with RG extract at 0.125, 0.25, and 0.5 mg/mL. After treatment of undifferentiated hESCs from day 2 to day 6 of culture, BrdU labeling showed that RG treatment increased the proliferation of hESCs, and the expression of Oct4 and Nanog was increased in RG-treated group. To find out the effects of RG on early differentiation stage cells, EBs were treated with RG extract for 10 days and attached for further differentiation. Immunostaining for three germ layer markers showed that RG treatment increased the expressions of Brachyury and HNF3beta on EBs. Also, RG treatment increased the expression of Brachyury in early-stage and of Nkx2.5 in late-stage hESC-derived CPs. These results demonstrate facilitating effects of RG extract on the proliferation and early differentiation of hESC. PMID- 20924498 TI - Semecarpus anacardium (Bhallataka) Alters the Glucose Metabolism and Energy Production in Diabetic Rats. AB - Glucose produced by gluconeogenesis and glycogenolysis plays an important role in aggravating hyperglycemia in diabetes, and altered mitochondrial function is associated with impaired energy production. The present study focuses on the effect of Semecarpus anacardium on carbohydrate metabolism and energy production in diabetic rats. Diabetes was induced by the administration of Streptozotocin at a dose of 50 mg/kg.b.wt. Three days after the induction, Semecarpus anacardium at a dose of 300 mg/kg.b.wt was administered for 21 days. After the experimental duration, the activities of the enzymes involved in Glycolysis, TCA cycle, gluconeogenesis, and glycogen were assayed in the liver and kidney of the experimental animals. In addition, to the complexes the protein expression of AKT and PI3K were assayed. The levels of the enzymes involved in Glycolysis and TCA cycle increased, while that of gluconeogensis decreased. The activities of the mitochondrial complexes were also favorably modulated. The expressions of PI3K and AKT also increased in the skeletal muscle. These effects may be attributed to the hypoglycemic and the antioxidative activity of Semecarpus anacardium. The results of the study revealed that Semecarpus anacardium was able to restore the altered activities of the enzymes involved in carbohydrate metabolism and energy production. PMID- 20924499 TI - Relaxation acupressure reduces persistent cancer-related fatigue. AB - Persistent cancer-related fatigue (PCRF) is a symptom experienced by many cancer survivors. Acupressure offers a potential treatment for PCRF. We investigated if acupressure treatments with opposing actions would result in differential effects on fatigue and examined the effect of different "doses" of acupressure on fatigue. We performed a trial of acupressure in cancer survivors experiencing moderate to severe PCRF. Participants were randomized to one of three treatment groups: relaxation acupressure (RA), high-dose stimulatory acupressure (HIS), and low-dose stimulatory acupressure (LIS). Participants performed acupressure for 12 weeks. Change in fatigue as measured by the Brief Fatigue Inventory (BFI) was our primary outcome. Secondary outcomes were assessment of blinding and compliance to treatment. Fatigue was significantly reduced across all treatment groups (mean +/ SD reduction in BFI: RA 4.0 +/- 1.5, HIS 2.2 +/- 1.6, LIS 2.7 +/- 2.2), with significantly greater reductions in the RA group. In an adjusted analysis, RA resulted in significantly less fatigue after controlling for age, cancer type, cancer stage, and cancer treatments. Self-administered RA caused greater reductions in fatigue compared to either HIS or LIS. The magnitude of the reduction in fatigue was clinically relevant and could represent a viable alternative for cancer survivors with PCRF. PMID- 20924500 TI - Anti-Hyperglycemic Properties of Crude Extract and Triterpenes from Poria cocos. AB - Poria cocos, Bai Fu Ling in Chinese, is used in traditional Chinese medicine to treat diabetes. However, its claimed benefits and mechanism are not fully understood. This study aimed to investigate the effect and action of P. cocos on type 2 diabetes. We first performed phytochemical analysis on the crude extract and factions of P. cocos. P. cocos crude extract at 50 mg/kg body weight or more significantly decreased blood glucose levels in db/db mice. Based on a bioactivity-directed fractionation and isolation (BDFI) strategy, chloroform fraction and subfractions 4 and 6 of the P. cocos crude extract possessed a blood glucose-lowering effect. Dehydrotumulosic acid, dehydrotrametenolic acid, and pachymic acid were identified from the chloroform sub-fractions 4, 3, and 2, respectively. Dehydrotumulosic acid had anti-hyperglycemic effect to a greater extent than dehydrotrametenolic acid and pachymic acid. Mechanistic study on streptozocin- (STZ-) treated mice showed that the crude extract, dehydrotumulosic acid, dehydrotrametenolic acid, and pachymic acid of P. cocos exhibited different levels of insulin sensitizer activity. However, the P. cocos crude extract and triterpenes appeared not to activate PPAR-gamma pathway. Overall, the data suggest that the P. cocos extract and its triterpenes reduce postprandial blood glucose levels in db/db mice via enhanced insulin sensitivity irrespective of PPAR-gamma. PMID- 20924501 TI - Photocatalytic hydrogen production from water in self-assembled supramolecular iridium-cobalt systems. AB - Supramolecular photosynthetic systems made up of the [Ir(ppy)(2)(bpy)](+) and [Co(bpy)(3)](2+) cores (ppy = 2-phenylpyridinate, bpy = 2,2'-bipyridine) are in situ self-assembled in aqueous media to generate H(2) upon visible light irradiation, where one of them recorded a relatively high turnover number of 20. PMID- 20924502 TI - Highly stable 7-N,N-dibutylamino-2-azaphenanthrene and 8-N,N-dibutylamino-2 azachrysene as a new class of second order NLO-active chromophores. AB - 7-N,N-Dibutylamino-2-azaphenanthrene (L(3)), 8-N,N-dibutylamino-2-azachrysene (L(4)) and related Ir(i) complexes or alkylated salts show high second-order NLO responses, as determined by the EFISH technique and DFT calculations. L(4) is appealing as building block for NLO active materials due to its unexpected large MUbeta(1.907)value and its very high thermal stability. PMID- 20924507 TI - Selective control of surface properties using hydrodynamic interactions. AB - Using computational modeling, we design nano-structured surfaces able to selectively regulate interactions between microchannel walls and flowing colloid polymer suspensions. Depending on the geometry of nanoscopic posts lining internal channel surfaces, suspended nanoparticles and polymeric chains can be either hydrodynamically attracted to channel walls or repelled to the bulk fluid. PMID- 20924506 TI - Synthesis and thermolytic behavior of tin(IV) formates: in search of recyclable metal-hydride systems. AB - The synthesis and characterization of the series of organotin formates together with their thermolytic behavior are described. The diformate Bu(n)(2)Sn{OC(O)H}(2) (1) was synthesized by the reaction of Bu(n)(2)SnH(2) with formic acid. The triorganotin monoformate compounds R(3)SnOC(O)H (R = Cy (cyclohexyl)) 3, Mes, (mesityl, 2,4,6-trimethylphenyl) 4, and Dmp (2,6 dimethylphenyl 5) were obtained by the reaction of R(3)SnOH with formic acid. Their X-ray crystal structures along with that of the previously reported formate (PhCH(2))(3)SnOC(O)H (2) were determined. The diformate 1 exhibits an extended two-dimensional polymeric structure in which six-coordinate tin centers are linked by formate bridges. The tribenzyltin formate (2) possesses a chain structure in which the five-coordinate Sn(CH(2)Ph)(3) units are bridged by formate ions. The cyclohexyl derivative 3 was observed to have a similar structure. In contrast, the Mes and Dmp derivatives 4 and 5 support monomeric structures in which the four-coordinate tin atom is bound to an oxygen of the formate ligand. Heating the compounds in various high boiling solvents produced no decomposition up to 120 degrees C in the case of 1 and refluxing a solution of 2 or 3 in mesitylene or diglyme left the starting material mostly unchanged, although 3 decomposed to an insoluble orange solid in refluxing decalin. In contrast, the heating of 4 and 5 in refluxing mesitylene led to elimination of CO to give the tin hydroxides. The results are in contrast to the known thermolytic behavior of R(3)SnOC(O)H (R = Pr(n) or Bu(n)) complexes, which eliminate CO(2) to generate R(3)SnH. Compounds 3-5 are rare examples of structurally characterized tin formates. PMID- 20924508 TI - Engineering of an enantioselective tyrosine aminomutase by mutation of a single active site residue in phenylalanine aminomutase. AB - By replacing a single active-site residue Cys107 with Ser in phenylalanine aminomutase (PAM), the enzyme gained tyrosine aminomutase (TAM) activity while retaining PAM activity and high enantioselectivity. This engineered enantioselective TAM also catalyzed formation of beta-tyrosine from p-coumaric acid and may prove to be useful for the synthesis of enantiopure beta-tyrosine and its derivatives. PMID- 20924514 TI - Amperometric proton selective sensors utilizing ion transfer reactions across a microhole liquid/gel interface. AB - A new cost-effective amperometric proton selective sensor utilizing a single microhole interface between two immiscible electrolyte solutions (ITIES) is developed. The sensing methodology is based on measuring currents associated with proton transfer across the interface assisted by a proton selective ionophore. The ellipse shaped micro-interface was first fabricated by simple mechanical punching with a sharp needle on a thin PVC film (12 MUm thick) commercially available as a food wrapping material. The microhole was then filled up with a gellified polyvinylchloride (PVC)-2-nitrophenyloctylether (NPOE) to create a single microhole liquid/liquid interface. Direct ion transfer reactions across the polarized interface serving as ion sensing platforms were studied using cyclic voltammetry. In order to enhance the selectivity of proton sensing, a proton selective ionophore, octadecyl isonicotinate (ETH1778), was incorporated into the organic gel layer and their electrochemical sensing characteristics were investigated using cyclic voltammetry and differential pulse stripping voltammetry. As an example, we employed the proton selective sensor for the determination of glucose concentrations. The detection scheme involves two steps: (i) protons are first generated by the oxidation of glucose with glucose oxidase in the aqueous phase; and (ii) the current associated with the proton transfer across the interface is then measured for correlating the concentration of glucose. PMID- 20924519 TI - Patterning osteogenesis by inducible gene expression in microfluidic culture systems. AB - The development of transitional interfacial zones between adjacent tissues remains a significant challenge for developing tissue engineering and regenerative medicine strategies. Using osteogenic differentiation as a model, we describe a novel approach to spatially regulate expression and secretion of the bone morphogenetic protein (BMP-2) in a two-dimensional field of cultured cells, by flow patterning the modulators of inducible BMP-2 gene expression. We first demonstrate control of gene expression, and of osteogenic differentiation of the cell line with inducible expression of BMP-2. Then we design laminar flow systems, with patterned delivery of Doxycycline (Dox), the expression modulator of BMP-2. The patterned concentration profiles were verified by computational simulation and dye separation experiments. Patterned differentiation experiments conducted in the flow systems for a period of three weeks showed the Dox concentration dependent osteogenic differentiation, as evidenced by mineral deposition. In summary, by combining inducible gene expression with laminar flow technologies, this study provided an innovative way to engineer tissue interfaces. PMID- 20924520 TI - Development of non-invasive Raman spectroscopy for in vivo evaluation of bone graft osseointegration in a rat model. AB - The use of bone structural allografts for reconstruction following tumor resection is widespread, although successful incorporation and regeneration remain uncertain. There are few non-invasive methods to fully assess the progress of graft incorporation. Computed tomography and MRI provide information on the morphology of the graft/host interface. Limited information is also available from DXA and ultrasound. Only few techniques can provide information on the metabolic status of the graft, such as the mineral and matrix composition of the regenerated tissue that may provide early indications of graft success or failure. To address this challenge, we discuss here the implementation of Raman spectroscopy for in vivo assessment of allograft implantation in a rat model. An array of optical fibers was developed to allow excitation and collection of Raman spectra through the skin of rat at various positions around the rat's tibia. The system is calibrated against locally constructed phantoms that mimic the morphology, optics and spectroscopy of the rat. The system was evaluated by carrying out transcutaneous Raman measurement on rat. Bone mineral and matrix Raman bands are successfully recovered. This new technology provides a non invasive method for in vivo monitoring of bone graft osseointegration. PMID- 20924521 TI - Experimental and theoretical study of rotationally inelastic diffraction of D2 from NiAl(110). AB - We present a detailed experimental and theoretical study of elastic and rotationally inelastic diffraction of D(2) from NiAl(110) in the energy range 85 150 meV. The experiments were performed using a high-resolution, fixed angle geometry apparatus. Quantum and classical dynamical calculations were performed by using a six-dimensional potential energy surface constructed upon interpolation of a set of DFT (density functional theory) data. We show that, although elastic diffraction peak intensities are accurately described by theory in the whole range of incidence energies and angles explored, significant discrepancies are obtained for RID peaks, especially for those involving rotational initial states with j(i) > 0. Possible reasons for this discrepancy are discussed. PMID- 20924522 TI - Correlation between polarity parameters and dielectric properties of [Na][TOTO]- a sodium ionic liquid. AB - The ionic liquid (IL) [Na][TOTO], with sodium as the cation and an oligoethercarboxylate as the anion, shows properties that differ significantly from conventional ionic liquids, like imidazolium salts. Its polarity, determined in the temperature range of (293-333) K from measurements of Reichardt's E value and the Kamlet-Taft parameters is extraordinarily low and matches the dielectric constant extrapolated from frequency dependent complex permittivity measurements. The dielectric spectra also reveal split dynamics with the dominating slow mode probably associated with the reorientation of -COO(-)...Na(+) ion pairs and the fast mode arising from the flexibility of the oligoethylene moieties of the anion. This assignment, supported by the derived effective dipole moments, argues against our previous hypothesis [O. Zech et al., Chem.-Eur. J., 2009, 15, 1341 1345] that salts, such as [Na][TOTO], have low melting points because of cation complexation in a pseudo crown ether-like fashion and resulting "intra-molecular" charge neutralization. The present data rule out a rigid chelate-like complex as the dominating species. Considering the present findings together with the viscosities of [TOTO](-) salts, a crosslinked structure of the ionic liquid with strong -COO(-)...Na(+) interactions and relatively weaker forces between cations and ether oxygen groups of the anions appears to be plausible. PMID- 20924523 TI - Direct assay of electropermeabilization in a 2D pseudo tissue. AB - An experimental validation of electropermeabilization inducing field distribution in tissue predicted by simulation for needle electrodes is described giving a direct visualization of the permeabilization of a 2D tissue. PMID- 20924524 TI - Internal mobilities and diffusion in an ionic liquid mixture. AB - The internal mobility gives the rate at which one ionic species moves relative to the other species present in an ionic mixture, it mirrors the differential strength of the interactions between different ionic species. In this work we examine the dependence of the internal mobilities of the Li(+) and K(+) ions on the composition in molten mixtures of LiF and KF. We compare them to the behaviour of the individual diffusion coefficients and the self-exchange velocities, which measure the rate at which an ion separates from its nearest neighbour coordination shell. The examination is made using molecular dynamics simulations with polarizable, first-principles parameterised interaction potentials which are shown to reproduce the limited available experimental data on the transport properties of these mixtures extremely well. The results confirm that the composition-dependence of the internal mobilities in LiF/KF follows the unusual type-II behaviour, which is not reflected in that of the diffusion coefficients or the self-exchange velocities. PMID- 20924525 TI - Synthesis, structure, and reductive elimination in the series Tp'Rh(PR3)(Ar(F))H; determination of rhodium-carbon bond energies of fluoroaryl substituents. AB - A series of complexes of the type Tp'Rh(PR(3))(Ar(F))H, where PR(3) = PMe(3) (3) and PMe(2)Ph (9), Ar(F) = C(6)F(5) (a), 2,3,4,5-C(6)F(4)H (b), 2,3,5,6-C(6)F(4)H (c), 2,4,6-C(6)F(3)H(2) (d), 2,3-C(6)F(2)H(3) (e), 2,5-C(6)F(2)H(3) (g), and 2 C(6)FH(4) (h) and Tp' = tris(3,5-dimethylpyrazolyl)borate, has been synthesized as stable crystalline compounds by the reactions of the [Tp'Rh(PR(3))] fragment with the corresponding fluorinated aromatic hydrocarbons, and their structures were characterized by NMR spectroscopy and elemental analysis together with X-ray crystallography. The kinetics of the reductive eliminations of fluoroarenes from complexes 3a-h in benzene-d(6) solutions at 140 degrees C were investigated, but were complicated by the formation of the rhodium(I) bisphosphine complex, Tp'Rh(PMe(3))(2) (4). On the other hand, thermal reactions of (9) in THF-d(8) solutions at 120 degrees C resulted in the formation of an intramolecular C-H bond activated complex of the phenyl group on the phosphorus atom, Tp'Rh(kappa(2) C(6)H(4)-2-PMe(2))H (7), which prevents the formation of the corresponding bisphosphine complex. The experimentally determined rates of the reductive eliminations of fluoroarenes from the complexes 9a-h and their kinetic selectivities for formation in competition with the metallacycle have been used to determine relative Rh-CAr(F) bond energies. The Rh-CAr(F) bond energy is found to be dependent on the number of ortho fluorines. A plot of Rh-CAr(F) vs. C-H bond strengths resulted in a line with a slope R(M-C/C-H) of 2.15 that closely matches the DFT calculated value (slope = 2.05). PMID- 20924526 TI - Effect of protonation on the electronic structure of aromatic molecules: naphthaleneH+. AB - Protonated naphthalene, the smallest protonated polycyclic aromatic hydrocarbon cation, absorbs in the visible, around 500 nm, which corresponds to an unusually large red shift with respect to the neutral naphthalene counterpart. PMID- 20924527 TI - A self-powered, one-step chip for rapid, quantitative and multiplexed detection of proteins from pinpricks of whole blood. AB - We describe an automated, self-powered chip based on lateral flow immunoassay for rapid, quantitative, and multiplex protein detection from pinpricks of whole blood. The device incorporates on-chip purification of blood plasma by employing inertial forces to focus blood cells away from the assay surface, where plasma proteins are captured and detected on antibody "barcode" arrays. Power is supplied from the capillary action of a piece of adsorbent paper, and sequentially drives, over a 40 minute period, the four steps required to capture serum proteins and then develop a multiplex immunoassay. An 11 protein panel is assayed from whole blood, with high sensitivity and high reproducibility. This inexpensive, self-contained, and easy to operate chip provides a useful platform for point-of-care diagnoses, particularly in resource-limited settings. PMID- 20924528 TI - Large-scale performance evaluation of e-homecare architectures using the WS-NS simulator. AB - BACKGROUND: E-homecare creates opportunities to provide care faster, at lower cost and higher levels of convenience for patients. As e-homecare services are time-critical, stringent requirements are imposed in terms of total response time and reliability, this way requiring a characterization of their network load and usage behavior. However, it is usually hard to build testbeds on a realistic scale in order to evaluate large-scale e-homecare applications. OBJECTIVE: This paper describes the design and evaluation of the Network Simulator for Web Services (WS-NS), an NS2-based simulator capable of accurately modeling service oriented architectures that can be used to evaluate the performance of e-homecare architectures. METHODS: WS-NS is applied to the Coplintho e-homecare use case, based on the results of the field trial prototype which targeted diabetes and multiple sclerosis patients. Network-unaware and network-aware service selection algorithms are presented and their performance is tested. RESULTS: The results show that when selecting a service to execute the request, suboptimal decisions can be made when selection is solely based on the service's properties and status. Taking into account the network links interconnecting the services leads to better selection strategies. Based on the results, the e-homecare broker design is optimized from a centralized design to a hierarchical region-based design, resulting in an important decrease of average response times. CONCLUSIONS: The WS-NS simulator can be used to analyze the load and response times of large-scale e-homecare architectures. An optimization of the e-homecare architecture of the Coplintho project resulted in optimized network overhead and more than 45% lower response times. PMID- 20924529 TI - Errata. PMID- 20924530 TI - Editorial. PMID- 20924531 TI - Characterizing ceramics and the interfacial adhesion to resin: II- the relationship of surface treatment, bond strength, interfacial toughness and fractography. AB - The clinical success of resin bonding procedures for indirect ceramic restorations and ceramic repairs depends on the quality and durability of the bond between the ceramic and the resin. The quality of this bond will depend upon the bonding mechanisms that are controlled in part by the surface treatment that promote micromechanical and/or chemical bonding to the substrate. The objective of this review is to correlate interfacial toughness (K A) with fracture surface morphological parameters of the dental ceramic-resin systems as a function of ceramic surface treatment. This analysis is designed to identify mechanisms that promote adhesion of these ceramic-resin systems and an appropriate bond test method to yield relevant adhesion performance data. PMID- 20924532 TI - Marginal leakage of polyacid-modified composite resin restorations in primary molars: an in vitro study. AB - The purpose of this in vitro study was to compare the marginal leakage in primary molars restored with 2 polyacid-modified composite resins (Dyract AP - Dentsply and F2000 - 3M) and a composite resin (Filtek Z250 - 3M) as control. First and second primary molars were used for preparation of cavities on the proximal surfaces, with extension of the gingival margin to the cementoenamel junction. Restorations were accomplished after total etching and application of the respective adhesive system, and were divided into groups according to the restorative system and the number of adhesive layers used. The teeth were stored in distilled water for 7 days, followed by thermocycling with 500 cycles at 5oC - 55oC, with one minute in each bath. Thereafter, teeth were prepared for immersion in 0.5% methylene blue solution for four hours. The teeth were sectioned in mesiodistal direction for assessment of dye penetration. According to the results of the Kruskal-Wallis test, the three restorative materials employed did not completely avoid marginal leakage at the gingival margin of primary molars. The marginal leakage of PMCR F2000 (4.06 and 3.95) displayed to be higher than the marginal leakage observed for the materials Dyract AP (2.7 and 2.55) and Filtek Z250 (2.25 and 2.43). The number of adhesive layers did not influence the degree of leakage of the three materials. PMID- 20924533 TI - Comparative study of rules employed for calculation of pediatric drug dosage. AB - The present study was conducted to evaluate the utilization of Clark's, Salisbury and Penna's rules and the Body Surface Area (BSA) formula for calculation of pediatric drug dosage, as well as their reliability and viability in the clinical use. These rules are frequently cited in the literature, but much controversy still exists with regards to their use. The pediatric drug dosage was calculated by utilization of the aforementioned rules and using the drugs Paracetamol, Dipyrone, Diclofenac Potassium, Nimesulide, Amoxicillin and Erythromycin, widely employed in Pediatric Dentistry. Weight and body surface areas were considered of children with ages between 1 and 12 years old as well as the dosage for the adult. The pediatric dosages achieved were compared to the predetermined dosages in mg kg-1 herein-named standard dosages. The results were submitted to the parametric test ANOVA and to the Tukey test (p<0,05). The antibiotics and Diclofenac provides acceptable utilization of the rules in pediatric dentistry, however for the Dipyrone, the dosages obtained by the rules suggest their clinical ineffectiveness. For the Paracetamol, the Penna's rule and the BSA formula should not be clinically employed, especially for children between 1 and 5 years old, once such dosages were much close to the hepatotoxic dosage of the drug. It can be concluded that the use of the rules for safe calculation of the pediatric drug dosage is possible and it depends on the used drug and age group. PMID- 20924534 TI - The influence of different screw tightening forces on the vertical misfit of implant-supported frameworks. AB - OBJECTIVES: The present in vitro study was designed to compare the differences in the vertical misfit of implant-supported frameworks using three different forces for tightening the bridge locking screws: fastening by hand until first resistance, and using torque drivers with 10 and 20Ncm. METHODS: The investigation was conducted based on the results given by 9 six-unit nickel chromium (2 abutments/ 4 pontics) screw-retained implant-supported frameworks. The structures were exposed to simulated porcelain firings. The marginal misfit measurements were made using a traveling measuring microscope at selected screw tightening forces: fastening by hand until first resistance, and using torque drivers with 10 and 20Ncm. The results were submitted to one-way ANOVA with repeated measures on one factor, and post hoc pairwise comparisons using Tukey test (5%). RESULTS: The mean marginal misfit of the frameworks, fastening the screws by hand until first resistance, was 41.56um (SD+/-12.45um). The use of torque driver devices caused a significant reduction in marginal opening (p<0.05). With the lowest torque available (10Ncm), the mean marginal discrepancy at the abutment-framework interface was reduced an average of 52% to a mean marginal opening of 19.71um (SD+/-2.97um). After the use of the 20Ncm torque driver, the mean marginal discrepancy of the frameworks was reduced an average of 69% to a mean marginal opening of 12.82um (SD+/-4.0um). Comparing the use of torque drivers with 10 and 20 Ncm torque, the means are not significantly different from one another. CONCLUSION: The seating force has an important effect on the vertical misfit measurements, once it may considerably narrow the vertical misfit gaps at the abutment-framework interface, thus leading to a misjudgment of the real marginal situation. PMID- 20924535 TI - MTA and calcium hydroxide for pulp capping. AB - This study evaluated the biocompatibility of mineral trioxide aggregate (MTA) after direct capping of exposed pulp tissue in dog's teeth. Class I cavities were prepared in 26 teeth from 3 adult dogs. MTA was applied over the exposed pulp in 13 teeth and paste of calcium hydroxide plus distilled water (control) was applied in the remaining 13 teeth. After 90 days, the animals were killed; the maxilla and mandible were dissected and sectioned to obtain individual roots. The samples were processed histologically. The pulp and periapical response observed with the use of MTA was similar to that of calcium hydroxide paste. In all specimens, there was a dentin bridge obliterating the exposure, an intact odontoblastic layer, no inflammatory cells, normal connective pulp tissue, normal apical and periapical regions and no bone tissue changes. Similar to calcium hydroxide, MTA presented excellent response when used for direct pulp capping. PMID- 20924536 TI - Evaluation of weight loss and surface roughness of compomers after simulated toothbrushing abrasion test. AB - This study aimed at analyzing the compomers wear by an "in vitro" toothbrushing abrasion test. The null hypotheses tested were that there would be no differences in weight loss and no significant changes in surface roughness of the compomers after this test. The utilized commercial brands were Dyract (Dentsply), Dyract AP (Dentsply), Compoglass F (Vivadent), Freedom (SDI), F2000 (3M ESPE), which were compared to the two resin composites Z100 (3M ESPE) and Silux Plus (3M ESPE). Ten cylindrical specimens for each commercial brand were prepared with 5mm diameter and 3mm thickness. An appropriate machine with soft bristle tips containing dentifrice solution and deionized water was used. A total of 100,000 brushing cycles were performed. The amount of weight loss was measured by the percentage alteration between the initial (before toothbrushing) and final weight (after toothbrushing), measured by a Sartorius analytical balance. The surface roughness change was determined by the percentage difference between initial and final means after 5 tracings by a T 1000 Hommel Tester roughness meter on the specimen's surfaces before and after toothbrushing abrasion test. The statistical analysis (Students paired t-test, ANOVA and Tukey, a=0.05) showed that all materials presented statistically significant weight loss and roughness increase after abrasion test. All compomers presented higher weight loss than resin composites. Freedom and Dyract AP presented the lowest weight loss among compomers. F2000 presented the worst abrasion resistance, without statistical differences with Dyract. For roughness changes, Dyract, Dyract AP, Z100, Compoglass F and Silux Plus showed the lowest surface roughness alteration, in increasing order, without statistical differences between them. Freedom was the statistically roughest material of the study. PMID- 20924537 TI - Physicochemical characterization of six commercial hydroxyapatites for medical dental applicatons as bone graft. AB - The aim of this work was to characterize six hydroxyapatites in granular form for applications in medicine and dentistry as bone graft and to compare with manufacturers' specification. These samples were produced by four different manufacturers, and all of them are easily available in the Brazilian market. Physicochemical characterization was carried out by using electron microscopy (SEM), X-ray diffraction (XRD), infrared spectroscopy (FTIR) and surface area (BET) measurements. The results show that just one hydroxyapatite sample exhibited characterisitics in perfect agreement with the manufacturers' specifications. The studied parameters, namely crystallinity, surface area and composition may be used to estimate hydroxyapatite's biodegradability and as a criterion for quality control. PMID- 20924538 TI - Evaluation of fracture resistance of endodontically treated teeth restored with prefabricated posts and composites with varying quantities of remaining coronal tooth structure. AB - OBJECTIVES: The aim of this study was to evaluate the influence of remaining coronal tooth structure on endodontically treated teeth restored with prefabricated posts and two different composites for core build-up: dual-cured resin (Enforce Core) and light-cured resin (Z-250). METHODS: Fourty freshly extracted canines were endodontically treated and divided into four groups: Group I - teeth with 3mm remaining coronal structure, restored with Enforce Core; Group II - teeth with 3mm remaining coronal structure, restored with Z-250; Group III - teeth with no remaining coronal structure, restored with Enforce; Group IV - teeth with no remaining coronal structure, restored with Z-250. After restoration, the teeth were embedded in acrylic resin and the fracture resistance was measured on a universal testing machine at 45 degrees to the long axis of the tooth until failure. RESULTS: Data were analyzed by two-way analysis of variance, which showed significant differences between groups (p=0.00). The Tukey test did not show significant differences between specimens with and without remaining coronal structure. Conversely, significant difference was observed between groups with different core build-up. The highest values of fracture resistance were found in the group restored with light-cured resin. SIGNIFICANCE: The remaining coronal tooth structure did not influence the resistance of endodontically treated teeth; however, the change of core build-up was able to modify this resistence. PMID- 20924539 TI - Influence of different auxiliary agents of biomechanical preparation in the filling of "artificially prepared" lateral canals. AB - The purpose of the present study was to evaluate the influence of some auxiliary agents of biomechanical preparation of the root canal on the filling of artificial lateral canals in extracted human teeth. A total of eighty single rooted teeth were employed, which were submitted to preparation of three artificial lateral canals in one of the proximal aspects at the cervical, middle and apical thirds, besides one in the buccal aspect. The main canals were prepared by Profile 0.4 rotary instruments through the crown-down technique and irrigated with the irrigants investigated, as follows: Group A - 1% sodium hypochlorite and final irrigation with trisodium EDTA for 5 minutes; Group B - Endogel (2% chlorhexidine gel); Group C - Endo PTC and Dakin's solution and final irrigation with Tergentol- Furacin; and Group D - File Eze. The root canals were obturated by the Tagger's hybrid technique and then radiographed for assessment of the penetration rate of the filling materials in the lateral canals. Analysis of the results demonstrated no statistically significant difference (p<0.05) between the irrigants both to each other and as regards the location (thirds and aspects) of the artificial lateral canals. PMID- 20924540 TI - Surface tension of calcium hydroxide associated with different substances. AB - The purpose of this study was to evaluate the surface tension of calcium hydroxide (CH) associated with different substances (deionized distilled water, camphorated paramonochlorophenol, 2% chlorhexidine digluconate, Otosporin, 3% sodium lauryl ether sulphate; Furacin, PMC Furacin) using tensiometer. The action of the substances studied on the dentinal structure enhances the property of surface tension. This method consists in the application of force to separate a platinum ring immersed in the substances. Thus, torsion was applied to the screw until the platinum ring separated during substances testing. Considering the methodology applied, the following can be concluded: distilled water alone or associated with CH presented a high surface tension (70.00 and 68.40 dynes/cm); calcium hydroxide in association with anionic detergent showed low surface tension (31.60 dynes/cm); camphorated paramonochlorophenol plus CH presented low surface tension (37.50 dynes/cm); 2% chlorhexidine associated with calcium hydroxide showed high surface tension values (58.00 dynes/cm); Otosporin plus calcium hydroxide showed low surface tension (35.40 dynes/cm); paramonochlorophenol Furacin mixed with calcium hydroxide presented surface tension equal to 45.50 dynes/cm; sodium hypochlorite presented high surface tension (75.00 dynes/cm). Antimicrobial agents more indicated in endodontics, i.e. CH, chlorhexidine and hypochlorite, presented the highest surface tension. PMID- 20924541 TI - Microscopic and radiographic analysis of the effect of particle size of demineralized bovine cancellous bone matrix on the repair of bone defects in femurs of rabbits. AB - The bone tissue has a great regenerative potential, with ability to completely restore its structure and original functions. In some situations, though, bone defects cannot be self-repaired, thus requiring the use of grafts for a correct treatment and good prognosis. This work aimed at microscopically analyzing the effect of the particle size of demineralized bovine cancellous bone matrix in micro and macrogranular forms on the repair of bone defects in femurs of rabbits, with blood clot used as control. At 1, 3 and 6 months after implantation of the materials, the animals were killed and the anatomic specimens were removed. A foreign body-type granulomatous reaction containing macrophages and multinucleated giant cells in contact with the implanted particles was observed. These results suggest a failure in demineralization and/or interruption of the antigenic potential during production of the biomaterial. It is concluded that the size of the particles did not influence the evolution of the repair process of bone defects, acting only as bone-filler substances, and that the material implanted should be improved by quality control during production, since it may represent a good alternative for bone graft. PMID- 20924542 TI - Biosecurity in public and private office. AB - Biosecurity is currently a concern for all health-related services, including dentistry, since infection control has a relevant importance. In dental practice, health-related occupations have contact with a great number of individuals who are potentially capable to transmit pathogens. This study comprised a descriptive evaluation of the universal precaution measures for infection control adopted by dental practitioners working at public and private offices in the city of Aracatuba, SP. Data collection was performed by a quiz with questions about individual and collective protection equipments. The results showed that the use of caps was reported by 55% of the professionals working at the public sector and 90% for the private sector. The use of masks and gloves was reported by all professionals surveyed; nevertheless, glove change between patients was not reported by 40% of professionals working at the public sector. There were more flaws in public offices as to the use of protective barriers, since except for the use of gloves, gowns and masks, the frequency of use of those barriers was smaller than at private offices. PMID- 20924543 TI - Surgical anatomy of the maxillary nerve in the zygomatic region. AB - Anatomic knowledge on the zygomatic fossa is of primary importance to improve the regional anesthetic technique of the maxillary nerve. Few reports in the literature have addressed the trajectory of the maxillary nerve and its branches in this region; thus, this study aimed at presenting information about the trajectory of these nerves. Thirty human half-heads of both genders were fixed in 10% formalin and demineralized in 5% nitric acid, and the maxillary nerve was dissected since its origin on the pterygopalatine fossa until penetration into the inferior orbital fissure. It was observed that the maxillary nerve sends one to three posterior superior alveolar branches and tuberal descendent branches, which supply the soft tissue structures of the region. The posterior superior alveolar nerves are inferiorly oriented near the maxillary tuberosity, where they penetrate the alveolar canals with the posterior superior alveolar artery and send small nerve branches that continue in an extraosseous trajectory. This study found that nearly 2/3 of the trajectory of the maxillary nerve is located in the zygomatic region, with a short segment (1/3) in the pterygopalatine fossa. PMID- 20924544 TI - Comparative analisys of three different diagnostic methods to evaluate carious activity in a community basis. AB - The present research has made a comparison between three distinct methods to evaluate carious activity in a community basis. The studied method was based in a modified DMFS/dmfs index including non-cavitated lesions. Two factors were analyzed: the possible reproduction of the inclusion of carious activity criteria and the presence of bacterial plaque. Thus, the three study groups presented with plaque, after supervised self-performed plaque removal with dental toothbrush and without plaque after professional prophylaxis, which corresponded to three diagnostic methods. The three exams took place one week apart from each other. For this analysis, a modified DMFS/dmfs index was proposed with alterations in diagnostic criteria due to the inclusion of carious activity parameters. The study was performed in a group of 30 children aged 11 years old. According to the results, the diagnostic method for carious activity in the three situations was reproducible and can be considered a proper approach to perform caries diagnosis in a community basis. PMID- 20924545 TI - Influence of gutta-percha points on the filling of simulated lateral canals. AB - The aim of this study was to investigate, in vitro, the percentage of filling of simulated lateral canals in teeth obturated with TP medium and standardized gutta percha points. Twenty human mandibular canines were prepared with LA Axxess (SybronEndo) and K3 Endo rotary system (SybronEndo) up to a #50 file, according to the Free Tip Preparation Technique. During instrumentation, the root canals were alternately irrigated with 1% sodium hypochlorite and 17% EDTA. Six artificial lateral canals were prepared at the apical third of each tooth. Then, the teeth were assigned to two groups (n=10): Group 1 - filled with TP medium master gutta-percha points (Dentsply, Mailleffer); Group 2 - filled with standardized master gutta-percha points (Dentsply, Mailleffer). Root canal filling was complemented with AH Plus sealer (Dentsply, Mailleffer) and accessory gutta-percha points (Dentsply, Mailleffer), according to the classic technique. The teeth were radiographed and the images obtained were digitized. Linear measurements of the percentage of filling of the artificial lateral canals in each group were accomplished on the Image Tool 2.02 software. Statistical analysis of the data using Mann-Whitney U non-parametric test evidenced significant difference (p<0.01) between the experimental groups. The group obturated with TP medium points yielded higher percentage of filling of the lateral canals. It may be concluded that the use of master gutta-percha points with larger taper resulted in better filling of the simulated lateral canals, as compared to the use of standardized master gutta-percha points. PMID- 20924546 TI - Six-month evaluation of ART one-surface restorations in a community with high caries experience in Brazil. AB - The aim of this study to evaluate the success rate in one-surface ART restorations placed in permanent molars using a glass ionomer cement especially developed for ART in a community with high caries experience; to evaluate the operator influence on its success, post-operative sensitivity and technique acceptance by patients. Prior to placement of the restorations, the Gingival Bleeding Index, Visible Plaque Index, DMFT, dmft indices and treatment needed were assessed. One hundred and fifty five one-surface restorations were placed in permanent molars of school children, according to the WHO ART manual, 1997. After 6 months, the success rate was verified clinically and by slides. At baseline, the mean DMFT was 2.56 (+/-1.08) and the mean dmft, 2.53 (+/-2.33). Operators A and B have placed 102 and 53 ART restorations respectively. The mean time of placement was 16 minutes and 25 seconds to operator A and 14 minutes and 43 seconds to operator B. At 6-month follow up, 152 ART restorations were evaluated and 97.3% were assessed to be successful. Two restorations were excluded from the sample because the ART restorations were replaced by amalgam fillings. Only 4 restorations have failed, in which 2 due to caries, 1 due to fistula presence and the other because the restoration was lost. Four patients reported postoperative sensitivity. At this study period, ART treatment seems to be suitable for its purpose. Further evaluations are necessary to the new glass ionomer cements especially developed for ART technique provided good results at 6-month follow up in a community with high DMFT and dmft indices. The success rate for one-surface cavities in permanent molars was 97.3%, and the studied indices seemed to have no influence in this early evolution period. PMID- 20924547 TI - Hydroxyl and calcium ions diffusion from endodontic materials through roots of primary teeth - in vitro study. AB - The purpose of this research was to evaluate the diffusion of calcium (Ca+2) and hydroxyl (OH-) ions from materials with a calcium hydroxide base - Ca(OH)2 through the intact roots of deciduous teeth. This diffusion of ions is important for periapical healing. Forty-six deciduous teeth were selected and instrumented to their working length with #40 files. The teeth were washed during cleaning and shaping with a 1% sodium hypochlorite (NaOCl) solution. The canals were dried with paper points. The teeth were divided into 4 groups based on the sealer type, with 10 specimens in each group. A fifth group of 6 teeth without sealer constituted the control group. The materials used as sealers were: Ca(OH)2 paste associated to propylene glycol (CaPE) thickened at the proportion of 2:1 w/v; UFSC (Federal University of Santa Catarina) paste - a mixture of 0.3g of zinc oxide with 0.3g of Ca(OH)2 with 0.2ml of olive oil 1:1 w/w; Vitapex(r) and Sealapex(r). The coronal access was sealed with a glass ionomer after the root had been filled with each sealer. A one-third apical surface and foramen was hard pressed with Araldite(r). The teeth were stored individually in flasks containing saline solution at 37oC and 100% humidity. The OH- and Ca+2 ions diffusion levels were determined using a pH meter and an atomic absorption spectrometer. Data were collected at 48 hours and at intervals of 7, 30, 45 and 60 days. Statistical analysis was performed using ANOVA to compare groups. In the pH evaluation, the CaPE group presented the largest OH- ions diffusion, which peaked at sixty days (p=0.0309), when compared to the other groups (p<0.0001). In relation to amount of Ca+2 ions released, the CaPE paste showed the best results, followed by the UFSC's paste. These results suggest that the CaPE paste was the material that allowed the highest diffusion of OH- and Ca+2 ions. PMID- 20924548 TI - Influence of light intensity and curing cycle on microleakage of Class V composite resin restorations. AB - The aim of this study was to determine the effect of a softstart polymerization method from Quartz-Tungsten-Halogen (QTH) and Plasma Arc (PAC) curing units on microleakage of Class V composite resin restorations with dentin cavosurface margins. Seventy-five bovine incisors received standardized class V cavities in all dentin margins. Teeth were divided into 5 equal groups according to the curing cycle. The cavities were incrementally restored with a composite resin (Single Bond/Z-100, 3M). Light curing was applied as follows: Group I: PAC light continuous-cycle curing at 1600 mW/cm2 for 3s; Group II: PAC light step-cycle curing (2s at 800 mW/cm2 then 4s at 1600 mW/cm2); Group III: QTH light continuous cycle curing at 400 mW/cm2 for 40s; Group IV: QTH light ramp-cycle curing (from 100 to 600 mW/cm2 in 15s followed by 25s at 600 mW/cm2); Group V: QTH light pulse delay curing (200 mW/cm2 for 3s followed by 3 min delay then 600 mW/cm2 for 30s). Teeth were stored in distilled water at 37oC for 30 days and then subjected to thermocycling for 500 cycles at 5 and 55oC. Root apices were sealed and teeth coated with nail varnish before they were immersed in 0.5% fuchsine red dye solution. Teeth were then sectioned and slices were scanned with a computer scanner to determine the area of dye leakage using a computer program (Image Tools). Images of tooth slices were also visually examined under magnification and dye penetration along the tooth/restoration interface was scored. Significant differences in the degree of dye penetration and leakage were detected between groups (p<.05). Groups I and II had significantly higher values of dye penetration and leakage than groups III, IV and V. In conclusion, the use of PAC light curing in a continuous or step cycle modes resulted in increased microleakage of Class V resin composite restorations compared with medium intensity QTH light curing. Pulse, ramp and continuous-cycle curing modes with QTH light resulted in similar degrees of microleakage. PMID- 20924549 TI - Cephalometric characterization of skeletal Class II, division 1 malocclusion in white Brazilian subjects. AB - One of the main points in Orthodontic studies is the growth and development of the craniofacial structures. In this study, skeletal cephalometric characteristics of Class II, division 1 malocclusion were assessed in lateral cephalograms. The experimental sample comprised 55 white Brazilian individuals of both genders, with an ANB angle of 4.5 degrees or higher. The mean age of the subjects was 13.5 years. Steiner and McNamara Jr cephalometric analyses were used in order to evaluate the relation between angular and linear positions of the apical bases, the dental and cranial structures, comparing with the values obtained in the control group (available at Bauru Dental School-USP). The results showed that, for the experimental group, the maxilla was well positioned in relation to the cranial base. The maxillomandibular relation showed an increased overjet, which was predictable based on criteria for sample selection. The geometrical proportion of the apical bases presented a small mandible and a normal sized maxilla. The craniofacial growth pattern presented a vertical tendency. The maxillary incisors were buccally inclined and well positioned by the linear evaluation. The mandibular incisors showed marked buccal inclination and protrusion. No statistically significant difference between genders was found. PMID- 20924550 TI - Evaluation of the bleached human enamel by Scanning Electron Microscopy. AB - Since bleaching has become a popular procedure, the effect of peroxides on dental hard tissues is of great interest in research. PURPOSE: The aim of this in vitro study was to perform a qualitative analysis of the human enamel after the application of in-office bleaching agents, using Scanning Electron Microscopy (SEM). MATERIALS AND METHODS: Twenty intact human third molars extracted for orthodontic reasons were randomly divided into four groups (n=5) treated as follows: G1- storage in artificial saliva (control group); G2- four 30-minute applications of 35% carbamide peroxide (total exposure: 2h); G3- four 2-hour exposures to 35% carbamide peroxide (total exposure: 8h); G4- two applications of 35% hydrogen peroxide, which was light-activated with halogen lamp at 700mW/cm2 during 7min and remained in contact with enamel for 20min (total exposure: 40min). All bleaching treatments adopted in this study followed the application protocols advised by manufacturers. Evaluation of groups submitted to 35% carbamide peroxide was carried out after two time intervals (30 minutes and 2 hours per session), following the extreme situations recommended by the manufacturer. Specimens were prepared for SEM analysis performing gold sputter coating under vacuum and were examined using 15kV at 500x and 2000x magnification. RESULTS: Morphological alterations on the enamel surface were similarly detected after bleaching with either 35% carbamide peroxide or 35% hydrogen peroxide. Surface porosities were characteristic of an erosive process that took place on human enamel. Depression areas, including the formation of craters, and exposure of enamel rods could also be detected. CONCLUSION: Bleaching effects on enamel morphology were randomly distributed throughout enamel surface and various degrees of enamel damage could be noticed. CLINICAL SIGNIFICANCE: In-office bleaching materials may adversely affect enamel morphology and therefore should be used with caution. PMID- 20924551 TI - [Kapandji-Sauve procedure with distal radioulnar fusion and segmental resection of the ulna]. AB - OBJECTIVE: The Kapandji-Sauve procedure aims at improvement of rotation in the distal radioulnar joint and reduction of pain. Cases of ulnar impaction syndrome can also be corrected during the same procedure. INDICATIONS: The most important indication is painful und restricted forearm rotation after fracture of the distal radius combined with obsolete dislocation or destruction of the distal radioulnar joint. CONTRAINDICATIONS: It is a salvage procedure and is contraindicated when reconstruction of the radioulnar joint or shortening of the ulna is possible. Further contraindications are rheumatic arthritis and osteoporosis. SURGICAL TECHNIQUE: The Kapandji-Sauve procedure creates a new distal rotatory joint due to distal radioulnar fusion and segmental resection of the distal ulna. POSTOPERATIVE MANAGEMENT: Forearm cast including the wrist for 3 4 weeks. Phyisiotherapy and intensive exercises of the fingers on postoperative day 1. After removing the cast, careful rotation exercises are possible. RESULTS: In 75 patients, the Kapandji-Sauve procedure was performed between 1990 and 2003. Failure was observed in one patient with a bony regeneration between the resected ulnar segment. In 3 cases, a nonunion of the radioulnar joint was found. After revision with bone grafting, bony consolidation of the joint was identified in all cases. In 2 cases, there were problems with the proximal ulnar stump, whereby this was corrected in one case by resection of a ball-type callus. In the other case, painful ulna-snapping was reduced by shortening of the ulna. In earlier follow-up with 45 patients and later long-turn follow-up, ranging from 3-12 years, not only were significant improvement of forearm rotation and reduction of pain observed, but also good patient satisfaction was found. PMID- 20924552 TI - [Tumor of the esophoagocardiac junction]. AB - The presence of heterotopic pancreatic tissue in the gastroesophageal junction is a very rare entity. An exact preoperative diagnosis is only rarely possible despite all available diagnostic procedures. We report on the case of a submucous tumor of the gastroesophageal junction which became symptomatic due to reflux problems and was successfully removed by endoscope-assisted laparoscopic resection. PMID- 20924553 TI - [Imaging of molecular structures of breasts with new sonography techniques]. AB - Sonography has become one of the most important imaging methods in breast diagnostics. Through the development of high-frequency transducers and the use of ultrasound contrast agents, the number of indications for sonography of the breast has continued to increase in recent years. Visualization of very small vessels under 100 um enables sensitive detection and quantification of tissue perfusion. Thus, breast ultrasound can play an essential role in answering questions about certain pathologies. Further technical advances, such as automated breast ultrasound systems, provide an essential step for standardization of investigations. Targeted ultrasound is a new important development of this technique. Specific markers which are conjugated with the surface of contrast medium microspheres allow targeted molecular endothelial structures to be selectively visualized and quantified. These developments will strengthen the role of sonography in the future as a non-invasive and easy to use method. PMID- 20924554 TI - Neighborhood characteristics and mental health: the relevance for mothers of infants in deprived English neighborhoods. AB - PURPOSE: Neighborhood features have been linked with adult mental-health problems, particularly depression. A recent comprehensive review indicated structural neighborhood features derived from data sources such as the census may be less important predictors of mental health problems than social processes but that most studies lack multiple neighborhood measures. The aim of the study is to investigate relations between multiple neighborhood factors (observations, interviewer ratings, UK Census data) and maternal mental-health problems. METHODS: 14,700 mothers with 9-month-old infants living in 195 deprived neighborhoods in England were interviewed, neighborhoods were observed and census data on employment, ethnic background and housing tenancy utilized. RESULTS: Lower (interviewer-rated) neighborhood quality and lower neighborhood prosperity predicted more mother-reported mental-health problems net of family-level predictors. Contrary to expectations detailed observations did not contribute additionally. CONCLUSIONS: Neighborhood conditions, though not as important as family factors and maternal characteristics, are sufficiently important to consider when planning mental health services; they can be assessed at relatively low cost by census data or professionals' ratings. PMID- 20924556 TI - Obesity and urinary incontinence in women: is the black box becoming grayer? PMID- 20924555 TI - Impact of albumin compared to saline on organ function and mortality of patients with severe sepsis. AB - PURPOSE: To determine the effect of random assignment to fluid resuscitation with albumin or saline on organ function and mortality in patients with severe sepsis. METHODS: Pre-defined subgroup analysis of a randomized controlled trial conducted in the intensive care units of 16 hospitals in Australia and New Zealand. RESULTS: Of 1,218 patients with severe sepsis at baseline, 603 and 615 were assigned to receive albumin and saline, respectively. The two groups had similar baseline characteristics. During the first 7 days mean arterial pressure was similar in the two groups, but patients assigned albumin had a lower heart rate on days 1 and 3 (p = 0.002 and p = 0.03, respectively) and a higher central venous pressure on days 1-3 (p < 0.005 each day). There was no difference in the renal or total Sequential Organ Failure Assessment score of the two groups; 113/603 (18.7%) of patients assigned albumin were treated with renal replacement therapy compared to 112/615 (18.2%) assigned saline (p = 0.98). The unadjusted relative risk of death for albumin versus saline was 0.87 [95% confidence interval (CI) 0.74-1.02] for patients with severe sepsis and 1.05 (0.94-1.17) for patients without severe sepsis (p = 0.06 for heterogeneity). From multivariate logistic regression analysis adjusting for baseline factors in patients with complete baseline data (919/1,218, 75.5%), the adjusted odds ratio for death for albumin versus saline was 0.71 (95% CI: 0.52-0.97; p = 0.03). CONCLUSIONS: Administration of albumin compared to saline did not impair renal or other organ function and may have decreased the risk of death. PMID- 20924557 TI - Lead migration after sacral neuromodulation: surgical revision in fascial versus tined anchoring systems. AB - INTRODUCTION AND HYPOTHESIS: Our objective was to compare risk of surgical revision after sacral neuromodulator lead migration based on the type of anchoring system. METHODS: We performed a retrospective cohort study of patients receiving sacral neuromodulation over 7 years. We compared surgical revision due to loss of efficacy accompanied by radiographic lead migration in fascial anchored versus tined leads. RESULTS: Of 112 patients, 28 (25%) underwent fascial anchoring, and 84 (75%) received tined leads. Within 2 years of implantation, lead migration occurred in 26% of fascial and 10% of tined anchoring systems (RR, 2.25 (95% confidence interval, 0.85-5.93)). Patients with fascial anchors were followed for a longer period of time. Therefore, Kaplan-Meier curves were compared showing no difference in risk of lead migration (p = 0.09). Four of eight (50%) lead migrations in tined leads occurred within the first 3 months after implantation. CONCLUSIONS: Two years after sacral neuromodulator implantation, lead migration is similar between fascial-anchored and tined leads. PMID- 20924558 TI - Diphenyl diselenide induces apoptotic cell death and modulates ERK1/2 phosphorylation in human neuroblastoma SH-SY5Y cells. AB - Diphenyl diselenide (PhSe)(2) is a synthetic organoselenium compound displaying glutathione peroxidase-like activity. Protective and antioxidant potential of (PhSe)(2) have been extensively investigated in in vivo and in vitro studies. In spite of this, there is a lack of studies addressed to the investigation of potential cytotoxic effect and signaling pathways modulated by this compound. Herein, we aimed to analyze the effects of 24-h treatment with (PhSe)(2) on cell viability and a possible modulation of signaling pathways in human neuroblastoma cell line SH-SY5Y. For this purpose, cells were incubated with (PhSe)(2) (0.3-30 MUM) for 24 h and cell viability, apoptotic cell death and modulation of MAPKs (ERK1/2 and p38(MAPK)), and PKC substrates phosphorylation was determined. (PhSe)(2) treatment significantly decreased cell viability and increased the number of apoptotic cells with induction of PARP cleavage. An increase in ERK1/2 phosphorylation was observed at (PhSe)(2) 3 MUM. In contrast, higher concentrations of the chalcogenide inhibited ERK1/2, p38(MAPK) and PKC substrate phosphorylation. Pre-treatment with ERK1/2 inhibitor, U0126, increased cell susceptibility to (PhSe)(2). Together, these data indicate a cytotoxic potential of (PhSe)(2) in a neuronal cell line, which appears to be mediated by the ERK1/2 pathway. PMID- 20924559 TI - Persistence of deposited metals in the lungs after stainless steel and mild steel welding fume inhalation in rats. AB - Welding generates complex metal fumes that vary in composition. The objectives of this study were to compare the persistence of deposited metals and the inflammatory potential of stainless and mild steel welding fumes, the two most common fumes used in US industry. Sprague-Dawley rats were exposed to 40 mg/m(3) of stainless or mild steel welding fumes for 3 h/day for 3 days. Controls were exposed to filtered air. Generated fume was collected, and particle size and elemental composition were determined. Bronchoalveolar lavage was done on days 0, 8, 21, and 42 after the last exposure to assess lung injury/inflammation and to recover lung phagocytes. Non-lavaged lung samples were analyzed for total and specific metal content as a measure of metal persistence. Both welding fumes were similar in particle morphology and size. Following was the chemical composition of the fumes-stainless steel: 57% Fe, 20% Cr, 14% Mn, and 9% Ni; mild steel: 83% Fe and 15% Mn. There was no effect of the mild steel fume on lung injury/inflammation at any time point compared to air control. Lung injury and inflammation were significantly elevated at 8 and 21 days after exposure to the stainless steel fume compared to control. Stainless steel fume exposure was associated with greater recovery of welding fume-laden macrophages from the lungs at all time points compared with the mild steel fume. A higher concentration of total metal was observed in the lungs of the stainless steel welding fume at all time points compared with the mild steel fume. The specific metals present in the two fumes were cleared from the lungs at different rates. The potentially more toxic metals (e.g., Mn, Cr) present in the stainless steel fume were cleared from the lungs more quickly than Fe, likely increasing their translocation from the respiratory system to other organs. PMID- 20924560 TI - Long-term detection of methyltestosterone (ab-) use by a yeast transactivation system. AB - The routinely used analytical method for detecting the abuse of anabolic steroids only allows the detection of molecules with known analytical properties. In our supplementary approach to structure-independent detection, substances are identified by their biological activity. In the present study, urines excreted after oral methyltestosterone (MT) administration were analyzed by a yeast androgen screen (YAS). The aim was to trace the excretion of MT or its metabolites in human urine samples and to compare the results with those from the established analytical method. MT and its two major metabolites were tested as pure compounds in the YAS. In a second step, the ability of the YAS to detect MT and its metabolites in urine samples was analyzed. For this purpose, a human volunteer ingested of a single dose of 5 mg methyltestosterone. Urine samples were collected after different time intervals (0-307 h) and were analyzed in the YAS and in parallel by GC/MS. Whereas the YAS was able to trace MT in urine samples at least for 14 days, the detection limits of the GC/MS method allowed follow-up until day six. In conclusion, our results demonstrate that the yeast reporter gene system could detect the activity of anabolic steroids like methyltestosterone with high sensitivity even in urine. Furthermore, the YAS was able to detect MT abuse for a longer period of time than classical GC/MS. Obviously, the system responds to long-lasting metabolites yet unidentified. Therefore, the YAS can be a powerful (pre-) screening tool with the potential that to be used to identify persistent or late screening metabolites of anabolic steroids, which could be used for an enhancement of the sensitivity of GC/MS detection techniques. PMID- 20924561 TI - Enhanced tyrosine hydroxylase phosphorylation in the nucleus accumbens and nucleus tractus solitarius-A2 cell group after morphine-conditioned place preference. AB - Although dopamine (DA) has been extensively implicated in the morphine-induced conditioned place preference (CPP; a measure of reward), noradrenaline (NA) and other systems may play a larger role than previously suspected. The mesolimbic DA system, comprised of projections from the ventral tegmental area (VTA) to the nucleus accumbens (NAc), receives noradrenergic innervations from the nucleus tractus solitaries (NTS)-A2 cell group and is modulated by NA. The purpose of the present study was to evaluate the turnover of DA and NA in the NAc and the site specific phosphorylation of TH in the NAc, VTA, and NTS on the CPP mice conditioned by morphine. A dose-effect curve for morphine-induced CPP (0.5-8 mg/kg, s.c.) was obtained using 6-day conditioning sessions followed by a CPP test. TH phosphorylation was determined by quantitative blot immunolabeling and immunohistochemistry using phosphorylation state-specific antibodies; NA and DA turnover was evaluated by high-performance liquid chromatography. Morphine induced CPP phosphorylates TH at serine (Ser)40 but not Ser31 in NAc, which is associated with an enhanced of DA and NA turnover. We also found that morphine induced CPP increased levels of TH phosphorylated at Ser31 and Ser40 in the NTS. The present study demonstrates that morphine-induced CPP might stimulate TH activity and accelerate DA and NA turnover in the NAc via a mechanism involving phosphorylation of TH. PMID- 20924562 TI - Characterization of proliferative effects of insulin, insulin analogues and insulin-like growth factor-1 (IGF-1) in human lung fibroblasts. AB - Insulin has been approved for inhaled application, but safety concerns remain, because of un-physiologically high insulin concentrations in the lung. Since insulin may act as growth factor, possible proliferative effects of insulin, insulin analogues and insulin-like growth factor-1 (IGF-1) on human lung fibroblasts were studied. As measure of proliferation [(3)H]-thymidine incorporation was studied in HEL-299, MRC-5, IMR-90 and primary human lung fibroblasts. In all cells, mRNA encoding IGF-1 receptors and two variants of insulin receptors was detected. Insulin and IGF-1 stimulated [(3)H]-thymidine incorporation in all cells. Comparison of the concentration-dependent effects in HEL-299 cells showed that IGF-1 and insulin glargine were more potent (EC(50), 3 and 6 nM) and more effective (maximum increase, by 135-150%) than insulin and insulin detemir (EC(50), 22 and 110 nM; maximum increase: by 80%). Proliferative effects of IGF-1 and insulin were inhibited to the same extent by an antibody (1H7) directed against the IGF-1 receptor alpha-subunit. Insulin-induced stimulation of [(3)H]-thymidine incorporation was reduced by 83% after siRNA mediated down-regulation of IGF-1 receptor by about 75%, but not affected by a similar down-regulation of the insulin receptor. Insulin and IGF-1 caused rapid up-regulation of the early genes FOS, EGR-1 and EGR-2 as well as of the gene coding for IGF-1. In conclusion, in human lung fibroblasts insulin exerts marked proliferative effects and the pharmacological profile of this response as well as specific receptor knock-down experiments suggest mediation via IGF-1 receptors. The risk of unwanted structural lung alterations by long-term inhalative application of insulin should be considered. PMID- 20924563 TI - The design and synthesis of alanine-based indolicidin derivatives with identical physicochemical properties and their separation using capillary electrophoresis. AB - Four novel alanine-based indolicidin peptide derivatives were designed containing one WPW motif and two alanine residues, resulting in peptides of similar sequence. The separation of these peptides with identical physicochemical properties including molar mass, charge, and secondary structure as characterized by circular dichroism spectroscopy is very difficult; and the separation of peptides with differing physicochemical properties has only previously been reported. Capillary electrophoresis parameters such as separation buffer concentration, separation buffer pH, capillary length, and separation voltage were investigated to optimize the analysis. Using optimized conditions of a background electrolyte containing 5 mM formic acid of pH 2.0, total capillary length of 51 cm and a voltage of 10 kV enabled a baseline separation of the four peptides. The relative standard deviation of the peak areas and migration times for method repeatability (n = 3) were found to be lower than 8% and 3%, respectively. In addition, reasoning for the separation of these peptides is proposed based on the acidity of the formic acid buffer and the hydrophobic grouping of the tryptophan residues in the peptide primary sequence. PMID- 20924564 TI - Microscreening toxicity system based on living magnetic yeast and gradient chips. AB - There is an increasing demand for easy and cost-effective methods to screen the toxicological impact of the growing number of chemical mixtures being generated by industry. Such a screening method has been developed using viable, genetically modified green fluorescent protein (GFP) reporter yeast that was magnetically functionalised and held within a microfluidic device. The GFP reporter yeast was used to detect genotoxicity by monitoring the exposure of the cells to a well known genotoxic chemical (methyl methane sulfonate, MMS). The cells were magnetised using biocompatible positively charged PAH-stabilised magnetic nanoparticles with diameters around 15 nm. Gradient mixing was utilised to simultaneously expose yeast to a range of concentrations of toxins, and the effective fluorescence emitted from the produced GFP was measured. The magnetically enhanced retention of the yeast cells, with their facile subsequent removal and reloading, allowed for very convenient and rapid toxicity screening of a wide range of chemicals. This is the first report showing magnetic yeast within microfluidic devices in a simple bioassay, with potential applications to other types of fluorescent reporter yeast in toxicological and biomedical research. The microfluidic chip offers a simple and low-cost screening test that can be automated to allow multiple uses (adapted to different cell types) of the device on a wide range of chemicals and concentrations. PMID- 20924565 TI - Nondestructive analysis of single crystals of selenide spinels by X-ray spectrometry techniques. AB - The paper presents possibilities and difficulties in nondestructive analysis of small multielement single crystals performed by means of X-ray spectrometry techniques: micro-X-ray fluorescence spectrometry (MU-XRF), energy-dispersive electron probe microanalysis (ED-EPMA), and X-ray photoelectron spectroscopy (XPS). The capability of the X-ray spectroscopy techniques in elemental analysis is demonstrated with the single crystals of selenide spinels of the general formula M(x)N(y)Cr(z)Se(4) (M(+2) and N(+3) are, for example, Zn(+2), V(+3), Ga(+3), Cd(+2), In(+3), and Sb(+3)). The results of the nondestructive analyses (MU-XRF, ED-EPMA, and XPS) are compared with those obtained by inductively coupled plasma optical emission spectrometry (ICP-OES) and wavelength-dispersive X-ray spectrometry (WDXRF) following sample digestion. The present study shows satisfactory agreement between the results of MU-XRF analysis performed using the standardless fundamental parameter method and the results obtained with the WDXRF and ICP-OES analyses. If the measured single crystal is precisely positioned, the difference between MU-XRF and wet analysis (WDXRF and ICP-OES) does not exceed 5% rel. The reliable results of ED-EPMA can be obtained only if the measured area is sufficiently large, i.e., of 200 * 300 MUm. Even if this condition is fulfilled, the relative difference between the ED-EPMA and the wet analysis may reach 10% rel. In case of the XPS analysis, the accuracy of results depends on the proper preparation of the sample surface. It should be free of contamination that can be obtained by scraping in situ in ultrahigh vacuum. The ion etching, commonly used for cleaning the surface, leads to preferential sputtering; therefore, the reliable results cannot be obtained. PMID- 20924566 TI - Chemical characterization of exhaled breath to differentiate between patients with malignant plueral mesothelioma from subjects with similar professional asbestos exposure. AB - Malignant pleural mesothelioma (MPM) is an aggressive tumour whose main aetiology is the long-term exposure to asbestos fibres. The diagnostic procedure of MPM is difficult and often requires invasive approaches; therefore, it is clinically important to find accurate markers for MPM by new noninvasive methods that may facilitate the diagnostic process and identify patients at an earlier stage. In the present study, the exhaled breath of 13 patients with histology-established diagnosis of MPM, 13 subjects with long-term certified professional exposure to asbestos (EXP) and 13 healthy subjects without exposure to asbestos (healthy controls, HC) were analysed. An analytical procedure to determine volatile organic compounds by sampling of air on a bed of solid sorbent and thermal desorption GC-MS analysis was developed in order to identify the compounds capable of discriminating among the three groups. The application of univariate (ANOVA) and multivariate statistical treatments (PCA, DFA and CP-ANN) showed that cyclopentane and cyclohexane were the dominant variables able to discriminate among the three groups. In particular, it was found that cyclohexane is the only compound able to differentiate the MPM group from the other two; therefore, it can be a possible marker of MPM. Cyclopentane is the dominant compound in the discrimination between EXP and the other groups (MPM and HC); then, it can be considered a good indicator for long-term asbestos exposure. This result suggests the need to perform frequent and thorough investigations on people exposed to asbestos in order to constantly monitor their state of health or possibly to study the evolution of disease over time. PMID- 20924567 TI - Ultrasensitive detection of malondialdehyde with surface-enhanced Raman spectroscopy. AB - Malondialdehyde (MDA) is a biomarker of lipid peroxidation that has been widely associated with food rancidity as well as many human diseases. Most current MDA detection methods involve MDA reaction with thiobarbituric acid (TBA), followed by UV-visible and/or fluorescence detection of high-performance liquid chromatography (HPLC)-separated TBA-MDA. Herein, we report the first proof-of concept study of surface-enhanced Raman detection of a TBA-MDA adduct using silver nanoparticles as the SERS substrate and the 632.8 nm HeNe laser as a Raman excitation source. Current SERS detection limit of TBA-MDA is 0.45 nM, ~100 times higher than the 36 nM fluorescence sensitivity recently reported with the HPLC purified TBA-MDA. Molecular specificity of the SERS technique was studied by comparing the SERS spectrum of TBA-MDA with those acquired with TBA adducts of other TBA-reactive compounds (TBARCs) that includes formaldehyde, acetaldehyde, butyraldehyde, trans-2-hexenal, and pyrimidine. Compared to TBA and TBA adducts with those TBARCs, the SERS activity of TBA-MDA adduct is significantly higher. The possibility of direct SERS detection of TBA-MDA in a reaction mixture (without HPLC separation) has also been investigated. PMID- 20924568 TI - Nanoparticles as contrast agents for in-vivo bioimaging: current status and future perspectives. AB - Nanoparticle-based contrast agents are quickly becoming valuable and potentially transformative tools for enhancing medical diagnostics for a wide range of in vivo imaging modalities. Compared with conventional molecular-scale contrast agents, nanoparticles (NPs) promise improved abilities for in-vivo detection and potentially enhanced targeting efficiencies through longer engineered circulation times, designed clearance pathways, and multimeric binding capacities. However, NP contrast agents are not without issues. Difficulties in minimizing batch-to batch variations and problems with identifying and characterizing key physicochemical properties that define the in-vivo fate and transport of NPs are significant barriers to the introduction of new NP materials as clinical contrast agents. This manuscript reviews the development and application of nanoparticles and their future potential to advance current and emerging clinical bioimaging techniques. A focus is placed on the application of solid, phase-separated materials, for example metals and metal oxides, and their specific application as contrast agents for in-vivo near-infrared fluorescence (NIRF) imaging, magnetic resonance imaging (MRI), positron emission tomography (PET), computed tomography (CT), ultrasound (US), and photoacoustic imaging (PAI). Clinical and preclinical applications of NPs are identified for a broad spectrum of imaging applications, with commentaries on the future promise of these materials. Emerging technologies, for example multifunctional and theranostic NPs, and their potential for clinical advances are also discussed. PMID- 20924569 TI - Word and position interference in stroop tasks: a behavioral and fMRI study. AB - One of the main features of the attentional system is the capability to select between relevant and irrelevant information. However, irrelevant information interferes with the processing of the relevant one. Using high-field magnetic resonance imaging, we examined the interference effect of a verbal (color-word) and a spatial (arrow-position) Stroop task on the activation of cortical areas known to be dedicated to the attentional control. Behaviorally, we found costs from the irrelevant information in both tasks; in the brain, we found a common neural network of activation that mainly involved the dorsolateral prefrontal cortex and the anterior cingulate cortex. However, the neural circuits involved in the two tasks overlapped only partially, since processing of words in the color-word Stroop task showed a wider and more right-lateralized activation, while spatial processing in the arrow-position Stroop task resulted in a more restricted and left-lateralized activation. PMID- 20924570 TI - Systemic uptake of miconazole during vaginal suppository use and effect on CYP1A2 and CYP3A4 associated enzyme activities in women. AB - PURPOSE: To investigate if the ordinary use of a vaginal suppository containing miconazole results in systemic absorption that is sufficient to affect the activities of CYP1A2 and CYP3A4, which are major drug- and steroid-metabolising enzymes. METHODS: In 20 healthy non-pregnant women aged 18-45 years, the serum concentration of miconazole was determined following the use of a vaginal suppository containing 1,200 mg miconazole. Enzyme activities of CYP1A2 and CYP3A4 were determined as metabolic ratios of caffeine (CMR = (AFMU + 1MU + 1MX)/17DMU) and quinidine (QMR = 3-hydroxy-quinidine/quinidine) respectively before and 34 h after insertion of the suppository. Miconazole was analysed by LC MS/MS, while caffeine and metabolites were analysed by HPLC-UV and quinidine and hydroxy-quinidine were analysed by HPLC fluorescence. RESULTS: All 20 women had measurable concentrations of miconazole in serum (mean +/- SD: 12.9 +/- 5.6 MUg/L; range: 3.5-24.6 MUg/L). Although not statistically significant, an association between the serum concentrations of miconazole and the inhibition of CYP1A2 activity was indicated. No relation was observed between the CYP3A4 activity and the miconazole serum concentration. CONCLUSIONS: Miconazole is absorbed via the vaginal mucosa to the systemic circulation in measurable concentrations. Our data indicate a concentration-dependent inhibition of CYP1A2, but the effect is negligible compared with the variation in the activity of CYP1A2 and is regarded to be of no clinical significance to the women. However, further studies on the ability of miconazole to be transferred across the placenta or to interfere with the placental function are warranted to secure safe use during pregnancy. PMID- 20924571 TI - Longitudinal evaluation of the SF-36 quality of life questionnaire in patients with kidney stones. AB - Although the 36-Item Short-Form General Health Survey (SF-36) has been utilized to assess quality of life (QoL) in cross-sectional studies, no longitudinal studies have evaluated this instrument in stone formers. Hence, we evaluated the performance of the SF-36 over time in a group of stone formers. From January to May 2007, the SF-36 was administered by independent interviewers to 155 patients with a history of stones, and 96 individuals subsequently completed a second questionnaire at a median interval of 18 months (10.3-28.5 months). Subjects were asked to report changes in stone status, interval procedures, and significant non stone related changes. Changes in individual and composite scores of SF-36 were compared. Among the 96 patients who completed two SF-36 surveys, 75 patients denied experiencing a stone episode within the month preceding their initial or follow-up SF-36 form. No statistically significant differences in any of the SF 36 domains or the aggregate physical or mental health composite scores over time were noted in these patients. A total of 18 patients reported a stone event within the month preceding completion of the initial questionnaire but no stone event prior to the follow-up survey. No clinically or statistically significant changes in any of the SF-36 domains between the first and follow-up questionnaire were seen among these 18 patients. The results show the stability of the SF-36 over time in patients with no change in their stone status. However, the absence of significant changes in the SF-36 despite a change in stone status suggests that the SF-36 may not be an adequate tool to monitor quality of life over time in stone patients. Validated, disease-specific questionnaires are needed to facilitate comparison of treatment strategies for stone disease. PMID- 20924572 TI - Impact of shock wave lithotripsy on heart rate variability in patients with urolithiasis. AB - The physiological response of the cardiac autonomic nervous system during shock wave lithotripsy (SWL) remains unclear. Heart rate variability (HRV) is an index of cardiac autonomic balance. This study aimed to analyze HRV during SWL in patients with urolithiasis. Electrocardiograms of patients who underwent SWL were obtained. Recordings were obtained before and after SWL. For each time point, the recordings were obtained continuously for 6 min, after which R wave-to-R wave (RR) intervals were extracted. The time digital sequence derived from RR intervals was the HRV signal. Time-domain analysis revealed that the mean of RR intervals (MRR) and standard deviation of normal beat-to-normal beat (NN) intervals (SDNN), but not the square root of the mean squared difference of successive NNs (RMSSD) or triangular interpolation of NN intervals (TINN), significantly increased during SWL. The increase in SDNN persisted after SWL but MRR returned to the initial level. Frequency-domain analysis revealed that very low frequency (VLF), low frequency (LF), and LF/high frequency (HF) ratio significantly increased after SWL, while there was no statistically significant difference in HF. Thus, the patients had significantly high MRR and SDNN during SWL and significantly high SDNN, VLF, LF, and LF/HF ratio after SWL. SWL could alter the functioning of the cardiac autonomic nervous system, resulting in reduction in sympathetic activity and increase in parasympathetic activity. Further studies with larger samples are required to confirm these findings and understand the underlying mechanisms. PMID- 20924573 TI - MRI of congenital urethroperineal fistula. AB - We present the MRI features of a congenital urethroperineal fistula diagnosed in a 12-year-old boy being evaluated after a single urinary tract infection. This diagnosis was initially suggested by voiding cystourethrogram and confirmed by MRI. Imaging revealed an abnormal fluid-filled tract arising from the posterior urethra and tracking to the perineal skin surface that increased in size during micturition. Surgical resection and histopathological evaluation of the abnormal tract confirmed the diagnosis of congenital urethroperineal fistula. MRI played important roles in confirming the diagnosis and assisting surgical planning. PMID- 20924574 TI - First and second branchial arch syndromes: multimodality approach. AB - First and second branchial arch syndromes (BAS) manifest as combined tissue deficiencies and hypoplasias of the face, external ear, middle ear and maxillary and mandibular arches. They represent the second most common craniofacial malformation after cleft lip and palate. Extended knowledge of the embryology and anatomy of each branchial arch derivative is mandatory for the diagnosis and grading of different BAS lesions and in the follow-up of postoperative patients. In recent years, many new complex surgical approaches and procedures have been designed by maxillofacial surgeons to treat extensive maxillary, mandibular and external and internal ear deformations. The purpose of this review is to evaluate the role of different imaging modalities (orthopantomogram (OPG), lateral and posteroanterior cephalometric radiographs, CT and MRI) in the diagnosis of a wide spectrum of first and second BAS, including hemifacial microsomia, mandibulofacial dysostosis, branchio-oto-renal syndrome, Pierre Robin sequence and Nager acrofacial dysostosis. Additionally, we aim to emphasize the importance of the systematic use of a multimodality imaging approach to facilitate the precise grading of these syndromes, as well as the preoperative planning of different reconstructive surgical procedures and their follow-up during treatment. PMID- 20924575 TI - MHC class II DRB diversity in raccoons (Procyon lotor) reveals associations with raccoon rabies virus (Lyssavirus). AB - In North America, the raccoon rabies virus (RRV) is an endemic wildlife disease which causes acute encephalopathies and is a strong selective force on raccoons (Procyon lotor), with estimates of ~85% of the population succumbing to the disease when epizootic. RRV is regarded as a lethal disease if untreated; therefore, no evolutionary response would be expected of raccoon populations. However, variable immune responses to RRV have been observed in raccoons indicating a potential for evolutionary adaptation. Studies of variation within the immunologically important major histocompatibility complex (MHC) have revealed relationships between MHC alleles and diseases in humans and other wildlife species. This enhances our understanding of how hosts and pathogens adapt and co-evolve. In this study, we used RRV as a model system to study host pathogen interaction in raccoons from a challenge study and from four wild populations that differ in exposure times and viral lineages. We investigated the potential role of Prlo-DRB polymorphism in relation to susceptibility/resistance to RRV in 113 RRV positive and 143 RRV negative raccoons. Six alleles were found to be associated with RRV negative status and five alleles with RRV positive animals. We found variable patterns of MHC associations given the relative number of selective RRV sweeps in the studied regions and correlations between MHC diversity and RRV lineages. The allelic associations established provide insight into how the genetic variation of raccoons may affect the disease outcome and this can be used to examine similar associations between other rabies variants and their hosts. PMID- 20924577 TI - YqhD: a broad-substrate range aldehyde reductase with various applications in production of biorenewable fuels and chemicals. AB - The Escherichia coli NADPH-dependent aldehyde reductase YqhD has contributed to a variety of metabolic engineering projects for production of biorenewable fuels and chemicals. As a scavenger of toxic aldehydes produced by lipid peroxidation, YqhD has reductase activity for a broad range of short-chain aldehydes, including butyraldehyde, glyceraldehyde, malondialdehyde, isobutyraldehyde, methylglyoxal, propanealdehyde, acrolein, furfural, glyoxal, 3-hydroxypropionaldehyde, glycolaldehyde, acetaldehyde, and acetol. This reductase activity has proven useful for the production of biorenewable fuels and chemicals, such as isobutanol and 1,3- and 1,2-propanediol; additional capability exists for production of 1 butanol, 1-propanol, and allyl alcohol. A drawback of this reductase activity is the diversion of valuable NADPH away from biosynthesis. This YqhD-mediated NADPH depletion provides sufficient burden to contribute to growth inhibition by furfural and 5-hydroxymethyl furfural, inhibitory contaminants of biomass hydrolysate. The structure of YqhD has been characterized, with identification of a Zn atom in the active site. Directed engineering efforts have improved utilization of 3-hydroxypropionaldehyde and NADPH. Most recently, two independent projects have demonstrated regulation of yqhD by YqhC, where YqhC appears to function as an aldehyde sensor. PMID- 20924578 TI - Decolourization of synthetic wastewater containing azo dyes by immobilized Phanerochaete chrysosporium in a continuously operated RBC reactor. AB - A laboratory-scale rotating biological contactor (RBC) reactor with immobilized fungal biomass of Phanerochaete chrysosporium was investigated for its performance in decolourizing synthetic wastewater containing single or mixture of azo dyes, Direct Red-80 (DR-80) and Mordant Blue-9 (MB-9). Decolourization efficiency in the continuously operated bioreactor was studied by varying dye inlet concentration and disc rotation speed at two different wastewater hydraulic retention times (HRTs), i.e. 24 and 48 h. Results from the single dye-containing experiments showed that the system could completely decolourize the wastewater for a maximum inlet dye concentration within the range 25-200 mg L(-1) and 48 h HRT in the reactor; for an inlet dye concentration above 200 mg L(-1), the decolourization efficiency slightly reduced up to 85% for the same HRT. However, wastewater containing DR-80 was found to be decolourized more efficiently compared to that containing MB-9. Further, the effect of increase in the disc rotation speed from 2 to 6 rpm in the study revealed no large differences in the decolourization efficiencies of the wastewaters. Similar results were obtained with wastewater containing the dyes together at various concentration combinations as per the two-level factorial design of experiments. Enzyme activities of lignin peroxidase and manganese peroxidase by the fungus were also analysed in the study, and the results indicated that while DR-80 showed a large negative effect on both the enzymes, MB-9 affected mainly the MnP activity by the fungus. PMID- 20924576 TI - Investigations on the microbial catabolism of the organic sulfur compounds TDP and DTDP in Ralstonia eutropha H16 employing DNA microarrays. AB - In this study, we have investigated the transcriptome of Ralstonia eutropha H16 during cultivation with gluconate in presence of 3,3'-thiodipropionic acid (TDP) or 3,3'-dithiodipropionic acid (DTDP) during biosynthesis of poly(3 hydroxybutyrate-co-3-mercaptopropionate). Genome-wide transcriptome analyses revealed several genes which were upregulated during cultivation in presence of the above-mentioned compounds. Obtained data strongly suggest that two ABC-type transport system and three probable extracytoplasmic solute receptors mediate the uptake of TDP and DTDP, respectively. In addition, genes encoding the hydrolase S adenosylhomocysteinase AhcY and the thiol-disulfide interchange proteins DsbA, DsbD, and FrnE were upregulated during cultivation on DTDP and, in case of AhcY and FrnE, on TDP as well. It is assumed that the corresponding enzymes are involved in the cleavage of TDP and DTDP. Several genes of the fatty acid metabolism exhibited increased expression levels: genes encoding two acetyltransferases, a predicted acyltransferase, the acetoacetyl-CoA reductase phaB3, an enoyl-CoA hydratase as well as an acyl dehydratase, an acetyl-CoA synthetase, two acyl-CoA dehydrogenases, the methylmalonyl-CoA mutase encoded by sbm1 and sbm2 and phaY1 were detected. Furthermore, ORF H16_A0217 encoding a hypothetical protein and exhibiting 54% amino acids identical to an acyl-CoA thioesterase from Saccharomonospora viridis was found to be highly upregulated. As the 2-methylcitrate synthase PrpC exhibited a three- to fourfold increased activity in cells grown in presence of TDP or DTDP as compared to gluconate, metabolization of the cleavage products 3MP and 3-hydroxypropionate to propionyl CoA is proposed. PMID- 20924579 TI - Pimp your landscape: a tool for qualitative evaluation of the effects of regional planning measures on ecosystem services. AB - The article presents the platform "Pimp your landscape" (PYL), which aims firstly at the support of planners by simulating alternative land-use scenarios and by an evaluation of benefits or risks for regionally important ecosystem services. Second, PYL supports an integration of information on environmental and landscape conditions into impact assessment. Third, PYL supports the integration of impacts of planning measures on ecosystem services. PYL is a modified 2-D cellular automaton with GIS features. The cells have the major attribute "land-use type" and can be supplemented with additional information, such as specifics regarding geology, topography and climate. The GIS features support the delineation of non cellular infrastructural elements, such as roads or water bodies. An evaluation matrix represents the core element of the system. In this matrix, values in a relative scale from 0 (lowest value) to 100 (highest value) are assigned to the land-use types and infrastructural elements depending on their effect on ecosystem services. The option to configure rules for describing the impact of environmental attributes and proximity effects on cell values and land-use transition probabilities is of particular importance. User interface and usage of the platform are demonstrated by an application case. Constraints and limits of the recent version are discussed, including the need to consider in the evaluation, landscape-structure aspects such as patch size, fragmentation and spatial connectivity. Regarding the further development, it is planned to include the impact of land management practices to support climate change adaptation and mitigation strategies in regional planning. PMID- 20924580 TI - The Indus irrigation system, natural resources, and community occupational quality in the delta region of Pakistan. AB - This study examines the impact of an elaborated irrigation system on the natural resources and society in the deltaic part of the Indus River in Pakistan. Time series information was collected to analyze the ecological and natural resource dynamics, and their impacts on the structure and quality of the occupations of the people in the Indus delta during pre- and post-irrigation system development periods. The information was collected through literature review, reconnaissance, structured questionnaire survey, focus group discussions, and interviews. The findings revealed that the expansion of the irrigation system and the resulting reduction in the downstream flow had their differential impacts on the various segments of downstream ecology and society. Some of the resources, for example the agricultural mudflats have been adversely affected due to the accelerated seawater intrusion that severely impinged on the paddy farms. On the other natural resources like mangroves, the impacts had been both negative and positive. On one hand, the diversity of the mangroves species had deteriorated while on other hand, the mangroves have benefited from such development because of the alleviated pressure of camel grazing as a result of the occupational change on the part of the camel herders. Furthermore, changes in the hydrological regimes had forced the paddy farmers and camel herders to switch to fishing as an alternative source of employment and income. Considering that currently about 87% people are already engaged primarily in marine fishery, this scenario is threatening the sustainability of the fishery resources as well as the livelihoods of all, the traditional and converted fishermen. The findings of the study are therefore meant to advocate the different treatments which should be accorded to the various segments of the downstream ecology and society during the planning of any remedial irrigation projects in order to mitigate the adverse impacts of the previous irrigation development strategies and of any water resources development to be carried out in the future. PMID- 20924581 TI - Cranes, crops and conservation: understanding human perceptions of biodiversity conservation in South Korea's Civilian Control Zone. AB - South Korea's Civilian Control Zone (CCZ), a relatively untouched area due to tight military oversight since the end of Korean War, has received considerable attention nationally and internationally for its rich biodiversity. However, the exclusion of local communities from the process of defining problems and goals and of setting priorities for biodiversity conservation has halted a series of biodiversity conservation efforts. Through qualitative research, we explored CCZ farmers' views of key problems and issues and also the sources of their opposition to the government-initiated conservation approaches. Key findings include the farmers' concerns about the impact of conservation restrictions on their access to necessary resources needed to farm, wildlife impacts on the value of rice and other agricultural goods they produce, and farmers' strong distrust of government, the military, and planners, based on their experiences with past conservation processes. The findings regarding farmers' perceptions should prove useful for the design of future participatory planning processes for biodiversity conservation in the CCZ. This case highlights how conservative measures, perceived to be imposed from above--however scientifically valuable--can be undermined and suggests the value that must be placed on communication among planners and stakeholders. PMID- 20924582 TI - Potential effects of dams on migratory fish in the Mekong River: lessons from salmon in the Fraser and Columbia Rivers. AB - We compared the effects of water resource development on migratory fish in two North American rivers using a descriptive approach based on four high-level indicators: (1) trends in abundance of Pacific salmon, (2) reliance on artificial production to maintain fisheries, (3) proportion of adult salmon that are wild- versus hatchery-origin, and (4) number of salmon populations needing federal protection to avoid extinction. The two rivers had similar biological and physical features but radically different levels of water resource development: the Fraser River has few dams and all are located in tributaries, whereas the Columbia River has more than 130 large mainstem and tributary dams. Not surprisingly, we found substantial effects of development on salmon in the Columbia River. We related the results to potential effects on migratory fish in the Mekong River where nearly 200 mainstem and tributary dams are installed, under construction, or planned and could have profound effects on its 135 migratory fish species. Impacts will vary with dam location due to differential fish production within the basin, with overall effects likely being greatest from 11 proposed mainstem dams. Minimizing impacts will require decades to design specialized fish passage facilities, dam operations, and artificial production, and is complicated by the Mekong's high diversity and productivity. Prompt action is needed by governments and fisheries managers to plan Mekong water resource development wisely to prevent impacts to the world's most productive inland fisheries, and food security and employment opportunities for millions of people in the region. PMID- 20924583 TI - A novel point mutation within the juxtamembrane domain of the flt3 gene in acute myeloid leukemia. PMID- 20924584 TI - Construction and expression of food-grade beta-galactosidase gene in Lactococcus Lactis. AB - Recombinant Lactococcus lactis MG1363/pMG36e-lacZ exhibiting high beta galactosidase activities were constructed by us in the previous study. However, erythromycin resistance present in these recombinants restricted their practical application in food preparation. This study was conducted to delete the gene coding for erythromycin resistance present in recombinant L. lactis, as a result of which these bacteria express food-grade beta-galactosidase. In this study, the recombinant plasmid pMG36e-lacZ was digested with restriction enzymes BclI and HpaI and the food-grade plasmid FGZW was rebuilt. FGZW was transformed into Escherichia coli JM109 and L. lactis MG1363. Erythromycin resistance, enzyme activity determination, gene sequencing and SDS-PAGE analysis indicated that these new recombinant bacteria lost erythromycin resistance and its relevant gene but still expressed beta-galactosidase activities, although a decrease in the expression of beta-galactosidase of these new strains was observed. The beta galactosidase food-grade expression system was successfully constructed and it could provide a new solution for the management of lactose intolerance. These results might promote the usage of gene-modified microorganisms and related technology in the food sector, which has the highest priority for food safety. PMID- 20924585 TI - Utility of diffusion-weighted imaging in the diagnosis of acute appendicitis. AB - OBJECTIVES: To evaluate the value of diffusion-weighted MRI (DWI) in the diagnosis of acute appendicitis. METHODS: 119 patients with acute appendicitis and 50 controls were enrolled in this prospective study. DWI was obtained with b factors 0, 500 and 1000 s/mm2 and were assessed with a visual scoring system by two radiologists followed by quantitative evaluation of the DW images and ADC maps. RESULTS: Histopathology revealed appendicitis in 79/92 patients (78%) who had undergone surgery. On visual evaluation, except for one patient with histopathologically proven appendicitis all inflamed appendixes were hyperintense on DWI (98.7%). Quantitative evaluation with DW signal intensities and ADC values revealed a significant difference with normal and inflamed appendixes (p < 0.001). The best discriminative parameter was signal intensity (b 500). With a cut-off value of 56 for the signal intensity the ratio had a sensitivity of 99% and a specificity of 97%. The cut-off ADC value at 1.66 mm2/s had a sensitivity of 97% and a specificity of 99%. CONCLUSION: DWI is a valuable technique for the diagnosis of acute appendicitis with both qualitative and quantitative evaluation. DWI increases the conspicuity of the inflamed appendix. We recommend using DWI to diagnose acute appendicitis. PMID- 20924586 TI - Modified Chrispin-Norman chest radiography score for cystic fibrosis: observer agreement and correlation with lung function. AB - OBJECTIVE: To test observer agreement and two strategies for possible improvement (consensus meeting and reference images) for the modified Chrispin-Norman score for children with cystic fibrosis (CF). METHODS: Before and after a consensus meeting and after developing reference images three observers scored sets of 25 chest radiographs from children with CF. Observer agreement was tested for line, ring, mottled and large soft shadows, for overinflation and for the composite modified Chrispin-Norman score. Correlation with lung function was assessed. RESULTS: Before the consensus meeting agreement between observers 1 and 2 was moderate-good, but with observer 3 agreement was poor-fair. Scores correlated significantly with spirometry for observers 1 and 2 (-0.7220, diagnosed with Peyronie's disease (PD) with disease duration and a stable penile deformity of at least 12 and 6 months, respectively, underwent reconstructive surgery. The curvature was dorsal in two, dorsal and left in two and dorsal and right in one patient. The patients were scheduled for follow-up at 1, 3 and 6 months. RESULTS: Placement of the Epiflex((r)) graft (size 20 * 40 mm) was performed after appropriate spatulation and fixation with 4-0 Monocryl sutures in all patients. Two of the patients also underwent a small plication of the convex side in order to achieve 100% straightening during artificial erection. All patients had an uneventful course and resumed successful sexual activity 1 month later. No penile deformity, infection, antigenicity or de novo erectile dysfunction was observed during the follow-up period. CONCLUSIONS: This is the first study on the use of an acellular, human dermis tissue graft for the surgical management of PD. Despite our small number of patients, we now routinely use this type of graft, due to its superior biomechanical properties, excellent results and maximum safety. Larger patient series with longer follow-up periods are needed to verify our results. PMID- 20924588 TI - A central pacemaker that underlies the production of seasonal and sexually dimorphic social signals: anatomical and electrophysiological aspects. AB - Our long-term goal is to approach the understanding of the anatomical and physiological bases for communication signal diversity in gymnotiform fishes as a model for vertebrate motor pattern generation. Brachyhypopomus gauderio emits, in addition to its electric organ discharge (EOD) at basal rate, a rich repertoire of rate modulations. We examined the structure of the pacemaker nucleus, responsible for the EOD rate, to explore whether its high output signal diversity was correlated to complexity in its neural components or regional organization. We confirm the existence of only two neuron types and show that the previously reported dorsal-caudal segregation of these neurons is accompanied by rostral caudal regionalization. Pacemaker cells are grouped dorsally in the rostral half of the nucleus, and relay cells are mainly ventral and more abundant in the caudal half. Relay cells are loosely distributed from the center to the periphery of the nucleus in correlation to somata size. Our findings support the hypothesis that regional organization enables a higher diversity of rate modulations, possibly offering distinct target areas to modulatory inputs. Since no anatomical or electrophysiological seasonal or sexual differences were found, we explored these aspects from a functional point of view in a companion article. PMID- 20924589 TI - Dysfunctional pain modulation in somatoform pain disorder patients. AB - To date, pain perception is thought to be a creative process of modulation carried out by an interplay of pro- and anti-nociceptive mechanisms. Recent research demonstrates that pain experience constitutes the result of top-down processes represented in cortical descending pain modulation. Cortical, mainly medial and frontal areas, as well as subcortical structures such as the brain stem, medulla and thalamus seem to be key players in pain modulation. An imbalance of pro- and anti-nociceptive mechanisms are assumed to cause chronic pain disorders, which are associated with spontaneous pain perception without physiologic scaffolding or exaggerated cortical activation in response to pain exposure. In contrast to recent investigations, the aim of the present study was to elucidate cortical activation of somatoform pain disorder patients during baseline condition. Scalp EEG, quantitative Fourier-spectral analyses and LORETA were employed to compare patient group (N = 15) to age- and sex-matched controls (N = 15) at rest. SI, SII, ACC, SMA, PFC, PPC, insular, amygdale and hippocampus displayed significant spectral power reductions within the beta band range (12-30 Hz). These results suggest decreased cortical baseline arousal in somatoform pain disorder patients. We finally conclude that obtained results may point to an altered baseline activity, maybe characteristic for chronic somatoform pain disorder. PMID- 20924591 TI - Acute hemorrhagic leukoencephalopathy associated with influenza A (H1N1) virus. PMID- 20924590 TI - Fcgamma receptor IIIb (CD16b) polymorphisms are associated with susceptibility to idiopathic pulmonary fibrosis. AB - An excess of neutrophils in the alveoli and lung interstitium has been described in idiopathic pulmonary fibrosis (IPF). Engagement of neutrophil Fcgamma receptors with IgG complexes may contribute to the pathogenesis of IPF. The neutrophil FcgammaRIIIb receptor occurs in two codominantly expressed allelic variants, NA1 and NA2, which exhibit different binding affinities for IgG1 and IgG3 subclasses. The aim of this study was to investigate whether FcgammaRIIIb genotype is associated with IPF susceptibility or disease progression. In a case control study we compared the distribution of FcgammaRIIIb NA1/2 polymorphisms in 142 patients with IPF and in 218 controls using allele-specific PCR amplification. Significant skewing in the distribution of FcgammaRIIIb genotypes was observed between patients with IPF and control subjects. In the IPF cohort, there was higher frequency of the NA1/NA1 genotype (0.19 vs. 0.07), and lower NA2/NA2 frequency (0.31 vs. 0.50; chi(2) = 17.71, df = 2, P < 0.001). The overall frequency of the NA1 allele was increased in IPF patients compared to controls (0.44 vs. 0.29; P < 0.0001, odds ratio [OR] = 1.93, 95% confidence interval [CI] = 1.42-2.64). Heterozygotes and homozygotes of the NA1 allele were at higher risk of developing IPF (OR = 2.19, 95% CI = 1.40-3.41, P = 0.0005), whereas the NA2 allele was protective against IPF (OR = 0.34, 95% CI = 0.17-0.65, P = 0.0014). There was no association of FcgammaRIIIb genotype with disease progression as assessed by serial lung function measurements. FcgammaRIIIb NA1/2 polymorphisms are associated with IPF disease susceptibility. These results support a role for immunological mechanisms contributing to IPF pathogenesis. PMID- 20924592 TI - Gliomatosis cerebri presenting as a recurrent cervical myelopathy. PMID- 20924593 TI - T1rho (T1rho) MR imaging in Alzheimer's disease and Parkinson's disease with and without dementia. AB - In the current study, we aim to measure T1rho (T (1rho)) in the hippocampus in the brain of control, Alzheimer's disease (AD), Parkinson's disease (PD), and PD patients with dementia (PDD), and to determine efficacy of T (1rho) in differentiating these cohorts. With informed consent, 53 AD patients, 62 PD patients, 11 PDD patients, and 46 age-matched controls underwent a standardized clinical assessment including mini-mental state examination (MMSE) and brain T (1rho) MRI on a 1.5-T clinical-scanner. T(1rho) maps were generated by fitting each pixel's intensity as a function of the spin-lock pulse duration. In control, AD, PD and PDD, mean +/- SE T (1rho) values in the right hippocampus (RH) were 92.15 +/- 2.00, 99.65 +/- 1.98, 85.68 +/- 1.87, 102.47 +/- 4.66 ms while in the left hippocampus (LH) these values were 90.16 +/- 1.82, 99.53 +/- 1.91, 84.33 +/- 2.03, 95.33 +/- 4.64 ms. Significant difference for both RH and LH T (1rho) across the groups (p < 0.001) was observed. Both RH and LH T (1rho) were significantly increased in AD compared to control (p = 0.034, p = 0.001) and PD (p < 0.001, p < 0.001). In control, both RH and LH T (1rho) values were significantly increased compared to PD (p = 0.031, p = 0.027) while compared to PDD only the RH T (1rho) value was significantly decreased (p = 0.043). Both RH and LH T (1rho) values in PD were significantly lower than PDD (p = 0.004, p = 0.032). No significant correlation between the T (1rho) and age as well as between T (1rho) and MMSE scores was observed. The serial measurement of T(1rho) in both AD and PD may provide the nature of disease progression and may contribute to their early diagnosis. PMID- 20924594 TI - Validity of a computerized version of the symbol digit modalities test in multiple sclerosis. AB - The Symbol Digit Modalities Test (SDMT) is a particularly sensitive measure of cognitive dysfunction in patients with multiple sclerosis (MS). While computerized versions have been developed for use in functional magnetic resonance imaging (fMRI), none has been validated in MS patients. The aim of this study was to validate a new computerized version of the SDMT for use in MS patients. We developed a novel computerized version of the SDMT (c-SDMT) which was completed by 119 MS patients and 38 healthy controls. Our version consisted of eight timed trials of nine symbols. Both groups also underwent cognitive testing with the Brief Repeatable Battery of Neuropsychological Tests (BRB-N) which included the 90-s paper SDMT (p-SDMT) scored according to the number of correct responses per each 15-s interval. The sensitivity and specificity of the c-SDMT and p-SDMT to detect overall cognitive impairment on the BRB-N was determined. MS patients performed significantly worse than controls on both the c SDMT (t = -6.1, p < 0.001) and p-SDMT (t = 5.7, p < 0.001). More MS patients were impaired on the c-SDMT than the p-SDMT (37% vs. 29%). The sensitivity and specificity of the SDMT was as follows: 71% and 84%, respectively, for the c SDMT, and 67% and 95%, respectively, for the p-SDMT. Both versions detected a significant group * time effect over the course of the individual trials, although the pattern of responses differed between them. Good test-retest reliability for the c-SDMT was shown (ICC = 0.94). The results support the validity of this version of the c-SDMT as a sensitive measure of cognitive dysfunction in MS. The methodology is also fMRI compatible. PMID- 20924595 TI - No evidence for a thermic effect of the dietary flavonol quercetin: a pilot study in healthy normal-weight women. AB - Our objective was to investigate the effect of quercetin supplementation on fasting resting energy expenditure (REE) and respiratory quotient (RQ) in humans. Six healthy, normal-weight women (mean age 25.5 +/- 1.6 years, body mass index 21.4 +/- 1.5 kg/m(2)) participated in a randomized, placebo-controlled, double blinded crossover study. Treatments were administered as capsules of 150 mg quercetin (aglycone) or placebo. The acute response was measured by indirect calorimetry for 3 h following ingestion. Blood pressure and pulse rate were assessed in 30-min intervals. On the following day, 24 h after capsule intake, a follow-up measurement was performed. Baseline (t (0)) REE adjusted for fat-free mass was 4.7 +/- 0.26 kJ/min (quercetin) and 4.8 +/- 0.35 kJ/min (placebo) and did not significantly change between baseline and end (t (180)) in either group (P = 0.992 for time effect in repeated measures analysis of variance; P = 0.581 for time * treatment interaction). Mean RQ was 0.78 +/- 0.04 (quercetin) and 0.77 +/- 0.04 (placebo). RQ values decreased slowly and to a similar extent during both treatments (P < 0.001 for time; quercetin, -0.09 +/- 0.05; placebo, -0.08 +/ 0.03; P = 0.877 for time * treatment interaction). Resting systolic and diastolic blood pressure, pulse pressure as well as resting pulse rate did not significantly change between baseline and end in either treatment group. No significant differences were found between the results of the baseline measurement and 24 h after treatment. In conclusion, the present pilot study provides no evidence for a thermic effect of quercetin in humans. PMID- 20924596 TI - The effect of recreational soccer training and running on postural balance in untrained men. AB - The aim of this study was to examine the effect of intense intermittent exercise performed as soccer training or interval running in comparison with continuous endurance running exercise on postural balance in young healthy untrained males. Young sedentary men were randomized to soccer training (SOC, n = 10), continuous running (RUN; n = 9), high-intensity interval running (INT; n = 7) or no training (CON; n = 9). Postural balance was evaluated pre and post 12 weeks of training using a 30-s single-leg stance test on a force plate (AMTI) to yield center of pressure (CoP) sway path and 1-min beam standing (Flamingo test). CoP sway length decreased by 18.2% (p < 0.01), 14.6% (p < 0.05) and 12.8% (p < 0.05) in SOC, INT and RUN, respectively. CoP sway area decreased in SOC (-30.2%; p < 0.01) and INT (-23.4%; p < 0.01) but remained unaffected in RUN. Acceleration parameters (Mean CoP acc, SD accX, SD accY) decreased in SOC only (17-19%, p < 0.05). All training groups demonstrated fewer falls (37-41%, p < 0.01) in the Flamingo test. No changes were observed in CON. Relationships (r > 0.40) were observed between pre training values in CoP sway area versus muscle fiber area, explosive muscle strength and countermovement jump velocity. Postural control was improved in response to 12 weeks of soccer training and high-intensity interval running, respectively, while less-marked changes were observed following continuous running. Notably, the reduced variability in CoP acceleration after soccer training indicates that this training regimen may produce superior improvements in postural sensory-motor function. PMID- 20924597 TI - Modulation of plasma adrenomedullin by epinephrine infusion during head up tilt. AB - We investigated whether head up tilt (HUT) with and without simultaneous epinephrine infusion modulate plasma adrenomedullin. We studied eight healthy male volunteers, using two 5 min 70 degrees HUT trials: control (saline infusion) and intervention (epinephrine infusion, titrated to a dose which increased supine systolic pressure by 20% above resting values). Protocols were randomized and separated by 2 weeks. Cardiac function and systolic time intervals, recorded using a phonocardiograph microphone, included left ventricular ejection time (LVET), pre-ejection period (PEP), PEP/LVET and electromechanical systole (QS2). Compared to saline infusion, epinephrine increased supine adrenomedullin (3.2 +/- 0.8 pmol/l, i.e., mean +/- SEM, respectively), heart rate (HR) (+11.3 +/- 2.6 bpm), systolic pressure (+18.4 +/- 2.6 mmHg) but decreased supine LVET, LVET corrected for HR (LVETi) and QS2-time (all p = 0.004). Despite similar HUT induced thoracic fluid shifts, reflected by similar thoracic impedance changes, HUT-induced adrenomedullin increases were minimal in epinephrine-supplemented men in comparison to controls (+8% vs. 42%). During HUT, epinephrine infusion decreased only the LVET (p = 0.039). Our findings confirm that short-term HUT increases plasma adrenomedullin. They further suggest that with increased supine epinephrine levels (epinephrine infusion clamping systolic arterial pressure at 120% control level), supine cardiac performance rises to a level similar to that during HUT, while adrenomedullin is still elevated with HUT. This might be in accordance with a 'dampening' role of adrenomedullin during catecholaminergic cardiovascular stimulation. As epinephrine is used as a drug to treat cardiac arrest and ventricular arrhythmias, our results may have important clinical/emergency resuscitation applications. PMID- 20924598 TI - Physicochemical properties of pore residues predict activation gating of Ca V1.2: a correlation mutation analysis. AB - Single point mutations in pore-forming S6 segments of calcium channels may transform a high-voltage-activated into a low-voltage-activated channel, and resulting disturbances in calcium entry may cause channelopathies (Hemara-Wahanui et al., Proc Natl Acad Sci U S A 102(21):7553-7558, 16). Here we ask the question how physicochemical properties of amino acid residues in gating-sensitive positions on S6 segments determine the threshold of channel activation of Ca(V)1.2. Leucine in segment IS6 (L434) and a newly identified activation determinant in segment IIIS6 (G1193) were mutated to a variety of amino acids. The induced leftward shifts of the activation curves and decelerated current activation and deactivation suggest a destabilization of the closed and a stabilisation of the open channel state by most mutations. A selection of 17 physicochemical parameters (descriptors) was calculated for these residues and examined for correlation with the shifts of the midpoints of the activation curve (DeltaV (act)). DeltaV (act) correlated with local side-chain flexibility in position L434 (IS6), with the polar accessible surface area of the side chain in position G1193 (IIIS6) and with hydrophobicity in position I781 (IIS6). Combined descriptor analysis for positions I781 and G1193 revealed that additional amino acid properties may contribute to conformational changes during the gating process. The identified physicochemical properties in the analysed gating sensitive positions (accessible surface area, side-chain flexibility, and hydrophobicity) predict the shifts of the activation curves of Ca(V)1.2. PMID- 20924599 TI - Effect of a temperature increase in the non-noxious range on proton-evoked ASIC and TRPV1 activity. AB - Acid-sensing ion channels (ASICs) are neuronal H(+)-gated cation channels, and the transient receptor potential vanilloid 1 channel (TRPV1) is a multimodal cation channel activated by low pH, noxious heat, capsaicin, and voltage. ASICs and TRPV1 are present in sensory neurons. It has been shown that raising the temperature increases TRPV1 and decreases ASIC H(+)-gated current amplitudes. To understand the underlying mechanisms, we have analyzed ASIC and TRPV1 function in a recombinant expression system and in dorsal root ganglion (DRG) neurons at room and physiological temperature. We show that temperature in the range studied does not affect the pH dependence of ASIC and TRPV1 activation. A temperature increase induces, however, a small alkaline shift of the pH dependence of steady-state inactivation of ASIC1a, ASIC1b, and ASIC2a. The decrease in ASIC peak current amplitudes at higher temperatures is likely in part due to the observed accelerated open channel inactivation kinetics and for some ASIC types to the changed pH dependence of steady-state inactivation. The increase in H(+) activated TRPV1 current at the higher temperature is at least in part due to a hyperpolarizing shift in its voltage dependence. The contribution of TRPV1 relative to ASICs to H(+)-gated currents in DRG neurons increases with higher temperature and acidity. Still, ASICs remain the principal pH sensors of DRG neurons at 35 degrees C in the pH range >=6. PMID- 20924602 TI - Congenital CMV: are we treating too many? PMID- 20924600 TI - Functional TRPV4 channels are expressed in mouse skeletal muscle and can modulate resting Ca2+ influx and muscle fatigue. AB - Skeletal muscle contraction is basically controlled by Ca(2+) release and its reuptake into the sarcoplasmic reticulum. However, the long-term maintenance of muscle function requires an additional Ca(2+) influx from extracellular. Several mechanisms seem to contribute to the latter process, such as store-operated Ca(2+) entry, stretch-activated Ca(2+) influx and resting Ca(2+) influx. Candidate channels that may control Ca(2+) influx into muscle fibers are the STIM proteins, Orai, and the members of the transient receptor potential (TRP) family of cation channels. Here we show that TRPV4, an osmo-sensitive cation channel of the vanilloid subfamily of TRP channels is functionally expressed in mouse skeletal muscle. Western blot analysis showed the presence of TRPV4-specific bands at about 85 and 100 kDa in all tested muscles. The bands were absent when muscle proteins from TRPV4 deficient mice were analyzed. Using the manganese quench technique, we studied the resting influx of divalent cations into isolated wild-type muscle fibers. The specific TRPV4-channel activator 4alpha-phorbol 12,13-didecanoate (4alpha-PDD) stimulated resting influx by about 60% only in wild-type fibers. Electrical stimulation of soleus muscles did not reveal changes in isometric twitch contractions upon application of 4alpha-PDD, but tetanic contractions (at 120 Hz) were slightly increased by about 15%. When soleus muscles were stimulated with a fatigue protocol, muscle fatigue was significantly attenuated in the presence of 4alpha-PDD. The latter effect was not observed with muscles from TRPV4(-/-) mice. We conclude that TRPV4 is functionally expressed in mouse skeletal muscle and that TRPV4 activation modulates resting Ca(2+) influx and muscle fatigue. PMID- 20924603 TI - Household poisoning cases from mercury brought from school. AB - Mercury has a number of unique and fascinating properties. It is present in the environment in several forms, both organic and inorganic. Each of these forms has somewhat unique properties that differentiate them from the other forms, but all are toxic to humans in one way or the others. Mercury has been proven to be a potential source of poisoning in children as a result of the inappropriate handling of a liquid mercury. The cases of metallic mercury vapor intoxication not associated with occupational exposure may occur in school science laboratories, from mercury dust and powders, from latex paint containing a mercury-based fungicide, and from normal wear or installation of dental amalgam fillings. Another source of toxic mercury exposure can be broken thermometers, barometers, or sphygmomanometers that may occur in the home, and children are often victims of environmental exposure. In this paper, we present three members of a family who were exposed to mercury brought home from school by a family member. Since the mercury exposure was not known, the initial presentation and clinical picture suggested a misdiagnosis, a contagious infectious disease, because the onset of symptoms occurred at different times in the same family members. A subsequent change to a diagnosis of mercury intoxication and chelation therapy with meso-2,3-dimercaptosuccinic acid was started. PMID- 20924604 TI - Nephrotic syndrome occurring during tiopronin treatment for cystinuria. AB - Cystinuria is an autosomal recessive disorder characterized with abnormal tubular reabsorption of cystine and dibasic amino acids leading to cystine urolithiasis. The classical form is caused by mutations in the SLC3A1 gene (OMIM 220100). The cornerstone of the treatment is high hydration and alkalization of the urine to achieve urine pH between 7.0 and 7.5, at which point, cystine solubility in the urine is optimal. These measures very often fail, and thus addition of sulfhydryl agents like penicillamine and tiopronin (mercaptopropionyl glycine) is recommended. Herein, we report a 3-year-old boy with cystinuria resulting in recurrent nephrolithiasis requiring surgery and extracorporeal shock wave lithotripsy. Nine months after introduction of tiopronin, the boy manifested generalized edema, oliguria, and biochemical indices of nephrotic syndrome. Tiopronin was withdrawn, and the boy was given only supportive treatment. Within 10 days, he entered into clinical and biochemical remission. Pediatricians should be aware of this adverse effect of tiopronin, and therefore, testing of the urine with strips or sulfosalicylic acid at least once weekly at home may be very helpful for early detection of proteinuria. PMID- 20924605 TI - Chronic pancreatitis in branched-chain organic acidurias--a case of methylmalonic aciduria and an overview of the literature. AB - A severe rare complication in patients with branched-chain organic acidurias (BCOA) is pancreatitis with a limited number of patients published so far. Here, we report on a patient with methylmalonic aciduria (MMA) who developed chronic pancreatitis after several episodes of acute pancreatitis. In addition, an overview is given about some previous published cases with BCOA who developed pancreatitis in the course of the disease. In half of the published MMA patients with pancreatitis, an acute pancreatitis was reported while the rest suffered from a chronic form of this disease. Acute pancreatitis in BCOA patients can clinically present in the context of recurrent vomiting and an impaired general physical condition even without typical signs of pancreatitis. Any form of pancreatitis should be ruled out in the assessment of acutely ill patients with BCOA. PMID- 20924606 TI - Remifentanil and propofol for weaning of mechanically ventilated pediatric intensive care patients. AB - Mechanically ventilated pediatric intensive care patients usually receive an analgesic and sedative to keep them comfortable and safe. However, common drugs like fentanyl and midazolam have a long context sensitive half time, resulting in prolonged sedation and an unpredictable extubation time. Children often awake slowly and struggle against the respirator, although their respiratory drive and their airway reflexes are not yet sufficient for extubation. In this pilot study, we replaced fentanyl and midazolam at the final phase of the weaning process with remifentanil and propofol. Twenty-three children aged 3 months-10 years were enrolled. Remifentanil and propofol revealed throughout excellent or good weaning conditions with rapid transition from hypnosis to the development of regular spontaneous breathing, airway protective reflexes, and an appropriate level of alertness. Extubation time following discontinuation of the remifentanil and propofol infusion was only 24 +/- 20 min (5-80 min). We conclude that the combination of remifentanil and propofol is a promising option to improve the weaning conditions of pediatric intensive care patients. Randomized controlled trials are needed to compare remifentanil and propofol with conventional weaning protocols. PMID- 20924607 TI - Early intravenous immunoglobin (two-dose regimen) in the management of severe Rh hemolytic disease of newborn--a prospective randomized controlled trial. AB - Phototherapy is the standard treatment in moderately severe hemolytic disease of newborn (HDN), whereas exchange transfusion (ET) is the second line in progressive cases. Intravenous immunoglobin (IVIG) has been suggested to decrease the need for ET. We aimed at assessing the efficacy of early two-dose regimens of IVIG to avoid unnecessary ET in severe Rh HDN. The study included 90 full-term neonates with Rh incompatibility unmodified by antenatal treatment and not eligible for early ET and which were randomly assigned into one of three groups: group (I), treated by conventional method; groups IIa and IIb received IVIG once at 12 h postnatal age if PT was indicated, in a dose of 0.5 and 1 g/kg, respectively. Analysis revealed 11 neonates (22%) in the conventional group and 2 (5%) in the intervention group who administered low-dose IVIG at 12 h, while none in group IIb required exchange transfusion (p = 0.03). Mean bilirubin levels were significantly lower during the first 96 h in the intervention group compared to the conventional group (p < 0.0001). Shorter duration of phototherapy (52.8 +/- 12.39 h) and hospital stay (3.25 +/- 0.71 days) in the IVIG group compared to conventional group (84 +/- 12.12 h and 4.72 +/- 0.78 days, p < 0.0001, respectively) were observed. We conclude that IVIG administration at 12 h was effective in the treatment of severe Rh HDN; the low-dose IVIG (0.5 g/kg) was as effective as high dose (1 g/kg) in reducing the duration of phototherapy and hospital stay, but less effective in avoiding exchange transfusion. PMID- 20924608 TI - Prevalence, associated determinants, and in vivo chemotherapeutic control of hard ticks (Acari: Ixodidae) infesting domestic goats (Capra hircus) of lower Punjab, Pakistan. AB - A total of 800 goats of various breeds, age, and sex were randomly selected from Muzaffargarh (M. garh) and Layyah districts of lower Punjab, Pakistan. The selected goats were visited twice a month to collect information about determinants influencing goat tick infestation prevalence. For acaricidal efficacy, 360 tick-infested adult goats were subjected to an acaricidal treatment and post-treatment quantitative assessment of tick burden. Quantification of adult tick detachment 24 h post-treatment and the duration of treatment efficacy were calculated. Overall prevalence of goat tick infestation in both study districts was 60.1% (481/800). The prevalence was higher in district M. garh than in district Layyah. Tehsil-wise prevalence in district Layyah was highest in tehsil Layyah followed in order by Chaubara and Karor. In district M. garh, highest prevalence was found in tehsil M. garh followed by Kot Addu, Alipur, and Jatoi. Hyalomma a. anatolicum (75.9%; 365/481) and Rhipicephalus sanguineus (24.1%; 116/481) were the predominant species in both the districts. The highest month-wise prevalence was 56.9% and 62.7% in Layyah and M. garh districts, respectively, during July 2008, and the minimum (0%) prevalence was reported in November and December, respectively. Regarding host determinants, female goats were more heavily infested (72.8%) than males (47.5%), and younger animals were (63.5%) more burdened than older ones (56.7%). Teddy goats were the most susceptible breeds followed in order by Beetal, cross-bred, Nachi, and Dera Din Pannah. The preferred sites of attachment were inside and outside of the ear. Both the ivermectin (IVM)- and cypermethrin (CYM)-treated groups resulted in significantly lower (P < 0.05) tick counts relative to controls on all post treatment counting days. The lowest tick burden in the IVM-treated group was significantly higher (P < 0.05) as compared to the CYM-treated group, the latter being close to zero. Hence, the in vivo efficacy trials of injectable IVM vs CYM pour-on revealed better results for the latter. These observations provided the first insights into what determinants impact goat tick infestation, and laid a foundation for planning of future control programs in the lower Punjab, Pakistan. PMID- 20924609 TI - Comparative genomic analysis of simple sequence repeats in three Plasmodium species. AB - Simple sequence repeats (SSRs) are known to be responsible for genetic complexities and play major roles in gene and genome evolution. To this respect, malaria parasites are known to have rapidly evolving and complex genomes with complicated and differential pathogenic behaviors. Hence, by studying the whole genome comparative SSRs patterns, one can understand genomic complexities and differential evolutionary patterns of these species. We herein utilized the whole genome sequence information of three Plasmodium species, Plasmodium falciparum, Plasmodium vivax, and Plasmodium knowlesi, to comparatively analyze genome-wide distribution of SSRs. The study revealed that despite having the smallest genome size, P. falciparum bears the highest SSR content among the three Plasmodium species. Furthermore, distribution patterns of different SSRs types (e.g., mono, di, tri, tetra, penta, and hexa) in term of relative abundance and relative density provide evidences for greater accumulation of di-repeats and marked decrease of mono-repeats in P. falciparum in comparison to other two species. Overall, the types and distribution of SSRs in P. falciparum genome was found to be different than that of P. vivax and P. knowlesi. The latter two species have quite similar SSR organizations in many aspects of the data. The results were discussed in terms of comparative SSR patterns among the three Plasmodium species, uniqueness of P. falciparum in SSR organization and general pattern of evolution of SSRs in Plasmodium. PMID- 20924611 TI - Imaging of the urinary tract: the role of CT and MRI. AB - Computed tomography (CT) and magnetic resonance imaging (MRI) are increasingly valuable tools for assessing the urinary tract in adults and children. However, their imaging capabilities, while overlapping in some respects, should be considered as complementary, as each technique offers specific advantages and disadvantages both in actual inherent qualities of the technique and in specific patients and with a specific diagnostic question. The use of CT and MRI should therefore be tailored to the patient and the clinical question. For the scope of this article, the advantages and disadvantages of these techniques in children will be considered; different considerations will apply in adult practice. PMID- 20924610 TI - The hypnozoite concept, with particular reference to malaria. AB - In 1978, the nature of the hypnozoite was discussed in an article that appeared in a relatively obscure journal, which is also where the term was adopted for Plasmodium (a little-known fact). As a result, that commentary on the use of the word "hypnozoite" has been almost completely overlooked. Although the publication is now more than three decades old, the analysis remains valid today. It is explained in the present paper that like "merozoite" and "sporozoite", the name "hypnozoite" is applicable not only to a latent stage in the life cycle of Plasmodium but to some apparently dormant forms of other kinds of apicomplexan parasites as well. Merozoites of different genera of parasitic protozoa are not necessarily the same biologically and/or otherwise. Similarly, although the hypnozoite concept relates primarily to pre-merozoite stages, some atypical post divisional apicomplexan forms might also be hypnozoites. Examples are likewise given of latent organisms that, in contrast, are clearly not hypnozoites, such as dormant merozoites in malaria infections. Lastly, the plasmodial hypnozoite is placed in context in relation to the relatively unfamiliar (nomenclaturally) malarial bradysporozoite, chronozoite, dormozoite, merophore, merosome and x body. This paper is based on a presentation by the author, as a Life Member of the American Society of Tropical Medicine and Hygiene, to its 59th Annual Meeting in Atlanta, Georgia, USA, 3-7 November 2010. PMID- 20924612 TI - Direct and indirect mortality in Florida during the 2004 hurricane season. AB - Previous studies have shown that natural disasters, and hurricanes in particular, have led to more deaths than those usually documented in short post-storm surveys. Such indirect deaths, thought to be related to dietary, stress or pre existing medical conditions, can exceed the number of direct deaths and may persist for weeks or even months beyond the event itself. In the present study, cumulative sum of deviations plots are used to quantify the number of direct and indirect deaths resulting from Hurricanes Charley, Frances, Ivan and Jeanne that made landfall in Florida in 2004. Results suggest that there was an elevated mortality for up to 2 months following each storm, resulting in a total of 624 direct and indirect deaths attributable to the storm. Trauma-related deaths that can be associated directly with the storm account for only ~4% of the total storm related mortality, while indirect mortality accounts for most storm-related deaths. Specifically, a large percentage of the elevated mortality was associated with heart (34%) and cancer-related deaths (19%), while diabetes (5%) and accident-related deaths (9%) account for a smaller but still significant percentage of the elevated mortality. The results further suggest that the elevated mortality was the result of additional deaths that would not have otherwise occurred within that 5 month period, and not simply a clustering of deaths that were inevitable between 1 August and 31 December 2004. The elevated mortality identified in this study is significantly greater than the official count of 31 direct and 113 indirect deaths resulting from the four hurricanes combined. This suggests a need for improved mortality counts and surveillance in order to better evaluate and identify effective prevention policies, and to identify preventable deaths. PMID- 20924613 TI - Elevational species shifts in a warmer climate are overestimated when based on weather station data. AB - Strong topographic variation interacting with low stature alpine vegetation creates a multitude of micro-habitats poorly represented by common 2 m above the ground meteorological measurements (weather station data). However, the extent to which the actual habitat temperatures in alpine landscapes deviate from meteorological data at different spatial scales has rarely been quantified. In this study, we assessed thermal surface and soil conditions across topographically rich alpine landscapes by thermal imagery and miniature data loggers from regional (2-km(2)) to plot (1-m(2)) scale. The data were used to quantify the effects of spatial sampling resolution on current micro-habitat distributions and habitat loss due to climate warming scenarios. Soil temperatures showed substantial variation among slopes (2-3 K) dependent on slope exposure, within slopes (3-4 K) due to micro-topography and within 1-m(2) plots (1 K) as a result of plant cover effects. A reduction of spatial sampling resolution from 1 * 1 m to 100 * 100 m leads to an underestimation of current habitat diversity by 25% and predicts a six-times higher habitat loss in a 2-K warming scenario. Our results demonstrate that weather station data are unable to reflect the complex thermal patterns of aerodynamically decoupled alpine vegetation at the investigated scales. Thus, the use of interpolated weather station data to describe alpine life conditions without considering the micro topographically induced thermal mosaic might lead to misinterpretation and inaccurate prediction. PMID- 20924614 TI - Explorative study on the aftercare of pediatric brain tumor survivors: a parents' perspective. AB - PURPOSE: Whilst the need for aftercare for long-term sequelae of brain tumor survivors is well known and evident, information from a parent's perspective is lacking on whether the need for aftercare is detected in time, and whether the aftercare is timely initiated and meets the needs for aftercare. METHODS: A survey regarding aftercare in five domains of long-term sequelae (neurocognitive, physical, emotional, social and parenting problems) was sent to 57 parents of survivors treated for a brain tumor in our center. RESULTS: Forty-two (74%) parents participated in this study. With a mean period of 8.1 years (SD = 3.9) since start of treatment, the majority of the survivors (mean age = 14.7 years, SD = 3.8) needed aftercare in several domains of functioning. This need was highest and most met for physical sequelae (N = 34), and lowest but still substantial and least met for parental difficulties (N = 11). Parents of survivors with surgery only as treatment reported a similar need for aftercare as those of survivors with adjuvant therapy. Most of the survivors received aftercare; however, substantial delay of aftercare and self-referral for aftercare were frequently reported. Furthermore, parents showed a lack of knowledge about and use of aftercare services. CONCLUSIONS: Increased awareness for the need for psychosocial aftercare is required. Coaching, psycho-educative programs about coping with the long-term sequelae and information about available specialized aftercare services are required to meet the needs of brain tumor survivors and their parents more adequately. PMID- 20924615 TI - Rebamipide has the potential to reduce the intensity of NSAID-induced small intestinal injury: a double-blind, randomized, controlled trial evaluated by capsule endoscopy. AB - BACKGROUND: A study reported that rebamipide was effective at reducing short-term nonsteroidal anti-inflammatory drug (NSAID)-induced enteropathy. The purpose of this study was to re-evaluate the effect of the co-administration of rebamipide on small intestinal injuries induced by short-term NSAID treatment. METHODS: Eighty healthy male volunteers were randomly assigned to two study groups: a control group (N = 40), which received NSAID (diclofenac sodium, 75 mg/day) and omeprazole (20 mg/day) treatment along with a placebo; and a rebamipide group, which received NSAID, omeprazole and rebamipide (300 mg/day). Small intestinal injuries (mucosal breaks plus denuded areas) were evaluated by capsule endoscopy before and after 14 days of treatment. RESULTS: A total of 38 control subjects and 34 rebamipide subjects completed the treatment and were evaluated by capsule endoscopy. NSAID therapy increased the mean number of mucosal injuries per subject from a basal level of 0.1 +/- 0.3 to 16 +/- 71 and 4.2 +/- 7.8 in the control and rebamipide groups, respectively, but the difference was not significant. The difference in the percentage of subjects with at least one mucosal injury post-treatment was also not significant (control 63%; rebamipide 47%). Limiting our analysis to subjects with mucosal injuries, rebamipide co treatment had the tendency to reduce the mean number of mucosal injuries per subject from 25 in the control group to 8.9 in the rebamipide group (multiple comparisons test; p = 0.088, Mann-Whitney U test; p = 0.038). CONCLUSIONS: Rebamipide co-therapy had the potential to reduce the intensity of small intestinal injury induced by 2-week administration of diclofenac. PMID- 20924616 TI - Reactivation of hepatitis B virus following rituximab-plus-steroid combination chemotherapy. AB - Reactivation of hepatitis B virus (HBV) has been reported as a fatal complication following systemic chemotherapy or other immunosuppressive therapy. The risk of HBV reactivation differs according to both the patient's HBV infection status prior to systemic chemotherapy and the degree of immunosuppression due to chemotherapy. For establishing an optimal strategy for hepatitis prevention and treatment, it is necessary to understand the characteristics, the clinical course and the risk factors for HBV reactivation and to recognize the difference between hepatitis B surface antigen (HBsAg)-positive and -negative patients with HBV reactivation. Among the important viral risk factors, HBV-DNA level and HBV related serum markers have been reported to be associated with HBV reactivation in addition to cccDNA, genotypes and gene mutations. Rituximab-plus-steroid combination chemotherapy has recently been identified as a host risk factor for HBV reactivation in hepatitis B core antibody (anti-HBc)-positive and/or hepatitis B surface antibody (anti-HBs) positive--but nonetheless HBsAg-negative- lymphoma patients. For these patients with resolved hepatitis B, preemptive therapy guided by serial HBV-DNA monitoring is a reasonable strategy to enable early diagnosis of HBV reactivation and initiation of antiviral therapy. In this review, we summarize the characteristics of HBV reactivation following rituximab plus-steroid combination chemotherapy, mainly in HBsAg-negative lymphoma patients, and propose a strategy for managing HBV reactivation. PMID- 20924618 TI - Injection therapy and denervation procedures for chronic low back pain: a systematic review--clinical value? PMID- 20924619 TI - Exercise increases neural stem cell proliferation surrounding the area of damage following rat traumatic brain injury. AB - Exercise enhances neuronal stem cell (NSC) proliferation and neurogenesis. However, the effect of exercise on NSC proliferation surrounding the area of damage after traumatic brain injury (TBI) is unknown. Here, we investigate the effect of running on NSC proliferation following TBI in the rat. Wistar rats received TBI and were randomly divided into two groups: (1) non-exercise group and (2) exercise group. The exercise group ran on a treadmill for 30 min/day at 22 m/min for 7 consecutive days. Immunohistochemistry was used to monitor NSC proliferation around the damaged area, and ex vivo techniques were used to isolate NSCs from the damaged region in both groups. The number of nestin- and Ki67-positive cells observed at 3 and 7 days after TBI was significantly greater in the exercise group than in the non-exercise group (P < 0.01). Furthermore, most nestin-positive cells in the exercise group co-localized with Ki67-positive cells. In ex vivo studies, spheres could be isolated from injured brain tissue from the exercise group at 3 and 7 days following TBI, but at only 3 days in the non-exercise group. The number of spheres isolated from injured brain tissue was greater in the exercise group than in the non-exercise group. Spheres were immunopositive for nestin and comprised NSCs that could differentiate into neurons and glia. Exercise increases the proliferation of NSCs around the damaged area following TBI. Therefore, exercise therapy (rehabilitation) in the early phase following TBI is important for recuperation from cerebral dysfunction induced by TBI. PMID- 20924617 TI - Dexmedetomidine-ketamine and midazolam-ketamine combinations for sedation in pediatric patients undergoing extracorporeal shock wave lithotripsy: a randomized prospective study. AB - PURPOSE: Extracorporeal shock wave lithotripsy (ESWL) requires sedation in pediatric patients. Dexmedetomidine is a relatively new agent used for sedation. The aim of this randomized prospective study was to compare the effects of dexmedetomidine-ketamine and midazolam-ketamine combinations on the recovery time, hemodynamic and respiratory variables, and side effects in pediatric patients undergoing ESWL. METHODS: Fifty pediatric patients aged between 2 and 15 years who were scheduled for elective ESWL were randomized into two groups. In Group D we applied dexmedetomidine at1 MUg/kg, given over 10 min, and a bolus of 1 mg/kg ketamine for sedation. In Group M we applied midazolam at a 0.05 mg/kg bolus dose 10 min before the procedure and a 1 mg/kg bolus of ketamine. We measured and monitored the hemodynamic variables, oxygen saturation, and recovery time, and we also monitored the side effects. RESULTS: Four patients in group D refused to complete the study; 21 patients in group D and 25 patients in group M completed the study. We found the recovery time [eye-opening time (9.3 +/- 4.5 vs. 16.2 +/- 6.5 min; p < 0.001), verbal response time (12.8 +/- 4.9 vs. 19.2 +/- 7.2 min; p < 0.001), and the cooperation time (17.1 +/- 5.0 vs. 23.3 +/- 7.7 min; p < 0.001)] to be shorter in the dexmedetomidine group. Also, the heart rate values were lower in the dexmedetomidine group at the 20th minute of the procedure (99.1 +/- 19.0 vs. 118.7 +/- 7.3 beats/min; p = 0.016). CONCLUSION: In this study we found the recovery time to be shorter, with hemodynamic stability, in the dexmedetomidine group, compared with the midazolam group. So we can conclude that dexmedetomidine may be a good and safe alternative agent for sedation, with a shorter recovery period than midazolam, in the pediatric population. PMID- 20924621 TI - Complete nucleotide sequences of a distinct bipartite begomovirus, bitter gourd yellow vein virus, infecting Momordica charantia. AB - Momordica charantia (Cucurbitaceae), a vegetable crop commonly cultivated throughout Pakistan, and begomoviruses, a serious threat to crop plants, are natives of tropical and subtropical regions of the world. Leaf samples of M. charantia with yellow vein symptoms typical of begomovirus infections and samples from apparently healthy plants were collected from areas around Lahore in 2004. Full-length clones of a bipartite begomovirus were isolated from symptomatic samples. The complete nucleotide sequences of the components of one isolate were determined, and these showed the arrangement of genes typical of Old World begomoviruses. The complete nucleotides sequence of DNA A showed the highest nucleotide sequence identity (86.9%) to an isolate of Tomato leaf curl New Delhi virus (ToLCNDV), confirming it to belong to a distinct species of begomovirus, for which the name Bitter gourd yellow vein virus (BGYVV) is proposed. Sequence comparisons showed that BGYVV likely emerged as a result of inter-specific recombination between ToLCNDV and tomato leaf curl Bangladesh virus (ToLCBDV). The complete nucleotide sequence of DNA B showed 97.2% nucleotide sequence identity to that of an Indian strain of Squash leaf curl China virus. PMID- 20924620 TI - Nuclear translocation of anamorsin during drug-induced dopaminergic neurodegeneration in culture and in rat brain. AB - Anamorsin, also called cytokine-induced apoptosis inhibitor 1 (CIAPIN1), was recently identified to confer resistance to apoptosis induced by growth factor deprivation and to be indispensible for hematopoiesis. Recently, it was demonstrated that anamorsin is also widely distributed in both fetal and adult tissues. In this study, we evaluated the tissue distribution of anamorsin in the central nervous system (CNS) during development. In situ hybridization and immunoblot analyses revealed that anamorsin mRNA and protein were both highly and widely expressed in various regions of the CNS, including the cerebral cortex, hippocampus, midbrain, cerebellum, medulla, and spinal cord. Based on these findings, we examined its cellular localization during drug-induced neurodegeneration in MN9D dopaminergic cells. Both immunocytochemical localization and immunoblot analyses indicated that cytosolic anamorsin was translocated into the nucleus in a time-dependent manner following treatment with a reactive oxygen species (ROS)-inducing drug, 6-hydroxydopamine (6-OHDA). Treatment of cells with the apoptosis-inducing reagent, staurosporine, did not appear to cause translocation of anamorsin into the nucleus. When cells were treated with the nuclear export inhibitor, Leptomycin B, alone or with 6-OHDA, nuclear anamorsin levels increased, indicating that nuclear influx and efflux of anamorsin are regulated by 6-OHDA treatment. In rat brain injected with 6-OHDA, nuclear translocation of anamorsin was identified in certain tyrosine hydroxylase (TH)-positive neurons as well as TH-negative cells. Furthermore, treatment of MN9D cells with hydrogen peroxide or ROS-inducing trace metals caused nuclear translocation of anamorsin. Taken together, our data indicate that nuclear translocation of anamorsin is a ROS-dependent event and may participate in the regulation of transcription of critical molecules during dopaminergic neurodegeneration. PMID- 20924622 TI - New potent biphalin analogues containing p-fluoro-L-phenylalanine at the 4,4' positions and non-hydrazine linkers. AB - We report the synthesis and the biological evaluation of two new analogues of the potent dimeric opioid peptide biphalin. The performed modification is based on the replacement of two key structural elements of the native biphalin, namely: the hydrazine bridge which joins the two palindromic moieties and the phenylalanine residues at the 4,4' positions of the backbone. The new analogues 9 and 10 contain 1,2-phenylenediamine and piperazine, respectively, in place of the hydrazidic linker and p-fluoro-L-phenylalanine residues at 4 and 4' positions. Binding values are: KMU(i)=0.51 nM and Kdelta(i)=12.8 nM for compound 9, KMU(i)=0.09 nM and Kdelta(i)=0.11 nM for analogue 10. PMID- 20924623 TI - Zinc induces disorder-to-order transitions in free and membrane-associated Thellungiella salsuginea dehydrins TsDHN-1 and TsDHN-2: a solution CD and solid state ATR-FTIR study. AB - Dehydrins are intrinsically unstructured proteins that are expressed in plants experiencing extreme environmental conditions such as drought or low temperature. Although their role is not completely understood, it has been suggested that they stabilize proteins and membrane structures during environmental stress and also sequester metals such as zinc. Here, we investigate two dehydrins (denoted as TsDHN-1 and TsDHN-2) from Thellungiella salsuginea. This plant is a crucifer that thrives in the Canadian sub-Arctic (Yukon Territory) where it grows on saline rich soils and experiences periods of both extreme cold and drought. We show using circular dichroism and attenuated total reflection-Fourier transform infrared spectroscopy that ordered secondary structure is induced and stabilized in these proteins, both in free and vesicle-bound form, by association with zinc. In membrane-associated form, both proteins have an increased proportion of beta strand conformation induced by the cation, in addition to the amphipathic alpha helices formed by their constituent K-segments. These results support the hypothesis that dehydrins stabilize plant plasma and organellar membranes in conditions of stress, and further that zinc may be an important co-factor in stabilization. Whereas dehydrins in the cytosol of a plant cell undergoing dehydration or temperature stress form bulk hydrogels and remain primarily disordered, dehydrins with specific membrane- or protein-associations will have induced ordered secondary structures. PMID- 20924624 TI - Synthesis and biological evaluation of new [Tc(N)(PS)]-based mixed-ligand compounds useful in the design of target-specific radiopharmaceuticals: the 2 methoxyphenylpiperazine dithiocarbamate derivatives as an example. AB - This study presents the first application of a general procedure based on the use of the [Tc(N)Cl(PS)(PPh(3))] species (PS is an alkyl phosphinothiolate ligand) for the preparation of Tc(N) target-specific compounds. [Tc(N)Cl(PS)(PPh(3))] selectively reacts with an appropriate dithiocarbamate ligand (S(?)Y) to give [Tc(N)(PS)(S(?)Y)] compounds. 1-(2-Methoxyphenyl)piperazine, which displays a potent and specific affinity for 5HT(1A) receptors, was selected as a functional group and conjugated to the dithiocarbamate unit through different spacers (L( n )). [(99m)Tc(N)(PS)(L( n ))] complexes were prepared in high yield (more than 90%). The chemical identity of (99m)Tc complexes was determined by high performance liquid chromatography comparison with the corresponding (99g)Tc complexes. All complexes were found to be inert toward transchelation with an excess of glutathione and cysteine. No notable biotransformation of the native compound into different species by the in vitro action of the serum and liver enzymes was shown. Nanomolar affinity for the 5HT(1A) receptor was obtained for [(99m)Tc(N)(PSiso)L(3)] (IC(50) = 1.5 nM); a reduction of the affinity was observed for the other complexes as a function of the shortening of the alkyl chain interposed between the dithiocarbamate and the pharmacophore. Negligible brain uptake was found from in vivo distribution data of [(99m)Tc(N)(PSiso)L(3)]. The key finding of this study is that the complexes maintained good affinity and selectivity for 5HT(1A) receptors, and the IC(50) value for [(99g)Tc(N)(PSiso)L(3)] being comparable to the IC(50) value found for WAY 100635. This result confirmed the possibility of preparing [(99m)Tc(N)(PS)]-based target-specific compounds without affecting the affinity and selectivity of the bioactive molecules for the corresponding receptors. PMID- 20924625 TI - Multiple templates-based homology modeling enhances structure quality of AT1 receptor: validation by molecular dynamics and antagonist docking. AB - We present a comparative account on 3D-structures of human type-1 receptor (AT1) for angiotensin II (AngII), modeled using three different methodologies. AngII activates a wide spectrum of signaling responses via the AT1 receptor that mediates physiological control of blood pressure and diverse pathological actions in cardiovascular, renal, and other cell types. Availability of 3D-model of AT1 receptor would significantly enhance the development of new drugs for cardiovascular diseases. However, templates of AT1 receptor with low sequence similarity increase the complexity in straightforward homology modeling, and hence there is a need to evaluate different modeling methodologies in order to use the models for sensitive applications such as rational drug design. Three models were generated for AT1 receptor by, (1) homology modeling with bovine rhodopsin as template, (2) homology modeling with multiple templates and (3) threading using I-TASSER web server. Molecular dynamics (MD) simulation (15 ns) of models in explicit membrane-water system, Ramachandran plot analysis and molecular docking with antagonists led to the conclusion that multiple template based homology modeling outweighs other methodologies for AT1 modeling. PMID- 20924626 TI - Coupling between the BLUF and EAL domains in the blue light-regulated phosphodiesterase BlrP1. AB - The first biochemical and structural characterization of the full-length active photoreceptor BlrP1 from Klebsiella pneumoniae was recently reported by Barends et al. [Nature 459:1015-1018, (2009)]. The light-regulated catalytic function of its C-terminal c-di-guanosine monophosphate phosphodiesterase, the EAL (Glu-Ala Leu) domain, is activated by the N-terminal sensor of blue light using the flavin adenine dinucleotide (BLUF) domain. We performed molecular dynamics simulations on the dimeric BlrP1 protein in order to examine the coupling regions that are presumably involved in transmitting light-induced structural changes which occur in the BLUF domain to the EAL domain. According to the results of simulations and an analysis of the hydrogen bonding between the respective polypeptide chains, the region containing the site on the alpha3alpha4 loop of BLUF is responsible for communication between the photosensing and catalytic domains in the dimeric BlrP1 protein. PMID- 20924627 TI - Serum cysteine proteases and their inhibitors in rheumatoid arthritis: relation to disease activity and radiographic progression. AB - This study aims to investigate the serum levels of cysteine proteases cathepsins B and H and their inhibitors stefin A, stefin B, and cystatin C, as well as traditional inflammatory markers such as C-reactive protein in patients with rheumatoid arthritis and to correlate these markers with scores of disease activity and radiographic progression. Seventy-two patients with rheumatoid arthritis were included from two previously described cohorts of patients with chronic polyarthritis. At inclusion, disease activity was assessed by a 28-joint count, patient global assessment, and serum C-reactive protein. Erosive status of hands and wrists was expressed by the Larsen score and recorded at inclusion and after 1 year. Serum levels of cathepsin B, cathepsin H, stefin A, stefin B, and cystatin C were determined by enzyme-linked immunosorbent assay. Neither cathepsin B nor cathepsin H serum levels were associated with disease activity, presence or progression of erosive disease. Number of swollen joints correlated with serum levels of stefin A and B and correlated negatively with cystatin C serum levels. Erosive disease was associated with high serum levels of C-reactive protein and stefin A and low serum levels of cystatin C. Progression of radiographic destruction was associated with high serum levels of C-reactive protein, stefin A and B, whereas serum levels of cystatin C were not associated with radiographic progression. The findings in this study support further investigation in the regulation of the activity of cathepsins and their inhibitors in erosive rheumatoid arthritis. PMID- 20924628 TI - A retrospective analysis of treatment outcomes in patients with hepatitis C related systemic vasculitis receiving intravenous methylprednisolone and cyclophosphamide. AB - The aim of this work is to describe the outcome of a series of patients with hepatitis C virus (HCV)-related vasculitis who were treated with corticosteroids and I.V. cyclophosphamide without receiving any antiviral therapy. The data of 16 patients with HCV infection and vasculitis were retrospectively analyzed for the treatment outcome in the present study. Eleven patients were females (68.8%) with a mean age of 49.6 +/- 10.0 years. Nine patients (56.2%) had medium-sized vessel vasculitis (group A) and seven patients (43.8%) had small vessel vasculitis (group B). Disease activity was assessed using the Birmingham Vasculitis Activity Score (BVAS 2003) and organ damage was assessed by the Vasculitis Damage Index (VDI). HCV infection was confirmed in all patients by the detection of antibodies to HCV in serum by ELISA and HCV RNA using qualitative PCR. Quantitative PCR was done using the branched DNA technique. None of our study patients had received antiviral therapy, but they all received I.V.-pulsed cyclophosphamide monthly for 6 months, then every 3 months for six times if needed, preceded by I.V. methylprednisolone. Twelve patients (75%) had undetectable viral load by the quantitative technique. The drop in mean BVAS recorded at different intervals was highly significant. Although there was a drop in the VDI mean between the first and second reading, it was not statistically significant. All patients responded to treatment. Seven patients (43.8%) had relapse. Two patients died (12.5%). One patient died from renal failure (group B) and another died from sepsis (group A). The treatment outcomes were not statistically significant between the two vasculitis groups. A subset of patients with HCV-related vasculitis and with low levels of viremia can be safely treated with corticosteroids and cyclophosphamide alone. Despite successful treatment, a significant proportion of patients relapse and some develop severe complications and death. PMID- 20924629 TI - Pretreatment with a novel aquaporin 4 inhibitor, TGN-020, significantly reduces ischemic cerebral edema. AB - We investigated the in vivo effects of a novel aquaporin 4 (AQP4) inhibitor 2 (nicotinamide)-1,3,4-thiadiazole, TGN-020, in a mouse model of focal cerebral ischemia using 7.0-T magnetic resonance imaging (MRI). Pretreatment with TGN-020 significantly reduced brain edema associated with brain ischemia, as reflected by percentage of brain swelling volume (%BSV), 12.1 +/- 6.3% in the treated group, compared to (20.8 +/- 5.9%) in the control group (p < 0.05), and in the size of cortical infarction as reflected by the percentage of hemispheric lesion volume (%HLV), 20.0 +/- 7.6% in the treated group, compared to 30.0 +/- 9.1% in the control group (p < 0.05). The study indicated the potential pharmacological use of AQP4 inhibition in reducing brain edema associated with focal ischemia. PMID- 20924630 TI - Gustatory dysfunction after mandibular zoster. AB - Varicella zoster, limited to the mandibular nerve, is rare. Classical symptoms are pain, hypesthesia and vesicular eruption restricted to the third trigeminal segment (V3). Little is known on taste affection after mandibular nerve zoster. We report two cases of patients suffering from mandibular zoster associated with subjective taste disorder. In both cases, gustatory measures confirmed ipsilateral hemiageusia of the anterior two-thirds of the tongue. After 2 months, the symptoms regressed and psychophysical measures came back to normal values, whereas post-zoster neuralgia lasted for more than 1 year. Gustatory dysfunction is a possible symptom after mandibular nerve zoster. In contrast to post-zoster neuralgia, taste function seems to recover quickly. PMID- 20924631 TI - A case of strictly unilateral migraine without aura transformed in an episodic hemicrania continua. AB - According to the diagnostic criteria of International Headache Society classification, hemicrania continua is a strictly unilateral continuous headache of moderate intensity with painful exacerbations associated with ipsilateral autonomic signs without pain-free periods. We report a case of a 42-year-old woman suffered of a remitting form of hemicrania continua evolved from a strictly unilateral migraine without aura. PMID- 20924632 TI - Myotonic dystrophies as a brain disorder. PMID- 20924633 TI - Usage of granulocyte colony-stimulating factor every 2 days is clinically useful and cost-effective for febrile neutropenia during early courses of chemotherapy. AB - BACKGROUND: In order to analyze the clinical activity and cost-effectiveness of granulocyte colony-stimulating factors (G-CSF), the prophylactic usage of G-CSF in patients treated with a single chemotherapy regimen during early courses was prospectively evaluated. METHODS: Thirty patients with newly diagnosed non Hodgkin lymphoma (NHL) treated with the first course of an R-CHOP regimen were enrolled randomly. After treatment with the first course of chemotherapy, a daily dose of G-CSF (lenograstim, 100 MUg) was administered to half (15 cases) of the patients, and a dose of G-CSF (100 MUg) was administered every other day to the other half of the patients when leukocytopenia (<1.5 * 10(9)/L) and/or neutropenia (<0.5 * 10(9)/L) occurred. Changes in leukocyte and neutrophil counts, prophylaxis, febrile neutropenia (FN) events, and cost performance between the two groups were analyzed. RESULTS: No significant difference between the two groups was observed in recoveries of leukocyte and neutrophil counts and evidence of FN. The only difference was the total cost of G-CSF. CONCLUSION: We concluded that every-other-day use of G-CSF was as clinically effective for the prophylaxis of FN as the daily use of G-CSF, and economically speaking, the administration of G-CSF every other day should be more beneficial for patients with NHL during early courses of R-CHOP chemotherapy. PMID- 20924635 TI - Electric-field-induced polarization and interactions of uncharged colloids in salt solutions. AB - The electric-field-induced charge distribution and potential around a colloidal sphere and rod in salt solutions are analyzed. The resulting field-induced colloid-colloid interactions are calculated for specific orientations. The colloids are assumed to be uncharged (or very weakly charged), such that the deflection of ion fluxes by the cores of the colloids is the dominant polarization mechanism (which is referred to as volume-polarization). Explicit expressions are derived for the frequency-dependent charge distribution and the potential in case of a symmetric electrolyte. It is shown that colloid-colloid interactions due to the induced charge distributions can be much larger than the thermal energy, and are therefore sufficiently strong to give rise to electric field-induced phase transitions. The present study is a first step towards a quantitative description of field-induced transitions for systems where volume polarization is the dominant polarization mechanism. PMID- 20924636 TI - Elasto- and electro-capillary instabilities of a nematic-isotropic interface: Experimental results. AB - Recently, we have shown the existence of an electro-capillary instability of a nematic-isotropic interface stabilized by a temperature gradient (P. Oswald, EPL 90, 16005 (2010)). This instability results from a competition between the destabilizing action of the electric Maxwell stress and the stabilizing action of the thermal and capillary forces. The control parameters are the temperature gradient G , the applied voltage V and the thickness h of the nematic layer. In this paper, we present new experimental results on this instability in both the linear and nonlinear regimes. In particular, very rich phase diagrams are mapped out in the (h, V) plane for three different values of G . The divergence of the growth time close to the onset of instability is also studied in detail. In addition, we show the existence at low voltages of another instability of the de Gennes type, where the elastic Ericksen stress is responsible for the destabilization. In this case, a hill-and-valley structure or a square array of umbilics develop at the interface depending on the values of h , V and G . PMID- 20924634 TI - Tumor-infiltrating lymphocytes and hepatocellular carcinoma: molecular biology. AB - Tumor-infiltrating lymphocytes (TIL) are one of the representative components of host antitumor immune responses. Both the quality and quantity of TIL determine the effect of the antitumor immune reaction. Previous studies have indicated that patients with cancers showing massive infiltration of CD8(+) T cells generally have a better clinical outcome. Conversely, patients with marked infiltration of immunosuppressive cells such as regulatory T cells tend to have a worse prognosis for several types of cancer. The density and distribution of TIL are also strongly affected by the trafficking route. Tumor-associated blood vessels in various cancers are structurally and functionally abnormal, and such abnormal vessels reportedly become an obstacle for infiltration of immune effector cells into tumors. Recently, understanding of the molecular mechanisms of lymphocyte trafficking has progressed rapidly. This review focuses on the mechanisms of lymphocyte trafficking to tumor cells and also discusses the importance of blood vessel for TIL trafficking, especially in relation to hepatocarcinogenesis. PMID- 20924637 TI - MicroRNA-128 downregulates Bax and induces apoptosis in human embryonic kidney cells. AB - MicroRNAs (miRNAs) are short ~21-nt non-coding RNA molecules that have been shown to regulate a number of biological processes. Previous reports have shown that overexpression of miR-128 in glioma cells inhibited cell proliferation. Literature also suggests that miR-128 negatively regulates prostate cancer cell invasion. Here, we show that overexpression of hsa-miR-128, a brain-enriched microRNA, induces apoptosis in HEK293T cells as elucidated by apoptosis assay, cell cycle changes, loss of mitochondrial membrane potential and multicaspase assay. By in silico analysis, we identified a putative target site within the 3' untranslated region (UTR) of Bax, a proapoptotic member of the apoptosis pathway. We found that ectopic expression of hsa-miR-128 suppressed a luciferase reporter containing the Bax-3' UTR and reduced the levels of Bax in HEK293T cells. Taken together, our study demonstrates that overexpression of hsa-miR-128 not only induces apoptosis in HEK293T cells but also is an endogenous regulator of Bax protein. PMID- 20924638 TI - E. coli lipopolysaccharide attenuates adenosine A(1) receptor-mediated increase in plasma exudation from the hamster cheek pouch. AB - OBJECTIVE AND DESIGN: To determine whether exposure to E. coli lipopolysaccharide (LPS) modulates adenosine A(1) receptor-induced increase in plasma exudation from the intact hamster cheek pouch microcirculation. METHODS AND RESULTS: Using intravital microscopy, we found that suffusion of R(-)-N(6)-(2-phenylisopropyl) adenosine (R(-)-PIA) (1.0 and 10.0 nM), a selective adenosine A(1) receptor agonist, onto the intact cheek pouch elicited significant, concentration dependent leaky site formation and increase in clearance of fluorescein thioisocyanate-dextran (mol mass, 70 kDa) from post-capillary venules (p < 0.05). These responses were significantly attenuated by pre-treatment of hamsters with LPS (p < 0.05). By contrast, LPS had no significant effects on CGS-21680-, a selective adenosine A(2A) receptor agonist, bradykinin- and substance P-induced increases in plasma exudation from the cheek pouch. CONCLUSION: These data indicate that LPS attenuates adenosine A(1) receptor-induced increase in plasma exudation in vivo in a specific fashion. We suggest that this phenomenon represents an endogenous anti-inflammatory cue to avoid excessive inflammation during Gram-negative bacterial infections. PMID- 20924639 TI - Effects of HSP70 on the compression force-induced TNF-alpha and RANKL expression in human periodontal ligament cells. AB - OBJECTIVE AND DESIGN: The aim of this study was to investigate the effect of heat shock protein 70 (HSP70) on the mRNA expression of tumor necrosis factor-alpha (TNF-alpha) and receptor activator of nuclear factor-kappa B ligand (RANKL) induced by compressive forces (CF) in human periodontal ligament (hPDL) cells. MATERIAL AND TREATMENT: hPDL cells were subjected to 1.0, 2.0, or 4.0 g/cm(2) of CF for 24 h, and were treated with recombinant human inducible HSP70 for 12 h. METHODS: The mRNA expression of HSP27, HSP70, HSP90, TNF-alpha, RANKL and OPG from hPDL cells subjected to CF was determined by real-time PCR. The protein production of HSP70 was determined by Western blot analysis and ELISA. RESULTS: The mRNA expression of HSP70, TNF-alpha and RANKL were found to be increased in a time- and magnitude-dependent manner, detectable at 12, 9, and 9 h, respectively. TNF-alpha and RANKL expression gradually decreased at 12 h with increasing HSP70 levels, and further decreased thereafter. Furthermore, exogenous HSP70 partially inhibited the CF-induced TNF-alpha and RANKL expression in a dose-dependent manner at 6 and 12 h. CONCLUSIONS: These results indicate that HSP70 may modulate the mRNA expression of TNF-alpha and RANKL in hPDL cells in response to CF. PMID- 20924641 TI - Multicenter phase II study of S-1 monotherapy as second-line chemotherapy for advanced biliary tract cancer refractory to gemcitabine. AB - Gemcitabine is widely used for the treatment of advanced biliary tract cancer (BTC) as first-line chemotherapy. However, there is no standard chemotherapy for patient with advanced BTC refractory to gemcitabine. We conducted a multicenter phase II study of S-1 monotherapy as second-line chemotherapy for patients with advanced BTC that were refractory to gemcitabine. S-1 was administered orally at a dose of 80 mg/m(2) for 28 days, followed by 14 days of rest. This regimen was repeated every 6 weeks. Tumor response was assessed every two cycles using the Response Evaluation Criteria in Solid Tumors version 1.0. Twenty-two patients were enrolled between March 2007 and January 2010, with 14 patients (64%) representing cases of recurrence after surgery. The overall response rate was 22.7%, and the overall disease control rate was 50.0%. The median overall survival time was 13.5 months (95% CI, 7.1-23.1 months) and the median time-to progression was 5.4 months (95% CI, 2.6-17.2 months). Grade 3/4 toxicities included neutropenia (5%) and anemia (5%). The most common non-hematological toxicities were nausea (27%), anorexia (55%), and pigmentation (32%). In conclusion, S-1 monotherapy is feasible and moderately efficacious second-line chemotherapy for advanced BTC. PMID- 20924640 TI - Riccardin D, a novel macrocyclic bisbibenzyl, induces apoptosis of human leukemia cells by targeting DNA topoisomerase II. AB - We studied the effect of riccardin D, a macrocyclic bisbibenzyl, which was isolated from the Chinese liverwort plant, on human leukemia cells and the underlying molecular mechanism. Riccardin D had a significant antiproliferative effect on human leukemia cell lines HL-60, K562 and its multidrug resistant (MDR) counterpart K562/A02 cells, but showed no effect on the topoisomerase-II deficient HL-60/MX2 cells, as measured by the 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide (MTT) assay. The pBR322 DNA relaxation assay revealed that riccardin D selectively inhibited the activity of topoisomerase II (topo II). The suppression of topo II activity by riccardin D was stronger than that of etoposide, a known topo II inhibitor. After treatment with riccardin D, nuclear extracts of leukemia K562 and K562/A02 cells left the majority of pBR322 DNA in a supercoiled form. Further examination showed that riccardin D effectively induced HL-60, K562 and K562/A02 apoptosis as evidenced by externalization of phosphatidylserine and formation of DNA ladder fragments. The activation of cytochrome c, caspase-9, caspase-3 and cleaved poly ADP-ribose polymerase (PARP) was also enhanced, as estimated by Western blot analysis. By contrast, riccardin D was unable to induce apoptosis in the topoisomerase-II-deficient HL-60/MX2 cells, indicating that the induction of apoptosis by riccardin D was due to the inhibition of topo II activity. In addition, riccardin D was able to significantly decrease P-glycoprotein (P-gp) expression in K562/A02 cells. Taken together, our data demonstrate that riccardin D is a novel DNA topo II inhibitor which can induce apoptosis of human leukemia cells and that it has therapeutic potential for both regular and MDR strains of leukemia cells. PMID- 20924642 TI - Antiangiogenic properties of an unusual benzo[k,l]xanthene lignan derived from CAPE (caffeic acid phenethyl ester). AB - Angiogenesis is normally a highly regulated process that occurs during development, reproduction, and wound repair. However, angiogenesis can also become a fundamental pathogenic process in cancer and several other diseases. To date, the synthesis of angiogenesis inhibitors has been researched in several ways also starting from bioactive plant compounds. In the present study, we tested both in an angiogenesis bioassay and in ovarian cell culture, the potential antiangiogenic effect of a natural-derived benzo[k,l]xanthene lignan (5). This unusual compound was synthesized through the biomimetic dimerization of CAPE (caffeic acid phenethyl ester), a bioactive component of honeybee propolis. The lignan showed a significant, dose-related inhibitory effect on new vessel growth in the angiogenesis bioassay and it inhibited Vascular Endothelial Growth Factor secretion in ovarian cell culture. Therefore, we indicate the natural derived benzo[k,l]xanthene lignan 5 as a potential new angiogenesis inhibitor. PMID- 20924643 TI - Frequency and management of troponin I elevation in patients treated with molecular targeted therapies in phase I trials. AB - BACKGROUND: Cardiotoxicity of molecular targeted therapies (MTT) is poorly understood and is being investigated among patients with metastatic solid tumours. The frequency of cardiac events among patients receiving MTT has been evaluated in various ways, particularly troponin elevations. PATIENTS AND METHODS: We prospectively evaluated cardiotoxicity among patients included in Phase 1 trials receiving molecular targeted therapies (MTT) for a metastatic solid tumour. At baseline, all patients were examined before the first cycle and monitored including a clinical examination, ECG and troponin I measurement. A trans-thoracic echocardiography was performed at baseline and before each cycle. Patients were enrolled in different trials investigating : an anti-VEGF monoclonal antibody, anti-VEGFR tyrosine kinase inhibitors, and a kinesin inhibitor. RESULTS: Among the 90 patients evaluated, 10 (11%) experienced chest pain and troponin I elevation (n = 2,20%) or asymptomatic troponin I elevation (n = 8, 80%) during follow-up. All patients were re-evaluated at the time of symptoms or troponin I elevation with trans-thoracic echocardiography, cardiac magnetic resonance and coronary angiography. All except one patient, had a normal LVEF during their re-evaluation. One patient exhibited ECG changes (T wave inversion). No QTc interval prolongation was found. On cardiac magnetic resonance, no late gadolinium myocardial enhancement was observed. All coronary angiographies were normal (no occlusion, or coronary stenosis >50%). All patients received beta blockers and aspirin. All Patients were re-challenged with the study drug and no cardiotoxicity was observed during follow up. CONCLUSION: Troponin elevations are frequent among patients receiving molecular targeted therapies. Re-challenging these patients after a careful evaluation and under medical treatment seems to be possible. The mechanism underlying troponin elevations does not seem to be associated with coronary occlusion nor with toxic myocarditis. PMID- 20924645 TI - Epidemiology and sociodemographic aspects of ocular traumatic injuries in Iran. AB - Although the incidence of ocular trauma has been clearly described in developed countries, few published data are available on the epidemiology and the effects of parameters that can influence the incidence and severity of ocular injuries in Iran. The present study tried to determine epidemiological aspects of ocular traumatic injuries and evaluate their effects on different types of ocular injury. The case series included 1950 consecutive patients with acute ophthalmic trauma presented to the emergency ward of Farabi Hospital in Tehran. Information was collected by interviewing patients and having them fill in a questionnaire. The final diagnosis was made by a medical resident. If there was a difficulty or doubt in diagnosis or classification, confirmation of diagnosis was made by senior faculty. Ocular injuries were classified into globe and non-globe injuries according to the site of injury. Mechanical globe injuries were classified according to Birmingham Eye Trauma Terminology (BETT) into closed and open injuries. The mean age of patients was 28.8 +/- 12.8 years; 87.6% were male. The most common causes of injury were work-related (49.0%) and chance events (42.0%). The most frequent ocular injury was globe injury (95.6%), including mechanical (77.6% closed and 5.9% open), chemical (7.6%), photic (2.3%) and thermal (2.2%) injuries. Non-globe injury also occurred in 10.8% of patients; both globe and non globe injuries occurred in 6.5% of patients. The hospitalization rate in all patients was 8.8%. Previous history of eye trauma was significantly more common in the group with isolated globe injuries (P < 0.001). History of eye trauma is a risk factor for globe injuries and female gender is a risk factor only for non globe injuries. These two factors may predict future eye injury and increase its risk by 5.2 and 1.6 times, respectively. PMID- 20924644 TI - Combining functional imaging and interstitial pressure measurements to evaluate two anti-angiogenic treatments. AB - BACKGROUND: Interstitial hypertension is responsible for poor capillary blood flow and hampered drug delivery. The efficacy of combined sorafenib/bevacizumab treatment given according to different administration schedules has been evaluated by measuring both interstitial pressure (IP) and quantitative dynamic contrast-enhanced ultrasonography (DCE-US) parameters in melanoma-bearing mice. MATERIAL AND METHODS: [corrected] Sixty mice were xenografted with B16F10 melanoma. Animals received a daily administration over 4 days (D0 to D3) of either sorafenib at 30 mg/kg, bevacizumab at 2.5 mg/kg alone, or different schedules of combined treatments. Perfusion parameters determined using an Aplio(r) sonograph (Toshiba) with SonoVue(r) contrast agent (Bracco) were compared to IP measurements using fiberoptic probes (Samba(r)) at D0, D2, D4, D8. RESULTS: The mean baseline IP values ranged between 6.55 and 31.29 mmHg in all the groups. A transient IP decrease occurred at D2 in all treated groups, and especially in the concomitant group which exhibited a significant IP reduction compared to D0. A significant decrease in both the peak intensity and the area under the curve was observed at D4 in the group with concomitant administration of both molecules which yielded maximal inhibition of the tumor volume and the number of vessels. No correlation was found between IP values and volume or perfusion parameters, indicating complex relationships between IP and vascularization. No IP gradients were found between the center and the periphery but IP values in these two regions were significantly correlated (R = 0.93). CONCLUSION: The results suggest that IP variations could be predictive of vascular changes and that one single IP measurement is sufficient to fully characterize the whole tumor. PMID- 20924646 TI - The distribution of visual field defects per quadrant in standard automated perimetry as compared to frequency doubling technology perimetry. AB - To test the ability of frequency doubling technology (FDT) perimetry to reveal defects in the same field quadrants as detected by standard automated perimetry (SAP). Ninety-two eyes with open-angle glaucoma and documented visual field defects by threshold SAP (Octopus Dynamic strategy) also underwent threshold FDT testing after successfully passing the FDT screening test. All eyes revealed varying stages of SAP defects while only 80 revealed FDT damage: 31:21 eyes in the early field loss stage, 36:35 in the moderate field loss stage, and 25:24 in the severe field loss stage in SAP versus FDT, respectively. SAP was able to detect abnormalities in 74 and 79% of the superotemporal, and inferotemporal quadrants, respectively, while the corresponding FDT figures were 70 and 69% for the same quadrants (P < 0.05 each). With regards to the nasal hemifield, SAP detected defects in 73 and 81% of the superonasal and inferonasal quadrants, respectively, compared to 69 and 66% for FDT (P < 0.001 each). The test duration per individual eye was significantly shorter with FDT than with SAP (P < 0.05). As well as the already established lower sensitivity of FDT compared to SAP, this study also demonstrated the significantly poorer ability of FDT in detecting the same field quadrant defects, especially in the early stages of glaucomatous damage. PMID- 20924647 TI - Signal enhancement in protein NMR using the spin-noise tuning optimum. AB - We have assessed the potential of an alternative probe tuning strategy based on the spin-noise response for application in common high-resolution multi dimensional biomolecular NMR experiments with water signal suppression on aqueous and salty samples. The method requires the adjustment of the optimal tuning condition, which may be offset by several 100 kHz from the conventional tuning settings using the noise response of the water protons as an indicator. Although the radio frequency-pulse durations are typically longer under such conditions, signal-to-noise gains of up to 22% were achieved. At salt concentrations up to 100 mM a substantial sensitivity gain was observed. PMID- 20924648 TI - Role of OsNPR1 in rice defense program as revealed by genome-wide expression analysis. AB - NPR1 is a central regulator of salicylic-acid (SA)-mediated defense signaling in Arabidopsis. Here, we report the characterization of OsNPR1, an Oryzae sativa (rice) ortholog of NPR1, focusing on its role in blast disease resistance and identification of OsNPR1-regulated genes. Blast resistance tests using OsNPR1 knockdown and overexpressing rice lines demonstrated the essential role of OsNPR1 in benzothiadiazole (BTH)-induced blast resistance. Genome-wide transcript profiling using OsNPR1-knockdown lines revealed that 358 genes out of 1,228 BTH upregulated genes and 724 genes out of 1,069 BTH-downregulated genes were OsNPR1 dependent with respect to BTH responsiveness, thereby indicating that OsNPR1 plays a more vital role in gene downregulation. The OsNPR1-dependently downregulated genes included many of those involved in photosynthesis and in chloroplast translation and transcription. Reduction of photosynthetic activity after BTH treatment and its negation by OsNPR1 knockdown were indeed reflected in the changes in Fv/Fm values in leaves. These results imply the role of OsNPR1 in the reallocation of energy and resources during defense responses. We also examined the OsNPR1-dependence of SA-mediated suppression of ABA-induced genes. PMID- 20924649 TI - Biodegradation of 4-chlorobenzoic acid by Pseudomonas aeruginosa PA01 NC. AB - A bacterial consortium capable of degrading chloroaromatic compounds was isolated from pulp and paper mill effluents by selective enrichment on 4-chlorobenzoic acid as sole source of carbon and energy. The four different bacterial isolates obtained from bacterial consortium were identified as Pseudomonas aeruginosa AY792969 (A), P. aeruginosa PA01 NC (B), Pseudomonas sp. ZZ5 DQ113452 (C) and Pseudomonas sp. AY762360 (D) based on their morphological and biochemical characteristics and by phylogenetic analysis based on 16S rRNA gene sequences. These bacterial isolates were found to be versatile in degrading a variety of chloroaromatic compounds including fluoro- and iodobenzoic acids. P. aeruginosa PA01 NC utilized 4-chlorobenzoic acid at 2 g/l as growth substrate. Biodegradation studies have revealed that this organism degraded 4-chlorobenzoic acid through 4-chlorocatechol which was further metabolized by ortho-cleavage pathway and the dechlorination occurred after the ring-cleavage. PMID- 20924651 TI - The alpha-isoform of class II phosphoinositide 3-kinase is necessary for the activation of ERK but not Akt/PKB. AB - Phosphoinositide 3-kinases (PI3Ks) are key enzymes that activate intracellular signaling molecules when a number of different growth factors bind to cell surface receptors. PI3Ks are divided into three classes (I, II, III), and enzymes of each class have different tissue specificities and physiological functions. The alpha-isoform (PI3K-C2alpha) of class II PI3Ks is considered ubiquitous and preferentially activated by insulin. Our previous study showed that suppression of PI3K-C2alpha leads to apoptotic cell death. The aim of this study is to determine whether depletion of PI3K-C2alpha affects ERK or PKB/Akt activity following stimulation with serum and insulin growth factors in Chinese hamster ovary cells expressing human insulin receptors (CHO-IR) and human HepG2 liver cells. Different antisense oligonucleotides (ODNs), which were designed based on the sequence of the C2 domain of the human PI3K-C2alpha gene, were transfected into cells to inhibit PI3K-C2alpha expression. Insulin- or serum-induced stimulation of ERK was significantly suppressed by depletion of PI3K-C2alpha, whereas phosphorylation of IRS-1 and the stimulation of PKB/Akt by insulin were not affected. The number of apoptotic cells was also increased by depletion of PI3K-C2alpha protein levels. Taken together, our data indicate that PI3K-C2alpha may be a crucial factor in the stimulation of ERK activity in response to serum or insulin, whereas it is less important for the stimulation of PKB/Akt activity in response to insulin. PMID- 20924650 TI - Functional genomics of tumor suppressor miR-196b in T-cell acute lymphoblastic leukemia. AB - Huge data accumulated in last few years have shown that differential expression of candidate miRNAs in normal versus transformed cell provides important insights into the pathogenesis of cancer including leukemias. In our previous report, we have revealed that miR-196b was significantly down-regulated in both EB-3 cells as well as B-cell ALL (acute lymphoblastic leukemia) patients as compared to their respective controls. We have unambiguously proven that miR-196b restoration in EB-3 cells leads to significant down-regulation of c-myc and its effector genes, i.e., human telomerase reverse transcriptase (hTERT), B-cell lymphoma/leukemia-2 (Bcl-2), apoptosis antagonizing transcription factor (AATF), and qualifies for tumor suppressor function in B-cell ALL. Keeping in view these results, the present study was aimed at dissecting the role of miR-196b and other miRNAs present near/within the genomic regions involved in genetic translocations characteristic of ALL in T-cell ALL cell lines and patient samples. We have demonstrated significant down-regulation in the expression of miR-196b in MOLT-4 and T-cell ALL patients with respect to the respective control cells. Transfection experiments revealed that none of the six identified miRNAs were able to knock down the expression of c-myc gene. Interestingly, it was found that miR-196b loses its ability to down-regulate c-myc gene expression in T-cell ALL as a consequence of mutations in target 3'-untranslated region (3'-UTR) of the c myc gene. Results of the present study revealed that miR-196b becomes non functional in T-cell ALL as a consequence of mutations in 3'-UTR of c-myc gene in T-cell ALL cellular models. PMID- 20924652 TI - Shotgun proteomic analysis of Emiliania huxleyi, a marine phytoplankton species of major biogeochemical importance. AB - Emiliania huxleyi is a unicellular marine phytoplankton species known to play a significant role in global biogeochemistry. Through the dual roles of photosynthesis and production of calcium carbonate (calcification), carbon is transferred from the atmosphere to ocean sediments. Almost nothing is known about the molecular mechanisms that control calcification, a process that is tightly regulated within the cell. To initiate proteomic studies on this important and phylogenetically remote organism, we have devised efficient protein extraction protocols and developed a bioinformatics pipeline that allows the statistically robust assignment of proteins from MS/MS data using preexisting EST sequences. The bioinformatics tool, termed BUDAPEST (Bioinformatics Utility for Data Analysis of Proteomics using ESTs), is fully automated and was used to search against data generated from three strains. BUDAPEST increased the number of identifications over standard protein database searches from 37 to 99 proteins when data were amalgamated. Proteins involved in diverse cellular processes were uncovered. For example, experimental evidence was obtained for a novel type I polyketide synthase and for various photosystem components. The proteomic and bioinformatic approaches developed in this study are of wider applicability, particularly to the oceanographic community where genomic sequence data for species of interest are currently scarce. PMID- 20924654 TI - A syrphid fly uses olfactory cues to find a non-yellow flower. AB - Syrphid flies are frequent flower visitors, but little is known about the cues they use to find flowers. We determined the importance of visual and olfactory cues in a flight cage bioassay using Cirsium arvense (Asteraceae) flower heads and experienced Episyrphus balteatus (Diptera, Syrphidae). We tested the response of antennae of the flies to headspace inflorescence scent samples by using gas chromatography coupled to electroantennography (GC-EAD). The bioassays revealed that both sexes of experienced flies rely on olfactory, not visual, cues to find C. arvense flower heads. The GC-EAD measurements demonstrated that male and female flies have olfactory receptors for several of the compounds emitted by the inflorescences. These electroantennographic-active compounds may be responsible for the attraction of flies to the C. arvense flower heads. Among the compounds eliciting an antennal response are methyl salicylate and 2-phenylethanol, which were previously described as syrphid attractants. Overall, our study demonstrates for the first time that a syrphid fly uses olfactory and not visual cues to find a pollen/nectar host-plant. PMID- 20924653 TI - In vivo methods to study uptake of nanoparticles into the brain. AB - Several in vivo techniques have been developed to study and measure the uptake of CNS compounds into the brain. With these techniques, various parameters can be determined after drug administration, including the blood-to-brain influx constant (K(in)), the permeability-surface area (PS) product, and the brain uptake index (BUI). These techniques have been mostly used for drugs that are expected to enter the brain via transmembrane diffusion or by carrier-mediated transcytosis. Drugs that have limitations in entering the brain via such pathways have been encapsulated in nanoparticles (based on lipids or synthetic polymers) to enhance brain uptake. Nanoparticles are different from CNS compounds in size, composition and uptake mechanisms. This has led to different methods and approaches to study brain uptake in vivo. Here we discuss the techniques generally used to measure nanoparticle uptake in addition to the techniques used for CNS compounds. Techniques include visualization methods, behavioral tests, and quantitative methods. PMID- 20924655 TI - Psychometric evaluation of the Problem Gambling Severity Index-Chinese version (PGSI-C). AB - The purpose of this study was to examine the psychometric properties of the Chinese 9-item Problem Gambling Severity Index (PGSI) derived from the 31-item Canadian Problem Gambling Index (CPGI) originally developed by Ferris and Wynne (2001). Exploratory factor analysis (EFA; n = 386; Group A data) and confirmatory factor analysis (CFA; n = 387; Group B data) on the Chinese student and community data (Mean age = 25.36 years) showed that a unifactorial model fitted the data with good reliability score (Cronbach's alpha = 0.77). The concurrent validity of the PGSI-C was good in terms of the Chinese data matching the expected correlation between PGSI-C and other variables or scales such as SOGS, gambling frequency, gambling urge, gambling cognitions, depression, anxiety, and stress. The scale also reported good discriminant and predictive validity. In sum, the PGSI-C has good psychometric properties and can be used among Chinese communities to identify at-risk problem gamblers. Implications and suggestions for future research are discussed. PMID- 20924656 TI - A comprehensive investigation on the cooperative branch effect on the optical properties of novel conjugated compounds. AB - This paper presents a variety of conjugated derivatives with different number of arms (4-styryl-triphenylamine: C1, 4,4'-di-styryltriphenylamine: C2, 4,4',4"-tri styryltriphenylamine: C3). The linear absorption and fluorescence maxima and the molar extinction coefficients are in the order of C1= 45 years, 277 developed epithelial ovarian cancer between 1995 and 2007. Multivariate Cox regression was performed. RESULTS: Among women who never used HT, greater adult weight gain, waist circumference and waist to-height ratio, but not adult BMI, increased risk of ovarian cancer. Compared to women who never used HT and had a stable adult weight, risk of ovarian cancer was increased in women who gained >= 40 lb (relative risk (RR) 1.8, 95% confidence interval (CI): 1.0-3.0) or used HT for >5 years (RR 2.3 95% CI: 1.3-4.1). Having both exposures (RR 1.9, 95% CI: 0.99-3.5), however, did not increase risk more than having either alone. Results were similar for waist circumference and weight to-height ratio; however, differences across HT groups were not statistically significant. CONCLUSIONS: This study suggests that abdominal adiposity and weight gain, but not overall obesity, increase ovarian cancer risk and that there may be a threshold level beyond which additional hormones, whether exogenous or endogenous, do not result in additional elevation in risk. However, large pooled analyses are needed to confirm these findings. PMID- 20924665 TI - Fertilization outcome, embryo development and birth after unstimulated IVM. AB - BACKGROUND/PURPOSES: A common observation in oocyte in vitro maturation (IVM) cycles is poor embryo quality. However, no study was dedicated to assess zygote and early cleavage embryo quality in IVM cycles. The objective of this study is to analyze fertilization outcome, embryo development and the resulting pregnancy and births in unstimulated IVM cycles. METHODS: IVM oocytes were collected 36 h post hCG and matured in vitro for 28-30 h. All oocytes were inseminated by ICSI. Resulting zygotes and embryos were assessed on day-1, 2 and 3, when transfers were made. RESULTS: The overall oocyte maturation and fertilization rates were 63% and 62%, respectively. Abnormal fertilization rate was 27%. [corrected] Ninety five and 14.6% of the 2Pn zygotes reached the 2-cell and 8-cell stage at day-2 and day-3, respectively. Embryo quality assessment on day-3 at transfer revealed that only 9% of the embryos were of very good quality. Most embryos showed developmental delay. An average of 3.29 embryos were transferred per patient resulting in implantation and clinical gestation rates of 16% and 32%, respectively. Overall 14 healthy babies were born and there is one ongoing pregnancy. CONCLUSION: Results show a significant rate of abnormal fertilization and poor embryo quality after IVM, which is reflected in a higher than average number of embryos being transferred. However, pregnancy, implantation and birth rates are reasonably high and allow us to consider IVM a valuable approach for the treatment of infertility in PCO or PCOS patients. PMID- 20924666 TI - Life cycle assessment (LCA) of solid waste management strategies in Tehran: landfill and composting plus landfill. AB - As circumstances of operating and maintenance activities for landfilling and composting in Tehran metropolis differ from those of cities in developed countries, it was concluded to have an environmental impact comparison between the current solid waste management (MSW) strategies: (1) landfill, and (2) composting plus landfill. Life cycle assessment (LCA) was used to compare these scenarios for MSW in Tehran, Iran. The Eco-Indicator 99 is applied as an impact assessment method considering surplus energy, climate change, acidification, respiratory effect, carcinogenesis, ecotoxicity and ozone layer depletion points of aspects. One ton of municipal solid waste of Tehran was selected as the functional unit. According to the comparisons, the composting plus landfill scenario causes less damage to human health in comparison to landfill scenario. However, its damages to both mineral and fossil resources as well as ecosystem quality are higher than the landfill scenario. Thus, the composting plus landfill scenario had a higher environmental impact than landfill scenario. However, an integrated waste management will ultimately be the most efficient approach in terms of both environmental and economic benefits. In this paper, a cost evaluation shows that the unit cost per ton of waste for the scenarios is 15.28 and 26.40 US$, respectively. Results show landfill scenario as the preferable option both in environmental and economic aspects for Tehran in the current situation. PMID- 20924667 TI - Pharmacologic modulation of parasympathetic activity in heart failure. AB - In the congestive heart failure state, autonomic dysregulation involves an increase in sympathetic tone and decrease in parasympathetic tone and is associated with increased mortality. It is possible that augmentation of the parasympathetic nervous system (PNS) with pharmacologic therapy may lead to improved symptoms and/or clinical outcomes. There are several new and established pharmacologic interventions that have been studied for their effect on the PNS, including antagonists of the renin-angiotensin system, beta-adrenergic antagonists, digoxin, and vasodilators. In this review, we discuss the current status of the published literature on pharmacologic influences on the PNS by both conventional and experimental drugs targeting heart failure as well as drugs that more directly influence vagal tone. While these analyses have been largely limited to putative surrogates for clinical outcomes like heart rate variability, and it is often difficult to differentiate between indirect and direct pharmacologic effects on the PNS, significant insight into potential mechanisms of action can be derived. The future evaluation of drugs in development for heart failure treatment should include a careful, scientifically sound exploration of the potential impact of the intervention on PNS activity. PMID- 20924668 TI - A comparative study on the composition and importance of free amino acids in semen of gilthead sea bream, Sparus aurata, and perch, Perca fluviatilis. AB - A comparative study was conducted on the free amino acid composition of gilthead sea bream, Sparus aurata, and perch, Perca fluviatilis. Also the effect of 21 free amino acids on sperm motility was investigated. Spermatozoa were incubated in species-specific motility-inhibiting saline solution containing the different amino acids for 48 h. Thereafter, the motility was activated and investigated using computer-assisted cell motility analysis. Twelve free amino acids, respectively, were detected in S. aurata and P. fluviatilis semen. Arginine, cysteine, glutamic acid, leucine, and methionine occurred in semen of both species. In S. aurata, arginine, glycine, hydroxyproline, lysine, and phenylalanine in concentrations of 1.25 and 2.50 mmol/l, methionine in a concentration of 2.5 mmol/l, and serine in a concentration of 1.25 mmol/l had a positive effect on the motility of spermatozoa. In P. fluviatilis, alanine, asparagine, cysteine, glycine, isoleucine, lysine, methionine, serine, threonine, and valine in concentrations of 2.50 mmol/l positively affected motility. From these data, it can be concluded that the amino acid composition and the effect on motility are species specific. Possible consequences for spermatozoa functionality are discussed. PMID- 20924669 TI - Physiological stress and innate immune response in gilthead sea bream (Sparus aurata) and sea bass (Dicentrarchus labrax) exposed to combination of trimethoprim and sulfamethoxazole (TMP-SMX). AB - The purpose of this study was to determine whether gilthead sea bream and sea bass treated with combination of trimethoprim and sulfamethoxazole (TMP-SMX) differed in terms of physiological and innate immune biomarkers. Fish were exposed to TMP-SMX at 40 ppm concentration for 1 h as a prophylactic usage. Plasma cortisol, glucose, electrolytes (Ca, P, Na, K, Cl, and Mg) as well as plasma lysozyme activity, C-reactive protein (CRP), and ceruloplasmin (Cp) were measured soon after treatment and following 24 and 48 h in normal sea water for recovery. Treatment with TMP-SMX in both gilthead sea bream and sea bass led to an increase in plasma cortisol and glucose. Fluctuations in some electrolytes were found after treatment and during recovery period, however, the ratios of monovalent ions in treated sea bream were similar to control. Hematocrit values as well as plasma lysozyme activity in gilthead sea bream and sea bass were not affected by the treatment. CRP in gilthead sea bream and Cp in sea bass responded to the treatment with decreased levels. Both gilthead sea bream and sea bass displayed a rapid physiological stress response and sensitivity to TMP-SMX exposure, which requires more than 48-h period for regaining homeostasis. PMID- 20924671 TI - Systemic gene delivery protects the photoreceptors in the retinal degeneration slow mouse. AB - The retinal degeneration slow (rds/rds) mouse was used to test photoreceptor protection by systemic gene delivery of non-erythropoietic forms of erythropoietin (EPO). Two Epo mutants were generated and packaged into recombinant adeno-associated virus (rAAV) serotype 2/5, controls included rAAV2/5.Epo and rAAV2/5.enhanced green fluorescent protein (eGFP). Mice were injected in the quadriceps at postnatal day seven and analyses were performed at postnatal day 90. Hematocrit, serum EPO levels, and outer nuclear layer (ONL) thickness were quantified. Hematocrit and serum EPO levels in rAAV2/5.eGFP, rAAV2/5.Epo, and rAAV2/5.EpoR103E treated mice were: 46%, 8 mU/ml; 63%, 117 mU/ml; and 52%, 332 mU/ml, respectively. The ONL from rds/rds mice treated with the Epo vectors were approximately twice as thick as the negative controls. This demonstrates that the photoreceptors can be protected without performing an intraocular injection and without increasing the hematocrit to unsafe levels. Intramuscular delivery of rAAV.EpoR103E is an attractive treatment for retinal degenerative diseases. PMID- 20924670 TI - The chronological characteristics of SOD1 activity and inflammatory response in the hippocampi of STZ-induced type 1 diabetic rats. AB - Because it appears that oxidative stress and inflammation are implicated with disease pathogenesis in the diabetic brain, many researchers have used streptozotocin (STZ)-induced diabetic animals to study superoxide production and the effects of superoxide scavengers like Cu,Zn-superoxide dismutase (SOD1). However, many studies have been conducted without considering temporal changes after STZ injection. Interestingly, though SOD activities were not significantly different among the groups, SOD1 and 4-hydroxy-2-nonenal (4-HNE) immunoreactivities were significantly enhanced at 3 weeks after an STZ injection (STZ3w) versus only marginal levels in sham controls, whereas microglial activity was remarkably reduced in injected rats at this time. However, SOD1 immunoreactivity and microglial activities were only at the sham level at STZ4w. The present study provides important information concerning cell damage by ROS generated by STZ. Microglial response was found to be inactivated at STZ3w and neuronal cells (NeuN) showed a non-significant tendency to be reduced in number at STZ4w except in the dentate gyrus. We speculated that the above oxidative stress-related events should be accomplished at STZ3w in the brains of STZ induced diabetes animal models. Therefore, the aim of the present study was to investigate chronological changes in SOD1 immunoreactivity associated with lipid peroxidation and inflammatory responses in the hippocampi of STZ-induced type I diabetic rats. PMID- 20924672 TI - Encapsulating peritoneal sclerosis: a single-center experience and review of the literature. AB - Encapsulating peritoneal sclerosis (EPS) is a serious and often fatal complication of long-term PD with severe malnutrition and poor prognosis. It causes progressive obstruction and encapsulation of the bowel. This retrospective study reviews our experience and that reviewed in the literature concerning EPS. It refers to a total of 1966 patients treated with chronic PD between 1974 and 2008. Twenty one of them (1.1%) developed EPS, with the incidence increasing with the duration of PD. Mean age of our patients with EPS was 43, ranging from 18 to 71 years, 8 were men and 13 women with a mean body mass index (BMI) of 21.6 kg/m(2). Only one patient had Type II diabetes, 15 patients had glomerular disease, and six of these 15 had an autoimmune disease such as Wegener's granulomatosis and SLE. Thirteen patients developed EPS while on PD, 7 within 2 years after transfer to HD, and only one after renal transplantation. However, 7 patients had a previous renal transplant before returning to PD and subsequently developing EPS. Interestingly, we did not observe more episodes of EPS after transplantation. In the patients who developed EPS, the peritonitis rate over the period of observation was 1/15.6 pt-months and was due to Staphylococcus aureus, coagulase-negative staphylococcus, Pseudomonas and fungi. A history of peritonitis was not a prerequisite for developing EPS, since one patient had no episodes of peritonitis and 4 had just one previous episode. Fifteen patients presented with peritonitis within 4 months before the diagnosis of EPS with particularly virulent micro-organisms such as S. aureus, Candida, Pseudomonas, Corynebacterium, and Peptostreptococcus. Eleven patients were treated with hypertonic dextrose solutions (4.25 g/dl of dextrose) and seven with icodextrin, indirectly suggesting problems with ultrafiltration. Nine of 21 patients were on beta-blockers. The diagnosis of EPS was made either surgically or radiologically with signs of small bowel obstruction in combination with severe malnutrition. Eleven of our patients (52%) had evidence of small bowel obstruction and 14 patients required total parenteral nutrition (TPN). Tamoxifen (10-20 mg daily) was started in 6 patients, 4 of whom are alive and 2 deceased 3 and 5 years after EPS was diagnosed. Of the 12 patients who were not given tamoxifen, 2 are alive and 10 died. No side effects of tamoxifen were reported. Only 7 of our patients (33%) died during the first year after the diagnosis of EPS. Currently, 4 patients are on HD and 3 have had a renal transplant. Six patients of the fourteen who underwent surgery (42.8%) died within the first 6 months after operation and five died after an average of 6.6 years, mostly due to cardiovascular causes, three are still alive. As EPS becomes more prevalent with longer duration of PD, large multicenter prospective studies are needed to establish its incidence and identify risk factors, therapeutic approach, and prognosis. PMID- 20924673 TI - Presence of age-associated low-grade inflammation does not worsen the body response to bacterial infection in old male rats. AB - In the field of frailty, there is an underlying hypothesis that chronic low-grade inflammation contributes to bad outcomes in response to a stressor. The host response to an Escherichia coli infection was assessed in 24 month old male rats exhibiting a chronic low-grade inflammation and in non-inflamed control rats. Mortality, weight loss and sarcopenia were the main outcomes measured. The presence of chronic low-grade inflammation did not affect post-infection mortality, body weight loss and tissue mass decreases. Infection-induced modifications of plasma acute phase proteins concentrations were not higher in low-grade inflamed than non-inflamed rats. Absolute synthesis rates of tissue proteins were independent of the initial inflammatory status, except for liver 10 days after infection. Altogether, age-associated chronic low-grade inflammation in male rats did not worsen the body response to bacterial infection. These results suggest that chronic low-grade inflammation is not an aggravating factor of the spiraling process leading to frailty. PMID- 20924674 TI - Past, present and future research directions with Pichia anomala. AB - The first International Pichia anomala Symposium provided a survey of past, recent and ongoing research on this yeast. The research community working with this yeast has focussed on several areas. Based on molecular data, a revision of the taxonomy is required: the name P. anomala is no longer applicable, as the genus Pichia is polyphyletic. The current debate centres on whether the yeast should be designated as Wickerhamomyces anomalus or if the previous name, Hansenula anomala, should be re-instated. The anti-microbial activities of this yeast received considerable attention during the symposium. H. anomala has been extensively studied as a biopreservation agent in many different post-harvest systems. Several mechanisms account for its anti-microbial activities, including the production of killer proteins and toxic volatile metabolites. Anti-idiotypic antibodies generating an "internal image" of a killer protein have been found to possess therapeutic activity against a broad range of microorganisms. A great diversity of H. anomala strains was reported at the symposium. Strains have been isolated from several food and feed systems and even from the intestine and reproductive organs of a malaria vector (Anopheles stephensi). Feed and food supplemented with certain H. anomala strains show an improved quality due, for example, to the addition of advantageous proteins and phytase activity. However, a number of apparent opportunistic pathogenic strains have also been isolated. Strain differentiation, especially the recognition of potentially pathogenic isolates, is an important challenge for the future commercialisation of this yeast. Future industrial and agricultural application of this yeast also raises questions of the economics of large-scale production, its survival during storage (formulation) and of safety regulations, all of which require further investigation. PMID- 20924675 TI - Intravenous immunoglobulin for the treatment of Clostridium difficile infection: a review. AB - Clostridium difficile infection (CDI) has increased sharply in incidence, mortality rate, and burden on the healthcare system over the past decade. Therefore, novel treatment modalities have been developed, including intravenous immunoglobulin (IVIG). The level of immune response to Clostridium difficile colonization is the major determinant of the magnitude and duration of clinical manifestations. This effect is mediated predominantly by serum IgG anti-toxin A antibodies. Based on this finding, anti-toxin A and B antibodies were successfully used in multiple in vitro and in vivo experimental settings to passively immunize hamsters in CDI models. In humans, IVIG was used as the source of those antibodies. Fifteen small, mostly retrospective and non-randomized reports documented IVIG's success in the treatment of protracted, recurrent, or severe CDI. Diarrhea resolution rates were higher in the former patient group, but the recurrence rates were similar. IVIG mechanism of action is neutralization of mainly toxin A through IgG anti-toxin A antibodies. Purified anti-toxin A and B antibodies were successfully used to decrease CDI recurrence rates among patients with no or one previous CDI episodes. In conclusion, the efficacy of IVIG for CDI treatment in animal models has been convincingly demonstrated. However, only few small non-randomized, mostly uncontrolled reports have been published on human subjects. A phase II trial results support the use of purified anti-toxin A and B antibodies to decrease CDI recurrence rates. Therefore, IVIG should currently only be used as adjunct therapy until results from large, randomized controlled trials are available. PMID- 20924676 TI - "Patients don't lie"; a view on adherence in asthma. AB - OBJECTIVE: The primary objective of this article is to examine the extent of self reported non-adherence among patients participating in a controlled trial of an asthma compliance optimization intervention. The secondary objective is to introduce a two-question questionnaire that is, in wording and design, a neutral tool for disclosure of non-adherence behaviour. METHOD: Data in this study was obtained as part of a controlled trial on an SMS monitoring and compliance intervention developed for Danish asthma patients. The trial was conducted from November 2007 to May 2008. A total of 244 patients participated in the study. Two new designed nonadherence questions were asked in immediate succession. This practice, along with the wording of the questions and use of the Web as medium, constitute a new approach to self-reported adherence assessment. RESULTS: A total of 43.9% of the participants in the trial reported non-adherence to the medical dosage regime for which they had, only one question earlier, documented their awareness. CONCLUSION: This illustrates that at least 43.9% of the participants in the trial dared to report nonadherence to asthma medication. PMID- 20924678 TI - A three-state mathematical model of hyperthermic cell death. AB - Thermal treatments for tissue ablation rely upon the heating of cells past a threshold beyond which the cells are considered destroyed, denatured, or killed. In this article, a novel three-state model for cell death is proposed where there exists a vulnerable state positioned between the alive and dead states used in a number of existing cell death models. Proposed rate coefficients include temperature dependence and the model is fitted to experimental data of heated co cultures of hepatocytes and lung fibroblasts with very small RMS error. The experimental data utilized include further reductions in cell viabilities over 24 and 48 h post-heating and these data are used to extend the three-state model to account for slow cell death. For the two cell lines employed in the experimental data, the three parameters for fast cell death appear to be linearly increasing with % content of lung fibroblast, while the sparse nature of the data did not indicate any co-culture make-up dependence for the parameters for slow cell death. A critical post-heating cell viability threshold is proposed beyond which cells progress to death; and these results are of practical importance with potential for more accurate prediction of cell death. PMID- 20924677 TI - Generic and therapeutic substitutions: are they always ethical in their own terms? AB - Cost containment-driven drug substitution, whether generic or therapeutic, is defined as switching to another drug because it is cheaper. So far, such substitutions have drawn their public legitimacy from the general belief that they would not compromise the clinical interests of patients and certainly not violate their right to decline them if they did. This article does not enter the debate on whether or not such substitutions must give exclusive priority to the patient's interests and choices in order to be ethical. Indeed, it acknowledges the plurality of views on this matter. It simply argues that when such substitutions involve a cheaper drug that is known to have different effects and side effects, or even a drug whose effects and side effects are unknown, they are potentially deleterious to the patient, and that no competent and well-informed patient would ever consent to them. Such substitutions are thus unethical in their very own terms. PMID- 20924679 TI - Acoustic microscopy analyses to determine good vs. failed tissue engineered oral mucosa under normal or thermally stressed culture conditions. AB - This study uses scanning acoustic microscopy (SAM) ultrasonic profilometry to determine acceptable vs. failed tissue engineered oral mucosa. Specifically, ex vivo-produced oral mucosal equivalents (EVPOMEs) under normal or thermally stressed culture conditions were scanned with the SAM operator blinded to the culture conditions. As seeded cells proliferate, they fill in and smooth out the surface irregularities; they then stratify and produce a keratinized protective upper layer. Some of these transformations could alter backscatter of ultrasonic signals and in the case of the thermally stressed cells, produce backscatter similar to an unseeded device. If non-invasive ultrasonic monitoring could be developed, then tissue cultivation could be adjusted to measure biological variations in the stratified surface. To create an EVPOME device, oral mucosa keratinocytes were seeded onto acellular cadaveric dermis. Two sets of EVPOMEs were cultured: one at physiological temperature 37 degrees C and the other at 43 degrees C. The specimens were imaged with SAM consisting of a single-element transducer: 61 MHz center frequency, 32 MHz bandwidth, 1.52 f#. Profilometry for the stressed and unseeded specimens showed higher surface irregularities compared to unstressed specimens. Elevated thermal stress retards cellular differentiation, increasing root mean square values; these results show that SAM can potentially monitor cell/tissue development. PMID- 20924680 TI - Spirituality and religiosity in urban adolescents with asthma. AB - Predictors of multiple dimensions of spirituality/religiosity (S/R) and adolescents' preferences for having S/R (e.g., prayer) addressed in hypothetical medical settings were assessed in a sample of urban adolescents with asthma. Of the 151 adolescents (mean age = 15.8, 60% female, 85% African-American), 81% said that they were religious and spiritual, 58% attended religious services in the past month, and 49% prayed daily. In multivariable models, African-American race/ethnicity and having a religious preference were associated with higher levels of S/R (R (2) = 0.07-0.25, P < .05). Adolescents' preferences for including S/R in the medical setting increased with the severity of the clinical situation (P < .05). PMID- 20924681 TI - The mortal soul in ancient Israel and Pauline Christianity: ramifications for modern medicine. PMID- 20924682 TI - Centering prayer as an alternative to mindfulness-based cognitive therapy for depression relapse prevention. AB - In the last two decades, mindfulness has made a significant impact on Western secular psychology, as evidenced by several new treatment approaches that utilize mindfulness practices to ameliorate mental illness. Based on Buddhist teachings, mindfulness offers individuals the ability to, among other things, decenter from their thoughts and live in the present moment. As an example, mindfulness-based cognitive therapy (MBCT) teaches decentering and mindfulness techniques to adults in an eight-session group therapy format so as to reduce the likelihood of depression relapse. Yet, some Christian adults may prefer to turn to their own religious heritage, rather than the Buddhist tradition, in order to stave off depression relapse. Thus, the purpose of this article is to present centering prayer, a form of Christian meditation that is rooted in Catholic mysticism, as an alternative treatment for preventing depression relapse in adults. I argue that centering prayer overlaps considerably with MBCT, which makes it a suitable treatment alternative for many Christians in remission from depressive episodes. PMID- 20924683 TI - Religion and spirituality in coping with advanced breast cancer: perspectives from Malaysian Muslim women. AB - This article is part of a larger study on the role of spirituality in coping with breast cancer among Malaysian Muslim women. The study seeks to reveal the meaning of the experience through the stories of three Muslim women surviving advanced breast cancer, to better understand the deep meanings that inform their experiences with spirituality and transformation as they cope with the challenges of breast cancer. Data were gathered using in-depth interview. Qualitative methods were used in identifying two themes--illness as an awakening and hope and freedom comes from surrendering to God. The themes were discussed in the context of two broad areas: (1) what are the new meanings these women discovered in their experiences with cancer; and (2) how did the new meanings change their lives? The study suggests that cancer survivors' experiences with cancer and their learning processes must be understood within the appropriate cultural context. This is especially so for spirituality. The common emphasis of spirituality on relationship with God, self and others, may significantly influence how people learn to live with cancer. PMID- 20924684 TI - Clinical, biochemical, and molecular analysis of combined methylmalonic acidemia and hyperhomocysteinemia (cblC type) in China. AB - The most common inborn error of cobalamin (cbl) metabolism in China is the cblC type characterized by combined methylmalonic acidemia and hyperhomocysteinemia. The clinical presentation is relatively nonspecific, such as feeding difficulty, recurrent vomiting, hypotonia, lethargy, seizures, progressive developmental delay, and mental retardation, together with anemia and metabolic acidosis. More specific biochemical findings include high levels of propionylcarnitine (C3), free carnitine (C3/C0), and acetylcarnitine (C3/C2) measured by tandem mass spectrometry (MS/MS), elevation of methylmalonic acid (MMA) measured by gas chromatography-mass spectrometry (GC-MS), and increased total homocysteine with normal or decreased methionine. We report on 50 Chinese patients with combined methylmalonic acidemia and hyperhomocysteinemia. Forty-six belonged to the cblC complementation group. Mutation analysis of the MMACHC gene was performed to characterize the mutational spectrum of cblC deficiency, and 17 different mutations were found. Most were clustered in exons 3 and 4, accounting for 91.3% of all mutant alleles. Two mutations were novel, namely, c.315 C>G (p.Y105X) and c.470 G>C(p.W157S). In terms of genotype-phenotype correlation, the c.609 G>A mutation was associated with early-onset disease when homozygous. Unlike previous reports from other populations, c.609 G>A (p.W203X) was the most frequent cblC mutation detected in our study of Chinese patients, affecting 51 of 92 MMACHC alleles (55.4%). The high prevalence of this nonsense mutation could have potential therapeutic significance for Chinese cblC patients. Besides traditional approaches consisting of hydroxocobalamin injections, carnitine, betaine, and protein restriction, novel drugs that target premature termination codons may have a role in the future. PMID- 20924685 TI - Enzyme replacement therapy for mucopolysaccharidosis VI--experience in Taiwan. AB - Information regarding the clinical outcome of enzyme replacement therapy (ERT) with recombinant human N-acetylgalactosamine 4-sulfatase (rhASB) for mucopolysaccharidosis (MPS) VI in Asian patients is limited. We reviewed nine Taiwanese patients with MPS VI (four males and five females; age range 1.4-21.1 years) treated with weekly intravenous infusions of rhASB (1.0 mg/kg) for at least 2 years. We assessed the biochemical and clinical response every 3 months. After 2 years of treatment, seven patients experienced improvement over baseline in the 6-min walk by a mean of 69.3 m (27.3%), and seven also increased the 3-min stair climb by a mean of 47 steps (35.7%). Shoulder range of motion in all patients improved, and Joint Pain and Stiffness Questionnaire scores improved by 0.597 points (30.5%). Four patients had improved pulmonary function [forced expiratory volume in 1 s increased by 0.130 L (26.3%) and forced vital capacity by 0.148 L (27.6%)]. The respiratory disturbance index decreased in the four patients who underwent polysomnography. A mean overall 51% decrease in urinary glycosaminoglycan excretion indicated a satisfactory biochemical response. ERT was well tolerated by all patients. This treatment is thus beneficial and appears to be safe for treatment of MPS VI in Taiwanese patients. PMID- 20924686 TI - Meningeal coccidioidomycosis diagnosed by real-time polymerase chain reaction analysis of cerebrospinal fluid. AB - We describe two cases of coccidioidal meningitis (CM) diagnosed using real-time polymerase chain reaction (PCR) analysis of cerebrospinal fluid. These cases highlight the promise of PCR as a diagnostic method to assist in the rapid diagnosis of CM. PMID- 20924687 TI - Children with Cushing's syndrome: Primary Pigmented Nodular Adrenocortical Disease should always be suspected. AB - Primary Pigmented Nodular Adrenocortical Disease (PPNAD) is a rare form of bilateral adrenocortical hyperplasia that is inherited in an autosomal dominant manner and leads to ACTH-independent Cushing's syndrome (CS). PPNAD may be isolated or associated with Carney Complex (CNC). For the diagnosis of PPNAD and CNC, in addition to the hormonal and imaging tests, searching for PRKAR1A mutations may be recommended. The aims of the present study are to discuss the clinical and molecular findings of two Brazilian patients with ACTH-independent CS due to PPNAD and to show the diagnostic challenge CS represents in childhood. Description of two patients with CS and the many sequential steps for the diagnosis of PPNAD is provided. Sequencing analysis of all coding exons of PRKAR1A in the blood, frozen adrenal nodules (patients 1 and 2) and testicular tumor (patient 1) is performed. After several clinical and laboratory drawbacks that misled the diagnostic investigation in both patients, the diagnosis of PPNAD was finally established and confirmed through pathology and molecular studies. In patient 1, sequencing of PRKAR1A gene revealed a novel heterozygous 10-bp deletion in exon 3, present in his blood, adrenal gland and testicular tumor. The etiologic diagnosis of endogenous CS in children is a challenge that requires expertise and a multidisciplinary collaboration for its prompt and correct management. Although rare, PPNAD should always be considered among the possible etiologies of CS, due to the high prevalence of this disease in this age group. PMID- 20924689 TI - [Beach promenade - beautiful beaches "the coast" considered with its tropical medical aspects]. PMID- 20924688 TI - Towards PET imaging of intact pancreatic beta cell mass: a transgenic strategy. AB - PURPOSE: We have generated transgenic mouse lines expressing the positron emission tomography (PET) reporter gene, sr39tk, under the control of the mouse insulin I promoter (MIP-sr39tk) to image endogenous islets using PET. PROCEDURES: The MIP-sr39tk transgene was constructed using the 8.3 kb fragment of the mouse insulin I promoter and the sr39tk coding sequence from the mrfp-hrl-ttk trifusion construct. Expression of sr39TK in beta cells was confirmed by fluorescence immunohistochemistry of pancreatic sections. Histological sections were used to determine beta cell mass, islet area and islet number. Beta cell function was determined using intraperitoneal glucose tolerance tests. For ex vivo biodistrubution, mice were injected i.v. with 9.25 MBq [(18)F]fluorohydroxymethyl butyl-guanine (FHBG), euthanized 1 h later and pancreata and other organs were collected and counted. For PET scans, mice were injected i.v. with 9.25 MBq [(18)F]FHBG, and dynamic scans were conducted for 1 h, followed by a 30 min static acquisition. To induce type 1 diabetes-like symptoms, MIP-sr39tk mice were injected i.p. with 40 mg/kg streptozotocin (STZ) once per day for five consecutive days, and biodistribution and PET scans were conducted thereafter. RESULTS: Ex vivo quantification of [(18)F]FHBG uptake in the pancreas showed a 4.5-fold difference in transgenic vs. non-transgenics, confirming that expression of sr39TK results in the retention of the PET tracer. In STZ-treated MIP-sr39tk mice, impairments in glucose tolerance and decreases in beta cell mass correlated significantly with a diminishment in [(18)F]FHBG uptake before fasting hyperglycemia became apparent. CONCLUSIONS: The MIP-sr39tk mouse demonstrates that PET imaging can detect changes in beta cell mass that precede the onset of diabetes. PMID- 20924690 TI - [Psychiatric manifestation of a dengue-encephalopathy]. AB - Psychiatric manifestation of dengue virus infections is seldom reported. Here a case is presented of a 21-year-old man who developed mainly neuropsychiatric symptoms which he caught one week after a feverish infection during his stay in India: troubles with concentration and memory, confusion, as well as depressive delusions and agoraphobia. Liquor diagnosis as well as CCT and MRI was mainly inconspicuous. The FDG-PET showed a diffuse lack of activity. IgM and IgG antibodies of dengue virus were positive. We interpreted these psychiatric symptoms as a result of a dengue virus infection. PMID- 20924691 TI - Pharmacodynamic interaction between lumefantrine and desbutyl-benflumetol in Plasmodium falciparum in vitro. AB - The pharmacodynamic interaction between lumefantrine and monodesbutyl-benflumetol has been investigated in 44 fresh isolates of patients with a Plasmodium falciparum infection from the region of Mae Sot (Thailand). Both substances proved to be effective against parasite maturation within the test concentration range, with monodesbutyl-benflumetol being effective at a lower concentration than lumefantrine. Synergism between the two substances was evaluated with a combination of lumefantrine and monodesbutyl-benflumetol at a ratio of 4.25:1. The geometric mean values for complete inhibition of schizont maturation were 1035.7 nM for lumefantrine, 655 nM for monodesbutyl-benflumetol and 222.5 nM for the combination of both. An analysis for interaction according to the method of Berenbaum indicates a moderate synergism at the IC(50), which gets stronger with increasing ICs and reaches the highest level at the IC(99). The geometric mean of the sums of the FIC(50) is 0.73, of the FIC(90) it is 0.37 and of the FIC(99) it is 0.25. PMID- 20924692 TI - Pulmonary ascariasis: two cases in Austria and review of the literature. AB - Ascariasis is the most common helminthic infection, with an estimated worldwide prevalence of 25%. The estimated mortality ranges from 0.8 to 1%. Second stage larvae pass through the intestinal wall and migrate via the portal vein system to the liver and then proceed to the lungs, where they may produce pneumonia and eosinophilia. Symptoms include wheezing, dyspnea, nonproductive cough, hemoptysis, and fever. Two cases of pulmonary ascariasis in Austrian males are reported. Both patients presented with dyspnea, nonproductive cough, fever, and eosinophilia (19 and 26%). One patient additionally had pulmonary infiltrates. Recent travel history was unremarkable in both individuals. Serology for Ascaris was positive twice in both patients, while microscopic examination of stool was negative for helminthic ova. Extensive diagnostic procedures were performed to rule out possible differentials for the patients symptoms. Both patients responded well to antiparasitic treatment with albendazole 400 mg and mebendazole 100 mg q12h for 3 days, respectively. This report highlights the importance of considering parasitic infection in patients presenting with eosinophilia and pulmonary symptoms also in Austria. PMID- 20924693 TI - A case of a facultative life-cycle diversification in the fluke Pleurogenoides sp. (Lecithodendriidae, Plagiorchiida). AB - Numerous specimens of the native, intestinal digenean fluke Pleurogenoides sp. (Lecithodendriidae, Plagiorchiida), a genus known for the simultaneous co existence of genuine adults and progenetic, adult-like metacercaria, were found by chance parasitizing in the oesophagus of a recently imported, tropical Bristly Bush Viper (Atheris hispida). The snake had before been force-fed with native water frogs, the assumed definitive host of these flukes. Hence water frogs act as the second intermediate host or as a paratenic host for Pleurogenoides flukes, as they must house progenetic fluke larvae, which develop to genuine adults when transmitted to an appropriate consecutive host, the ancestral definitive host, a reptile. The European Pleurogenoides fluke species seem to display a facultative life-cycle diversification, they can adjust their life-history strategy according to their immediate transmission opportunities. This phenotypic plasticity allows the parasite to respond quickly to any changes in the abundance of a host; usually this biological oddity results in a life-cycle truncation by the elimination of the definitive host. PMID- 20924694 TI - Host preference of tsetse: an important tool to appraise the Nagana risk of cattle in the cotton zone of Mali. AB - Nagana, a vector-borne epizootic caused by trypanosomes, severely constrains the use of draught animals in the cotton zone of south-eastern Mali. The disease causes considerable economic losses for the local farmers due to high mortality and morbidity ensuing productivity losses. Nagana is routinely controlled by the use of trypanocides and an overreliance on their use throughout past decades resulted in multiple drug resistance of trypanosomes in most parts of West Africa's cotton belt. Designing alternative, effective vector control strategies requires an identification of the preferred hosts of tsetse flies through blood meal analysis as a prerequisite for estimating infection risk. A survey was, therefore, conducted between November 2008 and April 2009, catching 474 Glossina species which were dissected. Blood meals were smeared on filter paper (Whatman((r))-FTA-Cards) for laboratory analysis. DNA extractions and amplification using universal vertebrate cytochrome b primers of 120 assorted samples detected 74 DNA-containing specimens. The subsequent use of cattle specific primers yielded 52 visible amplicons in the gel electrophoresis. Sequencing and BLASTN((r)) analysis of the remaining samples revealed 19 blood meals matching with existing sequences of the human genome in Genbank((r)). Two samples originated from crocodiles whereas one was unidentifiable. PMID- 20924695 TI - [Field study on the treatment of the feline ear canker caused by Otodectes cynotis with selamectin (Stronghold(r))]. AB - Otacariasis due to Otodectes cynotis (HERING, 1858) is a very frequent disease of the external ear canal in cats. Otodectes cynotis is the most common mange mite in carnivores. Several antiparasiticides are licensed for treatment. The purpose of this study was to evaluate the efficacy of a formulation containing selamectin (Stronghold((r)) Spot-on) for eradication of ear mites in cats under field conditions. Sixteen cats with otacariasis, presented in a small animal clinic, were treated with a single spot-on application of selamectin (Stronghold((r)) Spot-on, 6-17.3 mg/kg bdw.). On clinical and parasitological assessment days 14 and 28 clinical signs had subsided in ten cats. Furthermore all ear swabs were negative for mites and their developmental stages on D 14 and D 28. Selamectin was a practical and well-tolerated treatment of feline otacariasis for the cats included in this study. It was very well tolerated in all cats, local skin irritations on the neck did not occur. PMID- 20924696 TI - [The efficacy of anthelmintic drugs against horse strongyles in the area of Salzburg and preliminary results of selective anthelmintic treatment]. AB - In recent years more and more cases of anthelmintic resistant equine strongyles were reported. The latest developments are cases of resistance against macrocyclic lactones. In order to delay this process less anthelmintics and only those which have been previously tested for their efficacy on each individual farm should be used. During the grazing season 2008 faecal samples of 281 horses and 5 donkeys from 26 farms were analysed in the area of Salzburg. To 164 of these horses selective anthelmintic treatment was implemented. Every four weeks faecal samples from the 164 horses were quantitatively analysed for strongyle eggs using a modified McMaster technique. When more than 250 eggs per gram (EpG) of faeces were detected in a sample the horse was treated with an oral pyrantel product. In case of a subsequent faecal sample of the same horse with EpG > 250, Ivermectin, and after the third sample with EpG > 250, Moxidectin was administered. In the fall 2008, all 164 horses together with 117 additional horses and 5 donkeys were treated with Moxidectin plus Praziquantel independent of the faecal egg count. After each anthelmintic treatment a faecal egg count reduction test was performed. In total 1521 faecal samples were analysed. In 1065 samples (70%) no strongyle eggs were detected at all and only 109 samples (7%) had EpG > 250 values. After the treatment with Pyrantel a total of 49 faecal egg count reduction tests, after the treatment with Ivermectin 28 and after the administration of Moxidectin totally 109 faecal egg count reduction tests were performed. After the treatment with either Ivermectin or Moxidectin, all faecal egg count reductions were 100%. On one farm however, the mean reduction of strongyle eggs after the administration of pyrantel was 85.4% on day 14 and 74.9% on day 21. Therefore, faecal egg count reduction tests are strongly recommended whenever horses are treated with Pyrantel. PMID- 20924697 TI - Synergism between pyronaridine and retinol in Plasmodium vivax in vitro. AB - Estimates of the annual number of infections with Plasmodium vivax reach 391 million. So far the blood-schizontocidal therapy with chloroquine remained effective in most parts of the world, but reports about emerging resistance are increasing. The study had the objective of determining the pharmacodynamic interaction between pyronaridine and retinol in Plasmodium vivax, since pyronaridine is a potential alternative for chloroquine and an earlier study had shown strong synergism between pyronaridine and retinol in Plasmodium falciparum. The study was conducted at the Malaria Clinic of Mae Sot, Tak Province, Thailand, near the border to Myanmar. The in vitro observations followed the method of Tasanor. Successful tests were performed with 44 isolates. The mean IC(50), IC(90) and IC(99) values for pyronaridine were 9.8, 2069.6 and 162446.5 nM. The mean IC(50), IC(90) and IC(99) values for the combinations with retinol (corresponding to the 50th, 65th and 80th percentile of the physiological retinol levels in healthy adults) were 1.7, 542.8 and 59379.5 nM for pyronaridine + retinol "low", for the combination with retinol "medium" they were 0.5, 313.7 and 58891.4 nM and for the combination with retinol "high" they were 0.2, 96.7 and 16754.3 nM. These results suggest strong synergism between the two substances. PMID- 20924698 TI - Synergism between mefloquine and artemisinin and its enhancement by retinol in Plasmodium falciparum in vitro. AB - Following the advent of mefloquine resistance in Plasmodium falciparum in Thailand in the 1990s, the combined treatment of falciparum malaria with artesunate and mefloquine was found to be highly effective in treating and curing the patients in the affected areas. Monitoring of the clinical-parasitological response and of the in vitro sensitivity of P. falciparum was systematically conducted in order to detect any signs of failure of this type of artemisinin based combination treatment (ACT). In earlier observations the in vitro activity of artemisinin was found to be significantly enhanced when combined with retinol. The same applies to mefloquine. In order to check whether the synergism between artemisinin and mefloquine was maintained in the presence of retinol, the pharmacodynamic interaction of the three compounds was investigated in the western border area of Thailand. Successful parallel tests with mefloquine, artemisinin, retinol, mefloquine-artemisinin 5:1 as well as mefloquine artemisinin (5:1) + retinol low, medium and high were obtained with 43 fresh parasite isolates. The retinol concentrations in the low, medium and high formulations corresponded to the 50th, 65th and 80th percentile of the physiological mean concentrations in the blood of healthy adults. The IC(50), IC(90) and IC(99) values for mefloquine alone showed a further increase over the data of 2008. In the combinations with artemisinin and retinol moderate synergism was observed at the IC(50), but synergism increased strongly at the IC(90) and the IC(99). PMID- 20924699 TI - Sensitivity to artemisinin, mefloquine and quinine of Plasmodium falciparum in northwestern Thailand. AB - The increasing drug resistance of Plasmodium falciparum is a worldwide problem. The objective of the study was the assessment of the in vitro activity of artemisinin, mefloquine and quinine, in an area where P. falciparum is multi-drug resistant. The sensitivity tests were based on measuring the drug-dependent inhibition of schizont maturation. For the 43 successfully tested isolates the mean effective concentrations (IC(50) and IC(90)) for artemisinin were 0.0081 and 0.1372 MUM, respectively. For mefloquine the IC(50) was 0.1260 MUM and the IC(90) was 3.7345 MUM. Quinine showed an IC(50) of 0.2155 MUM and an IC(90) of 2.5040 MUM. All tested drugs showed a significant reduction in the effectiveness, compared with the results of former years. This suggests a further rise of resistance of local P. falciparum, which is alarming especially for artemisinin and quinine. PMID- 20924700 TI - Prevalence and pattern of spinal pathologies in a consecutive series of CTs/MRIs in an urban and rural Tanzanian hospital--a retrospective neuroradiological comparative analysis. AB - The prevalence of spinal pathologies in sub-saharan Africa has received little attention so far. The aim of the survey was to investigate and compare the prevalence pattern of spinal lesions in two different populations of Tanzania, one coming from the urban and semi-urban catchment area of Aga Khan Hospital in Dar es Salaam and the other coming from the rural catchment area of Haydom Lutheran Hospital in Mbulu, northern Tanzania. At the Aga Khan Hospital a total number of 1163 patients were included in the survey. In 50 cases (4.3%) no radiological findings were available and 150 patients (12.9%) showed no pathological abnormality. 90.4% (n = 1051) of screened population were classified in the category of extradural-extramedullary pathologies. Intradural extramedullary lesions were observed in only three cases (0.3%). Intramedullary pathologies accounted for 2.1% (n = 24). Mean age of the screened population was 46.6 years, male-female ratio 1.08:1. At the Haydom Lutheran Hospital 105 cases were included into the study. Twenty-six patients (24.8%) showed no pathological abnormalities. Extradural-extramedullary pathologies occurred in 72.4% (n = 76) of overall cases. However, intradural-extramedullary pathologies were not seen in Haydom. Intramedullary pathologies were diagnosed in two patients (1.9%). Mean age was with 39.8 years clearly younger compared to urban areas, male-female ratio being 1.21:1, only non-significantly higher than in the Aga Khan Hospital's population. Beside this, one of the main goals of this study was to assess the frequency of infections to the spinal cord and vertebral column in rural and urban Tanzania. Surprisingly there were only few radiological findings at the Aga Khan Hospital, which suggested diagnoses consistent with tropical diseases, a striking difference from rural Haydom Lutheran Hospital, where nearly 30% of all patients showed changes on radiograph consistent with infections/infestations. PMID- 20924701 TI - Imaging-based disease pattern in a consecutive series of cranial CTs and MRIs in a rural and an urban Tanzanian hospital: a comparative, retrospective, neuroradiological analysis. AB - The prevalence of neurological diseases and cranial pathologies in sub-Saharan Africa remains a very little investigated field. This study aims at providing an imaging-based overview of cranial pathologies in two Tanzanian hospitals and at identifying possible differences in the spectrum of diseases between rural and urban African populations. At rural Haydom Lutheran Hospital (Manyara region) the data of 726 patients were included in a retrospective survey. At urban Aga Khan Hospital (Dar es Salaam) the data of 1975 patients who had undergone Computed Tomography (CT) and of 537 Magnetic Resonance Imaging (MRI) patients were obtained. All three surveys showed a clear male preponderance within the populations. The median age of the patients was higher in the city (urban CT 48 years; range 0-95/MRI 39 years; 0.1-89; rural CT 32 years; 0-102). In the urban series stroke, extracranial infections, cerebral atrophy and tumours formed the main groups of diagnoses. Amongst rural patients traumatic pathologies, followed by stroke and cerebral infections/infestations were the most common diagnoses. The most striking differences were noticed with cases compatible with cerebral infections/infestations and hydrocephalus being reported more frequently in the rural population. On the other hand stroke and cerebral atrophy were more frequent amongst urban patients. In the rural catchment area the data of 51 HIV positive CT patients could be obtained, showing a clear female preponderance. Within the urban HIV-positive subgroup of CT patients (n = 57), the gender distribution was almost equal. Furthermore, in both HIV-positive populations the proportion "compatible with cerebral infections/infestations" was higher than amongst the overall study populations. In conclusion, cranial pathologies seem to differ widely in rural and urban areas of Tanzania in particular with respect to cerebral infections and vascular disease. PMID- 20924702 TI - Three years of bluetongue disease in central Europe with special reference to Germany: what lessons can be learned? AB - With few exceptions, vector-borne diseases have long been considered of minor importance in central and northern Europe. Since the advent of bluetongue disease (BTD) in 2006 and the 2007 chikungunya fever outbreak in Italy this attitude has changed. It is due to continuing globalization rather than to climate change that even central and northern Europe are at risk of new pathogens as well as vectors of disease entering and establishing. BTD was the first 'exotic' disease to arrive: it did not slowly spread northwards but jumped in through a still unknown entry point. Although indigenous Culicoides biting midge species had formerly been considered to be the vectors of the bluetongue virus (BTV) in the Mediterranean, nobody had expected BTD in more northern European areas free of C. imicola. When the disease broke out, the authorities were completely unprepared, particularly as neither data on the putative vectors nor biting midge specialists were available. Starting with about 2000 affected ruminant farming facilities in 2006 in the central western part of Europe, the virus managed to overwinter and spread in all directions in 2007, producing almost 60,000 outbreaks (farms affected) in ten European countries up to early 2008. At that time, vaccine administration against BTV serotype 8 was initiated, significantly decreasing the total number of holdings affected in the third transmission season (May 2008 to April 2009). From May 2009 onwards, relatively few cases of BTV-8 infections were notified in a total of only six European countries. Unfortunately, while the further fate of BTV-8 in Europe remains to be awaited, BTV-1 appears to be approaching from the south, with some 4900 outbreaks in France in 2008. Meanwhile, the results from various entomological monitoring projects have suggested biting midges of the C. obsoletus and C. pulicaris complexes as well as some other ceratopogonid species as the most likely BTV vectors in central Europe. The lesson to be learned from the BTD epidemic is once again that in the long term pro-action is better than mere reaction as it can considerably support and facilitate reaction: to avoid and manage outbreaks of emerging vector-borne diseases, essential prerequisites are to monitor the indigenous hematophagous arthropod fauna, to identify potential vectors and acquire knowledge on their biology, to educate medical entomologists and vector biologists, and to implement better control of imported goods and animals for pathogens and arthropod vectors. PMID- 20924703 TI - [Bats and other reservoir hosts of Filoviridae. Danger of epidemic on the African continent?--a deductive literature analysis]. AB - Ebola and Marburg virus, forming the Filoviridae family, cause hemorrhagic fever in countries of sub-Saharan Africa. These viral diseases are characterized by a sudden epidemic occurrence as well as a high lethality. Even though a reservoir host has not been approved yet, literature indicates the order of bats (Chiroptera) as a potential reservoir host. Significant references lead to a delineation of a hypothetical ecosystem of Filoviridae including Chiroptera. IgG specific Ebola-Zaire antibodies were detected in Hammer-headed Bats (Hypsignathus monstrosus), Epauletted Fruit Bats (Epomops franqueti), and Little Collared Fruit Bats (Myonycteris torquata) during Ebola outbreaks between 2001 and 2005 in Gabon and the Republic of the Congo. The discovery of IgG-specific-Marburg virus antibodies and virus-specific ribonucleic acid in Egyptian Fruit Bats (Rousettus aegyptiacus) provided further indication for the exploration of the reservoir host. In 2007, the Marburg virus isolation could for the first time be accomplished directly from apparently healthy and naturally infected Egyptian Fruit Bats (Rousettus aegyptiacus) in Kitaka Mine (Uganda). Risk groups can be defined through chronological reprocessing and interpretation of existing epidemic-outbreaks on the African continent and the search for infection reasons of the index cases. The following risk factors for an infection with Ebola or Marburg virus must be put into consideration: Contact with and consumption of wild animal carcasses, sightseeing in caves as well as work in mines. The focus of this review is the demonstration of risk profiles and their exposure to Chiroptera and other potential reservoir hosts. PMID- 20924704 TI - [Intestinal helminths in the works of Galen]. AB - Galen was undoubtedly one of the most important physicians in antiquity. He left a voluminous work which was edited by numerous scholars. The most capacious edition was done by Karl Gottlob Kuhn between 1821 and 1833, which is, besides other more recent editions, the major source for this work. Galen deals in his works with all aspects of medicine and with philosophy. The texts on intestinal helminths are spread over the whole works of Galen and give a deep insight of the understanding of parasitic diseases due to intestinal helminths in Antiquity. Intestinal helminths "vermes intestinales" are also subsumed as "lumbrici" of which three species are distinguished: "lati", "teretes" and "ascarides". Galen inherits the descriptions of these worms from the Corpus Hippocraticum and even indicates this once. Well defined amongst the "teretes" or "lumbrici rotundi" appears to be the roundworm Ascaris lumbricoides of today. Less clear are the descriptions of the other "smaller worms", so-called "ascarides". Due to the described symptoms it is possible to identify the threadworm Enterobius vermicularis "that infests mainly children". If Galen distinguished other "small" worm species could not be clarified from this text. The third "species" "Lumbrici lati", today's tape worms, are described separately and also the hunger they cause is mentioned. With his model of explanation for the genesis of the worms Galen combines medicine, philosophy and the Doctrine of the Four Humours which was valid at his time: intestinal worms originate from "putridity and warmth" and therefore stand opposite the life forms that evolve from semen. In addition to the descriptions of the parasites Galen gives advice how and by which means parasites can be fought. Their successful expulsion can be achieved using substances that have the properties "cool" and/or "dry" following the Doctrine of the Four Humours. Some of the medicines described are still used as drugs in our society amongst others: mint, cardamom or myrrh. PMID- 20924705 TI - ["There were the yellow spot is..." Durer's malaria: no valid diagnosis]. AB - There is a pen and water self portrait showing Albrecht Duerer, pointing to a spot below his ribs. In an inscription the artist declares that this area is painful. The drawing inspired authors in the past to diagnose a malaria infection which occurred presumably in the Netherlands during an excursion to the malarious area of Sealand in December 1520. Duerer mentions on his diary that the weather was cold and bad. This makes the presence of active, sporozoite-carrying mosquitoes and an infection very unlikely. Duerer reports fever attacks throughout his lifetime, not only after his return from the Netherlands. Considering the natural course of a Plasmodium vivax-infection it is not possible to accept the hypothesis that Duerer suffered from malaria and that this disease was the cause of his death at the age of 57. PMID- 20924706 TI - [Dreaded miasmas: Austrian scientists on board the frigate Novara pursue the secret of malaria]. AB - The term miasma was coined by Hippocrates of Kos. He introduced it to describe dangerous fumes from the ground that are transported by winds and can cause serious illnesses. Up until the late 19th century, miasmas from swamps were blamed for giving rise to and spreading so-called intermittent fever, cold fever, swamp fever or malaria. It was not until 1898 that the mosquito genus Anopheles was identified as the agent responsible for transmitting malaria. On 30 April 1857, the Austrian frigate Novara left Trieste to circumnavigate the globe. One of the medical officers on board, Dr. Eduard Schwarz, studied the composition of miasmas in detail and published his investigations in the medical section of the "Novara Chronicles" in 1861. Schwarz attributed the dreaded Nicobar fever to decomposition processes of organic material, which released dangerous miasmas that could only be eliminated by draining the swamps. Karl von Scherzer, the scientific director of the Novara expedition, collected exact information about the distribution range of the cinchona tree, which was said to be threatened with extinction, a rumor that later proved to be false. Quinine was gained from the bark of the tree and was used worldwide to treat malaria, pains, and fever. PMID- 20924708 TI - A hybrid approach for the control of axonal outgrowth: preliminary simulation results. AB - The possible control of axonal outgrowth during neural regeneration could be very useful not only from a neurobiological point of view, but also in the field of neural interfaces. In this manuscript, simulations are presented which investigate the possibility of guiding axons by using a hybrid approach based on the combined used of a chemical model and of a genetic algorithm. Microspheres embedding chemical cues on the basis of information provided by a genetic algorithm are placed to impose a desired trajectory on the axons. Two kinds of simulations were carried out: (i) tracking of linear trajectories; (ii) tracking of trajectories, which were reconstructed from real axonal extension. The results achieved during the simulations seem to confirm the possible use of this approach to guide axonal outgrowth, being the obtained trajectories congruent to possible actual situations. Moreover, the model can be easily extended to a three dimensional environment. PMID- 20924709 TI - Short chain saturated fatty acids decrease circulating cholesterol and increase tissue PUFA content in the rat. AB - This study investigates the effect of various dietary saturated fatty acid (SFA) profiles on plasma lipid parameters and tissue fatty acid composition in rats. The experiment was designed to monitor polyunsaturated fatty acids (PUFA) levels, while examining different amounts and types of SFA. Four isocaloric diets were prepared, containing 10-11 mol% of fatty acids (FA) as linoleic acid (LNA) and 2.5 mol% as alpha-linolenic acid (ALA), leading to an identical and well-balanced LNA/ALA ratio. The initial rapeseed oil/corn oil mixture providing ALA and LNA was enriched with olive oil to prepare the olive oil diet. The butterfat diet was supplemented with butterfat, containing short-chain SFA (C4:0-C10:0, 17 mol% of FA), lauric acid (C12:0, 3.2 mol%), myristic acid (C14:0, 10.5 mol%) and palmitic acid (C16:0, 14.5 mol%). The saturates diet was supplemented with trilaurin, trimyristin and tripalmitin to obtain the same level of lauric, myristic and palmitic acids as the butterfat diet, without the short-chain SFA. The trimyristin diet was enriched with trimyristin only. The results showed that the butterfat diet contributed to specific effects, compared to the olive oil diet and the saturates and trimyristin diets: a decrease in plasma total, LDL- and HDL cholesterol, higher tissue storage of ALA and LNA, and a higher level of (n-3) highly unsaturated fatty acids in some tissues. This study supports the hypothesis that in diets with identical well-balanced LNA/ALA ratios, short chain SFA may decrease circulating cholesterol and increase tissue polyunsaturated fatty acid content in the rat. PMID- 20924710 TI - Stratum corneum lipid structure investigated by EPR spin-probe method: application of terpenes. AB - Electron paramagnetic resonance (EPR) in conjunction with a slow-tumbling simulation was utilized for defining stratum corneum (SC) lipid structure. SC from the back of hairless mouse (HOS:HR-1) was stripped consecutively from one to three or four times using a glass plate coated with a cyanoacrylate resin. Aliphatic spin probes, 5-doxylstearic acid (5-DSA) and 3beta-doxyl-5alpha cholestane (CHL), were used to evaluate the SC ordering. EPR spectrum of 5-DSA incorporated in the SC demonstrated a characteristic peak for the first strip. A slow-tumbling simulation for 5-DSA showed clear differences in EPR intensities as well as ordering values (S(0)) of the SC for control and terpenes treated SC. The alpha-terpineol enhanced the permeation of the single chain 5-DSA about three times more than that of the control. However, EPR spectra of CHL in the SC did not show a clear difference for each strip, except for the signal intensity. The results imply that CHL permeates into SC lipid differently from 5-DSA. The enhancement of the 5-DSA is more significant than that of CHL. Therefore, the present results can be useful for various drug administrations via the skin. PMID- 20924711 TI - Complementary and alternative medicine use among cancer survivors: a population based study. AB - INTRODUCTION: The use of complementary and alternative medicine (CAM) among cancer survivors is high, yet less is known about reasons behind such use or the communication of CAM with conventional medical providers. METHODS: Cross sectional, multivariate logistic regression models were developed to evaluate the similarities and differences between cancer survivors and non-cancer controls in the 2007 National Health Interview Survey with 23,393 participants, including 1,471 cancer survivors. RESULTS: Among cancer survivors, 66.5% reported ever using CAM and 43.3% having used CAM in the past year. When compared with the general population, cancer survivors used CAM more often for general disease prevention, immune enhancement, and for pain (Adjusted Odds Ratio [AOR] 1.27, 95% Confidence Interval [CI] 1.10-1.48; AOR 1.32, 95% CI 1.05-1.62; AOR 1.42, 95% CI 1.05-1.92, respectively). Cancer survivors were more likely to use CAM because of recommendations from their provider (AOR 1.54, 95% CI 1.26-1.88) and were more likely to disclose their CAM use to their provider (AOR 1.45, 95% CI 1.22-1.72). DISCUSSIONS/CONCLUSIONS: When compared to the general population, cancer survivors were more likely to use CAM and communicate this use with providers, indicating a growing integration of CAM in conventional medical care. IMPLICATIONS FOR CANCER SURVIVORS: Cancer survivors are more likely than the general population to communicate CAM use with providers, suggesting greater integration of CAM use in conventional care. However, the majority of CAM use is still not being communicated to providers, indicating an important area for improvement in patient-centered care. PMID- 20924712 TI - Small-diameter bands lead to high complication rates in patients after laparoscopic adjustable gastric banding. AB - BACKGROUND: While weight loss is the primary goal of bariatric procedures, the impact of quality of life (QoL), comorbidity, and surgery-related complications continue to grow. We report on our results of patients up to 12 years of follow up undergoing laparoscopic adjustable gastric banding (LAGB). METHODS: Preoperative data of 153 patients treated with LAGB were collected retrospectively. Questionnaires were sent to patients to analyze weight loss, complications, and comorbidities. QoL was assessed using the Bariatric Qualit-of Life (BQL) questionnaire. RESULTS: Of the patients, 83.7% completed the questionnaire. Median follow-up was 8.7 years. Patients were divided into the following groups: Group A (band still in place), group B (band removed), and group C (revision surgery). A significant increase of excess BMI loss (EBL) was found in group A (p<0.0001): EBL was 36.1%, 42.8%, 41.8%, and 37.1% after 1, 3, 5, and 8 years, respectively. Group B showed a significant weight regain after band removal (p=0.007). One hundred ten reoperations were necessary in 67 patients (52.3%): slippage or pouch dilatation in 25.8%, band migration in 3.9%, band intolerance in 6.2%, and 62 revisions due to port complications. According to BQL, a higher EBL correlated with a significantly better assessment of QoL (p<0.0001). CONCLUSIONS: LAGB resulted in improvement of comorbidities and QoL in banded patients even though not all of them achieved the expected EBL. However, the high complication rate could influence patients' outcome. PMID- 20924713 TI - Re-sleeve gastrectomy for failed laparoscopic sleeve gastrectomy: a feasibility study. AB - BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) has been rapidly accepted as a valuable bariatric procedure before its effectiveness on weight loss in the long term is clearly demonstrated. We report a feasibility study including 13 patients undergoing a redo LSG for either progressive weight regain after initial weight loss of insufficient weight loss. METHODS: From October 2005 to April 2010, 13 patients underwent a re-sleeve gastrectomy procedure for progressive weight regain or insufficient weight loss (<50% of excess weight (EW)) associated with the persistence of the gastric fundus on upper gastrointestinal series. RESULTS: Mean initial body mass index (BMI) and EW were 44.6 (37-52.9) kg/m(2) and 61.8 (38.2-93.9) kg, respectively. There were ten comorbid conditions in five out of the 13 patients. The revision resulted in a mean BMI, percent of excess weight loss (%EWL), and percentage of excess BMI loss (%EBL) of 32.3 kg/m(2), 50.3%, and 57% at 1 month; 32 kg/m(2), 47.9%, and 54.5 at 6 months; and 27.5 kg/m(2), 71.4%, and 82.8% at 12 months, respectively. There was no morbidity. CONCLUSIONS: Laparoscopic revision of LSG is safe and effective in the short term to obtain substantial loss of weight and improvement in comorbidities. PMID- 20924714 TI - Zinc and iron concentration and SOD activity in human semen and seminal plasma. AB - The aim of the present study was to measure zinc (Zn) and iron (Fe) concentration in human semen and superoxide dismutase (SOD) activity in seminal plasma and correlate the results with sperm quality. Semen samples were obtained from men (N = 168) undergoing routine infertility evaluation. The study design included two groups based on the ejaculate parameters. Group I (n = 39) consisted of males with normal ejaculate (normozoospermia), and group II (n = 129) consisted of males with pathological spermiogram. Seminal Zn and Fe were measured in 162 samples (group I, n = 38; group II, n = 124) and SOD activity in 149 samples (group I, n = 37; group II, n = 112). Correlations were found between SOD activity and Fe and Zn concentration, and between Fe and Zn concentration. SOD activity was negatively associated with volume of semen and positively associated with rapid progressive motility, nonprogressive motility, and concentration. Negative correlation was stated between Fe concentration and normal morphology. Mean SOD activity in seminal plasma of semen from men of group I was higher than in seminal plasma of semen from men of group II. Fe concentration was higher in teratozoospermic males than in males with normal morphology of spermatozoa in group II. Our results suggest that Fe may influence spermatozoa morphology. PMID- 20924715 TI - Preconditioning of axillary buds in thidiazuron-supplemented liquid media improves in vitro shoot multiplication in Nyctanthes arbor-tristis L. AB - An efficient tissue culture technology has been designed for mass multiplication of Nyctanthes arbor-tristis L. by preculturing nodal explants in thidiazuron (TDZ)-supplemented liquid Murashige and Skoog (MS) media. Direct inoculation of nodal segments on semi-solid MS medium augmented with various concentrations of TDZ (0.1 to 0.9 MUM) produced shoots but with low regeneration response and few shoots per explant. Hence, nodal explants were pretreated with greater concentrations of TDZ (5 to 100 MUM) in liquid MS media for different durations (4, 8, 12, and 16 days) with the aim of improving shoot regeneration response from cultured explants. After pretreatment, explants were transferred to agar solidified hormone-free MS medium. Best response in terms of percent regeneration (94%), number of shoots per explant (20.00 +/- 1.15), and greatest shoot length (7.23 +/- 0.83 cm) were obtained with nodal segments pretreated in 75 MUM TDZ for 8 days. Similarly, root induction was obtained from pulse-treated microshoots for 24 h with 200 MUM indole-3-butyric acid (IBA) followed by their transfer to 1/2 MS medium which produced an average of 5.50 +/- 0.92 roots per microshoot. The rooted plantlets were transplanted to soil with 80% success rate. PMID- 20924716 TI - Duplication of Philadelphia chromosome and trisomy of chromosome 21 in a pediatric patient with acute lymphoblastic leukemia. AB - The evaluation of molecular and cytogenetic characteristics using novel techniques has significantly contributed into the insight of leukemia. In this study, immunoglobulin heavy chain gene rearrangements (V(H)D(H)J(H) region) were analyzed by polymerase chain reaction (PCR). Point mutations of the D835/I836 in the activation loop (AL) domain of the second tyrosine kinase domain of the fms related tyrosine kinase 3 (FLT3) gene and NRAS (neuroblastoma cell line) point mutations were also analyzed by PCR. Furthermore, sequence analysis of the V(H)D(H)J(H) region was performed, as well as, chromosomal aberrations were identified by interphase fluorescence in situ hybridization (iFISH) in a 12.5 year-old boy with acute lymphoblastic leukemia. Positive MRD was found in bone marrow samples obtained at various time points during and after treatment completion prior to relapse. Molecular analysis of the FLT3 gene mutations revealed an acquired a G -> T mutation at codon 835, which resulted to substitution of aspartate 835 for tyrosine (D835Y). Cytogenetic analysis with iFISH showed t(9;22) (q34;q11.2), with minor-BCR/ABL1 fusion gene in the majority of nuclei, while a subclone with duplication of the Philadelphia chromosome was observed. Triple signals of AML1 were detected in 80% of nuclei, which were compatible with trisomy of chromosome 21. BCR/ABL1 fusion gene, duplication of Philadelphia chromosome and persistence of MRD constitute inferior prognostic factors, while hyperdiploidy, trisomy of chromosome 21 and FLT3-AL mutations are related to better prognosis. The study of cytogenetic and molecular characteristics is essential in order to decide on the optimal treatment protocol in childhood leukemia. PMID- 20924717 TI - Activity of trabectidin in desmoplastic small round cell tumor. AB - Desmoplastic small round cell tumor (DSRCT) is a rare and aggressive cancer that typically arises in teenage boys. As a result of its low prevalence, there have been few studies of its treatment and impact on survival. Here, we report the case of a patient who was refractory to multiple drugs but remains stable with trabectedin. To our knowledge, this is the first published report that supports antitumoral activity of trabectedin in DSRCT. PMID- 20924718 TI - Bacterial enteropathogens and risk factors associated with childhood diarrhea. AB - OBJECTIVE: To investigate the etiology of bacterial enteropathogens causing diarrhea among children; to elucidate the risk factors, sign and symptoms involved in developing of infection; and to identify the antimicrobial susceptibility pattern. METHODS: Stool samples from diarrheal cases with clinical diagnosis of gastroenteritis compared to matched controls, were examined for detection of bacterial enteropathogens by conventional cultural method from February 2006 through January 2007. RESULTS: Ninety three of diarrheal cases comprising enteropathogen isolates. A recognized bacterial enteric pathogen was identified in 31% of the cases and 8% of the control group. The frequency of isolated enteropathogens from faeces of diarrheal cases was recorded in the following order, Enterohemorrhagic E. coli 8.3%, Shigella spp. 6.7%, Campylobacter jejuni 5%, Salmonella spp. 4%, Yersinia enterocolitica 2.7%, Aeromonas spp. 4.7%, and Plesiomonas spp. 1.3%. E.H.E coli, Shigella and Salmonella had shown a significant statistical association with diarrhea (p<0.05). Compared to matched uninfected control, multivariate analysis revealed that malnutrition status (OR adjusted 8.37; p<0.001) was the only independent factor associated with infection. Antibiotic susceptibility profile indicated that enteropathogens were generally susceptible to meropenem, ceftriaxone, followed by amikacin and ciprofloxacin. Almost all enteropathogens were resistant to ampicillin and amoxicillin. CONCLUSIONS: The results of this study emphasize the importance of bacterial enteropathogens in causing severe diarrhea in children. E.H.E. coli was the most predominant pathogen. Malnutrition was identified as the main independent risk factor associated with developing of infection. Ampicillin and amoxicillin should not be used as empirical treatment in acute diarrhea. PMID- 20924719 TI - Perinatal lethal Gaucher disease. AB - Perinatal Lethal Gaucher Disease (PLGD) is a rare form of Gaucher disease and is often considered a distinct form of type 2 Gaucher disease. The authors report on an infant who presented with progressive hepatosplenomegaly, ichthyosis, generalized skin edema and neonatal encephalopathy and died at 6 h of age. Autopsy revealed massive hepatosplenomegaly, ichthyosis, a diffuse collodion picture and histological evidence of infiltration by Gaucher cells in the liver, spleen, lung, thymus, lymph node and bone marrow. Genetic testing of the parents revealed both to be carriers of Gaucher disease. PMID- 20924720 TI - Causes of child deaths in India, 1985-2008: a systematic review of literature. AB - OBJECTIVE: To understand the causes of child deaths in order to implement appropriate child survival interventions in the country. We present a systematic review of studies reporting causes of child, infant, and neonatal deaths from India for 1985 to 2008. METHODS: PubMed, EMBASE, Google Scholar, and WHO regional databases were searched along with a hand search and personal communication with researchers in child health to obtain studies and reports for the database. Study data was summarized and analyzed using appropriate statistical tools. RESULTS: We identified 28 published/unpublished studies and reports (6 multi-centric and 22 single sites). There was one nation wide study and rest were from 15 unique sites in 9 different states of India. There were differences in study design and cause of death assignment methods between the studies, which made comparisons and synthesis difficult. The median percentage of causes of deaths in neonatal period were sepsis/pneumonia: 24.9% (Q1: 19.6% and Q3: 33.4%); asphyxia: 18.5% (Q1: 14.2% and Q3: 21.9%); and pre-maturity/LBW: 16.8% (Q1: 12.5% and Q3: 26.5%). Amongst the infants, sepsis/pneumonia, asphyxia, and prematurity/low birth weight (LBW) remain substantial causes of deaths. The median proportional contribution of neonatal deaths to total infant deaths was 48.5% (Q1: 36.5-Q3: 57.5%). The proportion of deaths due to infectious diseases like diarrhoea, pneumonia, and measles seem to be greater in infancy, in comparison to that in neonatal period. There was no statistically significant difference in the proportional contribution of neonatal deaths to total deaths occurring during infancy (<1 year) between the two equal periods before and after 1996 (p = 0.141). There also was no difference in the proportional contribution by cause of death assignment method (Verbal autopsy vs. other methods; p = 0.715) or by study setting (urban vs. rural; p = 0.175). The median percentage of neonatal deaths by day 1 is 36.7% (Range: 20.0-58.0%). The median cumulative percentage of neonatal deaths by day 3 was 49.7% (Range 35.0-64.6%), and 70.9% (Range: 46.5-92.3%) by day 7. In addition, the timing of deaths during neonatal period seems to be static during the last 2 decades, with majority of deaths occurring during first week of life. CONCLUSIONS: This review demonstrates the need for more studies with consistent methodological rigor investigating the causes of child death in India. We conclude that the structure of neonatal causes of death in India may be different from the rest of the world and that interventions to reduce neonatal deaths in first week of life may rapidly improve child survival in the country. PMID- 20924721 TI - p.R672C mutation of MYH3 gene in an Egyptian infant presented with Freeman Sheldon syndrome. AB - OBJECTIVE: To define the mutation type in a clinically suspected Egyptian child with Freeman-Sheldon syndrome (FSS); it involves certain skeletal malformations with some facial characteristics; skeletal malformations include camptodactyly with ulnar deviation, talipes equinovarus, while the facial characteristics include deep-sunken eyes with hypertelorism, long philtrum, small pinched nose and pursed mouth. METHODS: Amplification of exon 17 of the embryonic myosin heavy chain (MYH3) gene was done using one forward and two different reverse primers, and then the cleaned PCR product was sequenced. RESULT: A de novo missense mutation (c.2014C>T with replacement C > Y) in MYH3 gene leading to change of arginine at position 672 by cytosine in protein sequence. CONCLUSION: Mutation analysis remains to be the standard way for definitive diagnosis in FSS. The authors currently report, for the first time in an Egyptian infant aged 16 months who presented with FSS, a c.2014C>T missense mutation of MYH3 gene, with no family history or consanguinity. PMID- 20924722 TI - Utility of ApoB/ApoA1 ratio for the prediction of cardiovascular risk in children with metabolic syndrome. AB - OBJECTIVE: To assess whether apoB/apoA1 ratio is associated or not with metabolic syndrome in obese children. METHODS: A 198 obese children and 41 healthy control subjects were enrolled in a cross-sectional study. The apoB/apoA1 ratio and other metabolic syndrome components in obese children with/without metabolic syndrome were compared to healthy controls. RESULTS: The apoA1 level did not show significant difference (p = 0.664) but apoB level (p = 0.000) and apoB/apoA1 ratio (p = 0.001) were significantly higher in obese group than in control group. Also, the apoB/apoA1 ratio was significantly higher in obese children with metabolic syndrome when compared to obese children without metabolic syndrome (p = 0.007) and showed positive correlation with triglyceride (r = 0.404, p = 0.000) and negative correlation with high-density lipoprotein cholesterol (r = -0.593, p = 0.000). CONCLUSIONS: The apoB/apoA1 ratio is associated with metabolic syndrome in obese children. An elevated apoB/apoA1 ratio may constitute an important feature of the metabolic syndrome. There is a need for long term follow-up studies concerning cardiovascular risk in obese children with metabolic syndrome and high apoB/apoA1 ratio. PMID- 20924723 TI - Approach to a patient with connective tissue disease. AB - Connective tissue disease (CTDs), though rare in childhood, are an important cause of morbidity. Most of them involve multiple organ systems and are associated with presence of autoantibodies. Systemic lupus eryethematosus (SLE) is the most common CTD, the others being Juvenile dermatomyositis, systemic sclerosis, mixed connective disease and Sjogren syndrome. The clinical presentation of CTD in childhood can range from an acute severe illness mimicking a serious infection, to an insidious onset of disease with gradual accumulation of symptoms and signs over wks to months. The presence of multi-system involvement, evidence of inflammation and lack of any obvious cause should alert a clinician to the possibility of CTD. Diagnosis is usually clinical and features like malar rash, Raynaud's phenomenon, Gottron's rash, photosensitivity, oral ulcers suggest a possibility of CTD. Presence of autoantibodies like anti-nuclear antibodies, anti-dsDNA etc. provide supportive evidence to a diagnosis of CTD. Most CTDs are treated with immunosuppressive drugs with good success. Early recognition and prompt treatment results in excellent outcome. PMID- 20924724 TI - Neuroinformatics in clinical and translational medicine--novel approaches. PMID- 20924725 TI - 1H, 13C, 15N backbone and side-chain resonance assignments of the human Raf-1 kinase inhibitor protein. AB - Raf-1 kinase inhibitor protein (RKIP) plays a pivotal role in modulating multiple signaling networks. Here we report backbone and side chain resonance assignments of uniformly (15)N, (13)C labeled human RKIP. PMID- 20924726 TI - Advances in the evaluation and management of minimal hepatic encephalopathy. AB - Minimal hepatic encephalopathy (MHE) is a neurocognitive disorder that affects up to 80% of cirrhotic patients. Similar to overt hepatic encephalopathy, ammonia and oxidative stress play key roles in the pathogenesis of MHE. However, MHE is characterized by subtle deficits and psychomotor abnormalities that can only be elicited by specialized psychometric tests. Although no gold standard exists for the diagnosis, MHE remains an important entity for clinicians to recognize because of its negative impact on a patient's health-related quality of life and association with driving impairment and vehicle accidents. MHE has also been associated with an increased rate in the development of overt hepatic encephalopathy and increased mortality; therefore, identification and treatment should not be delayed. Treatment to date has been focused on reducing serum ammonia levels with agents such as lactulose, probiotics, and synbiotics. MHE is a real and growing problem that is epidemic in cirrhosis, and increasing awareness of this condition is necessary for adequate management of these patients. PMID- 20924727 TI - Novel approaches to inhibition of gastric acid secretion. AB - The gastric H,K-adenosine triphosphatase (ATPase) is the primary target for treatment of acid-related diseases. Proton pump inhibitors (PPIs) are weak bases composed of two moieties, a substituted pyridine with a primary pK(a) of about 4.0 that allows selective accumulation in the secretory canaliculus of the parietal cell, and a benzimidazole with a second pK(a) of about 1.0. Protonation of this benzimidazole activates these prodrugs, converting them to sulfenic acids and/or sulfenamides that react covalently with one or more cysteines accessible from the luminal surface of the ATPase. The maximal pharmacodynamic effect of PPIs as a group relies on cyclic adenosine monophosphate-driven H,K-ATPase translocation from the cytoplasm to the canalicular membrane of the parietal cell. At present, this effect can only be achieved with protein meal stimulation. Because of covalent binding, inhibitory effects last much longer than their plasma half-life. However, the short dwell-time of the drug in the blood and the requirement for acid activation impair their efficacy in acid suppression, particularly at night. All PPIs give excellent healing of peptic ulcer and produce good, but less than satisfactory, results in reflux esophagitis. PPIs combined with antibiotics eradicate Helicobacter pylori, but success has fallen to less than 80%. Longer dwell-time PPIs promise to improve acid suppression and hence clinical outcome. Potassium-competitive acid blockers (P-CABs) are another class of ATPase inhibitors, and at least one is in development. The P-CAB under development has a long duration of action even though its binding is not covalent. PPIs with a longer dwell time or P-CABs with long duration promise to address unmet clinical needs arising from an inability to inhibit nighttime acid secretion, with continued symptoms, delayed healing, and growth suppression of H. pylori reducing susceptibility to clarithromycin and amoxicillin. Thus, novel and more effective suppression of acid secretion would benefit those who suffer from acid-related morbidity, continuing esophageal damage and pain, nonsteroidal anti inflammatory drug-induced ulcers, and nonresponders to H. pylori eradication. PMID- 20924728 TI - Angiosarcoma of the oral cavity. AB - Angiosarcoma of the oral cavity is extremely rare. A 54-year-old woman consulted to our hospital because of mass of the left cheek next to the mandible. MRI showed a 1 cm tumor. Enucleation of the tumor was performed. Grossly, the tumor was not encapsulated and had a central cavity. Histologically, the tumor consisted of spindle and polygonal cells with hyperchromatic nuclei with nucleoli. Intracytoplasmic vacuoles and mitotic figure were scattered. Vasoformative channels were present in some areas. Lymphoid follicles were scattered in the tumor. The tumor was invasive into the surrounding tissue, and lymphovascular permeation was noted. The surgical margins were positive. Immunohistochemically, the tumor cells were positive for factor VIII-related antigen, CD31, CD34, vimentin, p53 protein, but negative for pancytokeratins, cytokeratin (CK) 7, CK 18, CK19, EMA, S100 protein, alpha-smooth muscle antigen, desmin, p63, synaptophysin, chromogranin, neuron-specific enolase, CD56, CD10, CD20, CD30, CD45RO, melanosome, myoglobin, KIT, and PDGFRA. The Ki-67 labeling was 46%. The lymphoid tissue in the tumor was positive for CD20, CD45, CD45RO, and CD10. A pathological diagnosis of angiosarcoma was made. No metastatic lesions are found now. Radical operation is planned now. PMID- 20924729 TI - Histiocytic sarcoma with two immunohistopathologically distinct populations. AB - This report is a case of histiocytic sarcoma (HS), in which tumor cells consist of two immunohistopathologically distinct populations (A) oval CD68+lysozyme+CD163- cells and (B) abundant cytoplasm or spindle-shaped CD68+lysozyme-CD163+ cells. Cervical lymph node was infiltrated mainly by population (A), where chemotherapy was quite effective. On the other hand, vast majority of infiltrated tumor cells in the hilar lymph node belonged to population (B), in which the cells were resistant to chemo-radiotherapy. Considering the poor prognosis of HS, the expression of CD163 could be a marker for resistance to chemo-radiotherapy. It is also notable that CD163-negative stage of HS may exist and still be reactive for the treatment. PMID- 20924730 TI - Establishment of an HS23 stromal cell-dependent myeloma cell line: fibronectin and IL-6 are critical. AB - A multiple myeloma (MM) cell line, MSG1, which depends on HS23 stromal cells for its survival, was established from the pleural effusion of a patient with MM who expressed the M-protein of IgA-lambda in his serum. During the first 2 months of culture, the myeloma cells survived on adhesive cells from the pleural effusion and, subsequently, they continued to proliferate on HS23 stromal cells. The phenotype of the established MSG1 cell line was: CD138(+), CD38(++), CD19-, CD56 , VLA-4(+), VEGFR1(+) and VEGFR2(+). Immunohistochemical staining also demonstrated expression of the IgA and lambda chain in MSG1 cytoplasm. Karyotype analysis indicated complex chromosomal abnormalities; hypertriploidy, including the deletion of chromosomes 13 and 17, and c-myc translocation. MSG1 cells continued to proliferate, not only when co-cultured with HS23 cells, but also when cultured only on fibronectin-coated plates with the supernatant of HS23 cells or with control medium containing IL-6. Tocilizumab, an anti-IL-6 receptor antibody, inhibited MSG1 survival under these conditions. Therefore, MSG1 may be a unique myeloma cell line that is useful for the study of cell adhesion-mediated drug resistance induced by adhesion molecules and IL-6 stimulation of myeloma cells. PMID- 20924731 TI - Bortezomib plus dexamethasone for relapsed or treatment refractory multiple myeloma: the collaborative study at six institutes in Kyoto and Osaka. AB - We conducted a retrospective collaborative investigation of bortezomib (Bor) plus dexamethasone (Dex) therapy (BD Tx) for 88 relapsed or refractory (Rel/Ref) MM patients at six institutes. One cycle BD Tx comprised of Bor (1.3 mg/m2/day) on days 1, 4, 8 and 11, and Dex on days 1, 2, 4, 5, 8, 9, 11 and 12, every 21 days, and the mean number of BD Tx cycles was 3. The overall response rate was 66.9%, the median overall survival (OS) was 510 days, and the median progression-free survival (PFS) was 113 days. Attainment of partial response (PR) with the first course of BD Tx associated with the longer OS and PFS and late good responder, while no patient who did not achieve PR with the first cycle attained better than very good PR (VGPR) with the subsequent BD Tx. Patient age of less than 64 years old also associated with the longer OS and PFS. In addition, both an earlier disease stage and Dex dosage had a significant impact on OS, while the attainment of VGPR within 2 cycles had a significantly longer PFS. Earlier BD Tx courses may be predictive for the subsequent therapeutic pathway of Rel/Ref MM. PMID- 20924732 TI - Acute renal failure associated with systemic polyoma BK virus activation in a patient with peripheral T-cell lymphoma. AB - Renal dysfunction associated with polyoma BK virus (BKV) reactivation usually occurs in the setting of profound immunosuppression related to renal transplantation and hematopoietic stem cell transplantation. However, it has been rarely described as a complication during the course of conventional chemotherapy. Here, we report a case of BKV-associated acute renal failure developed in a patient suffering from refractory peripheral T-cell lymphoma, not otherwise specified. After repetitive cycles of salvage chemotherapy, the patient developed fever and urinary frequency, rapidly followed by anuria that necessitated the emergent institution of hemodialysis. Cytologic examination of the urine revealed the presence of decoy cells and positive immunostaining for polyomavirus simian virus 40 antigen. High levels of BKV were detected in urine and plasma with quantitative real-time polymerase chain reaction, strongly suggesting that his renal failure was due to polyoma virus-associated nephropathy. This rare complication should be kept in mind in case of unexplained renal failure developed in immunodeficient patients undergoing cytotoxic chemotherapy. PMID- 20924733 TI - Educational program and testing using images for the standardization of breast cancer screening by ultrasonography. AB - BACKGROUND: To improve the quality of breast cancer screening by ultrasonography, both effective training and evaluation of the performance of the examiners of breast ultrasound are essential. METHODS: The Educational Committee of the Japan Association of Breast and Thyroid Sonology, an NPO, has established 2-day training programs on breast ultrasonography with tests at the end of the programs. The tests are performed using images to evaluate the ability of observers to detect and evaluate lesions on ultrasound. Ability to detect lesions was examined by using videos, and ability to evaluate lesions was examined by using still images. The results of tests taken by 422 physicians and 415 technologists were analyzed. RESULTS: In a comparison between physicians and technologists, the video specificity, the still image sensitivity, and the percentage of category agreement did not show any significant differences. The video sensitivity, the still image specificity, and the percentage of disease name agreement were significantly higher in technologists. Observers who had experienced <100 cases showed significantly poorer results in all subjects except for the video specificity in physicians and the still image specificity in technologists. CONCLUSIONS: Ultrasound technologists perform as well as physicians in recognizing and interpreting cancers on breast ultrasound, which supports their role in performing the initial screening examination. PMID- 20924734 TI - Association between CT imaging at follow-up and clinical outcomes in heel fractures. AB - The reliability of CT data for calcaneal fractures was evaluated, quantifying five CT parameters and investigating their association with clinical outcomes. Fifty-four intra-articular calcaneal fractures surgically treated were considered. Vertical and longitudinal alignment, calcaneal body height, position of sustentaculum tali and subtalar joint congruity were evaluated at 49 months (27-94) follow-up. Each parameter was then quantified and its association with the clinical outcome assessed by the Maryland Foot Score was evaluated. Better clinical outcomes showed a significant association with vertical/longitudinal realignment and with restoration of the calcaneal height. No significant association emerged with reconstruction of the thalamic joint facet congruity. Three-dimensional reconstruction of the calcaneus, in terms of vertical and longitudinal alignment, restoration of the height of the heel body even irrespective of a perfect joint congruity, seems today to be the main goal of the treatment. PMID- 20924735 TI - Quantitative and qualitative analysis and interpretation of CT perfusion imaging. AB - Coronary artery disease (CAD) remains the leading cause of death in the United States. Rest and stress myocardial perfusion imaging has an important role in the non-invasive risk stratification of patients with CAD. However, diagnostic accuracies have been limited, which has led to the development of several myocardial perfusion imaging techniques. Among them, myocardial computed tomography perfusion imaging (CTP) is especially interesting as it has the unique capability of providing anatomic- as well as coronary stenosis-related functional data when combined with computed tomography angiography (CTA). The primary aim of this article is to review the qualitative, semi-quantitative, and quantitative analysis approaches to CTP imaging. In doing so, we will describe the image data required for each analysis and discuss the advantages and disadvantages of each approach. PMID- 20924737 TI - Physician awareness and referral to national smoking cessation quitlines and web based resources. PMID- 20924736 TI - Oxidative stress in relation to telomere length maintenance in vascular smooth muscle cells following balloon angioplasty. AB - Telomeres are specialized DNA-protein complexes found at the tips of linear chromosomes. In this study, we investigated the effects of oxidative stress on telomeric length distribution of proliferating vascular smooth muscle cells following balloon injury in single or combined treatment of rabbits with either buthionine sulfoximine or taurine. Exposure to oxidative stress increased the balloon injury whereas taurine treatment significantly diminished L-buthionine sulfoximine-related intimal hyperplasia. Our results also showed that both variables had a significant influence on mean telomeric length distribution. PMID- 20924739 TI - [In citation process]. PMID- 20924740 TI - [Magnetic resonance spectroscopy in the central nervous system]. PMID- 20924741 TI - [Metabolic disorders with typical alterations in MRI]. AB - The classification of metabolic disorders according to the etiology is not practical for neuroradiological purposes because the underlying defect does not uniformly transform into morphological characteristics. Therefore typical MR and clinical features of some easily identifiable metabolic disorders are presented. Canavan disease, Pelizaeus-Merzbacher disease, Alexander disease, X-chromosomal adrenoleukodystrophy and adrenomyeloneuropathy, mitochondrial disorders, such as MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes) and Leigh syndrome as well as L-2-hydroxyglutaric aciduria are presented. PMID- 20924742 TI - [Value of MR spectroscopy in infectious and inflammatory brain diseases]. AB - Proton magnetic resonance spectroscopy (MRS) is a non-invasive method for measuring cerebral metabolite concentrations in various pathologic conditions. This review discusses the MRS findings in the most common infectious and inflammatory brain diseases. PMID- 20924743 TI - [Radiation hygiene in medical X-ray imaging, part 1: physical and technical basics]. AB - In this first part of a series of three articles on radiation hygiene in medical X-ray imaging the characteristics of X-rays, their interactions with matter and the components of X-ray equipment are described from a radiation protection point of view. The fundamental radiation protection measures like filtration and beam limitation are introduced as well as the various conventional and digital image receptor systems. Moreover the absorbed dose and other practical dose terms as well as metrological and theoretical methods for dose assessment are introduced. The aim of this paper is to explain the essential physical and technical basics of X-ray imaging and the assessment of the resulting radiation dose. PMID- 20924745 TI - Mapping genes Lr53 and Yr35 on the short arm of chromosome 6B of common wheat with microsatellite markers and studies of their association with Lr36. AB - The rust resistance genes Lr53 and Yr35, transferred to common wheat from Triticum dicoccoides, were reported previously to be completely linked on chromosome 6B. Four F (3) families were produced from a cross between a line carrying Lr53 and Yr35 (98M71) and the leaf rust and stripe rust susceptible genotype Avocet "S" and were rust tested using Puccinina triticina pathotype 53 1,(6),(7),10,11 and Puccinia striiformis f. sp. tritici pathotype 110 E143 A+. The homozygous resistant lines produced infection types of ";1-" and ";N" to these pathotypes, respectively. The Chi-squared tests indicated goodness-of-fit of the data for one leaf rust gene and one stripe rust gene segregation. Linkage analysis using this population demonstrated recombination of 3% between the genes. Microsatellite markers located on the short arm of chromosome 6B were used to map the genes, with the markers cfd1 and gwm508 being mapped approximately 1.1 and 4.5 cM, respectively, proximal to Lr53. Additional studies of the relationship between Lr36, also located on the short arm of chromosome 6B, and Lr53 indicated that the two genes were independent. PMID- 20924746 TI - Linkage analysis of a rare alkaloid present in a tetraploid potato with Solanum chacoense background. AB - The potato genotype ND4382-19 has Solanum chacoense Bitt. in its genetic background. Foliar alkaloid analysis of it and its progeny ND5873 (ND4382-19 * Chipeta) by gas chromatography-mass spectrometry (GC-MS) showed that, in addition to the expected alkaloids (solanidine, leptinidine, and acetyl-leptinidine), there was an aglycone of another rare alkaloid. Its molecular mass and some of the m/z fragment ions were similar to leptinidine, but the major fragment ion was the m/z 150 peak of solanidine. This fragmentation pattern suggested that this alkaloid is a solanidine-based compound with mass equal to leptinidine. Leptinidine differs from solanidine by an extra -OH group, but the GC-MS fragmentation pattern of the rare compound indicated hydroxylation at a different position than the C-23 of leptinidine. The exact chemical structure is still unknown, and further analysis, such as NMR will be necessary to determine the structure. Segregation analysis of ND5873 (ND4382-19 * Chipeta) showed that presence of this rare compound segregated in a 1:1 ratio, indicating that a single gene controlled its synthesis and/or accumulation in foliar tissue. Analysis with AFLP and microsatellite markers indicated that the locus controlling presence of this alkaloid resided on potato chromosome I, with the nearest flanking AFLP markers 0.6 and 9.4 cM apart. This rare alkaloid was present in the foliage and not detected in potato tubers. Its presence in leaves did not affect resistance/susceptibility to Colorado potato beetle. PMID- 20924747 TI - Secondary prevention program for osteoporotic fractures and long-term adherence to bisphosphonates. AB - Our purpose was to assess the impact of a secondary prevention program for osteoporotic fractures in patients with fragility fracture and to determine its effect on long-term compliance with bisphosphonate treatment. Persistence with bisphosphonate use was 71%. Attending follow-up visits was the only variable significantly associated with adherence to bisphosphonates. INTRODUCTION: The aim of this study is to assess the impact a secondary prevention program for osteoporotic fractures in a prospective cohort of patients with at least one fragility fracture and to determine the effect of this intervention on long-term compliance with bisphosphonate treatment. METHODS: All patients older than 50 years with a fragility fracture attended at the emergency department over a 2 year period were appointed for a clinical visit through a telephone call. Two follow-up controls at 4 and 12 months were scheduled. After a mean of 4 years, a telephone survey was conducted to assess compliance with treatment. RESULTS: Of 683 eligible patients, 380 (55.6%) were visited at the hospital. Previous treatment with bisphosphonates was recorded in 17.9% of patients. DXA scan was considered normal in 61 patients and revealed osteopenia in 184 and osteoporosis in 135. Pharmacological treatment was indicated in 90% of patients (alendronate in 76%). Among 241 patients who participated in the survey, eight patients had new fractures (four were on treatment with bisphosphonates and four had discontinued treatment). Of 187 patients in which bisphosphonates were prescribed at the initial visit, 133 (71.1%) continued using bisphosphonates. Attendance of scheduled visits was associated with adherence to bisphosphonates (odds ratio, 3.33; 95% confidence interval, 2.99-3.67). CONCLUSIONS: The efficacy of the program to recruit patients was 55%. In patients visited at the hospital, treatment with bisphosphonates increased from 17.9% to 76%. Persistence with bisphosphonate use after a mean of 4 years was 71%. Attending follow-up visits was significantly associated with adherence to bisphosphonates. PMID- 20924748 TI - Effect of vitamin D supplementation on muscle strength: a systematic review and meta-analysis. AB - This systematic review demonstrates that vitamin D supplementation does not have a significant effect on muscle strength in vitamin D replete adults. However, a limited number of studies demonstrate an increase in proximal muscle strength in adults with vitamin D deficiency. INTRODUCTION: The purpose of this study is to systematically review the evidence on the effect of vitamin D supplementation on muscle strength in adults. METHODS: A comprehensive systematic database search was performed. Inclusion criteria included randomised controlled trials (RCTs) involving adult human participants. All forms and doses of vitamin D supplementation with or without calcium supplementation were included compared with placebo or standard care. Outcome measures included evaluation of strength. Outcomes were compared by calculating standardised mean difference (SMD) and 95% confidence intervals. RESULTS: Of 52 identified studies, 17 RCTs involving 5,072 participants met the inclusion criteria. Meta-analysis showed no significant effect of vitamin D supplementation on grip strength (SMD -0.02, 95%CI 0.15,0.11) or proximal lower limb strength (SMD 0.1, 95%CI -0.01,0.22) in adults with 25(OH)D levels > 25 nmol/L. Pooled data from two studies in vitamin D deficient participants (25(OH)D <25 nmol/L) demonstrated a large effect of vitamin D supplementation on hip muscle strength (SMD 3.52, 95%CI 2.18, 4.85). CONCLUSION: Based on studies included in this systematic review, vitamin D supplementation does not have a significant effect on muscle strength in adults with baseline 25(OH)D >25 nmol/L. However, a limited number of studies demonstrate an increase in proximal muscle strength in adults with vitamin D deficiency. PMID- 20924749 TI - Parity and risk of hip fracture in postmenopausal women. AB - Hip fracture risk was assessed according to parity among postmenopausal women. Compared with nulliparous women, the fracture risk was lower in women with three or more births. INTRODUCTION: Parity was assessed for long-term prediction of hip fracture in postmenopausal women. METHODS: Postmenopausal women (n= 2,028) aged 45 or over with no history of hip fracture were studied. From 1978 to 1980, all of them had participated in a comprehensive health survey based on a nationally representative population sample. Emerging cases of hip fracture were identified from the National Hospital Discharge Register during a follow-up period extending up to 17 years. RESULTS: The risk of hip fracture was lower among parous women compared with nulliparous women. The model adjusted for age showed a significant inverse association between parity as a continuous variable and the risk of hip fracture [RR = 0.74; 95% confidence interval (CI), 0.61-0.90] per an increment of one standard deviation (2.4 births). Adjusted for age, menopausal age, level of education, body mass index, vitamin D status, alcohol consumption, smoking history, leisure time physical activity, and self-rated health, the relative risk was 0.50 (95% CI, 0.32-0.79) for women with three or more births and 0.85 (95% CI, 0.55-1.32) for women with one to two births as compared with nulliparous women. CONCLUSION: Parity, three or more births in particular, predicts a lowered risk of hip fracture in the long run. PMID- 20924750 TI - Profiling of hypothalamic and hippocampal gene expression in chronically stressed rats treated with St. John's wort extract (STW 3-VI) and fluoxetine. AB - RATIONALE: Hypericum perforatum L., known as St. John's wort (SJW), is used as a phytotherapeutic agent for the treatment of mild to moderate forms of depression. OBJECTIVES: The aim of the present study was to evaluate the effect of SJW extract (STW 3-VI; 250 and 500 mg/kg; p.o.) and fluoxetine (10 mg/kg, p.o.) on genes involved in the pathogenesis of depression using a chronic restraint stress (CRS) model in rats. Of particular interest was the assessment of similarities and differences between SJW extract and fluoxetine on the gene expression level in two different brain regions. RESULTS: Hypothalamic and hippocampal tissues were analyzed using the Affymetrix gene chip Rat Genome 230 2.0 Array, which comprises more than 30,000 rat transcripts. Limma program and PANTHER database were used to evaluate the microarray data. Genes involved in the pathways of inflammatory processes (Mapk8), oxidative stress (Gpx3, Gstm3, Sod3) or Alzheimer's disease (Sncb, Apbb1ip) were altered by both fluoxetine and SJW extract. For all groups, several signaling pathways were identified which could provide a link between the various hypotheses of depression. CONCLUSION: In conclusion, microarray analysis proved to be a valuable tool to identify a large number of genes and resulting pathways that may serve as novel drug targets or predict drug responsiveness for SJW or fluoxetine. Based on our comprehensive analysis, it was possible to identify similarities and differences between SJW and fluoxetine which may help to better understand their molecular action and, in addition, help to find novel treatment strategies for stress-related depression. PMID- 20924751 TI - Acute effects of MDMA (3,4-methylenedioxymethamphetamine) on EEG oscillations: alone and in combination with ethanol or THC (delta-9-tetrahydrocannabinol). AB - RATIONALE: Typical users of 3,4-methylenedioxymethamphetamine (MDMA or "ecstasy") are polydrug users, combining MDMA with alcohol or cannabis [most active compound: delta-9-tetrahydrocannabinol (THC)]. OBJECTIVES: The aim of the present study was to investigate whether co-administration of alcohol or THC with MDMA differentially affects ongoing electroencephalogram (EEG) oscillations compared to the administration of each drug alone. METHODS: In two separate experiments, 16 volunteers received four different drug conditions: (1) MDMA (100 mg); (2) alcohol clamp (blood alcohol concentration = 0.60/00) or THC (inhalation of 4, 6 and 6 mg, interval of 1.5 h); (3) MDMA in combination with alcohol or THC; and (4) placebo. Before and after drug administration, electroencephalography was recorded during an eyes closed resting state. RESULTS: Theta and alpha power increased after alcohol intake compared to placebo and reduced after MDMA intake. No interaction between alcohol and MDMA was found. Significant MDMA x THC effects for theta and lower-1-alpha power indicated that the power attenuation after the combined intake of MDMA and THC was less than the sum of each drug alone. For the lower-2-alpha band, the intake of MDMA or THC alone did not significantly affect power, but the intake of combined MDMA and THC significantly decreased lower-2 alpha power. CONCLUSIONS: The present findings indicate that the combined intake of MDMA and THC, but not of MDMA and alcohol, affects ongoing EEG oscillations differently than the sum of either one drug alone. Changes in ongoing EEG oscillations may be related to the impaired task performance that has often been reported after drug intake. PMID- 20924752 TI - Response requirement and increases in accuracy produced by stimulant drugs in a 5 choice serial reaction-time task in rats. AB - RATIONALE: Increased signal-detection accuracy on the 5-choice serial reaction time (5-CSRT) task has been shown with drugs that are useful clinically in treating attention deficit hyperactivity disorder (ADHD), but these increases are often small and/or unreliable. By reducing the reinforcer frequency, it may be possible to increase the sensitivity of this task to pharmacologically induced improvements in accuracy. METHODS: Rats were trained to respond on the 5-CSRT task on a fixed ratio (FR) 1, FR 3, or FR 10 schedule of reinforcement. Drugs that were and were not expected to enhance performance were then administered before experimental sessions. RESULTS: Significant increases in accuracy of signal detection were not typically obtained under the FR 1 schedule with any drug. However, d-amphetamine, methylphenidate, and nicotine typically increased accuracy under the FR 3 and FR 10 schedules. CONCLUSIONS: Increasing the FR requirement in the 5-CSRT task increases the likelihood of a positive result with clinically effective drugs, and may more closely resemble conditions in children with attention deficits. PMID- 20924753 TI - Effects of trifluoromethylphenylpiperazine (TFMPP) on interhemispheric communication. AB - BACKGROUND: 'Party Pills' containing trifluoromethylphenylpiperazine (TFMPP) and benzylpiperazine are legally available in many countries and marketed as safe alternatives to other illicit substances such as methamphetamine and methylenedioxymethamphetamine (or Ecstasy). They have gained huge popularity around the world, especially amongst young adults. However, there is no information currently available describing the acute neurophysiological effects of these psychoactive drugs in humans. The purpose of this study is to investigate the effects of TFMPP on central information processing speed in humans. METHODS: A randomised, double blind, placebo-controlled study using electroencephalography (EEG) was carried out to investigate the effects of TFMPP on interhemispheric transfer time (IHTT). Healthy, right-handed males (age: 25 +/ 5.6 years) were given placebo (n = 15) or TFMPP (0.94 mg/kg, oral, n = 15) and tested both pre- and 2 h post-drug administration. High-density EEG recordings (128 channels which were re-referenced using an average reference to make 129 electrodes) were used to record event-related potentials. The N160 component was defined as the biggest negative peak in the range between 140 and 220 ms after the event. The IHHTs were analysed by deducting the N160 latency obtained in the contralateral hemisphere from the N160 latency obtained in the hemisphere ipsilateral to stimulus signal. RESULTS: Statistical analysis using a split-plot design analysis of variance revealed that TFMPP significantly reduced the IHTT but did not affect reaction time. No statistically significant changes were observed in the placebo group. CONCLUSIONS: This study is the first to report the neurophysiological effects of TFMPP in humans and suggests that TFMPP may affect transmitter systems involved in speeding of interhemispheric communication in the male brain. PMID- 20924754 TI - Varenicline blocks nicotine intake in rats with extended access to nicotine self administration. AB - RATIONALE: Much evidence indicates that individuals use tobacco primarily to experience the psychopharmacological properties of nicotine. Varenicline, a partial alpha4beta2 nicotinic acetylcholine receptor (nAChR) agonist, is effective in reducing nicotine craving and relapse in smokers, suggesting that alpha4beta2 nAChRs may play a key role in nicotine dependence. In rats, the effect of varenicline on nicotine intake has only been studied with limited access to the drug, a model of the positive reinforcing effect of nicotine. Varenicline has not been tested on the increase in motivation to take nicotine in nicotine-dependent rats. OBJECTIVES: The present study evaluated the effects of varenicline on nicotine intake in rats with extended access to nicotine self administration (23 h/day), a condition leading to the development of nicotine dependence. We hypothesized that varenicline's effects on nicotine self administration would be greater in rats with extended than limited access to the drug and after forced abstinence rather than during baseline self-administration. RESULTS: Varenicline dose-dependently decreased nicotine self-administration in rats with limited (1 h/day) and extended (23 h/day) access. Despite an increased sensitivity to the motivational effects of abstinence on nicotine intake compared with limited-access rats, varenicline was equally effective in decreasing nicotine intake in dependent rats with extended access to nicotine. CONCLUSION: These results suggest that alpha4beta2 nAChRs are critical in mediating the positive reinforcing effects of nicotine but may not be a key element underlying the negative reinforcement process responsible for the increased nicotine intake after abstinence in dependent subjects. PMID- 20924755 TI - Frontiers of stent-assisted aneurysm coiling. PMID- 20924756 TI - Functional connectivity of the superior human temporal sulcus in the brain resting state at 3T. AB - INTRODUCTION: The superior temporal sulcus (STS) constitutes a polymodal associative area providing higher-order visual representation of other's action and emotion, necessary for imitation, empathizing, and mentalizing. In monkeys, STS is connected with the cerebellum, which is also involved in motor, emotional, and cognitive functions. However, in humans, very few data are available concerning the functional connectivity of polymodal STS in general and its functional links with the cerebellum, in particular. This study was therefore designed to investigate the intrinsically connected network of STS during the brain resting state with possible involvement of the cerebellum. METHODS: Data from 14 right-handed healthy volunteers were acquired at rest and analyzed by region of interest (ROI)-based functional connectivity. Blood-oxygen-level dependent (BOLD) signal fluctuations of separate six ROIs located in the right and left posterior, medial, and anterior STS were successively used to identify significant temporal correlations with BOLD signal fluctuations of other brain regions. RESULTS: Low-frequency BOLD signals of the right and left posterior, medial, and lateral STS share a common bilateral circuit encompassing the ventrolateral prefrontal, premotor/motor, insular, parietal temporal, occipital, and cerebellar cortices (lobules VI/VIIA), thalamus, and striatum. CONCLUSION: The STS-centered network (1) is intrinsically connected during the brain resting, (2) encompasses the whole caudalmost two thirds of STS, (3) may partly represent the whole STS structural connectivity, and includes the motor and cognitive neocerebellum (lobules VI/VIIA). PMID- 20924757 TI - Microstructural brain injury in post-concussion syndrome after minor head injury. AB - INTRODUCTION: After minor head injury (MHI), post-concussive symptoms commonly occur. The purpose of this study was to correlate the severity of post-concussive symptoms in MHI patients with MRI measures of microstructural brain injury, namely mean diffusivity (MD) and fractional anisotropy (FA), as well as the presence of microhaemorrhages. METHODS: Twenty MHI patients and 12 healthy controls were scanned at 3 T using diffusion tensor imaging (DTI) and high resolution gradient recalled echo (HRGRE) T2*-weighted sequences. One patient was excluded from the analysis because of bilateral subdural haematomas. DTI data were preprocessed using Tract Based Spatial Statistics. The resulting MD and FA images were correlated with the severity of post-concussive symptoms evaluated with the Rivermead Postconcussion Symptoms Questionnaire. The number and location of microhaemorrhages were assessed on the HRGRE T2*-weighted images. RESULTS: Comparing patients with controls, there were no differences in MD. FA was decreased in the right temporal subcortical white matter. MD was increased in association with the severity of post-concussive symptoms in the inferior fronto occipital fasciculus (IFO), the inferior longitudinal fasciculus and the superior longitudinal fasciculus. FA was reduced in association with the severity of post concussive symptoms in the uncinate fasciculus, the IFO, the internal capsule and the corpus callosum, as well as in the parietal and frontal subcortical white matter. Microhaemorrhages were observed in one patient only. CONCLUSIONS: The severity of post-concussive symptoms after MHI was significantly correlated with a reduction of white matter integrity, providing evidence of microstructural brain injury as a neuropathological substrate of the post-concussion syndrome. PMID- 20924760 TI - Land use intensity controls actinobacterial community structure. AB - Actinobacteria are major producers of secondary metabolites; however, it is unclear how they are distributed in the environment. DNA was extracted from forest, pasture and cultivated soils, street sediments (dust and material in place), and sediments affected by animal activity (e.g. guano, vermicompost) and characterised with two actinobacterial and a bacterial-specific 16S rDNA primer set. Amplicons (140/156) generated with the two actinobacterial-specific and amplicons (471) generated with bacterial-specific primers were analysed. Amplicons from actinobacterial-specific primer were disproportionately actinomycetal from animal-affected (soil) samples and street sediments and either verrucomicrobial (i.e. non-actinobacterial) and from a novel non-actinomycetal actinobacterial group for soils. Actinobacterial amplified ribosomal DNA restriction analysis and terminal restriction fragment length polymorphism fingerprints clustered by land use, with cultivated soils clustering apart from uncultivated soils. Actinobacterial amplicons generated with eubacterial primers were overwhelmingly from (116/126) street sediments; acidobacterial amplicons from soils (74/75). In two street samples, >90% of clones were actinomycetal. Actinomycetes are selected in terrestrial soils and sediments by cultivation, urbanisation and animal activity. PMID- 20924761 TI - Isotope-guided surgery for nonpalpable breast cancer. AB - BACKGROUND: The hook-wire technique is used to guide surgical excision of nonpalpable breast lesions. Recently, isotope has been used to guide the excision, and when sentinel node biopsy is performed during the same operation, the procedure is termed Sentinel Node and Occult Lesion Localization (SNOLL). We evaluated the use of this procedure for nonpalpable cancers in Chinese women. METHODS: Seventy-four patients underwent SNOLL before breast-conserving surgery. Intratumoral injection of sulfur colloid and lymphoscintigraphy (LSG) were performed. A gamma probe was used for resection planning and localization of the sentinel node (SN). Blue dye mapping was used in patients with negative LSG. Complete excision was defined as a tumor-free margin greater than 1 mm. RESULTS: The primary breast lesion was successfully removed in 73 patients (99%). Complete excision was achieved in 61 patients (82%). Drainage to axilla was detected by LSG in 53 patients (72%). The gamma probe was more sensitive than LSG and had an 82% SN identification rate. Patients with a positive LSG had a higher chance of SN localization by gamma probe than patients with a negative LSG (100% vs. 38%, p < 0.001). In patients with a negative LSG, supplementary blue dye mapping increased the SN localization rate from 38 to 90%. The SN identification rate was 97% in the whole series. CONCLUSION: Isotope-guided surgery was reliable, with a 99% localization rate for nonpalpable breast lesions and an 82% SN localization rate. The success rate of SN identification could be improved to 97% with the addition of blue dye mapping for patients with negative drainage on lymphoscintigraphy. PMID- 20924762 TI - Detection of type II endoleak after endovascular aortic repair: comparison between magnetic resonance angiography and blood-pool contrast agent and dual phase computed tomography angiography. AB - PURPOSE: This prospective study was designed to assess the diagnostic value of magnetic resonance angiography (MRA) with blood-pool contrast agent (gadofosveset) in the detection of type-II endoleak after endovascular aortic repair (EVAR). METHODS: Thirty-two patients with aortic aneurysms who had undergone EVAR were included in this study. All patients were examined by dual phase computed tomography angiography (CTA) as well as MRA with gadofosveset in the first-pass and steady-state phases. Two independent readers evaluated the images of CTA and MRA in terms of endoleak type II, feeding vessel, and image quality. RESULTS: Median follow-up-time after EVAR was 22 months (range 4 to 59). Endoleak type II was detected by CTA in 12 of 32 patients (37.5%); MRA detected endoleak in all of these patients as well as in another 9 patients (n = 21, 65.6%), of whom the endoleaks in 6 patients showed an increasing diameter. Most endoleaks were detected in the steady-state phase (n = 14). The decrease in diameter of the aneurysmal sac was significantly greater in the patients without a visible endoleak that was visible on MRA (P = 0.004). In the overall estimation of diagnostic accuracy, MRA was judged superior to CTA in 66% of all examinations. CONCLUSION: MRA with gadofosveset appeared superior to CTA, and has higher diagnostic accuracy, in the detection of endoleak after EVAR. PMID- 20924763 TI - [Histopathological diagnosis and differential diagnosis of colorectal serrated polys: findings of a consensus conference of the working group "gastroenterological pathology of the German Society of Pathology"]. AB - Until recently, two major types of colorectal epithelial polyps were distinguished: the adenoma and the hyperplastic polyp. While adenomas - because of their cytological atypia - were recognized as precursor lesions for colorectal carcinoma, hyperplastic polyps were perceived as harmless lesions without any potential for malignant progression, mainly because hyperplastic polyps lack cytological atypia. Meanwhile, it is evident that the lesions formerly classified as hyperplastic represent a heterogeneous group of polyps, some of which exhibit a significant risk of neoplastic progression. These lesions show characteristic epigenetic alterations not commonly seen in colorectal adenomas and progress to colorectal carcinoma via the so-called serrated pathway (CIMP pathway). This group of polyps is comprised not only of hyperplastic polyps, but also of sessile serrated adenomas (SSA), traditional serrated adenomas (TSA) and mixed polyps, showing serrated and "classical" adenomatous features. In a consensus conference of the working group of gastroenterological pathology of the German Society of Pathology, standardization of nomenclature and diagnostic criteria as well as recommendations for clinical management of these serrated polyps were formulated and are presented herein. PMID- 20924764 TI - Prospective study of a cementless total hip arthroplasty with a collum femoris preserving stem and a trabeculae oriented pressfit cup: minimun 6-year follow-up. AB - AIM: Tissue sparing hip prostheses are becoming more and more popular especially for the treatment of younger patients. The objective of this study was to evaluate the clinical and radiological results after insertion of a tissue sparing hip prosthesis. METHOD: In 47 consecutive non-selected patients (50 hips), the clinical and radiographic results of cementless total hip arthroplasty using a collum femoris preserving stem, a pressfit cup and an alumina polyethylene pairing were prospectively evaluated. The mean age at index-surgery was 58 (36-82) years, there were 38 women and 9 men. After a mean follow-up of 6.8 years (minimum 6.1 years), two patients had died and one patient underwent revision surgery due to aseptic loosening of the stem. RESULTS: The overall survival rate of the acetabular component was 100% and of the femoral component 98%. The mean Harris hip score at follow-up was 94 points. CONCLUSION: The mid term survival with this type of total hip arthroplasty is excellent and compares equal with uncemented straight stems in this age group. PMID- 20924765 TI - Involvement of root ABA and hydraulic conductivity in the control of water relations in wheat plants exposed to increased evaporative demand. AB - We studied the possible involvement of ABA in the control of water relations under conditions of increased evaporative demand. Warming the air by 3 degrees C increased stomatal conductance and raised transpiration rates of hydroponically grown Triticum durum plants while bringing about a temporary loss of relative water content (RWC) and immediate cessation of leaf extension. However, both RWC and extension growth recovered within 30 min although transpiration remained high. The restoration of leaf hydration and growth were enabled by increased root hydraulic conductivity after increasing the air temperature. The use of mercuric chloride (an inhibitor of water channels) to interfere with the rise on root hydraulic conductivity hindered the restoration of extension growth. Air warming increased ABA content in roots and decreased it in shoots. We propose this redistribution of ABA in favour of the roots which increased the root hydraulic conductivity sufficiently to permit rapid recovery of shoot hydration and leaf elongation rates without the involvement of stomatal closure. This proposal is based on known ability of ABA to increase hydraulic conductivity confirmed in these experiments by measuring the effect of exogenous ABA on osmotically driven flow of xylem sap from the roots. Accumulation of root ABA was mainly the outcome of increased export from the shoots. When phloem transport in air-warmed plants was inhibited by cooling the shoot base this prevented ABA enrichment of the roots and favoured an accumulation of ABA in the shoot. As a consequence, stomata closed. PMID- 20924766 TI - The spatial scale of density-dependent growth and implications for dispersal from nests in juvenile Atlantic salmon. AB - By dispersing from localized aggregations of recruits, individuals may obtain energetic benefits due to reduced experienced density. However, this will depend on the spatial scale over which individuals compete. Here, we quantify this scale for juvenile Atlantic salmon (Salmo salar) following emergence and dispersal from nests. A single nest was placed in each of ten replicate streams during winter, and information on the individual positions (+/-1 m) and the body sizes of the resulting young-of-the-year (YOY) juveniles was obtained by sampling during the summer. In six of the ten streams, model comparisons suggested that individual body size was most closely related to the density within a mean distance of 11 m (range 2-26 m). A link between body size and density on such a restricted spatial scale suggests that dispersal from nests confers energetic benefits that can counterbalance any survival costs. For the four remaining streams, which had a high abundance of trout and older salmon cohorts, no single spatial scale could best describe the relation between YOY density and body size. Energetic benefits of dispersal associated with reduced local density therefore appear to depend on the abundance of competing cohorts or species, which have spatial distributions that are less predictable in terms of distance from nests. Thus, given a trade off between costs and benefits associated with dispersal, and variation in benefits among environments, we predict an evolving and/or phenotypically plastic growth rate threshold which determines when an individual decides to disperse from areas of high local density. PMID- 20924767 TI - Complications of the treatment of endoscopic biliary strictures developing after liver transplantation. AB - BACKGROUND: Bile duct strictures remain a major source of morbidity after orthotopic liver transplantation (OLT). Endoscopic management by the conventional methods of biliary dilatation and/or stent placement has been successful, but sometimes severe complications occur, necessitating prolonged therapy. The aim of this study is to clarify the complications of the endoscopic approach for endoscopic dilatation and/or stent placement. METHOD: Of 46 patients who underwent living-donor liver transplantation, 10 were diagnosed as having anatomic biliary strictures by endoscopic retrograde cholangiopancreatography (ERCP). Two patients developing biliary strictures after deceased-donor liver transplantation were also enrolled in the study. For the purpose of comparison, 302 patients with a total of 550 consecutive ERCP cases (including 115 patients with 250 malignant bile duct strictures) were recruited in this study. Success rate, number of endoscopy sessions, the median procedure time for ERCP, and incidence of complications including post-ERCP pancreatitis were compared in the OLT cases and other cases. RESULTS: The following results were obtained in the OLT cases, malignant stricture cases, and all cases, respectively: mean number of endoscopy sessions was 3.62, 2.17, and 1.94 (P = 0.0216, P < 0.0001); post-ERCP pancreatitis occurred in 5 (12.5%), 10 (4.0%), and 19 cases (3.5%) (P = 0.0327, P = 0.0093); and severe pancreatitis occurred in 2 cases of OLT. In a univariate analysis for post-ERCP pancreatitis, OLT was extracted as the only significant risk factor. CONCLUSIONS: Endoscopic maneuvering for biliary dilatation and/or stent placement following OLT was associated with a higher risk of post-ERCP pancreatitis than the use of the same technique for the treatment of malignant biliary stricture. Endoscopic treatment after OLT was a significant risk factor for post-ERCP pancreatitis. PMID- 20924768 TI - Influence of parent vessel dominancy on fluid dynamics of anterior communicating artery aneurysms. AB - BACKGROUND: Parent vessel plays an important role in aneurysm formation and rupture. The diameter of either the A1 arteries is the peculiar key controlling the flow of the anterior communicating artery (ACOMA) aneurysms (ANs). OBJECTIVE: The purpose is to study the effect of parent vessel dominancy, that is, the diameter of the A1 artery, on the flow characteristics of the ACOMA ANs. METHODS: Numerical simulations for the flow patterns in six artificial models have been studied. Three models are designed with aneurysms and three models without. The two A1s were equal in two models. In the other two models, the nondominant A1 diameters were decreased by 50%. Again, the nondominant A1s were decreased by another 50% in the last two models. Each pair was designed with and without aneurysms in the ACOMA. FINDINGS: The ACOMA shows lower velocity magnitudes and wall shear stresses when the two A1s are equal. However, if one A1 is dominant with a 50% difference from the other A1, there is higher shear stress on the ACOMA itself and in the inflow zone of the aneurysm that increases more with further reduction of the nondominant A1 by another 50%. An area of high corner pressure at the bifurcation of the dominant A1 into the ACOMA and A2 exists and increases in value with the decrease of diameter of the other nondominant A1. CONCLUSION: Aneurysms located in the ACOMA with differences of 50% or more between the two A1s are subjected to more flow stresses. PMID- 20924769 TI - Comparison of stand-alone polyetheretherketone cages and iliac crest autografts for the treatment of cervical degenerative disc diseases. AB - BACKGROUND: Anterior cervical decompression and fusion (ACDF) is a widely accepted surgical procedure for the treatment of cervical degenerative disc diseases. This retrospective study was designed to analyze and compare the efficacy and outcomes of anterior cervical fusion using stand-alone polyetheretherketone (PEEK) cages and autogenous iliac crest grafts with the anterior cervical plating system. METHODS: A total of 72 consecutive patients suffering from cervical degenerative disc diseases treated with ACDF from June 2005 to Dec 2008 were enrolled in the study. Patients in group A (40 patients, 64 segments) had anterior interbody fusion with stand-alone PEEK cages and patients in group B (32 patients, 51 segments) with autogenous iliac crest graft combined with anterior plate fixation. The operative time and intraoperative blood loss were recorded. Clinical outcomes were evaluated using the Japanese Orthopaedic Association (JOA) scoring system; cervical lordosis, intervertebral height, and cervical fusion status were assessed on X-ray and computed tomography. FINDINGS: The mean follow-up period was 17.3 months in the stand-alone cage group and 23.2 months in the autologous iliac crest graft group. The operative time and intraoperative blood loss in group A were much less than those in group B (p < 0.05). All the patients in both groups got complete interbody fusion. Postoperative JOA scores in both group A and group B were more than the preoperative ones with significant differences, and the improvement rate of JOA scores had no statistical differences between group A and group B. Postoperative cervical physiological curvature and intervertebral height in both groups were better than the preoperative ones with statistical significances. CONCLUSIONS: The stand-alone PEEK cage is a good substitute for fusion in patients with cervical disc disease; it can effectively restore the cervical physiological curvature and the intervertebral height, facilitate radiological follow-up, cause few complications, and leads to satisfactory outcomes. PMID- 20924770 TI - Melon phloem-sap proteome: developmental control and response to viral infection. AB - In addition to small molecules such as sugars and amino acids, phloem sap contains macromolecules, including mRNA and proteins. It is generally assumed that all molecules in the phloem sap are on the move from source to sink, but recent evidence suggests that the macromolecules' direction of movement can be controlled by endogenous plant mechanisms. To test the hypothesis that the phloem sap protein profile is affected by local metabolic activities, we analyzed the phloem-sap proteome in young and mature tissues of melon plants. We also examined the effect of cucumber mosaic virus (CMV) infection and expression of CMV movement protein in transgenic melon plants on the phloem protein profile. Sap collected from cut sections of young stems or petioles contained specific proteins that were absent from sap collected from mature stems or petioles. Most of these proteins were involved in defense response and protection from oxidative stress, suggesting that they play a role in maintaining safe activity of the sieve tubes in young tissues. Phloem sap collected from CMV-infected plants and transgenic plants expressing the CMV movement protein contained only a few additional proteins with molecular masses of 18 to 75 kDa. Here again, most of the additional proteins were associated with stress responses. Our study indicated that the proteome of phloem sap is dynamic and under developmental control. Entry and exit of proteins from the sieve tube can be regulated at the tissue level. Moreover, the plant can maintain regulation of protein trafficking from companion cells to sieve elements under viral infection or other perturbations in plasmodesmal function. PMID- 20924771 TI - Influence of three mechanical bileaflet prosthetic valve designs on the three dimensional flow field inside a simulated aorta. AB - The current design of the bileaflet valve, the leaflets of which open outside first, differs significantly from the natural valve whose leaflets open center first. This difference generates a completely different flow field in the bileaflet valve compared to that in the natural heart valve. In a previous study, it was demonstrated that the valve design greatly affects the aortic flow field as well as the circulatory flow inside sinuses of Valsalva, using saline solution as a working fluid. A limited discussion on the turbulence flow field that could be generated by the valve was provided. In this continuation of that study, therefore, a dynamic PIV study was conducted to analyze the influence of the heart valve design on the aortic flow field, and particularly on the turbulent profile. This study also aimed to determine the influence of the viscosity of the testing fluid. Three bileaflet prostheses-the St. Jude Medical (SJM), the On-X, and the MIRA valves-were tested under pulsatile flow conditions. Flow through the central orifice of the SJM valve was slower than that through the newer designs. The newer designs tend to show strong flow through all orifices. The On-X valve generates simple jet-type flow while the MIRA valve with circumferentially curved leaflets generates a strong but three-dimensionally diffuse flow, resulting in a more complex flow field downstream of the aortic valve with higher turbulence. A 180 degrees orientation that is more popular clinically seems to provide a less diffuse flow than a 90 degrees orientation. The effect of increasing the viscosity was found to be an increase in the flow velocity through the central orifice and a more organized flow field for all of the valves tested. PMID- 20924772 TI - Childhood pineal parenchymal tumors: clinical and therapeutic aspects. AB - The aim of our study was to investigate the correlation of the clinical characteristic of pineal parenchymal tumors in children and adolescent with histopathological diagnosis and patient survival. Records of 27 patients with histologically diagnosed pineocytomas (n=16) and pineoblastoma (n=11) consecutively treated between 1991 and 2001 were reviewed retrospectively to identify factors predictive of aggressiveness. Among analyzed epidemiological, clinical, and radiological factors, we found that independent prognostic indicator in patients with childhood pineal parenchymal tumor was the extent of surgical resection. PMID- 20924773 TI - Orthostatic tolerance is difficult to predict in recurrent syncope patients. AB - OBJECTIVES: We tested the hypothesis that detailed anthropometric and hemodynamic measurements predict orthostatic tolerance in neurally mediated syncope patients. In addition, we tested whether orthostatic tolerance is related to syncope frequency in real life. BACKGROUND: Earlier studies in patients with neurally mediated syncope suggested that orthostatic heart rate and blood pressure responses predict the tilt table responses with high sensitivity and specificity. METHODS: We analyzed data from 157 consecutive patients (n = 100 exploratory cohort, n = 57 confirmatory cohort) with recurrent syncope in whom orthostatic tolerance was quantified as the time to (pre)syncope during head-up tilt testing combined with lower body negative pressure. We measured heart rate, brachial blood pressure, cardiac stroke volume, heart rate and blood pressure variability, and spontaneous baroreflex sensitivity supine and early during head-up tilt. RESULTS: The orthostatic heart rate increase showed the strongest correlation with orthostatic tolerance. The best multivariate model including age, supine diastolic blood pressure, supine blood pressure variability, as well as tilt induced changes in diastolic blood pressure and heart rate explained no more that 40% of the variability in orthostatic tolerance. The model failed to predict orthostatic tolerance in the confirmatory cohort. Frequency or number of free living syncopal episodes were only weakly related to orthostatic tolerance. CONCLUSIONS: In patients with neurally mediated syncope, orthostatic tolerance in the clinical laboratory is difficult to predict with a wide range of anthropometric and cardiovascular measurements and correlates poorly with syncope occurrence in real life. PMID- 20924775 TI - The world through a lens: a history of the Royal Society of London, and the discovery of the red blood cell. PMID- 20924774 TI - Tissue-type plasminogen activator gene targets thrombolysis in atriums. AB - Our previous investigations showed that retroviral gene transfer of tissue-type plasminogen activator (tPA) effectively targeted thrombolysis in vitro and in the model of inferior caval veins of rabbits. This study is to identify the target thrombolysis of retroviral vector recombinant pLEGFP-N1-tPA transferred into the tissue around the Dacron patch (the same materials making of the ring of mechanical valve) in left atriums of rabbits. 70 Dacron patches were transplanted into the left atriums of 70 New Zealand white rabbits. The rabbits were randomly divided into three groups according to the different handling methods, including local pLEGFP-N1-tPA transferred group (gene therapy group, 30 animals), pLEGFP-N1 transferred group (control group, 20 animals), medium DMEM + 10% neonate calf serum (NCS) injected group (blank control group, 20 animals). Samples of blood, Dacron pieces and left atriums (auricles) wall from half of above in each group were harvested on second day and another half were harvested on 75th day after surgery. The EGFP expression of harvested left atriums (auricles) wall were observed under the confocal. The thrombi on the surface of Dacron patches were detected by stereoscope and electron microscope. The tPA expression in left atriums (auricles) wall and in blood from left atriums were detected by Western blot and their thrombolysis and activities were observed and calculated in plasma plates. ELISA were used to identify the contents of tPA. No thrombus was seen on the surface of Dacron patches that were transplanted in left atriums by tPA locally transferring around them. Activity and content of tPA were high in local tissue of left atrium and in blood of left atrium. It demonstrated effectively thrombolysis by tPA rapidly, efficiently and long expressing. This puts the foundation of mechanical valve replacement model for tPA gene valve, next. PMID- 20924776 TI - Simultaneous expansion and harvest of hematopoietic stem cells and mesenchymal stem cells derived from umbilical cord blood. AB - The simultaneous expansion and harvest of hematopoietic stem cells and mesenchymal stem cells derived from umbilical cord blood were carried out using bioreactors. The co-culture of umbilical cord blood (UCB)-derived hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs) was performed within spinner flasks and a rotating wall vessel (RWV) bioreactor using glass-coated styrene copolymer (GCSC) microcarriers. The medium used was composed of serum-free IMDM containing a cocktail of SCF 15 ng.mL(-1), FL 5 ng.mL(-1), TPO 6 ng.mL(-1), IL-3 15 ng.mL(-1), G-CSF 1 ng.mL(-1) and GM-CSF 5 ng.mL(-1). Accessory stromal cells derived from normal allogeneic adipose tissue were encapsulated in alginate chitosan (AC) beads and used as feeding cells. The quality of the harvested UCB HSCs and MSCs was assessed by immunophenotype analysis, methylcellulose colony and multi-lineage differentiation assays. After 12 days of culture, the fold expansion of total cell numbers, colony-forming units (CFU-C), CD34(+)/CD45(+)/CD105(-) (HSCs) cells and CD34(-)/CD45(-)/CD105(+) (MSCs) cells using the RWV bioreactor were (3.7 +/- 0.3)- , (5.1 +/- 1.2)- , (5.2 +/- 0.4)- , and (13.9 +/- 1.2)-fold respectively, significantly better than those obtained using spinner flasks. Moreover, UCB-HSCs and UCB-MSCs could be easily separated by gravity sedimentation after the co-culture period as only UCB-MSCs adhered on to the microcarriers. Simultaneously, we found that the fibroblast-like cells growing on the surface of the GCSC microcarriers could be induced and differentiated towards the osteoblastic, chondrocytic and adipocytic lineages. Phenotypically, these cells were very similarly to the MSCs derived from bone marrow positively expressing the MSCs-related markers CD13, CD44, CD73 and CD105, while negatively expressing the HSCs-related markers CD34, CD45 and HLA-DR. It was thus demonstrated that the simultaneous expansion and harvest of UCB-HSCs and UCB-MSCs is possible to be accomplished using a feasible bioreactor culture system such as the RWV bioreactor with the support of GCSC microcarriers. PMID- 20924777 TI - What types of jobs do people with disabilities want? AB - INTRODUCTION: Do non-employed people with disabilities want to work, and if so, what types of jobs do they want? Researchers seeking to explain the low employment rate among people with disabilities have focused primarily on skill gaps, employment disincentives from disability income, accommodation mandates, and (to a lesser extent) employer attitudes and unwelcoming corporate cultures. There has been little attention paid to the attitudes of non-employed people with disabilities. METHODS: This paper uses the 2006 General Social Survey, a representative national survey of US adults that has disability information and a special supplement on worker preferences, to examine the above question. RESULTS: We find that, relative to their non-disabled counterparts, non-employed people with disabilities are (a) as likely to want a job but less likely to be actively searching, (b) as likely to have prior job experience, and (c) similar in their views of the importance of income, job security, and other valued job characteristics. The results, which vary little by type of impairment, indicate that the low employment rate of people with disabilities is not due to their reluctance to work or different job preferences. CONCLUSION: Combined with evidence that a large share of new jobs can be performed by people with disabilities, the findings point toward the value of dismantling barriers to employment facing many people with disabilities. PMID- 20924778 TI - Internet use, recreational travel, and HIV risk behaviors in men who have sex with men. AB - Previous studies have documented higher rates of HIV risk behavior in gay and bisexual men traveling for leisure. Most of these studies collected data in high risk tourist areas known for promoting alcohol and other substance use. The present study sampled a broader range of men by collecting data at a Gay Pride celebration, and asking participants about vacation experiences over the past 12 months. We also collected information about men's use of the Internet to find sexual partners before they traveled. Overall, two-thirds of participants reported recreational travel in the previous year. Of these men, 17% reported having sex with a new partner during their most recent vacation. Forty-three percent of the respondents were sexually active during their vacation. Sexually active participants reported a mean of 2.01 unprotected anal sex acts during their brief vacation stay (M = 6.2 days). Close to half of the sexually-active men reported having sex with a partner of unknown HIV status. Alcohol and drug use were associated with unprotected sex. Men who used the Internet to set up dates prior to travel reported significantly more sexual partners and were significantly more likely to report having sex with a new partner. Many gay and bisexual men on vacation report behaviors that may place their health at risk, including substance use and unprotected sexual activity. Interventions designed to reduce risk behaviors in this population are needed. PMID- 20924779 TI - Rural Latino youth park use: characteristics, park amenities, and physical activity. AB - Less than half of youth engage in sufficient physical activity to achieve health benefits. Key environmental factors of park and recreation spaces may influence youth physical activity. We sought to ascertain youth characteristics and behaviors that attract youth to parks with specific amenities and encourage physical activity while at the parks in a rural, predominantly Latino community. We examined the quality of amenities in the 13 parks and recreation spaces that middle school aged youth have access to in their community using the Environmental Assessment of Parks and Recreation Spaces (EAPRS) tool. Middle school students completed surveys in the school classroom (n = 1,102) regarding park use, physical activity, and intrapersonal characteristics (e.g., motivators). We used logistic regression to identify correlates of any park use, use of higher quality field and court parks, and active and sedentary park use. Younger age, participation in an after school activity, and identification of a team as a motivator were positively associated with any park use. Use of higher quality court and field parks was associated with participation in an after school activity and being Latino. The odds of being active in the parks were greater for boys and Latinos. Older age and alcohol use are correlated with being sedentary at the park, while odds of being sedentary at the park were lower for boys and youth who met physical activity guidelines. Organized team activities may encourage active use of higher quality fields and courts parks by Latino youth; thereby, increasing their level of physical activity. PMID- 20924780 TI - To be healthy and to live long, we have to exercise: psychosocial factors related to physical activity among Cambodian Americans. AB - Regular physical activity produces various health benefits; however, relatively few adults in the United States (US) get enough physical activity. Little is known about physical activity behaviors, and barriers and facilitators to physical activity among Cambodian-Americans. Cambodian Americans were recruited from community venues to participate in one-on-one interviews and focus groups. A total of 20 adults (10 women and 10 men) participated in one-on-one interviews and 37 adults (23 women and 14 men) participated in one of four focus groups. Fifteen of the 20 interviews and all the focus groups were conducted in Khmer. Participants were generally born in Cambodia and over two-thirds had a high school education or less. About one-half of the participants met or exceeded the 2008 US Department of Health and Human Services physical activity guidelines. Commonly reported types of physical activity were walking, running, and working out at the gym. Barriers to physical activity included lack of time, inconvenient work hours, and family responsibilities. Perceived benefits of physical activity included improved health, improved appearance, and reductions in stress. Sweating caused by physical activity was thought to produce a variety of health benefits. Data from this qualitative study could be used to inform the development of culturally-relevant physical activity survey measures and culturally-relevant physical activity interventions for Cambodian Americans. PMID- 20924781 TI - Impact of timing of sex education on teenage pregnancy in Nigeria: cross sectional survey of secondary school students. AB - The objective of this study was to explore whether the time at which sex education was provided had any impact on reported cases of unintended pregnancies. A cross-sectional survey of secondary school students and their teachers was conducted using self-administered questionnaires. The participants were 1,234 students aged 14-17 years and 46 teachers in 5 secondary schools in South Eastern Nigeria. The outcome measures were reported pregnancies within the last 3 years by type of school and class level; class level at the time of receiving sex education at school; and age at the time of receiving sex education at home. In all schools, sex education was provided at all the junior and senior secondary school levels (JSS and SSS, respectively). Overall, reported cases of unintended pregnancies were highest among the junior students. In the private schools, four in ten teachers reported pregnancies among JSS 3 students. Almost four in ten teachers in public schools reported pregnancies among JSS 2 students. Of all the students, about three in ten reported pregnancies among JSS 2 and 3 students respectively. At home, sex education was provided at the mean age of 16 years (SD +/- 2.2). All participants cited financial need and marital promise as major predisposing factors. About four in ten students did not use contraceptives during their first sexual experience. This study highlights the need to introduce sex education much earlier, possibly before the JSS levels. At home, sex education may have greater impact if provided before the age of 14 years. Efforts should be made to address the factors predisposing to teenage pregnancy. PMID- 20924782 TI - Dangerous subtlety: relationship-related determinants of consistency of condom use among female sex workers and their regular, non-commercial partners in Hai Phong, Viet Nam. AB - Research indicates female sex workers use condoms more consistently with their clients than with regular, non-commercial partners (partners). The purpose of this study was to better understand the relationship between couple communication and HIV risk behavior by examining (1) sex worker-partner divergence on communication measures and (2) the association between intra-couple communication divergence and consistent condom use. In this cross-sectional study, 50 sex workers and their partners in Hai Phong, Viet Nam were separately asked about their relationships and condom use. When asked about HIV risk communication in their relationship, sex workers reported significantly higher HIV communication content than their partners (p < 0.001). Higher communication divergence between partners was associated with a decreased likelihood of consistent condom use (OR 0.54 95% CI 0.30, 0.97). Sex workers urgently need interventions that build their communication skills and address their risk behavior in non-commercial relationships. PMID- 20924784 TI - Sequence analysis of the lactoferrin gene and variation of g.7605C->T in 10 Chinese indigenous goat breeds. AB - Much attention has been focused on the study of lactoferrin at the protein or nucleotide level in mice, humans, and cattle, but little is known about it in goats. The goat LF gene from 5' UTR to exon 17 was amplified, and the variation of g.7605C->T in 10 Chinese indigenous goat breeds was analyzed. Among the three ruminant species (cattle, sheep, and goats), the intron-exon distribution pattern was similar, and all the exons had the same length, but the length of introns varied greatly due to insertions or deletions. The frequency of allele T at g.7605C->T (50.12%) was a little higher than that of allele C (49.88%), and the genotype distribution differed greatly between goat populations. The g.7605C->T site showed higher genetic diversity in goat populations. The genetic differentiation was 0.0783, and gene flow was 2.9433 among the 10 Chinese indigenous goat populations. PMID- 20924783 TI - Scaling up circumcision programs in Southern Africa: the potential impact of gender disparities and changes in condom use behaviors on heterosexual HIV transmission. AB - Circumcision significantly reduces female-to-male transmission of HIV infection, but changes in behavior may influence the overall impact on transmission. We sought to explore these effects, particularly for societies where women have less power to negotiate safe sex. We developed a compartmental epidemic model to simulate the population-level impact of various circumcision programs on heterosexual HIV transmission in Soweto. We incorporated gender-specific negotiation of condom use in sexual partnerships and explored post-circumcision changes in condom use. A 5-year prevention program in which only an additional 10% of uncircumcised males undergo circumcision each year, for example, would prevent 13% of the expected new HIV infections over 20 years. Outcomes were sensitive to potential changes in behavior and differed by gender. For Southern Africa, even modest programs offering circumcision would result in significant benefits. Because decreases in male condom use could diminish these benefits, particularly for women, circumcision programs should emphasize risk-reduction counseling. PMID- 20924785 TI - Molecular cloning and expression profile analysis of three sunflower (Helianthus annuus) diterpene synthase genes. AB - ent-Kaurene, a key precursor of gibberellins, is formed by the action of two diterpene synthases (diTPSs), ent-copalyl diphosphate synthase (CPS), and ent kaurene synthase (KS). The full-length cDNAs of CPS- (HaCPS1L) and KS-like (HaKS2L and HaKS3L) genes were isolated from sunflower. The amino acid sequences of HaCPS1L, HaKS2L, and HaKS3L exhibit structural features and homology to diTPSs of several plant species involved in gibberellin biosynthesis. RT-PCR analysis indicates that the expression of all genes (HaCPS1L, HaKS2L, and HaKS3L) is highly regulated during growth and development. All three diTPSs are preferentially expressed in rapidly growing tissues. HaKS2L is expressed at a much lower level than the other two diTPS genes. During seed development, the high level of both HaCPS1L and HaKS3L transcripts correlated with the period of rapid growth of the embryo. The three diTPS genes are not subjected to feedback regulation by gibberellin activity. PMID- 20924786 TI - New graduates' conceptions of and approaches to veterinary professional practice, and relationships to achievement during an undergraduate internship programme. AB - New graduate veterinarians report differing experiences of the transition to practice. Some make a rapid transition to professional autonomy while others require prolonged and extensive support from their colleagues. Factors contributing to this variation are unclear. This study used phenomenography to analyse the conceptions of and approaches to veterinary professional practice (VPP) reported by new graduates in semi-structured interviews (n = 22). Quantitative statistical analysis was used to investigate links between the quality of graduates' experiences and their achievement during a comprehensive final year internship programme. Strong associations were identified between the quality of graduates' conceptions of and approaches to VPP. Links were also established between the quality of graduates' conceptions of VPP and their performance in practice prior to graduation. The outcomes of this research can be used to improve teaching and assessment during final year internships and enhance graduate attribute statements for professional degree programmes. The results also indicate that student learning research methodologies can be used to evaluate the quality of graduates' experiences in the workplace. This has implications for career outcomes research in a range of healthcare professions. PMID- 20924787 TI - Silica-supported sulfonic acid-functionalized ionic liquid coated with [bmim][PF6] as a scavenger for the synthesis of amides. AB - The methodology of using a silica gel-supported functionalized ionic liquid as a scavenger in the purification of parallel synthesis products was demonstrated. Silica-supported sulfonic acid-functional ionic liquid was synthesized by etherification, aminate, and quaternary aminate from activated silica gel and 3 chloropropyl trimethoxysilane, imidazole, and 1,4-butanesultone, which was followed by acidification using trifluoromethanesulfonic acid and anion exchange with potassium hexafluorophosphate. A conventional ionic liquid, 1-butyl-3 methylimidazolium hexafluorophosphate was then used to coat the surface of the silica gel. The silica-supported functionalized ionic liquid was used as a scavenger in the removal of excess amine in the parallel synthesis of amides. Desired products were obtained in excellent yields and purity with a sequestration time of less than 100 min at room temperature. After scavenging, the scavenger was easily filtered out and regenerated. PMID- 20924788 TI - Crisis visits and psychiatric hospitalizations among patients attending a community clinic in rural Southern California. AB - Ethnic minorities from disadvantaged socioeconomic backgrounds report increased utilization of mental health emergency services; however findings have been inconsistent across ethnic/racial groups. In this study we describe patients who present to a rural crisis unit in Southern California, examine rates of psychiatric hospitalizations across ethnic/racial groups, and investigate factors that are associated with increased psychiatric hospitalizations in this sample. This is a retrospective study of 451 racially and ethnically diverse patients attending a crisis unit in Imperial County, California. Chart review and data abstraction methods were used to characterize the sample and identify factors associated with psychiatric crises and subsequent hospitalizations. The sample was predominantly Latino/Hispanic (58.5%). Based on chart review, common psychosocial stressors which prompted a crisis center visit were: (a) financial problems; (b) homelessness; (c) partner or family conflict; (d) physical and health problems; (e) problems at school/work; (f) medication compliance; (g) aggressive behavior; (h) delusional behavior; (i) addiction and (j) anxiety/depression. Bivariate analyses revealed that Hispanics had a disproportionately lower rate of psychiatric hospitalizations while African Americans had a higher rate. Multivariate analyses which included demographic, clinical and psychosocial stressor variables revealed that being African American, having a psychotic disorder, and presenting as gravely disabled were associated with a higher likelihood of hospitalization while partner/family conflict was associated with a lesser likelihood in this rural community. These data elucidate the need for longitudinal studies to understand the interactions between psychosocial stressors, ethnicity and social support as determinants of psychiatric hospitalizations. PMID- 20924789 TI - Intimate partner violence among Iraqi immigrant women in Metro Detroit: a pilot study. AB - Violence against women is an important public health problem. The objective of this study was to examine the prevalence of intimate partner violence (IPV) among immigrant Iraqi women, and to explore the association between IPV and self-rated health. A pilot study using a previously published, self-report questionnaire was carried out among a convenience sampling of 55 Iraqi women in greater Detroit. The overall prevalence of controlling behavior, threatening behavior, and physical violence was 93, 76, and 80%, respectively. Approximately 40% of the women reported having poor or fair health, and 90% reported experiencing one or more types of psychosomatic symptoms. Self-rated health was inversely related to exposure to threatening behavior and physical violence, and positively related to knowledge of one's legal rights. The prevalence of IPV in this sample was high. Results indicated a significant association between exposure to IPV and women's physical health and psychosomatic symptoms. PMID- 20924790 TI - Report from the 4th annual Society of Cardiac Computed Tomography Japan Forum. PMID- 20924791 TI - Assessment of left ventricular volumes; reliable by gated SPECT? PMID- 20924792 TI - The culprit lesion score on multi-detector computed tomography can detect vulnerable coronary artery plaque. AB - Vulnerable plaques are characterized by large lipid cores, positive remodeling and small coronary calcium deposits. Multi-detector computed tomography (MDCT) has recently been shown to be able to characterize coronary artery plaques. The aim of this study was to evaluate culprit coronary lesions for differentiating acute coronary syndrome (ACS) from stable angina pectoris (SAP) using MDCT. 64 slice MDCT was conducted on 71 patients (ACS: 35, SAP: 36). The culprit coronary lesions were assessed according to the type and plaque attenuation (PA) of the plaque and the remodeling index (RI) as the ratio of the lesion and the reference area. The culprit lesion score (CLS) was defined as the sum of every score as 1.2 for a PA <= 60 Hounsfield units (HU), 1.1 for a RI >= 1.05 and 1.2 for a non calcified or spotty calcification. More spotty calcification (95.0% vs. 23.1%, P < 0.001), a lower PA (40.17 +/- 20.08 HU vs. 96.96 +/- 58.19 HU, respectively, P < 0.001) and a higher RI (1.44 +/- 0.43 vs. 0.90 +/- 0.44, respectively, P < 0.001) were observed in the ACS patients. Also, the CLS of the ACS patients was significantly higher than that of the SAP patients (3.07 +/- 0.63 vs. 1.18 +/- 1.12, respectively, P < 0.001). A CLS more than 2.0 helped us to differentiate ACS from SAP with a sensitivity of 97.1% and a specificity of 67.6%. The CLS might be a useful tool for differentiating ACS from SAP. PMID- 20924793 TI - Reproducibility in the assessment of noncalcified coronary plaque with 256-slice multi-detector CT and automated plaque analysis software. AB - We aimed to assess intra- and inter-observer reproducibility in evaluating volume and characteristics of non-calcified coronary plaques (NCPs) using a 256-slice multi-detector computed tomography (MDCT) angiography and dedicated automated plaque analysis software in asymptomatic individuals. Forty-two NCPs from 39 patients with a vessel diameter >2 mm were evaluated using a 256-slice MDCT with dedicated automated plaque analysis software. Two independent observers analyzed the characteristics of NCPs, including plaque volume (vol), mean CT number of the NCPs in Hounsfield units (HU(mean)), and remodeling index (RI). One of the observers repeated the evaluation of all datasets after an interval of at least 4 weeks. Bland-Altman analysis and concordance correlation coefficients (CCCs) were used to determine intra- and inter-observer variability. For vol measurements, the 95% limits of agreement were -21.6 and 13.2 mm(3), and -24.6 and 20.3 mm(3) for intra- and inter-observer variability, respectively. For HU(mean) measurements, the 95% limits of agreement were -22.2 and 20.8 HU, and -21.1 and 21.0 HU for intra- and inter-observer variability, respectively. For RI measurements, the 95% limits of agreement were -0.38 and 0.39, and -0.51 and 0.36 for intra- and inter-observer variability, respectively. The CCCs was very high for all measurements, ranging from 0.90 to 0.98. Using 256-slice MDCT with dedicated automated plaque analysis software, intra- and inter-observer reproducibility were excellent in evaluating the volume and characteristics of NCP in asymptomatic individuals. PMID- 20924794 TI - ASCI 2010 standardized practice protocol for cardiac magnetic resonance imaging: a report of the Asian society of cardiovascular imaging cardiac computed tomography and cardiac magnetic resonance imaging guideline working group. AB - These practice guidelines are recommended by the Asian Society of Cardiovascular Imaging (ASCI), the sole society in Asia designated for cardiovascular imaging, to provide a framework to healthcare providers for suggested essential elements in cardiac magnetic resonance (CMR) examinations of different disease spectra. The guideline is composed of recommendations on the general technique, acquisition of some basic modules, and protocols on stress tests. The protocols for specific diseases are provided in a table format for quick reference to be easily utilized for everyday clinical CMR. PMID- 20924795 TI - Induction of the mitochondria apoptosis pathway by phytohemagglutinin erythroagglutinating in human lung cancer cells. AB - BACKGROUND: Deregulation of apoptosis will influence the balance of cell proliferation and cell death, resulting in various fatal diseases that can include cancer. In prior research reports related to cancer therapy, phytohemagglutinin, a lectin extracted from red kidney beans, demonstrated the ability to inhibit the growth of human cancer cells. However, one of its isoforms, erythroagglutinating, has yet to be evaluated on its anticancer effects. METHODS: PHA-E was used to induce apoptosis of A-549 lung cancer cells and the possible signal transduction pathway was elucidated, as measured by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, G6PD release assay, flow cytometry, and Western blot analysis. RESULTS: PHA-E treatment caused a dose-dependent increase of cell growth inhibition and cytotoxicity on A-549 cells. In annexin V/propidium iodide [i.e., PI] and TUNEL (terminal deoxynucleotidyl transferase dUTP nick-end labeling)/PI assay, we found that the rate of apoptotic cells was raised as the concentration of PHA-E increased. Treatment of A-549 cells with PHA-E resulted in enhancing the release of cytochrome c, which thus activated an increase in caspase 9 and caspase 3, the upregulation of Bax and Bad, the downregulation of Bcl-2 and phosphorylated Bad, and finally the inhibition of the epidermal growth factor receptor and its downstream signal pathway PI3K/Akt and MEK/ERK. CONCLUSIONS: PHA-E can induce growth inhibition and cytotoxicity of lung cancer cells, which is mediated through an activation of the mitochondria apoptosis pathway. These results suggest that PHA-E can be developed into a new therapeutic treatment that can be applied as an effective anti-lung cancer drug in the near future. PMID- 20924796 TI - Analysis of prognostic factors and a proposed new classification for invasive papillary mucinous neoplasms. AB - BACKGROUND: The characteristics of invasive type-intraductal papillary mucinous neoplasm (invasive IPMN) have not been fully explored due to limited reports. Furthermore, a straightforward method is needed to describe its aggressiveness. The purpose of this study was to investigate prognostic factors and to examine the clinical significance of percentage pancreatic volume occupied by the invasive component in invasive IPMN. METHODS: Of 217 patients who underwent surgical resection with a diagnosis of IPMN between 2001 and 2008, 41 had invasive IPMC. We serially sectioned pancreatic parenchyma at 5-7-mm intervals. Whole slides were reviewed by a pancreas-biliary tract special pathologist, who determined the percentage pancreatic volumes occupied by the invasive components (IC%) in whole IPMN lesions. RESULTS: By multivariate analysis, perineural invasion, metastasis, AJCC stage, and invasive component percentage (IC%) significantly predicted prognosis. IC% was found to be significantly associated with survival. Patients with an IC% <10 had a 3-year survival rate (YSR) of 100%, whereas patients with an IC% >50% had a 3 YSR of 36.5% and those with an IC% of 10-50% had a 3 YSR of 71.4% (p = 0.041). CONCLUSIONS: In addition to conventional prognostic factors, such as AJCC stage and perineural invasion, the percentage of pancreatic volume occupied by the invasive component (IC%) appears to be an important prognostic factor in invasive IPMN. The concept of IC% is straightforward, semiquantitative, and objective, and offers a means of determining tumor aggressiveness; hence, it could be a means of classifying invasive IPMN. PMID- 20924797 TI - Environmental fluctuations and level of density-compensation strongly affects the probability of fixation and fixation times. AB - The probability of, and time to, fixation of a mutation in a population has traditionally been studied by the classic Wright-Fisher model where population size is constant. Recent theoretical expansions have covered fluctuating populations in various ways but have not incorporated models of how the environment fluctuates in combination with different levels of density compensation affecting fecundity. We tested the hypothesis that the probability of, and time to, fixation of neutral, advantageous and deleterious mutations is dependent on how the environment fluctuates over time, and on the level of density-compensation. We found that fixation probabilities and times were dependent on the pattern of autocorrelation of carrying capacity over time and interacted with density-compensation. The pattern found was most pronounced at small population sizes. The patterns differed greatly depending on whether the mutation was neutral, advantageous, or disadvantageous. The results indicate that the degree of mismatch between carrying capacity and population size is a key factor, rather than population size per se, and that effective population sizes can be very low also when the census population size is far above the carrying capacity. This study highlights the need for explicit population dynamic models and models for environmental fluctuations for the understanding of the dynamics of genes in populations. PMID- 20924798 TI - Demographics, nature and treatment of orthopaedic trauma injuries occurring in an agricultural context in the West of Ireland. AB - BACKGROUND: Farming is a major industry in the West of Ireland. This prospective study examined the age profile, nature and treatment of orthopaedic injuries occurring in agricultural surroundings presenting at the Orthopaedic Unit of Merlin Park Hospital, Galway. METHODS: The cohort consisted of 70 direct or indirect farm employees presenting with orthopaedic injuries caused in an accident occurring on a farm. RESULTS: There were significantly (P < 0.01) more male than female farmers (73 vs. 27%) with a mean age of 63 years (ranging from 13 to 87 years). Average number of out-patient visits related to the injury was 3.6. Injuries involving livestock resulted in the majority of accidents (P < 0.05) with a significant rise in the number of visits with increasing age (P < 0.01) with older patients having more severe injuries. Soft tissue injuries and fractures were commonly encountered. Complex fractures were the slowest injury to heal requiring eight subsequent out-patient visits. PMID- 20924799 TI - Regulation of calpain-2 in neurons: implications for synaptic plasticity. AB - The family of calcium-dependent neutral proteases, calpains, was discovered more than 30 years ago, but their functional roles in the nervous system under physiological or pathological conditions still remain unclear. Although calpain was proposed to participate in synaptic plasticity and in learning and memory in the early 1980s, the precise mechanism regarding its activation, its target(s) and the functional consequences of its activation have remained controversial. A major issue has been the identification of roles of the two major calpain isoforms present in the brain, calpain-1 and calpain-2, and the calcium requirement for their activation, which exceeds levels that could be reached intracellularly under conditions leading to changes in synaptic efficacy. In this review, we discussed the features of calpains that make them ideally suited to link certain patterns of presynaptic activity to the structural modifications of dendritic spines that could underlie synaptic plasticity and learning and memory. We then summarize recent findings that provide critical answers to the various questions raised by the initial hypothesis, and that further support the idea that, in brain, calpain-2 plays critical roles in developmental and adult synaptic plasticity. PMID- 20924801 TI - Benefit of heart rate reduction in heart failure. PMID- 20924800 TI - Association cortex hypoperfusion in mild dementia with Lewy bodies: a potential indicator of cholinergic dysfunction? AB - Dementia with Lewy bodies (DLB) is often associated with occipital hypometabolism or hypoperfusion, as well as deficits in cholinergic neurotransmission. In this study, 11 mild DLB, 16 mild AD and 16 age-matched controls underwent arterial spin-labeled perfusion MRI (ASL-pMRI) and neuropsychological testing. Patterns of cerebral blood flow (CBF) and cognitive performance were compared. In addition, combined ASL-pMRI and ChEI drug challenge (pharmacologic MRI) was tested as a probe of cholinergic function in 4 of the DLB participants. Frontal and parieto occipital hypoperfusion was observed in both DLB and AD but was more pronounced in DLB. Following ChEI treatment, perfusion increased in temporal and parieto occipital cortex, and cognitive performance improved on a verbal fluency task. If confirmed in a larger study, these results provide further evidence for brain cholinergic dysfunction in DLB pathophysiology, and use of pharmacologic MRI as an in vivo measure of cholinergic function. PMID- 20924803 TI - Off-label drug use in pediatric anesthesia and intensive care according to official and pediatric reference formularies. AB - PURPOSE: In pediatric practice, the official drug label often does not accurately reflect the contemporary use of many drugs prescribed to children. Therefore, clinicians frequently use contemporary drug references as a source of prescribing information instead of national formularies. The objective of this study was to compare drug prescriptions between two national formularies and two commonly used contemporary pediatric reference guidelines in the operating room/postanesthetic care unit (OR/PACU), pediatric intensive care unit (PICU), and neonatal intensive care unit (NICU). METHODS: We performed a retrospective chart review of patients admitted over a one-month period to the NICU and PICU, and for one week during the same month, we reviewed charts of patients in the OR/PACU. The data collected included patients' demographic information, drugs prescribed, and dosage information. We assessed conformity with two national formularies, the Canadian Compendium of Pharmaceuticals and Specialties (CPS) and France's 2009 Dictionnaire Vidal (Vidal), and two contemporary pediatric references, the Hospital for Sick Children Handbook and Formulary and the Lexi-Comp Pediatric Dosage Handbook. RESULTS: Across the three clinical units, 59.7% (95% confidence interval [CI] 57.1-62.1%) of prescriptions were identified as being off-label, as defined by the CPS formulary. The odds of having an off-label prescription would have been substantially lower if the contemporary pediatric references (odds ratio [OR] = 0.074; 95% CI 0.065-0.084) or Vidal (OR = 0.70; 95% CI 0.63-0.77) had been used to define the label (both P < 0.001 compared with the CPS). CONCLUSION: Drugs are less likely to be off-label if prescribed according to a contemporary pediatric reference rather than according to national formularies. Methodologies used to compile contemporary references might serve as templates to inform a drug's official label. PMID- 20924804 TI - Editorial: osteoimmunology. PMID- 20924806 TI - Comparison of MALDI TOF with conventional identification of clinically relevant bacteria. AB - BACKGROUND: A completely new approach to diagnose microbial agents at least one day earlier based on mass spectrometric analysis becomes possible in the microbiology laboratory: MALDI TOF: matrix-assisted laser desorption/ionisation time-of-flight. Comparison between results of the new procedure with those obtained by conventional testing is mandatory. METHODS: 204 clinical isolates grown on agar plates were analysed both, by the MALDI TOF Bruker microflex apparatus and by conventional identification using the VITEK II and API systems, both from bioMerieux. RESULTS: Of the identified isolates, 72 were gram-positive and 130 gram-negative; 2 were yeasts (candida). Concordance was seen with 61/72 (85%) of the Gram-positive bacteria and with 115/130 (88%) of the Gram-negative bacteria. In 27 samples (13.2%), a discrepancy of the species and/or genus was obvious. The discrepancy appeared with 16 gram-negative (12.2%) and with 11 gram positive germs (15.3%, n.s.). In the latter group, 6 samples showed discordance with Streptococcus pneumoniae (MALDI) and Streptococcus mitis/oralis (conventional identification) constellation. Among gram-negative samples, most differences occurred on the species level only, e.g. Enterobacter cloacae versus Enterobacter kobei. In 5 cases, discordance was major and appeared on the genus level: Enterobacter/Raoultella, Streptococcus/Gemella, Pseumdomonas/Burkholderia, Microbacter/Sphingomonas and Candida/Cryptococcus. The most outstanding difference was Microbacterium arborescens (MALDI TOF) and Sphingomonas paucimobilis (conventional). Molecular biological identification of two Streptococcus mitis group bacteria confirmed the erroneous diagnosis by MALDI TOF of Streptococcus pneumoniae. CONCLUSION: Good comparability between MALDI TOF analysis and conventional identification procedures (86.8%) but special caution is needed when identifying streptococcal species. PMID- 20924807 TI - Credit and authorship practices: educational and environmental influences. AB - A survey on credit issues of academic chemists in U.S. Ph.D.-granting institutions was conducted. The respondents rated 15 criteria for authorship of scientific publications; core intellectual contributions received the highest ratings although making a single suggestion that was essential to the successful completion of the project was rated very low. Acquisition of data was also rated highly. The respondents rated eight potential influences on their own "policy" toward giving credit; doing what "seems to be the right thing" was the highest rated influence followed by graduate educational experiences; professional society or other responsible conduct of research (RCR) institutional policies were rated, by far, the lowest. PMID- 20924808 TI - Open review of science publications. AB - Publication of scientific research in print is traditionally peer reviewed anonymously prior to publication, which is a time-tested process but has serious limitations. The advent of the Internet permits postpublication open review online after minimal review by the editors or the author-selected reviewers, which can be quick, that permits the authors to revise the content. Most meritorious articles published online may be selected for publication in print as annual or biennial collections. PMID- 20924809 TI - Commentary: the public health consequences of an industry-influenced psychiatric taxonomy: "attenuated psychotic symptoms syndrome" as a case example. AB - Determining the distribution of psychiatric disorders and developing sound preventive and intervention practices are pressing public health issues. Since at present mental disorders lack biological markers, psychiatric taxonomies must grapple with how best to address issues of validity and reliability. With the increasing congruence between the International Classification of Diseases (ICD 11) and the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) (American Psychiatric Association, 2010), it is imperative that decisions regarding the inclusion of new disorders be research-based and not unduly influenced by industry. The first draft of DSM-V, recently made public, has created a firestorm of controversy, for the DSM's nomenclature of disease or other pathology not only affects such disparate domains as jurisprudence and insurance claims but is also an instrument designed to facilitate research on psychopathology. PMID- 20924810 TI - Sigsearch: a new term for post hoc unplanned search for statistically significant relationships with the intent to create publishable findings. AB - Post-hoc secondary data analysis with no prespecified hypotheses has been discouraged by textbook authors and journal editors alike. Unfortunately no single term describes this phenomenon succinctly. I would like to coin the term "sigsearch" to define this practice and bring it within the teaching lexicon of statistics courses. Sigsearch would include any unplanned, post-hoc search for statistical significance using multiple comparisons of subgroups. It would also include data analysis with outcomes other than the prespecified primary outcome measure of a study as well as secondary data analyses of earlier research. PMID- 20924811 TI - The 10-word learning task in the differential diagnosis of early Alzheimer's disease and elderly depression: A cross-sectional pilot study. AB - OBJECTIVES: Identification of early Alzheimer's disease (AD) has become very important. Episodic memory tasks appear to have predictive power for indicating early AD. Deficits in encoding and storage processes that are characteristic of AD, however, must be distinguished from non-AD deficits that can also affect memory, including difficulties that may be present in depression. This pilot study was set up to ascertain whether a 10-word-list-learning task (delayed recognition and rate of forgetting) may be useful in making the differentiation between mild AD and depression. METHOD: A Dutch version of Rey's auditory verbal learning test was administered to 36 mild AD patients, 41 depressed patients, and 47 healthy controls. Data were analyzed in a cross-sectional manner. RESULTS: Receiver operating characteristic analyses showed that for differentiating mild AD and depression, both delayed recognition and percentage of forgetting have sufficient diagnostic accuracy. CONCLUSION: Percentage of forgetting had the highest diagnostic accuracy for differentiating mild AD and depressed patients and may be useful in the early detection of AD. PMID- 20924812 TI - The effects of enhanced program review and staff training on the management of aggression among clients in a long-term neurobehavioral rehabilitation program. AB - OBJECTIVE: This article examined the effects of staff training, staff support groups, and increased client behavior monitoring on the rate of physical aggression toward peers and objects in an older neurobehavioral population treated in a long-term neurorehabilitation program. METHODS: During the 15 months of data collection, programmatic enhancements were introduced including: Staff training and support groups, comprehensive assessment and individualized program development, and client-centered weekly and systemic monthly behavior management review. Incidents of physical aggression were assessed using staff report. Data were corroborated using multiple sources including, medical records, written incident reports, and Overt Aggression Scale-Modified for Neurorehabilitation - Extended (OAS-MNR-E). RESULTS: A total of 267 clients were present in the facility during the reporting period. The clients had neurobehavioral disability of various origins, 73% had a psychiatric diagnosis in addition to one or more medical diagnoses, and 58% had a dementia diagnosis. An already low rate of incidents of physical aggression per client month (0.02) was reduced by 77% following the implementation of programmatic enhancements. CONCLUSION: Enhanced systematic behavioral review of clients provided concurrently with staff training in non-aversive principles and ongoing staff support groups reduced the incidents of behavioral disregulation in older persons with psychiatric diagnoses, medical comorbidities, and neurobehavioral disabilities. PMID- 20924813 TI - Mediating effects of psychosocial factors on concerns about falling and daily activity in a multicomponent cognitive behavioral group intervention. AB - OBJECTIVES: Concerns about falling, or fear of falling, is highly common in old age and has adverse consequences. The development and understanding of interventions to reduce concerns about falling are therefore relevant. This study explored the mediating effects of psychosocial factors on trajectories of concerns about falling and daily activity in a multicomponent cognitive behavioral group intervention. METHOD: The study sample comprised 540 community dwelling adults aged 70 years or older, with concerns about falling and associated activity avoidance, who participated in a randomized controlled trial evaluating this intervention. Control beliefs, self-efficacy beliefs, outcome expectations, and social interactions, as potential mediators, and concerns about falling and daily activity, as outcome variables, were assessed at baseline, and at two, eight, and 14 months. Data were analyzed with mixed-effects regression models. RESULTS: Small to moderate statistically significant effects of the intervention on the potential mediators were found at nearly all follow-up assessments. Separate psychosocial factors showed modest mediating effects on the outcomes. When all mediators were taken into account simultaneously, 44-76% of the association between the intervention and the outcomes was explained. CONCLUSION: This study showed that the multicomponent cognitive behavioral intervention improved control beliefs, self-efficacy, outcome expectations, and social interactions. These variables mediated the association between the intervention and concerns about falling or daily activity in community-dwelling older adults. This knowledge may facilitate further improvement and development of interventions to reduce concerns about falling and to increase daily activity. PMID- 20924815 TI - Resident-to-resident relational aggression and subjective well-being in assisted living facilities. AB - PURPOSE: Research in settings similar to assisted living facilities suggests that relational aggression, an indirect and mature form of aggression, might occur in assisted living facilities. This empirical study investigates the existence of relational aggression in a sample of residents and the relationship between relational aggression and resident's subjective well-being. DESIGN AND METHODS: 121 residents from six assisted living facilities completed questionnaires assessing personal experiences as victims of relational aggression and subjective well-being. Also nurses reported on victimization of relational aggression for every participant. Linear regression models were used to examine the association between both reports of relational aggression and subjective well-being. RESULTS: Relational aggression was shown to exist in assisted living facilities according to both residents (prevalence: 19%) and nurses (prevalence: 41%). Chi-square testing revealed no association between ratings by nurses and residents. Self reports of victimization of relational aggression were related to depression, anxiety, satisfaction with life and social loneliness, but not to emotional loneliness. Nurse-reports of victimization of relational aggression were not related to subjective well-being. IMPLICATIONS: Self-reports of relational aggression seem to be better predictors of resident's well-being than nurse reports of relational aggression. Awareness of these findings and the discrepancy between nurse-reports and self-reports are important for practice and for future research regarding social dynamics and living arrangements in elderly care settings. PMID- 20924814 TI - Correlates of spirituality in older women. AB - INTRODUCTION: The role of spirituality in the context of mental health and successful aging is not well understood. In a sample of community-dwelling older women enrolled at the San Diego site of the Women's Health Initiative study, we examined the association between spirituality and a range of variables associated with successful cognitive and emotional aging, including optimism, resilience, depression, and health-related quality of life (HRQoL). METHODS: A detailed cross sectional survey questionnaire on successful aging was completed by 1973 older women. It included multiple self-reported measures of positive psychological functioning (e.g., resilience and optimism), as well as depression and HRQoL. Spirituality was measured using a five-item self-report scale constructed using two items from the Brief Multidimensional Measure of Religiosity/Spirituality and three items from Hoge's Intrinsic Religious Motivation Scale. RESULTS: Overall, 40% women reported regular attendance in organized religious practice, and 53% reported engaging in private spiritual practices. Several variables were significantly related to spirituality in bivariate associations; however, using model testing, spirituality was significantly associated only with higher resilience, lower income, lower education, and lower likelihood of being in a marital or committed relationship. CONCLUSIONS: Our findings point to a role for spirituality in promoting resilience to stressors, possibly to a greater degree in persons with lower income and education level. Future longitudinal studies are needed to confirm these associations. PMID- 20924816 TI - Silver Memories: implementation and evaluation of a unique radio program for older people. AB - OBJECTIVES: A unique radio program, Silver Memories, specifically designed to address social isolation and loneliness in older people by broadcasting music (primarily), serials and other programs relevant to the period when older people grew up--the 1920-1950s--first aired in Brisbane, Australia, in April 2008. The impact of the program upon older listeners' mood, quality of life (QOL) and self reported loneliness was independently evaluated. METHOD: One hundred and thirteen community-dwelling persons and residents of residential care facilities, aged 60 years and older participated in a three month evaluation of Silver Memories. They were asked to listen to the program daily and baseline and follow-up measures of depression, QOL and loneliness were obtained. Participants were also asked for their opinions regarding the program's quality and appeal. RESULTS: The results showed a statistically significant improvement in measures of depression and QOL from baseline to follow-up but there was no change on the measure of loneliness. The results did not vary by living situation (community vs. residential care), whether the participant was lonely or not lonely, socially isolated or not isolated, or whether there had been any important changes in the participant's health or social circumstances throughout the evaluation. CONCLUSION: It was concluded that listening to Silver Memories appears to improve the QOL and mood of older people and is an inexpensive intervention that is flexible and readily implemented. PMID- 20924817 TI - Older adults and smoking: Characteristics, nicotine dependence and prevalence of DSM-IV 12-month disorders. AB - OBJECTIVES: There are few studies investigating the characteristics of older smokers. Research on younger adults has determined that (1) the diagnostic and statistical manual (DSM) diagnosis of nicotine dependence (ND) excludes a sizable portion of the smoking population, and (2) younger smokers have high rates of comorbid DSM disorders. In this study, we sought to replicate these results in an older population. METHOD: Based on a large representative sample, we examined the smoking patterns in adults aged 50 and over (N = 2139). We describe the characteristics of the current smokers (n = 410). We identified differences in smoking characteristics and prevalence rates of DSM-IV 12-month diagnoses by smoking severity. RESULTS: Most smokers did not meet the criteria for DSM 12 month ND. Older smokers identified as having ND were first diagnosed at a relatively older age. Smokers with ND differed from smokers without a diagnosis in several ways: they smoked more; they had more symptoms of ND and had substantially higher rates of comorbid DSM 12-month disorders. Nonetheless, there were a number of older smokers with dependency symptoms who continue to smoke throughout their lifetimes, but never meet the criteria for ND. CONCLUSION: Smokers without ND are most likely to have a mood disorder whereas those smokers with ND are most likely to have an anxiety or substance use disorder. Smokers without ND still have relatively high rates of dependency symptoms. Given the late onset of ND, smoking dependence may be a progressive disorder. High rates of psychiatric disorders may interfere with smoking cessation. PMID- 20924818 TI - Prospective end-of-life treatment decisions and perceived vulnerability: Future time left to live and memory self-efficacy. AB - OBJECTIVE: Public policy and opinion support autonomous medical decision-making; however, research on perceptions related to future functioning that may influence health-related decisions is limited. Additional research is needed to understand individual perceptions for engaging in future life-sustaining treatment decisions. METHODS: Perceived time left to live and memory self-efficacy were assessed among 77 adults (M = 74.5 +/- 7.18 years) indicating preferences for cardiopulmonary resuscitation, mechanical ventilation, and artificial feeding and fluids in hypothetical illness scenarios. RESULTS: Participants with a more expansive perspective of future time, less perceived change in memory, greater perceived memory capacity, and greater depressive symptomatology and Blacks/African Americans had greater overall desire for treatment. CONCLUSION: Differences in perceived time left to live and memory beliefs affect treatment desires in ways that may not be recognized by families and/or physicians. Identifying perceptions associated with end-of-life treatment preferences may improve interventions that facilitate quality care through patient autonomy. PMID- 20924819 TI - Analysis of the moderating effect of self-efficacy domains in different points of the dementia caregiving process. AB - INTRODUCTION: Studies analyzing the moderator role of self-efficacy have centered their attention on the relationship between stressors and distress. However, drawing upon the stress and coping model, the moderator effects of self-efficacy may appear in the relationship between other key elements of the stress process. OBJECTIVES AND METHOD: The purpose of this study was to analyze, in a sample of 167 dementia family caregivers, (1) the moderating effect of self-efficacy for managing behavioral problems on the relationship between frequency of behavioral problems and burden; and (2) the moderating effect of self-efficacy for controlling upsetting thoughts on the relationship between burden and caregivers' distress (depression and anxiety). RESULTS: While no support has been found for the hypothesis that self-efficacy for managing behavioral problems moderates the relationship between frequency of behavioral problems and burden, our findings support the moderator role of self-efficacy for controlling upsetting thoughts in the relationship between burden and distress. No differences in distress measures are found between caregivers with high and low scores on self-efficacy for controlling upsetting thoughts when they report low levels of burden. However, when the levels of burden are high, caregivers with high self-efficacy for controlling upsetting thoughts report significantly lower levels of distress than caregivers with low self-efficacy for controlling upsetting thoughts. CONCLUSION: Self-efficacy for controlling upsetting thoughts may be particularly effective for caregivers who report high burden scores, attenuating the impact of burden on caregivers' distress (depression and anxiety). PMID- 20924820 TI - Unemployment during working life and mental health of retirees: results of a representative survey. AB - OBJECTIVES: The aim of this study was to examine differences in mental health and satisfaction with life in retired men and women depending on experienced unemployment during working life. METHOD: Based on a representative survey, 1396 retirees in the age range of 60-92 years were interviewed face-to-face, assessing two screening instruments for anxiety and depression as well as the Questions on Life Satisfaction questionnaire. Among others, analyses of variance were used to test the differences between groups with distinct experiences of unemployment periods. RESULTS: Retirees with the experience of repeated unemployment--but not with one-time unemployment--during working life reported worse mental health and satisfaction with life. Calculated effect sizes were 0.53 for anxiety, 0.42 for depression and between 0.21 and 0.51 for satisfaction with different domains of daily life. Differences between men and women emerged, but similarities dominated. Participants with higher current household incomes were found to be less affected. CONCLUSION: The experience of repeated unemployment periods during working life is associated with more psychosocial distress in retired men and women. Thus, unemployment may have serious negative implications even for persons retired already. PMID- 20924821 TI - An investigation into the validity of effort tests in a working age dementia population. AB - OBJECTIVES: Performance on neuropsychological tests can be influenced by non cognitive factors, including deliberate underperformance, stress, the need to fulfil a sick role, depression, un-cooperativeness, fatigue and unhappiness with the evaluative situation. Tests to detect suboptimal effort are becoming widely used in clinical practice and are based on their reported insensitivity to cognitive dysfunction. A diagnosis of dementia has life-changing implications for an individual of working age. It is therefore crucial that clinicians can be confident they have obtained a valid estimate of current cognitive functioning. This study aimed to establish whether mood or cognitive functioning adversely influenced performance on symptom validity tests (SVTs) in individuals with working age dementia, who were judged to be using full effort. METHOD: Forty-two participants with dementia diagnosed before the age of 65 completed measures of emotional and cognitive functioning and six SVTs. RESULTS: There were no significant correlations between emotional functioning and measures of effort. However, cognitive functioning, in particular new learning, was significantly related to SVT performance. Participants with mild dementia performed significantly better on all six SVTs than those with moderate/severe dementia. The results also suggest that the SVTs are not equally sensitive to cognitive dysfunction. Rey's Dot Counting Test (DCT) (times criterion) achieved 100% specificity, and was the only test passed by every participant. CONCLUSION: Rey's DCT is the only SVT that can be recommended for use in those under 65 years with possible dementia at this time until further validation studies are undertaken. PMID- 20924822 TI - Coping in old age with extreme childhood trauma: aging Holocaust survivors and their offspring facing new challenges. AB - OBJECTIVE: The Holocaust has become an iconic example of immense human-made catastrophes, and survivors are now coping with normal aging processes. Childhood trauma may leave the survivors more vulnerable when they are facing stress related to old age, whereas their offspring might have a challenging role of protecting their own parents from further pain. Here we examine the psychological adaptation of Holocaust survivors and their offspring in light of these new challenges, examining satisfaction with life, mental health, cognitive abilities, dissociative symptoms, and physical health. METHODS: Careful matching of female Holocaust survivors and comparison subjects living in Israel was employed to form a case-control study design with two generations, including four groups: 32 elderly female Holocaust survivors and 47 daughters, and 33 elderly women in the comparison group, and 32 daughters (total N = 174). Participants completed several measures of mental and physical health, and their cognitive functioning was examined. The current study is a follow-up of a previous study conducted 11 years ago with the same participants. RESULTS: Holocaust survivors showed more dissociative symptomatology (odds = 2.39) and less satisfaction with their life (odds = 2.79) as compared to a matched group. Nonetheless, adult offspring of Holocaust survivors showed no differences in their physical, psychological, and cognitive functioning as compared to matched controls. CONCLUSIONS: Holocaust survivors still display posttraumatic stress symptoms almost 70 years after the trauma, whereas no intergenerational transmission of trauma was found among the second generation. PMID- 20924823 TI - Who should make the decision on the use of GPS for people with dementia? AB - OBJECTIVES: In recent years advanced technologies, such as Global Positioning Systems (GPS), allow for tracking of human spatial activity and provide the ability to intervene to manage that activity. The purpose of this study is to examine the issue of who should decide about the use of electronic tracking using GPS for people with dementia. METHODS: Based on quantitative data collected from 296 participants comprising cognitively intact elderly, family caregivers of people with dementia, social workers, other professionals, and social work students, study participants were asked to rate nine different potential decision makers to make this decision. RESULTS: The results show that figures inside the family, particularly the spouse or the most involved family caregiver, were perceived more important in the decision-making process than figures outside the family, whereas the person with dementia was ranked third in the order of the figures. Since the decision to use GPS for tracking raises the ethical dilemma of personal safety versus autonomy and privacy of people with dementia, the findings seem to indicate that the reluctance of professional caregivers to assist family caregivers to make this decision is experienced as frustrating. CONCLUSIONS: The findings imply that in order to reach a balance between the wishes and interests of both people with dementia and their family caregivers, there is a need for more active involvement of the professional caregivers to facilitate the family decision-making process. PMID- 20924824 TI - Subjective memory complaints in the elderly: Prevalence and influence of temporal orientation, depression and quality of life in a population-based study in the city of Madrid. AB - OBJECTIVES: It is still a matter of debate whether variables such as education, sex, age, personality and others underlie subjective memory complaints (SMC). Our objectives are to study: the prevalence of memory complaints in the city of Madrid, the distribution of complaints in the population according to socio demographic variables and the related variables like cognitive performance, quality of life, perceived health status and functional ability. To our knowledge, this is the first study about the prevalence of SMC in Spain. METHODS: We adopted a transversal descriptive epidemiological study. The survey sample size is 1637 persons above 64 years. SMC were obtained through questions regarding memory complaints. RESULTS: 524 (32.4%) subjects reported SMC. The prevalence of SMC depends on age, education, sex, mood and cognitive performance. SMC rises from 24% in the 65-69 age groups to 57% in the 90 and above group. The percentage of subjects with SMC was 52.8% among persons diagnosed with depression or anxiety, and 28.7% among subjects without. Performance on cognitive tests such as orientation showed that subjects without orientation failures (81%) have a 22.2% SMC frequency and subjects who fail all the orientation items (4%) have a 93% frequency. A logistic regression analysis showed that those variables indicating a better prediction of group membership (SMC vs. controls) were orientation in time, quality of life and depression-anxiety. CONCLUSION: Complaints reflect various processes and are the result of various elements; however, our study highlights the importance of factors such as cognitive performance, depression-anxiety and quality of life. PMID- 20924825 TI - Self-awareness of memory function in Parkinson's disease in relation to mood and symptom severity. AB - OBJECTIVES: In clinical practice, discrepancies are observed between self and proxy reports of various aspects of Parkinson's disease (PD). This study aimed at assessing self-awareness of memory function in PD both by comparing patients' and caregivers' questionnaire ratings of the patients' memory and by correlating subjective ratings with verbal learning results. METHOD: Forty-five patient-proxy pairs participated in the study. Self-Rating Scale of Memory Functions was used as a questionnaire subjective measure. Auditory Verbal Learning Test (AVLT) was applied to assess verbal memory, Stroop test to assess cognitive control and Mini Mental State Examination (MMSE) for global cognitive assessment. RESULTS: Patient self-reports did not diverge appreciably from proxy reports when global scores were considered, but patient-proxy consistency was low for individual items with the exception of those referring to verbal recall. Both patient and proxy ratings were moderately correlated with the objective measures. Patient-proxy discrepancies were associated with lower verbal learning, poor cognitive control and more severe PD symptomatology. Moreover, depression was associated with patients' overestimation of symptoms. CONCLUSION: Self-awareness of memory function is relatively well preserved in PD, but is negatively affected by depressive symptoms. Patient-proxy discrepancies increase also with disease severity, degree of memory problems and cognitive control deficits. Caregivers seem to be unaware of the specificity of memory problems in PD and report only some of them, mainly those related to verbal recall. PMID- 20924826 TI - The utility of the spatial span in a clinical geriatric population. AB - Spatial Span subtest of the Wechsler Memory Scale has been viewed as an indicator of working memory and visuospatial processing. The current study examined the impact of cognitive impairment and its severity on Spatial Span performance. A neuropsychological battery including Spatial Span was administered to 538 individuals (65-89) who were grouped by consensus into Alzheimer's disease, Vascular Dementia, Amnestic Mild Cognitive Impairment, Non-Amnestic Mild Cognitive Impairment and cognitively normal. Increase in level of impairment resulted in a decrease in Spatial Span Total Score. A weak relationship between age and Spatial Span Total Score was found. Spatial Span Forward remains relatively stable regardless of level of impairment. Spatial Span Backward was more sensitive to severity. No significant differences were found between individuals diagnosed with Alzheimer's disease and those with Vascular Dementia suggesting similar deficit patterns in the cognitive abilities measured by the Spatial Span. Mild Cognitive Impairment groups and normals did not differ suggesting visuospatial processes are not affected early in the dementing process. PMID- 20924827 TI - Adult age differences in the ability to mentally transform object and body stimuli. AB - Cognitive neuroscience literature suggests a strong dissociation between the ability to mentally transform object and body stimuli (Hegarty & Waller, 2004). However, little is known about how this ability changes with age. This dissociation was explored in 20 younger (19-24 years) and 20 older (65-87 years) adults. Mental rotation of object stimuli was demonstrated for both age groups, suggesting that the neuro-cognitive network involved with performing (object based) mental transformations is relatively preserved in older age. Compared to young adults, older adults displayed the greatest decline in performance efficiency for the whole-body task. The authors propose that an age-related decline in the integrity of body-schema information may account for this change. PMID- 20924828 TI - Executive function, intellectual decline and daily living skills. AB - Understanding the cognitive changes associated with compromised daily living skills in elderly individuals is important for making appropriate recommendations about the capacity for independent functioning. To this end, we retrospectively examined data from 92 elderly individuals presenting with cognitive decline who were administered measures of executive functioning, general intelligence, and daily living skills. Multiple regression analyses were used to examine the relationship between executive functioning and daily living skills, while controlling for age, depression, and either IQ decline or current IQ. Executive functioning accounted for additional variance in a broad range of daily living skills after controlling for IQ decline. When FSIQ was used in the regression model rather than IQ decline, executive functioning was no longer uniquely associated with daily living skills. Executive functions appear to be important for daily living skills until a critical threshold of low intellectual functioning is reached, reflecting the combined influence of premorbid ability and the extent of intellectual decline. Our results suggest that understanding the relative contribution of different cognitive domains to functional decline in elderly individuals should take into account general intellectual functioning and estimated decline, and that the initiation and/or persistence of self-directed cognitive processes may be important for adaptive daily functioning. These findings have implications for making more evidence-based recommendations about the capacity for independent living. PMID- 20924829 TI - Effect of changing antiretroviral treatment eligibility criteria on patient load in Kampala, Uganda. AB - In many resource-poor countries, CD4 count thresholds of eligibility for antiretroviral treatment (ART) were initially low (<200 cells/mm(3)) but are now being increased to improve patient survival and to reduce HIV transmission. There are few quantitative data on the effect of such increases on the demand for ART. The objective of this study was to measure HIV prevalence and the proportion of HIV-positives eligible for antiretroviral therapy at different CD4 cut-off levels among users of public health care services in Kampala, Uganda. We recruited 1200 adults from three primary care clinics in Kampala, including equal numbers of family planning (FP) clients, pregnant women, adult patients with any complaint, and persons seeking HIV counseling and testing. All participants were screened for HIV and those positive had a CD4 count done. HIV prevalence in all patients was 16.9% (203/1200). ART eligibility based on CD4 counts significantly increased from 36% at a 200 cells/mm(3) cut-off to 44% at 250 cells and to 57% at 350 cells cut-off (p for chi(2) trend<0.001). We concluded that changing cut-off levels to higher CD4 counts will significantly increase patient load in Kampala's primary care clinics, but a phased implementation should minimize negative effects on quality of care. PMID- 20924830 TI - Intimate partner violence among HIV-positive persons in an urban clinic. AB - While the intersection of HIV/AIDS and intimate partner violence (IPV) has gained increased attention, little focus has been given to the relationship among minority men and men who have sex with men (MSM). This pilot study, conducted at an urban clinic, explores the IPV experiences of HIV-positive persons involved in both heterosexual and homosexual relationships. Fifty-six HIV-positive individuals were interviewed to assess for verbal, physical, and sexual IPV, and for HIV-related abuse and attitudes regarding routine IPV screening. Approximately three quarters (73%) of the sample reported lifetime IPV and 20% reported current abuse. Physical IPV (85%) was cited the most by abused participants. IPV rates were highest among African-Americans and MSM. More than one-fourth (29%) of those abused felt the abuse was related to their HIV status. A majority of participants favored IPV screening by providers, but felt it might increase risk of IPV. IPV and its association to HIV are significant issues among this sample. Findings support the need for developing new programs that address these epidemics simultaneously. PMID- 20924831 TI - Anxiety buffer disruption theory: a terror management account of posttraumatic stress disorder. AB - We present anxiety buffer disruption theory (ABDT) and provide a review of current evidence regarding the theory. ABDT is an application of terror management theory to explain diverse reactions to traumatic events and the onset and maintenance of posttraumatic stress disorder (PTSD). It posits that PTSD results from a disruption in one's anxiety-buffering mechanisms, which normally provide protection against anxiety in general and death anxiety in particular. The disruption of these mechanisms leaves the individual defenseless in the face of overwhelming anxiety, which leads to the major symptom clusters of PTSD: re experiencing, hyper-arousal, and avoidance. According to ABDT, because of the disruption in their anxiety-buffering mechanisms, individuals with PTSD symptoms do not respond to mortality reminders in the defensive ways that psychologically healthier individuals do. We review four sets of studies conducted in four different cultures and with people who have experienced different types of trauma, which reveal this atypical response pattern and lend support to ABDT. PMID- 20924832 TI - Sleep and ethnicity. PMID- 20924833 TI - Ethnicity moderates the influence of perceived social status on subjective sleep quality. AB - It has long been recognized that socioeconomic status (SES) influences health and health-related behaviors, and it has been suggested that the adverse impact of low SES on health may be partly mediated by poor sleep quality. The relation between sleep and objective and subjective measures of SES has only been explored in a preliminary manner, providing indirect evidence that associations between SES and health might be explained, in part, by disrupted sleep. However, it remains unclear whether low SES directly affects sleep quality or whether the SES sleep quality relation varies as a function of ethnicity given robust ethnic disparities across SES-related factors. This study examined the relation between perceived social status (i.e., individuals' perception of their socioeconomic standing) and subjective sleep quality among 149 college students, and examined the moderating effect of ethnicity to determine whether the magnitude or direction of association differed among Caucasian, Asian, and African Americans. Using hierarchical regressions and a dummy-coded ethnicity variable, results demonstrated significant moderation (DeltaR2 = 0.04, p = .02), such that both Asian (p = .04) and African Americans (p = .02) were significantly different from Caucasian Americans. Lower perceived social status was related to greater impairment in sleep quality for Asian Americans (beta = -.37, p < .01) and African Americans (beta = -.51, p < .01), but not Caucasian Americans (beta = .02, p = .87). These findings provide initial support for the negative impact of low perceived social status on sleep quality for specific subgroups of ethnic minorities. PMID- 20924834 TI - Differences in parental attitudes towards sleep and associations with sleep-wake patterns in Caucasian and Southeast Asian school-aged children in Australia. AB - Caucasian (N = 47) and Southeast (SE) Asian (N = 36) families completed a questionnaire on their attitudes toward sleep, as well as a 7-day sleep diary for their children aged 5 to 11 years. Cultural differences were found in the perceived importance of sleep, particularly compared to homework and belief of how much sleep a child needs. Differences were also found in sleep-wake behaviors and amount of time spent on homework, with SE Asian children reporting a shift in sleep timing and increased homework load compared to Caucasian counterparts. Parental attitudes toward sleep, perception of sleep need, and homework load were not associated with the regulation of actual sleep behaviors in children, regardless of cultural heritage. PMID- 20924835 TI - Childhood socioeconomic status and race are associated with adult sleep. AB - Race and current socioeconomic status (SES) are associated with sleep. Parental education, a commonly studied component of childhood SES, is predictive of adult health outcomes; yet, its impact on adult sleep remains unclear. In this study, the sleep of 128 Black and White adults was investigated. Participants with lower childhood SES (assessed via parental education) spent more time in Stage 2 sleep and less time in slow-wave sleep (SWS) than those with higher childhood SES. In addition, women from low childhood SES backgrounds took longer to fall asleep than women from high SES backgrounds. Black participants spent less time in SWS than their White counterparts, and an Age * Race interaction was detected in the prediction of subjective sleep quality. Results were not mediated via current SES or health practices. PMID- 20924836 TI - Race and ethnic variation in excessive daytime sleepiness: the multi-ethnic study of atherosclerosis. AB - This cross-sectional study utilized data from the Multi-Ethnic Study of Atherosclerosis (MESA). The sample included 5,173 older adults (mean age = 66.4 years) recruited from 6 field centers in the United States. Excessive daytime sleepiness (EDS) was evaluated using two measures: self-report of feeling excessively sleepy <= 5 days per month and the Epworth Sleepiness Scale (ESS) > 12. White participants were more likely than other groups to report EDS <= 5 days per month. After controlling for covariates, African American and Hispanic participants remained less likely to report EDS <= 5 days per month. African Americans were more likely to score > 12 on the ESS than White participants. Odds ESS > 12 in African American participants were attenuated but remained significant after controlling for covariates. Results indicate measurement of race/ethnic differences in EDS may result in conflicting estimates of race/ethnic variation. Furthermore, attenuation of differences in ESS < 12 suggests this measure has a stronger association with current health. PMID- 20924837 TI - Sleep disorders in African Americans and Caucasian Americans: a meta-analysis. AB - Previous research suggests that ethnic groups differ in the prevalence and severity of disordered sleep symptoms. This study used meta-analysis to determine the magnitude of ethnic differences between African Americans (AAs) and Caucasian Americans (CAs) in insomnia symptoms and sleep-disordered breathing (SDB). It also used moderator analyses to explore the variability in these effect sizes. Thirteen studies measuring insomnia symptoms and 10 studies measuring SDB met inclusion criteria and represented thousands of adult AAs and CAs. Results indicate AAs have a higher prevalence and greater severity of SDB, but CAs report more insomnia symptoms. These results indicate a need for a multi-ethnic approach to the assessment and treatment of sleep disorders. PMID- 20924838 TI - Ethnic differences in continuous positive airway pressure (CPAP) adherence in veterans with and without psychiatric disorders. AB - Continuous positive airway pressure (CPAP) is a safe, effective treatment for sleep apnea, yet adherence is notoriously problematic. Vulnerable populations that may be at increased risk of sleep apnea include African Americans (AAs) and individuals with psychiatric disorders, yet little is known about whether such individuals are at increased risk of CPAP non-adherence. This study examined rates of CPAP adherence in a large sample of AA and Caucasian American (CA) military veterans with and without comorbid mental health disorders. AAs used CPAP less than CAs throughout the first 3 months of treatment. AAs with mental health diagnoses showed the lowest CPAP adherence; additional research is needed to identify factors that may be increasing the risk for CPAP non-adherence in these individuals. PMID- 20924840 TI - The byssus of the zebra mussel (Dreissena polymorpha): spatial variations in protein composition. AB - The notorious biofouling organism Dreissena polymorpha (the zebra mussel) attaches to a variety of surfaces using a byssus, a series of protein threads that connect the animal to adhesive plaques secreted onto hard substrata. Here, the use of matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) to characterize the composition of different regions of the byssus is reported. All parts of the byssus show mass peaks corresponding to small proteins in the range of 3.7-7 kDa, with distinctive differences between different regions. Indeed, spectra from thread and plaques are almost completely non-overlapping. In addition, several peaks were identified that are unique to the interfacial region of the plaque, and therefore likely represent specialized adhesive proteins. These results indicate a high level of control over the distribution of proteins, presumably with different functions, in the byssus of this freshwater species. PMID- 20924841 TI - Dietary plant bioactives for poultry health and productivity. AB - 1. Plants and their biologically active chemical constituents, sometimes called secondary metabolites or bioactives, present numerous opportunities for the improvement of livestock production by inclusion in the diet. 2. Many such plant derived materials have well established therapeutic values in man; however, their potential as feed additives in animal production, particularly of poultry, remains largely unexploited. 3. There is increasing evidence indicating that they can be efficient in controlling diseases, and plant bioactives may also influence production parameters such as feed efficiency and product quality. 4. It has been reported that they may even replicate some of the effects of antibiotic growth promoters, which were banned from use in Europe from 2006. 5. This review assesses the status of plant bioactives in poultry production and their mode of action on avian physiology, particularly in the digestive tract. PMID- 20924842 TI - Comparison of the welfare of layer hens in 4 housing systems in the UK. AB - 1. The welfare of hens in 26 flocks (6 conventional cage, 6 furnished cage, 7 barn, 7 free-range) was assessed throughout the laying period using a combination of data on physical health, physiology and injurious pecking, collected by researchers on farm and during post-mortem analysis, and information submitted by producers. 2. There was an effect of housing system on 5 of the indicators recorded by researchers: gentle feather pecks given, feather damage score, proportion of hens with feather damage, proportion of the flock using perches, and faecal corticosterone. 3. Post-mortem analysis revealed several differences between housing systems in skin damage, plumage damage to the vent and abdomen, keel protrusion, bodyweight, and the proportion of hens that were vent pecked and that had old and recent keel fractures. 4. There was an effect of housing system on 5 indicators recorded by producers: proportion of egg shells with calcification spots, proportion of egg shells with blood stains, weight of hens found dead, temporal change in the proportion of egg shells with stains, and temporal change in proportion of hens found dead. 5. Each housing system had positive and negative aspects but overall, hens in barn systems had the highest prevalence of poor plumage condition, old fractures, emaciation, abnormal egg calcification, and the highest corticosterone. Hens in conventional cages sustained more fractures at depopulation than birds in other systems. Vent pecking was most prevalent in free-range flocks. The lowest prevalence of problems occurred in hens in furnished cages. 6. Although housing system had an influence on the hens' physical condition and physiological state, the high prevalence of emaciation, loss of plumage, fractures and evidence of stress is of concern across all housing systems, and suggests that the welfare of modern genotypes is poor. PMID- 20924843 TI - Effect of maternal rearing on lipid metabolism-related gene expression in offspring broilers during embryonic development. AB - 1. The aim of this study was to investigate the effect of maternal rearing on lipid metabolism and lipid metabolism-related gene expression in offspring broilers during embryonic development. 2. One hundred laying Sanhuang breeders were divided into two groups, and either floor-reared or cage-reared on the same diet. Liver and serum samples were extracted on days 14 and 19 of embryonic development and at hatching. The lipid metabolism related gene expressions of acetyl CoA carboxylase (ACC), fatty acid synthase (FAS), malic enzyme (ME), apolipoprotein B100(apoB100), sterol regulating element binding protein (SREBP 1c), carnitine palmitoyltransferase (CPT-1) and peroxisome proliferators activated receptor (PPARalpha) genes were determined using real time RT-PCR. 3. The results showed that embryonic weight, liver weight, serum and hepatic total cholesterol (TC) concentration and serum triglyceride (TG) content were not significantly different between the cage-reared group and the floor-reared group during embryonic development. However, embryonic weight, liver weight, serum and hepatic TC concentration and serum TG content in the cage-reared group were significantly higher than in the floor-reared group at hatching. 4. Hepatic ACC, FAS, SREBP-1c, ME and apoB genes expression were not significantly different between the cage-reared and the floor-reared groups during E9 and E14 development. Hepatic ME gene expression in the cage-reared group was higher than in the floor-reared group during E19 development. However, hepatic FAS, SREBP-1c, CPT-1 and PPARalpha gene expressions in the cage-reared group was higher than in the floor-reared group. 5. A change in the maternal regime could regulate lipid metabolism in offspring broilers during embryonic development, and especially at hatching. PMID- 20924844 TI - Localisation of the genomic sequence interval for the blue eggshell gene using an F2 resource population of Dongxiang chickens. AB - 1. In order to identify the molecular interval containing the blue shell gene (O locus), linkage analysis was conducted with three microsatellite markers, (TTA)(n), (TG)(n) and (tg)(n), and a SNP in intron 1 of SLCO1C1 (solute carrier organic anion transporter family, member 1C1; A locus) to map the O locus in an F2 resource population of Dongxiang chickens. 2. Linkage analysis based on 98 F2 hens resulted in estimation of the best map order of the O locus with other linked markers as: (TTA)(n)-(TG)(n)-A-O-(tg)(n). 3. Based on these results, we inferred that the O locus was located between the A and (tg)(n) loci, that is, Chr1:67,296,991-69,140,571, which is the first genomic sequence interval to be established for the blue eggshell gene. PMID- 20924845 TI - Effect of slaughter age and sex on the production output of South African Black ostriches. AB - 1. The effects of different slaughter ages and sex on the yield and quality of economically important end-products of slaughtered ostriches was examined to determine the most economic slaughter age for growing/finishing ostriches. Two batches of 4- and 6-month-old ostriches were assigned to 10 treatment groups and fed ad libitum up to slaughter ages of 8.5, 10.5, 12.5, 14.5 and 16.5 months. Slaughter weight, cold carcase yield, skin surface area, dry skin grade, feather yield and feed intake of ostriches were measured for each age. 2. Cold carcase yields and total feather yields of males were higher than females but yields of other products were similar. 3. Slaughter weight, cold carcase yield, skin surface area, dry skin grade, feather yield and feed intake increased with age with significant differences between most age groups. Cold carcase weight increased by approximately 2.2 kg and skin surface area increased by 3.1 dm3 with each additional month of growth but the quality (grade) of skins and the proportion of first grade skins decreased with increasing age. This, together with an increase in feed intake associated with age to slaughtering should be taken into account when determining the optimal slaughter age. 4. The set of biological variables established in this study can be used to determine the most economical slaughter age under varying market conditions. PMID- 20924846 TI - The effect of breed and feed-type on the sensory profile of breast meat in male broilers reared in an organic free-range system. AB - 1. Studies on the sensory profiling of male broiler breast meat were carried out to evaluate the effect of two very different broiler breeds (JA757 and New Hampshire), two different feed types (broiler and grower feed) and age at slaughter (82 and 110 d). 2. The sensory profiling consisted of a pilot study, 4 training sessions, and finally the assessment. During the training session a panel of 9 assessors defined 17 attributes, which were used to describe the smell, texture and flavour of the breast fillets. Each attribute was evaluated on a 15-cm unstructured line scale. 3. The breast meat became significantly less hard, and more juicy and tender in the New Hampshire at 110 d of age, whereas the opposite was found in JA757, which also acquired a more "sourish" flavour with age. The smell of "sweet/maize" and "bouillon" became weaker with age in JA757, but not in New Hampshire. 4. Several significant differences in relation to the main factors of breed and age were found. The traditional broiler hybrid JA757 did best for most smell and flavour attributes, whereas New Hampshire did best for the texture attributes. Age had a negative effect on the flavours and smell attributes "fresh chicken", "neck of pork" and "sweet maize", but a positive effect on the texture attribute "crumbly". In addition meat was more "stringy" at 110 d of age. 5. The flavours "neck of pork" and "umami" were significantly improved when JA757 was fed on the broiler feed and when New Hampshire was given the grower feed. The meat smelt more "sourish" at 82 d of age and less "sourish" at 110 d of age when the grower feed was consumed. Meat was significantly harder and stringier when JA757 was fed on the grower feed. This was not the case for New Hampshire. In general, the meat was significantly less crumbly and stringier with the grower feed. 6. Overall a very distinct difference in sensory profile was found between the two breeds. In addition different slaughter ages and feeding strategies should be taken into consideration in a niche production based on alternative genotypes. PMID- 20924847 TI - Sexing of newly-hatched chicks using DNA isolated from chorio-allantoic membrane samples by polymerase chain reaction in Denizli chicken. AB - 1. The aim of the present study was to determine the sex of newly-hatched chicks of Denizli chicken, a local Turkish breed, by polymerase chain reaction (PCR) using DNA extracted from the chorioallantoic membrane (CAM). 2. Fertilised eggs were incubated individually and a total of 20 CAM samples were collected following the hatching process. DNA was isolated from the CAM samples and PCR was performed using W-repeat (W) and 18 S ribosomal gene (R) primers. 3. Screening of the PCR products by agarose gel electrophoresis revealed that males have a single band (256 bp) and females have an extra second band (415 bp) as expected. 4. The present study describes a reliable, rapid, and simple multiplex PCR protocol that can be put into use to sex local breeds of chicken in which phenotypic sexing is impossible, using DNA isolated from the CAM that is discarded and remains attached to the egg shell following the hatching process. PMID- 20924848 TI - Marek's disease resistant/susceptible MHC haplotypes in Xiayan chickens identified on the basis of BLB2 PCR-RFLP and BLB2/BF2 sequence analyses. AB - 1. The aim was to analyse the variability of the BLB2/BF2 genes of Xiayan chickens to identify homozygous birds with resistance or susceptibility to Marek's disease (MD). 2. The experiment used two lines: birds from a common line were divided into Group A (unvaccinated) and Group B (vaccinated with herpesvirus of turkeys (HVT)); and birds from an MD-resistant line were divided into Group C (unvaccinated) and Group D (vaccinated with HVT). They were challenged intra abdominally with Marek's disease virus (MDV) and genomic DNA extracted from peripheral blood lymphocytes so that polymorphism of the BLB2/BF2 genes could be analysed using polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) and nucleotide sequence analysis. 3. A 374-bp fragment of the BLB2 gene was amplified from the samples and, after digesting with restriction enzymes Alu I, Cai I, Cfr I, Hin1 I, Hinf I and Rsa I for RFLP analysis, the 6 electrophoretic patterns were analysed. Seven homozygous genotypes were found and used tentatively to identify alleles of the BLB2 gene. 4. A 765-bp fragment of the BF2 gene was amplified from the 7 samples for cloning and sequencing. 5. Six homozygous birds were confirmed from the sequenced BLB2/BF2 gene. Four birds were resistant to MD. Three birds had identical nucleotide sequences and were highly homologous with MHC haplotype B6, which is MD resistant. One bird had high homology with the highly MD-resistant B21 haplotype, and two birds were susceptible and highly homologous to the B19 haplotype, which is highly MD susceptible. PMID- 20924849 TI - Effect of taurine on intestinal morphology and utilisation of soy oil in chickens. AB - 1. The objective of the present study was to investigate the effect of taurine on intestinal morphology and utilisation of dietary fatty acids in chicken. One-day old broilers chickens were fed with a maize- and soybean-based diet containing soy oil, and supplemented with taurine at either 0 or 0.5 g/kg. 2. Result showed that the total bile acid in blood and lipase activity in the small intestine were elevated in 3-week-old broilers given the taurine-supplemented diet. No differences were observed for total serum bile acid and lipase activity between the groups of 6-week-old broilers. 3. The development of the jejunum villus and ileum villus was inhibited, and the weight of jejunum and the relative height of intestinal mucosa were decreased in the chickens fed the taurine-supplemented diet. 4. The rate of diet fatty acid utilisation was not different between the groups of 3- and 6-week-old chickens. 5. Our results showed that dietary supplementation with taurine had no beneficial effect on intestinal morphology or utilisation of a soy oil diet in chickens. PMID- 20924850 TI - Effect of beta -glucanase and xylanase supplementation of barley- and rye-based diets on caecal microbiota of broiler chickens. AB - 1. The aim was to investigate the effect of grain type (barley or rye) and exogenous enzymes (beta-glucanase or xylanase) on the composition of chicken caecal microbiota as examined by classical culturing and molecular techniques (fluorescent in-situ hybridisation (FISH) and terminal-restriction fragment length polymorphism (T-RFLP)). 2. Plate counting revealed higher total numbers of anaerobic bacteria, lactic acid bacteria and yeasts in caecal contents of birds fed with rye-based diets than in birds fed with barley-based diets. 3. As assessed by FISH analysis, the most abundant bacterial groups in the broiler caeca were Clostridium coccoides-Eubacterium rectale followed by Bacteroides sp., Lactobacillus sp./Enterococcus sp., Bifidobacterium sp. and Enterobacteriaceae. For both cereal types, the enzyme supplementation significantly decreased the relative amount of Enterobacteriaceae. 4. The T-RFLP profiles indicated that the caecal microbiota of birds receiving rye-based diets was more diverse than that of birds fed on barley-based diets. 5. Irrespective of the method applied, the results indicate that the cereal type as well as the exogenous enzyme supplementation influence the microbiota in broiler chicken caeca, and may have the effect of reducing potentially pathogenic Enterobacteriaceae populations. PMID- 20924851 TI - Dietary limitation of isoleucine and valine in diets based on maize, soybean meal, and meat and bone meal for broiler chickens. AB - 1. The dietary limitation of isoleucine (Ile) and valine (Val) was evaluated in broilers. Common diets were given to all broilers from 0 to 28 d of age. Experimental diets were provided from 28 to 42 d of age. 2. The experimental test diet was based primarily on maize, soybean meal, and meat and bone meal, and formulated to satisfy all nutrient recommendations with the exception of Ile and Val. 3. Diets were supplemented with L-Ile and L-Val at either 0.5 or 1.0 g kg-1 of diet, alone or in combination. A diet composed only of commercially available amino acids and formulated to satisfy all nutrient requirements served as a positive control. 4. Body weight gain was depressed by the test diet, but recovered to a weight similar to birds fed on the positive control when Val was added to the test diet either alone or in combination with Ile. Feed efficiency improved when Val and Ile were simultaneously supplemented. 5. Abdominal fat yield was reduced with the combined supplementation of Val and Ile. Breast meat yield appeared to be more sensitive to Ile supplementation than to Val. 6. The results suggest that live performance may be more sensitive to Val, while breast meat yield was maximised with Ile supplementation. However, their combination is required for optimised growth and meat yield. PMID- 20924852 TI - Effects of Enterococcus faecium supplementation and floor type on performance, morphology of erythrocytes and intestinal microbiota in broiler chickens. AB - 1. The experiment was to study the effects of floor type and probiotic supplementation (Enterococcus faecium) on performance, morphology of erythrocytes and intestinal microbiota of male Ross 308 broiler chickens. 2. The experimental design was a factorial 2 * 2 with 6 replicates. The factors were floor type (wire floor versus wood shaving litter) and the presence or absence of probiotic. 3. Birds housed on wood shavings exhibited significantly improved weight gain and food intake. 4. Addition of E. faecium led to significantly decreased food intake and gizzard weight. Supplementation with E. faecium positively influenced the ileal and caecal microbiota, with a significant decrease in the population of Escherichia coli. 5. Erythrocyte length decreased and erythrocyte width increased in the birds housed on wood shavings. PMID- 20924853 TI - Auditory pathways and processes: implications for neuropsychological assessment and diagnosis of children and adolescents. AB - Neuroscience research on auditory processing pathways and their behavioral and electrophysiological correlates has taken place largely outside the field of clinical neuropsychology. Deviations and disruptions in auditory pathways in children and adolescents result in a well-documented range of developmental and learning impairments frequently referred for neuropsychological evaluation. This review is an introduction to research from the last decade. It describes auditory cortical and subcortical pathways and processes and relates recent research to specific conditions and questions neuropsychologists commonly encounter. Auditory processing disorders' comorbidity with ADHD and language-based disorders and research addressing the challenges of assessment and differential diagnosis are discussed. PMID- 20924854 TI - Developmental aspects of temporal and spatial visual attention: insights from the attentional blink and visual search tasks. AB - Frontal regions of the human cortex are thought to reach full maturation last in the course of development. The present report examines such development in the context of attentional tasks in the temporal (e.g., the attentional blink, AB, paradigm) and spatial (e.g., the visual search, VS, paradigm) domains. Here we show that the recovery from AB is progressively longer with younger age by studying 7-, 12-, 15-year-olds, and adults participating on a modified AB task. By contrast, we found no difference between 7-year-olds and adults in a VS task using the same target stimuli as in the AB task. This differential pattern of development between temporal and spatial attention is discussed in relation to visual working memory development, clinical populations, and general mechanisms of cortical development. PMID- 20924855 TI - Childhood facial emotion recognition and psychosis-like symptoms in a nonclinical population at 12 years of age: results from the ALSPAC birth cohort. AB - INTRODUCTION: Nonclinical psychotic symptoms (for example, low intensity or low frequency psychotic symptoms such as ideas of reference or single word auditory hallucinations) are common in adolescents and may be associated with an increased risk of developing a psychotic disorder in adulthood. Those at high risk of developing a psychotic disorder appear to perform poorly on facial emotion recognition tasks but the relationship between facial emotion recognition and nonclinical "psychosis like symptoms" (PLIKS) in children is unclear. We aimed to examine the association between childhood facial emotion recognition and PLIKS in adolescents. METHODS: Longitudinal study using a large birth cohort. 6455 subjects completed a semistructured clinical assessment for psychotic symptoms (the PLIKSi) at the mean age of 12.9 (SD=0.23). Facial emotion recognition (using the DANVA) was previously assessed at the age of 8 in the cohort. RESULTS: There was no increase in odds of reporting any PLIKS either in relation to the total score on the measure of facial emotion recognition or for the individual emotion scores of fear, sadness, anger, and happiness. Similar results were also found when examining more intense and/or more frequently experienced psychotic symptoms. CONCLUSIONS: Deficits in facial emotion recognition in 8-year-olds do not appear to predict later reporting of nonclinical psychotic symptoms in early adolescence. The results do not support the proposal that recognition of emotion is a trait phenomenon in those individuals at increased risk for psychosis. However, further research is warranted in older children/adolescents when more subtle emotion recognition deficits can be investigated. PMID- 20924856 TI - Generalized Fokker-Planck theory for electron and photon transport in biological tissues: application to radiotherapy. AB - In this paper, we study a deterministic method for particle transport in biological tissues. The method is specifically developed for dose calculations in cancer therapy and for radiological imaging. Generalized Fokker-Planck (GFP) theory [Leakeas and Larsen, Nucl. Sci. Eng. 137 (2001), pp. 236-250] has been developed to improve the Fokker-Planck (FP) equation in cases where scattering is forward-peaked and where there is a sufficient amount of large-angle scattering. We compare grid-based numerical solutions to FP and GFP in realistic medical applications. First, electron dose calculations in heterogeneous parts of the human body are performed. Therefore, accurate electron scattering cross sections are included and their incorporation into our model is extensively described. Second, we solve GFP approximations of the radiative transport equation to investigate reflectance and transmittance of light in biological tissues. All results are compared with either Monte Carlo or discrete-ordinates transport solutions. PMID- 20924857 TI - Modelling of peripheral fluid accumulation after a crystalloid bolus in female volunteers - a mathematical study. AB - OBJECTIVE: To simultaneously model plasma dilution and urinary output in female volunteers. METHODS: Ten healthy female non-pregnant volunteers, aged 21-39 years (mean 29), with a bodyweight of 58-67 kg (mean 62.5 kg) participated. No oral fluid or food was allowed between midnight and completion of the experiment. The protocol included an infusion of acetated Ringer's solution, 25 ml/kg over 30 min. Blood samples (4 ml) were taken every 5 min during the first 120 min, and thereafter the sampling rate was every 10 min until the end of the experiment at 240 min. A standard bladder catheter connected to a drip counter to monitor urine excretion continuously was used. The data were analysed by empirical calculations as well as by a mathematical model. RESULTS: Maximum urinary output rate was found to be 19 (13-31) ml/min. The subjects were likely to accumulate three times as much of the infused fluid peripherally as centrally; 1/MU = 2.7 (2.0-5.7). Elimination efficacy, E(eff), was 24 (5-35), and the basal elimination k(b) was 1.11 (0.28-2.90). The total time delay T(tot) of urinary output was estimated as 17 (11-31) min. CONCLUSION: The experimental results showed a large variability in spite of a homogenous volunteer group. It was possible to compute the infusion amount, plasma dilution and simultaneous urinary output for each consecutive time point and thereby the empirical peripheral fluid accumulation. The variability between individuals may be explained by differences in tissue and hormonal responses to fluid boluses, which needs to be further explored. PMID- 20924858 TI - A classification system for hospital-based infection outbreaks. AB - Outbreaks of infection within semi-closed environments such as hospitals, whether inherent in the environment (such as Clostridium difficile (C.Diff) or Methicillin-resistant Staphylococcus aureus (MRSA) or imported from the wider community (such as Norwalk-like viruses (NLVs)), are difficult to manage. As part of our work on modelling such outbreaks, we have developed a classification system to describe the impact of a particular outbreak upon an organization. This classification system may then be used in comparing appropriate computer models to real outbreaks, as well as in comparing different real outbreaks in, for example, the comparison of differing management and containment techniques and strategies. Data from NLV outbreaks in the Hull and East Yorkshire Hospitals NHS Trust (the Trust) over several previous years are analysed and classified, both for infection within staff (where the end of infection date may not be known) and within patients (where it generally is known). A classification system consisting of seven elements is described, along with a goodness-of-fit method for comparing a new classification to previously known ones, for use in evaluating a simulation against history and thereby determining how 'realistic' (or otherwise) it is. PMID- 20924859 TI - A computational method for reliable gait event detection and abnormality detection for feedback in rehabilitation. AB - In this paper, a gait event detection algorithm is presented that uses computer intelligence (fuzzy logic) to identify seven gait phases in walking gait. Two inertial measurement units and four force-sensitive resistors were used to obtain knee angle and foot pressure patterns, respectively. Fuzzy logic is used to address the complexity in distinguishing gait phases based on discrete events. A novel application of the seven-dimensional vector analysis method to estimate the amount of abnormalities detected was also investigated based on the two gait parameters. Experiments were carried out to validate the application of the two proposed algorithms to provide accurate feedback in rehabilitation. The algorithm responses were tested for two cases, normal and abnormal gait. The large amount of data required for reliable gait-phase detection necessitate the utilisation of computer methods to store and manage the data. Therefore, a database management system and an interactive graphical user interface were developed for the utilisation of the overall system in a clinical environment. PMID- 20924860 TI - Gaussian curvature analysis allows for automatic block placement in multi-block hexahedral meshing. AB - Musculoskeletal finite element analysis (FEA) has been essential to research in orthopaedic biomechanics. The generation of a volumetric mesh is often the most challenging step in a FEA. Hexahedral meshing tools that are based on a multi block approach rely on the manual placement of building blocks for their mesh generation scheme. We hypothesise that Gaussian curvature analysis could be used to automatically develop a building block structure for multi-block hexahedral mesh generation. The Automated Building Block Algorithm incorporates principles from differential geometry, combinatorics, statistical analysis and computer science to automatically generate a building block structure to represent a given surface without prior information. We have applied this algorithm to 29 bones of varying geometries and successfully generated a usable mesh in all cases. This work represents a significant advancement in automating the definition of building blocks. PMID- 20924861 TI - The influence of implant number and abutment design on the biomechanical behaviour of bone for an implant-supported fixed prosthesis: a finite element study in the upper anterior region. AB - It is always recommended to use more implants for supporting a prosthesis in the immediate loading condition than in the classical two-stage treatment procedure. By means of the finite element (FE) method, the influence of the number of implants used in immediately loaded fixed partial prosthesis (FPP) on the load distribution was investigated, considering the abutment geometry. Two 3D FE models were studied employing four implants to support a FPP in the premaxilla. One model was designed with straight abutments and the other with 20 degrees angled abutments. The results concerning implant displacements, stresses and strains were compared with those of two implant-supported FPPs, obtained in a previous study. A noticeable reduction in the determined biomechanical bone loading was observed with the use of more implants in supporting an immediately loaded prosthesis. This study confirms that the use of additional numbers of implants in an immediately loaded prosthesis is highly recommended. PMID- 20924862 TI - Modelling skeletal muscle fibre orientation arrangement. AB - Skeletal muscle tissues have complex geometries. In addition, the complex fibre orientation arrangement makes it quite difficult to create an accurate finite element muscle model. There are many possible ways to specify the complex fibre orientations in a finite element model, for example defining a local element coordinate system. In this paper, an alternative method using ABAQUS, which is combination of the finite element method and the non-uniform rational B-spline solid representation, is proposed to calculate the initial fibre orientations. The initial direction of each muscle fibre is specified as the tangent direction of the NURBS curve which the fibre lies on, and the directions of the deformed fibres are calculated from the initial fibre directions, the deformation gradients and the fibre stretch ratios. Several examples are presented to demonstrate the ability of the proposed method. Results show that the proposed method is able to characterise both the muscle complex fibre orientation arrangement and its complex mechanical response. PMID- 20924863 TI - A computational/experimental platform for investigating three-dimensional puzzle solving of comminuted articular fractures. AB - Reconstructing highly comminuted articular fractures poses a difficult surgical challenge, akin to solving a complicated three-dimensional (3D) puzzle. Preoperative planning using computed tomography (CT) is critically important, given the desirability of less invasive surgical approaches. The goal of this work is to advance 3D puzzle-solving methods towards use as a preoperative tool for reconstructing these complex fractures. A methodology for generating typical fragmentation/dispersal patterns was developed. Five identical replicas of human distal tibia anatomy were machined from blocks of high-density polyetherurethane foam (bone fragmentation surrogate), and were fractured using an instrumented drop tower. Pre- and post-fracture geometries were obtained using laser scans and CT. A semi-automatic virtual reconstruction computer program aligned fragment native (non-fracture) surfaces to a pre-fracture template. The tibiae were precisely reconstructed with alignment accuracies ranging from 0.03 to 0.4 mm. This novel technology has the potential to significantly enhance surgical techniques for reconstructing comminuted intra-articular fractures, as illustrated for a representative clinical case. PMID- 20924864 TI - Active food packaging evolution: transformation from micro- to nanotechnology. AB - Predicting which attributes consumers are willing to pay extra for has become straightforward in recent years. The demands for the prime necessity of food of natural quality, elevated safety, minimally processed, ready-to-eat, and longer shelf-life have turned out to be matters of paramount importance. The increased awareness of environmental conservation and the escalating rate of foodborne illnesses have driven the food industry to implement a more innovative solution, i.e. bioactive packaging. Owing to nanotechnology application in eco-favorable coatings and encapsulation systems, the probabilities of enhancing food quality, safety, stability, and efficiency have been augmented. In this review article, the collective results highlight the food nanotechnology potentials with special focus on its application in active packaging, novel nano- and microencapsulation techniques, regulatory issues, and socio-ethical scepticism between nano technophiles and nano-technophobes. No one has yet indicated the comparison of data concerning food nano- versus micro-technology; therefore noteworthy results of recent investigations are interpreted in the context of bioactive packaging. The next technological revolution in the domain of food science and nutrition would be the 3-BIOS concept enabling a controlled release of active agents through bioactive, biodegradable, and bionanocomposite combined strategy. PMID- 20924865 TI - Cinnamon and health. AB - Cinnamon has been used as a spice and as traditional herbal medicine for centuries. The available in vitro and animal in vivo evidence suggests that cinnamon has anti-inflammatory, antimicrobial, antioxidant, antitumor, cardiovascular, cholesterol-lowering, and immunomodulatory effects. In vitro studies have demonstrated that cinnamon may act as an insulin mimetic, to potentiate insulin activity or to stimulate cellular glucose metabolism. Furthermore, animal studies have demonstrated strong hypoglycemic properties. However, there are only very few well-controlled clinical studies, a fact that limits the conclusions that can be made about the potential health benefits of cinnamon for free-living humans. The use of cinnamon as an adjunct to the treatment of type 2 diabetes mellitus is the most promising area, but further research is needed before definitive recommendations can be made. PMID- 20924866 TI - The impact of heat-moisture treatment on molecular structures and properties of starches isolated from different botanical sources. AB - Heat-moisture treatment is a hydrothermal treatment that changes the physicochemical properties of starches by facilitating starch chain interactions within the amorphous and crystalline domains and/or by disrupting starch crystallites. The extent of these changes is influenced by starch composition, moisture content and temperature during treatment, and by the organization of amylose and amylopectin chains within native starch granules. During heat moisture treatment starch granules at low moisture levels [(<35% water (w/w)] are heated at a temperature above the glass transition temperature (T(g)) but below the gelatinization temperature for a fixed period of time. Significant progress in heat-moisture treatment has been made during the last 15 years, as reflected by numerous publications on this subject. Therefore, this review summarizes the current knowledge on the impact of heat-moisture treatment on the composition, granule morphology, crystallinity, X-ray pattern, granular swelling, amylose leaching, pasting properties, gelatinization and retrogradation parameters, and susceptibility towards alpha-amylase and acid hydrolysis. The application of heat moisture treatment in the food industry is also reviewed. Recommendations for future research are outlined. PMID- 20924867 TI - Snacking definitions: impact on interpretation of the literature and dietary recommendations. AB - Snacking is a ubiquitous practice that has increased in recent years. However, the impact of snacking on the diet is difficult to assess because a variety of approaches have been used to define snacking (and snack foods) in the literature. This lack of a universally accepted definition complicates interpretation of the literature and limits the development of science-based recommendations for consumers. The purpose of this review is to illustrate this problem by showing that the conclusions derived from the literature are heavily dependent on the definition used or implied by the authors. It is suggested that the a universally accepted definition for snacking be developed by a coalition of stakeholders to provide a template for future research, guidance for the food industry and to enable the development of well-substantiated dietary recommendations. PMID- 20924868 TI - Analyzing cranberry bioactive compounds. AB - There is a growing public interest for the North American cranberry (Vaccinium macrocarpon) as a functional food because of the potential health benefits linked to phytochemical compounds present in the fruit--the anthocyanin pigments, responsible for its brilliant red color, and other secondary plant metabolites (flavonols, flavan-3-ols, proanthocyanidins, and phenolic acid derivatives). Isolation of these phenolic compounds and flavonoids from a sample matrix is a prerequisite to any comprehensive analysis scheme. By far the most widely employed analytical technique for the characterization of these compounds has been high-performance liquid chromatography(HPLC) coupled with ultraviolet visible(UV/Vis) and mass spectrometer(MS) detection. This review covers the cranberry major bioactive compounds, the extraction and purification methods, and the analytical conditions for HPLC used to characterize them. Extraction, chromatographic separation and detection strategies, analyte determinations, and applications in HPLC are discussed and the information regarding methods of specific cranberry analyte analyses has been summarized in tabular form to provide a means of rapid access to information pertinent to the reader. PMID- 20924870 TI - Understanding change in global health policy: ideas, discourse and networks. AB - How is radical change in global health policy possible? Material factors such as economics or human resources are important, but ideational factors such as ideas and discourse play an important role as well. In this paper, I apply a theoretical framework to show how discourse made it possible for public and private actors to fundamentally change their way of working together--to shift from international public and private interactions to global health partnerships (GHPs)--and in the process create a new institutional mechanism for governing global health. Drawing on insights from constructivist analysis, I demonstrate how discourse justified, legitimised, communicated and coordinated ideas about the practice of GHPs through a concentrated network of partnership pioneers. As attention from health policy analysts turns increasingly to ideational explanations for answers to global health problems, this paper contributes to the debate by showing how, precisely, discourse makes change possible. PMID- 20924871 TI - Resilience in the context of culture: how women survive natural disasters. PMID- 20924872 TI - Understanding the disaster experience of older adults by gender: the experience of survivors of the 2007 earthquake in Peru. AB - We examine the experiences of older adult survivors of the August 2007 "Southern earthquake" in Peru within the cultural context of gender roles and family relationships. The data include 24 semistructured videotaped interviews conducted in Pisco in December 2007 with survivors of the earthquake aged 60-90. The responses, experiences, and adjustments of the older adult disaster survivors will be discussed in terms of their family and social support systems and gender roles. These older adults sustain their personal identities and deal with their health concerns in the aftermath of the earthquake in the context of these cultural systems of support. PMID- 20924873 TI - Challenges to older women's sense of self in the aftermath of Hurricane Katrina. AB - We examined the personal challenges older women faced as they began to rebuild their sense of self after Hurricane Katrina. In-depth interviews with 74 older women approximately 6 months after the disaster revealed challenges in four domains: maintaining social connections, family connections but loss of independence, reestablishing a sense of place, and managing their own health or the health of a loved one. Follow-up data gathered several months after the initial interviews from 21 of the older women indicated that feelings of displacement persisted as they dealt with health concerns, found a place to live, and managed family roles. PMID- 20924875 TI - In the eye of the storm: resilience and vulnerability among African American women in the wake of Hurricane Katrina. AB - We reviewed 17 studies of experiences of African Americans following Hurricane Katrina, with an emphasis on women. We conducted a literature search using major computerized databases, and we crossed-checked references in articles identified. All of the studies were published in peer-reviewed journals between 2006 and 2010. African American women were more likely than others to report that the hurricane experience produced mental health disorders and stress, disrupted social relationships, and strengthened faith and appreciation of families. African American women emphasized the need to preserve cultural memories, and they advocated for support and recovery. We offer suggestions for practitioners, policymakers, and researchers. PMID- 20924874 TI - After Hurricanes Katrina and Rita: gender differences in health and religiosity in middle-aged and older adults. AB - We examined health-related quality of life in adults in the Louisiana Health Aging Study (LHAS) after Hurricanes Katrina and Rita (HK/R) that made landfall on the U.S. Gulf Coast region in 2005. Analyses of pre- and post-disaster SF-36 scores yielded changes in physical function and bodily pain. Mental health scores were lower for women than men. Gender differences were observed in religious beliefs and religious coping, favoring women. Religious beliefs and religious coping were negatively correlated with physical function, implying that stronger reliance on religiosity as a coping mechanism may be more likely among those who are less physically capable. PMID- 20924876 TI - Emergency planning and long-term care: least paid, least powerful, most responsible. AB - As disasters can occur anywhere, planning to avoid emergencies is an international concern. Our research specifically addresses planning for the needs and safety of a vulnerable population, long-term care residents. Our initial purposes in this evaluation research were to assess the utility of a template to gather emergency management information for individual long-term care communities, to report on how prepared they are to cope with emergencies that have occurred elsewhere in areas like ours, and to assess the effectiveness of employing gerontology students in the planning process. As we began analyzing our data, we realized that it is imperative to consider whether it is possible for long-term care communities to respond effectively to disasters. In our findings we focus on the impact of gender in the planning process, the importance of size with regard to template utility, the positive and negative consequences of student aid, and the fact that gathering plans for individual long-term care communities may have detracted from collaborative community planning. PMID- 20924877 TI - Nonmedical prescription stimulant use among college students: why we need to do something and what we need to do. AB - This article summarizes recent research findings on nonmedical use of prescription stimulants and outlines a multi-pronged strategic approach for responding to this unique problem among college students. Students, health professionals, parents, the pharmaceutical industry, and institutions of higher education all play roles in this response. Moreover, the academic community should view the translation of research findings as an important responsibility that can help dispel the myths often perpetuated in the media. The nonmedical use of prescription stimulants is a complex behavior and should be viewed in the larger context of alcohol and drug involvement among young adults. Strategies to reduce nonmedical use of prescription stimulants might have direct application to the abuse of other prescription drugs, including opiates. PMID- 20924878 TI - Differences between adolescents who complete and fail to complete residential substance abuse treatment. AB - This study examined the admission characteristics associated with failure to complete residential substance abuse treatment among male adolescents. Of 160 admissions, 48 (30%) completed treatment. Having commercial health insurance (P= .005), having a family history of a substance use disorder (P= .05), and living with only one biological parent (P= .015) were admission characteristics associated with non-completion. Those reporting a history of physical or sexual abuse also appeared to be at risk for non-completion (P= .014); none of these participants completed the treatment. Interventions that improve residential substance abuse treatment retention for adolescents are needed. PMID- 20924879 TI - Advanced urine toxicology testing. AB - Urine toxicology screening testing is an important standard of care in the addiction and pain treatment setting, offering a reproducible, unbiased, and accurate laboratory test to monitor patients and provide objective support for clinical observations. It has been shown that physicians do not have proficiency in the ordering or interpretation of these tests. This article is an attempt to respond to that need. Current antibody-based enzymatic immunoassays (EIAs) used for urine toxicology screening are useful to detect classes of drugs (ex., opiate) but cannot determine which specific drug (ex., morphine) is present. Gas chromatography and mass spectroscopy can determine exactly which drugs are present, allowing prescribed (or illicit) opiates and benzodiazepines to be identified. This article will discuss principles and details of opiate and benzodiazepine EIA and gas chromatography and mass spectroscopy urine toxicology testing. The approach to detecting patients attributing positive opiate EIAs to prescription opiates who are using heroin or other opioids will be reviewed. Cases of controlled prescription drugs that do not produce the expected positive urine tests (ex., oxycodone producing negative opiate screening tests) will be discussed. How to differentiate codeine from heroin and the role of poppy seeds in toxicology will be examined. The case of an anti-depressant drug that produces false-positive benzodiazepine results and antibiotics that cause positive opiate urine toxicology results will be reviewed. Common benzodiazepines (ex., clonazepam and lorazepam) that do not reliably produce positive benzodiazepine EIAs will be discussed. The approach to detection and management of all these types of toxicology cases will be reviewed, and it is hoped that the analyses presented will impart an adequate information base to medical providers and staff members of drug treatment and pain centers, enabling them to order and interpret these tests in the clinic more effectively as an integrated part of whole patient care. PMID- 20924880 TI - Effect of ultra-rapid opiate detoxification on withdrawal syndrome. AB - The aim of study was determine the effect of ultra-rapid opiate detoxification (UROD) on the presence or absence of withdrawal syndrome in a group of patients with opiate dependency. In this study, withdrawal syndrome of 173 patients with opiate addiction was evaluated before and after UROD using the Objective Opioid Withdrawal Scale. Hence, each patient was observed for 5 minutes before UROD and at different hours afterward to observe any withdrawal sign. The most prevalent withdrawal sign before UROD was anxiety. Restlessness was the most prevalent finding at 1, 3, and 6 hours. After 12 hours, yawning was reported as the most prevalent finding in 39 participants. Anxiety was reported as the most prevalent finding in 61 participants after 24 hours. Patients with opioid dependency who underwent UROD showed the highest rate of withdrawal symptoms at one hour after anesthesia. Most of these symptoms subsided after 24 hours. UROD can be applied for detoxification of patients with opioid dependency with safety. PMID- 20924881 TI - Erectile dysfunction in opioid users: lack of association with serum testosterone. AB - This study describes the prevalence of erectile dysfunction (ED) among 57 men using illicit opioids who presented to a primary care program for buprenorphine therapy. Participants' mean age was 40 years and 34% reported ED. Low total testosterone was detected in 17% of those reporting ED, but total testosterone was not significantly associated with ED. Examining multiple comorbidities and laboratory parameters, only older age was significantly associated with ED (r = .27, P< .05). ED is highly prevalent among men abusing opioids, but low total testosterone is rarely the cause. PMID- 20924882 TI - Low rates of hepatitis A and B vaccination in patients with chronic hepatitis C at an urban methadone maintenance program. AB - Patients with chronic hepatitis C virus (HCV) are at increased risk for complications of liver disease if they become infected with the hepatitis A (HAV) or hepatitis B (HBV) viruses. The authors examined the rates of testing for HAV, HBV, and HCV, as well as rates of vaccination against HAV and HBV in patients with chronic HCV in a random sample (N = 207) of medical records of patients enrolled in a methadone maintenance program. Almost all patients reviewed were tested for HAV, HBV, and HCV. Of the 111 patients with chronic HCV, 53 (48.6%) and 68 (63%) lacked immunity to HAV and HBV, respectively. Of those lacking immunity, 29 (54.7%) and 2 (2.9%) were vaccinated for HAV and HBV, respectively. Despite high rates of testing for HAV, HBV, and HCV at a methadone maintenance program, approximately half of those with chronic HCV eligible for the HAV vaccine received it, and few of those eligible for HBV vaccine received it. PMID- 20924883 TI - Socioeconomic risk factors and depressive symptoms in alcohol use disorders among male suicides in South Tirol, Italy. AB - The aim of the current study was to evaluate whether socioeconomics risk factors and depressive symptoms are associated with suicide in men with alcohol use disorders in South Tirol, Italy. The authors hypothesize that socioeconomics inequalities interact with greater psychopathology in men with alcohol use disorders who committed suicide. The authors found a positive association between unstable work positions and low educational attainment and alcohol use disorders in individuals who committed suicide. The results point to the need for careful assessment of subsyndromal depression in individuals with alcohol use disorders, especially when abuse is associated with socioeconomic risk factors such as lower educational attainment and unemployment or employment instability. PMID- 20924884 TI - Population-based case-control study of DRD2 gene polymorphisms and alcoholism. AB - Several independent lines of evidence for genetic contributions to vulnerability to alcoholism exist. Dopamine is thought to play a major role in the mechanism of reward and reinforcement in response to alcohol. D2 dopamine receptor (DRD2) gene has been among the stronger candidate genes implicated in alcoholism. In this study, alcohol use was assessed in 196 randomly selected Kota individuals of Nilgiri Hills, South India. Six DRD2 SNPs were assessed in 81 individuals with alcoholism and 151 controls to evaluate the association between single nucleotide polymorphisms (SNPs) and alcoholism. Of the three models (dominant, recessive, and additive) tested for association between alcoholism and DRD2 SNPs, only the additive model shows association for three loci (rs1116313, TaqID, and rs2734835). Of six studied polymorphisms, five are in strong linkage disequilibrium forming onesingle haplotype block. Though the global haplotype analysis with these five SNPs was not significant, haplotype analysis using all six SNPs yielded a global P value of .033, even after adjusting for age. These findings support the importance of dopamine receptor gene polymorphisms in alcoholism. Further studies to replicate these findings in different populations are needed to confirm these results. PMID- 20924886 TI - Does breath carbon monoxide measure nicotine dependence? AB - The aim of the current study was the examination of exhaled breath carbon monoxide levels as a predictor for heaviness of smoking. In this regard, nicotine dependence was assessed among a representative sample of 1,870 Austrian male military conscripts in a cross-sectional setting. Participants completed the Heaviness of Smoking Index (a brief questionnaire for assessment of nicotine dependence), and their expired breath carbon monoxide levels were measured. The performance of carbon monoxide as a predictor of dependence levels was examined by means of Receiver-Operating-Characteristic Curve Analysis. Area Under the Curve, as well as sensitivity and specificity, were reported for each carbon monoxide cut-off level. The authors demonstrate that exhaled carbon monoxide levels serve as a satisfactory means to discriminate between smokers and non smokers, yielding optimal discrimination at a cut-off level >= 5.5 parts per million (ppm), with a sensitivity of 95% and a specificity of 83%. However, the results indicate that carbon monoxide levels do not discriminate adequately between different levels of severity of nicotine dependence. The study demonstrates exhaled carbon monoxide as a useful marker of smoking status but not of nicotine dependence. PMID- 20924885 TI - Injection-related venous disease and walking mobility. AB - Injection users are at risk for vascular injuries resulting in chronic venous disease (CVD). The authors examined walking mobility in relation to CVD for 713 individuals in methadone treatment. The authors used a cross-sectional, comparative design that was stratified on age, sex, ethnicity, and drug use. CVD was present in 92.3% of participants. The structural equation model supported the causal link between leg injection and CVD (.40, P<.001). The worse the mobility, the greater was the CVD classification (-.21, P<.001). CVD had an indirect effect on mobility through pain. CVD and pain need to be considered when assessing mobility in illicit drug users. PMID- 20924888 TI - The use and abuse of opioids. President's message. PMID- 20924889 TI - Reimagining nursing homes: the art of the possible. AB - Long-term care (LTC) needs to be reconceptualized. The current efforts to reinvent the nursing home perpetuate a flawed model of care. The heritage of the nursing home as the dominant model for LTC needs to be reexamined. The basic LTC building blocks--housing, services, and medical care--can be combined in various ways to meet consumers' needs and preferences. We need innovative solutions that can offer reasonable service while recognizing the value of acceptable risk taking. Modest personal care should not come at the price of surrendering one's autonomy. PMID- 20924890 TI - A further opinion on reimagining nursing homes. AB - A commentary of the article discussing the possible reimagining of long-term care (LTC) is provided. The reimagining article examines how to diminish the role of nursing homes in the LTC system. The text is provocative. It is also thought provoking. In this commentary I provide a further opinion that we could do better within the current system using the current resources. PMID- 20924891 TI - What the 2008 stock market crash means for retirement security. AB - The 2008 stock market crash raises concerns about retirement security, especially since the increased prevalence of 401(k) and similar retirement saving plans means that more Americans are now stakeholders in the equity market than in the past. Using a dynamic microsimulation model, this paper explores the ability of alternate future stock market scenarios to restore retirement assets. The authors find that those near retirement could fare the worst because they have no time to recoup their losses. Mid-career workers could fare better because they have more time to rebuild their wealth. They may even gain income if they buy stocks at low prices and get above-average rates of return. High-income groups will be the most affected because they are most likely to have financial assets and to be invested in the stock market. PMID- 20924892 TI - Access barriers to mental health services for older adults from diverse populations: perspectives of leaders in mental health and aging. AB - This project is based on the results of telephone surveys with 52 local, state, and national informed respondents including policymakers, county leaders, planners, and advocates in mental health and aging with a particular focus on the states of California and Florida. This article addresses challenges to access to mental health services for diverse older adults including barriers related to race and ethnicity, socioeconomic status, location, age, gender, immigrant status, language, sexual orientation, and diagnosis. The article also highlights broad themes that emerged including (1) the importance of outreach and transportation tailored to diverse elders, and (2) recruitment of diverse staff and training related to diversity. The article concludes with policy and practice recommendations to reduce these disparities in access to mental health services for diverse populations of older adults. PMID- 20924893 TI - The future of financing for long-term care: the Own Your Future campaign. AB - The purpose of this study was to examine the outreach effort and impact of a joint federal-state campaign, Own Your Future, promoting awareness and planning for long-term care (LTC) in the state of Washington. The study applied survey methodology to evaluate the extent of campaign dissemination, evidence of its impact on LTC planning behaviors, and barriers to purchasing private LTC insurance. A total of 3,198 survey responses from a randomly selected community sample and a Washington State employee sample (ages 51 to 71) were analyzed. Results indicated that the impact of the campaign was limited, both with respect to awareness of the campaign itself and to initiation of LTC planning behaviors. Quantitative data revealed a high prevalence of health-related problems (e.g., obesity, diabetes), inadequate knowledge of basic LTC-related information (e.g., cost, payers), and negative attitudes toward purchasing LTC insurance among respondents. Qualitative analyses suggested that respondents perceived significant problems related to affordability and accountability within the current LTC insurance industry. These possible barriers to the purchase of LTC insurance suggest targets to be addressed by policy makers seeking to find ways to offset the public costs of LTC. PMID- 20924894 TI - Aging in rural Japan--limitations in the current social care policy. AB - Owing to equal and increased opportunities for education and employment, today's trend in Japanese marriages is characterized by late and less frequent marriage. This paper discusses unavoidable diversity in rural families to point out the anticipated consequences of aging in rural areas and to discuss limitations in current public social care policies. Specifically, the averaged proportion of never-married and single persons at ages 45 to 49 and 50 to 54 in legally recognized depopulated cities, towns, and villages in Japan is calculated to illustrate the expected diversity in families in rural depopulated areas. It also illustrates the need for future studies to develop better social care policies for increasing numbers of single caregivers and single elders. PMID- 20924895 TI - Three new lignans from the seeds of Saussurea involucrata. AB - Three new lignans, arctigenin-4-O-(6''-O-acetyl-beta-d-glucoside) (1), arctigenin 4-O-(2''-O-acetyl-beta-d-glucoside) (2), and arctigenin-4-O-(3''-O-acetyl-beta-d glucoside) (3), together with two known lignans, were isolated from the seeds of Saussurea involucrata. Their structures were established by spectroscopic methods, mainly 1D and 2D NMR, and mass spectral analysis. PMID- 20924896 TI - New triterpenes from Salacia hainanensis Chun et How with alpha-glucosidase inhibitory activity. AB - Fractionation of the methanol extract from the roots of Salacia hainanensis Chun et How showing the potent inhibitory activity on alpha-glucosidase afforded two new lupane derivatives, 3alpha,28-dihydroxy-lup-20(29)-en-2-one (1) and 3alpha hydroxy-lup-20(29)-en-2-one (2), a new friedelane derivative, D:A-friedo-oleanane 7alpha,30-dihydroxy-3-one (3), and a novel natural product, 2,3-seco-lup-20(29) en-2,3-dioic acid (4), along with four known compounds (5-8). Their structures were established on the basis of spectral analysis, especially on the data afforded by 2D NMR and high-resolution mass spectra experiments. All of them showed a much stronger inhibiting activity on alpha-glucosidase than the positive control (acarbose, IC50 = 5.83 MUM). Constituents with alpha-glucosidase inhibitory activity from this plant are reported for the first time. PMID- 20924897 TI - The synthesis of puerarin derivatives and their protective effect on the myocardial ischemia and reperfusion injury. AB - Puerarin is a naturally occurring isoflavone and is frequently used for the treatment of cardiovascular symptoms in China. By the structural modification of the puerarin molecule at different positions, seven new puerarin derivatives were obtained, and their cardioprotective activities (in vitro and in vivo) were respectively evaluated. The finding that the activities of 3 and 8 markedly exceeded puerarin suggested that the acylated modification of phenolic hydroxyl at C-7 in the puerarin molecule may improve the cardioprotective activity, which will be an important reference for further structural optimization. PMID- 20924898 TI - Ethylenediamine: an effective reagent for deacetylation of natural products. AB - The use of ethylenediamine in methanol is described for the selective cleavage of the acetate group in nimbin (1) to 6-deacetyl nimbin (1a) under microwave irradiation. This method enables to deacetylate without affecting other functional groups such as alpha,beta-unsaturated ketone, ester, ether, etc. in certain tetranortriterpenoids and other acetate-containing natural compounds. PMID- 20924899 TI - Two new cytotoxic ent-clerodane diterpenoids from Scutellaria barbata. AB - Two new ent-clerodane diterpenoids have been isolated from Scutellaria barbata, and their structures were established by detailed spectroscopic analyses as (13R) 6alpha,7beta-dihydroxy-8beta,13-epoxy-11beta-nicotinyloxy-ent-clerodan-3-en-15,16 olide (scutelinquanine D, 1) and (11E)-6alpha-acetoxy-7beta,8beta-dihydroxy-ent clerodan-3,11,13-trien-15,16-olide (6-acetoxybarbatin C, 2). In vitro, the isolated two new compounds showed significant cytotoxic activities against three human cancer cell lines (HONE-1 nasopharyngeal, KB oral epidermoid carcinoma, and HT29 colorectal carcinoma cells), and gave IC(50) values in the range of 2.5-6.6 MUM. PMID- 20924900 TI - Three new dammarane-type triterpene saponins from the leaves of Panax ginseng C.A. Meyer. AB - Three new dammarane-type triterpene ginsenosides, together with six known ginsenosides, were isolated from the leaves of Panax ginseng C.A. Meyer. The new saponins were named as ginsenoside Rh11, ginsenoside Rh12, and ginsenoside Rh13. Their structures were elucidated as (20S)-3beta,6alpha,12beta,20 tetrahydroxydammara-25-ene-24-one 20-O-beta-d-glucopyranoside (1), (20S) 3beta,12beta,20,24,25-pentahydroxydammarane 20-O-beta-d-glucopyranoside (2), and (20S,23E)-3beta,12beta,20,25-tetrahydroxydammara-23-ene 20-O-beta-d glucopyranoside (3) on the basis of 1D and 2D NMR experiments and mass spectra. The known ginsenosides were identified as ginsenoside M(7cd), ginsenoside Rg6, ginsenoside Rb3, gypenoside XVII, gypenoside IX, and 20-(E)-ginsenoside F4. PMID- 20924901 TI - Two new 8-O-4'-type lignans from the stem of Schima superba and their cell growth inhibitory activities against human cancer cell lines. AB - Two new lignans (1 and 2) were isolated from the EtOH extracts of the stem of Schima superba, and elucidated as (7R,8S)-1-(3,4-dimethoxyphenyl)-2-O-(2-methoxy 4-omegahydroxypropylphenyl)propane-1,3-diol (1) and threo-1-(4-hydroxy-3 methoxyphenyl)-1-methoxy-2-{4-[1-formyl-(E)-vinyl]-2-methoxyphenoxy}-3-propanol (2) by spectral analysis. Compounds 1 and 2 showed cell growth inhibitory activity against HeLa, CNE, HepG-2, and HEp-2 cell lines. Compound 1 exhibited significant cytotoxicities with IC50 values of less than 4 MUg/ml against all the tested cell lines. PMID- 20924902 TI - In vitro and in vivo pharmacokinetics of two novel 1,3-cyclic propanyl phosphate ester prodrugs of 18beta-glycyrrhetic acid in rats. AB - The in vitro metabolism of two novel phosphate prodrugs of glycyrrhetic acid (GA) was studied by the method of incubation in the rat liver microsome and the in vivo plasma pharmacokinetics after injecting intravenously (i.v.) into six rats was investigated, respectively. The prodrugs diminished gradually with time and most of the parent drugs were released in 30 min in vitro. In this paper, the in vivo plasma concentration data were analyzed by compartmental modeling. Both the prodrugs and the corresponding released parent drugs could be described by a two compartment model, which existed for 48 h in rats. The t(1/2) increases remarkably after i.v. administration to rats when compared with injecting the parent drugs directly. PMID- 20924903 TI - Two new aromatic acids from Clerodendrum formicarum Gurke (Lamiaceae) of Cameroon. AB - The ethanolic extract of the leaves of Clerodendrum formicarum, a Lameacious plant of Cameroon, afforded two new salicylic acid derivatives named formoic acids A and B along with four known constituents which have been obtained for the first time from this source. They include flemingipanic acid, martynoside, verbascoside, and seguinoside K. Structures of all the isolated constituents have been elucidated with the aid of 1D and 2D NMR spectroscopic techniques. PMID- 20924904 TI - Salvianolic acid A displays cardioprotective effects in in vitro models of heart hypoxia/reoxygenation injury. AB - Oxidative stress induced by overproduction of reactive oxygen species (ROS) plays an important role in hypoxia/reoxygenation (H/R) injury. In the present study, effects of salvianolic acid A (1) on heart H/R injury through its antioxidant activity were examined, using a molecule-based ROS scavenging system and cardiomyocyte model of H/R injury, as well as isolated rat heart model. As a result, 1 showed a potent antioxidant activity, scavenging all of the tested ROS and DPPH (2,2-diphenyl-1-picrylhydrazyl). The antioxidant effect of 1 was also observed in cardiomyocytes exposed to H/R. Compound 1 remarkably decreased dihydroethidium and dichlorofluorescein fluorescence and increased cell viability and mitochondrial membrane potential, DeltaPsi(m), when compared to the H/R group. In isolated rat hearts exposed to H/R, 1 markedly increased the coronary flow, the peak of pressure development and the valley of pressure development, and significantly reduced the left ventricular end diastolic pressure when compared to the H/R group. These results suggested that 1 had significant protective effects against H/R-induced myocardial injury through its antioxidant activity. PMID- 20924905 TI - A novel brominated cuparene-derived sesquiterpene ether from the red alga Laurencia sp. AB - A novel brominated cuparene-derived sesquiterpene ether, 8,10-dibromo-3,7-epoxy laur-13-ol (1), was isolated from Laurencia sp. collected in South China Sea. Besides this, two known sesquiterpenes, (9beta)-aristol-1(10)-en-9-ol (2) and aristolone (3), were also yielded, and aristolone (3) was obtained from Laurencia for the first time. Their structures were elucidated by spectroscopic methods. PMID- 20924906 TI - A new diarylheptanoid from the bark of Alnus japonica. AB - A new diarylheptanoid, epihirsutanonol (1), was isolated from the bark of Alnus japonica, along with two known ones (2 and 3). Their structures were elucidated on the basis of extensive spectroscopic evidence. The new compound 1 showed significant hepatoprotective activity on the basis of t-butylhydroperoxide induced hepatocyte injury in vitro assay. PMID- 20924907 TI - Forensic, cultural, and systems issues in child sexual abuse cases--part 1: an introduction. AB - This article introduces the first in a two-part special issue focusing on forensic, cultural, and systems issues in child sexual abuse cases. The five articles contained in this issue include a diversity of perspectives on approaches to extended interviews and evaluations of child sexual abuse suspicions, an exploration of the ways culture affects child sexual abuse disclosure and reporting, considerations relevant to the management of a child's mental health needs while forensic process are ongoing, and the use of anatomical dolls in forensic interviews. We call for attention to several practice areas, including (a) prioritizing a child's mental health needs while minimizing disruption of forensic processes, (b) developing best practices and models of child sexual abuse assessment and evaluation when a one-session forensic interview is insufficient, (c) appropriately evaluating child sexual abuse concerns when they occur without a disclosure and/or in children with communication limitations, and (d) the integration of cultural sensitivity into interviews and evaluations. PMID- 20924908 TI - Cultural issues in disclosures of child sexual abuse. AB - Cultural norms affect the likelihood that child sexual abuse will be discovered by an adult or disclosed by a child. Cultural norms also affect whether abused children's families will report child sexual abuse to authorities. This article explores the ways ethnic and religious culture affect child sexual abuse disclosure and reporting, both in the United States and internationally. Guidelines for culturally sensitive child abuse interviewing are provided to facilitate disclosures of abuse from culturally diverse children in formal settings. PMID- 20924909 TI - The use of anatomical dolls as a demonstration aid in child sexual abuse interviews: a study of forensic interviewers' perceptions. AB - Given that most cases of child sexual abuse lack external corroborating evidence, children's verbal accounts of their experiences are of paramount importance to investigators. Forensic interviewers are charged with interviewing child victims and oftentimes use anatomical dolls. Yet, research on dolls has not caught up to practice in the field. Using a multimethod approach, this study presents new evidence on the function and value of using anatomical dolls as a demonstration aid. With a standardized protocol, forensic interviewers from an urban Midwestern Children's Advocacy Center evaluated the purpose and value of anatomical dolls in a forensic setting. Relationships between child characteristics and interviewer perceived value were examined using descriptive, bivariate findings and case examples. Using a large and diverse sample of children, the study found that forensic interviewers perceived children as able and willing to use dolls for purposes of clarification, consistency, distancing, and communication. Results are discussed in the context of real-world applications and best practices and provide an evidence-based foundation for future research. PMID- 20924910 TI - Child sexual abuse suspicions: treatment considerations during investigation. AB - This article addresses what, if any, psychotherapeutic interventions should be provided to meet the emotional and clinical needs of alleged child victims of sexual abuse while they await judicial determinations from the family, dependency, or criminal courts. The discussion emphasizes that to minimize iatrogenic outcomes, professionals involved in sexual abuse allegation cases should carefully establish and maintain professional role boundaries and take on only one role in a case. Professional roles may include an investigative forensic interviewer, court appointed forensic evaluator, and therapist. Special attention is given to complex issues that arise in child custody cases with allegations of child sexual abuse in family court. PMID- 20924911 TI - Allegations of sexual abuse of a child: what to do when a single forensic interview isn't enough. AB - This article describes the state of knowledge about extended assessments/forensic evaluations in situations of possible sexual abuse. It provides a critical review of the modest body of relevant research, describes two models for extended assessments, and presents descriptive survey findings of 62 professionals conducting extended assessments, most of whom conduct extended assessments intermittently as part of their other work on sexual abuse cases. Agencies should consider conducting extended assessments with young or traumatized children whose sexual abuse allegations are not resolved with a single interview as well as in complex child sexual abuse cases. PMID- 20924912 TI - The clinical-forensic dichotomy in sexual abuse evaluations: moving toward an integrative model. AB - We propose the use of an approach to evaluation that can be undertaken in a clinical setting when concerns regarding child sexual abuse are unclear or ambiguous and other systems are not involved, thus providing an option for the nondisclosing child often discussed in the "delayed disclosure" literature. This approach can also be appropriate for a child with a questionable prior disclosure not being served by other intervention systems. We have labeled this an "integrative" model, incorporating forensically sound practices into evaluations conducted in a clinical setting. The goals of this manuscript are to (a) provide a rationale for conducting child sexual abuse extended evaluations in a clinical setting, (b) delineate the purposes of such evaluations, (c) differentiate this "integrative" model from the forensic-clinical dichotomy framework discussed by Kuehnle (1996), and (d) briefly describe the format, which can be refined by future practice and research. PMID- 20924913 TI - Enhancing memory performance after organic brain disease relies on retrieval processes rather than encoding or consolidation. AB - Neuropsychological rehabilitation of memory performance is still a controversial topic, and rehabilitation studies have not analyzed to which stage of memory processing (encoding, consolidation, or retrieval) enhancement may be attributed. We first examined the efficacy of a computer training program for stroke patients, based on a previous study (Hildebrandt, Clausing, Janssen, & Modden, 2007a) for memory-impaired patients of a rehabilitation unit and compared it with the standard group treatment. In a second randomized controlled experiment, we trained two groups of 15 patients with mild to moderate memory disorders, caused by organic brain lesions, with the same two treatment approaches. We used several standard tests to analyze improvement of memory functions, focusing on separate parameters for encoding, consolidation, and retrieval. We developed for that purpose a new word-list learning test, which allowed assessment of response to novelty and a systematic comparison of free recall after learning of semantically structured and nonstructured word lists. The first treatment experiment showed significant improvement of verbal learning for patients treated with the computer software program. The second experiment showed that memory improvement was based exclusively on retrieval processes, whereas no specific change was found for encoding and consolidation. However, the two groups of the second experiment showed no significant differences for the treatment, although the absolute scores pointed in the same direction as in the first experiment. PMID- 20924914 TI - Comparison of Wechsler Memory Scale-Fourth Edition (WMS-IV) and Third Edition (WMS-III) dimensional structures: improved ability to evaluate auditory and visual constructs. AB - Dimensional structures underlying the Wechsler Memory Scale-Fourth Edition (WMS IV) and Wechsler Memory Scale-Third Edition (WMS-III) were compared to determine whether the revised measure has a more coherent and clinically relevant factor structure. Principal component analyses were conducted in normative samples reported in the respective technical manuals. Empirically supported procedures guided retention of dimensions. An invariant two-dimensional WMS-IV structure reflecting constructs of auditory learning/memory and visual attention/memory (C1 = .97; C2 = .96) is more theoretically coherent than the replicable, heterogeneous WMS-III dimension (C1 = .97). This research suggests that the WMS IV may have greater utility in identifying lateralized memory dysfunction. PMID- 20924915 TI - The need for a revised version of the Benton judgment of line orientation test. AB - The Judgment of Line Orientation Test (JLOT) is considered a valid task for the assessment of visuospatial perception, and, for this reason, it is also considered to be a sensitive tool able to discriminate between right-hemisphere damaged (RHD) patients and left-hemisphere-damaged (LHD) patients. In contrast with this view, we report evidence that the greater impairment in JLOT usually shown by RHD patients is unrelated to the supposed JLOT effectiveness in measuring visuospatial judgment ability and to the putative dominant role of the right hemisphere in visuospatial processing. JLOT is characterized by a left right structural asymmetry (i.e., left-side lines are easier to judge) that seriously undermines the test validity: This asymmetry interacts with ipsilesional attentional biases of brain-damaged patients and affects their performance. Results obtained with a JLOT version composed of both the original items and their mirror-reversed versions clearly indicate that the cognitive functions tested by the JLOT are distributed across the two hemispheres: LHD and RHD patients did not differ from each other or from their matched controls when their performances were compared on this balanced JLOT version. Impaired performances of either RHD or LHD patients were found only when performances in original and mirror-reversed items were considered separately. This suggests that the original JLOT cannot assess visuospatial perception independently from attentional biases. The test can be a powerful clinical tool, as long as both original and mirror-reversed items are used, and the standard scoring method is replaced by the evaluation of the individual lines of stimulus pairs. PMID- 20924916 TI - Disinfection of a wastewater flow treated by advanced primary treatment using O3, UV and O3/UV combinations. AB - This study was conducted to evaluate the ozone, UV and O3/UV processes for the reuse of sewage treatment plant effluent (Universidad Autonoma Metropolitana Azcapotzalco wastewater treatment plant). The ozone/UV process was compared to individual ozone and the UV processes and control parameters were total and fecal coliforms. Different ozone concentrations (6-12 mg O3/min) and different UV fluencies (6.7-20.12 mJ/cm2) were tested. It is possible to conclude than none of the processes achieved the disinfection levels required to comply with the Mexican standard NOM-003-SEMARNAT-1997. The continuous ozone process offered the lower total and fecal coliforms reductions, while UV light resulted a disinfection agent with higher germicide power than ozone. The maximum logarithmic reduction achieved due to the combined ozone/UV process was of 2.04 for fecal coliforms and of 2.17 for total coliforms. The next 8 combinations showed lower removal efficiencies, but always higher than those obtained with the single ozone or UV processes. The ozone/UV process was highly effective for the disinfection and a synergistic effect was observed. PMID- 20924917 TI - On-line measurement of oxidative degradation kinetics for trace gasoline contaminants in aqueous solutions and natural water by membrane introduction tandem mass spectrometry. AB - Membrane introduction mass spectrometry (MIMS) was used to directly monitor the loss of trace gasoline contaminants (benzene, toluene, 2-methylthiophene and methylcyclohexane) in nanomolar (ppb) aqueous solutions under a variety of UV induced advanced oxidation processes (AOP). The decay kinetics of these contaminants were followed simultaneously in "real-time" via tandem mass spectrometric techniques by re-circulating the reaction mixture in a closed loop over a semi-permeable membrane interface. The photocatalyzed degradations were observed to follow pseudo-first-order kinetics with rate constants ranging from 0.006 to 0.2 min-1 depending on the reaction conditions. We report rate enhancements for several UV-based advanced oxidative processes using physiosorbed titanium dioxide (TiO2/UV, TiO2/UV/O2, TiO2/UV/H2O2) and compare these to the direct photolysis of H2O2 under otherwise identical conditions. The relative degradation rates of 4 trace contaminants are reported for reactions carried out in the same solution. The degradation kinetics were also monitored directly in a natural surface water spiked with the same contaminant suite. The observed decay kinetics in the presence of TiO2 in air-saturated natural water were similar to those carried out in deionized water. However, when the photo-oxidation was enhanced by the addition of H2O2, the degradation was markedly slower in natural water relative to deionized water due to competition for photons by dissolved organic matter. This work further demonstrates the use of MIMS as a sensitive on line measurement technique for "in-situ" reaction monitoring of organic contaminants at environmentally relevant concentrations in complex solutions and reactive media. PMID- 20924918 TI - Mn(II) removal from groundwater with manganese oxide-coated filter media. AB - Removing soluble manganese from groundwater requires a strong chemical oxidant, such as ozone or potassium permanganate, or raising the pH to alkaline value (over pH 9). Biological or adsorption processes can also be applied. Filter media naturally or industrially coated with manganese oxide are effective in adsorptive manganese removal. In this work, a layer of commercial manganese oxide coated medium was added to the top of an experimental sand/anthracite filter column to improve manganese removal. The coated layer was ca 28 cm thick (20% of the total filter depth) and the sand layer was 110 cm thick. The coated layer enhanced the manganese removal markedly. Manganese removal increased by over 91%, and < 0.02 mg/L of manganese remained in the treated water. Also iron removal was enhanced. Filters with added coated layer recovered faster than reference filter from filter backwashes. Sodium hypochlorite feed, which was tested in regeneration of the filter medium, had a slight negative effect on the filter performance. PMID- 20924919 TI - Arsenic in drinking water wells on the Bolivian high plain: Field monitoring and effect of salinity on removal efficiency of iron-oxides-containing filters. AB - In the rural areas around Oruro (Bolivia), untreated groundwater is used directly as drinking water. This research aimed to evaluate the general drinking water quality, with focus on arsenic (As) concentrations, based on analysis of 67 samples from about 16 communities of the Oruro district. Subsequently a filter using Iron Oxide Coated Sand (IOCS) and a filter using a Composite Iron Matrix (CIM) were tested for their arsenic removal capacity using synthetic water mimicking real groundwater. Heavy metal concentrations in the sampled drinking water barely exceeded WHO guidelines. Arsenic concentrations reached values up to 964 MU g L-1 and exceeded the current WHO provisional guideline value of 10 MU g L-1 in more than 50% of the sampled wells. The WHO guideline of 250 mg L-1 for chloride and sulphate was also exceeded in more than a third of the samples, indicating high salinity in the drinking waters. Synthetic drinking water could be treated effectively by the IOCS- and CIM-based filters reducing As to concentrations lower than 10 MU g L-1. High levels of chloride and sulphate did not influence As removal efficiency. However, phosphate concentrations in the range from 4 to 24 mg L-1 drastically decreased removal efficiency of the IOCS based filter but had no effects on removal efficiency of the CIM-based filter. Results of this study can be used as a base for further testing and practical implementation of drinking water purification in the Oruro region. PMID- 20924920 TI - Removal of arsenic from drinking water by ferric hydroxide microcapsule-loaded alginate beads in packed adsorption column. AB - In this paper we have presented a unique low cost arsenic removal technique using ferric hydroxide microcapsule-loaded alginate beads (FHMCA) as an adsorbent in a continuous packed column. The microencapsulated particles of ferric hydroxide were produced in a spray dryer and subsequently coated with calcium alginate to form spherical beads of about 2 mm diameter. Batch experiments were conducted with these beads to generate isotherm data. The loading capacity was found to be 3.8 mg arsenic/gm of adsorbent. The experimental data conformed to Freundlich adsorption isotherm. A generalized mathematical model was also developed and the visual basic codes run with the physical parameters of the adsorbent and isotherm data that were evaluated experimentally was achieved for a continuous 75 days' operation. The safe disposal of the spent adsorbent was confirmed by the toxicity characteristic leaching procedure (TCLP) results. With known set of physical parameters of the adsorbent, input water flow rate and its arsenic concentration, the model could predict the number of days the column would run with output below a specific arsenic concentration. PMID- 20924921 TI - PHAHs in large reservoir sediments from Hebei and Hubei provinces, China. AB - This study was undertaken to investigate the current contamination status of polyhalogenated aromatic hydrocarbons (PHAHs) in sediments from large reservoirs located in Hebei and Hubei provinces in China. The concentrations of 21 polybrominated biphenyl (PBB) congeners, seven polybrominated diphenyl ether (PBDE) congeners, and 27 polychlorinated biphenyl (PCB) congeners in sediments were measured using the GC-MS/MS technique. Low-brominated PBBs (including 1, 3, 4, 10, 30, 31 and 53) were the most abundant PBB congeners and PBDEs 28, 47 and 99 were the most prevalent PBDE congeners in these samples. Among the three subfamilies of PHAHs, PCBs were the most predominant pollutants detected. The measured levels of PHAHs were compared with recent results reported in the literature and their respective sediment quality guidelines recommended by USEPA. The levels of PHAHs in the present study were generally lower than their respective threshold-effect levels, or were comparable to those reported in relatively uncontaminated freshwaters from other regions. This suggests that, in these reservoirs, toxic biological effects on aquatic biota--due to PHAH contamination of sediments--can be expected to be negligible. Thus, in terms of PHAHs, the sediments in the selected reservoirs are relatively uncontaminated. PMID- 20924922 TI - Sizes and polycyclic aromatic hydrocarbon composition distributions of nano, ultrafine, fine, and coarse particulates emitted from a four-stroke motorcycle. AB - Thus, this study was undertaken to determine the size distribution, concentration, species, and carcinogenic potency of particulate matter and particle-bound polycyclic aromatic hydrocarbons (PAHs) emitted from 4-st/mc at various speeds (idle, 15 km/h, 30 km/h). Approximately 80% of the particles emitted from the that is, they are primary inhalable particulates. The particle total number concentrations (TNCs) emitted while idling and at 15 and 30 km/h were 2.07 x 104, 2.35 x 104, and 2.60 x 104 #/cm3, respectively; i.e., they increased at elevated speeds. Notably, most of the particles emitted at 30 km/h had diameters of less than 0.65 MUm and contained higher percentages of total PAHs. Excluding incomplete combustion, we suspected that some of the lower molecular-weight PAHs [phenanthrene (PA), anthracene (Ant), pyrene (Pyr)] obtained in the fine particles at idle originated from unburned 95-octane unleaded fuel. When operated at 15 km/h, pyrolysis of the PAHs dominated, resulting in increased amounts of medium-molecular-weight PAHs {fluorene (FL), Pyr, benz[a]anthracene (BaA), chrysene (CHR)} in the ultrafine particles. Furthermore, at 30 km/h, more pyrosynthesis products {benzo[a]pyrene (BaP), indeno[1,2,3,-cd]pyrene (IND), dibenz[a,h]anthracene (DBA)}, induced through combustion at the correspondingly higher temperature, were exhausted with the nanoparticles. Although the total concentrations of BaP-equivalent emissions were inconsistent with the total PAHs, the nanoscale-sized particulates emitted from the 4-st/mc at higher speeds had the strongest PAH-related carcinogenic potencies, which should be a great concern. PMID- 20924923 TI - Surface modified activated carbon with beta-cyclodextrin--Part I. Synthesis and characterization. AB - Surface functional groups produced from oxidation (carboxylic acid, lactone, quinine, phenol, and nitro groups), reduction (alcohol and amine groups), and grafting (imine and hemi-acetal) reactions were characterized (using surface analysis and chemical methods) and compared with unmodified activated carbon (AC) materials. The untreated, surface-modified, and grafted activated carbon materials were characterized by various surface sensitive methods: Diffuse Reflectance Infrared Fourier Transform Spectroscopy, Scanning Electron Microscopy, Raman spectroscopy, thermogravimetry analysis, and Matrix Assisted Laser Desorption Ionization Time of Flight (MALDI-TOF) mass spectrometry. A chemical method (Boehm titration) was used for estimating the amount of surface bound acidic and basic functional groups. Nitrogen porosimetry was used to analyze the surface area (95-1350 m2/g) and pore volume (0-0.31 cm3/g) characteristics of AC, surface modified AC, and AC materials grafted with beta cyclodextrin. PMID- 20924924 TI - Surface-modified activated carbon with beta-cyclodextrin--Part II. Adsorption properties. AB - Sorption properties of surface modified activated carbon (AC) with p-nitrophenol (PNP) and methylene blue (MB) in aqueous solution were investigated. The calculated surface areas for AC and surface modified AC were compared using nitrogen sorption and a dye-based method. The surface areas of AC and the surface modified AC with glutaraldehyde (AC-beta-CD) (1:10:109) and 1,4-phenylene diisocyanate (ACPDICD) measured by nitrogen sorption were 1,269 m2/g, 103 m2/g, and 95 m2/g, respectively (Langmuir model) and 956 m2/g, 74 m2/g, and 69 m2/g (BET model), respectively. However, the calculated surface areas for the dye based method (PNP; pH 6.00) for AC, AC-beta-CD(1:10:109), and ACPDICD was 1,035 m2/g, 814 m2/g, and 76 m2/g (Langmuir model), respectively and 1,491 m2/g, 1,669 m2/g, and 92 m2/g (BET model), respectively. The corresponding surface areas for the dye-based method (MB; pH 8.40) for AC-beta-CD(1:10:109) and ACPDICD was 263 m2/g and 171 m2/g (Langmuir model), respectively and 1019 m2/g and 182 m2/g (BET model), respectively. The sorption capacity (Q(m)) and binding affinity characteristics [K(F)(L/g), K(L)(g/mol), and K(BET)(L/g)] were estimated at room temperature at equilibrium conditions using several sorption isotherm models. PMID- 20924925 TI - Anthropogenic sources and environmentally relevant concentrations of heavy metals in surface water of a mining district in Ghana: a multivariate statistical approach. AB - The levels of heavy metals in surface water and their potential origin (natural and anthropogenic) were respectively determined and analysed for the Obuasi mining area in Ghana. Using Hawth's tool an extension in ArcGIS 9.2 software, a total of 48 water sample points in Obuasi and its environs were randomly selected for study. The magnitude of As, Cu, Mn, Fe, Pb, Hg, Zn and Cd in surface water from the sampling sites were measured by flame Atomic Absorption Spectrophotometry (AAS). Water quality parameters including conductivity, pH, total dissolved solids and turbidity were also evaluated. Principal component analysis and cluster analysis, coupled with correlation coefficient analysis, were used to identify possible sources of these heavy metals. Pearson correlation coefficients among total metal concentrations and selected water properties showed a number of strong associations. The results indicate that apart from tap water, surface water in Obuasi has elevated heavy metal concentrations, especially Hg, Pb, As, Cu and Cd, which are above the Ghana Environmental Protection Agency (GEPA) and World Health Organisation (WHO) permissible levels; clearly demonstrating anthropogenic impact. The mean heavy metal concentrations in surface water divided by the corresponding background values of surface water in Obuasi decrease in the order of Cd > Cu > As > Pb > Hg > Zn > Mn > Fe. The results also showed that Cu, Mn, Cd and Fe are largely responsible for the variations in the data, explaining 72% of total variance; while Pb, As and Hg explain only 18.7% of total variance. Three main sources of these heavy metals were identified. As originates from nature (oxidation of sulphide minerals particularly arsenopyrite-FeAsS). Pb derives from water carrying drainage from towns and mine machinery maintenance yards. Cd, Zn, Fe and Mn mainly emanate from industry sources. Hg mainly originates from artisanal small-scale mining. It cannot be said that the difference in concentration of heavy metals might be attributed to difference in proximity to mining-related activities because this is inconsistent with the cluster analysis. Based on cluster analysis SN32, SN42 and SN43 all belong to group one and are spatially similar. But the maximum Cu concentration was found in SN32 while the minimum Cu concentration was found in SN42 and SN43. PMID- 20924926 TI - Male sexuality and Alfred Kinsey's 0-6 scale: toward "a sound understanding of the realities of sex". AB - Using a 0-6 scale, Alfred Kinsey demonstrated that the complexity of human sexuality could best be represented on a continuum rather than as a binary. Kinsey developed the scale from models created by his predecessors in human sex research. A primary intention of the scale was to eradicate sexual identity categories altogether in order to eliminate sexual identity-based persecutions and to promote equal rights. As proponents and opponents of homosexual rights both depended on constructions of sexual identity to advance their agendas, Kinsey's ideal was never realized. The scale nonetheless continues to challenge postmodern associations of identity and sexuality. PMID- 20924927 TI - Was Abraham Lincoln gay? AB - Scholars and historians are blind to Lincoln's same-sex inclinations in part because of a personal aversion to male homosexuality, but more importantly because they fail to perceive the vast differences between the sexual culture of antebellum America and that of our own time, especially in regard to male-male physical and emotional intimacy. This article brings those differences to light and sets Lincoln's life in the context of the sexual culture of his own time. This enables one to see that Lincoln's same-sex sexuality was not only unproblematic, but commonplace, if not typical, in his day. Revising the Myth of Lincoln in regard to his same-sex inclinations will have a positive effect on contemporary culture, especially on the education and socialization of young boys. PMID- 20924928 TI - Liberated and inclusive? An analysis of self-representation in a popular lesbian magazine. AB - Comparisons of a popular lesbian lifestyle magazine to a popular heterosexual women's magazine show that lesbian-controlled media do indeed expand representation when it comes to weight, age, and degree of femininity/masculinity, but not in terms of racial representation. An examination of the textual material and visual images also shows that the lesbian publication gives women a more active role, while the heterosexual magazine depicts females as more passive. However, the evidence also shows that the lesbian and heterosexual magazines have similar rates of objectification, but substantively, the lesbian magazine is less severe in degree of objectification. PMID- 20924929 TI - "Coming out" stories of gay and lesbian young adults. AB - Gay and lesbian young adults (N = 53) were interviewed about coming out to their parents. Analyses of memory content were conducted. Hypotheses related to disclosure were largely supported. Participants typically first disclosed their sexual orientation to a friend. More participants came out to their mother than their father. When disclosure was made to both parents, mothers were told prior to fathers. Mothers were often told using direct methods, whereas fathers were typically informed using indirect methods. Mothers tended to inquire about their sons' sexuality; mothers inquired less with daughters. Findings are discussed in relation to autobiographical memory, sexuality, and clinical literatures. PMID- 20924933 TI - A simplified building airflow model for agent concentration prediction. AB - A simplified building airflow model is presented that can be used to predict the spread of a contaminant agent from a chemical or biological attack. If the dominant means of agent transport throughout the building is an air-handling system operating at steady-state, a linear time-invariant (LTI) model can be constructed to predict the concentration in any room of the building as a result of either an internal or external release. While the model does not capture weather-driven and other temperature-driven effects, it is suitable for concentration predictions under average daily conditions. The model is easily constructed using information that should be accessible to a building manager, supplemented with assumptions based on building codes and standard air-handling system design practices. The results of the model are compared with a popular multi-zone model for a simple building and are demonstrated for building examples containing one or more air-handling systems. The model can be used for rapid concentration prediction to support low-cost placement strategies for chemical and biological detection sensors. PMID- 20924934 TI - Flow characteristics and spillage mechanisms of wall-mounted and jet-isolated range hoods. AB - The flow characteristics and oil mist spillages of wall-mounted and jet-isolated range hoods were studied experimentally. Flow patterns were examined using a laser-light, sheet-assisted, smoke flow visualization technique. Spillages were diagnosed by the locally averaged tracer gas concentration test method. Tracer gas concentration test results correlated well with those of flow visualizations. For the wall-mounted hood, primary leakages occur around the region near the front edge of a countertop due to boundary layer separation, as well as the region just below the lower edge of the side panels of the hood due to the expansion effect of plumes. Increasing the suction flow rate above some critical values may help to reduce leakages out of the lateral planes but would increase spillages around the front edge of the countertop. For the jet-isolated range hood, oil mists spread widely and present unsteady motions with a high degree of turbulence because insufficient free air is allowed to enter the space enclosed by the jets and rear wall. Spillages across the jets into the environment due to turbulent dispersion become significant. Increasing the suction flow rate above some critical values may help to reduce spillages, while increasing the jet velocity would increase turbulent dispersion and thus lead to larger leakages. PMID- 20924935 TI - Vibrator use among heterosexual men varies by partnership status: results from a nationally representative study in the United States. AB - This nationally representative study documents that vibrator use among heterosexually identified men in the United States is common, with 43.8% reporting use of a vibrator at some point in their lives, with most vibrator use by heterosexual men occurring within the context of sexual interactions with a female partner. Approximately 94% of male vibrator users reported that they had used a vibrator during sexual play with a partner, and 82% reported that they had used a vibrator during sexual intercourse. These data support the work of therapists and educators who often make recommendations for the incorporation of vibrators into partnered relationships. PMID- 20924936 TI - Sexual positions and sexual satisfaction of pregnant women. AB - The purpose of this study was to investigate the sexual positions and sexual satisfaction of women during pregnancy. The authors sampled pregnant women (N = 215) from outpatients registered at the antepartum clinic of a medical center in northern Taiwan. The authors gathered data on recent sexual satisfaction, general sexual satisfaction, and sexual position using a self-report, structured questionnaire. The results showed that coital frequency decreased from the first to third trimester (p < .05). The most common sexual position for pregnant women (67.6%) was man on top, face-to-face. Sexual position did not change significantly by trimester. More women with more sexual satisfaction than women with poor sexual satisfaction tended to adopt the woman-on-top, face-to-face, and abdominal-supportive sexual positions. PMID- 20924937 TI - Sexual dysfunction after radical prostatectomy: treatment failure or treatment delay? AB - This study defines characteristics of delayed help-seeking in men who fail phosphodiesterase-5 inhibitors (PDE5I) treatment for their post radical retropubic prostatectomy (RRP) erectile dysfunction (ED). Medical charts were reviewed retrospectively. All men were offered second line treatment with vacuum devices or intracavernous injection (ICI) and sex therapy. This study included thirty one patients. Average age at surgery was 60 years (SD = 5.3, range 46-70). Average period for second line help-seeking was 25.9 months (SD = 12.9, range 3 111). All subjects believed that surgery would not affect their sexual function. Twenty men (65%) used ICI as a second line treatment. Eleven men (35%) declined treatment, waiting for spontaneous recovery. In ICI sub-group, 5 men (25%) regained spontaneous erection within 7-10 months after initial treatment (16-19 months post-surgery). Seven men (35%) responded positively to PDE5I 3-5 months after starting ICI. Three men (15%) used vacuum device. None regained spontaneous erection. All 7 men (23%) who met sex therapist with their partner reported improved sexual life, even if ED wasn't resolved. Patients should receive comprehensive information about sexual recovery, to encourage early ED treatment after RRP and to overcome unwanted misconceptions regarding spontaneous recovery. PMID- 20924938 TI - Partner traits that predict relationship satisfaction for neurotic individuals in premarital relationships. AB - The purpose of this study was (a) to examine the degree of consensus between self reports of neuroticism and partner reports of neuroticism, (b) to explore how neuroticism is related to relationship satisfaction for both partners, and (c) to identify partner traits and skills that predict relationship satisfaction in committed premarital relationships in which one partner has neurotic traits. The results from 198 single, young adult couples who completed the Relationship Evaluation indicated the length of the relationship and their perceptions of their partners' empathy, flexibility, and clear-speaking skills predicted relationship satisfaction for neurotic women. Predictors of relationship satisfaction for neurotic men included perceptions of their partners' lack of criticism and flooding as well as high levels of kindness and empathy. Implications for couple therapy are discussed. PMID- 20924942 TI - The effect of French television sexual program content on the recall of sexual and nonsexual advertisements. AB - This study examined the impact of television program sexual content and explicit sexual advertisement content on memory for advertisements. Eighty-two French participants, aged 18 to 48 years, watched either a sexual program (Sex and the City) or a nonsexual program (Friends), with three sexual and three nonsexual adverts embedded within it. They then completed free- and cued-recall questionnaires testing their memory of the advertisements, as well as a gender identity scale. Overall, sexual advertisements were recalled (in free recall) better than nonsexual advertisements. Participants were found to recall adverts significantly better within the nonsexual program than within the sexual program. No interaction was found between program type and advertisement type: Sexual adverts were recalled better than nonsexual adverts within both programs. Males and females recalled sexual adverts equally, with no mediating effect of gender identity. Implications and limitations of the study are discussed. PMID- 20924943 TI - Using Ecological Momentary Assessment to investigate associations between ejaculatory latency and control in partnered and non-partnered sexual activities. AB - Ecological Momentary Assessment (EMA) was used to investigate associations between, and variations in, ejaculatory control and ejaculation latency time (ELT) over repeated measurements of sexual activities. Differences between measures recorded in partnered or non-partnered settings were also investigated. The sample consisted of 21 male Finns aged 18 years or above, contributing a total of 158 reports of partnered and non-partnered sexual activities over a six week period. In the context of non-partnered sexual activities, after controlling for within-subjects dependence, ELTs between events were predictive of one another, but ELT did not predict ejaculatory control when measured simultaneously, nor at subsequent events. Also, ejaculatory control could not predict simultaneously measured ELT or ejaculatory control at subsequent events. During partnered sexual activities, both ejaculatory control and ELT could be accurately predicted by observing ejaculatory control at prior events. In this context, ejaculatory control could also reliably predict simultaneously measured ELT. ELT or ejaculatory control during partnered sexual activity could not be predicted by observing ELT at prior events. Between-event correlations were generally low, indicating considerable variation in ejaculatory functioning over time. EMA is a thrifty assessment method for studying variations in ejaculatory function, and is likely suitable for studying sexual dysfunctions in general. PMID- 20924944 TI - Does the self drive mental time travel? AB - Research on autobiographical remembering has shown the intertwined relationship between the self and memory. Very little is known about the role of the self in the anticipation of the future. To investigate the association, European American (N=61) and Chinese (N=60) college students each reported two past autobiographical events and anticipated two future events, and described themselves in the past, present, and future. The results from a content analysis found that, regardless of culture, the future self and events were more positive and socially oriented than the past self and events. In general, European Americans provided more positive events and self-descriptions than Chinese. Men showed more personal focus in both experiences and self-descriptions than women at all time epochs. Importantly, independent of culture and gender, the self rather than the past events predicted the valence and personal focus of future events. These findings offer new insights into the dynamic relations between the self and episodic thinking. PMID- 20924945 TI - The effect of articulatory suppression on implicit and explicit false memory in the DRM paradigm. AB - Several studies have shown that reliable implicit false memory can be obtained in the DRM paradigm. There has been considerable debate, however, about whether or not conscious activation of critical lures during study is a necessary condition for this. Recent findings have revealed that articulatory suppression prevents subsequent false priming in an anagram task (Lovden & Johansson, 2003). The present experiment sought to replicate and extend these findings to an implicit word stem completion task, and to additionally investigate the effect of articulatory suppression on explicit false memory. Results showed an inhibitory effect of articulatory suppression on veridical memory, as well as on implicit false memory, whereas the level of explicit false memory was heightened. This suggests that articulatory suppression did not merely eliminate conscious lure activation, but had a more general capacity-delimiting effect. The drop in veridical memory can be attributed to diminished encoding of item-specific information. Superficial encoding also limited the spreading of semantic activation during study, which inhibited later false priming. In addition, the lack of item-specific and phenomenological details caused impaired source monitoring at test, resulting in heightened explicit false memory. PMID- 20924946 TI - Involuntary memory chaining versus event cueing: Which is a better indicator of autobiographical memory organisation? AB - Involuntary memory chains are spontaneous recollections of the past that occur in a sequence. Much like semantic memory priming, this memory phenomenon has provided some insights into the nature of associations in autobiographical memory. The event-cueing procedure (a laboratory-based memory sequencing task) has also provided some insights into the nature of autobiographical memory organisation. However, while both of these memory-sequencing phenomena have exhibited the same types of memory associations (conceptual associations and general-event or temporal associations), both have also produced discrepant results with respect to the relative proportions of such associations. This study investigated the possibility that the results from event cueing are artefacts of various memory production responses. Using a number of different approaches we demonstrated that these memory production responses cause overestimates of general-event association. We conclude that for this reason, the data from involuntary memory chains provide a better picture of the organisation of autobiographical memory. PMID- 20924947 TI - Imagery encoding and false recognition errors: Examining the role of imagery process and imagery content on source misattributions. AB - Imagery encoding effects on source-monitoring errors were explored using the Deese-Roediger-McDermott paradigm in two experiments. While viewing thematically related lists embedded in mixed picture/word presentations, participants were asked to generate images of objects or words (Experiment 1) or to simply name the items (Experiment 2). An encoding task intended to induce spontaneous images served as a control for the explicit imagery instruction conditions (Experiment 1). On the picture/word source-monitoring tests, participants were much more likely to report "seeing" a picture of an item presented as a word than the converse particularly when images were induced spontaneously. However, this picture misattribution error was reversed after generating images of words (Experiment 1) and was eliminated after simply labelling the items (Experiment 2). Thus source misattributions were sensitive to the processes giving rise to imagery experiences (spontaneous vs deliberate), the kinds of images generated (object vs word images), and the ways in which materials were presented (as pictures vs words). PMID- 20924948 TI - Childhood amnesia: Empirical evidence for a two-stage phenomenon. AB - The term childhood amnesia refers to the inability of adults to remember events from their infancy and early childhood. If we plot the number of memories that adults can recall as a function of age during childhood, the number of memories reported increases gradually as a function of age. Typically, this finding has been used to argue that gradual changes in memory development contribute to a gradual decline in childhood amnesia during the preschool period. Alternatively, it is possible that pooling data across participants has obscured more abrupt, stage-like changes in the remission of childhood amnesia. In the present study we examined the number and distribution of childhood memories for individual participants. Six adults were repeatedly interviewed about their childhood memories. We found that the distribution of adults' early childhood memories may be less continuous than pooled data suggest. This finding has important implications for current explanations of childhood amnesia. PMID- 20924949 TI - Wiping out memories: New support for a mental context change account of directed forgetting. AB - Costs and benefits of directed forgetting are observed when a between-list instruction to forget List 1 impairs List 1 recall while enhancing List 2 recall. These effects are often ascribed to intentional inhibition of List 1. Contrary to this inhibition account, we found that a forget instruction did not produce costs unless an explicit instruction to concentrate on List 2 was used (Experiment 1). Alternatively, costs may be ascribed to a shift in mental context between encoding and retrieval. Consistent with this mental context-change account, an unexpected task (wiping the computer screen and one's hands) produced costs comparable to a forget instruction, as did as a brief chat between lists (Experiment 2). A number-search task between lists produced neither costs nor benefits (Experiment 3), suggesting that mere distraction is insufficient for inducing mental context change. Our findings support the claim that mental context change underlies both intentional and unintentional forgetting. PMID- 20924950 TI - Personality traits and autobiographical memory: Openness is positively related to the experience and usage of recollections. AB - We examined the relationship between the Five-Factor Model of personality and the experience and overall usage of autobiographical memory in two studies. In both studies we found that Openness was related to the directive and self functions of overall usage. In addition, Openness was related to the vividness, reliving, coherence, and centrality of event to the person's identity and life story of concrete memories in Study 2, whereas this was not found in Study 1. For the remaining "Big Five" personality traits the results were less consistent across studies. Neuroticism was related to the self function in Study 1, but also to the directive function as well as to negative affect of concrete memories in Study 1. Extraversion was positively related to the social function as well as to conversational rehearsal of memories in Study 1, but this was also not replicated in Study 2. Finally, in both studies there were no significant relationships with regard to Agreeableness and Conscientiousness. Overall, the findings replicate and extend previous work showing a positive relationship between Openness and the experience and overall usage of autobiographical memory, whereas the roles for the remaining "Big Five" are less clear. PMID- 20924951 TI - Conceptual and non-conceptual repetition priming in category exemplar generation: Evidence from bilinguals. AB - One measure of conceptual implicit memory is repetition priming in the generation of exemplars from a semantic category, but does such priming transfer across languages? That is, do the overlapping conceptual representations for translation equivalents provide a sufficient basis for such priming? In Experiment 1 (N=96) participants carried out a deep encoding task, and priming between languages was statistically reliable, but attenuated, relative to within-language priming. Experiment 2 (N=96) replicated the findings of Experiment 1 and assessed the contributions of conceptual and non-conceptual processes using a levels-of processing manipulation. Words that underwent shallow encoding exhibited within language, but not between-language, priming. Priming in shallow conditions cannot therefore be explained by incidental activation of the concept. Instead, part of the within-language priming effect, even under deep-encoding conditions, is due to increased availability of language-specific lemmas or phonological word forms. PMID- 20924953 TI - Constraint therapy versus intensive training: implications for motor control and brain plasticity after stroke. AB - Many studies have demonstrated that constraint induced movement therapy (CIMT) improves upper limb motor impairment following stroke. This rehabilitation method combines constraint of the less-affected upperlimb with intensive training of the paretic limb. The aim of the present study was to evaluate, in a single case study, the respective effects of each of these two therapeutic interventions. The patient selected was a 32-year-old right-handed woman. Three and a half years prior to inclusion, she suffered a left capsular infarct responsible for a right hemiparesis. Several assessments were carried out before and after constraint therapy and then after intensive training. Each assessment included measures of hand function as well as a three-dimensional (3D) analysis of prehension. Results showed a significant improvement of motor performance after the constraint period and an additional amelioration after the intensive training period. Kinematic analysis showed that the transport phase of movement (movement time and velocity peaks) was improved after the constraint period, whereas the grasping phase (maximum grip aperture) was modified after intensive training. These data could reflect a specific effect of treatment on each phase of the prehension task, or a more general proximal-to-distal gradient of recovery. Although firm conclusions are not warranted on the basis of this single case study, we confirm the utility of 3D motion analysis to evaluate objectively the effectiveness of a therapeutic intervention. We also discuss the implications of our findings for understanding processes of motor control reorganisation. PMID- 20924954 TI - Design and synthesis of dually branched 5'-norcarbocyclic adenosine phosphonodiester analogue as a new anti-HIV prodrug. AB - A novel 3',4'-dimethyl-5'-norcarbocyclic adenosine phosphonic acid was prepared using acyclic stereoselective route from 4-hydroxybutan-2-one (4). To improve the cellular permeability and enhance the anti-HIV activity of this phosphonic acid, a (bis)SATE phosphonodiester nucleoside prodrug (20) was prepared and its chemical stability was evaluated. The newly synthesized bis(SATE) analogue (20) and its parent nucleoside phosphonic acid (18) were assayed for anti-HIV activity using an in vitro assay system in a CEM cell line. PMID- 20924955 TI - Hydroxyl-functionalized DNAs with different linkers and their complementary duplex stability. AB - Tert-butyldiphenylsilyl (TBDPS) was testified to be an appropriate orthogonal protecting group for novel 7-hydroxyl-functionalized 8-aza-7-deaza-2' deoxyadenosine analogues. It was stable in partial and complete hydrogenation reactions used for the different linker preparation. The corresponding phosphoramidites and hydroxyl-functionalized oligodeoxynucleotides were synthesized and identified. The thermal effect of the hydroxyl group with different linkers on DNA duplexes was evaluated. It provided a feasible strategy for the preparation of hydroxyl-functionalized DNAs for the nucleic acid research. PMID- 20924956 TI - DNA staining in agarose gels with Zn2+-cyclen-pyrene. AB - A pyrene-labeled Zn2+-cyclen complex for the staining of DNA in agarose gels is reported. The metal chelate coordinates reversibly to the DNA phosphate backbone, which induces the formation of pyrene excimers. The typical pyrene excimer emission is used for the detection of the DNA. Staining is limited to agarose gels and is less sensitive than ethidium bromide, but DNA amounts as low as 10 ng and short DNA strands (~300 b.p.) are detectable. Gel extraction as a standard technique in molecular biology was successfully performed after staining with Zn2+-cyclen-pyrene. Cytotoxicity tests on HeLa and V-79 cells reveal that the zinc-cyclen pyrene probe is significant less toxic compared to ethidium bromide. PMID- 20924957 TI - Cinnamic esters of acyclovir-synthesis and biological activity. AB - In the present study we have synthesized esters of acyclovir with cinnamic acids (p-coumaric, ferulic, and sinapic acids) and evaluated them for their antiviral and antioxidant potential. The antiviral activity of the newly synthesized compounds has been tested against human herpes virus 1 (HSV-1) in vitro. The results indicate that none of the synthesized compounds inhibits the tested virus strain. The antioxidant properties have been studied using 2,2-diphenyl-1 picrylhydrazyl (DPPH)* test. PMID- 20924958 TI - Studies on the synthesis of N'-acetyl aza-analogues of ganciclovir-unexpected liability of N'-(2-hydroxyethyl)-azanucleosides under basic conditions. AB - The O'-pivaloyl diesters of N'-acetyl-azanucleosides were obtained from N-[1,3 di(pivaloyloxy)prop-2-yl]-N-(pivaloyloxymethyl)acetamide and a silylated nucleobase under Vorbruggen's conditions. Unexpectedly, de-pivaloylation of the diesters under basic conditions afforded the corresponding nucleobase and N acetylserinol. Mechanistic investigations showed that these products result from the following cascade of spontaneous transformations initiated by the mono de pivaloylation of the starting diesters. N'-Deacetylation of the resultant mono esters via the intramolecular N-O acetyl migration is the key step of the cascade; the corresponding NH-azanucleosides in the form of O-acetyl-O'-pivaloyl diesters are formed. Fragmentation of these diester intermediates gives the nucleobase and O-acetyl-O'-pivaloylserinol. Conversion of the latter to N acetylserinol involves the selective O-N acetyl migration followed by de pivaloylation of the resulting N-acetyl-O-pivaloylserinol. PMID- 20924959 TI - Antioxidative and radiation modulating properties of guanosine-5'-monophosphate. AB - Employing enhanced chemiluminescence in luminol-p-iodophenol peroxidase system and coumarine-3-carboxylic acid, it was shown that guanosine-5'-monophosphate (GMP) appreciably reduces formation of H2O2 and hydroxyl radicals induced by x ray irradiation. Using immunoenzyme assay, we revealed that GMP lowered 8-oxo-7,8 dihydro-2'-deoxyguanosine (8-oxodGuo) formation in DNA in vitro after irradiation. The results of survival test have shown that mice being injected intraperitoneally with GMP after irradiation with a dose of 7 Gy had better survival rate than the control mice. GMP reduced leucopoenia and thrombocytopenia in irradiated mice. Obtained results give premises that GMP may be promising therapeutic agent for treatment of radiation injuries. PMID- 20924960 TI - Second international congress on nutrition and cancer. PMID- 20924961 TI - Association between the Mediterranean diet and cancer risk: a review of observational studies. AB - The aim of this article was to summarize the evidence concerning the association between Mediterranean dietary pattern and cancer risk in observational epidemiological studies. All the studies that met the following criteria were reviewed: human cohort and case-control studies that examined the effect of the Mediterranean diet as an entire food pattern (the combined effect of individual components of the Mediterranean diet) and whose results were published in English. Out of the 12 reviewed studies (7 cohort and 5 case-control), 10 studies (6 cohort and 4 case-control) provided some evidence that the Mediterranean diet was associated with a reduced risk of cancer incidence or mortality. Although the reviewed studies varied according to certain study characteristics, such as being set in different populations and studying different cancer outcomes, the existing evidence from observational studies collectively suggests that there is a "probable" protective role of the Mediterranean diet toward cancer in general. Specific results for several outcomes such as different cancer sites deserve additional evidence. This favorable effect of the Mediterranean diet on cancer reduction is of public health relevance, given the tendency of modern societies to shift toward a more U.S. and Northern European dietary pattern. PMID- 20924962 TI - Flavonoids, proanthocyanidins, and cancer risk: a network of case-control studies from Italy. AB - We considered flavonoids and proanthocyanidins in a network of multicentric Italian case-control studies including about 10,000 incident, histologically confirmed cases of selected cancers and over 16,000 controls. Odds ratios (ORs) for the highest vs. the lowest quintile of 6 classes of flavonoids and proanthocyanidins were estimated by multiple logistic regression models. Total flavonoids, flavanones, and flavonols were inversely related to oral and laryngeal cancers (ORs, respectively 0.56 and 0.60 for total flavonoids; 0.51 and 0.60 for flavanones; and 0.62 and 0.32 for flavonols). Flavanols were also inversely related to laryngeal cancer (OR = 0.64), whereas flavanones were inversely related to esophageal cancer (OR = 0.38). A reduced risk of colorectal cancer was found for high intake of anthocyanidins (OR = 0.67), flavonols (OR = 0.64), flavones (OR = 0.78), and isoflavones (OR = 0.76). Inverse relations with breast cancer were found for flavones (OR = 0.81) and flavonols (OR = 0.80). Flavonols (OR = 0.63) and isoflavones (OR = 0.51) were inversely associated to ovarian cancer, whereas flavonols (OR = 0.69) and flavones (OR = 0.68) were inversely associated to renal cancer. No association between flavonoids and prostate cancer emerged. We found inverse associations between proanthocyanidins and colorectal cancer. These associations appeared stronger for proanthocyanidins with a higher degree of polymerization (OR = 0.69 for >= 10 mers). PMID- 20924963 TI - Sun exposure, vitamin D, and risk of Hodgkin and non-Hodgkin lymphoma. AB - Similarities in the epidemiology of melanoma, other skin cancers, and non-Hodgkin lymphoma (NHL) have led to the hypothesis that UV exposure, the major risk factor for cutaneous cancers, could play a role on NHL risk too. Epidemiologic studies, however, including a pooled analysis of 10 case-control studies performed by the Interlymph consortium, have failed to confirm this hypothesis. If anything, an inverse association between sun exposure and NHL risk was reported, which appeared confined to recreational sun exposure. Given that sun exposure is the major determinant of vitamin D status in several populations and that vitamin D has been suggested to protect against cancer at several sites, it has been postulated that vitamin D may protect against NHL. Studies that have investigated the association of nutritional sources of vitamin D or serum levels of 25 hydroxy vitamin D-an indicator of vitamin D status-with NHL are scanty and not totally consistent. Thus, the epidemiologic evidence to date suggests that sun exposure is not likely to increase NHL risk, whereas the vitamin D-NHL relation remains largely undefined. The paucity of information on the relation of sun exposure or vitamin D with adult Hodgkin lymphoma (HL) or childhood lymphomas prevents any definite conclusion. PMID- 20924965 TI - STAMPs at the crossroads of cancer and nutrition. AB - Prostate cancer is the most diagnosed noncutaneous cancer among men in Western developed countries. Nutrition and environmental factors play a major role in the onset of the disease, but the molecular details for the contribution of each factor is elusive. In an effort to better understand the basic biology of prostate cancer, we identified a new protein family that is named the 6 trans membrane protein of prostate (STAMP) that appear to have important functions in prostate cancer. At least one member of the STAMP family is also implicated in metabolic homeostasis and nutrition response. Here, we review the current biology of the STAMP proteins and how they may be implicated in disease states including cancer and metabolic syndrome. PMID- 20924964 TI - Nanochemoprevention: sustained release of bioactive food components for cancer prevention. AB - Chemoprevention, especially through the use of naturally occurring phytochemicals capable of impeding the process of carcinogenesis at one or more steps, is an ideal approach for cancer management. Despite accomplished outcomes in preclinical settings, its applicability to humans has met with limited success for many reasons including inefficient systemic delivery and bioavailability of promising chemopreventive agents. We have recently introduced a novel concept of "nanochemoprevention" that utilizes nanotechnology for enhancing the outcome of chemoprevention (Cancer Res 69, 1712-1716, 2009). To establish the usefulness of nanochemoprevention in cancer management, we studied the efficacy of a well identified chemopreventive agent epigallocatechin-3-gallate (EGCG) encapsulated in polylactic acid (PLA) and polyethylene glycol (PEG) nanoparticles (hereafter referred to as nano-EGCG) in preclinical settings. Nano-EGCG was found to retain its biological effectiveness, with over 10-fold dose advantage compared to nonencapsulated EGCG for exerting its cell growth inhibition, proapoptotic, and angiogenic inhibitory effects. Nano-EGCG was also observed to be effective in inhibiting tumor cell growth in athymic nude mice, with over 10-fold dose advantage compared to nonencapsulated EGCG. The rate of degradation of nonencapsulated EGCG was rapid, with a complete degradation within 4 h, whereas nano-EGCG had a significantly longer half-life. This study provides a foundation for the use of nanoparticle-mediated delivery of natural products to enhance the bioavailability of active agents for their enhanced effective and chemopreventive potential. In doing this, it is hoped that perceived toxicity concerns associated with prolonged use of agents could also be minimized. Oral consumption is the most desirable and acceptable form of delivery of chemopreventive agents. One disadvantage of using PLA-PEG nanoparticles is its unstable nature in acidic environment; and therefore, it is not recommended for oral consumption. To overcome this obstacle, it will be important to develop nanoparticles encapsulating phytochemicals that are suitable for oral consumption. PMID- 20924966 TI - A nutrient approach to prostate cancer prevention: The Selenium and Vitamin E Cancer Prevention Trial (SELECT). AB - The Selenium and Vitamin E Cancer Prevention Trial (SELECT) randomized 35,533 healthy men, >55 yr old (>50 yr if African American), with normal digital rectal exams and prostate specific antigens <4 ng/ml to 1) 200 MUg/day l selenomethionine, 2) 400 IU/day all-rac-alpha-tocopheryl acetate (vitamin E), 3) both supplements, or 4) placebo for 7 to 12 yr. The hypotheses underlying SELECT, that selenium and vitamin E individually and together decrease prostate cancer incidence, derived from epidemiologic and laboratory evidence and significant secondary endpoints in the Nutritional Prevention of Cancer (selenium) and Alpha Tocopherol Beta-Carotene (vitamin E) trials. In SELECT, prostate cancer incidence did not differ among the 4 arms: hazard ratios [99% confidence intervals (CIs)] for prostate cancer were 1.13 (99% CI = 0.95-1.35, P = 0.06; n = 473) for vitamin E, 1.04 (99% CI = 0.87-1.24, P = 0.62; n = 432) for selenium, and 1.05 (99% CI = 0.88-1.25, P = 0.52; n = 437) for selenium + vitamin E vs. 1.00 (n = 416) for placebo. Statistically nonsignificant increased risks of prostate cancer with vitamin E alone [relative risk (RR) = 1.13, P = 0.06) and newly diagnosed Type 2 diabetes mellitus with selenium alone (RR = 1.07, P = 0.16) were observed. SELECT data show that neither selenium nor vitamin E, alone or together, in the doses and formulations used, prevented prostate cancer in this heterogeneous population of healthy men. PMID- 20924967 TI - Curcumin, the golden spice from Indian saffron, is a chemosensitizer and radiosensitizer for tumors and chemoprotector and radioprotector for normal organs. AB - Curcumin (diferuloylmethane), the yellow pigment in Indian saffron (Curcuma longa; also called turmeric, haldi, or haridara in the East and curry powder in the West), has been consumed by people for centuries as a dietary component and for a variety of proinflammatory ailments. Extensive research within the last decade in cell culture and in rodents has revealed that curcumin can sensitize tumors to different chemotherapeutic agents including doxorubicin, 5-FU, paclitaxel, vincristine, melphalan, butyrate, cisplatin, celecoxib, vinorelbine, gemcitabine, oxaliplatin, etoposide, sulfinosine, thalidomide, and bortezomib. Chemosensitization has been observed in cancers of the breast, colon, pancreas, gastric, liver, blood, lung, prostate, bladder, cervix, ovary, head and neck, and brain and in multiple myeloma, leukemia, and lymphoma. Similar studies have also revealed that this agent can sensitize a variety of tumors to gamma radiation including glioma, neuroblastoma, cervical carcinoma, epidermal carcinoma, prostate cancer, and colon cancer. How curcumin acts as a chemosensitizer and radiosensitizer has also been studied extensively. For example, it downregulates various growth regulatory pathways and specific genetic targets including genes for NF-kappaB, STAT3, COX2, Akt, antiapoptotic proteins, growth factor receptors, and multidrug-resistance proteins. Although it acts as a chemosensitizer and radiosensitizer for tumors in some cases, curcumin has also been shown to protect normal organs such as liver, kidney, oral mucosa, and heart from chemotherapy and radiotherapy-induced toxicity. The protective effects of curcumin appear to be mediated through its ability to induce the activation of NRF2 and induce the expression of antioxidant enzymes (e.g., hemeoxygenase-1, glutathione peroxidase, modulatory subunit of gamma-glutamyl-cysteine ligase, and NAD(P)H:quinone oxidoreductase 1, increase glutathione (a product of the modulatory subunit of gamma-glutamyl-cysteine ligase), directly quench free radicals, and inhibit p300 HAT activity. These preclinical studies are expected to lead to clinical trials to prove the potential of this age-old golden spice for treating cancer patients. PMID- 20924968 TI - Green tea and cancer prevention. AB - Extracts of green tea and green tea polyphenols have exhibited inhibitory effects against the formation and development of tumors at different organ sites in animals. These include animal models for skin, lung, oral cavity, esophagus, stomach, intestine, colon, liver, pancreas, bladder, mammary gland, and prostate cancers. In addition to suppressing cell proliferation, promoting apoptosis, and modulating signaling transduction, green tea polyphenols, especially (-) epigallocatechin-3-gallate, also inhibit cell invasion, angiogenesis, and metastasis. This article reviews data on the cancer preventive activities of green tea polyphenols, possible mechanisms involved, and the relationship between green tea consumption and human cancer risk. PMID- 20924969 TI - Review on molecular and therapeutic potential of thymoquinone in cancer. AB - Thymoquinone (TQ) is the predominant bioactive constituent present in black seed oil (Nigella sativa) and has been tested for its efficacy against cancer. Here, we summarize the literature about TQ's molecular mechanism of action and its ability to induce apoptosis and inhibit tumor growth in preclinical models. TQ has anti-inflammatory effects, and it inhibits tumor cell proliferation through modulation of apoptosis signaling, inhibition of angiogenesis, and cell cycle arrest. Chemosensitization by TQ is mostly limited to in vitro studies, and it has potential in therapeutic strategy for cancer. The results favor efficacy and enhancement of therapeutic benefit against tumor cells resistant to therapy based on cellular targets that are molecular determinants for cancer cell survival and progression. There have been attempts to synthesize novel analogs of TQ directed toward superior effects in killing tumor cells with more enhanced chemosensitizing potential than parent TQ compound. Based on published reports, we believe that further in-depth studies are warranted including investigation of its bioavailability and Phase I toxicity profiling in human subjects. The results from such studies will be instrumental in advancing this field in support of initiating clinical trials for testing the effects of this ancient agent in cancer therapy. PMID- 20924970 TI - Allicin purified from fresh garlic cloves induces apoptosis in colon cancer cells via Nrf2. AB - Allicin (diallyl thiosulfinate) is the best-known biologically active component in freshly crushed garlic extract. We developed a novel, simple method to isolate active allicin, which yielded a stable compound in aqueous solution amenable for use in in vitro and in vivo studies. We focused on the in vitro effects of allicin on cell proliferation of colon cancer cell lines HCT-116, LS174T, HT-29, and Caco-2 and assessed the underlying mechanisms. This allicin preparation exerted a time- and dose-dependent cytostatic effect on these cells at concentrations ranging from 6.2 to 310 MUM. Treatment with allicin resulted in HCT-116 apoptotic cell death as demonstrated by enhanced hypodiploid DNA content, decreased levels of B-cell non-Hodgkin lymphoma-2 (Bcl-2), increased levels of bax and increased capability of releasing cytochrome c from mitochondria to the cytosol. Allicin also induced translocation of NF-E2-related factor-2 (Nrf2) to the nuclei of HCT-116 cells. Luciferase reporter gene assay showed that allicin induces Nrf2-mediated luciferase transactivation activity. SiRNA knock down of Nrf2 significantly affected the capacity of allicin to inhibit HCT-116 proliferation. These results suggest that Nrf2 mediates the allicin-induced apoptotic death of colon cancer cells. PMID- 20924972 TI - Chemoprevention of colorectal cancer by targeting Janus kinase 3 with a rationally designed small molecule inhibitor. AB - The effects of the rationally designed JAK3 inhibitor JANEX-1 on the development of intestinal tumors in the APC(min) mouse model of familial adenomatous polyposis were examined. At a non-toxic dose level, >4 times lower than its day 30 LD(10), JANEX-1 was highly effective in preventing intestinal tumor development in Min mice, resulting in markedly improved survival outcomes. JAK3 inhibitors may, therefore, be useful in the chemoprevention of colorectal cancer. Here, an overview regarding the potential of JANEX-1 as a chemopreventive agent is provided. PMID- 20924971 TI - Colorectal cancer: chemopreventive role of curcumin and resveratrol. AB - Colorectal cancer (CRC) is a second leading cause of cancer deaths in the Western world. Currently there is no effective treatment except resection at a very early stage with or without chemotherapy. Of various epithelial cancers, CRC in particular has a potential for prevention, since most cancers follow the adenoma carcinoma sequence, and the interval between detection of an adenoma and its progression to carcinoma is usually about a decade. However no effective chemopreventive agent except COX-2 inhibitors, limited in their scope due to cardiovascular side effects, have shown promise in reducing adenoma recurrence. To this end, natural agents that can target important carcinogenic pathways without demonstrating discernible adverse effects would serve as ideal chemoprevention agents. In this review, we discuss merits of two such naturally occurring dietary agents-curcumin and resveratrol-for chemoprevention of CRC. PMID- 20924974 TI - Lycopene and chemotherapy toxicity. AB - Antineoplastic agents induce the production of free radicals and other reactive oxygen species (ROS) in biological systems. Cytotoxic effects of antineoplastic drugs depend on rapid proliferation of cancer cells. Oxidative stress occurring during chemotherapy may potentially interfere with these effects through reducing the rate of cell proliferation. ROS may also contribute to side effects that occur with chemotherapeutic agents such as doxorubicin-induced cardiotoxicity, cisplatin-induced nephrotoxicity, and bleomycin-induced pulmonary fibrosis. Lycopene is a major carotenoid present in tomatoes, and it is a potent antioxidant that may provide protection against cellular damage caused by ROS. Lycopene may reduce or prevent the side effects of chemotherapy due to its antioxidant and anti-inflammatory properties. This review focuses on the protective effects of lycopene against antineoplastic agent induced toxicity. PMID- 20924975 TI - Soy isoflavones in conjunction with radiation therapy in patients with prostate cancer. AB - Soy isoflavones sensitize prostate cancer cells to radiation therapy by inhibiting cell survival pathways activated by radiation. At the same time, soy isoflavones have significant antioxidant and anti-inflammatory activity, which may help prevent the side effects of radiation. Therefore, we hypothesized that soy isoflavones could be useful when given in conjunction with curative radiation therapy in patients with localized prostate cancer. In addition to enhancing the efficacy of radiation therapy, soy isoflavones could prevent the adverse effects of radiation. We conducted a pilot study to investigate the effects of soy isoflavone supplementation on acute and subacute toxicity (<=6 mo) of external beam radiation therapy in patients with localized prostate cancer. Forty-two patients with prostate cancer were randomly assigned to receive 200 mg soy isoflavone (Group 1) or placebo (Group 2) daily for 6 mo beginning with the first day of radiation therapy, which was administered in 1.8 to 2.5 Gy fractions for a total of 73.8 to 77.5 Gy. Adverse effects of radiation therapy on bladder, bowel, and sexual function were assessed by a self-administered quality of life questionnaire at 3 and 6 mo. Only 26 and 27 patients returned completed questionnaires at 3 and 6 mo, respectively. At each time point, urinary, bowel, and sexual adverse symptoms induced by radiation therapy were decreased in the soy isoflavone group compared to placebo group. At 3 mo, soy-treated patients had less urinary incontinence, less urgency, and better erectile function as compared to the placebo group. At 6 mo, the symptoms in soy-treated patients were further improved as compared to the placebo group. These patients had less dripping/leakage of urine (7.7% in Group 1 vs. 28.4% in Group 2), less rectal cramping/diarrhea (7.7% vs. 21.4%), and less pain with bowel movements (0% vs. 14.8%) than placebo-treated patients. There was also a higher overall ability to have erections (77% vs. 57.1%). The results suggest that soy isoflavones taken in conjunction with radiation therapy could reduce the urinary, intestinal, and sexual adverse effects in patients with prostate cancer. PMID- 20924976 TI - Soy isoflavones ameliorate the adverse effects of chemotherapy in children. AB - Genistein sensitizes cancer cells to chemotherapy and radiation by modulating cell survival pathways. At the same time, genistein's antioxidant and anti inflammatory effects may protect normal tissues from adverse effects of chemotherapy and radiation, which are largely due to oxygen-free radicals and inflammation. We conducted a small pilot study with a soy isoflavone mixture containing 8 mg of genistein in children receiving chemotherapy and/or radiation to investigate genistein's potential toxicity preventive effect. We monitored clinical and laboratory parameters in children with cancer who received their first cycle of chemotherapy without genistein and the subsequent cycles with genistein. Patients served as their own controls, and the clinical-laboratory data from the first cycle were compared to the data from subsequent cycles. Nine cycles of chemotherapy were administered without genistein and 57 cycles with genistein. Patients experienced less myelosuppression, mucositis, and infection when they received genistein with chemotherapy. During supplementation, serum genistein levels were 2 to 6 times higher compared to presupplementation levels. Patients who received abdominal radiation reported less pain and diarrhea when they took the genistein supplement. Further clinical investigation of soy isoflavones in pediatric cancer patients receiving chemotherapy and/or radiation should be conducted. PMID- 20924973 TI - Chemopreventive potential of natural compounds in head and neck cancer. AB - Head and neck squamous cell carcinoma (HNSCC) is one of the most fatal cancers worldwide. Despite advances in the management of HNSCC, the overall survival for patients has not improved significantly due to advanced stages at diagnosis, high recurrence rate after surgical removal, and second primary tumor development, which underscore the importance of novel strategies for cancer prevention. Cancer chemoprevention, the use of natural or synthetic compounds to prevent, arrest, or reverse the process of carcinogenesis at its earliest stages, aims to reverse premalignancies and prevent second primary tumors. Genomics and proteomics information including initial mutation, cancer promotion, progression, and susceptibility has brought molecularly targeted therapies for drug development. The development of preventive approaches using specific natural or synthetic compounds, or both, requires a depth of understanding of the cross-talk between cancer signaling pathways and networks to retain or enhance chemopreventive activity while reducing known toxic effects. Many natural dietary compounds have been identified with multiple molecular targets, effective in the prevention and treatment of cancer. This review describes recent advances in the understanding of the complex signaling networks driving cancer progression and of molecularly targeted natural compounds under preclinical and clinical investigation. PMID- 20924977 TI - Causal effects in psychotherapy: counterfactuals counteract overgeneralization. AB - Causal inference of psychotherapy effects is usually based on the theory of internal and external validity. The authors argue that as an inductive strategy it often leads to overgeneralization because it promotes neglect of specific clinical boundary conditions (such as practically relevant combinations of treatments, settings, patients, and therapists). Adding the counterfactual conceptualization of causal effects counteracts overgeneralization by considering individuals at a fixed time under two possible treatment conditions as basic units of a causal effect. Consequently, causal effects are regarded as varying in nature as local pieces of a global theory. The authors outline the main deductions from the counterfactual conceptualization with regard to understanding causality, average effects, bias, and study design and address some controversies in psychotherapy research. PMID- 20924978 TI - Reorienting of spatial attention in gaze cuing is reflected in N2pc. AB - Research has shown that gaze cuing of attention is reflected in the modulation of P1 and N1 components of ERPs time-locked to target onset. Studies focusing on cue locked analyses have produced mixed results. The present study examined ERP reflections of gaze cuing in further detail by recording electric brain activity from the scalp of participants engaged in a spatial cuing paradigm with noninformative gaze cues embedded in fearful, disgusted, or neutral faces. Unlike previous work, we focused on N2pc, a recent ERP index of attention shifting over space. Behavioral data showed that gaze-driven orienting was not influenced by facial expression. Importantly, electrophysiological data showed a significant amplitude modulation of the N2pc time-locked to target onset as a function of cue -target spatial congruence. This pattern, however, was independent of facial expression. The results are interpreted as evidence that N2pc can be used as a marker of reorienting of attention in spatially incongruent trials due to gaze cuing. The overall findings support the idea that the effects of facial expression on gaze cuing are weak and likely context-dependent. PMID- 20924980 TI - Are cognitive outcome and recovery different in civilian penetrating versus non penetrating brain injuries? AB - The present study sought to determine whether cognitive outcome and course of recovery in civilian penetrating brain injury due to gunshot can be distinguished from that of non-penetrating brain injury due to motor vehicle accident. Matched survivors of penetrating and non-penetrating brain injury were assessed with a brief neuropsychological test battery at inpatient rehabilitation, 1 year post injury, and 2 years post-injury. The traumatic brain injury groups were found to have patterns of performance marked by reliably distinct differences in isolated areas, with different cognitive predictors of brain injury type present in early versus later recovery. The degree of recovery over the first 2 years appeared to be quite similar for penetrating and non-penetrating injuries. PMID- 20924979 TI - Examination of the construct validity of ImPACTTM computerized test, traditional, and experimental neuropsychological measures. AB - Although computerized neuropsychological screening is becoming a standard for sports concussion identification and management, convergent validity studies are limited. Such studies are important for several reasons: reference to established measures is needed to establish validity; examination of the computerized battery relative to a more traditional comprehensive battery will help understand the strengths and limitations of the computer battery; and such an examination will help inform the output of the computerized battery. We compared scores on the ImPACTTM battery to a comprehensive battery of traditional neuropsychological measures and several experimental measures used in the assessment of sports related concussion in 54 healthy male athletes. Convergent validity was demonstrated for four of the five ImPACTTM domain scores. Two cognitive domains often compromised as a result of mild TBI were not directly identified by the ImPACTTM battery: sustained attention and auditory working memory. Affective symptoms correlated with performance on measures of attention and working memory. In this healthy sample the correlations between the domains covered by ImPACTTM and the neuropsychological battery supports ImPACTTM as a useful screening tool for assessing many of the cognitive factors related to mTBI. However, the data suggest other sources of data need to be considered when identifying and managing concussions. PMID- 20924981 TI - Utility of the DRS for predicting problems in day-to-day functioning. AB - Predicting the consequences of cognitive impairment relative to day-to-day functioning is challenging, especially when impairment is mild. This study examined the ability of the Dementia Rating Scale (DRS) to predict Record of Independent Living (ROIL) performances in 2469 individuals with varying levels of cognitive ability, and describes specific activities of daily life that are likely impacted given specific DRS scores. Lower DRS scores were associated with greater difficulty in activities of daily living (ADLs), and effects of age, education, and gender were negligible. From a DRS total score, a corresponding ROIL score range and its specific associated impairments were determined. Functional impairments were noted even at mild levels of cognitive impairment. The DRS is helpful for determining the level of assistance that is likely needed in daily care and planning future care needs. PMID- 20924982 TI - Equations for prorating the symptom validity scale (FBS) for the 370-item MMPI-2. AB - The Symptom Validity Scale (FBS), based on the 567-item form of the Minnesota Multiphasic Personality Inventory-2 (MMPI-2), has been shown to be a valid measure of symptom over-reporting. To extend its usefulness to the 370-item form, complete FBS scores (FBS) and FBS scores based on the 370-item form (FBS-S) were extracted from 707 protocols from various testing contexts. Regression analyses using the FBS-S score were developed to predict FBS scores. Results indicate that the full FBS score can be accurately prorated from the FBS-S. Calculated coefficients based on FBS-S score were slightly, but not meaningfully, better than a rationally derived proration in estimating the full FBS score. PMID- 20924983 TI - Use of the WAIS-III picture completion subtest as an embedded measure of response bias. AB - In the present study a large sample of credible patients (n = 172) scored significantly higher than a large sample of noncredible participants (n = 195) on several WAIS-III Picture Completion variables: Age Adjusted Scaled Score, raw score, a "Rarely Missed" index (the nine items least often missed by credible participants), a "Rarely Correct" index (nine items correct <26% of the time in noncredible participants and with at least a 25 percentage-point lower endorsement rate as compared to credible participants), and a "Most Discrepant" index (the six items that were the most discrepant in correct endorsement between groups-at least a 40 percentage point difference). Comparison of the various scores showed that the "Most Discrepant" index outperformed all the others in identifying response bias (nearly 65% sensitivity at 92.8% specificity as compared to at most 59% sensitivity for the other scores). While no differences in Picture Completion scores were observed between less-educated (<12 years) and better-educated (>=12 years) credible participants, noncredible participants with <12 years of education scored significantly poorer than noncredible participants with 12 or more years of education. On the "Most Discrepant" index, 76.7% of less educated noncredible participants were detected as compared to 58.3% of better educated noncredible participants. Results of the current study suggest that the Picture Completion subtest of the WAIS-III is an effective measure of response bias, and that it may have a unique role in identifying suboptimal effort in less educated test takers. PMID- 20924984 TI - Dyslexic and typical-reading children use vowel digraphs as perceptual units in reading. AB - Digraphs are graphemes that are composed of two letters like the "ou" in "soup". We hypothesized that the serial-reading strategy of dyslexic readers might interfere with the processing of digraphs. We used a letter-detection task to compare the processing of vowel digraphs in dyslexic and typical-reading children. Both groups were found to be slower in detecting a letter within a vowel digraph than in detecting a letter of a single-letter grapheme. The slower response to target letters embedded in a digraph was position independent in both groups. We also found that dyslexic children did not differ from typical-reading children in the detection of letters in words. These results indicate that typical-reading and dyslexic children process vowel digraphs as perceptual units and that dyslexic children do not show impairments in this early visual process. PMID- 20924985 TI - Masked priming effects are modulated by expertise in the script. AB - In a recent study using a masked priming same-different matching task, Garci'a Orza, Perea, and Munoz (2010) found a transposition priming effect for letter strings, digit strings, and symbol strings, but not for strings of pseudoletters (i.e., EPRI-ERPI produced similar response times to the control pair EDBI-ERPI). They argued that the mechanism responsible for position coding in masked priming is not operative with those "objects" whose identity cannot be attained rapidly. To assess this hypothesis, Experiment 1 examined masked priming effects in Arabic for native speakers of Arabic, whereas participants in Experiments 2 and 3 were lower intermediate learners of Arabic and readers with no knowledge of Arabic, respectively. Results showed a masked priming effect only for readers who are familiar with the Arabic script. Furthermore, transposed-letter priming in native speakers of Arabic only occurred when the order of the root letters was kept intact. In Experiments 3-7, we examined why masked repetition priming is absent for readers who are unfamiliar with the Arabic script. We discuss the implications of these findings for models of visual-word recognition. PMID- 20924986 TI - The influence of goal-state access cost on planning during problem solving. AB - Two problem-solving experiments investigated the relationship between planning and the cost of accessing goal-state information using the theoretical framework of the soft constraints hypothesis (Gray & Fu, 2004; Gray, Simms, Fu, & Schoelles, 2006). In Experiment 1, 36 participants were allocated to low, medium, and high access cost conditions and completed a problem-solving version of the Blocks World Task. Both the nature of planning (memory based or display based) and its timing (before or during action) changed with high goal-state access cost (a mouse movement and a 2.5-s delay). In this condition more planning before action was observed, with less planning during action, evidenced by longer first move latencies, more moves per goal-state inspection, and more short (<= 0.8 s) and long (>8 s) "preplanned" intermove latencies. Experiment 2 used an eight puzzle-like transformation task and replicated the effect of goal-state access cost when more complex planning was required, also confirmed by sampled protocol data. Planning before an episode of move making increased with higher goal-state access cost, and planning whilst making moves increased with lower access cost. These novel results are discussed in the context of the soft constraints hypothesis. PMID- 20924987 TI - The influence of expertise and of physical complexity on visual short-term memory consolidation. AB - We investigated whether the expertise of a perceiver and the physical complexity of a stimulus influence consolidation of visual short-term memory (VSTM) in a S1 S2 (Stimulus 1-Stimulus 2) change detection task. Consolidation is assumed to make transient perceptual representations in VSTM more durable, and it is investigated by postexposure of a mask shortly after offset of the perceived stimulus (S1; 17 to 483 ms). We presented colours, Chinese characters, pseudocharacters, and novel symbols to novices (Germans) or experts of Chinese language (Chinese readers). Physical complexity was manipulated by the number of strokes. Unfamiliar material was remembered worse than familiar material (Experiments 1, 2, and 3). For novices the absolute VSTM performance was better for physically simple than for complex material, whereas for experts the complexity did not matter-Chinese readers memorized Chinese characters (Experiment 3). Articulatory suppression did not change these effects (Experiment 2). We always observed a strong effect of SOA, but this effect was influenced neither by physical complexity nor by expertise; only the length of the interstimulus interval between S1 and the mask was relevant. This was observed even with short stimulus onset asynchrony (SOA) of 100 ms (Experiment 2) and in comparing colours and characters (Experiment 5). However, masks impaired memory if they were presented at the locations of the to-be-memorized items, but not beside them-that is, interference was location-based (Experiment 6). We explain the effect of SOA by the assumption that it takes time to stop encoding of information presented at item locations with the offset of S1. The increasing resistance against interference by irrelevant material appears as consolidation of S1. PMID- 20924988 TI - Increased Stroop interference with better second-language reading skill. AB - Skilled readers demonstrate remarkable efficiency in processing written words, unlike beginning readers for whom reading occurs more serially and places higher demands on visual attention. In the present study, we used the Stroop paradigm to investigate the relationship between reading skill and automaticity, in individuals learning a second language with a different orthographic system. Prior studies using this paradigm have presented a mixed picture, finding a positive, a negative, or no relationship between the size of Stroop interference and reading skills. Our results show that Stroop interference in the second language was positively related to reading skill (when controlled for interference in the first language). Furthermore, interference was positively related to objective but not subjective indices of the amount of exposure to the second language. We suggest that the lack of consistency in the results of earlier studies may be due, at least in part, to these studies looking at Stroop interference in isolation, rather than comparing interference between languages. PMID- 20924989 TI - Age distribution patterns of patients with conventional ductal adenocarcinoma of the pancreas. A single-institution study of 580 cases re-evaluated using current histopathological diagnostic criteria. AB - There are a few studies concerning epidemiology of pancreatic ductal adenocarcinoma (PDAC) in the Polish population. Analysis of age distribution patterns of patients with different types of cancer may be useful for studying their specific biology. In the present study we aimed to describe age distribution patterns of 580 patients with PDAC diagnosed in one centre during a 25-year period. All the histopathological diagnoses were re-reviewed using current histopathological diagnostic criteria. Age distributions of selected subpopulations of patients (defined based on gender, potential tumour resectability and type of the surgery) were compared using mean values, medians, age frequency density plots and logarithmic plots of age-specific frequencies. The mean and median values of patients' age were 60.8 y and 61.0 y, respectively. Females were approximately 2 y older than males at the time of PDAC diagnosis. Females with non-resectable PDAC were approximately 2 y older than females with resectable tumours. Mean age values of males with non-resectable and resectable PDAC were similar. Patients treated with pancreaticoduodenectomy were approximately 2 y older than patients undergoing other types of resections. Age distribution density plots showed that some subgroups of patients studied were somewhat heterogeneous and might include several yet poorly recognized clinico pathological entities. Logarithmic plots of age-specific frequencies showed that PDAC epidemiology is in concordance with a multistage theory of carcinogenesis. PDAC is an age-dependent cancer. Single-institutional pathology-oriented cancer epidemiological databases may add some information to population-based cancer registries. PMID- 20924990 TI - Investigations into human tracheal cartilage osseocalcineus metaplasia III. ventro-dorsal measurement of the thickness of human tracheal cartilages. AB - The aim of the study was to verify the hypothesis that osseocalcineus metaplasia present in the tracheal cartilage is conditioned by its thickness. The study group comprised 78 male tracheas (age ranging between 19 and 84 years, mean = 56.5 years +/-12.6 years), and 69 female tracheas (age ranging between 18 and 90 years, mean = 65.3 +/-14 years). Tracheal transverse segments (every 4 cm) were collected for histopathological examinations from organs fixed in 10% formalin solution. Typical paraffin specimens, 5 MUm thick, were measured in the horizontal position using the ocular micrometer (10 : 100 Zeiss) and Semiplan 3.2/0.10 objective. Differences between mean patient group and subgroup values were statistically verified. P = 0.05 was considered as statistically significant. Osseocalcineus metaplasia occurred 2.5-fold more often in male patients, in spite of the higher mean age of female patients (p < 0.001). The average male cartilage thickness was 50.32 +/-7.94 * 10-2 cm, while that of female patients was 38.44 +/-4.44 * 10-2 cm (p < 0.001). The average height of male patients (168.63 +/-27.14 cm) was significantly higher in comparison to female patients (157.2 +/-5.78 cm) (p < 0.001). The thickness of tracheal cartilages in men was significantly greater in metaplastic tracheas than in tracheas without metaplasia, as well as in changed cartilages as compared to unchanged ones in the same trachea. Considering both genders, the thickness of tracheal cartilages positively correlated with patient age (men: +0.44; p < 0.001; women: +0.293; p < 0.014), whereas height did not correlate with cartilage thickness. PMID- 20924991 TI - Immunofluorescent evaluation of renal biopsy: current point of view. AB - Immunomorphologic assessment of percutaneous renal biopsy became a standard procedure for establishing diagnosis in kidney disease in parallel with routine haematoxylin and eosin stained paraffin sections. Among various immunomorphologic techniques, direct immunofluorescence of cryosections with a panel of fluorochrome labelled polyclonal or monoclonal antibodies to various serum proteins turned out to be the most reliable and rapid diagnostic procedure. The panel of antibodies may be expanded to include those to microbial or tumour antigens, when needed. The authors specify major advantages of immunofluorescence for such task and potential pitfalls in the case of nonspecific staining. In the next step, various types of fluorescence within renal structures are confronted with particular kidney disorders. Special attention is paid to various types of glomerulonephritis. Lesions in transplanted kidney are also discussed and the role of deposition of C4d complement component along peritubular capillaries is underlined as the evidence of humoral anti-graft reaction. The article is supplemented with a detailed technical procedure for performing of immunofluorescent reaction and evaluation of kidney biopsy, including several control steps. PMID- 20924992 TI - Veterinary pathology trends in the light of The European Society of Veterinary Pathology Congresses in 1997-2009. AB - This paper presents the main trends in the activity of veterinary pathologists in the context of their oral presentations, short speeches and posters during annual congresses of the European Society of Veterinary Pathology (ESVP) in the years 1997-2009. During the thirteen analyzed congresses, 2668 presentations were prepared, including 72 plenary lectures, 946 short oral presentations and 1489 posters. Based on the analysis, organ pathology (779 presentations) was the most popular branch of pathology. Infectious and parasitic diseases (714 presentations) and oncology (563) were also quite popular. This paper analyzes also the role of congresses of the Society in disseminating knowledge on veterinary pathology and training pathologists in Europe as well as the trends in their scientific activity. PMID- 20924993 TI - Segmental congenital defect of the intestinal musculature. AB - Congenital defect of the small intestine muscular layer is rare cause of spontaneous bowel perforation or obstruction in premature infants. Etiology is still unknown. The authors report one case of segmental absence of small bowel muscular layer in preterm born infant. Some ideas concerning the pathogenesis of this entity and review of the literature is presented. PMID- 20924994 TI - Adenomatoid tumour of the adrenal gland: a case report and literature review. AB - Adenomatoid tumour (AT) is a rare, benign neoplasm of mesothelial origin, which usually occurs in the genital tract of both sexes. Occasionally these tumours are found in extra genital locations such as heart, pancreas, skin, pleura, omentum, lymph nodes, retroperitoneum, intestinal mesentery and adrenal gland. Histologically ATs show a mixture of solid and cystic patterns usually with focal presence of signet-ring like cells and scattered lymphoid infiltration. The most important thing about these tumours is not to mis-diagnose them as primary malignant or metastatic neoplasms. We present a case of an adrenal AT in a 29 year-old asymptomatic male. The tumour was an incidental finding during abdominal CT-scan for an unrelated condition. We also present a review of the literature concerning adrenal gland AT and give possible differential diagnosis. PMID- 20924995 TI - Cavernous haemangioma of the oviduct. AB - Haemangiomas represent benign tumours of vascular origin. Cavernous haemangiomas are formed by cavernally widened irregular vascular spaces, lined with endothelia with no signs of atypia. In the fallopian tube haemangiomas are rare. In the available literature, only six cases were noted. We present a clinical and morphological case of a 69-year-old woman with cavernous haemangioma of the oviduct. PMID- 20924996 TI - Refractory anaemia with ringed sideroblasts associated with marked thrombocytosis (RARS-T) with superimposed 5q-syndrome. AB - Refractory anaemia with ringed sideroblasts associated with marked thrombocytosis (RARS-T) is a rare entity belonging to myeloproliferative/myelodysplastic syndromes. Myelodysplastic syndrome (MDS) with isolated del(5q) is a category of MDS characterized by better prognosis and specific morphology. Herein we describe a 69-year-old male with anaemia and thrombocytosis presenting with coexisting features of both these rare diseases. After the description of the clinical data, we summarize the histopathologic, cytogenetic and molecular findings, as well as introduced treatment. Next, we discuss possible diagnostic options with reference to the relevant literature. PMID- 20924998 TI - Brain lesions in tuberous sclerosis complex. Review. AB - Tuberous sclerosis complex (TSC) is an autosomal dominant, multisystem disease characterized by the development of multiple hamartomas and benign or rarely malignant neoplasms distributed at various sites throughout the body, especially in the brain, skin, retina, kidney, heart, and lungs. Brain lesions in TSC include: cortical/subcortical glioneuronal tubers, subependymal glial nodules (SENs), and subependymal giant cell astrocytomas (SEGAs). Cortical tubers are characterized by a markedly disorganized cortical lamination with dysplastic aggregates of abnormal glial and neuronal elements, including giant cells. SENs consist of large cells, somewhat similar to the giant cells seen in tubers, accompanied by elongated glial cells. SENs are typically covered by a layer of ependyma and can grow over time and develop into subependymal giant cell astrocytomas. SEGAs consist of a mixed cell population of large ganglioid-like cells, spindle and giant cells with nuclear pleomorphism. Mitotic activity and necrosis might be observed in SEGAs but they should not be considered as features of malignancy. The clinical presentations of TSC result from mutations in either of two tumour suppressor genes: TSC1 (located on 9q34) or TSC2 (located on 16p13). The proteins encoded by TSC1 and TSC2 genes, hamartin and tuberin, respectively, form a heterodimer which suppresses the mammalian target of rapamycin (mTOR), a major cell growth and proliferation controller. Oral rapamycin therapy may induce regression of astrocytomas associated with TSC. In this review, the clinicopathological features of TCS and recent advantages in the diagnosis and genetics of TSC are presented. PMID- 20924999 TI - Dispersion of prion protein deposits around blood vessels in variant Creutzfeldt Jakob disease. AB - In variant Creutzfeldt-Jakob disease (vCJD), a disease linked to bovine spongiform encephalopathy (BSE), florid-type prion protein (PrP(sc)) deposits are aggregated around the larger diameter (> 10 um) cerebral microvessels. Clustering of PrP(sc) deposits around blood vessels may result from blood-borne prions or be a consequence of the cerebral vasculature influencing the development of the florid deposits. To clarify the factors involved, the dispersion of the florid PrP(sc) deposits was studied around the larger diameter microvessels in the neocortex, hippocampus, and cerebellum of ten cases of vCJD. In the majority of brain regions, florid deposits were clustered around the larger diameter vessels with a mean cluster size of between 50 um and 628 um. With the exception of the molecular layer of the dentate gyrus, the density of the florid deposits declined as a negative exponential function of distance from a blood vessel profile suggesting that diffusion of molecules from blood vessels is a factor in the formation of the florid deposits. Diffusion of PrP(sc) directly into the brain via the microvasculature has been demonstrated in vCJD in a small number of cases. However, the distribution of the prion deposits in vCJD is more likely to reflect molecular 'chaperones' diffusing from vessels and promoting the aggregation of pre-existing PrP(sc) in the vicinity of the vessels to form florid deposits. PMID- 20925000 TI - Submicroscopic pathology of human and experimental hydrocephalic cerebral cortex. AB - The ultrastructural pathology of cerebral cortex in human hydrocephalus is reviewed and compared with experimental hydrocephalus. Nerve cells show moderate and severe swelling. The neighboring neuropil exhibits notable enlargement of extracellular space, synaptic plasticity and degeneration, damage of myelinated axons, and myelination delay. The astrocytes display edematous changes and phagocytic activity. Glycogen rich- and glycogen-depleted astrocytes are observed. Some oligodendroglial cells exhibit normal morphology, and other exhibit hydropic changes. The capillary wall shows signs of blood-brain barrier dysfunction. The role of ischemia, oxidative stress, increased calcium concentration, activation of NMDA receptors, and disturbance of ion homeostasis are discussed in relationship with the fine structural alterations of hydrocephalic brain parenchyma. PMID- 20925001 TI - Spindle cell oncocytoma of the adenohypophysis - a clinicopathological and ultrastructural study of two cases. AB - Spindle cell oncocytoma (SCO) of the pituitary gland is a relatively recently established, very rare subtype of adenohypophysis tumours that was introduced as a distinct clinicopathological entity in the fourth edition of WHO classification of the central nervous system tumours (2007). It is non-endocrine neoplasm of the anterior pituitary that occurs in adults and usually follows a benign clinical course, corresponding to WHO grade I. Up to now, pituitary SCO have been reported occasionally and only 14 cases of SCO have been documented in the literature. Because of their rarity, the pathogenesis and natural history of these tumours have not been fully characterized. We report two additional cases of SCO occurring in females aged 63 years (Case 1) and 65 years (Case 2), who presented with pan-hypopituitarism, headache and visual field defect. In both cases, the magnetic resonance imaging showed solid sellar mass of moderate size with suprasellar extension. The clinical and radiological features suggested non functioning pituitary macroadenomas without evidence of invasive growth. One patient presented with tumour recurrence 3 years after undergoing the previous surgical removal of tumour, which was initially misdiagnosed as schwannoma. The first tumour was removed by transsphenoidal surgery and the second one by frontal craniotomy. Histologically and immunohistochemically, both tumours displayed the features typical for SCO of the pituitary. They were composed of interwoven fascicles of spindle cells exhibiting abundant eosinophilic cytoplasm of oncocytic or granular appearance. Mitoses were rarely observed and necrosis was absent. In one case, the advanced lymphocytic infliltration was observed within neoplastic tissue. The tumour cells exhibited immunoreactivity for S-100 protein, galectin-3, vimentin and epithelial membrane antigen but they were negative for GFAP, anterior pituitary neuroendocrine markers (prolactin, growth hormone, TSH, ACTH, FSH, LH), chromogranin, synaptophysin, cytokeratin CK (AE1/AE3), smooth muscle actin, desmin, CD34 and CD68. MIB1 labeling index did not exceed 10%. Ultrastructurally, the tumour cells were rich in mitochondria with lamellar cristae. Moreover, in Case 2 some tumour cells showed a number of giant mitochondria with severely destructed internal matrix. Spindle cell oncocytoma of the anterior pituitary is often misdiagnosed entity of uncertain histogenesis. It should be considered in the differential diagnosis of various sellar-region lesions of oncocytic morphology. PMID- 20925002 TI - Activation of Akt/mTOR pathway in a patient with atypical teratoid/rhabdoid tumor. AB - A typical teratoid/rhabdoid tumor (AT/RT) is a highly malignant childhood brain tumor. Most AT/RTs are shown to contain chromosome 22 mutation in the region of hSNF5/INI1 gene, whose protein product participates in chromatin remodeling. Although the presence of this mutation is well described, molecular pathways underlying AT/RT development are poorly, if at all, understood. In the current paper we evaluate a case of AT/RT with special consideration of two pathways often implicated in tumor development: protein kinase B (PKB or Akt) and extracellular signal-regulated kinase (Erk). First, we confirmed expression of typical protein pattern being unique for AT/RT, including epithelial membrane antigen, S-100 and glial fibrillary acidic protein. In molecular analyses we tested the sample for activity of Akt and Erk kinase cascade. We found that Erk pathway signaling in the tumor was not upregulated. Neither c-Raf, MAPK nor Erk were hyperphosphorylated. On the other hand, we detected significant phosphorylation of Akt, phosphoinositide-dependent kinase-1 (PDK1) and glycogen synthase kinase 3? (GSK-3?). At the same time, inhibitor of Akt pathway, phosphatase and tensin homolog (PTEN), was not upregulated. These results strongly support the hypothesis that Akt pathway contributes to chromatin remodeling disruption, promoting malignant transformation of AT/RT. PMID- 20925003 TI - Measurement of glycine in a brain and brain tumors by means of 1H MRS. AB - AIM: Evaluation of a peak at 3.55 ppm in a long echo time (TE) recognized as glycine (Gly) in the WHO grade II gliomas and central neurocytomas by means of 1H MRS. MATERIAL AND METHODS: Retrospective analysis of 19 patients with histopathologically confirmed WHO grade II glioma and 2 patients with central neurocytoma was conducted. 1H MRS (TE = 135 ms and TE = 144 ms) was performed with 1.5 T and 3.0 T scanners. Gly/Cr, Gly/Cho and Gly/NAA ratios were compared between the analysed groups. Additional analysis of a brain of 61 healthy volunteers was conducted. RESULTS: Glycine was distinguished in 12 out of 19 (63%) WHO grade II gliomas. Among those 12 WHO grade II gliomas only in 26% of a spectra Gly was recognized. In both central neurocytomas Gly was distinguished and in 43% of the spectra Gly was recognized. The ratio of Gly/Cr in central neurocytomas was higher than in WHO grade II gliomas (mean(CNC) 0.62 +/- 0.18 vs. mean(WHO II) 0.37 +/- 0.10; p < 0.001) but the ratio of Gly/Cho was lower (mean(CNC) 0.18 +/- 0.04 vs. mean(WHO II) 0.24 +/- 0.07; p < 0.001). There was no difference between analysed groups in terms of Gly/NAA ratio (mean(CNC) 0.36 +/- 0.09 vs. mean(WHO II) 0.36 +/- 0.14; p = NS). Only in 0.3% of the spectra of normal brain Gly was distinguished. CONCLUSIONS: Glycine is found in WHO II grade gliomas as well as in central neurocytomas, but only in a part of a tumor volume. It is necessary to perform 1H MRS of the whole tumor volume to confirm/exclude the presence of glycine. Glycine in a normal brain can not be identified by means of conventional 1H MRS performed by means of 1.5 T or 3.0 T scanners. PMID- 20925004 TI - Motor endplate remodeling in some cases with congenital myasthenic syndrome. AB - The architecture of motor endplates in three cases with congenital myasthenic syndrome (CMS) was compared with ultrastructure of the normal control neuromuscular junction (NMJ). The remodeling of postsynaptic region was observed in all three individuals. The most conspicuous abnormalities seen in the slow channel syndrome was the vacuolization and disorganization of secondary synaptic clefts which extended for beyoned the border of NMJ. Degenerated postsynaptic nuclei and junctional sarcoplasm were an additional feature of presented syndromes. The quite different feature of NMJ was observed in the DOK-7 deficient syndrome. The appearance of small, pale terminal axons, poorly developed postsynaptic membrane with the sparse secondary synaptic clefts and degenerated postsynaptic nuclei suggested impairment of postsynaptic region maturation. The conjunction of postsynaptic membrane paucity and its degeneration was a specific structural feature observed in the third syndrome with no established genetic defects. PMID- 20925005 TI - Cerebral amyloid angiopathy as a cause of an extensive brain hemorrhage in adult patient with Down's syndrome - a case report. AB - A case of 54-year old woman who deceased due to consequence of extensive brain hemorrhage is presented. The patient was admitted to our Department of Neurology due to progressive quadriparesis as a complication of the cervical spinal cord compressive myelopathy. On the third day after neurosurgical decompression of the spinal cord sudden worsening of neurological and general condition was observed, finally caused death. An autopsy study revealed an extensive brain lobar hemorrhage and a dorsal-ventral compression of the cervical spinal cord. Alzheimer's disease-type degenerative changes with concomitant CAA were seen in light microscope examination. Extensive foci of demyelination were found especially in dorsal funiculi of the cervical spinal cord. Smaller foci of demyelination were present in anterior funiculi due to the stenosis of vertebral canal. PMID- 20925006 TI - Primary spinal cord melanoma - a case report. AB - Authors present a case of a 57-year-old woman with primary spinal cord malignant melanoma. Intramedullary localization of primary melanoma is extremely rare. The patient presented neurological deficits such as lower limbs paresis and sensory loss. MRI examination showed intramedullar tumor located on the Th10 vertebra level. Surgical treatment with total removal of tumor was performed. Histopathological study confirmed melanoma. Subsequent chemotherapy was given. Tumor was successfully treated by neurosurgery; radio- and chemotherapy with disease free follow up of 9 months. Surgical treatment of melanoma in this location is extremely important as it leads to regression of neurological symptoms and improvement of the quality of life. PMID- 20925008 TI - [Relationship between in-hospital and peri-hospital mortality: Analysis of quality reports covering insured from local sickness funds]. AB - BACKGROUND AND OBJECTIVE: In-hospital mortality is a common criterion for evaluating the quality of medical care provided for inpatients. Besides general concerns, the call for a defined follow-up-period is the subject to be discussed. A project - abbreviated as QSR - covering insured from local health insurance funds now provides respective information. By this means, the relationship between in-hospital and peri-hospital mortality can be elaborated. PATIENTS AND METHODS: Data regarding in-hospital mortality, mortality 30 days, 90 days as well as one year after admission was gathered from QSR quality reports covering 31 hospitals of the HELIOS hospital group. The relationship between the various periods was determined by the non-parametric correlation coefficient, whereas trends were analyzed based on linear regression. RESULTS: There is a relevant (r between 0.552 and 0.908) and significant (p <= 0.006) relation between the various periods with respect to heart failure, cardiac infarction, and stroke or intracerebral haemorrhage. As to surgical fields, comparable results can be recognized. Fifteen out of 85 courses show a statistically significant trend. Only four courses are tangent to the threshold 1 applicable for the standard mortality ratio. CONCLUSION: The study revealed no imperative need to analyze mortality for longer follow-up-periods in order to assess quality of inpatient health care. Therefore, future efforts should concentrate on the identification of an adequate operand that supports best the hospitals in their internal quality management. PMID- 20925009 TI - [Unexplained chronic hypokalaemia in a young woman]. AB - HISTORY AND CLINICAL FINDINGS: The 27 year old female patient presented with chronic hypokalaemia known for 6 years and current potassium values of 1.8 mmol/l. She reported having diarrhea for a few days, fever was denied. INVESTIGATIONS: Physical examination revealed dry skin and mucosa and a slim nutritional status, laboratory investigations showed a hypokalaemic, hypochloraemic alkalosis and hypomagnesaemia. Our first suspicion was an eating disorder or abuse of diuretics or laxatives. Urine analysis showed a high concentration of potassium and chloride, a screening for diuretics was negative. Due to the electrolyte constellation we assumed a Gitelman's Syndrome which was confirmed by genetic testing. TREATMENT AND COURSE: After intravenous substitution of potassium and cessation of diarrhea the potassium values stabilised at 2.5 - 3.0 mmol/l. After being discharged she continued oral substitution of potassium and no such period of severe hypokalaemia occurred again. CONCLUSION: Establishing a diagnosis for patients with chronic hypokalaemia may present difficulties. Urine analysis can help to find reasons for electrolyte disorders. Via measurement of urinary chloride concentration repetitious vomiting as stigmatising diagnosis could be excluded. Urine analysis also led to the diagnosis Gitelman syndrome, an inherited renal tubular disorder, which is suspected to count for 50 % of unexplained chronic hypokalemia. PMID- 20925010 TI - [Primary hyperparathyroidism]. AB - Primary hyperparathyroidism is a common endocrine disease. Since introduction of automated routine measurement of serum calcium the detection of primary hyperparathyroidism has increased significantly. The classical symptoms such as kidney stones, gastrointestinal and bone manifestation are rarely seen nowadays. For this reason, an elevated parathyroid hormone level in a patient with hypercalcemia confirms primary hyperparathyroidism in 95 % of cases. Currently 80 % of these patients are asymptomatic, and therefore criteria for diagnosis and treatment have been discussed on several consensus conferences. After biochemical confirmation has been obtained further diagnostic test aim at locating the tumor should be by ultrasound and 99m TC-sestamibi scintigraphy. The improved diagnostic work-up had led to a better surgical approach with minimally invasive and endoscopic techniques. In addition, quick intraoperative parathyroid hormone measurements confirm immediately the success of surgical treatment. Non-surgical treatment in asymptomatic and elderly patients may be justified. Bisphosphonates are the first choice for medical treatment in patients with bone manifestation and cinacalcet may be given to patients to lower calcium and parathyroid hormone levels. PMID- 20925011 TI - [62-year-old patient with linear ecchymosis after stem cell transplantation]. PMID- 20925012 TI - [New aspects on "triple therapy" after coronary stent implantation]. AB - Antithrombotic/antiplatelet therapy after coronary stent implantation is recommended with a high level of evidence in international guidelines. However, antithrombotic/antiplatelet treatment in patients after coronary stent implantation and in addition with an indication for oral anticoagulation is still an open issue. So called "tripletherapy", the combination of oral anticoagulation with vitamin K-antagonists, clopidogrel and aspirin, is commonly used. This combination significantly increases incidence of minor and major bleedings, especially during long term use. The goal of this manuscript is to discuss the risks and potential benefit of "tripletherapy" in patients with an indication for oral anticoagulation after coronary stent implantation. PMID- 20925013 TI - [Ranolazine--an additional anti-anginal drug]. AB - Ranolazine is a new drug for use in patients with stable angina pectoris. Unlike other antianginal drugs ranolazine does not alter heart rate or systemic blood pressure. Inhibition of the persistent or late sodium current (I(Na,late)) by ranolazine reduces [Na(+) ](i)-dependent Ca(2+) overload and the effects of ischaemia. Moreover, ranolazine holds potential promise to be effective in treatment of atrial fibrillation and diastolic heart failure. PMID- 20925014 TI - [Evaluation of obesity in a 22-year-old female patient]. PMID- 20925015 TI - Continuously increasing sensitivity over three generations of TSH receptor autoantibody assays. AB - Thyroid stimulating hormone (TSH) receptor (TSHR) antibodies (TRAb) are the hallmarks in serological diagnosis of Graves' disease (GD, autoimmune hyperthyroidism). In the 1980s, the first generation liquid-phase TRAb assay with detergent solubilized porcine TSHR was introduced into routine thyroid serology and proved to be highly specific for GD, albeit with moderate sensitivity. In the 1990 s, second generation solid-phase TRAb assays with immobilized porcine or recombinant human TSHR became available, and were clearly more sensitive for Graves' disease without loss of specificity. Recently, third generation TRAb assays have been developed, in which the human thyroid stimulating monoclonal antibody M22 replaces bovine TSH as the competing reagent for TRAb binding to TSHR. Again, an improvement in functional sensitivity was reported for this latest assay generation. To investigate the analytical (aas) and functional assay sensitivity (fas) over 3 generations of TRAb assays, pooled serum samples from patients with GD were measured 10-fold in different assay lots over a few months. The 20% inter-assay coefficients of variation (CV) were calculated and compared taking into account the different calibrations of the assay generations. The fas continuously increased from about 8 U/l of MRC B65/122 in liquid phase TRAb assays, to about 1.0 IU/l (NIBSC 90/672) in TSH based solid phase TRAb assays and to about 0.3 IU/l (NIBSC 90/672) in the M22 based TRAb assay finally. In conclusion, the fas of TRAb measurements has been improved continuously over the last 3 decades. PMID- 20925016 TI - Serum and saliva adrenocortical hormones in obese diabetic men during submaximal exercise. AB - The aim of this study was to evaluate serum and saliva adrenocortical hormones and their relationships at rest and during submaximal exercise and recovery in 9 obese diabetic middle-aged men (BMI: 35.2 +/- 1.6 kg/m (2)). Blood and saliva samples were taken at rest, every 10 min of a 30-min cycling exercise at 70% of maximal heart rate, and after 10 min of recovery in order to analyze cortisol, dehydroepiandrosterone sulfate (DHEA-S) and dehydroepiandrosterone (DHEA). Serum and saliva cortisol increased significantly during recovery (p<0.05), but no significant difference was observed between the rest, exercise, and recovery DHEA S and DHEA concentrations. A strong correlation was found at rest between both serum and saliva cortisol (r=0.72, p<0.001) and DHEA-S and DHEA (r=0.93, p<0.001). Serum DHEA-S and saliva DHEA remained strongly correlated during and after the submaximal exercise (r=0.81, p<0.001), whereas a weaker but still significant relationship was observed between serum and saliva cortisol during and after the exercise (r=0.52, p<0.001). In conclusion, these results suggest that saliva adrenocortical hormones, and especially saliva DHEA, may offer a practical surrogate for serum concentrations during both rest and exercise in obese diabetic men. PMID- 20925017 TI - Differential effects of resveratrol and SRT1720 on lifespan of adult Caenorhabditis elegans. AB - Resveratrol and SRT1720 have been shown to act as sirtuin activators that may ameliorate type 2 diabetes and metabolic diseases in mice. Moreover, resveratrol extends lifespan in model organisms like C. elegans, N. FURZERI, and possibly D. melanogaster. The aim of the study was to test whether pharmacological concentrations of resveratrol and SRT1720 are capable of extending lifespan in a nematodal model organism for aging processes, the roundworm Caenorhabditis elegans. Several hundreds of adult C. ELEGANS roundworms were maintained on agar plates and fed E. COLI strain OP50 bacteria. Resveratrol (5 micromolar, 500 nanomolar) or SRT1720 (1 micromolar, 100 nanomolar) was applied to the agar to test whether they may promote longevity by quantifying survival in the presence and absence of the respective compounds. At a dose of 5 micromolar, which is pharmacologically relevant and 20 times lower than previously published concentrations, resveratrol significantly extends C. elegans lifespan by 3.6% (mean lifespan) and 3.4% (maximum lifespan). By unexpected contrast, SRT1720, which was previously proposed to be several hundred times more active than resveratrol, did not extend lifespan at none of the concentrations tested. Thus, in the model organisms C. elegans, resveratrol is capable of promoting longevity at a concentration that pharmacologically relevant and 20 times lower than previously published doses. The sirtuin activator SRT1720 did not extend lifespan, suggesting that in C. elegans, some relevant effects of resveratrol cannot be mimicked by SRT1720. PMID- 20925018 TI - Variable sensitivity to the glucocorticoid activity of cortisol in patients with primary adrenal insufficiency: assessment with ACTH profiles. AB - Our aim was to investigate the usefulness of circulating levels of adrenocorticotropic hormone (ACTH) and also salivary cortisol to monitor cortisone substitution in patients with Addison's disease. 13 patients with primary adrenal insufficiency (8 women and 5 men, age 44 +/- 11 years) received 12.5 mg cortisone acetate orally at 16:00 h and 25 mg at 07:00 h. Blood samples for cortisol and ACTH analysis were drawn every hour for 24 h, and also every half hour between 07:00 and 12:00 h. Samples for salivary cortisol were collected in parallel. Total ACTH levels showed large inter-individual variations and a diurnal rhythm with a nadir in the early evening at 19:00 (median 19 ng/l, range 2-434 ng/l) and high levels in the early morning, with a peak around 07:30 (median 844 ng/l, range 45-2,249 ng/l). Plasma cortisol concentrations showed 2 peaks distinct in time, but variable in height, 1-2 h after intake of cortisone. Plasma cortisol correlated significantly with ln(ACTH) at 17:00 h (r=-0.56), at 10:00 h (r=-0.51), and at 10.30 h (r=-0.57). When tested at different time points, ln(ACTH) at 10:00 to 12:00 h was negatively correlated with plasma cortisol between 08:30 and 12:00 h. Plasma cortisol was highly correlated to ln(salivary cortisol) most of the time points measured, but 30-60 min after intake of cortisone acetate the correlation disappeared. In conclusion, the large interindividual variation in ACTH levels most likely indicates varying sensitivity to cortisol with a need for individualized dosing schemes. Furthermore ACTH-determinations may be useful for dose titration of cortisol. PMID- 20925019 TI - In vivo activity of 11beta-hydroxysteroid dehydrogenase type 1 in man: effects of prednisolone and chenodesoxycholic acid. AB - The 11beta-hydroxysteroid dehydrogenases (11beta-HSDs) play a pivotal role in glucocorticoid (GC) action. 11beta-HSD1 is a predominant reductase, activating GCs from inert metabolites, whereas 11beta-HSD2 is a potent dehydrogenase inactivating GCs. Knowing the metabolic effects of GCs, a selective inhibition of 11beta-HSD1 represents a potential target for therapy of impaired glucose tolerance, insulin insensitivity and central obesity. In vitro, 11beta-HSD1 is selectively inhibited by chenodesoxycholic acid (CDCA) and upregulated under GC exposure. Therefore, we aimed to investigate the effects of CDCA and prednisolone on hepatic 11beta-HSD1 activity in vivo by measuring 11-reduction of orally given cortisone (E) acetate to cortisol (F). CDCA or placebo was given to 5 male healthy volunteers within a randomised cross-over trial before and after oral administration of 12.5 mg E acetate at 8:00 h. For measurement of in vivo effects of GCs on 11beta-HSD1 activity, hepatic reduction of 25 mg E acetate before and after treatment with prednisolone (30 mg for 6 days) was determined in 7 healthy males. Serum GC levels were determined using a fully automated liquid chromatographic system. CDCA had no effect on the activity of 11beta-HSD1 in vivo. Prednisolone therapy leads to a marked rise in serum F concentrations and an elevated F/E serum ratio. This proves GC-induced activation of hepatic 11beta HSD1, which could not be extinguished by a parallel increase of IGF-1 under prednisolone. CDCA does not affect in vivo activity of 11beta-HSD1 when given in therapeutic dosages. During GC treatment, increased hepatic activation of E to F may aggravate metabolic side effects of GCs such as seen in the metabolic syndrome. PMID- 20925020 TI - [Paraganglioma--a rare cause of mediastinal lesions]. AB - A 73-year-old female patient was admitted to our clinic for further clarification of a suspicious mediastinal lesion. Endosonographically, we performed a fine needle aspiration biopsy. Clinical and radiological findings as well as cytology hardened the suspicion of a paraganglioma as being the cause of the mediastinal lesion. Finally, this diagnosis was confirmed histologically after complete surgical resection of the lesion. This case report on a mediastinal paraganglioma includes a concise summary of diagnostic procedures and therapeutic options for this rare disease. PMID- 20925021 TI - [Late recurrence of renal cell carcinoma in a solitary enlarged paratracheal lymph node]. AB - We report on a 67-year-old male patient who had undergone treatment for renal cell carcinoma 19 years previously. A CT scan showed a solitary enlarged lymph node in the right upper paratracheal region. A specimen was obtained by endobronchial ultrasound with transbronchial needle aspiration. Cytological analysis revealed lymph node metastasis of the late relapsing renal cell carcinoma. PMID- 20925022 TI - Micropatterned hydrogenated amorphous carbon guides mesenchymal stem cells towards neuronal differentiation. AB - This study investigated how the design of surface topography may stimulate stem cell differentiation towards a neural lineage. To this end, hydrogenated amorphous carbon (a-C:H) groove topographies with width/spacing ridges ranging from 80/40MUm, 40/30MUm and 30/20MUm and depth of 24 nm were used as a single mechanotransducer stimulus to generate neural cells from human bone marrow mesenchymal stem cells (hBM-MSCs) in vitro. As comparative experiments, soluble brain-derived neurotrophic factor (BDNF) was used as additional biochemical inducer agent. Despite simultaneous presence of a-C:H micropatterned nanoridges and soluble BDNF resulted in the highest percentage of neuronal-like differentiated cells our findings demonstrate that the surface topography with micropatterned nanoridge width/spacing of 40/30MUm (single stimulus) induced hBM MSCs to acquire neuronal characteristics in the absence of differentiating agents. On the other hand, the alternative a-C:H ridge dimensions tested failed to induce stem cell differentiation towards neuronal properties, thereby suggesting the occurrence of a mechanotransducer effect exerted by optimal nano/microstructure dimensions on the hBM-MSCs responses. PMID- 20925023 TI - Micromass co-culture of human articular chondrocytes and human bone marrow mesenchymal stem cells to investigate stable neocartilage tissue formation in vitro. AB - Cell therapies for articular cartilage defects rely on expanded chondrocytes. Mesenchymal stem cells (MSC) represent an alternative cell source should their hypertrophic differentiation pathway be prevented. Possible cellular instruction between human articular chondrocytes (HAC) and human bone marrow MSC was investigated in micromass pellets. HAC and MSC were mixed in different percentages or incubated individually in pellets for 3 or 6 weeks with and without TGF-beta1 and dexamethasone (+/-T+/-D) as chondrogenic factors. Collagen II, collagen X and S100 protein expression were assessed using immunohistochemistry. Proteoglycan synthesis was evaluated applying the Bern score and quantified using dimethylmethylene blue dye binding assay. Alkaline phosphatase activity (ALP) was detected on cryosections and soluble ALP measured in pellet supernatants. HAC alone generated hyaline-like discs, while MSC formed spheroid pellets in +/-T+/-D. Co-cultured pellets changed from disc to spheroid shape with decreasing number of HAC, and displayed random cell distribution. In T-D, HAC expressed S100, produced GAG and collagen II, and formed lacunae, while MSC did not produce any cartilage-specific proteins. Based on GAG, collagen type II and S100 expression chondrogenic differentiation occurred in -T-D MSC co cultures. However, quantitative experimental GAG and DNA values did not differ from predicted values, suggesting only HAC contribution to GAG production. MSC produced cartilage-specific matrix only in +T+D but underwent hypertrophy in all pellet cultures. In summary, influence of HAC on MSC was restricted to early signs of neochondrogenesis. However, MSC did not contribute to the proteoglycan deposition, and HAC could not prevent hypertrophy of MSC induced by chondrogenic stimuli. PMID- 20925024 TI - Biocompatibility of alendronate-loaded acrylic cement for vertebroplasty. AB - This paper reports a biological evaluation of a non-resorbable acrylic cement loaded with alendronate for the treatment of osteoporotic vertebral compression fractures. The cement formulation was based on polymethyl methacrylate and acrylic monomers; one of these had covalently linked vitamin E residues. The same cement in the absence of alendronate was used as a control. The setting of the charged cement presented a maximum polymerization temperature of 44 degrees C, a setting time of 24 min, a residual monomer content lower than 3 wt.%, a compressive strength of 99+/-10 MPa and an elastic modulus of 1.2+/-0.2 GPa. Cytotoxicity studies using human osteoblast cultures revealed that the leachable substances of the alendronate loaded cement collected between 1 and 7 days decreased cell viability to values lower than 80%. However, morphological changes and cellular damage in cells produced by the extracts decreased with the leak time. Cell adhesion and growth on charged cement was significantly lower than on the control. Implantation of the cement paste in the intra-femoral cavity of rabbits showed that initially the osteogenic activity was evident for the cement charged with alendronate, and the osteosynthesis process took place mainly in the trabeculae and was manifested by the presence of a non-mineralised osseous spicule. The interface between material and adjacent bone tissue was initially characterized by a variable fibrous response that in many cases it appeared reduced to thin connective tissue after a 24-week-period. PMID- 20925025 TI - [Anticipating the future: the diagnosis of Alzheimer's disease in the predementia and prodromal phases]. PMID- 20925026 TI - [Five years' experience in a paediatric epilepsy unit]. AB - INTRODUCTION AND AIMS: The epilepsy monitoring unit is a space inside a hospital, which objective is to reproduce epileptic seizures in order to better study of an epileptic patient. We have analysed data from all the patients admitted to our pediatric epilepsy unit in the last 5 years. PATIENTS AND METHODS: 191 patients have been admitted in our unit, and we have obtained seizures in 186 admissions (monitoring efficacy, 85.9%). In this report we summarize characteristics of these children, type of seizures and treatment. RESULTS: The most frequent cause of epilepsy in our series is cortical development malformation. Patients are often late in their admission, with a median time of 3 to 4 years from epileptic onset to admission in the epilepsy unit. After the study, 22 patients underwent functional epilepsy surgery, all of them with excellent results, 9 patients underwent vagal nerve stimulator implantation and in 66 patients their previous pharmacological treatment was modified. CONCLUSIONS: The efficacy of our monitoring unit is similar to previously published, 85.9%. After the admission, we have changed diagnose in 57% of the patients and pharmacological treatment in 29%. We recommend the study in a monitoring epilepsy unit of every patient with refractory epilepsy, meaning an epilepsy that does not respond to 2-3 different appropriate treatments. PMID- 20925027 TI - [Post-stroke hemichorea: observation-based study of 15 cases]. AB - INTRODUCTION: Chorea is an infrequent complication of acute cerebrovascular disease or stroke. The pathophysiology, the exact location of the lesions and the clinical course of this type of chorea are still not fully understood. AIM: To conduct a retrospective observation-based study of patients diagnosed with vascular hemichorea in our centre. PATIENTS AND METHODS: The study involved consecutive patients diagnosed with this condition who were attended between the years 2004 and 2009. A descriptive analysis of their clinico-radiological characteristics and clinical symptoms was performed. RESULTS: Fifteen patients were included in the study, which represented 0.2% of the cases of stroke attended during the period under analysis. The mean age was 73 years. Twelve patients (80%) presented an ischaemic stroke and three patients (20%) had a haemorrhagic stroke. The location of the lesions varied. The most frequent site was in the lentiform nucleus, followed by those with located in the cortical, thalamic and sub thalamic regions. Eight patients (53%) did not require pharmacological treatment owing to the scarce repercussion of their symptoms or their rapid resolution. The most commonly employed treatment was haloperidol. The mean follow-up time was 17 months. Over that period, the hemi-chorea disappeared in 11 patients (73%), most of them before the end of the second month of progress of the disease. CONCLUSIONS: The variable topography of the lesions related to hemichorea is proof of the complexity of the functioning of the cortico-basal network to control movement and confirms the association between hemichorea and cortical lesions. PMID- 20925028 TI - [A study of subtelomeric rearrangements in 300 patients with mental retardation and multiple congenital anomalies: their clinical and molecular characterisation]. AB - INTRODUCTION: The study of mental retardation is one of the most complex fields in human genetics due to its high degree of clinical and genetic heterogeneity. About 50% of cases of mental retardation remain undiagnosed. It is known that about 6-10% of cases are due to subtelomeric rearrangements. Some of these are responsible for a clinically recognized phenotype, i.e. 1p36 or 22q13.33 microdeletion syndromes, but others affect few patients and are not well characterized. PATIENTS AND METHODS: We have analyzed 300 consecutive mentally retarded patients for subtelomeric rearrangements by MLPA. RESULTS: About 5.3% of patients presented subtelomeric rearrangements; from these, 75% contained de novo rearrangements and 18.7% included inherited aberrations from a healthy parent. In 14 cases, aberrations were likely related to disease and in two cases were putative polymorphisms. CONCLUSIONS: This study confirms the high frequency of subtelomeric rearrangements in mental retardation and reinforces the idea of a routine subtelomeric screening in these patients in order to get a correct diagnosis, establish genotype-phenotype correlations and offer an accurate genetic counseling. PMID- 20925029 TI - [Early diagnosis of Alzheimer's disease: the prodromal and preclinical phase]. AB - INTRODUCTION: Because Alzheimer's disease (AD) needs to be treated as soon as possible after onset, its early detection has become one of the core areas of research in the field of neurodegenerative diseases. DEVELOPMENT: Attempts to characterise the incipient phases of the disease have evolved from the appearance of the heterogeneous concept of mild cognitive impairment in the last twentieth century to the diagnostic criteria proposed for AD by current research. These criteria make it possible to perform an early diagnosis of AD (in the prodromal phase) that is at the same time aetiological, since it is backed up by objective biological markers which will be discussed in this work. Additionally, the article will also review the concept of preclinical AD, which is supported by evidence showing that the pathological process of AD begins years before the clinical manifestation of the disease. CONCLUSIONS: To date, this preclinical phase is the one that has received less attention from researchers, although the development of complex imaging techniques with new tracers appears to be a promising beginning to the coveted path towards the preclinical diagnosis of the disease. PMID- 20925030 TI - [Application of virtual reality in the motor aspects of neurorehabilitation]. AB - INTRODUCTION: Virtual reality allows the user to interact with elements within a simulated scene. In recent times we have been witness to the introduction of virtual reality-based devices as one of the most significant novelties in neurorehabilitation. AIM: To review the clinical applications of the developments based on virtual reality for the neurorehabilitation treatment of the motor aspects of the most frequent disabling processes with a neurological origin. DEVELOPMENT: A review was carried out of the Medline, Physiotherapy Evidence Database, Ovid and Cochrane Library databases up until April 2009. This was completed with a web search using Google. No clinical trial conducted on its effectiveness has been found to date. The information that was collected is based on the description of the various prototypes produced by the different groups involved in their development. In most cases they are clinical trials conducted with a small number of patients, which have focused more on testing the validity of the device and checking whether it works correctly than on attempting to prove its clinical effectiveness. Although most of the clinical applications refer to patients with stroke, there were also several applications for patients with spinal cord injuries, multiple sclerosis, Parkinson's disease or balance disorders. CONCLUSIONS: Virtual reality is a novel tool with a promising future in neurorehabilitation. Further studies are needed to demonstrate its clinical effectiveness as compared to the traditional techniques. PMID- 20925031 TI - [Autosomal recessive limb-girdle muscular dystrophy]. AB - Muscular dystrophies are a heterogeneous group of hereditary diseases characterized by loss of muscle and weakness of non neurogenic origin. They are caused by mutations in one or more genes involved in the formation of muscle cells. The discovery of several proteins in the muscle began with the discovery of dystrophin, 130 years after the clinical description of muscular dystrophy. Currently, due to a better understanding of the biology of normal and diseased muscle, has achieved a classification at the molecular level of different types of muscular dystrophies, according to the protein that is affected. This has been particularly important for limb girdle muscular dystrophies, which present clinical features that can lead to confusion with Duchenne muscular dystrophy. Moreover, in recent years has encouraged the development of therapies in the near future could provide a solution for restoring the function of the muscle fiber. PMID- 20925033 TI - [Juvenile stroke as the presenting symptom of a non-compaction cardiomyopathy]. PMID- 20925034 TI - [Topiramate as an effective therapeutic option in the treatment of West syndrome]. PMID- 20925035 TI - [Headache secondary to hyperthyroidism]. PMID- 20925036 TI - [A review of Memory Impairment Screen]. PMID- 20925037 TI - YhgC protects Bacillus anthracis from oxidative stress. AB - Bacillus anthracis can cause lethal inhalational anthrax and can be used as a bioweapon due to its ability to form spores and to survive under various environmental stress conditions. YhgC in bacilli are structural homologues of TRAP, a protein involved in stress response in staphylococci. To test the role of YhgC in B. anthracis, yhgC gene was deleted in B. anthracis strain Sterne and parent and mutant strains tested. Immunolocalization studies indicated that YhgC is clustered both on the cell surface and within the cytoplasm. Phenotypic analyses indicated that YhgC is an important factor for oxidative stress tolerance and for macrophage infection in vitro. Accordingly, transcriptomics studies indicated that yhgC has a profound effect on genes encoding for stress response regulatory proteins where it negatively regulates the expression of genes encoding for Class I and Class III stress response proteins belonging to the regulons hrcA (hrcA, grpE, dnaK, dnaJ, groEL and groES) and ctsR (ctsR, mcsA, mcsB, clpC/mecB, clpP1). Proteomics studies also indicated that YhgC positively regulates the expression of ClpP-2 and camelysin, which are proteins involved in adaptive responses and pathogenesis in various Gram-positive bacteria. Put together, these results suggest that YhgC is important for the survival of B. anthracis under oxidative stress conditions and thus inhibition of YhgC may compromise the ability of the bacteria to survive within the host. PMID- 20925038 TI - An intein-mediated site-specific click conjugation strategy for improved tumor targeting of nanoparticle systems. AB - The ability to modify and directly target nanoparticulate carriers has greatly increased their applicability in diagnostic and therapeutic studies. Generally essential to the targeting of nanoparticles is the bioconjugation of targeting ligands to the agent's surface. While bioconjugation techniques have steadily improved in recent years, the field is still plagued with inefficient conjugations reactions and/or the lack of site-specific coupling. To overcome these limitations, click chemistry and expressed protein ligation (EPL) are combined to produce a highly efficient, site-specific reaction. This new EPL click conjugation strategy is applied to create superparamagnetic iron oxide nanoparticles (SPIO) labeled with HER2/neu affibodies. These HER2-SPIO nanoparticles prove to be highly potent and receptor-specific in both in vitro cell studies and murine tumor models. Moreover, when EPL-click-derived HER2-SPIO are compared with SPIO that had been labeled with HER2 affibodies using other popular bioconjugation methods, they produce a statistically significant improvement in contrast enhancement upon cell binding. The EPL-click system is also successfully extended to other nanoparticle platforms (i.e., liposomes and dendrimers) highlighting the versatility of the approach. PMID- 20925039 TI - Liposome and lipid bilayer arrays towards biosensing applications. AB - Sensitive and selective biosensors for high-throughput screening are having an increasing impact in modern medical care. The establishment of robust protein biosensing platforms however remains challenging, especially when membrane proteins are involved. Although this type of proteins is of enormous relevance since they are considered in >60% of the pharmaceutical drug targets, their fragile nature (i.e., the requirement to preserve their natural lipid environment to avoid denaturation and loss of function) puts strong additional prerequisites onto a successful biochip. In this review, the leading approaches to create lipid membrane-based arrays towards the creation of membrane protein biosensing platforms are described. Liposomes assembled in micro- and nanoarrays and the successful set-ups containing functional membrane proteins, as well as the use of liposomes in networks, are discussed in the first part. Then, the complementary approaches to create cell-mimicking supported membrane patches on a substrate in an array format will be addressed. Finally, the progress in assembling free standing (functional) lipid bilayers over nanopore arrays for ion channel sensing will be reported. This review illustrates the rapid pace by which advances are being made towards the creation of a heterogeneous biochip for the high throughput screening of membrane proteins for diagnostics, drug screening, or drug discovery purposes. PMID- 20925040 TI - Tunable vancomycin releasing surfaces for biomedical applications. AB - Local drug delivery methods allow for the opportunity to supply potent multispectrum antibiotics such as vancomycin hydrochloride to sites of infection, while avoiding systemic toxicity. In this work, layer-by-layer assembly of polymer multilayer films is applied to create vancomycin delivery coatings. By taking advantage of the versatile layer-by-layer spray and dip coating techniques, thin films were generated based on electrostatic and other secondary interactions discovered to exist between the film components. The importance of film interdiffusion during growth in promoting interactions between film components is found to be critical in the direct incorporation of the weakly charged vancomycin drug in these multilayer films. The resulting coatings are engineered with unprecedented drug densities ranging from 17-220 MUg mm(-3) (approximately 20 wt%) for films that are micron to submicron scale in thickness, delivering vancomycin over timescales of 4 h to 2.5 days. The released drug is highly effective in inhibiting Staphylococcus aureus growth in vitro. Taking advantage of the difference in release characteristics between dip and spray assembled films, a composite film architecture was engineered to have both a bolus vancomycin release followed by a period of linear sustained drug release. The control over drug densities and release profiles displayed in this work is necessary to address the requirements of varying medical conditions, including those where immediate infection elimination is needed or long term infection prevention is required. PMID- 20925041 TI - Is ultrasound alone enough for prenatal screening of trisomy 18? A single centre experience in 69 cases over 10 years. AB - OBJECTIVES: To evaluate ultrasound scan and other prenatal screening tests for trisomy 18 in a regional obstetric unit and to review the management approach for women with positive trisomy 18 screening results. METHODS: Prenatal diagnosis databases were accessed to identify fetuses that had confirmed trisomy 18 karyotypes or were at high risk for trisomy 18 on second-trimester biochemical screening or first-trimester combined screening tests over a period of 10 years from 1 September 1997 to 30 September 2007. RESULTS: Sixty-nine women were confirmed to have trisomy 18 fetuses by karyotyping either prenatally (n = 61) or postnatally/post-miscarriage (n = 8) during the study period. The detection rate of ultrasound scan <= 14 weeks and 18 to 21 weeks to detect trisomy 18 was 92.7 and 100%, respectively. A total of 80 and 87% of fetuses had two or more ultrasound abnormalities detected in the <= 14 weeks and 18 to 21 weeks anomaly scans, respectively. Forty-eight women screened positive for trisomy 18 by second trimester biochemical screening with human chorionic gonadotrophin (hCG) and alpha fetoprotein (AFP). Only one was true positive (positive predictive value = 1/48 or 2%). Eleven women screened positive for trisomy 18 by first-trimester combined screening with nuchal translucency scan and maternal serum for pregnancy associated plasma protein A (PAPP-A) and hCG between 11 and 13 + 6 weeks. Three were true positive (positive predictive value = 3/11 or 27%). All four cases with positive screening had ultrasound abnormalities. CONCLUSIONS: Ultrasound scan for fetal anomalies is the most effective screening test for trisomy 18. A policy of conservative management for women with positive second-trimester biochemical screening or first-trimester combined screening for trisomy 18 is reasonable in the absence of ultrasound fetal abnormalities. Unnecessary invasive tests can be avoided. PMID- 20925042 TI - The relevant distinction between "progression" in ovarian cancer drug trials and the clinical decision to change therapy. PMID- 20925043 TI - Marijuana use and testicular germ cell tumors. AB - BACKGROUND: Since the early 1970s, the incidence of testicular germ cell tumors (TGCTs) in the United States has been increasing; however, potential environmental exposures accounting for this increase have not been identified. A previous study reported a significant association between frequent and long-term current marijuana users and TGCT risk. The purpose of this study was to evaluate the relation between marijuana use and TGCTs in a hospital-based case-control study. METHODS: TGCT patients diagnosed between January 1990 and October 1996 (n = 187) and male friend controls (n = 148) were enrolled in the study. All participants were between the ages of 18 and 50 at the time of diagnosis and resided in Texas, Louisiana, Arkansas, or Oklahoma. Associations of marijuana use and TGCTs were estimated using unconditional logistic regression, adjusting for age, race, prior cryptorchidism, cigarette smoking, and alcohol intake. RESULTS: Overall, patients with TGCTs were more likely to be frequent marijuana users (daily or greater) compared with controls (odds ratio [OR], 2.2; 95% confidence interval [CI], 1.0-5.1). Histological-specific analyses revealed that patients with nonseminoma were significantly more likely than controls to be frequent users (OR, 3.1; 95% CI, 1.2-8.2) and long-term (>= 10 years) users (OR, 2.4; 95% CI, 1.0-6.1). CONCLUSIONS: The finding of an association between frequent marijuana use and TGCTs, particularly among men with nonseminoma, was consistent with the findings of a previous report. Additional studies of marijuana use and TGCTs are warranted, especially studies evaluating the role of endocannabinoid signaling and cannabinoid receptors in TGCTs. PMID- 20925044 TI - A phase 2 trial of imatinib mesylate in patients with recurrent nonresectable chondrosarcomas expressing platelet-derived growth factor receptor-alpha or beta: An Italian Sarcoma Group study. AB - BACKGROUND: Chondrosarcoma (CS) is a rare and heterogeneous sarcoma in which, after failure of surgery and radiotherapy, chemotherapy plays only a marginal role. Different molecular pathways have been shown to be activated in CS; in particular, both isoforms of platelet-derived growth factor receptor (PDGFR) are expressed and phosphorylated. These observations prompted investigation of the activity of imatinib mesylate (IM) in patients with advanced CS in a phase 2 trial. METHODS: Between January 2007 and June 2009, patients with metastatic, nonresectable CS were treated with 400 mg of IM administered twice daily until disease progression or unacceptable toxicity. Two criteria determined patient trial eligibility: >= 1 prior line of chemotherapy and immunohistochemical expression of either PDGFR-alpha or PDGFR-beta. The primary objective of the trial was objective response. As secondary objectives, the authors selected progression-free survival (PFS) at 4 months, overall survival, and clinical benefit (EUDRACT number 2006-006446-33). RESULTS: Twenty-six patients were enrolled and all demonstrated PDGFR positivity and phosphorylation. No objective response was demonstrated. The 4-month PFS rate was 31% (95% confidence interval [95% CI], 16%-53%). The median overall survival was 11 months (95% CI, 6 months 15 months). Neither long-lasting freedom from disease progression nor clinical benefit was observed. The IM dose was temporarily reduced in 60%15 of the patients because of toxicity. CONCLUSIONS: IM was found to be relatively well tolerated, but failed to demonstrate meaningful clinical activity in terms of both objective response and freedom from disease progression. Advanced CS remains an incurable disease, and effective targeted therapies are still awaited. PMID- 20925045 TI - Abdominal wall malformations in a 15-year fetopathological study: accuracy of prenatal ultrasonography diagnosis. AB - OBJECTIVE: The aim of this study was to evaluate the characteristics and diagnostic accuracy of prenatal ultrasonography in the diagnosis of abdominal wall malformations. METHOD: The characteristics of 113 pregnancies terminated due to abdominal wall malformations were analyzed. RESULTS: In cases of gastroschisis and omphalocele, similar female dominance was observed. Among the associated malformations, those affecting the cardiovascular system and the extremities were especially common. Regarding the diagnostic accuracy of prenatal sonography, autopsy confirmed sonographic diagnoses in 91% of omphalocele cases and 79% of gastroschisis. CONCLUSION: Prenatal sonographic diagnosis is more accurate in omphaloceles than in gastroschisis. PMID- 20925047 TI - Haemoglobin level, proportion of haemoglobin Bart's and haemoglobin Portland in fetuses affected by homozygous alpha0-thalassemia from 12 to 40 weeks' gestation. AB - OBJECTIVES: To determine haematological parameters in fetuses affected by homozygous alpha(0)-thalassemia. METHODS: This was a cross-sectional retrospective study reviewing 546 blood samples (268 fetal and 278 neonatal cord) being collected between 1993 and 2006, from 12 weeks' gestation onwards for any indication, including the prenatal diagnosis of homozygous alpha(0)-thalassemia, other haematological disorders, hydrops or aneuploidy. The proportion of haemoglobin (Hb) fractions was determined by electrophoresis of haemolysate on cellulose acetate in all samples. RESULTS: There were significant differences in the haematological parameters between homozygous alpha(0)-thalassemia (n = 183) and control (n = 363) which were either heterozygous alpha(0)-thalassemia (alpha thalassemia trait) or normal. In homozygous alpha(0)-thalassemia, the median Hb level, proportion of Hb Bart's (gamma(4)) and Hb Portland 1(zeta(2)gamma(2)) were 6.4 g/dL, 77.5% and 22.5%, respectively. While the Hb level and the proportion of Hb Bart's increased significantly with gestation, the proportion of Hb Portland 1 decreased. The Hb level contributed by Hb Portland 1 remained around 1.4 g/dL throughout gestation. The proportion of mild, moderate and severe anaemia in the affected fetuses was 27.5, 32.7 and 39.8%, respectively. There was no significant difference in these proportions across different gestation (P = 0.231). There were no differences in the haematological parameters between hydropic and non hydropic fetuses. CONCLUSION: Although the degree of anaemia is mild in around one-quarter of the affected fetuses, the contribution by Hb Portland 1 (zeta(2)gamma(2)) to the Hb level was very low throughout gestation, and the affected fetuses may therefore be at risk for hypoxia. PMID- 20925048 TI - Human anelloviruses and the central nervous system. AB - Torque teno virus and related anelloviruses are a recent addition to the list of agents that cause chronic productive infections and high levels of plasma viraemia in humans. Many aspects of the natural history and pathogenesis of these under many respects surprising viruses are still poorly understood. In this review, we briefly outline the general properties of anelloviruses, examine what is currently known about the interactions they establish with the central nervous system (CNS), and discuss the possible pathological consequences. PMID- 20925046 TI - Trichostatin A restores Apaf-1 function in chemoresistant ovarian cancer cells. AB - BACKGROUND: Chemoresistance is the major factor limiting long-term treatment success in patients with epithelial ovarian cancers. Most cytotoxic drugs kill cells through apoptosis; therefore, defective execution of apoptotic pathways results in a drug-resistant phenotype in many tumor types. METHODS: A panel of ovarian cancer cell lines was screened for expression and function of the apoptosome components Apaf-1 and caspase-9. Expression levels were analyzed by immunohistochemistry and immunoblotting; Apaf-1 function was determined by assessing the ability of endogenous Apaf-1 to cleave caspase-9 in the presence or absence of cytochrome c. The effect of the histone deacetylase inhibitor trichostatin A on Apaf-1 expression and function was evaluated. RESULTS: The authors report here that the resistance of ovarian cancer cells to the proapoptotic effects of chemotherapy is due in part to deficient Apaf-1 activity. Although Apaf-1 is expressed in most ovarian cancers, the functional activity is impaired, as Apaf-1 has a diminished ability to recruit and activate caspase-9. Treatment of ovarian cancer cells with trichostatin A results in restoration of Apaf-1 function independent of alterations in Apaf-1 expression. Furthermore, treating chemoresistant cells with sublethal doses of trichostatin A restores Apaf-1 function and sensitizes cells to cisplatin-induced apoptosis. CONCLUSIONS: Targeting intrinsic pathway defects for therapeutic intervention may result in sensitizing tumors to standard chemotherapy or triggering apoptosis in the absence of other apoptotic signals. The identification of drugs that can use Apaf 1 when it is present, yet can overcome its functional inactivation, may be an important clinical advance. PMID- 20925049 TI - A fluorescence-based sequence-specific primer PCR for the screening of HLA B(*)57:01. AB - Abacavir (ABC) is an antiretroviral drug highly effective in the treatment of HIV, but its intake can cause severe hypersensitivity reaction (HSR). A strong association between HLA-B(*)57:01 and ABC HSRs was reported by several studies, which demonstrated that HLA-B(*)57:01 screening had a 100% negative predictive value and that it could accurately identify patients at high risk of ABC HSRs. We propose a new sequence-specific primer PCR assay based on fluorescence detection through CE which is highly sensitive, allowing the use of non-infective sources of DNA such as saliva and buccal swabs, in addition to blood and reproducible, allowing automation of the analytical process. The results of our study were first compared with a standard sequence-specific primer PCR technique and reported a concordance of 100%, and then a blind external validation further confirmed the accuracy of our method. PMID- 20925050 TI - Analysis of trace degradation products (decarboxylated diastereoisomers) of S adenosylmethionine by electrophoresis in capillaries with cationic coatings (N methylpolyvinylpyridinium or divalent barium). AB - Commercial preparations of S-adenosylmethionine (SAM) when analyzed in uncoated capillaries show a minute impurity believed to be decarboxylated (dc) SAM. By using two types of cationic coatings, thus reducing the electro-endo-osmotic flow (EOF), it was possible to separate this impurity into two diastereoisomers of dcSAM. The coatings evaluated for this purpose were: (i) N methylpolyvinylpyridinium, used under reversed EOF at acidic conditions (pH 4.0) and (ii) deposition of divalent barium at alkaline pH values (pH 9.4), providing reduced EOF. Under these conditions, it was possible to separate this impurity into two diastereoisomers, which by chemical synthesis were indeed proven to be dcSAM. It was further demonstrated that, in the alkylation of 5' methylthioadenosine by 3-bromopropylamine in bromidric acid to dcSAM, another minute impurity was present, proven, via mass spectrometry, to consist of S-(5' adenosyl)-3-thiopropylamine (decarboxylated and demethylated (dc-SAH)). The LOD for the two dcSAM diastereoisomers was assessed as 17.5 MUg/mL and their LOQ as 25.5 MUg/mL. By the barium-based protocol it was possible to quantify the dcSAM, present in a commercial sample of SAM, as a 0.1% impurity. PMID- 20925051 TI - Enantioseparation of DL-isocitric acid by a chiral ligand exchange CE with Ni(II) D-quinic acid system. AB - The ratio of citric acid to D-isocitric acid can be used to distinguish authentic and adulterated fruit juices. To separate DL-isocitric acid enantiomers, we used ligand exchange CE. D-Quinic acid was used as a chiral selector ligand and Mn(II), Fe(III), Co(II), Ni(II), Cu(II), and Zn(II) ions were used as the central ions of the chiral selector in the BGE. DL-Isocitric acid was found to be enantioseparated with the above metal ions except for Mn(II) ion. The optimum running conditions for the analysis of D- and L-isocitric acids along with citric acid, an isomer of isocitric acid, were found to be a BGE (pH 5.0) containing 30% ACN, 20 mM acetic acid, 20 mM NiSO(4), and 80 mM D-quinic acid. Under these conditions, DL-isocitric and citric acids in fruit juices were analyzed successfully. PMID- 20925052 TI - Identification of methylated regions with peak search based on Poisson model from massively parallel methylated DNA immunoprecipitation-sequencing data. AB - DNA methylation is one of the most important epigenetic modification types, which plays a critical role in gene expression. High efficient surveying of whole genome DNA methylation has been aims of many researchers for long. Recently, the rapidly developed massively parallel DNA-sequencing technologies open the floodgates to vast volumes of sequence data, enabling a paradigm shift in profiling the whole genome methylation. Here, we describe a strategy, combining methylated DNA immunoprecipitation sequencing with peak search to identify methylated regions on a whole-genome scale. Massively parallel methylated DNA immunoprecipitation sequencing combined with methylation DNA immunoprecipitation was adopted to obtain methylated DNA sequence data from human leukemia cell line K562, and the methylated regions were identified by peak search based on Poison model. From our result, 140 958 non-overlapping methylated regions have been identified in the whole genome. Also, the credibility of result has been proved by its strong correlation with bisulfite-sequencing data (Pearson R(2)=0.92). It suggests that this method provides a reliable and high-throughput strategy for whole genome methylation identification. PMID- 20925053 TI - Genomic N(6)-methyladenine determination by MEKC with LIF. AB - 2'-Deoxy-N(6)-methyladenosine (N(6)mdA) is frequently found in prokaryotic and unicellular eukaryotic genomes. Although methylated bases represent only a minor fraction of the genome, they, however, exhibit strong biological effects. Here, we report a fast and sensitive method for the quantification of global adenine methylation in DNA. The method is based on a recently developed procedure consisting of fluorescence labeling of deoxyribonucleotides with BODIPY FL EDA and analysis by CE with LIF. An oligodeoxyribonucleotide site specifically modified with N(6)mdA was used for peak assignment, to establish separation conditions and to determine the LOD. The method yielded a LOD for N(6)mdA of 280 pM (1.4 amol), which is equivalent to ~1 N(6)mdA per 10(4) normal nucleotides (0.01%) using 1 MUg of DNA as the matrix. After calibration with completely dam methylated lambda DNA, the assay was applied to the analysis of various DNAs. PMID- 20925054 TI - Investigation of the pH gradient formation and cathodic drift in microchip isoelectric focusing with imaged UV detection. AB - This paper reports the protein analysis by using microchip IEF carried on an automated chip system. We herein focused on two important topics of microchip IEF, the pH gradient and cathodic drift. The computer simulation clarified that the EOF could delay the establishment of pH gradient and move the carrier ampholytes (CAs) to cathode, which probably caused a cathodic drift to happen. After focusing, the peak positions of components in a calibration kit with broad pI were plotted against their pI values to know the actual pH gradient in a microchannel varying time. It was found that the formed pH gradient was stable, not decayed after readily steady state, and migrated to cathode at a rate of 10.0 MUm/s that determined by the experimental conditions such as chip material, internal surface coating and field strength. The theoretical pH gradient was parallel with the actual pH gradient, which was demonstrated in two types of microchip with different channel lengths. No compression of pH gradient was observed when 2% w/v hydroxypropyl methyl cellulose was added in sample and electrolytes. The effect of CAs concentration on current and cathodic drift was also explored. With the current automatic chip system, the calculated peak capacity was 23-48, and the minimal pI difference was 0.20-0.42 for the used single channel microchip with the effective length of 40.5 mm. The LOD for the analysis of CA-I and CA-II was around 0.32 MUg/mL by using normal imaged UV detection, the detected amount is ca. 0.07 ng. PMID- 20925055 TI - Metabolic alteration of HepG2 in scaffold-based 3-D culture: proteomic approach. AB - 3-D cell culture models are important in cancer biology since they provide improved understanding of tumor microenvironment. We have established a 3-D culture model using HepG2 in natural collagen-based scaffold to mimic the development of small avascular tumor in vivo. Morphological characterization showed that HepG2 colonies grew within the interior of the scaffold and showed enhanced extracellular matrix deposition. High levels of cell proliferation in the outermost regions of the scaffold created a hypoxic microenvironment in the 3 D culture system, as indicated by hypoxia-inducible factor-1alpha stabilization, detectable by Western blotting and immunohistochemistry. Proteomic studies showed decreased expression of several mitochondrial proteins and increased expression of proteins in anaerobic glycolysis under 3-D culture compared to monolayer culture. Creatine kinase was also upregulated in 3-D culture, indicating its possible role as an important energy buffer system under hypoxic microenvironment. Increased levels of proteins in nucleotide metabolism may relate to cellular energy. Thus, our results suggest that HepG2 cells under 3-D culture adapt their energy metabolism in response to hypoxic conditions. Metabolic alterations in the 3-D culture model may relate to physiological changes relevant to development of small avascular tumor in vivo and their study may improve future therapeutic strategies. PMID- 20925056 TI - Analysis of early events in the interaction between Fusarium graminearum and the susceptible barley (Hordeum vulgare) cultivar Scarlett. AB - A proteomic analysis was conducted to map the events during the initial stages of the interaction between the fungal pathogen Fusarium graminearum and the susceptible barley cultivar Scarlett. Quantification of fungal DNA demonstrated a sharp increase in fungal biomass in barley spikelets at 3 days after inoculation. This coincided with the appearance of discrete F. graminearum-induced proteolytic fragments of beta-amylase. Based on these results, analysis of grain proteome changes prior to extensive proteolysis enabled identification of barley proteins responding early to infection by the fungus. In total, the intensity of 51 protein spots was significantly changed in F. graminearum-infected spikelets and all but one were identified. These included pathogenesis-related proteins, proteins involved in energy metabolism, secondary metabolism and protein synthesis. A single fungal protein of unknown function was identified. Quantitative real-time RT-PCR analysis of selected genes showed a correlation between high gene expression and detection of the corresponding proteins. Fungal genes encoding alkaline protease and endothiapepsin were expressed during 1-3 days after inoculation, making them candidates for generation of the observed beta-amylase fragments. These fragments have potential to be developed as proteome-level markers for fungal infection that are also informative about grain protein quality. PMID- 20925057 TI - Proteomic analysis of human gastric juice: a shotgun approach. AB - Gastric juice is the most proximal fluid surrounding the stomach tissue. The analysis of gastric juice protein contents will thus be able to accurately reflect the pathophysiology of the stomach. This biological fluid is also a potential reservoir of secreted biomarkers in higher concentration as compared to the serum. Unlike the rest of the gastrointestinal fluids, there were very few studies reported on gastric juice proteome. To date, the proteins that routinely populate this biofluid are largely unknown. This is partly due to the technical difficulties in processing a sample that contains a collection of other gastrointestinal fluids, especially saliva. In this study, we attempt to profile the protein components of the gastric fluids from chronic gastritis patients using a direct shotgun proteomics approach. These data represent the first report of the proteome of human gastric juice with gastritis background. PMID- 20925058 TI - Labeling elastase digests with TMT: informational gain by identification of poorly detectable peptides with MALDI-TOF/TOF mass spectrometry. AB - The applicability of the less specific protease elastase for the identification of membrane and cytosolic proteins has already been demonstrated. MALDI as ionization technique particularly favors the detection of basic and to a lesser extent of weakly acidic peptides, whereas neutral peptides often remain undetected. Moreover, peptides below 700 Da are routinely excluded. In the following study, the advantage of additional information gained from tandem mass tag zero labeled peptides and the resultant increase in sequence coverage was evaluated. Through derivatization with tandem mass tag reagents, peptide measurement within the standard mass range of the MALDI reflector mode is achievable due to the mass increase. Compared to the unlabeled sample, peptides exhibiting relatively low molecular masses, pI values or higher hydrophobicity could be identified. PMID- 20925059 TI - Pseudo-neutral-loss scan for selective detection of phosphopeptides and N glycopeptides using liquid chromatography coupled with a hybrid linear ion trap/orbitrap mass spectrometer. AB - We describe a novel method, termed "pseudo-neutral-loss scan" MS, for selectively probing phosphopeptides and glycopeptides on a LTQ-Orbitrap mass spectrometer. The instrument has been programmed such that an in-source CID energy is applied to all species that eluted from LC column and were subsequently ionised in the electrospray ion source. Ion pairs that differ in the mass of a neutral loss of phosphoric acid or monosaccharide residues are automatically selected for CID MS/MS and further for multi-stage-activation MS3. Our method should prove useful for a highly selective and sensitive approach to identify phosphopeptides and glycopeptides from purified protein digestion without any further enrichment, and could potentially be of use in more complex mixture. PMID- 20925060 TI - An improved method to unravel phosphoacceptors in Ser/Thr protein kinase phosphorylated substrates. AB - Identification of the phosphorylated residues of bacterial Ser/Thr protein kinase (STPK) substrates still represents a challenging task. Herein, we present a new strategy allowing the rapid determination of phosphoacceptors in kinase substrates, essentially based on the dual expression of the kinase with its substrate in the surrogate E. coli, followed by MS analysis in a single-step procedure. The performance of this strategy is illustrated using two distinct proteins from Mycobacterium tuberculosis as model substrates, the GroEL2 and HspX chaperones. A comparative analysis with a standard method that includes mass spectrometry analysis of in vitro phosphorylated substrates is also addressed. PMID- 20925062 TI - Magnetic treatment of irrigation water and snow pea and chickpea seeds enhances early growth and nutrient contents of seedlings. AB - The effects of magnetic treatment of irrigation water and snow pea (Pisum sativum L var. macrocarpon) and Kabuli chickpea (Cicer arietinum L) seeds on the emergence, early growth and nutrient contents of seedlings were investigated under glasshouse conditions. The treatments included (i) magnetic treatment of irrigation water (MTW), (ii) magnetic treatment of seeds (MTS), (iii) magnetic treatment of irrigation water and seeds (MTWS) and (iv) no magnetic treatment of irrigation water or seeds as control treatment. A magnetic treatment device with two permanent magnets (magnetic induction: 3.5-136 mT) was used for the above treatments. Seeds were sown in washed sand and seedlings were harvested at 20 days. The results showed that MTW led to a significant (P < 0.05) increase in emergence rate index (ERI; 42% for snow pea and 51% for chickpea), shoot dry weight (25% for snow pea and 20% for chickpea) and contents of N, K, Ca, Mg, S, Na, Zn, Fe and Mn in both seedling varieties compared to control seedlings. Likewise, there were significant increases in ERI (33% for snow peas and 37% for chickpea), shoot dry weight (11% for snow pea and 4% for chickpea) and some nutrients of snow pea and chickpea seedlings with MTS in comparison with the controls. The results of this study suggest that both MTW and MTS have the potential to improve the early seedling growth and nutrient contents of seedlings. PMID- 20925061 TI - Molecular characterization of a trafficking organelle: dissecting the axonal paths of calsyntenin-1 transport vesicles. AB - Kinesin motors play crucial roles in the delivery of membranous cargo to its destination and thus for the establishment and maintenance of cellular polarization. Recently, calsyntenin-1 was identified as a cargo-docking protein for Kinesin-1-mediated axonal transport of tubulovesicular organelles along axons of central nervous system neurons. To further define the function of calsyntenin 1, we immunoisolated calsyntenin-1 organelles from murine brain homogenates and determined their proteome by MS. We found that calsyntenin-1 organelles are endowed with components of the endosomal trafficking machinery and contained the beta-amyloid precursor protein (APP). Detailed biochemical analyses of calsyntenin-1 immunoisolates in conjunction with immunocytochemical colocalization studies with cultured hippocampal neurons, using endosomal marker proteins for distinct subcompartments of the endosomal pathways, indicated that neuronal axons contain at least two distinct, nonoverlapping calsyntenin-1 containing transport packages: one characterized as early-endosomal, APP positive, the other as recycling-endosomal, APP negative. We postulate that calsyntenin-1 acts as a general mediator of anterograde axonal transportation of endosomal vesicles. In this role, calsyntenin-1 may actively contribute to axonal growth and pathfinding in the developing as well as to the maintenance of neuronal polarity in the adult nervous system; further, it may actively contribute to the stabilization of APP during its anterograde axonal trajectory. PMID- 20925063 TI - Orientation of paramecium swimming in a static magnetic field: Dependence on membrane lipid fluidity. AB - We studied the swimming orientation of the ciliated protozoan Paramecium aurelia in a static magnetic field (0.78 T). P. aurelia is a complex of species termed syngens, whose cell morphology appears similar on microscopic examination. In the magnetic field, the cells of some syngens gradually changed their swimming orientation so that they were swimming perpendicular or parallel to the magnetic field, although such sensitivity to magnetic fields differs between syngens. When the temperature of the cell suspension was raised, the magnetic sensitivity of the cells was decreased. On the other hand, when the cells were cultured beforehand at a high temperature, their magnetic sensitivity was increased. These results raise the possibility that membrane lipid fluidity, which is inversely proportional to the membrane lipid order, contributes to the magnetic orientation of syngens. In this study, measurements of membrane lipid fluidity obtained using fluorescence image analysis with the lipophilic dye, laurdan (6-lauroyl-2 dimethylaminonaphtalene), showed that the degree of membrane lipid fluidity was correlated with the differences in magnetic orientation between syngens. That is, the syngens with decreased membrane fluidity showed an increased degree of magnetic orientation. Therefore, the membrane lipid order is a key factor in the magnetic orientation of Paramecium swimming. PMID- 20925064 TI - Occupational exposure to electric fields and induced currents associated with 400 kV substation tasks from different service platforms. AB - The aim of the study was to investigate the occupational exposure to electric fields, average current densities, and average total contact currents at 400 kV substation tasks from different service platforms (main transformer inspection, maintenance of operating device of disconnector, maintenance of operating device of circuit breaker). The average values are calculated over measured periods (about 2.5 min). In many work tasks, the maximum electric field strengths exceeded the action values proposed in the EU Directive 2004/40/EC, but the average electric fields (0.2-24.5 kV/m) were at least 40% lower than the maximum values. The average current densities were 0.1-2.3 mA/m2 and the average total contact currents 2.0-143.2 uA, that is, clearly less than the limit values of the EU Directive. The average values of the currents in head and contact currents were 16-68% lower than the maximum values when we compared the average value from all cases in the same substation. In the future it is important to pay attention to the fact that the action and limit values of the EU Directive differ significantly. It is also important to take into account that generally, the workers' exposure to the electric fields, current densities, and total contact currents are obviously lower if we use the average values from a certain measured time period (e.g., 2.5 min) than in the case where exposure is defined with only the help of the maximum values. PMID- 20925066 TI - Distinguishing scan without evidence of dopaminergic depletion patients with asymmetric resting tremor from Parkinson's disease: a clinical diagnosis of dystonia is required. PMID- 20925065 TI - Parkinson's disease dementia can be easily detected in routine clinical practice. AB - Parkinson's disease (PD) is mainly characterized by its motor manifestations, but it is also frequently associated with dementia. Early diagnosis of PD dementia (PDD) is particularly important because effective cholinesterase inhibitor treatments are available. This study aimed at validating a short procedure for screening for PDD in routine clinical practice and which adopts recently published diagnostic criteria. One hundred eighty-eight patients with PD participated in the study. The examination procedure comprised three steps: standard clinical examination, a short cognitive function assessment fulfilling the requirements of the Movement Disorders Society (Mini Mental State Examination, five-word test, word generation task, and impact on daily life, including a questionnaire on compliance with medication) and an extensive evaluation of cognitive functions and behavior. After each step, the suspected presence or absence of dementia was recorded. After the short cognitive function assessment, PDD was suspected in 18.62% of the patients [95% confidence interval (CI): 13.32-24.93%]. After the extensive assessment, 21.81% (95% CI: 16.13 28.40%) met the criteria for probable PDD. The short battery's sensitivity and specificity were 65.85% (95% CI = 49.41-79.92%) and 94.56% (95% CI = 89.56 97.62%), respectively. A stepwise logistic regression analysis showed that use of a specific cut-off considerably enhanced the short battery's sensitivity (85.37%, 95% CI = 70.83-94.43%) without decreasing its specificity (83.67%, 95% CI = 76.69 89.25%). With an easy-to-use, short battery of tests that are commonly used in routine clinical practice, it is possible to diagnose PDD in accordance with reference criteria and with the same sensitivity and specificity as in a more extensive evaluation. PMID- 20925067 TI - Twice-daily, low-dose pramipexole in early Parkinson's disease: a randomized, placebo-controlled trial. AB - To compare the safety and efficacy of low dosages of pramipexole given twice daily (bid) in early Parkinson's disease (PD) with those of a standard 3 times daily (tid) regimen in a randomized, double-blind, placebo controlled trial involving 311 early PD patients not receiving dopaminergic treatment. Subjects were randomly assigned and followed on assigned treatment for 12 weeks with pramipexole at dosages of 0.5 mg bid, 0.75 mg bid, or 0.5 mg tid, or matching placebo. All subjects were dosed 3 times daily, with placebo if necessary, to maintain blinding. The primary outcome was the change from baseline to Week 12 in the Unified Parkinson Disease Rating Scale (UPDRS) total score (Parts I-III). All active dosages had similar antiparkinson efficacy showing reductions of 4-5 UPDRS points relative to placebo (p < 0.0001) for each comparison. Somnolence, fatigue, nausea, constipation, and peripheral edema were more common in the active treatment groups than in the placebo group, but their frequency did not vary by dosage. In this fixed dosage, randomized study pramipexole administered twice daily at a total daily dosage of 1.0-1.5 mg daily was of comparable efficacy and tolerability to a dosage of 0.5 mg tid over a 12-week treatment period in early PD. PMID- 20925068 TI - Gender differences in Parkinson's disease: clinical characteristics and cognition. AB - More men than women are diagnosed with Parkinson's disease (PD), and a number of gender differences have been documented in this disorder. Examples of clinical characteristics that appear in men more often than women include rigidity and rapid eye movement behavior disorder, whereas more women than men exhibit dyskinesias and depression. Differences between men and women in cognition have not been extensively examined, though there are reports of deficits in men in aspects of cognition that contribute to activities of daily living, in verbal fluency, and in the recognition of facial emotion, and deficits in women in visuospatial cognition. Side of disease onset may interact with gender to affect cognitive abilities. One possible source of male-female differences in the clinical and cognitive characteristics of PD is the effect of estrogen on dopaminergic neurons and pathways in the brain. This effect is not yet understood, as insight into how the fluctuation of estrogen over the lifetime affects the brain is currently limited. Further attention to this area of research will be important for accurate assessment and better management of PD. Attention should also be directed to multiple covariates that may affect clinical characteristics and cognition. Knowledge about differences in the presentation of PD symptoms in men and women and about the pathophysiology underlying those differences may enhance the accuracy and effectiveness of clinical assessment and treatment of the disease. PMID- 20925069 TI - Factors influencing the cognitive function in patients with multiple system atrophy. PMID- 20925071 TI - A motor cortex excitability and gait analysis on Parkinsonian patients. AB - Transcranial magnetic stimulation (TMS) parameters were recorded in a lower limb muscle and correlated with the gait parameters of 25 patients with Parkinson's disease (PD) with and without dopamine substitution treatment (DST) and 10 control subjects. Single and paired-pulse TMS were recorded in the tibialis anterior muscle (TA). Gait analysis was performed using a 3D motion analysis system. Parkinsonian patients (PP) did not differ from the control subjects (CS) in terms of relaxed motor threshold, active motor threshold (AMT), cortical silent period (CSP), motor-evoked potential (MEP) amplitude and area, or paired pulse TMS with short interstimulus intervals (ISI). At longer ISIs, paired-pulse TMS showed that the amplitudes of the conditioned MEPs were lower in untreated PP than in CS. DST partially compensated for this difference. Gait analysis showed that the gait of PP undergoing no treatment was slower and the stride length shorter than normal. Both of these parameters improved under DST, however. Analysis of data obtained on all the subjects combined showed that both of the latter parameters were correlated with the paired-pulse MEP amplitude and area at longer ISIs. In PP, the cortical areas responsible for the lower limb movements seem to undergo intracortical facilitation (ICF) impairments, whereas the intracortical inhibition process is normal. The ICF level was found to be associated to the stride length and the velocity. The fact that only these two gait parameters were found to be dopa responsive indicates that dopaminergic treatment may improve gait disorders by restoring the ICF. PMID- 20925070 TI - Autonomic and sensory symptoms and signs in incident, untreated Parkinson's disease: frequent but mild. AB - Although nonmotor symptoms are increasingly recognized as key features in Parkinson's disease (PD), the occurrence and severity of autonomic and sensory symptoms in patients with very early and untreated PD are poorly documented. Two hundred seven patients with newly diagnosed, untreated PD and 175 controls from the population-based Norwegian ParkWest study were included. Postural blood pressure and olfactory function were measured and eight autonomic and sensory symptoms assessed using interview-based rating scales. Autonomic and sensory symptoms were more frequent in patients compared with controls (mean number of symptoms 2.9 vs. 1.1; P < 0.001) and in the postural instability and gait difficulty motor-subtype vs. tremor dominant subtype (mean 3.3 vs. 2.5; P = 0.008). In the patient group, reduced olfaction (59%), urinary problems (47%), increased saliva or drooling (42%), constipation (39%), and sensory complaints (34%) were the most frequent symptoms. Daily activities were not affected by these symptoms in 58% of the patients, and the influence on daily activities was rated as "mild" or less for all of these symptoms in 90%. A higher Hoehn and Yahr stage was associated with a higher number of autonomic and sensory symptoms and with the occurrence of gastrointestinal symptoms. Autonomic and sensory symptoms are common in patients with untreated, early PD although the severity of these symptoms is mild, with little or no influence on daily activities. The high prevalence of increased saliva or drooling close to the time of diagnosis is noteworthy and not described earlier. PMID- 20925072 TI - Lacosamide, another therapeutic failure in essential tremor: an open-label trial. PMID- 20925073 TI - An magnetic resonance imaging T2*-weighted sequence at short echo time to detect putaminal hypointensity in Parkinsonisms. AB - At 1.5 T, T2*-weighted gradient echo (GE) sequences are more sensitive in revealing mineral deposition in the basal ganglia than standard T2 weighted sequences. T2*-weighted GE sequences, however, may detect putaminal hypointensities either in patients affected by parkinsonian syndromes or in healthy subjects. The aim of this study was to identify the magnetic resonance imaging (MRI) T2*-weighted sequence which more specifically detected putaminal hypointensities differentiating atypical parkinsonian syndromes from Parkinson's disease (PD) and control subjects. In a sample of 38 healthy subjects, we performed three T2*-weighted GE sequences at increasing time echo (TE; TE = 15 millisecond, TE = 25 millisecond, and echoplanar at TE = 40 millisecond; T2* sequences study). The sequence not showing any putaminal abnormality in the healthy subjects was then used to assess putaminal signal intensity in 189 patients with PD, 20 patients with multiple system atrophy (MSA), 41 patients with progressive supranuclear palsy (PSP), and in 150 age and sex-matched control subjects. In the T2* sequences study, the T2*-weighted TE = 15 (T2*/15) did not show any putaminal abnormalities in the healthy subjects. This sequence detected putaminal hypointensities in a significantly higher proportion of patients with MSA (35%, P < 0.05) and PSP (24.4%, P < 0.05) than in patients with PD (5.3%), but in none of the controls. The sensitivity of putaminal hypointensity in T2*/15 sequence was 25.4% for PD, 43.9% for PSP, and 55% for MSA versus controls whereas the specificity was 93.2% for all groups. Despite the suboptimal sensitivity, the high specificity of the T2*/15 sequence performed on routine MRI suggests its usefulness in clinical practice for identifying putaminal hypointensities associated with parkinsonian disorders. PMID- 20925074 TI - Comparison of orally dissolving carbidopa/levodopa (Parcopa) to conventional oral carbidopa/levodopa: A single-dose, double-blind, double-dummy, placebo controlled, crossover trial. AB - Levodopa use in fluctuating Parkinson's disease (PD) is complicated by an inconsistent and prolonged onset to clinical improvement. An orally dissolved carbidopa/levodopa (OD C/L) preparation (Parcopa UCB Pharma) is available in the United States. This offers potential advantages to shorten the duration from ingestion to clinical improvement. Surprisingly, this has never been clinically assessed. We tested 20 patients with fluctuating PD and a Unified Parkinson's Disease Rating Scale (UPDRS) "off" motor score of >= 25 in a 2-day, single-dose, double-blind, double-dummy, crossover study. Patients arrived in the morning in the practically defined "off" state and were randomly assigned to receive identical doses of either oral C/L and OD placebo or OD C/L and oral C/L placebo on 1st day and the reverse combination on a 2nd day. After training, patients underwent bilateral hand tapping at baseline and every 5 minutes for 60 minutes after dose ingestion. Stride length (SL) was recorded at 5-minute intervals with an ambulatory gait monitor. Patients identified their subjective latency to "on" and noted drug preferences and adverse events. They also underwent a UPDRS motor examination at baseline and 60 minutes after dose. Twenty subjects [15 male, age 68.7 (9.7), PD duration 13.4 (6.8)] completed. There were no significant group differences in tapping speed, subjective time to "on," latency of increased SL, or overall preference. However, all trends did favor OD C/L. Adverse events were similar. This small pilot study did not show significant group differences favoring OD C/L; however, larger studies may be justified, and individual patients may benefit. PMID- 20925075 TI - "Progressive delayed-onset postanoxic dystonia" diagnosed with PANK2 mutations 26 years after onset-an update. PMID- 20925076 TI - Screening of Brazilian families with primary dystonia reveals a novel THAP1 mutation and a de novo TOR1A GAG deletion. AB - The TOR1A and THAP1 genes were screened for mutations in a cohort of 21 Brazilian patients with Primary torsion dystonia (PTD). We identified a de novo delGAG mutation in the TOR1A gene in a patient with a typical DYT1 phenotype and a novel c.1A > G (p.Met1?) mutation in THAP1 in a patient with early onset generalized dystonia with speech involvement. Mutations in these two known PTD genes, TOR1A and THAP1, are responsible for about 10% of the PTD cases in our Brazilian cohort suggesting genetic heterogeneity and supporting the role of other genes in PTD. PMID- 20925077 TI - The 1918 influenza pandemic affected sex differentials in mortality: Comment on Sawchuk. PMID- 20925078 TI - Brief Communication: Shape analysis of the MT 1 proximal articular surface in fossil hominins and shod and unshod Homo. AB - As a follow-up study to Proctor et al. (Am J Phys Anthropol 135 (2008) 216-224), this study quantifies the first metatarsal proximal articular surface using three dimensional morphometrics to test for differences in articular surface shape between habitually shod and habitually unshod humans. In addition, differences in shape between Homo, Pan, Gorilla, and Hylobates are compared to the fossil hominin specimens A. L. 333-54, Stw 562, Stw 573 ("Little Foot"), OH 8, SKX 5017, and SK 1813. No difference in surface shape was found between habitually shod and habitually unshod humans. There is a clear quantitative division in articular surface shape between humans and apes that is more pronounced than a previous study by Proctor et al. (Am J Phys Anthropol 135 (2008) 216-224), due to additional landmarks present in this study. The specimen OH 8 is indistinguishable from modern Homo. The fossils A. L. 333-54, Stw 562, and Stw 573 are intermediate in shape between humans and apes. The specimens SKX 5017 and SK 1813 have a more apelike articular surface. When combined with other characteristics, this trait suggests that Paranthropus used a degree of abduction during locomotion that was much less than that in extant apes, but greater than that in Australopithecus, allowing for some small degree of grasping ability. PMID- 20925079 TI - Primate life histories and dietary adaptations: a comparison of Asian colobines and macaques. AB - Primate life histories are strongly influenced by both body and brain mass and are mediated by food availability and perhaps dietary adaptations. It has been suggested that folivorous primates mature and reproduce more slowly than frugivores due to lower basal metabolic rates as well as to greater degrees of arboreality, which can lower mortality and thus fecundity. However, the opposite has also been proposed: faster life histories in folivores due to a diet of abundant, protein-rich leaves. We compared two primate taxa often found in sympatry: Asian colobines (folivores, 11 species) and Asian macaques (frugivores, 12 species). We first described new data for a little-known colobine (Phayre's leaf monkeys, Trachypithecus phayrei crepusculus) from Phu Khieo Wildlife Sanctuary, Thailand. We then compared gestation periods, ages at first birth, and interbirth intervals in colobines and macaques. We predicted that heavier species would have slower life histories, provisioned populations would have faster life histories, and folivores would have slower life histories than frugivores. We calculated general regression models using log body mass, nutritional regime, and taxon as predictor variables. Body mass and nutritional regime had the predicted effects for all three traits. We found taxonomic differences only for gestation, which was significantly longer in colobines, supporting the idea of slower fetal growth (lower maternal energy) compared to macaques and/or advanced dental or gut development. Ages at first birth and interbirth intervals were similar between taxa, perhaps due to additional factors (e.g., allomothering, dispersal). Our results emphasize the need for additional data from wild populations and for establishing whether growth data for provisioned animals (folivores in particular) are representative of wild ones. PMID- 20925080 TI - Sex and age differences in the diet and ingestive behaviors of sooty mangabeys (Cercocebus atys) in the Tai Forest, Ivory Coast. AB - Members of the Cercocebus-Mandrillus clade are united by several morphological features, including expanded premolars which are argued to be associated with a preponderance of hard objects in the diet. We test the association between premolar expansion and hard object feeding by examining how different dental regions are used during food processing. We examined the diet and oral processing activities of sooty mangabeys (Cercocebus atys) in the Ivory Coast's Tai forest from August 2008 to September 2009. In addition to compiling diet profiles, we recorded the frequency that individuals performed four activities: 1) incising, 2) canine puncturing/scraping, 3) postcanine crushing (i.e., isometric biting), and 4) routine mastication (chewing cycles). Sooty mangabeys have a relatively narrow diet that consists largely of nuts/seeds, fruits, and invertebrates. While there are age and sex differences in diet, the most frequently consumed foods are similar across age and sex classes. The most frequently consumed foods are seeds of Sacoglottis gabonensis which are the hardest items in the sooty mangabey diet. Patterns of ingestive behavior vary with food type, but adults and nonadults (excluding infants dependent on mothers) of both sexes process similar foods. Premolar expansion in Cercocebus atys is associated with powerful crushing of hard objects of specific size and durophagy is a constant feature of sooty mangabey feeding ecology throughout ontogeny. PMID- 20925082 TI - Shedding light in the controversial terminology for platelet-rich products: platelet-rich plasma (PRP), platelet-rich fibrin (PRF), platelet-leukocyte gel (PLG), preparation rich in growth factors (PRGF), classification and commercialism. PMID- 20925081 TI - A new approach to the study of Romanization in Britain: a regional perspective of cultural change in late iron age and roman dorset using the siler and gompertz makeham models of mortality. AB - This is the first study of health in the Roman Empire to use the Siler and Gompertz-Makeham models of mortality to investigate the health consequences of the 43 AD conquest of Britain. The study examined late Iron Age and Romano British populations (N = 518) from Dorset, England, which is the only region of Britain to display continuity in inhumation burial practice and cemetery use throughout the two periods. Skeletal evidence for frailty was assessed using cribra orbitalia, porotic hyperostosis, periosteal lesions, enamel hypoplasia, dental caries, tuberculosis, and rickets. These health variables were chosen for analysis because they are reliable indicators of general health for diachronic comparison (Steckel and Rose: The backbone of history: health and nutrition in the western hemisphere (2002)) and are associated with the introduction of urbanism in Britain during the Roman period (Redfern: J Rom Archaeol Supp Series 64 (2007) 171-194; Redfern: Britannia 39 (2008a) 161-191; Roberts and Cox: Health and disease in Britain: from prehistory to the present day (2003)). The results show that levels of frailty and mortality were lower in the late Iron Age period, and no sex differences in mortality was present. However, post-conquest, mortality risk increased for children and the elderly, and particularly for men. The latter finding challenges received wisdom concerning the benefits of incorporation into the Empire and the higher status of the male body in the Roman world. Therefore, we conclude that the consequences of urbanism, changes in diet, and increased population heterogeneity negatively impacted health, to the extent that the enhanced cultural buffering of men did not outweigh underlying sex differences in biology that advantage women. PMID- 20925083 TI - Differentiation of mesenchymal stem cells in chitosan scaffolds with double micro and macroporosity. AB - Bone Marrow mesenchymal stem cells can be induced to differentiate into osteoblasts to regenerate damaged bone tissue using tissue engineering techniques. In this study, we examine the use of chitosan scaffolds with double pore structure prepared by an innovative method that combines freeze gelation (that produces micropores) and particle leaching out technique (that produces interconnected spherical macropores) seeking to enhance the osteogenic differentiation of goat bone marrow stromal cells (GBMSCs). The double pore architecture of the scaffold was characterized by scanning electron microscopy (SEM), microcomputed tomography and confocal laser scanning microscopy. The obtained hierarchical pore structure allowed very efficient seeding of GBMSCs that are able to occupy the whole volume of the scaffold, showing good adhesion and proliferation. GBMSCs were differentiated into osteoblasts as indicated by alkaline phosphatase activity and osteocalcin expression. The results of this study demonstrate that chitosan scaffold may be promising biomaterial for bone regeneration. PMID- 20925084 TI - The effect of various denier capillary channel polymer fibers on the alignment of NHDF cells and type I collagen. AB - If tissue engineers are to successfully repair and regenerate native tendons and ligaments, it will be essential to implement contact guidance to induce cellular and type I collagen alignment to replicate the native structure. Capillary channel polymer (CC-P) fibers fabricated by melt-extrusion have aligned micrometer scale surface channels that may serve the goal of achieving biomimetic, physical templates for ligament growth and regeneration. Previous work characterizing the behavior of normal human dermal fibroblasts (NHDF), on the 19 denier per filament (dpf) CC-P fibers, demonstrated a need for improved cellular and type I collagen alignment. Therefore, 5 and 9 dpf CC-P fibers were manufactured to determine whether their channel dimensions would achieve greater alignment. A 29 dpf CC-P fiber was also examined to determine whether cellular guidance could still be achieved within the larger dimensions of the fiber's channels. The 9 dpf CC-P fiber appeared to approach the topographical constraints necessary to induce the cellular and type I collagen architecture that most closely mirrored that of native ACL tissue. This work demonstrated that the novel cross-section of the CC-P fiber geometry could approach the necessary surface topography to align NHDF cells along the longitudinal axis of each fiber. PMID- 20925085 TI - Reliable protein structure refinement using a physical energy function. AB - In the past decade, significant progress has been made in protein structure prediction. However, refining models to a level of resolution that is comparable with experimental results and can be used in studies like enzymatic activity still remains a major challenge. We have previously demonstrated that our modular protein-solvent energy function, uniquely involving a potential of mean force description for hydrophobic solvation, works well in protein globular structure prediction and loop modeling. In this work, we couple protein-solvent energy function with our global optimization method stochastic perturbation with soft constraints and use them to refine a collection of template models from submitted predictions to recent Critical Assessment of Techniques for Protein Structure Prediction blind prediction contests. A prediction protocol based on a selection of structures with the lowest energy is able to successfully refine all of the test proteins, and, more importantly, our energy function does not show degradation in prediction when sampling is exhausted. PMID- 20925086 TI - Ab initio molecular geometry and anharmonic vibrational spectra of thiourea and thiourea-d4. AB - Potential energy surface (PES) of thiourea, SC(NH(2))(2), has been searched for stable conformers under C(1), C(s), C(2), and C(2v) symmetry constraints by post Hartree-Fock ab initio methods with electron correlation level varying from second-order Moeller-Plesset perturbation theory (MP2) to quadratic configuration interaction with single and double excitations (QCISD) and basis sets of double- and triple-zeta quality within 6-31+G(d,p) to aug-cc-pVTZ range. Thiourea conformers of C(2) and C(s) symmetry have been found as stationary points on the PES with no imaginary frequencies at MP2/6-31+G(d,p) level, whereas only the C(2) conformer seems as true minimum when basis sets containing more polarization and/or diffuse functions were used. At QCISD/cc-pVTZ level, only the C(2) thiourea conformer has been found as true minimum on the PES. Anharmonic vibrational spectra of C(2) conformers of thiourea and thiourea-d(4) have been computed by vibrational self-consistent field (VSCF) and correlation-corrected VSCF methods using quartic force field approximation at MP2/TZV+(2d,2p), and MP2/6-311+G(3df,2p) level and direct approach at MP2/6-31+G(2d,p) level. Both quartic force field and direct VSCF methods used PES expansion in curvilinear (internal) coordinates. Wavenumbers of fundamental, first overtone, and combination transitions of C(2) symmetry conformer have been calculated for natural abundance thiourea and thiourea-d(4) isotopomer. Anharmonic corrections originating from mean field and mode coupling effects vary from 5 to 60 cm(-1), whereas mode-mode correlation contribution seems significant in the case of nu(N H) stretching and delta(NH(2)) deformation modes (15-5 cm(-1)). Application of internal coordinates in the VSCF calculation results in slight underestimation of delta(NH(2)) deformation mode fundamentals and correct description of out-of plane large-amplitude tau(SCNH) modes. PMID- 20925087 TI - Activation method does not alter abnormal placental gene expression and development in cloned pigs. AB - Nuclear transfer efficiency is low and is thought to be caused by inadequate placental development. The objective of this study was to identify differentially expressed transcripts in pig placentas derived from in vivo fertilization, in vitro fertilization or nuclear transfer at Day 30 of gestation. Three activation methods were compared: electrical fusion/activation, electrical fusion/activation followed by treatment with reversible proteasomal inhibitor, MG132 or electrical fusion followed by activation with Thimerosal/DTT. Extraembryonic membranes were collected 30 days after artificial insemination (IVV) or embryo transfer (IVF and NT). Extraembryonic membrane cDNAs labeled with Cy5 and a reference cDNA labeled with Cy3 were hybridized to a pig reproductive tissue-specific 19,968 spot cDNA microarray. Images acquired and assessed by using Genepix Pro 4.0 were analyzed by Genespring 7.3.1. ANOVA (P < 0.05) identified 227 differentially expressed transcripts between the five treatments and 0 between the three activation methods. The nuclear transfer groups were pooled and compared to in vivo samples, identifying 34 up- and 19 down-regulated transcripts (>2-fold change, P < 0.05). Ten transcripts were validated by real-time PCR. UPTI, PAG2, and GLUD1 protein was quantified by Western blot and densitometry verified that UPTI and PAG2 proteins had an expression pattern that mirrored mRNA abundance (P < 0.05). Localization patterns were also determined for UPTI, PAG2, GLUD2 and 14-3-3 gamma in Day 35 extraembryonic membranes. Observed differences in gene and protein expression in nuclear transfer extraembryonic membranes indicate that an impaired fetal-maternal interface, and not the activation method, may be causing defects observed in cloned pigs. PMID- 20925088 TI - Transport properties of graphene nanoribbon-based molecular devices. AB - The electronic and transport properties of an edge-modified prototype graphene nanoribbon (GNR) slice are investigated using density functional theory and Green's function theory. Two decorating functional group pairs are considered, such as hydrogen-hydrogen and NH(2)-NO(2) with NO(2) and NH(2) serving as a donor and an acceptor, respectively. The molecular junctions consist of carbon-based GNR slices sandwiched between Au electrodes. Nonlinear I-V curves and quantum conductance have been found in all the junctions. With increasing the source drain bias, the enhancement of conductance is quantized. Several key factors determining the transport properties such as the electron transmission probabilities, the density of states, and the component of Frontier molecular orbitals have been discussed in detail. It has been shown that the transport properties are sensitive to the edge type of carbon atoms. We have also found that the accepter-donor functional pairs can cause orders of magnitude changes of the conductance in the junctions. PMID- 20925090 TI - Computational study of static first hyperpolarizability of donor-acceptor substituted (E)-benzaldehyde phenylhydrazone. AB - Various hybrid functionals (B3LYP, B97-2, PBE0, BMK, BH&HLYP, CAM-B3LYP, and LC omegaPBE) implemented in density functional theory were applied to give estimate of static first hyperpolarizabilty (beta(0)) of (E)-benzaldehyde phenylhydrazone designated as (E)-BPH. Against those of MP2 computations as a function of the underlying density functional, good agreement was obtained with the BH&HLYP and CAM-B3LYP functionals. The LC-omegaPBE functional and the B3LYP, PBE0, B97-2, and BMK functionals underestimated and overestimated beta(0), respectively. The basis set effect on the calculated beta(0) was also investigated. It turned out that the 6-311+G(2d,p) basis set provided excellent converged value of beta(0). On the basis of the calculated results, we investigated the substituent effect on beta(0) of donor-acceptor (D-A) substituted (E)-BPH systematically by using the BH&HLYP and CAM-B3LYP computations with the 6-311+G(2d,p) basis set. We proposed a Zwitterion structure to explain the calculated trend in the substituent effect and the enhanced hyperpolarizability of type II compounds (A-(E)-BPH-D) than type I compounds (D-(E)-BPH-A). Natural bonding orbital analysis carried out at BH&HLYP/6-311+G(2d,p)//B3LYP/6-31G(2df,p) level of theory substantiated the claim. PMID- 20925089 TI - Multipole electrostatics in hydration free energy calculations. AB - Hydration free energy (HFE) is generally used for evaluating molecular solubility, which is an important property for pharmaceutical and chemical engineering processes. Accurately predicting HFE is also recognized as one fundamental capability of molecular mechanics force field. Here, we present a systematic investigation on HFE calculations with AMOEBA polarizable force field at various parameterization and simulation conditions. The HFEs of seven small organic molecules have been obtained alchemically using the Bennett Acceptance Ratio method. We have compared two approaches to derive the atomic multipoles from quantum mechanical calculations: one directly from the new distributed multipole analysis and the other involving fitting to the electrostatic potential around the molecules. Wave functions solved at the MP2 level with four basis sets (6-311G*, 6-311++G(2d,2p), cc-pVTZ, and aug-cc-pVTZ) are used to derive the atomic multipoles. HFEs from all four basis sets show a reasonable agreement with experimental data (root mean square error 0.63 kcal/mol for aug-cc-pVTZ). We conclude that aug-cc-pVTZ gives the best performance when used with AMOEBA, and 6 311++G(2d,2p) is comparable but more efficient for larger systems. The results suggest that the inclusion of diffuse basis functions is important for capturing intermolecular interactions. The effect of long-range correction to van der Waals interaction on the hydration free energies is about 0.1 kcal/mol when the cutoff is 12A, and increases linearly with the number of atoms in the solute/ligand. In addition, we also discussed the results from a hybrid approach that combines polarizable solute with fixed-charge water in the HFE calculation. PMID- 20925091 TI - Supraglottitis in the era following widespread immunization against Haemophilus influenzae type B: evolving principles in diagnosis and management. AB - OBJECTIVES/HYPOTHESIS: To review the demographics, presentation, interventions, and outcomes of acute supraglottitis in the post-Haemophilus influenzae type B (Hib) vaccination era and make updated recommendations for treatment. STUDY DESIGN: Retrospective review. METHODS: Patients with the discharge diagnosis of acute epiglottitis or supraglottitis from two tertiary hospitals from 1995 to 2005 were identified. Patient characteristics, signs and symptoms at presentation, interventions, hospital course, and outcomes were reviewed and analyzed. RESULTS: Sixty adults and one child were identified. The most common presenting symptom was odynophagia (100%), followed by dysphagia (85%) and voice change (75%). Thirteen patients (21%) required airway intervention; 11 patients were intubated, and two required tracheotomy. Stridor, respiratory distress, tachycardia, tachypnea, rapid onset of symptoms, and shortness of breath were all associated with the need for airway intervention. Patients without any of these symptoms recovered without airway intervention. A total of 62% of patients were admitted to the intensive care unit (ICU), and the average length of ICU stay was 2.3 days. All patients were treated with intravenous antibiotics, most commonly ceftriaxone and ampicillin/sulbactam, and 87% of patients received at least one dose of steroids. The average overall length of stay was 3.8 days. There were no deaths. The use of corticosteroids was associated with shorter ICU and overall lengths of stay. CONCLUSIONS: The patient demographics, presentation, and course of supraglottitis have changed since the widespread use of the Hib vaccine. Recognizing the signs and symptoms associated with airway obstruction is important in the safe and effective management of this condition. PMID- 20925092 TI - Transradial approach for percutaneous closure of patent ductus arteriosus with the Amplatzer duct occluder II: a case report. AB - Percutaneous patent ductus arteriosus (PDA) closure is a safe and feasible treatment, and it is recommended over surgical approach in the majority of cases. Amplatzer duct occluder (ADO-AGA Medical Corporation, Golden Valley, MN) is the preferred device for transcatheter treatment of PDA. Recently, the ADO II (AGA Medical Corporation, Golden Valley, MN), allowing PDA closure through a small delivery catheter from an antegrade or retrograde approach, received the European Community mark approval. Here, we report, for the first time, successful PDA closure in a 66-year-old female with the ADO II device, using a transradial approach. PMID- 20925093 TI - Bifurcated aortic endograft limb occlusion managed with a novel method of isolated pharmacomechanical thrombectomy. AB - Limb occlusion of an aortic endograft is uncommon, however, it can result in permanent sequelae if management is delayed. We report the first case utilizing the Trellis device to achieve localized and prompt isolated pharmacomechanical thrombectomy (PMT) for the treatment of acute limb thrombosis of a bifurcated aortic endograft. PMID- 20925094 TI - Design, synthesis, and molecular-modeling study of aminothienopyridine analogues of tacrine for Alzheimer's disease. AB - 2-Amino-3-cyanothiophenes were successfully condensed with a number of cycloalkanones to afford tacrine analogues in a one-step reaction mediated with Lewis acid. The newly synthesized compounds have been tested for their ability to inhibit acetylcholine esterase (AChE) activity using tacrine as standard drug. Some of the tested compounds showed moderate inhibitory activity in comparison with tacrine, especially compounds 6a which displayed the highest inhibitory activity. Furthermore, molecular-modeling studies were performed in order to rationalize the obtained biological results. PMID- 20925095 TI - Difluorotetrahydropyridothiazinone: a selective beta-galactosidase inhibitor. AB - Selective difluorination, introducing a lactame moiety (instead of an amine) and a double bond in a trihydroxy-2-thiaquinolizidine derivative reverses the selectivity of the glycosidase inhibitor - a selective inhibitor for an alpha glucosidase is altered into an excellent, competitive inhibitor for a beta galactosidase. PMID- 20925096 TI - Rapid estimation of activation enthalpies for cytochrome-P450-mediated hydroxylations. AB - Cytochrome P450 (CYP) enzymes play a critical role in detoxication and bioactivation of xenobiotics; thus, the ability to predict the biotransformation rates and regioselectivity of CYP enzymes toward substrates is an important goal in toxicology and pharmacology. Here, we present the use of the semiempirical quantum chemistry method SAM1 to rapidly estimate relative activation enthalpies (DeltaH(?)) for the hydroxylation of aliphatic carbon centers of various substrates. The DeltaH(?) were determined via a reaction path calculation, in the reverse direction (RRP), using the iron-hydroxo-porphine intermediate and the substrate radical. The SAM1 DeltaH(?) were calculated via unrestricted Hartree Fock (UHF) and configuration interaction (CI) formalisms for both the doublet and quartet spin states. The SAM1 RRP DeltaH(?), after subtracting a correction factor, were compared with density functional theory (DFT) B3LYP activation energies for two sets of substrates and showed R(2) ranging from 0.69 to 0.89, and mean absolute differences ranging from 1.2 +/- 1.0 to 1.7 +/- 1.5 kcal/mol. SAM1 UHF and CI RRP calculation times were, on average, more than 200 times faster than those for the corresponding forward reaction path DFT calculations. Certain key transition-state (TS) geometry measurements, such as the forming O...H bond length, showed good correlation with the DFT values. These results suggest that the SAM1 RRP approach can be used to rapidly estimate the DFT activation energy and some key TS geometry measurements and can potentially be applied to estimate substrate hydroxylation rates and regioselectivity by CYP enzymes. PMID- 20925098 TI - Mapping spatial heterogeneity in Cu(In(1-x)Ga(x))Se2 nanocrystal-based photovoltaics with scanning photocurrent and fluorescence microscopy. PMID- 20925100 TI - Nanosheets of oxides and hydroxides: Ultimate 2D charge-bearing functional crystallites. AB - A wide variety of cation-exchangeable layered transition metal oxides and their relatively rare counterparts, anion-exchangeable layered hydroxides, have been exfoliated into individual host layers, i.e., nanosheets. Exfoliation is generally achieved via a high degree of swelling, typically driven either by intercalation of bulky organic ions (quaternary ammonium cations, propylammonium cations, etc.) for the layered oxides or by solvation with organic solvents (formamide, butanol, etc.) for the hydroxides. Ultimate two-dimensional (2D) anisotropy for the nanosheets, with thickness of around one nanometer versus lateral size ranging from submicrometer to several tens of micrometers, allows them to serve either as an ideal quantum system for fundamental study or as a basic building block for functional assembly. The charge-bearing inorganic macromolecule-like nanosheets can be assembled or organized through various solution-based processing techniques (e.g., flocculation, electrostatic sequential deposition, or the Langmuir-Blodgett method) to produce a range of nanocomposites, multilayer nanofilms, and core-shell nanoarchitectures, which have great potential for electronic, magnetic, optical, photochemical, and catalytic applications. PMID- 20925099 TI - Predicting posttraumatic stress symptoms in children following Hurricane Katrina: a prospective analysis of the effect of parental distress and parenting practices. AB - Research exhibits a robust relation between child hurricane exposure, parent distress, and child posttraumatic stress disorder (PTSD). This study explored parenting practices that could further explicate this association. Participants were 381 mothers and their children exposed to Hurricane Katrina. It was hypothesized that 3-7 months (T1) and 14-17 months (T2) post-Katrina: (a) hurricane exposure would predict child PTSD symptoms after controlling for history of violence exposure and (b) hurricane exposure would predict parent distress and negative parenting practices, which, in turn, would predict increased child PTSD symptoms. Hypotheses were partially supported. Hurricane exposure directly predicted child PTSD at T1 and indirectly at T2. Additionally, several significant paths emerged from hurricane exposure to parent distress and parenting practices, which were predictive of child PTSD. PMID- 20925101 TI - Woven electronic fibers with sensing and display functions for smart textiles. PMID- 20925102 TI - Controllable self-assembly of n-type semiconductors to microtubes and highly conductive ultralong microwires. PMID- 20925103 TI - Biocompatible charged and uncharged surfaces using nanoparticle films. PMID- 20925104 TI - Suspended single-crystal diamond nanowires for high-performance nanoelectromechanical switches. PMID- 20925106 TI - Protein tyrosine phosphatase activity is necessary for E-cadherin-activated Src signaling. AB - Co-operation between cadherin adhesion molecules and the cytoskeleton is a key aspect of tissue morphogenesis that is mediated by cortical signaling at adhesive junctions. One such signal is the non-receptor tyrosine kinase, Src, which acts in several pathways at epithelial junctions, including E-cadherin signaling itself. We now present two new insights into junctional Src signaling. Firstly, we report that upstream protein tyrosine phosphatase (PTP) activity is required to stimulate E-cadherin-activated Src signaling at junctions. Perturbing PTP activity with vanadate selectively reduced the activity of Src tyrosine kinases at junctions. Moreover, E-cadherin homophilic ligation could not stimulate Src signaling in vanadate-treated cells. Additionally, vanadate treatment phenocopied the effects of Src inhibition on the actin cytoskeleton, suggesting that PTP activity is required for the dynamic regulation of the actin cytoskeleton by cadherin-activated Src signaling. Secondly, we identified a role for PTP activated Src signaling in supporting apical junctional tension by targeting non muscle myosin IIB. The linear shape of the apical junctions was lost in PTP- and Src-inhibited cells, and inhibiting Src selectively affected the junctional localization of myosin IIB but not of myosin IIA. We conclude that PTP-activated Src signaling is a possible upstream regulator of myosin IIB at the epithelial zonula adherens. PMID- 20925105 TI - Force relaxation and thin filament protein phosphorylation during acute myocardial ischemia. AB - Ischemia impairs myocardial function and may contribute to the progression of heart failure. In this study, rats subjected to acute ischemia demonstrated reduced Ca(2+) -activated force as well as a decrease in myosin-binding protein C, titin, and Ser23/24 phosphorylation of troponin I (TnI). All three proteins have been demonstrated to be downstream targets of beta-adrenergic receptor activation (beta-AR), leading to the hypothesis that decreased beta-AR signaling during ischemia leads to reduced protein phosphorylation and reduced rate constants of force relaxation. To test this hypothesis, force relaxation transients were recorded from permeabilized perfused and ischemic rat heart fibers following photolysis of the caged chelator diazo-2. Relaxation transients were best fit by double exponential functions whereby the majority (>70%) of the force decline was described by the fast rate constant, which was ~5 times faster than the slow rate constant. However, rate constants of relaxation between perfused and ischemic fibers were not different, despite significant decreases in sarcomeric protein phosphorylation in ischemic fibers. Treatment of perfused fibers with a cAMP analog increased Ser23/24 phosphorylation of TnI, yet the rate constants of relaxation remained unchanged. Interestingly, similar treatment of ischemic fibers did not impact TnI phosphorylation or force relaxation transients. Therefore, acute ischemia does not influence the rate constants of relaxation of permeabilized fibers. These results also suggest that the physiological level of sarcomeric protein phosphorylation is unlikely to be the primary driver of relaxation kinetics in permeabilized cardiac muscle fibers. PMID- 20925107 TI - Lifetime imaging of FRET between red fluorescent proteins. AB - Numerous processes in cells can be traced by using fluorescence resonance energy transfer (FRET) between two fluorescent proteins. The novel FRET pair including the red fluorescent protein TagRFP and kindling fluorescent protein KFP for sensing caspase-3 activity is developed. The lifetime mode of FRET measurements with a nonfluorescent protein KFP as an acceptor is used to minimize crosstalk due to its direct excitation. The red fluorescence is characterized by a better penetrability through the tissues and minimizes the cell autofluorescence signal. The effective transfection and expression of the FRET sensor in eukaryotic cells is shown by FLIM. The induction of apoptosis by camptothecine increases the fluorescence lifetime, which means effective cleavage of the FRET sensor by caspase-3. The instruments for detecting whole-body fluorescent lifetime imaging are described. Experiments on animals show distinct fluorescence lifetimes for the red fluorescent proteins possessing similar spectral properties. PMID- 20925108 TI - 4D retrospective lineage tracing using SPIM for zebrafish organogenesis studies. AB - A study demonstrating an imaging framework that permits the determination of cell lineages during organogenesis of the posterior lateral line in zebrafish is presented. The combination of Selective Plane Illumination Microscopy and specific fluorescent markers allows retrospective tracking of hair cell progenitors, and hence the derivation of their lineages within the primodium. It is shown that, because of its superior signal-to-noise ratio and lower photo damaged properties, SPIM can provide significantly higher-quality images than Spinning Disk Confocal technology. This allows accurate 4D lineage tracing for the hair cells over tens of hours of primordium migration and neuromast development. PMID- 20925109 TI - Geriatric oncology field comes into its own: growing field advances but care questions remain. PMID- 20925112 TI - Nanoparticle PSA test helps predict likelihood of prostate cancer recurrence. PMID- 20925113 TI - Ectopic expression of GATA6 bypasses requirement for Grb2 in primitive endoderm formation. AB - Gene knockouts in mice have showed that Grb2 and GATA6 are essential for the formation of primitive endoderm in blastocysts. Here, we confirmed that implanted Grb2-null blastocysts lack primitive or extraembryonic endoderm cells either at E4.5 or E5.5 stages. We analyzed the relationship between Grb2 and GATA6 in the differentiation of embryonic stem (ES) cells to primitive endoderm in embryoid body models. Upon transfection with GATA6 expression vector, Grb2-null ES cells underwent endoderm differentiation as indicated by the expression of the extraembryonic endoderm markers Dab2 and GATA4. Transfection of GATA4 expression vector also had the same differentiation potency. When GATA6- or GATA4 transfected Grb2-null ES cells were allowed to aggregate, fragments of an endoderm layer formed on the surface of the spheroids. The results suggest that GATA6 is downstream of Grb2 in the inductive signaling pathway and the expression of GATA6 is sufficient to compensate for the defects caused by Grb2 deficiency in the development of the primitive and extraembryonic endoderm. PMID- 20925114 TI - The G-protein-coupled receptor, GPR84, is important for eye development in Xenopus laevis. AB - G-protein-coupled receptors (GPCRs) represent diverse, multifamily groups of cell signaling receptors involved in many cellular processes. We identified Xenopus laevis GPR84 as a member of the A18 subfamily of GPCRs. During development, GPR84 is detected in the embryonic lens placode, differentiating lens fiber cells, retina, and cornea. Anti-sense morpholino oligonucleotide-mediated knockdown and RNA rescue experiments demonstrate GPR84's importance in lens, cornea, and retinal development. Examination of cell proliferation using an antibody against histone H3 S10P reveals significant increases in the lens and retina following GPR84 knockdown. Additionally, there was also an increase in apoptosis in the retina and lens, as revealed by TUNEL assay. Reciprocal transplantation of the presumptive lens ectoderm between uninjected controls and morpholino-injected embryos demonstrates that GPR84 is necessary in the retina for proper development of the retina, as well as other eye tissues including the lens and cornea. PMID- 20925115 TI - Distinct troponin C isoform requirements in cardiac and skeletal muscle. AB - The zebrafish mutant silent partner is characterized by a dysmorphic, non contractile ventricle resulting in an inability to generate normal blood flow. We have identified the genetic lesion in the zebrafish homolog of the slow twitch skeletal/cardiac troponin C gene. Although human troponin C1 (TNNC1) is expressed in both cardiac and skeletal muscle, duplication of this gene in zebrafish has resulted in tissue-specific partitioning of troponin C expression and function. Mutation of the zebrafish paralog tnnc1a, which is expressed predominantly in the heart, results in a loss of contractility and myofibrillar organization within ventricular cardiomyocytes, while skeletal muscle remains functional and intact. We further show that defective contractility in the developing heart results in abnormal atrial and ventricular chamber morphology. Together, our results suggest that tnnc1a is required both for the function and structural integrity of the contractile machinery in cardiomyocytes, helping to clarify potential mechanisms of troponin C-mediated cardiomyopathy. PMID- 20925116 TI - White adipose tissue development in zebrafish is regulated by both developmental time and fish size. AB - Adipocytes are heterogeneous. Whether their differences are attributed to anatomical location or to different developmental origins is unknown. We investigated whether development of different white adipose tissue (WAT) depots in zebrafish occurs simultaneously or whether adipogenesis is influenced by the metabolic demands of growing fish. Like mammals, zebrafish adipocyte morphology is distinctive and adipocytes express cell-specific markers. All adults contain WAT in pancreatic, subcutaneous, visceral, esophageal, mandibular, cranial, and tail-fin depots. Unlike most zebrafish organs that form during embryogenesis, WAT was not found in embryos or young larvae. Instead, WAT was first identified in the pancreas on 12 days postfertilization (dpf), and then in visceral, subcutaneous, and cranial stores in older fish. All 30 dpf fish exceeding 10.6 mm standard length contained the adult repertoire of WAT depots. Pancreatic, esophageal, and subcutaneous WAT appearance correlated with size, not age, as found for other features appearing during postembryonic zebrafish development. PMID- 20925117 TI - Investigating giant (Gt) repression in the formation of partially overlapping pair-rule stripes. AB - Drosophila pair-rule genes are expressed in striped patterns with a precise order of overlap between stripes of different genes. We investigated the role of Giant (Gt) in the regulation of even-skipped, hairy, runt, and fushi tarazu stripes formed in the vicinity of Gt expression domains. In gt null embryos, specific stripes of eve, h, run, and ftz are disrupted. With an ectopic expression system, we verified that stripes affected in the mutant are also repressed. Simultaneously hybridizing gt misxpressing embryos with two pair-rule gene probes, we were able to distinguish differences in the repression of pairs of stripes that overlap extensively. Together, our results showed Gt repression roles in the regulation of two groups of partially overlapping stripes and that Gt morphogen activity is part of the mechanism responsible for the differential positioning of these stripes borders. We discuss the possibility that other factors regulate Gt stripe targets as well. PMID- 20925118 TI - EGR4 displays both a cell- and intracellular-specific localization pattern in the developing murine testis. AB - Spermatogenesis is an intricately regulated process of cellular differentiation transforming spermatogonial stem cells to spermatozoa. Elimination of the transcription factor EGR4 generates subfertile male mice yet the expression and function of EGR4 in the mammalian testis has yet to be fully investigated. We performed in situ hybridization and immunofluorescence to identify Egr4 transcript and protein localization in the developing murine testis. EGR4 was detected in both germ and somatic cells in the neonatal testis but was specific to germ cells inside the seminiferous epithelium from juvenile development onward. EGR4 also displayed distinct intracellular localization patterns within specific cell populations of the testis. In addition, Egr4-deficient testis tubules regress from relatively normal to Sertoli cell and undifferentiated spermatogonia only over time. Taken together, these data suggest that Egr4 may regulate spermatogenesis at multiple steps, with roles in the dividing Sertoli cells, peritubular myoid cells, and the meiotic and elongating haploid germ cell populations. PMID- 20925119 TI - AES/GRG5: more than just a dominant-negative TLE/GRG family member. AB - The human Transducin-like Enhancer of Split (TLE) and mouse homologue, Groucho gene-related protein (GRG), represent a family of conserved non-DNA binding transcriptional modulatory proteins divided into two subgroups based upon size. The long TLE/GRGs consist of four pentadomain proteins that are dedicated co repressors for multiple transcription factors (TF). The second TLE/GRG subgroup is composed of the Amino-terminal Enhancer of Split (AES) in humans and its mouse homolog GRG5 (AES/GRG5). In contrast to the dedicated co-repressor function of long TLE/GRGs, AES/GRG5 can both positively or negatively modulate various TF as well as non-TF proteins in a long TLE/GRG-dependent or -independent manner. Therefore, AES/GRG5 is a functionally dynamic protein that is not exclusively defined by its role as a long TLE/GRG antagonist. AES/GRG5 may function in various developmental and pathological processes but the functional characteristics of endogenous AES/GRG5 in a physiologically relevant context remains to be determined. PMID- 20925120 TI - Dynamic Lkb1-TORC1 signaling as a possible mechanism for regulating the endoderm intestine transition. AB - The intestinal epithelium arises from undifferentiated endoderm via a developmental program known as the endoderm-intestine transition (EIT). Previously we found that the target of rapamycin complex 1 (TORC1) regulates intestinal growth and differentiation during the EIT in zebrafish. Here we address a possible role for the tumor-suppressor kinase Lkb1 in regulating TORC1 in this context. We find that TORC1 activity is transiently upregulated during the EIT in both zebrafish and mouse. Concomitantly, Lkb1 becomes transiently localized to the nucleus, suggesting that these two phenomena may be linked. Morpholino-mediated knockdown of lkb1 stimulated intestinal growth via upregulation of TORC1, and also induced precocious intestine-specific gene expression in the zebrafish gut epithelium. Knockdown of tsc2, which acts downstream of lkb1, likewise induced early expression of intestine-specific genes. These data suggest that programmed localization of Lkb1 could represent a novel mechanism for regulating the EIT during intestinal development in vertebrates. PMID- 20925121 TI - Capsaicin induces apoptosis in SCC-4 human tongue cancer cells through mitochondria-dependent and -independent pathways. AB - Although there have been advances in the fields of surgery, radiotherapy, and chemotherapy of tongue cancer, the cure rates are still not substantially satisfactory. Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide) is the major pungent ingredient of hot chili pepper and has been reported to have an antitumor effect on many human cancer cell types. The molecular mechanisms of the antitumor effect of capsaicin are not yet completely understood. Herein, we investigated whether capsaicin induces apoptosis in human tongue cancer cells. Capsaicin decreased the percentage of viable cells in a dose-dependent manner in human tongue cancer SCC-4 cells. In addition, capsaicin produced DNA fragmentation, decreased the DNA contents (sub-G1 phase), and induced G0/G1 phase arrest in SCC 4 cells. We demonstrated that capsaicin-induced apoptosis is associated with an increase in reactive oxygen species and Ca2+ generations and a disruption of the mitochondrial transmenbrane potential (DeltaPsi(m)). Treatment with capsaicin induced a dramatic increase in caspase-3 and -9 activities, as assessed by flow cytometric methods. A possible mechanism of capsaicin-induced apoptosis is involved in the activation of caspase-3 (one of the apoptosis-executing enzyme). Confocal laser microscope examination also showed that capsaicin induced the releases of AIF, ATF-4, and GADD153 from mitochondria of SCC-4 cells. PMID- 20925122 TI - Antioxidant and metabolic impairment result in DNA damage in arsenic-exposed individuals with severe dermatological manifestations in Eastern India. AB - Arsenic is an environmental toxicant, free-radical generator, carcinogenic agent, and aging promoter. Recently, blood samples were analyzed from individuals (control- male 12, female 13; arsenic-exposed- male 16, female 14; and exposed to >=100 MUg/L As, >=10 y) with dermatological symptoms in few affected villages in Eastern India to unravel their hematopoietic, metabolic, and antioxidant profiles. White blood cells recovered from buffy coat were used for DNA fragmentation test. Present observation suggests that significant number of individuals developed pigmentation and palmoplantar hyperkeratosis with black brownish patch on their body and many of those developed carcinomas. Hematopoietic data show a significant increase in eosinophil and decrease in monocyte count in either sex. Though insignificant, an increase in neutrophil in female and lymphocyte count in male arsenic-exposed individuals are supported by the earlier report on sex dimorphic immune sensitization. Significant increase in serum alanine transaminase in both sexes and bilirubin only in male suggests the eventuality of hepatic disintegration. Arsenic exposure significantly decreased serum amylase in female. A significant decrease in antioxidant components like catalase, soluble thiol, and recently recognized uric acid worsened the situation by generating free radicals as observed in significant rise in malondialdehyde level, which finally increased DNA fragmentation and arsenic-associated mutagenesis and carcinogenesis. This could attribute to lowering in immune competence and related necrotic and/or apoptotic manifestations. PMID- 20925123 TI - Zebrafish calcium/calmodulin-dependent protein kinase II (cam-kii) inhibitors: expression patterns and their roles in zebrafish brain development. AB - Calcium/calmodulin-dependent protein kinase II (CaM-KII) plays a critical role in neuronal functions. In this report, we demonstrate the expression patterns, functional analysis, and development role of the two zebrafish CaM-KII inhibitors, cam-kiin1 and cam-kiin2. Both of these genes were detected in the 5 somite stage and are persistently expressed thereafter. The RNA transcripts of cam-kiin1 were prominently expressed in the forebrain and hindbrain regions, especially in the telencephalon, while cam-kiin2 was detected in the anterior brain region and neurons of the hindbrain. Through GST-pull down, co immunoprecipitation, and kinase assay, cam-kii inhibitors can bind to and reduce cam-kiialpha activity. However, no overt alternation of brain marker such as ngn1, otx2, and pax2.1 was observed in morphants received each one or combined MO. Our results suggest that the two cam-kii inhibitors exhibited distinct expression pattern and may play a minor role in zebrafish brain development. PMID- 20925124 TI - Sox17 and chordin are required for formation of Kupffer's vesicle and left-right asymmetry determination in zebrafish. AB - Kupffer's vesicle (KV), a ciliated fluid-filled sphere in the zebrafish embryo with a critical role in laterality determination, is derived from a group of superficial cells in the organizer region of the gastrula named the dorsal forerunner cells (DFC). We have examined the role of the expression of sox17 and chordin (chd) in the DFC in KV formation and laterality determination. Whereas sox17 was known to be expressed in DFC, its function in these cells was not studied before. Further, expression of chd in these cells has not been reported previously. Targeted knockdown of Sox17 and Chd in DFC led to aberrant Left-Right (L-R) asymmetry establishment, as visualized by the expression of southpaw and lefty, and heart and pancreas placement in the embryo. These defects correlated with the formation of small KVs with apparently diminished cilia, consistent with the known requirement for ciliary function in the laterality organ for the establishment of L-R asymmetry. PMID- 20925125 TI - Noninvasive quantification of T2 and concentrations of ascorbate and glutathione in the human brain from the same double-edited spectra. AB - The transverse relaxation times (T(2)) and concentrations of Ascorbate (Asc) and glutathione (GSH) were measured from a single dataset of double-edited spectra that were acquired at several TEs at 4 T in the human brain. Six TEs between 102 and 152 ms were utilized to calculate T(2) for the group of 12 subjects scanned five times each. Spectra measured at all six TEs were summed to quantify the concentration in each individual scan. LCModel fitting was optimized for the quantification of the Asc and GSH double-edited spectra. When the fitted baseline was constrained to be flat, T(2) was found to be 67 ms (95% confidence interval, 50-83 ms) for GSH and <=115 ms for Asc using the sum of spectra measured over 60 scans. The Asc and GSH concentrations quantified in each of the 60 scans were 0.62 +/- 0.08 and 0.81 +/- 0.11 umol/g [mean +/- standard deviation (SD), n = 60], respectively, using 10 umol/g N-acetylaspartate as an internal reference and assuming a constant influence of N-acetylaspartate and antioxidant T(2) relaxation in the reference solution and in vivo. The T(2) value of GSH was measured for the first time in the human brain. The data are consistent with short T(2) for both antioxidants. These T(2) values are essential for the absolute quantification of Asc and GSH concentrations measured at long TE, and provide a critical step towards addressing assumptions about T(2), and therefore towards the quantification of concentrations without the possibility of systematic bias. PMID- 20925126 TI - Considerations for measuring the fractional anisotropy of metabolites with diffusion tensor spectroscopy. AB - Diffusion tensor spectroscopy of metabolites in brain is challenging because of their lower diffusivity (i.e. less signal attenuation for a given b value) and much poorer signal-to-noise ratio relative to water. Although diffusion tensor acquisition protocols have been studied in detail for water, they have not been evaluated systematically for the measurement of the fractional anisotropy of metabolites such as N-acetylaspartate, creatine and choline in the white and gray matter of human brain. Diffusion tensor spectroscopy was performed in vivo with variable maximal b values (1815 or 5018 s/mm(2)). Experiments were also performed on simulated spectra and isotropic alcohol phantoms of various diffusivities, ranging from approximately 0.54 * 10(-3) to 0.13 * 10(-3) mm(2)/s, to assess the sensitivity of diffusion tensor spectroscopic parameters to low diffusivity, noise and b value. The low maximum b value of 1815 s/mm(2) yielded elevated fractional anisotropy (0.53-0.60) of N-acetylaspartate in cortical gray matter relative to the more isotropic value (0.25-0.30) obtained with a higher b value of 5018 s/mm(2); in contrast, the fractional anisotropy of white matter was consistently anisotropic with the different maximal b values (i.e. 0.43-0.54 for b = 1815 s/mm(2) and 0.47-0.51 for b = 5018 s/mm(2)). Simulations, phantoms and in vivo data indicate that greater signal attenuation, to a degree, is desirable for the accurate quantification of diffusion-weighted spectra for slowly diffusing metabolites. PMID- 20925127 TI - A fast black-blood sequence for four-dimensional cardiac manganese-enhanced MRI in mouse. AB - The increasing number of mouse models of cardiac diseases requires improvements in the current MRI tools. Anatomic and functional cardiac phenotyping by MRI calls for both time and space resolution in three dimensions. Black-blood contrast is often needed for the accurate delineation of myocardium and chambers, and is consistent with manganese contrast enhancement. In this article, we propose a fast, three-dimensional, time-resolved (four-dimensional), black-blood MRI sequence that allows mouse heart imaging at 10 periods of the cardiac cycle within 30 min at an isotropic resolution of 200 um. Two-dimensional imaging was possible within 80 s. Blood cancellation was achieved by employing bipolar gradients without the use of a double inversion recovery preparation scheme. Saturation slices were added in two-dimensional experiments for better blood nulling. The rapidity of the two-dimensional acquisition protocol allowed the measurement of the time course of contrast enhancement on manganese infusion. Owing to the very high contrast-to-noise ratio, manganese-enhanced MRI in four dimensions made possible the accurate assessment of regional cardiac volumes in healthy animals. In experimentally infarcted mice, the size of the ischemic zone could be measured easily with this method. The technique might be valuable in evaluating mouse heart diseases and their follow-up in longitudinal studies. PMID- 20925128 TI - Detection of fully refocused polyamine spins in prostate cancer at 7 T. AB - (1)H MRSI is often used at 1.5 or 3 T to study prostate cancer, where the ratio of choline + creatine to citrate is taken as a marker for tumour presence. Recently, the level of polyamines (mainly spermine) has been shown to improve specificity even further. However, the in vivo detection of these polyamines (at 3.1 ppm) is hampered by signal cancellation as a result of J-coupling effects and signal overlap with choline (3.2 ppm) and creatine (3.0 ppm) resonances. At higher magnetic field strengths, the chemical shift dispersion will increase, which allows the use of very selective radiofrequency pulses to refocus J-coupled spins. In this work, we added selective refocusing pulses to a semi-LASER (localisation based on adiabatic selective refocusing) sequence at 7 T, and optimised the inter-pulse timings of the sequence for fully refocused detection of spermine spins, whilst maintaining optimised detection of choline, creatine and the strongly coupled spin system of citrate. PMID- 20925129 TI - A mixture model of nuchal translucency thickness in screening for chromosomal defects: validation of a single operator dataset. AB - OBJECTIVE: (1) To validate the mixture model in a single operator dataset and (2) to compare the detection rates for fetal chromosomal defects obtained from the mixture model with those obtained from either the delta nuchal translucency (NT) or log multiple of the median (MoM) approach. METHODS: Database query, viable singletons [crown-rump length (CRL) 45-84 mm corresponding to 11-13(+6) weeks], December 1997 to November 2006, examined by Adam Gasiorek-Wiens, the statistical mixture model was applied. RESULTS: Seventy-four of 4171 were lost to follow-up (1.8%), 4097 singleton pregnancies included trisomy 21 (n = 34, 0.8%), trisomy 18 (n = 20, 0.5%), trisomy 13 (n = 8, 0.2%), Turner syndrome (n = 9, 0.2%) and other chromosomal abnormalities (n = 14, 0.3%). The main findings are that (1) the log transformed NT measurements follow a mixture of two Gaussian distributions and (2) the criteria to apply either the delta-NT or log MoM models are not met. In the normal group, the majority of NT measurements were dependent on the CRL, a small group showed a median independent of the CRL. In the abnormal group it was the opposite. For a 5% false-positive rate (FPR), the trisomy 21 detection rate was 83%. CONCLUSIONS: The use of the mixture model in a single operator dataset produces results compatible with the original study. The mixture model has thus been validated. PMID- 20925130 TI - Biosilicate(r) and low-level laser therapy improve bone repair in osteoporotic rats. AB - The aim of this study was to investigate the effects of a novel bioactive material (Biosilicate(r)) and low-level laser therapy (LLLT) on bone fracture consolidation in osteoporotic rats. Forty female Wistar rats were submitted to ovariectomy (OVX) to induce osteopenia. Eight weeks after surgery, the animals were randomly divided into four groups of 10 animals each: a bone defect control group (CG); a bone defect filled with Biosilicate group (BG); a bone defect filled with Biosilicate and irradiated with LLLT at 60 J/cm(2) group (BG60); and a bone defect filled with Biosilicate and irradiated with LLLT at 120 J/cm(2) group (BG120). Bone defects were surgically performed on both tibias. The size of particle used for Biosilicate was 180-212 um. Histopathological analysis showed that bone defects were predominantly filled with the biomaterial in specimens treated with Biosilicate. LLLT with either 60 or 120 J/cm(2) was able to increase collagen, Cbfa-1, VGEF and COX-2 expression in the circumjacent cells of the biomaterial. A morphometric analysis revealed that the Biosilicate + laser groups showed a higher amount of newly formed bone. Our results indicate that laser therapy improves bone repair process in contact with Biosilicate as a result of increasing bone formation, as well as COX-2 and Cbfa-1 immunoexpression, angiogenesis and collagen deposition in osteoporotic rats. PMID- 20925131 TI - Diagnostic utility of array-based comparative genomic hybridization (aCGH) in a prenatal setting. AB - OBJECTIVE: Array-based comparative genomic hybridization (aCGH) is a new technique for detecting submicroscopic deletions and duplications. There is limited information regarding its use in the prenatal setting. Here, we present our experience of 269 prenatal aCGHs between 2006 and 2009. METHOD: The indications for testing were fetal anomalies on ultrasound (U/S), advanced maternal age (AMA), family history of a disorder of unknown etiology, parental concern, abnormal routine karyotype and abnormal serum biochemical screening for common fetal aneuploidies. RESULTS: Of 15 cases with a known abnormal karyotype, 11 had a normal aCGH. This enabled us to reassure the families and the pregnancies were continued. The remaining four showed an abnormal aCGH, confirming the chromosomes were unbalanced, and were terminated. Of 254 cases with a normal karyotype, 3 had an abnormal aCGH and were terminated. Overall, new clinically relevant results were detected by aCGH in 18 cases, providing additional information for prenatal genetic counseling and risk assessment. CONCLUSION: Our results suggest that prenatal aCGH should be offered particularly in cases with abnormal U/S. We found the rate of detecting an abnormality by aCGH in low-risk pregnancies was 1:84, but larger studies will be needed to expand our knowledge and validate our conclusions. PMID- 20925132 TI - Epidemiologic study of aripiprazole use and the incidence of suicide events. AB - PURPOSE: Because second generation antipsychotics (SGA) might affect the risk of suicide, systematic assessment of suicide risk associated with SGA in the postmarketing setting is important and of interest to regulatory authorities. To fulfill a postmarketing request, our objective was to determine suicide event (attempted or completed) incidence in patients with schizophrenia or bipolar disorder, prescribed aripiprazole. METHODS: Using administrative data from three US sources, we assessed study endpoints of suicide attempts and death by suicide in patients aged >=18 enrolled continuously for >=3 months in their health plans before receiving their first ever antipsychotic (November 2002-December 2005). RESULTS: Among 20 489 antipsychotic users (8985 patient-years), unadjusted suicide event rates (per 1000 patient-years) were: 20.69 (aripiprazole); 23.99 (olanzapine); 32.33 (quetiapine); 19.69 (risperidone); 48.52 (ziprasidone). Compared with current users of other SGA combined, aripiprazole users did not have an increased risk of suicide events (crude hazard ratio (HR) = 0.79, 95%CI: 0.48-1.30; adjusted HR = 0.69, 95%CI: 0.42-1.14-(controlling for study site, age, sex, index prescription year, antipsychotic use history, other pharmacotherapy exposure, comorbidity presence, schizophrenia/bipolar disorder, suicide attempts, number inpatient/outpatient encounters). CONCLUSIONS: In this large, multi-site study, compared with other SGA combined, aripiprazole is not associated with an increased risk of suicide events in an inception cohort of patients with ICD 9/ICD-10 codes indicative of schizophrenia or bipolar disorder. PMID- 20925133 TI - Reduction of lipid accumulation in HepG2 cells by luteolin is associated with activation of AMPK and mitigation of oxidative stress. AB - The present study was carried out to investigate the lipid-lowering effect of luteolin by using a cell model of steatosis induced by palmitate. Incubation of HepG2 cells with palmitate markedly increased lipid accumulation (Oil Red O staining), the genes involved in lipogenesis, including fatty acid synthase (FAS) and its upstream regulator sterol regulatory element binding protein 1c (SREBP 1c), and reactive oxygen species (ROS) production. Luteolin enhanced the phosphorylation of AMP-activated protein kinase alpha (AMPKalpha) and its primary downstream targeting enzyme, acetyl-CoA carboxylase (ACC), up-regulated gene expression of carnitine palmitoyl transferase 1 (CPT-1), which is the rate limiting enzyme in mitochondrial fatty acid beta-oxidation, and down-regulated SREBP-1c and FAS mRNA levels in the absence and presence of palmitate. In addition, luteolin significantly decreased ROS production and ameliorated lipid accumulation in HepG2 cells caused by palmitate. Furthermore, intracellular triglyceride (TG) measurement indicated that the luteolin-mediated reduction of enhanced TG caused by palmitate was blocked by pretreatment with the AMPK inhibitor, compound C. The results suggested that the lipid-lowering effect of luteolin might be partially mediated by the up-regulation of CPT-1 and down regulation of SREBP-1c and FAS gene expression, possibly by activation of the AMPK signaling pathway, and partially might be through its antioxidative actions. PMID- 20925134 TI - Factors associated with caregiving burden and maternal pessimism in mothers of adolescents with an autism spectrum disorder in Taiwan. AB - Relative to the United States and other western countries, less research has focused on factors associated with caregiving burden and maternal pessimism in Taiwanese mothers of adolescents with an autism spectrum disorder (ASD). The characteristics of 50 adolescents with an ASD living at home in Taiwan and its association with caregiving burden and maternal pessimism were examined. The age range of adolescents with an ASD was from 10 to 18. Mothers, aged 35 to 55 years, completed self-report written questionnaires regarding their child's adaptive functioning and their own perceptions of caregiving burdens and concerns. Findings indicated that functional independence, severe maladaptive behaviours and severity of autism were predictive of maternal caregiving burden. Maternal pessimism was associated with functional independence and severity of autism. The findings of this study indicated that occupational therapy practitioners could focus on training functional independence of the individual with an ASD to meet the family's need in Taiwan. Researchers should pay significant attention to the lifespan issues of autism in Taiwanese families. The major limitations of this study were small sample size and without a comparison group. Future research using larger samples with a comparison group is needed. PMID- 20925135 TI - Psychological distress in women at risk for hereditary breast cancer: the role of family communication and perceived social support. AB - BACKGROUND: Hereditary breast cancer has a profound impact on individual family members and on their mutual communication and interactions. The way at-risk women cope with the threat of hereditary breast cancer may depend on the quality of family communication about hereditary breast cancer and on the perceived social support from family and friends. OBJECTIVE: To examine the associations of family communication and social support with long-term psychological distress in a group of women at risk for hereditary breast cancer, who opted either for regular breast surveillance or prophylactic surgery. METHODS: The study cohort consisted of 222 women at risk for hereditary breast cancer, who previously participated in a study on the psychological consequences of either regular breast cancer surveillance or prophylactic surgery. General and breast cancer specific distress, hereditary cancer-related family communication, perceived social support, and demographics were assessed. RESULTS: Using structural equation modelling, we found that open communication about hereditary cancer within the family was associated with less general and breast cancer specific distress. In addition, perceived support from family and friends was indirectly associated with less general and breast cancer-specific distress through open communication within the family. DISCUSSION: These findings indicate that family communication and perceived social support from friends and family are of paramount importance in the long-term adaptation to being at risk for hereditary breast cancer. Attention for these issues needs to be incorporated in the care of women at risk for hereditary breast cancer. PMID- 20925136 TI - Distress screening, rater agreement, and services in pediatric oncology. AB - OBJECTIVE: Empirically based data support the validity of the distress thermometer recommended by the National Comprehensive Cancer Network as a standard screen for patient distress. However, the feasibility and utility of the distress thermometer has not been studied in the pediatric oncology setting. We conducted a study to: (1) investigate the validity of an adapted distress thermometer with pediatric oncology patients, (2) assess the degree of agreement among different respondents, including physician and psychosocial staff, with respect to (a) the pediatric cancer patient's distress and (b) the caregiver/parent's distress, and (3) to evaluate the relationship between distress levels and the psychosocial services provided to patients and families. METHODS: Ninety-one patients and their English and Spanish-speaking caregivers were prospectively assessed at 3-month intervals for 1 year. The quantity of psychosocial services provided to each family was logged for a 12-month period. RESULTS: Convergent validity was demonstrated by reasonable agreement between the pediatric distress rating tool and standardized measures. Additionally, the demographic and medical predictors of distress were consistent with previously reported findings using more extensive assessment. There was reasonable agreement among multiple raters of the child's distress; however, there was discrepancy between self-ratings of caregiver distress and psychosocial staff ratings of caregiver distress. This difference in perception impacted the quantity of psychosocial services provided following the baseline assessment. CONCLUSION: The single-item distress thermometer is a viable option as a rapid screening tool of patient and caregiver distress to help efficiently identify those who should be evaluated further. PMID- 20925137 TI - Marital satisfaction of advanced prostate cancer survivors and their spousal caregivers: the dyadic effects of physical and mental health. AB - OBJECTIVE: Coping with the physical and mental side effects of diagnosis and treatment for advanced prostate cancer (APC) is a challenge for both survivors and their spousal caregivers. There is a gap in our current understanding of the dyadic adjustment process on marital satisfaction in this population. The current study sought to: (1) document levels of physical and mental health, and marital satisfaction, and (2) evaluate the relationship between physical and mental health with marital satisfaction in this understudied population. METHODS: APC survivors who had undergone androgen deprivation therapy within the past year and their spousal caregiver participated in the study (N = 29 dyads). Physical and mental health was assessed using the MOS SF-36 Health Survey and marital satisfaction was evaluated using the Dyadic Adjustment Scale. RESULTS: The Actor Partner Interdependence Model revealed strong relations between physical and mental health with marital satisfaction for both survivor and caregiver (actor effects). Furthermore, caregiver physical and mental health was related with the survivor's marital satisfaction (partner effect). CONCLUSIONS: Levels of mental health and marital satisfaction were comparable to community-based and prostate cancer samples, while physical health was higher. Marital satisfaction between APC survivors and their spousal caregivers may be influenced by both physical and mental health functioning. In particular, APC survivor functioning may affect his marital satisfaction as well as his spousal caregiver's. This has implications for psychosocial interventions for APC dyads. Further evaluation of the complex nature of survivor/caregiver dyadic adjustment in dealing with APC is necessary. PMID- 20925138 TI - Dyskerin and cancer: more than telomerase. The defect in mRNA translation helps in explaining how a proliferative defect leads to cancer. AB - Point mutations in the DKC1 gene that encodes dyskerin cause the rare inherited syndrome called X-linked dyskeratosis congenita, characterized by a failure of proliferating tissues and increased susceptibility to cancer. Dyskerin is a nucleolar protein with different functions, all fundamental to basic cellular events such as protein expression, growth, and proliferation. The two best characterized dyskerin activities are the stabilization of the telomerase RNA component, allowing the proper function telomerase enzymatic complex, and the modification of specific uridine residues of ribosomal RNA by converting them to pseudouridine, thus allowing proper ribosome processing and function. In light of the recent findings, this review focuses on the molecular pathogenesis of dyskeratosis congenita, discussing how a defect in ribosomal function might impact on the translation of a subset of mRNAs encoding for tumour suppressors, thus providing an explanation for the apparent paradox of dyskeratosis congenita in which reduced cell proliferation is associated with cancer susceptibility. In addition, the current evidence pointing to a role played by dyskerin in tumours in the general population is also discussed. PMID- 20925139 TI - Optimal caliper widths for propensity-score matching when estimating differences in means and differences in proportions in observational studies. AB - In a study comparing the effects of two treatments, the propensity score is the probability of assignment to one treatment conditional on a subject's measured baseline covariates. Propensity-score matching is increasingly being used to estimate the effects of exposures using observational data. In the most common implementation of propensity-score matching, pairs of treated and untreated subjects are formed whose propensity scores differ by at most a pre-specified amount (the caliper width). There has been a little research into the optimal caliper width. We conducted an extensive series of Monte Carlo simulations to determine the optimal caliper width for estimating differences in means (for continuous outcomes) and risk differences (for binary outcomes). When estimating differences in means or risk differences, we recommend that researchers match on the logit of the propensity score using calipers of width equal to 0.2 of the standard deviation of the logit of the propensity score. When at least some of the covariates were continuous, then either this value, or one close to it, minimized the mean square error of the resultant estimated treatment effect. It also eliminated at least 98% of the bias in the crude estimator, and it resulted in confidence intervals with approximately the correct coverage rates. Furthermore, the empirical type I error rate was approximately correct. When all of the covariates were binary, then the choice of caliper width had a much smaller impact on the performance of estimation of risk differences and differences in means. PMID- 20925140 TI - Metastatic Wilms' tumor in an adolescent successfully treated with multimodal pediatric therapy. PMID- 20925141 TI - Cerebral Vasospasm. PMID- 20925142 TI - Measurement of vasoactive neuropeptides in biological materials: problems and pitfalls from 30 years of experience and novel future approaches. PMID- 20925143 TI - Cartilage: Commonly used drugs prevent cartilage degradation. PMID- 20925145 TI - Spondyloarthropathies: Synergistic therapy protects bone in patients with AS. PMID- 20925144 TI - Pain: Diagnostic blocks-a pain in the back? PMID- 20925146 TI - Medical therapy of pericardial diseases: part II: Noninfectious pericarditis, pericardial effusion and constrictive pericarditis. AB - The treatment of pericardial diseases is largely empirical because of the relative lack of randomized trials compared with other cardiovascular diseases. The main forms of pericardial diseases that can be encountered in the clinical setting include acute and recurrent pericarditis, pericardial effusion with or without cardiac tamponade, and constrictive pericarditis. Medical treatment should be targeted at the cause as much as possible. In this article, the therapy of more common forms of noninfectious pericarditis (pericarditis in systemic autoimmune diseases and neoplastic pericardial disease), pericardial effusion, and constrictive pericarditis is reviewed. PMID- 20925147 TI - Reply: GnRHa to trigger final oocyte maturation: a time to reconsider. PMID- 20925148 TI - Connective tissue diseases: Plasmacytoid dendritic cells-perpetrators in SLE pathogenesis? PMID- 20925149 TI - Connective tissue diseases: Blood flow assessment at your fingertips. PMID- 20925150 TI - MMF for juvenile derMatoMyositis. PMID- 20925151 TI - Therapy: Rituximab has similar short-term safety and efficacy to cyclophosphamide in ANCA-associated vasculitis. PMID- 20925152 TI - Beyond dark and bright: towards a more holistic understanding of inter-group networks. AB - Networks are becoming a popular organizational form for structuring human activities. To date, scholars have addressed networks in a variety of fields, including sociology, economics, public administration, criminology, political science, and international security. However, little has been done so far to systematically examine the similarities, differences, and connections between network forms of organization across different academic disciplines. This has important implications for both theory and practice. The lack of attention paid to organizational similarities and differences prevents the exchange of knowledge developed across fields. In turn, policy-makers cannot take full advantage of existing research, and may miss opportunities to improve the work of some networks and combat that of others. To address this gap in the literature, this paper uses the combination of organizational environments and organizational goals to develop a new typology of inter-group networks, and thus improve our understanding of how human behaviour is coordinated through networks. PMID- 20925153 TI - Supplier behaviour and public contracting in the English agency nursing market. AB - The worldwide expansion in the use of private firms to deliver public services and infrastructure has promoted a substantial literature on public sector contract and relationship management. This literature is currently dominated by the notion that supplier relationships should be based upon trust. Less prominent are more sceptical approaches that emphasize the need to assiduously manage potential supplier exploitation and opportunism. This article addresses this imbalance by focusing upon the recent experience of the English National Health Service (NHS) in its dealings with its nursing agencies. Between 1997 and 2001, the NHS was subjected to considerable exploitation and opportunism. This forced managers to adopt a supply strategy based upon an assiduous use of e-auctions, framework agreements and quality audits. The article assesses the effectiveness of this strategy and reflects upon whether a more defensive approach to contract and relationship management offers a viable alternative to one based upon trust. PMID- 20925154 TI - Explaining the unexpected success of the smoking ban in Italy: political strategy and transition to practice, 2000-2005. AB - The approval (2003) and enforcement (2005) of a smoking ban in Italy have been viewed by many as an unexpectedly successful example of policy change. The present paper, by applying a processualist approach, concentrates on two policy cycles between 2000 and 2005. These had opposing outcomes: an incomplete decisional stage and an authoritative decision, enforced two years later. Through the analysis of the different phases of agenda setting, alternative specification and decision making, we have compared the quality of participation of policy entrepreneurs in the two cycles, their political strategies and, in these, the relevance of issue image. The case allows us to direct the attention of scholars and practitioners to an early phase of the policy implementation process - which we have named "transition to practice". This, managed with political strategy, might have strongly contributed to the final successful policy outcome. PMID- 20925155 TI - Implementing evidence-based policy in a network setting: road safety policy in the Netherlands. AB - In the early 1990s, in order to improve road safety in The Netherlands, the Institute for Road Safety Research (SWOV) developed an evidence-based "Sustainable Safety" concept. Based on this concept, Dutch road safety policy, was seen as successful and as a best practice in Europe. In The Netherlands, the policy context has now changed from a sectoral policy setting towards a fragmented network in which safety is a facet of other transport-related policies. In this contribution, it is argued that the implementation strategy underlying Sustainable Safety should be aligned with the changed context. In order to explore the adjustments needed, two perspectives of policy implementation are discussed: (1) national evidence-based policies with sectoral implementation; and (2) decentralized negotiation on transport policy in which road safety is but one aspect. We argue that the latter approach matches the characteristics of the newly evolved policy context best, and conclude with recommendations for reformulating the implementation strategy. PMID- 20925156 TI - Health tips. Care for an injured toe. PMID- 20925158 TI - Double vision. It may be more than eye trouble. PMID- 20925157 TI - Top ways to reduce your risk of developing diabetes. PMID- 20925159 TI - Hoarseness. Get your voice back. PMID- 20925160 TI - It seems as if my postnasal drip is getting worse as I age. Is there anything I can do about it? PMID- 20925161 TI - How is sex determined in insects? Preface. PMID- 20925162 TI - How is sex determined in insects? An epilogue. PMID- 20925163 TI - [Upper G.I cancer-esophageal and stomach neoplasm-]. PMID- 20925164 TI - [Current pathological knowledge of Barrett cancer]. PMID- 20925165 TI - Combination therapy with epinephrine and dexamethasone for bronchiolitis. PMID- 20925166 TI - Hookworm-related cutaneous larva migrans. PMID- 20925167 TI - A teaspoon in the stomach: How do we proceed from here? PMID- 20925168 TI - Profound metabolic acidosis from pyroglutamic acidemia: an underappreciated cause of high anion gap metabolic acidosis. AB - The workup of the emergency patient with a raised anion gap metabolic acidosis includes assessment of the components of "MUDPILES" (methanol; uremia; diabetic ketoacidosis; paraldehyde; isoniazid, iron or inborn errors of metabolism; lactic acid; ethylene glycol; salicylates). This approach is usually sufficient for the majority of cases in the emergency department; however, there are many other etiologies not addressed in this mnemonic. Organic acids including 5-oxoproline (pyroglutamic acid) are rare but important causes of anion gap metabolic acidosis. We present the case of a patient with profound metabolic acidosis with raised anion gap, due to pyroglutamic acid in the setting of malnutrition and chronic ingestion of acetaminophen. PMID- 20925169 TI - Acute compartment syndrome of the dorsal forearm following noncontact injury. AB - Acute compartment syndrome is a limb-threatening condition in which early diagnosis and surgical consultation for fasciotomy are required to preserve functional outcome. The diagnosis is typically considered in patients with traumatic mechanisms of injury such as a direct blow and crush to the compartment, particularly when there is a fracture in the same compartment. We report the case of a patient with acute compartment syndrome of the dorsal forearm that occurred as a result of an atypical noncontact traumatic mechanism. Establishing the diagnosis of compartment syndrome was complicated in this patient, as some of the signs and symptoms of acute compartment syndrome could have been attributed to the presence of a coexisting rupture of the extensor digitorum muscle. This report serves to remind emergency physicians that, although rare, acute compartment syndrome can result from exertional and noncontact traumatic mechanisms. PMID- 20925170 TI - Dantrolene for the treatment of MDMA toxicity. AB - MDMA (3,4-methylenedioxymethamphetamine), popularly known as "Ecstasy," was first introduced and patented by Merck & Co., Inc., in 1914 as an appetite suppressant. Currently, its primary role is as an illegal stimulant used to produce a euphoric effect during parties. This case report de scribes a 31-year-old man who, after taking 3 tablets of Ecstasy, presented to an emergency department with a decreased level of consciousness and became progressively hyperthermic and rigid. During the course of his acute illness, his temperature reached 42.2 degrees C rectally. He was given mechanical ventilation. He was aggressively cooled and dantrolene was initiated. Soon after the administration of dantrolene his temperature decreased and his rigidity began to resolve. The only complication was rhabdomyolysis with a creatine kinase level increasing to over 150 MUkat/L. This did not progress to acute renal failure. The patient made a full recovery and was discharged to psychiatry for assessment. PMID- 20925171 TI - Comments on pinnipeds in JAVMA cover art. PMID- 20925172 TI - [Positive affect and cardiovascular health]. PMID- 20925173 TI - [Patient's emotional reactions in cardiac rehabilitation: analysis and perspectives]. AB - SUBJECT: Evaluation and treatment of psychological diseases are often included in cardiology rehabilitation programs. The aim of this study was to analyze the emotional reactions in a very consistent sample of cardiac patients, hospitalized for a rehabilitation program. MATERIALS AND METHODS: The sample consisted of 5417 patients, 4563 males and 854 females, with a mean age of 57.36 +/- 9.15 (range 18 83). They were admitted in the period between 1995 and 2005 and completed the Cognitive Behavioral Assessment, Hospital form (CBA-H). RESULTS: Significant level of state- anxiety was shown by 27.8% of the subjects, 22.1% reported health related fears and 10% depressive symptoms. Women show higher scores in all of the three scales, and patients over 65 years scored higher in the depression scale. It is interesting to note that the mean scores in the three scales showed a progressive and significant decrease over the years. CONCLUSIONS: These data confirm that an accurate psychological screening can be extremely useful to support the Psychologist working in cardiac rehabilitation as it helps to plan more specifically the interventions, focusing on the objective patients' educational and psychological needs. PMID- 20925174 TI - Information about secondary prevention in coronary patients: a comparison between Italian and Brazilian application of MICRO-Q questionnaire. AB - BACKGROUND: The MICRO-Q (Maugerl CaRdiac preventiOn Questionnaire) is a self administered questionnaire addressed to the evaluation of information regarding secondary prevention in patients with coronary heart disease (CHD). The aim of this study was to compare the results from Italian and Brazilian application of MICRO-Q. METHODS: the instrument was administered to 500 coronary patients (250 Italian and 250 Brazilian), 117 female and 383 male, aged on average 61.16 years (SD = 9.74; range: 33-86), participants of cardiac rehabilitation programs. The Italian MICRO-Q has 26 items, 18 true statements and 8 false, with responses true, false and 'don't know', with three separate scores: correct, uncorrect and uncertain. The Brazilian MICRO-Q has 25 items, 18 true statements and 7 false, with the same responses and scores. To verify and compare results we used Independent-Sample T Test, ANOVA and Bonferroni Post-hoc. RESULTS: The analysis of mean total scores of Italian and Brazilian applications showed statistically significant differences for correct answers (p < 0.001) and for 'don't know' answers (p < 0.001). 18 statements had significant (p < 0.005) differences between applications in the two countries. CONCLUSION: Despite differences between Italy and Brazil, the analysis of MICRO-Q applications showed a similar mean score percent of correct answers, indicating enough knowledge about secondary prevention of CHD. PMID- 20925175 TI - Predictors and early outcome of prolonged mechanical ventilation in contemporary heart valve surgery. AB - BACKGROUND: During last decades mechanical ventilation has been an important support in the postoperative management of patients undergoing cardiac surgery. This study was designed to determine the predictors of prolonged mechanical ventilation (PMV) in patients undergoing heart valve surgery. METHODS: This retrospective study considered of 1056 patients who underwent isolated valve surgery at Tehran Heart Center from March 2002 to March 2009. PMV is considered as mechanical ventilation period of > or =24 hours at postoperative hospital stay in this study. RESULTS: PMV occurred in 6.6% of patients. Initial ventilation hours, atrial fibrillation, cardiac arrest and reintubation were the most prevalent postoperative complications. Preoperative renal failure, postoperative stroke, intra aortic balloon pump insertion, emergent operation, complete heart block, longer perfusion time were independent predictors of PMV in our patients. CONCLUSION: PMV is associated with significant comorbidities and increased hospital mortality. Strategies to delineate the patients at risk and to modify these risk factors by prophylactic measures should probably lead to a lower incidence of prolonged mechanical ventilation for patients undergoing isolated valve surgery. PMID- 20925176 TI - [Non ST ergometric variables in the diabetic patient and their prognostic significance]. AB - BACKGROUND: Recent research based on large number of patients has demonstrated that there are strong exercise predictors of cardiovascular events other than ST segment behaviour. Studies focused on non-ST segment variables in exercise testing (exercise capacity, chronotropic and pressure response, heart rate recovery) in diabetics are lacking. The aim of our study is to find out differences in the exercise-testing variables between diabetics and non and to evaluate their prognostic role. METHODS: We analyzed non ST-variables in 1172 patients undergoing exercise testing with Bruce protocol: diabetics vs. non diabetics: n=83 (7%) vs n=1089 (93%); mean age: 64.37 +/- 8.44 vs 60.44 +/- 11.44; males: n=56 (67.47%) vs n=665 (61.06%). Mean follow-up was 13.5 +/- 4 months. RESULTS: Follow-up data were available in 74 diabetics (89%), 14 (18,9%) presented cardiac events (death, infarction, coronaric revascularization, heart failure). Diabetics with events showed significantly worse 1st min Heart Rate (HR) and 3rd min Systolic Blood Pressure (SBP) recovery. CONCLUSIONS: Preliminary results highlight that non-ST variables (exercise time, chronotropic response, heart rate and blood pressure recovery) are significantly different in diabetics. Abnormal HR and SBP recovery identify a subgroup of diabetics at higher risk of cardiac events in the follow-up. PMID- 20925177 TI - An uncommon clinical condition: chronic thrombosis of the inferior vena cava. A case report and review of literature. AB - The lifetime incidence of deep vein thrombosis (DVT) is approximately 0.1% in general population and even more uncommon in subjects below 40 years of age. Thrombosis of the inferior vena cava (IVC) is an exceptionally rare clinical condition, with etiological factors similar to lower limb DVT. We present a case of post-traumatic chronic obstruction of the IVC in 41 years-old man, caused by a prolonged squatted position, while he was working as a bricklayer. We visited the patient fifteen years after the onset of the first clinical setting showing a severe post thrombotic syndrome, as a consequence of the already diagnosticated thrombosis, involving predominantly the right inferior leg. Thrombophilia screening tests showed patient to be a heterozygous carrier of methylenetetrahydrofolate reductase (MTHFR) gene mutation. Computed tomography (CT) scan confirmed the thrombotic obstruction of the infrahepatic IVC, both common iliac veins, right external and internal iliac veins, with multiple collateral pathways. Because of thrombosis extension, inherited prothrombotic condition and the young age of the patient, we decided to continue life-long oral anticoagulant therapy. PMID- 20925178 TI - Unusual case of myocardial injury induced by Escherichia coli sepsis. AB - The typical symptoms and signs of myocardial infarction are well known. Alterations in electrocardiogram (ECG), echocardiography or biochemical markers of myocardial necrosis are usually helpful to confirm the diagnosis. Some of these features, however, also occur in myocarditis, which is a potential differential diagnosis. We describe an unusual case of bacterial sepsis due to Escherichia coli that caused myocardial damage (myocarditis) with ECG changes mimicking acute myocardial infarction. The possible pathophysiological mechanisms of myocardial injury in sepsis are also reviewed. PMID- 20925179 TI - [Association of diet, exercise, and smoking modification with risk of early cardiovascular events after acute coronary syndromes]. PMID- 20925180 TI - [Job strain predicts recurrent events after a first acute myocardial infarction: The Stockholm Heart Epidemiology Program]. PMID- 20925182 TI - [Ethics and psychiatry]. PMID- 20925183 TI - [What are the ethics of care in mental health disorders?]. AB - Psychiatry is undergoing a major crisis, on both an institutional as well as a clinical level. Numerous players involved in psychiatry feel in difficulty and are increasingly raising questions as to what direction and meaning to give to their practice. It is in such a context that ethics can help us to progress, reflect and build the future together. It is high time to create the specific basis of ethics in psychiatry. PMID- 20925184 TI - [Mental health film festival and ethics]. AB - The mental health film festival is based on the respect of the patient as a subject and is a place where psychic suffering can be expressed. As a film is destined to be shown, there is a dilemma between the aesthetic and the therapeutic aspects and, it's in this link that the ethical dimension concerned by this kind of activity takes place. PMID- 20925185 TI - [Which policy for mental illness? Interview by Elisa Godart]. PMID- 20925186 TI - [The ethics of the nursing commitment in psychiatry]. AB - The referral nurse represents the care environment, he/she is the guarantor of the care plan and forms a commitment with regard to the patient. This positioning, arising from the empathy he/she has for the patient in a situation of vulnerability, may lead him/her to object to and question a medical decision. PMID- 20925187 TI - [Child psychiatry, the question of a kiss]. AB - What should child psychiatry care workers do when a child spontaneously embraces or kisses them? This questioning goes far beyond the fact of kissing and raises the question of the nature of the healthcare relationship and environment. While theoretical knowledge is necessary, it is not sufficient for achieving phronesis or "practical wisdom". PMID- 20925188 TI - [From policy to unique care in psychiatry, the place of ethics]. AB - Ethical reflection is an aid to psychiatrists in their role as caregiver and policy implementer. Ethics takes root in commitment, the act of resistance enables the caregiver not to be carried away by the dominant approach, but rather to be an individual subject respecting the singularity of others. PMID- 20925189 TI - [Ethics and psychiatry]. PMID- 20925190 TI - [The creation of an art workshop within a hospital]. AB - Organising an arts activity within a hospital unit is not simple. But if it is well thought out and forms part of a healthcare process, it can have an important role to play. An example at Montperrin hospital in Aix-en-Provence. PMID- 20925192 TI - [3/7. Psychiatric hospitals]. PMID- 20925191 TI - [Pathological gambling and psychiatric patients]. AB - There is a high prevalence of pathological gambling amongst the general population, but especially amongst subjects with psychiatric comorbidities with mood disorders or dependence on psychoactive substances. Early detection of this problem and a global, psychological, psychiatric and social treatment are essential for these patients, who are often in very difficult situations. PMID- 20925193 TI - [How the Feast of Corpus Christi at the psychiatric hospital of Sarthe became a historical event]. AB - Can the historian, passionate about archives, build a historical narrative based mainly on the memories of nurses? Could the caregivers, who are themselves players in the history of psychiatry write it? When the former hears the individual accounts of the latter, history is written. The history of the Feast of Corpus Christi at the psychiatric hospital of Le Mans. PMID- 20925194 TI - NFAT regulates CSF-1 gene transcription triggered by L-selectin crosslinking. AB - L-selectin is a member of the selectin family that play an important role both in mediating the initial capture and subsequent rolling of leukocytes along the endothelial cells. Furthermore, L-selectin can function as a signal molecule. In our previous studies, we reported that L-selectin ligation could regulate CSF-1 (colony-stimulating factor-1) gene transcription, in which AP-1 acts as a crucial transcriptional factor. Here we investigated the function of the NFAT in the CSF 1 gene transcriptional events. We found that overexpression of WT NFAT induce CSF 1 gene transcription greatly in the activated Jurkat cells. Furthermore, we found that NFAT can be recruited to the nucleus after L-selectin ligation, and the nuclear NFAT interacts with the CSF-1 promoter region to regulate CSF-1 gene transcription in the L-selectin ligation activated Jurkat cells. These results indicate that nuclear NFAT can activate CSF-1 gene transcription by connecting with the CSF-1 promoter in the signaling events induced by L-selectin ligation. PMID- 20925196 TI - In vitro effects of 2-methoxyestradiol-bis-sulphamate on cell growth, morphology and cell cycle dynamics in the MCF-7 breast adenocarcinoma cell line. AB - In the search for new and improved anticancer therapies, researchers have identified several potentially useful compounds. One of these agents is 2 methoxyestradiol-bis-sulphamate (2ME-BM), a sulphamoylated derivative of 2 methoxyestradiol. The objective of this study was to evaluate 2ME-BM's in vitro efficacy as antiproliferative agent in the MCF-7 breast adenocarcinoma cell line. Light- and fluorescent microscopy showed decreased cell density, increased apoptotic characteristics and significant ultrastructural aberrations indicative of autophagic cell death after 24 hours of exposure at a concentration of 0.4 microM. In addition, mitotic indices revealed that 2ME-BM induces a G2M block. The latter was confirmed by flow cytometric analyses where increased sub-G1 and G2/M fractions, as well as an increase in cyclin B1 levels were observed. Further in vitro research into the mechanism of this potentially useful anticancer compound is thus warranted. PMID- 20925195 TI - Variable number tandem repeats in the promoter region of prostacyclin synthase gene in choline deficient rats. AB - Weanling Sprague-Dawley rats were fed on a choline-deficient diet with hydrogenated vegetable oil and corn oil as lipids develop acute renal failure. Pathogenesis of the latter is controversial and an ischemic mechanism has been proposed. Arachidonic acid derivatives are involved in the regulation of vascular tonus. Vasospasm could be due to an increase in tromboxane A2-mediated vasoconstriction or to a decrease in prostacyclin-induced vasodilatation. Enzymes involved in the synthesis of both compounds are tromboxane A2- and prostacyclin synthase respectively. The aim of this study was to identify the variable number tandem repeats (VNTR) in the promoter region of prostacyclin synthase gene and verify if there exists a relationship between the occurrence of VNTR in those choline-deficient rats which die because of acute renal failure and those which do not. We verified the presence of the VNTR in the prostacyclin synthase rat gene, but we did not find any difference in the molecular weight of the alleles between experimental and control rats. Renal reparation of the acute kidney injury due to choline deficiency in some rats is not related with differences in VNTR in the promoter region of the prostacyclin synthase gene. PMID- 20925197 TI - Nuclear pores in luteal cells during pregnancy and after parturition and pup removal in the rat. A freeze-fracture study. AB - In a previous paper we described a pronounced increase of apoptotic nuclei in rat corpus luteum of pregnancy whose programmed chromatin degeneration was induced by the progesterone antagonist mifepristone. Those observations encouraged us to study the apoptotic nuclear membrane during pregnancy and after parturition and pup removal, by using a freeze-fracture technique which allows us to observe 'en face' the nuclear envelop and also permits nuclear pore counting. This study was complemented with the TUNEL assay (TdT-mediated dUTP nick-end labelling). Changes in nuclear pores during pregnancy begin with an intense reduction in number but still showing an even distribution on the nuclear membrane, never forming aggregations sharply separated from pore-free areas, which are characteristic of other apoptotic models. Electron microscopy of thin-sections shows, coincidently with findings in the freeze-fracture replicas, a moderately irregular aggregation of marginal heterochromatin condensations. After nuclear fragmentation and micronuclear formation, pores behave in the usual manner in other apoptotic models, i.e., mainly showing migrations of nuclear pores toward the chromatin free areas. The present results support the hypothesis that nuclear pore complexes are dynamic structures, which permit their migration toward nuclear membrane areas devoid of chromatin aggregations that might block the nucleocytoplasmic transport in such areas. PMID- 20925198 TI - CD44 is involved in CXCL-12 induced acute myeloid leukemia HL-60 cell polarity. AB - CXCL-12 and its receptor CXCR4 participate in breast cancer and melanoma cell metastasis to bone and lymphoid nodes. CD44, as a receptor for hyaluronic acid, is involved in lymphocyte recirculation, homing, adhesion and migration. But the role of CD44 in CXCL-12 induced leukemia cell migration still remains unclear. The present study showed that CXCL-12 stimulation induced the rapid internalization of CXCR4 and facilitated the formation of lamellipodia and uropod in acute leukemia cell line HL-60. CXCL-12 also induced CD44 translocation into the uropod, while CD44 remained evenly distributed on the untreated cell membranes. Results suggest that CD44 participates in CXCL-12 induced cell polarization and subsequent cell migration. PMID- 20925199 TI - Conflict of interest in peer-reviewed medical journals: the World Association of Medical Editors (WAME) position on a challenging problem. PMID- 20925200 TI - The Medical Council of India guidelines on industry-physician relationship: breaking the conspiracy of silence. PMID- 20925201 TI - Effect of a single dose of diethylcarbamazine, albendazole or both on the clearance of Wuchereria bancrofti microfilariae and antigenaemia among microfilaria carriers: a randomized trial. AB - BACKGROUND: Lymphatic filariasis is a major vector-borne parasitic disease. The global programme to eliminate lymphatic filariasis was launched in 1997 and currently over 570 million people are covered under it in 48 countries. Mass annual single-dose drug administration of diethylcarbamazine (DEC), co administrated with albendazole for 5-6 years and mass distribution of diethylcarbamazine-fortified salt are the two strategies for elimination of filariasis. METHODS: Asymptomatic volunteers residing in Puducherry, India were screened for microfilaria (mf) by examining nocturnal thick blood smears. Those testing positive were randomly assigned to receive a single dose of DEC (6 mg/kg body weight) or albendazole 400 mg or both. Participants were hospitalized for 5 days. Membrane filtration count was used to assess microfilaraemia and ELISA (Og4C3) assay to measure circulating filarial antigens (CFA). Measurements were done before treatment and at 1, 2 and 3 years post-treatment. Viability of the adult worms was assessed by looking for the filarial dance sign (FDS) using ultrasound examination of the scrotum in men with hydrocele. RESULTS: Fifty-four microfilaraemic Individuals were studied. The mf prevalence started decreasing only by day 180 posttreatment in the DEC group but much earlier in the other two groups (day 30 in the albendazole and day 90 in the DEC with albendazole group). The decrease in mfwas marginal (17.6%, 26.3% and 27.8%, respectively) by the end of year 1 posttreatment, but significant (96.7%, 78.6% and 93.3%, respectively) by the end of year 2 post-treatment (p < 0.05). By the end of year 3, the level decreased to 80% in the DEC, 90% in the albendazole and to 100% in the DEC and albendazole groups. However, the mf intensity decreased significantly (by 39%; p < 0.05) by day 7 post-treatment in both the DEC and DEC with albendazole groups, but only by day 30 in the albendazole group. In all the drug groups, the prevalence as well as intensity of CFA returned to pretreatment levels by the end of year 3 post-treatment. CONCLUSION: Annual single-dose administration of all the 3 drug regimens significantly reduced antigenaemia levels. There were no significant differences in the efficacy and overall pattern of CFA clearance between the 3 drug regimens. PMID- 20925202 TI - Circulating angiogenic factors in pregnancies complicated by pre-eclampsia. AB - BACKGROUND: Pre-eclampsia is an inflammatory disorder characterized by diffuse endothelial dysfunction possibly secondary to impaired trophoblast invasion of the spiral arteries during implantation. It is associated with alterations in maternal serum concentrations of vascular endothelial growth factor (VEGF), placental growth factor (PIGF) and soluble fms-like tyrosine kinase-1 (sFlt-1). We did a case-control study to ascertain whether pre-eclampsia is associated with changes in serum concentrations of VEGF, PIGF and sFlt-1 in Indian patients. METHODS: Serum samples were obtained from 40 women with pre-eclampsia and 40 normotensive, non-proteinuric pregnant women. The levels of VEGF, PIGF and sFlt-1 were analysed using ELISA. RESULTS: In the sera of pregnant women with pre eclampsia, the levels of sFlt-1 were significantly higher than those in the sera of normotensive, non-proteinuric pregnantwomen (median 11295.25 v. 2936.2 pg/ml, p < 0.0001), whereas there was a significant reduction in the levels of free VEGF (mean [SD] 170.53 [36.56] pg/ml v. 254.61 [47.39] pg/ml, p < 0.0001) and PIGF (mean [SD] 236.77 [93.70] pg/ml v. 744.98 [168.55] pg/ml, p < 0.0001). CONCLUSION: An increase in sFlt-1 levels and a simultaneous decrease in free VEGF and PIGF levels in the sera of women with pre-eclampsia as compared with normotensive, nonproteinuric pregnant women suggest that an imbalance between the levels of these pro- and anti-angiogenic factors'may have a role to play in the pathogenesis of pre-eclampsia. PMID- 20925203 TI - Environmental factors of households in five districts of Kerala affected by the epidemic of chikungunya fever in 2007. AB - BACKGROUND: Two epidemics of chikungunya fever were reported from Kerala in 2006 and 2007. We aimed to investigate the environmental factors of households affected by chikungunya fever and to estimate the proportion of population that suffered from the disease during the epidemic in 2007. METHODS: A cross-sectional survey was conducted in the 5 heavily affected districts of Kerala during October November 2007. The 2-stage sampling technique was used to collect data from 10 clusters, each having 18 houses from every district, by interviewing the subjects using a structured questionnaire. The sample size was 900. RESULTS: The proportion of the population affected by chikungunya fever was 57.1% (95% CI: 52.8%-61.4%). There was a significant association between location of houses and disease status. Houses located near a public conveyance facility (within 250 m) were relatively protected from the disease (OR 0.19 [0.06-0.60]). About 69% of the households perceived mosquito infestation as a problem and 46.6% used fumes to avoid mosquitoes. More than 42% of households were not using any anti-mosquito measures at the time of the survey. Stored drinking water was the most common potential breeding source in the houses (23.5%). Households which did not store water inside were protected from the disease (OR 0.22 [0.08-0.65]). CONCLUSION: The study indicated the persistence of favourable domestic and environmental factors after the epidemic, reflecting the necessity to strengthen anti-mosquito campaigns. PMID- 20925204 TI - CD46 polymorphism: a probable risk factor for recurrent spontaneous abortion in a northern Indian population. AB - BACKGROUND: CD46 is a complement regulatory glycoprotein. Certain polymorphic forms of the CD46 gene have been associated with recurrent pregnancy loss in the Caucasian population. We assessed the role of CD46 polymorphism in recurrent spontaneous abortion in our setting, as this has not been done on Indian subjects till date. METHODS: Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was carried out on 44 samples each from women with recurrent spontaneous abortion and normal pregnancy. Genotyping of the CD46 gene was done using 2.5% agarose gel. Statistical analysis was done using the TFPGA software. RESULTS: The absence of CD46H*1 homozygosity was more pronounced in women with recurrent spontaneous abortion in the Indian population. Of recurrent aborters, 9% had the H*1/*l genotype as compared to 30% of normal pregnant women. CONCLUSION: Although our data did not fit the Hardy-Weinberg equilibrium, this pilot study indicates that further increasing the sample size might clarify whether polymorphism in the first intron of the CD46 gene can be regarded as a risk factor for recurrent spontaneous abortion. PMID- 20925205 TI - Post-kala-azar dermal leishmaniasis (PKDL), HIV and pulmonary tuberculosis. AB - Post-kala-azar dermal leishmaniasis is usually a sequel to visceral leishmaniasis. A 25-year-old woman presented with hypopigmented maculopapular lesions all over the body for the past 4 years without any previous history of visceral leishmaniasis. She was on treatment for leprosy and pulmonary tuberculosis for the past 2 months, but did not show any improvement. Investigations confirmed that she had post-kala-azar dermal leishmaniasis associated with pulmonary tuberculosis and HIV-1 infection. She was started on treatment for the triad of diseases, and showed improvement. PMID- 20925206 TI - Should Vi typhoid vaccine be a part of the National Immunization Programme in India? PMID- 20925207 TI - Coffee and progression of liver disease. PMID- 20925208 TI - Chronic abdominal pain in children. AB - Chronic abdominal pain (CAP) continues to be a diagnostic and therapeutic challenge. It affects about 10% of school-going children and adolescents. Few Indian studies have reported an organic cause in 30%-40% of children with recurrent abdominal pain. In developing countries, parasitic infestations such as giardiasis and ascariasis are an important cause, of recurrent abdominal pain but their frequency has decreased over time. There is a paucity of data from India on the aetiology, epidemiology and management strategies for CAP, and there is no consensus on the clinical approach to this problem. We present a practical approach to CAP in children. The first step is to elicit a detailed history and do a thorough physical examination so as to categorize CAP according to the site of pain (epigastric, periumbilical or left lower quadrant), the predominant symptom associated with pain (dyspepsia, isolated pain or altered bowel habits) and to differentiate the pain as organic or functional based on the characteristics of pain and presence or absence of alarm signs. The second step is to do appropriate investigations, restricted to simple tests when functional pain is suspected (Level I) and more investigations (Level Ia) if there are alarm signs and pain appears to be organic in nature. Invasive investigations such as gastrointestinal endoscopy (Level II) may be reserved for those with possible organic pain. Level III investigations need to be done in a small percentage of children and include EEG, workup for food allergy and porphyria. The third step is management of organic CAP according to the aetiology, while for functional CAP the pharmacological and, rarely, psychological intervention is more difficult but should be done discreetly and tailored to the needs of the child. PMID- 20925209 TI - Mini-clinical examination (CEX) as a tool for formative assessment. PMID- 20925210 TI - The problem of compliance. PMID- 20925211 TI - An interesting meeting on medical ethics. PMID- 20925212 TI - Mental stress among medical students. PMID- 20925213 TI - Nurses: our standard-bearers. PMID- 20925214 TI - A glimmer of hope for prevention. PMID- 20925215 TI - Doctor, did you wash your hands? PMID- 20925216 TI - Madras Medical College: 175 years of medical heritage. PMID- 20925217 TI - Dr. Kotnis and China. PMID- 20925218 TI - Public health in India: law alone is insufficient for social change. PMID- 20925220 TI - Impact of personalized medicine on diagnostics and therapeutics. PMID- 20925221 TI - [Ethics in neonatal intensive care]. AB - Work summarises current data ideas of problems of ethical thinking and decision making in neonatology. Primary objective ethical questions of administration resuscitative and intensive care are outlined, as well as administration of care for babies, delivered on limit of viability, in the same way for children with high probability of serious damage in case of survival. Role of parents in decision making about to other administration care is discussed, some recommendation and instructions for communication with parents are handed up. Findings of extensive european study named EURONIC are shortly mentioned, study concerns problems of ethical dilemmas in neonatology in 8 European countries. Finally the categorization of newborns in ethical thinking is mentioned and present circumstances in Czech republic are remarked. PMID- 20925219 TI - Cortical venous thrombosis due to acquired hyperhomocysteinaemia. PMID- 20925222 TI - [Shoulder dystocia during vaginal delivery]. AB - Shoulder dystocia is defined as a complication of vaginal delivery that requires additional obstetric manoeuvres to release the shoulders of the baby. Reported incidence of shoulder dystocia is around 0.6-1.4%. Serious perinatal morbidity is associated with this type of complication. Brachial plexus injuries are one of the most important fetal complications of shoulder dystocia. Some cases results in permanent brachial plexus dysfunction. A high level of awareness and training for all birth attendants is recommended. The purpose of this article is to review the current evidence regarding the possible prediction and management of shoulder dystocia. PMID- 20925223 TI - [Perinatal brachial plexus palsy]. AB - Upper limbs palsy as a result of affliction of plexus brachialis nervous bunch is disorder, whose frequency moves among 0.42-5.1 / 1000 liveborn children. Delivery mechanism itself certain weighty, no however only cause rising paralysis. Some way paralysis rise already intrauterinne, some way then at surgical childbirth per sectionem caeseream. Brachial plexus palsy isn't benign disorder. If isn't this disorder in time diagnosed and accordingly treated, child threatens late aftermath, especially significant limitation of limbs movement with functional consequencies. PMID- 20925224 TI - [Repair of the 3rd and 4th degree obstetric perineal tear]. AB - OBJECTIVE: Summary of the current knowledge of repair of obstetric anal sphincter trauma. DESIGN: Review. SETTING: Department of Gynecology and Obstetrics, Charles University and University Hospital Pilsen. SUMMARY: Review of the current international literature covering the given problem. RCOG classification of obstetrics perineal trauma should always be used as it respects the anatomic structures together with the physiological functions of tissue involved in ano rectal continence. Two types of procedure: end-to-end approximation and overlapping of torn ends of the anal sphincter are both referred to and they are discussed with regards to the functional outcome of the repair. OPERATING CONDITIONS: Experience of the surgeon, operating theatre and its equipment, asepsis, lighting, operating instruments, anesthesia, material and type of suture, medication is described to increase the effectiveness of the repair. A delay in primary repair of up to 8-12 hours does not seem to be detrimental to the functional outcome of the procedure. Uncommon types of injury mentioned: segmented tear of internal anal sphincter, lateral tear of external anal sphincter. PMID- 20925225 TI - [Severe obstetrical injuries and anal incontinence]. AB - OBJECTIVE: Commentary to article. SUBJECT: Review article. SETTING: Gynecological and obstetrical clinic, First Faculty of Medicine and Faculty hospital Bulovka, Prague. SUBJECT AND METHOD: A summary of findings of the newest studies indicated on Medline. CONCLUSION: The problem of anal incontinence has a significant impact on the quality of life after its occurence and has an incidence of about 1.4% of the population. One of the risk factors is vaginal delivery. The prevalence of postpartal anal incontinence was found in one individual study to be 3-29%, the differences are certainly based on the type of questions. The same fluctuations and prevalence of anal sphincter injuries in one individual study was from 1.6 to 26.9%. The problem calls for a simple classification of obstetrical injuries and lacks a recommended approach to preventing and providing care for women with obstetrical injuries of the anal muscle sphincter. PMID- 20925226 TI - [Recombinant activated factor VII in the treatment of life threatening post partum haemorrhage; registry UniSeven in the Czech Republic]. AB - OBJECTIVE: To analyze the data related to the treatment of 80 Czech patients with life threatening postpartum haemorrhage recorded in the clinical registry UniSeven during years 2004-2009. DESIGN: Retrospective, observational, multicentre study. SETTINGS: ICU and Obstetrics departments of University and Regional hospitals in Czech Republic. MATERIAL AND METHODS: UniSeven is an international academic project of Masaryk University in Brno, Czech Republic, focused on recording of clinical data related to "off-label" use of rFVIIa (Novo Seven) in life threatening bleeding. Data of 80 case reports of post partum haemorrhage from the registry was analysed from the clinical (efficacy and safety) as well as laboratory aspects. RESULTS: In 97.5% of our patients the treatment with rFVIIa was able to control the bleeding. In 53 women (66.3%) only one dose of rFVIIa was sufficient to control the bleeding. The rest of the patient received two or more rFVIIa doses. First dose of rFVIIa given to patients who needed more than one dose was significantly lower (96.6 microg/kg) compared to patient succesfully treated with one dose only (110.6 microg/kg; p = 0.048). The mortality rate in our cohort of patients was 2.5%. We have not recorded any thrombembolic event as and adverse event related to the rFVIIa treatment. In 74.3% of patients where rFVIIa was administered before considering the hysterectomy, it was able to avoid hysterectomy what we consider to be a significant improvement of the patients' quality of life. CONCLUSIONS: Our data were also considered during the work up of national guidelines for the treatment of life threatening post-partum haemorrhage in the Czech Republic. PMID- 20925227 TI - [Thrombotic thrombocytopenic purpura in pregnancy. Case report]. AB - OBJECTIVE: Description of case of patient with rare thrombotic thrombocytopenic purpura in pregnancy. SUBJECT: Case report. SETTING: Department of Gynecology and Obstetrics, Charles University and University Hospital Motol, Prague. CONCLUSION: Thrombotic thrombocytopenic purpura (TTP) is a rare and substantial disorder characterized with combination of microangiopathic haemolytic anemia, consumption trombocytopenia and symptoms of organs dysfunction--especially kidneys and neurological deficiency. It's caused by production of microthrombi affecting small blood vessels. These palatelets-rich microtrombi are formed due to deficiency of the enzyme ADAMTS13--metalloprotease which is responsible for cleaving of ultralarge multimers of von Willebrand factor into smaller units. In our case report we describe patient with TTP in pregnancy. Therapy with corticosteroids and immunoglobulines was not effective, improvement of thrombocytopenia appeared after plasmapheresis (total count 14). The delivery was induced at term without complications. Target examination confirmed diagnosis of secondary TTP. PMID- 20925228 TI - [Uterine rupture in pregnancy--case study]. AB - OBJECTIVE: Analysis of two cases uterine rupture following caesarian section. SUBJECT: Two case studies. SETTING: Gynecological obstetrics clinic, First Medical Faculty and Faculty Hospital Bulovka, Prague. SUBJECT AND METHODS: The authors in their article describe two cases of rupture of the uterus in pregnancy prior to delivery. In both cases there was a history of cervicocorporal caesarian section. CONCLUSION: In the first case the patient was admitted from her home with bleeding, and signed a nonconsent form. The second case concerned a hospitalized patient, in which the first signs of uterine rupture were indicated by fetal heart rate. Both women underwent hysterectomy, paradoxically, in the first case the child was saved and discharged home in good health. PMID- 20925229 TI - [Analysis of cell free fetal DNA fragmentation rate in pregnant women during the course of gravidit]. AB - AIM OF STUDY: To assess cell free fetal DNA (cffDNA) fragmentation rate in pregnant women during the course of gravidity. STUDY DESIGN: QF PCR efficiency in cffDNA and quantitative analyses in particular cffDNA molecular size fractions. SETTING: The study was performed at Department of Medical Genetics and Fetal Medicine, University Hospital Olomouc. METHOD: 1. 363 plasma DNA samples from women in different week of pregnancy (from 4th w.g. to 37th w.g.) were tested for QF PCR efficiency in particular STRs and AMELX/Y. 2. Size fractionated cff DNA (150-300 bp, 300-500 bp, 500-760 bp) was quantified by QF PCR in 91 pregnant women (from 9th w.g. to 40th w.g.). 3. Size fractionated cff DNA from male fetuses was quantified by real time PCR (SRY/internal control) in 22 pregnant women (from 9th w.g. to 36th w.g.). RESULTS: 1. QF PCR efficiency decreased from longer to shorter molecules. 2. The only 500 -760 bp fraction showed cffDNA increase in relation to week of gravidity. 3. Indirect relation between amount of cffDNA and week of gravidity was found in 150-300 bp fraction by Real-time PCR. CONCLUSION: Assembling of all 3 approaches indicates increase of longer cffDNA molecules during the gravidity while level of the short cffDNA molecule fragments probably remains from the approximately 9th w.g. the same. PMID- 20925230 TI - [DNA analysis on Y chromosomal AZF region deletions in Slovak population]. AB - OBJECTIVE: Study on Y chromosomal AZF region deletions in Slovak population, application of DNA technique. DESIGN: Genetic-prospective study. SETTING: Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University in Bratislava. METHODS: For detecting microdeletions in the Y-chromosomal AZF region in men with fertility disorders and for identifying Y-specific sequences we used the method of polymerase chain reaction (PCR) with using three different sets of sY sequences. For a verification of the specific type of deletion we used also fluorescently labeled kit. RESULTS: Diagnoses of referred patients were divided into 2 groups: azoospermia, oligospermia. In the followed-up group of 822 patients there were 349 patients with azoospermia, 473 patients with oligospermia. Globally we reported 38 cases of deletions in the AZF region of the Y chromosome, i.e. 4.62%. 24 patients with deletion are from the group of patients with azoospermia, i.e. 6.88%, 14 patients are from the group of patients with oligospermia (2.95%). Considering particular types of deletions we recorded deletions in each region, AZFa, AZFb and AZFc, combinated AZFbc deletion, but also a complete deletion of the whole AZF region. CONCLUSION: The study confirmed that detection of microdeletions of the AZF region is significant from diagnostic and prognostic view and it pointed out the importance of selection criteria for selecting patients. PMID- 20925231 TI - [Guideline for prevention of RhD alloimmunization in RhD negative women]. AB - Events following which anti-D immunoglobulin should be given to all RhD negative women with no anti-D antibodies: First trimester indications (50 microg)- termination of pregnancy, spontaneous abortion followed by instrumentation, ectopic pregnancy, chorionic villus sampling, partial molar pregnancy; Second and third trimester indications (100 microg)--amniocentesis, cordocentesis, other invasive prenatal diagnostic or therapeutic procedures, spontaneous or induced abortion, intrauterine fetal death, attempt at external cephalic version of a breech presentation, abdominal trauma, obstetric haemorrhage; Antenatal prophylaxis at 28th weeks of gestation (250 microg); Delivery of an RhD positive infant * (100 microg); Minimal dose: before 20 weeks gestation--50 microg (250 IU), after 20 weeks gestation **--100 microg (500 IU); Timing: as soon as possible, but no later than 72 hours after the event. In cases where prevention of RhD alloimmunization is not performed within 72 hours of a potentially sensitising event, it is still reasonable to administer anti-D immunoglobulin (IgG anti-D) within 13 days, and in special cases, administration is still recommended up to a maximum interval of 28 days postpartum.; FMH (fetomaternal haemorrhage)--If the amount of fetal erythrocytes which entered the maternal circulation is quantitatively determined, administration of 10 microg IgG anti-D per 0.5 ml of fetal erythrocytes or 1 ml of whole blood is indicated. *also if the RhD type of the infant has not been determined or is in doubt, **in conjunction with a test to assess the volume of any fetomaternal hemorrhage. PMID- 20925232 TI - [Pregnant women alloimmunisation of non-RhD erythrocyte antigens: review article]. AB - OBJECTIVE: The aim of this review is to give comprehensive summary on alloimmunisation of non-RhD erythrocyte antibodies. DESIGN: Review. SETTING: Department of Obstetrics and Gynecology, University Hospital Ostrava, Department of Obstetrics and Gynecology, University Hospital Olomouc. SUBJECT AND METHOD: Based on literature analysis using database search engines PubMed, Google Scholar, Ovid and Proquest in field of non-RhD erytrocyte antibodies, there has been summarized up-to-date knowledge on irregular antibodies. CONCLUSION: Pregnant women alloimmunisation of non-RhD erythrocyte antigens gather importance in conjunction with relative increase of their occurence. Profylaxis is not possible. Although these erythrocyte antigens are able to induce antibody responce in mother and result in subsequent hemolytic disease of fetus and newborn. There are discussed most frequent non-RhD antibodies in the paper. PMID- 20925233 TI - [Local sperm antibodies and general levels of immunoglobulins in ovulatory cervical mucus]. AB - OBJECTIVE: The aim of our preliminary study was to compare the levels of total local sIgA and IgG with activity of detected sperm antibodies in ovulatory cervical mucus (OCM). SETTING: Department of Gyneacology and Obstetrics, Medical School and Faculty Hospital, Charles University, Plzen. METHODS: We screened samples of OCM from 12 pacients aged 26-31 (29,6 years on average) by radial immunodifusion (RID) to determine s IgA and IgG. Indirect MAR test was used for detection of spermagglutinationg antibodies. RESULTS: We found out by RID the average concentration of sIgA in OCM 567,84 mg/l (0 -1250,47) and the average concentration of IgG in OCM 23,57 mg/l (8,74-47,99). Antibody activity against sperm cells dominates in IgA with 6 pacients, in IgA with 1 patient, in IgA and IgG together with 1 infertile woman and in IgA and IgM isotypes together with 1 patient. No local sperm antibodies were determined with 3 patients. CONCLUSION: We proved the hypothesis, that the levels of spermagglutinating antibodies do not correlate with findings of total sIgA and IgG in OCM with our patients. PMID- 20925234 TI - [Measurement of bone mineral density by heel ultrasound and forearm DXA in clinical practice]. AB - OBJECTIVE: The comparation of two possibilities of bone mineral density measurement--ultrasound and dual energy x-ray absorptiometry. DESIGN: Open nonrandomized observation study. SETTING: Department of Obstetrics and Gynecology, 1st Faculty of Medicine Charles University and General Faculty Hospital Prague. METHODS: We examined 190 women with mean age 56 years by both methods--Lunar PIXI (dual energy x-ray absorptiometry) on forearm and CUBA Clinical (broadband ultrasound attenuation) on heel. We took personal history for menopause status, hormone replacement therapy, smoking, sport activity and age. RESULTS: The incidence of T-scores was the same for both methods, there were differences in Z-scores. In both methods we have seen the same tendencies of interaction with risk factors. Bone mineral density (BMD) respective T-score significantly decreased with age. There were no significant connections between BMD and body mass index (lineary regression test), hormone replacement therapy (paired t-test), smoking and physical exercise (Mann-Whitney U test). T-score was significantly (p < 0.003) lower in women with history of fracture (Mann-Whitney U test). CONCLUSION: In spite of totally different principles of measurement both methods are able to screen BMD. PMID- 20925235 TI - [Complications of radical oncogynecological operations]. AB - OBJECTIVE: Information sheet about the most frequently complications of radical oncogynecological operations. DESIGN: Literature review with case reports. SETTING: Department of Gynaecology and Obstetrics, Faculty of Medicine, Masaryk's University and Faculty Hospital, Brno. METHODS: Literature review about complications of radical oncogynecological operations with illustrative case reports. CONCLUSIONS: Radical oncogynecological operations, due to their size, associated with a higher morbidity compared with traditional gynecological surgery. The literature states morbidity parameters between 25-45% depending on the center of erudition and range of out performance. Basic division of surgical complications is on perioperative complications and postoperative complications, which are further divided into early and late. The most frequently intraoperative complication is large blood loss requiring the application of blood substitutes. Less common complications are injury to the urinary bladder, ureter, rarely bowel or neural structures, especially nerve obturatorius. Among early postoperative complications are dominated urological complications, particularly urinary bladder hypotonia, another important group are the vascular complications, ie trombembolia and bleeding. Between late postoperative complications is possible to define several basic groups, ie urology, intestinal, lymphovascular and complications associated with laparotomy wound suture. Prevention of complications should be based on several basic assumptions. These include adequate erudition and composition of the operating team, perfect knowledge of anatomical conditions in the pelvic retroperitoneum, the paraaortic, the paracaval and inguinal area, implementation radicality adequate performance in relation to the extent of the disease and developing new surgical techniques (eg nerve sparing surgery). Absolute necessity is also the possibility of interdisciplinary cooperation with other surgical disciplines, which is important both in terms of preventing complications, and for their event subsequent solutions. PMID- 20925236 TI - [Process of women's reproductive ageing--causes, evaluation and possible clinical usage]. AB - Women's fertility steeply decreases with increasing age, but the intensity of the decrease is individually significantly variable. The main cause of fertility drop is rapid decrease of ovarian follicle count. Deletion of ovarian follicles happens mainly by the mechanism of cell apoptosis. Nevertheless in the whole process participates also others exogenous and endogenous factors. At present new major steps in the complex ovarian ageing process has been identified and some innovative therapeutic strategies have been suggested to influence this process. At the end this paper evaluates currently available markers of ovarian reserve and its abilities to be used in routine clinical practice. PMID- 20925237 TI - [Optic neuritis in multiple sclerosis]. PMID- 20925238 TI - [The use of modern examination methods in early diagnosis of pigmentary glaucoma and pigmentary dispersion syndrome]. AB - AIM: To establish, using modern examination methods, the possibility to determine the damage of visual functions characteristic for glaucoma in pigmentary dispersion syndrome (PDS) earlier than using classical methods, and, if the pigmentary glaucoma (PG) differs in the visual functions damage from the primary open angle glaucoma (POAG). MATERIALS AND METHODS: The followed-up cohort of 21 persons (altogether examined 34 eyes) was divided into four groups: in the first group, there were the healthy controls and the next three groups were divided according to the type of the disease. The first group consisted of 10 eyes of 5 healthy persons (1 woman aged 50 years and 4 men in the age 23-45 years). The average refractive error in this group was -0.25 diopters. In the second group, 10 eyes of 7 patients with PDS (out of them 2 women at the age 55 and 56 years respectively, and 5 men, age 27-46 years) were included. The average refractive error in this group was -2.85 diopters. The third group comprised 9 eyes of 6 patients with PG (3 women aged 50-56 years and 3 men at the age 21-49 years). The average refractive error in this group was -5.0 diopters. The fourth group consisted of 5 eyes of 3 patients (one woman at the age of 44 years and two men at the age 35 and 50 years) with POAG. The average refractive error in this group was -1.0 diopter. The age structure in all groups was comparable. In the followed up cohort of 21 persons, the refractive error, the visual acuity, (EDTRS charts), gonioscopy (evaluated according to Spaeth classification), intraocular pressure (non-contact device Canon TX 10 and applanation tonometer Inami), visual field testing (Medmont M700), nerve fiber layer measurement (GDx -VCC), macular volume (MV - OCT Stratus), PR-ERG, PR-VEP (Retiscan according to the ISCEV methodology) were examined. RESULTS: The statistical evaluation of the results and their mutual comparing among separate groups with following outputs were performed: 1. The control group and the PDS group: statistically significant differences were established in GDx and MV. Statistically most significant were the differences in PR-ERG and PR-VEP amplitudes (t = 28, eventually 18.254 against the tabularized value 2.845). 2. The control group against the PG group: statistically significant differences were found in GDx, MV, and PR-ERG and PR-VEP amplitudes as well. 3. The control group against the POAG group: statistically significant differences were found in GDx and MV. Statistically most important difference was found in the PR-VEP amplitude (t = 63.973 against the tabularized value 3.012). 4. The PDS group versus PG group: statistically significant differences were found in GDx and MV as well. Statistically most important difference was found in the PR-VEP amplitude (t = 36.75 against the tabularized value 2,898). CONCLUSION: Using the modern diagnostic techniques, the PDS and PG may be differentiated. Statistically significant differences were found in GDx and in MV as well. The biggest difference was in PR-ERG and in PR-VEP. Differentiated slowing down of the excitations conduction speed in the visual evoked responses, which presents in PG and in PDS as well, may provide close proximity of both diseases. Because of that, it is appropriate to follow up the patients with the PDS in the same way as the glaucoma patients. PMID- 20925239 TI - [The ERG contribution in early diagnosis of chloroquine and hydroxychloroquine maculopathy]. AB - Derivates of chloroquine (Plaquenil, Delagil), used for long-term treatment of rheumatic diseases, may cause clinically proven irreversible maculopathy, which may progress even after the discontinuation of their application. The optimal early diagnosis of ocular toxicity of chloroquine or hydroxychloroquine drug remains controversial up to now. The aim of this review paper was to evaluate how appropriate is the indication of the electroretinographic (ERG) examination due to the early diagnosis of cumulative drug-related maculopathy. Photopic, pattern, and multifocal ERG (Retiscan, according to the ISCEV methodology) were examined in 10 patients (20 eyes) treated by means of antimalarics, 9 due to the rheumatoid arthritis (RA) and 1 due to the systemic lupus erythremathodes (SLE). The average age of the patients was 60 +/- 15 years, the treatment period was 10 +/- 11 years; the median of the treatment period was 5 years. The control group consisted of 12 healthy, age matched patients (20 eyes) without any obvious ocular pathology. In all of them, the complete ophthalmologic examination was performed: the best corrected visual acuity (BCVA) for far using the Snellen charts, intraocular pressure (IOP) measured by means of the non contact tonometer NIDEK NT-2000, the Amsler grid test, examination of the anterior segment and the posterior segment with the slit lamp. The entry criteria in both groups were BCVA 5/7,5 (0.67) and better, the IOP in the normal range, negative Amsler grid test, anterior segment without significant decrease of the transparency, and physiological posterior segment or with subtle granular pigment dysgrupancies in the macula only. The significant difference between the group treated with chloroquine or hydrochloroquine and the control group at the 1% level of significance was found in following parameters: in the photopic ERG the value of the b wave latency [ms], in pattern ERG, the values of the waves N35 - P50 [microV] and P50 - N95 [microV] amplitudes, and at the 5 % level of significance in photopic ERG, the wave a amplitude value [microV] and in multifocal ERG, the value of the P1 [ms] a N1 [ms] parts latency in the pericentral ring. It follows from the results, that the ERG examination is suitable for the early diagnosis drug cumulative maculopathy caused by chloroquine derivates. Optimal is the individual comparison of the ERG values of the patient before and in certain time intervals after the beginning of the chloroquine derivates treatment. PMID- 20925240 TI - [Implantation of the stenopeic aniridiae posterior chamber intraocular lens after the trauma--yes or no?]. AB - Perforating injuries involving the anterior as well as the posterior segment of the eye count among serious conditions requiring several consequential surgical treatments. The anatomical and functional result is often monocular partial or total aniridia together with aphakia. One among the possibilities to correct this condition is the secondary implantation of the stenopeic aniridiae posterior chamber intraocular lens (PC IOL). PMID- 20925241 TI - [Treatment of angioid streaks with anti-VEGF]. AB - PURPOSE: To evaluate the possibility to treat the chorioidal neovascularisation in angioid streaks with the help of Bevacizumab. Chorioidal neovascularisation is here the main reason responsible for destroying the vision and affects about 70 85% of patients with this disease. MATERIAL AND METHODS: 50 years old woman with 2 weeks anamnesis of worsening of vision on left eye. She claims deformed view in the middle of the visual field and mild decrease of visual acuity. BCVA was 0.9 and examination with Amsler grid showed line distorsion in the central part. After fundus examination, angiography and OCT we set diagnosis: angioid streaks complicated by subfoveal chorioidal neovascularisation. We proposed patient treatment with intravitreal Bevacizumab and subsequently started the therapy. RESULTS: One week after bevacizumab application, patient claims vanishing of vision distortion. In four weeks metamorphopsis completely disappeared and BCVA reached 1.2. OCT and FAG showed less leakage. After initial improvement and 7 months of stand still there comes again to vision deterioration (BCVA 0.7). We were obliged to reinject 1.25 mg of Bevacizumab and VA improved to 0.9 and also the deformation was less. Three months after second injection VA was again decreased and patient was treated with third injection. Patient is followed up for period of 12 months with mild deformation of picture and VA 0.7. It was not observed any side effect of treatment. CONCLUSIONS: The treatment of the chorioidal neovascularisation in angioid streaks is another possibility with the help of Bevacizumab.With this treatment can be delayed the devastation of VA with subfoveal neovascularization. It seems that the treatment is only temporally and during the 12 months follow up came to a few relapse. PMID- 20925242 TI - [Efficiency of vitrectomy in diabetic macular edema and morphometry of surgically removed of the internal limiting membrane]. AB - AIM: To evaluate the efficiency of vitrectomy with peeling of the internal limiting membrane (ILM) in eyes with diffuse and/or cystoid nontractional diabetic macular edema (ME) refractory to macular laser photocoagulation. Histopathologic and morphometric analysis of the ILM in diabetic eyes was performed. Thickness of the ILM was correlated with the level of glykosylated hemoglobin (HbA1c) and other clinical factors. MATERIAL AND METHODS: The prospective study involved 56 eyes of 52 diabetic patients with a mean age of 63 +/- 7.6 years. Vitrectomy with trypan blue-assisted ILM peeling was performed in standard way. Mean follow-up period was 8.7 months (range 3 - 19 months). The ILM was fixed immediately after peeling in 2.5% glutaraldehyde and submitted for electron microscopic evaluation. The ILM was photographed in standard magnification (x 5000) with the scale of 1 microm in the shot. RESULTS: Statistical analysis of the postoperative visual acuity (VA) in the study group of 56 eyes proved a general improvement with prevalence of the resulted VA in intervals 0.1-0.2 and 0.5-1.0 related to ETDRS chart. The VA was improved by at least 2 lines in 29 eyes of 56 eyes (51.8%), one line in 6 eyes (10.7%) and remained unchanged in 11 eyes (19.6%). The postoperative VA deteriorated by one line in 2 eyes (3.6%) and at least 2 lines in 8 eyes (14.3%). Morphometric analysis demonstrated a significant thickening of the ILM in all eyes with a mean thickness of the ILM 3.61 +/- 1.22 micro m. It was found that a higher thickness of the ILM is related to elevated HbA1c by both types of diabetes mellitus (DM) (p = 0.040). We also found significant dependence of ILM thickness in relation to duration of DM by comparison of men and women (p = 0.026) and significant correlation between ILM thickness and the age of diabetic patients related to their gender (p = 0.029). CONCLUSIONS: Vitrectomy with peeling of the ILM in eyes with chronic diffuse and/or cystoid nontractional diabetic ME mildly improves the VA and extends a hope for its stabilization. We confirmed increased thickness of the surgically peeled ILM and statistically significant correlations to elevated HbA1c by both types of DM and to further clinical characteristics of case series. Morphometric and histopathologic analyses of the ILM contribute to more objective evaluation of ultrastructure of the vitreomacular interface. PMID- 20925243 TI - [The influence of the idiopathic macular hole (IMH) surgery with the ILM peeling and gas tamponade on the electrical function of the retina]. AB - Many contemporary clinical papers establish positive influence of the pars plana vitrectomy (PPV) with the ILM (internal limiting membrane) peeling and gas tamponade in macular hole to the macular morphology. They prove diminishing or disappearing of the central scotoma and metamorphopsia and especially also improvement of the BCVA for far and near. The evaluation of the objective functional condition of the retina is still a discussed question. This paper concerns with the comparison of the electric functions of the retina before and after the IMH surgery with the ILM peeling and the gas tamponade. In the group 19 patients (8 men, 11 women), or 19 eyes with IMH were included. The average age was 69 +/- 6 years. The group consisted of patients with transparent optical media. In none of these patients was found other macular pathology than IMH. Nobody underwent other retinal surgery. The patients were examined 1 day before and 1 and 3 months after the surgery. During each control, the following examinations were performed: the Amsler grid examination, the best corrected visual acuity (BCVA) for far (EDRTS chart) and near (Jaeger optotypes), intraocular pressure measurement (non contact tonometer NIDEK NT-2000), examination of the anterior segment on the slit lamp, examination of the posterior segment biomicroscopically and by means of indirect ophthalmoscopy, examination of the photopic, pattern, and multifocal ERG (Retiscan, according to the ISCEV methodology), and OCT examination (Stratus OCT). If necessary, the ultrasound examination (Ultrascan Alcon) was performed as well. For the statistical evaluation of the ERG component values among the data files before the surgery (data file 1), 1 month after the surgery (data file 2), and 3 months after the surgery (data file 3), the non-parametric Wilcoxon pair test was used. In the photopic ERG, there was statistically significant prolongation of the latency b in data file 2 and 3 comparing to the data file 1 (p < 0.05). Comparing latency b of data file 1 to data file 2, there was found no statistical significance. Comparing other parameters of photopic ERG found no statistically significant difference among data files 1,2, and 3. In the multifocal ERG, there was found statistically significant elevation of the P1 amplitude according to the response density of given unit and the P1 amplitude in the central ring in data file 3 comparing to the data file 1 (p < 0.05). Comparison of other parameters was not statistically significant. In the paracentral ring, there was found statistically significant extension of the N1 and P1 latency in data file 3 comparing to the data file 1 (p < 0.05). Comparison of other parameters in the paracentral ring was not statistically significant. Statistically significant improvement of the retinal electric function in the central 4 degrees 3 months after the surgery, confirms the positive functional effect of the surgery to the fovea. In the fovea, the increase of the number of functional nerve cells of the outer layers of the retina occurs. On the other hand, in the parafoveolar region, as well as in the whole retina, 3 months after the surgery, statistically significant decrease of the function of the retina, meaning the time prolongation of the conduction in the outer layers of the retina, occurs. According also to our results, the peeling of the ILM in the IMH surgery remains, despite its unquestionable contribution, still a controversial technique. During the short, three months lasting, follow-up period, the functional improvement in the fovea occurred, but the functional decrease in the parafoveolar region which correlates in the large extent with area of the ILM peeling was found. The discussion about the ILM peeling indication in the earlier stages is adequate. We will further follow-up the development of the retinal electric function after the IMH surgery with ILM peeling and gas tamponade. PMID- 20925244 TI - [The use of intravitreal ranibizumab application in the treatment of post inflammatory neovascular membranes--a case report]. AB - The aim of this case report is to represent our experience with intravitreal application of ranibizumab in a patient with post-inflammatory neovascular membrane. Patient, a 46 years old male, complained about 3 months lasting metamorphopsia in the left eye. The classic post-inflammatory neovascular membrane was diagnosed by means of fluorescein angiography. The initial BCVA of the left eye was 4/6 (or 0.67). Two intravitreal injections of 0.5 mg ranibizumab each were applied. After two applications, the BCVA was 4/4 (or 1.0), there was no biomicroscopically detectable edema, and the OCT revealed reestablished foveolar depression. This condition remains stable even after 10 months after beginning of the treatment. The anti-VEGF treatment represents another possibility of the treatment of post-inflammatory neovascular membranes. PMID- 20925245 TI - [The use of molecular genetics techniques in clinical microbiology--final report from the workshop of the Molecular Microbiology Working Group TIDE]. AB - In the last decade, there has been a rapid development in the use of molecular genetics methods in clinical microbiology. Novel technologies bring new knowledge and approaches to various disciplines of microbiology--taxonomy, identification of microbes, clinical diagnosis, epidemiology of infectious diseases and antibiotic resistance. This article summarizes the conclusions from the workshop of the Molecular Microbiology Working Group TIDE held during the Second Annual Meeting of the Society for Medical Microbiology of the J. E. Purkyne Czech Medical Association. PMID- 20925246 TI - [Examination of mosquitoes collected in southern Moravia in 2006-2008 tested for arboviruses]. AB - The main goals of the study were to carry out virus isolation attempts on Vero cell cultures from mosquitoes collected in southern Moravia (Breclav district, Czech Republic) and to identify the isolates using a microtiter virus neutralization test. A total of 9.742 female mosquitoes belonging to 13 species were examined, and three viral strains were isolated, all from the mosquitoes collected in 2006: two of these isolates were identified as Tahyna Orthobunyavirus (both obtained from Aedes vexans mosquitoes) and one was West Nile flavivirus (obtained from Aedes rossicus mosquitoes). Ae. rossicus might be a new vector for West Nile virus. PMID- 20925247 TI - [Tick-borne encephalitis in the East Bohemia Region and its microbiological diagnostic pitfalls]. AB - AIM OF THE STUDY: The analysis of cases of tick-borne encephalitis (TBE) laboratory diagnosed at the Department of Virology of the Institute of Clinical Microbiology of the University Hospital in Hradec Kralove in 2003-2006 and comparison of the data from 2003-2006, 1999-2002 and 1995-1998. Another objective was to compare two routinely used ELISA (enzyme-linked immunosorbent assay) diagnostic kits for TBE. MATERIAL AND METHODS: The samples from 3284 patients tested by the Department of Virology of the University Hospital in Hradec Kralove in 2003-2006 were analyzed. The detection of the specific IgM and IgG antibodies in serum and cerebrospinal fluid specimens was performed using two ELISA diagnostic kits (Euroimmun, Germany, and Test-Line Ltd, Clinical Diagnostics, Czech Republic). Non-specific reactivity of IgM antibodies was only analyzed in 2004-2006. RESULTS: In 2003-2006, TBE was diagnosed in 163 patients of the University Hospital in Hradec Kralove aged from 3.5 months to 80 years. The number was by 48 cases (29%) higher than that in 1995-1998 and by 36 cases (22%) higher than that in 1999-2002. TBE was confirmed in 94 males (57.7%) and 69 females (42.3%). More than half of the patients were aged above 41 years (94/163, i.e., 57.6 %) and 60 patients (37 %) were older than 51 years. A biphasic course of infection was observed in 93/136 cases (68.4%). As many as 101/136 patients (74 %) had a history of a tick bite, one patient reported the consumption of non pasteurized milk. Thirty-eight (1.4 %) specimens showed non-specific reactivity of IgM antibodies. None of the cases showed cerebrospinal fluid reactivity in the absence of serum reactivity. CONCLUSIONS: Increase in the diagnosed TBE cases was reported in 2003-2006 in the East Bohemia Region. It was due mainly to more severe clinical forms of TBE that were more frequent than the milder ones. The distribution of the confirmed TBE cases remained unchanged in terms of age and sex, but the seasonal peak moved from summer to autumn. ELISA proved suitable for use in the routine diagnosis of TBE. Both of the tested commercial kits are of good quality. Nevertheless, in view of possible non-specific reactivity of IgM antibodies, IgG antibodies need to be tested in both the first acute serum specimen and paired sera. The detection of antibodies in cerebrospinal fluid is unlikely to be of diagnostic benefit for TBE. Close cooperation between the attending physician and clinical microbiologist is crucial. PMID- 20925248 TI - [Lipophilic yeasts of the genus Malassezia and skin diseases. I. Seborrhoeic dermatitis]. AB - Recent technological advances have revived the interest in Malassezia yeasts and their clinical role, which has long been a matter of controversy because of their fastidious nature in vitro and relative difficulty in isolation, cultivation and identification. Lipophilic yeasts of the genus Malassezia form a part of normal microbial flora of healthy human (and animal) skin, but they also have been associated with several dermatological diseases, like seborrhoeic dermatitis and atopic dermatitis. Our understanding of the interactions between Malassezia and the host might provide new opportunities to better control these often chronically relapsing diseases. PMID- 20925249 TI - [Pernicious anaemia--diagnostic benefit of the detection of autoantibodies against intrinsic factor and gastric parietal cells antigen H+/K+ ATPase]. AB - BACKGROUND: Pernicious anaemia is an autoimmune disease that causes acquired vitamin B12 deficiency. The diagnostic process includes the detection of typical changes in the blood count, low serum levels of vitamin B12, endoscopic and histological signs of gastritis and autoantibodies against the gastric parietal cells antigen H+/K+ ATPase and intrinsic factor. OBJECTIVE: Our aims were to establish immunological tests for the detection of autoantibodies against intrinsic factor and target gastric parietal cell antigen H+/K+ ATPase and to evaluate their diagnostic benefits in patients with pernicious anaemia. MATERIAL AND METHODS: Sera from 95 patients were tested for autoantibodies against H+/K+ ATPase and intrinsic factor by multiplex Luminex assay. The results were compared with those of the immunofluorescence assay for the detection of autoantibodies against gastric parietal cells and with the diagnostic criteria. RESULTS: The autoantibodies against gastric parietal cell H+/K+ ATPase had a sensitivity of 68.2% with a specificity of 91.7% for the diagnosis of pernicious anaemia. The respective rates for the autoantibodies against intrinsic factor were 40.9% and 98.6%. The combined sensitivity and specificity rates for both autoantibodies were 86.36% and 90.28%, respectively, the combined positive predictive value was 73.08% and the combined negative predictive value was 95.59%. CONCLUSION: The detection of both autoantibodies is helpful in diagnosing pernicious anaemia and the combination of the two assays increases diagnostic sensitivity. PMID- 20925250 TI - [Prevalence of anti-Epstein-Barr virus antibodies in children and adolescents with secondary immunodeficiency]. AB - Secondary immunodeficiency can be caused by multiple factors. We studied whether there is a relationship between secondary immunodeficiency and Epstein-Barr virus (EBV) infection in children and adolescents. The study group included 845 patients with common variable immunodeficiency aged from 2 to 18 years and 394 age-matched healthy controls. IgM and IgG antibodies against viral capsid antigen (VCA) and IgG antibodies against Epstein-Barr virus nuclear antigen 1 (EBNA-1) were quantitated by an enzyme-linked immunosorbent assay. A statistically significant difference (p = 0.004) in the prevalence of EBV infection was found between the immunodeficient children and controls, both aged 2 to 6 years. The statistically significant difference was confirmed in boys (p = 0.003), but not in girls of this age group. PMID- 20925251 TI - [Herpes zoster in the Czech Republic--epidemiology and clinical manifestations]. AB - Herpes zoster (shingles) is a viral infection of the skin that manifests itself as painful, unilateral vesicular rash. The causative agent is varicella-zoster virus (VZV). Primary infection with VZV causes chickenpox, a common childhood infection, and then the virus lies dormant in the sensory neural ganglia, reactivating to cause shingles. The most important complications are neurological disorders (in particular postherpetic neuralgia) and eye disorders. First-line therapy are antiviral agents. A single vaccine has been registered to date. Herpes zoster occurs sporadically in the Czech Republic and its incidence is long term stable. In 1990-2008 the average annual incidence was 6306 cases (61.3 cases/100,000 population), with the lowest number of 5511 cases (53.5/100,000) reported in 1991 and the highest number of 6,894 cases (67.6/100,000) reported in 2002. The incidence rate in females (69.9/100,000) was 1.4 times as high as in males (49.5/100,000). From the age perspective, the elderly are at a considerably higher risk of developing shingles. In 2008, the incidence rate was the highest in the age group 70 years (155.0/100,000). Nevertheless, the beginning of the upward trend is seen in the age group 45-49 years. Herpes zoster does not show any seasonal trend. PMID- 20925252 TI - [A simple method for the detection of CD154 (CD40L) on peripheral blood lymphocytes]. AB - OBJECTIVE: CD154 (also called CD40L) is a transmembrane glycoprotein predominantly expressed on the surface membrane of activated CD4+ T cells. Its receptor CD40 is present on all B cells, but also on other cells. The interaction CD154-CD40 is necessary for the optimal development of the adaptive immune response and also has consequences for the modulation of the inflammatory response. A defect in the expression of CD154 is pathognomonic of congenital immunodeficiency called X-linked Hyper-IgM syndrome (XHIGM). To detect the abnormality of CD154 is essential for making the diagnosis of XHIGM. MATERIAL AND METHODS: We worked out a microtest for the detection of CD154 expression on in vitro activated CD4+ T cells in whole blood and compared it with that on isolated cells from peripheral blood. Heparinized peripheral blood was activated with phorbol 12-myristate 13-acetate and ionomycin for 4 hours, labeled with monoclonal antibodies and analyzed by flow cytometry. Considering that the CD4 marker on the plasma membrane surface decreases during the activation, CD4+ T cells are mostly recognized as CD5+/CD8- cells. Their activation is monitored based on the expression of CD69. Three-colour immunofluorescence staining was used for simultaneous detection of CD154. RESULTS: Ten blood donors were tested. As little as 0.5 ml of heparinized whole blood is needed to complete the test. Optimal time for activation and detection of CD154 on T lymphocytes is 4 hours. We found that the number of CD4 molecules on the surface of T cells decreases during the activation. The expression of CD154 in our whole blood microtest is fully comparable with that in the test on isolated leukocytes. CONCLUSION: The presented microtest for the detection of CD154 on activated lymphocytes in whole blood is fast and blood saving, since as little as 0.5 ml of blood is needed to complete it. It can be recommended as the initial test for suspected hyper-IgM syndrome in children. We demonstrate that this screening method can help to detect also carriers of XHIGM. PMID- 20925253 TI - [Significance of the sentinel lymph node biopsy in early breast carcinomas]. AB - We present our experience regarding sentinel lymph node biopsy (SLNB) at St. Elizabeth Institute of Oncology during 48 months. From January 1st, 2006 until December 31st, 2009, we had performed SLNB in 269 patients. Primary tumour size was 0.3-3.5cm including non-invasive breast carcinoma (i.e. TIS, T1 and T2 of TNM classification). Invasive carcinoma accounted for 255 (94.8%) cases, while non invasive carcinoma for 14 (5.2%) cases. From total of 269 patients with invasive carcinoma, we used validation method in 157 (72.7%). In 255 patients with invasive carcinoma, sentinel node was not identified in 4 (1.6%) cases--in 1 patient with T1 invasive carcinoma and in 3 patients with T2 tumours. False negativity of sentinel node in T1 tumours was 4.3%. The incidence of macrometastases in sentinel nodes was confirmed using standard histopathologic examination with hematoxylin-eosin stain. In negative instances, the examination was then completed with serial sections and immunohistochemistry using cytoskeletal antibodies for confirmation of presence of micrometastases. In 6 (2.4%) cases, we found micrometastase in originally negative sentinel lymph node. Subsequent axillary dissection has not confirmed non-sentinel nodes involvement. PMID- 20925254 TI - [Ovarial hyperstimulation syndrome in the differential diagnostics of acute abdomen]. AB - INTRODUCTION: The massive world-wide development of assisted reproduction (AR) technology and marked increase of females with infertility treatment lead to different medical complications. One of them is ovarian hyperstimulatory syndrome (OHSS), potential fatal complication in AR. It demonstrates with abdominal discomfort, nauzea, vomitus, ascites, and general alteration. It can imitate an acute abdomen syndrome, and it can lead to the primary surgical assessment. AIM: The description of OHSS as a cause of an acute abdomen syndrome. METHODS: Authors present a case of OHSS with the symptomatology of acute abdomen, which was handled by surgeon, primarily. CONCLUSION: Consistent patient history, including gynecological history, and careful physical and laboratory examinations with relevant imaging methods lead to the elimination of invasive procedures. OHSS is the most actual in differential diagnosis of acute abdomen in fertile females for that reasons. PMID- 20925255 TI - [Laparoscopy in the management of invagination in pediatric patients]. AB - AIM: During the last decade, many articles on indications, contraindications, benefits and risks of laparoscopic desinvagination procedures in children have been presented in scientific literature. However, this therapeutic procedure has become a standard therapeutic option within the range of pediatric laparoscopic precedures. The aim of the authors was to establish this miniinvasive procedure in their clinic. PATIENTS AND METHODS: From January 2006 to December 2009, the authors operated 19 patients with ileocolonic invaginations, in whom prior hydrostatic desinvagination had failed. 11 pediatric patients underwent laparotomic revision. In 9 subjects, idiopatic invagination was detected, while in 2 subjects secondary intususception caused by a Meckel's diverticle was confirmed during the procedure. In 7 subjects aged 8-51 months, desinvagination was achieved using laparoscopic procedures. 3 ports were used during the procedures--one for optic devices, measuring 10 mm, was placed in the infraumbilical incision and 2 working ports of 5 mm were introduced into the left hypogastrium and the left mesogastrium. The desinvagination was achieved using a grasper and gentle traction on the invaginated colon. In two subjects with relapsing invagination, desinvagination was followed by ileo-coecopexy. In one subject, conversion was required during the laparoscopic procedure, because repositioning of the invaginated colon was not feasible. OUTCOMES: The mean duration of these laparoscopic procedures was 68.6 minutes and no intraoperative complications were recorded. Reallimentation was introduced on the first postoperative day, no reinvagination episodes were recorded and the mean duration of hospitalization was 4.3 days. CONCLUSION: Laparoscopic desinvagination has become a part of the algorithm for the management of invaginations in cases, where conservative approach failed, and should be used before open laparoscopic revision is indicated. However, the miniinvasive procedure must be performed by a surgeon with experience in laparoscopy. PMID- 20925256 TI - [Liver transplantations in children using reduced grafts]. AB - AIM: Liver transplantation is a life-saving procedure in patients with end stage liver disease. Five-year survival in patients indicated for transplantation based on standard indication criteria, has reached a rate over 80%. Shortage of suitable grafts remains the main problem in these procedures. While the situation in adult patients is relatively satisfactory, liver transplantations in children, mainly in the low-weight categories, remain a worldwide problem because of the absolute lack of suitable donors. In order to reduce mortality in the youngest patients on the waiting list, a concept of reduction of the adult graft for pediatric use was introduced in the early 1990s. Recent introduction of novel methods, such as split transplantations or transplantations between relatives, has resulted in lower mortality rates in the youngest recipients on the waiting lists. The author assesses a group of patients below 18 years of age, who underwent reduced liver graft transplantations in the Czech Republic. MATERIAL AND METHODS: From 1995 to 2009, a total of 43 patients below 18 years of age underwent transplantations, using 48 liver grafts. Further 17 children were sent abroad for transplantations, where a total of 23 liver grafts were used. Only patients who underwent transplantations using the liver grafts adjusted in IKEM were assessed in the patient group, i.e. 14 patients, resp. 16 liver grafts. Reduction was performed in 13 subjects. One subjects underwent transplantation between relatives and a liver split was used in two subjects. In the lowest weight category up to 10 kgs, 5 liver reductions were performed. OUTCOMES: Out of the total (n = 16), 4 grafts failed (2 were early postoperative failures, ie. within 2 postoperative days and 2 grafts failed in Month 5). The mean graft survival was 65 months. Within the youngest recipient age group (n = 5), no graft failure was recorded. The mean survival time is 26 months. CONCLUSION: Since 2007, the Czech Republic has been providing a program for all patients, including the lowest weight-category pediatric patients. To date data are satisfactory. No graft failure has been recorded in the category of the smallest (up to 10 kgs) pediatric patients. PMID- 20925257 TI - [Small intestine invagination in an adult]. AB - Bowel intussusception in adulthood is relatively rare. It is the cause of bowel movement disorders in around 1-5% of cases. In contrast to intussusception in childhood, where the cause is usually unclear, in adulthood the unequivocal causes are known in 70-90% of cases. These predominantly include benign tumours of the small intestine. The authors describe 2 case reports, where small bowel intussusception was the cause of the bowel movement disorder and non-specific abdominal pain. This clinical entity must be kept in mind as the possible cause of non-specific abdominal pain in adulthood. If a malignancy is suspected, then the rules of oncological surgery should be followed. PMID- 20925258 TI - [Treatment of upper gastrointestinal tract fistules in the surgical intensive care unit]. AB - The authors performed a retrospective analysis in a group of consecutively treated patients with upper GIT fistules (ie. fistules with internal orifices in the esophageal, gastric and proximal small intestine region), hospitalized in the Plzen hospital Surgical Clinic Septic Intensive Care Unit, from January 1, 2006 to December 31, 2008. The author assessed the results using statistical methods and he studied any causative relationship between the characteristics of the fistules, the treatment methods and the patients morbidity/mortality rates. PMID- 20925259 TI - [Results and complications of laparoscopic adjustable gastric banding--12 years experience]. AB - INTRODUCTION: Bariatric surgery is currently the only effective treatment for morbid obesity. The main advantage of laparoscopic adjustable gastric banding (LAGB) is that this operation is minimally invazive to the stomach and adjustable to the patient's needs. AIM: Few long-term studies regarding the outcome of LAGB for morbid obesity have so far been publised. We report our 12-year experience with this method. PATIENTS AND METHODS: On list of 100 patients (76% women, 24% men) operated since February 1998 until December 2006 we present results and complications, reoperations. Mean follow up was 5.2 years (0.5-11.8). Patients lost to follow up was 22% at 5 years and 33% at 8 years. Complications occurred in 38% patients. 12% of the patients needed reoperation. There was no mortality. CONCLUSION: From our 12-year experience, we can state that LAGB is an effective bariatric procedure for achieving weight loss. Because of the high complication and reoperation rate, it is necessary to select patients according specific criteria and choose experienced bariatric surgery. PMID- 20925260 TI - [Benefit of PET/CT in the preoperative staging in pancreatic carcinomas]. AB - OBJECTIVE: Prognosis of patients with pancreatic cancer is poor. Median survival from diagnosis without determining surgical treatment is 3-11 months, after surgical treatment between 13-20 months according to various studies. 5-year survival rate is below 5%. The only chance of cure remains a radical surgical resection. Early diagnosis and determining resectability of tumour is the most important objective in patients with pancreatic cancer. Aim of this work is to evaluate the benefits and define the role of 18F-FDG PET/CT in preoperative staging. MATERIAL AND METHODS: 195 patients (103 men, 92 women, mean age 66.7 year, range 32-88 years) with suspected pancreatic lesions underwent enhanced 18F FDG PET/CT in the preoperative staging in addition to standard investigative methods (ultrasonography, contrast enhanced CT, EUS, EUS FNA). All PET/CT findings were compared with standard methods (CT, EUS, EUS FNA), with peroperative findings and definitive histology in surgical patients as the reference standards. Interpretation of the extent of the tumor defined by TNM classification. Limitations of the local resectability was advanced local stage (T4) and presence of distant metastases (M1). RESULTS: In 195 patients with suspected pancreatic lesions was pre-operatively performed PET/CT in the period 1/2007-3/2009. 153 patients with pancreatic cancer, of which 72 was not suitable for radical surgery because of local inoperability or a generalization of the disease. The sensitivity of PET/CT in the capture of primary lesions was 92.2%, specificity 90.5%. False negative findings in 12 patients, false-positive results occurred in 4 cases, positive predictive value (PPV) 97.2%, negative predictive value (NPV) 76.0%. In the assessment of regional lymph nodes sensitivity was 51.9%, specificity 58.3%, PPV 58.3%,NPV 51.9%. In detection of distant metastases PET/CT reached sensitivity 82.8%, specificity 97.8%, PPV 96.9%, NPV 87.0%. PET/CT found distant metastases in 12 patients, which standard methods failed to detect. Surgery was cancelled in 15 patients (15.6%) with potentially resectable tumour based on the performance of PET/CT findings and the management of treatment was changed. CONCLUSION: PET/CT is highly sensitive and specific method suitable for preoperative staging of pancreatic cancer. It improves the selection of patients for surgery, who can benefit from and reduces the number of incorrectly indicated operations. PMID- 20925261 TI - [Uncommon rectal adenocarcinoma metastases]. AB - Rectal cancer treatment has become multimodal as a result of significant advances in imaging diagnostic, in surgery technique of re section and in neo and adjuvant therapy. The aim of the case report was to present a successfully treated adenocarcinoma recti and adenocarcinoma of hepatal flexurae with recidivistic metastasis and an extremely rare intergrowth of the metastasis into venous system. A 61 year old patient underwent low resection of recti according to Dixon because of well differentiated adenocarcinoma with classification T3N0M0. The patient was reoperated because of metastasis of adenocarcinoma in the abdominal wall (16 x 15 x 20 cm) after chemotherapy (FUL-5-fluorouracyl) and radiation dose of 50.4 Gy. The metastasis of abdominal wall was extirpated after another cycle of adjuvant therapy of FUL+Leukovorin. 26 months after the first operation, a new sessile polyp was found in the hepatal flexurae with histological finding of well differentiated adenocarcinoma. The patient underwent right hemicolectomy. Since lymphatic nodes were without metastasis, the patient was not indicated for chemotherapy. Two months later, the patient was admitted because of phlebothrombosis of left femoral vein. The patient underwent three reoperations with total extirpation of recidivistic tumor located in left thigh and received six cycles of Xeloda. Histological examination proved an intergrowth into great saphenous vein. Authors did not come across a case in the literature with an intergrowth of metastasis into venous system with a five year survival of a patient. The patient from this case report has no local relapse and metastasis six years after the first operation. PMID- 20925262 TI - [A rare complication following anastomosis suturing using a biofragmentable Valtrac anastomosis ring--a case review and literature overview]. AB - The use of Valtrac Ring since 1985 has brought about the ability of easier anastomosis suturing and shortening of the operative treatment. As other methods, also Valtrac ring has its disadvantages. Authors present a case report of a complication previously not described in the literature. A 67 year old patient, after right hemicolectomy with ileotransversoanastomosis with the help of Valtrac due to adenocarcinoma, underwent a control colonoscopy six month after operation. Small polyps in colon sigmoideum, colon descendens and transverse were removed and a tissue stripe with ulceration was found during the examination. The bioptic sample was taken from this stripe. After the application of Fragmine, the patient had a massive enterorhagia, which was not even resolved by adrenaline per colonoscopy. The patient underwent re-resection of ileotrasversoanastomosis. A ring of tissue, created by circular necrosis in the place of seroserous connection of biofragmentile ring of both of the lumens, was found in the tissue sample. Stenosis of the anastomosis, dehiscence, bleeding and fistulation are described in the literature as the most common complications after Valtrac use. The incidence is comparable with complications during anastomosis sutured by hand. We would like to bring this extremely rare complication to the attention to all surgeons and gastroenterologists, who perform endoscopic examinations in patients after this surgical procedure. PMID- 20925263 TI - [Surgical management of the failed back surgery syndrome (FBSS) using posterior lumbar interbody fusion (PLIF) with posterior transpedicular stabilization]. AB - INTRODUCTION: One of possibility of treatment FBSS is posterior lumbar interbody fusion, PLIF with posterior transpedicular stabilization. MATERIAL AND METHODS: Between January 2005 and December 2007, the prospective study of treatment failed back surgery syndrome patients with posterior lumbal interbody fusion and posterior transpedicular stabilization was performed at the Department of Neurosurgery University Hospital FNLP in Kosice. Physical examinations were performed before surgery, after surgery 30 days, and at 4 follow-up visits (3 months, 6 months, 12 months and 24 months). At each interval, patients outcomes measures, including visual analog scale pain rating VAS and Oswestry Disability Index ODI. RESULTS: At the Department of Neurosurgery, 58 failed back surgery syndrome patients were operated on between 1.1.205 and 31.12. 2007. Long term follow up was investigated in 47 patients, 11 patients were lost to follow-up. Postoperative complications were controlled 30 days after surgery. They were presented in 9 patients (19.14%). No patient died after surgery. The working ability was found in 23 patients 49%. Before surgery all patiens used analgesic, after surgery there were present decrese in using analgesic. Improvement quality of life and decrease pain measured with ODI and VAS were investigated. ODI before surgery was 71.7 and 24 months after surgery ODI was 37.7. VAS before surgery was 7.95 and 24 months after surgery VAS was 2.82. There were found statistically significant influence on decrease pain mesuares ODI and VAS after surgery p < 0.0001. CONCLUSION: Our study results show that PLIF with posterior transpedicular stabilization can be safely perfomed and that can allow decrease pain and improve quality of life in FBSS patients. PMID- 20925264 TI - [Submucous lipoma as a cause of invagination in adulthood]. AB - The casuistry describes the invagination that occurred to a 67-years old patient due to the small intestine lipom. The patient with the three-day abdominal pain and vomiting was admitted to the department of surgery. On the basis of the CT examination the patient underwent an operation for the invagination of the small inkotine. The resection of the invaginated loop, the anastomosis end to end were performed. Histologicaly the submucosus lipom was found. PMID- 20925265 TI - [Acute injuries of lateral ankle joint ligaments]. AB - Acute injuries of the lateral ankle ligaments are one of the most common form of injury involving the musculoskeletal apparatus. Treatment usually range from cast immobilisation or acute surgical repair to functional rehabilitation. The aim of our study was to evaluate the incidence of different grades of acute injuries of lateral ligaments of the ankle joint in our patients group and to compare the results of non surgical versus surgical treatment of third grade injuries. 3148 patients were treated for acute lateral ankle sprain in a period of 5 years at our department. Each patient had stress X-ray of the ankle for evaluation of instability at the first visit. From the 234 patients with third grade injury, 39 were enrolled in our study with non surgical treatment and 18 with surgical treatment. Each group was divided regarding to the age in two subgroups. Functional outcome was evaluated 12 and 24 months after injury with AOFAS clinical rating scale and Sports Ankle Rating System--Single Assessment Numeric Evaluation. Statistical analysis was done with Pearson's Chi quadrate test with P < 0.05. First grade injury was present in 62%, second grade in 31% and only 7% of the patients had third grade injury of the lateral ankle ligaments. Further only third grade injuries were studied. Statistically significant better results were seen in patients under the age of 25, in the patient group with surgical treatment compared to patients over 25 years of age. Also statistically significant better results were seen in patient with surgical treatment to non surgical treatment in each age group. No significant difference was observed in the non surgical treatment group regarding to age. Although the injuries of the ankle ligaments belong to the most common injuries of the musculoskeletal system, there is no consensus in the treatment of such disorders. Our experiences and the results of our study show, that surgical treatment in indicated cases provides better results in residual pain and instability of the ankle joint after acute injury of the lateral ankle ligaments.; PMID- 20925266 TI - [Hallux flexus--the result of posttraumatic entrapment of the flexor hallucis longus tendon in the tibial fracture site]. AB - Entrapment of flexor hallucis longus after tibial fracture is very rare. We present a case of entrapment of flexor hallucis longus in a case of 36 years old male, who sustain an open tibial fracture. Fracture was stabilised with intramedullary nail. As a conseqence of entrapment of FHL hallux flexus was presented. After release of FHL in musculotendinous junction full range of motion in interphalangaela joint of hallux was obtained. PMID- 20925267 TI - [Endocannabinoid system I--the role in regulation of physiology functions]. AB - Endocannabinoid system has a wide scale of actions on CNS and on peripheral tissues. The system consists of cannabinoid receptors CB1 and CB2, endocannabinoids and their biosynthetic and degrading enzymes. CB1 receptors in high density occur on presynaptic neuronal terminals in brain influencing neurotransmission thereby number of functions--pain perception, inhibition of stress reaction, regulation of motor functions, cognition, emotional reactions, regulation of food intake, psychical homeostasis and motivation. CB1 receptors are present in GIT cells, hepatocytes, adipocytes, pancreatic isles cells. Energy homeostasis is the main function in peripheral issues. CB2 receptors are present mainly in cells of immune system, in the cilliary body of eye, in testes, vasal cells, and intestinal smooth muscle cells. PMID- 20925268 TI - [Endocannabinoid system II--the role in addictive behaviour, depression and in pathology of eating behaviour]. AB - Endocannabinoid system is involved in the neurobiological mechanism underlying drug addiction in all known kinds of drugs including nicotine and alcohol. Recently, relationships between endocannabinoids and biological nature of depression and eating disorders were recognised. Polymorphisms of genes encoding CB1 receptors and genes encoding main degrading enzyme FAAH responsible for pathology in motivation and cognition were identified. PMID- 20925269 TI - [Have changes in the management of treatment of the patients with acute pancreatitis brought the expected result?]. AB - BACKGROUND: Mortality from severe acute pancreatitis (AP) has remarkably decreased (10-20%) during the last decades. However, many questions on the treatment of this disease remained opened. To extend the most recent professional literature which discuses the abovementioned problem, experience from the treatment of patients at the department where the authors work is presented. METHODS: Influenced by the new methods published in professional literature and under the circumstances at own workplace, the decision to change the management of the treatment of AP has been made. The management referred to the enteral nutrition, epidural analgesy, antibiotic prophylaxis, pushing the surgical operation to the later period in the case of infected necrosis. Comparing of two groups of patients--A (2003-2005 years) and B (2006-2008 years) the authors came to interesting results. RESULTS: Applying the new protocol we observed: increased percentage of patients with sterile necrosis from 46% to 58%, decreased number of surgical re-operations from 43% to 33% and decreased mortality from 53,8% to 18%. CONCLUSIONS: Applying changes in the management of treatment of the patients with the complicated form of acute pancreatitis, the authors achieved remarkable results. Nevertheless, these results have to be evaluated very cautiously, because the group of patients who have been treated by the novel approach has not been very large. PMID- 20925270 TI - [The occurrence of microcarcinomas in the patients after thyroidectomy- retrospective analysis]. AB - BACKGROUND: Microcarcinomas, minimum carcinomas, are tumours, which are in clinical practice defined as tumours < or = 1 cm in size. WHO defines thyroid microcarcinomas as tumours < or = 2 cm in size, which have different biological behaviour. The aim of the study was to analyze the occurrence of MC in post operative patients. METHODS: Using retrospective analysis we evaluated the occurrence of thyroid microcarcinoma in post-operative patients. Except for basic demographic data, carcinoma size and histological variance, the occurrence of bilateral impairment, presence of multi-focuses and occurrence of regional throat metastases were considerd. RESULTS: From 2004 to 2008 thyroid surgeries were performed in 400 patients. Microcarcinoma was diagnosed in 34 patients (8.5%), 5 men and 29 women. The average age of patients with microcarcinoma was 52 years, similarly to other patients undergoing surgery. Histologically, 32 cases (94%) were papillary carcinoma, from which 4 cases were papillary follicular and 2 were follicular carcinomas. There were multifocal findings of microcarcinomas in 5 patients (15%), and 4 patients (12%) had bilateral involvement. The average size of the tumours was 5 mm, sd 2.6. Two patients (6%) had metastases in the lymph nodes of the neck. Total thyroidectomies were carried out in 32 patients (94%) and hemithyroidectomies in 2 patients (6%). Five patients (15%), i. e. both patients with metastases in the lymph nodes of the neck and three patients with bilateral multifocal carcinomas underwent postoperative adjuvant radioiodine 131I ablation therapy. CONCLUSIONS: Due to the possibility of the future growth, metastasizing andreoccurrence, microcarcinomas cannot be considered harmless or almost insignificant findings. The increased risk of the MC occurrence was found in chronic lymphoplasmocellular thyroiditis (17%). PMID- 20925271 TI - [Addictive diseases and poverty]. AB - Poverty is one of the risk factors for substance dependence and pathological gambling. Poverty interacts with other, often more important, protective and risk factors. Healthcare facilities should take into account the social situation of their patients; for example they can provide relevant information about social services or mediate social help. Communication with patient's family or community is also beneficial. Patients, as part of their treatment, can be instructed how to handle money and debts. On the other hand charitable organizations should take into account addictive problems of their clients. PMID- 20925272 TI - [Twenty years of teaching of social sciences and humanistic subjects at the First Faculty of Medicine Charles University in Prague]. PMID- 20925273 TI - [Regimen for gravid women at turn of century]. PMID- 20925274 TI - [Postgenomic era, what comes after?]. AB - Though we start to speak about postgenomic era, the genomic era has not been finished yet and the structure, function and variability of our genome is being still intensively studied and these studies bring us continually new scientific information--more than we are able to digest. The classical genetics utilized phenotype observation for discovering the function of genetic information and proceeded to the molecular basis represented by nucleic acids. Determination of the nucleotide sequence of the human genome is the top outcome of the effort. At present, the function, regulatory pathways and genome modifications have become principal targets of our research. If we compare variability, it increases in the direction from human genome to transcriptome and to proteom reaching the highest level in phenome. Differences concern not only quantity, but also quality with the exception of genome which is relatively stable and "we hand over to our children what we have inherited from our parents"--all other levels undergo dynamic changes, and from this point of view are much less stable and under continuous influence of environment. To understand enviromental factors shaping our phenome, a long-term monitoring of our living functions will be necessary and an instrumental approach has to be looked for. PMID- 20925275 TI - [Mast cells--a new view of the old acquaintances]. AB - Mast cells are well known as the producers of histamine and major effectors of type 1 hypersensitivity. They play however an important role in many other physiological and pathological processes. Lesser-known is their role in the processes such as a termination of pregnancy and initiation of delivery. The mast cells are considered as the modulators of endocrine signals on the local reactions in uterus. Many substances produced by the mast cells have the angiogenic effects known primarily for their role in tumour growth, but they influence also embryonal and postnatal growth or process of wound healing. Mast cells also participate in a number of compensatory reactions in the tissue response to the mechanical load, hypoxia or inflammation (airway remodelling in asthma, remodelling of pulmonary vessels in chronic hypoxia, myocardial hypertrophy, liver cirrhosis, chronic pancreatitis). This review describes recent concepts of their role in labour, non-cancerous angiogenesis and remodelling of pulmonary vasculature during chronic hypoxia. PMID- 20925277 TI - [Ethanol and other psychoactive substances in fatal road traffic accidents in the Czech Republic in 2008]. AB - BACKGROUND: To map the recent prevalence of alcohol and other psychoactive substances in deceased victims of traffic accidents in the Czech Republic. MATERIAL AND METHODS: The studied sample consisted of individuals autopsied in the departments of forensic medicine who died during traffic accidents in 2008 and were toxicologically tested for one or more of the following substances: ethanol, volatile substances, cannabis, opiates, stimulants, cocaine, benzodiazepines, and barbiturates. Case definition involved alcohol cases with blood alcohol concentration (BAC) 0.2 g/kg and higher; with cannabis, detections of active THC metabolites only were taken into account; from cases where volatile substances (solvents) were detected we included into the positive cases only those where substances were not produced post mortem or in some physiological or pathological statuses. RESULTS: The sample consisted of 1,040 persons deceased in traffic accidents, of whom 582 (56.0%) were toxicologically tested for one or more of the substances listed above. The sample has been divided into two subsamples--one of 778 (74.8%) active participants of road traffic accidents (pedestrians, bicyclists, and drivers) and other subsample consisting of 262 (25.4%) non-active participants. Ethanol was found in 38.3% of 381 tested and at least one of other psychoactive substances was found in 11.7% of 384 tested active participants--of those, stimulants (mostly methamphetamine) were found most frequently (6.5% of 337 tested), cannabis (5.9% of 203 tested) and benzodiazepines (3.9% of 363 tested active participants). Drivers were positive for ethanol in 29.2% cases, for one or more of other psychoactive substances except ethanol in 12.7% cases, most frequently for stimulants (9.2%) and cannabis (6.2%). Professional drivers were found negative for ethanol and other psychoactive substance except of one case of methamphetamine (6.7%). CONCLUSION: The study confirms high prevalence of alcohol and other psychoactive substances, especially stimulants (methamphetamine), cannabis and benzodiazepines, among deceased participants of road traffic accidents including drivers in the Czech Republic. PMID- 20925276 TI - [Alterations in fatty acid composition of plasma and erythrocyte lipids in critically ill patients during sepsis]. AB - BACKGROUND: The overall fatty acid (FA) composition, and especially proportions of n-6 and n-3 polyunsaturated fatty acids in plasma and membrane lipids, greatly impacts on cell and organ functions as well as on many biological processes. MATERIAL AND METHODS: Polyunsaturated FA determine membrane fluidity and thus modulate activities of membrane proteins (enzymes, carriers and receptors). They also are precursors of pro- and anti-inflammatory eicosanoids and other autacoids (resolvins, protectins). Thus, alterations in lipid FA composition of critically ill patients affect reactivity of the organism to numerous pathological stimuli. The objective of this study was to analyse FA composition of plasma triacylglycerols, cholesteryl esters, plasma phospholipids and erythrocyte phospholipids in septic patients. RESULTS: The study group consisted of 30 septic patients, 19 of whom were available for three samplings: Sampling 1 was 24 hours after the onset of sepsis, Sampling 2 was 7 days after Sampling 1, and Sampling 3 was 7 days after recovery from sepsis. Eight septic patients died. Compared to healthy controls, a decrease in n-6 polyunsaturated fatty acids accompanied by increase in monounsaturated fatty acids in cholesteryl esters, plasma phospholipids and erythrocyte phospholipids persisted in all three samplings of septic patients. CONCLUSIONS: This effect of sepsis was significantly greater in cholesteryl esters and plasma phospholipids of non-surviving septic patients than in surviving ones. Moreover, non-survivors had lower proportions of n-3 polyunsaturated fatty acids in plasma phospholipids compared to survivors. The significant decrease in proportion of polyunsaturated fatty acids in lipids of septic patients in the course of sepsis reflects the severity of their critical state and supports the importance of appropriate nutritional polyunsaturated fatty acids supplementation. PMID- 20925278 TI - [The prevalence of metabolic syndrome in women with polycystic ovary syndrome]. AB - BACKGROUND: Polycystic ovary syndrome (PCOS) affects between 4-10% women of fertile age and is often connected with insulin resistance. We aimed to ascertain the prevalence of metabolic syndrome in Czech women with PCOS and to describe relations of different features of metabolic syndrome with insulin sensitivity. METHODS AND RESULTS: 179 women with PCOS. Clinical examination was done and blood lipid spectrum was measured. Euglycaemic hyperinsulinaemic clamp was done in 114 subjects. Metabolic syndrome (according to ATP III criteria) was detected in 28.7% women. The most frequent features were an increased waist circumference, decreased concentration of HDL - cholesterol (both in 96%), and increased blood pressure (88%). Increased triglycerides (49%) and impaired fasting blood glucose or diabetes mellitus type 2 (37.3%) were less common. The average insulin sensitivity described as corrected glucose disposal (Mk) was 34.9 +/- 12.70 micromol/kg/min. The most tight correlations was that of Mk and waist circumference (r = -0.896), weight (r = -0.875) and BMI (r = -0.844). CONCLUSION: The increased risk of metabolic syndrome and the decreased insulin sensitivity in polycystic ovary syndrome is tightly connected with obesity, especially with its abdominal type. PMID- 20925279 TI - [Gallstone ileus--the diagnostic and therapeutic challenge]. AB - Gallstone ileus as a complication of gallstone disease is a diagnostic as well as therapeutic challenge. Its development is frequently sneaking, so correct diagnosis and surgical therapy is often delayed. Thus morbidity and mortality is high. Concrement extraction by open enterotomy is a therapeutic choice. The discussed issue is if one-stage cholecystectomy and fistula closure should be done too. The paper presents a female patient with gallstone ileus treated with open enterotomy only, with no postoperative complication. The literature review follows. Authors conclude that one-stage procedure, if feasible, is acceptable method for the low risk patients. PMID- 20925280 TI - Teacher-as-researcher: theory-into-practice. AB - This introductory article establishes the foundation for a special issue of the American Annals of the Deaf on teacher action research. The authors first introduce the definition of the teacher-as-researcher model, formally known as teacher action research. Four elements of teacher action research are discussed in detail: cyclical, systematic, reflective, and collaborative. Next, the history of teacher action research is discussed. Subsequently, the multi-paradigmatic and multimethodological nature of teacher action research is proposed. Finally, as a means of guiding readers, the scope of the special issue is described. The introduction concludes with the suggestion that in-service and preservice teachers integrate theory into practice and engage in systematic inquiry into their own practice to develop the mindset necessary to cope with the pedagogical challenges they face on a daily basis. PMID- 20925281 TI - Teaching poetry: a descriptive case study of a poetry unit in a classroom of urban deaf adolescents. AB - A qualitative study was conducted that reflected an analysis of a 6-week poetry unit in a language arts classroom of 6th and 8th graders at a school for the deaf in a large city in the northeastern United States. The school served a large population of children of poverty who were of Latino and African American descent. The study was guided by 4 research questions: (a) Would students benefit from having American Sign Language (ASL) poetry as a part of the unit? (b) Would teachers' signing of poems increase students' understanding of the poems? (c) Could students analyze the meaning of poems independently? (d) Would students view writing poetry as a vehicle for expressing their feelings and ideas through themes that were important to them? The evidence provided support for affirmative answers to questions a, b, and d. PMID- 20925282 TI - The teaching and learning of multimeaning words within a metacognitively based curriculum. AB - The study explored the effects of an 8-week intervention in which a teacher/researcher used direct instruction to show the multiple meanings of 7 words to 4 deaf students ages 11-13 years in a school for the deaf. Applying conclusions from emerging research that links knowledge and strategy with metacognitive skills, the teacher/researcher used specific metacognitive strategies to facilitate both the acquisition of the concept of multimeaning words and the ability to distinguish one meaning from another while reading, and thus improved the students' reading comprehension. The study participants were able to increase their vocabulary of multimeaning words as well as their reading comprehension in general, and, overall, experienced an improvement in their observable understanding and confidence when approaching the task of reading. PMID- 20925283 TI - The impact of Visual Phonics on the phonological awareness and speech production of a student who is deaf: a case study. AB - The researchers explored the effectiveness of Visual Phonics as a reading instructional tool when used in conjunction with a modified version of the Fountas and Pinnell Kindergarten Phonics Curriculum (Fountas & Pinnell, 2002) with a preschool student who was deaf. The study participant was a 4-year-old deaf child who had a cochlear implant. The goal of the study was to determine whether the student's phonological awareness and speech production improved over the course of a 6-week intervention. Identical pre- and postintervention tests were administered to measure the extent of any improvement. It was found that Visual Phonics used with a phonics-based curriculum significantly increased phonological awareness and speech production. PMID- 20925284 TI - The use of graphic representations of sign language in leveled texts to support deaf readers. AB - The study considered whether adding sign language graphics to the books being used for reading instruction in a first-grade classroom would promote the literacy development of students who are deaf or hard of hearing. The researchers also sought to discover whether materials existed to put the process of modifying leveled texts within the reach of the typical classroom teacher, in terms of cost and procedure. Students' reading behaviors seemed to indicate that the presence of sign graphics supported their development as readers. The materials needed to create sign support for the English print in the leveled books were commercially available. PMID- 20925285 TI - What is your prediction? Teaching the metacognitive skill of prediction to a class of sixth- and seventh-grade students who are deaf. AB - The development of the metacognitive skill of prediction in deaf students in a middle school social studies classroom was explored in an action research study (Riel, 2006). After observation of this group of learners and assessment of current skills, a unit was developed that integrated the teaching of prediction into their study of the American Revolution. It was found that these students were already using some metacognitive skills in their social studies class, but through direct instruction they were able to make more and better predictions related to the content being studied. The study demonstrates how the social studies curriculum provided an opportunity for students to learn and implement metacognitive skills that helped them to understand the cause-and-effect relationships in history and eventually to become more active readers during a reading task. PMID- 20925286 TI - Did the preservice teacher-generated studies constitute actual instances of teacher-researcher studies, and were they consistent with notions of Dewey? AB - It is suggested that articles in an American Annals of the Deaf special issue on teacher action research constitute a 2-tiered metastudy: The first article serves as a literature review of the teacher-as-researcher notion; 5 subsequent articles form the data set for a higher-order teacher-as-researcher inquiry. It is maintained that the preservice teachers' work met the definition of teacher-as researcher in that they systematically investigated their own teaching/learning practices through a reflective lens, with the twin purposes of modifying their own practices and contributing to the theoretical in situ knowledge base of learning and teaching in general. It is also argued that this body of work is consistent with the stance on inquiry advocated by Columbia University's Teachers College and its Program in the Education of the Deaf and Hard of Hearing, and that teacher research reflected Dewey's notions of pragmatism, functionalism, constructivism, communication, and social advocacy. PMID- 20925287 TI - Talking openly about death. PMID- 20925288 TI - Does the new GMC guidance on good practice and decision making in end-of-life care go far enough? PMID- 20925289 TI - The Liverpool Care Pathway in intensive care: an exploratory study of doctor and nurse perceptions. AB - The Liverpool Care Pathway (LCP) provides an evidence-based framework of care for the dying patient and provides guidance on comfort measures, discontinuation of inappropriate interventions, anticipatory prescribing, holistic care and care of the family after death. End-of-life care is becoming an important issue in critical care, and the LCP has been adapted for use in intensive care units in the United Kingdom. A qualitative study using descriptive phenomenology was used to explore doctor and nurse experiences of the impact of the LCP in two intensive care units in a 1000-bed teaching hospital in the north-west Midlands. The staff experience of the LCP was dependent on their role, with mixed reports about frequency of use and level of education received on the LCP. Education and adequate support was identified as being pivotal to the successful implementation of any type of LCP. PMID- 20925290 TI - Perceptions of the impact of health-care services provided to palliative care clients and their carers. AB - A wide range of services are provided to palliative care clients to alleviate pain and improve their quality of life. The purpose of this study was to explore the perceptions of clients and their carers regarding palliative care services in New South Wales, Austalia. Ten patients and their carers (n = 7) were randomly selected from a sample of palliative care clients and were informed of the study and interviewed. Interview data were coded independently by three researchers and thematic analysis was undertaken. The themes identified were similar for both clients and carers and included: access to services; service provision; impact on way of life; usefulness of services; and staffing. An additional theme identified by clients was the burden of caregiving on carers. Knowledge of perceptions and concerns of client and carers is important to consider when planning palliative care services. PMID- 20925291 TI - Interprofessional collaboration in palliative nursing: what is the patient-family role? AB - Interprofessional collaboration occurs when health professionals from different disciplines work together to identify needs, solve problems, make joint decisions on how best to proceed, and evaluate outcomes collectively. Interprofessional collaboration supports patient-centred care and takes place through teamwork. Team interactions, wider organizational issues, and environmental structures, such as safety, quality, efficiency and effectiveness issues influence this model of care. These broader contextual influences affect practice where there are tensions between the ideals of interprofessional collaboration and the realities of practice. This is evident when the patient and family position in interprofessional collaboration is considered. This article will discuss factors that affect interprofessional collaboration in relation to patients and families in palliative care. First, a definition of interprofessional collaboration is given, followed by an outline of the need for interprofessional collaboration. A brief discussion of key issues that influence collaboration follows, and a review of the implications for practice is presented. PMID- 20925292 TI - An investigation into the perceived stressors for staff working in the hospice service. AB - This article reports on the findings of phase two of a study into stress and coaching needs in two hospices in the United Kingdom. Phase one was a cross sectional study to assess the levels of stress and the main stressors as experienced by members of staff working within these two hospices. Phase two of the study uses qualitative methodology with the purpose of obtaining a deeper understanding of the stressors as experienced by hospice staff. Two focus groups were held, one at each hospice, and the data were analysed using grounded theory as its theoretical framework. A further aim of the current study was to identify coaching needs among this staff group in order to develop a tailor-made coaching programme for this service. PMID- 20925293 TI - The meaning of hope from the perspective of Chinese advanced cancer patients in Hong Kong. AB - AIM: This article reports a study to examine the meaning of hope from the perspective of Chinese advanced cancer patients in Hong Kong. METHODS: Semi structured interviews were conducted with a convenience sample of advanced cancer patients recruited from the palliative care unit of a local hospital. Data were saturated after 17 participants were interviewed. Qualitative content analysis was adopted to analyse the data. FINDINGS: Hope as experienced by the participants was found to consist of five components: living a normal life, social support, actively letting go of control, reconciliation between life and death, and wellbeing of significant others. CONCLUSIONS: While hope is related to the wellbeing of patients with advanced cancer, successful palliative care partly depends on an awareness of the importance of hope in the end-of-life context and cultural sensitivity to the meanings behind it from the patients' own perspective. PMID- 20925295 TI - Baylor Medical Center Irving. PMID- 20925294 TI - The business of hospital charge capture. PMID- 20925296 TI - Safety-net technology helps INTEGRIS Health reduce denials. PMID- 20925297 TI - [What responsibilities in medication errors?]. PMID- 20925298 TI - [Individualized care for the premature newborn]. PMID- 20925299 TI - [Developmental support care, an invitation to interact]. AB - Foetal and neonatal development is a relatively recent science. Any child born prematurely, even without any apparent sequelae, may present problems subsequently. Care which aims to eliminate overstimulation and dys-stimulation and encourage the parent-child relationship forms the basis of developmental care programmes, in the interest of the premature newborn. PMID- 20925300 TI - [The Nidcap, care centred on the newborn]. AB - The Nidcap (Newborn individualised developmental care and assessment programme) sets out a well-thought-out framework of care centred on the infant. Body temperature, nutritional and hormonal regulation is close to that observed in utero and individual stimulation is adapted to the cerebral capacities of the newborn. It thereby favours the harmonious development of the infant. PMID- 20925301 TI - [Communicating with premature newborns through touch]. AB - How does the premature newborn perceive the outside world? The first sense developed by the foetus is touch. Through the physiology of sensoriality and brain maturation, touch can constitute an essential vector in communicating with and caring for the premature child. PMID- 20925302 TI - [Analgesia and sedation in premature newborns]. AB - Analgesics and sedatives are routinely prescribed in intensive care on intubated premature newborns, to ensure their comfort and limit pain. The results of two studies show that there is no significant link between prolonged exposure to these treatments and a more unfavourable long-term neurological outcome. PMID- 20925303 TI - [Gwenaelle and Laura, first fragile moments]. PMID- 20925304 TI - [Ethics of the care given to premature newborns]. AB - The treatment of premature newborns has evolved a lot in France over the last decade. It can be examined with regard to the four main principles of biomedical ethics: beneficence, non-maleficence, autonomy and justice. Consequently the combination of medical-nursing vigilance and individualised developmental care enables the premature baby to benefit from truly "ethical" healthcare. PMID- 20925305 TI - [Individualized care of premature newborns]. PMID- 20925306 TI - [Evendol, a pain assessment scale for pediatric emergency departments]. AB - Evendol is a behavioural scale used to objectively assess the pain felt by children under 7 in paediatric emergency departments. Boasting excellent validity criteria and easy to use, it also differentiates pain and anxiety. It is a very useful tool when caring for children in pain in emergency departments. PMID- 20925307 TI - [A nursing consultation to improve antiretroviral medication management in children]. AB - The size of the antiretroviral capsules which children infected with HIV have to take is a major problem. It often requires an assessment of the feasibility of taking this medication through a specialist nursing consultation. It is above all through adopting a suitable technique as well as the motivation of the children that this objective can be achieved. PMID- 20925308 TI - [The persistent crying of newborns and its treatment]. AB - The persistent and unexplained crying of newborns, attributed to colic, is a frequent problem in paediatrics. Usually considered harmless, it can however have consequences on the baby's behaviour and emotional regulation. Moreover, mothers often misinterpret the crying. Faced with the maternal anxiety which is often associated, treatment must be multifocal. PMID- 20925309 TI - [12/12. Drug intoxication]. PMID- 20925310 TI - [5/6. Obstetric delivery and confidentiality]. PMID- 20925311 TI - [Birthing and Living]. PMID- 20925312 TI - Local current mapping and patterning of reduced graphene oxide. AB - Conductive atomic force microscopy (C-AFM) has been used to correlate the detailed structural and electrical characteristics of graphene derived from graphene oxide. Uniform large currents were measured over areas exceeding tens of micrometers in few-layer films, supporting the use of graphene as a transparent electrode material. Moreover, defects such as electrical discontinuities were easily detected. Multilayer films were found to have a higher conductivity per layer than single layers. It is also shown that a local AFM-tip-induced electrochemical reduction process can be used to pattern conductive pathways on otherwise-insulating graphene oxide. Transistors with micrometer-scale tip reduced graphene channels that featured ambipolar transport and an 8 order of magnitude increase in current density upon reduction were successfully fabricated. PMID- 20925313 TI - Self-association of the adenoviral L4-22K protein. AB - Human adenovirus (Ad) is an icosahedral, double-stranded DNA virus that causes infections of the respiratory tract, urinary tract, and gastrointestinal tract. Assembly of virus particles requires condensation and encapsidation of the linear viral genome. This process requires sequence specific binding of two viral proteins, called IVa2 and L4-22K, to a conserved sequence located at the left end of the viral genome, called the packaging sequence (PS). IVa2 and an alternatively spliced form of L4-22K, called L4-33K, also function as transcriptional activators of the major late promoter (MLP), which encodes viral structural and core proteins. IVa2 and L4-33K bind to identical conserved DNA sequences downstream of the MLP, called the downstream element (DE), to activate transcription. To begin to dissect how the IVa2, L4-22K, and L4-33K proteins simultaneously function as transcriptional activators and DNA packaging proteins, we need to understand the thermodynamics of assembly of these proteins on DNA that contains the PS as well as the DE. Toward this end, we have characterized the self-assembly properties of highly purified, recombinant L4-22K protein. We show that L4-22K reversibly assembles into higher-order structures according to an indefinite, isodesmic assembly scheme. We show that the smallest polymerizing unit is likely the L4-22K monomer (s(20,w) = 2.16 +/- 0.04 S) and that the monomer assembles with itself and/or other aggregates with an equilibrium association constant, L, of 112 (102, 124) MUM(-1) (0.1 M NaCl, pH 7, 25 degrees C). A mechanistic consequence of an isodesmic, indefinite assembly process is that the free concentration of the smallest polymerizing unit cannot exceed 1/L. We discuss the implications of this observation with respect to the thermodynamics of assembly of L4-22K and IVa2 on the PS. PMID- 20925314 TI - Cell-based assay to quantify the antioxidant effect of food-derived carotenoids enriched in postprandial human chylomicrons. AB - We developed a new method to evaluate the antioxidant effect of food products in a biological system. The antioxidant status of HepG2 cells was quantified after incubation with postprandial human chylomicrons after the intake of vegetable products. Three subjects consumed in a meal a vegetable soup containing 8.4 mg of beta-carotene and 9 mg of lycopene. After 5 h, the subjects consumed a second meal without carotenoids. Blood samples were collected at basal time and every hour for 9 h. Chylomicrons were isolated from serum samples and used for both carotenoid quantification and HepG2 stimulation. Carotenoid in chylomicrons followed an inter-individual and bimodal carotenoid response. We demonstrated the antioxidant effect of postprandial chylomicrons in HepG2 at the time of maximum carotenoid concentration of chylomicrons with respect to basal time. This cell based assay seems to be a useful method to evaluate the antioxidant effect of fruit and vegetable products in a biological system. PMID- 20925315 TI - Structure-activity relationships of polyphenols to prevent lipid oxidation in pelagic fish muscle. AB - The influence of polymerization (number of monomers) and galloylation (content of esterified gallates) of oligomeric catechins (proanthocyanidins) on their effectiveness to prevent lipid oxidation in pelagic fish muscle was evaluated. Non-galloylated oligomers of catechin with diverse mean polymerization (1.9-3.4 monomeric units) were extracted from pine (Pinus pinaster) bark. Homologous fractions with galloylation ranging from 0.25 to <1 gallate group per molecule were obtained from grape (Vitis vinifera) and witch hazel (Hamamelis virginiana). The results showed the convenience of proanthocyanidins with medium size (2-3 monomeric units) and low galloylation degree (0.15-0.25 gallate group/molecule) to inhibit lipid oxidation in pelagic fish muscle. These optimal structural characteristics of proanthocyanidins were similar to those lately reported in fish oil-in-water emulsions using phosphatidylcholine as emulsifier. This finding suggests that the antioxidant behavior of polyphenols in muscle-based foods can be mimicked in emulsions prepared with phospholipids as emulsifier agents. The present data give relevant information to achieve an optimum use of polyphenols in pelagic fish muscle. PMID- 20925316 TI - Modeling intrinsically disordered proteins with bayesian statistics. AB - The characterization of intrinsically disordered proteins is challenging because accurate models of these systems require a description of both their thermally accessible conformers and the associated relative stabilities or weights. These structures and weights are typically chosen such that calculated ensemble averages agree with some set of prespecified experimental measurements; however, the large number of degrees of freedom in these systems typically leads to multiple conformational ensembles that are degenerate with respect to any given set of experimental observables. In this work we demonstrate that estimates of the relative stabilities of conformers within an ensemble are often incorrect when one does not account for the underlying uncertainty in the estimates themselves. Therefore, we present a method for modeling the conformational properties of disordered proteins that estimates the uncertainty in the weights of each conformer. The Bayesian weighting (BW) formalism incorporates information from both experimental data and theoretical predictions to calculate a probability density over all possible ways of weighting the conformers in the ensemble. This probability density is then used to estimate the values of the weights. A unique and powerful feature of the approach is that it provides a built-in error measure that allows one to assess the accuracy of the ensemble. We validate the approach using reference ensembles constructed from the five-residue peptide met-enkephalin and then apply the BW method to construct an ensemble of the K18 isoform of the tau protein. Using this ensemble, we indentify a specific pattern of long-range contacts in K18 that correlates with the known aggregation properties of the sequence. PMID- 20925317 TI - Positional effects on helical Ala-based peptides. AB - Helix-coil equilibrium studies are important for understanding helix formation in protein folding, and for helical foldamer design. The quantitative description of a helix using statistical mechanical models is based on experimentally derived helix propensities and the assumption that helix propensity is position independent. To investigate this assumption, we studied a series of 19-residue Ala-based peptides, to measure the helix propensity for Leu, Phe, and Pff at positions 6, 11, and 16. Circular dichroism spectroscopy revealed that substituting Ala with a given amino acid (Leu, Phe, or Pff) resulted in the following fraction helix trend: KXaa16 > KXaa6 > KXaa11. Helix propensities for Leu, Phe, and Pff at the different positions were derived from the CD data. For the same amino acid, helix propensities were similar at positions 6 and 11, but much higher at position 16 (close to the C-terminus). A survey of protein helices revealed that Leu/Phe-Lys (i, i + 3) sequence patterns frequently occur in two structural patterns involving the helix C-terminus; however, these cases include a left-handed conformation residue. Furthermore, no Leu/Phe-Lys interaction was found except for the Lys-Phe cation-pi interaction in two cases of Phe-Ala-Ala Lys. The apparent high helix propensity at position 16 may be due to helix capping, adoption of a 310-helix near the C-terminus perhaps with Xaa-Lys (i, i + 3) interactions, or proximity to the peptide chain terminus. Accordingly, helix propensity is generally position-independent except in the presence of alternative structures or in the proximity of either chain terminus. These results should facilitate the design of helical peptides, proteins, and foldamers. PMID- 20925318 TI - Molecular insights into the potential and temperature dependences of the differential capacitance of a room-temperature ionic liquid at graphite electrodes. AB - Molecular dynamics simulation studies of the structure and the differential capacitance (DC) for the ionic liquid (IL) N-methyl-N-propylpyrrolidinium bis(trifluoromethane)sulfonyl imide ([pyr(13)][TFSI]) near a graphite electrode have been performed as a function temperature and electrode potential. The IL exhibits a multilayer structure that extends 20-30 A from the electrode surface. The composition and ion orientation in the innermost layer were found to be strongly dependent on the electrode potential. While at potentials near the potential of zero charge (PZC), both cations and anions adjacent to the surface are oriented primarily perpendicular to the surface, the counterions in first layer orient increasingly parallel to the surface with increasing electrode potential. A minimum in DC observed around -1 V(RPZC) (potential relative to the PZC) corresponds to the point of highest density of perpendicularly aligned TFSI near the electrode. Maxima in the DC observed around +1.5 and -2.5 V(RPZC) are associated with the onset of "saturation", or crowding, of the interfacial layer. The asymmetry of DC versus electrode polarity is the result of strong interactions between the fluorine of TFSI and the surface, the relatively large footprint of TFSI compared to pyr(13), and the tendency of the propyl tails of pyr(13) to remain adsorbed on the surface even at high positive potentials. Finally, an observed decreased DC and the disappearance of the minimum in DC near the PZC with increasing temperature are likely due to the increasing importance of entropic/excluded volume effects (interfacial crowding) with increasing temperature. PMID- 20925319 TI - Effect of water electrolysis catalysts on carbon corrosion in polymer electrolyte membrane fuel cells. AB - A new approach to preventing electrochemical carbon corrosion in the cathode of polymer electrolyte membrane fuel cells (PEMFCs) was developed. The addition of 2 wt % IrO(2) (0.016 mg cm(-2)) to the catalyst layer of the cathode was demonstrated to reduce the electrochemical corrosion of carbon by 76% at 1.6 V(NHE) and 70 degrees C compared with a commercial Pt/C catalyst of the same Pt loading of 0.4 mg cm(-2) and under the same test conditions. The IrO(2) was shown to behave as a catalyst for water electrolysis, thereby removing water from the catalyst layer, which promoted electrochemical carbon corrosion. PMID- 20925320 TI - Pd-Ga intermetallic compounds as highly selective semihydrogenation catalysts. AB - The intermetallic compounds Pd(3)Ga(7), PdGa, and Pd(2)Ga are found to be highly selective semihydrogenation catalysts for acetylene outperforming established systems. The stability of the crystal and electronic structure under reaction conditions allows the direct relation of structural and catalytic properties and a knowledge-based development of new intermetallic catalyst systems. In the crystal structure of PdGa palladium is exclusively surrounded by gallium atoms. The alteration of the Pd coordination in PdGa leads to a strong modification of the electronic structure around the Fermi level in comparison to elemental Pd. Electronic modification and isolation of active sites causes the excellent catalytic semihydrogenation properties. PMID- 20925321 TI - Chalcogels: porous metal-chalcogenide networks from main-group metal ions. Effect of surface polarizability on selectivity in gas separation. AB - We report the synthesis of metal-chalcogenide gels and aerogels from anionic chalcogenide clusters and linking metal ions. Metal ions such as Sb(3+) and Sn(2+), respectively chelated with tartrate and acetate ligands, react in solution with the chalcogenide clusters to form extended polymeric networks that exhibit gelation phenomena. Chalcogenide cluster anions with different charge densities, such as [Sn(2)S(6)](4-) and [SnS(4)](4-), were employed. In situ rheological measurements during gelation showed that a higher charge density on the chalcogenide cluster favors formation of a rigid gel network. Aerogels obtained from the gels after supercritical drying have BET surface areas from 114 to 368 m(2)/g. Electron microscopy images coupled with nitrogen adsorption measurements showed the pores are micro (below 2 nm), meso (2-50 nm), and macro (above 50 nm) regions. These chalcogels possess band gaps in the range of 1.00 2.00 eV and selectively adsorb polarizable gases. A 2-fold increase in selectivity toward CO(2)/C(2)H(6) over H(2) was observed for the Pt/Sb/Ge(4)Se(10)-containing aerogel compared to aerogel containing Pt(2)Ge(4)S(10). The experimental results suggest that high selectivity in gas adsorption is achievable with high-surface-area chalcogenide materials containing heavy polarizable elements. PMID- 20925322 TI - Coordination copolymerization mediated by Zn4O(CO2R)6 metal clusters: a balancing act between statistics and geometry. AB - Isolated successes of coordination copolymerization for the production of microporous coordination polymers (MCPs) have been reported recently; the logic for this synthetic approach has not been established nor have the key features of the synthetic conditions needed to generalize the method. Here, we establish guidelines for application of the copolymerization technique by exploring coordination modes and report, in addition to details on two previous coordination copolymers with exceptional properties, three new MCPs: UMCM-3 (Zn(4)O(2,5-thiophenedicaboxylate)(1.2)(1,3,5-tris(4 carboxyphenyl)benzene)(1.2)), UMCM-4 (Zn(4)O(1,4 benzenedicarboxylate)((3)/(2))(4,4',4''-tricarboxytriphenylamine)), and UMCM-5 (Zn(4)O(1,4-naphthalenedicarboxylate)(1,3,5-tris(4 carboxyphenyl)benzene)((4)/(3))). The MCPs prepared by the copolymerization technique demonstrate Brunauer-Emmett-Teller (BET) surface areas between 3500 5200 m(2)/g and high pore volumes (1.64-2.37 cm(3)/g). In addition, the alignment of poly(3-hexylthiophene) within mesoporous channels of UMCM-1 is reported as a demonstration of the unique properties of these hosts. PMID- 20925323 TI - Toward the Lambertian limit of light trapping in thin nanostructured silicon solar cells. AB - We examine light trapping in thin silicon nanostructures for solar cell applications. Using group theory, we design surface nanostructures with an absorptance exceeding the Lambertian limit over a broad band at normal incidence. Further, we demonstrate that the absorptance of nanorod arrays closely follows the Lambertian limit for isotropic incident radiation. These effects correspond to a reduction in silicon mass by 2 orders of magnitude, pointing to the promising future of thin crystalline silicon solar cells. PMID- 20925325 TI - Plasmonic demultiplexer and guiding. AB - Two-dimensional plasmonic demultiplexers for surface plasmon polaritons (SPPs), which consist of concentric grooves on a gold film, are proposed and experimentally demonstrated to realize light-SPP coupling, effective dispersion, and multiple-channel SPP guiding. A resolution as high as 10 nm is obtained. The leakage radiation microscopy imaging shows that the SPPs of different wavelengths are focused and routed into different SPP strip waveguides. The plasmonic demultiplexer can thus serve as a wavelength division multiplexing element for an integrated plasmonic circuit and also as a plasmonic spectroscopy or filter. PMID- 20925326 TI - Concise synthesis of the oxapentacyclic core of cortistatin A. AB - A concise synthetic approach for constructing the oxapentacyclic framework of cortistatin A is described. The synthesis features a furan-oxyallyl [4 + 3] cycloaddition and double-intramolecular aldol reactions. In addition, an interesting core structure was obtained in 11 steps from furan by using our method. PMID- 20925328 TI - Convergent synthesis of geometrically disassembling dendrimers using Cu(I) catalyzed C-O bond formation. AB - The convergent synthesis of geometrically degradable dendrimers based on the 2,4 bis(hydroxymethyl)phenol subunit is presented. The key step of the synthetic scheme involves the CuI/3,4,7,8-tetramethyl-1,10-phenanthroline-catalyzed coupling of aryl iodides and alcohols. The synthesis and disassembly of these compounds is discussed. PMID- 20925327 TI - Partitioning and localization of environment-sensitive 2-(2'-pyridyl)- and 2-(2' pyrimidyl)-indoles in lipid membranes: a joint refinement using fluorescence measurements and molecular dynamics simulations. AB - Fluorescence of environment-sensitive dyes is widely applied to monitor local structure and solvation dynamics of biomolecules. It has been shown that, in comparison with a parent indole fluorophore, fluorescence of 2-(2'-pyridyl)-5 methylindole (5M-PyIn-0) and 2-[2'-(4',6'-dimethylpyrimidyl)]-indole (DMPmIn-0) is remarkably sensitive to hydrogen bonding with protic partners. Strong fluorescence, observed for these compounds in nonpolar and polar aprotic solvents, is efficiently quenched in aqueous solution. This study demonstrates that 5M-PyIn-0 and DMPmIn-0, which are almost nonemitting in aqueous solution, become highly fluorescent upon titrating with phospholipid vesicles. The fluorescence enhancement is accompanied by a significant blue shift of emission maximum. The Gibbs free energy of membrane partitioning, measured by the increase in the steady-state fluorescence intensities during transfer from an aqueous environment to a lipid bilayer, is very favorable for both compounds, being in a range from -7.1 to -8.0 kcal/mol and depending only slightly on lipid composition of the membrane. The fluorescence enhancement upon membrane partitioning is indicative of the loss of the specific hydrogen-bonding interactions between the excited fluorophore and water molecules, causing efficient fluorescence quenching in bulk water. This conclusion is supported by atomistic molecular dynamics (MD) simulations, demonstrating that both 5M-PyIn-0 and DMPmIn-0 bind rapidly and partition deeply into a lipid bilayer. MD simulations also show a rapid, nanosecond-scale decrease in the probability of solute-solvent hydrogen bonding during passive diffusion of the probe molecules from bulk water into a lipid bilayer. At equilibrium conditions, both 5M-PyIn-0 and DMPmIn-0 prefer deep localization within the hydrophobic, water-free region of the bilayer. A free energy profile of penetration across a bilayer estimated using MD umbrella sampling shows that both indole derivatives favor residence in a rather wide potential energy well located 10-15 A from the bilayer center. PMID- 20925329 TI - Halogenation of carbon substrates for increased reactivity with alkenes. AB - Carbon substrates are readily functionalized with alkene-containing molecules via an ultraviolet-light-catalyzed reaction, resulting in the formation of a carbon carbon bond with the surface. This reaction is typically performed on hydrogen terminated carbon substrates, limiting its utility as alkene molecules with low electron affinities do not readily attach to this surface. Recently, a wet chemical method for preparing bromine- and chlorine-terminated carbon substrates has been developed. Replacing the terminal hydrogen atoms with a halogen analog increases the surface's reactivity with alkene-containing molecules, affording a means of modifying the carbon substrate with the alkene molecules that do not readily attach to the hydrogen-terminated surface and with a greatly reduced reaction time. PMID- 20925330 TI - Novel acyclic diaminocarbene ligands with increased steric demand and their application in gold catalysis. AB - Sterically demanding and conformationally stable N,N'-ditertiaryalkyl-N,N' diphenyl acyclic diaminocarbenes (ADCs) were developed. Bulky ADC-Au catalysts not only showed competitive reactivities in hydroamination and enyne cyclization but also demonstrated unique ligand properties different from bulky N heterocyclic carbene (NHC) counterparts. PMID- 20925332 TI - Reversible dispersion of single-walled carbon nanotubes based on a CO2-responsive dispersant. AB - A CO(2)-responsive dispersant, N,N-dimethyl-N'-(pyren-1-ylmethyl) acetimidamidinium (PyAH(+)), which bears both a pyrene moiety and an amidinium cation, has been successfully synthesized. Through strong pi-pi interaction between the pyrene moiety and single-walled carbon nanotubes (SWNTs), we have demonstrated that PyAH(+) can be modified onto SWNT surfaces to promote the dispersion of SWNTs in water. Furthermore, taking advantage of gas triggered interconversions between the amidinium cation and amidine, reversible control on the solubility of SWNTs has been achieved simply through alternated bubbling of CO(2) and Ar. This work has demonstrated a new method for controlled dispersion and aggregation of SWNTs, and it may contribute to the development of gas responsive carbon materials. PMID- 20925333 TI - Quantitative model of the phase behavior of recombinant pH-responsive elastin like polypeptides. AB - Quantitative models are required to engineer biomaterials with environmentally responsive properties. With this goal in mind, we developed a model that describes the pH-dependent phase behavior of a class of stimulus responsive elastin-like polypeptides (ELPs) that undergo reversible phase separation in response to their solution environment. Under isothermal conditions, charged ELPs can undergo phase separation when their charge is neutralized. Optimization of this behavior has been challenging because the pH at which they phase separate, pHt, depends on their composition, molecular weight, concentration, and temperature. To address this problem, we developed a quantitative model to describe the phase behavior of charged ELPs that uses the Henderson-Hasselbalch relationship to describe the effect of side-chain ionization on the phase transition temperature of an ELP. The model was validated with pH-responsive ELPs that contained either acidic (Glu) or basic (His) residues. The phase separation of both ELPs fit this model across a range of pH. These results have important implications for applications of pH-responsive ELPs because they provide a quantitative model for the rational design of pH-responsive polypeptides whose transition can be triggered at a specified pH. PMID- 20925335 TI - Stability and reactivity of epsilon-chi-theta iron carbide catalyst phases in Fischer-Tropsch synthesis: controlling MU(C). AB - The stability and reactivity of epsilon, chi, and theta iron carbide phases in Fischer-Tropsch synthesis (FTS) catalysts as a function of relevant reaction conditions was investigated by a synergistic combination of experimental and theoretical methods. Combined in situ X-ray Absorption Fine Structure Spectroscopy/X-ray Diffraction/Raman Spectroscopy was applied to study Fe-based catalysts during pretreatment and, for the first time, at relevant high pressure Fischer-Tropsch synthesis conditions, while Density Functional Theory calculations formed a fundamental basis for understanding the influence of pretreatment and FTS conditions on the formation of bulk iron carbide phases. By combining theory and experiment, it was found that the formation of theta-Fe(3)C, chi-Fe(5)C(2), and epsilon-carbides can be explained by their relative thermodynamic stability as imposed by gas phase composition and temperature. Furthermore, it was shown that a significant part of the Fe phases was present as amorphous carbide phases during high pressure FTS, sometimes in an equivalent amount to the crystalline iron carbide fraction. A catalyst containing mainly crystalline chi-Fe(5)C(2) was highly susceptible to oxidation during FTS conditions, while a catalyst containing theta-Fe(3)C and amorphous carbide phases showed a lower activity and selectivity, mainly due to the buildup of carbonaceous deposits on the catalyst surface, suggesting that amorphous phases and the resulting textural properties play an important role in determining final catalyst performance. The findings further uncovered the thermodynamic and kinetic factors inducing the epsilon-chi-theta carbide transformation as a function of the carbon chemical potential MU(C). PMID- 20925334 TI - Expanding the genetic code of yeast for incorporation of diverse unnatural amino acids via a pyrrolysyl-tRNA synthetase/tRNA pair. AB - We report the discovery of a simple system through which variant pyrrolysyl-tRNA synthetase/tRNA(CUA Pyl) pairs created in Escherichia coli can be used to expand the genetic code of Saccharomyces cerevisiae. In the process we have solved the key challenges of producing a functional tRNA(CUA Pyl) in yeast and discovered a pyrrolysyl-tRNA synthetase/tRNA(CUA Pyl) pair that is orthogonal in yeast. Using our approach we have incorporated an alkyne-containing amino acid for click chemistry, an important post-translationally modified amino acid and one of its analogs, a photocaged amino acid and a photo-cross-linking amino acid into proteins in yeast. Extensions of our approach will allow the growing list of useful amino acids that have been incorporated in E. coli with variant pyrrolysyl tRNA synthetase/tRNA(CUA Pyl) pairs to be site-specifically incorporated into proteins in yeast. PMID- 20925336 TI - Lanthanide amides [(Me(3)Si)(2)N](3)Ln(MU-Cl)Li(THF)(3) catalyzed hydrophosphonylation of aryl aldehydes. AB - A highly efficient method for the synthesis of alpha-hydroxy phosphonates via lanthanide amides [(Me(3)Si)(2)N](3)Ln(MU-Cl)Li(THF)(3) catalyzed hydrophosphonylation of aromatic aldehydes was developed. The reactions produced the products in excellent yields in the presence of 0.1 mol % [(Me(3)Si)(2)N](3)La(MU-Cl)Li(THF)(3) at room temperature within 5 min. The existence of LiCl in the catalyst was a key factor affecting the catalytic activity. The mechanism for the process of high efficiency was proposed. PMID- 20925337 TI - Hydride-containing models for the active site of the nickel-iron hydrogenases. AB - The [NiFe]-hydrogenase model complex NiFe(pdt)(dppe)(CO)(3) (1) (pdt = 1,3 propanedithiolate) has been efficiently synthesized and found to be robust. This neutral complex sustains protonation to give the first nickel-iron hydride [1H]BF(4). One CO ligand in [1H]BF(4) is readily substituted by organophosphorus ligands to afford the substituted derivatives [HNiFe(pdt)(dppe)(PR(3))(CO)(2)]BF(4), where PR(3) = P(OPh)(3) ([2H]BF(4)); PPh(3) ([3H]BF(4)); PPh(2)Py ([4H]BF(4), where Py = 2-pyridyl). Variable temperature NMR measurements show that the neutral and protonated derivatives are dynamic on the NMR time scale, which partially symmetrizes the phosphine complex. The proposed stereodynamics involve twisting of the Ni(dppe) center, not rotation at the Fe(CO)(2)(PR(3)) center. In MeCN solution, 3, which can be prepared by deprotonation of [3H]BF(4) with NaOMe, is about 10(4) stronger base than is 1. X ray crystallographic analysis of [3H]BF(4) revealed a highly unsymmetrical bridging hydride, the Fe-H bond being 0.40 A shorter than the Ni-H distance. Complexes [2H]BF(4), [3H]BF(4), and [4H]BF(4) undergo reductions near -1.46 V vs Fc(0/+). For [2H]BF(4), this reduction process is reversible, and we assign it as a one-electron process. In the presence of trifluoroacetic acid, proton reduction catalysis coincides with this reductive event. The dependence of i(c)/i(p) on the concentration of the acid indicates that H(2) evolution entails protonation of a reduced hydride. For [2H](+), [3H](+), and [4H](+), the acid-independent rate constants are 50-75 s(-1). For [2H](+) and [3H](+), the overpotentials for H(2) evolution are estimated to be 430 mV, whereas the overpotential for the N protonated pyridinium complex [4H(2)](2+) is estimated to be 260 mV. The mechanism of H(2) evolution is proposed to follow an ECEC sequence, where E and C correspond to one-electron reductions and protonations, respectively. On the basis of their values for its pK(a) and redox potentials, the room temperature values of DeltaG(H*) and DeltaG(H-) are estimated as respectively as 57 and 79 kcal/mol for [1H](+). PMID- 20925338 TI - Molecular hydrogen "pairing" interaction in a metal organic framework system with unsaturated metal centers (MOF-74). AB - Infrared (IR) absorption spectroscopy measurements of molecular hydrogen in MOF 74-M (M = metal center) are performed as a function of temperature and pressure [to 45 kTorr (60 bar) at 300 K, and at lower pressures in the 20-200 K range] to investigate the nature of H(2) interactions with the unsaturated metal centers. A small shift (~ -30 cm(-1) with respect to the unperturbed H(2) molecule) is observed for the internal stretch frequency of H(2) molecules adsorbed on the metal site at low loading. This finding is in contrast to much larger shifts (~ 70 cm(-1)) observed in previous studies of MOFs with unsaturated metal centers (including MOF-74) and the general assumption that H(2) stretch shifts depend on adsorption energies (FitzGerald et al., Phys. Rev. B 2010, 81, 104305). We show that larger shifts (~ -70 cm(-1)) do occur, but only when the next available site ("oxygen" site) is occupied. This larger shift originates from H(2)-H(2) interactions on neighboring sites of the same pore, consistent with the short distance between H(2) in these two sites ~2.6 A derived from an analysis of neutron diffraction experiments of D(2)-D(2) at 4 K (Liu et al., Langmuir 2008, 24, 4772-4777). Our results at 77 K and low loading can be explained by a diffusion barrier against pair disruption, which should be enhanced by this interaction. Calculations indicate that the vibrational shifts do not correlate with binding energies and are instead very sensitive to the environment (interaction potential and H(2)-H(2) interactions), which complicates the use of variable temperature IR methods to calculate adsorption energies of specific adsorption sites. PMID- 20925339 TI - Mechanism and stereospecificity of a fully saturating polyketide synthase module: nanchangmycin synthase module 2 and its dehydratase domain. AB - Recombinant nanchangmycin synthase module 2 (NANS module 2), with the thioesterase domain from the 6-deoxyerythronolide B synthase (DEBS TE) appended to the C-terminus, was cloned and expressed in Escherichia coli. Incubation of NANS module 2+TE with (+/-)-2-methyl-3-keto-butyryl-N-acetylcysteamine thioester (1), the SNAC analog of the natural ACP-bound substrate, with methylmalonyl-CoA (MM-CoA) in the absence of NADPH gave 3,5,6-trimethyl-4-hydroxypyrone (2), identified by direct comparison with synthetic 2 by radio-TLC-phosphorimaging and LC-ESI(+)-MS-MS. The reaction showed k(cat) 0.5 +/- 0.1 min(-1) and K(m)(1) 19 +/ 5 mM at 0.5 mM MM-CoA and k(cat)(app) 0.26 +/- 0.02 min(-1) and K(m)(MM-CoA) 0.11 +/- 0.02 mM at 8 mM 1. Incubation in the presence of NADPH generated the fully saturated triketide chain elongation product as a 5:3 mixture of (2S,4R) 2,4-dimethyl-5-ketohexanoic acid (3a) and the diastereomeric (2S,4S)-3b. The structure and stereochemistry of each product was established by comparison with synthetic 3a and 3b by a combination of radio-TLC-phosphorimaging and LC-ESI(-) MS-MS, as well as chiral capillary GC-MS analysis of the corresponding methyl esters 3a-Me and 3b-Me. The recombinant dehydratase domain from NANS module 2, NANS DH2, was shown to catalyze the formation of an (E)-double bond by syn dehydration of the ACP-bound substrate anti-(2R,3R,4S,5R)-2,4-dimethyl-3,5 dihydroxyheptanoyl-ACP6 (4), generated in situ by incubation of (2S,3R)-2-methyl 3-hydroxypentanoyl-SNAC (5), methylmalonyl-CoA, and NADPH with the recombinant [KS6][AT6] didomain and ACP6 from DEBS module 6 along with the ketoreductase from the tylactone synthase module 1 (TYLS KR1). These results also indirectly establish the stereochemistry of the reactions catalyzed by the KR and enoylreductase (ER) domains of NANS module 2. PMID- 20925340 TI - Probing the oxyferrous and catalytically active ferryl states of Amphitrite ornata dehaloperoxidase by cryoreduction and EPR/ENDOR spectroscopy. Detection of compound I. AB - Dehaloperoxidase (DHP) from Amphitrite ornata is a heme protein that can function both as a hemoglobin and as a peroxidase. This report describes the use of 77 K cryoreduction EPR/ENDOR techniques to study both functions of DHP. Cryoreduced oxyferrous [Fe(II)-O(2)] DHP exhibits two EPR signals characteristic of a peroxoferric [Fe(III)-O(2)(2-)] heme species, reflecting the presence of conformational substates in the oxyferrous precursor. (1)H ENDOR spectroscopy of the cryogenerated substates shows that H-bonding interactions between His N(epsilon)H and heme-bound O(2) in these conformers are similar to those in the beta-chain of oxyferrous hemoglobin A (HbA) and oxyferrous myoglobin, respectively. Decay of cryogenerated peroxoferric heme DHP intermediates upon annealing at temperatures above 180 K is accompanied by the appearance of a new paramagnetic species with an axial EPR signal with g(?) = 3.75 and g(?) = 1.96, characteristic of an S = 3/2 spin state. This species is assigned to Compound I (Cpd I), in which a porphyrin pi-cation radical is ferromagnetically coupled with an S = 1 ferryl [Fe(IV)?O] ion. This species was also trapped by rapid freeze quench of the ambient-temperature reaction mixture of ferric [Fe(III)] DHP and H(2)O(2). However, in the latter case Cpd I is reduced very rapidly by a nearby tyrosine to form Cpd ES [(Fe(IV)?O)(porphyrin)/Tyr(*)]. Addition of the substrate analogue 2,4,6-trifluorophenol (F(3)PhOH) suppresses formation of the Cpd I intermediate during annealing of cryoreduced oxyferrous DHP at 190 K but has no effect on the spectroscopic properties of the remaining cryoreduced oxyferrous DHP intermediates and kinetics of their decay. These observations indicate that substrate (i) binds to oxyferrous DHP outside of the distal pocket and (ii) can reduce Cpd I to Cpd II [Fe(IV)?O]. These assumptions are also supported by the observation that F(3)PhOH has only a small effect on the EPR properties of radiolytically cryooxidized and cryoreduced ferrous [Fe(II)] DHP. EPR spectra of cryoreduced ferrous DHP disclose the multiconformational nature of the ferrous DHP precursor. The observation and characterization of Cpds I, II, and ES in the absence and in the presence of F(3)PhOH provides definitive evidence of a mechanism involving consecutive one-electron steps and clarifies the role of all intermediates formed during turnover. PMID- 20925341 TI - Nitroimino-tetrazolates and oxy-nitroimino-tetrazolates. AB - Highly energetic 1,1'-ethylenebis(oxy)bis(5-nitroimino-tetrazolate) salts were obtained by reacting equimolar quantities of the acidic 1,1' ethylenebis(oxy)bis(5-nitroimino-tetrazole) and energetic bases in aqueous solution. Additionally, metathesis of silver 1,1'-ethylenebis(oxy)bis(5 nitroimino-tetrazolate) with diaminoguanidinium chloride or triaminoguanidinium chloride gave the corresponding oxy-nitroimino-tetrazolate salt. These salts were fully characterized using IR and multinuclear NMR spectroscopy, elemental analysis, and differential scanning calorimetry (DSC), and, in some cases, 2.2H(2)O, 8.2H(2)O, 10, 13.2H(2)O and 14, with single crystal X-ray structuring. The heats of formation for all compounds were calculated with Gaussian 03 and then combined with measured densities to determine detonation pressures (P) and velocities (D) of the energetic materials (Cheetah 5.0). The impact sensitivities of all salts were found to be less than those of the parent compounds. The physical and detonation properties of these oxy-nitroimino-tetrazolate salts are comparable to the analogous newly prepared diaminoguanidinium and triaminoguanidinium 1,1'-ethylenebis(5-nitroimino-tetrazolate)s. PMID- 20925342 TI - Stereospecificity of the dehydratase domain of the erythromycin polyketide synthase. AB - The dehydratase (DH) domain of module 4 of the 6-deoxyerythronolide B synthase (DEBS) has been shown to catalyze an exclusive syn elimination/syn addition of water. Incubation of recombinant DH4 with chemoenzymatically prepared anti (2R,3R)-2-methyl-3-hydroxypentanoyl-ACP (2a-ACP) gave the dehydration product 3 ACP. Similarly, incubation of DH4 with synthetic 3-ACP resulted in the reverse enzyme-catalyzed hydration reaction, giving an ~3:1 equilbrium mixture of 2a-ACP and 3-ACP. Incubation of a mixture of propionyl-SNAC (4), methylmalonyl-CoA, and NADPH with the DEBS beta-ketoacyl synthase-acyl transferase [KS6][AT6] didomain, DEBS ACP6, and the ketoreductase domain from tylactone synthase module 1 (TYLS KR1) generated in situ anti-2a-ACP that underwent DH4-catalyzed syn dehydration to give 3-ACP. DH4 did not dehydrate syn-(2S,3R)-2b-ACP, syn-(2R,3S)-2c-ACP, or anti-(2S,3S)-2d-ACP generated in situ by DEBS KR1, DEBS KR6, or the rifamycin synthase KR7 (RIFS KR7), respectively. Similarly, incubation of a mixture of (2S,3R)-2-methyl-3-hydroxypentanoyl-N-acetylcysteamine thioester (2b-SNAC), methylmalonyl-CoA, and NADPH with DEBS [KS6][AT6], DEBS ACP6, and TYLS KR1 gave anti-(2R,3R)-6-ACP that underwent syn dehydration catalyzed by DEBS DH4 to give (4R,5R)-(E)-2,4-dimethyl-5-hydroxy-hept-2-enoyl-ACP (7-ACP). The structure and stereochemistry of 7 were established by GC-MS and LC-MS comparison of the derived methyl ester 7-Me to a synthetic sample of 7-Me. PMID- 20925343 TI - "Long-range" metal-ligand cooperation in H2 activation and ammonia-promoted hydride transfer with a ruthenium-acridine pincer complex. AB - The acridine-based pincer complex 1 exhibits an unprecedented mode of metal ligand cooperation involving a "long-range" interaction between the distal acridine C9 position and the metal center. Reaction of 1 with H(2)/KOH results in H(2) splitting between the Ru center and C9 with concomitant dearomatization of the acridine moiety. DFT calculations show that this process involves the formation of a Ru dihydride intermediate bearing a bent acridine ligand in which C9 is in close proximity to a hydride ligand followed by through-space hydride transfer. Ammonia induces transfer of a hydride from the Ru center of 1 to C9 of the flexible acridine pincer ligand, forming an unusual dearomatized fac-acridine PNP complex. PMID- 20925344 TI - Controlling charge separation and recombination rates in CdSe/ZnS type I core shell quantum dots by shell thicknesses. AB - Type I core/shell quantum dots (QDs) have been shown to improve the stability and conversion efficiency of QD-sensitized solar cells compared to core only QDs. To understand how the shell thickness affects the solar cell performance, its effects on interfacial charge separation and recombination kinetics are investigated. These kinetics are measured in CdSe/ZnS type I core/shell QDs adsorbed with anthroquinone molecules (as electron acceptor) by time-resolved transient absorption spectroscopy. We show that the charge separation and recombination rates decrease exponentially with the shell thickness (d), k(d) = k(0)e(-betad), with exponential decay factors beta of 0.35 +/- 0.03 per A and 0.91 +/- 0.14 per A, respectively. Model calculations show that these trends can be attributed to the exponential decrease of the 1S electron and hole densities at the QD surface with the shell thickness. The much steeper decrease in charge recombination rate results from a larger hole effective mass (than electron) in the ZnS shell. This finding suggests possible ways of optimizing the charge separation yield and lifetime by controlling the thickness and nature of the shell materials. PMID- 20925345 TI - PKU-10: a new 3D open-framework germanate with 13-ring channels. AB - PKU-10, a germanate with the formula [(CH(3))(4)N](3)Ge(11)O(19)(OH)(9), is synthesized under hydrothermal conditions, and its structure is determined by single-crystal X-ray diffraction data. PKU-10 possesses 3D intersected 13-ring channels and presents a new 6-connectedness linkage mode of the Ge(7) cluster, T(3)P(2)O, forming a pcu topological network. Each Ge(7) cluster is, in fact, surrounded by eight Ge(7) clusters in a nearly perfect cube because the hydrogen bonds between Ge(7) clusters are also taken into account. The structure-directing agent tetramethylammonium (TMA(+)) ions, locating in the channels, can be partially exchanged by Li(+) with retention of the germanate framework. The germanate framework collapses with decomposition of the TMA(+) ions at temperatures higher than 240 degrees C. PMID- 20925346 TI - Dynamics of phase separation in poly(acrylonitrile-butadiene-styrene)-modified epoxy/DDS system: kinetics and viscoelastic effects. AB - The dynamics of phase separation and final morphologies of poly(acrylonitrile butadiene-styrene) (ABS)-modified epoxy system based on diglycidyl ether of bisphenol A (DGEBA) cured with 4,4'-diaminodiphenylsulfone (DDS) have been monitored in situ throughout the entire curing process by using optical microscopy (OM), differential scanning calorimetry (DSC), rheometry, and small angle laser light scattering (SALLS). The evolution of phase separation and final morphologies with substructures were explored by OM. The final morphologies of the blend cured at 150 and 165 degrees C are of phase-inverted type and are quite different from the final morphologies of the same blend cured at 180 degrees C, in which the final morphologies are cocontinuous. AFM observations of the fully cured sample confirmed the existence of three different phases, the epoxy continuous phase, SAN (styrene/acrylonitrile) continuous phase, and PB droplets at the interface, with a strong tendency to stay at SAN continuous phase. Furthermore, the continuous epoxy phase contains SAN particles and the continuous SAN phase contains epoxy particles. Cure kinetics and rheological results correspond well with the viscoelastic phase separation revealed by OM. The SALLS results display clearly that the phase separation takes place according to nucleation and growth mechanism followed by spinodal decomposition. The development of light scattering patterns during the second stage phase separation follows the Cahn-Hilliard model of spinodal demixing. Furthermore, the evolution of the scattering vector follows a Maxwell-type relaxation equation establishing the viscoelastic behavior of phase separation. The relaxation time of phase separation can be described by the Williams-Landel-Ferry equation for viscoelasticity. As a whole, the dependence of phase separation on cure temperature and the development of final morphologies and the associated mechanisms were explored in detail for the complex epoxy/ABS system. PMID- 20925347 TI - Highly sensitive multiplexed heavy metal detection using quantum-dot-labeled DNAzymes. AB - We developed highly sensitive and specific nanosensors based on quantum dots (QDs) and DNAzyme for multiplexed detection of heavy metal ions in liquid. The QDs were coated with a thin silica layer for increased stability and higher quantum yield while maintaining a relatively small size for highly efficient energy transfer. The QD-DNAzyme nanosensors were constructed by conjugating quencher-labeled DNAzymes onto the surface of carboxyl-silanized QDs. In the presence of metal ions, the emission is restored due to the cleavage of DNAzymes. The detection could be completed within 25 min with a single laser excitation source. The detection limit of 0.2 and 0.5 nM was experimentally achieved for Pb(2+) and Cu(2+), respectively, which is a 50- and 70-fold improvement over the recent results obtained with dye molecules. Multiplexed detection was also demonstrated using two different colors of QDs, showing negligible cross-talk between the Pb(2+) detection and Cu(2+) detection. PMID- 20925348 TI - Nanohydroxyapatite-coated electrospun poly(l-lactide) nanofibers enhance osteogenic differentiation of stem cells and induce ectopic bone formation. AB - A combination of calcium phosphates with nanofibrous scaffolds holds promising potential for bone tissue engineering applications. In this study, nanohydroxyapatite (n-HA) was coated on the plasma-treated surface of electrospun poly(l-lactide) (PLLA) nanofibers and the capacity of fabricated scaffolds for bone formation was investigated in vitro using human cord blood derived unrestricted somatic stem cells (USSC) under osteogenic induction and in vivo after subcutaneous implantation. PLLA and n-HA-coated PLLA (n-HA/PLLA) scaffolds exhibited a nanofibrous structure with interconnected pores and suitable mechanical properties. These scaffolds were also shown to support attachment, spreading, and proliferation of USSC, as shown by their flattened normal morphology and MTT assay. During osteogenic differentiation, significantly higher values of ALP activity, biomineralization, and bone-related gene expression were observed on n-HA/PLLA compared to PLLA scaffolds. Subsequently, these markers were measured in higher amounts in USSC on PLLA nanofibers compared to TCPS. According to the in vivo results, ossification and formation of trabeculi was observed in the n-HA/PLLA scaffold compared to PLLA. Taking together, it was shown that nanofibrous structure enhanced osteogenic differentiation of USSC. Furthermore, surface-coated n-HA stimulated the effect of nanofibers on the orientation of USSC toward osteolineage. In addition, the n-HA/PLLA electrospun scaffold showed the capacity for ectopic bone formation in the absence of exogenous cells. PMID- 20925349 TI - Evaluation of conventional and alternative monitoring methods for a recreational marine beach with nonpoint source of fecal contamination. AB - The objectives of this work were to compare enterococci (ENT) measurements based on the membrane filter, ENT(MF) with alternatives that can provide faster results including alternative enterococci methods (e.g., chromogenic substrate (CS), and quantitative polymerase chain reaction (qPCR)), and results from regression models based upon environmental parameters that can be measured in real-time. ENT(MF) were also compared to source tracking markers (Staphylococcus aureus, Bacteroidales human and dog markers, and Catellicoccus gull marker) in an effort to interpret the variability of the signal. Results showed that concentrations of enterococci based upon MF (<2 to 3320 CFU/100 mL) were significantly different from the CS and qPCR methods (p < 0.01). The correlations between MF and CS (r = 0.58, p < 0.01) were stronger than between MF and qPCR (r <= 0.36, p < 0.01). Enterococci levels by MF, CS, and qPCR methods were positively correlated with turbidity and tidal height. Enterococci by MF and CS were also inversely correlated with solar radiation but enterococci by qPCR was not. The regression model based on environmental variables provided fair qualitative predictions of enterococci by MF in real-time, for daily geometric mean levels, but not for individual samples. Overall, ENT(MF) was not significantly correlated with source tracking markers with the exception of samples collected during one storm event. The inability of the regression model to predict ENT(MF) levels for individual samples is likely due to the different sources of ENT impacting the beach at any given time, making it particularly difficult to to predict short-term variability of ENT(MF) for environmental parameters. PMID- 20925350 TI - A structurally tunable DNA-based extracellular matrix. AB - The principles of DNA nanotechnology and protein engineering have been combined to generate a new class of artificial extracellular matrices. The potential of this material for ex vivo cellular scaffolding was demonstrated using experiments in which human cervical cancer cells were found to adhere strongly, stay alive, and grow with high migration rates. The use of DNA in our DNA/protein-based matrices makes these structures inherently amenable to structural tunability. By engineering single-stranded domains into the DNA portions, we were able to fine tune the scaffold's persistence length and stiffness as perceived by cells. This was used to direct the outcome of the cell's cytoskeletal arrangement and overall shape, the status of its signal transduction protein p-FAK, and the localization of its intracellular transcription factors FOXO1a. This contribution lays the groundwork for the facile and modular construction of programmable extracellular matrices that can bring about the systematic study and replication of the naturally occurring extracellular niche. PMID- 20925351 TI - Thermodynamic and kinetic properties of a red wine pigment: catechin-(4,8) malvidin-3-O-glucoside. AB - Catechin-(4,8)-malvidin-3-glucoside, a red pigment adduct (at acid pH) found in red wine and resulting from the reaction between malvidin-3-glucoside and flavan 3-ols during wine aging, was synthesized. The thermodynamic and kinetic constants of the network of chemical reactions were fully determined by stopped flow: (i) Direct pH jumps, from thermal equilibrated solutions at pH = 1.0 (flavylium cation, AH(+)), show three kinetic processes. The first one occurs within the mixing time of the stopped flow and leads to the formation of quinoidal bases A and/or A(-) depending on the final pH; the second one takes place with a rate constant equal to 0.075 + 33[H(+)] and was attributed to the hydration reaction that forms the pseudobases (hemiketals), B/B(-). The third process is much slower, 2 * 10(-4) s(-1), and is due to the cis-trans isomerization giving rise to a small fraction of trans-chalcones, Ct/Ct(-). (ii) Reverse pH jumps from the thermally equilibrated solution at moderate to neutral pH values back to a sufficiently acidic medium clearly distinguish three kinetic processes: the first one takes place within the dead time and is due to the protonation of the bases; the second process occurs with the same rate constant of the hydration reaction monitored by direct pH jumps and is attributed to the formation of flavylium cation from the B; the last process occurs with a rate constant of 1.8 s(-1), and results from the formation of AH(+) from Ct through B, reflecting the rate of the ring closure (tautomerization). The separation of the hydration from the tautomerization upon a reverse pH jump is only possible because at pH < 1 the former reaction is faster than the last. An identical situation was observed for malvidin-3-glucoside (oenin) for pH < 2. PMID- 20925352 TI - Enhanced ferroelectric switching characteristics of P(VDF-TrFE) for organic memory devices. AB - In the following work, we report an approach to shorten the ferroelectric switching time of P(VDF-TrFE) film by blending with as-synthesized gold nanoparticles. Ferroelectric hysteresis measurements give remnant polarization and coercive field of 8 MUC/cm(2) and 50 MV/m, respectively. A series of electric pulses was applied for the characterization of ferroelectric polymers, and the switching time response was evaluated. More than 3 orders of magnitude reduction in switching time is observed for the polymer film blended with nanoparticles of the amount 1 * 10(-6) wt %. The observed switching enhancements are discussed in terms of improved alignment of the ferroelectric crystal plane in the presence of the gold nanoparticles, whereby the aligned crystal planes experience a stronger effective field compared to the randomly oriented planes in pristine P(VDF-TrFE). PMID- 20925353 TI - Ion transport mechanism in glasses: non-Arrhenius conductivity and nonuniversal features. AB - In this article, we report non-Arrhenius behavior in the temperature-dependent dc conductivity of alkali ion conducting silicate glasses well below their glass transition temperature. In contrast to the several fast ion-conducting and binary potassium silicate glasses, these glasses show a positive deviation in the Arrhenius plot. The observed non-Arrhenius behavior is completely reproducible in nature even after prolonged annealing close to the glass transition temperature of the respective glass sample. These results are the manifestation of local structural changes of the silicate network with temperature and give rise to different local environments into which the alkali ions hop, revealed by in situ high-temperature Raman spectroscopy. Furthermore, the present study provides new insights into the strong link between the dynamics of the alkali ions and different sites associated with it in the glasses. PMID- 20925354 TI - Impact of head group charges, ionic sizes, and dielectric images on charge inversion: a Monte Carlo simulation study. AB - The ionic density profiles and corresponding integrated charge distribution close to an aqueous interface carrying charged functional groups of different valences exposed to mixed-salt solutions of 1:1 and 3:1 electrolytes were computed by use of extensive Monte Carlo simulations within the framework of the primitive model. The influence of varying ion sizes on charge inversion was analyzed, along with the crucial role of electrostatic images arising from dielectric discontinuities. For small sizes of charged species, it was found that charge inversion is enhanced by the presence of multivalent interfacial groups. Moreover, dielectric images further intensify the degree of charge inversion despite strong depletion effects. In particular, the onset of charge inversion shifts closer to the nonaqueous phase if the surface charge density is sufficiently low. These observations are opposite to the general belief of image repulsion. When large sized ions were considered, the degree of charge inversion was found to be independent of the structure of interfacial groups and to remain widely unaffected in the absence and presence of dielectric images. Overall, our results show that interionic excluded-volume interactions are an overwhelming factor in determining counterion condensation. In addition, the inclusion of ionic size asymmetry at weakly charged interface results in surface charge amplification, which becomes more pronounced with increasing valence of the interfacial groups. Our work emphasizes the fact that surface equilibria mainly result from a subtle balance between steric and charge correlations. PMID- 20925355 TI - Thermodynamic and molecular-scale analysis of new systems of water-soluble hydrate formers + CH4. AB - Among a variety of cyclic ether, cyclic ester, and cyclic ketone compounds, six new formers were found to form binary sII or sH hydrates with CH(4) gas. Hydrate phase equilibria for all the hydrate formers were measured. The results obtained showed distinct relationships between the hydrate-phase equilibrium curve and the molecular size of the guests. In addition, 2-methyltetrahydrofuran and 3 methyltetrahydrofuran, or 4-methyl-1,3-dioxane and 4-methyl-1,3-dioxolane, showed different hydrate structures even though they have similar chemical structures. Such structural differences can provide useful information on the critical guest size, which determines hydrate crystal structures according to the size of the captured guest. PMID- 20925356 TI - Cyclization and rearrangement reactions of a(n) fragment ions of protonated peptides. AB - a(n) ions are frequently formed in collision-induced dissociation (CID) of protonated peptides in tandem mass spectrometry (MS/MS) based sequencing experiments. These ions have generally been assumed to exist as immonium derivatives (-HN(+)?CHR). Using a quadrupole ion trap mass spectrometer, MS/MS experiments have been performed and the structure of a(n) ions formed from oligoglycines was probed by infrared spectroscopy. The structure and isomerization reactions of the same ions were studied using density functional theory. Overall, theory and infrared spectroscopy provide compelling evidence that a(n) ions undergo cyclization and/or rearrangement reactions, and the resulting structure(s) observed under our experimental conditions depends on the size (n). The a(2) ion (GG sequence) undergoes cyclization to form a 5-membered ring isomer. The a(3) ion (GGG sequence) undergoes cyclization initiated by nucleophilic attack of the carbonyl oxygen of the N-terminal glycine residue on the carbon center of the C-terminal immonium group forming a 7-membered ring isomer. The barrier to this reaction is comparatively low at 10.5 kcal mol(-1), and the resulting cyclic isomer (-5.4 kcal mol(-1)) is more energetically favorable than the linear form. The a(4) ion with the GGGG sequence undergoes head-to-tail cyclization via nucleophilic attack of the N-terminal amino group on the carbon center of the C-terminal immonium ion, forming an 11-membered macroring which contains a secondary amine and three trans amide bonds. Then an intermolecular proton transfer isomerizes the initially formed secondary amine moiety (-CH(2)-NH(2)(+)-CH(2)-NH-CO-) to form a new -CH(2)-NH-CH(2)-NH(2)(+)-CO- form. This structure is readily cleaved at the -CH(2)-NH(2)(+)- bond, leading to opening of the macrocycle and formation of a rearranged linear isomer with the H(2)C?NH(+)-CH(2)- moiety at the N terminus and the -CO-NH(2) amide bond at the C terminus. This rearranged linear structure is much more energetically favorable ( 14.0 kcal mol(-1)) than the initially formed imine-protonated linear a(4) ion structure. Furthermore, the barriers to these cyclization and ring-opening reactions are low (8-11 kcal mol(-1)), allowing facile formation of the rearranged linear species in the mass spectrometer. This finding is not limited to 'simple' glycine-containing systems, as evidenced by the IRMPD spectrum of the a(4) ion generated from protonated AAAAA, which shows a stronger tendency toward formation of the energetically favorable (-12.3 kcal mol(-1)) rearranged linear structure with the MeHC?NH(+)-CHMe- moiety at the N terminus and the -CO-NH(2) amide bond at the C terminus. Our results indicate that one needs to consider a complex variety of cyclization and rearrangement reactions in order to decipher the structure and fragmentation pathways of peptide a(n) ions. The implications this potentially has for peptide sequencing are also discussed. PMID- 20925358 TI - Interaction of arginine with proteins and the mechanism by which it inhibits aggregation. AB - Aqueous arginine solutions are used extensively for inhibiting protein aggregation. There are several theories proposed to explain the effect of arginine on protein stability, but the exact mechanism is still not clear. To understand the mechanism of protein cosolvent interaction, the intraprotein, protein-solvent, and intrasolvent interactions have to be understood. Molecular dynamics simulations of aqueous arginine solutions were carried out for experimentally accessible concentrations and temperature ranges to study the structure of the solution and its energetic properties and obtain insight into the mechanism by which arginine inhibits protein aggregation. Simulations of proteins (alpha-chymotrypsinogen A and melittin) were performed. Structurally, the most striking feature of the aqueous arginine solutions is the self association of arginine molecules. Arginine shows a marked tendency to form clusters with head to tail hydrogen bonding. Due to the presence of the three charged groups, there are several possible configurations in which arginine molecules interact. At relatively high concentrations, these arginine clusters associate with other clusters and monomeric arginine molecules to form large clusters. The hydrogen bonds between arginine molecules were found to be stronger than those between arginine and water, which makes the process of self association enthalpically favorable. From the simulation of the proteins in aqueous arginine solution, arginine is found to interact with the aromatic and charged side chains of surface residues. A probable mechanism of the effect of arginine on protein stability consistent with our findings is proposed. In particular, arginine interacts with aromatic and charged residues due to cation pi interaction and salt-bridge formation, respectively, to stabilize the partially unfolded intermediates. The self-interaction of arginine leads to the formation of clusters which, due to their size, crowd out the protein-protein interaction. The mechanisms proposed in the literature are analyzed on the basis of the simulation results reported in this paper and recent experimental data. PMID- 20925357 TI - Accurate determination of interstrand distances and alignment in amyloid fibrils by magic angle spinning NMR. AB - Amyloid fibrils are structurally ordered aggregates of proteins whose formation is associated with many neurodegenerative and other diseases. For that reason, their high-resolution structures are of considerable interest and have been studied using a wide range of techniques, notably electron microscopy, X-ray diffraction, and magic angle spinning (MAS) NMR. Because of the excellent resolution in the spectra, MAS NMR is uniquely capable of delivering site specific, atomic resolution information about all levels of amyloid structure: (1) the monomer, which packs into several (2) protofilaments that in turn associate to form a (3) fibril. Building upon our high-resolution structure of the monomer of an amyloid-forming peptide from transthyretin (TTR(105-115)), we introduce single 1-(13)C labeled amino acids at seven different sites in the peptide and measure intermolecular carbonyl-carbonyl distances with an accuracy of ~0.11 A. Our results conclusively establish a parallel, in register, topology for the packing of this peptide into a beta-sheet and provide constraints essential for the determination of an atomic resolution structure of the fibril. Furthermore, the approach we employ, based on a combination of a double-quantum filtered variant of the DRAWS recoupling sequence and multispin numerical simulations in SPINEVOLUTION, is general and should be applicable to a wide range of systems. PMID- 20925359 TI - Designing heteropolymers to fold into unique structures via water-mediated interactions. AB - Hydrophobic homopolymers collapse into globular structures in water driven by hydrophobic interactions. Here we employ extensive molecular dynamics simulations to study the collapse of heteropolymers containing one or two pairs of oppositely charged monomers. We show that charging a pair of monomers can dramatically alter the most stable conformations from compact globular to more open hairpin-like. We systematically explore a subset of the sequence space of one- and two-charge-pair polymers, focusing on the locations of the charge pairs. Conformational stability is governed by a balance of hydrophobic interactions, hydration and interactions of charge groups, water-mediated charged-hydrophobic monomer repulsions, and other factors. As a result, placing charge pairs in the middle, away from the hairpin ends, leads to stable hairpin-like structures. Turning off the monomer water attractions enhances hydrophobic interactions significantly leading to a collapse into compact globular structures even for two-charge-pair heteropolymers. In contrast, the addition of salt leads to open and extended structures, suggesting that solvation of charged monomer sites by salt ions dominates the salt-induced enhancement of hydrophobic interactions. We also test the ability of a predictive scheme based on the additivity of free energy of contact formation. The success of the scheme for symmetric two-charge-pair sequences and the failure for their flipped versions highlight the complexity of the heteropolymer conformation space and of the design problem. Collectively, our results underscore the ability of tuning water-mediated interactions to design stable nonglobular structures in water and present model heteropolymers for further studies in the extended thermodynamic space and in inhomogeneous environments. PMID- 20925360 TI - Sterol binding and membrane lipid attachment to the Osh4 protein of yeast. AB - Osh4 is an oxysterol-binding protein homologue found in yeast that is essential for the intracellular transport of sterols and cell life. In this study, molecular dynamics simulations were used to investigate the binding of ergosterol, 25-hydroxycholesterol, and lipid moieties to Osh4. The binding energies between both sterols and Osh4 were dominated by van der Waals interactions with residues within the sterol binding pocket, and were further stabilized by water-mediated interactions with polar residues at the bottom of the binding pocket (W46, Q96, Y97, N165, Q181). Only Q96 was able to form direct hydrogen bonds with each sterol. Possible lipid binding sites on the surface of Osh4 were identified by docking four lipid moieties modeled from different lipid head groups (phosphatidylcholine, phosphatidylserine, phosphatidylinositol(4,5)biphosphate, and phosphatidylinositol(3,4,5)triphosphate). Though lipids docked to several regions along the protein surface, the most commonly encountered regions were found along the beta-barrel region, a loop formed by residues 236-244, and the mouth of the sterol binding pocket. Several residues identified in these regions, such as K168, A169, K173, and E412, are either included or adjacent to residues experimentally implicated in Osh4 membrane binding. Lipid docking did not result in favorable binding regions on the alpha(7) helix or the distal binding surface, suggesting that protein backbone conformational changes are needed for membrane attachment in these regions. Ultimately, understanding how Osh4 attaches to cellular membranes and binds sterol will lead to a clear understanding of how this protein transports sterols between organelles in vivo. PMID- 20925362 TI - Carbanionic rearrangements of halomethylenecyclobutanes. Stereochemistry of the migrating group. AB - The unusual base-induced ring-enlargement of halomethylenecyclobutanes to 1 halocyclopentenes was examined with unsymmetrical and (13)C-labeled substrates to study regio- and stereochemical characteristics. Migration of a ring carbon atom (single migration) or simultaneous migration of a ring carbon atom and the halide (double migration) gives the ring-enlarged products. (13)C-labeling experiments established that both rearrangements occur with retention of configuration at the migrating center. These systems are suggested as models for the Fritsch Buttenberg-Wiechell (FBW) rearrangement. PMID- 20925361 TI - Synthesis of regioselectively functionalized benzo[b]thiophenes by combined ortho lithiation-halocyclization strategies. AB - An efficient synthesis of 3-halo-7-oxygen-functionalized benzo[b]thiophenes bearing different substituents at C-2 has been developed from N,N-diethyl O-3 halophenylcarbamates. The key steps are an ortho-lithiation reaction, which gives rise to 3-halo-2-sulfanylphenol derivatives, and a electrophilic cyclization. The subsequent functionalization of the prepared halobenzothiophenes allows the access of a wide variety of 2,3,7-regioselectively functionalized benzo[b]thiophenes in good overall yields. PMID- 20925363 TI - Dual reactivity of hydroxy- and methoxy- substituted o-quinone methides in aqueous solutions: hydration versus tautomerization. AB - 4-Hydroxy-6-methylene-2,4-cyclohexadien-1-one (1) and 4-methoxy-6-methylene-2,4 cyclohexadien-1-one (2) were generated by efficient (Phi = 0.3) photodehydration of 2-(hydroxymethyl)benzene-1,4-diol (3a) and 2-(hydroxymethyl)-4-methoxyphenol (4a), respectively. o-Quinone methides 1 and 2 can be quantitatively trapped as Diels-Alder adducts with ethyl vinyl ether or intercepted by good nucleophiles, such as azide ion (k(N3)(1) = 3.15 * 10(4) M(-1) s(-1) and k(N3)(2) = 3.30 * 10(4) M(-1) s(-1)). In aqueous solution, o-quinone methide 2 rapidly adds water to regenerate starting material (tau(H(2)O)(2) = 7.8 ms at 25 degrees C). This reaction is catalyzed by specific acid (k(H(+))(2) = 8.37 * 10(3) s(-1) M(-1)) and specific base (k(OH(-))(2) = 1.08 * 10(4) s(-1) M(-1)) but shows no significant general acid/base catalysis. In sharp contrast, o-quinone methide 1 decays (tau(H(2)O)(1) = 3.3 ms at 25 degrees C) via two competing pathways: nucleophilic hydration to form starting material 3a and tautomerization to produce methyl-p-benzoquinone. The disappearance of 1 shows not only specific acid (k(H(+))(1) = 3.30 * 10(4) s(-1) M(-1)) and specific base catalysis (k(OH( ))(1) = 3.51 * 10(4) s(-1) M(-1)) but pronounced catalysis by general acids and bases as well. The o-quinone methides 1 and 2 were also generated by the photolysis of 2-(ethoxymethyl)benzene-1,4-diol (3b) and 2-(ethoxymethyl)-4 methoxyphenol (4b), as well as from (2,5-dihydroxy-1-phenyl)methyl- (3c) and (2 hydroxy-5-methoxy-1-phenyl)methyltrimethylammonium iodides (4c). Short-lived (tau(25 degrees )(C) ~ 20 MUs) precursors of o-quinone methides 1 and 2 were detected in the laser flash photolysis of 3a,b and 4a,b. On the basis of their reactivity, benzoxete structures have been assigned to these intermediates. PMID- 20925364 TI - An oxidation induced by potassium metal. Studies on the anionic cyclodehydrogenation of 1,1'-binaphthyl to perylene. AB - Oxidative cyclization of 1,1'-binaphthyl (1) to perylene (2) can be achieved in essentially quantitative yield by the action of three or more equivalents of potassium metal in hot tetrahydrofuran. An overall reaction mechanism is proposed that accounts for all of the experimental observations reported by previous investigators and those from the present studies. The trans-6a,6b-dihydroperylene dianion (6(2-)) is believed to be the pivotal intermediate from which H(2) is lost. A radical chain reaction involving free hydrogen atoms (H(*)) in the two step propagation cycle is proposed to explain the formation of H(2) from 6(2-). Anionic cyclodehydrogenations of this sort are complementary to those performed under strongly acidic/oxidizing conditions, photochemically, or thermally (flash vacuum pyrolysis), and a better understanding of how they occur, together with the optimized synthetic protocol reported here, should encourage their wider use in organic synthesis. PMID- 20925365 TI - Temperature effect on the molecular interactions between ammonium ionic liquids and N,N-dimethylformamide. AB - In view of the wide scope of molecular interactions between the highly polar compound of N,N-dimethylformamide (DMF) and ammonium ionic liquids (ILs), we have measured thermophysical properties such as densities (rho) and ultrasonic sound velocities (u) over the whole composition range at temperatures ranging from 25 to 50 degrees C under atmospheric pressure. To gain some insight into the several aggregations of molecular interactions present in these mixed solvents, we predicted the excess molar volume (V(E)) and the deviations in isentropic compressibilities (DeltaK(s)) as a function of the concentration of IL. These results are fitted to the Redlich-Kister polynomials. The materials investigated in the present study included the hydroxide series of ammonium ILs of tetramethylammonium hydroxide [(CH(3))(4)N][OH] (TMAH), tetraethylammonium hydroxide [(C(2)H(5))(4)N][OH] (TEAH), and tetrapropylammonium hydroxide [(C(2)H(7))(4)N][OH] (TPAH). The intermolecular interactions and structural effects were analyzed on the basis of the measured and the derived properties. A qualitative analysis of the results is discussed in terms of the ion-dipole and ion-pair interactions, and hydrogen bonding between ILs and DMF molecules and their structural factors. PMID- 20925366 TI - Fluctuations in number of water molecules confined between nanoparticles. AB - We used molecular dynamics computer simulations to study the character of interactions between two nanoscale graphene plates in water and also between plates made of "carbon" atoms that have different interaction strength with water. Fluctuations in the number of water molecules in the confined space between plates are qualitatively similar when the plates are made of graphene or when the plates contain "carbon" atoms with weaker "carbon"-water interaction strength. We also observed that these fluctuations are strongly enhanced compared to the fluctuations observed next to a single plate. If the character of water fluctuations in the confined space determines the character of interactions, then it is possible to conclude that the interaction between graphene plates in water is hydrophobic. PMID- 20925367 TI - A three-step synthetic approach to asymmetrically functionalized 4H cyclopenta[2,1-b:3,4-b']dithiophenes. AB - A convenient and efficient three-step route toward both symmetrically and asymmetrically functionalized 4H-cyclopenta[2,1-b:3,4-b']dithiophenes has been developed. Using this method a broad collection of functionalized bridged bithiophenes can smoothly be accessed. Starting from 3-bromo-2,2'-bithiophene, prepared by Kumada coupling of 2-thienylmagnesium bromide with 2,3 dibromothiophene under Pd(dppf)Cl(2) catalysis, lithiation and subsequent reaction with dialkyl ketones afforded (a)symmetrically dialkylated tertiary alcohol derivatives. By means of final Friedel-Crafts dehydration cyclization in sulfuric acid medium, these derivatives were converted to 4,4-dialkyl-4H cyclopenta[2,1-b:3,4-b']dithiophenes. Upon replacement of the dialkyl ketone reagent by ethyl levulinate, an ester-functionalized 4H-cyclopenta[2,1-b:3,4 b']dithiophene was prepared, representing an attractive precursor for variously functionalized cyclopentadithiophene compounds. PMID- 20925368 TI - Application of Grote-Hynes theory to the reaction catalyzed by thymidylate synthase. AB - A theoretical study of dynamic effects on the rate-limiting step of the thymidylate synthase catalyzed reaction has been carried out by means of Grote Hynes theory, successfully predicting the values of the recrossing effects for a chemical reaction that involves the transfer of a classical light particle. The transmission coefficients, obtained at 278, 293, 303, and 313 K, are almost invariant and in all cases far from unity, revealing a significant coupling of the environment motions and the reaction coordinate. Nevertheless, their energetic contribution to the activation free energy represents less than 0.50 kcal/mol for each of the four tested temperatures. Calculation of the transmission coefficient for the isotopically labeled hydride transfer has rendered almost the same values, in agreement with the experimentally observed temperature-independent KIEs. Fourier transform of the time-dependent friction kernel at these four temperatures has allowed obtaining the transition-state friction spectra, which present very small dependence with temperature. Their analysis has led to the identification of some key vibrational modes governing the coupling between the reaction coordinate and the protein environment, thus identifying the relevant motions in the active site and obtaining a full picture of the role of each amino acid. PMID- 20925369 TI - Spin-transition-like behavior on one side in a nitroxide-copper(II)-nitroxide triad system. AB - The ground spin-state of [Cu(phpyNO)(2)(H(2)O)(2)](BF(4))(2) was switched between S(total) = 1/2 and 3/2 across 175 K. On warming, the space group was changed from P2(1)2(1)2(1) to C222(1) in a single-crystal-to-single-crystal manner, and the transient structure could be monitored by means of the crystallographic analysis. The copper-radical exchange coupling changed from 2J/k(B) = -463(3) to +312(6) K with rather small Cu-O-N-C(2py) twisting deformation on one side, while practically no distortion occurred on the other. PMID- 20925371 TI - Polarization transfer solid-state NMR for studying surfactant phase behavior. AB - The phase behavior of amphiphiles, e.g., lipids and surfactants, at low water content is of great interest for many technical and pharmaceutical applications. When put in contact with air having a moderate relative humidity, amphiphiles often exhibit coexistence between solid and liquid crystalline phases, making their complete characterization difficult. This study describes a (13)C solid state NMR technique for the investigation of amphiphile phase behavior in the water-poor regime. While the (13)C chemical shift is an indicator of molecular conformation, the (13)C signal intensities obtained with the CP and INEPT polarization transfer schemes yield information on molecular dynamics. A theoretical analysis incorporating the effect of molecular segment reorientation, with the correlation time tau(c) and order parameter S, shows that INEPT is most efficient for mobile segments with tau(c) < 0.01 MUs and S < 0.05, while CP yields maximal signal for rigid segments with tau(c) > 10 MUs and/or S > 0.5 under typical solid-state NMR experimental conditions. For liquid crystalline phases, where tau(c) < 0.01 MUs and 0 < S < 0.3, the observed CP and INEPT intensities serve as a gauge of S. The combination of information on molecular conformation and dynamics permits facile phase diagram determination for systems with solid crystalline, solid amorphous, anisotropic liquid crystalline, and isotropic liquid (crystalline) phases as demonstrated by experiments on a series of reference systems with known phase structure. Three solid phases (anhydrous crystal, dihydrate, gel), two anisotropic liquid crystalline phases (normal hexagonal, lamellar), and two isotropic liquid crystalline phases (micellar cubic, bicontinuous cubic) are identified in the temperature-composition phase diagram of the cetyltrimethylammonium succinate/water system. Replacing the succinate counterion with DNA prevents the formation of phases other than hexagonal and leads to a general increase of tau(c). PMID- 20925372 TI - DNA-mediated two-dimensional colloidal crystallization above different attractive surfaces. AB - We explore the formation of "floating" two-dimensional colloidal crystals above weakly attractive surfaces that are either positively or negatively charged. In particular, we studied crystal formation above positively charged poly-L-lysine poly(ethylene glycol) surfaces with and without short single-stranded DNA and above negatively charged bovine albumin serum-streptavidin multilayers. Confocal microscopy revealed the evolution of crystals several micrometers above all three surfaces. Interestingly, the "flying height" of crystals was found to depend on the surface coating. All crystalline structures remained remarkably stable over weeks, even under high salt conditions. Neither lifting the crystals nor lowering them by means of buoyancy forces destroyed them. PMID- 20925370 TI - Bishydrazide glycoconjugates for lectin recognition and capture of bacterial pathogens. AB - Bishydrazides are versatile linkers for attaching glycans to substrates for lectin binding and pathogen detection schemes. The alpha,omega-bishydrazides of carboxymethylated hexa(ethylene glycol) (4) can be conjugated at one end to unprotected oligosaccharides, then attached onto carrier proteins, tethered onto activated carboxyl-terminated surfaces, or functionalized with a photoactive cross-linking agent for lithographic patterning. Glycoconjugates of bishydrazide 4 can also be converted into dithiocarbamates (DTCs) by treatment with CS(2) under mild conditions, for attachment onto gold substrates. The immobilized glycans serve as recognition elements for cell-surface lectins and enable the detection and capture of bacterial pathogens such as Pseudomonas aeruginosa by their adsorption onto micropatterned substrates. A detection limit of 103 cfu/mL is demonstrated, using a recently introduced method based on optical pattern recognition. PMID- 20925373 TI - Multiasperity contact adhesion model for universal asperity height and radius of curvature distributions. AB - A new approach to the multiasperities contact interaction between two surfaces is presented. Each asperity is individually considered with its own different height and radius of curvature. Different materials, such as polyvinylchlorine (PVC) and stainless steel, are used as model systems. For each of the model materials, a set of asperities was generated using Monte Carlo method. Both asperity heights and radii were based on their statistical distributions experimentally obtained. Contact forces were determined for each asperity at a given distance between the two surfaces, while the deformation of each asperity was calculated according to the Johnson-Kendall-Roberts (JKR) or the Derjaguin-Muller-Toporov (DMT) model (depending on the material). The contribution of each asperity to the overall surface was summed, and the overall contact force was determined. The developed method was validated against contact force measurements obtained with atomic force microscopy (AFM). PMID- 20925375 TI - Classifying substrate specificities of membrane transporters from Arabidopsis thaliana. AB - Membrane transporters catalyze the active transport of molecules across biological barriers such as lipid bilayer membranes. Currently, the experimental annotation of which proteins transport which substrates is far from complete and will likely remain so for much longer. Therefore, it is highly desirable to develop computational methods that may aid in the substrate annotation of putative membrane transport proteins. Here, we measured the similarity of membrane transporters from Arabidopsis thaliana by their amino acid composition, higher sequence order information, amino acid characteristics, or sequence conservation. We considered the substrate classes amino acids, oligopeptides, phosphates, and hexoses. Substrate classification based on the amino acid frequency yielded an accuracy of 75% or higher. Integrating additional information improved the prediction performance to 90% and higher. PMID- 20925374 TI - Layer-by-layer assembled multilayer TiO(x) for efficient electron acceptor in polymer hybrid solar cells. AB - We demonstrate that TiO(x) nanocomposite films fabricated using electrostatic layer-by-layer (LbL) assembly improve the power conversion efficiency of photovoltaic cells compared to conventional TiO(x) films fabricated via the sol gel process. For this study, titanium precursor/poly(allylamine hydrochloride) (PAH) multilayer films were first deposited onto indium tin oxide-coated glass to produce TiO(x) nanocomposites (TiO(x)NC). The specific effect of the LbL processed TiO(x) on photovoltaic performance was investigated using the planar bilayer TiO(x)NC and highly regioregular poly(3-hexylthiophene) (P3HT) solar cells, and the P3HT/LbL TiO(x)NC solar cells showed a dramatic increase in power efficiency, particularly in terms of the short current density and fill factor. The improved efficiency of this device is mainly due to the difference in the chemical composition of the LbL TiO(x)NC films, including the much higher Ti(3+)/Ti(4+) ratio and the highly reactive facets of crystals as demonstrated by XPS and XRD measurement, thus enhancing the electron transfer between electron donors and acceptors. In addition, the grazing incidence wide-angle X-ray scattering (GIWAXS) study revealed the presence of more highly oriented P3HT stacks parallel to the substrate on the LbL TiO(x)NC film compared to those on the sol-gel TiO(x) films, possibly influencing the hole mobility of P3HT and the energy transfer near and at the interface between the P3HT and TiO(x) layers. The results of this study demonstrate that this approach is a promising one for the design of hybrid solar cells with improved efficiency. PMID- 20925376 TI - Direct surface force measurements of polyelectrolyte multilayer films containing nanocrystalline cellulose. AB - Polyelectrolyte multilayer films containing nanocrystalline cellulose (NCC) and poly(allylamine hydrochloride) (PAH) make up a new class of nanostructured composite with applications ranging from coatings to biomedical devices. Moreover, these materials are amenable to surface force studies using colloid probe atomic force microscopy (CP-AFM). For electrostatically assembled films with either NCC or PAH as the outermost layer, surface morphology was investigated by AFM and wettability was examined by contact angle measurements. By varying the surrounding ionic strength and pH, the relative contributions from electrostatic, van der Waals, steric, and polymer bridging interactions were evaluated. The ionic cross-linking in these films rendered them stable under all solution conditions studied although swelling at low pH and high ionic strength was inferred. The underlying polymer layer in the multilayered film was found to dictate the dominant surface forces when polymer migration and chain extension were facilitated. The precontact normal forces between a silica probe and an NCC capped multilayer film were monotonically repulsive at pH values where the material surfaces were similarly and fully charged. In contrast, at pH 3.5, the anionic surfaces were weakly charged but the underlying layer of cationic PAH was fully charged and attractive forces dominated due to polymer bridging from extended PAH chains. The interaction with an anionic carboxylic acid probe showed similar behavior to the silica probe; however, for a cationic amine probe with an anionic NCC-capped film, electrostatic double-layer attraction at low pH, and electrostatic double-layer repulsion at high pH, were observed. Finally, the effect of the capping layer was studied with an anionic probe, which indicated that NCC-capped films exhibited purely repulsive forces which were larger in magnitude than the combination of electrostatic double-layer attraction and steric repulsion, measured for PAH-capped films. Wherever possible, DLVO theory was used to fit the measured surface forces and apparent surface potentials and surface charge densities were calculated. PMID- 20925377 TI - Ferrocene embedded in an electrode-supported hybrid lipid bilayer membrane: a model system for electrocatalysis in a biomimetic environment. AB - An electrode-supported system in which ferrocene molecules are embedded in a hybrid bilayer membrane (HBM) has been prepared and characterized. The redox properties of the ferrocene molecules were studied by varying the lipid and alkanethiol building blocks of the HBM. The midpoint potential and electron transfer rate of the embedded ferrocene were found to be dependent on the hydrophobic nature of the electrolyte and the distance at which the ferrocene was positioned in the HBM relative to the electrode and the solution. Additionally, the ability of the lipid-embedded ferrocenium ions to oxidize solution phase ascorbic acid was evaluated and found to be dependent on the nature of the counterion. PMID- 20925378 TI - Meeting report: International Symposium on Intelligent Drug Delivery Systems, 2010. PMID- 20925379 TI - Seed coat phenolics and the developing silique transcriptome of Brassica carinata. AB - Structures for nine compounds were elucidated in seed coats of two genetically related Brassica carinata lines. The yellow-seeded line accumulated monomeric kaempferols, phenylpropanoids, and lignans, while extractable and unextractable proanthocyanidins and a high-performance liquid chromatography peak containing polymeric-like quercetin/lignan structures were strongly reduced. The brown seeded line accumulated large amounts of both types of proanthocyanidins (extractable and unextractable), as well as phenylpropanoids and lignans equivalent to the amounts in the yellow-seeded seed coats, but the brown-seeded seed coats lacked kaempferols. A Brassica napus 15K oligoarray experiment indicated that yellow-seeded siliques had more extreme gene expression changes and a 2.4-fold higher number of upregulated genes than brown-seeded siliques, including a host of transcription factors and genes with unknown function. Transcripts for six flavonoid genes (CHS, F3H, FOMT, DFR, GST, and TTG1) were lower and two (F3'H and FLS) were higher in yellow-seeded siliques, but expression of CHI, PAP1, and phenylpropanoid genes was unchanged. PMID- 20925380 TI - nematicidal carboxylic acids and aldehydes from Melia azedarach fruits. AB - Melia azedarach is a species gaining scientific interest mostly concerning its range of biological activities against agricultural target pests. The nematicidal melia methanol extract (MME) obtained from the fruits, acting against the phytonematode Meloidogyne incognita , is herein reported to contain hexadecanoic, acetic, and hexanoic acids as well as furfural, 5-hydroxymethylfurfural, 5 methylfurfural, and furfurol. All compounds were tested individually for nematicidal activity against the nematode second-stage juveniles, in paralysis experiments. The nematicidal activity was studied both after nematodes' immersion in treatment solutions and after exposure to test substance vapors. Clear dose and time response relationships were established at the dose ranges of 31.2-500 and 1-100 MUg/mL, concerning the aldehydes and carboxylic acids, respectively, implementing analogous predominance of nematicidal activity. Nevertheless, no synergistic effects were observed in respective mixture interaction bioassays among furfural, 5-hydroxymethylfurfural, 5-methylfurfural, and furfurol. Furfural was the most active bionematicidal compound reported herein for the first time as a natural constituent of M. azedarach. PMID- 20925381 TI - Multi-residue screening method to quantify mycotoxins in aqueous environmental samples. AB - Mycotoxins are naturally occurring secondary metabolites of fungi colonizing agricultural products on the field or during storage. In earlier work, we have shown that two common mycotoxins, i.e., zearalenone and deoxynivalenol, can be present at significant levels in the aquatic environment. This raises the question about the relevance of a wider range of mycotoxins in natural waters. In this investigation, we present the first validated method for analysis of some additional 30 mycotoxins in drainage, river, and wastewater treatment plant effluent water. The method includes solid-phase extraction over Oasis HLB cartridges, followed by liquid chromatography with electrospray ionization triple quadrupole mass spectrometry. Absolute method recoveries for 13 of the 33 mycotoxins were higher than 70% in wastewater treatment plant effluent (at 25 ng/L), and 27 compounds had method detection limits (MDLs) below 10 ng/L. The applicability of this method is illustrated with selected data from our ongoing monitoring campaigns. Specifically and for the first time, beauvericin and nivalenol were quantified in drainage and river water samples with mean concentrations of 6.7 and 4.3 ng/L and 6.1 and 5.9 ng/L, respectively. These compounds thus add to the complex mixture of natural and anthropogenic micropollutants in natural waters, where their ecotoxicological risk remains to be evaluated. PMID- 20925382 TI - Development and validation of a real-time PCR method for the detection of white mustard (Sinapis alba) in foods. AB - This paper presents a real-time PCR method allowing the detection of traces of white mustard ( Sinapis alba ) in complex food matrices. The primers and the probe are targeted at the gene coding for S. alba MADS D. The real-time PCR method was found to be specific for white mustard and did not show any cross reactivity with 67 biological species, including 12 members of the Brassicaceae family. The limit of detection, determined by analyzing serially diluted white mustard DNA extracts, was 1 pg of white mustard DNA/MUL, corresponding to 5 pg of white mustard DNA. In model sausages, the limit of detection was found to be 0.001% white mustard (corresponding to 10 ppm or 10 mg/kg). The real-time PCR method was applied to verify the correct declaration of 20 foodstuffs purchased from Austrian supermarkets. White mustard DNA was detected in one of three samples labeled with "may contain traces of mustard" and in one of seven samples without any information on the presence of mustard. PMID- 20925383 TI - Delaying effect of a wine Lactobacillus plantarum strain on the coloration and xanthylium pigment formation occurring in (+)-catechin and (-)-epicatechin wine model solutions. AB - This article reports for the first time on the capacity of a wine Lactobacillus plantarum strain to alter the oxidative coloration of (+)-catechin and (-) epicatechin hydroethanolic wine model solutions in the presence of Fe(2+) as catalyst. The time course of color development and pigment formation in the solutions was tracked over 42 days. The pigments formed were characterized as xanthylium structures regardless of the flavanol isomer present in the solution. The solutions supplied with Lactobacillus plantarum RM71 were oxidized at a slower rate, and consequently, its final color was less than that in the controls. The formation of both (+)-catechin and (-)-epicatechin-derived xanthylium pigments was also delayed over time in the presence of the bacterium compared to their respective cell-free controls. The delaying effects provided by L. plantarum on the oxidative coloration and the generation of xanthylium-derived pigments were more pronounced for the (-)-epicatechin than for the (+)-catechin model solutions. In view of these results and given that L. plantarum is naturally present in winemaking and generally recognized as a safe microorganism, the potential application of this bacterium as an antibrowning agent for wine is now opened. PMID- 20925384 TI - Antioxidative and anti-inflammatory protection from carnosine in the striatum of MPTP-treated mice. AB - Mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were used to examine the neuroprotective effects of carnosine. Carnosine at 0.5, 1, and 2 g/L was directly added to the drinking water for 4 weeks. MPTP treatment significantly depleted striatal glutathione content, reduced the activity of glutathione peroxidase (GPX), superoxide dismutase (SOD), and catalase, increased malondialdehyde and reactive oxygen species levels, and elevated interleukin-6, nitrite, and tumor necrosis factor-alpha production as well as enhanced inducible nitric oxide synthase (iNOS) activity in the striatum (P < 0.05). The preintake of carnosine significantly attenuated MPTP-induced glutathione loss, retained the activity of GPX and SOD, diminished oxidative stress, and lowered inflammatory cytokines and nitrite levels as well as suppressed iNOS activity (P < 0.05). MPTP treatment significantly suppressed GPX mRNA expression and enhanced iNOS mRNA expression (P < 0.05). Carnosine preintake significantly elevated GPX mRNA expression and declined iNOS mRNA expression (P < 0.05). Preintake of carnosine also significantly improved MPTP-induced dopamine depletion and maintained 3,4 dihydroxyphenylacetic acid and homovanillic acid levels (P < 0.05). These results suggest that carnosine could provide antioxidative and anti-inflammatory protection for the striatum against the development of Parkinson's disease. PMID- 20925385 TI - Identification of cytotoxic dimers in oxidation product from sesamol, a potent antioxidant of sesame oil. AB - Phytophenols of edible plants have recently attracted much attention as potent antioxidants and related bioactive substances. These antioxidative phytophenols are very oxidizable due to their chemical properties, and their oxidation products must accumulate in the oxidizing foods when they are contained as active ingredients. In this investigation, several phytophenols, which are well known as potent antioxidants in food science, were oxidized by oxygen in the presence of a catalytic amount of Ferric ion. Caffeic acid, catechin, chlorogenic acid, rosmarinic acid, and sesamol were quickly oxidized, whereas eugenol, resveratrol, rutin, and quercetin were not under the stated conditions. The oxidation product mixtures of the quickly oxidized phytophenols were next subjected to a cytotoxic assay using normal cells. Among the products, the oxidation product from sesamol showed a remarkably high cytotoxic activity. To clarify the cytotoxic principle of the oxidation products, an assay-guided fractionation and subsequent isolation of the oxidation compound of sesamol was carried out. Structure analysis of the isolated compounds revealed that they are new dimeric compounds (2-5) of sesamol. The cytotoxic activity of the dimers was evaluated from the population of dead cells by a flow cytometric analysis of rat thymocytes in the presence of 100 MUM of each compound. Compound 2 showed the most potent cytotoxic activity among them. Compound 2 has a typical conjugated carbonyl moiety and the moiety possibly contributes to its high toxicity from a structure-activity point of view. PMID- 20925386 TI - Interaction of curcumin with beta-lactoglobulin-stability, spectroscopic analysis, and molecular modeling of the complex. AB - Curcumin (diferuloyl methane) is the physiologically and pharmacologically active component of turmeric (Curcuma longa L.). Solubility and stability of curcumin are the limiting factors for realizing its therapeutic potential. beta Lactoglobulin (betaLG), the major whey protein, can solubilize and bind many small hydrophobic molecules. The stability of curcumin bound to betaLG in solution is enhanced 6.7 times, in comparison to curcumin alone (in aqueous solution). The complex formation of curcumin with betaLG has been investigated employing spectroscopic techniques. betaLG interacts with curcumin at pH 7.0 with an association constant of 1.04 +/- 0.1 * 10(5) M(-1) to form a 1:1 complex at 25 degrees C. Entropy and free energy changes for the interaction derived from the van't Hoff plot are 18.7 cal mol(-1) K(-1) and -6.8 kcal mol(-1) at 25 degrees C, respectively; the interaction is hydrophobic in nature. The interaction of betaLG with curcumin does not affect either the conformation or the state of association of betaLG. Competitive ligand binding measurements, binding studies with denatured betaLG, effect of pH on the curcumin-betaLG interaction, Forster energy transfer measurements, and molecular docking studies suggest that curcumin binds to the central calyx of betaLG. These binding studies have prompted the preparation and encapsulation of curcumin in betaLG nanoparticles. Nanoparticles of betaLG prepared by desolvation are found to encapsulate curcumin with >96% efficiency. The solubility of curcumin in betaLG nanoparticle is significantly enhanced to ~625 MUM in comparison with its aqueous solubility (30 nM). Nanoparticles of betaLG, by virtue of their ability to enhance solubility and stability of curcumin, may fit the choice as a carrier molecule. PMID- 20925387 TI - Ion binding to KcsA: implications in ion selectivity and channel gating. AB - Binding of K+ and Na+ to the potassium channel KcsA has been characterized from the stabilization observed in the heat-induced denaturation of the protein as the ion concentration is increased. KcsA thermal denaturation is known to include (i) dissociation of the homotetrameric channel into its constituent subunits and (ii) protein unfolding. The ion concentration-dependent changes in the thermal stability of the protein, evaluated as the Tm value for thermal-induced denaturation of the protein, may suggest the existence of both high- and low affinity K+ binding sites of KcsA, which lend support to the tenet that channel gating may be governed by K+ concentration-dependent transitions between different affinity states of the channel selectivity filter. We also found that Na+ binds to KcsA with a KD similar to that estimated electrophysiologically from channel blockade. Therefore, our findings on ion binding to KcsA partly account for K+ over Na+ selectivity and Na+ blockade and argue against the strict "snug fit" hypothesis used initially to explain ion selectivity from the X-ray channel structure. Furthermore, the remarkable effects of increasing the ion concentration, K+ in particular, on the Tm of the denaturation process evidence that synergistic effects of the metal-mediated intersubunit interactions at the channel selectivity filter are a major contributor to the stability of the tetrameric protein. This observation substantiates the notion of a role for ions as structural "effectors" of ion channels. PMID- 20925388 TI - Study of the inhibitory effect of water-soluble fullerenes on plant growth at the cellular level. AB - The effect of water-soluble fullerene C(70)(C(COOH)(2))(4-8) on plant growth was investigated, using the transgenic seedling lines expressing fluorescent makers. The retarded roots with shortened length and loss of root gravitropism were observed for seedlings grown in the fullerene-containing medium. Fluorescence imaging revealed the abnormalities of root tips in hormone distribution, cell division, microtubule organization, and mitochondrial activity. The study of the inhibitory effects at the cellular level provides new information on the phytotoxicity mechanism of fullerene. PMID- 20925389 TI - A rapid pathway toward a superb gene delivery system: programming structural and functional diversity into a supramolecular nanoparticle library. AB - Nanoparticles are regarded as promising transfection reagents for effective and safe delivery of nucleic acids into a specific type of cells or tissues providing an alternative manipulation/therapy strategy to viral gene delivery. However, the current process of searching novel delivery materials is limited due to conventional low-throughput and time-consuming multistep synthetic approaches. Additionally, conventional approaches are frequently accompanied with unpredictability and continual optimization refinements, impeding flexible generation of material diversity creating a major obstacle to achieving high transfection performance. Here we have demonstrated a rapid developmental pathway toward highly efficient gene delivery systems by leveraging the powers of a supramolecular synthetic approach and a custom-designed digital microreactor. Using the digital microreactor, broad structural/functional diversity can be programmed into a library of DNA-encapsulated supramolecular nanoparticles (DNA?SNPs) by systematically altering the mixing ratios of molecular building blocks and a DNA plasmid. In vitro transfection studies with DNA?SNPs library identified the DNA?SNPs with the highest gene transfection efficiency, which can be attributed to cooperative effects of structures and surface chemistry of DNA?SNPs. We envision such a rapid developmental pathway can be adopted for generating nanoparticle-based vectors for delivery of a variety of loads. PMID- 20925390 TI - Enhancement of neurite outgrowth in neuronal-like cells following boron nitride nanotube-mediated stimulation. AB - In this paper, we propose an absolutely innovative technique for the electrical stimulation of cells, based on piezoelectric nanoparticles. Ultrasounds are used to impart mechanical stress to boron nitride nanotubes incubated with neuronal like PC12 cells. By virtue of their piezoelectric properties, these nanotubes can polarize and convey electrical stimuli to the cells. PC12 stimulated with the present method exhibit neurite sprout 30% greater than the control cultures after 9 days of treatment. PMID- 20925391 TI - Targeting the polyamine transport system with benzazepine- and azepine-polyamine conjugates. AB - The polyamine transport system (PTS) whose activity is up-regulated in cancer cells is an attractive target for drug design. Two heterocyclic (azepine and benzazepine) systems were conjugated to various polyamine moieties through an amidine bound to afford 18 compounds which were evaluated for their affinity for the PTS and their ability to use the PTS for cell delivery. Structure-activity relationship studies and lead optimization afforded two attractive PTS targeting compounds. The azepine-spermidine conjugate 14 is a very selective substrate of the PTS that may serve as a vector for radioelements used for diagnoses or therapeutics in nuclear medicine. The nitrobenzazepine-spermine conjugate 28 is a very powerful PTS inhibitor with very low intrinsic cytotoxicity, able to prevent the growth of polyamine depleted cells in presence of exogenous polyamines. PMID- 20925392 TI - Low-temperature synthesis of CuInSe2 nanotube array on conducting glass substrates for solar cell application. AB - Highly ordered arrays of Cu-rich and -deficient CuInSe(2) nanotubes as well as ZnO/CuInSe(2) core/sheath nanocables have been synthesized on glass substrates by using ZnO nanorod arrays as sacrificial templates via a low-cost solution method. Chemical conversions from hexagonal ZnO to cubic ZnSe, hexagonal CuSe and tetragonal CuInSe(2) are demonstrated as a novel means for synthesis of I-III-VI nanomaterials. Large differences in their solubility product constant (K(sp)) are crucial for direct exchange in the conversions. In solvothermal reaction of ZnO/CuSe core/shell nanocables with InCl(3), the triethylene glycol solvent serves as a reducing agent for the reduction of cupric (Cu(2+)) to cuprous (Cu(+)) ions and also as an agent for the dissolution of ZnO cores. The absorption coefficient of the CuInSe(2) nanotubes in the visible region is on the order of 10(4) cm(-1). Photoelectrochemical solar cells were fabricated with arrays of ZnO/Cu(1.57+/-0.10)In(0.68+/-0.10)Se(2) and ZnO/CuSe nanocables. It was found that power conversion efficiency of the ZnO/Cu(1.57+/-0.10)In(0.68+/ 0.10)Se(2) cell is about two times higher than that based on ZnO/CuSe. PMID- 20925394 TI - Structure and dynamics of hydrated ion pairs in a hydrophobic environment. AB - The structure, energetics, and dynamics of different alkali halide ion pairs hydrated in a hydrophobic medium are studied using molecular dynamics computer simulations. One or two water molecules hydrating NaCl, NaI, KCl, KI, and KF in bulk carbon tetrachloride are considered. The ion pairs remain in contact throughout the simulations, so the structure of the hydration complex is well characterized. The ions' interaction energy and hydration structure are examined and correlated with the ion sizes and charges. For the first four salts, the stronger interaction of the water molecules with the cation than with the anion of the ion pair is in agreement with recent experiments. However, when the anion is significantly smaller than the cation (as in the case of KF, which was not studied experimentally), the opposite behavior is found. The asymmetry of interaction with the cation and the anion are further elucidated by examining hypothetical ion pairs made from equal-sized cations and anions and by defining an asymmetry hydration parameter, which is found to correlate well with the structural characteristics, as well as with the water molecules' reorientation dynamics. PMID- 20925393 TI - Hand-held spectroscopic device for in vivo and intraoperative tumor detection: contrast enhancement, detection sensitivity, and tissue penetration. AB - Surgery is one of the most effective and widely used procedures in treating human cancers, but a major problem is that the surgeon often fails to remove the entire tumor, leaving behind tumor-positive margins, metastatic lymph nodes, and/or satellite tumor nodules. Here we report the use of a hand-held spectroscopic pen device (termed SpectroPen) and near-infrared contrast agents for intraoperative detection of malignant tumors, based on wavelength-resolved measurements of fluorescence and surface-enhanced Raman scattering (SERS) signals. The SpectroPen utilizes a near-infrared diode laser (emitting at 785 nm) coupled to a compact head unit for light excitation and collection. This pen-shaped device effectively removes silica Raman peaks from the fiber optics and attenuates the reflected excitation light, allowing sensitive analysis of both fluorescence and Raman signals. Its overall performance has been evaluated by using a fluorescent contrast agent (indocyanine green, or ICG) as well as a surface-enhanced Raman scattering (SERS) contrast agent (pegylated colloidal gold). Under in vitro conditions, the detection limits are approximately 2-5 * 10(-11) M for the indocyanine dye and 0.5-1 * 10(-13) M for the SERS contrast agent. Ex vivo tissue penetration data show attenuated but resolvable fluorescence and Raman signals when the contrast agents are buried 5-10 mm deep in fresh animal tissues. In vivo studies using mice bearing bioluminescent 4T1 breast tumors further demonstrate that the tumor borders can be precisely detected preoperatively and intraoperatively, and that the contrast signals are strongly correlated with tumor bioluminescence. After surgery, the SpectroPen device permits further evaluation of both positive and negative tumor margins around the surgical cavity, raising new possibilities for real-time tumor detection and image-guided surgery. PMID- 20925395 TI - Sequence-dependent configurational entropy change of DNA upon intercalation. AB - We investigated the intercalation of an antitumor drug ellipticine into four adenine-thymine (AT) rich DNA duplexes with the focus on the configurational entropy, by means of molecular dynamics (MD) simulations. Two possible binding orientations of ellipticine in a DNA double helix were studied, and the orientation with the pyrrole nitrogen exposed into a major groove was identified as the more probable. The configurational entropy change of DNA is shown to contribute significantly to the binding free energy. The magnitude of this contribution depends on the exact DNA sequence. A detailed analysis revealed that the largest flexibility changes occurred in the sugar-phosphate backbone, resulting in an entropy gain in the most cases. The nucleobases were not involved in the changes of flexibility and entropy. BI/BII-like conformational transitions were observed after the intercalation of ellipticine, and the consequences of these transitions for the evaluation of entropy are discussed. PMID- 20925396 TI - Polyfluorinated compounds in residential and nonresidential indoor air. AB - Indoor air concentrations of fifteen volatile per- and polyfluorinated compounds (PFCs) (five fluorotelomer alcohols (FTOHs), three fluorotelomer acrylates (FTAs), three perfluorinated sulfonamido ethanols (FASEs), and three perfluorinated sulfonamides (FASAs)) were determined in residential and nonresidential indoor air environments. Air samples were taken with passive samplers, consisting of XAD-4 impregnated polyurethane foam (PUF) disks in steel housings. Impregnated PUF disks were extracted by fluidized bed extraction (FBE) using methyl-tert-butyl ether/acetone (1:1) and analyzed by gas chromatography mass spectrometry. Total PFC indoor air concentrations ranged from 8.2 to 458 ng m(-3). Individual PFC concentrations were between 42 pg m(-3) (6:2 FTA) and 209 ng m(-3) (8:2 FTOH). Concentrations of total FTOHs, FTAs, and FASAs + FASEs ranged from 0.2 to 152 ng m(-3) (FTAs), from 3.3 to 307 ng m(-3) (FTOHs), and from 4.4 to 148 ng m(-3) (FASAs + FASEs). Most elevated individual, group, and total PFC concentrations were detected in two stores selling outdoor equipment, one furniture shop, and one carpet shop. Indoor air concentrations were several orders of magnitude higher than published outdoor air concentrations indicating indoor air environments as sources for PFCs to the atmosphere. Concentrations were used to estimate human exposure to investigated PFCs. PMID- 20925397 TI - Arginine-assisted solubilization system for drug substances: solubility experiment and simulation. AB - The poor aqueous solubility of drug substances hampers their broader applications. This paper describes a de novo strategy to increase the aqueous solubility of drug substances using an arginine-assisted solubilization system (AASS) with alkyl gallates as model drug substances. Solubility experiments of alkyl gallates showed that arginine greatly increases the aqueous solubility of different alkyl gallates, whose aqueous solubilities differ widely. In contrast, lysine showed marginal effects on alkyl gallates solubility. Molecular dynamic simulation indicated a greater interaction of arginine with alkyl gallates than that of lysine, which reflects favorable interaction between the guanidinium group of arginine and the aromatic ring of alkyl gallates. Such interaction apparently disrupts association of alkyl gallate molecules, leading to solubilization. These results indicate AASS as a promising approach to solubilize poorly soluble drug substances containing aromatic ring structures. PMID- 20925398 TI - Toxicity of graphene and graphene oxide nanowalls against bacteria. AB - Bacterial toxicity of graphene nanosheets in the form of graphene nanowalls deposited on stainless steel substrates was investigated for both gram-positive and gram-negative models of bacteria. The graphene oxide nanowalls were obtained by electrophoretic deposition of Mg(2+)-graphene oxide nanosheets synthesized by a chemical exfoliation method. On the basis of measuring the efflux of cytoplasmic materials of the bacteria, it was found that the cell membrane damage of the bacteria caused by direct contact of the bacteria with the extremely sharp edges of the nanowalls was the effective mechanism in the bacterial inactivation. In this regard, the gram-negative Escherichia coli bacteria with an outer membrane were more resistant to the cell membrane damage caused by the nanowalls than the gram-positive Staphylococcus aureus lacking the outer membrane. Moreover, the graphene oxide nanowalls reduced by hydrazine were more toxic to the bacteria than the unreduced graphene oxide nanowalls. The better antibacterial activity of the reduced nanowalls was assigned to the better charge transfer between the bacteria and the more sharpened edges of the reduced nanowalls, during the contact interaction. PMID- 20925399 TI - Tautomerism and microsolvation in 2-hydroxypyridine/2-pyridone. AB - The Fourier transform microwave spectra of the hydrated forms of the tautomeric pair 2-pyridinone/2-hydroxypyridine (2PO/2HP) have been investigated in a supersonic expansion. Three hydrated species, 2PO-H2O, 2HP-H2O, and 2PO-(H2O)2, have been observed in the rotational spectrum. Each molecular complex was confidently identified by the features of the 14N quadrupole hyperfine structure of the rotational transitions. The presence of water affects the tautomeric equilibrium -N?C(OH)- <-> -NH-C(?O)-, which is shifted to the enol form for the bare molecules 2PO/2HP but to the keto tautomer for the hydrated forms. PMID- 20925400 TI - All-optical patterning of Au nanoparticles on surfaces using optical traps. AB - The fabrication of nanoscale devices would be greatly enhanced by "nanomanipulators" that can position single and few objects rapidly with nanometer precision and without mechanical damage. Here, we demonstrate the feasibility and precision of an optical laser tweezer, or optical trap, approach to place single gold (Au) nanoparticles on surfaces with high precision (approximately 100 nm standard deviation). The error in the deposition process is rather small but is determined to be larger than the thermal fluctuations of single nanoparticles within the optical trap. Furthermore, areas of tens of square micrometers could be patterned in a matter of minutes. Since the method does not rely on lithography, scanning probes or a specialized surface, it is versatile and compatible with a variety of systems. We discuss active feedback methods to improve positioning accuracy and the potential for multiplexing and automation. PMID- 20925401 TI - Modeling the structure and absorption spectra of stilbazolium merocyanine in polar and nonpolar solvents using hybrid QM/MM techniques. AB - We have performed Car-Parrinello mixed quantum mechanics/molecular mechanics (CP QM/MM) calculations for stilbazolium merocyanine (SM) in polar and nonpolar solvents in order to explore the role of solute molecular geometry, solvation shell structure, and different interaction mechanisms on the absorption spectra and its dependence on solvent polarity. On the basis of the average bond length values and group charge distributions, we find that the SM molecule remains in a neutral quinonoid form in chloroform (a nonpolar solvent) while it transforms to a charge-separated benzenoid form in water (a polar solvent). Based on a quantum mechanical/molecular mechanical response technique, with different MM descriptions for the water environment, absorption spectra were obtained as averages over configurations derived from the CP-QM/MM simulations. We show that for SM in water the solute polarization plays a major role in predictions of the lambda(max) and solvatochromic shift and that once this effect is included the contributions from solvent polarization and intermolecular charge transfer become less important. For SM in chloroform and water solvents, we have also performed absorption spectra calculations using a polarizable continuum model in order to address its relative performance compared to the QM/MM response technique. In the case of SM in water, our study supports the notion that, in order to predict accurate absorption spectra and solvatochromic shifts, it is important to use a discrete description of the solvent when it, as in water, is involved in site specific interaction with the solute molecule. The technique is thus shown to outperform the more conventional polarizable continuum model in predicting the solvatochromic shift. PMID- 20925402 TI - A density functional theory for studying ionization processes in water clusters. AB - A generalized Kohn-Sham (GKS) approach to density functional theory (DFT), based on the Baer-Neuhauser-Livshits range-separated hybrid, combined with ab initio motivated range-parameter tuning is used to study properties of water dimer and pentamer cations. The water dimer is first used as a benchmark system to check the approach. The present brand of DFT localizes the positive charge (hole), stabilizing the proton transferred geometry in agreement with recent coupled cluster calculations. Relative energies of various conformers of the water dimer cation compare well with previously published coupled cluster results. The GKS orbital energies are good approximations to the experimental ionization potentials of the system. Low-lying excitation energies calculated from time dependent DFT based on the present method compare well with recently published high-level "equation of motion-coupled-cluster" calculations. The harmonic frequencies of the water dimer cation are in good agreement with experimental and wave function calculations where available. The method is applied to study the water pentamer cation. Three conformers are identified: two are Eigen type and one is a Zundel type. The structure and harmonic vibrational structure are analyzed. The ionization dynamics of a pentamer water cluster at 0 K shows a fast <50 fs transient for transferring a proton from one of the water molecules, releasing a hydroxyl radical and creating a protonated tetramer carrying the excess hole. PMID- 20925404 TI - Cavity plasmonics: large normal mode splitting of electric and magnetic particle plasmons induced by a photonic microcavity. AB - We couple localized plasmon modes in nanowire pairs with resonator modes of a microcavity. Depending on the position of the nanowire pair in the resonator, the electric (symmetric) or magnetic (antisymmetric) plasmon mode is coupled, manifested by a huge anticrossing in the dispersion diagram. We explain this behavior by taking the symmetry and spatial distribution of the electric fields in the resonator into account. Experimental spectra verify the predicted mode splitting due to the resonant coupling and agree well with theory. Our work can serve as a model system for far-field plasmon-plasmon coupling and paves the way toward enhanced localized plasmon-plasmon interaction in photonically coupled three-dimensional Bragg structures. PMID- 20925403 TI - Computational analysis of HIV-1 protease protein binding pockets. AB - Mutations that arise in HIV-1 protease after exposure to various HIV-1 protease inhibitors have proved to be a difficult aspect in the treatment of HIV. Mutations in the binding pocket of the protease can prevent the protease inhibitor from binding to the protein effectively. In the present study, the crystal structures of 68 HIV-1 proteases complexed with one of the nine FDA approved protease inhibitors from the Protein Data Bank (PDB) were analyzed by (a) identifying the mutational changes with the aid of a developed mutation map and (b) correlating the structure of the binding pockets with the complexed inhibitors. The mutations of each crystal structure were identified by comparing the amino acid sequence of each structure against the HIV-1 wild-type strain HXB2. These mutations were visually presented in the form of a mutation map to analyze mutation patterns corresponding to each protease inhibitor. The crystal structure mutation patterns of each inhibitor (in vitro) were compared against the mutation patterns observed in in vivo data. The in vitro mutation patterns were found to be representative of most of the major in vivo mutations. We then performed a data mining analysis of the binding pockets from each crystal structure in terms of their chemical descriptors to identify important structural features of the HIV-1 protease protein with respect to the binding conformation of the HIV-1 protease inhibitors. Data mining analysis is performed using several classification techniques: Random Forest (RF), linear discriminant analysis (LDA), and logistic regression (LR). We developed two hybrid models, RF-LDA and RF-LR. Random Forest is used as a feature selection proxy, reducing the descriptor space to a few of the most relevant descriptors determined by the classifier. These descriptors are then used to develop the subsequent LDA, LR, and hierarchical classification models. Clustering analysis of the binding pockets using the selected descriptors used to produce the optimal classification models reveals conformational similarities of the ligands in each cluster. This study provides important information in understanding the structural features of HIV-1 protease which cannot be studied by other existing in vivo genomic data sets. PMID- 20925405 TI - High electrical conductivity antimony selenide nanocrystals and assemblies. AB - Antimony selenide is a promising thermoelectric material with a high Seebeck coefficient, but its figure of merit is limited by its low electrical conductivity. Here, we report a rapid and scalable (gram-a-minute) microwave synthesis of one-dimensional nanocrystals of sulfurized antimony selenide that exhibit 10(4)-10(10) times higher electrical conductivity than non-nanostructured bulk or thin film forms of this material. As the nanocrystal diameter increases, the nanowires transform into nanotubes through void formation and coalescence driven by axial rejection of sulfur incorporated into the nanowires from the surfactant used in our synthesis. Individual nanowires and nanotubes exhibit a charge carrier transport activation-energy of <60 meV arising from surface sulfur donor states. Nanocrystal assemblies also show high electrical conductivity, making the nanocrystals attractive building blocks to realize nanostructured thin film and bulk forms of this material for thermoelectric device applications. PMID- 20925406 TI - Origins of hole doping and relevant optoelectronic properties of wide gap p-type semiconductor, LaCuOSe. AB - LaCuOSe is a wide band gap (~2.8 eV) semiconductor with unique optoelectronic properties, including room-temperature stable excitons, high hole mobility ~8 cm(2)/(Vs), and the capability of high-density hole doping (up to 1.7 * 10(21) cm(-3) using Mg). Moreover, its carrier transport and doping behaviors exhibit nonconventional results, e.g., the hole concentration increases with decreasing temperature and the high hole doping does not correlate with other properties such as optical absorption. Herein, secondary ion mass spectroscopy and photoemission spectroscopy reveal that aliovalent ion substitution of Mg at the La site is not the main source of hole doping and the Fermi level does not shift even in heavily doped LaCuOSe:Mg. As the hole concentration increases, the subgap optical absorption becomes more intense, but the increase in intensity does not correlate quantitatively. Transmission electron microscopy indicates that planar defects composed of Cu and Se deficiencies are easily created in LaCuOSe. These observations can be explained via the existence of a degenerate low-mobility layer and formation of complex Cu and Se vacancy defects with the assistance of generalized gradient approximation band calculations. PMID- 20925407 TI - A series of (6,6)-connected porous lanthanide-organic framework enantiomers with high thermostability and exposed metal sites: scalable syntheses, structures, and sorption properties. AB - A series of microporous lanthanide-organic framework enantiomers, Ln(BTC)(H(2)O).(DMF)(1.1) (Ln = Y 1a, 1b; Tb 2a, 2b; Dy 3a, 3b; Er 4a, 4b; Yb 5a, 5b, BTC = 1,3,5-benzenetricarboxylate; DMF = N,N-dimethylformamide) with unprecedented (6,6)-connected topology have been prepared and characterized. All these compounds exhibit very high thermal stability of over 450 degrees C. The pore characteristics and gas sorption properties of these compounds were investigated at cryogenic temperatures by experimentally measuring nitrogen, argon, and hydrogen adsorption/desorption isotherms. The studies show that all these compounds are highly porous with surface areas of 1080 (1), 786 (2), 757 (3), 676 (4), and 774 m(2)/g (5). The amounts of the hydrogen uptakes, 1.79 (1), 1.45 (2), 1.40 (3), 1.51 (4), and 1.41 wt % (5) at 77 K (1 atm), show their promising H(2) storage performances. These porous materials with considerable surface areas, high voids of 44.5% (1), 44.8% (2), 47.7% (3), 44.2% (4), and 45.7% (5), free windows of 6-7 A, available exposed metal sites and very high thermal stability can be easily prepared on a large scale, which make them excellent candidates in many functional applications, such as, gas storage, catalysis, and so on. PMID- 20925408 TI - Formal [4 + 2] cycloaddition of alkoxy-substituted donor-acceptor cyclobutanes and aldehydes catalyzed by Yb(OTf)3. AB - The cycloaddition between 2-alkoxy-1,1-cyclobutane diesters and aromatic, heteroaromatic, or aliphatic aldehydes under Yb(OTf)(3) catalysis generates tetrahydropyrans in high yields with exclusive cis-stereochemistry. PMID- 20925409 TI - Extensive phosphorylation flanking the C-terminal functional domains of the measles virus nucleoprotein. AB - The measles virus nucleoprotein (vNP) is the first and most abundant protein in infected cells. It plays numerous important roles including the encapsidation of genomic viral RNA and the transcription of viral proteins. Intricate interactions with host cell proteins rely on the structural integrity of its functional domains. Although some of these functional domains are known, their structural features are still poorly understood. Here we identified multiple isoforms of measles vNP by two-dimensional differential gel electrophoresis (2D-DIGE) and 2D Western blot. These isoforms were further analyzed by matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF)/TOF using MS (PMF) and MSMS (PSD) and electrospray ionization (ESI)-ion trap using LC-ESI-ion trap MS(1), MS(2) (neutral loss), MS(3) (phosphosite). Both recombinant NP (rNP) and vNP were alpha-acetylated at the N-terminus. After tryptic or chymotryptic digestion, phosphopeptides were enriched and nine phosphorylation sites were identified and localized in the rNP, seven of which were also phosphorylated in vNP, probably by casein kinase 2. The phosphosites were all found within the intrinsically unstructured C-terminal domain. They clustered around functional domains involved in transcription and replication, as well as in sequences interacting with host cell proteins. This underlines the importance of these post-translational modifications. PMID- 20925410 TI - Fruitful adrenergic alpha(2C)-agonism/alpha(2A)-antagonism combination to prevent and contrast morphine tolerance and dependence. AB - The functional in vitro study of the enantiomers of imidazolines 4-7 highlighted the role played by the nature of the ortho phenyl substituent in determining the preferred alpha(2C)-AR configuration. Indeed, the (S) enantiomers of 4-6 or (R) enantiomer of 7 behave as eutomers and activate this subtype as full agonists; the corresponding distomers are partial agonists. Because in clinical pain management with opioids alpha(2C)-AR agonists, devoid of the alpha(2A)-AR mediated side effects, may represent an improvement over current therapies with clonidine like drugs, 4 and its enantiomers, showing alpha(2C)-agonism/alpha(2A) antagonism, have been studied in vivo. The data suggest that partial alpha(2C) activation is compatible with effective enhancement of morphine analgesia and reduction both of morphine tolerance acquisition and morphine dependence acquisition and expression. On the contrary, full alpha(2C)-activation appears advantageous in reducing morphine tolerance expression. Interestingly, the biological profile displayed by 4 (allyphenyline) and its eutomer (S)-(+)-4 has been found to be very unusual. PMID- 20925412 TI - Ytterbium triflate catalyzed synthesis of alkoxy-substituted donor-acceptor cyclobutanes and their formal [4 + 2] cycloaddition with imines: stereoselective synthesis of piperidines. AB - A new synthesis of 2-alkoxy-1,1-cyclobutane diesters and their first use in dipolar cycloadditions is reported. Both the formation of the donor-acceptor cyclobutanes and their subsequent annulation with in situ formed imines are catalyzed by Yb(OTf)(3). Cyclobutanes with carbon donor groups give piperidines with high trans stereoselectivity. PMID- 20925413 TI - Iron complexes for the catalytic transfer hydrogenation of acetophenone: steric and electronic effects imposed by alkyl substituents at phosphorus. AB - A series of iron(II) complexes, trans [Fe(NCMe)(2)(PR(2)CH(2)CH?NCH(2)CH(2)N?CHCH(2)PR(2))][BPh(4)](2) (5, R = Cy; 7, R = iPr; 9, R = Et) were prepared via the template synthesis in one-pot involving air-stable phosphonium dimers, [cyclo-(-PR(2)CH(2)CH(OH)-)(2)](Br)(2) (4, R = Cy; 6, R = iPr; 8, R = Et), KOtBu, [Fe(H(2)O)(6)][BF(4)](2) and ethylenediamine in acetonitrile. In the synthesis of 9, a methanol/acetonitrile solvent mixture was required; otherwise an intermediate iron bis(tridentate) complex, [Fe(PEt(2)CH(2)CH?NCH(2)CH(2)NH(2))(2)](2+), formed as determined by electrospray ionization mass spectrometry (ESI-MS). The crude iron(II) complexes from a template synthesis with ethylenediamine or (S,S)-1,2-diphenylethylenediamine are stirred in acetone under a CO atmosphere (~2 atm) overnight to displace a NCMe ligand; however, in addition to this, bromide displaces an NCMe ligand as well to form a new class of the iron complexes trans [Fe(CO)(Br)(PR(2)CH(2)CH?NCHR'CHR'N?CHCH(2)PR(2))](+) (10 R = Cy, R' = H; (S,S) 11, R = Cy, R' = Ph; 12, R = iPr, R' = H; (S,S)-13, R = iPr, R' = Ph; 14, R = Et, R' = H; (S,S)-15, R = Et, R' = Ph). These complexes were isolated in moderate yields (55-84%) as tetraphenylborate salts. Complexes 10-15 were tested for the catalytic transfer hydrogenation of acetophenone in basic iso-propanol at 25 and 50 degrees C. The complexes 10-13 (where R = Cy or iPr) were inactive while the complexes 14 and (S,S)-15 (where R = Et) were active at 25 degrees C but had better activity at 50 degrees C. Complex (S,S)-15 was higher in activity than complex 14, achieving turnover frequencies as high as 4100 h(-1), conversions of acetophenone to (R)-1-phenylethanol as high as 80% and an enantiomeric excess (e.e.) of 50% in the product. As catalysis progressed, the e.e. diminished to as low as 26%. PMID- 20925414 TI - Preparation, properties, and crystal structures of organometallic ionic liquids comprising 1-ferrocenyl-3-alkylimidazolium-based salts of bis(trifluoromethanesulfonyl)amide and hexafluorophosphate. AB - Bis(trifluoromethanesulfonyl)amide (TFSA), hexafluorophosphate (PF(6)(-)), and iodide salts of 1-ferrocenyl-3-alkylimidazolium were prepared and their thermal and physical properties, including the dependence on alkyl chain length (methyl hexadecyl), were investigated. The TFSA salts were highly viscous ionic liquids with melting points around room temperature. 1-Ferrocenyl-4-methyltriazolium salts were also prepared for comparison. The ferrocenylimidazolium and ferrocenyltriazolium cations showed redox waves for both the ferrocenyl moiety and the azolium moiety and exhibited corresponding charge-transfer bands at around 330 nm, which were analyzed using the Marcus-Hush model. Crystal structure determinations at low temperature revealed that the PF(6) and iodide salts form layerlike structures composed of ionic layers of the charged moieties. The TFSA salt exhibited short hydrogen-bond-like intermolecular contacts between the hydrogen atoms of the cation and oxygen atoms of the anion. PMID- 20925415 TI - A beneficial kinetic effect of an eta(5)-C5Me4H ligand. AB - C-H activation of benzene at 26 degrees C by (eta(5) C(5)Me(5))W(NO)(CH(2)CMe(3))(eta(3)-CH(2)CHCHMe) results after 4 h in the production of five new organometallic complexes, only two of which are isomers of the desired (eta(5)-C(5)Me(5))W(NO)(C(6)H(5))(eta(3)-CH(2)CHCHMe) compound. In contrast, the identical reaction involving the eta(5)-C(5)Me(4)H analogue affords only the phenyl complexes during the first 24 h, thereby facilitating their isolation in good yields. This striking difference in reactivity can be attributed to the lesser steric demands of the eta(5)-C(5)Me(4)H ligand that result in its complexes reacting at a significantly slower rate. PMID- 20925411 TI - Thermochemistry of proton-coupled electron transfer reagents and its implications. PMID- 20925416 TI - Experimental evidence for the pressure dependence of the reaction rate constant between acetic acid and hydroxyl radicals. AB - The reaction rate constant of acetic acid with the hydroxyl radical is measured at 93 Torr with our high-pressure flow system (HPFS) and found to display a negative temperature dependence that can be described by the Arrhenius expression, k(T) = (2.44 +/- 0.22) * 10(-14) exp ((1027 +/- 24)/T)) cm(3) molecule(-1) s(-1). Compared with our previously reported 7 Torr data, we find a noticeable pressure dependence. This dependence is observed to increase with decreasing temperature. This finding is consistent with a termolecular reaction mechanism. It is the first experimental evidence of the pressure dependence for this rate constant. A kinetics model is constructed, and the model results agree qualitatively with our experimental data. The extrapolated rate constant of the title reaction would be faster than previously believed at conditions of the upper troposphere/lower stratosphere, suggesting that the importance of acetic acid in its impact on HO(x) chemistry is currently underestimated. PMID- 20925417 TI - Insights into the mechanism of O2 formation and release from the Mn4O4L6 "cubane" cluster. AB - To probe photoinduced water oxidation catalyzed by the Mn4O4L6 cubane clusters, we have computationally studied the mechanism and controlling factors of the O2 formation from the [Mn4O4L6] catalyst, 6. It was demonstrated that dissociation of an L = H2PO2- ligand from 6 facilitates the direct O-O bond formation that proceeds with a 28.3 (33.4) kcal/mol rate-determining energy barrier at the transition state TS1. This step (the O-O single bond formation) of the reaction is a two-electron oxidation/reduction process, during which two oxo ligands are transformed into to MU2:eta2-O22- unit, and two ("distal") Mn centers are reduced from the 4+ to the 3+ oxidation state. Next two-electron oxidation/reduction occurs by "dancing" of the resulted O22- fragment between the Mn1 and Mn2/Mn(2') centers, keeping its strong coordination to the Mn(1')-center. As a result of this four-electron oxidation/reduction process Mn centers of the Mn4-core of I transform from {Mn1(III)-Mn(1')(III)-Mn2(IV)-Mn(2')(IV)} to {Mn1(II)-Mn(1')(II) Mn2(III)-Mn(2')(III)} in IV. In other words, upon O2 formation in cationic complex [Mn4O4L5](+), I, all four Mn-centers are reduced by one electron each. The overall reaction I -> TS1 -> II -> III -> TS2 -> IV -> TS3 -> V -> VI + O2 is found to be exothermic by 15.4 (10.5) kcal/mol. We analyze the lowest spin states and geometries of all reactants, intermediates, transition states, and products of the targeted reaction. PMID- 20925418 TI - Positioning and immobilization of individual quantum dots with nanoscale precision. AB - We demonstrate a technique for the precise immobilization of nanoscale objects at accurate positions on two-dimensional surfaces. We have developed a water-based photoresist that causes nanostructures such as colloidal quantum dots to segregate to a thin layer at surfaces. By combining this material with electroosmotic feedback control, we demonstrate the ability to position selected, individual quantum dots at specific locations and to immobilize them with 130 nm precision via localized UV exposure. PMID- 20925419 TI - Facially coordinating triamine ligands with a cyclic backbone: some structure stability correlations. AB - Metal complex formation of the two cyclic triamines 6-methyl-1,4-diazepan-6-amine (MeL(a)) and all-cis-2,4,6-trimethylcyclohexane-1,3,5-triamine (Me(3)tach) was studied. The structure of the free ligands (H(x)MeL(a))(x+) and H(x)Me(3)tach(x+) (0 <= x <= 3) was investigated by pH-dependent NMR spectroscopy and X-ray diffraction experiments. The crystal structure of (H(2)Me(3)tach)(p-O(3)S C(6)H(4)-CH(3))(2) showed a chair conformation with axial nitrogen atoms for the doubly protonated species. In contrast to a previous report, Me(3)tach was found to be a stronger base than the parent cis-cyclohexane-1,3,5-triamine (tach); pK(a)-values of H(3)Me(3)tach(3+) (25 degrees C, 0.1 M KCl): 5.2, 7.4, 11.2. The crystal structures of (H(3)MeL(a))(BiCl(6)).2H(2)O and (H(3)MeL(a))(ClO(4))Cl(2) exhibited two distinct twisted chair conformations of the seven membered diazepane ring. [Co(MeL(a))(2)](3+) (cis: 1(3+), trans: 2(3+)), trans [Fe(MeL(a))(2)](3+) (3(3+)), [(MeL(a))ClCd(MU(2)-Cl)](2) (4), trans [Cu(MeL(a))(2)](2+) (5(2+)), and [Cu(HMeL(a))Br(3)] (6) were characterized by single crystal X-ray analysis of 1(ClO(4))(3).H(2)O, 2Br(3).H(2)O, 3(ClO(4))(3).0.8MeCN.0.2MeOH, 4, 5Br(2).0.5MeOH, and 6.H(2)O. Formation constants and redox potentials of MeL(a) complexes were determined by potentiometric, spectrophotometric, and cyclovoltammetric measurements. The stability of [M(II)(MeL(a))](2+)-complexes is low. In comparison to the parent 1,4-diazepan-6 amine (L(a)), it is only slightly enhanced. In analogy to L(a), MeL(a) exhibited a pronounced tendency for forming protonated species such as [M(II)(HMeL(a))](3+) or [M(II)(MeL(a))(HMeL(a))](3+) (see 6 as an example). In contrast to MeL(a), Me(3)tach forms [M(II)L](2+) complexes (M = Cu, Zn) of very high stability, and the coordination behavior corresponds mainly to an "all-or-nothing" process. Molecular mechanics calculations showed that the low stability of L(a) and MeL(a) complexes is mainly due to a large amount of torsional strain within the pure chair conformation of the diazepane ring, required for tridentate coordination. This behavior is quite contrary to Me(3)tach and tacn (tacn =1,4,7 triazacyclononane), where the main portion of strain is already preformed in the free ligand, and the amount, generated upon complex formation, is comparably low. PMID- 20925420 TI - Facile synthesis of Koser's reagent and derivatives from iodine or aryl iodides. AB - The first one-pot synthesis of neutral and electron-rich [hydroxy(tosyloxy)iodo]arenes (HTIBs) from iodine and arenes is presented, thereby avoiding the need for expensive iodine(III) precursors. A large set of HTIBs, including a polyfluorinated analogue, can be obtained from the corresponding aryl iodide under the same conditions. The reaction proceeds under mild conditions, without excess reagents, and is fast and high-yielding. Together, the two presented routes give access to a wide range of HTIBs, which are useful reagents in a variety of synthetic transformations. PMID- 20925421 TI - N-phosphorylated imidazolium salts as precursors to 2- and 5-phosphorylated imidazoles and new imidazol-2-ylidenes featuring the PNCN unit. AB - It has been experimentally proven that the reaction of 1- or 1,2-disubstituted imidazoles with diorganylphosphorus(III) halides proceeds via initial formation of N-phosporylated imidazolium salts. Treatment of these salts with strong bases results in phosphorylation of the parent imidazoles at the 2- or 5-positions, correspondingly. In a previous case, imidazol-2-ylidenes are formed as intermediates. With both N1 and N3 atoms bearing sterically demanding or/and pi donating groups, deprotonation of 1,3-disubstituted imidazolium salts with NaN(SiMe(3))(2) afforded new stable N-phosphorus-substituted Arduengo-type carbenes. PMID- 20925422 TI - Facile synthesis of tetrahydro-1H-isoindolones via a sequential three-component copper-catalyzed coupling/propargyl-allenyl isomerization/[4 + 2] cyclization reaction. AB - An interesting sequential three-component copper-catalyzed coupling/propargyl allenyl isomerization/[4 + 2] cyclization reaction, providing a facile synthesis of highly substituted tetrahydro-1H-isoindolones from conjugated vinylic alkynes, imines, and alpha,beta-unsaturated enoic acid chlorides is reported. The most attractive feature of this transformation is that three stereogenic centers could be generated in one step with high diastereoselectivity. PMID- 20925424 TI - Recognition of nucleoplasmin by its nuclear transport receptor importin alpha/beta: insights into a complete import complex. AB - Nuclear import of the pentameric histone chaperone nucleoplasmin (NP) is mediated by importin alpha, which recognizes its nuclear localization sequence (NLS), and importin beta, which interacts with alpha and is in charge of the translocation of the NP/alpha/beta complex through the nuclear pore. Herein, we characterize the assembly of a functional transport complex formed by full-length NP with importin alpha/beta. Isothermal titration calorimetry (ITC) was used to analyze the thermodynamics of the interactions of importin alpha with beta, alpha with NP, and the alpha/beta heterodimer with NP. Our data show that binding of both importin alpha and alpha/beta to NP is governed by a favorable enthalpic contribution and that NP can accommodate up to five importin molecules per NP pentamer. Phosphomimicking mutations of NP, which render the protein active in histone chaperoning, do not modulate the interaction with importin. Using small angle X-ray scattering, we model the alpha/beta heterodimer, NP/alpha, and NP/alpha/beta solution structures, which reveal a glimpse of a complete nuclear import complex with an oligomeric cargo protein. The set of alternative models, equally well fitting the scattering data, yields asymmetric elongated particles that might represent consecutive geometries the complex can adopt when stepping through the nuclear pore. PMID- 20925423 TI - The alpha-helical C-terminal domain of full-length recombinant PrP converts to an in-register parallel beta-sheet structure in PrP fibrils: evidence from solid state nuclear magnetic resonance. AB - We report the results of solid state nuclear magnetic resonance (NMR) measurements on amyloid fibrils formed by the full-length prion protein PrP (residues 23-231, Syrian hamster sequence). Measurements of intermolecular 13C 13C dipole-dipole couplings in selectively carbonyl-labeled samples indicate that beta-sheets in these fibrils have an in-register parallel structure, as previously observed in amyloid fibrils associated with Alzheimer's disease and type 2 diabetes and in yeast prion fibrils. Two-dimensional 13C-13C and 15N-13C solid state NMR spectra of a uniformly 15N- and 13C-labeled sample indicate that a relatively small fraction of the full sequence, localized to the C-terminal end, forms the structurally ordered, immobilized core. Although unique site specific assignments of the solid state NMR signals cannot be obtained from these spectra, analysis with a Monte Carlo/simulated annealing algorithm suggests that the core is comprised primarily of residues in the 173-224 range. These results are consistent with earlier electron paramagnetic resonance studies of fibrils formed by residues 90-231 of the human PrP sequence, formed under somewhat different conditions [Cobb, N. J., Sonnichsen, F. D., McHaourab, H., and Surewicz, W. K. (2007) Proc. Natl. Acad. Sci. U.S.A. 104, 18946-18951], suggesting that an in-register parallel beta-sheet structure formed by the C terminal end may be a general feature of PrP fibrils prepared in vitro. PMID- 20925425 TI - Role of detection limits in drinking water regulation. AB - Some commentators on environmental science and policy have claimed that advances in analytical chemistry, reflected by an ability to detect contaminants at ever decreasing concentrations, lead to regulations stricter than justified by available toxicological data. We evaluate this claim in the context of drinking water regulation, with respect to contaminants regulated under the Safe Drinking Water Act (SDWA). We examine the relationships between historical and present maximum contaminant levels and goals in the greater context of detection capability and evaluate the extent to which different aspects of the regulatory apparatus (i.e., analytical capability, cost-benefit analysis, analysis of competing risks, and available toxicological data) influence the regulatory process. Our findings do not support the claim that decreases in detection limit lead to more stringent regulation in the context of drinking water regulation in the United States. Further, based on our analysis of the National Primary Drinking Water Regulation and existing United States Environmental Protection Agency approaches to establishing the practical quantifiable level, we conclude that in the absence of changes to the underlying toxicological model, regulatory revision is unlikely. PMID- 20925426 TI - TAT fusion protein transduction into isolated mitochondria is accelerated by sodium channel inhibitors. AB - Stringent control of ion and protein transport across the mitochondrial membranes is required to maintain mitochondrial function and biogenesis. In particular, the inner mitochondrial membrane is generally impermeable to proteins entering the matrix except via tightly regulated protein import mechanisms. Recently, cell penetrant peptides have been shown to move across the inner mitochondrial membrane in a manner suggesting an independent mechanism. HIV-1 transactivator of transcription (TAT) is an arginine-rich cell penetrant peptide, 47YGRKKRRQRRR57, which can transduce full-length proteins not only across the cell membrane but also into intracellular organelles. In this study, we investigated the ability of a TAT-containing protein to move into the mitochondrial matrix. Using a novel FACS assay for isolated, purified mitochondria, we show that TAT can deliver a modified fluorescent protein, mMDH-GFP, to the matrix of mitochondria and it is subsequently processed by the matrix peptidases. In addition, transduction of TAT mMDH-GFP into mitochondria is independent of canonical protein import pathways as well as mitochondrial membrane potential. In direct contrast to published reports regarding the cell membrane where the sodium channel inhibitor, amiloride, blocks endocytosis and inhibits TAT transduction, TAT transduction into mitochondria is markedly increased by this same sodium channel inhibitor. These results confirm that the cell penetrant peptide, TAT, can readily transduce a protein cargo into the mitochondrial matrix. These results also demonstrate a novel role for mitochondrial sodium channels in mediating TAT transduction into mitochondria that is independent of endocytotic mechanisms. The mechanism of TAT transduction into mitochondria therefore is distinctly different from transduction across the cell membrane. PMID- 20925427 TI - Active accumulation of gold nanorods in tumor in response to near-infrared laser irradiation. AB - Gold nanorods, rod-shaped gold nanoparticles, have strong absorbance in the near infrared region, and the absorbed light energy can be converted to heat, the so called photothermal effect. The gold nanorods were coated with thermoresponsive polymers, which have different phase transition temperatures that were controlled by adding comonomers, N,N-dimethylacrylamide (DMAA) or acrylamide (AAm) to N isopropylacrylamide (NIPAM). The phase transition temperatures of poly(NIPAM DMAA) and poly(NIPAM-AAm)-coated gold nanorods were 38 and 41 degrees C, respectively, while polyNIPAM-coated gold nanorods showed phase transition at 34 degrees C. Irradiation of the coated gold nanorods using the near-infrared laser induced a decrease in their sizes due to a phase transition of the polymer layers. Poly(NIPAM-AAm)-coated gold nanorods stably circulated in the blood flow without a phase transition after intravenous injection. Irradiation of near infrared light at a tumor after the injection resulted in the gold specifically accumulating in the tumor. This novel accumulation technique which combines a thermoresponsive polymer and the photothermal effect of the gold nanorods should be a powerful tool for targeted delivery in response to light irradiation. PMID- 20925428 TI - Lactosomes: structural and compositional classification of unique nanometer-sized protein lipid particles of human milk. AB - Milk fat globules (MFGs) are accepted primarily as triacylglycerol delivery systems. The identification of nanometer-sized lipid-protein particles termed "lactosomes" that do not contain triacylglycerol raises the question of their possible functions. MFGs were isolated by slow centrifugation, and lactosomes were isolated by ultracentrifugation at a density equivalent to plasma high density lipoproteins (HDL) (d > 1.063 g/mL) from human milk obtained from six volunteers at different lactation stages. Isolated lactosomes were analyzed and compared with MFGs for their size distribution, lipidome, proteome, and functional activity. Lactosomes from early milk, day 8, were found to be similar in size as those from mature milk >28 days, averaging ~ 25 nm in diameter. In total, 97 nonredundant proteins were identified in the MFG and lactosome fractions, 46 of which were unique to the MFG fraction and 29 of which were unique to the lactosome fraction. The proteins identified in the lactosome and MFG fractions were enriched with proteins identified with immunomodulatory pathways. Unlike MFGs and GM1-laden reconstituted HDL that served as a positive control, lactosomal binding capacity to cholera toxin was weak. Lipidomic analyses found that lactosomes were devoid of triacylglycerol and gangliosides, unlike MFGs, but rich in a variety of phospholipid species. The data found differences in structure, composition, and function between lactosomes and MFG, suggesting that these two particles are derived from different biosynthetic and/or secretory pathways. The results reveal a bioactive lipid-protein, nanometer-length scale particle that is secreted into milk not to supply energy to the infant but to play unique, protective, and regulatory roles. PMID- 20925430 TI - Effects of pH on the S(3) state of the oxygen evolving complex in photosystem II probed by EPR split signal induction. AB - The electrons extracted from the CaMn(4) cluster during water oxidation in photosystem II are transferred to P(680)(+) via the redox-active tyrosine D1 Tyr161 (Y(Z)). Upon Y(Z) oxidation a proton moves in a hydrogen bond toward D1 His190 (His(Z)). The deprotonation and reprotonation mechanism of Y(Z)-OH/Y(Z)-O is of key importance for the catalytic turnover of photosystem II. By light illumination at liquid helium temperatures (~5 K) Y(Z) can be oxidized to its neutral radical, Y(Z)(*). This can be followed by the induction of a split EPR signal from Y(Z)(*) in a magnetic interaction with the CaMn(4) cluster, offering a way to probe for Y(Z) oxidation in active photosystem II. In the S(3) state, light in the near-infrared region induces the split S(3) EPR signal, S(2)'Y(Z)(*). Here we report on the pH dependence for the induction of S(2)'Y(Z)(*) between pH 4.0 and pH 8.7. At acidic pH the split S(3) EPR signal decreases with the apparent pK(a) (pK(app)) ~ 4.1. This can be correlated to a titration event that disrupts the essential H-bond in the Y(Z)-His(Z) motif. At alkaline pH, the split S(3) EPR signal decreases with the pK(app) ~ 7.5. The analysis of this pH dependence is complicated by the presence of an alkaline induced split EPR signal (pK(app) ~ 8.3) promoted by a change in the redox potential of Y(Z). Our results allow dissection of the proton-coupled electron transfer reactions in the S(3) state and provide further evidence that the radical involved in the split EPR signals is indeed Y(Z)(*). PMID- 20925429 TI - Copper-doxorubicin as a nanoparticle cargo retains efficacy with minimal toxicity. AB - Repeated administration of chemotherapeutics is typically required for the effective treatment of highly aggressive tumors and often results in systemic toxicity. We have created a copper-doxorubicin complex within the core of liposomes and applied the resulting particle in multidose therapy. Copper and doxorubicin concentrations in the blood pool were similar at 24 h (~40% of the injected dose), indicating stable circulation of the complex. Highly quenched doxorubicin fluorescence remained in the blood pool over tens of hours, with fluorescence increasing only with the combination of liposome disruption and copper trans-chelation. At 48 h after injection, doxorubicin fluorescence within the heart and skin was one-fifth and one-half, respectively, of fluorescence observed with ammonium sulfate-loaded doxorubicin liposomes. After 28 days of twice per week doxorubicin administration of 6 mg/kg, systemic toxicity (cardiac hypertrophy and weight and hair loss) was not detected with the copper doxorubicin liposomes but was substantial with ammonium sulfate-loaded doxorubicin liposomes. We then incorporated two strategies designed to enhance efficacy, mTOR inhibition (rapamycin) to slow proliferation and therapeutic ultrasound to enhance accumulation and local diffusion. Tumor accumulation was ~10% ID/g and was enhanced approximately 2-fold with the addition of therapeutic ultrasound. After the 28-day course of therapy, syngeneic tumors regressed to a premalignant phenotype of ~(1 mm)(3) or could not be detected. PMID- 20925431 TI - 2D-DiGE analysis of the human endometrial secretome reveals differences between receptive and nonreceptive states in fertile and infertile women. AB - Endometrial secretions in the uterine cavity contain mediators important for endometrial receptivity and embryo implantation. Unbiased analysis of uterine fluid from a receptive versus nonreceptive time of the menstrual cycle and in fertile and infertile women will provide new insights into uterine receptivity. We hypothesized that proteomic analysis of human uterine lavages would identify proteins important for the establishment of pregnancy in humans. Lavages collected from fertile (n = 7) and infertile (n = 8) women during the midsecretory (MS) phase, and from fertile women during the midproliferative (MP) (n = 7) phase, were assessed using 2D-differential in gel electrophoresis (2D DiGE) over a pI 4-7 range. Statistical analysis revealed 7 spots that were significantly decreased in the MP compared to the MS phase, while 18 spots showed differential expression between fertile and infertile women. A number of proteins were identified by mass spectrometry, including antithrombin III and alpha-2 macroglobulin, whose production was confirmed in endometrial epithelium. Their staining pattern suggests roles during embryo implantation. Assessment of the human endometrial secretome has identified differences in the protein content of uterine fluid with respect to receptivity and fertility. PMID- 20925432 TI - S-alkylating labeling strategy for site-specific identification of the s nitrosoproteome. AB - S-nitrosylation, a post-translational modification of cysteine residues induced by nitric oxide, mediates many physiological functions. Due to the labile nature of S-nitrosylation, detection by mass spectrometry (MS) is challenging. Here, we developed an S-alkylating labeling strategy using the irreversible biotinylation on S-nitrosocysteines for site-specific identification of the S-nitrosoproteome by LC-MS/MS. Using COS-7 cells without endogenous nitric oxide synthase, we demonstrated that the S-alkylating labeling strategy substantially improved the blocking efficiency of free cysteines, minimized the false-positive identification caused by disulfide interchange, and increased the digestion efficiency for improved peptide identification using MS analyses. Using this strategy, we identified total 586 unique S-nitrosylation sites corresponding to 384 proteins in S-nitroso-N-acetylpenicillamine (SNAP)/l-cysteine-treated mouse MS-1 endothelial cells, including 234 previously unreported S-nitrosylated proteins. When the topologies of 84 identified transmembrane proteins were further analyzed, their S-nitrosylation sites were found to mostly face the cytoplasmic side, implying that S-nitrosylation occurs in the cytoplasm. In addition to the previously known acid/basic motifs, the ten deduced consensus motifs suggested that combination of local hydrophobicity and acid/base motifs in the tertiary structure contribute to the specificity of S-nitrosylation. Moreover, the S-nitrosylated cysteines showed preference on beta-strand, having lower relative surface accessibility at the S-nitrosocysteines. PMID- 20925433 TI - Toward the development of innovative bifunctional agents to induce differentiation and to promote apoptosis in leukemia: clinical candidates and perspectives. PMID- 20925434 TI - Novel 1',1'-chain substituted hexahydrocannabinols: 9beta-hydroxy-3-(1-hexyl cyclobut-1-yl)-hexahydrocannabinol (AM2389) a highly potent cannabinoid receptor 1 (CB1) agonist. AB - In pursuit of a more detailed understanding of the structural requirements for the key side chain cannabinoid pharmacophore, we have extended our SAR to cover a variety of conformationally modified side chains within the 9-keto and 9-hydroxyl tricyclic structures. Of the compounds described here, those with a seven-atom long side chain substituted with a cyclopentyl ring at C1' position have very high affinities for both CB1 and CB2 (0.97 nM < K(i) < 5.25 nM), with no preference for either of the two receptors. However, presence of the smaller cyclobutyl group at the C1' position leads to an optimal affinity and selectivity interaction with CB1. Thus, two of the C1'-cyclobutyl analogues, namely, (6aR,10aR)-3-(1-hexyl-cyclobut-1-yl)-6,6a,7,8,10,10a-hexahydro-1-hydroxy-6,6 dimethyl-9H-dibenzo[b,d]pyran-9-one and (6aR,9R,10aR)-3-(1-hexyl-cyclobut-1-yl) 6a,7,8,9,10,10a-hexahydro-6,6-dimethyl-6H-dibenzo[b,d]pyran-1,9 diol (7e-beta, AM2389), exhibited remarkably high affinities (0.84 and 0.16 nM, respectively) and significant selectivities (16- and 26-fold, respectively) for CB1. Compound 7e-beta was found to exhibit exceptionally high in vitro and in vivo potency with a relatively long duration of action. PMID- 20925436 TI - Preventability of drug-related harms - part I: a systematic review. AB - 'Preventability' is a crucial concept in the literature on adverse drug reactions (ADRs). We have carried out a systematic review in order to identify and analyse the approaches used to define 'preventability' in relation to ADRs. We have restricted this investigation to definitions of preventability and have not dealt with other aspects. We searched MEDLINE (1963-April 2009) and EMBASE (1980-April 2009), without language restriction, for papers in which preventability of ADRs was likely to be defined. We found 234 papers, of which we retrieved 231. Of these, 172 either contained original definitions of preventability or referred to other papers in which preventability was defined. Forty contained no definition, and 19 were not relevant. In the 172 papers selected, we identified eight different general approaches to defining the preventability of ADRs: (1) analysis without explicit criteria; (2) assessment by consensus; (3) preventability linked to error; (4) preventability linked to standards of care; (5) preventability linked to medication-related factors; (6) preventability linked to information technology; (7) categorization of harmful treatments in explicit lists; and (8) a combination of more than one approach. These approaches rely on two general methods: the judgement of one or more investigators or the use of pre-defined explicit criteria; neither is satisfactory. Specific problems include the weakness of consensus as a method (since experts can agree and yet be wrong), inadequacy of definition of standards of care, and circularity in several definitions of preventability. Furthermore, attempts to list all preventable effects are bound to be incomplete and will not always apply to an individual case. We conclude that an approach based on analysis of the mechanisms of adverse reactions and their clinical features could be preferable; such an approach is described in a companion paper (Part II) in this issue of Drug Safety. PMID- 20925437 TI - Preventability of drug-related harms - part II: proposed criteria, based on frameworks that classify adverse drug reactions. AB - BACKGROUND: 'Preventability' is a crucial concept in the literature on adverse drug effects. However, a systematic review of the definitions of preventability of adverse drug effects has suggested that none fits all circumstances. Furthermore, when the reliability of these definitions has been examined they have been found to be imperfect. OBJECTIVE: To propose and outline a method for determining the theoretical preventability of an adverse drug effect, based on frameworks for classifying adverse drug reactions - the EIDOS and DoTS methods. METHODS: EIDOS is based on the mechanism of action of the drug. It observes that a drug (an Extrinsic species) causes an adverse effect by interacting with an Intrinsic species that is its target when the two are Distributed together, and that the resulting pathophysiological Outcome (the adverse effect) causes the Sequela (the adverse reaction). DoTS observes that the Dose-relatedness of the adverse effect compared with the beneficial effect is relevant (determining toxic, collateral, or hypersusceptibility effects), that adverse effects have Time-courses (varying from immediate to delayed), and that there are individual Susceptibility factors. RESULTS AND DISCUSSION: We have elicited many published examples that show that each of these factors in the causation of an adverse drug effect can be adduced to assess its preventability. We have constructed a flowchart that illustrates how the processes can be logically analysed. CONCLUSIONS: This approach suggests methods for devising prospective preventive strategies and for deciding retrospectively whether an adverse reaction in an individual should have been prevented. PMID- 20925435 TI - Progressive multifocal leukoencephalopathy and newer biological agents. AB - Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disease of the brain due to a polyoma virus, JC virus. Despite the ubiquity of this virus, PML is rare and almost always seen in association with an underlying immunosuppressive condition. In the last 30 years, AIDS has been the most common predisposing factor. The observation of PML attending the use of certain monoclonal antibody therapies and other pharmacological agents has raised concerns about the safety profile of these agents, but has also provided a window into the pathogenesis of PML. Certain agents, such as the monoclonal antibodies natalizumab, an alpha4beta1 and alpha4beta7 integrin inhibitor, and efalizumab, an antibody directed against CD11a, appear to uniquely predispose to PML. Prior to their introduction for multiple sclerosis and Crohn's disease with respect to natalizumab, and psoriasis with respect to efalizumab, PML had never been observed with these disorders. PML occurring with other agents that currently carry US FDA-mandated 'black-box' warnings, such as rituximab, an antibody directed to CD20, or mycophenolate mofetil, a drug that inhibits T- and B-cell proliferation, typically occur in the background of underlying disorders that have already been identified as risks for PML. This review will focus on the available data regarding the risk for PML with monoclonal antibodies and other drugs. A biologically plausible explanation for the increased risk of PML will be proposed, as well as potential strategies for mitigating disease risk. PMID- 20925438 TI - Domperidone and ventricular arrhythmia or sudden cardiac death: a population based case-control study in the Netherlands. AB - BACKGROUND: Recently, a 4-fold increase in risk of sudden cardiac death (SCD) was reported for domperidone in a study that focused on corrected QT interval (QTc) prolonging drugs as a class and their association with SCD. OBJECTIVE: To evaluate the association between the use of domperidone and serious non-fatal ventricular arrhythmia (VA) and SCD in the general population. METHODS: We performed a population-based, case-control study during 1996-2007 in the Integrated Primary Care Information (IPCI) database, a longitudinal general practice research database in the Netherlands. We included all patients aged >=18 years without cancer in the source population. We studied the association between the use of domperidone by recency of use (current, past and none) and daily dose, and the risk of serious non-fatal VA or SCD. Cases were defined as a natural death due to cardiac causes heralded by abrupt loss of consciousness within 1 hour after the onset of acute symptoms or an unwitnessed, unexpected death of someone seen in a stable medical condition <24 hours previously with no evidence of a non-cardiac cause. Controls were randomly drawn from the source population and matched to cases on age, sex, practice and index date. We compared the exposure odds for SCD alone and VA plus SCD by means of conditional logistic regression while adjusting for all available confounders. In addition, we stratified by insurance type. RESULTS: The study population comprised 1366 cases (62 VA and 1304 SCD) and 14114 matched controls. Of all cases, ten patients were current domperidone users at the index date, all with SCD. The matched unadjusted odds ratio of domperidone and SCD was 3.72 (95% CI 1.72, 8.08). Daily doses >30 mg were associated with a significant increased risk of SCD (adjusted odds ratio [OR(adj)] 11.4 [95% CI 1.99, 65.2]). Since there was a near interaction with health insurance (p = 0.050), all analyses were stratified by insurance. In publicly insured patients, seven cases were current users at the index date. Current use was associated with a significant increased risk of SCD (OR(adj) 4.17 [95% CI 1.33, 13.1]). Amongst privately insured patients there was one domperidone-exposed case, and amongst non-insured there were two. CONCLUSIONS: Current use of domperidone, especially high doses, is associated with an increased risk of SCD. We could not demonstrate an effect of domperidone on non fatal VA due to absence of exposed cases. PMID- 20925439 TI - Temporal data mining for adverse events following immunization in nationwide Danish healthcare databases. AB - BACKGROUND: A rarely used opportunity in pharmacovigilance is data mining for adverse drug reactions (ADRs) in population-based healthcare databases. OBJECTIVE: To evaluate the potential of data mining for ADRs in the nationwide Danish healthcare databases. We specifically considered hospital contacts following measles, mumps and rubella (MMR) immunization. METHODS: We constructed a cohort consisting of all children born in Denmark from 1995 to 2007 (n = 918,831) with individual-level linked data on childhood vaccinations and hospital contacts from the nationwide Danish healthcare databases. We applied a cohort based data mining methodology to compare the observed versus the expected incidence of adverse event in different time periods relative to immunization. With this approach we evaluated temporal associations between MMR immunization and 5915 different diagnoses occurring in the cohort. In order to evaluate the ability of our approach to detect signals, we singled out a set of four adverse events previously recognized as being associated with the MMR vaccine. RESULTS: We were able to link a total of 3,162,251 hospital contacts and 5915 different diagnoses to the children in the cohort. Previously recognized temporal associations between adverse events (febrile convulsions, idiopathic thrombocytopenic purpura, lymphadenopathy and rash) and MMR immunization were identified in the Danish databases by our method. CONCLUSIONS: Data mining in the Danish population-based healthcare databases provides adequate ability to detect adverse events. Pharmacovigilance using electronic healthcare databases holds potential as an important supplement to traditional pharmacovigilance. PMID- 20925440 TI - Pharmacists' interventions in prescribing errors at hospital discharge: an observational study in the context of an electronic prescribing system in a UK teaching hospital. AB - BACKGROUND: Pharmacists have an essential role in improving drug usage and preventing prescribing errors (PEs). PEs at the interface of care are common, sometimes leading to adverse drug events (ADEs). This was the first study to investigate, using a computerized search method, the number, types, severity, pharmacists' impact on PEs and predictors of PEs in the context of electronic prescribing (e-prescribing) at hospital discharge. METHOD: This was a retrospective, observational, 4-week study, carried out in 2008 in the Medical and Elderly Care wards of a 904-bed teaching hospital in the northwest of England, operating an e-prescribing system at discharge. Details were obtained, using a systematic computerized search of the system, of medication orders either entered by doctors and discontinued by pharmacists or entered by pharmacists. Meetings were conducted within 5 days of data extraction with pharmacists doing their routine clinical work, who categorized the occurrence, type and severity of their interventions using a scale. An independent senior pharmacist retrospectively rated the severity and potential impact, and subjectively judged, based on experience, whether any error was a computer-related error (CRE). Discrepancies were resolved by multidisciplinary discussion. The Statistical Package for Social Sciences was used for descriptive data analysis. For the PE predictors, a multivariate logistic regression was performed using STATA 7. Nine predictors were selected a priori from available prescribers', patients' and drug data. RESULTS: There were 7920 medication orders entered for 1038 patients (doctors entered 7712 orders; pharmacists entered 208 omitted orders). There were 675 (8.5% of 7920) interventions by pharmacists; 11 were not associated with PEs. Incidences of erroneous orders and patients with error were 8.0% (95% CI 7.4, 8.5 [n = 630/7920]) and 20.4% (95% CI 18.1, 22.9 [n = 212/1038]), respectively. The PE incidence was 8.4% (95% CI 7.8, 9.0 [n = 664/7920]). The top three medications associated with PEs were paracetamol (acetaminophen; 30 [4.8%]), salbutamol (albuterol; 28 [4.4%]) and omeprazole (25 [4.0%]). Pharmacists intercepted 524 (83.2%) erroneous orders without referring to doctors, and 70% of erroneous orders within 24 hours. Omission (31.0%), drug selection (29.4%) and dosage regimen (18.1%) error types accounted for >75% of PEs. There were 18 (2.9%) serious, 481 (76.3%) significant and 131 (20.8%) minor erroneous orders. Most erroneous orders (469 [74.4%]) were rated as of significant severity and significant impact of pharmacists on PEs. CREs (n = 279) accounted for 44.3% of erroneous orders. There was a significant difference in severity between CREs and non-CREs (chi2 = 38.88; df = 4; p < 0.001), with CREs being less severe than non CREs. Drugs with multiple oral formulations (odds ratio [OR] 2.1; 95% CI 1.25, 3.37; p = 0.004) and prescribing by junior doctors (OR 2.54; 95% CI 1.08, 5.99; p = 0.03) were significant predictors of PEs. CONCLUSIONS: PEs commonly occur at hospital discharge, even with the use of an e-prescribing system. User and computer factors both appeared to contribute to the high error rate. The e prescribing system facilitated the systematic extraction of data to investigate PEs in hospital practice. Pharmacists play an important role in rapidly documenting and preventing PEs before they reach and possibly harm patients. Pharmacists should understand CREs, so they complement, rather than duplicate, the e-prescribing system's strengths. PMID- 20925441 TI - Comparison of three methods (consensual expert judgement, algorithmic and probabilistic approaches) of causality assessment of adverse drug reactions: an assessment using reports made to a French pharmacovigilance centre. AB - BACKGROUND: Different methods have been proposed for assessing a possible causal link between a drug treatment and an adverse event in individual patients. They approximately belong to three main categories: expert judgement, operational algorithms and probabilistic approaches. OBJECTIVE: To compare, in a set of actual drug adverse event reports, three different methods for assessing drug causality, each belonging to one of the three main categories: expert judgement, the algorithm used by the French pharmacovigilance centres since 1985, and a novel method based on the logistic function. METHODS: Fifty drug-event pairs were randomly sampled from the database of the Bordeaux pharmacovigilance centre, France. To serve as the gold standard, the probability for drug causation, from 0 to 1, was first determined for each drug-event pair by a panel of senior experts until consensus was reached. Causality was then assessed by members of the Bordeaux pharmacovigilance centre by using the French algorithm and the logistic method. Results expressed as a probability with the logistic method and as a score from 0 to 4 with the French algorithm were then compared with consensual expert judgement, as were the sensitivity, specificity and positive and negative predictive values. RESULTS: Probabilities ranged from 0.08 to 0.99 (median 0.58; mean 0.60) for experts versus 0.18-0.88 (median 0.73; mean 0.67) for the logistic method. Consensual expert judgement was not discriminant (p = 0.50) in ten cases. For the algorithm, only three of five causality scores were found, doubtful scores being clearly predominant (74%) followed by possible (16%) and probable (10%) scores. Sensitivity and specificity were 0.96 and 0.42, respectively, for the logistic method versus 0.42 and 0.92 for the algorithm. Positive and negative predictive values were 0.78 and 0.83, respectively, for the logistic method versus 0.92 and 0.42 for the algorithm. CONCLUSIONS: Agreement between the three approaches was poor, and only satisfactory for drug events judged as drug-induced by consensual expert judgement. The logistic method showed high sensitivity at the expense of poor specificity. Conversely, the algorithm had poor sensitivity but good specificity. The comparatively good sensitivity and positive predictive values of the logistic method suggest that it may be more useful in the routine or automated assessment of case reports of suspected but still unknown adverse drug reactions. With a substantial rate of false positives relative to true negatives (low specificity), the logistic method does not replace, but can be complemented by, critical clinical assessment of individual cases in evaluating drug-related risk. PMID- 20925442 TI - Pharmacokinetics of a new orodispersible tablet formulation of vardenafil: results of three clinical trials. AB - BACKGROUND: Vardenafil is a potent and highly selective oral phosphodiesterase type 5 (PDE-5) inhibitor that has been shown in numerous clinical trials and post marketing surveillance studies to be safe and effective for improving erectile function in men with erectile dysfunction (ED). Until recently, the drug was only available as a film-coated tablet (FCT). A new orodispersible tablet (ODT) formulation of vardenafil has been developed that disintegrates in the subject's mouth without the need for water or other liquids. OBJECTIVE: To characterize the pharmacokinetics of a new 10 mg ODT formulation of vardenafil. METHODS: Three clinical trials were conducted: (i) a randomized 4-fold crossover study to assess the effect of food and water on the pharmacokinetics of vardenafil ODT, compared with vardenafil FCT, in healthy men; (ii) a phase I study to assess single and multiple doses of vardenafil ODT, compared with a single dose of vardenafil FCT, in young and elderly men with ED; and (iii) a pharmacokinetic substudy of a phase III trial in men of broad age range with ED. RESULTS: Vardenafil ODT was rapidly absorbed after oral administration without water, with a similar pharmacokinetic profile to vardenafil FCT, except that the ODT exhibited significantly greater bioavailability. After a single dose, the geometric mean area under the plasma concentration-time curve from time zero to infinity (AUC(infinity)) of vardenafil ODT increased by 21-44% compared with the FCT. There was no consistent difference in geometric mean maximum vardenafil plasma concentration (C(max)) between the two formulations. Geometric mean AUC(infinity) and C(max) were increased by 41% and 24%, respectively, in men with ED aged >=65 years compared with those aged <65 years. Multiple dosing or administration of vardenafil ODT with food had no meaningful effect on the pharmacokinetics of vardenafil. Vardenafil ODT was well tolerated. CONCLUSION: Vardenafil ODT should be taken without water. Partial absorption of vardenafil through the oral mucosa results in an unexpected extent of suprabioavailability of the ODT formulation. Vardenafil ODT is a convenient formulation, with pharmacokinetic and safety characteristics that are appropriate for the treatment of ED. PMID- 20925443 TI - Cerium oxide nanoparticle-induced pulmonary inflammation and alveolar macrophage functional change in rats. AB - The use of cerium compounds as diesel fuel catalyst results in the emission of cerium oxide nanoparticles (CeO2) in the exhaust. This study characterized the potential effects of CeO2 exposure on lung toxicity. Male Sprague Dawley rats were exposed to CeO2 by a single intratracheal instillation at 0.15, 0.5, 1, 3.5 or 7 mg/kg body weight. At 1 day after exposure, CeO2 significantly reduced NO production, but increased IL-12 production, by alveolar macrophages (AM) in response to ex vivo lipopolysacchride (LPS) challenge, and caused AM apoptosis, through activation of caspases 9 and 3. CeO2 exposure markedly increased suppressor of cytokine signaling-1 at 1-day and elevated arginase-1 at 28-day post exposure in lung cells, while osteopontin was significantly elevated in lung tissue at both time points. CeO2 induced inflammation, cytotoxicity, air/blood barrier damage, and phospholipidosis with enlarged AM. Thus, CeO2 induced lung inflammation and injury in lungs which may lead to fibrosis. PMID- 20925444 TI - Genotoxicity of engineered nanomaterials. PMID- 20925445 TI - Gene toxicity studies on titanium dioxide and zinc oxide nanomaterials used for UV-protection in cosmetic formulations. AB - Titanium dioxide and zinc oxide nanomaterials, used as UV protecting agents in sunscreens, were investigated for their potential genotoxicity in in vitro and in vivo test systems. Since standard OECD test methods are designed for soluble materials and genotoxicity testing for nanomaterials is still under revision, a battery of standard tests was used, covering different endpoints. Additionally, a procedure to disperse the nanomaterials in the test media and careful characterization of the dispersed test item was added to the testing methods. No genotoxicity was observed in vitro (Ames' Salmonella gene mutation test and V79 micronucleus chromosome mutation test) or in vivo (mouse bone marrow micronucleus test and Comet DNA damage assay in lung cells from rats exposed by inhalation). These results add to the still limited data base on genotoxicity test results with nanomaterials and provide congruent results of a battery of standard OECD test methods applied to nanomaterials. PMID- 20925446 TI - Exploring the aneugenic and clastogenic potential in the nanosize range: A549 human lung carcinoma cells and amorphous monodisperse silica nanoparticles as models. AB - We explored how to assess the genotoxic potential of nanosize particles with a well validated assay, the in vitro cytochalasin-B micronucleus assay, detecting both clastogens and aneugens. Monodisperse Stober amorphous silica nanoparticles (SNPs) of three different sizes (16, 60 and 104 nm) and A549 lung carcinoma cells were selected as models. Cellular uptake of silica was monitored by ICP-MS. At non-cytotoxic doses the smallest particles showed a slightly higher fold induction of micronuclei (MNBN). When considering the three SNPs together, particle number and total surface area appeared to account for MNBN induction as they both correlated significantly with the amplitude of the effect. Using nominal or cellular dose did not show statistically significant differences. Likewise, alkaline comet assay and FISH-centromeric probing of MNBN indicated a weak and not statistically significant induction of oxidative DNA damage, chromosome breakage and chromosome loss. This line of investigation will contribute to adequately design and interpret nanogenotoxicity assays. PMID- 20925447 TI - Potential pulmonary effects of engineered carbon nanotubes: in vitro genotoxic effects. AB - The development of novel engineered nano-sized materials is a rapidly emerging technology with many applications in medicine and industry. In vitro and in vivo studies have suggested many deleterious effects of carbon nanotube exposure including granulomatous inflammation, release of cytosolic enzymes, pulmonary fibrosis, reactive oxygen damage, cellular atypia, DNA fragmentation, mutation and errors in chromosome number as well as mitotic spindle disruption. The physical properties of the carbon nanotubes make respiratory exposure to workers likely during the production or use of commercial products. Many of the investigations of the genotoxicity of carbon nanotubes have focused on reactive oxygen mediated DNA damage; however, the long thin tubular-shaped carbon nanotubes have a striking similarity to cellular microtubules. The similarity of carbon nanotubes to microtubules suggests a potential to interact with cellular biomolecules, such as the mitotic spindle, as well as the motor proteins that separate the chromosomes during cell division. Disruption of centrosomes and mitotic spindles would result in monopolar, tripolar, and quadrapolar divisions of chromosomes. The resulting aneuploidy is a key mechanism in the potential carcinogenicity of carbon nanotubes. PMID- 20925448 TI - Rationale of genotoxicity testing of nanomaterials: regulatory requirements and appropriateness of available OECD test guidelines. AB - The development of an environmental health and safety risk management system for nanoscale particle-types requires a base set of hazard data. Accurate determination of health and environmental risks of nanomaterials is a function of the integration of hazard and exposure datasets. Recently, a nanoparticle risk assessment strategy was promulgated and the components are described in a document entitled "Nanorisk framework" (www.nanoriskframework.com). A major component of the hazard evaluation includes a proposed minimum base set of toxicity studies. Included in the suggested studies were substantial particle characterization, a variety of acute hazard and environmental tests, concomitant with screening-type genotoxicity studies. The implementation of well-accepted genotoxicity assays for testing nanomaterials remains a controversial issue. This is because many of these genotoxicity tests were designed for screening general macroparticle chemicals and might not be suitable for the screening of nanomaterials (even of the same compositional material). Furthermore, no nanoparticle-type positive controls have been established or universally accepted for these tests. Although it is the comparative results of the test material vs. the negative or vehicle control that forms the basis for interpreting the results and potency of test materials in genetic toxicology assays, the lack of a nanoparticle-type positive control questions the suitability of the tests to identify nanomaterials with genotoxic properties. It is also not possible to establish historical positive control ranges that would confirm the sensitivity of the tests. Although several genetic toxicology tests have been validated for chemicals according to the Organisation for Economic Co-operation and Development (OECD) test guidelines, the relevance of these assays for nanoparticulate materials remains to be determined. In an attempt to remedy this issue, the OECD has established current projects designed to evaluate the relevance and reproducibility of safety hazard tests for representative nanomaterials, including genotoxicity assays (i.e., Steering Group 3 - Safety Testing of Representative Nanomaterials). In this article, we discuss our past approaches and experience in conducting genotoxicity assays (1) for a newly developed ultrafine TiO2 particle-type; and (2) in a recent inhalation study, evaluating micronucleus formation in rat erythrocytes following exposures to engineered amorphous nanosilica particles. It seems clear that the development of standardized approaches will be necessary in order to determine whether exposures to specific nanoparticle-types are associated with genotoxic events. The appropriateness of available genotoxicity test systems for nanomaterials requires confirmation and standardization. Accordingly, it seems reasonable to conclude that any specific regulatory testing requirements for nanoparticles would be premature at this time. PMID- 20925449 TI - Possible genotoxic mechanisms of nanoparticles: criteria for improved test strategies. AB - We review the mechanisms and pathways whereby nanoparticles might cause genotoxicity. Primary and secondary mechanisms are discussed in relation to the general particle toxicology paradigm. We also discuss how we might improve genotoxicity assays for nanoparticles. In this context we describe the role of the dispersion and the protein corona, the most relevant metric, choice of controls and new endpoints for genotoxicity along with the need for a structure activity model of NP genotoxicity. PMID- 20925450 TI - Prevalence and clinical features of pneumonia in patients with laboratory confirmed pandemic influenza A H1N1 2009 infection in South Korea. AB - During the early stages of the pandemic influenza A H1N1 2009 (pH1N1) outbreak in South Korea, the government recommended antiviral therapy with laboratory confirmation in specialized hospitals. Hence we had a unique opportunity to test all patients suspected to have pH1N1, including those who initially presented with a mild illness, such as those who were not in at-risk groups and who had an uncomplicated illness. We therefore evaluated the proportion and clinical features of pneumonia in patients with laboratory-confirmed pH1N1. Of the 3253 patients who visited Asan Medical Center, Seoul, South Korea, between 24 August and 19 October 2009 for a suspected pH1N1 infection (temperature >= 37.5 degrees C and at least 1 of the following symptoms: sore throat, cough, rhinorrhoea and nasal congestion), 553 (17%) were positive for pH1N1 by real-time reverse transcriptase polymerase chain reaction. Chest radiographs were performed in 96 (17%) of the 553 patients. Of the 553 patients, 30 (5%; 95% confidence interval (CI) 4-8%) had pneumonia, including 26 (86%) with viral pneumonia and 4 (14%) with bacterial pneumonia. So, the proportion of pneumonia in patients with laboratory-confirmed pH1N1 was at least 5%. Multivariate analysis indicated that dyspnoea (odds ratio (OR) 57.8, p < 0.001), wheezing (OR 19.3, p = 0.02), vomiting (OR 18.5, p < 0.001) and diarrhoea (OR 11.0, p = 0.001) were independently associated with pneumonia. Antiviral therapy at >48 h after the onset of symptoms (OR 2.1, p = 0.09) tended to be more common in patients with pneumonia than in those without pneumonia. PMID- 20925451 TI - Suppression of pulmonary host defenses and enhanced susceptibility to respiratory bacterial infection in mice following inhalation exposure to trichloroethylene and chloroform. AB - Numerous epidemiological studies have associated episodes of increased air pollution with increased incidence of respiratory disease, including pneumonia, croup, and bronchitis. Trichloroethylene (TCE) and chloroform are among 33 hazardous air pollutants identified by the U.S. Environmental Protection Agency as presenting the greatest threat to public health in the largest number of urban areas. Also, both are common indoor air pollutants. Here, we assessed the potential effects of TCE and chloroform on resistance to pulmonary bacterial infection and related alveolar macrophage (AM) function. CD-1 mice were exposed by inhalation to filtered air (control) or concentrations of TCE ranging from 5 to 200 ppm, or concentrations of chloroform ranging from 100 to 2000 ppm. Immediately following exposure, mice were challenged with an aerosol of Streptococcus zooepidemicus and monitored for clearance of bacteria from the lung and mortality. In separate experiments, exposed mice were injected intratracheally with viable bacteria and phagocytic function was evaluated in macrophages obtained from lung washes 30 min later. The NOEL for enhanced mortality to infection was 25 ppm for TCE and 500 ppm for chloroform. Relative to the air controls, differences in clearance of bacteria from the lung were noted in mice exposed to TCE (NOEL = 50 ppm) and to chloroform (NOEL 100 ppm), and differences in AM phagocytic index were noted for TCE (NOEL = 100 ppm) and for chloroform (NOEL < 100 ppm). The data support the utility of the S. zooepidemicus infectivity model in assessing potential increased risk of respiratory infection and suggest that delayed clearance of bacteria from the lung or decreased phagocytosis are viable alternatives to mortality as an endpoint. Collectively, these endpoints are among the most sensitive health effects reported for TCE. PMID- 20925452 TI - The Personal Factors of the International Classification of Functioning, Disability and Health in the literature - a systematic review and content analysis. AB - PURPOSE: This review provides an overview of the literature on the conceptualisation of the Personal Factors (PF) component of the International Classification of Functioning, Disability and Health (ICF). METHOD: A systematic literature review was carried out. Electronic searches were performed in Pubmed, Embase, PsycINFO, CINAHL and SSCI. Qualitative content analysis of statements about PF was conducted using inductive coding. RESULTS: The searches yielded 353 citations, 79 papers were eligible for analyses. Five hundred thirty-eight statements about PF were extracted, condensed and coded. Beside conceptual statements, 238 examples of potential PF as well as five attempts at classifying PF were found in the literature. PF were considered in relation to clinical service provision, assessment and intervention, in research and social security contexts. PF were seen to be related to various aspects of health, functioning, disability and the environment. CONCLUSIONS: The analysis of the literature shows that PF is seen as relevant to the application of the ICF in various settings. The review revealed a need for standardisation of PF. The literature points to the potential of PF in enhancing the understanding of functioning, disability and health, in facilitating interventions and services for people with disabilities, and strengthening the perspective of individuals in the ICF. PMID- 20925453 TI - Meta-analysis of a partially hydrolysed 100%-whey infant formula vs. extensively hydrolysed infant formulas in the prevention of atopic dermatitis. AB - OBJECTIVES: This study presents previously unpublished point and cumulative incidence rates and relative risks (RRs) for comparing a partially hydrolysed 100% whey-based infant formula, NAN-HA * (PHF-W) to extensively hydrolysed whey- (EHF-Whey) or casein-based (EHF-Casein) infant formulas in the prevention of atopic dermatitis (AD) in infants who cannot be breastfed exclusively. It also outlines methods to convert the above-mentioned data as well as data comparing PHF-W to cows' milk formula (SF) into inputs to be applied to a pharmacoeconomic model. * NAN-HA is a registered trade name of Nestle SA, Switzerland. METHODS: The incidence rates and RRs were obtained from a meta-analysis which analysed efficacy for PHF-W vs. EHF but did not present those. It took into consideration any relevant randomized controlled trial which compared the use of PHF-W with SF or EHF for the prevention of allergies. The primary outcomes of interest were the incidence, cumulative incidence and period prevalence of allergic manifestations and of AD in particular. Fifteen studies had been included for analysis of which six studies explored PHF-W vs. EHF. These results and PHF-W vs. SF data were adapted for inputs into a pharmacoeconomic model which used a spreadsheet decision-analytic economic model based on 3-month cycles to explore the cost effectiveness of PHF-W vs. SF and EHF. Weights were applied to the incidence rates and RRs for each reported time period which were then adapted into 3-month indicators. RESULTS: This meta-analysis for PHF-W (557 patients) vs. EHF-Whey (559 patients) yielded RR of 0.75 (0.54, 1.05) and 0.80 (0.63, 1.02) at 0-12 months and at 0-36 months, respectively. Corresponding RRs for PHF-W vs. EHF Casein (580 patients) were 1.06 (0.74, 1.53) at 0-12 months and 1.13 (0.87, 1.47) at 0-36 months. CONCLUSION: It appears that the efficacy of PHF-W falls within the range of that of both EHF formulas (whey and casein) and allows the application of these results in a pharmacoeconomic model. PMID- 20925454 TI - Economic evaluation of a 100% whey-based, partially hydrolysed formula in the prevention of atopic dermatitis among French children. AB - OBJECTIVE: A pharmacoeconomic analysis was performed to determine costs, consequences and cost effectiveness of a partially hydrolysed 100% whey-based infant formula, NAN HA, manufactured by Nestle S.A, Switzerland (PHF-W) and branded under Nidal Excel HA in France, in the prevention of atopic dermatitis (AD) in 'at risk' children when compared to standard cows' milk formula (SF) in France. METHODS: A decision-analytic economic model depicting AD treatment pathways, as well as resource utilisation and costs associated with the treatment of AD in healthy yet 'at risk' French newborns who cannot be exclusively breastfed was constructed for a 12-month time horizon, including an initial 6 months of intervention with formula consumption. Model inputs were based on the literature, official formularies and expert opinion. The modelled treatment pathways included a dietary management approach (formula change), a medical treatment approach and a combination thereof. The final outcome was the expected cost per avoided case of AD, yielding an incremental cost per avoided case (ICER) of AD when comparing subjects who used PHF-W versus SF. Outcomes were presented from three perspectives: the French Ministry of Health (MOH), the subjects' family and society as a whole. A secondary analysis also compared PHF-W to extensively hydrolysed formula (EHF) in prevention. RESULTS: The number of avoided AD cases by selecting PHF-W over SF was 13,356 cases in a birth cohort of 185,298 'at risk' infants. The base case analysis, at 65% reimbursement, yielded expected ICERs of ?1343, ? -624 (savings) and ?719 from the MOH, family and societal perspectives, respectively. From all three perspectives, the highest cost was attributable to formula. In case of a 35% reimbursement rate for PHF-W, the ICER was ?615 from the MOH perspective, while the use of PHF-W was cost neutral at 10% reimbursement. PHF-W was cost-saving against EHF (?98-?116 million savings depending on type of EHF), when this latter was used in prevention. One way and probabilistic sensitivity analyses confirmed the robustness of the model. CONCLUSION: Under a certain range of assumptions, this analysis based on predictive modelling has established the cost effectiveness of PHF-W in the prevention of AD in infants. PMID- 20925456 TI - Treatment of organic acidurias and urea cycle disorders. AB - Three steps are extremely important in emergency management (awaiting diagnosis) of organic acidurias and urea cycle disorders. The first is to obtain adequate samples (blood and urine) before any treatment, parenteral and/or enteral nutrition with protein-free solution and toxin removal procedures are the second step. Additional therapies with cofactors and vitamins are the last step. It is very important to quickly carry out this strategy every time we suspect an inborn error of metabolism. PMID- 20925457 TI - Fetal and early postnatal life roots of asthma. AB - The origins of asthma might be traced back to events occurring during fetal life. Reduced lung development has been shown to be a risk factor both for viral induced wheeze and allergic asthma. The evidence for a causal relationship between exposure to environmental tobacco smoke, chemical domestic products for cleaning, outdoor pollutants, and reduction in lung function is quite strong. Reduced maternal intake of vitamin E, vitamin D, and zinc, or increased use of paracetamol during pregnancy is associated with increased wheezing outcomes in children. The odds ratio for asthma onset is also increased in infants born from mothers with oligohydramnios, chorioamnionitis, hypertension, preeclampsia, diabetes and exposed to stressful events. The risk of developing allergic asthma is increased if the child is exposed in the first months of life to synthetic bedding and is enhanced by allergen exposure and an inadequate barrier function of the skin. In conclusion, several lines of evidence support the concept of fetal programming and very early life events in the development of the different phenotypes of asthma. Since some environmental triggers can be easily avoided and some protective factors can be easily implemented all efforts should be made to prevent intrauterine insults and early sensitization. PMID- 20925458 TI - Reduced brachial flow-mediated vasodilation in young adult ex extremely low birth weight preterm: a condition predictive of increased cardiovascular risk? AB - BACKGROUND: Sporadic data present in literature report how preterm birth and low birth weight constitute the risk factors for the development of cardiovascular diseases in later life. AIM: To assess the presence of potential alterations to endothelial function in young adults born preterm at extremely low birth weight (<1000 g; ex ELBW). METHOD: Thirty-two ex-ELBW subjects (10 males [M] and 22 females [F], aged 17-28 years, mean [+/- DS] 20.1 +/- 2.5 years) were compared with 32 healthy, age-matched subjects born at term (C, 9 M and 23 F). EXCLUSION CRITERIA: 1) pathological conditions known to affect endothelial function; 2) administration of drugs known to affect endothelial function. Endothelial function was assessed by non-invasive finger plethysmography, previously validated by the US Food and Drug Administration (Endopath; Itamar Medical Ltd., Cesarea, Israel). RESULTS: Endothelial function was significantly reduced in ex ELBW subjects compared to C (1.94 +/- 0.37 vs. 2.68 +/- 0.41, p < 0.0001). Moreover, this function correlated significantly with gestational age (r = 0.56, p < 0.0009) and birth weight (r = 0.63, p < 0.0001). CONCLUSIONS: The results obtained reveal a significant decrease in endothelial function of ex-ELBW subjects compared to controls, underlining a probable correlation with preterm birth and low birth weight. Taken together, these results suggest that an ELBW may underlie the onset of early circulatory dysfunction predictive of increased cardiovascular risk. PMID- 20925459 TI - A novel conditionally replicating "armed" adenovirus selectively targeting gastrointestinal tumors with aberrant wnt signaling. AB - Using conditionally replicating adenoviral vectors (CRAds) is a promising strategy in the treatment of solid tumors. The prospective of this study was to design a novel CRAd for the treatment of gastrointestinal cancer and show its efficacy in vitro, as well as in vivo. To determine if aberrant wnt signaling in tumor cells can be used to selectively drive viral replication, we analyzed six colorectal and hepatocellular cell lines, as well as 13 colorectal tumors and 17 gastric tumors, for beta-catenin mutation status or aberrant wnt signaling, both of which were found frequently. Based on these findings, a novel CRAd (Ad5F11.wnt E1A-hIL24) containing an E1A expression cassette driven by an artificial wnt promoter and delivering an apoptosis-inducing gene, interleukin-24 (IL24), was engineered. To enhance infection efficiency, the virus was pseudotyped by replacing adenovirus serotype 5 (Ad5) with Ad11 fiber. Ad5F11.wnt-E1A-hIL24 virus exhibited high selectivity toward cells with aberrant wnt signaling both in vitro and in mouse xenograft tumors. Transduction efficiency was significantly improved compared with that of nonpseudotyped control viruses. The proliferation of tumor cell lines, as well as tumor growth, in mouse xenografts could be profoundly inhibited by viral infection with Ad5F11.wnt-E1A-hIL24. The therapeutic effect was associated with increased apoptosis through caspase-3 activation. In addition, Ad5F11b vector exhibited a more favorable biodistribution, blood clearance, and transgene expression compared with conventional Ad5 vector after systemic or intratumoral injection in human gastrointestinal cancer xenografts. We think that our approach is a promising strategy in the treatment of gastrointestinal cancer, warranting further clinical investigation. PMID- 20925460 TI - Thymidine kinase gene modified bone marrow mesenchymal stem cells as vehicles for antitumor therapy. AB - Bone marrow mesenchymal stem cells (BMSCs) represent an important source of cells for tissue repair. The tropism of these cells to the sites of injury and tumors has been well established. Their tumor-homing properties make BMSCs good candidates as antitumor agent delivery vehicles. In this study, we showed that BMSCs have the ability to migrate toward various cancer cells, including prostate cancer cells in vitro and in vivo and incorporating into the tumor mass. When infected with herpes simplex virus thymidine kinase (TK) gene by lentiviral transduction, TK-BMSCs maintained their tumor tropism capabilities and significantly inhibited the growth of subcutaneous PC3 prostate cancer xenografts in nude mice, in the presence of prodrug ganciclovir (GCV). Xenogenic TK-BMSCs also survived and exerted a significant antitumor effect in an animal model bearing metastastic RIF-1 (fibrosarcoma) tumor in the presence of prodrug GCV. The present study demonstrated that overexpression of TK in BMSCs did not affect their multidifferentiation potentials and their specific homing capacities toward the tumor mass, and the TK-BMSCs alone did not cause any harmful side effects in vivo. The use of TK-BMSCs as tumor-specific delivery vehicles together with controlled prodrug treatment may be a safe and novel anticancer therapy approach. PMID- 20925461 TI - TGF-beta: friend or foe? The role of TGF-beta/SMAD signaling in epigenetic silencing of ovarian cancer and its implication in epigenetic therapy. AB - IMPORTANCE OF THE FIELD: The TGF-beta signaling pathway plays an important role in regulating numerous cellular processes including growth inhibition of ovarian surface epithelial (OSE) cells. However, epithelial ovarian cancer is refractory to the inhibitory functions of TGF-beta, and yet TGF-beta induces metastasis or epithelial-mesenchymal transition (EMT) in advanced ovarian cancer. How TGF-beta plays a certain role in one cell but a different role in its malignant counterpart is not fully understood. AREAS COVERED IN THIS REVIEW: The role of TGF-beta/SMAD signaling both in normal OSE cells and ovarian cancer as well as how dysregulation of this signaling pathway leads to epigenetic silencing of its downstream targets in ovarian neoplasias are reviewed. The therapeutic implication of this signaling pathway in epigenetic therapy of ovarian cancer are also discussed. WHAT THE READER WILL GAIN: The reader will gain insight on how dysregulation of TGF-beta signaling alters promoter methylation and histone modifications of TGF-beta downstream targets in ovarian cancer. TAKE HOME MESSAGE: Disruption of TGF-beta/SMAD signaling leads to epigenetic silencing of its target genes transiently through histone modifications but permanently by promoter hypermethylation. Targeting the TGF-beta signaling pathway may be a novel therapeutic strategy in ovarian cancer. PMID- 20925462 TI - Immunotoxicity activity of sesquiterpenoids from black galingale (Kaempferia parviflora Wall. Ex. Baker) against Aedes aegypti L. AB - The roots of black galingale (Kaempferia parviflora) were chloroform-extracted and the isolated two sesquiterpene and immunotoxicity effects were studied. The structures and stereochemistry of these compounds were established on the basis of analysis of spectra including UV, MS, (1)H-NMR, and (13)C-NMR as follows: 1 (4alpha-acetoxycadina-2,9-diene-1,8-dione), 2 (1alpha,3alpha,4beta-trihydroxy-9 cadinen-8-one). Compound 2 had a significant toxic effect against early fourth stage larvae of Aedes aegypti L. with an LC(50) value of 0.7 MUM and an LC(90) value of 3.8 MUM. The results could be useful in search for newer, safer, and more effective natural immunotoxicity agents against A. aegypti. PMID- 20925463 TI - Calculating a cure for cancer: managing medulloblastoma MATH1-ematically. PMID- 20925464 TI - From survival to survivorship: late side effects become an issue in high-grade glioma. PMID- 20925465 TI - Attention-deficit/hyperactivity disorder in persistent criminal offenders: the need for specialist treatment programs. PMID- 20925467 TI - The 7th International Congress of Neuroendocrinology (ICN2010) 11-15 July 2010, Rouen, France. AB - Neuroendocrinology has moved far beyond its initial focus on the regulation of pituitary hormone secretion. It now embraces not only the actions on the brain of a diverse range of 'new' hormones, such as leptin and ghrelin, but also the expanding roles of peptides as hormone-like messengers within the brain, controlling many fundamental behaviors and physiological processes. A recent International Congress of Neuroendocrinology highlighted the translational importance of some of these new insights. PMID- 20925469 TI - Brain tumor location and psychiatric symptoms: is there any association? A meta analysis of published case studies. AB - A meta-analytic study of reports of brain tumors and psychiatric symptoms for the past 50 years was conducted to examine potential associations between tumor location and psychiatric symptoms. Results demonstrated that there is a statistically significant association between anorexia symptoms and hypothalamic tumors. For the rest of the brain regions a statistically significant association could not be definitively determined. However, several of the regions demonstrated an increased likelihood of associated symptoms when compared with other regions. The methodological limitations of this analysis are discussed. PMID- 20925470 TI - Temozolomide: therapeutic limitations in the treatment of adult high-grade gliomas. AB - Temozolomide-based chemotherapy represents an incremental improvement in the treatment of patients with high-grade gliomas. Notwithstanding a survival benefit in a subset of patients with high-grade gliomas, temozolomide (TMZ; Temodar(r), Schering-Plough Pharmaceuticals, NJ, USA) is the primarily palliative treatment for the vast majority of patients. Indeed, for patients with newly diagnosed glioblastoma, the median increase in survival for treatment with TMZ and radiotherapy is only 2.5 months compared with radiotherapy alone. Additionally, recent studies suggest that 60-75% of patients with glioblastoma derive no benefit from treatment with TMZ. For the treatment of recurrent anaplastic gliomas, more than 50% of patients fail TMZ treatment with cancer progression at 6 months, demonstrating that TMZ is only a modestly effective chemotherapy. In addition, 15-20% of patients treated with TMZ develop clinically significant toxicity, which can leave further treatment unsafe. Despite the availability of TMZ, there is still a substantial need for a chemotherapeutic agent that is more effective and safe. In fact, there still remains a significant unmet need for more effective treatments of high-grade gliomas (improved palliation or cure), whether that treatment be by surgery, radiotherapy, chemotherapy or any yet to be developed type of treatment, such as 'targeted therapies'. PMID- 20925471 TI - Paraneoplastic neurological disorders. AB - The article provides an overview on the diagnosis and pathogenesis of paraneoplastic neurological disorders (PNDs), and subsequently the current therapeutic strategies in these patients. PNDs are nervous system dysfunctions in cancer patients, which are not due to a local effect of the tumor or its metastases. Most of these clinically defined syndromes in adults are associated with lung cancer, especially small-cell lung cancer, lymphoma and gynecological tumors. In a part of the PND, an overlapping of different clinical syndromes can be observed. Highly specific autoantibodies directed against onconeuronal antigens led to the current hypothesis of an autoimmune pathophysiology. Whereas the most central nervous PNDs are more T-cell-mediated, limbic encephalitis can be caused by pathogenic receptor autoantibodies. The PND of the neuromuscular junction and paraneoplastic autonomic neuropathy are mainly associated with receptor or ion channel autoantibodies. The childhood opsoclonus-myoclonus syndrome and the PNDs associated with receptor/ion channel autoantibodies often respond to immunosuppressive therapies, plasmapheresis and intravenous immunoglobulins. By contrast, most CNS PNDs associated with defined antineuronal antibodies directed against intracellular antigens only stabilize after tumor treatment. PMID- 20925472 TI - Clinical assessment and diagnosis of adults with attention-deficit/hyperactivity disorder. AB - Attention-deficit/hyperactivity disorder (ADHD) is a prevalent disorder in adult psychiatry, particularly in out-patient settings. There are no objective, laboratory-based tests that can establish this diagnosis. Present diagnostic criteria for ADHD are formulated primarily according to behavior in childhood, based on age inappropriate and impairing levels of hyperactivity, impulsivity and inattention. Other symptoms, such as mood instability and frustration intolerance, are not included in current criteria for ADHD, but are very prevalent in this patient group. ADHD is often comorbid with alcohol and substance abuse and other psychiatric disorders, in particular anxiety and personality disorders. Thus, the diagnostic assessment should both include a comprehensive clinical interview, rating scales for past and present symptoms and collateral information from multiple informants, as well as assessment of a broader spectrum of psychiatric and somatic conditions. As ADHD is associated with changes in brain function mediating different aspects of neuropsychological functions, assessment of those functions is important to understand the symptom patterns and to develop targeted treatment programs. Some topics for further research and for future developments of diagnostic criteria and tools are highlighted. PMID- 20925473 TI - Aggression in children with attention-deficit/hyperactivity disorder. AB - Research shows that aggression is an important associated feature of attention deficit/hyperactivity disorder (ADHD) and is important in understanding the impact of the disorder and its treatment. The occurrence of aggressive behavior in combination with ADHD does not appear to be spurious and the severity and/or presence of aggression and ADHD may significantly impact long-term prognosis. This article defines subtypes of aggression in relation to ADHD, identifies individual differences contributing to aggressive behavior in children with ADHD and discusses selected possible underlying mechanisms of aggression in ADHD, as well as current and emerging treatment approaches. Although aggressive behavior in children with ADHD is common, the reasons for this are not yet well understood. Multidisciplinary research should focus on investigating underlying mechanisms related to aggression in ADHD, as well as the utility of various treatment modalities. PMID- 20925475 TI - An 'integrative neuroscience' perspective on ADHD: linking cognition, emotion, brain and genetic measures with implications for clinical support. AB - There remains a translational gap between research findings and their implementation in clinical practice that applies to attention deficit/hyperactivity disorder (ADHD), as well as to other major disorders of brain health in childhood, adolescence and adulthood. Research studies have identified potential 'markers' to support diagnostic, functional assessment and treatment decisions, but there is little consensus about these markers. Of these potential markers, cognitive measures of thinking functions, such as sustaining attention and associated electrical brain activity, show promise in complementing the clinical management process. Emerging evidence highlights the relevance of emotional, as well as thinking, functions to ADHD. Here, we outline an integrative neuroscience framework for ADHD that offers one means to bring together cognitive measures of thinking functions with measures of emotion, and their brain and genetic correlates. Understanding these measures and the relationships between them is a first step towards the development of tools that will help to assess the heterogeneity of ADHD, and aid in tailoring treatment choices. PMID- 20925477 TI - Evaluation of the potential cytotoxicity of metals associated with implanted biomaterials (II). AB - The effects of metal ions on the cell DNA and RNA synthetic functions and the destruction of cell defensive system caused by metal ions were studied on the investigation of the effects of metal ions on cell alkaline phosphatase (ALP) activity and cell metabolism ability. The poisonous behaviours of metal ions [Cr (VI), Ni, V, Cr (III), Ag, and Al] on living tissue were both quantitatively and qualitatively measured. It was shown that Cr (VI) has a notable action on both cellular DNA and RNA synthetic functions, and following that, were Ni, V. The limitation action of Cr (III) on the synthetic abilities of DNA and RNA increased with the increase of Cr (III) concentration. Different to other five metal ions, the limitation of Al ion on RNA was greater than that on DNA. The limitation of V, Ag ions on DNA was same to that on RNA. Trace Cr (VI), in culture medium resulted in the decreasing of GSH in living tissue. Similar to that, a little higher Ni ion concentration seriously reduced the GSH content in living tissue. It was suggested that Cr (VI), Ni, might destroy and/or disturb the orientation of the microtubulin in cell skeleton. For other four metal ions, together with increasing the concentration in culture medium, the osmotic pressure increased. Consequently, more metal ions entered cell membrane, more GSH were lost in cell. PMID- 20925474 TI - The use of α-2A adrenergic agonists for the treatment of attention deficit/hyperactivity disorder. AB - Neuropsychiatric disorders involve dysfunction of the prefrontal cortex (PFC), a highly evolved brain region that mediates executive functioning. The dorsolateral PFC is specialized for regulating attention and behavior, while the ventromedial PFC is specialized for regulating emotion. These abilities arise from PFC pyramidal cell networks that excite each other to maintain goals and rules 'in mind'. Imaging studies have shown reduced PFC gray matter, weaker PFC connections and altered PFC function in patients with attention-deficit/hyperactivity disorder. Thus, medications that strengthen PFC network connections may be particularly useful for the treatment of attention-deficit/hyperactivity disorder and related disorders. Recent data show that compounds such as guanfacine can enhance PFC function by stimulating postsynaptic alpha-2A receptors on the dendritic spines of PFC pyramidal cells where networks interconnect. Stimulation of these receptors inhibits cAMP signaling, thus closing potassium channels and strengthening physiological connections. These actions may benefit patients with weak PFC function. PMID- 20925478 TI - Human umbilical cord blood-derived mesenchymal stem cells upregulate myelin basic protein in shiverer mice. AB - Human umbilical cord blood is a rich source of pluripotent mesenchymal stem cells and possesses significant advantages over other stem cell sources such as the embryo and bone marrow. In the present study, we aimed to investigate the potential of human umbilical cord blood-derived pluripotent mesenchymal stem cells (hUCB) to myelinate the axons of shiverer mice brains. We also investigated the effect of hUCB treatment on regulation of myelin basic protein in vitro in PC 12 cells, which are normally not myelinated. The results of our study clearly demonstrated that hUCB survive and migrate in vivo and has the potential to myelinate shiverer mice brains. The expression level of myelin basic protein, a major component of the myelin sheath, has been significantly increased in vivo and in vitro as revealed by Western blot, reverse transcription (RT)-polymerase chain reaction, immunohistochemistry, immunocytochemistry, and fluorescent in situ hybridization results. Further, transmission electron microscopic images of hUCB-treated shiverer mice brains showed several layers of myelin around the axons compared with a thin and fragmented layer of myelin in untreated animals. Moreover, the frequency of shivering was diminished 1 month after hUCB treatment in shiverer mice. Our results strongly indicated that hUCB transplantation could be an effective means of treating demyelinating or hypomyelinating disorders. PMID- 20925479 TI - Metabotropic glutamate receptor-5 and protein kinase C-epsilon increase in dorsal root ganglion neurons and spinal glial activation in an adolescent rat model of painful neck injury. AB - There is growing evidence that neck pain is common in adolescence and is a risk factor for the development of chronic neck pain in adulthood. The cervical facet joint and its capsular ligament is a common source of pain in the neck in adults, but its role in adolescent pain remains unknown. The aim of this study was to define the biomechanics, behavioral sensitivity, and indicators of neuronal and glial activation in an adolescent model of mechanical facet joint injury. A bilateral C6-C7 facet joint distraction was imposed in an adolescent rat and biomechanical metrics were measured during injury. Following injury, forepaw mechanical hyperalgesia was measured, and protein kinase C-epsilon (PKCE) and metabotropic glutamate receptor-5 (mGluR5) expression in the dorsal root ganglion and markers of spinal glial activation were assessed. Joint distraction induced significant mechanical hyperalgesia during the 7 days post-injury (p < 0.001). Painful injury significantly increased PKCE expression in small- and medium diameter neurons compared to sham (p < 0.05) and naive tissue (p < 0.001). Similarly, mGluR5 expression was significantly elevated in small-diameter neurons after injury (p < 0.05). Spinal astrocytic activation after injury was also elevated over sham (p < 0.035) and naive (p < 0.0001) levels; microglial activation was only greater than naive levels (p < 0.006). Mean strains in the facet capsule during injury were 32.8 +/- 12.9%, which were consistent with the strains associated with comparable degrees of hypersensitivity in the adult rat. These results suggest that adolescents may have a lower tissue tolerance to induce pain and associated nociceptive response than do adults. PMID- 20925480 TI - Benefits of sports participation for executive function in disabled athletes. AB - We investigated the effect of sports activity on physically-disabled individuals using behavioral and electrophysiological techniques. Visual go/no-go discriminative and simple response tasks were used. Participants included 17 disabled athletes, 9 from open-skill (wheelchair basketball) and eight from closed-skill (swimming) sports, and 18 healthy non-athletes. Reaction times of the disabled athletes were slower than those of healthy non-athletes on both tasks (7% and 13% difference, respectively). Intra-individual variations in reaction times, switch cost, and number of false alarms, were higher in the swimmers, but comparable to healthy non-athletes, in the basketball group. Event related potentials (ERPs) early components P1, N1, and P2 had longer latencies in the disabled athletes. The late P3 component had longer latency and smaller amplitude in the disabled athletes only in the discriminative response task. The N2 component, which reflected inhibition/execution processing in the discriminative response task, was delayed and reduced in the swimmer group, but was comparable to healthy subjects in the basketball group. Our results show that (1) the ERP components related to perceptual processing, and late components related to executive processing, were impaired in disabled subjects; and (2) open skill sports such as basketball may partially compensate for executive control impairment by fostering the stability of motor responses and favoring response flexibility. PMID- 20925481 TI - Interferon-gamma decreases chondroitin sulfate proteoglycan expression and enhances hindlimb function after spinal cord injury in mice. AB - Glial cells, including astrocytes and macrophages/microglia, are thought to modulate pathological states following spinal cord injury (SCI). In the present study, we evaluated the therapeutic effects of interferon-gamma (IFN-gamma), which is one of the cytokines regulating glial function, in a mouse contusive SCI model. We found that intraperitoneal injection of IFN-gamma significantly facilitated locomotor improvement following SCI. Immunohistochemistry demonstrated that IFN-gamma decreased the accumulation of chondroitin sulfate proteoglycans (CSPGs), which are critical axon outgrowth inhibitors produced by reactive astrocytes in the injured central nervous system (CNS). Quantitative real-time polymerase chain reaction (RT-PCR) and Western blotting demonstrated that neurocan, one of several CSPGs, was reduced in the spinal cords of IFN-gamma treated mice compared to vehicle-treated mice. Consistently, IFN-gamma inhibited the production of neurocan from activated astrocytes in vitro. In addition, IFN gamma treatment enhanced the number of serotonin-positive nerve fibers and myelinated nerve fibers around the lesion epicenter. We also found that glial cell line-derived neurotrophic factor (GDNF) and insulin-like growth factor-1 (IGF-1) were upregulated post-SCI following IFN-gamma treatment. Our results indicate that IFN-gamma exhibits therapeutic effects in mouse contusive SCI, presumably by reducing CSPG expression from reactive astrocytes and increasing the expression of neurotrophic factors. PMID- 20925482 TI - Regulation of snRNA gene expression by the Drosophila melanogaster small nuclear RNA activating protein complex (DmSNAPc). AB - The small nuclear RNAs (snRNAs) are an essential class of non-coding RNAs first identified over 30 years ago. Many of the well-characterized snRNAs are involved in RNA processing events. However, it is now evident that other small RNAs, synthesized using similar mechanisms, play important roles at many stages of gene expression. The accurate and efficient control of the expression of snRNA (and related) genes is thus critical for cell survival. All snRNA genes share a very similar promoter structure, and their transcription is dependent upon the same multi-subunit transcription factor, termed the snRNA activating protein complex (SNAPc). Despite those similarities, some snRNA genes are transcribed by RNA polymerase II (Pol II), but others are transcribed by RNA polymerase III (Pol III). Thus snRNA genes provide a unique opportunity to understand how RNA polymerase specificity is determined and how distinct transcription machineries can interact with a common factor. This review will describe efforts taken toward solving those questions by using the fruit fly as a model organism. Drosophila melanogaster SNAPc (DmSNAPc) binds to a proximal sequence element (PSEA) present in both Pol II and Pol III snRNA promoters. Just a few differences in nucleotide sequence in the Pol II and Pol III PSEAs play a major role in determining RNA polymerase specificity. Furthermore, these same nucleotide differences result in alternative conformations of DmSNAPc on Pol II and Pol III snRNA gene promoters. It seems likely that these DNA-induced alternative DmSNAPc conformations are responsible for the differential recruitment of the distinct transcriptional machineries. PMID- 20925483 TI - On the formation of figurative representations: An integrative psychoanalytic neurobiological framework. AB - This article approaches the process of symbolization with a formalized framework that aims to integrate psychoanalytic and neurobiological findings. The authors propose a framework consisting of unconscious and conscious areas. Each of the areas provides networks for storing memories. Psychoanalytically, mental networks contain memories either unconscious or conscious. Neurobiologically, there are subunits of neuronal networks crucial for the storage and recall of memories. Communication between these networks is based on selective memory recall in order to form, for example, figurative representations. PMID- 20925484 TI - The effectiveness of psychoanalytic-interactional psychotherapy in borderline personality disorder. AB - Different methods are available for the psychotherapeutic treatment of patients with severe personality disorders. In Germany, a special form of dynamically oriented therapy called psychoanalytic-interactional psychotherapy or method (PiM) has been clinically applied for many years. PiM was derived from psychoanalytic therapy and has been specifically adapted for the treatment of severely disordered patients, for example, patients with borderline personality disorders, prepsychotic disorders, addictions, and perversions. In a naturalistic study, the effectiveness of PiM was tested in a sample of patients with borderline personality disorders (N = 132). The patients were treated in the Clinic Tiefenbrunn near Goettingen. Standardized, reliable, and valid diagnostic instruments were used to study the treatment effects. According to the results, PiM achieved significant improvements in target symptoms, general symptoms, interpersonal problems, and contentedness with life. The results are discussed with regard to the treatment of severely disordered patients. PMID- 20925485 TI - Manualized psychodynamic-interactional group therapy for the treatment of somatoform pain disorders. AB - Medically unexplained and clinically significant symptoms of pain are highly prevalent in the general population. More than one third of all patients in general practices and various departments of hospitals suffer from somatoform disorders with pain being the main complaint of 70% of these patients. This treatment manual is the first disorder-specific, psychodynamically oriented treatment for these patients. Based on psychodynamic-interactional group psychotherapy, it focuses on disorder-specific aspects as well as on psychic and interpersonal problems which have resulted from adverse childhood experiences and insecure attachment. In three treatment phases comprising an "information and motivational phase" followed by "work" and ultimately "transfer" phase spread over a period of 6 to 7 months, between seven and nine patients were treated in 40 group therapy sessions. The group started with psychoeducational elements intended to inform them about their illness. Through the discussion and formulation of individual treatment goals, the patients are drawn into the work phase of the group therapy, in which the relationship of the patients in the group and their behavior is the main focus of the therapeutic interventions. PMID- 20925486 TI - Interrater reliability in unbalanced designs: A comment on Scholte et al. (2009). PMID- 20925493 TI - Comparing the shoulder impingement kinematics between circular and pumping strokes in manual wheelchair propulsion. AB - PURPOSE: The study aimed to investigate the glenohumeral kinematic difference between the circular and pumping strokes in manual wheelchair users. METHOD: This is a repeated measures design with randomised testing conditions. We recruited 10 manual wheelchair users and asked them to perform both the pumping and circular strokes on a stationary roller system. We used the Zebris motion analysis system to collect the 3-dimension glenohumeral motion data. RESULTS: The pumping and the circular strokes were similar in the starting and ending positions in the sagittal plane. However, the pumping stroke started at a significantly larger abduction and internal rotation and ended with a significantly larger abduction and even larger internal rotation, it also traveled more ranges in all three planes and stayed longer in the combined positions of rotation/flexion and rotation/abduction as compared to the circular stroke. CONCLUSIONS: The circular stroke appeared more advantageous than the pumping technique in the injury prevention prospect because the latter involved more flexion, abduction and internal rotation of the shoulder, which could add more impingement stresses to the joint. Clinicians may need to prescribe proper wheelchair propulsion techniques for their clients to avoid accumulating impingement stresses in the shoulder joints. PMID- 20925494 TI - Estimation of rac-amisulpride transfer into milk and of infant dose via milk during its use in a lactating woman with bipolar disorder and schizophrenia. AB - This case describes the transfer of the antipsychotic drug amisulpride into milk and the estimation of infant exposure via breastfeeding. The dyad investigated was a 28-year-old lactating woman and her 13-month-old daughter. The woman had been taking 400 mg of amisulpride daily for 9 days and provided eight milk samples and one blood sample over a 24-hour dose interval. Amisulpride concentrations in these samples were measured by high-performance liquid chromatography, and infant dose was calculated by standard methods. The infant's health and progress were evaluated by a neonatal pediatrician. Transfer of amisulpride into milk was high, with a milk:plasma distribution ratio of 19.5 (5,188 MUg/L in milk and 266 MUg/L in plasma). The average amisulpride concentration in milk was 3,562 MUg/L, which, when multiplied by an average milk intake of 0.15 L/kg/day, gave an absolute infant dose of 534 MUg/kg/day. The relative infant dose was 10.7% of the maternal weight-adjusted dose (5,000 MUg/kg/day), which is slightly above the usual 10% safety recommendation. The infant was in good health with an appropriate Denver development score for her age. She showed no acute drug-related adverse effects. Given that the infant had already benefited from 13 months of breastfeeding, that amisulpride has potential adverse effects, and that its relative infant dose was 10.7%, we recommended cessation of breastfeeding in the near-term. PMID- 20925495 TI - Breastfeeding knowledge and practices among rural women of punjab, India: a community-based study. AB - OBJECTIVES: Irrespective of the fact that breastfeeding in India is almost universal, psychosocial and cultural barriers still exists to early breastfeeding. The exact reasons for this delay are not clearly known. Hence we conducted this study to assess breastfeeding knowledge and practices and the factors influencing them among women in rural Punjab, India. METHODOLOGY: We interviewed 1,000 women in a community-based analytical cross-sectional study that was carried out in 20 villages of the District of Amritsar, Punjab, India, in 2005-2006 by standard cluster sampling. Time at initiation of breastfeeding and variables like understanding about the importance of colostrum, nutrition during lactation, and motivation by health workers were assessed. Statistical analysis was done by percentages compared with the chi2 test. RESULTS: Two hundred twenty-five respondents (23.8%) started breastfeeding their babies on the first day of birth, but in terms of early breastfeeding only 128 (13.5%) respondents put their babies on the breast within 4 hours of birth. Of the 1,000 respondents, 356 (35.6%) of the respondents were unaware of the importance of colostrum, 733 (77.6%) were not given advice on benefits of breastfeeding/weaning, and 306 (33.5%) of respondents had not increased their diet during lactation. CONCLUSIONS: Early breastfeeding knowledge and practices were suboptimal among the mothers in rural Punjab. Health education on breastfeeding and nutrition remains the dark area. Research and public health efforts like one-to-one "breastfeeding counseling and health education on nutrition" to the mother by health workers should be promoted. PMID- 20925496 TI - Cytology testing and proficiency: survey findings of the Practice Committee of Society for Pediatric Pathology. PMID- 20925497 TI - Undifferentiated embryonal sarcoma of the liver is associated with mesenchymal hamartoma and multiple chromosomal abnormalities: a review of eleven cases. AB - Undifferentiated embryonal sarcoma (UES) of the liver is a primitive mesenchymal, malignant neoplasm occurring in children. The link between UES and mesenchymal hamartoma (MH) is controversial. Whether they share the same histiogenesis, representing 2 ends of a spectrum, or are distinct entities is unclear. The genetic aberrations of these neoplasms are not well understood, although a common breakpoint (19q13.4) was recently identified. The purpose of this study was to elucidate immunohistochemical markers that may establish a link between the 2 tumors by reviewing cases of UES and MH. Cases of UES from 1990 to 2008 were identified. Clinical demographics were reviewed. Hematoxylin and eosin staining and immunohistochemical staining for vimentin, alpha-1 antitrypsin, and alpha fetoprotein were performed. Eleven children were diagnosed with UES. Five cases were seen arising in association with MH, and transitional zones were evident. The mean age at presentation was 10 years. To our knowledge, the 11-month-old patient is the youngest reported case of UES in concurrence with MH. All UES tumor cells were positive for vimentin, diastase-resistant periodic acid-Schiff stain, and alpha-1 antitrypsin. Chromosomal analysis of 3 UES cases, 2 arising with MH, showed complex karyotypes with no involvement of 19q13.4. We suggest a continuum between UES and MH. Although a chromosomal anomaly of 19q13.4 was not identified, a submicroscopic involvement of this locus cannot be excluded. Additionally, our analyses suggest that multiple chromosomal aberrations may be associated with the MH/UES spectrum. PMID- 20925498 TI - Avoiding osseous grafting in the atrophic posterior mandible for implant supported fixed partial dentures: a report of 2 cases. AB - Bone atrophy occurs after tooth extraction in the posterior mandible, placing the mandibular canal and its neural, arterial, and venous contents closer to the osseous facial aspect and the coronal crest. This proximity places the structure in danger of damage when dental implants are surgically placed to support fixed or removable prostheses. Several options are available to treat these areas for implant-supported fixed and removable complete or partial dentures. Osseous grafting and ridge expansion are surgical options that enable acceptance of standard sized dental implants but have serious morbidities. Additionally, vertical osseous augmentation is not predictable at this time. Narrow diameter dental implants can be placed to avoid the mandibular canal, but some bone volume situations preclude this. Very wide and very short (6.5 * 5 mm) dental implants may be placed at an angle in atrophic sites to successfully support fixed partial dentures. An anterior guidance occlusal scheme may be used in maxillary dentate patients or group function in maxillary complete denture patients. A 100 micron occlusal relief in fixed partial dentures in dentate patients may be required to account for natural tooth intrusion and to prevent occlusal overload of the implant-supported partial denture. PMID- 20925500 TI - Oral implantology for the traumatic brain injured patient: a case report. AB - Edentulous traumatic brain injured dental patients may be treated with dental implant-supported and retained acrylic-based complete dentures. Intraoral components should be minimized to present less of a surface area for plaque accumulation and to facilitate daily cleansing. A zero degree or lingualized occlusal scheme should be used. Prostheses may be truncated for patient comfort and gustatory function, so the potential for swallowing a prosthesis should be evaluated in each patient. PMID- 20925504 TI - Neutrophilic inclusions in a hunter. PMID- 20925506 TI - Spores of Clostridium difficile in Hospital Air. PMID- 20925507 TI - Achieving a quantitative understanding of antiretroviral drug efficacy. PMID- 20925510 TI - T cell subset enumeration and weekend HIV clinics: reliable performance of CD4 cell counts after 3 days. PMID- 20925511 TI - Final report of the Lyme disease review panel of the infectious diseases society of america: a pyrrhic victory? PMID- 20925516 TI - Study of outcomes associated with hyponatremia and hypernatremia in children. AB - Sodium is usually included in hospitals' critical values lists; however, the values at which sodium is considered to be life threatening (critical) vary among hospitals. Studies of outcomes associated with hyponatremia and hypernatremia in pediatric patients have not been published. We performed a retrospective chart review of sodium values of <124 mmol/L and >155 mmol/L that occurred during a 6 month period. Univariate and multivariate analyses for mortality risk were performed with the different variables. A total of 702 (1.32%) sodium tests fell in the study reference range, with 166 being <124 mmol/L and 536 being >155 mmol/L. Although not statistically significant, mortality was higher (38.5%) in patients with sodium values <= 120 mmol/L than in those with values >= 170 mmol/L (25%) or in patients with other values (<14%). Underlying conditions prevented assessment of morbidity associated with hyponatremia or hypernatremia. Treatment was instituted within 4 hours in 80% of cases (50% within 1 hour). Multivariate analysis showed increased risk of death for hyponatremic patients if they were premature or had heart abnormalities, while for hypernatremic patients the risk increased when other critical values were present. In conclusion, sodium levels of <= 120 mmol/L and >= 170 mmol/L have increased mortality in children; however, the risk of death is not statistically different when compared to risk in patients with milder hyponatremia and hypernatremia. Risk factors for death in hyponatremic and hypernatremic patients may primarily reflect the severity of the underlying conditions present in these children, such as prematurity and heart abnormalities, rather than the sodium derangement. PMID- 20925517 TI - Conjunctival concentrations of a new ophthalmic solution formulation of moxifloxacin 0.5% in cataract surgery patients. AB - PURPOSE: To compare the conjunctival concentrations of moxifloxacin after instillation of a single drop of moxifloxacin ophthalmic solution, 0.5% (Moxi) or a new 0.5% ophthalmic solution formulation (MAF) containing a retention-enhancing agent in patients undergoing cataract surgery. METHODS: This was a randomized, double-masked, parallel-group study. One hundred thirty patients scheduled for routine phacoemulsification and intraocular lens implantation were randomized to both treatment and post-dose sample collection time points. A single topical drop of Moxi or MAF was instilled in the study eye. At the designated time (0.25, 0.5, 1, 3, or 5 h post-dose), 2 conjunctival biopsy samples were obtained (N = 11-13 per treatment condition). Concentrations of moxifloxacin were determined using a validated ultra-performance liquid chromatography method. Moxifloxacin exposure [maximum mean moxifloxacin concentrations (C(max)) and area under the concentration-time curve (AUC)] was estimated from the observed concentration time data. RESULTS: The conjunctival moxifloxacin C(max), 43.8 MUg/g, for MAF was achieved at 0.25 h. This was 1.8-fold higher than the C(max) for Moxi (24.1 MUg/g), which was reached at 0.5 h post-dose. MAF AUC(0-3) was significantly greater than the AUC(0-3) of Moxi [50.5 (MUg.h)/g vs. 27.1 (MUg.h)/g; P < 0.05]. The conjunctival moxifloxacin C(max) for MAF was 337- to 730-fold greater than the reported minimum inhibitory concentration (MIC(90)) values for Staphylococcus aureus, Streptococcus pneumoniae, and Haemophilus influenzae. The C(max):MIC(90) ratios for Moxi ranged from 185 to 402. Conjunctival AUC(0-24):MIC(90) ratios ranged from 777 to 1,683 for MAF and from 625 to 1,355 for Moxi. CONCLUSIONS: The new MAF ophthalmic formulation of moxifloxacin provided higher peak levels of moxifloxacin in the conjunctiva tissue, and larger total tissue exposure than the current, commercially available formulation. The superior penetration of MAF observed in this study could translate into greater eradication of bacteria. PMID- 20925518 TI - Histologic and biomechanical evaluation of alumina-blasted/acid-etched and resorbable blasting media surfaces. AB - This study evaluated the early biomechanical fixation and bone-to-implant contact (BIC) of an alumina-blasted/acid-etched (AB/AE) compared with an experimental resorbable blasting media (RBM) surface in a canine model. Higher texturization was observed for the RBM than for the AB/AE surface, and the presence of calcium and phosphorus was only observed for the RBM surface. Time in vivo and implant surface did not influence torque. For both surfaces, BIC significantly increased from 2 to 4 weeks. PMID- 20925519 TI - Ticks parasitizing humans in Greece. AB - In summer 2008, two fatal cases were observed in Northeastern Greece: a Crimean Congo hemorrhagic fever (CCHF) case (first report in Greece) and a Mediterranean spotted fever case. In total, 537 ticks removed from humans who referred for this reason to the two hospitals of the region during June-September 2008 were identified. The vast majority of them (81.5%) were Rhipicephalus sanguineus, which is the main vector of Rickettsia conorii, while Hyalomma marginatum, the main vector of CCHF virus, accounted for 5.2%. The increased aggressiveness of R. sanguineus might be related to the weather conditions occurred during 2007-2008, while a variety of factors, including climate, might play a role in CCHF emergence. PMID- 20925520 TI - Borreliosis during pregnancy: a risk for the unborn child? AB - Little is known regarding the possible harmful effects of Borrelia infections in pregnancy, since such a risk analysis is difficult to perform. Transplacental transmission of Borrelia burgdorferi has been documented in several animal studies. Therefore, it had been thought that fetal infection and teratogenicity was possible from B. burgdorferi, especially considering the similarities between Lyme borreliosis and syphilis. However, several clinical, serological, and epidemiological studies have failed to confirm a causal association between B. burgdorferi infection and a pregnancy adverse outcome. Moreover, there have been no reported cases of transmission of Borrelia via breast milk. However, the therapeutic approach to pregnant women with Lyme disease should be antibiotic treatment, according to the clinical manifestation and the timing of the tick bite. An effective vaccine is not yet available and the prevention of Lyme borreliosis depends on public and physician education, and appropriate antibiotic therapy during pregnancy. PMID- 20925521 TI - Rickettsia spp. in wild small mammals in Lower Bavaria, South-Eastern Germany. AB - So far, data on the natural cycle of rickettsiae of the tick-borne spotted fever group (SFG) in Central Europe are barely available. Some studies showed the occurrence of different Rickettsia species in their arthropod vectors, but it is unclear which animals might have any kind of reservoir function. This survey was therefore set up to provide information on the occurrence of SFG rickettsiae in small mammals in Germany. A total of 124 rodents and insectivores were collected over a period of 3 years in Lower Bavaria, South-Eastern Germany. Screening for Rickettsia antibodies was performed using immunofluorescence with Rickettsia conorii and R. helvetica slides, and the comparability of sera and body fluids (transudates) was investigated in these assays. Further, real-time polymerase chain reaction (PCR) was used for screening of Rickettsial DNA in rodents and insectivores. Ear versus liver tissue was compared to evaluate the more suitable tissue for detection of specific DNA. Further, a new PCR targeting the 18S ribosomal nucleic acid was established as internal control. The results indicated that transudates are a sufficient alternative to proof infection in cases where no sera are available. Rickettsial DNA, that is, Rickettsia felis and R. helvetica, was found in seven animals with the ears proving to be a proper choice for PCR. Statistical analyses revealed that the presence of ectoparasites and the body size positively correlated with the occurrence of rickettsial DNA. Overall, our study suggests that rodents and other small mammals may act as reservoir hosts for Rickettsia. However, with the course of infection and its transmission in wild animals still unknown, further investigations are needed to better understand the natural cycle of SFG rickettsiae. PMID- 20925523 TI - The emergence of Staphylococcus aureus ST398. AB - The epidemiology of methicillin-resistant Staphylococcus aureus (MRSA) has changed dramatically over the past 15 years. Initially a nosocomial pathogen, newly emergent strains of MRSA have become increasingly common in the community among individuals lacking contact with healthcare. More recently, a third group of MRSA strains have been identified in association with livestock, particularly swine. These strains, termed livestock-associated MRSA, have now been identified in Europe, North America, and Asia in humans and animals. One molecular type, ST398, has been the dominant strain of livestock-associated MRSA identified to date. The emergence of this strain in animals and humans will be described in this review, including colonization and clinical infections caused by this strain. We also discuss lingering research questions and implications for controlling spread of this bacterium in an agricultural environment and beyond. PMID- 20925522 TI - Bird migration and risk for H5N1 transmission into Qinghai Lake, China. AB - The highly pathogenic avian influenza H5N1 virus still cause devastating effects to humans, agricultural poultry flocks, and wild birds. Wild birds are also detected to carry H5N1 over long distances and are able to introduce it into new areas during migration. In this article, our objective is to provide lists of bird species potentially involved in the introduction of highly pathogenic avian influenza H5N1 in Qinghai Lake, which is an important breeding and stopover site for aquatic birds along the Central Asian Flyway. Bird species were classified according to the following behavioral and ecological factors: migratory status, abundance, degree of mixing species and gregariousness, and the prevalence rate of H5N1 virus. Most of the high-risk species were from the family Anatidae, order Anseriformes (9/14 in spring, 11/15 in fall). We also estimated the relative risk of bird species involved by using a semi-quantitative method; species from family Anatidae accounted for over 39% and over 91% of the total risk at spring and fall migration periods, respectively. Results also show the relative risk for each bird aggregating site in helping to identify high-risk areas. This work may also be instructive and meaningful to the avian influenza surveillance in the breeding, stopover, and wintering sites besides Qinghai Lake along the Central Asian Flyway. PMID- 20925524 TI - Molecular epidemiology of yellow fever in Bolivia from 1999 to 2008. AB - Yellow fever (YF) is a serious public health problem in Bolivia since at least the 19th century. Surprisingly, very limited information has been made available to date regarding the genetic characterisation and epidemiology of Bolivian YF virus (YFV) strains. Here, we conducted the genetic characterization of 12 human isolates of YFV collected in Bolivia between 1999 and 2008, by sequencing and analysis of two regions of the viral genome: a fragment encoding structural proteins "PrM" (premembrane and envelope) and a distal region "EMF," spanning the end of the virus genome. Our study reveals a high genetic diversity of YFV strains circulating in Bolivia during the last decade: we identified not only "Peruvian-like" genotype II viruses (related to previously characterized Bolivian strains), but also, for the fist time, "Brazilian-like" genotype I viruses. During the complete period of the study, only cases of "jungle" YF were detected (i.e., circulation of YFV via a sylvatic cycle) with no cluster of urban cases. However, the very significant spread of the Aedes aegypti mosquito across Bolivian cities threatens the country with the reappearance of an urban YFV transmission cycle and thus is required a sustained epidemiological surveillance. PMID- 20925525 TI - Phenotypic variability and population structure of peridomestic Triatoma infestans in rural areas of the arid Chaco (Western Argentina): spatial influence of macro- and microhabitats. AB - Triatoma infestans, one of the main vectors of Trypanosoma cruzi, is strongly associated with rural human ecotopes. Infested peridomestic places could act as a source of house infestation as a result of the movement of vectors among habitats. The quantitative study of phenotypic traits and nutritional variables could be informative about the population structure and the relative mobility of vectors. This is the first approach toward analyzing the phenetic characteristics of T. infestans and the relationship with their potential role to invade and colonize other habitats in the arid Chaco region. This article compares the phenotypic structure of T. infestans populations living in chicken coops and goat corrals, analyzing the geometric morphometry of wings and heads, antennal phenotypes, and the nutritional status of 257 adults and nymphs. The study area remained untreated with insecticides during the 15 years before the present study. The insects collected in peridomestic structures located in two zones 80 km apart exhibited significant differences in their morphotypes, suggesting an environmental effect and/or the absence of individual exchange between zones. The population structure was clear in T. infestans from goat corrals and chicken coops in one zone and less pronounced in the other. These results suggest the existence of a different rate of individual exchange among ecotopes within each zone. Morphometric variables of heads and wings were significantly correlated in insects collected in goat corrals but not in chicken coops, suggesting a habitat effect and supporting the hypothesis of different canalization forces that affect the two organs. The nutritional status of adults indicated a low dispersal probability with zonal differences. This article provides the first combined morphometric analysis of the head of adults and fifth instar nymphs in triatomines and the first combined analysis of head and wing in T. infestans. PMID- 20925526 TI - Trypanosoma cruzi infection modulates the expression of Triatoma brasiliensis def1 in the midgut. AB - Antimicrobial peptides are an essential component of the insect immune system. One of the most ubiquitous is defensin, which has been identified in all examined insect orders. Triatoma brasiliensis (Heteroptera, Triatominae), the main Trypanosoma cruzi vector in semi-arid regions of north-eastern Brazil, expresses def1, a defensin encoding gene, predominantly in the anterior region (cardia and stomach) of the midgut. In the present study, we compared the transcript abundance of T. brasiliensis def1 in the anterior (stomach) and posterior midgut (small intestine) regions of naive bugs with those infected with a familiar T. cruzi isolate. In the stomach, only slight differences between the two insect groups were visible, whereas in the small intestine wide differences (up to 9.6 fold) between infected and noninfected bugs become apparent. The highly increased def1 transcript abundance at 20 days after the infective blood meal might be a response to the T. cruzi infection, suggesting a potential function of intestinal defensin in the parasite population control. PMID- 20925527 TI - Detection of Borrelia burgdorferi DNA in tick feces provides evidence for organism shedding during vector feeding. AB - Borrelia burgdorferi, the bacterium that causes Lyme disease, is transmitted to a susceptible host by Ixodes spp. tick bites. However, there is uncertainty whether B. burgdorferi are shed from ticks by the fecal route. In this study, B. burgdorferi-infected ticks were fed on mice while confined to a certain area of the skin by a capsule. During and after feeding, tick feces were collected and placed in Barbour-Stoenner-Kelley (BSK)-II media for cultivation and in sterile water for polymerase chain reaction (PCR) analysis. Although none of the tested samples were culture positive for B. burgdorferi, all but one of the fecal DNA samples from infected ticks were PCR positive. These results indicated that B. burgdorferi were shed from feeding ticks during defecation and suggest that the spirochetes did not remain viable once exposed to the outside environment. This finding has important ramifications for investigators interpreting B. burgdorferi specific PCR results when conducting tick transmission experiments. PMID- 20925528 TI - Prevention of dengue outbreaks through Aedes aegypti oviposition activity forecasting method. AB - Dengue has affected the north provinces of Argentina, mainly Salta province. The 2009 outbreak, with 5 deaths and >27,000 infected, was the most important, and the first to extend into the central area of the country. This article includes research on seasonal Aedes aegypti abundance variation in Oran City (Salta province), and determination of the date of mosquito population increase and an estimation of the date of maximum rate of increase as well as the intrinsic rate of natural increase (r), to detect the optimal time to apply vector control measures. Between September 2005 and March 2007, ovitraps were randomly distributed in the city to collect Ae. aegypti eggs. The variation observed in the number of collected eggs was described by fitting a third-degree polynomial by the least square method, allowing to determine the time when population increase began (week 1), after the temperate and dry season. Eggs were collected throughout the year, with the highest variation in abundance during the warm and rainy season, and the maximum value registered in February 2007. The rate of increase of the number of eggs laid per week peaked between weeks 9 and 10 after the beginning of the population increase (week 1). Week 1 depends on temperature, it occurs after getting over the thermal threshold and the needed accumulation of 160 degree-day is reached. Consequently, week 1 changes depending on temperature. Peak abundance of eggs during 2005-2006 was recorded on week 15 (after week 1); during 2006-2007, the peak was observed on week 22. Estimation of the intrinsic rate of natural increase (r) of Ae. aegypti is useful not only to determine optimal time to apply vector control measures with better cost-benefit, but also to add an insecticide control strategy against the vector to diminish the possibility of resistance. PMID- 20925529 TI - Serosurvey study of Toscana virus in domestic animals, Granada, Spain. AB - Toscana virus (TOSV) is transmitted by infected sandflies. In Mediterranean countries, TOSV is one of the major viral pathogens involved in aseptic meningitis and meningoencephalitis in humans. It remains unclear if there are animal reservoirs able to maintain the virus through the cold months of the year, when the vector is not circulating. From May to October of 2006 and 2007, we conducted a serosurvey study on domestic animals from Granada province (southern Spain). TOSV was investigated in 1186 serum samples from horses, goats, pigs, cats, dogs, sheep, and cows by serology (indirect fluorescence assay), viral culture, and RT-polymerase chain reaction. Specific anti-TOSV antibodies were detected in 429 (36.2%) serum samples. The highest seropositivity rates were observed in cats (59.6%) and dogs (48.3%). These results suggest that an important percentage of the domestic animals have been infected by TOSV. Significantly different seroprevalence rates were detected in goats among distinct geographical areas. All viral cultures were negative. TOSV was detected by RT-polymerase chain reaction in only one serum sample from a goat. Thus, the studied animals do not seem to act as reservoirs for TOSV; otherwise, they could be amplifying hosts for the virus. PMID- 20925530 TI - Elevated cervical white blood cell infiltrate is associated with genital HIV detection in a longitudinal cohort of antiretroviral therapy-adherent women. AB - BACKGROUND: Identification of factors associated with the presence of human immunodeficiency virus (HIV) in female genital secretions is critical for intervention strategies targeting transmission and eliminating replication of genital virus. We sought to monitor the prevalence of genital HIV shedding in antiretroviral therapy-adherent women over time and to assess changes in the genital microenvironment. METHODS: Levels of cell-free HIV (HIV RNA) and HIV infected cells (HIV DNA) were monitored in peripheral blood samples and cervical and vaginal fluid samples at monthly intervals in 11 women for 1 year. Genital tract infections and fluctuations in cervical and vaginal white blood cell counts were also evaluated at each study visit. RESULTS: Plasma HIV was undetectable at the majority of study visits; when detected, it was only at low levels. Throughout the study, genital HIV RNA and DNA were detected in each person. Combined genital HIV (RNA and DNA) was detected at 49.2% of study visits and was associated with an elevated concentration of cervical white blood cell infiltrate (odds ratio, 2.52 [95% confidence interval, 1.01-6.22]; P = .04). Infiltrate was not associated with a clinical disorder or patient-reported symptoms. CONCLUSIONS: Despite antiretroviral therapy adherence and clinically suppressed plasma viremia, HIV was intermittently detected in genital secretions and was associated with subclinical inflammation and cells trafficking to the cervical mucosa. PMID- 20925531 TI - Therapeutic recombinant murine activated protein C attenuates pulmonary coagulopathy and improves survival in murine pneumococcal pneumonia. AB - BACKGROUND: Recombinant human activated protein C (APC) improves survival of patients with severe sepsis; this beneficial effect is especially apparent in patients with pneumococcal pneumonia. The aim of this study was to determine the effect of APC treatment initiated after induction of pneumococcal pneumonia on pulmonary coagulation, inflammation, and survival, with or without concurrent antibiotic therapy. METHODS: Mice were infected intranasally with viable Streptococcus pneumoniae and were treated intraperitoneally after 24 h of infection with vehicle, recombinant mouse (rm) APC (125 MUg), ceftriaxone (500 MUg), or rm-APC plus ceftriaxone. Treatment with rm-APC or vehicle was repeated every 8 h for a maximum of 96 h. Animals were either killed 48 h after infection or were monitored in a survival study (with an extra dose of ceftriaxone given after 72 h). RESULTS: Rm-APC treatment inhibited pulmonary activation of coagulation, as reflected by lower levels of thrombin-antithrombin complexes and D-dimer. Rm-APC did not affect the pulmonary levels of 55 inflammatory mediators in the context of antibiotic therapy. Rm-APC added to ceftriaxone markedly improved survival, compared with ceftriaxone treatment alone. CONCLUSIONS: Rm-APC inhibits pulmonary activation of coagulation and, when added to antibiotic therapy, improves survival in murine pneumococcal pneumonia. PMID- 20925533 TI - Impact of dental and zygomatic implants on stress distribution in maxillary defects: a 3-dimensional finite element analysis study. AB - The aim of this study was to evaluate the stress distribution in the bone around dental and zygomatic implants for 4 different implant-supported obturator prostheses designs in a unilaterally maxillary defect using a 3-dimensional finite element stress analysis. A 3-dimensional finite element model of the human unilateral maxillary defect was constructed. Four different implant-supported obturator prostheses were modeled; model 1 with 2 zygomatic implants and 1 dental implant, model 2 with 2 zygomatic implants and 2 dental implants, model 3 with 2 zygomatic implants and 3 dental implants, and model 4 with 1 zygomatic implant and 3 dental implants. Bar attachments were used as superstructure. A 150-N vertical load was applied in 3 different ways, and von Mises stresses in the cortical bone around implants were evaluated. When the models (model 1-3) were compared in terms of number of implants, all of the models showed similar highest stress values under the first loading condition, and these values were less than under model 4 conditions. The highest stress values of models 1-4 under the first loading condition were 8.56, 8.59, 8.32, and 11.55 Mpa, respectively. The same trend was also observed under the other loading conditions. It may be concluded that the use of a zygomatic implant on the nondefective side decreased the highest stress values, and increasing the number of dental implants between the most distal and most mesial implants on the nondefective side did not decrease the highest stress values. PMID- 20925532 TI - Factors associated with prevalent abnormal anal cytology in a large cohort of HIV infected adults in the United States. AB - BACKGROUND: The prevalence of and risk factors for abnormal anal cytology among men and women with human immunodeficiency virus (HIV) infection have not been extensively investigated. METHODS: The Study to Understand the Natural History of HIV and AIDS in the Era of Effective Therapy (SUN study) is a prospective cohort study of HIV-infected patients in 4 US cities. Baseline questionnaires were administered and anal samples for cytology and human papillomavirus (HPV) detection and genotyping were collected. RESULTS: Among 471 men and 150 women (median age, 41 years), 78% of participants were receiving combination antiretroviral therapy, 41% had a CD4(+) cell count of >=500 cells/MUL, and 71% had an HIV RNA viral load of <400 copies/mL. The anal cytology results were as follows: 336 participants (54%) had negative results, 96 participants (15%) had atypical squamous cells, 149 participants (24%) had low-grade squamous intraepithelial lesions, and 40 participants (6%) had high-grade squamous intraepithelial lesions. In a multivariate analysis, abnormal anal cytology was associated with number of high-risk and low-risk HPV types (adjusted odds ratio [AOR] for both, 1.28; P < .001), nadir CD4(+) cell count of <50 cells/MUL (AOR, 2.38; P = .001), baseline CD4(+) cell count of <500 cells/MUL (AOR, 1.75; P = .004), and ever having receptive anal intercourse (AOR, 2.51; P < .001). CONCLUSION: HIV-infected persons with multiple anal HPV types or a nadir CD4(+) cell count of <50 cells/MUL have an increased risk for abnormal anal cytology. PMID- 20925535 TI - The midterm elections--high stakes for health policy. PMID- 20925536 TI - Reviving the FDA. PMID- 20925537 TI - Creating accountable care organizations. PMID- 20925538 TI - Images in clinical medicine. Huntington's chorea. PMID- 20925539 TI - Becoming accountable-opportunities and obstacles for ACOs. PMID- 20925540 TI - Low-cost lessons from Grand Junction, Colorado. PMID- 20925541 TI - The effects of the Affordable Care Act on workers' health insurance coverage. PMID- 20925534 TI - Clopidogrel with or without omeprazole in coronary artery disease. AB - BACKGROUND: Gastrointestinal complications are an important problem of antithrombotic therapy. Proton-pump inhibitors (PPIs) are believed to decrease the risk of such complications, though no randomized trial has proved this in patients receiving dual antiplatelet therapy. Recently, concerns have been raised about the potential for PPIs to blunt the efficacy of clopidogrel. METHODS: We randomly assigned patients with an indication for dual antiplatelet therapy to receive clopidogrel in combination with either omeprazole or placebo, in addition to aspirin. The primary gastrointestinal end point was a composite of overt or occult bleeding, symptomatic gastroduodenal ulcers or erosions, obstruction, or perforation. The primary cardiovascular end point was a composite of death from cardiovascular causes, nonfatal myocardial infarction, revascularization, or stroke. The trial was terminated prematurely when the sponsor lost financing. RESULTS: We planned to enroll about 5000 patients; a total of 3873 were randomly assigned and 3761 were included in analyses. In all, 51 patients had a gastrointestinal event; the event rate was 1.1% with omeprazole and 2.9% with placebo at 180 days (hazard ratio with omeprazole, 0.34, 95% confidence interval [CI], 0.18 to 0.63; P<0.001). The rate of overt upper gastrointestinal bleeding was also reduced with omeprazole as compared with placebo (hazard ratio, 0.13; 95% CI, 0.03 to 0.56; P = 0.001). A total of 109 patients had a cardiovascular event, with event rates of 4.9% with omeprazole and 5.7% with placebo (hazard ratio with omeprazole, 0.99; 95% CI, 0.68 to 1.44; P = 0.96); high-risk subgroups did not show significant heterogeneity. The two groups did not differ significantly in the rate of serious adverse events, though the risk of diarrhea was increased with omeprazole. CONCLUSIONS: Among patients receiving aspirin and clopidogrel, prophylactic use of a PPI reduced the rate of upper gastrointestinal bleeding. There was no apparent cardiovascular interaction between clopidogrel and omeprazole, but our results do not rule out a clinically meaningful difference in cardiovascular events due to use of a PPI. (Funded by Cogentus Pharmaceuticals; ClinicalTrials.gov number, NCT00557921.). PMID- 20925543 TI - Severe hypoglycemia and risks of vascular events and death. AB - BACKGROUND: Severe hypoglycemia may increase the risk of a poor outcome in patients with type 2 diabetes assigned to an intensive glucose-lowering intervention. We analyzed data from a large study of intensive glucose lowering to explore the relationship between severe hypoglycemia and adverse clinical outcomes. METHODS: We examined the associations between severe hypoglycemia and the risks of macrovascular or microvascular events and death among 11,140 patients with type 2 diabetes, using Cox proportional-hazards models with adjustment for covariates measured at baseline and after randomization. RESULTS: During a median follow-up period of 5 years, 231 patients (2.1%) had at least one severe hypoglycemic episode; 150 had been assigned to intensive glucose control (2.7% of the 5571 patients in that group), and 81 had been assigned to standard glucose control (1.5% of the 5569 patients in that group). The median times from the onset of severe hypoglycemia to the first major macrovascular event, the first major microvascular event, and death were 1.56 years (interquartile range, 0.84 to 2.41), 0.99 years (interquartile range, 0.40 to 2.17), and 1.05 years (interquartile range, 0.34 to 2.41), respectively. During follow-up, severe hypoglycemia was associated with a significant increase in the adjusted risks of major macrovascular events (hazard ratio, 2.88; 95% confidence interval [CI], 2.01 to 4.12), major microvascular events (hazard ratio, 1.81; 95% CI, 1.19 to 2.74), death from a cardiovascular cause (hazard ratio, 2.68; 95% CI, 1.72 to 4.19), and death from any cause (hazard ratio, 2.69; 95% CI, 1.97 to 3.67) (P<0.001 for all comparisons). Similar associations were apparent for a range of nonvascular outcomes, including respiratory, digestive, and skin conditions (P<0.01 for all comparisons). No relationship was found between repeated episodes of severe hypoglycemia and vascular outcomes or death. CONCLUSIONS: Severe hypoglycemia was strongly associated with increased risks of a range of adverse clinical outcomes. It is possible that severe hypoglycemia contributes to adverse outcomes, but these analyses indicate that hypoglycemia is just as likely to be a marker of vulnerability to such events. (Funded by Servier and the National Health and Medical Research Council of Australia; ClinicalTrials.gov number, NCT00145925.). PMID- 20925545 TI - Dystrophin immunity in Duchenne's muscular dystrophy. AB - We report on delivery of a functional dystrophin transgene to skeletal muscle in six patients with Duchenne's muscular dystrophy. Dystrophin-specific T cells were detected after treatment, providing evidence of transgene expression even when the functional protein was not visualized in skeletal muscle. Circulating dystrophin-specific T cells were unexpectedly detected in two patients before vector treatment. Revertant dystrophin fibers, which expressed functional, truncated dystrophin from the deleted endogenous gene after spontaneous in-frame splicing, contained epitopes targeted by the autoreactive T cells. The potential for T-cell immunity to self and nonself dystrophin epitopes should be considered in designing and monitoring experimental therapies for this disease. (Funded by the Muscular Dystrophy Association and others; ClinicalTrials.gov number, NCT00428935.). PMID- 20925546 TI - Profound deafness in childhood. PMID- 20925548 TI - Images in clinical medicine. A white hand and a red hand-erythromelalgia. PMID- 20925547 TI - Rejection of the kidney allograft. PMID- 20925549 TI - Clinical problem-solving. A heavy heart. PMID- 20925544 TI - Rolofylline, an adenosine A1-receptor antagonist, in acute heart failure. AB - BACKGROUND: Worsening renal function, which is associated with adverse outcomes, often develops in patients with acute heart failure. Experimental and clinical studies suggest that counterregulatory responses mediated by adenosine may be involved. We tested the hypothesis that the use of rolofylline, an adenosine A1 receptor antagonist, would improve dyspnea, reduce the risk of worsening renal function, and lead to a more favorable clinical course in patients with acute heart failure. METHODS: We conducted a multicenter, double-blind, placebo controlled trial involving patients hospitalized for acute heart failure with impaired renal function. Within 24 hours after presentation, 2033 patients were randomly assigned, in a 2:1 ratio, to receive daily intravenous rolofylline (30 mg) or placebo for up to 3 days. The primary end point was treatment success, treatment failure, or no change in the patient's clinical condition; this end point was defined according to survival, heart-failure status, and changes in renal function. Secondary end points were the post-treatment development of persistent renal impairment and the 60-day rate of death or readmission for cardiovascular or renal causes. RESULTS: Rolofylline, as compared with placebo, did not provide a benefit with respect to the primary end point (odds ratio, 0.92; 95% confidence interval, 0.78 to 1.09; P=0.35). Persistent renal impairment developed in 15.0% of patients in the rolofylline group and in 13.7% of patients in the placebo group (P=0.44). By 60 days, death or readmission for cardiovascular or renal causes had occurred in similar proportions of patients assigned to rolofylline and placebo (30.7% and 31.9%, respectively; P=0.86). Adverse-event rates were similar overall; however, only patients in the rolofylline group had seizures, a known potential adverse effect of A1-receptor antagonists. CONCLUSIONS: Rolofylline did not have a favorable effect with respect to the primary clinical composite end point, nor did it improve renal function or 60-day outcomes. It does not show promise in the treatment of acute heart failure with renal dysfunction. (Funded by NovaCardia, a subsidiary of Merck; ClinicalTrials.gov numbers, NCT00328692 and NCT00354458.). PMID- 20925550 TI - Illuminating the potential of pluripotent stem cells. PMID- 20925551 TI - Autoimmunity in a genetic disease-a cautionary tale. PMID- 20925552 TI - Microflora, helminths, and the immune system-who controls whom? PMID- 20925553 TI - Endovascular repair of abdominal aortic aneurysm. PMID- 20925554 TI - Hospital-acquired infections due to gram-negative bacteria. PMID- 20925555 TI - Incentives for drug development-the curious case of colchicine. PMID- 20925556 TI - Communicating the rhythm. PMID- 20925560 TI - A relaxed implant bed: implants placed after two weeks of osteotomy with immediate loading: a one year clinical trial. AB - A waiting period of 2 weeks after osteotomy increases the surrounding tissue activity to its maximum level as collagen formation and neoangiogenesis represent a relaxed and acceptable implant bed configuration. The aim of the present study was a clinical and radiologic evaluation of early osteotomy with implant placement delayed for 2 weeks with immediate loading in the anterior and premolar region with minimally invasive approach. Seven GS II implants (Osstem) were placed in 6 patients. Osteotomy was done followed by flap closure without placement of the implant. After waiting for approximately 2 weeks, implant placement was done, which was loaded immediately with provisional crown in implant protected occlusion. It was replaced by definitive restoration after 6-8 weeks, which was considered baseline. Implant stability and marginal bone levels were assessed with clinical and radiologic parameters at baseline, 6- and 12 month intervals. None of the implants were found mobile during the 1-year period. The average mean marginal bone loss was 0.4 mm over the 1-year follow-up period. In the present study, early osteotomy with delayed implant placement showed negligible crestal bone loss with no mobility. PMID- 20925561 TI - The business of telemedicine: strategy primer. AB - There is some tacit understanding that telemedicine can provide cost efficiency along with increased access and equality of care for the geographically disadvantaged. However, concrete strategic guidance for healthcare organizations to attain these benefits is fragmented and limited in existing literature. Telemedicine programs need to move from a grant-funded to a profit-centered status to sustain their existence. This article extends work presented at a recent American Telemedicine Association Business and Finance Special Interest Group course to provide a conceptual framework for strategic planning and for effectively implementing telemedicine programs. An expert panel of telemedicine coordinators provides insight and recommendations. PMID- 20925562 TI - Ambulance 12-lead electrocardiography transmission via cell phone technology to cardiologists. AB - This study demonstrates transmission of 12-lead electrocardiography (ECG) in an ambulance to the cell phone of the attendant emergency medical technician and then to the hospital and to cell phones of off-site cardiologists. The emergency medical technician cell phone receives Extensible Markup Language files generated by a Phillips Extensible Markup Language ECG instrument via Wi-Fi-based wireless network and then sends them to an ECG-processing server at the hospital over the mobile telephone network. After reducing ECG noises and artifacts, the server converts files to Digital Imaging and Communications in Medicine-based ECG reports stored in Picture Archiving and Communication System. These reports are sent to the cell phones of off-site cardiologists. Consequently, on-site Emergency Department physicians and off-site cardiologists can discuss ECG reports via Picture Archiving and Communication System on their computers or cell phones to prepare for the most appropriate treatment while the patient is on the way to the hospital. In conclusion, this 12-lead ECG transmission e-technology expands the functions of a 12-lead ECG instrument and facilitates more efficient prehospital cardiac care. PMID- 20925563 TI - A new, phonocardiography-based telemetric fetal home monitoring system. AB - The purpose of this article is to describe a new, phonocardiography-based fetal telemonitoring system, which, due to its passive nature, allows long-term measurements even at the home of the pregnant woman. The input element of the system was the home monitor with two sensors for recording the trans-abdominal fetal heart signal and the uterine contractions. The recorded signal was transmitted by mobile network and Internet to an Evaluation Center, where it was analyzed in detail to obtain information about possible dysfunction of the fetal heart. The investigations on this system made clear that by advanced processing of the recorded signal the system captured many additional cardiac features compared with the traditional ultrasound-based cardiotocographic procedure. PMID- 20925564 TI - Resident perceptions of a tele-intensive care unit implementation. AB - OBJECTIVE: Remote intensive care unit (ICU) monitoring (tele-ICU) may provide a means to address the shortage of intensive care physicians. However, the consequences of implementing a tele-ICU system for house staff education and clinical experience are unknown. The purpose of this study was to determine resident perceptions of the impact of a tele-ICU implementation on patient care, education, and the overall work environment. MATERIALS AND METHODS: Cross sectional survey of residents who rotated through the medical ICU within the first year after the implementation of a tele-ICU in a large, academically affiliated, community hospital. Each question was graded on a 5-point Likert scale. RESULTS: Thirty-five of 60 residents completed the survey (58% response rate). Sixty-three percent of residents reported that tele-ICU was associated with an improved ability to focus on urgent patient issues, and 46% thought that the tele-ICU helped them to feel less overwhelmed. Although most residents were neutral (51%), 37% agreed that the tele-ICU was a valuable educational experience. Seventy-seven percent reported that the tele-ICU integration was associated with improved patient safety, but many were concerned about the impact on continuity and communication. There was no perceived association with patient or family satisfaction. CONCLUSIONS: Our study suggests that a tele-ICU implementation in a medical ICU does not seem to have a negative impact on the educational experience of residents and is associated with perceived improvements in patient safety and quality. Future studies should objectively measure the educational impact of implementing a tele-ICU system. PMID- 20925565 TI - Implementation of a wireless device for real-time telemedical assistance of home ventilated amyotrophic lateral sclerosis patients: a feasibility study. AB - Neuromuscular disorders encompass a wide category of illnesses with a significant burden on the patient, family, and society. Telehome monitoring presents an alternative for closer follow-up, by ensuring timely transmission of data and prompting medical support before deterioration occurs. We used telehome monitoring devices for amyotrophic lateral sclerosis patients with respiratory failure in a clinic. This instrument directly acts as a digital recorder of parameters received from an external instrument, such as the bi-level ventilator, and contains an internal modem for direct connection to the Internet, thereby allowing bidirectional flexibility in collecting data and parameter changes whenever needed. The use and acceptance of the system was investigated with patients and all therapists involved. The instrument was found to be user friendly and effective by the researchers, being practical for both patients and therapists. Therefore, it can be integrated into a routine home care application based on a large respiratory rehabilitation center. The device was extensively tested, and in an ongoing randomized controlled study it is being investigated whether this management strategy is able to hasten the ventilator adaptation process and to diminish the overall utilization of health services, with concurrent economic viability. We conclude that home telemonitoring represents a positive contribution to the management of chronic patients and raised awareness of it should be considered in a near future. This portable telemonitoring device provides an opportune approach to better understand and recognize a ventilatory pattern through long-term ventilation monitoring in the home environment. PMID- 20925566 TI - MEDLINE versus EMBASE and CINAHL for telemedicine searches. AB - INTRODUCTION: Researchers in the domain of telemedicine throughout the world tend to search multiple bibliographic databases to retrieve the highest possible number of publications when conducting review projects. Medical Literature Analysis and Retrieval System Online (MEDLINE), Excerpta Medica Database (EMBASE), and Cumulative Index to Nursing and Allied Health Literature (CINAHL) are three popular databases in the discipline of biomedicine that are used for conducting reviews. Access to the MEDLINE database is free and easy, whereas EMBASE and CINAHL are not free and sometimes not easy to access for researchers in small research centers. OBJECTIVE: This project sought to compare MEDLINE with EMBASE and CINAHL to estimate what proportion of potentially relevant publications would be missed when only MEDLINE is used in a review project, in comparison to when EMBASE and CINAHL are also used. METHODS: Twelve simple keywords relevant to 12 different telemedicine applications were searched using all three databases, and the results were compared. RESULTS: About 9%-18% of potentially relevant articles would have been missed if MEDLINE had been the only database used. CONCLUSIONS: It is preferable if all three or more databases are used when conducting a review in telemedicine. Researchers from developing countries or small research institutions could rely on only MEDLINE, but they would loose 9%-18% of the potentially relevant publications. Searching MEDLINE alone is not ideal, but in a resource-constrained situation, it is definitely better than nothing. PMID- 20925567 TI - Cost savings of telemedicine utilization for child psychiatry in a rural Kansas community. AB - The costs of pediatric telemedicine services remain underreported and understudied; however, there is evidence that telepediatric services can be cost competitive with traditional ones. For 15 years, the University of Kansas Center for Telemedicine and Telehealth has been providing telemental health outreach from the University of Kansas Medical Center (KUMC). One service site is located in Crawford County, Kansas, which provides telepsychiatry services to children and adolescents. The purpose of this study was to examine the costs of operating the Crawford County site relative to accessing services at KUMC, the likely alternative service location. The cost of travel time to parents who accompanied a dependent to either location also was estimated. Patients and parents were examined over a 6-month period in 2006. One hundred thirty-two patients received 257 telemedicine psychiatric consultations during this period. Cost estimates for using the pediatric telemedicine service were assessed for all patients; however, travel and related costs were collected from a sample of 26 patient-parent dyads. The estimated costs of services were obtained using standard cost-accounting procedures. An average cost per consultation in Crawford County was $168.61. The cost savings in travel time and other expenses to parents and patients were substantial between use of the county site and KUMC. Subtracting average savings in travel costs to patients and parents produced an average cost of a telepsychiatry consult in Crawford County of only $30.99. This study was conducted over 6 months with a small number of observations; it should be replicated over a longer study period, with more patients, and with more data that might capture marginal costs of services. PMID- 20925568 TI - Making the invisible visible: near-infrared spectroscopy and phlebotomy in children. AB - AIM: Phlebotomy and venous cannulation are the most frequently performed and the most distressing invasive procedures in pediatrics. The aim of this pilot study was to assess whether a novel vein imaging system was advantageous for the identification of superficial veins, thus reducing the number of skin punctures. METHODS: The Vein Viewer was trialled in 50 children <16 years of age who required venous blood sampling or peripheral venous catheterization as part of their standard clinical care. A questionnaire with 10 questions about their experience of using this equipment was distributed to the pediatric doctors and nurses performing the procedures. RESULTS: During a 9-month period, 38 venipunctures and 12 cannulations were performed in 50 children (mean age 6.67 years). On average, 1.7 puncture attempts per child were necessary. Fifty questionnaires were completed by 11 consultants, 16 registrars, 20 senior house officers, and 3 nurses. Seventy-two percent rated the imaging device as useful, 8% as not useful, and 20% remained neutral. Visibility of the peripheral veins was improved in 76% of children, and the same as with room light in 24%. CONCLUSIONS: Near-infrared technology facilitated venipuncture and venous cannulation in a pediatric cohort. Further, controlled trials are required including children of specific age groups and those from ethnic minorities. PMID- 20925570 TI - Going home. PMID- 20925569 TI - Using telehealth for assessment of fetal alcohol spectrum disorder: the experience of two Canadian rural and remote communities. AB - INTRODUCTION: Telehealth has been used for fetal alcohol spectrum disorder (FASD) diagnostic assessment in select Manitoban communities since 2000. OBJECTIVE: The purpose of this study was to evaluate the FASD telehealth program within two rural and remote Northern Manitoban communities by comparing community practices from the perspective of professionals working with the FASD diagnostic clinics in these communities. Recommendations for the further development of FASD assessment by telehealth were made to further improve current implementation and guide expansion of the FASD telehealth program within the province. METHODOLOGY: Semistructured interviews were conducted from October 19 to December 11, 2009. Participants (N = 26) were comprised of professionals, including those in the education, social services, and health sectors. RESULTS AND RECOMMENDATIONS: Two themes emerged from the data and covered the perceived strengths and drawbacks with the program, and meaningful suggestions to improve the service. Participants regarded the FASD telehealth program as successful and useful, especially given the remote location of the communities and the lack of on-site services. Recommendations addressing the barriers pertaining to the process were made from the study's findings and available scientific literature. CONCLUSIONS: This study will provide a solid basis for the successful further development of the FASD telehealth programs. PMID- 20925571 TI - The Eighth International Conference on Smart Homes and Health Telematics 2010, July 22-24, 2010, Seoul, South Korea. PMID- 20925572 TI - Association of renin BglI polymphism with essential hypertension: a meta-analysis involving 1811 cases and 1626 controls. AB - In an effort to clarify association of an intronic polymorphism BglI in a renin gene with essential hypertension, we performed a meta-analysis of the case control association studies. Publications in the English language and human subjects were searched in PubMed and EMBASE as of July 10, 2009. A fixed-effects model was applied to pool data in the absence of between-studies heterogeneity, and a random-effects model otherwise. Data and study quality were assessed in duplicate. Publication bias was evaluated using the fail-safe number. From three studies with four populations including 1811 patients with essential hypertension and 1626 controls, we found a significant association of renin BglI B with an increased risk for essential hypertension (OR = 1.25; 95% CI, 1.11 to 1.41; P = 0.0002). In addition, significance persisted after assuming the dominant (OR = 1.30; 95% CI, 1.13 to 1.51; P = 0.0004) mode of inheritance, while no significance was observed for the recessive mode (OR = 1.46; 95% CI, 0.82 to 2.60; P = 0.20). The fail-safe number at the level of 0.05 supported these significant associations. In sum, our meta-analysis expands previous findings by showing that the presence of renin BglI B allele is associated with an increased risk in developing essential hypertension, and this effect might act in a dominant mode of inheritance. Further studies are warranted to fully address questions about the etiologic mechanisms of this positive association. PMID- 20925574 TI - Comparison of two different energy-based vascular sealing systems for the hemostasis of various types of arteries: a porcine model-evaluation of LigaSure ForceTriadTM. AB - BACKGROUND: The ForceTriadTM generator has been recently developed. This new electrosurgical generator would demonstrate improved quality and efficiency in blood vessel sealing. AIM: To compare currently available 10-mm laparoscopic electrosurgical devices with the LigaSureTM Vessel Sealing System and ForceTriad generator (Valleylab, Inc., a division of Tyco Healthcare) for use in vessel sealing. METHODS: Blood vessels of various types and diameters were harvested from alive four pigs using three instruments: LigaSure AtlasTM with LigaSure Vessel Sealing Generator (LSAt), LigaSure Atlas with ForceTriad Generator (LSAtFT), and EndoclipTM II (Autosuture, USSC; a division of Tyco Healthcare). A total of 100 arteries were processed by removal of fatty and connective tissue from the adventitia before sealing. An additional set of specimens was sealed and histopathologically analyzed after being stained with hematoxylin and eosin. RESULTS: The mean burst pressure was significantly higher with LSAtFT compared to LSAt (P < 0.01). The sealing process was significantly shorter with LSAtFT (P < 0.05). With regard to the degree of thermal injury, adventitial collagen denaturation and proximal thermal injury to the smooth muscle in the media of the vessel wall were less common with LSAtFT; however, the numbers were too small for statistical analysis. CONCLUSION: Both the LSAt and LSAtFT secured all vessel sizes to well above physiologic levels. The LSAtFT could be used more confidently in vessels up to 7 mm. Our findings indicate that LSAtFT could be a safer and more efficient instrument for advanced laparoscopic surgery. PMID- 20925573 TI - Injury-induced regulation of steroidogenic gene expression in the cerebellum. AB - Sex steroids assist adult neural tissue in the protection from and repair of damage resulting from neural injury; some steroids may be synthesized in the brain. Songbirds are especially useful models to explore steroidal neuroprotection and repair. First, the full suite of cholesterol transporters and steroidogenic enzymes are expressed in the zebra finch (ZF) brain. Second, estrogens promote recovery of behavioral function after damage to the adult ZF cerebellum. Third, the estrogen synthetic enzyme aromatase is rapidly upregulated in reactive glia following neural injury, including in the ZF cerebellum. We hypothesized that cerebellar injury would locally upregulate steroidogenic factors upstream of aromatase, providing the requisite substrate for neuroestrogen synthesis. We tested this hypothesis by lesioning the cerebellum of adult songbirds using both males and females that peripherally synthesize steroids in different amounts. We then used quantitative PCR to examine expression of mRNAs for the neurosteroidogenic factors TSPO, StAR, SCC, 3beta HSD, CYP17, and aromatase, at 2 and 8 days post-lesion. Compared to sham lesions, cerebellar lesions significantly upregulated mRNA levels of TSPO and aromatase. Sex differences in response to the lesions were detected for TSPO, StAR, and aromatase. All birds responded to experimental conditions by showing time dependent changes in the expression of TSPO, SCC, and aromatase, suggesting that acute trauma or stress may impact neurosteroidogensis for many days. These data suggest that the cerebellum is an active site of steroid synthesis in the brain, and each steroidogenic factor likely provides neuroprotection and promotes repair. PMID- 20925576 TI - Inhibition of X4-tropic HIV type 1 replication by knockdown of the cellular protein LEREPO4. AB - Human immunodeficiency virus 1 (HIV-1) and host cell factors show important mutual interactions. We found that HIV-1 infection induced expression of a likely ortholog of mouse immediate early response erythropoietin 4 (LEREPO4) in vitro. When LEREPO4 expression was suppressed by siRNA in P4-CCR5 cells, HIV-1 replication showed significantly reduced HIV-1 transcript and p24 protein levels as measured by quantitative PCR and ELISA, respectively. The LEREPO4 knockdown also had an inhibitory effect on HIV-1-LTR-driven reporter plasmid expression of beta-galactosidase. Furthermore, the inhibitory effect of LEREPO4 silencing on HIV-1 replication was confirmed in Jurkat T cells. The up-regulation of LEREPO4 by HIV-1 and the inhibition of HIV-1 replication mediated by knockdown of LEREPO4 may point to an important functional role of LEREPO4 as a novel HIV-1 dependency factor. PMID- 20925578 TI - Intravitreal tissue plasminogen activator and pneumatic displacement of submacular hemorrhage. AB - PURPOSE: We sought to evaluate the efficacy, safety, and visual outcome of intravitreal tissue plasminogen activator (t-pa) and pneumatic displacement to treat submacular hemorrhage. METHODS: In this retrospective, interventional case series, 46 consecutive eyes of 45 patients received intravitreal t-pa (50ug in 0.1 mL) and expansile gas (0.3 mL perfluoropropane) injection for submacular hemorrhage. Hemorrhages were secondary to exudative age-related macular degeneration in 28 eyes, idiopathic polypoidal choroidal vasculopathy (IPCV) in 11 eyes, retinal arterial macroaneurysm in 2 eyes, pathologic myopia in 3 eyes, and trauma in 1 eye. After surgery, patients maintained a supine position for the first 6 h and then remained prone for about 1 week. Outcome measures were visual acuity, displacement of submacular hemorrhage, and surgical complications. RESULTS: Complete displacement of thick blood out of the fovea was achieved in 40 of 45 eyes (89%), and partial displacement was achieved in 5 eyes (11%). Best postoperative visual acuity improved by 2 Snellen lines or greater in 21 of 45 eyes (46.67%). At a mean follow up of 15.64 months, final visual acuity improved by 2 Snellen lines or greater in 16 eyes (35.6%). The complication of breakthrough vitreous hemorrhage occurred in nine eyes (20%). Eyes with nonage related macular degeneration tended to have better final visual recovery, especially eyes with IPCV over extended follow up (P = 0.035). CONCLUSIONS: Intravitreal injection of t-pa and expansile gas was an effective and safe treatment for submacular hemorrhage. Our study features a considerable number of patients with IPCV, and the outcomes are favorable. PMID- 20925579 TI - Association of CYP2D6 single-nucleotide polymorphism with response to ophthalmic timolol in primary open-angle Glaucoma--a pilot study. AB - OBJECTIVES: We aimed to investigate whether CYP2D6 polymorphisms were associated with the intraocular pressure (IOP)-lowering effect and systemic complications (especially bradycardia) of ophthalmic timolol. METHODS: One hundred twenty-three primary open-angle glaucoma subjects (123 eyes) were treated with 0.5% aqueous formulations of ophthalmic timolol. IOP and heart rate were measured before and after timolol administration. DNA was extracted from venous leukocytes of all the subjects. Two single-nucleotide polymorphisms (SNPs) of CYP2D6, for example, rs16947 (2850C>T, R296C) and rs1135840 (4180C>G, S486T), were detected by restriction fragment length polymorphism analysis. RESULTS: Neither rs16947 (P = 0.339) nor rs1135840 (P = 0.903) genotype was statistically correlated with the IOP-lowering effect of timolol eye drops. The rs16947 genotype was significantly associated with occurrence of bradycardia in primary open-angle glaucoma patients (P = 0.021). The patients with rs16947 CT (P = 0.043) or TT (P = 0.043) were more inclined to bradycardia than those with rs16947 CC, although there was no significant difference between CT and TT (P = 0.177). The analysis of variance showed no significant difference in heart rate (P = 0.559) among GG, GC, and CC groups. CONCLUSIONS: CYP2D6 SNP rs16947 may confer susceptibility to timolol induced bradycardia. Patients with CC genotype were unlikely to suffer from timolol-induced bradycardia, whereas those with TT genotype were found to suffer from timolol-induced bradycardia. PMID- 20925577 TI - Doxycycline hydrogels as a potential therapy for ocular vesicant injury. AB - PURPOSE: The goals of this study were (1) to compare the injury at the basement membrane zone (BMZ) of rabbit corneal organ cultures exposed to half mustard (2 chloroethyl ethyl sulfide, CEES) and nitrogen mustard with that of in vivo rabbit eyes exposed to sulfur mustard (SM); (2) to test the efficacy of 4 tetracycline derivatives in attenuating vesicant-induced BMZ disruption in the 24-h period postexposure; and (3) to use the most effective tetracycline derivative to compare the improvement of injury when the drug is delivered as drops or hydrogels to eyes exposed in vivo to SM. METHODS: Histological analysis of hematoxylin and eosin-stained sections was performed; the ultrastructure of the corneal BMZ was evaluated by transmission electron microscopy; matrix metalloproteinase-9 was assessed by immunofluorescence; doxycycline as drops or a hydrogel was applied daily for 28 days to eyes exposed in vivo to SM. Corneal edema was assessed by pachymetry and the extent of neovascularization was graded by length of longest vessel in each quadrant. RESULTS: Injury to the BMZ was highly similar with all vesicants, but varied in degree of severity. The effectiveness of the 4 drugs in retaining BMZ integrity did not correlate with their ability to attenuate matrix metalloproteinase-9 expression at the epithelial-stromal border. Doxycycline was most effective on organ cultures; therefore, it was applied as drops or a hydrogel to rabbit corneas exposed in vivo to SM. Eyes were examined at 1, 3, 7, and 28 days after exposure. At 7 and 28 days after SM exposure, eyes treated with doxycycline were greatly improved over those that received no therapy. Corneal thickness decreased somewhat faster using doxycycline drops, whereas the hydrogel formulation decreased the incidence of neovascularization. CONCLUSIONS: Corneal cultures exposed to 2-chloroethyl ethyl sulfide and nitrogen mustard were effective models to simulate in vivo SM exposures. Doxycycline as drops and hydrogels ameliorated vesicant injury. With in vivo exposed animals, the drops reduced edema faster than the hydrogels, but use of the hydrogels significantly reduced neovascularization. The data provide proof of principle that a hydrogel formulation of doxycycline as a daily therapy for ocular vesicant injury should be further investigated. PMID- 20925580 TI - Successful treatment of Pseudallescheria boydii keratitis with topical natamycin as monotherapy. AB - PURPOSE: To report a case of Pseudallescheria boydii keratitis successfully treated with topical natamycin as monotherapy. METHODS: Interventional case report describing the clinical presentation, histopathologic findings, course, and treatment of a patient with P. boydii keratitis. RESULTS: A 50-year-old male electrician with a 4-day history of right eye pain and blurring of vision was referred. There was history of right eye injury while hammering and examining a hole in the ceiling. Examination showed a corneal abscess with overlying epithelial defect measuring 2 mm in diameter. Histopathologic investigation revealed septate hyaline cylindrical hyphae with acute angle branching and formation of oval to pyriform conidia truncated at the base, compatible with P. boydii. The patient was treated with topical natamycin 5%, which eradicated the infection, resulting in a final best-corrected visual acuity of 6/7.5. CONCLUSION: The fungus P. boydii can cause keratitis. The success rate for treatment was generally thought to be poor. Early detection and treatment is important in improving the outcome. This is believed to be the first reported case of P. boydii keratitis successfully treated with topical natamycin as monotherapy. PMID- 20925581 TI - Photodynamic therapy for polypoidal choroidal vasculopathy. PMID- 20925575 TI - Changes in the distribution of HIV type 1 subtypes D and A in Rakai District, Uganda between 1994 and 2002. AB - HIV-1 subtype D (HIV-1D) progresses to disease faster and has lower transmissibility than subtype A (HIV-1A). We examined whether these differences could lead to a population level change in the distribution of these subtypes over time. HIV-1 viral RNA was extracted from stored serum samples from HIV positive subjects participating in a population-based cohort study in Rakai, Uganda in 1994 and 2002. Portions of the viral proteins gag and gp41 were sequenced and subtyped. HIV-1 subtype assignments were generated for 773 subjects in 1994 and 812 subjects in 2002. The change in subtype distribution of the population as a whole as well as quartile age groups were examined for significant changes using a linear model. There was a significant decrease in the proportion of subjects infected with HIV-1D from 70.2% to 62.4% and a significant increase in subjects infected with HIV-1A from 16.7% to 23.3% over the 8-year period (p = 0.005). The most marked changes in proportion of HIV-1D and A were seen in the younger individuals (<25 and 25-30 years; p < 0.05). The percentages of subjects infected with HIV-1C and recombinant subtypes did not change significantly. Over this 8-year period, the overall viral population in this region evolved toward the less virulent HIV-1A strain, most likely as a consequence of the faster disease progression and lower transmissibility of HIV 1D. PMID- 20925582 TI - Intravitreal ranibizumab in the treatment of cystoid macular edema associated with retinitis pigmentosa. PMID- 20925583 TI - Genetic polymorphisms of glycine N-acyltransferase (GLYAT) in a French Caucasian population. AB - In humans, the glycine N-acyltransferase enzyme (GLYAT) is thought to be important in the detoxification of endogenous and xenobiotic compounds which contain a carboxylic acid group, such as benzoic, isovaleric, or acetylsalicylic acids. The aim of this work was to report a comprehensive investigation of GLYAT genetic polymorphisms in DNA samples from 55 subjects of French Caucasian origin, using polymerase chain reaction-single-strand conformation polymorphism and sequencing strategies. Seven different polymorphisms of the GLYAT gene were identified, including two polymorphisms in the 5' flanking region of the gene (g. 8457C>T and g.-8010A>G), two polymorphisms in intron 5 (g.13931A>G and g.13944C>T) and three missense mutations in exon 2 (g.49T>A; p.Ser17Thr), exon 5 (g.13886A>G; p.Asn156Ser) and exon 6 (g.14435C>T; p.Arg199Cys). In addition to the wild-type allele GLYAT*1 (2.7%), four novel alleles were identified: GLYAT*2A (75.5%), *2B (4.5%), *3 (16.4%) and *4 (0.9%), and five different genotypes. Localisation of the p.Ser17Thr and p.Arg199Cys missense mutations in predicted secondary structures suggest that these variants might have a potential role on the GLYAT protein activity. These results could be helpful in investigating the potential association of GLYAT variants with an incidence of reduced efficiency in xenobiotic carboxylic acids detoxification in humans. PMID- 20925584 TI - The metabolism and disposition of a potent inhibitor of hepatitis C virus NS3/4A protease. AB - Compound A ((1aR,5S,8S,10R,22aR)-5-tert-butyl-N-{(1R,2S)-1 [(cyclopropylsulfonyl)carbamoyl]-2-ethenylcyclopropyl}-14-methoxy-3,6-dioxo 1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10 methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[12,11-b]quinoline-8 carboxamide) is a prototype of a series of subnanomolar inhibitors of genotypes 1, 2, and 3 hepatitis C virus (HCV) NS3/4A proteases. HCV NS3/4A protease inhibitors have demonstrated high antiviral effects in patients with chronic HCV infection and are likely to form a key component of future HCV therapy. Compound A showed excellent liver exposure in rats, which is essential for compounds intended to treat HCV. The compound was mainly eliminated intact in bile and showed greater than dose proportional systemic exposure in rats. Compound A demonstrated time- and temperature-dependent uptake into rat and human hepatocytes and proved to be a substrate for rat hepatic uptake transporter Oatp1b2 and for human hepatic uptake transporters OATP1B1 and OATP1B3. The liver selectivity observed for this compound is likely to be due to transporter mediated hepatic uptake together with moderate passive permeability. Metabolism was mainly CYP3A-mediated and generated a reactive epoxide on the vinylcyclopropyl sulfonamide moiety that could be quenched by glutathione. Similar metabolic profiles of Compound A were obtained in liver microsomes of rats and humans. The oral bioavailability at 5 mg/kg was low due to extensive hepatic first-pass effect but clearly the intestinal absorption was enough to deliver a high amount of the compound to the liver. The metabolism and disposition properties of Compound A are particularly attractive to support its evaluation as a drug candidate for the treatment of hepatitis C. PMID- 20925585 TI - In vitro metabolism, glutathione conjugation, and CYP isoform specificity of epoxidation of 4-vinylphenol. AB - 4-Vinylphenol (4VP) has been identified as a minor urinary metabolite of styrene in rat and human volunteers. This compound has been shown to be more hepatotoxic and pneumotoxic than both styrene and styrene oxide at lower doses in rats and mice. To explore the possible toxicity mechanism of 4VP, the current study was conducted to investigate the metabolism of 4VP, the glutathione (GSH) conjugation of the metabolites of 4VP and its cytochrome P(450) (CYP) specificity in epoxidation in different microsomes in vitro. Incubations of 4VP with mouse lung microsomes afforded two major metabolites which were identified as 4-(2-oxiranyl) phenol of 4VP (4VPO) and 4VP catechol. 4VPO was found to react with GSH to form GSH conjugate and 4VP catechol was found to further be metabolized to electrophilic species which react with GSH to form the corresponding 4VP catechol GSH conjugates. Relative formation rates for those GSH conjugates and the regioisomer formation of 4VPO-GSH conjugates with both inhibitors of CYP 2F2 and CYP 2E1 in microsomal incubation condition were also investigated. This present study provides better insight on the lung toxicity seen with 4VP, the toxic metabolite of commercial styrene. PMID- 20925586 TI - Norwegian obstetricians' opinions about cesarean section on maternal request: should women pay themselves? AB - OBJECTIVE: to explore obstetricians' opinions on cesarean section (CS) on maternal request in the absence of a medical indication, and the potential to regulate CS on maternal request through financial incentives such as patient co payment. DESIGN: cross-sectional study. SETTING: Norway. POPULATION/SAMPLE: a total of 507 obstetricians (response rate 71%). METHODS: Questionnaire covering socio-demographic variables, professional experience and attitudes about CS on maternal request (such as willingness to perform, views on how CS on maternal request should be financed). MAIN OUTCOME MEASURES: obstetricians' opinions about CS on maternal request including funding and use of patient co-payments. RESULTS: clinical encounters with CS on maternal request were considered problematic from a clinical viewpoint by 62% of the respondents. While 35% considered the costs of CS on maternal request to be a public responsibility, 40% suggested use of co payments ranging from ?188- ?7,500. Male obstetricians less frequently considered CS on maternal request problematic and were more likely to favor public funding than females. Female obstetricians favored use of co-payments more often than males (64% female vs. 37% male obstetricians, chi(2) = 23.94, p < 0.001) and suggested higher co-payments. The median co-payment was ?1,875 for female and ?1,250 for male obstetricians (p < 0.001). CONCLUSIONS: the study supports the existence of a gender difference concerning obstetricians' responses to patient requested cesarean section. The results indicate that a substantial proportion of obstetricians welcome some form of constraint concerning cesarean section requests in the absence of a medical indication. PMID- 20925587 TI - Non-inferiority randomized trials, an issue between science and ethics: the case of the SYNTAX study. AB - Non-inferiority trials are questionable when death and serious complications are included among outcomes. The term itself "non-inferiority" is misleading, since such a study would not demonstrate that a new treatment is non-inferior to a control treatment, but simply that the inferiority would not reach a pre specified level, deemed as acceptable by the designers of the trial. Group cross over, assay-sensitivity and the need of a placebo arm are major issues for the reliability of non-inferiority trials. The SYNTAX trial for severe coronary artery disease was designed on a non-inferiority margin of 6.6%. In this paper we show that the SYNTAX designers were ready to accept up to 30% higher rate of death and major adverse events to claim the non-inferiority of percutaneous coronary intervention versus coronary artery bypass grafting. Eventually the SYNTAX study failed because percutaneous patients sustained an even higher rate of adverse events. We propose major caution in performing non-inferiority randomized trials. PMID- 20925588 TI - Laparoscopic reduction of intussusception in children by a single surgeon in comparison with open surgery. AB - The surgical approach for managing intussusception is controversial. In this study, a retrospective analysis of patients undergoing surgical reduction for intussusception over a period of five years was conducted. All patients received either open surgery or laparoscopic approach after failing enema reduction of intussusception. The clinical and operative data were collected and analyzed. Eight patients received open surgery (OPEN group), and 37 patients received laparoscopic surgery, while two (5.4%) of them converted to open surgery. The remaining 35 patients were included in the LAP group. There was no difference in age, gender, clinical symptoms and signs, duration of symptoms, level of intussusception, and complications between the OPEN and LAP groups. In contrast, the operation time and length of hospital stay in the LAP group were significantly shorter than those in the OPEN group (P = 0.013 and P = 0.001 respectively). No recurrence was disclosed in the OPEN group but three patients in the LAP group had recurrent intussusception (8.6%); however, the difference of the recurrence rate between these two groups was not statistically significant (P = 0.40). In conclusion, reducing intussusception with the laparoscopic approach is highly successful and can be performed first for stable patients requiring surgical intervention. PMID- 20925589 TI - Traumatic epidural haematoma of the posterior cranial fossa. AB - A posterior fossa epidural haematoma (EDH) is uncommon and the diagnosis is difficult because the clinical symptoms are non-specific. Therefore, a computed tomography scan is important for the early diagnosis and management. Thirty-four patients with a posterior fossa EDH were admitted between 2001 and 2008. A retrospective analysis of the clinical and radiographic findings with regard to outcome and prognostic factors was carried out. The Glasgow Coma Scale (GCS) score on admission was recorded to be: one in 3-5, five in 6-8, six in 9-12 and 22 patients in 13-15. The admission GCS score was the most valuable prognostic factor. Among the 28 patients with a GCS score of more than 9, 27 patients survived with good results; for the six patients with a GCS score of less than eight, two patients had good recovery and four patients had unfavourable outcome. The 15 patients that were conservatively treated and 14 out of the 19 patients surgically treated had a good recovery. Among the other surgically treated patients, two were moderately disabled, two remained in a vegetative state and one died (overall mortality 2.9%). An occipital fracture was present in 28 cases. Six patients with a diastatic fracture of the lambdoid suture had a more complicated venous sinus injury requiring early surgery compared to those with a simple linear fracture. The patients admitted with associated intracranial injuries, such as a contrecoup injury including subdural haemorrhage or traumatic subarachnoid haemorrhage had a poor outcome. The initial GCS score on admission and the presence of associated intracranial injuries were important factors associated with the patient prognosis. A diastatic fracture of the lambdoid suture was associated with complicated venous sinus injuries making surgery more difficult. PMID- 20925590 TI - Huge calcified chronic subdural haematoma. AB - Huge calcified chronic subdural hematoma is quite rare. We reported a such case in a old man. The intraoperative photographs of the case fully demonstrated the morphology of the calcified chronic subdural hematoma. PMID- 20925591 TI - Synergistic effect of emodin in combination with ampicillin or oxacillin against methicillin-resistant Staphylococcus aureus. AB - Methicillin-resistant Staphylococcus aureus (MRSA) is a substantial contributor to morbidity and mortality. In search of a natural products capable of inhibiting this multidrug resistant bacteria, we have investigated the antimicrobial activity of emodin (EM) isolated from Rheum palmatum L. (Polygonaceae) against 17 different strains of the bacterium. New antimicrobial activity was found using the paper disc diffusion method, agar dilution as well as checkerboard method. Against the 17 strains, the disc diffusion test was in the range of 18-30 mm, and the minimum inhibitory concentrations (MICs) of EM were in the range of 1.5-25 MUg/mL. From those results we performed the checkerboard test to determine the synergism of EM in combination with ampicillin (AM) or oxacillin (OX) against all strains. The combined activity of EM and two antimicrobial agents (AM, OX) against all strains resulted in a fractional inhibitory concentrations index (FICI) ranging from 0.37-0.5 and from 0.37-0.75, respectively. The effect of EM with AM and OX was found to be synergistic or partially synergistic. We found that EM reduced the MICs of AM and OX. EM and in combination with AM or OX could lead to the development of new combination antibiotics against MRSA infection. PMID- 20925592 TI - Natural sperm birefringence can be used to estimate sperm viability and morphology. AB - Semen parameters were evaluated by a variety of tests. A polarizing microscope (PM) which allows, in a single step, for the evaluation of the number, motility, viability of sperm using the phenomenon of birefringence was used. This approach avoids a Papanicolaou staining procedure modified for sperm (PAP) performed in fixed material. The aim of this study was to examine the birefringence of sperm structures, in live cells, for the direct analysis of morphology on fresh samples. Semen samples from 15 men of recently proven fertility and from 66 male patients who attended our center for semen analysis were examined by polarization microscope (PM) analysis in order to find an index representing a pool of sperm with normal morphology and progressive motility. The receiver operating characteristics (ROC) curves were used to determine the performance of the proposed diagnostic method. The difference between the two areas under the ROC curves (PAP=0.76 and PM=0.82) was quantitatively not significant (P=0.308); however, the curve of the PM method was always higher than the curve of PAP, revealing that, qualitatively, PM was more sensitive than PAP. The PM index can represent the percentage of motile sperm with normal morphology, which is the actual pool of sperm that can reach and fertilize the oocyte. We suggest a PM diagnostic cut-off value of 20%, since this value was the lowest found for individuals of proven fertility. PMID- 20925593 TI - Detection of pathogens in foods: the current state-of-the-art and future directions. AB - Over the last fifty years, microbiologists have developed reliable culture-based techniques to detect food borne pathogens. Although these are considered to be the "gold-standard," they remain cumbersome and time consuming. Despite the advent of rapid detection methods such as ELISA and PCR, it is clear that reduction and/or elimination of cultural enrichment will be essential in the quest for truly real-time detection methods. As such, there is an important role for bacterial concentration and purification from the sample matrix as a step preceding detection, so-called pre-analytical sample processing. This article reviews recent advancements in food borne pathogen detection and discusses future methods with a focus on pre-analytical sample processing, culture independent methods, and biosensors. PMID- 20925595 TI - Maternal omega-3 fatty acid supplementation and risk for perinatal maternal depression. AB - OBJECTIVE: A systematic review was conducted to assess the possible association between omega-3 polyunsaturated fatty acid (PUFA) supplementation and intake in the perinatal period and the risk of maternal perinatal depression. METHODS: Two PubMed searches and a BIOSIS Preview, a Web of Science and a PsychInfo search were conducted with the search terms 'DHA, pregnancy and depression' and 'omega-3 fatty acids, pregnancy and depression'. RESULTS: Ten articles - three longitudinal cohort studies, five randomized controlled trials and two pilot trials- that met selection criteria were reviewed. Six found no association, two found mixed results, and two found a positive association between omega-3 PUFAs and reduced incidence of maternal perinatal depression. The heterogeneity of results can be explained by dissimilar study designs, including differences in study duration, time period of measurement and number of participants, and in varied dosages and types of supplemental PUFAs. Some of the larger studies and those that found a positive effect were more likely to be using higher doses, close to 2 g of docosahexaeonic acid (DHA) + eicosapentaenoic acid (EPA), and began the supplementation earlier in pregnancy. CONCLUSIONS: Future RCTs to investigate the role of PUFA supplementation and risk for maternal perinatal depression should begin supplementation early in pregnancy and use a dosage closer to 2 g of DHA + EPA. Depression should also be measured using a diagnostic interview schedule in addition to a screener. PMID- 20925596 TI - Anti-IL-17A therapy protects against bone erosion in experimental models of rheumatoid arthritis. AB - Interleukin-17A (IL-17A) is a pro-inflammatory cytokine secreted by a subset of memory T cells and other innate immune cells. It is associated with rheumatoid arthritis (RA) due to IL-17A expression in RA synovial fluid. The severe bone erosive rat adjuvant-induced arthritis (rAIA) and mouse collagen-induced arthritis (mCIA) models were used to address the therapeutic efficacy of anti-IL 17A treatment with a focused investigation on bone protection. In the rAIA model, treatment with anti-IL-17A completely alleviated arthritis, lowered the level of receptor activator of NFkappaB ligand (RANKL), and inhibited structural damage to the bones. In the mCIA model, IL-17A neutralization coincident with arthritis development or in mice with established arthritis diminished joint swelling by inhibiting disease initiation and progression. Intriguingly, even the few joints that became outwardly severely inflamed in the presence of an anti-IL-17A antagonist had diminished joint histopathology scores compared to severely inflamed, control-treated mice. The bone-preserving property correlated with decreased RANKL message in severely inflamed paws of arthritic mice. These data identify IL-17A as a key factor in inflammation-mediated bone destruction and support anti-IL-17A therapy for the treatment of inflammatory bone diseases such as RA. PMID- 20925597 TI - Survivin: a target from brain cancer to neurodegenerative disease. AB - Apoptosis is an important contributing factor during neuronal death in a variety of neurodegenerative disorders, including multiple sclerosis, Parkinson's disease and sciatic nerve injury. Whereas several clinical and preclinical studies have focused on the neuroprotective effects of caspase inhibitors, their clinical benefits are still unclear. Here, we discuss novel alternative strategies to protect neuronal cells from apoptotic death using members of the inhibitors of apoptosis (IAP) family. We specifically review the different roles of survivin, which is an important member of the IAP family that serves a dual role in the inhibition of apoptosis as well as a vital role in mitosis and cell division. Due to the various roles of survivin during cell division and apoptosis, targeting this protein illustrates a new therapeutic window for the treatment of neurodegenerative diseases. PMID- 20925594 TI - K(ATP) channels process nucleotide signals in muscle thermogenic response. AB - Uniquely gated by intracellular adenine nucleotides, sarcolemmal ATP-sensitive K(+) (K(ATP)) channels have been typically assigned to protective cellular responses under severe energy insults. More recently, K(ATP) channels have been instituted in the continuous control of muscle energy expenditure under non stressed, physiological states. These advances raised the question of how K(ATP) channels can process trends in cellular energetics within a milieu where each metabolic system is set to buffer nucleotide pools. Unveiling the mechanistic basis of the K(ATP) channel-driven thermogenic response in muscles thus invites the concepts of intracellular compartmentalization of energy and proteins, along with nucleotide signaling over diffusion barriers. Furthermore, it requires gaining insight into the properties of reversibility of intrinsic ATPase activity associated with K(ATP) channel complexes. Notwithstanding the operational paradigm, the homeostatic role of sarcolemmal K(ATP) channels can be now broadened to a wider range of environmental cues affecting metabolic well-being. In this way, under conditions of energy deficit such as ischemic insult or adrenergic stress, the operation of K(ATP) channel complexes would result in protective energy saving, safeguarding muscle performance and integrity. Under energy surplus, downregulation of K(ATP) channel function may find potential implications in conditions of energy imbalance linked to obesity, cold intolerance and associated metabolic disorders. PMID- 20925598 TI - Ultrastructural analysis and electron microscopic localization of Nox4 in healthy and atherosclerotic human aorta. AB - During diverse pathological conditions, vascular smooth muscle cells (SMCs) characteristically change from a quiescent, contractile phenotype to a proliferative, synthetic state, migrate toward the intima, and synthesize excess extracellular matrix. Although reactive oxygen species (ROS) are generally considered to be toxic to cells, recent evidence suggests that they may also modulate multiple signaling pathways. The vascular system contains several sources of ROS, among which NADPH oxidases (NOXes) have been shown to take an important part in the regulation of cell function, with effects on growth and proliferation. In the present study, the authors investigate the ultrastructural features of SMCs and the expression profile of Nox4 in healthy and atherosclerotic human aorta to explore the possibility of a relationship between Nox4 and SMCs differentiation state. The data extend at the level of immunoelectron microscopy previous observations, demonstrating for the first time the precise distribution and the differential expression of Nox4 in the morphologically distinct SMC types of healthy and diseased human aorta. PMID- 20925599 TI - Abnormal nuclear structures (micronuclei, nuclear blebs, strings, and pockets) in a case of anaplastic giant cell carcinoma of the thyroid: an immunohistochemical and ultrastructural study. AB - The authors report a case of a 70-year-old woman with an anaplastic giant cell thyroid carcinoma, along with immunohistochemical and electron microscopic findings. Histologically, the tumor is characterized by mononucleated and multinucleated giant cells, lack of architectural cohesion, atypical mitoses, and extensive areas of coagulative necrosis. Tumor cells showed AE1/AE3 positivity as well as nuclear overexpression of p53 and ki-67. Semithin sections revealed multiple nuclei with heterogeneous size ranging from micronuclei to large-size (giant) nuclei. Micronuclei were confirmed by electron microscopy that disclosed also the presence of nuclear blebs, strings, and pockets. Morphological findings of these abnormal nuclear structures in conjunction with p53 and Ki-67 nuclear overexpression suggested a faulty mitotic checkpoint/mitotic catastrophe in the progression of anaplastic giant cell thyroid carcinoma. PMID- 20925601 TI - Caesarean section wound infection. PMID- 20925602 TI - Hypnosis for hyperemesis gravidarum. AB - Hyperemesis gravidarum--severe and persistent nausea and vomiting during pregnancy--can lead to serious negative health consequences for both mother and fetus. Appropriate evidence-based treatment for this illness is paramount. Studies describing hypnosis in the treatment of hyperemesis gravidarum (HG) were reviewed. A literature search was carried out using Cochrane, PsycINFO, PsycARTICLES, and Web of Knowledge databases. A total of 45 studies were identified by the search. Six studies fulfilled the inclusion criteria. Studies were reviewed in terms of study design, methodological quality, intervention and outcomes. Methodology between the studies differed but all reported encouraging positive outcomes. However, the quality of current evidence, based on the studies reviewed in this study, is not sufficient to establish if hypnosis is an effective treatment for HG. To be able to accurately assess the efficacy of hypnosis for HG, it is recommended that well-designed studies, e.g. randomised control trials, be carried out. PMID- 20925600 TI - Serotonin receptor signaling and regulation via beta-arrestins. AB - Serotonin receptors are the product of 15 distinct genes, 14 of which are G protein-coupled receptors. These receptors are expressed in a wide range of cell types, including distinct neuronal populations, and promote diverse functional responses in multiple organ systems. These receptors are important for mediating the in vivo effects of their cognate neurotransmitter, serotonin, as well as the endogenous tryptamines. In addition, the actions of many drugs are mediated, either directly or indirectly, through serotonin receptors, including antidepressants, antipsychotics, anxiolytics, sleep aids, migraine therapies, gastrointestinal therapeutics and hallucinogenic drugs. It is becoming increasingly evident that serotonin receptors can engage in differential signaling that is determined by the chemical nature of the ligand and that ligands that demonstrate a predilection for inducing a particular signaling cascade are considered to have "functional selectivity". The elucidation of the cellular signaling pathways that mediate the physiological responses to serotonin and other agonists is an active area of investigation and will be an onward looking focal point for determining how to effectively and selectively promote beneficial serotonergic mimicry while avoiding unwanted clinical side effects. This review highlights the modulation of serotonin 2A, 2C, and four receptors by beta-arrestins, which may represent a fulcrum for biasing receptor responsiveness in vivo. PMID- 20925603 TI - Pulmonary dysfunction in acute antepartum pyelonephritis and other pregnancy infections. PMID- 20925604 TI - Lymphoepithelioma-like carcinoma of the cervix. PMID- 20925605 TI - Does saline irrigation reduce the wound infection in caesarean delivery? AB - The aim of this prospective randomised study was to estimate the effect of saline wound irrigation before wound closure in the prevention of infection following caesarean delivery. Participants with indications for elective or emergency caesarean section were randomly allocated to two groups. A total of 260 women who underwent wound irrigation before wound closure and 260 did not. No demographic differences were identified between the groups. There were also no significant differences between the groups in terms of factors known to influence wound infection. The incidence of wound infection was 7.3% for the control group and 6.5% for the saline group; however, the difference was not significant (relative risk: 0.88; 95% confidence interval: 0.45-1.74; p=0.86). In conclusion, saline wound irrigation before wound closure did not reduce the infection rate in patients undergoing caesarean delivery. PMID- 20925606 TI - Iatrogenic bladder injuries during caesarean delivery: a case control study. AB - This study determined the rate, risk factors, management and outcome of bladder injury during caesarean section and suggests ways to improve the quality of care and reduce maternal morbidity and mortality. During the study period, there were 76 bladder injuries in 56,799 caesarean deliveries for an overall incidence of 0.13%. Women with a bladder injury were more likely to have had a prior caesarean delivery, as compared with the control group (72.4% vs 34.2%; p < 0.001). Cases were also more likely than controls to have had prior pelvic surgery. The presence of adhesions during the procedure was greater in the bladder injury group than the controls. In conclusion, our study suggests that a previous caesarean delivery is the most common risk factor for bladder injury during caesarean delivery. Moreover, the presence of labour, station of the presenting fetal part deeper than or equal to +1, and a large baby were independent risks for a bladder injury during caesarean delivery. Women requesting primary caesarean deliveries should be counselled about the potential for significant surgical complications in repeat caesarean deliveries when discussing the indications for a primary elective caesarean delivery. PMID- 20925607 TI - Intrapartum cardiotocograph interpretation by midwives and trainee obstetricians using a modified definition of a fetal heart rate deceleration. AB - The aim of this study was to assess cardiotocograph (CTG) interpretation by midwives and trainee obstetricians using the standard and a modified definition of fetal heart rate deceleration compared with consultant interpretation as the Gold Standard. A randomised survey using the online tool at: www.surveymonkey.com between 4 January and 24 April 2009, was conducted at a tertiary obstetric unit, UK. A total of 104 (~54%) health professionals responded, providing 1,118 responses with respect to the presence of decelerations on 13 anonymised CTGs. Five obstetric consultants (62.5%) provided expert opinion. Midwives and trainee obstetricians were more likely to concur with Consultant opinion when using the modified definition of fetal heart rate deceleration compared with the standard definition. Larger scale studies may be needed to further evaluate the usefulness of the modified definition. PMID- 20925608 TI - Thyroid autoantibodies and associated complications during pregnancy. AB - This study was undertaken to determine the presence of thyroid autoantibodies and associated pregnancy complications from 49 pregnant women with thyroid disease. There were 31 (63%) women with Graves' disease (GD) and 18 (37%) with primary hypothyroidism (PHT). A total of 26 (53.1%) women, 19 (61%) with GD and seven (39%) with PHT, had positive antibodies. Six had thyroid peroxidase antibodies (TPO), one with thyroglobulin antibody (TG) and eight had TSH receptor antibodies (TR). Two had a mixture of antibodies involving TG/TPO (one GD vs one PHT), four with TG/TPO/TR (all had GD) and five with TPO/TR (four with GD vs one with PHT). There were associations in women with positive thyroid antibodies and pre eclampsia (15.4%), abruptio placenta (4%), caesarean deliveries (31%), postpartum thyroiditis (19.2%) and abnormal neonatal thyroid function (15.4%). Women with positive thyroid antibodies in pregnancy need close care during and after pregnancy, as they can develop complications affecting both mother and fetus. PMID- 20925609 TI - Overweight and obesity in pregnancy do not adversely affect neonatal outcomes: new evidence. AB - We studied neonatal outcomes of infants of obese mothers in a cohort of 6,125 deliveries, using logistic multivariate analysis to remove the role of potential confounding variables. Although, as in previous reports, the crude unadjusted prevalence of several adverse neonatal outcomes was higher in these infants, the multivariable analysis revealed that only two outcomes remained significantly associated with maternal overweight and obesity: neonatal macrosomia (adjusted odds ratios aOR 1.4, p < 0.001) and meconium aspiration syndrome (aOR 1.6, p = 0.05), indicating that the unadjusted association with the other outcomes was caused by confounding factors. Nonetheless, as macrosomia is associated with increased health risks both to the mothers and their infants, and maternal obesity with considerable maternal morbidity during pregnancy, these results should not lead to complacency, but instead encourage better prevention of obesity in general and during pregnancy in particular. PMID- 20925610 TI - Role of interventional radiology in the management of morbidly adherent placenta. AB - The incidence of morbidly adherent placenta is rising and is directly proportional to the rate of rise of caesarean deliveries. Despite improvement in antenatal diagnosis, by accuracy of ultrasound and MRI techniques, placenta accreta is still associated with a high maternal morbidity rate. Management of pregnancies with a morbidly adherent placenta is extremely challenging and is becoming an increasingly common problem for maternity units globally. The main challenges include controlling the haemorrhage and dissection of the invaded tissues. Traditionally, these cases were managed by caesarean hysterectomy. There has now been a shift towards conservative management of placenta accreta, involving uterine and placental conservation, with the aid of interventional radiology by means of insertion of occluding balloons into appropriate vessels. We describe three cases of morbidly adherent placentas, managed at our unit where meticulous preoperative planning, multidisciplinary approach and the key role of interventional radiology led to a safe outcome for both the mother and the baby. PMID- 20925611 TI - Postpartum hypocalcaemia in Maiduguri, North-eastern Nigeria: a 10-year review. AB - The aim of maternal calcium homeostasis is to provide adequate calcium flux across the placenta during pregnancy and into breast milk during lactation, to ensure normal fetal and neonatal skeletal mineralisation. The objective of this study was to document the characteristics and outcome of patients who had postpartum hypocalcaemia. Cases of symptomatic postpartum hypocalcaemia managed over a 10-year period (1 January 1998 to 31 December 2007) at the University of Maiduguri Teaching Hospital, were retrospectively reviewed. A total of 34 cases were identified. The sociodemographic characteristics, corrected calcium level, duration of treatment, mode of delivery and the packed cell volume (PCV) were analysed using the EPI-INFO Version 3.4.3 statistical package. The mean age and parity were 24.29 +/- 5.88 and 3.39 +/- 2.32, respectively. All the patients presented with carpopedal spasm with or without associated symptoms. There was a direct relationship (R2 linear = 0.292, p = 0.001) between PCV and serum calcium. Multiparous women were significantly more affected than primiparae (chi2 = 15.08; p = 0.0005). Half of the patients presented within 1 week of onset of symptoms. In conclusion, the association between anaemia and postpartum hypocalcaemia needs further study to determine the cause and effect relationship. PMID- 20925612 TI - Severe anaemia in pregnancy: a tertiary hospital experience from northern India. AB - Anaemia is a major health problem among woman of reproductive age group, particularly in developing countries. We undertook this study to determine the maternal and perinatal outcome in patients with severe anaemia in pregnancy, with a haemoglobin concentration of < 7 g/dl. The in-hospital data were analysed for 12 months between January 2007 and December 2007 and 2.15% (n = 96) of women were found to have severe anaemia. Out of these, 18.75% had pre-term premature rupture of membranes and 5.12% of all deliveries were pre-term. Hypertensive diseases of pregnancy were seen in 17.7%; abruption in 3.12% and 9.37% had congestive cardiac failure. Postpartum haemorrhage was seen in 25.5% of the patients and 8.33% had puerperal pyrexia. Fetal distress was seen in 26% of and 33.33% had small for gestational age neonates; there were 16.66% stillbirths and 4.16% neonatal deaths. Of the 96 severely anaemic women, six died after admission. Our study shows that efforts must be taken towards safe motherhood and spreading awareness about the various consequences of anaemia, which is usually preventable with early correction. PMID- 20925613 TI - Laparoscopic assisted vaginal hysterectomy and bilateral salpingo-oophorectomy as a day surgery procedure: a promising option. AB - Laparoscopic surgical techniques are increasingly being used to treat gynaecological malignancies as studies confirm long-term results similar to open procedures. Within the UK National Health Service, there is a drive towards day of surgery admission and reducing inpatient stay. We audited the length of inpatient stay, acceptability to patients of day of surgery admission and timing of discharge and accessibility to early community follow-up, among women undergoing laparoscopic assisted vaginal hysterectomy and bilateral salpingo oophorectomy in our unit over a 6-month period. We show that women find short inpatient stays acceptable and that many can be safely discharged, with no postoperative hospital follow-up, within 24 h. Adequate pre-admission procedures and easy access to advice, post-discharge must be ensured. PMID- 20925614 TI - Microbiology of cysts/abscesses of Bartholin's gland: review of empirical antibiotic therapy against microbial culture. AB - Bartholin's glands are prone to obstruction at their opening into the vestibule, forming cysts which could be infected to become gland abscess. In our unit, treatment of Bartholin's abscess is usually surgical. In addition to surgical treatment, antimicrobial agents are often administered before microbial culture results are known. In this study, we aimed to determine the most common pathogens in Bartholin's glands abscess in our local population so that empiric antimicrobial therapy, if required, could be correctly directed. Among the 78 cases reviewed, there was positive microbial culture in 73.9%. Bartholin's abscess was commonly caused by opportunistic organisms, either as single agents or polymicrobial infections. Aerobic organisms were the commonest with coliforms being the most common bacteria. No cases of N. gonorrhoea or C. trachomatis were encountered. Flucloxacillin as a single agent was the most frequently prescribed antibiotic. Poly-pharmacy was common practice. It was concluded that whether adjuvant antibiotic therapy is necessary following surgical treatment of Bartholin's abscess is still controversial. Where antibiotics are required, the optimal initial therapy is not known. As poly-microbial infections are common, a broad spectrum agent like co-amoxiclav may be suitable for empirical treatment until culture results are known. PMID- 20925615 TI - NHS abortion services: referral pathways and outcomes. AB - The aim of this study was to assess the effectiveness of the different referral pathways to accessing abortion services. It was a retrospective observational study comparing abortion referral processes in two district hospitals. The results showed that 149 patients self-accessed the NHS abortion service in group A compared with group B of 365 formally referred patients. Half of the patients in each group had an appointment within 5 days of referral and nearly all within 2 weeks. However, 74% of patients in group A had their termination request met within 7 days of the initial appointment, compared with only 37% in group B (p = 0.0011). A total of 70% of terminations performed in group A were undertaken at less than 10 weeks' gestation, compared with only 31% in group B (p < 0.0001). It was concluded that the open referral pathway to accessing NHS abortion services, where available, appears to be effective in allowing more abortions to be undertaken at an early gestation. PMID- 20925616 TI - Fertility characteristics and family planning methods used by women delivering at a University Hospital in Eastern Turkey. AB - The aim of this study was to assess the fertility characteristics and family planning methods in the city of Elazig, Turkey. This cross-sectional descriptive study included all the women who had delivered babies at the Elazig Firat Medical Center Obstetrics and Gynecology Clinic. Across the entire group, the mean number of pregnancies was found to be 2.98 +/- 1.89. Among the family planning methods used, the first choice of most women was the condom, which ranked first with 32.2%; the oral contraceptive ranked second with 15.1%. The question, 'Have you ever used any contraceptive methods?' was asked and 55.4% answered 'yes'. The most common method was condom use. The most common method of contraception used by married women for the first time was the condom, and the most common method used during marriage was, again, the condom. PMID- 20925617 TI - Laparoscopy--or not--for management of unexplained infertility. AB - This study aimed at evaluating the role of laparoscopy in the management of unexplained infertility in a prospective randomised controlled trial. The study comprised of 255 patients as a study group and 257 patients as a control group. All women had unexplained infertility. Patients in the study group had laparoscopy followed by ovarian stimulation and timed intercourse for six cycles, while patients in the control group were treated directly with ovarian stimulation and timed intercourse for six cycles. Severe adhesions were found in one in each of the two groups, respectively. They were referred directly to the IVF/ICSI programme. Moderate pelvic endometriosis was demonstrated in three cases in the two groups. Again, severe endometriosis was found in two cases in the study groups and they were referred to the IVF/ICSI programme. After 6 months of follow-up, clinical pregnancy occurred in 114/255 (44.7%) in the study group and 107/257 (41.7%) in the control group and the difference was not statistically significant (p > 0.05). The miscarriage rate was similar in the two groups. We concluded that laparoscopy could be postponed when proceeding in the management of unexplained infertility, until ovarian stimulation and timed intercourse had been found to be unsuccessful in achieving pregnancy. PMID- 20925618 TI - How useful are the BSUG database outcome criteria: validation using the MESA questionnaire. AB - Urinary stress incontinence is common, but there is a wide range of prevalence which might account for variations in definition of incontinence and variations in study methodology. Our study assessed the validity and reliability of the British Society of Urogynaecology's (BSUG) database subjective outcome scores after the tension-free vaginal tape (TVT), by correlating these with the changes in the Medical Epidemiologic and Social Aspects of Ageing (MESA) questionnaire score. A total of 100 women with urodynamic stress incontinence underwent TVT, completed a MESA questionnaire preoperatively and at 6 months postoperatively. We also collected information about three outcome measures of the BSUG database, patients' global impression of outcome and stress and urge symptom analyses. Our study showed that the postoperative patients' global impression of outcome improved significantly in 85% of cases and had 73.89% reduction in mean MESA scores (p < 0.001). The outcome measures of the BSUG database relates well to symptom improvement, based on MESA scores and these subjective assessments currently used by the BSUG's database are a valid assessment of TVT outcome. PMID- 20925619 TI - Risk factors for mesh erosion complicating vaginal reconstructive surgery. AB - Synthetic mesh erosion is a recognised complication for pelvic floor repair surgery which occurs in 1-10% of patients. Our study aimed to evaluate the different risk factors involved in synthetic mesh erosion complicating vaginal reconstructive surgery at a general district hospital. A retrospective audit of 133 vaginal mesh reconstructive operations at Hinchingbrooke Hospital, Cambridgeshire, UK, was carried out. A total of 14 (10.53%) cases of mesh erosion into the vagina were reported. An increased rate of mesh erosion was associated with concurrent vaginal hysterectomy and previous vaginal reconstructive surgery (p < 0.05, RR 3.222, 95% CI 1.071-9.698 and p < 0.05, RR 4.571, 95% CI 1.58 13.23, respectively). The use of Safil(r) suture material (polyglycolic acid) was associated with a higher incidence of Gynecare Gynemesh(r) erosion (p < 0.05, OR = 9, 95% CI 1.073-75.5). It is concluded that this audit has shown the importance of analysing outcomes with all changes of practice, including the change of suture provider. PMID- 20925620 TI - Cervical cancer in Indian rural women: trends over two decades. AB - Worldwide, cervical cancer is considered to be the second commonest cancer as far as mortality and incidence is concerned and India contributes to about 20-30% of the global burden. This paper is based on analysis of records of persons suffering from various cancers over 25 years. Cervical cancer constituted 14.4% of all cancers of men and women put together, 28.8% of the cancers in women and 73.3% of all gynaecological cancer. The cases studied were divided into five Blocks: Block A 1983-1987; Block B 1988-1992; Block C 1993-1997; Block D 1998 2002 and Block E 2003-2007. A 2.34 times increase in cancer cases from Block A to Block E was seen; in women, overall cancer increased by 3.21 times; gynaecological cancer by 3.08 times; cervical cancer 2.91 and ovarian cancer 7.1 times. Cervical cancer in outpatients increased from 0.55% among all gynaecological cases in 1983, to 3.5% in 2007. Cervical cancer comprised of 1.05% of the newly registered outpatients and 70.09% of gynaecological cancer cases. Inpatient gynaecological cancer increased from 2.81% in 1983 to 9.81% in 2007. Out of all cervical cancer in women, cervical cancer was 34.7% in Block A (1983 1987) and 28.6 % in Block E (2003-2007). Of the cervical cancer cases, 43.8% belonged to the age group 30-49 years and 37.6% at 50-64 years. Cervical cancer in women with less than three births increased from 13.1% in Block A to 33.1% in Block E. The proportion of illiterate women or those with primary education was seven times more compared with those with secondary education. Our study revealed that cervical cancer still continues to rank first. Also the overall number of cancer cases has been increasing. PMID- 20925621 TI - A rare case of rheumatic chorea probably unmasked by pregnancy. PMID- 20925622 TI - Posterior reversible encephalopathy syndrome in a woman with pre-eclampsia. PMID- 20925623 TI - Hip pain in pregnancy: an unusual case of venous thrombosis. PMID- 20925624 TI - Maternal and fetal outcome in pregnancy-associated pure red cell aplasia. PMID- 20925625 TI - Placenta percreta: conservative treatment--segmental uterine resection with placenta in one piece. PMID- 20925626 TI - An unusual case of vaginal leiomyosarcoma in pregnancy. PMID- 20925627 TI - Limb body wall defect: three different presentations with abdominal wall defects. PMID- 20925628 TI - Discordant late onset lower urinary tract obstruction in a dizygotic twin pregnancy treated with vesicoamniotic shunt. PMID- 20925629 TI - Direct colo-labial Crohn's abscess mimicking Bartholinitis. PMID- 20925630 TI - Heterotopic pregnancy: tubal ectopic pregnancy with a viable IVF intrauterine pregnancy. PMID- 20925631 TI - Bowel perforation resulting from mesh erosion: a rare complication following abdominal sacrocolpopexy. PMID- 20925632 TI - Asymptomatic ureteric calculi. PMID- 20925633 TI - Primary ovarian leiomyoma in a postmenopausal woman. PMID- 20925634 TI - Sclerosing stromal tumour of the ovary associated with Meigs' syndrome and elevated CA125. PMID- 20925635 TI - Unusual presentation of invasive hydatidiform mole metastasizing to the lung. PMID- 20925636 TI - Stage III squamous cell carcinoma of the vulva with groin nodes metastasis in a patient with epidermolysis bullosa. PMID- 20925639 TI - Re: Narchi H, Skinner A. 2009. Infants of diabetic mothers with abnormal fetal growth missed by standard growth charts. Journal of Obstetrics and Gynaecology 29:609–613. PMID- 20925642 TI - Pentoxifylline and local honey for radiation-induced burn following breast conservative surgery. AB - INTRODUCTION: Breast-conserving therapy is currently the standard of management of breast cancer cases. Radiotherapy is an integral part of it; however, it has several complications. Radiation induced burn is a common complication of radiotherapy that requires more effective lines of management rather than the classically used ones. We investigated whether the addition of pentoxifylline (PTX) alone or in combination with topical honey is effective in its management compared to the standard measures. METHODS AND MATERIALS: In this prospective study, patients were randomly allocated into three groups each of 50 cases. Group A received standard burn treatment (control group). Group B received additionally 400 mg PTX twice daily. Group C received the same treatment as Group B with adding topical purified honey ointment. Patients were assessed initially and subsequently after 4 and 12 weeks, for projected coetaneous surface area (PCSA) of burn, pain severity, limitation of movement and exudation. RESULTS: There was a striking regression of the mean PCSAs of lesions among groups B and C at 12 weeks, with reduction rates (86+/-61%) and (76+/-58%) respectively (p<0.0001***). The addition of honey was associated with marked pain relieving effect and rescue of proper motion. Finally, honey was associated with shorter duration of treatment as 74% of group C patients completely recovered after 12 weeks, compared to only 54% and 36% of groups B and A in order. CONCLUSION: Combination of PTX and honey is an ideal measure for treatment of radiation-induced burn following breast conservative surgery. PMID- 20925643 TI - Nanotechnology for delivery of drugs and biomedical applications. AB - Nanotechnology is a multidisciplinary scientific field that deals with the formulation, preparation, characterization and application of structures, devices and systems at nanometric scale. Area of concern is interdisciplinary, but with peculiarities, among others, medicine, pharmacy, biophysics, electronics, bioengineering, and molecular biology. Interest for modern nanotechnology lies in the creation and use of structures which have new properties because of their small size as well as the possibility of using these systems to control or manipulate biological structures at nanometric or atomic level. It will open the way to diagnosis and medical treatment to molecular level. This paper covers various fundamental and applied aspects of nanotechnology, in its chapters: introduction; nanoparticles (therapeutic polymers, polymeric nanoparticles, non polymeric nanoparticles, liposomes, nanodevices) nanopharmaceutical systems used in diagnosis and therapy, in tissue engineering; pharmacokinetics and toxicity of nanoparticulate systems. Nanoparticulate systems have the potential to constitute a new generation of drug delivery systems. By their nature, nanodevices can be used as innovative diagnostic tool for detecting and monitoring disease, also for its treatment and use in developing new drugs. PMID- 20925644 TI - Overuse of PPIs in patients at admission, during treatment, and at discharge in a tertiary Spanish hospital. AB - BACKGROUND: The first generic PPI was introduced in Spain in 2001, and since then their prescriptions have increased steadily by about 200%. AIM: To evaluate the frequency of use and the appropriateness of indications of PPIs in hospitalised patients, and possible factors predicting their use. We also evaluated relevant PPI-drug interactions and serious adverse drug reactions (SADRs). METHODS: This was a cross-sectional, prescription-indication drug-utilisation study in hospitalised patients with follow-up until discharge. Sampling was random and stratified by services, and was calculated to obtain an error in the precision of prescription of +/-4% with a 95% confidence interval with maximum variability (50%). RESULTS: 328 patients were included; 28.65% were prescribed a PPI at admission, 82.62% were prescribed a PPI during hospitalisation, and 54.75% at discharge, with inappropriate indications in 74.47%, 61.25% and 80.24% respectively. The OR of being discharged with PPIs was 3.01(95% CI:2.17-4.18, p=0.000). The inappropriate indication most frequently seen at admission and at discharge was antiplatelet therapy. During hospitalisation it was prophylaxis for stress ulcer in patients at low risk. PPI prescription at admission remained at discharge in 75.90% of cases, 73.02% without an acceptable indication. Being >64 years old, taking >4 drugs, co-medication (NSAIDs, antiaggregation and anticoagulation), certain hospital departments and length of stay >15 days predicted 83.7% of prescriptions at discharge. Four relevant PPI-drug interactions were found, and 2 resulted in SADRs, thus the incidence per 1, 000 patients was 2.66 (Poisson 95% CI:0.62-7.23). CONCLUSIONS: There was a very high frequency of overuse of PPIs in inpatients and outpatients. Hospitalisation did not represent an opportunity for better prescription of PPIs. PMID- 20925645 TI - Cannabis-derived substances in cancer therapy--an emerging anti-inflammatory role for the cannabinoids. AB - Cannabinoids, the active components of the cannabis plant, have some clinical merit both as an anti-emetic and appetite stimulant in cachexic patients. Recently, interest in developing cannabinoids as therapies has increased following reports that they possess anti-tumour properties. Research into cannabinoids as anti-cancer agents is in its infancy, and has mainly focussed on the pro-apoptotic effects of this class of agent. Impressive anti-cancer activities have been reported; actions that are mediated in large part by disruptions to ubiquitous signalling pathways such as ERK and PI3-K. However, recent developments have highlighted a putative role for cannabinoids as anti inflammatory agents. Chronic inflammation has been associated with neoplasia for sometime, and as a consequence, reducing inflammation as a way of impacting cancer presents a new role for these compounds. This article reviews the ever changing relationship between cannabinoids and cancer, and updates our understanding of this class of agent. Furthermore, the relationship between chronic inflammation and cancer, and how cannabinoids can impact this relationship will be described. PMID- 20925646 TI - Exploratory study on the effects of biodegradable nanoparticles with drugs on malignant B cells and on a human/mouse model of Burkitt lymphoma. AB - The aim of this study was to determine if Rituximab coated Biodegradable Nanoparticles (BNPs) loaded with Chlorambucil and Hydroxychloroquine could induce apoptosis of B-Chronic Lymphocytic Leukemia (B-CLL), MEC-1 and BJAB cells in vitro and evaluate their toxic and therapeutic effects on a Human/Mouse Model of Burkitt Lymphoma at an exploratory, proof of concept scale. We found that Rituximab-Chlorambucil-Hydroxychloroquine BNPs induce a decrease in cell viability of malignant B cells in a dose-dependent manner. The mediated cytotoxicity resulted from apoptosis, and was confirmed by monitoring the B-CLL cells after Annexin V/propidium iodide staining. Additional data revealed that these BNPs were non toxic for healthy animals, and had prolonged survival in this mice model of human lymphoma. PMID- 20925647 TI - Clinical pharmacokinetics of ibuprofen arginine. AB - Currently, several ibuprofen compounds are available on the market, mainly differing in terms of pharmaceutical composition that influence the pharmacokinetic profile and eventually the onset of drug action. This review will mainly deal with the clinical pharmacokinetics of ibuprofen arginine, an alternative formulation specifically designed to improve the absorption of ibuprofen. Indeed, available data from studies in healthy volunteers have consistently shown that the formulation of ibuprofen arginine is characterized by prompt absorption of ibuprofen as compared to the conventional formulation at all tested doses with higher peak plasma concentration and lower Tmax values. This trend has been confirmed also in studies dealing with chiral ibuprofen pharmacokinetics. Most importantly, the shortening in the absorption time observed either with racemic mixture or with the S(+)-enantiomer of ibuprofen arginine did not imply a faster drug elimination eventually leading to inadequate daily drug exposure, as documented by T1/2 and AUC values being comparable to those measured with the free acid form. Taken together, the pharmacokinetic/dynamic characteristics of ibuprofen arginine can be considered particularly favorable for several clinical conditions, such as moderate/severe pain, in which a rapid pharmacologic effect is required. PMID- 20925648 TI - Reductions in medications with substantial weight loss with behavioral intervention. AB - Medical costs of obesity in the United States exceed $147 billion annually with medication costs making a sizable contribution. We examined medication costs associated with substantial weight losses in an intensive behavioral weight loss program. Inclusion criteria were medication use for obesity co-morbidities: hypertension, diabetes, dyslipidemia, degenerative joint disease, or gastroesophageal reflux disease. Group A, 83 obese patients on medications completed 8 weeks of classes, lost 19 kg in 20 weeks. Group B, 100 severely obese patients, lost 59 kg in 45 weeks. Medications were discontinued: Group A, 18%; Group B, 64%. Mean numbers of medications decreased significantly for all co morbidities. Mean numbers of daily medications, initial and final, respectively were: Group A, total, 3.0 +/- 0.2 (mean +/- SEM) and 1.7 +/- 0.2; Group B, total, 2.5 +/- 0.2 and 0.7 +/- 0.1. Monthly costs for all medications decreased significantly for all co-morbidities and were as follows: Group A, total, $249 +/ 25 and $153 +/- 19; Group B: total, $237 +/- 27 and $65 +/- 12. Medically supervised weight loss is very effective approach for improving cardiovascular risk factors and reducing medical costs. PMID- 20925649 TI - Immunogenicity of biotherapeutics: a need for consensus on flexibility of approach. PMID- 20925650 TI - Towards responsible, safe self-medication. PMID- 20925651 TI - Fibrosis in the anterior segments of the eye. AB - The anterior segment of the eye ball, i. e., cornea and conjunctiva, serves as the barrier to the external stimuli. Cornea is transparent and is a "window"of the light sense, while conjunctiva covers the sclera, the main part of the eyeshell. Fibrosis/scarring in cornea potentially impairs vision by the reduction of its transparency and the alteration of the regular curvature. Fibrotic reaction in conjunctiva is also of a clinical importance because inflammatory fibrosis in this tissue affects the physiology of the cornea and also of a problem post-eye surgery. In this review we discuss on the topic that is quite critical in vision. Although various growth factors are considered to be involved in, focus was put on the roles of transforming growth factorbeta (TGFbeta). PMID- 20925652 TI - Integrins modulate cellular fibrogenesis at multiple levels; Regulation of TGF beta signaling. AB - Fibrosis could occur in virtually any organ or tissue. The fibrotic lesion indolently disrupts the structure of the healthy organ, thereby hampering its proper function, consequence of which is devastating. Among the myriad factors that modulate fibrogenesis, transforming growth factor beta (TGF-beta) is one of the most studied and its central role for fibrotic disorders has been strongly suggested. Due to the pleiotropic nature of this cytokine, TGF-beta modulates multiple cellular responses throughout fibrogenesis. The complexity is supported by the TGF-beta receptor-specific phosphorylation of both the canonical, Smad-, and non-canonical, "non-Smad," pathways. The latter modulates Smad activity either independent of Smad or by phosphorylating the Smad linker region, distinct from those receptor-regulated. Despite the commodity of this mediator, the mechanism by which TGF-beta signaling causes specific pathogenesis and disease varies depending on the nature of the organ and the cells that compose that organ. Cells express a specific series of integrins that act as cellular sensors for the extracellular environment, determining subsequent cellular signals in a cell-type specific manner. Integrins may change their expression pattern under pathological conditions and contribute to the regulation of fibrogenesis via modulating ambient TGF-beta activity. This regulation includes release of active TGF-beta from its latent form and modulation of various signals downstream of integrin-engagement, which participate in the non-canonical regulation of TGF beta signaling. TGF-beta also induces expression of integrins, as well as their ligand extracellular matrix, generating an amplification loop. Furthermore, myriads of intracellular signaling molecules that associate with integrin engagement could non-canonically modulate TGF-beta signals. The entire picture of this mutual regulation between integrin and the TGF-beta pathways might be difficult to draw. Instead, this review intends to depict several critical aspects of this regulation, with examples from various types of fibrosis in different tissues to help understanding the integrin-modulation of fibrogenesis, a critical clue for therapeutic approaches to fibrosis. PMID- 20925653 TI - Phosphorylation-dependent association of the G4-1/G5PR regulatory subunit with IKKbeta negatively modulates NF-kappaB activation through recruitment of protein phosphatase 5. AB - The transcription factor NF-kappaB (nuclear factor kappaB) co-ordinates various gene expressions in response to diverse signals and is a critical regulator of inflammation and innate immunity. Several negative regulators of NF-kappaB have been identified as downstream targets of NF-kappaB and function as a feedback control of NF-kappaB activation. A few protein phosphatases have also been shown to inactivate NF-kappaB activation. However, little is known about how protein phosphatases detect and respond to NF-kappaB activation. In the present study, we report a regulatory subunit of PP5 (protein phosphatase 5), G4-1, that physically interacts with IKKbeta [IkappaB (inhibitor of NF-kappaB) kinase beta] and negatively regulates NF-kappaB activation. The association of G4-1 with IKKbeta depends on the kinase activity of IKKbeta. Mapping of the G4-1-binding domain of IKKbeta reveals that the serine-rich domain in the C-terminus of IKKbeta is required for G4-1 binding. When seven autophosphorylated serine residues in this domain were mutated to alanine, the mutant form of IKKbeta lost its ability to bind G4-1 and was more potent than the wild-type kinase to activate NF-kappaB. Knockdown of G4-1 enhanced TNFalpha (tumour necrosis factor alpha)-induced NF kappaB activity, and knockdown of PP5 totally abolished the inhibitory activity of G4-1 on NF-kappaB activation. The results of the present study suggest that G4 1 functions as an adaptor to recruit PP5 to the phosphorylated C-terminus of activated IKKbeta and to down-regulate the activation of IKKbeta. PMID- 20925654 TI - Ephrin-B3 binds to a sulfated cell-surface receptor. AB - The ephrins are a family of proteins known to bind the Eph (erythropoietin producing hepatocellular) receptor tyrosine kinase family. In the present paper, we provide data showing that ephrin-B3 binds a sulfated cell-surface protein on HEK-293T (human embryonic kidney-293 cells expressing the large T-antigen of simian virus 40) and HeLa cells, a binding that is nearly completely blocked by treatment of these cell lines with chlorate or heparinase, or by addition of the heavily sulfated glycosaminoglycan heparin. This indicates that heparan sulfate on these cells is essential for cell-surface binding of ephrin-B3. Heparin did not affect ephrin-B3 binding to EphB receptors expressed on transfected HEK-293T cells, indicating further that ephrin-B3 binds an alternative receptor which is a heparan sulfate proteoglycan. Site-directed mutagenesis analysis revealed that Arg178 and Lys179 are important for heparin binding of ephrin-B3 and also for ephrin-B3 binding to cells. These amino acids, when introduced in the non-heparin binding ephrin-B1, conferred the heparin-binding property. Functional studies reveal that ephrin-B3 binding to cells induces cellular signalling and influences cell rounding and cell spreading. In conclusion, our data provide evidence for an unknown ephrin-B3-binding cell-surface proteoglycan involved in cellular signalling. PMID- 20925655 TI - A hierarchical classification of polysaccharide lyases for glycogenomics. AB - Carbohydrate-active enzymes face huge substrate diversity in a highly selective manner using only a limited number of available folds. They are therefore subjected to multiple divergent and convergent evolutionary events. This and their frequent modularity render their functional annotation in genomes difficult in a number of cases. In the present paper, a classification of polysaccharide lyases (the enzymes that cleave polysaccharides using an elimination instead of a hydrolytic mechanism) is shown thoroughly for the first time. Based on the analysis of a large panel of experimentally characterized polysaccharide lyases, we examined the correlation of various enzyme properties with the three levels of the classification: fold, family and subfamily. The resulting hierarchical classification, which should help annotate relevant genes in genomic efforts, is available and constantly updated at the Carbohydrate-Active Enzymes Database (http://www.cazy.org). PMID- 20925656 TI - Annual Research Review: All mothers are not created equal: neural and psychobiological perspectives on mothering and the importance of individual differences. AB - Quality of mothering relies on the integrity of multiple physiological and behavioral systems and on two maternal factors, one proximal and one distal, that have a great impact on how a mother mothers: postpartum depression and early experiences. To mother appropriately requires the action of systems that regulate sensation, perception, affect, reward, executive function, motor output and learning. When a mother is at risk to engage in less than optimal mothering, such as when she is depressed or has experienced adversity in childhood, the function of many or all of maternal and related systems may be affected. In this paper, we will review what is currently known about the biological basis of mothering, with attention to literature on hormones but with a particular focus on recent advances in the fields of functional neuroimaging. Instead of discussing strictly 'maternal' brain imaging studies, we instead use a systems approach to survey important findings relevant to brain systems integral to and/or strongly related to the mothering experience: (a) social behavior; (b) reward and affect; (c) executive function; and (d) maternal behavior. We find that there are many commonalities in terms of the brain regions identified across these systems and, as we would expect, all are sensitive to the influence of, or function differently in the context of, depression and adverse early experience. It is likely that the similarity and cross-talk between maternal, affect and stress systems, observed behaviorally, hormonally and in the context of brain function, allows for mood disturbance and early adverse experiences to have a significant impact on the quality of mothering and the motivation to mother. PMID- 20925657 TI - Succinyl CoA Synthetase of Tobacco. AB - The isouition and partial purification of succinyl CoA synthetase from Nicotiana tabacum is described. Enzynio activity had a pH optimum of pH 7.0 and apparent Km values for succinic acid. ATF and MgCl(2) . are 3.5 * 10(-2) 5.7 * 10(-3) and 4.0 * 10(-3) M, respectively. The euzyme is specific in requirement for ATP. Enzyme activity was low in seed, decreased during germination and seedling development, then increased to maximum in physiologically mature leaf tissue. Plauts with the apical apical meristem removed had less euzyme activity in leaves but more enzyme activity in the roots than plants with apical meristem intact. Most enzyme activity observed was associated with the soluble fractions of the cell. PMID- 20925658 TI - Effects of flooding the root system of sunflower plants on the cytokin in content in the xylem sap. AB - The severe chlorosis observed in the lower most of flooded sunflower plants (Helianthus annuus L. cv. Tall Single) may lie initiated by a reduction in the import of cytokinins by the stoot from the flooded root system. Experiment indicates that during 12 hours following the release of flooding, plants previously flooded for 72 hours or less recover their ability to exude sap when the root systems are aerated, and the root systems synthesize and export amino acids to the shoot. Plants flooded for longer periods lose these abilities. The metabolic activity of the root apices declines parallel with the decline in eytnkinin concentration in the sap with increase in flooding time up to 72 hours. Flooding for 96 hours drastically reduce all four parameters of root activity. After flooding for this period there was a large increase in the number of blackened and tetrazolium-negative root apices which were in all probability dead. The correlation between the metabolic activity of the root apices and the total cytokinin content of the sap supports tbe view that root apices may be sites of cytokinin synthesis. PMID- 20925659 TI - Effect of Auxins and Light on Rooting Stem Cuttings of Populus nigra Salix tetrasperma, Ipomea fistulosa and Hibiscus notodus in Relation to Polarity. AB - The apical and basal ends of stem cuttings of Populus nigra, Salix tetrasperma, Ipomoea fistulosa and Hibiscus notodus were treated with 10 mg/l solutions of IAA and IBA for 24 hours and were planted either erect or inverted both in light and dark. Observations for the number of cuttings that rooted and the roots produced on them were recorded at weekly intervals. In Salix, Ipomoea and Hibiscus rooting was more on cuttings planted erect, while in populus it did not differ much with the manner of planting. The reduced rooting in inverted cuttings may be ascribed to the low level of endogenous auxin at the apex due to polar transport. An exogenous application of auxins enhanced rooting on inverted cuttings. In dark, roots on Populus and Salix cuttings were produced both above and within the rooting medium. The weak polarity of these two plants may be due to the potential root primordia reported in their stem. The formation of callus occurred on the top of Populus cuttings whether planted erect or inverted but it differentiated into branches on erect cuttings only. In those planted in an inverted position the callus failed to differentiate in spite of the application of kinetin, auxins, TIBA, coumarin and sucrose, and dried ultimately. PMID- 20925660 TI - The Effect of Deleterious Concentrations of Copper on the Photosynthesis of Chlorella pyrenoidosa. AB - If a single salt solution of CuSO(4) is used, Cu penetrates immediately iuto the plasma of Chlorella cells, reducing the rates of photosynthesis at both high and low illumination. If CuSO(4) is added to ordinary Osterlind culture-medium (pH 8) it takes some hours before any influence of deleterious concentrations of Cu is observed and initially only at light saturation. The algae must have been illuminated during the whole period. Maximum influence of CuSO(4) is found duriug the first 24 hours of treatment. A significant deleterious influence of Cu concentrations as low as about 1 MUg/l is found. The influence of Cu increases with decreasing concentrations of the alga. If a culture medium at pH 5 is used instead of the ordinary one at pH 8, copper concentrations ahout 10 times as high must he used be order to obtain the same deleterious effect. An increase of the cotncentration of K reduces the influence of Cu to some extent. These facts show that the effect of deleterious concentrations of Cu in halanced solutions is not due to a marked penelration of this ion into the plasma but to a binding to the cytoplasmic membrane whereby the celts i.a. become more or less unable to divide. The cells become saturated with assimilation products which have a depressant effect on the rate of photosynthesis. Other cations compete with Cu for the "active sites" on the membranes. PMID- 20925661 TI - Growth and Endogenous Gibberellin Content of Dormant Groundnut Embryonic-axes as Influenced by Leaching and GA(3). AB - Leacthing the excised embryonic-axes from dormant groundunt (Arachis hypogaea) seeds resulted in their growth. However, their growth was stunted compared to that of after-ripened ones. It is attributed to (1) the lower amount of gibberellin-like substances in the dry, dormant embryonic-axes than in the after ripened ones, and (2) the inability of the former to sythesise tbe tibberetllin as indicated by the lower content compared to the after-ripened ones kept in water. Exogenousty supplied GA(3) (0.1 mg/1) increased both the endogenous gibberellin and growth of the dormant, leached embryonic-axes to the level of after-ripened ones. PMID- 20925662 TI - Influence of the Maize Dwarf Mosaic Virns and Simazine upon the Buffer Soluble Proteins and Catalase Activity of a Virus-susceptible and a Virus-tolerant Variety of Zea mays. AB - Inbred corn varieties differing in their tolerance to the maize dwarf mosaic virus infection also differ in varietal character and host response to simazine. Oh 7B, a tolerant cv., has less total soluble and globulin proteins than the sensitive variety, H 55, but more Kjeldahl nitrogen, albumin protein and a doubling of catalase activity. Virus inoculation in Oh 7B causes a reduction in all three protein fractions, Kjeldahl nitrogen and catalase activity. Deleterious virus-simazine interaction does not occur with either variety and the observed varietal and host response differences in protein may account for the conflicting reports of other workers. PMID- 20925663 TI - Stomata constellation in the leaves of cotton, maize and wheat plants as a function of soil moisture and environment. AB - In two locations, one subtropical and the other semidesert, the following three agricultural plant species were studied: cotton, maize and wheat. In each zone species were examined in irrigated and nonirrigated experimental plols for four leaf parameters: density of stomata and epidermis cells and length of stomala and leaf area. The following conclusions follow from the results: 1) The water deficit in the soil accompanied by extreme climatic conditions (August-September) led to a significant increment in the density of stomata and epidermis cells; in some of the varieties a decrease in length of stomata was observed. The decrease in leaf area in the nonirrigated plant was accompanied by an increase in ash content. Identical xeromorphic changes were stated in selected leaves the area of which was equal to those of the irrigated plants. In spite of the maximal number of stomata per unit area on both sides of Ihe blade a full turgor was maintained in the cells of the nonirrigated plants during the hottest and driest months and they survived until rains started (Novemher), although no significant changes were then noted in soil moisture within the sphere of the root dispersion. PMID- 20925664 TI - Microbiology of saturated salt solutions and other harsh environments: v. Relation of inosine-5'-phosphate and carbohydrate to growth of wildtype and mutant penicillium in boric Acid and potassium chloride selective media. AB - The study of chemical stress tolerance in a Penicillium mutant was continued using KCl- and H(3) BO(3) -saturated glucose peptone broth as a basic growth medium. Growth was completely restricted to the mutant. Variations were the presence or absence of inosine-5'-phosphate (inosinic acid, IMP) and choice of carhohydrate which was substituted for glucose. All six monosaccharides used three hexoses, three pentoses - were essentially equivalent hence data are presented only for D-glucose and D-xylose. The other carbohydrates, sucrose, lactose, maltose and starch differed in their suitability as carbon sources. In the presence of the nionosaccharides the mutant can grow both in KCl and H(3) BO(3) media, but growth rates are greatly enhanced by IMP. Boric acid blocked sporulation under all conditions. KCl permitted spores of abnormal color to form without IMP, whereas spores of normal green color appeared in its presence. Media containing H(3) BO(3) and disaccharides or starch supported no growth, but addition of IMP stimulated growth without sporulation. In KCl media sucrose alone among the disaccharides and starch permit limited growth without IMP, but the nucleotide is required for sporogenesis. These results show that the role of nucleotides, especially IMP, is not limited to recovery from exposure to extreme salt effects, but also applies to growth in the continuing presence of quite different chemical stress conditions. PMID- 20925665 TI - Nutrition of Cosmarium turpinii. AB - A defined medium for Cosmarium turpinii Breb. was established. The optimal concentrations of major elements (Ca, N, P, S, and Mg) were detemiined, with the calcium level found to be most demanding. Iron, boron, and manganese were found to be essential micronutrient elements. Vitamin B(12) is also required, eitber as the planar group of cyanocobalamin alone or with adenine or benziniizole derivatives. Survival of cells during plateau pbase of growth can be extended by tbe addition of eitber 10(-3) M urea, isoleucine, or glycine. PMID- 20925666 TI - The effect of light on nitrate and nitrite assimilation by chlorella and ankistrodesmus. AB - Light stimulates the assimilation of nitrate and nitrite by two green algae, Chlorella pyrenoidosa and Ankistrodesmus braunii. Assimilation can be observed when the algae are illuminated in the absence of carbon dioxide under both aerobic and anaerobic conditions. The rates of assimilation by Chlorella do not depend on the presence of carbon dioxide, but Ankistrodesmus assimilates nitrate and nitrite more rapidly when cultures are illuminated in the presence of carbon dioxide than in its absence. The ratios of O(2) : NO(3') and O(2) : NO(2') vary from one experiment to the other and, with the exception of Chlorella cultures reducing nitrite they are higher than the 'expected' values of 2.0 and 1.5 respectively. Oxygen evolution accompanying nitrate and nitrite by algae illuminated in the absence of carbon dioxide is completely inhibited by DCMU at concentrations of 4 * 10(-6) M. However, nitrite assimilation by both Ankistrodesmus and Chlorella and nitrate assimilation by Ankistrodesmus are less sensitive to the inhibitor. PMID- 20925667 TI - Inhibition of Nitrogen-Fixing and Nitrifying Bacteria by Seed Plants: VI. Inhibitors from Euphorbia supina. AB - Euphorbia suinna occurs in the pioneer weed stage of succession in abandoned fields in several midwestern states of the United States. It was previously found to be very inhibitory to several test strains of nitrogen-fixing and nitrifying bacteria and to several associated seed plants. The present project was concerned wilh the identification of the chief inhibitors produced by that species, using appropriate column and paper chromatographic techniques, and by tests of bacterial inhibition employing the diffusion technique on solid media. Three hydrolyzable tannins were consistently isolated from extracts of the species. All three tannins and purified reagent tannic acid from at least two commercial sources yielded ellagic acid, gallic acid, and glucose on hydrolj'sis by acid or tannase. All yielded one or more additional phenolics which were not identified. The tannins from E. supina were all slightly different from each other and from commercial reagent tannic acid as indicated by different Rf's on paper, elution sequence from polyamide columns, and relative amounts of glucose, ellagic acid and gallic acid produced on hydrolysis. PMID- 20925668 TI - Some aspects of respiration and respiration inhibitors in low temperature effects of the cotton plant. AB - Respiration of leaf tissue from cotlon plants in the nine leaf stage was found to be severely reduced at temperatures below 15 degrees C. In another study, young cotton plants were exposed to chilling temperature (2.8 degrees C) for 72 hours and the ability of the plant tissues to recover respiration at normal temperatures (15 and 25 degrees C) was examined at periodic intervals. Chilling exposures of 12 hours injured cotton tissues as indicated by increased respiratiou of leaves and roots at 25 degrees C. Further chilling malerially reduced the capacity of the leaves to re-estahlish normal respiration rales at higher temperatures. Picolinic acid, Dexon and matonate were used to study the influence of respiratory inhibitors on the chill damage of the collon plants. The chemicals were applied six hours before cold exposure aud fhe growth and development of cold injured plants was studied to indicate the effectiveness of the treatments. Tissue weights at the final harvests indicated that picolinic acid and Dexon treated plants recovered better after cold injury than the untreated plauts. The results suggest thai 15 degrees C may be a critical temperaliire for many physiological processes of the cotton plant because the supply of energy needed for plant reactionsis restricted due to inadequate respiration. They also indicate that the disturhances in respiration are among the early effects of chilling colton plants and may be the cause of delayed growth and development of cotton plants subjccled to non-lethal chilling exposures. It is concluded that chemicals like picolinie acid and Dexon may he effective through protection of specific systems rather than a general reduction of respiration. PMID- 20925669 TI - Effets de l'acide gibberellique et de la kinetine sur le developpement de l'activitealpha-amylasique durant la croissance de l'Orge. AB - Effects of gibberellic acid and kinetic on alpha-amylase production during the germination of barley. - The action of gibberellic acid and kinetin, alone or combined at different concentrations, has been studied on alpha-amylase production in whole barley seedlings and in embryoless endosperms in course of the six first days of development in the dark. The classic activation of alpha amylase synthesis by gibberellic acid has been confirmed both in whole seeds and in embryoless endosperms. Kinetin inhibits alpha-amylase synthesis after the third day of germination but has no effect on isolated endosperms. When gibberellic acid and kinetin are given simultaneously gibberellic acid stimulated during the three first days just as it does alone, kinetin inhibits after the third day also as it was alone so that the two regulators act, without interactions, at different stages in the time. These effects of kinetin are be independent. A critical examination of the techniques used in the literature in the stud of amylase is made. PMID- 20925670 TI - Variations de quelques aclivites enzymatiques (peroxydase, catalase, AIA-oxydase) et de la teneur en polyphenols au cours de la germination de I'Orge. Influence de la kinetine. AB - Peroxidase catalase, IAA-oxidase and polyphenol content of growing barley coleoptile. Effect of kinetin. - Kinetin strongly inhibits root and coleoptile growth of germinating barley in the dark. Treated coleoptiles become senescent before the untreated ones. Soluble proteins content, peroxidase, catalase and IAA oxidase activity were greatly increased in treated coleoptiles while the level of polyphenols was reduced. These biochemical effects joined with the other property of kinetin to diminish alpha-amylase synthesis in the endosperm are discussed in relation to growth and in connection with the classic view of a cytokinin retarded senescence. PMID- 20925671 TI - An Interaction between the Effects of Kinetin and Gibberellin in Retarding Leaf Senescence. AB - The relation hetween the effects of kinetin and gibberellin on retardation of leaf senescence was studied. Leaf discs were incubated for five days in several hormone concentrations, the chlorophyll was extracted and its amount estimated spectrophotometrically. Investigation of leaves from actively growing plants of Taraxacum megalorrhizon and Tropaeolum majus showed that an interaction existed between the effect of both hormones. Leaf age, light intensity and day length had a marked effect on the degree of response to the hormonal treatments, hut the change in response effected by these conditions remained similar for both hormones. Possible interpretations of the interaction observed between the effects of kinetin and gibberellin are discussed. PMID- 20925672 TI - Pathways of IAA Production from Tryptophan by Plants and by Tbeir Epipbytic Bacteria: a Comparison: I. IAA Formation by Sterile Pea Sections in vivo as Inftuenced by IAA Oxidase Inbibitors and by Transaminase Coenzyme. AB - Under nonsterile conditions, IAA can be extracted from pea stem sections infiltrated with buffer, IAA, or tryptophan. This IAA has microbial origin, since its occurrence is prevented by antibiotics. All infiltrated IAA disappears in the sections. Under sterile conditions, several inhibitors of IAA oxidase prevent the complete disappearance of infiltrated IAA. Some of them permit, by preventing the disappearance of produced IAA, the formation in vivo of extractable IAA amounts from tryptophan. This IAA production is further increased by pyridoxal (phospbate), and by alpha-ketoglutarate. PMID- 20925673 TI - Phase-shift in Geotropical Oscillations - A Theoretical and Experimental Study. AB - Geotropically induced phase-shifts in circumnutations of Heliauthus annuus hypocotyls are studied. - Theoretical deductions from a previously developed theory for geotropical movements are made for the case of a short gravitational stimulation in different phase positions of an oscillating hypocotyl. - Experimental studies are performed to test the theoretical results. - The conclusions are drawn, that the theory mentioned can satisfactorily describe geotropically induced phase-shifts. A comparison with phase-shifts in photoperiodic systems is made. PMID- 20925674 TI - An investigation of bidirectional translocation in the Phloem. AB - Patterns of (14) CO(2) , assimilate movement in Vicia jaba plants having 7 nodes were studied. Bidirectional translocation occurred throughout most of the stem length when tracer was applied to leaves of various ages. To determine whether this bidirectional translocation occurs within single sieve tubes, a O.1 % solution of the fluorescent dye K-fluorescein was applied to a lightly scraped area on the stem in the middle of a young internode. After one hour the dye was present short distances above and below the treated area. Free-hand sections of the internode showed the dye to be localized in the traces of the larger leaves below tbe treated area and in the traces of the younger leaves above the treated area. The dye was never present in the same bundle both above and below the treated area, indicating that each bundle and sieve tube translocated the dye in only one direction. These results were confirmed using Phaseolus vulgaris, Vinca rosea, and Pelargonium hortum. A similar study in which petioles of young Ecballium elaterium leaves were treated showed that usually the phloem of one bundle translocated the dye in only one direction but in some cases the external phloem of the bicollateral bundles carried the dye toward the stem while the internal phloem carried the dye toward the blade. When longer time intervals were used in all these experiments, the dye sometimes appeared in the same phloem areas both above and below the treated area. This is explained by a lateral transfer of tracer within the phloem, either through secondary phloem or through bundle anastomoses at the nodes. PMID- 20925675 TI - Elimination of Geotropic Responsiveness in Roots of Cress (Lepidium sativum) by Removal of Statolith Starch. AB - Roots of garden cress (Lepidium sativum L.) seedlings were made starch-free by treatment with gibberellic acid and kinetic for 29 hours at 35 degrees C in the dark. After 3 hours of temperature adaptation at 21 degrees C the starch-depleted roots were unable to respond to gravity, but elongated 0.48 mm por hour. Under the same conditions control roots pretreated in plain water at 21 and at 35 degrees C elongated 0.64 and 0.33 mm per hour, respcetively (at 21 degrees C). When the hormone-treated seedlings were illuminated, their roots reformed starch after 20 to 24 hours; simultaneously the geotropic responsiveness was restored. The results are interpreted in support of the statolith theory. PMID- 20925676 TI - Free amino Acid pools and enzymes in teratonia and habituated tobaceo tissue cultures. AB - The free amino acid content of habituated (normal) and teratoma (abnormal) tobacco tissue cultured on white's medium were compared. Significant qualitative differences (twofold or more) were observed for serine, proline, alanine, leucine, phenylalanine, and lysine. There were qualitative differences in several unidentified ninhydrin sensitive compounds. One unknown which co-chromatographed with homo-serine was present in high concentrations (9.96 MUmol/g dry weight) in habituated but was lacking in teratoma tissue, Isoenzymes of an esterase, acid phosphatase, and oxidase were demonstrated in both tissues. The distinct differences in the isoenzyme pattern of acid phosphatase suggests a differential regulatory capacity of certain phosphomonoester intermediates and P(1) . The invertase activity was higher in habituated tissue, implying a greater capacity to utilize the sole carbon source, socrose. PMID- 20925677 TI - Stimulating Effect of Pentoses on the Utilization of Galactose in Ophiostoma multiannulatum. AB - The influence of some pentoses on the ability of the fungus Ophiostoma multiannulatum to grow on d-galactose was investigated. There is no measurable growth of the wild type Ophiostoma when galactose is the sole carhon source, d xylose has a stimulating effect on the utilization of galactose in this fungus. Even when d-xylose is added in low concentrations as compared to the concentration of galactose in the mixtures the growth-promoting effect is high. The xylose can be added in amounts which are directly growth-limiting. The addition of l-arabinose also results in growth on gatactose if the concentration ratio arabinose: galactose is selected high enough. The results are discussed and compared to previously published data on stimulating effects from other hexoses on the utitization of galactose in this fungus. PMID- 20925678 TI - Callus cultures of tomato mutants: I. Nutritional requirements. AB - Callus from hypocotyl, stem, and fruit tissue of tomato mutants was grown on a complex pea extract medium. The genotypes responded differently to the levels of nutrients and stimulators or inhibitors in the medium. Hypocotyl callus of yellow (r) tomato required K(2) SO(4) for quick establishment and continued steady growth for several months; callus of this mutant could also grow with 0.5 % dimethyl sulfoxide in the medium, although growth was less than the control. The red ghost (r(+) gh) mutant is sensitive to a toxic component in the pea extract, and makes its best growth with the standard minerals and vitamins, but in 1/2 concentration pea extract plus 5 % coconut water. Tangerine (t), red lutescent stem (r(+) l(2) ), and r(+) gh are mutants which respond differently to thiourea: t grows about the same at all concentrations, r(+) gh grows best at low thiourea, and r(+) l(2) grows best at the specific level of 20 mg/l thiourea. The recent active t or r(+) l(1) and r(+) l(2) isolates require supplementary auxin to which the older, slow-growing isolates do not respond. However, there is variation in growth response of different isolates of the same mutant. The several red (r(+) ) cultures are similar in their slow growth, but somewhat different in responses to specific nutrients. The recent (+) isolate is one of the most active cultures, in comparison to the slow growth of t callus isolated in 1964. It is therefore concluded that growth is affected both by the specific requirements of the mutant and by the age and vigor of isolates. PMID- 20925679 TI - Growth Regulators in Populus tremula I. Distribution of Auxin and Growth Inhibitors. AB - The content of acid ether-soluble auxins and inhibitors in vegetative tissues of aspen (Populus tremula L.) was determined with the Avena coleoptile straightgrowth assay. A growth promotor, tentativety identified as indol-3-yl acetic acid, occurred in highest concentration in the growing stem parts. It was also detected in various parts of the roots. Large amounts of inhibitors (inhihitor beta) were found in growing stem tissue and in upper mature stem parts. Considerably lower content of inhibitors was found in leaves, in the basal stem part and in the roots. Nonwoody growing roots and the wood of older root segments, especially, contained very smalt quantities of inhibitors. The elution volume of a part of the inhibitory activity on a Sephadex column was similar to that of abscisic acid. PMID- 20925680 TI - "Adaptation" and chromosome variability in excised roots of cereals. AB - Heteroploidy, often coinciding with phenotypic or metabolic changes, was found in cereal root cultures. In some cases the changes were apparent after only 4 passages and affected the roots of bread wheat as well as those containing all or some of the wheat and rye genomes. It is unsafe to assume that cultured organised tissues are cytologically stable. The cause of the abnormality is not known but possible mechanisms are discussed. PMID- 20925681 TI - The Adaptation of Plankton Algae IV. Light Adaptation in Different Algal Species. AB - Two types with regard to adaptation to different light intensities are described: tbe Chlorella type and the Cyclotella type. The Chlorella type is mostly found among the green algae, the Cyclotella type among the diatoms. The Chlorella type adapts to a new light intensity mainly by changing the pigment content. Therefore the cells adapted to a high light intensity have a lower chlorophyll a content per cell than cells adapted to a low light intensity. Light saturation is mostly rather low for cells adapted to low light intensities. The light-saturated rate of photosynthesisist mostly lower for cells adapted to a high light intensity than for cells adapted to a low light intensity. The actual photosynthesis is not much higher at a high light intensity than at a low one. The actual photosynthesis is the photosynthesis at the light intensity where the cells are grown. - The Cyclotella type adapts only by changing the light-saturated rate. The chlorophyll content is the same in cells grown at low and high light intensities. Light saturation for cells grown at a low light intensity is rather high. The light-saturated rate is much higher in the case examined at the high light intensity than at the low one. The actual photosynthesis is considerably higher for cells grown at the high light intensities than for cells grown at low light intensities.- The two adaptation types are not sharply separated since transition types occur. PMID- 20925682 TI - alpha-Aminoadipic Acid and alpha,E-Diaminopimelic Acid in Inoculated Pea Plants (Pisum sativum) and Root Nodule Bacteria (Rhizobium leguminosarum). AB - Observations were made on the content of alpha-aminoadipic acid and alpha aminophimelic acid (DAP) in pea plants, nodules and Rhizobium leguminosarum, strain HT3. The preparations were purified by ion exchange chromatography, Qualitative analyses were made by paper chromatography, and quantitative analyses by means of an automatic amino acid analysator. In the whole plant and seeds the content of alpha-aminoadipic acid soluble in 70% ethanol varied between 10 and 80 MUg/g dry weight. The shoot and red nitrogen fixing nodules contained more of this acid than roots and green inactive nodules. In the insoluble fraction of the shoot its concentration was 0.4-0.6 mg/g dry weight. alpha-Aminoadipic acid was not found in free living rhizobia, which again contained a considerable amount of alpha-aiaminopimelic acid, about 0.5 mg/g dry weight. The synthesis of DAP was intensive also in root nodules. In red nodules, which fixed molecular nitrogen, the content of DAP was 2.1 mg/g dry weight and in green inactive nodules 1.3 mg/g dry weight. It was shown that in the nodules DAP is closely connected with cell wall peptides of bacteroids. DAP could not be found in pea plants outside the nodules. PMID- 20925683 TI - The Effect of Various Aliphatic Aldehydes and Related Compounds on the Growth of Dipodascus aggregatus. AB - The growth of Dipodascus aggregatus in cultures inoculated with cells from the acceleration phase of growth was stimulated by the saturated and unbranched aliphatic C(3) C(4) , and C(6) to C(11) aldehydes (80 MUM]. Nonanal was most active in stimulating growth. The C(12) aldehyde inhibited growth. The C(5) , aldehyde generally inhibited growth. - Nonan did not affect growth. 2-Nonanone and 5-nonanone promoted growth insignificantly. - In cultures inoculated with cells from the exponential phase growth was unaffected or even inhibited by all the aldehydes tested. The C(4) , C(5) , C(10) , and C(11) aldehydes inhibited growth to a larger extent than nonanal. PMID- 20925685 TI - Associations between weight change over 8 years and baseline body mass index in a cohort of continuing and quitting smokers. AB - AIM: To examine the association between weight change and baseline body mass index (BMI) over 8 years in a cohort of continuing and quitting smokers. DESIGN: Prospective cohort. SETTING: Oxfordshire general practices nicotine patch/placebo trial with 8-year follow-up. PARTICIPANTS: Eighty-five participants were biochemically proven abstinent at 3, 6, 12 months and 8 years (abstainers). A total of 613 smoked throughout the 8 years (smokers), 26 quit for a whole year but were smoking again by 8 years (relapsed); 116 smoked for the first year but were abstinent at 8 years (late abstainers). MEASUREMENTS: Weight and BMI was measured at baseline and at 8 years. Regression models were used to examine weight gain by smoking status and the association of BMI at the time of quitting. FINDINGS: Abstainers gained 8.79kg [standard deviation (SD) 6.36; 95% confidence interval (CI) 7.42, 10.17]. Smokers gained 2.24 kg (SD 6.65; 95% CI 1.7, 2.77). Relapsed smokers gained 3.28 kg (SD 7.16; 95% CI 0.328, 6.24). Late abstainers gained 8.33 kg (SD 8.04; 95% CI 6.85, 9.81). The association between baseline BMI and weight change was modified by smoking status. In smokers there was a negative linear association of BMI, while in abstainers a J-shaped curve fitted best. These models estimated weight change over 8 years in abstainers of +9.8 kg, +7.8kg, +10.2kg, +19.4kg and in smokers of +3.9kg, +2.6kg, 1.0kg and -0.8kg, where BMI was 18, 23, 29 and 36, respectively. CONCLUSION: Obese smokers gain most weight on quitting smoking, while obese continuing smokers are likely to remain stable or lose weight. Obese quitters have the greatest need for interventions to ameliorate weight gain. PMID- 20925684 TI - Teaching community program clinicians motivational interviewing using expert and train-the-trainer strategies. AB - AIMS: The effectiveness of expert-led (EX) and train-the-trainer (TT) strategies was compared to a self-study approach (SS) for teaching clinicians motivational interviewing (MI). DESIGN: Twelve community treatment programs were assigned randomly to the three conditions. EX and TT conditions used skill-building workshops and three monthly supervision sessions guided by treatment integrity ratings, performance feedback and coaching techniques. Trainers in TT were first trained and certified in MI and then prepared carefully to deliver the workshops and supervise MI at their programs. Clinicians in SS only received the training materials. SETTING: Licensed out-patient and residential addiction and mental health treatment programs in the US state of Connecticut were involved in the study. PARTICIPANTS: Ninety-two clinicians who provided addiction treatment within these programs and had limited experience with MI participated in the study. MEASUREMENTS: Primary outcomes were the clinicians' MI adherence and competence and the percentage of clinicians meeting clinical trial standards of MI performance. Assessments occurred at baseline, post-workshop, post-supervision and at 12-week follow-up. FINDINGS: The study found EX and TT, in comparison to SS, improved clinicians' adherence and competence significantly, with higher percentages of clinicians reaching clinical trial standards of MI performance and few differences between EX and TT. CONCLUSIONS: This study supports the combined use of workshops and supervision to teach community program clinicians MI and suggests the train-the-trainer approach may be a feasible and effective strategy for disseminating empirically supported treatments. PMID- 20925686 TI - How best to measure change in evaluations of treatment for substance use disorder. AB - AIMS: To compare the performance of the Jacobson & Truax (JT) reliable change index (RCI) with three alternative methods, using data from individuals receiving treatment for substance use disorders. DESIGN: English National Treatment Outcome Monitoring Database for publicly funded specialist community pharmacological and psychosocial interventions. PARTICIPANTS: New adult admissions to treatment across England (1 January-31 December 2008), with in-treatment clinic progress review conducted after an average of 122.8 days for 18,163 individuals. MEASUREMENTS: Self-reported days using heroin, crack, cocaine powder and alcohol during the 4 weeks before admission and clinical review, recorded using the Treatment Outcomes Profile and analysed using a multi-level, mixed-linear model, with both observed and true scores to estimate the effect of regression to the mean (RTM). Differences in performance among the JT RCI and the alternative methods were assessed by the proportion assigned to a reliably 'improved', 'unchanged' or 'reliably deteriorated' category; level of agreement; difference in effect size for observed and true scores; and receiver operating characteristic parameters. FINDINGS: When compared to the alternative methods, the JT RCI was more conservative in assigning individuals to the improved category, and it showed no evidence of inferiority on any measure. For each method, all individuals categorized as reliably deteriorated and the majority of those categorized reliably improved had outcome scores which fell beyond that expected by RTM. Substituting true scores for observed scores moderated the size of the change effect associated with reduced use of the four substances, but this remained statistically significant. CONCLUSIONS: The Jacobson & Truax Reliable Change Index appears to be the optimal measure of change for evaluations of treatment for substance use disorder, in that it is the most conservative for assessing improvement and at least as accurate on all other criteria. Any evaluation of change needs to take account of regression to the mean. PMID- 20925687 TI - Gamma-butyrolactone (GBL) dependence and withdrawal. AB - AIM: To describe morbidity associated with gamma-butyrolactone (GBL) dependence, and outcomes of withdrawal. DESIGN: Case series. SETTING: Specialist out-patient clinic and affiliated in-patient detoxification unit. Patients with home support were offered the option of out-patient withdrawal management, based on high-dose diazepam and baclofen, titrated against withdrawal severity in an initial session lasting approximately 4 hours. Patients were then reviewed daily during the first 3 days of treatment, offered weekly follow-up for 4 weeks, and telephoned 2-4 months later. PARTICIPANTS: People dependent on GBL seeking detoxification. MEASUREMENTS: Drug history and social functioning were obtained by self-report in clinical interviews with a single clinician. Treatment completion, outcomes and adverse events associated with withdrawal are reported. FINDINGS: Patients reported impaired social functioning associated with GBL dependence and difficulty in accessing treatment. Nineteen patients commenced detoxification; 17 initially declined admission and were treated as out-patients. Mean diazepam dose in the first 24 hours was 75 mg (range 40-110 mg). Sixteen patients completed withdrawal, although several had lapses to GBL use during treatment. One patient developed delirium and required transfer to the in-patient detoxification unit. Most patients had persisting insomnia, anxiety and depression for weeks after withdrawal. CONCLUSIONS: GBL withdrawal can be managed in ambulatory settings, but needs to be backed up with seamless access to in-patient treatment if required. PMID- 20925689 TI - Dihydropyridines and multidrug resistance: previous attempts, present state, and future trends. AB - Multidrug resistance is defined as the resistance of a tumor cell to the cytotoxic action of divergent drugs used in chemotherapy. Dihydropyridines are a class of calcium channel antagonists that were discovered to have a multidrug resistance reversing effect and prompted investigations resulting in the synthesis of hundreds of new derivatives. Most of the investigators tried to achieve two goals: a decrease in Ca2(+) channel-blocking activity and an increase in the multidrug resistance reversing effect. Most of the synthesized compounds failed in the later stages of studies especially in clinical trials because of pharmacokinetic or pharmacodynamic limitations. Therefore, it will be necessary to include new methods, such as combinatorial synthesis, and, more importantly, to apply computational methods based on global structure-activity relationship models that consider all problems. Moreover, some compounds should be synthesized that are effective on several multidrug resistance targets. PMID- 20925688 TI - Revised dose schema of sublingual buprenorphine in the treatment of the neonatal opioid abstinence syndrome. AB - AIMS: More than half of infants exposed to opioids in utero develop neonatal abstinence syndrome (NAS) of severity to require pharmacological therapy. Current treatments are associated with prolonged hospitalization. We sought to optimize the dose of sublingual buprenorphine in the treatment of NAS. DESIGN: Randomized, Phase 1, open-label, active-control clinical trial comparing sublingual buprenorphine to oral morphine. SETTING: Large, urban, tertiary care hospital. PARTICIPANTS: Twenty-four term infants requiring pharmacological treatment for NAS. MEASUREMENTS: Outcomes were neonatal safety, length of treatment and length of hospitalization. FINDINGS: Sublingual buprenorphine was safe and effective. Infants treated with buprenorphine had a 23-day length of treatment compared to 38 days for those treated with morphine (P = 0.01), representing a 40% reduction. Length of hospital stay in the buprenorphine group was reduced 24%, from 42 to 32 days (P = 0.05). CONCLUSIONS: Sublingual buprenorphine was safe in NAS, with a substantial efficacy advantage over standard of care therapy with oral morphine. PMID- 20925690 TI - Combined in silico and experimental approach for drug design: the binding mode of peptidic and non-peptidic inhibitors to hsp90 N-terminal domain. AB - Heat shock protein 90 (Hsp90) is a prime target for antitumor therapies. The information obtained by molecular dynamics (MD) simulations is combined with NMR data to provide a cross-validated atomic resolution model of the complementary interactions of heat shock protein 90 with a peptidic (shepherdin) and a non peptidic (5-aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside, AICAR) inhibitor, showing antiproliferative and proapoptotic activity in multiple tumor cell lines. This approach highlights the relevant role of imidazolic moiety in the interaction of both antagonist molecules. In 5-aminoimidazole-4-carboxamide-1 beta-d-ribofuranoside bound state, one conformation of those present in solution is selected, where imidazolic, H4 and H5 protons have a key role in defining a non-polar region contacting heat shock protein 90 surface. The dynamic equilibrium between N-type and S-type puckered forms of 5-aminoimidazole-4 carboxamide-1-beta-d-ribofuranoside moiety is shown to be functional to inhibitor binding. The first experimental structural data on these inhibitors are presented and discussed as hints for future design of improved molecules. PMID- 20925691 TI - In silico exploration for identifying structure-activity relationship of MEK inhibition and oral bioavailability for isothiazole derivatives. AB - In this study, quantitative structure-activity/property models are developed for modeling and predicting both MEK inhibitory activity and oral bioavailability of novel isothiazole-4-carboxamidines. The models developed are thoroughly discussed to identify the key components that influence the inhibitory activity and oral bioavailability of the selected compounds. These selected descriptors serve as a first guideline for the design of novel and potent MEK inhibitors with desired ADME properties. PMID- 20925692 TI - Novel chalcones and 1,3,5-triphenyl-2-pyrazoline derivatives as antibacterial agents. AB - Novel sixteen chalcones and thirteen 1,3,5-triphenyl-2-pyrazolines were synthesized and characterized using FT-IR, HR-Mass, NMR (1H-NMR, 13C-NMR, 135 DEPT, 1H-1H CoSY and 1H and 13C CoSY) and XRD. These compounds were evaluated for their antibacterial activity against six micro-organisms, namely Bacillus subtilis NCIM 2718, Staphylococcus aureus NCIM 5021, Salmonella typhi NCIM 2501, Enterobacter aerogenes NCIM 5139, Pseudomonas aeruginosa NCIM 5029, and Proteus vulgaris NCIM 2813 by twofold dilution method using resazurin as the indicator dye. In the case of chalcones, compounds with hydroxyl and bromo substitutions in the B-ring favor activity and benzyloxy substitution irrespective of its position in the A-ring. In the case of 1,3,5-triphenyl-2-pyrazolines, chloro substitution in the A-ring favors activity. Hydrophilic/lipophilic balance of the compounds plays a major role in their antibacterial activity. PMID- 20925693 TI - Screening for in vitro antimycobacterial activity and three-dimensional quantitative structure-activity relationship (3D-QSAR) study of 4 (arylamino)coumarin derivatives. AB - The resurgence of tuberculosis and the emergence of multidrug-resistant strains of Mycobacteria necessitate the search for new classes of antimycobacterial agents. We have synthesized a small library of 50 analogues of 4 (arylamino)coumarins with various aromatic amines at the C(4) - position of the coumarin scaffold. The compounds were evaluated for antimycobacterial activity against Mycobacterium tuberculosis H(37) Rv with rifampicin as the standard. Of the molecules synthesized, compound 9 was found to be most potent with a minimum inhibitory concentration >6.25 MUg/mL for 100% inhibition. In an effort to develop new and more effective molecules in this series, the relationship between structure and activity was investigated by comparative molecular field analysis. Various models were generated using comparative molecular field analysis alone and comparative molecular field analysis plus a hydropathy field (HINT). In all, eight models were generated with atom-fit and field-fit alignment strategies. The comparative molecular field analysis models (Models 3a and 4a) based on field-fit alignment were the best with statistically good correlation coefficients (r2) and cross-validated q2. The values of r2(pred) for the validation set were 0.469 and 0.516. Based on the comparative molecular field analysis contours, some insights into the structure-activity relationship of the compounds could be gained. PMID- 20925694 TI - Predictive QSPR study of the dissociation constants of diverse pharmaceutical compounds. AB - The objective of the article was to perform a predictive analysis, based on quantitative structure-property relationships, of the dissociation constants (pK(a)) of different medicinal compounds (e.g., salicylic acid, salbutamol, lidocaine). Given the importance of this property in medicinal chemistry, it is of interest to develop theoretical methods for its prediction. The descriptors selection from a pool containing more than a thousand geometrical, topological, quantum-mechanical, and electronic types of descriptors was performed using the enhanced replacement method. Genetic algorithm and the replacement method (RM) techniques were used as reference points. A new methodology for the selection of the optimal number of descriptors to include in a model was presented and successfully used, showing that the best model should contain four descriptors. The best quantitative structure-property relationships linear model constructed using 62 molecular structures not previously used in this type of quantitative structure-property study showed good predictive attributes. The root mean squared error of the 26 molecules test set was 0.5600. The analysis of the quantitative structure-property relationships model suggests that the dissociation constants depend significantly on the number of acceptor atoms for H-bonds and on the number of carboxylic acids present in the molecules. PMID- 20925695 TI - 2-(pyrazin-2-yloxy)acetohydrazide analogs QSAR Study: An insight into the structural basis of antimycobacterial activity. AB - Quantitative structure activity relationship analysis based on classical Hansch approach was adopted on reported novel series of 2-(pyrazin-2 yloxy)acetohydrazide analogs. Various types of descriptors like topological, spatial, thermodynamic, and electronic were used to derive a quantitative relationship between the antitubercular activity and structural properties. The consensus scoring function showed a significant statistics of training and test set. Coefficient of determination (r2) of consensus model and predictive squared correlation coefficient (r2(pred)) were found to be 0.889 and 0.782, respectively. The model is not only able to predict the activity of test compounds but also explained the important structural features of the molecules in a quantitative manner. The study revealed that antimycobacterium activity is predominantly explained by the molecular connectivity indices of length 6, hydrogen donor feature of the analogs, and shape factors of the substituent. The comparative investigation of antibacterial activity against Staphylococcus aureus, Bacillus subtilis, Escherichia coli, and Salmonella typhi provided structural insights on how modulation of the molecular connectivity indices, energy of lowest unoccupied molecular orbital, accessible surface area, and moment of inertia of the analogs could be usefully made to optimize the antibacterial activity. PMID- 20925696 TI - A 54-year-old woman with a meningeal lesion compressing the medulla oblongata. AB - A 54-year-old woman had nausea, vomiting and personality changes since a few weeks. Paresis of the abducens and hypoglossal nerves on the left side, a right sided reduction of the visual field, discrete dysarthri*a and ataxia were diagnosed. Cranial magnetic resonance imaging demonstrated a contrast enhancing circular meningeal lesion of the foramen magnum. Histological examination revealed a granulomatous lesion of the meninges with focal necrosis, vasculitis and neutrophils indicating immune complex reactions. A diagnosis of primary meningeal Wegener's disease was made. Medication with low dose prednisolone led to complete remission of the lesion 1.5 years later. PMID- 20925697 TI - 17-year-old girl with headache and complex partial seizure. AB - Supratentorial cortical ependymoma is a rare clinical entity where ependymoma occurring in the cortex without any connection to the ventricular system since ependymoma usually arises from the lining of the ventricular system or central canal of spinal cord. There have been 14 such cases reported in the literature.We report the first case of a supratentorial extraaxial cortical anaplastic ependymoma with minimal cortical attachment in a 17-years-old girl, presented with headache and complex partial seizure. Histological features of anaplasia including numerous mitoses, necrosis and high Ki-67 lead to postoperative adjuvant radiation therapy although gross total resection was achieved. PMID- 20925699 TI - Is care still the 'essence' of nursing? PMID- 20925700 TI - Care provision for rural dwelling older people. PMID- 20925701 TI - Personal and social determinants of health services utilization by Mexican older people. AB - BACKGROUND: Increased healthcare needs among older individuals around the world demands a better understanding of factors influencing healthcare service utilization patterns. OBJECTIVE: To examine personal and social correlates to health services utilization among Mexican older persons. DESIGN AND METHODS: This was a cross-sectional study conducted between 2004 and 2006 with 2030 Mexican adults 60 years and older and based on a health services utilization framework. A two-stage cluster sampling with probability proportionate to size was used. Participants were randomly selected and recruited in four metropolitan areas in Northeastern Mexico. Chi-square and Pearson's chi-squared tests and logistic regression were used for data analyses. RESULTS: Significantly more women than men had lost a spouse and were illiterate. Also, females reported significantly poorer health, higher nutritional risk and lower ability to perform activities of daily and instrumental living than males. Predictors of healthcare utilization were: Having a caregiver during an illness; perceiving to have a health problem; being able to afford food, and having children. CONCLUSIONS: Predisposing, enabling and need factors are strong predictors of health services utilization among Mexican older persons. In addition, gender differences exist among this population in relation to health status, but not to health services demands. PMID- 20925702 TI - Functional health status among rural and urban older adults in Taiwan: the effect of personal control and social control. AB - AIM: To assess the relationship between perceived social control/personal control and functional health status among older adults in rural and urban Taiwan. BACKGROUND: The ageing of the population is poised to emerge as a preeminent worldwide phenomenon. It is assumed that even though older adults experience many decades of autonomy and independence, the potential for illness or bodily decline will induce a serious reduction in the level of perceived control in older adult populations. METHOD: This is a descriptive correlational study using a secondary data base, Social Environment and Biomarkers of Aging Study. Social Environment and Biomarkers of Aging Study is a nationally representative study of health outcomes in the Taiwanese population. RESULTS: Both perceived levels of social control and personal control had a statistically significant relationship with functional health status. Functional health status was significantly higher for urban older adults than their rural counterparts. CONCLUSIONS: Personal control and social control were both found to be predictors of functional health status. Major findings are supported by previous studies. RELEVANCE TO CLINICAL PRACTICE: Nurses should create programs and plan activities to assist older adults to enhance their perceptions of social control or personal control in order to improve the health status of older adults and minimize associated health care costs. PMID- 20925703 TI - Barriers to and facilitators of self-management adherence in Korean older adults with type 2 diabetes. AB - AIM: The aim of this study was to identify the barriers to and facilitators of self-management adherence in Korean older adults with type 2 diabetes. DESIGN AND METHODS: Qualitative data collected from 24 participants in three focus groups who had previously taken part in a diabetes self-management education programme in a community setting were analyzed using an interpretive method. RESULTS: The barriers to adherence to self-management included ageing-related physical and psychological changes, restrictions related to specific cultural factors, lack of self-discipline and poor understanding of self-management. Facilitators of self management were knowing the benefits of and having a system to reinforce self management, being the master of oneself by reshaping historical life habits and family support. The perceived barriers and facilitators differed with gender as a result of the characteristics of Korean culture. CONCLUSIONS: This study identified the major barriers to and facilitators of self-management adherence specific to Korean older adults with diabetes, which can be used to develop better diabetes self-management education programmes for this population. RELEVANCE TO CLINICAL PRACTICE: Korean nurses working with Korean older adults with diabetes can utilize the findings of this study to structure better tailored and culturally appropriate self-management programmes specific to older adults. PMID- 20925704 TI - Raising the bar of care for older people in Ontario emergency departments. AB - AIM: To describe the role of geriatric emergency management nurses as a catalyst for culture change in emergency department processes with the goal to improve care and outcomes of older people. BACKGROUND: The changing context and literature has called for a culture change within emergency department care to integrate principles of older people care into care delivery. There is a paucity of reports describing how geriatric emergency care models bring about a broader change in culture within the entire emergency department. METHODS: The Ontario Ministry of Health and Long-term Care in Canada established a programme to place geriatric emergency management nurses into emergency departments with the goal to improve delivery of care through development of unique, site-appropriate solutions. RESULTS: Geriatric emergency management nurses incorporate capacity building into their role to develop and strengthen the skills, instincts, abilities, process and resources of the emergency department. Care processes focus on areas of staffing, mobilization, comfort, medication, hygiene, nutrition/hydration, cognition, environment, equipment and stimulation. Multi modal educational strategies and advocacy promote appropriate person-centred care. Improved communication among care providers at key patient transition points remains a priority system-level improvement. CONCLUSION: Geriatric emergency management nurses work collaboratively with the emergency department team to facilitate change in the way that emergency department care is provided to the older person experiencing health emergencies. IMPLICATIONS FOR PRACTICE: Known strategies that have been effective in improving outcomes for older people within the hospital and residential care setting can be generalized into emergency department care. Further research into the effectiveness of these strategies in this environment is recommended. PMID- 20925705 TI - Quality of life: dementia and dignity. PMID- 20925706 TI - Dignity, dining and dialogue: reviewing the literature on quality of life for people with dementia. AB - AIM: To review contemporary literature on quality of life for people with dementia. BACKGROUND: One of the consequences of population ageing is the predicted increase in the incidence of dementia. While we can as yet do little to affect the course of the disease, health care professionals are well-placed to intervene to affect quality of life and quality of care for people with dementia. RESULTS: Research into quality of life for people with dementia has grown markedly over the last decade, in line with evolving conceptual and theoretical understandings of this complex concept. While much of the literature continues to focus on assessment and measurement of quality of life, emerging areas of interest are noted, including dialogue associated with personhood; dignity; and dining and mealtime experiences. CONCLUSION: Literature on quality of life for people with dementia is as diverse as the concept itself. Established and emerging areas of research suggest that this diversity will continue into the future as we strive to better understand quality of life for people with dementia in all its complexity. PMID- 20925707 TI - Dementia, dignity and quality of life: nursing practice and its dilemmas. AB - AIMS: The need for healthcare practitioners to respect the dignity of older people is widely recognised in England, where it has been given attention by politicians, professionals and health service regulators. This article aims to provide examples of how such ambitions may be used in practice development. METHODS: This article reports the use of five vignettes discussed by dementia care practitioners that explored the areas of dementia diagnosis, lying, incontinence, behavioural and psychological distress, and end of life care. FINDINGS: Each vignette promoted discussion of differences of perspectives about the ways to enhance the dignity of people with dementia in hospital, care home and community settings. The discussion confirmed that while dignity may be one quality indicator of good care potentially enhancing quality of life, it is not always straightforward. It may be more easily conceptualised when talking of physical care and treatment than other areas. CONCLUSION: The opportunity to debate the subject and to discuss practice examples revealed differences of opinion and moral perspectives between practitioners about the use and relevance of the term dignity. These need to be acknowledged in any debates about objective and subjective definitions of quality of life. PMID- 20925709 TI - Editorial: outcomes from gerontological nursing: considering person-centredness. PMID- 20925708 TI - Is quality of life being compromised in people with dementia in long-term care? AB - AIM: To outline the importance of understanding quality of life (QOL) in people with dementia living in long-term care. To consider several key research questions and some of the challenges and impact of neglecting knowledge transfer. BACKGROUND: There is a gap between the knowledge in the broad dementia research literature and transfer of knowledge into practice. Quality of life research and transfer of research into practice is one means by which health professionals can inform health and social care policy and improve care practice. DISCUSSION: There are a number of unanswered research questions in relation to QOL in people with dementia living in long term care. A selection of questions discussed in this paper relate to the impact of staff knowledge of mental health assessment and the importance of therapeutic communication, cognitive training programs and social biography, individual needs, weight and behavioural and psychological symptoms of dementia (BPSD), resident choice and the impact of the environment on QOL. CONCLUSION: Research methods used to assess QOL must not be too restrictive and mixed methods and data from multiple perspectives should be encouraged so that an extensive understanding is uncovered. Potential strategies to assist knowledge transfer in long-term care settings are needed. PMID- 20925710 TI - The care of older people with dementia in acute hospitals. AB - AIM: To explore the experiences of patients and nursing staff of the care received by older people with dementia in acute hospitals. BACKGROUND: The prevalence of dementia is steadily increasing as is the number of people with the condition requiring acute hospital care. Significant concerns about the quality of this care have been raised. There is a paucity of knowledge about the views of such care from the perspectives of people with dementia and nurses. METHOD: An ethnographic approach was used and data were collected thorough observation and interviews in one acute hospital in the United Kingdom. FINDINGS: Findings suggest that care for older people with dementia in acute hospitals is not always optimum although there are clear exceptions. Generally, people with dementia found the delivery of care and the experience of being in hospital distressing as they did not know what was happening and they were often ignored. Nurses strive to give good care but do not always achieve this. CONCLUSION: Bourdieu's Model of Practice assists in explaining why care is as it is. There is a clear need to improve current practice. RELEVANCE TO CLINICAL PRACTICE: It is imperative that innovative methods of developing practice are implemented and evaluated. Education alone will not lead to sustained changes in practice. Further research into this subject needs to be undertaken. PMID- 20925711 TI - Developing person-centred practice: nursing outcomes arising from changes to the care environment in residential settings for older people. AB - AIM: To present the nursing outcomes from the evaluation of developments in the care environment in residential settings for older people. DESIGN: The evaluation data reported here is derived from a larger national programme of work that focused on the development of person-centred practice in residential services for older people using an emancipatory practice development framework. A multi-method evaluation framework was utilised. Outcome data were collected at three time points between December 2007 and September 2009. The data reported here were collected using an instrument called the 'Person-Centred Nursing Index'. FINDINGS: Heavy workload was the main cause of stress among nurses. Personal and professional satisfaction with the job was scored highest by the total sample of nurses. Nineteen factors were examined using the Person-Centred Nursing Index. Statistically significant changes were observed in 12 of these. In addition, there were statistically significant changes in nurses' perceptions of caring, indicating a shift from a dominant focus on 'technical' aspects of care, to one where 'intimate' aspects of care were more highly valued. RELEVANCE TO CLINICAL PRACTICE: The findings highlight the importance of the development of effective teamwork, workload management, time management and staff relationships in order to create a culture where there is a more democratic and inclusive approach to practice and space for the formation of person-centred relationships. PMID- 20925712 TI - Changes in nursing home residents during an innovation based on the theory of gerotranscendence. AB - AIMS AND OBJECTIVES: The aim of the present study was to investigate how residents were affected when an intervention based on the theory of gerotranscendence and guidelines derived from the theory was introduced in a nursing home. BACKGROUND: The notion that communication is essential in staff resident interaction is widely accepted both in theory and practise, as is the notion that communicative behaviour influences patient outcomes. No studies as yet have focused on whether residents are influenced by staff use of guidelines derived from the theory of gerotranscendence. DESIGN: The study was explorative in nature and used a qualitative approach. METHODS: Data were collected through interviews with residents and participant observations; qualitative content analysis was performed. SAMPLE SIZE: six residents. RESULTS: The study shows that many residents reviewed and thought about their lives, and that this aspect changed during the study period. Some residents' descriptions of their situation revealed that certain changes in social life on the ward had occurred. These changes could be an effect of the intervention. RELEVANCE TO CLINICAL PRACTICE: For nurses working in gerontological care, it is a challenge to get to know and provide the best nursing care and individual treatment for each resident; this involves a holistic view helping residents in their ageing process. The use of guidelines derived from the theory of gerotranscendence could help nurses promote positive ageing and constitute one way of treating residents in a more individualized manner. PMID- 20925713 TI - Outcomes from the work of registered nurses working with older people in UK care homes. AB - AIMS AND OBJECTIVES: This research sought to illuminate the distinct contributions made by Registered Nurses (RNs) and Care Assistants (CAs) to outcomes for older people in UK (nursing) care homes and to identify the outcomes of their work. This paper reports on aspects relevant to RNs. BACKGROUND: Older people living in long-term residential care settings around the world are among the most vulnerable individuals within their communities and those with the most complex needs. Nursing has historically been fundamental in the delivery of these services but, in some countries, the role of Registered Nurses in residential care is coming under increasing scrutiny, particularly in the context of escalating costs and funding restrictions, a questioning of the need for a 24 hour 'health' professional presence in a 'social care' service and a lack of evidence on the distinct contribution that RNs make to outcomes in these settings. DESIGN: A multi-method qualitative interpretive approach, adopting a structure-process-outcome framework and grounded in the philosophical hermeneutics of Hans-Georg Gadamer (2003). METHODS: For Phase 1 of the study, RNs and CAs from care homes around the UK contributed examples of their work, which they identified as having made a 'significant' difference to older individuals. Phase 2 comprised researcher fieldwork (observations, interviews and documentary analysis) in three care homes around UK. Research participants included RNs, CAs, older residents, relatives, home managers and professionals working in the homes. RESULTS: RN roles in care homes are broad and multifaceted. Distinct outcomes of RN work are consequent to their caring and their knowledge and skills developed through broad experience in a range of healthcare settings. Outcomes for residents from RN work include enhanced personhood and wellbeing, improved health and function, the prevention of problems/adverse outcomes and enhanced quality of life. RN outcomes have positive impact on relatives, staff and the homes in general. CONCLUSIONS: There is potential to reconsider the broad, 'anything and everything' nature of the RN role in care homes identified in the research. However, given the complex healthcare needs of the current resident population, the 24-hour RN presence is deemed essential. PMID- 20925714 TI - Relationship centred outcomes focused on compassionate care for older people within in-patient care settings. AB - This paper describes outcomes from research titled Leadership in Compassionate Care. The research adopts a participatory action research approach, utilizing appreciative inquiry and relationship centred care. Outcomes of the research are based upon relationships between patients, families and staff. This paper focuses on in-patient care for older people. A range of data generation activities were undertaken including: observation, interviews using emotional touch points and reflective accounts. To highlight outcomes in compassionate care, this paper uses case studies from two participating services. Principles of compassionate care were derived from understanding experiences of patients, relatives and staff and initiating responsive action projects. The aim was to enhance the experience of relationship centred, compassionate care. The process of emotional touch points enabled a richer understanding of experience. In terms of outcomes for patients this involved, enhanced quality of time spent with family and opening up conversations between families and staff. Outcomes for families involved enhanced access to relevant information and the opportunity to make sense of their situation. Staff outcomes were gaining experience in working alongside family to co-create the service, enhanced understanding of the experiences of patients and relatives led to direct changes in individual and team practices. PMID- 20925715 TI - Constructions of dignity: a pre-requisite for flourishing in the workplace? AB - AIMS: To explore the relationship between nurses' understanding of dignity and how it is enhanced and developed in their practice environment. BACKGROUND: Dignity is a ubiquitous concept in an era of healthcare reform yet is referred to almost exclusively in terms of the quality of care delivered to support the experience of the patient rather than the caregivers engaged in the relationships of care. This article focuses on dignity in the professional life of nurses in aged care. METHOD: This is part of a doctoral study of the implementation of a palliative approach in residential aged care using emancipatory practice development methodology. Constructions of dignity were co-created with participants through creative reflective activities and subsequently analysed using reflexive methods and data from other sources within the study. RESULTS: Constructions of dignity and subsequent actions taken by nurses on their own behalf to articulate their experiences of transforming practice are interconnected with dignity enhancing relationships and emancipatory ways of working in practice development. CONCLUSIONS: Dignity enhancing ways of working in an active learning group and workplace have been interlinked with actions that promote person-centredness in developing a palliative approach to care. PMID- 20925716 TI - The use of life story work with people with dementia to enhance person-centred care. AB - BACKGROUND: Person-centred care has been linked with quality of care but difficulties remain in person-centred care being implemented in care practice. This study explores the use of life story work to enhance person-centred care with people with dementia. AIMS AND OBJECTIVES: The study investigates how life story work is: understood and developed in practice; experienced by all participants and affects the delivery and outcomes of care. DESIGN AND METHODS: The experience of older people with dementia, family carers and care staff in using life story work was explored within an NHS Health and Social Care Trust. A multiple case study design was adopted within a constructivist approach. Semi structured interviews, observation, conversations were employed. FINDINGS: Life story work has the potential to: enable care staff to see the person behind the patient; allow family carers to uphold their relatives' personhood; enable the voice of the person with dementia to be heard, verbally and non-verbally; be enjoyable for all concerned and enable the person with dementia to feel proud about themselves and their lives. CONCLUSION AND IMPLICATIONS FOR PRACTICE: Life story work has the potential to enhance person-centred care for older people with dementia and their families. Taking a practice development approach ensures that life story work can be implemented sensitively and is sustained in practice. PMID- 20925717 TI - Using drama to improve person-centred dementia care. AB - AIMS AND OBJECTIVES: We implemented a 12-week drama-based educational intervention to introduce to dementia practitioners person-centred care that emphasizes the notion of embodied selfhood (defined as non-verbal self expression). BACKGROUND: Person-centred dementia care guidelines emphasize the assessment of individual needs, and where appropriate, the use of non pharmacological interventions before resorting to pharmacological management. However, dementia care is not consistent with these guidelines suggesting conceptual limitations and reliance on passive knowledge translation strategies. DESIGN AND METHODS: Focus groups and semi-structured interviews with practitioners (n = 24) in two nursing homes in central Canada were undertaken to assess the effectiveness of the drama-based components of the intervention. RESULTS: Our findings suggest that drama was effective as an educational modality, and helped implement the person-centred approach into practice. Significant practice outcomes included: new awareness that residents' body movements and dispositions can convey meaning; seeking biographical information from families; increased time efficiency; and supporting residents' independence. CONCLUSIONS: Our findings make an important contribution to person-centred dementia care by broadening the notion of personhood, and by facilitating implementation using drama. IMPLICATIONS FOR PRACTICE: As an enhancement of person-centred care, the support of embodied selfhood may significantly improve residents' quality of life, quality of care, and practitioners' care-giving experience. PMID- 20925718 TI - 'Patient participation' in everyday activities in special care units for persons with dementia in Norwegian nursing homes. AB - AIM: The aim of this study was to explore 'patient participation' in everyday activities for persons with dementia living in special care units in nursing homes. BACKGROUND: Studies about how 'patient participation' appears in the context of special care units for persons with dementia are lacking. DESIGN: The study has an explorative design. METHOD: Grounded theory was chosen. Data collection was carried out by means of open observations and additional conversations with residents and personnel. Simultaneously, data analysis was performed with open, axial and selective coding. FINDINGS: The findings showed that 'patient participation' concerned 'A matter of presence' as the core category. The other categories described as 'presence of personnel' and 'presence of residents', were strongly connected to the core category as well as to each other. Presence of personnel comprised three levels; being there in body, which required physical presence; being there in mind, which required presence with all senses based on knowledge and competence; and being there in morality which was understood as being fully present, as it was based on humanistic values and included the two other levels. Presence of residents comprised 'ability and wish' and 'adaptation'. The presence of the personnel had a huge impact on the ability and will to participate of the residents. Organizational conditions concerning leadership, amount of personnel and routines as well as housing conditions concerning architecture and shared accommodation, could stimulate or hinder 'patient participation'. CONCLUSIONS AND IMPLICATIONS: The study highlighted the great impact of the personnel's presence in body, mind and morality on the participation capacity of the residents. The great importance of the nurse leaders was stressed, as they were responsible for organizational issues and served as role models. Group supervision of the personnel and their leaders would be an implication to propose, as these kinds of reflection groups offer opportunities to reflect on values, actions and routines. PMID- 20925719 TI - From health organization-centred standardization work process to a personhood centred care process in an Italian nursing home: effectiveness on bowel elimination model. AB - AIMS: An Italian nursing home's standardized work process redesign towards a personhood-centred nursing care is the focus of this study. The aim was to develop and implement a multi-method, personhood-centred, bowel elimination programme, to reduce the number of patients suffering from constipation and lessen the use of the invasive practises routinely adopted in nursing home (laxatives, enemas, rectal exploration). BACKGROUND: Although the importance of the application of personhood-centred care concepts in gerontology nursing has been widely recognized, the actual tendency of the Italian National Health System, which has few nursing resources for to the care of the older persons, is standardization. Standardization is enacted mainly by a functional pattern and carries the risk of using the same nursing answer to patient's different needs, priorities, preferences and histories. Constipation in older people living in nursing homes is one of the effects of extreme standardization. METHODS: A case crossover study design was adopted from 2006 to 2007. Twenty persons were enrolled in the programme. The multi-method programme included three phases: assessment (first phase), development/implementation (second) and evaluation (third phase). RESULTS: In the first phase, nine (45%) persons were constipated; in the third phase, only two (10%) were constipated (chi(2) 6.14, P = 0.013). The relative risk of being a constipated person in the first phase compared with the third phase was 4.5 (confidence interval 95%: 1.11-18.27). During the first phase 562 invasive procedures were observed (+/- 25.5, range: 2-85) for bowel elimination whereas during the third phase 120 were observed (+/- 12, range: 0 58). CONCLUSION: After the personhood-centred multi-method programme, seven persons have modified their bowel elimination pattern, and they were no longer constipated. The programme has also reduced the use of invasive procedures. The reduction of invasive practises might have affected positively the persons' quality of life, their comfort and also the workload of the nurses, reducing the time they needed for constipation management and using it for prevention strategies. PMID- 20925720 TI - Editorial: IJOPN enters a new stage as a stand alone journal. PMID- 20925721 TI - Editorial: 'the gift of understanding' section. PMID- 20925722 TI - Nurses' experiences of caring encounters with older people living in Swedish nursing homes. AB - Aim. The aim of the study was to describe and interpret the meaning of nurses' experiences of caring encounters with residents in nursing homes. Background. Life for residents in nursing homes can be characterized as a process of decreased physical and psychological resources. Therefore, encounters with nurses are important activities for providing meaning and security for the residents. Research in this field has previously focused on communication, attitudes and job satisfaction, but gives limited knowledge about what the human encounters in this context mean for the nurses. Method. A hermeneutic method was used in this study. Interviews were conducted with 14 nurses from two nursing homes about their experiences of caring encounters. The transcribed interview texts were interpreted as a whole. Results. In the interpretation of the text concerning the meaning of nurses' experiences of encounters with resident's four themes and 11 subthemes emerged. The comprehensive interpretation mainly showed possible ways available being present, being significant and being aware of opportunities for the nurse to find meaning in the encounter with the resident, but impossible ways as being inadequately were also revealed. Conclusion. This study shows the importance of caring encounters between nurses and residents in nursing homes. The good encounters provide various possible ways for nurses to find meaning and a sense of communion with residents. However, bad encounters, described as being inadequate, were found to inhibit nurses from finding meaning in their encounters with residents. Relevance to clinical practice. Meeting the needs of older people in nursing homes requires special knowledge about the importance of the caring encounter. Therefore, nurses in this care context need supervision and continuous education in order to gain relevant knowledge about the meaning of caring encounters for themselves and residents. PMID- 20925723 TI - A literature review on fatigue among older people in pain: prevalence and predictors. AB - Objective. The aim of the study was to survey existing research about fatigue among older people with chronic non-malignant pain. Method. A structured literature review was carried out using the Medline database. The terms 'fatigue' and 'tiredness' were used synonymously. These subject headings were combined with pain. A literature search was made in 2004 and included articles back to 1995. Results. The review of studies from the last decade resulted in 11 articles of relevance. The result showed that fatigue was common among older people and even more common among those in pain. However, there was discordance regarding the prevalence, and the figures ranged from 30% to 98%. Fatigue was found to be associated above all with pain, functional limitations/functioning, and low quality of life. No articles were found focusing on interventions against fatigue. Conclusions. Fatigue is common in old age and even more common when people are in pain. However, knowledge seems to be sparse especially regarding interventions in daily care. Thus, more studies are needed that focus on fatigue to get firm evidence about the prevalence among older people in pain. In addition, studies about interventions against fatigue are urgently needed so that the care of older people can include actions against fatigue and to improve quality of life. Relevance to clinical practice. It is of importance that fatigue is not ignored in the care of older people. By intervening against symptoms such as fatigue it will most likely ease the pain and improve quality of life. PMID- 20925724 TI - Loss of parents in childhood - associations with depression, loneliness, and attitudes towards life in older Finnish people. AB - Aim. This study examines the prevalence of parental loss in childhood of older generations in Finland and how it is associated with demographic variables, depression, feelings of loneliness and attitudes towards life in old age. Background. A parental loss is a significant trauma in a child's life. It has long-term consequences in late adulthood, such as depression in middle age. Loss of parent/parents has not been under concern in the nursing literature. Little is known about the prevalence of parental loss and its consequences in old age such as depression, inner feelings of loneliness and life attitudes. Methods. The data were collected with a postal questionnaire from a random sample of 3728 older people (>=75 years) in Finland who responded to a question concerning loss of a parent when respondent was age <=17 years. Results. Of those responding to the question concerning parental loss, 31.2% had lost their mother and/or father in the childhood (at age <=17 years). Loss of parents was associated with lower level of education, physically heavy lifetime work, and not being married. There was no statistically significant relation between the loss of parent/parents in the childhood and self-reported depression or loneliness in the old age. In addition, loss of parent/parents was not associated with any attitudes towards life, such as life satisfaction, plans for the future, zest for life or happiness. Conclusions. Surprisingly many people from older generations had lost their parent/parents in their childhood, but it is not associated with depression, feelings of loneliness or other attitudes towards life. Several explanations for this are discussed. Relevance to clinical practice. Loss of parents does not necessarily lead to older people's psychological frailty. Nurses should be cautious when making interpretations about older people's early life history. Among older people early losses may be a source of successful coping skills rather than a risk factor for depression, loneliness and pessimistic life attitudes. PMID- 20925725 TI - Hospitalized older peoples' views of health and health promotion. AB - Older peoples' health varies considerably and the number of older people who need hospital care will increase in the future. Traditionally, the focus of nursing care in hospitals is oriented towards diagnosis and treatment of disease, although health and health promotion are inherent in theories and definitions of nursing. This is an important issue in health politics, in new laws and regulations in Norway. However, it was difficult to find research-based knowledge about how nurses work with health promotion and health related to older hospitalized patients. This study aimed at describing older hospitalized patients' experiences of health and health promotion. The study used a descriptive and explorative qualitative design, with an interpretative phenomenological approach. Ten older hospitalized patients, recruited through purposeful sampling, were interviewed during their hospital stay. The informants described health as Being able to be the person I am, to do what I want to do, and feel well and have strength. Health promotion was described as Being enabled through being the person I am, through information and knowledge and through hope and motivation. The findings may be applied to nursing practice in order to focus on promotion of health as an individual process built upon the unique person's life and situation, supported by nursing care and medical treatment. PMID- 20925726 TI - Influences on nurses' communications with older people at the end of life: perceptions and experiences of nurses working in palliative care and general medicine. AB - Aim. This paper reports an exploratory study investigating nurses' perceptions and experiences regarding listening and talking to dying older people about issues relating to the end of life. Background. At the end of life, nurses need to be able to communicate with older people in an open and sensitive manner. Although studies highlight that many nurses feel ill-prepared to respond when patients express their concerns and needs about the end of life, few consider nurses' views of caring specifically for dying older people in acute medical settings. Methods. Focus groups and interviews were undertaken with a purposive sample of nurses, including students and support workers, on general medical and palliative care units (24 participants). These were recorded on mini-disc, transcribed verbatim and offered to participants for comment and clarification. Guided by the principles of the constant comparative technique, transcripts were analysed for broad similarities and differences in the data and participants given the opportunity to comment on the findings. Following the study, a workshop comprising participants and experts in the field reviewed and discussed the implications of the findings for practice. Results. Factors influencing nurses' communication with older people at the end of life, included: nurses' perceptions and experiences of talking and listening to older people; learning from other members of the multi-professional team; environmental and organizational constraints such as time, privacy and the culture of care; and perceived differences between the values of nurses and those of doctors and patients' families. All participants recognized the importance of communicating with older people at the end of life, but general medical nurses expressed the need for further support. Relevance to clinical practice. Fostering a palliative care approach, through education and organizational culture that focuses on person centred care and multi-professional teamwork in a supportive environment, is essential. This should ensure that nurses engage with older people in a meaningful way as they face the end of their lives. PMID- 20925727 TI - Editorial: End-of-life issues in long-term care - implications for practice. PMID- 20925728 TI - End-of-life care in long-term care settings for older people: a literature review. AB - Most if not all of end-of-life care for people living in long-term care facilities is provided within the facility. This type of care is likely to increase with population ageing. This paper presents a literature review of the published literature on end-of-life care in long-term care facilities such as nursing homes, aged care facilities, residential care homes and continuing care settings, published between 2000 and 2004. A subset of literature that focuses on the development of practice and the identification of interventions to promote the provision of end-of-life care in care homes is examined in detail. Twenty five papers are identified and these address modes of service delivery, the introduction of 'interventions' that facilitate care for individuals, and the development of tools. This work remains largely descriptive. Small-scale work dominates, reflecting the initial stages of knowledge development in this area of work. Suggestions for ways to expand the scope of the end-of-life care development work in long-term care settings are presented, as it is time to expand the horizons of these initiatives to become more rigorous and responsive to the needs of older people and their families in this care setting. PMID- 20925729 TI - The challenges in adopting care pathways for the dying for use in care homes. AB - An increasing number of older people are requiring palliative care within the care home setting. There are currently a number of initiatives that are generally gaining approval and being implemented within health care in general with the goal of improving standards of palliative care. These are the Integrated Care Pathway for the dying person, the Gold Standards Framework and the Preferred Place of Care document. The Liverpool Care Pathway is being used across a wide range of care settings to improve care in the last 24-48 hours of life and is being implemented in care homes as part of a national rollout programme. This article aims to explore some of the issues associated with the use of the care pathways in care homes, particularly without the input of additional resources and support for the care homes. It also questions the appropriateness of the pathway in its current format without further work on the specific palliative care needs of the residents dying in care homes. PMID- 20925730 TI - Palliative care in long-term care: a system in change. AB - The provision of palliative care for older people within the next decade will need to be substantially different to that provided today. In long-term care settings the achievement of quality palliative care will require attention to all levels of the health and social care system, in both its formal and informal manifestations. We suggest that long-term care facilities will become the hospices of the future, caring for older people with chronic conditions with a long trajectory to death, the most common being dementia. We see this progression as inevitable and appropriate if the right support is provided. We discuss the impact that transferability and sustainability has had on the present provision of palliative care for older people and how that may affect the future. Four forces which are important factors in public policy; leadership, a culture that supports learning throughout the care process, an emphasis on effective team development and the use of information technologies for quality activities are used as a framework for our vision of social planning. We then go on to discuss the impact of costs, workforce, service planning and public awareness as vital areas where progress needs to be carefully tackled. We suggest some likely poor outcomes if this planning does not occur, but indicate that if planning and implementation is effective then services can provide the kind of care the baby boomer generation seeks. PMID- 20925731 TI - Editorial. PMID- 20925732 TI - Students' ideals for nursing older people in practice. AB - Aim. Drawing on research exploring nursing students' experiences of working with older people, this paper aims to demonstrate how context and culture can impact on the realization of their ideals. Background. The principles underpinning individualized and person-centred approaches to care resonate with those focal to gerontologic nursing. Restrictive contexts of care and pervasive workplace cultures render nurses unable to deliver care in accord with these. Design and method. This interpretive study was informed by phenomenological-hermeneutic theory. A purposive sample (n = 10) was recruited from a single educational institution. Data were generated in two phases using loosely structured interviews and supplementary activity. Themes explicating their experiences were identified via systematized detailed analysis and issues pertaining to nursing students' orientation towards older people cut across these. Findings and discussion. Students perceived that older people were prone to depersonalization and marginalization, so sought to show respect by coming to know individuals, form human connections with them and personalize care accordingly. Giving respect, promoting personhood, asserting reciprocal identity and maintaining dignity were prominent features of this but were often frustrated by practices and cultures encountered in mainstream settings. Conclusions. Nursing students' approaches to older people are contextual and reflect elements of person-centred ideology. Their attempts upholding their ideals are liable to be subverted by workplace norms. Preparatory education should address these, assist students to learn how to attend to personhood in restrictive environments and offer targeted placements in age-specific and non-acute services. Relevance to clinical practice. Demographic trends mean that working with older people has increased significance for nurses in most settings. Person-centredness is seen as beneficial for older people but contemporary service imperatives and enduring practices are inhibitory, preventing entrants to nursing from developing related skills. PMID- 20925733 TI - Promoting breast health: older women's perceptions of an innovative intervention to enhance screening. AB - Aims and objectives. This study is a continuation of prior funded research in which we tested the use of age and ethnically sensitive video breast health kits to increase knowledge about breast cancer and enhance the screening practices of breast self-examination and mammography among older Caucasian and African American women. Background. Breast cancer is the most frequent cancer in women worldwide and accounts for 23% of all cancers. Mammography is currently the best procedure available for mass screening of breast cancer. However, underutilization of mammography is a problem among older women in the United States. Elders are at the greatest risk for developing and dying from breast cancer but they are the least likely group to be screened routinely with mammograms or to practice breast self-examination, particularly if they are African-American. Design. Participatory qualitative evaluation focus groups were used to assess the overall impact of the video kit intervention programme and to elucidate the quantitative findings of the original study. Methods. Four focus groups were conducted in two diverse settings with a purposive sample of 23 participants (N = 23). The overall sample was predominantly African-American (87%) with mean age of 71 +/- 7.9 years and mean education completed of 12 +/- 3.4 years. Results. Five major themes emerged from group discussions: usability and appeal of the intervention, fear and empowerment, personal relevance and intergenerational sharing, impact on screening behaviours, and story telling. Conclusions. Analyses suggest that customized media materials constructed especially for older African-American women empowered participants in this sample to action regarding their own breast health. Relevance to clinical practice. These findings may translate to global populations where risk is increasing but screening programmes are not widely available. Given that older women are historically difficult to access and impact, further design and evaluation of innovative and sensitive educational programmes such as the one described here are recommended. PMID- 20925734 TI - Preserving personhood in dementia research: a literature review. AB - The aim of this literature review was to investigate studies that actively engage older people with dementia in research 'with' rather than 'on' them. The focus of the paper is the methods that researchers have used to ensure that studies are ethical, meaningful and preserve the personhood of individuals. The intention is to present a selection of papers rather than undertake an exhaustive review. It is well recognized that the prevalence of dementia in older adults is increasing, this increase is reflected by a huge rise in the amount of research into this area. The biomedical model continues to dominate dementia research however there is a small, but growing, body of research that actively seeks to engage people with dementia. This increase in research that actively engages people with dementia has developed in parallel with the 'new culture' of dementia care in which Kitwood (Dementia Reconsidered: The Person Comes First. Open University Press, Buckingham, 1997) exhorts us to respect the personhood of people with dementia. This review identifies 22 studies that sought the views and experiences of older people with dementia. There is evidence in each paper that the researchers had given thought to ensuring that their work was ethical, meaningful and preserved the personhood of individuals. The skill with which this aim was achieved varied considerably from formulaic approaches to those that clearly demonstrate that the researchers have a mindset that is grounded in a powerful belief in, and application of, the concepts of genuine respect for older people with dementia. The examples of good practice that have been drawn from these papers have direct application to both future research and to the provision of clinical care. PMID- 20925735 TI - Moving forward together: evaluation of an action group involving staff and relatives within a nursing home for older people with dementia. AB - Background. This paper describes the implementation and evaluation of an action group within a nursing home for older people with dementia. Over a two-year period, researchers worked with staff, residents and relatives on a series of initiatives aimed at improving experiences of living and working within the home. The action group, involving staff, residents and their relatives was the vehicle through which a number of important changes were achieved. The project was underpinned by ideas about relationship-centred care and the Senses Framework. Methods. A constructivist methodology informed both the initial development and the evaluation of the project. This paper reports findings from interviews with staff and relatives and process recordings of group discussions. Findings. Data from the evaluation provide evidence of ways in which the project has contributed to creating the senses (security, significance, belonging, purpose, continuity and achievement) for each of the key stakeholder groups. Factors supporting and hindering the project were also identified. Conclusions. The development approach using the Senses Framework adopted within the project is a useful model for partnership working in settings providing continuing care for older people. Relevance to clinical practice. Findings from this small-scale but intensive project suggest that staff within care homes should seek to engage with a range of stakeholders in order to improve experiences for all involved in long-term care. Academic staff within schools of nursing should consider innovative, action oriented approaches to supporting developments within care homes. PMID- 20925736 TI - Editorial: delirium. PMID- 20925737 TI - Delirium: a new appraisal of an old problem. AB - Delirium is a prevalent condition associated with high morbidity and mortality. Studies investigating delirium date back centuries but the subject has received increased attention in the last two decades. This recent attention focuses on, risk factors, early recognition, consequences and management of delirium. The aim of this paper was to provide an updated review of issues concerning the assessment and identification of delirium. Assessment is central to the effective management but delirium continues to be under-recognized by the healthcare team. This review sets the scene for the following papers on practice and the future direction for the management of delirium. PMID- 20925738 TI - Delirium and older people: repositioning nursing care. AB - Aims. To critically examine the nursing care offered to older people who have been delirious. Background. Delirium occurs as a result of physiological imbalances resulting in an alteration in consciousness and cognitive impairment. Delirium is a prevalent and serious cognitive disorder experienced by older people. While there is a vast number of studies published utilizing quantitative methods, there remains a dearth of research relating to delirium in older people from a qualitative perspective. Design. A qualitative research design that utilized a critical gerontological framework underpinned this study. This framework drew on aspects of postmodernism and Foucault's understanding of discourse. Methods. Data sources included published documents on delirium, semi structured taped interviews with people over the age of 65 years who had been delirious (as well as their clinical notes), family members, Registered Nurses and a hospital doctor. A postmodern discourse analytic approach was used to interrogate the 20 sets of data collected. Findings. Textual analysis revealed the presence of two major discourses impacting on being an older person with delirium. These were identified as a nursing discourse of delirium and a personal discourse of delirium. A nursing discourse of delirium was largely focussed on the biomedical processes that resulted in a delirious episode. Conversely, a personal discourse of delirium highlights that there are other ways of 'knowing' about delirium through considering the narratives of older adults, and their families, when offering a nursing service to this group of people. Relevance to clinical practice. Nursing needs to critically examine all aspects of nursing care as it applies to older people who have delirium to ensure the rhetorical claims of the profession become the reality for consumers of health services. The use of critical gerontology provides nurses with the tools to challenge the status quo and uncover the multiple, varied, contradictory and complex representations of delirium in older people. Inherent within a personal discourse of delirium is the importance of incorporating into nursing care communicative and other relational activities, such as forming and maintaining a therapeutic relationship. PMID- 20925740 TI - Editorial: 'Evidence-based healthcare - a lot of bull?'. PMID- 20925739 TI - Delirium, nursing practice and the future. AB - The preceding papers have outlined the issues of under-recognition of delirium, aspects of assessment to improve this situation and presented an alternative discursive construction of delirious patients. With respect to the understandings from the first two papers, the authors intend to suggest a direction for future practice and research in the area of delirium. The discussion will start with an overview of current international practice. Approaches focussing on the specific care of team members or on multidisciplinary care have been reported as well as approaches that focus on a clinical expert such as a nurse specialist or those that focus care of patients with delirium in a specific identified clinical setting. The literature represents variable evidence of the success, or otherwise, of different initiatives. The authors intend to provoke debate on the care of delirious patients and indicate the priorities for the future management of delirium. PMID- 20925741 TI - Research use in the care of older people: a survey among healthcare staff. AB - Background. Sweden has one of the largest proportions of older people in the world. To manage the healthcare needs of an aging population, there has been an alteration from hospital care to community-based care. In these settings, the majority of staff is enrolled nurses (EN) and nurse aides (NA) without university education. Aim and design. The overall aim of this cross-sectional survey was to explore staff perceptions of factors related to research utilization in the care of older people. Method. Questionnaires covering research utilization and demographics were sent to all staff (n = 132) working in seven units in older people care. The response rate was 67% (n = 89). The respondents consisted of ENs/NAs (n = 63), Registered Nurses (RN) and rehabilitation professionals (RP) as physiotherapists and occupational therapists (RN/RP n = 26). Results. Most of staff reported positive attitudes towards research. The RNs/RPs stated more often than the ENs/NAs that they wanted to base their practice on research (81% vs. 25%; P = 0.001). The RNs/RPs also reported a greater extent of research use in daily practice (54% vs. 17%; P = 0.001). Support from colleagues (77% vs. 22%; P < 0.001) and unit managers (73% vs. 10%; P < 0.001) for implementing research findings was also more frequently reported by the RNs/RPs compared with the ENs/NAs. The majority of the ENs/NAs stated Do not know on many items concerning attitudes towards research, support for research utilization and actual use of research. Conclusions. Despite overall positive attitudes towards research, the majority of staff did not use research findings in daily practice. This was particularly valid for the EN/NA group. Relevance to clinical practice. There is an urgent need for managers and others in the care of older people to develop strategies for implementing evidence-based practice that involves the EN/NA group. PMID- 20925742 TI - Discharging older people from hospital to home: what do we know? AB - Aims and objectives. The aim of this literature review was to examine empirical research to date on hospital discharge and illuminate areas in need of further exploration. Background. Discharging older people from hospital has long been associated with difficulties and complications. With a steady increase in the ageing population in Ireland and their use of acute hospital services, the successful management of hospital discharge is now a central concern to health service management. Methods. Using a seven-step approach by Stolz et al. [Scandinavian Journal of Caring Sciences (2004) Vol. 18, 111-119] a keyword database search was conducted which revealed 44 studies that matched the author's inclusion criteria. Results. These studies uncover aspects of the discharge process that are in need of further research, and particularly suggest more rigour in the measurement of hospital discharge outcomes. Relevance to clinical practice. This review focuses on a very important clinical issue given the predicted increase in the use of acute services by older people and the known vulnerabilities of the interface between hospital and community settings. PMID- 20925743 TI - Restraint removal: tension between protective custody and human rights. AB - Aims and objectives. To describe the culture of an aged care facility relating to restraint use and provide insight into the process of changing to minimal restraint care. Background. In 1999, the accreditation process for residential aged care facilities (This term has been used in Australia since around 1997 and replaces the terms 'nursing homes' and 'hostels') in Australia was extended to include a review of restraint use, with the view to minimization. As using restraint had traditionally been viewed as acceptable, it was expected that there would be tensions involved for staff making the transition to providing minimal restraint care. Design. The research was situated within the qualitative paradigm and guided by symbolic interactionism, grounded theory, and case study. Methods. Data were collected through observation of instances of restraint, individual interviews with staff, and document analysis. Results. The transition to minimal restraint care was associated with tensions for staff. Whilst efforts had been made to make the facility restraint-free, bedrails were still in evidence, and were not necessarily viewed by staff as constituting restraint. Conclusions. Nurses may experience a tension between human rights and duty of care when adopting restraint-minimization practices. Relevance to clinical practice. Tensions may be alleviated by adopting a universal definition of restraint, acquiring physical resources and new skills in care delivery and modifying staff, resident and family attitudes towards the delivery of care. PMID- 20925745 TI - Editorial: risk. PMID- 20925744 TI - Older people's experience of participating in a reminiscence group with a gerotranscendental perspective: reminiscence group with a gerotranscendental perspective in practice. AB - Tornstam's theory of gerotranscendence provides the theoretical underpinning for two small reminiscence groups that met for eight weekly sessions in a Swedish daycentre. Tornstams's theoretical perspective provides a developmental model for understanding positive progressive changes in values, attitudes and behaviour in the second half of life. Practical guidelines derived from this theory informed the group-work approach used. Participants' opinions about their reminiscence experience were analysed to determine the relevance of gerotranscendental theory as a basis for understanding older people's use of reminiscence in the ageing process. The study aimed at investigating older peoples' experiences of participating in a reminiscence group with a gerotranscendental perspective. The study used a qualitative approach. Older people were invited to participate in reminiscence group sessions arranged at a daycentre. When the sessions were finished, participants were interviewed about their experience of the reminiscence group. Data were analysed and categorized by using qualitative methods. The participants were satisfied with the arrangement of the group sessions. All participants believed they had reminisced and thought much more about their childhood and also recalled other memories from their lives during the period. Three quite different views emerged of the recall experience and effects of participating in the reminiscence group: 'An activity like any other; an activity that led to thoughts about memories from life or an activity that influenced my thoughts about life.' Findings suggest that it is possible to arrange reminiscence groups from a gerotranscendental perspective that serve as an intervention in gerontological nursing. This paper provides some guidance concerning how this type of group may be arranged and the various categories of participant response that may be expected. PMID- 20925746 TI - Risk and ageing populations: practice development research through an international research network. AB - Background. Risk theories derive from a range of disciplines, with nursing traditionally concentrating on scientific medical perspectives. However, for older people, risk perception and management is filled with complexity and paradox, and the threat of focusing on physical safety only to the detriment of the well-being of the older person. Method. An international collaborative research network on risk in ageing populations has been developed, with 22 members in six countries (Britain, USA, India, South Africa, Australia and Northern Ireland). The network supports several independent projects, many of which have developed as a result of the network. An annual workshop for members has provided the opportunity to share and synthesize methodological experiences and to identify a developing model of risk for older people. Findings. The developing model highlights the importance for older people of engaging with risk in a positive way, and describes patterns of risk-philic and risk-phobic activity. The inter-relationship of the individual older person with their community, with practitioners and with society is specific to the context of different countries. Conclusion. Socio-critical practice development research can be a vehicle for advancing an understanding of risk theory for older people. Risk underpins concepts of choice and capacity to execute decisions. It is influenced by society, policy, health and social care services, and has a profound impact on the experiences of older people. PMID- 20925747 TI - Risk perception among older South Asian people in the UK with type 2 diabetes. AB - Aim. To report on a study which developed a knowledge of the experiences of South Asian people with diabetes in the UK in relation to socio-cultural and dietary practices, religion and ageing influences on the perception and understanding of risks. Background. South Asian people have enhanced vulnerability to poor health as a result of diabetes. Risk perception and management is culturally mediated, yet imperative to the behaviour adjustments required for diabetes management. Method. A grounded theory study with data collected by focus group with ethnic health development workers and individual interviews with 20 older people with diabetes. Where necessary, interpreters were involved in data collection. Findings. A number of issues influence the perception of risk among South Asian older people with diabetes: beliefs about its cause, perceived severity and its visibility, food and its social function, religion and beliefs about external control over their life span and diabetes management. People weighed up the risks in making decisions about issues such as dietary management and the emphasis placed on diabetes as a pathology. Conclusion. Good risk communication will maintain the current trend of improving patient's choice and self-management in health care, and there is a need for this to be sensitive to the particular issues faced by South Asians with diabetes in the UK. PMID- 20925748 TI - The risk to enduring relationships following the move to a care home. AB - Aim. To explore findings from a study which investigated the meanings that older people attributed to their experiences of living in a care home and consequently the risks that they identify in this. Background. There is evidence from this and other studies that being able to engage in long-time friendships is important to older people. The move to a care home has the potential to disrupt these relationships and there is a risk of breakdown of the friendships that have been valued throughout life. Method. A hermeneutic inquiry that explored the meaning that eight older people ascribed to their life in the care home. This paper focuses on the narratives that concerned relationships with long-time friends and the risks to these relationships. Results. The paper highlights the importance of engaging in meaningful relationships with other people. The participant's stories illuminated the importance of maintaining friendships following the move to a care home and how these had had a positive impact on their lives in that setting. With advancing age and increasing frailty the participants were acutely aware that their friendships were vulnerable to breakdown and they implemented a range of strategies to sustain their relationships with these people. Conclusion. The findings point to the importance of acknowledging the value of long-time friendships to older people and the need to support them in their efforts to sustain these relationships and reduce risks to them. PMID- 20925749 TI - Risk factors for elder abuse and neglect: brief descriptions of different scenarios in South Africa. AB - Aim. To describe various situations in which older people in South Africa are vulnerable. Background. Poverty compromises the health of many older people in South Africa but the circumstances and ways in which this is managed and risk thought of is poorly understood. This paper presents three scenarios that describe individual studies and provide insight into the factors influencing the lives of some older people. Method. Scenario 1 concerns people with dementia. Pilot work has collected interview data from four people with dementia, their four informal carers and three hospital nursing staff. Scenario 2 concerns an analysis of data collected routinely as part of the Halt Elder Abuse Line, a telephone-based service for people to report abuse. Scenario 3 concerns an interview study with farm workers who have retired and who are vulnerable to being displaced from the farms. Conclusion. A variety of policy, social and individual factors result in older people being vulnerable and continuing research is required to further develop an understanding of these dynamics of risk to promote changes to current policy and practices. PMID- 20925750 TI - Guest Editorial: Cultural transformation in nursing homes. PMID- 20925751 TI - Guest Editorial: Privacy and dignity in residential care homes: cross-cultural issues. PMID- 20925752 TI - A comparative study of nursing staff, care recipients' and their relatives' perceptions of quality of older people care. AB - BACKGROUND: Comparisons of different stakeholders' ratings of the quality of older people care can help to drive quality improvement. AIM: The aim was to compare staff, older care recipients' and their relatives' quality of care ratings. DESIGN: Cross-sectional questionnaire surveys in 2003 and 2004, using a repeated measures design on an organizational level. METHODS: Nursing staff, care recipients and relatives in two older people care organizations were included. The ratings of an overall quality grade, information, activities, general care and staff skills were compared between the respondent groups. RESULTS: Care recipients in both organizations rated the overall quality grade significantly higher than nursing staff and relatives. Staff ratings of the information given to care recipients were significantly more positive than care recipients' and relatives' ratings. All three groups gave lowest ratings to the quality of activities offered to care recipients, with lowest ratings from nursing staff. CONCLUSIONS: Concurrent measurements of staff, care recipients and relatives' care quality perceptions can provide a broad evaluation of an organization's strength and limitations. Relevance to clinical practice. Staff, care recipients' and relatives' perceptions can be useful for older people care organizations and decision makers in developing care processes and outcomes of care. PMID- 20925753 TI - Psychosocial group rehabilitation for lonely older people: favourable processes and mediating factors of the intervention leading to alleviated loneliness. AB - BACKGROUND: Loneliness among community-dwelling older people is a common problem, with serious health consequences. OBJECTIVES: The favourable processes and mediating factors of a psychosocial group rehabilitation intervention in alleviating older people's loneliness were evaluated. DESIGN: Altogether, 117 lonely, home-dwelling individuals (aged >=75 years) participated in a psychosocial group rehabilitation intervention. The content comprised (i) art and inspiring activities, (ii) group exercise and discussions or (iii) therapeutic writing and group therapy. METHODS: The psychosocial group rehabilitation intervention was evaluated from the group leaders' diaries and by observing the groups. Experiences of loneliness and social participation were collected by postintervention questionnaires from the participants. Data were analysed using methodological triangulation. RESULTS: Doing things together and sharing experiences with their peers inspired lively discussions, created a feeling of togetherness and led to participants' empowerment and increased self-esteem. The intervention socially activated the participants, and their feelings of loneliness had been alleviated during the intervention. CONCLUSION: Several common favourable processes and mediating factors were identified in the psychosocial group rehabilitation intervention that led to alleviation of loneliness among older people. Relevance to clinical practice. The psychosocial group rehabilitation intervention gives nurses an effective tool to support older people's psychosocial resources by activating them and alleviating their loneliness. PMID- 20925754 TI - 'Alone with my pain - it can't be explained, it has to be experienced'. A Norwegian in-depth interview study of pain in nursing home residents. AB - BACKGROUND: Nursing home residents often have pain as their everyday experiences and experience pain in silence. OBJECTIVES: The aim of this study was to gain an understanding of how nursing home residents experienced pain and how it influenced their lives and daily living. DESIGN: The present study applied a descriptive design. Fifteen residents from nursing homes were recruited among the participants in a larger quantitative study who reported having pain. METHODS: A qualitative method using in-depth interviews was used. The data were analysed applying Kvale's method of interpretive analysis. RESULTS: Two dimensions of pain were identified: physical pain and pain as suffering. These are described in relation to factors that influence the intensity and the consequences of pain experiences. CONCLUSIONS: Physical pain may be relieved by various means of pain management. The residents experienced pain as suffering because pain management was not timely, inappropriate, or insufficient and also because of the nature of their social situation in nursing homes. RELEVANCE TO CLINICAL PRACTICE: Caregivers in nursing homes need to understand how it feels for residents to live with pain, to be interested in and aware of their needs and finally to know how to respond to their pain and suffering. PMID- 20925755 TI - Effects of clear visual input and change in standing sequence on standing sway related to falls during night toilet use. AB - AIM: The aim of this study is to provide objective evidence that clear visual input and change in standing sequence can reduce fall risk related to night toilet use among hospitalized older patients. BACKGROUND: In hospitalized older patients, falls are likely to occur during night toileting needs. METHOD: Using a stabilometer, we measured and compared maximal standing sway for 10 seconds immediately after standing with three visual input modes in two standing patterns, comparing healthy younger adults (n=22) and older patients (n=19). The three modes are no visual input (mode 1), vague (mode 2), and clear visual input (mode 3). Standing sequences A and B are defined as supine-to-standing and supine to-sitting-to-standing, respectively. RESULTS: For a given visual mode, maximal moved distance was significantly greater for older patients than for younger adults with both standing patterns (P<0.0001). Both standing pattern B and clear visual input decreased maximal moved distance in younger adults and older patients. A greater maximal moved distance score indicated a greater fall risk. RELEVANCE TO CLINICAL PRACTICE: It is important for nurses to train older patients to turn on the light and perform standing pattern B, when going to the bathroom at night. In addition, it is advisable to confirm the placement of distinct visual markers on the way to the bathroom. PMID- 20925756 TI - An exploratory study of nurse aides' communication behaviours: giving 'positive regard' as a strategy. AB - AIM: The aim of this study was to identify the communication behaviours and strategies used by socially skilled geriatric nurse aides working with residents in long term care facilities. BACKGROUND: Communication skills are recognized as tools for establishing relationships and accomplishing care related tasks. A small but growing research literature exists within gerontology around geriatric nurse aide/resident communication. The present study was intended to contribute to this literature. DESIGN: This study used an exploratory qualitative design involving personal interviews with geriatric nurse aides. METHODS: Interviewers carried out 90-minute interviews with 16 nurse aides who worked at an assisted living facility or a nursing home. Of interest was the extent to which established systems for coding interactions could be used to code nurse aide/resident interactions, or whether new categories would emerge. RESULTS: The novel finding that all of the aides used a communication strategy that could be characterized as 'giving positive regard', defined as acknowledging the resident, treating the resident with respect. RELEVANCE TO CLINICAL PRACTICE: The category of 'giving positive regard' included specific behaviours which can be included as content in communication skill training programs. PMID- 20925757 TI - Using gaming workshops to prepare nursing students for caring for older people in clinical practice. AB - BACKGROUND: Older people are the least satisfied with the care they receive when they are acutely ill. Furthermore, within nurse education, nursing older people has been submerged rather than embedded in the acute focus of nursing curricula. Lecturers designed a 1-day gaming workshop to stimulate interest in nursing older people. AIM: To explore the influence of gaming workshops on undergraduate nursing students' learning about nursing older people. METHODS: Both quantitative and qualitative methods were used. A survey questionnaire was distributed pre- and postgaming workshops to a cohort of second year nursing students (n=100, 86% response rate). Students (n=9) were invited to participate in a semi-structured interview on completion of their placement. FINDINGS: Responses were significantly more positive for the questionnaire postworkshop when compared with the responses of preworkshop. Five themes were identified from the interviews, they included teacher interaction; level of student engagement with the topic; the effect of the teaching method; influence of the workshops on practice; working with older people. IMPLICATIONS FOR PRACTICE: Nursing students preferred this novel teaching method to lectures. They learned about appropriate and relevant care of older people, however, they seem to struggle to apply concepts related to caring for older people in the acute settings. PMID- 20925758 TI - Editorial: Disaster relief: older people and care needs. PMID- 20925759 TI - Mapping the vulnerability of older persons to disasters. AB - Older people sit at the centre of a unique constellation of factors that combine to increase their vulnerability to the negative effects of catastrophic events. The aim of this paper is to explore some of the factors that underlie this vulnerability. Attention will be directed at three broad factors that will be discussed in some depth, namely poverty, long standing health conditions and psychological trauma. The aim is not, however, to provide a comprehensive systematic review of existing research evidence regarding the older person and disasters. This is due in part to the paucity of studies that take as their primary focus the older population and disasters. Whilst poverty, chronic illness and psychological issues are discussed in this paper as separate issues, they are interconnected. A map of the synergies between factors is presented that places the older person at the centre of a network of vulnerabilities. Recommendations for strategic planning and clinical practice are made that address this complex problem. The hope is that with insightful preparation the older population can be spared then worse consequences of a disaster when it strikes. PMID- 20925760 TI - Perceptions of older people on disaster response and preparedness. AB - Most disasters occur in developing countries but in the last decade due to the increasing threat of floods, air disasters and terrorist threat, disaster response and preparedness is a growing global concern. Due to an ageing population across the world, older people now constitute a significant proportion of those at risk from disasters. This paper reports on a qualitative study carried out in Sri Lanka and in the United States where a group of older people were asked about aspects of disaster response and preparedness. The group from Sri Lanka (n=9) who had direct experience of the 2004 Indian Ocean Tsunami were asked how they perceived international aid relief and a group of white Caucasians from East Coast USA (n=8) were asked about disaster preparedness. Findings indicate that both groups had similar issues albeit that they were looking at different phases of the disaster cycle and from different cultural perspectives. Both groups identified issues related to, protecting the rights of the older person and preventing loss of independence in responding and preparing for a disaster, mistrust of government and access to resources and all expressed strong feelings of self-responsibility. PMID- 20925762 TI - Editorial: Nurses need to prevent the abuse of older people. PMID- 20925761 TI - Addressing the imbalance: empowering older people in disaster response and preparedness. AB - This paper explores the role of the nurse in empowering older people at all stages in the disaster cycle. Evidence points to the need to increase the level of consultation and inclusivity of older people on this topic. Caution is called for in relation to classifying older people as a vulnerable group in disasters without first recognising that older people are probably the richest resource within any culture when it comes to emergency planning and?or coping with disasters. Practical advice on how nurses can best assist older people is presented. PMID- 20925763 TI - Current legal responses to elder abuse. AB - Abstract. In this paper, legal provisions for dealing with elder abuse in social or healthcare settings will be considered. The need for such measures for detection and management of elder abuse will be highlighted. Interventions should take into account elderly victims' vulnerability, which may be due to physical and/or psychological dependence. The effectiveness of current interventions is limited due to a lack of cohesion and the absence of a specific legal framework. The term 'vulnerable adults' is broader than 'elder abuse'. It is difficult to estimate the extent of the problem of elder abuse because of the usually intimate settings within which it takes place - this may affect the strength of the evidence. The purpose of this paper is to encourage a debate on the effectiveness of current legal responses to elder abuse. The true figures of the incidence of abuse may never be known. Consequently, in criminal law trials, providing evidence on abuse can be very traumatic and intimidating for a victim because of the circumstances in which it generally takes place. The irony is that the likelihood of a criminal prosecution may be higher in more serious types of abuse where the evidence is overwhelming, on the basis of the res ipsa loquitor (facts speak for themselves) principle. The abuse in question may be domestic or institutional; the effects nevertheless are the same. PMID- 20925764 TI - Partnerships between older people and their carers in the management of medication. AB - Background. Responsibility for medication can be an integral part of the informal caring role. Aims and objectives. To explore partnerships between older people and their carers in the management of medication and consider the implications for health professionals. Methods. Older people and their carers were identified through community pharmacies in four randomly selected areas of England. Data regarding their activities, responsibilities and experiences of managing medication were collected in semi-structured interviews conducted in respondents' own homes. Ninety-four transcripts relating to 47 older people and their associated carers were analysed using a qualitative approach. Results. Responsibility for medication was shared to varying extents between older people and their carers, and different patterns of partnership were identified. Differing perspectives between older people and their carers regarding the role, purpose and need for medication were revealed. Underlying these perspectives were issues concerning the sharing/concealment of information, autonomy and control. Caring was also described as a dynamic process. Older people and carers commented on how sharing responsibilities for medication varied on a day-to-day basis, as well as expressing concern regarding the changing needs of the older person and the carer's capacity to cope. CONCLUSIONS: Older people and their carers work together in diverse and sometimes complex ways to manage medication. Problems included dilemmas relating to the sharing of information, patient determination, disputes about the control of medication and concerns about the future. RELEVANCE TO PRACTICE: These patterns of partnership need to be recognized and taken into account by health professionals when providing information, advice and support. They need to listen for indications of differing perspectives and be aware of their possible implications for adherence to medication regimens. In caring for older people, health professionals need to find a balance that respects their autonomy whilst providing support for carers to enable them to be effective in their roles. PMID- 20925765 TI - Caring connections with older persons with dementia in an acute hospital setting a hermeneutic interpretation of the staff nurse's experience. AB - BACKGROUND: The literature highlights the challenges inherent in caring for older persons with dementia in the acute care context. However despite concerns relating to the quality of care available to persons with dementia in this setting, there is a paucity of research with which to guide practice. Specifically the existing literature lacks in-depth knowledge on nurses' experiences. AIM: The aim of this paper is to report the findings of a study exploring nurses' experiences of caring for older persons with dementia in an acute hospital setting. METHODS: Using a hermeneutic approach, a purposive sample of seven nurses was interviewed regarding the research phenomenon. Interview texts were subjected to thematic content analysis. Multiple data sources were employed to expand the horizon of understanding including: the textual data, personal and professional understandings, reflective journal data and conceptual frameworks derived from theoretical and research literature. The data were collected in 2002. RESULTS: The findings reported here relate to the theme 'Meeting the patient as a person'. Meaningful care for the older person with dementia in the acute context required a respectful connection with the patient as person, which required establishing a bond with the person. The meaning of the caring experience was found to relate to the personhood of both the nurse and the patient, experienced within the context of relationship. To make this connection it was necessary to work with those who knew the patient best i.e. relatives/carers. CONCLUSIONS: Despite the contextual limitations of the acute setting, the importance of knowing and respecting the person with dementia and the centrality of relationship as the medium within which caring is experienced is demonstrated. However, nurses lack specific knowledge on which to base care. Further research is therefore recommended to identify how care which promotes the integrity of the person with dementia may be effectively operationalized across the acute care setting. PMID- 20925766 TI - The impact of sensory impairment on social interaction between residents in care homes. AB - Aim. The aim was to draw on older people's narratives to illuminate the experience of living in a care home and the impact that vision and hearing impairments have on the individual's ability to engage in social interactions with other residents. Methods. The paper draws on two research studies, first, a hermeneutic inquiry examining the meaning ascribed to living in a care home, the second, a constructivist study, exploring relationships between residents, families and staff. Both studies drew on older people's narrative accounts to explore their experiences of living in a care home. On independently interpreting the narratives a similar theme emerged around the challenges to social interactions experienced by residents with sight and/or hearing impairment. This resulted in a cross study analysis to further illuminate this theme. Findings. The cross study analysis highlighted the difficulties residents experience in interacting with others, in the home, as a consequence of sight and/or hearing impairment, and the potential impact this had on feelings of social isolation. This is illustrated through narratives from two residents, one with sight impairment and the other with hearing loss. The narratives highlight the problems these people encountered and how resilient they were in adjusting to their sensory loss and maintaining social interactions. One conclusion from the study is the need for more empirical work in this area. Relevance to clinical practice. The paper identifies a number of issues for practice including staff taking a more proactive role in screening for, and managing, visual and hearing impairments in residents. Also the vital role staff play in ensuring the environment optimizes the residents' ability to fully engage in the residential community. PMID- 20925767 TI - Editorial: wandering. PMID- 20925768 TI - What's new about wandering behaviour? An assessment of recent studies. AB - Problem. The number and quality of studies on wandering and other behaviours has lagged that of biological sciences in the field of dementia research. Recent studies of wandering are examined for quantity, rigour, and findings. Approach. Medline, CINAHL and PsychInfo were searched systematically for studies of wandering. Research reports were reviewed and data was abstracted to characterise quantity and rigour. Study findings were organised by topic and summarised. Results. Between 2003 and 2005 inclusive, 47 studies met inclusion criteria. The largest proportion of studies was quantitative and descriptive; an explicit theory or framework guided about half of the studies. Major findings encompassed quantification and description, epidemiology, associated factors, and intervention and management of wandering. Conclusions. The growing body of research on wandering in becoming more rigorous. Newer measures of wandering have strong psychometric properties. Wandering occurs in multiple dementias and affects patients in larger numbers as dementia worsens. Wandering manifests similarly across cultural/ethnic groups and care settings and is associated with falls and increased mortality. A variety of interventions have been evaluated, but studies lack rigour. PMID- 20925769 TI - Implementing the wandering evidence for older people with dementia: key issues for nurses and carers. AB - This paper explores and discusses key issues for nurses and carers in implementing the evidence from the recent assessment of wandering studies conducted by Algase. Wandering is one of the most burdensome of all the behavioural symptoms and is increasing as the prevalence rates of dementia rise with the aging of the population. Wandering describes a diverse pattern of behaviour from aimless walking and pacing through to elopement. Until recently, the empirical evidence in relation to wandering and its implications for caring for older people has seriously lagged behind other research. However, several studies have led to important advances in the management of wandering and despite there being in some instances methodological deficiencies and modest efficacy, nurses, carers and older people who wander will benefit from the findings. PMID- 20925771 TI - Editorial. PMID- 20925770 TI - Wandering into the future: reconceptualizing wandering 'A natural and good thing'. AB - There is still significant scope for improvement in knowledge on wandering in dementia and in the care of persons with dementia who wander. Although progress in research-derived knowledge is evident over the last 15 years, the current state of practice is influenced by an immature research base where the clarification of what wandering is still needs to be achieved. This is fuelled by research which to date, has framed wandering as a problem behaviour and generally starts from the premise that it needs to be prevented or severely controlled. People with dementia may think and feel differently about wandering, as will be suggested in this paper. The voices of those who have experiential expertise of dementia and wandering need to be included in the debate on wandering to influence both nursing research and practice. In regard to the practice context, it is suggested that there is little evidence to suggest that screening for wandering, assessment of wandering, person-centred and evidence-based care planning and interventions or evaluation are yet the norm for older persons with dementia. Thus, these areas must be the priorities for the immediate future. Whilst at a theoretical level, there are three key issues that require attention in the future: the orientation of research on wandering including reconceptualizing wandering to address the lack of theoretical frameworks to explain wandering, addressing the need some care settings might have with application of research and recognition of the experiential expertise of older persons with dementia. PMID- 20925772 TI - The meaning of good and bad care in the community care: older people's lived experiences. AB - In spite of a considerable body of research in the past decades on what does or does not constitute good care for older people, there are still few studies addressing this question in which older people narrate their experiences of being dependent on community care. This study was therefore carried out aiming to explore older people's lived experiences of what good and bad care meant to them, when it was offered by community care services. Nineteen older persons in three Swedish communities participated in the study, which used a phenomenological hermeneutic approach. Data were collected through unstructured interviews and Colaizzi's framework was utilized in the analysis of the data. The key theme arising from the analysis was that of being encountered as a human being by caregivers who, through the provision of safe and secure care, provide opportunities for living life as usual. When any of these circumstances are lacking, bad care will be the consequence. As the general intention in society is to ensure good quality of care to older people as well as others, the findings in our study should have important implications for providers of community care for older people. PMID- 20925773 TI - Facilitating best practice in aged care: exploring influential factors through critical incident technique. AB - Aim. The focus of this study is on the perspective of facilitators of evidence based aged care in long-term care (LTC) homes about the factors that influence the outcome of their efforts to encourage nursing staff use of best practice knowledge. Design. Critical incident technique was used to examine facilitators' experiences. Methods. Thirty-four participants submitted critical incident stories about their facilitation experiences through face-to-face interviews, telephone interviews, and/or a web-based written questionnaire. The resultant 123 stories were analysed using an inductive qualitative approach. Results. Factors at individual and contextual levels impacted the success of facilitators' work. The approaches and traits of facilitators as well as the emotionality and intellectual capacity of nursing staff were the individual factors of influence. On a contextual level, the inherent leadership, culture, and workload demands within LTC homes, as well as externally imposed standards were influential. Conclusions. Primary factors influencing the facilitation of best aged care in LTC homes appear to be largely relational in nature and intimately connected to the emotionality of those who work within these settings. Enhancing the interactional patterns amongst staff and leaders as well as promoting a positive emotional climate may be particularly effective in promoting better aged care nursing practice. PMID- 20925774 TI - Nurses' opinions about a web-based distance course in a specialist education programme for the care of older people: a questionnaire study. AB - Aim. The aim of the present study was to investigate students' opinions about a web-based distance learning course that was part of a specialist education programme. Background. Most registered nurses (RNs) who work with older people in Sweden do not have a specialist education in caring for older people. Design. Survey. Method. The study was a descriptive survey with both qualitative and quantitative questions. Results. The students found the web-based course very useful for their theoretical and professional development. New perspectives on ageing, increased knowledge about analysing and describing theories as well as practising interviews and qualitative analysis as methods were appreciated by the students. Conclusions. One way for RNs in Sweden to get a university specialist education in the care of older people is to have a distance web-based course, as it allows flexibility and improves the students' theoretical and professional knowledge and communication skills. Relevance for clinical practice. Managers working in care for older people settings and educators will be interested in this study's finding that distance learning is a useful strategy for providing education for RNs who work with older people. PMID- 20925775 TI - Dignity as experienced by nursing home staff. AB - Aims and objectives. To explore nursing home staff members' experiences of what dignity in end of life care means to older people and to themselves. Background. Dignity is a concept often used in end-of-life care, but its meaning is rarely clarified. Design. Qualitative descriptive study. Methods. Content analysis. This study is based on interviews with 21 staff members in four different nursing homes in Sweden. Findings. The results show that staff members balanced between providing for the older person's physical needs while wishing to be able to deliver a 'deeper' level of care. The older people's dignity is presented in the main theme: Feeling trust - Showing respect. The staff members' dignity is presented in the main theme: Maintaining self-respect - Being shown respect. Threats to dignity are presented in the main theme: conflicts between the ideal and the reality. Conclusions. The results reveal that nursing home staff members deal with a moral conflict between what they are able to deliver and what they would like to provide in the care of older people. Relevance to clinical practice. To promote older people's dignity, there is a need to take account of staff members' work situation. Supervision and continuous education could be one way of achieving this. PMID- 20925776 TI - Prevention, detection and intervention with delirium in an acute care hospital: a feasibility study. AB - Background. The prevalence of delirium in acute care hospitals ranges from 5 86%. Delirious patients are at greater risk of negative health outcomes and their care is often more costly. Aim. To determine the feasibility of a full-scale trial to test the effectiveness of an intervention designed to improve delirium prevention, detection and intervention in an acute care hospital. Design. A delirium prevention protocol was designed by an interdisciplinary group of clinicians and implemented on intervention unit patients who passed a mental status screen, were at high risk for delirium according to the modified NEECHAM scale, and met other eligibility criteria. These patients were reviewed at daily interdisciplinary team meetings and team recommendations were placed in the patient's chart. On the usual care unit, physicians were notified if their patients were at high risk, but the delirium protocol was not implemented. Methods. The delirium protocol was pilot tested with 35 high risk patients on an Acute Care for Elders (ACE) unit. Outcomes were compared to 35 high risk patients on a similar medical unit without the delirium protocol. Results. The main outcome examined whether there is a difference in average day 3 modified NEECHAM scores comparing the intervention and control groups. The mean modified NEECHAMs on day 3 were not statistically significantly different (intervention group 3.76 and control group 3.24) (P= 0.368). Baseline NEECHAM scores did not correlate well with development of delirium (P = 0.204). A history of confusion during a previous hospitalization was the strongest predictor of developing delirium during the current hospitalization. Conclusion. This pilot study was not powered to detect an effect of the intervention, however, feasibility for a fully powered trial was established. Relevance to clinical practice. Completion of the NEECHAM screen every shift was not considered burdensome for either nurses or patients and may help identify acute delirium. PMID- 20925777 TI - Nursing staff's description of a good encounter in nursing homes. AB - Background. It has been stated that there is too little research on what constitutes good communication and good encounters in nursing homes. Aim and objectives. The aim of the present study was to examine nursing staff members' views on what is important in caring encounters with older people living in nursing homes. Design. A qualitative descriptive study using focus group interviews with staff in a nursing home in Sweden. Method. Focus group interviews, analysed using qualitative content analysis. Results. Three main themes emerged describing nursing staff members' opinions about the content of good encounters: 'Caring encounters from the perspective of equality', 'Caring encounters from the perspective of integrity' and 'Caring encounters from the perspective of promoting security'. Conclusions. The nursing staff had theoretical knowledge of what constitutes a good caring encounter, but they seemed to need more supervision and training to develop their ways of encountering older people as well as to become stronger in their professional role. When performing such training with staff, the methodology of appreciative inquiry could be a powerful tool. Relevance to clinical practice. It is important to help staff become empowered and to help them develop and improve their encounters with older care recipients. PMID- 20925778 TI - Differences in health status of older people aged 65 and above after total hip replacement compared with the normal population: a cross-sectional study. AB - Aim. The aim of the study was to describe the health status of older patients with osteoarthrosis following total hip replacement and to compare their health status with population norms in order to analyse the need for a rehabilitation programme after total hip replacement. Background. Total hip replacement is a very efficient operation in terms of pain relief and improvement of walking ability. However, after the operation some patients still report low health status. Method. A cross-sectional study including 287 older patients aged 65-74 and 75+ years who had had total hip replacement within the previous 12 months was performed. Patients from five Danish counties received a mailed questionnaire requesting information about their health status and demographic data. The Short Form 36 measures eight domains of importance of health. The scores related to each dimension are transformed to an interval scale ranging from 0 (worst score) to 100 (best score). Danish population norm data were used as reference point. Results. In total, 287 (91.4%) patients responded. The patients completed the questionnaire 207 (114) days after surgery within a range of 10-360 days. In all eight health domains patients reported significantly lower scores than the age specific norm population. Conclusion. Our results indicate that health status is scored lower for patients after total hip replacement. This implies that there might be a need for further postoperative rehabilitation based on the identification of problems experienced by patients in the postoperative period. Relevance to clinical practice. Patients health status is a predictor for well being, quality of life and survival. Older people need rehabilitation after surgery to reduce dysfunction and improve perception of health. Our results demonstrate a need for further studies examining problems experienced by patients in the postoperative period. Intervention research is needed before such a programme can be implemented. PMID- 20925779 TI - Editorial: Research culture - connecting what we do with what we know. PMID- 20925780 TI - The research/practice nexus: underlying assumptions about the nature of research uptake into practice in literature pertaining to care of the older person. AB - Much has been written about the link between practice and research in the nursing and health literature. The literature from fields of practice relating to care of the older person is no exception. Enhancing best practice to effectively meet the needs and desires of older people, and provide an optimal working environment for those providing that care, requires sustainable synergies between research and practice. However, the perception of a gap(s) between 'what we know' and 'what we do' persists in the writing in relation to the care of older people, as it does in healthcare more broadly. Rather than attempting to provide an exhaustive descriptive review of the literature, this paper reports on, and provides an analysis of, two broad thematic areas that are reflected in much of the writing about research and practice relevant to the care of older people. The first thematic area relates to literature that presupposes a linear/passive view of research uptake. The second thematic area includes literature that conceptualizes research uptake as dynamic/active. The discussion focuses on what these thematic areas can tell us about enhancing and optimizing synergies and connections between research and practice relating to care of the older person. PMID- 20925781 TI - Taking action to close the research/practice divide. AB - In this paper we focus at the level of individual project to explore aspects of the nexus between research and practice. Using a research project that sought to explore and understand care transitions for older people as the vehicle for our discussion, we examine how the process by which a research project itself is thought about, conceptualized, developed and conducted influences knowledge translation and ways to get research into practice, and conversely practice into research. Processes and strategies we engaged in throughout this research project to promote the transfer of knowledge both among and between researchers, practitioners and the wider practice community are highlighted. PMID- 20925783 TI - Editorial. PMID- 20925782 TI - Connecting what we do with what we know: building a community of research and practice. AB - How to think about, develop, maintain and optimize connections between research and practice remains a vexed and contested area in the increasingly complex multidisciplinary and inter-professional practice that constitutes contemporary healthcare and service delivery. A body of literature challenging linear and passive notions of research uptake has emerged which views research uptake as a dynamic, contextualized and active process. This paper explores the development of a successful and exciting community of research and practice involving a university and an aged care organization in Australia. The community of research and practice is premised on dynamic, contextual and active interaction between research and practice; where the categories of research and practice are not mutually exclusive or static; and where community is more than just a structure to facilitate collaborative research projects. It is proposed that the idea of a community of research and practice is a useful one in terms of seeking to better understand and provide strategies for knowledge translation between researchers and practitioners and those who are both. PMID- 20925784 TI - Developing a questionnaire to measure nurses' attitudes towards hospitalized older people. AB - A number of studies have used generic measures to evaluate nurses' attitudes toward hospitalized older people. Those measures do not consider the context in which nurses meet older people and the influence that this may have on nurses' attitudes. The aims and objectives of the study were to develop a questionnaire from focus group data to evaluate nurses' attitudes towards hospitalized older people. To evaluate the psychometric properties of the questionnaire the design included a qualitative and quantitative phase. The method used for the qualitative phase was focus group interviews with the intention of identifying the phenomena that may indicate nurses' attitudes towards older people. The quantitative phase included the development and psychometric testing of an attitudinal questionnaire. Samples for the qualitative phase included Registered Nurses from the care of older people setting; Registered Nurses from the acute setting; nursing students and nurse teachers. The sample for the quantitative phase included nursing students (numbering 355). Ten themes were identified through thematic analysis. Eighty items were extrapolated from the qualitative analysis and used to formulate a questionnaire which was then distributed to the nursing students. On analysis, the reliability was 0.78. Further analysis using Principal Components Analysis (P.C.A.) with orthogonal rotation indicated that 45 items loaded on to eight factors. Results of the quantitative analysis indicated that there was a strong correlation between the thematic analysis and the P.C.A. The results would suggest that there may be important and relevant domains that are worthy of further study into nurses' attitudes towards older people. If the domains identified are useful for identifying negative attitudes towards older people, then strategies can be implemented to try and reduce negative attitudes in clinical practice. PMID- 20925785 TI - An evaluation of the effectiveness of an educational and experiential intervention on nursing students' attitudes towards older people. AB - Objectives. This paper reports the results of a study that aimed to evaluate the effectiveness of an educational and experiential intervention on nursing students' attitudes towards older people. Background. With repeated exposure to very sick older people in hospitals or nursing homes, nursing students are at risk of adopting stereotypical views about this section of the population as frail and dependent. Design. A pre- and post-test design was used to conduct the study. Methods. Using Kogan's Attitudes Towards Old People Scale, the attitudes of nursing students were tested at the beginning of a degree programme in Adult Nursing (n = 130) and one year later (n = 94) following a series of visits to a well-older person in the community. Results. Nursing students reported positive attitudes towards older people and these were retained throughout the first year of their nurse training. No statistically significant differences were found associated with any of the five independent variables in either pre- or postintervention students. Conclusions. The attitudes of nursing students towards older people remained positive. While it is possible that the experiential and educational interventions utilized in this study may have contributed to the retention of positive attitudes, further research is required to test this hypothesis. Relevance to clinical practice. Nurses have a major role to play in responding to the health and social care needs of older people and their families. The cultivation of positive attitudes is a key factor in enabling practising nurses to respond to this challenge. PMID- 20925786 TI - Discharge of the older person from the emergency department - the perceptions of health professionals. AB - Aims of study. This study aimed to examine the management of the older person in preparation for discharge home from an emergency department by exploring the perceptions of health professionals on procedures undertaken particularly in relation to the planned support, supply of medications, dressings, and contact information given to patients. An additional aim related to the perceived satisfaction levels of older patients and their carers. Background. It is imperative that older patients are adequately prepared for discharge home from the emergency department so as to avoid unnecessary anxiety, increase in health problems and possible re-attendance or admission to hospital. Design. The sample in this study comprised the total population (n = 222) of all medical and nursing staff in both the emergency department and the primary care area. Methods. The method adopted was a survey approach which employed the use of standardized questionnaires comprising both open and closed questioning styles. Results. The data obtained identified results similar to previous research in that a discrepancy exists between hospital and community staff in relation to the procedures undertaken when discharging older people from the emergency department, such as arranging follow-up care and appointments and giving the patient relevant contact numbers and dressings. Conclusion. The findings of this study support previous research in that there is a need to provide patients with planned support, aids and appliances, clear instructions and relevant contact numbers on discharge from the emergency department. Relevance to clinical practice. Good quality discharge planning is essential for a continuum of care for older people discharged from the emergency department. While patient education is often difficult in the busy emergency department, the provision of relevant information to older patients prior to discharge is essential particularly in relation to prescribed medications and wound care. PMID- 20925787 TI - Self-perceived health among older women living in their own residence. AB - Aim. The aim was to characterize women who perceived themselves as healthy and to compare them with women who perceived themselves as less healthy with regard to demographical, social, medical and functional factors. Another aim was to describe changes within the healthy group after one year. Background. Self perceived health is influenced by several factors, of which diseases and illness are only a part. Method and participants. Two hundred and seventy-eight women, 75 and 80 years old, of which 50% (n = 139) perceived themselves as healthy and less healthy, respectively. Data were collected by using the Nottingham Health Profile, Geriatric Depression Scale, Mini Nutritional Assessment, Mini Mental State Examination and Philadelphia Geriatric Center Multilevel Assessment Instrument, in two examinations at intervals of one year. Results. The women in the healthy group were characterized as having no or low depression symptoms (P = 0.016), better physical mobility (P = 0.029) and better physical health (P < 0.001). Furthermore no or less pain, fewer doctor visits, more energy and fewer negative emotional reactions were predictors for self-perceived health in the healthy group at the one-year follow-up. Conclusion. The most important predictors associated with perceiving oneself as healthy were no or few depression symptoms, physical mobility and good physical health. Relevance to clinical practice. Attention has to be paid to women's mood, physical health, mobility, pain and energy to help them stay healthy. PMID- 20925788 TI - Prevalence of falls with minor and major injuries and their associated factors among older adults in long-term care facilities. AB - Aims and objectives. The objectives of this study were to determine the prevalence of falls with minor and major injuries and identify their risk factors. Background. Falls among residents of long-term care facilities (LTCF) constitute a significant health issue. Design. This is a secondary analysis of a cross-sectional study carried out among older people (n = 2332). Methods. This is a descriptive study focusing on the secondary analysis of a cross-sectional study carried out with a group of older people (n = 2332) in 28 LTCF in Quebec City, Canada. Research assistants collected original data for each resident from two sources: structured simultaneous interviews with two nurses per unit from each of the homes and a review of the residents' medical files. Results. 7.2% of subjects had a fall leading to minor injuries and 10.1% a fall leading to major injuries. Risk factors associated with fall-related minor injury are young age, male gender and cognitive impairment. Factors associated with fall-related major injury were functional autonomy and length of stay. In further statistical analysis, controlling for functional autonomy, disruptive behaviours and neuroleptic use were found associated with fall-related major injury. Conclusions. This study demonstrates that the factors associated with fall related minor injury are different from those associated with fall-related major injury. Relevance to clinical practice. This study suggests that nurses working with LTCF residents who are concerned about the prevention of fall-related major injury, may contribute to a reduction in such falls through optimal management of behavioural problems and neuroleptic use. PMID- 20925789 TI - Editorial: mental health issues for older people. PMID- 20925790 TI - Models of mental health care for older adults: a review of the literature. AB - Aim. This paper reviews literature that draws on models of mental health care for older adults. Background. It is predicted that as a consequence of the aging of the population the incidence of mental health disorders, common in older populations, will also rise. Many such disorders can be successfully managed if detected early. Assessment and management requires collaboration between health professionals who are skilled and educated in the management of older adults with mental illness and the use of models of care appropriate to this population. Results. The paucity of research in this area is demonstrated. Conclusion. The need for mental health nurses to challenge current models of mental health care for older adults is identified so that they take on an expanded and developed specialist role in care of older adults with mental illness. PMID- 20925791 TI - A needs-based model for older people's mental health. AB - Abstract Background. Mental health services for older people in South Tyneside (UK) have adopted a person-centred service model that is 'needs-led'. This service model uses Local Authority 'Fair Access to Care Services' (FACS) eligibility criteria to ensure fair and equal access to mental health services for older people in South Tyneside based upon their level of mental health need. This is achieved by the application of mental health specific criteria within the FACS framework. Aims. This paper describes how stakeholders from statutory and non-statutory organizations in South Tyneside, in consultation with service users and carers, collaborated to produce the model and the application into practice of the model. Furthermore, the development of specific indicators of level of mental health needs supplementary to FACS, as commonly shared and understood language across boundaries is described. Conclusions. The model is argued as the basis for collaboration and empowerment of practitioners across organizations to drive and lead positive change and is an essential and appropriate framework for the commissioning of services in addition to ensuring the appropriate and timely provision of needs-led services for older people with mental health needs. PMID- 20925792 TI - Mental health community liaison in aged care: a service of value to all. AB - Aim. This paper describes an effective community nursing role in which mental health care is brought to long-term care in a way that restores and promotes mental health wellbeing in the older person, builds understanding between clinicians, and develops staff confidence in attending to the whole needs of residents of nursing homes. Background. Mental health is a significant issue in the ageing population and there is much that mental health nurses as well as staff in long-term care can do to promote early detection of problems, facilitate effective treatment and build coping in the older person and family so that they recover from grief or depression issues and go on to make this stage of life satisfying and rewarding. Conclusions. The mental health nurse liaison role is a useful contribution to comprehensive aged care in the community. The role provides support to clinicians enabling them to develop skills and expand their area of practice, whilst creating an environment in which the needs of the client may also be better understood and thereby met. PMID- 20925793 TI - New directions in mental health practice with older people: Canadian strategies for mental health reform. AB - Aim and objective. The purpose of this article is to draw attention to problems in the Canadian health system that must be overcome if Canada is to ensure that older people can access the services they need. Background. Projections suggest that 20% of Canadians will be aged 65+ by 2021. If current prevalence rates for mental illness continue, this will result in a significant increase in the number of older Canadians with or at risk for mental illness and mental health problems. Design. Findings of the final report of the Standing Committee on Social Affairs, Science and Technology are summarized and related to the intended role and primary strategy of the proposed Canadian Mental Health Commission. Methods. The relevance of the Interprofessional Education for Collaborative Patient Centred Practice initiative launched by Health Canada is then considered in light of the intention that the Commission adopt collaboration with relevant stakeholders as its primary strategy for achieving mental health reform. Conclusions. Fragmentation in service delivery must be overcome if older Canadians are to receive age appropriate mental health services when and where they need them. Yet there is little evidence that the degree of interprofessional collaboration required can be achieved. Relevance to clinical practice The reforms advocated by the Senate Committee are widely embraced but evidence is needed on how mental health and other professionals can best learn to work together in the interests of older people and other mental health consumers. PMID- 20925794 TI - Models of mental health care for older people: implications for practice. PMID- 20925795 TI - Editorial: The need to be a global community. PMID- 20925796 TI - Incontinence: prevalence, management, staff knowledge and professional practice environment in rehabilitation units. AB - Background. Bladder and bowel incontinence is a major health care problem, which adversely affects the lives of many individuals living at home or in health service facilities. Current approaches to continence care emphasize comfort, safety and reduction of risk, rather than detailed individualized assessment and management. The literature illustrates a gap between evidence and actual practice and emphasizes the context of care as being a key element for successful implementation of evidence based practice. Aims. To identify prevalence of bowel and bladder incontinence and its management, investigate continence knowledge and describe the professional practice environment within a rehabilitation unit for older people. Method. An integrated evaluation of continence prevalence, staff knowledge and the work environment was adopted. Results. Findings revealed a high incidence of incontinence (60% urinary, 3% faecal, 37% mixed) a lack of specific continence assessment and specific rationale for treatment decisions or continuation of care. The focus was on continence containment rather than on proactive management. Staff demonstrated a reasonable knowledge of incontinence causation and treatment as measured by the staff knowledge audit. The evaluation of the work environment indicated a low to moderate perception of control over practice (2.39), autonomy in practice (2.87), nurse doctor relationship (2.67) and organizational support (2.67). PMID- 20925797 TI - Predicting needs for nursing home admission - does sense of coherence delay nursing home admission in care dependent older people? A longitudinal study. AB - Objectives. This study examined predisposing, enabling and need variables (Andersen's Behavioral Model) influencing the need for nursing home admission (NHA) in older people receiving home nursing care. In particular, the potential role of coping ability, measured as 'sense of coherence' (SOC), was studied. Design, sample, and measurements. A survey with baseline- and follow-up data after a 2-year period was undertaken with 208 patients aged 75+. The measures used were: gender, education, age, social visits, SOC, social provision scale (SPS), self-rated health (SRH), general health questionnaire (GHQ), clinical dementia rating (CDR), Barthel activities of daily living (ADL) index, and registered illnesses (RI). A Cox proportional model was used to examine factors that could explain risk of NHA. Results. Measures with predictive properties were Barthel ADL index, SPS, SRH, and gender. SOC, along with subjective health complaints, general health questionnaire, RI and social visits did not predict NHA. Conclusions. It is concluded that the patients' subjective evaluations of both their health and perceived social support were important predictors of future NHA needs, and should be seriously taken into consideration, along with the more commonly used objective measures of ADL and CDR. PMID- 20925798 TI - Impact of community care in enabling older people with complex needs to remain at home. AB - Aim. This aim of the study was to explore the impact of community care in enabling older people with complex needs to remain at home. Background. Changing demographic trends and successive government policies have led to an increase in the number of older people with complex needs residing in the community. Design. A qualitative approach using semi-structured interviews was used to collect data from older people (n = 17) and carers (n = 14). Method. Social workers were asked to identify community dwelling older people (65+ years) with multiple needs requiring interventions from a range of health and social care practitioners. Results. Community care enabled older people with complex needs who would otherwise have required residential or nursing home care to remain in their own homes. This was the expressed wish of both the older people and carers interviewed. Conclusions. The provision of high-quality community care for older people is a globally significant challenge and one that requires creative solutions, both at a local and strategic level. Relevance to clinical practice. Nurses and other health and social care professionals need to understand the significance of 'home' for older people and take steps to ensure that additional and appropriate resources are targeted towards community care. PMID- 20925799 TI - From alert commander to passive spectator: older male carers' experience of receiving formal support. AB - Aim. The aim was to describe older male carers' experience of receiving formal support. Background. To older male carers, creating new roles seems to be important. Their need for support in their caregiving is poorly understood. Design. A qualitative approach with a critical perspective on men and masculinities was used. Participants. Focus groups comprising a total of 11 men were used. Methods. Qualitative content analysis was adopted. Results. Three categories of response were found: 'using ad hoc solutions for maintaining a protective environment', 'coping but being left behind' and 'recapturing the caregiving role'. Discussion. Not only the quantity of support services offered to older male carers but also their quality dimension, based on a genuine understanding of the men's support needs, must be addressed. Conclusions. Professional caregivers attempt to relieve the men of their care obligations entirely. A reciprocal arrangement involving the men as partners, instead, may help them to regard their caring experience as valuable, which is important to their self-image. Relevance to clinical practice. These men's socially based networks need to be recognized by professional caregivers as important, to reframe the men's identity and notion of masculinity. PMID- 20925800 TI - Veteran preferences for end-of-life care. AB - Understanding one's disease and prognosis is a difficult thing for anyone to be faced with. Thinking about end-of-life issues can be incredibly stressful, and this is true for individuals who have knowledge of the options and services that are available to them. Not having knowledge about these issues can make facing decisions confusing, to the point of impossible. In addition, not having awareness of options when facing a terminal illness could mean missing out on receiving a lot of healthcare needs that others who have been provided with education and planning around these issues are afforded with. It is necessary that this very important aspect of care, education about palliative care, hospice, comfort care and advanced directives begin in primary care clinics, before individuals find themselves in acute care with so many unknowns. PMID- 20925801 TI - Implementation of the abilities-focused approach to morning care of people with dementia by nursing staff. AB - Background. The efficacy of the abilities-focused approach to morning care has been demonstrated in two studies. However, the extent to which nurses are aware of and actually implement abilities-focused interventions in day-to-day practice is not known. Aim. The study aimed to determine the type and number of abilities focused interventions delivered by nursing staff to residents with dementia during morning care. Methods. A one-group repeated measure design was used. Seventy-nine nursing staff attended an educational session to instruct them in the application of abilities-focused interventions. Data on the type and number of interventions used by nurses were obtained before, after and 3-months following attendance at the session. Data were collected through participants' self-report and observation. Results. Most nursing staff used abilities-focused interventions when providing morning care. Introduction to resident, orientation to resident and conversation with resident were three types of interventions most often applied over time. The number of interventions implemented increased after attendance at the education session and returned to baseline level at 3-month follow-up. Conclusions. Future research is recommended to examine the long-term effects of alternative designs of educational sessions. PMID- 20925802 TI - Editorial: Urinary incontinence. PMID- 20925803 TI - Promoting urinary continence with older people: a selective literature review. AB - As the population of older people increases so does the prevalence of urinary incontinence experienced. Despite its complex aetiology most of the contributing factors are reversible, when accurate assessment leads to the development of a person-centred continence care plan. This selective literature review highlights that a change in perspective among older people and healthcare professionals will enable a focus on bladder rehabilitation and proactive approaches to managing urinary incontinence, even in the very frail population. The need to design tools to facilitate such developments is discussed together with the need for greater focus on educational support that considers the wider context and the multiple factors that influence practice. PMID- 20925804 TI - Promoting urinary continence with older people: key issues for nurses. AB - Urinary incontinence is one of the most common and distressing of the conditions experienced by older people. It is not just associated with physical and cognitive frailty but also features significantly in the fit community living population. Urinary incontinence is known to be hidden and under-reported. Yet the needs of older people across the globe in relation to urinary incontinence will increase with the changing demography. Palliative strategies to contain urinary incontinence predominate in practice, although the reasons for this are not fully understood. Conservative approaches including lifestyle adjustments and behavioural therapies form the mainstay of active continence promotion but their routine use by nurses working with older people seems to be minimal. Promoting continence with older people is an area of practice long overdue for significant and sustainable practice development. PMID- 20925805 TI - Overcoming the barriers to optimum continence care: the need for an expanded approach to implementation. AB - In spite of a growing body of evidence to show that urinary incontinence is treatable or symptoms can be significantly improved in the majority of older people significant shortfalls in the quality of continence care are highlighted consistently in the international literature. The key barriers to providing optimal continence care for older people points to a need to address change not only from an individual practitioner perspective but also at the levels of the multidisciplinary team and organization. Examples of some emerging implementation frameworks that incorporate the broader context in which change occurs in 'real world' practice are introduced which may serve as useful guides. It is argued that if national and international standards of good practice for continence care are to be achieved, implementation methods have to take account of the complex interplay of patient, practitioner, social and organizational factors that mediate change. PMID- 20925806 TI - Editorial: Gerontological nursing research - do we have a lifespan approach? PMID- 20925807 TI - Coaching patients to self-care: a primary responsibility of nursing. AB - Aim. To explore the process nurses use to guide and support patients to actively re-establish self-care. Background. The movement of hospitalized patients from less to more independence is primarily a nursing responsibility. Studies of nursing practice in inpatient rehabilitation settings have begun to shed some light on this, but as yet there is limited understanding of the actual skills nurses use to support patients to re-establish self-care. Method. This study used grounded theory. Microanalysis and constant comparative analysis of data collected during interviews with, and observation of, registered and enrolled nurses during everyday nursing practice in five inpatient rehabilitation units facilitated open, axial and selective coding. Relevant literature was woven into the final theory. Findings. To facilitate patient transition from the role of acute care patient to rehabilitation patient actively reclaiming self-care, nurses engaged in a three-phase process known as coaching patients to self-care. The three phases were: easing patients into rehabilitation, maximizing patient effort and providing graduated assistance. Conclusion. Coaching patients to self care is a primary activity and technology of rehabilitation nursing. Relevance to clinical practice. Patients in a variety of settings would benefit from nurses incorporating coaching skills into their nurse-patient interactions. PMID- 20925808 TI - Risk management dilemmas in dementia care: an organizational survey in three UK countries. AB - Aims and objectives. The overall project aimed to understand the variability of the construction of risk in dementia care from the perspective of the person with dementia, family carers and practitioners with the intention of developing negotiated partnerships in risk management. This paper focuses on the objective of identifying the understandings of risk by practitioners. Background. Risk management can result in a 'safety first' approach to care practices, but this may be disempowering for people with dementia. Design. This paper describes the results of the first stage of the study: a survey to service managers or equivalent in health, social and voluntary sector care organizations in three countries of the UK. Methods. Data from this stage was collection by postal questionnaire (n = 46). Results. Risk was portrayed as a multidimensional concept and clustered around three themes: (1) Risk and Independence, (2) Risk and Resource, and (3) Organizational Risk Management. Conclusions. Very wide understandings of risk are identifiable, ranging from avoidance of physical harm through to managed risk taking to improve quality of life, and to an appreciation of the impact of organizational and professional patterns of behaviour resulting in harm to the person with dementia. Relevance to clinical practice. Obtaining information about the perspectives of others may help to illuminate some of the dilemmas experienced by staff in this study, and the development of risk assessment frameworks may assist staff to resolve some of these. PMID- 20925809 TI - Improving the oral health of older people in long-term residential care: a review of the literature. AB - Background. Unrefutable evidence now links poor oral health with the development of preventable systemic illnesses and debilitating conditions that threaten quality of life and life itself. This is especially significant for an increasing older population who are dependent on others for care. Aims and objectives. The majority of studies analysing the oral health of older dependent people in long term residential care have been undertaken by dental professionals. This critical literature review examines the issue from a nursing perspective because nursing care providers have a fundamental role in daily oral health provision for dependent residents. Conclusions. Multiple barriers were found to negatively impact on daily oral healthcare provision, including lack of care provider education, oral health values, availability of resources, implementation of supportive policies, documentation and oral health assessment tools. Relevance to clinical practice. The nursing profession, at all levels, must become pro-active in removing financial, political and workforce barriers that impact negatively on oral health outcomes. A multi-faceted approach is required to address these barriers, including development and implementation of oral health education programmes, assessment screening tools, care plans, documentation, supply of oral hygiene aids and the appointment of oral care 'champions'. PMID- 20925810 TI - Editorial: Preventing neglect in formal care settings. PMID- 20925811 TI - Elder abuse and neglect: the nurse's responsibility in care of the older person. AB - This paper presents a review of elder abuse and contextualizes it within selected publications which demonstrate the complexity of the topic. Such complexity is enmeshed within discourses of elder abuse and the interpretation within culture and professional discourses. This paper considers the discursive and practice silence in nursing with a particular focus on neglect. The publications selected are judged to represent key areas of discourses of elder abuse and neglect, rather than a wide-ranging literature review. PMID- 20925812 TI - The concept of frailty and its significance in the consequences of care or neglect for older people: an analysis. AB - Older people, and particularly those of advanced age, become increasingly vulnerable to the consequences of abuse or neglect and, since the birth of specialist services for older people, researchers and clinicians have sought to understand the reasons for this. ?Multi-agency work across the UK is developing innovative strategies, protocols and tools to support investigation into situations of possible neglect in formal care settings. Emerging within this work has been a dilemma concerning which terminology should be used to most accurately describe care in specific situations, for example should care be described as 'inadequate' or 'poor', or as 'neglect'. One key element in this decision is the consequence, or consequences, of the care for the vulnerable person, i.e. its impact on the individual. Because of the complex changes which accompany ageing, and particularly older age, this is not straightforward. Is a person's health deteriorating as a consequence of ageing or disease? Are factors such as mental state or motivation impacting on their health? Is this the trajectory that their health would naturally follow? Or is the deterioration a direct consequence of the care that they have, or have not, been given? And, if so, to what degree? Identifying ways of addressing these questions could support the development of a lexicon of terms and definitions which could be used to accurately define specific categories of neglect in specific circumstances.?This paper describes the practice based dilemmas that prompted this work. It briefly sets a historical context for contemporary understandings of the mechanisms that render older people particularly vulnerable to the effects of neglect. Some perspectives on defining neglect are offered. The paper then outlines the findings of a literature review and concepts analysis of the term frailty. It offers a new definition of frailty and explains the theoretical approach within which this nests. The paper concludes with a discussion on the implications of frailty as a consequence of care or neglect for older people. PMID- 20925813 TI - The development of the West Sussex institutional care neglect risk assessment tool: a reflective analysis using Mezirow's transformative learning framework. AB - The protection of vulnerable people is becoming more understood internationally, and in the UK standards of care for frail older people is now receiving appropriate attention (CSCI 2009, The state of social care in England 2007-2008. Commission for Social Care Inspection, London). Although many people continue to live in their own homes, even when they are very frail, many receive long term care in institutional settings, and are dependent on the standards, practices, belief systems and culture of the staff who care for them. As society becomes more intolerant of sub standard services, more adult protection investigations are being carried out to establish whether frail people are being neglected. Within West Sussex England, the multi agency safeguarding team addressed the dilemma of how to assess the risk to other residents in a formal care setting, when concerns had been raised about a small number of people who are resident in that place. The Consultant Nurse, used intuitive and craft knowledge, including examination of clinical evidence as audit data, collected as part of her practice, to examine how to assess the risk to others in formal care settings where care had been identified as neglectful for some of the residents. This paper uses the reflective framework of Mezirow transformative learning theory (http://en.wikipedia.org/wiki/Transformative_learning) to examine the development of a neglect risk assessment tool and highlight the issues identified by a consultant nurse in examining concerns about poor care and neglect in formal care settings. The final section of the paper describes the new Neglect Risk Assessment Tool developed in West Sussex, England, and offers case examples illustrating its use in practice. PMID- 20925814 TI - Shifting the focus: outcomes of care for older people. AB - Internationally there is commitment to work towards eradicating the abuse of older people and to develop services that promote their equality, dignity and human rights. The emphasis on service users is gradually increasing and, along with this, the focus within health and social care policy, service provision and professional practice is shifting. In UK health and social care policy the emphasis on service structure and provision is being replaced by a focus on outcomes for service users, including outcomes which patients themselves evaluate. The focus of UK Adult Protection services is also shifting from intervention to prevention through developing greater understanding of the factors which contribute to abuse, changing attitudes towards entrenched poor care, identifying preventative services and safeguarding vulnerable adults. Nursing literature is also beginning to acknowledge the evolution of an outcomes focus. This paper discusses the shifting emphasis in UK health and social care in the safeguarding of vulnerable people and in nursing practice. It offers an overview of literature on outcomes. The paper then describes a research study which sought to identify outcomes of care for older people living in UK care homes. The outcomes framework developed through the research is offered, along with a discussion of the advantages of an outcome-focused approach to care and some of the remaining challenges. A case example is offered to illustrate an outcomes-focused approach. Finally, the paper draws conclusions on how shifting the focus of care delivery from traditional problem-orientated approaches and ritualized practice towards the outcomes of care that individual older people choose and evaluate for themselves offers potential towards eradicating abuse and neglect in formal care settings. PMID- 20925815 TI - Guest Editorial: Health literacy in later life. PMID- 20925816 TI - Development and psychometric testing of a new geriatric spiritual well-being scale. AB - Aims and objectives. Assess the psychometric properties of a new geriatric spiritual well-being scale (GSWS), specifically designed for older adults. Background. Religiosity and spiritual wellness must be measured as two distinct concepts to prevent confounding them as synonymous among atheist and agnostic population. Design. A test-retest survey design was used to estimate the psychometric properties. Methods. A convenience sample of 138 community-dwelling older adults was drawn from the inner city of Detroit. Data were collected using telephone survey interviews. Data analyses included descriptive statistics, structural equation modelling, reliability analyses, and point-biserial correlations. Results. The factorial validity of the proposed model was not supported by the data. Fit indices were chi(2) = 185.98, d.f. = 98, P < 0.00, goodness-of-fit index of 0.85, comparative fit index of 0.87 and root mean error of approximation of 0.08, indicating a mediocre fit. Reliability statistics for the subscales ranged from being poor (0.36) to good (0.84) with an acceptable overall scale alpha of 0.76. Participants' performance stability and criterion related validity were also supported. Conclusions. The GSWS is an age-specific assessment tool that was developed specifically to address a population's cultural diversity. Future research endeavors will be to test the psychometric properties of this scale in culturally diverse older adult populations for further instrument development. Relevance to clinical practice. Nurses need to recognize that agnostics/atheists have spiritual needs that do not include religious beliefs or practices. Thus, assessing patients' religious beliefs and practices prior to assessing spiritual well-being is essential to prevent bias. PMID- 20925817 TI - Delirium and older people: what are the constraints to best practice in acute care? AB - An Australian research team conducted a six-month acute care pilot study in a medical ward of a large hospital in New South Wales. Aim. To explore ways health practitioners might redesign their practice to include prevention, early detection and management of delirium in older people based on the best current practice. Method and design. Participatory action research (PAR) was selected as the best approach for involving ward staff to make sustainable clinical practice decisions. The PAR group comprised research academics and eight clinicians from the ward. Thirteen PAR sessions were held over 5 months. Clinicians described care of patients with delirium. Stories were analysed to identify constraints to best practice. Following PAR group debate about concerns and issues, there were actions toward improved practice taken by clinicians. Relevance to clinical practice. The following constraints to best practice were identified: delayed transfer of patients from the Emergency Department; routine ward activities were not conducive to provision of rest and sleep; assisting with the patient's orientation was not possible as relatives were not able to accompany and/or stay with the older patient. Underreporting of delirium and attributing confusion to dementia was viewed as an education deficit across disciplines. A wide range of assessment skills was identified as prerequisites for working in this acute care ward, with older people and delirium. Clinicians perceived that management driven by length of a patient's stay was incongruent with best practice delirium care which required more time for older patients to recover from delirium. Two significant actions towards practice improvement were undertaken by this PAR group: (i) development of a draft delirium alert prevention protocol and (ii) a separate section of the ward became a dedicated space for the care of patients with delirium. A larger study is being planned across a variety of settings. PMID- 20925818 TI - Hip fractures and cognitive state: patient outcomes and proxies' perceptions of the rehabilitation period. AB - Background. Numerous studies are available on hip fracture and rehabilitation outcomes, some mention dementia but very few from a family/proxy perspective. Aim. To investigate whether cognitive state influences the hip fracture patients' rehabilitation outcomes as well as the proxies' perceptions of the 6 month rehabilitation period. Design. A survey with structured and unstructured questions. Statistics and content analysis. Methods. The questionnaire was sent to 40 proxies of hip fracture patients with and without cognitive impairment, 32 replied. Statistics and content analysis were used to analyse the data. Results. In the cognitively impaired group, physical function decreased (P = 0.0241) as well as locomotion (P = 0.0005) compared to pre-fracture. This group mainly participated in rehabilitation sessions in institutions (P = 0.0001) and their main support came from nursing staff. The cognitively impaired group assessed the rehabilitation period as being of a much lower quality than the cognitively intact group (P = 0.0048). In the impaired group, hindrances to rehabilitation were low level of staffing, and lack of access to rehabilitation resources such as physiotherapists. Conclusions and relevance for clinical practice. Hip fracture patients are a dichotomous group and cognition is decisive for physical and social outcomes as well as type of rehabilitation support. PMID- 20925819 TI - Factors supporting self-management in Parkinson's disease: implications for nursing practice. AB - Aim. To identify the factors associated with better self-management in people with moderate to high levels of Parkinson's disease following an acute illness event. Design and methods. A prospective, descriptive study conducted with 75 persons with Parkinson's disease over the age of 55, collected twice: within a week of an acute event and 1 month later, after resuming usual life at home. Participants completed a questionnaire on self-rated health status, self efficacy, sense of coherence, symptom monitoring and medication and general self management. Background. Parkinson's disease is a chronic neurological condition that affects many dimensions of life, including threats to self-identity and confidence in self-management. Self-management has the potential to reduce costs through decreased hospital admissions, disease progression and avoidance of complications. While evidence for the relationships between self-management and self-efficacy and sense of coherence has been demonstrated in some chronic illness groups, this has not previously been demonstrated in Parkinson's disease. Results. The independent predictors of better self-management were not being hospitalized in the last 6 months, more frequent symptom checking and better self efficacy for self-management. The influence of other factors on self-management, such as sense of coherence, was mediated through self-efficacy. Support of family and others was associated with better self-efficacy both directly and through an improved sense of coherence. Conclusions and relevance to nursing practice. The presence of informal support plays an important role in sustaining self-efficacy and sense of coherence and hence self-management in persons with Parkinson's disease. Since these attributes are amenable to change, nurses are in a good position to encourage participation in Parkinson's support groups, teach self management skills through regular symptom monitoring and to assess and promote self-efficacy and sense of coherence. PMID- 20925820 TI - Formal and informal care in relation to activities of daily living and self perceived health among older care-dependent individuals in Norway. AB - Background. Research about formal care of older home-dwelling people in the Nordic countries is comprehensive, while research on informal care has been less inclusive. Aim. To describe self-reported activities of daily living and perceived health, and to relate them to amount and types of formal and informal care received by a group of care-dependent, home-dwelling older individuals in Norway. Design and methods. A sample consisting of 242 persons aged 75+ years receiving home nursing services. Data were collected by means of structured interviews with questions about activities of daily living (ADL), amount and types of formal and informal care and demographic variables. Descriptive statistics, chi-square test, Mann-Whitney U-test and multiple stepwise regression were used in the analyses. Results. ADL dependency was the only predictor for explaining quantity of home nursing received. Those who received a generous amount of formal care also received a lot of care and support from informal networks. The type of care from the two sources differed. The home nurses performed PADL tasks. While the informal caregivers offered help with IADL tasks. Conclusion. This study of receiving help in this group of older people in Norway shows that formal and informal care resources complement one another. PMID- 20925821 TI - Editorial: Developing user-centred services. PMID- 20925822 TI - Discovery Interviews: a mechanism for user involvement. AB - Discovery Interviews have become widely used in the UK National Health Service as a service improvement tool and patient involvement mechanism. This first paper in a series of three explores the development of Discovery Interviews in the NHS in the context of explicit central government policy of the development of patient centred services and user involvement in shaping health service organization and delivery. It draws on the published literature on Discovery Interviews to date, including that on evaluation. PMID- 20925823 TI - Discovery Interviews with older people: reflections from a practitioner. AB - This paper reports on a nurse consultant's experiences of using Discovery Interview technique with older patients and their relatives about their urgent care experiences. PMID- 20925824 TI - Service improvement using patient narratives: engaging with the issues. AB - In this paper, the authors reflect on data quality issues arising from a UK project that trained senior practitioners to undertake Discovery Interviews with older people and their relatives about their urgent care experiences. These reflections are used to explore the potential for qualitative research methods to inform the development of the Discovery Interview technique. PMID- 20925825 TI - Editorial. PMID- 20925826 TI - The impact of residential respite care on the behaviour of older people with dementia: literature review. AB - Aim. The aim of this review was to examine the impact of residential respite care on the behaviour displayed by older people with dementia. Background. Relocation of older people with dementia to a different care setting could have a negative impact on their behaviour. If such a response is anticipated, a short term admission to a residential aged care facility for respite care would appear to be futile for the older person and their home caregiver. Therefore, it is important to know what the outcomes of residential respite care are in relation to behaviour for older people with dementia. Methods. A literature search was undertaken and papers emerged from a range of disciplines. The search terms 'respite'; 'respite care'; 'residential respite care'; 'short-stay', 'short term', 'overnight stays/admissions', 'behav*' and various combinations of these terms were used to find relevant publications in English from Ageline, CINAHL, Medline and, Psychinfo databases dating from 1966. Other key publications were located when searching through the reference lists of retrieved publications. A limited body of literature on residential respite care for older people with dementia was revealed. Results. Six studies were identified, which met the criteria of residential respite care as the intervention and behaviour as an outcome. Conclusions. The studies had a variety of methodological limitations and produced contradictory findings. The strength of the studies was the reporting of outcomes for respite recipients who are usually overlooked in the outcomes for respite research. Relevance to clinical practice. Residential respite care has great anecdotal support but more empirical and evaluative research is needed on outcomes for the respite recipients. PMID- 20925827 TI - Evaluating the context within which continence care is provided in rehabilitation units for older people. AB - Aim. This paper presents the first phase of an all Ireland 2-year study between the University of Ulster and University College Cork, to determine the contextual indicators that enable or hinder person centred continence care and management in rehabilitation settings for older people. The primary outcome of the study was the development of a tool to enable practitioners to assess the practice context within which continence care is provided. The main focus of this paper is the value of understanding practice 'context' (culture, leadership and evaluation) and its impact to the provision of person centred continence care. Background. The literature highlights the effect of continence problems on the quality of life of older people. Incontinence is often seen by health care professionals and older people as an inevitable consequence of ageing and difficult to treat. Furthermore, health care professionals do not always have the necessary skills and knowledge of best practice in continence care and treatments. The Promoting Action on Research Implementation in Health Services (PARIHS) framework utilized in the study proposes that successful implementation of evidence in practice is dependent on the inter-relationship of three key elements; the nature of the evidence, the quality of the context and expert facilitation. Kitson et al. propose that for successful implementation, evidence needs to be robust, the context receptive to change and appropriate facilitation is needed. Consequently understanding practice 'context' and its impact on the provision of person centred continence care is of value. Methods. Case study methodology with several data collection methods was utilized to measure all aspects of 'context' as identified by the PARIHS framework. Methods include: Royal College of Physicians Audit Scheme, Staff Knowledge questionnaire, semi-structured observation of practice and multidisciplinary focus groups. Findings. The data were analysed in two stages. Stage 1 using both qualitative and quantitative (SPSS 12) methods. Stage 2 analysed all the data utilizing the characteristics of context from the PARIHS framework in order to identify the strong and weak characteristics of the context within which continence care was provided. Continence care and management in this study was found to be focused on continence containment rather than proactive management. The evidence suggests that the context (leadership, culture and evaluation) was weak and not conducive to person centred continence care and management. Conclusion. An analysis of the data using the context framework provided a picture of the context within the units and the identification of the specific contextual issues hindering and enabling the delivery of person centred continence care. This process has thus, added to our understanding of the importance of context to the provision of person-centred care. PMID- 20925828 TI - Urinary tract infection: under treated and investigated: an examination of the nursing management of urinary tract infections in nursing home residents experiencing impaired cognition. AB - This research in nursing management of urinary tract infections in nursing home residents experiencing impaired cognition was informed through qualitative naturalistic enquiry. The findings suggest the response to this infective process lacks cohesive planning and the dearth of available evidence concerning the nursing management in this cohort has the potential to lead to detrimental health outcomes. The study exposes the complexities of issues which impact on satisfactory outcome. PMID- 20925829 TI - Training primary care nurses in late-life depression: knowledge, attitude and practice changes. AB - Aim. This paper reports on the uptake of a two-day late-life depression training programme with primary care nurses and its impact on knowledge, attitudes and the use of a brief screening protocol following training. Background. Late-life depression is a common condition associated with medical illnesses, impaired psychosocial functioning and risk for suicide. Although treatable, it is under recognized in primary care. Nurses have an important contribution to make to its detection, yet few studies have focused on training primary care nurses for this role. Design. An uncontrolled pre- and post-test design was used. Data were collected using the Late-Life Depression Quiz, the Depression Attitude Questionnaire (DAQ) and an Impact on Clinical Practice Questionnaire at 1 and 3 months. Seventy-three nurses commenced training and 66 completed the programme out of a total of 253 invited to participate. Results. Statistically significant differences were found between pre- and post-training for knowledge about late life depression (P < 0.0005). No significant association was found between age, length of experience, level of contact and pre-training knowledge scores. Attitudes towards depression were more optimistic following training which were significant for nine of the DAQ statements (P < 0.05). However, when the overall level of significance was adjusted for multiple testing of 20 DAQ items, two remained statistically significant (P < 0.0025). Finally, a 77% response rate to the 1-month practice questionnaire and a 52% at 3 months showed that nurses were using the screening measure (mean 5.0, SD 7.71; mean 5.6, SD 7.71 respectively). Conclusion. A short training programme on late-life depression was effective in producing both knowledge and attitude change in primary care nurses. The use of a short two-item depression screening measure prompted nurses to complete more in depth assessment for depression. Relevance to clinical practice. Training primary care nurses to identify and manage older persons with depression is essential to improve quality of life. PMID- 20925830 TI - Palliative care in nursing homes: exploring care assistants' knowledge. AB - Aim. To explore the level of palliative care knowledge and to identify educational needs of care assistants (CAs) working within a nursing home context. Background. In the United Kingdom (UK) many patients at the end-of-life are admitted to (or reside in) nursing homes, where they receive care from unqualified CAs who have little formal training. Mandatory training in specific skills to meet palliative care needs are absent. Method. Questionnaire to CAs in 48 of 91 private nursing homes in one UK region. Findings. A population of 1135 CAs were targeted with a response rate of 45% (n = 508). A high proportion of CAs in this sample required information about the philosophy and principles of palliative care. Results support the need for an educational initiative to improve palliative care in nursing homes. Conclusion. Although recognized as a common place of death for older people, CAs are often unprepared to provide end of-life care to nursing home residents. It is recommended that attention be given towards developing the skills and knowledge of this staff group. PMID- 20925831 TI - Challenges in community health nursing of old migrant patients in Norway - an exploratory study. AB - Old people of non-western minority backgrounds are an invisible group in Norway in several ways: in the national debate about the ageing population, in geriatric health care services, and in the general picture of ethnic minorities. There is a lack of knowledge about health and care amongst old migrants. This study aimed at exploring nurse managers' perceptions of the content of community health nursing care of older people from non-western countries of origin, and the challenges associated with caring for this group of patients. The study took place in a medium-sized Norwegian community, a mostly urban area with surrounding rural areas. The community health nursing system was organized in six districts with nurses in management positions, covering nursing homes, special housing and home based care. Data were collected by a questionnaire with structured and open-ended questions answered by 18 nurse managers. The data provided scarce information, but indicated a lack of systematic cultural care assessments. Community health nursing of old non-western migrant patients was described as deficient and a demanding burden. The challenges were captured in four themes: language barriers, family involvement in care, deficiencies in cultural competency and the need for development. Increased competency, action and local responsibility were identified as propositions to manage the challenges. The lack of awareness and knowledge concerning cultural issues found in this study highlights the need for further development and research on this topic. PMID- 20925832 TI - Researching with centenarians. AB - Aims and objectives. The objectives were shaped by ways in which to best engage the readers' curiosity about being 100 years old. Background. In the effort to reverse negative stereotyping associated with older people, the aim was to produce a book of individual stories for public readership that had the power to combat ageism and to present alternative constructions. Methods. Twenty-four centenarians were interviewed. Each person was asked to retell, using their own words, something about themselves and the social context that had shaped their lives. Centenarians could select whatever was foremost in their minds; an aspect of their lives that they wanted to share. We asked a few standard questions: What is it like to have lived one hundred years? What, in your opinion, has contributed to longevity? What matters today? A conversational approach to interviewing was adopted with the use of prompts to encourage story telling. Results. Centenarians privileged talking about their early years, childhood, going to school and first employment. Although most people could relate to a country upbringing and fewer years at school, subsequent life experiences and opportunities were diverse. Advice to others who desired a long life was keeping active, leading a simple life, eating well, working hard, maintaining an interest in events and surroundings, helping others and being moderate in all things. Maintaining a sense of humour was thought to be important. Loss of eyesight, mostly in the last few years, had been a profound disruption in the lives, creating new dependencies. Extensive family cohesion and frequent contact with others who cared was a profound feature. There appears to be a matter of fact appraisal of difficulties, losses and sadness but these were considered to be part of life and not particularly extraordinary. It seemed that these people had made a successful transition to living beyond 100 years old by leaving stress behind and moving on. Embedded in the stories of centenarians was a sense of self that was strong and resilient. Conclusions. The book containing 24 separate stories was published by Penguin. Sharing the stories of centenarians provided an opportunity to engage with the public readership and help shape wider social perceptions of older people as worth listening to. Relevance to clinical practice. In this paper, alternatives to dominant stories about ageing are presented and challenge the negative stereotyping of older people and its associated notions of decline, dementia, decay and death. Its relevance to clinical practice is precisely to show that older people are worth listening to. Moreover their ordinary lives make interesting, popular readership. Although the stories were primed to reach a wide public audience, we argue that its health promotion message and our creative effort to combat negative stereotypes can filter to healthcare delivery. PMID- 20925833 TI - Editorial: sexuality. PMID- 20925834 TI - Sexuality, health care and the older person: an overview of the literature. AB - Abstract. This paper reviews recent literature around sexuality, health care and the older person. The construction of sexuality and the importance of sexuality to older people are discussed, as is sexual diversity in old age, and sexuality and health. Also discussed are the myths and stereotypes associated with this topic, and the medical, social, healthcare, and institutional barriers to sexuality and sexual health in later life. PMID- 20925835 TI - Barriers to the expression of sexuality in the older person: the role of the health professional. AB - Sexuality is an important contributing factor to quality of life and sense of well-being. All adults have the right to express their sexuality, regardless of their age. Research indicates, however, that older people frequently experience barriers to the expression of their sexuality. Many of these barriers are influenced by the health professionals and services that care for them. This paper will outline these barriers and identify strategies that the healthcare professional can implement to help improve practice in this area. PMID- 20925836 TI - Sexuality: from stigma, stereotypes and secrecy to coming out, communication and choice. AB - Ageism and sexism have been remarkably successful in portraying sexuality as the preserve of young people and stereotyping older people as asexual. Older people have colluded in the stereotype by passing as asexual and generally keeping secret their ongoing interest in, or expression of, sexuality. The labelling as 'deviant' and associated stigma experienced by people who dare to breach societal stereotypes are recognized as tools used by powerful vested interests to maintain and manage the norms and values of society. Despite the sanctions, people do find ways of resisting, and over time norms and values change. This paper notes the centrality of sexuality to identity and argues that nursing is pivotally placed to recognize and value the older person's sexuality and support older people to 'come out' and re-claim the sexuality of their choice. It provides a provocative vision of how care and attitudes might look in 2025. PMID- 20925837 TI - Guest Editorial: My home life programme. PMID- 20925838 TI - How nursing home staff deal with residents who talk about death. AB - Aims. The overall aim of this study was to gain knowledge about how nursing staff treat and communicate with residents who talk about death and about their reasons for their treatment as well as to investigate how staff explain residents' reasons for talking about death. Background. Studies have established that nursing staff have problems in dealing with patients who talk about death and that staff do not know how they should relate to talking about death. Method. A qualitative explorative design. Interviews with staff were performed and analysed using a qualitative content analysis. Findings. Staff descriptions of their various ways of dealing with a situation in which residents talk about death could be divided into two qualitatively different main categories: 'allow and facilitate talk about death' and 'avoid talk about death'. The most common explanation provided by staff in all categories was that they acted the way they did because they did not know how to address discussions about death. Staff members' descriptions of residents' reasons for talking about death were quite different. Conclusions. The study indicates that nursing staff need to reflect on their own attitudes towards death and that they need to develop further. Their behaviour may depend on each staff member's individual attitudes and development. Nursing staff need training in and knowledge about how to communicate with residents who talk about death. This knowledge could be acquired through training, guidance and joint reflection in groups. PMID- 20925839 TI - Predictors of medication compliance among older heart failure patients. AB - Aim. To examine relationships between psycho-social and patho-physiological measures in explaining medication compliance in older heart failure (HF) patients. Background. Self-efficacy is a predictor not only of medication compliance, but also health recovery. How older HF patients conceptualize and manage this life-threatening event is central to ongoing rehabilitation. Regulating ongoing medical and lifestyle changes in the rehabilitation process requires that any underlying negative affect be productively managed by the use of appropriate coping strategies. Method. Using an exploratory correlational design, 51 older HF patients were asked to complete the Beck Depression Inventory, Beliefs about Medication and Diet Questionnaire, Reactions to Daily Events Questionnaire and Self-regulation scale. A self-report measure of medication compliance was obtained as part of a semi-structured interview. The study was conducted in 2003-2004. Results. Using descriptive statistics, patho physiological and psychosocial characteristics were given. Independent t-tests were used to assess the gender effects. Pairwise correlations were used to examine the relationships between presenting circumstances, psychosocial characteristics, medication compliance beliefs and self-reported medication compliance behaviours. All positive coping strategies and self-regulation were associated with positive intentions in medication compliance. Males were more inclined towards proactive coping and self-regulatory strategies than were females. Increased depressive symptoms were linked to carelessness in compliance. A belief in medication compliance was associated with a reduced likelihood of carelessness Conclusion. Bandura's three conditions for agency in rehabilitation, self-efficacy and goal-directed intention appeared to be important even in the early phase of the programme. Positive coping strategies and self-regulation suggests a positive basis for medication compliance and more successful ongoing rehabilitation for older HF patients. We identify a significantly enhanced educative role for nurses in this context. Relevance to clinical practice. We suggest that nurses dealing with compliance issues among older patients need to monitor behaviour through addressing both the quality of affect during the patient's response to HF (self-concept, -esteem and -efficacy) as well as the quality of health-related metacognitive knowledge underlying the self-regulatory decisions (such as the patients conceptions of 'wellness' and the strategic knowledge underpinning its achievement and maintenance). PMID- 20925840 TI - Older peoples' personal care needs: an analysis of care provision: care provision and the roles of key healthcare personnel. AB - Aims and Objectives. The study aimed to investigate and evaluate the provision of personal care for older patients within the acute care setting. Specific objectives included: (i) exploration of older peoples' perceptions of personal care provision; (ii) evaluation of nursing documentation related to personal cleansing and dressing care; (iii) identification of personnel responsible for personal cleansing and dressing care; (iv) identification of personal cleansing and dressing ward facilities; (v) development of a tool for use in the assessment and planning of personal hygiene and dressing care. Background. The maintenance of individual hygiene and dressing needs are key activities of living and constitute important aspects of personal care. This is an area of care which to date has attracted limited empirical enquiry. This paper reports on the findings from an evaluation study which sought to examine key aspects of personal care provision. Design. A quantitative multi-method research design was adopted. Methods. The methods used included patient interviews (n = 20), documentary analysis (n = 100) and a review of ward facilities (n = 5). Data were analysed using descriptive and non-parametric statistics. Results. Data suggest little patient involvement in decision-making regarding the provision of personal care. Documentary analysis highlighted limited assessment and care planning related to this key aspect of care. The key role of healthcare assistants in meeting personal care needs was highlighted and results indicated diversity in the availability of ward facilities. Conclusion. Inadequacies in the provision of personal care for older patients in the acute care setting are highlighted. While state-of-the-art ward facilities are desirable, they are not the determining factor in quality personal care. The key role of healthcare assistants in personal care provision is emphasized. A more structured approach to the assessment and planning of personal care is recommended. Relevance to clinical practice. A more individualized and person-centered approach to personal care is required. To facilitate this, a systematic assessment of personal hygiene and dressing needs is recommended using a structured format (Personal Hygiene and Dressing Chart) in order to address older peoples' needs related to this key activity during hospital stay. PMID- 20925841 TI - Emergency hospital admissions for ill-defined conditions amongst older people: a review of the literature. AB - Objective. To conduct a review of the literature on frequency and characteristics of emergency hospital admissions of older people for ill-defined conditions. Background. Emergency hospital admissions for ill-defined conditions are increasing for older people. Despite concern about this trend little is known about the frequency or characteristics of such admissions in emergency medical settings. Method. Relevant papers were identified by searching Medline, Cinahl, Web of Science and other databases. Papers that met inclusion criteria were selected. A descriptive analysis approach was taken. Results. Eighteen studies met the inclusion criteria for the review, all descriptive, survey or cohort studies. None directly investigated the patient group. Some relevant data were available, particularly in relation to frequency of admissions for ill-defined conditions. Conclusions. There is a paucity of research on the patient group, but the evidence available suggests the incidence of these admissions is high in emergency settings and in many countries. Future research on incidence in specific settings, appropriateness of admissions and patient characteristics is urgently required. Relevance to clinical practice. As the population ages increased numbers of older people will be admitted to hospital for ill-defined conditions. Nursing interventions may contribute to future management of these patients. PMID- 20925843 TI - Editorial: gerotranscendence. PMID- 20925842 TI - Experiences of health and well-being, a question of adjustment and compensation - views of older people dependent on community care. AB - Most studies concerning older people's health and well-being have focused on their ill health, disease and complaints and have mainly been conducted with a quantitative design. Hence, there is still a need for qualitative studies in which these peoples' own views on health and well-being are shown, especially when they are dependent on health care in a community setting. A qualitative approach was used in the study reported here and aimed at obtaining a deeper understanding of older peoples' own views about their health and well-being. Interviews were carried out on two occasions with 19 older people living in their own homes and in sheltered accommodation. The data were analysed using content analysis. The findings suggested that the possibility to feel healthy was dependent both on the older person's own ability to adjust or compensate to their situation, and on how their caregivers, relatives and friends could compensate for the obstacles the older person faced. The subcategories that captured the informants' experiences of health and ill health were described as positive and negative poles of autonomy, togetherness, tranquillity and security in daily life. The significance of the caregivers was clearly evident. Their competence, commitment and treatment were prerequisites for the older person's ability to experience health in spite of being dependent on care. PMID- 20925844 TI - The theory of gerotranscendence as applied to gerontological nursing - Part I. AB - Introduction. This article outlines the theory of gerotranscendence - a psychosocial theory of ageing developed by Lars Tornstam, a Swedish Sociology professor. Description of the theory. Through his theory of gerotranscendence, Tornstam has introduced a new understanding of ageing, stating that human development is a life-long process that continues into old age and that, when optimized, ends in a new perspective. The theory of gerotranscendence focuses on two phenomena: the old person and the ageing process itself. The theory describes both the experience of growing old and the characteristics of a normal and positive old age. Foundation and empirical base of the theory. The theory is based on both the ideas and theories of others as well as on empirical studies. Relevance of the theory and its application in nursing. The theory of gerotranscendence could provide new key concepts for understanding the developmental process of ageing and the transition into old age. This theory facilitates the possibility of structuring care for older people in addition to guiding it. Because the theory describes development and the meaning of development in older age, it is possible to discuss how care of older people could be structured as well as how staff caring for older people could promote the process of ageing. PMID- 20925845 TI - The theory of gerotranscendence in practice: guidelines for nursing - Part II. AB - Aim. The aims of this article were to describe both how guidelines were derived from the theory of gerotranscendence and the actual guidelines. It also discusses the relevance of guidelines to practice. Background. This article describes how guidelines were derived from the theory of gerotranscendence as well as the content of the guidelines and how they could be used. The view of ageing introduced by the theory may have several consequences for nursing staff members' attitudes and treatment of older people, as it offers a new understanding of living in old age. Resultant guidelines. Concrete guidelines at three levels - focusing on the individual, activity and organization - were derived using focus groups. The guidelines describe different ways to support older people in their process towards gerotranscendence. Conclusion. The theory of gerotranscendence and the guidelines could help support nursing staff in their attitude towards older people and could be used as a supplement to enrich the present care. PMID- 20925846 TI - Adoption of an innovation based on the theory of gerotranscendence by staff in a Nursing home - Part III. AB - This article presents an intervention involving introduction of the theory of gerotranscendence and practical guidelines derived from the theory. A qualitative method was used with triangulation of methods in data collection and analysis. Both the theory of gerotranscendence and the theory of innovation were used as frameworks in the analysis. Introducing this new perspective constituted an abstract intervention. It involved nursing staff changing their interpretations and values with respect to ageing and their treatment of older people in ways not compatible with extant values. The 'early adopters' were staff members who felt acquainted with the essential ideas of the theory because they perceived in themselves a personal developmental process in line with the theory. The innovation attributes, described in the innovation theory, explained some of the problems associated with adopting the guidelines. PMID- 20925847 TI - Editorial: A lot of things are happening with nursing and older people. PMID- 20925848 TI - Guest Editorial: 'Boundaries and barriers': redefining older people nursing in the 21st century. PMID- 20925849 TI - Attitudes of Egyptian nursing home residents towards staying in a nursing home: a qualitative study. AB - Aim. The aim of this study was to identify the attitudes of Egyptian nursing home residents towards staying in a nursing home and to differentiate between various types of these attitudes. Background. The number of older persons in Egypt who require nursing care is increasing. In response, nursing homes in bigger cities like Cairo were founded, although family care seems to be the prevalent norm. Methods. Semi-structured guideline interviews were performed with 21 residents from four different nursing homes in Cairo. Interviews were analyzed using qualitative content analysis. Findings. One category of resident was those who were sent to the nursing home by persons closely related to them. Another category made their own decision to move to a nursing home. Relationships with social networks and self-help abilities are factors of importance in influencing decision-making. Conclusion. Nursing homes in Egypt fulfil different functions for different types of older persons. Charitable institutions are a last resort for those with no income and a disrupted social network. For better off older persons, nursing homes may provide the benefits of socialising with peers and receiving medical treatment. PMID- 20925850 TI - Need for uniqueness in older women: an exploratory look. AB - Problem. Information about older women dwells on age-related illness and disabilities yet, other empowering traits could be promoting positive forces. Aim. While everyone desires some distinctiveness, this study explores higher levels of the motivational construct need for uniqueness (NU) in older women. NU concepts are: 1) perceived feelings of being or thinking different, 2) outspoken social behaviour, and 3) creative consumer consumption. Design. An exploratory, descriptive cross-sectional study provided quantitative data and focus groups generated qualitative data. Major results. Significant differences in all three NU concepts were evident between 87 (42%) with no/weak NU and 122 (58%) who 'preferred to be different from other people'. Focus groups provided examples over their lifetime within the context of their societal expectations. Relevance to clinical practice. The nurse's strategy to partner with older women to individualize their care and teaching will be important in maintaining their well being. Examining their decision-making with how they respond to perceived feelings of being or thinking different (such as taking risks), how outspoken are they, and their patterns of consumer consumption are a few questions that could be asked to examine an older woman's NU. Further research examining specific health care decisions in those with NU will also be needed to note their responses toward future self-care activities. PMID- 20925851 TI - Decrepit death as a discourse of death in older age: implications for policy. AB - Background. In Australia, care of the older person dying in residential aged care is contentious. This paper reports on selected results of a study of aged and palliative care policies, undertaken to elicit discourses of dying in aged care environments. Aims. To gain understanding of the relationship of policy to practice and to highlight commonalities and differences between aged and palliative care policies. Design and method. Utilizing discourse analysis, a range of palliative care and aged care documents were analysed, to explicate layers of complexity. Two divergent discourses emerged in the data organization. Results. The dominant palliative care discourse about dying decries an 'undeserved death'; the discourse about an older dying person is described as 'decrepit death'. These competing discourses provide a framework for examining emerging national policy work to improve care of the dying. Conclusions. Dying in residential aged care has been hidden and unacknowledged by the community. The challenge of providing more equitable care has recently received significant government policy attention. Relevance to clinical practice. Policy influences practice; both aged care and palliative care nurses, could benefit from understanding the place of policy in implementing changes on behalf of those in their care. PMID- 20925852 TI - Staying in 'the stream of life': rehabilitation of older people in their own homes following total hip replacement. AB - Background. According to World Health Organization (WHO), rehabilitation should be based on the person's entire situation with a focus on body functions, level of activity, participation and environment. But different types of investigations show an unclear concept of rehabilitation in professional nursing. Aims and objectives. This study aims to identify older persons' (>=75 years of age) experiences of the rehabilitation process after total hip replacement. Design and methods. Qualitative interviews were undertaken with six persons who were rehabilitated in their own homes following total hip replacement. The interviews were guided by Max van Manen's phenomenological methodology with its focus on the life world as described through patients' experience of time, space, body and interpersonal relations. Results. Staying in the stream of life confirmed the importance of the life world. What is essential in the rehabilitation process is to get back into everyday life as soon as possible and participate in activities which are meaningful and which are linked to being at home where 'you can be who you are'. The home is the framework for being in the stream of life, and it provides the centre of gravity for the people's welfare. Conclusion. Staying in the stream of life is about being the author of one's own meaningful life. It takes into account life phenomena embodied in the maintenance aspect of health care; dignity in relation to identity and integrity; and an understanding of the dialectical relation between frailty and strength. Relevance to clinical practice. Rather than focusing exclusively on patient participation and goal directed activity, nursing actions should integrate life phenomena as key aspects of rehabilitation with older people in their own right. PMID- 20925853 TI - Validity and reliability testing of the Oulu patient classification: instrument within primary health care for the older people. AB - Aim. The aim of the study was to evaluate the reliability and validity of The Oulu Patient Classification (OPC) instrument to see whether the instrument that has been developed for hospital care is valid and useful within primary health care for older people. Background. Although different patient classification instruments have been under development since the 1960s, this is still a very important research area today. Method. Inter-rater reliability testing of the OPC instrument was undertaken. The inter-rater reliability was tested through parallel classification (n = 1722). Validity testing was conducted as an expert validation of the manual for the OPC instrument, using a questionnaire during June and July of 2005 (n = 61). Results. The inter-rater reliability testing achieved over 70% consensus, Cohen's Kappa showed a strong consensus for OPC classifications (0.65). The reliability measured with Cronbach's Alpha was also acceptable. Conclusion. The results show that the OPC instrument provides a good overview of the patient's care needs and is a reliable instrument within primary health care for older people. PMID- 20925854 TI - Social support and networks in health promotion of older people: a case study in Brazil. AB - Aim. This research aimed at identifying social support for older people and their families. Background. The Brazilian National Policy for Older People's Health, created in 1998, is based on the promotion of healthy ageing, aiming at encouraging older people to remain in their environment and independently exert their functions in society. Nursing has engaged in this process, seeking to provide integrated care to the older person and family. Method. A case study with multiple participants was carried out. The inclusion criteria were families of older people over 70 years old who attended a Family Health Unit in the interior of the State of Minas Gerais, Brazil. Data were collected between April and June, 2007. In-depth interviews, genograms and ecomaps were used to collect data, which were categorized by thematic content analysis. Results. Three families participated in this study, totalling seven participants. Conclusions. The older people's families depend on institutional networks for their health maintenance. Spirituality and religion are mixed and are very expressive sources of support. Relevance to clinical practice. Assessing social support and networks can favour nursing interventions in order to intensify social interactions, promote leisure and help the families of older people to cope with life changes. PMID- 20925855 TI - Hope: a construct central to living with chronic obstructive pulmonary disease. AB - Background. Hope plays an integral role in health and illness and may assist individuals to cope in difficult and adverse circumstances, for instance when living with an illness such as chronic obstructive pulmonary disease (COPD), which can demand continuous adaptation. Aim. This paper reports the meaning of hope in people living with COPD as described by seven participants involved in a home-based pulmonary maintenance program. Methods. Using an interpretive phenomenological approach a purposive sample of seven participants were interviewed to understand participants' experiences of the phenomena of hope. An interpretative description is provided. Results. Thematic analysis revealed a number of themes, including that hope persists despite chronic illness and the unpredictable dilemmas of living with COPD. Many benefits were found to be gained from involvement in a home-based pulmonary maintenance program, including increasing exercise capacity, hope and wellbeing. Conclusion. Despite the limitations imposed by living with COPD participants revealed a determination to live as normal a life as possible. The pulmonary maintenance program was pivotal in assisting participants to improve exercise capacity, hope and wellbeing. Nurses may have a role to play in helping people with COPD maintain or regain hope. PMID- 20925857 TI - Editorial. PMID- 20925856 TI - 'I love nursing, but..'- qualitative findings from Australian aged-care nurses about their intrinsic, extrinsic and social work values. AB - Aim. The aim of this qualitative analysis - a component of a larger survey study, was to provide insights and understandings about intrinsic and extrinsic work values for nurses in aged-care. Background. Intrinsic and extrinsic work values impact on nurses' job satisfaction and ultimately nursing retention. This study contributes further to knowledge development in this area by building on a previous work values study in aged-care nursing. Methods. This paper presents the qualitative research findings from the final open-ended question from a survey of nurses employed in the aged-care sector in the State of Queensland, Australia in 2007. Data from a cohort of 105 aged care sector nurses was analysed relying on deductive content analysis. Findings. Two intrinsic work values emerged - low morale and images of nursing and two extrinsic work values emerged remuneration and working conditions. The work value 'working conditions' comprised four aspects of aged-care work, specifically staff turnover, workplace violence, care team membership specifically the Assistants-in-Nursing and paperwork. A single social workplace value 'support by management' is discussed as identified as important to these nurses. Conclusion. Qualitative insights into aged-care nurses' intrinsic and extrinsic work values suggest that work satisfaction is low. Workforce policy makers and employers of nurses in aged-care need to comprehend the relationship between job satisfaction, retention and work values. Relevance to clinical practice. These findings have implications for recruitment, retention and workforce planning within the aged-care environment. PMID- 20925858 TI - Human rights: Care of the human spirit. PMID- 20925859 TI - Innovative approach to health promotion for the over 45s: using a health check log. AB - Objectives. To determine effectiveness of the health check log (HCL) in promoting health-related quality of life and health awareness, health monitoring skills and timely consultation with health professionals for a cohort of community-dwelling people over 45 years, compared with a similar cohort not recording the HCL. Design. An exploratory longitudinal study using a quasi experimental methodology and data triangulation. Outcome measures included the SF 36 health survey; a semi-structured participant feedback survey and participant focus group discussions. Sample. A convenience sample (n = 309) of community dwellers over the age of 45 living in the South Eastern Sydney/Illawarra Area Health Service, Sydney, Australia. Results. The majority of participants recording the HCL reported health benefits. The SF-36 health survey found younger age is a predictor for positive change in 'social functioning' (beta = -0.14, t = 2.25, P < 0.05), while non-pension income was a predictor of positive 'physical functioning' (beta = 0.12, t = 2.02, P < 0.05) and 'general health' (beta = 0.13, t = 2.11, P < 0.05). Alternatively, full-time employment (beta = -0.12, t = 2.02, P < 0.05) and not living alone (beta = 0.18, t = 3.09, P < 0.01) predicted negative change in 'role - physical'. Participant reactions to recording the HCL via feedback survey and focus group discussions were mostly positive. Conclusions. The majority who maintained the HCL benefited by achieving improved health and knowledge of health monitoring, which was, however, moderated by age, income source, employment status and living arrangements. PMID- 20925860 TI - Support networks of older people living in the community. AB - Aim. The aim of the study was to identify the social support networks of older people living in the community in Ireland using Wenger's (1994) network typology. Background. The population of older people in the community is increasing. With increasing age and changes in family circumstances a substantial proportion of older people will require social, psychological and instrumental support. However a lack of adequate social support networks for vulnerable older people can result in poor health, loneliness and isolation. Method. A national, cross-sectional telephone survey of 683 people aged between 65 and 99 years was undertaken using the Practitioner Assessment of Network Type as the basis for identifying social support networks. Results. The results demonstrated that the majority of older people were living in stable and supportive social networks and reported high levels of contact with family, friends and neighbours. However, a significant minority of older people were living in vulnerable networks. Older people in these networks are susceptible to loneliness, isolation and poor emotional and physical health. Conclusion. Through the identification of people in vulnerable networks, nurses working both in the hospital and community setting can ensure that formal support is aimed at providing care to older people who do not have access to informal care networks. Furthermore, the predictive utility of the Practitioner Assessment Network Type (PANT) can enable nurses to identify people at risk of poor social support. PMID- 20925861 TI - Relatives' experiences of encountering the older person with acute confusional state: experiencing unfamiliarity in a familiar person. AB - Aims and objectives. The aim was to understand the lived experience of close relatives encountering older persons with acute confusional state. Background. Little is known about relatives of patients with acute confusional state and their experiences while encountering a family member exhibiting acute confusional state. Design. A descriptive phenomenological research approach was used. Methods. Data were collected by interviewing 10 close relatives of older people with acute confusional state at two hospital wards. Results. Relatives experience the encounter as encountering a familiar person who has suddenly become unfamiliar, struggling to separate the familiar from the unfamiliar and trying to understand the causes of acute confusional state and the behaviour of the person. Six constituents illuminate the phenomenon: 'change in the other person', 'rapid and unexpected changes', 'experiencing insecurity in the encounter', 'trusting or mistrusting the other person', 'experiencing loss' and 'experiencing exposure'. Relevance to clinical practice. It is important for professional carers to support relatives on how to encounter the person with acute confusional state, and to co-operate with relatives to gain knowledge about the unique person behind the acute confusional state. Conclusion. Relatives' difficulties in dealing with strong emotions evoked within the encounter, experiencing limitation and lack of trust is essential knowledge for professional carers in all care settings. PMID- 20925862 TI - The reliability of the Hendrich Fall Risk Model in a geriatric hospital. AB - Aims and objectives. The purpose of this study was to test the interrater reliability of the Hendrich Fall Risk Model, an instrument to identify patients in a hospital setting with a high risk of falling. Background. Falls are a serious problem in older patients. Valid and reliable fall risk assessment tools are required to identify high-risk patients and to take adequate preventive measures. Methods. Seventy older patients were independently and simultaneously assessed by six pairs of raters made up of nursing staff members. Consensus estimates were calculated using simple percentage agreement and consistency estimates using Spearman's rho and intra class coefficient. Results. Percentage agreement ranged from 0.70 to 0.92 between the six pairs of raters. Spearman's rho coefficients were between 0.54 and 0.80 and the intra class coefficients were between 0.46 and 0.92. Conclusions. Whereas some pairs of raters obtained considerable interobserver agreement and internal consistency, the others did not. Therefore, it is concluded that the Hendrich Fall Risk Model is not a reliable instrument. The use of more unambiguous operationalized items is preferred. Relevance to clinical practice. In practice, well operationalized fall risk assessment tools are necessary. Observer agreement should always be investigated after introducing a standardized measurement tool. PMID- 20925863 TI - A study of nurses' knowledge of a palliative approach in residential aged care facilities. AB - Aim. To identify residential aged care nurses' current knowledge of palliative care for older residents in need of end-of-life care. Background. Recently, there has been a growing interest in the delivery of palliative care in residential aged care facilities. While it is recognized that aged care nurses do possess palliative care knowledge the actual level of their knowledge has not been well documented. Design/method. An analytical study using a validated questionnaire tool - Palliative Care Quiz for Nursing, developed by Ross et al. [Journal of Advanced Nursing23 (1996) 126-137], combined with a demographic survey of Registered Nurses and assistants in nursing working in five high care residential aged care facilities in inner city region of Sydney, Australia. Results. The total Palliative Care Quiz for Nursing score possible was 20. The mean score for Registered Nurses was 11.7 (SD 3.1) and for AINs 5.8 (SD 3.3), the difference between scores being significant (t = 8.7, df 95, P = 0.000). Misconceptions in palliative care were identified for both the groups of carers. Conclusion. This research has highlighted the need for ongoing palliative care education for both the groups of primary carers. Relevance to clinical practice. The findings of this research highlight the existing palliative care knowledge of residential aged care nurses and provides evidence for education programmes. PMID- 20925864 TI - Editorial: care homes. PMID- 20925865 TI - Older people actively reconstruct their life in a care home. AB - The research reported here aimed to present the stories of care home residents through an interpretative study that was informed by a biographical approach and narrative method. Eight older people who lived in four different care homes in England participated in a sequence of up to eight narrative interviews over a six month period. The findings revealed how the older people tried to live as active biographical agents who were instrumental in shaping their own life in a care home. They were able to do this to a greater or lesser extent through the implementation of a range of resident-led strategies. The understanding of care home life that was developed through this study offers an alternative biography for living in care homes that is not only possible but achievable. This is a biography of frail older people who are active in reconstructing their life following the move to a care home, and living lives that are meaningful, purposeful and enjoyable. This sits in contrast to the standard biography that dominates current understanding of care home life that of older people merely 'existing' for the most part of their days. This image provides a vision for long term care for older people, which is grounded in the views and aspirations of older people. PMID- 20925866 TI - Using relationships to develop practice that values the contribution of older people, families and staff. AB - Relationships between staff, residents and their families have emerged within the literature as fundamental to the experiences of life within the community of a care home. While there is consensus in the literature that such relationships are central to caring processes, there is a dearth of studies that have explained how different factors contribute to the formation of relationships. The research reported here aims to describe the nature of relationships and develop an interpretive framework to understand how relationships influence the experience of residents, families and staff in care homes. This paper is based on the findings from a constructivist inquiry. Data were collected in three care homes using participant observation, interviews and focus groups with older people, families and staff. Constructivist methodology seeks to share multiple perceptions between participants with the aim of creating a joint construction. This process, known as the hermeneutic dialectic supported the development of shared meanings as views and ideas were shared between participants. The findings suggested that three types of relationships are developed within care homes: pragmatic; personal and responsive and reciprocal. These relationships are influenced by a range of factors that include leadership, team working and the contributions made by residents, families and staff. PMID- 20925867 TI - Living bereavement: an exploration of healthcare workers' responses to loss and grief in an NHS continuing care ward for older people. AB - This article reports on research rooted in a work based education project and the theme of loss was chosen by the participating care staff who felt it was central to their work with dependent older people. They coined the phrase 'living bereavement' meaning the complex responses and grief reactions of those experiencing and bearing witness to the multiple losses endured in continuing care environments. Aim. The research was to identify the emotional demand of living bereavement and to explore and develop care staff's capacity to work with it. Methods. Qualitative methods including participant observation and Reflective Work Groups were used to generate and analyse data over a three year period. A psychoanalytic dimension was added to the research through participation in a supervision group facilitated by a psychotherapist. Findings. In the article the key message from the findings, that there is an intense emotional demand in care work related to loss and grief in continuing care environments, is explained. The trajectory of living bereavement is discussed and illustrated with examples. Implications for practice. Some emotional aspects of the care work were glossed over or ignored which affected the way care was delivered. This may have been because the feelings were disturbing or painful to deal with. It is important to support staff working with difficult feelings so that emotional aspects of their work can be acknowledged and thought about. PMID- 20925868 TI - The Norwegian teaching home program: developing a model for systematic practice development in the nursing home sector. AB - Background. In the mid-1990s, there was persistent critique of the quality of care provided in residential aged care facilities in Norway, in line with similar concerns expressed in many other countries. Difficulties recruiting qualified staff and high turnover led to difficult working conditions. Little prestige was associated with providing geriatric care. Collaboration between educational institutions, universities and elderly care institutions with the purpose of strengthening education, competence development, practice development and research within elderly care was poorly developed. The Norwegian teaching nursing home (NTNH) program was launched to address these issues. Aim. The purpose of the NTNH was to contribute to the quality of care of frail older persons by improving the competence of staff, improving the prestige of working with older people, stimulating development of services, facilitating research into the care of older persons, and developing good learning environments for students. Methods. The NTNH-program was developed over a period of seven years, applying a participatory action research design. Progressing through four phases, it involved a number of people and institutions across Norway. Results. Formal and informal competence of staff was increased. A large number of practice development projects contributed to increased quality of care in selected problem areas. Models of competence development were disseminated to other institutions, thereby improving the level of competence beyond the NTNHs. Learning conditions for students were improved. Following a formal evaluation of the program, teaching nursing homes (TNHs) were established on a permanent basis in 2004, with financial support from the Department of Health and Social Services. In 2008, a total of 20 TNHs are part of the NTNH program. Conclusions. The NTNH program led to permanent establishment of a series of TNHs responsible for contributing to competence development, practice development and research on a continuous basis in order to secure high levels of care to the Norwegian nursing home population. The program has created substantial enthusiasm within the nursing home sector and has increased the prestige of these institutions. PMID- 20925869 TI - Current situation of German care homes. AB - Aim. The aim of this paper is to explore the situation of and current developments in the German care home sector. Background. Germany, like other Western countries, faces demographic change and subsequently tries to develop structures and processes to achieve a care system which can tackle the increasing number of people in need of care with a variety of quality services. Policy strives to set up structures and instruments to enhance the quality of service provision. Discussion. Figures show that the structures in the care sector are changing in favour to increased privatization of homes, a slight increase in size and improved building structures. In order to tackle the expected changes, a mix of low and high skilled qualification and new job profiles arise in the care sector. Other changes to be observed are the development of new living arrangements and the utilization of new technologies to support the care process. Conclusion. This contribution looks at the socio-demographic changes in care, the statutory developments and the structures of care homes as well as current discussions on future developments. PMID- 20925870 TI - Calling for an international dialogue on quality of life in care homes. AB - meyer j. & owen t. (2008) International Journal of Older People Nursing 3, 291 294?Calling for an international dialogue on quality of life in care homes. PMID- 20925871 TI - Editorial: The importance of dignity. PMID- 20925872 TI - Tactile stimulation associated with nursing care to individuals with dementia showing aggressive or restless tendencies: an intervention study in dementia care. AB - Aim. This study aimed to describe from documentation both the caregivers' experiences of giving tactile stimulation to five people with moderate-to-severe dementia and who showed aggressive or restless tendencies, and the changes seen in them. Background. Clinical experiences indicate that tactile stimulation can contribute to a feeling of trust and confirmation as well as to improving communication, promoting relaxation and easing pain. There is, however, very little scientific documentation of the effects of touch massage for people with dementia. Design. From caregivers' documentation (28 weeks) of experiences, the giving of tactile stimulation to five randomly selected people with dementia showing aggressive or restless tendencies and the subsequent changes noticed. Method. The documentation was analysed by using qualitative content analysis. Results. All residents displayed signs of positive feelings and relaxation. The caregivers stated that they felt able to interact with the residents in a more positive way and that they felt they had a warmer relationship with them. Conclusion. Tactile stimulation can be seen as a valuable way to communicating non-verbally, of giving feedback, confirmation, consolation or a feeling of being valuable and taken care of. Relevance to clinical practice. Tactile stimulation has to be administered with respect and care, and given from a relational ethics perspective. Otherwise, there is a risk that tactile stimulation will be used merely as a technique instead of as a part of an effort to achieve optimal good, warm nursing care. PMID- 20925873 TI - A model of event-generated dependence in older adults. AB - Aims and objectives. The proposed model of event-generated dependence characterizes dependence in older adults as an emergent phenomenon that may arise from interaction between the older adult with compromised health and the social environment, resulting in altered reciprocity. Background. Pejorative characterizations of dependence in older adults influence nursing care negatively. Concept analyses recommend the recognition that dependence is interactive in nature, not an inherent trait of the individual, and that dependence involves changes in interpersonal reciprocity. Conclusions. The model provides a testable causal path between dependence and psychological outcomes. Relevance to clinical practice. The event generated dependence model can sensitize nurses to an alternative view of dependence. It is important for nurses to recognize their role in determining the social environment of care, attend to the promotion of reciprocity with older adults as care is provided, and incorporate changes in their attitudes toward inequitable reciprocity. PMID- 20925874 TI - Life situation and daily life in a nursing home as described by nursing home residents in Sweden. AB - Aims and objectives. The overall aim of this study was to investigate nursing home residents' opinion of their life situation in a nursing home and of their earlier life. Background. Few studies have focused on residents' perception of their daily life and life situation in nursing homes. Design. A qualitative explorative design was used. Methods. Residents in a nursing home were interviewed and qualitative content analysis was performed. Results. The views of life residents described and how they apprehended their situation were quite different. The findings give an understanding of what it is like to live in a nursing home and show that residents apprehend their situation in very different ways. All individuals who were content with their situation in the nursing home were also content with their earlier life. Relevance to clinical practice. For the nurse in gerontological care, it is a challenge to get to know each resident and to provide the best nursing care and the best individual treatment for each resident. Another challenge is to help each resident find a life in the nursing home that is acceptable for him/her, and one aspect of this involves helping residents in their ageing process. The present study highlights what an important role staff have in relation with nursing home residents. PMID- 20925875 TI - Designing a Resource Guide to help promote health in caregiving. AB - Aim. To describe development of a Resource Guide, one component of a theory based intervention. The Guide contains information and ideas to illuminate caregivers' self-care knowledge as a basis for organizing and reinforcing self care activities. Background. Inherent in the complexity of caregiving roles is the emergence of caregiving as a responsibility, often overshadowing caregiver's personal care needs. Health care professionals can partner with caregivers to promote caregiver health. Self-Care TALK is a multimodal intervention to support this partnership. Methods. Two theoretical perspectives guided Resource Guide content; adult learning theory and the schema model of cognitive behavioural theory. Materials to stimulate conversations about caregivers' personal concerns about self-care were adapted from extant literature. Sources of information were chosen based on caregivers' learning needs and images of health. Areas of development focused on content, reading level/readability, graphic design, and self-evaluation. Results. The Resource Guide standardizes Self-Care TALK protocol while personalizing caregivers' self-care. The Resource Guide provides structure for conversations about what self-care is and ways to promote health. Conclusion. The Resource Guide promotes a learning environment that complements interests and experiences of older caregivers. Use of the Guide supports and extends caregivers' self-care vocabularies, and helps clarify self-care schemas and health promotion. PMID- 20925876 TI - Coming and staying: a qualitative exploration of Registered Nurses' experiences working in nursing homes. AB - Aim. This paper reports on a qualitative study that explored the reasons why Registered Nurses (RNs) chose to work in nursing homes in Southern Ontario, Canada and what factors attracted them to remain. Background. There is a paucity of information about factors associated with the recruitment and retention of RNs within long-term care (LTC) in Canada. As the population of older people is growing in Canada and elsewhere, it is essential that we better understand what attracts RNs to work and remain in this setting. Design and method. A case study approach was used in this study of nine RNs working in three nursing homes. Data were collected through in-depth interviews. Findings. Six sub-themes were identified: 'Job of Choice', 'Job of Convenience', 'Caring for the Residents', 'A Supportive Environment', 'Heavy Workload' and 'Supervisory Role of the RN'. Conclusion. Nurses chose to work in the nursing home because it was a 'Job of Convenience'. However, characteristics of the organizational environment played a major role in their remaining. Also, the caring relationship with residents played a role in the nurses remaining in this setting. Relevance to clinical practice. Strategies are provided that nurse managers may consider when planning recruitment and retention activities for LTC settings. PMID- 20925877 TI - A comparative review of the Katz ADL and the Barthel Index in assessing the activities of daily living of older people. AB - Assessment of a patient's functional ability to perform activities of daily living is an essential part of nursing. Measuring the functional ability of older adults is a potent predictor of a patient's morbidity and hospital outcome. The information generated from assessment scales is only constructive if the information generated is clinically useful and scientifically reliable. The Katz activities of daily living and the Barthel Index are two of the oldest competing indices for assessing activities of daily living. The Katz activities of daily living and the Barthel Index evaluate a patient's function in terms of level of independence or dependence when performing certain activities required for daily living. This paper will compare their significance and usefulness to nursing practice of the older adult. As information is gathered and interpreted to complete these assessment scales, the relative merits in specific situations of these two oldest competing indices need to be considered to ensure their appropriateness and sensitivity. Often, with the use of assessment scales for activities of daily living, the results often tend to be subjective and lack a systematic approach. Subjective assessment of patients makes it difficult to evaluate the effectiveness of treatments, leading to bias and the misinterpretation of data. This may be critical in the care of older adults, where presenting problems are often complex and multi-dimensional. As assessment of functional ability has become more important to nursing practice, this paper will investigate the Katz activities of daily living and the Barthel Index for reliability and explore the variations that exist between the two indices. Although research on assessment scales has been ongoing since the work of Katz et al. (1963) there remains conceptual issues as to what constitutes activities of daily living and defining terminology associated with the measurement. PMID- 20925879 TI - Editorial: volunteers. PMID- 20925878 TI - Staff-family relationships in nursing home care: a typology of challenging behaviours. AB - Aim. This paper draws on data from a study which investigated how Australian nursing home staff constructed staff-family relationships. Background. Working with the family in aged care to provide the best care possible is consistent with modern nursing philosophy which espouses holistic care. The quality and enjoyment of the experience however, is frequently fraught with problems and challenges for both the staff and the family involved. Design. A qualitative constructivist design as described by Guba and Lincoln [Fourth Generation Evaluation. Sage Publications, London.] was used. Method. Thirty paid caregivers drawn from eight nursing homes were interviewed about their experiences of working with residents' families. A constant comparative method of data analysis was used to arrive at the findings. Results. This paper reports on seven themes under the category of 'unacceptable behaviours'. These themes describe a range of attitudes and behaviours exhibited by families which staff members found undesirable. Conclusions. Staff members found a number of family behaviours challenging. Nursing home staff perceives the family as subordinate to their needs and want to retain control of the work environment. Relevance to clinical practice. Nursing home staff need to move away from custodial models of care focused on 'getting the work done' and develop more family friendly work practices that are inclusive of the needs of the family and view them as equal partners in care. PMID- 20925880 TI - Working with volunteers: key issues for gerontological nursing - Literature scan. AB - This article explores volunteering with older people through a study of the literature, mainly from the UK. The discussion is grouped around five themes: organization, support, sustainability, stereotypes and boundaries. The article discusses nurses' roles in working with volunteers and volunteer coordinators. It notes that older people are often volunteers themselves. A number of areas for future research are outlined. PMID- 20925881 TI - Working with volunteers: key issues for gerontological nursing - Application to practice the contribution of volunteers in a long-term care setting: a case study. AB - Adopting a case study approach, this paper examines the impact of a volunteers scheme in a large Jewish care home within the UK. Good practice is articulated, opportunities and challenges identified, with specific reference to religious and cultural beliefs and the role of the volunteer coordinator is examined. The paper concludes that teamwork and the role of the volunteer coordinator is pivotal to the ongoing success of the volunteer scheme. PMID- 20925882 TI - Working with volunteers: key issues for gerontological nursing - Future challenges. AB - To ensure that older people have access to all the advice, information and support they need nurses are increasingly expected to work with volunteers and the wider Voluntary and Community Sector. This article charts some of the current issues facing the sector so that nurses can collaborate more effectively, respect the contribution that volunteers can make and ultimately deliver well being, independence and choice. The focus is on recent policy in England which has sought to modernize and equip the Voluntary and Community Sector to meet National Health Service priorities. However, the underpinning themes and issues are likely to have broader resonance for volunteering in an international context. Trends in commissioning (service procurement) are identified which are likely to influence the future role and numbers of volunteers working in health and social care. Throughout this article key issues for nurse practitioners are discussed: What is the changing role of the volunteer? Can volunteers deliver significant extra capacity? What are the workforce implications? What are the risks and outcomes for older people? PMID- 20925883 TI - Guest Editorial: The right to walk - an older person's human right. PMID- 20925884 TI - Personhood and dementia: revisiting Tom Kitwood's ideas. AB - Person-centred care is often cited as an aim of gerontological nursing and promotion of personhood is said to be the basis for person-centred care. As such, it forms a cornerstone value for many gerontological nurses, particularly those working in dementia care. Tom Kitwood's ideas and definition of personhood are widely referred to in the literature and used in the dementia care field. More recently, there is a move to critique and partially reject Kitwood's ideas on personhood. This paper has three aims: (i) to explore some central ideas around key theories of personhood (ii) to critique Kitwood's work on personhood. (iii) To summarize current critiques of Kitwood's ideas and provide a response that outlines why Kitwoods' ideas are still relevant. It is suggested many critiques ignore Kitwoods' ultimate purpose; that of moral concern for 'others'. However, the main criticism put forward in this paper is that, rather than completely rejecting personhood theories, Kitwood locates his work on what it means to be a person within a traditional Cartesian personhood framework, albeit from a revised or pragmatic viewpoint. Finally, it is suggested that definitions of persons and personhood need to take account of the body and time (corporeality and temporality) and gerontological nursing may want to reassess how much allegiance is given to basing nursing frameworks on the concept of personhood. PMID- 20925885 TI - Still going strong: perceptions of the body among 85-year-old people in Sweden. AB - Background. Studies on the lived experience of an aging body are scarce. Aim and objectives. The aim of this study was to illuminate the experiences of the body among elderly people. Design. This study is part of the Umea 85+ Study, a cross sectional investigation into successful aging and threats against successful aging. The present study has an explorative design. Methods. The text from 40 thematic interviews with 85-year-olds was analysed using qualitative content analysis. Results. Two themes and seven subthemes were developed. The theme: Still going strong encompassed the subthemes of Exercising and being active, Caring for one's body, Standing on one's own two feet and Feeling healthy. The theme: Adapting to a failing body encompassed the subthemes of Not being able to perform activities and manage by oneself, Feeling fatigued and Compensating for bodily decline. Conclusions. The participants felt that the body was still a source of pleasure, in spite of its defects. Assistive devices were important for the maintenance of independence when the body declined. Relevance to clinical practice. When caring for elderly people with declining bodily function, it is important to have appropriate and well-tested equipment in readiness. PMID- 20925886 TI - Natural activity: an explorative study of the interplay between cage-birds and older people in a Swedish hospital setting. AB - Aim. The aim of this study was to describe the interaction between cage-birds and older people as it arises in spontaneous situations in a Swedish hospital ward setting. Background. Older people are at risk of being affected by mental fatigue because of various age-related reductions and disease. Mental fatigue manifests itself through a reduced ability to concentrate. The method of alleviating mental fatigue with the use of stimulating natural settings or animal assisted activities is so far unexplored in Sweden and subsequently it is important to study the method in a Swedish context to implement it as a recognized nursing intervention in the care of older people. Design. The study had an explorative observational design, and was conducted at a geriatric ward with a consecutive selection of participants. Method. The observations were analysed using a constant comparative method influenced by Grounded Theory. 'Attention restorative theory' was used as the theoretical framework to guide the study. Result. Our findings indicate that animal-assisted therapy has a positive effect on involuntary attention and mental restoration, as well as on enhanced social behaviour among older people. Relevance to clinical practice. The result strengthens the assumption that animal companionship should be considered a beneficial nursing intervention for older people to prevent mental fatigue. PMID- 20925887 TI - Engaging older people with dementia in research: myth or possibility. AB - Aim. The aim of this paper was to explore a range of strategies that were used to enable older people with dementia to become actively engaged in research 'with' rather than 'on' them. Background. It is well recognized that the prevalence of dementia in older adults is increasing. This increase is reflected by a huge rise in the amount of research in this area. The biomedical model continues to dominate dementia research; however, the last two decades have seen an increased interest in studies that seek the views of people with dementia. A review of literature that has actively engaged people with dementia suggests that research can be conducted in such ways that are both ethical and meaningful. These studies demonstrate that this group has a valuable contribution to research studies. Discussion. This literature establishes that it is possible to engage people with dementia in research, the majority of studies have tended to focus on those in the earlier stages of the disease. This paper demonstrates, through the use of a set of criteria which were specifically developed to evaluate this type of work, how people even with advanced dementia were engaged in research about their experience of acute hospital care in ways that were both meaningful and ethical. Conclusion. This paper demonstrates that it is possible to actively engage older people with dementia, even those in the more advanced stages of the disease, in research. It is essential that researchers understand ethical principles and are able to apply these sensitively and flexibly. PMID- 20925888 TI - To both be like a captain and fellow worker of the caring team: the meaning of Nurse Assistants' expectations of Registered Nurses in Swedish residential care homes. AB - Aim. To describe the expectations of and to illuminate the meaning of the Nurse Assistants' (NA) expectations of Registered Nurses (RN) who are responsible for the care of older people living in residential care homes in Sweden. Background. Older people in Sweden who are provided with residential care are extremely frail and incapable of independent living. Therefore, when providing care, RN and NA encounter older people who require a great deal of care. An important precondition for the provision of satisfactory care is to have adequate collaboration between NAs and RNs and their expectations of each other. In this paper, the focus is on the NAs expectations of the RNs. Method. The study is based on a qualitative approach and a phenomenological-hermeneutical method. Ten NAs were interviewed and asked to narrate as freely as possible, about their expectations of RNs. The narratives were audio taped and transcribed verbatim. The analytical process includes the following steps; naive reading, structural analysis, comprehensive understanding and reflection. Results. The RNs were expected to take responsibility for being fellow human beings and experts in providing care as well as always available to participate in caring. The RNs were expected to make stand-alone decisions and create a sense of safety for both older people and the NAs and have the courage to work alone and create a safe environment for both the older people and the NAs. The meaning of these expectations was that the RNs are like a captain in providing care, but at the same time, fellow workers. Conclusion. When the RNs do not meet the NAs expectations, there is a risk of conflict and therefore also a risk that an unsafe environment being created when caring for older people. PMID- 20925889 TI - Shielding or caging? Healthcare staffs' views on fall risk and protection in Stockholm. AB - Aim. To describe Registered Nurses' and enrolled nurses' views and reasoning on falls, fall risk, use of physical restraints and patients' safety and security in nursing homes. Background. Nursing home patients frequently suffer from diseases which require medication. Both Registered Nurses and enrolled nurses must make decisions about how to protect patients from falls and fall-related injuries. Physical restraints are frequently used. When patients are unable to understand or do not wish to limit their freedom of movement, staff must consider each decision carefully. Method. A qualitative approach was used. Data were analysed using a thematic content analysis method. Findings. Staff have sufficient knowledge about which pathologically related conditions lead to fall risk. An insufficient number of staff on duty jeopardizes patient safety. Wheelchairs with safety belts, and bed rails, are sometimes used. For Registered Nurses it was not an easy decision to use restraints. Enrolled nurses' actions were based on standard procedure, to protect and supervise patients. Conclusion. Staff often use restraints to protect their patients, even though this may mean compromising the patient's integrity. Relevance to clinical practice. Nurses, occupational therapists, physiotherapists and physicians should plan the care together. Restrictive measures should be adapted to each individual patient. PMID- 20925890 TI - Unmet expectations: why nursing home staff leave care work. AB - Background. The shortages of healthcare professionals have been a common topic in care of older people. Aim and objectives. The aim of the present study was to illuminate what caused the nursing home caregivers to decide to leave their employment. Design. A two-year intervention study was performed in three nursing homes in Sweden. Method. This qualitative interview study was conducted with 18 caregivers who decided to leave their employment during the first year. Content analysis was the method used to analyse the interviews. Result. The caregivers' decisions to leave their work in care of older people could be encompassed in one main category: 'Unmet Expectations'. Their experiences were lack of encouragement and trust and professional development. Feelings of insecurity, different opinions on the care delivered, being disregarded and betrayed followed as did thoughts of leaving work and pursing other opportunities. Conclusion. The main findings indicated that organizational work pressure with information about pending financial cutbacks caused the caregivers to leave the nursing homes. Relevance to clinical practice. The study's results show the value of meeting the needs of caregivers, as caregivers consider that they meet the needs of the older people. Optimal use of caregivers' skills, experiences, competence and respect for their aspirations is also likely to result in cost-efficient care. PMID- 20925891 TI - Editorial: older people maintaining well-being. PMID- 20925892 TI - Older people maintaining well-being: discussion of key literature. AB - This paper describes the process of initial searching for publications on older people and well-being, and discusses some of the difficulties in doing this is a field where key terms are diverse. The paper selects some publications which were judged to be particularly significant or interesting, rather than an inclusive and fully comprehensive literature report. PMID- 20925893 TI - Older people maintaining well-being: an International Appreciative Inquiry study. AB - This paper reports on the progress of an international study investigating older people's strategies for maintaining well-being in the UK, Germany, South Africa and Australia. It uses an Appreciative Inquiry framework for investigation. PMID- 20925894 TI - Older people maintaining well-being: implications for future developments. AB - This paper indicates the ways in which the strategies which older people have developed for maintaining well-being could be explored further. This exploration, it is argued, is necessary given the scarcity of research in this field, which reduces the impact that these strategies might have for practice. PMID- 20925895 TI - Editorial: 'They sentenced me to 20 years of boredom'. PMID- 20925896 TI - The feasibility of developing a standards rating system for all Australian government aged care homes. AB - Aims and objectives. The main objective of this project was to investigate the likelihood of creating an easily understood rating system for all aged care homes. A secondary objective was to canvas the feasibility of alternative systems that could better inform aged care consumers. Background. Standards rating systems are used internationally to enable comparisons in healthcare. In Australia, the performance of numerous services and products are measured according to the star system of ratings, yet despite their widespread use, star ratings remain absent from the healthcare industry. Methods. A National Consultative Group (NCG) consisting of key stakeholder representatives was consulted, and a literature review performed on existing standards (or 'star') rating systems. Telephone interviews were conducted with representatives from aged care homes, as well as consumers. Results. A standards rating system for aged care homes was not found to be feasible in the current climate. However, an alternative system that emphasises empowering aged care consumers, such as one that allows consumers to search for an aged care home using their own criteria of preference, was considered more feasible. Conclusion. The need for information to assist consumer choice - limited as it may be - is real. Ways of providing more consumer friendly, useful information need to be further explored and developed. Recommendations are made for future work in this area. PMID- 20925897 TI - Multiprofessional collaboration promoting home care clients' personal resources: perspectives of older clients. AB - Home care can be decisive in supporting older people in the home environment. However, one professional in home care cannot take the whole responsibility for promotion alone; on the contrary multiprofessional collaboration is needed. The aim of the study is to describe the experiences of multiprofessional collaboration in promoting personal resources among older home care clients (75+ years) in Finland. The data were collected by unstructured interviews with 21 older home care clients. Their mean age was 83.5 years, ranging from 75 to 91, with 17 female and four male participants. Inductive content analysis was used to analyze the data. The interviewees described the work of professionals from four perspectives: expertise, communication, decision-making and responsibility. Multiprofessional collaboration promoted the personal resources of interviewees with physical, psychological and social support. This study showed that the professionals worked as being expert-oriented: in the multiprofessional collaboration, each expert took care of his/her own part of the client's situation. This included the risk,, that the client's overall situations remained uncharted. However, the client's overall situation is a very important aspect when professionals suppport older people living in their own homes as long as possible. This study revealed the need for developing collaboration skills between social and health care professionals so that the staffs serve the needs of aged clients better together. PMID- 20925898 TI - Factors related to fatigue among older patients with heart failure in primary health care. AB - Aim. Our aim was to explore the relationship between fatigue and physical, mental, social and demographic factors among older patients with heart failure, with special reference to gender. Background. If interventions aimed at preventing or alleviating fatigue are to be successful, more knowledge about factors associated with fatigue is needed. Design. A cross-sectional design was used. Methods. Forty-nine patients aged 77.7 +/- 8.7 years (21 men and 28 women) with verified heart failure from one primary healthcare centre answered a questionnaire including Multi-dimensional Fatigue Inventory, 36-item Short-Form Health Survey, Geriatric Depression Scale, Self-Transcendence Scale, Resilience Scale, Social Provision Scale and demographic variables. Descriptive statistics and multiple linear regression analyses were conducted. Results. Levels of general fatigue were high (mean 14.6 +/- 3.9). Female gender (beta = 0.280, P = 0.033) and role function for physical reasons (beta = -0.458, P = 0.001) explained 36% of the variance in general fatigue. Conclusions. Fatigue was more closely related to limitations in role functioning for physical reasons than to reduced physical function per se or to mental and social factors. Women reported more fatigue than men. Relevance to clinical practice. Caregivers should examine the impact of fatigue in everyday life for each individual. PMID- 20925899 TI - Older immigrants' experiences of their life situation in the context of receiving public care in Sweden. AB - Objectives. The aim of this study was to illuminate older immigrants' experience of their life situation in the context of receiving public care in Sweden. Background. To meet the varying needs from the growing number of older immigrants, more knowledge about the experience of their life situation, health, illness and family ties is needed, especially in the context of receiving public health care and service. Methods. Data were collected through interviews with sixteen immigrants aged 65 years and older, originally from nine different countries, living in Southern Sweden and receiving continuous care and service. The texts were analysed using qualitative content analysis. Results. The overall impression from the texts was that the informants expressed a debt of gratitude to Swedish society. Their experience could be understood as - being burdened with health complaints; experiencing painful losses; wanting to manage by oneself and feeling exposed and deserted. Conclusions. The results show that older immigrants are vulnerable when receiving public care. This was related to previous life events, cultural differences as well as communication difficulties. When planning for and providing care for older immigrants, it is important to be aware of their exposed situation and to acknowledge their life history and family context. PMID- 20925900 TI - A mapper's reflection on Dementia Care Mapping with older residents living in a nursing home. AB - Aim and objective. This paper explores reflection stemming from a Dementia Care Mapper's own learning and development concerning person-centred care with older residents living in a dementia specific nursing home. Background. Dementia Care Mapping has been employed in few Australian residential care facilities to promote person-centred care and the well-being of residents. Reflection has also been used selectively in some practices to improve and evaluate the care process. However, contemporary nursing literature has failed to highlight the usefulness of applying reflection following Dementia Care Mapping with older residents. Method. The mapper's reflections arose from the Dementia Care Mapping observation of five older residents and writing a daily reflective journal. Findings. From the reflection, a dominant major theme emerged named as the Learning Experience from Mapping Residents with two sub-themes entitled Mapper's Identification of Resident's Unique Needs and Mapper's Empowerment of Clinicians. Dementia Care Mapping recommendations from the mapper's experience highlighted effective approaches to conducting Dementia Care Mapping in residential care facilities. Conclusions. The valuable process of reflection to Dementia Care Mapping provided the mapper with clinical insights. Further from the mapper's final reflection, a poem entitled Come Back Mind, Come Back to Me was conceived and penned. Relevance to clinical practice. The mapper's engagement in ongoing reflection incorporated with Dementia Care Mapping has the potential to promote best practice for the care of older people living in aged care facilities. PMID- 20925901 TI - Best practice for the management of older people with dementia in the acute care setting: a review of the literature. AB - Aim. This paper reviews the theoretical and research-based literature related to the management of people with chronic confusion as a consequence of dementia in the acute care setting. Background. People aged 65 years and over are at increased risk of poor outcomes when admitted to the acute care setting as a result of comorbity and mismanagement of their chronic confusion. The challenge of caring for people with dementia in acute care is one that requires special attention. Results. The theoretical literature outlines a number of principles of care necessary for best practice in the care of people with dementia. A number of different models of care are reported in the literature and some evaluative research has been undertaken to assess the benefits of the different models. Conclusion. There are a number of interventions that if put into place in acute care may improve care of people with dementia and reduce the burden of care. There is emerging evidence that interventions such as staff education, skilled expertise, standardized care protocols and environmental modification help to meet the needs of people with dementia in acute hospital settings. This paper adds to our current understanding of management of dementia in the acute care setting, an area that demonstrates the need to move from descriptive to intervention studies to ensure evidence for care of persons with a dementing condition. PMID- 20925902 TI - Transitions in men's caring identities: experiences from home-based care to nursing home placement. AB - Objectives. The aim of this study is to describe, from a gender identity perspective, the experiences of older men involved in the process of caring for a partner at home and the placement into a nursing home. Background. Few studies have paid attention to the importance of gender when considering the social experiences of older men providing care for an ill spouse and finally placing a partner in a nursing home. Further understanding is much needed of how older men experience the process of caring for a spouse from a gender identity perspective. Design. A qualitative constructivist approach was adopted for this study. Participants. Data consists of interviews with seven men that have been informal carers and experienced the placement of their wife in a nursing home. Methods. Interviews were analysed with a constructivist approach. Results. The results indicate that men go through two transitions in their gender identity during the caregiving process and placement. From the mutual loving relationship of being a loving husband, the social responsibility of daily care of their wives changes the situation into that of being a caring husband, and finally with the move to a nursing home there is a transition from intimate care to a relationship based on friendship. Conclusions. The results show that older caregiving men undergo a process involving a reconstruction of gender identity. To formally recognize men's caring activities and to make them sustainable, we believe that men in an informal caring relationship need support. Relevance to clinical practice. Nurses need to recognize the identity struggles resulting in sadness and suffering that are related to changes in men's lives during the caregiving process. Understanding the dynamics and changes that occur when men take on a caring task is important for the development of their role as carers. PMID- 20925903 TI - Editorial: ageing, spirituality and nursing. PMID- 20925904 TI - A review of the literature in 2006. AB - In this, the first of three papers, attention is drawn to the literature for one year, reflecting a sample of the interrelated themes of ageing, spirituality and nursing. It is clear that nurses are unsure how to include this component of care in their daily practice. However, with the rapidly increasing ageing population, and the recent escalation of literature on spirituality, it seems timely to analyse some of these findings and to consider the implications for practice. Some of the major emerging themes have been identified in this paper, with a view to further exploration of the themes in the second paper, and expanding the discussion in the third paper. PMID- 20925905 TI - Application to practice guidelines. AB - Drawing on the international literature for 2006 as discussed in the previous paper, this paper explores key issues for translating the evidence into practice. It brings the themes of ageing, spirituality and nursing more sharply into focus, providing practical suggestions for care in a variety of settings. Taking seven identified themes into consideration, the paper draws out implications for practice from each theme. This discussion is intended to provide encouragement for nurses to consider the spiritual domain in holistic care, not as an optional extra but as the centre of a dynamic partnership with the older people in their care. The paper concludes with recommendations for further research and development work. PMID- 20925906 TI - Practice development in aged care nursing of older people: the perspective of ageing and spiritual care. AB - This third paper on older people nursing and spirituality moves beyond the literature reviewed in the two previous papers, exploring directions for the practice and continuing research in this field. Issues of chronic illness challenge nurses working with older people to focus on continuing health promotion and opportunities for spiritual promotion of resilience and transcendence. The changes from monocultural to multicultural societies challenge nurses to know how to provide culturally and faith appropriate care. The extension of palliative care to the needs of those growing older and dying is noted as an important area for developing spiritual care. It is asserted that spiritual assessment forms a basis for the provision of spiritual care for all of these themes. Ethical perspectives of older people nursing must be carefully addressed as frail and vulnerable older people struggle with issues of compromised autonomy. Further research should focus on spirituality as seen through the eyes of older people and examine the interface between nurses and patients, where the relationship becomes the guiding basis for practice. Education in nursing courses and through continuing programmes of education is needed to ensure adequate understanding of spirituality in the nursing role. PMID- 20925907 TI - Abstracts of the 26th Patient Classification Systems International (PCSI) Working Conference. Munich, Germany. September 15-18, 2010. PMID- 20925908 TI - Density-equalizing mapping and scientometric benchmarking of European allergy research. AB - Due to the great socioeconomic burden of allergic diseases, research in this field which is important for environmental medicine is currently increasing. Therefore the European Union has initiated the Global Allergy and Asthma European network (GA2LEN). However, despite increasing research in the past years detailed scientometric analyses have not been conducted so far. This study is the first scientometric analysis in a field of growing interest. It analyses scientific contributions in European allergy research between 2001 and 2007. Three different meetings of the European Academy of Allergy and Clinical Immunology were analysed for contributions and an increase in both the amount of research and networks was found. PMID- 20925909 TI - An integrated analysis of molecular aberrations in NCI-60 cell lines. AB - BACKGROUND: Cancer is a complex disease where various types of molecular aberrations drive the development and progression of malignancies. Large-scale screenings of multiple types of molecular aberrations (e.g., mutations, copy number variations, DNA methylations, gene expressions) become increasingly important in the prognosis and study of cancer. Consequently, a computational model integrating multiple types of information is essential for the analysis of the comprehensive data. RESULTS: We propose an integrated modeling framework to identify the statistical and putative causal relations of various molecular aberrations and gene expressions in cancer. To reduce spurious associations among the massive number of probed features, we sequentially applied three layers of logistic regression models with increasing complexity and uncertainty regarding the possible mechanisms connecting molecular aberrations and gene expressions. Layer 1 models associate gene expressions with the molecular aberrations on the same loci. Layer 2 models associate expressions with the aberrations on different loci but have known mechanistic links. Layer 3 models associate expressions with nonlocal aberrations which have unknown mechanistic links. We applied the layered models to the integrated datasets of NCI-60 cancer cell lines and validated the results with large-scale statistical analysis. Furthermore, we discovered/reaffirmed the following prominent links: (1) Protein expressions are generally consistent with mRNA expressions. (2) Several gene expressions are modulated by composite local aberrations. For instance, CDKN2A expressions are repressed by either frame-shift mutations or DNA methylations. (3) Amplification of chromosome 6q in leukemia elevates the expression of MYB, and the downstream targets of MYB on other chromosomes are up-regulated accordingly. (4) Amplification of chromosome 3p and hypo-methylation of PAX3 together elevate MITF expression in melanoma, which up-regulates the downstream targets of MITF. (5)Mutations of TP53 are negatively associated with its direct target genes. CONCLUSIONS: The analysis results on NCI-60 data justify the utility of the layered models for the incoming flow of cancer genomic data. Experimental validations on selected prominent links and application of the layered modeling framework to other integrated datasets will be carried out subsequently. PMID- 20925910 TI - MetAssimulo: simulation of realistic NMR metabolic profiles. AB - BACKGROUND: Probing the complex fusion of genetic and environmental interactions, metabolic profiling (or metabolomics/metabonomics), the study of small molecules involved in metabolic reactions, is a rapidly expanding 'omics' field. A major technique for capturing metabolite data is 1H-NMR spectroscopy and this yields highly complex profiles that require sophisticated statistical analysis methods. However, experimental data is difficult to control and expensive to obtain. Thus data simulation is a productive route to aid algorithm development. RESULTS: MetAssimulo is a MATLAB-based package that has been developed to simulate 1H-NMR spectra of complex mixtures such as metabolic profiles. Drawing data from a metabolite standard spectral database in conjunction with concentration information input by the user or constructed automatically from the Human Metabolome Database, MetAssimulo is able to create realistic metabolic profiles containing large numbers of metabolites with a range of user-defined properties. Current features include the simulation of two groups ('case' and 'control') specified by means and standard deviations of concentrations for each metabolite. The software enables addition of spectral noise with a realistic autocorrelation structure at user controllable levels. A crucial feature of the algorithm is its ability to simulate both intra- and inter-metabolite correlations, the analysis of which is fundamental to many techniques in the field. Further, MetAssimulo is able to simulate shifts in NMR peak positions that result from matrix effects such as pH differences which are often observed in metabolic NMR spectra and pose serious challenges for statistical algorithms. CONCLUSIONS: No other software is currently able to simulate NMR metabolic profiles with such complexity and flexibility. This paper describes the algorithm behind MetAssimulo and demonstrates how it can be used to simulate realistic NMR metabolic profiles with which to develop and test new data analysis techniques. MetAssimulo is freely available for academic use at http://cisbic.bioinformatics.ic.ac.uk/metassimulo/. PMID- 20925911 TI - Estimation of incidence and social cost of colon cancer due to nitrate in drinking water in the EU: a tentative cost-benefit assessment. AB - BACKGROUND: Presently, health costs associated with nitrate in drinking water are uncertain and not quantified. This limits proper evaluation of current policies and measures for solving or preventing nitrate pollution of drinking water resources. The cost for society associated with nitrate is also relevant for integrated assessment of EU nitrogen policies taking a perspective of welfare optimization. The overarching question is at which nitrogen mitigation level the social cost of measures, including their consequence for availability of food and energy, matches the social benefit of these measures for human health and biodiversity. METHODS: Epidemiological studies suggest colon cancer to be possibly associated with nitrate in drinking water. In this study risk increase for colon cancer is based on a case-control study for Iowa, which is extrapolated to assess the social cost for 11 EU member states by using data on cancer incidence, nitrogen leaching and drinking water supply in the EU. Health costs are provisionally compared with nitrate mitigation costs and social benefits of fertilizer use. RESULTS: For above median meat consumption the risk of colon cancer doubles when exposed to drinking water exceeding 25 mg/L of nitrate (NO3) for more than ten years. We estimate the associated increase of incidence of colon cancer from nitrate contamination of groundwater based drinking water in EU11 at 3%. This corresponds to a population-averaged health loss of 2.9 euro per capita or 0.7 euro per kg of nitrate-N leaching from fertilizer. CONCLUSIONS: Our cost estimates indicate that current measures to prevent exceedance of 50 mg/L NO3 are probably beneficial for society and that a stricter nitrate limit and additional measures may be justified. The present assessment of social cost is uncertain because it considers only one type of cancer, it is based on one epidemiological study in Iowa, and involves various assumptions regarding exposure. Our results highlight the need for improved epidemiological studies. PMID- 20925912 TI - Patterns of molecular and phenotypic diversity in pearl millet [Pennisetum glaucum (L.) R. Br.] from West and Central Africa and their relation to geographical and environmental parameters. AB - BACKGROUND: The distribution area of pearl millet in West and Central Africa (WCA) harbours a wide range of climatic and environmental conditions as well as diverse farmer preferences and pearl millet utilization habits which have the potential to lead to local adaptation and thereby to population structure. The objectives of our research were to (i) assess the geographical distribution of genetic diversity in pearl millet inbreds derived from landraces, (ii) assess the population structure of pearl millet from WCA, and (iii) identify those geographical parameters and environmental factors from the location at which landraces were sampled, as well as those phenotypic traits that may have affected or led to this population structure. Our study was based on a set of 145 inbred lines derived from 122 different pearl millet landraces from WCA. RESULTS: Five sub-groups were detected within the entire germplasm set by STRUCTURE. We observed that the phenotypic traits flowering time, relative response to photoperiod, and panicle length were significantly associated with population structure but not the environmental factors which are expected to influence these traits in natural populations such as latitude, temperature, or precipitation. CONCLUSIONS: Our results suggested that for pearl millet natural selection is compared to artificial selection less important in shaping populations. PMID- 20925913 TI - Tissue distribution of cloxacillin after intramammary administration in the isolated perfused bovine udder. AB - BACKGROUND: Various intramammary suspensions containing cloxacillin benzathine are registered for use in cattle as antibiotics for intramammary use at drying off. To ensure antibacterial efficacy, the glandular tissue concentration of an antimicrobial agent must be sufficient. Since the possibilities to measure concentrations in the different areas of the glandular tissue in vivo are very limited, it was the aim of the present study to examine the distribution of cloxacillin in vitro using the isolated perfused bovine udder. METHODS: Mammary glands taken at slaughter from healthy lactating cows were perfused in vitro with warmed and gassed Tyrode solution. 600 mg cloxacillin benzathine were administered as Orbenin Extra Dry Cow by the intramammary route to six front and rear quarters each. Samples of glandular tissue--at different distances from and vertical to the teat right up to the udder base--were gathered from the treated quarters after 6 h. Perfusate was also sampled before and hourly after treatment for 6 h. The cloxacillin content of the tissue samples and perfusate samples was analysed by high performance liquid chromatography. RESULTS: The concentration of cloxacillin in the glandular tissue of front quarters measured 6 h after administration tended to decrease with increasing vertical distance from the teat. The decrease pattern of the concentration was not quite clear in rear quarters. A considerable variation in the tissue concentrations of cloxacillin was obvious, which reflects in vivo conditions. The concentrations measured in the perfusate samples were below the limit of quantification at all time points, indicating limited absorption of the antibiotic from the glandular tissue. CONCLUSION: After intramammary administration of the dry off product containing cloxacillin benzathine concentrations of more than 0.5 MUg/g (MIC) were reached in all regions of the front and rear quarters. PMID- 20925914 TI - Continuous glucose monitors prove highly accurate in critically ill children. AB - INTRODUCTION: Hyperglycemia is associated with increased morbidity and mortality in critically ill patients and strict glycemic control has become standard care for adults. Recent studies have questioned the optimal targets for such management and reported increased rates of iatrogenic hypoglycemia in both critically ill children and adults. The ability to provide accurate, real-time continuous glucose monitoring would improve the efficacy and safety of this practice in critically ill patients. The aim of our study is to determine if a continuous, interstitial glucose monitor will correlate with blood glucose values in critically ill children. METHODS: We evaluated 50 critically ill children age 6 weeks to 16 years old with a commercially available continuous glucose monitor (CGM; Medtronic Guardian(r)). CGM values and standard blood glucose (BG) values were compared. During the study, no changes in patient management were made based on CGM readings alone. RESULTS: Forty-seven patients had analyzable CGM data. A total of 1,555 CGM and routine BG measurements were compared using Clarke error grid and Bland-Altman analysis. For all readings, 97.9% were within clinically acceptable agreement. The mean absolute relative difference between CGM and BG readings was 15.3%. For the 1,555 paired CGM and BG measurements, there is a statistically significant linear relationship between CGM values and BG (P < .0001). A high degree of clinical agreement existed in three subpopulation analyses based on age, illness severity, and support measures. This included some of our smallest patients (that is, < 12 months old), those who required vasopressors, and those who were treated for critical illness hyperglycemia. CONCLUSIONS: In one of the largest studies to date, in a highly vulnerable ICU population, CGM values have a clinically acceptable correlation with the BG values now used diagnostically and therapeutically. Our data contest the theoretical concerns posed by some regarding CGM use in the ICU. The existing medical evidence may now support a role for CGM devices in the identification and management of hyperglycemia in diverse ICU settings. PMID- 20925915 TI - A comparison of ARMS and DNA sequencing for mutation analysis in clinical biopsy samples. AB - BACKGROUND: We have compared mutation analysis by DNA sequencing and Amplification Refractory Mutation SystemTM (ARMSTM) for their ability to detect mutations in clinical biopsy specimens. METHODS: We have evaluated five real-time ARMS assays: BRAF 1799T>A, [this includes V600E and V600K] and NRAS 182A>G [Q61R] and 181C>A [Q61K] in melanoma, EGFR 2573T>G [L858R], 2235-2249del15 [E746 A750del] in non-small-cell lung cancer, and compared the results to DNA sequencing of the mutation 'hot-spots' in these genes in formalin-fixed paraffin embedded tumour (FF-PET) DNA. RESULTS: The ARMS assays maximised the number of samples that could be analysed when both the quality and quantity of DNA was low, and improved both the sensitivity and speed of analysis compared with sequencing. ARMS was more robust with fewer reaction failures compared with sequencing and was more sensitive as it was able to detect functional mutations that were not detected by DNA sequencing. DNA sequencing was able to detect a small number of lower frequency recurrent mutations across the exons screened that were not interrogated using the specific ARMS assays in these studies. CONCLUSIONS: ARMS was more sensitive and robust at detecting defined somatic mutations than DNA sequencing on clinical samples where the predominant sample type was FF-PET. PMID- 20925916 TI - The effectiveness of M-health technologies for improving health and health services: a systematic review protocol. AB - BACKGROUND: The application of mobile computing and communication technology is rapidly expanding in the fields of health care and public health. This systematic review will summarise the evidence for the effectiveness of mobile technology interventions for improving health and health service outcomes (M-health) around the world. FINDINGS: To be included in the review interventions must aim to improve or promote health or health service use and quality, employing any mobile computing and communication technology. This includes: (1) interventions designed to improve diagnosis, investigation, treatment, monitoring and management of disease; (2) interventions to deliver treatment or disease management programmes to patients, health promotion interventions, and interventions designed to improve treatment compliance; and (3) interventions to improve health care processes e.g. appointment attendance, result notification, vaccination reminders.A comprehensive, electronic search strategy will be used to identify controlled studies, published since 1990, and indexed in MEDLINE, EMBASE, PsycINFO, Global Health, Web of Science, the Cochrane Library, or the UK NHS Health Technology Assessment database. The search strategy will include terms (and synonyms) for the following mobile electronic devices (MEDs) and a range of compatible media: mobile phone; personal digital assistant (PDA); handheld computer (e.g. tablet PC); PDA phone (e.g. BlackBerry, Palm Pilot); Smartphone; enterprise digital assistant; portable media player (i.e. MP3 or MP4 player); handheld video game console. No terms for health or health service outcomes will be included, to ensure that all applications of mobile technology in public health and health services are identified. Bibliographies of primary studies and review articles meeting the inclusion criteria will be searched manually to identify further eligible studies. Data on objective and self-reported outcomes and study quality will be independently extracted by two review authors. Where there are sufficient numbers of similar interventions, we will calculate and report pooled risk ratios or standardised mean differences using meta-analysis. DISCUSSION: This systematic review will provide recommendations on the use of mobile computing and communication technology in health care and public health and will guide future work on intervention development and primary research in this field. PMID- 20925917 TI - Effects of inbreeding and genetic modification on Aedes aegypti larval competition and adult energy reserves. AB - BACKGROUND: Genetic modification of mosquitoes offers a promising strategy for the prevention and control of mosquito-borne diseases. For such a strategy to be effective, it is critically important that engineered strains are competitive enough to serve their intended function in population replacement or reduction of wild mosquitoes in nature. Thus far, fitness evaluations of genetically modified strains have not addressed the effects of competition among the aquatic stages and its consequences for adult fitness. We therefore tested the competitive success of combinations of wild, inbred and transgenic (created in the inbred background) immature stages of the dengue vector Aedes aegypti in the presence of optimal and sub-optimal larval diets. RESULTS: The wild strain of Ae. aegypti demonstrated greater performance (based on a composite index of survival, development rate and size) than the inbred strain, which in turn demonstrated greater performance than the genetically modified strain. Moreover, increasing competition through lowering the amount of diet available per larva affected fitness disproportionately: transgenic larvae had a reduced index of performance (95-119%) compared to inbred (50-88%) and wild type larvae (38-54%). In terms of teneral energy reserves (glycogen, lipid and sugar), adult wild type mosquitoes had more reserves directly available for flight, dispersal and basic metabolic functions than transgenic and inbred mosquitoes. CONCLUSIONS: Our study provides a detailed assessment of inter- and intra-strain competition across aquatic stages of wild type, inbred, and transgenic mosquitoes and the impact of these conditions on adult energy reserves. Although it is not clear what competitive level is adequate for success of transgenic strains in nature, strong gene drive mechanisms are likely to be necessary in order to overcome competitive disadvantages in the larval stage that carryover to affect adult fitness. PMID- 20925918 TI - DiffCoEx: a simple and sensitive method to find differentially coexpressed gene modules. AB - BACKGROUND: Large microarray datasets have enabled gene regulation to be studied through coexpression analysis. While numerous methods have been developed for identifying differentially expressed genes between two conditions, the field of differential coexpression analysis is still relatively new. More specifically, there is so far no sensitive and untargeted method to identify gene modules (also known as gene sets or clusters) that are differentially coexpressed between two conditions. Here, sensitive and untargeted means that the method should be able to construct de novo modules by grouping genes based on shared, but subtle, differential correlation patterns. RESULTS: We present DiffCoEx, a novel method for identifying correlation pattern changes, which builds on the commonly used Weighted Gene Coexpression Network Analysis (WGCNA) framework for coexpression analysis. We demonstrate its usefulness by identifying biologically relevant, differentially coexpressed modules in a rat cancer dataset. CONCLUSIONS: DiffCoEx is a simple and sensitive method to identify gene coexpression differences between multiple conditions. PMID- 20925919 TI - A probabilistic cell model in background corrected image sequences for single cell analysis. AB - BACKGROUND: Methods of manual cell localization and outlining are so onerous that automated tracking methods would seem mandatory for handling huge image sequences, nevertheless manual tracking is, astonishingly, still widely practiced in areas such as cell biology which are outside the influence of most image processing research. The goal of our research is to address this gap by developing automated methods of cell tracking, localization, and segmentation. Since even an optimal frame-to-frame association method cannot compensate and recover from poor detection, it is clear that the quality of cell tracking depends on the quality of cell detection within each frame. METHODS: Cell detection performs poorly where the background is not uniform and includes temporal illumination variations, spatial non-uniformities, and stationary objects such as well boundaries (which confine the cells under study). To improve cell detection, the signal to noise ratio of the input image can be increased via accurate background estimation. In this paper we investigate background estimation, for the purpose of cell detection. We propose a cell model and a method for background estimation, driven by the proposed cell model, such that well structure can be identified, and explicitly rejected, when estimating the background. RESULTS: The resulting background-removed images have fewer artifacts and allow cells to be localized and detected more reliably. The experimental results generated by applying the proposed method to different Hematopoietic Stem Cell (HSC) image sequences are quite promising. CONCLUSION: The understanding of cell behavior relies on precise information about the temporal dynamics and spatial distribution of cells. Such information may play a key role in disease research and regenerative medicine, so automated methods for observation and measurement of cells from microscopic images are in high demand. The proposed method in this paper is capable of localizing single cells in microwells and can be adapted for the other cell types that may not have circular shape. This method can be potentially used for single cell analysis to study the temporal dynamics of cells. PMID- 20925920 TI - Rationale and design of the Exercise Intensity Trial (EXCITE): A randomized trial comparing the effects of moderate versus moderate to high-intensity aerobic training in women with operable breast cancer. AB - BACKGROUND: The Exercise Intensity Trial (EXcITe) is a randomized trial to compare the efficacy of supervised moderate-intensity aerobic training to moderate to high-intensity aerobic training, relative to attention control, on aerobic capacity, physiologic mechanisms, patient-reported outcomes, and biomarkers in women with operable breast cancer following the completion of definitive adjuvant therapy. METHODS/DESIGN: Using a single-center, randomized design, 174 postmenopausal women (58 patients/study arm) with histologically confirmed, operable breast cancer presenting to Duke University Medical Center (DUMC) will be enrolled in this trial following completion of primary therapy (including surgery, radiation therapy, and chemotherapy). After baseline assessments, eligible participants will be randomized to one of two supervised aerobic training interventions (moderate-intensity or moderate/high-intensity aerobic training) or an attention-control group (progressive stretching). The aerobic training interventions will include 150 mins.wk-1 of supervised treadmill walking per week at an intensity of 60%-70% (moderate-intensity) or 60% to 100% (moderate to high-intensity) of the individually determined peak oxygen consumption (VO2peak) between 20-45 minutes/session for 16 weeks. The progressive stretching program will be consistent with the exercise interventions in terms of program length (16 weeks), social interaction (participants will receive one-on one instruction), and duration (20-45 mins/session). The primary study endpoint is VO2peak, as measured by an incremental cardiopulmonary exercise test. Secondary endpoints include physiologic determinants that govern VO2peak, patient reported outcomes, and biomarkers associated with breast cancer recurrence/mortality. All endpoints will be assessed at baseline and after the intervention (16 weeks). DISCUSSION: EXCITE is designed to investigate the intensity of aerobic training required to induce optimal improvements in VO2peak and other pertinent outcomes in women who have completed definitive adjuvant therapy for operable breast cancer. Overall, this trial will inform and refine exercise guidelines to optimize recovery in breast and other cancer survivors following the completion of primary cytotoxic therapy. TRIAL REGISTRATION: NCT01186367. PMID- 20925922 TI - A novel real-time PCR assay for specific detection and quantification of Mycobacterium avium subsp. paratuberculosis in milk with the inherent possibility of differentiation between viable and dead cells. AB - BACKGROUND: Mycobacterium avium subsp. paratuberculosis (MAP) is the etiological agent of paratuberculosis (Johne's disease) in ruminants and is suggested to be one of the etiologic factors in Crohn's disease in humans. Contaminated milk might expose humans to that pathogen. The aim of the present study was to develop a novel real-time PCR assay providing the additional possibility to detect viable Mycobacterium avium subsp. paratuberculosis (MAP) based on the MAP-specific Mptb52.16 target. The design included an internal amplification control to identify false negative results. FINDINGS: Inclusivity and exclusivity tested on 10 MAP strains, 22 non-MAP mycobacteria, and 16 raw milk microflora strains achieved 100%. The detection limit in artificially contaminated raw milk was 2.42 * 101 MAP cells/ml milk. In a survey of naturally contaminated samples obtained from dairy herds with a known history of paratuberculosis, 47.8% pre-milk and 51.9% main milk samples tested positive. Real-time PCR-derived MAP-specific bacterial cell equivalents (bce) ranged from 1 * 100 to 5.1 * 102 bce/51 ml; the majority of samples had less than one bce per ml milk. Expression of the chosen target was detected in artificially contaminated raw milk as well as inoculated Dubos broth, thus confirming the real-time PCR assay's potential to detect viable MAP cells. CONCLUSIONS: Concentrating the DNA of a large sample volume in combination with the newly developed real-time PCR assay permitted quantification of low levels of MAP cells in raw milk and pasteurized milk. The selected target Mptb52.16 - is promising with regard to the detection of viable MAP. Future studies integrating quantitative DNA- and RNA-based data might provide important information for risk assessment concerning the presence of MAP in raw milk and pasteurized milk. PMID- 20925921 TI - Seeking treatment for symptomatic malaria in Papua New Guinea. AB - BACKGROUND: Malaria places a significant burden on the limited resources of many low income countries. Knowing more about why and where people seek treatment will enable policy makers to better allocate the limited resources. This study aims to better understand what influences treatment-seeking behaviour for malaria in one such low-income country context, Papua New Guinea (PNG). METHODS: Two culturally, linguistically and demographically different regions in PNG were selected as study sites. A cross sectional household survey was undertaken in both sites resulting in the collection of data on 928 individuals who reported suffering from malaria in the previous four weeks. A probit model was then used to identify the factors determining whether or not people sought treatment for presumptive malaria. Multinomial logit models also assisted in identifying the factors that determined where people sought treatments. RESULTS: Results in this study build upon findings from other studies. For example, while distance in PNG has previously been seen as the primary factor in influencing whether any sort of treatment will be sought, in this study cultural influences and whether it was the first, second or even third treatment for a particular episode of malaria were also important. In addition, although formal health care facilities were the most popular treatment sources, it was also found that traditional healers were a common choice. In turn, the reasons why participants chose a particular type of treatment differed according to the whether they were seeking an initial or subsequent treatments. CONCLUSIONS: Simply bringing health services closer to where people live may not always result in a greater use of formal health care facilities. Policy makers in PNG need to consider within-country variation in treatment-seeking behaviour, the important role of traditional healers and also ensure that the community fully understands the potential implications of not seeking treatment for illnesses such as malaria at a formal health care facility. PMID- 20925923 TI - Detection of Babesia divergens in southern Norway by using an immunofluorescence antibody test in cow sera. AB - BACKGROUND: The incidence of bovine babesiosis, caused by Babesia divergens (Apicomplexa: Piroplasmida) has decreased markedly since the 1930 s, but may re emerge as a consequence of climate change and changes in legislation and pasturing practices. This is a potentially serious disease, with both economical and animal welfare consequences. Therefore, there is a need to survey the distribution of B. divergens. METHODS: We tested sera from 306 healthy pastured cows from 24 farms along the southern Norwegian coast by using an indirect immunofluorescence IgG antibody test (IFAT). Fractions of seropositive cows were compared by calculating 95% CI. RESULTS: The results of this test showed that 27% of the sera were positive for B. divergens antibodies. The fraction of antibody positive sera that we detected showed a two-humped distribution, with a high fraction of positives being found in municipalities in the western and eastern parts of the study area, while the municipalities between these areas had few or no positive serum samples. CONCLUSIONS: Neither the farmers' observations nor the Norwegian Dairy Herd Recording System give an adequate picture of the distribution of bovine babesiosis. Serological testing of cows by using IFAT is a convenient way of screening for the presence of B. divergens in an area. PMID- 20925924 TI - Cloning and characterization of a novel alternatively spliced transcript of the human CHD7 putative helicase. AB - BACKGROUND: The CHD7 (Chromodomain Helicase DNA binding protein 7) gene encodes a member of the chromodomain family of ATP-dependent chromatin remodeling enzymes. Mutations in the CHD7 gene are found in individuals with CHARGE, a syndrome characterized by multiple birth malformations in several tissues. CHD7 was identified as a binding partner of PBAF complex (Polybromo and BRG Associated Factor containing complex) playing a central role in the transcriptional reprogramming process associated to the formation of multipotent migratory neural crest, a transient cell population associated with the genesis of various tissues. CHD7 is a large gene containing 38 annotated exons and spanning 200 kb of genomic sequence. Although genes containing such number of exons are expected to have several alternative transcripts, there are very few evidences of alternative transcripts associated to CHD7 to date indicating that alternative splicing associated to this gene is poorly characterized. FINDINGS: Here, we report the cloning and characterization by experimental and computational studies of a novel alternative transcript of the human CHD7 (named CHD7 CRA_e), which lacks most of its coding exons. We confirmed by overexpression of CHD7 CRA_e alternative transcript that it is translated into a protein isoform lacking most of the domains displayed by the canonical isoform. Expression of the CHD7 CRA_e transcript was detected in normal liver, in addition to the DU145 human prostate carcinoma cell line from which it was originally isolated. CONCLUSIONS: Our findings indicate that the splicing event associated to the CHD7 CRA_e alternative transcript is functional. The characterization of the CHD7 CRA_e novel isoform presented here not only sets the basis for more detailed functional studies of this isoform, but, also, contributes to the alternative splicing annotation of the CHD7 gene and the design of future functional studies aimed at the elucidation of the molecular functions of its gene products. PMID- 20925925 TI - Trend of Entamoeba histolytica infestation in Kolkata. AB - BACKGROUND: Entamoeba histolytica infection is found almost all over the world and is highly endemic and a major cause of parasitic diarrhoea particularly in the developing countries. METHODS: A systemic surveillance was set up at the Infectious Disease hospital, Kolkata, India between November 2007 and October 2009 for understanding the trend of E. histolytica infection in Kolkata. Fecal samples were collected from diarrhoeal patients attending the hospital, under the surveillance system and processed for detection of E. histolytica. RESULTS: During the last two years about 2500 diarrhoeal samples were collected and screened for E. histolytica. About 3.6% were positive for E. histolytica. As compared to the earlier years, E. histolytica infection was observed to be less amongst patients screened during the last two years. No seasonality was observed in Kolkata although in the neighboring tropical country Bangladesh, a typical seasonality of E. histolytica infection was noticed. CONCLUSION: The study indicates that the detection rate of E. histolytica infection amongst diarrhoeal patients in Kolkata is decreasing during the last two years than that of Bangladesh. PMID- 20925926 TI - Clinical outcomes of seasonal influenza and pandemic influenza A (H1N1) in pediatric inpatients. AB - BACKGROUND: In April 2009, a novel influenza A H1N1 (nH1N1) virus emerged and spread rapidly worldwide. News of the pandemic led to a heightened awareness of the consequences of influenza and generally resulted in enhanced infection control practices and strengthened vaccination efforts for both healthcare workers and the general population. Seasonal influenza (SI) illness in the pediatric population has been previously shown to result in significant morbidity, mortality, and substantial hospital resource utilization. Although influenza pandemics have the possibility of resulting in considerable illness, we must not ignore the impact that we can experience annually with SI. METHODS: We compared the outcomes of pediatric patients <=18 years of age at a large urban hospital with laboratory confirmed influenza and an influenza-like illness (ILI) during the 2009 pandemic and two prior influenza seasons. The primary outcome measure was hospital length of stay (LOS). All variables potentially associated with LOS based on univariable analysis, previous studies, or hypothesized relationships were included in the regression models to ensure adjustment for their effects. RESULTS: There were 133 pediatric cases of nH1N1 admitted during 2009 and 133 cases of SI admitted during the prior 2 influenza seasons (2007-8 and 2008-9). Thirty-six percent of children with SI and 18% of children with nH1N1 had no preexisting medical conditions (p = 0.14). Children admitted with SI had 1.73 times longer adjusted LOS than children admitted for nH1N1 (95% CI 1.35 2.13). There was a trend towards more children with SI requiring mechanical ventilation compared with nH1N1 (16 vs.7, p = 0.08). CONCLUSIONS: This study strengthens the growing body of evidence demonstrating that SI results in significant morbidity in the pediatric population. Pandemic H1N1 received considerable attention with strong media messages urging people to undergo vaccination and encouraging improved infection control efforts. We believe that this attention should become an annual effort for SI. Strong unified messages from health care providers and the media encouraging influenza vaccination will likely prove very useful in averting some of the morbidity related to influenza for future epidemics. PMID- 20925927 TI - Trajectories of maternal symptoms of anxiety and depression. A 13-year longitudinal study of a population-based sample. AB - BACKGROUND: There is a lack of population-based studies of developmental trajectories following mothers throughout the whole child-rearing phase and there are few longitudinal studies focusing on both symptoms of depression and anxiety. The aim of the current study is to identify latent trajectory groups based on counts of symptoms of anxiety and depression among mothers throughout the child rearing phase and the relations of the latent groups to maternal socio demographic variables. METHODS: Data is from a prospective, longitudinal study of nearly 1000 families in Norway followed from when the index children were 18 months until they were 14.5 years old (the TOPP study). The study used latent profile analysis (LPA) to identify latent groups of mothers with distinct trajectories across time of symptom counts. Latent group differences on socio demographic variables were tested with one-way ANOVAs, chi-square tests and exact tests. RESULTS: Six trajectories based on maternal scores from six waves of data collection of symptoms of anxiety and depression were identified; a 'No symptoms' group with mothers without symptoms; a 'Low' group with mothers reporting low symptom levels; a 'Moderate-low' group with mothers reporting moderately low symptom levels; a 'Moderate' group with mothers with moderate symptoms; a 'High chronic' group with mothers with overall high symptom levels; and a 'Low-rising' group with mothers starting with a low symptom level that increased over time. The mothers in the High-chronic symptom group differed from the other mothers on several socio-demographic variables. They were significantly younger than the mothers in the Low group comprising the oldest mothers. The mothers in the High chronic group had significantly lower education, were less likely to have paid work and were less likely to be living with a partner than the mothers in the other groups. CONCLUSIONS: The study shows socio-demographic differences between mothers classified into six trajectory groups based on symptoms of anxiety and depression covering 13 years of the child-rearing period. Specific socio demographic risk factors characterised mothers in the High-chronic symptom group. Identifying subgroups with enduring problems might inform more targeted preventive efforts. PMID- 20925928 TI - Comparison of real-time PCR and microscopy for malaria parasite detection in Malawian pregnant women. AB - BACKGROUND: New diagnostic tools for malaria are required owing to the changing epidemiology of malaria, particularly among pregnant women in sub-Saharan Africa. Real-time PCR assays targeting Plasmodium falciparum lactate dehydrogenase (pfldh) gene may facilitate the identification of a high proportion of pregnant women with a P. falciparum parasitaemia below the threshold of microscopy. These molecular methods will enable further studies on the effects of these submicroscopic infections on maternal health and birth outcomes. METHODS: The pfldh real-time PCR assay and conventional microscopy were compared for the detection of P. falciparum from dried blood spots and blood smears collected from the peripheral blood of 475 Malawian women at delivery. A cycle threshold (Ct) of the real-time PCR was determined optimizing the sensitivity and specificity of the pfldh PCR assay compared to microscopy. A real-time PCR species-specific assay was applied to identify the contribution to malaria infections of three Plasmodium species (P. falciparum P. ovale and P. malariae) in 44 discordant smear and pfldh PCR assay results. RESULTS: Of the 475 women, P. falciparum was detected in 11 (2.3%) by microscopy and in 51 (10.7%) by real-time PCR; compared to microscopy, the sensitivity of real-time PCR was 90.9% and the specificity 91.2%. If a Ct value of 38 was used as a cut-off, specificity improved to 94.6% with no change in sensitivity. The real-time PCR species-specific assay detected P. falciparum alone in all but four samples: two samples were mixed infections with P. falciparum and P. malariae, one was a pure P. malariae infection and one was a pfldh PCR assay-positive/species-specific assay-negative sample. Of three P. malariae infections detected by microscopy, only one was confirmed by the species-specific assay. CONCLUSIONS: Although microscopy remains the most appropriate method for clinical malaria diagnosis in field settings, molecular diagnostics such as real-time PCR offer a more reliable means to detect malaria parasites, particularly at low levels. Determination of the possible contribution of these submicroscopic infections to poor birth outcomes and maternal health is critical. For future studies to investigate these effects, this pfldh real-time PCR assay offers a reliable detection method. PMID- 20925929 TI - (Not) Keeping the stem straight: a proteomic analysis of maritime pine seedlings undergoing phototropism and gravitropism. AB - BACKGROUND: Plants are subjected to continuous stimuli from the environment and have evolved an ability to respond through various growth and development processes. Phototropism and gravitropism responses enable the plant to reorient with regard to light and gravity. RESULTS: We quantified the speed of maritime pine seedlings to reorient with regard to light and gravity over 22 days. Seedlings were inclined at 15, 30 and 45 degrees with vertical plants as controls. A lateral light source illuminated the plants and stem movement over time was recorded. Depending on the initial angle of stem lean, the apical response to the lateral light source differed. In control and 15 degrees inclined plants, the apex turned directly towards the light source after only 2 h. In plants inclined at 30 degrees and 45 degrees , the apex first reoriented in the vertical plane after 2 h, then turned towards the light source after 24 h. Two-dimensional gel electrophoresis coupled with mass spectrometry was then used to describe the molecular response of stem bending involved in photo- and gravi tropism after 22 hr and 8 days of treatment. A total of 486 spots were quantitatively analyzed using image analysis software. Significant changes were determined in the protein accumulation of 68 protein spots. Early response gravitropic associated proteins were identified, which are known to function in energy related and primary metabolism. A group of thirty eight proteins were found to be involved in primary metabolism and energy related metabolic pathways. Degradation of Rubisco was implicated in some protein shifts. CONCLUSIONS: Our study demonstrates a rapid gravitropic response in apices of maritime pine seedlings inclined >30 degrees . Little or no response was observed at the stem bases of the same plants. The primary gravitropic response is concomitant with a modification of the proteome, consisting of an over accumulation of energy and metabolism associated proteins, which may allow the stem to reorient rapidly after bending. PMID- 20925930 TI - The association between demographic factors, user reported experiences and user satisfaction: results from three casualty clinics in Norway. AB - BACKGROUND: User reported experiences and satisfaction are increasingly used as basis for quality indicators in the health sector. However, there is limited understanding of factors associated with user reported experiences and satisfaction with casualty clinics. METHODS: A random sample of 542 patients that had contacted any of three casualty clinics from mid April to mid May 2008 was mailed a questionnaire. A reminder was sent to non-respondents after six weeks. Descriptive statistics for four user reported experiences scales and 20 single items are presented. Multivariate regression analysis was used to assess associations between background variables and user reported experiences, and between user reported experiences and user satisfaction. RESULTS: 225 (41.5%) patients, carers and guardians returned a completed questionnaire. Users reported most positive experiences with the doctor services and the nursing services at the casualty clinics; on a scale from 0 to 100, where 100 is the best possible experience the doctor scale was 82 and the nursing scale 81. Users reported least positive experiences with the organization of the casualty clinic, with a scale score of 65. Self perceived health was associated with user satisfaction, while self perceived health and age were associated with user reported experiences with organization of the clinics. A range of user reported experience domains were related to user satisfaction, after controlling for socio-demographic variables, including experiences with doctor services at the clinics, organization of the clinics, information and self perceived incorrect treatment. CONCLUSIONS: Users report positive experiences with the three casualty clinics, with organization as the aspect with largest improvement potential. The importance of age and health status for users' experiences and satisfaction with casualty clinics was shown, but a range of user reported experiences with the clinics were the most important predictors for user satisfaction. PMID- 20925931 TI - Evaluation of the late life disability instrument in the Lifestyle Interventions and Independence for Elders Pilot (LIFE-P) study. AB - BACKGROUND: The late life disability instrument (LLDI) was developed to assess limitations in instrumental and management roles using a small and restricted sample. In this paper we examine the measurement properties of the LLDI using data from the Lifestyle Interventions and Independence for Elders Pilot (LIFE-P) study. METHODS: LIFE-P participants, aged 70-89 years, were at elevated risk of disability. The 424 participants were enrolled at the Cooper Institute, Stanford University, University of Pittsburgh, and Wake Forest University. Physical activity and successful aging health education interventions were compared after 12-months of follow-up. Using factor analysis, we determined whether the LLDI's factor structure was comparable with that reported previously. We further examined how each item related to measured disability using item response theory (IRT). RESULTS: The factor structure for the limitation domain within the LLDI in the LIFE-P study did not corroborate previous findings. However, the factor structure using the abbreviated version was supported. Social and personal role factors were identified. IRT analysis revealed that each item in the social role factor provided a similar level of information, whereas the items in the personal role factor tended to provide different levels of information. CONCLUSIONS: Within the context of community-based clinical intervention research in aged populations, an abbreviated version of the LLDI performed better than the full 16 item version. In addition, the personal subscale would benefit from additional research using IRT. TRIAL REGISTRATION: The protocol of LIFE-P is consistent with the principles of the Declaration of Helsinki and is registered at http://www.ClinicalTrials.gov (registration # NCT00116194). PMID- 20925932 TI - Edelfosine-induced metabolic changes in cancer cells that precede the overproduction of reactive oxygen species and apoptosis. AB - BACKGROUND: Metabolic flux profiling based on the analysis of distribution of stable isotope tracer in metabolites is an important method widely used in cancer research to understand the regulation of cell metabolism and elaborate new therapeutic strategies. Recently, we developed software Isodyn, which extends the methodology of kinetic modeling to the analysis of isotopic isomer distribution for the evaluation of cellular metabolic flux profile under relevant conditions. This tool can be applied to reveal the metabolic effect of proapoptotic drug edelfosine in leukemia Jurkat cell line, uncovering the mechanisms of induction of apoptosis in cancer cells. RESULTS: The study of 13C distribution of Jukat cells exposed to low edelfosine concentration, which induces apoptosis in <=5% of cells, revealed metabolic changes previous to the development of apoptotic program. Specifically, it was found that low dose of edelfosine stimulates the TCA cycle. These metabolic perturbations were coupled with an increase of nucleic acid synthesis de novo, which indicates acceleration of biosynthetic and reparative processes. The further increase of the TCA cycle fluxes, when higher doses of drug applied, eventually enhance reactive oxygen species (ROS) production and trigger apoptotic program. CONCLUSION: The application of Isodyn to the analysis of mechanism of edelfosine-induced apoptosis revealed primary drug-induced metabolic changes, which are important for the subsequent initiation of apoptotic program. Initiation of such metabolic changes could be exploited in anticancer therapy. PMID- 20925933 TI - Intraindividual variability (IIV) in an animal model of ADHD - the Spontaneously Hypertensive Rat. AB - Attention-deficit/hyperactivity disorder (ADHD) is characterized by numerous behaviors including inattention, hyperactivity and impulsiveness. ADHD-affected individuals also have high intra-individual variability (IIV) in reaction time. The genetic control of IIV is not well understood. The single study of the genetics of this phenomenon in humans detected only marginal associations between genotypes at two candidate genes for ADHD and variability in response time. The Spontaneously Hypertensive Rat (SHR/NCrl) is an animal model of ADHD, expressing high activity, inattention and impulsive behavior during operant and task tests. The SHR might be useful for identifying genes for variability, but it is not known whether it also expresses high IIV, as is symptomatic of ADHD. We therefore conducted an investigation of IIV in the SHR. We used 16 SHR/NCrl rats and 15 Wistar-Kyoto (WKY/Nico) controls applying a reinforcement schedule used in the validation of the SHR as an animal model of ADHD. We represented IIV as the average absolute deviation of individual behavior within the five 18-min segments of each experimental session from the average behavioral trait value within that session ('individual phenotypic dispersion', PDi). PDi for hyperactivity, impulsiveness and inattention in the SHR and WKY rats was analyzed using nonparametric ranking by experimental session. SHR/NCrl rats had higher PDi than WKY/Nico controls for impulsiveness and inattention. There was a significant upward trend for PDi over experimental segments within sessions for attention in SHR rats, but not in WKY. PDi for hyperactivity was correlated with PDi for impulsiveness and we therefore excluded observations associated with short IRTs (< 0.67 s); dispersion in hyperactivity outside this interval was also significantly higher in SHR rats than in WKY rats. Some studies indicate the sharing of symptoms of hyperactivity and impulsiveness in SHR and ADHD-affected humans; high IIV in operant behavioral metrics suggests that the SHR may be useful in elucidating the genetic basis for IIV in humans. PMID- 20925935 TI - Clinical expert guidelines for the management of cough in lung cancer: report of a UK task group on cough. AB - BACKGROUND: Cough is a common and distressing symptom in lung cancer patients. The clinical management of cough in lung cancer patients is suboptimal with limited high quality research evidence available. The aim of the present paper is to present a clinical guideline developed in the UK through scrutiny of the literature and expert opinion, in order to aid decision making in clinicians and highlight good practice. METHODS: Two systematic reviews, one focusing on the management of cough in respiratory illness and one Cochrane review specifically on cancer, were conducted. Also, data from reviews, phase II trials and case studies were synthesized. A panel of experts in the field was also convened in an expert consensus meeting to make sense of the data and make clinical propositions. RESULTS: A pyramid of cough management was developed, starting with the treatment of reversible causes of cough/specific pathology. Initial cough management should focus on peripherally acting and intermittent treatment; more resistant symptoms require the addition of (or replacement by) centrally acting and continuous treatment. The pyramid for the symptomatic management starts from the simpler and most practical regimens (demulcents, simple linctus) to weak opioids to morphine and methadone before considering less well-researched and experimental approaches. CONCLUSION: The clinical guidelines presented aim to provide a sensible clinical approach to the management of cough in lung cancer. High quality research in this field is urgently required to provide more evidence based recommendations. PMID- 20925934 TI - Monitoring of malaria parasite resistance to chloroquine and sulphadoxine pyrimethamine in the Solomon Islands by DNA microarray technology. AB - BACKGROUND: Little information is available on resistance to anti-malarial drugs in the Solomon Islands (SI). The analysis of single nucleotide polymorphisms (SNPs) in drug resistance associated parasite genes is a potential alternative to classical time- and resource-consuming in vivo studies to monitor drug resistance. Mutations in pfmdr1 and pfcrt were shown to indicate chloroquine (CQ) resistance, mutations in pfdhfr and pfdhps indicate sulphadoxine-pyrimethamine (SP) resistance, and mutations in pfATPase6 indicate resistance to artemisinin derivatives. METHODS: The relationship between the rate of treatment failure among 25 symptomatic Plasmodium falciparum-infected patients presenting at the clinic and the pattern of resistance-associated SNPs in P. falciparum infecting 76 asymptomatic individuals from the surrounding population was investigated. The study was conducted in the SI in 2004. Patients presenting at a local clinic with microscopically confirmed P. falciparum malaria were recruited and treated with CQ+SP. Rates of treatment failure were estimated during a 28-day follow-up period. In parallel, a DNA microarray technology was used to analyse mutations associated with CQ, SP, and artemisinin derivative resistance among samples from the asymptomatic community. Mutation and haplotype frequencies were determined, as well as the multiplicity of infection. RESULTS: The in vivo study showed an efficacy of 88% for CQ+SP to treat P. falciparum infections. DNA microarray analyses indicated a low diversity in the parasite population with one major haplotype present in 98.7% of the cases. It was composed of fixed mutations at position 86 in pfmdr1, positions 72, 75, 76, 220, 326 and 356 in pfcrt, and positions 59 and 108 in pfdhfr. No mutation was observed in pfdhps or in pfATPase6. The mean multiplicity of infection was 1.39. CONCLUSION: This work provides the first insight into drug resistance markers of P. falciparum in the SI. The obtained results indicated the presence of a very homogenous P. falciparum population circulating in the community. Although CQ+SP could still clear most infections, seven fixed mutations associated with CQ resistance and two fixed mutations related to SP resistance were observed. Whether the absence of mutations in pfATPase6 indicates the efficacy of artemisinin derivatives remains to be proven. PMID- 20925936 TI - Robust assignment of cancer subtypes from expression data using a uni-variate gene expression average as classifier. AB - BACKGROUND: Genome wide gene expression data is a rich source for the identification of gene signatures suitable for clinical purposes and a number of statistical algorithms have been described for both identification and evaluation of such signatures. Some employed algorithms are fairly complex and hence sensitive to over-fitting whereas others are more simple and straight forward. Here we present a new type of simple algorithm based on ROC analysis and the use of metagenes that we believe will be a good complement to existing algorithms. RESULTS: The basis for the proposed approach is the use of metagenes, instead of collections of individual genes, and a feature selection using AUC values obtained by ROC analysis. Each gene in a data set is assigned an AUC value relative to the tumor class under investigation and the genes are ranked according to these values. Metagenes are then formed by calculating the mean expression level for an increasing number of ranked genes, and the metagene expression value that optimally discriminates tumor classes in the training set is used for classification of new samples. The performance of the metagene is then evaluated using LOOCV and balanced accuracies. CONCLUSIONS: We show that the simple uni-variate gene expression average algorithm performs as well as several alternative algorithms such as discriminant analysis and the more complex approaches such as SVM and neural networks. The R package rocc is freely available at http://cran.r-project.org/web/packages/rocc/index.html. PMID- 20925937 TI - Impact of maternal metabolic abnormalities in pregnancy on human milk and subsequent infant metabolic development: methodology and design. AB - BACKGROUND: Childhood obesity is on the rise and is a major risk factor for type 2 diabetes later in life. Recent evidence indicates that abnormalities that increase risk for diabetes may be initiated early in infancy. Since the offspring of women with diabetes have an increased long-term risk for obesity and type 2 diabetes, the impact of maternal metabolic abnormalities on early nutrition and infant metabolic trajectories is of considerable interest. Human breast milk, the preferred food during infancy, contains not only nutrients but also an array of bioactive substances including metabolic hormones. Nonetheless, only a few studies have reported concentrations of metabolic hormones in human milk specifically from women with metabolic abnormalities. We aim to investigate the impact of maternal metabolic abnormalities in pregnancy on human milk hormones and subsequently on infant development over the first year of life. The objective of this report is to present the methodology and design of this study. METHODS/DESIGN: The current investigation is a prospective study conducted within ongoing cohort studies of women and their offspring. Pregnant women attending outpatient obstetrics clinics in Toronto, Canada were recruited. Between April 2009 and July 2010, a total of 216 pregnant women underwent a baseline oral glucose tolerance test and provided medical and lifestyle history. Follow-up visits and telephone interviews are conducted and expected to be completed in October 2011. Upon delivery, infant birth anthropometry measurements and human breast milk samples are collected. At 3 and 12 months postpartum, mothers and infants are invited for follow-up assessments. Interim telephone interviews are conducted during the first year of offspring life to characterize infant feeding and supplementation behaviors. DISCUSSION: An improved understanding of the link between maternal metabolic abnormalities in pregnancy and early infant nutrition may assist in the development of optimal prevention and intervention strategies and in the protection of nutritionally vulnerable offspring who are at risk for obesity and diabetes later in life. PMID- 20925938 TI - A randomized, placebo-controlled, double-blind, prospective trial to evaluate the effect of vildagliptin in new-onset diabetes mellitus after kidney transplantation. AB - BACKGROUND: New-onset diabetes mellitus after transplantation (NODAT), a frequent and serious complication after transplantation, is associated with decreased graft and patient survival. Currently, it is diagnosed and treated primarily according to existing guidelines for type II diabetes. To date, only a few trials have studied antidiabetic drugs in patients with NODAT. Vildagliptin is a novel dipeptidyl peptidase-4 (DPP-4) inhibitor that improves pancreatic islet function by enhancing both alpha- and beta-cell responsiveness to increased blood glucose. Experimental data show potential protective effects of DPP-4 inhibitors on islet function after exogenous stress stimuli including immunosuppressants. Therefore, the therapy of NODAT with this class of compounds seems attractive. At present, vildagliptin is used to treat type II diabetes as monotherapy or in combination with other antidiabetic drugs, since that it efficiently decreases glycated hemoglobin (HbA1c) values. Additionally, vildagliptin has been shown to be safe in patients with moderately impaired kidney function. This study will evaluate the safety and efficacy of vildagliptin monotherapy in renal transplant recipients with recently diagnosed NODAT. METHODS/DESIGN: This study is a randomized, placebo-controlled, double-blind, prospective phase II trial. Using the results of routinely performed oral glucose tolerance tests (OGTT) in stable renal transplant patients at our center, we will recruit patients without a history of diabetes and a 2 h glucose value surpassing 200 mg/dl (11.1 mmol/l). They are randomized to receive either 50 mg vildagliptin or placebo once daily. A total of 32 patients with newly diagnosed NODAT will be included. The primary endpoint is the difference in the 2 h glucose value between baseline and the repeated OGTT performed 3 months after treatment start, compared between the vildagliptin- and the placebo-group. Secondary endpoints include changes in HbA1c and fasting plasma glucose (FPG). The safety of vildagliptin in renal transplant patients will be assessed by the number of symptomatic hypoglycemic episodes (glucose <72 mg/dl or 4 mmol/l), the number of adverse events, and possible medication-associated side-effects. DISCUSSION: NODAT is a severe complication after kidney transplantation. Few trials have assessed the safety and efficacy of antidiabetic drugs for these patients. The purpose of this study is to assess the safety and efficacy of vildagliptin in renal transplant patients with NODAT. TRIAL REGISTRATION: ClinicalTrials.gov NCT00980356. PMID- 20925939 TI - An increase in the burden of neonatal admissions to a rural district hospital in Kenya over 19 years. AB - BACKGROUND: Most of the global neonatal deaths occur in developing nations, mostly in rural homes. Many of the newborns who receive formal medical care are treated in rural district hospitals and other peripheral health centres. However there are no published studies demonstrating trends in neonatal admissions and outcome in rural health care facilities in resource poor regions. Such information is critical in planning public health interventions. In this study we therefore aimed at describing the pattern of neonatal admissions to a Kenyan rural district hospital and their outcome over a 19 year period, examining clinical indicators of inpatient neonatal mortality and also trends in utilization of a rural hospital for deliveries. METHODS: Prospectively collected data on neonates is compared to non-neonatal paediatric (<= 5 years old) admissions and deliveries' in the maternity unit at Kilifi District Hospital from January 1(st) 1990 up to December 31(st) 2008, to document the pattern of neonatal admissions, deliveries and changes in inpatient deaths. Trends were examined using time series models with likelihood ratios utilised to identify indicators of inpatient neonatal death. RESULTS: The proportion of neonatal admissions of the total paediatric <= 5 years admissions significantly increased from 11% in 1990 to 20% by 2008 (trend 0.83 (95% confidence interval 0.45-1.21). Most of the increase in burden was from neonates born in hospital and very young neonates aged < 7 days. Hospital deliveries also increased significantly. Clinical diagnoses of neonatal sepsis, prematurity, neonatal jaundice, neonatal encephalopathy, tetanus and neonatal meningitis accounted for over 75% of the inpatient neonatal admissions. Inpatient case fatality for all <= 5 years declined significantly over the 19 years. However, neonatal deaths comprised 33% of all inpatient death among children aged <= 5 years in 1990, this increased to 55% by 2008. Tetanus 256/390 (67%), prematurity 554/1,280(43%) and neonatal encephalopathy 253/778(33%) had the highest case fatality. A combination of six indicators: irregular respiration, oxygen saturation of <90%, pallor, neck stiffness, weight < 1.5 kg, and abnormally elevated blood glucose > 7 mmol/l predicted inpatient neonatal death with a sensitivity of 81% and a specificity of 68%. CONCLUSIONS: There is clear evidence of increasing burden in neonatal admissions at a rural district hospital in contrast to reducing numbers of non neonatal paediatrics' admissions aged <= 5 years. Though the inpatient case fatality for all admissions aged <= 5 years declined significantly, neonates now comprise close to 60% of all inpatient deaths. Simple indicators may identify neonates at risk of death. PMID- 20925940 TI - Analysis of Alzheimer's disease severity across brain regions by topological analysis of gene co-expression networks. AB - BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder involving variations in the transcriptome of many genes. AD does not affect all brain regions simultaneously. Identifying the differences among the affected regions may shed more light onto the disease progression. We developed a novel method involving the differential topology of gene coexpression networks to understand the association among affected regions and disease severity. METHODS: We analysed microarray data of four regions--entorhinal cortex (EC), hippocampus (HIP), posterior cingulate cortex (PCC) and middle temporal gyrus (MTG) from AD affected and normal subjects. A coexpression network was built for each region and the topological overlap between them was examined. Genes with zero topological overlap between two region-specific networks were used to characterise the differences between the two regions. RESULTS AND CONCLUSION: Results indicate that MTG shows early AD pathology compared to the other regions. We postulate that if the MTG gets affected later in the disease, post-mortem analyses of individuals with end-stage AD will show signs of early AD in the MTG, while the EC, HIP and PCC will have severe pathology. Such knowledge is useful for data collection in clinical studies where sample selection is a limiting factor as well as highlighting the underlying biology of disease progression. PMID- 20925941 TI - Assessing time to pulmonary function benefit following antibiotic treatment of acute cystic fibrosis exacerbations. AB - BACKGROUND: Cystic Fibrosis (CF) is a life-shortening genetic disease in which ~80% of deaths result from loss of lung function linked to inflammation due to chronic bacterial infection (principally Pseudomonas aeruginosa). Pulmonary exacerbations (intermittent episodes during which symptoms of lung infection increase and lung function decreases) can cause substantial resource utilization, morbidity, and irreversible loss of lung function. Intravenous antibiotic treatment to reduce exacerbation symptoms is standard management practice. However, no prospective studies have identified an optimal antibiotic treatment duration and this lack of objective data has been identified as an area of concern and interest. METHODS: We have retrospectively analyzed pulmonary function response data (as forced expiratory volume in one second; FEV1) from a previous blinded controlled CF exacerbation management study of intravenous ceftazidime/tobramycin and meropenem/tobramycin in which spirometry was conducted daily to assess the time course of pulmonary function response. RESULTS: Ninety five patients in the study received antibiotics for at least 4 days and were included in our analyses. Patients received antibiotics for an average of 12.6 days (median = 13, SD = 3.2 days), with a range of 4 to 27 days. No significant differences were observed in mean or median treatment durations as functions of either treatment group or baseline lung disease stage. Average time from initiation of antibiotic treatment to highest observed FEV1 was 8.7 days (median = 10, SD = 4.0 days), with a range of zero to 19 days. Patients were treated an average of 3.9 days beyond the day of peak FEV1 (median = 3, SD = 3.8 days), with 89 patients (93.7%) experiencing their peak FEV1 improvement within 13 days. There were no differences in mean or median times to peak FEV1 as a function of treatment group, although the magnitude of FEV1 improvement differed between groups. CONCLUSIONS: Our results suggest that antibiotic response to exacerbation as assessed by pulmonary function is essentially complete within 2 weeks of treatment initiation and relatively independent of the magnitude of pulmonary function response observed. PMID- 20925942 TI - Distinct expression patterns of mitochondrially localized YFP in neuronal subsets in the retina of three transgenic mouse lines. AB - BACKGROUND: Transgenic labels that allow the visualization of specific populations of neurons have proven to be powerful tools for research. Further developing such resources to label additional cell types and specific organelles within these cell will provide additional experimental opportunities. FINDINGS: The retinal expression profile of a mitochondria-localized yellow fluorescent protein (YFP) in each of three transgenic mouse lines was determined. Each line, Mito-R, Mito-Y and Mito-Z, expresses YFP in distinct and reproducible populations of retinal neurons. In the Mito-R line, YFP is expressed in most or all retinal ganglion cells (RGCs) and photoreceptors making this line useful for studying axonal transport in diseases such as glaucoma and photoreceptor degeneration related to transport of mitochondria into the inner segments. In the Mito-Y line, YFP is expressed in many cell types in the dorsal retina and in a rough mosaic population of RGCs in the rest of the retina, making this line useful for study of how retinal mosaics are organized. In the Mito-Z line, YFP is expressed in a subset of RGCs, amacrine cells, bipolar cells and photoreceptors. The Mito-Z line is inserted on the X-Chromosome, resulting in X-inactivation mosaicism in female mice carrying a single copy of the transgene. In the female hemizygous retina, expression is present in distinct clonal columns, making this transgenic line useful for analysis of clonal proliferation and lateral migration of retinal neurons. CONCLUSION: The retinal expression profiles of three transgenic mouse lines that express a mitochondrially localized YFP were characterized in this study. These lines will allow researchers to isolate and identify cell types within the retina and to study retinal mitochondrial trafficking and disease. PMID- 20925943 TI - Factors associated with access to HIV care and treatment in a prevention of mother to child transmission programme in urban Zimbabwe. AB - BACKGROUND: This cross-sectional study assessed factors affecting access to antiretroviral therapy (ART) among HIV-positive women from the prevention of mother to child transmission HIV programme in Chitungwiza, Zimbabwe. METHODS: Data were collected between June and August 2008. HIV-positive women attending antenatal clinics who had been referred to the national ART programme from January 2006 until December 2007 were surveyed. The questionnaire collected socio demographic data, treatment-seeking behaviours, and positive or negative factors that affect access to HIV care and treatment. RESULTS: Of the 147 HIV-positive women interviewed, 95 (65%) had registered with the ART programme. However, documentation of the referral was noted in only 23 (16%) of cases. Of the 95 registered women, 35 (37%) were receiving ART; 17 (18%) had not undergone CD4 testing. Multivariate analysis revealed that participants who understood the referral process were three times more likely to access HIV care and treatment (OR = 3.21, 95% CI 1.89-11.65) and participants enrolled in an HIV support group were twice as likely to access care and treatment (OR = 2.34, 95% CI 1.13-4.88). Those living with a male partner were 60% less likely to access care and treatment (OR = 0.40, 95% CI 0.16-0.99). Participants who accessed HIV care and treatment faced several challenges, including long waiting times (46%), unreliable access to laboratory testing (35%) and high transport costs (12%). Of the 147 clients surveyed, 52 (35%) women did not access HIV care and treatment. Barriers included perceived long queues (50%), competing life priorities, such as seeking food or shelter (33%) and inadequate referral information (15%). CONCLUSIONS: Despite many challenges, the majority of participants accessed HIV care. Development of referral tools and decentralization of CD4 testing to clinics will improve access to ART. Psychosocial support can be a successful entry point to encourage client referral to care and treatment programmes. PMID- 20925944 TI - Web 2.0 and internet social networking: a new tool for disaster management?- lessons from Taiwan. AB - BACKGROUND: Internet social networking tools and the emerging web 2.0 technologies are providing a new way for web users and health workers in information sharing and knowledge dissemination. Based on the characters of immediate, two-way and large scale of impact, the internet social networking tools have been utilized as a solution in emergency response during disasters. This paper highlights the use of internet social networking in disaster emergency response and public health management of disasters by focusing on a case study of the typhoon Morakot disaster in Taiwan. DISCUSSION: In the case of typhoon disaster in Taiwan, internet social networking and mobile technology were found to be helpful for community residents, professional emergency rescuers, and government agencies in gathering and disseminating real-time information, regarding volunteer recruitment and relief supplies allocation. We noted that if internet tools are to be integrated in the development of emergency response system, the accessibility, accuracy, validity, feasibility, privacy and the scalability of itself should be carefully considered especially in the effort of applying it in resource poor settings. SUMMARY: This paper seeks to promote an internet-based emergency response system by integrating internet social networking and information communication technology into central government disaster management system. Web-based networking provides two-way communication which establishes a reliable and accessible tunnel for proximal and distal users in disaster preparedness and management. PMID- 20925945 TI - The cost of reducing starting RNA quantity for Illumina BeadArrays: a bead-level dilution experiment. AB - BACKGROUND: The demands of microarray expression technologies for quantities of RNA place a limit on the questions they can address. As a consequence, the RNA requirements have reduced over time as technologies have improved. In this paper we investigate the costs of reducing the starting quantity of RNA for the Illumina BeadArray platform. This we do via a dilution data set generated from two reference RNA sources that have become the standard for investigations into microarray and sequencing technologies. RESULTS: We find that the starting quantity of RNA has an effect on observed intensities despite the fact that the quantity of cRNA being hybridized remains constant. We see a loss of sensitivity when using lower quantities of RNA, but no great rise in the false positive rate. Even with 10 ng of starting RNA, the positive results are reliable although many differentially expressed genes are missed. We see that there is some scope for combining data from samples that have contributed differing quantities of RNA, but note also that sample sizes should increase to compensate for the loss of signal-to-noise when using low quantities of starting RNA. CONCLUSIONS: The BeadArray platform maintains a low false discovery rate even when small amounts of starting RNA are used. In contrast, the sensitivity of the platform drops off noticeably over the same range. Thus, those conducting experiments should not opt for low quantities of starting RNA without consideration of the costs of doing so. The implications for experimental design, and the integration of data from different starting quantities, are complex. PMID- 20925946 TI - Dimethylthiourea protects against chlorine induced changes in airway function in a murine model of irritant induced asthma. AB - BACKGROUND: Exposure to chlorine (Cl2) causes airway injury, characterized by oxidative damage, an influx of inflammatory cells and airway hyperresponsiveness. We hypothesized that Cl2-induced airway injury may be attenuated by antioxidant treatment, even after the initial injury. METHODS: Balb/C mice were exposed to Cl2 gas (100 ppm) for 5 mins, an exposure that was established to alter airway function with minimal histological disruption of the epithelium. Twenty-four hours after exposure to Cl2, airway responsiveness to aerosolized methacholine (MCh) was measured. Bronchoalveolar lavage (BAL) was performed to determine inflammatory cell profiles, total protein, and glutathione levels. Dimethylthiourea (DMTU;100 mg/kg) was administered one hour before or one hour following Cl2 exposure. RESULTS: Mice exposed to Cl2 had airway hyperresponsiveness to MCh compared to control animals pre-treated and post treated with DMTU. Total cell counts in BAL fluid were elevated by Cl2 exposure and were not affected by DMTU treatment. However, DMTU-treated mice had lower protein levels in the BAL than the Cl2-only treated animals. 4-Hydroxynonenal analysis showed that DMTU given pre- or post-Cl2 prevented lipid peroxidation in the lung. Following Cl2 exposure glutathione (GSH) was elevated immediately following exposure both in BAL cells and in fluid and this change was prevented by DMTU. GSSG was depleted in Cl2 exposed mice at later time points. However, the GSH/GSSG ratio remained high in chlorine exposed mice, an effect attenuated by DMTU. CONCLUSION: Our data show that the anti-oxidant DMTU is effective in attenuating Cl2 induced increase in airway responsiveness, inflammation and biomarkers of oxidative stress. PMID- 20925947 TI - Factors that influenced county system leaders to implement an evidence-based program: a baseline survey within a randomized controlled trial. AB - BACKGROUND: Despite the burgeoning number of well-validated interventions that have been shown in randomized trials to produce superior outcomes compared to usual services, it is estimated that only 10% of public systems deliver evidence based mental health services. In California, for example, more than 15,000 children are placed in group homes or residential centers with some evidence of iatrogenic effects. The present study evaluates the willingness among county leaders of child public service systems to adopt a new evidence-based model, Multidimensional Treatment Foster Care, (MTFC), as a way to decrease the prevalence of out-of-home placements. Specifically, the study examines how county level socio-demographic factors and child public service system leaders' perceptions of their county's organizational climate influence their decision of whether or not to consider adopting MTFC. METHODS: Two levels were examined in this study: Stable and historical factors from 40 California counties gathered from public records including population size, number of entries into out-of-home care, financing of mental health services, and percent minority population; and system leaders' perceptions of their county's organizational climate and readiness for change measured via a web-based survey. The number of days-to consent was the primary outcome variable defined as the duration of time between being notified of the opportunity to implement MTFC and the actual signing of a consent form indicating interest in considering implementation. Survival analysis methods were used to assess the predictors of this time-to-event measure. The present study is part of a larger randomized trial comparing two methods of implementation where counties are randomized to one of three time cohorts and two implementation conditions. RESULTS: The number of entries into care was the primary predictor of days-to-consent. This variable was significantly correlated to county size. System leader's perceptions of positive climate and organizational readiness for change also contributed to but did not mediate or moderate the days-to-consent. CONCLUSIONS: System leaders' decision to consider implementing a new evidence-based model was influenced most by their objective need for the program and next by their perception of the county's organizational climate and motivation to change. These findings highlight the importance of understanding the fit between the needs of the systems or agencies and the potential for addressing those needs with the proposed new program. PMID- 20925948 TI - Exercise rehabilitation on home-dwelling patients with Alzheimer's disease--a randomized, controlled trial. Study protocol. AB - BACKGROUND: Besides cognitive decline, Alzheimer's disease (AD) leads to physical disability, need for help and permanent institutional care. The trials investigating effects of exercise rehabilitation on physical functioning of home dwelling older dementia patients are still scarce. The aim of this study is to investigate the effectiveness of intensive exercise rehabilitation lasting for one year on mobility and physical functioning of home-dwelling patients with AD. METHODS: During years 2008-2010, patients with AD (n = 210) living with their spousal caregiver in community are recruited using central AD registers in Finland, and they are offered exercise rehabilitation lasting for one year. The patients are randomized into three arms: 1) tailored home-based exercise twice weekly 2) group-based exercise twice weekly in rehabilitation center 3) control group with usual care and information of exercise and nutrition. Main outcome measures will be Guralnik's mobility and balance tests and FIM-test to assess physical functioning. Secondary measures will be cognition, neuropsychiatric symptoms according to the Neuropsychiatric Inventory, caregivers' burden, depression and health-related quality of life (RAND-36). Data concerning admissions to institutional care and the use and costs of health and social services will be collected during a two year follow-up. DISCUSSION: To our knowledge this is the first large scale trial exploring whether home-dwelling patients with AD will benefit from intense and long-lasting exercise rehabilitation in respect to their mobility and physical functioning. It will also provide data on cost-effectiveness of the intervention. TRIAL REGISTRATION: ACTRN12608000037303. PMID- 20925949 TI - Dopaminergic reward system: a short integrative review. AB - Memory is an essential element to adaptive behavior since it allows consolidation of past experience guiding the subject to consider them in future experiences. Among the endogenous molecules that participate in the consolidation of memory, including the drug-seeking reward, considered as a form of learning, is dopamine. This neurotransmitter modulates the activity of specific brain nucleus such as nuclei accumbens, putamen, ventral tegmental area (VTA), among others and synchronizes the activity of these nuclei to establish the neurobiological mechanism to set the hedonic element of learning. We review the experimental evidence that highlights the activity of different brain nuclei modulating the mechanisms whereby dopamine biases memory towards events that are of motivational significance. PMID- 20925950 TI - Effects of dihydrocapsiate on adaptive and diet-induced thermogenesis with a high protein very low calorie diet: a randomized control trial. AB - BACKGROUND: Dihydrocapsiate (DCT) is a natural safe food ingredient which is structurally related to capsaicin from chili pepper and is found in the non pungent pepper strain, CH-19 Sweet. It has been shown to elicit the thermogenic effects of capsaicin but without its gastrointestinal side effects. METHODS: The present study was designed to examine the effects of DCT on both adaptive thermogenesis as the result of caloric restriction with a high protein very low calorie diet (VLCD) and to determine whether DCT would increase post-prandial energy expenditure (PPEE) in response to a 400 kcal/60 g protein liquid test meal. Thirty-three subjects completed an outpatient very low calorie diet (800 kcal/day providing 120 g/day protein) over 4 weeks and were randomly assigned to receive either DCT capsules three times per day (3 mg or 9 mg) or placebo. At baseline and 4 weeks, fasting basal metabolic rate and PPEE were measured in a metabolic hood and fat free mass (FFM) determined using displacement plethysmography (BOD POD). RESULTS: PPEE normalized to FFM was increased significantly in subjects receiving 9 mg/day DCT by comparison to placebo (p < 0.05), but decreases in resting metabolic rate were not affected. Respiratory quotient (RQ) increased by 0.04 in the placebo group (p < 0.05) at end of the 4 weeks, but did not change in groups receiving DCT. CONCLUSIONS: These data provide evidence for postprandial increases in thermogenesis and fat oxidation secondary to administration of dihydrocapsiate. TRIAL REGISTRATION: clinicaltrial.govNCT01142687. PMID- 20925951 TI - Randomised phase I/II study to evaluate carbon ion radiotherapy versus fractionated stereotactic radiotherapy in patients with recurrent or progressive gliomas: the CINDERELLA trial. AB - BACKGROUND: Treatment of patients with recurrent glioma includes neurosurgical resection, chemotherapy, or radiation therapy. In most cases, a full course of radiotherapy has been applied after primary diagnosis, therefore application of re-irradiation has to be applied cauteously. With modern precision photon techniques such as fractionated stereotactic radiotherapy (FSRT), a second course of radiotherapy is safe and effective and leads to survival times of 22, 16 and 8 months for recurrent WHO grade II, III and IV gliomas.Carbon ions offer physical and biological characteristics. Due to their inverted dose profile and the high local dose deposition within the Bragg peak precise dose application and sparing of normal tissue is possible. Moreover, in comparison to photons, carbon ions offer an increased relative biological effectiveness (RBE), which can be calculated between 2 and 5 depending on the GBM cell line as well as the endpoint analyzed. Protons, however, offer an RBE which is comparable to photons.First Japanese Data on the evaluation of carbon ion radiation therapy for the treatment of primary high-grade gliomas showed promising results in a small and heterogeneous patient collective. METHODS DESIGN: In the current Phase I/II CINDERELLA-trial re-irradiation using carbon ions will be compared to FSRT applied to the area of contrast enhancement representing high-grade tumor areas in patients with recurrent gliomas. Within the Phase I Part of the trial, the Recommended Dose (RD) of carbon ion radiotherapy will be determined in a dose escalation scheme. In the subsequent randomized Phase II part, the RD will be evaluated in the experimental arm, compared to the standard arm, FSRT with a total dose of 36 Gy in single doses of 2 Gy.Primary endpoint of the Phase I part is toxicity. Primary endpoint of the randomized part II is survival after re irradiation at 12 months, secondary endpoint is progression-free survival. DISCUSSION: The Cinderella trial is the first study to evaluate carbon ion radiotherapy for recurrent gliomas, and to compare this treatment to photon FSRT in a randomized setting using an ion beam delivered by intensity modulated rasterscanning. TRIAL REGISTRATION: NCT01166308. PMID- 20925952 TI - A novel mutation in the sterol 27-hydroxylase gene of a woman with autosomal recessive cerebrotendinous xanthomatosis. AB - Mutations of the gene encoding the mitochondrial enzyme sterol 27-hydroxylase (CYP27A1 gene) cause defects in the cholesterol pathway to bile acids that lead to the storage of cholestanol and cholesterol in tendons, lenses and the central nervous system. This disorder is the cause of a clinical syndrome known as cerebrotendinous xanthomatosis (CTX). Since 1991 several mutations of the CYP27A1 gene have been reported. We diagnosed the clinical features of CTX in a caucasian woman. Serum levels of cholestanol and 7alpha-hydroxycholesterol were elevated and the concentration of 27-hydroxycholesterol was reduced. Bile alcohols in the urine and faeces were increased. The analysis of the CYP27A1 gene showed that the patient was a compound heterozygote carrying two mutations both located in exon 8. One mutation is a novel four nucleotide deletion (c.1330-1333delTTCC) that results in a frameshift and the occurrence of a premature stop codon leading to the formation of a truncated protein of 448 amino acids. The other mutation, previously reported, is a C - > T transition (c. c.1381C > T) that converts the glutamine codon at position 461 into a termination codon (p.Q461X). These truncated proteins are expected to have no biological function being devoid of the cysteine residue at position 476 of the normal enzyme that is crucial for heme binding and enzyme activity. PMID- 20925953 TI - A relational conceptual framework for multidisciplinary health research centre infrastructure. AB - Although multidisciplinary and team-based approaches are increasingly acknowledged as necessary to address some of the most pressing contemporary health challenges, many researchers struggle with a lack of infrastructure to facilitate and formalise the requisite collaborations. Specialised research centres have emerged as an important organisational solution, yet centre productivity and sustainability are frequently dictated by the availability and security of infrastructure funds.Despite being widely cited as a core component of research capacity building, infrastructure as a discrete concept has been rather analytically neglected, often treated as an implicit feature of research environments with little specification or relegated to a narrow category of physical or administrative inputs. The terms research infrastructure, capacity, and culture, among others, are deployed in overlapping and inconsistent ways, further obfuscating the crucial functions of infrastructure specifically and its relationships with associated concepts.The case is made for an expanded conceptualisation of research infrastructure, one that moves beyond conventional 'hardware' notions. Drawing on a case analysis of NEXUS, a multidisciplinary health research centre based at the University of British Columbia, Canada, a conceptual framework is proposed that integrates the tangible and intangible structures that interactively underlie research centre functioning.A relational approach holds potential to allow for more comprehensive accounting of the returns on infrastructure investment. For those developing new research centres or seeking to reinvigorate existing ones, this framework may be a useful guide for both centre design and evaluation. PMID- 20925955 TI - Radioiodine remnant ablation of differentiated thyroid cancer does not further increase oxidative damage to membrane lipids - early effect. AB - INTRODUCTION: Radioiodine (131I) therapy is widely accepted as an essential part of therapeutic regimens in many cases of differentiated thyroid cancer. Radiation induced oxidative damage to macromolecules is a well known phenomenon. Frequently examined process to evaluate oxidative damage to macromolecules is lipid peroxidation (LPO), resulting from oxidative damage to membrane lipids. The aim of the study was to examine serum LPO level in hypothyroid (after total thyroidectomy) cancer patients subjected to ablative activities of 131I. MATERIALS AND METHODS: The study was carried out in 21 patients (18 females and 3 males, average age 52.4 +/- 16.5 years) after total thyroidectomy for papillary (17 patients) or follicular (4 patients) thyroid carcinoma. Hypothyroidism was confirmed by increased TSH blood concentration (BRAHMS, Germany), measured before 131I therapy. Activity of 2.8 - 6.9 GBq of 131I was administered to the patients orally as sodium iodide (OBRI, Poland). Concentrations of malondialdehyde + 4 hydroxyalkenals (MDA + 4-HDA), as an index of LPO (LPO-586 kit, Calbiochem, USA), were measured in blood serum just before 131I administration (day "0") and on the days 1-4 after 131I therapy. Sera from 23 euthyroid patients served as controls. Correlations between LPO and TSH or 131I activity were calculated. RESULTS: Expectedly, serum LPO level, when measured before 131I therapy, was several times higher (p < 0.00001) in cancer patients than in healthy subjects, which is probably due to hypothyroidism caused by total thyroidectomy. However, we did not observe any differences between LPO levels after and before 131I therapy. LPO did not correlate with TSH concentration. In turn, negative correlation was found between 131I activity and LPO level on the day "2" after radioiodine treatment. CONCLUSIONS: Radioiodine remnant ablation of differentiated thyroid cancer does not further increase oxidative damage to membrane lipids, at least early, after therapy. PMID- 20925954 TI - The origin of Eastern European Jews revealed by autosomal, sex chromosomal and mtDNA polymorphisms. AB - BACKGROUND: This study aims to establish the likely origin of EEJ (Eastern European Jews) by genetic distance analysis of autosomal markers and haplogroups on the X and Y chromosomes and mtDNA. RESULTS: According to the autosomal polymorphisms the investigated Jewish populations do not share a common origin, and EEJ are closer to Italians in particular and to Europeans in general than to the other Jewish populations. The similarity of EEJ to Italians and Europeans is also supported by the X chromosomal haplogroups. In contrast according to the Y chromosomal haplogroups EEJ are closest to the non-Jewish populations of the Eastern Mediterranean. MtDNA shows a mixed pattern, but overall EEJ are more distant from most populations and hold a marginal rather than a central position. The autosomal genetic distance matrix has a very high correlation (0.789) with geography, whereas the X-chromosomal, Y-chromosomal and mtDNA matrices have a lower correlation (0.540, 0.395 and 0.641 respectively). CONCLUSIONS: The close genetic resemblance to Italians accords with the historical presumption that Ashkenazi Jews started their migrations across Europe in Italy and with historical evidence that conversion to Judaism was common in ancient Rome. The reasons for the discrepancy between the biparental markers and the uniparental markers are discussed. PMID- 20925956 TI - Self-reported use of complementary and alternative medicine (CAM) products in topical treatment of diabetic foot disorders by diabetic patients in Jeddah, Western Saudi Arabia. AB - BACKGROUND: There is little published on current Saudi diabetic patients' practices when they are exposed to foot disorders such as open wound, ulcer, and skin cracks. These factors are usually influenced by local culture and communities beliefs. The aim of the current study was to identify the pattern of patients' use of CAM products in dealing with diabetic foot disorders topically in a group of diabetic patients. FINDINGS: A Cross-sectional descriptive study of a representative cohort of diabetic patients living in Jeddah, Saudi Arabia was designed. A pre-designed questionnaire to identify local diabetics' practices in dealing topically with foot disorders including open wound, chronic ulcer, and skin cracks was designed. Questionnaire was administered by a group of trained nutrition female students to diabetics face to face living in their neighborhood. A total of 1634 Saudi diabetics were interviewed. Foot disorders occurred in approximately two thirds of the respondents 1006 (61.6%). Out of the 1006 patients who had foot disorders, 653 reported trying some sort of treatment as 307 patients (47.1%) used conventional topical medical treatment alone, 142 (21.7%) used CAM products alone, and 204 (31.2%) used both treatments. The most commonly used CAM product by the patients was Honey (56.6%) followed by Commiphora Molmol (Myrrh) in (37.4%) and Nigellia Sativa (Black seed) in (35.1%). The least to be used was Lawsonia inermis (Henna) in (12.1%). Ten common natural preparations used topically to treat diabetic foot disorders were also identified. CONCLUSIONS: The use of CAM products in topical treatment of diabetic foot disorders is fairly common among Saudi diabetic patients. Honey headed the list as a solo topical preparation or in combination with other herbs namely black seeds and myrrh. The efficacy of the most common products needs further research. PMID- 20925957 TI - Pharmacokinetic targeting of intravenous busulfan reduces conditioning regimen related toxicity following allogeneic hematopoietic cell transplantation for acute myelogenous leukemia. AB - Optimal conditioning therapy for hematopoietic cell transplantation (HCT) in acute myelogenous leukemia (AML) remains undefined. We retrospectively compared outcomes of a consecutive series of 51 AML patients treated with oral busulfan (1 mg/kg every 6 hours for 4 days) and cyclophosphamide (60 mg/kg IV * 2 days) - (Bu/Cy) with 100 consecutive AML patients treated with pharmacokinetic targeted IV busulfan (AUC < 6000 MUM/L*min per day * 4 days) and fludarabine (40 mg/m2 * 4 days) - (t-IV Bu/Flu). The Bu/Cy and t-IV Bu/Flu groups significantly differed according to donor relation, stem cell source, aGVHD prophylaxis, remission status, primary vs. secondary disease, median age, and % blasts prior to HCT (p < 0.01 for each). Conditioning with t-IV Bu/Flu reduced early toxicity including idiopathic pneumonia syndrome (IPS) and hepatic veno-occlusive disease (VOD). Additionally, the trajectory of early NRM (100 day: 16% vs. 3%, and1 year: 25% vs. 15% for Bu/Cy and t-IV Bu/Flu, respectively) favored t-IV Bu/Flu. Grade II-IV aGVHD (48% vs. 82%, p < 0.0001), as well as moderate/severe cGVHD (7% vs. 40%, p < 0.0001) differed between the Bu/Cy and t-IV Bu/Flu groups, due to the predominance of peripheral blood stem cells in the t-IV Bu/Flu group. Pharmacokinetic targeting of intravenous busulfan in combination with fludarabine is associated with reduced conditioning regimen related toxicity compared to oral busulfan and cyclophosphamide. However, multivariable analysis did not demonstrate significant differences in overall survival (p = 0.78) or non-relapse mortality (p = 0.6) according to conditioning regimen delivered. PMID- 20925958 TI - WestREN: a description of an Irish academic general practice research network. AB - BACKGROUND: Primary care research networks have been established internationally since the 1960s to enable diverse practitioners to engage in and develop research and education and implement research evidence.The newly established Western Research and Education Network (WestREN) is one such network consisting of a collaboration between the Discipline of General Practice at NUI Galway and 71 West of Ireland general practices. In September 2009 all member practices were issued with a questionnaire with two objectives: to describe the structure and characteristics of the member practices and to compare the results to the national profile of Irish general practice. METHODS: A postal survey was used followed by one written and one email reminder. RESULTS: A response rate of 73% (52/71) was achieved after two reminders.Half of practices were in a rural location, one quarter located in an urban setting and another quarter in a mixed location.Ninety-four per cent of general practitioners practice from purpose built or adapted premises with under 6% of practices being attached to the general practitioner's residence. Over 96% of general practitioners use appointment systems with 58% using appointment only.All practices surveyed were computerised, with 80% describing their practices as 'fully computerised'. Almost 60% of general practitioners are coding chronic diagnoses with 20% coding individual consultations. Twenty-five per cent of general practitioners were single-handed with the majority of practices having at least two general practitioners, and a mean number of general practitioners of 2.4. Ninety-two per cent of practices employed a practice nurse with 30% employing more than one nurse.Compared to the national profile, WestREN practices appear somewhat larger, and more likely to be purpose-built and in rural areas. National trends apparent between 1982 and 1992, such as increasing computerisation and practice nurse availability, appear to be continuing. CONCLUSIONS: WestREN is a new university affiliated general practice research network in Ireland. Survey of its initial membership confirms WestREN practices to be broadly representative of the national profile and has provided us with valuable information on the current and changing structure of Irish general practice. PMID- 20925959 TI - The clinical potential of microRNAs. AB - MicroRNAs are small noncoding RNAs that function to control gene expression. These small RNAs have been shown to contribute to the control of cell growth, differentiation and apoptosis, important features related to cancer development and progression. In fact, recent studies have shown the utility of microRNAs as cancer-related biomarkers. This is due to the finding that microRNAs display altered expression profiles in cancers versus normal tissue. In addition, microRNAs have been associated with cancer progression. In this review, the mechanisms to alter microRNA expression and their relation to cancer will be addressed. Moreover, the potential application of microRNAs in clinical settings will also be highlighted. Finally, the challenges regarding the translation of research involving microRNAs to the clinical realm will be discussed. PMID- 20925960 TI - Dynamic, mating-induced gene expression changes in female head and brain tissues of Drosophila melanogaster. AB - BACKGROUND: Drosophila melanogaster females show changes in behavior and physiology after mating that are thought to maximize the number of progeny resulting from the most recent copulation. Sperm and seminal fluid proteins induce post-mating changes in females, however, very little is known about the resulting gene expression changes in female head and central nervous system tissues that contribute to the post-mating response. RESULTS: We determined the temporal gene expression changes in female head tissues 0-2, 24, 48 and 72 hours after mating. Females from each time point had a unique post-mating gene expression response, with 72 hours post-mating having the largest number of genes with significant changes in expression. At most time points, genes expressed in the head fat body that encode products involved in metabolism showed a marked change in expression. Additional analysis of gene expression changes in dissected brain tissues 24 hours post-mating revealed changes in transcript abundance of many genes, notably, the reduced transcript abundance of genes that encode ion channels. CONCLUSIONS: Substantial changes occur in the regulation of many genes in female head tissues after mating, which might underlie aspects of the female post-mating response. These results provide new insights into the physiological and metabolic changes that accompany changes in female behaviors. PMID- 20925961 TI - Development of an EGFRvIII specific recombinant antibody. AB - BACKGROUND: EGF receptor variant III (EGFRvIII) is the most common variant of the EGF receptor observed in human tumors. It results from the in frame deletion of exons 2-7 and the generation of a novel glycine residue at the junction of exons 1 and 8. This novel juxtaposition of amino acids within the extra-cellular domain of the EGF receptor creates a tumor specific and immunogenic epitope. EGFRvIII expression has been seen in many tumor types including glioblastoma multiforme (GBM), breast adenocarcinoma, non-small cell lung carcinoma, ovarian adenocarcinoma and prostate cancer, but has been rarely observed in normal tissue. Because this variant is tumor specific and highly immunogenic, it can be used for both a diagnostic marker as well as a target for immunotherapy. Unfortunately many of the monoclonal and polyclonal antibodies directed against EGFRvIII have cross reactivity to wild type EGFR or other non-specific proteins. Furthermore, a monoclonal antibody to EGFRvIII is not readily available to the scientific community. RESULTS: In this study, we have developed a recombinant antibody that is specific for EGFRvIII, has little cross reactivity for the wild type receptor, and which can be easily produced. We initially designed a recombinant antibody with two anti-EGFRvIII single chain Fv's linked together and a human IgG1 Fc component. To enhance the specificity of this antibody for EGFRvIII, we mutated tyrosine H59 of the CDRH2 domain and tyrosine H105 of the CDRH3 domain to phenylalanine for both the anti-EGFRvIII sequence inserts. This mutated recombinant antibody, called RAb(DMvIII), specifically detects EGFRvIII expression in EGFRvIII expressing cell lines as well as in EGFRvIII expressing GBM primary tissue by western blot, immunohistochemistry (IHC) and immunofluorescence (IF) and FACS analysis. It does not recognize wild type EGFR in any of these assays. The affinity of this antibody for EGFRvIII peptide is 1.7 * 107 M-1 as determined by enzyme-linked immunosorbent assay (ELISA). CONCLUSION: This recombinant antibody thus holds great potential to be used as a research reagent and diagnostic tool in research laboratories and clinics because of its high quality, easy viability and unique versatility. This antibody is also a strong candidate to be investigated for further in vivo therapeutic studies. PMID- 20925963 TI - HER2 testing on core needle biopsy specimens from primary breast cancers: interobserver reproducibility and concordance with surgically resected specimens. AB - BACKGROUND: Accurate evaluation of human epidermal growth factor receptor type-2 (HER2) status based on core needle biopsy (CNB) specimens is mandatory for identification of patients with primary breast cancer who will benefit from primary systemic therapy with trastuzumab. The aim of the present study was to validate the application of HER2 testing with CNB specimens from primary breast cancers in terms of interobserver reproducibility and comparison with surgically resected specimens. METHODS: A total of 100 pairs of archival formalin-fixed paraffin-embedded CNB and surgically resected specimens of invasive breast carcinomas were cut into sections. All 100 paired sections were subjected to HER2 testing by immunohistochemistry (IHC) and 27 paired sections were subjected to that by fluorescence in situ hybridization (FISH), the results being evaluated by three and two observers, respectively. Interobserver agreement levels in terms of judgment and the concordance of consensus scores between CNB samples and the corresponding surgically resected specimens were estimated as the percentage agreement and kappa statistic. RESULTS: In CNB specimens, the percentage interobserver agreement of HER2 scoring by IHC was 76% (kappa = 0.71) for 3 * 3 categories (0-1+ versus 2+ versus 3+) and 90% (kappa = 0.80) for 2 * 2 categories (0-2+ versus 3+). These levels were close to the corresponding ones for the surgically resected specimens: 80% (kappa = 0.77) for 3 * 3 categories and 92% (kappa = 0.88) for 2 * 2 categories. Concordance of consensus for HER2 scores determined by IHC between CNB and the corresponding surgical specimens was 87% (kappa = 0.77) for 3 * 3 categories, and 94% (kappa = 0.83) for 2 * 2 categories. Among the 13 tumors showing discordance in the mean IHC scores between the CNB and surgical specimens, the results of consensus for FISH results were concordant in 11. The rate of successful FISH analysis and the FISH positivity rate in cases with a HER2 IHC score of 2+ differed among specimens processed at different institutions. CONCLUSION: It is mandatory to study HER2 on breast cancers, and either CNB or surgical specimen can be used. PMID- 20925962 TI - Treatment results for hypopharyngeal cancer by different treatment strategies and its secondary primary--an experience in Taiwan. AB - PURPOSE: The aim of this study was to evaluate treatment results in our hypopharyngeal cancer patients. PATIENTS AND METHODS: A total of three hundred and ninety five hypopharyngeal cancer patients received radical treatment at our hospital; 96% were male. The majority were habitual smokers (88%), alcohol drinkers (73%) and/or betel quid chewers (51%). All patients received a CT scan or MRI for tumor staging before treatment. The stage distribution was stage I: 2 (0.5%); stage II: 22 (5.6%); stage III: 57 (14.4%) and stage IV: 314 (79.5%). Radical surgery was used first in 81 patients (20.5%), and the remaining patients (79.5%) received organ preservation-intended treatment (OPIT). In the OPIT group, 46 patients received radiotherapy alone, 156 patients received chemotherapy followed by radiotherapy (CT/RT) and 112 patients received concomitant chemo radiotherapy (CCRT). RESULTS: The five-year overall survival rates for stages I/II, III and IV were 49.5%, 47.4% and 18.6%, respectively. There was no significant difference in overall and disease-specific survival rates between patients who received radical surgery first and those who received OPIT. In the OPIT group, CCRT tended to preserve the larynx better (p = 0.088), with three year larynx preservation rates of 44.8% for CCRT and 27.2% for CT/RT. Thirty seven patients developed a second malignancy, with an annual incidence of 4.6%. CONCLUSIONS: There was no survival difference between OPIT and radical surgery in hypopharyngeal cancer patients at our hospital. CCRT may offer better laryngeal preservation than RT alone or CT/RT. However, prospective studies are still needed to confirm this finding. Additionally, second primary cancers are another important issue for hypopharyngeal cancer management. PMID- 20925964 TI - Over-expression of HO-1 on mesenchymal stem cells promotes angiogenesis and improves myocardial function in infarcted myocardium. AB - Heme oxygenase-1 (HO-1) is a stress-inducible enzyme with diverse cytoprotective effects, and reported to have an important role in angiogenesis recently. Here we investigated whether HO-1 transduced by mesenchymal stem cells (MSCs) can induce angiogenic effects in infarcted myocardium. HO-1 was transfected into cultured MSCs using an adenoviral vector. 1 * 106 Ad-HO-1-transfected MSCs (HO-1-MSCs) or Ad-Null-transfected MSCs (Null-MSCs) or PBS was respectively injected into rat hearts intramyocardially at 1 h post-myocardial infarction. The results showed that HO-1-MSCs were able to induce stable expression of HO-1 in vitro and in vivo. The capillary density and expression of angiogenic growth factors, VEGF and FGF2 were significantly enhanced in HO-1-MSCs-treated hearts compared with Null MSCs-treated and PBS-treated hearts. However, the angiogenic effects of HO-1 were abolished by treating the animals with HO inhibitor, zinc protoporphyrin. The myocardial apoptosis was marked reduced with significantly reduced fibrotic area in HO-1-MSCs-treated hearts; Furthermore, the cardiac function and remodeling were also significantly improved in HO-1-MSCs-treated hearts. Our current findings support the premise that HO-1 transduced by MSCs can induce angiogenic effects and improve heart function after acute myocardial infarction. PMID- 20925965 TI - Application of tumor-node-metastasis staging 2002 version in locally advanced hepatocellular carcinoma: is it predictive of surgical outcome? AB - BACKGROUND: Locally advanced (pT3-4N0M0) hepatocellular carcinoma (HCC) is a heterogeneous group of tumors, which consists of four different categories, including HCC with "multiple tumors more than 5 cm", "major vascular invasion", "invasion of adjacent organs", and "perforation of visceral peritoneum". The aim of our study was to verify whether the 2002 version of the Tumor-Node-Metastasis staging system could predict surgical outcomes in patients with locally advanced HCC. METHODS: We retrospectively reviewed 298 patients with pT3-4N0M0 HCC who underwent hepatic resection from 1993 to 2000 in an academic tertiary hospital. Overall survival (OS) and cumulative recurrence rate (CRR) of the four categories of locally advanced HCC patients were compared. RESULTS: In multivariate analysis, major vascular invasion was identified as the most significant factor (HR = 3.291, 95% CI 2.362-4.584, P < 0.001) followed by cirrhosis status on OS, and was found to be the only independent factor of CRR (HR = 2.242, 95% CI 1.811 3.358, P < 0.001) in patients with locally advanced HCC. Among the four categories of locally advanced HCC, OS was significantly worse, and CRR was significantly higher in patients with HCC with major vascular invasion (pT3) than with multiple tumors more than 5 cm (pT3); or tumor invasion of adjacent organs (pT4); or perforation of visceral peritoneum (pT4). No significant differences were observed in OS or CRR between the latter three groups of patients. CONCLUSIONS: HCC with major vascular invasion, which are classified as pT3 under the current TNM staging, have the worst prognosis when compared with the other categories of pT3-4 disease. There is a need to redefine the T classification and to stratify locally advanced HCC. PMID- 20925966 TI - Rationale, design, and results of the first screening round of a comprehensive, register-based, Chlamydia screening implementation programme in the Netherlands. AB - BACKGROUND: Implementing Chlamydia trachomatis screening in the Netherlands has been a point of debate for several years. The National Health Council advised against implementing nationwide screening until additional data collected from a pilot project in 2003 suggested that screening by risk profiles could be effective. A continuous increase in infections recorded in the national surveillance database affirmed the need for a more active approach. Here, we describe the rationale, design, and implementation of a Chlamydia screening demonstration programme. METHODS: A systematic, selective, internet-based Chlamydia screening programme started in April 2008. Letters are sent annually to all 16 to 29-year-old residents of Amsterdam, Rotterdam, and selected municipalities of South Limburg. The letters invite sexually active persons to login to http://www.chlamydiatest.nl with a personal code and to request a test kit. In the lower prevalence area of South Limburg, test kits can only be requested if the internet-based risk assessment exceeds a predefined value. RESULTS: We sent invitations to 261,025 people in the first round. One-fifth of the invitees requested a test kit, of whom 80% sent in a sample for testing. The overall positivity rate was 4.2%. CONCLUSIONS: This programme advances Chlamydia control activities in the Netherlands. Insight into the feasibility, effectiveness, cost-effectiveness, and impact of this large-scale screening programme will determine whether the programme will be implemented nationally. PMID- 20925968 TI - International Society of Sports Nutrition: 7th Annual ISSN Conference and Expo Clearwater Beach, FL, USA. 24-26 June 2010. Abstracts. PMID- 20925967 TI - Singling out genetic disorders and disease. AB - Preimplantation genetic diagnosis (PGD) involves testing of single cells biopsied from oocytes and/or embryos generated in vitro. As only embryos unaffected for a given genetic condition are transferred to the uterus, it avoids prenatal diagnosis and termination of pregnancy. Follow-up data from PGD pregnancies, deliveries and children show an acceptable live birth rate and, so far, no detrimental effects of the procedure have been observed. Of course, the long-term health outcome is currently unknown. PGD was first performed in 1990 and remained an experimental procedure for a number of years. Now, two decades later, it is regarded as an established alternative to prenatal diagnosis: its use has expanded, the range of applications has broadened, and continuous technical progress in single-cell testing has led to high levels of efficiency and accuracy. The current gold standard methods (single-cell multiplex-PCR for monogenic diseases and interphase fluorescence in situ hybridization for chromosomal aberrations) are being replaced by single-cell whole genome amplification and array technology. These generalized methods substantially reduce the pre-PGD workload and allow more automated genome-wide analysis. The implementation of laboratory accreditation schemes brings the field at the same level of routine diagnostics. This article reviews the state of the art and considers indications, accuracy and current technical changes in the field of PGD. PMID- 20925969 TI - Cannabis use at a young age is associated with psychotic experiences. AB - BACKGROUND: Cannabis use is associated with psychosis and a range of subclinical psychiatric symptoms. The strength of this association depends on dosage and age at first use. The current study investigates whether level of cannabis exposure and starting age are associated with specific profiles of subclinical symptoms. METHOD: We collected cross-sectional data from a young adult population sample by administering an online version of the Community Assessment of Psychic Experiences (CAPE). Cannabis exposure was quantified as the amount of Euros spent on cannabis per week and the age of initial cannabis use. The primary outcome measure was the odds ratio (OR) to belong to the highest 10% of scores on the total CAPE and the positive-, negative- and depressive symptom dimensions. RESULTS: In 17 698 adolescents (mean age 21.6, s.d.=4.2 years), cannabis use at age 12 years or younger was strongly associated with a top 10% score on psychotic experiences [OR 3.1, 95% confidence interval (CI) 2.1-4.3] and to a lesser degree with negative symptoms (OR 1.7, 95% CI 1.1-2.5). The OR of heavy users (>?25/week) for negative symptoms was 3.4 (95% CI 2.9-4.1), for psychotic experiences 3.0 (95% CI 2.4-3.6), and for depressive symptoms 2.8 (95% CI 2.3 3.3). CONCLUSIONS: Early start of cannabis use is strongly associated with subclinical psychotic symptoms and to a lesser degree with negative symptoms, while smoking high amounts of cannabis is associated with increased levels of all three symptom dimensions: psychotic, negative and depressive. These results support the hypothesis that the impact of cannabis use is age specific. PMID- 20925970 TI - Repetitive transcranial magnetic stimulation reduces cortisol concentrations in bulimic disorders. AB - BACKGROUND: In people with bulimic eating disorders, exposure to high-calorie foods can result in increases in food craving, raised subjective stress and salivary cortisol concentrations. This cue-induced food craving can be reduced by repetitive transcranial magnetic stimulation (rTMS). We investigated whether rTMS has a similar effect on salivary cortisol concentrations, a measure of hypothalamic-pituitary-adrenal axis (HPAA) activity. METHOD: We enrolled twenty two female participants who took part in a double-blind randomized sham controlled trial on the effects of rTMS on food craving. Per group, eleven participants were randomized to the real or sham rTMS condition. The intervention consisted of one session of high-frequency rTMS delivered to the left dorsolateral prefrontal cortex (DLPFC). Salivary cortisol concentrations were assessed at four time points throughout the 90-min trial. To investigate differences in post-rTMS concentrations between the real and sham rTMS groups, a random-effects model including the pre-rTMS cortisol concentrations as covariates was used. RESULTS: Salivary cortisol concentrations following real rTMS were significantly lower compared with those following sham rTMS. In this sample, there was also a trend for real rTMS to reduce food craving more than sham rTMS. CONCLUSIONS: These results suggest that rTMS applied to the left DLPFC alters HPAA activity in people with a bulimic disorder. PMID- 20925971 TI - The heterogeneity of antipsychotic response in the treatment of schizophrenia. AB - BACKGROUND: Schizophrenia is a heterogeneous disorder in terms of patient response to antipsychotic treatment. Understanding the heterogeneity of treatment response may help to guide treatment decisions. This study was undertaken to capture inherent patterns of response to antipsychotic treatment in patients with schizophrenia, characterize the subgroups of patients with similar courses of response, and examine illness characteristics at baseline as possible predictors of response. METHOD: Growth mixture modeling (GMM) was applied to data from a randomized, double-blind, 12-week study of 628 patients with schizophrenia or schizo-affective disorder treated with risperidone or olanzapine. RESULTS: Four distinct response trajectories based on Positive and Negative Syndrome Scale (PANSS) total score over 12 weeks were identified: Class 1 (420 patients, 80.6%) with moderate average baseline PANSS total score showing gradual symptom improvement; Class 2 (65 patients, 12.5%) showing rapid symptom improvement; Class 3 (24 patients, 4.6%) with high average baseline PANSS total score showing gradual symptom improvement; and Class 4 (12 patients, 2.3%) showing unsustained symptom improvement. Latent class membership of early responders (ER) and early non-responders (ENR) was determined based on 20% symptom improvement criteria at 2 weeks and ultimate responders (UR) and ultimate non-responders (UNR) based on 40% symptom improvement criteria at 12 weeks. Baseline factors with potential influence on latent class membership were identified. CONCLUSIONS: This study identified four distinct treatment response patterns with predominant representation of responders or non-responders to treatment in these classes. This heterogeneity may represent discrete endophenotypes of response to treatment with different etiologic underpinnings. PMID- 20925972 TI - A randomized trial of unilateral and bilateral prefrontal cortex transcranial magnetic stimulation in treatment-resistant major depression. AB - BACKGROUND: Although several studies have reported that repetitive transcranial magnetic stimulation (rTMS) treatment has demonstrable efficacy in patients with depression, the parameters needed to optimize therapeutic efficacy remain unclear. To this end we determined the efficacy of low-frequency right rTMS to the dorsolateral prefrontal cortex (DLPFC) compared to two forms of bilateral rTMS to the DLPFC: (1) sequential low-frequency right-sided followed by high frequency left-sided rTMS and (2) sequential low-frequency rTMS to both hemispheres. METHOD: A total of 219 patients with treatment-resistant depression (TRD) were randomized to a 4-week course of rTMS applied with one of the three treatment conditions. Outcomes were assessed with standard rating scales. RESULTS: Overall, slightly more than 50% of the patients achieved clinical response criteria. There was no substantial difference in response between the unilateral and bilateral treatment groups. Successful response to rTMS was predicted by a greater degree of baseline depression severity. CONCLUSIONS: There is no substantial difference in efficacy between unilateral right-sided rTMS and the two forms of bilateral rTMS assessed in the study. Furthermore, our results call into question the specificity between frequency and laterality and rTMS response. PMID- 20925975 TI - Dynamics within site selectively templated and tagged xerogel sensor platforms. AB - In a nitrobenzo-2-oxa-1,3-diazole (NBD) -based, 9-anthrol-responsive site selectively templated and tagged xerogel (SSTTX) sensor platform, there are two reporter molecule site types (responsive and non-responsive) that are responsible for the observed fluorescence signals. These NBD sites function independently. Site 1 alone binds the target analyte and yields an analyte-dependent signal. This signal arises from analyte binding decreasing the photo-induced electron transfer (PET) efficiency between a strategically placed amine residue and the excited NBD reporter molecule within the template site. Site 2 does not respond to analyte, it is not fully formed, and it manifests itself as a background signal. In an n-octyl residue-free SSTTX, the local microviscosity sensed by the site 1 NBD reporter molecules in the absence and presence of target analyte is ~260 cP and ~540 cP, respectively. These local microviscosity values are substantially greater in comparison to free NBD dissolved in THF (eta = 0.46 cP at 298 K, phi ~25 ps). As the SSTTX n-octyl content is increased, the local microviscosity sensed by the site 1 NBD reporter molecules in the absence and presence of target analyte is ~360 cP and ~760 cP, respectively. This behavior is consistent with the n-octyl chains crowding the cybotactic region surrounding the site 1 NBD reporter molecules. This n-octyl-induced site 1 "crowding" is also associated with improved analyte binding to site 1 and better overall SSTTX analytical performance. PMID- 20925976 TI - Drop coating deposition Raman spectroscopy of fluorescein isothiocyanate labeled protein. AB - Using bovine serum albumin (BSA) as the model protein, normal Raman spectra of fluorescein isothiocyanate (FITC) conjugated protein were systematically studied for the first time using both solution and the drop coating deposition Raman (DCDR) sampling techniques. The FITC-BSA Raman spectra are dominated by the FITC Raman features that are strongly pH dependent. Current DCDR detection sensitivity obtained with a 10:1 FITC-BSA conjugate is 45 fmol in terms of total protein consumption and ~15 attomol at laser probed volume. Unlike the FITC-BSA solution Raman spectra, where the FITC Raman features are photostable, concurrent FITC fluorescence and Raman photobleaching is observed in the DCDR spectra of FITC BSA. While the FITC Raman photobleaching follows a single exponential decay function with a time constant independent of the FITC labeling ratio, the fluorescence background photobleaching is much more complicated and it depends strongly on the FITC labeling ratio and sample conditions. Mechanistically, the FITC Raman photobleaching is believed to be due to photochemical reaction of the FITC molecules in the electronically excited state. The FITC fluorescence photobleaching involves both concentration quenching and photochemical quenching, and the latter may involve a photochemical intermediate that is fluorescence inactive but Raman active. PMID- 20925977 TI - First steps of in situ surface-enhanced Raman scattering during shipboard experiments. AB - It is shown that the surface-enhanced Raman scattering (SERS) technique can be applied to detect organic molecules during in situ experiments. To this purpose, we used trans-1,2-bis(4-pyridyl)ethylene (BPE) as a target molecule. Adsorbed on the SERS chemosensor surface and excited under laser, the vibration modes of the molecules can be identified. SERS chemosensors are based on quartz substrates functionalized by silanization and partially coated with gold nanoparticles. SERS measurements during shipboard experiments were made with a home-made in situ Raman spectrometer connected to a marinized micro-fluidic system. The device was designed to host chemosensors in order to ensure measurements with a flow cell. A theoretical limit of detection was estimated in the range of picomolar (pM) concentrations based on Freundlich isotherm calculations. PMID- 20925978 TI - Chemical reduction method for preparation of silver nanoparticles on a silver chloride substrate for application in surface-enhanced infrared optical sensors. AB - A new method for the preparation of silver nanoparticles (AgNPs) on silver chloride discs was developed to integrate the unique properties of plasmonic nanoparticles into infrared optical sensing technologies. AgNP layers exhibiting strong infrared surface enhancement were prepared by reacting silver chloride discs in a solution containing hydrazine, which acts as a reducing agent. The silver ions in the outer layer of the disc could be reduced under proper conditions and the reduced silver coagulated to form suitable AgNPs for surface enhanced infrared absorption (SEIRA) measurements. To examine the influences of the reaction solution composition and also to optimize preparation of SEIRA substrates, factors such as pH value, reaction time, and concentration of reducing agent were examined. Results indicated that both the concentrations of hydrazine and hydroxide strongly influenced the SEIRA signals. The strongest signals were observed when AgNPs on a AgCl substrate were prepared by using a reducing solution of 20 mM NaOH with 0.75 mM hydrazine. Using the optimized substrates, intense SEIRA spectra were observed with an enhancement factor around two orders of magnitude compared to measurements made using conventional sampling techniques. PMID- 20925979 TI - A study of glutathione molecules adsorbed on silver surfaces under different chemical environments by surface-enhanced Raman scattering in combination with the heat-induced sensing method. AB - In this study, surface-enhanced Raman scattering (SERS) in combination with a heat-induced sensing technique has been applied for investigating molecular orientations of glutathione molecules adsorbed on silver colloidal nanoparticles under different chemical environments, which has enabled us to further study how glutathione molecules are adsorbed on the silver surfaces. Factors that may affect the configurations of glutathione molecules adsorbed on the silver nanocolloids have been investigated. By observing the relative enhancement factors of SERS bands due to individual functional groups contributed from different terminals, the affinity between the different functional groups of glutathione and the silver surfaces under different conditions has been sorted and the orientations of glutathione molecules adsorbed on the silver surfaces have been investigated. PMID- 20925980 TI - Qualitative analysis using Raman spectroscopy and chemometrics: a comprehensive model system for narcotics analysis. AB - The rapid, on-site identification of illicit narcotics, such as cocaine, is hindered by the diverse nature of the samples, which can contain a large variety of materials in a wide concentration range. This sample variance has a very strong influence on the analytical methodologies that can be utilized and in general prevents the widespread use of quantitative analysis of illicit narcotics on a routine basis. Raman spectroscopy, coupled with chemometric methods, can be used for in situ qualitative and quantitative analysis of illicit narcotics; however, careful consideration must be given to dealing with the extensive variety of sample types. To assess the efficacy of combining Raman spectroscopy and chemometrics for the identification of a target analyte under real-world conditions, a large-scale model sample system (633 samples) using a target (acetaminophen) mixed with a wide variety of excipients was created. Materials that exhibit problematic factors such as fluorescence, variable Raman scattering intensities, and extensive peak overlap were included to challenge the efficacy of chemometric data preprocessing and classification methods. In contrast to spectral matching analyte identification approaches, we have taken a chemometric classification model-based approach to account for the wide variances in spectral data. The first derivative of the Raman spectra from the fingerprint region (750 1900 cm(-1)) yielded the best classifications. Using a robust segmented cross validation method, correct classification rates of better than ~90% could be attained with regression-based classification, compared to ~35% for SIMCA. This study demonstrates that even with very high degrees of sample variance, as evidenced by dramatic changes in Raman spectra, it is possible to obtain reasonably reliable identification using a combination of Raman spectroscopy and chemometrics. The model sample set can now be used to validate more advanced chemometric or machine learning algorithms being developed for the identification of analytes such as illicit narcotics. PMID- 20925981 TI - Characterization of automotive paint clear coats by ultraviolet absorption microspectrophotometry with subsequent chemometric analysis. AB - Clear coats have been a staple in automobile paints for almost thirty years and are of forensic interest when comparing transferred and native paints. However, the ultraviolet (UV) absorbers in these paint layers are not typically characterized using UV microspectrophotometry, nor are the results studied using multivariate statistical methods. In this study, measurements were carried out by UV microspectrophotometry on 71 samples from American and Australian automobiles, with subsequent chemometric analysis of the absorbance spectra. Sample preparation proved to be vital in obtaining accurate absorbance spectra and a method involving peeling the clear coat layer and not using a mounting medium was preferred. Agglomerative hierarchical clustering indicated three main groups of spectra, corresponding to spectra with one, two, and three maxima. Principal components analysis confirmed this clustering and the factor loadings indicated that a substantial proportion of the variance in the data set originated from specific spectral regions (230-265 nm, 275-285 nm, and 300-370 nm). The three classes were well differentiated using discriminant analysis, where the cross validation accuracy was 91.6% and the external validation accuracy was 81.1%. However, results showed no correlation between the make, model, and year of the automobiles. PMID- 20925982 TI - Interactions of vitamin K3 with herring-sperm DNA using spectroscopy and electrochemistry. AB - By means of ultraviolet-visible (UV-Vis) and fluorescence spectra, the binding ratio between vitamin K(3) and herring-sperm DNA in a physiological pH environment (pH = 7.40) was determined as n(K3):n(DNA) = 2:1, and the binding constants of vitamin K(3) binding to DNA at different temperatures were determined as K(theta)(298K) = 1.28 * 10(5) L.mol(-1) and K(theta)(310K) = 7.19 * 10(4) L.mol(-1), which were confirmed using the double reciprocal method are Delta(r)H(m)(theta) = -3.57 * 10(4) J.mol(-1), Delta(r)G(m)(theta) = -2.92 * 10(4) J.mol(-1), and Delta(r)S(m)(theta) = 217.67 J.mol(-1)K(-1). The driving power of this process was enthalpy. An intercalation binding of the vitamin K(3) with DNA was supported by a competitive experiment using acridine orange (AO) as a spectral probe. By combination analysis of the Scatchard method and cyclic voltammetry, we suggested that the interaction mode between vitamin K(3) and herring-sperm DNA would be a mixed mode. The quinonoid, duality fused-ring of vitamin K(3) can intercalate into the base pairs of DNA, and there is an electrostatic binding along with intercalation binding. PMID- 20925983 TI - Association of indigo with zeolites for improved color stabilization. AB - The durability of an organic color and its resistance against external chemical agents and exposure to light can be significantly enhanced by hybridizing the natural dye with a mineral. In search for stable natural pigments, the present work focuses on the association of indigo blue with several zeolitic matrices (LTA zeolite, mordenite, MFI zeolite). The manufacturing of the hybrid pigment is tested under varying oxidizing conditions, using Raman and ultraviolet-visible (UV-Vis) spectrometric techniques. Blending indigo with MFI is shown to yield the most stable composite in all of our artificial indigo pigments. In the absence of defects and substituted cations such as aluminum in the framework of the MFI zeolite matrix, we show that matching the pore size with the dimensions of the guest indigo molecule is the key factor. The evidence for the high color stability of indigo@MFI opens a new path for modeling the stability of indigo in various alumino-silicate substrates such as in the historical Maya Blue pigment. PMID- 20925984 TI - Self-consistent algorithm for calibrating spectrometers to picometer accuracy over the entire wavelength range. AB - Spectrometer calibration accuracies are of high importance for a wide range of applications. Typically, one calibrates the spectrometer with a calibration lamp, providing distinct and well-defined calibration lines. However, for small spectral ranges, where only two calibration lines are present, the calibration becomes inaccurate. We present a high-precision nonlinear wavelength calibration method, which is based on two or more reference lines from a calibration lamp. The additional key element introduced is a Fabry-Perot multilayer structure that yields multiple sharp transmission maxima of similar intensity over the full spectrometer range under broad-band illumination (e.g., white-light source). An iterative algorithm is put forward to obtain a self-consistent calibration of picometer precision over the full spectrometer range. In regions distant from calibration lines the accuracy is enhanced by at least a factor of two compared to conventional methods. PMID- 20925985 TI - Numerical correction of detector channel cross-talk using full-spectrum fluorescence correlation spectroscopy. AB - Fluorescence correlation spectroscopy (FCS) uses fluctuations in the fluorescence collected from a small illuminated volume to measure dynamic processes of fluorophores. In traditional FCS, spectral overlap produces cross-talk in dedicated detector channels, undermining the accuracy of measurements of molecular interactions. Here, the experimental realization of full-spectrum fluorescence correlation spectroscopy is described and coupled with multivariate data analysis to numerically correct detector cross-talk, isolating spectra and fluctuation traces of mixture components in spite of overlap. Application of this methodology is illustrated using the measurement of the diffusion constant of labeled polystyrene in hydroxypropyl cellulose in the presence of a persistent dye. Additionally, the results show that full-spectrum FCS with multivariate analysis can isolate and characterize signals from unanticipated sample components. PMID- 20925986 TI - Sensitive chemiluminescence determination of thirteen cephalosporin antibiotics with luminol-copper(II) reaction. AB - A new chemiluminescence reaction, the luminol-Cu(2+) reaction, was investigated for the determination of thirteen (13) cephalosporin antibiotics, namely cefalexin, cefadroxil, cefradine, cefazolin sodium, cefaclor, cefuroxime axetil, cefotaxime sodium, cefoperazone sodium, ceftriaxone sodium, ceftazidime, cefetamet pivoxil hydrochloride, cefixime, and cefpodoxime. It was found that, without adding any special oxidant, strong chemiluminescent (CL) signal could be produced from the reaction of the alkaline luminol with the above-mentioned antibiotics in the presence of Cu(2+). The experimental conditions for the reaction were carefully optimized with flow-injection mode. The detection limits are 0.3 ng/mL cefalexin, 3 ng/mL cefadroxil, 0.3 ng/mL cefradine, 0.02 MUg/mL cefazolin sodium, 0.8 ng/mL cefaclor, 0.02 MUg/mL cefuroxime axetil, 5 ng/mL cefotaxime sodium, 0.02 MUg/mL cefoperazone sodium, 0.8 ng/mL ceftriaxone sodium, 1 ng/mL ceftazidime, 0.08 ng/mL cefetamet pivoxil hydrochloride, 0.8 ng/mL cefixime, and 2 ng/mL cefpodoxime. The proposed method was validated by direct application to commercial formulations and spiked milk samples containing cefradine. A possible reaction mechanism is also discussed. PMID- 20925987 TI - Nondestructive assessment of engineered cartilage constructs using near-infrared spectroscopy. AB - Noninvasive assessment of engineered cartilage properties would enable better control of the developing tissue towards the desired structural and compositional endpoints through optimization of the biochemical environment in real time. The objective of this study is to assess the matrix constituents of cartilage using near-infrared spectroscopy (NIRS), a technique that permits full-depth assessment of developing engineered tissue constructs. Mid-infrared (mid-IR) and NIR data were acquired from full-thickness cartilage constructs that were grown up to 4 weeks with and without mechanical stimulation. Correlations were assessed between established mid-IR peak areas that reflect the relative amount of collagen (amide I, amide II, and 1338 cm(-1)) and proteoglycan (PG), (850 cm(-1)), and the integrated area of the NIR water absorbance at 5190 cm(-1). This analysis was performed to evaluate whether simple assessment of the NIR water absorbance could yield information about matrix development. It was found that an increase in the mid-IR PG absorbance at 850 cm(-1) correlated with the area of the NIR water peak (Spearman's rho = 0.95, p < 0.0001). In the second analysis, a partial least squares method (PLS1) was used to assess whether an extended NIR spectral range (5400-3800 cm(-1)) could be utilized to predict collagen and proteoglycan content of the constructs based on mid-IR absorbances. A subset of spectra was randomly selected as an independent prediction set in this analysis. Average of the normalized root mean square errors of prediction of first-derivative NIR spectral models were 7% for 850 cm(-1) (PG), 11% for 1338 cm(-1) (collagen), 8% for amide II (collagen), and 8% for amide I (collagen). These results demonstrate the ability of NIRS to monitor macromolecular content of cartilage constructs and is the first step towards employing NIR to assess engineered cartilage in situ. PMID- 20925988 TI - Determination of organic and inorganic carbon in forest soil samples by mid infrared spectroscopy and partial least squares regression. AB - Analyses of organic and inorganic carbon are of great interest in the field of soil analyses. Soil samples from a national monitoring project were provided for this study, including more than 130 forest sites from Austria. We investigated the humus layers (if present undecomposed litter (L), of mixed samples of F- (intermediate decomposed organic matter) and H-(highly decomposed organic matter) (FH)) and upper mineral soil layers (0-5 and 5-10 cm) of the samples. Mid infrared spectra were recorded and evaluated by their band areas; subsequently we calculated models with the partial least squares approach. This was done by correlating calculated data of the mid-infrared spectra with gas-volumetrically determined carbonate values and measurements of organic carbon from an elemental analyzer. For carbonate determination, this approach gave satisfying results. For measurements of organic carbon, it was necessary to discriminate into humus layers and mineral soils or even more groups to obtain satisfactory correlations between spectroscopically determined and conventionally measured values. These additional factors were the presence of carbonate, the forest type, and the dominant tree species. In mineral soils, fewer subdivisions were necessary to obtain useful results. In humus layers, groupings of sites with more similar characteristics had to be formed in order to obtain satisfying results. The conclusion is that the chemical background of soil organic matter leading to different proportions of functional groups, especially in the less humified organic matter of the humus layers, plays a key role in analyses with mid infrared spectroscopy. Keeping this in mind, the present approach has a significant potential for the prediction of properties of forest soil layers, such as, e.g., carbonate and organic carbon contents. PMID- 20925989 TI - Hydrogel network formation revised: high-resolution magic angle spinning nuclear magnetic resonance as a powerful tool for measuring absolute hydrogel cross-link efficiencies. AB - In the present work, high-resolution magic angle spinning (hr-MAS) NMR spectroscopy is applied as a straightforward nondestructive technique to quantify unreacted methacrylamide functionalities in cross-linked gelatin hydrogels. By adjusting several cross-linking parameters including the ultraviolet (UV) irradiation time and the photo-initiator concentration, the cross-linking degree can be easily varied. Remarkably, under all experimental conditions typically applied for hydrogel development, no more than 40% of the methacrylamide moieties present have reacted. The hr-MAS based approach to determine the cross-linking efficiency is shown to provide an innovative and more convenient alternative to the well-established classical techniques. In addition, the results obtained are in good correlation with mechanical analysis data. PMID- 20925990 TI - Characterization of a variable angle reflection Fourier transform infrared accessory modified for surface plasmon resonance spectroscopy. AB - The Harrick AutoSeagull variable angle reflection accessory for Fourier transform infrared (FT-IR) spectrometers provides access to various spectroscopic techniques in a highly flexible platform. In particular, its ability to perform total internal reflection measurements is of interest because it also forms the basis for surface plasmon resonance (SPR) spectroscopy in prism-based configurations. The work presented here discusses the modification of the AutoSeagull to perform SPR spectroscopy, allowing for easy incorporation of the technique into most common FT-IR spectrometers. The wavelength dependency of the dielectric constant of the plasmon-supporting metal (in our case, gold) is largely responsible for the sensitivity attributed to changes in the sample's refractive index (RI) monitored by SPR spectroscopy. Furthermore, the optical properties of gold are such that when near-infrared (NIR) and/or mid-infrared (mid-IR) wavelengths are used to excite surface plasmons, higher sensitivities to RI changes are experienced compared to surface plasmons excited with visible wavelengths. The result is that in addition to instrumental simplicity, SPR analysis on FT-IR spectrometers, as permitted by the modified AutoSeagull, also benefits from the wavelength ranges accessible. Adaptation of the AutoSeagull to SPR spectroscopy involved the incorporation of slit apertures to minimize the angular spread reaching the detector, resulting in sharper SPR "dips" but at the cost of noisier spectra. In addition, discussion of the system's analytical performance includes comparison of dip quality as a function of slit size, tailoring of the dip minima location with respect to incident angle, and sensitivity to bulk RI changes. PMID- 20925991 TI - A new method to obtain Fourier transform infrared spectra free from water vapor disturbance. AB - Infrared absorption bands due to water vapor in the mid-infrared regions often obscure important spectral features of the sample. Here, we provide a novel method to collect a qualified infrared spectrum without any water vapor interference. The scanning procedure for a single-beam spectrum of the sample is divided into two stages under an atmosphere with fluctuating humidity. In the first stage, the sample spectrum is measured with approximately the same number of scans as the background. If the absorbance of water vapor in the spectrum is positive (or negative) at the end of the first stage, then the relative humidity in the sample compartment of the spectrometer is changed by a dry (or wet) air blow at the start of the second stage while the measurement of the sample spectrum continues. After the relative humidity changes to a lower (or higher) level than that of the previously collected background spectrum, water vapor peaks will become smaller and smaller with the increase in scanning number during the second stage. When the interfering water lines disappear from the spectrum, the acquisition of a sample spectrum is terminated. In this way, water vapor interference can finally be removed completely. PMID- 20925992 TI - Modern management of mild-to-moderate joint pain due to osteoarthritis: a holistic approach. AB - Osteoarthritis (OA) is the most common form of arthritis and it is often associated with significant disability and impaired quality of life. Once thought to be caused by an age-related 'wearing out' of articular cartilage, it is now recognized to be a dynamic process in which cartilage degradation alternates with repair. Several expert guidelines for the management of OA exist, which concur in their recommendations for a stepwise approach to the employment of pharmacological agents and the introduction of suggestions to extend the use of agents such as topical non-steroidal anti-inflammatory drugs, especially for mild to-moderate forms of the disease. They also emphasize the importance of non pharmacological measures, such as nutraceuticals, education, diet, exercise and the use of aids in improving signs and symptoms and slowing progression. In many countries, effective medicinal and nutraceutical agents are available 'over-the counter'. This review explains the modern approach to the management of mild-to moderate osteoarthritic pain. PMID- 20925993 TI - Patient perceptions concerning pain management in the treatment of rheumatoid arthritis. AB - Previous qualitative studies have revealed discrepancies between patients' and physicians' perceptions of rheumatoid arthritis (RA) and its treatment. Questionnaires were administered to 2795 patients with RA (756 from Europe; 2039 from the USA) to measure patients' perceptions regarding pain management in RA. Although the majority of patients reported their RA as somewhat-to-completely controlled, 75% of European and 82% of US patients reported their pain as moderate-to-severe in the previous 2 months. The majority of European (60%) and US (65%) patients reported dissatisfaction with their arthritis pain. Patients' pain levels corresponded with their disease severity. A higher percentage of patients who reported severe pain were being treated for depression than those who had moderate or mild pain. Patients in the USA rated pain relief as the top required benefit from their RA medication. A comprehensive examination of patients' perspectives regarding pain could lead to better patient care and pain management strategies. PMID- 20925994 TI - Remifentanil reduces the incidence of post-operative delirium. AB - A secondary exploratory analysis of data from an observational study was used to study the influence of the opioid used for intraoperative anaesthesia on the incidence of post-operative delirium. Patients who had been admitted to the recovery room following elective general anaesthesia were divided into those who had received fentanyl or remifentanil. For unbiased patient analysis, matched pairs were built with respect to gender, age, physical status, anaesthetic type and surgery duration. In 752 patients, the overall incidence of delirium was 9.9% in the recovery room and 3.8% on the first post-operative day. Compared with the remifentanil group, the fentanyl group had a significantly higher incidence of delirium in the recovery room (12.2% versus 7.7%) and on the first post-operative day (5.8% versus 1.9%). Delirium in the recovery room and on the first post operative day were both associated with a significantly prolonged post-operative hospital stay. The choice of intraoperative opioid influences the incidence of post-operative delirium. Remifentanil was associated with a lower incidence of post-operative delirium in the early post-operative period. PMID- 20925996 TI - The influence of prenatal counselling on postpartum contraceptive choice. AB - This study tested the hypothesis that individual counselling in the third trimester would increase postpartum contraceptive use to a greater extent than only providing an educational leaflet. A total of 180 third trimester pregnant women of mean age 28.3 years who were attending Marmara University Hospital for prenatal care were enrolled. One-third were randomly allocated to receive prenatal contraceptive counselling and the remaining two-thirds (control group) received an educational leaflet. Participants were followed-up at 6 - 9 months postpartum. The majority of subjects (91.5%) wanted to use contraception after delivery but 26.7% did not know which method to use. At follow-up, 79.6% of all women had begun a postpartum contraceptive regime and 68.7% were using a modern contraceptive method. Overall, there was no statistically significant difference in postpartum contraception use between the control and intervention groups in this study population. It is, therefore, concluded that prenatal counselling was not superior to educational leaflets for increasing the use of effective and modern postpartum contraception. PMID- 20925995 TI - Short-term effectiveness of ultrasound therapy in knee osteoarthritis. AB - This randomized, placebo-controlled, double-blind study was designed to investigate the short-term efficacy of ultrasound therapy in 90 patients with knee osteoarthritis (OA). Patients were randomly assigned to three groups: group 1 received continuous ultrasound, group 2 received pulsed ultrasound, and group 3 received a 'sham' (placebo) ultrasound for 5 min each session. All treatments were applied once a day for 5 days a week for 2 weeks, i.e. a total treatment duration of 10 days. Compared with baseline, significant improvements were observed in the visual analogue scale pain scores and the Western Ontario and McMaster Universities osteoarthritis index (WOMAC) scores in all three groups. The reductions in pain and WOMAC scores were significantly higher in patients treated with pulsed ultrasound than in the placebo group. In conclusion, pulsed ultrasound therapy is a safe and effective treatment modality in patients with knee OA. Further research is required to investigate the long-term efficacy of pulsed ultrasound therapy in knee OA. PMID- 20925997 TI - Clinical outcomes of ovulation induction with metformin, clomiphene citrate and human menopausal gonadotrophin in polycystic ovary syndrome. AB - This pilot study evaluated the effects of coadministration of metformin with clomiphene citrate (CC) and human menopausal gonadotrophin (HMG) in women with CC resistant polycystic ovary syndrome (PCOS). Sixty women with PCOS were randomly assigned to receive 3 months' treatment with metformin or placebo together with CC and HMG. Transvaginal ultrasound was used to monitor follicular development and ovulation was induced by human chorionic gonadotrophin (HCG). The number of dominant follicles, the oestradiol level on the day HCG was given and the amount of HMG required were significantly lower in the metformin group than in the placebo group, whereas the mono-ovulatory rate and pregnancy rate in the third cycle were significantly higher. The cumulative pregnancy rate in the metformin group (43.3%) was higher than in the placebo group (20.0%), but this difference did not reach statistical significance. In conclusion, coadministration of metformin with CC and HMG reduced the amount of HMG required and increased the mono-ovulatory rate and pregnancy rate. PMID- 20925998 TI - Usefulness of C-arm angiographic computed tomography for detecting iodized oil retention during transcatheter arterial chemoembolization of hepatocellular carcinoma. AB - Transcatheter arterial chemoembolization (TACE) with iodized oil and anticancer agents is widely used for hepatocellular carcinoma (HCC) treatment. To assess C arm angiographic computed tomography (CCT) for detecting iodized oil retention during TACE, CCT images were obtained of 40 tumours (24 HCC patients). The primary CCT images showed complete iodized oil retention patterns (type I) in 29/40 (73%) tumours, at which point embolization was terminated; incomplete iodized oil retention requiring further iodized oil embolization occurred in 11/40 (28%) tumours and, of these, complete iodized oil retention patterns were achieved in eight tumours. Conventional CT scanning employed 1 week later showed the same iodized oil retention patterns as demonstrated in the latest CCT images (37/40 [93%] tumours). In 24 additional HCC patients who underwent TACE but not CCT (control group), conventional CT scans obtained 1 week after TACE showed complete iodized oil retention in 32/42 (76%) tumours. The rate of complete iodized oil retention pattern was significantly higher in patients undergoing CCT. It is concluded that the distribution of iodized oil within HCC lesions can be demonstrated on CCT images during TACE, helping to achieve complete iodized oil filling of tumours and, thereby, improving therapeutic effects. PMID- 20925999 TI - A comparison of the proximal femoral nail antirotation device and dynamic hip screw in the treatment of unstable pertrochanteric fracture. AB - This prospective randomized study compared the outcome of elderly patients with an unstable pertrochanteric fracture, treated with a proximal femoral nail antirotation device (PFNA; n = 51) or a dynamic hip screw (DHS; n = 55). All patients in the DHS group and nine in the PFNA group had open reductions. Incisions were significantly shorter for the PFNA than the DHS group. Blood loss and the number of patients requiring post-operative blood transfusions were significantly greater, but operation and fluoroscopy times were significantly shorter, for the DHS versus the PFNA group. Time to mobilization with a frame was significantly shorter in the PFNA group, and post-operative complications were more common in the DHS group. Poor fracture reduction led to three revisions. All fractures in both groups united during follow-up. The PFNA allowed earlier mobilization and faster recovery than the DHS. The PFNA is a highly acceptable, minimally invasive implant for unstable fractures. PMID- 20926000 TI - Clinicopathological implications of tumour-associated macrophages and vascularization in sinonasal melanoma. AB - This study investigated tumour-associated macrophages (TAMs) and their effects on tumour vascularization in sinonasal melanoma (SNM). Data on 45 patients with SNM undergoing surgery were reviewed retrospectively. Tumour sections were analysed immunohistochemically for TAMs, microvessels, lymph vessels, and vasculogenic mimicry in both intra- and peritumoural areas. The density of intratumoural TAMs was associated with tumour thickness and with overall survival in SNM stages I and II but there were no correlations between micro- or lymph vessel density and TAM infiltration. Greater TAM infiltration was observed in tumour tissues with vasculogenic mimicry although this was not statistically significant. These data suggest that high intratumoural TAM infiltration is associated with tumour aggressiveness and a poor prognosis for SNM, and that activation of macrophages can be polarized by different micro-environments. TAMs could be potential prognostic indicators for patients with SNM. PMID- 20926001 TI - Effectiveness of a systemic antibiotic followed by topical ionized solution as surgical site infection prophylaxis. AB - The aim of this randomized, double-blind clinical trial was to determine the effectiveness of systemic antibiotic application followed by either topical ionized solution (IS) or topical saline solution (placebo) as surgical site infection (SSI) prophylaxis in appendectomy for non-perforated appendicitis. Prophylactic antibiotic was administered pre-incision and either topical IS or placebo was applied pre-suturing to 529 patients, who were then monitored for 30 days. When topical IS was used, SSI relative risk was 0.739 (95% CI 0.537, 1.019) and the SSI prevention rate was 26.06% (CI -1.8%, 46.3%). The number needed to treat was 14.80 patients and the number needed to harm was 209 in order for SSI to be avoided. In conclusion, there was a trend for topical IS prophylaxis to reduce SSI frequency in patients undergoing appendectomy for non-perforated appendicitis, but the result was not statistically significant. PMID- 20926002 TI - Celecoxib inhibits beta-catenin-dependent survival of the human osteosarcoma MG 63 cell line. AB - Cyclo-oxygenase (COX)-2 inhibitors may exert antitumour effects through COX-2 independent mechanisms. This study investigated the effects of the COX-2 inhibitor celecoxib on the viability of the human osteosarcoma MG-63 cell line and its beta-catenin signalling pathway. Cell viability and apoptosis were examined in celecoxib-treated cells or after beta-catenin knockdown in vitro. Analyses were performed to detect glycogen synthase kinase (GSK)-3beta, phosphorylated GSK-3beta, beta-catenin, c-Myc and cyclin D1 proteins, and mRNA levels of beta-catenin, c-Myc and CCND1 (encoding cyclin D1). beta-Catenin was shown to be required for MG63 cell survival and celecoxib exerted an inhibitory effect on the viability of cultured MG-63 cells in a time- and dose-dependent manner. beta-Catenin protein decreased in the cytosol and nucleus following celecoxib treatment (from 6 h after initiation of treatment onwards; lowest protein levels were reached at > 72 h). Significant reductions in beta-catenin, c Myc and CCND1 mRNA were observed. Celecoxib inhibited MG-63 cell viability, possibly by activating GSK-3beta and inhibiting beta-catenin-dependent gene transcription, suggesting a role for celecoxib in osteosarcoma treatment. PMID- 20926003 TI - Granulocyte colony-stimulating factor attenuates chronic neuroinflammation in the brain of amyloid precursor protein transgenic mice: an Alzheimer's disease mouse model. AB - Recent evidence suggests that inflammatory mechanisms contribute significantly to the progression of Alzheimer's disease. Granulocyte colony-stimulating factor (G CSF) is an anti-inflammatory immunomodulator, but the mechanism of its anti inflammatory effect is unclear. This study was designed to investigate whether G CSF could inhibit inflammation in a mouse model of Alzheimer's disease through an alpha7 nicotinic acetylcholine receptor (alpha7 nAChR) pathway. Mice transgenic for the V171I mutant amyloid precursor protein (APP) were injected subcutaneously with G-CSF 50 MUg/kg per day or phosphate-buffered saline (PBS; control group) for 7 days, and wild-type C57/BL6 mice were injected with PBS daily for 7 days. Mice were killed on days 7, 14 and 28 after treatment began. Levels of alpha7 nAChR protein were significantly increased and levels of interleukin-1beta, tumour necrosis factor-alpha and nuclear factor-kappaB (NF-kappaB) protein were significantly decreased in the brain of APP transgenic mice in response to G-CSF. Levels of alpha7 nAChR protein correlated negatively with NF-kappaB levels. It is concluded that G-CSF might attenuate inflammation by down-regulating NF-kappaB and up-regulating alpha7 nAChR in the brain of APP transgenic mice, indicating a potential new therapeutic approach to Alzheimer's disease. PMID- 20926004 TI - The value of dihydrouracil/uracil plasma ratios in predicting 5-fluorouracil related toxicity in colorectal cancer patients. AB - This study investigated the relationship between the dihydrouracil/uracil (UH(2)/U) plasma ratio, a surrogate marker of dihydropyrimidine dehydrogenase (DPD) activity, and 5-fluorouracil (5-FU)-related early toxicity. Plasma UH(2)/U ratios were determined in 68 colorectal cancer patients and 100 healthy controls. A cut-off value indicative of DPD deficiency was calculated using receiver operator characteristics. Patients experiencing toxicity were screened for the DPD G-to-A point mutation within the 5'-splicing donor site of intron 14 (IVS14+1G>A). Overall, 24/68 patients (35%) experienced toxicity (all grades) and abnormal UH(2)/U ratios were demonstrated in 21/24 (87.5%) patients. Drug concentrations up to 130 times the recommended level were found in 13/24 (54%) patients experiencing toxicity. One patient experiencing toxicity was a heterozygous carrier of the IVS14+1G>A mutation. A low UH(2)/U plasma ratio had a sensitivity of 0.87 and specificity of 0.93 for predicting 5-FU-induced toxicity. Systematic detection of DPD-deficient patients using the UH(2)/U ratio could optimize 5-FU-based chemotherapy and minimize life-threatening toxicity. PMID- 20926005 TI - Thymic expression of the main immunogenic region of titin in thymomatous myasthenia gravis. AB - Antititin antibody occurs in the serum of myasthenia gravis (MG) patients with thymoma (MGT), and is a diagnostic marker for the disease. The mechanism that triggers MGT development is, however, unclear. This study evaluated the role of the main immunogenic region (MIR) of titin in MGT pathogenesis. Titin MIR antiserum (antibody titre 1:16) was obtained and an in situ immunohistochemical study of thymomatous tissue samples was performed. Strong immunostaining for titin MIR was observed on epithelial cell membranes in MGT patients, and the degree of immunostaining was directly proportional to the number of epithelial cells in thymomatous tissue. Serum antititin antibody levels were closely related to titin MIR levels in thymoma cells; however, titin MIR levels did not appear to be related to MG severity. Antititin antibody may be a good surrogate marker for thymoma but is probably not involved in the pathogenesis of MGT. PMID- 20926006 TI - Effect of antegrade graft cardioplegia combined with passive graft perfusion in on-pump coronary artery bypass grafting. AB - Patients undergoing on-pump coronary artery bypass graft (CABG) with proximal graft anastomosis were randomly divided into groups that received antegrade cardioplegic infusion only via the aortic root (group A) or antegrade cardioplegic infusion via the aortic root and additional cardioplegia via vein or free arterial grafts after completion of each distal anastomosis (group B). The group B patients also received bypass graft perfusion with warm arterial blood just after removal of the cross-clamp until the proximal graft anastomosis was completed. The need for defibrillation and inotropic support during separation from cardiopulmonary bypass (CPB), and total CPB time were significantly lower in group B than in group A. Group B also had significantly lower peak cardiac troponin I levels 12 h after operation compared with group A and this was more pronounced in subgroups with severe right coronary artery stenosis and poor left ventricular ejection fraction than in the whole population. It is concluded that antegrade graft cardioplegia and graft perfusion with warm blood during proximal graft anastomosis may improve myocardial protection. PMID- 20926007 TI - Expression of activin A and follistatin in glioblastoma and their effects on U87 in vitro. AB - In some cancer cell lines, the gene encoding activin A (inhibin betaA [INHBA]) is over-expressed and enhances cancer proliferation. Protein levels of activin A and follistatin were assessed in glioblastoma and normal brain tissues in this study, and the effect of activin A and follistatin treatment on the proliferation of U87 human glioblastoma cells in vitro was also studied. High levels of activin A were observed in glioblastomas compared with normal brain tissue. In contrast, follistatin levels were similar between the two tissues. [(3)H]Thymidine assay showed that activin A (3 - 30 ng/ml) produced a dose-dependent increase in DNA synthesis of U87 cells compared with controls. Flow cytometric analyses showed that activin A increased the proliferative index of U87 cells compared with controls. Activin A also induced up-regulation of p-SMAD2/3 in a dose-dependent manner. Treatment of U87 cells with follistatin blocked these activin A-induced effects. The disequilibrium between activin A and follistatin may play a role in the development of glioblastoma. PMID- 20926008 TI - Distribution of lysosome-associated membrane proteins-1 and -2, and cathepsin D in eosinophilic granular bodies: possible relationship to cyst development in pilocytic astrocytomas. AB - Pilocytic astrocytomas are usually cystic; cyst formation within these tumours may result in increased intracranial pressure, due to the effect of their mass, and contribute to cerebral damage. Eosinophilic granular bodies (EGBs) are produced abundantly in pilocytic astrocytomas but their role in disease progression remains unknown. Immunohistochemistry studies showed EGBs to exhibit pronounced reactivity to antibodies against lysosome-associated membrane proteins (LAMP)-1 and LAMP-2, and the lysosomal enzyme cathepsin D. Both LAMP-1 and LAMP-2 showed peripheral rim and granular staining patterns. The EGBs were scattered widely across cysts and, where EGBs aggregated in clusters, were usually close to areas of fluid in the cysts. Most EGBs had nuclei either attached or close by, indicating that the EGBs may be derived from anucleated astrocytes. The results suggest that EGBs, together with other factors, may play a role in the development of cysts in pilocytic astrocytomas. PMID- 20926009 TI - Influence of thyroid hormones and transforming growth factor-beta1 on cystatin C concentrations. AB - Serum cystatin C concentrations are reported to increase in the hyperthyroid state. Serum concentrations of cystatin C and transforming growth factor-beta1 (TGF-beta1) were measured in patients with thyroid dysfunction, and the effects of 3,5,3'-tri-iodothyronine (T(3)) and TGF-beta1 on cystatin C production in human hepatoblastoma (Hep G2) cells were studied. Serum concentrations of cystatin C and TGF-beta1 were significantly higher in patients with Graves' disease compared with control subjects. Significantly positive correlations were observed between thyroid hormones and cystatin C, thyroid hormones and TGF-beta1, and TGF-beta1 and cystatin C in patients with thyroid dysfunction. Serum concentrations of cystatin C and TGF-beta1 decreased after treatment for hyperthyroidism. Cystatin C mRNA levels and cystatin C secretion were increased by T(3) and TGF-beta1 in cultured Hep G2 cells. These results suggest that serum cystatin C concentrations increase in patients with hyperthyroidism. The mechanisms for this may involve elevation of serum TGF-beta1 levels and the stimulatory effects of T(3) and TGF-beta1 on cystatin C production. PMID- 20926010 TI - Update on the incidence of metamizole sodium-induced blood dyscrasias in Poland. AB - Metamizole sodium (metamizole) is a popular non-opioid analgesic and a common non prescription product in Poland. Controversy exists regarding the level of risk of agranulocytosis or aplastic anaemia associated with its use. Two previous pharmacovigilance studies conducted in Poland found the risk was low. Twenty-four of the 25 haematology centres that provide specialist care for the 30 million adults in Poland participated in this prospective 12-month study. Twenty-one cases of agranulocytosis, 48 of aplastic anaemia, 15 of neutropenia and 11 of pancytopenia were reported. Of these cases, three (two agranulocytosis; one aplastic anaemia) were judged as being possibly related to metamizole. Crude estimates of the rate of agranulocytosis and aplastic anaemia associated with metamizole were 0.16 and 0.08 cases/million person-days of use, respectively. Ongoing national safety surveillance in Poland shows that, despite the possibility of drug-induced blood dyscrasias with metamizole, the risk is very low. PMID- 20926011 TI - Prognostic value of protease-activated receptor 2 expression in oesophageal squamous cell carcinoma. AB - Protease-activated receptor-2 (PAR-2) is essential for the initiation and development of tumours, suggesting that the detection of PAR-2 expression might serve as a clinical marker in the prediction or diagnosis of clinical outcomes of malignant neoplasia. Using immunohisto chemical methods, this study investigated whether the detection of PAR-2 protein had clinical implications for patients with oesophageal squamous cell carcinoma (OSCC). PAR-2 protein was present at a high level in primary OSCC sites but at a low level in normal oesophageal tissue. The level of PAR-2 protein in tumours was significantly correlated with the clinical stage and histological grade of disease. Patients with tumours highly positive for PAR-2 protein had a significantly worse prognosis than those with lower PAR-2 levels. Thus, the over-expression of PAR-2 is a characteristic feature of OSCC and suggests that the immuno histochemical detection of raised levels of PAR-2 may be a potentially useful prognostic indicator. PMID- 20926012 TI - Plasma cathepsin L and its related pro/antiangiogenic factors play useful roles in predicting rich coronary collaterals in patients with coronary heart disease. AB - Cathepsin L enhances angiogenesis by increasing extracellular matrix degradation and remodelling. This study investigated whether plasma cathepsin L could be used as a biomarker to predict collateral formation in patients with coronary heart disease (CHD). Patients with CHD (n = 218; aged 67 +/- 11 years) underwent coronary angiography and were categorized as having either 'poor' or 'rich' collaterals. Plasma cathepsin L, the proangiogenic placenta growth factor (PLGF) and the antiangiogenic factors, cystatin C and endostatin, were measured. Elevated cathepsin L and PLGF levels were independently and significantly associated with enhanced collateral formation in patients with CHD; subgroup analyses also showed a significant correlation in patients with diabetes and acute coronary syndrome. Plasma endostatin and cystatin C levels were not significantly correlated with coronary collateral formation. Plasma cathepsin L and PLGF, acting as important modulators of angiogenesis, could be used as biomarkers to predict coronary collateral formation in patients with CHD. PMID- 20926013 TI - Efficacy of a multimodal analgesia protocol in total knee arthroplasty: a randomized, controlled trial. AB - A total of 100 osteoarthritis patients undergoing unilateral total knee arthroplasty were randomly assigned to receive either a multimodal analgesia protocol, comprising oral celecoxib and tramadol before and after surgery and intra-articular injection of large doses of morphine, ropivacaine, adrenaline and betamethasone during surgery (trial group), or oral and intra-articular placebo (control group). All patients received patient-controlled analgesia for 48 h after surgery. Morphine consumption up to 48 h after surgery was significantly lower in the trial than in the control group. Compared with the control group, the trial group had significantly lower visual analogue scale (VAS) scores for pain at rest from 6 h to 7 days after surgery and significantly lower VAS scores during activity from 24 h to 7 days after surgery. Active straight leg raise and active 90 degrees knee flexion were achieved sooner and range of knee movement at postoperative days 1 - 15 were significantly greater in the trial group. Postoperative wound healing, infection, blood pressure, heart rate, rash, respiratory depression, urinary retention and deep vein thrombosis were similar in the two groups, but nausea and vomiting were significantly less frequent in the trial group. PMID- 20926015 TI - Establishment of a paclitaxel resistant human breast cancer cell strain (MCF 7/Taxol) and intracellular paclitaxel binding protein analysis. AB - Multidrug resistance of tumours is one of the most important factors that leads to chemotherapy failure. A multidrug-resistant breast cancer cell line, MCF 7/Taxol, was established from the drug-sensitive parent cell line MCF-7. The biological properties of MCF-7/Taxol, including its drug resistance profile and profile of paclitaxel binding proteins, were analysed and compared with the parent cell line. A number of paclitaxel binding proteins were present in MCF-7 cells but absent from MCF-7/Taxol cells, namely heat shock protein 90, actinin and dermcidin precursor. The identification of differential paclitaxel binding proteins between the multidrug-resistant MCF-7/Taxol cell line and the parent drug-sensitive cell line MCF-7 provides insight into possible mechanisms involved in resistance to these chemotherapy drugs. PMID- 20926014 TI - Combined inhibitory effects of celecoxib and fluvastatin on the growth of human hepatocellular carcinoma xenografts in nude mice. AB - This study was designed to investigate the in vivo growth inhibitory effects of celecoxib, a cyclo-oxygenase-2 inhibitor, and fluvastatin, a 3-hydroxy-3 methylglutaryl coenzyme A reductase inhibitor, on the hepatocellular carcinoma (HCC) cell line, BEL-7402. Athymic nude mice implanted with BEL-7402 cells were given celecoxib and fluvastatin, either alone or in combination, and the effect of treatment on tumour growth was evaluated after 6 weeks. The combination of celecoxib and fluvastatin enhanced inhibition of tumour growth, induction of apoptosis, inhibition of tumour cell proliferation, and inhibition of tumour angiogenesis compared with either treatment alone. The combination of celecoxib and fluvastatin also increased levels of the cyclin-dependent kinase inhibitor p21(Waf1/Cip1), decreased levels of p-Akt, myeloid cell leukaemia-1 (Mcl-1) and survivin protein, but had no effect on Akt protein levels in tumours. These results suggest that celecoxib combined with fluvastatin would be more efficacious for the treatment of HCC than either treatment alone and this combination of therapy warrants further research. PMID- 20926016 TI - Efficacy of tamsulosin 0.4 mg/day in relieving double-J stent-related symptoms: a randomized controlled study. AB - This study evaluated the efficacy of tamsulosin in improving stent-related symptoms and quality of life in patients with in-dwelling double-J ureteral stents. A total of 42 patients (15 males and 27 females) with ureteral stent placement following ureteroscopy, percutaneous nephrolithotomy or balloon dilatation, were prospectively randomized into two groups of 21 patients. Group I received 0.4 mg tamsulosin once daily for 4 weeks and group II was a non-placebo, non-treatment control. All patients completed the International Prostate Symptom Score (IPSS) and SF-36 questionnaires at 2 and 4 weeks post-operatively. The IPSS scores for irritative and obstructive symptoms were significantly lower in group I than group II at both 2 and 4 weeks. Among the eight domains of SF-36, role limitation due to physical health and bodily pain was significantly better in group I at 2 and 4 weeks. General health was also significantly better in group I at 2 weeks. Tamsulosin improved both urinary symptoms and quality of life without causing serious side-effects. PMID- 20926017 TI - Effect of local gentamicin application on healing and wound infection in patients with modified radical mastectomy: a prospective randomized study. AB - This study investigated the effects of Gentacoll implants on healing in patients (n = 44) undergoing modified radical mastectomy and axillary dissection. Group I, the Gentacoll group (n = 22), underwent surgery followed by insertion of 10 * 10 * 0.5 cm Gentacoll implants (280 mg collagen sponge plus 200 mg gentamicin sulphate) into the axillary area and under the flap area of the breast before wound closure. Group II, the control group (n = 22), underwent surgery without the application of Gentacoll. Neither group received oral or parenteral post operative antibiotic therapy. Outcome measures included wound infection, seroma formation, total drainage volumes, drain removal time and duration of hospital stay. Post-operative infection rate, seroma formation, drainage volumes and duration of hospital stay were significantly reduced in the Gentacoll group compared with the control group. In conclusion, the application of Gentacoll significantly improved post-operative outcomes in patients undergoing modified radical mastectomy. PMID- 20926018 TI - YKL-40 protein levels and clinical outcome of human endometrial cancer. AB - The secreted glycoprotein YKL-40 is a member of the chitinase family and elevated serum YKL-40 levels have been reported to be associated with reduced survival in several malignancies, including endometrial cancer. This study investigated immunoreactivity to YKL-40 protein and its prognostic implications in endometrial cancer. Levels of YKL-40 protein in normal endometrium (n = 42), endometrial hyperplasia (n = 40) and endometrial adeno carcinoma (n = 68) were examined using immunohistochemistry. YKL-40 immunoreactivity was significantly higher in endometrial adenocarcinoma compared with hyperplastic and normal endo metrium. In addition, high immuno reactivity of YKL-40 protein was associated with advanced stage, high histological grade, lymph node metastasis and lympho vascular invasion. Moreover, positive immunoreactivity for YKL-40 was a significant predictor of poor prognosis, as measured by estimated progression-free survival and estimated overall survival, compared with negative immunoreactivity. In conclusion, high YKL-40 immuno reactivity in endometrial cancer may be associated with poor prognosis. PMID- 20926019 TI - Impact of modified treatment in echocardiographically confirmed pseudo-pulseless electrical activity in out-of-hospital cardiac arrest patients with constant end tidal carbon dioxide pressure during compression pauses. AB - This study evaluated the ability of focused echocardiography (FE) and capnography to differentiate between pulseless electrical activity (PEA) and pseudo-PEA in out-of-hospital cardiac arrest, and the potential survival benefits with modified treatment. In PEA patients with stable end-tidal carbon dioxide pressure (P(et)CO(2)) during the compression pause and concomitant FE showing cardiac kinetic activity, the compression pause was prolonged for 15 s and an additional 20 IU vasopressin was administered. If pulselessness persisted, compressions were continued. Fifteen of the 16 patients studied (94%) achieved restoration of spontaneous circulation (ROSC); eight patients (50%) attained a good neurological outcome (Cerebral Performance Category 1 - 2). In an historical PEA group with stable P(et)CO(2) values (n = 48), ROSC was achieved in 26 patients (54%); four patients (8%) attained Cerebral Performance Category 1 - 2. Echocardiographical verification of the pseudo-PEA state enabled additional vasopressor treatment and cessation of chest compressions, and was associated with significantly higher rates of ROSC, survival to discharge and good neurological outcome. PMID- 20926020 TI - Reduction in left supplementary motor area grey matter in adult female fibromyalgia sufferers with marked fatigue and without affective disorder: a pilot controlled 3-T magnetic resonance imaging voxel-based morphometry study. AB - This study aimed to test the hypothesis that structural grey matter brain changes might occur in the chronic intractable pain disorder fibromyalgia when this is associated with marked fatigue in the absence of a DSM-IV-TR (Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision) diagnosis of affective disorder. High-resolution 3-T cerebral magnetic resonance imaging scans were acquired in 10 female, right-handed, non-smoking, white Caucasian subjects: five patients with fibromyalgia associated with marked fatigue and five age matched healthy women. Voxel-wise generalized linear modelling of the processed neuroanatomical data using permutation-based non-parametric testing, forming clusters at t > 2.3 and testing clusters for significance at P < 0.05, corrected for multiple comparisons across space, revealed significantly lower grey matter density in the patients with fibromyalgia and marked fatigue in the left supplementary motor area. This brain region plays an important role in cognitive or executive control and in the translation of painful cognition; these functions are impaired in fibromyalgia associated with marked fatigue. PMID- 20926021 TI - Relationship between the acid-inhibitory effects of two proton pump inhibitors and CYP2C19 genotype in Japanese subjects: a randomized two-way crossover study. AB - This two-way crossover study investigated possible differences between the proton pump inhibitors, omeprazole and rabeprazole, in their effect on gastric acid secretion in Japanese subjects with differing cytochrome P450, family 2, subfamily C, polypeptide 19 (CYP2C19) genotypes. A total of 23 Helicobacter pylori-negative healthy volunteers received omeprazole 20 mg/day and rabeprazole 10 mg/day. Each drug treatment was given for a continuous 7-day period allocated in random order, with an interval of at least 1 week between drug treatment periods to allow for wash-out. Intragastric pH was measured on days 1 and 7. Overall median intragastric pH levels at 7 and 8 h after the first administration were significantly higher with omeprazole. There was no significant difference in intragastric pH in homozygous extensive metabolizers, whereas intragastric pH was significantly higher with omeprazole in combined data from heterozygous extensive metabolizers and poor metabolizers at 6, 7 and 8 h after the first drug administration. There were no significant differences in intragastric pH between omeprazole and rabeprazole irrespective of genotype on day 7 of administration. In conclusion, on day 1 the time to onset of the antisecretory action of 20 mg/day omeprazole was more rapid than that of 10 mg/day rabeprazole in Japanese individuals who have a higher incidence of the CYP2C19 poor metabolizer genotype, however by day 7 no difference in antisecretory effect was found, regardless of genotype. PMID- 20926022 TI - Short-term corneal endothelial changes after laser-assisted subepithelial keratectomy. AB - To investigate the short-term effects of laser-assisted subepithelial keratectomy (LASEK) on the corneal endothelium, 10 patients undergoing LASEK for myopia without complications (20 eyes) were observed. Each eye was evaluated by slit lamp biomicroscopy and non-contact specular microscopy pre-operatively, and at 15 min, 1 day and 1 week post-operatively. The decrease in endothelial cell density was statistically significant at 15 min post-operatively, and the difference between pre-operative and 15-min post-operative coefficient of variation of cell size was also statistically significant. The percentage of hexagonal cells was significantly different from baseline levels at 15 min and at 1 day post operatively. All parameters at 1 week post-operatively were not statistically different from those observed pre-operatively. Immediate changes in endothelial cell number and morphology occurred following LASEK, but endothelial morphology returned to the pre-operative condition after 1 week. Long-term follow-up is needed to identify further consequences of this procedure. PMID- 20926023 TI - Sociotropic or autonomous personality and problem solving in peritoneal dialysis patients. AB - This study investigated the sociotropic and autonomous personality characteristics and perceived problem solving ability of continuous ambulatory peritoneal dialysis (CAPD) patients, and their relationship with quality of life. The study included 14 CAPD patients and 54 healthy volunteers. Sociotropy and autonomy scores were significantly higher in CAPD patients than in the healthy control group. Among CAPD patients, there was a significant correlation between problem solving and serum phosphate, parathormone levels and erythrocyte sedimentation rate. There was a negative correlation between total dialysis time and sociotropy in CAPD patients, and a positive correlation between general health/pain perception and autonomy. Appropriate medical management, time on dialysis and positive self-perception of health were correlated with better problem solving ability and higher autonomous but lower sociotropic personality styles. PMID- 20926024 TI - Increased levels of soluble vascular endothelial cadherin are associated with poor outcome in severe sepsis. AB - Endothelial cells are thought to play a key role in sepsis pathogenesis: vascular endothelial damage occurs in severe sepsis and multiple organ dysfunction. Soluble vascular endothelial cadherin (VE-cadherin) levels were investigated in a prospective study involving 28 consecutive critically ill patients with or without severe sepsis who were admitted to surgical intensive care; 13 healthy age-matched volunteers were included as controls. Soluble VE-cadherin levels increased significantly in patients with severe sepsis compared with ill patients without severe sepsis and healthy controls. There was a significant linear correlation between soluble VE-cadherin levels and illness severity scores. Soluble VE-cadherin levels were significantly higher in patients who died compared with survivors. In vitro cell culture showed that serum from patients with severe sepsis greatly decreased VE-cadherin staining at intercellular junctions and total VE-cadherin expression in human umbilical cord vein endothelial cells. These findings suggest that endothelial cells play an important role in the poor outcome of patients with severe sepsis. PMID- 20926025 TI - Effect of narrow-band UVB phototherapy on soluble cell adhesion molecules in patients with psoriasis vulgaris. AB - This study investigated the effect of narrow-band ultraviolet B (NB-UVB) phototherapy on serum levels of the soluble cell adhesion molecules sE-selectin, sP-selectin, sL-selectin and soluble intercellular adhesion molecule-1 (sICAM-1) in 58 patients with psoriasis vulgaris. Psoriasis Area and Severity Index (PASI) scores significantly decreased after treatment, confirming the efficacy of NB-UVB phototherapy. Serum levels of sE-selectin also decreased significantly after treatment, and levels of sICAM-1 showed a significant correlation with PASI score and with levels of sE-selectin. The efficacy of NB-UVB phototherapy in improving psoriatic lesions may be a function of decreased serum levels of E-selectin. These findings emphasize the complex roles of soluble cell adhesion molecules in the immunopathogenesis of psoriasis. PMID- 20926026 TI - Type I plasminogen activator inhibitor 4G allele frequency is associated with chronic venous insufficiency. AB - Chronic venous insufficiency (CVI) is a common disease associated with poor quality of life. Genetic polymorphisms causing coagulation abnormalities may account for some of the CVI pathogenesis. Type I plasminogen activator inhibitor (PAI-1) is responsible for fibrinolytic system regulation, and plasma levels of PAI-1 are strongly correlated with PAI-1 4G/5G gene polymorphism. The association between PAI-1 4G/5G gene polymorphism and CVI was investigated. In 34 consecutive patients with clinically overt CVI, the PAI-1 4G/4G polymorphism was detected in three cases (8.8%); the 4G/5G polymorphism was detected in 28 (82.4%). In 34 age- and sex-matched controls, the PAI-1 4G/4G polymorphism was detected in one case (2.9%) and the 4G/5G polymorphism was detected in 14 cases (41.2%). The PAI-1 4G allele was found significantly more frequently in CVI patients than in controls. The 4G allele was associated with a 3.25-fold increase in CVI risk. Thus, a relationship between CVI and the PAI-1 4G allele is apparent. PMID- 20926027 TI - Effect of high-dose vitamin C on oxygen free radical production and myocardial enzyme after tourniquet ischaemia-reperfusion injury during bilateral total knee replacement. AB - This study investigated the effects of high-dose vitamin C on oxygen free radical production and cardiac enzymes after tourniquet application and ischaemia reperfusion injury during bilateral total knee replacement (TKR) in elderly patients. In the vitamin C (VC) group (VC group, n = 16), during surgery, patients received a priming bolus of 0.06 g/kg vitamin C with 100 ml saline followed by 0.02 g/kg vitamin C mixed with 30 ml saline, intravenously. The control group (n = 16) received no intra-operative vitamin C. In the VC group, malondialdehyde levels were lower, and arterial oxygen tension and mean blood pressure were higher, than in controls after post-operative deflation of both knee tourniquets. Troponin I levels were lower in the VC group than in controls 8 h post-operation. Administering high-dose vitamin C during bilateral TKR could prevent oxygen free radical production and a decline in arterial oxygen tension and mean blood pressure induced by ischaemia-reperfusion injury, thereby protecting the myocardium. PMID- 20926028 TI - Improved prediction from revised injury severity classification (RISC) over trauma and injury severity score (TRISS) in an independent evaluation of major trauma patients. AB - The usefulness of the Revised Injury Severity Classification (RISC) analysis was compared with that of the Trauma and Injury Severity Score (TRISS) for evaluating the quality of treatment of severely injured patients at the General Hospital Celje, Slovenia. Over a period of 2 years, data from a cohort of 155 patients treated at the General Hospital Celje were included in the Traumaregister Deutsche Gesellschaft fur Unfallchirurgie. The structure of the patient group was compared with that in the registry, and TRISS and RISC analyses were performed. The M statistic (0.83) showed a good match of the distribution of probability of survival between groups. Evaluation of RISC (area under the curve [AUC] 0.94, Hosmer-Lemeshow test 3.5) demonstrated the efficacy of this method in the patient group. TRISS (AUC 0.89, Hosmer-Lemeshow test 21.1) was not a reliable instrument for analysis of treatment of major trauma patients. We believe that RISC should replace TRISS for evaluation of the treatment of major trauma patients. PMID- 20926029 TI - Immunohistochemical analysis and biological behaviour of gastric glomus tumours: a case report and review of the literature. AB - Gastric glomus tumours are rare and clinically recognized as benign. Nevertheless, some show biological behaviour similar to that of malignant lesions. During the last 40 years, we have encountered only one gastric glomus tumour. Analysis of frozen sections of this tumour suggested a mesenchymal tumour with malignant potential. Three mitoses per 50 high-power fields, with no cytological abnormalities, were observed. Tumour cells were positive for alpha smooth muscle actin, vimentin and actin but negative for CD117, S-100 protein, creatine kinase, desmin, CD68, collagen type IV, CD34 and p53. The post-operative period was uneventful. During 37 months' follow-up, no recurrence or metastasis was detected and a benign course was considered likely. Literature on the immunohistochemistry and biological behaviour of gastric glomus tumours was also reviewed. Immunohistochemical studies are helpful in the differential diagnosis of gastric glomus tumours: although most are benign, malignancy cannot be excluded. Thus, long-term follow-up of the patient is necessary. PMID- 20926030 TI - Aggressive angiomyxoma of the vulva: case report and literature review. AB - Aggressive angiomyxoma is a rare softtissue tumour, typically occurring in the female pelvis and carrying a high risk of local infiltration and relapse. Surgery remains the first line of treatment, however some adjuvant treatments, such as gonadotrophin-releasing hormone (GnRH) agonists, have been used for primary treatment and for treatment against tumour recurrence. We describe a case of vulvar aggressive angiomyxoma in a 31-year old woman who underwent surgical excision of the tumour. Diagnosis was made on the basis of histopathological examination and positive immunohistochemical staining with oestrogen and progesterone receptors. Postsurgery, a GnRH agonist (3.75 mg triptorelin) was injected intramuscularly every month for 3 months to prevent tumour recurrence and, to date, no relapse has been observed. Whether treatment is with surgery, hormone therapy or both, it is clear that aggressive angiomyxoma requires close, long-term follow-up to monitor for disease recurrence and that the individualization of each case is essential for adequate management. PMID- 20926031 TI - Isolated primary non-Hodgkin's lymphoma of the thoracic spine: a case report with a review of the literature. AB - A case of isolated primary non-Hodgkin's lymphoma of the spine is presented along with a review of previous cases reported in the literature. An 80-year old immunocompetent man was admitted with progressive numbness and weakness of both lower extremities of 2 weeks' duration. Magnetic resonance imaging (MRI) of the cervicothoracic spine revealed an extradural spinal mass at the T1 - T3 level, with invasion into the T3 vertebral body. The lesion was at first thought to be a metastatic tumour. Because of the manifestations of compression, the patient underwent laminectomy and posterior decompression. Histopathological examination revealed diffuse large B-cell non-Hodgkin's lymphoma. All other investigations (including computed tomography of the chest and abdomen, bone scan, peripheral blood examination and tumour marker examination) were negative for occult disease. This case demonstrates that neurosurgeons should be aware of the occurrence of isolated primary spinal lymphoma, which should be included in the differential diagnosis of metastatic tumours. PMID- 20926032 TI - Statistical significance in genetic association studies. PMID- 20926033 TI - Immunological and hematological changes in patients with hyperthyroidism or hypothyroidism. AB - AIMS: Thyroid hormones have been shown to influence the immune system and haematopoiesis. The aim of this study was to evaluate some immunological and hematological parameters in peripheral blood of hypo- or hyperthyroid women. MATERIALS AND METHODS: Blood samples were collected from 50 women with hypothyroid disease, 50 women with hyperthyroid disease and a control group consisting of 50 sex - and age - matched euthyroid subjects. Thyroid function assesed according to measurent of T3, T4 and TSH levels. The complete blood count (CBC), total and differential counts of white blood cells (WBC), serum levels of immunoglobulins (IgG, IgA, IgM and IgE) and C3 and C4 complement components determined in three groups by using standard immunological and hematological methods. RESULTS: In hyperthyroid women the mean serum concentrations of IgG (2312.4+/-584 mg/dl), IgA (296+/- 87 mg/dl) and IgE ( 301+/- 264 IU/ml) were significantly higher than those found in the control group (1539+/- 974 mg/dl, P < 0.0003; 234+/- 116 mg/dl, P < 0.01; 109.8+/-115 IU/ml, P < 0.0001, respectively) and the mean MCV was significantly lower in comparison with the euthyroid group (P < 0.05). Hypothyroid patients had higher serum IgE concentrations in comparison with the euthyroid group (179.8+/- 218 IU/ml vs. 109.8+/- 115 IU/ml; P < 0.047). The mean serum C3 concentration in hypothyroid patients was also significantly higher in comparison with the euthyroid group (138.7+/- 36.6 mg/ml vs. 117.8+/- 32.1 mg/dl; P < 0.01). In the hypothyroid group the mean eosinophil count was markedly higher in comparison with the hyperthyroid group (P < 0.06) and the mean count of RBC and the levels of some RBC-related indices, such as hematocrit and hemoglobin, were significantly lower in comparison with the euthyroid group (P < 0.05). CONCLUSION: These results indicate hypergammablobulinemia and lower MVC in hyperythyroid patients, and higher IgE levels, C3 levels and eosinophil count as well as anemia in hypothyroid patients. PMID- 20926034 TI - Effect of ex vivo-expanded gammadelta-T cells combined with galectin-1 antibody on the growth of human cervical cancer xenografts in SCID mice. AB - OBJECTIVE: To investigate the antitumor activity of ex vivo-expanded gammadelta-T cells derived from tumor-infiltrating lymphocytes(gammadeltaTILs) from cervical cancer patients when combined with galectin-1 antibody and studied both in vitro and in vivo. METHODS: The presence of gammadeltaTILs in cervical cancer specimens was detected by immunohistochemistry and gammadeltaTILs were expanded using the solid-phase antibody method. The expression of galectin-1 by the human cervical cancer cell line, SiHa, was measured by Western blot and ELISA. In vitro cytotoxic activities of expanded gammadeltaTILs, with or without galectin-1 inhibitor, were determined using the LDH-release test. In vivo antitumor activity of gammadeltaTILs, combined with galectin-1 antibody, was evaluated using the SCID mouse model. RESULTS: gammadeltaTILs existed in the cervical cancer and the percentage of TCRgammadelta(+) cells in gammadeltaTILs after ex vivo expansion was 91.2+/-1.2% detected by flow cytometry. SiHa cell expressed and secreted galectin-1 as measured by Western blot and ELISA. Expanded gammadeltaTILs from human cervical cancer demonstrated marked cytotoxicity to SiHa or Hela cells. In comparison with non-treated group, the cytotoxicity of gammadelta TILs towards SiHa or Hela cell was significantly increased when effector and target cells were incubated with either lactose or galectin-1 antibody at E/T ratio of 1:1 (p < 0.05). gammadeltaTILs, in combination with galectin-1 antibody treatment, significantly suppressed the growth of xenografts in SCID mice, in comparison with all other groups (p < 0.05). gammadeltaTILs alone also showed the ability to inhibit tumour growth in vivo, but were more efficient when combined with specific antibody (p < 0.05). CONCLUSION: Taken together, our results suggest that gammadelta-T cells, combined with galectin-1 antibody treatment, could be a more effective adoptive immunotherapy for patients with cervical cancer than traditional adoptive immunotherapy methods. PMID- 20926035 TI - C-reactive protein, vitamin B12 and C677T polymorphism of N-5,10 methylenetetrahydrofolate reductase gene are related to insulin resistance and risk factors for metabolic syndrome in Chinese population. AB - PURPOSE: Metabolic syndrome (MS) and type 2 diabetes mellitus (T2DM) are complex diseases affected by both dietary intake and genetic background. Whether N-5, 10 methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism, high sensitivity C-reactive protein (hs-CRP) and dietary components folate and vitamin B12 are associated with MS in Asian has not been determined. METHODS: We hypothesized that MTHFR gene C677T, folate, vitamin B12 and hs-CRP are associated with MS and factors related to MS in northern Han Chinese. To test this hypothesis, MTHFR C677T gene polymorphism was determined by PCR-RFLP, serum insulin, folate and vitamin B12 levels by radioimmunoassay, and hs-CRP by immunoturbidimetry in newly diagnosed T2DM patients with MS (118) and without MS (40), and in 55 healthy subjects. RESULTS: Results indicated that MS-associated T2DM accounts for 75% of newly diagnosed T2DM in Han Chinese. Serum hs-CRP was higher and serum vitamin B12 was lower in subjects with TT genotype in comparison with those with CC or CT genotypes. Total T frequency was significantly higher in MS-associated T2DM patients (45.3%) compared to 26.3% in non-MS-associated T2DM patients. MTHFR C677T gene polymorphism and vitamin B12 levels were associated with MS-associated T2DM. CONCLUSION: MTHFR C677T gene polymorphism may contribute to insulin resistance in Han Chinese with MS by increasing hs-CRP and decreasing vitamin B12, and consequently play an important role in development of MS associated T2DM. PMID- 20926036 TI - Diagnosis and treatment of juxta-ampullary duodenal diverticulum. AB - OBJECTIVE: To summarize the diagnosis and treatment of juxta-ampullary duodenal diverticulum (JAD) in our hospital. METHODS: Of 5000 consecutive endoscopic retrograde cholangiopancreatography (ERCP) performed in our department, 225 patients were diagnosed with JAD and treated. All patients were classified based on the location of Ampullae of Vater in relation to the duodenal diverticulum. Of the 225 JAD patients, 96 patients (43%) required surgery. RESULTS: The 225 patients with JAD were divided into Type A (146 cases, 65%) or Type B (79 cases, 35%). Type A patients presented with papillae near the diverticulum or in its margin. In this type, 36 patients (25%) presented with diverticulitis, bleeding, perforation or cholelithiasis, and were treated surgically. Type B patients presented with papillae inside the diverticulum. Among them, 60 patients (76%) had complications requiring surgery. CONCLUSIONS: JAD can be divided into two types based on location of the papillae. ERCP was the primary method of diagnosing JAD and patients with severe complications required surgical intervention. PMID- 20926037 TI - Clinical outcome and left ventricular remodeling in AMI patients with insufficient myocardial reperfusion after recanalization. AB - AIM: Myocardial contrast echocardiography (MCE) is effective in predicting myocardial viability and functional recovery on a segmental level in patients with acute myocardial infarction (AMI). In this study, we investigated whether insufficient myocardial reperfusion plays an important role in left ventricular (LV) remodeling and functional recovery in patients with thrombolysis in myocardial infarction (TIMI) flow grade 3 and corrected TIMI frame count (CTFC) < 40 after recanalization of the infarct-related artery. METHOD: Patients underwent intracoronary injection of microbubbles for echocardiographic assessment of myocardial microvascular perfusion, wall motion score, LV volume and ejection function (EF) at baseline, 30 minutes, one month and six months after recanalization. The patients with MCESI < 1 were considered to have insufficient myocardial reperfusion (group A, n=11), while the patients with MCESI>=1 were considered to have sufficient myocardial reperfusion (group B, n=47) after AMI recanalization. RESULTS: The wall motion score index (WMSI) and the left ventricular ejection fraction (LVEF) showed significant improvement at 1 month and 6 months in group B, but only at six months in group A. Left ventricular end systolic and end-diastolic volumes (LVESV and LVEDV) were also significantly decreased at one and six months in group B. WMSI, LVESV, LVEDV and LVEF were significantly improved in group B in comparison with group A at one month and six months (P < 0.01). By six months, significant correlations were seen in all patients between MCESI and changes in LVESV, LVEDV and LVEF at 6 months. Similar correlations were observed between the myocardial regional blood flow (Q) and changes in LVESV , LVEDV and LVEF. CONCLUSION: Insufficient myocardial reperfusion was a strong independent predictor of LV remodeling and functional recovery in AMI patients with TIMI flow grade 3 and CTFC < 40 after recanalization. MCE has important additional value for prognosis and risk assessment in patients with acute myocardial infarction following recanalization. PMID- 20926038 TI - Effects of statin use on total oxidant and antoxidant capacity and ceruloplasmin activity. AB - PURPOSE: Oxidative damage plays an important role in atherosclerosis development. Statin drugs have anti-oxidant properties, but the clinical value of their antioxidant properties remains unclear. In this study, our aims were: (1) to assess the anti-oxidant effects of statins in patients with coronary artery disease (CAD) using a newly developed valid measure of total oxidant and anti oxidant capacity; and (2) to identify whether statins influence ceruloplamin levels. METHODS: Within a cross-sectional study, 67 dyslipidemic CAD patients on atorvastatin for at least three months were compared with 69 age- and gender matched CAD patients not using atorvastatin. All patients were either newly diagnosed with or already had established CAD. Patients and controls were selected from among patients who had undergone coronary angiography for a variety of reasons. Immediately prior to angiography, plasma total oxidant and antioxidant capacity and ceruloplasmin (Cp) levels were measured by means of a relatively new and highly-reliable method. RESULTS: Total oxidant capacity levels were significantly lower and total antioxidant capacity significantly higher in those on atorvastatin; serum seruloplasmin levels also were significanly increased in the atorvastatin groups (all p < 0.05). On multivariate analysis, atorvastatin use was a significant determinant of Cp increase, independent of any antioxidant effect. CONCLUSIONS: This study clearly demonstrates increased anti oxidant capacity and decreased oxidative stress with statin use. Atorvastatin use may also increase Cp levels although this effect appears to be independent of its anti-oxidant effects. PMID- 20926039 TI - Prior intense exercise reduces arterial carbon dioxide pressure in extreme obesity. AB - PURPOSE: Unlike normal weight individuals, individuals with extreme obesity do not show a decrease in arterial carbon dioxide pressure (PaCO2) from rest to peak exercise. This indicates that breathing is compromised. The objective of this study was to determine if prior high intensity exercise lowers PaCO2 in comparison with a first bout, normalized for the same metabolic rate. METHODS: Oxygen consumption during incremental, ramped exercise was matched to constant workload exercise (75% of peak power). Both protocols were to volitional exhaustion 39 +/- 8 min apart. Eleven obese subjects (BMI = 47 +/- 8 kg/m2, aerobic capacity = 2.3 +/- 0.6 L/min) were evaluated. Forty paired samples were obtained at the same metabolic rate between the two protocols. RESULTS: The mean absolute difference and 95% CI were large for arterial oxygen pressure (PaO2) = 9 (6, 11) mmHg and alveolar to arterial oxygen pressure difference (AaDO2) = 7 (5, 8) mmHg. The mean absolute difference for arterial oxyhemoglobin saturation (%SaO2) = 0.5 (0.4, 0.7) %; PaCO2 = 4 (3, 4) mmHg; physiological dead space to tidal volume ratio (VD/VT) = 0.04 (0.03, 0.05); and alveolar ventilation (VA) = 3 (2, 4) L/min. The recovery period after the first bout of exercise reduced the PaCO2 by 3 mmHg when matched for similar metabolic rates. Constant workload exercise predicted VA, %SaO2, V(D)/V(T), and PaCO2, but not PaO2 or AaDO2 during incremental exercise at similar metabolic rates. CONCLUSION: Given a sufficient chemical stimulus, obese subjects will attempt to breathe more, although this does not mean more VA, which removes CO2. PMID- 20926040 TI - Comparison of total oxidant/antioxidant status in unconjugated hyperbilirubinemia of newborn before and after conventional and LED phototherapy: A prospective randomized controlled trial. AB - PURPOSE: We evaluated and compared the oxidant and antioxidant status of hyperbilirubinemic infants before and after the two forms of phototherapy: conventional and LED phototherapy, in order to identify the optimal treatment method. METHOD: Thirty newborns exposed to conventional (Group I) phototherapy and 30 infants exposed to LED phototherapy (Group II) were studied. The serum total antioxidant capacity (TAC) and the total oxidant status (TOS) were assessed by EREL's method. RESULTS: There were no statistically significant differences in TAC or TOS levels between Group I and Group II prior to phototherapy, and no statistically significant difference in TAC levels between the two groups after phototherapy; however, TOS levels were significantly lower in Group II compared to Group I after phototherapy. Oxidative stress index (OSI) increased after conventional phototherapy (p < 0.05) CONCLUSION: The increase in TOS following conventional phototherapy was not not observed following LED phototherapy. This difference should be considered when using phototherapy. PMID- 20926041 TI - [Titles of persons]. PMID- 20926042 TI - [Telomeres--the beginning and the end]. PMID- 20926043 TI - [Telomeres and telomerase]. AB - In 2009 the Nobel Prize in Medicine was awarded to EH Blackburn, CW Greider and JW Szostak for their work on "How chromosomes are protected by telomeres and the enzyme telomerase". Telomeres are specialized DNA structures localized at the end of linear chromosomes. Telomeres are known as the biological clock of the cell, since they shorten with each cell division. Telomerase can elongate telomeres. Telomeres protect chromosome ends against being recognized as double stranded DNA breaks, and are thought to be a guard against cancer. It has furthermore been suggested that telomeres may play a role in aging and age-related diseases. PMID- 20926044 TI - [The role of telomeres in cancer]. AB - Telomeres are a double-edged sword when it comes to cancer. On one hand, telomeres limit the cells' ability to divide and thereby restrict the uninhibited growth seen in cancer. On the other hand, short telomeres can initiate the chromosome instability that characterizes cancer. Diseases with the combination of short telomeres and high cancer risk are seen, but until now the use of telomeres as predictors of cancer has, in general, been unsuccessful. Telomeres and telomerase play an important role in further cancer development. Researchers are trying to exploit this in the development of new cancer therapies. PMID- 20926045 TI - [The role of telomeres in aging-related disease]. AB - Telomeres are specialized DNA structures, protecting the ends of linear chromosomes. The association between telomeres and cellular aging is well established, and it has been shown that there is a negative correlation between telomere length and chronological age for many types of human tissue. On the other hand, the association between telomere length and mortality is poor. Nevertheless, it has been suggested that telomeres may play a role in the development of many aging-related diseases. This has led to attempts to develop telomere-elongating treatment. PMID- 20926046 TI - [Smoking among more than 45,000 randomly sampled Danish women and men]. AB - INTRODUCTION: The aim of the study was to describe smoking and examine the association between socio-demographic factors (age, educational level and degree of urbanization) and smoking status, age at smoking initiation and heavy smoking. MATERIAL AND METHODS: The study is based on data from two cross-sectional surveys conducted in 2004 and 2006 among randomly sampled women and men (18-45 years). A total of 22,199 women (response rate: 81.4%) and 23,080 men (response rate: 71.0%) were included in the study. RESULTS: One third of the participating women and men reported being smokers. The majority smoked more than 15 cigarettes/day (59% women, 74% men). The proportion of never smokers was higher among the youngest. The proportion of daily smokers was lowest in the youngest age groups, especially among women. The prevalence of daily smokers was highest among participants with limited education, among women living in the southern suburbs of Copenhagen, and among men living in peripheral rural areas. In the multivariate analysis, smoking more than 15 cigarettes/day was strongly associated with age (less prevalent among the youngest) and educational level (more prevalent among participants with limited education). Age at smoking initiation seemed to decrease, as it was lowest among the youngest participants and among those with the lowest educational level. CONCLUSION: Fewer and particularly fewer young persons start smoking. However, we found an uneven distribution in the proportion of smokers especially in relation to educational level but also in relation to degree of urbanization. PMID- 20926047 TI - [Improved survival in children with neuroblastoma]. AB - INTRODUCTION: The aims of the present study were to analyze whether changes in incidence and mortality rates have taken place in Denmark during the period 1981 2005, and whether the distribution of known prognostic factors has changed during this period. MATERIAL AND METHODS: A total of 206 children below 15 years of age with neuroblastoma or ganglioneuroblastoma who were diagnosed in Denmark between 1981 and 2005. RESULTS: The incidence was 8.68 per million children below 15 years of age (world standard 9.6) and 43.5 per million children below 12 months of age and these incidences have remained unchanged since 1970. The mortality rate has decreased steadily during the study period. The prognostic factors age, stage and site of primary tumour did not change during the study period and were not different from those reported by others. 32% of the children were below 12 months of age at diagnosis. 53% of the children had metastatic disease. The overall 5-year survival increased over the study period from 38% in 1981-1985 to 69% in 2001-2005. A significant increase in the survival of children > 12 months of age with stage 4 disease was also observed. Relapse/disease progression more than three years from diagnosis occurred in only 2% of patients. The median time from relapse to death was three months. CONCLUSION: The survival of children with neuroblastoma in Denmark has increased significantly over the last 25 years. PMID- 20926048 TI - [Extreme levels of hyperlipidaemia as a cause of acute pancreatitis]. AB - Hypertriglyceridaemia is an uncommon cause of acute pancreatitis, accounting for 1-4% of cases. In the case of lipoprotein-lipase mutations, lipid levels may rise to extreme levels during acute pancreatitis. In this case a 29-year-old female was hospitalized several times due to acute pancreatitis. She presented with extreme lipid levels and difficulty in blood testing. While the correlation of acute pancreatitis and hyperlipidaemia is known, awareness of its association with defects in lipid metabolism could, in this case, have furthered diagnostic and prevented repeated hospitalizations. PMID- 20926049 TI - [Intraplacental choriocarcinoma]. AB - Choriocarcinoma is found in 1/20,000-40,000 pregnancies. The disease typically presents with symptomatic metastases. We present a case of incidentally discovered intraplacental choriocarcinoma. A gravida 7 at 35 + 4 weeks' gestation presented because of abdominal pain and decreased foetal movement. An acute Caesarean was performed with the delivery of a hypotonic, anaemic girl with an Apgar score of 0/1. Choriocarcinoma typically presents as yellow areas, resembling intraplacental infarction. Consequently, the incidence is probably higher than presumed. PMID- 20926050 TI - [Second-degree burn in a pregnant woman]. AB - The incidence of burn injuries in pregnancy is low. Nevertheless, burns can cause maternal and foetal mortality and should be treated aggressively if substantial. Minor burns may frequently be managed without hospitalization. A 27-year-old primigravid woman with a gestational age of 38+6 presented with an abdominal partial-thickness burn covering 3% of her total body surface area. Conservative treatment was conducted in the emergency department. Medical induction of labour was performed. A healthy boy was delivered vaginally within 36 hours after the injury. PMID- 20926051 TI - [Rare form of Creutzfeldt-Jakob disease]. AB - Creutzfeldt-Jakob disease (CJD) is the most common type of prion disease. A considerable variation in disease phenotype is seen, primarily influenced by a naturally occurring polymorphism in the prion protein gene. We present a case of sporadic CJD of atactic type. Molecular genetic analysis showed a VV polymorphism at codon 129 in the prion protein gene. The various polymorphisms at codon 129 and their influence on the clinical picture and pathology are briefly discussed. PMID- 20926052 TI - [Picture of the month: imported malaria]. PMID- 20926053 TI - [Sociophysiology: basic processes of empathy]. AB - The aim of this review is to describe sociophysiological and social cognitive processes that underlie the complex phenomenon of human empathy. Automatic reflexive processes such as physiological contagion and action mirroring are mediated by the mirror neuron system. They are a basis for further processing of social signals and a physiological link between two individuals. This link comprises simultaneous activation of shared motor representations. Shared representations lead implicitly via individual associations in the limbic and vegetative system to a shared affective state. These processes are called sociophysiology. Further controlled- reflective, self-referential processing of those social signals leads to explicit, conscious representations of others' minds. Those higher-order processes are called social cognition. The interaction of physiological and cognitive social processes lets arise the phenomenon of human empathy. PMID- 20926054 TI - [Neurocognition and social cognition in patients with schizophrenia or mood disorders]. AB - OBJECTIVE: Overview on the current knowledge regarding neurocognition and social cognition in patients with schizophrenia or mood disorders. METHODS: Selective literature research on deficits in neurocognition and social cognition intrinsic to schizophrenia and mood disorders, their occurrence and effects. RESULTS: Deficits in neurocognition and social cognition are more pronounced in patients with schizoprenia than in those with mood disorders. However, regardless of diagnosis these impairments have significant negative impact on the patients' subjective and functional outcome. CONCLUSIONS: It is important to consider cognitive deficits as an integral part of a treatment approach to achieve mental stabilization in patients with schizophrenia or mood disorders. PMID- 20926055 TI - [Increasing criminality in patients with schizophrenia: fiction, logical consequence or avoidable side effect of the mental health reforms?]. AB - OBJECTIVE: The reforms of general mental health care aimed at a substantial improvement of the situation of the mentally ill. We examined the question of a possible association between the mental health reforms and the steady increase of the population of forensic mental hospitals becoming apparent since the introduction of community psychiatry. RESULTS: All recent publications report a moderate albeit statistically significantly increased risk of criminality in patients suffering from schizophrenia, which becomes more obvious in severe, violent offences. In homicide it comes up to the 10-fold of that of the general population. Comorbid substance abuse has a substantial impact on the extent of illegal behaviour, however, even under consideration of alcohol abuse the risk of homicide amounts to about the 7-fold of that of the general population. Nearly all European countries give account on a remarkable increase of the incidence and prevalence rates of mentally disordered offenders. Patients suffering from schizophrenia are disproportionately affected by this development. However, the substantially increased risk of homicide in schizophrenic patients, reported already in the pre-reform era, remained stable over time. Accordingly, the rate of patients admitted to forensic-psychiatric treatment because of offences of minor severity is on the rise. CONCLUSION: This development cannot be explained by single details of the mental health reforms, which show remarkable regional differences concerning numbers of mental hospital beds, ways of service provision, legal preconditions and rates of criminality and substance abuse. Rather, national and international data suggest changes of general societal attitudes to be the crucial factor. They have resulted in changes concerning the self-understanding of the representatives of modern mental healthcare. As aggressive behaviour is not integrated in the understanding of schizophrenia of present-day psychiatry, the objective needs of a subgroup of severely and chronically ill psychotic patients with high rates of comorbid substance abuse, lack of insight and compliance are increasingly neglected. The denial of these facts promotes the shift of 'difficult-to-treat patients' into forensic psychiatric facilities and damages the reputation of psychiatry. PMID- 20926056 TI - [The German language version of the Camberwell Assessment of Need for the Elderly (CANE) among dementia patients]. AB - OBJECTIVE: The purpose of the present study was to assess the needs of dementia patients using the German language version of the Camberwell Assessment of Need for the Elderly (CANE) and to investigate the internal consistency of German language. METHODS: A sample of 45 dementia patients was investigated using the German CANE. Data were collected from family caregivers. RESULTS: Most dementia patients showed a multitude of problems. In most cases, support was provided more frequently from informal caregivers than from social or medical services. Internal consistency ranged between 0.797 and 0.900 (Cronbach's Alpha). CONCLUSIONS: The high frequency of problems indicates the importance of long-term planning of services for dementia patients. The internal consistency of the German CANE was sufficiently high. PMID- 20926057 TI - [The psychometric value of the Verbal Short-Term Memory Scale by Arnold & Kohlmann in psychiatry]. AB - OBJECTIVE: Of various tests used to determine verbal short-term-memory deficits in mentally ill persons the Verbal Short-Term Memory Scale by Arnold and Kohlmann meets the important criteria of being fast, user-friendly and every day life like, despite its old norms and questionable validity. The aim of this study was to assess the psychological value of this instrument by correlating it with those two subtests of the standardized Wechsler Memory Scale (WMS), which assess verbal shortterm memory. METHODS: 478 random patients at a university psychiatric hospital, who were referred for psychological testing, were examined with the Verbal Short-Term Memory Scale by Arnold & Kohlmann and the subtests "Logical Memory" and "Verbal Paired Associates" of the Wechsler Memory Scale. RESULTS: Performance by the total sample on both memory tests was in the lowest or just below the range of dispersion for normal values. All scales of both tests showed significant positive correlation. CONCLUSIONS: Despite its age the Verbal Short Term Memory Scale by Arnold & Kohlmann is especially recommended for quick differential diagnosis of a patient's memory in an acute psychiatric examination. PMID- 20926059 TI - [Are eating disorders addictions?]. AB - The various eating disorders, anorexia nervosa, bulimia nervosa, and binge-eating disorder, are characterized by severe disturbances in eating behavior and are seen as typical "psychosomatic disorders". The subdivision of anorexia nervosa into two subtypes, namely "anorexia nervosa restricting type" and "anorexia nervosa bulimic type" has proved to be very good. It is to be assumed that eating disorders are not a homogeneous group, and that the various subtypes of eating disorders are also heterogeneous at several levels. Co-morbid psychiatric disorders, especially affective disorders, anxiety disorders, substance-related disorders, and personality disorders, are often found in eating- disordered patients. Many anorectics of the restrictive type and orthorectics show co-morbid psychiatric disorders such as anxiety disorders, obsessive-compulsive disorders, and avoidant or obsessive-compulsive personality disorders, while a co-morbidity of affective disorders, addiction, personality disorders, especially multi impulsivity and borderline personality disorder, is frequently found in anorectics of bulimic type, bulimics, and binge eaters. Addictive behavior manifests itself in permanent preoccupation with food and eating, withdrawal symptoms, continuation of disturbed eating behavior in spite of negative consequences, loss of control, and frequent relapse. There are some indications that there is a basic psychological disturbance common to eating disorders, especially bulimia nervosa, and to substance-related disorders, namely a personality disorder with an emotional instability and multi-impulsivity. The possible associations between eating disorders and mental disorders, particularly addictions, will be discussed. PMID- 20926058 TI - [Quality assurance of take-over from in-patient to out-patient care: experiences in Lower Austria]. AB - OBJECTIVE: Community mental health teams (CMHT) provide support for severely disabled, chronic mentally ill patients. In this study, referrals to CMHT by a psychiatric hospital in Lower Austria were analysed, as were the first few weeks of care for referred patients. METHODS: Referrals to CMHT of a catchment area (pop 250.000) were analysed for 2002- 2006. RESULTS: In the first 6 months of each year, 124 to 189 patients were referred to CMHT. Between 2002 and 2006, the percentage of affective disorders (ICD-10: F3: 40.0 %), and substance use disorders (F1: 38.9 %) within the referrals diminished, as compared to patients suffering from schizophrenia (F2 initially 25.4 % of referrals vs. 49.7 %) and personality disorders (F6 initially 6.4 % of referrals vs. 22.4 %). In 30.7 % vs. 56.6 % of patients, CMHT workers managed to establish contact to patients after discharge from hospital. They actively sought contact with 39.9 to 74.6 % of referred patients (by means of telephone calls, letters, home visits, etc.). In 26.5 to 46.9 % of the referrals, continuous care was planned. CONCLUSIONS: This study emphasizes the advantage of specific referrals to CMHT, if care for severely disabled individuals is needed and should be provided. Furthermore, a description of outreach activities, which are intended to maintain contact with patients characterized by poor compliance, is presented. These activities are not yet part of routine care in German speaking countries. PMID- 20926060 TI - [Sexual addiction: chimera or clinical syndrom? A plea for a clinical conceptualization]. AB - The phenomenon of sexual addiction as a clinical syndrom is discussed controversially. The article first deals with some mythological, historical and literary sources, which have been an inspiration for the nomenclature, e.g. nymphomania. Scientific research started in the 19th century, but also a classification in terms of a morally contaminated pathology, which led to barbaric forms of "therapies" and procedures, especially for women. The ICD-10 and the DSM-IV do not contain categories that correspond with the clinical experience of many experts. The application of the WHO criteria should be possible, but this might fail due to big intercultural and individual differences in defining normal sexuality as the point of origin for pathological aberrances. Later some nosological concepts and therapeutic approaches are presented. The criticism of the term of "sexual addiction" is followed by the criticism of the criticism. The article ends with the conviction, that it should be a useful and reasonable challenge for psychiatrists to come to a reliable classification of this disorder to provide easier access to serious and professional help to those who often suffer enormous pain and shame. PMID- 20926061 TI - Surfactants and wetting at superhydrophobic surfaces: water solutions and non aqueous liquids. AB - Wetting studies regarding amphiphilic molecules and adsorption properties on highly water repellent solid surfaces play key roles in research and technology, with increasing interest both in fundamental and application fields. Nevertheless the wetting properties of aqueous surfactant solutions, non aqueous liquids or immiscible phases on superhydrophobic (SH) solid surfaces have been so far rarely investigated. In this work the authors give an overview on this topic reviewing the literature available together with preliminary results concerning the influence of the distribution properties of surfactants between two immiscible phases. Transition between wetting states can be also considered a possible development of these studies based on switching mechanisms. PMID- 20926063 TI - Driver behaviour at rail level crossings: responses to flashing lights, traffic signals and stop signs in simulated rural driving. AB - Australian road and railway authorities have made a concerted effort to reduce the number of rail level crossings, particularly the higher risk passive crossings that are protected by devices such as 'give way' or 'stop' signs. To improve this situation, passive level crossings are often upgraded with active controls such as flashing red lights. Traffic signals may provide good safety outcomes at level crossings but remain untested. The primary purpose of this research was to compare driver behaviour at two railway level crossings with active controls, flashing red lights and traffic signals, to behaviour at the current standard passive level crossing control, a stop sign. Participants drove the MUARC advanced driving simulator for 30 min. During the simulated drive, participants were exposed to three level crossing scenarios. Each scenario consisted of one of three level crossing control types, and was associated with an oncoming train. Mean vehicle speed on approach to the level crossings decreased more rapidly in response to flashing lights than to traffic signals. While speed on approach was lowest for the stop-sign condition, the number of non compliant drivers (i.e., those who did not stop) at the crossing was highest for this condition. While results indicate that traffic signals at rail level crossings do not appear to offer any safety benefits over and above flashing red lights, further avenues of research are proposed to reach more definitive conclusions. Compliance was lowest for the passive crossing control which provides further support for the ongoing passive crossing upgrades in Australia. PMID- 20926064 TI - Epithelial Na+ channel (ENaC) expression in obstructive sialadenitis of the submandibular gland. AB - BACKGROUND AND OBJECTIVES: The epithelial sodium channel (ENaC) has a critical role in the control of sodium balance, blood volume, blood pressure and viscosity of extracellular water. In submandibular gland disease, viscosity of the saliva plays an important role in the pathophysiology. However, there has been little study into the relationship between expression of ENaC and obstructive sialadenitis. The aim of this study was to elucidate the ENaC expression in excretory duct obstruction of the submandibular gland. MATERIALS AND METHODS: Seven-week old male Sprague-Dawley 12 rats were enrolled in the study. The rats were decapitated and histological changes of the submandibular gland tissue examined on days 0, 1, 3, 7, 14 and 21 after submandibular gland duct ligation. The expression of ENaC mRNA in the submandibular gland tissue was tested by reverse transcriptase-polymerase chain reaction (RT-PCR). Quantitative analysis of the ENaC protein was performed through Western blotting and tissue localization of the protein was performed by immunohistochemical staining. RESULTS: By real time RT-PCR, the expression of ENaC (alpha, beta, gamma) mRNA increased after ligation of the submandibular gland duct. alpha and gamma ENaC mRNA expression began to increase after 1 day. But beta ENaC mRNA expression began to increase significantly after 14 days. The increase of ENaC mRNA expression lasted for 3 weeks. The expression of ENaC (alpha, beta, gamma) protein was identified by Western blotting analysis, and ENaC protein was localized in ductal epithelial cells by immunohistochemistry. CONCLUSION: The expression of ENaC (alpha, beta, gamma) was increased by excretory duct ligation of the submandibular gland in rats and ENaC was considered to have a certain role in the pathogenesis of obstructive sialadenitis. PMID- 20926065 TI - To include or not to include? A response to the meta-analysis of heart rate variability and depression. PMID- 20926066 TI - Infralimbic D2 receptors are necessary for fear extinction and extinction-related tone responses. AB - BACKGROUND: Fear extinction is dependent on plasticity in the infralimbic prefrontal cortex, an area heavily innervated by midbrain dopaminergic inputs. Dopamine D2 receptors are concentrated in infralimbic output neurons that are involved in the suppression of conditioned fear after extinction. Here, we examined the specific role of infralimbic D2 receptors in mediating associative learning underlying fear extinction using the selective D2 antagonist raclopride. METHODS: Raclopride was administered systemically or infused into the infralimbic prefrontal cortex before fear extinction, and extinction retention was tested the following day. Rats were also prepared for single-unit recording in the infralimbic prefrontal cortex to assess the effect of raclopride on firing properties. RESULTS: We found that systemic injection of raclopride given before extinction impaired retrieval of extinction when rats were tested drug-free the next day but also induced catalepsy during extinction training. To determine whether impaired extinction was due to impaired motor function or disruption of extinction consolidation, we infused raclopride directly into the infralimbic prefrontal cortex. Raclopride infused immediately before extinction training did not produce motor deficits but impaired recall of extinction when tested drug free. Furthermore, in animals that underwent extinction training, systemic raclopride reduced the tone responsiveness of infralimbic prefrontal cortex neurons in layers 5/6, with no changes in average firing rate. CONCLUSIONS: We suggest that D2 receptors facilitate extinction by increasing the signal-to-noise of infralimbic prefrontal cortex neurons that consolidate extinction. PMID- 20926067 TI - Basic impairments in regulating the speed-accuracy tradeoff predict symptoms of attention-deficit/hyperactivity disorder. AB - BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is characterized by poor optimization of behavior in the face of changing demands. Theoretical accounts of ADHD have often focused on higher-order cognitive processes and typically assume that basic processes are unaffected. It is an open question whether this is indeed the case. METHOD: We explored basic cognitive processing in 25 subjects with ADHD and 30 typically developing children and adolescents with a perceptual decision-making paradigm. We investigated whether individuals with ADHD were able to balance the speed and accuracy of decisions. RESULTS: We found impairments in the optimization of the speed-accuracy tradeoff. Furthermore, these impairments were directly related to the hyperactive and impulsive symptoms that characterize the ADHD-phenotype. CONCLUSIONS: These data suggest that impairments in basic cognitive processing are central to the disorder. This calls into question conceptualizations of ADHD as a "higher-order" deficit, as such simple decision processes are at the core of almost every paradigm used in ADHD research. PMID- 20926068 TI - Disruption of white matter integrity in bipolar depression as a possible structural marker of illness. AB - BACKGROUND: Diffusion tensor imaging allows the study of integrity of white matter (WM) tracts. Literature suggests that WM integrity could be altered in bipolar disorder. Heterogeneity of brain imaging methods, the studied samples, and drug treatments make localization, nature, and severity of the WM abnormalities unclear. METHODS: We applied tract-based spatial statistics of diffusion tensor imaging measures to compare fractional anisotropy (FA), mean, and radial diffusivity of the WM skeleton in a group of 40 consecutively admitted inpatients affected by a major depressive episode without psychotic features with a diagnosis of bipolar disorder type I and 21 unrelated healthy volunteers from the general population. RESULTS: Compared with control subjects, patients showed lower FA in the genu of the corpus callosum and in anterior and right superior posterior corona radiata and higher values of radial diffusivity in WM tracts of splenium, genu and body of corpus callosum, right mid-dorsal part of the cingulum bundle, left anterior and bilateral superior and posterior corona radiata, bilateral superior longitudinal fasciculus, and right posterior thalamic radiation. Patients had no brain areas with higher FA or lower diffusivity values than control subjects. CONCLUSIONS: Reduced FA with increased mean and radial diffusivity suggests significant demyelination and/or dysmyelination without axonal loss. Comparing our findings with other observations in homogeneous samples of euthymic and manic patients, it can be hypothesized that changes in measures of WM integrity might parallel illness phases of bipolar illness. PMID- 20926069 TI - A daguerreotype of Phineas Gage? PMID- 20926070 TI - Positive correlation in the bisection of long and short horizontal Oppel-Kundt illusory gradients: Implications for the interpretation of the "cross-over" effect in spatial neglect. AB - Right brain damaged patients with left spatial neglect typically bisect long horizontal lines to the right of their midpoint. However, bisections of very short lines can favour the emergence of a paradoxical "cross-over" effect in which lines are bisected to the left of the true midpoint. It has been suggested that in healthy participants similar variations in the position of the subjective line midpoint can be observed in the bisections of long and short Oppel-Kundt (O K) illusory gradients (Savazzi et al., 2007). This analogy was taken as proof that patients with neglect suffer a distorted representation of horizontal space that is equivalent to illusory distortions that O-K gradients induce in the intact brain (Savazzi et al., 2007). In contrast to this proposal, however, it has been noted that reversal of O-K illusion with short gradients was never described in literature (Doricchi et al., 2008). To resolve this incongruence, it was argued that such a reversal can be observed in healthy participants showing strong conventional illusory effects with long gradients (Savazzi, 2008). This proposal suggests that the greater the shift in the conventional direction of the illusion for long gradients, the greater the shift in the opposite direction with equivalent short gradients (i.e., negative correlation). Here we tested this hypothesis in a sample of 100 healthy participants who bisected horizontal O-K illusory gradients of different lengths (2, 4, 8 and 16cm). We found no reversal of O-K illusion with short gradients and a positive, rather than negative, correlation between bisection of long and short gradients. Participants showing strong illusory effects in the bisection of long gradients showed analogous effects in the bisection of very short ones. These findings do not support the space anisometry interpretation of line bisection performance and the cross-over effect in patients with neglect. PMID- 20926071 TI - Gene expression analysis of a new source of human oocytes and embryos for research and human embryonic stem cell derivation. AB - OBJECTIVE: To create developmentally competent embryos from failed-to-fertilize oocytes for use in infertility research and human embryonic stem cell derivation. DESIGN: Attempts to recover developmental potential of failed-to-fertilize oocytes were made by using either parthenogenetic activation or reinsemination by intracytoplasmic sperm injection. Resulting embryos were cultured to various stages up to and including blastocyst, and single embryos exhibiting normal development were analyzed for gene expression by quantitatively profiling representative transcripts. SETTING: Hospital-based assisted reproductive technology laboratory and University academic laboratories. PATIENT(S): One hundred sixty-five couples undergoing assisted fertility treatment. INTERVENTION(S): Metaphase II stage oocytes were either parthenogenetically activated or reinseminated with donor sperm, then allowed to develop up to and including the blastocyst stage. MAIN OUTCOME MEASURE(S): Gene expression analysis was performed on oocytes and embryos by quantitative reverse transcriptase polymerase chain reaction for markers of developmental competence. RESULT(S): Fertilization occurred in 65% of the activated or reinseminated oocytes, which resulted in a blastocyst formation rate of 8%. Evaluation of a number of developmentally important genes in those embryos exhibiting normal development revealed profile and levels of expression similar to control embryos. One blastocyst from an activated oocyte yielded a novel pluripotent stem cell line indistinguishable from those derived from embryos surplus to infertility treatment. CONCLUSION(S): Clinically unusable oocytes represent a valuable alternative source of normal human embryos for human infertility and stem cell research without conflicting with patient treatment. PMID- 20926072 TI - A proposed new system of coding and injury classification for arteries in the trunk and extremities. AB - STUDY DESIGN: Retrospective review of arterial injury with prospective intra observer and inter-observer analyses. AIM: To introduce a new classification system for arterial injuries in the extremities and trunk. METHODS: Retrospective review of all patients with arterial injuries treated at a level I trauma centre during a 3.5-year period. Major arteries were located and coded, and the arteries' lesion was categorised in reference to the alphanumeric format of the AO fracture coding system and injury classification. Each major artery was coded in a numeric format and further divided into three segments: proximal, middle and distal. The severity of artery injury was classified into different types and subtypes in an alphanumeric format. Inter-observer and intra-observer reliabilities were tested. RESULTS: Systemic arteries were coded and arterial injuries were classified in the alphanumeric notation. The intra- and inter observers' reliabilities were found to be acceptable in the application of the new system. CONCLUSION: The preliminary data demonstrate that the new coding and injury classification system for arteries in the trunk and extremities are reliable and efficient for data storage and retrieval, and provide a favourable environment for discussion among different physicians or centres. PMID- 20926073 TI - Haemodynamic instability resulting from a low energy pubic ramus fracture in a 78 year-old woman. A case report and review of the literature. PMID- 20926074 TI - Obstetric violence: a new legal term introduced in Venezuela. PMID- 20926075 TI - Predictive validity of the Hendrich fall risk model II in an acute geriatric unit. AB - BACKGROUND: Falls are the most common adverse events reported in acute care hospitals, and older patients are the most likely to fall. The risk of falling cannot be completely eliminated, but it can be reduced through the implementation of a fall prevention program. A major evidence-based intervention to prevent falls has been the use of fall-risk assessment tools. Many tools have been increasingly developed in recent years, but most instruments have not been investigated regarding reliability, validity and clinical usefulness. OBJECTIVES: This study intends to evaluate the predictive validity and inter-rater reliability of Hendrich fall risk model II (HFRM II) in order to identify older patients at risk of falling in geriatric units and recommend its use in clinical practice. DESIGN: A prospective descriptive design was used. SETTING: The study was carried out in a geriatric acute care unit of an Italian University hospital. PARTICIPANTS: All over 65 years old patients consecutively admitted to a geriatric acute care unit of an Italian University hospital over 8-month period were enrolled. METHODS: The patients enrolled were screened for the falls risk by nurses with the HFRM II within 24h of admission. The falls occurring during the patient's hospital stay were registered. Inter-rater reliability, area under the ROC curve, sensitivity, specificity, positive and negative predictive values and time for the administration were evaluated. RESULTS: 179 elderly patients were included. The inter-rater reliability was 0.87 (95% CI 0.71-1.00). The administration time was about 1min. The most frequently reported risk factors were depression, incontinence, vertigo. Sensitivity and specificity were respectively 86% and 43%. The optimal cut-off score for screening at risk patients was 5 with an area under the ROC curve of 0.72. The risk factors more strongly associated with falls were confusion and depression. CONCLUSIONS: As falls of older patients are a common problem in acute care settings it is necessary that the nurses use specific validate and reliable fall risk assessment tools in order to implement the most effective prevention measures. Our findings provided supporting evidence to the choice of the HFRM II to screen older patients at risk of falling in acute care settings. PMID- 20926076 TI - Relationships of mitral annular calcification to cardiovascular risk factors: the Multi-Ethnic Study of Atherosclerosis (MESA). AB - BACKGROUND: Mitral annular calcification (MAC) is a fibrous, degenerative calcification of the mitral valve. The relationship between MAC and cardiovascular disease (CVD) risk factors is not well defined. Thus, we performed a cross-sectional study to determine which CVD risk factors are independently associated with MAC in the Multi-Ethnic Study of Atherosclerosis (MESA). METHODS: MESA includes 6814 women and men ages 45-84 years old without apparent CVD in 4 ethnic groups (12% Chinese, 38% Caucasian, 22% Hispanic, and 28% African American). MAC was defined by presence of calcium in the mitral annulus by cardiac computed tomography at enrollment. Multivariable logistic regression was used to evaluate relationships between MAC and CVD risk factors. RESULTS: The overall prevalence of MAC was 9%. The prevalence of MAC was highest in Caucasians (12%), followed by Hispanics (10%), African Americans (7%) and was lowest in Chinese (5%). Characteristics associated with MAC included age (p<0.01), female gender (p<0.01), increased body mass index (BMI) (p=0.03), and former smoking status (p<0.008). The MAC group had a higher prevalence of hypertension, diabetes mellitus (DM), and family history of heart attack (all p<0.001). After adjusting for all variables, age, female gender, diabetes mellitus, and increased BMI remained strongly associated with MAC. CONCLUSIONS: Age, female gender, DM, and increased BMI were significantly associated with MAC. Prevalence of MAC was strongly associated with female gender and increasing age in all ethnicities. PMID- 20926077 TI - Anti-inflammatory salicylate beneficially modulates pre-existing atherosclerosis through quenching of NF-kappaB activity and lowering of cholesterol. AB - OBJECTIVE: Inflammation plays an important role in all stages of atherosclerosis, but little is known about the therapeutic effects of quenching inflammation in already existing atherosclerotic lesions. Putative beneficial effects of salicylate, an inhibitor of NF-kappaB activation, were studied in mice with established lesions. METHODS: ApoE*3-Leiden mice received a high-cholesterol diet (HC) to establish atherosclerotic lesions. Reference mice (REF) were sacrificed to determine the lesion area at the start of two interventions. In one intervention group HC diet feeding was continued, but the diet contained salicylate (HC+SAL). As salicylate not only quenches inflammation but also reduces plasma cholesterol, a second intervention group was fed a low-cholesterol diet (LC) resulting in cholesterol levels comparable to HC+SAL. The effects of these interventions on lesion area and composition were assessed after 8 and 16 weeks. RESULTS: HC+SAL markedly reduced hepatic NF-kappaB activity compared to REF, and was significantly more effective than LC diet feeding. HC+SAL and LC also quenched aortic NF-kappaB activity. While continuing HC diet typically further increases total lesion area, 16 weeks of intervention with HC+SAL and LC halted further disease progression and resulted in lesion sizes comparable to that of REF. At the same time, lesion composition was significantly improved, particularly with salicylate. Strikingly, HC+SAL resulted in a lower lesional macrophage content and a greater plaque stability index (ratio of collagen to macrophage area) than LC. CONCLUSION: Anti-inflammatory salicylate reduces atherosclerotic macrophage content and increases lesion stability of pre-existing plaques through quenching of NF-kappaB activity and reducing plasma cholesterol. PMID- 20926078 TI - Impact of statin pretreatment on the incidence of plaque rupture in ST-elevation acute myocardial infarction. AB - OBJECTIVE: Several studies in experimental animals have shown that statins stabilize atheromatous plaques by increasing fibrous-cap thickness. However, direct evidence linking the use of statins to the incidence of plaque rupture in humans is lacking. We investigated whether statin treatment before the onset of ST-elevation myocardial infarction (STEMI) influences the incidence of plaque rupture detected by intravascular ultrasound (IVUS). METHODS: The study enrolled 458 patients with STEMI who were admitted within 6h from symptom onset. IVUS interrogation was performed before percutaneous coronary intervention. RESULTS: Plaque ruptures were detected in 262 patients (57%). Patients with statin pretreatment (n=68) had a lower incidence of plaque rupture than those without (37% vs. 61%, p<0.001). Univariate analysis revealed that smoking (p=0.003), lower high-density lipoprotein cholesterol (p=0.001), and a lack of statin pretreatment (p<0.001) were associated with a higher incidence of plaque rupture. Multivariate logistic regression analysis identified statin pretreatment as a negative determinant of plaque rupture independent of age, gender, coronary risk factors, and all other medications (odds ratio 0.35; 95% CI 0.19-0.66, p=0.001). Positive remodeling was also associated with plaque rupture (p<0.001), and the relationship between statin pretreatment and a lower incidence of plaque rupture persisted after adjustment for positive remodeling (odds ratio 0.42; 95% CI 0.22 0.80, p=0.009). CONCLUSIONS: Statin treatment before the onset of STEMI is associated with a lower incidence of plaque rupture, suggesting that the prevention of plaque rupture may be a crucial mechanism underlying clinical benefits associated with statins. PMID- 20926079 TI - Non-invasive assessment of failure torque in rat bones with simulated lytic lesions using computed tomography based structural rigidity analysis. AB - This study applies CT-based structural rigidity analysis (CTRA) to assess failure torque of rat femurs with simulated lytic defects at different locations (proximal and distal femur) and diameters (25% and 50% of the cross-section at the site), and compared the results to those obtained from mechanical testing. Moreover, it aims to compare the correlation coefficients between CTRA-based failure torque and DXA-based aBMD versus actual failure torque. Twenty rats were randomly assigned to four equal groups of different simulated lesions based on size and location. Femurs from each animal underwent micro-computed tomography to assess three-dimensional micro-structural data, torsional rigidity using structural rigidity analysis and dual energy X-ray absorptiometry to assess bone mineral density. Following imaging, all specimens were subjected to torsion. Failure torque predicted from CT-derived structural rigidity measurements was better correlated with mechanically derived failure torque [R(2)=0.85] than was aBMD from DXA [R(2)=0.32]. In summary, the results of this study suggest that computed tomography based structural rigidity analysis can be used to accurately and quantitatively measure the mechanical failure torque of bones with osteolytic lesions in an experimental rat model. Structural rigidity analysis can provide more accurate predictions on maximal torque to mechanical failure than dual energy X-ray absorptiometry based on bone mineral density. PMID- 20926080 TI - Mechanical recovery of dentin following remineralization in vitro--an indentation study. AB - This study sought to gain insights into the steps leading to remineralization and mechanical recovery of hydrated dentin. Mechanical recovery in water was hypothesized to result from effective mineral matrix binding and to occur from the innermost regions outwards due to an increase in the number of nucleation sites. Partially demineralized (0.05 M acetate, pH=5.0, 8h) dentin was remineralized using calcium and phosphate solutions of 10.1 or 9.8 degree of saturation (DS) for hydroxyapatite (pH=7.4) for 4, 8 or 24h. Remineralization used a constant solution composition approach, which allowed for a continuous mineral growth with relatively constant thermodynamic driving forces. Crystal growth rates (R) were calculated using concentrations of calcium and phosphate. Before and after de- and re-mineralization, specimens had their surface and cross section elastic moduli measured using AFM-nanoindentation in water. DS=10.1 provided higher R and higher mechanical recovery at the surface (p<0.0001). Cross sectional measurements showed that subsurface mechanical recovery occurred from the innermost demineralized areas gradually outwards for both groups with no statistical differences at different DS, thus suggesting that remineralization is driven by mineral growth within nucleation sites with preserved collagen fibrils. Further, mechanical recovery appeared to initially obey a heterogeneous pattern, which vanished with time. This study provides evidence of mechanical recovery of hydrated dentin after remineralization and novel insights into the steps leading to mechanical recovery of carious dentin. PMID- 20926081 TI - Evaluation of waist-mounted tri-axial accelerometer based fall-detection algorithms during scripted and continuous unscripted activities. AB - It is estimated that by 2050 more than one in five people will be aged 65 or over. In this age group, falls are one of the most serious life-threatening events that can occur. Their automatic detection would help reduce the time of arrival of medical attention, thus reducing the mortality rate and in turn promoting independent living. This study evaluated a variety of existing and novel fall-detection algorithms for a waist-mounted accelerometer based system. In total, 21 algorithms of varying degrees of complexity were tested against a comprehensive data-set recorded from 10 young healthy volunteers performing 240 falls and 120 activities of daily living (ADL) and 10 elderly healthy volunteers performing 240 scripted ADL and 52.4 waking hours of continuous unscripted normal ADL. Results show that using an algorithm that employs thresholds in velocity, impact and posture (velocity+impact+posture) achieves 100% specificity and sensitivity with a false-positive rate of less than 1 false-positive (0.6 false positives) per day of waking hours. This algorithm is the most suitable method of fall-detection, when tested using continuous unscripted activities performed by elderly healthy volunteers, which is the target environment for a fall-detection device. PMID- 20926082 TI - Liquid chromatography/mass spectrometry compatible approaches for the quantitation of folic acid in fortified juices and cereals using aqueous normal phase conditions. AB - Folic acid was separated under aqueous normal phase (ANP) conditions with Diamond HydrideTM columns and quantitated in fortified cereal and juice matrices using high performance liquid chromatography/ultraviolet absorption (HPLC-UV) and liquid chromatography/mass spectrometry (LC-MS) based methodologies. The folic acid was well-resolved from matrix components under the ANP conditions studied and allowed for the direct analyses of the fortified juices and cereals without the sample cleanup that is often required for other reported LC-based approaches. The calibration curve obtained from the LC-MS analyses demonstrated good linearity (R(2)=0.9997) in the studied concentration range of 0.05-0.5 mg/L. The spiked flour percent recovery was 90% with HPLC-UV and 91% with LC-MS. Spiked juice percent recovery was 102% with LC-MS. However, analyses of juices were unsatisfactory either in terms of recovery or sensitivity. Therefore, analyses of juices will either need to be performed by LC-MS or, if by HPLC-UV, will require sample cleanup. Three cereals and one juice were analyzed with the methods. PMID- 20926083 TI - Rapid affinity purification of erythropoietin from biological samples using disposable monoliths. AB - Identification of post-translational modifications of proteins in biological samples often requires access to preanalytical purification and concentration methods. In the purification step high or low molecular weight substances can be removed by size exclusion filters, and high abundant proteins can be removed, or low abundant proteins can be enriched, by specific capturing tools. In this paper is described the experience and results obtained with a recently emerged and easy to-use affinity purification kit for enrichment of the low amounts of EPO found in urine and plasma specimens. The kit can be used as a pre-step in the EPO doping control procedure, as an alternative to the commonly used ultrafiltration, for detecting aberrantly glycosylated isoforms. The commercially available affinity purification kit contains small disposable anti-EPO monolith columns (6 MUL volume, O7 mm, length 0.15 mm) together with all required buffers. A 24 channel vacuum manifold was used for simultaneous processing of samples. The column concentrated EPO from 20 mL urine down to 55 MUL eluate with a concentration factor of 240 times, while roughly 99.7% of non-relevant urine proteins were removed. The recoveries of Neorecormon (epoetin beta), and the EPO analogues Aranesp and Mircera applied to buffer were high, 76%, 67% and 57%, respectively. The recovery of endogenous EPO from human urine was 65%. High recoveries were also obtained when purifying human, mouse and equine EPO from serum, and human EPO from cerebrospinal fluid. Evaluation with the accredited EPO doping control method based on isoelectric focusing (IEF) showed that the affinity purification procedure did not change the isoform distribution for rhEPO, Aranesp, Mircera or endogenous EPO. The kit should be particularly useful for applications in which it is essential to avoid carry-over effects, a problem commonly encountered with conventional particle-based affinity columns. The encouraging results with EPO propose that similar affinity monoliths, with the appropriate antibodies, should constitute useful tools for general applications in sample preparation, not only for doping control of EPO and other hormones such as growth hormone and insulin but also for the study of post-translational modifications of other low abundance proteins in biological and clinical research, and for sample preparation prior to in vitro diagnostics. PMID- 20926084 TI - Hydrophilic interaction chromatography of intact, soluble proteins. AB - The separation of intact proteins by means of Hydrophilic Interaction Chromatography (HILIC) was demonstrated with human apoA-I, recombinant human apoM, and equine cytochrome C. Five different commercially available HILIC columns were compared. Using one of these columns, different glycosylated isoforms of apoM were separated from each other and from the aglyco-form. PMID- 20926085 TI - The obstruction factor in size-exclusion chromatography. 1. The intraparticle obstruction factor. AB - We report the first of a series of studies on the obstruction factor gamma in size-exclusion chromatography (SEC). Here, using narrow dispersity polymer standards we examine how the intraparticle obstruction factor gamma(p) depends individually on a number of analyte properties, column characteristics, and user defined parameters. Far from being constant, gamma(p) is seen to vary with analyte molar mass and solvent, as well as with the pore size and particle size of the column packing material, sometimes in seemingly counterintuitive manner. Over the limited temperature range accessible to our equipment, however, no statistically significant change in gamma(p) with temperature was discovered. The results presented should be applicable to forms of packed column chromatography other than SEC. The latter technique, however, presents a convenient test bed for quantitative determination of the obstruction factor, due to minimized sorptive mass transfer and longitudinal diffusion contributions to band broadening in most forms of SEC. PMID- 20926086 TI - Rapid automated screening, identification and quantification of organic micro contaminants and their main transformation products in wastewater and river waters using liquid chromatography-quadrupole-time-of-flight mass spectrometry with an accurate-mass database. AB - In this study we have developed and evaluated an analytical method for a rapid automated screening and confirmation of a large number of organic micro contaminants (almost 400) and also the quantification of the positive findings in water samples of different types (surface and wastewaters) using liquid chromatography-electrospray quadrupole-time-of-flight mass spectrometry (LC QTOFMS) based on the use of an accurate-mass database. The created database includes data not only on the accurate masses of the target ions but also on the characteristic in-source fragment ions, isotopic pattern and retention time data. This customized database was linked to commercially available software which extracted all the potential compounds of interest from the LC-QTOFMS raw data of each sample and matched them against the database to search for targeted compounds in the sample. The detailed fragmentation information has also been used as a powerful tool for the automatic identification of unknown compounds and/or transformation products with similar structures to those of known organic contaminants included in the database. The database can be continually enlarged. To confirm identification of compounds which have no fragment ions (or fragments with low intensity/relative abundance) from in-source CID fragmentation or isomers which are not distinguished within full single mass spectra, a "Targeted MS/MS" method is developed. Thereafter, these compounds can be further analyzed using the collision energy (CE) in QTOF-MS/MS mode. Linearity and limits of detection were studied. Method detection limits (MDLs) in effluent wastewater and river waters were, in most cases, lowers or equal to 5 and 2 ng/L, respectively. Only 15 compounds had MDLs between 5 and 50 ng/L in effluent wastewater matrix. We obtained a linearity of the calibration curves over two orders of magnitude. The method has been applied to real samples and the results obtained reveal that most of the pharmaceutically active compounds contained in the created database were present in the water samples with concentrations in the range of ng/L and MUg/L levels and in most of the samples between 2 and 15 pesticides of the 300 contained in the database were also detected. In addition to the compounds included in the database, some degradation products were found, thus revealing the method as a useful tool for the analysis of organic micro-contaminants in waters. PMID- 20926087 TI - Evaluation of the enantioselectivity of glycogen-based dual chiral selector systems towards basic drugs in capillary electrophoresis. AB - Several chiral reagents including cyclodextrins (CDs) and derivatives, crown ethers, proteins, chiral surfactants and polymers have been involved in dual selector systems for enantioseparation of a series of chiral compounds by capillary electrophoresis (CE). In comparison to the chiral reagents above mentioned, there is no report concerning the use of polysaccharides in dual chiral CE system. In this paper we first investigate the enantioselectivity of polysaccharide-based dual selector systems towards some chiral drugs. During our recent work, glycogen belonging to the class of branched polysaccharides has been used as a novel chiral selector in CE. In this study, three glycogen-based dual chiral CE systems have been established for enantiomeric separations of several racemic basic drugs consisting of duloxetine, cetirizine, citalopram, sulconazole, laudanosine, amlodipine, propranolol, atenolol and nefopam. These three dual systems combined glycogen (neutral polysaccharide) with chondroitin sulfate A (CSA, ionic polysaccharide), beta-CD and HP-beta-CD, respectively. It was found that the dual system of glycogen/CSA exhibited good enantioselective properties toward the tested drugs. More importantly, compared to the single selector systems, synergistic effect was observed when glycogen was used with CSA for most of the analytes. This indicated the enhancement of enantioseparation observed for these analytes in glycogen/CSA system might be due to some favorable interaction effects between glycogen and CSA. Moreover, in order to evaluate the stereoselectivity of glycogen/CSA, the influences of buffer pH and selector concentration on enantioseparation of the studied drugs were also investigated. PMID- 20926088 TI - Repeated probing of Southwestern blots using alkaline phosphatase stripping. AB - Southwestern blotting is when a DNA sequence is used to probe DNA-binding proteins on an electrophoretic gel blot. It would be highly desirable to be able to probe a blot repeatedly with different DNA sequences. Alkaline phosphatase can remove 5'-phosphoryl groups from DNA and radiolabeled 5'-(32)P-DNA probes are commonly used in Southwestern blotting. Here is shown that once probed, the radioisotope signal on the blot can be effectively removed by brief digestion with alkaline phosphatase, and the blot can then be repeatedly probed at least six times with different DNA probes. This exceeds the repetitions possible with another commonly used method using SDS. The technique can be used with either one dimensional or multi-dimensional Southwestern blots and does not have a large effect on the phosphorylation state of the blotted proteins. An alternative method using T4 polynucleotide kinase stripping is also introduced but was less well characterized. PMID- 20926089 TI - Determination of cyclic and linear siloxanes in soil samples by ultrasonic assisted extraction and gas chromatography-mass spectrometry. AB - A rapid method, based on sonication-assisted extraction in small columns (SAESC) and subsequent quantification and identification by gas chromatography-mass spectrometry (GC-MS), was developed for the determination of cyclic and linear siloxanes in soil. In the experiments with spiked samples (10-50 ng g(-1)), the recovery of cyclic and linear siloxanes ranged from 87.7 to 108.0% and from 84.9 to 107.6%, respectively. The validated method was used to determine the levels of these compounds in various types of soil samples collected from different locations in Spain. The cyclic siloxanes, decamethylcyclopentasiloxane (D5) and dodecamethylcyclohexasiloxane (D6) were detected in all the soil samples analyzed at concentrations from 9.2 to 56.9 ng g(-1) for D5 and from 5.8 to 27.1 ng g(-1) for D6 in agricultural soils and from 22 to 184 ng g(-1) for D5 and from 28 to 483 ng g(-1) for D6 in industrial soils. The total linear siloxanes concentrations (L5-L14) (sum of the 10 congeners) ranged from 191 to 292 ng g(-1) in agricultural soils and from 1411 to 8532 ng g(-1) in industrial soils. PMID- 20926090 TI - Characterization and identification of steroidal alkaloids in Fritillaria species using liquid chromatography coupled with electrospray ionization quadrupole time of-flight tandem mass spectrometry. AB - Liquid chromatography coupled with electrospray ionization quadrupole time-of flight tandem mass spectrometry (LC/ESI-QTOF-MS/MS) was performed to study the fragmentation behaviors of steroidal alkaloids from Fritillaria species, the antitussive and expectorant herbs widely used in traditional Chinese medicine. We propose, herein, a strategy that combining key diagnostic fragment ions and the relative abundances and amounts of major fragment ions (the ions exceeding 10% in abundance) to distinguish different sub-classes of Fritillaria alkaloids (FAs). It was found that hydrogen rearrangement and induction effects result in ring cleavage of the basic skeletons occurred in the MS/MS process and produced characteristic fragment ions, which are useful for structural elucidation. This method was finally used to investigate the primary steroidal alkaloids in the extracts of eight major Fritillaria species. As a result, 41 steroidal alkaloids (29 cevanine type, 1 jervine type, 6 veratramine type and 5 secosolanidine type alkaloids) were selectively identified in these Fritillaria species. Twenty-six compounds were unambiguously identified by comparing with the reference compounds and 15 compounds were tentatively identified or deduced according to their MS/MS data. Logical fragmentation pathways for different types of FAs have been proposed and are useful for the identification of these types of steroidal alkaloids in natural products especially when there are no reference compounds available. PMID- 20926091 TI - Strategies for the elimination of matrix effects in the liquid chromatography tandem mass spectrometry analysis of the lipophilic toxins okadaic acid and azaspiracid-1 in molluscan shellfish. AB - Considerable efforts are being made worldwide to replace in vivo assays with instrumental methods of analysis for the monitoring of marine biotoxins in shellfish. Analysis of these compounds by the preferred technique of liquid chromatography tandem mass spectrometry (LC-MS/MS) is challenged by matrix effects associated with the shellfish tissues. In methods validation, assessment of matrix interferences is imperative to ensure the validity and accuracy of results being produced. Matrix interferences for the analysis of okadaic acid (OA) and azaspiracid 1 (AZA1) were assessed using acidic methods on electrospray triple stage quadrupole (TSQ) and hybrid quadrupole time of flight (QToF) instruments by the use of matrix matched standards for different tissue types. Using an acidic method no matrix interference and suppression was observed on the TSQ for OA and AZA1 respectively, whilst the opposite was observed on the QToF; matrix enhancement for OA and no matrix interference for AZA1. The suppression of AZAs on the TSQ was found to be due to interfering compounds being carried over from previous injections. The degree of suppression is very much dependant on the tissue type ranging from 15 to 70%. Several strategies were evaluated to eliminate these interferences, including the partitioning of the extract with hexane, optimisation of the chromatographic method and the use of on-line SPE. Hexane clean up did not have any impact on matrix effects. The use of an alkaline method and a modified acidic method eliminated matrix suppression for AZA1 on the TSQ instrument while an on-line SPE method proved to be effective for matrix enhancement of OA on the QToF. PMID- 20926092 TI - Lab on a chip packing of submicron particles for high performance EOF pumping. AB - The packing of submicrometer sized silica beads inside a microchannel was enabled by a novel method which avoids the complication and limitations of generating a frit using conventional approaches and the restriction of flow using a submicrometer sized weir. A micrometer sized weir and two short columns of 5 MUm and 800 nm silica beads packed in succession behind the weir together functioned as a high pressure frit to allow the construction of a primary packed bed of 390 nm silica beads. This packed bed microchannel was tested as an EOF pump, wherein it exhibited superior performance with regards to pressure tolerance, i.e., sustaining good flow rate under extremely high back pressure, and maximal pressure generation. Under a modest applied electric field strength of 150 V/cm, the flow rate against a back pressure of 1200 psi (~8.3 MPa) was 40 nL/min, and the maximal pressure reached 1470 psi (~10 MPa). This work has demonstrated that it is possible to create a high performance packed bed microchannel EOF pump using nanometer sized silica beads, as long as proper care is taken during the packing process to minimize the undesirable mixing of two different sized particles at the boundaries between particle segments and to maximize the packing density throughout the entire packed bed. PMID- 20926093 TI - Temperature dependent dendritic domain shapes in Langmuir monolayers of tetradecanoyl N-ethanolamide at the air-water interface. AB - The effect of temperature on the surface phase behavior of tetradecanoyl N ethanolamide (NHEA-14) in Langmuir monolayers at the air-water interface has been investigated by film balance and Brewster angle microscopy (BAM). It has been observed that dendritic domains are formed in the coexistence region between liquid-expanded (LE) and liquid-condensed (LC) phases at different temperatures. At 10 and 15 degrees C, the domains are four-armed dendrites having wide arms which have a tendency to be fractal while growing in size. At 20 degrees C, five armed dendritic domains are formed. At a temperature higher than 20 degrees C, the domains are mainly six-armed dendrites having very narrow and sharp arms. The formation of dendritic domains should be due to the presence of interfacial hydrogen bonding among the head groups of the amphiphile. Increased dehydration of the head groups with an increase in the temperature should be responsible for the temperature dependency of the dendritic domain shapes in the monolayers of NHEA-14. PMID- 20926094 TI - Multi-nuclear liquid state NMR investigation of the effects of pH and addition of polyethyleneglycol on the long-term hydrolysis and condensation of tetraethoxysilane. AB - The long-time behavior of the hydrolysis and condensation reaction of the tetraethoxysilane (TEOS) pre-solution at different pH values with and without addition of polyethyleneglycol (PEG) for various aging times was characterized by liquid (1)H, (13)C, and (29)Si NMR spectroscopy. After aging, the alcohol is released in the TEOS pre-solution without addition of PEG at pH 3 and 9. On the other hand, the hydrolysis and condensation rates of the TEOS pre-solutions with addition of PEG at pH 3 and 9 increase except for the TEOS pre-solution with addition of PEG 2000 at pH 9. However, the hydrolysis and condensation rates of the TEOS pre-solutions with and without addition of PEG at pH 5 and 7 are almost the same before and after aging. The effects of the pH values, polymer size and aging times on the hydrolysis and condensation reaction of the TEOS pre-solutions are discussed. PMID- 20926095 TI - Facile fabrication of free-standing colloidal-crystal films by interfacial self assembly. AB - This paper reports a rapid and facile method of preparing free-standing colloidal crystals from monodisperse charged polystyrene (PS) microspheres. Mixed solvents (ethanol/water) were used as the dispersion medium in the self-assembly process of colloidal crystals. By a simple "floating self-assembly" method, PS microspheres floated on the surface of liquid and self-assembled into large area of three-dimensional (3D) ordered colloidal crystals within 15 min. Then epichlorohydrin was added in as a cross-linking agent to strengthen the colloidal crystal film. After cross-linking reactions between the microspheres, the obtained colloidal-crystal film was free-standing and could be easily transferred to other substrates. Using tetrabutyl titanate as a titania precursor, 3D porous TiO(2) materials with rodlike skeletal structure were fabricated from the prepared free-standing colloidal crystal. This work provides a facile method to fabricate free-standing colloidal-crystal film, which can be used as an ideal template for the preparation of porous materials. PMID- 20926096 TI - The hydrophobicity of silicone-based oils and surfactants and their use in reactive microemulsions. AB - In this work, for the first time, the Hydrophilic-Lipophilic Difference (HLD) framework for microemulsion formulation has been applied to silicone oils and silicone alkyl polyether surfactants. Based on the HLD equations and recently introduced mixing rules, we have quantified the hydrophobicity of the oils according to the equivalent alkane carbon number (EACN). We have found that, in a reference system containing sodium dihexyl sulfosuccinate (SDHS) as the surfactant, 0.65 centistoke (cSt) and 3.0 cSt silicone oils behave like n dodecane and n-pentadecane, respectively. Silicone alkyl polyether surfactants were found to have characteristic curvatures ranging 3.4-18.9, exceeding that of most non-ionic surfactants. The introduction of methacrylic acid (MAA) and hydroxyethyl methacrylate (HEMA) to the aqueous phase caused a significant negative shift in HLD, indicative of an aqueous phase that is less hydrophilic than pure water. The more hydrophobic surfactants (largest positive curvatures) were used in order to compensate for this effect. These findings have led to the formulation of bicontinuous microemulsions (MUEs) containing silicone oil, silicone alkyl polyether and reactive monomers in aqueous solution. Ternary phase diagrams of these systems revealed the potential for silicone-containing polymer composites with bicontinuous morphologies. These findings have also helped to explain the phase behavior of formulations previously reported in literature, and could help in providing a systematic, consistent approach to future silicone oil based microemulsion formulation. PMID- 20926097 TI - Fabrication of superparamagnetic macroporous Fe3O4 and its derivates using colloidal crystals as templates. AB - In this paper, we reported the preparation of superparamagnetic macroporous Fe(3)O(4) and its derivates using organic colloidal crystal as templates and their catalytic activity for chemical vapor deposition. The poly(styrene-methyl methacrylate-acrylic acid) (P(St-MMA-AA)) copolymer colloids were deposited in an orderly manner onto the silicon surface, together with the infiltration of the Fe(3)O(4) nanoparticles into the interspaces of the colloids. The formed hybrid colloidal crystal subsequently was immersed in tetrahydrofuran to remove the organic components fully to obtain a macroporous Fe(3)O(4) framework with three dimensional porous structure. The macroporous Fe(3)O(4) exhibits superparamagnetism due to the magnetic coupling of Fe(3)O(4) nanoparticles in the structure. Macroporous Fe(2)O(3) and Fe materials were obtained based on oxidization and reduction of the macroporous Fe(3)O(4), respectively. It was demonstrated that the macroporous Fe(3)O(4) materials possess catalytic activity and can induce growth of carbon nanotubes. PMID- 20926098 TI - Construction and deconstruction of multilayer films containing polycarboxybetaine: effect of pH and ionic strength. AB - The influences of pH and NaCl concentration of dipping solutions and the pH and NaCl concentration of disintegration solutions on the disintegration behaviors of poly(4-vinylpyridiniomethanecarboxylate) (PVPMC)/poly(sodium 4-styrenesulfonate) (PSS) (PVPMC/PSS) multilayer films were investigated by ultraviolet-visible spectroscopy (UV-vis), Fourier transform infrared spectroscopy (FT-IR), quartz crystal microbalance (QCM) and atomic force microscopy (AFM). It was found that the disintegration rates and degrees of PVPMC/PSS multilayer films in neutral water could be well controlled by changing pH of dipping solutions and immersion time during the disintegration process. Furthermore, PVPMC/PSS multilayer films could be disintegrated completely and rapidly in pH 8 alkali solution or physiological condition (i.e., 0.15 M NaCl solution). The controllable disintegration of PVPMC/PSS multilayer films was then utilized to fabricate PEC/PSS free-standing multilayer films, in which PEC was a positively charged polyelectrolyte complex made from excessive poly(diallyldimethylammonium) (PDDA) and PSS. The experimental results indicated that the disintegration rates of PVPMC/PSS sacrificial sublayer strongly affected the integrity of the resultant PEC/PSS free-standing multilayer films. Only free-floating PEC/PSS was released from neutral water by disintegrating PVPMC/PSS multilayer sublayers. However, large size flat and tube-like PEC/PSS free-standing multilayer films with good mechanical properties were obtained facilely from pH 8 alkali solution and 0.15 M NaCl solution, respectively. The preparation of such free-standing films at physiological condition may be useful in the biological or medical application. PMID- 20926099 TI - Connecting instances to promote children's relational reasoning. AB - The practice of learning from multiple instances seems to allow children to learn about relational structure. The experiments reported here focused on two issues regarding relational learning from multiple instances: (a) what kind of perceptual situations foster such learning and (b) how particular object properties, such as complexity and similarity, interact with relational learning. Two kinds of perceptual situations were of interest here: simultaneous view, where instances are viewed at once, and sequential view, where instances are viewed one at a time (one right after the other). We examined the influence of particular perceptual situations and object properties using two tests of relational reasoning: a common match-to-sample task, where new instances are compared with a common sample, and a variable match-to-sample task, where new instances are compared with a sample that varies on each trial. Experiments 1 and 2 indicate that simultaneous presentation of even highly dissimilar instances, one simple and one complex, effectively connects them together and improves relational generalization in both match-to-sample tasks. Experiment 3 shows that simple samples are more effective than complex ones in the common match-to-sample task. However, when one instance is not used a common sample and various pairs of instances are simply compared, as in Experiment 4, simple and rich instances are equally effective at promoting relational learning. These results bear on our understanding of how children connect instances and how those initial connections affect learning and generalization. PMID- 20926100 TI - Prospective study of pandysmaturation and adult mental disorder in high-risk and normal-risk offspring. AB - More than 50 years ago, Fish postulated that a special form of early abnormal neurodevelopment, "pandysmaturation", defined a priori as constituting retarded cranial development in the first year of life, combined with delay in early motor milestone attainment, was related to genetic risk for schizophrenia, and was associated with schizophrenia-spectrum disorders in young adulthood. Fish confirmed this in a very small sample. We retested Fish's postulation in a larger prospective study. Pandysmaturation was blindly investigated through medical records and prospective researcher and maternal observations, studying 75 "high risk" offspring of women with a history of schizophrenia or affective psychosis and 91 "normal-risk" offspring. Subjects were studied prospectively from mother's pregnancy to 22 years of age, at which time the offspring were independently assessed for schizophrenia-spectrum and affective disorders. Pandysmaturation (n = 13, with 10 "definite" and 3 "probable" degrees) was significantly related to genetic risk for schizophrenia (Odds Ratio 4.9, p = 0.02) but not to genetic risk for affective disorders (OR 1.2, p = 0.81). Pandysmaturation was significantly associated with schizophrenia-spectrum (OR 6.2, p = 0.02), but not affective (OR 0.9, p = 0.90), disorders in young adulthood. Pandysmaturation was more strongly associated than was retarded cranial development, motor milestone delay, or social/cognitive milestone delay by itself. Pandysmaturation has efficacy as an early life risk-indicator of schizophrenia-spectrum disorder in young adulthood at least in subjects at genetic risk, strengthening the evidence for a generally genetic-based neurodevelopmental model of schizophrenia-spectrum (as contrasted with affective) disorders. Pandysmaturation is a risk-indicator for future schizophrenia-spectrum disorder, for potential use in scientific studies and clinical practice. PMID- 20926101 TI - Ultrastructural differences in rectus sheath of hernia patients and healthy controls. AB - BACKGROUND: The etiology of inguinal hernia remains unclear. Research data indicate the presence of pathologic alterations within the connective tissue; their exact character remains the subject of dispute. The search for new methods to diagnose connective tissue abnormalities, and thoroughly explain the character of the ultrastructural alterations, continues. MATERIALS AND METHODS: The study group included 10 male patients aged 18-60 y (five with primary inguinal hernia and five with acute appendicitis with no history of hernia). A specimen of the rectus muscle sheath was harvested from all of them upon surgery. The tissue samples were fixed and examined by spectrofluorometry and fluorescence microscopy, yielding fluorescence spectra and microscopic fluorescence images. RESULTS: Both techniques have demonstrated significant differences between the biopsy samples harvested from hernia patients and healthy controls. The groups of fluorescence spectra were shifted relative to each other and showed maximum emission at different wavelengths after excitation with 350 nm light (arbitrarily chosen for one of the cross-link proteins). The spectra obtained for healthy controls were more homogenous, while the spectra of the hernia samples differed even between each other. In microscopic images, the difference was a more chaotic distribution of fluorophores in the samples obtained from hernia patients. CONCLUSIONS: The evidence of significant differences between the samples harvested from the same location from hernia patients and healthy controls, found by fluorescence techniques, indicates the presence of abnormalities in the connective tissue forming the rectus muscle sheath. This area is not a part of the hernial defect, therefore, we can assume that the changes can be attributed to a generalized process. PMID- 20926102 TI - Overexpression of p35 in Min6 pancreatic beta cells induces a stressed neuron like apoptosis. AB - Cdk5 activity has been implicated in brain development and the regulation of many neuronal processes. Recently, the expression of p35 and Cdk5 activity has been reported in pancreatic beta cells. Decreased Cdk5 activity enhanced glucose stimulated insulin secretion. This suggests that Cdk5 may play an important role in the regulation of insulin secretion. To further understand how Cdk5 regulates insulin secretion in glucose-stimulated pancreatic beta cells, we first confirmed the presence of a low level of p35 in pancreatic Min6 cells. Next, in a time course experiment in high glucose (25 mM) we showed that endogenous p35 increased gradually accompanied by a 3-fold increase in Cdk5 activity by 16 h. Insulin secretion, however, doubled after 2 h followed by progressive downregulation, negatively correlated with Cdk5 activity. On the other hand, overexpression of p35 in these cells resulted in more than a three-fold increase in Cdk5 activity within 2 h coupled to a 50% reduction in insulin secretion in both high and low (3 mM) glucose. Most significantly, cells overexpressing p35, treated with high glucose for 4 h, showed induction of p25, the p35-derived truncated fragment which hyperactivates Cdk5 in neurons. As a result, insulin secretion was inhibited and cells became apoptotic. Roscovitine or co-infection of dominant negative Cdk5 (dnCdk5) with p35 increased insulin secretion and inhibited apoptosis. These results suggest that the model for deregulation and hyperactivation of Cdk5 in neurodegeneration may apply to the pathology seen in type 2 diabetes (T2DM). It is consistent with the view that Alzheimer's disease and T2DM are linked metabolically and pathologically by Cdk5 in a number of ways. PMID- 20926103 TI - Microscopic polyangiitis presenting with medullary infarct. AB - Microscopic polyangiitis is a small vessel vasculitis which is rarely associated with ischemic stroke. Cerebrovascular disease has rarely been reported in connection with this disease. It may cause fatal hemorrhage, hemorrhagic conversion and multiple lacunar infarcts. We report here a 55-year-old woman with left medullary oblangata infarction without any symptoms of microscopic polyangiitis. During hospitalization, retinal ischemia, mononeuritis multiplex and pulmonary infiltration developed. Sural nerve biopsy was concomitant with small vessel vasculitis. Elevated CRP and sedimentation and positive P-ANCA led to confirmation of a diagnosis of microscopic polyangiitis. Our patient is a rare case of microscopic polyangiitis presenting with medullary infarction. Although the characteristics of this disease are well-known, the first symptom can be a medullary infarction, which has not been reported in literature before. PMID- 20926104 TI - Redo transapical aortic valve implantation: feasibility of a repeat approach through the left ventricular apex. PMID- 20926105 TI - Results of mitral valve repair for Barlow disease (bileaflet prolapse) via right minithoracotomy versus conventional median sternotomy: a randomized trial. AB - OBJECTIVE: The results of mitral repair for complex Barlow valves are adequate and support earlier intervention. It is unknown whether these results are reproducible in the context of minimally invasive surgery via right minithoracotomy. METHODS: We randomized patients with Barlow mitral disease (bileaflet prolapse) to have conventional open repair via median sternotomy (MS group) or minimally invasive (MI group) repair. Repair was done using polytetrafluoroethylene chordal reimplantation for both leaflets. In the MI group, we adopted right minithoracotomy, peripheral cannulation, external aortic clamping, and surgery under direct vision. RESULTS: Both groups comprised 70 patients. The operative and the cardiopulmonary bypass times were significantly longer in the MI group (P = .003 and P = .012). Mitral repair was successful in 98.5% MI patients and 100% MS patients. Operative mortality was comparable. The mean mechanical ventilation time, intensive care unit stay, and hospital stay were lower in the MI group (P = .014, P =.02, and P = .03,). Mean pain score was lower in the MI group at postoperative days 2 and 4. At follow-up, the freedom from moderate (2+) or severe (3+ or 4+) mitral regurgitation was 98% versus 97% (P = .9). Two patients underwent reoperation (1 in each group) for late failure of repair. The Kaplan-Meier analysis confirmed these results. CONCLUSIONS: Our data indicate that the optimal standard-of-care results of mitral repair for complex disease (Barlow) are reproducible in the minimally invasive settings through right minithoracotomy and direct vision. The minimally invasive technique can be proposed for complex mitral disease and early referral of these patients can be encouraged. PMID- 20926106 TI - Temporal changes in Sphingomonas and Mycobacterium populations in mangrove sediments contaminated with different concentrations of polycyclic aromatic hydrocarbons (PAHs). AB - The change in community diversity and structure of the indigenous, dominant, polycyclic aromatic hydrocarbon (PAH)-degrading bacterial genera, Sphingomonas and Mycobacterium, due to contamination in the environment is not very well known. A combination of PCR-DGGE with specific primers and a cultivation dependent microbiological method was used to detect different populations of Sphingomonas and Mycobacterium in mangrove sediments. The structure of the entire bacterial community (including Sphingomonas) did not show a shift due to environmental contamination, whereas the diversity of Mycobacterium populations in mangrove sediments with higher PAH contamination increased from exposure between Day 0 and Day 30. The isolated Mycobacterium strains migrated to the same position as the major bands of the bacterial communities in Mycobacterium specific DGGE. A dioxygenase gene system, nidA, which is commonly found in PAH degrading Mycobacterium strains, was also detected in the more highly contaminated sediment slurries. The present study revealed that Mycobacterium species were the dominant PAH-degraders and played an important role in degrading PAHs in contaminated mangrove sediments. PMID- 20926107 TI - Water for life. PMID- 20926108 TI - [Pulmonary hypertension: the contribution of MDCT to the diagnosis of its different types]. AB - Pulmonary hypertension is characterized by progressive involvement of the pulmonary vessels that leads to increased vascular resistance and consequently to right ventricular failure. Vascular lesions are a common factor in a wide spectrum of diseases, and their result, pulmonary hypertension, is a severe clinical condition with a poor prognosis that worsens the normal course of the diseases to which it is associated (COPD, collagen disease, sarcoidosis, and congenital or acquired heart disease). It is important for pulmonary hypertension to be diagnosed as early as possible because nowadays drugs can reduce mortality and improve the quality of life; furthermore, some types of pulmonary hypertension (e.g., chronic thromboembolism and those associated with some congenital heart diseases like left-to-right shunt) can be treated surgically. In cases of suspected pulmonary hypertension, imaging methods can confirm the diagnosis, suggest a cause, help choose the most appropriate treatment, and monitor the response to treatment. This review describes the approach to pulmonary hypertension using different imaging techniques; special emphasis is given to the role of multidetector CT (MDCT), which makes it possible to study all the organs in the thorax in a single acquisition. We review the radiological signs of pulmonary hypertension and the current (Dana Point) radiological criteria for classifying the type of hypertension based on alterations in the lung parenchyma, mediastinum, pleural spaces, and pericardium, as well as on the study of the chambers of the heart. PMID- 20926109 TI - Advantages and limits of real-time PCR assay and PCR-restriction fragment length polymorphism for the identification of cutaneous Leishmania species in Tunisia. AB - Cutaneous leishmaniasis (CL), a public health problem in Tunisia, is associated to three species: Leishmania (L.) infantum, L. major and L. killicki. Accurate and sensitive procedures for the diagnostic of Leishmania infection and for species identification are required to enable adequate treatment and appropriate control measures. Several PCR-methods are applied for the diagnosis and the identification of Leishmania parasites such as PCR-restriction fragment length polymorphism (PCR-RFLP), DNA sequencing, hybridization probes and real-time PCR (RT-PCR). In this study, PCR-RFLP and RT-PCR were performed on skin scrapings from 27 patients with confirmed CL by microscopic examination, in order to compare their usefulness and efficiency for identification of Leishmania species in routine diagnostic laboratories. Identification of Leishmania species was successfully achieved in 96.3% and 81.5% respectively. Agreement between using internal transcribed spacer 1 (ITS1)-PCR-RFLP and kDNA-RT-PCR assays was 70% (19/27). Characterization problems using RT-PCR were mainly due to the difficulties in analyzing the melting temperatures. ITS1-PCR-RFLP and kDNA-RT-PCR presented an interesting alternative to conventional methods for the identification of Leishmania parasites from clinical samples. Both PCR assays can be used in a routine diagnostic, however, further prospective studies including largest sampling, are required to determine their performances in a routine use. PMID- 20926110 TI - Classical swine H1N1 influenza viruses confer cross protection from swine-origin 2009 pandemic H1N1 influenza virus infection in mice and ferrets. AB - The hemagglutinin of the 2009 pandemic H1N1 influenza virus is a derivative of and is antigenically related to classical swine but not to seasonal human H1N1 viruses. We compared the A/California/7/2009 (CA/7/09) virus recommended by the WHO as the reference virus for vaccine development, with two classical swine influenza viruses A/swine/Iowa/31 (sw/IA/31) and A/New Jersey/8/1976 (NJ/76) to establish the extent of immunologic cross-reactivity and cross-protection in animal models. Primary infection with 2009 pandemic or NJ/76 viruses elicited antibodies against the CA/7/09 virus and provided complete protection from challenge with this virus in ferrets; the response in mice was variable and conferred partial protection. Although ferrets infected with sw/IA/31 virus developed low titers of cross-neutralizing antibody, they were protected from pulmonary replication of the CA/7/09 virus. The data suggest that prior exposure to antigenically related H1N1 viruses of swine-origin provide some protective immunity against the 2009 pandemic H1N1 virus. PMID- 20926111 TI - Virus inactivation by silver doped titanium dioxide nanoparticles for drinking water treatment. AB - Photocatalytic inactivation of viruses and other microorganisms is a promising technology that has been increasingly utilized in recent years. In this study, photocatalytic silver doped titanium dioxide nanoparticles (nAg/TiO(2)) were investigated for their capability of inactivating Bacteriophage MS2 in aqueous media. Nano-sized Ag deposits were formed on two commercial TiO(2) nanopowders using a photochemical reduction method. The MS2 inactivation kinetics of nAg/TiO(2) was compared to the base TiO(2) material and silver ions leached from the catalyst. The inactivation rate of MS2 was enhanced by more than 5 fold depending on the base TiO(2) material, and the inactivation efficiency increased with increasing silver content. The increased production of hydroxyl free radicals was found to be responsible for the enhanced viral inactivation. PMID- 20926113 TI - Benzyl-penicillin (Penicillin G) transformation in aqueous solution at low temperature under controlled laboratory conditions. AB - Antibiotics are released into the environment in a variety of ways: via wastewater effluent as a result of incomplete metabolism in the body after use in human therapy, as runoff after use in agriculture, through improper disposal by private households or hospitals or through insufficient removal by water treatment plants. Unlike in most European countries, in Arctic regions effluents are not suitably treated prior to their release into the aquatic environment. Also, many of the scattered human settlements in remote regions of the Arctic do not possess sewage treatment facilities and pharmaceutical residues therefore enter the aqueous environment untreated. Only limited data are available on the biodegradation of antibiotics under Arctic conditions. However, such information is needed to estimate the potential harm of antibiotics for the environment. Pen G is used in this study since it is a widely prescribed antibiotic compound whose environmental properties have not yet been investigated in detail. Thus, for a very first assessment, the OECD approved biodegradation Zahn-Wellens test (ZWT, OECD 302 B) was used to study biodegradation and non-biotic elimination of the antibiotic Benzyl-penicillin (Pen-G) at different temperatures (5 degrees C, 12.5 degrees C and 20 degrees C). The testing period was extended from the OECD standard of 28-42d. In addition to dissolved organic carbon (DOC), Pen-G levels and major transformation products were recorded continuously by LC-ion-trap MS/MS. DOC monitoring revealed considerable temperature dependence for the degradation process of Pen-G. DOC loss was slowest at 5 degrees C and considerably faster at 12.5 degrees C and 20 degrees C. In the initial step of degradation it was found that Pen-G was hydrolyzed. This hydrolyzed Pen-G was subsequently further degraded by decarboxylation, the result of which was 2-(5,5 dimethyl-1,3-thiazolidin-2-yl)-2-(2-phenylacetamido)acetic acid. Furthermore, direct elimination of 2-phenyl-acetaldehyde from the hydrolyzed and decarboxylated Pen-G also led to the formation of 2-[amino(carboxy)methyl]-5,5 dimethyl-1,3-thiazolidone-4-carboxylic acid. Since biodegradation slows down considerably at a low temperature, the resulting transformation products had considerably longer residence times at 5 degrees C compared to higher temperature conditions within the 42-d experiment. The results presented here clearly demonstrate that a risk assessment for pharmaceuticals present in low ambient temperature environments (i.e. the Arctic) cannot be based on test results obtained under standard laboratory conditions (i.e. 20 degrees C ambient temperatures). PMID- 20926112 TI - Influence of an additional amino group on the potency of aminoadamantanes against influenza virus A. II - Synthesis of spiropiperazines and in vitro activity against influenza A H3N2 virus. AB - Spiro[piperidine-2,2'-adamantane] 4 is one of the most potent synthetic anti influenza A aminoadamantanes or other cage structure amines tested so far. Based on previous results Tataridis et al. (2007) [5h] which demonstrate the boost of in vitro potency by the presence of an additional amino group, we examined whether the incorporation of a second amino group into this heterocycle would increase the anti-influenza A virus activity. The new synthetic molecules 5-7 are capable of forming two hydrogen bonds within the receptor. We identified the diamino derivatives 5 and 6, which are active against influenza A H3N2 virus although less potent than amantadine and its equipotent spiropiperidine 4. PMID- 20926114 TI - Characterization of trace element geochemistry in continuous flow-through microcosms: a preliminary step to environmentally meaningful ecotoxicological experiments. AB - The increasing use of freshwater/sediment microcosms in geochemical and ecotoxicological studies requires additional efforts to characterize and understand their functioning and the main parameters that can influence the pollutants' behavior and bioavailability inside the microcosms themselves. In this study, we investigated the geochemical behavior of four elements (Cr(III), Cu, Cd, and Pb) in microcosms containing one type of natural water and sediment. The microcosms were operated under flow-through conditions with continuous metal spiking (2.5-40 MUgL(-1) for Cr(III) and Pb; 1.25-20 MUgL(-1) for Cu and Cd) over a period of 1 month. During this period, metal concentrations and partitioning between colloidal and truly dissolved phases in the microcosm water columns showed very little variability indicating that the system rapidly reached and maintained a steady state. Metal concentrations in pore waters also showed little variability, while Cd, Cr, and Pb levels in the top layer of sediments increased linearly from day 0 to day 28 (no significant variations in sedimentary Cu levels were observed). These features make this type of microcosms particularly suitable for ecotoxicological studies with zooplanktonic or epibenthic organisms. Characterizing the geochemical properties of microcosms provides critical information for properly interpreting microcosms-based ecotoxicity data and for reducing uncertainty in laboratory-to-field extrapolation. PMID- 20926115 TI - Letter to the editor re Lettmeier et al. (2010): proposal for a revised reference concentration (RfC) for mercury vapour in adults, Sci Total Environ (2010, doi:10.1016/j.scitotenv.2010.04.027). PMID- 20926116 TI - Coagulation responses after a submaximal exercise in sickle cell trait carriers. PMID- 20926117 TI - PLA2G7 gene polymorphisms and coronary heart disease risk: a meta-analysis. AB - INTRODUCTION: Variants of PLA2G7 gene have been reported to be associated with coronary heart disease (CHD) since ten years ago, but the available data on this relationship are inconsistent. A meta-analysis was conducted to assess the effect of PLA2G7 gene on CHD. MATERIALS AND METHODS: Association studies were identified from the databases of PubMed, EMbase, Chinese National Knowledge Infrastructure (CNKI) and Wanfang by two investigators and pooled effects (odds ratio (OR), together with 95% confidence interval (CI)) were calculated. RESULTS: 14 association studies focusing on three polymorphisms (A379V, V279F and R92H) in PLA2G7 gene and risk of CHD were included in meta-analysis, covering a total of 8,280 cases and 5,656 controls. Concerning R92H, a significantly increased CHD risk was observed in recessive model, with an OR of 1.31(1.02, 1.68). Nevertheless, combined analyses of studies of the A379V and V279F variants showed no significant overall association with CHD, yielding ORs of 0.99(0.85, 1.15) and 1.09(0.88, 1.35) in allelic analysis, with strong evidence of heterogeneity. Similar results were also obtained in dominant and recessive models. CONCLUSIONS: The results indicate 92H allele had probably increased the risk of CHD, while the hypothesized effects of A379V and V279F polymorphisms on CHD cannot be confirmed in present data. However, given the limited number of studies and the potential biases, the influence of these polymorphisms on CHD risk needs further investigation. PMID- 20926118 TI - Resveratrol, a phytoestrogen found in red wine, down-regulates protein S expression in HepG2 cells. AB - INTRODUATION: Resveratrol, a phytoestrogen present at a high concentration in red wine, has been reported to possess many health benefit effects that are protective against age-related diseases. Protein S (PS), an important anticoagulant factor in the protein C (PC) anticoagulant pathway, is mainly synthesized by hepatocytes, and its plasma level is decreased in high-estrogen conditions such as pregnancy and oral contraceptive use. The aim of this study was to investigate whether resveratrol affects PS expression in HepG2 cells. MATERIALS AND METHODS: The secreted and intracellular levels of PS were determined by an enzyme-linked ligandsorbent assay and Western blotting. The mRNA expressions of PS, PC and beta chain of C4b-binding protein (C4BP-beta) were analyzed by reverse transcription-polymerase chain reaction. The PS gene promotor activities in HepG2 cells transiently expressing estrogen receptor (ER) alpha were examined by a luciferase reporter assay. RESULTS: Resveratrol dose- and time dependently down-regulated the PS expression in HepG2 cells at a transcriptional level, resulting in a significant decrease in secreted PS; however, the PC and C4BP-beta mRNA expressions were not affected. This action of resveratrol was not mediated through either the ER signaling or those of mitogen-activated protein kinases and protein kinase C. Piceatannol, a hydroxylated metabolite of resveratrol, and genistein, an isoflavone found in soy products, also down regulated the PS expression. CONCLUSIONS: Resveratrol down-regulates the PS expression in HepG2 cells in an ER-independent manner, and the two phenolic hydroxyls at carbon-3 and -5 of resveratrol may be involved in this function. PMID- 20926119 TI - Retrievable inferior vena cava filters are not getting retrieved: where is the gap? AB - OBJECTIVE: The purpose of this study is to assess the retrieval rate and the predictors of successful retrieval of Retrievable Inferior Vena Cava (RIVC) filters. METHODS: We retrospectively reviewed the medical records of adult patients who had RIVC filter placements from 2004-2008. We excluded patients who died or were lost to follow-up and those who refused or had unsuccessful retrieval. We collected demographic and clinical data including indications for placement and follow-up. Successful retrieval was defined as objective evidence of retrieval by medical records. RESULTS: Over a 4 year period, we identified 351 patients who had RIVC filter placements. We excluded 99 patients (65 died, 24 decided to leave filter in place, 7 had unsuccessful retrieval and 3 lost follow up). Majority of the filters were placed for surgical patients (161, 63.9%). Of 252 eligible patients for retrieval, only 47 filters were successfully retrieved yielding a retrieval rate of 18.7%. We identified three predictors for successful retrieval: Male gender, home discharge and follow up with procedural service. CONCLUSION: In this large cohort we found that the retrieval rate of retrievable IVCF is extremely low consistent with national statistics. Male patients, patients who were discharged home and patients who were followed by the procedural service had higher chance of successful retrieval. We recommend that procedural service placing the filter should ascertain adequate follow-up. We are not certain why more males had successful retrieval than females. Further studies are necessary to investigate this finding. PMID- 20926120 TI - Incidence of cytomegalovirus-associated thrombosis and its risk factors: a case control study. AB - INTRODUCTION: Cytomegalovirus (CMV)-associated thrombosis has been reported sporadically in the medical literature until now. However, thrombosis incidence and its risk factors have never been studied in a cohort of patients with acute CMV infection. MATERIALS AND METHODS: A retrospective case-control study. Medical charts and imaging study reports of all consecutive patients diagnosed with acute CMV infection during the years 2005-2006 in a tertiary medical center were reviewed for the presence of arterial and/or venous thromboses, and their acquired as well as inherited predispositions. The control group included age matched and sex-matched consecutive patients, in whom acute CMV infection was excluded. Laboratory tests used for acute CMV infection diagnosis/exclusion were also matched, including serology, antigenemia, and PCR. RESULTS: Included were 140 patients with acute CMV infection (study group) and 140 consecutive matched patients in whom acute CMV infection was excluded (control group). Among the control group, none of the patients had thrombosis, while among the study group, nine (6.4%; p=0.003) patients had thrombosis: five (3.6%; p=0.025) patients had arterial thrombosis and four (2.9%; p=0.045) patients had venous thrombosis. Binary logistic regression analysis showed that acute CMV infection was independently associated with thrombosis among the whole cohort (p=0.004), while use of oral contraceptives/hormones or pregnancy were independently associated with thrombosis among patients with acute CMV infection (p=0.043). CONCLUSIONS: Thrombosis in patients with acute CMV infection is not rare. Acute CMV infection is associated with thrombosis independent of other risk factors for thrombosis. We hope to raise physician's awareness to the association between acute CMV infection and thrombosis. PMID- 20926121 TI - Regarding the manuscript of Huang et al. published in Acta Histochemica (doi:10.1016/j.acthis.2010.06.003). PMID- 20926122 TI - Decreased expression of CD36 in circumvallate taste buds of high-fat diet induced obese rats. AB - Mammals spontaneously prefer lipid rich foods. Overconsumption of high-fat diet leads to obesity and related diseases. Recent findings indicate that taste may participate in the orosensory perception of dietary lipids and the fatty taste may contribute to a preference for and excessive consumption of dietary fat. CD36, a trans-membrane glycoprotein, which is located in the taste buds of circumvallate papillae of rodents, appears to be a plausible receptor for this fatty taste. Obese subjects present a stronger preference for fatty foods, though the mechanisms involved are complex and are not fully investigated. Our data from immunofluorescence and real-time RT-PCR showed that the expression levels of CD36 in circumvallate taste buds were significantly lower in high-fat diet induced obese rats as compared with that of control rats fed a normal diet. These results suggest that decreased expression of CD36 in circumvallate taste buds of high-fat diet induced obese rats may be associated with diminished fatty taste sensitivity and in order to compensate the preference for dietary fat, rats consume more fatty foods. Therapeutic strategies designed to alter or manipulate CD36 expression or function in taste buds may have important implications in treating obesity and related diseases. PMID- 20926123 TI - The value of p16ink4a expression by fluorescence in situ hybridization in triage for high risk HPV positive in cervical cancer screening. AB - OBJECTIVES: The aim of this study is to evaluate the effect of fluorescence in situ hybridization (FISH) detection for p16ink4a expression as an alternative triage for high risk HPV positive women in cervical cancer screening. METHODS: Totally 191 cervical cell specimens from women with HPV positive were collected. The p16ink4a expression by FISH and liquid-based thin-layer cytology was performed and followed by colposcopy with or without biopsied histologic examination for all participants. The relationship between p16ink4a expression and histologic diagnosis, as well as cytology was analyzed. RESULTS: The positive rate of p16ink4a was 5.35% in normal or inflammation cases, 56.67% in CIN 1, 83.78% in CIN 2-3, 100.00% in carcinoma, respectively, with a significance between =CIN 2 (P<0.001). The p16ink4a expression presented a concordance trend as cytology grading, with a positive rate of 9.28% in NILM, 33.33% in ASCUS, 53.37% in LSIL, 81.25% in ASC-H, and 95% in HSIL, respectively. Compared with cytology, FISH detection for p16ink4a had a higher accuracy (84.8% vs. 74.34%), higher sensitivity (87.75% vs. 52.00%) and similar specificity (83.84% vs. 88.79%) for predicting >=CIN 2 lesions. CONCLUSIONS: FISH detection specific to p16ink4a presents a high consistency with cytologic grading and has a higher accuracy for predicting high grade CIN than cytology in high risk HPV positive women. Our findings suggest that FISH detection for p16ink4a is a potential alternative triage for high-risk HPV positive women in cervical cancer screening. PMID- 20926124 TI - Vitamin D receptor binds to the epsilon germline gene promoter and exhibits transrepressive activity. AB - BACKGROUND: Recently, an increased incidence of allergic diseases has been associated with vitamin D deficiency. We demonstrated previously that calcitriol, the active form of vitamin D, inhibits epsilon germline transcription, a prerequisite for IgE production. However, the underlying mechanisms remain unexplored. OBJECTIVE: We sought to investigate whether the epsilon germline gene promoter (Iepsilon) represents a primary vitamin D receptor (VDR) target. Therefore we investigated VDR binding to Iepsilon, analyzed VDR-complex composition in more detail, and delineated its functional consequences. METHODS: The VDR binding to Iepsilon in human B cells, the composition of the VDR recruited complex, and the acetylation pattern were investigated by means of chromatin immunoprecipitation. The calcitriol-mediated action on Iepsilon was analyzed by using a reporter gene assay. RESULTS: We demonstrate that Iepsilon is a possible VDR target. Calcitriol-activated VDR binds together with retinoid X receptor alpha to the Iepsilon region. The heterodimer interacts with silencing mediator for retinoid and thyroid hormone receptors, which recruits histone deacetylase (HDAC) 1 and HDAC3. The inhibition of silencing mediator for retinoid and thyroid hormone receptors or HDACs reversed the site-specific deacetylation of histones 3 and 4 and the calcitriol-driven inhibition of the epsilon germline transcription. The VDR-complex transrepressive actions on Iepsilon were confirmed in a reporter assay. CONCLUSION: We show here that inhibition of IgE production by calcitriol is mediated by its transrepressive activity through the VDR corepressor complex affecting chromatin compacting around the Iepsilon region. Our findings shed new light on mechanisms of VDR transrepression and understanding of IgE regulation. PMID- 20926125 TI - Uniform definition of asthma severity, control, and exacerbations: document presented for the World Health Organization Consultation on Severe Asthma. AB - Asthma is a global health problem affecting around 300 million individuals of all ages, ethnic groups and countries. It is estimated that around 250,000 people die prematurely each year as a result of asthma. Concepts of asthma severity and control are important in evaluating patients and their response to treatment, as well as for public health, registries, and research (clinical trials, epidemiologic, genetic, and mechanistic studies), but the terminology applied is not standardized, and terms are often used interchangeably. A common international approach is favored to define severe asthma, uncontrolled asthma, and when the 2 coincide, although adaptation may be required in accordance with local conditions. A World Health Organization meeting was convened April 5-6, 2009, to propose a uniform definition of severe asthma. An article was written by a group of experts and reviewed by the Global Alliance against Chronic Respiratory Diseases review group. Severe asthma is defined by the level of current clinical control and risks as "Uncontrolled asthma which can result in risk of frequent severe exacerbations (or death) and/or adverse reactions to medications and/or chronic morbidity (including impaired lung function or reduced lung growth in children)." Severe asthma includes 3 groups, each carrying different public health messages and challenges: (1) untreated severe asthma, (2) difficult-to-treat severe asthma, and (3) treatment-resistant severe asthma. The last group includes asthma for which control is not achieved despite the highest level of recommended treatment and asthma for which control can be maintained only with the highest level of recommended treatment. PMID- 20926126 TI - Quality of life and pets. PMID- 20926127 TI - Intrinsic and extrinsic motivation in early adolescents' friendship development: friendship selection, influence, and prospective friendship quality. AB - Friendships are essential for adolescent social development. However, they may be pursued for varying motives, which, in turn, may predict similarity in friendships via social selection or social influence processes, and likely help to explain friendship quality. We examined the effect of early adolescents' (N = 374, 12-14 years) intrinsic and extrinsic friendship motivation on friendship selection and social influence by utilizing social network modeling. In addition, longitudinal relations among motivation and friendship quality were estimated with structural equation modeling. Extrinsic motivation predicted activity in making friendship nominations during the sixth grade and lower friendship quality across time. Intrinsic motivation predicted inactivity in making friendship nominations during the sixth, popularity as a friend across the transition to middle school, and higher friendship quality across time. Social influence effects were observed for both motives, but were more pronounced for intrinsic motivation. PMID- 20926128 TI - Development and in vivo evaluation of an oral drug delivery system for paclitaxel. AB - The aim of the present study was to investigate the effect of poly(acrylic acid) cysteine (PAA-cysteine) exhibiting a molecular mass of 100 and 250 kDa and reduced glutathione (GSH) on the absorption of the P-glycoprotein (P-gp) and cytochrome P450 (CYP450) substrate paclitaxel in vitro and in vivo. In vitro transport studies were performed with Caco-2 monolayers. Furthermore, the delivery system based on PAA-cysteine, GSH and paclitaxel was evaluated in vivo in rats. In vitro, the formulation comprising 0.5% (m/v) PAA-cysteine (100 kDa)/0.5% (m/v) GSH improved the transport of paclitaxel 6.7-fold (P(app) = 8.7 +/- 1.3 * 10(-6) cm/s) in comparison to paclitaxel itself serving as buffer only control (P(app) = 1.3 +/- 0.4 * 10(-6) cm/s). Moreover, in the presence of the formulation containing 0.5% (m/v) PAA-cysteine (250 kDa)/0.5% (m/v) GSH paclitaxel absorption was even 7.4-fold (P(app) = 9.7 +/- 0.3 * 10(-6) cm/s) improved in comparison to the buffer only control. In vivo, the oral administration of formulations containing 1 mg of paclitaxel, 1 mg of GSH and 8 mg of PAA-cysteine (100 kDa or 250 kDa) resulted in an improved paclitaxel plasma concentration and bioavailability. The area under the plasma concentration-time curve (AUC(0-8)) of paclitaxel was 4.7-fold and 5.7-fold improved in comparison to the oral formulation containing paclitaxel alone, respectively. Moreover, c(max) was improved by 6.3-fold and even 7.3-fold in comparison to the oral formulation containing paclitaxel alone, respectively. Thus, according to the achieved results it is suggested that PAA-cysteine in combination with GSH would be a potentially valuable tool for improving the oral bioavailability of P-gp and CYP450 substrates such as paclitaxel. PMID- 20926129 TI - Tocopheryl oligochitosan-based self assembling oligomersomes for siRNA delivery. AB - Amphiphilic alpha-tocopherol oligochitosan conjugates were constructed by conjugating alpha-tocopherol succinate to water soluble oligochitosans with various molecular weights. In aqueous medium, the tocopherol oligochitosan conjugates self-assembled to single layered oligomersomes. The sizes of alpha tocopherol-oligochitosan-based oligomersomes (TCOsomes) could be controlled by chain lengths of oligochitosans. The mean sizes of TCOsomes were 220 and 377 nm as the sizes of oligochitosans were 4000 and 12,500, respectively. For all TCOsomes formed in this study, polydispersity indexes were in the ranges of 0.111 0.256. Cryo-TEM images showed clear thickening in the unilamellar layer of TCOsomes upon complexation with siRNAs. Zeta potentials decreased as the ratios of siRNA/TCOsomes increased. TCOsomes self-assembled from tocopherol oligochitosan 4K (TCOsome(4K)) significantly enhanced the cellular uptake of siRNAs (>98%), and reduced the expression of target proteins more effectively than did Lipofectamine 2000. In tumor xenografted mice, the intratumoral administration of siMcl-1 using TCOsomes substantially silenced the expression of Mcl-1 and prevented the growth of tumor. The hematoxylin-eosin staining showed the apoptosis of cells in the tissues of the mice treated with siMcl 1/TCOsome(4K) complexes, but not with siGL2/TCOsome(4K) complexes. The self assembling and size-controllable oligomersomes might be suitable for effective in vivo delivery of siRNAs. PMID- 20926130 TI - The biological properties of iron oxide core high-density lipoprotein in experimental atherosclerosis. AB - Lipoproteins are a family of plasma nanoparticles responsible for the transportation of lipids throughout the body. High-density lipoprotein (HDL), the smallest of the lipoprotein family, measures 7-13 nm in diameter and consists of a cholesteryl ester and triglyceride core that is covered with a monolayer of phospholipids and apolipoproteins. We have developed an iron oxide core HDL nanoparticle (FeO-HDL), which has a lipid based fluorophore incorporated in the phospholipid layer. This nanoparticle provides contrast for optical imaging, magnetic resonance imaging (MRI) and transmission electron microscopy (TEM). Consequently, FeO-HDL can be visualized on the anatomical, cellular and sub cellular level. In the current study we show that the biophysical features of FeO HDL closely resemble those of native HDL and that FeO-HDL possess the ability to mimic HDL characteristics both in vitro as well as in vivo. We demonstrate that FeO-HDL can be applied to image HDL interactions and to investigate disease settings where HDL plays a key function. More generally, we have demonstrated a multimodal approach to study the behavior of biomaterials in vitro as well as in vivo. The approach allowed us to study nanoparticle dynamics in circulation, as well as nanoparticle targeting and uptake by tissues and cells of interest. Moreover, we were able to qualitatively assess nanoparticle excretion, critical for translating nanotechnologies to the clinic. PMID- 20926131 TI - The biocompatibility of titanium cardiovascular devices seeded with autologous blood-derived endothelial progenitor cells: EPC-seeded antithrombotic Ti implants. AB - Implantable and extracorporeal cardiovascular devices are commonly made from titanium (Ti) (e.g. Ti-coated Nitinol stents and mechanical circulatory assist devices). Endothelializing the blood-contacting Ti surfaces of these devices would provide them with an antithrombogenic coating that mimics the native lining of blood vessels and the heart. We evaluated the viability and adherence of peripheral blood-derived porcine endothelial progenitor cells (EPCs), seeded onto thin Ti layers on glass slides under static conditions and after exposure to fluid shear stresses. EPCs attached and grew to confluence on Ti in serum-free medium, without preadsorption of proteins. After attachment to Ti for 15 min, less than 5% of the cells detached at a shear stress of 100 dyne / cm(2). Confluent monolayers of EPCs on smooth Ti surfaces (Rq of 10 nm), exposed to 15 or 100 dyne/cm(2) for 48 h, aligned and elongated in the direction of flow and produced nitric oxide dependent on the level of shear stress. EPC-coated Ti surfaces had dramatically reduced platelet adhesion when compared to uncoated Ti surfaces. These results indicate that peripheral blood-derived EPCs adhere and function normally on Ti surfaces. Therefore EPCs may be used to seed cardiovascular devices prior to implantation to ameliorate platelet activation and thrombus formation. PMID- 20926133 TI - Homer regulation of native plasma membrane calcium channels in A431 cells. AB - Homers are adapter proteins that play a significant role in the organization of calcium signaling protein complexes. Previous functional studies linked Homer proteins to calcium influx in nonexcitable cells. These studies utilized calcium imaging or whole-cell current recordings. Because of limited resolution of these methods, an identity of Homer-modulated ion channels remained unclear. There are several types of plasma membrane calcium influx channels in A431 cells. In the present study, we demonstrated that Homer dissociation resulted in specific activation of I(min) channels but not of I(max) channels in inside-out patches taken from A431 cells. In contrast, inositol 1,4,5-trisphosphate activated both I(min) and I(max) channels in inside-out patches. Short (1a) and long (1c) forms of Homer had different effects on I(min) channel activity. Homer 1a but not Homer 1c activated I(min) in the patches. This study indicates that I(min) channels are specifically regulated by Homer proteins in A431 cells. PMID- 20926132 TI - Multilayered silk scaffolds for meniscus tissue engineering. AB - Removal of injured/damaged meniscus, a vital fibrocartilaginous load-bearing tissue, impairs normal knee function and predisposes patients to osteoarthritis. Meniscus tissue engineering solution is one option to improve outcomes and relieve pain. In an attempt to fabricate knee meniscus grafts three layered wedge shaped silk meniscal scaffold system was engineered to mimic native meniscus architecture. The scaffolds were seeded with human fibroblasts (outside) and chondrocytes (inside) in a spatial separated mode similar to native tissue, in order to generate meniscus-like tissue in vitro. In chondrogenic culture in the presence of TGF-b3, cell-seeded constructs increased in cellularity and extracellular matrix (ECM) content. Histology and Immunohistochemistry confirmed maintenance of chondrocytic phenotype with higher levels of sulfated glycosaminoglycans (sGAG) and collagen types I and II. Improved scaffold mechanical properties along with ECM alignment with time in culture suggest this multiporous silk construct as a useful micro-patterned template for directed tissue growth with respect to form and function of meniscus-like tissue. PMID- 20926134 TI - Ionotropic NMDA and P2X1/5 receptors mediate synaptically induced Ca2+ signalling in cortical astrocytes. AB - Local, global and propagating calcium (Ca(2+)) signals provide the substrate for glial excitability. Here we analyse Ca(2+) permeability of NMDA and P2X(1/5) receptors expressed in cortical astrocytes and provide evidence that activation of these receptors trigger astroglial Ca(2+) signals when stimulated by either endogenous agonists or by synaptic release of neurotransmitters. The Ca(2+) permeability of the ionotropic receptors was determined by reversal potential shift analysis; the permeability ratio P(Ca)/P(K) was 3.1 for NMDA receptors and 2.2 for P2X(1/5) receptors. Selective stimulation of ionotropic receptors (with NMDA and alpha,beta-methyleneATP) in freshly isolated cortical astrocytes induced ion currents associated with transient increases in cytosolic Ca(2+) concentration ([Ca(2+)](i)). Stimulation of neuronal afferents in cortical slices triggered glial synaptic currents and [Ca(2+)](i) responses, which were partially blocked by selective antagonists of NMDA (D-AP5 and UBP141) and P2X(1/5) (NF449) receptors. We conclude that ionotropic receptors contribute to astroglial Ca(2+) signalling and may provide a specific mechanism for fast neuronal-glial signalling at the synaptic level. PMID- 20926135 TI - Baseline predictors of visual acuity and retinal thickness outcomes in patients with retinal vein occlusion: Standard Care Versus COrticosteroid for REtinal Vein Occlusion Study report 10. AB - OBJECTIVE: To investigate baseline factors associated with visual acuity and central retinal thickness outcomes in patients with macular edema secondary to retinal vein occlusion in the Standard Care versus COrticosteroid for REtinal Vein Occlusion (SCORE) Study. DESIGN: Two multicenter, randomized clinical trials: one evaluating participants with central retinal vein occlusion (CRVO) and one evaluating participants with branch retinal vein occlusion (BRVO). PARTICIPANTS: Participants with follow-up data of 1 year or more, including 238 with CRVO and 367 with BRVO. METHODS: Visual acuity was measured by the electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) method, and central retinal thickness was measured by optical coherence tomography (OCT). Regression analysis related these outcomes to 20 baseline measures. Multiple P values were adjusted to control the false discovery rate. MAIN OUTCOME MEASURES: Outcome measures of visual acuity letter score included absolute change from baseline, a gain of >= 15 from baseline, and a loss of >= 15 from baseline. Outcome measures of center point thickness included absolute change from baseline, a measurement of <= 250 MUm, and a measurement of >= 500 MUm. Outcomes were assessed at 1 and 2 years. RESULTS: For CRVO and BRVO, younger age was associated with improved visual acuity and central retinal thickness outcomes. For CRVO, triamcinolone treatment and less severe anatomic abnormalities of the retina (center point thickness and areas of retinal hemorrhage, thickening, and fluorescein leakage) were predictive of better visual acuity outcomes. For BRVO, no history of coronary artery disease was predictive of improved visual acuity outcomes. For center point thickness outcomes, shorter duration of macular edema was associated with improvement in both disease entities. For CRVO, higher baseline visual acuity letter score was predictive of favorable OCT outcomes. For BRVO, lower baseline visual acuity letter score, presence of dense macular hemorrhage, and no prior grid photocoagulation were predictive of favorable OCT outcomes. CONCLUSIONS: Several factors were predictive of better visual acuity outcomes and more favorable OCT outcomes, including younger age and shorter duration of macular edema, respectively. These factors may assist clinicians in predicting disease course for patients with CRVO and BRVO. PMID- 20926136 TI - Interaction of copper(II) with the non-steroidal anti-inflammatory drugs naproxen and diclofenac: synthesis, structure, DNA- and albumin-binding. AB - Copper(II) complexes with the non-steroidal anti-inflammatory drugs (NSAIDs) naproxen and diclofenac have been synthesized and characterized in the presence of nitrogen donor heterocyclic ligands (2,2'-bipyridine, 1,10-phenanthroline or pyridine). Naproxen and diclofenac act as deprotonated ligands coordinated to Cu(II) ion through carboxylato oxygens. The crystal structures of (2,2' bipyridine)bis(naproxenato)copper(II), 1, (1,10 phenanthroline)bis(naproxenato)copper(II), 2 and bis(pyridine)bis(diclofenac)copper(II), 4 have been determined by X-ray crystallography. The UV study of the interaction of the complexes with calf thymus DNA (CT DNA) has shown that the complexes can bind to CT DNA with (2,2' bipyridine)bis(naproxenato)copper(II) exhibiting the highest binding constant to CT DNA. Competitive study with ethidium bromide (EB) indicates that the complexes can displace the DNA-bound EB suggesting strong competition with EB. The cyclic voltammograms of the complexes recorded in the presence of CT DNA have shown that the complexes can bind to CT DNA by the intercalative binding mode which has also been verified by DNA solution viscosity measurements. The NSAID ligands and their complexes exhibit good binding propensity to human or bovine serum albumin protein having relatively high binding constant values. The biological properties of the previously reported complexes [Cu(2)(naproxenato)(4)(H(2)O)(2)], [Cu(2)(diclofenac)(4)(H(2)O)(2)] and [Cu(naproxenato)(2)(pyridine)(2)(H(2)O)] have been also evaluated. The dinuclear complexes exhibit similar affinity for CT DNA as the 2,2'-bipyridine or 1,10-phenanthroline containing complexes. The pyridine containing complexes exhibit the lowest affinity for CT DNA and the lowest ability to displace EB from its EB-DNA complex. PMID- 20926137 TI - Hydroxyquinoline based binders: promising ligands for chelatotherapy? AB - We report here a thorough physico-chemical study of the coordination properties of clioquinol, an oxine-type active neurological drug in Alzheimer's disease, toward biologically relevant divalent metal ions (Cu, Zn, Ni, Co and Mn). Using a fruitful combination of electrospray mass spectrometry, absorption spectrophotometry and potentiometry, we have characterized the mono- and bis chelated metal ion species. The determination of the stability constants showed a classical thermodynamic behavior along the studied series with the cupric complexes being by far the most stable species. Our data are discussed within the scope of Alzheimer's disease. PMID- 20926138 TI - Infants' representations of three-dimensional occluded objects. AB - Infants' ability to represent objects has received significant attention from the developmental research community. With the advent of eye-tracking technology, detailed analysis of infants' looking patterns during object occlusion have revealed much about the nature of infants' representations. The current study continues this research by analyzing infants' looking patterns in a novel manner and by comparing infants' looking at a simple display in which a single three dimensional (3D) object moves along a continuous trajectory to a more complex display in which two 3D objects undergo trajectories that are interrupted behind an occluder. Six-month-old infants saw an occlusion sequence in which a ball moved along a linear path, disappeared behind a rectangular screen, and then a ball (ball-ball event) or a box (ball-box event) emerged at the other edge. An eye-tracking system recorded infants' eye-movements during the event sequence. Results from examination of infants' attention to the occluder indicate that during the occlusion interval infants looked longer to the side of the occluder behind which the moving occluded object was located, shifting gaze from one side of the occluder to the other as the object(s) moved behind the screen. Furthermore, when events included two objects, infants attended to the spatiotemporal coordinates of the objects longer than when a single object was involved. These results provide clear evidence that infants' visual tracking is different in response to a one-object display than to a two-object display. Furthermore, this finding suggests that infants may require more focused attention to the hidden position of objects in more complex multiple-object displays and provides additional evidence that infants represent the spatial location of moving occluded objects. PMID- 20926141 TI - The functional significance of the TGM2 gene in schizophrenia: a correlation of SNPs and circulating IL-2 levels. AB - The present study was undertaken to genotype four single nucleotide polymorphisms, which were previously found to be associated with schizophrenia, in 77 patients with schizophrenia and 52 control subjects in order to assess their genotypic association with plasma IL-2 levels. Kruskal-Wallis analysis revealed an association between rs4811528 and plasma IL-2 levels in the patient group (chi(2)=7.60, df=2, p=0.022) but not in the control group; binary logistic regression also confirmed the association of rs4811528 with altered IL-2 secretion (chi(2)=8.191, df=3, p=0.042) after adjustment for age and sex. TGM2 may be involved in dysfunction of the immune system in schizophrenia. PMID- 20926142 TI - Expression of the alpha7 nAChR subunit duplicate form (CHRFAM7A) is down regulated in the monocytic cell line THP-1 on treatment with LPS. AB - We investigated the expression of the partially duplicated alpha7 nAChR subunit gene in three monocytic cell lines: THP-1, U937 and Mono-Mac-6. Qualitative PCR revealed the presence of the classic alpha7 gene in these lineages, but real-time PCR showed the exclusive expression of alpha7dup. Both mRNA and protein levels were reduced in THP-1 upon LPS challenge, and it was found that transcriptional down-regulation was mediated by a direct mechanism dependent on NF-kappaB as its specific inhibitor parthenolide prevented the reduction in the alpha7dup transcript. Such precise regulation suggests that alpha7dup may specifically participate in the inflammatory response of the innate immune system. PMID- 20926139 TI - A tune in "a minor" can "b major": a review of epidemiology, illness course, and public health implications of subthreshold depression in older adults. AB - BACKGROUND: With emphasis on dimensional aspects of psychopathology in development of the upcoming DSM-V, we systematically review data on epidemiology, illness course, risk factors for, and consequences of late-life depressive syndromes not meeting DSM-IV-TR criteria for major depression or dysthymia. We termed these syndromes subthreshold depression, including minor depression and subsyndromal depression. METHODS: We searched PubMed (1980-Jan 2010) using the terms: subsyndromal depression, subthreshold depression, and minor depression in combination with elderly, geriatric, older adult, and late-life. Data were extracted from 181 studies of late-life subthreshold depression. RESULTS: In older adults subthreshold depression was generally at least 2-3 times more prevalent (median community point prevalence 9.8%) than major depression. Prevalence of subthreshold depression was lower in community settings versus primary care and highest in long-term care settings. Approximately 8-10% of older persons with subthreshold depression developed major depression per year. The course of late-life subthreshold depression was more favorable than that of late life major depression, but far from benign, with a median remission rate to non depressed status of only 27% after >=1 year. Prominent risk factors included female gender, medical burden, disability, and low social support; consequences included increased disability, greater healthcare utilization, and increased suicidal ideation. LIMITATIONS: Heterogeneity of the data, especially related to definitions of subthreshold depression limit our ability to conduct meta analysis. CONCLUSIONS: The high prevalence and associated adverse health outcomes of late-life subthreshold depression indicate the major public health significance of this condition and suggest a need for further research on its neurobiology and treatment. Such efforts could potentially lead to prevention of considerable morbidity for the growing number of older adults. PMID- 20926143 TI - Can we predict community-wide effects of herbicides from toxicity tests on macrophyte species? AB - Macrophyte communities play an essential role in the way freshwater ecosystems function. It is thus of great concern to understand how environmental factors, especially anthropogenic ones, influence their composition and diversity. The aim of this study was to examine whether the effects of a herbicide mixture (50% atrazine, 35% isoproturon, 15% alachlor) on single macrophyte species can be used to predict its impact at a community level. In a first experiment we tested the sensitivity of six species (Azolla filiculoides, Ceratophyllum demersum, Elodea canadensis, Lemna minor, Myriophyllum spicatum and Vallisneria spiralis) grown separately and exposed to 0.6-600 MUg L(-1) of the herbicide mixture. In a second experiment, conducted in microcosms, we tested the effects of herbicides on macrophyte assemblages composed of the same six species exposed to 0, 6 or 60 MUg L(-1) of the herbicide mixture. Species grown separately exhibited growth inhibition at 60 and 600 MUg L(-1). At 600 MUg L(-1) the sensitivity differed significantly between species. V. spiralis was the most resistant species, C. demersum, M. spicatum and E. canadensis exhibited intermediate sensitivities, and A. filiculoides and L. minor were the most sensitive species. In microcosms, community biomass and Shannon evenness index were reduced after 8 weeks at 60 MUg L(-1). Communities also exhibited changes in their composition: the relative and absolute abundance of C. demersum increased at 6 MUg L(-1), while the relative abundance of V. spiralis increased at 60 MUg L(-1). These results are in agreement with the individual responses of these species to the herbicides. It is therefore concluded that short-term effects of herbicides on simple macrophyte communities can be predicted from the sensitivity of individual species. However, further investigations are required to examine whether longer term effects can be predicted as well, especially in more complex communities. PMID- 20926144 TI - Minor symptoms of depression in patients with congenital heart disease have a larger impact on quality of life than limited exercise capacity. AB - OBJECTIVE: In patients with congenital heart disease quality of life is only marginally associated with exercise capacity. The aim of this study was to determine the prevalence of depression and its impact on quality of life and exercise capacity. PATIENTS AND METHODS: From November 2007 to October 2009 a total of 767 patients (352 female, 14-67 years) with various congenital heart diseases (37 palliated/native cyanotic, 57 Fontan, 74 Transposition of the Great Arteries (TGA) after atrial switch, 50 other TGA, 136 Fallot, 38 Ebstein, 47 Pulmonic stenosis/regurgitation, 68 aortic coarctation, 103 aortic stenosis, 90 isolated shunts, 67 other) completed the health-related quality of life questionnaire SF-36 and the German translation of the "Center for Epidemiologic Studies Depression Scale" (CES-D) to assess depressive symptoms. Afterwards a cardiopulmonary exercise test was performed. RESULTS: Only 66 patients (8.6%) showed depressive symptoms fulfilling the CES-D definition for depression. The total prevalence of depression was lower than in the general population (Wilcoxon test, p<0.001) and did not differ substantially in between the diagnostic subgroups (Kruskal-Wallis test, p=0.195). CES-D score was correlated to all of the nine dimensions of quality of life (r=-0.170 to r=-0.740, p<0.001) and less pronounced to exercise capacity (r=-0.164, p<0.001). Correlation of peak oxygen uptake to quality of life was weaker than the CES-D scores in all subscales of life quality. CONCLUSIONS: Patients with congenital heart disease are rarely depressive. However, even minor depressive symptoms have a stronger impact on quality of life than limited exercise capacity as seen in many patients. PMID- 20926145 TI - The impact of rapid atrial pacing on ADMA and endothelial NOS. AB - BACKGROUND: The endothelial nitric oxide synthase (eNOS) inhibitor asymmetric dimethylarginine (ADMA) is a well-established risk factor for oxidative stress, vascular dysfunction, and congestive heart failure. The aim of the present study was to determine the impact of rapid atrial pacing (RAP) on ADMA levels and eNOS expression. METHODS AND RESULTS: ADMA levels were studied in 60 age- and gender matched patients. Thirty five patients had persistent atrial fibrillation (AF)>= 4months. In AF-patients, parameters were studied before and 24h after electrical cardioversion. Moreover, ADMA, eNOS expression, and calcium-handling proteins were studied in pigs subjected to RAP as well as in endothelial cell (EC) cultures. ADMA level was significantly higher in AF compared to sinus rhythm patients (p=0.024). ADMA was highest in AF-patients, who also showed elevated troponin T (TnT) levels. Moreover, ADMA showed a significant linear correlation to TnT (r=0.47; p<0.01). After electrical cardioversion ADMA returned to normal within 24h. In pigs, RAP for 7h increased ADMA levels (p=0.018) and TnI (p<0.05), and reduced mRNA expression of ventricular and aortic eNOS (-80%; p<0.05) compared to sham-control. However, ADMA per se did not affect eNOS mRNA level in EC cultures. CONCLUSION: The current study shows that acute and persistent episodes of atrial tachyarrhythmia are associated with elevated ADMA levels accompanied by increased ischemic myocardial markers. Moreover, RAP increases ADMA and down-regulates eNOS expression in an ADMA-independent manner. We conclude that the combination of these two separate and potentially synergistic mechanisms may contribute to long-term vascular injury during atrial tachyarrhythmia. PMID- 20926146 TI - Down-regulation of CREB-binding protein expression blocks thrombin-mediated endothelial activation by inhibiting acetylation of NF-kappaB. AB - OBJECTIVES: CREB-binding protein (CBP) belongs to a unique class of transcription co-activators possessing histone acetyltransferase (HAT) activity. The aim of the present study was to evaluate the role of CBP in thrombin-induced endothelial activation, and also explore the underlying mechanism. METHODS: Leukocyte endothelial adhesion was calculated as the proportion of the labeled-neutrophils that adhered to ECs relative to all neutrophils applied. Levels of adhesion molecules were analyzed by real-time RT-PCR and western blot. Electrophoretic mobility shift assay and NF-kappaB reporter assay were performed to evaluate NF kappaB activation. Acetylation of NF-kappaB was measured with immunoprecipitation and western blot assay. To detect the CBP-HAT activity, acetyl residues on an acetylated histone H4 was analyzed. RESULTS: Leukocyte-endothelial adhesion induced by thrombin was markedly attenuated in endothelial cells with CBP knockdown. The decreased adhesion was paralleled by the reduction of vascular cell adhesion molecule-1, intercellular adhesion molecule-1 and E-selectin. Furthermore, CBP silencing suppressed thrombin-mediated NF-kappaB activation, and this inhibitory effect was associated with decreased acetylation of NF-kappaB and CBP-HAT activity. CONCLUSIONS: Our results indicate that CBP is involved in the regulation of endothelial activation via NF-kappaB-dependent pathway. Down regulation of CBP may play a role in returning ECs from a pre-inflammatory status to a quiescent state in the pathogenesis of atherosclerosis. PMID- 20926147 TI - Left ventricular function and energy homeostasis in patients with type 1 diabetes with and without microvascular complications. AB - BACKGROUND: This study was performed to assess left ventricular (LV) energy metabolism and function in patients with type 1 diabetes with or without overt microvascular complications. METHODS: We performed cardiac Magnetic Resonance Imaging (MRI) and (31)P spectroscopy (MRS) in 24 patients with overt microvascular complications and in 15 carefully selected patients without complications in spite of a long duration of the disease (>20 years) and matched for anthropometric features. 31 healthy subjects served as a control group. RESULTS: Systolic function was preserved in all study subjects. Patients with overt complications showed a higher LV wall mass/end diastolic volume ratio and altered parameters of diastolic function when compared to patients without complications and to controls. They were also characterized by lower PCr/ATP ratio (a recognized marker of energy metabolism). No effect of HbA1c was detected within groups. CONCLUSIONS: In patients with type 1 diabetes 1) overt microvascular complications were associated with altered LV geometry, diastolic function and energy metabolism 2) in patients without complications and duration of disease >20 years no association with these alterations were found despite poor glycemic control. The features of this highly selected subgroup of patients demonstrated that long lasting chronic hyperglycemia per se is not sufficient to induce abnormality of cardiac energy metabolism and that additional yet to be identified (metabolic or genetic) factors must be important contributing factors. PMID- 20926148 TI - Human plasma complement C3 is independently associated with coronary heart disease, but only in heavy smokers (the CODAM study). AB - BACKGROUND: Complement C3 is an emerging risk factor for coronary heart disease (CHD) and is particularly increased in the metabolic syndrome. A direct effect of smoking on structure and function of complement C3 has been suggested. HYPOTHESIS: Smoking behavior may affect the cardiovascular risk that is associated with plasma complement C3. METHODS: The association between plasma C3 and CHD was studied in the CODAM (Cohort on Diabetes and Atherosclerosis Maastricht) study population (n=562, 61% male) with examination of effect modification by smoking. RESULTS: The overall prevalence of CHD was 23.3%. Higher plasma C3 levels were associated with a higher CHD prevalence, and there was a significant interaction with heavy smoking (p=0.01). In never & light smokers, the univariate OR for CHD per 1s.d. (0.33 g/L) increase in C3 was 1.09 [95% confidence interval (CI) 0.85-1.41] (p=0.505) whereas in heavy smokers it was 2.05 [1.43-2.93] (p<0.001). The association in the group of heavy smokers remained significant (OR 2.38 [1.54-3.68], p<0.001) after adjustment for traditional risk factors for cardiovascular disease and also after further adjustment for other cardiometabolic risk factors, i.e. the metabolic syndrome, CRP and insulin resistance (HOMA2IR) (OR C3 between 2.16 and 2.29, all p <= 0.001). CONCLUSION: Human plasma complement C3 is associated with prevalent CHD, but only in heavy smokers, and this association is independent of important metabolic cardiovascular risk factors. PMID- 20926149 TI - Intensity-modulated radiation therapy in newly diagnosed glioblastoma: a systematic review on clinical and technical issues. AB - BACKGROUND AND PURPOSE: Intensity-modulated radiation therapy (IMRT) could represent a new tool to improve the therapeutic ratio in the treatment of glioblastoma. This systematic review investigates the evidence behind the application of IMRT to glioblastoma, assessing the potential benefits from both the clinical and dosimetrical perspective. MATERIALS AND METHODS: Two independent researchers systematically identified all relevant articles available on PubMed and MEDLINE databases until December 2009. RESULTS: Ultimately, seventeen studies were included in the analysis, for a total of 204 treated patients and 148 patient datasets used in planning studies. Most dosimetrical studies provided statistical analysis. Clinical series did not include any randomized controlled study, ultimately hindering a meta-analysis. From the dosimetrical point of view, conformal radiotherapy and IMRT provide similar results in terms of target coverage, while IMRT is better in terms of dose conformity, in reducing the maximum dose to the organs at risk and in healthy brain sparing. In clinical reports, a wide variability was recorded concerning dose per fraction, total dose, and chemotherapy administration. A comprehensive qualitative comparison with literature on similar non-IMRT clinical series showed that in most IMRT series excellent compliance and low rates of toxicity were recorded. Hypofractionated regimens in association with chemotherapy showed results that are even superior to the standard treatment. CONCLUSIONS: According to the available data, the dosimetrical advantages of IMRT translate into the clinical capability of delivering higher dose levels in a shorter time. This approach in glioblastoma patients with good prognosis suggests the possibility of improving outcomes without an increase in toxicity. PMID- 20926150 TI - Inactivation of Escherichia coli O157:H7 and Salmonella spp. on alfalfa seeds by caprylic acid and monocaprylin. AB - Alfalfa and other seed sprouts have been implicated in several Escherichia coli O157:H7 and Salmonella spp. human illness outbreaks in the U.S. Continuing food safety issues with alfalfa seeds necessitate the need for discovery and use of novel and effective antimicrobials. The potential use of caprylic acid (CA) and monocaprylin (MC) for reducing E. coli O157:H7 and Salmonella spp. populations on alfalfa seeds was evaluated. The effectiveness of three concentrations of CA and MC (25, 50, and 75 mM) to reduce E. coli O157:H7 and Salmonella spp. populations in 0.1% peptone water and on alfalfa seeds was evaluated. Surviving populations of E. coli O157:H7 and Salmonella spp. were enumerated by direct plating on tryptic soy agar (TSA). Non-inoculated alfalfa seeds were soaked for up to 120 min to evaluate the effect of CA and MC solutions on seed germination rate. For planktonic cells, the efficacy of the treatments was: 75 MC > 50 MC > 25 MC > 75 CA > 50 CA > 25 CA. Both E. coli O157:H7 and Salmonella spp. were reduced to below the detection limit (0.6 log CFU/ml) within 10 min of exposure to 75 MC from initial populations of 7.65 +/- 0.10 log CFU/ml and 7.71 +/- 0.11 log CFU/ml, respectively. Maximum reductions of 1.56 +/- 0.25 and 2.56 +/- 0.17 log CFU/g for E. coli O157:H7 and Salmonella spp., respectively, were achieved on inoculated alfalfa seeds (from initial populations of 4.74 +/- 0.62 logCFU/g and 5.27+/-0.20logCFU/g, respectively) when treated with 75 MC for 90 min. Germination rates of CA or MC treated seeds ranged from 84% to 99%. The germination rates of CA or MC soaked seeds and water soaked seeds (control) were similar (P > 0.05) for soaking times of <= 90 min. Monocaprylin (75 mM) can be used to reduce E. coli O157:H7 and Salmonella spp. on alfalfa seeds without compromising seed viability. PMID- 20926151 TI - Multigenic expression analysis as an approach to understanding the behaviour of Oenococcus oeni in wine-like conditions. AB - The correct performance of wine malolactic fermentation (MLF) depends on the metabolic characteristics of the Oenococcus oeni strain/s responsible for this process. This study characterizes four O. oeni strains, which behave differently in terms of malolactic performance, the citric acid use related to acetic acid production, and stress adaptation. Metabolic evolution and its associated enzymatic activities were studied and the transcriptional response of the genes related to MLF, citrate metabolism and stress response was compared among strains. A higher initial expression of both the malolactic enzyme and the encoding gene mleA may be related to faster MLF. The initial transcriptional levels of citrate lyase (citE) proved indicative of early citrate consumption. Moreover, the strains that performed best in wine-like conditions presented a much higher relative expression of several stress responsive genes, particularly hsp18, clpP, ctsR and rmlB. Finally, an inter-strain comparison of the transcriptional levels of selected genes at different times during MLF proved a useful tool in characterizing strains based on their metabolic behaviour. PMID- 20926153 TI - Association between cardiorespiratory fitness and arterial stiffness in men with the metabolic syndrome. AB - AIMS: We tested the hypothesis that high cardiorespiratory fitness (fitness) is associated with lower levels of arterial stiffness in 1035 (age 52 +/- 6 years) men with and without the metabolic syndrome. METHODS: Arterial stiffness was derived from brachial-ankle pulse wave velocity (baPWV). Fitness was directly measured by peak oxygen uptake during a standard treadmill test. RESULTS: Men with the metabolic syndrome (n = 168) had significantly higher baPWV than men without the metabolic syndrome (1424 +/- 175 cm/s vs. 1333 +/- 150 cm/s, p < 0.05). When separated according to quartiles of fitness, men with and without the metabolic syndrome in the highest quartile of fitness had significantly lower baPWV compared to men in the lowest quartile of fitness (p < 0.05). Fitness was inversely correlated with baPWV in men with (p = -0.29, p < 0.05) and without the metabolic syndrome (p = -0.22, p < 0.05). There was no differences in baPWV levels between fit men with the metabolic syndrome and unfit men without the metabolic syndrome (fit/MetS; 1366 +/- 140 vs. unfit/no MetS; 1401 +/- 194 cm/s, p = 0.81). CONCLUSIONS: These results demonstrate that high fitness is inversely associated with arterial stiffness in men with and without the metabolic syndrome. Increased arterial stiffness in the metabolic syndrome is attenuated by high fitness. PMID- 20926152 TI - Asthma, chronic obstructive pulmonary disease, and type 2 diabetes in the Women's Health Study. AB - BACKGROUND: Chronic airway inflammation in asthma or chronic obstructive pulmonary disease (COPD) may be involved in the pathogenesis of type 2 diabetes; however, prospective data have been limited. METHODS: A prospective cohort of 38,570 women who were aged >= 45 years, free of cardiovascular disease and cancer at baseline, and free of diabetes at baseline and in the first 12 months were analyzed. We classified all women into three groups according to the presence and absence of self-reported asthma or COPD (including emphysema, chronic bronchitis, and bronchiectasis). RESULTS: During a median follow-up of 12.2 years, 2472 incident type 2 diabetes events were documented. Women who had ever reported asthma or COPD were associated with an increased diabetes risk; the multivariate RRs were 1.37 (95% CI, 1.20-1.57) for women who had asthma alone and 1.38 (95% CI, 1.14-1.67) for COPD without asthmatic symptoms. Furthermore, these associations were not significantly modified by age, smoking status, physical activity, BMI, alcohol intake, hormone replacement therapy, menopausal status or randomized treatment. CONCLUSIONS: Asthma and COPD were individually and independently associated with an increased risk of type 2 diabetes in women, indicating that chronic airway inflammation may contribute to diabetes pathogenesis. PMID- 20926154 TI - The impacts of thiazolidinediones on circulating C-reactive protein levels in different diseases: a meta-analysis. AB - OBJECTIVES: Thiazolidinediones (TZDs), including rosiglitazone and pioglitazone, are widely used as antidiabetic agents. Here we present an updated meta-analysis of the respective effects of rosiglitazone and pioglitazone on the levels of C reactive protein (CRP), a biomarker and predictor of CAD risks. METHODS AND RESULTS: PubMed and EMBASE were systematically searched using the terms "C reactive protein" and "rosiglitazone" or "pioglitazone" or "thiazolidinedione". A total of 59 rosiglitazone studies and 36 pioglitazone studies were included for evaluation. These were classified as 2-group studies and 1-group studies according to their study design. Standard mean difference (SMD) of CRP and 95% CI were calculated to evaluate the effect of TZDs on CRP. The overall SMD for rosiglitazone treatment is -0.392 (95% CI, [-0.446, -0.338]) in 2-group studies and -0.424 (95% CI, [-0.501, -0.346]) in 1-group studies. The overall SMD for pioglitazone treatment is -0.577 (95% CI, [-0.732, -0.421]) in 2-group studies and -0.327 (95% CI, [-0.439, -0.216]) in 1-group studies. Moreover, TZDs were found to significantly reduce CRP levels in both diabetes mellitus (DM) and non DM patients. CONCLUSIONS: Our meta-analysis suggested that both rosiglitazone and pioglitazone significantly decrease serum CRP levels. TZDs presented their CRP lowering effect in both DM and non-DM patients. PMID- 20926155 TI - RFID-initiated workflow control to facilitate patient safety and utilization efficiency in operation theater. AB - OBJECTIVE: To control the workflow for surgical patients, we in-cooperate radio frequency identification (RFID) technology to develop a Patient Advancement Monitoring System (PAMS) in operation theater. METHODS: The web-based PAMS is designed to monitor the whole workflow for the handling of surgical patients. The system integrates multiple data entry ports Across the multi-functional surgical teams. Data are entered into the system through RFID, bar code, palm digital assistance (PDA), ultra-mobile personal computer (UMPC), or traditional keyboard at designated checkpoints. Active radio-frequency identification (RFID) tag can initiate data demonstration on the computer screens upon a patient's arrival at any particular checkpoint along the advancement pathway. RESULTS: The PAMS can manage the progress of operations, patient localization, identity verification, and peri-operative care. The workflow monitoring provides caregivers' instant information sharing to enhance management efficiency. CONCLUSION: RFID-initiate surgical workflow control is valuable to meet the safety, quality, efficiency requirements in operation theater. PMID- 20926156 TI - PDF equations for advective-reactive transport in heterogeneous porous media with uncertain properties. AB - We consider advective-reactive solute transport in porous media whose hydraulic and transport properties are uncertain. These properties are treated as random fields, which renders nonlinear advection-reaction transport equations stochastic. We derive a deterministic equation for the probability density function (PDF) of the concentration of a solute that undergoes heterogeneous reactions, e.g., precipitation or dissolution. The derivation treats exactly (without linearization) a reactive term in the transport equation which accounts for uncertainty (randomness) in both flow velocity and kinetic rate constants but requires a closure, such as a Large-Eddy-Diffusivity (LED) approximation used in the present analysis. No closure is required when reaction rates are the only source of uncertainty. We use exact concentration PDFs obtained for this setting to analyze the accuracy of our general, LED-based PDF equations. PMID- 20926157 TI - Empirical correlations to estimate agglomerate size and deposition during injection of a polyelectrolyte-modified Fe0 nanoparticle at high particle concentration in saturated sand. AB - Controlled emplacement of polyelectrolyte-modified nanoscale zerovalent iron (NZVI) particles at high particle concentration (1-10 g/L) is needed for effective in situ subsurface remediation using NZVI. Deep bed filtration theory cannot be used to estimate the transport and deposition of concentrated polyelectrolyte-modified NZVI dispersions (>0.03 g/L) because particles agglomerate during transport which violates a fundamental assumption of the theory. Here we develop two empirical correlations for estimating the deposition and transport of concentrated polyelectrolyte-modified NZVI dispersions in saturated porous media when NZVI agglomeration in porous media is assumed to reach steady state quickly. The first correlation determines the apparent stable agglomerate size formed during NZVI transport in porous media for a fixed hydrogeochemical condition. The second correlation estimates the attachment efficiency (sticking coefficient) of the stable agglomerates. Both correlations are described using dimensionless numbers derived from parameters affecting deposition and agglomeration in porous media. The exponents for the dimensionless numbers are determined from statistical analysis of breakthrough data for polyelectrolyte-modified NZVI dispersions collected in laboratory scale column experiments for a range of ionic strength (1, 10, and 50mM Na(+) and 0.25, 1, and 1.25 mM Ca(2+)), approach velocity (0.8 to 55 * 10(-4)m/s), average collector sizes (d(50)=99 MUm, 300 MUm, and 880 MUm), and polyelectrolyte surface modifier properties. Attachment efficiency depended on approach velocity and was inversely related to collector size, which is contrary to that predicted from classic filtration models. High ionic strength, the presence of divalent cations, lower extended adsorbed polyelectrolyte layer thickness, decreased approach velocity, and a larger collector size promoted NZVI agglomeration and deposition and thus limited its mobility in porous media. These effects are captured quantitatively in the two correlations developed. The application and limitations of using the correlations for preliminary design of in situ NZVI emplacement strategies is discussed. PMID- 20926158 TI - Phosphorus-deficiency reduces aluminium toxicity by altering uptake and metabolism of root zone carbon dioxide. AB - The role of phosphorus (P) status in root-zone CO(2) utilisation for organic acid synthesis during Al(3+) toxicity was assessed. Root-zone CO(2) can be incorporated into organic acids via Phosphoenolpyruvate carboxylase (PEPC, EC 4.1.1.31). P-deficiency and Al(3+) toxicity can induce organic acid synthesis, but it is unknown how P status affects the utilisation of PEPC-derived organic acids during Al(3+) toxicity. Two-week-old Solanum lycopersicum seedlings were transferred to hydroponic culture for 3 weeks. The hydroponic culture consisted of a standard Long Ashton nutrient solution containing either 0.1MUM or 1mM P. Short-term Al(3+) toxicity was induced by a 60-min exposure to a pH-buffered solution (pH 4.5) containing 2mM CaSO(4) and 50MUM AlCl(3). Al(3+) toxicity induced a decline in root respiration, adenylate concentrations and an increase in root-zone CO(2) utilisation for both P sufficient and P-deficient plants. However during Al(3+) toxicity, P deficiency enhanced the incorporation and metabolism of root-zone CO(2) via PEPC. Moreover, P deficiency led to a greater proportion of the PEPC-derived organic acids to be exuded during Al(3+) toxicity. These results indicate that P-status can influence the response to Al(3+) by inducing a greater utilisation of PEPC-derived organic acids for Al(3+) detoxification. PMID- 20926159 TI - Comparative analysis of proteome changes induced by the two spotted spider mite Tetranychus urticae and methyl jasmonate in citrus leaves. AB - Citrus plants are currently facing biotic and abiotic stresses. Therefore, the characterization of molecular traits involved in the response mechanisms to stress could facilitate selection of resistant varieties. Although large cDNA microarray profiling has been generated in citrus tissues, the available protein expression data are scarce. In this study, to identify differentially expressed proteins in Citrus clementina leaves after infestation by the two-spotted spider mite Tetranychus urticae, a proteome comparison was undertaken using two dimensional gel electrophoresis. The citrus leaf proteome profile was also compared with that of leaves treated over 0-72h with methyl jasmonate, a compound playing a key role in the defense mechanisms of plants to insect/arthropod attack. Significant variations were observed for 110 protein spots after spider mite infestation and 67 protein spots after MeJA treatments. Of these, 50 proteins were successfully identified by liquid chromatography-mass spectrometry tandem mass spectrometry. The majority constituted photosynthesis- and metabolism related proteins. Five were oxidative stress associated enzymes, including phospholipid glutathione peroxidase, a salt stressed associated protein, ascorbate peroxidase and Mn-superoxide dismutase. Seven were defense-related proteins, such as the pathogenesis-related acidic chitinase, the protease inhibitor miraculin-like protein, and a lectin-like protein. This is the first report of differentially regulated proteins after T. urticae attack and exogenous MeJA application in citrus leaves. PMID- 20926160 TI - Efficient synthesis of 6-(hetero)arylthieno[3,2-b]pyridines by Suzuki-Miyaura coupling. Evaluation of growth inhibition on human tumor cell lines, SARs and effects on the cell cycle. AB - A wide variety of new bi(hetero)aryl derivatives of the thieno[3,2-b]pyridine skeleton was obtained in high to excellent yields (65-91%) by Suzuki-Miyaura cross-coupling of the methyl 3-amino-6-bromothieno[3,2-b]pyridine-2-carboxylate, recently reported by us, with aryl or heteroaryl pinacolboranes or potassium trifluoroborates. The coupling products obtained were evaluated for their growth inhibitory effect on three human tumor cell lines, representing different tumor models, MCF-7 (breast adenocarcinoma), A375-C5 (melanoma) and NCI-H460 (non-small cell lung cancer). Some of the compounds showed an interesting activity against the tested cell lines, with GI50 values in the MUM range, and it was possible to establish some structure-activity relationships (SARs). Several compounds presented GI50 values below 15 MUM, particularly a bithiophene and an o-aniline thienopyridine derivative. The first presented selectivity for MCF-7 and NCI-H460 cell lines, with very low GI50 values (0.7-1.0 MUM), while the latter was active against the three cell lines tested in this study, also presenting very low GI50 values (2.5-4.2 MUM). The effect of these two compounds on cell cycle progression was analyzed in the NCI-H460 cell line. Results showed that both compounds interfered with the normal cell cycle distribution. PMID- 20926161 TI - Novel alkyl- and arylcarbamate derivatives with N-benzylpiperidine and N benzylpiperazine moieties as cholinesterases inhibitors. AB - The study presents synthesis and biological activity of novel alkyl- and arylcarbamate derivatives with N-benzylpiperidine and N-benzylpiperazine moieties designed as cholinesterases inhibitors. These fragments turned out to determine compounds' selectivity between AChE and BuChE. Derivatives of N-benzylpiperazine (16-25) were selective BuChE inhibitors with 3-(2-(4-benzylpiperazin-1-yl)-2 oxoethyl)-phenyl butylcarbamate (22) being the most potent compound (pIC50=5.00) while a series of carbamate derivatives of N-benzylpiperidine (5-14) displayed non-selective BuChE/AChE inhibitory activity. Molecular modelling studies point out significant differences between orientations of these two groups of compounds in the active site of AChE, which can be an explanation of their different biological activity. PMID- 20926162 TI - Old phenothiazine and dibenzothiadiazepine derivatives for tomorrow's neuroprotective therapies against neurodegenerative diseases. AB - From an in-house library of compounds, five phenothiazines and one dibenzothiadiazepine were selected to be tested in neuroprotective and cholinergic assays. Three of them, derived from the N-alkylphenothiazine, the N acylaminophenothiazine, and the 1,4,5-dibenzo[b,f]thiadiazepine system, protected human neuroblastoma cells against oxidative stress generated by both exogenous and mitochondrial free radicals. They could also penetrate the CNS, according to an in vitro blood-brain barrier model, and an N-acylaminophenothiazine derivative behaved as a selective inhibitor of butyrylcholinesterase. Free radical capture and/or promotion of antioxidant protein biosynthesis are mechanisms that can be implicated in their neuroprotective actions. Due to their excellent pharmacological properties and the fact that they were not biologically explored in the past, one N-acylaminophenothiazine and one 1,4,5-dibenzo[b,f]thiadiazepine have been selected to develop two new series that are currently in progress. PMID- 20926163 TI - Molecular docking and QSAR study on steroidal compounds as aromatase inhibitors. AB - In order to develop more potent, selective and less toxic steroidal aromatase (AR) inhibitors, molecular docking, 2D and 3D hybrid quantitative structure activity relationship (QSAR) study have been conducted using topological, molecular shape, spatial, structural and thermodynamic descriptors on 32 steroidal compounds. The molecular docking study shows that one or more hydrogen bonds with MET374 are one of the essential requirements for the optimum binding of ligands. The QSAR model obtained indicates that the aromatase inhibitory activity can be enhanced by increasing SIC, SC_3_C, Jurs_WNSA_1, Jurs_WPSA_1 and decreasing CDOCKER interaction energy (ECD), IAC_Total and Shadow_XZfrac. The predicted results shows that this model has a comparatively good predictive power which can be used in prediction of activity of new steroidal aromatase inhibitors. PMID- 20926164 TI - Identification of efficient fluorophores for the direct labeling of DNA via rolling circle amplification (RCA) polymerase phi29. AB - The enzymatic incorporation as well as the spectroscopic properties and photochemical stability of a series of fluorescent labels differing in dye class, charge, and rigidity were studied to identify new tools for signal enhancement in situ on microarrays without secondary labeling. These fluorophores were chosen to spectrally match or resemble the golden standard Cy3. With the rhodamine DY-555, that is three times more emissive than Cy3, we found a bright and stable chromophore, the spectroscopic properties of which are minimally influenced by dye microenvironment. PMID- 20926165 TI - [Penicilliosis in Vietnam: a series of 94 patients]. AB - PURPOSE: Haiphong is the second city of Vietnam most affected by HIV infection. Penicilliosis represents the third leading cause of opportunistic infection. However, this systemic fungal infection remains poorly knew by practitioners. This study aimed to clarify the clinical, diagnostic and therapeutic aspects of penicilliosis. METHODS: It is a descriptive study, prospective and retrospective, conducted over a 3-year period in Viet Tiep hospital, Haiphong. RESULTS: With 94 cases, penicilliosis represented 11% of opportunistic infections. The patients were young (mean: 33 years) and male (87%). The main symptoms were persistent fever (99%), weight loss (88%), skin lesions (86%), hepatomegaly (69%) and lymphadenopathy (68%). Anemia was noted in 77% of cases. The average CD4 count was 29/MUL. The culture of skin biopsies and blood culture were positive for Penicillium marneffei in 94% and 90% of cases, respectively. Despite antiretroviral and antifungal therapy, the mortality rate was 18%. Itraconazole monotherapy, administered in 53 patients due to the unavailability of amphotericin B, did not significantly affect the survival compared to the recommended treatment received by the 41 other patients. CONCLUSION: In Haiphong, penicilliosis is one of the most frequent and severe opportunistic infections of AIDS. The diagnosis should be considered in all febrile and immunocompromised patients having spent time in Vietnam. The prognosis can be improved by early diagnosis through the blood culture and a good adherence to an appropriate antifungal therapy. PMID- 20926166 TI - Iranian staff nurses' attitudes toward nursing students. AB - INTRODUCTION: Clinical education is an indispensible part of the nursing education. Clinical nurses play an important role in this teaching learning process. The quality and quantity of student-nurse interactions in the clinical area can either facilitate or hamper students' learning. The rationale of this research was to probe into staff nurses' attitudes toward nursing students within the context of clinical education in Iran. The nursing literature seems wanting in issues related to staff nurses' attitudes toward nursing students. Thus, we draw on Peplau's interpersonal relations in nursing to address staff-student relationship. That is, the nursing student was taken as the client. METHODS: A descriptive cross-sectional design was selected for this study. The entire staff nurses of Medical and Surgical units (n=82) employed at Dr Fatemi and Imam Khomeini hospitals of Ardabil medical sciences university were selected. Stagg's questionnaire and a demographic tool were used to gather data. Attitudes were measured using a five-point Likert scale. Attitudes of staff nurses were inspected using cross tabulations and frequencies. FINDINGS: The results demonstrated that attitude scores toward nursing students were low and moderate. Some nurses (45.71%) believed that working with students is pleasant and most (98.57%) have thought that staff should have a good relationship with nursing students. Furthermore, staff nurses pointed out that the there is a need to overhaul the educational system of nursing students (94.3%), that nursing students do not acquire the sufficient clinical skill (67.14%), and that the students are not prepared enough for the clinical task (51.43%). CONCLUSION: According to the results of the staffs' feelings on the relationship between nurse and student, it seems that nurses should cultivate an atmosphere which ends to empathy, assurance and sincerity of nursing students. PMID- 20926167 TI - National survey of how acupuncture education is organised for Swedish midwives. AB - OBJECTIVE: in Sweden, acupuncture education is required before midwives can use the method in clinical practice. Courses in acupuncture are usually organised by private individuals or companies, and each health facility decides on the adequacy of the educational package. Therefore, there is no overall standard or quality control for free-standing courses of acupuncture education for midwives. The aim of this study was to survey the education given to Swedish midwives in the use of acupuncture treatment in the obstetric area. DESIGN: a postal survey using a structured questionnaire. SETTING: organisers of acupuncture education. PARTICIPANTS: 18 acupuncture instructors. MEASUREMENTS AND FINDINGS: acupuncture courses were usually organised outside universities and colleges. The courses were similar in terms of extent and content, and were mainly based on a Western medical approach. The recommended indications were extensive despite a lack of scientific evidence. The most common instructor profile was a midwife without any academic degree. KEY CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: courses differed considerably in the extent to which they were research based. Continuing professional education for midwives should be given at the same academic level, at least, as basic midwifery education. PMID- 20926168 TI - The specificity of fatiguing protocols affects scapular orientation: Implications for subacromial impingement. AB - BACKGROUND: shoulder impairments are often associated with altered scapular kinematics. As muscles control scapular movement, functionally altering muscle performance through fatigue may produce scapular kinematics that mimic those of injured patients. The aim of this study was to examine if changes in scapular tilt, rotation and pro/retraction following two different upper extremity fatiguing protocols have any implications with respect to subacromial impingement. METHODS: scapular orientation was monitored during posturally constrained static holds (at 0 degrees , 45 degrees and 90 degrees of humeral elevation) before and after two fatiguing protocols, one global and one local. Both protocols are associated with producing changes in shoulder skeletal arrangement. FINDINGS: following the global fatiguing protocol, there was significantly more scapular posterior tilt (P<0.01) and upward rotation (P<0.02), particularly at 90 degrees humeral elevation. No changes in scapular orientation occurred following the local fatiguing protocol. INTERPRETATION: scapular orientation changes following muscle fatigue acted to increase the subacromial space. Thus, the rotator cuff muscles, not the scapular stabilizers, have more influence on actively preventing mechanical subacromial impingement. The lack of evidence of reduction of the subacromial space thus implicates superior humeral head translation as a more likely primary mechanism of the initiation of subacromial impingement. PMID- 20926169 TI - Translating HIV interventions into practice: community-based organizations' experiences with the diffusion of effective behavioral interventions (DEBIs). AB - Efficacious behavioral interventions developed to address the spread of HIV/STIs are currently being disseminated in the USA through a national diffusion program (DEBI) spearheaded by the Centers for Disease Control and Prevention (CDC). Understanding how interventions are translated to real world settings is necessary to further scientific knowledge of this process and to facilitate future translation efforts in public health. Prior studies have begun to elucidate how agencies translate behavioral interventions into practice, but further work is needed. Guided by the ADAPT framework, we examined agencies' assessment, preparation, and implementation of interventions. Our qualitative interview-based study focused on six community-based agencies in California (United States) funded to implement three group-level HIV interventions. Findings showed considerable variation in the extent to which agencies engaged in assessment and broad-based preparation and in the ease with which agencies implemented the interventions. The findings provide insight into the process that agencies undergo in the translation of effective behavioral interventions and illustrate how agencies can inform logic models that guide translation. We also identify relevant dimensions of existing models, including the ADAPT framework and Rogers's (1995, 2005) diffusion of innovations in organizations, that have value for agencies that are translating research to practice. PMID- 20926170 TI - Spirituality within the family and the prevention of health risk behavior among adolescents in Bangkok, Thailand. AB - This study investigates the influences of a family's spiritual beliefs and practices on substance use and sexual risk behaviors among young adolescents 13 14 years old in Bangkok, Thailand. Independent predictor variables are the parents' and teens' spiritual beliefs and practices in Buddhism and parental monitoring behaviors. The study uses data from the 2007 Baseline Survey of the Thai Family Matters Project, which adapted a U.S. based family prevention program for Thai culture. A representative sample of 420 pairs of parents and teens from the Bangkok metropolitan area was recruited to participate in the study. Structural equation models indicate that positive direct and indirect associations of the spirituality of parents and teens within a family and the prevention of adolescent risk behaviors are significant and consistent. PMID- 20926171 TI - [The complete dorsum nasal island flap based on the superior alar artery]. AB - The complete dorsal nasal aesthetic unit can be raised in a vascular island flap based on the superior alar artery, at the level of the nasalis muscle. This flap uses the vertical glabellar cutaneous laxity. It hides scars between the nasal aesthetics units and its distal rotation point allows a pure translation of the nasal skin without distortions encountered when using medial canthal rotation flaps. This local flap is reliable and had been successfully used for four patients without complications or secondary procedures. It allows large reconstructions for up to 25 mm defects leaving minimal scars. It represents an interesting alternative for the reconstruction of defects of the nasal tip or supra tip of the nose, and has also been used for alar reconstructions. PMID- 20926172 TI - [Incidence of symptomatic and asymptomatic chronic thromboembolic pulmonary hypertension]. AB - INTRODUCTION AND OBJECTIVES: To assess the incidence of long-term symptomatic and asymptomatic chronic thromboembolic pulmonary hypertension (CTEPH) in a cohort of patients with acute symptomatic pulmonary embolism (PE), and the potential risk factors for its diagnosis. METHODS: We conducted a prospective, long-term, follow up study in 110 consecutive patients with an acute episode of pulmonary embolism (PE). All patients underwent transthoracic echocardiography (TTE) two years after the diagnosis of PE was made. If systolic pulmonary artery pressure exceeded 40 mm Hg and there was evidence of residual PE either by ventilation-perfusion or CT scan, patients underwent right heart catheterisation to confirm the diagnosis. In asymptomatic patients, right heart catheterisation was performed if a repeated TTE still demonstrated persistent pulmonary hypertension six months after the first. RESULTS: CTEPH was diagnosed in 10 (6 patients during follow-up, and 4 at the end of the study) of the 110 patients (9.1%; 95% confidence interval [CI], 3.7 to 14.5%). All patients showed symptoms related to the disease according to a structured questionnaire. In the multivariate regression analysis, only concomitant age (relative risk [RR] 1.2 per age; 95% CI, 1.0 to 1.3; P=0.03) and previous PE (RR 5.7; IC 95%, 1.5 a 22.0; P=0.01) were independent predictors of CTEPH. CONCLUSIONS: CTEPH cumulative incidence appears to be higher than previously reported. All patients had symptoms related to the disease. PMID- 20926173 TI - Comparison of surface cooling and invasive cooling for rapid induction of mild therapeutic hypothermia in pigs--effectiveness of two different devices. AB - AIM OF THE STUDY: The effectiveness and safety of non-invasive surface cooling was compared to invasive endovascular cooling in an animal model. METHODS: Eight healthy pigs (29-38 kg) were cooled twice, starting in the first 4 pigs with unique surface cooling pads followed by endovascular cooling. In the second 4 pigs the order was reversed. The goal was to quickly lower pulmonary artery temperature from 38 to 33 degrees C. A paired t-test was used to compare cooling rates ( degrees C/h, mean+/-standard deviation) between both cooling techniques. RESULTS: Mean non-invasive surface cooling rate (11.9+/-3.8 degrees C/h) significantly exceeded mean invasive cooling rate (3.9+/-0.7 degrees C/h; p<0.001). The mean difference in cooling rates was 8.0+/-3.6 degrees C/h. No surface cooling related adverse skin reactions were observed. CONCLUSIONS: Surface cooling is a simple method for achieving fast cooling rates. In our animal model, non-invasive cooling was three times faster than rapid endovascular cooling without overshoot. PMID- 20926174 TI - Acute myocardial infarction might cause aortic dissection. PMID- 20926175 TI - Pain relief in outpatient hysteroscopy: a survey of current UK clinical practice. AB - BACKGROUND: Outpatient hysteroscopy is increasingly being used as a cost effective alternative to in-patient hysteroscopy under general anaesthesia. Like other outpatient gynaecological procedures, however, it has the potential to cause pain severe enough for the procedure to be abandoned. There are no national guidelines on pain relief for outpatient hysteroscopy. METHODS: A postal survey of UK gynaecologists was carried out to evaluate current clinical practice regarding methods of pain relief used during office hysteroscopy. A total of 250 questionnaires were sent out and 115 responses received. RESULTS: Outpatient hysteroscopy was offered by 76.5% of respondents. Respondents reported a wide variation in the use of routine and rescue analgesia, and also in the nature of the analgesia used. One-quarter of those offering outpatient hysteroscopy used no form of analgesia. CONCLUSION: The results showed that whilst there is no consensus on the type of analgesia provided, rescue analgesia is commonly being used, particularly in the form of intracervical blocks. PMID- 20926178 TI - A plea to young surgeons dealing with radical prostatectomy patients: invest your time and intellectual energy in optimizing your research methodology and keep your feet on the ground. PMID- 20926176 TI - Expression and knockdown of cellular prion protein (PrPC) in differentiating mouse embryonic stem cells. AB - The mammalian cellular prion protein (PrP(C)) is a highly conserved glycoprotein that may undergo conversion into a conformationally altered isoform (scrapie prion protein or PrP(Sc)), widely believed to be the pathogenic agent of transmissible spongiform encephalopathies (TSEs). Although much is known about pathogenic PrP conversion and its role in TSEs, the normal function of PrP(C) is poorly understood. Given the abundant expression of PrP(C) in the developing mammalian CNS and the spatial association with differentiated stages of neurogenesis, recently it has been proposed that PrP(C) participates in neural cell differentiation. In the present study, we investigated the role of PrP(C) in neural development during early embryogenesis. In bovine fetuses, PrP(C) was differentially expressed in the neuroepithelium, showing higher levels at the intermediate and marginal layers where more differentiated states of neurogenesis were located. We utilized differentiating mouse embryonic stem (ES) cells to test whether PrP(C) contributed to the process of neural differentiation during early embryogenesis. PrP(C) showed increasing levels of expression starting on Day 9 until Day 18 of ES cell differentiation. PrP(C) expression was negatively correlated with pluripotency marker Oct-4 confirming that ES cells had indeed differentiated. Induction of ES cells differentiation by retinoic acid (RA) resulted in up-regulation of PrP(C) at Day 20 and nestin at Day 12. PrP(C) expression was knocked down in PrP-targeted siRNA ES cells between Days 12 and 20. PrP(C) knockdown in ES cells resulted in nestin reduction at Days 16 and 20. Analysis of bovine fetuses suggests the participation of PrP(C) in neural cell differentiation during early embryogenesis. The positive association between PrP(C) and nestin expression provide evidence for the contribution of PrP(C) to ES cell differentiation into neural progenitor cells. PMID- 20926179 TI - Unruptured intracranial aneurysm as a cause of cerebral ischemia. AB - BACKGROUND: Unruptured intracranial artery aneurysms (IAs) can be revealed by cerebral ischemia. Little is known on the clinical course and outcome of patients with this condition. We report our findings in a consecutive series of 15 such patients. METHODS: We retrospectively analyzed patients with ischemic stroke (IS) or transient ischemic attack (TIA), unruptured IA on the symptomatic cerebral artery, and no other potential cause of cerebral ischemia consecutively treated in a tertiary stroke unit. RESULTS: Fifteen patients (ten women, and five men) were identified. Their mean age was 49.7 years (range, 37-80 years). Ten patients presented with IS, and five with TIA. The median diameter of IA was 7.5mm (range, 2.5-23 mm). Aneurysm thrombosis was found on imaging in 9/10 patient with IS, and 1/5 patients with TIA (p=0.017). Thirteen patients were given an antiplatelet agent. Mean follow-up until last visit or treatment of aneurysm was 393 days (median 182 days; range, 6-1825 days). There was no ischemic recurrence. Partial or complete recanalization of aneurysm thrombosis occurred in 7/10 patients. Two patients, both with initial aneurysmal thrombosis and on antiplatelet therapy, experienced aneurysm rupture. CONCLUSION: Unruptured IA is a rare cause of IS/TIA. IS is associated with aneurysm thrombosis. Our findings suggest that aneurysm thrombosis is a dynamic process which is associated with a low rate of ischemic recurrence on antiplatelet therapy but may be followed by subarachnoid hemorrhage. PMID- 20926180 TI - Spinal meningiomas: age-related features. AB - OBJECTIVES: Spinal meningiomas mainly occur in old patients, with a remarkable female prevalence. This study investigates the different features between younger and older patients in an adult population (>18 years). MATERIALS AND METHODS: A surgical series of 120 adult patients operated on for spinal meningiomas at the Neurosurgical Clinic of the "Federico II" University of Naples is reviewed. In this series 117 patients with a sporadic spinal meningioma were divided in two groups: group I including 30 patients (25.6%) younger than 50 years of age, group II including 87 patients (74.4%) older than 50 years. 3 patients had a spinal meningioma and neurofibromatosis. Several parameters, including sex, predisposing factors, tumor location and growth, histology, recurrences, proliferation index Ki-67 LI, and outcome, are considered and compared in the two age groups. RESULTS: Group I showed an incidence of high cervical spine (C1-C4) meningiomas higher than group II (23.3% vs 3.4%, p=0.026) and lower rate of thoracic tumors (60% vs 82.7%, p=0.04). No significant differences of histological type and Ki-67 LI were found. Group I had 2 cases of atypical meningiomas (6.6% vs 0%, ns). Recurrences occurred in 6.6% of group I and 2.6% of group II, with no significance. In recurrent meningiomas values of Ki-67 LI were significantly higher than values in not recurrent meningiomas (p=0.0001), whereas no difference of estrogen and progesterone receptor expression was noted. CONCLUSIONS: Younger adult patients with spinal meningiomas show not rare occurrence of NF (9%) and significantly higher incidence of high cervical and lower incidence of thoracic localizations with respect to the older patients. On the other hand, there are not significant differences of histology, Ki-67 LI and recurrence rate, excepting for a slight difference for atypical meningiomas. PMID- 20926181 TI - Steroid hormone receptors in cancer development: a target for cancer therapeutics. AB - The steroid hormone receptors (SHRs) are ligand-dependent intracellular transcription factors that are known to influence the development and growth of many human cancers. SHRs pass signals from a steroid/hormone to the target genes by interacting with specific response element DNA sequences and various coregulatory proteins that consists of activators and/or corepressors. Disruptions in physiological functions of SHRs leads to several types of malignancies such as breast cancer, leukemia and lymphoma, prostate cancer, ovarian cancer, and lung cancer among others. Steroids/hormones/SHRs and their coregulators have opened up a unique window for novel steroid-based targeted therapies for cancer. Thus, dysregulation of SHR signaling in cancers compared with normal tissues can be exploited to target drugs that prevent and treat human cancers. In recent years, hormonal therapy has made a major contribution to the treatment of several cancers including reduced recurrence rates and longer survival rates. Development of various steroid receptor modulators and their potential therapeutic efficacies has provided us a great opportunity to effectively manage diseases like cancer in future. In this review article, we have summarized up-to-date knowledge of the role of SHRs in the development and progression of cancers, and potential endocrine-based therapeutic approaches to tackle these diseases. PMID- 20926182 TI - Global DNA hypomethylation-induced DeltaNp73 transcriptional activation in non small cell lung cancer. AB - p73 possesses an extrinsic P1 promoter and an intrinsic P2 promoter controlling the expression of the pro-apoptotic TAp73 isoforms and the anti-apoptotic DeltaNup73 isoforms respectively. In this study, we investigated the DNA methylation status of both promoters as a means of epigenetic transcriptional control of their corresponding isoforms in 102 primary non-small cell lung carcinomas (NSCLCs). We demonstrated that while P1 hypermethylation-associated reduction of TAp73 mRNA levels is relatively infrequent, the P2 hypomethylation associated over-expression of DeltaNup73 mRNA is a frequent event, particularly among squamous cell carcinomas. P2 hypomethylation strongly correlated with LINE 1 element hypomethylation, indicating that DeltaNup73 over-expression may be a passive consequence of global DNA hypomethylation. PMID- 20926183 TI - RETRACTED: A novel class of specific Hsp90 small molecule inhibitors demonstrate in vitro and in vivo anti-tumor activity in human melanoma cells. AB - This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy).This article has been retracted at the request of the Authors. Following an investigation by Pfizer, Figures 2, 5B and 5C appear to be duplications and hence the conclusions in the manuscript cannot be verified. The Authors apologize for this inconvenience. PMID- 20926184 TI - Screening for novel antibacterial agents based on the activities of compounds on metabolism of Escherichia coli: a microcalorimetric study. AB - The emergence and prevalence of resistance to antibacterial agents is a pressing threaten for human health. Screening for novel antibacterial agents targeting not only multiplying but also non-multiplying bacteria using appropriate approach is in great demand. In this study, the microcalorimetric method was used to measure the metabolic curves of E. coli growth affected by chenodeoxycholic acid (CDCA) and ursodeoxycholic acid (UDCA). By analyzing the metabolic curves and thermo- kinetic/dynamic parameters, the antibacterial activities of CDCA and UDCA on multiplying and non-multiplying bacteria of Escherichia coli (E. coli) were evaluated. The results illustrated that, for the multiplying metabolism of E. coli, the two compounds controlled the anaerobic fermentative, with IC(50(1)) (half-inhibitory concentration) of 566.2 MUg/mL for CDCA and 573.6 MUg/mL for UDCA, respectively, but had no effective action on aerobic metabolism of the bacteria. The action of the two compounds on the non-multiplying metabolism was studied by taking the heat output of E. coli in the stationary phase as the additive guideline of the activity. The values of IC(50(2)) were 543.4 and 547.5 MUg/mL, and MSC(50) (minimum stationary-cidal concentration 50) were 532.6 and 537.3 MUg/mL for CDCA and UDCA, respectively. So, CDCA had more powerful antibacterial activity on E. coli than UDCA either for multiplying bacteria or non-multiplying metabolism, and they both showed stronger activities on non multiplying metabolism than on multiplying metabolism of the bacteria. The microcalorimetric method should be strongly suggested in screening novel antibacterial agents for fighting against multidrug-resistant bacteria. PMID- 20926185 TI - A comparative study among different photochemical oxidation processes to enhance the biodegradability of paper mill wastewater. AB - Advanced oxidation processes including UV, UV/H(2)O(2), Fenton reaction (Fe(II)/H(2)O(2)) and photo-Fenton process (Fe(II)/H(2)O(2)/UV) for the treatment of paper mill wastewater will be investigated. A comparison among these techniques is undertaken with respect to the decrease of chemical oxygen demand (COD) and total suspended solids (TSS) and the evolution of chloride ions. Optimum operating conditions for each process under study revealed the effect of the initial amounts of Fe(II) and hydrogen peroxide. Of the tested processes, photo-Fenton process was found to be the fastest one with respect to COD and TSS reduction of the wastewater within 45 min reaction time under low amounts of Fe(II) and hydrogen peroxide of 0.5 and 1.5mg/L, respectively, and amounted to 79.6% and 96.6% COD and TSS removal. The initial biodegradability of the organic matter present in the effluent, estimated as the BOD(5)/COD, was low 0.21. When the effluent was submitted to the different types of AOPs used in this study, the biodegradability increases significantly. Within 45 min of reaction time, the photo-Fenton process appears as the most efficient process in the enhancement of the biodegradability of the organic matter in the effluent and the BOD(5)/COD ratio increased from 0.21 to 0.7. PMID- 20926186 TI - Adsorption of divalent heavy metal ions from water using carbon nanotube sheets. AB - Removal of some divalent heavy metal ions (Cu(2+), Zn(2+), Pb(2+), Cd(2+), Co(2+)) from aqueous solutions using carbon nanotube (CNT) sheets was performed. CNT sheets were synthesized by chemical vapor deposition of cyclohexanol and ferrocene in nitrogen atmosphere at 750 degrees C, and oxidized with concentrated nitric acid at room temperature and then employed as adsorbent for water treatment. Langmuir and Freundlich isotherms were used to describe the adsorption behavior of heavy metal ions by oxidized CNT sheets. The obtained results demonstrated that the oxidized CNT sheets can be used as an effective adsorbent for heavy metal ions removal from water. It was found out that kinetics of adsorption varies with initial concentration of heavy metal ions. Preference of adsorption onto the oxidized CNT sheets can be ordered as Pb(2+)>Cd(2+)>Co(2+)>Zn(2+)>Cu(2+). Using the oxidized CNT sheets, waste water treatment without CNT leakage into water is economically feasible. Therefore, CNT sheets have good potential application in environmental protection. PMID- 20926187 TI - Kinetics of Fe(3)O(4)-CoO/Al(2)O(3) catalytic ozonation of the herbicide 2-(2,4 dichlorophenoxy) propionic acid. AB - The presence of Fe(3)O(4)-CoO/Al(2)O(3) can improve degradation efficiency significantly during the ozonation of the herbicide 2-(2,4-dichlorophenoxy) propionic acid (2,4-DP). The main factors affecting degradation efficiency, such as pH, the catalyst concentration and addition of the scavenger, were investigated. The kinetics of the catalytic ozonation are also discussed. The results indicate that two factors, the oxidation after adsorption of 2,4-DP and the oxidation of hydroxyl radicals (OH), lead to a great enhancement in ozonation efficiency during the catalytic ozonation of 2,4-DP in the presence of Fe(3)O(4) CoO/Al(2)O(3), in which the oxidation of the OH plays an important role. Under controlled conditions, the apparent reaction rate constants for the degradation of 2,4-DP were determined to be 2.567 * 10(-4)s(-1) for O(3) and 1.840 * 10(-3)s( 1) for O(3)/Fe(3)O(4)-CoO/Al(2)O(3). The results from the analysis of the reaction kinetics using the relative method showed that O(3)/Fe(3)O(4) CoO/Al(2)O(3) possessed a larger R(ct) (R(ct) is defined as the ratio of the .OH exposure to the O(3) exposure, R(ct) = ?C(t)(OH) dt/C(t)O(3)dt) than O(3), indicating that O(3)/Fe(3)O(4)-CoO/Al(2)O(3) produced more hydroxyl radicals. PMID- 20926188 TI - Selective inhibition of nitrite oxidation by chlorate dosing in aerobic granules. AB - Partial nitrification was successfully achieved with addition of 5mM KClO(3) in the aerobic granules system. Batch tests demonstrated that KClO(3) selectively inhibited nitrite-oxidizing bacteria (NOB) but not ammonia-oxidizing bacteria (AOB). During stable partial nitrification, the influent pH was kept at 7.8-8.2, while the DO and temperature were not controlled in the SBR. When the NH(4)-N and COD levels were kept at 100mg/l and 400mg/l in the influent, the NH(4)-N and COD removal efficiencies reached 98.93% and 78.65%, respectively. The NO(2)-N accounted for 92.95% of the NO(chi)-N (NO(2)-N+NO(3)-N) in the effluent. Furthermore, about 90% of the chlorate was reduced to nontoxic chloride, thus it would not cause environmental problem. SEM showed that the main composition of the aerobic granules was bacilli and coccus bacteria. FISH analysis revealed that AOB became the dominant nitrifying bacteria, whereas NOB were detected only in low abundance. Chlorate could be used to control the development and maintenance of aerobic granules sludge for partial nitrification. PMID- 20926189 TI - Modified native cellulose fibers--a novel efficient adsorbent for both fluoride and arsenic. AB - Native cellulose fibers were surface modified by poly(N,N-dimethyl aminoethyl methacrylate) (PDMAEMA) to generate an anion adsorbent, which was characterized by scanning electron microscopy, fourier transform infrared spectroscopy and elemental analyzer. This adsorbent had high efficiency in removal of F(-), AsO(2)(-) and AsO(4)(3-) from aqueous solutions, even at low initial concentrations. Adsorption kinetics showed that the adsorption equilibrium could be reached within 1 min. The distribution coefficient did not change with adsorbent dose, indicating the adsorption was a homogenous process. Langmuir, Freundlich and Temkin models were used to fit the adsorption isotherms. Based on the parameters calculated from the models, the adsorption capacity was in the order of AsO(4)(3-)?AsO(2)(-)>F(-), and the adsorption was a favorable process. Compared with Freundlich and Temkin models, the isotherms followed Langmuir model a little better. PMID- 20926190 TI - Mechanisms of association between obesity and chronic pain in the elderly. AB - Chronic pain is more common in the elderly and impairs functioning and quality of life. Though obesity, defined by body mass index (BMI), has been associated with pain prevalence among older adults, the mechanism of this association remains unclear. We examined components of the metabolic syndrome, insulin resistance, a marker of inflammation, and the presence of painful comorbidities as possible mediators of this association. Participants were 407 individuals aged >70 in the Einstein Aging Study. Chronic pain and pain over the last 3 months were defined using the Total Pain Index (TPI). Insulin resistance was modeled as fasting insulin, HOMA and QUICKI. High sensitivity C-reactive protein was used as a marker of inflammation. Cross-sectional logistic regression models were constructed to assess the associations of these factors with prevalent pain, adjusted for other known pain correlates. Prevalence of chronic pain was 52%. Of the clinical components of metabolic syndrome, central obesity was significantly associated with pain (OR 2.03, 95% CI 1.36-3.01). After adjustment for insulin resistance, inflammation, and pain-related comorbidities, central obesity predicted higher TPI scores (OR 1.55, 95% CI 1.04-2.33) and nearly doubled the risk of chronic pain (OR 1.70, 95% CI 1.05-2.75). Central obesity is the metabolic syndrome component showing the strongest independent association with pain, and the relationship is not explained by markers of insulin resistance or inflammation, nor by the presence of osteoarthritis or neuropathy. PMID- 20926191 TI - Generalized expansion of nociceptive reflex receptive fields in chronic pain patients. AB - Widespread central hypersensitivity is present in chronic pain and contributes to pain and disability. According to animal studies, expansion of receptive fields of spinal cord neurons is involved in central hypersensitivity. We recently developed a method to quantify nociceptive receptive fields in humans using spinal withdrawal reflexes. Here we hypothesized that patients with chronic pelvic pain display enlarged reflex receptive fields. Secondary endpoints were subjective pain thresholds and nociceptive withdrawal reflex thresholds after single and repeated (temporal summation) electrical stimulation. 20 patients and 25 pain-free subjects were tested. Electrical stimuli were applied to 10 sites on the foot sole for evoking reflexes in the tibialis anterior muscle. The reflex receptive field was defined as the area of the foot (fraction of the foot sole) from which a muscle contraction was evoked. For the secondary endpoints, the stimuli were applied to the cutaneous innervation area of the sural nerve. Medians (25-75 percentiles) of fraction of the foot sole in patients and controls were 0.48 (0.38-0.54) and 0.33 (0.27-0.39), respectively (P=0.008). Pain and reflex thresholds after sural nerve stimulation were significantly lower in patients than in controls (P<0.001 for all measurements). This study provides for the first time evidence for widespread expansion of reflex receptive fields in chronic pain patients. It thereby identifies a mechanism involved in central hypersensitivity in human chronic pain. Reverting the expansion of nociceptive receptive fields and exploring the prognostic meaning of this phenomenon may become future targets of clinical research. PMID- 20926193 TI - Effects of temperature on heat pain adaptation and habituation in men and women. AB - We recently reported that women report greater pain adaptation and habituation to moderately painful heat stimuli than men (Hashmi and Davis [16]); but slightly lower temperatures were needed to evoke moderate pain in the women. Hardy et al (1962) and LaMotte (1979) suggested that pain adaptation is most prominent at modest noxious heat temperatures and may occur at temperatures close to pain thresholds. Thus, as a follow-up to our previous study, we examined the role of absolute temperature in pain adaptation and habituation in men and women and assessed whether pain threshold impacts these findings. We hypothesised that pain adaptation and habituation would be more prominent at low and moderate temperatures, and that higher temperatures would induce pain adaptation and habituation in women but not in men. We further hypothesized that pain adaptation would not be correlated with pain thresholds. To test this, we obtained continuous ratings of pain evoked by 44.5-47.5 degrees C stimuli applied to the dorsal foot of men and women. Each run consisted of three 30s stimuli at the same temperature with a 60s inter-stimulus interval. Women showed within-stimulus adaptation of total pain at all temperatures, but men showed significant adaptation to temperatures less than 47 degrees C. There were no sex differences in inter-stimulus habituation and both men and women reported habituation to temperatures less than 46 degrees C. Pain thresholds did not correlate with pain adaptation. These data highlight the temperature-sensitivity and sex differences of pain adaptation and habituation. PMID- 20926192 TI - Sex-specificity and estrogen-dependence of kappa opioid receptor-mediated antinociception and antihyperalgesia. AB - This investigation determined whether the activation of the kappa opioid receptor (KOR) in the spinal cord produces estrogen-dependent, sex-specific modulation of acute and inflammation-induced persistent nociception. We demonstrate for the first time that KOR antinociception and gene expression are enhanced by exogenous or endogenous estrogen in the female. The lack of KOR antinociception and KOR gene expression are not altered by the hormonal status (testosterone or estrogen) in males. Cannulae were implanted intrathecally in male, gonadectomized male (GDX), intact and ovariectomized female (OVX) Sprague-Dawley rats. Estradiol was injected subcutaneously, 48h before testing (GDX+E and OVX+E). Intrathecal injection of U50,488H, a selective KOR agonist, dose dependently increased heat evoked tail flick latencies (TFLs) in proestrous and OVX+E groups, but not in male, GDX, GDX+E, OVX, and diestrous groups. Further, estrogen dose-dependently enhanced the effect of U50,488H in OVX rats. KOR selective antagonist, nor binaltorphimine (Nor-BNI), blocked the antinociceptive effect of U50,488H. U50,488H reversed the carrageenan-induced thermal hyperalgesia in OVX+E rats, but not in male or OVX rats. However, U50,488H treatment did not alter mechanical thresholds in any group, with or without inflammation. KOR gene expression was enhanced in proestrous and OVX+E groups as compared to any other group. We conclude that selective activation of KOR in the spinal cord produces sex specific, stimulus- and estrogen-dependent attenuation of acute and inflammatory pain in the rat via estrogen-induced upregulation of the KOR gene expression in the spinal cord. These findings may further implicate estrogen dependence of KOR effects in learning, epilepsy, stress response, addiction etc. PMID- 20926194 TI - Longitudinal study of an outbreak of Trypanosoma evansi infection in equids and dromedary camels in Israel. AB - An outbreak of trypanosomoasis caused by Trypanosoma evansi involving horses, camels and donkeys occurred in a farm in Israel. A longitudinal study of two outbreak phases was conducted which included clinical monitoring, blood smears, packed cell volume (PCV), serology and polymerase chain reaction (PCR) followed by reverse dot blot (RDB) for the molecular detection of infection. This was the first reported T. evansi outbreak in domestic animals in Israel. Most of the camels on the farm (8/10; 80%) were diagnosed with T. evansi infection whereas infection was less prevalent in the horses (3/7; 43%) and donkeys (6/13; 46%). Clinical disease was evident in 4 camels and 1 horse exhibiting characteristic clinical signs, anemia and parasitemia detected on blood smears and by positive RDB. Six other animals were diagnosed as asymptomatic latent carriers by positive RDB and 6 additional animals were only seropositive and were considered suspected carriers. A significant difference was found in the mean PCV between symptomatic and latent carriers with severe anemia observed only in the symptomatic animals. An anaphylactic-like reaction, fatal in one case, was observed in 2 camels diagnosed with severe trypanosome parasitemia immediately following treatment with melarsenoxide cysteamine. Furthermore, recurrence of infection was documented in one camel 4 months post treatment. PMID- 20926195 TI - Injuries and deaths at a pub fire in Bangkok, Thailand on New Year's Eve 2009. AB - This investigation describes the 67 people who died and the 153 who were hospitalized from a New Years' Eve fire in a Bangkok pub. We interviewed survivors and reviewed medical charts and forensic reports of decedents. Survivors were young (median age 27 years), single (84.7%) and lived in Thailand (93.6%). Most were on the concert floor when the fire started (74.0%), became aware of danger when they saw flames (61.5%) and escaped through the main entry door (42.9%). Common injuries were burns (75.6%), smoke inhalation (47.4%) and open wounds (32.1%). The decedents' median age was 27 years and 88.1% lived in Thailand. Most of the dead bodies were found at or near the main entrance. The main causes of death were asphyxia (88.1%) or burn (10.4%). Soot was present in the trachea of 95.5% of the decedents. Carboxyhemoglobin level in 37.5% was in the toxic range. The average percent of body surface burned was 75.0%. Loss of consciousness in the pub (RR 3.5, 95% CI 1.7-7.3) was a risk factor for severe injury and smoke inhalation (RR 9.3, 95% CI 3.1-28.0) was a risk factor for death. PMID- 20926196 TI - Incidence and risk factors of vancomycin-resistant enterococcus colonization in burn unit patients. AB - This study was aimed to identify the incidence of vancomycin-resistant enterococcus (VRE) colonization in burn patients, to collate risk factors for colonization and to determine the VRE resistance profile to different antimicrobial agents. This prospective study was carried out on the burn unit, during the period from September 2008 to January 2010, in 128 patients who were hospitalized at least 3 weeks or more. Periodic swabs were taken from burn wound, rectal, axillary, umblicaly and throat regions of the patients on admission and 7th, 14th, 21st days of hospitalization. Demographics and known risk factors were retrieved and assessed by statistical methods. Only 20 patients (15.6%) were colonized with enterococci on admission and these strains isolated from rectal, umblical and throat samples were sensitive to vancomycin. Initial VRE isolation was made in the first samples from the rectum of two patients on the 7th day. The rates of rectal, umblical, throat and axillary colonization increased to 21.9%, 3.1%, 3.1% and 3.1% at 28th day, respectively. VRE strains were the first isolated from burn wounds of only one patient (0.8%) on the 14th day and the colonization rate increased to 7.0% at the 28th day. Our study indicated that rectal colonization was seen more than other sites of colonization and was strictly correlate to colonizing enterococci between burn wound and other body regions. Multivariate analyses showed that glycopeptide use, burn depth and total burn surface area were independent risk factors for acquisition of VRE. All VSE strains were susceptible to teicoplanin, tigecycline and linezolid. VSE strains were more resistant to gentamicin and streptomycin, and VRE strains were more resistant to penicillin and ampicillin. The present study showed tigecycline and linezolid to be most active agents against VRE strains. The determined VRE colonization and risk factors of VRE acquisition are expected to be useful in establishing guidelines for preventing VRE infection in burn unit. PMID- 20926197 TI - Topically applied rhGM-CSF for the wound healing: a systematic review. AB - The process of wound healing involves a complex interplay of cells, mediators, growth factors and cytokines. GM-CSF has been shown to be involved in a number of processes essential in this event. Topically applied rhGM-CSF has been reported to successfully treat wounds with diverse etiology, including burns, chronic venous leg ulcers, pressure ulcers, and leprosy ulcers, both in animal experiments and clinical studies. To evaluate the effect of the rhGM-CSF on wound healing, 8 RCT studies and 23 clinical studies and case reports are collected for analysis of the evidence. The overall effects of rhGM-CSF on the healing of wound are diverse. Topically applied rhGM-CSF is beneficial for deep partial-thickness burn wounds, chronic leg ulcers, and leprosy ulcers. rhGM-CSF may have a positive effect on other type of chronic ulcers such as pressure ulcers and cancer related ulcers, but the evidence is not sufficient for generalised use at present. rhGM CSF is suggested have no accelerating effect on the healing of healthy wounds or surgical incisions. PMID- 20926198 TI - Differences in the relative involvement of peripherally released interleukin (IL) 6, brain IL-1beta and prostanoids in mediating lipopolysaccharide-induced fever and sickness behavior. AB - Although peripherally released interleukin (IL)-6 is critical for fever, its role in sickness behaviors, in particular anorexia and lethargy, induced by lipopolysaccharide (LPS) administration appears to be less important. Using quantifiable measures of fever, anorexia and lethargy, that is, body temperature, food intake and voluntary wheel-running, we investigated whether the less-than essential role for IL-6 in mediating sickness behaviors compared to fever implies important roles for other inflammatory mediators, particularly IL-1beta and prostanoids, in these responses. Male Sprague-Dawley rats were randomly assigned to receive one of the following three injections before receiving a subcutaneous (SC) injection of LPS (250 MUg/kg) or saline: (1) intraperitoneal injection of pre-immune serum or antiserum to IL-6 (IL-6AS), to reduce the biological activity of peripherally released IL-6; (2) intracerebroventricular injection of vehicle or a caspase-1 inhibitor, to inhibit the production of mature IL-1beta; or (3) intraperitoneal injection of vehicle or one of the two doses (1 or 10 mg/kg) of diclofenac, a nonselective cyclooxygenase inhibitor shown to block the formation of prostanoids. LPS administration induced fever, anorexia and lethargy with an accompanying increase in IL-6 and IL-1beta concentrations in the circulation and IL-1beta in the brain. Rats pre-treated with: (1) IL-6AS had reduced plasma levels of bioactive IL-6, no fever and attenuated sickness behaviors; (2) the caspase-1 inhibitor had reduced concentrations of IL-1beta in the pre-frontal cortex, hypothalamus and hippocampus, and attenuated fever and sickness behaviors; (3) diclofenac had a dose-dependent attenuation in fever and sickness behaviors. Doses of diclofenac which completely abolished fever however had lesser effects on anorexia and lethargy. Our results confirm a difference in the sensitivity of sickness responses to IL-6 antagonism and identify that it may be related to different levels of sensitivity or responsiveness in brain regions and/or mechanisms, to prostanoids, IL-1beta, or IL-6 itself. PMID- 20926199 TI - Temporally controlled multiple-gene delivery in scaffolds: A promising strategy to enhance bone regeneration. AB - Bone defects sometimes require more effective repair regimens than conventional clinical therapies can provide. On account of this, tissue-engineered scaffolds have emerged as a promising alternative. Scaffolds that release genes encoding growth factors (GFs) offer additional benefits for bone regeneration in comparison with scaffolds providing protein delivery. The present gene delivery systems focus on unitary or dual genes delivery without controlled release. In the meantime, evidences indicate that bone formation is a complex cascade of events, in which time-dependent expression of multiple growth factors is involved. In our hypothesis, a temporally controlled, multi-gene delivery system embedded in a scaffold matrix can be fabricated; such a system is capable of mimicking the expression of growth factor profile in osteogenesis. Consequently, bone regeneration can be promoted by sequential gene expression of multiple growth factors. PMID- 20926200 TI - Hypothalamic opioid-melanocortin appetitive balance and addictive craving. AB - Whilst the parallels between drug and food craving are receiving increasing attention, the recently elucidated complex physiology of the hypothalamic appetite regulatory centres has been largely overlooked in the efforts to understand drug craving which is one of the most refractory and problematic aspects of drug and behavioural addictions. Important conceptual gains could be made by researchers from both appetite and addiction neuroscience if they were to have an improved understanding of each others' disciplines. It is well known in addiction medicine that the use of many substances is elevated in opiate dependency. There is voluminous evidence of very high rates of drug use in opiate agonist maintained patients, and the real possibility exists that opiate agonist therapy therefore increases drug craving. Conversely, opiate antagonist therapy with naloxone or naltrexone has been shown to reduce most chemical and behavioural addictions, and naltrexone is now being developed together with bupropion as the anti-obesity drug "Contrave". Hypothalamic melanocortins, particularly alpha-MSH, are known to constitute the main brake to consumptive behaviour of food. There is a well described antagonism between melanocortins and opioids at many loci including the hypothalamus. Administration of exogenous opiates is known to both suppress alpha-MSH and to stimulate hedonic food consumption. Opiate maintenance programs are associated with weight gain. As monoamines, opioids and cannabinoids are known to be involved in appetite regulation, and as endorphin opioids are known to be perturbed in other addictions, further exploration of the hypothalamic appetite regulatory centre would appear to be an obvious, albeit presently largely overlooked, locus in which to study drug and other craving mechanisms. PMID- 20926201 TI - Consumer acceptance of high pressure processed beef-based chilled ready meals: the mediating role of food-related lifestyle factors. AB - The aim of this research was to investigate the effects of high pressure processing (HPP) on consumer acceptance for chilled ready meals manufactured using a low-value beef cut. Three hundred consumers evaluated chilled ready meals subjected to 4 pressure treatments and a non-treated control monadically on a 9 point scale for liking for beef tenderness and juiciness, overall flavour, overall liking, and purchase intent. Data were also collected on consumers' food consumption patterns, their attitudes towards food by means of the reduced food related lifestyle (FRL) instrument, and socio-demographics. The results indicated that a pressure treatment of 200 MPa was acceptable to most consumers. K-means cluster analysis identified 4 consumer groups with similar preferences, and the optimal pressure treatments acceptable to specific consumer groups were identified for those firms that would wish to target attitudinally differentiated consumer segments. PMID- 20926202 TI - Oxidative and color stability of cooked ground pork containing lotus leaf (Nelumbo nucifera) and barley leaf (Hordeum vulgare) powder during refrigerated storage. AB - This study aimed to evaluate the oxidative and color stability of cooked ground pork containing lotus leaf powder at 0.1 (LP1) and 0.5% (LP2) as well as barley leaf powder at 0.1 (BP1) and 0.5% (BP2) during refrigerated storage for 10 days. The oxidative stability of these powders was compared with butylhydroxytoluene (BHT). LP1 had higher a* and lower b* values than the control (-) over 4 days (p<0.05). The pH values of the ground pork samples made with addition of LP and BHT decreased until day 4 and then increased. Thiobarbituric acid-reactive substance (TBARS) values were lowest in LP2 on day 10 (p<0.05). The ground pork samples containing LP and BP had lower peroxide values (POVs) and conjugated dienes (CD) compared to the control (-).These results indicate that LP or BP can be incorporated into ground pork to effectively retard oxidation after cooking. PMID- 20926203 TI - Relationship between plasma cells and hepatic stellate cells in autoimmune hepatitis. AB - Autoimmune hepatitis is an inflammatory chronic disease of the liver, which frequently results in cirrhosis. The present study aimed to verify the relationship between plasma cells and stellate cells in autoimmune hepatitis. Thirty-three pre-treatment, 11 post-treatment, and 10 normal liver biopsies were reviewed. Sirius Red staining (for semi-quantitative analysis of hepatic fibrosis) and immunohistochemistry were carried out: double staining for smooth muscle alpha-actin and plasma cell marker (for detection and localization of activated hepatic stellate cells and plasma cells, respectively); and single staining for glial fibrillary acid protein (for detection of hepatic stellate cells). We found an increase in the stellate cell population, mainly with an activated phenotype in autoimmune hepatitis, compared to the control group (liver specimens with no histological evidence of liver disease, obtained from patients undergoing hepatic resection for benign liver mass). A positive significant correlation was observed between stellate cells and scores of fibrosis (measured by Sirius Red) and the number of plasma cells. Additionally, there was a co localization of plasma cells and activated stellate cells. We also observed a reduction in the number of plasma cells, hepatic stellate cells, and fibrosis in patients who had successfully been treated and had a second liver biopsy post treatment. Our findings support that the number of plasma cells can be a surrogate marker for the severity of liver disease, reflecting the number of hepatic stellate cells and the amount of fibrosis. It remains to be seen if this is a result of a direct interaction between the plasma cells and hepatic stellate cells or the response to the same stimulus that affects both cellular types. PMID- 20926204 TI - Multiple meningioma with different grades of malignancy: case report with genetic analysis applying single-nucleotide polymorphism array and classical cytogenetics. AB - Multiple meningiomas with synchronous tumor lesions represent only 1-9% of all meningiomas and usually show a uniform histology. The simultaneous occurrence of different grades of malignancy in these nodules is observed in only one third of multiple meningiomas. We report a case of a sporadic multiple meningioma presenting with different histopathological grades (WHO I and II). The tumor genome of both nodules was analyzed by GTG-banding, spectral karyotyping (SKY), locus-specific FISH, and single nucleotide polymorphism array (SNP-A) karyotyping. GTG-banding and SKY revealed 25 structural and 33 numerical aberrations with a slightly increased aberration frequency in the WHO grade II nodule. We could confirm terminal deletions on chromosomes 1p [ish del(1)(p36)(p58-,pter-) 16.5% WHO grade I and 20.9% WHO grade II], partial deletions on 22q, and/or monosomy 22 (monosomy 22 14% WHO grade I and 34% WHO grade II) as the most frequent aberrations in both meningioma nodules. In the meningioma WHO grade II, in addition, a de novo paracentric inversion within chromosomal band 1p36 was detectable. Furthermore, for meningiomas de novo, dicentric chromosomes 4 could be identified in both tumor nodules. We also detected previously published segmental uniparental disomy regions 1p31.1, 6q14.1, 10q21.1, and 14q23.3 in normal control DNA of the patient and in both tumor nodules. Taken together, we describe a very rare case of multiple meningioma with overlapping but also distinct genetic aberration patterns in two nodules of different WHO grades of malignancy. PMID- 20926205 TI - [Modern management of cervical intraepithelial neoplasia: a proposal for a risk assessment method in colposcopic decision-making]. AB - Recent improve in the understanding of the natural progression of cervical intraepithelial neoplasia (CIN) and in the knowledge of treatments pregnancy related morbidity in addition with progression in mean age of first pregnancy brings out the need to rethink CIN management. Efficient tools are therefore needed to optimize therapeutic indications and destructive techniques have to be reconsidered. Because there is no superior technique for treating CIN in terms of treatment failure, the choice of a treatment method will not depend on this criteria but on the overall consideration of its characteristics, advantages and limitations put in balance with age of women, plan of pregnancy as well as CIN severity, risk of progression and of microinvasion misdiagnosis. The use of a "risk assessment method" based on five criteria: colposcopic impression, transformation zone type and size, age and agreement between cytology and histology would allow for proper evaluation of the risk of microinvasion misdiagnosis. Depending on their severity, each of these five criteria would be graded from 1 to 3. The presence of at least one grade 3 criteria would warrant the need for excisional treatment, preferably large loop excision of the transformation zone, allowing for histological analysis and reliable diagnosis. Ablative technique could be reasonably considered for only one grade 2 criteria or if all criteria are grade 1, reflecting good prognosis. Such risk assessment method requires to be prospectively evaluated. PMID- 20926206 TI - [An unusual endometritis]. AB - We report a case of pyometra without any related risk factor. This leads to a severe septic shock. Evolution was successful because of quick surgical management. We report literature management of such infection. Although pyometra is an uncommon disease, it should be kept in mind as delayed management may lead to fatal outcome. PMID- 20926207 TI - [Statement of conscience in trisomy 21 screening: pregnant women's free will jeopardized]. PMID- 20926208 TI - Ovine footrot: new approaches to an old disease. AB - Footrot is a bacterial disease that has substantial economic and welfare impacts in sheep and can be difficult to manage. Research is focussed on reducing the impact that footrot has on farmers and their flocks and better understanding the aetiology of the disease. Key areas of current research include, developing better vaccines, deploying tailored vaccines in a specific and targeted fashion on individual farms, analysing and developing better farm management practices to suit specific sheep farming environments, elucidating the virulence genes and bacterial population dynamics that drive footrot and using genetic testing in combination with selective breeding to produce stock that are more resilient to disease. PMID- 20926209 TI - Characterization of Arcanobacterium abortisuis by phenotypic properties and by sequencing the 16S-23S rDNA intergenic spacer region. AB - The present study was designed to characterize phenotypically and genotypically nine Arcanobacterium abortisuis strains collected from specimen of pigs in a period of nine years. All nine A. abortisuis strains and A. abortisuis reference strain DSM 19515 displayed a synergistic hemolytic reaction with Staphylococcus aureus beta-hemolysin, Rhodococcus equi, and Arcanobacterium haemolyticum indicator strains and showed the typical biochemical properties of this species. The species identity could be confirmed by identification and sequencing of the 16S-23S rDNA intergenic spacer region (ISR), which appeared to be a useful target for genotypic characterization of this bacterial species. The A. abortisuis strains of the present study were isolated from specimen of pigs together with various other bacterial species indicating that the pathogenic importance of this newly described species remains to be elucidated. PMID- 20926210 TI - Controlled doe exposure as biostimulation of buck rabbits. AB - Female exposure of males could be a low-cost biostimulation option that benefits AI in commercial rabbit operations by improving buck rabbits reproductive performance. The objective of the study was to evaluate exposure of buck rabbits to females as a biostimulation option to improve reproductive potential. Treatments were: exposure (biostimulated) or not (control) of bucks to does. Bucks were New Zealand White, 15-month-old, sexually experienced and fertile. Experimental design was completely random with nine replications, experimental unit was one buck. Doe exposure was permanent using replacement pubertal does housed in an adjacent wire-mesh cage and changed for new ones every other week. Semen collection lasted 14 weeks (late winter and early spring) twice a week with two ejaculates at each collection. Analyses of variance were under a mixed model: treatments, ejaculate number and season were fixed and rabbit random effects and buck weight at each collection as covariable. Biostimulated bucks showed greater (P<0.05) reproductive potential due to: 7% lesser reaction time (greater libido); and increased semen volume (40%), sperm motility (29%), sperm per ejaculate (31%), normal alive motile sperm (65%) and number of semen doses (64%). Semen characteristics differed by season in control bucks but not in doe exposed bucks (treatment * ejaculate number, P<0.05). Reproductive potential in spring was greater (P<0.05) than in winter in both treatments. Doe exposure is a biostimulation method that improves sexual drive and sperm production and quality of buck rabbits. PMID- 20926211 TI - Clinical fractures cluster in time after initial fracture. AB - A history of fractures is a well recognised risk factor for a new clinical fracture. However, this subsequent fracture risk is not constant, but fluctuates over time, with the greatest increase in the years immediately after the initial fracture, followed by a gradual waning of risk toward the population risk. The clustering of fractures occurred regardless of age, gender and initial fracture location. It is therefore likely that fracture risk models, which take into account this fluctuation of fracture risk over time, will be more relevant in predicting an individual's subsequent fracture risk. Regardless of the cause of this clustering, these studies all strongly support the need for early action after an initial fracture to reduce the preventable risk of subsequent fractures with medical interventions that have been shown to immediately decrease the risk of fractures. PMID- 20926212 TI - Congenital infection-like syndrome with intracranial calcification. AB - Congenital infection-like syndrome includes multiple disorders. Although novel syndromes have recently been described and their genetic defects identified, many cases remain unclassified. Here we report a patient with neuroradiologic findings of intracranial calcification and cerebellar hypoplasia, and clinical features of growth retardation, progressive pancytopenia, interstitial pneumonia, and immune abnormality. Our patient had a phenotypic overlap with Aicardi-Goutieres syndrome and Hoyeraal-Hreidarsson syndrome, despite the absence of mutation in their responsible genes. PMID- 20926213 TI - Hyperpyrexia resulting in encephalopathy in a 14-month-old patient with cblC disease. AB - Cobalamin C (cblC) defect, the most common inborn error of cobalamin metabolism, is a multisystem disorder usually presenting with progressive neurological, haematological and ophthalmological signs. We report on a cblC patient diagnosed in the newborn age who developed nearly normal during the first year of life. During an upper respiratory tract infection with severe hyperpyrexia at the age of 14months he developed an acute encephalopathic crisis resulting in severe mental retardation and marked internal and external cerebral atrophy. Hyperacute encephalopathic crises have not been observed so far in patients with cblC defect. It remains unclear, if this association is incidental or if the underlying metabolic defect may have predisposed the brain tissue to hyperpyrexia induced damage. PMID- 20926214 TI - Aeroportia and gastric pneumatosis due to gastroparesia. PMID- 20926215 TI - Simultaneous quantification of dextromethorphan and its metabolites dextrorphan, 3-methoxymorphinan and 3-hydroxymorphinan in human plasma by ultra performance liquid chromatography/tandem triple-quadrupole mass spectrometry. AB - A rapid and sensitive ultra performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) method has been developed and validated for the simultaneous quantitative determination of dextromethorphan (DM) and its metabolites dextrorphan (DX), 3-methoxymorphinan (3MM) and 3-hydroxymorphinan (3HM), in human lithium heparinized plasma. The extraction involved a simple liquid-liquid extraction with 1 ml n-butylchloride from 200MUl aliquots of plasma, after the addition of 20 MUl 4% (v/v) ammonium hydroxide and 100 MUl stable labeled isotopic internal standards in acetonitrile. Chromatographic separations were achieved on an Aquity UPLC((r)) BEH C(18) 1.7 MUm 2.1 mm x 100mm column eluted at a flow-rate of 0.250 ml/min on a gradient of acetonitrile. The overall cycle time of the method was 7 min, with elution times of 1.3min for DX and 3HM, 2.8 min for 3MM and 2.9min for DM. The multiple reaction monitoring transitions were set at 272>215 (m/z), at 258>133 (m/z), at 258>213 (m/z) and at 244>157 (m/z) for DM, DX, 3MM and 3HM, respectively. The calibration curves were linear (r2>=0.995) over the range of 0.500-100 nM with the lower limit of quantitation validated at 0.500 nM for all compounds, which is equivalent to 136, 129, 129 and 122 pg/ml for DM, DX, 3MM and 3HM, respectively. Extraction recoveries were constant, but ranged from 39% for DM to 83% for DX. The within run and between-run precisions were within 11.6%, while the accuracy ranged from 92.7 to 110.6%. The applicability of the bioanalytical method was demonstrated and is currently implemented in a clinical trial to study DM as probe-drug for individualized tamoxifen treatment in breast cancer patients. PMID- 20926216 TI - Microfluidic direct injection method for analysis of urinary 4 (methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) using molecularly imprinted polymers coupled on-line with LC-MS/MS. AB - The work described in this paper involves development of a high-throughput on line microfluidic sample extraction method using capillary micro-columns packed with MIP beads coupled with tandem mass spectrometry for the analysis of urinary NNAL. The method was optimized and matrix effects were evaluated and resolved. The method enabled low sample volume (200 MUL) and rapid analysis of urinary NNAL by direct injection onto the microfluidic column packed with molecularly imprinted beads engineered to NNAL. The method was validated according to the FDA bioanalytical method validation guidance. The dynamic range extended from 20.0 to 2500.0 pg/mL with a percent relative error of +/-5.9% and a run time of 7.00 min. The lower limit of quantitation was 20.0 pg/mL. The method was used for the analysis of NNAL and NNAL-Gluc concentrations in smokers' urine. PMID- 20926217 TI - A general static-headspace gas chromatographic method for determination of residual benzene in oral liquid pharmaceutical products. AB - Sodium benzoate is used in oral liquid pharmaceutical products for its anti microbial properties. The benzoate salts present in liquid pharmaceutical products can potentially generate residual levels of free benzene during manufacturing of the drug product and or during the shelf-life of the product under its storage conditions. To ensure the safety and quality of the pharmaceutical products (containing benzoate in the formulation), a selective and sensitive analytical method is required to monitor residual benzene in oral liquid pharmaceutical products. In this paper, we report the development and validation of a general static-headspace gas chromatographic (SH-GC) method to determine residual benzene in oral liquid pharmaceutical products. The liquid pharmaceutical drug product sample is dissolved in dimethylsulfoxide (DMSO) in a GC headspace vial. A DB-624 capillary column (30 m x 0.32 mm I.D. and 1.8 MUm film thickness) was used under isothermal conditions with a flame ionization detection (FID). The benzene peak was well separated from all other volatile compounds that are present in the formulation of a number of liquid drug products. This method was successfully validated using a representative oral liquid pharmaceutical drug product. The limit of detection of the method for benzene is 0.5 ppm which met the 2 ppm limit of current ICH guideline for residual benzene in pharmaceutical products. PMID- 20926218 TI - The prevalence and characteristics of Streptococcus pneumoniae isolates expressing serotypes 6C and 6D in Hong Kong prior to the introduction of the 7 valent pneumococcal conjugate vaccine. AB - A study was conducted to determine the prevalence of the 2 newly described types, 6C and 6D, among pneumococcal isolates collected in Hong Kong before availability of the 7-valent pneumococcal conjugate vaccine. A total of 154 serogroup 6 isolates obtained from nasopharynx (n = 106), blood (n = 22), respiratory (n = 24), and cerebrospinal fluid (CSF) (n = 2) during 1995 to 2001 were analyzed by polymerase chain reaction typing. Five nasopharyngeal and 2 sputum isolates were found to belong to 6C and 6D, respectively. The isolates were genetically diverse, but one 6C and two 6D isolates exhibited some clonal relationship. Phylogenetic analysis of the wchA-wciN(beta)-wciO nucleotide sequences showed that the Hong Kong 6C/6D isolates had 2 allelic profiles, which were more closely related to 6C/6D isolates from Fijian and Korea than were those from Brazil and the United States. However, all of the wciP gene sequences for both Hong Kong and non-Hong Kong isolates clustered together: 6C isolates with the wciP-9 allele and 6D isolates with the wciP-5 allele. In conclusion, the prevalence of the 2 newly described serotypes was low before the era of the pneumococcal conjugate vaccine. Nonetheless, results from the molecular studies indicated that the evolution of the capsular genes have involved complex pathways. PMID- 20926219 TI - Evaluation of 4 polymerase chain reaction protocols for cultured Leishmania spp. typing. AB - Leishmaniasis is a disease caused by the protozoan Leishmania resulting in a variety of clinical manifestations, from self-healing skin lesions to fatal visceral disease. The development of polymerase chain reaction (PCR)-based techniques has made species identification easier, faster, and less labor intensive. The main targets for PCR amplification include kinetoplastid DNA (kDNA), miniexon, and conserved regions such as the internal transcribed spacer. The objective of this work was to evaluate 4 different PCR techniques designed to type Leishmania using laboratory strains. Parasites were subjected to 4 PCR procedures using specific Leishmania primers for miniexon (designated A1 and A2) and kDNA (designated B1 and B2, C1 and C2, and D1, D2 and D3). Discrimination between some species and the 2 main subgenera Leishmania and Viannia was achieved. Unweighted pair group method analysis resulted in the expected clustering of the 2 species from the subgenus Leishmania. However, some species in the subgenus Viannia could not be distinguished, representing a continued challenge for PCR-based protocols. Results are discussed in terms of advantages, limitations, and reproducibility of these 4 PCR-based techniques in the taxonomy of Leishmania. PMID- 20926220 TI - Comparative evaluation of 3 selective media for primary isolation of Helicobacter pylori from gastric biopsies under routine conditions. AB - This study evaluates 3 selective media (Pylori agar [bioMerieux, France], BD Helicobacter agar, modified [Becton Dickinson, USA], and an in-house medium) designed for Helicobacter pylori isolation. Ninety-eight strains were isolated from 400 gastric biopsies. The media were equally efficient for Helicobacter pylori's growth. However, contaminations were only observed using commercial media. PMID- 20926221 TI - Emergence of 16S rRNA methylase gene armA and cocarriage of bla(IMP-1) in Pseudomonas aeruginosa isolates from South Korea. AB - Of the 100 multidrug-resistant Pseudomonas aeruginosa isolates from a Korean hospital, 14 isolates that were resistant to all aminoglycosides tested carried 16S rRNA methylase gene armA. Fourteen armA-positive isolates were classified into 8 pulsotypes. Seven armA-positive isolates cocarried bla(IMP-1). This study is the first report of occurrence of armA in P. aeruginosa. PMID- 20926222 TI - Soluble Fas ligand is another good diagnostic marker for tuberculous pleurisy. AB - Soluble Fas ligand (sFasL) is abundant in effusions of tuberculous (TB) pleurisy; however, its diagnostic value has not been scrutinized. We collected pleural effusions from 79 patients, including 23 with TB pleurisy and 56 without TB, and measured sFasL, adenosine deaminase (ADA), and interferon-gamma (IFN-gamma) concentrations of each specimen. The median of the sFasL concentration of the TB group was 57.3 pg/mL, which was significantly higher than that of the non-TB group (27.4 pg/mL) (P < 0.001). When cutoff value was 39.85 pg/mL, the sensitivity and specificity of sFasL were 95.7% and 80.4%, respectively. The area under the receiver operating characteristic curve for sFasL was not significantly different from those of ADA and IFN-gamma. Soluble FasL concentrations of TB patients were significantly higher than those of parapneumonic effusion subgroup (P = 0.039). In conclusion, pleural effusion sFasL is another good diagnostic marker for TB pleurisy. PMID- 20926223 TI - Rapid differentiation of VGII/AFLP6 genotype within Cryptococcus gattii by polymerase chain reaction. AB - VGII/AFLP6 genotype, also considered to be a cryptic species within Cryptococcus gattii, is an emerging pathogen and always related to higher incidence of C. gattii infection. Here, a polymerase chain reaction-based method with specific primers was developed to rapid differentiation of this emerging pathogen. PMID- 20926224 TI - Gluteal injection site granuloma. PMID- 20926225 TI - What should laypersons know about cancer? Towards an operational definition of cancer literacy. AB - OBJECTIVE: To operationally define cancer literacy, understanding which aspects of cancer are important to be known by a layperson to be considered cancer literate. METHODS: A Delphi study in three consecutive rounds was conducted among a panel of Swiss cancer experts (oncologists, GPs, nurses from oncology wards, social workers, public health experts). RESULTS: The result of the Delphi process is a first operational definition of the concept of cancer literacy, a list of the aspects of cancer that, in the expert's view, laypeople should know to be considered cancer literate. CONCLUSIONS: We have now an idea of what should be known about cancer. The study also provides us with some useful hints about what should be communicated about cancer, e.g. via public communication campaigns, school education, or media. PRACTICE IMPLICATIONS: The operational definition of the concept can be used for the development and the validation of a measure of cancer literacy, not anymore limited to basic literacy and numeracy skills. PMID- 20926226 TI - Informing abortion counseling: an examination of evidence-based practices used in emotional care for other stigmatized and sensitive health issues. AB - OBJECTIVE: Emotional care is an important component of abortion services. Evidence-based counseling for other stigmatized and sensitive health issues may be informative for the improvement of abortion counseling. METHODS: We searched the literature for practices used in emotional care for stigmatized and sensitive health issues. We made analytic choices for the selection of articles using the "constant comparative method," a grounded theory technique. We selected practices that were effective in supporting coping and improving psychosocial adjustment. Findings were synthesized and analyzed to draw evidence-based implications for abortion counseling. RESULTS: We uncovered nine practices used in emotional care for stigmatized and sensitive health issues that have been shown to support coping or improve psychological adjustment. The techniques and interventions identified were: self-awareness assessments, peer counseling, decision aids, encouraging active client participation, supporting decision satisfaction, support groups, Internet-based support, ongoing telephone counseling, and public artistic expression. CONCLUSION: A variety of patient-centered, evidence-based interventions used for other health issues are applicable in emotional care for abortion. Evaluation of these practices in the abortion counseling setting can determine their appropriateness and effectiveness. PRACTICE IMPLICATIONS: Abortion care providers may be able to integrate additional patient-centered practices to support coping or improve psychological adjustment after abortion. PMID- 20926227 TI - Ontogenic expression profiles of thyroid-specific genes in embryonic and hatching chicks. AB - The last trimester of the embryonic life of chickens is marked by a steady increase in circulating thyroxine (T(4)) levels, reaching a maximum around hatching. We have measured thyroidal mRNA expression levels of several genes involved in the biosynthesis of T(4), namely sodium/iodine symporter (NIS), thyroglobulin (Tg), thyroid peroxidase (TPO), thyrotropin receptor (TSHR), and thyroid transcription factor 1 (TTF-1), during this period. Subsequently, we measured the expression of these genes in more detail during the entire hatching process and compared the gene expression profiles with concomitant changes in intrathyroidal and circulating thyroid hormone levels. We found that NIS and TPO mRNA expression increased significantly in the perinatal period, whereas Tg mRNA expression rose gradually throughout the last week of embryogenesis but was stable during hatching. TSHR and TTF-1 mRNA levels did not change significantly during the last week of embryonic development and hatching. Our results suggest that the elevated plasma T(4) levels observed in the developmental period studied are caused by an increased synthesis and secretion of T(4) by the thyroid gland. Augmented expression of Tg may play an important role in the increasing T(4) production during the last week of embryonic development, whereas increased NIS and TPO expression around hatching allows the thyrocytes to boost T(4) synthesis even further. PMID- 20926228 TI - Prepubertal ethanol exposure alters hypothalamic transforming growth factor-alpha and erbB1 receptor signaling in the female rat. AB - Glial-derived transforming growth factor alpha (TGFalpha) activates the erbB1/erbB2 receptor complex on adjacent glial cells in the medial basal hypothalamus (MBH). This receptor activation stimulates the synthesis and release of prostaglandin-E(2) (PGE(2)) from the glial cells, which then induces the release of prepubertal luteinizing hormone-releasing hormone (LHRH) secretion from nearby nerve terminals; thus, showing the importance of glial-neuronal communications at the time of puberty. Ethanol (EtOH) is known to cause depressed prepubertal LHRH secretion and delayed pubertal development. In this study, we assessed whether short-term EtOH exposure could alter the hypothalamic glial to glial signaling components involved in prepubertal PGE(2) secretion. Immature female rats began receiving control or EtOH diets beginning when 27 days old. The animals were killed by decapitation after 4 and 6 days of treatment and confirmed to be in the late juvenile stage of development. Blood and brain tissues were collected for gene, protein, and hormonal assessments. Real-time polymerase chain reaction (PCR) analysis demonstrated that EtOH did not affect basal levels of erbB1 gene expression in the MBH. Expression of total erbB1 protein was also unaffected; however, the EtOH caused suppressed phosphorylation of erbB1 protein in the MBH at both 4 and 6 days (P<.01) as revealed by Western blotting. Phosphorylation and total protein levels of erbB2 receptor were not affected by EtOH exposure. Because this receptor is critical for PGE(2) synthesis/release, which mediates the secretion of LHRH, we assessed whether in vivo EtOH exposure could affect the release of PGE(2). EtOH exposure for 6 days suppressed (P<.01) basal levels of PGE(2) released into the medium. The effects of 4- and 6-day EtOH exposure on gene and protein expressions of TGFalpha, an upstream component in the activation of erbB1/erbB2, were also studied. The levels of TGFalpha mRNA were increased markedly at 4 days (P<.001), but declined to near basal levels by 6 days in the EtOH-treated animals. The EtOH caused increases in TGFalpha protein expression at both 4 (P<.001) and 6 (P<.01) days; hence, suggesting that the EtOH inhibited release of the peptide. We confirmed this inhibition by showing decreased (P<.01) TGFalpha released from MBHs incubated in vitro following 6 days of EtOH exposure in vivo. Thus, these results demonstrate that EtOH is capable of interfering with hypothalamic glial to glial signaling processes involved in prepubertal PGE(2) secretion. PMID- 20926229 TI - Prognostic factors in stages II/III/IV and stages III/IV endometrioid and serous adenocarcinoma of the endometrium. AB - AIMS: To explore and to compare the outcome of patients diagnosed with stage II/III/IV and stage III/IV endometrioid adenocarcinoma (EAC) with their serous carcinoma (USC) counterparts. MATERIALS AND METHODS: A total of 107 patients (73 EAC and 34 USC) were evaluated. For statistical analysis, the following baseline variables were considered for their prognostic value: the patient's age at presentation, the tumor size, the depth of myometrial invasion (MI), the lympho vascular involvement (LVI) and the USC and the EAC subtypes (considered as binary variables). Disease free survival (DFS), death of disease (DOD) and overall survival (OS) were assessed using univariate and multiple Cox proportional hazards models. RESULTS: In univariate analysis, USC tends to recur more frequently than EAC (p = 0.004), a finding that disappeared in multivariate analysis. Furthermore, tumor histology had no significance in predicting the tumor outcomes. Among all of the prognostic factors and after adjusting for the aforementioned variables, MI >=50% was the only independent factor in predicting DOD in stages II/III/IV (p = 0.009) and in stages III/IV (p = 0.004). MI was also an independent predictive factor for OS (p = 0.02) and early recurrences in stages III/IV. LVI was the only independent factor in predicting recurrences (p = 0.004) in stages II/III/IV but not in stages III/IV. CONCLUSION: Based on our study, tumor histology was not a significant factor in predicting disease outcome in stages II/III/IV and II/IV. Despite our limited sample size, we believe that our findings provide meaningful insights into the clinical study of endometrial cancer patients which in turn warrants further investigation. PMID- 20926230 TI - Radiographic results of femoral tunnel drilling through the anteromedial portal in anterior cruciate ligament reconstruction. AB - PURPOSE: The goal of this study was to determine the femoral tunnel position by use of the head of a metallic femoral interference screw as a reference marker. In addition, we present postoperative films from an anatomically placed single bundle anterior cruciate ligament with femoral interference screw fixation using the anteromedial portal drilling technique. METHODS: Two surgeons evaluated 43 random postoperative radiographs in patients who underwent anterior cruciate ligament reconstruction by a single surgeon. Four measurements were taken on lateral knee radiographs with superimposed condyles for each patient. These included the total sagittal diameter of the lateral condyle measured along the Blumensaat line (A1), the maximum intercondylar height from the Blumensaat line to the condyle edge along the center of the screw head (B1), the distance from the center of the screw head to the most dorsal contour of the lateral condyle (A2), and the distance from the center of the screw head to the Blumensaat line (B2). The latter 2 values were then expressed as percentages of the lengths A1 and B1. From the anteroposterior (AP) films, the angle between the axis of the screw and anatomic axis of the femur was determined. RESULTS: The center of the screw head was 31.3% of the Blumensaat line and 24.8% of the condylar height. The axis of the screw was found to be 43 degrees from the anatomic axis of the femur on the AP radiographs. CONCLUSIONS: The mean center of the screw head was 31.3% of the Blumensaat line and 24.8% of the condylar height. The mean axis of the screw was found to be 43 degrees from the anatomic axis of the femur on the AP radiographs. Furthermore, we have described the appearance of a lateral radiograph with this technique. LEVEL OF EVIDENCE: Level III, diagnostic study. PMID- 20926231 TI - Krackow locking stitch versus locking premanufactured loop stitch for soft-tissue fixation: a biomechanical study. AB - PURPOSE: To biomechanically compare construct elongation under loading conditions and to compare load to failure for the locking premanufactured loop stitch versus the Krackow stitch. METHODS: Twenty porcine Achilles tendons were randomly assigned to receive the locking Krackow stitch with No. 2 FiberWire (Arthrex, Naples, FL) or the locking premanufactured loop stitch with No. 2 FiberLoop (SpeedWhip; Arthrex). Each tendon was pre-tensioned 3 times at 100 mm/min to 100 N for removal of slack, preloaded to 50 N to simulate tension applied clinically, and cyclically loaded at 200 mm/min to 200 N for 200 cycles. Total elongation of both suture strands was measured at each stage. Each tendon was loaded to failure. RESULTS: Elongation (mean +/- standard deviation) in the Krackow group and the SpeedWhip group did not differ with initial loading at 50 N (4.5 +/- 1.0 mm and 5.0 +/- 1.7 mm, respectively; P = .4) or with cyclic loading (15.6 +/- 5.7 mm and 17.0 +/- 2.6 mm, respectively; P = .5). Load to failure was significantly higher in the SpeedWhip group as compared with the Krackow group (344.0 +/- 23.1 N and 301.3 +/- 24.4 N, respectively; P = .001). CONCLUSIONS: In a porcine tendon model, the locking loop stitch group was not significantly different regarding construct elongation with initial or cyclic loading compared with the Krackow stitch group. These findings suggest that the locking loop stitch has adequate strength to serve as an alternative to the Krackow stitch in procedures where the Krackow stitch is used. The elongation data suggest that augmentation or protection with early stress postoperatively would be needed with the locking loop stitch as with the Krackow stitch clinically. CLINICAL RELEVANCE: Similar elongation in the 2 constructs suggests that this locking loop stitch has adequate strength to serve as an alternative to the Krackow stitch in procedures where the Krackow stitch is used. PMID- 20926232 TI - Open-wedge osteotomy using an internal plate fixator in patients with medial compartment gonarthritis and varus malalignment: 3-year results with regard to preoperative arthroscopic and radiographic findings. AB - PURPOSE: Our purpose was to evaluate the 3-year clinical results of patients with medial-compartment osteoarthritis of the knee and varus malalignment who underwent open-wedge high tibial osteotomy (HTO) with an internal plate fixator (TomoFix; Synthes, Solothurn, Switzerland). Clinical results are correlated with arthroscopic and radiographic findings at the time of surgery. METHODS: This study included 69 patients with a minimum follow-up of 36 months who underwent open-wedge HTO for medial-compartment osteoarthritis of the knee. Knee function was assessed before surgery and at 6, 12, 24, and 36 months after HTO by use of subjective International Knee Documentation Committee and Lysholm scores. Arthroscopic findings before HTO and radiographic assessment of the metaphyseal deformity of the proximal tibia (tibial bone varus angle) were correlated with clinical outcome. RESULTS: A significant continuous increase in International Knee Documentation Committee score from 47.25 +/- 18.71 points before surgery to 72.72 +/- 17.15 points at 36 months after HTO was found (P < .001). Grade of cartilage damage of the medial compartment and partial-thickness defects of the lateral compartment did not significantly influence clinical outcome (P > .05 at all time points). The tibial bone varus angle was correlated significantly with greater improvement and better clinical outcome after HTO (P < .01). The overall complication rate of 8.6% was mostly related to surgical causes; nevertheless, a high proportion of patients reported discomfort related to the implant at some point during the follow-up period (40.6%). CONCLUSIONS: Open-wedge osteotomy by use of the TomoFix system leads to reliable 3-year results. Results do not depend on the severity of medial cartilage defects, whereas partial-thickness defects of the lateral compartment seem to be well tolerated. The prognostic relevance of patellofemoral cartilage defects remains unclear. Local irritation of the implant was observed in a significant number of patients. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 20926233 TI - An unusual complication of neurogenic bladder. PMID- 20926234 TI - Pseudoaneurysm of the popliteal artery in a patient with multiple hereditary exostoses. AB - We present an interesting case of a 14-year-old girl with multiple hereditary exostoses. She presented with a few days history of a pulsative mass in the distal third of the right upper thigh. Leg radiography showed multiple exostoses of distal femur, proximal tibia, and fibula. Large pseudoaneurysm of popliteal artery was found in Doppler sonography. The diagnosis was verified with multi slice computed tomography of both legs along with the digital subtraction angiography of right leg. The patient then underwent surgery. After surgery the patient's vascular status was regular, with no signs of pseudoaneurysm. PMID- 20926235 TI - A case of rectal obstruction caused by bilateral internal iliac artery aneurysms. AB - In this article, we report a rare case of rectal obstruction caused by bilateral internal iliac artery aneurysms that required open surgical repair. A 73-year-old man was admitted to our hospital complaining of abdominal pain and persistent constipation for >1 month. Computed tomography demonstrated bilateral internal iliac artery aneurysms, 5.0 and 7.0 cm each in diameter, which occupied the intrapelvic space. An urgent surgery was performed to reduce the volume of the aneurysms and release the obstructed rectum. The postoperative course was uneventful, in which he had good evacuation. Aneurysms in the iliac region can be a good indication for the use of newly developed endovascular devices; however, open surgery should be considered without delay to avoid ileus or subileus symptoms when the aneurysms cause space-occupying complications. PMID- 20926236 TI - The significance of endoleaks in thoracic endovascular aneurysm repair. AB - BACKGROUND: Endoleak is one of the rare complications that occur after thoracic endovascular aneurysm repair (TEVAR). The aim of this study was to assess the incidence of endoleaks and the predictive factors for their occurrence, as well as their effect on secondary interventions after TEVAR. METHODS: Medical and radiological data of all TEVAR procedures performed between 2004 and 2008 were entered prospectively into our database and reviewed retrospectively. Primary endpoints included were the incidence and the type of endoleak, aneurysmal sac expansion, and secondary interventions. RESULTS: In all, 67 patients (18 women and 49 men; mean age, 67 +/- 14 years) were treated consecutively for descending thoracic aortic aneurysms (mean diameter: 69 +/- 18 mm) by TEVAR during the observed period, using 83 stent-grafts (11 Cook TX2, 31 Gore TAG, and 41 Medtronic Valiant), with a median follow-up of 27 months (range: 2-64). In 13 of 67 patients, 14 (19.4%) endoleaks were diagnosed, of which 71% (10 of 14) were type I, 29% (4 of 14) were type II, and none were type III. Ten endoleaks (71%) were diagnosed on the first postoperative computed tomographic angiography at 1 month, and the other four (29%) developed later on. Predictive factors for endoleaks on univariate analysis included age (p = 0.04), length of the proximal neck immediately after the left subclavian artery (p = 0.04), the fusiform morphology of the descending thoracic aortic aneurysms (p = 0.04), and the type of stent-graft used (p = 0.02). Eight of the 10 type I endoleaks (80%) were successfully treated by endovascular means, using proximal cuffs (n = 5) or distal extensions (n = 3). None of type II endoleaks were treated by secondary intervention. The six endoleaks treated conservatively were all associated with a significant mean increase of their aneurysmal sac (+3.2 +/- 2.6 mm) during follow up. No secondary conversion to open surgery was performed to treat an endoleak. CONCLUSIONS: On the basis of the study, it seems as if endoleaks are detected in one of the five patients treated with TEVAR during follow-up period, particularly if they are old with a proximal and fusiform aneurysm. Short- and mid-term follow up suggest that most type I endoleaks can successfully be treated by endovascular techniques and that type II endoleaks treated conservatively require a close radiological monitoring. PMID- 20926237 TI - Endovascular treatment of elective abdominal aortic aneurysms: independent predictors of early and late mortality. AB - BACKGROUND: The purpose of this study was to review our personal experience with patients who underwent elective endovascular repair of abdominal aortic aneurysms so as to detect the predictors of early and late mortality. METHODS: Between November 2000 and June 2008, a total of 235 consecutive patients (218 men; mean age: 71.9 +/- 8.0 years, range: 48-95 years) underwent endovascular repair of abdominal aortic aneurysms. Comorbidities were defined by using the Society for Vascular score grading system and the preoperative risk grade on the basis of the classification of the American Society of Anesthesiologists (ASA). Physical examination and spiral computed tomography were planned at 1, 4, and 12 months after the procedure, and on a yearly basis thereafter. Contrast-enhanced ultrasonography and plain X-rays were also performed. RESULTS: Primary technical success rate was 97% (228 of 235 cases). The overall hospital mortality was 2.1% (n = 5), ranging from 1.2% and 2.8% for patients with an ASA of score 2 and 3, respectively, to 7.7% for patients with an ASA score of 4. Multivariable analysis confirmed chronic renal failure (OR: 12.12, 95% CI: 1.83-80.17, p = 0.010) and transrenal endograft (OR: 9.61, 95% CI: 1.01-91.57, p = 0.049) as the only independent predictors of early mortality. Follow-up was completed for all 230 patients who were discharged, with a mean follow-up period of 26.3 +/- 22.7 months (maximum: 92 months). Kaplan-Meier analysis revealed a reduced survival rate for older patients (p < 0.001) and patients with a larger aneurysm (p < 0.001). A reduced survival rate was also demonstrated for women and patients with higher ASA scores (p = 0.007, and p = 0.003, respectively). In multivariate Cox analysis, ASA score, age, diameter of the aneurysm, and being female independently affected long-term survival. CONCLUSION: On the basis of our experience, it was concluded that chronic renal failure and the endograft configuration were independent predictors of early mortality. Also, older patients, women, and patients with larger aneurysms and higher ASA scores had the poorest late survival rates. PMID- 20926238 TI - Inferior mesenteric artery aneurysm in the setting of chronic colonic vascular ectasia. AB - Colonic vascular ectasia is a condition characterized by dilated submucosal veins, venules, or capillaries found commonly in patients with lower gastrointestinal hemorrhage. We present a case of colorectal ectasia associated with ischemia and an inferior mesenteric artery aneurysm. These pathologic findings may be the result of the vascular ectasia and may add to the natural history of this condition. PMID- 20926239 TI - Midterm results of endovascular repair of thoracic aortic false aneurysm formation after coarctation repair. AB - BACKGROUND: The aim of this study was to evaluate the short-term and midterm results of endovascular repair of false aneurysm formation after coarctation repair. METHODS: Between November 1998 and August 2009, seven patients underwent endovascular repair for false aneurysm formation after coarctation repair (two women, five men; mean age: 45.4 +/- 12.1 years; range: 30-60 years). Follow-up computed tomography scans were performed at 1 week, 3 months, 6 months, and annually thereafter. RESULTS: All endografts were successfully deployed (Excluder TAG in three patients, Talent in one patient, Valiant in three patients). Among them, six patients underwent hybrid technique with supra-aortic debranching and simultaneous or staged endovascular stent grafting as follows: transposition of the left common carotid artery (LCCA) into the brachiocephalic trunk which was later followed by transposition of the left subclavian artery into the LCCA in one case and transposition of the left subclavian artery into the LCCA in remaining five cases. No major complications occurred. A mean follow-up of 44.8 +/- 41.3 months (range: 1-131 months) demonstrated no endoleak, rupture, conversion, or migration. CONCLUSIONS: Short-and mid-term results of endovascular treatment of false aneurysm formation after coarctation repair favor the proposition of endovascular repair as a first-line treatment option. Long-term survival studies are mandatory to determine the efficacy and durability of this technique. PMID- 20926240 TI - Peripheral arterial disease in octogenarians and nonagenarians: factors predicting survival. AB - BACKGROUND: To describe the prevalence and character of complications associated with revascularization procedures as a result of peripheral arterial disease in octogenarians and nonagenarians and to assess their overall survival depending on baseline characteristics, type of treatment modality, and possible procedure related complications. A retrospective clinical study was carried out. METHODS: A total of 383 patients aged >80 years, referred with suspected peripheral arterial disease, were categorized into octogenarians and nonagenarians. Data regarding cardiovascular risk factors, comorbidities, type of treatment, and possible procedure-related complications were collected from patients' files. The cohort was followed up for total mortality until December 31, 2007, by means of record linkage with the National Causes of Death Register. RESULTS: A total of 57 (14.9%) patients were treated surgically, whereas 71 (18.5%) underwent an endovascular procedure. Conservative treatment was chosen significantly more often for nonagenarians (p = 0.032). Postoperative complications (nonfatal, 13.2%; fatal, 3.1%) were equally distributed between the age groups and genders (p = 0.840 and p = 0.820, respectively) but were significantly more common after surgical procedures (p < 0.001 for both fatal and nonfatal complications). As expected, the overall survival was significantly poorer among nonagenarians as compared with octogenarians (33 vs. 45 months, respectively; p < 0.001). Older age, critical limb ischemia (CLI), and males were independently associated with mortality (odds ratio [OR]: 1.89, 95% confidence levels [CI]: 1.18-3.04; OR: 3.72, 95% CI: 2.34-5.91; and OR: 1.77, 95% CI: 1.10-2.80, respectively). The survival for nonagenarian men with CLI was 24 months and for women 28, regardless of the treatment modality. CONCLUSIONS: Octo- and nonagenarians seem to tolerate arterial reconstruction relatively well. Endovascular interventions should be favored over surgical procedures as they are associated with fewer complications. At the same time, the life expectancy of nonagenarians with CLI is limited to approximately 2 years, irrespective of the method of treatment. Further studies should be conducted to clarify the actual effect of vascular reconstructions among the elderly population with regard to benefits of both costs and quality of life. PMID- 20926241 TI - Surgical repair of a giant pseudoaneurysm of the right common carotid artery following a gunshot. AB - Common carotid pseudoaneurysms are very rare. The authors report a case of a 18 year-old patient with 11 cm large posttraumatic pseudoaneurysm of the right common carotid artery caused by a gunshot in the neck. The patient also had a right hemiplegia, secondary to the left sylvian artery stroke and aphasia. A surgical repair was undertaken with an approach including a total sternotomy. The aneurysm was excluded and a saphenous vein patch was used to repair the 2-cm defect on the arterial wall. The postoperative period was uneventful. This is probably the largest carotid artery aneurysm ever described. The potential hazards of an aneurysm of the common carotid artery indicate that surgical treatment is warranted particularly in a patient with a past history of controlateral stroke. PMID- 20926242 TI - Chylothorax after thoracoabdominal aneurysm repair: efficacy of somatostatin. AB - Chylothorax is a rare but serious complication that presents after thoracoabdominal aortic aneurysm surgery. There are insufficient data to reach a consensus on how to manage it. Some researchers have suggested early reoperation for high output drainage. We present the case of a patient who underwent thoracoabdominal aortic replacement and who subsequently developed postoperative chylothorax. High output (>1,000 mL per day) chest tube drainage until postoperative day 4 drastically decreased and stopped in a week with the administration of somatostatin and total parenteral nutrition which helped avoid a major re-exploration. Surgery should be reserved as an option only for patients with persistent leaks that do not respond to somatostatin therapy. PMID- 20926243 TI - Endovascular repair of ruptured thoracic aortic aneurysms: predictors of procedure-related stroke. AB - BACKGROUND: Thoracic endovascular aortic repair (TEVAR) is a valuable tool in the treatment of ruptured descending thoracic aortic aneurysm (rDTAA). A major complication of this procedure is stroke. We investigated the incidence and risk factors for stroke after TEVAR for rDTAA. METHODS: We retrospectively evaluated the outcomes of all patients who were treated with TEVAR for rDTAA at seven institutions between 2002 and 2009. A total of 92 patients were identified, with a mean age of 69.4 +/- 11 years and 67% were men. Multivariable logistic regression analysis was used to investigate risk factors for stroke, including demographics, comorbidities, aneurysm, and procedural details. RESULTS: The 30 day mortality was 17.4% (n = 16), and 7.6% (n = 7) suffered from procedure related stroke. Four of seven patients with stroke (57.1%) expired within 30 days, compared with 12 (14.1%) of the patients without stroke (OR, 8.11; p = .004). In multivariable regression analysis, increasing age was associated with an increased risk of stroke (OR, 1.38; 95% CI, 1.08-1.76; p = .010), whereas more recent procedures were associated with a reduced risk of stroke (OR, 0.52; 95% CI, 0.28-0.97; p = .039). The aneurysm-related survival at 1 year after TEVAR was 42.9% for patients who suffered from stroke, and 77.6% for those without stroke (p = .006). CONCLUSIONS: Endovascular repair of rDTAA is associated with a considerable risk of stroke, and stroke is an important cause of 30-day mortality in this patient group. Particularly older patients are at risk for developing stroke after endovascular repair of rDTAA. The risk of stroke decreased significantly over time in this evaluation. PMID- 20926244 TI - Brain injury after carotid revascularization: outcomes, mechanisms, and opportunities for improvement. AB - BACKGROUND: The most worrisome complication of carotid revascularization is neurologic injury, typically manifesting as a perioperative stroke. However, patients undergoing these procedures are at risk for a broad spectrum of neurologic injury. We sought to perform a systematic review of neurologic injury after carotid revascularization to guide future quality improvement efforts focused on reducing potentially preventable events. METHODS: Using a specified search strategy, we evaluated the mechanisms of neurologic injury, the measurement of neurobehavioral outcomes, and use of neuroimaging to evaluate carotid revascularization outcomes, and the application of these techniques in current registries and clinical trials of carotid revascularization. RESULTS: We found that neurologic injury after carotid revascularization results from three broad etiologies: atheroembolic, thrombotic, and hypo/hyperperfusion. Broad variation exists across studies examining neurobehavioral outcomes. Of the 47 studies examining the effect of carotid endarterectomy on neurobehavioral functioning, 25 found that some aspect of cognition improved, 12 revealed no change in cognition, and 10 revealed declines in some aspect of cognition. There is a wide variation in the measurement of neurologic outcomes in clinical registries and trials. In reviewing 13 industry-sponsored registries of carotid artery stenting and 10 randomized trials of carotid endarterectomy and carotid artery stenting, registries were less likely to use validated neurologic assessment scales, independent neurologic examinations, and neuroimaging to establish outcomes than randomized trials. CONCLUSIONS: Despite a considerable body of evidence, there is a lack of consensus in determining optimal strategies for the assessment and characterization of neurologic injury and its effect on neurobehavioral outcomes after carotid revascularization, especially among industry-sponsored trials. As a result, rates of neurologic outcomes varied considerably across studies, registries, and clinical trials. Future efforts to correlate neuroimaging with cognitive outcomes may offer insight into methods to decrease neurologic injury after carotid revascularization. PMID- 20926245 TI - Extracorporeally irradiated autograft-prosthetic composite arthroplasty with vascular reconstruction for primary bone tumor of the proximal tibia. AB - The proximal tibia is a common site for primary bone tumors. Proximal tibial tumors may invade the adjacent soft-tissue by destroying the cortex and may further invade neurovascular bundles. We treated a patient with primary bone tumor of the proximal tibia with neurovascular invasion by extracorporeally irradiated autograft-prosthetic composite arthroplasty with vascular reconstruction. In cases of concomitant allograft arthroplasty and vascular reconstruction, we recommend that vascular reconstruction be performed before arthroplasty to minimize ischemia time. Good oncological and functional outcomes were achieved 75 months after surgery. Therefore, this reconstruction technique can be considered as a good treatment option. PMID- 20926246 TI - Endovascular treatment of a huge cervical carotid artery pseudoaneurysm with Wallgraft prosthesis. AB - Traumatic pseudoaneurysm of the internal carotid artery (ICA) is a rare cause of epistaxis, which may be life-threatening if left untreated. We report the case of a massive epistaxis from left ICA pseudoaneurysm. Our patient was a 38 year-old man with the history of a severe traffic accident 13 years ago. The pseudoaneurysm was treated with the placement of a Wallgraft prosthesis inside the carotid artery. After the endovascular treatment, the left ICA remained patent and no recurrent hemorrhage was noted in the 1 year follow up after the procedure. PMID- 20926247 TI - Abdominal infectious aortitis caused by Streptococcus pneumoniae: a case report and literature review. AB - We report a case of a 75-year-old man who had been complaining of fever and pelvic pain for 3 weeks. First angio-computed tomography (CT) characteristics and blood culture led to suspicion of a pneumococcal-infected aortic aneurysm, which however was not confirmed by the surgeon. The abdominal infectious aortitis caused by Streptococcus pneumoniae was affirmed by a second angio-CT performed 7 days later. Without further delay, the patient underwent surgery for resection of mycotic aneurysm and in situ reconstruction with aortobiiliac homograft, in association with antibiotics. He died 10 days after the surgery as a result of severe sepsis in a polyvalent intensive care unit. This case report highlights the severity of this pathology. We reviewed the relevant literature related to Streptococcal pneumoniae mycotic aneurysm located in the abdominal aorta, including 29 more cases. Various microorganisms have already been associated with mycotic aneurysms, including S pneumoniae. Infectious aortitis remains a rare disease. It is extremely important to establish an early diagnosis but it may be delayed because clinical manifestations are usually nonspecific. However, if left untreated it is always lethal. Antibiotic in combination with complete surgical excision of the infected aorta is the treatment of reference. This therapeutic association dramatically improved patient survival. PMID- 20926248 TI - Use of a totally implantable access port through the external jugular vein when the cephalic vein approach is not feasible. AB - BACKGROUND: We report our experience of using a totally implantable access port (TIAP) through the external jugular vein (EJV) when the cephalic vein (CV) approach is not feasible. METHODS: We reviewed 197 cases involving TIAP implantation through the EJV in a single medical center between January 1995 and January 2009. All the ports were implanted after the CV approach was found unfeasible. Patient characteristics, operating time, and early and late complications were recorded. RESULTS: The mean patient age was 50 years (range: 33-75). The mean operating time was 54.5 +/- 7.5 minutes. Early complications within the first 30 postoperative days included port hematoma (2%) and catheter migration (2%). The late postoperative complications included catheter occlusion (2.5%), venous thrombosis (2%), and port infection (1.5%). There were no complications associated with TIAP disconnection. CONCLUSIONS: The EJV approach is an easy and safe alternative method for TIAP implantation when the CV approach is not feasible. This method can avoid conversion to percutaneous puncture of the subclavian vein, which could result in life-threatening complications such as pneumothorax and hemothorax. In patients with breast cancer or those who are contraindicated for TIAP implantation on the opposite side, the EJV cutdown approach provides an alternative route with comfortable and satisfactory results as complications with this approach are rare. PMID- 20926249 TI - Is the good-imitator-poor-talker profile syndrome-specific in Down syndrome?: evidence from standardised imitation and language measures. AB - The emergence of the Down syndrome (DS) behavioural phenotype during early development may be of great importance for early intervention. The main goal of this study was to investigate the good-imitator-poor-talker developmental profile in DS at preschool age. Twenty children with Down syndrome (DS; mean nonverbal mental age NMA 1 y10 m) and 15 children with non-specific mental retardation (NS MR; mean NMA 1 y11 m) participated in this study. The Preschool Imitation and Praxis Scale (PIPS) and the Dutch version of the MacArthur-Bates Communicative Development Inventories (N-CDI) were used to determine absolute and relative (contrasted to a nonverbal mental age reference) imitation and language abilities. Results revealed that there was clear evidence for a good-imitator poor-talker profile in preschoolers with DS. However, only the advanced bodily imitation ability seems to be syndrome-specific. Clinical implications of these findings are considered. PMID- 20926250 TI - Some phonatory and resonatory characteristics of the rock, pop, soul, and Swedish dance band styles of singing. AB - This investigation aims at describing voice function of four nonclassical styles of singing, Rock, Pop, Soul, and Swedish Dance Band. A male singer, professionally experienced in performing in these genres, sang representative tunes, both with their original lyrics and on the syllable /pae/. In addition, he sang tones in a triad pattern ranging from the pitch Bb2 to the pitch C4 on the syllable /pae/ in pressed and neutral phonation. An expert panel was successful in classifying the samples, thus suggesting that the samples were representative of the various styles. Subglottal pressure was estimated from oral pressure during the occlusion for the consonant [p]. Flow glottograms were obtained from inverse filtering. The four lowest formant frequencies differed between the styles. The mean of the subglottal pressure and the mean of the normalized amplitude quotient (NAQ), that is, the ratio between the flow pulse amplitude and the product of period and maximum flow declination rate, were plotted against the mean of fundamental frequency. In these graphs, Rock and Swedish Dance Band assumed opposite extreme positions with respect to subglottal pressure and mean phonation frequency, whereas the mean NAQ values differed less between the styles. PMID- 20926251 TI - Vowel harmonic amplitude differences in persons with vocal nodules. AB - BACKGROUND: Spectrum is a fast Fourier transform-generated power spectrum extracted from the speech sample. It is reported to provide a quantitative acoustic index of the degree of glottal abduction and adduction in voices perceived to be breathy or pressed. In the present study, it was hypothesized that there would be abnormal reduction of higher harmonic amplitudes relative to the amplitude of the first harmonics in the subjects with vocal nodules and hence the present study was carried out. METHOD: One hundred twenty participants were divided into clinical group and control group. They were instructed to phonate /a/ at their most comfortable pitch and loudness. Fourier transformation of the recorded acoustic signal was first performed to create a spectrum. Amplitudes were measured for the first and second harmonics (H1 and H2) as well as the harmonics at the first, second, and third formants (A1, A2, and A3) using the Computerized Speech Science Lab (Kay Pentax, Lincoln, NJ). RESULTS: There was a significant difference between the means of two groups for all the parameters, such as H1-H2, H1-A1, H1-A2, and H1-A3 at P<0.05. The obtained results are discussed with respect to the underlying pathophysiology. CONCLUSIONS: The present study investigated the vowel harmonic amplitude differences in persons with vocal nodules. The results revealed a significant difference between the two groups for the vowel harmonic amplitude differences. This particular measure could be used to track the changes following the vocal treatment. PMID- 20926252 TI - Evidence for heterozygous abnormalities of the elastin gene (ELN) affecting the quantity of vocal fold elastic fibers: a pilot study. AB - OBJECTIVES: To investigate the effects of a heterozygous elastin gene (Eln) abnormality (deletion of one Eln allele) on the structural characteristics of the vocal fold lamina propria using a mouse model of human disease. STUDY DESIGN: Cross-sectional between-subjects design. METHODS: Five mice, four with heterozygous Eln deletions (Eln +/-) serving as an animal model for the human disease supravalvular aortic stenosis and one normal wild-type control (Eln +/+) were used for this study. Vocal folds were obtained from each animal and stained for the protein elastin using histochemical methods. Descriptive data from qualitative visual inspection and quantitative data from microscopic digital image analysis were collected to determine the staining density of elastic fibers within the vocal fold lamina propria. RESULTS: Qualitative visual inspection revealed greater staining density (eg, a greater quantity) for elastic fibers in the Eln +/+ animal. Quantitative measurements using digital pixel analysis of staining density revealed significant differences between mice with the two genotypes, confirming the qualitative findings. CONCLUSIONS: Results suggest that Eln requires two functioning alleles for normal structural development of the vocal fold lamina propria. This pilot evidence supports the hypothesis of a structural etiology causing altered vocal function in humans with a similar genotype. PMID- 20926253 TI - Comparative analysis of the closed quotient for lip and tongue trills in relation to the sustained vowel /epsilon/. AB - Various types of trill exercises have been used for a long time as a tool in the treatment and preparation of the voice. Although they are reported to produce vocal benefits in most subjects, their physiology has not yet been studied in depth. The aim of this study was to compare the mean and standard deviation of the closed quotient in exercises of lip and tongue trills with the sustained vowel /epsilon/ in opera singers. Ten professional classical (operatic) singers, reportedly in perfect laryngeal health, served as subjects for this study and underwent electroglottography. During the examination, the subjects were instructed to deliver the sustained vowel /epsilon/ and lip and tongue trills in a same preestablished frequency and intensity. The mean values and standard deviation of the closed quotient were obtained using the software developed for this purpose. The comparison of the results was intrasubjects; maximum intensities were compared only among them and so were minimum intensities. The means of closed quotient were statistically significant only in the strong intensities, and the lip trill was different from the tongue trill and the sustained vowel /epsilon/. The standard deviation of the closed quotient distinguished the sustained vowel /epsilon/ from the lip and tongue trills in the two intensities. We concluded that there is oscillation of the closed quotient during the exercises of tongue and lip trills, and the closed quotient is higher during the performance of exercises of the lip trill, when compared with the two other utterances, only in the strong intensities. PMID- 20926254 TI - Effect of tonsillectomy on the adult voice. AB - OBJECTIVES AND HYPOTHESIS: Anecdotal evidence suggests that tonsillectomy has no deleterious consequences on a person's voice under normal vocal demand. However, whether the enlarged dimensions of the oropharynx after tonsillectomy impair the quality of a professional voice user remains unclear. Therefore, we designed a study to determine whether adult tonsillectomy altered the resonance characteristics of the vocal tract in any way and whether these changes were transient or permanent. STUDY DESIGN: This is a prospective observational study with full institutional ethical approval. METHODS: All adult patients presenting for tonsillectomy for recurrent tonsillitis in our institution were recruited. Their voice was recorded preoperatively, postoperatively, and at 4 weeks postoperatively. The values of the first four formants were calculated in all recordings. The oropharyngeal dimensions were measured preoperatively and postoperatively. Tonsillar weights and volumes were also measured. RESULTS: The first formant was noted to rise postoperatively. The average value of F2 and F3 did not alter postoperatively or at 4 weeks. However, it was noted that the fourth formant was not universally present preoperatively but was present in all patients postoperatively and at 4 weeks. CONCLUSIONS: Altering the dimensions of the oropharynx after tonsillectomy causes the first formant to rise but has no effect on the third and fourth formants. However, the fourth formant appears in patients who previously did not demonstrate it. The fourth formant was present in a greater proportion of male patients preoperatively than female patients, but it was universally present postoperatively and at 4 weeks in both sexes. This suggests that increasing the horizontal dimensions of the oropharynx has a nontransient effect on the higher order formants of the voice. PMID- 20926255 TI - Partial misspecification of survey design features sufficed to severely bias estimates of health-related outcomes. AB - OBJECTIVE: Surveys frequently deviate from simple random sampling through the use of unequal probability sampling, stratified sampling, and multistage sampling. This work uses a survey of public health to systematically illustrate the effects of incompletely accounting for strata, clustering, and weights. STUDY DESIGN AND SETTING: Data analysis was based on the Study of Health in Pomerania (n=4,308, 20 79 years), a two-stage regional survey with high sampling fractions at the first stage. Effects of survey design features comprising weights, stratification, clustering, and finite population correction on point and variance estimates of lifestyle indicators and clinical parameters were assessed. RESULTS: Misspecifications of the survey design substantially affected both the point estimates of health characteristics and their standard errors (SEs). The strongest bias in SEs concerned the omission of the second sampling stage. Ignoring the sampling design led to minor differences in variance estimates from the complete setup. Weighting predominantly affected point estimates of lifestyle factors. CONCLUSION: A partial misspecification of survey design elements may bias variance estimates severely and is sometimes even more harmful compared with completely neglecting design elements. If subgroups are sampled at different rates, weighting is of particular relevance with regard to prevalence estimates of lifestyle indicators. PMID- 20926256 TI - No inconsistent trial assessments by NICE and IQWiG: different assessment goals may lead to different assessment results regarding subgroup analyses. PMID- 20926257 TI - PubMed had a higher sensitivity than Ovid-MEDLINE in the search for systematic reviews. AB - OBJECTIVE: To compare the performance of Ovid-MEDLINE vs. PubMed for identifying randomized controlled trials of methotrexate (MTX) in patients with rheumatoid arthritis (RA). STUDY DESIGN AND SETTING: We created search strategies for Ovid MEDLINE and PubMed for a systematic review of MTX in RA. Their performance was evaluated using sensitivity, precision, and number needed to read (NNR). RESULTS: Comparing searches in Ovid-MEDLINE vs. PubMed, PubMed retrieved more citations overall than Ovid-MEDLINE; however, of the 20 citations that met eligibility criteria for the review, Ovid-MEDLINE retrieved 17 and PubMed 18. The sensitivity was 85% for Ovid-MEDLINE vs. 90% for PubMed, whereas the precision and NNR were comparable (precision: 0.881% for Ovid-MEDLINE vs. 0.884% for PubMed and NNR: 114 for Ovid-MEDLINE vs. 113 for PubMed). CONCLUSION: In systematic reviews of RA, PubMed has higher sensitivity than Ovid-MEDLINE with comparable precision and NNR. This study highlights the importance of well-designed database-specific search strategies. PMID- 20926258 TI - Survival distributions impact the power of randomized placebo-phase design and parallel groups randomized clinical trials. AB - OBJECTIVES: The study evaluated the power of the randomized placebo-phase design (RPPD)-a new design of randomized clinical trials (RCTs), compared with the traditional parallel groups design, assuming various response time distributions. In the RPPD, at some point, all subjects receive the experimental therapy, and the exposure to placebo is for only a short fixed period of time. STUDY DESIGN AND SETTING: For the study, an object-oriented simulation program was written in R. The power of the simulated trials was evaluated using six scenarios, where the treatment response times followed the exponential, Weibull, or lognormal distributions. The median response time was assumed to be 355 days for the placebo and 42 days for the experimental drug. RESULTS: Based on the simulation results, the sample size requirements to achieve the same level of power were different under different response time to treatment distributions. The scenario where the response times followed the exponential distribution had the highest sample size requirement. In most scenarios, the parallel groups RCT had higher power compared with the RPPD. CONCLUSION: The sample size requirement varies depending on the underlying hazard distribution. The RPPD requires more subjects to achieve a similar power to the parallel groups design. PMID- 20926259 TI - Decreased Neuregulin 1 C-terminal fragment in Brodmann's area 6 of patients with schizophrenia. AB - Neuregulin 1 (NRG1) is a susceptibility gene for schizophrenia. A decrease in NRG1-ErbB4 signalling has also been associated with the disease. beta-amyloid precursor protein-cleaving enzyme (BACE1) processes type III NRG1 precursor, a major neuregulin variant expressed in the brain, to release NRG1 fragments that trigger signalling events and activation of neurotransmitter receptors. Experimental evidence suggests that muscarinic acetylcholine receptors (CHRM) regulate BACE1 expression. Having recently shown that CHRM1 levels are decreased selectively in frontal cortex regions of a subpopulation of schizophrenic patients (muscarinic receptor deficit schizophrenia, MRDS) we aimed to compare the protein expression of BACE1 and NRG1 in the agranular frontal cortex Brodmann's area 6 of SCZ subjects with normal levels of CHRM1 (N = 19), MRDS (N = 20), and age/gender-matched non-psychiatric (healthy) controls (HC; N = 20). Western blot analysis of post-mortem samples showed that the levels of BACE1 and full-length NRG1 precursor (130 kDa) did not differ significantly between the three groups. In contrast, the levels of the NRG1 C-terminal fragment (NRG1-CTF) were decreased by approximately 50% in both schizophrenic groups compared to the HC group (p<0.0027). The ratio of NRG1-CTF versus NRG1 precursor was significantly reduced in the SCZ groups compared to the HC group (p = 0.051). There was no correlation between the levels of either full-length NRG1, NRG1-CTF, or BACE1 and the final recorded doses of antipsychotic drugs for the subjects with schizophrenia. A positive correlation was found between BACE1 and full length NRG1 precursor in the HC group (r(2) = 0.671, p<0.001) but not in the schizophrenic groups. These data suggest that the proteolytic processing of NRG1 is impaired in schizophrenia. PMID- 20926260 TI - The meaning of childhood attention-deficit hyperactivity symptoms in patients with a first-episode of schizophrenia-spectrum psychosis. AB - OBJECTIVE: To examine childhood ADHD symptoms in regard to their association with a number of illness-related variables including risk factors, early neurodevelopment, premorbid functioning and clinical characteristics in patients with schizophrenia-spectrum psychoses. METHODS: One-hundred and twenty-two first episode patients with DSM-IV schizophrenia-spectrum disorders were retrospectively assessed by means of their biological mothers for childhood ADHD symptoms. Using correlational analyses and hierarchical regression models, the severity of ADHD symptoms was examined in relation to familial liability to schizophrenia, obstetric complications, milestones attainment delay, premorbid functioning during childhood and adolescence, age at illness onset, episode psychopathology and response to treatment after one-month trial with antipsychotic medication. RESULTS: Twenty-one patients (17%) met DSM-IV criteria for childhood ADHD. Univariate analyses showed that severity of childhood ADHD symptoms was related to male gender, obstetric complications, delayed milestones attainment, poor school functioning and an earlier age of onset of psychotic symptoms. Hierarchical regression analyses showed that severity of childhood ADHD symptoms was independently predicted by obstetric complications and neurodevelopmental delay, with no further variables entering in the regression models. Path analyses showed that obstetric complications had both direct and indirect effects, through neurodevelopmental delay, on ADHD symptoms. CONCLUSIONS: These findings are consistent with a neurodevelopmental model of schizophrenia and with the hypothesis of shared environmental risk factors between ADHD and schizophrenia-spectrum disorders. Childhood ADHD symptoms in schizophrenia-spectrum disorders appear to be an epiphenomenon of obstetric complications and early neurodevelopment delay with no further influence on the clinical expression of the illness. PMID- 20926261 TI - Epiplakin accelerates the lateral organization of keratin filaments during wound healing. AB - BACKGROUND: Epiplakin (EPPK) belongs to the plakin family of cytolinker proteins and, resembling other members of the plakin family such as BPAG1 (an autoantigen of bullous pemphigoid) and plectin, EPPK has plakin repeat domains (PRDs) that bind to intermediate filaments. Elimination of EPPK by gene targeting in mice resulted in the acceleration of keratinocyte migration during wound healing. EPPK is expressed in proliferating keratinocytes at wound edges and, in view of its putative function in binding to keratin, we postulated that the keratin network in EPPK-null (EPPK(-/-)) mice might be disrupted during wound healing. OBJECTIVE: To examine this hypothesis and to determine the precise localization of EPPK in relation to keratin filaments, we compared the non-wounded and wounded epidermis of wild-type and EPPK(-/-) mice. METHODS: Non-wounded epidermis and wounded epidermis from wild-type and EPPK(-/-) mice were examined by immunofluorescence staining and electron microscopy before and after double immunostaining. RESULTS: EPPK was colocalized with keratin 17 (K17) more extensively than with other keratins examined in wounded epidermis. The expression of K5, K10, K6, and K17 was the same in EPPK(-/-) mice after wounding as in normal mice, but diameters of keratin filaments were reduced in EPPK(-/-) keratinocytes. Electron microscopy after immunostaining revealed that EPPK colocalized with K5, K10 and K6 after wounding in wild-type mice. CONCLUSION: Our data indicate that EPPK accelerates keratin bundling in proliferating keratinocytes during wound healing and suggest that EPPK might contribute to reinforcement of keratin networks under mechanical stress. PMID- 20926262 TI - In vivo development of antimicrobial resistance in Pseudomonas aeruginosa strains isolated from the lower respiratory tract of Intensive Care Unit patients with nosocomial pneumonia and receiving antipseudomonal therapy. AB - Pseudomonas aeruginosa causes severe nosocomial pneumonia in Intensive Care Unit (ICU) patients, with an increased prevalence of multiresistant strains. We examined the impact of the use of antipseudomonal antibiotic(s) on the susceptibility of P. aeruginosa isolated from ICU patients with clinically suspected hospital-acquired pneumonia collected in five teaching hospitals (110 non-duplicate initial isolates; 62 clonal pairs of initial and last isolates during treatment). Minimum inhibitory concentrations (MICs) were determined for amikacin, ciprofloxacin, meropenem, piperacillin/tazobactam (TZP), cefepime and ceftazidime (used in therapy) as well as five reporter antibiotics (aztreonam, colistin, gentamicin, piperacillin and ticarcillin) using Clinical and Laboratory Standards Institute (CLSI) methodology. Susceptibility was assessed according to European Committee on Antimicrobial Susceptibility Testing (EUCAST) and CLSI breakpoints. Resistance rates prior to treatment exceeded 25% for cefepime, ceftazidime, piperacillin, ticarcillin and aztreonam (EUCAST and CLSI) and for gentamicin, TZP and colistin (EUCAST only). The highest rates of cross-resistance were noted for ceftazidime and cefepime and the lowest rate for amikacin. Mean MIC values were systematically higher in isolates from patients previously exposed (1 month) to the corresponding antibiotic. For clonal pairs, a systematic increase in MIC between initial and last isolates (significant for amikacin, cefepime, meropenem and TZP) was noted. There was a significant correlation between the use of antibiotics (adjusted for respective proportional use of each drug) and loss of susceptibility at the population level when using EUCAST breakpoints. The high level of resistance of P. aeruginosa in ICU patients with nosocomial pneumonia as well as its further increase during treatment severely narrows the already limited therapeutic options. Further observational studies and the development of early diagnosis for resistant isolates are warranted. PMID- 20926263 TI - Effect of ceftobiprole on the normal human intestinal microflora. AB - Ceftobiprole is a new broad-spectrum pyrrolidinone cephem active against meticillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecalis and Gram-negative bacteria such as Enterobacteriaceae and Pseudomonas spp. The purpose of the present study was to investigate the effect of administration of ceftobiprole on the normal intestinal microflora. Twelve healthy subjects (six males and six females) aged 20-31 years received ceftobiprole 500 mg by intravenous infusion every 8h for 7 days. Plasma samples were collected on Days -1, 1, 4, 7, 10, 14 and 21 for determination of drug concentration by biological and chemical methods. Faecal samples were collected on Days -1, 2, 4, 7, 10, 14 and 21. For analysis of the microflora, faecal specimens were cultured on non-selective and selective media. Different colony types were counted, isolated in pure culture and identified to genus level. All new colonising aerobic and anaerobic bacteria were tested for susceptibility to ceftobiprole. Plasma concentrations of ceftobiprole 10 min after completion of infusion were as follows: Day 1, 14.7-23.6 mg/L; Day 4, 15.9-24.5 mg/L; and Day 7, 15.9-23.9 mg/L. No ceftobiprole was detected in plasma on Days -1, 10, 14 and 21. No measurable concentrations of ceftobiprole were found in faeces on Days -1, 2, 4, 7, 10, 14 and 21. There were minor changes in the numbers of enteric bacteria, enterococci and Candida albicans and there were moderate changes in the numbers of bifidobacteria, lactobacilli, clostridia and Bacteroides spp. during the same period. No Clostridium difficile strains or toxins were found. No new colonising aerobic and anaerobic bacteria with ceftobiprole minimum inhibitory concentrations of >= 4 mg/L were found. Ceftobiprole had no significant ecological impact on the human intestinal microflora. PMID- 20926265 TI - The microstructural integrity of the corpus callosum and associated impulsivity in alcohol dependence: a tractography-based segmentation study using diffusion spectrum imaging. AB - Previous post-mortem and structural magnetic resonance imaging (MRI) studies in patients with alcohol dependence have demonstrated abnormalities of brain white matter. The present study investigated the microstructural integrity in the corpus callosum and the associations of this integrity with neurobehavioral assessments. Twenty-five male cases fulfilling the DSM-IV diagnosis of alcohol dependence and 15 male control subjects were scanned using a 3T MRI system. Callosal fiber tracts were reconstructed by diffusion spectrum imaging tractography and were subdivided into seven functionally distinct segments. The microstructural integrity was quantified in terms of generalized fractional anisotropy (GFA). Compared with normal subjects, men with alcohol dependence showed lower GFA values on all segments of the corpus callosum. The segment interconnecting the bilateral orbitofrontal cortices was the most affected. The score on the Barratt Impulsivity Scale showed an inverse relationship with GFA on the callosal fiber tracts connecting the bilateral orbitofrontal cortices. Furthermore, the duration of regular use was negatively associated with GFA on the callosal fiber tracts connecting the bilateral temporal and parietal cortices. Our findings suggest that a high self-rated impulsivity level was associated with low anisotropy in white matter of corpus callosum sectors extending to the orbitofrontal cortex. PMID- 20926264 TI - Suicide attempts in a prospective cohort of patients with schizophrenia treated with sertindole or risperidone. AB - The incidence of suicide attempts (fatal and non-fatal) was analysed in a prospective cohort of patients with schizophrenia randomly assigned to sertindole (4905 patients) or risperidone (4904 patients) in a parallel-group open-label study with blinded classification of outcomes (the sertindole cohort prospective study--SCoP). The total exposure was 6978 and 7975 patient-years in the sertindole and risperidone groups, respectively. Suicide mortality in the study was low (0.21 and 0.28 per 100 patients per year with sertindole and risperidone, respectively). The majority (84%) of suicide attempts occurred within the first year of treatment. Cox's proportional hazards model analysis of the time to the first suicide attempt, reported by treating psychiatrists and blindly reviewed by an independent expert group according to the Columbia Classification Algorithm of Suicide Assessment (both defining suicide attempts by association of suicidal act and intent to die), showed a lower risk of suicide attempt for sertindole-treated patients than for risperidone-treated patients. The effect was statistically significant with both evaluation methods during the first year of randomized treatment (hazard ratios [95% CI]: 0.5 [0.31-0.82], p=0.006; and 0.57 [0.35 0.92], p=0.02, respectively). With classification by an independent safety committee using a broader definition including all incidences of intentional self harm, also those without clear suicidal intent, the results were not significant. A history of previous suicide attempts was significantly associated with attempted suicides in both treatment groups. PMID- 20926266 TI - [Risks of energy drinks in youths]. AB - The market value for energy drinks is continually growing and the annual worldwide energy drink consumption is increasing. However, issues related to energy drink ingredients and the potential for adverse health consequences remain to be elucidated. This aim of the present paper is to review the current knowledge on putative adverse effects of energy drinks, especially in youths. There are many energy drink brands in the worldwide market, even if only few brands are available in France. Although the energy drink content varies, these beverages often contain taurine, caffeine, vitamins B and carbohydrates. These drinks vary widely in both caffeine content (80 to 141 mg per can) and caffeine concentration. Except caffeine, the effects of energy drink ingredients on physical and cognitive performances remain controversial. Researchers identified moderate positive effects of energy drinks on performances, whereas others found contrary results. The adverse effects of energy drink can be related to either the toxicity of ingredients or specific situations in which energy drinks are used such as ingestion in combination with alcohol. Although the issue of taurine induced toxic encephalopathy has been addressed, it is likely that the risk of taurine toxicity after energy drink consumption remains low. However, whether the prolonged use of energy drinks providing more than 3g taurine daily remains to be examined in the future. The consumption of energy drinks may increase the risk for caffeine overdose and toxicity in children and teenagers. The practice of consuming great amounts of energy drink with alcohol is considered by many teenagers and students a primary locus to socialize and to meet people. This pattern of energy drink consumption explains the enhanced risk of both caffeine and alcohol toxicity in youths. Twenty five to 40% of young people report consumption of energy drink with alcohol while partying. Consumption of energy drinks with alcohol during heavy episodic drinking is at risk of serious injury, sexual assault, drunk driving, and death. However, even after adjusting for alcohol consumption, students who consume alcohol mixed with energy drinks had dramatically higher rates of serious alcohol-related consequences. It has been reported that the subjective perceptions of some symptoms of alcohol intoxication are less intense after the combined ingestion of the alcohol plus energy drink; however, these effects are not detected in objective measures of motor coordination and visual reaction time. PMID- 20926267 TI - [Alcopops: systemic and dental consequences]. AB - Alcopops are highly-sweetened premixed spirit-based drinks. Ready to drink and sold in small bottles, it contains between 3 and 5 % alcohol by volume, sugars, citric and malic acid with a pH around 3. Their success is attributed to the fact that spirits are more palatable and better tasting with a fruity flavour, similar to non alcoholic beverages. Especially aimed at female teenagers in search for the alcohol effect while disliking its strong taste, it has been sold in Europe for 15 years. So called "designer drinks" are often consumed during the weekend, binge-drinked with some friends. The frequent consumption has severe consequences on general health, which includes body overweight due to the amount of sugar, and alcohol-related consequences of utmost importance considering consumer's young age. Moreover, alcopops may introduce to the consumption of alcohol and induce addiction. Consequences on oral health may include dental erosion. Erosion is a premature loss of mineralized tissues (enamel and dentin), due to the contact with acids. The low pH of these drinks and the increased risk of vomiting because of an excessive alcohol intake could potentially lead to substantial damage to the teeth. The treatment depends on the erosion stage. The medical professionals should be aware of the possible implications relating to alcopops' consumption. Some preventive advices can be given to the teenagers and to their parents: reduce acids consumptions, do not brush the teeth immediately after an acid drink and regularly visit a dentist. PMID- 20926268 TI - Tumour shrinkage and contour change during radiotherapy increase the dose to organs at risk but not the target volumes for head and neck cancer patients treated on the TomoTherapy HiArtTM system. AB - AIMS: To quantify the changes in contours of the target and organs at risk and the differences between planned and delivered doses to the target and organs at risk during the course of radiotherapy in head and neck cancer patients treated with intensity-modulated radiotherapy on the TomoTherapy HiArtTM system. MATERIALS AND METHODS: Five patients with squamous cell carcinoma of the head and neck treated with radical chemoradiotherapy using the TomoTherapy HiArt system were included in the study. The target volumes were treated to three different dose levels depending on the level of clinical risk for harbouring disease. Patient positions were assessed daily with megavoltage computed tomography (MVCT) and positional correction made before each treatment when necessary. MVCTs were superimposed on to the planning kilovoltage computed tomography images for each patient and target volumes and organ at risk volumes were re-outlined on MVCT images. Doses to clinical target volumes and organs at risk were recalculated to show the actual delivered doses. RESULTS: There was shrinkage in the volume of the parotid glands during treatment in all cases. The mean volume reduction in the ipsilateral parotid gland was more marked at 30.2%, compared with the contralateral parotid glands. However, the mean percentage dose per fraction increase was higher in the contralateral parotid glands at 24%, compared with the ipsilateral parotids. The calculated doses were higher than the planned doses in all CTV-54, CTV-60 and CTV-68, but the mean dose differences were modest, in the range 1.3-2.4%. CONCLUSIONS: We have shown that there were considerable changes in the volume and dose to the parotids during treatment. The changes in volume and dose to the clinical target volume were more modest in comparison. Adaptive radiotherapy planning can be helpful in improving the dose to the parotid glands. However, its role in the optimisation of the dosage to the clinical target volume is less likely to result in a significant clinical benefit. PMID- 20926269 TI - Skeletal muscle choristoma in the lung of a female Sprague-Dawley rat: a case report. AB - In this report we describe a choristoma in the lung of a female placebo rat. The lesion was observed microscopically in the central part of the left lung lobe and was characterized by a nodule consisting of well-differentiated skeletal muscle cells. The muscle fibers were haphazardly organized giving the nodule a poorly demarcated border. Choristoma is a very rare lesion. PMID- 20926270 TI - The aryl hydrocarbon receptor: fine-tuning the immune-response. AB - Triggers involved in the development of an autoimmune disease, and those that are part of determining its level of severity, are a major focus of current investigative efforts. However, factors that increase the risk to disease may not be similar to those that determine its severity or its pace of progression. The aryl hydrocarbon receptor (AhR) has been highlighted as having a potential regulatory role in these processes. Here we describe the recent findings of the possible involvement of AhR in the initiation and inhibition of immune responses. PMID- 20926271 TI - Efficacy of intravenous immunoglobulin for small fiber neuropathy associated with sarcoidosis. AB - BACKGROUND: Small fiber neuropathy (SFN) is commonly associated with sarcoidosis and can cause significant morbidity to afflicted patients. The appropriate treatment of this condition, when associated with sarcoidosis, is not well established. METHODS: Descriptive case series of three patients with sarcoidosis and SFN. The presenting clinical features, skin biopsy results, autonomic reflex screen and quantitative sudomotor axon reflex testing (QSART) findings, and response to therapy are delineated. RESULTS: We describe three patients with biopsy-proven sarcoidosis who developed intractable neuropathic pain and/or symptoms related to associated autonomic dysfunction despite treatment with various immunosuppressive medications and narcotic analgesics. QSART showed evidence of a postganglionic sudomotor abnormality in one patient and was normal in the other two. Skin biopsy findings were abnormal, demonstrating a non-length dependent sensory SFN in all three patients. Painful neuropathic symptoms, as well as symptoms related to dysautonomia from SFN responded significantly to treatment with intravenous immunoglobulin (IVIG). CONCLUSION: IVIG appears to be effective in relieving symptoms from SFN associated with sarcoidosis, suggesting an underlying immune mechanism. Larger prospective, controlled studies would be needed to confirm this response to IVIG and to further elucidate the underlying pathobiology behind this association with sarcoidosis. PMID- 20926272 TI - The impact of gas exchange measurement during exercise in pulmonary sarcoidosis. AB - BACKGROUND: Pulmonary sarcoidosis shows a remarkable heterogeneity of phenotypes ranging from bihilar lymphadenopathy to progressive fibrosis. Individual disease assessment is demanding and requires sensible, practical measures. We tested whether gas exchange measurements during exercise reflects disease activity and clinical course in sarcoidosis. METHODS: In 149 patients with proven pulmonary sarcoidosis the alveolar-arterial oxygen pressure gradient (P(A-a)O(2)) during exercise was assessed and compared with chest X-ray typing, pulmonary function, single breath-diffusing capacity for carbon monoxide (DL(CO)), serological markers, cell composition of bronchoalveolar lavage fluid (BALF) and clinical course. Patients were categorized according to thresholds of P(A-a)O(2) during exercise. MEASUREMENTS AND MAIN RESULTS: Chest X-ray typing, pulmonary function, DL(CO) and the need for immunosuppressive treatment differed between the disease categories based on P(A-a)O(2) during exercise (p < 0.0001 each). Patients with an impairment of gas exchange during exercise also showed elevated levels of neopterin (p = 0.002) and higher percentages of neutrophils (p = 0.013) and eosinophils (p < 0.0001) in BALF. Multivariate regression analysis showed that forced vital capacity (FVC) (p = 0.009) and P(A-a)O(2) during exercise (p < 0.0001) were independently associated with a prolonged need for immunosuppressive treatment (>1 year), but not DL(CO). About 50% (n = 75) of the study population showed a normal spirometry. Even in this subgroup 23% had an impaired gas exchange during exercise, which correlated with chest X-ray types (p < 0.0001) and the need for immunosuppressive treatment (p < 0.005). CONCLUSIONS: Impaired gas exchange during exercise reflects disease activity and its extent and is associated with a prolonged need for immunosuppressive treatment during follow-up in patients with pulmonary sarcoidosis. PMID- 20926273 TI - Reply to: Kelly et al. Alpha-1-antitrypsin deficiency. PMID- 20926274 TI - Reducing H2S production by O2 feedback control during large-scale sewage sludge composting. AB - Hydrogen sulfide (H(2)S) production patterns and the influence of oxygen (O(2)) concentration were studied based on a well operated composting plant. A real time, online multi-gas detection system was applied to monitor the concentrations of H(2)S and O(2) in the pile during composting. The results indicate that H(2)S was mainly produced during the early stage of composting, especially during the first 40 h. Lack of available O(2) was the main reason for H(2)S production. Maintaining the O(2) concentration higher than 14% in the pile could reduce H(2)S production. This study suggests that shortening the interval between aeration or aerating continuously to maintain a high O(2) concentration in the pile was an effective strategy for restraining H(2)S production in sewage sludge composting. PMID- 20926275 TI - Urchinlike MnO2 nanoparticles for the direct electrochemistry of hemoglobin with carbon ionic liquid electrode. AB - In this paper an urchinlike MnO(2) nanoparticle was synthesized by hydrothermal method and applied to the protein electrochemistry for the first time. By using a carbon ionic liquid electrode (CILE) as the basal electrode, hemoglobin (Hb) was immobilized on the surface of CILE with chitosan (CTS) and MnO(2) nanoparticle composite materials. Spectroscopic results indicated that Hb molecules retained its native structure in the composite film. A pair of well-defined redox peaks appeared on the cyclic voltammogram with the formal peak potential as -0.180 V (vs. SCE), which indicated that direct electron transfer of Hb was realized on the modified electrode. The result can be attributed to the specific characteristic of MnO(2) nanoparticle and the advantages of CILE, which facilitated the electron transfer rate. The fabricated CTS-MnO(2)-Hb/CILE showed good electrocatalytic ability to the reduction of trichloroacetic acid (TCA). Under the optimal conditions the catalytic current was in linear to TCA concentration in the range from 0.5 to 16.0 mmol L(-1) with the detection limit calculated as 0.167 mmol L(-1) (3sigma). The result indicated that urchinlike MnO(2) nanoparticle had the potential application in the third generation electrochemical biosensors. PMID- 20926276 TI - Rapid nested-PCR for tyrosinase gene detection on chip. AB - The availability of non-invasive, fast and sensitive technologies for detection of circulating cancer cells is still a critical need of clinical oncology, particularly for diagnosis of aggressive and highly metastatic tumors, like malignant melanoma. Here we present the first nested polymerase chain reaction process carried out by a microfabricated, hybrid plastic-glass microfluidic chip on the tyrosinase gene, a predictive marker for melanoma diagnosis. The device is a hybrid system consisting of a glass microchannel embedded in an elastomeric matrix, and operating in flow-oscillating modality on a droplet of biological sample. The convection heat transfer and the temperature distribution inside the carrier fluid in the device are investigated. The oil responds to temperature changes with a characteristic time around 53 s, and exhibits three different thermal gradients along the capillary, with temperature variations below 4 degrees C in correspondence of heater electrodes. The sample heating/cooling rates in the chip are as high as 16 degrees C/s, allowing rapid processes. The nested polymerase chain reaction process is performed in less than 50 min, namely more than four times faster than in a standard thermocycler. The rapidity of the analysis method, combined with the simple and low-cost fabrication, reduced sample evaporation, and flexibility of the overall microfluidic platform, make it promising for the detection of events of tumor spreading. PMID- 20926277 TI - Highly reproducible immunoassay of cancer markers on a gold-patterned microarray chip using surface-enhanced Raman scattering imaging. AB - This paper reports a highly reproducible immunoassay of cancer markers using surface-enhanced Raman scattering (SERS) imaging. SERS is a highly sensitive detection method but it is limited in its ability to achieve reproducible signal enhancement because of the difficulty with precisely controlling the uniform distribution of hot junctions. Consequently, inconsistent enhancement prevents the wide exploitation of SERS detection as a bio-detection tool for quantitative analysis. To resolve this problem, we explored the use of a SERS imaging-based immunoassay. For this purpose, Raman reporter-labeled hollow gold nanospheres (HGNs), were manufactured and antibodies were immobilized onto their surfaces for targeting specific antigens. After the formation of sandwich immunocomplexes using these functional HGNs on the surfaces of gold patterned wells, the SERS mapping images were measured. For target protein markers, 12*9 pixels were imaged using a Raman mapping technique in the 0-10(-4) g/mL concentration range, and the SERS signals for 66 pixels were averaged. Here, the SERS imaging-based assay shows much better correlations between concentration and intensity than does the conventional point-based assay. The limits of detection were determined to be 0.1 pg/mL and 1.0 pg/mL for angiogenin (ANG) and alpha-fetoprotein (AFP), respectively. This detection sensitivity is increased by three or four orders of magnitude over that of conventional ELISA method. The detectable dynamic range for SERS imaging (10(-4)-10(-12) g/mL) is also much wider than that for ELISA (10(-6)-10(-9) g/mL). PMID- 20926278 TI - Improving immunosensor performances using an acoustic mixer on droplet microarray. AB - A major drawback of protein microarrays is the lack of control of ligand immobilization at the surface of the chip which limits their performances and thus their impacts in in vitro diagnosis. To improve antibody (Ab) grafting during the spotting process on commercialized gold SPRi chips, we propose to produce a chaotic flow in every spotted droplet, by using an acoustic field, in order to disrupt the steady state of the reaction of Ab grafting. Our results show that acoustic mixing during Ab binding at the biochips surface increases their biorecognition performances of a mean factor of 2.7 in comparison with Ab layer grafted in a passive mode. Moreover, it increases statistically the homogeneity of the response over all the surface of the chips. PMID- 20926279 TI - HDR imaging evaluation of a NT-proBNP test with a mobile phone. AB - The determination of NT-proBNP levels is key for the monitoring of patients with diagnosed heart failure and it is a routine measurement typically performed at health care centers, which would benefit from decentralized alternatives. Here we investigate the quantitative evaluation of a well-established NT-proBNP test using a standard mobile phone (Nokia 6720) as measuring platform rather than a dedicated instrument. A Java ME software developed for this application controls the illumination and imaging of the proBNP test under defined time intervals, which enables the composition of multi-exposure sets that are processed as high dynamic range (HDR) images for contrast enhancement. The results show that HDR processing significantly increases the sensitivity and resolution of the technique achieving a performance within the diagnostics range. These results demonstrate the feasibility to exploit a ubiquitous device to decentralize the evaluation of a routine test and identify key processing alternatives to bring the performance of such systems within the diagnostics range. PMID- 20926280 TI - Gold nanoparticles-decorated amine-terminated poly(amidoamine) dendrimer for sensitive electrochemical immunoassay of brevetoxins in food samples. AB - A sensitive electrochemical immunosensor for the fast screening of brevetoxin B (BTX-2) in food samples was developed by means of immobilizing BTX-2-bovine serum albumin conjugate (BTX-2-BSA) on the gold nanoparticles-decorated amine terminated poly(amidoamine) dendrimers (AuNP-PAADs). The presence of gold nanoparticles greatly improved the conductivity of the PAADs, and three dimensional PAADs increased the surface coverage of the biomolecules on the electrode. Under optimal conditions, three types of immunosensor, i.e. with AuNPs, PAADs, or AuNP-PAADs, were used for the determination of BTX-2 in a competitive-type immunoassay format using horseradish peroxidase-labeled anti-BTX antibodies (HRP-anti-BTX-2) as trace in the H(2)O(2)-o-phenylenediamine (o-PD) system. A low detection limit (LOD) of 0.01 ng/mL and a wide dynamic working linear range of 0.03-8 ng/mL BTX-2 using AuNP-PAADs as matrices were obtained in comparison with those of only using AuNP or PAADs. Intra-batch assay precision was substantially improved by resorting to the AuNP-PAADs manifold. The proposed method features unbiased identification of negative (blank) and positive samples. No significant differences were encountered in the analysis of the spiking real samples between the electrochemical immunosensor and liquid chromatography for the determination of BTX-2. Importantly, this method provided a biocompatible immobilization and a promising immunosensing platform for analytes with small molecules in the analysis and detection of food safety. PMID- 20926281 TI - Nanostructured digital microfluidics for enhanced surface plasmon resonance imaging. AB - The advances in genomics and proteomics have unveiled an exhaustive catalogue of biomarkers that can potentially be used as diagnostic and prognostic indicators of genetic and infectious diseases. Current thrust in biosensor development is towards rapid, real-time, label-free and highly sensitive detection of the indicative biomarkers. While surface plasmon resonance imaging (SPRi) biosensors could potentially be the best suited candidate for biomarker-based diagnosis, important milestones need to be reached. Commercially available SPRi instrumentation is currently limited by the flow-cell technology to serial-sample processing and has limited sensitivity for the detection of markers present at low concentration. In this paper, we have implemented an approach to enhance sample handling and increase the sensitivity of the SPRi detection technique. We have developed a digital microfluidic platform with an integrated nanostructured biosensor interface that allows for rapid, ultra-low volume, sensitive, and automated on-chip SPRi detection of DNA hybridization reactions. Through the exploitation of electromagnetic properties of nanofabricated periodic gold nanoposts, SPRi signal was increased by 200% with the estimated limit of detection of 500 pM (90 attomoles). Using the versatile fluidic manipulation provided by the digital microfluidics, rapid and parallel target identification was achieved on multiple array elements within 1 min using 180 nL sample volume. By delivering multiple target analytes in individually addressable low volume droplets, without external pumps and fluidic interconnects, the overall assay time, cost and complexity was reduced. The proposed platform allows extreme versatility in the manipulation of precious low volume samples which makes this technology very suitable for diagnostic applications. PMID- 20926282 TI - Size-controllable quartz nanostructure for signal enhancement of DNA chip. AB - A mask-free, cost-effective dry-etching method for the fabrication of height- and spacing-controlled, pillar-like nanostructures was established in order to detect DNA molecules. The height and spacing of the quartz nanostructure were regulated by successive O(2) and CF(4) reactive ion etching times. The height and spacing of the nanostructures were tuned between 118 and 269 nm and between 107 and 161 nm, respectively. Probe DNA was immobilized on the structure and hybridized with fluorescently-labeled target DNA. Increases in the height and spacing of the nanopillar structure positively correlated with the fluorescence intensity of bound DNA. Usage of the nanostructure increased the DNA detection limit by up to 100-fold. PMID- 20926284 TI - Protein-based hybrid catalysts--design and evolution. AB - Artificial metalloenzymes result from the introduction of a catalytically competent non-native metal cofactor within a protein environment. In the present contribution, we summarize the recent achievements in the design and the optimization of such protein-based hybrid catalysts, with an emphasis on enantioselective transformations. The second part outlines the milestones required to achieve en masse production, screening and directed evolution of artificial metalloenzymes. In the spirit of Darwinian evolution, this will allow the full potential of such protein-based hybrid catalysts to be fully unraveled, thus complementing both homogeneous and enzymatic catalysis. PMID- 20926283 TI - Strong cation exchange (SCX) based analytical methods for the targeted analysis of protein post-translational modifications. AB - The multidimensional combination of strong cation exchange (SCX) chromatography and reversed phase chromatography has emerged as a powerful approach to separate peptides originating from complex samples such as digested cellular lysates or tissues before analysis by mass spectrometry, enabling the identification of over 10,000s of peptides and thousands of proteins in a single sample. Although, such multidimensional chromatography approaches are powerful, the in-depth analysis of protein post-translational modifications still requires additional sample preparation steps, involving the specific enrichment of peptides displaying the targeted modification. Here, we describe how in particular SCX chromatography can be used for the targeted analysis of important post-translational modifications, such as phosphorylation and N-terminal acetylation. Compared to other methods, SCX is less labor-intensive and more robust, and therefore likely more easily adaptable to main-stream research laboratories. PMID- 20926285 TI - Endoscopic plantar fascia release, calcaneal drilling and calcaneal spur removal for management of painful heel syndrome. AB - BACKGROUND: The pathogenesis of painful heel syndrome is multifactorial including plantar fasciitis, increased intra-osseous pressure of the os calcis, calcaneal periostitis and presence of calcaneal spur. The currently used endoscopic treatment of painful heel syndromes involves endoscopic plantar fascia release alone without addressing other pathological changes. OBJECTIVES: To evaluate the clinical outcome of endoscopic plantar fascia release, calcaneal drilling and calcaneal spur removal. METHODS: The study was conducted on 22 cases/24 feet with idiopathic painful heel syndrome resistant to conservative treatment. All cases were treated by plantar fasciotomy; calcaneal drilling and calcaneal spur removal using a modified cannula trocar system. Evaluation of pain was done using VAS and functional evaluation was done using the Modified Mayo Scoring System for Plantar Fasciotomy. Also patient's satisfaction was evaluated by direct questionnaire. RESULTS: There was statistically significant improvement in the mean VAS from 82.81 (+/-7.8 std) preoperative to 6.63 (+/-2.75 std) and the Mayo score form 7.05 (+/-3.67 std) preoperative to 87.5 (+/-4.81 std) at 2 years follow up (P<0.05). The satisfaction rate was 85% with no major complications. CONCLUSION: Endoscopic plantar fascia release with calcaneal drilling and calcaneal spur removal has high success rate and patient's satisfaction rate when compared to published reports on isolated endoscopic plantar release. PMID- 20926286 TI - Genomics and systems approaches in the mammalian circadian clock. AB - The circadian clock is an endogenous oscillator that regulates daily rhythms in behavior and physiology. In recent years, systems biology and genomics approaches re-shaped our view of the clock. Our understanding of outputs that regulate behavior and physiology has been enhanced through gene expression profiling and proteomic analyses. Systems approaches uncovered underlying principles of transcriptional regulation and robustness of the oscillator through perturbation analysis and synthetic methods. Finally, new clock components and modifiers were identified through cell-based screening efforts and proteomics. PMID- 20926287 TI - Getting ready to move: transmitted information in the corticospinal pathway during preparation for movement. AB - Corticospinal interactions are considered to play a key role in executing voluntary movements. Nonetheless several different studies have shown directly and indirectly that these interactions take place long before movement starts, when preparation for forthcoming movements dominates. When motor-related parameters are continuously processed in several premotor cortical sites, segmental circuitry is directly exposed to this processing via descending pathways which originate from these sites in parallel to descending fibers that derive from primary motor cortex. Recent studies have highlighted the functional role of these interactions in priming downstream elements for the ensuing motor actions. Time-resolved analysis has further emphasized the dynamic properties of pre-movement preparatory activity. PMID- 20926288 TI - Localisation of phosphorylated mTOR expression is critical to tumour progression and outcomes in patients with endometrial cancer. AB - Correlations between mammalian target of rapamycin (mTOR) expression, and clinicopathological features, outcome and Akt expression in endometrial endometrioid adenocarcinoma (EEC) were investigated. Tumour samples were obtained from 82 patients with EEC who had undergone hysterectomy, and phosphorylated mTOR (p-mTOR) and Akt (p-Akt) expression in the cytoplasm and nucleus was analysed by immunohistochemical staining. Nuclear p-mTOR was significantly elevated in poorly differentiated tumours and positively correlated with lymph node involvement (P = 0.05). Nuclear p-mTOR expression was associated with significantly shorter relapse-free survival (RFS) (P<0.01) and slightly shorter overall survival (OS) (P = 0.08). Cytoplasmic expression of p-mTOR was not correlated with any clinicopathological factors. Although not significant, cytoplasmic p-mTOR expression was associated with shorter PFS and OS (P = 0.09, P = 0.283, respectively). Neither cytoplasmic nor nuclear p-Akt expression was associated with clinicopathological factors or with survival. Localisation of p-mTOR may be critical for tumour progression and outcomes in patients with EEC. PMID- 20926289 TI - Structure, morphology and thermal characteristics of banana nano fibers obtained by steam explosion. AB - In this work, cellulose nanofibers were extracted from banana fibers via a steam explosion technique. The chemical composition, morphology and thermal properties of the nanofibers were characterized to investigate their suitability for use in bio-based composite material applications. Chemical characterization of the banana fibers confirmed that the cellulose content was increased from 64% to 95% due to the application of alkali and acid treatments. Assessment of fiber chemical composition before and after chemical treatment showed evidence for the removal of non-cellulosic constituents such as hemicelluloses and lignin that occurred during steam explosion, bleaching and acid treatments. Surface morphological studies using SEM and AFM revealed that there was a reduction in fiber diameter during steam explosion followed by acid treatments. Percentage yield and aspect ratio of the nanofiber obtained by this technique is found to be very high in comparison with other conventional methods. TGA and DSC results showed that the developed nanofibers exhibit enhanced thermal properties over the untreated fibers. PMID- 20926290 TI - Bacterial transformation and biodegradation processes simulation in horizontal subsurface flow constructed wetlands using CWM1-RETRASO. AB - The performance and reliability of the CWM1-RETRASO model for simulating processes in horizontal subsurface flow constructed wetlands (HSSF CWs) and the relative contribution of different microbial reactions to organic matter (COD) removal in a HSSF CW treating urban wastewater were evaluated. Various different approaches with diverse influent configurations were simulated. According to the simulations, anaerobic processes were more widespread in the simulated wetland and contributed to a higher COD removal rate [72-79%] than anoxic [0-1%] and aerobic reactions [20-27%] did. In all the cases tested, the reaction that most contributed to COD removal was methanogenesis [58-73%]. All results provided by the model were in consonance with literature and experimental field observations, suggesting a good performance and reliability of CWM1-RETRASO. According to the good simulation predictions, CWM1-RETRASO is the first mechanistic model able to successfully simulate the processes described by the CWM1 model in HSSF CWs. PMID- 20926292 TI - Comparative study of cellulose waste versus organic waste as substrate in a sulfate reducing bioreactor. AB - The biodegradability and comparative effectiveness in treatment of acid mine drainage of ten locally available organic waste materials were examined. pH of AMD increased from 2.70 to 6.25, 7.10 and 7.50 with buffalo, cow and goat manures whereas cellulosic wastes increased the pH within the range of 4.83-5.32 in laboratory scale single substrate bioreactors. Significant reduction was observed in Eh, acidity and sulfate with manures in treated AMD. Maximum metal removal efficiency was 99.3%, 99.9%, 99.8%, 99.1%, 99.1%, and 73.8% for Fe, Cu, Zn, Ni, Co and Mn in maximum retention period of 10 days. The highest efficiency of metal removal was observed in bioreactors with manures as single substrate. The effectiveness of substrate depends on its biodegradation ability, the results with cellulosic waste indicates it may need more than 10 days to biodegrade. Biodegradability of organic waste was evaluated according to COD/SO(4)(2-) and C/N ratio and the ratios of 0.48-0.57 and 22.22-23.00 respectively were adequate parameters for activity of sulfate reducing bacteria and pollutant removal efficiency. PMID- 20926291 TI - Effect of aspartate and glutamate on the fate of enhanced biological phosphorus removal process and microbial community structure. AB - This study investigated the fate of enhanced biological phosphorus removal (EBPR) and changes in microbial speciation in a sequencing batch reactor (SBR) fed with aspartate and glutamate. It involved SBR operation for 288 days, batch tests for observation of metabolic functions together with microscopic and phylogenetic analyses. Polyphosphate accumulating organisms (PAOs) were observed in abundance with complete removal of phosphorus. Fluorescence in situ hybridization (FISH) combined with 4',6-dia-midino-2-phenylindole (DAPI) staining confirmed the accumulation of polyphosphate by Rhodocyclus-related and Actinobacterial PAOs. Aspartate seemed to favor the competitive growth of Rhodocyclus-related PAOs since EBPR population used the common biochemical pathways followed by Rhodocyclus-related PAOs in the aspartate fed batch tests. In the glutamate fed batch reactors, however, Actinobacterial PAOs appeared to be competitively selected which explains the lower levels of PHA generation. Even though operational conditions did not change, effective EBPR could not be maintained during the latter part of the study. PMID- 20926293 TI - Chalcone HTMC causes in vitro selective cytotoxicity, cell-cycle G1 phase arrest through p53-dependent pathway in human lung adenocarcinoma A549 cells, and in vivo tumor growth suppression. AB - The present Letter identified 2'-hydroxy-2,3,4',6'-tetramethoxychalcone (HTMC) as a potent in vitro cytotoxic agent with selective activity against cell lines derived from human lung cancer. In A549 lung adenocarcinoma cells, HTMC caused G1 phase cell-cycle arrest. HTMC treatment also led to an inhibition of cell-cycle regulatory proteins phosphorylation of cdc2 (Tyr(15) and Tyr(161)) and Rb (Ser(795) and Ser(807/811)), which was accompanied by the accumulation of tumor suppressor genes p53 and p21. In addition, in vivo data demonstrated that HTMC act as a tumor growth suppressing agent. PMID- 20926294 TI - 3-Urea-1-(phenylmethyl)-pyridones as novel, potent, and selective EP3 receptor antagonists. AB - A series of 3-urea-1-(phenylmethyl)-pyridones was discovered as novel EP(3) antagonists via high-throughput screening and subsequent optimization. The synthesis, structure-activity relationships, and optimization of the initial hit that resulted in potent and selective EP(3) receptor antagonists such as 11g are described. PMID- 20926295 TI - Range of motion and repeatability of knee kinematics for 11 clinically relevant motor tasks. AB - Standard gait analysis reports knee joint rotations in the three anatomical planes without addressing their different levels of reliability. Most clinical studies also restrict analysis to knee flexion-extension, because knee abduction adduction and axial rotation are small with respect to the corresponding amount of measurement artefact. This study analyses a set of 11 motor tasks, in order to identify those that are adequately repeatable and that can induce greater motion at the knee than walking. Ten volunteers (mean +/- SD age: 29 +/- 9 years) each underwent three motion analysis sessions on different days with a standard gait analysis system and protocol. In each session they performed normal walking, walking with sidestep and crossover turns, ascent onto and descent off a step, descent with sidestep and crossover turns, chair rise, mild and deep squats, and lunge. Range and repeatability of motions in the three anatomical planes were compared by ANOVA. The sidestep turns showed a range of axial rotation significantly larger than that in walking (about 8 degrees ), while maintaining similar levels of repeatability. Ascent, chair rise, squat, and lunge showed greater flexion ranges than walking; among these, ascent was the most repeatable. The results show that turning increases knee axial rotation in young subjects significantly. Further, squats and lunges, currently of large interest in orthopaedics and sports research, have smaller repeatability, likely accounted for to the smaller constraints than in the traditional motor tasks. PMID- 20926296 TI - The microanatomical structure of the cistern of the lamina terminalis. AB - Microanatomical dissection was performed on 14 formalin-fixed human cadaveric head specimens to provide information relevant for surgical procedures involving the cistern of the lamina terminalis (LT). The cistern of the LT was located in the midline of the telencephalon and was tent-shaped. The superior wall was located between the septal areas bilaterally, the lateral walls leaned laterally downwards, the anterior wall was the integrated line of the bilateral leptomeninges, the posterior and the inferoposterior walls were composed of the LT, the inferior margin was the arachnoid membrane between the optic nerves, and the inferoanterior wall usually formed a recess in front of the optic chiasm. In summary, the shape of the cistern of the LT is relatively constant, which is helpful for predicting the direction of hemorrhage of an aneurysm of the anterior communicating artery; in distinguishing its neural, vascular, and fibrous contents; and guiding surgical procedures. PMID- 20926297 TI - Surgical management of large solid hemangioblastomas of the posterior fossa. AB - From January 2000 to January 2009, 15 patients presented with large solid hemangioblastomas of the posterior fossa; eight of these patients were also diagnosed with von Hippel-Lindau (VHL) disease. Diagnostic imaging showed large vascular lesions. All 15 patients underwent surgery through a suboccipital ipsilateral, modified far-lateral, suboccipital midline or suboccipital supracerebellar approach. Preoperative embolization was attempted in seven patients. Complete removal of the tumor was performed in all patients. An overall neurological improvement was observed in 11 of the 15 patients, corresponding to 61.5%. During follow-up, six patients, all with VHL disease, developed recurrence. Two patients died of renal cell carcinoma after 1 year. Our favorable outcomes suggest that surgical resection is the optimal treatment for patients with large solid hemangioblastomas of the posterior fossa. With improved microsurgical techniques and a better understanding of the vascular pattern of this type of tumor, total microsurgical removal can be performed with low mortality. PMID- 20926298 TI - Living without 30nm chromatin fibers. AB - Eukaryotic genomes must be folded and compacted to fit within the restricted volume of the nucleus. According to the current paradigm, strings of nucleosomes, termed 10nm chromatin fibers, constitute the template of transcriptionally active genomic material. The majority of the genome is maintained in a silenced state through higher-order chromatin assemblies, based on the 30nm chromatin fiber, which excludes activating regulatory factors. New experimental approaches, however, including chromatin conformation capture and cryo-electron microscopy, call into question the in situ evidence for the 30nm chromatin fiber. We suggest that the organization of the genome based on 10nm chromatin fibers is sufficient to describe the complexities of nuclear organization and gene regulation. PMID- 20926299 TI - Quantification of the difference between 3D CT and plain radiograph for measurement of the position of medial unicompartmental knee replacements. AB - The aim of this study was to quantify the differences in measurements obtained from 3D Computed Tomography and plain radiograph, for the positioning of the tibial component of the Oxford unicompartmental knee replacement. Post-operative 3D Computed Tomography data and plain radiographs (long antero-posterior (AP) and short lateral) were obtained for 28 knees of patients who had undergone medial unicompartmental knee replacement. Parameters of the orientation/positioning of the tibial component: Varus/valgus, posterior tibial slope and rotation were measured with both modalities. Bland-Altman plots were used to calculate the 1.96 standard deviation limits of agreement (LOA) between imaging modalities. Intra class correlation was used to assess inter-method and inter-rater reliability (>0.81 = very good reliability). Radiographs were less reliable in all parameters, when compared with 3D CT (intra class correlation coefficients: tibial rotation 0.94 vs 0.96, varus/valgus 0.76 vs 0.94, and posterior tibial slope 0.82 vs 0.92). The LOA were -4.9 degrees to 3.4 degrees for varus/valgus (bias -0.7 degrees , one third >3 degrees different); -4.9 degrees to 0.1 degrees for posterior tibial slope (bias -2.4 degrees , one third >3 degrees different); and -20.6 degrees to 16.1 degrees for rotation (bias -2.2 degrees , one third >10 degrees different). There was some disagreement between measurement by 3D Computed Tomography and plain radiograph for all three parameters of tibial component orientation, especially tibial rotation. This will be particularly relevant to research into the relationship between the accuracy of implant positioning/orientation and patient satisfaction/implant survival rates. This method offers a more reliable standard for the reporting of knee arthroplasty. PMID- 20926300 TI - Synthesis and evaluation of macrocyclic amino acid derivatives for tumor imaging by gallium-68 positron emission tomography. AB - (68)Ga PET imaging in clinical oncology represents a notable development because the availability of (68)Ga is not dependent on a cyclotron. Furthermore, labeled amino acid derivatives have been proven to be useful for the imaging many tumor types. In the present study, we synthesized beta-aminoalanine, gamma aminohomoalanine, and lysine conjugates of macrocyclic bifunctional chelating agents, such as, NOTA (1a-c) and DOTA (2a-c). The compounds produced were found to be potential useful as (68)Ga-PET imaging agents. In particular, they showed high tumor uptakes in vitro and in vivo, and had high labeling yields and excellent stabilities. The co-ordination chemistry of NOTA-monoamide compound 1a was studied by multinuclear NMR. In vitro studies showed that the synthesized compounds were taken up by cancer cells more than controls ((68)Ga-NOTA and (68)Ga-DOTA). Furthermore, in vivo studies showed that they have high tumor to muscle and tumor to blood ratios, and small-animal PET imaging revealed high tumor uptakes as compared with other organs, and high bladder activities, indicating rapid renal excretion. These results might motivate the use of (68)Ga amino acid PET for tumor diagnosis. PMID- 20926301 TI - Indapamide-like benzenesulfonamides as inhibitors of carbonic anhydrases I, II, VII, and XIII. AB - A series of novel 2-chloro-5-[(1-benzimidazolyl- and 2 benzimidazolylsulfanyl)acetyl]benzene-sulfonamides were designed and synthesized. Their binding to recombinant human carbonic anhydrase (hCA) isozymes I, II, VII, and XIII was determined by isothermal titration calorimetry and thermal shift assay. The designed S-alkylated benzimidazole derivatives exhibited stronger binding than the indapamide-like N-alkylated benzimidazoles, with the K(d) reaching about 50-100 nM with drug-targeted hCAs VII and XIII. The cocrystal structures of selected compounds with hCA II were determined by X-ray crystallography, and structural features of the binding event were revealed. PMID- 20926302 TI - Structured illumination microscopy of autofluorescent aggregations in human tissue. AB - Sections from human eye tissue were analyzed with Structured Illumination Microscopy (SIM) using a specially designed microscope setup. In this microscope the structured illumination was generated with a Twyman-Green Interferometer. This SIM technique allowed us to acquire light-optical images of autofluorophore distributions in the tissue with previously unmatched optical resolution. In this work the unique setup of the microscope made possible the application of SIM with three different excitation wavelengths (488, 568 and 647 nm), thus enabling us to gather spectral information about the autofluorescence signal. PMID- 20926303 TI - Separation of 90Y from 90Sr by a solvent extraction method using N,N,N',N' tetraoctyl diglycolamide (TODGA) as the extractant. AB - The relative extraction efficiency of N,N,N',N'-tetraoctyl diglycolamide (TODGA) towards Y(3+) and Sr(2+) was investigated from HNO(3) as well as HCl medium. The separation factor (S.F.) values were found to be much higher in HCl medium as compared to those obtained from HNO(3) medium. Based on the high separation factor values obtained in the HCl media, a separation method for (90)Y from (90)Sr (containing (90)Y in secular equilibrium) has been developed in the present work. The purity of the separated (90)Y was ascertained from its decay profile and half-life measurements. The extracted species was determined to be Y(X)(3) . 3TODGA where X(-) is the nitrate or the chloride anion. The thermodynamic parameters were also determined and the two phase extraction constants (log K(ex)) were calculated. The extraction of Y(III) was highly exothermic and entropy destabilized and was equally favourable from both HNO(3) medium as well as HCl medium. PMID- 20926304 TI - A new and simple calibration-independent method for measuring the beam energy of a cyclotron. AB - This work recommends a new and simple-to-perform method for measuring the beam energy of an accelerator. The proposed method requires the irradiation of two monitor foils interspaced by an energy degrader. The primary advantage of the proposed method, which makes this method unique from previous energy evaluation strategies that employ the use of monitor foils, is that this method is independent of the detector efficiency calibration. This method was evaluated by performing proton activation of (nat)Cu foils using both a cyclotron and a tandem Van de Graaff accelerator. The monitor foil activities were read using a dose calibrator set to an arbitrary calibration setting. Excellent agreement was noted between the nominal and measured proton energies. PMID- 20926305 TI - Canna indica flower: New source of anthocyanins. AB - In this study the red flowers of Canna indica (Cannaceae) were extracted by using sonicator and isolation of anthocyanins have been carried out. Four anthocyanin pigments have been isolated apart from quercetin and lycopene. They are Cyanidin 3-O-(6''-O-alpha-rhamnopyranosyl)-beta-glucopyranoside (1), Cyanidin-3-O-(6''-O alpha-rhamnopyranosyl)-beta-galactopyranoside (2), Cyanidin-3-O-beta glucopyranoside (3) and Cyanidin-O-beta-galactopyranoside (4). These compounds were isolated by using HPLC and their structures were subsequently determined on the basis of spectroscopic analyses, i.e., (1)H NMR, (13)C NMR, HMQC, HMBC, ESI MS, FTIR, UV-Visible etc. The isolated compounds showed good antioxidant activity thus makes it suitable for use in food coloration and as a nutraceutical. Thus it is a promising pigment source for food applications. PMID- 20926306 TI - Predictors of postoperative decline in quality of life after major lung resections. AB - OBJECTIVE: Severe impairment in quality of life (QoL) is one of the major patients' fears about lung surgery. Its prediction can be valuable information for both patients and physicians. The objective of this study was to identify predictors of clinically relevant decline of the physical and emotional components of QoL after lung resection. METHODS: This is a prospective observational study on 172 consecutive patients submitted to lobectomy or pneumonectomy (2007-2008). QoL was assessed before and 3 months after operation through the administration of the Short Form 36v2 survey. The relevance of the perioperative changes in physical component summary (PCS) and mental component summary (MCS) scales was measured by the Cohen's effect size (mean change of the variable divided by its baseline standard deviation). An effect size >0.8 is regarded as large and clinically relevant. QoL changes were dichotomized according to this threshold. Logistic regression and bootstrap analyses were used to identify reliable predictors of large decline in PCS and MCS. RESULTS: A total of 48 patients (28%) had a large decline in the PCS scale and 26 (15%) in the MCS scale. Patients with a better preoperative physical functioning (p=0.0008) and bodily pain (p=0.048) scores and those with worse mental health (p=0.0007) scores were those at higher risk of a relevant physical deterioration. Patients with a lower predicted postoperative forced expiratory volume in 1s (ppoFEV1; p=0.04), higher preoperative scores of social functioning (p=0.02) and mental health (p=0.06) were those at higher risk of a relevant emotional deterioration. The following logistic equations were derived to calculate the risk of decline in physical or emotional components of QoL, respectively: risk of physical decline: lnR/(1+R): -11.6+0.19XPF, physical functioning+0.05XBP, bodily pain-0.05XMH, mental health; risk of emotional decline: ln R1/(1+R1): -8.06 0.03XppoFEV1+0.11XSF+0.055XMH. CONCLUSIONS: A consistent proportion of patients undergoing lung resection exhibit an important postoperative worsening in their QoL. We were able to identify reliable risk factors and predictive equations estimating this decline. These findings may be used as selection criteria for efficacy trials on perioperative physical rehabilitation or psychological treatments, during preoperative counseling, in the surgical decision-making process and for selecting those patients who would benefit from physical and emotional supportive programs. PMID- 20926307 TI - UV-shielding property, photocatalytic activity and photocytotoxicity of ceria colloid solutions. AB - UV-shielding property, photocatalytic activity and cytotoxicity (including photocytotoxicity) of citrate-stabilized ceria colloid solutions were studied. It was established that UV-shielding property (namely, the sun protection factor, the critical absorption wavelength and the UVA/UVB-ratio) of ceria nanoparticles are as good as those of titanium dioxide and zinc oxide nanoparticles. It was further demonstrated that ceria nanoparticles possesses substantially lower photocatalytic activity, which additionally decreases upon decrease in ceria particle size. It was found that colloid ceria solutions are non-toxic to mouse fibroblasts (L929) and fibroblast-like cells of African Green monkey (VERO). Moreover, ceria nanoparticles are capable to protect these cells from UV irradiation-induced damage. It was proposed that nanocrystalline ceria could be used not only as UV-blocking material, but also as prophylactic and even therapeutic compound for sunburns treatment. PMID- 20926308 TI - Native IL-32 is released from intestinal epithelial cells via a non-classical secretory pathway as a membrane-associated protein. AB - Although IL-32 has been shown to be induced under various pathological conditions, a detailed understanding of native IL-32 intracellular distribution and mechanism of release from cells has not been reported. We examined the expression of IL-32 in the intestinal epithelial cell line HT-29 following TNFalpha and IFNgamma co-stimulation. The subcellular localization of induced IL 32 was associated with the membrane of lipid droplet-like structures and vacuolar structures that co-localized with markers of endosomes and lysosomes. Prolonged co-stimulation resulted in cell death and appearance of IL-32 in the culture medium. IL-32 released from co-stimulated HT-29 cells was found in a detergent sensitive particulate fraction, and in a step density gradient the IL-32 particulate was buoyant, suggesting association with a membrane-bound vesicle. Upon Triton X-114 partitioning, most of the IL-32 partitioned to the detergent phase, suggesting hydrophobic characteristics. When IL-32-containing vesicles were subjected to protease K treatment, a protease resistant ~12kDa fragment was generated from ~24kDa IL-32. We propose that under these conditions, native IL-32 is released via a non-classical secretory route perhaps involving multi-vesicular bodies and exosomes. Demonstration of membrane association for both intracellular and released IL-32 suggests this unique cytokine may have a complex biosynthetic pathway and mechanism of action. PMID- 20926309 TI - Targeted ion parking for the quantitation of biotherapeutic proteins: concepts and preliminary data. AB - Targeted ion parking (or TIPing) is the first quantitative application of ion/ion reactions for mass spectrometry. In TIPing, intact biotherapeutic proteins are electrosprayed as intact molecules (no digestion) and, as expected, many multiply protonated species are produced (e.g., (M + 7H)(7+), (M + 8H)(8+), etc.). Several of these multiply charged species are selectively isolated using a quadrupole mass analyzer and then contained in a linear ion trap. The protein ions are then subjected to a proton-transfer reaction with a reagent anion. The ions undergo sequential charge reduction (e.g., to (M + 6H)(6+)) during a defined reaction period. Applying a low-amplitude waveform to the trap during this reaction time stops the ion/ion reaction at a chosen (and predicted) charge state for the protein. This funnels the analyte ions into a single channel with relatively high efficiency (>50% of reactant ion signal is converted into product ion signal) that can be used for quantitation. In TIPing, the target protein's molecular weight and charge state distribution are the only prerequisite knowledge required. This information can be acquired experimentally or can be easily predicted based upon amino acid sequences. Preliminary data for a biotherapeutic protein, a domain antibody, were collected using TIPing coupled online with liquid chromatography (LC-TIPing). The LC-TIPing data demonstrate a linear response for samples from 10-1000 ng/mL extracted from a complex plasma sample, demonstrating the analytical potential for TIPing. PMID- 20926310 TI - Maximal voluntary isometric contraction exercises: a methodological investigation in moderate knee osteoarthritis. AB - PURPOSE: The objectives were, (i) to determine whether differences exist in relative activation amplitudes for participants with asymptomatic knees and participants with moderate medial compartment knee osteoarthritis during a series of maximal effort contractions and (ii) to determine whether maximum activations occurred on similar exercises for both groups. SCOPE: Sixty-eight participants with asymptomatic knees and 68 participants with moderate medial compartment knee osteoarthritis completed eight standardized 3-s maximal voluntary isometric exercises. Maximal electromyographic amplitudes were identified for a 100 ms window from three quadriceps, two gastrocnemius and two hamstring muscle sites for each exercise. For each exercise, amplitudes were normalized to percent of the absolute maximum activation (%MVIC). Frequency counts for exercises eliciting absolute maximum amplitudes were recorded. Analysis of variance models determined exercise and group main effects and interactions in relative amplitudes (%MVIC) for each muscle. CONCLUSION: The exercises produced similar relative activation amplitudes between groups. The highest relative amplitude occurred for gastrocnemius during standing plantarflexion (86-93%MVIC), for the vasti during knee extension (45 degrees ) and (15 degrees ) (81-86%MVIC), for rectus femoris during knee extension (15 degrees ) (89%MVIC) and for hamstring muscles during knee flexion (15 degrees ) and prone knee flexion (55 degrees ) (81-94%MVIC). No single exercise elicited absolute maximum activation for every participant for each muscle, supporting the value of using an exercise series for normalization purposes. PMID- 20926311 TI - Optimal screw placement for base plate fixation in reverse total shoulder arthroplasty. AB - HYPOTHESIS: Scapular cortical thickness has not been fully characterized from the perspective of determining optimal screw placement for securing the glenoid base plate in reverse shoulder arthroplasty. MATERIALS AND METHODS: Twelve fresh frozen cadaveric scapulae underwent high resolution CT scans with 3-dimensional reconstructions and wall thickness analysis. Digital base plates were positioned and virtual screws were placed according to 2 scenarios: A - intraosseous through the entire course and exits a "safe region" with no known neurovascular structures; B - may leave and re-enter the bone and penetrates the thickest cortical region accessible regardless of adjacent structures. RESULTS: For scenario A, the optimal screw configurations were: (superior screw) length = 35 mm, 9 degrees superior, 2 degrees posterior; (inferior screw-A) length = 34 mm, 16 degrees inferior, 5 degrees anterior; (inferior screw-B) length = 31 mm, 31 inferior, 4 posterior; (posterior screw) length 19 mm, 29 degrees inferior, 3 degrees anterior. For scenario B: (superior screw) length = 36 mm, 28 degrees superior, 10 degrees anterior; (inferior screw) length = 35 mm, 19 degrees inferior, 4 degrees anterior; (posterior screw) length 37 mm, 23 degrees superior, 3 degrees anterior. The anterior screw was consistent between scenarios A and B, averaged 29 mm in length and was directed 16 degrees inferior and 14 degrees posterior. CONCLUSION: Thicker cortical regions were present in the lateral aspect of the suprascapular notch, scapular spine base, anterior/superior aspect of inferior pillar and junction of glenoid neck and scapular spine. Regions with high cortical thickness were accessible for both scenarios except for the posterior screw in scenario A. PMID- 20926312 TI - Functional and radiographic long-term outcomes of hemiarthroplasty for proximal humeral fractures. AB - BACKGROUND: Hemiarthroplasty is the preferred surgical procedure for 3- and 4 part proximal humeral fractures. Our retrospective study examined functional and radiographic outcomes at 2- and 5-year follow-up in patients who received a hemiarthroplasty for 3- and 4-part proximal humeral fractures. MATERIALS AND METHODS: Forty-seven consecutive patients of a single surgeon treated with a cemented shoulder hemiarthroplasty between 2000 and 2006 were followed up. Standard surgical technique was used in all cases. Postoperative radiographs were compared with radiographs at 2 and 5 years along with active range of motion and functional outcomes scores. RESULTS: Twenty-five patients were examined at 2 years and twenty-two at 2 and 5 years. The mean age was 61 years. The mean acromiohumeral distance decreased from 10.3 mm postoperatively to 8.5 mm at 2 years and 6.7 mm at 5 years (P <= .001). More patients had stem osteolysis and tuberosity reabsorption at 2 and 5 years compared with postoperatively (P = .016 and P <= .001, respectively). The University of California, Los Angeles score decreased from 26.0 to 22.3 (P = .045); the Constant score decreased from 61.1 to 50.1 (P = .01); the Simple Shoulder Test 12 score decreased from 7.7 to 6.2 (P = .018); and the American Shoulder and Elbow Surgeons score decreased from 70.4 to 58.8 (P = .015). Pain scores increased from 2- to 5-year follow-up (P = .018). The range-of-motion measures changed little from the 2-to 5-year follow-up. CONCLUSIONS: Hemiarthroplasty has a high rate of long-term complications. Increases in acromiohumeral distance, stem osteolysis, and tuberosity reabsorption were observed between 2- and 5-year follow-up. Pain scores and functional outcomes worsened. No improvement in range of motion was observed. PMID- 20926313 TI - Deltoid compartment syndrome is a surgical emergency. PMID- 20926314 TI - Mechanical soft tissue property validation in tissue engineering using magnetic resonance imaging experimental research. AB - RATIONALE AND OBJECTIVES: To perform magnetic resonance imaging (MRI) scans regarding material parameter and model validation in computational simulations of mechanical interaction of human soft-tissue with body-supporting devices, enhanced medical prognosis in pressure sore prophylaxis, and comfort optimization in automotive and aircraft seating. MATERIALS AND METHODS: In vivo human gluteal fat and passive muscle tissue material parameters of a volunteer evaluated via combined MRI numerical method and body-supporting foam material parameters employed in finite element (FE) simulations of tissue-support interaction were verified by a defined loading scenario using MRI. MRI of the loaded configurations were performed and compared with simulation results for displacement field information. RESULTS: Deformation of gluteal skin/fat and passive muscle-tissue and support material under interacting loading using numerical simulation complied with the MRI results. Accordance was found for deformed skin surface and internal fat-muscle tissue boundaries by superimposing experimental and numerical outputs. Further evidence of established through in vivo gluteal tissue parameters was thus provided and tissue material isotropy assumption was shown for use in simulated buttock loading interactions. Additionally, a new concept of FE model validation regarding non-MRI-sensitive materials such as polyurethane foam was introduced comprising peripheral surface visualization. CONCLUSION: Imaging techniques are essential in biomechanical modeling and provide key information regarding model validation and validity assessment. PMID- 20926315 TI - Comparison of different tumor response criteria in patients with hepatocellular carcinoma after systemic therapy with the multikinase inhibitor sorafenib. AB - RATIONALE AND OBJECTIVES: The aim of this study was to compare tumor changes in patients with hepatocellular carcinoma receiving sorafenib using evaluation criteria of the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL) as opposed to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. MATERIALS AND METHODS: Twenty-five patients with inoperable hepatocellular carcinoma receiving oral sorafenib underwent magnetic resonance imaging at baseline and follow-up every 8 weeks (range, 2-19 weeks; mean, 7.6 weeks). Data were evaluated retrospectively. Survey time until progression ranged from 5 to 102 weeks (mean, 25.6 weeks), with a total of 54 target lesions being monitored. Additionally, evaluation of serum alpha-fetoprotein was performed at follow-up. RESULTS: The best response at follow-up using RECIST resulted in rates of 4% objective response (complete remission or partial remission), 24% (progressive disease), and 72% (stable disease). In contrast, AASLD and EASL criteria identified objective responses in 28% and 48%. Twenty percent of all patients classified as having progressive disease by RECIST were identified as having "pseudo" progression due to extensive necrosis. Eleven percent of patients classified as having stable disease by RECIST were disclosed as essentially progressive. AASLD area and AASLD diameter disclosed 36% and 40% of patients as having partial remission, respectively, whereas EASL criteria discovered only 24%. There was no significant correlation between serum alpha-fetoprotein progression and AASLD, EASL, or RECIST evaluation criteria. CONCLUSIONS: Response monitoring via functional criteria such as AASLD or EASL criteria is likely to more accurately reflect vital tumor burden in hepatocellular carcinoma compared to RECIST. PMID- 20926316 TI - An interactive web-based tool for detecting verification (work-up) bias in studies of the efficacy of diagnostic imaging. AB - RATIONALE AND OBJECTIVES: Diagnostic tests are validated by comparison against a "gold standard" reference test. When the reference test is invasive or expensive, it may not be applied to all patients. This results in biased estimates of the sensitivity and specificity of the diagnostic test. This type of bias is called "verification bias" and is a common problem in imaging research. The purpose of this study was to create an interactive web-based tool to help detect the presence of prevalence of verification bias in data. MATERIALS AND METHODS: The web-based tool was written using well-documented and freely available open-source software (HTML, Apache, Ruby, and R). Our calculator is currently hosted on a Mac OS X server, but should run with minor changes on most other platforms. RESULTS: Our program applies user-supplied study data to generate a global sensitivity analysis plot containing noncorrected and corrected values of sensitivity and specificity and 95% confidence intervals for these estimates. Interpretation of the global sensitivity analysis (GSA) plot is relatively simple. Because the characteristic GSA "butterfly" plot contains all possible values of sensitivity and specificity, any indices lying outside of this butterfly are therefore incompatible with the data, confirming that they are biased. CONCLUSIONS: Our online calculator makes it easy for investigators to use global sensitivity analysis to demonstrate the presence of significant verification bias and to estimate bias-corrected values of sensitivity and specificity. PMID- 20926317 TI - Gd-EOB-DTPA enhanced micro-MR imaging of hepatic tumors in H-ras 12V transgenic mice. AB - RATIONALE AND OBJECTIVES: The aims of this study were to evaluate the morphologic characteristics and growth pattern of hepatic tumors in H-ras 12V transgenic (TG) mice using a micro-magnetic resonance (MR) system and to assess the usefulness of gadolinium ethoxybenzyl diethylenetriamine penta-acetic acid (Gd-EOB-DTPA) enhancement for the detection of hepatic tumors in these mice. MATERIALS AND METHODS: Hepatocellular carcinoma lines were established to allow insertion of the H-ras 12V transgene under the control of the albumin enhancer/promoter. Seven H-ras 12V TG mice and four wild-type mice were included in this study. The mice underwent various MR imaging examinations, including T1-weighted imaging (repetition time, 300 ms; echo time, 11 ms), Gd-EOB-DTPA-enhanced T1-weighted imaging (dose, 0.025 mmol/kg), and T2-weighted imaging (repetition time, 3500 ms; echo time, 36 ms), with a 4.7-T MR scanner, at 4, 6, 8, and 9 months of age. All mice were euthanized after the final MR imaging procedure, except for one TG mouse and two wild-type mice that were euthanized after MR imaging procedures at 4 months of age. For imaging analysis, the tumor characteristics in each MR sequence, including tumor size, number, and signal intensity (SI), were recorded, and the contrast-to-noise ratio and contrast enhancement ratio were calculated to quantify the SI of the tumor. The MR images were correlated with the findings of histopathologic examinations. RESULTS: No tumors were detected in the four wild type mice. In the six TG mice, a total of 67 tumors were found in histopathologic specimens obtained at 9 months of age. Of the 67 tumors, 62 were detected on Gd EOB-DTPA-enhanced T1-weighted images with fat saturation. The majority of hepatic tumors showed high SI on T1-weighted images without fat saturation. The SI diminished on T1-weighted images with fat saturation. The tumor contrast-to-noise ratio for Gd-EOB-DTPA-enhanced T1-weighted imaging was significantly better than that for the other sequences. The tumors were histopathologically confirmed as hepatocellular adenomas (n = 32) and well-differentiated hepatocellular carcinomas (n = 35). CONCLUSIONS: Micro-MR imaging can reveal the characteristics of hepatic tumors in a live murine model. Gd-EOB-DTPA-enhanced T1-weighted imaging is helpful in the detection of hepatic tumors in H-ras 12V TG mice. PMID- 20926318 TI - Quantitative evaluation of the peripheral nerve blood perfusion with high frequency contrast-enhanced ultrasound. AB - RATIONALE AND OBJECTIVES: The blood perfusion of peripheral nerves plays an important role in regeneration after nerve injury. Previous studies have shown that it is possible to quantitatively assess the blood perfusion of the tissue using contrast-enhanced ultrasound (CEUS). The aim of this study was to evaluate the feasibility of CEUS for quantitative assessment of the blood perfusion of the sciatic nerve in normal New Zealand white rabbits and to compare these parameters to those of surrounding skeletal muscle and the main artery in the thigh. MATERIALS AND METHODS: CEUS of the bilateral sciatic nerves was performed in 12 normal New Zealand white rabbits after a bolus injection of SonoVue (0.13 mL/kg). Pulse-inversion harmonic imaging was used for real-time CEUS. The blood perfusion of the left sciatic nerve was compared to that of its surrounding muscle, the arterial branch in the thigh, and the contralateral side. RESULTS: The supplying arteries in the sciatic nerve could be demonstrated during the early phase of CEUS, followed by the homogeneous enhancement of the whole nerve. The area under the curve and the perfusion index of the sciatic nerve were higher than those of the surrounding muscle and lower than those of the arterial branch in the thigh (both P values = .000). The maximum intensity of the sciatic nerve was similar to that of skeletal muscle and lower than that of the arterial branch. The time to peak was not significantly different among the sciatic nerve, skeletal muscle, and arterial branch (P = .551). There were no differences in area under the curve, mean transit time, perfusion index, maximum intensity, and time to peak between the left and right sciatic nerves (P > .05). CONCLUSIONS: CEUS may be a feasible method for the quantitative assessment of blood perfusion of the peripheral nerves. PMID- 20926319 TI - Costs associated with angiogenesis inhibitor therapies for metastatic renal cell carcinoma in clinical practice: results from a medical chart review study. AB - OBJECTIVE: To estimate costs for treatment of mRCC patients receiving angiogenesis inhibitors (AI) using resource utilization data from medical charts. MATERIALS AND METHODS: A retrospective chart review was performed in two U.S. tertiary oncology centers. Non-trial mRCC patients treated from 04/2003 to 06/2008, >= 18 years old, and with >= 1 prescription for sunitinib (SU; n = 57), sorafenib (SOR; n = 62), or >= 1 intravenous (i.v.) administration bevacizumab (BEV; n = 25) as first AI were included. Per-patient-per-month (PPPM) costs ($2008) were estimated for drug, i.v. administration, office visits, procedures, and AE treatments. AI drug costs were estimated by applying Average Wholesale Price to treatment course. Office visit and procedure costs were based on private insurance reimbursement. Hospitalization costs were based on HCUP National Inpatient Sample charges for AEs and were converted to costs. ER visit cost was based on national average from Medical Expenditure Panel Survey. RESULTS: Median treatment duration (mo) was 10.5 (SU), 8.1 (SOR), 7.9 (BEV). Average daily oral dosage was 32 mg (SU), 690 mg (SOR); average dose per i.v. administration was 871 mg (BEV). Total PPPM costs were $7,945 (SU), $6,990 (SOR), $15,189 (BEV). AI drugs accounted for the majority of PPPM costs ($5,639 [SU], $5,214 [SOR], $13,664 [BEV]), followed by procedures ($1,420 [SU], $1,004 [SOR], $749 [BEV]), and AE treatments ($729 [SU], $636 [SOR], $291 [BEV]). CONCLUSIONS: BEV patients incurred about twice the cost of SU patients and more than twice the cost of SOR patients, mainly due to higher drug and i.v. administration costs. Patients who received SU incurred the highest cost for AE management. PMID- 20926320 TI - Renal artery dissection during repositioning of a mal-deployed aortic endograft with suprarenal fixation. AB - Endograft mal-deployment during endovascular aneurysm repair (EVAR) may cause renal artery (RA) occlusion. We report bilateral RA occlusion following insertion of an endograft with suprarenal barb fixation. Attempted salvage using the 'pull down' technique caused right RA dissection. Despite bilateral RA stenting, the right kidney was atrophic on an ultrasound scan at 6 months. This potential hazard of devices with suprarenal barb fixation should be considered when repositioning is attempted. PMID- 20926321 TI - Blocking the saphenofemoral junction during ultrasound-guided foam sclerotherapy- assessment of a presumed safety-measure procedure. AB - OBJECTIVES: Ultrasound-guided foam sclerotherapy (UGFS) is a technique in which a mixture of sclerosing drug and gas is used to treat varicose veins. Several authors have demonstrated transient systemic effects after UGFS. These effects are not well understood but probably originate from a systemic distribution of the sclerosing foam. Therefore, safety measures have been developed to prevent foam from flowing into the deep venous system. The aim of the study is to evaluate whether blockage of the saphenofemoral (SF) junction by either manual compression or surgical ligation prevents microbubbles from leaking into the deep venous circulation. METHODS: To detect the distribution of microbubbles, radioactive pertechnetate (99mTcO4-) was added to the foam solution. Initially, in vitro trials were performed in the laboratory to investigate the effect of 99mTc on foam stability. The time taken for foam to liquefy was measured for foam alone and for the mixture with 99mTc. In subsequent research, eight varicose great saphenous veins (GSVs) were treated by UGFS. In three patients, this treatment was preceded by surgical ligation of the SF junction. In three patients, the groin was manually compressed during UGFS. In two patients, UGFS was performed without compression of the groin. RESULTS: In vitro, 99mTc did not influence foam stability; after 2.6 min all foam had reduced to liquid, regardless of whether 99mTc had been added or not. In vivo trials showed that all patients showed a decrease in the cumulative amount of 99mTc detected in the GSV following polidocanol-99mTc mixture injection. However, the decrease of radioactivity was slightly reduced when compression or ligation of the SF junction was performed. CONCLUSIONS: Blocking the SF junction during UGFS using either manual compression or ligation does not prevent, but may reduce the flow of foam into the femoral vein. PMID- 20926322 TI - Cucurbitacin D induces fetal hemoglobin synthesis in K562 cells and human hematopoietic progenitors through activation of p38 pathway and stabilization of the gamma-globin mRNA. AB - The search for novel therapeutic candidates targeting fetal hemoglobin (HbF) activation to reduce the imbalance of globin genes is regarded as a promising approach for the clinical management of sickle cell disease and beta-thalassemia. For the first time, we identified cucurbitacin D (CuD), an oxygenated tetracyclic triterpenoid, as a molecular entity inducing gamma-globin gene expression and HbF synthesis in K562 cells and human hematopoietic progenitors from a beta thalassemia patient. CuD demonstrated a higher potency in HbF induction when compared with hydroxyurea, which was revealed by the evidence that CuD results in a higher fetal cell percentage and greater HbF content in K562 cells, in addition, to being less cytotoxic. Moreover, CuD also promotes higher HbF expression in primary erythroid cells. In the study to elucidate the molecular mechanisms of CuD's action, our data indicated that CuD-stimulated HbF synthesis was mediated by p38 pathway activation. At the post-transcriptional level, CuD treatment led to a significant elongation of the gamma-globin mRNA half-life in K562 cells. Taken together, the results suggest that CuD may be a potential therapeutic agent for beta-hemoglobinopathies, including sickle cell anemia and beta-thalassemia. PMID- 20926323 TI - Reversible magnetic resonance imaging and spectroscopy abnormalities in the course of vigabatrin treatment for West syndrome. AB - Transient magnetic resonance imaging (MRI) hyperintensity of globus pallidi, thalami, dentate nuclei and cerebral peduncles has recently been described in a significant number of young children during treatment with vigabatrin for infantile spasms. We describe two children with infantile spasms treated with vigabatrin, investigated with consecutive MRI as well as magnetic resonance spectroscopy (MRS). Hyperintensity developed during high dose vigabatrin treatment and remitted totally after dose reduction in one case, and cessation in the other. Abnormalities on MRS, suggesting an increase in the glutamine glutamate complex in the basal ganglia, were found in both cases while on vigabatrin treatment. These changes remitted in the first case after reduction of vigabatrin dose and when seizure free and with a normalized EEG, but persisted in the second case following cessation of vigabatrin without remission of seizure activity. PMID- 20926324 TI - An open-label Phase I/II clinical trial of pyrimethamine for the treatment of patients affected with chronic GM2 gangliosidosis (Tay-Sachs or Sandhoff variants). AB - Late-onset GM2 gangliosidosis is an autosomal recessive, neurodegenerative, lysosomal storage disease, caused by deficiency of beta-hexosaminidase A (Hex A), resulting from mutations in the HEXA (Tay-Sachs variant) or the HEXB (Sandhoff variant) genes. The enzyme deficiency in many patients with juvenile or adult onset forms of the disease results from the production of an unstable protein, which becomes targeted for premature degradation by the quality control system of the smooth endoplasmic reticulum and is not transported to lysosomes. In vitro studies have shown that many mutations in either the alpha or beta subunit of Hex A can be partially rescued, i.e. enhanced levels of both enzyme protein and activity in lysosomes, following the growth of patient cells in the presence of the drug, pyrimethamine. The objectives of the present clinical trial were to establish the tolerability and efficacy of the treatment of late-onset GM2 gangliosidosis patients with escalating doses of pyrimethamine, to a maximum of 100 mg per day, administered orally in a single daily dose, over a 16-week period . The primary objective, tolerability, was assessed by regular clinical examinations, along with a panel of hematologic and biochemical studies. Although clinical efficacy could not be assessed in this short trial, treatment efficacy was evaluated by repeated measurements of leukocyte Hex A activity, expressed relative to the activity of lysosomal beta-glucuronidase. A total of 11 patients were enrolled, 8 males and 3 females, aged 23 to 50 years. One subject failed the initial screen, another was omitted from analysis because of the large number of protocol violations, and a third was withdrawn very early as a result of adverse events which were not drug-related. For the remaining 8 subjects, up to a 4-fold enhancement of Hex A activity at doses of 50 mg per day or less was observed. Additionally marked individual variations in the pharmacokinetics of the drug among the patients were noted. However, the study also found that significant side effects were experienced by most patients at or above 75 mg pyrimethamine per day. We concluded that pyrimethamine treatment enhances leukocyte Hex A activity in patients with late-onset GM2 gangliosidosis at doses lower than those associated with unacceptable side effects. Further plans are underway to extend these trials and to develop methods to assess clinical efficacy. PMID- 20926325 TI - Body composition analysis in late-onset Pompe disease. AB - Pompe disease is an inherited metabolic disorder caused by alpha-glycosidase deficiency. The adult onset form is mainly characterized by progressive proximal muscle weakness and respiratory dysfunction. The aim of the present study is to evaluate body composition in adult patients before and after enzyme replacement therapy (ERT). Body composition was examined at baseline by means of dual x-ray absorptiometry (DXA) in nine adult patients and after different time periods in six of them who received ERT. Total BMD (bone mineral density) was initially mildly decreased in two patients, while femoral neck BMD was decreased in five patients. On the other hand fat mass was increased in the majority of patients, while body mass index (BMI) was high in four. ERT administration did not seem to induce obvious BMD changes in any patient. Conclusively, the greater femoral neck BMD involvement may be attributed to the lower mechanical load applied by the selectively weakened muscles, whereas the increased fat mass may be the result of metabolic and nutritional derangement. PMID- 20926327 TI - [First French transfusions (1667-1668)]. AB - The pioneers of blood transfusion first appeared in the 17th century, mainly in France and England, through animal experimentation, followed by some attempts in the healthy or sick. In France, the names of Dom Robert and Jean-Baptiste Denis belong to the beginning of the adventure of transfusion. Transfusions were then made with a total lack of knowledge of immunological danger. Following the death of a transfused patient, a death most likely related to acute intravascular hemolysis, the practice of transfusion was prohibited, on both sides of the Channel, by decision of Parliament. PMID- 20926326 TI - Seroepidemiological study of Pneumocystis jirovecii infection in healthy infants in Chile using recombinant fragments of the P. jirovecii major surface glycoprotein. AB - OBJECTIVES: To characterize the seroepidemiological features of Pneumocystis jirovecii infection in healthy Chilean children using overlapping fragments (A, B, C) of the P. jirovecii major surface glycoprotein (Msg). METHODS: Serum antibodies to MsgA, MsgB, and MsgC were measured every 2 months by enzyme-linked immunosorbent assay (ELISA) in 45 Chilean infants from about age 2 months to 2 years. RESULTS: Peak antibody levels (usually reached at age 6 months) and the force (or rate) of infection were somewhat greater for MsgC than for MsgA. Significant seasonal variation in antibody levels was only found with MsgA. Respiratory infections occurred in most children, but nasopharyngeal aspirates were of limited value in detecting the organism. In contrast, serological responses commonly occurred, and higher levels only to MsgC were significantly related to the number of infections. CONCLUSIONS: Serological responses to recombinant Msg fragments provide new insights into the epidemiological and clinical features of P. jirovecii infection of early childhood. MsgA, the amino terminus fragment, is more sensitive in detecting seasonal influences on antibody levels, whereas MsgC is better able to detect changes in antibody levels in response to clinical infection. PMID- 20926328 TI - An open-loop controlled active lung simulator for preterm infants. AB - We describe the underlying theory, design and experimental evaluation of an electromechanical analogue infant lung to simulate spontaneous breathing patterns of preterm infants. The aim of this work is to test the possibility to obtain breathing patterns of preterm infants by taking into consideration the air compressibility. Respiratory volume function represents the actuation pattern, and pulmonary pressure and flow-rate waveforms are mathematically obtained through the application of the perfect gas and adiabatic laws. The mathematical model reduces the simulation interval into a step shorter than 1 ms, allowing to consider an entire respiratory act as composed of a large number of almost instantaneous adiabatic transformations. The device consists of a spherical chamber where the air is compressed by four cylinder-pistons, moved by stepper motors, and flows through a fluid-dynamic resistance, which also works as flow rate sensor. Specifically designed software generates the actuators motion, based on the desired ventilation parameters, without controlling the gas pneumatic parameters with a closed-loop. The system is able to simulate tidal volumes from 3 to 8 ml, breathing frequencies from 60 to 120 bpm and functional residual capacities from 25 to 80 ml. The simulated waveforms appear very close to the measured ones. Percentage differences on the tidal volume waveform vary from 7% for the tidal volume of 3 ml, down to 2.2-3.5% for tidal volumes in the range of 4-7 ml, and 1.3% for the tidal volume equal to 8 ml in the whole breathing frequency and functional residual capacity ranges. The open-loop electromechanical simulator shows that gas compressibility can be theoretically assessed in the typical pneumatic variable range of preterm infant respiratory mechanics. PMID- 20926329 TI - Patient tolerance of neuromuscular electrical stimulation (NMES) in the presence of orthopaedic implants. AB - Neuromuscular electrical stimulation (NMES) may help reduce the incidence of deep vein thrombosis (DVT) in the postoperative total hip and knee arthroplasty patient. However, discomfort associated with stimulus may reduce patient acceptance of NMES as therapy. The aim of this study was to determine if patient comfort and tolerance of NMES was affected by applying stimulation in proximity to an orthopaedic implant. There was a concern that this may cause a concentration of current around the metal which could result in hypersensitivity of NMES and reduce its effectiveness. Twenty patients took part in this study, 10 total hip and 10 total knee arthroplasty patients. Each patient was at least 3 weeks post surgery. NMES was applied to the calf muscles of each leg using skin surface electrodes. Four excitatory levels were recorded, which were: sensory threshold, motor threshold, pain threshold and pain tolerance. Following this, patients underwent a 5 min stimulation session and indicated their overall comfort level on a visual analogue scale. Measurements of peak venous velocity, mean velocity and volume flow were recorded by duplex scanning from the popliteal vein at rest and in response to NMES elicited contractions during this session. Finally, patients completed a short verbal interview detailing their experience with the NMES treatment. The blood flow results showed increases in peak venous velocities, mean velocities and volume flow produced by NMES of 200%, 60% and 60% respectively when compared to resting blood flow. Comfort assessment indicated that the presence of a metallic implant did not give rise to hypersensitivity due to NMES. Patients found the application of calf muscle NMES comfortable and acceptable as a treatment. We conclude that the use of NMES on postoperative orthopaedic patients can be safely administered as a DVT prevention method. PMID- 20926330 TI - Networks, resources and agencies: on the character and production of enabling places. AB - The study of therapeutic landscapes, restorative places and enabling environments - what might collectively be referred to as enabling places - has revealed much of the relationship between place and health promotion. However, it is arguable that this work has only partially accounted for the diverse therapeutic features of enabling places and the various means of their production. Drawing on Bruno Latour, this paper introduces a conceptual logic of enabling places grounded in the analysis of enabling resources. Three categories of enabling resources will be considered: social, affective and material resources. It will be argued that enabling places are composed in diverse actor-networks, facilitating access to enabling resources and supporting the development of novel agencies or capacities. This draws attention to the various networks and associations that promote health and wellbeing, as well as the resources and agencies necessary to maintain these states. The paper concludes that the analysis of enabling resources, and the networks and agencies that comprise them, provides a novel basis for describing the character and production of enabling places, as well as the diverse benefits associated with them. PMID- 20926332 TI - Virus-derived small interfering RNAs at the core of plant-virus interactions. AB - Once a virus enters a cell, viral double-stranded RNA (dsRNA) is targeted by the RNA silencing machinery to initiate a cascade of regulatory events directed by viral small interfering RNAs (vsiRNAs). Recent genetic and functional studies along with the high-throughput sequencing of vsiRNAs have shed light on the genetic and structural requirements for virus targeting, the origins and compositions of vsiRNAs and their potential for controlling gene expression. The precise nature of the triggering molecules of virus-induced RNA silencing or the targeting constraints for viral genome recognition and processing represent outstanding questions that will be discussed in this review. The contribution of vsiRNAs to antiviral defense and host genome modifications has profound implications for our understanding of viral pathogenicity and host specificity in plants. PMID- 20926333 TI - Spherical aberration in relation to visual performance in contact lens wear. AB - INTRODUCTION: The aim of the present study was to evaluate changes in spherical aberration and their effect on visual quality (visual acuity and contrast sensitivity) in both distance and near with different non-custom-made contact lenses. METHODS: A wavefront analyser was used to measure the aberrations in each subject's eyes uncorrected and with the contact lenses: a standard lens and two aspherical contact lenses. High-contrast visual acuity at distance was measured with Test-Chart 2000 (100% contrast) and at near with Sloan ETDRS Near Point chart (100% contrast). Low-contrast visual acuity at distance was measured with Test-Chart 2000 (10% contrast) and contrast measurements at near with Mars letter contrast sensitivity chart. RESULTS: Mean spherical aberration was positive for all pupil sizes in the uncorrected eye, residual spherical aberration was close to zero with the standard lens for all pupil sizes, whereas the two aspheric contact lenses over-corrected spherical aberration. The changes in aberration were statistically significant (p < 0.05) with all lenses. No significant difference could be detected between trial frame correction, spherical and aspherical soft contact lens designs with respect to visual quality. This was the case for both distance and near. CONCLUSION: The results are in line with previous studies and indicate that non-custom-made spherical aberration control contact lenses have little effect on visual quality as defined in this study. PMID- 20926334 TI - Multi-tasking of somatic embryogenesis receptor-like protein kinases. AB - Receptor-like protein kinases (RLKs) are transmembrane proteins crucial for cell to-cell and cell-to-environment communications. The extracellular domain of a RLK is responsible for perception of a specific extracellular ligand to trigger a unique intercellular signaling cascade, often via phosphorylation of cellular proteins. The signal is then transduced to the nucleus of a cell where it alters gene expression. There are more than 610 RLKs in Arabidopsis thaliana, only a handful of them have been functionally characterized. This review focuses on recent advances in our understanding of a small group of RLKs named somatic embryogenesis receptor-like protein kinases (SERKs). SERKs act as coreceptors in multiple signaling pathways via their physical interactions with distinct ligand binding RLKs. PMID- 20926335 TI - Sending mixed messages: auxin-cytokinin crosstalk in roots. AB - Despite their relatively simple appearance, roots are incredibly complex organs that are highly adapted to differing environments. Many aspects of root development are co-ordinated by subtle spatial differences in the concentrations of the phytohormones auxin and cytokinin. Events from the formation of a root during embryogenesis to the determination of the network of lateral roots are controlled by interactions between these hormones. Recently, interactions have been defined where auxin signaling promotes the expression of cytokinin signaling inhibitors, cytokinin signaling promotes the expression of auxin signaling inhibitors and finally where cytokinin signaling regulates the complex network of auxin transport proteins to position zones of high auxin signaling. We are witnessing a period of discovery in which we are beginning to understand how these hormonal pathways communicate to regulate root formation. PMID- 20926331 TI - mda-7/IL-24: a unique member of the IL-10 gene family promoting cancer-targeted toxicity. AB - Melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24) is a unique member of the IL-10 gene family that displays nearly ubiquitous cancer specific toxicity, with no harmful effects toward normal cells or tissues. mda 7/IL-24 was cloned from human melanoma cells by differentiation induction subtraction hybridization (DISH) and promotes endoplasmic reticulum (ER) stress culminating in apoptosis or toxic autophagy in a broad-spectrum of human cancers, when assayed in cell culture, in vivo in human tumor xenograft mouse models and in a Phase I clinical trial in patients with advanced cancers. This therapeutically active cytokine also induces indirect antitumor activity through inhibition of angiogenesis, stimulation of an antitumor immune response, and sensitization of cancer cells to radiation-, chemotherapy- and antibody-induced killing. PMID- 20926336 TI - Brillouin study of photopolymerization process of two-monomer systems. AB - The results of Brillouin scattering investigations of two-component system: 2,2 bis[4-(2-hydroxy-3-methacryloxypropoxy)phenyl]propane/polyethylene glycol methacrylate (bis-GMA/PEGMM) containing 0, 30, 50, 70, 85 and 100 mol% of PEGMM are presented. For the first time the Brillouin spectroscopy was used to monitor the progress of the polymerization process. The polymerization was initiated by ultraviolet radiation (lambda=365 nm), at temperature 20 degrees C and 40 degrees C. Some of the physical parameters characteristic for this system such as velocity V, adiabatic compressibility beta(ad) and attenuation coefficient alpha of the acoustic waves have been estimated from Brillouin spectra as a functions of the polymerization time. The obtained results have been discussed in terms of changes of the elastic properties of the two-component system occurring during polymerization process and their dependence on bis-GMA/PEGMM system composition. PMID- 20926337 TI - Analytical sensitivity of four HIV combined antigen/antibody assays using the p24 WHO standard. AB - BACKGROUND: The Common Technical Specifications for HIV-1 p24 assays published in 2009 fixed the lower limit of detection for obtaining C.E. approval at 2 IU/ml against the WHO standard (first international reference, code NIBSC 90/636); it was previously 50 pg/ml. Some recent fourth generation HIV assays that simultaneously detect antigen and antibody are equivalent to p24 assays, but they were mainly evaluated using p24 antigen standards in pg/ml and little is known of their performance with the IU/ml standard. OBJECTIVES: To evaluate four of the combined serological assays most commonly used for HIV diagnosis in France against the WHO standard in IU/ml. STUDY DESIGN: The analytical sensitivity of four combined p24 antigen and antibody assays (ARCHITECT HIV Ag/Ab Combo, AxSYM HIV Ag/Ab Combo, VIDAS HIV DUO Quick and VIDAS HIV DUO Ultra) and of one p24 assay (VIDAS HIV p24 II) were determined using dilutions of the WHO standard. RESULTS: Four of the five assays had a lower limit of detection below 2 IU/ml: 1.24 for ARCHITECT Combo, 0.66 for VIDAS DUO Ultra, 0.43 for VIDAS DUO Quick and 0.73 to 1.15 for VIDAS p24, while that of AxSYM was close to 2 (1.94-2.25). CONCLUSIONS: We have provided the first data on the lower limit of detection of HIV combined assays using the IU/ml WHO standard and demonstrated the need for a single international standard for comparing assays. We recommend the use of this approach in medical laboratory to validate on site their methods. PMID- 20926338 TI - FLO11 is essential for pellicle formation by wild pellicle-forming yeasts isolated from contaminated wines. AB - The Deltaflo11/Deltaflo11 disruptant strains constructed from three wild yeast strains, which were independently isolated from pellicles formed on the surface of contaminated stored wines, completely lost their ability to form pellicles. The FLO11 expression level of the pellicle-forming strains was much higher than that of non-pellicle-forming wine strains. Cell surface hydrophobicity of the Deltaflo11/Deltaflo11 disruptant strains was as high as that of the parental pellicle-forming strains. These findings indicate that FLO11 is essential for unfavorable pellicle formation of wild pellicle-forming yeasts by mechanisms other than increasing cell surface hydrophobicity. PMID- 20926339 TI - Brewer's yeast cell wall affects microbiota composition and decreases Bacteroides fragilis populations in an anaerobic gut intestinal model. AB - Brewer's yeast cell wall (BYC) has been reported to have prebiotic activity that improves the microbiotal composition of the human gut. To understand the precise effect of BYC on gut microbiota and its metabolism, we used a three-stage continuous-flow reactor system that mimicked the environment of the large intestine. The reactor system was able to maintain the bacterial community stably for a week. The Bacteroides fragilis population decreased drastically after the addition of BYC into this system while the number of Lactobacillus was stably maintained. In addition, propionate and acetate levels increased drastically. This metabolic change correlated with an increase in a number of specific operational taxonomic units annotated to the genus Veillonella and Megasphaella. These results suggest that BYC affects the composition of microbiota in an in vitro model system. PMID- 20926340 TI - Stroke phases responses around maximal lactate steady state in front crawl. AB - The objective of this study was to analyze changes in stroke rate (SR), stroke length (SL) and stroke phases (entry and catch, pull, push and recovery) when swimming at (MLSS) and above (102.5% MLSS) the maximal lactate steady state. Twelve endurance swimmers (21+/-8 year, 1.77+/-0.10 m and 71.6+/-7.7 kg) performed in different days the following tests: (1) 200- and 400-m all-out tests, to determine critical speed (CS), and; (2) 2-4 30-min sub-maximal constant speed tests, to determine the MLSS and 102.5% MLSS. There was significant difference among MLSS (1.22+/-0.05 ms(-1)), 102.5% MLSS (1.25+/-0.04 ms(-1)) and CS (1.30+/-0.08 ms(-1)). SR and SL were maintained between the 10th and 30th minute of the test swum at MLSS and have modified significantly at 102.5% MLSS (SR - 30.9+/-3.4 and 32.2+/-3.5 cycles min(-1) and SL - 2.47+/-0.2 and 2.38+/-0.2 m cycle(-1), respectively). All stroke phases were maintained at 10th and 30th minute at MLSS. However, the relative duration of propulsive phase B (pull) increased significantly at 102.5% MLSS (21.7+/-3.4% and 22.9+/-3.9%, respectively). Therefore, the metabolic condition may influence the stroke parameters (SR and SL) and stroke strategy to maintain the speed during swim tests lasting 30 min. PMID- 20926341 TI - Percutaneous coronary intervention in very elderly patients. In-hospital mortality and clinical outcome. AB - BACKGROUND: There are very few data about percutaneous coronary intervention (PCI) in very elderly patients. This study was aimed at assessing the demographic, clinical and angiographic features, procedural characteristics and in-hospital results of very elderly patients (VEP), aged >=85 years undergoing PCI and comparing their results with those of a control group (CG) of patients younger than 85 years undergoing PCI throughout the same period of time. METHODS AND RESULTS: Between November 2004 and January 2007, 1699 consecutive PCI procedures were evaluated, 102 (6%) PCI procedures were performed in VEP and 1597 (94%) in patients <85 years. The mean age in the VEP group was 87.4 +/- 2.4 years vs. 66.7 +/- 11.2 years in the CG (p<0.0001). There were more females in the VEP group 49% vs. 22% than in the CG p<0.0001. Acute coronary syndromes (ACS) were a more frequent indication for PCI in VEP than in the CG: ST segment elevation myocardial infarction (STEMI) 14.7% vs. 8.3%, p = 0.025 and non-ST segment elevation acute coronary syndromes 54.9% vs. 43.5%, p = 0.024. The proportion of drug-eluting stents used, although high in both groups, was lower in VEP than in the CG (86.5% vs. 92.9%, p = 0.005). Angiographic lesion success rates were similar in both groups (95.9%). Global unadjusted in-hospital mortality was higher in the VEP group in comparison with the CG 3.9% vs. 0.68%, p = 0.01. The difference in mortality was due only to PCI in patients presenting with STEMI (26.6% in VEP group vs. 3.7% in the CG p = 0.007). There were no in-hospital deaths in VEP presenting with stable coronary syndromes or other ACS. There were no differences in unadjusted in-hospital myocardial infarction, new revascularisation or stroke between both groups. CONCLUSIONS: In patients >=85 years old, PCI seems effective and carries an acceptable in-hospital mortality rate. The presence of STEMI substantially increases the risk of in-hospital death. PMID- 20926343 TI - The use of simulation to address the acute care skills deficit in pre registration nursing students: a clinical skill perspective. AB - The increase in patient acuity in primary and secondary settings is continuing, with a corresponding increase in the need for technological competence in these areas. Evidence, however, both nationally and internationally, suggests that these expectations are not being met. This paper offers a review of the literature on acute care, with a specific focus on pre-registration nursing students and the development of acute care skills. Three themes are discussed: factors contributing to the acute care skills deficit, the knowledge and skills required to work in acute care and strategies used to support the acquisition of acute care skills. In response to the review, and based upon the evidence-based solutions identified, the clinical skills team at Bournemouth University designed and developed two teaching sessions, using simulation and role play to support the acquisition of acute care skills in pre-registration students. Student evaluations identify that their knowledge, competence and confidence in this area have increased following the teaching sessions, although caution remains regarding transferability of these skills into the practice environment. PMID- 20926344 TI - Extra corporeal photo chemotherapy (ECP) in acute and chronic GVHD. PMID- 20926342 TI - The molecular mechanisms underlying the pharmacological actions of ER modulators: implications for new drug discovery in breast cancer. AB - Our understanding of the molecular mechanisms underlying the pharmacological actions of estrogen receptor (ER) ligands has evolved considerably in recent years. Much of this knowledge has come from a detailed dissection of the mechanism(s) of action of the Selective Estrogen Receptor Modulators (SERMs) tamoxifen and raloxifene, so called for their ability to function as ER agonists or antagonists depending on the tissue in which they operate. These mechanistic insights have had a significant impact on the discovery of second generation SERMs, some of which are in late stage clinical development for the treatment/prevention of breast cancer as well as other estrogenopathies. In addition to the SERMs, however, have emerged the Selective Estrogen Degraders (SERDs), which as their name suggests, interact with and facilitate ER turnover in cells. One drug of this class, fulvestrant, has been approved as a third line treatment for ER-positive metastatic breast cancer. Whereas the first generation SERMs/SERDs were discovered in a serendipitous manner, this review will highlight how our understanding of the molecular pharmacology of ER ligands has been utilized in the development of the next generation of SERMs/SERDs, some of which are likely to have a major impact on the pharmacotherapy of breast cancer. PMID- 20926345 TI - Emergent therapy with therapeutic plasma exchange in acute recurrent pancreatitis due to severe hypertriglyceridemia. AB - Hypertriglyceridemia causes acute pancreatitis in 1.3-3.8% of patients. We report here on two cases with severe (triglyceride level >1000 mg/dL) hypertriglyceridemia-induced acute recurrent pancreatitis. Both patients had uncontrolled hypertriglyceridemia and suffered from acute pancreatitis. No cause of secondary hypertriglyceridemia was detected. While stage E pancreatitis (Ranson's score: 2) was diagnosed in the first case, stage D pancreatitis with a null Ranson's score was detected in the second case. Both patients were treated with classical treatment with fluid replacement, analgesic, antibiotics and discontinuation of oral intake. Therapeutic plasma exchange (TPE) with fresh frozen plasma was performed consecutively and with two procedures on the 2nd and 3rd day in the first case. After TPE, while the triglyceride levels decreased from 4408 to 302 mg/dL, the amylase levels dropped from 4234 to 171 IU/L. In the second case, TPE was performed once daily. After TPE, the levels of triglyceride and amylase decreased from 2210 mg/dL and 1618 IU/L to 154 mg/dL and 110 IU/L, respectively. Local and systemic complications due to acute pancreatitis were not observed. Clinical signs and laboratory values improved. At the two-year follow up of both patients, acute pancreatitis had not recurred with regular fenofibrate treatment. Hypertriglyceridemia should be considered in patients with acute recurrent pancreatitis. Although there is no definitive evidence for early application of TPE in severe hypertriglyceridemia-induced acute pancreatitis yet, therapy with TPE may be of benefit, improving the clinical course. PMID- 20926346 TI - Treatment of diabetic ulcers, using autologous platelet and fibrinic gel. Experience the FIBRINET(r) device. AB - There is evidence that platelets may be used locally as a source of growth factors that play a fundamental role in wound healing. From October 2008 to September 2009, at Tor Vergata Rome University Hospital, seven patients were enrolled in the study. All of these patients had ulcers with a extension over 3.5 cm(2). Four patients achieved a total recovery of the ulcers, while three experienced a reduction of the diameter of the ulcers. Our data are preliminary, but it is possible to suggest that recovery of the ulcers using the FIBRINET(r) system is related to platelet activation in the specific ulcer area. PMID- 20926347 TI - HIV status in discordant couples in sub-Saharan Africa: a systematic review and meta-analysis. AB - BACKGROUND: Most couples affected by HIV/AIDS in sub-Saharan Africa live in discordant relationships. Men are thought to be the index case in most relationships, and most social marketing and awareness campaigns are focused on men. We investigated serodiscordance in stable relationships to establish the gender balance of index-case infections. METHODS: We did a systematic review, random-effects meta-analysis, and meta-regression of published and unpublished studies enrolling discordant couples and assessed the proportion of men and women that were index cases. We repeated the analysis with data from demographic and health surveys (DHS) from the 14 countries that have documented the HIV status of couples. Our primary outcome was the total number of HIV discordant couples, including the proportion of HIV-positive women. FINDINGS: We included data from 27 cohorts of 13,061 couples and DHS data from 14 countries of 1145 couples. The proportion of HIV-positive women in stable heterosexual serodiscordant relationships was 47% (95% CI 43-52), which shows that women are as likely as men to be the index partner in a discordant couple. DHS data (46%, 41-51) and our sensitivity analysis (47%, 43-52) showed similar findings. Meta-regression showed that urban versus rural residence (odds ratio 0.31, 95% CI 0.22-0.39), latitude (beta coefficient 0.02, 0.023-0.034), gender equality (beta coefficient -0.42, 0.56 to -0.27), HIV prevalence (beta coefficient -0.037, -0.04 to -0.030), and older age (beta coefficient 0.20, 0.08-0.32) were associated with the proportion of female index cases. INTERPRETATION: Our study shows the need to focus on both sexes in HIV prevention strategies, such as promotion of condom use and mitigation of risk behaviours. FUNDING: None. PMID- 20926348 TI - Polydimethylsiloxane (macroplastique(r)) injection for vesicoureteral reflux in duplex ureters: a comparison with single renal systems. AB - OBJECTIVE: VUR in patients with a duplex system (DS) is often treated by open surgery. The aim of this study was to evaluate the efficacy of subureteric polydimethylsiloxane (Macroplastique((r))) injection (SMING) in the management of VUR in duplex and single (SS) renal systems. PATIENTS AND METHODS: Fifteen children (24 refluxing renal units) with VUR in DS underwent SMING. VUR was more frequent in the lower moiety. VUR was graded moderate/severe in 88% of renal units. There was a history of urinary tract infections in 40% of cases. The outcome for DS patients was compared with 44 children (60 refluxing renal units) with moderate/severe VUR in SS. RESULTS: The VUR resolution/improvement rate was 88% in DS and 95% in SS patients. Ureteric reimplantation was required because of recurrent VUR in 13% and 7% of DS and SS groups, respectively. Transient ureteral obstruction was observed in 1/15 and 5/44 patients. Two required double-J ureteric stenting for 3 months. CONCLUSION: SMING seems an effective treatment for VUR in both DS and SS patients, even in severe cases. The complication rate does not significantly differ between the two groups. PMID- 20926349 TI - Idiopathic high-flow priapism in a pediatric patient. AB - High-flow priapism is a very rare condition in children. The most common cause is perineal trauma, which is a major cause of arterio-cavernosal fistula. A few pediatric patients have high-flow priapism without an obvious cause. There are many therapeutic modalities for this condition, depending on the etiology. We report a case of idiopathic high-flow priapism in a 6-year-old boy who underwent repeated superselective embolization. PMID- 20926350 TI - Localizing and lateralizing features of auras and seizures. AB - The symptomatology of auras and seizures is a reflection of activation of specific parts of the brain by the ictal discharge, the location and extent of which represent the symptomatogenic zone. The symptomatogenic zone is presumably, though not necessarily, in close proximity to the epileptogenic zone, the area responsible for seizure generation, the complete removal or disconnection of which is necessary for seizure freedom. Knowledge about the symptomatogenic zone in focal epilepsy is acquired through careful video/EEG monitoring and behavioral correlation of seizures and electrical stimulation studies. Ictal symptomatogy provides important lateralizing and/or localizing information in the presurgical assessment of epilepsy surgery candidates. As the initial symptoms of epileptic seizures, many types of auras have highly significant localizing or lateralizing value. Similarly, motor signs during focal and secondary generalized seizures, language manifestations, and autonomic features offer reliable clues to the delineation of the epileptogenic zone. Some focal epilepsies (e.g., neocortical temporal lobe epilepsy, insular lobe epilepsy, temporal-plus epilepsies, and parieto-occipital lobe epilepsy) generate seizure manifestations that mimic temporal lobe epilepsy, potentially contributing to surgical failure. To optimize surgical outcome, careful interpretation of ictal symptomatology in conjunction with other components of the presurgical evaluation is required. PMID- 20926351 TI - Cardiorespiratory and electroencephalographic responses to exhaustive acute physical exercise in people with temporal lobe epilepsy. AB - We evaluated physiological and electroencephalographic responses during a cardiopulmonary exercise test (CPET) in people with epilepsy. Behavioral outcomes of people with epilepsy were also compared with those of healthy controls. Thirty eight subjects (19 people with epilepsy and 19 controls) participated in this study. Poor outcomes in the behavioral analyses (habitual level of physical activity and quality of life) were observed in the people with epilepsy. With respect to the CPET, V.O(2max) (14.6%) and V.O(2) at anaerobic threshold (16.1%) were significantly lower in the epilepsy group than in the control group. Although not statistically significant, a decrease in the number of epileptiform discharges was observed between the rest state and exercise (82%) and between the rest state and recovery period (74%). In conclusion, the lower aerobic fitness in people with epilepsy observed may be associated with their sedentary habits. Moreover, our findings reinforce the hypothesis that exhaustive exercise is not a seizure-inducing factor. PMID- 20926352 TI - Long-term neuropsychological follow-up of a child with Kluver-Bucy syndrome. AB - We describe the case of a 10-year-old girl who developed behavioral changes consistent with Kluver-Bucy Syndrome following Listeria meningoencephalitis at 21/2 years of age. MRI at age 4 revealed evidence of diffuse brain atrophy with predominant temporal lobe involvement. Electroencephalograpy at 91/2 years of age showed abnormal electrical discharges from the left temporal area. Follow-up MRI with volumetric analysis of the mesial temporal structures at 9 years of age demonstrated decreased hippocampal volume bilaterally. Consistent with the morphological abnormalities, serial neuropsychological evaluations demonstrated expressive and receptive language impairment and an amnestic syndrome that significantly decreased her ability to make new declarative memories and maintain adequate academic progress. PMID- 20926353 TI - A structured questionnaire predicts if convulsions are epileptic or nonepileptic. AB - OBJECTIVE: Therapy for convulsive seizures is usually initiated on the basis of clinical assessment, without video/EEG confirmation, but a nonepileptic origin may eventually be demonstrated. This study evaluates the diagnostic value of a witness-questionnaire in distinguishing between convulsive epileptic seizures (CES) and convulsive nonepileptic seizures (CNES). METHODS: We prospectively identified all adult patients admitted for video/EEG evaluation of convulsive attacks and interviewed the "best" witness using 12 questions on ictal and postictal features. RESULTS: Video/EEG diagnosed CES in 19 and CNES in 26 patients. The predictive accuracy of the questionnaire was 84.4%. Six features were strong predictors of CNES diagnosis: ictal eye closure, presence of side-to side movements, prolonged seizure duration, and three postictal breathing features (not loud, shallow, no snoring). CONCLUSION: A structured witness questionnaire distinguishes CES and CNES and will help in selecting patients for early video/EEG evaluation and rapid initiation of appropriate therapy. PMID- 20926354 TI - Parents report more ADHD symptoms than do teachers in children with epilepsy. AB - Children with epilepsy have a high rate of attention deficit/hyperactivity disorder (ADHD), yet parent-teacher agreement on ADHD symptoms in epilepsy is unknown despite the need to assess symptoms across settings such as home and school. Parent-teacher agreement on ADHD ratings was investigated in 208 children with epilepsy (mean age = 11.2, SD = 3.6) using the ADHD Rating Scale IV, along with associations with demographic variables, epilepsy severity, adaptive level, and quality of life. Children were four times more likely to be identified as having clinically elevated ADHD symptoms when parent ratings were the benchmark versus teachers. Agreement was highest for children with more severe ADHD symptoms, for the Hyperactivity-Impulsivity dimension of behavior, and for children with broadly normal adaptive behavior. Higher parent and teacher ADHD ratings were related to reduced quality of life, but unrelated to epilepsy severity. Exclusive reliance on parent or teacher ratings may yield variable rates of ADHD symptoms in children with epilepsy. PMID- 20926355 TI - Psychometric Properties of the Spanish Version of the Tampa Scale for Kinesiophobia (TSK). AB - The Tampa Scale for Kinesiophobia (TSK) is one of the most frequently employed measures for assessing pain-related fear in pain patients. Although the TSK has been translated into different languages, a Spanish version of the TSK has not been available, up to now. Thus, the aim of this study was to validate the Spanish version of the TSK in 2 different pain samples: A heterogeneous chronic pain sample (n = 125) and a musculoskeletal acute pain sample (n = 86). Factor analysis revealed a 2-factor model of 11 items replicated on both samples, named TSK-11. The instrument obtained shows good reliability (internal consistency and stability) and validity (convergent and predictive), with the advantage of brevity. Evidence is provided on discriminant validity between both TSK factors (called Activity Avoidance and Harm). The Harm factor shows the best predictive validity, as it predicts pain persistence, catastrophizing, depression, and pain intensity scores after 6 months. Changes in the Activity Avoidance factor are positively correlated with changes in catastrophizing and anxiety, and negatively associated with changes in functional status. The results of this study point to the relative contribution of both components of pain-related fear to pain adjustment. PERSPECTIVE: This article presents the Spanish version of the TSK. Factor analysis revealed a 2-factor model (called Activity Avoidance and Harm). The version obtained shows good reliability and validity. Results provide clinicians with access to a measure of pain-related fear for Spanish-speaking pain patients, offering the advantage of brevity. PMID- 20926356 TI - Dissecting axes of autonomic control in humans: Insights from neuroimaging. AB - The combination of functional brain imaging with measurement of peripheral autonomic responses in humans can provide insight into the embodiment of mental processes and the integration of cognition and emotion with changes in somatic physiology. Initial studies in healthy people and patents validate inferences from more detailed animal experiments regarding the organization of central autonomic control. In particular these have illustrated the coupling of behaviour with sympathetic arousal. Over the last two decades, the growth of emotional neuroscience alongside advances in functional brain imaging has fuelled investigations of relationships between perception, feeling states, somatic and autonomic bodily reactions. These studies have driven a more mechanistic understanding of brain systems through which bodily state is regulated and modified to support adaptive behaviour. In parallel, they have enabled the application of human neuroimaging to autonomic neuroscience. Specific methodological challenges are posed by combining physiological recordings with neuroimaging techniques, particularly functional magnetic resonance brain imaging, which are nevertheless addressable. Using such methods, the neural correlates of dynamic autonomic control has been systematically examined in studies of healthy individuals and patients with specific autonomic dysfunction (including autonomic failure, autonomic (neurally) mediated syncope and the postural tachycardia syndrome). These studies reveal antagonistic interaction of systems underpinning autonomic cardiovascular control (involving mid and subgenual cingulate cortices) and partial organ-specificity of other axes of autonomic response. Current and anticipated technical advances, including the integration of autonomically-focused microneurography and neural stimulation with advanced neuroimaging, will continue to provide detailed insight into dynamics of autonomic control. Translating these insights into clinical benefits remains a priority. PMID- 20926357 TI - [Apical left ventriculotomy for closure of muscular ventricular septal defects. Is it a safe procedure?]. PMID- 20926358 TI - Preoperative assessment of soft tissue deficiency in the temporal region with reverse engineering. PMID- 20926360 TI - Erratum to the titles of two articles published in Orthopaedics and Traumatology: Surgery and Research. PMID- 20926359 TI - Brachydactyly, anonychia and a deformed nasal tip in a 16-year-old girl: a case report. AB - The current report describes a case of a 16-year-old girl with a rare combination of nasal dysmorphology, anonychia and brachydactyly of hands and feet. The combination of hand and nasal malformations suggested a type B brachydactyly. Genetic investigation, however, revealed Cooks syndrome with unexplained facial dysmorphology. Concerning her cosmetic complaints, options for surgical treatment were discussed. It was decided to treat only the nasal deformity by open rhinoplasty, leaving the nail deformities undisturbed. PMID- 20926361 TI - Neointimal tissue rupture as a mechanism of myocardial infarction very late following implantation of bare metal stents. Insights from optical coherence tomography. PMID- 20926362 TI - Primary hepatic (extranodal) lymphoma: utility of [(18)F]fluorodeoxyglucose PET/CT. AB - Primary hepatic lymphoma is extremely rare. Although the utility of fluorodeoxyglucose (FDG)-positron emission tomography (PET) for imaging extranodal lymphoma has been reported, there is very little literature describing its use in primary hepatic lymphoma. This case report demonstrates the effect of FDG-PET/computed tomography (CT) in a case of unifocal primary hepatic lymphoma and its usefulness in the assessment of treatment response. PMID- 20926364 TI - Cardiac lymphoma causing coronary compression, pericardial effusion, and atrioventricular block. PMID- 20926363 TI - Impairment of endothelial progenitor cell function and vascularization capacity by aldosterone in mice and humans. AB - AIMS: Hyperaldosteronism is associated with vascular injury and increased cardiovascular events. Bone marrow-derived endothelial progenitor cells (EPCs) play an important role in endothelial repair and vascular homeostasis. We hypothesized that hyperaldosteronism impairs EPC function and vascularization capacity in mice and humans. METHODS AND RESULTS: We characterized the effects of aldosterone and mineralocorticoid receptor (MR) blockade on EPC number and function as well as vascularization capacity and endothelial function. Treatment of human EPC with aldosterone induced translocation of the MR and impaired multiple cellular functions of EPC, such as differentiation, migration, and proliferation in vitro. Impaired EPC function was rescued by pharmacological blockade or genetic ablation of the MR. Aldosterone protein kinase A (PKA) dependently increased reactive oxygen species formation in EPC. Aldosterone infusion in mice impaired EPC function, EPC homing to vascular structures and vascularization capacity in a MR-dependent but blood pressure-independent manner. Endothelial progenitor cells from patients with primary hyperaldosteronism compared with controls of similar age displayed reduced migratory potential. Impaired EPC function was associated with endothelial dysfunction. MR blockade in patients with hyperaldosteronism improved EPC function and arterial stiffness. CONCLUSION: Endothelial progenitor cells express a MR that mediates functional impairment by PKA-dependent increase of reactive oxygen species. Normalization of EPC function may represent a novel mechanism contributing to the beneficial effects of MR blockade in cardiovascular disease prevention and treatment. PMID- 20926365 TI - Acute right heart overload due to pulmonary artery obstruction caused by ruptured aortic dissection. PMID- 20926366 TI - Pneumomediastinum after implantable cardiac defibrillator implantation. PMID- 20926367 TI - Age-related temporal and parietal cortical thinning in autism spectrum disorders. AB - Studies of head size and brain volume in autism spectrum disorders have suggested that early cortical overgrowth may be followed by prematurely arrested growth. However, the few investigations quantifying cortical thickness have yielded inconsistent results, probably due to variable ages and/or small sample sizes. We assessed differences in cortical thickness between high-functioning adolescent and young adult males with autism spectrum disorders (n = 41) and matched typically developing males (n = 40). We hypothesized thinner cortex, particularly in frontal, parietal and temporal regions, for individuals with autism spectrum disorders in comparison with typically developing controls. Furthermore, we expected to find an age * diagnosis interaction: with increasing age, more pronounced cortical thinning would be observed in autism spectrum disorders than typically developing participants. T(1)-weighted magnetization prepared rapid gradient echo 3 T magnetic resonance imaging scans were acquired from high functioning males with autism spectrum disorders and from typically developing males matched group-wise on age (range 12-24 years), intelligence quotient (>= 85) and handedness. Both gyral-level and vertex-based analyses revealed significantly thinner cortex in the autism spectrum disorders group that was located predominantly in left temporal and parietal regions (i.e. the superior temporal sulcus, inferior temporal, postcentral/superior parietal and supramarginal gyri). These findings remained largely unchanged after controlling for intelligence quotient and after accounting for psychotropic medication usage and comorbid psychopathology. Furthermore, a significant age * diagnosis interaction was found in the left fusiform/inferior temporal cortex: participants with autism spectrum disorders had thinner cortex in this region with increasing age to a greater degree than did typically developing participants. Follow-up within group comparisons revealed significant age-related thinning in the autism spectrum disorders group but not in the typically developing group. Both thinner temporal and parietal cortices during adolescence and young adulthood and discrepantly accelerated age-related cortical thinning in autism spectrum disorders suggest that a second period of abnormal cortical growth (i.e. greater thinning) may be characteristic of these disorders. PMID- 20926368 TI - Gait ataxia in essential tremor is differentially modulated by thalamic stimulation. AB - Patients with advanced stages of essential tremor frequently exhibit tandem gait ataxia with impaired balance control and imprecise foot placement, resembling patients with a cerebellar deficit. Thalamic deep brain stimulation, a surgical therapy for otherwise intractable cases, has been shown to improve tremor, but its impact on cerebellar-like gait difficulties remains to be elucidated. Eleven patients affected by essential tremor (five females; age 69.8 +/- 3.9 years; disease duration 24.4 +/- 11.2 years; follow-up after surgery 24.7 +/- 20.3 months) were evaluated during the following conditions: stimulation off, stimulation on and supra-therapeutic stimulation. Ten age-matched healthy controls served as the comparison group. Locomotion by patients and controls was assessed with (i) overground gait and tandem gait; (ii) balance-assisted treadmill tandem gait and (iii) unassisted treadmill gait. The two treadmill paradigms were kinematically analysed using a 3D opto-electronic motion analysis system. Established clinical and kinesiological measures of ataxia were computed. During stimulation off, the patients exhibited ataxia in all assessment paradigms, which improved during stimulation on and worsened again during supra therapeutic stimulation. During over ground tandem gait, patients had more missteps and slower gait velocities during stimulation off and supra-therapeutic stimulation than during stimulation on. During balance-assisted tandem gait, stimulation on reduced the temporospatial variability in foot trajectories to nearly normal values, while highly variable (ataxic) foot trajectories were observed during stimulation off and supra-therapeutic stimulation. During unassisted treadmill gait, stimulation on improved gait stability compared with stimulation off and supra-therapeutic stimulation, as demonstrated by increased gait velocity and ankle rotation. These improvements in ataxia were not a function of reduced tremor in the lower limbs or torso. In conclusion, we demonstrate the impact of thalamic stimulation on gait ataxia in patients with essential tremor with improvement by stimulation on and deterioration by supra therapeutic stimulation, despite continued control of tremor. Thus, cerebellar dysfunction in these patients can be differentially modulated with optimal versus supra-therapeutic stimulation. The cerebellar movement disorder of essential tremor is due to a typical cerebellar deficit, not to trembling extremities. We hypothesize that deep brain stimulation affects two major regulating circuits: the cortico-thalamo-cortical loop for tremor reduction and the cerebello-thalamo cortical pathway for ataxia reduction (stimulation on) and ataxia induction (supra-therapeutic stimulation). PMID- 20926369 TI - World Health Organization definition of myocardial infarction: 2008-09 revision. AB - BACKGROUND: WHO has played a leading role in the formulation and promulgation of standard criteria for the diagnosis of coronary heart disease and myocardial infarction since early 1970s. METHODS: The revised definition takes into consideration the following: well-resourced settings can use the ESC/ACC/AHA/WHF definition, which has new biomarkers as a compulsory feature; in resource constrained settings, a typical biomarker pattern cannot be made a compulsory feature as the necessary assays may not be available; the definition must also have provision for diagnosing non-fatal events with incomplete information on cardiac biomarkers and the ECG; to facilitate epidemiologic monitoring definition must recognize fatal events with incomplete or no information on cardiac biomarkers and/or ECG and/or autopsy and/or coronary angiography. RESULTS: Category A definition is the same as ESC/ACC/AHA/WHF definition of MI, and can be applied to settings with no resource constraints. Category B definition of MI is to be applied whenever there is incomplete information on cardiac bio-markers together with symptoms of ischaemia and the development of unequivocal pathological Q waves. Category C definition (probable MI) is to be applied when individuals with MI may not satisfy Category A or B definitions because of delayed access to medical services and/or unavailability of electrocardiography and/or laboratory assay of cardiac biomarkers. In these situations, the term probable MI should be used when there is either ECG changes suggestive of MI or incomplete information on cardiac biomarkers in a person with symptoms of ischaemia with no evidence of a non-coronary reason. CONCLUSIONS: This article presents the 2008-09 revision of the World Health Organization (WHO) definition of myocardial infarction (MI) developed at a WHO expert consultation. PMID- 20926370 TI - Is education causal? Yes. PMID- 20926371 TI - Distribution of hyperglycaemia and related cardiovascular disease risk factors in low-income countries: a cross-sectional population-based survey in rural Uganda. AB - BACKGROUND: Data on non-communicable disease (NCD) burden are often limited in developing countries in Africa but crucial for planning and implementation of prevention and control strategies. We assessed the prevalence of related cardiovascular disease risk factors (hyperglycaemia, high blood pressure and obesity) in a longstanding population cohort in rural Uganda. METHODS: Trained field staff conducted a cross-sectional population-based survey of cardiovascular disease risk indicators using a questionnaire and simple measurements of body mass index (BMI), waist and hip circumference, waist/hip ratio (WHR), blood pressure and random plasma glucose. All members of the population cohort aged >=13 years were eligible to participate in the survey. RESULTS: Of the 4801 males and 5372 females who were eligible, 2719 (56.6%) males and 3959 (73.7%) females participated in the survey. Male and female participants had a mean standard deviation (SD) age of 31.8 (18.4) years and 33.7 (17.6) years, respectively. The observed prevalences of probable diabetes (glucose >11.0 mmol/l) and probable hyperglycaemia (7.0-11.0 mmol/l) were 0.4 and 2.9%, respectively. Less than 1% of males and 4% of females were obese (BMI >=30 kg/m(2)), with 3.6% of males and 14.5% of females being overweight (BMI 25.0-29.9 kg/m(2)). However, in women, the prevalence of abdominal obesity was high (71.3% as measured by WHR and 31.2% as measured by waist circumference). The proportions of male and female current regular smokers were low (13.7 and 0.9%, respectively). The commonest cardiovascular disease risk factor was high blood pressure, with an observed prevalence of 22.5% in both sexes. CONCLUSIONS: Population-based data on the burden of related cardiovascular disease risk factors can aid in the planning and implementation of an effective response to the double burden of communicable diseases and NCDs in this rural population of a low-income country undergoing epidemiological transition. PMID- 20926372 TI - A tandem SH2 domain in transcription elongation factor Spt6 binds the phosphorylated RNA polymerase II C-terminal repeat domain (CTD). AB - Spt6 is an essential transcription elongation factor and histone chaperone that binds the C-terminal repeat domain (CTD) of RNA polymerase II. We show here that Spt6 contains a tandem SH2 domain with a novel structure and CTD-binding mode. The tandem SH2 domain binds to a serine 2-phosphorylated CTD peptide in vitro, whereas its N-terminal SH2 subdomain, which we previously characterized, does not. CTD binding requires a positively charged crevice in the C-terminal SH2 subdomain, which lacks the canonical phospho-binding pocket of SH2 domains and had previously escaped detection. The tandem SH2 domain is apparently required for transcription elongation in vivo as its deletion in cells is lethal in the presence of 6-azauracil. PMID- 20926373 TI - Noncanonical tandem SH2 enables interaction of elongation factor Spt6 with RNA polymerase II. AB - Src homology 2 (SH2) domains are mostly found in multicellular organisms where they recognize phosphotyrosine-containing signaling proteins. Spt6, a conserved transcription factor and putative histone chaperone, contains a C-terminal SH2 domain conserved from yeast to human. In mammals, this SH2 domain recognizes phosphoserines rather than phosphotyrosines and is essential for the recruitment of Spt6 by elongating RNA polymerase II (RNAPII), enabling Spt6 to participate in the coupling of transcription elongation, chromatin modulation, and mRNA export. We have determined the structure of the entire Spt6 C-terminal region from Antonospora locustae, revealing the presence of two highly conserved tandem SH2 domains rather than a single SH2 domain. Although the first SH2 domain has a canonical organization, the second SH2 domain is highly noncanonical and appears to be unique in the SH2 family. However, both SH2 domains have phosphate-binding determinants. Our biochemical and genetic data demonstrate that the complete tandem, but not the individual SH2 domains, are necessary and sufficient for the interaction of Spt6 with RNAPII and are important for Spt6 function in vivo. Furthermore, our data suggest that binding of RNAPII to the Spt6 tandem SH2 is more extensive than the mere recognition of a doubly phosphorylated C-terminal domain peptide by the tandem SH2. Taken together, our results show that Spt6 interaction with RNAPII via a novel arrangement of canonical and noncanonical SH2 domains is crucial for Spt6 function in vivo. PMID- 20926374 TI - Butyrate-rich colonic microenvironment is a relevant selection factor for metabolically adapted tumor cells. AB - The short chain fatty acid (SCFA) butyrate is a product of colonic fermentation of dietary fibers. It is the main source of energy for normal colonocytes, but cannot be metabolized by most tumor cells. Butyrate also functions as a histone deacetylase (HDAC) inhibitor to control cell proliferation and apoptosis. In consequence, butyrate and its derived drugs are used in cancer therapy. Here we show that aggressive tumor cells that retain the capacity of metabolizing butyrate are positively selected in their microenvironment. In the mouse xenograft model, butyrate-preselected human colon cancer cells gave rise to subcutaneous tumors that grew faster and were more angiogenic than those derived from untreated cells. Similarly, butyrate-preselected cells demonstrated a significant increase in rates of homing to the lung after intravenous injection. Our data showed that butyrate regulates the expression of VEGF and its receptor KDR at the transcriptional level potentially through FoxM1, resulting in the generation of a functional VEGF:KDR autocrine growth loop. Cells selected by chronic exposure to butyrate express higher levels of MMP2, MMP9, alpha2 and alpha3 integrins, and lower levels of E-cadherin, a marker for epithelial to mesenchymal transition. The orthotopic model of colon cancer showed that cells preselected by butyrate are able to colonize the animals locally and at distant organs, whereas control cells can only generate a local tumor in the cecum. Together our data shows that a butyrate-rich microenvironment may select for tumor cells that are able to metabolize butyrate, which are also phenotypically more aggressive. PMID- 20926375 TI - The sphingosine kinase 1 inhibitor 2-(p-hydroxyanilino)-4-(p chlorophenyl)thiazole induces proteasomal degradation of sphingosine kinase 1 in mammalian cells. AB - Sphingosine kinase 1 (SK1) is an enzyme that catalyzes the phosphorylation of sphingosine to produce the bioactive lipid sphingosine 1-phosphate (S1P). We demonstrate here that the SK1 inhibitor, SKi (2-(p-hydroxyanilino)-4-(p chlorophenyl)thiazole) induces the proteasomal degradation of SK1 in human pulmonary artery smooth muscle cells, androgen-sensitive LNCaP prostate cancer cells, MCF-7 and MCF-7 HER2 breast cancer cells and that this is likely mediated by ceramide as a consequence of catalytic inhibition of SK1 by SKi. Moreover, SK1 is polyubiquitinated under basal conditions, and SKi appears to increase the degradation of SK1 by activating the proteasome. In addition, the proteasomal degradation of SK1a and SK1b in androgen-sensitive LNCaP cells is associated with the induction of apoptosis. However, SK1b in LNCaP-AI cells (androgen independent) is less sensitive to SKi-induced proteasomal degradation and these cells are resistant to SKi-induced apoptosis, thereby implicating the ubiquitin proteasomal degradation of SK1 as an important mechanism controlling cell survival. PMID- 20926376 TI - Structure-based catalytic optimization of a type III Rubisco from a hyperthermophile. AB - The Calvin-Benson-Bassham cycle is responsible for carbon dioxide fixation in all plants, algae, and cyanobacteria. The enzyme that catalyzes the carbon dioxide fixing reaction is ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco). Rubisco from a hyperthermophilic archaeon Thermococcus kodakarensis (Tk-Rubisco) belongs to the type III group, and shows high activity at high temperatures. We have previously found that replacement of the entire alpha-helix 6 of Tk-Rubisco with the corresponding region of the spinach enzyme (SP6 mutant) results in an improvement of catalytic performance at mesophilic temperatures, both in vivo and in vitro, whereas the former and latter half-replacements of the alpha-helix 6 (SP4 and SP5 mutants) do not yield such improvement. We report here the crystal structures of the wild-type Tk-Rubisco and the mutants SP4 and SP6, and discuss the relationships between their structures and enzymatic activities. A comparison among these structures shows the movement and the increase of temperature factors of alpha-helix 6 induced by four essential factors. We thus supposed that an increase in the flexibility of the alpha-helix 6 and loop 6 regions was important to increase the catalytic activity of Tk-Rubisco at ambient temperatures. Based on this structural information, we constructed a new mutant, SP5-V330T, which was designed to have significantly greater flexibility in the above region, and it proved to exhibit the highest activity among all mutants examined to date. The thermostability of the SP5-V330T mutant was lower than that of wild-type Tk Rubisco, providing further support on the relationship between flexibility and activity at ambient temperatures. PMID- 20926377 TI - Ablation of skeletal muscle triadin impairs FKBP12/RyR1 channel interactions essential for maintaining resting cytoplasmic Ca2+. AB - Previously, we have shown that lack of expression of triadins in skeletal muscle cells results in significant increase of myoplasmic resting free Ca(2+) ([Ca(2+)](rest)), suggesting a role for triadins in modulating global intracellular Ca(2+) homeostasis. To understand this mechanism, we study here how triadin alters [Ca(2+)](rest), Ca(2+) release, and Ca(2+) entry pathways using a combination of Ca(2+) microelectrodes, channels reconstituted in bilayer lipid membranes (BLM), Ca(2+), and Mn(2+) imaging analyses of myotubes and RyR1 channels obtained from triadin-null mice. Unlike WT cells, triadin-null myotubes had chronically elevated [Ca(2+)](rest) that was sensitive to inhibition with ryanodine, suggesting that triadin-null cells have increased basal RyR1 activity. Consistently, BLM studies indicate that, unlike WT-RyR1, triadin-null channels more frequently display atypical gating behavior with multiple and stable subconductance states. Accordingly, pulldown analysis and fluorescent FKBP12 binding studies in triadin-null muscles revealed a significant impairment of the FKBP12/RyR1 interaction. Mn(2+) quench rates under resting conditions indicate that triadin-null cells also have higher Ca(2+) entry rates and lower sarcoplasmic reticulum Ca(2+) load than WT cells. Overexpression of FKBP12.6 reverted the null phenotype, reducing resting Ca(2+) entry, recovering sarcoplasmic reticulum Ca(2+) content levels, and restoring near normal [Ca(2+)](rest). Exogenous FKBP12.6 also reduced the RyR1 channel P(o) but did not rescue subconductance behavior. In contrast, FKBP12 neither reduced P(o) nor recovered multiple subconductance gating. These data suggest that elevated [Ca(2+)](rest) in triadin-null myotubes is primarily driven by dysregulated RyR1 channel activity that results in part from impaired FKBP12/RyR1 functional interactions and a secondary increased Ca(2+) entry at rest. PMID- 20926378 TI - STIM1-dependent and STIM1-independent function of transient receptor potential canonical (TRPC) channels tunes their store-operated mode. AB - Ca(2+) influx by store-operated Ca(2+) channels is a key component of the receptor-evoked Ca(2+) signal. In all cells examined, transient receptor potential canonical (TRPC) channels mediate a significant portion of the receptor stimulated Ca(2+) influx. Recent studies have revealed how STIM1 activates TRPC1 in response to store depletion; however, the role of STIM1 in TRPC channel activation by receptor stimulation is not fully understood. Here, we established mutants of TRPC channels that could not be activated by STIM1 but were activated by the "charge-swap" mutant STIM1(K684E,K685E). Significantly, WT but not mutant TRPC channels were inhibited by scavenging STIM1 with Orai1(R91W), indicating the STIM1 dependence and independence of WT and mutant TRPC channels, respectively. Importantly, mutant TRPC channels were robustly activated by receptor stimulation. Moreover, STIM1 and STIM1(K684E,K685E) reciprocally affected receptor-activated WT and mutant TRPC channels. Together, these findings indicate that TRPC channels can function as STIM1-dependent and STIM1-independent channels, which increases the versatility of TRPC channel function and their role in receptor-stimulated Ca(2+) influx. PMID- 20926379 TI - The suppression of CRMP2 expression by bone morphogenetic protein (BMP)-SMAD gradient signaling controls multiple stages of neuronal development. AB - The formation of the functional mammalian cerebral cortex requires a concerted control of neurogenesis, neuronal migration, and neuronal morphogenesis. However, molecular mechanisms that control these processes are not well understood. We have found that the BMP signaling downstream transcription factor SMAD1 and CRMP2 (collapsin response mediator protein-2) are inversely and complementarily expressed in the developing neocortex. BMPs can suppress CRMP2 expression in cortical cells. Our ChIP assay demonstrates that both SMAD1 and -4 bind to CRMP2 promoter in the neocortex, and overexpression of SMAD1 and 4 in vivo suppresses CRMP2 expression. RNA interference of CRMP2 and overexpression of dominant negative forms of CRMP2 in utero cause accumulation of multipolar cells in the ventricular, subventricular, and intermediate zones and suppresses neurite outgrowth, suggesting that CRMP2 is required for multipolar to bipolar transition for directional neuronal migration and neurite outgrowth. Thus, our study reveals a novel mechanism that the BMP-SMAD signaling pathway controls neuronal migration and neurite outgrowth by suppressing the transcription of CRMP2. PMID- 20926380 TI - NMR-derived topology of a GFP-photoprotein energy transfer complex. AB - Forster resonance energy transfer within a protein-protein complex has previously been invoked to explain emission spectral modulation observed in several bioluminescence systems. Here we present a spatial structure of a complex of the Ca(2+)-regulated photoprotein clytin with its green-fluorescent protein (cgGFP) from the jellyfish Clytia gregaria, and show that it accounts for the bioluminescence properties of this system in vitro. We adopted an indirect approach of combining x-ray crystallography determined structures of the separate proteins, NMR spectroscopy, computational docking, and mutagenesis. Heteronuclear NMR spectroscopy using variously (15)N,(13)C,(2)H-enriched proteins enabled assignment of backbone resonances of more than 94% of the residues of both proteins. In a mixture of the two proteins at millimolar concentrations, complexation was inferred from perturbations of certain (1)H-(15)N HSQC resonances, which could be mapped to those residues involved at the interaction site. A docking computation using HADDOCK was employed constrained by the sites of interaction, to deduce an overall spatial structure of the complex. Contacts within the clytin-cgGFP complex and electrostatic complementarity of interaction surfaces argued for a weak protein-protein complex. A weak affinity was also observed by isothermal titration calorimetry (K(D) = 0.9 mM). Mutation of clytin residues located at the interaction site reduced the degree of protein-protein association concomitant with a loss of effectiveness of cgGFP in color-shifting the bioluminescence. It is suggested that this clytin-cgGFP structure corresponds to the transient complex previously postulated to account for the energy transfer effect of GFP in the bioluminescence of aequorin or Renilla luciferase. PMID- 20926381 TI - Alternatively expressed domains of AU-rich element RNA-binding protein 1 (AUF1) regulate RNA-binding affinity, RNA-induced protein oligomerization, and the local conformation of bound RNA ligands. AB - AU-rich element RNA-binding protein 1 (AUF1) binding to AU-rich elements (AREs) in the 3'-untranslated regions of mRNAs encoding many cytokines and other regulatory proteins modulates mRNA stability, thereby influencing protein expression. AUF1-mRNA association is a dynamic paradigm directed by various cellular signals, but many features of its function remain poorly described. There are four isoforms of AUF1 that result from alternative splicing of exons 2 and 7 from a common pre-mRNA. Preliminary evidence suggests that the different isoforms have varied functional characteristics, but no detailed quantitative analysis of the properties of each isoform has been reported despite their differential expression and regulation. Using purified recombinant forms of each AUF1 protein variant, we used chemical cross-linking and gel filtration chromatography to show that each exists as a dimer in solution. We then defined the association mechanisms of each AUF1 isoform for ARE-containing RNA substrates and quantified relevant binding affinities using electrophoretic mobility shift and fluorescence anisotropy assays. Although all AUF1 isoforms generated oligomeric complexes on ARE substrates by sequential dimer association, sequences encoded by exon 2 inhibited RNA-binding affinity. By contrast, the exon 7-encoded domain enhanced RNA-dependent protein oligomerization, even permitting cooperative RNA-binding activity in some contexts. Finally, fluorescence resonance energy transfer-based assays showed that the different AUF1 isoforms remodel bound RNA substrates into divergent structures as a function of protein:RNA stoichiometry. Together, these data describe isoform-specific characteristics among AUF1 ribonucleoprotein complexes, which likely constitute a mechanistic basis for differential functions and regulation among members of this protein family. PMID- 20926382 TI - Oxidative stress inhibits vascular K(ATP) channels by S-glutathionylation. AB - The K(ATP) channel is an important player in vascular tone regulation. Its opening and closure lead to vasodilation and vasoconstriction, respectively. Such functions may be disrupted in oxidative stress seen in a variety of cardiovascular diseases, while the underlying mechanism remains unclear. Here, we demonstrated that S-glutathionylation was a modulation mechanism underlying oxidant-mediated vascular K(ATP) channel regulation. An exposure of isolated mesenteric rings to hydrogen peroxide (H(2)O(2)) impaired the K(ATP) channel mediated vascular dilation. In whole-cell recordings and inside-out patches, H(2)O(2) or diamide caused a strong inhibition of the vascular K(ATP) channel (Kir6.1/SUR2B) in the presence, but not in the absence, of glutathione (GSH). Similar channel inhibition was seen with oxidized glutathione (GSSG) and thiol modulating reagents. The oxidant-mediated channel inhibition was reversed by the reducing agent dithiothreitol (DTT) and the specific deglutathionylation reagent glutaredoxin-1 (Grx1). Consistent with S-glutathionylation, streptavidin pull down assays with biotinylated glutathione ethyl ester (BioGEE) showed incorporation of GSH to the Kir6.1 subunit in the presence of H(2)O(2). These results suggest that S-glutathionylation is an important mechanism for the vascular K(ATP) channel modulation in oxidative stress. PMID- 20926383 TI - A molecular switch between the outer and the inner vestibules of the voltage gated Na+ channel. AB - Voltage-gated ion channels are transmembrane proteins that undergo complex conformational changes during their gating transitions. Both functional and structural data from K(+) channels suggest that extracellular and intracellular parts of the pore communicate with each other via a trajectory of interacting amino acids. No crystal structures are available for voltage-gated Na(+) channels, but functional data suggest a similar intramolecular communication involving the inner and outer vestibules. However, the mechanism of such communication is unknown. Here, we report that amino acid Ile-1575 in the middle of transmembrane segment 6 of domain IV (DIV-S6) in the adult rat skeletal muscle isoform of the voltage-gated sodium channel (rNa(V)1.4) may act as molecular switch allowing for interaction between outer and inner vestibules. Cysteine scanning mutagenesis of the internal part of DIV-S6 revealed that only mutations at site 1575 rescued the channel from a unique kinetic state ("ultra-slow inactivation," I(US)) produced by the mutation K1237E in the selectivity filter. A similar effect was seen with I1575A. Previously, we reported that conformational changes of both the internal and the external vestibule are involved in the generation of I(US). The fact that mutations at site 1575 modulate I(US) produced by K1237E strongly suggests an interaction between these sites. Our data confirm a previously published molecular model in which Ile-1575 of DIV-S6 is in close proximity to Lys-1237 of the selectivity filter. Furthermore, these functional data define the position of the selectivity filter relative to the adjacent DIV-S6 segment within the ionic permeation pathway. PMID- 20926384 TI - Adenosine A2A receptor is involved in cell surface expression of A2B receptor. AB - The A2A and A2B adenosine receptors (A2AR and A2BR) are implicated in many physiological processes. However, the mechanisms of their intracellular maturation and trafficking are poorly understood. In comparative studies of A2AR versus A2BR expression in transfected cells, we noticed that the levels of cell surface expression of A2BR were significantly lower than those of A2AR. A large portion of the A2BR was degraded by the proteasome. Studies of cell surface expression of A2BR chimeric molecules in transfectants suggested that A2BR does not have the dominant forward transport signal for export from the endoplasmic reticulum to the cell surface. A2BR surface expression was increased in A2BR chimeras where the A2BR carboxyl terminus (CT) was replaced or fused with the A2AR CT. Co-transfection of A2AR with A2BR enhanced surface expression of A2BR though the F(X)(6)LL motif in the A2AR CT. The requirements of A2AR expression for better A2BR cell surface expression was not only established in transfectants but also confirmed by observations of much lower levels of A2BR-induced intracellular cAMP accumulation in response to A2BR-activating ligand in splenocytes from A2AR(-/-) mice than in wild type mice. The results of mechanistic studies suggested that poor A2BR expression at the cell surface might be accounted for mainly by the lack of a dominant forward transport signal from the endoplasmic reticulum to the plasma membrane; it is likely that A2BR forms a hetero-oligomer complex for better function. PMID- 20926385 TI - Identification of a residue in helix 2 of rice plasma membrane intrinsic proteins that influences water permeability. AB - Molecular selection, ion exclusion, and water permeation are well known regulatory mechanisms in aquaporin. Water permeability was found to be diverse in different subgroups of plasma membrane intrinsic proteins (PIPs), even though the residues surrounding the water holes remained the same across the subgroups. Upon homology modeling and structural comparison, a conserved Ala/Ile(Val) residue difference was identified in helix 2 that affected the conformation of the NPA region and consequently influenced the water permeability. The residue difference was found to be conservative within the two subgroups of PIPs in rice as well as in other plants. Functional tests further confirmed the prediction via site directed mutagenesis where replacement of Ala(103) or Ala(102) in respective OsPIP1;1 or OsPIP1;3 with Val yielded 7.0- and 2.2-fold increases in water transportation, and substitution of Ile(98) or Val(95) in respective OsPIP2;3 or OsPIP2;7 with Ala resulted in 73 or 52% reduction of water transportation. Based on structural analyses and molecular dynamics simulations, we proposed that the difference in water permeability was attributed to the orientation variations of helix 2 that modified water-water and water-protein interactions. PMID- 20926387 TI - The eukaryotic translation elongation Factor 1Bgamma has a non-guanine nucleotide exchange factor role in protein metabolism. AB - The turnover of damaged proteins is critical to cell survival during stressful conditions such as heat shock or oxidative stress. The accumulation of misfolded proteins in the endoplasmic reticulum (ER) is toxic to cells. Therefore these proteins must be efficiently exported from the ER and degraded by the proteasome or the vacuole. Previously it was shown that the loss of eukaryotic elongation factor 1Bgamma (eEF1Bgamma) from the yeast Saccharomyces cerevisiae results in resistance to oxidative stress. Strains lacking eEF1Bgamma show severe defects in protein turnover during conditions of oxidative stress. Furthermore, these strains accumulate a greater amount of oxidized proteins, which correlates with changes in heat shock chaperones. These strains show severe defects in vacuole morphology and defects related to the maturation of carboxypeptidase Y that is not dependent on the catalytic subunit of the eEF1B complex as a guanine nucleotide exchange factor. Finally, eEF1Bgamma co-immunoprecipitates with an essential component of ER-Golgi transport vesicles. Taken together, these results support a broader protein metabolism role for eEF1Bgamma. PMID- 20926386 TI - Blocking O-linked GlcNAc cycling in Drosophila insulin-producing cells perturbs glucose-insulin homeostasis. AB - A dynamic cycle of O-linked GlcNAc (O-GlcNAc) addition and removal is catalyzed by O-GlcNAc transferase and O-GlcNAcase, respectively, in a process that serves as the final step in a nutrient-driven "hexosamine-signaling pathway." Evidence points to a role for O-GlcNAc cycling in diabetes and insulin resistance. We have used Drosophila melanogaster to determine whether O-GlcNAc metabolism plays a role in modulating Drosophila insulin-like peptide (dilp) production and insulin signaling. We employed transgenesis to either overexpress or knock down Drosophila Ogt(sxc) and Oga in insulin-producing cells (IPCs) or fat bodies using the GAL4-UAS system. Knockdown of Ogt decreased Dilp2, Dilp3, and Dilp5 production, with reduced body size and decreased phosphorylation of Akt in vivo. In contrast, knockdown of Oga increased Dilp2, Dilp3, and Dilp5 production, increased body size, and enhanced phosphorylation of Akt in vivo. However, knockdown of either Ogt(sxc) or Oga in the IPCs increased the hemolymph carbohydrate concentration. Furthermore, phosphorylation of Akt stimulated by extraneous insulin in an ex vivo cultured fat body of third instar larvae was diminished in strains subjected to IPC knockdown of Ogt or Oga. Knockdown of O GlcNAc cycling enzymes in the fat body dramatically reduced neutral lipid stores. These results demonstrate that altered O-GlcNAc cycling in Drosophila IPCs modulates insulin production and influences the insulin responsiveness of peripheral tissues. The observed phenotypes in O-GlcNAc cycling mimic pancreatic beta-cell dysfunction and glucose toxicity related to sustained hyperglycemia in mammals. PMID- 20926388 TI - Characterization of FdmV as an amide synthetase for fredericamycin A biosynthesis in Streptomyces griseus ATCC 43944. AB - Fredericamycin (FDM) A is a pentadecaketide natural product that features an amide linkage. Analysis of the fdm cluster from Streptomyces griseus ATCC 43944, however, failed to reveal genes encoding the types of amide synthetases commonly seen in natural product biosynthesis. Here, we report in vivo and in vitro characterizations of FdmV, an asparagine synthetase (AS) B-like protein, as an amide synthetase that catalyzes the amide bond formation in FDM A biosynthesis. This is supported by the findings that (i) inactivation of fdmV in vivo afforded the DeltafdmV mutant strain SB4027 that abolished FDM A and FDM E production but accumulated FDM C, a biosynthetic intermediate devoid of the characteristic amide linkage; (ii) FdmV in vitro catalyzes conversion of FDM C to FDM B, a known intermediate for FDM A biosynthesis (apparent K(m) = 162 +/- 67 MUM and k(cat) = 0.11 +/- 0.02 min(-1)); and (iii) FdmV also catalyzes the amidation of FDM M-3, a structural analog of FDM C, to afford amide FDM M-6 in vitro, albeit at significantly reduced efficiency. Preliminary enzymatic studies revealed that, in addition to the common nitrogen sources (L-Gln and free amine) of class II glutamine amidotransferases (to which AS B belongs), FdmV can also utilize L-Asn as a nitrogen donor. The amide bond formation in FDM A biosynthesis is proposed to occur after C-8 hydroxylation but before the carbaspirocycle formation. PMID- 20926389 TI - Genomics-driven reconstruction of acinetobacter NAD metabolism: insights for antibacterial target selection. AB - Enzymes involved in the last steps of NAD biogenesis, nicotinate mononucleotide adenylyltransferase (NadD) and NAD synthetase (NadE), are conserved and essential in most bacterial species and are established targets for antibacterial drug development. Our genomics-based reconstruction of NAD metabolism in the emerging pathogen Acinetobacter baumannii revealed unique features suggesting an alternative targeting strategy. Indeed, genomes of all analyzed Acinetobacter species do not encode NadD, which is functionally replaced by its distant homolog NadM. We combined bioinformatics with genetic and biochemical techniques to elucidate this and other important features of Acinetobacter NAD metabolism using a model (nonpathogenic) strain Acinetobacter baylyi sp. ADP1. Thus, a comparative kinetic characterization of PncA, PncB, and NadV enzymes allowed us to suggest distinct physiological roles for the two alternative, deamidating and nondeamidating, routes of nicotinamide salvage/recycling. The role of the NiaP transporter in both nicotinate and nicotinamide salvage was confirmed. The nondeamidating route was shown to be transcriptionally regulated by an ADP-ribose responsive repressor NrtR. The NadM enzyme was shown to possess dual substrate specificity toward both nicotinate and nicotinamide mononucleotide substrates, which is consistent with its essential role in all three routes of NAD biogenesis, de novo synthesis as well as the two salvage pathways. The experimentally confirmed unconditional essentiality of nadM provided support for the choice of the respective enzyme as a drug target. In contrast, nadE, encoding a glutamine-dependent NAD synthetase, proved to be dispensable when the nondeamidating salvage pathway functioned as the only route of NAD biogenesis. PMID- 20926390 TI - Crystal structure of Leishmania major oligopeptidase B gives insight into the enzymatic properties of a trypanosomatid virulence factor. AB - Oligopeptidase B (OPB) is a serine peptidase with dibasic substrate specificity. It is found in bacteria, plants, and trypanosomatid pathogens, where it has been identified as a virulence factor and potential drug target. In this study we expressed active recombinant Leishmania major OPB and provide the first structure of an oligopeptidase B at high resolution. The crystallographic study reveals that OPB comprises two domains, a catalytic and a propeller domain, linked together by a hinge region. The structure has been determined in complex with the oligopeptide, protease-inhibitor antipain, giving detailed information on the enzyme active site and extended substrate binding pockets. It shows that Glu-621 plays a critical role in the S1 binding pocket and, along with Phe-603, is largely responsible for the enzyme substrate specificity in P1. In the S2 binding pocket, Tyr-499 was shown to be important for substrate stability. The structure also allowed an investigation into the function of residues highlighted in other studies including Glu-623, which was predicted to be involved in the S1 binding pocket but is found forming an inter-domain hydrogen bond. Additional important salt bridges/hydrogen bonds between the two domains were observed, highlighting the significance of the domain interface in OPB. This work provides a foundation for the study of the role of OPBs as virulence factors in trypanosomatids. It could facilitate the development of specific OPB inhibitors with therapeutic potential by exploiting its unique substrate recognition properties as well as providing a model for OPBs in general. PMID- 20926391 TI - O-linked beta-N-acetylglucosamine (O-GlcNAc) regulates stress-induced heat shock protein expression in a GSK-3beta-dependent manner. AB - To investigate the mechanisms by which O-linked beta-N-acetylglucosamine modification of nucleocytoplasmic proteins (O-GlcNAc) confers stress tolerance to multiple forms of cellular injury, we explored the role(s) of O-GlcNAc in the regulation of heat shock protein (HSP) expression. Using a cell line in which deletion of the O-GlcNAc transferase (OGT; the enzyme that adds O-GlcNAc) can be induced by 4-hydroxytamoxifen, we screened the expression of 84 HSPs using quantitative reverse transcriptase PCR. In OGT null cells the stress-induced expression of 18 molecular chaperones, including HSP72, were reduced. GSK-3beta promotes apoptosis through numerous pathways, including phosphorylation of heat shock factor 1 (HSF1) at Ser(303) (Ser(P)(303) HSF1), which inactivates HSF1 and inhibits HSP expression. In OGT null cells we observed increased Ser(P)(303) HSF1; conversely, in cells in which O-GlcNAc levels had been elevated, reduced Ser(P)(303) HSF1 was detected. These data, combined with those showing that inhibition of GSK-3beta in OGT null cells recovers HSP72 expression, suggests that O-GlcNAc regulates the activity of GSK-3beta. In OGT null cells, stress induced inactivation of GSK-3beta by phosphorylation at Ser(9) was ablated providing a molecular basis for these findings. Together, these data suggest that stress-induced GlcNAcylation increases HSP expression through inhibition of GSK 3beta. PMID- 20926392 TI - Admission rates and in-hospital mortality for hip fractures in England 1998 to 2009: time trends study. AB - BACKGROUND: Fractures of the proximal femur are an important public health concern. The incidence of hip fractures is an index of osteoporosis burden. There have been no recent studies examining national trends in hip fractures in England. METHODS: We used national data for 1998-2009 from the English Hospital Episode Statistics database. Patients with an admission for hip fracture (574,482 admissions) were identified. RESULTS: Between 1998 and 2009, there was little change in age-standardized hip fracture rates (102.0-101.8 fractures per 100,000 person-years), but age-standardized in-hospital mortality decreased by 16.5% (95% CI (confidence interval): -18.5 to -8.4%) (126.9-106.0 deaths per 1000 hip fracture admissions). The majority of hip fractures and deaths occurred in females and older people. A socioeconomic gradient of 25.9% difference (95% CI: 15.7-36.1%) existed for mortality in 2008 (93.5-117.7 per 1000). CONCLUSIONS: Hip fracture rates have not decreased in England since 1998, although inpatient mortality rates have declined. There is a socioeconomic gradient for in-hospital hip fracture deaths. PMID- 20926393 TI - Cellular and viral chromatin proteins are positive factors in the regulation of adenovirus gene expression. AB - The adenovirus genome forms chromatin-like structure with viral core proteins. This complex supports only a low level of transcription in a cell-free system, and thus core proteins have been thought to be negative factors for transcription. The mechanism how the transcription from the viral DNA complexed with core proteins is activated in infected cells remains unclear. Here, we found that both core proteins and histones are bound with the viral DNA in early phases of infection. We also found that acetylation of histone H3 occurs at the promoter regions of viral active genes in a transcription-independent manner. In addition, when a plasmid DNA complexed with core proteins was introduced into cells, core proteins enhanced transcription. Knockdown of TAF-I, a remodeling factor for viral core protein-DNA complexes, reduces the enhancement effect by core proteins, indicating that core proteins positively regulate viral transcription through the interaction with TAF-I. We would propose a possible mechanism that core proteins ensure transcription by regulating viral chromatin structure through the interaction with TAF-I. PMID- 20926394 TI - Structural basis for the dual RNA-recognition modes of human Tra2-beta RRM. AB - Human Transformer2-beta (hTra2-beta) is an important member of the serine/arginine-rich protein family, and contains one RNA recognition motif (RRM). It controls the alternative splicing of several pre-mRNAs, including those of the calcitonin/calcitonin gene-related peptide (CGRP), the survival motor neuron 1 (SMN1) protein and the tau protein. Accordingly, the RRM of hTra2-beta specifically binds to two types of RNA sequences [the CAA and (GAA)(2) sequences]. We determined the solution structure of the hTra2-beta RRM (spanning residues Asn110-Thr201), which not only has a canonical RRM fold, but also an unusual alignment of the aromatic amino acids on the beta-sheet surface. We then solved the complex structure of the hTra2-beta RRM with the (GAA)(2) sequence, and found that the AGAA tetra-nucleotide was specifically recognized through hydrogen-bond formation with several amino acids on the N- and C-terminal extensions, as well as stacking interactions mediated by the unusually aligned aromatic rings on the beta-sheet surface. Further NMR experiments revealed that the hTra2-beta RRM recognizes the CAA sequence when it is integrated in the stem loop structure. This study indicates that the hTra2-beta RRM recognizes two types of RNA sequences in different RNA binding modes. PMID- 20926395 TI - The use of quaternary ammonium disinfectants selects for persisters at high frequency from some species of non-tuberculous mycobacteria and may be associated with outbreaks of soft tissue infections. AB - BACKGROUND: Non-tuberculous mycobacteria (NTM) are increasingly important as opportunistic infections after major and minor surgical procedures, likely because they are ubiquitous and not effectively killed by many commonly used disinfectants. Outbreaks of soft tissue infections with NTM appeared related to the use of commercial disinfectants based on quaternary ammonium compounds (QACs). METHODS: We studied the survival of clinical and environmental isolates of Mycobacterium abscessus, Mycobacterium massiliense, Mycobacterium chelonae and Mycobacterium fortuitum after 20 min, 60 min or 24 h exposures to different QACs, and the surviving bacteria were then re-exposed to QACs to see if the percentage of surviving bacteria had increased. The bacteria were labelled with a dnaA-gfp fusion and their level of QAC resistance monitored as increasing fluorescence. The QAC-resistant bacteria were then serially restreaked onto non-selective medium and retested for QAC survival. RESULTS: The frequency of survivors was <1 in 10(5) bacteria with Mycobacterium smegmatis, but >1 in 100 with the other mycobacteria studied. Different environmental and clinical isolates had similar QAC MICs, but QAC survivors of each strain were resistant. The QAC-surviving strains reverted to the original, non-resistant phenotype after several passages on non-selective medium. CONCLUSIONS: QACs should not be used in settings where even minimally invasive procedures are performed, as they select for a non genetically determined reversible resistant phenotype that appears at high frequency with several rapidly growing mycobacterial species associated with healthcare-related infections. M. smegmatis behaves differently and is not an adequate model for testing the activity of disinfectants against NTM. PMID- 20926396 TI - Severity assessment of skin and soft tissue infections: cohort study of management and outcomes for hospitalized patients. AB - BACKGROUND: Skin and soft tissue infections (SSTIs) are caused by bacterial invasion of the skin and underlying soft tissues and can present with a wide spectrum of signs, symptoms and illness severity. They are a common indication for antimicrobial therapy. However, there are few data on treatment outcomes or the validity of clinical severity scores. METHODS: Two hundred and five adult patients admitted to Ninewells Hospital, Scotland in 2005, and treated with antibiotics for SSTI, were identified. They were stratified into four classes of severity (class IV = most severe) based on sepsis, co-morbidity and their standardized early warning score (SEWS). Empirical antimicrobial therapy by severity class was compared with the recommendations of a UK guideline. RESULTS: Thirty-five different empirical antimicrobial regimens were prescribed. Overall, 43% of patients were over-treated, this being particularly common in the lowest severity class I (65% patients). Thirty-day mortality was 9% (18/205) and 17 patients (8%) died during their index admission. Mortality (30 day) and inadequate therapy increased with severity class: I, no sepsis or co-morbidity (45% patients, 1% mortality, 14% therapy inadequate); II, significant co morbidity but no sepsis (32% patients, 11% mortality, 39% therapy inadequate); III, sepsis but SEWS <4 (17% of patients, 17% mortality, 39% therapy inadequate); and IV, sepsis plus SEWS >= 4 (6% of patients, 33% mortality, 92% therapy inadequate). CONCLUSIONS: SSTI in hospital is associated with significant mortality. Choice of empirical therapy is not evidence based, with significant under-treatment of severely ill patients. PMID- 20926397 TI - Pharmacodynamics of empirical antibiotic monotherapies for an intensive care unit (ICU) population based on Canadian surveillance data. AB - OBJECTIVES: To evaluate, using Monte Carlo simulation, the pharmacodynamics (PD) of empirical antibiotic monotherapies for serious infections consistent with Canadian intensive care unit (ICU) surveillance data. METHODS: Meropenem, piperacillin/tazobactam and cefepime, along with ceftobiprole, a broad-spectrum cephalosporin active against methicillin-resistant Staphylococcus aureus (MRSA), were tested at standard and highest recommended doses with and without prolonged infusion times (t'). Population pharmacokinetic models were used to simulate antibiotic serum concentrations (n = 5000). Cumulative target attainment (CTA) at >50%, >75% and 100% fT( > MIC) (percentage of time free concentrations exceed the MIC) targets were determined based on ICU surveillance data including 4798 pathogens, most commonly methicillin-susceptible S. aureus (20.1%), Escherichia coli (15.2%) and Pseudomonas aeruginosa (12.3%). RESULTS: With standard doses, ceftobiprole (500 mg every 8 h, t' 2 h) had 0.90 CTA at the >50% fT( > MIC) target while meropenem (1 g every 8 h, t' 0.5 h), piperacillin/tazobactam (3.375 g every 6 h, t' 0.5 h) and cefepime (2 g every 12 h, t' 0.5 h) reached >50% fT( > MIC) in 0.79-0.82 of the population (0.84-0.88 when MRSA was excluded). Piperacillin/tazobactam had the largest reduction in CTA at the >75% and 100% fT( > MIC) targets requiring prolonged infusions to maintain comparable PD. For all agents, prolonged infusions and/or high doses were required to achieve >0.9 CTA at the lowest target, to reach higher targets or to cover less susceptible pathogens such as P. aeruginosa. CONCLUSIONS: This study provides important comparative data on empirical antibiotic monotherapies in an ICU setting including preliminary data on ceftobiprole. Ceftobiprole was most active overall, but similar to meropenem, piperacillin/tazobactam (lowest target only) and cefepime when MRSA was excluded. Prolonged infusions in particular and high doses were effective at improving antibiotic PD. PMID- 20926398 TI - Clld7, a candidate tumor suppressor on chromosome 13q14, regulates pathways of DNA damage/repair and apoptosis. AB - Chronic lymphocytic leukemia deletion gene 7 (Clld7) is a candidate tumor suppressor on chromosome 13q14. Clld7 encodes an evolutionarily conserved protein that contains an RCC1 domain plus broad complex, tramtrack, bric-a-brac (BTB), and POZ domains. In this study, we investigated the biological functions of Clld7 protein in inducible osteosarcoma cell lines. Clld7 induction inhibited cell growth, decreased cell viability, and increased gamma-H2AX staining under conditions of caspase inhibition, indicating activation of the DNA damage/repair pathway. Real-time PCR analysis in tumor cells and normal human epithelial cells revealed Clld7 target genes that regulate DNA repair responses. Furthermore, depletion of Clld7 in normal human epithelial cells conferred resistance to apoptosis triggered by DNA damage. Taken together, the biological actions of Clld7 are consistent with those of a tumor suppressor. PMID- 20926399 TI - Multiple injections of electroporated autologous T cells expressing a chimeric antigen receptor mediate regression of human disseminated tumor. AB - Redirecting T lymphocyte antigen specificity by gene transfer can provide large numbers of tumor-reactive T lymphocytes for adoptive immunotherapy. However, safety concerns associated with viral vector production have limited clinical application of T cells expressing chimeric antigen receptors (CAR). T lymphocytes can be gene modified by RNA electroporation without integration-associated safety concerns. To establish a safe platform for adoptive immunotherapy, we first optimized the vector backbone for RNA in vitro transcription to achieve high level transgene expression. CAR expression and function of RNA-electroporated T cells could be detected up to a week after electroporation. Multiple injections of RNA CAR-electroporated T cells mediated regression of large vascularized flank mesothelioma tumors in NOD/scid/gammac(-/-) mice. Dramatic tumor reduction also occurred when the preexisting intraperitoneal human-derived tumors, which had been growing in vivo for >50 days, were treated by multiple injections of autologous human T cells electroporated with anti-mesothelin CAR mRNA. This is the first report using matched patient tumor and lymphocytes showing that autologous T cells from cancer patients can be engineered to provide an effective therapy for a disseminated tumor in a robust preclinical model. Multiple injections of RNA-engineered T cells are a novel approach for adoptive cell transfer, providing flexible platform for the treatment of cancer that may complement the use of retroviral and lentiviral engineered T cells. This approach may increase the therapeutic index of T cells engineered to express powerful activation domains without the associated safety concerns of integrating viral vectors. PMID- 20926400 TI - REO-10: a phase I study of intravenous reovirus and docetaxel in patients with advanced cancer. AB - PURPOSE: REOLYSIN (Oncolytics Biotech) consists of a wild-type oncolytic reovirus, which has selective cytotoxicity for tumor cells while sparing normal cells. In a phase I study as a single agent, repeated infusions of reovirus were safe with evidence of antitumor activity. Preclinical studies indicate potential for synergy between reovirus and chemotherapeutic agents. A multicenter, phase I dose escalation study was designed to assess the safety of combining reovirus with docetaxel chemotherapy in patients with advanced cancer. EXPERIMENTAL DESIGN: Patients received 75 mg/m(2) docetaxel (day 1) and escalating doses of reovirus up to 3 * 10(10) TCID(50) (days 1-5) every 3 weeks. RESULTS: Twenty-five patients were enrolled, and 24 patients were exposed to treatment, with 23 completing at least one cycle and 16 suitable for response assessment. Dose limiting toxicity of grade 4 neutropenia was seen in one patient, but the maximum tolerated dose was not reached. Antitumor activity was seen with one complete response and three partial responses. A disease control rate (combined complete response, partial response, and stable disease) of 88% was observed. Immunohistochemical analysis of reovirus protein expression was observed in posttreatment tumor biopsies from three patients. CONCLUSION: The combination of reovirus and docetaxel is safe, with evidence of objective disease response, and warrants further evaluation in a phase II study at a recommended schedule of docetaxel (75 mg/m(2), three times weekly) and reovirus (3 * 10(10) TCID(50), days 1-5, every 3 weeks). PMID- 20926401 TI - EML4-ALK fusion gene assessment using metastatic lymph node samples obtained by endobronchial ultrasound-guided transbronchial needle aspiration. AB - PURPOSE: Anaplastic lymphoma kinase (ALK) fusion genes represent novel oncogenes for non-small cell lung cancers (NSCLC). Several ALK inhibitors have been developed, and are now being evaluated in ALK-positive NSCLC. The feasibility of detecting ALK fusion genes in samples obtained by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) was determined. The clinicopathologic characteristics of ALK-positive lung cancer were also analyzed. EXPERIMENTAL DESIGN: From April 2008 to July 2009, NSCLC cases with hilar/mediastinal lymph node metastases detected by EBUS-TBNA were enrolled. Positive expression of ALK fusion protein was determined using immunohistochemistry, and ALK gene rearrangements were further examined to verify the translocation between ALK and partner genes using fluorescent in situ hybridization and reverse transcription-PCR. Direct sequencing of PCR products was performed to identify ALK fusion variants. RESULTS: One hundred and nine cases were eligible for the analysis using re-sliced samples. Screening of these specimens with immunohistochemistry revealed ALK positivity in seven cases (6.4%), all of which possessed echinoderm microtubule-associated protein-like 4 ALK fusion genes as detected by fluorescent in situ hybridization and reverse transcription-PCR. All ALK-positive cases had an adenocarcinoma histology and possessed no EGFR mutations. Compared with ALK-negative cases, ALK-positive cases were more likely to have smaller primary tumors (P < 0.05), to occur at a younger age (<60 years; P < 0.05), and to occur in never/light smokers (smoking index < 400; P < 0.01). Mucin production was frequently observed in ALK-positive adenocarcinomas (29.4%; P < 0.01). CONCLUSIONS: EBUS-TBNA is a practical and feasible method for obtaining tissue from mediastinal and hilar lymph nodes that can be subjected to multimodal analysis of ALK fusion genes in NSCLC. PMID- 20926402 TI - The tissue is the issue: personalized medicine for non-small cell lung cancer. AB - The development of molecular markers is crucial for improving therapy in advanced non-small cell lung cancer (NSCLC). Here, we review perspectives of biomarker driven personalized therapy in NSCLC, with particular reference to the detection of EML4-ALK gene rearrangements. Different molecular assays, validation, and clinical application to different types of tissue specimens are discussed. PMID- 20926403 TI - Predicting intention to biobank: a national survey. AB - BACKGROUND: The success of human population biobanks are dependent on the publics' willingness to participate. This research aimed to determine those factors important in determining the public's intention to donate a biological sample to a publicly funded biobank, and allow that sample to be linked with medical records. METHODS: A national sample of 1000 Australians was surveyed via telephonic interviews. Questions included the reported likelihood that respondents would participate in biobank research, ratings of trust in biobanks, beliefs that biobank research will lead to improved health care and general ratings of comfort with blood taking and DNA analysis. RESULTS: The sample reported a high level of trust in university biobanks, a strong belief that biobank research will lead to improved health care and a strong willingness to participate in biobank research. Using structural equation modelling, trust in the biobank was found to be the most important determinant of intention to participate in biobank research, followed by general comfort with blood taking and DNA analysis, belief in health-care benefits and higher education. Gender, age, parental status and experience of genetic conditions were not significantly associated with intention to participate. CONCLUSIONS: Australians are generally willing to participate in biobank research, and this is strongly determined by trust. While benefit beliefs and comfort with research are also relevant, higher trust was associated with intention regardless of these factors, suggesting reasons other than concern for improved health care are important in determining the publics' willingness to participate in biobank research. PMID- 20926404 TI - Determinants of self-rated health in Spain: differences by age groups for adults. AB - BACKGROUND: Identifying factors associated with self-rated health (SRH) in two age groups (16-49 and >= 50 years) in the context of action for health promotion in adults. METHODS: The data used came from the household and adults questionnaires of the National Health Survey of Spain for 2006. SRH was categorized as positive (very positive or positive) and negative (fair, poor or very poor). Odds ratios for positive SRH compared with negative SRH were calculated using logistic regression models for complex samples. The determinants of the positive SRH were obtained for the total population and for two age groups. RESULTS: Among the population aged >= 16 years, 66.6% reports positive SRH, 78.6% in the 16- to 49-year-old group and 47.7% in the >= 50-year-old group. SRH worsens with age until the age of 49, whereas 50 years onwards older report better health than the younger. The influence of lifestyle on the SRH varies by age group among adults as well: in the younger age groups, obesity, smoking and non-alcohol are associated with poor SRH; in contrast, physical exercise only in leisure time and enough sleeping hours are associated with positive SRH in the >= 50-year-old population. CONCLUSIONS: The factors associated with SRH differ across age groups, particularly for lifestyle. Understanding the differences between the factors associated with the positive SRH is highly relevant for the design of specific programmes aimed at improving public health. PMID- 20926406 TI - Children's self-regulation in eating: associations with inhibitory control and parents' feeding behavior. AB - OBJECTIVE: Children who self-regulate while eating and children who show high global self-regulation abilities, such as inhibitory control, are less likely to be overweight than children who do not show the same capacities for self regulation. This study examined the association between child self-regulation in eating and inhibitory control, and investigated whether self-regulation is related to parents' restrictive feeding practices. METHOD: Sixty-three parents reported on their 3- to 9-year-old children's self-regulation in eating, inhibitory control, and their own feeding practices. RESULTS: Self-regulation in eating and inhibitory control were positively correlated, r = .54. Self regulation in eating predicted parents' use of restrictive feeding practices above and beyond children's inhibitory control and parents' concerns about their children's weight, p < .01. CONCLUSIONS: When parents believed their children could self-regulate, they used less restrictive feeding practices. Because restriction can compromise self-regulatory abilities, early interventions should teach parents about children's nascent abilities in this domain. PMID- 20926405 TI - Parental involvement and adolescents' diabetes management: the mediating role of self-efficacy and externalizing and internalizing behaviors. AB - OBJECTIVE: To examine mediating processes linking parental involvement to diabetes management (adherence and metabolic control) during adolescence. METHODS: A total of 252 young adolescents (M age = 12.49 years, SD = 1.53, 53.6% females) with type 1 diabetes reported their parents' involvement in diabetes management (relationship quality, monitoring, and behavioral involvement), their own externalizing and internalizing behaviors, diabetes-self efficacy, and adherence behaviors. HbA1c was drawn from medical records. RESULTS: SEM analyses indicated that the associations of mothers' and fathers' relationship quality with diabetes outcomes were mediated by adolescents' perceptions of self-efficacy and externalizing behaviors, and the associations of fathers' monitoring and behavioral involvement with adherence were partially mediated by adolescents' self-efficacy. There were also direct (non-mediated) associations between mothers' monitoring and adherence, and fathers' monitoring and adherence and metabolic control. CONCLUSIONS: Quality of the parent-adolescent relationship and monitoring are important for better adherence and metabolic control among adolescents through higher diabetes self-efficacy. PMID- 20926407 TI - Brief report: Preliminary findings from a pilot health care transition education intervention for adolescents and young adults with special health care needs. AB - OBJECTIVE: To assess acceptability and feasibility of a school-based health care transition education intervention designed to equip adolescents and young adults (A/YA) who have special health care needs with important health literacy, self advocacy, and self-determination skills. METHODS: A qualitative research approach was used to assess a 40-hr curriculum implemented with 137 A/YA in 13 high school special education classes. Three focus groups were conducted with 15 students and 7 educators. Participants were questioned about perceived relevance, readability, interest, ease of implementation and completeness of the curriculum. RESULTS: All focus group participants said the curriculum was highly relevant and valuable. Teachers reported little difficulty with ease of implementation, though the reading level appeared high for some students. CONCLUSIONS: This intervention model shows promise for empowering A/YA with special health care needs to become more independent in managing their health care, and warrants further development and evaluation. The curriculum is available at http://health.usf.edu/medicine/pediatrics/ad_med/resources.htm. PMID- 20926408 TI - The cold pressor task: is it an ethically acceptable pain research method in children? AB - OBJECTIVES: The cold pressor task (CPT) is an experimental method of inducing pain. Ethical concerns have been raised regarding the nontherapeutic induction of pain in children. The objectives of this study were to describe the ethical challenges and acceptability of the CPT from the perspective of researchers, children and parents. METHODS: Study 1:16 researchers completed a survey regarding their experiences obtaining ethical approval and use of the CPT in pediatric research. Study 2: 175 children and 194 parents answered questions about their experiences participating in studies that used the CPT. RESULTS: Full ethics board review was generally required. Adverse events were rare and transient. The majority of researchers, children, and parents reported positive experiences with the CPT. CONCLUSIONS: The CPT is judged by researchers, children, and parents to be an acceptable research method. The CPT can be used ethically in pediatric research with appropriate study safeguards. PMID- 20926409 TI - Early detection of 5-FU-induced acute leukoencephalopathy on diffusion-weighted MRI. AB - A 59-year-old man treated with 5-fluorouracil and cisplatin for advanced oesophageal cancer presented abnormal behaviour and subsequently developed impairment of cognitive function, dysphagia and dysarthria on the fifth day of the treatment. Although brain computed tomography revealed no abnormal findings, brain magnetic resonance imaging using diffusion-weighted imaging clearly revealed the presence of a high signal intensity in the deep white matter of the bilateral cerebral hemispheres, including the corpus callosum symmetrically. A diagnosis of acute leukoencephalopathy was reached based on these findings. His clinical symptoms normalized four days after the discontinuation of the chemotherapy. Improvement in magnetic resonance imaging findings was delayed compared with that of clinical symptoms; however, the high signal intensity detected in the deep white matter had disappeared completely five months after the onset of symptoms. Early detection of drug-induced leukoencephalopathy is important as the clinical symptoms can be reversed by early discontinuation of the causative drug. Diffusion-weighted magnetic resonance imaging is a useful modality for the early detection and definitive diagnosis of this characteristic encephalopathy. PMID- 20926410 TI - Metastatic hepatocellular carcinoma in the tympanic membrane. AB - Primary tympanic membrane cancer is very rare; metastatic cancer to the tympanic membrane is extremely rare and presents diagnostic challenges. We report a case of metastatic hepatocellular carcinoma in the tympanic membrane. The presenting symptom was hearing loss. Physical examination revealed a friable granulomatous mass over the left anterior tympanic membrane extended from the external auditory canal. Computed tomography scan of the temporal bone revealed one soft tissue mass involving the left external auditory canal and tympanic membrane. A left middle ear mass biopsy was performed. The tumor cells were uniformly positive for cytokeratin and hepatocyte paraffin-1, confirming a diagnosis of metastatic tympanic membrane. A tympanic membrane mass might easily be misdiagnosed and improperly treated. This case serves as a reminder that the differential diagnosis of acute hearing loss in cancer patients should include the metastasis occurring in the auditory canal or tympanic membrane, and that tissue biopsies are necessary to establish the definitive diagnosis for such lesions. PMID- 20926411 TI - Two consecutive cases of platinum-refractory pulmonary pleomorphic carcinoma that showed dramatic responses to MAID (mesna, doxorubicin, ifosfamide and dacarbazine) chemotherapy. AB - When oncologists encounter patients with pulmonary pleomorphic carcinoma, most cases have recurrent disease after surgery or metastatic disease. Previous studies have suggested that patients with pleomorphic carcinoma have extremely poor responses to chemotherapy regimens commonly used for non-small cell lung cancer and have a dismal prognosis. This report describes two consecutive patients with platinum-refractory pulmonary pleomorphic carcinoma who received doxorubicin, ifosfamide plus dacarbazine chemotherapy. Both patients showed dramatic responses to this combination chemotherapy and the treatment effect was sustained for 7 and 9 months, respectively. Our report strongly suggests that the treatment approaches to patients with pulmonary pleomorphic carcinoma should differ from the approaches to patients with other common types of non-small cell lung cancer. Doxorubicin, ifosfamide plus dacarbazine chemotherapy may have an important role in the treatment of patients with pulmonary pleomorphic carcinoma. PMID- 20926412 TI - Outcomes and tolerability of systemic chemotherapy for pancreatic or biliary cancer patients aged 75 years or older. AB - BACKGROUND: The incidence of pancreatic or biliary tract cancer is increasing in our aging population, but little is known of treatment outcomes in elderly patients with pancreatic or biliary tract cancer. PATIENTS AND METHODS: Patients with pancreatic or biliary tract cancer who received chemotherapy in our institute between September 2007 and August 2009 were retrospectively reviewed to compare treatment outcomes between the elderly (aged 75 years or older) and the younger patients. Data were collected of patient backgrounds, adverse events and dose intensity within the first two cycles and overall survival time. RESULTS: Of the 102 who met the inclusion criteria, 19 were elderly who were introduced to full dose chemotherapy. Medication for their comorbidities was required in 15 (79%) of the 19 elderly patients and in 27 (33%) of 83 younger patients. The frequencies of haematological adverse events of grades 3 or 4 were 42% and 39%, and those of non-haematological adverse events were 21% and 16%, for the elderly and younger, respectively. Similar dose intensities were delivered to the elderly and younger. Also, similar proportions of elderly and younger received dose reductions. There was no difference in overall survival between the elderly and the younger. CONCLUSION: No clear difference in treatment outcomes was seen between the elderly and the younger patients who received gemcitabine alone. Gemcitabine chemotherapy appears to be safe and the same treatment effect was seen even in older patients with pancreatic or biliary tract cancer. PMID- 20926413 TI - The importance of evaluation of DNA amplificability in KRAS mutation testing with dideoxy sequencing using formalin-fixed and paraffin-embedded colorectal cancer tissues. AB - OBJECTIVE: We evaluated DNA amplificability to achieve a 100% success rate in KRAS mutation testing with dideoxy sequencing using formalin-fixed and paraffin embedded colorectal cancer tissue samples obtained from a recent clinical trial. METHODS: We evaluated the effects of deparaffinization, formalin fixation or storage time, and amplicon size on the amplificability of DNAs extracted from 19 formalin-fixed and paraffin-embedded colorectal cancer tissue samples. We subjected to KRAS mutation analysis 112 samples from metastatic colorectal cancer patients in 31 hospitals enrolled in a Phase II trial of a second-line FOLFIRI (5 fluorouracil+ leucovorin + irinotecan) + cetuximab regimen. RESULTS: Deparaffinization, formalin fixation and storage times did not appear to affect the recovery and amplificability of DNAs. However, amplicon size had a remarkable effect on the amplificability of DNAs. The smaller fragments with a size of <=278 bp (96-278 bp) were successfully amplified with polymerase chain reaction in all samples tested, whereas the larger fragments with a size of >=298 bp (298-565 bp) were not amplified. All samples from our clinical trial were successfully analyzed using three sets of primers with the amplicon sizes of 201, 221 and 240 bp, and KRAS mutations in exons 2 and 3 were detected in 49 of the 112 cases (43.8%). CONCLUSIONS: These data suggest that the evaluation of DNA amplificability and amplicon size is important for the success of mutation detection tests such as the KRAS test with dideoxy sequencing using formalin fixed and paraffin-embedded tissue samples in the clinical setting. PMID- 20926414 TI - Benefit of laparoscopic radical nephrectomy in patients with a high BMI. AB - OBJECTIVE: The aim of the present study was to analyze all relevant data collected thus far at our hospital in order to compare the laparoscopic vs. open techniques in terms of the intraoperative results and to analyze whether patients with a higher BMI may derive greater benefit from laparoscopy. METHODS: We reviewed the medical records of 93 patients treated with laparoscopic nephrectomy and 91 patients treated with the open method at our institution. We analyzed the data with the aim of determining what kind of factor would be associated with an increase in estimated blood loss and prolongation of operative time, and we compared the results for laparoscopic and open nephrectomy. RESULTS: A statistically significant correlation was observed between body mass index and operating time (P = 0.018) or estimated blood loss (P = 0.017) in laparoscopic nephrectomy. Multivariate analysis demonstrated that body mass index was an independent risk factor for prolonged operating time (P = 0.030, odds ratio = 1.174). In the open nephrectomy patients, body mass index also had a significant correlation with operating time (P < 0.001) and estimated blood loss (P < 0.001). Multivariate analysis also revealed that operating time depended on body mass index (P < 0.001, odds ratio = 1.348) and tumor size (P = 0.030, odds ratio = 1.320), and the odds ratio of body mass index was higher than that in laparoscopic nephrectomy. CONCLUSIONS: As body mass index increases, both laparoscopic nephrectomy and open nephrectomy become technically more difficult. However, our data showed that for patients with a high body mass index, the laparoscopic approach is comparatively safer and of greater benefit. PMID- 20926415 TI - Overexpression of FurA in Anabaena sp. PCC 7120 reveals new targets for this regulator involved in photosynthesis, iron uptake and cellular morphology. AB - Previous genomic analyses of the filamentous nitrogen-fixing cyanobacterium Anabaena sp. PCC 7120 have identified three ferric uptake regulator (Fur) homologs with low sequence identities and probably different functions in the cell. FurA is a constitutive protein that shares the highest homology with Fur from heterotrophic bacteria and appears to be essential for in vitro growth. In this study, we have analysed the effects of FurA overexpression on the Anabaena sp. phenotype and investigated which of the observed alterations were directly operated by FurA. Overexpression of the regulator led to changes in cellular morphology, resulting in shorter filaments with rounded cells of different sizes. The furA-overexpressing strain showed a slower photoautotrophic growth and a marked decrease in the oxygen evolution rate. Overexpression of the regulator also decreased both catalase and superoxide dismutase activities, but did not lead to an increase in the levels of intracellular reactive oxygen species. By combining phenotypic studies, reverse transcription-PCR analyses and electrophoretic mobility shift assays, we identified three novel direct targets of FurA, including genes encoding a siderophore outer membrane transporter (schT), bacterial actins (mreBCD) and the PSII reaction center protein D1 (psbA). The affinity of FurA for these novel targets was markedly affected by the absence of divalent metal ions, confirming previous evidence of a critical role for the metal co-repressor in the function of the regulator in vivo. The results unravel new cellular processes modulated by FurA, supporting its role as a global transcriptional regulator in Anabaena sp. PCC 7120. PMID- 20926416 TI - Ion and oxygen fluxes in the unicellular alga Eremosphaera viridis. AB - Plasma membrane fluxes of the large unicellular model algal cell Eremosphaera viridis (De Bary) were measured under various light regimes to explore the role of plasma membrane fluxes during photosynthesis and high light-induced chloroplast translocation. Plasma membrane fluxes were measured directly and non invasively with self-referencing ion-selective (H(+), Ca(2+), K(+) and Cl(-)) potentiometric microelectrodes and oxygen amperometric microelectrodes. At light irradiances high enough to induce chloroplast migration from the cell periphery to its center, oxygen evolution declined to respiratory net O(2) uptake prior to any significant chloroplast translocation, while net K(+) and Cl(-) influx increased during the decline in photosynthetic activity (and the membrane potential depolarized). The results suggest that chloroplast translocation is not the cause of the cessation of O(2) evolution at high irradiance. Rather, the chloroplast translocation may play a protective role: shielding the centrally located nucleus from damaging light intensities. At both high and low light intensities (similar to ambient growth conditions), there was a strong inverse correlation between H(+) net fluxes and respiratory and photosynthetic net O(2) fluxes. A similar inverse relationship was also observed for Ca(2+) net fluxes, but only at higher light intensities. The net H(+) fluxes are small relative to the buffering capacity of the cell, but are clearly related to both photosynthetic and respiratory activity. PMID- 20926417 TI - Analogs of the CLV3 peptide: synthesis and structure-activity relationships focused on proline residues. AB - CLAVATA3 (CLV3) is a plant peptide hormone in which the proline residues are post translationally hydroxylated and glycosylated. CLV3 plays a key role in controlling the stem cell mass in the shoot meristem of Arabidopsis thaliana. In a previous report, we identified a dodecapeptide (MCLV3) from CLV3-overexpressing Arabidopsis calli; MCLV3 was the smallest functional peptide derived from the CLV3 precursor. Here, we designed a series of MCLV3 analogs in which proline residues were substituted with proline derivatives or N-substituted glycines (peptoids). Peptoid substitution at Pro9 decreased bioactivity without affecting specific binding to the CLV1-related protein in cauliflower membrane. These findings suggest that peptoid-substituted peptides would be lead compounds for developing potential agonists and antagonists of CLV3. PMID- 20926418 TI - CopyMap: localization and calling of copy number variation by joint analysis of hybridization data from multiple individuals. AB - SUMMARY: The program package CopyMap identifies copy number variation from oligo hybridization and CGH data. Using a time-dependent hidden Markov model to combine evidence of copy number variants (CNVs) across multiple carriers, CopyMap is substantially more accurate than standard hidden Markov methods in identifying CNVs and calling CNV-carriers. Moreover, CopyMap provides more precise estimates of CNV-boundaries. AVAILABILITY: The C-source code and detailed documentation for the program CopyMap is available on the Internet at http://www.sph.umich.edu/csg/szoellner/ PMID- 20926419 TI - GeneMANIA Cytoscape plugin: fast gene function predictions on the desktop. AB - The GeneMANIA Cytoscape plugin brings fast gene function prediction capabilities to the desktop. GeneMANIA identifies the most related genes to a query gene set using a guilt-by-association approach. The plugin uses over 800 networks from six organisms and each related gene is traceable to the source network used to make the prediction. Users may add their own interaction networks and expression profile data to complement or override the default data. AVAILABILITY AND IMPLEMENTATION: The GeneMANIA Cytoscape plugin is implemented in Java and is freely available at http://www.genemania.org/plugin/. PMID- 20926420 TI - ALCHEMY: a reliable method for automated SNP genotype calling for small batch sizes and highly homozygous populations. AB - MOTIVATION: The development of new high-throughput genotyping products requires a significant investment in testing and training samples to evaluate and optimize the product before it can be used reliably on new samples. One reason for this is current methods for automated calling of genotypes are based on clustering approaches which require a large number of samples to be analyzed simultaneously, or an extensive training dataset to seed clusters. In systems where inbred samples are of primary interest, current clustering approaches perform poorly due to the inability to clearly identify a heterozygote cluster. RESULTS: As part of the development of two custom single nucleotide polymorphism genotyping products for Oryza sativa (domestic rice), we have developed a new genotype calling algorithm called 'ALCHEMY' based on statistical modeling of the raw intensity data rather than modelless clustering. A novel feature of the model is the ability to estimate and incorporate inbreeding information on a per sample basis allowing accurate genotyping of both inbred and heterozygous samples even when analyzed simultaneously. Since clustering is not used explicitly, ALCHEMY performs well on small sample sizes with accuracy exceeding 99% with as few as 18 samples. AVAILABILITY: ALCHEMY is available for both commercial and academic use free of charge and distributed under the GNU General Public License at http://alchemy.sourceforge.net/ CONTACT: mhw6@cornell.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 20926421 TI - MEDELLER: homology-based coordinate generation for membrane proteins. AB - MOTIVATION: Membrane proteins (MPs) are important drug targets but knowledge of their exact structure is limited to relatively few examples. Existing homology based structure prediction methods are designed for globular, water-soluble proteins. However, we are now beginning to have enough MP structures to justify the development of a homology-based approach specifically for them. RESULTS: We present a MP-specific homology-based coordinate generation method, MEDELLER, which is optimized to build highly reliable core models. The method outperforms the popular structure prediction programme Modeller on MPs. The comparison of the two methods was performed on 616 target-template pairs of MPs, which were classified into four test sets by their sequence identity. Across all targets, MEDELLER gave an average backbone root mean square deviation (RMSD) of 2.62 A versus 3.16 A for Modeller. On our 'easy' test set, MEDELLER achieves an average accuracy of 0.93 A backbone RMSD versus 1.56 A for Modeller. AVAILABILITY AND IMPLEMENTATION: http://medeller.info; Implemented in Python, Bash and Perl CGI for use on Linux systems; Supplementary data are available at http://www.stats.ox.ac.uk/proteins/resources. PMID- 20926422 TI - TURNIP: tracking unresolved nucleotide polymorphisms in large hard-to-assemble regions of repetitive DNA sequence. AB - TURNIP comprises a suite of Perl scripts and modules that facilitates the resolution of microheterogeneity within hard-to-assemble repetitive DNA sequences. TURNIP was originally developed for the Saccharomyces Genome Resequencing Project (SGRP) within which the ribosomal DNA (rDNA) of 36 strains of S.cerevisiae were analysed to investigate the occurrence of potential polymorphisms. Here, 'partially resolved SNPs', or pSNPs, as well as indels, were found to be far more prevalent than previously suspected. More generally, the TURNIP software ascertains degrees of variation between large tandem repeats within a single locus, offering insights into mechanisms of genome stability and gene conversion in any organism for which genome sequence data are available. AVAILABILITY: The TURNIP source code, results files and online help are available at http://www.ncyc.co.uk/software/turnip.html. PMID- 20926423 TI - GPCRRD: G protein-coupled receptor spatial restraint database for 3D structure modeling and function annotation. AB - SUMMARY: G protein-coupled receptors (GPCRs) comprise the largest family of integral membrane proteins. They are the most important class of drug targets. While there exist crystal structures for only a very few GPCR sequences, numerous experiments have been performed on GPCRs to identify the critical residues and motifs. GPCRRD database is designed to systematically collect all experimental restraints (including residue orientation, contact and distance maps) available from the literature and primary GPCR resources using an automated text mining algorithm combined with manual validation, with the purpose of assisting GPCR 3D structure modeling and function annotation. The current dataset contains thousands of spatial restraints from mutagenesis, disulfide mapping distances, electron cryo-microscopy and Fourier-transform infrared spectroscopy experiments. AVAILABILITY: http://zhanglab.ccmb.med.umich.edu/GPCRRD/ CONTACT: zhng@umich.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 20926424 TI - Robust relationship inference in genome-wide association studies. AB - MOTIVATION: Genome-wide association studies (GWASs) have been widely used to map loci contributing to variation in complex traits and risk of diseases in humans. Accurate specification of familial relationships is crucial for family-based GWAS, as well as in population-based GWAS with unknown (or unrecognized) family structure. The family structure in a GWAS should be routinely investigated using the SNP data prior to the analysis of population structure or phenotype. Existing algorithms for relationship inference have a major weakness of estimating allele frequencies at each SNP from the entire sample, under a strong assumption of homogeneous population structure. This assumption is often untenable. RESULTS: Here, we present a rapid algorithm for relationship inference using high throughput genotype data typical of GWAS that allows the presence of unknown population substructure. The relationship of any pair of individuals can be precisely inferred by robust estimation of their kinship coefficient, independent of sample composition or population structure (sample invariance). We present simulation experiments to demonstrate that the algorithm has sufficient power to provide reliable inference on millions of unrelated pairs and thousands of relative pairs (up to 3rd-degree relationships). Application of our robust algorithm to HapMap and GWAS datasets demonstrates that it performs properly even under extreme population stratification, while algorithms assuming a homogeneous population give systematically biased results. Our extremely efficient implementation performs relationship inference on millions of pairs of individuals in a matter of minutes, dozens of times faster than the most efficient existing algorithm known to us. AVAILABILITY: Our robust relationship inference algorithm is implemented in a freely available software package, KING, available for download at http://people.virginia.edu/~wc9c/KING. PMID- 20926425 TI - Community case management in Nicaragua: lessons in fostering adoption and expanding implementation. AB - Community case management (CCM) as applied to child survival is a strategy that enables trained community health workers or volunteers to assess, classify, treat and refer sick children who reside beyond the reach of fixed health facilities. The Nicaraguan Ministry of Health (MOH) and Save the Children trained and supported brigadistas (community health volunteers) in CCM to improve equitable access to treatment for pneumonia, diarrhoea and dysentery for children in remote areas. In this article, we examine the policy landscape and processes that influenced the adoption and implementation of CCM in Nicaragua. Contextual factors in the policy landscape that facilitated CCM included an international technical consensus supporting the strategy; the role of government in health care provision and commitment to reaching the poor; a history of community participation; the existence of community-based child survival strategies; the decentralization of implementation authority; internal MOH champions; and a credible catalyst organization. Challenges included scepticism about community level cadres; resistance from health personnel; operational gaps in treatment norms and materials to support the strategy; resource constraints affecting service delivery; tensions around decentralization; and changes in administration. In order to capitalize on the opportunities and overcome the challenges that characterized the policy landscape, stakeholders pursued various efforts to support CCM including sparking interest, framing issues, monitoring and communicating results, ensuring support and cohesion among health personnel, supporting local adaptation, assuring credibility and ownership, joint problem solving, addressing sustainability and fostering learning. While delineated as separate efforts, these policy and implementation processes were dynamic and interactive in nature, balancing various tensions. Our qualitative analysis highlights the importance of supporting routine monitoring and documentation of these strategic operational policy and management issues vital for CCM success. We also demonstrate that while challenges to CCM adoption and implementation exist, they are not insurmountable. PMID- 20926426 TI - Methylation profiling identifies 2 groups of gliomas according to their tumorigenesis. AB - Extensive genomic and gene expression studies have been performed in gliomas, but the epigenetic alterations that characterize different subtypes of gliomas remain largely unknown. Here, we analyzed the methylation patterns of 807 genes (1536 CpGs) in a series of 33 low-grade gliomas (LGGs), 36 glioblastomas (GBMs), 8 paired initial and recurrent gliomas, and 9 controls. This analysis was performed with Illumina's Golden Gate Bead methylation arrays and was correlated with clinical, histological, genomic, gene expression, and genotyping data, including IDH1 mutations. Unsupervised hierarchical clustering resulted in 2 groups of gliomas: a group corresponding to de novo GBMs and a group consisting of LGGs, recurrent anaplastic gliomas, and secondary GBMs. When compared with de novo GBMs and controls, this latter group was characterized by a very high frequency of IDH1 mutations and by a hypermethylated profile similar to the recently described glioma CpG island methylator phenotype. MGMT methylation was more frequent in this group. Among the LGG cluster, 1p19q codeleted LGG displayed a distinct methylation profile. A study of paired initial and recurrent gliomas demonstrated that methylation profiles were remarkably stable across glioma evolution, even during anaplastic transformation, suggesting that epigenetic alterations occur early during gliomagenesis. Using the Cancer Genome Atlas data set, we demonstrated that GBM samples that had an LGG-like hypermethylated profile had a high rate of IDH1 mutations and a better outcome. Finally, we identified several hypermethylated and downregulated genes that may be associated with LGG and GBM oncogenesis, LGG oncogenesis, 1p19q codeleted LGG oncogenesis, and GBM oncogenesis. PMID- 20926427 TI - Acute cardiac effects of neuregulin-1/ErbB signalling. PMID- 20926428 TI - Translation and commercialization of regenerative medicines. PMID- 20926429 TI - Alignment hierarchies: engineering architecture from the nanometre to the micrometre scale. AB - Natural tissues are built of metabolites, soluble proteins and solid extracellular matrix components (largely fibrils) together with cells. These are configured in highly organized hierarchies of structure across length scales from nanometre to millimetre, with alignments that are dominated by anisotropies in their fibrillar matrix. If we are to successfully engineer tissues, these hierarchies need to be mimicked with an understanding of the interaction between them. In particular, the movement of different elements of the tissue (e.g. molecules, cells and bulk fluids) is controlled by matrix structures at distinct scales. We present three novel systems to introduce alignment of collagen fibrils, cells and growth factor gradients within a three-dimensional collagen scaffold using fluid flow, embossing and layering of construct. Importantly, these can be seen as different parts of the same hierarchy of three-dimensional structure, as they are all formed into dense collagen gels. Fluid flow aligns collagen fibrils at the nanoscale, embossed topographical features provide alignment cues at the microscale and introducing layered configuration to three dimensional collagen scaffolds provides microscale- and mesoscale-aligned pathways for protein factor delivery as well as barriers to confine protein diffusion to specific spatial directions. These seemingly separate methods can be employed to increase complexity of simple extracellular matrix scaffolds, providing insight into new approaches to directly fabricate complex physical and chemical cues at different hierarchical scales, similar to those in natural tissues. PMID- 20926430 TI - Colourful parrot feathers resist bacterial degradation. AB - The brilliant red, orange and yellow colours of parrot feathers are the product of psittacofulvins, which are synthetic pigments known only from parrots. Recent evidence suggests that some pigments in bird feathers function not just as colour generators, but also preserve plumage integrity by increasing the resistance of feather keratin to bacterial degradation. We exposed a variety of colourful parrot feathers to feather-degrading Bacillus licheniformis and found that feathers with red psittacofulvins degraded at about the same rate as those with melanin and more slowly than white feathers, which lack pigments. Blue feathers, in which colour is based on the microstructural arrangement of keratin, air and melanin granules, and green feathers, which combine structural blue with yellow psittacofulvins, degraded at a rate similar to that of red and black feathers. These differences in resistance to bacterial degradation of differently coloured feathers suggest that colour patterns within the Psittaciformes may have evolved to resist bacterial degradation, in addition to their role in communication and camouflage. PMID- 20926431 TI - The cosmopolitan maternal heritage of the Thoroughbred racehorse breed shows a significant contribution from British and Irish native mares. AB - The paternal origins of Thoroughbred racehorses trace back to a handful of Middle Eastern stallions, imported to the British Isles during the seventeenth century. Yet, few details of the foundation mares were recorded, in many cases not even their names (several different maternal lineages trace back to 'A Royal Mare'). This has fuelled intense speculation over their origins. We examined mitochondrial DNA from 1929 horses to determine the origin of Thoroughbred foundation mares. There is no evidence to support exclusive Arab maternal origins as some historical records have suggested, or a significant importation of Oriental mares (the term used in historic records to refer to Middle East and western Asian breeds including Arab, Akhal-Teke, Barb and Caspian). Instead, we show that Thoroughbred foundation mares had a cosmopolitan European heritage with a far greater contribution from British and Irish Native mares than previously recognized. PMID- 20926432 TI - Self-organization of cellular structures induced by the overexpression of nuclear envelope proteins: a correlative light and electron microscopy study. AB - The mechanisms by which the supramolecular order is formed inside the cell nucleus remain poorly understood. So far, two major hypotheses - ordered assembly and stochastic self-organization - have been discussed. To determine which mechanism is responsible for the formation of nuclear envelope, cells overexpressing one of the nuclear envelope proteins (lamin A, lamin B1, pom121 or ndc1) were investigated. According to the ordered assembly model, the presence of an excessive amount of a component has no effect in the formation of the normal structure of a nuclear envelope because it is programmed and cannot be distorted. In contrast, according to the self-organization concept, there is no such strictly determined cellular structures, and an excessive amount of even one component will affect the cellular organization. In the present study, formation of a redundant nuclear envelope was observed in the case of lamin B1 and lamin A overexpression. In the case of the nucleoporins pom121 and ndc1, no incorporation of the overexpressed proteins into the nuclear envelope was observed on the first day after transfection; however, the remodeling of endoplasmic reticulum elements and the formation of membrane aggregates in the cytoplasm were observed. After mitosis, pom121 from the cytoplasmic aggregates was translocated into the redundant nuclear envelope in which it induced inner nuclear membrane protrusions. Therefore, our results indicate that the formation of the nuclear envelope is not predetermined and that an excessive amount of even one protein component can affect cellular structure formation. This study concluded that nuclear envelope formation is achieved by the self-organization mechanism. PMID- 20926435 TI - Footprints pull origin and diversification of dinosaur stem lineage deep into Early Triassic. AB - The ascent of dinosaurs in the Triassic is an exemplary evolutionary radiation, but the earliest phase of dinosaur history remains poorly understood. Body fossils of close dinosaur relatives are rare, but indicate that the dinosaur stem lineage (Dinosauromorpha) originated by the latest Anisian (ca 242-244 Ma). Here, we report footprints from the Early-Middle Triassic of Poland, stratigraphically well constrained and identified using a conservative synapomorphy-based approach, which shifts the origin of the dinosaur stem lineage back to the Early Olenekian (ca 249-251 Ma), approximately 5-9 Myr earlier than indicated by body fossils, earlier than demonstrated by previous footprint records, and just a few million years after the Permian/Triassic mass extinction (252.3 Ma). Dinosauromorph tracks are rare in all Polish assemblages, suggesting that these animals were minor faunal components. The oldest tracks are quadrupedal, a morphology uncommon among the earliest dinosauromorph body fossils, but bipedality and moderately large body size had arisen by the Early Anisian (ca 246 Ma). Integrating trace fossils and body fossils demonstrates that the rise of dinosaurs was a drawn-out affair, perhaps initiated during recovery from the Permo-Triassic extinction. PMID- 20926433 TI - Targeted deletion of endothelial lipase increases HDL particles with anti inflammatory properties both in vitro and in vivo. AB - Previous studies have shown that targeted deletion of endothelial lipase (EL) markedly increases the plasma high density lipoprotein cholesterol (HDL-C) level in mice. However, little is known about the functional quality of HDL particles after EL inhibition. Therefore, the present study assessed the functional quality of HDL isolated from EL(-/-) and wild-type (WT) mice. Anti-inflammatory functions of HDL from EL(-/-) and WT mice were evaluated by in vitro assays. The HDL functions such as PON-1 or PAF-AH activities, inhibition of cytokine-induced vascular cell adhesion molecule-1 expression, inhibition of LDL oxidation, and the ability of cholesterol efflux were similar in HDL isolated from WT and EL(-/ ) mice. In contrast, the lipopolysaccharide-neutralizing capacity of HDL was significantly higher in EL(-/-) mice than that in WT mice. To evaluate the anti inflammatory actions of HDL in vivo, lipopolysaccharide-induced systemic inflammation was generated in these mice. EL(-/-) mice showed higher survival rate and lower expression of inflammatory markers than WT mice. Intravenous administration of HDL isolated from EL(-/-) mice significantly improved the mortality after lipopolysaccharide injection in WT mice. In conclusion, targeted disruption of EL increased HDL particles with preserved anti-inflammatory and anti-atherosclerotic functions. Thus, EL inhibition would be a useful strategy to raise 'good' cholesterol in the plasma. PMID- 20926436 TI - Genetic diversity, parasite prevalence and immunity in wild bumblebees. AB - Inbreeding and a consequent loss of genetic diversity threaten small, isolated populations. One mechanism by which genetically impoverished populations may become extinct is through decreased immunocompetence and higher susceptibility to parasites. Here, we investigate the relationship between immunity and inbreeding in bumblebees, using Hebridean island populations of Bombus muscorum. We sampled nine populations and recorded parasite prevalence and measured two aspects of immunity: the encapsulation response and levels of phenoloxidase (PO). We found that prevalence of the gut parasite Crithidia bombi was higher in populations with lower genetic diversity. Neither measure of immune activity was correlated with genetic diversity. However, levels of PO declined with age and were also negatively correlated with parasite abundance. Our results suggest that as insect populations lose heterozygosity, the impact of parasitism will increase, pushing threatened populations closer to extinction. PMID- 20926437 TI - Experimental peripheral administration of oxytocin elevates a suite of cooperative behaviours in a wild social mammal. AB - The evolution and expression of different forms of cooperative behaviour (e.g. feeding, guarding, sentinel duties, etc.) are usually studied independently, with few studies considering them as a single syndrome. However, studies investigating individuals' investment across a suite of different behaviours reveal that they are correlated, suggesting a single mechanism determining the evolution and expression of cooperative behaviours. A hormonal mechanism could achieve this, and one possibility is oxytocin (OT), which affects several prosocial or alloparental behaviours independently. We show, using a double-blind experiment, that peripheral administration of OT to social, free-living meerkats Suricata suricatta elevates a suite of cooperative behaviours. Treated individuals increase their contributions to communal, cooperative activities (digging, guarding, pup-feeding and associating with pups) and decrease initiation of aggressive interactions, compared with a saline control. This suggests that different forms of cooperative behaviour form a single syndrome with a common causal basis. If our peripherally administered OT acts in the same way as the naturally released hormone, then a general tendency to prosociality may be modulated by this hormonal system. Therefore, it may be difficult for an individual to decouple expression of cooperative behaviours that provide the practitioner with benefits from those that provide the recipient with benefits. It may also explain why social species typically exhibit a suite of cooperative behaviours, without having to invoke independent evolution of each. PMID- 20926438 TI - Dispersal and diversity in the earliest North American sauropodomorph dinosaurs, with a description of a new taxon. AB - Sauropodomorph dinosaurs originated in the Southern Hemisphere in the Middle or Late Triassic and are commonly portrayed as spreading rapidly to all corners of Pangaea as part of a uniform Late Triassic to Early Jurassic cosmopolitan dinosaur fauna. Under this model, dispersal allegedly inhibited dinosaurian diversification, while vicariance and local extinction enhanced it. However, apomorphy-based analyses of the known fossil record indicate that sauropodomorphs were absent in North America until the Early Jurassic, reframing the temporal context of their arrival. We describe a new taxon from the Kayenta Formation of Arizona that comprises the third diagnosable sauropodomorph from the Early Jurassic of North America. We analysed its relationships to test whether sauropodomorphs reached North America in a single sweepstakes event or in separate dispersals. Our finding of separate arrivals by all three taxa suggests dispersal as a chief factor in dinosaurian diversification during at least the early Mesozoic. It questions whether a 'cosmopolitan' dinosaur fauna ever existed, and corroborates that vicariance, extinction and dispersal did not operate uniformly in time or under uniform conditions during the Mesozoic. Their relative importance is best measured in narrow time slices and circumscribed geographical regions. PMID- 20926439 TI - The influence of maternal effects on indirect benefits associated with polyandry. AB - Despite numerous and diverse theoretical models for the indirect benefits of polyandry, empirical support is mixed. One reason for the difficulty in detecting indirect benefits of polyandry may be that these are subtle and are mediated by environmental effects, such as maternal effects. Maternal effects may be especially important if females allocate resources to their offspring depending on the characteristics of their mating partners. We test this hypothesis in the burying beetle Nicrophorus vespilloides, a species that provides extensive and direct parental care to offspring. We used a fully factorial design and mated females to one, two, three, four or five different males and manipulated conditions so that their offspring received reduced (12 h) or full (ca 72 h) maternal care. We found that average offspring fitness increased with full maternal care but there was no significant effect of polyandry or the interaction between the duration of maternal care and the level of polyandry on offspring fitness. Thus, although polyandry could provide a mechanism for biasing paternity towards high quality or compatible males, and variation in parental care matters, we found no evidence that female N. vespilloides gain indirect benefits by using parental care to bias the allocation of resources under different mating conditions. PMID- 20926440 TI - Is oxidative stress a physiological cost of reproduction? An experimental test in house mice. AB - Investment in reproduction is costly and frequently decreases survival or future reproductive success. However, the proximate underlying causes for this are largely unknown. Oxidative stress has been suggested as a cost of reproduction and several studies have demonstrated changes in antioxidants with reproductive investment. Here, we test whether oxidative stress is a consequence of reproduction in female house mice (Mus musculus domesticus), which have extremely high energetic demands during reproduction, particularly through lactation. Assessing oxidative damage after a long period of reproductive investment, there was no evidence of increased oxidative stress, even when females were required to defend their breeding territory. Instead, in the liver, markers of oxidative damage (malonaldehyde, protein thiols and the proportion of glutathione in the oxidized form) indicated lower oxidative stress in reproducing females when compared with non-reproductive controls. Even during peak lactation, none of the markers of oxidative damage indicated higher oxidative stress than among non reproductive females, although a positive correlation between protein oxidation and litter mass suggested that oxidative stress may increase with fecundity. Our results indicate that changes in redox status occur during reproduction in house mice, but suggest that females use mechanisms to cope with the consequences of increased energetic demands and limit oxidative stress. PMID- 20926441 TI - Candidate genes versus genome-wide associations: which are better for detecting genetic susceptibility to infectious disease? AB - Technological developments allow increasing numbers of markers to be deployed in case-control studies searching for genetic factors that influence disease susceptibility. However, with vast numbers of markers, true 'hits' may become lost in a sea of false positives. This problem may be particularly acute for infectious diseases, where the control group may contain unexposed individuals with susceptible genotypes. To explore this effect, we used a series of stochastic simulations to model a scenario based loosely on bovine tuberculosis. We find that a candidate gene approach tends to have greater statistical power than studies that use large numbers of single nucleotide polymorphisms (SNPs) in genome-wide association tests, almost regardless of the number of SNPs deployed. Both approaches struggle to detect genetic effects when these are either weak or if an appreciable proportion of individuals are unexposed to the disease when modest sample sizes (250 each of cases and controls) are used, but these issues are largely mitigated if sample sizes can be increased to 2000 or more of each class. We conclude that the power of any genotype-phenotype association test will be improved if the sampling strategy takes account of exposure heterogeneity, though this is not necessarily easy to do. PMID- 20926442 TI - Convergent evolution of kin-based sociality in a lizard. AB - Studies of social birds and mammals have produced extensive theory regarding the formation and dynamics of kin-based social groups in vertebrates. However, comparing kin dynamics in birds and mammals to social reptiles provides the opportunity to identify selective factors that promote independent origins of kin sociality across vertebrates. We combined a 5-year mark-recapture study with a DNA microsatellite analysis of relatedness in a social lizard (Xantusia vigilis) to examine the formation and stability of kin groups. We found that these lizards are highly sedentary and that groups often form through the delayed dispersal of offspring. Groups containing juveniles had higher relatedness than adult-only groups, as juveniles were commonly found in aggregations with at least one parent and/or sibling. Groups containing nuclear family members were more stable than groups of less-related lizards, as predicted by social theory. We conclude that X. vigilis aggregations conform to patterns of kin sociality observed in avian and mammalian systems and represent an example of convergent evolution in social systems. We suggest that kin-based sociality in this and other lizards may be a by-product of viviparity, which can promote delayed juvenile dispersal by allowing prolonged interaction between a neonate and its mother. PMID- 20926443 TI - Sex allocation in haplodiploids is mediated by egg size: evidence in the spider mite Tetranychus urticae Koch. AB - Haplodiploid species display extraordinary sex ratios. However, a differential investment in male and female offspring might also be achieved by a differential provisioning of eggs, as observed in birds and lizards. We investigated this hypothesis in the haplodiploid spider mite Tetranychus urticae, which displays highly female-biased sex ratios. We show that egg size significantly determines not only larval size, juvenile survival and adult size, but also fertilization probability, as in marine invertebrates with external fertilization, so that female (fertilized) eggs are significantly larger than male (unfertilized) eggs. Moreover, females with on average larger eggs before fertilization produce a more female-biased sex ratio afterwards. Egg size thus mediates sex-specific egg provisioning, sex and offspring sex ratio. Finally, sex-specific egg provisioning has another major consequence: male eggs produced by mated mothers are smaller than male eggs produced by virgins, and this size difference persists in adults. Virgin females might thus have a (male) fitness advantage over mated females. PMID- 20926445 TI - Back to the future. PMID- 20926444 TI - Caste-specific visual adaptations to distinct daily activity schedules in Australian Myrmecia ants. AB - Animals are active at different times of the day and their activity schedules are shaped by competition, time-limited food resources and predators. Different temporal niches provide different light conditions, which affect the quality of visual information available to animals, in particular for navigation. We analysed caste-specific differences in compound eyes and ocelli in four congeneric sympatric species of Myrmecia ants, with emphasis on within-species adaptive flexibility and daily activity rhythms. Each caste has its own lifestyle: workers are exclusively pedestrian; alate females lead a brief life on the wing before becoming pedestrian; alate males lead a life exclusively on the wing. While workers of the four species range from diurnal, diurnal-crepuscular, crepuscular-nocturnal to nocturnal, the activity times of conspecific alates do not match in all cases. Even within a single species, we found eye area, facet numbers, facet sizes, rhabdom diameters and ocelli size to be tuned to the distinct temporal niche each caste occupies. We discuss these visual adaptations in relation to ambient light levels, visual tasks and mode of locomotion. PMID- 20926446 TI - The use of 'specials' in primary care. AB - Most drugs prescribed for patients as part of their NHS treatment are licensed medicinal products. However, there are rare occasions when a patient needs a formulation or strength that is not available as a licensed form, or needs to avoid ingredients that provoke allergy. To address such needs, many specially prepared products are produced by specialist manufacturing units. These so-called 'specials', unlike licensed medicines, are not assessed for safety or efficacy by a regulatory body.1 Prescribers are often unaware of the costs of specials. Here we explore some of the issues associated with specials in primary care and whether their use represents good value for money. PMID- 20926447 TI - OTC tamsulosin for benign prostatic hyperplasia. AB - Earlier this year, tamsulosin, an alpha blocker previously only available on prescription, became available for sale by pharmacists as a treatment for functional symptoms of benign prostatic hyperplasia (BPH) in men aged 45-75 years (Flomax Relief MR - Boehringer Ingelheim). A television advert for the over-the counter (OTC) product claims that it is a "simple and effective" treatment that can relieve symptoms within 1 week, allowing the user to "take control of your annoying pee problems".1 Here we review the evidence on tamsulosin and assess whether its availability as an OTC product confers worthwhile advantages. PMID- 20926448 TI - Do corticosteroids improve outcome in meningitis? AB - Despite significant advances in prevention of meningitis through vaccination, and in improved antimicrobial treatment, the disease still kills around 340,000 people worldwide each year.1 Around 75% of these deaths occur in Africa and South East Asia and around 3% in Europe.1 The mortality rate for bacterial meningitis is 10-30% and sequelae, such as cranial nerve impairment, particularly leading to hearing loss, occur in 5-40% of patients.2 Whether adjunctive corticosteroid treatment improves the outcome in bacterial meningitis through an anti inflammatory effect has been a long-standing controversy. Here we review the role of adjunctive corticosteroids in the management of children (aged over 1 month) and adults with bacterial or tuberculous meningitis. PMID- 20926450 TI - Naturally occurring germline and tumor-associated mutations within the ATP binding motifs of PTEN lead to oxidative damage of DNA associated with decreased nuclear p53. AB - Somatic and germline mutations in PTEN (phosphatase and tensin homolog deleted on chromosome 10) are found in sporadic cancers and Cowden syndrome patients, respectively. Recent identification of naturally occurring cancer and germline mutations within the ATP-binding motifs of PTEN (heretofore referred to as PTEN ATP-binding mutations) has revealed that these mutations disrupted the subcellular localization and tumor-suppressor activity of PTEN. However, very little is known about the underlying mechanisms of PTEN ATP-binding mutations in tumorigenesis. Here we show that these mutations impair PTEN's function both qualitatively and quantitatively. On the one hand, PTEN ATP-binding mutants lose their phosphatase activity and the effect of downregulation of cyclin D1. On the other, the mislocalized mutant PTEN results in a significantly decreased nuclear p53 protein level and transcriptional activity, enhanced production of reactive oxygen species, induction of Cu/Zn superoxide dismutase as well as dramatically increased DNA double-strand breaks (DSBs). When compared with wild-type PTEN, the ATP-binding mutant PTEN has reduced half-life in vitro and decreased protein expression levels in vivo. Our data, thus, reveal a novel mechanism of tumorigenesis in patients with germline or somatic mutations affecting PTEN ATP binding motifs, i.e. qualitative and quantitative impairment of PTEN due to the loss of its phosphatase activity, and nuclear mislocalization, resulting in rapid PTEN protein degradation, suppression of p53-mediated transcriptional activity, loss of protection against oxidative stress as well as accumulation of spontaneous DNA DSBs. PMID- 20926451 TI - The connexin26 S17F mouse mutant represents a model for the human hereditary keratitis-ichthyosis-deafness syndrome. AB - Mutations in the GJB2 gene coding for connexin26 (Cx26) can cause a variety of deafness and hereditary hyperproliferative skin disorders in humans. In this study, we investigated the Cx26S17F mutation in mice, which had been identified to cause the keratitis-ichthyosis-deafness (KID) syndrome in humans. The KID syndrome is characterized by keratitis and chronic progressive corneal neovascularization, skin hyperplasia, sensorineural hearing loss and increased carcinogenic potential. We have generated a conditional mouse mutant, in which the floxed wild-type Cx26-coding DNA can be deleted and the Cx26S17F mutation is expressed under control of the endogenous Cx26 promoter. Homozygous mutants are not viable, whereas the surviving heterozygous mice show hyperplasia of tail and foot epidermis, wounded tails and annular tail restrictions, and are smaller than their wild-type littermates. Analyses of auditory brainstem responses (ABRs) indicate an ~35 dB increased hearing threshold in these mice, which is likely due to the reduction of the endocochlear potential by 20-40%. Our results indicate that the Cx26S17F protein, which does not form functional gap junction channels or hemichannels, alters epidermal proliferation and differentiation in the heterozygous state. In the inner ear, reduced intercellular coupling by heteromeric channels composed of Cx26S17F and Cx30 could contribute to hearing impairment in heterozygous mice, while remaining wild-type Cx26 may be sufficient to stabilize Cx30 and partially maintain cochlear homeostasis. The phenotype of heterozygous mice resembles many of the symptoms of the human KID syndrome. Thus, these mice represent an appropriate model to further investigate the disease mechanism. PMID- 20926452 TI - The beta1 subunit of the Na,K-ATPase pump interacts with megalencephalic leucoencephalopathy with subcortical cysts protein 1 (MLC1) in brain astrocytes: new insights into MLC pathogenesis. AB - Megalencephalic leucoencephalopathy with subcortical cysts (MLC) is a rare congenital leucodystrophy caused by mutations in MLC1, a membrane protein of unknown function. MLC1 expression in astrocyte end-feet contacting blood vessels and meninges, along with brain swelling, fluid cysts and myelin vacuolation observed in MLC patients, suggests a possible role for MLC1 in the regulation of fluid and ion homeostasis and cellular volume changes. To identify MLC1 direct interactors and dissect the molecular pathways in which MLC1 is involved, we used NH2-MLC1 domain as a bait to screen a human brain library in a yeast two-hybrid assay. We identified the beta1 subunit of the Na,K-ATPase pump as one of the interacting clones and confirmed it by pull-downs, co-fractionation assays and immunofluorescence stainings in human and rat astrocytes in vitro and in brain tissue. By performing ouabain-affinity chromatography on astrocyte and brain extracts, we isolated MLC1 and the whole Na,K-ATPase enzyme in a multiprotein complex that included Kir4.1, syntrophin and dystrobrevin. Because Na,K-ATPase is involved in intracellular osmotic control and volume regulation, we investigated the effect of hypo-osmotic stress on MLC1/Na,K-ATPase relationship in astrocytes. We found that hypo-osmotic conditions increased MLC1 membrane expression and favoured MLC1/Na,K-ATPase-beta1 association. Moreover, hypo-osmosis induced astrocyte swelling and the reversible formation of endosome-derived vacuoles, where the two proteins co-localized. These data suggest that through its interaction with Na,K-ATPase, MLC1 is involved in the control of intracellular osmotic conditions and volume regulation in astrocytes, opening new perspectives for understanding the pathological mechanisms of MLC disease. PMID- 20926453 TI - The KRAB-containing zinc-finger transcriptional regulator ZBRK1 activates SCA2 gene transcription through direct interaction with its gene product, ataxin-2. AB - Gene transcription is controlled by transcriptional regulators acting with specific co-regulators to allow gene activation and repression. Here, we report the identification of the KRAB-containing zinc-finger transcriptional regulator, ZBRK1, as an interaction partner of the SCA2 gene product ataxin-2. Furthermore, we discovered that an elevated ZBRK1 level resulted in increased ataxin-2 levels, whereas interference on transcriptional and protein levels of ZBRK1 yielded reduced ataxin-2 levels, suggesting that a complex comprising ZBRK1 and ataxin-2 regulates SCA2 gene transcription. A bioinformatic analysis utilizing the known ZBRK1 consensus DNA-binding motif revealed ZBRK1-binding sites in the SCA2 promoter. These predicted sites were experimentally validated by chromatin immunoprecipitation experiments along with luciferase-based promoter analyses corroborating that SCA2 gene transcription is controlled by a ZBRK1/ataxin-2 complex. Finally, we demonstrate that SCA2 gene transcription is significantly reduced in colon tumors possessing low ZBRK1 transcripts. Thus, our results provide first evidence that ataxin-2 acts as a co-regulator of ZBRK1 activating its own transcription, thereby representing the first identified ZBRK1 co activator. PMID- 20926454 TI - Toxic encephalopathy in elderly patients during treatment with capecitabine: literature review and a case report. AB - Capecitabine is now-a-days rapidly replacing 5-Fluorouracil in daily clinical practice. Neurologic toxicity during a treatment with fluoropyrimidines, as 5 fluorouracil, represents a well-known side-effect, largely described in literature. Central nervous system (CNS) toxicity, mainly encephalopathy with or without seizures, occurs occasionally even when conventional doses are used. CNS toxicity incidence increases markedly when the blood-brain barrier is either overwhelmed or bypassed (Hildebrand J. Neurological complications of cancer chemotherapy. Curr Opin Oncol 2006; 18: 321-324). Peripheral nervous system (PNS) toxicity is more common because proximal and distal extremities of the peripheral nerves are not protected by a blood-brain like barrier and peripheral neuropathy remains a major limiting factor for the administration of conventional doses of several agents (Saif W, Wood TE, McGee PJ and Diasio RB. Peripheral neuropathy associated with capecitabine, Anticancer Drugs 2004;15: 767-771). Capecitabine is a prodrug of 5-fluorouracil, more easily administered by mouth; its transformation in 5-fluorouracil is performed in the liver. There are only a few reports on the toxic neurological side-effects of capecitabine. We describe in our report a rare case of toxic encephalopathy in a 82-year-old female, with a brief review of literature. In the literature reviewed, we found 12 neurologic episodes due to capecitabine lasting between a few days till some months. All clinical symptoms of the cases described in literature, obtained a complete regression with the discontinuation of capecitabine. A relation was not found with dihydropyrimidine dehydrogenase (DPD) mutation, also if pharmacologic and pharmacogenetic assessment should be done for this drug, especially in old patients. Toxic encephalopathy represents a rare event during capecitabine treatment and on the bases of the data found, is fairly managed in the clinical setting. The knowledge of the natural history of the toxic effect allows the use of the drug also in old patients. PMID- 20926455 TI - Stability of unused reconstituted bortezomib in original manufacturer vials. AB - BACKGROUND. Bortezomib is a modified dipeptidyl boronic acid analogue used to treat multiple myeloma, mantle cell lymphoma, and, more recently, renal transplantation graft rejection. As per manufacturer recommendations, bortezomib is to be administered within 8 h of preparation or may be stored for up to 8 h in the vial or a syringe following reconstitution. Preserving unused reconstituted bortezomib beyond these 8 h may allow for cost savings. This study aims to examine the stability of unused reconstituted bortezomib when stored at 4 degrees C for up to 15 days. METHODS: Using an LC-MS/MS assay, the concentration of reconstituted bortezomib was measured at predetermined time points following storage at 4 degrees C in the manufacturer vial. Percent bortezomib remaining at a time point was calculated versus initial bortezomib concentration. RESULTS: The concentrations of bortezomib were found to be 51.93 ng/mL+/-4.60 after 1 day of storage, 57.40 ng/mL+/-4.77 after 8 days of storage, and 49.43 ng/mL+/-2.85 after 15 days of storage. The percent of bortezomib remaining was 110.53% and 95.19% after 8 days and 15 days, respectively. CONCLUSION: Unused reconstituted bortezomib is stable for up to 15 days stored at 4 degrees C in the original manufacturer vial. Such use of bortezomib may improve cost efficiency by reducing bortezomib waste. PMID- 20926456 TI - Explaining autism: Ten reasons to focus on the developing self. AB - My aim in this paper is to present reasons for adopting a focus on the development of self/other-awareness when characterizing the developmental psychopathology of autism. The strengths of such a position include an emphasis on children's emotional relations with embodied persons as foundational for their growing understanding of minds. I give special attention to the process of identifying with the attitudes of others, and experience of other-person-centred emotions, for the development of communication and thinking. The study of limitations in these aspects of self-other relatedness among individuals with autism is pivotal for understanding the pathogenesis of the syndrome. PMID- 20926458 TI - Theory of own mind in autism: Evidence of a specific deficit in self-awareness? AB - Assuming that self-awareness is not a unitary phenomenon, and that one can be aware of different aspects of self at any one time, it follows that selective impairments in self-awareness can occur. This article explores the idea that autism involves a particular deficit in awareness of the 'psychological self', or 'theory of own mind'. This hypothesised deficit renders individuals with autism spectrum disorder (ASD) at least as impaired at recognising their own mental states as at recognising mental states in other people. This deficit, it is argued, stands in contrast to an apparently typical awareness of the 'physical self' amongst people with autism. Theoretical implications of the empirical evidence are discussed. PMID- 20926457 TI - Self-referenced processing, neurodevelopment and joint attention in autism. AB - This article describes a parallel and distributed processing model (PDPM) of joint attention, self-referenced processing and autism. According to this model, autism involves early impairments in the capacity for rapid, integrated processing of self-referenced (proprioceptive and interoceptive) and other referenced (exteroceptive) information. Measures of joint attention have proven useful in research on autism because they are sensitive to the early development of the 'parallel' and integrated processing of self- and other-referenced stimuli. Moreover, joint attention behaviors are a consequence, but also an organizer of the functional development of a distal distributed cortical system involving anterior networks including the prefrontal and insula cortices, as well as posterior neural networks including the temporal and parietal cortices. Measures of joint attention provide early behavioral indicators of atypical development in this parallel and distributed processing system in autism. In addition it is proposed that an early, chronic disturbance in the capacity for integrating self- and other-referenced information may have cascading effects on the development of self awareness in autism. The assumptions, empirical support and future research implications of this model are discussed. PMID- 20926459 TI - Delayed video self-recognition in children with high functioning autism and Asperger's disorder. AB - Two studies are reported which investigate delayed video self-recognition (DSR) in children with autistic disorder and Asperger's disorder relative to one another and to their typically developing peers. A secondary aim was to establish whether DSR ability is dependent on metarepresentational ability. Children's verbal and affective responses to their image were also measured. Three groups of male children between 5 and 9 years, comprising 15 with high-functioning autistic disorder (HFA), 12 with Asperger's disorder (AspD), and 15 typically developing (TD) children, participated in Study 1. Study 2 included two groups of younger children (18 HFA; 18 TD) aged 4 to 7 years. Participant groups in each study were equally able to recognize themselves using delayed video feedback, and responded to their marked image with positive affect. This was so even amongst children with HFA who were impaired in their performance on false belief tasks, casting doubt on a metarepresentational basis of DSR. PMID- 20926460 TI - Poor awareness of symptoms of oesophageal cancer. AB - Oesophageal cancer presents as advanced disease; in the majority of patients the symptoms are present for many months prior to diagnosis. Dysphagia has been described as the key to an early diagnosis of oesophageal cancer. This study aims to assess the public perception of the importance of this symptom. Ninety-six patients completed a questionnaire. This evaluated patient understanding of symptoms of dysphagia compared to the finding of a breast lump, haemoptysis, chest pain and loss of weight concerning urgency, probable cause of symptoms and treatment required. Sixty-five patients (71%) would visit their GP within 24 h of finding a breast lump or suffering from haemoptysis (82%) or having chest pain (82%). Forty-seven patients (51%) who experienced dysphagia would seek medical advice after one week and further 18 (19%) after one month (P<0.0001). Only eight patients (10%) associated dysphagia with cancer compared to 53 patients (57%) with the finding of a breast lump (P<0.031). This study concludes that there is poor understanding of the main symptoms of oesophageal cancer. New health campaigns are needed if the cancer is to be detected at an earlier and potentially curable stage. PMID- 20926461 TI - Feasibility of cell transplantation with a left ventricular assist device to improve the success rate of left ventricular assist device removal: the first experiment. AB - Left ventricular assist devices (LVADs) greatly support heart recovery, but recurrent heart failure after LVAD removal limits their use as 'a bridge to recovery'. The combination of LVADs and cell transplantation (CTx) is expected to be effective to improve the success rate of LVAD removal. We investigated the feasibility of combined CTx therapy and LVAD support with a new heterotopic rat heart-lung transplantation model that could simulate LVAD support and LVAD removal. The heart and both lungs of a rat were heterotopically transplanted, and the heart was kept unloaded for two weeks. The heart was then reloaded for two weeks (LVAD group). Syngenic smooth muscle cells were transplanted into the hearts that had been unloaded for a week, and the hearts were kept unloaded for another week and then reloaded (CT-LVAD group). In the unloaded state, CTx could reduce the left ventricle (LV) volume more effectively than LVAD therapy alone (P<0.01) and maintain the LV volume even after the hearts were reloaded (P<0.01). The results suggest that CTx with LVAD support can prevent recurrent LV dilation after LVAD removal and improve the success rate of LVAD removal. PMID- 20926462 TI - Chest tube management following pulmonary lobectomy: change of protocol results in fewer air leaks. AB - Much controversy exists regarding the management of chest tubes following pulmonary lobectomy. The objective of this study was to analyse the effect of a new chest tube management protocol on clinical features, such as postoperative air leak, drain characteristics, 30-day postoperative complications and length of hospital stay. We retrospectively analysed 133 patients who underwent pulmonary lobectomy, from January 2005 to December 2008. A new chest tube protocol was introduced on 1 January 2007 and included placement of a single chest tube and early conversion to water seal. The chest tube was removed when air leak had resolved and (non-chylous) fluid drainage was <400 ml/day. The results of patients in the old (n=68) and the new protocol (n=65) were compared. In the new protocol group the median duration of air leak and duration of chest tube drainage declined significantly. Also the length of hospital stay decreased significantly to a median of eight days. The number of reinterventions and 30-day morbidity and mortality rates did not differ significantly. Our data suggest that placement of a single chest tube and early conversion to water seal decreases the duration of air leak and chest tube drainage and length of hospital stay. PMID- 20926463 TI - Analytical characteristics of the Roche highly sensitive troponin T assay and its application to a cardio-healthy population. AB - BACKGROUND: It is desirable that current assays for cardiac troponin (cTn) are able to meet the recommended criterion that the diagnosis and risk assessment of patients present with symptoms of myocardial infarction requires a rise and fall in cTn with at least one point above the 99th percentile of a reference population. We have evaluated the analytical characteristics of the new highly sensitive troponin T (hs-TnT) assay to see if it meets this criterion and applied it to a carefully defined, cardio-healthy Australian reference population. METHODS: An imprecision profile was determined for the Roche hs-TnT assay (Roche Diagnostics, Sydney, Australia) using multiple samples analysed on nine separate occasions. The distribution of troponin T was determined using 104 samples from a cardio-healthy population. RESULTS: The new hs-TnT assay meets the specifications of a coefficient of variation of 10% at the 99th percentile of our cardio-healthy reference population. Of the 104 samples analysed 44 showed troponin T concentrations above the manufacturer's quoted limit of detection. Age and gender differences in the median and 99th percentile troponin T concentration were observed. CONCLUSIONS: The new hs-TnT assay shows improved precision and sensitivity at very low troponin concentration. We have shown that a significant number of individuals in this cardio-healthy population had detectable circulating troponin concentration. With many apparently healthy people having detectable troponin, clinical judgement will become more important in interpreting troponin results. PMID- 20926464 TI - Spironolactone interference in the immunoassay of androstenedione. AB - BACKGROUND: In an evaluation of androstenedione results from patient serum samples using the Siemens Immulite 2500 analyser and manual Coat-A-Count (CAC) methods, three outliers were evident with grossly elevated results in the CAC assay. METHODS: The clinic notes of three patients with apparently high serum androstenedione concentrations by the CAC assay were checked for medications. The samples were all from patients with polycystic ovary syndrome taking 100-200 mg/d of a steroidal antiandrogen (spironolactone). Two other patients on 50 mg spironolactone per day had less markedly higher androstendione results with the CAC assay. In a further five patients who were selected since they were on spironolactone and had high androstenedione results by the CAC method, spironolactone was temporarily withdrawn and fresh blood samples obtained for analysis. RESULTS: Spironolactone treatment was associated with higher androstenedione concentrations measured by the CAC assay that reverted to normal on treatment withdrawal. Based on a single test with spironolactone at 1000 ng/mL, the manufacturer reported only 0.109% interference in the CAC assay. CONCLUSIONS: Spironolactone (and/or its metabolites) may interfere in the Siemens CAC assay for androstenedione but not in the Immulite 2500 assay. This experience highlights the need for information from clinicians on drug treatment when laboratory investigations are requested. Drug interferences in immunoassay are common and need evaluation beyond tests performed to certify laboratory reagents. PMID- 20926465 TI - Commutability of National Institute of Standards and Technology standard reference material 1955 homocysteine and folate in frozen human serum for total folate with automated assays. AB - BACKGROUND: The aim of the present study was to evaluate standard reference material (SRM) 1955 commutability as a reference material for serum folate using automated methods. We also designed so as to reduce the intermethod variability present in different automated methods. METHODS: Using a microbiological assay related to the 'information value' of SRM 1955 as a comparison method, we investigated the possibility of standardization for the assay values of serum folate as measured by the automated methods (Access, Centaur and Elecsys). In the assay of 50 patient sera by these automated methods, we corrected observed values by the SRM 1955 and compared with comparison values. RESULTS: The observed values of SRM 1955 Levels I, II and III were within or outside (but near) a 95% prediction interval obtained from patient sera by the automated methods. The normalized residuals obtained from SRM 1955 were within +/-3.0 (in SD units), which enabled us to conclude that the SRM 1955 had a physicochemical characterization similar to native serum. Twelve patients were assessed as hypofolataemia (<6.0 ng/mL) and 38 patients as normal (>=6.0 ng/mL). Before correction, folate levels in six of 12 patients were lower than 6.0 ng/mL, and those in seven of 38 patients were higher than 6.0 ng/mL with the automated methods. After correction, low levels were found in four of 12 patients, and normal levels were found in 33 of 38 patients. CONCLUSIONS: The use of SRM 1955 would help to reduce the intermethod variability present in different automated methods for serum folate measurement. PMID- 20926466 TI - Hyperprolactinaemia and mental illness. PMID- 20926467 TI - Clinical biochemistry of hyperthermia. AB - Heatstroke is the most severe form of heat-related disorders that include mild heat intolerance, heat exhaustion and heat stress. The incidence of heat-related disorders is increasing due to several factors that include climate change, co morbidities and drug usage. Patients with heatstroke present with a core body temperature above 40 degrees C, multiorgan dysfunction and central nervous system disorder. The pathogenesis of heatstroke is not fully understood; however, heat shock proteins, inflammatory cytokines and their modulators have been implicated. The clinical biochemistry laboratory plays an important role in the management of patients with heatstroke. Biochemical findings in patients with heatstroke include elevated urea, creatinine, cardiac and skeletal muscle enzymes, myoglobin and troponin. There is also biochemical evidence of metabolic acidosis, respiratory alkalosis, hepatic injury with elevated enzyme levels as well as abnormal hematological and coagulation indices. This review article aims at increasing awareness of the biochemical changes seen in patients with heatstroke and their possible role in prognosis and in elucidating the pathogenesis of heatstroke. PMID- 20926468 TI - Calculation of the 99th percentile upper reference limit and clinical decision concentration of the Abbott STAT TnI assay. PMID- 20926469 TI - Acute pancreatitis. AB - Acute pancreatitis (AP) is an important cause of morbidity and mortality worldwide and the annual incidence appears to be increasing. It presents as a mild self-limiting illness in 80% of patients. However, one-fifth of these develop a severe complicated life-threatening disease requiring intensive and prolonged therapeutic intervention. Alcohol and gallstone disease remain the commonest causes of AP but metabolic abnormalities, obesity and genetic susceptibility are thought be increasingly important aetiological factors. The prompt diagnosis of AP and stratification of disease severity is essential in directing rapid delivery of appropriate therapeutic measures. In this review, the range of diagnostic and prognostic assays, severity scoring systems and radiological investigations used in current clinical practice are described, highlighting their strengths and weaknesses. Increased understanding of the complex pathophysiology of AP has generated an array of new potential diagnostic assays and these are discussed. The multidisciplinary approach to management of severe pancreatitis is outlined, including areas of controversy and novel treatments. PMID- 20926470 TI - An audit of management of patients with borderline increased plasma-free metanephrines. AB - BACKGROUND: Measurement of plasma-free metanephrine plus normetanephrine (PFM) is the best screening test for phaeochromocytoma. While clearly raised levels are diagnostic, borderline increases may be associated with factors such as stress and medications, and should prompt a repeat study after interfering factors are withdrawn. METHODS: PFM results reported by a teaching hospital laboratory over a 12-month period were extracted from the laboratory information system. All borderline raised results were examined for a subsequent repeat test (as recommended by attached interpretative comment) and those not repeated were followed up by examination of case-notes or questionnaires to doctors. RESULTS: Of 111 patients with borderline increased PFM which did not normalize on repeat measurement, 33 were from the hospital and 78 from outside locations. Hospital notes for 27 out of 33 hospital-patients (82%) could be reviewed, and 49 completed questionnaires (63% of 78 sent out) were received from outside locations. Of these 76 patients thus followed up, the test was not repeated in 55 (72%) cases with borderline increased PFM. Of 10 patients with an adrenal mass and borderline PFM, only three had PFM repeated. Of another nine patients with undetermined final diagnosis and borderline PFM, only three had the test repeated. CONCLUSION: Seventy-two per cent of borderline increased PFM results were not followed up with appropriate repeat testing, potentially leading to missed detection of phaeochromocytoma. A stronger interpretative comment may encourage appropriate repeat testing in more cases with borderline increased PFM and suspected phaeochromocytoma. PMID- 20926471 TI - Serum aspirin esterase activity is lower in end-stage renal disease patients than in healthy control subjects and increases after haemodialysis. AB - BACKGROUND: Studies regarding aspirin metabolism can be important in patients with renal failure who have an increased risk of cardiovascular diseases. We undertook this study to assess the aspirin esterase (AE) status in end-stage renal disease (ESRD) patients. METHODS: A total of 42 patients on long-term haemodialysis (HD) with a mean dialysis course of 6.1 y were recruited. RESULTS: Serum AE levels were 44% lower and cholinesterase (ChE) levels were 22% lower in ESRD patients before dialysis as compared with control subjects (P = 0.0001). A very strong correlation was found between AE and ChE levels. AE levels increased on average 28% after dialysis with adjustments for age, gender, total cholesterol, triglyceride and high-density lipoprotein cholesterol (P = 0.002). In addition, ChE levels were significantly increased (48%) after dialysis (P = 0.0001). Changes in AE activity were significantly and positively correlated with those of ChE (r = 0.427, P = 0.005). When we adjusted for several confounders, we found that the changes in AE activity operated by dialysis are significant independently of age, gender, aspirin (ASA) intake, cholesterol, triglycerides, high-density lipoprotein cholesterol and ChE. CONCLUSIONS: We report that serum AE activity is significantly lower in ESRD and that treatment by HD results in an increase of activity. We confirm that AE is associated with lipid parameters and ChE. Our results show variations in ASA catabolism between the dialysis sessions, suggesting an oscillating pattern in ASA disposal in these patients. The mechanisms for reduced AE activity in uraemia and the effects of HD need further investigation. PMID- 20926472 TI - Analysis of serum bile acids by isotope dilution-mass spectrometry to assess the performance of routine total bile acid methods. AB - BACKGROUND: WEQAS, one of the largest EQA (External Quality Assessment) providers in the UK, offers a bile acid EQA scheme, with linear serum pools containing cholic acid, deoxycholic acid and chenodeoxycholic acid, reflecting levels observed in obstructive cholestasis. Total bile acids are currently measured routinely by non-specific enzymatic methods. Traceability of results to the SI unit utilizing reference target values is the preferred method of comparison of returned results where available, ensuring the transfer of accuracy from definitive methods to routine methods. METHODS: Target values have been assigned to EQA material utilizing isotope dilution gas chromatography mass spectrometry (ID-GCMS). The methodology was based on published routine methods and adapted for use as a ID-GCMS target method. The total bile acid target value was reported as the sum of the three major bile acids measured: cholic acid, deoxycholic acid and chenodeoxycholic acid. RESULTS: The produced target values have been used to assess the performance of total bile acid methods. A degree of variability was observed between the third-generation enzyme-formazan methods and the fifth generation thio-NADH methods. Additionally, the Sentinel results showed a positive bias in comparison to their peer formazan method group. CONCLUSION: The use of ID-GCMS target results provides a common comparison for resumed results in EQA schemes, highlighting any method differences. Thus can then aid in the harmonisation of results observed for each of the different methods. PMID- 20926473 TI - Serum fetuin A/alpha2HS-glycoprotein levels in patients with non-alcoholic fatty liver disease: relation with liver fibrosis. AB - BACKGROUND: Serum concentrations of fetuin A/alpha2HS-glycoprotein (AHSG) have been linked to human metabolic alterations and can serve as an indicator of liver cell function. We assayed serum levels of AHSG in patients with non-alcoholic fatty liver disease (NAFLD), a hepatic manifestation of the metabolic syndrome, and examined their association with clinical, biochemical and histological phenotypes. METHODS: Serum AHSG levels were determined by enzyme linked immunosorbent assay in 99 patients with biopsy-proven NAFLD and 75 age- and gender-matched controls. RESULTS: Serum AHSG levels were significantly higher in patients with NAFLD (940 +/- 120 MUg/mL) compared with healthy controls (800 +/- 130 MUg/mL, Student's t test, P < 0.001). Bivariate analyses (Spearman's rank correlation) in patients with NAFLD showed a statistically significant association between AHSG levels and insulin resistance as assessed by the HOMA (homeostasis model assessment) index (r = 0.31, P < 0.01) and the liver fibrosis score index (r = 0.36, P < 0.001). The association between AHSG and fibrosis remained statistically significant even after adjustment for potential confounders, including the HOMA index ([beta] = 1.65, t = 2.38, P < 0.05). CONCLUSION: Serum AHSG levels are significantly increased in adult patients with biopsy-proven NAFLD and are associated with insulin resistance. Importantly, our pilot data indicate that serum AHSG levels may identify NAFLD patients with higher fibrosis scores. PMID- 20926474 TI - Cortisol measurement in patients receiving metyrapone therapy. AB - Current guidance recommends titrating the dose of metyrapone against serum cortisol concentration, in patients under medical management of Cushing's syndrome. In the UK, this almost always involves measuring serum cortisol concentration by immunoassay, the performance of which is questionable in the presence of altered steroid metabolism. Sera from two patients receiving metyrapone were analysed using a liquid chromatography tandem mass spectrometry (MS) steroid assay to identify which steroids, if any, were elevated in these patients. In addition, control serum was spiked with a series of steroids to identify any potential positive interferences in a cortisol immunoassay. Serum 11 deoxycortisol concentration was elevated in both of the patients studied. One patient also had an elevated serum 17-hydroxyprogesterone concentration and the other an elevated androstenedione. In addition, the results of the interference studies indicated that the cortisol immunoassay was susceptible to interference from 11-deoxycortisol, 17-hydroxyprogesterone and 21-deoxycortisol. However, the magnitude of interference, in the serum cortisol immunoassay, due to these three steroids could not account for the discrepancy between the cortisol concentrations measured by immunoassay and those measured by MS. Both clinicians and laboratory staff should be aware of these interferences when monitoring patients undergoing treatment with metyrapone, and consequently serum should be measured in these patients by MS, not by immunoassay. PMID- 20926475 TI - Patients with mild Alzheimer's disease should have access to drugs, says draft NICE guidance. PMID- 20926476 TI - Recombinant factor VIIa reduces bleeding after blunt liver injury in coagulopathic, hypofibrinogenaemic pigs. AB - BACKGROUND: Recombinant factor VIIa (rFVIIa) has been successfully used in various clinical conditions to treat severe coagulopathy, but its efficacy may be affected by the underlying conditions. We therefore investigated the efficacy of rFVIIa treatment under conditions of hypofibrinogenaemia in a pig model of blunt liver injury. METHODS: Severe haemodilution was instigated in four groups of seven anaesthetized pigs. Before inflicting liver injury, animals were assigned to receive either 70 mg kg(-1) fibrinogen (fibrinogen group) or placebo (control group). Thirty seconds after injury, rFVIIa (180 ug kg(-1)) (rFVIIa and fibrinogen+rFVIIa groups) or vehicle (control and fibrinogen groups) was administered. Haemodynamic variables, coagulation parameters, and blood loss were monitored for 2 h. Histology was examined to evaluate the presence of thrombi and the consistency of liver injury. RESULTS: At the end of the observation period, total blood loss [median (range)] decreased in all intervention groups [fibrinogen: 1275 (1221-1439) ml, P=0.036; rFVIIa: 966 (923-1136) ml, P=0.008; fibrinogen+rFVIIa: 678 (475-756) ml, P=0.008] when compared with control animals [blood loss: 1752 (1735-2221) ml]. The mortality rate in the control group was 100%, whereas only 42% of fibrinogen-substituted animals died (P=0.023). All animals treated with rFVIIa or fibrinogen+rFVIIa (P<0.001) survived and no signs of thromboembolism were observed. CONCLUSIONS: rFVIIa under conditions of hypofibrinogenaemia exhibited a positive impact on coagulation parameters and a reduction in blood loss. These effects were significantly improved after prior substitution with fibrinogen. PMID- 20926477 TI - Safety implications of the Boyle-Davis mouth gag and tracheal tube position in tonsillectomy. AB - BACKGROUND: The risk of death after tonsillectomy is extremely small, and is mostly caused by the direct or indirect effects of haemorrhage or anaesthetic complications. These complications include aspiration, accidental dislodgement of the tracheal tube (TT), and pneumothorax or pneumomediastinum. The Boyle-Davis mouth gag (BDG) is a device used to visualize the oropharynx and stabilize the TT during tonsillectomy. We postulate that a deployed BDG may influence the position of the TT, and potentially result in silent aspiration, accidental extubation, and unilateral pulmonary ventilation. This has not, to our knowledge, been evaluated before. The aim of this prospective, pilot study was to evaluate the displacement of the TT upon opening and closing the BDG, in an objective manner. METHODS: Patients undergoing tonsillectomy with/without adenoidectomy at a regional department underwent flexible bronchoscopy to evaluate the changes in position of the TT tip with the BDG in an open and closed position, relative to the position of the carina. RESULTS: Twenty-three patients were enrolled into the study. Deploying the BDG resulted in TT displacement in 96% of patients. The mean displacement was 9.5 mm (range -10 to +27 mm). CONCLUSIONS: We believe that this study raises concerns not previously highlighted, on how manipulating a BDG may influence the TT position. It may serve to explain additional mechanisms of potentially fatal anaesthetic complications such as TT dislodgement, unilateral ventilation, and pneumothorax, particularly in paediatric patients, after tonsillectomy. PMID- 20926478 TI - Differential impacts of modes of anaesthesia on the risk of stroke among preeclamptic women who undergo Caesarean delivery: a population-based study. AB - BACKGROUND: This study compared the stroke-free survival rates and hazard ratios (HRs) for stroke between preeclamptic women who received general anaesthesia and those who received neuraxial anaesthesia for Caesarean section (CS). METHODS: This study used 2002-7 data from the Taiwan National Health Insurance Research Database. The stroke-free survival rate was estimated by the Kaplan-Meier method. The log-rank test was used to examine the difference in the stroke-free survival rates between general, spinal, and epidural anaesthesia. The Cox proportional hazard regression was used to estimate the HR for general anaesthesia. RESULTS: A total of 303 862 women underwent CS of which 8567 had preeclampsia (75 stroke cases) and 295 295 did not (303 stroke cases). The stroke-free survival rate was significantly lower in the preeclamptic women who received general anaesthesia when compared with those who received epidural (P=0.008) or spinal anaesthesia (P<0.001) within the 6 yr period after the index delivery. There was no statistically significant difference between spinal and epidural anaesthesia in terms of stroke rate (P=0.143). The unadjusted HR of stroke for general anaesthesia was 2.81 [95% confidence interval (CI), 1.69-4.64; P<0.001]. After adjusting for potential confounders, the adjusted HR for general anaesthesia was 2.38 (95% CI, 1.33-4.28; P=0.004) compared with neuraxial anaesthesia over a 1-6 yr follow-up period. CONCLUSIONS: In this study, general anaesthesia for CS delivery was associated with increased risk of stroke when compared with neuraxial anaesthesia in preeclamptic women. PMID- 20926480 TI - Hungry for profit. PMID- 20926479 TI - Pharmacokinetics and pharmacodynamics of the short-acting sedative CNS 7056 in sheep. AB - BACKGROUND: CNS 7056 is a new short-acting esterase-metabolized benzodiazepine. We report the first pharmacokinetic (PK) and pharmacodynamic (PD) study of CNS 7056 and its inactive metabolite CNS 7054 in sheep. METHODS: The stability of CNS 7056 in blood samples was examined ex vivo. Six sheep were prepared with physiological instrumentation, and were given doses of 0.37, 0.74, and 1.47 mg kg(-1) (2 min infusion) of CNS 7056 in alternating order on separate days. RESULTS: CNS 7056 was degraded in warm whole sheep blood (23% over 2 h), but not in plasma or blood stored on ice. Using non-compartmental analysis (NCA), CNS 7056 had a mean (sd) clearance of 4.52 (0.96) litre min(-1) and a terminal half life of 21.3 (10.9) min. There was a rapid conversion of CNS 7056 to its metabolite CNS 7054, which had a terminal half-life of 22.5 (3.4) min. The arterial kinetics of CNS 7056 could be described by a three-compartment model, with volumes of 1.9, 3.9, and 79 litre, a clearance of 4.2 litre min(-1), and inter-compartmental clearances of 2.85 and 1.44 litre min(-1), while the metabolite could be described by a two-compartment model. Cardiac output was an important covariate. Sedation as measured by the alpha power band of the EEG showed rapid onset and offset. The t(1/2,)(k)(e0) for sedation was 1.78 min, and the EC(50) was 0.10 ug ml(-1). CONCLUSIONS: CNS 7056 has PK-PD properties compatible with its potential human use as a short-acting i.v. sedative. PMID- 20926481 TI - Climate Change. Giving it 10%. PMID- 20926483 TI - Rosiglitazone and the need for a new drug safety agency. PMID- 20926486 TI - Depressed about depression. PMID- 20926487 TI - Confusion and delays beset WHO's management of H1N1 pandemic. PMID- 20926489 TI - A baby with noisy breathing. PMID- 20926491 TI - Towards an end to stillbirths. PMID- 20926490 TI - Variation in rates of caesarean section among English NHS trusts after accounting for maternal and clinical risk: cross sectional study. AB - OBJECTIVE: To determine whether the variation in unadjusted rates of caesarean section derived from routine data in NHS trusts in England can be explained by maternal characteristics and clinical risk factors. DESIGN: A cross sectional analysis using routinely collected hospital episode statistics was performed. A multiple logistic regression model was used to estimate the likelihood of women having a caesarean section given their maternal characteristics (age, ethnicity, parity, and socioeconomic deprivation) and clinical risk factors (previous caesarean section, breech presentation, and fetal distress). Adjusted rates of caesarean section for each NHS trust were produced from this model. SETTING: 146 English NHS trusts. Population Women aged between 15 and 44 years with a singleton birth between 1 January and 31 December 2008. MAIN OUTCOME MEASURE: Rate of caesarean sections per 100 births (live or stillborn). RESULTS: Among 620 604 singleton births, 147 726 (23.8%) were delivered by caesarean section. Women were more likely to have a caesarean section if they had had one previously (70.8%) or had a baby with breech presentation (89.8%). Unadjusted rates of caesarean section among the NHS trusts ranged from 13.6% to 31.9%. Trusts differed in their patient populations, but adjusted rates still ranged from 14.9% to 32.1%. Rates of emergency caesarean section varied between trusts more than rates of elective caesarean section. CONCLUSION: Characteristics of women delivering at NHS trusts differ, and comparing unadjusted rates of caesarean section should be avoided. Adjusted rates of caesarean section still vary considerably and attempts to reduce this variation should examine issues linked to emergency caesarean section. PMID- 20926492 TI - Variation in caesarean delivery rates. PMID- 20926493 TI - The role of inattention and social perception and performance in two subtypes of ADHD. AB - This study evaluated the social perception and social functioning of children with Attention Deficit Hyperactivity Disorder-Combined (ADHD-C), ADHD predominately inattentive (ADHD-PI), and controls. Two-hundred and seventy children with ADHD-C, ADHD-PI, or controls were evaluated using direct and indirect measures of social functioning. The ADHD-C and ADHD-PI groups showed significant differences in interpretation of emotional and nonverbal cues on a direct measure of social perception compared with controls. The number of inattentive symptoms was significantly related to poor performance for interpretation of both emotional and nonverbal cues, whereas hyperactivity and impulsivity symptoms showed a less robust relation. Children with ADHD-C were rated by parents and teachers as showing significant problems with social performance and problem behaviors compared with those with ADHD-PI or with controls. These findings show a link between inattention and social perception that is separate from impulsivity difficulties. These findings have important implications for treatment. PMID- 20926495 TI - Sensitivity and specificity of the ankle--brachial index to diagnose peripheral artery disease: a structured review. AB - The ankle-brachial index (ABI) is a simple, inexpensive diagnostic test for peripheral artery disease (PAD). However, it has shown variable accuracy for identification of significant stenosis. The authors performed a structured review of the sensitivity and specificity of ABI <= 0.90 for the diagnosis of PAD. MEDLINE, EMBASE, Cochrane databases, Science Citation Index database, and Biological Abstracts database were searched for studies of the sensitivity and specificity of using ABI <= 0.90 for the diagnosis of PAD. Eight studies comprising 2043 patients (or limbs) met the inclusion criteria. The result indicated that, although strict inclusion criteria on studies were formulated, different reference standards were found in these studies, and methods of ABI determination and characteristics of populations varied greatly. A high level of specificity (83.3-99.0%) and accuracy (72.1-89.2%) was reported for an ABI <= 0.90 in detecting >= 50% stenosis, but there were different levels of sensitivity (15-79%). Sensitivity was low, especially in elderly individuals and patients with diabetes. In conclusion, the test of ABI <= 0.90 can be a simple and useful tool to identify PAD with serious stenosis, and may be substituted for other non invasive tests in clinical practice. PMID- 20926494 TI - Genetic ancestry and lower extremity peripheral artery disease in the Multi Ethnic Study of Atherosclerosis. AB - Using self-report of race/ethnicity, African Americans consistently have a higher prevalence of peripheral artery disease (PAD) compared to other ethnic groups. We aimed to determine the associations between estimated genetic admixture and PAD among African and Hispanic Americans. We studied the association between genetic ancestry and PAD among 1417 African and Hispanic American participants in the Multi-Ethnic Study of Atherosclerosis who were genotyped for ancestry informative markers (AIMs). PAD was defined as an ankle-brachial index (ABI) < 0.90. The overall prevalence of PAD among the 712 self-identified African American subjects was 15.2% and 4.6% among the 705 self-identified Hispanic Americans. A one standard deviation increment in European ancestry was associated with non significant reductions in the odds for PAD among African (OR: 0.96 [95% CI: 0.78 1.18]) and Hispanic Americans (0.84 [0.58-1.23]), while the same increment in Native American ancestry was significantly associated with a lower odds of PAD in Hispanic Americans (0.56 [0.36-0.96]). Adjustment for demographic variables, field center, cardiovascular disease (CVD) risk factors and inflammatory markers strengthened the odds for European ancestry among African (0.85 [0.66-1.10]) and Hispanic Americans (0.68 [0.41-1.11]). The magnitude of the association for Native American ancestry among Hispanic Americans did not materially change (0.56 [0.29-1.09]). In conclusion, a higher percent Native American ancestry in Hispanics is associated with a lower odds of PAD while in both Hispanics and African Americans, greater European ancestry does not appear to be associated with lower odds for PAD. PMID- 20926496 TI - Polymorphisms of the hypoxia-inducible factor 1 gene and peripheral artery disease. AB - Hypoxia-inducible factor 1 (HIF1) is a key regulator of angiogenesis and is involved in inflammation, which are two important features of the pathogenesis of peripheral artery disease (PAD). The gene for the HIF1-alpha subunit (HIF1A) carries two common mis-sense mutations, P582S (C>T, rs11549465) and A588T (G>A, rs11549467), which both have been related to increased trans-activation capacity of HIF1-alpha. The aim of the present study was to analyze the role of these polymorphisms in PAD. The study was designed as a case-control study including 917 patients with documented PAD and 969 control subjects. HIF1A genotypes were determined by exonuclease (TaqMan) assays. HIF1A P582S genotype frequencies were not significantly different between PAD patients (PP 82.2%; PS 16.5%; SS 1.3%) and control subjects (83.2%; 15.3%; 1.5%; p = 0.72). Similarly, HIF1A A588T genotype frequencies did not differ significantly between PAD patients (AA 95.9%; AT 4.1%) and control subjects (AA 96.8%; AT 3.2%; p = 0.28). In a multivariate logistic regression analysis including age, sex, smoking, diabetes, arterial hypertension and hypercholesterolemia, neither the HIF1A P582S polymorphism (odds ratio: 1.26; 95% confidence interval 0.92-1.74; p = 0.16) nor the A588T polymorphism (odds ratio: 1.17; 95% confidence interval 0.59-2.35; p = 0.66) was significantly associated with the presence of PAD. Both polymorphisms were furthermore not associated with age at onset of PAD, Fontaine stage of the disease or the ankle/brachial index of patients. We conclude that functional polymorphisms in the HIF1A gene do not contribute to susceptibility to PAD. PMID- 20926498 TI - Impact of venous thromboembolism, venous stasis syndrome, venous outflow obstruction and venous valvular incompetence on quality of life and activities of daily living: a nested case-control study. AB - The role of venous stasis syndrome (VSS) mechanisms (i.e. venous outflow obstruction [VOO] and venous valvular incompetence [VVI]) on quality of life (QoL) and activities of daily living (ADL) is unknown. The objective of this study was to test the hypotheses that venous thromboembolism (VTE),VSS,VOO and VVI are associated with reduced QoL and ADL. This study is a follow-up of an incident VTE case-control study nested within a population-based inception cohort of residents from Olmsted County, MN, USA, between 1966 and 1990. The study comprised 232 Olmsted County residents with a first lifetime VTE and 133 residents without VTE. Methods included a questionnaire and physical examination for VSS; vascular laboratory testing for VOO and VVI; assessment of QoL by SF36 and of ADL by pertinent sections from the Older Americans Resources and Services (OARS) and Arthritis Impact Measurement Scales (AIMS2) questionnaires. Of the 365 study participants, 232 (64%), 161 (44%), 43 (12%) and 136 (37%) had VTE, VSS, VOO and VVI, respectively. Prior VTE was associated with reduced ADL and increased pain, VSS with reduced physical QoL and increased pain, and VOO with reduced physical QoL and ADL.VVI was not associated with QoL or ADL. In conclusion,VSS and VOO are associated with worse physical QoL and increased pain. VOO and VTE are associated with impaired ADL. We hypothesize that rapid clearance of venous outflow obstruction in individuals with acute VTE will improve their QoL and ADL. PMID- 20926499 TI - Diagnosis of venous thromboembolism: an update. AB - Deep vein thrombosis (DVT) and pulmonary embolism (PE) cannot be diagnosed solely on a clinical basis owing to the lack of sensitivity and specificity of clinical signs and symptoms. Phlebography and pulmonary angiography are invasive and resource-demanding imaging modalities. Because the prevalence of DVT and PE is relatively low (typically 20% or less) among clinically suspected individuals, submitting all of them to imaging would not be cost-effective. Therefore, non invasive diagnostic algorithms have been developed that include clinical probability assessment and D-dimer measurement. These initial steps allow the selection of patients who require non-invasive imaging: compression ultrasonography in cases of suspected DVT and multidetector computed tomography (CT) angiography in cases of suspected PE. This review gives a critical appraisal of the sequential steps of the diagnostic work-up in suspected DVT or PE. PMID- 20926497 TI - Cholinergic activation of hematopoietic stem cells: role in tobacco-related disease? AB - Tobacco use is associated with an increase in the white blood cell (WBC) count. This association has been attributed to bronchopulmonary inflammation and/or infection. It is not known if nicotine itself may play a role. The objective of this study was to determine whether nicotine itself could affect the WBC count, and to determine whether this was due to a direct effect on hematopoietic stem cells (HSC). C57Bl6J mice received nicotine orally, and measurements of the WBC count, bone marrow and spleen cellularity, and HSC count were made. To determine the functionality of HSCs, irradiated animals received bone marrow transplants from vehicle or nicotine-treated mice. Nicotine increased leukocytes in the peripheral blood, bone marrow and spleen. The peripheral red cell and platelet count were unaffected. Nicotine increased the frequency of HSC in the bone marrow. Isolated long-term HSCs from nicotine-treated mice transplanted into irradiated mice regenerated all hematopoietic cell lineages, demonstrating the functional competence of those HSCs. HSCs expressed nicotinic acetylcholine receptors (nAChRs), as documented by FITC-conjugated alpha-bungarotoxin binding. Nicotine increased soluble Kit ligand, consistent with stem cell activation. In conclusion, the data suggest a new mechanism for the increased WBC associated with tobacco use. The effect of nicotine to activate hematopoiesis may contribute to tobacco-related diseases. PMID- 20926500 TI - Mesenteric venous thrombosis. AB - First differentiated from arterial causes of acute mesenteric ischemia 75 years ago, acute mesenteric venous thrombosis (MVT) is an uncommon disorder with non specific signs and symptoms, the diagnosis of which requires a high index of suspicion. The location, extent, and rapidity of thrombus formation determine whether intestinal infarction ensues. Etiologies, when identified, usually can be separated into local intra-abdominal factors and inherited or acquired hypercoagulable states. The diagnosis is most often made by contrast-enhanced computed tomography, though angiography and exploratory surgery still have important diagnostic as well as therapeutic roles. Anticoagulation prevents clot propagation and is associated with decreased recurrence and mortality. Thrombectomy and thrombolysis may preserve questionably viable bowel and should be considered under certain circumstances. Evidence of infarction mandates surgery and resection whenever feasible. Although its mortality rate has fallen over time, acute MVT remains a life-threatening condition requiring rapid diagnosis and aggressive management. Chronic MVT may manifest with complications of portal hypertension or may be diagnosed incidentally by noninvasive imaging. Management of chronic MVT is directed against variceal hemorrhage and includes anticoagulation when appropriate; mortality is largely dependent on the underlying risk factor. PMID- 20926501 TI - Fibrinolysis for acute pulmonary embolism. AB - Acute pulmonary embolism (PE) presents as a constellation of clinical syndromes with a variety of prognostic implications. Patients with acute PE who have normal systemic arterial blood pressure and no evidence of right ventricular (RV) dysfunction have an excellent prognosis with therapeutic anticoagulation alone. Normotensive acute PE patients with evidence of RV dysfunction are categorized as having submassive PE and comprise a population at intermediate risk for adverse events and early mortality. Patients with massive PE present with syncope, systemic arterial hypotension, cardiogenic shock, or cardiac arrest and have the highest risk for short-term mortality and adverse events. The majority of deaths from acute PE are due to RV pressure overload and subsequent RV failure. The goal of fibrinolysis in acute PE is to rapidly reduce RV afterload and avert impending hemodynamic collapse and death. Although generally considered to be a life-saving intervention in massive PE, fibrinolysis remains controversial for submassive PE. Successful administration of fibrinolytic therapy requires weighing benefit versus risk. Major bleeding, in particular intracranial hemorrhage, is the most feared complication of fibrinolysis. Alternatives to fibrinolysis for acute PE, including surgical embolectomy, catheter-assisted embolectomy, and inferior vena cava (IVC) filter insertion, should be considered when contraindications exist or when patients have failed to respond to an initial trial of fibrinolytic therapy. Patients with massive and submassive PE may be best served by rapid triage to specialized centers with experience in the administration of fibrinolytic therapy and the capacity to offer alternative advanced therapies such as surgical and catheter-assisted embolectomy. PMID- 20926502 TI - SVM Annual Meeting--April 2010 Cleveland, OH, USA. PMID- 20926503 TI - Images in vascular medicine: Renal arteriovenous fistula. PMID- 20926504 TI - Images in vascular medicine: Hypoglossal nerve palsy due to internal carotid artery dissection. PMID- 20926505 TI - Characterization and heterologous expression of a new matrix attachment region binding protein from the unicellular green alga Dunaliella salina. AB - Although interactions between the nuclear matrix and special regions of chromosomal DNA called matrix attachment regions (MARs) are implicated in various nuclear functions, the understanding of the regulatory mechanism of MARs is still poor. A few MAR-binding proteins (MARBP) have been isolated from some plants and animals, but not from the unicellular algae. Here, we identify a novel MAR binding protein, namely DMBP-1, from the halotolerant alga Dunaliella salina. The cDNA of DMBP-1 is 2322-bp long and contains a 1626 bp of an open reading frame encoding a polypeptide of 542 amino acids (59 kDa). The DMBP-1 expressed in Escherichia coli specifically binds A/T-rich MAR DNA. The DMBP-1 fused to green fluorescent protein appears only inside the nuclei of Chinese hamster ovarian cells transfected with the pEGFP-MBP, indicating that the protein is located in the nuclei. The findings mentioned above may contribute to better understanding of the nuclear matrix-MAR interactions. PMID- 20926506 TI - Retinoid treatment of Emphysema in Patients on the Alpha-1 International Registry. The REPAIR study: study design, methodology and quality control of study assessments. AB - Emphysema is characterized by the destruction of alveolar wall and enlargement of alveolar airspaces, resulting in a reduction of the total lung gas exchange area, loss of lung elastic recoil and hyperinflation. The REPAIR study (Retinoid treatment of Emphysema in Patients on the Alpha-1 International Registry) is the first proof-of-concept study of a new potential disease-modifying drug, Palovarotene(c), an orally active, gamma selective retinoid agonist in patients with emphysema secondary to alpha-1-antitrypsin deficiency (AATD) as a model population for the general smoke-induced emphysema population. This article describes the study design as well as the effectiveness of the quality control that was implemented on the key efficacy endpoints, based on data derived from the placebo-treated subjects. In this multicentre, multinational study the implementation of standardized procedures included: careful site selection, use of trained staff, regular monitoring and machine calibration, use of biological controls and regular feedback to sites by an independent quality control centre. All of these procedures resulted in high-quality measurements of lung density, spirometry, static lung volumes and gas transfer. It was also confirmed that CT lung density was the most sensitive endpoint followed by TLco, FEV(1) and RV measured by body box. PMID- 20926507 TI - The relationship between gastroesophageal reflux and asthma: an update. AB - Asthma and gastroesophageal reflux disease (GERD) are both common conditions and, hence, they often coexist. However, asthmatics have been found to have a much greater prevalence of GERD symptoms than the general population. There remains debate regarding the underlying physiologic mechanism(s) of this relationship and whether treatment of GERD actually translates into improved asthma outcomes. Based on smaller trials with somewhat conflicting results regarding improved asthma control with treatment of GERD, current guidelines recommend a trial of GERD treatment for symptomatic asthmatics even without symptoms of GERD. However, recently a large multicenter trial demonstrated that the treatment of asymptomatic GERD with proton-pump inhibitors did not improve asthma control in terms of pulmonary function, rate of asthma exacerbations, asthma-related quality of life, or asthma symptom frequency. These data suggest empiric treatment of asymptomatic GERD in asthmatics is not a useful practice. This review article provides an overview of the epidemiology and pathophysiologic relationships between asthma and GERD as well as a summary of current data regarding links between treatment of GERD with asthma outcomes. PMID- 20926508 TI - Patient doses in CT examinations in Switzerland: implementation of national diagnostic reference levels. AB - Diagnostic reference levels (DRLs) were established for 21 indication-based CT examinations for adults in Switzerland. One hundred and seventy-nine of 225 computed tomography (CT) scanners operated in hospitals and private radiology institutes were audited on-site and patient doses were collected. For each CT scanner, a correction factor was calculated expressing the deviation of the measured weighted computed tomography dose index (CTDI) to the nominal weighted CTDI as displayed on the workstation. Patient doses were corrected by this factor providing a realistic basis for establishing national DRLs. Results showed large variations in doses between different radiology departments in Switzerland, especially for examinations of the petrous bone, pelvis, lower limbs and heart. This indicates that the concept of DRLs has not yet been correctly applied for CT examinations in clinical routine. A close collaboration of all stakeholders is mandatory to assure an effective radiation protection of patients. On-site audits will be intensified to further establish the concept of DRLs in Switzerland. PMID- 20926509 TI - Evaluation of paediatric X-ray doses in Moroccan university hospitals. AB - This work evaluates the entrance skin dose (ESD), the body organ dose (BOD) and the effective dose (E) for chest X-ray exposures of paediatric patients. Two Moroccan university hospitals in Rabat, composed of two departments, and one in Casablanca with one paediatric compartment has been considered. For reasons of confidentiality, the departments are named A, B and C. Patients were divided into four age groups: 0-1, 1-5, 5-10 and 10-15 y, so that the results could be compared with previous published data found in the literature. The results have been calculated with the use of the Dose Cal software. Results of mean ESD for the age interval 1-5 y and antero-posterior (AP) projection are: 162 uGy for hospital A, 91 uGy for hospital B and 105 uGy for hospital C. The diagnostic reference levels (DRLs) of 100 uGy for this age range is exceeded in hospital A, while in the other two hospitals results were within the DRL and comparable with the results found in Brazil, Soudan, Nigeria and other radiological centres inpean Countries. The results of BOD and E showed that for the three departments, the BOD varies in the same proportion as the ESD. The highest values are those of hospital A. For the PA examination, the dose is reduced compared with the AP projection, especially for sensitive organs. PMID- 20926510 TI - Considerations and preliminary design of patient exposure registry. AB - To aid in protecting patients from unnecessary exposures and to reduce radiation burdens to the public, a system for tracking a patient's medical exposure history and related radiation doses would be a useful tool. A patient-centred exposure registry, the Patient Exposure Registry (PER), is a mechanism that provides this tracking. This article outlines the objectives of the proposed Canadian PER together with considerations and preliminary design of the registry. Implementation strategy is discussed. The strategy will allow many initiatives progressing in parallel such as backward data mining and forward development in order to make this important registry a reality in the near future. PMID- 20926511 TI - Evaluation of geometric efficiency and radiation exposure in z-axis for volume scan. AB - The International Electrotechnical Commission (IEC) recommended that a display be provided on the operating console of medical computed tomography (CT) scanners when the geometric efficiency (GE) in the z-axis is 70% or less. Taking into account the increase in the number of detector rows and the changes in the scanning method, the present study was conducted to review the GE and to evaluate the exposure dose in the z-axis direction. The GE for a single-rotation scan was calculated in accordance with IEC-606024 Ed. 2. The findings of the present study suggest that 320-row area detector computed tomography volume scan (single axial scan with no table movement in which it just happened to use a very large beam width) extends 18.8 mm beyond the nominal beam collimation, even when the GE is >70%. However, compared with the helical scan, which is the present mainstream of CT examinations, the dose beyond the scan length is narrower in volume scan for a limited scan length of 160 mm or less. PMID- 20926512 TI - Clinical application of a novel sliver nanoparticles biosensor based on localized surface plasmon resonance for detecting the microalbuminuria. AB - In order to explore the clinical application of the nanobiosensor based on localized surface plasmon resonance (LSPR), we used our LSPR biosensor to detect the microalbuminuria in this work. The sliver nanoparticles were fabricated by using nanosphere lithography. The anti-human albumin antibody was immobilized on the sensor surface by amine coupling method. The different concentrations of commercial albumin and albumin in urine samples from three mild preeclampsia patients were determined according to the peak of LSPR extinction spectra. Under optimum conditions, our results showed that the biosensor displayed a detection limit of 1 ng/ml and wide dynamic range of 1 ng/ml to 1 MUg/ml. Furthermore, the microalbuminuria of three patients was determined by our biosensor within a short assay time, without sample purification. This biosensor proposed herein is easy to prepare and could be used for low-cost, rapid, label-free, and sensitive screening of the microalbuminuria. This approach provides a promising platform for developing clinical diagnostic applications. PMID- 20926513 TI - Osteogenic growth peptide enhances the proliferation of bone marrow mesenchymal stem cells from osteoprotegerin-deficient mice by CDK2/cyclin A. AB - To promote bone formation is one of the fundamental strategies in osteoporosis treatment and fractures repair. As one of the stimulators on bone formation, osteogenic growth peptide (OGP) increases both proliferation and differentiation of the osteoblasts in vitro and in vivo, in which osteoprotegerin (OPG) has been suggested being involved. In this study, we evaluated the effects of OGP on bone marrow mesenchymal stem cells (MSCs) from OPG-deficient mice in vitro by 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, alkaline phosphatase (ALP) activity assay, real-time polymerase chain reaction, and western blot analysis. Results showed that OGP stimulated MSC proliferation and increased the expression of CDK2 and cyclin A in MSCs both at mRNA and protein levels. However, no differentiative effect of OGP was shown as ALP activity and the expression levels of Runx2 and Osterix were not increased significantly by OGP. Our study suggested that OGP may increase the bone formation in OPG-deficient mice by stimulating MSC proliferation rather than differentiation, and probably by triggering CDK2/cyclin A pathway. PMID- 20926514 TI - Genome-wide gene expression profiling reveals aberrant MAPK and Wnt signaling pathways associated with early parthenogenesis. AB - Mammalian parthenogenesis could not survive but aborted during mid-gestation, presumably because of lack of paternal gene expression. To understand the molecular mechanisms underlying the failure of parthenogenesis at early stages of development, we performed global gene expression profiling and functional analysis of parthenogenetic blastocysts in comparison with those of blastocysts from normally fertilized embryos. Parthenogenetic blastocysts exhibited changes in the expression of 749 genes, of which 214 had lower expression and 535 showed higher expressions than fertilized embryos using a minimal 1.8-fold change as a cutoff. Genes important for placenta development were decreased in their expression in parthenote blastocysts. Some maternally expressed genes were up regulated and paternal-related genes were down-regulated. Moreover, aberrantly increased Wnt signaling and reduced mitogen-activated protein kinase (MAPK) signaling were associated with early parthenogenesis. The protein level of extracellular signal-regulated kinase 2 (ERK2) was low in parthenogenetic blastocysts compared with that of fertilized blastocysts 120 h after fertilization. 6-Bromoindirubin-3'-oxime, a specific glycogen synthase kinase-3 (GSK-3) inhibitor, significantly decreased embryo hatching. The expression of several imprinted genes was altered in parthenote blastocysts. Gene expression also linked reduced expression of Xist to activation of X chromosome. Our findings suggest that failed X inactivation, aberrant imprinting, decreased ERK/MAPK signaling and possibly elevated Wnt signaling, and reduced expression of genes for placental development collectively may contribute to abnormal placenta formation and failed fetal development in parthenogenetic embryos. PMID- 20926515 TI - Murine mammary epithelial stem cells: discovery, function, and current status. AB - An entire mammary epithelial outgrowth, capable of full secretory differentiation, may comprise the progeny of a single cellular antecedent, i.e., may be generated from a single mammary epithelial stem cell. Early studies showed that any portion of an intact murine mammary gland containing epithelium could recapitulate an entire mammary epithelial tree on transplantation into an epithelium-free mammary fat pad. More recent studies have shown that a hierarchy of mammary stem/progenitor cells exists among the mammary epithelium and that their behavior and maintenance is dependent on signals generated both locally and systemically. In this review, we have attempted to develop the scientific saga surrounding the discovery and characterization of the murine mammary stem/progenitor cell hierarchy and to suggest further approaches that will enhance our knowledge and understanding of these cells and their role in both normal development and neoplasia. PMID- 20926516 TI - Bacterial nanomachines: the flagellum and type III injectisome. AB - The bacterial flagellum and the virulence-associated injectisome are complex, structurally related nanomachines that bacteria use for locomotion or the translocation of virulence factors into eukaryotic host cells. The assembly of both structures and the transfer of extracellular proteins is mediated by a unique, multicomponent transport apparatus, the type III secretion system. Here, we discuss the significant progress that has been made in recent years in the visualization and functional characterization of many components of the type III secretion system, the structure of the bacterial flagellum, and the injectisome complex. PMID- 20926518 TI - Cost-efficient design of occupational exposure assessment strategies--a review. AB - When designing a strategy for collecting occupational exposure data, both economic and statistical performance criteria should be considered. However, very few studies have addressed the trade-off between the cost of obtaining data and the precision/accuracy of the exposure estimate as a research issue. To highlight the need of providing cost-efficient designs for assessing exposure variables in occupational research, the present review explains and critically evaluates the concepts and analytical tools used in available cost efficiency studies. Nine studies were identified through a systematic search using two algorithms in the databases PubMed and ScienceDirect. Two main approaches could be identified in these studies: 'comparisons' of the cost efficiency associated with different measurement designs and 'optimizations' of resource allocation on the basis of functions describing cost and statistical efficiency. In either case, the reviewed studies use simplified analytical tools and insufficient economic analyses. More research is needed to understand whether these drawbacks jeopardize the guidance on cost-efficient exposure assessment provided by the studies, as well as to support theoretical results by empirical data from occupational life. PMID- 20926519 TI - Body composition assessed by the 4-component model and association with lung function in 6-12-y-old children with cystic fibrosis. AB - BACKGROUND: Malnutrition is an indicator of a poor prognosis in patients with cystic fibrosis (CF). Previous body-composition (BC) studies in children with CF used 2-component models (2CMs) to assess fat mass (FM) and fat-free mass (FFM), but to our knowledge no study has used the gold-standard 4-component model (4CM), which allows for a more accurate evaluation of the nature of both elements. OBJECTIVE: We measured BC by using the 4CM in 6-12-y-old children with CF to 1) compare findings with those of healthy, matched control children and reference data; 2) relate BC to lung spirometry [forced expired volume in 1 s (FEV1)]; and 3) compare findings with those from more commonly used 2CM techniques. DESIGN: One hundred clinically stable children with CF (57% girls) aged 6-12 y were measured by using the 4CM. Children with CF underwent spirometry (FEV1). RESULTS: Girls with CF had significantly less FM than did healthy girls, even after adjustment for height and pubertal status; boys with CF had higher body mass index SD scores than did healthy boys. FM in girls was positively associated with the FEV1 percentage predicted. The 2CM FM was significantly different from the 4CM FM, with differences dependent on sex and condition, although most techniques identified a relation between FM and FEV1 in girls. CONCLUSIONS: Although shorter than healthy children, boys with CF were heavier and had a BC within the normal range; however, girls with CF had lower FM than did healthy girls, and this was associated with poorer lung function. Given the worse prognosis in girls, this finding merits more attention. The reliability of 2CM techniques varied with sex and health status. PMID- 20926517 TI - Nuclear speckles. AB - Nuclear speckles, also known as interchromatin granule clusters, are nuclear domains enriched in pre-mRNA splicing factors, located in the interchromatin regions of the nucleoplasm of mammalian cells. When observed by immunofluorescence microscopy, they usually appear as 20-50 irregularly shaped structures that vary in size. Speckles are dynamic structures, and their constituents can exchange continuously with the nucleoplasm and other nuclear locations, including active transcription sites. Studies on the composition, structure, and dynamics of speckles have provided an important paradigm for understanding the functional organization of the nucleus and the dynamics of the gene expression machinery. PMID- 20926520 TI - Skipping breakfast: longitudinal associations with cardiometabolic risk factors in the Childhood Determinants of Adult Health Study. AB - BACKGROUND: The long-term effects of skipping breakfast on cardiometabolic health are not well understood. OBJECTIVE: The objective was to examine longitudinal associations of breakfast skipping in childhood and adulthood with cardiometabolic risk factors in adulthood. DESIGN: In 1985, a national sample of 9-15-y-old Australian children reported whether they usually ate breakfast before school. During follow-up in 2004-2006, 2184 participants (26-36 y of age) completed a meal-frequency chart for the previous day. Skipping breakfast was defined as not eating between 0600 and 0900. Participants were classified into 4 groups: skipped breakfast in neither childhood nor adulthood (n = 1359), skipped breakfast only in childhood (n = 224), skipped breakfast only in adulthood (n = 515), and skipped breakfast in both childhood and adulthood (n = 86). Diet quality was assessed, waist circumference was measured, and blood samples were taken after a 12-h fast (n = 1730). Differences in mean waist circumference and blood glucose, insulin, and lipid concentrations were calculated by linear regression. RESULTS: After adjustment for age, sex, and sociodemographic and lifestyle factors, participants who skipped breakfast in both childhood and adulthood had a larger waist circumference (mean difference: 4.63 cm; 95% CI: 1.72, 7.53 cm) and higher fasting insulin (mean difference: 2.02 mU/L; 95% CI: 0.75, 3.29 mU/L), total cholesterol (mean difference: 0.40 mmol/L; 95% CI: 0.13, 0.68 mmol/L), and LDL cholesterol (mean difference: 0.40 mmol/L; 95% CI: 0.16, 0.64 mmol/L) concentrations than did those who ate breakfast at both time points. Additional adjustments for diet quality and waist circumference attenuated the associations with cardiometabolic variables, but the differences remained significant. CONCLUSIONS: Skipping breakfast over a long period may have detrimental effects on cardiometabolic health. Promoting the benefits of eating breakfast could be a simple and important public health message. PMID- 20926521 TI - Haptoglobin genotype modifies the association between dietary vitamin C and serum ascorbic acid deficiency. AB - BACKGROUND: Haptoglobin (which is encoded by the Hp gene) is a hemoglobin-binding protein that has antioxidant properties and a common polymorphism that consists of 2 structurally different alleles: Hp1 and Hp2. The capacity of Hp2 to inhibit oxidation and vitamin C depletion is less than that of Hp1, but the influence on vitamin C requirements remains unknown. OBJECTIVE: This study aimed to determine whether the Hp polymorphism modifies the association between dietary vitamin C and serum ascorbic acid deficiency (<11 MUmol/L). DESIGN: Nonsmoking men and women (n = 1046) between 20 and 29 y of age participated in the Toronto Nutrigenomics and Health Study. Blood samples were collected after the subjects had fasted overnight to determine serum ascorbic acid concentrations by HPLC and for genotyping. A 196-item food-frequency questionnaire was used to estimate vitamin C intake. RESULTS: A gene-diet interaction on serum ascorbic acid was observed (P = 0.02). The overall odds ratio (95% CI) for serum ascorbic acid deficiency was 2.84 (1.73, 4.65) for subjects who did not meet the Recommended Dietary Allowance for vitamin C compared with those who did. The corresponding odds ratios were 4.77 (2.36, 9.65) for the Hp2-2 genotype and 1.69 (0.80, 3.63) for carriers of the Hp1 allele. CONCLUSIONS: Individuals with the Hp2-2 genotype had an increased risk of deficiency if they did not meet the Recommended Dietary Allowance for vitamin C, whereas carriers of the Hp1 allele did not. The findings suggest that the greater antioxidant capacity of Hp1 might spare serum ascorbic acid. PMID- 20926523 TI - Science trumps politics: urinary sodium data challenge US dietary sodium guideline. PMID- 20926522 TI - Afebrile Plasmodium falciparum parasitemia decreases absorption of fortification iron but does not affect systemic iron utilization: a double stable-isotope study in young Beninese women. AB - BACKGROUND: Iron deficiency anemia (IDA) affects many young women in sub-Saharan Africa. Its etiology is multifactorial, but the major cause is low dietary iron bioavailability exacerbated by parasitic infections such as malaria. OBJECTIVE: We investigated whether asymptomatic Plasmodium falciparum parasitemia in Beninese women would impair absorption of dietary iron or utilization of circulating iron. DESIGN: Iron absorption and utilization from an iron-fortified sorghum-based meal were estimated by using oral and intravenous isotope labels in 23 afebrile women with a positive malaria smear (asexual P. falciparum parasitemia; > 500 parasites/MUL blood). The women were studied while infected, treated, and then restudied 10 d after treatment. Iron status, hepcidin, and inflammation indexes were measured before and after treatment. RESULTS: Treatment reduced low-grade inflammation, as reflected by decreases in serum ferritin, C reactive protein, interleukin-6, interleukin-8, and interleukin-10 (P < 0.05); this was accompanied by a reduction in median serum hepcidin of ~ 50%, from 2.7 to 1.4 nmol/L (P < 0.005). Treatment decreased serum erythropoietin and growth differentiation factor 15 (P < 0.05). Clearance of parasitemia increased geometric mean dietary iron absorption (from 10.2% to 17.6%; P = 0.008) but did not affect systemic iron utilization (85.0% compared with 83.1%; NS). CONCLUSIONS: Dietary iron absorption is reduced by ~ 40% in asymptomatic P. falciparum parasitemia, likely because of low-grade inflammation and its modulation of circulating hepcidin. Because asymptomatic parasitemia has a protracted course and is very common in malarial areas, this effect may contribute to IDA and blunt the efficacy of iron supplementation and fortification programs. This trial was registered at clinicaltrials.gov as NCT01108939. PMID- 20926524 TI - Vitamin D deficiency and anthropometric indicators of adiposity in school-age children: a prospective study. AB - BACKGROUND: Cross-sectional studies have indicated that vitamin D serostatus is inversely associated with adiposity. It is unknown whether vitamin D deficiency is a risk factor for the development of adiposity in children. OBJECTIVE: We investigated the associations between vitamin D serostatus and changes in body mass index (BMI; in kg/m2), skinfold-thickness ratio (subscapular-to-triceps), waist circumference, and height in a longitudinal study in children from Bogota, Colombia. DESIGN: We quantified plasma 25-hydroxyvitamin D [25(OH)D] concentrations in baseline samples of a randomly selected group of 479 schoolchildren aged 5-12 y and classified vitamin D status as deficient [25(OH)D concentrations < 50 nmol/L], insufficient [25(OH)D concentrations >= 50 and < 75 nmol/L], or sufficient [25(OH)D concentrations >= 75 nmol/L]. We measured anthropometric variables annually for a median of 30 mo. We estimated the average change in each anthropometric indicator according to baseline vitamin D status by using multivariate mixed linear regression models. RESULTS: Vitamin D-deficient children had an adjusted 0.1/y greater change in BMI than did vitamin D sufficient children (P for trend = 0.05). Similarly, vitamin D-deficient children had a 0.03/y (95% CI: 0.01, 0.05/y) greater change in subscapular-to-triceps skinfold-thickness ratio and a 0.8 cm/y (95% CI: 0.1, 1.6 cm/y) greater change in waist circumference than did vitamin D-sufficient children. Vitamin D deficiency was related to slower linear growth in girls (-0.6 cm/y, P = 0.04) but not in boys (0.3 cm/y, P = 0.34); however, an interaction with sex was not statistically significant. CONCLUSION: Vitamin D serostatus was inversely associated with the development of adiposity in school-age children. PMID- 20926525 TI - Gender, age, body mass index, and IGF-I individually and jointly determine distinct GH dynamics: analyses in one hundred healthy adults. AB - BACKGROUND: GH secretion is quantifiable as mean, peak, and nadir GH concentrations; degree of irregularity (approximate entropy); and spikiness (brief staccato-like fluctuations). HYPOTHESIS: Distinct GH dynamics reflect relatively distinct (combinations of) subject variables, such as gender, age, body mass index (BMI), and IGF-I concentrations. LOCATION: The study took place at a clinical translational research unit. SUBJECTS: Subjects included 100 healthy adults ages 20-77 yr (59 women and 41 men), BMI 18-42 kg/m(2), and IGF-I 9.2-38 nmol/liter. MEASURES: Immunofluorometric GH assay was done on 10-min samples collected for 24 h. RESULTS: Stepwise forward-selection multivariate regression analysis revealed that mean GH concentrations were simultaneously determined (overall r = 0.36; P < 0.001) by gender (higher in women, P < 0.001), BMI (negatively, P < 0.001), and IGF-I (positively, P < 0.001). Peak GH levels were influenced (r = 0.28) by both BMI (P < 0.001) and IGF-I (P = 0.001). Nadir GH values were jointly affected by gender (higher in women, P = 0.005) and BMI (negatively, P = 0.001). GH approximate entropy was triply defined (r = 0.29) by gender (greater irregularity in women, P < 0.001), age (P = 0.022), and BMI (P = 0.008) and dually (r = 0.25) by gender (P = 0.0001) and BMI (P = 0.017) if sex steroids were included. GH spikiness was determined (r = 0.29) by gender (higher in women, P = 0.0016) and BMI (positively, P = 0.0002). CONCLUSION: In healthy adults, combinations of gender, age, BMI, and IGF-I specify distinct GH dynamics, thus requiring balanced representation of these variables in comparative GH studies. PMID- 20926526 TI - Weight loss after therapy of hypothyroidism is mainly caused by excretion of excess body water associated with myxoedema. AB - CONTEXT: In hypothyroidism, resting energy expenditure (REE) is reduced and weight gain is common. Physical activity contributes to the total daily energy expenditure, and changes in physical activity might contribute to hypothyroid associated weight changes. OBJECTIVE: The objective of the present study was to evaluate mechanisms involved in body weight changes associated with hypothyroidism. DESIGN, SETTING, AND PARTICIPANTS: We conducted a 1-yr controlled follow-up study on outpatients newly diagnosed with hypothyroidism (n = 12) and a euthyroid measurement control group (n = 10). MAIN OUTCOME AND INTERVENTIONS: Changes in body mass and composition (dual-energy x-ray analysis scan), REE (indirect calorimetry), and spontaneous physical activity (pedometers and two different questionnaires) were studied before and after 12 months of L-T(4) therapy or observation (control group). RESULTS: TSH changed from 102 (85) to 2.2 (2.1) mU/liter mean (SD) and free T(4) from 4.5 (2.1) to 18 (3.3) pmol/liter after 1 yr of treatment. Body weight decreased from 83.7 (16.4) to 79.4 (16.0) kg (P = 0.002) due to change in the lean mass subcompartment only (P = 0.001) because fat and bone mass was virtually unchanged. Significant increase was observed in REE and in physical activity measured with questionnaires but not measured as daily steps. No significant changes were observed in the control group. CONCLUSION: L-T(4) therapy of hypothyroidism associated with significant decrease in body weight and increase in REE. Physical activity measured with questionnaires increased significantly, but not number of daily steps. Despite changes in REE and body weight, fat mass was unchanged during the study. We propose that total body energy equilibrium is maintained during treatment of hypothyroidism and that weight loss observed during such treatment is caused by excretion of excess body water associated with untreated myxoedema. PMID- 20926527 TI - Short- and long-term outcome of patients with pseudo-vitamin D deficiency rickets treated with calcitriol. AB - BACKGROUND: Pseudo-vitamin D deficiency rickets (PDDR; OMIM 264700) is a rare autosomal recessive disorder caused by mutations in the CYP27B1 gene, leading to an inability to synthesize 1alpha,25-dihydroxyvitamin D(3) (calcitriol). The long term (>1 yr) effects of calcitriol replacement treatment have not been reported. MATERIALS AND METHODS: Thirty-nine patients (20 females) with PDDR received calcitriol for periods of 2.0-26 yr. In 21 patients, data were available at diagnosis and during the first 2 yr of treatment with calcitriol. Twenty-five patients had reached their final height at the time of this analysis. RESULTS: The most common presenting features were active rickets, neurological signs, and short stature. Treatment with calcitriol resulted in the normalization of biochemical parameters and mean lumbar spine areal bone mineral density z-scores within 3 months, whereas height z-scores increased more gradually. As to long term effects, adult patients who had received calcitriol before the pubertal growth spurt (n = 11) had normal height, whereas patients who were treated with calcitriol only after puberty (n = 14) on average were short (height z-score 2.2). Lumbar spine areal bone mineral density z-scores were normal in all patients who had achieved final height. Nine women had 19 pregnancies, which all were without complications. All newborns were eucalcemic at birth. CONCLUSION: Treatment with calcitriol started in infancy results in short- and long-term correction of all clinical, biochemical, and radiological abnormalities related to PDDR. PMID- 20926528 TI - PVALB, a new Hurthle adenoma diagnostic marker identified through gene expression. AB - CONTEXT: A better means to accurately identify malignant thyroid nodules and to distinguish them from benign tumors is needed. We previously identified markers for detecting thyroid malignancy, with sensitivity estimated at or close to 100%. One lingering problem with these markers was that false positives occurred with Hurthle cell adenomas (HCA) which lowered test specificity. METHODS: To locate accurate diagnostic markers, we profiled in depth the transcripts of a HCA and a Hurthle cell carcinoma (HCC). From 1146 differentially expressed genes, 18 transcripts specifically expressed in HCA were tested by quantitative PCR in a wide range of thyroid tumors (n = 76). Sensibility and specificity were calculated using receiver operating characteristic (ROC). Selected markers were further validated in an independent set of thyroid tumors (n = 82) by immunohistochemistry. To define the panel that would yield best diagnostic accuracy, these markers were tested in combination with our previous identified markers. RESULTS: Seventeen of the 18 genes showed statistical significance based on a mean relative level of expression (P < 0.05). KLK1 (sensitivity = 0.97) and PVALB (sensitivity = 0.94) were the best candidate markers. The combination of PVALB and C1orf24 increased specificity to >97% and maintained sensitivity for detection of carcinoma. CONCLUSION: We identified tumor markers that can be used in combination for a more accurate preoperative diagnosis of thyroid nodules and for postoperative diagnosis of thyroid carcinoma in tumor sections. This improved test would help physicians rapidly focus treatment on true malignancies and avoid unnecessary treatment of benign tumors, simultaneously improving medical care and reducing costs. PMID- 20926529 TI - Moderate doses of hGH (0.64 mg/d) improve lipids but not cardiovascular function in GH-deficient adults with normal baseline cardiac function. AB - CONTEXT: Data regarding effects of lower-dose GH on cardiopulmonary function in GH-deficient (GHD) adults are limited. OBJECTIVES: The objective was to assess effects of lower-dose GH on exercise capacity and echocardiographic parameters in GHD adults. DESIGN: The study was a 6-month double-blind, placebo-controlled randomized trial. SETTING: The study was conducted at the General Clinical Research Center. PARTICIPANTS: Thirty hypopituitary adults with GHD were studied. INTERVENTION: Subjects were randomized to recombinant human GH or placebo for 6 months, followed by open-label recombinant human GH for 12 months. MAIN OUTCOME MEASURES: Primary endpoints were exercise duration, maximal oxygen consumption, and left ventricular ejection fraction. Secondary endpoints were echocardiographic indices of systolic and diastolic function, left ventricular mass, lipids, and body composition. RESULTS: In the 6-month double-blind phase, mean GH dose was 0.64 mg/d. Mean IGF-I sd score increased from -4.5 to -1.0. Exercise duration, maximal oxygen consumption, left ventricular ejection fraction, and other echocardiographic parameters were normal at baseline and did not change. GH decreased total and low-density lipoprotein cholesterol by 7.5% (P = 0.016) and 14.7% (P = 0.002) (P = 0.04 vs. placebo). Mean lean body mass increased by 2.2 kg (P = 0.004), fat mass decreased by 1.7 kg (P = 0.21), and percent body fat decreased by 2.5% (P = 0.018), although between-group changes were not significant. CONCLUSIONS: Human GH did not improve exercise performance or echocardiographic parameters or decrease fat mass but significantly decreased total and low-density lipoprotein cholesterol, increased IGF-I, and increased lean body mass. These results indicate that responses to human GH are variable and should be assessed at baseline and during treatment. PMID- 20926530 TI - Mitochondrial localization and regulation of BRAFV600E in thyroid cancer: a clinically used RAF inhibitor is unable to block the mitochondrial activities of BRAFV600E. AB - CONTEXT: The oncogenic BRAF(V600E) mutation results in an active structural conformation characterized by greatly elevated ERK activity. However, additional cellular effects caused by subcellular action of BRAF(V600E) remain to be identified. OBJECTIVE: To explore these effects, differences in the subcellular localization of wild-type and mutant BRAF in thyroid cancer were investigated. RESULTS: A significant proportion of endogenous and exogenous BRAF(V600E), but not wild-type BRAF, was detected in the mitochondrial fraction, similar to other BRAF mutants including BRAF(V600D), BRAF(V600K), BRAF(V600R), and BRAF(G469A), which showed elevated kinase activity and mitochondrial localization. Induced expression of BRAF(V600E) suppressed the apoptotic responses against staurosporine and TNFalpha/cycloheximide. Interestingly, the mitochondrial localization and antiapoptotic activities of BRAF(V600E) were unaffected by sorafenib and U0126 suppression of MAPK kinase (MEK) and ERK activities. Similarly, although the RAF inhibitor sorafenib effectively inhibited MEK/ERK activation, it did not block the mitochondrial localization of BRAF(V600E). In addition, inducible expression of BRAF(V600E) increased the glucose uptake rate and decreased O(2) consumption, suggesting that BRAF(V600E) reduces mitochondrial oxidative phosphorylation, a signature feature of cancer cells. Again, these metabolic alterations resulted by BRAF(V600E) expression were not affected by the treatment of thyroid cells by sorafenib. Therefore, RAF and MEK inhibitors are unable to block the antiapoptotic activity of BRAF(V600E) or correct the high glucose uptake rate and glycolytic activity and suppressed mitochondrial oxidative phosphorylation induced by BRAF(V600E). CONCLUSIONS: The mitochondrial localization observed in oncogenic BRAF mutants might be related to their altered responses to apoptotic stimuli and characteristic metabolic phenotypes found in thyroid cancer. The inability of MEK and RAF inhibitors, U0126 and sorafenib, respectively, to block the mitochondrial localization of BRAF(V600E) has additional therapeutic implications for BRAF(V600E)-positive thyroid cancers. PMID- 20926531 TI - Cross-sectional versus longitudinal associations of lean and fat mass with pQCT bone outcomes in children. AB - CONTEXT: Cross-sectional associations for lean mass (LM) and fat mass (FM) with bone may not reflect longitudinal associations. OBJECTIVE: Cross-sectional and longitudinal associations of LM and FM with radial bone measurements in children were compared. DESIGN AND PARTICIPANTS: We conducted a longitudinal study on 370 (232 females) children, 8-18 yr of age. MAIN OUTCOME MEASURES: LM and FM were measured by dual-energy absorptiometry. Peripheral quantitative computed tomography at the 4% radius (4R) and 20% radius (20R) measured bone mineral content (BMC), volumetric bone mineral density (vBMD), area, and strength [polar stress strain index (pSSI)]. RESULTS: Males at 20R had negative FM cross sectional and longitudinal associations with cortical area and BMC and pSSI (P < 0.02); negative cross-sectional association with total area (P < 0.001); and negative longitudinal association with cortical thickness (P < 0.001). Females at 20R had FM cross-sectional association with total area, cortical BMC, and pSSI and longitudinal associations with cortical BMC and area, vBMD, and pSSI that went from positive to negative with age and, in some cases, varied with menarche. Both sexes at 4R had a negative FM cross-sectional association with BMC and area (P < 0.001) but negative longitudinal association with vBMD (P < 0.05). LM associations with bone outcomes were generally positive, except for negative longitudinal associations with cortical BMC and vBMD in young females (P < 0.01). LM associations were greater magnitude than FM associations and often depended on age. CONCLUSIONS: For males and older females, cross-sectional associations indicated a reduced bone size with higher FM, whereas longitudinal associations showed a decrease in cortical area without changes in bone size. LM was positively associated with BMC and area. PMID- 20926532 TI - The Thyroid Epidemiology, Audit, and Research Study (TEARS): the natural history of endogenous subclinical hyperthyroidism. AB - OBJECTIVE: For patients with subclinical hyperthyroidism (SH), the objective of the study was to define the rates of progression to frank hyperthyroidism and normal thyroid function. DESIGN: Record-linkage technology was used retrospectively to identify patients with SH in the general population of Tayside, Scotland, from January 1, 1993, to December 31, 2009. PATIENTS: All Tayside residents with at least two measurements of TSH below the reference range for at least 4 months from baseline and normal free T(4)/total T(4) and total T(3) concentrations at baseline were included as potential cases. Using a unique patient identifier, data linkage enabled a cohort of SH cases to be identified from prescription, admission, and radioactive iodine treatment records. Cases younger than 18 yr of age were also excluded from the study. OUTCOME MEASURES: The status of patients was investigated at 2, 5, and 7 yr after diagnosis. RESULTS: We identified 2024 cases with SH, a prevalence of 0.63% and an incidence of 29 per 100,000 in 2008. Most SH cases without thyroid treatment remained as SH at 2 (81.8%), 5 (67.5%), and 7 yr (63.0%) after diagnosis. Few patients (0.5 0.7%) developed hyperthyroidism at 2, 5, and 7 yr. The percentage of SH cases reverting to normal increased with time: 17.2% (2 yr), 31.5% (5 yr), and 35.6% (7 yr), and this was more common in SH patients with baseline TSH between 0.1 and 0.4 mU/liter. CONCLUSION: Very few SH patients develop frank hyperthyroidism, whereas a much larger proportion revert to normal, and many remain with SH. PMID- 20926533 TI - Metformin versus placebo from first trimester to delivery in polycystic ovary syndrome: a randomized, controlled multicenter study. AB - CONTEXT: Metformin is widely prescribed to pregnant women with polycystic ovary syndrome (PCOS) in an attempt to reduce pregnancy complications. Metformin is not approved for this indication, and evidence for this practice is lacking. OBJECTIVES: Our objective was to test the hypothesis that metformin, from first trimester to delivery, reduces pregnancy complications in women with PCOS. DESIGN AND SETTING: We conducted a randomized, placebo-controlled, double-blind, multicenter study at 11 secondary care centers. PARTICIPANTS: The participants were 257 women with PCOS, in the first trimester of pregnancy, aged 18-42 yr. INTERVENTION: We randomly assigned 274 singleton pregnancies (in 257 women) to receive metformin or placebo, from first trimester to delivery. MAIN OUTCOME MEASURES: The prevalence of preeclampsia, gestational diabetes mellitus, preterm delivery, and a composite of these three outcomes is reported. RESULTS: Preeclampsia prevalence was 7.4% in the metformin group and 3.7% in the placebo group (3.7%; 95% CI, -1.7-9.2) (P=0.18). Preterm delivery prevalence was 3.7% in the metformin group and 8.2% in the placebo group (-4.4%; 95%, CI, -10.1-1.2) (P=0.12). Gestational diabetes mellitus prevalence was 17.6% in the metformin group and 16.9% in the placebo group (0.8%; 95% CI, -8.6-10.2) (P=0.87). The composite primary endpoint prevalence was 25.9 and 24.4%, respectively (1.5%; 95% CI, -8.9-11.3) (P=0.78). Women in the metformin group gained less weight during pregnancy compared with those in the placebo group. There was no difference in fetal birth weight between the groups. CONCLUSIONS: Metformin treatment from first trimester to delivery did not reduce pregnancy complications in PCOS. PMID- 20926534 TI - Effects of exercise on insulin resistance and body composition in overweight and obese women with and without polycystic ovary syndrome. AB - CONTEXT: Polycystic ovary syndrome (PCOS) is an insulin-resistant (IR) state. Visceral fat (VF) is independently associated with IR. OBJECTIVES: The objectives of the study were to explore mechanisms underpinning IR by assessing the effect of exercise training on IR and body composition in overweight PCOS and non-PCOS women. DESIGN: This was a prospective exercise intervention study. SETTING AND PARTICIPANTS: The study was conducted at an academic medical center. Participants included 20 overweight PCOS and 14 overweight non-PCOS women. INTERVENTION: The intervention included 12 wk of intensified aerobic exercise (3 h/wk). MAIN OUTCOME MEASURES: IR on euglycemic hyperinsulinemic clamp, body composition including abdominal visceral and sc fat distribution by computer tomography and lipids was measured. RESULTS: PCOS subjects were more IR (P = 0.02) and had more VF (P = 0.04 age adjusted) than non-PCOS women. In PCOS women, IR correlated with VF (r = -0.78, P < 0.01). With exercise training, both groups maintained weight but within PCOS, VF (-12.0 cm(2), P = 0.03) and within non-PCOS abdominal sc fat (-40.2 cm(2), P = 0.02) decreased. Despite exercise-induced improvement in IR within PCOS (+27.9 mg . m(-2) . min(-1), P = 0.03), no relationship with decreased VF (r = -0.08, P = 0.84) and no differential changes in IR and VF between groups were noted. Triglycerides decreased within PCOS (-0.27 mmol/liter, P = 0.02) and decreased differentially between groups (P < 0.01). CONCLUSIONS: Higher IR was related to increased VF in PCOS, suggesting an etiological role for VF in intrinsic IR in PCOS; however, changes with exercise intervention did not support a causal relationship. Triglycerides were modulated more by exercise training in PCOS than non-PCOS women. Within-group exercise-induced reductions in cardiometabolic risk factors including IR, triglycerides, and VF in PCOS were observed without significant weight loss and if confirmed in future controlled trials, suggest weight loss should not be the sole focus of exercise programs. PMID- 20926535 TI - Demethylation of TMS1 gene sensitizes thyroid cancer cells to TRAIL-induced apoptosis. AB - CONTEXT: TMS1 is a tumor suppressor gene that encodes for caspase recruitment domain containing regulatory protein and has been shown to be hypermethylated in various cancers. However, its methylation status has not been investigated in thyroid cancer. Therefore, we studied the methylation of TMS1 and its functional consequence in thyroid cancer. DESIGN: The methylation status of the promoter region of the TMS1 gene was determined using methylation-specific PCR in 40 papillary thyroid cancer samples, 10 normal thyroid tissue, and seven thyroid cancer cell lines. RT-PCR and Western blot analysis were used to assess the expression levels. 5-aza-2'-deoxycytidine was used to demethylate the thyroid cancer cell lines. Cell viability and apoptosis was determined by dimethylthiazoldiphenyltetra-zoliumbromide and flow cytometry. RESULTS: Twenty three percent of the papillary thyroid carcinoma samples were found to be methylated for the TMS1 gene. Two of seven thyroid cell lines were either completely or partially methylated for the TMS1 gene. The treatment of methylated thyroid cancer cell lines with 5-aza-2'-deoxycytidine resulted in the demethylation of the TMS1 gene leading to the restoration of its expression. After demethylation, treatment of cells with TNF-related apoptosis-inducing ligand (TRAIL) led to the induction of apoptosis via activation of caspases-8, caspase-3, and poly(ADP-ribose) polymerase. Interestingly, gene silencing of TMS1 using TMS1-specific small interfering RNA prevented TRAIL-mediated apoptosis. CONCLUSION: Our results demonstrated that the TMSI gene is methylated in thyroid cancer cells and repression of methylation by 5-aza-2'-deoxycytidine restored expression of the TMS1 gene and sensitized cells to TRAIL-induced apoptosis. These findings suggest that the TMS1 gene can be targeted by combination of demethylating agents with TRAIL to induce efficient apoptosis in thyroid cancer cells. PMID- 20926536 TI - Comprehensive genetic analysis of 182 unrelated families with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. AB - BACKGROUND: Genetic analysis is commonly performed in patients with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. STUDY OBJECTIVE: The objective of the study was to describe comprehensive CYP21A2 mutation analysis in a large cohort of CAH patients. METHODS: Targeted CYP21A2 mutation analysis was performed in 213 patients and 232 parents from 182 unrelated families. Complete exons of CYP21A2 were sequenced in patients in whom positive mutations were not identified by targeted mutation analysis. Copy number variation and deletions were determined using Southern blot analysis and PCR methods. Genotype was correlated with phenotype. RESULTS: In our heterogeneous U.S. cohort, targeted CYP21A2 mutation analysis did not identify mutations on one allele in 19 probands (10.4%). Sequencing identified six novel mutations (p.Gln262fs, IVS8+1G>A, IVS9 1G>A, p.R408H, p.Gly424fs, p.R426P) and nine previously reported rare mutations. The majority of patients (79%) were compound heterozygotes and 69% of nonclassic (NC) patients were compound heterozygous for a classic and a NC mutation. Duplicated CYP21A2 haplotypes, de novo mutations and uniparental disomy were present in 2.7% of probands and 1.9 and 0.9% of patients from informative families, respectively. Genotype accurately predicted phenotype in 90.5, 85.1, and 97.8% of patients with salt-wasting, simple virilizing, and NC mutations, respectively. CONCLUSIONS: Extensive genetic analysis beyond targeted CYP21A2 mutational detection is often required to accurately determine genotype in patients with CAH due to the high frequency of complex genetic variation. PMID- 20926538 TI - Approach to assigning gender in 46,XX congenital adrenal hyperplasia with male external genitalia: replacing dogmatism with pragmatism. AB - The goal of sex assignment is to facilitate the best possible quality of life for the patient. Factors such as reproductive system development, sexual identity, sexual function, and fertility are important considerations in this regard. Although some DSD gender assignments are relatively straightforward, those with midstage genital ambiguity and unclear gonadal function represent a major challenge. A recent major change in DSD care has been to encourage a male assignment for 46,XY infants with ambiguous genitalia who have evidence of testicular function and in utero central nervous system androgen exposure. In contrast, assignment of virilized 46,XX DSD patients remains female when ovaries and internal organs are present, regardless of the extent of virilization of the external genitalia. In this paper, we propose consideration of male assignment for these 46,XX patients who have fully developed male genitalia based on available outcome data. PMID- 20926537 TI - Genetic studies reveal the role of the endocrine and metabolic systems in aging. AB - Aging is a natural process that involves a general decline in many physiological functions, resulting in loss of function and eventually death. Extensive research is being performed in order to elucidate the biology of aging, especially with the advent of newer molecular and genetic methodologies. The endocrine system plays a major role in orchestrating cellular interactions, metabolism, growth, and senescence. Thus, researchers traditionally used hormones as tools to induce and examine specific biological effects that are associated with aging. Furthermore, because our recent knowledge on hormonal action expanded significantly, downstream pathways and genetic determinants currently prevail in aging research. In this review, we will summarize the effects of several hormones on human aging and longevity and present recent data from the Longevity Genes Study performed at Albert Einstein College of Medicine, looking at the phenotype and genotype of centenarians and their offspring. We will demonstrate that genetic factors that are associated with human longevity are heritable and may contribute not only to quantitative longevity but also to protection from age dependent disease and exceptional good health. PMID- 20926539 TI - Ectopic thyroid gland causing dysphonia: imaging and molecular studies. PMID- 20926540 TI - Toward excellence in testosterone testing: a consensus statement. AB - BACKGROUND: Testosterone assays are widely used. However, deficiencies in these assays limit their broad and effective implementation and threaten the health of those patients whose medical care relies upon its accurate measurement. Furthermore, the translation of research findings into information useful for patient care, such as new evidence-based clinical guidelines, is not possible unless both research and clinical assays are held to higher standards than are currently required. A group of concerned stakeholders was convened to address this problem. METHODS: Representatives of multiple professional societies, government, and industry, having a stake in ensuring that testosterone levels are measured accurately and reliably, met to identify goals, objectives, and actions necessary to bring about the standardization of assays for testosterone. RESULTS: To ensure highly accurate testosterone testing that will result in improved diagnosis, treatment, and prevention of disease through the use of standardized assays, a series of recommendations were agreed upon. The recommendations included the following: technical improvements for assay standardization; education of health care providers, patients, and all others concerned with testosterone testing; plans to encourage all concerned journals, government agencies, and health insurance companies to support this effort; and encouragement to manufacturers to develop better and more cost effective assays. CONCLUSION: A preliminary timeline was set out to implement the recommendations of the Group. PMID- 20926541 TI - IGF-I: panacea or poison? PMID- 20926542 TI - To beta-e or not to beta-e replicating after 30: retrospective dating of human pancreatic islets. PMID- 20926543 TI - Elevated insulin-like growth factor-I values in children with Prader-Willi syndrome compared with growth hormone (GH) deficiency children over two years of GH treatment. AB - BACKGROUND: Children with Prader-Willi syndrome (PWS) are routinely treated with GH and have a response comparable with that observed in children with GH deficiency (GHD). OBJECTIVE: The objective of the study was to compare changes in serum IGF-I, IGF binding protein 3 (IGFBP-3), IGF-I to IGFBP-3 molar ratio, and growth velocity during the first 2 yr of GH therapy in PWS and GHD children. SUBJECTS AND METHODS: Thirty-three children with PWS (14 boys, 4.9 +/- 3.8 yr) and 591 with GHD (351 boys, 9.6 +/- 3.6 yr), all naive to GH treatment, were included in this study. Serum IGF-I and IGFBP-3 were measured at 0, 6, 12, and 24 months of GH therapy. The mean initial dose of GH was 0.9 and 1 mg/m(2) . d in the PWS and GHD groups, respectively. RESULTS: Mean +/- SD IGF-I sdscore (SDS) and IGFBP-3 SDS were significantly higher in PWS compared with GHD. The IGF-I to IGFBP-3 molar ratio was significantly lower at baseline and subsequently not different. Despite significantly lower GH doses in PWS children at 6, 12, and 24 months (P = 0.021, P = 0.021, P = 0.001), IGF-I reached 2.8 +/- 1.2 SDS at 24 months (72% of values > 2 SDS), and remained at 0.7 +/- 1.6 SDS in GHD children (17% of values > 2 SDS). IGFBP-3 did not exceed 2 SDS in either group. There was no significant change in the IGF-I to IGFBP-3 molar ratio. CONCLUSIONS: IGF-I SDS increases to a greater extent in PWS than GHD. Bioavailable IGF-I is apparently not different, suggesting that any possible safety issues related to elevated IGF I are similar in both groups. PMID- 20926544 TI - Allele polymorphisms of tumor integrins correlate with peritoneal carcinosis capability of gastric cancer cells in radically resected patients. AB - BACKGROUND: Preclinical studies suggested that integrins are relevant for gastric cancer diffusion. We investigated integrins polymorphisms role in determining peritoneal carcinosis or hematogenous metastases in radically resected gastric cancer. PATIENTS AND METHODS: Integrins genotyping was carried out on pT3 radically resected gastric tumors recurring with either peritoneal-only carcinosis or hematogenous metastases. RESULTS: The following factors resulted independently associated with peritoneal carcinosis or hematogenous metastases: the A genotype of rs2269772 (ITGA3) [odds ratio (OR) for peritoneal carcinosis: 22.2, 95% confidence interval 1.2-40, P=0.03], the G genotype of rs2269772 (ITGA3) (OR for hematogenous metastases: 5.5, 95% confidence interval 2.2-14.15, P=0.0003), the C genotype of rs11902171 (ITGV) (OR for peritoneal carcinosis: 6.8, 95% confidence interval 1.3-33.4, P=0.01), the G genotype of rs11902171 (ITGV) (OR for hematogenous metastases: 2.5, 95% confidence interval 1.1-5.7, P = 0.02), diffuse histology (OR for peritoneal carcinosis: 4.7, 95% confidence interval 1.9-11.3, P=0.0005) and intestinal histology (OR for hematogenous metastases: 4.2, 95% confidence interval 1.9-9.9, P=0.0008). CONCLUSIONS: Tumor histology represents a crucial issue conditioning tumoral behavior; genotyping of rs2269772 (ITGA3) and rs11902171 (ITGV) may be a further asset in the definition of high-risk patients for peritoneal carcinosis among those relapsing after curative resection. The selection tool deriving from this analysis may allow an optimal use of innovative treatment strategies. PMID- 20926545 TI - Evaluation of psychosocial distress in patients treated in a community-based oncology group practice in Germany. AB - BACKGROUND: Systematic evaluation of psychosocial distress in oncology outpatients is an important issue. We assessed feasibility and benefit of standardized routine screening using the Distress Thermometer (DT) and Problem List (PL) in all patients of our community-based hematooncology group practice. PATIENTS AND METHODS: One thousand four hundred forty-six patients were screened between July 2008 and September 2008. Five hundred randomly selected patients were sent a feedback form. RESULTS: The average distress level was 4.7, with 37% indicating a distress level >5. Patients with nonmalignant diseases (81% autoimmune diseases or hereditary hemochromatosis) showed the highest distress level of 5.2. Most distressed were patients who just learned about relapse or metastases (6.4), patients receiving best supportive care (5.4) and patients receiving adjuvant antihormonal therapy (5.4). Ninety-seven percent of patients appreciated to speak to their doctor about their distress. Fifty-six percent felt better than usual after this consultation. CONCLUSION: DT and PL are feasible instruments to measure distress in hematooncology outpatients receiving routine care. DT and PL are able to improve doctor-patient communication and thus should be implemented in routine patient care. The study shows that distress is distributed differently between individuals, disease groups and treatment phases. PMID- 20926546 TI - Role of KRAS let-7 LCS6 SNP in metastatic colorectal cancer patients. PMID- 20926547 TI - Dietary supplement use patterns in men with prostate cancer: the Cancer Prostate Sweden study. AB - BACKGROUND: In a European setting, we know little about the use of dietary supplements among men with prostate cancer (PCa) and to what extent lifestyle, disease or other factors influence such use. PATIENTS AND METHODS: We evaluated supplement use in 1127 men with incident PCa and in 900 population controls in Sweden. Age-adjusted binary regression with an identity link was carried out to estimate prevalence differences and corresponding 95% confidence intervals (CIs). Modifying effects of lifestyle- and diet-related factors were explored by statistical assessment of additive interaction. RESULTS: Among men with PCa, 542 individuals (48%) had used supplements, which was a 10% (95% CI: 5.9%-15%) higher prevalence than among population controls. Among individuals with high intake of fatty fish, vegetables, and phytoestrogens, but low intake of saturated fat, supplement use was 29% (95% CI: 18%-41%) more common in men with PCa than in population controls. We found no evidence of heterogeneity by categories of education, smoking history, body mass index, fiber, fruit, or phytoestrogen intake, treatment, or disease stage. CONCLUSION: Supplement use is common in Swedish men with PCa, especially among those with a healthy dietary pattern. PMID- 20926548 TI - First evidence of oncologic neuropathic pain prevalence after screening 8615 cancer patients. Results of the On study. AB - BACKGROUND: Thirty percent to ninety percent of cancer patients suffer from pain, including neuropathic pain (NP), which results in great burden for cancer patients. Thus, it was of great interest to determine NP prevalence in cancer patients in Spain, to raise awareness of the condition, and aiming to improve management of cancer NP. PATIENTS AND METHODS: A 1-month follow-up prospective epidemiological multicenter study was conducted to assess prevalence and management of NP in Spanish oncologic units. The first 10 cancer patients at each unit diagnosed with NP by the validated Douleur Neuropathique 4 questionnaire (DN4) were recruited. RESULTS: Of 8615 screened patients, 2567 (30%) suffered from pain. From these, 33% had NP according to investigators and 19% according to DN4 test. Three hundred and sixty-six patients (mean age 62.6 years; 61.2% male) were recruited. Pain decrease at 1 month was greater in patients with metastases (P<0.01) and depended on treatment (P<0.05), with 'oxycodone' showing 50.4% pain relief. CONCLUSIONS: NP prevalence in cancer pain is 33%. DN4 reports only about half the cancer NP cases diagnosed by clinicians. Pharmaceutical treatment of cancer pain, including NP, has a greater effect in patients with metastases and seems to depend on the specific treatment used. PMID- 20926549 TI - Evolution in management of testicular seminoma: population-based outcomes with selective utilization of active therapies. AB - BACKGROUND: In this article, we report the evolution of treatment with increased use of active surveillance for stage I disease as well as risk-adapted chemotherapy for disseminated disease and associated outcomes of testicular seminoma in a contemporary population-based cohort. METHODS: All patients with histologically confirmed seminoma referred from 1999 to 2008 to the British Columbia Cancer Agency or Providence Cancer Center were retrospectively reviewed. Both institutions manage 90% of testicular cancers in their respective area. RESULTS: A total of 649 patients were included. Clinical stage (CS) distribution: CSI/II/III n=545/87/17. For CSI, there was a progressive and marked decrease in the utilization of prophylactic radiation (RT), and corresponding increase in the use of active surveillance. No deaths related to seminoma were reported in CSI patients. CSII or CSIII patients received RT or International Germ Cell Cancer Collaborative Group (IGCCCG) risk-appropriate chemotherapy with 101 of 104 patients being in long-term remission and 3 patients dying from treatment complications. For the entire seminoma population, <1% of patients died of seminoma or treatment after a median follow-up of 47 months (range 2-130 months). CONCLUSIONS: Progressive application of policies of active surveillance and earlier initiation of IGCCCG risk-adapted chemotherapy result in nearly universal control for all patients presenting with seminoma while reducing the burden of treatment. PMID- 20926550 TI - Metabolic and signaling aspects underpinning the regulation of plant carbon nitrogen interactions. AB - In addition to light and water, CO(2) and mineral elements are required for plant growth and development. Among these factors, nitrogen is critical, since it is needed to synthesize amino acids, which are the building elements of protein, nucleotides, chlorophyll, and numerous other metabolites and cellular components. Therefore, nitrogen is required by plants in higher quantities and this investment in nitrogen supports the use of CO(2), water, and inorganic nitrogen to produce sugars, organic acids, and amino acids, the basic building blocks of biomass accumulation. This system is maintained by complex metabolic machinery, which is regulated at different levels according to environmental factors such as light, CO(2), and nutrient availability. Plants integrate these signals via a signaling network, which involves metabolites as well as nutrient-sensing proteins. Due to its importance, much research effort has been expended to understand how carbon and nitrogen metabolism are integrated and regulated according to the rates of photosynthesis, photorespiration, and respiration. Thus, in this article, we both discuss recent advances in carbon/nitrogen metabolisms as well as sensing and signaling systems in illuminated leaves of C3 plants and provide a perspective of the type of experiments that are now required in order to take our understanding to a higher level. PMID- 20926551 TI - Sex-related differences in morphological, physiological, and ultrastructural responses of Populus cathayana to chilling. AB - Low temperature is one of the abiotic factors limiting plant growth and productivity. Yet, knowledge about sex-related responses to low temperature is very limited. In our study, the effects of low, non-freezing temperature on morphological, physiological, and ultrastructural traits of leaves in Populus cathayana Rehd. males and females were investigated. The results showed that 4 degrees C temperature caused a chilling stress, and females suffered from greater negative effects than did males. At the early growth stage of development, chilling (4 degrees C) significantly inhibited plant growth, decreased net photosynthesis rate (P(n)), stomatal conductance (g(s)), transpiration (E), and chlorophyll pigments (Chl), and increased intercellular CO(2) concentration (C(i)), chlorophyll a/b (Chl a/b), proline, soluble sugar and H(2)O(2) contents, and ascorbate peroxidase (APX) activity in both sexes, whereas peroxidase (POD) and glutathione reductase (GR) activities decreased and thiobarbituric acid reactive substance (TBARS) content increased only in females. Chilling stress also caused chloroplast changes and an accumulation of numerous plastoglobules and small vesicles in both sexes. However, disintegrated chloroplasts and numerous tilted grana stacks were only found in chilling-stressed females. Under chilling stress, males showed higher Chl and soluble sugar contents, and higher superoxide dismutase (SOD), POD, and GR activities than did females. In addition, males exhibited a better chloroplast structure and more intact plasma membranes than did females under chilling stress. These results suggest that sexually different responses to chilling are significant and males possess a better self protection mechanism than do females in P. cathayana. PMID- 20926552 TI - Understanding plant response to nitrogen limitation for the improvement of crop nitrogen use efficiency. AB - Development of genetic varieties with improved nitrogen use efficiency (NUE) is essential for sustainable agriculture. Generally, NUE can be divided into two parts. First, assimilation efficiency involves nitrogen (N) uptake and assimilation and second utilization efficiency involves N remobilization. Understanding the mechanisms regulating these processes is crucial for the improvement of NUE in crop plants. One important approach is to develop an understanding of the plant response to different N regimes, especially to N limitation, using various methods including transcription profiling, analysing mutants defective in their normal response to N limitation, and studying plants that show better growth under N-limiting conditions. One can then attempt to improve NUE in crop plants using the knowledge gained from these studies. There are several potential genetic and molecular approaches for the improvement of crop NUE discussed in this review. Increased knowledge of how plants respond to different N levels as well as to other environmental conditions is required to achieve this. PMID- 20926553 TI - Maize meiotic mutants with improper or non-homologous synapsis due to problems in pairing or synaptonemal complex formation. AB - During meiotic prophase homologous chromosomes find each other and pair. Then they synapse, as the linear protein core (axial element or lateral element) of each homologous chromosome is joined together by a transverse central element, forming the tripartite synaptonemal complex (SC). Ten uncloned Zea mays mutants in our collection were surveyed by transmission electron microscopy by making silver-stained spreads of SCs to identify mutants with non-homologous synapsis or improper synapsis. To analyse the mutants further, zyp1, the maize orthologue of the Arabidopsis central element component ZYP1 was cloned and an antibody was made against it. Using antibodies against ZYP1 and the lateral element components AFD1 and ASY1, it was found that most mutants form normal SCs but are defective in pairing. The large number of non-homologous synapsis mutants defective in pairing illustrates that synapsis and pairing can be uncoupled. Of the ten mutants studied, only dsy2 undergoes normal homologous chromosome recognition needed for homologous pairing. The dsy2 mutation fails to maintain the SC. ZYP1 elongation is blocked at zygotene, and only dots of ZYP1 are seen at prophase I. Another mutant, mei*N2415 showed incomplete but homologous synapsis and ASY1 and AFD1 have a normal distribution. Although installation of ZYP1 is initiated at zygotene, its progression is slowed down and not completed by pachytene in some cells and ZYP1 is not retained on pachytene chromosomes. The mutants described here are now available through the Maize Genetics Cooperation Stock Center (http://maizecoop.cropsci.uiuc.edu/). PMID- 20926554 TI - Positive outlook as a moderator of the effectiveness of an HIV/STI intervention with adolescents in detention. AB - Justice-involved adolescents engage in high levels of risky sexual behavior, underscoring the need for targeted, effective, prevention interventions geared toward this population. In a randomized controlled trial, 484 detained adolescents received a theory-based intervention or an information-only control. We have previously demonstrated that the theory-based intervention was superior to the control condition in changing theoretical mediators and in producing longitudinal decreases in risky sexual behavior. In the present study, we examined differential response to the intervention based on the adolescents' level of positive outlook (composed of self-esteem, perceived control over the future and optimism toward the future). Changes to putative theoretical mediators (attitudes, perceived norms, self-efficacy and intentions) were measured immediately post-intervention, and behavioral data were obtained 3, 6, 9 and 12 months later. Positive outlook significantly moderated program effects both in the context of the mediational path model and in the context of the longitudinal growth model. Specifically, intervention effects were strongest for those scoring relatively lower on the positive outlook dimension, whereas adolescents high in positive outlook demonstrated greater attitudes and self-efficacy and decreased risky sexual behavior, regardless of condition. Findings are discussed in terms of targeting and tailoring of intervention content. PMID- 20926555 TI - Orthodontic treatment need in a 12-year-old population in the Western Sahara. AB - The aim of this study was to establish orthodontic treatment need according to the Dental Aesthetic Index (DAI) and Aesthetic Component (AC) and Dental Health Component (DHC) of the Index of Orthodontic Treatment Need (IOTN) and to determine its association with gender among Saharan schoolchildren. The study was carried out in accordance with World Health Organization (WHO) recommendations for oral health surveys at 12 years of age. The sample comprised 248 Sahrawi children (135 girls and 113 boys) living in refugee camps in Tindouf, Algeria. None of the children had previously received any orthodontic treatment. A chi square test was used to analyse the IOTN results by gender, and a Student's t test was employed for the DAI results. The mean DAI was 23.32 with a standard deviation of 6.05, 4 percent with a very severe and 9.2 per cent with severe malocclusion. Orthodontic treatment need was 16.1 and 2.0 percent, respectively, according to grades 4 and 5 of the IOTN DHC, 13.7 percent according to the IOTN AC, and 28.6 percent according to the modified IOTN (IOTN DHC grades 4-5 and/or IOTN AC grades 8-10). There were no statistically significant differences by gender. The orthodontic treatment need of Western Saharan schoolchildren is similar to that reported by many recent studies in European and in Sub-Saharan countries. PMID- 20926556 TI - Factors influencing the stability of miniscrews. A retrospective study on 300 miniscrews. AB - The aim of this study was to investigate, over a period of approximately 3 years, the reactions to orthodontic loading of a type V titanium miniscrew. In this retrospective study, conducted in a private practice, the records of 300 miniscrews inserted in 132 consecutive patients (80 females, 60.6 percent) by the same surgeon were evaluated. The mean age of the patients was 23.2 years. Three types of miniscrews (type A: diameter 1.5 mm, length 9 mm; type B: diameter 1.5 mm, length 11 mm; and type C: diameter 1.3 mm, length 11 mm) were used. The clinical variables evaluated included the loading time and location of the miniscrew in relation to the gingiva and root. The success rates with different variables were compared using chi-square or Fisher's exact test where appropriate. A cumulative survival rate of 81 percent (243/300) was found using Kaplan-Meier analysis, with an optimum success rate for the 1.3 mm wide miniscrew inserted in the attached gingiva, with immediate loading applied. Cox proportional hazard regression showed significant differences between success rate and the following parameters: gender, loading time, gingival or bone localization, and diameter of the miniscrews. Considering the clinically controllable parameters, and within the limits of this retrospective study, 1.3 mm diameter miniscrews inserted in attached gingiva and immediately loaded had the most favourable prognosis. PMID- 20926557 TI - Determinants of tetherin antagonism in the transmembrane domain of the human immunodeficiency virus type 1 Vpu protein. AB - Tetherin (BST2/CD317) potently restricts the particle release of human immunodeficiency virus type 1 (HIV-1) mutants defective in the accessory gene vpu. Vpu antagonizes tetherin activity and induces its cell surface downregulation and degradation in a manner dependent on the transmembrane (TM) domains of both proteins. We have carried out extensive mutagenesis of the HIV-1 NL4.3 Vpu TM domain to identify three amino acid positions, A14, W22, and, to a lesser extent, A18, that are required for tetherin antagonism. Despite the mutants localizing indistinguishably from the wild-type (wt) protein and maintaining the ability to multimerize, mutation of these positions rendered Vpu incapable of coimmunoprecipitating tetherin or mediating its cell surface downregulation. Interestingly, these amino acid positions are predicted to form one face of the Vpu transmembrane alpha helix and therefore potentially contribute to an interacting surface with the transmembrane domain of tetherin either directly or by modulating the conformation of Vpu oligomers. While the equivalent of W22 is invariant in HIV-1/SIVcpz Vpu proteins, the positions of A14 and A18 are highly conserved among Vpu alleles from HIV-1 groups M and N, but not those from group O or SIVcpz that lack human tetherin (huTetherin)-antagonizing activity, suggesting that they may have contributed to the adaption of HIV-1 to human tetherin. PMID- 20926558 TI - Evolved variants of the membrane protein can partially replace the envelope protein in murine coronavirus assembly. AB - The coronavirus small envelope (E) protein plays a crucial, but poorly defined, role in the assembly of virions. To investigate E protein function, we previously generated E gene point mutants of mouse hepatitis virus (MHV) that were defective in growth and assembled virions with anomalous morphologies. We subsequently constructed an E gene deletion (DeltaE) mutant that was only minimally viable. The DeltaE virus formed tiny plaques and reached optimal infectious titers many orders of magnitude below those of wild-type virus. We have now characterized highly aberrant viral transcription patterns that developed in some stocks of the DeltaE mutant. Extensive analysis of three independent stocks revealed that, in each, a faster-growing virus harboring a genomic duplication had been selected. Remarkably, the net result of each duplication was the creation of a variant version of the membrane protein (M) gene that was situated upstream of the native copy of the M gene. Each different variant M gene encoded an expressed protein (M*) containing a truncated endodomain. Reconstruction of one variant M gene in a DeltaE background showed that expression of the M* protein markedly enhanced the growth of the DeltaE mutant and that the M* protein was incorporated into assembled virions. These findings suggest that M* proteins were repeatedly selected as surrogates for the E protein and that one role of E is to mediate interactions between transmembrane domains of M protein monomers. Our results provide a demonstration of the capability of coronaviruses to evolve new gene functions through recombination. PMID- 20926559 TI - Mice lacking alpha/beta and gamma interferon receptors are susceptible to junin virus infection. AB - Junin virus (JUNV) causes a highly lethal human disease, Argentine hemorrhagic fever. Previous work has demonstrated the requirement for human transferrin receptor 1 for virus entry, and the absence of the receptor was proposed to be a major cause for the resistance of laboratory mice to JUNV infection. In this study, we present for the first time in vivo evidence that the disruption of interferon signaling is sufficient to generate a disease-susceptible mouse model for JUNV infection. After peripheral inoculation with virulent JUNV, adult mice lacking alpha/beta and gamma interferon receptors developed disseminated infection and severe disease. PMID- 20926560 TI - Transforming growth factor beta is a major regulator of human neonatal immune responses following respiratory syncytial virus infection. AB - Respiratory syncytial virus (RSV) is a major cause of morbidity and mortality. Previous studies have suggested that T-cell responses may contribute to RSV immunopathology, which could be driven by dendritic cells (DCs). DCs are productively infected by RSV, and during RSV infections, there is an increase of DCs in the lungs with a decrease in the blood. Pediatric populations are particularly susceptible to severe RSV infections; however, DC responses to RSV from pediatric populations have not been examined. In this study, primary isolated DCs from cord blood and adult peripheral blood were compared after RSV infection. Transcriptional profiling and biological network analysis identified transforming growth factor beta (TGF-beta) and associated signaling molecules as differentially regulated in the two age groups. TGF-beta1 was decreased in RSV infected adult-blood DCs but increased in RSV-infected cord blood DCs. Coculture of adult RSV-infected DCs with autologous T cells induced secretion of gamma interferon (IFN-gamma), interleukin 12p70 (IL-12p70), IL-2, and tumor necrosis factor alpha (TNF-alpha). Conversely, coculture of cord RSV-infected DCs and autologous T cells induced secretion of IL-4, IL-6, IL-1beta, and IL-17. Addition of purified TGF-beta1 to adult DC-T-cell cocultures reduced secretion of IFN gamma, IL-12p70, IL-2, and TNF-alpha, while addition of a TGF-beta chemical inhibitor to cord DC-T-cell cocultures increased secretion of IL-12p70. These data suggest that TGF-beta acts as a major regulator of RSV DC-T-cell responses, which could contribute to immunopathology during infancy. PMID- 20926561 TI - Amphipathic alpha-helix AH2 is a major determinant for the oligomerization of hepatitis C virus nonstructural protein 4B. AB - Nonstructural protein 4B (NS4B) is a key organizer of hepatitis C virus (HCV) replication complex formation. It induces a specific membrane rearrangement, designated membranous web, that serves as a scaffold for the HCV replication complex. However, the mechanisms underlying membranous web formation are poorly understood. Based on fluorescence resonance energy transfer (FRET) and confirmatory coimmunoprecipitation analyses, we provide evidence for an oligomerization of NS4B in the membrane environment of intact cells. Several conserved determinants were found to be involved in NS4B oligomerization, through homotypic and heterotypic interactions. N-terminal amphipathic alpha-helix AH2, comprising amino acids 42 to 66, was identified as a major determinant for NS4B oligomerization. Mutations that affected the oligomerization of NS4B disrupted membranous web formation and HCV RNA replication, implying that oligomerization of NS4B is required for the creation of a functional replication complex. These findings enhance our understanding of the functional architecture of the HCV replication complex and may provide new angles for therapeutic intervention. At the same time, they expand the list of positive-strand RNA virus replicase components acting as oligomers. PMID- 20926562 TI - Association of potent human antiviral cytidine deaminases with 7SL RNA and viral RNP in HIV-1 virions. AB - 7SL RNA promotes the formation of the signal recognition particle that targets secretory and membrane proteins to the endoplasmic reticulum. 7SL RNA is also selectively packaged by many retroviruses, including HIV-1. Here, we demonstrate that 7SL RNA is an integral component of the viral ribonucleoprotein (RNP) complex containing Gag, viral genomic RNA, and tRNA(3)(Lys). Only the potent anti HIV-1 cytidine deaminases can bind to 7SL RNA and target to HIV-1 RNP. A conserved motif in the amino-terminal region of A3G is important for 7SL RNA interaction. The weak anti-HIV-1 A3C did not interact with 7SL RNA and failed to target to viral RNPs, despite efficient virion packaging. However, a chimeric construct of A3C plus the 7SL-binding amino terminus of A3G did target to viral RNPs and showed enhanced anti-HIV-1 activity. 7SL RNA binding is a conserved feature of human anti-HIV-1 cytidine deaminases. Thus, potent anti-HIV-1 cytidine deaminases have evolved to possess a unique RNA-binding ability for precise HIV-1 targeting and viral inhibition. PMID- 20926563 TI - Genomic profiling of tumor necrosis factor alpha (TNF-alpha) receptor and interleukin-1 receptor knockout mice reveals a link between TNF-alpha signaling and increased severity of 1918 pandemic influenza virus infection. AB - The influenza pandemic of 1918 to 1919 was one of the worst global pandemics in recent history. The highly pathogenic nature of the 1918 virus is thought to be mediated in part by a dysregulation of the host response, including an exacerbated proinflammatory cytokine response. In the present study, we compared the host transcriptional response to infection with the reconstructed 1918 virus in wild-type, tumor necrosis factor (TNF) receptor-1 knockout (TNFRKO), and interleukin-1 (IL-1) receptor-1 knockout (IL1RKO) mice as a means of further understanding the role of proinflammatory cytokine signaling during the acute response to infection. Despite reported redundancy in the functions of IL-1beta and TNF-alpha, we observed that reducing the signaling capacity of each of these molecules by genetic disruption of their key receptor genes had very different effects on the host response to infection. In TNFRKO mice, we found delayed or decreased expression of genes associated with antiviral and innate immune signaling, complement, coagulation, and negative acute-phase response. In contrast, in IL1RKO mice numerous genes were differentially expressed at 1 day postinoculation, including an increase in the expression of genes that contribute to dendritic and natural killer cell processes and cellular movement, and gene expression profiles remained relatively constant at later time points. We also observed a compensatory increase in TNF-alpha expression in virus-infected IL1RKO mice. Our data suggest that signaling through the IL-1 receptor is protective, whereas signaling through the TNF-alpha receptor increases the severity of 1918 virus infection. These findings suggest that manipulation of these pathways may have therapeutic benefit. PMID- 20926564 TI - HIV-1 continues to replicate and evolve in patients with natural control of HIV infection. AB - Elucidating mechanisms leading to the natural control of HIV-1 infection is of great importance for vaccine design and for understanding viral pathogenesis. Rare HIV-1-infected individuals, termed HIV-1 controllers, have plasma HIV-1 RNA levels below the limit of detection by standard clinical assays (<50 to 75 copies/ml) without antiretroviral therapy. Although several recent studies have documented persistent low-grade viremia in HIV-1 controllers at a level not significantly different from that in HIV-1-infected individuals undergoing treatment with combination antiretroviral therapy (cART), it is unclear if plasma viruses are undergoing full cycles of replication in vivo or if the infection of new cells is completely blocked by host immune mechanisms. We studied a cohort of 21 HIV-1 controllers with a median level of viremia below 1 copy/ml, followed for a median of 11 years. Less than half of the cohort carried known protective HLA types (B*57/27). By isolating HIV-1 RNA from large volumes of plasma, we amplified single genome sequences of both pro-rt and env longitudinally. This study is the first to document that HIV-1 pro-rt and env evolve in this patient group, albeit at rates somewhat lower than in HIV-1 noncontrollers, in HLA B*57/27-positive, as well as HLA B*57/27-negative, individuals. Viral diversity and adaptive events associated with immune escape were found to be restricted in HIV-1 controllers, suggesting that replication occurs in the face of less overall immune selection. PMID- 20926565 TI - Immature and transitional B cells are latency reservoirs for a gammaherpesvirus. AB - Gammaherpesviruses, including Kaposi's sarcoma-associated herpesvirus (KSHV; also known as human herpesvirus 8 [HHV-8]), Epstein-Barr virus (EBV), and murine gammaherpesvirus 68 (MHV68; also known as gammaherpesvirus 68 [gammaHV68] or murine herpesvirus 4 [MuHV-4]), establish lifelong latency in the resting memory B cell compartment. However, little is known about how this reservoir of infected mature B cells is maintained for the life of the host. In the context of a normal immune system, the mature B cell pool is naturally maintained by the renewable populations of developing B cells that arise from hematopoiesis. Thus, recurrent infection of these developing B cell populations could allow the virus continual access to the B cell lineage and, subsequent to differentiation, the memory B cell compartment. To begin to address this hypothesis, we examined whether MHV68 establishes latency in developing B cells during a normal course of infection. In work described here, we demonstrate the presence of viral genome in bone marrow pro-pre-B cells and immature B cells during early latency and immature B cells during long-term latency. Further, we show that transitional B cells in the spleen are latently infected and express the latency-associated nuclear antigen (LANA) throughout chronic infection. Because developing B cells normally exhibit a short life span and a high rate of turnover, these findings suggest a model in which gammaherpesviruses may gain access to the mature B cell compartment by recurrent seeding of developing B cells. PMID- 20926566 TI - Efficient activation of the severe acute respiratory syndrome coronavirus spike protein by the transmembrane protease TMPRSS2. AB - The distribution of the severe acute respiratory syndrome coronavirus (SARS-CoV) receptor, an angiotensin-converting enzyme 2 (ACE2), does not strictly correlate with SARS-CoV cell tropism in lungs; therefore, other cellular factors have been predicted to be required for activation of virus infection. In the present study, we identified transmembrane protease serine 2 (TMPRSS2), whose expression does correlate with SARS-CoV infection in the upper lobe of the lung. In Vero cells expressing TMPRSS2, large syncytia were induced by SARS-CoV infection. Further, the lysosome-tropic reagents failed to inhibit, whereas the heptad repeat peptide efficiently inhibited viral entry into cells, suggesting that TMPRSS2 affects the S protein at the cell surface and induces virus-plasma membrane fusion. On the other hand, production of virus in TMPRSS2-expressing cells did not result in S protein cleavage or increased infectivity of the resulting virus. Thus, TMPRSS2 affects the entry of virus but not other phases of virus replication. We hypothesized that the spatial orientation of TMPRSS2 vis-a-vis S protein is a key mechanism underling this phenomenon. To test this, the TMPRSS2 and S proteins were expressed in cells labeled with fluorescent probes of different colors, and the cell-cell fusion between these cells was tested. Results indicate that TMPRSS2 needs to be expressed in the opposing (target) cell membrane to activate S protein rather than in the producer cell, as found for influenza A virus and metapneumoviruses. This is the first report of TMPRSS2 being required in the target cell for activation of a viral fusion protein but not for the S protein synthesized in and transported to the surface of cells. Our findings suggest that the TMPRSS2 expressed in lung tissues may be a determinant of viral tropism and pathogenicity at the initial site of SARS-CoV infection. PMID- 20926567 TI - Tetrameric ring formation of Epstein-Barr virus polymerase processivity factor is crucial for viral replication. AB - The Epstein-Barr virus BMRF1 DNA polymerase processivity factor, which is essential for viral genome replication, exists mainly as a C-shaped head-to-head homodimer but partly forms a ring-shaped tetramer through tail-to-tail association. Based on its molecular structure, several BMRF1 mutant viruses were constructed to examine their influence on viral replication. The R256E virus, which has a severely impaired capacity for DNA binding and polymerase processivity, failed to form replication compartments, resulting in interference of viral replication, while the C95E mutation, which impairs head-to-head contact in vitro, unexpectedly hardly affected the viral replication. Also, surprisingly, replication of the C206E virus, which is expected to have impairment of tail-to tail contact, was severely restricted, although the mutant protein possesses the same in vitro biochemical activities as the wild type. Since the tail-to-tail contact surface is smaller than that of the head-to-head contact area, its contribution to ring formation might be essential for viral replication. PMID- 20926568 TI - Multiple functions of Rice dwarf phytoreovirus Pns10 in suppressing systemic RNA silencing. AB - RNA silencing is a potent mechanism of antiviral defense response in plants and other organisms. For counterdefense, viruses have evolved a variety of suppressors of RNA silencing (VSRs) that can inhibit distinct steps of a silencing pathway. We previously identified Pns10 encoded by Rice dwarf phytoreovirus (RDV) as a VSR, the first of its kind from double-stranded RNA (dsRNA) viruses. In this study we investigated the mechanisms of Pns10 function in suppressing systemic RNA silencing in the widely used Nicotiana benthamiana model plant. We report that Pns10 suppresses local and systemic RNA silencing triggered by sense mRNA, enhances viral replication and/or viral RNA stability in inoculated leaves, accelerates the systemic spread of viral infection, and enables viral invasion of shoot apices. Mechanistically, Pns10 interferes with the perception of silencing signals in recipient tissues, binds double-stranded small interfering RNA (siRNAs) with two-nucleotide 3' overhangs, and causes the downregulated expression of RDR6. These results significantly deepen our mechanistic understanding of the VSR functions encoded by a dsRNA virus and contribute additional evidence that binding siRNAs and interfering with RDR6 expression are broad mechanisms of VSR functions encoded by diverse groups of viruses. PMID- 20926569 TI - Order to the viral universe. PMID- 20926570 TI - Antibody to the E3 glycoprotein protects mice against lethal venezuelan equine encephalitis virus infection. AB - Six monoclonal antibodies were isolated that exhibited specificity for a furin cleavage site deletion mutant (V3526) of Venezuelan equine encephalitis virus (VEEV). These antibodies comprise a single competition group and bound the E3 glycoprotein of VEEV subtype I viruses but failed to bind the E3 glycoprotein of other alphaviruses. These antibodies neutralized V3526 virus infectivity but did not neutralize the parental strain of Trinidad donkey (TrD) VEEV. However, the E3 specific antibodies did inhibit the production of virus from VEEV TrD-infected cells. In addition, passive immunization of mice demonstrated that antibody to the E3 glycoprotein provided protection against lethal VEEV TrD challenge. This is the first recognition of a protective epitope in the E3 glycoprotein. Furthermore, these results indicate that E3 plays a critical role late in the morphogenesis of progeny virus after E3 appears on the surfaces of infected cells. PMID- 20926571 TI - The inhibitory action of P56 on select functions of E1 mediates interferon's effect on human papillomavirus DNA replication. AB - The interferon (IFN)-induced protein P56 inhibits human papillomavirus (HPV) DNA replication by binding to HPV E1, which has several distinct functions in initiating viral DNA replication. Here, we determined that P56 inhibited HPV type 18 (HPV18) E1's DNA helicase activity, E2 binding, and HPV Ori sequence-specific DNA binding but not nonspecific DNA binding. We observed that deletion of a single amino acid, F399, produced an E1 mutant that could not bind P56. This E1 mutant retained its ability to support Ori DNA replication, but this activity was not inhibited by IFN, demonstrating that P56 is the principal executor of the anti-HPV action of IFN. PMID- 20926572 TI - Hepatitis C virus nonstructural protein 5A: biochemical characterization of a novel structural class of RNA-binding proteins. AB - Hepatitis C virus (HCV) nonstructural protein 5A (NS5A) exhibits a preference for G/U-rich RNA in vitro. Biological analysis of the NS5A RNA-binding activity and its target sites in the genome will be facilitated by a description of the NS5A RNA complex. We demonstrate that the C-4 carbonyl of the uracil base and, by inference, the C-6 carbonyl of the guanine base interact with NS5A. U-rich RNA of 5 to 6 nucleotides (nt) is sufficient for high-affinity binding to NS5A. The minimal RNA-binding domain of NS5A consists of residues 2005 to 2221 (referred to as domain I-plus). This region of the protein includes the amino-terminal domain I as well as the subsequent linker that separates domains I and II. This linker region is the site of adaptive mutations. U-rich RNA-binding activity is not observed for an NS5A derivative containing only residues 2194 to 2419 (domains II and III). Mass spectrometric analysis of an NS5A-poly(rU) complex identified domains I and II as sites for interaction with RNA. Dimerization of NS5A was demonstrated by glutaraldehyde cross-linking. This dimerization is likely mediated by domain I-plus, as dimers of this protein are trapped by cross linking. Dimers of the domain II-III protein are not observed. The monomer-dimer equilibrium of NS5A shifts in favor of dimer when U-rich RNA is present but not when A-rich RNA is present, consistent with an NS5A dimer being the RNA-binding competent form of the protein. These data provide a molecular perspective of the NS5A-RNA complex and suggest possible mechanisms for regulation of HCV and cellular gene expression. PMID- 20926573 TI - Glycine 184 in nonstructural protein NS1 determines the virulence of influenza A virus strain PR8 without affecting the host interferon response. AB - The nonstructural protein NS1 of influenza A virus counteracts the interferon (IFN) system and thereby promotes viral replication. NS1 has acquired different mechanisms to limit induction of IFN. It prevents double-stranded RNA (dsRNA) and RIG-I-mediated activation of interferon regulatory factor 3 (IRF3), and it blocks posttranscriptional processing of cellular mRNAs by binding to the cleavage and polyadenylation specificity factor (CPSF). Using a mouse-adapted A/PR/8/34 virus and reverse genetics to introduce specific mutations in NS1 which eliminate one or both functions, we determined the relative contributions of these two activities of NS1 to viral virulence in mice. We found that a functional RNA binding motif was required for IFN suppression and virulence. Restoration of CPSF binding in the NS1 protein of wild-type A/PR/8/34 virus, which cannot bind CPSF due to mutations in the central binding motif at positions 103 and 106, resulted in enhanced virulence. Surprisingly, if CPSF binding was abolished by substituting glycine for arginine at position 184 in the classical NS1-CPSF binding motif, the mutant virus replicated much more slowly in mice, although the mutated NS1 protein continued to repress the IFN response very efficiently. Our results show that a functional RNA-binding motif is decisive for NS1 of A/PR/8/34 virus to suppress IFN induction. They further demonstrate that in addition to its contribution to CPSF binding, glycine 184 strongly influences viral virulence by an unknown mechanism which does not involve the IFN system. PMID- 20926574 TI - Antiviral immunity following smallpox virus infection: a case-control study. AB - Outbreaks of smallpox (i.e., caused by variola virus) resulted in up to 30% mortality, but those who survived smallpox infection were regarded as immune for life. Early studies described the levels of neutralizing antibodies induced after infection, but smallpox was eradicated before contemporary methods for quantifying T-cell memory were developed. To better understand the levels and duration of immunity after smallpox infection, we performed a case-control study comparing antiviral CD4(+) and CD8(+) T-cell responses and neutralizing antibody levels of 24 smallpox survivors with the antiviral immunity observed in 60 smallpox-vaccinated (i.e., vaccinia virus-immune) control subjects. We found that the duration of immunity following smallpox infection was remarkably similar to that observed after smallpox vaccination, with antiviral T-cell responses that declined slowly over time and antiviral antibody responses that remained stable for decades after recovery from infection. These results indicate that severe, potentially life-threatening disease is not required for the development of sustainable long-term immunity. This study shows that the levels of immunity induced following smallpox vaccination are comparable in magnitude to that achieved through natural variola virus infection, and this may explain the notable success of vaccination in eradicating smallpox, one of the world's most lethal diseases. PMID- 20926575 TI - Excessive RNA splicing and inhibition of HIV-1 replication induced by modified U1 small nuclear RNAs. AB - HIV-1 RNA undergoes a complex splicing process whereby over 40 different mRNA species are produced by alternative splicing. In addition, approximately half of the RNA transcripts remain unspliced and either are used to encode Gag and Gag Pol proteins or are packaged into virions as genomic RNA. It has previously been shown that HIV-1 splicing is regulated by cis elements that bind to cellular factors. These factors either enhance or repress definition of exons that are flanked by the HIV-1 3' splice sites. Here we report that expression of modified U1 snRNPs with increased affinity to HIV-1 downstream 5' splice sites and to sequences within the first tat coding exon act to selectively increase splicing at the upstream 3' splice sites in cotransfected 293T cells. This results in a decrease of unspliced viral RNA levels and an approximately 10-fold decrease in virus production. In addition, excessive splicing of viral RNA is concomitant with a striking reduction in the relative amounts of Gag processing intermediates and products. We also show that T cell lines expressing modified U1 snRNAs exhibit reduced HIV-1 replication. Our results suggest that induction of excessive HIV-1 RNA splicing may be a novel strategy to inhibit virus replication in human patients. PMID- 20926576 TI - Human T-lymphotropic virus type 1 Tax protein complexes with P-TEFb and competes for Brd4 and 7SK snRNP/HEXIM1 binding. AB - Positive transcription elongation factor b (P-TEFb) plays an important role in stimulating RNA polymerase II elongation for viral and cellular gene expression. P-TEFb is found in cells in either an active, low-molecular-weight (LMW) form or an inactive, high-molecular-weight (HMW) form. We report here that human T lymphotropic virus type 1 (HTLV-1) Tax interacts with the cyclin T1 subunit of P TEFb, forming a distinct Tax/P-TEFb LMW complex. We demonstrate that Tax can play a role in regulating the amount of HMW complex present in the cell by decreasing the binding of 7SK snRNP/HEXIM1 to P-TEFb. This is seen both in vitro using purified Tax protein and in vivo in cells transduced with Tax expression constructs. Further, we find that a peptide of cyclin T1 spanning the Tax binding domain inhibits the ability of Tax to disrupt HMW P-TEFb complexes. These results suggest that the direct interaction of Tax with cyclin T1 can dissociate P-TEFb from the P-TEFb/7SK snRNP/HEXIM1 complex for activation of the viral long terminal repeat (LTR). We also show that Tax competes with Brd4 for P-TEFb binding. Chromatin immunoprecipitation (ChIP) assays demonstrated that Brd4 and P TEFb are associated with the basal HTLV-1 LTR, while Tax and P-TEFb are associated with the activated template. Furthermore, the knockdown of Brd4 by small interfering RNA (siRNA) activates the HTLV-1 LTR promoter, which results in an increase in viral expression and production. Our studies have identified Tax as a regulator of P-TEFb that is capable of affecting the balance between its association with the large inactive complex and the small active complex. PMID- 20926578 TI - cis-Acting sequences that contribute to synthesis of minus-strand DNA are not conserved between hepadnaviruses. AB - Hepadnaviruses are DNA viruses that are found in several mammalian and avian species. These viruses replicate their genome through reverse transcription of an RNA intermediate termed pregenomic RNA (pgRNA). pgRNA is reverse transcribed by the viral polymerase into a minus-strand DNA, followed by synthesis of the plus strand DNA. There are multiple cis-acting sequences that contribute to the synthesis of minus-strand DNA for human hepatitis B virus (HBV). Less is known about the cis-acting sequences of avian hepadnaviruses that contribute to synthesis of minus-strand DNA. To identify cis-acting sequences of duck hepatitis B virus (DHBV) and heron hepatitis B virus (HHBV), we analyzed variants containing 200-nucleotide (nt) deletions. Most variants of DHBV synthesized minus strand DNA to 50 to 100% of the wild-type (WT) level, while two variants synthesized less than 50%. For HHBV, most variants synthesized minus-strand DNA to less than 50% the WT level. These results differ from those for HBV, where most of the genome can be removed with little consequence. HBV contains a sequence, phi, that contributes to the synthesis of minus-strand DNA. It has been proposed that DHBV has an analogous sequence. We determined that the proposed phi sequence of DHBV does not contribute to the synthesis of minus-strand DNA. Finally, we found that the DR2 sequence present in all hepadnaviruses is important for synthesis of minus-strand DNA in both DHBV and HHBV but not in HBV. These differences in cis-acting sequences suggest that the individual hepadnaviruses have evolved differences in their mechanisms for synthesizing minus-strand DNA, more so than for other steps in replication. PMID- 20926577 TI - Metagenomic analysis of the viromes of three North American bat species: viral diversity among different bat species that share a common habitat. AB - Effective prediction of future viral zoonoses requires an in-depth understanding of the heterologous viral population in key animal species that will likely serve as reservoir hosts or intermediates during the next viral epidemic. The importance of bats as natural hosts for several important viral zoonoses, including Ebola, Marburg, Nipah, Hendra, and rabies viruses and severe acute respiratory syndrome-coronavirus (SARS-CoV), has been established; however, the large viral population diversity (virome) of bats has been partially determined for only a few of the ~1,200 bat species. To assess the virome of North American bats, we collected fecal, oral, urine, and tissue samples from individual bats captured at an abandoned railroad tunnel in Maryland that is cohabitated by 7 to 10 different bat species. Here, we present preliminary characterization of the virome of three common North American bat species, including big brown bats (Eptesicus fuscus), tricolored bats (Perimyotis subflavus), and little brown myotis (Myotis lucifugus). In samples derived from these bats, we identified viral sequences that were similar to at least three novel group 1 CoVs, large numbers of insect and plant virus sequences, and nearly full-length genomic sequences of two novel bacteriophages. These observations suggest that bats encounter and disseminate a large assortment of viruses capable of infecting many different animals, insects, and plants in nature. PMID- 20926579 TI - Elevated circulating IGF-I promotes mammary gland development and proliferation. AB - Animal studies have shown that IGF-I is essential for mammary gland development. Previous studies have suggested that local IGF-I rather than circulating IGF-I is the major mediator of mammary gland development. In the present study we used the hepatic IGF-I transgenic (HIT) and IGF-I knockout/HIT (KO-HIT) mouse models to examine the effects of enhanced circulating IGF-I on mammary development in the presence and absence of local IGF-I. HIT mice express the rat IGF-I transgene under the transthyretin promoter in the liver and have elevated circulating IGF-I and normal tissue IGF-I levels. The KO-HIT mice have no tissue IGF-I and increased circulating IGF-I. Analysis of mammary gland development reveals a greater degree of complexity in HIT mice as compared to control and KO-HIT mice, which demonstrate similar degrees of mammary gland complexity. Immunohistochemical evaluation of glands of HIT mice also suggests an enhanced degree of proliferation of the mammary gland, whereas KO-HIT mice exhibit mammary gland proliferation similar to control mice. In addition, HIT mice have a higher percentage of proliferating myoepithelial and luminal cells than control mice, whereas KO-HIT mice have an equivalent percentage of proliferating myoepithelial and luminal cells as control mice. Thus, our findings show that elevated circulating IGF-I levels are sufficient to promote normal pubertal mammary epithelial development. However, HIT mice demonstrate more pronounced mammary gland development when compared to control and KO-HIT mice. This suggests that both local and endocrine IGF-I play roles in mammary gland development and that elevated circulating IGF-I accelerates mammary epithelial proliferation. PMID- 20926580 TI - BAX-dependent and BAX-independent regulation of Kiss1 neuron development in mice. AB - The Kiss1 gene and its product kisspeptin are important regulators of reproduction. In rodents, Kiss1 is expressed in the hypothalamic arcuate (ARC) and anteroventral periventricular (AVPV)/rostral periventricular (PeN) nuclei. In the AVPV/PeN, females have more Kiss1 and tyrosine hydroxylase (TH) neurons than males. We explored the ontogeny of the Kiss1 sex difference, and the role of cell death in establishing Kiss1 and TH cell number. We also determined whether Kiss1 cells in AVPV/PeN coexpress TH. AVPV/PeN Kiss1 neurons were first detected in both sexes on postnatal d 10, but the Kiss1 sex difference did not emerge until postnatal d 12. The role of BAX-mediated apoptosis in generating this sex difference was tested in adult Bax knockout (KO) and wild-type mice. Deletion of Bax did not diminish the sex difference in Kiss1 expression in the AVPV/PeN. TH expression was sexually dimorphic in the AVPV of both wild-type and Bax KO mice but, unlike Kiss1, was not sexually dimorphic in the PeN of either genotype. Double-label analysis determined that most Kiss1 neurons coexpress TH mRNA, but many TH neurons do not coexpress Kiss1, especially in the PeN. These findings suggest that several subpopulations of TH cells reside within the AVPV/PeN, only one of which coexpresses Kiss1. In the ARC, Kiss1 cell number was markedly increased in Bax KO mice of both sexes, indicating that although BAX-dependent apoptosis does not generate the sex difference in either Kiss1 or TH expression in AVPV/PeN, BAX does importantly regulate Kiss1 cell number in the ARC. PMID- 20926581 TI - Rapid signaling actions of environmental estrogens in developing granule cell neurons are mediated by estrogen receptor beta. AB - Estrogenic endocrine disrupting chemicals (EDCs) constitute a diverse group of man-made chemicals and natural compounds derived from plants and microbial metabolism. Estrogen-like actions are mediated via the nuclear hormone receptor activity of estrogen receptor (ER)alpha and ERbeta and rapid regulation of intracellular signaling cascades. Previous study defined cerebellar granule cell neurons as estrogen responsive and that granule cell precursor viability was developmentally sensitive to estrogens. In this study experiments using Western blot analysis and pharmacological approaches have characterized the receptor and signaling modes of action of selective and nonselective estrogen ligands in developing cerebellar granule cells. Estrogen treatments were found to briefly increase ERK1/2-phosphorylation and then cause prolonged depression of ERK1/2 activity. The sensitivity of granule cell precursors to estrogen-induced cell death was found to require the integrated activation of membrane and intracellular ER signaling pathways. The sensitivity of granule cells to selective and nonselective ER agonists and a variety of estrogenic and nonestrogenic EDCs was also examined. The ERbeta selective agonist DPN, but not the ERalpha selective agonist 4,4',4'-(4-propyl-[1H]-pyrazole-1,3,5-triyl) trisphenol or other ERalpha-specific ligands, stimulated cell death. Only EDCs with selective or nonselective ERbeta activities like daidzein, equol, diethylstilbestrol, and bisphenol A were observed to induce E2-like neurotoxicity supporting the conclusion that estrogen sensitivity in granule cells is mediated via ERbeta. The presented results also demonstrate the utility of estrogen sensitive developing granule cells as an in vitro assay for elucidating rapid estrogen-signaling mechanisms and to detect EDCs that act at ERbeta to rapidly regulate intracellular signaling. PMID- 20926582 TI - hCG-induced down-regulation of PPARgamma and liver X receptors promotes periovulatory progesterone synthesis by macaque granulosa cells. AB - An ovulatory stimulus induces the rapid and dramatic increase in progesterone synthesis by the primate ovarian follicle. However, little is known about the early events leading to the shift from estrogen to progesterone production. Because steroidogenesis represents an aspect of cholesterol metabolism, it was hypothesized that transcription factors regulating cholesterol balance would be among the earliest to change in response to an ovulatory stimulus. Granulosa cells were isolated from rhesus monkey follicles following controlled ovarian stimulation protocols before or up to 24 hr after an ovulatory human chorionic gonadotropin (hCG) bolus. The peroxisome proliferator-activated receptor-gamma (PPARG) and the liver X receptors [nuclear receptor (NR)1H2, NR1H3] decreased within 3 hr of hCG, as did the reverse cholesterol transporters ATP-binding cassette (ABC)A1 and ABCG1. Treatment of granulosa cells isolated before an ovulatory stimulus with hCG and rosiglitizone resulted in an increase in NR1H3 and ABCG1, and decreased steroidogenic acute regulatory (STAR) protein and scavenger receptor-BI (SCARB1). A liver X receptor agonist attenuated hCG-induced progesterone synthesis in vitro and increased the expression of ABCA1 and ABCG1, and suppressed STAR, P450 side-chain cleavage A1, hydroxysteroid dehydrogenase 3B, and SCARB1. These data suggest that an initial action of LH/CG on the primate preovulatory follicle is to rapidly reduce the expression of PPARG, resulting in reduced NR1H3 with the consequence shifting the balance from cholesterol efflux via ABCA1 and ABCG1 to cholesterol uptake (SCARB1) and metabolism (STAR, P450 side-chain cleavage A1, hydroxysteroid dehydrogenase 3B). That the regulation of PPARG and the liver X receptors occurs within 3 hr strongly indicates that early events in the primate luteinizing follicle are critical to successful ovulation and luteal formation. PMID- 20926584 TI - Intrauterine position affects estrogen receptor alpha expression in the ventromedial nucleus of the hypothalamus via promoter DNA methylation. AB - There is well-established evidence in many mammalian species for effects of the intrauterine position (IUP) (the sex-specific positioning of the embryo) on postnatal brain function and behavior. We found that the IUP affects estrogen receptor (ER)alpha expression in adult female rats in the ventrolateral region of the hypothalamic ventromedial nucleus (vlVMH), which is associated with sexual behavior. The ERalpha expression level in the vlVMH was higher in females that developed in utero between two male siblings (2M females) than in those that developed between female siblings (2F females). We also found that the cytosine methylation status across the ERalpha promoter in the vlVMH was affected by the IUP, with greater methylation in 2F females. These findings showed a negative correlation between ERalpha expression levels in the vlVMH and methylation frequency in the ERalpha promoter. This suggests that genomic methylation sustains the effect of the fetal IUP on ERalpha expression in the vlVMH. PMID- 20926583 TI - Evidence of a role for insulin-like growth factor binding protein (IGFBP)-3 in metabolic regulation. AB - IGF-binding protein (IGFBP)-3 is a metabolic regulator that has been shown to inhibit insulin-stimulated glucose uptake in murine models. This finding contrasts with epidemiological evidence of decreased serum IGFBP-3 in patients with type 2 diabetes. The purpose of this study was to clarify the role of IGFBP 3 in metabolism. Four-week-old male IGFBP-3(-/-) and control mice were subjected to a high-fat diet (HFD) for 12 wk. IGFBP-3(-/-) mice were heavier before the initiation of HFD and at the end of the study period. Resting metabolic rate was significantly decreased in knockout mice; however, respiratory exchange ratio was not significantly different. Fasting blood glucose and insulin levels were significantly elevated in IGFBP-3(-/-) mice. However, IGFBP-3(-/-) mice had relatively normal glucose tolerance because the relative glucose excursion over time was not different between the groups. During hyperinsulinemic clamps, IGFBP 3(-/-) mice had increased basal hepatic glucose production, but after insulin stimulation, no differences in hepatic glucose production were observed. A second cohort of older IGFBP-3(-/-) mice on HFD displayed unexpected evidence of hepatic steatosis. In summary, glucose tolerance and clamp testing indicate that IGFBP-3( /-) mice preserve insulin sensitivity despite evidence of increased basal glucose turnover and hepatic steatosis. We provide evidence that genetic deletion of IGFBP-3 modulates hepatic carbohydrate and lipid metabolism. PMID- 20926586 TI - Kisspeptin-10 inhibits angiogenesis in human placental vessels ex vivo and endothelial cells in vitro. AB - Recent studies suggest that kisspeptin (a neuropeptide central to the regulation of gonadotrophin secretion) has diverse roles in human physiology, including a putative role in implantation and placental function. Kisspeptin and its receptor are present in human blood vessels, where they mediate vasoconstriction, and kisspeptin is known to inhibit tumor metastasis and trophoblast invasion, both processes involving angiogenesis. We hypothesized that kisspeptin contributes to the regulation of angiogenesis in the reproductive system. The presence of the kisspeptin receptor was confirmed in human placental blood vessels and human umbilical vein endothelial cells (HUVEC) using immunochemistry. The ability of kisspeptin-10 (KP-10) (a shorter biologically active processed peptide) to inhibit angiogenesis was tested in explanted human placental arteries and HUVEC using complementary ex vivo and in vitro assays. KP-10 inhibited new vessel sprouting from placental arteries embedded in Matrigel and tube-like structure formation by HUVEC, in a concentration-dependent manner. KP-10 had no effect on HUVEC viability or apoptosis but induced concentration-dependent inhibition of proliferation and migration. In conclusion, KP-10 has antiangiogenic effects and, given its high expression in the placenta, may contribute to the regulation of angiogenesis in this tissue. PMID- 20926585 TI - Retrograde endocannabinoid signaling reduces GABAergic synaptic transmission to gonadotropin-releasing hormone neurons. AB - Cannabinoids suppress fertility via reducing hypothalamic GnRH output. gamma Aminobutyric acid (GABA)(A) receptor (GABA(A)-R)-mediated transmission is a major input to GnRH cells that can be excitatory. We hypothesized that cannabinoids act via inhibiting GABAergic input. We performed loose-patch electrophysiological studies of acute slices from adult male GnRH-green fluorescent protein transgenic mice. Bath application of type 1 cannabinoid receptor (CB1) agonist WIN55,212 decreased GnRH neuron firing rate. This action was detectable in presence of the glutamate receptor antagonist kynurenic acid but disappeared when bicuculline was also present, indicating GABA(A)-R involvement. In immunocytochemical experiments, CB1-immunoreactive axons formed contacts with GnRH neurons and a subset established symmetric synapses characteristic of GABAergic neurotransmission. Functional studies were continued with whole-cell patch-clamp electrophysiology in presence of tetrodotoxin. WIN55,212 decreased the frequency of GABA(A)-R-mediated miniature postsynaptic currents (mPSCs) (reflecting spontaneous vesicle fusion), which was prevented with the CB1 antagonist AM251, indicating collectively that activation of presynaptic CB1 inhibits GABA release. AM251 alone increased mPSC frequency, providing evidence that endocannabinoids tonically inhibit GABA(A)-R drive onto GnRH neurons. Increased mPSC frequency was absent when diacylglycerol lipase was blocked intracellularly with tetrahydrolipstatin, showing that tonic inhibition is caused by 2 arachidonoylglycerol production of GnRH neurons. CdCl(2) in extracellular solution can maintain both action potentials and spontaneous vesicle fusion. Under these conditions, when endocannabinoid-mediated blockade of spontaneous vesicle fusion was blocked with AM251, GnRH neuron firing increased, revealing an endogenous endocannabinoid brake on GnRH neuron firing. Retrograde endocannabinoid signaling may represent an important mechanism under physiological and pathological conditions whereby GnRH neurons regulate their excitatory GABAergic inputs. PMID- 20926587 TI - Inhibition of the type 2 iodothyronine deiodinase underlies the elevated plasma TSH associated with amiodarone treatment. AB - The widely prescribed cardiac antiarrhythmic drug amiodarone (AMIO) and its main metabolite, desethylamiodarone (DEA), have multiple side effects on thyroid economy, including an elevation in serum TSH levels. To study the AMIO effect on TSH, mice with targeted disruption of the type 2 deiodinase gene (D2KO) were treated with 80 mg/kg AMIO for 4 wk. Only wild-type (WT) mice controls developed the expected approximate twofold rise in plasma TSH, illustrating a critical role for D2 in this mechanism. A disruption in the D2 pathway caused by AMIO could interfere with the transduction of the T4 signal, generating less T3 and softening the TSH feedback mechanism. When added directly to sonicates of HEK-293 cells transiently expressing D2, both AMIO and DEA behaved as noncompetitive inhibitors of D2 [IC(50) of >100 MUm and ~5 MUm, respectively]. Accordingly, D2 activity was significantly decreased in the median eminence and anterior pituitary sonicates of AMIO-treated mice. However, the underlying effect on TSH is likely to be at the pituitary gland given that in AMIO-treated mice the paraventricular TRH mRNA levels (which are negatively regulated by D2-generated T3) were decreased. In contrast, AMIO and DEA both exhibited dose-dependent inhibition of D2 activity and elevation of TSH secretion in intact TalphaT1 cells, a pituitary thyrotroph cell line used to model the TSH feedback mechanism. In conclusion, AMIO and DEA are noncompetitive inhibitors of D2, with DEA being much more potent, and this inhibition at the level of the pituitary gland contributes to the rise in TSH seen in patients taking AMIO. PMID- 20926588 TI - NOD2 activation induces muscle cell-autonomous innate immune responses and insulin resistance. AB - Insulin resistance is associated with chronic low-grade inflammation in vivo, largely mediated by activated innate immune cells. Cytokines and pathogen-derived ligands of surface toll-like receptors can directly cause insulin resistance in muscle cells. However, it is not known if intracellular pathogen sensors can, on their own, provoke insulin resistance. Here, we show that the cytosolic pattern recognition receptors nucleotide-binding oligomerization domain-containing protein (NOD)1 and NOD2 are expressed in immune and metabolic tissues and hypothesize that their activation in muscle cells would result in cell-autonomous responses leading to insulin resistance. Bacterial peptidoglycan motifs that selectively activate NOD2 were directly administered to L6- GLUT4myc myotubes in culture. Within 3 h, insulin resistance arose, characterized by reductions in each insulin-stimulated glucose uptake, GLUT4 translocation, Akt Ser(473) phosphorylation, and insulin receptor substrate 1 tyrosine phosphorylation. Muscle cell-autonomous responses to NOD2 ligand included activation of the stress/inflammation markers c-Jun N-terminal kinase, ERK1/2, p38 MAPK, degradation of inhibitor of kappaBalpha, and production of proinflammatory cytokines. These results show that NOD2 alone is capable of acutely inducing insulin resistance within muscle cells, possibly by activating endogenous inflammatory signals and/or through cytokine production, curbing upstream insulin signals. NOD2 is hence a new inflammation target connected to insulin resistance, and this link occurs without the need of additional contributing cell types. This study provides supporting evidence for the integration of innate immune and metabolic responses through the involvement of NOD proteins and suggests the possible participation of cell autonomous immune responses in the development of insulin resistance in skeletal muscle, the major depot for postprandial glucose utilization. PMID- 20926589 TI - Molecular cloning, characterization, and chromosome mapping of reptilian estrogen receptors. AB - In many vertebrates, steroid hormones are essential for ovarian differentiation during a critical developmental stage as well as promoting the growth and differentiation of the adult female reproductive system. Although studies have been extensively conducted in mammals and a few fish, amphibians, and bird species, the molecular mechanisms of sex steroid hormone (estrogens) action have been poorly examined in reptiles. Here, we evaluate hormone receptor and ligand interactions in two species of snake, the Okinawa habu (Protobothrops flavoviridis, Viperidae) and the Japanese four-striped rat snake (Elaphe quadrivirgata, Colubridae) after the isolation of cDNAs encoding estrogen receptor alpha (ESR1) and estrogen receptor beta (ESR2). Using a transient transfection assay with mammalian cells, the transcriptional activity of reptilian (Okinawa habu, Japanese four-striped rat snake, American alligator, and Florida red-belly freshwater turtle) ESR1 and ESR2 was examined. All ESR proteins displayed estrogen-dependent activation of transcription via an estrogen-response element-containing promoter; however, the responsiveness to various estrogens was different. Further, we determined the chromosomal locations of the snake steroid hormone receptor genes. ESR1 and ESR2 genes were localized to the short and long arms of chromosome 1, respectively, whereas androgen receptor was localized to a pair of microchromosomes in the two snake species examined. These data provide basic tools that allow future studies examining receptor-ligand interactions and steroid endocrinology in snakes and also expands our knowledge of sex steroid hormone receptor evolution. PMID- 20926590 TI - Specific involvement of gonadal hormones in the functional maturation of growth hormone releasing hormone (GHRH) neurons. AB - Growth hormone (GH) is the key hormone involved in the regulation of growth and metabolism, two functions that are highly modulated during infancy. GH secretion, controlled mainly by GH releasing hormone (GHRH), has a characteristic pattern during postnatal development that results in peaks of blood concentration at birth and puberty. A detailed knowledge of the electrophysiology of the GHRH neurons is necessary to understand the mechanisms regulating postnatal GH secretion. Here, we describe the unique postnatal development of the electrophysiological properties of GHRH neurons and their regulation by gonadal hormones. Using GHRH-eGFP mice, we demonstrate that already at birth, GHRH neurons receive numerous synaptic inputs and fire large and fast action potentials (APs), consistent with effective GH secretion. Concomitant with the GH secretion peak occurring at puberty, these neurons display modifications of synaptic input properties, decrease in AP duration, and increase in a transient voltage-dependant potassium current. Furthermore, the modulation of both the AP duration and voltage-dependent potassium current are specifically controlled by gonadal hormones because gonadectomy prevented the maturation of these active properties and hormonal treatment restored it. Thus, GHRH neurons undergo specific developmental modulations of their electrical properties over the first six postnatal weeks, in accordance with hormonal demand. Our results highlight the importance of the interaction between the somatotrope and gonadotrope axes during the establishment of adapted neuroendocrine functions. PMID- 20926591 TI - Commentary: the year in circadian rhythms. AB - The circadian clock orchestrates intrinsic timing in most organisms and controls a large variety of physiological and metabolic programs. In my presentation "The Year in Circadian Rhythms" at the Endocrine Society meeting (San Diego, June 2010) I reviewed some of the recent spectacular developments of the field. The exceptional interest that circadian rhythms have suscitated during the past two decades has caused a remarkable increase in the number of researchers and of committed resources dedicated to the field. This has also generated the promise of potentially novel pharmacological strategies. Indeed, specific molecular pathways of circadian regulation have been recently linked to endocrine and metabolic control, as well as cell cycle and proliferation. Importantly, circadian gene expression involves an important proportion of cellular genes, underscoring the role played by dynamic mechanisms of chromatin remodeling. This suggests that the circadian machinery could have evolved as a privileged molecular interface between cellular metabolism and epigenetic control. PMID- 20926592 TI - Limited utility of oral glucose tolerance test in biochemically active acromegaly. AB - CONTEXT: Measurement of GH after oral glucose tolerance test (OGTT) is used for the diagnosis and surveillance of acromegaly. However, there are major discrepancies between glucose-suppressed GH and plasma IGF1 as indices of biochemical activity of acromegaly in patients with relatively mild GH oversecretion. This study was aimed to assess the performance of OGTT in patients with acromegaly and variable GH outputs. METHODS: Forty adults with newly diagnosed, untreated acromegaly (15 with GH >4.3 MUg/l and 25 with GH <4.3 MUg/l) and elevated IGF1 levels were studied. All underwent Q10 min for 24 h sampling for GH followed by an OGTT. RESULTS: Postglucose nadir GH (GHn) correlated significantly to 24 h GHn, mean 24 h GH, and baseline GH (P<0.001 for all comparisons). GHn correlated significantly to IGF1 z-scores for the 'low' GH group and for the entire group (P<0.0001 for both comparisons), but not for the 'high' GH group. None of the patients with mean GH >4.3 MUg/l had GHn below 1 MUg/l. In contrast, 13 out of 25 patients (52%) with GH <4.3 MUg/l showed GHn lower than 1 MUg/l, and 7 of them (28%) had GHn lower than 0.4 MUg/l. These groups did not differ significantly either for average or for maximal GH suppression in OGTT. CONCLUSIONS: Our data show that suppressibility of GH by glucose in acromegaly is a function of the degree of GH hypersecretion and that OGTT has only limited diagnostic value in patients with biochemically active acromegaly but only mildly increased GH output. PMID- 20926593 TI - Pituitary apoplexy: re-evaluation of risk factors for bleeding into pituitary adenomas and impact on outcome. AB - OBJECTIVE: To assess frequency, symptoms and outcome of pituitary apoplexy (PA) among pituitary adenoma patients, to gain better insight into risk factors for bleeding into pituitary adenoma and to estimate the sequelae of PA by means of a matched control group. METHOD: By reviewing charts of 574 patients with pituitary adenoma, we analysed incidence, symptoms and outcome of PA and potential risk factors for developing PA by means of a control group (patients with pituitary adenoma without PA). RESULTS: In total, 42 suffered from PA, all had macroadenomas; 30/217 male (14%) and 12/179 female (7%) macroadenoma patients, 32/194 patients with clinically non-functioning (16.5%) and 10/202 with clinically active (5.0%) macroadenoma were affected. Antithrombotic therapy predisposed patients to PA (P=0.026), diabetes mellitus and hypertension did not (P=1.00). Patients with PA and pituitary adenoma patients without PA had similar frequencies of hypopituitarism (45 vs 48%, P>0.05) and visual field defects (38 vs 55%, P>0.05), but ophthalmoplegia was significantly more common (76 vs 5%, P<0.001) in patients with PA. Nearly all patients were treated by surgery; most recovered from ophthalmoplegia, whereas visual function improved only moderately. Endocrine outcome was worse in patients with PA than in patients without PA. CONCLUSIONS: Male sex and characteristics of the adenoma itself (especially tumour size and tumour type) rather than patient's cardiovascular risk factors such as diabetes and hypertension seem to predispose to PA; antithrombotic therapy may also be important. PMID- 20926594 TI - Wnt receptors, bone mass, and fractures: gene-wide association analysis of LRP5 and LRP6 polymorphisms with replication. AB - OBJECTIVE: Genes explaining the susceptibility to osteoporosis have not been fully elucidated. Our objective was to explore the association of polymorphisms capturing common variations of the lipoprotein receptor-related protein (LRP) 5 and 6 genes, encoding two Wnt receptors, with femoral neck bone mineral density (BMD) and osteoporotic fractures of the spine and the hip. DESIGN: Cross sectional, case-control, and replication genetic association study. METHODS: Thirty-nine tagging and functional single nucleotide polymorphisms (SNPs) were analyzed in a group of 1043 postmenopausal women and 394 women with hip fractures. The results were replicated in a different group of 342 women. RESULTS: Three SNPs of the LRP6 gene were associated with BMD (nominal uncorrected P values <0.05) in the discovery cohort. One showed a significant association after multiple test correction; two of them were also associated in the replication cohort, with a combined standardized mean difference of 0.51 (P=0.009) and 0.47 (P<0.003) across rs11054704 and rs2302685 genotypes. In the discovery cohort, several LRP5 SNPs were associated with vertebral fractures (odds ratio (OR) 0.67; P=0.01), with hip fractures (unadjusted ORs between 0.59 and 1.21; P=0.005-0.033, but not significant after multiple test adjustment or age adjustment), and with height and the projected femoral neck area, but not with BMD. Transcripts of LRP5 and LRP6 were similarly abundant in bone samples. CONCLUSIONS: In this study, we found common polymorphisms of LRP5 associated with osteoporotic fractures, and polymorphisms of the LRP6 gene associated with BMD, thus suggesting them as likely candidates to contribute to the explaination of the hereditary influence on osteoporosis. PMID- 20926595 TI - Genetic hyperthyroidism: hyperthyroidism due to activating TSHR mutations. AB - Three syndromes affecting the thyroid gland are described in the literature separately: familial nonautoimmune hyperthyroidism, sporadic congenital nonautoimmune hyperthyroidism, and autonomous adenomas. Recent studies have shown that these three syndromes are caused by similar activating mutations of the TSH receptor gene (TSHR), and that the consequences of these mutations on the physiology and gene expression of the thyroid are qualitatively, but not quantitatively, similar. The three syndromes and two suggested unrecognized variants are in fact facets of the same disease, genetic hyperthyroidism due to TSHR mutations, the expression of which depends on the intensity of activation, its timing, and on the number of affected cells. PMID- 20926596 TI - A phylogenetic model for investigating correlated evolution of substitution rates and continuous phenotypic characters. AB - The comparative approach is routinely used to test for possible correlations between phenotypic or life-history traits. To correct for phylogenetic inertia, the method of independent contrasts assumes that continuous characters evolve along the phylogeny according to a multivariate Brownian process. Brownian diffusion processes have also been used to describe time variations of the parameters of the substitution process, such as the rate of substitution or the ratio of synonymous to nonsynonymous substitutions. Here, we develop a probabilistic framework for testing the coupling between continuous characters and parameters of the molecular substitution process. Rates of substitution and continuous characters are jointly modeled as a multivariate Brownian diffusion process of unknown covariance matrix. The covariance matrix, the divergence times and the phylogenetic variations of substitution rates and continuous characters are all jointly estimated in a Bayesian Monte Carlo framework, imposing on the covariance matrix a prior conjugate to the Brownian process so as to achieve a greater computational efficiency. The coupling between rates and phenotypes is assessed by measuring the posterior probability of positive or negative covariances, whereas divergence dates and phenotypic variations are marginally reconstructed in the context of the joint analysis. As an illustration, we apply the model to a set of 410 mammalian cytochrome b sequences. We observe a negative correlation between the rate of substitution and mass and longevity, which was previously observed. We also find a positive correlation between omega = dN/dS and mass and longevity, which we interpret as an indirect effect of variations of effective population size, thus in partial agreement with the nearly neutral theory. The method can easily be extended to any parameter of the substitution process and to any continuous phenotypic or environmental character. PMID- 20926597 TI - Primary controls on species richness in higher taxa. AB - The disparity in species richness across the tree of life is one of the most striking and pervasive features of biological diversity. Some groups are exceptionally diverse, whereas many other groups are species poor. Differences in diversity among groups are frequently assumed to result from primary control by differential rates of net diversification. However, a major alternative explanation is that ecological and other factors exert primary control on clade diversity, such that apparent variation in net diversification rates is a secondary consequence of ecological limits on clade growth. Here, I consider a likelihood framework for distinguishing between these competing hypotheses. I incorporate hierarchical modeling to explicitly relax assumptions about the constancy of diversification rates across clades, and I propose several statistics for a posteriori evaluation of model adequacy. I apply the framework to a recent dated phylogeny of ants. My results reject the hypothesis that net diversification rates exert primary control on species richness in this group and demonstrate that clade diversity is better explained by total time-integrated speciation. These results further suggest that it may not possible to estimate meaningful speciation and extinction rates from higher-level phylogenies of extant taxa only. PMID- 20926599 TI - The structural basis of blood group A-related glycolipids in an A3 red cell phenotype and a potential explanation to a serological phenomenon. AB - Glycolipids from the red cells of a rare blood group A subgroup individual, expressing the blood group A(3) phenotype with the classical mixed-field agglutination phenomenon, A(2(539G>A))/O(1) genotype, and an unusual blood group A glycolipid profile, were submitted to a comprehensive biochemical and structural analysis. To determine the nature of blood group A glycolipids in this A(3) phenotype, structural determination was carried out with complementary techniques including proton nuclear magnetic resonance (1D and 2D), mass spectrometry (MS) (nano-electrospray ionization/quadrupole time-of-flight and tandem mass spectrometry) and thin layer chromatography with immunostaining detection. As expected, total blood group A structures were of low abundance, but contrary to expectations extended-A type 2 and A type 3 glycolipids were more dominant than A hexaglycosylceramides based on type 2 chain (A-6-2 glycolipids), which normally is the major A glycolipid. Several para-Forssman (GalNAcbeta3GbO(4)) structures, including extended forms, were identified but surmised not to contribute to the classic mixed-field agglutination of the A(3) phenotype. It is proposed that the low level of A antigen combined with an absence of extended branched glycolipids may be the factor determining the mixed field agglutination phenomenon in this individual. PMID- 20926598 TI - DNA methylation and histone H3-K9 modifications contribute to MUC17 expression. AB - MUC17 glycoprotein is a membrane-associated mucin that is mainly expressed in the digestive tract. It has been suggested that MUC17 expression is correlated with the malignancy potential of pancreatic ductal adenocarcinomas (PDACs). In the present study, we provided the first report of the MUC17 gene expression through epigenetic regulation such as promoter methylation, histone modification and microRNA (miRNA) expression. Near the transcriptional start site, the DNA methylation level of MUC17-negative cancer cell lines (e.g. PANC1) was high, whereas that of MUC17-positive cells (e.g. AsPC-1) was low. Histone H3-K9 (H3-K9) modification status was also closely related to MUC17 expression. Our results indicate that DNA methylation and histone H3-K9 modification in the 5' flanking region play a critical role in MUC17 expression. Furthermore, the hypomethylation status was observed in patients with PDAC. This indicates that the hypomethylation status in the MUC17 promoter could be a novel epigenetic marker for the diagnosis of PDAC. In addition, the result of miRNA microarray analysis showed that five potential miRNA candidates existed. It is also possible that the MUC17 might be post-transcriptionally regulated by miRNA targeting to the 3' untranslated region of its mRNA. These understandings of the epigenetic changes of MUC17 may be of importance for the diagnosis of carcinogenic risk and the prediction of outcomes for cancer patients. PMID- 20926600 TI - Time, species, and separating their effects on trait variance in clades. PMID- 20926601 TI - Characterization of molecular forms of N-terminal B-type natriuretic peptide in vitro. AB - BACKGROUND: The heterogeneity of circulating peptides may influence the interpretation of results from N-terminal profragment of BNP (NT-proBNP) assays. Our objective was to characterize the heterogeneity for better usability of the assays. METHODS: Endogenous proBNP was purified from patient samples and treated with trifluoromethanesulfonic acid (chemical deglycosylation). The human proBNP gene was introduced into rat hearts by adenoviral transfer. Cell lysates and plasma samples containing proBNP-derived peptides were analyzed by chromatography. The fate of exogenous recombinant NT-proBNP added to fresh whole blood samples was followed by immunoassays and chromatography. The main NT-proBNP components were isolated and identified by mass spectrometry. RESULTS: Immunoreactive NT-proBNP in human plasma comprised several molecular forms, as did circulating immunoreactive human NT-proBNP after adenoviral transfer of human proBNP cDNA into rat ventricular myocardium. Incubation of recombinant NT proBNP(1-76) in human plasma or serum resulted in multiple components with the 2 major components identified as NT-proBNP(1-36) and NT-proBNP(1-62/64). Profiling by different antisera and chromatography indicated masking of the non-mid-region epitopes likely due to formation of oligomers. More than 75% of the original immunoreactivity in the mid-region epitope was retained after 3-week storage of plasma samples at room temperature. CONCLUSIONS: There is marked heterogeneity in immunoreactive NT-proBNP in plasma not related to glycosylation. The mid-region epitope of NT-proBNP is stable even in harsh storage conditions. Careful choice of antibody epitopes can yield extraordinarily robust assays. PMID- 20926602 TI - HMGA proteins regulate the expression of FGF2 in uterine fibroids. AB - In human fibroids genes encoding the high-mobility proteins containing the 'AT hook' DNA-binding motif (HMGA) are frequently affected by non-random chromosomal rearrangements. Thus, the different proteins and their derivatives resulting from these genomic rearrangements can be assumed to be involved in the genesis of these tumors by activation of largely identical downstream pathways. Constructs encoding HMGA proteins and their relevant derivatives were overexpressed in human myometrial cells, and RNA isolated from these cells was hybridized to filter arrays. Four genes were either up- or down-regulated at least 2-fold after overexpression of either of the HMGA genes and their derivatives. FGF2 (fibroblast growth factor 2) was one of these genes, and we were then able to show by microarray analyses that tumors with rearrangements of the HMGA2 locus (n = 8) expressed significantly higher levels of FGF2 than those with an apparently normal karyotype (n = 47). Accordingly, by quantitative real-time PCR uterine leiomyomas with rearrangements of the HMGA2 locus were found to express significantly higher levels of FGF2 than those with an apparently normal karyotype with a linear relationship between the expression of FGF2 and the level of HMGA2 overexpression as well as the tumor size. The results of western blot analyses confirmed these findings. Moreover, stimulation of myometrial tissue by FGF1, a strong inducer of HMGA2, leads to an increase of HMGA2 as well as FGF2 expression. In conclusion, the results contribute to the understanding of the association between the overexpression of HMGA proteins, the regulation of FGF2 expression and the size of fibroids. PMID- 20926603 TI - Non-apoptotic Fas-induced regulation of cytokines in undifferentiated and decidualized human endometrial stromal cells depends on caspase-activity. AB - Fas has originally been described as a member of the death-receptor family, mediating apoptosis upon stimulation by Fas-ligand (FasL). However, Fas expressing human endometrial stromal cells (ESCs) are resistant to Fas-mediated apoptosis. Since the implanting embryo secretes FasL, we examined whether Fas mediates non-apoptotic effects in human ESCs in vitro. ESCs were isolated from hysterectomy specimens, decidualized using progesterone and 17beta-estradiol and incubated with an activating anti-Fas antibody, recombinant FasL and a caspase inhibitor. Leukemia inhibitory factor (LIF), interleukin (IL)-11, -6, -8, monocyte chemoattractant protein (MCP)-1 and RANTES (Regulated on Activation Normal T cell Expressed and Secreted) were measured using ELISA and real-time RT PCR. Viability of ESCs was determined using an MTT assay. Caspase-activity was measured by luminescent assays. Activation of nuclear factor (NF)-kappaB was detected by in-cell western and transcription factor assays. LIF and IL-11 in undifferentiated and IL-8 in decidualized ESCs were up-regulated by non-apoptotic Fas-signaling. In contrast, IL-6, MCP-1 and RANTES were not regulated by Fas. Caspases were activated upon Fas-stimulation and the Fas-mediated effects on LIF, IL-11 and -8 were reversed by caspase-inhibition. The transcription factor NF kappaB was not activated in ESCs after stimulation of Fas. These results suggest a differential regulatory role of caspase-dependent Fas-signaling at the feto maternal interface during early implantation. Remarkably, this typical death machinery mediates non-apoptotic effects in the human endometrium rather than inducing apoptosis. PMID- 20926604 TI - Dietary glycemic load is a predictor of age-related hearing loss in older adults. AB - Age-related hearing loss is a frequent disability in older adults and nutrition could play a role in the development of this condition. Carbohydrate nutrition [including dietary glycemic index (GI) and load (GL)] may be linked to hearing loss. We aimed to determine the association between carbohydrate nutrition (including mean dietary GI and GL, and the dietary intakes of carbohydrate and sugar), starch, cereal and total fiber, and age-related hearing loss. The Blue Mountains Hearing Study is a population-based survey of age-related hearing loss (1997-1999 to 2002-2004). Hearing loss was measured in 2956 participants (aged >=50 y) and was defined as the pure-tone average of frequencies 0.5, 1.0, 2.0, and 4.0 kHz > 25 dB hearing level. Dietary data were collected in a semiquantitative FFQ. A purpose-built database based on Australian GI values was used to calculate the mean GI. A higher mean dietary GI was associated with an increased prevalence of any hearing loss, comparing quintiles 1 (lowest) and 5 (highest), [multivariable-adjusted odds ratio = 1.41 (95% CI = 1.01-1.97)]. Participants in the highest quartile of mean dietary GL intake compared with those in the lowest quartile had a 76% greater risk of developing incident hearing loss (P-trend = 0.04). Higher carbohydrate and sugar intakes were associated with incident hearing loss (P-trend = 0.03 and P-trend = 0.05, respectively). In summary, a high-GL diet was a predictor of incident hearing loss, as was higher intake of total carbohydrate. Hence, high postprandial glycemia might be a potential underlying biological mechanism in the development of age-related hearing loss. PMID- 20926605 TI - Modular processing in the hand representation of primate primary somatosensory cortex coexists with widespread activation. AB - Neurons in the hand representation of primary somatosensory cortex (area 3b) are known to have discretely localized receptive fields; and these neurons form modules that can be visualized histologically as distinct digit and palm representations. Despite these indicators of the importance of local processing in area 3b, widespread interactions between stimuli presented to locations across the hand have been reported. We investigated the relationship of neuron firing rate with distance from the site of maximum activation in cortex by recording from a 100-electrode array with electrodes spaced 400 MUm apart, implanted into the area 3b hand representation in anesthetized owl monkeys. For each stimulated location on the hand, the electrode site where neurons had the highest peak firing rate was defined as the peak activation site. The lesser firing rates of neurons at all other electrode sites in the grid were compared with the firing rates of neurons at the peak activation site. On average, peak firing rates of neurons decreased rapidly with distance away from the peak activation site. The effect of distance on the variance of firing rates was highly significant (P < 0.0001). However, individual neurons retained high firing rates for distances over 3 mm. The clear decline in firing rate with distance from the most activated location indicates that local processing is emphasized in area 3b, while the distance of neurons with reduced but maintained firing rates <=3-4 mm from the site of best activation demonstrated widespread activation in primary somatosensory cortex. PMID- 20926606 TI - The bidirectionality of motor learning in the vestibulo-ocular reflex is a function of cerebellar mGluR1 receptors. AB - Bidirectional changes in synaptic transmission have the potential to optimize the control of movement. However, it can be difficult to establish a causal relationship between the bidirectionality of synaptic plasticity and bidirectional changes in the speed of actual movements. We asked whether metabotropic glutamate receptor 1 (mGluR1) receptors, which participate in cerebellar long-term depression (LTD), are necessary for bidirectional motor learning in the vestibulo-ocular reflex (VOR). Cerebellar LTD and long-term potentiation (LTP) are thought to cause increases and decreases, respectively, in the gain of the VOR; the direction of learning depends on the behavioral protocol. We injected either the mGluR1 agonist (S)-DHPG or the antagonist YM 298198 bilaterally into the flocculus of alert cats, and then induced motor learning. In the presence of YM 298198, the VOR gain decreased in gain-up, as well as in gain-down protocols. (S)-DHPG augmented gain-up learning. Gain-down learning was not significantly affected by either drug. These results supported the hypothesis that gain-up learning relies on cerebellar LTD, but gain-down learning relies on a different mechanism. In the absence of mGluR1 activity, cerebellar LTD may be replaced with LTP, permitting learning in only one direction. PMID- 20926607 TI - Examining the auditory nerve fiber response to high rate cochlear implant stimulation: chronic sensorineural hearing loss and facilitation. AB - Neural prostheses, such as cochlear and retinal implants, induce perceptual responses by electrically stimulating sensory nerves. These devices restore sensory system function by using patterned electrical stimuli to evoke neural responses. An understanding of their function requires knowledge of the nerves responses to relevant electrical stimuli as well as the likely effects of pathology on nerve function. We describe how sensorineural hearing loss (SNHL) affects the response properties of single auditory nerve fibers (ANFs) to electrical stimuli relevant to cochlear implants. The response of 188 individual ANFs were recorded in response to trains of stimuli presented at 200, 1,000, 2,000, and 5,000 pulse/s in acutely and chronically deafened guinea pigs. The effects of stimulation rate and SNHL on ANF responses during the 0-2 ms period following stimulus onset were examined to minimize the influence of ANF adaptation. As stimulation rate increased to 5,000 pulse/s, threshold decreased, dynamic range increased and first spike latency decreased. Similar effects of stimulation rate were observed following chronic SNHL, although onset threshold and first spike latency were reduced and onset dynamic range increased compared with acutely deafened animals. Facilitation, defined as an increased nerve excitability caused by subthreshold stimulation, was observed in both acute and chronic SNHL groups, although the magnitude of its effect was diminished in the latter. These results indicate that facilitation, demonstrated here using stimuli similar to those used in cochlear implants, influences the ANF response to pulsatile electrical stimulation and may have important implications for cochlear implant signal processing strategies. PMID- 20926608 TI - Differing neurophysiologic mechanosensory input from glabrous and hairy skin in juvenile rats. AB - Sensory afferents in skin encode and convey thermal and mechanical conditions, including those that threaten tissue damage. A small proportion of skin, the glabrous skin of the distal extremities, is specialized to explore the environment in fine detail. Aside from increased innervation density, little is known regarding properties of mechanosensory afferents to glabrous skin in younger animals that explain the exquisite precision and high contrast in rapidly sampling physical structures, including those that threaten injury. To assess this, we obtained intact neuronal intracellular recordings in vivo from 115 mechanosensitive afferent neurons from lumbar and thoracic dorsal root ganglia in juvenile rats. Two characteristics were unique to glabrous skin: a threefold higher proportion of fast-conducting to slow-conducting afferents that were high threshold mechanosensitive nociceptors compared with hairy skin and a twofold faster conduction velocity of fast-conducting nociceptors compared with hairy skin. Additionally differences were found in mechanical thresholds between glabrous skin and hairy skin for each fiber type. These differences reflect and help explain the rapid response of skin specialized to explore the physical environment. Additionally, these results highlight potential limitations of using passive electrical properties and conduction velocity alone to characterize primary afferents without knowledge of the skin type they innervated. PMID- 20926609 TI - Influence of fatigue on hand muscle coordination and EMG-EMG coherence during three-digit grasping. AB - Fingertip force control requires fine coordination of multiple hand muscles within and across the digits. While the modulation of neural drive to hand muscles as a function of force has been extensively studied, much less is known about the effects of fatigue on the coordination of simultaneously active hand muscles. We asked eight subjects to perform a fatiguing contraction by gripping a manipulandum with thumb, index, and middle fingers while matching an isometric target force (40% maximal voluntary force) for as long as possible. The coordination of 12 hand muscles was quantified as electromyographic (EMG) muscle activation pattern (MAP) vector and EMG-EMG coherence. We hypothesized that muscle fatigue would cause uniform changes in EMG amplitude across all muscles and an increase in EMG-EMG coherence in the higher frequency bands but with an invariant heterogeneous distribution across muscles. Muscle fatigue caused a 12.5% drop in the maximum voluntary contraction force (P < 0.05) at task failure and an increase in the SD of force (P < 0.01). Although EMG amplitude of all muscles increased during the fatiguing contraction (P < 0.001), the MAP vector orientation did not change, indicating that a similar muscle coordination pattern was used throughout the fatiguing contraction. Last, EMG-EMG coherence (0-35 Hz) was significantly greater at the end than at the beginning of the fatiguing contraction (P < 0.01) but was heterogeneously distributed across hand muscles. These findings suggest that similar mechanisms are involved for modulating and sustaining digit forces in nonfatiguing and fatiguing contractions, respectively. PMID- 20926610 TI - Synchrony in normal and focal epileptic brain: the seizure onset zone is functionally disconnected. AB - Synchronization of local and distributed neuronal assemblies is thought to underlie fundamental brain processes such as perception, learning, and cognition. In neurological disease, neuronal synchrony can be altered and in epilepsy may play an important role in the generation of seizures. Linear cross-correlation and mean phase coherence of local field potentials (LFPs) are commonly used measures of neuronal synchrony and have been studied extensively in epileptic brain. Multiple studies have reported that epileptic brain is characterized by increased neuronal synchrony except possibly prior to seizure onset when synchrony may decrease. Previous studies using intracranial electroencephalography (EEG), however, have been limited to patients with epilepsy. Here we investigate neuronal synchrony in epileptic and control brain using intracranial EEG recordings from patients with medically resistant partial epilepsy and control subjects with intractable facial pain. For both epilepsy and control patients, average LFP synchrony decreases with increasing interelectrode distance. Results in epilepsy patients show lower LFP synchrony between seizure generating brain and other brain regions. This relative isolation of seizure generating brain underlies the paradoxical finding that control patients without epilepsy have greater average LFP synchrony than patients with epilepsy. In conclusion, we show that in patients with focal epilepsy, the region of epileptic brain generating seizures is functionally isolated from surrounding brain regions. We further speculate that this functional isolation may contribute to spontaneous seizure generation and may represent a clinically useful electrophysiological signature for mapping epileptic brain. PMID- 20926611 TI - Hyperexcitable substantia nigra dopamine neurons in PINK1- and HtrA2/Omi deficient mice. AB - The electrophysiological properties of substantia nigra pars compacta (SNC) dopamine neurons can influence their susceptibility to degeneration in toxin based models of Parkinson's disease (PD), suggesting that excitotoxic and/or hypoactive mechanisms may be engaged during the early stages of the disease. It is unclear, however, whether the electrophysiological properties of SNC dopamine neurons are affected by genetic susceptibility to PD. Here we show that deletion of PD-associated genes, PINK1 or HtrA2/Omi, leads to a functional reduction in the activity of small-conductance Ca(2+)-activated potassium channels. This reduction causes SNC dopamine neurons to fire action potentials in an irregular pattern and enhances burst firing in brain slices and in vivo. In contrast, PINK1 deletion does not affect firing regularity in ventral tegmental area dopamine neurons or substantia nigra pars reticulata GABAergic neurons. These findings suggest that changes in SNC dopamine neuron excitability may play a role in their selective vulnerability in PD. PMID- 20926612 TI - Social and ecological regulation of a decision-making circuit. AB - Ecological context, sensory inputs, and the internal physiological state are all factors that need to be integrated for an animal to make appropriate behavioral decisions. However, these factors have rarely been studied in the same system. In the African cichlid fish Astatotilapia burtoni, males alternate between two phenotypes based on position in a social hierarchy. When dominant (DOM), fish display bright body coloration and a wealth of aggressive and reproductive behavioral patterns that make them conspicuous to predators. Subordinate (SUB) males, on the other hand, decrease predation risk by adopting cryptic coloration and schooling behavior. We therefore hypothesized that DOMs would show enhanced startle-escape responsiveness to compensate for their increased predation risk. Indeed, behavioral responses to sound clicks of various intensities showed a significantly higher mean startle rate in DOMs compared with SUBs. Electrophysiological recordings from the Mauthner cells (M-cells), the neurons triggering startle, were performed in anesthetized animals and showed larger synaptic responses to sound clicks in DOMs, consistent with the behavioral results. In addition, the inhibitory drive mediated by interneurons (passive hyperpolarizing potential [PHP] cells) presynaptic to the M-cell was significantly reduced in DOMs. Taken together, the results suggest that the likelihood for an escape to occur for a given auditory stimulus is higher in DOMs because of a more excitable M-cell. More broadly, this study provides an integrative explanation of an ecological and social trade-off at the level of an identifiable decision-making neural circuit. PMID- 20926614 TI - Topographic organization of excitatory and inhibitory commissural connections in the superior colliculi and their functional roles in saccade generation. AB - Our electrophysiological study showed that there are topographic connections between excitatory and inhibitory commissural neurons (CNs) in one superior colliculus (SC) and tectoreticular neurons (TRNs) in the opposite SC. To obtain morphological evidence for these topographic commissural connections between the SCs, tracers were injected into various parts of the SC, the inhibitory burst neuron (IBN) area and Forel's field H (FFH), in the cat. Retrogradely labeled CNs were classified into three types according to their somatic areas and identified as GABA-positive or -negative immunohistochemically. Caudal SC injections labeled small GABA-positive CNs (<200 MUm(2)) in the deep layers of the opposite rostral SC. Rostral SC injections mainly labeled medium-sized GABA-negative CNs (200-700 MUm(2)) in the upper intermediate layer of the opposite rostral SC and small GABA positive CNs in its deeper layers. Lateral SC injections labeled small GABA positive CNs in the opposite medial SC and mainly medium-sized GABA-negative CNs in its lateral part. Medial SC injections labeled small GABA-positive CNs in the lateral SC and medium-sized GABA-negative CNs in the medial SC. In comparison, TRNs projecting to the FFH or IBN region were large (>700 MUm(2)) and medium sized. Many of the medium-sized GABA-negative CNs were TRNs projecting to the FFH. These results indicate that mirror-symmetric excitatory pathways link medial to medial (upper field) and lateral to lateral (lower field) parts of the SCs, whereas upper and lower field representations are linked by reciprocal inhibitory pathways in the tectal commissure. These connections presumably play important roles in conjugate upward and downward vertical saccades. PMID- 20926613 TI - Astrocytes in the retrotrapezoid nucleus sense H+ by inhibition of a Kir4.1 Kir5.1-like current and may contribute to chemoreception by a purinergic mechanism. AB - Central chemoreception is the mechanism by which CO(2)/pH sensors regulate breathing in response to tissue pH changes. There is compelling evidence that pH sensitive neurons in the retrotrapezoid nucleus (RTN) are important chemoreceptors. Evidence also indicates that CO(2)/H(+)-evoked adenosine 5' triphosphate (ATP) release in the RTN, from pH-sensitive astrocytes, contributes to chemoreception. However, mechanism(s) by which RTN astrocytes sense pH is unknown and their contribution to chemoreception remains controversial. Here, we use the brain slice preparation and a combination of patch-clamp electrophysiology and immunohistochemistry to confirm that RTN astrocytes are pH sensitive and to determine mechanisms by which they sense pH. We show that pH sensitive RTN glia are immunoreactive for aldehyde dehydrogenase 1L1, a marker of astrocytes. In HEPES buffer the pH-sensitive current expressed by RTN astrocytes reversed near E(K(+)) (the equilibrium potential for K(+)) and was inhibited by Ba(2+) and desipramine (blocker of Kir4.1-containing channels), characteristics most consistent with heteromeric Kir4.1-Kir5.1 channels. In bicarbonate buffer, the sodium/bicarbonate cotransporter also contributed to the CO(2)/H(+)-sensitive current in RTN astrocytes. To test the hypothesis that RTN astrocytes contribute to chemoreception by a purinergic mechanism, we used fluorocitrate to selectively depolarize astrocytes while measuring neuronal activity. We found that fluorocitrate increased baseline activity and pH sensitivity of RTN neurons by a P2-receptor-dependent mechanism, suggesting that astrocytes may release ATP to activate RTN chemoreceptors. We also found in bicarbonate but not HEPES buffer that P2-receptor antagonists decreased CO(2) sensitivity of RTN neurons. We conclude that RTN astrocytes sense CO(2)/H(+) in part by inhibition of a Kir4.1 Kir5.1-like current and may provide an excitatory purinergic drive to pH sensitive neurons. PMID- 20926615 TI - The episodic nature of spike trains in the early visual pathway. AB - An understanding of the neural code in a given visual area is often confounded by the immense complexity of visual stimuli combined with the number of possible meaningful patterns that comprise the response spike train. In the lateral geniculate nucleus (LGN), visual stimulation generates spike trains comprised of short spiking episodes ("events") separated by relatively long intervals of silence, which establishes a basis for in-depth analysis of the neural code. By studying this event structure in both artificial and natural visual stimulus contexts and at different contrasts, we are able to describe the dependence of event structure on stimulus class and discern which aspects generalize. We find that the event structure on coarse time scales is robust across stimulus and contrast and can be explained by receptive field processing. However, the relationship between the stimulus and fine-time-scale features of events is less straightforward, partially due to a significant amount of trial-to-trial variability. A new measure called "label information" identifies structural elements of events that can contain <=30% more information in the context of natural movies compared with what is available from the overall event timing. The first interspike interval of an event most robustly conveys additional information about the stimulus and is somewhat more informative than the event spike count and much more informative than the presence of bursts. Nearly every event is preserved across contrast despite changes in their fine-time-scale features, suggesting that--at least on a coarse level--the stimulus selectivity of LGN neurons is contrast invariant. Event-based analysis thus casts previously studied elements of LGN coding such as contrast adaptation and receptive field processing in a new light and leads to broad conclusions about the composition of the LGN neuronal code. PMID- 20926616 TI - Physiological basis for inhibition of morphine and improgan antinociception by CC12, a P450 epoxygenase inhibitor. AB - Many analgesic drugs, including MU-opioids, cannabinoids, and the novel nonopioid analgesic improgan, produce antinociception by actions in the rostral ventromedial medulla (RVM). There they activate pain-inhibiting neurons, termed "OFF-cells," defined by a nociceptive reflex-related pause in activity. Based on recent functional evidence that neuronal P450 epoxygenases are important for the central antinociceptive actions of morphine and improgan, we explored the convergence of opioid and nonopioid analgesic drug actions in RVM by studying the effects of the P450 epoxygenase inhibitor CC12 on the analgesic drug-induced activation of these OFF-cells and on behavioral antinociception. In rats lightly anesthetized with isoflurane, we recorded the effects of intraventricular morphine and improgan, with and without CC12 pretreatment, on tail flick latency and activity of identified RVM neurons: OFF-cells, ON-cells (pronociceptive neurons), and neutral cells (unresponsive to analgesic drugs). CC12 pretreatment preserved reflex-related changes in OFF-cell firing and blocked the analgesic actions of both drugs, without interfering with the increase in spontaneous firing induced by improgan or morphine. CC12 blocked suppression of evoked ON cell firing by improgan, but not morphine. CC12 pretreatment had no effect by itself on RVM neurons or behavior. These data show that the epoxygenase inhibitor CC12 works downstream from receptors for both MU-opioid and improgan, at the inhibitory input mediating the OFF-cell pause. This circuit-level analysis thus provides a cellular basis for the convergence of opioid and nonopioid analgesic actions in the RVM. A presynaptic P450 epoxygenase may therefore be an important target for development of clinically useful nonopioid analgesic drugs. PMID- 20926617 TI - Sleep and synaptic renormalization: a computational study. AB - Recent evidence indicates that net synaptic strength in cortical and other networks increases during wakefulness and returns to a baseline level during sleep. These homeostatic changes in synaptic strength are accompanied by corresponding changes in sleep slow wave activity (SWA) and in neuronal firing rates and synchrony. Other evidence indicates that sleep is associated with an initial reactivation of learned firing patterns that decreases over time. Finally, sleep can enhance performance of learned tasks, aid memory consolidation, and desaturate the ability to learn. Using a large-scale model of the corticothalamic system equipped with a spike-timing dependent learning rule, in agreement with experimental results, we demonstrate a net increase in synaptic strength in the waking mode associated with an increase in neuronal firing rates and synchrony. In the sleep mode, net synaptic strength decreases accompanied by a decline in SWA. We show that the interplay of activity and plasticity changes implements a control loop yielding an exponential, self-limiting renormalization of synaptic strength. Moreover, when the model "learns" a sequence of activation during waking, the learned sequence is preferentially reactivated during sleep, and reactivation declines over time. Finally, sleep-dependent synaptic renormalization leads to increased signal-to-noise ratios, increased resistance to interference, and desaturation of learning capabilities. Although the specific mechanisms implemented in the model cannot capture the variety and complexity of biological substrates, and will need modifications in line with future evidence, the present simulations provide a unified, parsimonious account for diverse experimental findings coming from molecular, electrophysiological, and behavioral approaches. PMID- 20926619 TI - Characterization of digoxin uptake in sandwich-cultured human hepatocytes. AB - Digoxin is a drug that is commonly used to treat congestive heart failure. Because of digoxin's narrow therapeutic index, patients are susceptible to drug drug interaction-mediated cardiotoxicity. Digoxin is primarily cleared renally; however, a significant component of clearance is due to multidrug resistance 1 mediated transport into bile. Digoxin is reported to be actively transported into human hepatocytes by the organic anion-transporting polypeptide 1B3 (OATP1B3); however, further characterization has not been fully described. The purpose of this study was to investigate the hepatic uptake mechanisms of [(3)H]digoxin using sandwich-cultured human hepatocytes (SCHH) and transporter-expressing cells. Digoxin uptake in SCHH involves both a saturable (carrier-mediated) process and a passive (nonsaturable) process. At low concentrations, the saturable component exhibited an apparent K(m) of 2.39 MUM and a V(max) of 4.49 pmol/(min . mg protein). The calculated passive diffusion clearance was 1.25 MUl/(min . mg protein). Uptake of [(3)H]digoxin in SCHH was not inhibited by a variety of substrates or inhibitors for OATP1B1, OATP1B3, OATP2B1, organic anion transporter 2, organic cation transporter 1, and monocarboxylate transporter 8. Cytochalasin B, which inhibits glucose transporters, did not significantly inhibit digoxin uptake, whereas the flavonoids quercetin and rutin inhibited uptake by ~50%. Nonlabeled digoxin inhibited [(3)H]digoxin uptake by ~50%. Studies with OATP-transfected human embryonic kidney cells or oocytes showed that digoxin is not a substrate of OATP1B1, OATP2B1, or OATP1B3. In conclusion, the data suggest that digoxin uptake in SCHH involves both saturable and passive processes. The saturable process is mediated by an as yet undetermined digoxin transporter(s). PMID- 20926618 TI - A gain-of-function mutation of Arabidopsis cryptochrome1 promotes flowering. AB - Plants use different classes of photoreceptors to collect information about their light environment. Cryptochromes are blue light photoreceptors that control deetiolation, entrain the circadian clock, and are involved in flowering time control. Here, we describe the cry1-L407F allele of Arabidopsis (Arabidopsis thaliana), which encodes a hypersensitive cryptochrome1 (cry1) protein. Plants carrying the cry1-L407F point mutation have elevated expression of CONSTANS and FLOWERING LOCUS T under short-day conditions, leading to very early flowering. These results demonstrate that not only the well-studied cry2, with an unequivocal role in flowering promotion, but also cry1 can function as an activator of the floral transition. The cry1-L407F mutants are also hypersensitive toward blue, red, and far-red light in hypocotyl growth inhibition. In addition, cry1-L407F seeds are hypersensitive to germination inducing red light pulses, but the far-red reversibility of this response is not compromised. This demonstrates that the cry1-L407F photoreceptor can increase the sensitivity of phytochrome signaling cascades. Molecular dynamics simulation of wild-type and mutant cry1 proteins indicated that the L407F mutation considerably reduces the structural flexibility of two solvent-exposed regions of the protein, suggesting that the hypersensitivity might result from a reduced entropic penalty of binding events during downstream signal transduction. Other nonmutually exclusive potential reasons for the cry1-L407F gain of function are the location of phenylalanine-407 close to three conserved tryptophans, which could change cry1's photochemical properties, and stabilization of ATP binding, which could extend the lifetime of the signaling state of cry1. PMID- 20926620 TI - Toxicological evaluation of acyl glucuronides of nonsteroidal anti-inflammatory drugs using human embryonic kidney 293 cells stably expressing human UDP glucuronosyltransferase and human hepatocytes. AB - The chemical reactivity of acyl glucuronide (AG) has been thought to be associated with the toxic properties of drugs containing carboxylic acid moieties, but there has been no direct evidence that AG formation was related to the toxicity. In the present study, the cytotoxicity and genotoxicity of AGs were investigated. Human embryonic kidney (HEK) 293 cells stably expressing UDP glucuronosyltransferase (UGT) 1A3 (HEK/UGT1A3) were constructed to assess the cytotoxicity of AGs, and HEK/UGT1A4 cells were also used as a negative reference. After exposure to nonsteroidal anti-inflammatory drugs (NSAIDs) such as naproxen (1 mM), diclofenac (0.1 mM), ketoprofen (1 mM), or ibuprofen (1 mM) for 24 h, HEK/UGT1A3 cells produced AG in a time-dependent manner. However, HEK/UGT1A4 cells hardly produced AG. The cytotoxicity of HEK/UGT1A3 cells was not increased compared with that of HEK/UGT1A4 cells. In addition, the AG formed in NSAID treated human hepatocytes was decreased from one-third to one-ninth by treatment with (-)-borneol, an inhibitor of acyl glucuronidation, but the cytotoxicity was increased. These results indicated that AG formation reflected the detoxification process in human hepatocytes. Furthermore, the possibility of genotoxicity from the AG formed in NSAID-treated HEK/UGT cells was investigated by the comet assay, and DNA damage was not detected in any HEK/UGT cell lines. In conclusion, the in vitro cytotoxic and genotoxic effects of the AGs of NSAIDs were investigated and AG was not found to be a causal factor in the toxicity. PMID- 20926621 TI - Identification of human liver cytochrome P450 enzymes involved in the metabolism of SCH 530348 (Vorapaxar), a potent oral thrombin protease-activated receptor 1 antagonist. AB - Vorapaxar (SCH 530348), a potent oral thrombin protease-activated receptor 1 antagonist, is being developed as an antiplatelet agent for patients with established vascular disease. The objective of this study was to identify the human liver cytochrome P450 (P450) enzyme(s) responsible for the metabolism of SCH 530348. Human liver microsomes metabolized SCH 530348 to M19, an amine metabolite formed via carbamate cleavage, and M20 (monohydroxy-SCH 530348). Recombinant human CYP3A4 exhibited the most activity (11.5% profiled radioactivity) for the formation of M19, followed by markedly less substrate conversion with CYP1A1 and CYP2C19. Trace levels of M19, a major excreted human metabolite, were detected with CYP1A2, CYP3A5, and CYP4F3A. Formation of M19 by human liver microsomes was inhibited 89% by ketoconazole (IC(50), 0.73 MUM), 34% by tranylcypromine, and 89% by anti-CYP3A4 monoclonal antibody. There was a significant correlation between the rate of M19 formation and midazolam 1' hydroxylation (r = 0.75) or M19 formation and testosterone 6beta-hydroxylation (r = 0.92). The results of screening, inhibition, and correlation studies confirmed that CYP3A4 is the major P450 enzyme responsible for M19 formation from SCH 530348. In contrast, formation of M20, a major circulating human metabolite at steady state, was primarily catalyzed by CYP3A4 and CYP2J2. M20 is pharmacologically equipotent to SCH 530348, whereas M19 is an inactive metabolite. Formation of M20 by human liver microsomes was inhibited 89% by ketoconazole, 75% by astemizole (a CYP2J2 inhibitor), and 43% by CYP3A4 monoclonal antibody. These results suggest that CYP3A4 and CYP2J2 are both involved in the formation of M20 metabolite. PMID- 20926623 TI - Ethosuximide was superior to valproate and lamotrigine in controlling seizures and minimising side effects. PMID- 20926622 TI - Which injuries may indicate child abuse? AB - Making the decision as to whether an injury is a result of child abuse or not is stressful for both the family involved and the clinical team. It is not a decision that is taken lightly, and with an increasing expectation by the investigating agencies, lawyers and the public in general, to ensure that it is based on explicit 'evidence', clinicians need to be up to date with the latest scientific publications in the field. This article aims to summarise the current evidence in relation to all physical injuries except those pertaining to the central nervous system, which will form a separate article. It will examine the pattern of accidental and abusive bruises, fractures, burns, abdominal injuries and oral injuries focusing on discriminating features and necessary investigations. PMID- 20926624 TI - Assessment and investigation of the child with disordered development. AB - Every paediatrician, generalist or specialist, at every level and in every setting will come across the child or young person with disordered development and has a duty of care to ensure that appropriate assessment and investigations are undertaken, if each individual is to be given the best possible opportunities to achieve the highest possible level of participation and enjoy the best possible quality of life. Using a structured approach, all paediatricians have the potential to make a significant positive difference and should seek every opportunity to do so, even if seeing the child for an entirely different reason. Key messages of this article include: (1) each child is unique and requires careful, individual, clinical assessment and thought before any investigations are undertaken; (2) there is no single list of appropriate tests to be done for all children with disordered development; (3) the clinical judgement of the experienced clinician (expert triage) is more helpful than 'guidelines' in deciding which investigations to do; (4) clinical networking with colleagues in paediatric neurodisability, neurology, clinical genetics, metabolic paediatrics, and so on, is essential to achieve the highest possible yield from investigations and to reduce the number, discomfort and expense of inappropriate investigations; (5) the more effort and thought that goes into formulating differential diagnoses, the more appropriate the investigations are likely to be and the higher the likely diagnostic hit rate. Diagnostic hit rates up to 80% have been reported in the literature for those with severe learning disabilities and this is likely to be even higher once microarray comparative genomic hybridisation becomes more widely available. PMID- 20926625 TI - Medical and prehospital care training in UK fire and rescue services. PMID- 20926626 TI - Asymptomatic common carotid artery dissection caused by blunt injury. PMID- 20926627 TI - The reliability of vital signs in estimating pain severity among adult patients treated by paramedics. AB - BACKGROUND: The aim of this study was to examine the strength of correlation between initial pain severity score and systolic blood pressure, heart rate and respiratory rates among adults reporting pain in the prehospital setting as a means of validating the presence and severity of pain. METHODS: A retrospective cohort study was conducted including all adults with a Glasgow Coma Score >12 assessed by paramedics in a metropolitan area over a 7 day period in 2005. Pain was self-scored by patients using a 0-10 numeric rating scale (NRS). RESULTS: Of the patients transported, 1766/3357 (53%) reported pain, and an NRS score was recorded for 1286. Median age was 57 years, 51% were women, and median initial NRS was six. Mean heart rate was 85 (95% CI 84 to 86), mean systolic blood pressure was 139 mmHg (95% CI 138 to 141) and mean respiratory rate was 18 (95% CI 18 to 18). There was no significant correlation between NRS and heart rate (r=0.002, p=0.61, 95% CI -0.007 to +0.011) or blood pressure (r=-0.0007, p=0.81, 95% CI -0.007 to +0.005), although this was statistically significant for initial pain score and respiratory rate (r 0.058, p=0.001, 95% CI 0.024 to 0.093). CONCLUSION: A lack of any meaningful correlation between pain scores and changes in vital signs in this population demonstrates that these signs cannot be used to validate the severity of pain reported by adult patients. PMID- 20926628 TI - A prospective review of the use of ketamine to facilitate endotracheal intubation in the helicopter emergency medical services (HEMS) setting. AB - INTRODUCTION: Ketamine is a dissociative agent used for sedation and intubation in various clinical settings. Despite its proven haemodynamic safety, ketamine has not been widely used in prehospital medicine. This study examined the use of ketamine in helicopter emergency medical services (HEMS). METHODS: This prospective cohort study enrolled all patients transported by a single HEMS program in whom ketamine was used to facilitate intubation. Data were collected using standard forms by two independent trained research staff. Demographics, medical condition, intubation conditions, vital signs (pre and post drug administration) and complications were recorded. Proportions, medians with IQR, change scores and CIs are reported; differences were compared using paired t tests. RESULTS: During the 2-year study period, 71 patients received ketamine to facilitate endotracheal intubation. Ketamine was used most often in men (52 (73%)), and the median age was 49 years (IQR: 31, 69). Most patients were adults (70 (99%)) with medical illnesses (42 (59%)); 37 (52%) intubations were performed at the sending hospital, and 30 (42%) were performed on scene. A paramedic performed the intubation in 58 cases (82%). The median ketamine dose was 80 mg (IQR: 60, 100; ~ 1mg/kg); 53 (75%) patients also received a paralytic agent. Mean arterial pressure (2.3 mmHg; 95% CI: -8.0 to 3.3) and heart rate (0.45 beats/min, 95% CI: -4.9 to 4.0) changes failed to reach statistical or clinical significance. No differences were found between patients with suspected concomitant head injury and other patients with respect to ketamine dose, changes in vital signs and complications. Complications included: one (1.4%) interstitial IV, five (7%) failed intubations, five (7%) hypotension and four (6%) hypertension episodes, one (1%) bradycardia, two (3%) tachycardia and five (7%) deaths. CONCLUSIONS: Ketamine is an effective agent in facilitating intubation in a HEMS environment. Complications are similar to use in the controlled Emergency Department setting. PMID- 20926629 TI - Exercise reduces oxidative stress but does not alleviate hyperinsulinemia or renal dopamine D1 receptor dysfunction in obese rats. AB - Impairment of renal dopamine D1 receptor (D1R)-mediated natriuresis is associated with hypertension in humans and animal models, including obese Zucker rats. We have previously reported that treatment of these rats with antioxidants or insulin sensitizers reduced insulin levels and oxidative stress, restored D1R mediated natriuresis, and reduced blood pressure. Furthermore, the redox sensitive transcription factor, nuclear factor-kappaB (NF-kappaB), has been implicated in impairment of D1R-mediated natriuresis during oxidative stress. In this study, we investigated the effect of exercise on insulin levels, oxidative stress, nuclear translocation of NF-kappaB, blood pressure, albuminuria, and D1R mediated natriuresis. The exercise protocol involved treadmill exercise from 3 wk of age for 8 wk. Exercise reduced oxidative stress, nuclear translocation of NF kappaB, and albuminuria. However, exercise did not reduce plasma insulin levels or blood pressure. Also, selective D1R agonist (SKF-38393)-mediated increases in sodium excretion and guanosine 5'-O-(3-thiotriphosphate) binding were impaired in obese rats compared with lean rats, and exercise did not restore this defect. We conclude that, while exercise is beneficial in reducing oxidative stress and renal injury, reducing insulin levels may be required to restore D1R-mediated natriuresis in this model of obesity and metabolic syndrome. Furthermore, this study supports previous observations that restoring D1R function contributes to blood pressure reduction in this model. PMID- 20926630 TI - Drosophila provides rapid modeling of renal development, function, and disease. AB - The evolution of specialized excretory cells is a cornerstone of the metazoan radiation, and the basic tasks performed by Drosophila and human renal systems are similar. The development of the Drosophila renal (Malpighian) tubule is a classic example of branched tubular morphogenesis, allowing study of mesenchymal to-epithelial transitions, stem cell-mediated regeneration, and the evolution of a glomerular kidney. Tubule function employs conserved transport proteins, such as the Na(+), K(+)-ATPase and V-ATPase, aquaporins, inward rectifier K(+) channels, and organic solute transporters, regulated by cAMP, cGMP, nitric oxide, and calcium. In addition to generation and selective reabsorption of primary urine, the tubule plays roles in metabolism and excretion of xenobiotics, and in innate immunity. The gene expression resource FlyAtlas.org shows that the tubule is an ideal tissue for the modeling of renal diseases, such as nephrolithiasis and Bartter syndrome, or for inborn errors of metabolism. Studies are assisted by uniquely powerful genetic and transgenic resources, the widespread availability of mutant stocks, and low-cost, rapid deployment of new transgenics to allow manipulation of renal function in an organotypic context. PMID- 20926631 TI - Expression and role of serum and glucocorticoid-regulated kinase 2 in the regulation of Na+/H+ exchanger 3 in the mammalian kidney. AB - Serum and glucocorticoid-regulated kinase 2 (sgk2) is 80% identical to the kinase domain of sgk1, an important mediator of mineralocorticoid-regulated sodium (Na(+)) transport in the distal nephron of the kidney. The expression pattern and role in renal function of sgk2 are virtually uncharacterized. In situ hybridization and immunohistochemistry of rodent kidney coupled with real-time RT PCR of microdissected rat kidney tubules showed robust sgk2 expression in the proximal straight tubule and thick ascending limb of the loop of Henle. Sgk2 expression was minimal in distal tubule cells with aquaporin-2 immunostaining but significant in proximal tubule cells with Na(+)/H(+) exchanger 3 (NHE3) immunostaining. To ascertain whether mineralocorticoids regulate expression of sgk2 in a manner similar to sgk1, we examined sgk2 mRNA expression in the kidneys of adrenalectomized rats treated with physiological doses of aldosterone together with the glucocorticoid receptor antagonist RU486. Northern blot analysis and in situ hybridization showed that, unlike sgk1, sgk2 expression in the kidney was not altered by aldosterone treatment. Based on the observation that sgk2 is expressed in proximal tubule cells that also express NHE3, we asked whether sgk2 regulates NHE3 activity. We heterologously expressed sgk2 in opossum kidney (OKP) cells and measured Na(+)/H(+) exchange activity by Na(+)-dependent cell pH recovery. Constitutively active sgk2, but not sgk1, stimulated Na(+)/H(+) exchange activity by >30%. Moreover, the sgk2-mediated increase in Na(+)/H(+) exchange activity correlated with an increase in cell surface expression of NHE3. Together, these results suggest that the pattern of expression, regulation, and role of sgk2 within the mammalian kidney are distinct from sgk1 and that sgk2 may play a previously unrecognized role in the control of transtubular Na(+) transport through NHE3 in the proximal tubule. PMID- 20926632 TI - Global gene expression profiling in early-stage polycystic kidney disease in the Han:SPRD Cy rat identifies a role for RXR signaling. AB - Han:SPRD Cy is a spontaneous rat model of polycystic kidney disease (PKD) caused by a missense mutation in Pkdr1. Cystogenesis in this model is not clearly understood. In the current study, we performed global gene expression profiling in early-stage PKD cyst development in Cy/Cy kidneys and normal (+/+) kidneys at 3 and 7 days of postnatal age. Expression profiles were determined by microarray analysis, followed by validation with real-time RT-PCR. Genes were selected with over 1.5-fold expression changes compared with age-matched +/+ kidneys for canonical pathway analysis. We found nine pathways in common between 3- and 7-day Cy/Cy kidneys. Three significantly changed pathways were designated "Vitamin D Receptor (VDR)/Retinoid X Receptor (RXR) Activation," "LPS/IL-1-Mediated Inhibition of RXR Function," and "Liver X Receptor (LXR)/RXR Activation." These results suggest that RXR-mediated signaling is significantly altered in developing kidneys with mutated Pkdr1. In gene ontology analysis, the functions of these RXR-related genes were found to be involved in regulating cell proliferation and organ morphogenesis. With real-time RT-PCR analysis, the upregulation of Ptx2, Alox15b, OSP, and PCNA, major markers of cell proliferation associated with the RXR pathway, were confirmed in 3- and 7-day Cy/Cy kidneys compared with 3-day +/+ kidneys. The increased RXR protein was observed in both the nucleus and cytoplasm of cystic epithelial cells in early-stage Cy/Cy kidneys, and the RXR-positive cells were strongly positive for PCNA staining. Taken together, cell proliferation and organ morphogenesis signals transduced by RXR-mediated pathways may have important roles for cystogenesis in early-stage PKD in this Pkdr1-mutated Cy rat. PMID- 20926633 TI - Telomerase immortalization of principal cells from mouse collecting duct. AB - Recently, the use of overexpression of telomerase reverse transcriptase (TERT) has led to the generation of immortalized human cell lines. However, this cell immortalization approach has not been reported in well-differentiated mouse cells, such as renal epithelial cells. We sought to establish and then characterize a mouse collecting duct cell line, using ectopic expression of mTERT. Isolated primary cortical collecting duct (CCD) cell lines were transduced with mouse (m)TERT, using a lentiviral vector. mTERT-negative cells did not survive blasticidin selection, whereas mTERT-immortalized cells proliferated in selection media for over 40 subpassages. mTERT messenger RNA and telomerase activity was elevated in these cells, compared with an SV40-immortalized cell line. Flow cytometry with Dolichos biflorus agglutinin was used to select the CCD principal cells, and we designated this cell line mTERT-CCD. Cells were well differentiated and exhibited morphological characteristics typically found in renal epithelial cells, such as tight junction formation, microvilli, and primary cilia. Further characterization using standard immunofluorescence revealed abundant expression of aquaporin-2 and the vasopressin type 2 receptor. mTERT-CCD cells exhibited cAMP-stimulated/benzamil-inhibited whole cell currents. Whole cell patch-clamp currents were also enhanced after a 6-day treatment with aldosterone. In conclusion, we have successfully used mTERT to immortalize mouse collecting duct cells that retain the basic in vivo phenotypic characteristics of collecting duct cells. This technique should be valuable in generating cell lines from genetically engineered mouse models. PMID- 20926634 TI - Hypertension resistance polymorphisms in ROMK (Kir1.1) alter channel function by different mechanisms. AB - The renal outer medullary K(+) (ROMK) channel plays a critical role in renal sodium handling. Recent genome sequencing efforts in the Framingham Heart Study offspring cohort (Ji W, Foo JN, O'Roak BJ, Zhao H, Larson MG, Simon DB, Newton Cheh C, State MW, Levy D, and Lifton RP. Nat Genet 40: 592-599, 2008) recently revealed an association between suspected loss-of-function polymorphisms in the ROMK channel and resistance to hypertension, suggesting that ROMK activity may also be a determinant of blood pressure control in the general population. Here we examine whether these sequence variants do, in fact, alter ROMK channel function and explore the mechanisms. As assessed by two-microelectrode voltage clamp in Xenopus oocytes, 3/5 of the variants (R193P, H251Y, and T313FS) displayed an almost complete attenuation of whole cell ROMK channel activity. Surface antibody binding measurements of external epitope-tagged channels and analysis of glycosylation-state maturation revealed that these variants prevent channel expression at the plasmalemma, likely as a consequence of retention in the endoplasmic reticulum. The other variants (P166S, R169H) had no obvious effects on the basal channel activity or surface expression but, instead, conferred a gain in regulated-inhibitory gating. As assessed in giant excised patch-clamp studies, apparent phosphotidylinositol 4,5-bisphosphate (PIP(2)) binding affinity of the variants was reduced, causing channels to be more susceptible to inhibition upon PIP(2) depletion. Unlike the protein product of the major ROMK allele, these two variants are sensitive to the inhibitory affects of a G protein-coupled receptor, which stimulates PIP(2) hydrolysis. In summary, we have found that hypertension resistance sequence variants inhibit ROMK channel function by different mechanisms, providing new insights into the role of the channel in the maintenance of blood pressure. PMID- 20926635 TI - Molecular studies of influenza B virus in the reverse genetics era. AB - Recovery of an infectious virus of defined genetic structure entirely from cDNA and the deduction of information about the virus resulting from phenotypic characterization of the mutant is the process of reverse genetics. This approach has been possible for a number of negative-strand RNA viruses since the recovery of rabies virus in 1994. However, the recovery of recombinant orthomyxoviruses posed a greater challenge due to the segmented nature of the genome. It was not until 1999 that such a system was reported for influenza A viruses, but since that time our knowledge of influenza A virus biology has grown dramatically. Annual influenza epidemics are caused not only by influenza A viruses but also by influenza B viruses. In 2002, two groups reported the successful recovery of influenza B virus entirely from cDNA. This has allowed greater depth of study into the biology of these viruses. This review will highlight the advances made in various areas of influenza B virus biology as a result of the development of reverse genetics techniques for these viruses, including (i) the importance of the non-coding regions of the influenza B virus genome; (ii) the generation of novel vaccine strains; (iii) studies into the mechanisms of drug resistance; (iv) the function(s) of viral proteins, both those analogous to influenza A virus proteins and those unique to influenza B viruses. The information generated by the application of influenza B virus reverse genetics systems will continue to contribute to our improved surveillance and control of human influenza. PMID- 20926636 TI - Recombinants between Deformed wing virus and Varroa destructor virus-1 may prevail in Varroa destructor-infested honeybee colonies. AB - We have used high-throughput Illumina sequencing to identify novel recombinants between Deformed wing virus (DWV) and Varroa destructor virus-1 (VDV-1), which accumulate to higher levels than DWV in both honeybees and Varroa destructor mites. The recombinants, VDV-1(VVD) and VDV-1(DVD), exhibit crossovers between the 5'-UTR and the regions encoding the structural (capsid) and non-structural viral proteins. This implies that the genomes are modular and that each region may evolve independently, as demonstrated in human enteroviruses. Individual honeybee pupae were infected with a mixture of observed recombinants and DWV. A strong correlation was observed between VDV-1(DVD) levels in honeybee pupae and associated mites, suggesting that this recombinant, with a DWV-derived 5'-UTR and non-structural protein region flanking a VDV-1-derived capsid-encoding region, is better adapted to transmission between V. destructor and honeybees than the parental DWV or a recombinant bearing the VDV-1-derived 5'-UTR (VDV-1(VVD)). PMID- 20926637 TI - Varroa destructor is an effective vector of Israeli acute paralysis virus in the honeybee, Apis mellifera. AB - The Israeli acute paralysis virus (IAPV) is a significant marker of honeybee colony collapse disorder (CCD). In the present work, we provide the first evidence that Varroa destructor is IAPV replication-competent and capable of vectoring IAPV in honeybees. The honeybees became infected with IAPV after exposure to Varroa mites that carried the virus. The copy number of IAPV in bees was positively correlated with the density of Varroa mites and time period of exposure to Varroa mites. Further, we showed that the mite-virus association could possibly reduce host immunity and therefore promote elevated levels of virus replication. This study defines an active role of Varroa mites in IAPV transmission and sheds light on the epidemiology of IAPV infection in honeybees. PMID- 20926638 TI - Evolutionary history of dog rabies in Brazil. AB - Although dogs are considered to be the principal transmitter of rabies in Brazil, dog rabies had never been recorded in South America before European colonization. In order to investigate the evolutionary history of dog rabies virus (RABV) in Brazil, we performed a phylogenetic analysis of carnivore RABV isolates from around the world and estimated the divergence times for dog RABV in Brazil. Our estimate for the time of introduction of dog RABV into Brazil was the late-19th to early-20th century, which was later than the colonization period but corresponded to a period of increased immigration from Europe to Brazil. In addition, dog RABVs appeared to have spread to indigenous animals in Brazil during the latter half of the 20th century, when the development and urbanization of Brazil occurred. These results suggest that the movement of rabid dogs, along with human activities since the 19th century, promoted the introduction and expansion of dog RABV in Brazil. PMID- 20926639 TI - The variable regions of hepatitis C virus glycoprotein E2 have an essential structural role in glycoprotein assembly and virion infectivity. AB - The three variable regions of hepatitis C virus (HCV) glycoprotein E2 can be removed simultaneously from the E2 ectodomain (residues 384-661) without affecting folding or CD81 binding. In this study, we show that deletion of hypervariable region (HVR) 2 or the intergenotypic variable region (igVR) in the context of the E1E2 polyprotein eliminates formation of heterodimers, reduces CD81 binding and abolishes virus entry. The replication competence of genomic RNA transcribed from the JFH1 infectious HCV clone was not affected by the HVR1, HVR2 or igVR deletions in transfected Huh7.5 cells. However, infectivity of the resultant cell-culture-derived HCV (HCVcc) was abolished by HVR2 or igVR deletions, while deletion of HVR1 led to a 5- to 10-fold reduction in infectivity. Serial passage of cells transfected with genomes lacking HVR1 generated reverted viruses with wild-type levels of infectivity. Sequencing of viral cDNA obtained after full reversion revealed mutations in E1 (I262L) and E2 (N415D) that were present in 35 and 27 % of clones, respectively. Insertion of N415D into HVR1-deleted HCV genomes conferred wild-type levels of infectivity, while I262L increased infectivity by 2.5-fold. These results suggest that HVR2 and the igVR, but not HVR1, are essential for structural integrity and function of the HCV glycoprotein heterodimer. PMID- 20926640 TI - Different seasons with decreased performance of immunochemical faecal occult blood tests in colorectal cancer screening. PMID- 20926642 TI - Evidence for neuroinflammation and neuroprotection in HCV infection-associated encephalopathy. AB - OBJECTIVE: Fatigue, mood disturbances and cognitive dysfunction are frequent in patients infected with hepatitis C virus (HCV) who have mild liver disease. The reason is still unclear. The present study aims to gain more insight into the pathomechanism by combining an extensive neuropsychological examination with magnetic resonance spectroscopy in four different brain regions in a patient group covering the whole spectrum of neuropsychiatric findings in patients afflicted with HCV who have only mild liver disease. METHODS: 53 HCV-positive patients with only mild liver disease and differing degrees of neuropsychiatric symptoms were studied with single-voxel MRS of the parietal white matter, occipital grey matter, basal ganglia and pons. Brain metabolite concentrations were quantitatively analysed by using LCmodel. MRS data were compared to those of 23 healthy controls adjusted for age, and analysed for relationships with the extent of neuropsychiatric symptoms. RESULTS: Choline (p=0.02), creatine (p=0.047) and N-acetyl-aspartate plus N-acetyl-aspartyl-glutamate (NN, p=0.02) concentrations in the basal ganglia and choline concentrations in the white matter (p=0.045) were significantly higher in the patients than in controls. Interestingly, the difference was most evident for the patients with low fatigue scores (eg, white matter: choline: p=0.001, creatine: p=0.003, NN: p=0.031). Myo inositol differed significantly between groups in the white (p=0.001) and grey matter (p=0.003). Fatigue correlated negatively with white matter NN, choline and creatine and myo-inositol levels in white and grey matter and basal ganglia (p<0.01). CONCLUSION: As the increase of choline, creatine and myo-inositol are usually interpreted to indicate glial activation and macrophage infiltration in chronic inflammation and slow virus infections of the brain the present data endorse the hypothesis, that HCV infection may induce neuroinflammation and brain dysfunction. The concomitant increase of NN and the negative correlation to the extent of fatigue suggest a cerebral compensatory process after HCV infection. PMID- 20926643 TI - Composition and energy harvesting capacity of the gut microbiota: relationship to diet, obesity and time in mouse models. AB - BACKGROUND AND AIMS: Increased efficiency of energy harvest, due to alterations in the gut microbiota (increased Firmicutes and decreased Bacteroidetes), has been implicated in obesity in mice and humans. However, a causal relationship is unproven and contributory variables include diet, genetics and age. Therefore, we explored the effect of a high-fat (HF) diet and genetically determined obesity (ob/ob) for changes in microbiota and energy harvesting capacity over time. METHODS: Seven-week-old male ob/ob mice were fed a low-fat diet and wild-type mice were fed either a low-fat diet or a HF-diet for 8 weeks (n=8/group). They were assessed at 7, 11 and 15 weeks of age for: fat and lean body mass (by NMR); faecal and caecal short-chain fatty acids (SCFA, by gas chromatography); faecal energy content (by bomb calorimetry) and microbial composition (by metagenomic pyrosequencing). RESULTS: A progressive increase in Firmicutes was confirmed in both HF-fed and ob/ob mice reaching statistical significance in the former, but this phylum was unchanged over time in the lean controls. Reductions in Bacteroidetes were also found in ob/ob mice. However, changes in the microbiota were dissociated from markers of energy harvest. Thus, although the faecal energy in the ob/ob mice was significantly decreased at 7 weeks, and caecal SCFA increased, these did not persist and faecal acetate diminished over time in both ob/ob and HF-fed mice, but not in lean controls. Furthermore, the proportion of the major phyla did not correlate with energy harvest markers. CONCLUSION: The relationship between the microbial composition and energy harvesting capacity is more complex than previously considered. While compositional changes in the faecal microbiota were confirmed, this was primarily a feature of high-fat feeding rather than genetically induced obesity. In addition, changes in the proportions of the major phyla were unrelated to markers of energy harvest which changed over time. The possibility of microbial adaptation to diet and time should be considered in future studies. PMID- 20926644 TI - Distinguishing Menetrier's disease from its mimics. AB - OBJECTIVE: Menetrier's disease (MD) is a rare hypertrophic gastropathy characterised by giant rugal folds, hypochlorhydria, protein loss and a classic constellation of symptoms (nausea, vomiting, abdominal pain and peripheral oedema). It is considered a clinical diagnosis that may at times be difficult to establish. Firm diagnostic criteria for MD are proposed by delineating the clinicopathological features that best differentiate MD from its mimics. METHOD: 48 patients referred to Vanderbilt University Medical Center for consideration of enrolment in a clinical trial of treatment of patients with MD with cetuximab were evaluated for a definitive diagnosis by assessing the clinical presentation, pertinent laboratory values and histopathological features. RESULTS: MD was confirmed in 25 of the 48 patients (52%). The remaining 23 patients were considered to be mimics of MD, the most common diagnoses being gastric polyps or polyposis syndromes (13/23, 57%). Gastric slides were available from 40 of the 48 patients for detailed histological analysis (22/25 MD and 18/23 non-MD). Foveolar hyperplasia, glandular tortuosity and dilation, and a marked reduction in parietal cell number were present in all 22 cases of MD. Lamina propria smooth muscle hyperplasia and oedema characterised most cases (18/22 and 19/22, respectively). More than half had prominent eosinophils (11/22) and/or plasma cells (12/22) in the lamina propria. The clinical presentation of patients with MD was characterised by significantly younger age of onset, male predominance and increased vomiting compared with non-MD patients, and a lower prevalence of anaemia compared with MD patients with polyps. There was a trend towards increased frequency of peripheral oedema in patients with MD compared with non-MD patients. CONCLUSIONS: MD is most accurately diagnosed by clinicohistopathological analysis including oesophagogastroduodenoscopy with gastric pH, appropriate laboratory tests (complete blood count, serum albumin, serum gastrin, Helicobacter pylori and cytomegalovirus serology) and full thickness mucosal biopsy of the involved gastric mucosa. PMID- 20926646 TI - Cause-effect relationship between the hepatitis C virus and insulin resistance at the time of direct antiviral therapy. PMID- 20926645 TI - Severe polyposis in Apc(1322T) mice is associated with submaximal Wnt signalling and increased expression of the stem cell marker Lgr5. AB - BACKGROUND AND AIMS: Adenomatous polyposis coli (APC) is a tumour suppressor gene mutated in the germline of patients with familial adenomatous polyposis (FAP) and somatically in most colorectal cancers. APC mutations impair beta-catenin degradation, resulting in increased Wnt signalling. The most frequent APC mutation is a codon 1309 truncation that is associated with severe FAP. A previous study compared two mouse models of intestinal tumorigenesis, Apc(R850X) (Min) and Apc(1322T) (1322T), the latter a model of human codon 1309 changes. 1322T mice had more severe polyposis but, surprisingly, these tumours had lower levels of nuclear beta-catenin than Min tumours. The consequences of these different beta-catenin levels were investigated. METHODS: Enterocytes were isolated from 1322T and Min tumours by microdissection and gene expression profiling was performed. Differentially expressed Wnt targets and other stem cell markers were validated using quantitative PCR, in situ hybridisation and immunohistochemistry. RESULTS: As expected, lower nuclear beta-catenin levels in 1322T lesions were associated with generally lower levels of Wnt target expression. However, expression of the Wnt target and stem cell marker Lgr5 was significantly higher in 1322T tumours than in Min tumours. Other stem cell markers (Musashi1, Bmi1 and the Wnt target Cd44) were also at higher levels in 1322T tumours. In addition, expression of the Bmp antagonist Gremlin1 was higher in 1322T tumours, together with lower Bmp2 and Bmp4 expression. CONCLUSIONS: The severe phenotype caused by truncation of Apc at codon 1322 is associated with an increased number of stem cells. Thus, a submaximal level of Wnt signalling favours the stem cell phenotype and this may promote tumorigenesis. A level of Wnt signalling exists that is too high for optimal tumour growth. PMID- 20926647 TI - Mapping of cortical activity in the first two decades of life: a high-density sleep electroencephalogram study. AB - Evidence that electroencephalography (EEG) slow-wave activity (SWA) (EEG spectral power in the 1-4.5 Hz band) during non-rapid eye movement sleep (NREM) reflects plastic changes is increasing (Tononi and Cirelli, 2006). Regional assessment of gray matter development from neuroimaging studies reveals a posteroanterior trajectory of cortical maturation in the first three decades of life (Shaw et al., 2008). Our aim was to test whether this regional cortical maturation is reflected in regional changes of sleep SWA. We evaluated all-night high-density EEG (128 channels) in 55 healthy human subjects (2.4-19.4 years) and assessed age related changes in NREM sleep topography. As in adults, we observed frequency specific topographical distributions of sleep EEG power in all subjects. However, from early childhood to late adolescence, the location on the scalp showing maximal SWA underwent a shift from posterior to anterior regions. This shift along the posteroanterior axis was only present in the SWA frequency range and remained stable across the night. Changes in the topography of SWA during sleep parallel neuroimaging study findings indicating cortical maturation starts early in posterior areas and spreads rostrally over the frontal cortex. Thus, SWA might reflect the underlying processes of cortical maturation. In the future, sleep SWA assessments may be used as a clinical tool to detect aberrations in cortical maturation. PMID- 20926648 TI - Nogo-A stabilizes the architecture of hippocampal neurons. AB - Although the role of myelin-derived Nogo-A as an inhibitor of axonal regeneration after CNS injury has been thoroughly described, its physiological function in the adult, uninjured CNS is less well known. We address this question in the hippocampus, where Nogo-A is expressed by neurons as well as oligodendrocytes. We used 21 d in vitro slice cultures of neonatal hippocampus where we applied different approaches to interfere with Nogo-A signaling and expression and analyze their effects on the dendritic and axonal architecture of pyramidal cells. Neutralization of Nogo-A by function-blocking antibodies induced a major alteration in the dendrite structure of hippocampal pyramidal neurons. Although spine density was not influenced by Nogo-A neutralization, spine type distribution was shifted toward a more immature phenotype. Axonal complexity and length were greatly increased. Nogo-A KO mice revealed a weak dendritic phenotype resembling the effect of the antibody treatment. To discriminate a possible cell autonomous role of Nogo-A from an environmental, receptor-mediated function, we studied the effects of short hairpin RNA-induced knockdown of Nogo-A or NgR1, a prominent Nogo-A receptor, within individual neurons. Knockdown of Nogo-A reproduced part of the dendritic and none of the spine or axon alterations. However, downregulation of NgR1 replicated the dendritic, the axonal, and the spine alterations observed after Nogo-A neutralization. Together, our results demonstrate that Nogo-A plays a major role in stabilizing and maintaining the architecture of hippocampal pyramidal neurons. Mechanistically, although the majority of the activity of Nogo-A relies on a receptor-mediated mechanism involving NgR1, its cell-autonomous function plays a minor role. PMID- 20926649 TI - Transcriptional control of KCNQ channel genes and the regulation of neuronal excitability. AB - Regulation of the resting membrane potential and the repolarization of neurons are important in regulating neuronal excitability. The potassium channel subunits Kv7.2 and Kv7.3 play a key role in stabilizing neuronal activity. Mutations in KCNQ2 and KCNQ3, the genes encoding Kv7.2 and Kv7.3, cause a neonatal form of epilepsy, and activators of these channels have been identified as novel antiepileptics and analgesics. Despite the observations that regulation of these subunits has profound effects on neuronal function, almost nothing is known about the mechanisms responsible for controlling appropriate expression levels. Here we identify two mechanisms responsible for regulating KCNQ2 and KCNQ3 mRNA levels. We show that the transcription factor Sp1 activates expression of both KCNQ2 and KCNQ3, whereas the transcriptional repressor REST (repressor element 1-silencing transcription factor) represses expression of both of these genes. Furthermore, we show that transcriptional regulation of KCNQ genes is mirrored by the correlated changes in M-current density and excitability of native sensory neurons. We propose that these mechanisms are important in the control of excitability of neurons and may have implications in seizure activity and pain. PMID- 20926650 TI - Smooth operator: avoidance of subharmonic bifurcations through mechanical mechanisms simplifies song motor control in adult zebra finches. AB - Like human infants, songbirds acquire their song by imitation and eventually generate sounds that result from complicated neural networks and intrinsically nonlinear physical processes. Signatures of low-dimensional chaos such as subharmonic bifurcations have been reported in adult and developing zebra finch song. Here, we use methods from nonlinear dynamics to test whether adult male zebra finches (Taenopygia guttata) use the intrinsic nonlinear properties of their vocal organ, the syrinx, to insert subharmonic transitions in their song. In contrast to previous data on the basis of spectrographic evidence, we show that subharmonic transitions do not occur in adult song. Subharmonic transitions also do not arise in artificially induced sound in the intact syrinx, but are commonly generated in the excised syrinx. These findings suggest that subharmonic transitions are not used to increase song complexity, and that the brain controls song in a surprisingly smooth control regimen. Fast, smooth changes in acoustic elements can be produced by direct motor control in a stereotyped fashion, which is a more reliable indicator of male fitness than abrupt acoustic changes that do not require similarly precise control. Consistent with this view is the presence of high fidelity at every level of motor control, from telencephalic premotor areas to superfast syringeal muscles. PMID- 20926652 TI - Role of the cerebellar cortex in conditioned goal-directed behavior. AB - Learning a new goal-directed behavioral task often requires the improvement of at least two processes, including an enhanced stimulus-response association and an optimization of the execution of the motor response. The cerebellum has recently been shown to play a role in acquiring goal-directed behavior, but it is unclear to what extent it contributes to a change in the stimulus-response association and/or the optimization of the execution of the motor response. We therefore designed the stimulus-dependent water Y-maze conditioning task, which allows discrimination between both processes, and we subsequently subjected Purkinje cell-specific mutant mice to this new task. The mouse mutants L7-PKCi, which suffer from impaired PKC-dependent processes such as parallel fiber to Purkinje cell long-term depression (PF-PC LTD), were able to acquire the stimulus-response association, but exhibited a reduced optimization of their motor performance. These data show that PF-PC LTD is not required for learning a stimulus-response association, but they do suggest that a PKC-dependent process in cerebellar Purkinje cells is required for optimization of motor responses. PMID- 20926651 TI - Sleep deprivation triggers inducible nitric oxide-dependent nitric oxide production in wake-active basal forebrain neurons. AB - Sleep loss negatively impacts performance, mood, memory, and immune function, but the homeostatic factors that impel sleep after sleep loss are imperfectly understood. Pharmacological studies had implicated the basal forebrain (BF) inducible nitric oxide (NO) synthase (iNOS)-dependent NO as a key homeostatic factor, but its cellular source was obscure. To obtain direct evidence about the cellular source of iNOS-generated NO during sleep deprivation (SD), we used intracerebroventricular perfusion in rats of the cell membrane-permeable dye diaminofluorescein-2/diacetate (DAF-2/DA) that, once intracellular, bound NO and fluoresced. To circumvent the effects of neuronal NOS (nNOS), DAF-2/DA was perfused in the presence of an nNOS inhibitor. SD led to DAF-positive fluorescence only in the BF neurons, not glia. SD increased expression of iNOS, which colocalized with NO in neurons and, more specifically, in prolonged wakefulness-active neurons labeled by Fos. SD-induced iNOS expression in wakefulness-active neurons positively correlated with sleep pressure, as measured by the number of attempts to enter sleep. Importantly, SD did not induce Fos or iNOS in stress-responsive central amygdala and paraventricular hypothalamic neurons, nor did SD elevate corticosterone, suggesting that the SD protocol did not provoke iNOS expression through stress. We conclude that iNOS-produced neuronal NO is an important homeostatic factor promoting recovery sleep after SD. PMID- 20926653 TI - Distinct frontoparietal networks set the stage for later perceptual identification priming and episodic recognition memory. AB - Recent imaging evidence suggests that a network of brain regions including the medial temporal lobe, ventrolateral prefrontal cortex, and dorsal posterior parietal cortex supports the successful encoding of long-term memories. Other areas, like the ventral posterior parietal and dorsolateral prefrontal cortices, have been associated with encoding failure rather than success. In line with the transfer-appropriate processing view, we hypothesized that distinct neural networks predict successful encoding depending on whether the later memory test draws primarily on perceptual or conceptual memory representations. Following an encoding phase, memory was assessed in a combined incidental perceptual identification and intentional recognition memory test. We found that during encoding, activation in ventral posterior parietal and dorsolateral prefrontal cortex predicted successful perceptual identification priming, whereas activation in ventrolateral prefrontal and dorsal posterior parietal cortex predicted successful recognition memory. Extending recent theories of attention to memory, the results suggest that ventral parietal regions support stimulus-driven attention to perceptual item features, forming memories accessed by later perceptual memory tests, whereas dorsal parietal regions support attention to meaningful item features, forming memories accessed by later conceptual memory tests. PMID- 20926655 TI - Targeting NMNAT1 to axons and synapses transforms its neuroprotective potency in vivo. AB - Axon and synapse degeneration are common components of many neurodegenerative diseases, and their rescue is essential for effective neuroprotection. The chimeric Wallerian degeneration slow protein (Wld(S)) protects axons dose dependently, but its mechanism is still elusive. We recently showed that Wld(S) acts at a non-nuclear location and is present in axons. This and other recent reports support a model in which Wld(S) protects by extranuclear redistribution of its nuclear NMNAT1 portion. However, it remains unclear whether cytoplasmic NMNAT1 acts locally in axons and synapses or at a non-nuclear site within cell bodies. The potency of axon protection by non-nuclear NMNAT1 relative to Wld(S) also needs to be established in vivo. Because the N-terminal portion of Wld(S) (N70) localized to axons, we hypothesized that it mediates the trafficking of the NMNAT1 portion. To test this, we substituted N70 with an axonal targeting peptide derived from amyloid precursor protein, and fused this to NMNAT1 with disrupted nuclear targeting. In transgenic mice, this transformed NMNAT1 from a molecule unable to inhibit Wallerian degeneration, even at high expression levels, into a protein more potent than Wld(S), able to preserve injured axons for several weeks at undetectable expression levels. Preventing NMNAT1 axonal delivery abolished its protective effect. Axonally targeted NMNAT1 localized to vesicular structures, colocalizing with extranuclear Wld(S), and was cotransported at least partially with mitochondria. We conclude that axonal targeting of NMNAT activity is both necessary and sufficient to delay Wallerian degeneration, and that promoting axonal and synaptic delivery greatly enhances the effectiveness. PMID- 20926654 TI - Control of exocytosis by synaptotagmins and otoferlin in auditory hair cells. AB - In pre-hearing mice, vesicle exocytosis at cochlear inner hair cell (IHC) ribbon synapses is triggered by spontaneous Ca(2+) spikes. At the onset of hearing, IHC exocytosis is then exclusively driven by graded potentials, and is characterized by higher Ca(2+) efficiency and improved synchronization of vesicular release. The molecular players involved in this transition are still unknown. Here we addressed the involvement of synaptotagmins and otoferlin as putative Ca(2+) sensors in IHC exocytosis during postnatal maturation of the cochlea. Using cell capacitance measurements, we showed that Ca(2+)-evoked exocytosis in mouse IHCs switches from an otoferlin-independent to an otoferlin-dependent mechanism at postnatal day 4. During this early exocytotic period, several synaptotagmins (Syts), including Syt1, Syt2 and Syt7, were detected in IHCs. The exocytotic response as well as the release of the readily releasable vesicle pool (RRP) was, however, unchanged in newborn mutant mice lacking Syt1, Syt2 or Syt7 (Syt1(-/-), Syt2(-/-) and Syt7(-/-) mice). We only found a defect in RRP recovery in Syt1(-/ ) mice which was apparent as a strongly reduced response to repetitive stimulations. In post-hearing Syt2(-/-) and Syt7(-/-) mutant mice, IHC synaptic exocytosis was unaffected. The transient expression of Syt1 and Syt2, which were no longer detected in IHCs after the onset of hearing, indicates that these two most common Ca(2+)-sensors in CNS synapses are not involved in mature IHCs. We suggest that otoferlin underlies highly efficient Ca(2+)-dependent membrane membrane fusion, a process likely essential to increase the probability and synchrony of vesicle fusion events at the mature IHC ribbon synapse. PMID- 20926656 TI - Histone H1 poly[ADP]-ribosylation regulates the chromatin alterations required for learning consolidation. AB - Memory formation requires changes in gene expression, which are regulated by the activation of transcription factors and by changes in epigenetic factors. Poly[ADP]-ribosylation of nuclear proteins has been postulated as a chromatin modification involved in memory consolidation, although the mechanisms involved are not well characterized. Here we demonstrate that poly[ADP]-ribose polymerase 1 (PARP-1) activity and the poly[ADP]-ribosylation of proteins over a specific time course is required for the changes in synaptic plasticity related to memory stabilization in mice. At the molecular level, histone H1 poly[ADP]-ribosylation was evident in the hippocampus after the acquisition period, and it was selectively released in a PARP-1-dependent manner at the promoters of cAMP response element-binding protein and nuclear factor-kappaB dependent genes associated with learning and memory. These findings suggest that histone H1 poly[ADP]-ribosylation, and its loss at specific loci, is an epigenetic mechanism involved in the reprogramming of neuronal gene expression required for memory consolidation. PMID- 20926657 TI - Left hemisphere lateralization for language in right-handers is controlled in part by familial sinistrality, manual preference strength, and head size. AB - We investigated the effects of familial sinistrality (FS+; presence of left handedness in one's close relatives), manual preference strength (MPS), and head size on the hemispheric lateralization of language in right-handers. Functional magnetic resonance imaging was used to map 49 individuals while listening to a story in their mother tongue. We found that individuals who had both the FS+ trait and weak MPS had no left hemisphere dominance for this lexicosyntactic task, whereas others showed a leftward functional asymmetry. In addition, the smaller the brain size, the smaller the leftward asymmetry for language, independent of FS and MPS. None of these effects were observed when the same subjects performed a spatial attention task that elicited right hemispheric functional asymmetry. These results demonstrate that the left hemisphere dominance for language in right-handers is a variable controlled, in part, by a number of specific factors, including FS, MPS, and head size. PMID- 20926658 TI - POSH is an intracellular signal transducer for the axon outgrowth inhibitor Nogo66. AB - Myelin-derived inhibitors limit axon outgrowth and plasticity during development and in the adult mammalian CNS. Nogo66, a functional domain of the myelin-derived inhibitor NogoA, signals through the PirB receptor to inhibit axon outgrowth. The signaling pathway mobilized by Nogo66 engagement of PirB is not well understood. We identify a critical role for the scaffold protein Plenty of SH3s (POSH) in relaying process outgrowth inhibition downstream of Nogo66 and PirB. Blocking the function of POSH, or two POSH-associated proteins, leucine zipper kinase (LZK) and Shroom3, with RNAi in cortical neurons leads to release from myelin and Nogo66 inhibition. We also observed autocrine inhibition of process outgrowth by NogoA, and suppression analysis with the POSH-associated kinase LZK demonstrated that LZK operates downstream of NogoA and PirB in a POSH-dependent manner. In addition, cerebellar granule neurons with an RNAi-mediated knockdown in POSH function were refractory to the inhibitory action of Nogo66, indicating that a POSH-dependent mechanism operates to inhibit axon outgrowth in different types of CNS neurons. These studies delineate an intracellular signaling pathway for process outgrowth inhibition by Nogo66, comprised of NogoA, PirB, POSH, LZK, and Shroom3, and implicate the POSH complex as a potential therapeutic target to enhance axon outgrowth and plasticity in the injured CNS. PMID- 20926659 TI - Functional requirements for reward-modulated spike-timing-dependent plasticity. AB - Recent experiments have shown that spike-timing-dependent plasticity is influenced by neuromodulation. We derive theoretical conditions for successful learning of reward-related behavior for a large class of learning rules where Hebbian synaptic plasticity is conditioned on a global modulatory factor signaling reward. We show that all learning rules in this class can be separated into a term that captures the covariance of neuronal firing and reward and a second term that presents the influence of unsupervised learning. The unsupervised term, which is, in general, detrimental for reward-based learning, can be suppressed if the neuromodulatory signal encodes the difference between the reward and the expected reward-but only if the expected reward is calculated for each task and stimulus separately. If several tasks are to be learned simultaneously, the nervous system needs an internal critic that is able to predict the expected reward for arbitrary stimuli. We show that, with a critic, reward-modulated spike-timing-dependent plasticity is capable of learning motor trajectories with a temporal resolution of tens of milliseconds. The relation to temporal difference learning, the relevance of block-based learning paradigms, and the limitations of learning with a critic are discussed. PMID- 20926660 TI - Ca2+-dependent desensitization of TRPV2 channels is mediated by hydrolysis of phosphatidylinositol 4,5-bisphosphate. AB - TRPV2 is a member of the transient receptor potential family of ion channels involved in chemical and thermal pain transduction. Unlike the related TRPV1 channel, TRPV2 does not appear to bind either calmodulin or ATP in its N-terminal ankyrin repeat domain. In addition, it does not contain a calmodulin-binding site in the distal C-terminal region, as has been proposed for TRPV1. We have found that TRPV2 channels transiently expressed in F-11 cells undergo Ca(2+)-dependent desensitization, similar to the other TRPVs, suggesting that the mechanism of desensitization may be conserved in the subfamily of TRPV channels. TRPV2 desensitization was not altered in whole-cell recordings in the presence of calmodulin inhibitors or on coexpression of mutant calmodulin but was sensitive to changes in membrane phosphatidylinositol 4,5-bisphosphate (PIP(2)), suggesting a role of membrane PIP(2) in TRPV2 desensitization. Simultaneous confocal imaging and electrophysiological recording of cells expressing TRPV2 and a fluorescent PIP(2)-binding probe demonstrated that TRPV2 desensitization was concomitant with depletion of PIP(2). We conclude that the decrease in PIP(2) levels on channel activation underlies a major component of Ca(2+)-dependent desensitization of TRPV2 and may play a similar role in other TRP channels. PMID- 20926662 TI - Auditory cortical neurons convey maximal stimulus-specific information at their best frequency. AB - Sensory neurons are often thought to encode information about their preferred stimuli. It has also been proposed that neurons convey the most information about stimuli in the flanks of their tuning curves, where firing rate changes most steeply. Here we demonstrate that the responses of rat auditory cortical neurons convey maximal stimulus-specific information about sound frequency at their best frequency, rather than in the flanks of their tuning curves. Theoretical work has shown that stimulus-specific information shifts from tuning curve slope to peak as neuronal variability increases. These results therefore suggest that with respect to the most informative regions of the tuning curve, auditory cortical neurons operate in a regime of high variability. PMID- 20926661 TI - Hippocampal c-Jun-N-terminal kinases serve as negative regulators of associative learning. AB - In the adult mouse, signaling through c-Jun N-terminal kinases (JNKs) links exposure to acute stress to various physiological responses. Inflammatory cytokines, brain injury and ischemic insult, or exposure to psychological acute stressors induce activation of hippocampal JNKs. Here we report that exposure to acute stress caused activation of JNKs in the hippocampal CA1 and CA3 subfields, and impaired contextual fear conditioning. Conversely, intrahippocampal injection of JNKs inhibitors sp600125 (30 MUm) or D-JNKI1 (8 MUm) reduced activity of hippocampal JNKs and rescued stress-induced deficits in contextual fear. In addition, intrahippocampal administration of anisomycin (100 MUg/MUl), a potent JNKs activator, mimicked memory-impairing effects of stress on contextual fear. This anisomycin-induced amnesia was abolished after cotreatment with JNKs selective inhibitor sp600125 without affecting anisomycin's ability to effectively inhibit protein synthesis as measured by c-Fos immunoreactivity. We also demonstrated milder and transient activation of the JNKs pathway in the CA1 subfield of the hippocampus during contextual fear conditioning and an enhancement of contextual fear after pharmacological inhibition of JNKs under baseline conditions. Finally, using combined biochemical and transgenic approaches with mutant mice lacking different members of the JNK family (Jnk1, Jnk2, and Jnk3), we provided evidence that JNK2 and JNK3 are critically involved in stress-induced deficit of contextual fear, while JNK1 mainly regulates baseline learning in this behavioral task. Together, these results support the possibility that hippocampal JNKs serve as a critical molecular regulator in the formation of contextual fear. PMID- 20926663 TI - Wnts influence the timing and efficiency of oligodendrocyte precursor cell generation in the telencephalon. AB - Oligodendrocyte precursor cells (OPCs) are generated from multiple progenitor domains in the telencephalon in developmental succession from ventral to dorsal. Previous studies showed that Wnt signaling inhibits the differentiation of OPCs into mature oligodendrocytes. Here we explored the hypothesis that Wnt signaling limits the generation of OPCs from neural progenitors during forebrain development. We manipulated Wnt signaling in mouse neural progenitor cultures and found that Wnt signaling influences progenitors cell autonomously to alter the production of OPCs, and that endogenous Wnt signaling in these cultures limits the efficiency of generating OPCs from neural progenitors. To examine these events in vivo, we electroporated a soluble Wnt inhibitor or a dominant-negative transcriptional regulator into embryonic mouse neocortical ventricular zone before the usual onset of OPC production and showed that decreasing Wnt signaling in cortical progenitors results in early production of OPCs. Our studies indicate that Wnt signaling influences the timing and extent of OPC production in the developing telencephalon. PMID- 20926664 TI - Hyperpolarization-activated currents in gonadotropin-releasing hormone (GnRH) neurons contribute to intrinsic excitability and are regulated by gonadal steroid feedback. AB - Pulsatile release of gonadotropin-releasing hormone (GnRH) is required for fertility and is regulated by steroid feedback. Hyperpolarization-activated currents (I(h)) play a critical role in many rhythmic neurons. We examined the contribution of I(h) to the membrane and firing properties of GnRH neurons and the modulation of this current by steroid milieu. Whole-cell voltage- and current clamp recordings were made of GFP-identified GnRH neurons in brain slices from male mice that were gonad-intact, castrated, or castrated and treated with estradiol implants. APV, CNQX, and bicuculline were included to block fast synaptic transmission. GnRH neurons (47%) expressed a hyperpolarization-activated current with pharmacological and biophysical characteristics of I(h). The I(h) specific blocker ZD7288 reduced hyperpolarization-induced sag and rebound potential, decreased GnRH neuron excitability and action potential firing, and hyperpolarized membrane potential in some cells. ZD7288 also altered the pattern of burst firing and reduced the slope of recovery from the after hyperpolarization potential. Activation of I(h) by hyperpolarization increased spike frequency, whereas inactivation of I(h) by depolarization reduced spike frequency. Castration increased I(h) compared with that in gonad-intact males. This effect was reversed by in vivo estradiol replacement. Together, these data indicate I(h) provides an excitatory drive in GnRH neurons that contributes to action potential burst firing and that estradiol regulates I(h) in these cells. As estradiol is the primary central negative feedback hormone on GnRH neuron firing in males, this provides insight into the mechanisms by which steroid hormones potentially alter the intrinsic properties of GnRH neurons to change their activity. PMID- 20926665 TI - Multiple desensitization mechanisms of mechanotransducer channels shape firing of mechanosensory neurons. AB - How desensitization of mechanotransducer currents regulates afferent signal generation in mammalian sensory neurons is essentially unknown. Here, we dissected desensitization mechanisms of mechanotransducer channels in rat sensory neurons that mediate the sense of touch and pain. We identified four types of mechanotransducer currents that distribute differentially in cutaneous nociceptors and mechanoreceptors and that differ in desensitization rates. Desensitization of mechanotransducer channels in mechanoreceptors was fast and mediated by channel inactivation and adaptation, which reduces the mechanical force sensed by the transduction channel. Both processes were promoted by negative voltage. These properties of mechanotransducer channels suited them to encode the dynamic parameters of the stimulus. In contrast, inactivation and adaptation of mechanotransducer channels in nociceptors had slow time courses and were suited to encode duration of the stimulus. Thus, desensitization properties of mechanotransducer currents relate to their functions as sensors of phasic and tonic stimuli and enable sensory neurons to achieve efficient stimulus representation. PMID- 20926666 TI - Differential patterns of inputs create functional zones in central nucleus of inferior colliculus. AB - Distinct pathways carry monaural and binaural information from the lower auditory brainstem to the central nucleus of the inferior colliculus (ICC). Previous anatomical and physiological studies suggest that differential ascending inputs to regions of the ICC create functionally distinct zones. Here, we provide direct evidence of this relationship by combining recordings of single unit responses to sound in the ICC with focal, iontophoretic injections of the retrograde tracer Fluoro-Gold at the physiologically characterized sites. Three main patterns of anatomical inputs were observed. One pattern was identified by inputs from the cochlear nucleus and ventral nucleus of the lateral lemniscus in isolation, and these injection sites were correlated with monaural responses. The second pattern had inputs only from the ipsilateral medial and lateral superior olive, and these sites were correlated with interaural time difference (ITD)-sensitive responses to low frequency (<500 Hz). A third pattern had inputs from a variety of olivary and lemniscal sources, notably the contralateral lateral superior olive and dorsal nucleus of the lateral lemniscus. These were correlated with high frequency ITD sensitivity to complex acoustic stimuli. These data support the notion of anatomical regions formed by specific patterns of anatomical inputs to the ICC. Such synaptic domains may represent functional zones in ICC. PMID- 20926667 TI - Convergence of presenilin- and tau-mediated pathways on axonal trafficking and neuronal function. AB - Alzheimer's disease (AD) is a significant and growing health problem in the aging population. Although definitive mechanisms of pathogenesis remain elusive, genetic and histological clues have implicated the proteins presenilin (PS) and tau as key players in AD development. PS mutations lead to familial AD, and although tau is not mutated in AD, tau pathology is a hallmark of the disease. Axonal transport deficits are a common feature of several neurodegenerative disorders and may represent a point of intersection of PS and tau function. To investigate the contribution of wild-type, as opposed to mutant, tau to axonal transport defects in the context of presenilin loss, we used a mouse model postnatally deficient for PS (PS cDKO) and expressing wild-type human tau (WtTau). The resulting PS cDKO;WtTau mice exhibited early tau pathology and axonal transport deficits that preceded development of these phenotypes in WtTau or PS cDKO mice. These deficits were associated with reduced neurotrophin signaling, defective learning and memory and impaired synaptic plasticity. The combination of these effects accelerated neurodegeneration in PS cDKO;WtTau mice. Our results strongly support a convergent role for PS and tau in axonal transport and neuronal survival and function and implicate their misregulation as a contributor to AD pathogenesis. PMID- 20926668 TI - Morphine- and CaMKII-dependent enhancement of GIRK channel signaling in hippocampal neurons. AB - G-protein-gated inwardly rectifying potassium (GIRK) channels, which help control neuronal excitability, are important for the response to drugs of abuse. Here, we describe a novel pathway for morphine-dependent enhancement of GIRK channel signaling in hippocampal neurons. Morphine treatment for ~20 h increased the colocalization of GIRK2 with PSD95, a dendritic spine marker. Western blot analysis and quantitative immunoelectron microscopy revealed an increase in GIRK2 protein and targeting to dendritic spines. In vivo administration of morphine also produced an upregulation of GIRK2 protein in the hippocampus. The mechanism engaged by morphine required elevated intracellular Ca(2+) and was insensitive to pertussis toxin, implicating opioid receptors that may couple to Gq G-proteins. Met-enkephalin, but not the MU-selective (DAMGO) and delta-selective (DPDPE) opioid receptor agonists, mimicked the effect of morphine, suggesting involvement of a heterodimeric opioid receptor complex. Peptide (KN-93) inhibition of CaMKII prevented the morphine-dependent change in GIRK localization, whereas expression of a constitutively activated form of CaMKII mimicked the effects of morphine. Coincident with an increase in GIRK2 surface expression, functional analyses revealed that morphine treatment increased the size of serotonin-activated GIRK currents and Ba(2+)-sensitive basal K(+) currents in neurons. These results demonstrate plasticity in neuronal GIRK signaling that may contribute to the abusive effects of morphine. PMID- 20926669 TI - Spatiotemporal coupling between hippocampal acetylcholine release and theta oscillations in vivo. AB - Both acetylcholine (ACh) and theta oscillations are important for learning and memory, but the dynamic interaction between these two processes remains unclear. Recent advances in amperometry techniques have revealed phasic ACh releases in vivo. However, it is unknown whether phasic ACh release co-occurs with theta oscillations. We investigated this issue in the CA1 region of urethane anesthetized male rats using amperometric and electrophysiological recordings. We found that ACh release was highly correlated with the appearance of both spontaneous and induced theta oscillations. Moreover, the maximal ACh release was observed around or slightly above the pyramidal layer. Interestingly, such release lagged behind theta initiation by 25-60 s. The slow ACh release profile was matched by the slow firing rate increase of a subset of medial-septal low firing-rate neurons. Together, these results establish, for the first time, the in vivo coupling between phasic ACh release and theta oscillations on spatiotemporal scales much finer than previously known. These findings also suggest that phasic ACh is not required for theta initiation and may instead operate synergistically with theta oscillations to promote neural plasticity in the service of learning and memory. PMID- 20926670 TI - Quantitative analysis of synaptic vesicle Rabs uncovers distinct yet overlapping roles for Rab3a and Rab27b in Ca2+-triggered exocytosis. AB - Rab GTPases are molecular switches that orchestrate protein complexes before membrane fusion reactions. In synapses, Rab3 and Rab5 proteins have been implicated in the exo-endocytic cycling of synaptic vesicles (SVs), but an involvement of additional Rabs cannot be excluded. Here, combining high resolution mass spectrometry and chemical labeling (iTRAQ) together with quantitative immunoblotting and fluorescence microscopy, we have determined the exocytotic (Rab3a, Rab3b, Rab3c, and Rab27b) and endocytic (Rab4b, Rab5a/b, Rab10, Rab11b, and Rab14) Rab machinery of SVs. Analysis of two closely related proteins, Rab3a and Rab27b, revealed colocalization in synaptic nerve terminals, where they reside on distinct but overlapping SV pools. Moreover, whereas Rab3a readily dissociates from SVs during Ca(2+)-triggered exocytosis, and is susceptible to membrane extraction by Rab-GDI, Rab27b persists on SV membranes upon stimulation and is resistant to GDI-coupled Rab retrieval. Finally, we demonstrate that selective modulation of the GTP/GDP switch mechanism of Rab27b impairs SV recycling, suggesting that Rab27b, probably in concert with Rab3s, is involved in SV exocytosis. PMID- 20926671 TI - Estrogen receptor beta activity modulates synaptic signaling and structure. AB - Brain-synthesized estrogen has been shown to influence synaptic structure, function, and cognitive processes. However, the molecular mechanisms underlying the rapid effects of estrogen on the dendritic spines of cortical neurons are not clear. Estrogen receptor beta (ERbeta) is expressed in cortical neurons, and ERbeta knock-out mice display impaired performance in cortically mediated processes, suggesting that signaling via this receptor has profound effects on cortical neuron function. However, the effect of rapid signaling via ERbeta on dendritic spines and the signaling pathways initiated by this receptor in cortical neurons are unknown. Here, we show that activation of ERbeta with the specific agonist WAY-200070 results in increased spine density and PSD-95 (postsynaptic density-95) accumulation in membrane regions. Activation of ERbeta by WAY-200070 also resulted in the phosphorylation of p21-activated kinase (PAK) and extracellular signal-regulated kinase 1/2 (ERK1/2) in cultured cortical neurons, suggesting a mechanism for the regulation of the actin cytoskeleton. Moreover, we found that aromatase, an enzyme critical for estrogen production, is present at presynaptic termini, supporting a role for brain-synthesized estrogen as a neuromodulator in the cortex. These results implicate ERbeta signaling in controlling dendritic spine morphology, in part via a PAK/ERK1/2-dependent pathway, and provide mechanistic insight into the rapid cellular effects of estrogen on brain function. PMID- 20926673 TI - Oscillatory dipoles as a source of phase shifts in field potentials in the mammalian auditory brainstem. AB - A popular model of binaural processing, proposed by Jeffress (1948), states that external interaural time delays (ITDs) are compensated by internal axonal delays allowing ITD to be spatially represented by a population of coincidence detectors in the medial superior olive (MSO). Isolating single-neuron responses in MSO is difficult because of the presence of a strong extracellular field potential known as the neurophonic, so that few studies have tested Jeffress's key prediction. Phase delays in the nucleus laminaris neurophonic in owls have been observed and are consistent with a Jeffress-like model. Here, we recorded neurophonic responses in cat MSO to monaural tones at locations along its dendritic axis. Fourier analysis of the neurophonic was used to extract amplitude and phase at the stimulus frequency. Amplitude, as a function of depth, showed two peaks separated by a dip. A half-cycle phase shift was observed at depths close to the dip, over a wide frequency range. Current source density analysis for contralateral (ipsilateral) stimulation shows a current source close to the neurophonic amplitude peak and a sink a few hundred micrometers ventromedially (dorsolaterally). These results are consistent with a dipole configuration: contralateral (ipsilateral) excitation causes a current sink at the ventromedial (dorsolateral) dendrites and a source at the soma and dorsolateral (ventromedial) dendrites. Incorporating these results in a dipole model explains the phase and amplitude patterns observed. We conclude that the half-cycle phase shift is consistent with a current dipole, making it difficult to derive measurements of axonal delays from the neurophonic. PMID- 20926672 TI - Attention protects the fidelity of visual memory: behavioral and electrophysiological evidence. AB - Recall from visual memory is vulnerable to the influence of task-irrelevant information, including the remembered, prototypical value of stimuli seen previously. Wilken and Ma (2004) proposed that this distortion of recall was actually adaptive, with the task-irrelevant information compensating for imperfections of memory. We tested their proposal by using trial-by-trial oscillations in the electroencephalogram's alpha band (8-14 Hz) collected from human subjects as a marker for the strength of visual attention. Subjects' recall of stimulus spatial frequency showed a systematic error, namely a shift toward the prototypical value of previously seen stimuli. The magnitude of this prototype effect was strongly related to the amplitude of alpha band oscillations recorded at posterior sensor locations during the first 100 ms after stimulus onset. Our results support the hypothesis that the prototype effect is compensatory for imprecision in memory. Moreover, the attentional modulation of alpha activity during the encoding of the target stimulus is consistent with the view that attention sharpens the neural responses that are elicited by the task relevant stimulus. PMID- 20926674 TI - Tuning curves for movement direction in the human visuomotor system. AB - Neurons in macaque primary motor cortex (M1) are broadly tuned to arm movement direction. Recent evidence suggests that human M1 contains directionally tuned neurons, but it is unclear which other areas are part of the network coding movement direction and what characterizes the responses of neuronal populations in those areas. Such information would be highly relevant for the implementation of brain-computer interfaces (BCIs) in paralyzed patients. We used functional magnetic resonance imaging adaptation to identify which areas of the human brain show directional selectivity and the degree to which these areas are affected by the type of motor act (to press vs to grasp). After adapting participants to one particular hand movement direction, we measured the release from adaptation during occasional test trials, parametrically varying the angular difference between adaptation and test direction. We identified multiple areas broadly tuned to movement direction, including M1, dorsal premotor cortex, intraparietal sulcus, and the parietal reach region. Within these areas, we observed a gradient of directional selectivity, with highest directional selectivity in the right parietal reach region, for both right- and left-hand movements. Moreover, directional selectivity was modulated by the type of motor act to varying degrees, with the largest effect in M1 and the smallest modulation in the parietal reach region. These data provide an important extension of our knowledge about directional tuning in the human brain. Furthermore, our results suggest that the parietal reach region might be an ideal candidate for the implementation of BCI in paralyzed patients. PMID- 20926675 TI - Dendritic growth in medial prefrontal cortex and cognitive flexibility are enhanced during the postpartum period. AB - The postpartum period is associated with numerous hormonal changes, some of which have been linked to detrimental effects on the medial prefrontal cortex (mPFC), a brain region involved in cognition. Here, we investigated whether mPFC structure and function are negatively influenced during the postpartum period, an outcome that might be predicted by the maternal hormonal milieu. Mother rats were tested on an attentional set-shifting task, and dendritic architecture of layer 2/3 mPFC pyramidal neurons was analyzed. Mother rats exhibited increased dendritic spine number in the mPFC, an effect that coincided with improved attention and behavioral flexibility. These findings suggest that the postpartum period is associated with promotion of neuronal growth in the mPFC and enhanced cognitive function. PMID- 20926676 TI - Generation of black-dominant responses in V1 cortex. AB - Consistent with human perceptual data, we found many more black-dominant than white-dominant responses in layer 2/3 neurons of the macaque primary visual cortex (V1). Seeking the mechanism of this black dominance of layer 2/3 neurons, we measured the laminar pattern of population responses (multiunit activity and local field potential) and found that a small preference for black is observable in early responses in layer 4Cbeta, the parvocellular-input layer, but not in the magnocellular-input layer 4Calpha. Surprisingly, further analysis of the dynamics of black-white responses in layers 4Cbeta and 2/3 suggested that black-dominant responses in layer 2/3 were not generated simply because of the weak black dominant inputs from 4Cbeta. Instead, our results indicated the neural circuitry in V1 is wired with a preference to strengthen black responses. We hypothesize that this selective wiring could be due to (1) feedforward connectivity from black-dominant neurons in layer 4C to cells in layer 2/3 or (2) recurrent interactions between black-dominant neurons in layer 2/3, or a combination of both. PMID- 20926677 TI - Serotonin, but not N-methyltryptamines, activates the serotonin 2A receptor via a beta-arrestin2/Src/Akt signaling complex in vivo. AB - Hallucinogens mediate many of their psychoactive effects by activating serotonin 2A receptors (5-HT(2A)R). Although serotonin is the cognate endogenous neurotransmitter and is not considered hallucinogenic, metabolites of serotonin also have high affinity at 5-HT(2A)R and can induce hallucinations in humans. Here we report that serotonin differs from the psychoactive N-methyltryptamines by its ability to engage a beta-arrestin2-mediated signaling cascade in the frontal cortex. Serotonin and 5-hydroxy-L-tryptophan (5-HTP) induce a head-twitch response in wild-type (WT) mice that is a behavioral proxy for 5-HT(2A)R activation. The response in beta-arrestin2 knock-out (betaarr2-KO) mice is greatly attenuated until the doses are elevated, at which point, betaarr2-KO mice display a head-twitch response that can exceed that of WT mice. Direct administration of N-methyltryptamines also produces a greater response in betaarr2-KO mice. Moreover, the inhibition of N-methyltransferase blocks 5-HTP induced head twitches in betaarr2-KO mice, indicating that N-methyltryptamines, rather than serotonin, primarily mediate this response. Biochemical studies demonstrate that serotonin stimulates Akt phosphorylation in the frontal cortex and in primary cortical neurons through the activation of a beta arrestin2/phosphoinositide 3-kinase/Src/Akt cascade, whereas N-methyltryptamines do not. Furthermore, disruption of any of the components of this cascade prevents 5-HTP-induced, but not N-methyltryptamine-induced, head twitches. We propose that there is a bifurcation of 5-HT(2A)R signaling that is neurotransmitter and beta arrestin2 dependent. This demonstration of agonist-directed 5-HT(2A)R signaling in vivo may significantly impact drug discovery efforts for the treatment of disorders wherein hallucinations are part of the etiology, such as schizophrenia, or manifest as side effects of treatment, such as depression. PMID- 20926679 TI - NMDA-mediated regulation of DSCAM dendritic local translation is lost in a mouse model of Down's syndrome. AB - Down's syndrome cell adhesion molecule (DSCAM) belongs to the Down's syndrome critical region of human chromosome 21, and it encodes a cell adhesion molecule involved in dendrite morphology and neuronal wiring. Although the function of DSCAM in the adult brain is unknown, its expression pattern suggests a role in synaptic plasticity. Local mRNA translation is a key process in axonal growth, dendritogenesis, and synaptogenesis during development, and in synaptic plasticity in adulthood. Here, we report the dendritic localization of DSCAM mRNA in the adult mouse hippocampus, where it associates with CPEB1 [cytoplasmic polyadenylation element (CPE) binding protein 1], an important regulator of mRNA transport and local translation. We identified five DSCAM isoforms produced by alternative polyadenylation bearing different combinations of regulatory CPE motifs. Overexpression of DSCAM in hippocampal neurons inhibited dendritic branching. Interestingly, dendritic levels of DSCAM mRNA and protein were increased in hippocampal neurons from Ts1Cje mice, a model of Down's syndrome. Most importantly, DSCAM dendritic translation was rapidly induced by NMDA in wild type, but not in Ts1Cje neurons. We propose that impairment of the NMDA-mediated regulation of DSCAM translation may contribute to the alterations in dendritic morphology and/or synaptic plasticity in Down's syndrome. PMID- 20926678 TI - Testing the reward prediction error hypothesis with an axiomatic model. AB - Neuroimaging studies typically identify neural activity correlated with the predictions of highly parameterized models, like the many reward prediction error (RPE) models used to study reinforcement learning. Identified brain areas might encode RPEs or, alternatively, only have activity correlated with RPE model predictions. Here, we use an alternate axiomatic approach rooted in economic theory to formally test the entire class of RPE models on neural data. We show that measurements of human neural activity from the striatum, medial prefrontal cortex, amygdala, and posterior cingulate cortex satisfy necessary and sufficient conditions for the entire class of RPE models. However, activity measured from the anterior insula falsifies the axiomatic model, and therefore no RPE model can account for measured activity. Further analysis suggests the anterior insula might instead encode something related to the salience of an outcome. As cognitive neuroscience matures and models proliferate, formal approaches of this kind that assess entire model classes rather than specific model exemplars may take on increased significance. PMID- 20926680 TI - Dysfunction of heterotrimeric kinesin-2 in rod photoreceptor cells and the role of opsin mislocalization in rapid cell death. AB - Due to extensive elaboration of the photoreceptor cilium to form the outer segment, axonemal transport (IFT) in photoreceptors is extraordinarily busy, and retinal degeneration is a component of many ciliopathies. Functional loss of heterotrimeric kinesin-2, a major anterograde IFT motor, causes mislocalized opsin, followed by rapid cell death. Here, we have analyzed the nature of protein mislocalization and the requirements for the death of kinesin-2-mutant rod photoreceptors. Quantitative immuno EM showed that opsin accumulates initially within the inner segment, and then in the plasma membrane. The light-activated movement of arrestin to the outer segment is also impaired, but this defect likely results secondarily from binding to mislocalized opsin. Unlike some other retinal degenerations, neither opsin-arrestin complexes nor photoactivation were necessary for cell loss. In contrast, reduced rod opsin expression provided enhanced rod and cone photoreceptor survival and function, as measured by photoreceptor cell counts, apoptosis assays, and ERG analysis. The cell death incurred by loss of kinesin-2 function was almost completely negated by Rho-/-. Our results indicate that mislocalization of opsin is a major cause of photoreceptor cell death from kinesin-2 dysfunction and demonstrate the importance of accumulating mislocalized protein per se, rather than specific signaling properties of opsin, stemming from photoactivation or arrestin binding. PMID- 20926681 TI - C-jun inhibits mammary apoptosis in vivo. AB - c-jun, which is overexpressed in a number of human cancers encodes a critical component of the AP-1 complex. c-jun has been shown to either induce or inhibit cellular apoptosis. Germ line deletion of both c-jun alleles is embryonically lethal. To determine the role of the endogenous c-jun gene in apoptosis, we performed mammary epithelial cell-targeted somatic deletion using floxed c-jun (c jun(f/f)) conditional knockout mice. Laser capture microdissection demonstrated endogenous c-jun inhibits expression of apoptosis inducing genes and reactive oxygen species (ROS)-reducing genes (MnSOD, catalase). ROS have been implicated in apoptosis and undergo enzymatic elimination via MnSOD and CuZnSOD with further detoxification via catalase. c-jun-mediated survival was in part dependent on ROS production. c-jun-mediated repression of MnSOD and catalase occurred via mitochondrial complex I and NOX I. Collectively, these studies define a pivotal role of endogenous c-jun in promoting cell survival via maintaining mitochondrial integrity and expression of the key regulators of ROS production. PMID- 20926682 TI - Vav3 is involved in GABAergic axon guidance events important for the proper function of brainstem neurons controlling cardiovascular, respiratory, and renal parameters. AB - Vav3 is a phosphorylation-dependent activator of Rho/Rac GTPases that has been implicated in hematopoietic, bone, cerebellar, and cardiovascular roles. Consistent with the latter function, Vav3-deficient mice develop hypertension, tachycardia, and renocardiovascular dysfunctions. The cause of those defects remains unknown as yet. Here, we show that Vav3 is expressed in GABAegic neurons of the ventrolateral medulla (VLM), a brainstem area that modulates respiratory rates and, via sympathetic efferents, a large number of physiological circuits controlling blood pressure. On Vav3 loss, GABAergic cells of the caudal VLM cannot innervate properly their postsynaptic targets in the rostral VLM, leading to reduced GABAergic transmission between these two areas. This results in an abnormal regulation of catecholamine blood levels and in improper control of blood pressure and respiration rates to GABAergic signals. By contrast, the reaction of the rostral VLM to excitatory signals is not impaired. Consistent with those observations, we also demonstrate that Vav3 plays important roles in axon branching and growth cone morphology in primary GABAergic cells. Our study discloses an essential and nonredundant role for this Vav family member in axon guidance events in brainstem neurons that control blood pressure and respiratory rates. PMID- 20926683 TI - TatB functions as an oligomeric binding site for folded Tat precursor proteins. AB - Twin-arginine-containing signal sequences mediate the transmembrane transport of folded proteins. The cognate twin-arginine translocation (Tat) machinery of Escherichia coli consists of the membrane proteins TatA, TatB, and TatC. Whereas Tat signal peptides are recognized by TatB and TatC, little is known about molecular contacts of the mature, folded part of Tat precursor proteins. We have placed a photo-cross-linker into Tat substrates at sites predicted to be either surface-exposed or hidden in the core of the folded proteins. On targeting of these variants to the Tat machinery of membrane vesicles, all surface-exposed sites were found in close proximity to TatB. Correspondingly, incorporation of the cross-linker into TatB revealed multiple precursor-binding sites in the predicted transmembrane and amphipathic helices of TatB. Large adducts indicative of TatB oligomers contacting one precursor molecule were also obtained. Cross linking of Tat substrates to TatB required an intact twin-arginine signal peptide and disappeared upon transmembrane translocation. Our collective data are consistent with TatB forming an oligomeric binding site that transiently accommodates folded Tat precursors. PMID- 20926684 TI - beta1A integrin is a master regulator of invadosome organization and function. AB - Invadosomes are adhesion structures involved in tissue invasion that are characterized by an intense actin polymerization-depolymerization associated with beta1 and beta3 integrins and coupled to extracellular matrix (ECM) degradation activity. We induced the formation of invadosomes by expressing the constitutive active form of Src, SrcYF, in different cell types. Use of ECM surfaces micropatterned at the subcellular scale clearly showed that in mesenchymal cells, integrin signaling controls invadosome activity. Using beta1-/- or beta3-/- cells, it seemed that beta1A but not beta3 integrins are essential for initiation of invadosome formation. Protein kinase C activity was shown to regulate autoassembly of invadosomes into a ring-like metastructure (rosette), probably by phosphorylation of Ser785 on the beta1A tail. Moreover, our study clearly showed that beta1A links actin dynamics and ECM degradation in invadosomes. Finally, a new strategy based on fusion of the photosensitizer KillerRed to the beta1A cytoplasmic domain allowed specific and immediate loss of function of beta1A, resulting in disorganization and disassembly of invadosomes and formation of focal adhesions. PMID- 20926685 TI - The roles of two distinct regions of PINCH-1 in the regulation of cell attachment and spreading. AB - Cells attach to the extracellular matrix (ECM) through integrins to form focal adhesion complexes, and this process is followed by the extension of lamellipodia to enable cell spreading. PINCH-1, an adaptor protein essential for the regulation of cell-ECM adhesion, consists of five tandem LIM domains and a small C-terminal region. PINCH-1 is known to interact with integrin-linked kinase (ILK) and Ras suppressor protein 1 (Rsu-1); however, the precise mechanism by which this complex regulates cell-ECM adhesion is not fully understood. We report here that the LIM1 domain of PINCH-1, which associates with ILK to stabilize the expression of this protein, is sufficient for cell attachment but not for cell spreading. In contrast, the C-terminal region of PINCH-1, which binds to Rsu-1, plays a pivotal role in cell spreading but not in cell attachment. We also show that PINCH-1 associates with Rsu-1 to activate Rac1 and that Rac1 activation is necessary for cell spreading. Thus, these data reveal how specific domains of PINCH-1 direct two independent pathways: one utilizing ILK to allow cell attachment, and the other recruiting Rsu-1 to activate Rac1 in order to promote cell spreading. PMID- 20926686 TI - Hepatocyte growth factor inhibits apoptosis by the profibrotic factor angiotensin II via extracellular signal-regulated kinase 1/2 in endothelial cells and tissue explants. AB - Hepatocyte growth factor (HGF), an endogenous tissue repair factor, attenuates apoptosis in many primary cell types, but the mechanism is not completely understood. Our laboratory demonstrated that angiotensin (Ang) II activates the intrinsic apoptotic pathway in primary endothelial cells (ECs) via reduction of the antiapoptotic protein Bcl-x(L). Ang II decreased Bcl-x(L) mRNA half-life by reducing its binding to nucleolin, a protein that normally binds a 3' AU-rich region and stabilizes Bcl-x(L) mRNA. We hypothesized HGF may block apoptosis induced by Ang II. We used primary EC and ex vivo cultures of rat lung tissue to investigate HGF inhibition of Ang II-induced apoptosis. Our data indicated HGF abrogated Ang II-induced apoptosis by inhibiting cytochrome c release, caspase-3 activation, and DNA fragmentation. RNA-immunoprecipitation experiments demonstrated that HGF stabilized Bcl-x(L) mRNA by increasing nucleolin binding to the 3'-untranslated region that was associated with cytoplasmic localization of nucleolin. Cytoplasmic localization of nucleolin and Bcl-x(L) mRNA stabilization required HGF activation of extracellular signal-regulated kinase (ERK)1/2, but not phosphatidylinositol 3-kinase. HGF also blocked Ang II-induced caspase-3 activation and lactate dehydrogenase release in tissue explants in an ERK dependent manner. PMID- 20926687 TI - Inner/Outer nuclear membrane fusion in nuclear pore assembly: biochemical demonstration and molecular analysis. AB - Nuclear pore complexes (NPCs) are large proteinaceous channels embedded in double nuclear membranes, which carry out nucleocytoplasmic exchange. The mechanism of nuclear pore assembly involves a unique challenge, as it requires creation of a long-lived membrane-lined channel connecting the inner and outer nuclear membranes. This stabilized membrane channel has little evolutionary precedent. Here we mapped inner/outer nuclear membrane fusion in NPC assembly biochemically by using novel assembly intermediates and membrane fusion inhibitors. Incubation of a Xenopus in vitro nuclear assembly system at 14 degrees C revealed an early pore intermediate where nucleoporin subunits POM121 and the Nup107-160 complex were organized in a punctate pattern on the inner nuclear membrane. With time, this intermediate progressed to diffusion channel formation and finally to complete nuclear pore assembly. Correct channel formation was blocked by the hemifusion inhibitor lysophosphatidylcholine (LPC), but not if a complementary shaped lipid, oleic acid (OA), was simultaneously added, as determined with a novel fluorescent dextran-quenching assay. Importantly, recruitment of the bulk of FG nucleoporins, characteristic of mature nuclear pores, was not observed before diffusion channel formation and was prevented by LPC or OA, but not by LPC+OA. These results map the crucial inner/outer nuclear membrane fusion event of NPC assembly downstream of POM121/Nup107-160 complex interaction and upstream or at the time of FG nucleoporin recruitment. PMID- 20926688 TI - RRP1B targets PP1 to mammalian cell nucleoli and is associated with Pre-60S ribosomal subunits. AB - A pool of protein phosphatase 1 (PP1) accumulates within nucleoli and accounts for a large fraction of the serine/threonine protein phosphatase activity in this subnuclear structure. Using a combination of fluorescence imaging with quantitative proteomics, we mapped the subnuclear localization of the three mammalian PP1 isoforms stably expressed as GFP-fusions in live cells and identified RRP1B as a novel nucleolar targeting subunit that shows a specificity for PP1beta and PP1gamma. RRP1B, one of two mammalian orthologues of the yeast Rrp1p protein, shows an RNAse-dependent localization to the granular component of the nucleolus and distributes in a similar manner throughout the cell cycle to proteins involved in later steps of rRNA processing. Quantitative proteomic analysis of complexes containing both RRP1B and PP1gamma revealed enrichment of an overlapping subset of large (60S) ribosomal subunit proteins and pre-60S nonribosomal proteins involved in mid-late processing. Targeting of PP1 to this complex by RRP1B in mammalian cells is likely to contribute to modulation of ribosome biogenesis by mechanisms involving reversible phosphorylation events, thus playing a role in the rapid transduction of cellular signals that call for regulation of ribosome production in response to cellular stress and/or changes in growth conditions. PMID- 20926690 TI - Increased apoptosis in bovine blastocysts exposed to high levels of IGF1 is not associated with downregulation of the IGF1 receptor. AB - The hypothesis that high concentrations of IGF1 can impair embryo development was investigated in a bovine in vitro model to reflect conditions in polycystic ovary syndrome (PCOS) patients. Embryos were either cultured in the absence or presence of a physiological (100 ng/ml) or supraphysiological (1000 ng/ml) IGF1 concentration. Cell allocation, apoptosis, transcript and protein expression of selected genes involved in apoptosis, glucose metabolism and the IGF system were analysed. Supraphysiological IGF1 concentration did not improve blastocyst formation over controls, but induced higher levels of apoptosis, decreased TP53 protein expression in the trophectoderm and increased the number of cells in the inner cell mass (ICM). The increase in ICM cells corresponded with an increase in IGF1 receptor (IGF1R) protein in the ICM. A small, but significant, percentage of blastocysts displayed a hypertrophic ICM, not observed in controls and virtually absent in embryos treated with physiological concentrations of IGF1. Physiological IGF1 concentrations increased total IGF1R protein expression and upregulated IGFBP3 transcripts leading to an increase in blastocyst formation with no effects on cell number or apoptosis. In conclusion, the results support the hypothesis of detrimental effects of supraphysiological IGF1 concentrations on early pregnancy. However, our results do not support the premise that increased apoptosis associated with high levels of IGF1 is mediated via downregulation of the IGF1R as previously found in preimplantation mouse embryos. This in vitro system with the bovine preimplantation embryo reflects critical features of fertility in PCOS patients and could thus serve as a useful model for in-depth mechanistic studies. PMID- 20926689 TI - Differential modulation of keratin expression by sulforaphane occurs via Nrf2 dependent and -independent pathways in skin epithelia. AB - Treatment with the natural chemical sulforaphane (SF) ameliorates skin blistering in keratin 14 (K14)-deficient mice, correlating with the induction of K16 and K17 in the basal layer of epidermis (Kerns et al., PNAS 104:14460, 2007). Here we address the basis for the SF-mediated K16 and K17 induction in mouse epidermis in vivo. As expected, induction of K16 partly depends on the transcription factor Nrf2, which is activated by SF exposure. Strikingly, K17 induction occurs independently of Nrf2 activity and parallels the decrease in glutathione occurring shortly after epidermal exposure to SF. Pharmacological manipulation of glutathione levels in mouse epidermis in vivo alters K17 and K16 expression in the expected manner. We present findings suggesting that select MAP kinases participate in mediating the Nrf2- and glutathione-dependent alterations in K16 and K17 levels in SF-treated epidermis. These findings advance our understanding of the effect of SF on gene expression in epidermis, point to a role for glutathione in mediating some of these effects, and establish that SF induces the expression of two contiguous and highly related genes, K16 and K17, via distinct mechanisms. PMID- 20926691 TI - Pregnancy and interferon tau regulate DDX58 and PLSCR1 in the ovine uterus during the peri-implantation period. AB - Interferon tau (IFNT), the pregnancy recognition signal in ruminants, abrogates the luteolytic mechanism for maintenance of the corpus luteum for production of progesterone (P(4)). This study examined the expression of DEAD (Asp-Glu-Ala-Asp) box polypeptide 58 (DDX58) and phospholipid scramblase 1 (PLSCR1) mRNAs in the ovine uterus as these genes were increased most in 2fTGH (STAT1 positive) cells by IFNT. The results of this study indicated that IFNT regulates expression of DDX58 and PLSCR1 mRNAs in the ovine uterus, which confirmed the results of the in vitro transcriptional profiling experiment with the 2fTGH (parental STAT1 positive) and U3A (STAT1 null) cell lines. Steady-state levels of DDX58 and PLSCR1 mRNAs increased in cells of the ovine uterus between days 12 and 20 of pregnancy, but not between days 10 and 16 of the estrous cycle. The expression of DDX58 and PLSCR1 mRNAs was greatest in endometrial stromal cells, but there was transient expression in uterine luminal and superficial glandular epithelial cells. P(4) alone did not induce expression of DDX58 and PLSCR1 mRNAs; however, intrauterine injections of IFNT did induce expression of DDX58 and PLSCR1 mRNAs in the endometria of nonpregnant ewes independent of effects of P(4). These results indicate that IFNT induces expression of DDX58 and PLSCR1 in ovine endometrial cells via the classical STAT1-mediated cell signaling pathway. Based on their known biological effects, DDX58 and PLSCR1 are IFN-stimulated genes, which may increase the antiviral status of cells of the pregnant uterus to protect against viral infection and/or enhance secretion of type I IFNs that inhibit viral replication. PMID- 20926692 TI - A small set of extra-embryonic genes defines a new landmark for bovine embryo staging. AB - Axis specification in mouse is determined by a sequence of reciprocal interactions between embryonic and extra-embryonic tissues so that a few extra embryonic genes appear as 'patterning' the embryo. Considering these interactions as essential, but lacking in most mammals the genetically driven approaches used in mouse and the corresponding patterning mutants, we examined whether a molecular signature originating from extra-embryonic tissues could relate to the developmental stage of the embryo proper and predict it. To this end, we have profiled bovine extra-embryonic tissues at peri-implantation stages, when gastrulation and early neurulation occur, and analysed the subsequent expression profiles through the use of predictive methods as previously reported for tumour classification. A set of six genes (CALM1, CPA3, CITED1, DLD, HNRNPDL, and TGFB3), half of which had not been previously associated with any extra-embryonic feature, appeared significantly discriminative and mainly dependent on embryonic tissues for its faithful expression. The predictive value of this set of genes for gastrulation and early neurulation stages, as assessed on naive samples, was remarkably high (93%). In silico connected to the bovine orthologues of the mouse patterning genes, this gene set is proposed as a new trait for embryo staging. As such, this will allow saving the bovine embryo proper for molecular or cellular studies. To us, it offers as well new perspectives for developmental phenotyping and modelling of embryonic/extra-embryonic co-differentiation. PMID- 20926693 TI - Contributions of conventional and heavy-chain IgG to immunity in fetal, neonatal, and adult alpacas. AB - In addition to conventional immunoglobulins, camelids produce antibodies that do not incorporate light chains into their structures. These so-called heavy-chain (HC) antibodies have incited great interest in the biomedical community, as they have considerable potential for biotechnological and therapeutic application. Recently, we have begun to elucidate the immunological functions of HC antibodies, yet little is known about their significance in maternal immunity or about the B lymphocytes that produce them. This study describes the application of isotype-specific reagents toward physiological assessments of camelid IgGs and the B cells that produce them. We document the specificities of monoclonal antibodies that distinguish two conventional IgG1 isotypes and two HC IgG3 variants produced by alpacas. Next, we report that the relative concentrations of five isotypes are similar in serum, milk, and colostrum; however, following passive transfer, the concentrations of HC IgG2 and IgG3 declined more rapidly than the concentration of conventional IgG1 in the sera of neonates. Finally, we assessed the distribution of B cells of distinct isotypes within lymphoid tissues during fetal and adult life. We detected IgG1, IgG2, and IgG3 in lymphocytes located in lymph node follicles, suggesting that HC B cells affinity mature and/or class switch. One IgG3 isotype was present in B cells located in ileal Peyer's patches, and one conventional IgG1 isotype was detected in splenic marginal zone B cells. Our findings contribute to the growing body of knowledge pertaining to HC antibodies and are compatible with functional specialization among conventional and HC IgGs in the alpaca. PMID- 20926695 TI - Detection of humoral response using a recombinant heat shock protein 70, DnaK, of Mycoplasma haemofelis in experimentally and naturally hemoplasma-infected cats. AB - Hemoplasmas is the trivial name given to a group of erythrocyte-parasitizing bacteria of the genus Mycoplasma. Of the feline hemoplasmas, Mycoplasma haemofelis is the most pathogenic, while "Candidatus Mycoplasma haemominutum" and "Candidatus Mycoplasma turicensis" are less pathogenic. Shotgun libraries of fragmented M. haemofelis genomic DNA were constructed, and random colonies were selected for DNA sequencing. In silico-translated amino acid sequences of putative open reading frames were compared to mass spectrometry data from M. haemofelis protein spots identified as being immunogenic by two-dimensional gel electrophoresis and Western blotting. Three of the spots matched the predicted sequences of a heat shock protein 70 (DnaK) homolog, elongation factor Ts, and a fragment of phosphoglycerate kinase found during library screening. A full-length copy of the M. haemofelis dnaK gene was cloned into Escherichia coli and recombinantly expressed. Recombinant M. haemofelis DnaK was purified and then used in Western blotting and an enzyme-linked immunosorbent assay (ELISA) to investigate the humoral immune response during acute infection in cats experimentally infected with M. haemofelis, "Ca. Mycoplasma haemominutum," or "Ca. Mycoplasma turicensis". The recombinant M. haemofelis DnaK ELISA also was used to screen clinical samples submitted for hemoplasma PCR testing to a commercial laboratory (n = 254). Experimentally infected cats became seropositive following infection, with a greater and earlier antibody response seen in cats inoculated with M. haemofelis than those seen in cats inoculated with "Ca. Mycoplasma haemominutum" or "Ca. Mycoplasma turicensis," by both Western blotting and ELISA. Of the clinical samples, 31.1% had antibodies detected by the ELISA but only 9.8% were positive by PCR for one or more hemoplasmas. PMID- 20926694 TI - Porcine reproductive and respiratory syndrome virus infection at the time of porcine circovirus type 2 vaccination has no impact on vaccine efficacy. AB - Several porcine circovirus type 2 (PCV2) vaccines are now commercially available and have been shown to be effective at decreasing the occurrence of porcine circovirus-associated disease (PCVAD). Many herds are coinfected with PCV2 and porcine reproductive and respiratory syndrome virus (PRRSV). Some producers and veterinarians are concerned that if pigs are vaccinated for PCV2 at or near the time that they are typically infected with PRRSV, the efficacy of the PCV2 vaccine will be compromised. The impact of PRRSV on PCV2 vaccination is unclear and has not been investigated under controlled conditions. The objective of the present study was to determine whether the presence of PRRSV viremia has an effect on the efficacy of commercial PCV2 vaccinations. Three-week-old PCV2 negative conventional pigs with passively derived anti-PCV2 antibodies were either vaccinated with one of three commercial PCV2 vaccines or left nonvaccinated. A portion of the pigs were infected with PRRSV 1 week prior to PCV2 vaccination. To determine vaccine efficacy, a PCV2 challenge was conducted at 8 weeks of age. PCV2 vaccination, regardless of PRRSV infection status at the time of vaccination, was similarly effective in inducing an anti-PCV2 IgG response in the presence of maternally derived immunity and in protecting the pigs from PCV2 challenge, as determined by a reduction in the level of PCV2 viremia and a reduction in the prevalence and amount of PCV2 antigen in lymphoid tissues in vaccinated pigs compared to nonvaccinated pigs. The results indicate that acute PRRSV infection at the time of PCV2 vaccination has no adverse effect on PCV2 vaccine efficacy. PMID- 20926696 TI - Immunization with truncated recombinant protein SpaC of Erysipelothrix rhusiopathiae strain 715 serovar 18 confers protective immunity against challenge with various serovars. AB - Previously, we showed that surface protective antigen (Spa) proteins of Erysipelothrix rhusiopathiae can be classified into three molecular species-SpaA, SpaB, and SpaC-and that SpaC is the most broadly cross-protective antigen among the three Spa proteins. In this study, we examined the ability of the alpha helical domain, which comprises the N-terminal half of SpaC, to elicit cross protective immunity in mice and pigs. Mice actively immunized with the full length protein (rSpaC664) or the alpha-helical domain (rSpaC427), but not the C terminal domain (rSpaC253), were protected against challenge with E. rhusiopathiae serovars 1a, 2, 6, 19, and 18 expressing heterologous (SpaA or SpaB) and homologous (SpaC) Spas. The alpha-helical domain seemed to provide better protection than rSpaC664, although the differences did not reach statistical significance. Similarly, mice passively immunized with rabbit anti rSpaC664 or anti-rSpaC427 sera, but not anti-rSpaC253 serum, were protected from challenge with various serovars. Pigs immunized with SpaC427 also developed specific antibodies against Spa proteins and were protected from challenge with the highly virulent heterologous E. rhusiopathiae strain Fujisawa (serovar 1a). Taken together, these results demonstrate for the first time the striking protective efficacy of the alpha-helical domain-mediated immunization in both mice and pigs, thereby highlighting its utility as the most promising candidate for the development of a safe and effective vaccine against erysipelas. PMID- 20926697 TI - Simultaneous measurement of antigen-stimulated interleukin-1 beta and gamma interferon production enhances test sensitivity for the detection of Mycobacterium bovis infection in cattle. AB - In order to identify cytokines that may be useful as candidates for inclusion in diagnostic tests for Mycobacterium bovis infection in cattle, we compared the levels of gamma interferon (IFN-gamma), interleukin 1beta (IL-1beta), IL-4, IL 10, IL-12, macrophage inflammatory protein 1beta (MIP-1beta), and tumor necrosis factor alpha (TNF-alpha) in whole-blood cultures from tuberculosis (TB) reactor animals or TB-free controls following stimulation with M. bovis-specific antigens (purified protein derivative from M. bovis [PPD-B] or ESAT-6/CFP-10). In addition to IFN-gamma responses, the production of IL-1beta and TNF-alpha was also statistically significantly elevated in TB reactor cattle over that in uninfected controls following stimulation with PPD-B or ESAT-6/CFP-10 peptides. Thus, we evaluated whether the use of these two additional readouts could disclose further animals not detected by measuring IFN-gamma alone. To this end, receiver operating characteristic (ROC) analyses were performed to define diagnostic cutoffs for positivity for TNF-alpha and IL-1beta. These results revealed that for ESAT-6/CFP-10-induced responses, the use of all three readouts (IFN-gamma, TNF-alpha, and IL-1beta) in parallel increased the sensitivity of detection of M. bovis-infected animals by 11% but also resulted in a specificity decrease of 14%. However, applying only IFN-gamma and IL-1beta in parallel resulted in a 5% increase in sensitivity without the corresponding loss of specificity. The results for PPD-B-induced responses were similar, although the loss of specificity was more pronounced, even when only IFN-gamma and IL-1beta were used as readout systems. In conclusion, we have demonstrated that the use of an additional readout system, such as IL-1beta, can potentially complement IFN-gamma by increasing overall test sensitivity for the detection of M. bovis infection in cattle. PMID- 20926698 TI - Seroprevalence of pertussis among Danish patients with cough of unknown etiology. AB - The common perception that pertussis is only a childhood disease is not correct. Vaccination or infection with Bordetella pertussis provides only short-lived protection against pertussis-and the majority of the population is consequently at risk of contracting pertussis. We evaluated the seroprevalence of pertussis antibodies (IgG against pertussis toxin) in serum samples from 265 Danish patients, aged 8 years and older, with coughs of unknown etiology. Depending on the cutoff chosen, we found that 2.6% to 10.9% of these patients were seropositive for pertussis. Of 178 patients with a reported duration of cough between 2 weeks and 3 months, 3.4% to 12.4% were seropositive for pertussis, indicating recent infection. Our study indicates that B. pertussis infection may be underdiagnosed among older children and adults with coughs in Denmark. PMID- 20926699 TI - Molecular cloning of an immunogenic protein of Baylisascaris procyonis and expression in Escherichia coli for use in developing improved serodiagnostic assays. AB - Larva migrans caused by Baylisascaris procyonis is an important zoonotic disease. Current serological diagnostic assays for this disease depend on the use of the parasite's larval excretory-secretory (ES) antigens. In order to identify genes encoding ES antigens and to generate recombinant antigens for use in diagnostic assays, construction and immunoscreening of a B. procyonis third-stage larva cDNA expression library was performed and resulted in identification of a partial length cDNA clone encoding an ES antigen, designated repeat antigen 1 (RAG1). The full-length rag1 cDNA contained a 753-bp open reading frame that encoded a protein of 250 amino acids with 12 tandem repeats of a 12-amino-acid long sequence. The rag1 genomic DNA revealed a single intron of 837 bp that separated the 753-bp coding sequence into two exons delimited by canonical splice sites. No nucleotide or amino acid sequences present in the GenBank databases had significant similarity with those of RAG1. We have cloned, expressed, and purified the recombinant RAG1 (rRAG1) and analyzed its diagnostic potential by enzyme-linked immunosorbent assay. Anti-Baylisascaris species-specific rabbit serum showed strong reactivity to rRAG1, while only minimal to no reactivity was observed with sera against the related ascarids Toxocara canis and Ascaris suum, strongly suggesting the specificity of rRAG1. On the basis of these results, the identified RAG1 appears to be a promising diagnostic antigen for the development of serological assays for specific detection of B. procyonis larva migrans. PMID- 20926700 TI - Development, characterization, and application of monoclonal antibodies against severe acute respiratory syndrome coronavirus nucleocapsid protein. AB - Five monoclonal antibodies (MAbs) against recombinant nucleocapsid protein (NP) of severe acute respiratory syndrome (SARS)-causing coronavirus (CoV) were developed by hybridoma technology. Epitope mapping by Western blotting showed that these anti-SARS-CoV NP MAbs bind to distinct domains of NP. These anti-SARS CoV NP MAbs, with their high specificity, are potentially ideal candidates for developing early and sensitive diagnostic assays for SARS-CoV. PMID- 20926701 TI - Development and characterization of protective Haemophilus parasuis subunit vaccines based on native proteins with affinity to porcine transferrin and comparison with other subunit and commercial vaccines. AB - Haemophilus parasuis is the agent responsible for causing Glasser's disease, which is characterized by fibrinous polyserositis, polyarthritis, and meningitis in pigs. In this study, we have characterized native outer membrane proteins with affinity to porcine transferrin (NPAPT) from H. parasuis serovar 5, Nagasaki strain. This pool of proteins was used as antigen to developed two vaccine formulations: one was adjuvanted with a mineral oil (Montanide IMS 2215 VG PR), while the other was potentiated with a bacterial neuraminidase from Clostridium perfringens. The potential protective effect conferred by these two vaccines was compared to that afforded by two other vaccines, consisting of recombinant transferrin-binding protein (rTbp) A or B fragments from H. parasuis, Nagasaki strain, and by a commercially available inactivated vaccine. Five groups of colostrum-deprived piglets immunized with the vaccines described above, one group per each vaccine, and a group of nonvaccinated control animals were challenged intratracheally with a lethal dose (3 * 108 CFU) of H. parasuis, Nagasaki strain. The two vaccines containing rTbps yielded similar results with minimal protection against death, clinical signs, gross and microscopic lesions, and H. parasuis invasion. In contrast, the two vaccines composed of NPAPT antigen and commercial bacterin resulted in a strong protection against challenge (without deaths and clinical signs), mild histopathological changes, and no recovery of H. parasuis, thus suggesting their effectiveness in preventing Glasser's disease outbreaks caused by serovar 5. PMID- 20926702 TI - Serum intercellular adhesion molecule 1 variations in young children with acute otitis media. AB - Acute otitis media (AOM) is an inflammatory reaction in the middle ear, most often occurring in young children. Streptococcus pneumoniae, nontypeable Haemophilus influenzae, and Moraxella catarrhalis are the most common bacteria isolated. Intercellular adhesion molecule 1 (ICAM-1) is involved in the innate immune response to infection by microorganisms, in effective antigen presentation, and in subsequent T-cell activation. Here we prospectively studied levels of serum soluble ICAM-1 (sICAM-1) before, at the time of, and after antimicrobial treatment of AOM in a group of 138 children ages 6 to 30 months. Middle ear fluids were collected by tympanocentesis to identify otopathogens. We found that (i) serum levels of sICAM-1 were significantly higher in S. pneumoniae , nontypeable H. influenzae-, and M. catarrhalis-infected children than in well children (P < 0.001), confirming that a systemic inflammatory response occurs during AOM; (ii) sICAM-1 levels varied from no elevation (110 ng/ml) to elevation to high levels (maximum, 1,470 ng/ml) among children with AOM; (iii) in paired samples, sICAM-1 levels increased 4- to 20-fold when children developed AOM compared to their sICAM-1 levels before infection; and (iv) the level of sICAM-1 returned to the pre-AOM level at the convalescent stage of AOM after successful antimicrobial therapy. We conclude that AOM often causes a systemic inflammatory reaction, as measured by elevation of the serum sICAM-1 level, and that a high variability in sICAM-1 responses occurs with the presence of otopathogens during AOM. PMID- 20926703 TI - Sensitive assay for quantification of hepatitis B virus mutants by use of a minor groove binder probe and peptide nucleic acids. AB - Lamivudine is the first nucleoside analogue that was shown to have a potent effect on hepatitis B virus (HBV). However, the emergence of mutants resistant or cross-resistant to nucleoside/nucleotide analogues remains a serious problem. Several assays for the detection and quantification of antiviral-resistant mutants have been reported, but it has been difficult to measure the amounts of mutants accurately, especially when the target strain is a minor component of the mixed population. It has been shown that accurate measurement of a minor strain is difficult as long as a matching reaction with a single probe is included in the assay. We developed a new method for the quantification of lamivudine resistant strains in a mixed-virus population by real-time PCR using minor groove binder probes and peptide nucleic acids, and we achieved a wide and measurable range, from 3 to 10 log10 copies/ml, and high sensitivity, with a discriminative limit of 0.01% of the predominant strain. The clinical significance of measuring substitutions not only of M204 but also of L180 residues of HBV polymerase was demonstrated by this method. This assay increases the versatility of a sensitive method for the quantification of a single-nucleotide mutation in a heterogeneous population. PMID- 20926705 TI - Detection of a novel astrovirus in brain tissue of mink suffering from shaking mink syndrome by use of viral metagenomics. AB - In 2000, farmed mink kits in Denmark were affected by a neurological disorder. The characteristic clinical signs included shaking, staggering gait, and ataxia. The disease, given the name shaking mink syndrome, was reproduced by the inoculation of brain homogenate from affected mink kits into healthy ones. However, the etiology remained unknown despite intensive efforts. In this study, random amplification and large-scale sequencing were used, and an astrovirus was detected in the brain tissue of three experimentally infected mink kits. This virus also was found in the brain of three mink kits naturally displaying the disease but not in the six healthy animals investigated. The complete coding region of the detected astrovirus was sequenced and compared to those of both a mink astrovirus associated with preweaning diarrhea and to a recently discovered human astrovirus associated with a case of encephalitis in a boy with x-linked agammaglobulinemia. The identities were 80.4 and 52.3%, respectively, showing that the virus described in this study was more similar to the preweaning diarrhea mink astrovirus. For the nonstructural coding regions the sequence identity was around 90% compared to that of the astrovirus, which is associated with preweaning diarrhea in mink. The region coding for the structural protein was more diverse, showing only 67% sequence identity. This finding is of interest not only because the detected virus may be the etiological agent of the shaking mink syndrome but also because this is one of the first descriptions of an astrovirus found in the central nervous system of animals. PMID- 20926704 TI - Diagnosis of pulmonary tuberculosis in HIV-positive patients by microscopic observation drug susceptibility assay. AB - The microscopic observation drug susceptibility assay (MODS) is a novel and promising test for the early diagnosis of tuberculosis (TB). We evaluated the MODS assay for the early diagnosis of TB in HIV-positive patients presenting to Pham Ngoc Thach Hospital for Tuberculosis and Lung Diseases in southern Vietnam. A total of 738 consecutive sputum samples collected from 307 HIV-positive individuals suspected of TB were tested by smear, MODS, and the mycobacteria growth indicator tube method (MGIT). The diagnostic sensitivity and specificity of MODS compared to the microbiological gold standard (either smear or MGIT) were 87 and 93%, respectively. The sensitivities of smear, MODS, and MGIT were 57, 71, and 75%, respectively, against clinical gold standard (MODS versus smear, P<0.001; MODS versus MGIT, P=0.03). The clinical gold standard was defined as patients who had a clinical examination and treatment consistent with TB, with or without microbiological confirmation. For the diagnosis of smear-negative patients, the sensitivities of MODS and MGIT were 38 and 45%, respectively (P=0.08). The median times to detection using MODS and MGIT were 8 and 11 days, respectively, and they were 11 and 17 days, respectively, for smear-negative samples. The original bacterial/fungal contamination rate of MODS was 1.1%, while it was 2.6% for MGIT. The cross-contamination rate of MODS was 4.7%. In conclusion, MODS is a sensitive, specific, and rapid test that is appropriate for the detection of HIV-associated TB; its cost and ease of use make it particularly useful in resource-limited settings. PMID- 20926706 TI - Susceptibility profiles, molecular epidemiology, and detection of KPC-producing Escherichia coli isolates from the New York City vicinity. AB - The detection of Enterobacteriaceae carrying the carbapenemase KPC has been problematic. Thirty isolates of KPC-possessing Escherichia coli were gathered from hospitals in New York City and Connecticut. The imipenem, meropenem, doripenem, and ertapenem MIC50 values were 4, 2, 1, and 4 MUg/ml, respectively. Over half of the isolates belonged to a single ribotype. Using an ertapenem breakpoint of 0.25 MUg/ml would efficiently detect these isolates. PMID- 20926707 TI - Improved detection of Bartonella DNA in mammalian hosts and arthropod vectors by real-time PCR using the NADH dehydrogenase gamma subunit (nuoG). AB - We used a whole-genome scanning technique to identify the NADH dehydrogenase gamma subunit (nuoG) primer set that is sensitive and specific enough to detect a diverse number of Bartonella species in a wide range of environmental samples yet maintains minimal cross-reactivity to mammalian host and arthropod vector organisms. PMID- 20926708 TI - Isolation of a novel Orientia species (O. chuto sp. nov.) from a patient infected in Dubai. AB - In July 2006, an Australian tourist returning from Dubai, in the United Arab Emirates (UAE), developed acute scrub typhus. Her signs and symptoms included fever, myalgia, headache, rash, and eschar. Orientia tsutsugamushi serology demonstrated a 4-fold rise in antibody titers in paired serum collections (1:512 to 1:8,192), with the sera reacting strongest against the Gilliam strain antigen. An Orientia species was isolated by the in vitro culture of the patient's acute blood taken prior to antibiotic treatment. The gene sequencing of the 16S rRNA gene (rrs), partial 56-kDa gene, and the full open reading frame 47-kDa gene was performed, and comparisons of this new Orientia sp. isolate to previously characterized strains demonstrated significant sequence diversity. The closest homology to the rrs sequence of the new Orientia sp. isolate was with three strains of O. tsutsugamushi (Ikeda, Kato, and Karp), with a nucleotide sequence similarity of 98.5%. The closest homology to the 47-kDa gene sequence was with O. tsutsugamushi strain Gilliam, with a nucleotide similarity of 82.3%, while the closest homology to the 56-kDa gene sequence was with O. tsutsugamushi strain TA686, with a nucleotide similarity of 53.1%. The molecular divergence and geographically unique origin lead us to believe that this organism should be considered a novel species. Therefore, we have proposed the name "Orientia chuto," and the prototype strain of this species is strain Dubai, named after the location in which the patient was infected. PMID- 20926709 TI - Histoplasma capsulatum prosthetic valve endocarditis with negative fungal blood cultures and negative histoplasma antigen assay in an immunocompetent patient. AB - We report a case of Histoplasma capsulatum endocarditis in which Histoplasma antigen assay and fungal blood cultures were negative. The diagnosis was made by microscopic examination and culture of the excised valve. Histoplasma capsulatum should be considered in the differential diagnosis of culture-negative endocarditis in regions where it is endemic and in travelers. PMID- 20926710 TI - Molecular phylogeny and proposal of two new species of the emerging pathogenic fungus Saksenaea. AB - Saksenaea is a monotypic genus belonging to the order Mucorales and capable of producing severe human infections. Through a polyphasic study based on analysis of the sequences of the internal transcribed spacer (ITS) region, domains D1 and D2 of the 28S rRNA gene, and the elongation factor 1alpha (EF-1alpha) gene, as well as by evaluation of relevant morphological and physiological characteristics of a set of clinical and environmental strains, we have demonstrated that Saksenaea vasiformis is a complex of species. We propose as new species Saksenaea oblongispora, characterized by oblong sporangiospores and unable to grow at 42 degrees C, and Saksenaea erythrospora, characterized by large sporangiophores and sporangia and by ellipsoid sporangiospores, biconcave in the lateral view. Itraconazole, posaconazole, and terbinafine were active against all isolates included in the study, while amphotericin B, voriconazole, and the echinocandins showed low activity. PMID- 20926711 TI - Feasibility study of a human papillomavirus E6 oncoprotein test for diagnosis of cervical precancer and cancer. AB - In a feasibility study using a prototype, lateral-flow test for human papillomavirus type 16, 18, and/or 45 (HPV16/18/45) E6 oncoproteins, 51 of 75 (68%; 95% confidence interval [95% CI] of 56 to 78%) of HPV16/18/45 DNA-positive specimens from women with a diagnosis of CIN3+ (cervical intraepithelial neoplasia grade 3+ or cervical cancer) tested positive for HPV16/18/45 E6 oncoprotein. None of 16 (95% CI of 0 to 37%) HPV16/18/45 DNA-positive cervical specimens from women with a negative or CIN1 diagnosis tested positive for HPV16/18/45 E6 oncoprotein. PMID- 20926712 TI - Evaluation of time to detection of Mycobacterium tuberculosis in broth culture as a determinant for end points in treatment trials. AB - Time to detection of Mycobacterium tuberculosis in broth culture was examined for utility as a treatment efficacy end point. Of 146 patients in a phase IIB trial, a decreased mean time to detection was found in 5 with treatment failure. Time to detection in an analysis-of-covariance model was associated with lung cavities, less intensive treatment, and differences in the bactericidal effects of treatment regimens. PMID- 20926713 TI - Incidence of and risk factors for community-associated methicillin-resistant Staphylococcus aureus acquired infection or colonization in intensive-care-unit patients. AB - The incidence of and risk factors for acquiring community-associated methicillin resistant Staphylococcus aureus (CA-MRSA) among patients staying in intensive care units (ICUs) remain unclear. We enrolled patients staying in two ICUs at the Far Eastern Memorial Hospital during the period of 1 September 2008 to 30 September 2009 to clarify this issue. Surveillance cultures for MRSA were taken from nostril, sputum or throat, axillae, and the inguinal area in all enrolled patients upon admission to the ICU, every 3 days thereafter, and on the day of discharge from the ICU. For each MRSA isolate, we performed multilocus sequence typing, identified the type of staphylococcal cassette chromosome mec, detected the presence of the Panton-Valentine leukocidin gene, and conducted drug susceptibility tests. Among the 1,906 patients who were screened, 203 patients were carriers of MRSA before their admission to the ICU; 81 patients acquired MRSA during their stay in the ICU, including 31 who acquired CA-MRSA. The incidence rates of newly acquired MRSA and CA-MRSA during the ICU stay were 7.9 and 3.0 per 1,000 patient-days, respectively. Prior usage of antipseudomonal penicillins and antifungals and the presence of a nasogastric tube were found to be independent risk factors for acquiring CA-MRSA during the ICU stay when data for CA-MRSA carriers and patients without carriage of MRSA were compared (P=0.0035, 0.0330, and 0.0262, respectively). Prior usage of carbapenems was found to be a protective factor against acquiring CA-MRSA when data for patients with CA-MRSA and those with health care-associated MRSA acquired during ICU stay were compared (P=0.0240). PMID- 20926714 TI - Normalized resistance interpretation as a tool for establishing epidemiological MIC susceptibility breakpoints. AB - Normalized resistance interpretation (NRI) utilizes the fact that the wild-type population on the sensitive side is not affected by resistance development, and therefore a normalized reconstruction of the peak can be performed. The method was modified for MIC distributions by the introduction of helper variables, in between values assigned the mean of the neighboring numbers of isolates. This method was used on Staphylo- coccus aureus and Escherichia coli MIC distributions for 27 antimicrobials each and obtained from the EUCAST (European Committee on Antimicrobial Susceptibility Testing) website (http://www.eucast.org/mic_distributions/). The number of isolates in each of the 54 distributions ranged from 40 to 124,472. NRI produced normalized distributions in all cases. Cutoff values were calculated for +2.0 and +2.5 standard deviations (SD) above the means and then rounded up to nearest regular MIC dilution step. EUCAST also show cutoff values, ECOFF values, which were used as the reference. The NRI generated +2.0 SD values showed the best agreement with 26 of 27 within +/-1 dilution step and 17 exactly on the ECOFF values for Staphylococcus aureus, and 25 of 27 within +/-1 dilution step and 14 right on the ECOFF values for Escherichia coli. NRI offers an objective method for the reconstruction of the wild-type population in an MIC distribution for a given bacterial species and an antimicrobial agent. This method offers a new tool in comparative susceptibility studies such as global surveillance of resistance, as well as in quality control in individual laboratories. PMID- 20926716 TI - Report from the 2009 AOA North American Traveling Fellowship. PMID- 20926717 TI - Does a trauma course improve resident performance on the trauma domain of the OITE? AB - BACKGROUND: Lecture-based courses are common in orthopaedic surgery; however, their effectiveness in improving medical knowledge has not been widely assessed. The Orthopaedic Trauma Association conducts a resident trauma course that occurs four to six weeks prior to the Orthopaedic In-Training Examination (OITE). The purposes of this study were to determine whether residents who had taken this course performed better on the trauma domain of the OITE and to compare the effect of the course with the effect of a focused rotation in orthopaedic trauma. METHODS: The percentile scores on the trauma domain of the OITE for forty-seven residents in postgraduate year (PGY) 2 were reviewed. Twenty-nine residents who took a trauma course within six weeks before the OITE were compared with eighteen residents who took the course after the OITE. As a secondary analysis, the effect of a trauma rotation for the same PGY-2 residents before and after the OITE was also assessed. Baseline orthopaedic knowledge was assessed with use of the overall OITE percentage scores. RESULTS: The trauma domain scores were not significantly better among the residents who took the course (mean and standard deviation, 62.2 +/- 9.9) compared with those who had not taken it (mean, 59.2 +/- 6.2) (p = 0.2). A significant difference (p = 0.04) was found for a trauma rotation, with the residents who had a trauma rotation scoring better (mean, 64.5 +/- 6.8) than the residents who had not (mean, 58.8 +/- 8.9). The subgroup of residents who had both a course and a trauma rotation before the test scored significantly better (p = 0.01) than the subgroup that had neither of these experiences before the test (mean, 65.6 +/- 8.0 and 56.9 +/- 6.4, respectively). CONCLUSIONS: An orthopaedic trauma course alone does not enhance an orthopaedic resident's trauma medical knowledge as assessed on a standardized test. However, a trauma rotation before, and in particular the combination of both a course and a trauma rotation, can improve trauma test scores. PMID- 20926718 TI - Commentary on an article by Captain Brian R. Waterman, MD, et al.: "the epidemiology of ankle sprains in the United States". PMID- 20926719 TI - Commentary on an article by Stavros Thomopoulos, PhD, et al.: "the effects of exogenous basic fibroblast growth factor on intrasynovial flexor tendon healing in a canine model". PMID- 20926720 TI - Development of fatty atrophy after neurologic and rotator cuff injuries in an animal model of rotator cuff pathology. AB - BACKGROUND: Detachment of a tendon from its osseous insertion, as can be the case with severe rotator cuff injuries, leads to atrophy of and increased fat in the corresponding muscle. We sought to validate a rotator cuff injury model in the rabbit and to test the hypothesis that tenotomy of a rotator cuff tendon would consistently create muscle atrophy and fatty degeneration analogous to the changes that occur after injury to a nerve innervating the same muscle. METHODS: New Zealand white rabbits were divided into three groups: (1) partial rotator cuff tear without retraction of the muscle, (2) complete rotator cuff tear with retraction of the muscle, and (3) nerve transection of the subscapular nerve. Animals were killed at two or six weeks after injury, and the muscles were analyzed for weight, cross-sectional area, myosin fiber-type composition, and fat content. In addition, the subscapular nerve was harvested at two weeks and evaluated for neuronal injury. RESULTS: At six weeks after injury, the rabbit muscles in the complete tenotomy and nerve transection groups had significant decreases in wet mass and increases in fat content relative to the control groups. Fat accumulation had a similar spatial pattern at six weeks in both the nerve transection and complete tenotomy groups. Such changes were not seen in the partial tenotomy group. No change was found in muscle myosin fiber-type composition. At two weeks after injury, subscapular nerves in the complete tenotomy group showed gross evidence of neuronal injury. CONCLUSIONS: This study establishes the rabbit subscapularis muscle as a valid model to study the muscular changes associated with rotator cuff tears. Our data suggest that the muscular changes associated with complete tenotomy are comparable with those seen with denervation of the muscle and suggest that chronic rotator cuff tears may induce a neurologic injury. PMID- 20926721 TI - The epidemiology of ankle sprains in the United States. AB - BACKGROUND: Ankle sprain has been studied in athletic cohorts, but little is known of its epidemiology in the general population. A longitudinal, prospective epidemiological database was used to determine the incidence and demographic risk factors for ankle sprains presenting to emergency departments in the United States. It was our hypothesis that ankle sprain is influenced by sex, race, age, and involvement in athletics. METHODS: The National Electronic Injury Surveillance System (NEISS) was queried for all ankle sprain injuries presenting to emergency departments between 2002 and 2006. Incidence rate ratios were then calculated with respect to age, sex, and race. RESULTS: During the study period, an estimated 3,140,132 ankle sprains occurred among an at-risk population of 1,461,379,599 person-years for an incidence rate of 2.15 per 1000 person-years in the United States. The peak incidence of ankle sprain occurred between fifteen and nineteen years of age (7.2 per 1000 person-years). Males, compared with females, did not demonstrate an overall increased incidence rate ratio for ankle sprain (incidence rate ratio, 1.04; 95% confidence interval, 1.00 to 1.09). However, males between fifteen and twenty-four years old had a substantially higher incidence of ankle sprain than their female counterparts (incidence rate ratio, 1.53; 95% confidence interval, 1.41 to 1.66), whereas females over thirty years old had a higher incidence compared with their male counterparts (incidence rate ratio, 2.03; 95% confidence interval, 1.65 to 2.65). Compared with the Hispanic race, the black and white races were associated with substantially higher rates of ankle sprain (incidence rate ratio, 3.55 [95% confidence interval, 1.01 to 6.09] and 2.49 [95% confidence interval, 1.01 to 3.97], respectively). Nearly half of all ankle sprains (49.3%) occurred during athletic activity, with basketball (41.1%), football (9.3%), and soccer (7.9%) being associated with the highest percentage of ankle sprains during athletics. CONCLUSIONS: An age of ten to nineteen years old is associated with higher rates of ankle sprain. Males between fifteen and twenty-four years old have higher rates of ankle sprain than their female counterparts, whereas females over thirty years old have higher rates than their male counterparts. Half of all ankle sprains occur during athletic activity. PMID- 20926722 TI - The effects of exogenous basic fibroblast growth factor on intrasynovial flexor tendon healing in a canine model. AB - BACKGROUND: Studies have demonstrated that flexor tendon repair strength fails to increase in the first three weeks following suturing of the tendon, a finding that correlates closely with the timing of many clinical failures. The application of growth factors holds promise for improving the tendon-repair response and obviating failure in the initial three weeks. METHODS: The effects of basic fibroblast growth factor on flexor tendon healing were evaluated with use of a canine model. Operative repair followed by the sustained delivery of basic fibroblast growth factor, at two different doses, was compared with operative repair alone. Histological, biochemical, and biomechanical methods were used to evaluate the tendons twenty-one days after repair. RESULTS: Vascularity, cellularity, and adhesion formation were increased in the tendons that received basic fibroblast growth factor as compared with the tendons that received operative repair alone. DNA concentration was increased in the tendons that received 1000 ng of basic fibroblast growth factor (mean and standard deviation, 5.7 +/- 0.7 MUg/mg) as compared with the tendons that received 500 ng of basic fibroblast growth factor (3.8 +/- 0.7 MUg/mg) and the matched control tendons that received operative repair alone (4.5 +/- 0.9 MUg/mg). Tendons that were treated with basic fibroblast growth factor had a lower ratio of type-I collagen to type-III collagen, indicating increased scar formation compared with that seen in tendons that received operative repair alone (3.0 +/- 1.6 in the group that received 500-ng basic fibroblast growth factor compared with 4.3 +/- 1.0 in the paired control group that received operative repair alone, and 3.4 +/- 0.6 in the group that received 1000-ng basic fibroblast growth factor compared with 4.5 +/- 1.9 in the paired control group that received operative repair alone). Consistent with the increases in adhesion formation that were seen in tendons treated with basic fibroblast growth factor, the range of motion was reduced in the group that received the higher dose of basic fibroblast growth factor than it was in the paired control group that received operative repair alone (16.6 degrees +/- 9.4 degrees in the group that received 500 ng basic fibroblast growth factor, 13.4 degrees +/- 6.1 degrees in the paired control group that received operative repair alone, and 29.2 degrees +/- 5.8 degrees in the normal group [i.e., the group of corresponding, uninjured tendons from the contralateral forelimb]; and 15.0 degrees +/- 3.8 degrees in the group that received 1000 ng basic fibroblast growth factor, 19.3 degrees +/- 5.5 degrees in the paired control group that received operative repair alone, and 29.0 degrees +/- 8.8 degrees in the normal group). There were no significant differences in tendon excursion or tensile mechanical properties between the groups that were treated with basic fibroblast growth factor and the groups that received operative repair alone. CONCLUSIONS: Although basic fibroblast growth factor accelerated the cell proliferation phase of tendon healing, it also promoted neovascularization and inflammation in the earliest stages following the suturing of the tendon. Despite a substantial biologic response, the administration of basic fibroblast growth factor failed to produce improvements in either the mechanical or functional properties of the repair. Rather, increased cellular activity resulted in peritendinous scar formation and diminished range of motion. PMID- 20926723 TI - Effects of workers' compensation on the diagnosis and surgical treatment of patients with hand and wrist disorders. AB - BACKGROUND: Workers' Compensation differs from standard insurance, and it is unclear how or if Workers' Compensation insurance influences the diagnosis and treatment of hand and wrist disorders. The aim of this study was to compare the diagnosis and course of treatment of hand disorders between patients with Workers' Compensation insurance and patients with standard insurance. METHODS: The complete medical records of patients who visited an academic orthopaedic hand clinic between January 2005 and January 2007 were reviewed, and information on patient history, utilization of diagnostic tests, diagnosis, surgery, and wait time to surgery was collected. Patients with Workers' Compensation insurance and those with other, third-party coverage were analyzed and compared. Patients without insurance were excluded from this study. RESULTS: 1413 patients (representing 2121 diagnoses) were included in the study. One hundred and sixteen patients (8%) had Workers' Compensation insurance and 1297 patients (92%) had standard insurance. Patients with Workers' Compensation insurance were younger than patients with standard insurance (mean age, forty-three years compared with fifty years, respectively; p < 0.05) and were also more likely to be male (50% compared with 40%, respectively; p = 0.04). Generally, Workers' Compensation patients more often had neurological conditions (p < 0.01), but there was no significant difference in the most common diagnoses between the two groups. Patients with Workers' Compensation underwent surgery slightly more often than did patients with standard insurance (44% compared with 35%, respectively; p = 0.07) and had a higher average number of visits before undergoing surgery (2.3 visits compared with 1.2 visits, respectively; p < 0.05). Twenty-three (45%) of the fifty-one patients with Workers' Compensation insurance who received a diagnosis indicating the need for surgery underwent surgery after the first visit, compared with 316 (69%) of 458 patients with standard insurance (p < 0.05). Patients with Workers' Compensation insurance were more likely than patients with standard insurance to undergo electrodiagnostic testing (26% compared with 15%, respectively; p < 0.01) or magnetic resonance imaging (16% compared with 9%, respectively; p = 0.02). CONCLUSIONS: Compared with patients receiving standard insurance, patients receiving Workers' Compensation insurance have a greater number of clinic visits before undergoing surgery and receive more diagnostic testing. More research is needed to explore these differences and their potential clinical and economic consequences. PMID- 20926724 TI - Hypovitaminosis D in patients scheduled to undergo orthopaedic surgery: a single center analysis. AB - BACKGROUND: Vitamin D is essential for optimal bone health and muscle function. An alarmingly high rate of vitamin-D deficiency in the general population has been reported recently. The purpose of the present study was to characterize the extent of low serum levels of vitamin D among orthopaedic surgery patients. METHODS: We performed a retrospective chart review of 723 patients who were scheduled for orthopaedic surgery between January 2007 and March 2008. Preoperative serum 25-hydroxyvitamin D (25[OH]D) levels were measured. The prevalence of normal (>=32 ng/mL), insufficient (<32 ng/mL), and deficient (<20 ng/mL) vitamin-D levels was determined. Logistic regression was used to assess risk factors for insufficient (<32 ng/mL) 25(OH)D levels. RESULTS: Overall, 43% of all patients had insufficient serum vitamin-D levels, and, of these, 40% had deficient levels. Among the orthopaedic services, the highest rates of low serum vitamin-D levels were seen in the trauma and sports services, in which the rates of abnormal (insufficient and deficient) vitamin-D levels were 66% and 52%, respectively. The lowest rate of abnormal vitamin-D levels was seen in the metabolic bone disease service. Patients between the ages of fifty-one and seventy years were 35% less likely to have low vitamin-D levels than patients between the ages of eighteen and fifty years (p = 0.018). The prevalence of low vitamin-D levels was significantly higher in men (p = 0.006). Individuals with darker skin tones (blacks and Hispanics) were 5.5 times more likely to have low vitamin-D levels when compared with those with lighter skin tones (whites and Asians) (p < 0.001). CONCLUSIONS: The prevalence of low serum levels of vitamin D among patients undergoing orthopaedic surgery is very common. Given the importance of vitamin D in musculoskeletal health, such low levels may negatively impact patient outcomes. PMID- 20926725 TI - Repair of a deficient abductor mechanism with Achilles tendon allograft after total hip replacement. AB - BACKGROUND: Abductor mechanism insufficiency after total hip arthroplasty is a rare but debilitating problem. The diagnosis is difficult, and when the condition is recognized there are few successful treatment options. The purpose of this study was to review our experience with a surgical technique involving use of a fresh-frozen Achilles tendon allograft with an attached calcaneal bone graft to reconstruct a deficient abductor mechanism after total hip arthroplasty. METHODS: From 2003 to 2006, we performed seven abductor reconstructions with an Achilles tendon allograft in patients with abductor deficiency after total hip arthroplasty. At a mean of twenty-nine months after the total hip arthroplasty, all seven patients had symptoms of lateral hip pain and abductor muscle weakness as demonstrated by a Trendelenburg test. The abductor tendon rupture was diagnosed on the basis of an arthrogram and was confirmed at surgery. RESULTS: Before the reconstruction, the average Harris hip score was 34.7 points and the average pain score was 11.4 points. After a minimum duration of follow-up of twenty-four months, the average Harris hip score was 85.9 points and the average pain score was 38.9 points. CONCLUSIONS: Abductor reconstruction with an Achilles tendon allograft with a calcaneal bone block attached to the greater trochanter can produce substantial relief of pain, increased abductor muscle strength, decreased limp, and improvements in the Trendelenburg sign and in function at the time of early follow-up. PMID- 20926726 TI - Outcomes associated with the internal fixation of long-bone fractures proximal to traumatic amputations. AB - BACKGROUND: Preservation of optimal residual limb length following a traumatic amputation can be challenging. The purpose of this study was to determine if acceptable results can be achieved by definitive fixation of a long-bone fracture proximal to a traumatic amputation. METHODS: We identified thirty-seven active duty military service members who underwent internal fixation of a long-bone fracture proximal to a traumatic amputation. Functional status was assessed with the Tegner activity level scale and prosthesis use. Secondary outcome measures were the development of nonunion, infection, and heterotopic ossification. RESULTS: Twelve patients (32%) underwent amputation and fracture in the same osseous segment. Ten patients (27%) sustained bilateral traumatic amputations, and eight (22%) had a major fracture of the contralateral extremity. The median times to fracture fixation and amputation closure were twelve days and nineteen days, respectively, after the injury. The mean Tegner activity score was 3.32 (range, 1 to 6); patients with isolated extremity injuries had significantly higher Tegner scores than those with severe bilateral injuries (3.59 and 2.38, respectively; p = 0.04). Thirty-three patients (89%) developed an infection requiring surgical debridement. However, all fractures were treated until union occurred, and amputation level salvage was successful in all instances. Heterotopic ossification developed in twenty-eight patients (76%), with operative excision required in eleven patients (39%). CONCLUSIONS: High complication rates, but acceptable final results, can be achieved with internal fixation of a fracture proximal to a traumatic amputation to preserve functional joint levels or salvage residual limb length. PMID- 20926727 TI - Reliability and validity of radiographic measurements in hindfoot varus and valgus. AB - BACKGROUND: Clinical decision-making in the treatment of foot deformities is based primarily on the results of the physical examination and the radiographic findings. The purpose of this study was to determine the validity and reliability of commonly used radiographic measurements of hindfoot valgus and varus deformities. METHODS: Seventy-two patients with hindfoot deformity (thirty-six hindfoot valgus, mean age 15.5 years; thirty-six hindfoot varus, mean age 30.2 years) were evaluated. Nine representative indices on weight-bearing radiographs were assessed. Three examiners measured the radiographic indices at two sessions, and intraobserver and interobserver reliability was determined. Discriminant validity of the radiographic measurements between hindfoot valgus and varus was evaluated. The correlation with pedobarographic findings in evaluating the distribution of foot pressure during gait was assessed for convergent validity. RESULTS: Naviculocuboid overlap, anteroposterior talonavicular coverage angle, anteroposterior talus-first metatarsal angle, calcaneal pitch angle, and lateral talus-first metatarsal angle showed excellent reliability. Naviculocuboid overlap, anteroposterior talonavicular coverage angle, and anteroposterior talus first metatarsal angle showed excellent discriminant validity (in terms of effect size r) and convergent validity (in terms of correlation coefficients with pedobarography). CONCLUSIONS: Naviculocuboid overlap, anteroposterior talonavicular coverage angle, and anteroposterior talus-first metatarsal angle are reliable and valid measures for the evaluation of hindfoot valgus and varus deformities. PMID- 20926728 TI - Diversity based on race, ethnicity, and sex between academic orthopaedic surgery and other specialties: a comparative study. AB - BACKGROUND: Previous studies have demonstrated a lack of diversity in orthopaedics; however, it is unclear whether this observation is unique to orthopaedics or similar to other surgical fields. The present study compares diversity in the field of orthopaedics with diversity in other surgical and nonsurgical fields. To our knowledge, no previous study has placed this issue in a comparative perspective between specialties at both the residency and faculty levels. METHODS: Public registries from 2006 and 2007 were used to determine the composition (according to race, ethnicity, and sex) of the orthopaedic workforce in the United States, including medical students, orthopaedic residents, orthopaedic faculty, and full professors. The diversity of orthopaedic residents and faculty was then compared with that in five other specialties. In addition, the applicant pools to orthopaedic and general surgery residencies were compared. RESULTS: Within the 2006 orthopaedic workforce, there was a significant decrease in the representation of African-Americans, Hispanics/Latinos, Asian-Americans, and women from medical schools to orthopaedic residencies (p < 0.001). African Americans, Hispanics/Latinos, and Asian-Americans were underrepresented among orthopaedic faculty compared with their representation in orthopaedic residency programs (p < 0.05). Furthermore, women and Asian-Americans were disproportionately underrepresented as full professors compared with their presence on the faculty at academic orthopaedic institutions (p < 0.05). When compared with other surgical specialties, African-Americans and Hispanics/Latinos made up a significantly smaller proportion of orthopaedic residents than general surgery residents and neurological surgery. Orthopaedic surgery had the lowest representation of female residents and faculty (p < 0.05 for all comparisons). In examining the applicant pool, orthopaedic surgery was less diverse than general surgery (p < 0.001). Furthermore, African-American and Hispanic/Latino orthopaedic applicants also submitted a lower average number of applications than Whites or Asian-Americans. CONCLUSIONS: Our findings suggest that on a comparative basis, orthopaedic surgery lags behind general surgery and other surgical and nonsurgical fields in terms of the representation of minorities and women. Thus, given similar capabilities and qualifications of applicants, a concerted effort could be made to recruit more diverse residents and faculty. PMID- 20926729 TI - Extreme enchondromatosis: a report of two cases and review of the literature. PMID- 20926730 TI - Displaced longitudinal stress fracture of the patella: a case report. PMID- 20926731 TI - Suprascapular neuropathy. AB - Suprascapular neuropathy has often been overlooked as a source of shoulder pain. The condition may be more common than once thought as it is being diagnosed more frequently. Etiologies for suprascapular neuropathy may include repetitive overhead activities, traction from a rotator cuff tear, and compression from a space-occupying lesion at the suprascapular or spinoglenoid notch. Magnetic resonance imaging is useful for visualizing space-occupying lesions, other pathological entities of the shoulder, and fatty infiltration of the rotator cuff. Electromyography and nerve conduction velocity studies remain the standard for diagnosis of suprascapular neuropathy; however, data on interobserver reliability are limited. Initial treatment of isolated suprascapular neuropathy is typically nonoperative, consisting of physical therapy, nonsteroidal anti inflammatory drugs, and activity modification; however, open or arthroscopic operative intervention is warranted when there is extrinsic nerve compression or progressive pain and/or weakness. More clinical data are needed to determine if treatment of the primary offending etiology in cases of traction from a rotator cuff tear or compression from a cyst secondary to a labral tear is sufficient or whether concomitant decompression of the nerve is warranted for management of the neuropathy. PMID- 20926732 TI - Thoracic mass in a cynomolgus macaque (Macaca fascicularis). AB - A male cynomolgus macaque at the age of 3 years and 11 months suffered sudden cardiac arrest during a surgical operation. This animal had been clinically asymptomatic for 6 months from the acclimatization period to death. At necropsy, a white mass approximately 5 cm in diameter was found at the base of the heart. Histopathologically, the mass consisted of a granuloma with a number of multinucleated giant cells and multiple necrotic foci. Fungal hyphae characterized by parallel cell walls, distinct septa, and branching were observed in the lesion. The granuloma extended into the thoracic lymph nodes and the subepicardium of the left atrium, compressed the bronchioli, and was separated from the pulmonary parenchyma by a thick fibrous layer. The hyphal morphology and results of polymerase chain reaction assays demonstrated that the pathogen was Aspergillus sp. PMID- 20926733 TI - Intestinal atresia and ectopia in a bovine fetus. AB - A 2-year-old Red Holstein cow was presented with uterine torsion at 235 days of pregnancy. The fetus extracted by cesarean section had weak vital signs and marked abdominal distention. An edematous pouch that contained tubular structures with peristaltic activity was associated with the umbilical cord. Because of poor prognosis, both dam and fetus were euthanized. At necropsy, the fetus had severe distention of the forestomachs, abomasum, and proximal small intestine; absence of distal small intestine, cecum, and proximal colon; atresia of the 2 blind ends of the intestine; and atrophy of distal colon and rectum. The tubular structures associated with the umbilical cord were identified as the segments of intestine that were absent in the fetus. Intestinal atresia combined with ectopia may be caused by local ischemia during temporary herniation and rotation of the fetal gut into the extraembryonic coelom. The close connection between ectopic intestine and amniotic sheath of the umbilical cord in this case may have facilitated vascularization and allowed development and viability of the ectopic intestine. PMID- 20926735 TI - Paranasal sinus masses of Rocky Mountain bighorn sheep (Ovis canadensis canadensis). AB - This article describes 10 cases of paranasal sinus masses in Rocky Mountain bighorn sheep (Ovis canadensis canadensis). Among 21 bighorns that were examined from 11 herds in Colorado, 10 individuals (48%) from 4 herds (36%) had masses arising from the paranasal sinuses. Affected animals included 9 of 17 females (53%) and 1 of 4 males (25%), ranging in age from approximately 2 years to greater than 10 years. Defining gross features of these masses included unilateral or bilateral diffuse thickening of the respiratory lining of the maxillary and/or frontal sinuses, with abundant seromucinous exudate in the affected sinus cavities. Defining histologic features of these masses included chronic inflammation and proliferation of mesenchymal and epithelial cells of the mucosa and submucosa. Epithelial changes included hyperplasia of mucosal epithelium, hyperplasia of submucosal glands and ducts, and neoplasia (adenocarcinoma). Mesenchymal changes included submucosal myxedema, submucosal fibroplasia/fibrosis, bone destruction, and neoplasia (myxomatous fibroma). Specific immunohistochemistry and polymerase chain reaction for Jaagsiekte sheep retrovirus and enzootic nasal tumor virus were performed with negative results. PMID- 20926736 TI - Suppression of proliferation and invasive behavior of human metastatic breast cancer cells by dietary supplement BreastDefend. AB - AIM: The study was to evaluate the effect of the dietary supplement BreastDefend (BD) on the proliferation and invasive behavior of highly metastatic human breast cancer cells in vitro. METHODS: Cell proliferation and cytotoxicity of BD was evaluated in MDA-MB-231 cells treated with BD (0-40 MUg/mL) by MTT assay and trypan blue staining, respectively. Expression of cell cycle regulatory genes were determined by DNA-microarray analysis. Effect of BD on invasiveness was assessed by cellular adhesion, migration, and invasion assays. RESULTS: BD treatment of cells MDA-MB-231 resulted in the cytostatic inhibition of cell proliferation with IC(50) 22.2, 19.1, and 17.5 MUg/mL for 24, 48, and 72 hours, respectively. The inhibition of proliferation was mediated by the upregulation expression of CCNG1, CHEK1, CDKN1C, GADD45A, and E2F2, whereas BD downregulated expression of CCNA1 and CDK6 genes. The induction of expression of GADD45A and inhibition of expression of cyclin A1 (gene CCNA1) by BD was also confirmed on the protein level. BD treatment suppressed the invasive behavior of MDA-MB-231 cells by the inhibition of cellular adhesion, migration, and invasion. This inhibition of invasiveness was mediated by the suppression of secretion of urokinase plasminogen activator (uPA), and by the downregulation of expression of CXCR4 in breast cancer cells treated with BD. CONCLUSION: BD inhibits proliferation and invasive behavior of the highly metastatic human breast cancer cells in vitro. BD may have a therapeutic potential for prevention or treatment of highly metastatic breast cancers. PMID- 20926734 TI - Ulcerative typhlocolitis associated with Helicobacter mastomyrinus in telomerase deficient mice. AB - Telomerase deficiency induces early senescence and defects in proliferating cell populations, but in mice it has not been associated with inflammatory bowel disease. Genetically engineered mice lacking either telomerase reverse transcriptase (TERT) or telomerase RNA were examined for chronic diarrhea and wasting. Affected mice had pasty stools, thickened nondistensible colon walls, and contracted ceca. Histologically, the cecal mucosa was largely replaced by inflammatory infiltrate consisting of plasma cells, neutrophils, lymphocytes, and macrophages with marked widespread fibrosis and ulceration. Remaining epithelium was disorganized and hyperplastic, with multifocal dysplasia. Colonic mucosa was markedly hyperplastic with similar inflammation and epithelial dysplasia. Multifocal adenomatous hyperplasia, but no inflammation, was present in the small intestine. Microaerophilic spiral bacteria with 16S rRNA gene sequences identical to Helicobacter mastomyrinus were isolated from the colon and cecum. Severe granulomatous typhlocolitis without epithelial dysplasia developed in germ-free recombination-activating gene (RAG) knockout (KO) recipients of CD4+ T cells and inoculated with cecal contents from affected TERT KO mice and in specific pathogen-free recipient RAG KO mice and interleukin-10 KO mice inoculated with H mastomyrinus. Typhlocolitis in mice given H mastomyrinus was more severe than in mice given Helicobacter hepaticus. Telomerase-deficient mice are susceptible to helicobacter-associated typhlocolitis. H mastomyrinus causes severe disease in susceptible mouse strains. PMID- 20926737 TI - Proteomic and functional analyses reveal the potential involvement of endoplasmic reticulum stress and alpha-CP1 in the anticancer activities of oridonin in HepG2 cells. AB - Oridonin has been shown to exhibit therapeutic effects against hepatocellular carcinoma (HCC) in vitro and in vivo. This study aimed to identify the anti-HCC mechanisms of oridonin in HepG2 cells using proteomic and functional analyses. MTT assay showed that oridonin treatment for 24 hours dose-dependently inhibited cell growth with an IC(50) value of 40.4 MUM. Treatment with 40 MUM oridonin for 24 hours induced apoptosis determined by nuclear morphologic changes of DAPI stained cells and flow cytometric analysis of annexin V-FITC/PI-stained cells, which was accompanied by Grp78 upregulation and alpha-CP1 downregulation identified by proteomic analysis. Immunoblot analysis for the endoplasmic reticulum (ER) stress- related proteins demonstrated that the expression levels of phosphorylated PERK (p-PERK) and CHOP were increased, whereas PERK, ATF-6, and IRE-1 expression levels were decreased. Knockdown of alpha-CP1 expression with siRNA significantly increased cell death and apoptosis in control and oridonin treated HepG2 cells. Together, these data provide proteomic and functional evidence for the potential involvement of ER stress and alpha-CP1 in the antiproliferative and apoptotic activities of oridonin in HepG2 cells, which shed new light on the action mechanisms of oridonin in HCC management. PMID- 20926738 TI - Biomarkers for early detection of Alzheimer disease. AB - The existence of an effective biomarker for early detection of Alzheimer disease would facilitate improved diagnosis and stimulate therapeutic trials. Multidisciplinary clinical diagnosis of Alzheimer disease is time consuming and expensive and relies on experts who are rarely available outside of specialty clinics. Thus, many patients do not receive proper diagnosis until the disease has progressed beyond stages in which treatments are maximally effective. In the clinical trial setting, rapid, cost-effective screening of patients for Alzheimer disease is of paramount importance for the development of new treatments. Neuroimaging of cortical amyloid burden and volumetric changes in the brain and assessment of protein concentrations (eg, beta-amyloid 1-42, total tau, phosphorylated tau) in cerebrospinal fluid are diagnostic tools that are not widely available. Known genetic markers do not provide sufficient discriminatory power between different forms of dementia to be useful in isolation. Recent studies using panels of biomarkers for diagnosis of Alzheimer disease or mild cognitive impairment have been promising, though no such studies have been cross validated in independent samples of subjects. The ideal biomarker enabling early detection of Alzheimer disease has not yet been identified. PMID- 20926739 TI - Current treatments for patients with Alzheimer disease. AB - There is neither proven effective prevention for Alzheimer disease nor a cure for patients with this disorder. Nevertheless, a spectrum of biopsychosocial therapeutic measures is available for slowing progression of the illness and enhancing quality of life for patients. These measures include a range of educational, psychological, social, and behavioral interventions that remain fundamental to effective care. Also available are a number of pharmacologic treatments, including prescription medications approved by the US Food and Drug Administration for Alzheimer disease, "off-label" uses of medications to manage target symptoms, and controversial complementary therapies. Physicians must make the earliest possible diagnosis to use these treatments most effectively. Physicians' goals should be to educate patients and their caregivers, to plan long-term care options, to maximally manage concurrent illnesses, to slow and ameliorate the most disabling symptoms, and to preserve effective functioning for as long as possible. The authors review the various current treatments for patients with Alzheimer disease. PMID- 20926740 TI - Investigational medications for treatment of patients with Alzheimer disease. AB - Development of effective treatments for patients with Alzheimer disease has been challenging. Currently approved treatments include acetylcholinesterase inhibitors and the N-methyl-D-aspartate receptor antagonist memantine hydrochloride. To investigate treatments in development for patients with Alzheimer disease, the author conducted a review of the literature. New approaches for treatment or prevention focus on several general areas, including cholinergic receptor agonists, drugs to decrease beta-amyloid and tau levels, antiinflammatory agents, drugs to increase nitric oxide and cyclic guanosine monophosphate levels, and substances to reduce cell death or promote cellular regeneration. The author focuses on medications currently in clinical trials. Cholinergic agents include orthostatic and allosteric muscarinic M1 agonists and nicotinic receptor agonists. Investigational agents that target beta-amyloid include vaccines, antibodies, and inhibitors of beta-amyloid production. Anti inflammatory agents, including nonsteroidal anti-inflammatory drugs, the natural product curcumin, and the tumor necrosis factor alpha inhibitor etanercept, have also been studied. Some drugs currently approved for other uses may also show promise for treatment of patients with Alzheimer disease. Results of clinical trials with many of these investigational drugs have been disappointing, perhaps because of their use with patients in advanced stages of Alzheimer disease. Effective treatment may need to begin earlier-before neurodegeneration becomes severe enough for symptoms to appear. PMID- 20926741 TI - Alzheimer disease: update on basic mechanisms. AB - Alzheimer disease is the most common form of dementia in the aged population. Pathologically, Alzheimer disease is characterized by progressive synaptic and neuronal loss and the presence of diagnostic amyloid plaques, consisting of fibril b-amyloid peptide aggregates and neurofibrillary tangles containing hyperphosphorylated tau protein filaments. Although plaques and tangles were originally considered the mediators of neurotoxicity in Alzheimer disease, recent research has underscored the roles of soluble beta-amyloid oligomers and tau molecules. Furthermore, new evidence has re-emphasized the important roles of endocytic, autophagic, and lysosomal pathways in Alzheimer disease pathogenesis including the finding that deficiency or mutations in the gene that encodes presenilin 1 (the most common cause for early-onset familial Alzheimer disease) impairs the maturation of the lysosomal proton pump. The author discusses recent developments in the perspective of Alzheimer disease pathogenesis and potential therapeutic interventions. PMID- 20926742 TI - Modern care for patients with Alzheimer disease: rationale for early intervention. AB - More than 5 million people in the United States are afflicted with Alzheimer disease, a condition that is the seventh leading cause of death in the nation. Lacking definitive disease-modifying treatments, modern care for individuals with Alzheimer disease is necessarily multimodal, combining the use of approved pharmaceutic agents (ie, acetylcholinesterase inhibitors, N-methyl-D-aspartate receptor antagonists, antipsychotics), lifestyle and behavioral interventions, and components of palliative care. Some promising experimental treatments are undergoing clinical trials, including immunotherapy to prevent the deposition of beta-amyloid, a protein implicated as an etiologic factor in the disease. The authors briefly examine the rationale and methods for screening patients for early indications of the onset of Alzheimer disease. They also describe current and potential treatments for patients with this disease. PMID- 20926743 TI - Recruitment of subjects into clinical trials for Alzheimer disease. AB - Alzheimer disease is a devastating neurodegenerative disorder affecting millions of Americans. It reduces the ability of the individual to remain independent, places a burden on caregivers, and substantially increases healthcare costs. New treatments are being tested in numerous clinical trials with the goal of preventing or delaying the onset of Alzheimer disease, slowing or modifying the disease's course, or finding a cure for patients with the disease. Alzheimer disease research can successfully proceed only if individuals who have this illness are willing to participate in clinical trials. However, recruitment and retention of subjects in clinical trials for Alzheimer disease is a challenging task. Furthermore, because of reductions in decision-making capacities of individuals with Alzheimer disease, clinical trials also need to involve caregivers. The present article delineates unique hurdles encountered in the recruitment process for Alzheimer disease clinical trials. The article also identifies strategies for effective recruitment of subjects in Alzheimer disease clinical trials, including guidelines to help principal investigators and clinical research coordinators reach recruitment goals. PMID- 20926744 TI - Alzheimer disease: the crisis is upon us. PMID- 20926745 TI - p21-activated kinase 4 regulates ovarian cancer cell proliferation, migration, and invasion and contributes to poor prognosis in patients. AB - Ovarian cancer is a lethal gynecological malignancy, and to improve survival, it is important to identify novel prognostic and therapeutic targets. In this study, we present a role for p21-activated kinase 4 (Pak4) in ovarian cancer progression. We show a significant association between increased expression of Pak4 and its activated form, phosphorylated (p)-Pak4 Ser(474), with metastasis of ovarian cancers, shorter overall and disease-free survival, advanced stage and high-grade cancers, serous/clear cell histological subtypes, and reduced chemosensitivity. Pak4 overexpression was also observed in ovarian cancer cell lines. Pak4 and p-Pak4 expression were detected both in the nucleus and cytoplasm of ovarian cancer cells, in vitro as well as in vivo. Stable knockdown of Pak4 in ovarian cancer cell lines led to reduced cell migration, invasion, and proliferation, along with reduced c-Src, ERK1/2, and epidermal growth factor receptor (EGFR) activation and decreased matrix metalloproteinase 2 (MMP2) expression. Conversely, Pak4 overexpression promoted ovarian cancer cell migration and invasion in a c-Src, MEK-1, MMP2, and kinase-dependent manner, and induced cell proliferation through the Pak4/c-Src/EGFR pathway that controls cyclin D1 and CDC25A expression. Stable knockdown of Pak4 also impeded tumor growth and dissemination in nude mice. This report reveals the association between Pak4 and important clinicopathologic parameters, suggesting Pak4 to be a significant prognostic marker and potential therapeutic molecular target in ovarian cancer. The implied possible cross-talk between Pak4 and EGFR suggests the potential of dual targeting of EGFR and Pak4 as a unique therapeutic approach for cancer therapy. PMID- 20926746 TI - Crowding and function reunite. PMID- 20926747 TI - Long-distance inflammatory and genotoxic impact of cancer in vivo. PMID- 20926748 TI - FERONIA as an upstream receptor kinase for polar cell growth in plants. PMID- 20926749 TI - Vascular endothelial platelet endothelial cell adhesion molecule 1 (PECAM-1) regulates advanced metastatic progression. AB - Most patients who die from cancer succumb to treatment-refractory advanced metastatic progression. Although the early stages of tumor metastasis result in the formation of clinically silent micrometastatic foci, its later stages primarily reflect the progressive, organ-destructive growth of already advanced metastases. Early-stage metastasis is regulated by multiple factors within tumor cells as well as by the tumor microenvironment (TME). In contrast, the molecular determinants that control advanced metastatic progression remain essentially uncharacterized, precluding the development of therapies targeted against it. Here we show that the TME, functioning in part through platelet endothelial cell adhesion molecule 1 (PECAM-1), drives advanced metastatic progression and is essential for progression through its preterminal end stage. PECAM-1-KO and chimeric mice revealed that its metastasis-promoting effects are mediated specifically through vascular endothelial cell (VEC) PECAM-1. Anti-PECAM-1 mAb therapy suppresses both end-stage metastatic progression and tumor-induced cachexia in tumor-bearing mice. It reduces proliferation, but not angiogenesis or apoptosis, within advanced tumor metastases. Because its antimetastatic effects are mediated by binding to VEC rather than to tumor cells, anti-PECAM-1 mAb appears to act independently of tumor type. A modified 3D coculture assay showed that anti-PECAM-1 mAb inhibits the proliferation of PECAM-1-negative tumor cells by altering the concentrations of secreted factors. Our studies indicate that a complex interplay between elements of the TME and advanced tumor metastases directs end-stage metastatic progression. They also suggest that some therapeutic interventions may target late-stage metastases specifically. mAb-based targeting of PECAM-1 represents a TME-targeted therapeutic approach that suppresses the end stages of metastatic progression, until now a refractory clinical entity. PMID- 20926750 TI - Influence of severe renal impairment on the pharmacokinetics of clazosentan. AB - The purpose of this open-label, parallel-group study was to investigate the effect of severe renal impairment on the pharmacokinetics (PK), tolerability, and safety of clazosentan, an intravenous endothelin receptor antagonist. Clazosentan was administered as a continuous intravenous infusion of 1 mg/h for a period of 6 hours in 9 subjects with severe renal impairment (group A) and 8 healthy subjects (group B) (creatinine clearance <30 mL/min and >80 mL/min, respectively). The subjects in both groups were well matched for sex, body mass index, and age (+/ 10 years). The PK parameters of clazosentan were calculated by both model independent and model-dependent methods. The differences in the PK parameters between the subjects with severe renal impairment and healthy subjects were minor. The geometric means for area under the curve (AUC) during the infusion, AUC(0-t), (AUC from zero to time t of the last measured concentration above the limit of quantification) AUC(0-infinity) (AUC from zero to infinity), and concentration at steady state were 7%, 8%, 8%, and 8%, respectively, higher in group A than in group B. The results obtained after 2-compartmental modeling were in agreement with those obtained after noncompartmental analysis. Administration of clazosentan was well tolerated in both groups. The data suggest that there is no need for dose adjustment of clazosentan in patients with renal impairment. PMID- 20926751 TI - Clinical pharmacokinetics of tonapofylline: evaluation of dose proportionality, oral bioavailability, and gender and food effects in healthy human subjects. AB - Tonapofylline is an antagonist of adenosine A1 receptor being developed for heart failure. In the present studies, pharmacokinetic characteristics, including dose proportionality, bioavailability, and effects of gender and food, were evaluated in healthy subjects receiving single-dose tonapofylline (0.2-375 mg) in a parallel or crossover design. Following oral administration, tonapofylline concentrations mostly peaked within 3 hours and declined over time in a multiple phasic manner. Based on a power model, dose proportionality of peak concentration (C(max)), area under the time-concentration curve for all values (AUC(all)), and area under the time-concentration curve to infinity (AUC(inf)) was concluded in a clinical setting. The bioavailability of tonapofylline was 81.2% (90% confidence interval, 70.6%-93.5%). Following intravenous administration, the steady-state volume of distribution of tonapofylline was estimated to be 756 mL/kg. The total clearance of tonapofylline was low (64.8 mL/h/kg), approximately 5% of hepatic blood flow. The terminal half-life was variable within groups and ranged from 11.2 to 24.2 hours across the dose range. Female subjects showed significantly higher C(max), AUC(all), and AUC(inf) than male subjects (P < .05). Food decreased C(max) by approximately 39%, whereas it did not appear to affect AUC(all) and AUC(inf). The intersubject variability of the pharmacokinetic parameters of tonapofylline was generally less than 30%. In these studies, a single dose of tonapofylline was safe and well tolerated. PMID- 20926752 TI - Incidence and contributors to potential drug-drug interactions in hospitalized patients. AB - Drug-drug interactions (DDIs) are drug combinations that result in pharmacological or clinical responses that differ from solitary administration. Previous studies of DDIs have been limited to particular drugs or particular patient populations. The authors performed a retrospective cohort study of all adults admitted to a teaching hospital between 1999 and 2005. All medications administered to patients were identified and compared with a standard reference of important DDIs. The authors measured the potential DDI incidence density as the percentage of time in the hospital during which patients were exposed to at least 1 DDI and used multivariate Poisson regression to determine its determinants. A total of 19.3% of 140 349 hospitalizations had at least 1 potential DDI. The potential DDI incidence density was 18.8%. Factors having the greatest influence on potential DDI incidence density included increased patient age (adjusted rate ratio patient >75 years vs <30 years, 2.25; 95% CI, 2.15 2.35), increased number of drug orders (adjusted rate ratio, 2.27 [2.23-2.30] for logarithm), and patient service (adjusted rate ratio, 1.49 [1.46-1.52] for surgical vs medical service). Potential DDIs were present during one fifth of hospitalization time. PMID- 20926753 TI - Pharmacokinetics, pharmacodynamics, and safety of ticagrelor in volunteers with mild hepatic impairment. AB - Ticagrelor, a P2Y12 receptor antagonist that inhibits ADP-induced platelet aggregation (IPA), has demonstrated improved outcomes in patients with acute coronary syndromes compared with clopidogrel. Because ticagrelor undergoes extensive hepatic elimination, this study evaluated the effect of mild hepatic impairment on its pharmacokinetics, pharmacodynamics, and safety. A single oral 90-mg ticagrelor dose was administered to volunteers with and without hepatic impairment (10 with Child-Pugh class A; 10 with normal liver function). Absorption of ticagrelor and formation of its active metabolite, AR-C124910XX, were rapid in both groups. Ticagrelor exposure was higher in hepatically impaired volunteers (maximum concentration [C(max)] 12%; area under the plasma concentration-time curve from time 0 to infinity [AUC] 23%) compared with controls. AR-C124910XX exposure was also higher in hepatic impairment (C(max) 17%; AUC 66%). Ticagrelor is highly protein bound (>99.8%); the unbound fraction in plasma was comparable in volunteers with hepatic impairment and controls. Overall, IPA parameters were not significantly different between groups, and similar IPA-concentration profiles were observed. Ticagrelor was well tolerated in both groups, and no adverse events were reported. In conclusion, mild hepatic impairment resulted in modestly higher exposure to ticagrelor and AR-C124910XX, without subsequent effects on pharmacodynamics or tolerability. Based on these data, no ticagrelor dosage adjustment is needed in patients with mild hepatic impairment. PMID- 20926754 TI - Effects of BG9928, an adenosine A1 receptor antagonist, in patients with congestive heart failure. AB - Previous studies suggest that adenosine A1 receptor antagonists may promote natriuresis without deleterious effects on renal function. This study evaluated renal and hemodynamic effects as well as safety, pharmacokinetics, and tolerability of BG9928, a selective adenosine A1-receptor antagonist, in patients with heart failure. In this multicenter, randomized, double-blind, placebo controlled, dose-escalation study, 33 patients received a single dose of BG9928 (0.03, 0.3, 1.0, or 3.0 mg/kg) or placebo intravenously. Change from baseline in urinary sodium excretion for the 8-hour postdose interval was greater for all dosing groups versus placebo. The 0.03-mg/kg and 0.3-mg/kg groups had significant reductions in body weight versus placebo (-0.8 kg, -1.1 kg, 0.3 kg, respectively; P < 005). No changes in creatinine clearance or hemodynamic parameters were observed among any of the BG9928 groups versus placebo. However, pulmonary capillary wedge pressure tended to decrease and correlated with weight loss. Across the range of doses studied, pharmacokinetic parameters were linear and predictable. One patient who received the highest dose (3.0 mg/kg) developed seizures, and no further patients received that dose. Single intravenous BG9928 doses of up to 1.0 mg/kg were well tolerated and increased sodium excretion without worsening renal function. Further studies are needed to determine the clinical benefit of adenosine A1 receptor antagonism. PMID- 20926755 TI - Population pharmacokinetic analysis and dosing regimen optimization of aprotinin in neonates and young infants undergoing cardiopulmonary bypass. AB - The objective of this study was to determine an optimal dosing regimen for maintaining the therapeutic target range of aprotinin in neonates and young infants during cardiopulmonary bypass (CPB). A total of 27 patients scheduled for open heart surgery were enrolled. Aprotinin was administered a 25 000 KIU (kallikrein inhibition unit)/kg bolus before operation, a 35 000 KIU/kg for CPB circuit priming, and a 12 500 KIU/kg/hour continuous infusion intra- and immediate postoperative period. Blood samples were obtained at 12 time points per patient. Population pharmacokinetic modeling and Monte-Carlo simulations were used to optimize the aprotinin dosing regimen. No mortality or aprotinin-related complication was encountered. A CPB adjusted 2-compartment model best fit the data. Clearance was 687 mL/hour during CPB and 350 mL/hour pre- and post-CPB, and corresponding volumes of distribution were 1577 mL and 1352 mL, respectively. The simulations conducted showed that more than twice the dose administered in this study is required to maintain the target concentration of aprotinin. The pharmacokinetics of aprotinin appears to be affected more sensitively by CPB in neonates and young infants than in adults. Therefore, dosage adjustment considering these pharmacokinetic differences and the influence of CPB is needed in neonates and young infants. PMID- 20926756 TI - Activated sterol regulatory element-binding protein-2 suppresses hepatocyte nuclear factor-4-mediated Cyp3a11 expression in mouse liver. AB - Sterol regulatory element-binding protein-2 (SREBP-2) is a key transcription factor for the cholesterol homeostasis. Recent studies have suggested the association of CYP3A enzymes, major drug-metabolizing enzymes, with cholesterol metabolism. In the present study, we have investigated a possible involvement of SREBP-2 in hepatic Cyp3a11 expression. Feeding a low-cholesterol diet (LCD) to mice activated hepatic SREBP-2 whereas it attenuated hepatic Cyp3a11 expression. These phenomena were reversed by cholesterol supplementation to LCD. In reporter assays, the overexpression of constitutively active SREBP-2 reduced Cyp3a11 reporter activity through the region from -1581 to -1570 of Cyp3a11. This region contained a putative hepatocyte nuclear factor-4alpha (HNF-4alpha) binding motif, and HNF-4alpha, but not SREBP-2, bound to the motif in in vitro binding assays. With the mutation or deletion of this motif, the SREBP-2-dependent suppression of Cyp3a11 expression disappeared in reporter assays. In pull-down assays and coimmunoprecipitation assays, SREBP-2 bound to peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha), a major coactivator for HNF 4alpha, via its transactivation domain and inhibited the interaction between HNF 4alpha and PGC-1alpha in vitro. A mutant SREBP-2 lacking the transactivation domain consistently failed to reduce Cyp3a11 reporter activity. Furthermore, PGC 1alpha overexpression relieved the SREBP-2-mediated reduction of Cyp3a11 reporter activity. Finally, chromatin immunoprecipitation assays demonstrated that the extent of PGC-1alpha binding to the Cyp3a11 promoter was reduced by LCD-feeding in mouse livers. In conclusion, activated SREBP-2 interacts with PGC-1alpha in mouse livers at reduced cholesterol intake. This results in the reduced PGC 1alpha recruitment to HNF-4alpha on the Cyp3a11 promoter and the subsequent down regulation of Cyp3a11 expression. PMID- 20926757 TI - Development of a selective small-molecule inhibitor of Kir1.1, the renal outer medullary potassium channel. AB - The renal outer medullary potassium (K+) channel, ROMK (Kir1.1), is a putative drug target for a novel class of loop diuretic that would lower blood volume and pressure without causing hypokalemia. However, the lack of selective ROMK inhibitors has hindered efforts to assess its therapeutic potential. In a high throughput screen for small-molecule modulators of ROMK, we previously identified a potent and moderately selective ROMK antagonist, 7,13-bis(4-nitrobenzyl)-1,4,10 trioxa-7,13-diazacyclopentadecane (VU590), that also inhibits Kir7.1. Because ROMK and Kir7.1 are coexpressed in the nephron, VU590 is not a good probe of ROMK function in the kidney. Here we describe the development of the structurally related inhibitor 2,2'-oxybis(methylene)bis(5-nitro-1H-benzo[d]imidazole) (VU591), which is as potent as VU590 but is selective for ROMK over Kir7.1 and more than 65 other potential off-targets. VU591 seems to block the intracellular pore of the channel. The development of VU591 may enable studies to explore the viability of ROMK as a diuretic target. PMID- 20926758 TI - Impaired overload-induced hypertrophy is associated with diminished mTOR signaling in insulin-resistant skeletal muscle of the obese Zucker rat. AB - Recent data have suggested that insulin resistance may be associated with a diminished ability of skeletal muscle to undergo hypertrophy (Paturi S, Gutta AK, Kakarla SK, Katta A, Arnold EC, Wu M, Rice KM, Blough ER. J Appl Physiol 108: 7 13, 2010). Here we examine the effects of insulin resistance using the obese Zucker (OZ) rat with increased muscle loading on the regulation of the mammalian target of rapamycin (mTOR) and its downstream signaling intermediates 70-kDa ribosomal protein S6 kinase (p70S6k), ribosomal protein S6 (rpS6), eukaryotic elongation factor 2 (eEF2), and eukaryotic initiation factor 4E-binding protein 1 (4E-BP1). Compared with that observed in lean Zucker (LZ) rats, the degree of soleus muscle hypertrophy as assessed by changes in muscle wet weight (LZ: 35% vs. OZ: 16%) was significantly less in the OZ rats after 3 wk of muscle overload (P < 0.05). This diminished growth in the OZ rats was accompanied by significant impairments in the ability of the soleus to undergo phosphorylation of mTOR (Ser(2448)), p70S6k (Thr(389)), rpS6 (Ser(235/236)), and protein kinase B (Akt) (Ser(473) and Thr(308)) (P < 0.05). Taken together, these data suggest that impaired overload-induced hypertrophy in insulin-resistant skeletal muscle may be related to decreases in the ability of the muscle to undergo mTOR-related signaling. PMID- 20926759 TI - Effects of high-altitude hypoxia on the hormonal response to hypothalamic factors. AB - Acute and chronic exposure to high altitude induces various physiological changes, including activation or inhibition of various hormonal systems. In response to activation processes, a desensitization of several pathways has been described, especially in the adrenergic system. In the present study, we aimed to assess whether the hypophyseal hormones are also subjected to a hypoxia-induced decrease in their response to hypothalamic factors. Basal levels of hormones and the responses of TSH, thyroid hormones, prolactin, sex hormones, and growth hormone to the injection of TRH, gonadotropin-releasing hormone, and growth hormone-releasing hormone (GHRH) were studied in eight men in normoxia and on prolonged exposure (3-4 days) to an altitude of 4,350 m. Thyroid hormones were elevated at altitude (+16 to +21%), while TSH levels were unchanged, and follicle stimulating hormone and prolactin decreased, while leutinizing hormone was unchanged. Norepinephrine and cortisol levels were elevated, while no change was observed in levels of epinephrine, dopamine, growth hormone (GH), IGF-1, and IGFBP-3. The mean response to hypothalamic factors was similar in both altitudes for all studied hormones, although total T4 was lower in hypoxia during 45 to 60 min after injection. The effect of hypoxia on the hypophyseal response to hypothalamic factors was similar among subjects, except for the GH response to GHRH administration. We conclude that prolonged exposure to high-altitude hypoxia induces contrasted changes in hormonal levels, but the hypophyseal response to hypothalamic factors does not appear to be blunted. PMID- 20926761 TI - Dietary protein regulates hepatic constitutive protein anabolism in rats in a dose-dependent manner and independently of energy nutrient composition. AB - We had previously observed that drastic increases in protein consumption greatly modified hepatic protein anabolism in rats, but the confounding effects of other macronutrient changes or a moderate protein increase to generate the same modifications have not yet been established. This study examined the metabolic and hormonal responses of rats subjected to 14-day isoenergetic diets containing normal, intermediate, or high-protein levels (NP: 14% of energy, IP: 33%, HP: 50%) and different carbohydrate (CHO) to fat ratios within each protein level. Fasted or fed rats (n = 104) were killed after the injection of a flooding dose of (13)C-valine. The hepatic protein content increased in line with the dietary protein level (P < 0.05). The hepatic fractional synthesis rates (FSR) of protein were significantly influenced by both the protein level and the nutritional state (fasted vs. fed) (P < 0.0001) but not by the CHO level, reaching on average 110%/day, 92%/day, and 83%/day in rats fed the NP, IP, and HP diets, respectively. The FSR of plasma albumin and muscle did not differ between diets, while feeding tended to increase muscle FSR. Proteolysis, especially the proteasome-dependent system, was down-regulated in the fed state in the liver when protein content increased. Insulin decreased with the CHO level in the diet. Our results reveal that excess dietary protein lowers hepatic constitutive, but not exported, protein synthesis rates, independently of the other macronutrients, and related changes in insulin levels. This response was observed at the moderate levels of protein intake (33%) that are plausible in a context of human consumption. PMID- 20926760 TI - Encoding of the cough reflex in anesthetized guinea pigs. AB - We have previously described the physiological and morphological properties of the cough receptors and their sites of termination in the airways and centrally in the nucleus tractus solitarius (nTS). In the present study, we have addressed the hypothesis that the primary central synapses of the cough receptors subserve an essential role in the encoding of cough. We found that cough requires sustained, high-frequency (>=8-Hz) afferent nerve activation. We also found evidence for processes that both facilitate (summation, sensitization) and inhibit the initiation of cough. Sensitization of cough occurs with repetitive subthreshold activation of the cough receptors or by coincident activation of C fibers and/or nTS neurokinin receptor activation. Desensitization of cough evoked by repetitive and/or continuous afferent nerve activation has a rapid onset (<60 s) and does not differentiate between tussive stimuli, suggesting a central nervous system-dependent process. The cough reflex can also be actively inhibited upon activation of other airway afferent nerve subtypes, including slowly adapting receptors and pulmonary C-fibers. The sensitization and desensitization of cough are likely attributable to the prominent, primary, and unique role of N methyl-d-aspartate receptor-dependent signaling at the central synapses of the cough receptors. These attributes may have direct relevance to the presentation of cough in disease and for the effectiveness of antitussive therapies. PMID- 20926762 TI - Effect of intracerebroventricular benzamil on cardiovascular and central autonomic responses to DOCA-salt treatment. AB - DOCA-salt treatment increases mean arterial pressure (MAP), while central infusion of benzamil attenuates this effect. The present study used c-Fos immunoreactivity to assess the role of benzamil-sensitive proteins in the brain on neural activity following chronic DOCA-salt treatment. Uninephrectomized rats were instrumented with telemetry transmitters for measurement of MAP and with an intracerebroventricular (ICV) cannula for benzamil administration. Groups included rats receiving DOCA-salt treatment alone, rats receiving DOCA-salt treatment with ICV benzamil, and appropriate controls. At study completion, MAP in vehicle-treated DOCA-salt rats reached 142 +/- 4 mmHg. In contrast DOCA-salt rats receiving ICV benzamil had lower MAP (124 +/- 3 mmHg). MAP in normotensive controls was 102 +/- 3 mmHg. c-Fos immunoreactivity was quantified in the supraoptic nucleus (SON) and across subnuclei of the hypothalamic paraventricular nucleus (PVN), as well as other cardiovascular regulatory sites. Compared with vehicle-treated normotensive controls, c-Fos expression was increased in the SON and all subnuclei of the PVN, but not in other key autonomic nuclei, such as the rostroventrolateral medulla. Moreover, benzamil treatment decreased c-Fos immunoreactivity in the SON and in medial parvocellular and posterior magnocellular neurons of the PVN in DOCA-salt rats but not areas associated with regulation of sympathetic activity. Our results do not support the hypothesis that DOCA-salt increases neuronal activity (as indicated by c-Fos immunoreactivity) of other key regions that regulate sympathetic activity. These results suggest that ICV benzamil attenuates DOCA-salt hypertension by modulation of neuroendocrine-related PVN nuclei rather than inhibition of PVN sympathetic premotor neurons in the PVN and rostroventrolateral medulla. PMID- 20926763 TI - Gut T1R3 sweet taste receptors do not mediate sucrose-conditioned flavor preferences in mice. AB - Most mammals prefer the sweet taste of sugars, which is mediated by the heterodimeric T1R2+T1R3 taste receptor. Sugar appetite is also enhanced by the post-oral reinforcing actions of the nutrient in the gut. Here, we examined the contribution of gut T1R3 (either alone or as part of the T1R3+T1R3 receptor) to post-oral sugar reinforcement using a flavor-conditioning paradigm. We trained mice to associate consumption of a flavored solution (CS+) with intragastric (IG) infusions of a sweetener, and a different flavored solution (CS-) with IG infusions of water (23 h/day); then, we measured preference in a CS+ vs. CS- choice test. In experiment 1, we predicted that if activation of gut T1R3 mediates sugar reinforcement, then IG infusions of a nutritive (sucrose) or nonnutritive (sucralose) ligand for this receptor should condition a preference for the CS+ in B6 wild-type (WT) mice. While the mice that received IG sucrose infusions developed a strong preference for the CS+, those that received IG sucralose infusions developed a weak avoidance of the CS+. In experiment 2, we used T1R3 knockout (KO) mice to examine the necessity of gut T1R2+T1R3 receptors for conditioned flavor preferences. If intact gut T1R3 (or T1R2+T1R3) receptors are necessary for flavor-sugar conditioning, then T1R3 KO mice should not develop a sugar-conditioned flavor preference. We found that T1R3 KO mice, like WT mice, acquired a strong preference for the CS+ paired with IG sucrose infusions. The KO mice were also like WT mice in avoiding a CS+ flavor paired with IG sucralose infusions These findings provide clear evidence that gut T1R3 receptors are not necessary for sugar-conditioned flavor preferences or sucralose-induced flavor avoidance in mice. PMID- 20926764 TI - Calcium handling in zebrafish ventricular myocytes. AB - The zebrafish is an important model for the study of vertebrate cardiac development with a rich array of genetic mutations and biological reagents for functional interrogation. The similarity of the zebrafish (Danio rerio) cardiac action potential with that of humans further enhances the relevance of this model. In spite of this, little is known about excitation-contraction coupling in the zebrafish heart. To address this issue, adult zebrafish cardiomyocytes were isolated by enzymatic perfusion of the cannulated ventricle and were subjected to amphotericin-perforated patch-clamp technique, confocal calcium imaging, and/or measurements of cell shortening. Simultaneous recordings of the voltage dependence of the L-type calcium current (I(Ca,L)) amplitude and cell shortening showed a typical bell-shaped current-voltage (I-V) relationship for I(Ca,L) with a maximum at +10 mV, whereas calcium transients and cell shortening showed a monophasic increase with membrane depolarization that reached a plateau at membrane potentials above +20 mV. Values of I(Ca,L) were 53, 100, and 17% of maximum at -20, +10, and +40 mV, while the corresponding calcium transient amplitudes were 64, 92, and 98% and cell shortening values were 62, 95, and 96% of maximum, respectively, suggesting that I(Ca,L) is the major contributor to the activation of contraction at voltages below +10 mV, whereas the contribution of reverse-mode Na/Ca exchange becomes increasingly more important at membrane potentials above +10 mV. Comparison of the recovery of I(Ca,L) from acute and steady-state inactivation showed that reduction of I(Ca,L) upon elevation of the stimulation frequency is primarily due to calcium-dependent I(Ca,L) inactivation. In conclusion, we demonstrate that a large yield of healthy atrial and ventricular myocytes can be obtained by enzymatic perfusion of the cannulated zebrafish heart. Moreover, zebrafish ventricular myocytes differed from that of large mammals by having larger I(Ca,L) density and a monophasically increasing contraction-voltage relationship, suggesting that caution should be taken upon extrapolation of the functional impact of mutations on calcium handling and contraction in zebrafish cardiomyocytes. PMID- 20926765 TI - Catestatin in rat RVLM is sympathoexcitatory, increases barosensitivity, and attenuates chemosensitivity and the somatosympathetic reflex. AB - The fundamental role and corollary effects of neuropeptides that govern cardiorespiratory control in the brain stem are poorly understood. One such regulatory peptide, catestatin [Cts, human chromogranin A-(352-372)], noncompetitively inhibits nicotinic-cholinergic-stimulated catecholamine release. Previously, we demonstrated the presence of chromogranin A mRNA in brain stem neurons that are important for the maintenance of arterial pressure. In the present study, using immunofluorescence histochemistry, we show that Cts immunoreactivity is colocalized with tyrosine hydroxylase in C1 neurons of the rostral ventrolateral medulla (RVLM, n = 3). Furthermore, we investigated the effects of Cts on resting blood pressure, splanchnic sympathetic nerve activity, phrenic nerve activity, heart rate, and adaptive reflexes. Cts (1 mM in 50 nl or 100 MUM in 50-100 nl) was microinjected into the RVLM in urethane-anesthetized, vagotomized, ventilated Sprague-Dawley rats (n = 19). Cardiovascular responses to stimulation of carotid baroreceptors, peripheral chemoreceptors, and the sciatic nerve (somatosympathetic reflex) were analyzed. Cts (1 mM in 50 nl) increased resting arterial pressure (28 +/- 3 mmHg at 2 min postinjection), sympathetic nerve activity (15 +/- 3% at 2 min postinjection), and phrenic discharge amplitude (31 +/- 4% at 10 min postinjection). Cts increased sympathetic barosensitivity 40% (slope increased from -0.05 +/- 0.01 before Cts to -0.07 +/- 0.01 after Cts) and attenuated the somatosympathetic reflex [1st peak: 36% (from 132 +/- 32.1 to 84.0 +/- 17.0 MUV); 2nd peak: 44% (from 65.1 +/- 21.4 to 36.6 +/- 14.1 MUV)] and chemoreflex (blood pressure response to anoxia decreased 55%, sympathetic response decreased 46%). The results suggest that Cts activates sympathoexcitatory bulbospinal neurons in the RVLM and plays an important regulatory role in adaptive reflexes. PMID- 20926766 TI - Tetrahydrobiopterin does not affect end-organ responsiveness to norepinephrine mediated vasoconstriction in aged skin. AB - We have recently demonstrated that tetrahydrobiopterin (BH(4)) augments reflex vasoconstriction (VC) in aged skin. Although this appears to occur through its role in norepinephrine (NE) biosynthesis, the extent with which vascular mechanisms are affected are unknown. We hypothesized that localized BH(4) supplementation would not affect the VC response to exogenous NE when sympathetic nerves were blocked. Two microdialysis fibers were placed in bretylium tosylate pretreated (presynaptically blocks neurotransmitter release from sympathetic adrenergic nerve terminals; iontophoresis, 200 MUA for 20 min) 3-cm(2) forearm skin of 10 young (Y) and 10 older (O) subjects for perfusion of 1) Ringer (control) and 2) 5 mM BH(4). While local skin temperature was clamped at 34 degrees C, six concentrations of NE (10(-12), 10(-10), 10(-8), 10(-6), 10(-4), 10(-2) M) were infused at each drug-treated site. Cutaneous vascular conductance (CVC) was calculated (CVC = laser Doppler flux/mean arterial pressure) and normalized to baseline (%DeltaCVC(base)). Despite prejunctional adrenergic blockade, NE-mediated VC was blunted in aged skin at each NE dose (10(-12): -12 +/- 2 vs. -21 +/- 2; 10(-10): -15 +/- 2 vs. -27 +/- 1; 10(-8): -22 +/- 2 vs. -32 +/- 2; 10(-6): -27 +/- 2 vs. -38 +/- 1; 10(-4): -52 +/- 3 vs. -66 +/- 5; 10(-2): 62 +/- 3 vs. -75 +/- 4%DeltaCVC(base); P < 0.01), and this response was not affected by pretreatment with BH(4) (P > 0.05). Localized BH(4) did not affect end-organ responsiveness to exogenous NE, suggesting that the effects of BH(4) on cutaneous VC are primarily isolated to the NE biosynthetic pathway. PMID- 20926767 TI - Late-gestational systemic hypoxia leads to a similar early gene response in mouse placenta and developing brain. AB - Late-gestational intrauterine hypoxia represents a well-known risk factor of acquired perinatal brain injury. Cell type and age-specific sensitivity of hypoxia-responsive genes to low-oxygen partial pressure is to be considered in the screening for early indicators of fetoplacental tissue hypoxia. To identify early hypoxia-induced alterations in gene expression during late-gestational hypoxia (6% O(2), 6 h; gestational day 20) we compared primary mouse placenta and brain transcriptomes using high-density oligonucleotide microarrays. Upregulation of candidate marker genes for hypoxia was confirmed by quantitative RT-PCR and immunohistochemistry. Both developing brain and placenta were highly responsive to systemic hypoxia at the level of gene expression involving hypoxia-inducible transcription factor (HIF)-dependent genes and immediate early genes (IEG) (Fos, Jun, Egr1, Bhlhb2), apoptosis-promoting factors (Bnip3, Dusp1, Ier3) that were all upregulated, and genes modulating RNA binding and translation (Rbm3, Thap2, Lig4, Rbm12b) that mainly were downregulated. Functional activity of the HIF system was obvious from elevated expression of various known HIF target genes (Adm, Vegf, Hk2, Pdk1, Bnip3, Ier3, Dusp-1), indicating immediate availability among early response to acute hypoxia. In addition, genes not yet described as being hypoxia related were identified that are involved in angiogenesis/cell differentiation (Gna13, Gab2), mRNA processing, and embryonic development. RT-PCR of placenta and brain tissues confirmed upregulation of selected HIF target genes and IEG. These data indicate that the early hypoxia-induced genomic response of the placenta mirrors that of developing brain in a temporally parallel manner. Our observations implicate future diagnostic options to identify fetal and cerebral tissue hypoxia. PMID- 20926768 TI - Effect of the estrous cycle and surgical ovariectomy on energy balance, fuel utilization, and physical activity in lean and obese female rats. AB - This study presents an in-depth analysis of the effects of obesity on energy balance (EB) and fuel utilization in adult female rats, over the estrous cycle and immediately after surgical ovariectomy (OVX), to model pre- and postmenopausal states, respectively. Female Wistar rats were fed a high-fat (46%) diet for 16 wk to produce mature lean and obese animals. Stage of estrous was identified by daily vaginal lavage, while energy intake (EI), total energy expenditure (TEE), and fuel utilization were monitored in a multichamber indirect calorimeter and activity was monitored by infrared beam breaks. Metabolic monitoring studies were repeated during the 3-wk period of rapid OVX-induced weight gain. Component analysis of TEE was performed to determine the nonresting and resting portions of energy expenditure. Obesity was associated with a greater fluctuation in EB across the estrous cycle. Cycling obese rats were less active, expended more energy per movement, and oxidized more carbohydrate than lean rats. The changes in EB over the cycle in lean and obese rats were driven by changes in EI. Finally, OVX induced a large positive energy imbalance in obese and lean rats. This resulted primarily from an increase in EI in both groups, with little change in TEE following OVX. These observations reveal a dominant effect of obesity on EB, fuel utilization, and activity levels in cycling rats, which has implications for studies focused on obesity and EB in female rodents. PMID- 20926769 TI - Computational fluid dynamic analysis of flow velocity waveform notching in umbilical arteries. AB - Umbilical artery Doppler velocimetry waveform notching has long been associated with umbilical cord abnormalities, such as distortion, torsion, and/or compression (i.e., constriction). The physical mechanism by which the notching occurs has not been elucidated. Flow velocity waveforms (FVWs) from two dimensional pulsatile flows in a constricted channel approximating a compressed umbilical cord are analyzed, leading to a clear relationship between the notching and the constriction. Two flows with an asymmetric, semi-elliptical constriction are computed using a stabilized finite-element method. In one case, the constriction blocks 75% of the flow passage, and in the other the constriction blocks 85%. Channel width and prescribed flow rates at the channel inflow are consistent with typical cord diameters and flow rates reported in the literature. Computational results indicate that waveform notching is caused by flow separation induced by the constriction, giving rise to a vortex (core) wave and associated eddies. Notching in FVWs based on centerline velocity (centerline FVW) is directly related to the passage of an eddy over the point of measurement on the centerline. Notching in FVWs based on maximum cross-sectional velocity (envelope FVW) is directly related to acceleration and deceleration of the fluid along the vortex wave. Results show that notching in envelope FVW is not present in flows with less than a 75% constriction. Furthermore, notching disappears as the vortex wave is attenuated at distances downstream of the constriction. In the flows with 75 and 85% constriction, notching of the envelope FVW disappears at ~3.8 and ~4.3 cm (respectively) downstream of the constriction. These results are of significant medical importance, given that envelope FVW is typically measured by commercial Doppler systems. PMID- 20926770 TI - Inhibition of cell adhesion by anti-P-selectin aptamer: a new potential therapeutic agent for sickle cell disease. AB - Adhesive interactions between circulating sickle red blood cells (RBCs), leukocytes, and endothelial cells are major pathophysiologic events in sickle cell disease (SCD). To develop new therapeutics that efficiently inhibit adhesive interactions, we generated an anti-P-selectin aptamer and examined its effects on cell adhesion using knockout-transgenic SCD model mice. Aptamers, single-stranded oligonucleotides that bind molecular targets with high affinity and specificity, are emerging as new therapeutics for cardiovascular and hematologic disorders. In vitro studies found that the anti-P-selectin aptamer exhibits high specificity to mouse P-selectin but not other selectins. SCD mice were injected with the anti-P selectin aptamer, and cell adhesion was observed under hypoxia. The anti-P selectin aptamer inhibited the adhesion of sickle RBCs and leukocytes to endothelial cells by 90% and 80%, respectively. The anti-P-selectin aptamer also increased microvascular flow velocities and reduced the leukocyte rolling flux. SCD mice treated with the anti-P-selectin aptamer demonstrated a reduced mortality rate associated with the experimental procedures compared with control mice. These results demonstrate that anti-P-selectin aptamer efficiently inhibits the adhesion of both sickle RBCs and leukocytes to endothelial cells in SCD model mice, suggesting a critical role for P-selectin in cell adhesion. Anti-P-selectin aptamer may be useful as a novel therapeutic agent for SCD. PMID- 20926771 TI - X-linked lymphoproliferative disease due to SAP/SH2D1A deficiency: a multicenter study on the manifestations, management and outcome of the disease. AB - X-linked lymphoproliferative disease (XLP1) is a rare immunodeficiency characterized by severe immune dysregulation and caused by mutations in the SH2D1A/SAP gene. Clinical manifestations are varied and include hemophagocytic lymphohistiocytosis (HLH), lymphoma and dysgammaglobulinemia, often triggered by Epstein-Barr virus infection. Historical data published before improved treatment regimens shows very poor outcome. We describe a large cohort of 91 genetically defined XLP1 patients collected from centers worldwide and report characteristics and outcome data for 43 patients receiving hematopoietic stem cell transplant (HSCT) and 48 untransplanted patients. The advent of better treatment strategies for HLH and malignancy has greatly reduced mortality for these patients, but HLH still remains the most severe feature of XLP1. Survival after allogeneic HSCT is 81.4% with good immune reconstitution in the large majority of patients and little evidence of posttransplant lymphoproliferative disease. However, survival falls to 50% in patients with HLH as a feature of disease. Untransplanted patients have an overall survival of 62.5% with the majority on immunoglobulin replacement therapy, but the outcome for those untransplanted after HLH is extremely poor (18.8%). HSCT should be undertaken in all patients with HLH, because outcome without transplant is extremely poor. The outcome of HSCT for other manifestations of XLP1 is very good, and if HSCT is not undertaken immediately, patients must be monitored closely for evidence of disease progression. PMID- 20926772 TI - High doses of mother's lymphocyte infusion to treat EBV-positive T-cell lymphoproliferative disorders in childhood. AB - Donor lymphocyte infusion is an alternative treatment for Epstein-Barr virus (EBV)-associated lymphoproliferative disorders (LPDs) but with risk of graft versus-host diseases (GVHDs). According to the fetal-maternal microchimerism tolerance, we assumed that maternal lymphocyte infusion may be effective without causing GVHD. In 54 cases when a child required cytotherapy or hematopoietic stem cell transplantation, we studied the mother for child-mother microchimerism with use of insertion-deletion polymorphisms as allogeneic markers and a combination of nested polymerase chain reaction (PCR) and real-time quantitative PCR. Thirteen mothers were child-microchimerism-positive at the ratio of 10(-5)-10( 3). Among them, 5 children had non-transplant-associated, EBV(+) T-cell LPD. In these 5 cases, high doses of human leukocyte antigen-haploidentical maternal peripheral blood mononuclear cells (> 10(8)/kg/infusion) were infused 1-4 times. Symptoms of all 5 patients improved between 3 and 10 days after the infusion; thereafter, 3 cases showed complete remission for 6-18 months without further therapy and 2 had partial remission. During the period of observation, none developed obvious GVHD. By quantitative PCR, in some patients maternal cells were found to be eliminated or decreased after infusions, indicating existence of host versus-graft reaction. We suggest that high doses of mother's lymphocyte infusion may be an effective and safe treatment for non-transplant-associated EBV(+) T cell LPD. PMID- 20926773 TI - Secondary solid cancers after allogeneic hematopoietic cell transplantation using busulfan-cyclophosphamide conditioning. AB - Risks of secondary solid cancers among allogeneic hematopoietic cell transplant (HCT) recipients who receive conditioning without total body irradiation are not well known. We evaluated the incidence and risk factors for solid cancers after HCT using high-dose busulfan-cyclophosphamide conditioning in 4318 recipients of first allogeneic HCT for acute myeloid leukemia in first complete remission (N = 1742) and chronic myeloid leukemia in first chronic phase (N = 2576). Our cohort represented 22 041 person-years at risk. Sixty-six solid cancers were reported at a median of 6 years after HCT. The cumulative-incidence of solid cancers at 5 and 10 years after HCT was 0.6% and 1.2% among acute myeloid leukemia and 0.9% and 2.4% among chronic myeloid leukemia patients. In comparison to general population incidence rates, HCT recipients had 1.4* higher than expected rate of invasive solid cancers (95% confidence interval, 1.08-1.79, P = .01). Significantly elevated risks were observed for tumors of the oral cavity, esophagus, lung, soft tissue, and brain. Chronic graft-versus-host disease was an independent risk factor for all solid cancers, and especially cancers of the oral cavity. Recipients of allogeneic HCT using busulfan-cyclophosphamide conditioning are at risk for developing solid cancers. Their incidence continues to increase with time, and lifelong cancer surveillance is warranted in this population. PMID- 20926774 TI - The role of HMGB1 in efferocytosis: when the dead go unburied. Focus on "HMGB1 inhibits macrophage activity in efferocytosis through binding to the alphavbeta3 integrin". PMID- 20926775 TI - Inhibition of voltage-gated K+ channels in dendritic cells by rapamycin. AB - Rapamycin, an inhibitor of the serine/threonine kinase mammalian target of rapamycin (mTOR), is a widely used immunosuppressive drug. Rapamycin affects the function of dendritic cells (DCs), antigen-presenting cells participating in the initiation of primary immune responses and the establishment of immunological memory. Voltage-gated K(+) (Kv) channels are expressed in and impact on the function of DCs. The present study explored whether rapamycin influences Kv channels in DCs. To this end, DCs were isolated from murine bone marrow and ion channel activity was determined by whole cell patch clamp. To more directly analyze an effect of mTOR on Kv channel activity, Kv1.3 and Kv1.5 were expressed in Xenopus oocytes with or without the additional expression of mTOR and voltage gated currents were determined by dual-electrode voltage clamp. As a result, preincubation with rapamycin (0-50 nM) led to a gradual decline of Kv currents in DCs, reaching statistical significance within 6 h and 50 nM of rapamycin. Rapamycin accelerated Kv channel inactivation. Coexpression of mTOR upregulated Kv1.3 and Kv1.5 currents in Xenopus oocytes. Furthermore, mTOR accelerated Kv1.3 channel activation and slowed down Kv1.3 channel inactivation. In conclusion, mTOR stimulates Kv channels, an effect contributing to the immunomodulating properties of rapamycin in DCs. PMID- 20926776 TI - Roles and controls of mTOR in the heart. Focus on "mTOR attenuates the inflammatory response in cardiomyocytes and prevents cardiac dysfunction in pathological hypertrophy". PMID- 20926777 TI - Identification and functional implication of a Rho kinase-dependent moesin-EBP50 interaction in noradrenaline-stimulated artery. AB - Ezrin, radixin, and moesin (ERM) proteins are known to be substrates of Rho kinase (ROCK), a key player in vascular smooth muscle regulation. Their function in arteries remains to be elucidated. The objective of the present study was to investigate ERM phosphorylation and function in rat aorta and mesenteric artery and the influence of ERM-binding phosphoprotein 50 (EBP50), a scaffold partner of ERM proteins in several cell types. In isolated arteries, ERM proteins are phosphorylated by PKC and ROCK with different kinetics after either agonist stimulation or KCl-induced depolarization. Immunoprecipitation of EBP50 in noradrenaline-stimulated arteries allowed identification of its interaction with moesin and several other proteins involved in cytoskeleton regulation. This interaction was inhibited by Y27632, a ROCK inhibitor. Moesin or EBP50 depletion after small interfering RNA transfection by reverse permeabilization in intact mesenteric arteries both potentiated the contractility in response to agonist stimulation without any effect on contractile response induced by high KCl. This effect was preserved in ionomycin-permeabilized arteries. These results indicate that, in agonist-stimulated arteries, the activation of ROCK leads to the binding of moesin to EBP50, which interacts with several components of the cytoskeleton, resulting in a decrease in the contractile response. PMID- 20926778 TI - Changes in mitochondrial surface charge mediate recruitment of signaling molecules during apoptosis. AB - Electrostatic interactions with negative lipids contribute to the subcellular localization of polycationic proteins. In situ measurements using cytosolic probes of surface charge indicate that normal mitochondria are not noticeably electronegative. However, during apoptosis mitochondria accrue negative charge and acquire the ability to attract cationic proteins, including K-Ras. The marked increase in the surface charge of mitochondria occurs early in apoptosis, preceding depolarization of their inner membrane, cytochrome c release, and flipping of phosphatidylserine across the plasmalemma. Using novel biosensors, we determined that the increased electronegativity of the mitochondria coincided with and was likely attributable to increased exposure of cardiolipin, which is dianionic. Ectopic (over)expression of cardiolipin-binding proteins precluded the increase in surface charge and inhibited apoptosis, implying that mitochondrial exposure of negatively charged lipids is required for progression of programmed cell death. PMID- 20926779 TI - Thyroid hormone inhibits ERK phosphorylation in pressure overload-induced hypertrophied mouse hearts through a receptor-mediated mechanism. AB - Pressure overload-induced cardiac hypertrophy results in a pathological type of hypertrophy with activation of signaling cascades like the extracellular signal regulated kinase (ERK) pathway, which promotes negative cardiac remodeling and decreased contractile function. In contrast, thyroid hormone mediates a physiological type of hypertrophy resulting in enhanced contractile function. In addition, thyroid hormone action is diminished in pressure overload-induced cardiac hypertrophy. We hypothesized that thyroid hormone status modulates ERK activity and that administration of thyroid hormone could alter the activity of this kinase in cardiac hypertrophy induced by pressure overload. ERK is activated by phosphorylation; accordingly, we investigated phosphorylation of ERK in hearts of control, hypothyroid, and hyperthyroid mice. In addition, the effect of T3 treatment on ERK phosphorylation in hypertrophied hearts from transverse aortic constricted (TAC) mice was investigated. Results showed that phosphorylated ERK (p-ERK) was decreased by 25% in hyperthyroid mice. In contrast, hypothyroid mice presented increased p-ERK by 80%. TAC mice presented a greater than fourfold increase of p-ERK compared with control mice. Interestingly, T3 administration dramatically canceled TAC-induced ERK phosphorylation (36% lower compared with control). Raf-1 is upstream of the ERK pathway. TAC mice presented a 45% increase in phospho-Raf-1 (Ser338). T3 treatment inhibited this effect of pressure overload and further decreased p-Raf-1 (Ser338) by 37%, compared with control. Overexpression of thyroid hormone receptor-alpha in cultured cardiomyocytes potentiated the inhibitory effect of T3 on ERK phosphorylation. We concluded that thyroid hormone has an inhibitory effect on the Raf-1/ERK pathway. Furthermore, treatment of TAC mice with T3 inhibited Raf-1/ERK pathway by a thyroid hormone receptor-dependent mechanism. PMID- 20926780 TI - Rab5a-mediated localization of claudin-1 is regulated by proteasomes in endothelial cells. AB - Tight junctions composed of transmembrane proteins, including claudin, occludin, and tricellulin, and peripheral membrane proteins are a major barrier to endothelial permeability, whereas the role of claudin in the regulation of tight junction permeability in nonneural endothelial cells is unclear. This study demonstrates that claudin-1 is dominantly expressed and depletion of claudin-1 using small interfering RNA (siRNA) increased tight junction permeability in EA hy.926 cells, indicating that claudin-1 is a crucial regulator of endothelial tight junction permeability. The ubiquitin-proteasome system has been implicated in the regulation of endocytotic trafficking of plasma membrane proteins. Therefore, the involvement of proteasomes in the localization of claudin-1 was investigated by pharmacological and genetic inhibition of proteasomes using a proteasome inhibitor, N-acetyl-Leu-Leu-Nle-CHO, and siRNA against the beta5 subunit of the 20S proteasome, respectively. Claudin-1 was localized at cell-cell contact sites in control cells. Claudin-1 was localized in the cytoplasm in association with Rab5a and EEA-1, a marker of early endosome, following inhibition of proteasomes. Depletion of Rab5a using siRNA reversed the localization of claudin-1 induced by inhibition of proteasomes. These data suggest that proteasomes regulate claudin-1 localization at the plasma membrane, which changes upon proteasomal inhibition to a Rab5a-mediated endosomal localization. PMID- 20926782 TI - Regulation of CFTR chloride channel macroscopic conductance by extracellular bicarbonate. AB - The CFTR contributes to Cl- and HCO3- transport across epithelial cell apical membranes. The extracellular face of CFTR is exposed to varying concentrations of Cl- and HCO3- in epithelial tissues, and there is evidence that CFTR is sensitive to changes in extracellular anion concentrations. Here we present functional evidence that extracellular Cl- and HCO3- regulate anion conduction in open CFTR channels. Using cell-attached and inside-out patch-clamp recordings from constitutively active mutant E1371Q-CFTR channels, we show that voltage-dependent inhibition of CFTR currents in intact cells is significantly stronger when the extracellular solution contains HCO3- than when it contains Cl-. This difference appears to reflect differences in the ability of extracellular HCO3- and Cl- to interact with and repel intracellular blocking anions from the pore. Strong block by endogenous cytosolic anions leading to reduced CFTR channel currents in intact cells occurs at physiologically relevant HCO3- concentrations and membrane potentials and can result in up to ~50% inhibition of current amplitude. We propose that channel block by cytosolic anions is a previously unrecognized, physiologically relevant mechanism of channel regulation that confers on CFTR channels sensitivity to different anions in the extracellular fluid. We further suggest that this anion sensitivity represents a feedback mechanism by which CFTR dependent anion secretion could be regulated by the composition of the secretions themselves. Implications for the mechanism and regulation of CFTR-dependent secretion in epithelial tissues are discussed. PMID- 20926781 TI - Role of epithelial HCO3- transport in mucin secretion: lessons from cystic fibrosis. AB - The invitation to present the 2010 Hans Ussing lecture for the Epithelial Transport Group of the American Physiological Society offered me a unique, special, and very surprising opportunity to join in saluting a man whom I met only once, but whose work was the basis, not only for my career, but also for finding the molecular defect in the inherited disease cystic fibrosis (CF). In this context, I will venture to make the tribute with a new explanation of why a mutation in a single gene that codes for an anion channel can cause devastation of multiple epithelial systems with pathogenic mucus. In so doing, I hope to raise awareness of a new role for that peculiar anion around which so much physiology revolves, HCO(3)(-). I begin by introducing CF pathology as I question the name of the disease as well as the prevalent view of the basis of its pathology by considering: 1) mucus, 2) salt, and 3) HCO(3)(-). I then present recent data showing that HCO(3)(-) is required for normal mucus discharge, and I will close with conjecture as to how HCO(3)(-) may support mucus discharge and why the failure to transport this electrolyte is pathogenic in CF. PMID- 20926783 TI - Pathways for ATP release by bovine ciliary epithelial cells, the initial step in purinergic regulation of aqueous humor inflow. AB - ATP release by nonpigmented (NPE) and pigmented (PE) ciliary epithelial cells is the enabling step in purinergic regulation of aqueous humor formation, but the release pathways are unknown. We measured ATP release from primary cultures of bovine mixed NPE and PE (bCE) cells and transformed bovine NPE and PE cells, using the luciferin-luciferase reaction. Hypotonicity-triggered bCE ATP release was inhibited by the relatively selective blocker of pannexin-1 (PX1) hemichannels (probenecid, 1 mM, 47 +/- 2%), by a connexin inhibitor (heptanol, 1 mM, 49 +/- 4%), and by an inhibitor of vesicular release (bafilomycin A1, 25 +/- 2%), but not by the P2X(7) receptor (P2RX(7)) antagonist KN-62. Bafilomycin A1 acts by reducing the driving force for uptake of ATP from the cytosol into vesicles. The reducing agent dithiothreitol reduced probenecid-blockable ATP release. Similar results were obtained with NPE and PE cell lines. Pannexins PX1 3, connexins Cx43 and Cx40, and P2RX(7) were identified in native cells and cell lines by RT-PCR. PX1 mRNA expression was confirmed by Northern blots; its quantitative expression was comparable to that of Cx43 by real-time PCR. Heterologous expression of bovine PX1 in HEK293T cells enhanced swelling activated ATP release, inhibitable by probenecid. We conclude that P2RX(7) independent PX1 hemichannels, Cx hemichannels, and vesicular release contribute comparably to swelling-triggered ATP release. The relatively large response to dithiothreitol raises the possibility that the oxidation-reduction state is a substantial regulator of PX1-mediated ATP release from bovine ciliary epithelial cells. PMID- 20926784 TI - Drug-induced deactivation of inhibitory networks predicts pathological gambling in PD. AB - OBJECTIVE: Some patients with Parkinson disease (PD) develop pathological gambling when treated with dopamine agonists (DAs). However, little is known about DA-induced changes in neuronal networks that may underpin this drug-induced change in behavior in vulnerable individuals. In this case-control study, we aimed to investigate DA-induced changes in brain activity that may differentiate patients with PD with DA-induced pathological gambling (gamblers) from patients with PD without such a history (controls). METHODS: Following overnight withdrawal of antiparkinsonian medication, patients were studied with H2(15)O PET before and after administration of DA (3 mg apomorphine) to measure changes in regional cerebral blood flow as an index of regional brain activity during a card selection game with probabilistic feedback. RESULTS: We observed that the direction of DA-related activity change in brain areas that are implicated in impulse control and response inhibition (lateral orbitofrontal cortex, rostral cingulate zone, amygdala, external pallidum) distinguished gamblers from controls. DA significantly increased activity in these areas in controls, while gamblers showed a significant DA-induced reduction of activity. CONCLUSIONS: We propose that in vulnerable patients with PD, DAs produce an abnormal neuronal pattern that resembles those found in nonparkinsonian pathological gambling and drug addiction. DA-induced disruption of inhibitory key functions--outcome monitoring (rostral cingulate zone), acquisition and retention of negative action outcome associations (amygdala and lateral orbitofrontal cortex)--together with restricted access of those areas to executive control (external pallidum)--may well explain loss of impulse control and response inhibition in vulnerable patients with PD, thereby fostering the development of pathological gambling. PMID- 20926785 TI - Pathological gambling in PD: did the devil make me do it? PMID- 20926786 TI - Cost-effectiveness of multimodal CT for evaluating acute stroke. AB - OBJECTIVE: Multimodal CT, including noncontrast CT (NCCT), CT with contrast, CT angiography (CTA), and perfusion CT (CTP), is increasingly used in acute stroke patients to identify candidates for endovascular therapy. Our goal is to explore the cost-effectiveness of multimodal CT as a diagnostic test. METHODS: A Markov model compared multimodal CT to NCCT in a hypothetical cohort of nonhemorrhagic stroke patients presenting within 3 hours of symptom onset who were potential IV tPA candidates. Patients who failed to improve after IV tPA or in whom IV tPA was contraindicated were candidates for endovascular therapy. Direct costs (2008 USD), outcomes, and probabilities were obtained from the literature. RESULTS: For the 3-month time horizon, multimodal CT had lower costs (-$1,716), had greater quality-adjusted life-years (QALYs, 0.004), and was the cost-effective choice 100% of the time for a willingness-to-pay of $100,000/QALY (probabilistic sensitivity analysis). The number needed to screen with multimodal CT to avoid 1 diagnostic angiogram was 2. Over a lifetime, multimodal CT had lower costs ( $2,058), had greater QALYs (0.008), and was cost-effective, with a 90.1% likelihood, for a willingness-to-pay of $100,000/QALY. CONCLUSIONS: Multimodal CT appears to be a cost-saving screening tool over the short term. However, additional data regarding clinical outcomes following multimodal CT-guided intra arterial treatment are needed before the long-term cost-effectiveness can be suitably addressed. This analysis can be incorporated into future discussions of multimodal CT as a diagnostic test for unselected patients, within and beyond the 3-hour IV tPA time window. PMID- 20926787 TI - Removing interictal fast ripples on electrocorticography linked with seizure freedom in children. AB - BACKGROUND: Fast ripples (FR, 250-500 Hz) detected with chronic intracranial electrodes are proposed biomarkers of epileptogenesis. This study determined whether resection of FR-containing neocortex recorded during intraoperative electrocorticography (ECoG) was associated with postoperative seizure freedom in pediatric patients with mostly extratemporal lesions. METHODS: FRs were retrospectively reviewed in 30 consecutive pediatric cases. ECoGs were recorded at 2,000 Hz sampling rate and visually inspected for FR, with reviewer blinded to the resection and outcome. RESULTS: Average age at surgery was 9.1 +/- 6.7 years, ECoG duration was 11.8 +/- 8.1 minutes, and postoperative follow-up was 27 +/- 4 months. FRs were undetected in 6 ECoGs with remote or extensive lesions. FR episodes (n = 273) were identified in ECoGs from 24 patients, and in 64% FRs were independent of spikes, sharp waves, voltage attenuation, and paroxysmal fast activity. Of these 24 children, FR-containing cortex was removed in 19 and all became seizure-free, including 1 child after a second surgery. The remaining 5 children had incomplete FR resection and all continued with seizures postoperatively. In 2 ECoGs, the location of electrographic seizures matched FR location. FR-containing cortex was found outside of MRI and FDG-PET abnormalities in 6 children. CONCLUSION: FRs were detected during intraoperative ECoG in 80% of pediatric epilepsy cases, and complete resection of FR cortex correlated with postoperative seizure freedom. These findings support the view that interictal FRs are excellent surrogate markers of epileptogenesis, can be recorded during brief ECoG, and could be used to guide future surgical resections in children. PMID- 20926788 TI - Impaired ATP kinetics in failing in vivo mouse heart. AB - BACKGROUND: The hypothesis that the failing heart may be energy-starved is supported in part by observations of reduced rates of adenosine 5'-triphosphate (ATP) synthesis through the creatine kinase (CK) reaction, the primary myocardial energy reservoir, in patients with heart failure (HF). Although murine models have been used to probe HF pathophysiology, it has not been possible to noninvasively measure the rate of ATP synthesis through CK in the in vivo mouse heart. The purpose of this work was to exploit noninvasive spatially localized magnetic resonance spectroscopy techniques to measure ATP flux through CK in in vivo mouse hearts and determine the extent of any reductions in murine HF. METHODS AND RESULTS: The Triple Repetition Time Saturation Transfer (TRiST) magnetic resonance spectroscopy method of measuring ATP kinetics was first validated in skeletal muscle, rendering similar results to conventional saturation transfer magnetic resonance spectroscopy. In normal mouse hearts, the in vivo CK pseudo-first-order-rate constant, k(F), was 0.32+/-0.03 s(-1) (mean+/ SD) and the rate of ATP synthesis through CK was 3.16+/-0.47 MUmol/g/s. Thoracic aortic constriction reduced k(F) by 31% (0.23+/-0.03 s(-1), P<0.0001) and ATP synthesis through CK by 51% (1.54+/-0.25 MUmol/g/s, P<0.0001), values analogous to those in failing human hearts. CONCLUSIONS: Despite the small size and high murine heart rate, the ATP synthesis rate through CK is similar in vivo in murine and human hearts and comparably reduced in HF. Because murine thoracic aortic constriction shares fundamental energetic similarities with human HF, this model and new magnetic resonance spectroscopy approach promise a powerful means to noninvasively probe altered energetics in HF. PMID- 20926789 TI - IL-2 and IL-4 stimulate MEK1 expression and contribute to T cell resistance against suppression by TGF-beta and IL-10 in asthma. AB - The T cell-driven airway inflammation in chronic asthma is uninhibited and sustained. We examined the resistance of T cells from asthmatic patients against suppression by TGF-beta, IL-10 and glucocorticoids and explored its signaling mechanism. CD4(+)CD25(-) T cells from allergic asthmatic subjects demonstrated increased TCR-stimulated proliferation as compared with healthy and chronic obstructive pulmonary disease controls. This proliferation was resistant to inhibition by TGF-beta, IL-10, and dexamethasone and to anergy induction. CD4 T cells from asthmatic patients, but not chronic obstructive pulmonary disease, allergic rhinitis, and healthy subjects, showed increased expression of MEK1, heightened phosphorylation of ERK1/2, and increased levels of c-Fos. IL-2 and IL 4 stimulated the expression of MEK1 and c-Fos and induced T cell resistance. The inhibition of MEK1 reversed, whereas induced expression of c-Fos and JunB promoted T cell resistance against TGF-beta- and IL-10-mediated suppression. We have uncovered an IL-2- and IL-4-driven MEK1 induction mechanism that results in heightened ERK1/2 activation in asthmatic T cells and make them resistant to certain inhibitory mechanisms. PMID- 20926790 TI - Blockade of programmed death-1 pathway rescues the effector function of tumor infiltrating T cells and enhances the antitumor efficacy of lentivector immunization. AB - Despite intensive effort, the antitumor efficacy of tumor vaccines remains limited in treating established tumors regardless of the potent systemic tumor specific immune response and the increases of tumor infiltration of T effector cells. In the current study, we demonstrated that although lentivector (lv) immunization markedly increased Ag-dependent tumor infiltration of CD8 and CD4 T cells and generated Ag-specific antitumor effect, it simultaneously increased the absolute number of myeloid-derived suppressor cells and regulatory T cells in the tumor lesions. In addition, lv immunization induced expression of programmed death-ligand 1 in the tumor lesions. Furthermore, the tumor-infiltrating CD8 T cells expressed high levels of programmed death-1 and were partially dysfunctional, producing lower amounts of effector cytokines and possessing a reduced cytotoxicity. Together, these immune-suppression mechanisms in the tumor microenvironment pose a major obstacle to effective tumor immunotherapy and may explain the limited antitumor efficacy of lv immunization. The loss of effector function in the tumor microenvironment is reversible, and the effector function of CD8 T cells in the tumor could be partially rescued by blocking programmed death-1 and programmed death-ligand 1 pathway in vitro and in vivo, resulting in enhanced antitumor efficacy of lv immunization. These data suggest that immunization alone may exacerbate immune suppression in the tumor lesions and that methods to improve the tumor microenvironment and to rescue the effector functions of tumor-infiltrating T cells should be incorporated into immunization strategies to achieve enhanced antitumor efficacy. PMID- 20926791 TI - The beta-human chorionic gonadotropin-related peptide LQGV exerts anti inflammatory effects through activation of the adrenal gland and glucocorticoid receptor in C57BL/6 mice. AB - The systemic inflammatory response syndrome is a complex host response to a variety of clinical insults, generally leading to severe pathology. The human chorionic gonadotropin beta-chain-related tetrapeptide leucine-glutamine-glycine valine (LQGV) reduces hemorrhagic and LPS-induced systemic inflammatory response syndrome, but its mechanisms of action are not yet fully understood. Through the combination of in vivo, in vitro, and ex vivo approaches, we demonstrate that LQGV actively stimulates corticosterone production in mice and thereby suppresses in vivo TLR4-directed inflammation upon LPS administration. Blocking in vivo glucocorticosteroid receptor signaling reduced the prosurvival effect of LQGV. Also, upon multiple TLR activation by heat-killed Listeria monocytogenes, splenocytes from LQGV-treated mice produced significantly less TNF-alpha and IL 6, which was absent after in vitro blockage of the glucocorticosteroid receptor. Using adrenal gland and adrenal cell line cultures, we show that LQGV stimulates corticosterone production. Moreover, by using specific pharmacological inhibitors of the adrenocorticotropic hormone (ACTH) and luteinizing hormone receptors as well as of cAMP signaling, we demonstrate that LQGV stimulates the ACTH receptor. These data show that the beta-human chorionic gonadotropin-related tetrapeptide LQGV stimulates adrenal glucocorticosteroid production through activation of the ACTH receptor with consequent glucocorticoid receptor activation and immunosuppression in C57BL/6 mice. PMID- 20926792 TI - Beta7 integrin deficiency suppresses B cell homing and attenuates chronic ileitis in SAMP1/YitFc mice. AB - Lymphocyte recruitment to intestinal tissues depends on beta(7) integrins. In this study, we studied disease severity and lymphocyte recruitment into the small intestine in SAMP1/YitFc mice, which develop chronic ileitis with similarity to human Crohn's disease. To assess the role of beta(7) integrins in chronic ileitis, we generated SAMP1/YitFc lacking beta(7) integrins (SAMP1/YitFc Itgb7(-/ )) using a congenic strain developed via marker-assisted selection. We analyzed ileal inflammation in SAMP1/YitFc and SAMP1/YitFc Itgb7(-/-) mice by histopathology and the distribution of T and B lymphocytes in the mesenteric lymph nodes (MLNs) by flow cytometry. Short-term (18 h) adoptive transfer experiments were used to study the in vivo homing capacity of T and B lymphocytes. In both young (<20 wk) and old (20-50 wk) SAMP1/YitFc Itgb7(-/-) mice, ileitis was reduced by 30-50% compared with SAMP1/YitFc mice. SAMP1/YitFc Itgb7(-/-) mice showed a dramatic 67% reduction in the size of their MLNs, which was caused by a 85% reduction in lymphocyte numbers and reduced short-term B cell homing. Flow cytometric analysis revealed a highly significant decrease in the percentage of B cells in MLNs of SAMP1/YitFc Itgb7(-/-) mice. Cotransfer of SAMP1/YitFc MLN B cells but not SAMP1/YitFc Itgb7(-/-) MLN B cells along with CD4(+) T cells resulted in exacerbated ileitis severity in SCID mice. Our findings suggest that beta(7) integrins play an essential role in spontaneous chronic ileitis in vivo by promoting homing of disease-exacerbating B cells to MLNs and other intestinal tissues. PMID- 20926793 TI - Synergistic effect of IL-6 and IL-4 in driving fate revision of natural Foxp3+ regulatory T cells. AB - Expression of forkhead transcription factor Foxp3 defines a distinct lineage of naturally arising regulatory T cells (nTregs) that is segregated from effector CD4(+) T cells during early development in the thymus. It remains elusive whether nTregs can convert into effector cells by turning off their Foxp3 expression and, if so, whether Th17 is a default alternative fate choice. In this report we provide compelling evidence showing that effector T cell-polarizing cytokines IL 6 and IL-4 can act synergistically to induce marked downregulation and inactivation of Foxp3 gene expression in mouse nTregs, and consequently the loss of suppressor phenotype and functions. However, the resulting Foxp3(-) cells are not polarized and do not express IL-17 or other Th17-associated genes. Therefore, nTreg fate revision is not restricted to the Treg-Th17 axis and is likely to represent a rather broad phenomenon with divergent outcomes. PMID- 20926794 TI - Contribution of astrocyte-derived IL-15 to CD8 T cell effector functions in multiple sclerosis. AB - The contribution of local factors to the activation of immune cells infiltrating the CNS of patients with multiple sclerosis (MS) remains to be defined. The cytokine IL-15 is pivotal in the maintenance and activation of CD8 T lymphocytes, a prominent lymphocyte population found in MS lesions. We investigated whether astrocytes are a functional source of IL-15 sufficient to enhance CD8 T lymphocyte responses and whether they provide IL-15 in the inflamed CNS of patients with MS. We observed that human astrocytes in primary cultures increased surface IL-15 levels upon activation with combinations of proinflammatory cytokines. Expanded human myelin autoreactive CD8 T lymphocytes cultured with such activated astrocytes displayed elevated lytic enzyme content, NKG2D expression, and Ag-specific cytotoxicity. These functional enhancements were abrogated by anti-IL-15-blocking Abs. Immunohistochemical analysis of brain tissue sections obtained from patients with MS demonstrated colocalization for IL 15 and the astrocyte marker glial fibrillary acidic protein within white matter lesions. The majority of astrocytes (80-90%) present in demyelinating MS lesions expressed IL-15, whereas few astrocytes in normal control brain sections had detectable IL-15. IL-15 could be detected in the majority of Iba-1-expressing microglia in the control sections, albeit in lower numbers when compared with microglia/macrophages in MS lesions. Furthermore, infiltrating CD8 T lymphocytes in MS lesions were in close proximity to IL-15-expressing cells. Astrocyte production of IL-15 resulting in the activation of CD8 T lymphocytes ascribes a role for these cells as contributors to the exacerbation of tissue damage during MS pathogenesis. PMID- 20926795 TI - IL-33 mediates inflammatory responses in human lung tissue cells. AB - IL-33 is a member of the IL-1 family and mediates its biological effects via the ST2 receptor, which is selectively expressed on Th2 cells and mast cells. Although polymorphic variation in ST2 is strongly associated with asthma, it is currently unclear whether IL-33 acts directly on lung tissue cells at sites of airway remodeling. Therefore, we aimed to identify the IL-33-responsive cells among primary human lung tissue cells. ST2 mRNA was expressed in both endothelial and epithelial cells but not in fibroblasts or smooth muscle cells. Correspondingly, IL-33 promoted IL-8 production by both endothelial and epithelial cells but not by fibroblasts or smooth muscle cells. Transfection of ST2 small interference RNA into both endothelial and epithelial cells significantly reduced the IL-33-dependent upregulation of IL-8, suggesting that IL-33-mediated responses in these cells occur via the ST2 receptor. Importantly, Th2 cytokines, such as IL-4, further enhanced ST2 expression and function in both endothelial and epithelial cells. The IL-33-mediated production of IL-8 by epithelial cells was almost completely suppressed by corticosteroid treatment. In contrast, the effect of corticosteroid treatment on the IL-33-mediated responses of endothelial cells was only partial. IL-33 induced activation of both ERK and p38 MAPK in endothelial cells but only ERK in epithelial cells. p38 MAPK was required for the IL-33-mediated responses of endothelial cells, whereas ERK was required for IL-33-mediated IL-8 production by epithelial cells. Taken together, these findings suggest that IL-33-mediated inflammatory responses of lung tissue cells may be involved in the chronic allergic inflammation of the asthmatic airway. PMID- 20926796 TI - NKG2D initiates caspase-mediated CD3zeta degradation and lymphocyte receptor impairments associated with human cancer and autoimmune disease. AB - Deficiencies of the T cell and NK cell CD3zeta signaling adapter protein in patients with cancer and autoimmune diseases are well documented, but mechanistic explanations are fragmentary. The stimulatory NKG2D receptor on T and NK cells mediates tumor immunity but can also promote local and systemic immune suppression in conditions of persistent NKG2D ligand induction that include cancer and certain autoimmune diseases. In this paper, we provide evidence that establishes a causative link between CD3zeta impairment and chronic NKG2D stimulation due to pathological ligand expression. We describe a mechanism whereby NKG2D signaling in human T and NK cells initiates Fas ligand/Fas-mediated caspase-3/-7 activation and resultant CD3zeta degradation. As a consequence, the functional capacities of the TCR, the low-affinity Fc receptor for IgG, and the NKp30 and NKp46 natural cytotoxicity receptors, which all signal through CD3zeta, are impaired. These findings are extended to ex vivo phenotypes of T and NK cells among tumor-infiltrating lymphocytes and in peripheral blood from patients with juvenile-onset lupus. Collectively, these results indicate that pathological NKG2D ligand expression leads to simultaneous impairment of multiple CD3zeta dependent receptor functions, thus offering an explanation that may be applicable to CD3zeta deficiencies associated with diverse disease conditions. PMID- 20926797 TI - A nonredundant role for IL-21 receptor signaling in plasma cell differentiation and protective type 2 immunity against gastrointestinal helminth infection. AB - Pathogen-specific Ab production following infection with the gut-dwelling roundworm Heligmosomoides polygyrus is critical for protective immunity against reinfection. However, the factors required for productive T cell-B cell interactions in the context of a type 2-dominated immune response are not well defined. In the present study, we identify IL-21R signaling as a critical factor in driving pathogen-specific plasma cell differentiation and protective immunity against H. polygyrus in mice. We show that B cells require direct IL-21R signals to differentiate into CD138(+) plasma cells. In contrast, IL-21R signaling is dispensable for germinal center formation, isotype class switching, and Th2 and T follicular helper cell differentiation. Our studies demonstrate a selective role for IL-21 in plasma cell differentiation in the context of protective antiparasitic type 2 immunity. PMID- 20926798 TI - Substance P upregulates cyclooxygenase-2 and prostaglandin E metabolite by activating ERK1/2 and NF-kappaB in a mouse model of burn-induced remote acute lung injury. AB - Acute lung injury (ALI) is a major cause of mortality in burn patients, even without direct inhalational injury. Identification of early mediators that instigate ALI after burn and of the molecular mechanisms by which they work are of high importance but remain poorly understood. We previously reported that an endogenous neuropeptide, substance P (SP), via binding neurokinin-1 receptor (NK1R), heightens remote ALI early after severe local burn. In this study, we examined the downstream signaling pathway following SP-NK1R coupling that leads to remote ALI after burn. A 30% total body surface area full-thickness burn was induced in male BALB/c wild-type (WT) mice, preprotachykinin-A (PPT-A) gene deficient mice, which encode for SP, and PPT-A(-/-) mice challenged with exogenous SP. Local burn injury induced excessive SP-NK1R signaling, which activated ERK1/2 and NF-kappaB, leading to significant upregulation of cyclooxygenase (COX)-2, PGE metabolite, and remote ALI. Notably, lung COX-2 levels were abrogated in burn-injured WT mice by L703606, PD98059, and Bay 11 7082, which are specific NK1R, MEK-1, and NF-kappaB antagonists, respectively. Additionally, burn-injured PPT-A(-/-) mice showed suppressed lung COX-2 levels, whereas PPT-A(-/-) mice injected with SP showed augmented COX-2 levels postburn, and administration of PD98059 and Bay 11-7082 to burn-injured PPT-A(-/-) mice injected with SP abolished the COX-2 levels. Furthermore, treatment with parecoxib, a selective COX-2 inhibitor, attenuated proinflammatory cytokines, chemokines, and ALI in burn-injured WT mice and PPT-A(-/-) mice injected with SP. To our knowledge, we show for the first time that SP-NK1R signaling markedly elevates COX-2 activity via ERK1/2 and NF-kappaB, leading to remote ALI after burn. PMID- 20926799 TI - No requirement of trans presentations of IL-15 for human CD8 T cell proliferation. AB - The trans presentation of IL-15 by cells expressing the specific high-affinity receptor alpha-chain (IL-15Ralpha) to cells expressing the signaling receptor beta-chain and gamma-chain is essential for the generation and maintenance of CD8 memory T cells, NK cells, and NKT cells in an in vivo mouse system. We have also demonstrated in vitro that cell-surface IL-15Ralpha on cells expressing all the receptor components present IL-15 to receptor beta-chain/gamma-chain coexpressed on the same cell surface (cis presentation). However, although mouse CD8 T cells express all the IL-15R components, they show no evidence of cis presentation. In this study, we demonstrate that increased expression of mouse IL-15Ralpha in mouse CD8 T cells by retrovirus-mediated gene transfer changes the ability of the T cell to use cis presentation on the cell surface, indicating that cis presentation requires high expression of mouse IL-15Ralpha on the cell surface. Using cell lines expressing human or mouse receptors, we demonstrate that cis presentation occurs more efficiently in the human receptor-ligand combination than in that of the mouse system. Moreover, we found that primary human CD8 T cells do not require trans presentation of human IL-15 in vitro. These findings raise the possibility that the maintenance and generation of memory CD8 T cells are achieved via distinct mechanisms in humans and mice. Therefore, careful study of the human immune system, rather than extrapolation from the murine model, is necessary to achieve more complete understanding of memory CD8 T cell development in humans. PMID- 20926800 TI - Neutropenia enhances lung dendritic cell recruitment in response to Aspergillus via a cytokine-to-chemokine amplification loop. AB - Current understanding of specific defense mechanisms in the context of neutropenic infections is limited. It has previously been reported that invasive aspergillosis, a prototypic opportunistic infection in neutropenic hosts, is associated with marked accumulation of inflammatory dendritic cells (DCs) in the lungs. Given recent data indicating that neutrophils can modulate immune responses independent of their direct microbial killing, we hypothesized that neutropenia impacts the host response to Aspergillus by determining the migration and phenotype of lung DCs. Inflammatory DCs, but not other DC subsets, were found to accumulate in the lungs of neutropenic hosts challenged with killed or live attenuated Aspergillus as compared with nonneutropenic hosts, indicating that the accumulation was independent of neutrophil microbicidal activity. The mechanism of this accumulation in neutropenic hosts was found to be augmented influx of DCs, or their precursors, from the blood to the lungs. This effect was attributable to greatly elevated lung TNF expression in neutropenic as compared with nonneutropenic animals. This resulted in greater lung expression of the chemokine ligands CCL2 and CCL20, which, in turn, mediated enhanced recruitment of TNF-producing inflammatory DCs, resulting in a positive feedback cycle. Finally, in the context of neutropenic invasive aspergillosis, depletion of DCs resulted in impaired fungal clearance, indicating that this mechanism is protective for the host. These observations identify what we believe is a novel defense mechanism in invasive aspergillosis that is the result of alterations in DC traffic and phenotype and is specific to neutropenic hosts. PMID- 20926802 TI - Transforming growth factor Beta regulates proliferation and invasion of rat placental cell lines. AB - Implantation of an embryo in the endometrium is a critical step for continuation of pregnancy, and implantation failure is a major cause of infertility. In rats, the implantation process involves invasion of the endometrial epithelial lining by the trophoblastic cells in order to reach the underlying stromal cells. Transforming growth factor beta (TGFB) is a multifunctional cytokine that regulates proliferation, differentiation, and invasiveness of multiple cell lineages. We used rat HRP-1 and RCHO-1 placental cell lines to perform this study. HRP-1 cells were derived from midgestation chorioallantoic placental explants of the outbred Holtzman rat, whereas RCHO-1 cells were established from a rat choriocarcinoma. MTT proliferation assays revealed that each TGFB isoform decreased HRP-1 cell growth in a dose-dependent manner, whereas RCHO-1 cells were resistant to the growth-suppressive effect of TGFB1 and TGFB3. Only TGFB2 reduced RCHO-1 cell proliferation. Activation of ERK, MAPK14 (p38 MAPK), or SMAD pathways is known to play a role in cell proliferation, and we found that TGFB activates these pathways in both HRP-1 and RCHO-1 cells in an isoform-specific manner. MTT proliferation assays revealed that ERK pathway is partially implicated in TGFB3 reduced HRP-1 cell proliferation. Hoechst nuclear staining and caspase-3 cleavage demonstrated that TGFB isoforms failed to induce apoptosis in both cell lines. Matrigel invasion assays showed that both HRP-1 and RCHO-1 cells exhibit intrinsic invasive ability under untreated conditions. The capacity of HRP-1 cells to invade the Matrigel was selectively increased by TGFB2 and TGFB3, whereas all TGFB isoforms could increase the invasiveness of RCHO-1 cells. These important functional studies progressively reveal a key role for TGFB in regulating proliferation and invasiveness of placental cells. PMID- 20926801 TI - Estrogen, efferent ductules, and the epididymis. AB - Estrogen's presence in the male reproductive system has been known for over 60 years, but its potential function in the epididymis remains an important area of investigation. Estrogen is synthesized by germ cells, producing a relatively high concentration in rete testis fluid. There are two estrogen receptors (ESR), the presence of which in the head of the epididymis is well documented and consistent between species; however, in other regions of the epididymis, their expression appears to be isotype, species, and cell specific. ESR1 is expressed constitutively in the epididymis; however, its presence is downregulated by high doses of estrogen, making the design of experiments complicated, as the phenotype of the Cyp19a1(-/-) mouse does not resemble that of the Esr1(-/-) mouse. Ligand independent and DNA-binding Esr1 mutant models further demonstrate the complexity and importance of both signaling pathways in maintenance of efferent ductules and epididymis. Data now reveal the presence of not only classical nuclear receptors, but also cytoplasmic ESR and rapid responding membrane receptors; however, their importance in the epididymis remains undetermined. ESR1 regulates ion transport and water reabsorption in the efferent ducts and epididymis, and its regulation of other associated genes is continually being uncovered. In the male, some genes, such as Aqp9 and Slc9a3, contain both androgen and estrogen response elements and are dually regulated by these hormones. While estrogen pathways are a necessity for fertility in the male, future studies are needed to understand the interplay between androgens and estrogens in epididymal tissues, particularly in cell types that contain both receptors and their cofactors. PMID- 20926803 TI - Labor and inflammation increase the expression of oxytocin receptor in human amnion. AB - The oxytocin/oxytocin receptor (OXT/OXTR) system plays an important role in the regulation of parturition. The amnion is a major source of prostaglandins and inflammatory cytokine synthesis, which increase both before and during labor. Amnion is a noncontractile tissue; therefore, the role played by OXT/OXTR in this tissue will be fundamentally different from the role played in myometrial contractions. In the present study, we demonstrate increased OXTR mRNA and protein concentrations in human amnion epithelial cells associated with the onset of labor. We show that incubation of primary human amnion epithelial cells with IL1B results in a rapid, transient up-regulation of OXTR mRNA expression, which peaks in prelabor samples after 6 h. Incubation of prelabor amnion epithelial cells with OXT results in a marked increase of prostaglandin E(2) synthesis, and we demonstrate that OXT activates the extracellular signal-regulated protein kinase signal transduction pathway to stimulate up-regulation of cyclo-oxygenase 2 in human amnion epithelial cells. The increased ability of human amnion to produce prostaglandins in response to OXT treatment suggests a complementary role for the OXT/OXTR system in the activation of human amnion and the onset of labor. PMID- 20926804 TI - Cryopreservation of canine embryos. AB - The assisted reproductive techniques (ARTs) such as in vitro fertilization, embryo transfer, and cryopreservation of gametes have contributed considerably to the development of biomedical sciences in addition to improving infertility treatments in humans as well as the breeding of domestic animals. However, ARTs used in canine species have strictly limited utility when compared with other mammalian species, including humans. Although successful somatic cell cloning has been reported, artificial insemination by frozen semen to date is only available for the improved breeding and reproduction for companion and working dogs as well as guide dogs for the blind. We describe here the successful cryopreservation of embryos and subsequent embryo transfer in dogs. Canine embryos were collected from excised reproductive organs after artificial insemination and subsequently cryopreserved by a vitrification method. When the 4-cell to morula stage of cryopreserved embryos were nonsurgically transferred into the uteri of nine recipient bitches using a cystoscope, five recipients became pregnant and four of them delivered a total of seven pups. The cryopreservation of embryos in canine species will facilitate the transportation and storage of genetic materials and will aid in the elimination of vertically transmitted diseases in dogs. In addition, this technique will contribute to the improved breeding of companion and working dogs such as guide dogs, drug-detecting dogs, and quarantine dogs. PMID- 20926805 TI - Disparate binding of three types of vitellogenin to multiple forms of vitellogenin receptor in white perch. AB - Three types of white perch (Morone americana) vitellogenin (VtgAa, VtgAb, and VtgC) were purified, labeled with digoxigenin (DIG), and subjected to Vtg receptor (Vtgr) binding assays in 96-well plates coated with perch ovarian membrane proteins or to ligand blotting procedures. Binding specificity was evaluated by incubating membrane protein preparations with constant amounts of DIG-Vtg tracer (VtgAa, VtgAb, VtgC, or a mixture of VtgAa and VtgAb [VtgAa/b]) alone or in the presence of unlabeled Vtg ligands. At 250-fold excess molar concentration relative to the tracer, VtgAa and VtgAb were each able to displace only approximately 50% of bound DIG-VtgAa/b, but VtgAa/b could fully displace DIG VtgAa and DIG-VtgAb under the same conditions. Over a broad range of excess molar ratios, unlabeled VtgAa and VtgAb each displaced their respective DIG-Vtg tracer much more effectively than each did the heterologous tracer (DIG-VtgAb and DIG VtgAa, respectively). Ligand blotting revealed three forms of Vtgr, a large receptor (>212 kDa) that bound only to VtgAa and two smaller receptors (~ 116 and ~ 110.5 kDa) that bound preferentially to VtgAb. The VtgC did not specifically bind to ovarian membrane proteins in either assay. Collectively, these results indicate the presence of a system of multiple ovarian Vtgrs with disparate binding to the three types of Vtg present in higher-order teleosts (Acanthomorpha). To our knowledge, this is the first report on binding of multiple types of Vtg to multiple forms of Vtgr in any vertebrate. PMID- 20926806 TI - Differential gene expression in ovaries of pregnant pigs with high and low prolificacy levels and identification of candidate genes for litter size. AB - Previous results from a genome scan in an F(2) Iberian * Meishan pig intercross showed several chromosome regions associated with litter size traits in this species. In order to identify candidate genes underlying these quantitative trait loci (QTL), we performed an ovary gene expression analysis during the sow's pregnancy. F(2) sows were ranked by their estimated breeding values for prolificacy: six sows with the highest estimated breeding value (EBV) (i.e., high prolificacy) and six sows with the lowest EBV (low prolificacy) were selected. Samples were hybridized using an Affymetrix GeneChip porcine genome array. Statistical analysis with a mixed model approach identified 221 differentially expressed probes, representing 189 genes. These genes were functionally annotated in order to identify genetic pathways overrepresented in this list. Among the functional groups most represented was, in first position, immune system response activation against external stimulus. The second group consisted of integrated genes that regulate maternal homeostasis by complement and coagulation cascades. A third group was involved in lipid and fatty acid enzymes of metabolic processes, which participate in the steroidogenesis pathway. In order to identify powerful candidate genes for prolificacy, the second approach of this study was to merge microarray data with the QTL positional information affecting litter size, previously detected in the same experimental cross. As a result, we have identified 27 differentially expressed genes colocalizing with QTL for litter size traits, which fulfill the biological, positional, and functional criteria. PMID- 20926807 TI - Activin A balances Sertoli and germ cell proliferation in the fetal mouse testis. AB - Activin affects many aspects of cellular development, including those essential for reproductive fitness. This study examined the contribution of activin A to murine fetal testicular development, revealing contrasting outcomes of activin actions on Sertoli cells and gonocytes. Shortly after sex determination, from Embryonic Day 12.5 (E12.5) through to birth (0 dpp), the activin A subunit transcript (Inhba) level rises in testis but not ovary, followed closely by the Inha transcript (encoding the inhibitory inhibin alpha subunit). Activin receptor transcript levels also change, with Acvr1 (encoding ALK2) and Acvr2b (ActRIIB) significantly higher and lower, respectively, at 0 dpp compared with E13.5 and E15.5. Transcripts encoding the signaling mediators Smad1, Smad3, and Smad4 were higher at 0 dpp compared with E13.5 and E15.5, whereas Smad2, Smad5, and Smad7 were lower. Detection of phosphorylated (P-)SMAD2/3 in nearly all testis cell nuclei indicated widespread transforming growth factor beta (TGFB) and/or activin ligand signaling activity. In contrast to wild-type littermates, activin betaA subunit knockout (Inhba(-/-)) mice have significantly smaller testes at birth, attributable to a 50% lower Sertoli cell number and decreased Sertoli cell proliferation from E13.5. Inhba(-/-) testes contained twice the normal gonocyte number at birth, with some appearing to bypass quiescence. Persistence of widespread P-SMAD2/3 in Inhba(-/-) cells indicates other TGFB superfamily ligands are active in fetal testes. Significant differences in Smad and cell cycle regulator transcript levels correlating to Inhba gene dosage correspond to differences in Sertoli and germ cell numbers. In Inhba(-/-) testes, Cdkn1a (encoding p21(cip1)), identified previously in fetal gonocytes, was lower at E13.5, whereas Cdkn1b (encoding p(27kip1) in somatic cells) was lower at birth, and cyclin D2 mRNA and protein were lower at E15.5 and 0 dpp. Thus, activin A dosage contributes to establishing the balance between Sertoli and germ cell number that is ultimately required for adult male fertility. PMID- 20926808 TI - Apoptosis in mouse amniotic epithelium is induced by activated macrophages through the TNF receptor type 1/TNF pathway. AB - The amniotic epithelium is in direct contact with the amniotic fluid and has tight junctions. The amniotic tight junctions function as a barrier to restrict fluid flux via the amniotic membrane during midpregnancy in the mouse. However, during late pregnancy, amniotic fluid volume significantly decreases in association with the disruption of amniotic tight junctions. The disruption of amniotic tight junctions is caused by apoptosis in the amniotic epithelium on Embryonic Day 17 (E17). In this study, we examine the molecular mechanisms underlying apoptosis of the amniotic epithelium of the mouse. We found that from E16, the number of activated macrophages that express high levels of NOS2 and tumor necrosis factor (TNF) increase in amniotic fluid. TNF receptor type 1 (TNFR1) was detectable from E16 onward. On E17, amniotic epithelial cells expressing TNFR1 became TUNEL positive, suggesting that TNF/TNFR1 signaling may initiate apoptosis. To further confirm the role of TNF/TNFR1 signaling, WP9QY, a TNFR1 antagonist, was injected into the amniotic cavity and was found to significantly reduce the numbers of apoptotic cells in the E17 amniotic epithelium. Furthermore, dehydroxymethylepoxyquinomicin, a specific nuclear factor-kappa B inhibitor, was found to inhibit TNF production in macrophages and amniotic apoptosis in vivo. Finally, we showed that injection of TNF into the amniotic cavity induces early onset of apoptosis. These results indicate that amniotic apoptosis is induced by the TNF pathway via TNFR1 expressed in the amniotic epithelial cells and that activation of macrophages may trigger amniotic apoptosis. PMID- 20926809 TI - Investigating unstable fixation in patients with macular disease. AB - PURPOSE: To assess the effect on visual acuity of compensating fixation instability by controlling retinal image motion in people with macular disease. METHODS: Ten patients with macular disease participated in this study. Crowded and noncrowded visual acuity were measured using an eye tracking system to compensate for fixation instability. Four conditions, corresponding to four levels of retinal image motion, were tested: no compensation (normal motion), partial compensation (reduced motion), total compensation (no motion), and overcompensation (increased motion). Fixation stability and the number of preferred retinal loci were also measured. RESULTS: Modulating retinal image motion had the same effect on crowded and noncrowded visual acuity (P = 0.601). When fixation instability was overcompensated, acuity worsened by 0.1 logMAR units (P < 0.001) compared with baseline (no compensation) and remained equal to baseline for all other conditions. CONCLUSIONS: In people with macular disease, retinal image motion caused by fixation instability does not reduce either crowded or noncrowded visual acuity. Acuity declines when fixation instability is overcompensated, showing limited tolerance to increased retinal image motion. The results provide evidence that fixation instability does not improve visual acuity and may be a consequence of poor oculomotor control. PMID- 20926810 TI - Multifocal electroretinograms predict onset of diabetic retinopathy in adult patients with diabetes. AB - PURPOSE: The authors' previous models predicted local formation of diabetic retinopathy (DR) in adults with diabetes and existing retinopathy. Here they derived a multivariate model for local prediction of DR onset in patients with no previous retinopathy. METHODS: Seventy-eight eyes from 41 diabetes patients were tested annually for several years. The presence or absence of DR at the last study visit was the outcome measure, and measurements of risk factors from the previous visit were used for prediction. Logistic regression was used to assess the relationship between DR development and 7 factors: multifocal ERG (mfERG) implicit time (IT) Z-score, sex, diabetes duration, blood glucose, HbA1c, age, and diabetes type. Thirty-five retinal zones, spanning 45 degrees , were constructed from the mfERG stimulus elements. The maximum IT Z-score for each zone was calculated based on data from 50 control subjects. ROC curve analysis, using fivefold cross-validation, was used to determine the model's predictive properties. RESULTS: Mild DR developed in 80 of 2730 retinal zones (3%) in 29 of 78 eyes (37%). Multivariate analysis showed mfERG IT to be predictive for DR development in a zone after adjusting for diabetes type. The multivariate model has a sensitivity of 80% and a specificity of 74%. CONCLUSIONS: mfERG IT is a good predictor of DR onset, 1 year later, in patients with diabetes without DR. It can be used to assess the risk for DR development in these patients and may be a valuable outcome measure in evaluation of novel prophylactic therapeutics directed at impeding DR. PMID- 20926811 TI - Fatty Acid uptake and incorporation into phospholipids in the rat lens. AB - PURPOSE: Phospholipids are a major component of lens fiber cells and influence the activity of membrane proteins. Previous investigations of fatty acid uptake by the lens are limited. The purpose of the present study was thus to determine whether exogenous fatty acids could be taken up by the rat lens and incorporated into molecular phospholipids. METHODS: Lenses were incubated with fluorescently labeled palmitic acid and then analyzed by confocal microscopy. Concurrently, lenses incubated with either fluorescently labeled palmitic acid or the more physiologically relevant (13)C(18)-oleic acid were sectioned into nuclear and cortical regions and analyzed by highly sensitive and structurally selective electrospray ionization tandem mass spectrometry techniques. RESULTS: The detection of fluorescently labeled palmitic acid, even after 16 hours of incubation, was limited to approximately the outer 25% to 30% of the rat lens. Mass spectrometry also revealed the presence of free (13)C(18)-oleic acid in the cortex but not the nucleus. No evidence could be found for incorporation of fluorescently labeled palmitic acid into phospholipids; however, a low level of (13)C(18)-oleic acid incorporation into phosphatidylethanolamine (PE), specifically PE (PE 16:0/(13)C(18) 18:1) was detected in the lens cortex after 16 hours. CONCLUSIONS: These data demonstrate that uptake of exogenous (e.g., dietary fatty acids) by the lens and their incorporation into phospholipids is minimal, most likely occurring only during de novo synthesis in the outermost region of the lens. This finding adds support to the hypothesis that once synthesized there is no active remodeling or turnover of fiber cell phospholipids. PMID- 20926812 TI - A role of corneal mechanical adaptation in contact lens-related dry eye symptoms. AB - PURPOSE: To compare corneal mechanical adaptation measured psychophysically in contact lens wearers with or without dry eye symptoms. METHODS: Two groups of contact lens wearers were recruited. One group (symptomatic) consisted of subjects with dry eye symptoms (according to the subjective evaluation of symptom of dryness [SeSoD] questionnaire). The second control group (asymptomatic) consisted of subjects reporting no symptoms. There were 32 (aged 20 to 42 years, 6 males and 26 females) and 29 subjects (aged 21 to 36 years, 9 males and 20 females) in the symptomatic and asymptomatic groups, respectively. Mechanical stimulus thresholds of the cornea were determined using a Belmonte pneumatic esthesiometer and the ascending method of limits. Then three stimulus intensity groups (subthreshold, threshold, and suprathreshold) were applied to the eye in random order, each 20 times. Subjects rated the intensity of the stimuli using a scale of zero to four. The rating data from the two groups were compared by Friedman nonparametric ANOVA. Adaptation was defined as the reduction in subsequent ratings compared with earlier ones. RESULTS: No significant difference was seen in subjects' thresholds in both groups (P = 0.22). The symptomatic group rated their sensations to suprathreshold stimuli higher than the asymptomatic group. More importantly, there was significant adaptation with suprathreshold mechanical stimulation in the asymptomatic group (P = 0.006) but not in the symptomatic group (P = 0.08). There was no adaptation during threshold and subthreshold stimulus sessions in either group. CONCLUSIONS: Adaptation was found to suprathreshold mechanical stimuli in the asymptomatic group but not in the symptomatic group. PMID- 20926813 TI - Cell delivery with fixed amniotic membrane reconstructs corneal epithelium in rabbits with limbal stem cell deficiency. AB - PURPOSE: To explore the feasibility and efficacy of a cell delivery system using amniotic membrane (AM) fixed by a novel biomembrane-fixing device (BMFD) for corneal epithelium reconstruction in rabbits with limbal stem cell deficiency (LSCD). METHODS: Sixty female rabbits with LSCD were created and randomly assigned to three groups of 20 each: LSCD rabbits without treatment (the control), LSCD rabbits treated with BMFD-fixed AM (BMFD-AM), and rabbits treated with male human limbal epithelial cells delivered with BMFD-fixed AM (BMFD AM+cells). They were followed up with slit lamp observation and corneal fluorescein staining for 14 days. Cytokeratin K3 and K4 and mucin 5AC were used to evaluate corneal conjunctivalization. Sry gene detection was used to trace the delivered cells. RESULTS: The corneal re-epithelialization time was 5.60 +/- 0.46 days in the BMFD-AM+cell group, significantly shorter (P < 0.05) than in the LSCD (12.45 +/- 0.65 days) and the BMFD-AM (9.25 +/- 0.51 days) groups. Conjunctivalization and neovascularization were observed to be severe in the LSCD group and moderate in the BMFD-AM group. The prevention of conjunctivalization in the BMFD-AM+cell group was evidenced by positive K3/K12 and negative MUC5AC and K4 observed on re-epithelialized corneal epithelium. The histologic sections at different time points and positive Sry gene expression indicated that the delivered cells adhered to the wounded corneal surface and proliferated well. CONCLUSIONS: These findings demonstrate that the BMFD with fixed AM served well as a cell delivery system for the ocular surface. The delivered limbal epithelial cells promoted corneal re-epithelialization and prevented corneas from conjunctivalization and neovascularization in rabbits with experimental LSCD. PMID- 20926814 TI - Intravitreal injections of neurotrophic factors secreting mesenchymal stem cells are neuroprotective in rat eyes following optic nerve transection. AB - PURPOSE: To evaluate the neuroprotective effect of intravitreal injections of neurotrophic factors secreting mesenchymal stem cells (NTF-SCs) on the survival of retinal ganglion cells (RGCs) in rat eyes after optic nerve transection (ONT). METHODS: Rat and human bone marrow-derived mesenchymal stem cells (MSCs) were induced to secrete high levels of NTF. The neuroprotective effect from intravitreally injected untreated MSCs or NTF-SCs was compared with that from PBS injections using an ONT model in 146 rats. RGCs were labeled by applying rhodamine dextran to the orbital optic nerve or by injecting Fluorogold into the superior colliculus. Cell- and saline-treated eyes were compared 8 days after ONT. For tracking, MSCs and NTF-SCs were labeled with PKH26 and analyzed at 2 hours and at 10, 17, and 24 days using immunohistochemistry and RT-PCR. RESULTS: Mean RGC survival at 8 days after transection increased significantly after intravitreal injections of human NTF-SCs (69% +/- 3%) or of untreated human MSCs (66% +/- 5%) versus PBS (46% +/- 3%; P = 0.0005 and P = 0.03, respectively). In an additional set of experiments, human NTF-SCs versus PBS were significantly neuroprotective, but bone marrow-derived rat NTF-SCs were not (P = 0.001 and P = 0.1, respectively). Immunohistochemistry demonstrated that human-derived MSCs, human NTF-SCs, and rat-derived NTF-SCs survived at least 24 days after intravitreal injection. CONCLUSIONS: Bone marrow-derived MSCs can deliver NTFs by intravitreal injection and can be neuroprotective after ONT. This approach might be further studied to deliver NTFs by autotransplantation in glaucomatous eyes. PMID- 20926815 TI - A novel method for the induction of experimental glaucoma using magnetic microspheres. AB - PURPOSE: The development of a method for the sustained elevation of intraocular pressure in experimental glaucoma based on the anterior chamber injection of paramagnetic microbeads. METHODS: Unilateral glaucoma was induced in adult male Norwegian Brown rats by the injection of paramagnetic polystyrene microspheres. A handheld 0.45 Tesla magnet was used to draw the beads into the iridocorneal angle to impede aqueous drainage via the trabecular meshwork. RESULTS: Elevated intraocular pressures (IOPs) were induced in 61 rats, resulting in a mean elevation of 5.8 mm Hg +/- 1.0 (SEM) relative to the contralateral control eye. The mean duration of sustained IOP elevation (defined as >5 mm Hg relative to the control eye for at least 7 consecutive days) after a single injection was 12.8 days +/- 0.9 (SEM, maximum duration 27 days). In all eyes, the visual axis remained clear from the time of injection, with minimal inflammation after injection. Retinal ganglion cell loss was determined in 21 animals (mean integral IOP, 194.5 mm Hg days +/- 87.5 [SEM]) as 36.4% +/- 2.4 (SEM) compared with the contralateral, untreated eye. CONCLUSIONS: The use of paramagnetic microbeads for the occlusion of the iridocorneal angle produces a sustained elevation of IOP with fewer injections and avoids the risk of visual axis occlusion. It represents a simple and effective method for the induction of experimental glaucoma. PMID- 20926816 TI - In vivo quantification of bacterial keratitis with optical coherence tomography. AB - PURPOSE: To quantify the human corneal inflammatory response in treated bacterial keratitis with long-wavelength anterior segment optical coherence tomography (AS OCT). METHODS: Patients with clinically suspected bacterial keratitis were recruited from the corneal service at Southampton Eye Unit, UK. Patients underwent AS-OCT and slit-lamp examination on presentation (day 0) and days 3, 7, and 14 of treatment. Corneal thickness (CT) in the infiltrated area, infiltrate thickness (IT), and infiltrate width (IW) were measured on high-resolution AS-OCT scans. Mean values for each day and rates of change for each interval were calculated and compared (one-way ANOVA, paired t-test). RESULTS: Twenty-six eyes of 26 patients were recruited. Mean CT and IT on presentation were 905 MUm and 388 MUm, respectively. On days 3, 7, and 14, CT and IT decreased to 753 MUm and 320 MUm (P < 0.01), 678 MUm and 296 MUm (P < 0.01), and 584 MUm and 207 MUm (P < 0.01), respectively. Mean IW, 1498 MUm on presentation, did not change during treatment (P > 0.30). Mean daily rate of CT reduction was faster in the early (days 0-3) compared to late (days 7-14) phase (4.49% vs. 1.33%, P = 0.006). Mean daily rate of IT reduction was no different in early, middle, and late phases (5.41% vs. 1.19% vs. 3.38%, P > 0.01). In the late phase, IT decreased faster than CT (3.38% vs. 1.33%, P = 0.003). CONCLUSIONS: CT and IT decreased significantly by day 3 in resolving bacterial keratitis. The rapid early phase reduction in IT and CT was followed by rapid late phase IT reduction. This study demonstrates that serial AS-OCT examination can be used to monitor in vivo the clinical course of inflammatory disease. PMID- 20926817 TI - The relationship between retinal arteriolar and venular calibers is genetically mediated, and each is associated with risk of cardiovascular disease. AB - PURPOSE: Retinal arteriolar and venular calibers are highly heritable and associated with cardiovascular disease. This study was designed to investigate the relative influence of genetic and environmental factors on the high phenotypic correlation (r = 0.59) between these two traits and to assess the shared and specific influence of established and novel cardiovascular disease risk factors on them. METHODS: A total of 1463 Caucasian female twins (706 monozygotic and 757 dizygotic), between 24 and 79 years of age, underwent retinal photography from which retinal arteriolar (mean, 153.75 +/- 22.1 MUm, SD) and venular (mean, 232.1 +/- 36.6 MUm) calibers were measured with semiautomated software. A bivariate heritability model was used to assess the genetic and environmental influences underlying both specific trait variance and the covariance between the vessel traits. The investigation was an assessment of phenotypic associations between retinal arteriolar and venular calibers and cardiovascular disease risk factors. RESULTS: Additive genetic factors accounted for approximately three fourths of the covariance between retinal arteriolar and venular calibers within the cohort. This finding was replicated in a sample of 1981 twins from the Australian Twins Eye Study. The partial correlation showed that known risk factors accounted for only 5% of the covariance between arteriolar and venular calibers. Novel associations were found between venular caliber and beta-cell function (P = 0.011) and insulin sensitivity (P = 0.002). CONCLUSIONS: These results suggest that future gene-mapping studies may identify pleiotropic genetic variants influencing both retinal arteriolar and venular calibers. Genetic variants associated with retinal caliber and (risk factors for) cardiovascular disease should provide new etiologic insights into this complex disease. PMID- 20926818 TI - Changes in retinal sensitivity in geographic atrophy progression as measured by microperimetry. AB - PURPOSE: To characterize changes in macular sensitivity during geographic atrophy (GA) progression using microperimetry. METHODS: Retinal sensitivity in the macular area was evaluated by microperimetry in 10 patients with bilateral GA, with adequate data obtained in 9 of 10 patients (n = 18 eyes). Patients had been enrolled in an interventional trial in which one eye had been randomized to treatment and the other eye observed. No treatment effect with regard to GA growth and microperimetric measurements was detected, and all eyes were analyzed. Microperimetric assessments of the central 20 degrees of the macula were performed every 6 months over 24 months. Parameters analyzed included number of scotomatous points, mean retinal sensitivity of responding points, and fixation stability. Autofluorescence imaging and fundus photography were also obtained. RESULTS: Microperimetric parameters demonstrated statistically significant changes as a function of time. Mean number of scotomatous points increased significantly with time (P = 0.004) at a rate of 4.4 points/year. Mean retinal sensitivities of all points, all responding points, and all perilesional points all decreased significantly with time (P < 0.003), as did fixation quality within the 2 degrees and 4 degrees circles (P < 0.002). The growth of GA lesion area was associated with the changes in the number of scotomatous points (P = 0.01) but not with changes in the other microperimetric parameters. CONCLUSIONS: Macular sensitivity and fixation quality undergo progressive change during the GA progression, reflecting alterations in macular function extending beyond the GA lesion proper. Microperimetric measurements may provide useful functional outcome measures for the clinical study of GA. PMID- 20926820 TI - Correlation of corneal acoustic and elastic properties in a canine eye model. AB - PURPOSE: To examine the correlation between corneal acoustic impedance and Young's modulus in a canine eye model. METHODS: Twenty canine globes were recovered from healthy animals. Corneal acoustic impedance was measured in the intact globes using two methods: a quantitative ultrasound spectroscopy method and the reflection amplitude method. The intraocular pressure was maintained at 10 mm Hg during the ultrasound measurements. Corneal strips were then prepared for standard uniaxial tensile tests. Young's moduli at various strain levels and those at a loading level equivalent to that for ultrasound measurements were compared with the acoustic impedance of the same cornea. RESULTS: The mean acoustic impedance of the canine corneas was 1.72 +/- 0.05 MPa . s/m using the quantitative ultrasound spectroscopy method and 1.71 +/- 0.04 MPa . s/m using the reflection amplitude method. Young's secant modulus was 1.07 +/- 0.48 MPa at 1% strain and 2.01 +/- 0.98 MPa at 5% strain, and the tangent modulus was 1.28 +/- 0.69 and 3.16 +/- 0.71 MPa, respectively. Significant linear correlations between acoustic impedance and Young's modulus (at 1%-5% strains) were found in the measured canine corneas. The correlation remained strong when comparing the two parameters measured under equivalent loading. CONCLUSIONS: This study suggests a potentially strong correlation between corneal acoustic impedance and Young's modulus at low strain levels. If such correlation also exists in the human eye, it may allow the noninvasively determined acoustic impedance to be used as a surrogate for Young's modulus, which is difficult to obtain in vivo. PMID- 20926819 TI - XIAP therapy increases survival of transplanted rod precursors in a degenerating host retina. AB - PURPOSE: To assess the survival of rod precursor cells transplanted into the Rd9 mouse, a model of X-linked retinal degeneration, and the effect of antiapoptotic therapy with X-linked inhibitor of apoptosis (XIAP) on preventing cell loss. METHODS: Dissociated retinal cells from P4 Nrlp-GFP mice were transplanted into the subretinal space of 2-, 5-, and 8-month-old Rd9 mice. Histology, immunohistochemistry, and quantification of integrated cells were performed every month for up to 3 months after transplantation. XIAP delivery to donor cells was accomplished by transfection with adenoassociated virus (AAV-XIAP). Intraretinal activation of immune modulators was assessed using a quantitative real-time polymerase chain reaction-based immune response array. RESULTS: GFP-positive rod precursors were able to integrate into the outer nuclear layer (ONL) of the Rd9 retina. Transplanted cells underwent morphologic differentiation with the formation of inner and outer segments and synaptic projections to bipolar cells. Integration of donor cells into the ONL increased as a function of host age at the time of transplantation. The number of integrated cells was maximal at 1 month after transplantation and then decreased with time. Survival of integrated cells was significantly increased when donor cells were pretreated with AAV-XIAP. We did not detect any donor cell-specific activation of inflammation within the host retina. CONCLUSIONS: Survival of integrated cells decreases with time after transplantation but can be significantly increased with XIAP antiapoptotic therapy. Preventing programmed cell death through XIAP therapy may be an important component of future therapeutic retinal cell transplantation strategies. PMID- 20926822 TI - Cytokeratin 8 is expressed in human corneoconjunctival epithelium, particularly in limbal epithelial cells. AB - PURPOSE: The purpose of this study was to investigate the expression of cytokeratin (CK) 8 in the corneoconjunctival epithelium. METHODS: In 17 cadaveric corneoscleral discs and 3 other discs, the presence of CK8 alone or CK8, together with CK3, CK15, vimentin, and integrin alpha6, was investigated by using indirect immunohistochemistry on radial cryosections. Four corneoscleral discs stored in organ culture were used for the preparation of tangential sections of the limbus and for the isolation of limbal epithelial cells and their subsequent cultivation. CK8 expression was examined by RT-PCR in the corneal, limbal, and conjunctival epithelium. RESULTS: Sixty percent of the cadaveric corneoscleral samples and all samples stored in organ culture revealed positivity for CK8 in the basal epithelial layer of the limbus. Positive basal cells formed a single line or separated clusters. The signal for CK8 became weaker toward the surface of the limbal epithelium. The colocalization of CK8 with vimentin and CK15 in the limbus was also found. CK3 showed only occasional positivity in some of the surface limbal cells. The expression of integrin alpha6 in the basal membrane was absent or decreased under the CK8-positive clusters. Cell cultures revealed strong positivity for CK8 in approximately 80% of the cultured cells, and CK8 expression in the cornea, limbus, and conjunctiva was determined by RT-PCR. CONCLUSIONS: The study demonstrates the strong expression of CK8 in limbal epithelial basal cells, which is maintained during the differentiation and migration of the limbal cells toward the central corneal epithelium. PMID- 20926821 TI - Visual activity before and after the onset of juvenile myopia. AB - PURPOSE: To investigate visual activities before and after the onset of juvenile myopia. METHODS: The subjects were 731 incident myopes (-0.75 D or more myopia on cycloplegic autorefraction in both meridians) and 587 emmetropes (between -0.25 and +1.00 D) in the Collaborative Longitudinal Evaluation of Ethnicity and Refractive Error (CLEERE) Study. Parents supplied visual activity data annually. Data from myopic children 5 years before through 5 years after myopia onset were compared to data from age-, sex-, and ethnicity-matched models of children who remained emmetropic. RESULTS: Hours per week spent reading or using a computer/playing video games did not differ between the groups before myopia onset; however, hours per week for both activities were significantly greater in myopes than in emmetropes at onset and in 4 of the 5 years after onset by 0.7 to 1.6 hours per week. Hours per week spent in outdoor/sports activities were significantly fewer for children who became myopic 3 years before onset through 4 years after onset by 1.1 to 1.8 hours per week. Studying and TV watching were not significantly different before myopia onset. CONCLUSIONS: Before myopia onset, near work activities of future myopic children did not differ from those of emmetropes. Those who became myopic had fewer outdoor/sports activity hours than the emmetropes before, at, and after myopia onset. Myopia onset may influence children's near work behavior, but the lack of difference before onset argues against a major causative role for near work. Less outdoor/sports activity before myopia onset may exert a stronger influence on development than near work. PMID- 20926823 TI - Identifying the critical success factors in the coverage of low vision services using the classification analysis and regression tree methodology. AB - PURPOSE: To identify the critical success factors (CSF) associated with coverage of low vision services. METHODS: Data were collected from a survey distributed to Vision 2020 contacts, government, and non-government organizations (NGOs) in 195 countries. The Classification and Regression Tree Analysis (CART) was used to identify the critical success factors of low vision service coverage. Independent variables were sourced from the survey: policies, epidemiology, provision of services, equipment and infrastructure, barriers to services, human resources, and monitoring and evaluation. Socioeconomic and demographic independent variables: health expenditure, population statistics, development status, and human resources in general, were sourced from the World Health Organization (WHO), World Bank, and the United Nations (UN). RESULTS: The findings identified that having >50% of children obtaining devices when prescribed (chi(2) = 44; P < 0.000), multidisciplinary care (chi(2) = 14.54; P = 0.002), >3 rehabilitation workers per 10 million of population (chi(2) = 4.50; P = 0.034), higher percentage of population urbanized (chi(2) = 14.54; P = 0.002), a level of private investment (chi(2) = 14.55; P = 0.015), and being fully funded by government (chi(2) = 6.02; P = 0.014), are critical success factors associated with coverage of low vision services. CONCLUSIONS: This study identified the most important predictors for countries with better low vision coverage. The CART is a useful and suitable methodology in survey research and is a novel way to simplify a complex global public health issue in eye care. PMID- 20926824 TI - Foveal structure and thickness of retinal layers long-term after surgical peeling of idiopathic epiretinal membrane. AB - PURPOSE: To better understand the long-term effect of idiopathic epiretinal membrane peeling on retinal anatomy, the foveal structure and the thickness of individual retinal layers were analyzed with frequency-domain optical coherence tomography (fdOCT). The long-term postoperative course of macular thickness was followed. METHODS: fdOCT scans were obtained from the horizontal midline in 33 eyes long-term (mean 46 +/- 13 months) after surgery and in 30 eyes of age matched controls. Raw images were exported, and the thickness of retinal layers was measured with a manual segmentation procedure aided by a customized computer program. Macular thickness was quantified over time with the time-domain (td) OCT Fast Macular Thickness program. RESULTS: Thickness of retinal layers between the outer nuclear and the ganglion cell plus inner plexiform layers in the horizontal midline of the fovea and the nasal parafovea was greater than normal, whereas that of the RPE, photoreceptor, and retinal nerve fiber layers was not different from controls. Twelve of 33 eyes had a foveal pit though the median foveal shape was distorted. Central macular thickness quantified with tdOCT remained increased, whereas the decrease of nasal macular thickness toward normal values was incomplete and delayed to 35 months after surgery. Superior, temporal, and inferior macular thickness returned to normal 12 to 14 months after surgery. CONCLUSIONS: Long-term after surgery, the fovea and the nasal parafovea remain thickened between the outer nuclear layer and the ganglion cell layer, whereas the superior, temporal, and inferior macular thickness returns to normal. Long term observations are required in the assessment of macular recovery from mechanical stress. PMID- 20926825 TI - Human orbital muscle: a new point of view from the fetal development of extraocular connective tissues. AB - PURPOSE: In the human body, the orbital muscle is a limited smooth-muscle tissue extending between hard tissues. To provide better understanding of its function, the authors re-examined its development in fetuses. METHODS: Using 20 human fetuses (12-25 weeks of gestation), semiserial horizontal or sagittal paraffin sections were prepared at intervals of 20 to 100 MUm. In addition to routine histology, the authors performed silver staining as well as immunohistochemistry for alpha smooth-muscle actin (SMA), vimentin, S100 protein, and tyrosine hydroxylase. RESULTS: Up to 12 weeks, the orbital muscle appeared as a plate-like mesenchymal condensation between the ciliary and sphenopalatine ganglia. Up to 15 weeks, the thick smooth-muscle layer provided an inferoposterior wall for the orbit. A notable feature was a difference in fatty tissue development between the ocular (anterior) and posterior sides of the orbital muscle. At 20 and 25 weeks, SMA immunoreactivity and the amount of smooth-muscle basal lamina were decreased, in contrast to an increase in the number of collagenous fiber bundles. Nerves for the orbital muscle are unlikely to contain sympathetic fibers until 15 weeks. CONCLUSIONS: The authors hypothesize that, in the early stage, the orbital muscle separates the orbital content from the surrounding loose spaces to maintain conditions adequate for the development of orbital fat and other connective tissues. Later, the orbital muscle is replaced by collagenous fibers and seems to provide guidance for calcification of the inferoposterior bony orbital wall. Vimentin-positive osteoprogenitor cells appear to migrate from the perichondrium of the sphenoid and ethmoid. PMID- 20926827 TI - Peripheral refraction and refractive error in singapore chinese children. AB - PURPOSE: Peripheral hyperopia was hypothesized to stimulate axial elongation. This study describes peripheral refraction and its associations with central refractive error in young Singapore Chinese children. METHODS: Two hundred fifty children aged 40 months or older recruited from the Strabismus, Amblyopia, and Refractive Error in Young Singapore Children study were included in this analysis. Peripheral refraction was measured after pupil dilation using an infrared autorefractor. A total of five measurements were captured: central visual axis and 15 degrees and 30 degrees eccentricities in the nasal and temporal visual fields. RESULTS: The mean age of the participants recruited was 83 +/- 36 months. There were 37 children with high and moderate myopia (<=-3 D; 14.8%), 81 with low myopia (-2.99 to -0.5 D; 32.4%), 84 with emmetropia (-0.49 to 1.0 D; 33.6%), and 47 with hyperopia (>1.0 D; 18.8%). Compared with the central axis, children with high and moderate myopia had relative hyperopia at all peripheral eccentricities (P < 0.001), whereas children with low myopia had relative hyperopia only at the temporal and nasal 30 degrees (P < 0.001), but not at the nasal and temporal 15 degrees . Children with emmetropia and hyperopia had peripheral relative myopia at all eccentricities (P < 0.001). A significant correlation between the nasal and temporal refractive error at 30 degrees was noted (Spearson's correlation coefficient = 0.85, P < 0.001). CONCLUSIONS: Young myopic Singapore Chinese children had relative hyperopia in the periphery. This study substantiates previous studies in older children and in Caucasian subjects. PMID- 20926826 TI - Interaction of recombinant myocilin with the matricellular protein SPARC: functional implications. AB - PURPOSE: Myocilin is an extracellular glycoprotein with unknown function that is associated with glaucoma. Calpain II cleaves recombinant myocilin within the linker region of the protein, releasing the C-terminal olfactomedin domain from the N-terminal domain. The authors previously reported that myocilin interacts with the C-terminal region of hevin, a secretory glycoprotein belonging to the SPARC family of matricellular proteins. This study aims to investigate the interaction of myocilin with SPARC. METHODS: Protein-protein interactions were evaluated by the yeast two-hybrid system. The positive interactions were confirmed by solid-phase binding assays using Ni-chelating HPLC purified recombinant proteins and coexpression of recombinant proteins in HEK-293T cells. Coexpression of myocilin, SPARC, and hevin in ocular tissues was identified by immunoflorescence microscopy, Western blot, and array-based gene profiling. RESULTS: Yeast two-hybrid analyses showed that myocilin interacted with the highly conserved C-terminal extracellular calcium binding (EC) domain within SPARC and hevin. Solid-phase binding assays confirmed these interactions and showed that both myocilin and its C-terminal olfactomedin fragment interacted noncovalently with SPARC and a peptide containing the EC domain of SPARC. Full length myocilin interacted with higher affinity with SPARC and its EC domain than the myocilin C-terminal fragment. Coexpression of the two recombinant proteins in HEK-293T cells also indicated their intracellular interaction. CONCLUSIONS: Recombinant myocilin and SPARC interact through their C-terminal domains. The data suggest that the proteolytic processing of myocilin modulates this interaction as well as the interactions of myocilin with other extracellular matrix and matricellular proteins, further supporting a functional role for this proteolytic cleavage. PMID- 20926828 TI - Use of tissue cross-reactivity studies in the development of antibody-based biopharmaceuticals: history, experience, methodology, and future directions. AB - Tissue cross-reactivity (TCR) studies are screening assays recommended for antibody and antibody-like molecules that contain a complementarity-determining region (CDR), primarily to identify off-target binding and, secondarily, to identify sites of on-target binding that were not previously identified. At the present time, TCR studies involve the ex vivo immunohistochemical (IHC) staining of a panel of frozen tissues from humans and animals, are conducted prior to dosing humans, and results are filed with the initial IND/CTA to support first-in human clinical trials. In some cases, a robust TCR assay cannot be developed, and in these cases the lack of a TCR assay should not prevent a program from moving forward. The TCR assay by itself has variable correlation with toxicity or efficacy. Therefore, any findings of interest should be further evaluated and interpreted in the context of the overall pharmacology and safety assessment data package. TCR studies are generally not recommended for surrogate molecules or for comparability assessments in the context of manufacturing/cell line changes. Overall, the design, implementation, and interpretation of TCR studies should follow a case-by-case approach. PMID- 20926829 TI - Deletion of the nuclear isoform of poly(ADP-ribose) glycohydrolase (PARG) reveals its function in DNA repair, genomic stability and tumorigenesis. AB - Poly(ADP-ribose) metabolism, mediated mainly by poly(ADP-ribose) polymerase (PARP) 1 and poly(ADP-ribose) glycohydrolase (PARG), regulates various cellular processes in response to genotoxic stress. PARP1 has been shown to be important in multiple cellular processes, including DNA repair, chromosomal stability, chromatin function, apoptosis and transcriptional regulation. However, whether PARP1's polymer synthesizing activity or polymer homeostasis is responsible for these functions remains largely unknown. Given a concerted action of multiple PARPs and unique PARG in the homeostasis of poly(ADP-ribosyl)ation, PARG is hypothesized to function in these processes. The lethal phenotype of the PARG null mutation in mouse embryos, however, hampers further investigation on biological function of PARG. Here, we show that mouse embryonic fibroblasts carrying a hypomorphic mutation of PARG, i.e. lacking the nuclear 110 kD isoform (PARG(110)(-/-)), have defects in the repair of DNA damage caused by various genotoxic agents. PARG(110)(-/-) cells exhibit genomic instability, characterized by a high frequency of sister chromatid exchange, micronuclei formation and chromosomal aberrations. Moreover, mutant cells contain supernumerary centrosomes, another hallmark of genomic instability, which correlates with an accumulation of S-phase cells after replication poison. Intriguingly, PARG(110)( /-) cells accumulate more Rad51 foci in response to hydroxyurea, indicative of a defective repair of replication fork damage. Finally, PARG(110)(-/-) mice are susceptible to diethylnitrosamine-induced hepatocellular carcinoma. These data demonstrate that the homeostasis of poly(ADP-ribosyl)ation is important for an efficient DNA repair of damaged replication forks and for stabilizing the genome, thereby preventing carcinogenesis. PMID- 20926830 TI - Developmental toxicity testing of biopharmaceuticals in nonhuman primates: previous experience and future directions. AB - Developmental toxicity studies for pharmaceutical safety testing are designed to evaluate potential adverse effects of drug treatment on pregnancy and on the developing embryo/fetus. Biopharmaceuticals present specific challenges for developmental toxicity testing because the pharmacology of these molecules, which are frequently human-specific proteins, is often restricted to humans and nonhuman primates (NHPs). For those species-restricted molecules, the only option for the evaluation of potential effects on development of the human biopharmaceutical is to use NHPs. This article reviews each of the stages of development in cynomolgus macaques (the most frequently used NHP) and the potential exposure of the embryo, fetus, and infant following administration of a biopharmaceutical during pregnancy and lactation. Because the purpose of the NHP developmental studies is to identify potential human risks, a comparison between macaque and human development and potential exposure has been made when possible. Understanding the potential exposure of the conceptus relative to critical periods in development is essential to designing a scientifically based study that adequately addresses human risks. Some options for NHP study designs, including the option of combining end points into a single study, and the pros and cons of each of the study options have been reviewed. Developmental studies for biopharmaceuticals in NHPs need to be optimally designed on a case-by-case basis taking into consideration the pharmacology of the molecule, the type of molecule (antibody or non-antibody), the potential exposure relative to the development of potential target organs, the clinical use, and the ethical considerations associated with the use of NHPs. PMID- 20926831 TI - Opening up to precompetitive collaboration. AB - In order to enhance biomedical research and development efficiency and innovation, nontraditional research collaborations have emerged that feature the sharing of information, resources, and capabilities. Although many of these so called precompetitive collaborations are in the field of oncology, the lessons they offer are broadly applicable to other subfields of translational medicine. PMID- 20926832 TI - The Bayh-Dole Act turns 30. AB - On 12 December 1980, in the waning days of the lame duck session of the 96th Congress, the U.S. Senate passed the University and Small Business Patent Procedures Act, now known as the Bayh-Dole Act, a seemingly obscure act that allowed universities to claim title to inventions that had been made with federal funding. It is unlikely that many present that day realized what a dramatic impact that act would have. Data clearly show that it played a critical role in rejuvenating the entire U.S. economic system, transforming it from a manufacturing base to an innovation base. Yet ironically, the act has passionate critics. PMID- 20926833 TI - Effects of AIN457, a fully human antibody to interleukin-17A, on psoriasis, rheumatoid arthritis, and uveitis. AB - Interleukin-17A (IL-17A) is elaborated by the T helper 17 (T(H)17) subset of T(H) cells and exhibits potent proinflammatory properties in animal models of autoimmunity, including collagen-induced arthritis, experimental autoimmune encephalomyelitis, and experimental autoimmune uveitis. To determine whether IL 17A mediates human inflammatory diseases, we investigated the efficacy and safety of AIN457, a human antibody to IL-17A, in patients with psoriasis, rheumatoid arthritis, and chronic noninfectious uveitis. Patients with chronic plaque-type psoriasis (n = 36), rheumatoid arthritis (n = 52), or chronic noninfectious uveitis (n = 16) were enrolled in clinical trials to evaluate the effects of neutralizing IL-17A by AIN457 at doses of 3 to 10 mg/kg, given intravenously. We evaluated efficacy by measuring the psoriasis area and severity index (PASI), the American College of Rheumatology 20% response (ACR20) for rheumatoid arthritis, or the number of responders for uveitis, as defined by either vision improvement or reduction in ocular inflammation or corticosteroid dose. AIN457 treatment induced clinically relevant responses of variable magnitude in patients suffering from each of these diverse immune-mediated diseases. Variable response rates may be due to heterogeneity in small patient populations, differential pathogenic roles of IL-17A in these diseases, and the different involvement or activation of IL-17A-producing cells. The rates of adverse events, including infections, were similar in the AIN457 and placebo groups. These results support a role for IL-17A in the pathophysiology of diverse inflammatory diseases including psoriasis, rheumatoid arthritis, and noninfectious uveitis. PMID- 20926834 TI - PGC-1alpha, a potential therapeutic target for early intervention in Parkinson's disease. AB - Parkinson's disease affects 5 million people worldwide, but the molecular mechanisms underlying its pathogenesis are still unclear. Here, we report a genome-wide meta-analysis of gene sets (groups of genes that encode the same biological pathway or process) in 410 samples from patients with symptomatic Parkinson's and subclinical disease and healthy controls. We analyzed 6.8 million raw data points from nine genome-wide expression studies, and 185 laser-captured human dopaminergic neuron and substantia nigra transcriptomes, followed by two stage replication on three platforms. We found 10 gene sets with previously unknown associations with Parkinson's disease. These gene sets pinpoint defects in mitochondrial electron transport, glucose utilization, and glucose sensing and reveal that they occur early in disease pathogenesis. Genes controlling cellular bioenergetics that are expressed in response to peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) are underexpressed in Parkinson's disease patients. Activation of PGC-1alpha results in increased expression of nuclear-encoded subunits of the mitochondrial respiratory chain and blocks the dopaminergic neuron loss induced by mutant alpha-synuclein or the pesticide rotenone in cellular disease models. Our systems biology analysis of Parkinson's disease identifies PGC-1alpha as a potential therapeutic target for early intervention. PMID- 20926835 TI - Association of khat chewing with increased risk of stroke and death in patients presenting with acute coronary syndrome. AB - OBJECTIVE: To evaluate the prevalence and significance of khat chewing in patients with acute coronary syndrome (ACS). PATIENTS AND METHODS: From January 29, 2007, through July 29, 2007, 8176 consecutive patients presenting with ACS were enrolled in a prospective, multicenter study from 6 adjacent Middle Eastern countries. RESULTS: Of the 8176 study patients, 7242 (88.6%) were non-khat chewers, and 934 (11.4%) were khat chewers, mainly of Yemeni origin. Khat chewers were older (57 vs 56 years; P=.01) and more likely to be men (85.7% vs 74.5%) compared with non-khat chewers. Non-khat chewers were more likely to have diabetes mellitus, hypertension, dyslipidemia, obesity, and prior history of coronary artery disease and revascularization. Cigarette smoking was more prevalent in khat chewers, and they were more likely to present greater than 12 hours after onset of symptoms compared with non-khat chewers. At admission, khat chewers had higher heart rate, Killip class, and Global Registry of Acute Coronary Events risk scores. Khat chewers had a significantly higher risk of cardiogenic shock, stroke, and mortality. After adjustment of baseline variables, khat chewing was an independent risk factor for in-hospital mortality (odds ratio, 1.9; 95% confidence interval, 1.3-2.7; P<.001) and stroke (odds ratio, 2.7; 95% confidence interval, 1.3-5.9; P=.01). CONCLUSION: In this large cohort of patients with ACS, khat chewing was prevalent and was associated with increased risk of stroke and death. In the context of increasing global migration, a greater awareness of potential widespread practices is essential. PMID- 20926837 TI - Stenotic arterial lesions in a young woman. PMID- 20926836 TI - Human herpesvirus 6 infection as a trigger of multiple sclerosis. AB - We systematically reviewed the existing evidence to determine whether a relationship exists between infection with human herpesvirus 6 (HHV-6) and multiple sclerosis (MS) and, if so, to define the strength of that relationship. The following terms were used in searches of the Entrez-PubMed database (1966 2009): human herpes virus 6, HHV 6, demyelination, multiple sclerosis, pathogenesis, diagnosis, serology, cerebrospinal fluid, IgG antibodies, IgM antibodies, PCR, and lymphoproliferative techniques. Study quality was assessed using the criteria proposed by Moore and Wolfson and by the classification criteria used by the Canadian Task Force on the Periodic Health Examination. Studies were categorized both by experimental technique and by quality (high [A], intermediate [B], and low [C]) as determined by the Moore and Wolfson criteria. Overall, 25 (41%) of 61 studies, 15 (60%) of which were classified as A quality, reached a statistically significant result. According to the Canadian Task Force classification, all studies were categorized as evidence of quality II-1. Limitations of the available experimental techniques and perspectives for future research are discussed. The current review supports the need for further, objective, evidence-based examination of the relationship between HHV-6 infection and multiple sclerosis. PMID- 20926838 TI - Dynamic medium produces caprine embryo from preantral follicles grown in vitro. AB - The aim of this study was to develop a dynamic culture medium containing FSH, LH and EGF to promote the in vitro development of oocytes obtained from goat preantral follicles to complete maturation and to improve the capacity of these oocytes for in vitro fertilization (IVF) and embryo production. For experiment I, preantral follicles were cultured for 18 days in medium supplemented with increasing concentrations of FSH (T1 - control) or in control medium added LH alone or in association with EGF: T2 (LH 50 ng/ml), T3 (LH 50 ng/ml + EGF 50 ng/ml), T4 (LH 50 ng/ml + EGF 100 ng/ml), T5 (LH 100 ng/ml), T6 (LH 100 ng/ml + EGF 50 ng/ml) and T7 (LH 100 ng/ml + EGF 100 ng/ml). For experiment II, preantral follicles were cultured only in the culture medium used in T7, and after 18 days, their oocytes underwent in vitro maturation (IVM) followed by IVF. At the end of the culture period, T3, T4 and T7 had a positive influence on the daily follicular growth rate. Oocytes grown in T4 and T7 had a meiosis resumption percentage significantly superior to the other treatments. Two embryos were obtained, in which preantral follicles in medium supplemented with 100 ng/ml LH and 100 ng/ml EGF (T7). In conclusion, our sequential culture system was able to promote the in vitro growth of preantral follicles, promoting their oocyte maturation and caprine embryo production from preantral follicles. PMID- 20926839 TI - Asymmetric syncytial expression of GLUT9 splice variants in human term placenta and alterations in diabetic pregnancies. AB - Glucose transport from the maternal to fetal side of the placenta is critical for fetal growth and development due to the absence of fetal gluconeogenesis. Human GLUT9, existing as 2 isoforms, is a novel member of the transporter family. This study investigated the localization and relative expression levels of these isoforms in the human term placenta from both control and diabetic patients. Placenta samples were collected from normal pregnancies and those complicated by maternal diabetes (White classifications A1, A2, and B). Antibodies specific for the different isoforms were used to detect expression. Both forms of the protein are expressed in syncytiotrophoblast cells. Subcellular fractionation revealed an asymmetrical expression pattern with GLUT9a on basal membranes, whereas GLUT9b localizes to microvillus membranes. Expression of both isoforms is significantly increased in placental tissue from diabetic pregnancies. Altered expression of GLUT9 in the placenta may play a role in the fetal pathophysiology associated with diabetes-complicated pregnancies. PMID- 20926840 TI - Results from a clinical multidisciplinary weight management program. AB - BACKGROUND/OBJECTIVE: Published data regarding outcomes of pediatric behavioral weight management are mainly from research interventions. The authors wished to explore outcomes from a clinical program. METHODS: A retrospective analysis of data from obese adolescents enrolled in the Michigan Pediatric Outpatient Weight Evaluation and Reduction program (April 2007 to June 2008). The multidisciplinary program included group sessions, individual visits, and exercise classes. Linear regression was used to explore associations between change in body mass index (BMI) and age, sex, race, and insurance. RESULTS: N = 67. Mean age was 14.5 years; 71% female, 50% Medicaid enrollees, and 30% African American. Mean initial BMI was 40. Mean change in BMI was -2.3 for those completing the 24-week program (n = 48; P < .01). Reduction in BMI was not associated with participants' demographic characteristics. CONCLUSIONS: A clinical multidisciplinary weight loss program for adolescents can lead to decreases in BMI after 24 weeks. Further work is needed to assess long-term outcomes. PMID- 20926841 TI - How far can toddlers reach onto a standard kitchen countertop? PMID- 20926842 TI - Four-month-old infant with macrocephaly and prominent scalp veins. PMID- 20926843 TI - Development of predictive quantitative structure-activity relationship models of epipodophyllotoxin derivatives. AB - Epipodophyllotoxins are the most important anticancer drugs used in chemotherapy for various types of cancers. To further, improve their clinical efficacy a large number of epipodophyllotoxin derivatives have been synthesized and tested over the years. In this study, a quantitative structure-activity relationship (QSAR) model has been developed between percentage of cellular protein-DNA complex formation and structural properties by considering a data set of 130 epipodophyllotoxin analogues. A systematic stepwise searching approach of zero tests, missing value test, simple correlation test, multicollinearity test, and genetic algorithm method of variable selection was used to generate the model. A statistically significant model (r((train))(2) = 0.721; q(cv)(2) = 0.678) was obtained with descriptors such as solvent-accessible surface area, heat of formation, Balaban index, number of atom classes, and sum of E-state index of atoms. The robustness of the QSAR models was characterized by the values of the internal leave-one-out cross-validated regression coefficient (q(cv)(2)) for the training set and r((test))(2) for the test set. The root mean square error between the experimental and predicted percentage of cellular protein-DNA complex formation (PCPDCF) was 0.194 and r((test))(2) = 0.689, revealing good predictability of the QSAR model. PMID- 20926844 TI - High-throughput screen for Escherichia coli heat shock protein 70 (Hsp70/DnaK): ATPase assay in low volume by exploiting energy transfer. AB - Members of the heat shock protein 70 (Hsp70) family of molecular chaperones are emerging as potential therapeutic targets. Their ATPase activity has classically been measured using colorimetric phosphate detection reagents, such as quinaldine red (QR). Although such assays are suitable for 96-well plate formats, they typically lose sensitivity when attempted in lower volume due to path length and meniscus effects. These limitations and Hsp70's weak enzymatic activity have combined to create significant challenges in high-throughput screening. To overcome these difficulties, the authors have adopted an energy transfer strategy that was originally reported by Zuck et al. (Anal Biochem 2005;342:254-259). Briefly, white 384-well plates emit fluorescence when irradiated at 430 nm. In turn, this intrinsic fluorescence can be quenched by energy transfer with the QR based chromophore. Using this more sensitive approach, the authors tested 55,400 compounds against DnaK, a prokaryotic member of the Hsp70 family. The assay performance was good (Z' ~0.6, coefficient of variation ~8%), and at least one promising new inhibitor was identified. In secondary assays, this compound specifically blocked stimulation of DnaK by its co-chaperone, DnaJ. Thus, this simple and inexpensive adaptation of a colorimetric method might be suitable for screening against Hsp70 family members. PMID- 20926845 TI - The contribution of health technology assessment, health needs assessment, and health impact assessment to the assessment and translation of technologies in the field of public health genomics. AB - The European Union has named genomics as one of the promising research fields for the development of new health technologies. Major concerns with regard to these fields are, on the one hand, the rather slow and limited translation of new knowledge and, on the other hand, missing insights into the impact on public health and health care practice of those technologies that are actually introduced. This paper aims to give an overview of the major assessment instruments in public health [health technology assessment (HTA), health needs assessment (HNA) and health impact assessment (HIA)] which could contribute to the systematic translation and assessment of genomic health applications by focussing at population level and on public health policy making. It is shown to what extent HTA, HNA and HIA contribute to translational research by using the continuum of translational research (T1-T4) in genomic medicine as an analytic framework. The selected assessment methodologies predominantly cover 2 to 4 phases within the T1-T4 system. HTA delivers the most complete set of methodologies when assessing health applications. HNA can be used to prioritize areas where genomic health applications are needed or to identify infrastructural needs. HIA delivers information on the impact of technologies in a wider scope and promotes informed decision making. HTA, HNA and HIA provide a partly overlapping and partly unique set of methodologies and infrastructure for the translation and assessment of genomic health applications. They are broad in scope and go beyond the continuum of T1-T4 translational research regarding policy translation. PMID- 20926846 TI - Factors associated with participation in providing buccal cell DNA for a genetic epidemiologic study. AB - AIMS: Our aim was to investigate factors associated with participation in buccal cell DNA collection using a large-scale prospective cohort study. METHODS: Of the 183,634 Korea Medical Insurance Corporation (KMIC) prospective cohort study enrollees, 44,773 (36,794 men) were randomly selected. Buccal cell collection kits were mailed and collected from March to September 2004. Epidemiologic characteristics measured at baseline (1990 or 1992) and during follow-up (1998) were compared between respondents and nonrespondents. RESULTS: Among the 13,084 (29.2%) respondents, 78.7% submitted usable samples (DNA concentration >=3 MUg). After adjustments for either or both age and family history of chronic disease, participation in men was positively associated with old age, a family history of chronic disease, low subjective health status, and regular exercise, and negatively associated with current smoking status. In women, only old age was associated with participation. Low body mass index (BMI) (<18.5 kg/m(2)), blood pressure, total cholesterol, and fasting blood glucose level were negatively associated with participation in men after adjustments for age and family history of chronic disease, but not in women, except for low BMI. CONCLUSIONS: In this study, collecting buccal cell DNA by mailed survey has a low success rate (29%), and there appear to be a nonresponse bias and gender differences in the collection process. PMID- 20926847 TI - Quality of care indicators for muscle-invasive bladder cancer. AB - OBJECTIVE: To define a set of quantifiable quality of care indicators (QIs) to measure the standard of care in our institute given to patients with muscle invasive bladder cancer (MIBC). PATIENTS AND METHODS: Possible QIs were defined and selected by a multidisciplinary project group from recent literature, guidelines, and/or consensus within the project group. In a retrospective study a baseline for each QI was assessed and compared to a predefined benchmark. RESULTS: Four categories of QIs were selected: (1) care management, (2) accessibility and time management, (3) professional competence, and (4) patient factors. A list of 26 QIs was created. In the retrospective study, it became evident that 22 QIs failed to reach their benchmark, because of (1) an inadequate process of care (n = 5), (2) insufficient care given (n = 14), and (3) data not retrievable in retrospective study design (n = 2). Adjustments were made in the different processes of care in order to improve quality of care. CONCLUSIONS: In the face of a complete lack of a QoC registration system for MIBC, we listed 26 quantifiable QIs, to measure QoC in our own institute. Our process of care did not meet 22 of the benchmarks, after which adjustments were made. This QoC registration method is a first step in defining applicable quality of care indicators, for implementation in the clinical practice. PMID- 20926848 TI - Evidence in a human fetus of micrognathia and cleft lip as potential effects of early cytomegalovirus infection. AB - Human cytomegalovirus (CMV) infection is one of the most frequent congenital infections, affecting 0.2-2% of all live births. Approximately 30-50% of pregnant women are seronegative at the beginning of pregnancy, and 1% will develop primary infection during pregnancy. Fetal CMV infection is associated with a phenotype that has been described to include central nervous system anomalies, hydrops fetalis and oligohydramnios. Impaired first branchial arch development as well as orofacial clefts after CMV infection have been shown in animal models. We present a case in which ultrasound examination at 29 weeks of gestation revealed marked micrognathia and slight cleft lip as well as multiple signs of fetal infection. We focus on the detection of fetal face and skull anomalies. PMID- 20926849 TI - Surgical management of the newborn with congenital diaphragmatic hernia. AB - Despite advances in the surgical treatment and medical management over the last 20 years, neonates with congenital diaphragmatic hernia (CDH) remain one of the most challenging patient groups for all clinicians. Treatment strategies have shifted from emergent surgical repair and maximum ventilatory support to delayed repair and preoperative hemodynamic stabilization with lung-sparing ventilation strategies and extracorporeal membrane oxygenation. Subsequently, overall survival has improved to as high as 80% in some centers. However, specific treatment criteria are vague and highly variable amongst centers. This lack of consensus of these treatment modalities remains elusive due to the heterogeneity in disease severity as well as heterogeneity in patient care amongst centers. As a result of the rare incidence of disease and limited experience of individual centers, the evidence for CDH is typically reported as a homogenous disease largely supported by case series and networked-based studies. To better evaluate the data and compare treatment strategies, a classification and stratification of disease and centers is needed. PMID- 20926850 TI - The impact of the 2007 ATS/IDSA diagnostic criteria for nontuberculous mycobacterial disease on the diagnosis of nontuberculous mycobacterial lung disease. AB - BACKGROUND: In 2007, the American Thoracic Society (ATS) and Infectious Disease Society of America (IDSA) published new diagnostic guidelines for nontuberculous mycobacterial (NTM) disease. Bacteriological criteria have become simpler compared to the 1997 ATS diagnostic criteria. OBJECTIVE: For assessing the impact of the 2007 ATS/IDSA diagnostic criteria, we compared the diagnosis rate and time to diagnosis of NTM lung disease using the 1997 and 2007 ATS guidelines. METHODS: Sixty-four patients who had excreted Mycobacterium intracellulare, M. avium, M. abscessus or M. kansasii at least one time in their respiratory specimens at Chonnam National University Hospital were reviewed. The 1997 ATS and 2007 ATS/IDSA guidelines were applied to these patients. RESULTS: Thirty-seven of 64 patients (57.8%) were diagnosed with NTM lung disease by the 1997 ATS criteria. When the 2007 ATS/IDSA criteria were applied, 6 patients were newly diagnosed with NTM lung disease. The diagnosis rate significantly increased from 57.8 to 67.2% (p < 0.001). The time to diagnosis in the 1997 ATS and 2007 ATS/IDSA guidelines was 46.4 +/- 53.0 and 36.2 +/- 38.5 days, respectively (p = 0.002). CONCLUSION: These data suggest that we can shorten the time to diagnose NTM lung disease and diagnose more simply by using the 2007 ATS/IDSA guidelines. Further study will be needed to assess that these changes affect the management of NTM disease. PMID- 20926851 TI - Everything you always wanted to know about sex ... in flies. AB - 'Everything you always wanted to know about sex' is a workshop organized as part of the annual Drosophila Research Conference of the Genetics Society of America. This workshop provides an intellectual venue for interaction among research groups that study sexual dimorphism from the molecular, evolutionary, genomic, and behavioral perspectives. The speakers summarize the key ideas behind their research for people working in other fields, outline unsolved questions, and offer their opinions about future directions. The 2010 workshop highlighted the power of the Drosophila model for understanding sexual dimorphism at levels ranging from cell biology and gene regulation to population genetics and genome evolution, and demonstrated the importance of cross-disciplinary interactions in the study of sex. In this respect, Drosophila sets a good example for research in other organisms, including humans and their mammalian relatives. PMID- 20926852 TI - Cladistic analysis reveals brainless urbilateria. PMID- 20926853 TI - On the origin and evolution of the tripartite brain. AB - The many different nervous systems found in bilaterally symmetric animals may indicate that the tripartite brain appeared several times during the course of bilaterian evolution. However, comparative developmental genetic evidence in arthropods, annelids, urochordates, and vertebrates suggests that the development of a tripartite brain is orchestrated by conserved molecular mechanisms. Similarities in the underlying genetic programs do not necessarily reflect a common origin of structures. Nevertheless, 3 lines of evidence support a monophyletic origin of the tripartite brain and possibly also an elongated central nervous system (CNS): structural homology, character identity networks, and the functional equivalence of character identity genes. Monophyly of the brain also implies that the brain was secondarily reduced and lost multiple times during the course of evolution, leading to extant brainless bilaterians. The likelihood of secondary loss can be estimated by metazoan divergence times and through reconstructed cases such as limb loss in tetrapods or eye loss in fish. When scaled to molecular clock dates, monophyly of the tripartite brain indicates that existing brainless Bilateria had several hundred million years' time for the secondary modification and eventual loss of a primitive/ancestral brain and CNS. To corroborate this conjecture, ancestral character identity genes of living brainless Bilateria can be tested for their potential to substitute Drosophila or Mus homologs in tripartite brain development. PMID- 20926854 TI - Cellular scaling rules for the brains of an extended number of primate species. AB - What are the rules relating the size of the brain and its structures to the number of cells that compose them and their average sizes? We have shown previously that the cerebral cortex, cerebellum and the remaining brain structures increase in size as a linear function of their numbers of neurons and non-neuronal cells across 6 species of primates. Here we describe that the cellular composition of the same brain structures of 5 other primate species, as well as humans, conform to the scaling rules identified previously, and that the updated power functions for the extended sample are similar to those determined earlier. Accounting for phylogenetic relatedness in the combined dataset does not affect the scaling slopes that apply to the cerebral cortex and cerebellum, but alters the slope for the remaining brain structures to a value that is similar to that observed in rodents, which raises the possibility that the neuronal scaling rules for these structures are shared among rodents and primates. The conformity of the new set of primate species to the previous rules strongly suggests that the cellular scaling rules we have identified apply to primates in general, including humans, and not only to particular subgroups of primate species. In contrast, the allometric rules relating body and brain size are highly sensitive to the particular species sampled, suggesting that brain size is neither determined by body size nor together with it, but is rather only loosely correlated with body size. PMID- 20926855 TI - Cellular scaling rules for primate spinal cords. AB - The spinal cord can be considered a major sensorimotor interface between the body and the brain. How does the spinal cord scale with body and brain mass, and how are its numbers of neurons related to the number of neurons in the brain across species of different body and brain sizes? Here we determine the cellular composition of the spinal cord in eight primate species and find that its number of neurons varies as a linear function of cord length, and accompanies body mass raised to an exponent close to 1/3. This relationship suggests that the extension, mass and number of neurons that compose the spinal cord are related to body length, rather than to body mass or surface. Moreover, we show that although brain mass increases linearly with cord mass, the number of neurons in the brain increases with the number of neurons in the spinal cord raised to the power of 1.7. This faster addition of neurons to the brain than to the spinal cord is consistent with current views on how larger brains add complexity to the processing of environmental and somatic information. PMID- 20926856 TI - Central projections of primary sensory afferents to the spinal dorsal horn in the long-tailed stingray, Himantura fai. AB - The central projections of primary sensory afferents innervating the caudal region of the pectoral fin of the long-tailed stingray (Himantura fai) were labeled by applying the lipophilic carbocyanine dye DiI to the dorsal roots in fixed tissue. These observations were complemented by examination of hemotoxylin and eosin-stained paraffin sections of the dorsal root entry zone, and transmission electron microscopy of the dorsal horn. Transverse sections of the sensory nerve and dorsal root revealed two distinct myelinated axon sizes in the sensory nerve. Although the thick and thin axons do not appear to group together in the sensory nerves and dorsal root, they segregate into a dorsally directed bundle of thin fibers and a more horizontally directed bundle of thick fibers soon after entering the spinal cord. In DiI-labeled horizontal sections, fibers were observed to enter the spinal cord and diverge into rostrally and caudally directed trajectories. Branching varicose axons could be traced in the dorsal horn gray matter in the segment of entry and about half of the adjacent rostral and caudal segments. In transverse and sagittal sections, DiI-labeled afferents were seen to innervate the superficial and, to a lesser extent, deeper laminae of the dorsal horn, but not the ventral horn. Electron microscopy of unlabeled dorsal horn sections revealed a variety of synaptic morphologies including large presynaptic elements (some containing dense-core vesicles) making synaptic contacts with multiple processes in a glomerular arrangement; in this respect, the synaptic ultrastructure is broadly similar to that seen in the dorsal horn of rodents and other mammals. PMID- 20926857 TI - The organization of CRF neuronal pathways in toads: Evidence that retinal afferents do not contribute significantly to tectal CRF content. AB - Previous work has suggested that the peptide corticotropin-releasing factor (CRF) acts to inhibit visually guided feeding in anurans, but little is known about potential targets for CRF within the subcortical visuomotor circuitry. Here we investigated the relationship between CRF neuronal organization and visual pathways in toads. CRF-immunoreactive (ir) neurons and fibers were widely distributed throughout the ventral subpallial telencephalon and hypothalamus, although few fibers were found in telencephalic areas, such as the striatum, that are known to project to the tectum in anurans. Large populations of CRF-ir cells were observed in the bed nucleus of the stria terminalis and preoptic area as well as in the ventral infundibular hypothalamus. CRF-ir neurons and fibers also were observed in several midbrain and brain stem areas. Colchicine treatment significantly enhanced CRF-ir neurons and fibers throughout the brain, and revealed CRF-ir cell groups in several brain areas (including the dorsal hypothalamus) that were not observed in untreated animals. Intrinsic CRF immunoreactive neurons were routinely observed in cell layer 8 and sometimes in layer 6 of the optic tectum in both untreated and colchicine-treated animals. CRF was detected in toad optic tectum by radioimmunoassay, although tectal CRF content was less than that of the hypothalamus and forebrain. Unilateral eye ablation did not affect CRF content of the contralateral optic tectum. We conclude that CRF-producing neurons are widely distributed in several areas of the toad brain known to be involved in regulating the behavioral, autonomic and endocrine response to stressors, including the optic tectum and several brain areas known to project to the optic tectum. Furthermore, retinal afferents do not contribute significantly to tectal CRF content. PMID- 20926858 TI - Biweekly vinorelbine and gemcitabine as second-line treatment and beyond in non small cell lung cancer. AB - BACKGROUND: To evaluate the activity and tolerance of gemcitabine (GEM) in combination with vinorelbine (VRL) in pretreated patients with advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Fifteen patients with advanced NSCLC who had disease progression after a cisplatin- or taxane-based front-line regimen were enrolled into a 2-stage design trial and were treated with VRL 30 mg/m2 i.v. for 10 min followed by GEM 1,200 mg/m2 i.v. for 30 min on days 1 and 15 of each 28-day cycle. Chemotherapy was given for 6 cycles unless disease progression or unacceptable toxicity was seen. The patients' median age was 64 years and the performance status (WHO) was 0 (n = 7), 1 (n = 5), and 2 (n = 3). The treatment was second line for 10 (67%) and third line or more for 5 (33%) patients. RESULTS: No complete or partial responses were observed. Stable disease was seen in 4 (27%) patients and progressive disease in 11 (73%). The median time to tumor progression was 3 months (range 1-12) and the median survival was 4 months (range 2-31). Severe myelotoxicity was infrequent. Grade 2 neutropenia was observed in 2 (13%) patients, grade 2 thrombocytopenia in 1 (7%), and grade 2 anemia in 3 (20%). Nonhematologic toxicities were very mild and easily manageable. CONCLUSION: The GEM plus VRL combination at the present doses and schedule is a safe but ineffective regimen; therefore, it is not recommended as second-line treatment in patients with advanced NSCLC. PMID- 20926859 TI - Effects of legal antibiotic restrictions on consumption of broad-spectrum beta lactam antibiotics, glycopeptides and amphotericin B. AB - In 2002, antimicrobial drugs were the most frequently prescribed drugs in Turkey. On February 15, 2003, the Turkish Government implemented a new Budget Application Instruction (BAI) to promote rational antibiotic usage in order to decrease the costs. This BAI restricted the reimbursement of certain antibiotics without prescription or approval by the infectious diseases specialists (IDS). The purpose of this study is to evaluate the effect of BAI on antibiotic consumption for the 3 years before and 2 years after its implementation, according to IMS Health Office findings. Based on the data of the IMS Health Turkey Office, the amount of some broad-spectrum antibiotics (piperacillin/tazobactam, imipenem, meropenem, cefoperazone/sulbactam, ceftazidime, cefepime, teicoplanin, vancomycin, and amphotericin B) that were prescribed by IDS between 2000 and 2002 and between 2003 and 2004 are determined. The Anatomical Therapeutic Chemical classification and the defined daily dose (DDD)/1,000 methodology are used to calculate antibiotic consumption. Total antibiotic consumption before BAI, in 2000, 2001 and 2002 was 0.091, 0.107 and 0.119 DDD/1,000 inhabitant-days, respectively, and after BAI, in 2003 and 2004, 0.137 and 0.135 DDD/1,000 inhabitant-days, respectively. Average utilization of antibiotics before the implementation of BAI was 0.105 DDD and increased to 0.136 DDD after BAI. Antibiotic consumption has increased 1.3-fold after the implementation of BAI. However, the effect of restricted antibiotic utilization was revealed especially in the second year after BAI. The consumption of antimicrobials decreased to 0.135 in 2004 while it was 0.137 in 2003. PMID- 20926860 TI - Low endotoxin release from Escherichia coli and Bacteroides fragilis during exposure to moxifloxacin. AB - BACKGROUND: Bacterial endotoxin is known to act as a potent trigger of disseminated coagulation and septic shock. During clinical antibiotic treatment, endotoxin may be released from Gram-negative bacteria. It is known that antibiotic classes differ in their ability to induce endotoxin release. AIM: It was the aim of this study to test the endotoxin-liberating potential of different antibiotics with activity against Escherichia coli and Bacteroides fragilis. METHODS: In vitro test models were used to evaluate the endotoxin-liberating potential of moxifloxacin, a 4th-generation quinolone with antianaerobic activity. Bacteria were exposed to moxifloxacin at 2*, 10* and 50* the minimal inhibitory concentration. Endotoxin release was measured by enzyme-linked immunosorbent and Limulus amoebocyte lysate assays. Comparator drugs were ceftazidime and imipenem, i.e. antibiotics with known high and low endotoxin liberating potential, respectively. As a parameter for biological responses to endotoxin, the release of proinflammatory cytokines (tumor necrosis factor-alpha, interleukin-1beta) from monocytes/macrophages was quantified with bioassays. RESULTS: In all test systems, release of endotoxin during exposure of bacteria to moxifloxacin was minimal or low and comparable with that of imipenem. CONCLUSIONS: Moxifloxacin has a low potential to cause endotoxin-mediated detrimental clinical effects. Concerning its endotoxin-releasing properties, moxifloxacin appears to be a choice equivalent to the carbapenems. PMID- 20926862 TI - Chemokines in inflammatory bowel diseases. AB - Uncontrolled activation of mucosal effector cells has been identified as the main pathogenic mechanism involved in the initiation and perpetuation of mucosal inflammation in inflammatory bowel diseases (IBD). The sustained activation of these cells leads to the aberrant production of various pro-inflammatory mediators, which co-ordinated action amplifies the inflammatory process. In this setting a network of tissue-specific chemoattractant cytokines (chemokines) and their corresponding receptors have been implicated as main contributors in the initiation and perpetuation of the inflammatory reaction in IBD. They are produced by a variety of inflammatory cells present in IBD lesions, as well as endothelial and epithelial cells. Chemokines not only control the multistep process of leukocyte adhesion to and migration across the endothelium, but also the release of lipid mediators and oxygen radicals from leukocytes, the modulation of tumorigenesis, release of matrix metalloproteinases and tissue fibrosis. Numerous data indicate that that intestinal chemokine expression is non selectively up-regulated in IBD and correlates with disease activity. The development of selective inhibitors for chemokines or chemokine receptors, based on a more complete understanding of the immunopathogenic role of chemokines in intestinal inflammation, will be of great interest as potential novel therapeutic strategies in IBD. PMID- 20926864 TI - New insights into IBD epidemiology: Are there any lessons for treatment? AB - Changing trends in the epidemiology of IBD provide an opportunity to examine possible etiological hypotheses. Why did IBD emerge in developed nations in the middle of the 20th century? Why did it emerge initially as ulcerative colitis but now Crohn's disease has become the predominate form of IBD in developed nations? Why is IBD emerging in recent years in developing nations and why is it that ulcerative colitis is the predominate form in these countries? In this chapter we will explore what is known about environmental issues that impact on disease presentation and where they provide opportunities for therapy. Managing smoking cessation in Crohn's disease is substantiated by evidence showing that smokers have a worse course of disease than non-smokers or than persons who quit smoking. Introducing nicotine to patients with ulcerative colitis has not brought the positive results anticipated with the widespread observation that smoking cessation was associated with flaring of this disease. Assessing and managing stress in both Crohn's disease and ulcerative colitis has emerged as an important consideration for clinicians caring for patients with IBD, especially for patients with active disease who may develop maladaptive coping mechanisms. Recent data suggest that stress may antedate flares. It is unknown what may induce changes in the gut flora of patients with IBD compared to controls. There are suggestions that antibiotic use in childhood and specific diets particularly those lower in omega-3 fatty acids may impact on disease presentation and the common mechanism may be through alteration of gut flora. For at-risk families (where there are affected family members) perhaps greater vigilance with antibiotic use in childhood and ensuring diets are higher in omega-3 fatty acids can be considered. In the future there may be approaches to modulate gut flora either with antibiotics targeted against identified noxious microbes or with selective probiotics that can rebalance the gut dysbiosis. PMID- 20926863 TI - Genes and environment: how will our concepts on the pathophysiology of IBD develop in the future? AB - Inflammatory bowel disease (IBD) has long been known to arise from the interplay between host and environmental factors. From this, a picture is currently emerging in which IBD is likely the result of a continuum of diseases that range from mono- and oligogenically inherited familial forms at one extreme to sporadic forms at the other extreme, which are polygenic in origin and strongly influenced by environmental factors and especially those of infectious origin. The recent expansion of knowledge on the genetic underpinning of IBD has revealed several converging and inter-related functional host pathways that are central to the pathogenesis of these disorders. These include pathways such as autophagy, intracellular bacterial sensing and the unfolded protein response, which play specific roles at the interface between the host and the highly complex microbial communities within the intestines. As such they focus on the functional relationship between the intestinal epithelium and the unique microbial and immune environments along its luminal and abluminal surfaces. Thus, the genetic and environmental factors which are relevant to IBD seem to have the common property of influencing disease by virtue of their specific impact upon the functional relationship between these microbial communities and the intestinal immune system. PMID- 20926865 TI - Smoking, physical activity, nutrition and lifestyle: environmental factors and their impact on IBD. AB - Current smoking increases the risk of developing Crohn's disease and worsens its course, increasing the need for steroids, immunosuppressants, and re-operations. On the contrary, smoking protects against ulcerative colitis and after disease onset improves its course, decreasing the need for colectomy. Smoking cessation improves Crohn's disease and worsens ulcerative colitis. Achieving smoking cessation in Crohn's disease is thus an important goal of therapy, whereas patients with ulcerative colitis should not be discouraged to quit, because the beneficial effect of smoking for their disease is counterbalanced by the deleterious respiratory and cardiovascular effects of tobacco. Physical activity improves quality of life without detrimental effect on disease activity, and may contribute to increase muscle mass and to prevent osteoporosis. Regarding nutrition, a Western diet may be associated with an increased risk of IBD, and a case-control study revealed an increased consumption of linoleic acid before diagnosis of ulcerative colitis. Liquid diets may improve Crohn's disease flares and decrease the need for steroids; however, there are no defined diets able to improve the disease course, and in Crohn's disease, supplementation with omega-3 fatty acids did not show a significant benefit. Obesity is becoming more prevalent in IBD and may be associated with higher disease activity. In total, adhering to four simple lifestyle factors - never smoking, physical activity, prudent diet and body mass index <25 - may have a strong impact both on the prevention of major chronic diseases and on the course of IBD. PMID- 20926866 TI - New serologic markers for inflammatory bowel disease diagnosis. AB - Inflammatory bowel diseases (IBD) are chronic intestinal disorders where, in genetically susceptible hosts, an intestinal microorganism triggers an over reactive immune response. Antibodies against luminal antigens are specifically associated with Crohn's disease (CD). In addition to the previously described antibodies antineutrophil cytoplasmic (auto)antibodies (ANCA), anti-Saccharomyces cerevisiae antibodies (ASCA), OmpC, I2 and CBir1 Flagellin, new anti-glycan antibodies were recently added to the armamentarium of serologic markers in IBD. Glycans are sugars associated with proteins, abundant on many living cells. The anti-glycan antibodies are directed against laminaribioside, chitobioside, mannobioside and mannan residues and are designated anti-laminaribioside carbohydrate antibodies (ALCA), anti-chitobioside carbohydrate antibodies (ACCA), anti-mannobioside carbohydrate antibodies (AMCA) and gASCA, respectively. Anti laminarin IgA (Anti-L), and anti-chitin IgA (Anti-C) are new members of this family. Laminarin and chitobioside are capable of stimulating the innate immune system, thus the finding of antibodies against these glycans suggests a connection between the adaptive and innate arms of the immune response in CD patients. The contribution of serologic markers, specifically the anti-glycan antibodies, to IBD diagnosis may be in differentiating IBD from other gastrointestinal diseases, and between CD and ulcerative colitis (UC), in better classifying undetermined colitis and for decision-making prior to proctocolectmy in UC patients. The anti-glycan antibodies are specifically important in ASCA negative CD patients. Correlation between serologic markers and genetic variations may contribute to reclassifying IBD into new and more homogeneous subclasses. Their significance in diagnosing populations at risk, such as unaffected relatives of IBD patients and CD patients prior to diagnosis, is under current investigation. PMID- 20926867 TI - Can serologic markers help determine prognosis and guide therapy? AB - The search for biologic markers that can assess the natural history and perhaps predict the course of an individual's disease - including response to treatments over time - has become an important focus of inflammatory bowel disease research. The knowledge of an individual's prognosis can help physicians and patients make important management decisions and aid communication on risks and benefits of disease and treatment. PMID- 20926868 TI - CT enterography: is it the current state-of-the-art for small bowel diagnostics? AB - CT enterography has rapidly emerged as the preferred small bowel imaging modality at several tertiary care medical centers. It utilizes negative or neutral oral contrast agents to enhance small bowel mural assessments. A high sensitivity and specificity for active inflammation and its ability to detect extra-intestinal disease set CT enterography apart from more traditional imaging methods. It has also been shown to be of great value for the detection of occult penetrating disease, changing physician level of confidence, and altering management plans in a large proportion of patients. Concerns regarding radiation exposure will likely become less of an issue with new dose reduction techniques. CT enterography has begun to revolutionize Crohn's disease evaluations for luminal and extraluminal disease, and its role will likely continue to expand in diagnostic and management algorithms. PMID- 20926869 TI - MRI enterography: the future of small bowel diagnostics? AB - MRI plays an increasing role in small bowel imaging of Crohn's disease. MR enterography (MRE) without nasojejunal intubation and radiation exposure offers similar results compared to MR enteroclysis (with intubation) and should be therefore the preferred method. Sensitivity and specificity is comparable to that of CT enterography. Capsule endoscopy is obviously superior to MRE in detecting superficial lesions, but this is limited to the mucosa and stenosis has to be excluded before examination using imaging, like MRE. There are no convincing studies in the literature regarding assessment of disease activity with imaging. Moreover, there is no consensus in the literature about a suitable reference standard. PMID- 20926870 TI - Capsule and balloon endoscopy: When are they really needed in patients with inflammatory bowel diseases? AB - The evaluation of the small bowel in patients with suspected or established IBD is generally performed by radiologic techniques. Capsule endoscopy and balloon enteroscopy may offer additional advantages in the evaluation of small bowel inflammation in patients with suspected small bowel involvement but negative prior radiologic evaluation. This review summarizes the current clinical status of capsule and balloon enteroscopy in patients with suspected or established IBD. PMID- 20926871 TI - Chromoendoscopy: what is its true value for ulcerative colitis surveillance? AB - Advanced imaging technologies are enabling targeted biopsies or endoscopic resections due to better visualization of the mucosal architecture. This new concept of 'smart biopsies' is in particular important for patients with higher risk for development cancer (e.g. ulcerative colitis) but can also be beneficial for screening purposes. This short review will focus on new imaging modalities like chromoendoscopy, digital chromoendoscopy, high-definition endoscopy and confocal laser endomicroscopy in the lower GI tract which will be crucial in the future to detect colorectal neoplasia earlier then before. PMID- 20926872 TI - Supportive therapy in IBD: what additional diagnoses and conditions must be treated? AB - Despite advances in our understanding of inflammatory bowel disease (IBD) pathogenesis and increased ability to treat patients with severe and refractory disease, patients continue to suffer from disease complications, and increasing numbers of both Crohn's disease (CD) and ulcerative colitis (UC) patients are admitted annually in the USA. The rapid evolution in IBD medications and treatment paradigms has contributed to a disparity in clinical care which may vary between expert centers routinely treating large numbers of IBD patients and hospitals with low annual IBD admissions. High-volume centers handling in excess of 150 IBD annual admissions have improved operative and inpatient outcomes compared with hospitals caring for IBD patients less frequently. Although the precise reason for this disparity in clinical outcomes is not known, we hypothesize that expert centers provide superior IBD supportive therapy. This supportive care includes additional diagnostic and therapeutic approaches to help patients achieve optimal outcomes. We review information regarding disparities in the quality of IBD clinical care then focus on supportive therapy for IBD patients, including diagnostic approaches to identify confounding factors contributing to poor IBD outcome, supportive therapeutic approaches to optimize the outcome in hospitalized IBD patients, and future directions exploring brain body interaction in the treatment of pain, stress and sleep deprivation in patients suffering from IBD. PMID- 20926873 TI - What is the patient's perspective: How important are patient-reported outcomes, quality of life and disability? AB - Inflammatory bowel disease (IBD) is known to influence physical, psychological, familial and social dimensions of life. Over the past two decades, attention has been focused on the ability of IBD to alter patients' quality of life. A number of general and disease-specific scales have been used to assess quality of life in patients with IBD. The Inflammatory Bowel Disease Questionnaire (IBDQ) is the most widely disease-specific tool used in clinical trials. Forty to fifty million individuals in the USA now live with potentially disabling conditions. Disability usually refers to an individual's inability to perform a task successfully. Disability refers to the problems that are experienced in different areas or health domains, whereas quality of life refers to how the individual feels about these limitations and restrictions. Data about disability are objective descriptions that differ from subjective appraisals such as quality of life, well being, and personal satisfaction with life. For instance, difficulties in walking (disability) may be in stark contrast to how the individual feels about this difficulty (quality of life). It should be emphasized that the concepts of health related quality of life and disability are different but not mutually exclusive. When compared to quality of life, disability remains poorly investigated in IBD. Work is the only dimension of disability that has been widely assessed in IBD. Similar to multiple sclerosis and rheumatoid arthritis, developing a specific instrument capable of evaluating disability in IBD is a prerequisite to undertaking clinical trials aimed at identifying therapies capable of changing their clinical course. PMID- 20926874 TI - Evolving concepts in IBD therapy: What should be studied in the future? AB - New knowledge regarding the etiopathophysiology of inflammatory bowel diseases (IBD) may provide new approaches for treatment. The most convincing concept at the moment is a defective mucosal barrier due to inappropriate recognition of the luminal flora or to a defective defense against those bacteria. These concepts indicate that the paradigm of immune suppression may not be the optimal concept. Therefore variable approaches to improve the barrier function or to modulate luminal components have to be studied in the future. This includes probiotics, bile acid receptor agonists, Toll-like receptor agonists and many other as yet hypothetical ideas. We still have much to learn about the concepts mentioned in order to achieve the goals of treatment, i.e. avoiding structural damage and complications. PMID- 20926875 TI - Does treatment schedule matter? Once daily versus divided doses of 5-ASAs. AB - Sulfasalazine was the first 5-ASA used to treat ulcerative colitis (UC). Because of tolerability issues, it was administered in a three times a day schedule in order to try to minimize side effects. With the development of sulfa-free 5-ASA products, the controlled trials used historical clinical experience and in vitro pharmacokinetic studies to dose their therapies to perhaps be in the most favorable light possible. However, it became clear over the years that outside of the context of a clinical trial, t.i.d. or even q.i.d. dosing led to lower patient satisfaction and overall adherence. Research demonstrated that upwards of 40% of patients were not taking their maintenance 5-ASA, and many patients cited unintentional forgetfulness as the reason. It became clear that simplifying the regimen was paramount for acceptable outcomes. Early pilot data and then controlled trials demonstrated the efficacy and safety of twice daily 5-ASA for active and quiescent UC. Now several large controlled trials demonstrate the non inferiority and increased patient adherence and satisfaction with once daily dosing. MMX mesalamine was the first 5-ASA to receive US FDA approval in a once daily regimen. Results from the PODIUM and QDIEM trials have demonstrated acceptable effectiveness rates with favorable side effect profiles. Adherence rates remain high in real-world settings when medication is given once daily and data now suggest that once daily may be more effective than more frequently. It thus appears that the majority of patients with UC, whether with active or quiescent disease, can be treated with once daily 5-ASA. PMID- 20926876 TI - New keys to maintenance treatment in ulcerative colitis. AB - Maintenance treatment in ulcerative colitis often fails to prevent flares and long term complications. The first key to maintenance is to use effective therapy, even when patients become asymptomatic. The second key is to communicate the importance of adherence to patients, and to help them achieve long term adherence. Simplified dosing schedules are of some benefit, but the bond between patient and doctor, and the patient's belief in the efficacy of the therapy are essential. Decreased co-pays (a fixed amount paid by patients seeking care that is not reimbursed my medical insurance) have been associated with increased adherence, and incentives for patients may be a cost-effective approach to improving adherence. While the most substantial data on the association between adherence and clinical outcomes is in 5-ASAs, non-adherence can also limit the efficacy of thiopurines and biologics. The third key to maintenance treatment is monitoring and maintaining control of inflammation. Decreased histologic and endoscopic damage to the colon has been associated with decreased risk of colon cancer. The most cost-effective way to monitor smoldering inflammation is not known, but endoscopy, structured symptom indices, and biomarkers may be valuable approaches. The fourth key to maintenance treatment is optimizing immunomodulator therapy with thiopurines, and possibly methotrexate in the future. The fifth key to maintenance treatment in ulcerative colitis is maintaining biologic efficacy by avoiding low trough levels and being vigilant for subclinical inflammation and symptom recurrence at the end of dose intervals. Combination therapy with immunomodulators improves trough levels in Crohn's, and may prove to have benefits for the maintenance of biologic efficacy in ulcerative colitis. PMID- 20926877 TI - Phosphatidylcholine (lecithin) and the mucus layer: Evidence of therapeutic efficacy in ulcerative colitis? AB - Colonic mucus protects against attacks from bacteria in stool. One component of mucus is phosphatidylcholine (PC) which is thought to be arranged as continuous lamellar layer in the apical mucus and to be responsible for establishing a protective hydrophobic surface. This 'intestinal surfactant' plays a key role in mucosal defense. Thus, a defective PC layer contributes to the development of inflammation. Analysis of rectoscopically acquired mucus aliquots revealed a 70% decrease in PC content in ulcerative colitis (UC) compared to Crohn's disease (CD) and healthy controls - independent of disease activity. Accordingly, we propose that lack of mucus PC is a key pathogenetic factor in UC. In clinical studies a delayed-release oral PC preparation (rPC) was found to substitute the lack of PC in rectal mucus. Indeed, in non-steroid-treated active UC, 53% of rPC patients reached remission [clinical activity index (CAI) <=3] compared to 10% of placebo patients (p <= 0.001). Endoscopic and histologic findings improved concomitantly. A second trial with 60 chronic-active, steroid-dependent UC patients was conducted to test for steroid-sparing effects. Complete steroid withdrawal with a concomitant achievement of remission (CAI <=3) or clinical response (>=50% CAI improvement) was reached in 15 PC-treated patients (50%) but only in 3 (10%) placebo patients (p = 0.002). In conclusion, intrinsic reduction of PC (lecithin) in colonic mucus may be a key pathogenetic feature of UC. Topical supplement of PC by a delayed-released oral PC preparation is effective in resolving inflammatory activity of UC and may develop to a first-choice therapy for this disease. PMID- 20926878 TI - The role of biologics in ulcerative colitis. AB - Since the introduction of anti-TNF agents for the treatment of Crohn's disease there has been interest in the potential for treating ulcerative colitis with biological therapies. Early observational series suggested a benefit in the setting of severe, hospitalized patients. However, the recent completion of two large multi-center, double-blind placebo-controlled trials confirmed a role for infliximab for outpatients with refractory, moderate-severe disease with evidence for clinical remissions, mucosal healing, and a reduction in colectomies. Despite this evidence, there are numerous questions remaining regarding the optimal positioning in the setting of moderate-severe disease, potential benefits of concomitant immune suppression and the need for maintenance treatment after induction therapy. Additional clinical trials have demonstrated a less profound benefit for adalimumab at similar doses that are used in Crohn's disease. Other biological agents that have targeted T cells such as visiluzimab and abatacept were not demonstrated to be effective in controlled trials. PMID- 20926879 TI - Timing and indications for colectomy in chronic ulcerative colitis: Surgical consideration. AB - Total proctocolectomy (TPC) cures a patient of the intestinal manifestation of chronic ulcerative colitis. The timing of surgery during the illness will influence the choice of operation, the frequency of post-operative complications, and the long-term functional outcomes. Surgery is divided into emergency, urgent, and elective procedures. Emergency cases are performed for complications of fulminant colitis: hemorrhage, perforation, toxic megacolon or sepsis. A subtotal colectomy (STC) with a Brooke ileostomy (BI) is the procedure of choice. STC removes the bulk of the disease, allows the patient's health to be restored, medication to be withdrawn, and permits a future restorative operation. Urgent operations occur in hospitalized patients with continued symptoms after seven days of maximal medical therapy. Once again the preferred operation is a STC-BI. Indications for elective colectomy include: persistent symptoms despite maximal medical therapy, medication side-effects, persistent chronic disease state, dysplasia/malignancy. Elective surgical options include TPC-BI, TPC with ileal pouch anal anastomosis (IPAA), or STC-BI. The choice of operation is based upon patient preference and preoperative physiologic and functional status. Factors associated with increased post-operative complications are weight loss >10%, multiple preoperative blood transfusions, albumin <3.0 gm/dl, and degree of immuno-suppression. In high-risk patients, STC-BI should be performed. IPAA can be performed later after the patient's health is restored. In conclusion, numerous factors affect the timing and choice of operation in patients with CUC. Avoiding complications in IPAA patients is essential as they negatively impact the long-term function and durability of the IPAA. PMID- 20926880 TI - Hepatotoxicity of agents used in the management of inflammatory bowel disease. AB - Patients with inflammatory bowel disease (IBD) are at risk for hepatobiliary disease and toxicity, and the diagnosis of drug-induced liver disease in patients being treated for IBD can represent a clinical challenge. There are a number of disease states associated with IBD, which are primary sclerosing cholangitis, cholangiocarcinoma and autoimmune hepatitis. There is a wide spectrum of hepatic injury that can occur from the agents used to treat IBD, such as acute or chronic hepatic injury directly attributable to the drugs used to treat IBD (e.g. sulfasalazine, mesalamine, thiopurines, methotrexate, TNF antagonists, quinolone antibiotics); liver toxicity from drugs used to treat complications of immunomodulators and TNF antagonists (e.g. isoniazid for treatment of reactivation tuberculosis), and exacerbation of underlying chronic viral hepatitis with infliximab and other TNF antagonists. Thiopurines are also associated with the development of hepatic vascular lesions, such as nodular regenerative hyperplasia and peliosis hepatic. In addition, biologics can be associated with the reactivation of underlying chronic viral hepatitis, mandating universal screening prior to initiation of TNF-alpha antagonist therapy. PMID- 20926881 TI - Epstein-Barr virus, lymphoma risk and the potential role of HIV infection in IBD patients undergoing immunosuppression. AB - For decades, lymphoma has been considered a dreaded and untoward complication of autoimmune disorders, including inflammatory bowel disease (IBD). Yet until recently, the data linking inflammatory bowel disease with an increased risk for lymphoma has been equivocal. With the publication of the CESAME trial in 2009, a greater understanding of lymphoma risk has begun to emerge. In this Falk Symposium paper, I discuss the available data from studies that interrogated the relationship between lymphoma and IBD, thiopurines and TNFalpha-directed agents. While recent data has clarified some aspects of lymphoma epidemiology in patients with IBD, causality and the mechanisms that underlie it remain very poorly understood. PMID- 20926882 TI - Vaccines and inflammatory bowel disease. AB - Patients with inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, are at increased risk for infection due to both their underlying disease and the immunosuppressive therapy used to treat the disease. Numerous groups and papers support the routine vaccination of IBD patients, yet many opportunities to vaccinate this vulnerable population are missed. While immunogenicity may be somewhat attenuated, some protection is likely to be provided, especially when vaccination is performed during periods of reduced immunosuppression. Live viral vaccines should be avoided during periods of more intense immunosuppression; further specific guidance on this as well as information on individual vaccines is provided. PMID- 20926883 TI - State-of-the-art: Immunosuppression and biologic therapy. AB - Azathioprine and 6-mercaptopurine are orally administered immunosuppressive drugs which are effective for the treatment of Crohn's disease and ulcerative colitis. Azathioprine is rapidly converted to 6-mercaptopurine after administration. 6 Mercaptopurine is then either converted to the putative active metabolites, the 6 thioguinine nucleotides, or inactivated by the enzyme xanthine oxidase to 6 thiouric acid or alternatively inactivated to 6-methylmercaptopurine by the enzyme thiopurine methyltransferase. Thiopurine methyltransferase activity is genetically determined, with one in 300 patients having low or absent enzyme activity, one in 10 patients having intermediate enzyme activity, and 9 in 10 patients having normal enzyme activity. Patients with intermediate or low thiopurine methyltransferase activity are at risk for early leukopenia. Higher erythrocyte 6-thioguinine nucleotide concentrations are associated with a greater likelihood of clinical response. Azathioprine is modestly effective for Crohn's disease and ulcerative colitis. Toxicity associated with azathioprine includes infection and lymphoma. Anti-TNF therapy with infliximab, adalimumab, and certolizumab pegol is effective for induction and maintenance treatment of Crohn's disease, and infliximab is effective for ulcerative colitis. Toxicity associated with anti-TNF therapy includes infection and lymphoma. Combination therapy with infliximab and azathioprine is more effective for inducing and maintaining steroid-free remission and mucosal healing then monotherapy with either drug alone. Strategies to reduce immunogenicity of anti-TNF agents include combination therapy with azathioprine and administration of a loading dose followed by systematic maintenance dosing. Higher serum trough concentrations of infliximab occur more frequently in patients receiving combination therapy with azathioprine and are associated with better clinical outcomes. Combination therapy is associated with an increased relative risk of opportunistic infection, but is not associated with an increased absolute risk of serious infection. Clinical practice should change such that combination therapy with an anti-TNF agent and azathioprine replace azathioprine in patients failing first line therapy with mesalamine and/or steroids. PMID- 20926884 TI - What options do we have for induction therapy for Crohn's disease? AB - The first goal of Crohn's disease treatment is to induce a response. The choice of induction therapy depends on a number of factors. First, disease severity will dictate the level of intensity of treatment. Moderate to severely active Crohn's disease needs to be treated more aggressively than mild disease. Second, it is important to consider the disease distribution, since some medications (e.g. 5 aminosalicylates, budesonide, antibiotics) are more effectively delivered to the small bowel or the colon. Third, prior medications need to be considered. A patient naive to immunomodulators and anti-TNF agents will be managed very differently from a patient who has already failed two anti-TNF drugs. A fourth critical factor is considering the individual patient. The balance of benefits and risks will depend upon the patient's expected disease course, and how much risk they are at personally for serious adverse events related to treatment. In addition, patients' preferences for treatment need to be addressed since they will choose therapies differently based on their personal experience with symptoms, thresholds for risk taking, and fears about their disease and treatment. The basic armamentarium for induction therapy for Crohn's disease includes: 5-aminosalicylates, antibiotics, budesonide, systemic corticosteroids, thiopurines, methotrexate, and anti-TNF agents. These drugs can be used alone or combined in difference treatment algorithms to optimize therapy. The art of treating the IBD patient is in understanding the options and being able to apply an individualized regimen based upon unique patient and disease factors. PMID- 20926885 TI - How rapidly should remission be achieved? AB - The major goal of therapy in inflammatory bowel disease is to induce remission. Remission has multiple definitions - clinical remission, where the patient's symptoms have remitted, and endoscopic remission, in which there has been complete mucosal healing. Mucosal healing is a harder endpoint of remission but may be more difficult to achieve. In clinical trials we are forced to use activity indices such as the Crohn's disease activity index that may not completely reflect the endoscopic and histologic state of the bowel. Ideally we would like to see remission as quickly as possible to improve patient quality of life. The time to remission varies between different therapeutic approaches. Steroids tend to have a rapid clinical effect with remission seen in some patients as early as two weeks. In early anti-TNF trials, a single dose of infliximab lead to 27% remission at two weeks compared to 4% of placebo patients. Adalimumab and certolizumab have similar reports of early induction of remission. Mesalamine in Crohn's disease has inconsistent and delayed remission rates, whereas in ulcerative colitis, response and remission rates are more consistent in the three-week time frame. Azathioprine and 6-mercaptopurine have delayed onset of action but may induce remission as early as six weeks if dosing is optimized. In this presentation induction of clinical remission and mucosal healing in Crohn's disease and ulcerative colitis will be discussed. The impact of early remission on disease course will also be reviewed. PMID- 20926886 TI - Fistula treatment: The unresolved challenge. AB - In population-based studies, up to 50% of patients with Crohn's disease suffer from fistulas. Fistulas pose a considerable morbidity including permanent sphincter and perineal tissue destruction as well as professional and personal disabilities. Treatment options have progressed in recent years and fistula closure and fibrosis of the fistula track is achieved in some patients. Depending on severity of symptoms and fistula location, different medical and surgical therapies can be chosen. Internal fistulas such as ileoileal or ileocecal fistulas are either asymptomatic and do not require intervention or they are symptomatic and need surgery alone. They always carry a risk of abscess formation. Symptomatic perianal fistulizing disease can be treated with antibiotics (i.e. metronidazole and ciprofloxacin) for three months and/or immunosuppressant therapy (6-mercaptopurine or azathioprine). More complex cases require therapy with anti-TNF agents. Only few and preliminary data exist on cyclosporine A, tacrolimus or methotrexate in fistulizing Crohn's disease. Therefore, these therapies should mainly be used as second-line therapies. Surgery is reserved for the treatment of perianal sepsis in the presence of abscesses and refractory disease or complications of fistulas, or used in combination with pharmacological approaches. The surgical interventions in perianal disease consist of surgical drainage with or without seton placement, transient ileostomy, or in severe cases, proctectomy. The classification of fistulas in patients with Crohn's disease remains poorly defined and largely investigator dependent. The unresolved challenges in fistula treatment warrant randomized controlled trials for existing and future treatment strategies as well as a better classification system to compare available studies. PMID- 20926887 TI - Speech disfluency types of fluent and stuttering individuals: age effects. IALP Student Award. AB - OBJECTIVE: The purpose of the present study was to quantify and compare the typology of speech disruptions presented by stuttering and fluent Brazilian Portuguese-speaking children, adolescents and adults. SUBJECTS AND METHODS: Participants were 150 individuals, with ages between 4.0 and 49.11 years, who were divided into six groups: children who stutter (n = 25), children who do not stutter (n = 25), adolescents who stutter (n = 25), adolescents who do not stutter (n = 25), adults who stutter (n = 25) and adults who do not stutter (n = 25). For each participant, the frequency of stuttering-like disfluencies (SLD) and other disfluencies was calculated based on the video recordings of spontaneous speech samples. RESULTS: The results obtained for SLD were significant when comparing stuttering and fluent individuals. In children who stutter, adolescents who stutter, and adults who stutter, a higher frequency of SLD was found. Other disfluencies did not differentiate the groups. CONCLUSION: The age factor did not qualify quantitatively any of the groups, but indicated qualitative differences (in terms of the type of speech disfluencies) between groups. The results revealed similarities when compared with studies carried out in different languages. PMID- 20926888 TI - The effect of smoking on the dysphonia severity index in females. AB - OBJECTIVE: This study investigated the capability of the Dysphonia Severity Index (DSI) and its component measures to reveal differences in vocal capability between groups of young adult female smokers and nonsmokers. PATIENTS AND METHODS: The subjects were 30 female nonsmokers and 30 female smokers between the ages of 18 and 24 years. Data on the DSI components (maximum phonation time, MPT; highest phonational frequency, F(0 high); lowest intensity, I(low), and jitter) were collected, followed by calculation of the DSI. RESULTS: Significant differences between groups were observed on the DSI, with reduced DSI scores in smokers primarily due to reductions in F(0 high) and increases in I(low). A strong partial correlation between MPT and the DSI in smokers may be indicative of reductions in respiratory support and/or phonatory control. CONCLUSIONS: Significant group differences in the DSI and component measures may be indicative of early changes in vocal function secondary to smoking. Reductions in frequency and dynamic range are consistent with the possibility of increased vocal fold mass in smokers. The results indicate that significant differences in the DSI between groups may be observed in subjects with perceptually normal vocal quality and with normal levels of vocal perturbation. PMID- 20926889 TI - Objective vocal parameters in Farsi-speaking adults with Down syndrome. AB - Previous studies have indicated significant differences in vocal parameters between children with Down syndrome and normal children. This study was performed to see whether there is a significant dissociation between normal adults and adults with Down syndrome in terms of some vocal parameters. The participants were 22 adults with Down syndrome and 22 normal adults matched for age and gender. We measured jitter, shimmer, fundamental frequency (F0), and maximum phonation time (MPT). The results showed a significantly higher F0 and a significantly lower jitter in the Down syndrome group compared to the control group, while the average amounts of MPT and shimmer were not different. Moreover, the shimmer and jitter of females in both groups were lower than those of males. These findings might be the result of a physiological retardation of the larynx rather than mental retardation in the Down syndrome population. PMID- 20926890 TI - Connexin channel-dependent signaling pathways in inflammation. AB - Inflammation is a highly regulated process with common but also specific characteristics in each tissue affected. Recruitment of leukocytes from the blood to the injured tissue is an important early step in the inflammatory cascade. This review highlights the role of connexins (Cxs) in the regulation of both acute and chronic inflammatory processes. Cxs form gap junction channels that provide a cytoplasmic continuity between adjacent cells allowing the intercellular exchange of ions and metabolites. Their structural halves form connexons or hemichannels. Each of them consists of 6 Cx proteins and hemichannels not taking part in gap junction formation but facilitating the release of small molecules such as ATP. Based on the differential distribution of various Cxs in different tissues such as the brain, lung capillaries and large blood vessels, our aim was to analyze the specific roles of Cxs in the inflammatory process in these tissues. Three typical sites of inflammation were chosen to shed light on similarities and differences in several types of responses: (1) atherosclerosis as a model for chronic inflammation, (2) the lung as an example of acute inflammation and (3) the 'immune-privileged' environment of the brain to highlight specific reactions of the vasculature to ischemic damage and inflammation at this site. PMID- 20926891 TI - RCAN1 regulates vascular branching during Xenopus laevis angiogenesis. AB - BACKGROUND/AIMS: The mechanisms that regulate the size-related morphologies of various blood vessels from the aorta to capillary vessels are still poorly understood. In this study, we evaluate the involvement of regulator of calcineurin 1 (RCAN1), a regulatory protein in the calcineurin/NFAT signal transduction pathway, in vascular morphology to gain further insight into these mechanisms. METHODS AND RESULTS: We first generated 2 types of vasculature in vitro from the same source of human umbilical vein endothelial cells by fibrin gel assay. We found that RCAN1 was significantly upregulated in large vessels with low branching frequencies when compared with small vessels with high branching frequencies. Next, to clarify whether RCAN1 regulates the branching of blood vessels in vivo, we injected RCAN1 mRNA into fertilized Xenopus laevis eggs. Overexpression of RCAN1 decreased the number of branching points that sprouted from intersomitic vessels during X. laevis angiogenesis. In addition, coexpression of calcineurin A, a target of RCAN1, could rescue RCAN1-suppressed vascular branching. CONCLUSIONS: These results provide in vivo evidence of RCAN1 regulated vascular branching which may play a role in the patterning of morphologically different vasculature. PMID- 20926892 TI - Induced chromosome deletion in a Williams-Beuren syndrome mouse model causes cardiovascular abnormalities. AB - AIMS: The Williams-Beuren syndrome (WBS) is a genetic disorder caused by a heterozygous ~1.5-Mb deletion. The aim of this study was to determine how the genetic changes in a Wbs mouse model alter Eln expression, blood pressure, vessel structure, and abdominal aortic wall dynamics in vivo. METHODS: Elastin (ELN) transcript levels were quantified by qRT-PCR and blood pressure was measured with a tail cuff system. M-mode ultrasound was used to track pulsatile abdominal aortic wall motion. Aortas were sectioned and stained to determine medial lamellar structure. RESULTS: ELN transcript levels were reduced by 38-41% in Wbs mice lacking one copy of the ELN gene. These mice also had a 10-20% increase in mean blood pressure and significantly reduced circumferential cyclic strain (p < 0.001). Finally, histological sections showed disorganized and fragmented elastin sheets in Wbs mice, but not the characteristic increase in lamellar units seen in Eln(+/-) mice. CONCLUSIONS: The deletion of Eln in this Wbs mouse model results in lower gene expression, hypertension, reduced cyclic strain, and fragmented elastin sheets. The observation that the number of medial lamellar units is normal in Wbs deletion mice, which is in contrast to Eln(+/-) mice, suggests other genes may be involved in vascular development. PMID- 20926893 TI - Ccm1 regulates microvascular morphogenesis during angiogenesis. AB - Cerebral cavernous malformations (CCMs) are characterized by abnormally dilated intracranial capillaries that have a propensity to bleed. The development of some CCMs in humans has been attributed to mutations in CCM1 and CCM2 genes. In animal models, major cardiovascular defects caused by both gene mutations have been observed. However, the effects of the loss of Ccm function on the microvasculature in animal models are less defined. Using high-resolution imaging in vivo, we demonstrated that the loss of Ccm1 in zebrafish embryos leads to failed microvascular lumenization during angiogenesis due to impaired intraendothelial vacuole formation and fusion. No developmental changes during vasculogenesis and the initial stage of angiogenesis were observed, being in contrast to prior reports. In vivo zebrafish studies were further substantiated by in vitro findings in human endothelial cells that elucidated the biochemical pathways of CCM1 deficiency. We found that CCM1 regulates angiogenic microvascular lumen formation through Rac1 small GTPase. In summary, Ccm1 has been identified as a key angiogenic modulator in microvascular tubulogenesis. Additionally, the microvascular pathology observed in developing Ccm1 mutant zebrafish embryos mirrors that seen in human CCM lesions, suggesting that zebrafish might provide a superior animal model to study the pathogenesis of human CCM. PMID- 20926894 TI - Marfan syndrome decreases Ca2+ wave frequency and vasoconstriction in murine mesenteric resistance arteries without changing underlying mechanisms. AB - BACKGROUND/AIMS: Vascular smooth muscle in Marfan syndrome, a connective tissue disorder caused by mutations in FBN1 encoding fibrillin-1, is associated with decreased tonic contraction. As Ca(2+) waves are tightly associated with vasoconstriction, we hypothesized decreased tonic contraction in Marfan syndrome is due to aberrant Ca(2+) wave signaling. METHODS: Isometric force and intracellular Ca(2+) were measured from second-order mesenteric arteries from mice heterozygous for the Fbn1 allele encoding a cysteine substitution (Fbn1(C1039G/+)). RESULTS: Phenylephrine concentration-dependently induced tonic contraction associated with sustained repetitive oscillations in intracellular [Ca(2+)] in both control and Marfan vessels, although Marfan vessels displayed significantly decreased Ca(2+) wave frequency and decreased number of cells exhibiting waves. Inhibition of sarcoplasmic reticulum Ca(2+) re-uptake by cyclopiazonic acid abolished Ca(2+) waves, dramatically decreasing tonic contraction. Nifedipine significantly reduced Ca(2+) wave frequency and tonic contraction, while the nifedipine-insensitive component was abolished by SKF 96365. Ca(2+) waves and tonic contraction were abolished by 2 aminoethoxydiphenylborate, but were unaffected by ryanodine or tetracaine. CONCLUSION: Phenylephrine-induced Ca(2+) waves underlie tonic contraction in resistance-sized mesenteric arteries and appear to be produced by repetitive cycles of regenerative Ca(2+) release from the sarcoplasmic reticulum. Decreased frequency of Ca(2+) waves in Marfan syndrome appears to be responsible for reduced tonic contraction. PMID- 20926895 TI - Acute tumor lysis syndrome - a rare complication in the treatment of solid tumors. PMID- 20926896 TI - Expression pattern of the ASPP family members in endometrial endometrioid adenocarcinoma. AB - BACKGROUND: Apoptosis-stimulating protein of p53 (ASPP) family members can stimulate the apoptotic function of p53 but have no impact on its cell cycle arrest function. MATERIAL AND METHODS: The expression pattern of the ASPP family consisting of ASPP1, ASPP2, and iASPP was examined by immunohistochemistry in 45 formalin-fixed and paraffin-embedded endometrial endometrioid adenocarcinoma (EEA) specimens and 26 normal endometrial tissue (NET) samples. RESULTS: The expression rates of ASPP1 and ASPP2 in EEA were significantly lower than those in NET (p < 0.05). However, the iASPP expression rate in EEA was statistically higher in contrast to NET (p < 0.05). Expression of ASPP1 and iASPP in EEA had no correlation with any clinicopathological features (p > 0.05). iASPP was associated with grade, invasion, and lymph node metastasis (p < 0.05). CONCLUSIONS: It is a novel finding that the expression pattern of the ASPP family members has respective pathological and clinical implications in EEA, and iASPP might be a candidate target for EEA therapy. PMID- 20926897 TI - A phase III randomized equivalence study of biosimilar filgrastim versus Amgen filgrastim in patients receiving myelosuppressive chemotherapy for breast cancer. AB - BACKGROUND: Filgrastim was developed to treat chemotherapy-induced neutropenia. This phase III study was designed to demonstrate bioequivalence of Amgen filgrastim and a biosimilar filgrastim developed by Hospira (Study GCF071; sponsored by Hospira). PATIENTS AND METHODS: Breast cancer patients suitable for treatment with doxorubicin and docetaxel in the neoadjuvant/adjuvant or first line metastatic setting were enrolled at 37 European centers. Patients were randomized (2:1) to receive Hospira filgrastim or Amgen filgrastim, after the end of chemotherapy. Filgrastim (5 MUg/kg/day) was administered under double-blind conditions. Primary endpoint to demonstrate bioequivalence was duration of severe neutropenia (DSN) in cycle 1. RESULTS: 184 patients were randomized to Hospira filgrastim and 95 to Amgen filgrastim. Mean DSN in cycle 1 was similar with Hospira filgrastim (1.6 days; n = 165) and Amgen filgrastim (1.3 days; n = 85), meeting predefined criteria for bioequivalence. Secondary endpoints supporting bioequivalence included mean time to absolute neutrophil count recovery and incidence of febrile neutropenia. The most common treatment-related adverse event with Hospira filgrastim was grade 1-2 bone pain. CONCLUSIONS: Hospira filgrastim and Amgen filgrastim are bioequivalent in efficacy with similar safety profiles. Hospira filgrastim may be useful for the prophylaxis of complications related to neutropenia caused by chemotherapy. PMID- 20926898 TI - Population-based patterns of care in the first-line treatment of patients with advanced esophagogastric adenocarcinoma in Germany. AB - BACKGROUND: Randomized studies proved the efficacy of new drugs for the systemic treatment of advanced gastric cancer in the past 5 years. However, little is known about the use of firstline chemotherapy in clinical practice in patients with advanced or metastatic adenocarcinoma of the esophagogastric junction (AEG) and the stomach. We investigated temporal trends in therapy and factors influencing treatment decisions for these patients during a 4-year period. PATIENTS AND METHODS: 1058 patients (median age 67 years) with advanced AEG or gastric cancers undergoing treatment decisions were documented with the Therapiemonitor(r) in 2006-2009. Therapiemonitor collects population-based data regarding treatment decisions and strategies. Time trends of drug use and intensity in the first-line treatment were analyzed in the entire patient group and according to age (cut-off 65 years) and Karnofsky performance status (KPS; cut-off 80%). RESULTS: Over time, the use of oxaliplatin and docetaxel as well as capecitabine increased while cisplatin and irinotecan use slightly declined. The use of chemotherapy triplets rose from 10.1% in 2006 to 47.0% in 2009. Treatment patterns significantly varied by age and KPS: Older patients were significantly less likely to receive chemotherapy triplets, cisplatin and docetaxel but tended to more often receive oxaliplatin. Likewise, triplets, cisplatin and docetaxel were less frequently used in patients with KPS < 80%, while capecitabine and irinotecan were significantly more often used in this patient group. CONCLUSIONS: A clear tendency towards the use of more intensive chemotherapy regimens in patients with AEG and gastric cancer was observed over time. Older or less fit patients were treated preferably with monotherapy or chemotherapy doublets during 2006-2009. Oxaliplatin and docetaxel use has substantially risen. PMID- 20926899 TI - Merkel cell carcinoma of the gluteal region with ipsilateral metastasis into the pancreatic graft of a patient after combined kidney-pancreas transplantation. AB - BACKGROUND: Merkel cell carcinoma (MCC) is a rare tumour of the skin that predominantly affects elderly or immunocompromised patients. The malignant transformation of Merkel cells is currently considered to be related to an infection with Merkel cell polyomavirus. CASE REPORT: We present the case of a 62 year-old man who developed a Merkel cell polyomavirus-positive MCC in a non-UV exposed part of the right gluteal region 8 years after combined kidney-pancreas transplantation. Following excision and radical re-excision of the tumour, no adjuvant radiotherapy was indicated because of the risk of adjacent pancreatic graft failure. Despite adjustment of the immunosuppressive therapy with conversion to sirolimus, the tumour generalised and metastasised into the pancreatic graft, leading to its failure. Subsequent chemotherapy did not affect the course of the disease, and the patient died 9 months after diagnosis. CONCLUSIONS: To our knowledge, we present the first case of MCC associated with metastatic involvement of the transplanted pancreas followed by its subsequent failure. Given the highly aggressive course of the disease in patients after organ transplantation, MCC therapy should be sufficiently aggressive from the time of diagnosis and should not be influenced by attempts to preserve graft function. PMID- 20926900 TI - Spontaneous pneumothorax during chemotherapy: a case report. AB - BACKGROUND: Spontaneous pneumothorax (SP) associated with malignant disease is relatively infrequent but has important diagnostic and therapeutic implications. CASE REPORT: We describe a case of SP that occurred during chemotherapy with ifosfamide and doxorubicin in a patient with an advanced pleomorphic sarcoma. The pneumothorax developed secondary to the rapid regression of peripheral pulmonary metastases presumably resulting in bronchopleural fistula formation. After treatment with chest tube drainage, the patient recovered and chemotherapy could be continued without further complications. DISCUSSION: We discuss different pathophysiological mechanisms and the clinical context of SP in sarcoma patients and give an overview of the literature and different treatment options. PMID- 20926901 TI - Acute tumor lysis syndrome after transarterial chemoembolization for well differentiated hepatocellular carcinoma with neuroendocrine features. AB - BACKGROUND: Acute tumor lysis syndrome (ATLS) was gradually considered as a separate entity or condition associated with bulk tumor treatment. There are few reports of ATLS following transarterial chemoembolization (TACE) in patients with hepatocellular carcinoma (HCC). Primary HCCs with neuroendocrine features are also extremely rare. CASE REPORT: We report such a rare case of well differentiated (WD)-HCC with neuroendocrine features, which presented with ATLS after TACE. The patient was a 54-year-old female. Needle biopsy of the liver histologically confirmed WD-HCC. On the 5th postoperative day, the patient was identified as having ATLS. Hemodialysis was done while her renal functions recovered. In the follow-up visits, computed tomography results showed distinct reduction in tumor size. CONCLUSIONS: When a large HCC with rich blood supply undergoes TACE, we should pay attention to the possibility of ATLS. Close monitoring after antineoplastic therapy in high-risk patients is warranted. PMID- 20926902 TI - Fatal reactivation of occult hepatitis B virus infection after rituximab and chemotherapy in lymphoma: necessity of antiviral prophylaxis. AB - The anti-CD20 monoclonal antibody rituximab has been used extensively in the treatment of B-cell lymphoma. However, several studies reported hepatitis B virus (HBV) reactivation after rituximab administration. The majority of these cases have been described in chronic carriers of HBV, whereas reactivation in occult hepatitis B carriers is relatively rare. We report a fatal case of fulminant hepatitis B that occurred in a B-cell lymphoma patient with occult hepatitis B after rituximab-containing chemotherapy, which raised the necessity of antiviral prophylaxis in this setting. PMID- 20926903 TI - Recapitulation of ras oncogene mutations in breast cancer. AB - Several human breast cancer cell lines have been shown to contain mutational activation of Ras oncogenes. The goal of this review is to clarify the physiology and biochemical pathways of Ras family oncogenes in order to understand thoroughly the mechanisms behind Ras gene mutations. Ras genes are involved in the early stages of mammary oncogenesis through augmented expression of the normal p21 protein. Recognition of the mechanisms resulting in aberrant expression of Ras, as well as unveiling the influence of the Ras family gene activation in the Ras signaling pathway, should have a major impact on clarifying the oncogenetic process, possibly offering candidate therapy and prevention strategies. PMID- 20926904 TI - Mitomycin C in patients with gynecological malignancies. AB - Mitomycin C (MMC) is an effective cytostatic agent used in the treatment of patients with gynecological malignancies and breast carcinoma. This review presents and discusses the current treatment options with MMC in patients with breast, cervical, and vulvar carcinomas, as well as rarer gynecological malignancies. New combinations and developments are also presented and their potential clinical relevance is examined. Consequently, also for the next years a MMC-containing chemotherapy continues to be a relevant part of an individualized therapy despite numerous innovative new drugs, especially for the salvage therapy of metastatic breast cancer and the simultaneous radiochemotherapy of other gynecological malignancies. PMID- 20926905 TI - [Oncology research and treatment in Germany]. PMID- 20926906 TI - [Clinical research in Germany at the example of oncology]. AB - Oncology is a major topic at many German universities. Research in oncology is funded by various programs of the Federal Ministry of Education and Research, the German Research Council, and by charities. Programs such as the foundation of coordinating centers for clinical research or the Program of Excellence of the German Cancer Aid to establish Comprehensive Cancer Centers in Germany shall improve the quality of clinical research in oncology. This is important because the 14th amendment of the German Medicines Law has markedly raised the standards for the design and conduct of clinical trials, accompanied by a substantial increase in costs. Consequently,the pharmaceutical industry plays an ever increasing role in funding of clinical trials in oncology in Germany, but is mostly focused on the further development of their own products. In addition, research in clinical oncology often suffers from the fact that it takes a long time from the design of a trial to its publication, making it more difficult to achieve academic goals such as a habilitation. In the future, an improved training of medical doctors in clinical research and a further improved public funding structure for clinical research in oncology, e.g. by a National German Cancer Center,could be advantageous. PMID- 20926907 TI - [Open questions in the drug therapy of tumors with new active substances]. AB - At the time of market authorization and/or the expansion of indication of new oncology drugs, it is often not possible to reliably measure the relevant benefit for the patient. The conception of the clinical studies, on which the market authorization and/or expansion of indication is based, orients itself primarily at the regulatory requirements of the regulatory authorities. In addition, their results are frequently published only incompletely or some time after the end of the clinical study. To clarify these outstanding questions regarding the individual treatment of patients, independent,science-initiated clinical studies after the market authorization are required. However, the execution of these studies is obstructed due to insufficient financial means as well as by regulations and the low evaluation of such studies by the academia. Further challenges result from the high costs of innovative oncologic therapies, which burden the resources of the statutory and private health insurance providers(GKV, PKV) who are confronted with an aging population and a rising prevalence of tumor cases. Independent post-market authorization clinical studies need to be completed in order to ensure a need-oriented and efficient treatment with new oncologic substances. New perspectives result by connecting the reimbursement of the costs of innovative therapies by the GKV and PKV to the generation of evidence in the context of clinical studies, thus improving the medical care of tumor patients as well as the efficient handling of limited health resources. PMID- 20926908 TI - [The Coordinating Centers for Clinical Trials (KKS) and the KKS Network: competence for clinical research]. AB - The Network of the Coordination Centers for Clinical Trials (CTCs; Koordinierungszentren fur Klinische Studien(KKS)) comprises 17 institutions working as scientific service provider for universities, study groups, the pharmaceutical and medical devices industry as well as additional clients associated with clinical research. The CTCs have established planning and conduct of clinical trials according to Good Clinical Practice (GCP) guidelines,with a wide range of study support in academia. One focus according to indications is cancer. Expertise in hematological/oncological research can be requested nationwide and cross-institutional. The KKS network currently cooperates with medical societies and other, even European networks in 20 countries and has been established as a strong platform for oncological trials. PMID- 20926909 TI - [Funding and sponsorship of clinical trials in oncology]. AB - The lack of clinical trials represents a bottleneck in the future of the German health care system. Although central organizations as the G-BA (Federal Joint Committee), the IQWiG (Institute for Quality and Efficiency in Health Care) or the INEK (Institute for Hospital Reimbursement), which were established during the last years as central boards for the decision process in health care, use the results of high-quality trials as basis of their decisions, the off-label use as an implicit way of clinical trial promotion by German sickness funds to reduce the cost of care in this special setting has at the same time been combatted in recent years.Thereby, an important basis for the development of oncological therapies through clinical studies was abolished and completely impeded. Also, the underlying conditions of investigator-initiated clinical trials caused more effort because of new legislation. The trend of prioritization in the German health care system based on short resources and the use of study-based evidence for decision-making must lead to the establishment of a new and effective financing and funding of clinical trials. Sickness funds must also be involved in this funding. G-BA and IQWiG, who are castigators of the quality and sponsoring of investigator-initiated clinical trials, must in conclusion postulate basic conditions for successful financing and funding of clinical trials in consideration of their duties and responsibilities. PMID- 20926910 TI - [Demographic change and cancer]. AB - BACKGROUND: The demographic changes in Germany lead to a modified age structure of the population towards a growing proportion of elderly people. As many diseases like cancer usually appear in higher age groups, increasing numbers of cases are expected. The quantification of this development is an important indicator of the future burden of the health system. MATERIAL AND METHODS: Currently available age- and sex-specific incidence rates of the most frequent cancer sites, based on population-based cancer registries, were assigned 'ceteris paribus' to the expected populations of the years 2030, 2050 and 2060 (12th coordinated population prediction, predicted by the Federal Statistical Office). RESULTS: The number of incident cancer cases will increase from 494,000 in 2010 to 642,000 in 2050 (+26%). There are considerable differences among the different cancer sites (-29% to +47%). CONCLUSIONS: Caused by demographic changes, sizably higher numbers of incident cancer cases have to be expected in the future in Germany. The declining population will cause an even more strongly increasing cancer burden in the population. PMID- 20926911 TI - [Clinical trials and personalized medicine in oncology?]. AB - Clinical trials aim to evaluate benefits of therapeutic or diagnostic procedures for a 'standardized' cohort rather than for individual patients. On the other hand, 'personalized medicine' focuses on the prediction of potential benefits or risks for individuals in as much detail as possible.Currently, clinical trials may still implement the known predictive and/or prognostic factors, as they generally address relatively large groups of patients bearing a well-identified factor and therefore defining an 'enriched' patient cohort. In the near future, as more and more factors for stratification will become available,it is likely that patient cohorts become smaller--hopefully with an increase in the observed effect. Therefore, innovative designs of clinical trials are warranted to integrate the needs of better stratification in smaller patient subsets. PMID- 20926912 TI - [Relevance of clinical trials for the decision-making process within the bodies of the self-government]. AB - Clinical studies are the central basis on which the decision-making process regarding reimbursement of medical interventions of the bodies of the self government is founded. For many of these reimbursement questions that await a decision, studies with a sufficient certainty of results are absent. Even though the self-government has instruments on hand with which it may initiate clinical trials (i.e. the deferment of a decision of the Federal Joint Committee) or support them (German Social Code, Book V,S 35c), the possibilities of a remedy of this deficit itself are limited. A continuous and sound advancement and funding of the development of structures that lead to the conduct of the required clinical trials, independently of particular interests (e.g. of the pharmaceutical industry), is urgently needed. PMID- 20926913 TI - Intonational differences between L1 and L2 english in South Africa. AB - Previous studies have shown that characteristics of a person's first language (L1) may transfer to a second language (L2). The current study looks at the extent to which this holds for aspects of intonation as well. More specifically, we investigate to what extent traces of the L1 can be discerned in the way intonation is used in the L2 for two functions: (1) to highlight certain words by making them sound more prominent and (2) to signal continuation or finality in a list by manipulating the speech melody. To this end, the article presents an explorative study into the way focus and boundaries are marked prosodically in Zulu, and it also compares such prosodic functions in two variants of English in South Africa, i.e., English spoken as an L1, and English spoken as an L2/additional language by speakers who have Zulu as their L1. The latter language is commonly referred to as Black South African English. This comparison is interesting from a typological perspective, as Zulu is intonationally different from English, especially in the way prosody is exploited for signalling informationally important stretches of speech. Using a specific elicitation procedure, we found in a first study that speakers of South African English (as L1) mark focused words and position within a list by intonational means, just as in other L1 varieties of English, whereas Zulu only uses intonation for marking continuity or finality. A second study focused on speakers of Black South African English, and compared the prosody of proficient versus less proficient speakers. We found that the proficient speakers were perceptually equivalent to L1 speakers of English in their use of intonation for marking focus and boundaries. The less proficient speakers marked boundaries in a similar way as L1 speakers of English, but did not use prosody for signalling focus, analogous to what is typical of their native language. Acoustic observations match these perceptual results. PMID- 20926914 TI - A laryngographic and laryngoscopic study of Northern Vietnamese tones. AB - A laryngographic and laryngoscopic study of tone production in Northern Vietnamese, a language whose tones combine both fundamental frequency (f0) modulations and voice qualities (phonation types), was conducted with 5 male and 5 female speakers. Results show that the f0 contours of Northern Vietnamese tones are not only attributable to changes in vocal fold length and tension (partly through changes in larynx height), but that f0 drops are also largely caused by the glottal configurations responsible for the contrastive voice qualities associated with some of the tones. We also find that voice quality contrasts are mostly due to glottal constriction: they occasionally involve additional ventricular fold incursion and epiglottal constriction, but these articulations are usually absent. PMID- 20926915 TI - On the phonetics of intensifying emphasis in German. AB - This paper presents an exploratory study in the field of emphasis in German. It provides a comprehensive acoustic analysis for a type of emphasis that intensifies lexical meanings either positively or negatively. A speech corpus was recorded using an elicitation method adapted to yield natural-sounding, conversational, expressive speech under controlled conditions. Supporting the distinction between positive and negative intensification, two clearly different phonetic profiles emerged. These phonetic profiles of positive and negative intensification involve voice quality as well as the dynamics of the speech signal across its segmental and prosodic layers. By means of these profiles, the intensifying emphases were correctly classified by a discriminant analysis as positive or negative in around 90% of the cases. Moreover, indications were found for a third type of intensifying emphasis, which was called 'reinforcement'. Its multidimensional phonetic profile falls in between the ones of positive and negative intensification. PMID- 20926919 TI - Genistein activates endothelial nitric oxide synthase in broiler pulmonary arterial endothelial cells by an Akt-dependent mechanism. AB - Deregulation of endothelial nitric oxide synthase (eNOS) plays an important role in the development of multiple cardiovascular diseases. Our recent study demonstrated that genistein supplementation attenuates pulmonary arterial hypertension in broilers by restoration of endothelial function. In this study, we investigated the molecular mechanism by using broiler pulmonary arterial endothelial cells (PAECs). Our results showed that genistein stimulated a rapid phosphorylation of eNOS at Ser(1179) which was associated with activation of eNOS/NO axis. Further study indicated that the activation of eNOS was not mediated through estrogen receptors or tyrosine kinase inhibition, but via a phosphatidylinositol 3-kinase (PI3K)/Akt-dependent signaling pathway, as the eNOS activity and related NO release were largely abolished by pharmacological inhibitors of PI3K or Akt. Thus, our findings revealed a critical function of Akt in mediating genistein-stimulated eNOS activity in PAECs, partially accounting for the beneficial effects of genistein on the development of cardiovascular diseases observed in animal models. PMID- 20926918 TI - Endoplasmic reticulum stress (ER-stress) by 2-deoxy-D-glucose (2DG) reduces cyclooxygenase-2 (COX-2) expression and N-glycosylation and induces a loss of COX 2 activity via a Src kinase-dependent pathway in rabbit articular chondrocytes. AB - Endoplasmic reticulum (ER) stress regulates a wide range of cellular responses including apoptosis, proliferation, inflammation, and differentiation in mammalian cells. In this study, we observed the role of 2-deoxy-D-glucose (2DG) on inflammation of chondrocytes. 2DG is well known as an inducer of ER stress, via inhibition of glycolysis and glycosylation. Treatment of 2DG in chondrocytes considerably induced ER stress in a dose- and time-dependent manner, which was demonstrated by a reduction of glucose regulated protein of 94 kDa (grp94), an ER stress-inducible protein, as determined by a Western blot analysis. In addition, induction of ER stress by 2DG led to the expression of COX-2 protein with an apparent molecular mass of 66-70kDa as compared with the normally expressed 72-74 kDa protein. The suppression of ER stress with salubrinal (Salub), a selective inhibitor of eif2-alpha dephosphorylation, successfully prevented grp94 induction and efficiently recovered 2DG- modified COX-2 molecular mass and COX-2 activity might be associated with COX-2 N-glycosylation. Also, treatment of 2DG increased phosphorylation of Src in chondrocytes. The inhibition of the Src signaling pathway with PP2 (Src tyrosine kinase inhibitor) suppressed grp94 expression and restored COX-2 expression, N-glycosylation, and PGE2 production, as determined by a Western blot analysis and PGE2 assay. Taken together, our results indicate that the ER stress induced by 2DG results in a decrease of the transcription level, the molecular mass, and the activity of COX-2 in rabbit articular chondrocytes via a Src kinase-dependent pathway. PMID- 20926920 TI - Comparative proteomics study of freshly isolated, in vitro cultured, and proliferating islet preparation cells. AB - BACKGROUND: In vitro islet expansion has recently drawn interest for its potential application in diabetes therapy, while how islet cells adapt to in vitro circumstances is not quite clear. AIM: Proteomics changes of cultivated islet cells under different conditions were examined in this study. MATERIAL/SUBJECTS AND METHODS: A comparative proteomics study was performed on fresh isolated islet cells, cultured cells and in vitro proliferating islet cells stimulated by basic fibroblast growth factor via electrophoresis and liquid chromatography in tandem with mass spectrometry. RESULTS: In total, 1897 proteins were identified in this study. Hierarchical analysis revealed substantial changes in the proteome during cultivation but relatively less difference between different culture conditions. Over 100 proteins showed significantly different expression levels between groups, most of which are involved in metabolism or cell process pathways. Overall, the detected proteins were involved in 152 known pathways. Furthermore, in-depth investigation suggested that some proteins, such as extracellular signal-regulated protein kinases and Rac, might play key roles in the proliferation, apoptosis, and differentiation of in vitro cultured islet cells. CONCLUSION: We established comparative proteome references of fresh and cultured islet cells, which could provide useful information for future islet transplantation strategy. PMID- 20926922 TI - HIV in Asia: universal access in sight. PMID- 20926921 TI - Fasting and post-prandial adipose tissue lipoprotein lipase and hormone-sensitive lipase in obesity and type 2 diabetes. AB - BACKGROUND: Fasting and post-prandial abnormalities of adipose tissue (AT) lipoprotein lipase (LPL) and hormone- sensitive lipase (HSL) activities may have pathophysiological relevance in insulin-resistant conditions. AIM: The aim of this study was to evaluate activity and gene expression of AT LPL and HSL at fasting and 6 h after meal in two insulin-resistant groups - obese with Type 2 diabetes and obese without diabetes - and in non-diabetic normal-weight controls. MATERIAL/SUBJECTS AND METHODS: Nine obese subjects with diabetes, 10 with obesity alone, and 9 controls underwent measurements of plasma levels of glucose, insulin, and triglycerides before and after a standard fat-rich meal. Fasting and post-prandial (6 h) LPL and HSL activities and gene expressions were determined in abdominal subcutaneous AT needle biopsies. RESULTS: The diabetic obese subjects had significantly lower fasting and post-prandial AT heparin-releasable LPL activity than only obese and control subjects (p<0.05) as well as lower mRNA LPL levels. HSL activity was significantly reduced in the 2 groups of obese subjects compared to controls in both fasting condition and 6 h after the meal (p<0.05), while HSL mRNA levels were not different. There were no significant changes between fasting and 6 h after meal measurements in either LPL or HSL activities and gene expressions. CONCLUSIONS: Lipolytic activities in AT are differently altered in obesity and Type 2 diabetes being HSL alteration associated with both insulin-resistant conditions and LPL with diabetes per se. These abnormalities are similarly observed in the fasting condition and after a fat-rich meal. PMID- 20926923 TI - Catalyzing HIV prevention in Asia: from individual to population level impact. AB - OBJECTIVE: HIV prevention in Asia has two sides, modest overall coverage of individual services, yet some leading examples of population impact at national level. This review assesses the coverage of individual services and the additional components required to catalyze population level impact in Asia. METHODS: The review first assesses the latest data on the coverage of services by most-at-risk populations and country. The Asian Epidemic Model is used to estimate the coverage levels of these services required to reduce HIV incidence. Information on the services, unit costs, and coverage is used to define a priority prevention package that is affordable and can lead to high population coverage. Analysis of national programs, epidemiology, and behavior data is undertaken to identify additional factors required and barriers to population level prevention impact. RESULTS: HIV prevention has shown variable coverage across Asia, with less than one in two sex workers, one in five injecting drug users, and one in two men who have sex with men reached with services. In addition, coverage of prevention of mother-to-child transmission is still low at 32%. Yet modeling suggests 60-80% coverage of all most-at-risk populations is required to reduce HIV incidence. National situations show the importance of implementing a priority package of HIV prevention to high coverage rapidly, combined with intense engagement of most-at-risk populations. DISCUSSION: HIV prevention at population level requires universal access to priority services alongside mobilization of all most-at-risk populations. It is only where service delivery and social change models of prevention have been combined effectively that HIV has declined. This helps explain the paradox in Asian HIV prevention, modest overall service delivery with some key national HIV prevention successes. PMID- 20926924 TI - Injection drug use, HIV and the current response in selected low-income and middle-income countries. AB - Over half of the world's estimated opiate users reside in Asia, including an estimated 3.9 million injecting drug users (IDUs). Injection drug use is a significant factor in determining the course of HIV epidemics, particularly during the early stages of epidemics in Asian countries. Several countries report high HIV prevalence in this population and IDUs account for a large proportion of reported infections. The purpose of this review is to examine the current status of the epidemic, the availability and coverage of select interventions recommended by WHO, United Nations Office on Drugs and Crimes (UNODC) and United Nations Joint Programme on HIV/AIDS (UNAIDS), resource requirements for scaling up harm reduction in Asia, gaps in the national response, barriers to implementation and recommendations for overcoming barriers to scaling up prevention, treatment and care services for IDUs in the region. PMID- 20926925 TI - Risk and vulnerability: do socioeconomic factors influence the risk of acquiring HIV in Asia? AB - HIV epidemics in Asia have been mainly concentrated among certain population groups such as injecting drug users, sex workers and their clients and men who have sex with men (MSM). HIV risk has also been associated with labour migrants and their partners. Many of the people at risk through these behaviours are very poor, and this raises the question that poverty and social deprivation may be underlying factors that drive the adoption of risk behaviours and can be regarded as 'determinants' of vulnerability to HIV infection in Asia. The study presents some observations of the socioeconomic pattern of HIV spread in Asia, using country-level and household-level data. The discussion then draws tentative conclusions about what is known concerning the mechanisms influencing the risk of HIV acquisition in Asia and what they might imply for programme design and policy. In summary, the data presented here do not support the hypothesis that HIV epidemics in Asia are primarily driven by poverty and social deprivation, though sex inequality and education for women and girls are strongly associated factors. There is clearly a multidimensional relationship between the risk of HIV infection and a host of underlying social and cultural factors that confound any attempt at a single explanation for the HIV epidemic in Asia or elsewhere. There is an undeniable need for further research through multicountry studies and better analysis of existing household data, as well as through further investigation of the quantitative relationship between the barriers to HIV services and the risk of infection. The key message for policy is to seek a broad balance between a focus on prevention and treatment for the higher-risk behaviours without losing sight of the importance of programmes that address vulnerability and behavioural change among the sexually active adult population. The implication of these findings for the allocation of resources for downstream factors such as risk behaviours as well as upstream development factors is briefly discussed. PMID- 20926926 TI - A review of the epidemiology of HIV infection and prevention responses among MSM in Asia. AB - OBJECTIVE: To review the epidemiology of HIV infection and prevention responses among men who have sex with men (MSM) in Asia. METHODS: A review of the existing scientific literature and governmental and non-governmental reports regarding the epidemiology of HIV infection and prevention responses among MSM in Asia. RESULTS: Data show that HIV infection is now widespread among MSM throughout Asia. With the exception of the Philippines and Timor Leste, all countries for which information is available show epidemics of HIV infection among MSM, particularly in urban areas. Double-digit HIV prevalence among MSM is found in cities in China, Taiwan, India, Myanmar and Thailand. Incidence data, although scarce, confirm the ongoing transmission of HIV among MSM. Reports of new HIV diagnoses in MSM have been increasing in recent years, particularly in the developed economies of East Asia. HIV prevention responses have started in most Asian countries, but while the exact coverage and investment of such responses remain unclear, coverage seems to be far from the 60-80% level needed to have an effect on the HIV epidemic. Both Government and donor investment in prevention programs for MSM remain inadequate, especially when compared with the contribution of male-to-male transmission to the overall burden of the HIV epidemic. CONCLUSION: Enlarged HIV prevention coverage and increased financial investment are necessary to reduce the spread of HIV infection among MSM in Asia. PMID- 20926927 TI - AIDS in Asia amid competing priorities: a review of national responses to HIV. AB - INTRODUCTION: The paper reviews progress in addressing the HIV epidemic and questions whether at the midway mark to the conclusion of the Millennium Development Goal set for 2015, the goal number 6 of halting and reversing the HIV epidemic will be reached. METHODS: Fourteen 2008 United Nations General Assembly Special Session on HIV/AIDS country progress reports and 18 country reports on Universal Access 2009 were analyzed. Data on national HIV strategic plans was also provided by 18 countries that participated in the regional training on costed national strategic plans 15-16 September, in Bangkok in 2008. RESULTS: Four countries with substantial populations in Asia are on track to achieve Millennium Development Goal 6. Elsewhere, elements of a potentially effective response are being introduced, but the degree of urgency and scale needed to curb the epidemics are not yet evident. Most national programmes still lack key planning components for the operation and financing of the response. Only 13 national strategic plans explicitly address the three key populations at higher risk for HIV. One third of the countries that have designed plans for effective interventions have not costed them. DISCUSSION: Early successes in controlling HIV epidemics in Asia may not be sustainable in the future. There is an urgent need to make prevention scale-up as robust as treatment scale-up and to focus programmes on high impact prevention, which directly contributes to reduction of new HIV infection. A necessary objective is to convince policy makers that the emergency posed by HIV continues. PMID- 20926928 TI - Missed opportunities for HIV testing and counselling in Asia. PMID- 20926929 TI - Essential elements of strategic information systems to guide focused HIV responses in south and south-east Asia. AB - Strategic information is fundamental to the formulation and delivery of effective HIV programmes, but generating that information is a complex process, for which most countries in south and south-east Asia lack capacity and supporting structures. Although most countries in this region have made tremendous strides in collecting relevant data, advances in the ability to translate that data into strategic information and evidence for action, have not kept pace. To overcome these shortcomings, this paper presents a comprehensive approach to collecting strategic information and building the capacity to use it effectively, which is based on experience in the successful use of data in different countries in south and south-east Asia. The system recommended here requires that staff and resources carry out four major functions: implement an early alert and response system allowing for the timely collection, synthesis and use of information to respond quickly to emerging epidemics; carefully analyze data to develop policy scenarios and resource projections to guide decision-making; periodically evaluate the impact of the current response and make recommendations to improve it; and engage policy-makers in ways that proactively promote improvements to current programmes based on evidence. At present, countries in this region are carrying out these functions in an ad-hoc and uncoordinated manner, if at all. The establishment and resourcing of structures dedicated to fulfilling these functions in an organized and coordinated manner are required to counteract the formidable barriers and challenges that inhibit the use of Asia's wealth of data for maximum benefit. PMID- 20926930 TI - Scale-up of national antiretroviral therapy programs: progress and challenges in the Asia Pacific region. AB - BACKGROUND: There has been tremendous scale-up of antiretroviral therapy (ART) services in the Asia Pacific region, which is home to an estimated 4.7 million persons living with HIV/AIDS. We examined treatment scale-up, ART program practices, and clinical outcome data in the nine low-and-middle-income countries that share over 95% of the HIV burden in the region. METHODS: Standardized indicators for ART scale-up and treatment outcomes were examined for Cambodia, China, India, Indonesia, Myanmar, Nepal, Papua New Guinea, Thailand, and Vietnam using data submitted by each country to the WHO/The Joint United Nations Programme on HIV/AIDS (UNAIDS)/UNICEF joint framework tool for monitoring the health sector response to HIV/AIDS. Data on ART program practices were abstracted from National HIV Treatment Guidelines for each country. RESULTS: At the end of 2009, over 700,000 HIV-infected persons were receiving ART in the nine focus countries. Treatment coverage varies widely in the region, ranging from 16 to 93%. All nine countries employ a public health approach to ART services and provide a standardized first-line nonnucleoside reverse transcriptase inhibitor based regimen. Among patients initiated on first-line ART in these countries, 65 88% remain alive and on treatment 12 months later. Over 50% of mortality occurs in the first 6 months of therapy, and losses to follow-up range from 8 to 16% at 2 years. CONCLUSION: Impressive ART scale-up efforts in the region have resulted in significant improvements in survival among persons receiving therapy. Continued funding support and political commitment will be essential for further expansion of public sector ART services to those in need. To improve treatment outcomes, national programs should focus on earlier identification of persons requiring ART, decentralization of ART services, and the development of stronger healthcare systems to support the provision of a continuum of HIV care. PMID- 20926931 TI - Asia can afford universal access for AIDS prevention and treatment. AB - This paper draws on published reports, data from the Global Fund to Fight AIDS, Tuberculosis, and Malaria and the Asian Development Bank, and analysis by the Commission on AIDS in Asia to estimate financial resources required to achieve universal access for HIV in low-income and middle-income countries of Asia. It explores optimal use of available resources to mount effective response to AIDS in Asia against an uncertain economic climate. Although there is global commitment to tackle the HIV pandemic, available financing falls short of minimum requirements to achieve universal access to prevention and treatment. To support essential HIV priorities in Asia, the Commission on AIDS in Asia estimated annual resource needs to be US$ 3.1 billion. Yet, in 2007, according to one study, estimated total public spending on AIDS in 14 major Asian countries was only US$ 0.9 billion. Hence, scarce resources need to be carefully applied to address the concentrated HIV epidemics in Asia and achieve universal coverage by prioritizing investment in high-impact interventions to maximally avert new infections and deaths, intensifying multisectoral efforts through catalytic financing that mainstreams HIV interventions into existing services, particularly for low-impact prevention programs, and ensuring countries with growing economies mobilize increased amounts of domestic funding to match international financing. PMID- 20926932 TI - An inappropriate tool: criminal law and HIV in Asia. AB - BACKGROUND: Asian countries have applied criminal sanctions widely in areas directly relevant to national HIV programmes and policies, including criminalization of HIV transmission, sex work, homosexuality and drug injection. This criminalization may impede universal access to HIV prevention and treatment services in Asia and undermine vulnerable people's ability to be part of the HIV response. OBJECTIVE: To review the status of application of criminal law in key HIV-related areas in Asia and analyze its impact. METHODS: Review of literature and application of human rights norms to analysis of criminal law measures. RESULTS AND CONCLUSION: Criminal laws in the areas considered here and their enforcement, while intended to reduce HIV transmission, are inappropriate and counterproductive with respect to health and human rights. Governments should remove punitive laws that impede the HIV response and should ensure meaningful participation of people living with HIV, people who use illicit drugs, sex workers and men who have sex with men in combating stigma and discrimination and developing rights-centered approaches to HIV. PMID- 20926933 TI - HIV epidemics and prevention responses in Asia and Eastern Europe: lessons to be learned? AB - OBJECTIVE: This paper describes characteristics of the HIV epidemics in Eastern Europe and Central Asia (EECA) and Asia and Central Asia, and draws comparisons between these regions. It focuses on the role that key populations continue to play in HIV transmission in both regions, the challenges that this poses and the implications for appropriate policy and practice. METHODS: Review of available data - particularly from the Global Fund to Fight AIDS, Tuberculosis and Malaria, and the United Nations Joint Programme on HIV/AIDS. RESULTS: In many countries across both regions, insufficient attention is paid to fully understanding HIV transmission and risks within key populations driving the HIV epidemics. However, it is clear that at-risk populations such as people who inject drugs, sex workers and their clients, and men who have sex with men (MSM) play important roles in HIV transmission both in Asia and EECA. The extent to which this role has been identified, accepted and targeted for HIV prevention, treatment and care is highly varied. There are several cases of good practice in terms of HIV programming and funding, but also many challenges. CONCLUSION: There is much that HIV decision-makers and policy-makers in both regions can learn from one another in this field. At-risk populations must be identified, supported and engaged in order to achieve universal access to HIV prevention, treatment and care. PMID- 20926934 TI - Know your epidemic, know your response: targeting HIV in Asia. AB - This article provides an overview of the HIV epidemic in Asia, the context within which the epidemic is evolving, and the key actions to address the challenges faced by countries and risk groups. HIV epidemics across Asia are predominantly concentrated among most-at-risk populations. Although there have been many successes in the HIV response in Asia over the past decade, great challenges clearly remain - especially when addressing most-at-risk populations, who are often criminalized, marginalized, and discriminated against. These groups face significant legal and social barriers to accessing HIV prevention and treatment services. In order to reach the Millennium Development Goal of halting and reversing the spread of HIV by 2015 and to achieve universal access to HIV treatment, these barriers must be overcome across Asia. High-impact programs must be targeted at those in need, with continuous and predictable funding for a sustainable response that incorporates prevention and treatment scale-up. Strong political leadership and the involvement of affected communities are key to developing a systematic and comprehensive response. The potential consequences of inaction in Asia are enormous: even small increases in the HIV prevalence levels in the region will translate into vast numbers of new HIV infections due to the sheer size of the population. PMID- 20926935 TI - Liver x receptors: a potential therapeutic target for modulating the atherosclerotic process. AB - Liver X receptors (LXRs) are nuclear receptors that play a major role in the expression of genes which are involved in lipid metabolism. LXRs are part of the superfamily of steroid receptors that work to deliver metabolic signals on the transcriptional level to either suppress or activate target genes. LXRs, once ligand-activated, work by forming heterodimers with the retinoid X receptor, after which they act as transcription factors by binding to the promoter region of deoxyribonucleic acid sequences, thereby affecting gene expression. Specifically, LXR has been shown to be involved with genes that help in the modulation of lipid metabolism, therein having a significant effect on the development or propagation of atherosclerosis. This review paper will discuss the overall function of LXRs and their role in lipid metabolism, and will help identify possible therapeutic modulators of LXRs that can be used for the prevention and treatment of atherosclerosis. PMID- 20926936 TI - The autonomic nervous system in cardiac electrophysiology: an elegant interaction and emerging concepts. AB - The autonomic nervous system plays an integral role in the modulation of normal cardiac electrophysiology. This is achieved via a complex network of pre- and postganglionic sympathetic and parasympathetic fibers that synapse on extrinsic and intrinsic cardiac ganglia and ultimately directly innervate cardiac myocytes. Alterations in autonomic tone may induce changes in local cellular electrophysiology that may manifest clinically in a number of ways, ranging from changes in heart rate to changes in heart rhythm. These relationships between autonomic tone and the evolution of cardiac dysrhythmias are areas of evolving research, with increasing evidence for a key role for autonomic ganglia in the pathogenesis of atrial fibrillation and sympathetic nerves in the predilection toward ventricular tachycardia in areas of myocardial scar. In this review, we highlight what is known about the anatomy and physiology of the cardiac autonomic nervous system, the evidence supporting the relationship of autonomic tone to clinically significant arrhythmias, and a variety of mechanisms (eg, direct ion channel effects) and diagnostic tools that exist to help define this relationship. Further emphasized are potential future avenues of research needed to elucidate the relationship between changes in normal autonomic tone and the pathogenesis of cardiac arrhythmias. PMID- 20926937 TI - Functional mitral regurgitation. AB - Functional mitral regurgitation (MR) is a common clinical entity which will likely increase in the future due to predicted demographic changes. It is also associated with poor long-term survival. The anatomic structure of the mitral valve apparatus is complex and consists of several components, each of which can be affected by a variety of diseases resulting in MR. In primary MR, the valvular incompetence is caused by compromised or structurally disrupted components of the valve apparatus; the valve in functional MR is structurally normal, with the regurgitation resulting from failure of coaptation of the mitral valve leaflets without coexisting structural changes of the valve itself. Therefore, we defined functional MR as a systolic retrograde flow from the left ventricle into the left atrium due to reduction and/or elimination of the normal systolic coaptation of the mitral valve leaflets. A slow progression of the symptoms is typical for this valve disease and often ends in irreversible left ventricular dysfunction. The pathophysiology and treatment of functional MR are quite complex. This article reviews and summarizes the existing literature, with a focus on the pathophysiology and current treatment of functional MR. PMID- 20926938 TI - Chronic coronary disease in the post-COURAGE Era: a new paradigm. AB - In recent decades, there have been substantial declines in the morbidity and mortality rates of cardiovascular disease. Nonetheless, cardiologists have sometimes been slow to amend prevailing concepts and alter established clinical strategies even when compelling new evidence comes to light. Recent studies have underscored the systemic nature of coronary artery disease, its early age at onset, and its high prevalence in the general population. Prevention and treatment approaches should fully incorporate these concepts. Furthermore, prevention of the most devastating complications of chronic coronary artery disease-sudden death and acute coronary events-should be given the highest priority. PMID- 20926939 TI - The pleiotropic effects of the hydroxy-methyl-glutaryl-CoA reductase inhibitors in cardiovascular disease: a comprehensive review. AB - The hydroxy-methyl-glutaryl-CoA reductase inhibitors (statins) are used extensively in the treatment of hyperlipidemia, and in the long-term prevention of coronary artery disease and stroke. They have also demonstrated a benefit in a variety of other cardiovascular disease processes. These secondary actions are known as pleiotropic effects. An updated discussion on the pleiotropy of statins is provided, and emphasizes the importance of randomized, placebo-controlled trials to further elucidate the potential benefits of these non-lipid-lowering actions in the treatment of cardiovascular disease. PMID- 20926940 TI - Relaxin: a new approach for the treatment of acute congestive heart failure. AB - Relaxin, a naturally-occurring hormone in the insulin family, was discovered to have a physiologic role in pregnancy. Named initially for its relaxing effect on the pubic ligament, relaxin receptors have since been found to be widely distributed in many organs in both males and females. Acting through multiple pathways, including the stimulation of gelatinases leading to activation of endothelin type B receptors and subsequently nitric oxide, relaxin has been shown to cause vasodilation. In animal models and studies in humans, relaxin has been shown to increase cardiac output and renal perfusion. Due to these effects, relaxin has been examined as a treatment for acute heart failure. The results of phase I and II trials have shown favorable clinical trends without any major adverse events, suggesting that relaxin has the potential to be an effective medication for acute heart failure in conjunction with or in place of current treatments. PMID- 20926943 TI - Current world literature. PMID- 20926941 TI - Novel agents for the treatment of hyponatremia: a review of conivaptan and tolvaptan. AB - Hyponatremia is the most commonly encountered electrolyte abnormality. If uncorrected, it can lead to seizure, coma, or death due to brain stem herniation. Once the serum osmolality and volume status of the patient is determined, treatment should be initiated to correct the serum sodium by 8 to 12 mEq/L within the first 24 hours. Arginine vasopressin (AVP) antagonists represent a new class of drugs indicated to treat hypervolemic and euvolemic hyponatremia. Conivaptan is a nonselective AVP antagonist that is available intravenously, and tolvaptan is a V2 selective AVP antagonist that is available as an oral tablet. Both agents produce highly effective and safe aquaresis to increase serum Na levels. Both agents have limited data in heart failure patients, but have been shown to produce significant decreases in pulmonary capillary wedge pressure, body weight, and signs and symptoms of heart failure. Neither drug has been approved for the treatment of heart failure, to date. There were no cases of osmotic demyelination syndrome with these agents, and the most common adverse events during studies were dry mouth and thirst. Overall, both conivaptan and tolvaptan are promising agents that can be used in hospitalized patients. Further studies are needed to assess the appropriateness of their use in symptomatic hyponatremic patients, and to determine their benefits in terms of disease outcome and length of stay to justify the high acquisition costs. PMID- 20926944 TI - Zoledronic acid induces cell-cycle prolongation in murine lung cancer cells by perturbing cyclin and Ras expression. AB - Zoledronic acid (ZOL) was shown earlier to prolong survival in animal models of lung cancer. The aim of this study was to examine whether alteration of intracellular cyclins, cyclin-dependent kinases, cyclin-dependent kinase inhibitors, retinoblastoma, and Ras protein expression and E2F localization are among the possible antilung cancer mechanisms driven by ZOL. Furthermore, we used geranylgeraniol to test whether the mevalonate pathway is involved in the antitumor effects of ZOL against lung cancer. Line-1 cells, a murine lung adenocarcinoma cell line, were examined. ZOL significantly slowed the growth of these cells both in vitro and in vivo. The ZOL-treated cells typically arrested at the S/G2/M phase of the cell cycle, accompanied by increased intracellular levels of cyclin A, B1, and CDC2 and decreased levels of cyclin D, p21, p27, phosphorylated retinoblastoma, and Ras. In addition, ZOL affected the distribution of E2F. When geranylgeraniol was added to the ZOL-treated cells, either in vitro or in vivo, tumor growth, cell-cycle progression, the expression of certain cyclins, and cyclin-related regulatory proteins were partially returned to that of untreated controls. Therefore, ZOL elicits cell-cycle prolongation that seems to be associated with alterations in the levels of certain cyclins and cyclin-related regulatory proteins. Furthermore, the mevalonate pathway regulates ZOL-induced murine lung cancer inhibition both in vitro and in vivo. PMID- 20926945 TI - Synthesis of protopanaxadiol derivatives and evaluation of their anticancer activities. AB - Protopanaxadiol (PPD), an aglycon of ginseng saponins, has shown anticancer activity in earlier studies. Here, we have reported the semisynthesis of nine PPD derivatives with acetyl substitutions. Subsequently, the antiproliferative effects of these nine analogs on different human cancer cell lines have been investigated. Compounds 1, 3, and 5 showed more significant and more potent antiproliferative activity compared with PPD and other derivatives. A flow cytometric assay indicated that compounds 1, 3, and 5 arrested cell cycle progression in the G1 phase and significantly induced apoptosis of cancer cells. PMID- 20926946 TI - Differences in 5-HT1A receptor-mediated hypothermia in rats with low or high exploratory activity. AB - Alterations in the serotonin (5-HT) system and the 5-HT1A receptor function have a significant role in anxiety-related and depression-related states. This study investigated the stress-induced hyperthermia (SIH) response and sensitivity to the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)-tetraline in rats with persistently low or high levels of exploratory activity (LE and HE, respectively), of which the LE rats show more anxiety-like and depressive-like phenotypes. No differences in the SIH in response to novel cage or injection stress were found using rectal temperature measurements. However, the LE rats had significantly less pronounced decreases in SIH in response to the 0.3 mg/kg dose of 8-hydroxy-2-(di-n-propylamino)-tetraline. Exploratory behaviour correlated significantly and positively with the magnitude of change in body temperature in response to the 5-HT1A receptor agonist. This finding suggests a less effective 5 HT1A function in the LE rats and implicates the 5-HT1A receptor in the anxiety component of passive behaviour in novel surroundings. PMID- 20926947 TI - Inhibitory avoidance memory deficit induced by scopolamine: interaction with glutamatergic system in the nucleus accumbens. AB - The possible involvement of N-methyl-D-aspartate (NMDA) receptors of the nucleus accumbens (NAc) in amnesia induced by scopolamine was investigated. An inhibitory (passive) avoidance task was used for memory assessment in male Wistar rats. The results revealed that intra-NAc administration of a nonselective muscarinic acetylcholine antagonist, scopolamine (1 and 2 g/rat) impaired memory consolidation in the animals when tested 24 h later. Post-training intra-NAc administration of NMDA (0.005 and 0.01 g/rat) also impaired memory consolidation, whereas post-training intra-NAc administration of the NMDA receptor antagonist, MK-801 (0.5, 1 and 1.5 g/rat) did not. Intra-NAc co-administration of an ineffective dose of NMDA with ineffective doses of scopolamine (0.25 and 0.5 g/rat) after training had no significant effect on memory consolidation, but intra-NAc injections of effective doses of NMDA (0.005 and 0.01 g/rat) prevented the amnesic effect of an effective dose of scopolamine (2 g/rat). In contrast, intra-NAc co-administration of MK-801 (0.5, 1 and 1.5 g/rat) along with an effective dose of scopolamine (2 g/rat) did not prevent the effect of the latter drug. It can be concluded that NMDA receptors in the NAc are involved in the modulation of memory consolidation that was affected by scopolamine. PMID- 20926948 TI - The effects of spironolactone on atrial remodeling in patients with preserved left ventricular function after an acute myocardial infarction: a randomized follow-up study. AB - OBJECTIVES: Atrial remodeling is an important part of cardiac remodeling after acute myocardial infarction (AMI). The aim of this study was to evaluate the effect of spironolactone on atria in patients with preserved left ventricular (LV) functions after AMI by using two-dimensional and tissue Doppler imaging techniques (TDI). METHODS: The study consisted of 110 patients with AMI, successfully revascularized with percutaneous coronary intervention, ejection fraction greater than or equal to 40%, and Killip class I-II. Patients were randomized into two groups: conventional therapy (n=55) and additional spironolactone of 25 mg/day with standard conventional therapy (n=55). Echocardiography was performed in the first 48-72 h of AMI and during 6 months of follow-up. Left atrial volume index and emptying fraction were obtained. The peak regional atrial contraction velocity, the time between the onset of p-wave on the monitor ECG and the onset, peak, and the end (TE) of the atrial contraction wave on the tissue Doppler technique curve were measured. RESULTS: The left atrial volume index and left atrium (LA) dimensions did not significantly change in either group. In the spironolactone group, left atrial emptying fraction increased compared with both baseline value (from 53.0 +/- 0.16 to 57.0 +/- 0.13 P=0.011) and conventional therapy group (from 50.0 +/- 0.17 to 47.0 +/- 0.16, P=0.013). The atrial contraction velocity did not change but the LA-TE, interatrial septum-TE, and right atrium-TE were prolonged in the conventional therapy group. CONCLUSION: Additional spironolactone therapy provided a little benefit on LA remodeling and atrial electromechanic properties in patients with AMI and preserved LV functions. PMID- 20926949 TI - Serum choline levels in patients with stable angina and acute coronary syndromes: relation to the severity of coronary artery disease. AB - OBJECTIVE: We sought to investigate whether serum choline levels are increased across the spectrum of coronary artery disease (CAD) manifestations and correlate with the severity of coronary stenosis. METHODS: A total of 36 patients with acute coronary syndrome (ACS) [22 patients with non-ST-segment elevation ACS and 14 patients with ST-segment elevation acute myocardial infarction (STEMI)], 22 patients with stable angina pectoris (SAP), and 18 controls were recruited for the study. In ACS patients, serum choline levels were measured on admission, and at 24 and 48 h thereafter, using high-performance liquid chromatography. The severity of CAD was assessed using the Gensini score. RESULTS: Serum choline levels on admission were significantly higher in the entire group of patients with ACS than in controls. The highest level of choline was observed in the STEMI group, followed by the SAP, and the non-ST-segment elevation ACS groups. Serum choline levels decreased gradually in patients with STEMI over the 48-h period. Serum choline levels on admission, and at 24 or 48 h thereafter, did not correlate with the presence of CAD neither in patients with ACS (P=0.78, 0.98 and 0.98, respectively) nor in those with SAP (P=0.92). CONCLUSION: Our results suggest that serum choline levels are increased in ACS patients. However, there was no clear correlation between levels of choline and the severity and extent of CAD in this patient group. PMID- 20926950 TI - Adjunctive pharmacologic therapy in percutaneous coronary intervention: part I antiplatelet therapy. AB - Ischemic heart disease is a major cause of morbidity and mortality throughout the world. Percutaneous coronary intervention (PCI) has rapidly evolved from balloon angioplasty to drug-eluting stents over the past 25 years and has become an important treatment option for coronary heart disease. During PCI, atherosclerotic plaque disruption and the endothelium denudation stimulate both platelet aggregation and the thrombus generation. Therefore, pharmacological adjuvant therapies to protect the procedure-related thrombotic complication during PCI are indispensable. In addition to aspirin, whose benefit has been clearly shown in ischemic heart disease, clopidogrel and prasugrel have shown to dramatically reduce the rate of thrombosis after stent placement. The introduction of glycoprotein IIb/IIIa inhibitors has further improved the results of PCI especially in high-risk patients. In addition, several new drugs with antiplatelet or with antithrombin activities are currently under development. PMID- 20926951 TI - A summer of cricket: prospective evaluation of all contacts with medical services at Edgbaston cricket ground during summer 2009. AB - OBJECTIVES: Crowd contact rates with medical services at cricket matches are unknown. The aim of this study was to detail every contact made with medical services at an international test cricket ground, whether medical or not. METHODS: Prospective, observational study of 22 matches, from county to international level, over the 2009 summer cricket season at Edgbaston Cricket Ground, Birmingham, UK. RESULTS: Four hundred and forty-four contacts from 22 matches attended by 183 387 spectators produced an incidence rate of 24/10 000. Nearly three-quarters of contacts were male (74%, n=325) and the mean age was 36 years (95% confidence interval 35-38 years). Contact rates increased with crowd size (Pearson's coefficient 0.877, P<0.001). The majority of the presentations were for new illness or injury [262 (59%)]. There was a high proportion of 'opportunistic' presentations [111 (25%)], which included advice or treatment for existing wounds or injuries, requests to use medical facilities (e.g. injecting insulin) and nonmedical contacts (e.g. repair of clothes). Eighteen patients were either sent home directly, to a minor injuries unit or to hospital. Seven ambulance transfers to hospital were required [2% (7/444)]. CONCLUSION: Contact rates with medical services at cricket matches were high (24/10 000 spectators), probably because of longer and multiday events. Match day services are often used for opportunistic and nonmedical contacts at large sports stadia, which produced nearly one-quarter of contacts over a summer of cricket at Edgbaston. This study adds unique and comprehensive data of medical requirements for crowds at all-day and multiday events. PMID- 20926952 TI - The relative efficacy of adenosine versus verapamil for the treatment of stable paroxysmal supraventricular tachycardia in adults: a meta-analysis. AB - OBJECTIVE: Verapamil and adenosine are the most common agents used to treat paroxysmal supraventricular tachycardia (PSVT). We performed a systematic review and meta-analysis to determine the relative effectiveness of these drugs and to examine their respective adverse effect profiles. METHODS: We searched MEDLINE, EMBASE, CINAHL, the Cochrane database, and international clinical trial registers for randomized controlled trials comparing adenosine (or adenosine compounds) with verapamil for the treatment of PSVT in stable adult patients. The primary outcome was rate of reversion to sinus rhythm. Secondary outcome was occurrence of pooled adverse events. Odds ratios and 95% confidence intervals (CIs) were calculated using a random effects model (RevMan v5). RESULTS: Eight trials were appropriate and had the available data. The reversion rate for adenosine was 90.8% (95% CI: 87.3-93.4%) compared with 89.9% for verapamil (95% CI: 86.0 92.9%). The pooled odds ratio for successful reversion was 1.27 (95% CI: 0.63 2.57) favouring adenosine. This was not statistically significant. There was a higher rate of minor adverse effects described with adenosine (16.7-76%) compared with verapamil (0-9.9%). The rate of hypotension was lower with adenosine [0.6% (95% CI: 0.1-2.4%)] compared with verapamil [3.7% (95% CI: 1.9-6.9%)]. CONCLUSION: Adenosine and verapamil have similar efficacy in treating PSVT. Adenosine has a higher rate of minor adverse effects, and of overall adverse effects, whereas verapamil has a higher rate of causing hypotension. A decision between the two agents should be made on a case-by-case basis and ideally involve informed discussion with the patient where appropriate. PMID- 20926953 TI - Osteoporosis in patients with primary biliary cirrhosis. AB - Metabolic bone disease has been recognized as an important complication of chronic liver disease particularly in cholestatic disorders [primary biliary cirrhosis (PBC) and primary sclerosing cholangitis] and after liver transplantation. It includes osteoporosis and more rarely osteomalacia, which is more frequent in severe malabsorption and advanced liver disease. The pathogenesis of this disorder is complex and is likely to be multifactorial. Regardless of the etiology of osteoporosis in PBC patients, they have an increased risk of spontaneous or low-trauma fracturing leading to significant patient morbidity, deterioration of quality of life, and even patient mortality. The development of bone densitometry has allowed assessment of bone mass and then contributed in estimating the fracture risk. The gold standard of bone mineral density measurement is currently the dual- energy X-ray absorptiometry. Recommendations formulated by the World Health Organization have reported the diagnostic ranges of osteoporosis based on the t-score: patient with osteoporosis has a t-score less than -2.5 SD, osteopenia has a t-score between -1.0 and -2.5 SD and a normal individual has a t-score more than -1.0 SD. The risk of fracture shows a correlation with bone mineral density but no fracture threshold was determined and the best site of characterizing the hip fracture risk is the measure of the bone mineral density of the proximal femur. The treatment of osteoporosis in patients with PBC is largely based on trials of patients with postmenopausal osteoporosis as there are a few and smaller studies of osteoporotic patients with PBC. Bisphosphonates seem to be effective in biliary disease and are more tolerated. PMID- 20926954 TI - Tuberculosis in patients receiving antiretroviral treatment: incidence, risk factors, and prevention strategies. AB - OBJECTIVE: To determine tuberculosis (TB) incidence rates and risk factors among individuals receiving antiretroviral treatment (ART). DESIGN: Observational cohort in Johannesburg, South Africa. METHODS: Incident TB was classified as early (less than 6 months of ART) or late (greater than 6 months of ART) incident TB. CD4 cell counts, viral load, body mass index, and hemoglobin were measured 6 monthly. Hazard ratios for factors associated with early and late incident TB were assessed using Cox proportional hazards regression. RESULTS: During 13,416 person-years of follow-up, 501 TB cases occurred among 7536 individuals, corresponding to a 10% risk in the first 4 years of ART and an overall incidence rate of 4.2 cases/100 person-years. The highest incidence rate (21.7 per 100 person-years) was observed in the first 3 months of ART among people with CD4 count below 50 cells/mm3. Low baseline CD4 count, anemia, and low body mass index were the strongest risk factors for early incident TB. Low updated CD4 count, low updated body mass index, anemia, and high viral load on ART were strong risk factors for late incident TB. CONCLUSIONS: Severity of HIV disease and unfavorable response to ART are associated with early and late incident TB, respectively. Early ART initiation and intensified TB screening at ART initiation are crucial to reduce incident TB. PMID- 20926956 TI - Self-evaluation of the cognitive effects of electroconvulsive therapy. AB - OBJECTIVES: Using standard self-evaluation questionnaires, numerous studies have found that subjective memory improves shortly after electroconvulsive therapy (ECT). This change covaries strongly with depression severity and is not associated with objective amnestic effects or treatment parameters. We examined subjective evaluations of ECT's cognitive effects using a novel interview that directly inquired about global impact, in contrast to the standard method of inquiring about specific aspects of cognition. METHODS: We conducted a prospective, randomized, double-masked trial comparing the effects of pulse width (0.3 vs 1.5 milliseconds) and electrode placement (right unilateral vs bilateral) on cognitive outcomes. Subjective evaluations were obtained before and during the week after the randomized ECT course, using the Cognitive Failures Questionnaire, the Squire Memory Complaint Questionnaire, and the novel Global Self-Evaluation of Memory. An extensive neuropsychological battery was administered at these time points. RESULTS: Cognitive Failures Questionnaire and Squire Memory Complaint Questionnaire scores improved at post-ECT relative to pre-ECT, strongly covaried with depression severity (24-item Hamilton Depression Rating Scale scores) but not with objective amnestic deficits or treatment parameters. In contrast, the treatment conditions differed in post-ECT Global Self-Evaluation of Memory scores, and these scores were associated with objective amnestic effects. CONCLUSIONS: In contrast to standard methods, direct questioning about global impact resulted in more negative views about ECT's cognitive effects, concordance with objective cognitive measures, and differences among treatment conditions. Patients may be more accurate in their assessment of ECT's adverse effects than had previously been suggested. PMID- 20926955 TI - Dissociation of CD154 and cytokine expression patterns in CD38+ CD4+ memory T cells in chronic HIV-1 infection. AB - Expression of the activation antigen CD38 on T cells is a strong predictor of the risk of HIV disease progression, but it is not known whether CD38 is a marker or mediator of dysfunction. We examined the relationship between CD38 expression and responses to T-cell receptor stimulation in central memory and effector memory CD4 T cells in HIV-infected persons and in healthy controls. Basal CD38 expression was preserved by blocking golgi transport with brefeldin A. Intracellular expression of interleukin 2, interferon gamma, and CD154 was measured after stimulating peripheral blood mononuclear cells with the superantigen staphylococcal enterotoxin B with or without anti-CD28 costimulation. Interferon-gamma responses were comparable or increased in stimulated CD38 memory cells, and the interleukin 2 responses of costimulated CD38 central memory cells were decreased in HIV infection. In CD38 cells and especially in CD38 cells of HIV-infected persons, stimulated memory cells more often failed to express CD154 (CD40 ligand) when induced to express cytokine. A dissociated cytokine and CD154 expression by memory CD4 T cells may impair interactions between T cells and antigen-presenting cells, contribute to impaired immunity and help explain the relationship between CD38 expression and disease progression in chronic HIV infection. PMID- 20926957 TI - 7-year survey after percutaneous dilatational tracheotomy on a medical intensive care unit. AB - PURPOSE: Percutaneous dilatational tracheotomy (PDT) is a well-established procedure in intensive care medicine. Several reports confirm a low acute and long-term complication rate. However, dilatational tracheotomy is still often postponed even in patients that are under ventilator support for more than 2 weeks. We present a retrospective study analyzing the subjective long-term results after percutaneous tracheotomy performed at our medical intensive care unit between 2002 and 2008. METHODS: We used a modified method described by Ciaglia for tracheotomy. We selected 649 patients eligible for the survey among those who had received PDT between 2002 and 2008 and had been dismissed from hospital alive. RESULTS: The return rate was 38.5% with 29.8% of the questionnaires being completed by the patients; in 32 cases, relatives reported of the patients' death. No patient experienced wound infection; none needed surgical wound revision. Dysarthria was reversible in all 16 cases; 2 patients reported a persistent hoarseness that was preexisting in both cases. One patient experienced a tracheal stenosis and received a tracheal stent; one other required a permanent tracheotomy because of a nonresectable granulation tissue. The overall rate of long-term complications associated with the long-term ventilation and the PDT was 1.8%. CONCLUSIONS: Percutaneous dilatational tracheotomy is an easily performed, cost-saving method for long-term ventilated patients with a low rate of acute and long-term complications even in old and multimorbid internal medicine patients. PMID- 20926958 TI - The risks and benefits of a modified digital tourniquet. PMID- 20926959 TI - Suprapatellar versus infra-patellar intramedullary nail insertion of the tibia: a cadaveric model for comparison of patellofemoral contact pressures and forces. AB - PURPOSE: To quantify patellofemoral contact pressures and forces during infrapatellar (IP) and suprapatellar (SP) intramedullary tibial nail insertion. METHODS: Fresh-frozen hemicadavers with intact lower extremities and pelves were used for this study. A standard IP entry portal was used on nine tibiae, whereas an SP entry portal was used in eight tibiae. A digital electronic pressure sensor system was used to dynamically measure peak pressures within the patellofemoral joint during each procedure. Data were continuously recorded from the start to completion of each procedure. Mean pressure and force as well as peak contact pressures recorded were then compared between the two techniques. RESULTS: Mean patellofemoral pressures and forces as well as peak contact pressures were higher in the SP group than the IP group. The mean peak contact pressure was 0.90 MPa (range, 0.48-1.26 MPa) during IP nailing. The mean peak contact pressure on the patella and femoral condyles was 1.84 MPa (range, 1.09-2.95 MPa) and 2.13 MPa (range, 1.10-2.86 MPa), respectively, during SP nailing. CONCLUSIONS: It is known that structural integrity of articular cartilage is compromised at impact loads exceeding 25 MPa, and chondrocyte apoptosis can occur at sustained loads of as little as 4.5 MPa in immature bovine cartilage. The results of this study indicate that although the patellofemoral contact pressures are higher with SP nail insertion, they remain below the values reported to be detrimental to articular cartilage. Based on these data, we do not believe that the SP entry portal poses a significant risk to the viability or structural integrity of the articular cartilage of the patellofemoral joint. Clinical correlation is needed. PMID- 20926960 TI - Stiffness of knee-spanning external fixation systems for traumatic knee dislocations: a biomechanical study. AB - OBJECTIVE: The purpose of this study was to compare the relative stiffness of four common external fixation (XF) configurations used to span and stabilize the knee after knee dislocation. METHODS: Synthetic composite femora and tibiae connected with cords were used to simulate a knee. Four configurations of external fixation were tested: anterior femoral pins with monotube (XF1), anterolateral femoral pins with monotube (XF2), anterolateral femoral pins with two connecting rods (XF3), and hinged ring fixator (XF4). Six specimens of each configuration were loaded nondestructively in varus/valgus, anterior-to-posterior shear, flexion/extension, axial compression, internal/external torsion, and failure in varus. RESULTS: XF2 was stiffer than XF1 in varus, valgus, and axial loading (P < 0.01) demonstrating that anterolateral pins provided greater stiffness than anterior femoral pins. XF3 was stiffer than XF2 in varus, valgus, and anterior-to-posterior shear (P < 0.002), indicating that two connecting rods provided greater stiffness than the monotube. XF4 was similar to the other configurations in anterior-to-posterior shear and torsion, indicating the hinged frame provided adequate stability. The average load to failure in varus mode was 250 N-m, which was far beyond the nondestructive loading of all specimens. There was no statistical difference between the different constructs in load to failure. CONCLUSIONS: The stiffest construct for external fixation of a knee dislocation was achieved when pins were placed anterior lateral on the femur and two connecting rods were used. A stiffer construct may provide a better clinical outcome and we therefore recommend this frame configuration. PMID- 20926961 TI - Dorsalis pedis artery pseudoaneurysm after Lisfranc surgery. AB - We present a 44-year-old man who sustained a Lisfranc dislocation complicated by a dorsalis pedis pseudoaneurysm. This case represents a rare complication of a commonly performed orthopaedic procedure. PMID- 20926962 TI - Does the zone of injury in combat-related Type III open tibia fractures preclude the use of local soft tissue coverage? AB - OBJECTIVES: Does the large zone of injury in high-energy, combat-related open tibia fractures limit the effectiveness of rotational flap coverage? DESIGN: Retrospective consecutive series. SETTING: This study was conducted at Brooke Army Medical Center, Walter Reed Army Medical Center, and National Naval Medical Center between March 2003 and September 2007. PATIENTS/PARTICIPANTS: We identified 67 extremities requiring a coverage procedure out of 213 consecutive combat-related Type III open diaphyseal tibia fractures. INTERVENTION: The 67 Type III B tibia fractures were treated with rotational or free flap coverage. MAIN OUTCOME MEASURES: Flap failure, reoperation, infection, amputation, time to union, and visual pain scale. RESULTS: There were no differences between the free and rotational flap cohorts with respect to demographic information, injury characteristics, or treatment before coverage. The reoperation and amputation rates were significantly lower for the rotational coverage group (30% and 9%) compared with the free flap group (64% and 36%; P = 0.05 and P = 0.03, respectively). The coverage failure rate was also lower for the rotational flap cohort (7% versus 27%, P = 0.08). The average time to fracture union for the free flap group was 9.5 months (range, 5-15.8 months) and 10.5 months (range, 3-41 months) for the rotational flap group (P = 0.99). CONCLUSIONS: There was a significantly lower amputation and reoperation rate for patients treated with rotational coverage. Contrary to our hypothesis and previous reports, the zone of injury in combat-related open tibia fractures does not preclude the use of local rotational coverage when practicable. PMID- 20926963 TI - The retropatellar portal as an alternative site for tibial nail insertion: a cadaveric study. AB - OBJECTIVE: To define spatial relationships between major intra-articular structures of the knee and the entry site of a tibial nail inserted using a retropatellar portal. DESIGN: Cadaveric study using 16 fresh-frozen limbs. SETTING: University-affiliated cadaver and anatomy laboratory. RESULTS: The mean distance of the nail entry site and the medial and lateral menisci were 6.6 +/- 3.2 mm and 6.4 +/- 4.4 mm, respectively. The distance to the medial and lateral articular surfaces were 5.6 +/- 3.6 mm and 7.4 +/- 4.2 mm, respectively. The mean distance to the anterior cruciate ligament footprint was 7.5 +/- 3.5 mm. The lateral meniscus was never injured during the procedure. The anterior cruciate ligament was undisturbed in all specimens. The medial meniscus was injured 1 to 2 mm in 12.5% of specimens. The intermeniscal ligament was injured 1 to 2 mm in 81.2% of the specimens. CONCLUSION: The intermeniscal ligament and medial meniscus are at the most risk during intramedullary nailing of the tibia using the retropatellar technique. This may be corrected by avoiding an excessively medial start point. Damage to the intermeniscal ligament and medial meniscus occurs more commonly with the retropatellar portal, but this damage was never more than 1 to 2 mm. This risk, however, appears similar to the pattern and incidence of injury that occurred in prior studies investigating tibial nail insertion through a standard patellar tendon approach. The retropatellar technique demands clinical investigation to further define both its safety and its use. PMID- 20926964 TI - Extruded osteoarticular distal tibia: success at 18-month follow-up with reimplantation. AB - Extruded bone is a rare complication of open fractures associated with high energy. We describe a case of bony extrusion involving an osteoarticular segment of distal tibial treated with reimplantation and internal fixation with 18-month follow-up. PMID- 20926965 TI - Retropatellar technique for intramedullary nailing of proximal tibia fractures: a cadaveric assessment. AB - OBJECTIVE: To investigate if the radiographically correct and anatomically safe starting point and the appropriate sagittal plane vector could be obtained using a retropatellar technique for proximal tibia fractures treated with an intramedullary device. METHODS: We performed a cadaveric and radiographic study utilizing 16 limbs. We performed a retropatellar approach via longitudinal quadriceps split, passed a specialized trocar through the patellofemoral joint and onto the superior aspect of the tibia, and inserted Kirschner wires into the anatomic safe zone of the tibial plateau at 0, 10, 20, 30, 40, and 50 degrees of knee flexion utilizing biplanar fluoroscopy. We recorded knee flexion with a goniometer and the entrance vector of the Kirschner wire in relation to the anterior tibial cortex. SETTING: University-affiliated cadaver and anatomy laboratory. RESULTS: There was a progressive increase in the ability to obtain the correct anatomical start site from 1 of 16 (6.25%) at full extension to 12 of 16 (75%) at 50 degrees of knee flexion (P = 0.00098). A statistically significant decrease in the average sagittal plane entrance vector in relation to the anterior tibial cortex was found from 23.1 degrees at full extension to -0.41 degrees at 50 degrees of knee flexion (P < 0.0001). CONCLUSIONS: The retropatellar technique allows the radiographically defined correct start site to be localized, particularly at higher degrees of knee flexion. More favorable intramedullary nail insertion angles were possible with the retropatellar technique, particularly with knee flexion angles greater than 20 degrees. The retropatellar technique demands further investigations to further delineate its advantages, limitations, and possible risks to local anatomy. PMID- 20926966 TI - Repeated bout effect is not correlated with intraindividual variability during muscle-damaging exercise. AB - The aim of this study was to test the hypothesis that the repeated bout effect depends on intraindividual variability during a second bout of eccentric exercise. Eleven healthy men performed 2 resistance training bouts consisting of maximal eccentric exercise (EE1 and EE2) using the knee extensor muscles. The interval between the exercise bouts was 2 weeks and consisted of 10 sets of 12 repetitions at 160 degrees . s(-1). Maximal isokinetic concentric torque at 30 degrees . s(-1) was measured before the bouts and 2 minutes and 24 hours thereafter. Muscle soreness score and creatine kinase activity were determined before and after exercise. Intraindividual variability in torque during each eccentric repetition was measured during exercise. Repeated bout effect manifested after EE2: Muscle soreness was less, the shift in optimal knee joint angle to a longer muscle length was less, and the decrease in isokinetic concentric torque 2 minutes after exercise was less for EE2 compared with that for EE1. During concentric (isokinetic) contraction, length-dependent changes in isokinetic torque (IT) occurred after both EE1 and EE2: The shorter the muscle length, the greater the change in IT. There was a significant relationship between the decrease in maximal isokinetic knee extension torque 24 hours after EE1 and intraindividual variability of EE1 (R2 = 0.71, p < 0.05), but this relationship was not significant for EE2 (R2 = 0.18). It seems that intraindividual variability during eccentric exercise protects against muscle fatigue and damage during the first exercise bout but not during a repeat bout. These findings may be useful to coaches who wish to improve muscle function in resistance training with less depression in muscle function and discomfort of their athletes, specifically, when muscle is most sensitive to muscle-damaging exercise. PMID- 20926967 TI - Effect of varying rest intervals between sets of assistance exercises on creatine kinase and lactate dehydrogenase responses. AB - To examine the effects of different rest intervals between sets on serum creatine kinase (CK) and lactate dehydrogenase (LDH) activity, 10 men (age = 25.6 +/- 2.2 years, height = 173.1 +/- 7.1 cm, and body mass = 75.9 +/- 10.0 kg) participated in a randomized within-subject design that involved 4 resistance exercise sessions. Each session consisted of 4 sets of 10 repetitions with 10 repetition maximum loads for the chest press, pullover, biceps curl, triceps extension, leg extension, and prone leg curl. The sessions differed only in the length of the rest interval between sets and exercises, specifically: 60, 90, 120, 180 seconds. Serum CK and LDH were significantly (p < 0.05) elevated 24-72 hours after each session, with no significant differences between rest intervals (p = 0.94 and p = 0.99, respectively). The mechanical stress imposed by the 4 resistance exercise sessions invoked similar damage to the muscle fibers independent of the rest interval between sets. These data indicate that the accumulated volume of work is the primary determinant of muscle damage in trained subjects who are accustomed to resistance exercise with short rest intervals. PMID- 20926968 TI - Exercise-induced inspiratory muscle fatigue during swimming: the effect of race distance. AB - Exercise-induced inspiratory muscle fatigue (IMF) has been quantified for several sports. However, it is not yet known if, or to what extent, IMF is determined by the competition distance. The aim of the present study was to assess the influence of 3 different competitive front-crawl swimming race distances on the magnitude of IMF. Ten well-trained swimmers from a local swim team participated in the study and on separate days completed maximal 100-, 200-, and 400-m time trials (TTs). Before and after each trial, maximal inspiratory pressure (MIP) was measured and %IMF determined from pre- and post-time-trial differences in MIP. The heart rate (HR) and rate of perceived dyspnea (RPD) was also assessed. For all distances, posttrial MIP was lower than pretrial MIP, though this was only significant for 100 m (p < 0.05). There were no differences between distances for absolute posttrial MIP. The %IMF after the 100-m TT (8.2 +/- 4.1%) was, however, significantly greater than the 400 m (4.9 +/- 3.8%) TT (p < 0.05) but not 200-m TT. There were no differences between trials for HR or RPD (p > 0.05). There were no relationships between %IMF and mean pretrial MIP (r = -0.28, p > 0.05) or between %IMF and time for any TT (100 m, r = 0.25; 200 m, r = 0.34; 400 m r = 0.18; p > 0.05). The lack of difference between trials for posttrial absolute MIP suggests that race distance during swimming does not substantially influence the degree of IMF. PMID- 20926969 TI - Another great idea from a nurse. PMID- 20926970 TI - Reducing neonatal pain during routine heel lance procedures. AB - PURPOSE: To measure the difference in pain scores for newborns who were held and swaddled while undergoing routine heel lance procedures compared to newborns who were lying on their backs and not swaddled during heel lance. Additionally, we sought to compare the total amount of time it took to collect the specimens in each group. DESIGN AND METHODS: A total of 42 neonates recruited from a large tertiary hospital were enrolled in a randomized controlled trial. Infants in the experimental group (n = 22) were swaddled and held in an upright position during routine heel lance procedures while neonates in the control group (n = 20) remained in a standard care position. Pain was measured with the Neonatal Inventory Pain Scale (NIPS) at two points in time for each group (just before the heel lance procedure and at the completion of the heel lance). Total collection time was measured using a stopwatch accurate to 1/100th of a second. Specimen quality was measured based on the number of rejected specimens for each group. Descriptive statistics and t tests were used to analyze the data. RESULTS: The mean NIPS score for neonates who were swaddled and held during the procedure (experimental group) was significantly lower (M = 1.3, SD = .9) than the score for infants in the standard position (control group) (M = 2.7, SD = 1.3), t (40) = -4.48, p < .001. Although the total collection time was lower for infants who were swaddled (2 minutes and 17 seconds, SD = 59) versus (2 minutes and 47 seconds, SD = 85) for controls, this was not a statistically significant difference (p = .45). CLINICAL IMPLICATIONS: Swaddling combined with positioning neonates upright during routine heel lance procedures offers nurses a nonpharmacologic method of neonatal pain reduction for heel sticks. This technique can be easily implemented on any unit independent of facility protocols. Furthermore, the technique is not associated with any cost or policy development, making it more likely that nurses can use it in practice. PMID- 20926971 TI - Leptin and its intracellular signaling pathway maintains the neurosphere. AB - Leptin is associated with the maintenance of epidermal growth factor (EGF) reactive neural lineage cells, including the neural progenitors. One-day treatment with leptin (10, 100, or 1000 ng/ml) followed by EGF treatment increased the number of small-sized and mid-sized colonies compared with the nonleptin treatment. Leptin prevented the inactivation of the phosphatidylinositol 3-kinase (PI3 K) and extracellular signal regulated kinase (ERK) pathways in neurosphere cells cultured in the non-EGF medium. Bromodeoxyuridine (BrdU) incorporation into the neurosphere cells induced by leptin was suppressed by LY294002, a PI3 K inhibitor, but not by U0126, a MEK1/2 inhibitor, which activates ERK1/2, although U0126 decreased phosphorylated extracellular signal regulated kinase levels. These results suggest that leptin maintains the self-renewal ability and EGF reactivity of immature neural lineage cells and the signal is mediated, at least in part, by the PI3 K pathway. PMID- 20926972 TI - Neuronal collagen XVII is localized to lipofuscin granules. AB - We have earlier shown that collagen XVII is expressed by neurons in the human brain, although its exact intracellular location and function have remained unknown. In this study we have localized collagen XVII specifically to neuronal lipofuscin granules using electron microscopy in autopsy samples from the human brainstem. Our results show that collagen XVII expression is mainly confined to an ultrastructurally definable, specific type of lipofuscin granule. The function of neuronal collagen XVII remains unclear. However, as the functional significance of lipofuscin remains debated, the presence of collagen XVII in just some types of lipofuscin may be helpful in the process of exploring the variety of neuronal, age-related lipopigments, which are as yet defined operationally rather than functionally or structurally. PMID- 20926973 TI - Intense dopamine innervation of the subventricular zone in Huntington's disease. AB - Dopamine exerts a robust promoting effect on adult neurogenesis. Here, we report the presence of an intense dopamine (tyrosine hydroxylase immunoreactive) zone along the ventricular border of the caudate nucleus in patients with Huntington's disease, but not in age-matched controls. This thin (150-400 microm) paraventricular zone was composed of numerous small and densely packed dopamine axon varicosities and overlapped the deep layers of the subventricular zone. Immunoreactivity in the paraventricular zone was 50% higher than in adjacent striatal areas. This intense dopamine zone concurs with the striking increase of neurogenesis noted in the subventricular zone of Huntington's disease patients and indicates that dopamine might play a crucial role in intrinsic mechanisms designed to compensate for the massive striatal neuronal losses that occur in Huntington's disease. PMID- 20926974 TI - Expression of connexin29 and 32 in the penumbra region after traumatic brain injury of mice. AB - Connexins (Cx) are transmembrane proteins forming vertebrate gap junction channels for direct cell-cell communication. We found that the expressions of two Cx family members, Cx29 and Cx32, were progressively increased in the sharp border of injury penumbra regions after cryotraumatic brain injury. Although these two Cxs are expressed exclusively in the oligodendrocytes in the normal cerebral cortex, their expressions were increased in the astrocytes and microglia localized in the injury border. Highly selective induction of Cxs in the injury border suggests that altered Cxs may contribute to the propagations of injury related and/or regeneration signals after acute brain injury. PMID- 20926975 TI - Chronic pedunculopontine nucleus stimulation restores functional connectivity. AB - The mechanisms of deep brain stimulation (DBS) are poorly understood. Earlier, high-frequency DBS has been thought to represent a depolarization block of the target area and low-frequency stimulation has been thought to 'drive' neuronal activity. We investigated the long-term effect of low-frequency DBS in a longitudinal imaging study of a patient who received bilateral pedunculopontine nucleus stimulation. We used the diffusion tensor imaging techniques including probabilistic tractography and topographic mapping to analyze long-term changes in connectivity with low-frequency DBS. Post-DBS connectivity analysis suggested a normalization of pathological pedunculopontine nucleus connectivity with DBS therapy. These findings may help elucidate the mechanisms of DBS, suggesting neuroplasticity involving a reorganization of target connectivity long term. This is the first reported case showing neuroimaging evidence of neuroplasticity after low-frequency DBS. PMID- 20926976 TI - Monitoring of 2-deoxy-2-[18F]fluoro-D-glucose uptake in tumor-bearing mice using high-sensitivity projection imaging: compared with PET imaging. AB - OBJECTIVE: To investigate the feasibility of using high-sensitivity projection [F]fluoro-deoxyglucose imaging to monitor chemotherapeutic efficacy in BALB/c mice bearing CT-26 tumor implants. METHODS: A planar positron imaging system (PPIS)-4800 and a microPET R4 were used for projection and tomographic imaging, respectively. Six disks filled with different volumes of F-FDG solution were scanned by PPIS for calibration check. Tumor-bearing mice were treated with saline (control) or cyclophosphamide by intraperitoneal injections. Tumor responses were evaluated by both PPIS and microPET imaging. RESULTS: The disk activity ratios obtained from PPIS were 1.00: 1.30: 1.98: 2.48: 2.73: 3.53 with corresponding volume ratios of 1.0: 1.5: 2.0: 2.5: 3.0: 3.5. PPIS imaging in tumor-bearing mice showed that the tumor/non-tumor ratios were 1.62, 2.12, 3.03, 4.46, and 3.61 on days 7, 10, 13, 17, and 20, respectively, after tumor inoculation. In addition, PPIS was used to monitor the chemotherapeutic effect of cyclophosphamide on tumor-bearing mice. The correlation coefficients between the tumor sizes and tumor/non-tumor ratios for microPET and PPIS were 0.63 and 0.72, respectively, in the control group, and were 0.98 and 0.81, respectively, in the cyclophosphamide-treated group. CONCLUSION: This study showed that PPIS imaging is a feasible modality for monitoring tumor responses. These results suggest that PPIS, a potential high-throughput screening imaging system, may be used for the preclinical evaluation of tumor response to new anticancer drugs using murine tumor models. PMID- 20926977 TI - Utility of fluorodeoxyglucose-positron emission tomography in the identification of new lesions in lung cancer patients for the assessment of therapy response. AB - PURPOSE: Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) has added positron emission tomography (PET) as an optional complement for the detection of new lesions. In this study, we evaluate the utility of fluorodeoxyglucose (FDG)-PET in the identification of new lesions and progressive disease not recognized on computed tomography (CT) in patients with nonsmall cell lung cancer (NSCLC) undergoing therapy. MATERIALS AND METHODS: Seventy patients (30 female, 40 male; mean age 67+/-14 years, range, 39-94 years) with NSCLC underwent FDG-PET before and after chemotherapy and/or radiotherapy, whereas 69 patients underwent CT imaging. Overall (OS) and progression-free survivals (PFS) were calculated for RECIST 1.1 with CT alone, RECIST 1.1 with PET for the identification of new lesions, visual PET, and semiquantitative PET using a change in standardized uptake value ranging from -15 to -50%. RESULTS: PET identified new lesions in 26 patients, resulting in 10 patients (14.5%) being upgraded to progressive disease. The combination of CT and PET for the detection of new lesions improved the prediction of survival (OS: P=0.0491 for all stages and P=0.0033 for stage IV; PFS: P=0.0045 for stage IV) compared with CT imaging alone (OS: P=0.1362 for all stages and P=0.1625 for stage IV; PFS: P=0.0632 for stage IV). Furthermore, a change in standardized uptake value of -35% was the most discriminative for the prediction of survival for the semiquantitative PET approach (OS: P=0.0393 for all stages, P=0.0051 for stage IV; PFS: P=0.0092 for stage IV) and more discriminative than the visual PET approach (OS: P=0.2699 for all stages, P=0.0105 for stage IV; PFS: P=0.014 for stage IV). CONCLUSION: FDG PET is helpful in identifying new lesions in NSCLC patients, resulting in the improved assessment of therapy response with CT imaging combined with FDG-PET compared with CT imaging alone. Although RECIST 1.1 includes FDG-PET only as an optional adjunct, we recommend the implementation of PET imaging in the assessment of therapy response. PMID- 20926978 TI - Distribution pattern of 68Ga-DOTATATE in disease-free patients. AB - PURPOSE: 68Ga-DOTA-DPhe1,Tyr3-octreotate (68Ga-DOTATATE) is a somatostatin analogue that shows high affinity for somatostatin receptor subtype 2 (sst2) and has been used for imaging neuroendocrine tumours. However, normal uptake patterns and potential pitfalls have not been described with this high-sensitivity radiotracer. The aim of this study was therefore to outline the normal distribution pattern of 68Ga-DOTATATE in disease-free patients, to provide standardized uptake values (SUVs) of various organs and to compare our results with the current knowledge on sst2 receptor expression in vitro. METHODS: 68Ga DOTATATE PET/computed tomography was performed in 42 patients (15 men and 27 women). Approximately 145 MBq of tracer was injected intravenously and imaging was performed using a GE Discovery ST PET/computed tomography scanner. SUVs were calculated on the reconstructed images for various organs. RESULTS: 68Ga-DOTATATE uptake was noted in the sst2-expressing organs such as pituitary, thyroid, stomach wall, spleen, adrenals, kidneys, pancreas and prostate and in the liver and salivary glands, with excreted activity in the bowel and in the pelvicalyceal system of the kidneys and urinary bladder. The SUVs ranged from 0.1 to 48.8 in the organs considered. Potential pitfalls in interpreting the 68Ga-DOTATATE uptake in organs such as thyroid, pancreas lymph nodes and bowel were identified. CONCLUSION: This study shows the distribution pattern of 68Ga-DOTATATE outlines the range of SUVs for various organs in disease-free patients and identifies some of the potential pitfalls encountered during imaging. PMID- 20926979 TI - Erythropoietin requires endothelial nitric oxide synthase to counteract TNF [alpha]-induced microcirculatory dysfunction in murine striated muscle. AB - In the present study, we aimed to evaluate whether erythropoietin (EPO) treatment may exert nonhematopoietic endothelial protection against TNF-[alpha]-induced microvascular inflammation and to determine the involvement of the nitric oxide (NO)-producing enzyme isoforms endothelial NO synthase (eNOS) and inducible NO synthase (iNOS). Murine dorsal skinfold chambers of wild-type (WT) animals were topically stimulated with TNF-[alpha] after pretreatment with epoetin beta (1,000 IU/kg body weight i.p.) or physiological saline. Leukocyte behavior, microvascular perfusion, and apoptosis were assessed by in vivo fluorescence microscopy. To study the involvement of NO, we compared eNOS-deficient (eNOS-/-) and iNOS-deficient (iNOS-/-) mice with WT animals. TNF-[alpha]-associated leukocyte activation, perfusion failure, and apoptosis were substantially attenuated in EPO-pretreated WT mice, which was accompanied by marked reduction of perivascular infiltration with F4/80-stained macrophages. The anti inflammatory protective effects of EPO were abolished in eNOS-/-, but not in iNOS /- mice, both with unaffected intercellular adhesion molecule 1 expression. However, the antiapoptotic effect of EPO was maintained in both eNOS-/- and iNOS /- mice, indicating that this mechanism might rather be independent of NO. We conclude that EPO treatment elicits protection against TNF-[alpha]-induced microcirculatory dysfunction, depending on NO derived from endothelial cells, but not on the inducible isoform. PMID- 20926980 TI - Inhibition of glycogen synthase kinase 3[beta] activity with lithium in vitro attenuates sepsis-induced changes in muscle protein turnover. AB - Loss of lean body mass is a characteristic feature of the septic response, and the mechanisms responsible for this decrease and means of prevention have not been fully elucidated. The present study tested the hypothesis that in vitro treatment of skeletal muscle with lithium chloride (LiCl), a glycogen synthase kinase (GSK) 3 inhibitor, would reverse both the sepsis-induced increase in muscle protein degradation and inhibition of protein synthesis. Sepsis decreased GSK-3[beta] phosphorylation and increased GSK-3[beta] activity, under basal conditions. Sepsis increased muscle protein degradation, with a concomitant increase in atrogin 1 and MuRF1 mRNA and 26S proteosome activity. Incubation of septic muscle with LiCl completely reversed the increased GSK-3[beta] activity and decreased proteolysis to basal nonseptic values, but only partially reduced proteosome activity and did not diminish atrogene expression. Lithium chloride also did not ameliorate the sepsis-induced increase in LC3-II, a marker for activated autophagy. In contrast, LiCl increased protein synthesis only in nonseptic control muscle. The inability of septic muscle to respond to LiCl was independent of its ability to reverse the sepsis-induced increase in eukaryotic initiation factor (eIF) 2B[varepsilon] phosphorylation, decreased eIF2B activity, or the reduced phosphorylation of FOXO3, but instead was more closely associated with the continued suppression of mTOR (mammalian target of rapamycin) kinase activity (e.g., reduced phosphorylation of 4E-BP1 and S6). These data suggest that in vitro lithium treatment, which inhibited GSK-3[beta] activity, (a) effectively reversed the sepsis-induced increase in proteolysis, but only in part by a reduction in the ubiquitin-proteosome pathway and not by a reduction in autophagy; and (b) was ineffective at reversing the sepsis-induced decrease in muscle protein synthesis. This lithium-resistant state seems mediated at the level of mTOR and not eIF2/eIF2B. Hence, use of GSK-3[beta] inhibitors in the treatment of sepsis may not be expected to fully correct the imbalance in muscle protein turnover. PMID- 20926981 TI - A prospective randomized trial using blood volume analysis in addition to pulmonary artery catheter, compared with pulmonary artery catheter alone, to guide shock resuscitation in critically ill surgical patients. AB - Measurement of blood volume (BV) may guide fluid and red blood cell management in critically ill patients when capillary leak from shock and fluid resuscitation makes assessment of intravascular volume difficult. This is a prospective randomized trial of critically ill surgical patients with septic shock, severe sepsis, severe respiratory failure, and/or cardiovascular collapse. The control group received fluid management based on pulmonary artery catheter parameters and red blood cell transfusions based on hematocrit values. The BV group received fluid and red blood cell transfusions based on BV analyses in addition to pulmonary artery catheter parameters. Blood volume was measured using the radioisotope tracer technique with iodine 131-labeled albumin. This allowed direct measurement of plasma volume and calculation of the red blood cell volume. The control group was blinded to the BV results. There were statistically significantly more times when the control group (compared with the BV group) demonstrated hypervolemia (48% vs. 37%) and red blood cell deficiency (33% vs. 16%). There was a delay in red blood cell transfusions administered to the control group by 1.5 +/- 2 days at which time the abnormality became clinically evident. Blood volume analyses provided additional information to the clinicians resulting in a change in treatment in 44% of the time to patients randomized to the BV group. The mortality rates were significantly different between the two groups (8% for the BV group and 24% in the control group; P = 0.03). Blood volume measurements allowed the physicians to promptly treat physiologic disturbances in both red blood cell volume and plasma volume, resulting in improved survival. PMID- 20926982 TI - Pathway analysis in microarray data: a comparison of two different pathway analysis devices in the same data set. AB - Oligonucleotide microarray technology has been developed to a very powerful and favorable biotechnique. However, it is an explicit challenge to judge the potential biological meaning of such extensive amounts of data. There are various commercially available or free-software applications for pathway analyses on microarray data on the market. The aim of the present study was to test whether pathway analyses on the same data set using different commercially available devices lead to roughly comparable or massively diverging results and, if so, to give potential explanations. Two different commercially available pathway analysis programs (GeneGo and Pathway Studio 6) have been elected. The programs have been compared concerning their different analyses tools, underlying databases, database constructions, and network-building algorithms. The same data set has been uploaded into two different programs. Pathway analysis was performed according to the following three criteria: the five top networks, the five top diseases, and the five top canonical networks that are associated with the uploaded gene list. The different programs differ in extracting their information from the literature, in database construction, and network-building algorithms. The "top networks," as suggested by the programs as to be "most important," substantially differ from each other and share only one same gene. Concerning the most represented diseases in the data set, there are certain overlaps but no uniform results in the different applications. Pathway analyses of microarray data using preformed software devices offer valuable options for investigating on the biological relevance and function of a focus gene set. However, there is no standard in constructing such programs. This leads to substantial differences when investigating on the same data set using different devices. The intention of this work is to sensitize for the potentialities and also pitfalls doing pathway analysis using automated software tools. PMID- 20926983 TI - Pretreatment with berberine and yohimbine protects against LPS-induced myocardial dysfunction via inhibition of cardiac I-[kappa]B[alpha] phosphorylation and apoptosis in mice. AB - Myocardial dysfunction is a common complication in sepsis and significantly contributes to the mortality of patients with septic shock. Our previous study demonstrated that pretreatment with berberine (Ber) protected against the lethality induced by LPS, which was enhanced by yohimbine, an [alpha]2-adrenergic receptor antagonist, and Ber combined with yohimbine also improved survival in mice subjected to cecal ligation and puncture. However, no studies have examined whether Ber and yohimbine reduce LPS-induced myocardial dysfunction. Here, we report that pretreatment with Ber, Ber combined with yohimbine, or yohimbine significantly reduced LPS-induced cardiac dysfunction in mice. LPS-provoked cardiac apoptosis, I-[kappa]B[alpha] phosphorylation, IL-1[beta], TNF-[alpha], and NO production were attenuated by pretreatment with Ber and/or yohimbine, whereas cardiac Toll-like receptor 4 mRNA expression, malondialdehyde content, and superoxide dismutase activity were not affected. These data demonstrate for the first time that pretreatment with Ber and/or yohimbine prevents LPS-induced myocardial dysfunction in mice through inhibiting myocardial apoptosis, cardiac I [kappa]B[alpha] phosphorylation, and TNF-[alpha], IL-1[beta], and NO production, suggesting that activation of [alpha]2-adrenergic receptor in vivo may be responsible at least in part for LPS-induced cardiac dysfunction, and Ber in combination with yohimbine may be a potential agent for preventing cardiac dysfunction during sepsis. PMID- 20926984 TI - Leukotriene b4 and its metabolites prime the neutrophil oxidase and induce proinflammatory activation of human pulmonary microvascular endothelial cells. AB - Leukotrienes are proinflammatory lipid mediators, derived from arachidonic acid via 5-lipoxygenase (5-LO). Leukotriene B4 (LTB4) is an effective polymorphonuclear neutrophil (PMN) chemoattractant, as well as being a major product of PMN priming. Leukotriene B4 is rapidly metabolized into products that are thought to be inactive, and little is known about the effects of LTB4 on the pulmonary endothelium. We hypothesize that LTB4 and its metabolites are effective PMN priming agents and cause proinflammatory activation of pulmonary endothelial cells. Isolated PMNs were primed (5 min, 37 degrees C) with serial concentrations 10 to 10 M of LTB4 and its metabolites: 6-trans-LTB4, 20-OH-LTB4, and 20-COOH LTB4, and then activated with fMLP. Primary human pulmonary microvascular endothelial cells (HMVECs) were incubated with these lipids (6 h, 37 degrees C, 5% CO2), and intercellular adhesion molecule 1 was measured by flow cytometry. Polymorphonuclear neutrophil adhesion was measured by myeloperoxidase assays, and to ensure that these reactions were specific to the LTB4 receptors, BLT1 and BLT2 were antagonized with CP105,696 (BLT1) or silenced with siRNA (BLT1 and BLT2). Leukotriene B4 and its metabolites primed PMNs over a wide range of concentrations, depending on the specific metabolite. In addition, at high concentrations these lipids also caused increases in the surface expression of intercellular adhesion molecule 1 on HMVECs and induced HMVEC-mediated adhesion of PMNs. Silencing of BLT2 abrogated HMVEC activation, and blockade of BLT1 inhibited the observed PMN priming activity. We conclude that LTB4 and its omega oxidation and nonenzymatic metabolites prime PMNs over a range of concentrations and activate HMVECs. These data have expanded the repertoire of causative agents in acute lung injury and postinjury multiple organ failure. PMID- 20926985 TI - STY39, a novel alpha-melanocyte-stimulating hormone analogue, attenuates bleomycin-induced pulmonary inflammation and fibrosis in mice. AB - Various anti-inflammatory agents have been used to treat acute or chronic lung injury-induced pulmonary fibrosis (PF). However, the efficacy of the available treatments is disappointing, and new therapies are urgently needed. In the current study, we investigated the effect of a novel alpha-melanocyte-stimulating hormone analog, STY39, on bleomycin (BLM)-induced pulmonary inflammation and fibrosis in mice. C57BL/6 mice received an intratracheal injection of BLM before being treated with STY39 (0.625, 1.25, or 2.5 mg/kg, i.p.) once a day for 14 consecutive days. Various parameters, reflecting the inflammatory reaction, metabolism of extracellular matrix, myofibroblast proliferation, and degree of fibrosis in the lung, were evaluated. We found that STY39 significantly improved the survival of mice with lethal BLM-induced lung injury, limited body weight loss and the increase in the lung index, reduced the mRNA expression of types I and III procollagen and the production of hydroxyproline in the lung, diminished myofibroblast proliferation, and ultimately reduced BLM-induced lung damage. Further investigation revealed that, in a dose-dependent manner, STY39 treatment inhibited leukocyte migration into the lung; reduced the production of TNF-alpha, IL-6, macrophage inflammatory protein 2, and transforming growth factor beta1 in the lung; and altered the ratio of matrix metalloproteinase 1 to tissue inhibitors of metalloproteinase 1. These findings suggest that STY39 attenuates BLM-induced experimental PF by limiting the inflammatory reaction through the inhibition of proinflammatory and profibrosis cytokines and by accelerating the metabolism of extracellular matrix. Therefore, STY39 may be an effective therapy for preventing PF. PMID- 20926986 TI - Estrogen augments the protection of hypertonic saline treatment from mesenteric ischemia-reperfusion injury. AB - Either estrogen or hypertonic saline (HTS) administration can decrease lung inflammation after ischemia-reperfusion. The present study investigated whether combined treatment with estrogen and HTS could provide further protection from mesenteric ischemia-reperfusion (MSIR) injury. Male C3H/HeOuJ mice were randomly segregated into the following groups: sham-operated (sham), vehicle treatment followed by MSIR (vehicle treated), estrogen treatment followed by MSIR (estrogen treated), HTS treatment and MSIR (HTS treated), and combined treatment of estrogen plus HTS and MSIR (combined treated). In MSIR, mice were subjected to mesenteric ischemia for 60 min followed by reperfusion for 30 min. The histology of the lung and the gut was obtained. Lung injury was evaluated by lung edema and myeloperoxidase (MPO) activity; lung protein expression of macrophage migration inhibitory factor (MIF), toll-like receptor-4 (TLR4), phosphorylated inhibitory kappaBalpha (p-IkappaBalpha), and inducible nitric oxide synthetase (iNOS) were assayed. Survival analysis was monitored after MSIR for 120 min. Compared with those in the sham-treated group, the lung water ratio, MPO activity, and expressions of MIF, TLR4, p-IkappaBalpha, and iNOS were significantly increased in the vehicle-treated group. Diminished MIF, TLR4, p-IkappaBalpha, and iNOS expressions were found in the estrogen-treated group, whereas suppression of p IkappaBalpha and iNOS was found in the HTS-treated group. Treatment with estrogen or HTS decreased the lung water and MPO activity. The combined treatment of estrogen and HTS further significantly diminished p-IkappaBalpha and iNOS expression, lung edema, and MPO activity and improved the inflammation of the lung and the morphology of the gut in histology compared with the results of a single treatment of estrogen or HTS. Survival analysis showed significantly increased survival in the combination-treated group compared with survival in the HTS-treated group. In conclusion, compared with single-agent use, treatment combining estrogen and HTS further decreases lung p-IkappaBalpha and iNOS expressions, as well as the degree of lung injury. These effects may result in better rates of survival from MSIR injury. PMID- 20926987 TI - Challenges to effective research in acute trauma resuscitation: consent and endpoints. AB - Selection of study endpoints is one of the most important decisions in the design of effective clinical trials. Late mortality (e.g., 28 days) is an unambiguous endpoint, accepted by regulatory agencies, but it is viewed as problematic among researchers in the study of resuscitation for acute trauma injury with hemorrhagic shock. In February 2008, physicians, ethicists, statisticians, and research scientists from the military, academia, industry, the Federal Drug Administration, and the National Heart Lung and Blood Institute gathered to discuss the obstacles confronting the trauma community in their efforts to improve patient outcomes. The primary meeting objective was to generate preliminary suggestions for a series of follow-up meetings that will develop consensus guidelines for the design of large multicenter clinical trials. Twenty short presentations and discussions, summarized here, outlined the group's concerns and suggestions. Successful and failed, completed or ongoing, clinical studies provided insight as to endpoints that may be of value for future trauma and shock studies. In addition to the importance of appropriate endpoints in study design, other related topics were discussed, including trauma epidemiology, patient enrollment and inclusion criteria, community consultation and the difficulty of obtaining informed consent in acute trauma research, and the inclusion of quality of life in composite endpoints. The consensus was that more discussion was needed and that consideration of new endpoints for clinical trials in emergency trauma research was a worthwhile and necessary goal. PMID- 20926988 TI - The effect of the intrathoracic pressure regulator on hemodynamics and cardiac output. AB - The intrathoracic pressure regulator (ITPR) (CirQLator; Advanced Circulatory Systems Inc, Roseville, Minn) is a novel, noninvasive device intended to increase cardiac output and blood pressure in hypovolemic or cardiogenic shock by generating a continuous low-level intrathoracic vacuum in between positive pressure ventilations. Although there are robust data supporting the benefit of the ITPR in multiple animal models of shock, the device has not been used in humans.The goals of this study were to evaluate both the safety and efficacy of the ITPR in humans. Twenty patients undergoing coronary artery bypass graft surgery were enrolled in this phase 1 study. Intraoperative use of both pulmonary artery pressure monitoring and transesophageal echocardiography (TEE) was required for study inclusion. Hemodynamic variables as well as TEE measurements of left ventricular performance were collected at baseline and after the ITPR device was activated, before surgical incision. Thermodilution cardiac output increased significantly with the application of the ITPR (4.9 vs. 5.5 L/min; P = 0.017). Similarly, cardiac output was measured by TEE (5.1 vs. 5.7 L/min; P = 0.001).There were significant increases in pulmonary artery systolic blood pressures (35 vs. 38 mmHg; P G 0.001) and mean pulmonary artery pressures (24 vs. 26 mmHg; P = 0.008). There were no significant differences in systemic blood pressures, left ventricular volumes, stroke volume, or ejection fraction as measured by TEE. Using two different measurement techniques, application of the ITPR increased cardiac output in normovolemic anesthetized patients who underwent coronary artery bypass graft before sternotomy. These data suggest that the ITPR has the potential to safely and effectively increase cardiac output in humans. PMID- 20926990 TI - Kounis syndrome. AB - The association between acute coronary events and acute allergic reactions has been recognized for several years. The first reported case occurred in 1950, during an allergic reaction to penicillin. In 1991, Kounis and Zavras described the syndrome of allergic angina and allergic myocardial infarction, currently known as Kounis syndrome. Two subtypes have been described: type I, which occurs in patients without predisposing factors for coronary artery disease and is caused by coronary artery spasm, and type II, which occurs in patients with angiographic evidence of coronary disease when the allergic events induce plaque erosion or rupture. This syndrome has been reported in association with a variety of medical conditions, environmental exposures, and medication exposures. Entities such as Takotsubo cardiomyopathy, drug-eluted stent thrombosis, and coronary allograft vasculopathy appear to be associated with this syndrome. In this review, we discuss the pathobiology, clinical features, associated entities, and management of Kounis syndrome. PMID- 20926989 TI - Liver X receptor alpha activation with the synthetic ligand T0901317 reduces lung injury and inflammation after hemorrhage and resuscitation via inhibition of the nuclear factor kappaB pathway. AB - Liver X receptor alpha (LXRalpha) is a nuclear transcription factor that regulates lipid metabolism. Recently, it has been shown that activation of LXRalpha with synthetic ligands has anti-inflammatory effects in atherosclerosis and chemical-induced dermatitis. We investigated the effect of the LXRalpha agonist, T0901317, on lung inflammation in a rodent model of hemorrhagic shock. Hemorrhagic shock was induced in male rats by withdrawing blood to a goal mean arterial blood pressure of 50 mmHg. Blood pressure was maintained at this level for 3 h, at which point rats were rapidly resuscitated with shed blood. Animals were then treated with T0901317 (50 mg . kg) or vehicle i.p. and sacrificed at 1, 2, and 3 h after resuscitation. Treatment with T0901317 significantly improved the cardiac and stroke volume indices as well as the heart rate of rats during the resuscitation period as compared with vehicle-treated rats. The T0901317 treated animals showed significant improvement in the plasma level of lactate, whereas base deficit and bicarbonate levels both trended toward improvement. The T0901317-treated animals also showed lower levels of plasma cytokines and chemokines monocyte chemoattractant protein 1, macrophage inflammatory protein 1alpha, TNF-alpha, KC, and IL-6. Lung injury and neutrophil infiltration were reduced by treatment with T0901317, as evaluated by histology and myeloperoxidase assay. At molecular analysis, treatment with T0901317 increased nuclear LXRalpha expression and DNA binding while also inhibiting activation of nuclear factor kappaB, a proinflammatory transcription factor, in the lung. Thus, our data suggest that LXRalpha is an important modulator of the inflammatory response and lung injury after severe hemorrhagic shock, likely through the inhibition of the nuclear factor kappaB pathway. PMID- 20926991 TI - Universal MRSA nasal surveillance: characterization of outcomes at a tertiary care center and implications for infection control. AB - BACKGROUND: Recognition of methicillin-resistant Staphylococcus aureus (MRSA) nasal carriage by active surveillance cultures has been widely debated. Our institution implemented universal nasal screening by polymerase chain reaction (PCR) for MRSA and isolation of screen positive patients in December 2007. Here we present data about the correlation between screen positivity and subsequent development of infection and the impact of isolation on surgical site infection rates. METHODS: This was a retrospective, observational study from January 1, 2008, through June 30, 2008, on all inpatient admissions with a nasal MRSA PCR screen. Genotype of 15 MRSA blood isolates was determined utilizing the Diversilab(r) (bioMerieux, Hazelwood, MO) system. A phenotypic rule was deduced and utilized for analyzing all MRSA clinical isolates. RESULTS: 5375 patients were screened at <=48 hours following admission. 581 MRSA positive nasal carriers (10.80%) were identified. 496 (85.3%) were asymptomatic MRSA nasal carriers. There were a total of 158 MRSA clinical infections. 85 (14.6%) MRSA nasal carriers had clinical infection. Of the 4794 (89.1%) non-nasally colonized patients, 73 (1.5%) had MRSA clinical infection. MRSA surgical site infection rate remained unchanged during the intervention period. Phenotypic predictive rule inferred 59.8% community-acquired MRSA (CA-MRSA) infections and 40% hospital acquired MRSA (HA-MRSA) infections. CONCLUSIONS: Our study showed a positive correlation between having a nasal screen positivity and subsequent development of infection. Isolation of MRSA screen positive patients alone as an intervention did not reduce the surgical site infection rates. Since most of our isolates are CA-MRSA, our institution is implementing several new interventions to further reduce the incidence of HA-MRSA conditions. PMID- 20926992 TI - Lemierre syndrome: a rare disease affecting previously healthy, young individuals. PMID- 20926993 TI - Exposure-related effects of atazanavir on the pharmacokinetics of raltegravir in HIV-1-infected patients. AB - Raltegravir (RAL) is primarily metabolized by uridine diphosphate-glucorunosyl transferase 1A1 (UGT1A1). Atazanavir (ATV), a strong inhibitor of UGT1A1, has been shown to increase plasma concentrations of RAL by approximately 50% in healthy volunteers. However, the extent of this interaction has not been studied in HIV-infected patients. A pharmacokinetic study was performed in 22 HIV infected adults treated with 400 mg RAL plus 300 mg ATV 300 twice a day. Both drugs showed high pharmacokinetic variability (RAL AUC 0-12 7649 +/- 4862 ng*h/mL; ATV AUC 0-12 = 19237 +/- 13136 ng*h/mL). Notably, RAL trough concentrations were significantly higher compared with those measured in HIV subjects (n = 24) on RAL plus nucleoside reverse transcriptase inhibitors (506 +/ 411 versus 177 +/- 262 ng/mL, P < 0.01). A significant correlation was found between RAL and ATV area under the curve (AUC) (r = 0.611, P = 0.005). Notably, patients with ATV AUC 0-12 above the mean or with concentrations exceeding the half maximal inhibitory concentration for UGT1A1 had twofold higher RAL AUCs compared with patients with lower ATV exposure. Coadministration of ATV significantly increased plasma concentrations of RAL, especially in HIV-1 infected patients exposed to high concentrations of the protease inhibitor. This pharmacokinetic drug interaction could be handled by routine measurements of ATV trough concentrations and by the assessment of plasma RAL concentrations 2 to 3 hours after the morning drug intake. PMID- 20926994 TI - Assessment of infant dose through milk in a lactating woman taking amisulpride and desvenlafaxine for treatment-resistant depression. AB - This study presents the case of a 35-year-old breastfeeding mother who delivered her fourth child 5 months previously and was prescribed 100 mg amisulpride twice daily and 250 mg desvenlafaxine in the morning for treatment-resistant depression. Arriving at this regimen took approximately 2 months postbirth. Because she was keen to continue breastfeeding her infant, and published data on the use of amisulpride and desvenlafaxine were very limited, the clinical team sought assistance from the therapeutic drug monitoring laboratory to quantify infant dose-exposure to guide consideration of continuing breastfeeding. A sampling schedule for milk and plasma from mother and plasma from her infant was agreed and drug concentrations were measured by high-performance liquid chromatography. Absolute (theoretic) infant dose (MUg/kg/d) was calculated as the product of the average concentration in milk and an assumed milk intake of 0.15 L/kg/day (294 mg/kg/day for desvenlafaxine and 183 mg/kg/day for amisulpride), and relative infant dose was estimated as absolute infant dose expressed as a percentage of the maternal dose in MUg/kg/day (7.8% for desvenlafaxine and 6.1% for amisulpride). Consistent with the infant being partially breastfed, the ratio of drug in the infant's plasma to that in mother's plasma was lower at 1.7% for desvenlafaxine and 3.9% for amisulpride. A pediatric assessment of the infant found achievement of expected developmental progress for age and no detectable drug-related adverse effects. Assessing the safety of breastfeeding was difficult because it involved simultaneous use of two drugs for which there was limited previous experience. However, after discussion of the infant dose-exposure data and lack of adverse effects, the mother elected to continue partial breastfeeding for the next few months. The clinical team plans a reassessment of the infant's progress in 3 months. PMID- 20926995 TI - A simple and sensitive high-performance liquid chromatographic method for the determination of vinflunine and 4-O-deacetylvinflunine from human blood. AB - Vinflunine (VFL) is the first bifluorinated tubulin-targeted agent obtained through a semi synthetic process using superacidic chemistry. Pharmacologic models evidenced a high degree of activity from several cancer lines. The intravenous formulation of VFL (Javlor, Pierre Fabre Medicament, Boulogne, France) is registered for bladder cancer and is undergoing Phase III trials for nonsmall cell lung and breast cancer. To support most of the pharmacokinetic studies in humans, a sensitive high-performance liquid chromatography bioanalytical method coupled with ultraviolet detection was developed and validated for the simultaneous quantification of VFL and its active metabolite 4 O-deacetylvinflunine. The two compounds, together with 17-bromovinorelbine, used as an internal standard, were extracted from blood (1 mL) by a liquid-liquid process under basic conditions using diethyl ether. The organic phase was then back-extracted with HCl 0.1 mol/L. Analysis was performed through a cyano column and detection was set at 268 nm. Total analysis run time was less than 15 minutes. The assay was sensitive for the two compounds to at least 2 ng/mL and calibration curves were linear up to 200 ng/mL. The between-run imprecision and the mean inaccuracy were lower than 7% and 8.3%, respectively. Blood samples were stable when stored at -70 degrees C over 24 months. The long-term reproducibility and the suitability of this analytical method were demonstrated through the analysis of about 6000 biologic samples during the clinical development of intravenous VFL. This method is adequately sensitive to monitor the blood concentrations observed at the recommended dose defined in a clinical setting. PMID- 20926996 TI - Population pharmacokinetic analysis of mycophenolic acid coadministered with either tasocitinib (CP-690,550) or tacrolimus in adult renal allograft recipients. AB - Tasocitinib (CP-690,550) is an orally active Janus kinase inhibitor that is in development for prophylaxis of acute rejection after kidney transplantation and for the treatment of select autoimmune diseases. The current study was conducted to evaluate the systemic exposure of mycophenolic acid (MPA) in de novo kidney transplant patients when coadministered with tasocitinib compared with exposure in patients receiving tacrolimus, which has no effect on MPA pharmacokinetics. Plasma MPA concentrations were obtained from 17 adult patients who received either 15 mg or 30 mg tasocitinib twice daily (eight patients) or tacrolimus (nine patients) after kidney transplantation. All patients also received concomitant mycophenolate mofetil, prednisone, and basiliximab induction. The median mycophenolate mofetil dose was 1000 mg twice daily. A two-compartment population pharmacokinetic model estimating oral clearance, between-patient variability in oral clearance, central volume of distribution, and residual variability in combination with historical estimates of first-order absorption rate constant, intercompartmental clearance, and peripheral volume of distribution adequately described the sparse MPA data. Based on individual estimates oral clearance from the population pharmacokinetic model, mean steady state area under the concentration-time curve values for a mycophenolate mofetil dose of 1000 mg twice daily were 63 mg.hr/L (22%) and 59 mg.hr/L (36%) for the tasocitinib and tacrolimus groups, respectively. These results indicate that tasocitinib does not influence systemic MPA exposure. PMID- 20926997 TI - Are intra-articular corticosteroid injections better than conventional TENS in treatment of rotator cuff tendinitis in the short run? A randomized study. AB - AIM: Rotator cuff problems are common causes of pain and restriction of movement in shoulder. The aim of this study to compare the effect of intra-articular injection of corticosteroid and conventional transcutaneous electrical nerve stimulator (TENS) treatment in treatment of rotator cuff tendinitis. METHODS: Subjects were randomly allocated into Group 1 (intra-articular injection of corticosteroid) and Group 2 (conventional transcutaneous electrical nerve stimulation-TENS). Outcome measurements were performed using the Visual Analogue Scale (VAS) for pain, range of motion (ROM), the Shoulder Disability Questionnaire (SDQ), the Short Form-36 (SF-36), and Beck Depression Scale (BDS) questionnaires and paracetamol consumption. RESULTS: In both groups, significant improvement was observed in all weeks in VAS, ROM and SDQ scores (P<0.05). Improvement was detected in most of the SF36 scores at the end of the treatment in both groups (P<0.05), while no significant change was observed in BDI score (P>0.05). In both treatment groups, paracetamol consumption decreased in time (P<0.05). When the groups were compared, a significant difference was found between the groups in favor of Group 1 in terms of VAS-at night and VAS-at rest in weeks 1, 4 and 12, and VAS-during movement in week 1 and 12 (P<0.05). The comparison of two groups revealed a significant difference in favor of Group 1 in weeks 1 in the passive abduction and the active and passive IR ROM measurements (P<0.05). There was also a significant difference in favor of Group 1 observed in weeks 1 in SDQ scores (P<0.05). CONCLUSION: Intra-articular injection of corticosteroid and conventional TENS are efficient in the treatment of rotator cuff tendinitis. When two treatments are compared, it may be concluded that intra articular steroid injection was more effective especially in the first weeks regarding pain, ROM and disability. Otherwise, use of TENS allow to patients to increase activity level, improve function and quality of life like that in our study. TENS, as it is cheaper, non-invasive, more easily performed and efficient, may be preferable for the treatment of shoulder pain. Further studies are needed to include these results in the prospective treatment guidelines. PMID- 20926998 TI - Does short-wave diathermy increase the effectiveness of isokinetic exercise on pain, function, knee muscle strength, quality of life, and depression in the patients with knee osteoarthritis? A randomized controlled clinical study. AB - BACKGROUND: Knee osteoarthritis (OA) is a painful condition causing disability and muscle weakness. Shortwave diathermy (SWD) is one of several physical therapy modalities and used predominantly as a pain reduction modality in the clinical practice. However, the efficacy of SWD in knee OA is still inconclusive. AIM: The aim of this study was to determine if SWD increase the effectiveness of isokinetic exercise on pain, function, muscle strength, quality of life and depression in patients with OA. DESIGN: This was a randomised, controlled clinical trial. SETTING: Inpatient Physiotherapy Department. POPULATION: Forty women aged between 42 and 74 years, with a diagnosis of bilateral primary knee OA. METHODS: Patients were sequentially randomized into two groups. Group 1 (N.=20) received SWD and isokinetic muscular strengthening exercises. Group 2 (N.=20) served as control group and they received isokinetic exercises only. Both of the programs were performed three days a week, for a duration of four weeks, and a total of 12 sessions. Patients were assessed before treatment (BT), after treatment (AT), and at a three-month follow-up (F). Outcome measures included visual analogue scale, Western Ontario and McMaster University Osteoarthritis Index, six minute walking distance, isokinetic muscle testing, Short Form 36 and Beck depression index. RESULTS: The patients with OA in each group had significant improvements in pain, disability, depression, walking distance, muscle strength, and quality of life AT and F when compared with their initial status (P<0.05). There was no statistically significant difference between the groups according to all the parameters regarding the change scores between AT-BT test and F-BT test (P>0.05) except some isokinetic peak torque measurements (F-BT scores of extension right 60 degrees , 120 degrees and flexion right 60 degrees ). CONCLUSION: Use of SWD in addition to isokinetic exercise program seems to have no further significant effect in terms of pain, disability, walking distance, muscle strength, quality of life and depression in patients with knee OA. CLINICAL REHABILITATION IMPACT: Considering the time and cost of combination therapy is now, the isokinetic exercise program, as it is efficient, may be preferable for the treatment of knee OA, alone. PMID- 20926999 TI - Quality indicators indicate good adherence to the clinical practice guideline on "Osteoarthritis of the hip and knee" and few prognostic factors influence outcome indicators: a prospective cohort study. AB - BACKGROUND: Evaluation with quality indicators of adherence to the clinical practice guideline on "Osteoarthritis of the hip and knee" and of treatment outcomes. AIM: Furthermore to determine prognostic factors for outcome indicators. DESIGN: Prospective cohort study. POPULATION: Twenty-seven well informed physical therapists recorded patient and treatment characteristics of 103 community-dwelling patients referred by a general practitioner diagnosed with osteoarthritis of hip or knee. METHODS: With selected process and outcome indicators adherences to the guideline and treatment outcomes were assessed. Prognostic factors were calculated for Algofunctional Index (AI) and Visual Analogue Scale (VAS) for pain (decreases of <=25% indicating "poor outcome"), number of sessions (>12) and duration of treatment (>6 weeks), using multivariate logistic regression models. RESULTS: Process indicators showed that information & advice was given to 95% of the patients and functions and activities were exercised in 97% respectively 87%. Aftercare was arranged for 46% of the patients, that was clearly lower than the benchmark of 90%. Outcome indicators VAS-pain and AI decreased by 45% and 36%, respectively. The combination ">12 months" duration of complaints and age >=65" was associated with a "poor outcome" on AI (OR 2.53; 95% CI 1.01-6.38). Co-morbidity (OR 2.8; 95% CI 1.17-6.88), and "VAS-pain at baseline >=51 mm" (OR 3.1; 95% CI 1.34-7.23) were associated with a higher number of treatment sessions. CONCLUSION AND CLINICAL REHABILITATION IMPACT: and Quality indicators showed that a group of well-informed physical therapists could to a large extent adhere to key recommendations of the guideline and that clinically relevant improvements were obtained in terms of pain and physical functioning. Prognostic factors for poorer outcome on outcome indicators were comorbidity, a higher pain score at baseline and the combination ">12 months' duration of complaints and age >=65". PMID- 20927000 TI - Does hippotherapy improve balance in persons with multiple sclerosis: a systematic review. AB - AIM: Multiple sclerosis (MS) leads to changes in balance due to the breakdown of a number of neurological processes. Hippotherapy utilizes the movement of the horse to provide sensory feedback and has been used as a therapeutic intervention for different neurological conditions. Little is known about the effects of hippotherapy in MS. The purpose of this study is to systematically review and examine the evidence for hippotherapy as an intervention to improve balance in persons with MS. METHODS: Major electronic databases were searched for articles relating to hippotherapy, MS and balance. Only full length articles published in peer reviewed journals that were written in English or translated into English were included. Articles were assessed using a modified quality index that was used for descriptive purposes only and did not exclude any study from the review. RESULTS: All studies examined in this review were either case-control or case series. Collectively all three studies reported improvements in balance. Pre-test and post-test Berg Balance Scale scores in two studies revealed that primary progressive MS demonstrated the greatest amount of change after hippotherapy compared to other subtypes of MS. CONCLUSION: Hippotherapy has a positive effect on balance in persons with MS and has an added benefit of enhancing quality of life. The data is limited and further research will lead to a greater knowledge base and has the potential to increase accessibility for hippotherapy to be used as a rehabilitation modality. PMID- 20927001 TI - Gait analysis in a patient with severe Charcot-Marie-Tooth disease: a case study with a new orthotic device for footdrop. AB - Management of footdrop in severe Charcot-Marie-Tooth (CMT) patients is a challenge owing to the combination of quadriceps muscle weakness, distal muscular atrophy, sensory impairment and poor soft tissue resistance to the placement of an orthotic device. We present a case study of a patient who gradually became unable to use his ankle-foot orthoses because they hampered the compensative movements required to stabilize his knees passively and caused pain. The aim of this report is to describe orthotic management in such a severe CMT case and to present a new orthotic device that we devised for the footdrop in this patient. We provided him with 3 different footdrop devices, each of which was highly elastic to allow knee hyperextension, and left him free to decide which one to use: 1) the silicone-ankle-foot orthoses were rapidly discarded because of pain; 2) the Codivilla support was not used because of discomfort and poor aesthetic appearance; 3) a new device, called the "Soft Footdrop Insert" (SFI), consisting of a sheet of Veolform, a reticulated polyolephinic foam, stuck to the counter of midcalf boots, was found to be effective, comfortable, pain-free and aesthetically acceptable, and was consequently used the vast majority of the time. At a 3-year follow-up, an instrumental gait analysis, in which ordinary shoes were compared with the Codivilla support and the SFI, revealed that both the Codivilla support and the SFI controlled footdrop more effectively than ordinary shoes and increased swing and mean velocity; in addition, the SFI yielded the best gait performances. We think that a soft, invisible device, such as the SFI, may satisfy the needs of CMT patients and improve compliance with orthoses-wearing for footdrop. PMID- 20927002 TI - The ankle-foot orthosis improves balance and reduces fall risk of chronic spastic hemiparetic patients. AB - BACKGROUND: Ankle foot orthoses (AFO) are commonly used orthotic device in order to restore the ankle foot function and to improve the balance and gait in post stroke hemiparetic patients. However, there remain some discussions about their effectiveness on long term hemiparetic patients who had mild to moderate spasticity. AIM: To investigate the relative effect of prefabricated thermoplastic posterior leaf spring AFO (PLS-AFO) on balance and fall risk. DESIGN: A cross-over interventional study SETTING: The Department of PMR of a tertiary hospital. POPULATION: Twenty-five chronic post-stroke long duration hemiparetic patients who had Ashworth grade 1-2 spasticity at affected calf muscles and lower limb Brunnstrom stage 2-3 and also able to walk independently without an assistive device. METHODS: Berg Balance Scale (BERG), and the postural stability test (PST) and the fall risk test (FRT) of Biodex balance systems were used for the assessments. All of the patients were assessed with AFO and without AFO. All assessments were made with footwear. RESULTS: The mean post-stroke duration was 20,32+/-7,46 months. The BERG scores were 42,12+/-9,05 without AFO and 47,52+/-7,77 with AFO; the overall stability scores of FRT were 3,35+/-1,97 without AFO and 2,69+/-1,65 with AFO (P<0,001). CONCLUSION: It was found that the prefabricated thermoplastic PLS-AFO improve balance and provide fall risk reduction in chronic post-stroke ambulatory hemiparetic patients who had mild to moderate spasticity on their affected lower limb. CLINICAL REHABILITATION IMPACT: These results encourage the usage of AFO on long duration hemiparetic patients in order to provide better balance and lesser fall risk. PMID- 20927004 TI - The ICF Core Set for stroke from the perspective of physicians: a worldwide validation study using the Delphi technique. AB - BACKGROUND: The ICF Core Set for stroke is an application of the International Classification of Functioning, Disability and Health (ICF) and represents the typical spectrum of problems in functioning of patients with stroke. AIM: The aim of this study was to validate the ICF Core Set for stroke from the perspective of physicians. DESIGN: Observational. SETTING: Other. POPULATION: Physicians experienced in stroke treatment. METHODS: Physicians experienced in stroke treatment were asked about the patients' problems, patients' resources and aspects of environment that physicians take care of in a three-round electronic mail survey using the Delphi technique. The responses were linked to the ICF by two persons. The degree of agreement was calculated using Kappa statistic. RESULTS: Eighty-eight physicians in 30 countries named 2142 patients' problems that covered all ICF components. Two hundred seventy-seven ICF categories were linked to these. Kappa statistic for agreement reached 0.68 with a 95% confidence interval of 0.66-0.69. Although 28 ICF categories were not represented in the ICF Core Set for stroke, only four of them were considered as important by at least 75% of the participants. Those categories addressed sensations associated with cardiovascular and respiratory functions, urinary excretory functions, involuntary movement functions and sensations related to muscle and movement functions. CONCLUSION: The validity of the ICF components Body structures, Activities and Participation, and Environ-mental Factors was fully supported. Only some body functions were identified that were not covered and need to be investigated further. PMID- 20927003 TI - The perception of involved professionals towards research feasibility and usefulness: lessons from the Multi-Site Trial on Efficacy of Constraint Induced Movement Therapy in Children with Hemiplegia. AB - BACKGROUND: In the last decades, the world of rehabilitation has been more and more calling for clear evidence to support intervention and numerous research programs have been developed. At stake, relatively little research on opinions and attitude of rehabilitation personnel involved in research conducted in real clinical settings has been carried out. AIM: To explore the opinion of professionals involved in a national clinical trial on research. DESIGN: Multicentre cross-sectional study. SETTING: 19 rehabilitation centres/services (4 research institutes, 15 local rehabilitation services). POPULATION: All professional participating to a multi-centre clinical trial on the effects of Constraint Induced Movement Therapy on children with hemiplegic cerebral palsy. METHODS: A 15-questions questionnaire inquiring feasibility, usefulness, products, costs, judgement and perceptions about clinical research in rehabilitation was administered. RESULTS: Among those working in one of the 19 rehabilitation centres part of the multicentric study, 76 professionals were asked to fill in the questionnaire. 68 professionals answered (89.4% of response rate). More than 75% of the sample thinks that its rehabilitation centre is suited to develop clinical research. Research results useful for the development of their daily activities (new tools for the assessment of children, to demonstrate the efficacy of a new treatment option and to learn a new way of working, and to strengthen the ties within the working team). Research is costly in terms of personal time and effort, but it can modify the rehabilitation praxis (assessment tools, the relationship with colleagues/patients). 98% of the interviewees declared the willingness to participate to other research projects. CONCLUSION AND CLINICAL REHABILITATION IMPACT: This survey highlights the importance of conducting research in local rehabilitation services, not only in terms of generation of new evidences, but also in terms of building networks, sharing experiences and knowledge, connecting with centers of excellence and providing a specific training for research conduction. PMID- 20927006 TI - Managing spasticity with drugs. AB - Spasticity is a common symptom observed after pyramidal system lesion. The treatment of spasticity has considerably changed during last years, notably with the generalization of Botulinum toxin use. However, the treatment of spasticity should consider all therapeutic possibility in accordance with patient status and objective. Drugs are only a part of the treatment and physical therapy must always be used. Others treatments such as surgery, orthosis, occupational therapy must also be discussed individually. Several guidelines are now available for Botulinum toxin treatment but only the French guidelines consider all drug therapies. This review addresses the different drugs commonly used on the basis of an extensive review of literature. Some facts are clearly established by randomized controlled trials but a certain number of questions remains unclear and only clinical experience and consensus can guide injectors. PMID- 20927005 TI - Is health-related-quality of life of stroke patients influenced by neurological impairments at one year after stroke? AB - AIM: The aim of this study was to evaluate which neurological impairments on discharge from rehabilitation services are associated with a worse outcome in terms of health related-quality of life (HRQoL) one year after stroke. METHODS: We enrolled 528 first-time stroke patients in a multicenter observational study involving 18 Italian inpatients rehabilitation centers. Neurological impairment related factors, socio-demographic and general clinical variables and process indicators were considered independent variables at discharge. Outcome was represented by the following dependent variables of HRQoL: EuroQoL-5D questionnaire (5D-EQoL) and its derived index (Eq-Index) and a Visual Analogue Score (QoL-VAS). RESULTS: The strongest predictors of lower HRQoL were an incomplete limbs motor recovery. An incomplete lower limb motor recovery was associated with a lower HRQoL only in the "mobility" domains, whereas a incomplete upper limb motor recovery could predict a lower HRQoL in all domains except "mobility". Regarding cognitive impairments, the presence of neglect at discharge was associated with a lower HRQoL in "self-care", "pain-discomfort" and "anxiety-depression". Female gender, presence of urinary catheter seemed to exert a much lesser role in predicting HRQoL. CONCLUSION: The results of this study suggest that upper limb motor impairments may have a detrimental impact on the patient's perceived HRQoL one year after stroke. PMID- 20927007 TI - Five-step clinical assessment in spastic paresis. AB - Among the three main factors of motor impairment that emerge in chronological order following a lesion to central motor pathways, the last two antagonize movement: 1) stretch-sensitive paresis, a reduction of agonist motor unit recruitment upon voluntary command, worsened by antagonist stretch; 2) soft tissue contracture, and 3) muscle overactivity. Types of muscle overactivity include 1) spasticity, an increase in the velocity-dependent response to muscle stretch, measured at rest; 2) spastic dystonia, i.e., chronic tonic muscle activity at rest, sensitive to stretch of the dystonic muscle and 3) spastic co contraction, an inappropriate degree of antagonistic contraction during voluntary agonist command, sensitive to stretch of the co-contracting muscle. A five-step clinical assessment may closely parallel this phenomenology, in which the first four steps aim at quantifying the antagonistic potential of each muscle group. Step-1 measures passive range of motion, i.e., the angle of arrest upon slow stretch of the muscle group assessed (minimizing spastic dystonia), which provides insight on soft tissue length and extensibility. Step-2 measures the angle of catch or clonus upon fast passive stretch of the muscle group assessed, which provides insight on stretch reflex excitability. Step-3 measures the range of active motion against the muscle group assessed, a net result of agonist recruitment minus the combined resistance from passive soft tissue stiffness and spastic co-contraction in the muscle group assessed. Step-4 measures the maximal frequency of rapid alternating movements along the maximal active range of motion, evaluating Step-3 performance repeatability. Step-5 evaluates active function, using for example a walking test (10 m or 2 min) for lower limb and the Modified Frenchay Scale for upper limb assessment, and perceived function through patient global subjective assessment. PMID- 20927008 TI - Rehabilitation procedures in the management of spasticity. AB - Spasticity is a major disabling symptom in many patients with spinal and/or cerebral lesions. During functional movements, spasticity manifests itself within the complex condition of the "spastic movement disorder". The pathophysiology of the spastic movement disorder relies on multiple factors including abnormal supraspinal drive, abnormal control of reflex activities, and changes in muscle mechanical properties. The most widely used procedures for management of spasticity are represented by pharmacological treatment aimed at inhibiting reflex hyperexcitability. In the last decades, several non pharmacological procedures for treating spasticity have been put forward, including muscle stretching, muscle reinforcement, physical agents and pain management. These procedures may have both neurophysiological and biomechanical effects on the spastic movement disorder. In the present paper, the literature concerning non pharmacological procedures in the treatment of spasticity was reviewed and discussed, taking into account the multifaceted pathophysiology of the spastic movement disorder. Although further research in this field is recommended, existing evidence supports the potential role of rehabilitation interventions as a therapeutic tool, which could be integrated with traditional pharmacological procedures in the management of the spastic movement disorder. PMID- 20927009 TI - EJPRM systematic continuous update on Cochrane reviews in rehabilitation: news from the 3rd 4th and 5th Issues of 2010. AB - AIM: Since 2007 we focused our attention as EJPRM to the best available clinical evidence as offered by the Cochrane Collaboration. Due to the absence of a specific Rehabilitation Group (only a Field exists), reviews of PRM interest are in different groups and not easy to find. Consequently, the EJPRM offer the service of listing and presenting all these reviews systematically. The aim of the present paper was to systematically review all the new rehabilitation papers published in the 3rd 4th and 5th Issues of 2010 from the Cochrane Library in order to provide to physicians involved in the field a summary of the best evidence nowadays available. METHODS: The author systematically searched all the new papers of rehabilitative interest in the 3rd 4th and 5th Issues of 2010 of the Cochrane Library. The retrieved papers have been then divided in subgroups on the base of the topic and the Cochrane Groups. RESULTS: The number of included papers was 8, 7 of these were new reviews. Four new reviews deal with neurological rehabilitation, being performed by the Stroke group, 2 with musculoskeletal disorders, 1 with cardiac rehabilitation. Moreover, 1 review from the Back Group the has been updated. CONCLUSION: The Cochrane Collaboration and his product, the Cochrane Library, are really relevant instruments to improve EBM in medical practice and thus also in the Rehabilitation Field. The present paper can help Rehabilitation Specialists to easily retrieve the conclusions of the most relevant and updated reviews in order to change their clinical practice in a more rapid and effective way. PMID- 20927010 TI - Disability seen from within. AB - An old physician describes with a ad auto-hironic humor the changes by ageing, with all the insight that the medical profession can give on the process of progressive disability. PMID- 20927012 TI - Open access to scientific research: where are we and where are we going? Facts and figures on the occasion of the 2010 Open Access Week (October 18-24). AB - This contribution is aimed at presenting a sort of "state of the art" of Open Access on the occasion of the 2010 international Open Access Week, to be held from October 18 to October 24. We shall see facts and figures about open archives and the mandates to deposit; about Open Access journals; about impact and citation advantages for the researchers, and about economic sustainability. PMID- 20927013 TI - Special issue on PET/CT and radiotherapy. Foreword. PMID- 20927014 TI - PET/CT for radiotherapy: image acquisition and data processing. AB - This paper focuses on acquisition and processing methods in positron emission tomography/computed tomography (PET/CT) for radiotherapy (RT) applications. The recent technological evolutions of PET/CT systems are described. Particular emphasis is dedicated to the tools needed for the patient positioning and immobilization, to be used in PET/CT studies as well as during RT treatment sessions. The effect of organ and lesion motion due to patient's respiration on PET/CT imaging is discussed. Breathing protocols proposed to minimize PET/CT spatial mismatches in relation to respiratory movements are illustrated. The respiratory gated (RG) 4D-PET/CT techniques, developed to measure and compensate for organ and lesion motion, are then introduced. Finally a description is provided of different acquisition and data processing techniques, implemented with the aim at improving: i) image quality and quantitative accuracy of PET images, and ii) target volume definition and treatment planning in RT, by using specific and personalised motion information. PMID- 20927015 TI - PET/CT and radiotherapy : data transfer, radiotherapy workflow and quality assurance. AB - The development of new technologies in radiation therapy has made it possible to introduce more sophisticated techniques that can deliver the prescribed dose with more conformation and accuracy and to apply dose escalation protocols without increasing the risk of healthy tissue damage. This has consented the simultaneous delivery of different dose levels to different parts of the target, making it possible to boost those tumour sub-volumes that are considered more radio resistant. The use of PET for radiotherapy planning purposes has become increasingly important in the last few years, because of its ability to provide valuable biologic and functional data. PET imaging can affect the treatment strategy definition and improve the target delineation and the assessment of therapy response. The most attractive aspect is the perspective to deliver differential doses inside target volumes for areas of different biologic behaviour based on functional imaging, moving closer to the goals of biologically conformal radiation therapy. Each single step of PET/CT-guided radiotherapy workflow, needs to be performed following high standard procedures, within a rigorous and appropriate quality assurance protocol to minimize the sources of errors and to maximize the efficacy of PET imaging in radiation therapy, ensuring safe and effective use of the technology. The present paper focuses on aspects concerning the use of PET/CT in radiation treatment process, with the aim to delineate different possible approaches to its clinical application and to highlight the critical aspects of the various subprocesses. PMID- 20927016 TI - Functional target volume delineation for radiation therapy on the basis of positron emission tomography and the correlation with histopathology. AB - Accurate target volume delineation becomes more and more important for modern high-precision radiotherapy. During the last years, molecular imaging using positron emission tomography (PET) has been shown to be of high clinical impact on diagnosis, staging and/or restaging of many malignancies. Therefore, the integration of PET-data into the radiotherapy planning process is of high interest in radio-oncology. During the last years a number of automatic and semi automatic PET-based volume delineation methods have been developed which will be presented in this review. We will not only describe those algorithms currently used in clinical settings, but also present some of the latest developments in this highly dynamic field of research. Furthermore, validation of different segmentation approaches against histopathology is discussed. PMID- 20927017 TI - Hypoxia PET/CT imaging: implications for radiation oncology. AB - Hypoxia, a condition of reduced partial pressure of oxygen in tissue, is an important determinant of poor tumor response to radiation treatment. Many invasive and non-invasive methods and approaches have been investigated to detect tumor hypoxia for response prediction and to facilitate modulation of radiation treatment. In this review we discuss the biological consequences of tumor hypoxia, methods of measuring regional tumor hypoxia with positron emission tomography (PET) tracers and applications for radiation oncology. PMID- 20927018 TI - Use of PET/CT for staging and radiation therapy planning in patients with non small cell lung cancer. AB - Positron emission tomography (PET) and more recently PET/computed tomography (CT) scanning represent major advances in the imaging of lung cancer and have an especially high impact on the management of patients who are candidates for potentially curative or "radical" radiotherapy (RT). This article reviews the current status of PET and PET/CT for staging patients before RT and considers the use of PET and PET/CT images for target volume definition. The relevant literature on the use of PET for staging lung cancer is reviewed and placed in the context of patients who are candidates for RT. Research that specifically considers the use of PET for RT planning is considered critically and some promising areas for future research are discussed. The available literature is almost exclusively devoted to non small cell lung cancer (NSCLC) with few relevant studies of small cell lung cancer (SCLC). The primary PET radiopharmaceutical shown to have value for staging and RT planning is 18F fluorodeoxyglucose (FDG). In prospective studies where PET imaging was used to stage radical RT candidates, 25-30% of patients were excluded from radical therapy because of PET detected advanced disease. In all studies where "PET assisted" and conventional target or treatment volumes were compared, there were major differences between PET and conventional volumes. Because PET-assisted staging is proven to be significantly more accurate than conventional staging and because all studies show major differences between PET-assisted and conventional treatment volumes in NSCLC, routine use of PET/CT for RT planning is recommended. PMID- 20927019 TI - Impact of PET/CT on planning of radiotherapy in head and neck cancer. AB - Radiation therapy (RT) has a prominent role in the treatment of locally advanced head and neck cancer. Image and biologically guided intensity modulated RT are becoming strongholds of state-of-the-art management with positron emission tomography (PET)/computed tomography (CT) as the preferred diagnostic tool in treatment planning. The procedures required in the workflow from diagnosis to treatment plan are complex and consensus on optimal image acquisition, reconstruction parameters and contouring methods remains to be established. In spite of this the potential of PET/CT-based treatment planning has been widely recognized and many large referral centres have adopted the technique in either a routine or an experimental setting. PET/CT with 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) assists in selection of correct treatment goal and dose optimisation and increases the confidence of contouring process modifying treatment plan in most patients. For dose escalation and adaptive RT strategies PET may provide regional distribution of desired tumour characteristics such as hypoxic, metabolically active or rapidly proliferating sub-volumes. It is expected that within a few years PET/CT will be recommended for all patients presenting with stage III-IV disease considering the obvious benefits associated with more accurate volumetric presentation of primary and locoregional disease and the improved opportunities to conform and escalate RT dose in an attempt to improve therapeutic gain. PMID- 20927020 TI - PET/CT and radiotherapy in gynecological cancer. AB - Molecular imaging, in particular, positron emission tomography (PET), has brought an additional dimension to management of patients with cancer and to radiation therapy planning. The combination of PET and computed tomography (CT) in a single system (PET/CT) to form an inherently fused anatomical and functional dataset has provided an imaging modality which could be used as the prime tool in the delineation of tumour volumes and the preparation of patient treatment plans, especially when integrated with virtual simulation. PET imaging (typically using 18F-FDG) can provide data on metabolically active tumour volumes. These functional data have the potential to modify treatment volumes and to guide treatment delivery to cells with particular metabolic characteristics. Depending on its sensitivity and specificity, 18F-FDG PET has been shown to influence the selection of target volumes also in gynecological cancer. The potential of such data from PET was recognized at an early stage and was integrated into the radiotherapy treatment for some gynecological malignancies. In particular 18F-FDG PET has been demonstrated to be useful in patients with cervical cancer candidate to radiotherapy; preliminary data suggest a potential use also in patients with endometrial cancer, uterine sarcoma and ovarian cancer. This paper reviews the state of the art of the integration of PET and PET/CT applications in radiotherapy, and the use of 18F-FDG PET in disease staging, patient selection, treatment planning and treatment evaluation in gynaecological malignancies, in particular in patients with cervical cancer, endometrial cancer, uterine sarcoma and ovarian cancer. PMID- 20927021 TI - PET/CT and radiotherapy in prostate cancer. AB - Radiotherapy is one of the corner stone treatments for patients with prostate cancer. Especially for locally advanced tumors radiotherapy +/- adjuvant androgen deprivation treatment is standard of care. This brings up the need for accurate assessment of extra prostatic tumor growth and/or the presence of nodal metastases for selection of the optimal radiation dose and treatment volume. Morphological imaging like transrectal ultra sound, computed tomography (CT) and magnetic resonance imaging (MRI) are routinely used but are limited in their accuracy in detecting extra prostatic extension and nodal metastases. In this article we present a structured review of the literature on positron emission tomography (PET)/CT and radiotherapy in prostate cancer patients with emphasis on: 1) the pretreatment assessment of extra prostatic tumor extension, nodal and distant metastases; 2) the intraprostatic tumor characterization and radiotherapy treatment planning; and 3) treatment evaluation and the use of PET/CT in guidance of salvage treatment. PET/CT is not an appropriate imaging technique for accurate T-staging of prostate cancer prior to radiotherapy. Although macroscopic disease beyond the prostatic capsule and into the periprostatic fat or in seminal vesicle is often accurately detected, the microscopic extension of prostate cancer remains undetected. Choline PET/CT holds a great potential as a single step diagnostic procedure of lymph nodes and skeleton, which could facilitate radiotherapy treatment planning. At present the use of PET/CT for treatment planning in radiotherapy is still experimental. Choline PET based tumor delineation is not yet standardized and different segmentation-algorithms are under study. However, dose escalation using dose-painting is feasible with only limited increases of the doses to the bladder and rectum wall. PET/CT using either acetate or choline is able to detect recurrent prostate cancer after radiotherapy but stratification of patients for any local salvage treatment has not been addressed in the current literature. PMID- 20927022 TI - Testing of microbial contamination during the preparation of the radiocompound [90Y]DOTATOC for clinical trials: a process validation study by Media Fill approach. AB - AIM: Radioisotopes used in nuclear radiopharmacy possess short half-lives, not allowing enough time to wait for completion of sterility tests. Moreover, carrying out sterility tests on highly radioactive solutions inside the hospital microbiology laboratory arises concerns about radioprotection. Therefore, the release of radiopharmaceuticals for injection is allowed in microbial analysis. For this reason, the effectiveness of the aseptic procedures has to be continuously assessed in order to guarantee the safety of the drug. The aim of this study was to validate the sterile preparation of [90Y]DOTATOC by means of media fill test. METHODS: In order to validate the process, a simulation test was used: the media fill test. To apply this method, operators simulated each step of the process using culture medium (Triptic Soy Broth, TSB) instead of actual radiopharmaceutical product. Media fill test procedure has been subdivided into 5 phases, from the simulation of reagent preparation through the dispensing operations up to ward delivery. After every step, the processed medium was incubated at 35 degrees C for 14 days. If the compounding procedures are adequately performed, no growth of microorganisms will be detected. RESULTS: Microbiological analyses, carried out on all vials obtained at the end of each step, showed no microbial growth. For this reason, sterility tests were considered satisfactory. CONCLUSION: Application of media-fill test allowed both to validate operative modality used for [90Y]-DOTATOC handling and to attest the ability of operators who worked on it. Additionally, a correct quality control of the radiopharmaceutical i.v. preparations allows clinic infections control and prevention. PMID- 20927023 TI - Comparison of efficacy of 2220 MBq versus 3700 MBq I-131 for ablation of thyroid remnant in patients with differentiated thyroid cancer. AB - AIM: We evaluated the efficacy of two doses of I-131 (2220 MBq versus 3700 MBq) after thyroid hormone withdrawal for thyroid remnant ablation postoperatively in patients with differentiated thyroid cancer (DTC). METHODS: A total of 133 patients with DTC were studied retrospectively. Group 1 (N.=48) included patients with a primary tumor less than 4 cm in mean diameter and confined to the thyroid gland that received an average ablation dose of 2220 MBq. Group 2 (N.=81) included patients with a primary tumor equal to or greater than 4 cm in mean diameter and/or with vascular invasion and/or intrathyroidal lymphovascular invasion and/or microscopic extrathyroidal extension that received an average ablation dose of 3700 MBq. There was no significant difference between the two groups in terms of demographic characteristics or the radioiodine uptake in the neck (2.86+2.31% versus 2.84+1.21%, P=0.97). The success of the remnant ablation was judged by the standard institutional protocol: I-123 whole body scan (WBS) and serum Thyroglobulin (Tg) level after thyroid hormone withdrawal or preparation with recombinant human TSH (rhTSH) 6-12 months after ablation. RESULTS: Overall, remnant ablation was successful in 121/133 (91%) patients. There was no statistically significant difference in the success of ablation between Group 1 and Group 2 (87.5% versus 93%, P=0.273). CONCLUSION: Therefore, for thyroid remnant ablation after thyroid hormone withdrawal, an administered I 131 dose of 2220 MBq is just as effective as 3700 MBq and has the potential for fewer longterm side effects. PMID- 20927024 TI - Exploring dopaminergic activity in ring chromosome 20 syndrome: a SPECT study. AB - AIM: Several lines of evidence indicate that the dopaminergic system may play a role in the propagation of epileptic seizures and, indeed, DOPA metabolism impairment has recently been demonstrated in PET studies of ring chromosome 20 [r(20)] patients. We conducted a study looking for correlations between r(20) mosaicism, other clinical variables and both pre-synaptic dopamine transporter (DAT) expression and post-synaptic D2 receptor density. METHODS: Five patients with r(20) and epilepsy were enrolled in the study. DAT expression and D2 density were measured by single photon emission tomography (SPECT) imaging with 185 MBq of [123I]ioflupane and [123I]IBZM, respectively, on different days. Linear correlations between r(20) mosaicism, clinical variables and binding of [123I]ioflupane or [123I]IBZM were examined. RESULTS: A significant correlation between seizure frequency and r(20) mosaicism was detected (r=0.903, P<0.05), along with a negative correlation between r(20) mosaicism and binding of [123I]ioflupane in the putamen and in the caudate nucleus (r=-0.692 and r=-807; P<0.05). Seizure frequency was positively correlated with post-synaptic D2 density (r=0.925, P<0.05). CONCLUSION: Striatal neurons are involved in r(20) epilepsy; the relationship found between r(20) mosaicism and DAT expression suggests that drugs acting on the dopaminergic system could have a place in the treatment of this rare form of epilepsy. PMID- 20927026 TI - The ESRC Centre for Population Change - working in partnership with ONS and GROS. PMID- 20927027 TI - Stability and change in fertility intentions in Britain, 1991-2007. AB - The very low fertility experienced in several European countries in recent decades in the presence of higher intended family sizes has renewed interest in fertility intentions data. While the overall level of childbearing in Britain over the past few decades has remained relatively stable and high in comparison with many other European countries, we have seen sizeable increases in the age at which childbearing starts. This study uses data from the 1991 to 2007 General Household Surveys to examine trends in family intentions data in an attempt to arrive at a better understanding of these recent fertility developments. First, time trends in intended family size are compared with trends in observed fertility. Next, aggregate changes in intentions regarding the level and timing of fertility across the life course for cohorts are investigated together with the extent to which these aggregate intentions are matched by the subsequent childbearing of cohorts. Finally, both change across the life course and uncertainty in family intentions are examined. We conclude by discussing what these findings might tell us about contemporary reproductive decision making. PMID- 20927028 TI - National and international graduate migration flows. AB - This article examines the nature of national and international graduate migration flows in the UK. Migration equations are estimated with microdata from a matched dataset of Students and Destinations of Leavers from Higher Education, information collected by the Higher Education Statistical Agency. The probability of migrating is related to a set of observable characteristics using multinomial logit regression. The analysis suggests that migration is a selective process with graduates with certain characteristics having considerably higher probabilities of migrating, both to other regions of the UK and abroad. PMID- 20927029 TI - The demographic characteristics and economic activity patterns of carers over 50: evidence from the English Longitudinal Study of Ageing. AB - Studies on informal care provision have often focused on the provision of care for persons with a long term physical or mental ill-health or disability, or problems related to old age. However, the provision of care and support more broadly, for example in the form of childcare for grandchildren, can also impact on various aspects of a carer's life, such as their employment (if under the state retirement age), lifetime earnings and, by extension, pension income in later life. This article uses data from Wave 3 of the English Longitudinal Study of Ageing (ELSA) to explore the demographic characteristics, caring patterns, health status and economic activity patterns of carers aged over 50 in England. The results suggest that the nature of care provision differs across age groups, and that caring can be quite a different experience for older men and women. This article also sheds light on the characteristics of 'round-the-clock' carers, a relatively under-researched group which makes up just over one fifth of all carers aged 50 and over. PMID- 20927030 TI - Migration in later life: evidence from the British Household Panel Study. AB - This article uses data from the British Household Panel Study over the period 1991 - 2007 to examine the factors associated with residential mobility among people aged 50 and over. In line with earlier research, the likelihood of migrating, that is, changing address, is found to vary according to the demographic and socio-economic characteristics of the older person. Those in late middle age (50-59) and the oldest-old (90 and over) were most likely to move. Migration was also strongly associated with changes in partnership, health and economic status during the last 12 months, highlighting the importance of seeing migration within a life course context with certain life course events such as divorce, widowhood or retirement being important triggers for prompting a move. As divorce and remarriage become more common in later life, 'relationship driven migration' is likely to become more important, adding a new category to the classical typology of later life migration. PMID- 20927031 TI - A comparison of official population projections with Bayesian time series forecasts for England and Wales. AB - We compare official population projections with Bayesian time series forecasts for England and Wales. The Bayesian approach allows the integration of uncertainty in the data, models and model parameters in a coherent and consistent manner. Bayesian methodology for time-series forecasting is introduced, including autoregressive (AR) and stochastic volatility (SV) models. These models are then fitted to a historical time series of data from 1841 to 2007 and used to predict future population totals to 2033. These results are compared to the most recent projections produced by the Office for National Statistics. Sensitivity analyses are then performed to test the effect of changes in the prior uncertainty for a single parameter. Finally, in-sample forecasts are compared with actual population and previous official projections. The article ends with some conclusions and recommendations for future work. PMID- 20927032 TI - A cross country review of the validation and/or adjustment of census data. AB - This article reviews existing procedures employed by various countries in the evaluation of, and/or adjustment, either of census data, or of population estimates based upon census data. The work was carried out to ensure all potential demographic techniques are considered by the ONS for the post census evaluation process of the 2011 Census. PMID- 20927033 TI - Change in living arrangements following death of a partner in England and Wales, 1971 to 2001. AB - Understanding trends and changes in the circumstances of couples separated by death is important for policy initiatives to reduce vulnerabilities associated with end of life care and for those who live on. This article uses widow(er)hood statistics and census data from the Office for National Statistics Longitudinal Study. It examines changes in couples' living arrangements and households at four successive censuses from 1971 to 2001 and shows how these differ by age and gender on the death of a spouse or partner. Findings draw attention to the effects of ageing and mortality improvements as well as wider social and economic trends in family and household formation, residential independence in older age, and policy developments on long-term care provision for older people. PMID- 20927034 TI - An analysis of patient register data in the Longitudinal Study - what does it tell us about the quality of the data? AB - This article uses data for members of the ONS Longitudinal Study (LS) from both Census 2001 enumeration and patient registrations "frozen" on census day 2001 from the National Health Service Central Register (NHSCR) to examine potential sources of difference in area of usual residence.Overall 95.7 per cent of ONS LS members enumerated at census resided in the same area as recorded on the NHSCR data. Where areas differed, or the ONS LS member was not on the NHSCR on census day, subsequent NHSCR records were examined. Records flagged on the NHSCR as ONS LS members in England and Wales on census day but with no census record were also investigated. PMID- 20927035 TI - Bidirectional relationship between chronic kidney and periodontal disease: a study using structural equation modeling. AB - Periodontal disease is associated with diabetes, heart disease, and chronic kidney disease (CKD), relationships postulated to be due in part to vascular inflammation. A bidirectional relationship between CKD and periodontal disease is plausible, though this relationship has not been previously reported. In this study, we assessed the potential for connections between CKD and periodontal disease, and mediators of these relationships using structural equation models of data from 11,211 adults >= 18 years of age who participated in the Third National Health and Nutrition Examination Survey. Multivariable logistic regression models were used to test the hypothesis that periodontal disease was independently associated with CKD. Given the potential that the periodontal disease and CKD relationship may be bidirectional, a two-step analytic approach was used that involved tests for mediation and structural equation models to examine more complex direct and indirect effects of periodontal disease on CKD, and vice versa. In two separate models, periodontal disease (adjusted odds ratio of 1.62), edentulism (adjusted odds ratio of 1.83), and the periodontal disease score were associated with CKD when simultaneously adjusting for 14 other factors. Altogether, three of four structural equation models support the hypothesized relationship. Thus, our analyses support a bidirectional relationship between CKD and periodontal disease, mediated by hypertension and the duration of diabetes. PMID- 20927036 TI - Quality of care and mortality are worse in chronic kidney disease patients living in remote areas. AB - Many patients with non-dialysis dependent chronic kidney disease (CKD) live far from the closest nephrologist; although reversible, this might constitute a barrier to optimal care. In order to evaluate outcomes, we selected 31,452 outpatients older than 18 years with an estimated glomerular filtration rate (eGFR) less than 45 ml/min per 1.73 m2 who had serum creatinine measured at least once during 2005 in Alberta, Canada. We then used logistic regression to examine the association between outcomes of 6545 patients who lived more than 50 km from the nearest nephrologist. Over a median follow-up of 27 months, 7684 participants died and 15,075 were hospitalized at least once. Compared with those living within 50 km, those further away were significantly less likely to visit a nephrologist or a multidisciplinary CKD clinic within 18 months of the index measurement of the eGFR. Similarly, remote dwellers with diabetes were significantly less likely to have hemoglobin A1c evaluated within 1 year of the index eGFR measurement, to have urinary albumin assessed biannually, or to receive an angiotensin converting enzyme inhibitor or receptor blocker in the setting of diabetes or proteinuria. Remote-dwelling participants were also significantly more likely to die or be hospitalized during follow-up than those living closer. Thus, among people with CKD, remote dwellers were less likely to receive specialist care, recommended laboratory testing, and appropriate medications, and were more likely to die or be hospitalized compared with those living closer to a nephrologist. PMID- 20927037 TI - The rhesus protein RhCG: a new perspective in ammonium transport and distal urinary acidification. AB - Urinary acidification is a complex process requiring the coordinated action of enzymes and transport proteins and resulting in the removal of acid and the regeneration of bicarbonate. Proton secretion is mediated by luminal H(+)-ATPases and requires the parallel movement of NH3, and its protonation to NH4(+), to provide sufficient buffering. It has been long assumed that ammonia secretion is a passive process occurring by means of simple diffusion driven by the urinary trapping of ammonium. However, new data indicate that mammalian cells possess specific membrane proteins from the family of rhesus proteins involved in ammonia/MUm permeability. Rhesus proteins were first identified in yeast and later also in plants, algae, and mammals. In rodents, RhBG and RhCG are expressed in the collecting duct, whereas in humans only RhCG was detected. Their expression increases with maturation of the kidney and accelerates after birth in parallel with other acid-base transport proteins. Deletion of RhBG in mice had no effect on renal ammonium excretion, whereas RhCG deficiency reduces renal ammonium secretion strongly, causes metabolic acidosis in acid-challenged mice, and impairs restoration of normal acid-base status. Microperfusion experiments or functional reconstitution in liposomes demonstrates that ammonia is the most likely substrate of RhCG. Similarly, crystal structures of human RhCG and the homologous bacterial AmtB protein suggest that these proteins may form gas channels. PMID- 20927038 TI - Raloxifene, a selective estrogen receptor modulator, is renoprotective: a post hoc analysis. AB - Estrogens have a protective effect on kidney fibrosis in several animal models. Here, we tested the effect of raloxifene, an estrogen receptor modulator, on the change in serum creatinine or estimated glomerular filtration rate (eGFR) and incident kidney-related adverse events. We performed a post-hoc analysis of the multiple outcomes of raloxifene evaluation trial, a double-masked, placebo controlled randomized clinical trial encompassing 7705 post-menopausal women (aged 31-80 years) with osteoporosis. Participants were randomized to either of two doses of raloxifene, 60 or 120 mg/day, or placebo. Serum creatinine was measured at a central laboratory at baseline and annually. Adverse events were assessed every 6 months and uniformly categorized. Compared with those in the placebo group, participants on raloxifene had a slower yearly rate of increase in creatinine (significant at the low dose) and a significantly slower yearly rate of decrease in eGFR for both doses over 3 years of follow-up. Raloxifene was associated with significantly fewer kidney-related adverse events compared with placebo. Thus, treatment with raloxifene was safe and renoprotective. Clinical trials of raloxifene in post-menopausal women with kidney disease designed to look at kidney outcomes are needed to confirm these findings. PMID- 20927039 TI - Pharmacotherapy of urolithiasis: evidence from clinical trials. AB - Urolithiasis is a worldwide problem with significant health and economic burdens. Medical therapy that alters the course of stone disease has enormous medical and financial impact. Urolithiasis is a final manifestation of a broad range of etiologies and pathogenesis. The modest progress in understanding the pathophysiology has hampered successful development of targeted therapy. Current regimens are based mostly on rational alteration of urinary biochemistry and physical chemistry to lower the risk of precipitation. In terms of pharmacotherapy, there are drugs to successfully improve hypercalciuria, hypocitraturia, aciduria, hyperuricosuria, and hypercystinuria. These agents have been proven to be effective in randomized controlled trials in improving urinary biochemical and physicochemical risk factors, as well as clinical outcomes. Although our current regimens have clearly improved the management and lives of stone formers, there are still clearly identifiable immense voids in the knowledge of pathophysiology of stone disease that can be filled with combined basic science and clinical studies. PMID- 20927040 TI - Rapid fluid removal during dialysis is associated with cardiovascular morbidity and mortality. AB - Patients receiving hemodialysis have high rates of cardiovascular morbidity and mortality that may be related to the hemodynamic effects of rapid ultrafiltration. Here we tested whether higher dialytic ultrafiltration rates are associated with greater all-cause and cardiovascular mortality, and hospitalization for cardiovascular disease. We used data from the Hemodialysis Study, an almost-7-year randomized clinical trial of 1846 patients receiving thrice-weekly chronic dialysis. The ultrafiltration rates were divided into three categories: up to 10 ml/h/kg, 10-13 ml/h/kg, and over 13 ml/h/kg. Compared to ultrafiltration rates in the lowest group, rates in the highest were significantly associated with increased all-cause and cardiovascular-related mortality with adjusted hazard ratios of 1.59 and 1.71, respectively. Overall, ultrafiltration rates between 10-13 ml/h/kg were not associated with all-cause or cardiovascular mortality; however, they were significantly associated among participants with congestive heart failure. Cubic spline interpolation suggested that the risk of all-cause and cardiovascular mortality began to increase at ultrafiltration rates over 10 ml/h/kg regardless of the status of congestive heart failure. Hence, higher ultrafiltration rates in hemodialysis patients are associated with a greater risk of all-cause and cardiovascular death. PMID- 20927041 TI - Toll-like receptor 4 regulates early endothelial activation during ischemic acute kidney injury. AB - Ischemic acute kidney injury (AKI) triggers an inflammatory response which exacerbates injury that requires increased expression of endothelial adhesion molecules. To study this further, we used in situ hybridization, immunohistology, and isolated endothelial cells, and found increased Toll-like receptor 4 (TLR4) expression on endothelial cells of the vasa rectae of the inner stripe of the outer medulla of the kidney 4 h after reperfusion. This increase was probably due to reactive oxygen species, known to be generated early during ischemic AKI, because the addition of hydrogen peroxide increased TLR4 expression in MS1 microvascular endothelial cells in vitro. Endothelial TLR4 may regulate adhesion molecule (CD54 and CD62E) expression as they were increased on endothelia of wild type but not TLR4 knockout mice in vivo. Further, the addition of high-mobility group protein B1, a TLR4 ligand released by injured cells, increased adhesion molecule expression on endothelia isolated from wild-type but not TLR4 knockout mice. TLR4 was localized to proximal tubules in the cortex and outer medulla after 24 h of reperfusion. Thus, at least two different cell types express TLR4, each of which contributes to renal injury by temporally different mechanisms during ischemic AKI. PMID- 20927042 TI - Direct targeting of fibroblast growth factor-inducible 14 protein protects against renal ischemia reperfusion injury. AB - Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is known to have pivotal roles in various inflammatory processes. The TWEAK receptor, fibroblast growth factor-inducible 14 (Fn14), has various unique functions under physiological and pathological conditions; however, the therapeutic potential of its direct targeting remains unknown. Here, we found that Fn14 expression was highly upregulated in ischemic renal tissues and tubular epithelial cells of patient biopsies and experimental animal models of renal injury. To clarify the function of Fn14 in ischemia reperfusion injury, we coincubated renal tubular cells with ITEM-2, an anti-Fn14 blocking monoclonal antibody, and found that it inhibited the production of proinflammatory cytokines and chemokines after injury. Furthermore, Fn14 blockade downregulated the local expression of several proinflammatory mediators, reduced accumulation of neutrophils and macrophages in ischemic tissues, and inhibited tubular cell apoptosis. Importantly, Fn14 blockade attenuated the development of chronic fibrosis after ischemia reperfusion injury and significantly prolonged the survival of lethally injured mice. Thus, we conclude that Fn14 is a critical mediator in the pathogenesis of ischemia reperfusion injury. PMID- 20927043 TI - Angiotensin II diminishes the effect of SGK1 on the WNK4-mediated inhibition of ROMK1 channels. AB - ROMK1 channels are located in the apical membrane of the connecting tubule and cortical collecting duct and mediate the potassium secretion during normal dietary intake. We used a perforated whole-cell patch clamp to explore the effect of angiotensin II on these channels in HEK293 cells transfected with green fluorescent protein (GFP)-ROMK1. Angiotensin II inhibited ROMK1 channels in a dose-dependent manner, an effect abolished by losartan or by inhibition of protein kinase C. Furthermore, angiotensin II stimulated a protein kinase C sensitive phosphorylation of tyrosine 416 within c-Src. Inhibition of protein tyrosine kinase attenuated the effect of angiotensin II. Western blot studies suggested that angiotensin II inhibited ROMK1 channels by enhancing its tyrosine phosphorylation, a notion supported by angiotensin II's failure to inhibit potassium channels in cells transfected with the ROMK1 tyrosine mutant (R1Y337A). However, angiotensin II restored the with-no-lysine kinase-4 (WNK4)-induced inhibition of R1Y337A in the presence of serum-glucocorticoids-induced kinase 1 (SGK1), which reversed the inhibitory effect of WNK4 on ROMK1. Moreover, protein tyrosine kinase inhibition abolished the angiotensin II-induced restoration of WNK4-mediated inhibition of ROMK1. Angiotensin II inhibited ROMK channels in the cortical collecting duct of rats on a low sodium diet, an effect blocked by protein tyrosine kinase inhibition. Thus, angiotensin II inhibits ROMK channels by two mechanisms: increasing tyrosine phosphorylation of the channel and synergizing the WNK4-induced inhibition. Hence, angiotensin II may have an important role in suppressing potassium secretion during volume depletion. PMID- 20927045 TI - Disrupted activity in the hippocampal-accumbens circuit of type III neuregulin 1 mutant mice. AB - Neuregulin 1 (Nrg1), a schizophrenia susceptibility gene, is involved in fundamental aspects of neurodevelopment. Mice lacking any one of the several isoforms of Nrg1 have a variety of schizophrenia-related phenotypes, including deficits in working memory and sensorimotor gating, loss of spines in pyramidal neurons in the ventral subiculum, loss of dendrites in cortical pyramidal cells, loss of parvalbumin-positive interneurons in the prefrontal cortex, and altered plasticity in corticolimbic synapses. Mice heterozygous for a disruption in exon 7 of the Nrg1 gene lack Type III (cysteine-rich-domain-containing) isoforms and have sensorimotor gating deficits that may involve changes in the activity of a circuit involving projections from the ventral hippocampus (vHPC) to medium spiny neurons in the nucleus accumbens (nACC). To explore the neural basis of these deficits, we examined electrophysiological activity in the nACC and vHPC of these mice. Under urethane anesthesia, bursts of spontaneous activity propagated from the vHPC to the nACC in both wild-type and mutant mice. However, these bursts were weaker in mutant nACC, with reduced local field potential amplitude and spiking activity. Single units in mutant nACC fired less frequently within the bursts, and more frequently outside of the bursts. Moreover, within-burst nACC spiking was less modulated by vHPC activity, as determined by phase-locking to the low-frequency oscillatory components of the bursts. These data suggest that the efficacy of vHPC input to the nACC is reduced in the Type III Nrg1 heterozygotes, supporting a role for Nrg1 in the functional profile of hippocampal-accumbens synapses. PMID- 20927044 TI - How human electrophysiology informs psychopharmacology: from bottom-up driven processing to top-down control. AB - This review surveys human event-related brain potential (ERP) and event-related magnetic field (ERF) approaches to psychopharmacology and psychopathology, and the way in which they complement behavioral studies and other neuroimaging modalities. The major paradigms involving ERP/ERF are P50 suppression, loudness dependent auditory evoked potential (LDAEP), mismatch negativity (MMN), P300, mental chronometry, inhibitory control, and conflict processing (eg, error related negativity (ERN)). Together these paradigms cover a range of more bottom up driven to more top-down controlled processes. A number of relationships between the major neurotransmitter systems and electrocortical mechanisms are highlighted. These include the role of dopamine in conflict processing, and perceptual processing vs motor preparation; the role of serotonin in P50 suppression, LDAEP, and MMN; glutamate/NMDA and MMN; and the role of acetylcholine in P300 generation and memory-related processes. A preliminary taxonomy for these relationships is provided, which should be helpful in attuning possible new treatments or new applications of existing treatments to various disorders. PMID- 20927046 TI - Stress and alcohol cues exert conjoint effects on go and stop signal responding in male problem drinkers. AB - Stress, cues, and pharmacological priming are linked with relapse to addictive behavior. Increased salience and decreased inhibitory control are thought to mediate the effects of relapse-related stimuli. However, the functional relationship between these two processes is unclear. To address this issue, a modified Stop Signal Task was employed, which used Alcohol, Neutral, and Non Words as Go stimuli, and lexical decision as the Go response. Subjects were 38 male problem drinkers (mean Alcohol Dependence Scale (ADS) score: 18.0). Uncontrollable noise (~ 10 min at 110 dB) was the stressor; nonalcoholic placebo beer (P-Beer) was the cue manipulation, and alcohol (0.7 g/kg), the pharmacological prime. Half the sample received alcohol, and half P-Beer. Stress and beverage (test drink vs soft drink) were manipulated within subjects on two sessions, with half the sample receiving active manipulations together and half receiving them separately. Go response time (RT) and Stop Signal RT (SSRT) were slower to Alcohol than Neutral words. Stress augmented this bias. Alcohol and P Beer impaired overall SSRT. Stress impaired neither overall SSRT nor Go RT. SSRT to Neutral words and Non-Words correlated inversely with Go RT to Alcohol and Neutral words, and Non-Words. ADS correlated directly with SSRT to Alcohol words. A resource allocation account was proposed, whereby diversion of limited resources to salient cues effectively yoked otherwise independent Go and Stop processes. Disturbances of prefrontal norepinephrine and dopamine were cited as possibly accounting for these effects. Treatments that optimize prefrontal catecholamine transmission may deter relapse by reducing disinhibitory effects of salient eliciting stimuli. PMID- 20927047 TI - Central and peripheral administration of secretin inhibits food intake in mice through the activation of the melanocortin system. AB - Secretin (Sct) is released into the circulation postprandially from the duodenal S-cells. The major functions of Sct originated from the gastrointestinal system are to delay gastric emptying, stimulate fluid secretion from pancreas and liver, and hence optimize the digestion process. In recent years, Sct and its receptor (Sctr) have been identified in discrete nuclei of the hypothalamus, including the paraventricular nucleus (PVN) and the arcuate nucleus (Arc). These nuclei are the primary brain sites that are engaged in regulating body energy homeostasis, thus providing anatomical evidence to support a functional role of Sct in appetite control. In this study, the effect of Sct on feeding behavior was investigated using wild-type (wt), Sct(-/-), and secretin receptor-deficient (Sctr(-/-)) mice. We found that both central and peripheral administration of Sct could induce Fos expression in the PVN and Arc, suggesting the activation of hypothalamic feeding centers by this peptide. Consistent with this notion, Sct was found to increase thyrotropin-releasing hormone and melanocortin-4 receptor (Mc4r) transcripts in the PVN, and augment proopiomelanocortin, but reduces agouti-related protein mRNA expression in the Arc. Injection of Sct was able to suppress food intake in wt mice, but not in Sctr(-/-) mice, and that this effect was abolished upon pretreatment with SHU9119, an antagonist for Mc4r. In summary, our data suggest for the first time that Sct is an anorectic peptide, and that this function is mediated by the melanocortin system. PMID- 20927048 TI - Deconstructing antiobesity compound action: requirement of serotonin 5-HT2B receptors for dexfenfluramine anorectic effects. AB - The now-banned anorectic molecule, dexfenfluramine, promotes serotonin release through a serotonin transporter-dependent mechanism, and it has been widely prescribed for the treatment of obesity. Previous studies have identified that 5 HT(2B) receptors have important roles in dexfenfluramine side effects, that is, pulmonary hypertension, plasma serotonin level regulation, and valvulopathy. We thus investigated a putative contribution of 5-HT(2B) receptors in dexfenfluramine-dependent feeding behavior in mice. Interestingly, the hypophagic response to dexfenfluramine (3-10 mg/kg) observed in wild-type mice (1-4 h) was eliminated in mice lacking 5-HT(2B) receptors (5-HT(2B)(-/-)). These findings were further validated by the lack of hypophagic response to dexfenfluramine in wild-type mice treated with RS127445, a highly selective and potent antagonist (pKi=8.22 +/- 0.24). Using microdialysis, we observed that in 5-HT(2B)(-/-) awake mice, the dexfenfluramine-induced hypothalamic peak of serotonin release (1 h) was strongly reduced (fourfold) compared with wild type. Moreover, using hypothalamic synaptosomes, we established the serotonergic neuron autonomous properties of this effect: a strong serotonin release was observed upon dexfenfluramine stimulation of synaptosome preparation from wild type but not from mice lacking active 5-HT(2B) receptors. These findings strongly suggest that activation of presynaptic 5-HT(2B) receptors is a limiting step in the serotonin transporter dependent-releasing effect of dexfenfluramine, whereas other serotonin receptors act downstream with respect to feeding behavior. PMID- 20927051 TI - Infectious disease: do steroids benefit patients with bacterial meningitis? PMID- 20927049 TI - Risk-assessment and coping strategies segregate with divergent intrinsic aerobic capacity in rats. AB - Metabolic function is integrally related to an individual's susceptibility to, and progression of, disease. Selective breeding for intrinsic treadmill running in rats has produced distinct lines of high- or low-capacity runners (HCR and LCR, respectively) that exhibit numerous physiological differences. To date, the role of intrinsic aerobic capacity on behavior and stress response in these rats has not been addressed and was the focus of these studies. HCR and LCR rats did not differ in their locomotor response to novelty or behavior in the light/dark box. In contrast, immobility in the forced swim test was higher in LCR rats compared with HCR rats, regardless of desipramine treatment. Although both HCR and LCR rats responded to cat odor with decreased exploration and increased risk assessment, HCR rats showed greater contextual conditioning to cat odor. HCR rats exhibited higher expression of corticotropin-releasing hormone in the central nucleus of the amygdala, as well as heavier adrenal and thymus weight. Corticosterone was comparable among HCR and LCR rats at light/dark transitions, and in response to unavoidable cat odor. HCR rats, however, exhibited a greater corticosterone response following the light/dark box. These experiments show that the LCR phenotype associates with decreased risk assessment in response to salient danger signals and passive coping. In contrast, HCR rats show a more naturalistic strategy in that they employ active coping and a more vigilant and cautious response to environmental novelty and salient danger signals. Within this context, we propose that intrinsic aerobic capacity is a central feature mechanistically linking complex metabolic disease and behavior. PMID- 20927052 TI - Parkinson disease: deep brain stimulation versus best medical therapy for PD. PMID- 20927050 TI - Regulation of hippocampal cannabinoid CB1 receptor actions by adenosine A1 receptors and chronic caffeine administration: implications for the effects of Delta9-tetrahydrocannabinol on spatial memory. AB - The cannabinoid CB(1) receptor-mediated modulation of gamma-aminobutyric acid (GABA) release from inhibitory interneurons is important for the integrity of hippocampal-dependent spatial memory. Although adenosine A(1) receptors have a central role in fine-tuning excitatory transmission in the hippocampus, A(1) receptors localized in GABAergic cells do not directly influence GABA release. CB(1) and A(1) receptors are the main targets for the effects of two of the most heavily consumed psychoactive substances worldwide: Delta(9)-tetrahydrocannabinol (THC, a CB(1) receptor agonist) and caffeine (an adenosine receptor antagonist). We first tested the hypothesis that an A(1)-CB(1) interaction influences GABA and glutamate release in the hippocampus. We found that A(1) receptor activation attenuated the CB(1)-mediated inhibition of GABA and glutamate release and this interaction was manifested at the level of G-protein activation. Using in vivo and in vitro approaches, we then investigated the functional implications of the adenosine-cannabinoid interplay that may arise following chronic caffeine consumption. Chronic administration of caffeine in mice (intraperitoneally, 3 mg/kg/day, for 15 days, >12 h before trials) led to an A(1)-mediated enhancement of the CB(1)-dependent acute disruptive effects of THC on a short-term spatial memory task, despite inducing a reduction in cortical and hippocampal CB(1) receptor number and an attenuation of CB(1) coupling with G protein. A(1) receptor levels were increased following chronic caffeine administration. This study shows that A(1) receptors exert a negative modulatory effect on CB(1) mediated inhibition of GABA and glutamate release, and provides the first evidence of chronic caffeine-induced alterations on the cannabinoid system in the cortex and hippocampus, with functional implications in spatial memory. PMID- 20927053 TI - Stroke: predicting the risk of poststroke epilepsy-why and how? PMID- 20927054 TI - Neuro-oncology: Therapeutic benefits of reirradiation for recurrent brain tumors. PMID- 20927055 TI - Parkinson disease: deep brain stimulation in Parkinson disease-what went wrong? PMID- 20927057 TI - CT colonography: Ready for prime time? PMID- 20927058 TI - Con: CT colonography-not yet ready for community-wide implementation. PMID- 20927059 TI - A balancing view: the good, the bad, and the unknown. PMID- 20927060 TI - Update from the GI program directors' caucus. PMID- 20927061 TI - Self-dilation for resistant, benign esophageal strictures. PMID- 20927062 TI - Editorial: Cancer surveillance in achalasia: better late than never? AB - Patients with achalasia have an increased risk for the development of esophageal squamous cell cancer. Endoscopic surveillance in long-standing achalasia has been advocated by some, but the most recent American Society of Gastrointesinal Endoscopy guidelines regard current data as insufficient to support such an approach. In this issue of the American Journal of Gastroenterology, Leeuwenburgh and colleagues report on the results of a long-term prospective study with fixed surveillance intervals. The authors confirm earlier observations of an increased cancer risk after 10 years of symptomatic achalasia. Despite some limitations, this study and earlier data suggest that it might be worthwhile to consider endoscopic surveillance in patients with long-standing achalasia. PMID- 20927065 TI - Editorial: Treatment of patients with HCV-related cirrhosis with peginterferon and ribavirin: Swinging the pendulum toward treatment. AB - Patients with hepatitis C virus-related cirrhosis are at increased risk for hepatic decompensation and hepatocellular carcinoma (HCC). They also responded less well to standard therapy compared with those without cirrhosis. Several recent studies have demonstrated that patients with cirrhosis can be safely treated and those who achieve a sustained virological response have better clinical outcomes compared with nonresponders. These results support treatment for patients with compensated cirrhosis. In addition, cirrhotic patients should be monitored after a sustained virological response is obtained, because some patients remain at risk for complications of liver disease, particularly HCC. Newer, more effective therapy is needed for patients with cirrhosis. PMID- 20927068 TI - Irritable bowel syndrome and diverticular disease: association or misdiagnosis? PMID- 20927071 TI - "Short" double-balloon or single-balloon enteroscope for ERCP in patients with billroth II gastrectomy or Roux-en-Y anastomosis. PMID- 20927072 TI - Remaining in an upright position is suboptimal for transnasal gastroscopy. PMID- 20927074 TI - Scleroderma with a twist. PMID- 20927075 TI - Hepatosplenic T-cell lymphoma in inflammatory bowel disease: a possible thiopurine-induced chromosomal abnormality. PMID- 20927076 TI - Crohn's disease masquerading as idiopathic amyloidosis and nephrotic syndrome for 2 years before diagnosis. PMID- 20927077 TI - A case of ulcerative colitis associated with autoimmune hemolytic anemia successfully treated by autologous hematopoietic stem cell transplantation. PMID- 20927078 TI - Methanogenic flora and constipation: many doubts for a pathogenetic link. PMID- 20927084 TI - Prediction of neutropenia-related effects of a new combination therapy with the anticancer drugs BI 2536 (a Plk1 inhibitor) and pemetrexed. AB - This study investigated the feasibility of predicting the neutropenia-related effects of a therapy that combines the investigational drug BI 2536 (inhibitor of Polo-like kinase 1) and pemetrexed, an approved anticancer drug. Predictions were arrived at using the pharmacokinetic/pharmacodynamic (PK/PD) parameters of each of the drugs obtained from monotherapy studies and assuming that the neutropenic effect is additive when the drugs are administered as a combination therapy. Subsequently, a PK/PD model was developed to determine whether this assumption of additive effect was reasonable in relation to these two drugs. All analyses and simulations were performed using the population approach in NONMEM, version VI. PMID- 20927085 TI - Following the money in epilepsy therapeutics. PMID- 20927102 TI - An unprecedented nucleic acid capture mechanism for excision of DNA damage. AB - DNA glycosylases that remove alkylated and deaminated purine nucleobases are essential DNA repair enzymes that protect the genome, and at the same time confound cancer alkylation therapy, by excising cytotoxic N3-methyladenine bases formed by DNA-targeting anticancer compounds. The basis for glycosylase specificity towards N3- and N7-alkylpurines is believed to result from intrinsic instability of the modified bases and not from direct enzyme functional group chemistry. Here we present crystal structures of the recently discovered Bacillus cereus AlkD glycosylase in complex with DNAs containing alkylated, mismatched and abasic nucleotides. Unlike other glycosylases, AlkD captures the extrahelical lesion in a solvent-exposed orientation, providing an illustration for how hydrolysis of N3- and N7-alkylated bases may be facilitated by increased lifetime out of the DNA helix. The structures and supporting biochemical analysis of base flipping and catalysis reveal how the HEAT repeats of AlkD distort the DNA backbone to detect non-Watson-Crick base pairs without duplex intercalation. PMID- 20927103 TI - Oxidative stress induces angiogenesis by activating TLR2 with novel endogenous ligands. AB - Reciprocity of inflammation, oxidative stress and neovascularization is emerging as an important mechanism underlying numerous processes from tissue healing and remodelling to cancer progression. Whereas the mechanism of hypoxia-driven angiogenesis is well understood, the link between inflammation-induced oxidation and de novo blood vessel growth remains obscure. Here we show that the end products of lipid oxidation, omega-(2-carboxyethyl)pyrrole (CEP) and other related pyrroles, are generated during inflammation and wound healing and accumulate at high levels in ageing tissues in mice and in highly vascularized tumours in both murine and human melanoma. The molecular patterns of carboxyalkylpyrroles are recognized by Toll-like receptor 2 (TLR2), but not TLR4 or scavenger receptors on endothelial cells, leading to an angiogenic response that is independent of vascular endothelial growth factor. CEP promoted angiogenesis in hindlimb ischaemia and wound healing models through MyD88 dependent TLR2 signalling. Neutralization of endogenous carboxyalkylpyrroles impaired wound healing and tissue revascularization and diminished tumour angiogenesis. Both TLR2 and MyD88 are required for CEP-induced stimulation of Rac1 and endothelial migration. Taken together, these findings establish a new function of TLR2 as a sensor of oxidation-associated molecular patterns, providing a key link connecting inflammation, oxidative stress, innate immunity and angiogenesis. PMID- 20927105 TI - Seismic evidence of negligible water carried below 400-km depth in subducting lithosphere. AB - Strong evidence exists that water is carried from the surface into the upper mantle by hydrous minerals in the uppermost 10-12 km of subducting lithosphere, and more water may be added as the lithosphere bends and goes downwards. Significant amounts of that water are released as the lithosphere heats up, triggering earthquakes and fluxing arc volcanism. In addition, there is experimental evidence for high solubility of water in olivine, the most abundant mineral in the upper mantle, for even higher solubility in olivine's high pressure polymorphs, wadsleyite and ringwoodite, and for the existence of dense hydrous magnesium silicates that potentially could carry water well into the lower mantle (deeper than 1,000 km). Here we compare experimental and seismic evidence to test whether patterns of seismicity and the stabilities of these potentially relevant hydrous phases are consistent with a wet lithosphere. We show that there is nearly a one-to-one correlation between dehydration of minerals and seismicity at depths less than about 250 km, and conclude that the dehydration of minerals is the trigger of instability that leads to seismicity. At greater depths, however, we find no correlation between occurrences of earthquakes and depths where breakdown of hydrous phases is expected. Lastly, we note that there is compelling evidence for the existence of metastable olivine (which, if present, can explain the distribution of deep-focus earthquakes) west of and within the subducting Tonga slab and also in three other subduction zones, despite metastable olivine being incompatible with even extremely small amounts of water (of the order of 100 p.p.m. by weight). We conclude that subducting slabs are essentially dry at depths below 400 km and thus do not provide a pathway for significant amounts of water to enter the mantle transition zone or the lower mantle. PMID- 20927104 TI - ETV1 is a lineage survival factor that cooperates with KIT in gastrointestinal stromal tumours. AB - Gastrointestinal stromal tumour (GIST) is the most common human sarcoma and is primarily defined by activating mutations in the KIT or PDGFRA receptor tyrosine kinases. KIT is highly expressed in interstitial cells of Cajal (ICCs)-the presumed cell of origin for GIST-as well as in haematopoietic stem cells, melanocytes, mast cells and germ cells. Yet, families harbouring germline activating KIT mutations and mice with knock-in Kit mutations almost exclusively develop ICC hyperplasia and GIST, suggesting that the cellular context is important for KIT to mediate oncogenesis. Here we show that the ETS family member ETV1 is highly expressed in the subtypes of ICCs sensitive to oncogenic KIT mediated transformation, and is required for their development. In addition, ETV1 is universally highly expressed in GISTs and is required for growth of imatinib sensitive and resistant GIST cell lines. Transcriptome profiling and global analyses of ETV1-binding sites suggest that ETV1 is a master regulator of an ICC GIST-specific transcription network mainly through enhancer binding. The ETV1 transcriptional program is further regulated by activated KIT, which prolongs ETV1 protein stability and cooperates with ETV1 to promote tumorigenesis. We propose that GIST arises from ICCs with high levels of endogenous ETV1 expression that, when coupled with an activating KIT mutation, drives an oncogenic ETS transcriptional program. This differs from other ETS-dependent tumours such as prostate cancer, melanoma and Ewing sarcoma where genomic translocation or amplification drives aberrant ETS expression. It also represents a novel mechanism of oncogenic transcription factor activation. PMID- 20927107 TI - A redox switch in angiotensinogen modulates angiotensin release. AB - Blood pressure is critically controlled by angiotensins, which are vasopressor peptides specifically released by the enzyme renin from the tail of angiotensinogen-a non-inhibitory member of the serpin family of protease inhibitors. Although angiotensinogen has long been regarded as a passive substrate, the crystal structures solved here to 2.1 A resolution show that the angiotensin cleavage site is inaccessibly buried in its amino-terminal tail. The conformational rearrangement that makes this site accessible for proteolysis is revealed in our 4.4 A structure of the complex of human angiotensinogen with renin. The co-ordinated changes involved are seen to be critically linked by a conserved but labile disulphide bridge. Here we show that the reduced unbridged form of angiotensinogen is present in the circulation in a near 40:60 ratio with the oxidized sulphydryl-bridged form, which preferentially interacts with receptor-bound renin. We propose that this redox-responsive transition of angiotensinogen to a form that will more effectively release angiotensin at a cellular level contributes to the modulation of blood pressure. Specifically, we demonstrate the oxidative switch of angiotensinogen to its more active sulphydryl bridged form in the maternal circulation in pre-eclampsia-the hypertensive crisis of pregnancy that threatens the health and survival of both mother and child. PMID- 20927106 TI - Jasmonate perception by inositol-phosphate-potentiated COI1-JAZ co-receptor. AB - Jasmonates are a family of plant hormones that regulate plant growth, development and responses to stress. The F-box protein CORONATINE INSENSITIVE 1 (COI1) mediates jasmonate signalling by promoting hormone-dependent ubiquitylation and degradation of transcriptional repressor JAZ proteins. Despite its importance, the mechanism of jasmonate perception remains unclear. Here we present structural and pharmacological data to show that the true Arabidopsis jasmonate receptor is a complex of both COI1 and JAZ. COI1 contains an open pocket that recognizes the bioactive hormone (3R,7S)-jasmonoyl-l-isoleucine (JA-Ile) with high specificity. High-affinity hormone binding requires a bipartite JAZ degron sequence consisting of a conserved alpha-helix for COI1 docking and a loop region to trap the hormone in its binding pocket. In addition, we identify a third critical component of the jasmonate co-receptor complex, inositol pentakisphosphate, which interacts with both COI1 and JAZ adjacent to the ligand. Our results unravel the mechanism of jasmonate perception and highlight the ability of F-box proteins to evolve as multi-component signalling hubs. PMID- 20927108 TI - Neurogenic bowel management after spinal cord injury. PMID- 20927109 TI - Long-term exposure to elevated blood pressure and mortality from cardiovascular disease in a Japanese population: the Ibaraki Prefectural Health Study. AB - High blood pressure (BP) has been well established as a leading risk factor for both cardiovascular disease and mortality in general. However, the effect of long term exposure to elevated BP on mortality risks in Asian populations remains unclear. The purpose of this study was to investigate the effects of time averaged BP levels over 5 years on subsequent cardiovascular disease mortalities in a Japanese population. A total of 46,484 adults (14,771 men and 31,713 women) aged 40-79 years, who had no history of stroke or heart disease and who underwent health checkups in Ibaraki prefecture, Japan, in 1993 and 1998 were followed up through 2005. Hazard ratios (HRs) for mortality were estimated using a Cox proportional hazard model. Multivariate HRs (95% confidence interval) associated with a 10 mm Hg increase in systolic BP were measured in 1993 and 1998, and their averages were 1.11 (1.05-1.16), 1.13 (1.07-1.18) and 1.17 (1.10-1.27), respectively. Multivariate HRs for a 10 mm Hg increase in time-averaged systolic BP were 1.12 (1.03-1.21) in men and 1.24 (1.13-1.35) in women. The subgroup analysis of antihypertensive use showed that multivariate HRs for time-averaged systolic BP were 1.20 (1.11-1.29) in sustained non-users and 1.17 (1.04-1.32) in sustained users. Similar results were also obtained for diastolic BP. In conclusion, long-term exposure to elevated BP substantially associates with excess risk for cardiovascular disease mortality among Japanese subjects, irrespective of antihypertensive medication use. Thus, appropriate management of BP is important in both users and non-users of antihypertensive medication. PMID- 20927110 TI - Mechanical stretch potentiates angiotensin II-induced proliferation in spontaneously hypertensive rat vascular smooth muscle cells. AB - Angiotensin II (AngII) stimulates vascular smooth muscle cell (VSMC) proliferation; however, the effect of AngII on cell proliferation in the presence of mechanical force is not clear. We investigated the mechanism of AngII-induced cell proliferation mediated by mechanical stretch in VSMCs of both normotensive and hypertensive rats. VSMCs obtained from the thoracic aortas of 8-week-old Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) were stretched by a Flex culture system. Mechanical stretch significantly upregulated protein expression of AngII type 1 (AT1) receptor, epidermal growth factor (EGF) receptor and mitogen-activated protein kinase phosphatase-1 in both SHR and WKY VSMCs; however, there was no significant difference in these changes between the cells from SHR and WKY. Mechanical stretch attenuated AngII-induced phosphorylation of extracellular signal-regulated kinase (ERK) 1/2, ERK kinase (MEK) and EGF receptor; it also attenuated [3H] thymidine incorporation and cell proliferation in VSMC of WKY. In contrast, the effects of AngII were augmented by mechanical stretch in VSMC of SHR. AngII-induced ERK 1/2 phosphorylation and cell proliferation in SHR were inhibited by pretreatment with an AT1 receptor blocker, candesartan and an inhibitor of MEK, PD98059. Moreover, pretreatment with an EGF receptor tyrosine kinase inhibitor, AG1478, also blocked upregulation of AngII induced ERK 1/2 phosphorylation induced by stretch in SHR VSMCs. This study demonstrates that mechanical stretch augments SHR VSMC proliferation through an AT1/EGF receptor/ERK-dependent pathway. These findings may provide new insights into the signaling mechanisms whereby AngII exerts its growth-promoting effects on vasculature in a hypertensive state. PMID- 20927111 TI - The combined impact of blood pressure category and glucose abnormality on the incidence of cardiovascular diseases in a Japanese urban cohort: the Suita Study. AB - Few prospective studies have examined the combined impact of blood pressure (BP) categories and glucose abnormalities on the incidence of cardiovascular disease (CVD) in the general Asian population. This study aimed to examine the effect of the combined risks of these factors on the incidence of CVD in a general Japanese population. We studied 5321 Japanese individuals (aged 30-79 years), without CVD at baseline, who received follow-up for an average of 11.7 years. Serum fasting glucose categories were defined according to the 2003 American Diabetes Association recommendations. BP categories were defined by the 2009 Japanese Society of Hypertension Guidelines for the Management of Hypertension. The Cox proportional hazard ratios (HRs) for CVD according to the serum glucose and BP categories were calculated. In 62,036 person-years of follow-up, we documented 364 CVD events (198 stroke and 166 coronary heart disease (CHD)). Compared with normoglycemic subjects, the multivariable HRs (95% confidence intervals (CIs)) for CVD, CHD and stroke were 1.25 (1.00-1.58), 1.46 (1.04-2.04) and 1.11 (0.81 1.52), respectively, in individuals with impaired fasting glucose (IFG), whereas these values were 2.13 (1.50-3.03), 2.28 (1.34-3.88) and 2.08 (1.29-3.35), respectively, in individuals with diabetes mellitus (DM). Compared with normoglycemic and optimal blood pressure (BP) subjects, increased risks of CVD were observed in the normoglycemic subjects with high-normal BP or hypertension, the IFG subjects with normal or higher BP, and the DM subjects regardless of BP category (P-value for interaction=0.046). In conclusion, the high-normal BP subjects in all glucose categories and the normal BP subjects with IFG showed increased risk of CVD in this Japanese population. Further investigation of larger cohorts of DM subjects should be conducted to better understand this phenomenon. PMID- 20927113 TI - Mean and yearly changes in blood pressure with age in the metabolic syndrome: the DESIR study. AB - Systolic and diastolic blood pressure (SBP; DBP) increase with age, but after 45 years of age, the yearly change in DBP (DeltaDBP) tends to be smaller in comparison with the yearly change in SBP (DeltaSBP), which increases with age. The effect of the metabolic syndrome (MetS) on this yearly change has never been explored. In a 9-year longitudinal cohort Data from an Epidemiologic Study on the Insulin Resistance syndrome (DESIR) study, we examined 1308 men and 1325 women, aged 30-65 years, who had never been treated for hypertension. SBP and DBP were measured at four examinations 3 years apart, and pulse pressure (PP) and yearly changes (DeltaSBP, DeltaDBP and DeltaPP) were calculated. SBP and PP increased with age to a higher degree in patients with the MetS. In men and women with the MetS, DBP remained nearly constant, but in those without the MetS, DBP increased. After adjusting for baseline values, DeltaSBP and DeltaPP increased by 0.5 mm Hg per year for every additional 10 years from baseline. These correlations with age were similar for men and women, and the yearly change was always higher than in those with the MetS. In contrast, DeltaDBP increased very slowly until 50 years of age and then decreased similarly for those with and without the MetS. The increase in PP with age, a marker of vascular aging, was determined to begin earlier in the present study than has been shown in the past, and the MetS amplified this effect. This new aspect of the MetS might modify clinical management leading to earlier drug treatment, particularly in regard to both endothelial dysfunction and increased arterial stiffness. PMID- 20927114 TI - Microangiopathy and visual deficits characterize the retinopathy of a spontaneously hypertensive rat model with type 2 diabetes and metabolic syndrome. AB - Retinopathy has been increasing in prevalence as a consequence of type 2 diabetes and a cluster of coexisting risk factors characterized as the metabolic syndrome. However, the combined effects of these conditions on the retina are poorly understood. Therefore, we focused on the spontaneously hypertensive corpulent rat (SHR/N-cp), a model with type 2 diabetes, obesity and features of the metabolic syndrome to characterize retinal changes at a structural and functional level. SHR/N-cp males at 4 and 8 months of age were used in this study. Metabolic parameters and blood pressure were measured by standard methods. Morphology was investigated by histological techniques supplemented by nicotinamide adenine dinucleotide phosphate-diaphorase staining of whole mounts and fluorescein angiography to analyze the retinal vasculature. The in vivo function of the retina was examined by electroretinography (ERG). Obese SHR/N-cp rats were hypertensive and showed significant increases in body weight, serum levels of glucose, triglycerides, total cholesterol and urinary glucose excretion compared with lean controls (P < 0.01 for each). Histology indicated an overall intact integrity of the retina and aspects of microangiopathy in obese SHR/N-cp rats. ERG revealed intact processing of light signals but significantly decreased amplitudes of b-waves for all (P < 0.01) and of a-waves for some examined light intensities (P < 0.05). Oscillatory potentials were significantly protracted (P < 0.01), whereas amplitudes were not reduced. Microangiopathy and electroretinographic deficits combine to produce an early non-proliferative retinopathy phenotype in the obese SHR/N-cp rats. Thus, this model represents a valuable experimental tool to obtain further insights into the mechanisms of retinopathy in the context of obesity, type 2 diabetes and metabolic syndrome. PMID- 20927112 TI - Effects of valsartan and amlodipine on cardiorenal protection in Japanese hypertensive patients: the Valsartan Amlodipine Randomized Trial. AB - The Valsartan Amlodipine Randomized Trial, a multicenter, prospective, randomized, open-labeled, blinded-end point trial, was designed to compare the beneficial effects of the angiotensin II receptor blocker valsartan and the calcium channel blocker amlodipine on cardiovascular events in Japanese essential hypertensive patients. The primary end point was a composite of all-cause death, sudden death, cerebrovascular death, cardiac events, vascular events and renal events. The secondary endpoints were effects on left ventricular hypertrophy, cardiac sympathetic nerve activity and renal function. A total of 1021 patients were enrolled in the present trial. The mean follow-up period was 3.4 years. There were no significant differences in blood pressure (BP) levels between the valsartan group and the amlodipine group throughout the trial. There was no significant difference in the primary endpoint between the two groups (hazard ratio: 1.0, P = 0.843). No difference in any event category of the primary endpoint was noted for either group. However, we observed a significant reduction of left ventricular mass index, as determined by echocardiography, in the valsartan group compared with the amlodipine group. We also observed a significant decrease in cardiac sympathetic nerve activity in the valsartan group but not in the amlodipine group. Moreover, there was a significant reduction in the urinary albumin to creatinine ratio in the valsartan group but not in the amlodipine group. Therefore, although BP levels were well controlled and remained equal in the two groups, valsartan had more protective effects on the heart and kidney than amlodipine in Japanese hypertensive patients. PMID- 20927116 TI - Prevalence of primary aldosteronism among prehypertensive and stage 1 hypertensive subjects. AB - Recent studies have reported a high prevalence of primary aldosteronism among patients with severe hypertension. However, the prevalence of this disease among normotensive and mildly hypertensive patients has not been determined. The aim of this study was to examine the prevalence of primary aldosteronism among prehypertensive and stage 1 hypertensive subjects. A total of 292 adult subjects with hypertension or prehypertension was screened for primary aldosteronism. Subjects with a plasma aldosterone concentration (ng per 100 ml) to plasma renin activity (ng ml(-1) h(-1)) ratio (ARR) above 20 underwent confirmatory captopril suppression testing. A total of 54 subjects (18.5%) had an ARR above 20. A captopril suppression test was performed in 17 of 54 subjects with probable primary aldosteronism. The test confirmed the diagnosis of primary aldosteronism in 11 (64.7%) of 17 patients, giving a least prevalence of 3.8% for this disease. The 11 patients with primary aldosteronism had a mean +/- s.d. systolic blood pressure of 139 +/- 4 mm Hg, diastolic blood pressure of 95 +/- 10 mm Hg and serum potassium of 4.46 +/- 0.48 mEq l(-1) at the time of screening test. The prevalence of primary aldosteronism as could be assessed in this study was at least 6.8% in prehypertensive patients, 3.3% in stage 1 hypertensive patients and 3.1% in stage 2 hypertensive patients. In conclusion, this study suggests a high prevalence of primary aldosteronism among prehypertensive and stage 1 hypertensive Japanese patients. Significant numbers of prehypertensive individuals may have subclinical forms of this disease. PMID- 20927115 TI - The therapeutic importance of home blood pressure assessment and combination antihypertensive therapy for achieving target blood pressure control: Ibaraki hypertension assessment trial. AB - Tight blood pressure (BP) control is important for the prevention of cardiovascular disease in hypertensive patients. A cross-sectional study of 2339 patients from 101 clinics and hospitals in Ibaraki Prefecture was performed to evaluate BP control with the patients' current antihypertensive medication. Group A (n=892) included high-risk hypertensive patients with at least one of the following risk factors: diabetes mellitus, chronic kidney disease or a history of myocardial infarction. Group B (n=586) included patients <65 years old and Group C (n=859) included patients >=65 years old. Both groups B and C included hypertensive patients without the above risk factors. A mean of 1.8+/-1.0 antihypertensive drugs per patient were prescribed. A total of 35.8% of all patients received monotherapy, 40% received a combination of three therapies and 20.3% received more than three kinds of drugs. The percentage of patients achieving the target BP at the office and at home was significantly higher in Group C than in the other groups (P<0.001). A combination of more than two antihypertensive drugs, including a high dose of either an angiotensin receptor blocker or a calcium channel blocker, was frequently prescribed to Group A to achieve the target office BP. Although the target BP should be lower in Group A (given their comorbidities), the absolute BP value and the number of medications were similar to the other groups. In conclusion, we demonstrated that physicians should treat hypertension more intensively with a combination of more than two antihypertensive drugs, using a high dose to achieve the target BP. In addition, it is important to teach hypertensive patients the clinical importance of monitoring their BP at home and the need to achieve home BP targets. PMID- 20927117 TI - Role of the nitric oxide metabolic pathway and prostanoids in the pathogenesis of endothelial dysfunction and essential hypertension in young men. AB - The aim of this study was to explore the role of selected prostanoids and the nitric oxide (NO) metabolic pathway in the pathogenesis of endothelial dysfunction (ED) in young men with and without essential hypertension (HTN). A total of 70 men aged 18-40 years old (23 hypertensive and 47 normotensive) were investigated. Initial metabolite concentrations of the NO pathway (asymmetric dimethylarginine, L-arginine and symmetric dimethylarginine), selected cardiovascular risk markers (serum lipids, creatinine, glucose and high sensitivity C-reactive protein), oxidative stress markers (malonylodialdehyde, thiol index and nitrotyrosine) and prostanoids (thromboxane B2 (TxB(2)) and 6 keto-prostaglandin F (PGF)-1-alpha) were measured. Ultrasound assessment of endothelial function (flow-mediated vasodilation (FMD)) of the brachial artery was studied before and after intravenous infusion of L-arginine (16.0 g). All measurements were repeated after oral administration of indomethacin (75 mg per day) for 2 days. The prevalence of ED was similar in both hypertensive and normotensive groups. A lower baseline plasma level of 6-keto-PGF-1-alpha and a higher baseline of TxB(2) were observed in the hypertensive group. A different response to indomethacin assessed by prostanoid levels was observed and was dependent on the presence of HTN. No significant differences in metabolites of the NO pathway were observed at either baseline or following indomethacin treatment. In hypertensive patients, L-arginine and indomethacin had a synergistic positive effect on FMD. ED in young normotensive men primarily depends on NO deficiency. In young hypertensive men, disorders in prostanoid metabolism have important roles in decreasing NO bioavailability. The high prevalence of ED in potentially healthy subjects suggests that the ultrasound FMD measurement is an important tool in the stratification of cardiovascular risk. PMID- 20927118 TI - Blood pressure overshoot after tilt reversal in patients with familial amyloidotic polyneuropathy. AB - The pathophysiology of the hemodynamic responses to postural stress in familial amyloidotic polyneuropathy (FAP) remains to be elucidated. The aim of the study was to evaluate hemodynamic responses after tilt reversal in FAP. Systolic blood pressure (BP) and heart rate variability (HRV) were analyzed in the baseline, 70 degrees upright position, and after tilt reversal in 15 FAP patients and 14 healthy controls. Beat-to-beat BP was recorded with a Finapres device. Maximum systolic BP after tilt reversal was increased with 22 +/- 13 mm Hg in FAP patients as compared with baseline (BP overshoot), whereas controls showed a significantly lower BP overshoot (8 +/- 6 mm Hg, P < 0.001). In all states, total spectral power and the power of the low and high frequency components were all significantly lower than those of the controls (P < 0.01). In a linear regression analysis adjusted for age, we found a significant inverse relation between BP overshoot and HRV (total spectral power, power of the low-frequency and high frequency components) in all three states (standardized beta between -0.74 to 0.53, P < 0.01). Five FAP patients presented a trial arrhythmia precluding HRV analysis: four of those presented BP overshoots >= 12 mm Hg. BP overshoot may be a marker to assess the progression of cardiac autonomic dysfunction, especially as heart arrhythmia in many FAP patients prevent HRV analysis. In addition, assessment of the post-tilt BP reaction points to possible treatment modalities for orthostatic hypotension at least in the early stages of the disease. PMID- 20927119 TI - Immunology and cell biology publication of the year award 2009. PMID- 20927120 TI - Variations in/nearby genes coding for JAZF1, TSPAN8/LGR5 and HHEX-IDE and risk of type 2 diabetes in Han Chinese. AB - Several genetic loci (JAZF1, CDC123/CAMK1D, TSPAN8/LGR5, ADAMTS9, VEGFA and HHEX IDE) were identified to be significantly related to the risk of type 2 diabetes and quantitative metabolic traits in European populations. Here, we aimed to evaluate the impacts of these novel loci on type 2 diabetes risk in a population based case-control study of Han Chinese (1912 cases and 2041 controls). We genotyped 13 single-nucleotide polymorphisms (SNPs) in/near these genes and examined the differences in allele/genotype frequency between cases and controls. We found that both IDE rs11187007 and HHEX rs1111875 were associated with type 2 diabetes risk (for both variants: odds ratio (OR)=1.15, 95% confidence interval (CI) 1.04-1.28, P=0.009). In a meta-analysis where we pooled our data with the three previous studies conducted in East Asians, we found that the variants of JAZF1 rs864745 (1.09 (1.03-1.16); P=3.49 * 10(-3)) and TSPAN8/LGR5 rs7961581 (1.11(1.05-1.17); P=1.89 * 10(-4)) were significantly associated with type 2 diabetes risk. In addition, the meta-analysis (7207 cases and 8260 controls) also showed that HHEX rs1111875 did have effects on type 2 diabetes in Chinese population (OR=1.15(1.10-1.21); P=1.93 * 10(-8)). This large population-based study and meta-analysis further confirmed the modest effects of the JAZF1, TSPAN8/LGR5 and HHEX-IDE loci on type 2 diabetes in Chinese and other East Asians. PMID- 20927121 TI - Familiar Meniere's disease restricted to 1.48 Mb on chromosome 12p12.3 by allelic and haplotype association. AB - Meniere's disease (MD) is a disorder of the inner ear characterized by episodes of vertigo, tinnitus and fluctuating sensorineural hearing loss. Most MD cases are sporadic, but 5-15% of patients are familial following an autosomal dominant mode of inheritance with incomplete penetrance. We have previously identified a candidate gene region for MD on chromosome 12p12.3 using linkage analysis. We genotyped 15 Swedish families segregating familial MD (FMD) to further clarify the role of chromosome 12p in a larger cohort of families. Highly polymorphic marker loci were analyzed over the 16-Mb candidate region in affected and healthy family members as well as in control subjects. The results revealed allelic association between FMD and several individual polymorphic marker alleles and single-nucleotide polymorphisms. Moreover, a common three-marker haplotype spanning 1.48 Mb co-segregates with FMD in 60% of the families investigated, forming the core of a possible ancestral haplotype associated with FMD in Sweden. PMID- 20927122 TI - Prevalence of male sexual dysfunction among Ghanaian populace: myth or reality? AB - This study was designed to investigate the prevalence and type of sexual dysfunction (SD) in healthy sexually active Ghanaian men of fertile age. Sexual functioning was determined in 300 healthy Ghanaian men with the Golombok Rust Inventory of Sexual Satisfaction (GRISS) questionnaire leaving in Kumasi metropolis, between December 2009 and April 2010. All men had a steady heterosexual relationship for at least 2 years before enrollment in the study. Of the 300 men selected, 255 (85%) completed the survey; the overall prevalence of SD in these subjects was 66%. The most prevalent areas of difficulty were infrequency (70.2%), premature ejaculation (64.7%), dissatisfaction with sexual acts (61.2%), impotency (59.6%), nonsensuality (59.2%), noncommunication (56.9%) and avoidance (49.0%). There were positive correlation between SD, impotence, dissatisfaction and age. The prevalence rate of SD in Ghanaian men is high and related to age. PMID- 20927123 TI - TAT-mediated delivery of a DNA repair enzyme to skin cells rapidly initiates repair of UV-induced DNA damage. AB - UV light causes DNA damage in skin cells, leading to more than one million cases of non-melanoma skin cancer diagnosed annually in the United States. Although human cells possess a mechanism (nucleotide excision repair) to repair UV-induced DNA damage, mutagenesis still occurs when DNA is replicated before repair of these photoproducts. Although human cells have all the enzymes necessary to complete an alternate repair pathway, base excision repair (BER), they lack a DNA glycosylase that can initiate BER of dipyrimidine photoproducts. Certain prokaryotes and viruses produce pyrimidine dimer-specific DNA glycosylases (pdgs) that initiate BER of cyclobutane pyrimidine dimers (CPDs), the predominant UV induced lesions. Such a pdg was identified in the Chlorella virus PBCV-1 and termed Cv-pdg. The Cv-pdg protein was engineered to contain a nuclear localization sequence (NLS) and a membrane permeabilization peptide (transcriptional transactivator, TAT). Here, we demonstrate that the Cv-pdg-NLS TAT protein was delivered to repair-proficient keratinocytes and fibroblasts, and to a human skin model, where it rapidly initiated removal of CPDs. These data suggest a potential strategy for prevention of human skin cancer. PMID- 20927125 TI - Exploring the "hair growth-wound healing connection": anagen phase promotes wound re-epithelialization. AB - When the skin is damaged, a variety of cell types must migrate, proliferate, and differentiate to reform a functional barrier to the external environment. Recent studies have shown that progenitor cells residing in hair follicles (HFs) are able to contribute to this re-epithelialization of wounds in vivo. However, the influence of the hair cycle on wound healing has not previously been addressed. Here, we have exploited spontaneous postnatal hair-cycle synchronicity in mice to systematically examine the influence of the different hair-cycle stages on murine skin wound healing. We report significant acceleration of healing during the anagen phase of HF cycling in vivo, associated with alterations in epithelial, endothelial, and inflammatory cell types. Intriguingly, gene profiling data reveal a clear correlation between the transcription of genes beneficial for wound healing and those upregulated during the anagen phase of the hair cycle in unwounded skin. These findings, which demonstrate a previously unappreciated association between HF cycling and wound healing, reveal numerous molecular correlates for further investigation. PMID- 20927124 TI - Propionibacterium acnes activates the IGF-1/IGF-1R system in the epidermis and induces keratinocyte proliferation. AB - Propionibacterium acnes has a major role in the development of acne lesions. IGF 1 stimulates the proliferation of keratinocytes via an activation of the IGF-1 receptor (IGF-1R). Zinc has been proven to work efficiently against inflammatory acne and to modulate the IGF-1 system. Our objectives were to study the modulation of IGF-1 and IGF-1R expression by P. acnes extracts and to determine their modulation by zinc gluconate. In vivo, we analyzed biopsies of acne lesions and healthy skin, and in vitro we used skin explants incubated with two P. acnes extracts--membrane fraction (MF) and cytosolic proteins--with or without zinc. IGF-1 and IGF-1R expression was evaluated using immunohistochemistry, and the IGF 1 production in supernatants was measured by ELISA. Then, IGF-1 and IGF-1R mRNA levels were analyzed using quantitative PCR on normal human epidermal keratinocytes (NHEKs). IGF-1 and IGF-1R were overexpressed in acne lesions. MF increased IGF-1 and IGF-1R expression in the epidermis of explants and was associated with an overexpression of both Ki-67 and filaggrin. Zinc had the effect of downregulating IGF-1 and IGF-1R levels. These observations were confirmed at the mRNA level for IGF-1R in NHEKs. These results demonstrate that P. acnes can induce the formation of comedones by stimulating the IGF/IGF-1R system. Moreover, zinc downregulates this pathway. PMID- 20927126 TI - Polymorphisms in IL10 are associated with total Immunoglobulin E levels and Schistosoma mansoni infection intensity in a Brazilian population. AB - Interleukin (IL)-10 is a regulatory cytokine of the helper T cell type 2 (TH2) pathway, which underlies both the host defense to helminthic infection and atopic diseases, including asthma. Although IL10 promoter polymorphisms are associated with increased atopy risk, IL10 variation has not been thoroughly explored in schistosomiasis-endemic populations. Three atopy-related IL10 promoter polymorphisms (rs1800896, rs1800871 and rs1800872), complemented by six tagging single-nucleotide polymorphisms (SNPs), were genotyped in 812 individuals in 318 nuclear families from a schistosomiasis-endemic area in Brazil. Associations between markers and total serum Immunoglobulin E (tIgE) levels, indicating non specific activation of the TH2 pathway, and Schistosoma mansoni fecal egg counts, indicating burden of infection reflecting effectiveness of schistosomiasis host immunity, were performed using family-based transmission disequilibrium tests for quantitative traits (QTDTs). Alleles A, T and A at the three promoter SNPs rs1800896, rs1800871 and rs1800872 were associated with high tIgE levels in the same direction as in atopy populations (P=0.0008, 0.026 and 0.045), but not with egg counts. IL10 promoter polymorphisms appear to influence non-specific tIgE levels, but not schistosomiasis-specific immunity. The tagging SNP rs3024495 was associated with high S. mansoni egg counts (P=0.005), suggesting a novel locus in IL10 may influence clinically relevant burden of infection. PMID- 20927127 TI - PTX3 genetic variations affect the risk of Pseudomonas aeruginosa airway colonization in cystic fibrosis patients. AB - Cystic fibrosis (CF) is a common life-threatening autosomal recessive disorder in the Caucasian population, and the gene responsible is the CF transmembrane conductance regulator (CFTR). Patients with CF have repeated bacterial infection of the airways caused by Pseudomonas aeruginosa (PA), which is one of the predominant pathogen, and endobronchial chronic infection represents a major cause of morbidity and mortality. Pentraxin 3 (PTX3) is a gene that encodes the antimicrobial protein, PTX3, which is believed to have an important role in innate immunity of lung. To address the role of PTX3 in the risk of PA lung colonization, we investigated five single nucleotide polymorphisms of PTX3 gene in 172 Caucasian CF patients who were homozygous for the F508del mutation. We observed that PTX3 haplotype frequencies were significantly different between patients with PA colonization, as compared with noncolonized patients. Moreover, a protective effect was found in association with a specific haplotype (odds ratio 0.524). Our data suggest that variations within PTX3 affect lung colonization of Pseudomonas in patients with CF. PMID- 20927128 TI - Characteristics of resistant hypertension: ageing, body mass index, hyperaldosteronism, cardiac hypertrophy and vascular stiffness. AB - Resistant hypertension (RHTN) includes patients whose blood pressure (BP) is controlled with the use of four or more antihypertensive medications, and is referred to as 'controlled resistant hypertension' (CRH). While specifically comparing patients with CRH and uncontrolled resistant hypertension (UCRH), we hoped to identify distinguishing characteristics that would provide insight into factors contributing to resistance to antihypertensive therapies. RHTN patients were identified as controlled (CRH, n=43) or uncontrolled (UCRH, n=47). No statistical differences were observed between the CRH and UCRH subgroups with respect to age and gender. The body mass index, aldosterone-renin ratio and pulse wave velocity (PWV) were significantly higher in UCRH patients. Although both subgroups showed increased cardiac mass, left ventricular mass index was significantly higher in UCRH compared with CRH patients. Multivariate linear regression analysis indicated that PWV was significantly dependent on age in both UCRH and CRH patients; however, the influence of ageing was more pronounced in the former subgroup. Older age, greater vascular stiffness, higher aldosterone levels and greater left ventricular hypertrophy were significantly associated with lack of BP control in patients with RHTN. These findings suggest important possibilities in terms of preventing and better treating RHTN. PMID- 20927129 TI - Further study of chromosome 7p22 to identify the molecular basis of familial hyperaldosteronism type II. AB - Familial hyperaldosteronism type II (FH-II) is an inherited form of hyperaldosteronism associated with hypertension in most patients. The mutations that cause FH-II are unknown, but linkage analysis has mapped them to chromosome 7p22. As FH-II is clinically indistinguishable from sporadic primary aldosteronism, a common and treatable condition, unravelling the cause of FH-II has important implications for these sporadic cases. To investigate whether FH-II is caused by large deletions or insertions, we examined the virtual karyotype of four pairs of affected and unaffected individuals using high-density bead chips. We also sequenced the coding regions of five 7p22 candidate genes that were prioritized because of their putative role in cell growth. We found no evidence of single-nucleotide polymorphism (SNP) copy number variation between pairs, and from the widest gap on the chip, chromosome 7p22 deletions or insertions exceeding ~50 kb in these pedigrees can be excluded. We found 15 SNPs (two of which were novel), but none of them were non-synonymous and segregated with the disease in the FH-II pedigrees. We have been able to exclude large genomic deletions or insertions at 7p22 and refine the candidate gene list for this locus, but the mutations causing FH-II remain elusive. PMID- 20927131 TI - A DEAB-sensitive aldehyde dehydrogenase regulates hematopoietic stem and progenitor cells development during primitive hematopoiesis in zebrafish embryos. AB - Although aldehyde dehydrogenase (ALDH) activity has become a surrogate of hematopoietic stem and progenitor cells (HSPCs), its function during hematopoiesis was unclear. Here, we examined its role in zebrafish hematopoiesis based on pharmacological inhibition and morpholino (MO) knockdown. Zebrafish embryos were treated with diethylaminobenzaldehyde (DEAB, 1 MUmol/l) between 0- and 48 hour-post-fertilization (hpf). MOs targeting aldhs were injected between 1 and 4-cell stage. The effects on hematopoiesis were evaluated at different stages. DEAB treatment between 0 and 18 hpf increased gene expression associated with HSPC (scl, lmo2), erythropoiesis (gata1, alpha- and beta-eHb) and myelopoiesis (spi1) as well as gfp(+) cells in dissociated Tg(gata1:gfp) embryos. The effects were ameliorated by all-trans retinoic acid (1 nmol/l). Definitive hematopoiesis and the erythromyeloid precursors were unaffected. In all, 14 out of 15 zebrafish aldhs were detectable by reverse transcription PCR in 18 hpf embryos, of which only aldh1a2 and aldh16a1 were expressed in sites pertinent to hematopoiesis. Molecular targeting by MOs was demonstrated for 15 aldhs, but none of them, even in combined aldh1a2 and aldh1a3 knockdown, recapitulated the hematopoietic expansion in DEAB-treated embryos. In conclusion, DEAB expands HSPC population during primitive hematopoiesis through inhibition of aldh and retinoic acid synthesis. The specific aldh isoform(s) remains to be determined. PMID- 20927132 TI - HMGB1-induced autophagy promotes chemotherapy resistance in leukemia cells. AB - Autophagy, a tightly regulated lysosome-dependent catabolic pathway, is important in the regulation of cancer development and progression and in determining the response of tumor cells to anticancer therapy. However, the role of autophagy in leukemia still remains largely unknown. Here we show that high-mobility group box 1 (HMGB1), the best characterized damage-associated molecular pattern, was released from leukemia cell lines after chemotherapy-induced cytotoxicity and activated autophagy to protect against injury. Treatment with HMGB1-neutralizing antibodies increased the sensitivity of leukemia cells to chemotherapy; whereas, exogenous HMGB1 rendered these cells more resistant to drug-induced cytotoxicity. Moreover, exogenous HMGB1 increased autophagy as evaluated by increased expression of the autophagic marker microtubule-associated protein light chain 3 II, degradation of sequestosome 1 (p62) and autophagosome formation. Furthermore, knockdown or pharmacological inhibition of either phosphoinositide 3-kinase-III or extracellular signal-regulated kinase kinase mitogen-activated protein kinase kinase/extracellular signal-regulated protein kinase inhibited HMGB1-induced autophagy. Taken together, these results suggest that HMGB1 release after chemotherapy is a critical regulator of autophagy and a potential drug target for therapeutic interventions in leukemia. PMID- 20927133 TI - Reduced methyl-CpG protein binding contributing to miR-184 expression in umbilical cord blood CD4+ T-cells. PMID- 20927134 TI - CEBPA methylation as a prognostic biomarker in patients with de novo acute myeloid leukemia. AB - Hypermethylation of the distal CEBPA promoter region has been reported to result in the downregulation of CEBPA expression in several malignancies. However, the clinical implication of CEBPA hypermethylation in acute myeloid leukemia (AML) remains unclear. To investigate the correlation between CEBPA hypermethylation and clinical features in AML, quantitative MassARRAY analyses for CEBPA methylation status were performed on a cohort of 193 patients. High CEBPA methylation group (CEBPA(high-meth), n=28) and low methylation group (CEBPA(low meth), n=165) were defined by using two-way hierarchical clustering. With a median follow-up of 48 months, among the 125 patients receiving standard induction therapy, CEBPA(high-meth) was associated with better treatment response (complete remission rate 93.3% versus 73.6%, P=0.116). In patients with normal karyotype and without CEBPA and NPM1 mutations, the CEBPA(high-meth) had longer overall survival (OS) than the CEBPA(low-meth) (P=0.028). Multivariate analysis further supported that the CEBPA methylation was an independent prognostic factor for disease free-survival (hazard ratio=0.416; 95% confidence interval, 0.223 0.777, P=0.006) and OS (hazard ratio=0.406; 95% confidence interval, 0.166-0.996, P=0.050). We conclude that CEBPA methylation status is a useful prognostic biomarker for AML patients. PMID- 20927135 TI - Sendai virus vectors. Pushing the envelope in the lung. PMID- 20927136 TI - Skeletal muscle cells: from local inflammatory response to active immunity. AB - The skeletal muscles are the major living component of the human body. They are constituted by stable cells, the myofibres, and by adult multipotent stem cells, the satellite cells, which can multiply to regenerate and repair the damaged tissues. Injections of DNA in muscle cells have been used to produce recombinant proteins with opposite goals: somatic reparation of genetic defects, which needs to elicit no inflammatory or immune response, and DNA vaccination, which needs a robust immune response. Because of possible therapeutical interventions, a growing body of information is being produced dealing with every aspect of the myofibres during inflammatory and autoimmune responses: skeletal muscle-antigen presenting cell (APC) interaction and intrinsic APC capabilities of myoblasts and myocytes, the response to released cytokines and their endogenous production, the regulation of Toll-like receptors and major histocompatibility complex expression. According to these data, the muscle tissue is now emerging no longer as a passive bystander, but more as an active player that, when correctly manipulated, can drive tolerance or immunization to these de novo produced proteins. In the present review, we summarize the recent developments on the control of muscle immune function. PMID- 20927137 TI - Supervised classification of microbiota mitigates mislabeling errors. PMID- 20927138 TI - Comparative metagenomics of microbial communities inhabiting deep-sea hydrothermal vent chimneys with contrasting chemistries. AB - Deep-sea hydrothermal vent chimneys harbor a high diversity of largely unknown microorganisms. Although the phylogenetic diversity of these microorganisms has been described previously, the adaptation and metabolic potential of the microbial communities is only beginning to be revealed. A pyrosequencing approach was used to directly obtain sequences from a fosmid library constructed from a black smoker chimney 4143-1 in the Mothra hydrothermal vent field at the Juan de Fuca Ridge. A total of 308,034 reads with an average sequence length of 227 bp were generated. Comparative genomic analyses of metagenomes from a variety of environments by two-way clustering of samples and functional gene categories demonstrated that the 4143-1 metagenome clustered most closely with that from a carbonate chimney from Lost City. Both are highly enriched in genes for mismatch repair and homologous recombination, suggesting that the microbial communities have evolved extensive DNA repair systems to cope with the extreme conditions that have potential deleterious effects on the genomes. As previously reported for the Lost City microbiome, the metagenome of chimney 4143-1 exhibited a high proportion of transposases, implying that horizontal gene transfer may be a common occurrence in the deep-sea vent chimney biosphere. In addition, genes for chemotaxis and flagellar assembly were highly enriched in the chimney metagenomes, reflecting the adaptation of the organisms to the highly dynamic conditions present within the chimney walls. Reconstruction of the metabolic pathways revealed that the microbial community in the wall of chimney 4143-1 was mainly fueled by sulfur oxidation, putatively coupled to nitrate reduction to perform inorganic carbon fixation through the Calvin-Benson-Bassham cycle. On the basis of the genomic organization of the key genes of the carbon fixation and sulfur oxidation pathways contained in the large genomic fragments, both obligate and facultative autotrophs appear to be present and contribute to biomass production. PMID- 20927139 TI - Structure of the human gastric bacterial community in relation to Helicobacter pylori status. AB - The human stomach is naturally colonized by Helicobacter pylori, which, when present, dominates the gastric bacterial community. In this study, we aimed to characterize the structure of the bacterial community in the stomach of patients of differing H. pylori status. We used a high-density 16S rRNA gene microarray (PhyloChip, Affymetrix, Inc.) to hybridize 16S rRNA gene amplicons from gastric biopsy DNA of 10 rural Amerindian patients from Amazonas, Venezuela, and of two immigrants to the United States (from South Asia and Africa, respectively). H. pylori status was determined by PCR amplification of H. pylori glmM from gastric biopsy samples. Of the 12 patients, 8 (6 of the 10 Amerindians and the 2 non Amerindians) were H. pylori glmM positive. Regardless of H. pylori status, the PhyloChip detected Helicobacteriaceae DNA in all patients, although with lower relative abundance in patients who were glmM negative. The G2-chip taxonomy analysis of PhyloChip data indicated the presence of 44 bacterial phyla (of which 16 are unclassified by the Taxonomic Outline of the Bacteria and Archaea taxonomy) in a highly uneven community dominated by only four phyla: Proteobacteria, Firmicutes, Actinobacteria and Bacteroidetes. Positive H. pylori status was associated with increased relative abundance of non-Helicobacter bacteria from the Proteobacteria, Spirochetes and Acidobacteria, and with decreased abundance of Actinobacteria, Bacteroidetes and Firmicutes. The PhyloChip detected richness of low abundance phyla, and showed marked differences in the structure of the gastric bacterial community according to H. pylori status. PMID- 20927140 TI - [Minimally invasive posterior approach in total hip arthroplasty. Prospective randomised trial]. AB - BACKGROUND: Our working hypothesis was that minimally invasive surgery was superior to conventional surgery for total hip arthroplasty procedure. We compared THR results in the minimally invasive posterior approach with THR results in the conventional posterior approach. METHODS: Prospective, randomised trial. Fifty patients were selected and then divided into two groups based on treatment (minimally invasive posterior approach or conventional posterior approach). DATA COLLECTED: Perioperative bleeding, postoperative pain, time of recovery, component orientation, complications and functional results. One year follow-up. RESULTS: No differences were found in blood loss, surgical time, component orientation, rate of complications or functional result. The minimally invasive lateral approach produced less postoperative pain and a faster recovery, with a shorter hospital stay and earlier walking-start, and a positive economic impact with 5% of the total process cost saved. CONCLUSIONS: Minimally invasive surgery permits less postoperative pain, faster recovery and a positive economic saving, without differences in the rest of the items studied. PMID- 20927141 TI - [Nephritic colic management in an emergency room of a referral hospital]. AB - BACKGROUND: To evaluate the diagnostic and therapeutic management of patients with nephritic colic in a referral hospital, their monitoring and the incidence of alternative diagnoses. METHODS: This is a retrospective review of 182 randomly selected patients who presented a clinical diagnosis compatible with nephritic colic in a referral hospital. In these cases initial treatment, monitoring and alternative diagnoses have been evaluated. RESULTS: Fifty-five point four percent of the patients were male, the mean age was 47.7 years and 40% of the cases were in spring. Urinalysis was carried out in every patient (62.7% dipstick and 72% urinary sediment); they were pathological in over 70%. In 26.4% of cases renal function deteriorated, always transiently. Abdominal radiography (81.9%) was the most frequently diagnostic test performed, followed by ultrasound (25.8%). Treatment included a serum therapy in 31.3%; metamizol (61%) was the most commonly used analgesic followed by ketorolac (44.5%). More than one non steroidal anti-inflammatory was used by 46.2%. Hospital admission was required by 24 patients, and 5 of them needed emergency surgery. Twenty-four point one percent of patients had relapses during the next six months. Forty-one point six percent were referred to urology discharge on from the emergency room. Eighteen point one percent of patients had alternative diagnoses; acute pyelonephritis was the most frequent of these (55%). CONCLUSIONS: In our work we found a significant variation in the diagnostic and therapeutic management of these patients. The use of clinical guidelines could help us to unify the management of patients with nephritic colic, both in the emergency room and on discharge. Due to the high prevalence of alternative diagnoses, we have to systematically exclude more serious diseases. PMID- 20927142 TI - [Body composition and energy metabolism in women with excess body weight]. AB - BACKGROUND: The objective of this paper is to evaluate body composition and energy expenditure in women with excess body weight. METHODS: There was a non randomized, cross-sectional study with 40 women, [26 with excess weight (G1) and 14 eutrophic (G2)]. The following evaluations were made: dietetic, anthropometric and body composition (electrical bioimpedance), physical activity (three dimensional accelerometer) and energy expenditure, basal and resting (indirect calorimetry). RESULTS: The energy intake and physical activity did not differ between groups. The parameters of body composition were higher in G1, except total body water. There was a relationship between energy expenditure and body composition. The lean mass was the biggest determinant of energy expenditure. There was no difference in metabolic parameters between groups, but lower nutrient oxidation and increased metabolic efficiency in G1 was suggested. CONCLUSION: Excess weight was associated with body composition and energy expenditure changes that justify the accumulation of body fat. PMID- 20927143 TI - [Analysis of weekly mortality as a tool for the early detection of alerts in public health]. AB - BACKGROUND: There is a growing interest in public health in monitoring indicators in real time that permit immediate action to be taken. The aim of this study is to evaluate the utility of the analysis of weekly mortality for the early detection of alerts in public health. METHODS: We analysed the early reception of mortality (ERM) from five computerised civil registers in Navarre and gathered 70% of total mortality (TM) for the 2003-2007 period. We identified the weeks when mortality exceeded the threshold calculated on the basis of the five previous years. We analysed the correspondence of these excesses in mortality with flu levels of incidence and with high atmospheric temperatures. RESULTS: The was moderate concordance between the alerts detected from the information proceeding from the ERM and TM sources (Kappa index 0.59; CI 95% 0.42-0.76). Both sources behaved analogously in the detection of excesses of mortality when these occurred in weeks of severe flu, with 13 and 12 alerts respectively. In relation to high temperatures, TM only generated alerts in the years when heat waves were declared, while ERM also generated them in other weeks which were hot but did not reach the heat wave threshold. CONCLUSION: The early availability of results, the acceptable concordance between sources and the high percentage of excesses of mortality attributable to identified public health problems, show the potential utility of monitoring weekly mortality in epidemiological surveillance. PMID- 20927144 TI - [Care for immigrant patients: facts and professionals' perception in 6 primary health care zones in Navarre]. AB - BACKGROUND: To describe utilisation of health care services and motives for consultation in Primary Care in the native and the immigrant population, and compare this with the perception of primary care professionals. METHODS: Data was collected on health care activity during the year 2006 for all people registered (N=86,966) in the 6 basic health care zones with the highest proportion of immigrants (14.4%) and on the following variables: country of origin, age, sex, year of inscription in the public health service. The health card and OMI-AP programme databases were used. A qualitative methodology of focus groups and in depth interviews was employed. RESULTS: Seventy-two point four percent of immigrants requested care from the primary care professionals in 2006, of whom 50% proceeded from Ecuador and 70% were between 25 and 44 years old. Eighty-two percent of the natives made consultations and required more referrals to specialised care than the immigrants of the same age group. The most frequent consultation with natives and with immigrants was "acute respiratory infections" (7 to 23% according to age group). The second most frequent with immigrants was "administrative problems". The consultations with immigrants were not related to preventive aspects such as smoking and there were more consultations (p>0.001) for gynaeco-obstetric episodes (10.7%) and those related to work (19%) or psychosomatic problems (8.5%). The perception of the primary care professionals was that the immigrants carry out more consultations than the natives and generate a certain "disorder" in the clinic. CONCLUSION: Immigrants use healthcare services less than the native population. Nonetheless, this fact is not perceived in this way by the primary care professionals. Fewer preventive activities are carried out with immigrants, who suffer from more labour and psychosomatic problems. PMID- 20927145 TI - [Narcolepsy: update on etiology, clinical features and treatment]. AB - Narcolepsy is a disease that involves an alteration in the generation and organisation of sleep. The main symptoms are excessive daytime sleepiness and cataplexy, followed by hypnagogic hallucinations, sleep paralysis and disrupted nocturnal sleep. The prevalence of typical narcolepsy oscillates between 25-50: 100.000 in general. Recently there has been a peak incidence in patients born in the month of March. According to the new classification, the Multiple Sleep Latency Test (MSLT) is mandatory for diagnosing narcolepsy without cataplexy, and advisable for diagnosing narcolepsy with cataplexy. Until now, the attempt has been made to control each symptom by its own specific treatment. At present, new American and European treatment guidelines propose new drugs that act on all the symptoms. The application of new criteria of diagnosis and treatment has improved the diagnosis, giving better options of treatment. PMID- 20927146 TI - [Family and chronic paediatric illness]. AB - Pediatric illnesses are always a family problem. Hospitalization, treatments and their long term consequences constitute a challenge for the family. In this paper, we describe the structural, procedural and emotional alterations that affect the family dynamic. We argue that the child should be treated within the family context and propose a multi-dimensional intervention model centered on the family's singularities and specific needs, the support available in their environment, the development of capacities and resilience, and also the organization of user-centered services that are coordinated with all the services provided by the community. PMID- 20927148 TI - [Humoral hypercalcemia in mixed endometrial carcinoma]. AB - Hypercalcemia secondary to neoplastic disease is a frequent entity caused in the majority of cases by ectopic secretions of PTHrP. Despite this there are certain tumours, such as uterine carcinomas, in which this type of paraneoplastic manifestation has been described very little. We present a case of humoral hypercalcemia in a mixed endometrial carcinoma. PMID- 20927147 TI - [Jaundice secondary to giant pancreatic serous cystoadenoma]. AB - Serous cystadenoma is the second most frequent pancreatic cystic neoplasm and accounts for 1-2% of exocrine neoplasms of the pancreas. Recently, they have been identified more frequently, due to the improvement in imaging techniques. Differential diagnosis should be performed with mucinous cystoadenoma, due to the latter's potential for malignant transformation. We present the case of a female patient who underwent examination for painless jaundice and cholestasis, with a final diagnosis of pancreatic serous cystoadenoma. PMID- 20927150 TI - [Loa Loa and Mansonella perstans coinfection in a patient from Guinea]. AB - We present a case of mixed infection by two filariae (Loa loa and Mansonella perstans). It seems that the infection was suspected due to a pronounced eosinophilia in a routine analysis. Sheathed and unsheathed microfilariae were observed in the spread of peripheral blood, which enabled a diagnosis to be established of mixed infection by filariae. The definitive diagnosis of the species was carried out at the National Centre of Microbiolgy of Majadahonda. A treatment was initiated with dietilcarbamazina and mebendazole which resulted in the patient's being cured and in the elimination of the microfilariae in the patient's blood. Filariasis is still endemic in many countries. Due to the increase of travellers to such zones and the migratory movements from such areas it is not unusual for us to come across such a diagnosis. The implantation of massive treatments against filariae in endemic zones by the World Health Organisation is reducing their transmission and is managing to eliminate the disease in some areas. PMID- 20927149 TI - Rupture of hepatic artery aneurysm associated with ischemic hepatitis. AB - Hepatic artery aneurysms are scarcely reported, mainly because of non-specific symptoms. More often, they are incidental findings during imaging studies to investigate other acute or chronic abdominal conditions. These aneurysms are usually detected in the sixth decade of life, predominantly among males. We report the case of a 69 year-old female with an unsuspected huge hepatic artery aneurysm associated with ischemic hepatitis. Suspicion of aneurysm arose during imaging studies to clarify the origin of jaundice and abdominal pain. After establishment of the diagnosis, but before open surgery, there was a spontaneous rupture of the aneurysm, which caused hemoperitoneum and death. The necropsy study confirmed ischemic hepatitis. Hepatic artery aneurysms are second among the visceral aneurysms, and may cause abdominal pain, jaundice, and hemorrhagic events. One should suspect abdominal aneurysms in elderly patients with unclear abdominal pain, and this hypothesis should be ruled out by imaging studies. PMID- 20927151 TI - Obstructive sleep apnoea syndrome. PMID- 20927152 TI - Adult cochlear implants in New Zealand--a chronic funding issue. PMID- 20927153 TI - Societal costs of obstructive sleep apnoea syndrome. AB - AIM: To estimate the societal costs of obstructive sleep apnoea syndrome (OSAS) in New Zealand and develop a simulation tool to evaluate treatment options. METHOD: Treatment profiles, availability, uptake, and costs were based on services in the Wellington Region, and were used to develop a decision analytic model with micro costing of each potential outcome. Sensitivity analyses were conducted with 10,000 Monte Carlo simulations randomly varying each model parameter between high and low estimates. RESULTS: Total annual societal costs of OSAS for New Zealanders aged 30-60 years were estimated at $40 million (range $33 $90 million) or $419 per case, with accidents being the major contributor. This included 58% direct medical, 13% direct non-medical, 25% indirect, and 3% intangible costs. The estimated incremental net cost of treating OSAS was $389 per case treated (range $338-$427). The estimated incremental net direct medical cost per quality of life year (QALY) gained was $94 (range $56-$310). CONCLUSION: The estimated incremental direct medical cost per QALY gained by OSAS treatment is well below the average QALY cost ($6865) for drugs selected by PHARMAC to receive government subsidy for use in the healthcare system. Thus, the analysis strongly supports the cost effectiveness of OSAS treatment. PMID- 20927154 TI - Exploring knowledge and attitudes of taxi drivers with regard to obstructive sleep apnoea syndrome. AB - AIM: To examine the attitudes of taxi drivers towards symptoms of obstructive sleep apnoea syndrome (OSAS), and to determine whether these attitudes could influence their health and safety as a professional driver. METHOD: Qualitative research based on three focus groups conducted in Wellington, New Zealand. Participants were 27 taxi drivers who had a high pre-test risk for obstructive sleep apnoea. Assignment to focus groups was based on self-identification as being Maori and Pacific peoples, New Zealand European, or non-Maori and non Pacific. RESULT: Participants described avoidance of health issues and dissatisfaction with their general practitioners. These attitudes were attributable to: (i) lack of knowledge, (ii) deliberate avoidance, and (iii) fear of loss of employment and income. CONCLUSIONS: The attitudes and level of knowledge of the focus group participants lead us to make the following recommendations. Drivers need systematic education about the effects of insufficient sleep and of OSAS on driving skills and safety. Taxi managers and drivers should cooperate to develop and implement safe driving policies to manage driver fatigue. Clear guidelines are need for drivers, managers, and healthcare professionals on the diagnosis and treatment of sleep disorders among drivers, and their potential consequences for driver licensing. PMID- 20927155 TI - Improved speech discrimination after cochlear implantation in the Southern Cochlear Implant Adult Programme. AB - AIM: To assess the rate and amount of improvement in speech discrimination scores following cochlear implant (CI) at the Southern Cochlear Implant Programme-Adult (SCIPA). METHODS: A retrospective review of those implanted between 1999 and 2008 at SCIPA. We recorded type of implant, age of onset of deafness, age at implant, aetiology, and speech discrimination test (hearing in noise test, HINT) results pre-implant and over time post-implant. RESULTS: The mean post-implant HINT score (auditory alone) for the 78 patients who had follow-up up to nine months was 74%, and at 18 months (52 patients) was 81%, compared with a mean pre-implant score of 15%. Performance plateaued at around 6 months post-implant. Age at operation was unrelated to outcome but earlier onset of deafness (and higher percentage of life deaf) gave a poorer outcome. Medium pre-implant scores were associated with lower post-implant scores than those with low or high pre-implant scores. CONCLUSIONS: Our results compare favourably with world-wide standards. Benefit in speech discrimination appears to plateau 6 months post-implant. A shorter duration of deafness or percentage of life spent deaf gives better results, but patients with very poor pre-implant functioning may in fact perform better at long term follow up than those with slightly better pre-implant functioning. PMID- 20927156 TI - Nasal fractures: patient satisfaction following closed reduction. AB - AIM: Nasal fractures are commonly treated by primary closed reduction. However, studies suggest this produces unacceptable functional and aesthetic results. Many patients require revision surgery. We aimed to assess patient satisfaction following closed reduction of nasal fractures. METHODS: Retrospective chart review of patients with nasal fractures treated by closed reduction at the Wellington Regional Plastic, Maxillofacial and Burns Unit, New Zealand over a 2 year period was undertaken. Digital manipulation under general anaesthetic was performed. Patients were followed-up by telephone with a structured interview. RESULTS: Of 116 consecutive patients, 74 (65%) were successfully contacted. 65 (88%) were satisfied with functional outcome, and 64 (86%) with aesthetic outcome. Of the 34 patients reporting incomplete correction, 12 (35%) would consider revision surgery. CONCLUSION: Patients treated with closed reduction of nasal fracture performed under general anaesthetic with digital manipulation reported high levels of satisfaction with functional and aesthetic outcomes. Revision rate is low. PMID- 20927157 TI - Self-dilation for refractory oesophageal strictures: an Auckland City Hospital study. AB - AIM: To determine the demographics, indications and long-term outcomes of patients using self-dilators for refractory oesophageal strictures. METHODS: Patients with oesophageal strictures who performed self-dilation were analysed retrospectively. Patients who were still alive were also interviewed via telephone. RESULTS: A total of 8 patients were analysed and 2 patients had since died. Most patients were in the 20-29 age group (n=4) when they first attempted self-dilation. The most common cause for oesophageal strictures was ingestion of corrosive (n=5). Each patient underwent on average 20 endoscopies (including endoscopic dilations) before attempting self-dilations. 1 patient developed oesophageal perforation during endoscopic dilation. 3 patients were still using self-dilators at the time of analysis. All the patients were only using lubricants (K-Y jelly) and none required topical anaesthetic such as Xylocaine throat spray. CONCLUSIONS: Oesophageal self-dilators were well-tolerated and complications were rare. By reducing the need for endoscopies, they are potentially cost-effective. However, patients must receive proper education before they are able to administer this treatment with confidence. PMID- 20927158 TI - Getting tangled in red tape: the challenges of doing clinical research in New Zealand. AB - Regulations and the number of forms that require completion remain a major frustration for researchers attempting to establish a clinical research project. It is essential that clinical research is of the highest standard and abides by ethical principles. However, the duplication of information required and lack of co-ordination between national and local ethics and research committees is a hindrance to conducting clinical research. This publication highlights the pitfalls in our current system with a case study, and suggests changes to the ethical review process that may aid researchers in establishing clinical research. PMID- 20927159 TI - MRI imaging of the inner ear for Meniere's disease. PMID- 20927160 TI - Bilateral superior canal dehiscence syndrome. PMID- 20927161 TI - Inadvertent swallowing of toothbrush. PMID- 20927162 TI - Poland syndrome: rare presentation in two cases. AB - Poland syndrome was first described in 1840 by Alfred Poland while still a medical student and the other components of the syndrome were described at London Guy's Hospital following the dissection of a cadaver's hand, which had hypoplasia and syndactyly. The incidence of Poland syndrome has been reported to be 1 in 30,000 live births. In the present case report, two Poland syndrome patients with ipsilateral hypomastia and a reduction in the axillary/pectoral hairs diagnosed during adulthood are presented; one patient was affected on the left side and had widespread cafe au lait spots, and the other patient had respiratory dysfunction due to multiple rib anomalies. PMID- 20927163 TI - Reassessing Cartwright--understanding the factual record. PMID- 20927164 TI - A patient's response to recent criticisms of the findings in the report of the Cervical Cancer Inquiry 1988. PMID- 20927165 TI - A response to Dr Paul Patten. Re: a particular relationship. PMID- 20927166 TI - Comment on the book review of The Cartwright Papers in the NZMJ. PMID- 20927167 TI - A retrospective study: response to Dr McCredie. Re: consequences in women of participating in a study of the natural history of cervical intraepithelial neoplasia 3. PMID- 20927168 TI - A response to Ms Sandercock and Dr Burls regarding the methods used in the analysis for our first paper 'Natural history of cervical neoplasia and risk of invasive cancer in women diagnosed with cervical intraepithelial neoplasia 3'. PMID- 20927169 TI - Intravenous antibiotics. PMID- 20927170 TI - Long-term benefit of increasing the prominence of a quitline number on cigarette packaging: 3 years of Quitline call data. PMID- 20927171 TI - Is New Zealand lagging behind other OECD countries in measures to reduce alcohol related harm? PMID- 20927172 TI - A comparative study on the adverse effects of flunixin, ketoprofen and phenylbutazone in miniature donkeys: haematological, biochemical and pathological findings. AB - AIM: To evaluate the adverse effects of flunixin, ketoprofen and phenylbutazone when administered I/V to clinically normal miniature donkeys. METHODS: Twenty clinically normal adult (2.0-2.5 years old) male miniature donkeys weighing 113 136 kg and 0.81- 0.86 m tall were randomly assigned to one of four groups, and administered either saline (n=5), 1.0 mg/kg flunixin (n=5), 2.2 mg/kg ketoprofen (n=5), or 4.4 mg/kg phenylbutazone (n=5) I/V at 0800 hours on Day 1, then every 12 h, for 12 days. The animals were observed every 8 h, and examined physically daily. Blood, faeces and urine samples were collected daily from all donkeys, for haematological indices and enzyme activities, occult blood, and urinalysis, respectively. Immediately after euthanasia, complete post-mortem examinations were performed on all donkeys, and gross lesions recorded. Histopathology was conducted on a wide range of tissues. RESULTS: Clinically, mild anorexia and diarrhoea were observed during the study only in donkeys treated with phenylbutazone. There was an effect of treatment with the non-steroidal anti-infl ammatory drugs (NSAID) on red blood cell (RBC) counts, packed cell volume (PCV) and enzyme activities, but not on urine. Lesions were observed in the glandular mucosa of the stomach of all donkeys treated with NSAID, including ulceration in most. Also, in donkeys treated with NSAID, hyperaemia, erosion and ulceration of the gastrointestinal tract, and congestion of the liver, kidney and spleen, were observed. Microscopically, hepatic and renal lesions comprised biliary hyperplasia and interstitial nephritis, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: The gastrointestinal, hepatic and renal lesions observed in the donkeys treated with NSAID demonstrated the toxic potential of NSAID, which was greatest for animals treated with phenylbutazone, less for flunixin, and least for ketoprofen. When use of these compounds is contemplated in clinical cases, the risk of adverse effects and the comparative toxic potential should be considered, together with the efficacy of the compound for the condition being treated. PMID- 20927173 TI - Low levels of antibacterial drug resistance expressed by Gram-negative bacteria isolated from poultry carcasses in New Zealand. AB - AIM: To provide baseline data on the levels and patterns of antibacterial drug resistance expressed by Gram-negative bacteria isolated from poultry carcasses in New Zealand. METHODS: Between July and December 2006, isolates of Escherichia coli (n=407) and Salmonella spp. (n=3) originating from carcass-rinse samples were submitted by testing laboratories affiliated to five major poultry processing plants. Isolates of Campylobacter jejuni (n=193) originating from retail poultry carcasses in 2005-2006 were retrieved from the Massey University archives. All isolates underwent disc diffusion susceptibility testing against panels of 12 (Enterobacteriaceae) and six (Campylobacter spp.) antibacterial drugs. Cephalothin-resistance in isolates of E. coli was confirmed using ETest strips, and confirmation of the resistance phenotypes for a subset of C. jejuni isolates used microbroth dilution assays. Patterns within the resistance phenotypes of the isolates were investigated using hierarchical clustering, and logistic regression modelling. RESULTS: The majority of isolates (71.5% E. coli, 99% C. jejuni, and all three Salmonella spp. isolates) were fully susceptible to the drugs that were tested. Four (1%) E. coli isolates showed resistance to three or more drugs. The proportions of susceptible E. coli differed between the five processing plants. Resistances were detected in E. coli isolates, using disc diffusion to cephalothin (18.2%), ampicillin (4.4%), tetracycline (4.4%) and gentamicin (1.5%). There was an association between cephalothin-resistant isolates of E. coli and decreased susceptibility to gentamicin. Using ETests to ascertain the minimum inhibitory concentrations (MIC) of E. coli for cephalothin gave inconsistent results. One of 193 C. jejuni isolates was resistant to erythromycin, and microbroth dilution assays confirmed that this panel of C. jejuni was generally susceptible to antibacterial drugs. CONCLUSIONS: The levels of resistance shown by Gram-negative bacteria isolated from chicken carcasses in New Zealand are among the lowest reported around the world. No resistance to extended-spectrum cephalosporin drugs was detected in E. coli, suggesting that CTX-M and AmpC beta-lactamases are rare or absent. Salmonella spp. are rarely isolated from poultry carcasses during routine testing in New Zealand, and the isolates identified during this study were fully susceptible to the drugs tested. A panel of C. jejuni isolates originating from retail poultry carcasses were susceptible to first-line and second-line antibacterial drugs. The use of cephalothin as a marker of resistance to first-generation cephalosporins may not be appropriate for non-type-specific E. coli of animal origin. PMID- 20927174 TI - Association of microsatellite polymorphisms with immune responses to a killed Mycobacterium avium subsp. paratuberculosis vaccine in Merino sheep. AB - AIM: To study the association of polymorphisms at five microsatellite loci with immune responses to a killed Mycobacterium avium subsp. paratuberculosis (Map) vaccine. METHODS: Merino sheep (504 vaccinates and 430 unvaccinated controls) from a long-term Johne's vaccine trial undertaken on three different properties in the Central Tablelands of New South Wales, Australia, were genotyped for five microsatellite markers located in three immunologically significant chromosome regions. The marker loci included three from the major histocompatibility complex (MHC), namely DYMS1, OLADRB and SMHCC1; and one each from the solute carrier family 11 member 1 (SLC11A1), OVINRA1, and the interferon-gamma (IFN-gamma), o(IFN)-gamma, gene regions. Associations between immune responses and genetic polymorphisms at the marker loci were examined by analysing both allelic and genotypic effects. RESULTS: The o(IFN)-gamma locus had only two alleles, whereas the other four loci exhibited extensive polymorphism, with the number of alleles ranging from 10 (OVINRA1) to 21 (DYMS1), resulting in 30-92 genotypes per locus. Heterozygosities varied between 37% (o(IFN)-gamma) and 87% (SMHCC1), while information on polymorphic contents ranged from 0.31 (o(IFN)-gamma) to 0.87 (DYMS1). Each of the three properties exhibited unique allelic and genotypic frequencies. Analysis of immune response data revealed strong antibody and IFN gamma responses as early as 2 months post-vaccination. Immune responses in control animals on all three properties remained consistently low, except for slightly elevated IFN-gamma responses at a few time-points on two properties, concomitant with exposure to natural infection. Genotype-phenotype association analyses revealed a number of marker genotypes/alleles to be significantly associated with antibody and IFN-gamma responses. However, the effects of only five genotypes (one each at DYMS1, OLADRB, SMHCC1, OVINRA1 and o(IFN)-gamma) and three alleles (one each at o(IFN)-gamma, DYMS1and OLADRB) on IFN-gamma responses were consistent across the three properties. CONCLUSION: Considering the significance of IFN-gamma responses in protection against Map, it is possible that the genotypes/alleles identified might have a role in protective immune responses to natural Map infections, and further studies are warranted to confirm this. PMID- 20927175 TI - Effect of setting a maximum milking time, from peak lactation, on production, milking time and udder health. AB - AIM: To examine the effect of setting a maximum milking time, from peak lactation until drying-off, on production, duration of milking, and udder health of dairy cows. METHODS: Forty cows were assigned in twin-pairs to be either milked until cups were removed at a milk flow-rate threshold of 0.35 kg/minute (Control), or until cups were removed at a milk flow-rate threshold of 0.35 kg/minute, or maximum time, whichever came first (MaxT). The maximum time was set by determining the milking time of the 70th percentile cow when ranked from fastest to slowest, irrespective of yield. The milking routine was typical of that practised on dairy farms in New Zealand, and involved no pre-milking preparation. The study began at peak lactation (68 (SD 7) days in milk; DIM) and continued for 26 weeks. Duration of milking and milk yield were measured for each milking. Composition of milk was determined from weekly herd tests, and milk quality from fortnightly somatic cell counts (SCC). Completeness of milking and teat condition were assessed during the study. The bacterial status of quarter milk samples was determined at the beginning and end of the study, and all treated cases of clinical mastitis recorded. ANOVA was used to examine the effect of treatment group on variables of interest. RESULTS: Total milk, fat and protein yields during the study period did not differ between treatments. On average, 30.3% of the morning and 27.6% of the afternoon milkings of MaxT cows reached the maximum time at which cups were removed, and were therefore shortened. While the average milking time of the slowest-milking cow was longer for the Control compared with MaxT group in Weeks 1-18, the average milking time did not differ between treatments. There was no difference in overall SCC, and the incidence of clinical mastitis, or the percentage of infected quarters at drying-off, was similar for the MaxT and Control cows. CONCLUSION: The results show that setting a maximum milking time can reduce the milking time of slower-milking cows in a herd without compromising overall herd production and udder health. CLINICAL RELEVANCE: Although the numbers of cows in the study were small there was no evidence of a major increase in SCC, or subclinical or clinical mastitis when a maximum milking time was set for slower-milking cows. PMID- 20927176 TI - Investigation of a pig herd with animals seropositive for classical swine fever and where porcine circovirus-associated disease had been diagnosed. AB - AIM: To investigate the cause of classical swine fever (CSF) virus-seropositive animals in a nucleus pig-breeding herd in New Zealand, where porcine circovirus associated disease had been diagnosed. CASE HISTORY AND CLINICAL FINDINGS: An exotic disease investigation was undertaken to exclude CSF and porcine reproductive and respiratory syndrome (PRRS) on a nucleus pig-breeding herd comprising approximately 300 breeding sows, 1,000 weaners, and 650 grower pigs. The herd was experiencing poor reproductive performance in sows, and breeding records showed a declining farrowing rate attributable to a single manager. The growing pigs (10-15 weeks old) were experiencing respiratory disease and wasting, and the mortality rate by pen varied between 9 and 20%. Post-mortem changes in affected grower pigs were consistent with circovirus-associated diseases. DIAGNOSTIC TESTING: Serological screening using an IDEXX-ELISA gave negative results for PRRS virus antibodies, but two grower pigs and one sow tested positive for CSF virus antibodies. These three seropositive animals remained positive to CSF virus, using three commercial ELISA test kits, over 27 weeks. A newly developed virus neutralisation test (VNT), using a New Zealand isolate of border disease (BD) virus, demonstrated that the seropositive pig sera had higher antibody titres to BD virus than to bovine viral diarrhoea (BVD) virus and CSF virus. PCR performed on tonsil, kidney, ileum and spleen gave negative results for CSF virus, and histopathology on lymph nodes, intestine, lung, kidney, liver and brain showed no evidence of the disease. Virus isolation performed on a number of samples was negative. CLINICAL RELEVANCE: The seropositive samples for CSF virus found in this investigation were likely to be a cross reaction to a pestivirus other than CSF virus. The finding of a possible endemic pestivirus capable of being transmitted between sheep and pigs on this farm may explain findings from previous serological survey work in New Zealand, and supports experience elsewhere, where BD virus was found to be the predominant ruminant pestivirus infecting pigs. The results show that pestivirus cross reactivity can result in unexpectedly high titres, and that testing with a full set of (local) pestiviruses is necessary to reach the correct conclusion. The investigation has direct relevance where pig herds with a low seroprevalence are encountered during surveillance for CSF. PMID- 20927177 TI - Necrotising fasciitis in a bull due to infection with Arcanobacterium haemolyticum. AB - CASE HISTORY: A 2-year-old Hereford bull was lame for one week before becoming recumbent. CLINICAL AND PATHOLOGICAL FINDINGS: The scrotum and ventral perineal region were cold and blackened caudally. The semimembranosus and semitendinosus muscles were firm on palpation. The bull was subject to euthanasia, and necropsy revealed that the skin and S/C tissues of the caudal half of the scrotum were grey and necrotic. The caudal and distal aspects of the semimembranosus and semitendinosus muscles were grey and necrotic to a depth of approximately 15 cm, and these changes appeared to track along fascial planes. The tissue had an offensive smell, and large amounts of flocculent, watery, brown fluid and some gas were present. Histology of affected muscle and S/C tissues revealed coagulative necrosis, with oedema and large numbers of bacteria that were predominantly Gram-positive rods. Adjacent blood vessels contained thrombi while the epidermis overlying the affected areas appeared diffusely necrotic, suggesting infarction. Culture of the fluid yielded a pure growth of Arcanobacterium spp., which was identified as Arcanobacterium haemolyticum, using an API Coryne biochemical test strip. DIAGNOSIS: Necrotising fasciitis and myositis due to Arcanobacterium haemolyticum. CLINICAL RELEVANCE: Arcanobacterium haemolyticum has not previously been reported as a cause of necrotising fasciitis in any species. Necrotising fasciitis is probably an under-reported condition in cattle due to its clinical similarity to clostridial disease. PMID- 20927178 TI - Presumptive Nocardia spp. infection in a dog treated with cyclosporin and ketoconazole. AB - CASE HISTORY: A dog that had received 8 months of cyclosporin and ketoconazole therapy for treatment of atopic dermatitis subsequently developed severe neurological disease, that failed to respond to treatment with trimethoprim sulphadiazine and clindamycin. HISTOPATHOLOGICAL FINDINGS: Histopathological examination of the pulmonary parenchyma and spinal cord revealed loose aggregates of Gram-positive, partially acid-fast, fine, beaded, filamentous bacteria, most consistent with Nocardia spp. DIAGNOSIS: A presumptive diagnosis was made of disseminated nocardiosis of the spinal cord and lungs. CLINICAL RELEVANCE: Nocardia spp. is an opportunistic actinomycete that may cause disseminated disease, particularly in immunocompromised animals. Cyclosporin is used in veterinary medicine to control immune-mediated and allergic disorders, with few reported adverse side effects. This case gives further evidence that involvement of the spinal cord in nocardiosis of the central nervous system (CNS) carries a poor prognosis, and opportunistic infection by Nocardia spp. may be a potential complication of immunosuppressive cyclosporin therapy in the dog. PMID- 20927179 TI - Obstructive urolithiasis in a Saanen goat in New Zealand, resulting in a ruptured bladder. AB - CASE HISTORY: A 3-year-old male, castrated Saanen goat was presented with an acute onset of vocalisation, abdominal discomfort and 'tail-flagging'. CLINICAL FINDINGS: Radiographs, including a positive-contrast study, indicated obstructive urolithiasis, and evidence of rupture of the urethra. Analysis of uroliths identified calcium carbonate crystals. Amputation of the urethral process could not re-establish urethral patency, so a tube cystotomy was performed but also was not successful. Eighteen days after admission, a perineal urethrostomy was performed. However, the goat's condition deteriorated 12 days after the urethrostomy, and the owner consented to euthanasia of the animal. Post-mortem examination revealed a hole 2x1 cm on the dorsal aspect of the bladder, and a necrotic focus measuring approximately 2x3 cm ventrally. DIAGNOSIS: Obstructive urolithiasis, with ruptured bladder and urethra. CLINICAL RELEVANCE: Obstructive urolithiasis is probably an under-reported condition of castrated male goats in New Zealand. PMID- 20927181 TI - Synthesis and characterisation of coating polyurethane cationomers containing fluorine built-in hard urethane segments. AB - Polyurethane cationomers were synthesised in the reaction of 4,4' methylenebis(phenyl isocyanate) with polyoxyethylene glycol (M = 2,000) or poly(tetrafluoroethyleneoxide-co-difluoromethylene oxide) alpha,omega diisocyanate and N-methyl diethanolamine. Amine segments were built-in to the urethane-isocyanate prepolymer in the reaction with 1-bromobutane or formic acid, and then they were converted to alkylammonium cations. The obtained isocyanate prepolymers were then extended in the aqueous medium that yielded stable aqueous dispersions which were applied on the surfaces of test poly(tetrafluoroethylene) plates. After evaporation of water, the dispersions formed thin polymer coatings. (1)H, (13)C NMR and IR spectral methods were employed to confirm chemical structures of synthesised cationomers. Based on (1)H NMR and IR spectra, the factors kappa and alpha were calculated, which represented the polarity level of the obtained cationomers. The DSC, wide angle X-ray scattering and atom force microscopy methods were employed for the microstructural assessment of the obtained materials. Changes were discussed in the surface free energy and its components, as calculated independently according to the method suggested by van Oss-Good, in relation to chemical and physical structures of cationomers as well as morphology of coating surfaces obtained from those cationomers. Fluorine incorporated into cationomers (about 30%) contributed to lower surface free energy values, down to about 15 mJ/m(2). That was caused by gradual weakening of long-range interactions within which the highest share is taken by dispersion interactions. PMID- 20927182 TI - The fruits of collaboration in a multidisciplinary field. AB - Collaboration between researchers and between research organizations is generally considered a desirable course of action, in particular by some funding bodies. However, collaboration within a multidisciplinary community, such as the Computer Human Interaction (CHI) community, can be challenging. We performed a bibliometric analysis of the CHI conference proceedings to determine if papers that have authors from different organization or countries receive more citations than papers that are authored by members of the same organization. There was no significant difference between these three groups, indicating that there is no advantage for collaboration in terms of citation frequency. Furthermore, we tested if papers written by authors from different organizations or countries receive more best paper awards or at least award nominations. Papers from only one organization received significantly fewer nominations than collaborative papers. PMID- 20927183 TI - Characterizing a scientific elite: the social characteristics of the most highly cited scientists in environmental science and ecology. AB - In science, a relatively small pool of researchers garners a disproportionally large number of citations. Still, very little is known about the social characteristics of highly cited scientists. This is unfortunate as these researchers wield a disproportional impact on their fields, and the study of highly cited scientists can enhance our understanding of the conditions which foster highly cited work, the systematic social inequalities which exist in science, and scientific careers more generally. This study provides information on this understudied subject by examining the social characteristics and opinions of the 0.1% most cited environmental scientists and ecologists. Overall, the social characteristics of these researchers tend to reflect broader patterns of inequality in the global scientific community. However, while the social characteristics of these researchers mirror those of other scientific elites in important ways, they differ in others, revealing findings which are both novel and surprising, perhaps indicating multiple pathways to becoming highly cited. PMID- 20927184 TI - Identification of small interfering RNA targeting Signal Transducer and Activator of Transcription 6: Characterisation and selection of candidates for pre-clinical development. AB - The interleukin (IL)-13 pathway and its associated transcription factor, signal transducer and activator of transcription 6 (STAT6), have been clearly implicated in the pathogenesis of bronchial asthma. We have developed a system to effectively screen the STAT6 gene for targeting with small interfering (si) RNA molecules. By incorporating an in silico and in vitro screening system we were able to identify fourteen siRNA molecules suitable for pre-clinical drug development. Furthermore, we were able to demonstrate that modification of certain siRNAs, designed to improve in vivo longevity, was possible without significant loss of target knockdown efficacy and that the siRNA produced by our selection process did not induce demonstrable interferon responses. These data suggest that several STAT6-targeting siRNA suitable for pre-clinical development are available for potential use in the treatment of asthma. PMID- 20927185 TI - Continuous differential impedance spectroscopy of single cells. AB - A device for continuous differential impedance analysis of single cells held by a hydrodynamic cell trapping is presented. Measurements are accomplished by recording the current from two closely-situated electrode pairs, one empty (reference) and one containing a cell. We demonstrate time-dependent measurement of single cell impedance produced in response to dynamic chemical perturbations. First, the system is used to assay the response of HeLa cells to the effects of the surfactant Tween, which reduces the impedance of the trapped cells in a concentration dependent way and is interpreted as gradual lysis of the cell membrane. Second, the effects of the bacterial pore-forming toxin, Streptolysin-O are measured: a transient exponential decay in the impedance is recorded as the cell membrane becomes increasingly permeable. The decay time constant is inversely proportional to toxin concentration (482, 150, and 30 s for 0.1, 1, and 10 kU/ml, respectively). ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10404-009-0534-2) contains supplementary material, which is available to authorized users. PMID- 20927186 TI - Genetic architecture of complex traits and accuracy of genomic prediction: coat colour, milk-fat percentage, and type in Holstein cattle as contrasting model traits. AB - Prediction of genetic merit using dense SNP genotypes can be used for estimation of breeding values for selection of livestock, crops, and forage species; for prediction of disease risk; and for forensics. The accuracy of these genomic predictions depends in part on the genetic architecture of the trait, in particular number of loci affecting the trait and distribution of their effects. Here we investigate the difference among three traits in distribution of effects and the consequences for the accuracy of genomic predictions. Proportion of black coat colour in Holstein cattle was used as one model complex trait. Three loci, KIT, MITF, and a locus on chromosome 8, together explain 24% of the variation of proportion of black. However, a surprisingly large number of loci of small effect are necessary to capture the remaining variation. A second trait, fat concentration in milk, had one locus of large effect and a host of loci with very small effects. Both these distributions of effects were in contrast to that for a third trait, an index of scores for a number of aspects of cow confirmation ("overall type"), which had only loci of small effect. The differences in distribution of effects among the three traits were quantified by estimating the distribution of variance explained by chromosome segments containing 50 SNPs. This approach was taken to account for the imperfect linkage disequilibrium between the SNPs and the QTL affecting the traits. We also show that the accuracy of predicting genetic values is higher for traits with a proportion of large effects (proportion black and fat percentage) than for a trait with no loci of large effect (overall type), provided the method of analysis takes advantage of the distribution of loci effects. PMID- 20927187 TI - Understanding uncertainties in model-based predictions of Aedes aegypti population dynamics. AB - BACKGROUND: Aedes aegypti is one of the most important mosquito vectors of human disease. The development of spatial models for Ae. aegypti provides a promising start toward model-guided vector control and risk assessment, but this will only be possible if models make reliable predictions. The reliability of model predictions is affected by specific sources of uncertainty in the model. METHODOLOGY/PRINCIPAL FINDINGS: This study quantifies uncertainties in the predicted mosquito population dynamics at the community level (a cluster of 612 houses) and the individual-house level based on Skeeter Buster, a spatial model of Ae. aegypti, for the city of Iquitos, Peru. The study considers two types of uncertainty: 1) uncertainty in the estimates of 67 parameters that describe mosquito biology and life history, and 2) uncertainty due to environmental and demographic stochasticity. Our results show that for pupal density and for female adult density at the community level, respectively, the 95% prediction confidence interval ranges from 1000 to 3000 and from 700 to 5,000 individuals. The two parameters contributing most to the uncertainties in predicted population densities at both individual-house and community levels are the female adult survival rate and a coefficient determining weight loss due to energy used in metabolism at the larval stage (i.e. metabolic weight loss). Compared to parametric uncertainty, stochastic uncertainty is relatively low for population density predictions at the community level (less than 5% of the overall uncertainty) but is substantially higher for predictions at the individual-house level (larger than 40% of the overall uncertainty). Uncertainty in mosquito spatial dispersal has little effect on population density predictions at the community level but is important for the prediction of spatial clustering at the individual-house level. CONCLUSION/SIGNIFICANCE: This is the first systematic uncertainty analysis of a detailed Ae. aegypti population dynamics model and provides an approach for identifying those parameters for which more accurate estimates would improve model predictions. PMID- 20927189 TI - Chemosensitization of Trypanosoma congolense strains resistant to isometamidium chloride by tetracyclines and enrofloxacin. AB - BACKGROUND: Because of the development of resistance in trypanosomes to trypanocidal drugs, the livelihood of millions of livestock keepers in sub Saharan Africa is threatened now more than ever. The existing compounds have become virtually useless and pharmaceutical companies are not keen on investing in the development of new trypanocides. We may have found a breakthrough in the treatment of resistant trypanosomal infections, through the combination of the trypanocide isometamidium chloride (ISM) with two affordable veterinary antibiotics. METHODOLOGY/PRINCIPAL FINDINGS: In a first experiment, groups of mice were inoculated with Trypanosoma congolense strains resistant to ISM and either left untreated or treated with (i) tetracycline, (ii) ISM or (iii) the combination of the antibiotic and the trypanocide. Survival analysis showed that there was a significant effect of treatment and resistance to treatment on the survival time. The groups treated with ISM (with or without antibiotic) survived significantly longer than the groups that were not treated with ISM (P<0.01). The group treated with the combination trypanocide/antibiotic survived significantly longer than the group treated with ISM (P<0.01). In a second experiment, groups of cattle were inoculated with the same resistant trypanosome strain and treated with (i) ISM, (ii) ISM associated with oxytetracycline or (iii) ISM associated with enrofloxacine. All animals treated with ISM became parasitaemic. In the groups treated with ISM-oxytetracycline and ISM-enrofloxacine, 50% of the animals were cured. Animals from the groups treated with a combination trypanocide/antibiotic presented a significantly longer prepatent period than animals treated with ISM (p<0.001). The impact of the disease on the haematocrit was low in all ISM treated groups. Yet, it was lower in the groups treated with the combination trypanocide/antibiotic (p<0.01). CONCLUSIONS/SIGNIFICANCE: After optimization of the administration protocol, this new therapeutic combination could constitute a promising treatment for livestock infected with drug resistant T. congolense. PMID- 20927190 TI - Leishmania-specific surface antigens show sub-genus sequence variation and immune recognition. AB - BACKGROUND: A family of hydrophilic acylated surface (HASP) proteins, containing extensive and variant amino acid repeats, is expressed at the plasma membrane in infective extracellular (metacyclic) and intracellular (amastigote) stages of Old World Leishmania species. While HASPs are antigenic in the host and can induce protective immune responses, the biological functions of these Leishmania specific proteins remain unresolved. Previous genome analysis has suggested that parasites of the sub-genus Leishmania (Viannia) have lost HASP genes from their genomes. METHODS/PRINCIPAL FINDINGS: We have used molecular and cellular methods to analyse HASP expression in New World Leishmania mexicana complex species and show that, unlike in L. major, these proteins are expressed predominantly following differentiation into amastigotes within macrophages. Further genome analysis has revealed that the L. (Viannia) species, L. (V.) braziliensis, does express HASP-like proteins of low amino acid similarity but with similar biochemical characteristics, from genes present on a region of chromosome 23 that is syntenic with the HASP/SHERP locus in Old World Leishmania species and the L. (L.) mexicana complex. A related gene is also present in Leptomonas seymouri and this may represent the ancestral copy of these Leishmania-genus specific sequences. The L. braziliensis HASP-like proteins (named the orthologous (o) HASPs) are predominantly expressed on the plasma membrane in amastigotes and are recognised by immune sera taken from 4 out of 6 leishmaniasis patients tested in an endemic region of Brazil. Analysis of the repetitive domains of the oHASPs has shown considerable genetic variation in parasite isolates taken from the same patients, suggesting that antigenic change may play a role in immune recognition of this protein family. CONCLUSIONS/SIGNIFICANCE: These findings confirm that antigenic hydrophilic acylated proteins are expressed from genes in the same chromosomal region in species across the genus Leishmania. These proteins are surface-exposed on amastigotes (although L. (L.) major parasites also express HASPB on the metacyclic plasma membrane). The central repetitive domains of the HASPs are highly variant in their amino acid sequences, both within and between species, consistent with a role in immune recognition in the host. PMID- 20927191 TI - Mycobacterium africanum--review of an important cause of human tuberculosis in West Africa. AB - Mycobacterium africanum consists of two phylogenetically distinct lineages within the Mycobacterium tuberculosis complex, known as M. africanum West African 1 and M. africanum West African 2. These lineages are restricted to West Africa, where they cause up to half of human pulmonary tuberculosis. In this review we discuss the definition of M. africanum, describe the prevalence and restricted geographical distribution of M. africanum West African 1 and 2, review the occurrence of M. africanum in animals, and summarize the phenotypic differences described thus far between M. africanum and M. tuberculosis sensu stricto. PMID- 20927192 TI - Urinary collagen fragments are significantly altered in diabetes: a link to pathophysiology. AB - BACKGROUND: The pathogenesis of diabetes mellitus (DM) is variable, comprising different inflammatory and immune responses. Proteome analysis holds the promise of delivering insight into the pathophysiological changes associated with diabetes. Recently, we identified and validated urinary proteomics biomarkers for diabetes. Based on these initial findings, we aimed to further validate urinary proteomics biomarkers specific for diabetes in general, and particularity associated with either type 1 (T1D) or type 2 diabetes (T2D). METHODOLOGY/PRINCIPAL FINDINGS: Therefore, the low-molecular-weight urinary proteome of 902 subjects from 10 different centers, 315 controls and 587 patients with T1D (n = 299) or T2D (n = 288), was analyzed using capillary-electrophoresis mass-spectrometry. The 261 urinary biomarkers (100 were sequenced) previously discovered in 205 subjects were validated in an additional 697 subjects to distinguish DM subjects (n = 382) from control subjects (n = 315) with 94% (95% CI: 92-95) accuracy in this study. To identify biomarkers that differentiate T1D from T2D, a subset of normoalbuminuric patients with T1D (n = 68) and T2D (n = 42) was employed, enabling identification of 131 biomarker candidates (40 were sequenced) differentially regulated between T1D and T2D. These biomarkers distinguished T1D from T2D in an independent validation set of normoalbuminuric patients (n = 108) with 88% (95% CI: 81-94%) accuracy, and in patients with impaired renal function (n = 369) with 85% (95% CI: 81-88%) accuracy. Specific collagen fragments were associated with diabetes and type of diabetes indicating changes in collagen turnover and extracellular matrix as one hallmark of the molecular pathophysiology of diabetes. Additional biomarkers including inflammatory processes and pro-thrombotic alterations were observed. CONCLUSIONS/SIGNIFICANCE: These findings, based on the largest proteomic study performed to date on subjects with DM, validate the previously described biomarkers for DM, and pinpoint differences in the urinary proteome of T1D and T2D, indicating significant differences in extracellular matrix remodeling. PMID- 20927193 TI - Inferring regulatory networks from expression data using tree-based methods. AB - One of the pressing open problems of computational systems biology is the elucidation of the topology of genetic regulatory networks (GRNs) using high throughput genomic data, in particular microarray gene expression data. The Dialogue for Reverse Engineering Assessments and Methods (DREAM) challenge aims to evaluate the success of GRN inference algorithms on benchmarks of simulated data. In this article, we present GENIE3, a new algorithm for the inference of GRNs that was best performer in the DREAM4 In Silico Multifactorial challenge. GENIE3 decomposes the prediction of a regulatory network between p genes into p different regression problems. In each of the regression problems, the expression pattern of one of the genes (target gene) is predicted from the expression patterns of all the other genes (input genes), using tree-based ensemble methods Random Forests or Extra-Trees. The importance of an input gene in the prediction of the target gene expression pattern is taken as an indication of a putative regulatory link. Putative regulatory links are then aggregated over all genes to provide a ranking of interactions from which the whole network is reconstructed. In addition to performing well on the DREAM4 In Silico Multifactorial challenge simulated data, we show that GENIE3 compares favorably with existing algorithms to decipher the genetic regulatory network of Escherichia coli. It doesn't make any assumption about the nature of gene regulation, can deal with combinatorial and non-linear interactions, produces directed GRNs, and is fast and scalable. In conclusion, we propose a new algorithm for GRN inference that performs well on both synthetic and real gene expression data. The algorithm, based on feature selection with tree-based ensemble methods, is simple and generic, making it adaptable to other types of genomic data and interactions. PMID- 20927195 TI - Malignant transformation of non-neoplastic Barrett's epithelial cells through well-defined genetic manipulations. AB - BACKGROUND: Human Barrett's cancer cell lines have numerous, poorly-characterized genetic abnormalities and, consequently, those lines have limited utility as models for studying the early molecular events in carcinogenesis. Cell lines with well-defined genetic lesions that recapitulate various stages of neoplastic progression in Barrett's esophagus would be most useful for such studies. METHODOLOGY/PRINCIPAL FINDINGS: To develop such model cell lines, we started with telomerase-immortalized, non-neoplastic Barrett's epithelial (BAR-T) cells, which are spontaneously deficient in p16, and proceeded to knock down p53 using RNAi, to activate Ras by introducing oncogenic H-Ras(G12V), or both. BAR-T cells infected with either p53 RNAi or oncogenic H-Ras(G12V) alone maintained cell-to cell contact inhibition and did not exhibit anchorage-independent growth in soft agar. In contrast, the combination of p53 RNAi knockdown with expression of oncogenic H-Ras(G12V) transformed the p16-deficient BAR-T cells, as evidenced by their loss of contact inhibition, by their formation of colonies in soft agar, and by their generation of tumors in immunodeficient mice. CONCLUSIONS/SIGNIFICANCE: Through these experiments, we have generated a number of transformed and non-transformed cell lines with well-characterized genetic abnormalities recapitulating various stages of carcinogenesis in Barrett's esophagus. These lines should be useful models for the study of carcinogenesis in Barrett's esophagus, and for testing the efficacy of chemopreventive and chemotherapeutic agents. PMID- 20927194 TI - Functional metagenomics: a high throughput screening method to decipher microbiota-driven NF-kappaB modulation in the human gut. AB - BACKGROUND/AIM: The human intestinal microbiota plays an important role in modulation of mucosal immune responses. To study interactions between intestinal epithelial cells (IECs) and commensal bacteria, a functional metagenomic approach was developed. One interest of metagenomics is to provide access to genomes of uncultured microbes. We aimed at identifying bacterial genes involved in regulation of NF-kappaB signaling in IECs. A high throughput cell-based screening assay allowing rapid detection of NF-kappaB modulation in IECs was established using the reporter-gene strategy to screen metagenomic libraries issued from the human intestinal microbiota. METHODS: A plasmid containing the secreted alkaline phosphatase (SEAP) gene under the control of NF-kappaB binding elements was stably transfected in HT-29 cells. The reporter clone HT-29/kb-seap-25 was selected and characterized. Then, a first screening of a metagenomic library from Crohn's disease patients was performed to identify NF-kappaB modulating clones. Furthermore, genes potentially involved in the effect of one stimulatory metagenomic clone were determined by sequence analysis associated to mutagenesis by transposition. RESULTS: The two proinflammatory cytokines, TNF-alpha and IL 1beta, were able to activate the reporter system, translating the activation of the NF-kappaB signaling pathway and NF-kappaB inhibitors, BAY 11-7082, caffeic acid phenethyl ester and MG132 were efficient. A screening of 2640 metagenomic clones led to the identification of 171 modulating clones. Among them, one stimulatory metagenomic clone, 52B7, was further characterized. Sequence analysis revealed that its metagenomic DNA insert might belong to a new Bacteroides strain and we identified 2 loci encoding an ABC transport system and a putative lipoprotein potentially involved in 52B7 effect on NF-kappaB. CONCLUSIONS: We have established a robust high throughput screening assay for metagenomic libraries derived from the human intestinal microbiota to study bacteria-driven NF-kappaB regulation. This opens a strategic path toward the identification of bacterial strains and molecular patterns presenting a potential therapeutic interest. PMID- 20927196 TI - Smoking and gamma-glutamyltransferase: opposite interactions with alcohol consumption and body mass index. AB - BACKGROUND: Smoking has recently been suggested to synergistically interact with alcohol intake as a determinant of serum gamma-glutamyltransferase (gamma-GT), an emergent powerful predictor of disease and mortality. This study investigated whether this also applies to higher smoking and alcohol exposure ranges and to body mass index (BMI), which likewise is strongly associated with gamma-GT. METHODOLOGY/PRINCIPAL FINDINGS: Analyses were based on occupational health examinations of more than 15,000 German male workers aged 16-64 years, predominantly from the construction industry. Sociodemographics and other health related information were collected during the exam. Joint associations of smoking and alcohol consumption or BMI with elevated or log-transformed gamma-GT were examined by tabulation and multiple adjusted regression models. Cigarette smoking exerted no effect on gamma-GT in teetotalers, but there was a statistically significant effect of smoking among participants with higher alcohol consumption intensity, odds of elevated gamma-GT being increased by 24% and 27% per additional 10 cigarettes smoked per day in subjects drinking 61-90 and >90 gram alcohol per day, respectively (P for interaction = 0.039). The interaction was opposite for BMI, where no association was seen in obese subjects, whereas odds of elevated gamma-GT were increased by 24% per 10 cigarettes below 25 kg/m(2) (P for interaction = 0.040). This novel interaction was replicable in an independent cohort. CONCLUSION: The evidence for opposite interactions of smoking with alcohol and BMI as determinants of serum gamma-GT suggests that different physiological pathways are responsible for the associations between these factors. PMID- 20927198 TI - MOTHER'S EMPLOYMENT DEMANDS, WORK-FAMILY CONFLICT, AND ADOLESCENT DEVELOPMENT. AB - This study revisited the old research question of whether or not maternal employment would adversely affect children's development. We reframed the question by asking how a mother's temporal employment demands might be linked to child development. We used longitudinal data from a sample of 340 white, lower- to middle-class, dual-earner families living in the rural Midwest of the United States. The data were obtained from questionnaires and videotaped observations, and were informed by the mother, the father, the adolescent child, and a trained observer. As predicted, we found a strong relationship between a mother's temporal employment demands and work-family conflict, which was significantly associated with her emotional distress. A husband's egalitarian gender ideology was found to reduce the mother's emotional distress. Maternal distress was then negatively associated with nurturant and involved parenting, which in turn predicted a reduction in the adolescent child's emotional and behavioral problems over time. PMID- 20927197 TI - Re-examination of the Controversial Coexistence of Traumatic Brain Injury and Posttraumatic Stress Disorder: Misdiagnosis and Self-Report Measures. AB - The coexistence of traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD) remains a controversial issue in the literature. To address this controversy, we focused primarily on the civilian-related literature of TBI and PTSD. Some investigators have argued that individuals who had been rendered unconscious or suffered amnesia due to a TBI are unable to develop PTSD because they would be unable to consciously experience the symptoms of fear, helplessness, and horror associated with the development of PTSD. Other investigators have reported that individuals who sustain TBI, regardless of its severity, can develop PTSD even in the context of prolonged unconsciousness. A careful review of the methodologies employed in these studies reveals that investigators who relied on clinical interviews of TBI patients to diagnose PTSD found little or no evidence of PTSD. In contrast, investigators who relied on PTSD questionnaires to diagnose PTSD found considerable evidence of PTSD. Further analysis revealed that many of the TBI patients who were initially diagnosed with PTSD according to self-report questionnaires did not meet the diagnostic criteria for PTSD upon completion of a clinical interview. In particular, patients with severe TBI were often misdiagnosed with PTSD. A number of investigators found that many of the severe TBI patients failed to follow the questionnaire instructions and erroneously endorsed PTSD symptoms because of their cognitive difficulties. Because PTSD questionnaires are not designed to discriminate between PTSD and TBI symptoms or determine whether a patient's responses are accurate or exaggerated, studies that rely on self-report questionnaires to evaluate PTSD in TBI patients are at risk of misdiagnosing PTSD. Further research should evaluate the degree to which misdiagnosis of PTSD occurs in individuals who have sustained mild TBI. PMID- 20927199 TI - Transferencias intergeracionais privadas na Amazonia rural brasileira. AB - What motivates family members to share resources? Past research argues for, on the one hand, love and altruism, and on the other, the expectation of reciprocity. Drawing on this literature, this paper examines intergenerational transfers between small farmers and their non-coresident children in the rural area around the city of Altamira, Para, Brazil. We apply GoM (Grade of Membership) models to create profiles of private transfers, using data collected in 2005 by a team from Indiana University. The results show three profiles: low intergenerational transfers, high levels of transfers of visits and help, and high levels of transfers of visits and money. There is no clear difference in profile by birth order, but we do find sex differences in profile. Men are more likely to send money while women provide time transfers (work and visits). Upward transfers are most common from children with high levels of education or living in urban areas, suggesting a repayment of prior investments made by parents. Thus, our empirical evidence supports theories arguing that transfers are motivated by intertemporal contracts between parents and children, and that altruistic theories of family transfers should be rethought among rural agricultural populations in contexts characterized by many environmental and institutional challenges. PMID- 20927200 TI - An Integrated Genetic-Genomic Approach for the Identification of Novel Cancer Loci in Mice Sensitized to c-Myc-Induced Apoptosis. AB - Deregulated c-Myc is associated with a wide range of human cancers. In many cell types, overexpression of c-Myc potently promotes cell growth and proliferation concomitant with the induction of apoptosis. Secondary genetic events that shift this balance either by increasing growth and proliferation or limiting apoptosis are likely to cooperate with c-Myc in tumorigenesis. Here, the authors have performed large-scale insertional mutagenesis in EMU-c-myc mice that, through mdm2 loss of function mutations, are sensitized to apoptosis. The authors chose to use this genetic background based on the hypothesis that the high level of apoptosis induced by c-Myc overexpression in MDM2-deficient mice would act as a rate-limiting barrier for lymphoma development. As a result, it was predicted that the spectrum of retroviral insertions would be shifted toward loci that harbor antiapoptotic genes. Nine novel common insertion sites (CISs) specific to mice with this sensitized genetic background were identified, suggesting the presence of novel antiapoptotic cancer genes. Moreover, cross-comparing the data to the Retroviral Tagged Cancer Gene Database, the authors identified an additional 23 novel CISs. Here, evidence is presented that 2 genes, ppp1r16b and hdac6, identified at CISs, are bona fide cellular oncogenes. This study highlights the power of combining unique sensitized genetic backgrounds with large-scale mutagenesis as an approach for identifying novel cancer genes. PMID- 20927201 TI - Labor Migration, Drug Trafficking Organizations, and Drug Use: Major Challenges for Transnational Communities in Mexico. AB - In our article, we present the recent findings of our ethnographic field study on drug use and the emergence of a drug use culture in transnational communities in Mexico. Transnational communities are part of a larger migratory labor circuit that transcends political borders and are not restricted to a single locality. Transnational migrants and returning immigrants link the multiple localities through their social networks. In southern Guanajuato, Mexico, using a transnational migration paradigm, we examined the manner in which transnational migration and drug trafficking organizations are contributing to a growing drug problem in these communities. We found that transnational migrants and returning immigrants, including deported workers, introduce drugs and drug use practices, and contribute to the creation of a drug use culture within the communities. The social conditions in the community that foster and proliferate drug use are many: the erosion of the traditional family, truncated kinship bases, and new social formations. These conditions are all consequences of migration and emigration. Recent drug cartel activities are also contributing to this growing drug problem. The cartels have aggressively targeted these communities because of availability of money, existing drug use, a drug use culture, and the breakdown of traditional deterrents to substance abuse. Although a number of communities in three municipalities were part of our study, we focus on two: Lindavista, a rancho, Progreso, a municipal seat. Our field study in Mexico, one of four sequential ethnographic field studies conducted in Guanajuato and Pennsylvania, was completed over a six month period, from September, 2008, through February, 2009, using traditional ethnography. The four field studies are part of a larger, ongoing, three-year bi-national study on drug use among transnational migrants working in southeastern Pennsylvania. This larger study, near its third and final year, is funded by the National Institute of Drug Abuse. PMID- 20927203 TI - Vulnerable, but strong: The spinal cord-injured patient during rehabilitation. AB - A traumatic spinal cord injury affects the body to an extent that the patient requires the assistance of others to survive and recover. The rehabilitation phase puts the patient in a vulnerable position and involves a considerable amount of strength on the patient's part. The aim of this paper is to explore the vulnerability of the spinal cord patient and how this vulnerability connects to the necessary strength, as the patient struggles to survive the injury and get through the rehabilitation.The circumstances of 12 traumatic spinal cord-injured patients were observed in the rehabilitation unit and after discharge.A phenomenological-hermeneutic narrative approach applying Ricoeur's theory was used. Data were collected by field observation and interviews during the first 2 years after the spinal cord injury.The patient's strength during the rehabilitation was portrayed by their endurance and from their narratives of how they handled difficult situations. The patient's perception of vulnerability varied, and strength was mobilised as a response to the vulnerability to overcome the imbalance between demands and resources. Vulnerability should therefore refer to a person's experience of the situation rather than the person, as it may hinder the professionals' open, explorative approach towards the person. PMID- 20927204 TI - Gene therapy within our vision: Illustrating the genetic paradigm. PMID- 20927202 TI - Assessment of health claims, content, and safety of herbal supplements containing Ginkgo biloba. AB - BACKGROUND: European Regulation 1924/2006 states that all health claims made on foods need to be substantiated scientifically. OBJECTIVE: To apply the PASSCLAIM criteria for the scientific substantiation of health claims on foods to herbal supplements containing Ginkgo biloba. Evaluation of three selected claimed health effects for G. biloba (improvement of blood circulation, improvement of symptoms of old age, and improvement of memory) was achieved through review of publicly available scientific data. A total of 35 human intervention studies were evaluated. Commercially available products claimed to contain mainly G. biloba (N=29) were randomly sampled in the Netherlands and analyzed for their content on ginkgo extract. Also, a toxicological risk assessment was performed. RESULTS: The three selected health claims investigated could not be substantiated. This was mainly because of a lack of data from studies in healthy volunteers. In most studies results performed with a 24% standardized G. biloba extract were described. However, our chemical analysis showed that 25 of the 29 sampled products did not contain the required minimum 24% standardized extract. Moreover, in most preparations the content of substances typical for G. biloba did not conform to what was declared on the label. Since toxicity data for G. biloba are very limited, a safety limit could not be established. CONCLUSIONS: Evidence is lacking for three health claims of herbal products with G. biloba. Neither safety nor efficacy can be guaranteed at the recommended daily dose. The multidisciplinary approach described in this paper provides good insight into issues that are relevant for the evaluation of health claims for herbal food supplements. PMID- 20927205 TI - Gene therapy in ophthalmology. AB - It has been more than a year since ophthalmologists and scientists under Dr. Robin Ali's team at the Moorsfield Eye Hospital and the Institute of Ophthalmology, University College London, successfully treated patients with a severely blinding disease, Leber's congenital amaurosis (LCA) using gene therapy. This success does not look to be transient, and this achievement in gene replacement therapy clinical trial for LCA has instilled hope in numerous families with patients suffering from this and similar retinal degenerative diseases, for whom restoration of lost vision has remained a distant dream so far. The encouragement that this success has given is expected to also lead to start of clinical trials for other blinding ocular diseases for which gene therapy experiments at the laboratory and animal levels have been successful. This article reviews the various studies that have led to the understanding of gene therapy outcomes in human ocular diseases and attempts to provide a brief sketch of successful clinical trials. PMID- 20927206 TI - Changes in intraocular pressure after clear corneal phacoemulsification in normal patients. AB - PURPOSE: To evaluate changes in intraocular pressure (IOP) after clear corneal phacoemulsification (CCP) in normal patients. MATERIALS AND METHODS: A prospective study including 273 normal patients selected for cataract extraction by CCP. Intraocular pressure was recorded on the 15(th) day, l(st), 2(nd), 3(rd) month and 6 months after surgery. STATISTICAL ANALYSIS: For statistical analysis, Epi Info was used to determine the statistical significance of changes in IOP. RESULTS: The mean age of 96 women and 177 men was 71 +/- 12 years. The mean IOP before surgery was 14.18 +/- 3.4 mmHg. Our patients showed a mean decrease in IOP of 2.25 mmHg (16%) compared to preoperative values. Change in IOP was not related to lens thickness (P = 0.12), but significantly correlated with change in anterior chamber depth (ACD) (P = 0.002). The postoperative IOP was inversely related to preoperative ACD (P = 0.012). Age, sex and axial length were not significantly related to IOP reduction (P = 0.2-0.5) CONCLUSION: CCP was associated with a statistically significant reduction in IOP. The exact mechanism by which cataract surgery results in IOP reduction is unclear. CCP can be performed with the intent of achieving better IOP control. PMID- 20927207 TI - Epidemiological profile of fungal keratitis in urban population of West Bengal, India. AB - BACKGROUND: Corneal diseases are one of the major causes of visual loss and blindness, second only to cataract. Amongst corneal diseases, microbial keratitis is a major blinding disease. In some countries, fungal keratitis accounts for almost 50% of patients with culture-proven microbial keratitis. AIM: This study was conducted to determine the epidemiological characteristics of fungal keratitis in an urban population of West Bengal and identify the specific pathogenic organisms. METHODS: The charts of patients with microbial keratitis who attended the Cornea Services of Priyamvada Birla Aravind Eye Hospital from January to December 2008 were retrospectively reviewed. Records of patients with 10% KOH mount and culture positive fungal keratitis were analyzed for epidemiological features, laboratory findings and treatment outcomes. RESULTS: Of the 289 patients of microbial keratitis included in the study, 110 patients (38.06%) were diagnosed with fungal keratitis (10% KOH mount positive). Of the 110 patients, 74 (67.27%) fitted the study inclusion criteria (10% KOH mount and culture positive). Forty five of 74 patients (60.81%) in the study group were in the older age group (>50 years). Ocular trauma in 35 cases (47.29%) was identified as a high risk factor and vegetative injuries in 17 cases (22.97%) were identified as a significant cause for fungal keratitis. Maximum organism source was from corneal scrapings in 41 cases (55%). The predominant fungal species isolated was Aspergillus sp (55.40%) followed by Candida albicans 14 cases (18.91%) and Fusarium sp. in 8 cases (10.81%). Agricultural activity related ocular trauma was the principal cause of mycotic keratitis and males were more commonly affected. Thirty of 74 cases (40.55%) of the culture positive patients healed with corneal scar formation with medical treatment whereas 44 cases (59.45%) required therapeutic keratoplasty. CONCLUSION: Fungal keratitis is an important cause of microbial keratitis with injury to the cornea being a leading predisposing factor. Although Aspergillus sp. was implicated in most of the patients in our study population, Candida sp. were found in higher numbers than previously reported. Keratitis caused by filamentous fungi responds adequately to medical management. Therapeutic keratoplasty continues to remain an important treatment modality in infections with Candida sp. Early diagnosis with prompt identification of the pathogenic organism is mandatory to initiate appropriate therapy and thereby reduce morbidity. PMID- 20927209 TI - Combined autologous and allograft limbal cell transplantation with penetrating keratoplasty in a case of chemical corneal burn patient. AB - A patient with chemical corneal burn presented two months after the acute episode of chemical injury to his right eye (OD) and was diagnosed with severe limbal stem cell deficiency and with vascularized corneal opacity OD. Limbal cell transplantation and penetrating keratoplasty (PKP) was performed. The autologous and allograft limbal tissue included peripheral cornea, limbus and conjunctiva obtained from contralateral eye and cadaveric eye bank cornea. Central corneal button was used for a PKP with 32 intermittent sutures. One year after the procedure, the corneal surface remains clear with a best corrected visual acuity of 6/12 (-2.00 DS / -2.75 DC-/ 150 degrees . Eighteen sutures are still in place; no vascularization has extended beyond the host graft junction. Ocular surface is wetting well with no filamentary keratitis.Combined autologous and allograft limbal cell transplant can be performed for severe deficiency of corneal stem cells in a patient with chemical corneal burn. PMID- 20927208 TI - The determinants of trichiasis recurrence differ at one and two years following lid surgery in Vietnam: A community-based intervention study. AB - AIM: To compare determinants for recurrence of trichiasis at one and two years following lid surgery in Vietnam. STUDY DESIGN: Community-based intervention study. METHODS: This study was carried out between 2000 and 2003 in four trachoma endemic districts of Vietnam. Trained trichiasis surgeons performed modified Cuenod Nataf lid surgery on 648 eyes of 472 patients with Trachomatous trichiasis (TT). Trained investigators collected information on ocular and lid status before surgery and at one and two years following surgery. Trichiasis recurrence was calculated after adjusting for one or both eyes of each operated individual. RESULTS: Fifty-six eyes developed recurrence at one year with adjusted prevalence of 8.8% (95% CI 6.60-11.01). One hundred and one eyes [15.9% (95% CI 13.04 18.72)] had recurrence two years following surgery. Female gender, older age group, study area, severe grade of trachomatous scarring (TS), past history of lid surgery, postoperative suture adjustment and surgeon were risk factors for recurrence at the end of one year. Study area and previous lid surgery were risk factors for recurrence in the second year. Recurrence at one year could be predicted if study area and severity of Trachomatous Scarring (TS) are known. CONCLUSIONS: One and two year recurrence rates with modified Cuenod Nataf lid surgeries for TT in Vietnam were acceptably low. Early recurrence could be reduced by proper case selection. However, late recurrence seems to be dependent on interaction of risk factors. Only age of the patient was the reliable predictor of recurrence. PMID- 20927210 TI - Vidi, vini, vinci: External ophthalmomyiasis infection that occurred, and was diagnosed and treated in a single day: A rare case report. AB - Ophthalmomyiasis is an infestation of eye with larvae or maggots of certain flies. Oestrus ovis (sheep nasal botfly) belonging to family Oestridae is the most common cause of human myiasis. We describe here an acute presentation of a case of external ophthalmomyiasis, i.e., infestation of conjunctiva due to first instar larvae of Oestrus ovis. In this case report the occurrence, diagnosis and treatment all took place in the setting of a single day. Prompt treatment by removal of larvae mechanically followed by instillation of antibiotic and steroid eye drops helped to prevent serious complications. The taxonomic identification of fly is also important as some fly species are capable of penetrating deeper tissues of eyes, which is sight threatening. PMID- 20927211 TI - Idiopathic choroidal neovascular membrane in a young female. AB - A case of idiopathic choroidal neovascular membrane (CNVM) is described in a 17 year-old female patient. On initial examination her vision was counting fingers at one meter in the left eye (OS) and Fluorescein angiography showed a well defined hyperfluorescent area corresponding to the CNVM. Intravitreal bevacizumab was injected into OS, and at a five-week follow-up visit, visual acuity improved to 20/100 OS. This case is unusual, in that the CNVM developed in a young lady with no significant past medical history and with the absence of a choroidal or retinal pigment epithelial disease process that may be associated with a CNVM. PMID- 20927212 TI - Orbital manifestations of Langerhans Cell Histiocytosis: A report of three cases. AB - Langerhans Cell Histiocytosis (LCH) is a spectrum of disorders characterized by accumulation of histiocytes in various tissues. It is rarely encountered in ophthalmic practice and has an affinity for the orbit. We report three patients with LCH involving the lateral orbital wall, each with a different form of the condition. PMID- 20927213 TI - Orbital venous-lymphatic malformation: Role of imaging. PMID- 20927214 TI - VMD2 mutational analysis in a Japanese family with Best macular dystrophy. PMID- 20927215 TI - Canaliculitis: Are we missing the diagnosis? PMID- 20927216 TI - Twelve-year-old boy with decreased vision in his right eye. PMID- 20927217 TI - Subhyaloid hemorrhage as the presenting sign of pregnancy-induced hypertension. PMID- 20927218 TI - Glamour of technology. PMID- 20927219 TI - Dosimetry evaluation of SAVI-based HDR brachytherapy for partial breast irradiation. AB - Accelerated partial breast irradiation (APBI) with high dose rate (HDR) brachytherapy offers an excellent compact course of radiation due to its limited number of fractions for early-stage carcinoma of breast. One of the recent devices is SAVI (strut-adjusted volume implant), which has 6, 8 or 10 peripheral source channels with one center channel. Each channel can be differentially loaded. This paper focuses on the treatment planning, dosimetry and quality assurance aspects of HDR brachytherapy implant with GammaMed Plus HDR afterloader unit. The accelerated PBI balloon devices normally inflate above 35 cc range, and hence these balloon type devices cannot be accommodated in small lumpectomy cavity sizes. CT images were obtained and 3-D dosimetric plans were done with Brachyvision planning system. The 3-D treatment planning and dosimetric data were evaluated with planning target volume (PTV)_eval V90, V95, V150, V200 skin dose and minimum distance to skin. With the use of the SAVI 6-1 mini device, we were able to accomplish an excellent coverage - V90, V95, V150 and V200 to 98%, 95%, 37 cc (<50 cc volume) and 16 cc (<20 cc volume), respectively. Maximum skin dose was between 73% and 90%, much below the prescribed dose of 34 Gy. The minimum skin distance achieved was 5 to 11 mm. The volume that received 50% of the prescribed radiation dose was found to be lower with SAVI. The multi-channel SAVI based implants reduced the maximum skin dose to markedly lower levels as compared to other modalities, simultaneously achieving best dose coverage to target volume. Differential-source dwell-loading allows modulation of the radiation dose distribution in symmetric or asymmetric opening of the catheter shapes and is also advantageous in cavities close to chest wall. PMID- 20927220 TI - Comparative dosimetry of GammaMed Plus high-dose rate Ir brachytherapy source. AB - The comparative dosimetry of GammaMed (GM) Plus high-dose rate brachytherapy source was performed by an experiment using 0.1-cc thimble ionization chamber and simulation-based study using EGSnrc code. In-water dose measurements were performed with 0.1-cc chamber to derive the radial dose function (r = 0.8 to 20.0 cm) and anisotropy function (r = 5.0 cm with polar angle from 10 degrees to 170 degrees ). The nonuniformity correction factor for 0.1-cc chamber was applied for in-water measurements at shorter distances from the source. The EGSnrc code was used to derive the dose rate constant (Lambda), radial dose function g(L)(r) and anisotropy function F(r, theta) of GM Plus source. The dosimetric data derived using EGSnrc code in our study were in very good agreement relative to published data for GM Plus source. The radial dose function up to 12 cm derived from measured dose using 0.1-cc chamber was in agreement within +/-3% of data derived by the simulation study. PMID- 20927221 TI - Optimized point dose measurement for monitor unit verification in intensity modulated radiation therapy using 6 MV photons by three different methodologies with different detector-phantom combinations: A comparative study. AB - The study was aimed to compare accuracy of monitor unit verification in intensity modulated radiation therapy (IMRT) using 6 MV photons by three different methodologies with different detector phantom combinations. Sixty patients were randomly chosen. Zero degree couch and gantry angle plans were generated in a plastic universal IMRT verification phantom and 30*30*30 cc water phantom and measured using 0.125 cc and 0.6 cc chambers, respectively. Actual gantry and couch angle plans were also measured in water phantom using 0.6 cc chamber. A suitable point of measurement was chosen from the beam profile for each field. When the zero-degree gantry, couch angle plans and actual gantry, couch angle plans were measured by 0.6 cc chamber in water phantom, the percentage mean difference (MD) was 1.35%, 2.94 % and Standard Deviation (SD) was 2.99%, 5.22%, respectively. The plastic phantom measurements with 0.125 cc chamber Semiflex ionisation chamber (SIC) showed an MD=4.21% and SD=2.73 %, but when corrected for chamber-medium response, they showed an improvement, with MD=3.38 % and SD=2.59 %. It was found that measurements with water phantom and 0.6cc chamber at gantry angle zero degree showed better conformity than other measurements of medium detector combinations. Correction in plastic phantom measurement improved the result only marginally, and actual gantry angle measurement in a flat- water phantom showed higher deviation. PMID- 20927222 TI - Portable and wide-range solid-state transmission densitometer for quality control in film radiography. AB - In biology, materials science, radiography quality control or film dosimetry in radiotherapy, a transmission densitometer is useful for measurements of optical density. The design proposed here is oriented to quality control in radiographic films. The instrument described here utilizes low-cost solid-state devices and is easy to construct. The use of 1-watt white light-emitting diode in this densitometer enables low power consumption and a cold light source. Moreover, the instrument does not need a reference light, which results in decreasing the number of parts and reducing the overall size of the apparatus. PMID- 20927223 TI - Quantitation of normal metabolite concentrations in six brain regions by in-vivoH MR spectroscopy. AB - This study examined the concentrations of brain metabolites visible to in vivo(1)H-Magnetic Resonance Spectroscopy ((1)H-MRS) at 1.5 T in a sample of 28 normal subjects. Quantitation was attempted for inositol compounds, choline units, total creatine and N-acetyl moieties, using open-source software. Six brain regions were considered: frontal and parietal white matter, medial temporal lobe, thalamus, pons and cerebellum. Absolute concentrations were derived using tissue water as an internal reference and using an external reference; metabolite signal intensity ratios with respect to creatine were also calculated. The inter individual variability was smaller for absolute concentrations (internal reference) as compared to that for signal intensity ratios. Significant regional variability in concentration was found for all metabolites, indicating that separate normative values are needed for different brain regions. The values obtained in this study can be used as reference in future studies, provided the same methodology is followed; it is confirmed that despite unsuccessful attempts in the past, smaller coefficients of variation can indeed be obtained through absolute quantification. PMID- 20927224 TI - Comparison of dosimetric characteristics of Siemens virtual and physical wedges for ONCOR linear accelerator. AB - Dosimetric properties of virtual wedge (VW) and physical wedge (PW) in 6- and 10 MV photon beams from a Siemens ONCOR linear accelerator, including wedge factors, depth doses, dose profiles, peripheral doses, are compared. While there is a great difference in absolute values of wedge factors, VW factors (VWFs) and PW factors (PWFs) have a similar trend as a function of field size. PWFs have stronger depth dependence than VWF due to beam hardening in PW fields. VW dose profiles in the wedge direction, in general, match very well with those of PW, except in the toe area of large wedge angles with large field sizes. Dose profiles in the nonwedge direction show a significant reduction in PW fields due to off-axis beam softening and oblique filtration. PW fields have significantly higher peripheral doses than open and VW fields. VW fields have similar surface doses as the open fields, while PW fields have lower surface doses. Surface doses for both VW and PW increase with field size and slightly with wedge angle. For VW fields with wedge angles 45 degrees and less, the initial gap up to 3 cm is dosimetrically acceptable when compared to dose profiles of PW. VW fields in general use less monitor units than PW fields. PMID- 20927225 TI - Impact of tissue heterogeneity corrections in stereotactic body radiation therapy treatment plans for lung cancer. AB - This study aims at evaluating the impact of tissue heterogeneity corrections on dosimetry of stereotactic body radiation therapy treatment plans. Four dimensional computed tomography data from 15 low stage non-small cell lung cancer patients was used. Treatment planning and dose calculations were done using pencil beam convolution algorithm of Varian Eclipse system with Modified Batho Power Law for tissue heterogeneity. Patient plans were generated with 6 MV co planar non-opposing four to six field beams optimized with tissue heterogeneity corrections to deliver a prescribed dose of 60 Gy in three fractions to at least 95% of the planning target volume, keeping spinal cord dose <10 Gy. The same plans were then regenerated without heterogeneity correction by recalculating previously optimized treatment plans keeping identical beam arrangements, field fluences and monitor units. Compared with heterogeneity corrected plans, the non corrected plans had lower average minimum, mean, and maximum tumor doses by 13%, 8%, and 6% respectively. The results indicate that tissue heterogeneity is an important determinant of dosimetric optimization of SBRT plans. PMID- 20927226 TI - Longitudinal volume analysis from computed tomography: Reproducibility using adrenal glands as surrogate tumors. AB - This study aims to determine the precision (reproducibility) of volume assessment in routine clinical computed tomography (CT) using adrenal glands as surrogate tumors. Seven patients at our institution were identified retrospectively as having received numerous abdominal CT scans (average 13.1, range 5 to 20). The adrenal glands were used as surrogate tumors, assuming no actual volume change. Left and right adrenal gland volumes were assessed by hand segmentation for each patient scan. Over 1240 regions of interest were outlined in total. The reproducibility, expressed as the coefficient of variation (COV), was used to characterize measurement precision. The average volumes were 5.9 and 4.5 cm(3) for the left and right adrenal gland, respectively, with COVs of 17.8% and 18.9%, respectively. Using one patient's data (20 scans) as an example surrogate for a spherical tumor, it was calculated that a 13% change in volume (4.2% change in diameter) could be determined with statistical significance at P=0.05. For this case, cursor positioning error in linear measurement of object size, by even 1 pixel on the CT image, corresponded to a significant change in volume (P=0.05). The precision of volume determination was dependent on total volume. Precision improved with increasing object size (r(2) =0.367). Given the small dimensions of the adrenal glands, the ~18% COV is likely to be a high estimate compared to larger tumors. Modern CT scanners working with thinner sections (i.e. <1 mm) are likely to produce better measurement precision. The use of volume measurement to quantify changing tumor size is supported as a more precise metric than linear measurement. PMID- 20927227 TI - Marching Toward Hair Research: HAIRINDIA 2010. PMID- 20927228 TI - Sixth world congress for hair research cairns-on the great barrier reef, australia, 16-19 june, 2010. PMID- 20927229 TI - Aging of the hair follicle pigmentation system. AB - Skin and hair phenotypes are powerful cues in human communication. They impart much information, not least about our racial, ethnic, health, gender and age status. In the case of the latter parameter, we experience significant change in pigmentation in our journey from birth to puberty and through to young adulthood, middle age and beyond. The hair follicle pigmentary unit is perhaps one of our most visible, accessible and potent aging sensors, with marked dilution of pigment intensity occurring long before even subtle changes are seen in the epidermis. This dichotomy is of interest as both skin compartments contain melanocyte subpopulations of similar embryologic (i.e., neural crest) origin. Research groups are actively pursuing the study of the differential aging of melanocytes in the hair bulb versus the epidermis and in particular are examining whether this is in part linked to the stringent coupling of follicular melanocytes to the hair growth cycle. Whether some follicular melanocyte subpopulations are affected, like epidermal melanocytes, by UV irradiation is not yet clear. A particular target of research into hair graying or canities is the nature of the melanocyte stem compartment and whether this is depleted due to reactive oxygen species-associated damage, coupled with an impaired antioxidant status, and a failure of melanocyte stem cell renewal. Over the last few years, we and others have developed advanced in vitro models and assay systems for isolated hair follicle melanocytes and for intact anagen hair follicle organ culture which may provide research tools to elucidate the regulatory mechanisms of hair follicle pigmentation. Long term, it may be feasible to develop strategies to modulate some of these aging-associated changes in the hair follicle that impinge particularly on the melanocyte populations. PMID- 20927230 TI - Photoaggravation of hair aging. AB - Photoaggravation of hair aging includes various chemical and physical changes in fiber properties which lead to an increase in fiber porosity, loss of mechanical strength and an increase in surface roughness. These changes come from lipid oxidation, disulfide bond cleavage, tryptophan degradation and cysteic acid formation. Hair exposed to sunlight is claimed to be more brittle, stiffer and drier than before irradiation and exhibits a reduced water-absorption capacity. Hair pigments function to provide photochemical protection to hair proteins. Hair pigments accomplish this protection by absorbing and filtering the impinging radiation and subsequently dissipating this energy as heat. However, in the process of protecting the hair proteins from light, the pigments are degraded or bleached. Dark hair is more resistant to photodegradation than light hair, because of the higher photostability of eumelanin compared to pheomelanin. Integral lipids of hair fibers are degraded by ultraviolet light, as well as by visible light, helping to explain the weakening of the cell membrane complex exposed to light radiation. PMID- 20927231 TI - Trichomycoses. AB - Hair infection by fungal agents, also called trichomycoses, is one of the common concerns in human beings. The common agents causing hair infections are dermatophytes, Malassezia species and those causing piedra. The former two can give rise to considerable discomfort and also cause immune-mediated reactions in the form of kerion and dermatophytids. The etiopathogenesis of trichomycoses, along with its clinical aspects and the management, are briefed here. PMID- 20927232 TI - Hair evaluation methods: merits and demerits. AB - Various methods are available for evaluation (for diagnosis and/or quantification) of a patient presenting with hair loss. Hair evaluation methods are grouped into three main categories: Non-invasive methods (e.g., questionnaire, daily hair counts, standardized wash test, 60-s hair count, global photographs, dermoscopy, hair weight, contrasting felt examination, phototrichogram, TrichoScan and polarizing and surface electron microscopy), semi invasive methods (e.g., trichogram and unit area trichogram) and invasive methods (e.g., scalp biopsy). Any single method is neither 'ideal' nor feasible. However, when interpreted with caution, these are valuable tools for patient diagnosis and monitoring. Daily hair counts, wash test, etc. are good methods for primary evaluation of the patient and to get an approximate assessment of the amount of shedding. Some methods like global photography form an important part of any hair clinic. Analytical methods like phototrichogram are usually possible only in the setting of a clinical trial. Many of these methods (like the scalp biopsy) require expertise for both processing and interpreting. We reviewed the available literature in detail in light of merits and demerits of each method. A plethora of newer methods is being introduced, which are relevant to the cosmetic industry/research. Such methods as well as metabolic/hormonal evaluation are not included in this review. PMID- 20927233 TI - Reliability of hamilton-norwood classification. AB - BACKGROUND: Hamilton-Norwood scale (HNS) has been largely used to assess clinically the severity of androgenetic alopecia (AGA), especially for therapeutical trials and even to establish its association with important diseases such as ischemic heart disease and prostate cancer. OBJECTIVE: To study HNS reproducibility in the hands of dermatologists and dermatology residents. MATERIALS AND METHODS: Seven dermatologists and 16 residents in dermatology classified 43 photographs of male heads with different degrees of AGA. In a second study, 8 appraisers (3 dermatologists and 5 residents in dermatology) examined 56 pictures with the same procedure and repeated the observation 3 months later. In the first study, the inter-rater agreement was estimated by calculating an intra-class correlation coefficient (ICC). In the second study, for intra-rater repeatability, each rater's scores from session 1 were paired with his/her scores for the same subjects in session 2, and the ordinary least products linear regression was calculated. RESULTS: In the first study, the concordance of appraisers was unsatisfactory (ICC = 0.63-0.68)]. In the second study, repeatability was poor, without any significant difference between dermatologists and dermatology residents. COMMENT: Reliability of HNS is unsatisfactory even in the hands of expert appraisers. To obtain better reliability, the number of classes should be reduced, but with such reduction HNS would be usable to classify patients only in a broad way. PMID- 20927235 TI - Male androgenetic alopecia: population-based study in 1,005 subjects. AB - CONTEXT: Male androgenetic alopecia (AGA) is a common condition. There is limited information on its prevalence and patterns. AIMS: (1). To find the prevalence and most common pattern (2). To correlate the age and pattern of alopecia. SETTINGS AND DESIGN: Population-based study. MATERIALS AND METHODS: This is a population based study from the public. The selection was random. The method involved was asking the age and, if found to between 30 and 50 years, the scalp was examined for alopecia and the pattern was determined using the Hamilton Norwood classification. RESULTS: Of 1,005 subjects, the youngest was 30 years old and the oldest 49 years old, with a mean age of 37.05 +/- standard deviation 4.79. 39.2% of the subjects were in the age group of 30-35, 34.4% in the 36-40 year age group, 26.0% in the 41-45 years age group and 0.4% in the 46-50 years age group. Five hundred and eighty-three subjects (58%) had AGA, the most common type being grade II (27.27%) followed by grade I (22.12%) and grade III (21.78%). 47.5% (P = 0.003) had pattern alopecia in the 30-35 years age group, 58.7% in the 36-40 years age group (P = 0.8) and 73.2% in the 41-45 years age group (P <= 0.001). In the 30-35 years age group, grade I was 51.18%, grade II was 42.77% and grade VI was 18.52%. In the 41-45 years age group, grade I was 13.38%, grade III was 33.85% and grade VI was 66.67%. CONCLUSIONS: Fifty-eight percent of the male population aged 30-50 years had AGA. Its grade increased with increase in age. 12.9% of the male population had grades IV to VI, and would benefit from hair transplantation while 44.1% had grades I to III and are potential candidates for medical treatment. PMID- 20927234 TI - Dermoscopy in female androgenic alopecia: method standardization and diagnostic criteria. AB - OBJECTIVE: Establishing the trichoscopy criteria of female androgenic alopecia (FAGA). DESIGN: Trichoscopy images were retrospectively evaluated. SETTING: Dermatologic hospital-based clinic and private practice offices. PATIENTS AND METHODS: One hundred and thirty-one females (59 with androgenic alopecia, 33 with chronic telogen effluvium (CTE), 39 healthy controls). The diagnosis was based on clinical examination and confirmed by histopatology. MAIN OUTCOME MEASURE: Trichoscopy results obtained in frontal, occipital and both temporal areas of the scalp under a 20-fold and 70-fold magnification, including average hair thickness, number of 'yellow dots' and vellus hairs, number of hairs in one pilosebaceous unit and percentage of follicular ostia with perifollicullar hyperpigmentation. RESULTS: Average hair thickness in frontal area versus occiput was, respectively, 0.061 +/- 0.008 mm versus 0.058 +/- 0.007 mm in healthy controls, 0.047 +/- 0.007 mm versus 0.052 +/- 0.008 mm in androgenic alopecia and 0.056 +/- 0.007 mm versus 0.053 +/- 0.009 mm in CTE. Mean percentage of thin hairs (< 0.03 mm) in androgenic alopecia was 20.9 +/- 12% and was significantly higher than in healthy controls (6.15 +/- 4.6%, P < 0.001) or in CTE (10.4 +/- 3.9%, P < 0.001). The number of yellow dots, pilosebaceous units with only one hair and with perifollicular hyperpigmentation was significantly increased in androgenic alopecia. Classification and Regression Tree Analysis was performed to establish diagnostic criteria for FAGA. CONCLUSION: FAGA may be differentiated from CTE based on trichoscopy criteria. Major criteria are ratio of (1) more than four yellow dots in four images (70-fold magnification) in the frontal area, (2) lower average hair thickness in the frontal area compared to the occiput and (3) more than 10% of thin hairs (below 0.03 mm) in the frontal area. Minor criteria encompass increased frontal to occipital ratio of (1) single-hair pilosebaceous units, (2) vellus hairs and (3) perifollicular discoloration. Fulfillment of two major criteria or one major and two minor criteria allows to diagnose FAGA based on trichoscopy with a 98% specificity. PMID- 20927236 TI - Videodermoscopy does not enhance diagnosis of scalp contact dermatitis due to topical minoxidil. AB - BACKGROUND: Videodermoscopy (VD) is a noninvasive diagnostic tool that provides useful information for the differential diagnosis of scalp disorders. OBJECTIVES: The aim of this study was to investigate if dermoscopy may help the clinician in the diagnosis of contact dermatitis of the scalp. MATERIALS AND METHODS: We analyzed the dermoscopic images taken from 7 patients with contact dermatitis due to topical minoxidil, 6 patients complaining of intense scalp itching during treatment with topical minoxidil but with negative patch tests and 19 controls. The following dermoscopic patterns described for scalp diseases were evaluated: Vascular patterns (simple loops, twisted loops and arborizing lines), follicular/perifollicular patterns (yellow dots, empty ostia, white dots, peripilar signs), white scales, yellow scales, follicular plugging, hair diameter diversity, honeycomb pattern and short regrowing hairs. Findings were graded from 0-4, according to severity in 20-fold magnifications. Statistical analysis included univariate analysis and Chi-square test by SPSS version 12. RESULTS: There were no statistical differences in the analysis of the vascular patterns and scales between the 3 groups. CONCLUSIONS: We were not able to detect dermoscopic features that can help the clinician in distinguishing scalp contact dermatitis due to topical minoxidil from other conditions that cause severe scalp itching. In particular, minoxidil contact dermatitis does not produce increase or alterations in the morphology of the scalp vessels or significant scalp scaling when evaluated with dermoscopy. PMID- 20927238 TI - White piedra in a mother and daughter. AB - White Piedra is a superficial fungal infection of the hair caused by Trichosporon asahii. It is also known as trichomycosis nodosa or trichomycosis nodularis. We report two cases of White Piedra in a mother and her daughter for the rarity of such occurrence. PMID- 20927237 TI - Immunofluoresence of the outer root sheath in anagen and telogen hair: an aid to diagnosis in pemphigus. AB - Desmoglein 1 and 3 are distributed in the outer root sheath (ORS) of the hair follicle. Direct immunofluoresence (DIF) pattern of ORS in cases of pemphigus resembles the DIF pattern of the perilesional skin. We performed a DIF of the anagen and telogen hair ORS in a case of pemphigus and correlated it with the DIF findings of perilesional skin. Telogen hair ORS promises to be a useful tool in performing DIF for the purpose of diagnosis and follow-up in cases of pemphigus. PMID- 20927239 TI - Minoxidil topical foam: a new kid on the block. PMID- 20927240 TI - Bamboo Hair in Netherton's Syndrome. PMID- 20927241 TI - Stem cell therapy: the eventual future. PMID- 20927242 TI - Embedding clinical trials in clinical practice: Harvesting experience and winnowing evidence. PMID- 20927243 TI - Adaptive design clinical trials: Methodology, challenges and prospect. AB - New drug development is a time-consuming and expensive process. Recently, there has been stagnation in the development of novel compounds. Moreover, the attrition rate in clinical research is also on the rise. Fearing more stagnation, the Food and Drug Administration released the critical path initiative in 2004 and critical path opportunity list in 2006 thus highlighting the need of advancing innovative trial designs. One of the innovations suggested was the adaptive designed clinical trials, a method promoting introduction of pre specified modifications in the design or statistical procedures of an on-going trial depending on the data generated from the concerned trial thus making a trial more flexible. The adaptive design trials are proposed to boost clinical research by cutting on the cost and time factor. Although the concept of adaptive designed clinical trials is round-the-corner for the last 40 years, there is still lack of uniformity and understanding on this issue. This review highlights important adaptive designed methodologies besides covering the regulatory positions on this issue. PMID- 20927244 TI - Renal effects of Mammea africana Sabine (Guttiferae) stem bark methanol/methylene chloride extract on L-NAME hypertensive rats. AB - OBJECTIVE: The present study aims at evaluating the effects of methanol/methylene chloride extract of the stem bark of Mammea africana on the renal function of L NAME treated rats. MATERIAL AND METHODS: Normotensive male Wistar rats were divided into five groups respectively treated with distilled water, L-NAME (40 mg/kg/day), L-NAME + L-arginine (100 mg/kg/day), L-NAME + captopril (20 mg/kg/day) or L-NAME + M. africana extract (200 mg/kg/day) for 30 days. Systolic blood pressure was measured before and at the end of treatment. Body weight was measured at the end of each week. Urine was collected 6 and 24 h after the first administration and further on day 15 and 30 of treatment for creatinine, sodium and potassium quantification, while plasma was collected at the end of treatment for the creatinine assay. ANOVA two way followed by Bonferonni or one way followed by Tukey were used for statistical analysis. RESULTS: M. africana successfully prevented the rise in blood pressure and the acute natriuresis and diuresis induced by L-NAME. When given chronically, the extract produced a sustained antinatriuretic effect, a non-significant increase in urine excretion and reduced the glomerular hyperfiltration induced by L-NAME. CONCLUSIONS: The above results suggest that the methanol/methylene chloride extract of the stem bark of M. africana may protect kidney against renal dysfunction and further demonstrate that its antihypertensive effect does not depend on a diuretic or natriuretic activity. PMID- 20927245 TI - Effects of ethanol extract of Ficus bengalensis (bark) on inflammatory bowel disease. AB - OBJECTIVE: The present study was designed to evaluate the effects of ethanol extract of Ficus bengalensis Linn. bark (AEFB) on inflammatory bowel disease (IBD). MATERIALS AND METHODS: Effects of AEFB were studied on 2,4,6 trinitrobenzenesulfonic acid (TNBS, 0.25 ml 120 mg/ml in 50% ethanol intrarectally, on first day only) induced IBD in rats. The effects of co administration of prednisolone (2 mg/kg) and AEFB (250, 500 mg/kg) for 21 days were evaluated. Animals sacrificed at end of the experiment and various histopathological parameters like colon mucosal damage index (CMDI) and disease activity index (DAI) were assessed. In the colon homogenate malondialdehyde (MDA), myeloperoxidase (MPO), superoxide dismutase (SOD), and nitric oxide (NO) levels and in mesentery % mast cell protection was also measured. RESULTS: Rats treated with only TNBS showed more score of CMDI and DAI, higher MDA, NO, MPO, and lower SOD activity as compared to the control group. Treatment with AEFB significantly declined both indices scores and decreased the MPO, MDA, NO, and increased the SOD activity. AEFB also increased the % mast cell protection compared to alone TNBS-treated animals. CONCLUSION: In our study, we found that AEFB has a significant protective effect in the IBD in rats that is comparable to that of prednisolone and may be because of the presence of flavonoids, terpenoids, and phenolic compounds. PMID- 20927246 TI - Mechanism of cardioprotective effect of erythropoietin-induced preconditioning in rat heart. AB - OBJECTIVE: The cardioprotective potential of human recombinant erythropoietin (alpha) (Epo) against ischemia-reperfusion-induced injury is well known. But, the underlying mechanisms are not well elucidated. The aim of this study was to characterize the mechanism involved in the cardioprotective effect of Epo-induced preconditioning in isolated rat heart. MATERIALS AND METHODS: The heart was mounted on a Langendorff apparatus. After 10 min of stabilization, four cycles of ischemic preconditioning (IPC) were given followed by 30 min of global ischemia and 120 min of reperfusion. Epo preconditioning was induced by four cycles of 5 min perfusion of K-H solution containing Epo (1.0 U/ml) followed by 5 min perfusion with K-H solution. Myocardial infarct size was estimated macroscopically using the triphenyltetrazolium chloride staining technique. The extent of myocardial injury was measured by release of lactate dehydrogenase and creatine kinase-MB in the coronary effluent. RESULTS: The present study demonstrates that Epo preconditioning was almost as effective as IPC. Administration of Wortmannin (100 nM), a PI-3K inhibitor, or Chelerythrine (1 uM), a protein kinase-C (PKC) inhibitor, or AG490 (5 uM), a JAK-2 inhibitor, significantly attenuated the cardioprotective effects of Epo-induced preconditioning. CONCLUSION: Our result suggest that the cardioprotective potential of Epo-induced preconditioning in isolated rat heart was due to an interplay of the JAK-2, PI-3K and PKC pathways. Inhibition of any one of the three pathways was sufficient to block the cardioprotective effect of Epo-induced preconditioning in isolated rat heart. PMID- 20927247 TI - Antidiabetic activity of Cassia occidentalis (Linn) in normal and alloxan-induced diabetic rats. AB - OBJECTIVE: To evaluate the hypoglycemic activity of various extracts, petroleum ether, chloroform and aqueous extract of Cassia occidentalis in normal and alloxan-induced diabetic rats. MATERIALS AND METHODS: Petroleum ether, chloroform and aqueous extract of whole plant of Cassia occidentalis were orally tested at the dose of 200 mg/kg for hypoglycemic effect in normal and alloxan-induced diabetic rats. In addition, changes in body weight, serum cholesterol, triglyceride and total protein levels, assessed in the ethanol extract-treated diabetic rats, were compared with diabetic control and normal animals. Histopathological observations during 21 days treatment were also evaluated. RESULTS: Aqueous extract of C. occidentalis produced a significant reduction in fasting blood glucose levels in the normal and alloxan-induced diabetic rats. Apart from aqueous extract, petroleum ether extract showed activity from day 14 and chloroform extract showed activity from 7 days. Significant differences were observed in serum lipid profiles (cholesterol and triglyceride), serum protein, and changes in body weight by aqueous extract treated-diabetic animals, when compared with the diabetic control and normal animals. Concurrent histopathological studies of the pancreas of these animals showed comparable regeneration by extract which were earlier necrosed by alloxan. CONCLUSION: Aqueous extract of C. occidentalis exhibited significant antihyperglycemic activity in normal and alloxan-induced diabetic rats. They also showed improvement in parameters like body weight and serum lipid profiles as well as histopathological studies showed regeneration of beta-cells of pancreas and so might be of value in diabetes treatment. PMID- 20927248 TI - Nature of action of Sitagliptin, the dipeptidyl peptidase-IV inhibitor in diabetic animals. AB - OBJECTIVE: The aim of this study was to evaluate the dipeptidyl peptidase-IV (DPP IV) inhibitor sitagliptin with respect to mode of inhibition and its in vivo duration of inhibition and efficacy in type 2 diabetes animal model. MATERIALS AND METHODS: DPP-IV enzyme assay was carried out in human plasma (10 MUL) or human recombinant enzyme (10 ng) using H-Gly-Pro-AMC as a substrate. The competitive nature was estimated by plotting IC(50) values measured at different substrate concentrations on the Y axis and substrate concentration on the X axis. The tight binding nature was estimated by plotting IC(50) values measured at different plasma volumes on the Y axis and plasma volumes on the X axis. Fast binding kinetics was assessed by progressive curves at different inhibitor concentrations in the DPP-IV assay. The reversibility of the inhibitor was assessed by a dissociation study of the DPP-IV-sitagliptin complex. Durations of DPP-IV inhibition and efficacy were shown in ob/ob mice dosed at 10 mg/kg, p.o. RESULTS: Sitagliptin is a competitive, reversible, fast and tight binding DPP-IV inhibitor. In ob/ob mice, 10 mg/kg, (p.o.) showed a long duration of inhibition of > 70% at 8 h. The duration was translated into long duration of efficacy (~ 35% glucose excursion at 8 h) in the same model and the effect was comparable to vildagliptin. CONCLUSION: The DPP-IV inhibitor sitagliptin behaves as a competitive, tight, and fast binding inhibitor. Sitagliptin differs mechanistically from vildagliptin and exhibits comparable efficacy to that of latter. The finding may give an understanding to develop-second generation DPP-IV inhibitors with desired kinetic profiles. PMID- 20927249 TI - Evaluation of Cassia occidentalis for in vitro cytotoxicity against human cancer cell lines and antibacterial activity. AB - OBJECTIVE: To evaluate the in vitro cytotoxicity and antibacterial properties of Cassia occidentalis (whole plant) via alcoholic, hydro-alcoholic, and aqueous extracts against eight human cancer cell lines from six different tissues and four bacterial strains. MATERIAL AND METHODS: in vitro cytotoxicity against the human cancer cells, cultured for 48h in presence of different concentrations C. occidentalis extracts and percentage of cell viability, was evaluated using the sulforhodamine-B (SRB) assay. The antibacterial activity was performed using the standard protocol against bacterial strains. RESULTS: It was observed that aqueous extract of C. occidentalis (whole plant) had more potential than hydro alcoholic and alcoholic extracts against HCT-15, SW-620, PC-3, MCF-7, SiHa, and OVCAR-5 human cancer cell lines at 100, 30, and 10 MUg/ml in a dose-dependent manner. The hydro-alcoholic extract showed potential against Bacillus subtillis. CONCLUSION: The plant can be explored for the possible development of lead molecules for drug discovery. PMID- 20927250 TI - Propofol and priapism. AB - Propofol-induced priapism in a 25-year-old male confirmed by rechallenge is reported for its rarity and to create awareness among practitioners, because propofol is used frequently in India for the induction and maintenance of anesthesia or sedation. The probable mechanisms are highlighted. Because propofol causes low-flow priapism, early alleviation is essential to minimize and/or avert the long-term complications. PMID- 20927251 TI - Rifampicin-induced thrombocytopenia. AB - In the treatment of tuberculosis there are special therapeutic problems related to adverse effects of drugs, compliance to treatment, and microbial resistance. Thrombocytopenia is an uncommon but potentially fatal adverse effect of certain anti-tubercular drugs when the incriminating drug is taken by a susceptible individual. We report a case of rifampicin-induced thrombocytopenia, which although rare, needs attention. PMID- 20927252 TI - Unusual nail pigmentation following cyclophosphamide-containing chemotherapy regimen. AB - Cyclophosphamide therapy may rarely cause pigmentation of the nails which is of different patterns. We report a patient who developed pigmentation of nails after six cycles of cyclophosphamide, methotrexate, and 5-flourouracil chemotherapy, each repeated after 28 days for breast cancer. The patient developed nail pigmentation that started proximally and spread distally and involved all the nails of both hands and feet except the second and third toenails of right foot. Using Naranjo ADR Probability Scale, the case revealed a "probable" association with cyclophosphamide. PMID- 20927253 TI - Diffuse skeletal pain after administration of alendronate. AB - BACKGROUND: Osteoporosis is caused by bone resorption in excess of bone formation, and bisphosphonates, are used to inhibit bone resorption. Alendronate, a biphosphonate, is effective for both the treatment and prevention of osteoporosis in postmenopausal women. Side effects are relatively few and prominently gastrointestinal. Musculoskeletal pain may be an important side effect in these patients. We presented a patient admitted to our out-patient clinic with diffuse skeletal pain after three consecutive administration of alendronate. CONCLUSION: We conclude that patients with osteoporosis can report pain, and bisphosphonate-related pain should also be considered before ascribing this complaint to osteoporosis. PMID- 20927254 TI - Capreomycin-induced optic neuritis in a case of multidrug resistant pulmonary tuberculosis. AB - A patient of multidrug-resistant pulmonary tuberculosis was prescribed an anti tubercular regimen containing capreomycin. Patient developed optic neuritis 3 months after starting treatment. Investigations did not reveal any specific cause for this ocular condition and on discontinuing capreomycin his vision recovered. We conclude that capreomycin is the cause of reversible optic neuritis in our case. PMID- 20927255 TI - Drug safety monitoring in patients of movement disorders of a tertiary care hospital. AB - BACKGROUND: Movement disorders (MD) are neurological conditions that affect the speed, fluency, quality, and ease of movement and commonly include Parkinson's disease, tremor and dystonias. Drugs are important causes of MD, and the incidence and prevalence of such disorders are possibly underappreciated because of the lack of recognition. OBJECTIVES: To assess the incidence of all adverse drug reactions (ADRs) and estimate the prevalence of drug-induced MD among patients attending the clinic. MATERIALS AND METHODS: This prospective observational study was conducted at an outpatient referral MD clinic of a tertiary care hospital for 1 year. The demographic data, drug intake, diagnosis, and ADRs experienced by the subjects were recorded. Causality assessment was done by Naranjo's scale. RESULTS: Incidence of ADR among patients who attended this clinic was 19.7% (151 out of 768 patients experienced at least one ADR). A total of 299 ADRs were detected out of which 30.8% were gastrointestinal, 28.4% psychiatric, and 26% MD effects. The commonly implicated suspect drugs were levodopa (37.8%) and trihexyphenidyl (25.1%). The prevalence of drug-induced MD was 10.15% and drug-induced dyskinesias and dystonias were the most common. CONCLUSION: MDs are clinically important neurological disorders which are often caused by drugs and interestingly drugs used for its management are also associated with high incidence of ADRs. Hence these ADRs should be carefully monitored. PMID- 20927257 TI - A survey on postgraduate pharmacology education in India. PMID- 20927256 TI - Pharmacovigilance on olanzapine. PMID- 20927258 TI - The need for introducing medication vials tailored for pediatric use. Where do we stand? PMID- 20927259 TI - Effect of participation in a clinical trial on glycemic control in type 2 diabetic patients. PMID- 20927260 TI - SJA is now on PubMed. PMID- 20927261 TI - Personalized intravenous regional anesthesia. PMID- 20927262 TI - Comparison of epidural ropivacaine and ropivacaine clonidine combination for elective cesarean sections. AB - BACKGROUND AND AIM: Neuraxial adjuvants augment the action of local anesthetics. The aim is to determine the qualitative and quantitative aspects of epidural block of ropivacaine 0.75% versus ropivacaine 0.75% with clonidine for elective cesarean section. SETTINGS AND DESIGN: A randomized double-blind study was conducted among 51 healthy parturients, scheduled for elective cesarean section, at Gian Sagar Medical College and Hospital, Banur, Punjab, India. MATERIALS AND METHODS: Epidural block was administered with 20 ml of ropivacaine 0.75% (group R) and ropivacaine 0.75% and clonidine 75 ug (group RC) and anesthetic level was achieved minimum until T6-T7 dermatome. Onset time of analgesia, sensory and motor block levels, maternal heart rate and blood pressure, neonatal Apgar scores, postoperative analgesic dose and adverse events were recorded. RESULTS: Fifty one patients were enrolled in this study and were subjected to statistical analysis. Groups were comparable with regard to demographic data, neonatal Apgar scores and incidences of side effects except for the higher incidence of dry mouth in patients of RC group. Onset of analgesia was much shorter in RC group along with prolonged duration of analgesia. The incidence of bradycardia and hypotension was more in RC group as compared to R group which was statistically significant. The dose requirement for postoperative pain relief was significantly lesser in RC group. CONCLUSIONS: The addition of 75 ug clonidine to isobaric epidural ropivacaine results in longer, complete and effective analgesia with similar block properties and helped to reduce the effective dose of ropivacaine when compared with plain ropivacaine for cesarean delivery. PMID- 20927263 TI - Does the use of ketamine or nitroglycerin as an adjuvant to lidocaine improve the quality of intravenous regional anesthesia? AB - AIMS: To compare and evaluate the effect of adding ketamine or nitroglycerin (NTG) as adjuncts to lidocaine for intravenous regional anesthesia (IVRA) on intraoperative and postoperative analgesia, sensorial and motor block onset times, and tourniquet pain. SETTINGS AND DESIGN: A prospective, randomized, double-blind study was carried out. MATERIALS AND METHODS: Seventy-five patients undergoing hand surgery were divided into three groups as follows: control group receiving lidocaine 2%, LK group receiving lidocaine 2% with ketamine, and LN group administered lidocaine 2% with NTG. Sensory and motor blocks' onset and recovery times were recorded. Visual analog scale (VAS) for tourniquet pain was measured after tourniquet application and it was also used to measure postoperative pain. Analgesic consumption for tourniquet pain and postoperatively were recorded. RESULTS: Sensory block onset times were shorter in the LK (4.4 +/- 1.2 minutes) and LN (3.5 +/- 0.9 minutes) groups compared with the control group (6.5 +/- 1.1 minute) (P < 0.0001) and motor block onset times were shorter in the LK (7.3 +/- 1.6 minutes) and LN (3.6 +/- 1.2 minutes) groups compared with the control group (10.2 +/- 1.5 minutes) (P< 0.0001). Sensory recovery time prolonged in the LK (6.7 +/- 1.3 minutes) and LN (6.9 +/- 1.1 minutes) groups compared with the control group (5.3 +/- 1.4 minutes) (P = 0.0006 and < 0.0001, respectively). Motor recovery time prolonged in the LK (8.4 +/- 1.4 minutes) and LN (7.9 +/- 1.1 minutes) groups compared with the control group (7.1 +/- 1.3 minutes) (P = 0.0014 and 0.023, respectively). The sensory and motor block onset times were also shorter in LN group than in the LK group (3.5 +/- 0.9 versus 4.4 +/- 1.2 minutes, P=0.004; and 3.6 +/- 1.2 versus 7.3 +/- 1.6 minutes, P < 0.0001, respectively). The amount of fentanyl required for tourniquet pain was less in adjuvant groups when compared with control group. It was 13.6 +/- 27.9 and 27.6 +/- 34.9 ug in LK group and LN groups, respectively, versus 54.8 +/- 28 ug in the control group. VAS scores of tourniquet pain were higher at 10, 20, 30, 40 minutes in the control group compared with the other study groups (P < 0.0001). It was also higher in LN group compared with LK group at 30 and 40 minutes (P < 0.001). Postoperative VAS scores were higher for the first 4 h in control group compared with the other study groups (P< 0.0001). CONCLUSIONS: The adjuvant drugs (ketamine or NTG) when added to lidocaine in IVRA were effective in improving the overall quality of anesthesia, reducing tourniquet pain, increasing tourniquet tolerance and improving the postoperative analgesia in comparison to the control group. Ketamine as an adjuvant produced better tolerance to tourniquet than the other groups. NTG as an adjuvant produced faster onset of sensory and motor blockades in comparison to other groups. PMID- 20927264 TI - Mixed venous versus central venous oxygen saturation in patients undergoing on pump beating coronary artery bypass grafting. AB - OBJECTIVE: To examine the validity of central venous oxygen saturation (ScvO(2)) as a numerical substitution of mixed venous oxygen saturation (SvO(2)) in adult patients undergoing normothermic on pump beating coronary artery bypass grafting (CABG). MATERIALS AND METHODS: Prospective clinical observational study was done at King Khalid University Hospital, King Saud University, Riyadh, Kingdom of Saudi Arabia. Thirty four adult patients scheduled for coronary artery surgery were included. Patients were monitored by a pulmonary artery catheter (PAC) as a part of our routine intraoperative monitoring. SvO(2) and ScvO(2) were simultaneously measured 15 minutes (T1) and 30 minutes (T2) after induction of anesthesia, 15 and 30 minutes after initiation of cardiopulmonary bypass (T3 and T4), and 15 and 30 minutes after admission to intensive care unit (T5 and T6). RESULTS: ScvO(2) showed higher reading than SvO(2) all through our study. Our results showed perfect positive statistically significant correlation between SvO(2) and ScvO(2) at all data points. Individual mean of difference (MOD) between both the readings at study time showed MOD of 1.34 and 1.44 at T1 and T2 simultaneously. This MOD was statistically insignificant, but after on pump beating normothermic bypass was initiated; MOD was 5.2 and 4.4 at T3 and T4 with high statistical significance. In ICU, MOD continues to have high statistical significance, MOD was 6.3 at T5 and at T6 it was 4.6. CONCLUSIONS: In on pump beating CABG patients; ScvO(2) and SvO(2) are not interchangeable numerically. ScvO(2) is useful in the meaning of trend; our data suggest that ScvO(2) is equivalent to SvO(2) , only in the course of clinical decisions as long as absolute values are not required. PMID- 20927265 TI - Survival after in-hospital cardiopulmonary resuscitation in a major referral center. AB - AIM: This study was undertaken to assess the demographics, clinical parameters and outcomes of patients undergoing cardiopulmonary resuscitation (CPR), by the code blue team at our center to compare with other centers. MATERIALS AND METHODS: Data were collected retrospectively from all adult patients who underwent CPR at our hospital from 2007 to 2008. CPR was performed on 290 patients and it was given 313 times. Clinical outcomes of interest were survival at the end of CPR and survival at discharge from the hospital. Factors associated with survival were evaluated via binomial and chi square-tests. RESULTS: Of the 290 patients included, 95 patients (30.4%) had successful CPR. However, only 35 patients (12%) were alive at discharge. The majority requiring CPR were above 60 years of age (61.7%). Males required CPR more than females. There were 125 women (43.1%) and 165 males (56.9%) aged 3 to 78 (average 59.6) years. Majority (179) of the cases (61.7%) were above 60 years of age. Regarding the various wards, 54 cases (17.3%) were in the internal medicine ward, 63 cases (20.1%) in the surgery ward, 1 case (0.3%) in the clinic, 11 cases (3.5%) in the paraclinic, 116 cases (37.1%) in the emergency (ER), 55 cases (17.5%) in the Intensive Care Unit (ICU) and Coronary Care Unit (CCU), and 13 cases (4.2%) were in other wards. Cardiac massage was done in 133 cases (42.5%), defibrillation only via electroshock 3 cases (1%), and both were used in177 cases (56.5%). The ER had the most cases of CPR. Both cardiac massage and electroshock defibrillation were needed in most cases. CONCLUSION: In-hospital CPR for cardiopulmonary arrest was associated with 30.4% success at our center at the end of CPR but only 12% were alive at discharge. Duration of CPR >10 minutes was predictive of significantly decreased survival to discharge. PMID- 20927266 TI - Comparison of two drug combinations in total intravenous anesthesia: Propofol ketamine and propofol-fentanyl. AB - BACKGROUND AND AIMS: Keeping in consideration the merits of total intravenous anesthesia (TIVA), a genuine attempt was made to find the ideal drug combinations which can be used in general anesthesia. This study was conducted to evaluate and compare two drug combinations of TIVA using propofol-ketamine and propofol fentanyl and to study the induction, maintenance and recovery characteristics following anesthesia with these techniques. SETTINGS AND DESIGN: A case control study was conducted, which included 100 patients, in the department of Anaesthesiology and Intensive care, Government Medical College and Hospital, Patiala. PATIENTS AND METHODS: A hundred patients between the ages of 20 and 50 years of either gender were divided into two groups of 50 each, and they underwent elective surgery of approximately 1 h duration. Group I received propofol-ketamine while group II received propofol-fentanyl for induction and maintenance of anesthesia. All the results were tabulated and analyzed statistically with student's unpaired t-test and chi-square test. RESULTS: Propofol-fentanyl combination produced a significantly greater fall in pulse rate (PR; 9.28% versus 0.23%) and in both systolic (7.94% versus 0.12%) and diastolic blood pressures (BP; 8.10% versus 0.35%) as compared to propofol-ketamine during induction of anesthesia. Propofol-ketamine combination produced stable hemodynamics during maintenance phase while on the other hand propofol-fentanyl was associated with a slight increase in both PR and BP. During recovery, ventilation score was better in group I while movement and wakefulness score was better in group II. Mean time to protrusion of tongue and lifting of head was shorter in group I. CONCLUSIONS: Both propofol-ketamine and propofol-fentanyl combinations produce rapid, pleasant and safe anesthesia with only a few untoward side effects and only minor hemodynamic effects. PMID- 20927267 TI - Comparison of classic peribulbar anesthesia and new entry point (single percutaneous injection technique) in vitroretinal surgery. AB - PURPOSE: To describe the method that seeks to improve the administration of regional anesthesia for vitroretinal surgery avoiding the risk of potential complications associated with other techniques through comparison of safety and efficacy of classic peribulbar anesthesia versus single percutaneous technique using a prospective, randomized clinical trial. MATERIALS AND METHODS: One hundred patients were randomized to classic peribulbar and single percutaneous peribulbar technique after informed consent. Pain during administration of anesthesia, during surgery was graded on a visual analogue pain scale and compared for both techniques. Globe akinesia, analgesia and IOP measurements before and after administration of anesthesia, detection of distribution of local anesthetic agent by ultrasound scanning and complications related were also compared. RESULTS: Twenty out of 50 (40%) patients of group 1(classic pirebulbar) and 36/50 (72%) of group II (single percutaneous technique) experience no pain during administration of anesthesia. Scores for globe akinesia and anesthesia were less satisfactory in group 1 and supplemental blocks required in 8% of the patients while in group II all of the patients (100%) showed proper globe akinesia and anesthesia. There were significant elevation in mean IOP following injection in both groups and the incidence of subconjunctival haemorrhage, chemosis and echymosis were more frequent in group 1. CONCLUSION: Single percutaneous peribulbar technique proved to be a safe and efficient technique that offers excellent anesthesia and akinesia with less complication for various ophthalmic procedures. PMID- 20927268 TI - Conventional mechanical ventilation. AB - The provision of mechanical ventilation for the support of infants and children with respiratory failure or insufficiency is one of the most common techniques that are performed in the Pediatric Intensive Care Unit (PICU). Despite its widespread application in the PICUs of the 21st century, before the 1930s, respiratory failure was uniformly fatal due to the lack of equipment and techniques for airway management and ventilatory support. The operating rooms of the 1950s and 1960s provided the arena for the development of the manual skills and the refinement of the equipment needed for airway management, which subsequently led to the more widespread use of endotracheal intubation thereby ushering in the era of positive pressure ventilation. Although there seems to be an ever increasing complexity in the techniques of mechanical ventilation, its successful use in the PICU should be guided by the basic principles of gas exchange and the physiology of respiratory function. With an understanding of these key concepts and the use of basic concepts of mechanical ventilation, this technique can be successfully applied in both the PICU and the operating room. This article reviews the basic physiology of gas exchange, principles of pulmonary physiology, and the concepts of mechanical ventilation to provide an overview of the knowledge required for the provision of conventional mechanical ventilation in various clinical arenas. PMID- 20927269 TI - Dynamic left ventricular outflow tract obstruction complicating aortic valve replacement: A hidden malefactor revisited. AB - It is known that a dynamic left ventricular outflow tract (LVOT) obstruction exists in patients, following aortic valve replacement (AVR) and is usually considered to be benign. We present a patient with dynamic LVOT obstruction following AVR, who developed refractory cardiogenic shock and expired inspite of various treatment strategies. This phenomenon must be diagnosed early and should be considered as a serious and potentially fatal complication following AVR. The possible mechanisms and treatment options are reviewed. PMID- 20927270 TI - Severe lingual tonsillar hypertrophy and the rationale supporting early use of wire-guided retrograde intubation. AB - An expanding body of literature exists which describes the airway challenges and management options for lingual tonsillar hypertrophy (LTH). The use of retrograde intubation to secure a patient's airway in the setting of LTH has been previously unreported and should be considered early in the event of a cannot intubate, cannot ventilate scenario. A 55-year-old man, who had previously been described as an easy intubation, presented an unexpected cannot intubate, cannot ventilate scenario secondary to LTH. Various noninvasive airway maneuvers were attempted to restore ventilation without success. We describe the advantages of early use of wire-guided retrograde intubation as an alternative to a surgical airway for obtaining a secure airway in a patient with LTH, in whom noninvasive airway management maneuvers have failed. Multiple different noninvasive approaches to management of LTH have been previously described including the laryngeal tube, laryngeal mask airway, and fiberoptic bronchoscopy. Unfortunately, none of these noninvasive airway maneuvers successfully ventilated this patient and an invasive airway became necessary. Retrograde intubation is a less invasive alternative to the surgical airway with potentially less risk for complications. Retrograde intubation may be particularly effective in the setting of LTH as it may stent open an otherwise occluded airway and allow passage of an endotracheal tube. Skillful use of this technique should be considered early as a viable option in any case of unexpected difficult intubation due to LTH. PMID- 20927271 TI - Difficult intubation management in a child with I-cell disease. AB - I-cell disease (mucolipidosis II) is a rare metabolic disorder resulting from the deficiency of a specific lysosomal enzyme, N-acetylglucosamine-1 phosphotransferease. Developmental delay and growth failure are common presentations of I-cell disease. Psychomotor deterioration is rapid and progressive. Some physical signs such as hip dislocations, inguinal hernia, hepatomegaly, joint limitation, and skin changes may be present at birth. Coarse facial features and skeletal abnormalities become more conspicuous with time. The life expectancy of children with this condition is poor, with death usually occurring around the fifth year. A case report of the anesthetic management of gingivectomy with multiple dental extractions in a 5-year-old Omani female with I cell disease is presented. The problems faced and their management during anesthesia are described. PMID- 20927272 TI - Endotracheal tube defects: Hidden causes of airway obstruction. AB - Manufacturing defects of endotracheal tube (ETT) are still encountered in anesthesia practice. Many such defects go unnoticed during routine inspection prior to their use. Such defects in ETT may lead to partial or complete airway obstruction in an intubated patient. We report a case of partial airway obstruction with a prepacked, single use, uncuffed ETT due to a manufacturing defect in the form of a plastic meniscus at the distal end of the tube. This case report highlights the significance of standard monitoring of ventilation and the role of a vigilant clinician in detecting such defects in avoiding critical events as can arise from the use of such defective ETTs. It also emphasizes the need for double checking ETTs prior to their use. PMID- 20927273 TI - Ventricular tachycardia during microdebrider-assisted turbinectomy: An electrocardiographic artifact. AB - Interference of monitored electrocardiogram is common during different surgical procedures using electrical equipment. The electrical devices used induce artifacts in the electrocardiographic tracing, which may resemble serious arrhythmia. We describe a case of electrocardiographic artifact resembling ventricular tachycardia with the use of a Storz unidrive microdebrider during inferior turbinectomy under general anesthesia. This case report highlights the importance of knowledge of various equipment-related electrocardiographic artifacts in avoiding unnecessary and harmful therapeutic interventions. PMID- 20927274 TI - Pulmonary artery catheter entrapment in cardiac surgery. AB - A pulmonary artery catheter (PAC) is an important tool in the preoperative cardiac management, and it provides measurements which helps in the patient management During open heart surgery the catheter tends to rest against the anterior lateral wall of the right atrium where the catheter may be caught by a suture in the cannulation for cardiopulmonary bypass. We describe a very rare complication which is inadvertent surgical suturing of the PAC to the inferior vena cava that necessitated reopening the chest, cutting, the suture and removing the catheter. PMID- 20927275 TI - Pseudo loss of resistance in epidural space localization. PMID- 20927276 TI - Ultrasound guided femoral nerve block: An essential pain management modality in emergency settings for femur fractures. PMID- 20927277 TI - State of the Globe: Rabies is Still Rampant and Needs Action. PMID- 20927278 TI - Surveying Infections among Pregnant Women in the Niger Delta, Nigeria. AB - BACKGROUND: There is paucity of epidemiological data on infectious diseases among antenatal mothers in Bayelsa State of the Niger Delta, Nigeria. AIMS: The aim of this study was to determine the seroprevalence of the serological markers Human immunodeficiency virus-antibody (HIV-Ab), Hepatitis B surface antigen(HBsAg), Hepatitis C virus antibody(HCV-A)and antibodies to T. pallidum among pregnant women in Yenagoa, Bayelsa State, South-South Nigeria. SETTINGS AND DESIGN: This is a cross-sectional study which was carried out in Yenagoa city, the heart of the Niger Delta, Nigeria. MATERIALS AND METHODS: Human immunodeficiency virus (HIV) antibodies were detected by using "Determine" HIV-1/2 test strip (Abbott Laboratories, Japan); hepatitis B surface antigen (HBsAg), antibodies to hepatitis C virus (anti-HCV) and antibodies to T. pallidum were carried out using ACON rapid test strips (ACON Laboratories, USA). All positive samples for HIV, HBV and HCV were confirmed using the Clinotech diagnostic enzyme-linked immunosorbent assay (ELISA) test kits (Clinotech Laboratories, USA), while all reactive samples to Treponema pallidum antibodies were confirmed by the Treponema pallidum hemagglutination (TPHA) test (Lorne Laboratories Ltd., UK). All test procedures were carried out according to the manufacturers' instructions. STATISTICAL ANALYSIS USED: The data generated were coded, entered, validated and analyzed using Statistical Package for Social Science (SPSS), version 12.0, and Epi info. The seroprevalence of syphilis, HBsAg, HCV and HIV was expressed for the entire study group by age, sex and other demographic features using Pearson chi-square analysis. Values below 0.05 were considered statistically significant. RESULTS: A total of 1,000 apparently healthy pregnant women aged between 15 and 44 years with a mean of 27.34+/-5.43 years were screened. In terms of percentage, 89.4% of the subjects were married, and 10.6% were without formal husbands. The overall seroprevalence of HIV, HBsAg, HCV and syphilis was found to be 4.1%, 5.3%, 0.5% and 5.0%, respectively. CONCLUSIONS: High prevalence of some infectious diseases was observed in the present study, which may pose serious health risk to women of reproductive age in this region. It is important to point out that there is need to improve antenatal care of pregnant women by mandatory screening for these infectious diseases. PMID- 20927279 TI - Current Knowledge Attitudes, and Practices of Healthcare Providers about Leprosy in Assam, India. AB - BACKGROUND: Leprosy is a chronic infectious disease that is associated with serious morbidity and is a disease of public health concern because of the case load and the social stigma attached to the disease. AIM: To understand the knowledge of, and attitudes towards, leprosy amongst healthcare providers in Assam, India. SETTINGS AND DESIGN: This cross-sectional study was conducted during March to June 2007 in different health institutions of the Kamrup district of Assam. RESULTS: Among the program managers interviewed, only half were organizing training sessions, and 37.5% were involved in supervision of the program activities at the periphery level. Among the program managers who were involved with leprosy elimination, only half were organizing training session and 37.5% were involved in supervision of the program activities at the periphery level. Medical officers consistently demonstrated higher knowledge about leprosy, followed by health supervisors and multipurpose workers (MPWs), including nursing staff. Regarding training status with regard to leprosy, 90% of medical officers, 80% of health supervisors and around 87% of MPWs (83% of male MPWs and 89% of female MPWs) had attended training programs on leprosy. Regarding WHO MDT, 80% of health supervisors, 84.8% of male MPWs and 86.2% of female MPWs had an idea of MDT and treatment duration of various categories of patients. CONCLUSIONS: These observations suggest that there appear to be adequate knowledge and positive behavior among healthcare providers with regard to leprosy in this part of India. However, there is still a need to organize training programs at regular intervals to train new recruits, as well as reinforce and update the knowledge of those already trained. PMID- 20927280 TI - Retrospective analysis of suspected rabies cases reported at bugando referral hospital, mwanza, Tanzania. AB - AIMS: The aim of this study was to determine the incidence of humans being bitten by rabies-suspected animals, and the victims' adherence to post-exposure prophylaxis (PEP) regimen. MATERIALS AND METHODS: A retrospective analysis of data of victims treated at Bugando Medical Centre during the period 2002-2006 (n=5 years) was done. RESULTS: A total of 767 bite injuries inflicted by rabies suspected animals were reported, giving a mean annual incidence of ~58 cases per 100,000 (52.5% males, 47.5% females). The proportion of children bitten was relatively higher than that of adults. All victims were treated by using inactivated diploid-cell rabies vaccine and were recommended to appear for the second and third doses. However, only 28% of the victims completed the vaccination regime. Domestic dogs were involved in 95.44% of the human bite cases, whereas cats (3.9%), spotted hyena (Crocuta crocuta) (0.03%), vervet monkey (Cercopithecur aethiops) (0.01%) and black-backed jackal (0.01%) played a minor role. The majority of rabies-suspected case reports were from Nyamagana district and occurred most frequently from June to October each year. CONCLUSIONS: In conclusion, this study revealed that incidences of humans being bitten by dogs suspected of rabies are common in Tanzania, involve mostly children, and victims do not comply with the prophylactic regimen. Rigorous surveillance to determine the status of rabies and the risk factors for human rabies, as well as formulation and institution of appropriate rabies-control policies, is required. PMID- 20927281 TI - Solar disinfection improves drinking water quality to prevent diarrhea in under five children in sikkim, India. AB - BACKGROUND: Solar radiations improve the microbiological quality of water and offer a method for disinfection of drinking water that requires few resources and no expertise and may reduce the prevalence of diarrhea among under-five children. AIMS AND OBJECTIVES: To find out the reduction in the prevalence of diarrhea in the under-five children after consumption of potable water treated with solar disinfection method. MATERIALS AND METHODS: This was a population-based interventional prospective study in the urban slum area of Mazegoan, Jorethang, south Sikkim, during the period 1(st) May 2007 to 30(th) November 2007 on 136 children in the under-five age group in 102 households selected by random sampling. Main outcome measure was the assessment of the reduction of the prevalence of diarrhea among under-five children after consumption of potable water treated with solar disinfection method practiced by the caregivers in the intervention group keeping water in polyethylene terephthalate (PET) bottles as directed by the investigators. The data were collected by the interview method using a pre-tested questionnaire prepared on the basis of socio-demographics and prevalence of diarrhea. The data were subjected to percentages and chi-square tests, which were used to find the significance. RESULTS: After four weeks of intervention among the study group, the diarrhea prevalence was 7.69% among solar disinfection (SODIS) users, while 31.82% prevalence was observed among non-users in that period; the reduction in prevalence of diarrhea was 75.83%. After eight weeks of intervention, the prevalence of diarrhea was 7.58% among SODIS users and 31.43% among non-users; the reduction in diarrhea was 75.88% in the study group. The findings were found to be statistically significant. CONCLUSIONS: In our study, we observed that the prevalence of diarrhea decreased significantly after solar disinfection of water was practiced by the caregivers keeping potable water in PET bottles in the intervention group. PMID- 20927282 TI - Time of default in tuberculosis patients on directly observed treatment. AB - BACKGROUND: Default remains an important challenge for the Revised National Tuberculosis Control Programme, which has achieved improved cure rates. OBJECTIVES: This study describes the pattern of time of default in patients on DOTS. SETTINGS AND DESIGN: Tuberculosis Unit in District Tuberculosis Centre, Yavatmal, India; Retrospective cohort study. MATERIALS AND METHODS: This analysis was done among the cohort of patients of registered at the Tuberculosis Unit during the year 2004. The time of default was assessed from the tuberculosis register. The sputum smear conversion and treatment outcome were also assessed. STATISTICAL ANALYSIS: Kaplan-Meier plots and log rank tests. RESULTS: Overall, the default rate amongst the 716 patients registered at the Tuberculosis Unit was 10.33%. There was a significant difference in the default rate over time between the three DOTS categories (log rank statistic= 15.49, P=0.0004). Amongst the 331 smear-positive patients, the cumulative default rates at the end of intensive phase were 4% and 16%; while by end of treatment period, the default rates were 6% and 31% in category I and category II, respectively. A majority of the smear positive patients in category II belonged to the group 'treatment after default' (56/95), and 30% of them defaulted during re-treatment. The sputum smear conversion rate at the end of intensive phase was 84%. Amongst 36 patients without smear conversion at the end of intensive phase, 55% had treatment failure. CONCLUSIONS: Patients defaulting in intensive phase of treatment and without smear conversion at the end of intensive phase should be retrieved on a priority basis. Default constitutes not only a major reason for patients needing re-treatment but also a risk for repeated default. PMID- 20927283 TI - High-level Aminoglycoside Resistance and Reduced Susceptibility to Vancomycin in Nosocomial Enterococci. AB - OBJECTIVES: The objectives of the present study were to identify the species of enterococci isolated from nosocomial infections and to determine the antibiotic susceptibility pattern with reference to high-level aminoglycosides and vancomycin. MATERIALS AND METHODS: Enterococci were isolated from various clinical samples collected from patients after 72 hours of hospitalization. Various species of Enterococcus were identified by standard methods. High-level aminoglycoside resistance and vancomycin susceptibility in enterococci were detected by disk-diffusion and agar-screen methods. RESULTS: One hundred eighty enterococcal strains were isolated from various clinical samples. Various species of Enterococcus - Enterococcus fecalis 130 (72.22%), Enterococcus casseliflavus 24 (13.33%), Enterococcus fecium 17 (9.44%), Enterococcus durans 7 (3.89%) and Enterococcus dispar 2 (1.11%) - were isolated. The highest resistance to aminoglycoside was observed among E. fecium, followed by E. durans, E. fecalis and E. casseliflavus, both by disk-diffusion and agar-screen methods. The high level aminoglycoside resistance (HLAR) was significantly (P<0.05) higher in E. fecium by agar-screen method. All enterococci showed minimum inhibitory concentration (MIC) of <=8 MUg/mL to vancomycin. Sixteen (12.31%) E. fecalis and 3 (12.5%) E. fecium strains were intermediately resistant to vancomycin (MIC= 8 MUg/mL), whereas other strains were susceptible to vancomycin. CONCLUSION: The occurrence of high-level aminoglycoside resistance in enterococcal isolates in our setup was high. Even though none of the enterococcal strains showed resistance to vancomycin, yet reduced susceptibility to vancomycin was noticed in our study. This would require routine testing of enterococcal isolates for HLAR and vancomycin susceptibility. Agar-screen method was found to be superior to disk-diffusion method in detecting resistant strains to aminoglycosides and vancomycin. PMID- 20927284 TI - Correlates of Vaginal Colonization with Group B Streptococci among Pregnant Women. AB - BACKGROUND: A study of genital colonization by group B streptococcus (GBS) was conducted in pregnant women in their third trimester, which is a known risk factor of morbidity and mortality among newborns. AIMS: The present study was undertaken to study the prevalence and the correlates of vaginal colonization by GBS among pregnant women. SETTING AND DESIGN: This observational cross-sectional study was conducted during September 2002 to March 2004 on 524 pregnant women. MATERIALS AND METHODS: Three high vaginal swabs were obtained from all the pregnant women admitted at term and in preterm labor. Two swabs were used for aerobic culture and the third one for gram staining. The first set of swabs was cultured on 5% Sheep blood agar plates. The second set of swabs were inoculated into Todd-Hewitt broth and then subcultured in 5% Sheep blood agar plates. The main outcome measures were the presence of GBS infection in comparison to the age group, gravida, gestational age, premature rupture of membrane (PROM), preterm labor and association with febrile spells of the present pregnancy. RESULTS: The culture positivity rate of GBS was 4.77% and coexistent organisms isolated were Candida species (36%), Staphylococcus aureus (8%) and Enterococcus species (8%). Culture positivity in the age group of 18-25 years was 5.71%, of which 5.74% were in their first pregnancy. The correlation between age group and gravida with GBS culture positivity was statistically insignificant. The culture positivity in <36 weeks of gestational age was 6.93%. This relation was statistically significant. Twenty-eight percent developed PROM. Sixty-four percent of culture positives had preterm labor. CONCLUSION: GBS infection among pregnant women was significantly correlated with the gestational age, PROM and preterm labor. In pregnancy GBS colonization causes asymptomatic bacteriuria or UTI. It is a well known cause of puerperal infections with amnionitis, endometritis and sepsis being the most commonly reported infections.[5]. PMID- 20927285 TI - Oviposition Deterrence Induced by Ocimum kilimandscharicum and Ocimum suave Extracts to Gravid Anopheles gambiae s.s (Diptera: Culicidae) in Laboratory. AB - BACKGROUND: In most of the past decades, mosquito control has been done by the use of indoor residual spray and insecticides-treated bed nets. The control of mosquitoes by targeting the breeding sites (larval habitat) has not been given priority. Disrupting the oviposition sensory detection of mosquitoes by introducing deterrents of plant origin, which are cheap resources, might be add value to integrated vector control. Such knowledge is required in order to successfully manipulate the behavior of mosquitoes for monitoring or control. MATERIALS AND METHODS: Twenty gravid mosquitoes were placed in a cage measuring 30 * 30 * 30 cm for oviposition. The oviposition media were made of different materials. Experiments were set up at 6:00 pm, and eggs were collected for counting at 7:30 am. Mosquitoes were observed until they died. The comparisons of the number of eggs were made between the different treatments. RESULTS: There was significant difference in the number of eggs found in control cups when compared with the number of eggs found in water treated with Ocimum kilimandscharicum (OK) (P=0.02) or Ocimum suave (OS) (P=0.000) and that found in water with debris treated with OK (P=0.011) or OS (P=0.002). There was no significant difference in the number of eggs laid in treated water and the number of eggs laid in water with debris treated either with OK (P=0.105) or OS (P=0.176). Oviposition activity index for both OS and OK experiments lay in a negative side and ranged from -0.19% to -1%. The results show that OS and OK deter oviposition in An.gambiae s.s. CONCLUSIONS: Further research needs to be done on the effect of secondary metabolites of these plant extracts as they decompose in the breeding sites. In the event of favorable results, the potential of these plant extracts can be harnessed on a larger scale. PMID- 20927286 TI - Preventing Post-Transfusion Hepatitis by screening blood donors for IgM Antibody to Hepatitis B core antigen. PMID- 20927288 TI - Quinolone and cephalosporin resistance in enteric Fever. AB - Enteric fever is a major public health problem in developing countries. Ciprofloxacin resistance has now become a norm in the Indian subcontinent. Novel molecular substitutions may become frequent in future owing to selective pressures exerted by the irrational use of ciprofloxacin in human and veterinary therapeutics, in a population endemic with nalidixic acid-resistant strains. The therapeutics of ciprofloxacin-resistant enteric fever narrows down to third- and fourth-generation cephalosporins, azithromycin, tigecycline and penems. The first line antimicrobials ampicillin, chloramphenicol and co-trimoxazole need to be rolled back. Antimicrobial surveillance coupled with molecular analysis of fluoroquinolone resistance is warranted for reconfirming novel and established molecular patterns for therapeutic reappraisal and for novel-drug targets. This review explores the antimicrobial resistance and its molecular mechanisms, as well as novel drugs in the therapy of enteric fever. PMID- 20927287 TI - Human immunodeficiency virus and leishmaniasis. AB - The Leishmaniases are a group of diseases transmitted to humans by the bite of a sandfly, caused by protozoan parasites of the genus Leishmania. Various Leishmania species infect humans, producing a spectrum of clinical manifestations. It is estimated that 350 million people are at risk, with a global yearly incidence of 1-1.5 million for cutaneous and 500,000 for visceral Leishmaniasis (VL). VL is a major cause of morbidity and mortality in East Africa, Brazil and the Indian subcontinent. Co-infection with human immunodeficiency virus (HIV) alters the immune response to the disease. Here we review the immune response to Leishmania in the setting of HIV co-infection. Improved understanding of the immunology involved in co-infections may help in designing prophylactic and therapeutic strategies against Leishmaniasis. PMID- 20927289 TI - Extended-spectrum beta-lactamases in Gram Negative Bacteria. AB - Extended-spectrum beta-lactamases (ESBLs) are a group of plasmid-mediated, diverse, complex and rapidly evolving enzymes that are posing a major therapeutic challenge today in the treatment of hospitalized and community-based patients. Infections due to ESBL producers range from uncomplicated urinary tract infections to life-threatening sepsis. Derived from the older TEM is derived from Temoniera, a patient from whom the strain was first isolated in Greece. beta lactamases, these enzymes share the ability to hydrolyze third-generation cephalosporins and aztreonam and yet are inhibited by clavulanic acid. In addition, ESBL-producing organisms exhibit co-resistance to many other classes of antibiotics, resulting in limitation of therapeutic option. Because of inoculum effect and substrate specificity, their detection is also a major challenge. At present, however, organizations such as the Clinical and Laboratory Standards Institute (formerly the National Committee for Clinical Laboratory Standards) provide guidelines for the detection of ESBLs in Klebsiella pneumoniae, K. oxytoca, Escherichia coli and Proteus mirabilis. In common to all ESBL-detection methods is the general principle that the activity of extended-spectrum cephalosporins against ESBL-producing organisms will be enhanced by the presence of clavulanic acid. Carbapenems are the treatment of choice for serious infections due to ESBL-producing organisms, yet carbapenem-resistant isolates have recently been reported. ESBLs represent an impressive example of the ability of gram-negative bacteria to develop new antibiotic-resistance mechanisms in the face of the introduction of new antimicrobial agents. Thus there is need for efficient infection-control practices for containment of outbreaks; and intervention strategies, e.g., antibiotic rotation to reduce further selection and spread of these increasingly resistant pathogens. PMID- 20927290 TI - Methicillin and Vancomycin Resistant S. aureus in Hospitalized Patients. AB - S. aureus is the major bacterial cause of skin, soft tissue and bone infections, and one of the commonest causes of healthcare-associated bacteremia. Hospital associated methicillin-resistant S. aureus (MRSA) carriage is associated with an increased risk of infection, morbidity and mortality. Screening of high-risk patients at the time of hospital admission and decolonization has proved to be an important factor in an effort to reduce nosocomial transmission. The electronic database Pub Med was searched for all the articles on "Establishment of MRSA and the emergence of vancomycin-resistant S. aureus (VRSA)." The search included case reports, case series and reviews. All the articles were cross-referenced to search for any more available articles. A total of 88 references were obtained. The studies showed a steady increase in the number of vancomycin-intermediate and vancomycin-resistant S. aureus. Extensive use of vancomycin creates a selective pressure that favors the outgrowth of rare, vancomycin-resistant clones leading to heterogenous vancomycin intermediate S. aureus hVISA clones, and eventually, with continued exposure, to a uniform population of vancomycin-intermediate S. aureus (VISA) clones. However, the criteria for identifying hVISA strains have not been standardized, complicating any determination of their clinical significance and role in treatment failures. The spread of MRSA from the hospital to the community, coupled with the emergence of VISA and VRSA, has become major concern among healthcare providers. Infection-control measures, reliable laboratory screening for resistance, appropriate antibiotic prescribing practices and avoidance of blanket treatment can prevent long-term emergence of resistance. PMID- 20927291 TI - Cephalosporin Resistance in Neisseria gonorrhoeae. AB - Gonorrhea, a disease of public health importance, not only leads to high incidence of acute infections and complications but also plays a major role in facilitating human immunodeficiency virus (HIV) acquisition and transmission. One of the major public health needs for gonorrhea control is appropriate, effective treatment. However, treatment options for gonorrhea are diminishing as Neisseria gonorrhoeae have developed resistance to several antimicrobial drugs such as sulfonamides, penicillin, tetracyclines and quinolones. Antimicrobial resistance (AMR) surveillance of N. gonorrhoeae helps establish and maintain the efficacy of standard treatment regimens. AMR surveillance should be continuous to reveal the emergence of new resistant strains, monitor the changing patterns of resistance, and be able to update treatment recommendations so as to assist in disease control. Current treatment guidelines recommend the use of single dose injectable or oral cephalosporins. The emergence and spread of cephalosporin resistant and multi drug resistant N. gonorrhoeae strains, represents a worrying trend that requires monitoring and investigation. Routine clinical laboratories need to be vigilant for the detection of such strains such that strategies for control and prevention could be reviewed and revised from time to time. It will be important to elucidate the genetic mechanisms responsible for decreased susceptibility and future resistance. There is also an urgent need for research of safe, alternative anti-gonococcal compounds that can be administered orally and have effective potency, allowing high therapeutic efficacy (greater than 95.0% cure rate). PMID- 20927293 TI - Kikuchi-fujimoto disease from eastern India. AB - Kikuchi's disease, a rare disorder which usually presents with fever painful lymphadenopathy, rash and arthritis, all of which are close mimickers of infective and immunological disorders. It is essentially a histopathological diagnosis and tests to rule out other connective tissue disorders or infective etiology must be undertaken. We present a series of two cases of kikuchi fujimoto's disease presenting primarily with lymphadenopathy and fever in all cases. The first is a case of generalized lymphadenopathy and the second case of kikuchi's disease with SLE, a rare association. Lymph node excision biopsy and histopathology documented Kikuchi Fujimoto disease in above cases. All the cases improved on follow up and had no residual stigmata. PMID- 20927294 TI - Case Series of Adenocarcinoma of the Prostate Associated with Schistosoma haematobium Infection in Tanzania. AB - In endemic areas, schistosomiasis has been associated with the pathogenesis of bladder, prostate, colorectal and renal carcinoma. However, the relationship between prostate cancer and schistosomiasis infection remains controversial. Here we present a series of three cases from Tanzania of prostatic adenocarcinoma associated with urinary schistosomiasis. PMID- 20927292 TI - Multidrug resistant acinetobacter. AB - Emergence and spread of Acinetobacter species, resistant to most of the available antimicrobial agents, is an area of great concern. It is now being frequently associated with healthcare associated infections. Literature was searched at PUBMED, Google Scholar, and Cochrane Library, using the terms 'Acinetobacter Resistance, multidrug resistant (MDR), Antimicrobial Therapy, Outbreak, Colistin, Tigecycline, AmpC enzymes, and carbapenemases in various combinations. The terms such as MDR, Extensively Drug Resistant (XDR), and Pan Drug Resistant (PDR) have been used in published literature with varied definitions, leading to confusion in the correlation of data from various studies. In this review various mechanisms of resistance in the Acinetobacter species have been discussed. The review also probes upon the current therapeutic options, including combination therapies available to treat infections due to resistant Acinetobacter species in adults as well as children. There is an urgent need to enforce infection control measures and antimicrobial stewardship programs to prevent the further spread of these resistant Acinetobacter species and to delay the emergence of increased resistance in the bacteria. PMID- 20927295 TI - Bilateral Thalamic Hyperintensities in a case of Viral Encephalitis. PMID- 20927296 TI - Hepatitis B, needle stick and medical workers. PMID- 20927297 TI - Hepatitis C and helicobacter pylori. PMID- 20927298 TI - A cross-sectional study among medical residents with noninvasive rapid serological test for helicobacter pylori. PMID- 20927299 TI - Multiple-ring enhancing lesions in an immunocompetent adult. PMID- 20927300 TI - Severe rhabdomyolysis associated in meningococcemia. PMID- 20927301 TI - Drug resistant urinary isolates of pseudomonas aeruginosa and acinetobacter species. PMID- 20927302 TI - Mycoplasmotic giant cell epitheliomatous inverted papillary carcinoma of the aural canal. PMID- 20927303 TI - Psychopharmacological treatment status in outpatients with bipolar disorder: a clinical survey in Germany. AB - OBJECTIVE: The objective of this epidemiological study was to evaluate the current treatment status as well as the acceptance of medication and satisfaction with life in outpatients with bipolar disorder in Germany. METHODS: Data for this cross-sectional epidemiologic survey was collected between February 15th, 2006 and May 31st, 2006. Three hundreds six bipolar euthymic outpatients under routine treatment conditions were included in the study. Forty one practicing psychiatrists used a clinical interview to evaluate the current treatment status, acceptance of current medication, and current life satisfaction. RESULTS: The majority of patients suffered from "pure" bipolar-II-disorder (50.6%), followed by 23.0% with "pure" bipolar-I-disorder. Apart from these patients, 12.9% of all participants had a history of mixed episodes and 5.6% a history of rapid cycling. Mean duration of bipolar disorder was 10.6 years. The majority of patients (54.3%) received psychopharmacological monotherapy. Combination therapy was administered in 45.9% of the patients, 39.3% receiving two agents, and 6.6% three agents. Antidepressants (64.1%) were the most common combination medications. Monotherapy was used preferably in bipolar-I- (62.7%) and bipolar-II-disorders (56.2%), combination therapy predominantly in patients with a history of mixed episodes (57.7%) and rapid cycling (55.0%). Half of the patients (49.2%) were able to hold an occupation. 84.2% of all patients were satisfied with their medication. Overall, patients evaluated their life satisfaction between "good" and "satisfactory" (2.69 according to German school grades where 1 is the highest and 6 the lowest mark). Patients receiving lithium, valproate or antidepressants as monotherapy rated above the mean, patients with combination therapy, carbamazepine monotherapy or medications summarized as "others" rated below the mean. CONCLUSION: Most of the German outpatients received a pharmacotherapy that is recommended in the guidelines of bipolar disorder. The use of (atypical) antipsychotics was low. Conversely, the incidence of treatment with tricyclic antidepressants (not guideline compatible), was observed to be relatively high. Irrespective of their medication, in Germany patients with bipolar disorder show a high acceptance of their pharmacotherapy, and rate their life satisfaction as high. Nonetheless, half of the evaluated patients were not able to pursue a profession. Besides the disease age, gender and family life e.g., child care may also play a confounding role regarding the unemployment statistics. PMID- 20927304 TI - The positive and negative affect schedule: psychometric properties of the korean version. AB - OBJECTIVE: The Positive and Negative Affect Schedule (PANAS) was developed as a measure of positive affect (PA) and negative affect (NA). The aim here is to examine the factor structure and concurrent validity of the Korean version of the Positive and Negative Affect Schedule (K-PANAS) in a clinical sample in Korea. METHODS: K-PANAS was administered to a clinical sample in Korea. Internal consistency, test-retest reliability, and confirmatory factor analysis (CFA) were undertaken to examine the factorial structure and reliability of the K-PANAS. RESULTS: The reliability of K-PANAS is satisfactory. CFA showed that several of the models commonly used in Western populations provided an insufficient fit. The modified model provided a more adequate fit to the data. CONCLUSION: The authors demonstrate that the K-PANAS has adequate psychometric properties, and that findings obtained in the West using PANAS were partially replicated. PMID- 20927305 TI - Current use of depression rating scales in mental health setting. AB - OBJECTIVE: This study was to investigate the current use of depression rating scales by psychiatrists and clinical psychologists in Korea. METHODS: The questionnaires from many psychiatrists and clinical psychologists were included in the analysis. The questionnaire was composed of items about examining the percentage of patients clinically using depression rating scales, reasons for not use of them, the degree of satisfaction, the perceived agreement rate between the result of depression rating scales and doctor's clinical interview in the evaluation of patients with depressive symptoms. Data were analyzed by chi(2) and independent t-test. RESULTS: The clinical use of depression rating scales was more frequent in the psychologists than in the psychiatrists. The purposes for using depression rating scales were assessed into six areas, there was no significant difference in between two groups, and both groups pointed out their purpose as rating of severity and screening. The reasons for not using scales were that their interview may be sufficient for diagnosis and assessment of depressive patients and they are not familiar with the use of depression rating scales. The psychiatrists usually prefer the Beck Depression Inventory (BDI), Hamilton Depression Rating Scale and Symptom Checklist 90-Revision (SCL-90-R) in order of frequency, and the clinical psychologists are more likely to use the BDI, Minnesota Multiphasic Personality Inventory and SCL-90-R. Overall rate of satisfaction in the use of the scales was 67.29+/-14.45% and overall perceived agreement rate was 70.89+/-16.45%. CONCLUSION: Currently used depression rating scales at the clinical practice were not various. Therefore, to heighten clinicians' utility of these depression rating scales measures, either educational efforts or advertisements, or both, will be necessary to spread them wildly. PMID- 20927306 TI - Impairment of Concept Formation Ability in Children with ADHD: Comparisons between Lower Grades and Higher Grades. AB - OBJECTIVE: We investigated executive functions (EFs), as evaluated by the Wisconsin Card Sorting Test (WCST), and other EF between lower grades (LG) and higher grades (HG) in elementary-school-age attention deficit hyperactivity disorder (ADHD) children. METHODS: We classified a sample of 112 ADHD children into 4 groups (composed of 28 each) based on age (LG vs. HG) and WCST performance [lower vs. higher performance on WCST, defined by the number of completed categories (CC)] Participants in each group were matched according to age, gender, ADHD subtype, and intelligence. We used the Wechsler intelligence Scale for Children 3rd edition to test intelligence and the Computerized Neurocognitive Function Test-IV, which included the WCST, to test EF. RESULTS: Comparisons of EFs scores in LG ADHD children showed statistically significant differences in performing digit spans backward, some verbal learning scores, including all memory scores, and Stroop test scores. However, comparisons of EF scores in HG ADHD children did not show any statistically significant differences. Correlation analyses of the CC and EF variables and stepwise multiple regression analysis in LG ADHD children showed a combination of the backward form of the Digit span test and Visual span test in lower-performance ADHD participants significantly predicted the number of CC (R(2)=0.273, p<0.001). CONCLUSION: This study suggests that the design of any battery of neuropsychological tests for measuring EF in ADHD children should first consider age before interpreting developmental variations and neuropsychological test results. Researchers should consider the dynamics of relationships within EF, as measured by neuropsychological tests. PMID- 20927307 TI - Efficacy and tolerability of aripiprazole: a 26-week switching study from oral antipsychotics. AB - OBJECTIVE: To determine if the maintenance effectiveness and tolerability of aripiprazole demonstrated in a 12-week study were maintained in an extension phase (up to 26 weeks). METHODS: This study was the extension of our switching study from other antipsychotics to aripiprazole in symptomatically stable patients with schizophrenia or schizoaffective disorder. All the patients were randomly assigned to the aripiprazole group or the non-aripiprazole group. The effectiveness analysis consisted of the comparison of the upper bound of the 95% confidence interval (CI) of the mean Clinical Global Impression-Improvement (CGI I) score to 4 (no change) at the end of the study. RESULTS: At the baseline, the aripiprazole group (n=135) and the non-aripiprazole group (n=31) were comparable with respect to their mean ages, gender distribution, baseline Positive and Negative Syndrome Scale scores, and Clinical Global Impression-Severity (CGI-S) scores. The study showed that the mean CGI-I score was 2.92 (95% CI: 2.72-3.12) in the aripiprazole group and 2.81 (95% CI: 2.35-3.26) in the non-aripiprazole group at 26 weeks. In the aripiprazole group, the remission rates at 12 and 26 weeks were 74.8% and 72.6%, respectively, and 80.2% of the patients with remission at 12 weeks maintained their remission state until the end of the study. About one-fourth of the patients in the aripiprazole group reported one or more spontaneous treatment-emergent adverse events, such as insomnia, headache, and nausea. CONCLUSION: This study suggested that most clinically stable outpatients with schizophrenia maintain their remission states after being switched to aripiprazole, without serious symptom aggravation and adverse events over a course of 26 weeks. PMID- 20927308 TI - Genetic Association Study of the Alpha 7 Nicotinic Receptor (CHRNA7) with the Development of Schizophrenia and Bipolar Disorder in Korean Population. AB - OBJECTIVE: CHRNA7 has been shown to be a strong candidate gene for schizophrenia and bipolar disorder. It is located on chromosome 15q13-q14, which is one of the replicated linkage spots for schizophrenia and bipolar disorder. METHODS: We conducted an association study to determine whether previous positive association is replicable in the Korean population. We included 254 patients with schizophrenia, 193 patients with bipolar disorder type I, 38 patients with bipolar disorder type II, 64 schizoaffective disorder patients, and 349 controls. All subjects were ethnically Korean. A total of 898 subjects were included, and genotyping was done for three single nucleotide polymorphisms (SNPs) of CHRNA7. These three intronic SNPs were rs2337506 (A/G), rs6494223 (C/T), and rs12916879 (A/G). RESULTS: There was only one marginally significant association; this association was between rs12916879 and bipolar disorder type I in the male subgroup. In both the allele and genotype distributions, we found a weak signal (Chi-squared=3.57, df=1, p=0.06 for allele, Chi-squared=7.50, df=2, p=0.02 for genotype) only. Unphased haplotype analysis could not provide additional support for this finding. No SNP was associated with schizophrenia or any other affected groups in this Korean sample. The associative finding is marginal and inconclusive. CONCLUSION: We could not replicate positive association in other ethnic groups previously studied. This suggests possible heterogeneity in the genes associated with schizophrenia and bipolar disorders. Because of structural complexity of the CHRNA7 gene and the limited statistical power of this study, further genetic studies with more SNPs and larger samples covering various populations, along with more fine molecular exploration of the CHRNA7 gene structure, are required. PMID- 20927309 TI - Increased glycogen synthase kinase-3beta mRNA level in the hippocampus of patients with major depression: a study using the stanley neuropathology consortium integrative database. AB - OBJECTIVE: Glycogen synthase kinase-3beta (GSK-3beta) has become recognized as a broadly influential enzyme affecting diverse range of biological functions, including gene expression, cellular architecture, and apoptosis. The results of previous studies suggest that GSK-3beta activity may be increased in the brain of patients with major depressive disorders (MDD). A recent animal study reported increased GSK-3beta messenger ribonucleic acid (mRNA) level in the hippocampus of those with depression. However, few studies have investigated GSK-3beta activity in the brain of patients with MDD. METHODS: In order to test whether patients with MDD have an increase in GSK-3beta activity in the brain compared to normal controls, we explored GSK-3beta expression level in all brain regions by using the Stanley Neuropathology Consortium Integrative Database (SNCID), which is a web-based method of integrating the Stanley Medical Research Institute data sets. RESULTS: The level of GSK-3beta mRNA expression in the hippocampus was significantly increased in the MDD group (n=8) compared with the control group (n=12, p<0.05). Spearman's test also reveals that GSK-3beta mRNA expression levels were significantly correlated with nitric oxide synthase 1 (NOS1)(rho=0.70, p<0.0001) and stathmin-like 3 (STMN3)(rho=0.70, p<0.0001) in the hippocampus. CONCLUSION: Our results correspond with the results of previous animal studies that reported increased GSK-3beta activity in the hippocampus of those with depression. Our findings also suggest that oxidative stress-induced neuronal cell death and abnormal synaptic plasticity in the hippocampus may play important roles in the pathophysiology of major depression. PMID- 20927310 TI - Frontal Dysfunction Underlies Depression in Mild Cognitive Impairment: A FDG-PET Study. AB - OBJECTIVE: Depression is a very common symptom in people with mild cognitive impairment (MCI), a preclinical stage of Alzheimer's disease (AD), and in those with clinically evident AD. Moreover, MCI individuals with depression show a higher conversion rate to clinical AD than those without depression. This study aimed to elucidate the functional neuroanatomical substrate of depression in MCI. METHODS: Thirty-six patients were recruited from a University Hospital-based cohort; 18 of these subjects had MCI with depression (MCI_D); the remaining 18 subjects were age- and gender-matched, and had MCI with no depression (MCI_ND). For comparison, 16 cognitively normal (CN) elderly individuals were also included. All subjects underwent Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) scanning and regional cerebral glucose metabolism was compared among the three groups by a voxel-based method. The relationship between severity of depression, as measured by Hamilton Rating Scale for Depression (HRSD) scores, and glucose metabolism was also investigated. RESULTS: MCI_D showed lower glucose metabolism in the right superior frontal gyrus than MCI_ND. There was a significant negative correlation between HRSD score and glucose metabolism at the same frontal region for overall MCI subjects. When compared with CN, both MCI_D and MCI_ND showed decreased glucose metabolism in the precuneus, while MCI_D had, in addition, reduced metabolism in other diffuse brain regions. CONCLUSION: Given previous observations on depression in AD, our results suggest that functional disruption of the frontal region, known to be associated with primary or other secondary depression, underlies depression in preclinical AD as well as clinically evident AD. PMID- 20927311 TI - Changes in Cerebral Cortex and Limbic Brain Functions after Short-Term Paroxetine Treatment in Panic Disorder: An [F]FDG-PET Pilot Study. AB - OBJECTIVE: Panic disorder (PD) is a common and often chronic psychiatric illness, and serotonin-specific reuptake inhibitors (SSRIs) are the drugs of choice for the treatment of PD. Previous studies suggested the cerebral cortex and limbic brain structures played a major role in the development of PD, but the therapeutic effect of SSRIs on specific brain structures remains unclear in PD. We examined the changes in PD patients' glucose metabolism using the [(18)F] Fluorodeoxy-glucose-positron emission tomography (FDG-PET) before and after 12 weeks of paroxetine treatment. METHODS: We assessed the brain glucose metabolism of 5 PD patients, using the [(18)F]FDG-PET, and treated them with paroxetine (12.5-37.5 mg/day) for 12 weeks. Then, we compared before and after treatment PET images of the patients, using voxel-based statistical analysis and a post hoc regions of interest analysis. Furthermore, we measured the patients' clinical variables, including information from the Panic Disorder Severity Scale (PDSS), Clinical Global Impression for Severity (CGI-S), and Hamilton Anxiety Rating Scale (HAMA). RESULTS: After 12 weeks of paroxetine treatment, the patients showed significant clinical improvement in terms of PDSS, CGI-S and HAMA scores (12.8+/-1.8 vs. 3.8+/-2.3, 4.6+/-0.5 vs. 2.0+/-1.4, and 15.2+/-4.0 vs. 5.0+/-1.2, respectively; all p values<0.05). After treatment, patients' glucose metabolism increased significantly in global brain areas: the right precentral gyrus, right middle frontal gyrus, right amygdala, right caudate body, right putamen, left middle frontal gyrus, left precentral gyrus, left insula, left parahippocampal gyrus, and left inferior frontal gyrus (All areas were significant at uncorrected p<0.001 and cluster level corrected p<0.05). CONCLUSION: In these PD patients, cerebral cortex and limbic brain functions changed after short-term treatment with paroxetine. The therapeutic action of paroxetine may be related to altered glucose metabolism at both the cerebral cortex and limbic brain areas. PMID- 20927312 TI - Retrospective case series of aripiprazole augmentation in pervasive developmental disorders. AB - Due to co-morbidities and treatment resistant nature of pervasive developmental disorder (PDD), diverse combinations of regimens have been tried. This retrospective study aimed to explore adjunctive use of aripiprazole in children with PDD. Changes in illness severity were measured by Clinical Global Impression of Severity (CGI-S) and Clinical Global Impression of Improvement (CGI-I) in 14 aripiprazole-treated patients with PDD. Improvement of illness severity was observed after aripiprazole add-on (5.8+/-0.8 to 4.9+/-1.0, Z=-2.75, p=0.001). Mean dosage was 7.7 mg/day [standard deviation (SD) 3.3, range 5-15]. A higher mean dosage was observed in group with improvement in symptoms (t=-2.33, df =12, p=0.004). The target symptoms most effectively improved after using aripiprazole were positive psychotic symptoms (mean CGI-I: 2.0+/-1.4, 3 responders/4 patients, 75% response) followed by aggressive behavior (2.5+/-1.7, 3/4, 75%), self injurious behavior (2.0+/-1.0, 2/3, 67%), stereotypic behavior (2.7+/-1.2, 2/3, 67%), tic (2.8+/-1.0, 2/4, 50%), irritability (3.5+/-2.1, 1/2, 50%), obsessive behavior (2.5+/-2.1, 1/3, 33%), hyperactivity (3.4+/-1.6, 3/7, 43%) and mood fluctuation (3, 0/1, no response). Five patients (35%) discontinued aripiprazole due to treatment-emergent adverse effects (akathisia, insomnia, withdrawal). The results of this study suggest that aripiprazole augmentation may be used safely in maladaptive behaviors of some populations of PDD. However, future studies are required to confirm these preliminary findings. PMID- 20927313 TI - Association between Estrogen Receptor Gene Polymorphisms and Depression in Post Menopausal Women: A Preliminary Study. AB - Post-menopausal women experience variable biological and psychological changes. The effect of reduced levels of estrogen can effect on post-menopausal depression. Estrogen triggers physiological responses by binding to the estrogen receptor (ER). Two subtypes of ER, ERa and ERb are now known. We investigated the significance of ERa and ERb polymorphisms and post-menopasal depression in this study. Forty three women with post-menopausal depression and 63 post-menopausal women without depression as normal controls were recruited. Polymerase chain reaction-restriction fragment length polymorphism method was used to investigate genotypes of ERa and ERb polymorphisms. Genotypes of PvuII and XbaI polymorphism of ERa receptor were significantly different in patients with post-menopausal depression comparing with controls. Genotypes of ERb did not show association with post-menopausal depression. Our study showed that ERa receptor polymorphism had an association with depression in post-menopausal women. It suggests that investigation of ER genes and their functions might be important for understanding pathophysilogical mechanism of post-menopausal depression. PMID- 20927314 TI - Cholestatic jaundice induced by duloxetine in a patient with major depressive disorder. AB - Duloxetine is a balanced and potent serotonin and noradrenaline reuptake inhibitor (SNRI) and has adverse effects that are commonly associated with such drugs, including nausea, dry mouth, constipation, insomnia, and dizziness. Recently, duloxetine-induced liver injury has also been observed in patients with preexisting liver disease or chronic alcohol use. We investigated the effects of duloxetine in a healthy young adult with major depressive disorder (MDD) but no risk factors, and found that his total bilirubin level increased to 3.3 mg/dL and he developed jaundice after 5 months of duloxetine treatment. Discontinuation of duloxetine treatment saw his total bilirubin level decrease to 1.8 mg/dL. Thus, the administration of duloxetine might induce liver injury in a patient with MDD. However, the limitations of this single case report must be acknowledged. Although the cause of hepatic dysfunction in this case remains to be elucidated, clinicians should monitor liver function carefully after duloxetine treatment. Further investigations with a larger sample are needed. PMID- 20927315 TI - Characterization and mechanistic studies of a novel melanoma-targeting construct containing IkappaBa for specific inhibition of nuclear factor-kappaB activity. AB - The transcription factor nuclear factor-kappaB (NF-kappaB) is a central mediator of growth and homeostasis for both normal and neoplastic cells. IkappaBalpha is the natural intracellular inhibitor of NF-kappaB and can effectively complex with and thereby inhibit the biologic activity and translocation of NF-kappaB to the nucleus. We designed a fusion protein designated IkappaBalpha/scFvMEL composing of human IkappaBalpha and the single-chain antibody scFvMEL, targets melanoma gp240 antigen. Cells treated with IkappaBalpha/scFvMEL before irradiation showed specifically inhibition of both constitutive and radiation-induced NF-kappaB activity on gp240 antigen-positive A375M cells. Pretreatment of A375M cells with IkappaBalpha/scFvMEL significantly sensitized melanoma cells to ionizing radiation assessed using a clonogenic survival assay. Mechanistic studies showed that IkappaBalpha/scFvMEL, when exogenously added to A375M cells, could be coimmunoprecipitated with the p65 subunit of NF-kappaB. IkappaBalpha/scFvMEL inhibited in a time and/or dose-dependent manner of tumor necrosis factor alpha- or radiation-induced NF-kappaB activity in vitro. IkappaBalpha/scFvMEL was also shown to specifically inhibit the translocation of the NF-kappaB p65 subunit to the cell nucleus and NF-kappaB-mediated gene transcription. Further, initial studies showed that mice bearing well-established A375M xenografts were treated (intravenously) with IkappaBalpha/scFvMEL and showed a significant suppression of tumor growth. We also observed a decrease in levels of Bcl-2 and Bcl-XL signaling events downstream of NF-kappaB in the tumor model. These studies demonstrate for the first time that tumor cell-targeted delivery of IkappaBalpha may be beneficial for the treatment of melanoma when combined with standard anticancer therapies such as radiation. PMID- 20927316 TI - An anti-urokinase plasminogen activator receptor antibody (ATN-658) blocks prostate cancer invasion, migration, growth, and experimental skeletal metastasis in vitro and in vivo. AB - Urokinase plasminogen activator receptor (uPAR) is a multidomain protein that plays important roles in the growth, invasion, and metastasis of a number of cancers. In the present study, we examined the effects of administration of a monoclonal anti-uPAR antibody (ATN-658) on prostate cancer progression in vitro and in vivo. We examined the effect of treatment of ATN-658 on human prostate cancer cell invasion, migration, proliferation, and regulation of intracellular signaling pathways. For in vivo studies, PC-3 cells (1 x 10(6)) were inoculated into the right flank of male Balb C nu/nu mice through subcutaneous or through intratibial route (2 x 10(5)) of male Fox Chase severe combined immunodeficient mice to monitor the effect on tumor growth and skeletal metastasis. Treatment with ATN-658 resulted in a significant dose-dependent decrease in PC-3 cell invasion and migration without affecting cell doubling time. Western blot analysis showed that ATN-658 treatment decreased the phosphorylation of serine/threonine protein kinase B (AKT), mitogen-activated protein kinase (MAPK), and focal adhesion kinase (FAK) without affecting AKT, MAPK, and FAK total protein expression. In in vivo studies, ATN-658 caused a significant decrease in tumor volume and a marked reduction in skeletal lesions as determined by Faxitron x-ray and micro-computed tomography. Immunohistochemical analysis of subcutaneous and tibial tumors showed a marked decrease in the levels of expression of pAKT, pMAPK, and pFAK, consistent with the in vitro observations. Results from these studies provide compelling evidence for the continued development of ATN-658 as a potential therapeutic agent for the treatment of prostate and other cancers expressing uPAR. PMID- 20927317 TI - A critical role of c-Cbl-interacting protein of 85 kDa in the development and progression of head and neck squamous cell carcinomas through the ras-ERK pathway. AB - Activation of the transforming growth factor (TGF) alpha/epidermal growth factor receptor (EGFR)-mediated signaling pathway is a common mechanism for dysregulated growth of head and neck squamous cell carcinoma (HNSCC). c-Cbl-interacting protein of 85 kDa (CIN85) is an adaptor protein that facilitates EGFR internalization. Little is known, however, about a role of CIN85 in EGFR signaling as well as its relevance to tumor development and progression of HNSCC. Here, we demonstrate that CIN85 is highly expressed in HNSCC tumor samples compared with adjacent normal tissues, and this overexpression is significantly correlated with advanced clinical stage. The experiments using CIN85 overexpressing and knockdown HNSCC cell lines showed that CIN85 promotes HNSCC growth and facilitates EGFR internalization without apparently affecting phosphorylation of EGFR. Moreover, CIN85 promoted TGF-alpha-induced activation of Ras and phosphorylation of downstream molecules such as c-Raf, MEK, and extracellular signal-regulated kinase, leading to expression of c-Myc that is critical for sustained proliferation of HNSCC. Taken together, these findings suggest that CIN85 not only controls EGFR internalization but also promotes the EGFR-mediated tumor development and progression, and thus, CIN85 may serve as a potential therapeutic target in a subset of HNSCC. PMID- 20927318 TI - Specific targeting of tumor endothelial cells by a shiga-like toxin-vascular endothelial growth factor fusion protein as a novel treatment strategy for pancreatic cancer. AB - PURPOSE: Tumor endothelial cells express vascular endothelial growth factor receptor 2 (VEGFR-2). VEGF can direct toxins to tumor vessels through VEGFR-2 for antiangiogenic therapy. This study aimed to selectively damage the VEGFR-2 overexpressing vasculature of pancreatic cancer by SLT-VEGF fusion protein comprising VEGF and the A subunit of Shiga-like toxin which inhibits protein synthesis of cells with high VEGFR-2 expression. EXPERIMENTAL DESIGN: Expression of VEGF and VEGF receptors was evaluated in human pancreatic cancer cells (AsPC 1, HPAF-2) and in normal human endothelial cells (HUVEC) by reverse transcription polymerase chain reaction. Cells were treated with SLT-VEGF (0.1-10 nM), and cell viability, proliferation, and endothelial tube formation were assessed. Orthotopic pancreatic cancer (AsPC-1, HPAF-2) was induced in nude mice. Animals were treated with SLT-VEGF fusion protein alone or in combination with gemcitabine. Treatment began 3 days or 6 weeks after tumor induction. Primary tumor volume and dissemination were determined after 14 weeks. Microvessel density and expression of VEGF and VEGF receptors were analyzed by immunohistochemistry. RESULTS: SLT-VEGF did not influence proliferation of pancreatic cancer cells; HUVECs (low-level VEGFR-2) reduced their proliferation rate and tube formation but not their viability. SLT-VEGF fusion protein reduced tumor growth and dissemination, increasing 14-week survival (AsPC-1, up to 75%; HPAF-2, up to 83%). Results of gemcitabine were comparable with SLT-VEGF monotherapy. Combination partly increased the therapeutic effects in comparison to the respective monotherapies. Microvessel density was reduced in all groups. Intratumoral VEGFR-2 expression was found in endothelial but not in tumor cells. CONCLUSIONS: SLT-VEGF is toxic for tumor vasculature rather than for normal endothelial or pancreatic cancer cells. SLT-VEGF treatment in combination with gemcitabine may provide a novel approach for pancreatic cancer. PMID- 20927320 TI - Longitudinal magnetic resonance imaging-based assessment of vascular changes and radiation response in androgen-sensitive prostate carcinoma xenografts under androgen-exposed and androgen-deprived conditions. AB - Prostate cancer (PCa) patients receive androgen-deprivation therapy (ADT) to reduce tumor burden. However, complete eradication of PCa is unusual, and recurrent disease is evident within approximately 2 years in high-risk patients. Clinical evidence suggests that combining ADT with radiotherapy improves local control and disease-free survival in these patients compared with radiotherapy alone. We investigated whether vascularization of androgen-sensitive PCa xenografts changed after ADT and whether such therapy affected radiation response. CWR22 xenografts received combinations of ADT by castration (CWR22-cas) and 15 Gy of single-dose irradiation. At a shortest tumor diameter of 8 mm, vascularization was visualized by dynamic contrast-enhanced magnetic resonance imaging before radiation and 1 and 9 days after radiation. Voxel-wise quantitative modeling of contrast enhancement curves extracted the hemodynamic parameter K(trans), reflecting a combination of permeability, density, and blood flow. Tumor volumes and prostate-specific antigen (PSA) were monitored during the experiment. The results showed that K(trans) of CWR22-cas tumors 36+/-4 days after ADT was 47.1% higher than K(trans) of CWR22 tumors (P = .01). CWR22-cas tumors showed no significant changes in K(trans) after radiation, whereas K(trans) of CWR22 tumors at day 1 decreased compared with pretreatment values (P = .04) before a continuous increase from day 1 to day 9 followed (P = .01). Total PSA in blood correlated positively to tumor volume (r = 0.59, P < .01). In conclusion, androgen-exposed xenografts demonstrated radiation-induced reductions in vascularization and tumor volumes, whereas androgen-deprived xenografts showed increased vascularization and growth inhibition, but no significant additive effect of radiation. PMID- 20927319 TI - Gene expression levels as predictive markers of outcome in pancreatic cancer after gemcitabine-based adjuvant chemotherapy. AB - BACKGROUND AND AIMS: The standard palliative chemotherapy for pancreatic ductal adenocarcinoma (PDAC) is gemcitabine-based chemotherapy; however, PDAC still presents a major therapeutic challenge. The aims of this study were to investigate the expression pattern of genes involved in gemcitabine sensitivity in resected PDAC tissues and to determine correlations of gene expression with treatment outcome. MATERIALS AND METHODS: We obtained formalin-fixed paraffin embedded (FFPE) tissue samples from 70 patients with PDAC. Of the 70 patients, 40 received gemcitabine-based adjuvant chemotherapy (AC). We measured hENT1, dCK, CDA, RRM1, and RRM2 messenger RNA (mRNA) levels by quantitative real-time reverse transcription-polymerase chain reaction and determined the combined score (GEM score), based on the expression levels of hENT1, dCK, RRM1, and RRM2, to investigate the association with survival time. By determining the expression levels of these genes in endoscopic ultrasound-guided fine needle aspiration (EUS FNA) cytologic specimens, we investigated the feasibility of individualized chemotherapy. RESULTS: High dCK (P = .0067), low RRM2 (P = .003), and high GEM score (P = .0003) groups had a significantly longer disease-free survival in the gemcitabine-treated group. A low GEM score (<2) was an independent predictive marker for poor outcome to gemcitabine-based AC as shown by multivariate analysis (P = .0081). Altered expression levels of these genes were distinguishable in microdissected neoplastic cells from EUS-FNA cytologic specimens. CONCLUSIONS: Quantitative analyses of hENT1, dCK, RRM1, and RRM2 mRNA levels using FFPE tissue samples and microdissected neoplastic cells from EUS-FNA cytologic specimens may be useful in predicting the gemcitabine sensitivity of patients with PDAC. PMID- 20927321 TI - Syndecan-1-dependent suppression of PDK1/Akt/bad signaling by docosahexaenoic acid induces apoptosis in prostate cancer. AB - Evidence indicates that diets enriched in n-3 polyunsaturated fatty acids (n-3 PUFAs) reduce the risk of prostate cancer, but biochemical mechanisms are unclear. Syndecan-1 (SDC-1), a transmembrane heparan sulfate proteoglycan, supports the integrity of the epithelial compartment. In tumor cells of epithelial lineage, SDC-1 is generally downregulated. This may result in perturbation of homeostasis and lead to progression of malignancy. Our studies have shown that the n-3 PUFA species, docosahexaenoic acid (DHA), increases SDC-1 expression in prostate tissues of Pten knockout (Pten(P-/-)) mice/cells and human prostate cancer cells. We have now determined that DHA-mediated up-regulation of SDC-1 induces apoptosis. Bovine serum albumin-bound DHA and exogenous human recombinant SDC-1 ecotodomain were delivered to PC3 and LNCaP cells in the presence or absence of SDC-1 small interfering (si)RNA. In the presence of control siRNA, both DHA and SDC-1 ectodomain induced apoptosis, whereas SDC-1 silencing blocked DHA-induced but not SDC-1 ectodomain-induced apoptosis. Downstream effectors of SDC-1 signaling linked to n-3 PUFA-induced apoptosis involved the 3'-phosphoinositide-dependent kinase 1 (PDK1)/Akt/Bad integrating network. A diet enriched in n-3 PUFA decreased phosphorylation of PDK1, Akt (T308), and Bad in prostates of Pten(P-/-) mice. Similar results were observed in human prostate cancer cells in response to DHA and SDC-1 ectodomain. The effect of DHA on PDK1/Akt/Bad signaling was abrogated by SDC-1 siRNA. These findings define a mechanism by which SDC-1-dependent suppression of phosphorylation of PDK1/Akt/Bad mediates n-3 PUFA-induced apoptosis in prostate cancer. PMID- 20927322 TI - Short hairpin RNA-mediated fibronectin knockdown delays tumor growth in a mouse glioma model. AB - Glioblastoma multiforme is the most common and lethal primary brain tumor. Glioma progression depends on the rapid proliferation of tumor cells accompanied by an acute immunosuppressive environment, facilitated mainly by tumor infiltration of regulatory T cells (Tregs). In this study, we characterize the role of fibronectin, a high-molecular weight extracellular matrix glycoprotein secreted by tumor cells, in controlling glioma progression and in mediating immunosuppression. Fibronectin binds to membrane-spanning integrin receptors and plays an important role in cell signaling, in defining cellular shape, in mobility, and in regulating the cell cycle. We found that inhibition of fibronectin expression in glioma cells, using short hairpin RNA-mediated silencing of gene expression, delayed cell proliferation in vitro. This delayed growth is explained, in part, by the observed reduced expression of integrin beta(1) fibronectin receptor, which was restored by the inhibition of proteosomal activity. In our analysis of the downstream signaling targets of integrin beta(1), we demonstrated reduced phosphorylation of Src kinase and STAT-3. We also observed reduced survivin expression that induced a three-fold increased accumulation of fibronectin-knockdown cells in the G(2)/M phase. In an experimental animal model, the fibronectin knockdown tumors had a mean survival advantage of 23 days over wild-type tumors. Moreover, brain samples of animals bearing fibronectin-knockdown tumors showed delayed Treg recruitment. Collectively, we propose that fibronectin is a key mediator of glioma progression because its inhibition delays both tumor progression and immunosuppression. PMID- 20927323 TI - Protein phosphatase 2A negatively regulates eukaryotic initiation factor 4E phosphorylation and eIF4F assembly through direct dephosphorylation of Mnk and eIF4E. AB - The eukaryotic translation initiation factor 4E (eIF4E) is frequently overexpressed in human cancers and is associated with cellular transformation, tumorigenesis, and metastatic progression. It is known that Mnks can phosphorylate eIF4E. Protein phosphatase 2A (PP2A) functions as a tumor suppressor, and it was previously suggested to regulate eIF4E phosphorylation. However, how PP2A regulates eIF4E phosphorylation has not been fully addressed. In this study, we have not only validated the role of PP2A in regulation of eIF4E phosphorylation but also demonstrated the mechanism underlying this process. Inhibition of PP2A using either okadaic acid or PP2A small interfering RNA (siRNA) increased eIF4E phosphorylation, which could be abolished by the presence of the Mnk inhibitor CGP57380 or deficiency of Mnk genes. Thus, Mnks are involved in PP2A-mediated regulation of eIF4E phosphorylation. Moreover, a dephosphorylation assay revealed that PP2A could directly dephosphorylate Mnk1 and eIF4E. m(7)GTP pull-down assay detected more eIF4G and phospho-eIF4E and less 4EBP-1 in PP2A siRNA-transfected cells than in control siRNA-transfected cells, indicating an increased cap binding of eIF4F complex. Accordingly, okadaic acid treatment or PP2A knockdown increased the levels of c-Myc and Mcl-1, which are proteins known to be regulated by a cap-dependent translation mechanism. Taken together, we conclude that PP2A negatively regulates eIF4E phosphorylation and eIF4F complex assembly through dephosphorylation of Mnk and eIF4E, thus suggesting a novel mechanism by which PP2A exerts its tumor-suppressive function. PMID- 20927324 TI - The unfolded protein response protects from tau neurotoxicity in vivo. AB - The unfolded protein response is a critical system by which the cell handles excess misfolded protein in the secretory pathway. The role of the system in modulating the effects of aggregation prone cytosolic proteins has received less attention. We use genetic reporters to demonstrate activation of the unfolded protein response in a transgenic Drosophila model of Alzheimer's disease and related tauopathies. We then use loss of function genetic reagents to support a role for the unfolded protein response in protecting from tau neurotoxicity. Our findings suggest that the unfolded protein response can ameliorate the toxicity of tau in vivo. PMID- 20927325 TI - ERK3 is required for metaphase-anaphase transition in mouse oocyte meiosis. AB - ERK3 (extracellular signal-regulated kinase 3) is an atypical member of the mitogen-activated protein (MAP) kinase family of serine/threonine kinases. Little is known about its function in mitosis, and even less about its roles in mammalian oocyte meiosis. In the present study, we examined the localization, expression and functions of ERK3 during mouse oocyte meiotic maturation. Immunofluorescent analysis showed that ERK3 localized to the spindles from the pre-MI stage to the MII stage. ERK3 co-localized with alpha-tubulin on the spindle fibers and asters in oocytes after taxol treatment. Deletion of ERK3 by microinjection of ERK3 morpholino (ERK3 MO) resulted in oocyte arrest at the MI stage with severely impaired spindles and misaligned chromosomes. Most importantly, the spindle assembly checkpoint protein BubR1 could be detected on kinetochores even in oocytes cultured for 10 h. Low temperature treatment experiments indicated that ERK3 deletion disrupted kinetochore-microtubule (K-MT) attachments. Chromosome spreading experiments showed that knock-down of ERK3 prevented the segregation of homologous chromosomes. Our data suggest that ERK3 is crucial for spindle stability and required for the metaphase-anaphase transition in mouse oocyte maturation. PMID- 20927326 TI - Age-correlated gene expression in normal and neurodegenerative human brain tissues. AB - BACKGROUND: Human brain aging has received special attention in part because of the elevated risks of neurodegenerative disorders such as Alzheimer's disease in seniors. Recent technological advances enable us to investigate whether similar mechanisms underlie aging and neurodegeneration, by quantifying the similarities and differences in their genome-wide gene expression profiles. PRINCIPAL FINDINGS: We have developed a computational method for assessing an individual's "physiological brain age" by comparing global mRNA expression datasets across a range of normal human brain samples. Application of this method to brains samples from select regions in two diseases--Alzheimer's disease (AD, superior frontal gyrus), frontotemporal lobar degeneration (FTLD, in rostral aspect of frontal cortex ~BA10)--showed that while control cohorts exhibited no significant difference between physiological and chronological ages, FTLD and AD exhibited prematurely aged expression profiles. CONCLUSIONS: This study establishes a quantitative scale for measuring premature aging in neurodegenerative disease cohorts, and it identifies specific physiological mechanisms common to aging and some forms of neurodegeneration. In addition, accelerated expression profiles associated with AD and FTLD suggest some common mechanisms underlying the risk of developing these diseases. PMID- 20927327 TI - Xenopus egg extracts increase dynamics of histone H1 on sperm chromatin. AB - BACKGROUND: Linker histone H1 has been studied in vivo and using reconstituted chromatin, but there have been few systematic studies of the effects of the cellular environment on its function. Due to the presence of many other chromatin factors and specific chaperones such as RanBP7/importin beta that regulate histone H1, linker histones likely function differently in vivo than in purified systems. METHODOLOGY/PRINCIPAL FINDINGS: We have directly compared H1 binding to sperm nuclei in buffer versus Xenopus egg extract cytoplasm, and monitored the effects of adding nuclear import chaperones. In buffer, RanBP7 decondenses sperm nuclei, while H1 binds tightly to the chromatin and rescues RanBP7-mediated decondensation. H1 binding is reduced in cytoplasm, and H1 exhibits rapid FRAP dynamics in cytoplasm but not in buffer. RanBP7 decreases H1 binding to chromatin in both buffer and extract but does not significantly affect H1 dynamics in either condition. Importin beta has a lesser effect than RanBP7 on sperm chromatin decondensation and H1 binding, while a combination of RanBP7/importin beta is no more effective than RanBP7 alone. In extracts supplemented with RanBP7, H1 localizes to chromosomal foci, which increase after DNA damage. Unlike somatic H1, the embryonic linker histone H1M binds equally well to chromatin in cytoplasm compared to buffer. Amino-globular and carboxyl terminal domains of H1M bind chromatin comparably to the full-length protein in buffer, but are inhibited ~10-fold in cytoplasm. High levels of H1 or its truncations distort mitotic chromosomes and block their segregation during anaphase. CONCLUSION/SIGNIFICANCE: RanBP7 can decondense sperm nuclei and decrease H1 binding, but the rapid dynamics of H1 on chromatin depend on other cytoplasmic factors. Cytoplasm greatly impairs the activity of individual H1 domains, and only the full-length protein can condense chromatin properly. Our findings begin to bridge the gap between purified and in vivo chromatin systems. PMID- 20927328 TI - Postural strategies and sensory integration: no turning point between childhood and adolescence. AB - In this study, we investigated the sensory integration to postural control in children and adolescents from 5 to 15 years of age. We adopted the working hypothesis that considerable body changes occurring during these periods may lead subjects to under-use the information provided by the proprioceptive pathway and over-use other sensory systems such as vision to control their orientation and stabilize their body. It was proposed to determine which maturational differences may exist between the sensory integration used by children and adolescents in order to test the hypothesis that adolescence may constitute a specific phase in the development of postural control. This hypothesis was tested by applying an original protocol of slow oscillations below the detection threshold of the vestibular canal system, which mainly serves to mediate proprioceptive information, to the platform on which the subjects were standing. We highlighted the process of acquiring an accurate sensory and anatomical reference frame for functional movement. We asked children and adolescents to maintain a vertical stance while slow sinusoidal oscillations in the frontal plane were applied to the support at 0.01 Hz (below the detection threshold of the semicircular canal system) and at 0.06 Hz (above the detection threshold of the semicircular canal system) with their eyes either open or closed. This developmental study provided evidence that there are mild differences in the quality of sensory integration relative to postural control in children and adolescents. The results reported here confirmed the predominance of vision and the gradual mastery of somatosensory integration in postural control during a large period of ontogenesis including childhood and adolescence. The youngest as well as the oldest subjects adopted similar qualitative damping and segmental stabilization strategies that gradually improved with age without reaching an adult's level. Lastly, sensory reweighting for postural strategies as assessed by very slow support oscillations presents a linear development without any qualitative turning point between childhood and adolescence. PMID- 20927329 TI - Interferon alpha induces establishment of alphaherpesvirus latency in sensory neurons in vitro. AB - BACKGROUND: Several alphaherpesviruses, including herpes simplex virus 1 (HSV-1) and pseudorabies virus (PRV), establish lifelong latency in neurons of the trigeminal ganglion (TG). Although it is thought that efficient establishment of alphaherpesvirus latency is based on a subtle interplay between virus, neurons and the immune system, it is not clear which immune components are of major importance for the establishment of latency. METHODOLOGY/PRINCIPAL FINDINGS: Here, using an in vitro model that enables a natural route of infection, we show that interferon alpha (IFNalpha) has the previously uncharacterized capacity to induce a quiescent HSV-1 and PRV infection in porcine TG neurons that shows strong similarity to in vivo latency. IFNalpha induced a stably suppressed HSV-1 and PRV infection in TG neurons in vitro. Subsequent treatment of neurons containing stably suppressed virus with forskolin resulted in reactivation of both viruses. HSV and PRV latency in vivo is often accompanied by the expression of latency associated transcripts (LATs). Infection of TG neurons with an HSV-1 mutant expressing LacZ under control of the LAT promoter showed activation of the LAT promoter and RT-PCR analysis confirmed that both HSV-1 and PRV express LATs during latency in vitro. CONCLUSIONS/SIGNIFICANCE: These data represent a unique in vitro model of alphaherpesvirus latency and indicate that IFNalpha may be a driving force in promoting efficient latency establishment. PMID- 20927331 TI - QKI-7 regulates expression of interferon-related genes in human astrocyte glioma cells. AB - BACKGROUND: The human QKI gene, called quaking homolog, KH domain RNA binding (mouse), is a candidate gene for schizophrenia encoding an RNA-binding protein. This gene was shown to be essential for myelination in oligodendrocytes. QKI is also highly expressed in astrocytes, but its function in these cells is not known. METHODS/PRINCIPAL FINDINGS: We studied the effect of small interference RNA (siRNA)-mediated QKI depletion on global gene expression in human astrocyte glioma cells. Microarray measurements were confirmed with real-time quantitative polymerase chain reaction (qPCR). The presence of QKI binding sites (QRE) was assessed by a bioinformatic approach. Viability and cell morphology were also studied. The most significant alteration after QKI silencing was the decreased expression of genes involved in interferon (IFN) induction (P = 6.3E-10), including IFIT1, IFIT2, MX1, MX2, G1P2, G1P3, GBP1 and IFIH1. All eight genes were down-regulated after silencing of the splice variant QKI-7, but were not affected by QKI-5 silencing. Interestingly, four of them were up-regulated after treatment with the antipsychotic agent haloperidol that also resulted in increased QKI-7 mRNA levels. CONCLUSIONS/SIGNIFICANCE: The coordinated expression of QKI-7 splice variant and IFN-related genes supports the idea that this particular splice variant has specific functions in astrocytes. Furthermore, a role of QKI-7 as a regulator of an inflammatory gene pathway in astrocytes is suggested. This hypothesis is well in line with growing experimental evidence on the role of inflammatory components in schizophrenia. PMID- 20927330 TI - Mechanical stress activates Smad pathway through PKCdelta to enhance interleukin 11 gene transcription in osteoblasts. AB - BACKGROUND: Mechanical stress rapidly induces DeltaFosB expression in osteoblasts, which binds to interleukin (IL)-11 gene promoter to enhance IL-11 expression, and IL-11 enhances osteoblast differentiation. Because bone morphogenetic proteins (BMPs) also stimulate IL-11 expression in osteoblasts, there is a possibility that BMP-Smad signaling is involved in the enhancement of osteoblast differentiation by mechanical stress. The present study was undertaken to clarify whether mechanical stress affects BMP-Smad signaling, and if so, to elucidate the role of Smad signaling in mechanical stress-induced enhancement of IL-11 gene transcription. METHODOLOGY/PRINCIPAL FINDINGS: Mechanical loading by fluid shear stress (FSS) induced phosphorylation of BMP-specific receptor regulated Smads (BR-Smads), Smad1/5, in murine primary osteoblasts (mPOBs). FSS rapidly phosphorylated Y311 of protein kinase C (PKC)delta, and phosphorylated PKCdelta interacted with BR-Smads to phosphorylate BR-Smads. Transfection of PKCdelta siRNA or Y311F mutant PKCdelta abrogated BR-Smads phosphorylation and suppressed IL-11 gene transcription enhanced by FSS. Activated BR-Smads bound to the Smad-binding element (SBE) of IL-11 gene promoter and formed complex with DeltaFosB/JunD heterodimer via binding to the C-terminal region of JunD. Site directed mutagenesis in the SBE and the AP-1 site revealed that both SBE and AP-1 sites were required for full activation of IL-11 gene promoter by FSS. CONCLUSIONS/SIGNIFICANCE: These results demonstrate that PKCdelta-BR-Smads pathway plays an important role in the intracellular signaling in response to mechanical stress, and that a cross-talk between PKCdelta-BR-Smads and DeltaFosB/JunD pathways synergistically stimulates IL-11 gene transcription in response to mechanical stress. PMID- 20927332 TI - Investigation of KIF6 Trp719Arg in a case-control study of myocardial infarction: a Costa Rican population. AB - BACKGROUND AND METHODOLOGY: The 719Arg allele of KIF6 (rs20455) was associated with coronary events in Caucasian participants of five prospective studies. We investigated whether this KIF6 variant was associated with non-fatal myocardial infarction (MI) in a case-control study of an admixed population from the Central Valley of Costa Rica. Genotypes of the KIF6 variant were determined for 4,134 men and women. Cases (1,987) had survived a first MI; controls (2,147) had no history of MI and were matched to cases by age, sex, and area of residence. We tested the association between the KIF6 719Arg allele and non-fatal MI by conditional logistic regression and adjusted for admixture of founder populations. PRINCIPAL FINDINGS: Compared with the reference Trp/Trp homozygotes, KIF6 719Arg carriers were not at significantly higher risk for non-fatal MI in this study after adjustment for traditional risk factors or admixture (OR= 1.12; 95%CI, 0.98 1.28). Heterozygotes of the KIF6 Trp719Arg variant were at increased risk of non fatal MI: the adjusted odds ratio was 1.16 (95% confidence interval, 1.01-1.34), but this association would not be significant after a multiple testing correction. CONCLUSIONS/SIGNIFICANCE: We found that carriers of the KIF6 719Arg allele were not at increased risk of non-fatal MI in a case-control study of Costa Ricans living in the Central Valley of Costa Rica. PMID- 20927333 TI - Delayed onset of experimental autoimmune encephalomyelitis in Olig1 deficient mice. AB - BACKGROUND: Olig1 is a basic helix-loop-helix (bHLH) transcription factor that is essential for oligodendrogenesis and efficient remyelination. However, its role in neurodegenerative disorders has not been well-elucidated. METHODOLOGY/PRINCIPAL FINDINGS: Here we investigated the effects of Olig1 deficiency on experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). We show that the mean disease onset of myelin oligodendrocyte glycoprotein (MOG)-induced EAE in Olig1(-/-) mice is significantly slower than wide-type (WT) mice (19.8 +/- 2.2 in Olig1(-/-) mice and 9.5 +/- 0.3 days in WT mice). In addition, 10% of Olig1(-/-) mice did not develop EAE by the end of the observation periods (60 days). The severity of EAE, the extent of demyelination, and the activation of microglial cells and astrocytes in spinal cords, were significantly milder in Olig1(-/-) mice compared with WT mice in the early stage. Moreover, the visual function, as assessed by the second-kernel of multifocal electroretinograms, was better preserved, and the number of degenerating axons in the optic nerve was significantly reduced in Olig1(-/-) mice. Interestingly, Olig1 deficiency had no effect on T cell response capability, however, it reduced the expression of myelin proteins such as MOG, myelin basic protein (MBP) and myelin-associated glycoprotein (MAG). The expression of Olig2 remained unchanged in the optic nerve and brain, and it was reduced in the spinal cord of Olig1(-/-) mice. CONCLUSIONS/SIGNIFICANCE: Our results suggest that the Olig1 signaling pathways may be involved in the incidence rate and the severity of neurological symptoms in MS. PMID- 20927334 TI - Genome-based microsatellite development in the Culex pipiens complex and comparative microsatellite frequency with Aedes aegypti and Anopheles gambiae. AB - BACKGROUND: Mosquitoes in the Culex pipiens complex are among the most medically important vectors for human disease worldwide and include major vectors for lymphatic filariasis and West Nile virus transmission. However, detailed genetic studies in the complex are limited by the number of genetic markers available. Here, we describe methods for the rapid and efficient identification and development of single locus, highly polymorphic microsatellite markers for Cx. pipiens complex mosquitoes via in silico screening of the Cx. quinquefasciatus genome sequence. METHODOLOGY/PRINCIPAL FINDINGS: Six lab colonies representing four Cx. pipiens and two Cx. quinquefasciatus populations were utilized for preliminary assessment of 38 putative loci identified within 16 Cx. quinquefasciatus supercontig assemblies (CpipJ1) containing previously mapped genetic marker sequences. We identified and validated 12 new microsatellite markers distributed across all three linkage groups that amplify consistently among strains representing the complex. We also developed four groups of 3-5 microsatellite loci each for multiplex-ready PCR. Field collections from three cities in Indiana were used to assess the multiplex groups for their application to natural populations. All were highly polymorphic (Mean = 13.0 alleles) per locus and reflected high polymorphism information content (PIC) (Mean = 0.701). Pairwise F(ST) indicated population structuring between Terre Haute and Fort Wayne and between Terre Haute and Indianapolis, but not between Fort Wayne and Indianapolis. In addition, we performed whole genome comparisons of microsatellite motifs and abundance between Cx. quinquefasciatus and the primary vectors for dengue virus and malaria parasites, Aedes aegypti and Anopheles gambiae, respectively. CONCLUSIONS/SIGNIFICANCE: We demonstrate a systematic approach for isolation and validation of microsatellites for the Cx. pipiens complex by direct screen of the Cx. quinquefasciatus genome supercontig assemblies. The genome density of microsatellites is greater in Cx. quinquefasciatus (0.26%) than in Ae. aegypti (0.14%), but considerably lower than in An. gambiae (0.77%). PMID- 20927335 TI - Human microRNA oncogenes and tumor suppressors show significantly different biological patterns: from functions to targets. AB - MicroRNAs (miRNAs) are small noncoding RNAs which play essential roles in many important biological processes. Therefore, their dysfunction is associated with a variety of human diseases, including cancer. Increasing evidence shows that miRNAs can act as oncogenes or tumor suppressors, and although there is great interest in research into these cancer-associated miRNAs, little is known about them. In this study, we performed a comprehensive analysis of putative human miRNA oncogenes and tumor suppressors. We found that miRNA oncogenes and tumor suppressors clearly show different patterns in function, evolutionary rate, expression, chromosome distribution, molecule size, free energy, transcription factors, and targets. For example, miRNA oncogenes are located mainly in the amplified regions in human cancers, whereas miRNA tumor suppressors are located mainly in the deleted regions. miRNA oncogenes tend to cleave target mRNAs more frequently than miRNA tumor suppressors. These results indicate that these two types of cancer-associated miRNAs play different roles in cancer formation and development. Moreover, the patterns identified here can discriminate novel miRNA oncogenes and tumor suppressors with a high degree of accuracy. This study represents the first large-scale bioinformatic analysis of human miRNA oncogenes and tumor suppressors. Our findings provide help for not only understanding of miRNAs in cancer but also for the specific identification of novel miRNAs as miRNA oncogenes and tumor suppressors. In addition, the data presented in this study will be valuable for the study of both miRNAs and cancer. PMID- 20927336 TI - Building a morphogen gradient without diffusion in a growing tissue. AB - In many developmental systems, spatial pattern arises from morphogen gradients, which provide positional information for cells to determine their fate. Typically, diffusion is thought to be the mechanism responsible for building a morphogen gradient. An alternative mechanism is investigated here. Using mathematical modeling, we demonstrate how a non-diffusive morphogen concentration gradient can develop in axially growing tissue systems, where growth is due to cell proliferation only. Two distinct cases are considered: in the first, all cell proliferation occurs in a localized zone where active transcription of a morphogen-producing gene occurs, and in the second, cell proliferation is uniformly distributed throughout the tissue, occurring in both the active transcription zone and beyond. A cell containing morphogen mRNA produces the morphogen protein, hence any gradient in mRNA transcripts translates into a corresponding morphogen protein gradient. Proliferation-driven growth gives rise to both advection (the transport term) and dilution (a reaction term). These two key mechanisms determine the resultant mRNA transcript distribution. Using the full range of uniform initial conditions, we show that advection and dilution due to cell proliferation are, in general, sufficient for morphogen gradient formation for both types of axially growing systems. In particular, mRNA transcript degradation is not necessary for gradient formation; it is only necessary with localized proliferation for one special value of the initial concentration. Furthermore, the morphogen concentration decreases with distance away from the transcription zone, except in the case of localized proliferation with the initial concentration sufficiently large, when the concentration can either increase with distance from the transcription zone or sustain a local minimum. In both localized and uniformly distributed proliferation, in order for a concentration gradient to form across the whole domain, transcription must occur in a zone equal to the initial domain size; otherwise, it will only form across part of the tissue. PMID- 20927337 TI - Decreased fat storage by Lactobacillus paracasei is associated with increased levels of angiopoietin-like 4 protein (ANGPTL4). AB - BACKGROUND: Intervention strategies for obesity are global issues that require immediate attention. One approach is to exploit the growing consensus that beneficial gut microbiota could be of use in intervention regimes. Our objective was to determine the mechanism by which the probiotic bacteria Lactobacillus paracasei ssp paracasei F19 (F19) could alter fat storage. Angiopoietin-like 4 (ANGPTL4) is a circulating lipoprotein lipase (LPL) inhibitor that controls triglyceride deposition into adipocytes and has been reported to be regulated by gut microbes. METHODOLOGY/PRINCIPAL FINDINGS: A diet intervention study of mice fed high-fat chow supplemented with F19 was carried out to study potential mechanistic effects on fat storage. Mice given F19 displayed significantly less body fat, as assessed by magnetic resonance imaging, and a changed lipoprotein profile. Given that previous studies on fat storage have identified ANGPTL4 as an effector, we also investigated circulating levels of ANGPTL4, which proved to be higher in the F19-treated group. This increase, together with total body fat and triglyceride levels told a story of inhibited LPL action through ANGPTL4 leading to decreased fat storage. Co-culture experiments of colonic cell lines and F19 were set up in order to monitor any ensuing alterations in ANGPTL4 expression by qPCR. We observed that potentially secreted factors from F19 can induce ANGPTL4 gene expression, acting in part through the peroxisome proliferator activated receptors alpha and gamma. To prove validity of in vitro findings, germ-free mice were monocolonized with F19. Here we again found changes in serum triglycerides as well as ANGPTL4 in response to F19. CONCLUSIONS/SIGNIFICANCE: Our results provide an interesting mechanism whereby modifying ANGPTL4, a central player in fat storage regulation, through manipulating gut flora could be an important gateway upon which intervention trials of weight management can be based. PMID- 20927338 TI - Crystal structure of a complex between amino and carboxy terminal fragments of mDia1: insights into autoinhibition of diaphanous-related formins. AB - Formin proteins direct the nucleation and assembly of linear actin filaments in a variety of cellular processes using their conserved formin homology 2 (FH2) domain. Diaphanous-related formins (DRFs) are effectors of Rho-family GTPases, and in the absence of Rho activation they are maintained in an inactive state by intramolecular interactions between their regulatory N-terminal region and a C terminal segment referred to as the DAD domain. Although structures are available for the isolated DAD segment in complex with the interacting region in the N terminus, it remains unclear how this leads to inhibition of actin assembly by the FH2 domain. Here we describe the crystal structure of the N-terminal regulatory region of formin mDia1 in complex with a C-terminal fragment containing both the FH2 and DAD domains. In the crystal structure and in solution, these fragments form a tetrameric complex composed of two interlocking N+C dimers. Formation of the tetramer is likely a consequence of the particular N terminal construct employed, as we show that a nearly full-length mDia1 protein is dimeric, as are other autoinhibited N+C complexes containing longer N-terminal fragments. The structure provides the first view of the intact C-terminus of a DRF, revealing the relationship of the DAD to the FH2 domain. Delineation of alternative dimeric N+C interactions within the tetramer provides two general models for autoinhibition in intact formins. In both models, engagement of the DAD by the N-terminus is incompatible with actin filament formation on the FH2, and in one model the actin binding surfaces of the FH2 domain are directly blocked by the N-terminus. PMID- 20927339 TI - Quantification of three-dimensional cell-mediated collagen remodeling using graph theory. AB - BACKGROUND: Cell cooperation is a critical event during tissue development. We present the first precise metrics to quantify the interaction between mesenchymal stem cells (MSCs) and extra cellular matrix (ECM). In particular, we describe cooperative collagen alignment process with respect to the spatio-temporal organization and function of mesenchymal stem cells in three dimensions. METHODOLOGY/PRINCIPAL FINDINGS: We defined two precise metrics: Collagen Alignment Index and Cell Dissatisfaction Level, for quantitatively tracking type I collagen and fibrillogenesis remodeling by mesenchymal stem cells over time. Computation of these metrics was based on graph theory and vector calculus. The cells and their three dimensional type I collagen microenvironment were modeled by three dimensional cell-graphs and collagen fiber organization was calculated from gradient vectors. With the enhancement of mesenchymal stem cell differentiation, acceleration through different phases was quantitatively demonstrated. The phases were clustered in a statistically significant manner based on collagen organization, with late phases of remodeling by untreated cells clustering strongly with early phases of remodeling by differentiating cells. The experiments were repeated three times to conclude that the metrics could successfully identify critical phases of collagen remodeling that were dependent upon cooperativity within the cell population. CONCLUSIONS/SIGNIFICANCE: Definition of early metrics that are able to predict long-term functionality by linking engineered tissue structure to function is an important step toward optimizing biomaterials for the purposes of regenerative medicine. PMID- 20927340 TI - Novel Gd nanoparticles enhance vascular contrast for high-resolution magnetic resonance imaging. AB - BACKGROUND: Gadolinium (Gd), with its 7 unpaired electrons in 4f orbitals that provide a very large magnetic moment, is proven to be among the best agents for contrast enhanced MRI. Unfortunately, the most potent MR contrast agent based on Gd requires relatively high doses of Gd. The Gd-chelated to diethylene-triamine penta-acetic acid (DTPA), or other derivatives (at 0.1 mmole/kg recommended dose), distribute broadly into tissues and clear through the kidney. These contrast agents carry the risk of Nephrogenic Systemic Fibrosis (NSF), particularly in kidney impaired subjects. Thus, Gd contrast agents that produce higher resolution images using a much lower Gd dose could address both imaging sensitivity and Gd safety. METHODOLOGY/PRINCIPAL FINDINGS: To determine whether a biocompatible lipid nanoparticle with surface bound Gd can improve MRI contrast sensitivity, we constructed Gd-lipid nanoparticles (Gd-LNP) containing lipid bound DTPA and Gd. The Gd-LNP were intravenously administered to rats and MR images collected. We found that Gd in Gd-LNP produced a greater than 33-fold higher longitudinal (T(1)) relaxivity, r(1), constant than the current FDA approved Gd-chelated contrast agents. Intravenous administration of these Gd-LNP at only 3% of the recommended clinical Gd dose produced MRI signal-to-noise ratios of greater than 300 in all vasculatures. Unlike current Gd contrast agents, these Gd-LNP stably retained Gd in normal vasculature, and are eliminated predominately through the biliary, instead of the renal system. Gd-LNP did not appear to accumulate in the liver or kidney, and was eliminated completely within 24 hrs. CONCLUSIONS/SIGNIFICANCE: The novel Gd-nanoparticles provide high quality contrast enhanced vascular MRI at 97% reduced dose of Gd and do not rely on renal clearance. This new agent is likely to be suitable for patients exhibiting varying degrees of renal impairment. The simple and adaptive nanoparticle design could accommodate ligand or receptor coating for drug delivery optimization and in vivo drug-target definition in system biology profiling, increasing the margin of safety in treatment of cancers and other diseases. PMID- 20927341 TI - Insights into the genetic history of French cattle from dense SNP data on 47 worldwide breeds. AB - BACKGROUND: Modern cattle originate from populations of the wild extinct aurochs through a few domestication events which occurred about 8,000 years ago. Newly domesticated populations subsequently spread worldwide following breeder migration routes. The resulting complex historical origins associated with both natural and artificial selection have led to the differentiation of numerous different cattle breeds displaying a broad phenotypic variety over a short period of time. METHODOLOGY/PRINCIPAL FINDINGS: This study gives a detailed assessment of cattle genetic diversity based on 1,121 individuals sampled in 47 populations from different parts of the world (with a special focus on French cattle) genotyped for 44,706 autosomal SNPs. The analyzed data set consisted of new genotypes for 296 individuals representing 14 French cattle breeds which were combined to those available from three previously published studies. After characterizing SNP polymorphism in the different populations, we performed a detailed analysis of genetic structure at both the individual and population levels. We further searched for spatial patterns of genetic diversity among 23 European populations, most of them being of French origin, under the recently developed spatial Principal Component analysis framework. CONCLUSIONS/SIGNIFICANCE: Overall, such high throughput genotyping data confirmed a clear partitioning of the cattle genetic diversity into distinct breeds. In addition, patterns of differentiation among the three main groups of populations- the African taurine, the European taurine and zebus--may provide some additional support for three distinct domestication centres. Finally, among the European cattle breeds investigated, spatial patterns of genetic diversity were found in good agreement with the two main migration routes towards France, initially postulated based on archeological evidence. PMID- 20927342 TI - Identification of thioaptamer ligand against E-selectin: potential application for inflamed vasculature targeting. AB - Active targeting of a drug carrier to a specific target site is crucial to provide a safe and efficient delivery of therapeutics and imaging contrast agents. E-selectin expression is induced on the endothelial cell surface of vessels in response to inflammatory stimuli but is absent in the normal vessels. Thus, E-selectin is an attractive molecular target, and high affinity ligands for E-selectin could be powerful tools for the delivery of therapeutics and/or imaging agents to inflamed vessels. In this study, we identified a thiophosphate modified aptamer (thioaptamer, TA) against E-selectin (ESTA-1) by employing a two step selection strategy: a recombinant protein-based TA binding selection from a combinatorial library followed by a cell-based TA binding selection using E selectin expressing human microvascular endothelial cells. ESTA-1 selectively bound to E-selectin with nanomolar binding affinity (K(D) = 47 nM) while exhibiting minimal cross reactivity to P- and L-selectin. Furthermore, ESTA-1 binding to E-selectin on the endothelial cells markedly antagonized the adhesion (over 75% inhibition) of sLe(x) positive HL-60 cells at nanomolar concentration. ESTA-1 also bound specifically to the inflamed tumor-associated vasculature of human carcinomas derived from breast, ovarian, and skin but not to normal organs, and this binding was highly associated with the E-selectin expression level. Similarly, intravenously injected ESTA-1 demonstrated distinct binding to the tumor vasculature in a breast cancer xenograft model. Together, our data substantiates the discovery of a thioaptamer (ESTA-1) that binds to E-selectin with high affinity and specificity, thereby highlighting the potential application of ESTA-1 for E-selectin targeted delivery. PMID- 20927343 TI - Crystal structure of the Formin mDia1 in autoinhibited conformation. AB - BACKGROUND: Formin proteins utilize a conserved formin homology 2 (FH2) domain to nucleate new actin filaments. In mammalian diaphanous-related formins (DRFs) the FH2 domain is inhibited through an unknown mechanism by intramolecular binding of the diaphanous autoinhibitory domain (DAD) and the diaphanous inhibitory domain (DID). METHODOLOGY/PRINCIPAL FINDINGS: Here we report the crystal structure of a complex between DID and FH2-DAD fragments of the mammalian DRF, mDia1 (mammalian diaphanous 1 also called Drf1 or p140mDia). The structure shows a tetrameric configuration (4 FH2 + 4 DID) in which the actin-binding sites on the FH2 domain are sterically occluded. However biochemical data suggest the full-length mDia1 is a dimer in solution (2 FH2 + 2 DID). Based on the crystal structure, we have generated possible dimer models and found that architectures of all of these models are incompatible with binding to actin filament but not to actin monomer. Furthermore, we show that the minimal functional monomeric unit in the FH2 domain, termed the bridge element, can be inhibited by isolated monomeric DID. NMR data on the bridge-DID system revealed that at least one of the two actin binding sites on the bridge element is accessible to actin monomer in the inhibited state. CONCLUSIONS/SIGNIFICANCE: Our findings suggest that autoinhibition in the native DRF dimer involves steric hindrance with the actin filament. Although the structure of a full-length DRF would be required for clarification of the presented models, our work here provides the first structural insights into the mechanism of the DRF autoinhibition. PMID- 20927344 TI - Controlled trials in children: quantity, methodological quality and descriptive characteristics of pediatric controlled trials published 1948-2006. AB - BACKGROUND: The objective of this study was to describe randomized controlled trials (RCTs) and controlled clinical trials (CCTs) in child health published between 1948 and 2006, in terms of quantity, methodological quality, and publication and trial characteristics. We used the Trials Register of the Cochrane Child Health Field for overall trends and a sample from this to explore trial characteristics in more detail. METHODOLOGY/PRINCIPAL FINDINGS: We extracted descriptive data on a random sample of 578 trials. Ninety-six percent of the trials were published in English; the percentage of child-only trials was 90.5%. The most frequent diagnostic categories were infectious diseases (13.2%), behavioural and psychiatric disorders (11.6%), neonatal critical care (11.4%), respiratory disorders (8.9%), non-critical neonatology (7.9%), and anaesthesia (6.5%). There were significantly fewer child-only studies (i.e., more mixed child and adult studies) over time (P = 0.0460). The proportion of RCTs to CCTs increased significantly over time (P<0.0001), as did the proportion of multicentre trials (P = 0.002). Significant increases over time were found in methodological quality (Jadad score) (P<0.0001), the proportion of double-blind studies (P<0.0001), and studies with adequate allocation concealment (P<0.0001). Additionally, we found an improvement in reporting over time: adequate description of withdrawals and losses to follow-up (P<0.0001), sample size calculations (P<0.0001), and intention-to-treat analysis (P<0.0001). However, many trials still do not describe their level of blinding, and allocation concealment was inadequately reported in the majority of studies across the entire time period. The proportion of studies with industry funding decreased slightly over time (P = 0.003), and these studies were more likely to report positive conclusions (P = 0.028). CONCLUSIONS/SIGNIFICANCE: The quantity and quality of pediatric controlled trials has increased over time; however, much work remains to be done, particularly in improving methodological issues around conduct and reporting of trials. PMID- 20927345 TI - Functional connectivity of the posteromedial cortex. AB - As different areas within the PMC have different connectivity patterns with various cortical and subcortical regions, we hypothesized that distinct functional modules may be present within the PMC. Because the PMC appears to be the most active region during resting state, it has been postulated to play a fundamental role in the control of baseline brain functioning within the default mode network (DMN). Therefore one goal of this study was to explore which components of the PMC are specifically involved in the DMN. In a sample of seventeen healthy volunteers, we performed an unsupervised voxelwise ROI-based clustering based on resting state functional connectivity. Our results showed four clusters with different network connectivity. Each cluster showed positive and negative correlations with cortical regions involved in the DMN. Progressive shifts in PMC functional connectivity emerged from anterior to posterior and from dorsal to ventral ROIs. Ventral posterior portions of PMC were found to be part of a network implicated in the visuo-spatial guidance of movements, whereas dorsal anterior portions of PMC were interlinked with areas involved in attentional control. Ventral retrosplenial PMC selectively correlated with a network showing considerable overlap with the DMN, indicating that it makes essential contributions in self-referential processing, including autobiographical memory processing. Finally, ventral posterior PMC was shown to be functionally connected with a visual network.The paper represents the first attempt to provide a systematic, unsupervised, voxelwise clustering of the human posteromedial cortex (PMC), using resting-state functional connectivity data. Moreover, a ROI-based parcellation was used to confirm the results. PMID- 20927346 TI - Changes in waist circumference and mortality in middle-aged men and women. AB - BACKGROUND: Waist circumference (WC) adjusted for body mass index (BMI) is positively associated with mortality, but the association with changes in WC is less clear. We investigated the association between changes in WC and mortality in middle-aged men and women, and evaluated the influence from concurrent changes in BMI. METHODOLOGY/PRINCIPAL FINDINGS: Data on 26,625 healthy men and women from the Danish Diet, Cancer and Health study was analyzed. WC and BMI were assessed in 1993-97 and in 1999-02. Information on mortality was obtained by linkage to the Danish central Person Register. Hazard ratios (HR) were estimated with Cox regression models. During 6.7 years of follow-up, 568 and 361 deaths occurred among men and women, respectively. Changes in WC were positively associated with mortality (HR per 5 cm for the sexes combined = 1.09 (1.02 : 1.16) with adjustment for covariates, baseline WC, BMI and changes in BMI), whereas changes in BMI were inversely associated with mortality (HR per kg/m2 for the sexes combined = 0.91 (0.86, 0.97) with adjustment for covariates, baseline WC, BMI and changes in WC). Associations between changes in WC and mortality were not notably different in sub-groups stratified according to changes in BMI, baseline WC or when smokers or deaths occurring within the first years of follow-up were excluded. CONCLUSIONS/SIGNIFICANCE: Changes in WC were positively associated with mortality in healthy middle-aged men and women throughout the range of concurrent changes in BMI. These findings suggest a need for development of prevention and treatment strategies targeted against redistribution of fat mass towards the abdominal region. PMID- 20927347 TI - Cartilaginous epiphyses in extant archosaurs and their implications for reconstructing limb function in dinosaurs. AB - Extinct archosaurs, including many non-avian dinosaurs, exhibit relatively simply shaped condylar regions in their appendicular bones, suggesting potentially large amounts of unpreserved epiphyseal (articular) cartilage. This "lost anatomy" is often underappreciated such that the ends of bones are typically considered to be the joint surfaces, potentially having a major impact on functional interpretation. Extant alligators and birds were used to establish an objective basis for inferences about cartilaginous articular structures in such extinct archosaur clades as non-avian dinosaurs. Limb elements of alligators, ostriches, and other birds were dissected, disarticulated, and defleshed. Lengths and condylar shapes of elements with intact epiphyses were measured. Limbs were subsequently completely skeletonized and the measurements repeated. Removal of cartilaginous condylar regions resulted in statistically significant changes in element length and condylar breadth. Moreover, there was marked loss of those cartilaginous structures responsible for joint architecture and congruence. Compared to alligators, birds showed less dramatic, but still significant changes. Condylar morphologies of dinosaur limb bones suggest that most non coelurosaurian clades possessed large cartilaginous epiphyses that relied on the maintenance of vascular channels that are otherwise eliminated early in ontogeny in smaller-bodied tetrapods. A sensitivity analysis using cartilage correction factors (CCFs) obtained from extant taxa indicates that whereas the presence of cartilaginous epiphyses only moderately increases estimates of dinosaur height and speed, it has important implications for our ability to infer joint morphology, posture, and the complicated functional movements in the limbs of many extinct archosaurs. Evidence suggests that the sizes of sauropod epiphyseal cartilages surpassed those of alligators, which account for at least 10% of hindlimb length. These data suggest that large cartilaginous epiphyses were widely distributed among non-avian archosaurs and must be considered when making inferences about locomotor functional morphology in fossil taxa. PMID- 20927348 TI - Targeting the PI3K/Akt cell survival pathway to induce cell death of HIV-1 infected macrophages with alkylphospholipid compounds. AB - BACKGROUND: HIV-1 infected macrophages and microglia are long-lived viral reservoirs persistently producing viral progenies. HIV-1 infection extends the life span of macrophages by promoting the stress-induced activation of the PI3K/Akt cell survival pathway. Importantly, various cancers also display the PI3K/Akt activation for long-term cell survival and outgrowth, and Akt inhibitors have been extensively searched as anti-cancer agents. This led us to investigate whether Akt inhibitors could antagonize long-term survival and cytoprotective phenotype of HIV-1 infected macrophages. PRINCIPAL FINDINGS: Here, we examined the effect of one such class of drugs, alkylphospholipids (ALPs), on cell death and Akt pathway signals in human macrophages and a human microglial cell line, CHME5, infected with HIV-1 BaL or transduced with HIV-1 vector, respectively. Our findings revealed that the ALPs, perifosine and edelfosine, specifically induced the death of HIV-1 infected primary human macrophages and CHME5 cells. Furthermore, these two compounds reduced phosphorylation of both Akt and GSK3beta, a downstream substrate of Akt, in the transduced CHME5 cells. Additionally, we observed that perifosine effectively reduced viral production in HIV-1 infected primary human macrophages. These observations demonstrate that the ALP compounds tested are able to promote cell death in both HIV-1 infected macrophages and HIV-1 expressing CHME5 cells by inhibiting the action of the PI3K/Akt pathway, ultimately restricting viral production from the infected cells. SIGNIFICANCE: This study suggests that Akt inhibitors, such as ALP compounds, may serve as potential anti-HIV-1 agents specifically targeting long living HIV-1 macrophages and microglia reservoirs. PMID- 20927349 TI - Studies on a novel serine protease of a DeltahapADeltaprtV Vibrio cholerae O1 strain and its role in hemorrhagic response in the rabbit ileal loop model. AB - BACKGROUND: Two well-characterized proteases secreted by Vibrio cholerae O1 strains are hemagglutinin protease (HAP) and V. cholerae protease (PrtV). The hapA and prtV knock out mutant, V. cholerae O1 strain CHA6.8DeltaprtV, still retains residual protease activity. We initiated this study to characterize the protease present in CHA6.8DeltaprtV strain and study its role in pathogenesis in rabbit ileal loop model (RIL). METHODOLOGY/PRINCIPAL FINDINGS: We partially purified the residual protease secreted by strain CHA6.8DeltaprtV from culture supernatant by anion-exchange chromatography. The major protein band in native PAGE was identified by MS peptide mapping and sequence analysis showed homology with a 59-kDa trypsin-like serine protease encoded by VC1649. The protease activity was partially inhibited by 25 mM PMSF and 10 mM EDTA and completely inhibited by EDTA and PMSF together. RIL assay with culture supernatants of strains C6709 (FA ratio 1.1+/-0.3 n = 3), CHA6.8 (FA ratio 1.08+/-0.2 n = 3), CHA6.8DeltaprtV (FA ratio 1.02+/-0.2 n = 3) and partially purified serine protease from CHA6.8DeltaprtV (FA ratio 1.2+/-0.3 n = 3) induced fluid accumulation and histopathological studies on rabbit ileum showed destruction of the villus structure with hemorrhage in all layers of the mucosa. RIL assay with culture supernatant of CHA6.8DeltaprtVDeltaVC1649 strain (FA ratio 0.11+/-0.005 n = 3) and with protease incubated with PMSF and EDTA (FA ratio 0.3+/-0.05 n = 3) induced a significantly reduced FA ratio with almost complete normal villus structure. CONCLUSION: Our results show the presence of a novel 59-kDa serine protease in a DeltahapADeltaprtV V. cholerae O1 strain and its role in hemorrhagic response in RIL model. PMID- 20927350 TI - Epigenetic transgenerational actions of vinclozolin on promoter regions of the sperm epigenome. AB - Previous observations have demonstrated that embryonic exposure to the endocrine disruptor vinclozolin during gonadal sex determination promotes transgenerational adult onset disease such as male infertility, kidney disease, prostate disease, immune abnormalities and tumor development. The current study investigates genome wide promoter DNA methylation alterations in the sperm of F3 generation rats whose F0 generation mother was exposed to vinclozolin. A methylated DNA immunoprecipitation with methyl-cytosine antibody followed by a promoter tilling microarray (MeDIP-Chip) procedure was used to identify 52 different regions with statistically significant altered methylation in the sperm promoter epigenome. Mass spectrometry bisulfite analysis was used to map the CpG DNA methylation and 16 differential DNA methylation regions were confirmed, while the remainder could not be analyzed due to bisulfite technical limitations. Analysis of these validated regions identified a consensus DNA sequence (motif) that associated with 75% of the promoters. Interestingly, only 16.8% of a random set of 125 promoters contained this motif. One candidate promoter (Fam111a) was found to be due to a copy number variation (CNV) and not a methylation change, suggesting initial alterations in the germline epigenome may promote genetic abnormalities such as induced CNV in later generations. This study identifies differential DNA methylation sites in promoter regions three generations after the initial exposure and identifies common genome features present in these regions. In addition to primary epimutations, a potential indirect genetic abnormality was identified, and both are postulated to be involved in the epigenetic transgenerational inheritance observed. This study confirms that an environmental agent has the ability to induce epigenetic transgenerational changes in the sperm epigenome. PMID- 20927351 TI - CD1d expression in paneth cells and rat exocrine pancreas revealed by novel monoclonal antibodies which differentially affect NKT cell activation. AB - BACKGROUND: CD1d is a nonpolymorphic MHC class I-like molecule which presents nonpeptide ligands, e.g. glycolipids, to NKT cells. These cells are known to have multiple effects on innate and adaptive immune responses and on the development of pathological conditions. In order to analyze CD1d expression and function in the rat, the first rat CD1d-specific monoclonal antibodies (mAbs) were generated. METHODOLOGY/PRINCIPAL FINDINGS: Two mAbs, WTH-1 and WTH-2, were generated which bound equally well to cell surface-expressed rat and mouse CD1d. Their non overlapping epitopes were mapped to the CD1d heavy chain. Flow cytometry and immunohistological analyses revealed a nearly identical degree and pattern of CD1d expression for hematopoieitic cells of both species. Notable is also the detection of CD1d protein in mouse and rat Paneth cells as well as the extremely high CD1d expression in acinar exocrine cells of the rat pancreas and the expression of CD4 on rat marginal zone B cells. Both mAbs blocked alpha galactosylceramide recognition by primary rat and mouse NKT cells. Interestingly, the two mAbs differed in their impact on the activation of various autoreactive T cell hybridomas, including the XV19.2 hybridoma whose activation was enhanced by the WTH-1 mAb. CONCLUSIONS/SIGNIFICANCE: The two novel monoclonal antibodies described in this study, allowed the analysis of CD1d expression and CD1d restricted T cell responses in the rat for the first time. Moreover, they provided new insights into mechanisms of CD1d-restricted antigen recognition. While CD1d expression by hematopoietic cells of mice and rats was extremely similar, CD1d protein was detected at not yet described sites of non-lymphatic tissues such as the rat exocrine pancreas and Paneth cells. The latter is of special relevance given the recently reported defects of Paneth cells in CD1d(-/ ) mice, which resulted in an altered composition of the gut flora. PMID- 20927352 TI - Predators are attracted to the olfactory signals of prey. AB - BACKGROUND: Predator attraction to prey social signals can force prey to trade off the social imperatives to communicate against the profound effect of predation on their future fitness. These tradeoffs underlie theories on the design and evolution of conspecific signalling systems and have received much attention in visual and acoustic signalling modes. Yet while most territorial mammals communicate using olfactory signals and olfactory hunting is widespread in predators, evidence for the attraction of predators to prey olfactory signals under field conditions is lacking. METHODOLOGY/PRINCIPAL FINDINGS: To redress this fundamental issue, we examined the attraction of free-roaming predators to discrete patches of scents collected from groups of two and six adult, male house mice, Mus domesticus, which primarily communicate through olfaction. Olfactorily hunting predators were rapidly attracted to mouse scent signals, visiting mouse scented locations sooner, and in greater number, than control locations. There were no effects of signal concentration on predator attraction to their prey's signals. CONCLUSIONS/SIGNIFICANCE: This implies that communication will be costly if conspecific receivers and eavesdropping predators are simultaneously attracted to a signal. Significantly, our results also suggest that receivers may be at greater risk of predation when communicating than signallers, as receivers must visit risky patches of scent to perform their half of the communication equation, while signallers need not. PMID- 20927353 TI - Calcium gluconate in phosphate buffered saline increases gene delivery with adenovirus type 5. AB - BACKGROUND: Adenoviruses are attractive vectors for gene therapy because of their stability in vivo and the possibility of production at high titers. Despite exciting preclinical data with various approaches, there are only a few examples of clear efficacy in clinical trials. Effective gene delivery to target cells remains the key variable determining efficacy and thus enhanced transduction methods are important. METHODS/RESULTS: We found that heated serum could enhance adenovirus 5 mediated gene delivery up to twentyfold. A new protein-level interaction was found between fiber knob and serum transthyretin, but this was not responsible for the observed effect. Instead, we found that heating caused the calcium and phosphate present in the serum mix to precipitate, and this was responsible for enhanced gene delivery. This finding could have relevance for designing preclinical experiments with adenoviruses, since calcium and phosphate are present in many solutions. To translate this into an approach potentially testable in patients, we used calcium gluconate in phosphate buffered saline, both of which are clinically approved, to increase adenoviral gene transfer up to 300-fold in vitro. Gene transfer was increased with or without heating and in a manner independent from the coxsackie-adenovirus receptor. In vivo, in mouse studies, gene delivery was increased 2-, 110-, 12- and 13-fold to tumors, lungs, heart and liver and did not result in increased pro-inflammatory cytokine induction. Antitumor efficacy of a replication competent virus was also increased significantly. CONCLUSION: In summary, adenoviral gene transfer and antitumor efficacy can be enhanced by calcium gluconate in phosphate buffered saline. PMID- 20927354 TI - Cost-effectiveness of pooled nucleic acid amplification testing for acute HIV infection after third-generation HIV antibody screening and rapid testing in the United States: a comparison of three public health settings. AB - BACKGROUND: Detection of acute HIV infection (AHI) with pooled nucleic acid amplification testing (NAAT) following HIV testing is feasible. However, cost effectiveness analyses to guide policy around AHI screening are lacking; particularly after more sensitive third-generation antibody screening and rapid testing. METHODS AND FINDINGS: We conducted a cost-effectiveness analysis of pooled NAAT screening that assessed the prevention benefits of identification and notification of persons with AHI and cases averted compared with repeat antibody testing at different intervals. Effectiveness data were derived from a Centers for Disease Control and Prevention AHI study conducted in three settings: municipal sexually transmitted disease (STD) clinics, a community clinic serving a population of men who have sex with men, and HIV counseling and testing sites. Our analysis included a micro-costing study of NAAT and a mathematical model of HIV transmission. Cost-effectiveness ratios are reported as costs per quality adjusted life year (QALY) gained in US dollars from the societal perspective. Sensitivity analyses were conducted on key variables, including AHI positivity rates, antibody testing frequency, symptomatic detection of AHI, and costs. Pooled NAAT for AHI screening following annual antibody testing had cost effectiveness ratios exceeding US$200,000 per QALY gained for the municipal STD clinics and HIV counseling and testing sites and was cost saving for the community clinic. Cost-effectiveness ratios increased substantially if the antibody testing interval decreased to every 6 months and decreased to cost saving if the testing interval increased to every 5 years. NAAT was cost saving in the community clinic in all situations. Results were particularly sensitive to AHI screening yield. CONCLUSIONS: Pooled NAAT screening for AHI following negative third-generation antibody or rapid tests is not cost-effective at recommended antibody testing intervals for high-risk persons except in very high incidence settings. PMID- 20927355 TI - Are drug companies living up to their human rights responsibilities? The Merck perspective. AB - BACKGROUND TO THE DEBATE: The human rights responsibilities of drug companies have been considered for years by nongovernmental organizations, but were most sharply defined in a report by the UN Special Rapporteur on the right to health, submitted to the United Nations General Assembly in August 2008. The "Human Rights Guidelines for Pharmaceutical Companies in relation to Access to Medicines" include responsibilities for transparency, management, monitoring and accountability, pricing, and ethical marketing, and against lobbying for more protection in intellectual property laws, applying for patents for trivial modifications of existing medicines, inappropriate drug promotion, and excessive pricing. Two years after the release of the Guidelines, the PLoS Medicine Debate asks whether drug companies are living up to their human rights responsibilities. Sofia Gruskin and Zyde Raad from the Harvard School of Public Health say more assessment is needed of such responsibilities; Geralyn Ritter, Vice President of Global Public Policy and Corporate Responsibility at Merck & Co. argues that multiple stakeholders could do more to help States deliver the right to health; and Paul Hunt and Rajat Khosla introduce Mr. Hunt's work as the UN Special Rapporteur on the right to the highest attainable standard of health, regarding the human rights responsibilities of pharmaceutical companies and access to medicines. PMID- 20927356 TI - Are drug companies living up to their human rights responsibilities? Moving toward assessment. AB - BACKGROUND TO THE DEBATE: The human rights responsibilities of drug companies have been considered for years by nongovernmental organizations, but were most sharply defined in a report by the UN Special Rapporteur on the right to health, submitted to the United Nations General Assembly in August 2008. The "Human Rights Guidelines for Pharmaceutical Companies in relation to Access to Medicines" include responsibilities for transparency, management, monitoring and accountability, pricing, and ethical marketing, and against lobbying for more protection in intellectual property laws, applying for patents for trivial modifications of existing medicines, inappropriate drug promotion, and excessive pricing. Two years after the release of the Guidelines, the PLoS Medicine Debate asks whether drug companies are living up to their human rights responsibilities. Sofia Gruskin and Zyde Raad from the Harvard School of Public Health say more assessment is needed of such responsibilities; Geralyn Ritter, Vice President of Global Public Policy and Corporate Responsibility at Merck & Co. argues that multiple stakeholders could do more to help States deliver the right to health; and Paul Hunt and Rajat Khosla introduce Mr. Hunt's work as the UN Special Rapporteur on the right to the highest attainable standard of health, regarding the human rights responsibilities of pharmaceutical companies and access to medicines. PMID- 20927358 TI - Drug companies should be held more accountable for their human rights responsibilities. PMID- 20927357 TI - Genomic fossils calibrate the long-term evolution of hepadnaviruses. AB - Because most extant viruses mutate rapidly and lack a true fossil record, their deep evolution and long-term substitution rates remain poorly understood. In addition to retroviruses, which rely on chromosomal integration for their replication, many other viruses replicate in the nucleus of their host's cells and are therefore prone to endogenization, a process that involves integration of viral DNA into the host's germline genome followed by long-term vertical inheritance. Such endogenous viruses are highly valuable as they provide a molecular fossil record of past viral invasions, which may be used to decipher the origins and long-term evolutionary characteristics of modern pathogenic viruses. Hepadnaviruses (Hepadnaviridae) are a family of small, partially double stranded DNA viruses that include hepatitis B viruses. Here we report the discovery of endogenous hepadnaviruses in the genome of the zebra finch. We used a combination of cross-species analysis of orthologous insertions, molecular dating, and phylogenetic analyses to demonstrate that hepadnaviruses infiltrated repeatedly the germline genome of passerine birds. We provide evidence that some of the avian hepadnavirus integration events are at least 19 My old, which reveals a much deeper ancestry of Hepadnaviridae than could be inferred based on the coalescence times of modern hepadnaviruses. Furthermore, the remarkable sequence similarity between endogenous and extant avian hepadnaviruses (up to 75% identity) suggests that long-term substitution rates for these viruses are on the order of 10(-8) substitutions per site per year, which is a 1,000-fold slower than short-term rates estimated based on the sequences of circulating hepadnaviruses. Together, these results imply a drastic shift in our understanding of the time scale of hepadnavirus evolution, and suggest that the rapid evolutionary dynamics characterizing modern avian hepadnaviruses do not reflect their mode of evolution on a deep time scale. PMID- 20927359 TI - Effectiveness of chest physiotherapy in infants hospitalized with acute bronchiolitis: a multicenter, randomized, controlled trial. AB - BACKGROUND: Acute bronchiolitis treatment in children and infants is largely supportive, but chest physiotherapy is routinely performed in some countries. In France, national guidelines recommend a specific type of physiotherapy combining the increased exhalation technique (IET) and assisted cough (AC). Our objective was to evaluate the efficacy of chest physiotherapy (IET + AC) in previously healthy infants hospitalized for a first episode of acute bronchiolitis. METHODS AND FINDINGS: We conducted a multicenter, randomized, outcome assessor-blind and parent-blind trial in seven French pediatric departments. We recruited 496 infants hospitalized for first-episode acute bronchiolitis between October 2004 and January 2008. Patients were randomly allocated to receive from physiotherapists three times a day, either IET + AC (intervention group, n=246) or nasal suction (NS, control group, n=250). Only physiotherapists were aware of the allocation group of the infant. The primary outcome was time to recovery, defined as 8 hours without oxygen supplementation associated with minimal or no chest recession, and ingesting more than two-thirds of daily food requirements. Secondary outcomes were intensive care unit admissions, artificial ventilation, antibiotic treatment, description of side effects during procedures, and parental perception of comfort. Statistical analysis was performed on an intent-to-treat basis. Median time to recovery was 2.31 days, (95% confidence interval [CI] 1.97 2.73) for the control group and 2.02 days (95% CI 1.96-2.34) for the intervention group, indicating no significant effect of physiotherapy (hazard ratio [HR]=1.09, 95% CI 0.91-1.31, p=0.33). No treatment by age interaction was found (p=0.97). Frequency of vomiting and transient respiratory destabilization was higher in the IET + AC group during the procedure (relative risk [RR]=10.2, 95% CI 1.3-78.8, p=0.005 and RR=5.4, 95% CI 1.6-18.4, p=0.002, respectively). No difference between groups in bradycardia with or without desaturation (RR=1.0, 95% CI 0.2 5.0, p=1.00 and RR=3.6, 95% CI 0.7-16.9, p=0.10, respectively) was found during the procedure. Parents reported that the procedure was more arduous in the group treated with IET (mean difference=0.88, 95% CI 0.33-1.44, p=0.002), whereas there was no difference regarding the assessment of the child's comfort between both groups (mean difference=-0.07, 95% CI -0.53 to 0.38, p=0.40). No evidence of differences between groups in intensive care admission (RR=0.7, 95% CI 0.3-1.8, p=0.62), ventilatory support (RR=2.5, 95% CI 0.5-13.0, p=0.29), and antibiotic treatment (RR=1.0, 95% CI 0.7-1.3, p=1.00) was observed. CONCLUSIONS: IET + AC had no significant effect on time to recovery in this group of hospitalized infants with bronchiolitis. Additional studies are required to explore the effect of chest physiotherapy on ambulatory populations and for infants without a history of atopy. TRIAL REGISTRATION: ClinicalTrials.gov NCT00125450. PMID- 20927360 TI - Clever cattle parasite captures cell division machinery. PMID- 20927361 TI - The transforming parasite Theileria co-opts host cell mitotic and central spindles to persist in continuously dividing cells. AB - The protozoan parasite Theileria inhabits the host cell cytoplasm and possesses the unique capacity to transform the cells it infects, inducing continuous proliferation and protection against apoptosis. The transforming schizont is a multinucleated syncytium that resides free in the host cell cytoplasm and is strictly intracellular. To maintain transformation, it is crucial that this syncytium is divided over the two daughter cells at each host cell cytokinesis. This process was dissected using different cell cycle synchronization methods in combination with the targeted application of specific inhibitors. We found that Theileria schizonts associate with newly formed host cell microtubules that emanate from the spindle poles, positioning the parasite at the equatorial region of the mitotic cell where host cell chromosomes assemble during metaphase. During anaphase, the schizont interacts closely with host cell central spindle. As part of this process, the schizont recruits a host cell mitotic kinase, Polo-like kinase 1, and we established that parasite association with host cell central spindles requires Polo-like kinase 1 catalytic activity. Blocking the interaction between the schizont and astral as well as central spindle microtubules prevented parasite segregation between the daughter cells during cytokinesis. Our findings provide a striking example of how an intracellular eukaryotic pathogen that evolved ways to induce the uncontrolled proliferation of the cells it infects usurps the host cell mitotic machinery, including Polo-like kinase 1, one of the pivotal mitotic kinases, to ensure its own persistence and survival. PMID- 20927362 TI - Misspecifications of stimulus presentation durations in experimental psychology: a systematic review of the psychophysics literature. AB - BACKGROUND: In visual psychophysics, precise display timing, particularly for brief stimulus presentations, is often required. The aim of this study was to systematically review the commonly applied methods for the computation of stimulus durations in psychophysical experiments and to contrast them with the true luminance signals of stimuli on computer displays. METHODOLOGY/PRINCIPAL FINDINGS: In a first step, we systematically scanned the citation index Web of Science for studies with experiments with stimulus presentations for brief durations. Articles which appeared between 2003 and 2009 in three different journals were taken into account if they contained experiments with stimuli presented for less than 50 milliseconds. The 79 articles that matched these criteria were reviewed for their method of calculating stimulus durations. For those 75 studies where the method was either given or could be inferred, stimulus durations were calculated by the sum of frames (SOF) method. In a second step, we describe the luminance signal properties of the two monitor technologies which were used in the reviewed studies, namely cathode ray tube (CRT) and liquid crystal display (LCD) monitors. We show that SOF is inappropriate for brief stimulus presentations on both of these technologies. In extreme cases, SOF specifications and true stimulus durations are even unrelated. Furthermore, the luminance signals of the two monitor technologies are so fundamentally different that the duration of briefly presented stimuli cannot be calculated by a single method for both technologies. Statistics over stimulus durations given in the reviewed studies are discussed with respect to different duration calculation methods. CONCLUSIONS/SIGNIFICANCE: The SOF method for duration specification which was clearly dominating in the reviewed studies leads to serious misspecifications particularly for brief stimulus presentations. We strongly discourage its use for brief stimulus presentations on CRT and LCD monitors. PMID- 20927363 TI - Meta-analysis of relationships between human offtake, total mortality and population dynamics of gray wolves (Canis lupus). AB - Following the growth and geographic expansion of wolf (Canis lupus) populations reintroduced to Yellowstone National Park and central Idaho in 1995-1996, Rocky Mountain wolves were removed from the endangered species list in May 2009. Idaho and Montana immediately established hunting seasons with quotas equaling 20% of the regional wolf population. Combining hunting with predator control, 37.1% of Montana and Idaho wolves were killed in the year of delisting. Hunting and predator control are well-established methods to broaden societal acceptance of large carnivores, but it is unprecedented for a species to move so rapidly from protection under the Endangered Species Act to heavy direct harvest, and it is important to use all available data to assess the likely consequences of these changes in policy. For wolves, it is widely argued that human offtake has little effect on total mortality rates, so that a harvest of 28-50% per year can be sustained. Using previously published data from 21 North American wolf populations, we related total annual mortality and population growth to annual human offtake. Contrary to current conventional wisdom, there was a strong association between human offtake and total mortality rates across North American wolf populations. Human offtake was associated with a strongly additive or super additive increase in total mortality. Population growth declined as human offtake increased, even at low rates of offtake. Finally, wolf populations declined with harvests substantially lower than the thresholds identified in current state and federal policies. These results should help to inform management of Rocky Mountain wolves. PMID- 20927364 TI - Phylogenetic and molecular characterization of H9N2 influenza isolates from chickens in Northern China from 2007-2009. AB - The repeated transmission to pigs and humans, and the long-term endemicity in terrestrial poultry of H9N2 viruses in China lend urgency to the study of their ecology and pathogenicity. In the present paper, we reported an H9N2 virus sublineage isolated from chickens in northern China from 2007 to 2009 has high lethality for mice. Phylogenetic analysis of the full genome indicated that six representative H9N2 isolates shared high homology to each other, and they clustered in the same sublineage with other H9N2 viruses isolated recently in northern China. The isolates were double-reassortant viruses containing M genes similar to A/Quail/Hong Kong/G1/97 (H9N2) and the other seven gene segments from A/Chicken/Shanghai/F/98 (H9N2). These six isolates were capable of replicating in the lungs of infected chickens without producing observable clinical signs of disease or death. However, they were highly lethal to mice with mortality rates as high as 100% (14/14) without prior adaptation. The affected mice exhibited severe respiratory syndromes and diffuse lung injury. The H9N2 viruses could be detected in multiple organs of the infected mice, including hearts, livers, spleens, lungs and kidneys. Our findings demonstrated that H9N2 viruses isolated from the chickens in northern China have established a stable sublineage with enhanced pathogenicity to mice, suggesting that urgent attention will need to be paid to the transmission of H9N2 viruses from chickens to mammals. PMID- 20927365 TI - Rhesus monkeys (Macaca mulatta) do recognize themselves in the mirror: implications for the evolution of self-recognition. AB - Self-recognition in front of a mirror is used as an indicator of self-awareness. Along with humans, some chimpanzees and orangutans have been shown to be self aware using the mark test. Monkeys are conspicuously absent from this list because they fail the mark test and show persistent signs of social responses to mirrors despite prolonged exposure, which has been interpreted as evidence of a cognitive divide between hominoids and other species. In stark contrast with those reports, the rhesus monkeys in this study, who had been prepared for electrophysiological recordings with a head implant, showed consistent self directed behaviors in front of the mirror and showed social responses that subsided quickly during the first experimental session. The self-directed behaviors, which were performed in front of the mirror and did not take place in its absence, included extensive observation of the implant and genital areas that cannot be observed directly without a mirror. We hypothesize that the head implant, a most salient mark, prompted the monkeys to overcome gaze aversion inhibition or lack of interest in order to look and examine themselves in front of the mirror. The results of this study demonstrate that rhesus monkeys do recognize themselves in the mirror and, therefore, have some form of self awareness. Accordingly, instead of a cognitive divide, they support the notion of an evolutionary continuity of mental functions. PMID- 20927366 TI - DAAM1 is a formin required for centrosome re-orientation during cell migration. AB - BACKGROUND: Disheveled-associated activator of morphogenesis 1 (DAAM1) is a formin acting downstream of Wnt signaling that is important for planar cell polarity. It has been shown to promote proper cell polarization during embryonic development in both Xenopus and Drosophila. Importantly, DAAM1 binds to Disheveled (Dvl) and thus functions downstream of the Frizzled receptors. Little is known of how DAAM1 is localized and functions in mammalian cells. We investigate here how DAAM1 affects migration and polarization of cultured cells and conclude that it plays a key role in centrosome polarity. METHODOLOGY/PRINCIPAL FINDINGS: Using a specific antibody to DAAM1, we find that the protein localizes to the acto-myosin system and co-localizes with ventral myosin IIB-containing actin stress fibers. These fibers are particularly evident in the sub-nuclear region. An N-terminal region of DAAM1 is responsible for this targeting and the DAAM1(1-440) protein can interact with myosin IIB fibers independently of either F-actin or RhoA binding. We also demonstrate that DAAM1 depletion inhibits Golgi reorientation in wound healing assays. Wound-edge cells exhibit multiple protrusions characteristic of unpolarized cell migration. Finally, in U2OS cells lines stably expressing DAAM1, we observe an enhanced myosin IIB stress fiber network which opposes cell migration. CONCLUSIONS/SIGNIFICANCE: This work highlights the importance of DAAM1 in processes underlying cell polarity and suggests that it acts in part by affecting the function of acto-myosin IIB system. It also emphasizes the importance of the N-terminal half of DAAM1. DAAM1 depletion strongly blocks centrosomal re polarization, supporting the concept that DAAM1 signaling cooperates with the established Cdc42 associated polarity complex. These findings are also consistent with the observation that ablation of myosin IIB but not myosin IIA results in polarity defects downstream of Wnt signaling. The structure-function analysis of DAAM1 in cultured cells parallels more complex morphological events in the developing embryo. PMID- 20927367 TI - Genome-wide DNA methylation maps in follicular lymphoma cells determined by methylation-enriched bisulfite sequencing. AB - BACKGROUND: Follicular lymphoma (FL) is a form of non-Hodgkin's lymphoma (NHL) that arises from germinal center (GC) B-cells. Despite the significant advances in immunotherapy, FL is still not curable. Beyond transcriptional profiling and genomics datasets, there currently is no epigenome-scale dataset or integrative biology approach that can adequately model this disease and therefore identify novel mechanisms and targets for successful prevention and treatment of FL. METHODOLOGY/PRINCIPAL FINDINGS: We performed methylation-enriched genome-wide bisulfite sequencing of FL cells and normal CD19(+) B-cells using 454 sequencing technology. The methylated DNA fragments were enriched with methyl-binding proteins, treated with bisulfite, and sequenced using the Roche-454 GS FLX sequencer. The total number of bases covered in the human genome was 18.2 and 49.3 million including 726,003 and 1.3 million CpGs in FL and CD19(+) B-cells, respectively. 11,971 and 7,882 methylated regions of interest (MRIs) were identified respectively. The genome-wide distribution of these MRIs displayed significant differences between FL and normal B-cells. A reverse trend in the distribution of MRIs between the promoter and the gene body was observed in FL and CD19(+) B-cells. The MRIs identified in FL cells also correlated well with transcriptomic data and ChIP-on-Chip analyses of genome-wide histone modifications such as tri-methyl-H3K27, and tri-methyl-H3K4, indicating a concerted epigenetic alteration in FL cells. CONCLUSIONS/SIGNIFICANCE: This study is the first to provide a large scale and comprehensive analysis of the DNA methylation sequence composition and distribution in the FL epigenome. These integrated approaches have led to the discovery of novel and frequent targets of aberrant epigenetic alterations. The genome-wide bisulfite sequencing approach developed here can be a useful tool for profiling DNA methylation in clinical samples. PMID- 20927368 TI - Visualization of coronary wall atherosclerosis in asymptomatic subjects and patients with coronary artery disease using magnetic resonance imaging. AB - BACKGROUND: Magnetic resonance imaging (MRI) is sensitive to early atherosclerotic changes such as positive remodeling in patients with coronary artery disease (CAD). We assessed prevalence, quality, and extent of coronary atherosclerosis in a group of healthy subjects compared to patients with confirmed CAD. METHODOLOGY: Twenty-two patients with confirmed CAD (15M, 7F, mean age 60.4 +/- 10.4 years) and 26 healthy subjects without history of CAD (11M, 15F, mean age 56.1 +/- 4.4 years) underwent MRI of the right coronary artery (RCA) and vessel wall (MR-CVW) on a clinical 1.5T MR-scanner. Wall thickness measurements of both groups were compared. PRINCIPAL FINDINGS: Stenoses of the RCA (both < and >=50% on CAG) were present in all patients. In 21/22 patients, stenoses detected at MRI corresponded to stenoses detected with conventional angiography. In 19/26 asymptomatic subjects, there was visible luminal narrowing in the MR luminography images. Fourteen of these subjects demonstrated corresponding increase in vessel wall thickness. In 4/26 asymptomatic subjects, vessel wall thickening without luminal narrowing was present. Maximum and mean wall thicknesses in patients were significantly higher (2.16 vs 1.92 mm, and 1.38 vs 1.22 mm, both p<0.05). CONCLUSIONS: In this cohort of middle-aged individuals, both patients with stable angina and angiographically proven coronary artery disease, as well as age-matched asymptomatic subjects. exhibited coronary vessel wall thickening detectable with MR coronary vessel wall imaging. Maximum and mean wall thicknesses were significantly higher in patients. The vast majority of asymptomatic subjects had either positive remodeling without luminal narrowing, or non-significant stenosis. TRIAL REGISTRATION: ClinicalTrials.gov NCT00456950. PMID- 20927369 TI - An improved strategy for generating forces in steered molecular dynamics: the mechanical unfolding of titin, e2lip3 and ubiquitin. AB - One of the applications of Molecular Dynamics (MD) simulations is to explore the energetic barriers to mechanical unfolding of proteins such as occurs in response to the mechanical pulling of single molecules in Atomic Force Microscopy (AFM) experiments. Although Steered Molecular Dynamics simulations have provided microscopic details of the unfolding process during the pulling, the simulated forces required for unfolding are typically far in excess of the measured values. To rectify this, we have developed the Pulsed Unconstrained Fluctuating Forces (PUFF) method, which induces constant-momentum motions by applying forces directly to the instantaneous velocity of selected atoms in a protein system. The driving forces are applied in pulses, which allows the system to relax between pulses, resulting in more accurate unfolding force estimations than in previous methods. In the cases of titin, ubiquitin and e2lip3, the PUFF trajectories produce force fluctuations that agree quantitatively with AFM experiments. Another useful property of PUFF is that simulations get trapped if the target momentum is too low, simplifying the discovery and analysis of unfolding intermediates. PMID- 20927370 TI - Land use, macroalgae, and a tumor-forming disease in marine turtles. AB - Wildlife diseases are an increasing concern for endangered species conservation, but their occurrence, causes, and human influences are often unknown. We analyzed 3,939 records of stranded Hawaiian green sea turtles (Chelonia mydas) over 28 years to understand fibropapillomatosis, a tumor-forming disease linked to a herpesvirus. Turtle size is a consistent risk factor and size-standardized models revealed considerable spatial and temporal variability. The disease peaked in some areas in the 1990s, in some regions rates remained constant, and elsewhere rates increased. Land use, onshore of where the turtles feed, may play a role. Elevated disease rates were clustered in watersheds with high nitrogen footprints; an index of natural and anthropogenic factors that affect coastal eutrophication. Further analysis shows strong epidemiological links between disease rates, nitrogen-footprints, and invasive macroalgae and points to foraging ecology. These turtles now forage on invasive macroalgae, which can dominate nutrient rich waters and sequester environmental N in the amino acid arginine. Arginine is known to regulate immune activity, promote herpesviruses, and contribute to tumor formation. Our results have implications for understanding diseases in aquatic organisms, eutrophication, herpesviruses, and tumor formation. PMID- 20927371 TI - Analysis of beta-globin chromatin micro-environment using a novel 3C variant, 4Cv. AB - Higher order chromatin folding is critical to a number of developmental processes, including the regulation of gene expression. Recently developed biochemical techniques such as RNA TRAP and chromosome conformation capture (3C) have provided us with the tools to probe chromosomal structures. These techniques have been applied to the beta-globin locus, revealing a complex pattern of interactions with regions along the chromosome that the gene resides on. However, biochemical and microscopy data on the nature of beta-globin interactions with other chromosomes is contradictory. Therefore we developed a novel 4C variant, Complete-genome 3C by vectorette amplification (4Cv), which allows an unbiased and quantitative method to examine chromosomal structure. We have used 4Cv to study the microenvironment of the beta-globin locus in mice and show that a significant proportion of the interactions of beta-globin are inter-chromosomal. Furthermore, our data show that in the liver, where the gene is active, beta globin is more likely to interact with other chromosomes, compared to the brain where the gene is silent and is more likely to interact with other regions along the same chromosome. Our data suggest that transcriptional activation of the beta globin locus leads to a change in nuclear position relative to the chromosome territory. PMID- 20927372 TI - Hfq is a global regulator that controls the pathogenicity of Staphylococcus aureus. AB - The Hfq protein is reported to be an RNA chaperone, which is involved in the stress response and the virulence of several pathogens. In E. coli, Hfq can mediate the interaction between some sRNAs and their target mRNAs. But it is controversial whether Hfq plays an important role in S. aureus. In this study, we found that the deletion of hfq gene in S. aureus 8325-4 can increase the surface carotenoid pigments. The hfq mutant was more resistant to oxidative stress but the pathogenicity of the mutant was reduced. We reveal that the Hfq protein can be detected only in some S. aureus strains. Using microarray and qRT-PCR, we identified 116 genes in the hfq mutant which had differential expression from the wild type, most of which are related to the phenotype and virulence of S. aureus. Among the 116 genes, 49 mRNAs can specifically bind Hfq protein, which indicates that Hfq also acts as an RNA binding protein in S. aureus. Our data suggest that Hfq protein of S. aureus is a multifunctional regulator involved in stress and virulence. PMID- 20927373 TI - Processing interrogative sentence mood at the semantic-syntactic interface: an electrophysiological research in Chinese, German, and Polish. AB - BACKGROUND: Languages differ in the marking of the sentence mood of a polar interrogative (yes/no question). For instance, the interrogative mood is marked at the beginning of the surface structure in Polish, whereas the marker appears at the end in Chinese. In order to generate the corresponding sentence frame, the syntactic specification of the interrogative mood is early in Polish and late in Chinese. In this respect, German belongs to an interesting intermediate class. The yes/no question is expressed by a shift of the finite verb from its final position in the underlying structure into the utterance initial position, a move affecting, hence, both the sentence's final and the sentence's initial constituents. The present study aimed to investigate whether during generation of the semantic structure of a polar interrogative, i.e., the processing preceding the grammatical formulation, the interrogative mood is encoded according to its position in the syntactic structure at distinctive time points in Chinese, German, and Polish. METHODOLOGY/PRINCIPAL FINDINGS: In a two-choice go/nogo experimental design, native speakers of the three languages responded to pictures by pressing buttons and producing utterances in their native language while their brain potentials were recorded. The emergence and latency of lateralized readiness potentials (LRP) in nogo conditions, in which speakers asked a yes/no question, should indicate the time point of processing the interrogative mood. The results revealed that Chinese, German, and Polish native speakers did not differ from each other in the electrophysiological indicator. CONCLUSIONS/SIGNIFICANCE: The findings suggest that the semantic encoding of the interrogative mood is temporally consistent across languages despite its disparate syntactic specification. The consistent encoding may be ascribed to economic processing of interrogative moods at various sentential positions of the syntactic structures in languages or, more generally, to the overarching status of sentence mood in the semantic structure. PMID- 20927374 TI - Improving decision speed, accuracy and group cohesion through early information gathering in house-hunting ants. AB - BACKGROUND: Successful collective decision-making depends on groups of animals being able to make accurate choices while maintaining group cohesion. However, increasing accuracy and/or cohesion usually decreases decision speed and vice versa. Such trade-offs are widespread in animal decision-making and result in various decision-making strategies that emphasize either speed or accuracy, depending on the context. Speed-accuracy trade-offs have been the object of many theoretical investigations, but these studies did not consider the possible effects of previous experience and/or knowledge of individuals on such trade offs. In this study, we investigated how previous knowledge of their environment may affect emigration speed, nest choice and colony cohesion in emigrations of the house-hunting ant Temnothorax albipennis, a collective decision-making process subject to a classical speed-accuracy trade-off. METHODOLOGY/PRINCIPAL FINDINGS: Colonies allowed to explore a high quality nest site for one week before they were forced to emigrate found that nest and accepted it faster than emigrating naive colonies. This resulted in increased speed in single choice emigrations and higher colony cohesion in binary choice emigrations. Additionally, colonies allowed to explore both high and low quality nest sites for one week prior to emigration remained more cohesive, made more accurate decisions and emigrated faster than emigrating naive colonies. CONCLUSIONS/SIGNIFICANCE: These results show that colonies gather and store information about available nest sites while their nest is still intact, and later retrieve and use this information when they need to emigrate. This improves colony performance. Early gathering of information for later use is therefore an effective strategy allowing T. albipennis colonies to improve simultaneously all aspects of the decision-making process--i.e. speed, accuracy and cohesion--and partly circumvent the speed-accuracy trade-off classically observed during emigrations. These findings should be taken into account in future studies on speed-accuracy trade-offs. PMID- 20927375 TI - Bioinvasion in a Brazilian bay: filling gaps in the knowledge of southwestern Atlantic biota. AB - BACKGROUND: Biological invasions are a major cause of global species change. Nevertheless, knowledge about the distribution and ecology of introduced species is regionally biased, and many gaps in knowledge exist for most developing countries. METHODOLOGY/PRINCIPAL FINDINGS: To study the zoobenthos on the hard substratum of the Ilha Grande Bay, a survey was conducted on both natural and artificial substrata at three depths and seven sites. The species recorded were classified as native, cryptogenic or introduced. Multivariate analyses were conducted to assess the prevalence of introduced species in these communities and to compare the distribution of species on natural and artificial substrata of this bay to identify possible discrepancies in habitat use. Of the 61 species, 25 were cryptogenic, 10 were introduced and 26 were native. Similar numbers of introduced species were found on both natural and artificial substrata, though the community composition was significantly different between them. We also compared the species composition of the Ilha Grande Bay survey to other inventories taken around the world. The highest similarities were found between the Ilha Grande Bay inventory and the Atlantic coastal region (Tampa Bay, USA and the Gulf of Mexico), American Samoa and Pearl Harbor (USA) inventories. CONCLUSIONS/SIGNIFICANCE: This study presents the first published comprehensive list of hard substratum sessile marine invertebrate species in a Brazilian bay. The high percentage of cryptogenic species reveals gaps in both zoological records and information on introduced species for the Brazilian coast. The introduced species successfully colonized different sites in the Ilha Grande Bay, including both natural and artificial substrata. In addition, we find that artificial structures may not be good surrogates for natural rocky shores and may represent an ecological threat. Comparisons with other inventories suggest a history of broad-scale invasion, though more evidence is needed to support this conclusion. PMID- 20927376 TI - Ontology-based meta-analysis of global collections of high-throughput public data. AB - BACKGROUND: The investigation of the interconnections between the molecular and genetic events that govern biological systems is essential if we are to understand the development of disease and design effective novel treatments. Microarray and next-generation sequencing technologies have the potential to provide this information. However, taking full advantage of these approaches requires that biological connections be made across large quantities of highly heterogeneous genomic datasets. Leveraging the increasingly huge quantities of genomic data in the public domain is fast becoming one of the key challenges in the research community today. METHODOLOGY/RESULTS: We have developed a novel data mining framework that enables researchers to use this growing collection of public high-throughput data to investigate any set of genes or proteins. The connectivity between molecular states across thousands of heterogeneous datasets from microarrays and other genomic platforms is determined through a combination of rank-based enrichment statistics, meta-analyses, and biomedical ontologies. We address data quality concerns through dataset replication and meta-analysis and ensure that the majority of the findings are derived using multiple lines of evidence. As an example of our strategy and the utility of this framework, we apply our data mining approach to explore the biology of brown fat within the context of the thousands of publicly available gene expression datasets. CONCLUSIONS: Our work presents a practical strategy for organizing, mining, and correlating global collections of large-scale genomic data to explore normal and disease biology. Using a hypothesis-free approach, we demonstrate how a data driven analysis across very large collections of genomic data can reveal novel discoveries and evidence to support existing hypothesis. PMID- 20927377 TI - The market triumph of ecotourism: an economic investigation of the private and social benefits of competing land uses in the Peruvian Amazon. AB - Annual revenue flow to developing countries for ecotourism (or nature-based tourism) could be as large as US$ 210*10(12), providing an enormous financial incentive against habitat loss and exploitation. However, is ecotourism the most privately and/or socially valuable use of rainforest land? The question is rarely answered because the relevant data, estimates of profits and fixed costs, are rarely available. We present a social cost-benefit analysis of land use in an ecotourism cluster in the Tambopata region of Amazonian Peru. The net present value of ecotourism-controlled land is given by the producer surplus (profits plus fixed costs of ecotourism lodges): US$ 1,158 ha(-1), which is higher than all currently practiced alternatives, including unsustainable logging, ranching, and agriculture. To our knowledge, this is the first sector-wide study of profitability and producer surplus in a developing-country ecotourism sector and the first to compare against equivalent measures for a spectrum of alternative uses. We also find that ecotourism-controlled land sequesters between 5.3 to 8.7 million tons of above-ground carbon, which is equivalent to between 3000-5000 years of carbon emissions from the domestic component of air and surface travel between the gateway city of Cusco and the lodges, at 2005 emission rates. Ecotourism in Tambopata has successfully monetized the hedonic value of wild nature in Amazonian Peru, and justifies the maintenance of intact rainforest over all alternative uses on narrow economic grounds alone. PMID- 20927378 TI - Genetic and molecular functional characterization of variants within TNFSF13B, a positional candidate preeclampsia susceptibility gene on 13q. AB - BACKGROUND: Preeclampsia is a serious pregnancy complication, demonstrating a complex pattern of inheritance. The elucidation of genetic liability to preeclampsia remains a major challenge in obstetric medicine. We have adopted a positional cloning approach to identify maternal genetic components, with linkages previously demonstrated to chromosomes 2q, 5q and 13q in an Australian/New Zealand familial cohort. The current study aimed to identify potential functional and structural variants in the positional candidate gene TNFSF13B under the 13q linkage peak and assess their association status with maternal preeclampsia genetic susceptibility. METHODOLOGY/PRINCIPAL FINDINGS: The proximal promoter and coding regions of the positional candidate gene TNFSF13B residing within the 13q linkage region was sequenced using 48 proband or founder individuals from Australian/New Zealand families. Ten sequence variants (nine SNPs and one single base insertion) were identified and seven SNPs were successfully genotyped in the total Australian/New Zealand family cohort (74 families/480 individuals). Borderline association to preeclampsia (p = 0.0153) was observed for three rare SNPs (rs16972194, rs16972197 and rs56124946) in strong linkage disequilibrium with each other. Functional evaluation by electrophoretic mobility shift assays showed differential nuclear factor binding to the minor allele of the rs16972194 SNP, residing upstream of the translation start site, making this a putative functional variant. The observed genetic associations were not replicated in a Norwegian case/control cohort (The Nord Trondelag Health Study (HUNT2), 851 preeclamptic and 1,440 non-preeclamptic women). CONCLUSION/SIGNIFICANCE: TNFSF13B has previously been suggested to contribute to the normal immunological adaption crucial for a successful pregnancy. Our observations support TNFSF13B as a potential novel preeclampsia susceptibility gene. We discuss a possible role for TNFSF13B in preeclampsia pathogenesis, and propose the rs16972194 variant as a candidate for further functional evaluation. PMID- 20927379 TI - Ultra high throughput sequencing in human DNA variation detection: a comparative study on the NDUFA3-PRPF31 region. AB - BACKGROUND: Ultra high throughput sequencing (UHTS) technologies find an important application in targeted resequencing of candidate genes or of genomic intervals from genetic association studies. Despite the extraordinary power of these new methods, they are still rarely used in routine analysis of human genomic variants, in part because of the absence of specific standard procedures. The aim of this work is to provide human molecular geneticists with a tool to evaluate the best UHTS methodology for efficiently detecting DNA changes, from common SNPs to rare mutations. METHODOLOGY/PRINCIPAL FINDINGS: We tested the three most widespread UHTS platforms (Roche/454 GS FLX Titanium, Illumina/Solexa Genome Analyzer II and Applied Biosystems/SOLiD System 3) on a well-studied region of the human genome containing many polymorphisms and a very rare heterozygous mutation located within an intronic repetitive DNA element. We identify the qualities and the limitations of each platform and describe some peculiarities of UHTS in resequencing projects. CONCLUSIONS/SIGNIFICANCE: When appropriate filtering and mapping procedures are applied UHTS technology can be safely and efficiently used as a tool for targeted human DNA variations detection. Unless particular and platform-dependent characteristics are needed for specific projects, the most relevant parameter to consider in mainstream human genome resequencing procedures is the cost per sequenced base-pair associated to each machine. PMID- 20927380 TI - Equitoxic doses of 5-azacytidine and 5-aza-2'deoxycytidine induce diverse immediate and overlapping heritable changes in the transcriptome. AB - BACKGROUND: The hypomethylating agent 5-Azacytidine (5-Aza-CR) is the first drug to prolong overall survival in patients with myelodysplastic syndrome (MDS). Surprisingly, the deoxyribonucleoside analog 5-Aza-2'deoxycytidine (5-Aza-CdR) did not have a similar effect on survival in a large clinical trial. Both drugs are thought to exert their effects after incorporation into DNA by covalent binding of DNA methyltransferase (DNMT). While 5-Aza-CdR is incorporated into only DNA, 5-Aza-CR is also incorporated into RNA. Here, we have analyzed whether this difference in nucleic acid incorporation may influence the capacities of these drugs to regulate the expression of mRNA and microRNAs (miRNA), which may potentially affect the activities of the drugs in patients. METHODOLOGY/PRINCIPAL FINDINGS: A hematopoietic (HL-60; acute myeloid leukemia) and a solid (T24; transitional cell carcinoma) cancer cell line were treated with equitoxic doses of 5-Aza-CR and 5-Aza-CdR for 24 hrs, and the immediate (day 2) and lasting (day 8) effects on RNA expression examined. There was considerable overlap between the RNAs heritably upregulated by both drugs on day 8 but more RNAs were stably induced by the deoxy analog. Both drugs strongly induced expression of cancer testis antigens. On day 2 more RNAs were downregulated by 5-Aza-CR, particularly at higher doses. A remarkable downregulation of miRNAs and a significant upregulation of tRNA synthetases and other genes involved in amino acid metabolism was observed in T24 cells. CONCLUSIONS/SIGNIFICANCE: Overall, this suggests that significant differences exist in the immediate action of the two drugs, however the dominant pattern of the lasting, and possible heritable changes, is overlapping. PMID- 20927381 TI - Identification of an archaeal presenilin-like intramembrane protease. AB - BACKGROUND: The GXGD-type diaspartyl intramembrane protease, presenilin, constitutes the catalytic core of the gamma-secretase multi-protein complex responsible for activating critical signaling cascades during development and for the production of beta-amyloid peptides (Abeta) implicated in Alzheimer's disease. The only other known GXGD-type diaspartyl intramembrane proteases are the eukaryotic signal peptide peptidases (SPPs). The presence of presenilin-like enzymes outside eukaryots has not been demonstrated. Here we report the existence of presenilin-like GXGD-type diaspartyl intramembrane proteases in archaea. METHODOLOGY AND PRINCIPAL FINDINGS: We have employed in vitro activity assays to show that MCMJR1, a polytopic membrane protein from the archaeon Methanoculleus marisnigri JR1, is an intramembrane protease bearing the signature YD and GXGD catalytic motifs of presenilin-like enzymes. Mass spectrometry analysis showed MCMJR1 could cleave model intramembrane protease substrates at several sites within their transmembrane region. Remarkably, MCMJR1 could also cleave substrates derived from the beta-amyloid precursor protein (APP) without the need of protein co-factors, as required by presenilin. Two distinct cleavage sites within the transmembrane domain of APP could be identified, one of which coincided with Abeta40, the predominant site processed by gamma-secretase. Finally, an established presenilin and SPP transition-state analog inhibitor could inhibit MCMJR1. CONCLUSIONS AND SIGNIFICANCE: Our findings suggest that a primitive GXGD-type diaspartyl intramembrane protease from archaea can recapitulate key biochemical properties of eukaryotic presenilins and SPPs. MCMJR1 promises to be a more tractable, simpler system for in depth structural and mechanistic studies of GXGD-type diaspartyl intramembrane proteases. PMID- 20927382 TI - A role for calcium-permeable AMPA receptors in synaptic plasticity and learning. AB - A central concept in the field of learning and memory is that NMDARs are essential for synaptic plasticity and memory formation. Surprisingly then, multiple studies have found that behavioral experience can reduce or eliminate the contribution of these receptors to learning. The cellular mechanisms that mediate learning in the absence of NMDAR activation are currently unknown. To address this issue, we examined the contribution of Ca(2+)-permeable AMPARs to learning and plasticity in the hippocampus. Mutant mice were engineered with a conditional genetic deletion of GluR2 in the CA1 region of the hippocampus (GluR2 cKO mice). Electrophysiology experiments in these animals revealed a novel form of long-term potentiation (LTP) that was independent of NMDARs and mediated by GluR2-lacking Ca(2+)-permeable AMPARs. Behavioral analyses found that GluR2-cKO mice were impaired on multiple hippocampus-dependent learning tasks that required NMDAR activation. This suggests that AMPAR-mediated LTP interferes with NMDAR dependent plasticity. In contrast, NMDAR-independent learning was normal in knockout mice and required the activation of Ca(2+)-permeable AMPARs. These results suggest that GluR2-lacking AMPARs play a functional and previously unidentified role in learning; they appear to mediate changes in synaptic strength that occur after plasticity has been established by NMDARs. PMID- 20927383 TI - Quantitative phosphoproteomics of proteasome inhibition in multiple myeloma cells. AB - BACKGROUND: The proteasome inhibitor bortezomib represents an important advance in the treatment of multiple myeloma (MM). Bortezomib inhibits the activity of the 26S proteasome and induces cell death in a variety of tumor cells; however, the mechanism of cytotoxicity is not well understood. METHODOLOGY/PRINCIPAL FINDINGS: We investigated the differential phosphoproteome upon proteasome inhibition by using stable isotope labeling by amino acids in cell culture (SILAC) in combination with phosphoprotein enrichment and LC-MS/MS analysis. In total 233 phosphoproteins were identified and 72 phosphoproteins showed a 1.5 fold or greater change upon bortezomib treatment. The phosphoproteins with expression alterations encompass all major protein classes, including a large number of nucleic acid binding proteins. Site-specific phosphopeptide quantitation revealed that Ser38 phosphorylation on stathmin increased upon bortezomib treatment, suggesting new mechanisms associated to bortezomib-induced apoptosis in MM cells. Further studies demonstrated that stathmin phosphorylation profile was modified in response to bortezomib treatment and the regulation of stathmin by phosphorylation at specific Ser/Thr residues participated in the cellular response induced by bortezomib. CONCLUSIONS/SIGNIFICANCE: Our systematic profiling of phosphorylation changes in response to bortezomib treatment not only advanced the global mechanistic understanding of the action of bortezomib on myeloma cells but also identified previously uncharacterized signaling proteins in myeloma cells. PMID- 20927384 TI - Variations and determinants of hospital costs for acute stroke in China. AB - BACKGROUND: The burden of stroke is high and increasing in China. We modelled variations in, and predictors of, the costs of hospital care for patients with acute stroke in China. METHODS AND FINDINGS: Baseline characteristics and hospital costs for 5,255 patients were collected using the prospective register based ChinaQUEST study, conducted in 48 Level 3 and 14 Level 2 hospitals in China during 2006-2007. Ordinary least squares estimation was used to determine factors associated with hospital costs. Overall mean cost of hospitalisation was 11,216 Chinese Yuan Renminbi (CNY) (~US$1,602) per patient, which equates to more than half the average annual wage in China. Variations in cost were largely attributable to stroke severity and length of hospital stay (LOS). Model forecasts showed that reducing LOS from the mean of 20 days for Level 3 and 18 days for Level 2 hospitals to a duration of 1 week, which is common among Western countries, afforded cost reductions of 49% and 19%, respectively. Other lesser determinants varied by hospital level: in Level 3 hospitals, health insurance and the occurrence of in-hospital complications were each associated with 10% and 18% increases in cost, respectively, whilst treatment in a teaching hospital was associated with approximately 39% decrease in cost on average. For Level 2 hospitals, stroke due to intracerebral haemorrhage was associated with a 19% greater cost than for ischaemic stroke. CONCLUSIONS: Changes to hospital policies to standardise resource use and reduce the variation in LOS could attenuate costs and improve efficiencies for acute stroke management in China. The success of these strategies will be enhanced by broader policy initiatives currently underway to reform hospital reimbursement systems. PMID- 20927385 TI - eIF4A inhibition allows translational regulation of mRNAs encoding proteins involved in Alzheimer's disease. AB - Alzheimer's disease (AD) is the main cause of dementia in our increasingly aging population. The debilitating cognitive and behavioral symptoms characteristic of AD make it an extremely distressing illness for patients and carers. Although drugs have been developed to treat AD symptoms and to slow disease progression, there is currently no cure. The incidence of AD is predicted to increase to over one hundred million by 2050, placing a heavy burden on communities and economies, and making the development of effective therapies an urgent priority. Two proteins are thought to have major contributory roles in AD: the microtubule associated protein tau, also known as MAPT; and the amyloid-beta peptide (A beta), a cleavage product of amyloid precursor protein (APP). Oxidative stress is also implicated in AD pathology from an early stage. By targeting eIF4A, an RNA helicase involved in translation initiation, the synthesis of APP and tau, but not neuroprotective proteins, can be simultaneously and specifically reduced, representing a novel avenue for AD intervention. We also show that protection from oxidative stress is increased upon eIF4A inhibition. We demonstrate that the reduction of these proteins is not due to changes in mRNA levels or increased protein degradation, but is a consequence of translational repression conferred by inhibition of the helicase activity of eIF4A. Inhibition of eIF4A selectively and simultaneously modulates the synthesis of proteins involved in Alzheimer's disease: reducing A-beta and tau synthesis, while increasing proteins predicted to be neuroprotective. PMID- 20927386 TI - Modeling the cost-effectiveness of the integrated disease surveillance and response (IDSR) system: meningitis in Burkina Faso. AB - BACKGROUND: Effective surveillance for infectious diseases is an essential component of public health. There are few studies estimating the cost effectiveness of starting or improving disease surveillance. We present a cost effectiveness analysis the Integrated Disease Surveillance and Response (IDSR) strategy in Africa. METHODOLOGY/PRINCIPAL FINDINGS: To assess the impact of the IDSR in Africa, we used pre- and post- IDSR meningococcal meningitis surveillance data from Burkina Faso (1996-2002 and 2003-2007). IDSR implementation was correlated with a median reduction of 2 weeks to peak of outbreaks (25(th) percentile 1 week; 75(th) percentile 4 weeks). IDSR was also correlated with a reduction of 43 meningitis cases per 100,000 (25(th)-40: 75(th)-129). Assuming the correlations between reductions in time to peak of outbreaks and cases are related, the cost-effectiveness of IDSR was $23 per case averted (25(th)-$30; 75(th)--cost saving), and $98 per meningitis-related death averted (25(th)-$140: 75(th)--cost saving). CONCLUSIONS/SIGNIFICANCE: We cannot absolutely claim that the measured differences were due to IDSR. We believe, however, that it is reasonable to claim that IDSR can improve the cost-effectiveness of public health surveillance. PMID- 20927387 TI - A genome-wide association study of red blood cell traits using the electronic medical record. AB - BACKGROUND: The Electronic Medical Record (EMR) is a potential source for high throughput phenotyping to conduct genome-wide association studies (GWAS), including those of medically relevant quantitative traits. We describe use of the Mayo Clinic EMR to conduct a GWAS of red blood cell (RBC) traits in a cohort of patients with peripheral arterial disease (PAD) and controls without PAD. METHODOLOGY AND PRINCIPAL FINDINGS: Results for hemoglobin level, hematocrit, RBC count, mean corpuscular volume, mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration were extracted from the EMR from January 1994 to September 2009. Out of 35,159 RBC trait values in 3,411 patients, we excluded 12,864 values in 1,165 patients that had been measured during hospitalization or in the setting of hematological disease, malignancy, or use of drugs that affect RBC traits, leaving a final genotyped sample of 3,012, 80% of whom had >=2 measurements. The median of each RBC trait was used in the genetic analyses, which were conducted using an additive model that adjusted for age, sex, and PAD status. We identified four genomic loci that were associated (P<5 * 10(-8)) with one or more of the RBC traits (HBLS1/MYB on 6q23.3, TMPRSS6 on 22q12.3, HFE on 6p22.1, and SLC17A1 on 6p22.2). Three of these loci (HBLS1/MYB, TMPRSS6, and HFE) had been identified in recent GWAS and the allele frequencies, effect sizes, and the directions of effects of the replicated SNPs were similar to the prior studies. CONCLUSIONS: Our results demonstrate feasibility of using the EMR to conduct high throughput genomic studies of medically relevant quantitative traits. PMID- 20927388 TI - Susceptible and protective HLA class 1 alleles against dengue fever and dengue hemorrhagic fever patients in a Malaysian population. AB - BACKGROUND: The human leukocyte antigen alleles have been implicated as probable genetic markers in predicting the susceptibility and/or protection to severe manifestations of dengue virus (DENV) infection. In this present study, we aimed to investigate for the first time, the genotype variants of HLA Class 1(-A and B) of DENV infected patients against healthy individuals in Malaysia. METHODOLOGY/PRINCIPAL FINDINGS: This study was carried out with 92 dengue disease patients and 95 healthy controls from three different ethnic groups (Malay, Chinese and Indian) in Malaysia. All patients with clinical and laboratory confirmation of DENV infection were typed for the HLA-A and B loci, using polymerase chain reaction-sequence specific primer techniques. In our total population, a significant increase for HLA-B*53 (P = 0.042, Pc = 1.008) allele and a significant decrease for A*03 (P = 0.015, Pc = 0.18, OR = 5.23, 95% CI = 1.19-23.02) and B*18 (P = 0.017, Pc = 0.408) alleles were noted in DHF patients as compared to healthy donors. We also observed that in the Malay DHF patients, allele B*13 (P = 0.049, Pc = 1.176, OR = 0.18, 95% CI = 0.03-0.90) was present at a significantly higher frequency in this population while allele HLA-B*18 (P = 0.024, Pc = 0.576) was seen to be negatively associated with DHF. CONCLUSIONS/SIGNIFICANCE: These are the first findings on genetic polymorphisms in our population and we conclude that: (1) In our total population, HLA-B*53 probably involve in disease susceptibility, while the HLA-A*03 and HLA-B*18 may confer protection from progression to severe disease; (2) In the Malay population, HLA-B*13 and B*18 are probably associated in disease susceptibility and protection, respectively. These results could furnish as a valuable predictive tool to identify ethnically different individuals at risk and/or protection from severe forms of DENV infection and would provide valuable informations for the design of future dengue vaccine. PMID- 20927389 TI - Cyclosporine A-sensitive, cyclophilin B-dependent endoplasmic reticulum associated degradation. AB - Peptidyl-prolyl cis/trans isomerases (PPIs) catalyze cis/trans isomerization of peptide bonds preceding proline residues. The involvement of PPI family members in protein refolding has been established in test tube experiments. Surprisingly, however, no data is available on the involvement of endoplasmic reticulum (ER) resident members of the PPI family in protein folding, quality control or disposal in the living cell. Here we report that the immunosuppressive drug cyclosporine A (CsA) selectively inhibits the degradation of a subset of misfolded proteins generated in the ER. We identify cyclophilin B (CyPB) as the ER-resident target of CsA that catalytically enhances disposal from the ER of ERAD-L(S) substrates containing cis proline residues. Our manuscript presents the first evidence for enzymatic involvement of a PPI in protein quality control in the ER of living cells. PMID- 20927390 TI - An efficient multistrategy DNA decontamination procedure of PCR reagents for hypersensitive PCR applications. AB - BACKGROUND: PCR amplification of minute quantities of degraded DNA for ancient DNA research, forensic analyses, wildlife studies and ultrasensitive diagnostics is often hampered by contamination problems. The extent of these problems is inversely related to DNA concentration and target fragment size and concern (i) sample contamination, (ii) laboratory surface contamination, (iii) carry-over contamination, and (iv) contamination of reagents. METHODOLOGY/PRINCIPAL FINDINGS: Here we performed a quantitative evaluation of current decontamination methods for these last three sources of contamination, and developed a new procedure to eliminate contaminating DNA contained in PCR reagents. We observed that most current decontamination methods are either not efficient enough to degrade short contaminating DNA molecules, rendered inefficient by the reagents themselves, or interfere with the PCR when used at doses high enough to eliminate these molecules. We also show that efficient reagent decontamination can be achieved by using a combination of treatments adapted to different reagent categories. Our procedure involves gamma- and UV-irradiation and treatment with a mutant recombinant heat-labile double-strand specific DNase from the Antarctic shrimp Pandalus borealis. Optimal performance of these treatments is achieved in narrow experimental conditions that have been precisely analyzed and defined herein. CONCLUSIONS/SIGNIFICANCE: There is not a single decontamination method valid for all possible contamination sources occurring in PCR reagents and in the molecular biology laboratory and most common decontamination methods are not efficient enough to decontaminate short DNA fragments of low concentration. We developed a versatile multistrategy decontamination procedure for PCR reagents. We demonstrate that this procedure allows efficient reagent decontamination while preserving the efficiency of PCR amplification of minute quantities of DNA. PMID- 20927391 TI - Ultrafast mid-IR laser scalpel: protein signals of the fundamental limits to minimally invasive surgery. AB - Lasers have in principle the capability to cut at the level of a single cell, the fundamental limit to minimally invasive procedures and restructuring biological tissues. To date, this limit has not been achieved due to collateral damage on the macroscale that arises from thermal and shock wave induced collateral damage of surrounding tissue. Here, we report on a novel concept using a specifically designed Picosecond IR Laser (PIRL) that selectively energizes water molecules in the tissue to drive ablation or cutting process faster than thermal exchange of energy and shock wave propagation, without plasma formation or ionizing radiation effects. The targeted laser process imparts the least amount of energy in the remaining tissue without any of the deleterious photochemical or photothermal effects that accompanies other laser wavelengths and pulse parameters. Full thickness incisional and excisional wounds were generated in CD1 mice using the Picosecond IR Laser, a conventional surgical laser (DELight Er:YAG) or mechanical surgical tools. Transmission and scanning electron microscopy showed that the PIRL laser produced minimal tissue ablation with less damage of surrounding tissues than wounds formed using the other modalities. The width of scars formed by wounds made by the PIRL laser were half that of the scars produced using either a conventional surgical laser or a scalpel. Aniline blue staining showed higher levels of collagen in the early stage of the wounds produced using the PIRL laser, suggesting that these wounds mature faster. There were more viable cells extracted from skin using the PIRL laser, suggesting less cellular damage. beta-catenin and TGF-beta signalling, which are activated during the proliferative phase of wound healing, and whose level of activation correlates with the size of wounds was lower in wounds generated by the PIRL system. Wounds created with the PIRL systsem also showed a lower rate of cell proliferation. Direct comparison of wound healing responses to a conventional surgical laser, and standard mechanical instruments shows far less damage and near absence of scar formation by using PIRL laser. This new laser source appears to have achieved the long held promise of lasers in minimally invasive surgery. PMID- 20927392 TI - Cognitive functioning in patients with bipolar disorder: association with depressive symptoms and alcohol use. AB - BACKGROUND: Cognitive dysfunction is clearly recognized in bipolar patients, but the degree of impairment varies due to methodological factors as well as heterogeneity in patient populations. The goal of this study was to evaluate cognitive functioning in bipolar patients and to assess its association with depressive symptoms. Post hoc the relationship with lifetime alcohol use disorder was explored. METHODOLOGY/PRINCIPAL FINDINGS: The study included 110 bipolar patients and 75 healthy controls. Patients with severe depressive symptoms, (hypo)manic symptoms and current severe alcohol use disorder were excluded. Diagnoses were evaluated via the Mini-International Neuropsychiatric Interview. Cognitive functioning was measured in domains of psychomotor speed, speed of information processing, attentional switching, verbal memory, visual memory, executive functioning and an overall mean score. Severity of depression was assessed by the Inventory of Depressive Symptomatology-self rating. Patients were euthymic (n = 46) or with current mild (n = 38) or moderate (n = 26) depressive symptoms. Cognitive impairment was found in 26% (z-score 2 or more above reference control group for at least one domain) of patients, most prominent in executive functioning (effect size; ES 0.49) and speed of information processing (ES 0.47). Depressive symptoms were associated with dysfunction in psychomotor speed (adjusted beta 0.43; R(2) 7%), speed of information processing (adjusted beta 0.36; R(2) 20%), attentional switching (adjusted beta 0.24; R(2) 16%) and the mean score (adjusted beta 0.23; R(2) 24%), but not with verbal and visual memory and executive functioning. Depressive symptoms explained 24% of the variance in the mean z-score of all 6 cognitive domains. Comorbid lifetime alcohol use (n = 21) was not associated with cognitive dysfunction. CONCLUSIONS/SIGNIFICANCE: Cognitive dysfunction in bipolar disorder is more severe in patients with depressive symptoms, especially regarding speed and attention. Therefore, interpretation of cognitive functioning in patients with depressive symptoms should be cautious. No association was found between cognitive functioning and lifetime comorbid alcohol use disorder. PMID- 20927393 TI - Relating mutant genotype to phenotype via quantitative behavior of the NADPH redox cycle in human erythrocytes. AB - BACKGROUND: The NADPH redox cycle plays a key role in antioxidant protection of human erythrocytes. It consists of two enzymes: glucose-6-phosphate dehydrogenase (G6PD) and glutathione reductase. Over 160 G6PD variants have been characterized and associated with several distinct clinical manifestations. However, the mechanistic link between the genotype and the phenotype remains poorly understood. METHODOLOGY/PRINCIPAL FINDINGS: We address this issue through a novel framework (design space) that integrates information at the genetic, biochemical and clinical levels. Our analysis predicts three qualitatively-distinct phenotypic regions that can be ranked according to fitness. When G6PD variants are analyzed in design space, a correlation is revealed between the phenotypic region and the clinical manifestation: the best region with normal physiology, the second best region with a pathology, and the worst region with a potential lethality. We also show that Plasmodium falciparum, by induction of its own G6PD gene in G6PD-deficient erythrocytes, moves the operation of the cycle to a region of the design space that yields robust performance. CONCLUSIONS/SIGNIFICANCE: In conclusion, the design space for the NADPH redox cycle, which includes relationships among genotype, phenotype and environment, illuminates the function, design and fitness of the cycle, and its phenotypic regions correlate with the organism's clinical status. PMID- 20927394 TI - Stressful dieting: nutritional conditions but not compensatory growth elevate corticosterone levels in zebra finch nestlings and fledglings. AB - Unfavourable conditions throughout the period of parental care can severely affect growth, reproductive performance, and survival. Yet, individuals may be affected differently, depending on the developmental period during which constraints are experienced. Here we tested whether the nestling phase compared to the fledgling phase is more susceptible to nutritional stress by considering biometry, physiology, sexually selected male ornaments and survival using zebra finches (Taeniopygia guttata) as a model species. As nestlings (day 0-17) or fledglings (day 17-35), subjects were raised either on low or high quality food. A low quality diet resulted in significantly elevated baseline corticosterone titres in both nestlings and fledglings. Subjects showed substantial compensatory growth after they had experienced low quality food as nestlings but catch-up growth did neither lead to elevated baseline corticosterone titres nor did we detect long term effects on biometry, male cheek patch, or survival. The compensation for temporally unfavourable environmental conditions reflects substantial phenotypic plasticity and the results show that costs of catch-up growth were not mediated via corticosterone as a physiological correlate of allostatic load. These findings provide new insights into the mechanisms and plasticity with which animals respond to periods of constraints during development as they may occur in a mistiming of breeding. PMID- 20927395 TI - The role of the focal adhesion protein PINCH1 for the radiosensitivity of adhesion and suspension cell cultures. AB - Focal adhesion (FA) signaling mediated by adhesion to extracellular matrix and growth factor receptors contributes to the regulation of the cellular stress response to external stimuli. Critical to focal adhesion assembly and signaling is the adapter protein PINCH1. To evaluate whether the prosurvival function of PINCH1 in radiation cell survival depends on cell adhesion, we examined PINCH1(fl/fl) and PINCH1(-/-) mouse embryonic fibroblasts and human cancer cell lines. Here, we found that the enhanced cellular radiosensitivity mediated by PINCH1 depletion observed under adhesion conditions is conserved when cells are irradiated under suspension conditions. This unsuspected finding could not be explained by the observed modification of adhesion and growth factor associated signaling involving FAK, Paxillin, p130(CAS), Src, AKT, GSK3beta and ERK1/2 under suspension and serum withdrawal relative to adhesion conditions with serum. Our data suggest that the adapter protein PINCH1 critically participates in the regulation of the cellular radiosensitivity of normal and malignant cells similarly under adhesion and suspension conditions. PMID- 20927396 TI - CRISPR associated diversity within a population of Sulfolobus islandicus. AB - BACKGROUND: Predator-prey models for virus-host interactions predict that viruses will cause oscillations of microbial host densities due to an arms race between resistance and virulence. A new form of microbial resistance, CRISPRs (clustered regularly interspaced short palindromic repeats) are a rapidly evolving, sequence specific immunity mechanism in which a short piece of invading viral DNA is inserted into the host's chromosome, thereby rendering the host resistant to further infection. Few studies have linked this form of resistance to population dynamics in natural microbial populations. METHODOLOGY/PRINCIPAL FINDINGS: We examined sequence diversity in 39 strains of the archeaon Sulfolobus islandicus from a single, isolated hot spring from Kamchatka, Russia to determine the effects of CRISPR immunity on microbial population dynamics. First, multiple housekeeping genetic markers identify a large clonal group of identical genotypes coexisting with a diverse set of rare genotypes. Second, the sequence-specific CRISPR spacer arrays split the large group of isolates into two very different groups and reveal extensive diversity and no evidence for dominance of a single clone within the population. CONCLUSIONS/SIGNIFICANCE: The evenness of resistance genotypes found within this population of S. islandicus is indicative of a lack of strain dominance, in contrast to the prediction for a resistant strain in a simple predator-prey interaction. Based on evidence for the independent acquisition of resistant sequences, we hypothesize that CRISPR mediated clonal interference between resistant strains promotes and maintains diversity in this natural population. PMID- 20927397 TI - Axonal-transport-mediated gene transduction in the interior of rat bone. AB - BACKGROUND: Gene transduction has been considered advantageous for the sustained delivery of proteins to specific target tissues. However, in the case of hard tissues, such as bone, local gene delivery remains problematic owing to anatomical accessibility limitations of the target sites. METHODOLOGY/PRINCIPAL FINDINGS: Here, we evaluated the feasibility of exogenous gene transduction in the interior of bone via axonal transport following intramuscular administration of a nonviral vector. A high expression level of the transduced gene was achieved in the tibia ipsilateral to the injected tibialis anterior muscle, as well as in the ipsilateral sciatic nerve and dorsal root ganglia. In sciatic transection rats, the gene expression level was significantly lowered in bone. CONCLUSIONS/SIGNIFICANCE: These results suggest that axonal transport is critical for gene transduction. Our study may provide a basis for developing therapeutic methods for efficient gene delivery into hard tissues. PMID- 20927399 TI - Superoxide flashes in mouse skeletal muscle are produced by discrete arrays of active mitochondria operating coherently. AB - Reactive Oxygen Species (ROS) constitute important intracellular signaling molecules. Mitochondria are admitted sources of ROS, especially of superoxide anions through the electron transport chain. Here the mitochondria-targeted ratiometric pericam (RPmt) was used as a superoxide biosensor, by appropriate choice of the excitation wavelength. RPmt was transfected in vivo into mouse muscles. Confocal imaging of isolated muscle fibers reveals spontaneous flashes of RPmt fluorescence. Flashes correspond to increases in superoxide production, as shown by simultaneous recordings of the fluorescence from MitoSox, a mitochondrial superoxide probe. Flashes occur in all subcellular populations of mitochondria. Spatial analysis of the flashes pattern over time revealed that arrays of mitochondria work as well-defined superoxide-production-units. Increase of superoxide production at the muscle fiber level involves recruitment of supplemental units with no increase in per-unit production. Altogether, these results demonstrate that superoxide flashes in muscle fibers correspond to physiological signals linked to mitochondrial metabolism. They also suggest that superoxide, or one of its derivatives, modulates its own production at the mitochondrial level. PMID- 20927398 TI - Alpha-adducin Gly460Trp polymorphism and hypertension risk: a meta-analysis of 22 studies including 14303 cases and 15961 controls. AB - BACKGROUND: No clear consensus has been reached on the alpha-adducin polymorphism (Gly460Trp) and essential hypertension risk. We performed a meta-analysis in an effort to systematically summarize the possible association. METHODOLOGY/PRINCIPAL FINDINGS: Studies were identified by searching MEDLINE and EMBASE databases complemented with perusal of bibliographies of retrieved articles and correspondence with original authors. The fixed-effects model and the random-effects model were applied for dichotomous outcomes to combine the results of the individual studies. We selected 22 studies that met the inclusion criteria including a total of 14303 hypertensive patients and 15961 normotensive controls. Overall, the 460Trp allele showed no statistically significant association with hypertension risk compared to Gly460 allele (P = 0.69, OR = 1.02, 95% CI 0.94-1.10, P(heterogeneity)<0.0001) in all subjects. Meta-analysis under other genetic contrasts still did not reveal any significant association in all subjects, Caucasians, East Asians and others. The results were similar but heterogeneity did not persist when sensitivity analyses were limited to these studies. CONCLUSIONS/SIGNIFICANCE: Our meta-analysis failed to provide evidence for the genetic association of alpha-adducin gene Gly460Trp polymorphism with hypertension. Further studies investigating the effect of genetic networks, environmental factors, individual biological characteristics and their mutual interactions are needed to elucidate the possible mechanism for hypertension in humans. PMID- 20927400 TI - Near scale-free dynamics in neural population activity of waking/sleeping rats revealed by multiscale analysis. AB - A neuron embedded in an intact brain, unlike an isolated neuron, participates in network activity at various spatial resolutions. Such multiple scale spatial dynamics is potentially reflected in multiple time scales of temporal dynamics. We identify such multiple dynamical time scales of the inter-spike interval (ISI) fluctuations of neurons of waking/sleeping rats by means of multiscale analysis. The time scale of large non-Gaussianity in the ISI fluctuations, measured with the Castaing method, ranges up to several minutes, markedly escaping the low-pass filtering characteristics of neurons. A comparison between neural activity during waking and sleeping reveals that non-Gaussianity is stronger during waking than sleeping throughout the entire range of scales observed. We find a remarkable property of near scale independence of the magnitude correlations as the primary cause of persistent non-Gaussianity. Such scale-invariance of correlations is characteristic of multiplicative cascade processes and raises the possibility of the existence of a scale independent memory preserving mechanism. PMID- 20927402 TI - Adjacent nucleotide dependence in ncRNA and order-1 SCFG for ncRNA identification. AB - BACKGROUND: Non-coding RNAs (ncRNAs) are known to be involved in many critical biological processes, and identification of ncRNAs is an important task in biological research. A popular software, Infernal, is the most successful prediction tool and exhibits high sensitivity. The application of Infernal has been mainly focused on small suspected regions. We tried to apply Infernal on a chromosome level; the results have high sensitivity, yet contain many false positives. Further enhancing Infernal for chromosome level or genome wide study is desirable. METHODOLOGY: Based on the conjecture that adjacent nucleotide dependence affects the stability of the secondary structure of an ncRNA, we first conduct a systematic study on human ncRNAs and find that adjacent nucleotide dependence in human ncRNA should be useful for identifying ncRNAs. We then incorporate this dependence in the SCFG model and develop a new order-1 SCFG model for identifying ncRNAs. CONCLUSIONS: With respect to our experiments on human chromosomes, the proposed new model can eliminate more than 50% false positives reported by Infernal while maintaining the same sensitivity. The executable and the source code of programs are freely available at http://i.cs.hku.hk/~kfwong/order1scfg. PMID- 20927403 TI - Sustained spindle-assembly checkpoint response requires de novo transcription and translation of cyclin B1. AB - BACKGROUND: Microtubule-targeting drugs induce mitotic delay at pro-metaphase by preventing the spindle assembly checkpoint to be satisfied. However, especially after prolonged treatments, cells can escape this arrest in a process called mitotic slippage. The mechanisms underlying the spindle assembly checkpoint and slippage are not fully understood. It has been generally accepted that during mitosis there is a temporary shutdown of high-energy-consuming processes, such as transcription and translation. However, the synthesis of specific proteins is maintained or up-regulated since protein synthesis is necessary for entry into and progression through mitosis. METHODOLOGY/PRINCIPAL FINDINGS: In this work we investigated whether the mitotic arrest caused by the mitotic checkpoint is independent of transcription and translation. By using immunofluorescent microscopy and western blotting, we demonstrate that inhibition of either of these processes induces a shortening of the mitotic arrest caused by the nocodazole treatment, and ultimately leads to mitotic slippage. Our western blotting and RTQ-PCR results show that inhibition of transcription during mitotic arrest does not affect the expression of the spindle checkpoint proteins, whereas it induces a significant decrease in the mRNA and protein levels of Cyclin B1. The exogenous expression of Cyclin B1 substantially rescued the mitotic phenotype in nocodazole cells treated with the inhibitors of transcription and translation. CONCLUSIONS/SIGNIFICANCE: This work emphasizes the importance of transcription and translation for the maintenance of the spindle assembly checkpoint, suggesting the existence of a mechanism dependent on cyclin B1 gene regulation during mitosis. We propose that continuous transcription of mitotic regulators is required to sustain the activation of the spindle assembly checkpoint. PMID- 20927401 TI - Lipoic acid attenuates inflammation via cAMP and protein kinase A signaling. AB - BACKGROUND: Abnormal regulation of the inflammatory response is an important component of diseases such as diabetes, Alzheimer's disease and multiple sclerosis (MS). Lipoic acid (LA) has been shown to have antioxidant and anti inflammatory properties and is being pursued as a therapy for these diseases. We first reported that LA stimulates cAMP production via activation of G-protein coupled receptors and adenylyl cyclases. LA also suppressed NK cell activation and cytotoxicity. In this study we present evidence supporting the hypothesis that the anti-inflammatory properties of LA are mediated by the cAMP/PKA signaling cascade. Additionally, we show that LA oral administration elevates cAMP levels in MS subjects. METHODOLOGY/PRINCIPAL FINDINGS: We determined the effects of LA on IL-6, IL-17 and IL-10 secretion using ELISAs. Treatment with 50 ug/ml and 100 ug/ml LA significantly reduced IL-6 levels by 19 and 34%, respectively, in T cell enriched PBMCs. IL-17 levels were also reduced by 35 and 50%, respectively. Though not significant, LA appeared to have a biphasic effect on IL-10 production. Thymidine incorporation studies showed LA inhibited T cell proliferation by 90%. T-cell activation was reduced by 50% as measured by IL-2 secretion. Western blot analysis showed that LA treatment increased phosphorylation of Lck, a downstream effector of protein kinase A. Pretreatment with a peptide inhibitor of PKA, PKI, blocked LA inhibition of IL-2 and IFN gamma production, indicating that PKA mediates these responses. Oral administration of 1200 mg LA to MS subjects resulted in increased cAMP levels in PBMCs four hours after ingestion. Average cAMP levels in 20 subjects were 43% higher than baseline. CONCLUSIONS/SIGNIFICANCE: Oral administration of LA in vivo resulted in significant increases in cAMP concentration. The anti-inflammatory effects of LA are mediated in part by the cAMP/PKA signaling cascade. These novel findings enhance our understanding of the mechanisms of action of LA. PMID- 20927404 TI - The adaptive function of masturbation in a promiscuous African ground squirrel. AB - BACKGROUND: Studies of animal mating systems increasingly emphasize female multiple mating and cryptic sexual selection, particularly sperm competition. Males under intense sperm competition may manipulate sperm quantity and quality through masturbation, which could waste sperm and decrease fertility. I examined the factors influencing masturbation by male Cape ground squirrels (Xerus inauris) in light of a number of functional hypotheses. METHODOLOGY: Observational data on a marked population of squirrels were collected in east central Namibia using scan and all-occurrences sampling. FINDINGS: Masturbation was far more frequent on days of female oestrus and mostly occurred after copulation. Masturbation rates were higher in dominant males, which copulate more, than in subordinates and increased with number of mates a female accepts. CONCLUSIONS: These results suggest that masturbation in this species was not a response to sperm competition nor a sexual outlet by subordinates that did not copulate. Instead masturbation could function as a form of genital grooming. Female Cape ground squirrels mate with up to 10 males in a 3-hr oestrus, and by masturbating after copulation males could reduce the chance of infection. Sexually transmitted infections (STIs) can profoundly affect fertility, and their consequences for mating strategies need to be examined more fully. PMID- 20927405 TI - A selection fit mechanism in BMP receptor IA as a possible source for BMP ligand receptor promiscuity. AB - BACKGROUND: Members of the TGF-beta superfamily are characterized by a highly promiscuous ligand-receptor interaction as is readily apparent from the numeral discrepancy of only seven type I and five type II receptors available for more than 40 ligands. Structural and functional studies have been used to address the question of how specific signals can be deduced from a limited number of receptor combinations and to unravel the molecular mechanisms underlying the protein protein recognition that allow such limited specificity. PRINCIPAL FINDINGS: In this study we have investigated how an antigen binding antibody fragment (Fab) raised against the extracellular domain of the BMP receptor type IA (BMPR-IA) recognizes the receptor's BMP-2 binding epitope and thereby neutralizes BMP-2 receptor activation. The crystal structure of the complex of the BMPR-IA ectodomain bound to the Fab AbD1556 revealed that the contact surface of BMPR-IA overlaps extensively with the contact surface for BMP-2 interaction. Although the structural epitopes of BMPR-IA to both binding partners coincides, the structures of BMPR-IA in the two complexes differ significantly. In contrast to the structural differences, alanine-scanning mutagenesis of BMPR-IA showed that the functional determinants for binding to the antibody and BMP-2 are almost identical. CONCLUSIONS: Comparing the structures of BMPR-IA bound to BMP-2 or bound to the Fab AbD1556 with the structure of unbound BMPR-IA shows that binding of BMPR-IA to its interaction partners follows a selection fit mechanism, possibly indicating that the ligand promiscuity of BMPR-IA is inherently encoded by structural adaptability. The functional and structural analysis of the BMPR-IA binding antibody AbD1556 mimicking the BMP-2 binding epitope may thus pave the way for the design of low-molecular weight synthetic receptor binders/inhibitors. PMID- 20927406 TI - An upstream Hfq binding site in the fhlA mRNA leader region facilitates the OxyS fhlA interaction. AB - BACKGROUND: To survive, bacteria must be able to adapt to environmental stresses. Small regulatory RNAs have been implicated as intermediates in a variety of stress-response pathways allowing dynamic gene regulation. The RNA binding protein Hfq facilitates this process in many cases, helping sRNAs base pair with their target mRNAs and initiate gene regulation. Although Hfq has been identified as a critical component in many RNPs, the manner by which Hfq controls these interactions is not known. METHODOLOGY/PRINCIPAL FINDINGS: To test the requirement of Hfq in these mRNA-sRNA complexes, the OxyS-fhlA system was used as a model. OxyS is induced in response to oxidative stress and down regulates the translation of fhlA, a gene encoding a transcriptional activator for formate metabolism. Biophysical characterization of this system previously used a minimal construct of the fhlA mRNA which inadvertently removed a critical element within the leader sequence of this mRNA that effected thermodynamics and kinetics for the interaction with Hfq. CONCLUSIONS/SIGNIFICANCE: Herein, we report thermodynamic, kinetic and structural mapping studies during binary and ternary complex formation between Hfq, OxyS and fhlA mRNA. Hfq binds fhlA mRNA using both the proximal and distal surfaces and stimulates association kinetics between the sRNA and mRNA but remains bound to fhlA forming a ternary complex. The upstream Hfq binding element within fhlA is similar to (ARN)(x) elements recently identified in other mRNAs regulated by Hfq. This work leads to a kinetic model for the dynamics of these complexes and the regulation of gene expression by bacterial sRNAs. PMID- 20927407 TI - Finding new genes for non-syndromic hearing loss through an in silico prioritization study. AB - At present, 51 genes are already known to be responsible for Non-Syndromic hereditary Hearing Loss (NSHL), but the knowledge of 121 NSHL-linked chromosomal regions brings to the hypothesis that a number of disease genes have still to be uncovered. To help scientists to find new NSHL genes, we built a gene-scoring system, integrating Gene Ontology, NCBI Gene and Map Viewer databases, which prioritizes the candidate genes according to their probability to cause NSHL. We defined a set of candidates and measured their functional similarity with respect to the disease gene set, computing a score ( S S M avg) that relies on the assumption that functionally related genes might contribute to the same (disease) phenotype. A Kolmogorov-Smirnov test, comparing the pair-wise distribution on the disease gene set with the distribution on the remaining human genes, provided a statistical assessment of this assumption. We found at a p-value < 2.2.10 (-16) that the former pair-wise is greater than the latter, justifying a prioritization strategy based on the functional similarity of candidate genes respect to the disease gene set. A cross-validation test measured to what extent the S S M avg ranking for NSHL is different from a random ordering: adding 15% of the disease genes to the candidate gene set, the ranking of the disease genes in the first eight positions resulted statistically different from a hypergeometric distribution with a p-value = 2.04.10(-5) and a power > 0.99. The twenty top scored genes were finally examined to evaluate their possible involvement in NSHL. We found that half of them are known to be expressed in human inner ear or cochlea and are mainly involved in remodeling and organization of actin formation and maintenance of the cilia and the endocochlear potential. These findings strongly indicate that our metric was able to suggest excellent NSHL candidates to be screened in patients and controls for causative mutations. PMID- 20927408 TI - Neuroimaging study designs, computational analyses and data provenance using the LONI pipeline. AB - Modern computational neuroscience employs diverse software tools and multidisciplinary expertise to analyze heterogeneous brain data. The classical problems of gathering meaningful data, fitting specific models, and discovering appropriate analysis and visualization tools give way to a new class of computational challenges--management of large and incongruous data, integration and interoperability of computational resources, and data provenance. We designed, implemented and validated a new paradigm for addressing these challenges in the neuroimaging field. Our solution is based on the LONI Pipeline environment [3], [4], a graphical workflow environment for constructing and executing complex data processing protocols. We developed study-design, database and visual language programming functionalities within the LONI Pipeline that enable the construction of complete, elaborate and robust graphical workflows for analyzing neuroimaging and other data. These workflows facilitate open sharing and communication of data and metadata, concrete processing protocols, result validation, and study replication among different investigators and research groups. The LONI Pipeline features include distributed grid-enabled infrastructure, virtualized execution environment, efficient integration, data provenance, validation and distribution of new computational tools, automated data format conversion, and an intuitive graphical user interface. We demonstrate the new LONI Pipeline features using large scale neuroimaging studies based on data from the International Consortium for Brain Mapping [5] and the Alzheimer's Disease Neuroimaging Initiative [6]. User guides, forums, instructions and downloads of the LONI Pipeline environment are available at http://pipeline.loni.ucla.edu. PMID- 20927409 TI - Desynchronization of neocortical networks by asynchronous release of GABA at autaptic and synaptic contacts from fast-spiking interneurons. AB - Networks of specific inhibitory interneurons regulate principal cell firing in several forms of neocortical activity. Fast-spiking (FS) interneurons are potently self-inhibited by GABAergic autaptic transmission, allowing them to precisely control their own firing dynamics and timing. Here we show that in FS interneurons, high-frequency trains of action potentials can generate a delayed and prolonged GABAergic self-inhibition due to sustained asynchronous release at FS-cell autapses. Asynchronous release of GABA is simultaneously recorded in connected pyramidal (P) neurons. Asynchronous and synchronous autaptic release show differential presynaptic Ca(2+) sensitivity, suggesting that they rely on different Ca(2+) sensors and/or involve distinct pools of vesicles. In addition, asynchronous release is modulated by the endogenous Ca(2+) buffer parvalbumin. Functionally, asynchronous release decreases FS-cell spike reliability and reduces the ability of P neurons to integrate incoming stimuli into precise firing. Since each FS cell contacts many P neurons, asynchronous release from a single interneuron may desynchronize a large portion of the local network and disrupt cortical information processing. PMID- 20927410 TI - Inferring the dynamics of diversification: a coalescent approach. AB - Recent analyses of the fossil record and molecular phylogenies suggest that there are fundamental limits to biodiversity, possibly arising from constraints in the availability of space, resources, or ecological niches. Under this hypothesis, speciation rates decay over time and biodiversity eventually saturates, with new species emerging only when others are driven to extinction. This view of macro evolution contradicts an alternative hypothesis that biodiversity is unbounded, with species ever accumulating as they find new niches to occupy. These contrasting theories of biodiversity dynamics yield fundamentally different explanations for the disparity in species richness across taxa and regions. Here, we test whether speciation rates have decayed or remained constant over time, and whether biodiversity is saturated or still expanding. We first derive a general likelihood expression for internode distances in a phylogeny, based on the well known coalescent process from population genetics. This expression accounts for either time-constant or time-variable rates, time-constant or time-variable diversity, and completely or incompletely sampled phylogenies. We then compare the performance of different diversification scenarios in explaining a set of 289 phylogenies representing amphibians, arthropods, birds, mammals, mollusks, and flowering plants. Our results indicate that speciation rates typically decay over time, but that diversity is still expanding at present. The evidence for expanding-diversity models suggests that an upper limit to biodiversity has not yet been reached, or that no such limit exists. PMID- 20927411 TI - A widespread chromosomal inversion polymorphism contributes to a major life history transition, local adaptation, and reproductive isolation. AB - The role of chromosomal inversions in adaptation and speciation is controversial. Historically, inversions were thought to contribute to these processes either by directly causing hybrid sterility or by facilitating the maintenance of co adapted gene complexes. Because inversions suppress recombination when heterozygous, a recently proposed local adaptation mechanism predicts that they will spread if they capture alleles at multiple loci involved in divergent adaptation to contrasting environments. Many empirical studies have found inversion polymorphisms linked to putatively adaptive phenotypes or distributed along environmental clines. However, direct involvement of an inversion in local adaptation and consequent ecological reproductive isolation has not to our knowledge been demonstrated in nature. In this study, we discovered that a chromosomal inversion polymorphism is geographically widespread, and we test the extent to which it contributes to adaptation and reproductive isolation under natural field conditions. Replicated crosses between the prezygotically reproductively isolated annual and perennial ecotypes of the yellow monkeyflower, Mimulus guttatus, revealed that alternative chromosomal inversion arrangements are associated with life-history divergence over thousands of kilometers across North America. The inversion polymorphism affected adaptive flowering time divergence and other morphological traits in all replicated crosses between four pairs of annual and perennial populations. To determine if the inversion contributes to adaptation and reproductive isolation in natural populations, we conducted a novel reciprocal transplant experiment involving outbred lines, where alternative arrangements of the inversion were reciprocally introgressed into the genetic backgrounds of each ecotype. Our results demonstrate for the first time in nature the contribution of an inversion to adaptation, an annual/perennial life-history shift, and multiple reproductive isolating barriers. These results are consistent with the local adaptation mechanism being responsible for the distribution of the two inversion arrangements across the geographic range of M. guttatus and that locally adaptive inversion effects contribute directly to reproductive isolation. Such a mechanism may be partially responsible for the observation that closely related species often differ by multiple chromosomal rearrangements. PMID- 20927412 TI - How and why chromosome inversions evolve. PMID- 20927413 TI - Are drug companies living up to their human rights responsibilities? The perspective of the former United Nations Special Rapporteur (2002-2008). AB - BACKGROUND TO THE DEBATE: The human rights responsibilities of drug companies have been considered for years by nongovernmental organizations, but were most sharply defined in a report by the UN Special Rapporteur on the right to health, submitted to the United Nations General Assembly in August 2008. The "Human Rights Guidelines for Pharmaceutical Companies in relation to Access to Medicines" include responsibilities for transparency, management, monitoring and accountability, pricing, and ethical marketing, and against lobbying for more protection in intellectual property laws, applying for patents for trivial modifications of existing medicines, inappropriate drug promotion, and excessive pricing. Two years after the release of the Guidelines, the PLoS Medicine Debate asks whether drug companies are living up to their human rights responsibilities. Sofia Gruskin and Zyde Raad from the Harvard School of Public Health say more assessment is needed of such responsibilities; Geralyn Ritter, Vice President of Global Public Policy and Corporate Responsibility at Merck & Co. argues that multiple stakeholders could do more to help States deliver the right to health; and Paul Hunt and Rajat Khosla introduce Mr. Hunt's work as the UN Special Rapporteur on the right to the highest attainable standard of health, regarding the human rights responsibilities of pharmaceutical companies and access to medicines. PMID- 20927414 TI - Knoop hardness of five composites cured with single-peak and polywave LED curing lights. AB - OBJECTIVE: To compare the ability of four light-emitting diode (LED) curing lights to polymerize five composite resins in 10 seconds at 4 and 8 mm. METHOD AND MATERIALS: Two second-generation, single-peak LED curing lights (Bluephase 16i, Ivoclar Vivadent, and LEDemetron II, Kerr) and two third-generation polywave LED curing lights (UltraLume 5, Ultradent, and Bluephase G2, Ivoclar Vivadent) were compared. Three examples of each brand of curing light were used, and their light outputs were measured with a spectro-radiometer. Five composite resins (Filtek Supreme A2B, 3M ESPE; Vit-l-escence A2, Ultradent; Aelite LS Posterior A2, Bisco; and Tetric EvoCeram A2 and Tetric EvoCeram Bleach M, both Ivoclar Vivadent) were polymerized for 10 seconds at 4 and 8 mm from the end of the light guide. The Knoop microhardness (KHN50gf) was measured at 49 locations across the top and bottom surfaces of the specimens to determine the ability of each light to cure each brand of composite in 10 seconds. RESULTS: At 4 and 8 mm, the Bluephase G2 light delivered the broadest spectral range of wavelengths, greatest irradiance, and energy density. The Bluephase G2 always produced harder, better cured resins compared to the other three lights. Overall, the ability of the lights to cure these five composites was ranked from highest to lowest: Bluephase G2, UltraLume 5, Bluephase 16i, and LEDemetron II (ANOVA with REGWQ multiple comparison test, P < .01). CONCLUSION: This study suggests that polywave LED curing lights should be used in preference to single-peak LED curing lights. PMID- 20927415 TI - Short-term in situ/ex vivo study of the anticariogenic potential of a resin modified glass-ionomer cement associated with adhesive systems. AB - OBJECTIVE: As resin-modified glass-ionomer cement (RMGIC) is an adhesive material, its association to dentin bonding agents (DBAs) was previously proposed. This study investigated the adjunctive behavior of an RMGIC with etch and-rinse bonding systems under in situ/ex vivo cariogenic challenge. METHOD AND MATERIALS: Bovine enamel blocks (3 3 3 3 2 mm) were randomly assigned to group VP, Vitremer + its own primer (3M ESPE); group VSB, Vitremer + Single Bond (3M ESPE); and group VPB, Vitremer + Prime and Bond 2.1 (Dentsply). Two blocks of each group were randomly placed in an acrylic palatal appliance, so each appliance included six blocks. Volunteers (n = 10) wore these appliances according to given instructions to promote a sucrose challenge eight times/day for 15 days. After this period, the blocks were removed from the devices and cleaned, and demineralization was assessed through longitudinal microhardness analysis (Knoop indenter, 25 g/5 s). Data were submitted to three-way ANOVA and Tukey test (P < .05). RESULTS: No treatment was able to completely avoid demineralization. All materials showed a statistically significant difference in mineral loss when the microhardness on the outer enamel was compared with deeper regions (P < .05). CONCLUSION: Association of the tested RMGICs with etch-and rinse DBAs did not seem to be more beneficial against caries than the conventional treatment with RMGIC. PMID- 20927416 TI - Diagnostic value of NobelGuide to minimize the need for reconstructive surgery of jaws before implant placement: a review. AB - OBJECTIVE: To test if using a CAD/CAM system might reduce the necessity of bone augmentation in patients with atrophic maxillary arches before implant therapy. METHOD AND MATERIALS: Twenty male and female patients consecutively scheduled for bone augmentation of the jaw before implant surgery were included in this study, with a total of 29 jaws (maxillary and mandibular) to analyze for the implant supported fixed prosthesis group and 19 maxillary arches for the implant supported removable prosthesis group. NobelGuide System (Nobel Biocare), Autocad System (Autodesk), and routine manual CT measurements of available bone were used in this study. RESULTS: The total results of the mean values of the fixed prosthesis group plus the mean values of the removable prosthesis group showed a statistically significant difference between the NobelGuide intervention score and both manual (P = .004) and Autocad (P = .001) measurements. CONCLUSIONS: The NobelGuide System represents a viable diagnostic device to reduce the entity or avoid bone reconstructive surgery before implant placements in the atrophic maxilla and mandible. PMID- 20927417 TI - An unusual triplication of primary teeth-a rare case report. AB - Odontogenic anomalies can occur as a result of conjoining or twinning defects. This article reports the case of fusion in a 10-year-old boy in relation to the primary maxillary right incisors. Clinicoradiographic examination revealed the presence of triple teeth, ie, fusion between the maxillary right incisors along with a supernumerary tooth on the labial surface. The offending triple tooth was extracted under local anesthesia. The extracted tooth was sectioned using a hard tissue microtome at three levels-the coronal, middle root, and apical levels, respectively-and these sections were visualized under a stereomicroscope. Based on the histologic findings, a final diagnosis of fusion was confirmed. A brief review of the literature on triple teeth is also presented. PMID- 20927418 TI - Chondrosarcoma of the maxilla mimicking pulp disease on initial presentation. AB - Chondrosarcomas are malignant mesenchymal tumors characterized by the differentiation of pure hyaline cartilage, and they are relatively uncommon in jawbones. Chondrosarcoma of the jaws usually presents as a painless mass or swelling associated with loosening of the associated teeth. This report describes an unusual case of chondrosarcoma that mimicked pulp disease on initial presentation in the maxilla of a 22-year-old man. The relevant literature is reviewed regarding clinicopathologic features and therapeutic management of chondrosarcomas. PMID- 20927419 TI - Long-term antibacterial surface properties of composite resin incorporating polyethyleneimine nanoparticles. AB - OBJECTIVE: The development of new longer-lasting composite resins is an urgent public health need. It has been shown that surface roughness of composite resins is increased by Streptococcus mutans biofilm in vitro and further that incorporation of small amounts of antibacterial nanoparticles (polyethyleneimine [PEI]) into composite resins renders a strong antibacterial effect against S mutans biofilm. The present study tested the hypotheses that incorporation of PEI nanoparticles into composite resins prevents the increase of surface roughness caused by S mutans biofilm and that PEI incorporation into composite resin has a long-lasting antibacterial effect. METHOD AND MATERIALS: Composite resin incorporating PEI nanoparticles was characterized using contact angle goniometry, X-ray photoelectron spectroscopy (XPS), and SEM. Six-month-aged samples were tested for antibacterial effect against S mutans using the direct contact test. Surface roughness following 1 month of bacterial challenge was depicted using atomic force microscopy (AFM). RESULTS: Contact angle increased following PEI incorporation, and XPS revealed surface iodide and nitrogen elements. Direct contact test results showed that 6-month-aged composite resins incorporating PEI nanoparticles completely inhibited S mutans growth (P < .05). AFM analysis showed an increase in root mean square roughness following bacterial challenge in composite resin samples (P < .05); no effect was depicted in samples incorporating PEI. CONCLUSION: Changing the surface properties of composite resins by incorporating PEI antibacterial nanoparticles may improve their clinical performance both by inhibiting bacterial growth and by preventing changes in the surface roughness. PMID- 20927420 TI - Optical integration and fluorescence: a comparison among restorative materials with spectrophotometric analysis. AB - OBJECTIVE: To evaluate the optical integration and fluorescence of three contemporary restorative materials used for incisoproximal restorations. METHOD AND MATERIALS: A microfilled hybrid composite (Amaris, VOCO; MHC), a nanofilled hybrid composite (Grandio, VOCO; NHC), and an experimental ormocer (VOCO; ORM) were used to consecutively restore 10 extracted incisors with incisoproximal restorations using the natural layering concept, mimicking the natural anatomy of the tooth. Before and after placement of each restoration, the teeth were photographed under standardized conditions (direct, indirect, and fluorescent light), and spectrophotometric measurements (SpectroShade, Handy Dental Type 713000, MHT) were made using a black-and-white background. Between measurements, the teeth were allowed to rehydrate for 2 weeks. Ten independent evaluators scored each light condition using an optical integration score on a scale from 0 to 10 (0 = worst optical integration, restoration can be easily distinguished from remaining tissue; 10 = optimal optical integration). Differences in L*a*b and DE values and optical integration scores were statistically analyzed using ANOVA. RESULTS: MHC obtained the highest optical integration and fluorescence scores (P < .01), followed by NHC, although there were no statistically significant differences found among DE of the restorative materials. ORM achieved the worst optical integration and fluorescence. CONCLUSION: The microfilled hybrid composite obtained the highest optical integration scores (P < .01), followed by the nanofilled hybrid composite. The experimental ormocer showed the least favorable optical behavior. Spectrophotometric measurements showed no statistically significant differences among all three restorative materials. PMID- 20927421 TI - Comparison of the three-dimensional correctness of impression techniques: a randomized controlled trial. AB - OBJECTIVE: In vitro studies showed superior impression correctness for one-stage impressions. However, clinical data, especially clinical trials, are lacking in this matter. The aim of the study was to investigate the three-dimensional correctness of impressions for final restorations applying three different impression techniques. METHOD AND MATERIALS: Three impressions each were made from 48 patients with different techniques using metal stock trays. In a randomized order, one-stage putty-wash, two-stage putty-wash, and monophase impressions (respectively, Dimension Penta H and Garant L, Dimension Penta H Quick and Garant L Quick, Impregum Penta; 3M ESPE) were made with either polyvinyl siloxane or polyether materials. The double-cord technique was applied at all abutment teeth. Factors potentially influencing the correctness of the impressions were recorded. The precision of the impressions was three dimensionally analyzed using the resulting gypsum models. Discrepancies between the impressions were calculated using the one-stage putty-wash impression as reference. RESULTS: Discrepancies between the one-stage putty-wash impressions and the monophase impressions are significantly lower compared with two-stage putty-wash impressions. The depth of the most subgingival portion of the preparation margin significantly influences the discrepancies between the impression techniques. CONCLUSION: In light of the major influence of clinical parameters on impression correctness, one-stage procedures should be favored. These findings support the results of in vitro investigations. PMID- 20927422 TI - A randomized clinical evaluation of triclosan-containing dentifrice and mouthwash association in the control of plaque and gingivitis. AB - OBJECTIVE: The aim of this double-blind study was to evaluate the clinical efficacy of the association of triclosan-containing mouthrinse and dentifrice on biofilm and gingivitis reduction. METHOD AND MATERIALS: Forty patients with a diagnosis of gingivitis were selected and randomly divided into four groups (n = 10): group TT-triclosan-containing mouthrinse and triclosan-containing dentifrice; group CT-control mouthrinse and triclosan-containing dentifrice; group TC-triclosan-containing mouthrinse and control dentifrice; group CC-control mouthrinse and control dentifrice. Patients were evaluated by a calibrated examiner using a quantitative Plaque Index and Gingivitis Index at 0, 15, and 30 days. Intragroup analysis was performed by Friedman test and intergroup analysis by Kruskal-Wallis. RESULTS: Intragroup evaluation revealed a statistically significant reduction in Plaque Index for groups that used triclosan, independently of the group (TT, CT, and TC) (P < .05). Intergroup analysis suggested that only the group that used the association of triclosan dentifrice and mouthrinse (group TT) demonstrated statistically reduced Plaque Index at 30 days, when compared to the control group (CC) (P < .05). With regard to gingivitis reduction, no difference was observed between groups, although the association presented a faster reduction in bleeding levels. CONCLUSION: Only the association of triclosan dentifrice and triclosan mouthrinse statistically reduced Plaque Index, when compared to the control group; however, regarding the additional benefits to gingivitis control, more studies should be done to confirm the results. PMID- 20927423 TI - Implant-supported oral rehabilitation of a patient with systemic lupus erythematosus: case report and review of the literature. AB - Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease with multisystemic involvement. Immune-suppressive drugs used in the treatment of the disease can increase the risk of infection and delay healing, which are of concern in dental-treatment procedures. Because of the involvement of the salivary glands, the composition and amount of saliva released are usually altered in patients with SLE. Significantly lowered salivary flow rate causes difficulties during dental procedures and makes it difficult to maintain oral hygiene and conserve both fixed and removable prostheses. This case report presents a patient who had an extremely dry mouth and oral lesions due to SLE and describes how oral rehabilitation was achieved with implant-supported fixed dentures. To the best of our knowledge, this is the first report of the use of oral implants in a patient with SLE. Dental practitioners should consider dental implants as a preferred treatment choice in the oral rehabilitation of patients with SLE. PMID- 20927424 TI - Wrong tooth extraction: root cause analysis. AB - OBJECTIVE: Errors made by clinicians in dental practice require changes in the original planning of patient management. The purpose of this study was to analyze events that led to wrong tooth extraction. METHOD AND MATERIALS: A total of 54 insurance claims for wrong tooth extractions were reported and evaluated by Medical Consultants International from 1993 to 2004. Data were collected and analyzed according to parameters regarding the clinician who performed the procedure, the nature of the referral for extraction, the demographics of the patient, the venue in which the extraction took place, the reason for the error, and the nature of the insurance claim. RESULTS: General practitioners performed 72% of the extractions, 49% of the referring clinicians were orthodontists, 74% of the errors were made during extraction, and 77% of the errors were made in polyclinics. CONCLUSIONS: Errors during treatment and poor communication among clinicians led to extraction of the wrong teeth. This can be avoided by greater caution on the part of the extracting clinician when following the treatment plan. Guidelines toward this end are recommended. PMID- 20927425 TI - Pigmentary demarcation lines (Futcher lines): an orofacial case. AB - Pigmentary demarcation lines are rare physiologic pigmentations shaped as lines of deeper discoloration with abrupt transition from less pigmented areas. These lines are known and seen by dermatologists in the skin of African, Indian, and Japanese patients, usually females. No report of intraoral pigmentary demarcation lines was found in the literature. This article presents a rare case of pigmentary demarcation lines of the skin of the face and oral mucosa, which should be of interest to the general dentist. PMID- 20927426 TI - Gingival crevicular fluid biochemical markers in periodontal disease: a cross sectional study. AB - OBJECTIVE: To evaluate the levels of interleukin-1b (IL-1b) and alkaline phosphatase (ALP) in gingival crevicular fluid (GCF) and correlate these measurements with clinical characteristics of healthy patients and patients with gingivitis and periodontitis. METHOD AND MATERIALS: Thirty-six individuals were subdivided into three groups of 12: control, gingivitis, and periodontitis groups. GCF samples were obtained from 2 sites for each patient. GCF volume was measured with the Periotron 8000; IL-1b levels were evaluated using the ELISA technique; ALP was measured by the kinetic method. RESULTS: Mean levels of IL-1b and ALP in the 3 groups were, respectively, 22.34 +/- 16.53 MUL/site and 7.68 +/- 2.46 U/L in the control group; 41.46 +/- 27.98 MUL/site and 9.80 +/- 1.53 U/L in the gingivitis group; and 105.97 +/- 89.26 MUL/site and 11.56 +/- 1.82 U/L in the periodontitis group. The amount of IL-1b in the periodontitis group was significantly higher than in the other groups, but no significant difference was found between the control group and the gingivitis group. The amount of ALP differed significantly among the 3 groups (P < .05). A positive correlation was observed among IL-1b levels, GCF volume, and probing depth. There was no evidence for a correlation between IL-1b and ALP levels. CONCLUSION: Monitoring immune markers may give additional information on healthy or diseased sites. PMID- 20927427 TI - Novel metal complexes containing a chiral trinitrogen isoindoline-based pincer ligand: in situ synthesis and structural characterization. AB - The first synthesis and characterization of metal coordinated complexes containing in situ prepared chiral trinitrogen 1,3-bis(4,5-dihydrooxazol-2 ylimino)isoindoline-based pincer ligands are reported. Two zinc complexes, isolated as Zn(L)(2), where L = 1,3-bis(4,5-dihydro-4-(R)-phenyloxazol-2 ylimino)isoindoline ((R,R)-5) or 1,3-bis(4,5-dihydro-4-(S)-iso-propyloxazol-2 ylimino)isoindoline ((S,S)-6), respectively, are reported. Complexes Zn((R,R) 5)(2) and Zn((S,S)-6)(2) were prepared in situ through the condensation of phthalonitrile with enantiopure 2-amino-4-(R)-phenyloxazoline ((R)-3) or 2-amino 4-(S)-iso-propyloxazoline ((S)-4) in the presence of ZnCl(2) at 80 degrees C in dry toluene over 3-4 days. The characterizations of Zn((R,R)-5)(2) and Zn((S,S) 6)(2) in both the solid (X-ray crystallography) and solution (multinuclear NMR spectroscopy) states are reported. PMID- 20927428 TI - Regioselective functionalization of iminophosphoranes through Pd-mediated C-H bond activation: C-C and C-X bond formation. AB - The orthopalladation of iminophosphoranes [R(3)P=N-C(10)H(7)-1] (R(3) = Ph(3) 1, p-Tol(3) 2, PhMe(2) 3, Ph(2)Me 4, N-C(10)H(7)-1 = 1-naphthyl) has been studied. It occurs regioselectively at the aryl ring bonded to the P atom in 1 and 2, giving endo-[Pd(MU-Cl)(C(6)H(4)-(PPh(2=N-1-C(10)H(7))-2)-kappa-C,N](2) (5) or endo-[Pd(MU-Cl)(C(6)H(3)-(P(p-Tol)(2)=N-C(10)H(7)-1)-2-Me-5)-kappa-C,N](2) (6), while in 3 the 1-naphthyl group is metallated instead, giving exo-[Pd(MU Cl)(C(10)H(6)-(N=PPhMe(2))-8)-kappa-C,N](2) (7). In the case of 4, orthopalladation at room temperature affords the kinetic exo isomer [Pd(MU Cl)(C(10)H(6)-(N=PPh(2)Me)-8)-kappa-C,N](2) (11exo), while a mixture of 11exo and the thermodynamic endo isomer [Pd(MU-Cl)(C(6)H(4)-(PPhMe=N-C(10)H(7)-1)-2)-kappa C,N](2) (11endo) is obtained in refluxing toluene. The heating in toluene of the acetate bridge dimer [Pd(MU-OAc)(C(10)H(6)-(N=PPh(2)Me)-8)-kappa-C,N](2) (13exo) promotes the facile transformation of the exo isomer into the endo isomer [Pd(MU OAc)(C(6)H(4)-(PPhMe=N-C(10)H(7)-1)-2)-kappa-C,N](2) (13endo), confirming that the exo isomers are formed under kinetic control. Reactions of the orthometallated complexes have led to functionalized molecules. The stoichiometric reactions of the orthometallated complexes [Pd(MU-Cl)(C(10)H(6) (N=PPhMe(2))-8)-kappa-C,N](2) (7), [Pd(MU-Cl)(C(6)H(4)-(PPh(2)[=NPh)-2)](2) (17) and [Pd(MU-Cl)(C(6)H(3)-(C(O)N=PPh(3))-2-OMe-4)](2) (18) with I(2) or with CO results in the synthesis of the ortho-halogenated compounds [PhMe(2)P=N-C(10)H(6) I-8] (19), [I-C(6)H(4)-(PPh(2)=NPh)-2] (21) and [Ph(3)P=NC(O)C(6)H(3)-I-2-OMe-5] (23) or the heterocycles [C(10)H(6)-(N=PPhMe(2))-1-(C(O))-8]Cl (20), [C(6)H(5) (N=PPh(2)-C(6)H(4)-C(O)-2]ClO(4) (22) and [C(6)H(3)-(C(O)-1,2-N-PPh(3))-OMe-4]Cl (24). PMID- 20927429 TI - Metabolic probes for imaging endosymbiotic bacteria within toxic dinoflagellates. AB - Fluorescence microscopy offers an important tool for the study of complex biological phenomena such as symbiosis. Here we identify a strategy that adapts the unique differences between the secondary metabolism in host and guest symbiotic species to selectively image endosymbiotic organisms. The method is demonstrated by application to the complex symbiotic relationships in toxic marine dinoflagellates. PMID- 20927430 TI - LiCl-Promoted Pd(II)-catalyzed ortho carbonylation of N,N-dimethylbenzylamines. AB - Palladium-catalyzed highly regioselective carbonylation of substituted N,N dimethylbenzylamines with the assistance of LiCl was developed. The ortho functionalized N,N-dimethylbenzylamine was further transformed into ortho-methyl benzoate under mild conditions. These two transformations could be combined into one pot to produce the desired product in moderate yield. Applications of this methodology to synthesize the fragments of variolaric acid were also studied. PMID- 20927431 TI - Densely integrated array of chemiresistor vapor sensors with electron-beam patterned monolayer-protected gold nanoparticle interface films. AB - Use of electron-beam induced crosslinking to pattern films of monolayer-protected gold nanoparticles (MPNs) onto a chemiresistor (CR) sensor array is described. Each of the four CRs comprises a 100 um(2) set of interdigital electrodes (IDEs) with 100 nm widths and spaces, separated from adjacent devices by 4 um. Films of four MPNs, each with a different thiolate monolayer, were successively patterned on the IDEs. Vapor exposures yield rapid, reversible changes in CR resistances and differential vapor sensitivities comparable to those reported for larger CRs with unpatterned MPN films. The array response patterns facilitate vapor discrimination. This is the smallest MPN-coated CR array yet reported. The advantages of using such an array as the detector in microfabricated gas chromatographic analyzers are considered. PMID- 20927432 TI - A novel multi-functional magnetic Fe-Ti-V spinel catalyst for elemental mercury capture and callback from flue gas. AB - A novel magnetic Fe-Ti-V spinel catalyst showed an excellent performance for elemental mercury capture at 100 degrees C, and the formed HgO can be catalytically decomposed by the catalyst at 300 degrees C to reclaim elemental mercury and regenerate the catalyst. PMID- 20927433 TI - Self-organization of electron acceptor molecules on graphene. AB - Graphene grown on Ir(111) electronically decouples adsorbed molecules from the metallic substrate and allows the study of their self-organization on surfaces. We study two electron acceptor molecules from the same family. The intermolecular interaction, attractive for TCNQ and repulsive for F(4)-TCNQ, dictates the molecular ordering. PMID- 20927434 TI - Alkyne insertion into cyclometallated pyrazole and imine complexes of iridium, rhodium and ruthenium; relevance to catalytic formation of carbo- and heterocycles. AB - The cyclometallated complexes [MCl(C^N)(ring)] (HC^N = 2-phenylpyrazole, M = Ir, Rh ring = Cp*; M = Ru, ring = p-cymene) readily undergo insertion reactions with RC=CR (R = CO(2)Me, Ph) to give mono insertion products, the rhodium complex also reacts with PhC=CH regiospecifically to give an analogous product. The products of the reactions of the cyclometallated imine complexes [MCl(C^N)Cp*] (HC^N = PhCH=NR, R = Ph, CH(2)CH(2)OMe, Me; M = Ir, Rh) with PhC=CPh depend on the substituent R; when R = CH(2)CH(2)OMe a monoinsertion is observed, however for R = Me the initial insertion product is unstable, undergoing reductive elimination with loss of the organic fragment, and for R = Ph no metal-containing product is isolated. With PhC=CH the cyclometallated imine complexes can give mono or di insertion products. The implications for catalytic synthesis of carbo- and heterocycles by a tandem C-H activation, alkyne insertion mechanism are discussed. PMID- 20927435 TI - Terphenyl substituted derivatives of manganese(II): distorted geometries and resistance to elimination. AB - Reaction of {Li(THF)Ar'MnI(2)}(2) (Ar' = C(6)H(3)-2,6-(C(6)H(2)-2,6-(i)Pr(3))(2)) with LiAr', LiC=CR (R = (t)Bu or Ph), or (C(6)H(2)-2,4,6-(i)Pr(3))MgBr(THF)(2) afforded the diaryl MnAr'(2) (1), the alkynyl salts Ar'Mn(C=C(t)Bu)(4){Li(THF)}(3) (2) and Ar'Mn(C=CPh)(3)Li(3)(THF)(Et(2)O)(2)(MU(3) I) (3), and the manganate salt {Li(THF)}Ar'Mn(MU-I)(C(6)H(2)-2,4,6-(i)Pr(3)) (4), respectively. Complex 4 reacted with one equivalent of (C(6)H(2)-2,4,6 (i)Pr(3))MgBr(THF)(2) to afford the homoleptic dimer {Mn(C(6)H(2)-2,4,6 (i)Pr(3))(MU-C(6)H(2)-2,4,6-(i)Pr(3))}(2) (5), which resulted from the displacement of the bulkier Ar' ligand in preference to the halogen. The reaction of the more crowded {Li(THF)Ar*MnI(2)}(2) (Ar* = C(6)H(3)-2,6-(C(6)H(2)-2,4,6 (i)Pr(3))(2)) with Li(t)Bu gave complex Ar*Mn(t)Bu (6). Complex 1 is a rare monomeric homoleptic two-coordinate diaryl Mn(II) complex; while 6 displays no tendency to eliminate beta-hydrogens from the (t)Bu group because of the stabilization supplied by Ar*. Compounds 2 and 3 have cubane frameworks, which are constructed from a manganese, three carbons from three acetylide ligands, three lithiums, each coordinated by a donor, plus either a carbon from a further acetylide ligand (2) or an iodide (3). The Mn(II) atom in 4 has an unusual distorted T-shaped geometry while the dimeric 5 features trigonal planar manganese coordination. The chloride substituted complex Li(2)(THF)(3){Ar'MnCl(2)}(2) (7), which has a structure very similar to that of {Li(THF)Ar'MnI(2)}(2), was also prepared for use as a possible starting material. However, its generally lower solubility rendered it less useful than the iodo salt. Complexes 1-7 were characterized by X-ray crystallography and UV-vis spectroscopy. Magnetic studies of 2-4 and 6 showed that they have 3d(5) high-spin configurations. PMID- 20927436 TI - Novel use of fluorescent glucose analogues to identify a new class of triazine based insulin mimetics possessing useful secondary effects. AB - There is an urgent need to discover new compounds that effectively treat diabetes by mimicking the action of insulin (insulin mimetics). Traditional approaches to studying anti-diabetic agents in cells are inconvenient for screening chemical libraries to identify insulin mimetics. 2-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4 yl)amino)-2-deoxyglucose (2-NBDG) and 6-NBDG are fluorescent analogues of glucose that could be employed in screening. However, there are no published data about the use of these analogues to identify new insulin mimetics. We have developed a screening system based on 6-NBDG using 3T3-L1 adipocytes in a 96-well culture plate format. 6-NBDG was found to produce a larger signal than 2-NBDG in this screening system. 6-NBDG uptake in 3T3-L1 adipocytes was sensitive to insulin, known insulin mimetics, inhibitors of glucose transport and insulin-sensitizing compounds. To validate our screening system, a chemical library of 576 tagged, triazine-based small molecules was screened. The screening results were identical to that obtained from a commercial enzyme-based glucose assay. Two inducers of glucose uptake were shown to be non-cytotoxic and confirmed as insulin mimetic compounds by their inhibition of epinephrine-stimulated free fatty acid release from adipocytes. These novel insulin mimetics functioned at a markedly lower concentration than two widely studied insulin mimetics, zinc(ii) complexes and vanadium compounds, and also showed novel, beneficial effects on endothelial cell function (a key determinant of secondary complications in diabetes). The discovery of new insulin mimetics using 6-NBDG validates the use of this probe in the development of large-scale, cell-based screening systems based on the uptake of fluorescent-tagged glucose analogues. This research should aid the development of novel strategies to discover new drugs and drug targets for combating the increasing prevalence of diabetes. PMID- 20927437 TI - A highly selective OFF-ON fluorescent sensor for zinc in aqueous solution and living cells. AB - A novel compound, 2-p-tolyl-1H-imidazo[4,5-f][1,10]phenanthrolinium hydrogenselenite (HMPIP.HSeO(3), C1), shows a peculiar OFF-ON fluorescent response to Zn(2+) in aqueous solution and living cells. PMID- 20927438 TI - Superior SWNT dispersion by amino acid based amphiphiles: designing biocompatible cationic nanohybrids. AB - Stable aqueous SWNT dispersion up to 92% was achieved using amino acid based amphiphiles through a structure-property investigation. The nanohybrids showed remarkable serum stability and biocompatibility to mammalian cells. PMID- 20927440 TI - A naked-eye visible and fluorescence "turn-on" probe for acetyl-cholinesterase assay and thiols as well as imaging of living cells. AB - A resorufin derivative with a DBS group (probe 1) was designed and investigated for the detection of acetylcholinesterase (AChE) and inhibitor screening. The new assay is based on cascade enzymatic and chemical reactions of ATC, AChE and probe 1, and it can be carried out in a dual-signal detection mode. Moreover, the results show that probe 1 can be used for cell fluorescence staining. PMID- 20927441 TI - Effect of diluent chain length on the performance of the electrochemical DNA sensor at elevated temperature. AB - Here we report the effect of passivating diluent chain length and sensor interrogation temperature on the electrochemical DNA (E-DNA) sensor's mismatch discrimination capability. Both stem-loop and linear probe-based E-DNA sensors were constructed with various diluents, including 6-mercapto-1-hexanol and longer chain hydroxyl-terminated alkanethiols. Contrary to previously reported results, we find that the E-DNA sensors work optimally in the presence of the longer chain diluents, signified by the enhanced % signal suppression observed upon target hybridization. Of note, the sensors' signaling efficiency maintains even when interrogated at an elevated temperature, permitting the use of stringent temperature conditions to improve sensor specificity. For example, a stem-loop E DNA sensor fabricated with 8-mercapto-1-octanol, when employed at 47 degrees C, produces signal suppression of 79%, 35% and 1.6% for the perfect match, single base mismatch, and 2-base mismatch DNA targets, respectively. In addition to the significant enhancement in sensor discrimination capacity, high temperature operation also improves hybridization kinetics. Our results also suggest that the stem-loop E-DNA sensors demonstrate better mismatch discrimination capability when compared to the linear probe system under the same experimental condition. PMID- 20927439 TI - Identification of epigenetic DNA modifications with a protein nanopore. AB - Two DNA bases, 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (hmC), marks of epigenetic modification, are recognized in immobilized DNA strands and distinguished from G, A, T and C by nanopore current recording. Therefore, if further aspects of nanopore sequencing can be addressed, the approach will provide a means to locate epigenetic modifications in unamplified genomic DNA. PMID- 20927442 TI - Improved Cope-type hydroamination reactivity of hydrazine derivatives. AB - A systematic investigation on the metal-free, Cope-type hydroamination reactivity of hydrazides and analogues is reported. Optimization of the hydrazide structure resulted in more facile intramolecular reactivity and enabled intermolecular reactions of alkenes, thus providing a direct approach to polysubstituted hydrazides. PMID- 20927448 TI - Rapid isolation and detection of cancer cells by utilizing integrated microfluidic systems. AB - The present study reports a new three-dimensional (3D) microfluidic platform capable of rapid isolation and detection of cancer cells from a large sample volume (e.g. ~1 mL) by utilizing magnetic microbead-based technologies. Several modules, including a 3D microfluidic incubator for the magnetic beads to capture cancer cells, a microfluidic control module for sample transportation and a nucleic acid amplification module for genetic identification, are integrated into this microsystem. With the incorporation of surface-modified magnetic beads, target cancer cells can be specifically recognized and conjugated onto the surface of the antibody-coated magnetic microbeads by utilizing a swirling effect generated by the new 3D microfluidic incubator, followed by isolating and purifying the magnetic complexes via the incorporation of an external magnet and a microfluidic control module, which washes away any unbound waste solution. Experimental results show that over 90% of the target cancer cells can be isolated from a large volume of bio-samples within 10 min in the 3D microfluidic incubator. In addition, the expressed genes associated with ovarian and lung cancer cells can also be successfully amplified by using the on-chip nucleic acid amplification module. More importantly, the detection limit of the developed system is found to be 5 * 10(1) cells mL(-1) for the target cancer cells, indicating that this proposed microfluidic system may be adapted for clinical use for the early detection of cancer cells. Consequently, the proposed 3D microfluidic system incorporated with immunomagnetic beads may provide a promising automated platform for the rapid isolation and detection of cancer cells with a high sensitivity. PMID- 20927449 TI - An unusual ten-connected self-penetrating metal-organic framework based on tetranuclear cobalt clusters. AB - The unusual ten-connected self-penetrating metal-organic framework based on tetranuclear cobalt clusters has been synthesized and characterized, which represents the highest-connected uninodal network topology presently known for self-penetrating systems. PMID- 20927450 TI - Multimode hydriding/dehydriding reactions of CaPd. AB - Combined thermodynamical and structural studies have confirmed the occurrence of multimode hydriding/dehydriding reactions of CaPd that vary depending on temperature, and that these reactions proceed via hydrogen solution/dissolution in the temperature range 273-523 K and via phase decomposition/recombination in the temperature range 523-773 K. PMID- 20927451 TI - Relative basicities toward metal triflates Lewis acids by electrospray mass spectrometry. AB - The relative Lewis basicity of a series of phosphoryl compounds toward cations M(n+)(OTf)(n-1) derived from triflate salts, M(OTf)(n), is ranked using electrospray mass spectrometry according to competitive adduct formation. PMID- 20927452 TI - Phosphine-mediated disulfide metathesis in aqueous media. AB - Dynamic carbohydrate systems have been efficiently generated through phosphine mediated disulfide metathesis in aqueous media. The protein compatibility and binding features of the dynamic systems were demonstrated in situ using (1)H STD NMR. PMID- 20927453 TI - A large volume, portable, real-time PCR reactor. AB - A point-of-care, diagnostic system incorporating a portable thermal cycler and a compact fluorescent detector for real-time, polymerase chain reaction (PCR) on disposable, plastic microfluidic reactors with relatively large reaction volume (ranging from 10 uL to 100 uL) is described. To maintain temperature uniformity and a relatively fast temperature ramping rate, the system utilizes double-sided heater that features a master, thermoelectric element and a thermal waveguide connected to a second thermoelectric element. The waveguide has an aperture for optical coupling between a miniature, fluorescent reader and the PCR reaction chamber. The temperature control is accomplished with a modified, feedforward, variable structural proportional-integral-derivative controller. The temperature of the liquid in the reaction chamber tracks the set-point temperature with an accuracy of +/- 0.1 degrees C. The transition times from one temperature to another are minimized with controllable overshoots (< 2 degrees C) and undershoots (< 5 degrees C). The disposable, single-use PCR chip can be quickly inserted into a thermal cycler/reader unit for point-of-care diagnostics applications. The large reaction chamber allows convenient pre-storing of dried, paraffin-encapsulated PCR reagents (polymerase, primers, dNTPs, dyes, and buffers) in the PCR chamber. The reagents are reconstituted "just in time" by heating during the PCR process. The system was tested with viral and bacterial nucleic acid targets. PMID- 20927454 TI - Bringing natural products into the fold - exploring the therapeutic lead potential of secondary metabolites for the treatment of protein-misfolding related neurodegenerative diseases. AB - A review with 187 references, describing natural products that exhibit bioactive properties relevant to the treatment of protein aggregation-related neurodegenerative diseases (e.g., Huntington's, Parkinson's, and prion diseases) and comparing the chemical properties of these secondary metabolite leads to compounds in clinical use for treating central nervous system conditions. PMID- 20927456 TI - Computational study of ethene hydroarylation at [Ir(kappa(2)-OAc)(PMe3)Cp]+. AB - Density functional theory calculations have been employed to model ethene hydroarylation using an [Ir(kappa(2)-OAc)(PMe(3))Cp](+) catalyst, 1. The reaction proceeds via: (i) an acetate-assisted C-H activation of benzene via an AMLA-6 transition state; (ii) rate-limiting insertion of ethene into the Ir-Ph bond; and (iii) protonolysis of the beta-phenylethyl species by HOAc. A range of competing processes are assessed, the most important of which are the C-H activation of ethene at 1 and trapping of the beta-phenylethyl intermediate with ethene. The former process gives rise to Ir-vinyl species which can then access further ethene insertion to give stable allyl by-products. A comparison with other ethene hydroarylation catalysts reported in the literature is presented. PMID- 20927455 TI - Design, synthesis and evaluation of beta-lactam antigenic peptide hybrids; unusual opening of the beta-lactam ring in acidic media. AB - beta-Lactam peptides were envisioned as conformational constraints in antigenic peptides (APs). Three different beta-lactam tripeptides of varying flexibility were prepared in solution and incorporated in place of the central part of the altered melanoma associated antigenic peptide Leu(27)-Melan-A(26-35) using solid phase synthesis techniques. Upon TFA cleavage from the solid support, an unexpected opening of the beta-lactam ring occurred with conservation of the amide bond. After adaptation of the solid phase synthesis strategy, beta-lactam peptides were successfully obtained and both opened and closed forms were evaluated for their capacity to bind to the antigen-presenting class-I MHC HLA-A2 protein system. None of the closed beta-lactam peptides bound to HLA-A2, but their opened variants were shown to be moderate to good HLA-A2 ligands, one of them being even capable of stimulating a Melan-A-specific T cell line. PMID- 20927457 TI - DFT study of the mechanism of benzocyclobutene formation by palladium-catalysed C(sp3)-H activation: role of the nature of the base and the phosphine. AB - DFT(B3PW91) calculations of the mechanism of the intramolecular C(sp(3))-H arylation of 2-bromo-tert-butylbenzene to form benzocyclobutene catalysed by Pd(PR(3)) (R = Me, (t)Bu) and a base (acetate, bicarbonate, carbonate) show that the preferred mechanism is highly dependent on the nature of the phosphine and the base used in the calculations. With the experimental reagents (P(t)Bu(3) and carbonate) the rate-determining step is C-H activation with the base coordinated trans to the C-H bond. An agostic interaction of a geminal C-H bond with respect to the bond to be cleaved induces a lowering of the activation barrier. PMID- 20927458 TI - Integration of paper-based microfluidic devices with commercial electrochemical readers. AB - The combination of simple Electrochemical Micro-Paper-based Analytical Devices (EuPADs) with commercially available glucometers allows rapid, quantitative electrochemical analysis of a number of compounds relevant to human health (e.g., glucose, cholesterol, lactate, and alcohol) in blood or urine. PMID- 20927459 TI - Differentiation between normal and tumor vasculature of animal and human glioma by FTIR imaging. AB - Malignant gliomas are very aggressive tumors, highly angiogenic and invading heterogeneously the surrounding brain parenchyma, making their resection very difficult. To overcome the limits of current diagnostic imaging techniques used for gliomas, we proposed using FTIR imaging, with a spatial resolution from 6 to 10 MUm, to provide molecular information for their histological examination, based on discrimination between normal and tumor vasculature. Differentiation between normal and tumor blood vessel spectra by hierarchical cluster analysis was performed on tissue sections obtained from xenografted brain tumors of Rag gamma mice 28 days after intracranial implantation of glioma cells, as well as for human brain tumors obtained in clinics. Classical pathological examination and immunohistochemistry were performed in parallel to the FTIR spectral imaging of brain tissues. First on the animal model, classification of FTIR spectra of blood vessels could be performed using spectral intervals based on fatty acyl (3050-2800 cm(-1)) and carbohydrate (1180-950 cm(-1)) absorptions, with the formation of two clusters corresponding to healthy and tumor parts of the tissue sections. Further data treatments on these two spectral intervals provided interpretable information about the molecular contents involved in the differentiation between normal and tumor blood vessels, the latter presenting a higher level of fatty acyl chain unsaturation and an unexpected loss of absorption from osidic residues. This classification method was further successfully tested on human glioma tissue sections. These findings demonstrate that FTIR imaging could highlight discriminant molecular markers to distinguish between normal and tumor vasculature, and help to delimitate areas of corresponding tissue. PMID- 20927460 TI - Enhanced permanganate chemiluminescence. AB - The significant enhancement of acidic potassium permanganate chemiluminescence by Mn(II) results from the concomitant presence of permanganate and Mn(III) in the reagent solution, which enables rapid production of the excited Mn(II) emitter with a wide range of analytes. Furthermore, the key Mn(III) co-reactant can be quickly generated by reducing permanganate with sodium thiosulfate, instead of the slow (~24 h) equilibration required when Mn(ii) is used. The emission from reactions with analytes such as tyrosine and fenoterol was over two orders of magnitude more intense than with the traditional permanganate reagent. PMID- 20927461 TI - Conformational control in a bipyridine linked pi-conjugated oligomer: cation mediated helix unfolding and refolding. AB - A chiral pi-conjugated oligomer having alternate bipyridine and carbazole moieties connected through acetylinic bonds undergoes helical folding in chloroform-acetonitrile (40/60, v/v) as evident by fluorescence and circular dichroism changes. In the presence of transition metal cations such as Zn(2+) defolding of the helical conformation occurs. Upon decomplexation of the cation with EDTA, the helical conformation is regained. PMID- 20927462 TI - In situ imaging of usnic acid in selected Cladonia spp. by vibrational spectroscopy. AB - In this study, we demonstrate the first in situ detection of usnic acid (UA) in selected species of the lichen Cladonia, using FPA-FTIR imaging and Raman microscopy. Fruticose lichens present a variety of defensive mechanisms, one of which is the production of UA. This polyketide secondary metabolite, produced by certain lichenized fungi, has a protective function for the lichen that includes a strong absorption in the ultraviolet range. Upon confirming the distinct spectral signature of UA in lichen tissue, we mapped its distribution in Cladonia arbuscula, Cladonia uncialis and Cladonia sulphurina tissues. Spectroscopic images were obtained from cryosectioned lichen fragments embedded in media and from hand-sectioned fragments that were media-free. UA was present in the pycnidia, and younger walls of C. arbuscula and C. uncialis, the spore-producing region of a C. uncialis apothecium, and in both the younger and older soredia of C. sulphurina. The localization of UA in lichens is an important precursor to future work that includes the identification of the gene cluster responsible for its biosynthesis. Our results show that FTIR and Raman imaging can be an effective way to study the distribution of natural products in lichens with micron-scale precision. PMID- 20927463 TI - Pyrazine-bridged Dy2 single-molecule magnet with a large anisotropic barrier. AB - Utilization of the strong electron-withdrawing ligand, hfac, leads to a novel dinuclear dysprosium single-molecule magnet featuring a pyrazine bridge with a large anisotropic barrier. PMID- 20927464 TI - Anatase TiO(2) microspheres with exposed mirror-like plane {001} facets for high performance dye-sensitized solar cells (DSSCs). AB - Anatase TiO(2) microspheres with exposed mirror-like plane {001} facets were successfully synthesized via a facile hydrothermal process. The photoanode composed of TiO(2) microsphere top layer shows an improved DSSCs efficiency owing to the superior light scattering effect of microspheres and excellent light reflecting ability of the mirror-like plane {001} facets. PMID- 20927465 TI - Effects of the biological backbone on stacking interactions at DNA-protein interfaces: the interplay between the backbone...pi and pi...pi components. AB - The (gas-phase) MP2/6-31G*(0.25) pi...pi stacking interactions between the five natural bases and the aromatic amino acids calculated using (truncated) monomers composed of conjugated rings and/or (extended) monomers containing the biological backbone (either the protein backbone or deoxyribose sugar) were previously compared. Although preliminary energetic results indicated that the protein backbone strengthens, while the deoxyribose sugar either strengthens or weakens, the interaction calculated using truncated models, the reasons for these effects were unknown. The present work explains these observations by dissecting the interaction energy of the extended complexes into individual backbone...pi and pi...pi components. Our calculations reveal that the total interaction energy of the extended complex can be predicted as a sum of the backbone...pi and pi...pi components, which indicates that the biological backbone does not significantly affect the ring system through pi-polarization. Instead, we find that the backbone can indirectly affect the magnitude of the pi...pi contribution by changing the relative ring orientations in extended dimers compared with truncated dimers. Furthermore, the strengths of the individual backbone...pi contributions are determined to be significant (up to 18 kJ mol(-1)). Therefore, the origin of the energetic change upon model extension is found to result from a balance between an additional (attractive) backbone...pi component and differences in the strength of the pi...pi interaction. In addition, to understand the effects of the biological backbone on the stacking interactions at DNA-protein interfaces in nature, we analyzed the stacking interactions found in select DNA-protein crystal structures, and verified that an additive approach can be used to examine the strength of these interactions in biological complexes. Interestingly, although the presence of attractive backbone...pi contacts is qualitatively confirmed using the quantum theory of atoms in molecules (QTAIM), QTAIM electron density analysis is unable to quantitatively predict the additive relationship of these interactions. Most importantly, this work reveals that both the backbone...pi and pi...pi components must be carefully considered to accurately determine the overall stability of DNA-protein assemblies. PMID- 20927466 TI - Atomic force microscopy of DNA at high humidity: irreversible conformational switching of supercoiled molecules. AB - Three topologically different double-stranded DNA molecules of the same size (bps) have been imaged in air on mica using amplitude modulation atomic force microscopy (AM AFM) under controlled humidity conditions. At very high relative humidity (>90% RH), localized conformational changes of the DNA were observed, while at lower RH, the molecules remained immobile. The conformational changes occurred irreversibly and were driven principally by superhelical stress stored in the DNA molecules prior to binding to the mica surface. The binding mechanism of the DNA to the mica (surface equilibration versus kinetic trapping) modulated the extent of the conformational changes. In cases where DNA movement was observed, increased kinking of the DNA was seen at high humidity when more surface water was present. Additionally, DNA condensation behavior was also present in localized regions of the molecules. This study illustrates that changes in the tertiary structure of DNA can be induced during AFM imaging at high humidity on mica. We propose that AM AFM in high humidity will be a useful technique for probing DNA topology without some of the drawbacks of imaging under bulk solution. PMID- 20927467 TI - A straightforward approach towards 5-substituted thiazolylpeptides via the thio Ugi-reaction. AB - A wide range of 5-substituted thiazoles are easily accessible via cross coupling of thiazolyl triflates. These activated thiazoles can be obtained by Ugi reactions using thioacids (thio-Ugi-reaction) and subsequent cyclisation of the endo thiopeptides formed with triflic anhydride. In addition, cyclisations with acyl halides give rise to 5-acyloxysubstituted derivatives. PMID- 20927468 TI - Total syntheses of the furanosesquiterpenes crassifolone and dihydrocrassifolone via an Au(I)-catalysed intramolecular Michael addition reaction. AB - The racemic modifications of title natural products 1 and 2 have been synthesised for the first time. The key step was the Au(i)-catalysed conversion of the furanyl-substituted ynone 13 into the annulated furan 14. PMID- 20927469 TI - Convenient synthesis of Cu3(BTC)2 encapsulated Keggin heteropolyacid nanomaterial for application in catalysis. AB - Nanomaterial of Cu(3)(BTC)(2) (BTC = benzene tricarboxylic acid) incorporating Keggin heteropolyacid conveniently prepared at room temperature and recovered by freeze drying outperforms ultrastable Y zeolite in acid catalysed esterification reaction. PMID- 20927470 TI - Sandwich probes: two simultaneous reactions for templated nucleic acid detection. AB - Fluorescence-quenched nucleic acid probes with reactive moieties at both the 5' and 3' ends are synthesized and tested for reaction with two adjacent nucleophile containing DNAs. These probes improve signal to background over singly reactive probes and can discriminate single nucleotide polymorphisms in the target DNA or RNA. PMID- 20927471 TI - Novel PEG-organized biocompatible fluorescent nanoparticles doped with an ytterbium cyanoporphyrazine complex for biophotonic applications. AB - The preparation and properties are described of two types of novel PEG-organized nanoparticles including silica-modified uniform disk-shaped nanoparticles doped with a fluorescent ytterbium cyanoporphyrazine complex; a large enhancement of red emission for both types of nanoparticles is observed in physiological liquids owing to their binding to biomolecules. PMID- 20927472 TI - Click-triazole: coordination of 2-(1,2,3-triazol-4-yl)-pyridine to cations of traditional tetrahedral geometry (Cu(I), Ag(I)). AB - Coordination studies of the pyridine-triazole diad to copper(i) and silver(i) reveal the potential and conditions for the solution- and solid-state self assembly of supramolecular architectures based on this motif. PMID- 20927473 TI - Facile synthesis of highly active and stable Pt-Ir/C electrocatalysts for oxygen reduction and liquid fuel oxidation reaction. AB - A facile room temperature synthesis technique has been developed for Pt-Ir/C electrocatalysts for applications to low-temperature fuel cells. The prepared Pt(x)Ir(y) electrocatalyst was highly stable and active toward the oxygen reduction reaction (ORR), as well as liquid fuel oxidation reaction with high CO tolerance. PMID- 20927474 TI - Improvement of proteolytic efficiency towards low-level proteins by an antifouling surface of alumina gel in a microchannel. AB - A microfluidic reactor has been developed for rapid enhancement of protein digestion by constructing an alumina network within a poly(ethylene terephthalate) (PET) microchannel. Trypsin is stably immobilized in a sol-gel network on the PET channel surface after pretreatment, which produces a protein resistant interface to reduce memory effects, as characterized by X-ray fluorescence spectrometry and electroosmotic flow. The gel-derived network within a microchannel provides a large surface-to-volume ratio stationary phase for highly efficient proteolysis of proteins existing both at a low level and in complex extracts. The maximum reaction rate of the encapsulated trypsin reactor, measured by kinetic analysis, is much faster than in bulk solution. Due to the microscopic confinement effect, high levels of enzyme entrapment and the biocompatible microenvironment provided by the alumina gel network, the low-level proteins can be efficiently digested using such a microreactor within a very short residence time of a few seconds. The on-chip microreactor is further applied to the identification of a mixture of proteins extracted from normal mouse liver cytoplasm sample via integration with 2D-LC-ESI-MS/MS to show its potential application for large-scale protein identification. PMID- 20927479 TI - The influence of reaction conditions on the Diels-Alder cycloadditions of 2-thio 3-chloroacrylamides; investigation of thermal, catalytic and microwave conditions. AB - The Diels-Alder cycloadditions of cyclopentadiene and 2,3-dimethyl-1,3-butadiene to a range of 2-thio-3-chloroacrylamides under thermal, catalytic and microwave conditions is described. The influence of reaction conditions on the outcome of the cycloadditions, in particular the stereoselectivity and reaction efficiency, is discussed. While the cycloadditions have been attempted at the sulfide, sulfoxide and sulfone levels of oxidation, use of the sulfoxide derivatives is clearly beneficial for stereoselective construction of Diels-Alder cycloadducts. PMID- 20927480 TI - Synthesis and structure of azole-fused indeno[2,1-c]quinolines and their anti mycobacterial properties. AB - Prompted by our discovery of a new class of conformationally-locked indeno[2,1 c]quinolines as anti-mycobacterials, compounds 2a and 3a (Fig. 1; MIC < 0.39 MUg mL(-1) and 0.78 MUg mL(-1), respectively)(14) with a freely rotating C2-imidazolo substituent, we herein describe the synthesis of pentacyclic azole-fused quinoline derivatives 4 and 5, in which we have restricted the rotation of the C2 imidazolo moiety by fusing it to the adjacent quinoline-nitrogen to give a five membered fused azole heterocycle. The idea of locking the flexibility of the system by conformational constraint was simply to reduce its entropy, thereby reducing the overall free-energy of its binding to the target receptor. Out of 22 different azole-fused indeno[2,1-c]quinoline derivatives, seven structurally distinct compounds, 9, 15, 17, 25, 27, 28 and 29, have shown 79-99% growth inhibition of Mycobacterium tuberculosis H37Rv at a fixed dose of 6.25 MUg mL( 1). The efficacies of these compounds were evaluated in vitro for 8/9 consecutive days using the BACTEC radiometric assay upon administration of single dose on day one. Of these, two compounds, 9 and 28, inhibited growth of M. tuberculosis very effectively at MIC < 0.39 MUg mL(-1) (0.89 MUM and 1 MUM, respectively). These active compounds 9, 15, 17, 25, 27, 28 and 29 were screened for their cytotoxic effect on mammalian cells (human monocytic cell line U937), which showed that the human cell survival is almost unperturbed (100% survival), except for compound 25, hence these new compounds with new scaffolds have been identified as potent anti-mycobacterials, virtually with no toxicity. Thus these "hit" molecules constitute our important "leads" for further optimization by structure-activity relationship against TB. PMID- 20927481 TI - Synthesis of oxygen heterocycles by regioselective Heck reaction. AB - The regioselective Heck arylation of unsaturated alcohols is utilized as the key step in a convenient one-pot procedure for the production of 2,2-disubstituted tetrahydrofurans and tetrahydropyrans. The arylation reaction is effected with a palladium-diphosphine catalyst alongside a hydrogen bond donor; this is followed by the introduction of a Bronsted acid to the reaction mixture, affording the oxygen heterocycles in moderate yields. PMID- 20927482 TI - Highly sensitive and selective colorimetric and off-on fluorescent probe for Cu(2+) based on rhodamine derivative. AB - A new probe for Cu(2+) based on the Cu(2+)- induced reversible ring-opening mechanism of the rhodamine spirolactam was described. It displayed a highly selective and sensitive "turn-on" fluorescent and colorimetric response toward Cu(2+). PMID- 20927483 TI - Cationic zinc complexes: a new class of catalyst for living lactide polymerization at ambient temperature. AB - Cationic zinc complexes of a bis(phosphinimine) pincer ligand have been prepared. Methylzinc and zinc-lactate complexes have been structurally characterized, and the latter is the first cationic metal complex to promote coordination-insertion polymerization of lactide at ambient temperature. This novel catalyst system is remarkably active and also exhibits living character. A detailed investigation of the kinetics and mechanism of the polymerization process has been undertaken. PMID- 20927484 TI - Identification of phospholipid scramblase 1 as a biomarker and determination of its prognostic value for colorectal cancer. AB - The purpose of this study was to examine the expression of phospholipid scramblase 1 (PLSCR1) in tumor tissues and plasma specimens of patients with colorectal cancer (CRC), as well as analyze its association with clinical parameters. The expression levels of PLSCR1 protein in 104 matched CRC and adjacent normal tissue sections and 50 pairs of CRC tissue blocks were determined by use of immunohistochemical and Western blot analyses, respectively. To evaluate the diagnostic potential of PLSCR1, the plasma levels of PLSCR1 were investigated in 111 additional subjects (59 CRC patients and 52 healthy controls) by Western blot. PLSCR1 was overexpressed in malignant adenocarcinoma tissues compared with normal colorectal mucosa (P < 0.001). In addition, the plasma level of PLSCR1 was not only significantly elevated in CRC patients compared with healthy individuals (P < 0.001), but it was also substantially increased in early stage CRC (P < 0.001). Importantly, the overall sensitivity and specificity of PLSCR1 for CRC detection were 80% and 59.6%, respectively. The area under the ROC curve of PLSCR1 for CRC diagnosis is 0.75, which increases to 0.8 if combined with the measurement of carcinoembryonic antigen. Univariate analysis with the Cox regression model revealed that elevated PLSCR1 expression indicated a poor prognosis for CRC. This study showed that PLSCR1 protein levels were significantly elevated in both the cancer tissue and plasma of CRC patients. Moreover, the plasma levels of PLSCR1 were significantly elevated in patients with early stage CRC compared with healthy individuals, suggesting that PLSCR1 might be used as a noninvasive serological diagnostic and prognostic biomarker for CRC. PMID- 20927485 TI - Identification of treatment efficacy-related host factors in chronic hepatitis C by ProteinChip serum analysis. AB - Recent development of proteomic array technology, including protein profiling coupling ProteinChip array with surface-enhanced laser desorption ionization time of-flight mass spectrometry (SELDI-TOF/MS), provides a potentially powerful tool for discovery of new biomarkers by comparison of its profiles according to patient phenotypes. We used this approach to identify the host factors associated with treatment response in patients with chronic hepatitis C (CHC) receiving a 48 wk course of pegylated interferon (PEG-IFN) alpha 2b plus ribavirin (RBV). Protein profiles of pretreatment serum samples from 32 patients with genotype 1b and high viral load were conducted by SELDI-TOF/MS by using the three different ProteinChip arrays (CM10, Q10, IMAC30). Proteins showed significantly different peak intensities between sustained virological responders (SVRs), and non-SVRs were identified by chromatography, SDS-PAGE, TOF/MS and tandem mass spectrometry (MS/MS) assay. Eleven peak intensities were significantly different between SVRs and non-SVRs. The three SVR-increased peaks could be identified as two apolipoprotein (Apo) fragments and albumin and, among the eight non-SVR-increased proteins, four peaks identified as two iron-related and two fibrogenesis-related protein fragments, respectively. Multivariate analysis showed that the serum ferritin and three peak intensity values (Apo A1, hemopexin and transferrin) were independent variables associated with SVRs, and the area under the receiver operating characteristic (ROC) curves for SVR prediction by using the Apo A1/hemopexin and hemopexin/transferrin were 0.964 and 0.936. In conclusion, pretreatment serum protein profiling by SELDI-TOF/MS is variable for identification of response-related host factors, which are useful for treatment efficacy prediction in CHC receiving PEG-IFN plus RBV. Our data also may help us understand the mechanism for treatment resistance and development of more effective antiviral therapy targeted toward the modulation of lipogenesis or iron homeostasis in CHC patients. PMID- 20927487 TI - Stress at work--a risk factor for depression? PMID- 20927488 TI - Calciphylaxis in POEMS syndrome: A case treated with etidronate. PMID- 20927486 TI - Hypertrophic scarring and keloids: pathomechanisms and current and emerging treatment strategies. AB - Excessive scars form as a result of aberrations of physiologic wound healing and may arise following any insult to the deep dermis. By causing pain, pruritus and contractures, excessive scarring significantly affects the patient's quality of life, both physically and psychologically. Multiple studies on hypertrophic scar and keloid formation have been conducted for decades and have led to a plethora of therapeutic strategies to prevent or attenuate excessive scar formation. However, most therapeutic approaches remain clinically unsatisfactory, most likely owing to poor understanding of the complex mechanisms underlying the processes of scarring and wound contraction. In this review we summarize the current understanding of the pathophysiology underlying keloid and hypertrophic scar formation and discuss established treatments and novel therapeutic strategies. PMID- 20927489 TI - Difference in impact of neurobehavioural dysfunction on Activities of daily living performance between right and left hemispheric stroke. AB - OBJECTIVE: To explore whether persons with right- and left-sided cerebrovascular accidents differ significantly in mean impact of neurobehavioural impairments on ability to perform activities of daily living. DESIGN AND SUBJECTS: Retrospective study of data from 215 persons (103 right-sided, 112 left-sided cerebrovascular accident). The Activities of daily living-focused Occupation-based Neurobehavioral Evaluation was used to evaluate ability on an activities of daily living scale and the impact of neurobehavioural impairment on ability on another scale. METHODS: To control for possible differences in activities of daily living ability between groups, analysis of covariance, with activities of daily living ability as a covariate, was used to test for a significant difference in impact of neurobehavioural impairments on activities of daily living ability between groups. RESULTS: Expected moderate correlation (r = -0.57) was obtained between activities of daily living ability and neurobehavioural impact measures, and there was no difference in mean neurobehavioural impact measures between groups (F [1, 212] = 2.910, p = 0.090). CONCLUSION: This study is the first to explore directly the impact of neurobehavioural impairment on activities of daily living ability. While persons with right-sided and left-sided cerebrovascular accidents may differ in type of neurobehavioural impairments, direct evaluation of the impact of such impairments on activities of daily living ability reveals no difference between groups. PMID- 20927491 TI - Isokinetic muscle evaluation of quadriceps in patients with chronic obstructive pulmonary disease. AB - RATIONALE: Muscle debility has a significant impact on health-related quality of life in subjects with chronic obstructive pulmonary disease (COPD), and is correlated to exacerbation and even mortality. Assessing muscle strength is extremely relevant. Lack of standardisation in numbers of sets and rest interval in isokinetic test protocol can lead to distinct results, making com- prehension and comparisons among studies difficult. AIM: To analyse the effect of two sets and three different rest intervals on isokinetic strength measurement of quadriceps tests, in order to define the adequate test protocol. METHODS: Subjects with severe or very severe COPD underwent three isokinetic tests to evaluate knee extensor muscle strength, at an angular velocity of 60 degrees ?s 1, with rest intervals of 30, 60 and 120 seconds. Each test consisted of two sets of five repetitions, during which peak torque, total work and fatigue index were measured. RESULTS: In 20 studied subjects (66.1 +/- 7.4 years, 70 +/- 10.8 kg, 167.4 +/- 6.2 cm, FEV1 36.5 +/- 10.1%), there were no significant differences in peak torque, total work and fatigue index, independent of number of sets or rest interval between sets. CONCLUSION: In subjects with severe or very severe COPD, quadriceps muscle strength can be evaluated by an isokinetic protocol with one set of five repetitions. If two sets are performed, a rest interval of 30 seconds is enough to ensure muscle recovery between sets. PMID- 20927490 TI - Genital psoriasis: A systematic literature review on this hidden skin disease. AB - It is well known that the genital skin may be affected by psoriasis. However, little is known about the prevalence and clinical appearance of genital psoriasis, and genital skin is often neglected in the treatment of psoriatic patients. We performed an extensive systematic literature search for evidence based data on genital psoriasis with respect to epidemiology, aetiology, clinical and histopathological presentation, diagnosis and treatment. Three bibliographical databases (PubMed, EMBASE and the Cochrane Library) were used as data sources. Fifty-nine articles on genital psoriasis were included. The results show that psoriasis frequently affects the genital skin, but that evidence-based data with respect to the efficacy and safety of treatments for genital psoriasis are extremely limited. An advised treatment paradigm for genital psoriasis, based on the levels of evidence, is: first-line: (weak) topical corticosteroids; second line: vitamin D preparations or tar-based treatments. PMID- 20927492 TI - Impact of combined exercise on chronic obstructive pulmonary patients' state of health. AB - AIM: The aim of the study was to evaluate the effectiveness of a 10-week combined training programme (aerobic and strength exercise) compared to an aerobic training programme, and respiratory physiotherapy on COPD patients' health. METHODS: Fifty subjects with moderate to severe COPD were randomly assigned to two groups. Combined group (CG, n=25) who underwent combined training, and aerobic group (AG, n=25) who underwent aerobic training. These were compared with fifty COPD subjects who underwent respiratory physiotherapy, breathing control and bronchial clearance techniques (RP group, n = 50). We evaluated health state through two questionnaires, St. George's Respiratory Questionnaire (SGRQ) and SF 36, at the beginning and at the end of the programme. RESULTS: The CG group showed differences (p<0.0001) in modification rates in state of health compared to the AG and RP groups in the activity (64 +/- 9%, 19 +/- 7%, 1 +/- 15%) , impact (35 +/- 5%, 20 +/- 18%, 1 +/- 14%) and total (41 +/- 9%, 26 +/- 17%, 1 +/- 15%) domains assessed by the SGRQ, and the physical function (109 +/- 74%, 22 +/- 12%, 0.1 +/- 18%), physical role (52 +/- 36%, 11 +/- 15%, 1.3 +/- 21%) and vitality (83 +/- 39%, 14 +/- 38%) domains assessed by SF-36. CONCLUSION: These results suggest that combined training in subjects with COPD appears to be a more effective method, with better clinical changes, and improvements in health state perception. PMID- 20927493 TI - Risk factors for readmission after hospital discharge in chronic obstructive pulmonary disease. The role of quality of life indicators. AB - AIMS: To identify demographic, clinical, functional and inherent quality of life (QOL) and depression factors with impact on use of the Emergency Services (ES) or readmission after hospital discharge for acute exacerbation of chronic obstructive pulmonary disease (COPD) over a period of 66 weeks. QOL was evaluated by the St. George's Respiratory Questionnaire (SGRQ). The Beck Depression Inventory assessed depression. We prospectively evaluated 45 patients (84.4% male, median age 73 years, stage IV 51%). The median total SGRQ score was 50.6, with a greater impact on symptoms, especially in younger patients (r=-0.425; p=0.043), and activity limitation than emotional impact of the disease. More than half were depressed. Worse QOL meant depression (R=0.699; p=0.02). Low FEV1 correlated with depression (r=-0.46; p =0.05) but not with QOL. Long-acting anti cholinergic bronchodilator and inhaled steroids improved QOL. Almost 85% of patients used ES (25.8% for exacerbated COPD). Rate of hospital readmission for all reasons and exacerbated COPD was 64.9% and 33.3%. The number of readmissions (all reasons) was correlated with age (R=0.48; p=0003), cor pulmonale (R=-0.46; p=0.03) and QOL (R=0.67; p=0.004). Depressed patients (R=0.51; p=004), with low FEV1 (R=-0413; p=0.04) and with cor pulmonale (R=-046, p=0.005) had more inhospital days for exacerbation of COPD. QOL and depression are variables to consider in the evaluation and treatment of patients with COPD as part of a set of clinical and functional data that can predict the risk of readmission after hospital discharge for exacerbated COPD. PMID- 20927494 TI - Early nasal continuous positive airway pressure versus INSURE in VLBW neonates. AB - BACKGROUND: Evidence suggests the INSURE strategy (INtubate-SURfactant administration and Extubate to nasal continuous positive airway pressure [nCPAP]) is superior to mechanical ventilation (MV) with rescue surfactant for the management of respiratory distress syndrome (RDS) in very low birth weight (VLBW) neonates. There is limited data, however, to assess whether INSURE is superior to nCPAP alone. We aimed to compare these two strategies regarding early and late outcomes. METHODS: Retrospective cohort study from Jan/2002 to Aug/2008. We included VLBW neonates with gestational age (GA) <= 30 weeks registered in the Vermont Oxford Network that used either nCPAP alone (nCPAP group, N=40), or with INSURE (INSURE group, N=56). We assessed early (RDS, need for rescue surfactant, and CPAP failure with MV) and late outcomes (chronic lung disease of prematurity (CLD), mortality, and composite outcome of mortality and/or CLD). RESULTS: Neonates in the INSURE group had lower mean GA, while other baseline variables were comparable. The proportion of RDS was significantly superior in the nCPAP group (53% vs. 30%; adjusted OR [95% CI] - 0.2 [0.1-0.6]). Therapeutic surfactant was administered to all cases with RDS in the nCPAP group, but to none from the INSURE group. MV was more frequently required in the nCPAP group (11/ 40, 28% vs. 9/ 56, 12%; p=0.04). No statistically significant differences were found in either of the late outcomes. CONCLUSION: The use of nCPAP alone in VLBW neonates with GA <= 30 weeks may be associated with slightly poorer early outcomes than the INSURE strategy, but there were no significant differences in CLD or mortality. PMID- 20927495 TI - The influence of an undergraduate scientific initiation programme on the professional profile of new physicians. AB - INTRODUCTION: This paper studies the influence of a Scientific Initiation Programme (SIP) on the professional profile of new doctors from a Brazilian university. AIM AND METHODS: Evaluate fifty-two new doctors divided into two groups matched by sex, age and academic performance and differing only in participation in the SIP. Professional and socioeconomic data were collected, including schooling of parents; average income before, during and after the medical course; current professional situation; results of exams for civil servant recruitment; and titles and degrees obtained after graduation. RESULTS: Significant differences were found only in civil servant recruitment exam results (p = 0.0098) and in income after graduation (p = 0.02), which were both higher in the non-SIP group. Only one doctor got a M.Sc. degree after graduation, but many of them in both groups obtained technical titles, and had papers presented at congresses or published. CONCLUSIONS: Apparently, taking part in a SIP led to lower income and worse civil servant recruitment exam results. However, this may only reflect a transient phase in a long-term process. New research currently under way will answer this remaining question, now that more time has elapsed since graduation. PMID- 20927496 TI - [Latent tuberculosis infection treatment. Current recommendations]. AB - Diagnosis and treatment of latent infection with Mycobacterium tuberculosis (LTBI), significantly reduces the risk of developing active tuberculosis and the transmission of the disease in the community. LTBI screening must pass by the exclusion of active disease (symptoms enquiry and chest radiography) and assessment of immune response to Mycobacterium tuberculosis testing with the tests currently available - tuberculin skin test and interferon -gamma release assay (IGRA). The choice of treatment must take into account the efficacy and side effects associated with the same. This document provides updated recommendations on latent tuberculosis infection treatment. Topics covered include whom to test for TB and reviewed LTBI treatment regimens. PMID- 20927497 TI - [Non-infectious pulmonary complications after the hematopoietic stem cell transplantation]. AB - Pulmonary complications are important cause of mortality and morbidity after hematopoietic stem cell transplantation, in 30% to 60% of the patients. Improvements in prophylaxis and treatment of infectious complications have been increasing the rate of non-infectious complications. Early diagnosis and treatment of those complications can significantly change the evolution of hematopoietic stem cell transplantation receptors. The objective of this study is to review the most frequent non-infection complications associated to hematopoietic stem cell transplantation since the first bone marrow transplantation performed in 1957. A systematic literature review was performed, using the PICO strategy to ask the questions. The descriptors hematopoietic stem cell transplantation, non-infectious pulmonary complications, systematic review, in portuguese and their english correspondents, were used to access the following databases: MEDLINE, EBM, Embase, Cocrane Library, LILACS and SciELO. In this review, 263 studies were identified, from which 31 were selected for full analyzis. The non-infection pulmonary complications most frequently found were: bronchiolitis obliterans, bronchiolitis obliterans organizing pneumonia, pulmonary edema, idiopathic pneumonia syndrome, delayed pulmonary toxicity syndrome, diffuse alveolar hemorrhage, engrafment syndrome and pulmonary cytolitic thrombi. PMID- 20927498 TI - [Nasal and laryngeal sarcoidosis - case presentation]. AB - The authors present the case of a 41-year-old woman with nasal and laryngeal involvement by sarcoidosis, review the literature and discuss the otolaryngologic manifestations, the diagnostic evaluation, treatment and prognostic of this entity. PMID- 20927499 TI - [Primary ciliary dyskinesia revisited: based on three clinical reports]. AB - Primary ciliary dyskinesia is a genetically and clinically heterogeneous disorder. Its pathogenesis reflects structural and functional compromise of the cilia. Common clinical manifestations include recurrent upper and lower respiratory tract infections and infertility, as well as situs inversus totalis in half of the affected patients. Besides its rarity and phenotypic heterogeneity its diagnosis usually requires a high suspicion index. The main purpose of this paper is to review the pathogenesis, clinical features, diagnostic and therapeutic approaches of primary ciliary dyskinesia beyond the discussion of three clinical reports. We report the cases of three patients all with a past history of neonatal respiratory distress and two with situs inversus totalis. The subsequent clinical manifestations included lower airway symptoms in two patients (chronic productive cough and recurrent pneumonia and wheezing) and upper respiratory tract disease in all patients. Age at primary ciliary dyskinesia diagnosis differed considerably among patients (8 months, 5 and 12 years). The two patients with later diagnosis had already obstructive lung function compromise at the time of diagnosis. The authors discuss the different clinical patterns presented, therapeutic strategies and the clinical progression that ensued, factors possibly implicated in late diagnosis and its prognostic consequences. The main goal is to emphasize early and/or prevalent clinical features of primary ciliary dyskinesia in order to promote clinical awareness and early recognition of the disease. PMID- 20927500 TI - [Congenital lobar emphysema of the newborn. Report of four clinical cases]. AB - INTRODUCTION: Congenital lobar emphysema (CLE) is a rare anomaly of lung development that presents in the neonatal period in about 50% of the cases. The authors report four clinical cases of congenital lobar emphysema in the newborn. CLINICAL CASES: Four term newborns, 3M/ 1F, were admitted for respiratory distress starting between 20 hours of life and 18 days. The chest x -ray at admission was suggestive of CLE and the diagnosis was confirmed by computorized tomography. The CLE affected the right upper lobe in three cases and the medium lobe in one case. All patients were treated with lobectomy. The pathological study of the surgical specimens confirmed the diagnosis in the four cases, and revealed hypoplasia of the bronquiolar tree cartilage in three. CONCLUSIONS: Our series is according to literature regarding to male gender preponderance, clinical presentation, different time to diagnosis, unilobar involvement and no identification of an evident aetiology in one case. Surgical treatment was universal. PMID- 20927501 TI - [Persistent left atrial thrombus in atrial fibrillation under oral anticoagulation]. AB - The case of a 78-year-old female patient who suffered atrial fibrillation and persistent thrombus in the left atrial appendage despite sufficient anticoagulation is reported. The case is chosen to demonstrate the complexity inherent in prophylaxis as well as risk evaluation of thromboembolism on the basis of clinical and echocardiographic criteria. We also discuss transesophageal echocardiography as the standard diagnostic procedure for detection of intracardiac thrombi prior to cardioversion as well as cardiac computer tomography as an alternative. PMID- 20927502 TI - Serial NT-proBNP measurements for risk stratification of patients with decompensated heart failure. AB - PURPOSE: NT-proBNP is an important prognostic predictor in patients with heart failure. However, it is unknown whether a change of NT-proBNP plasma levels in the early phase of decompensation might be of additional prognostic value in patients with acute decompensation of heart failure. METHODS AND RESULTS: NT proBNP plasma levels of 116 patients with decompensated heart failure from ischemic/non-ischemic origin were measured at baseline and at 12, 24 and 48 h after hospital admission. Baseline levels and changes of plasma levels within the first 48 h were correlated with 30-day mortality. In all patients, NT-proBNP 12 h after admission was highest and superior with respect to the prediction of 30-day mortality compared to plasma levels on admission. In total, 38 patients died within the first 30 days. In these patients absolute NT-proBNP plasma levels were significantly higher and the increase within 12 h after admission was more pronounced compared to survivors (p<0.001). NT-proBNP at 12 h after admission also had the highest predictive value for the 30-day mortality rate in patients with acute myocardial infarction. The increase of NT-proBNP plasma levels within 12 h after admission had the highest predictive value in patients suffering from decompensated heart failure. CONCLUSIONS: NT-proBNP is a powerful marker of 30 day mortality in patients with decompensated heart failure of ischemic and non ischemic origin. Compared with single baseline measurements, serial measurements of NT-proBNP plasma levels within 12 h after hospital admission may be used to increase the predictive value of NT-proBNP with regard to the early identification of patients who are at high risk of mortality. PMID- 20927503 TI - [Disseminated papules in a patient with acute myeloid leukemia]. AB - Cryptococcosis most commonly occurs in immunosuppressed patients. The pathogen is the yeast Cryptococcus neoformans. This article reports on the case of a 20-year old female patient with acute myeloid leukemia who suddenly developed disseminated livid red papules and papulovesicles. The clinical picture and in particular the histopathology findings led to the diagnosis of cutaneous cryptococcosis, which was successfully treated with amphotericin B. For the differential diagnosis generalized herpes zoster, erythema exudativum multiforme and disseminated molluscum contagiosum must be considered. To confirm the diagnosis attempts can also be made to culture the pathogen from skin biopsy preparations. Furthermore, fungal spores can be rapidly and simply detected with the Tzanck test. PMID- 20927504 TI - Designer lymphocytes to fight cancer: a helping hand from modern molecular biology. PMID- 20927505 TI - Patellofemoral osteoarthritis in patients with operative treatment for patellar dislocation: a magnetic resonance-based analysis. AB - PURPOSE: the clinical role of patellofemoral (PF) osteoarthrosis (OA) in the outcome after PF stabilizing surgery is poorly understood. The study hypothesis was that PF cartilage lesions and OA are associated with a poor long-term outcome after PF stabilizing surgery. METHODS: the study cohort included thirty-seven patients who underwent PF stabilizing surgery by traditional nonanatomic procedures and were evaluated a minimum of 10 years (range 10-21) after surgery. PF OA was assessed by magnetic resonance (MR) images and plain radiographs obtained at follow-up. Median patient age at follow-up was 33 years (29-43). RESULTS: at the final follow-up, PF full-thickness cartilage lesions were observed on MR images in 29 (78%) patients. Only 46% of the patients reported satisfaction at follow-up, and dissatisfaction was associated with PF OA (full thickness articular cartilage loss on MR images; P = 0.022). Especially high incidence, 89%, of medial patellar facet cartilage lesions were found among the patients dissatisfied with the result (16/18 patients) (n.s.). Eight (22%) of the 37 patients reported recurrent patellar instability episodes at follow-up. Median Kujala score was 83 points (range 55-98). CONCLUSION: patellofemoral OA is a significant long-term risk of nonanatomic surgery for patellar instability and has a greater impact on subjective outcome than residual instability more than 10 years after surgery. PMID- 20927506 TI - Standardized combined cryotherapy and compression using Cryo/Cuff after wrist arthroscopy. AB - PURPOSE: cryotherapy and compression as integral part of the RICE regimen are thought to improve treatment outcome after sport injuries. Using standardized cryotherapy and compression perioperatively has been reported with conflicting clinical results. The impact of combined cryotherapy and compression is compared to standard care among patients undergoing wrist arthroscopy. METHODS: fifty-six patients undergoing wrist arthroscopy were assessed, 54 patients were randomized to either Cryo/Cuff (3 * 10 min twice daily) or standard care over 3 weeks. Follow-up clinical visits were at postoperative days 1, 8, and 21. One patient in each group was lost during follow-up. Fifty-two patients were analyzed. Statistics were performed as Intention-to-treat analysis. Outcome parameters were pain, three-dimensional volume of the wrist, range of motion, and DASH score. RESULTS: the Cryo/Cuffgroup had a 49% reduction in pain level (VAS 3.5 +/- 0.4 vs. VAS 1.8 +/- 0.2 on the 21st postoperative day) when compared to a reduction of 41% in the control group (VAS 5.1 +/- 0.6 preoperatively vs. VAS 3.0 +/- 0.5 on the 21st postoperative day). Swelling and range of motion were not as significantly different between the two groups as were DASH scores (DASH-score Cryo/Cuff group preoperatively 37.3 +/- 3.5 and postoperatively 36.9 +/- 3.5; DASH-score control group preoperatively 42.8 +/- 4.3 and postoperatively 41.9 +/- 4.9). The CONSORT score reached 17 out of 22. CONCLUSION: there was no significant effect of additional home-based combined cryotherapy and compression using the Cryo/Cuff wrist bandage, following wrist arthroscopy regarding pain, swelling, range of motion, and subjective impairment assessed using the DASH score over 3 weeks in comparison with the control group. PMID- 20927507 TI - Fluoro-Free navigated retrograde drilling of osteochondral lesions. AB - PURPOSE: Retrograde drilling of osteochondral lesions (OCLs) is a recommended, but demanding operative approach for revascularization of lesions in stage 1-3 according to Berndt and Harty after failed conservative treatment. The gold standard of intraoperative driller guidance is fluoroscopic control. Limitations are a 2D visualization of a 3D procedure and sometimes limited view of the OCL in fluoroscopy, leading to increased radiation exposure. A new image-free navigation procedure was evaluated for practicability and precision in first clinical applications. METHODS: In a period of 7 months, retrograde drillings were performed in eight patients (3x femoral condyle, 5x talus) using the new Fluoro Free navigation procedure without rigidly fixed reference bases. RESULTS: In total, 29 retrograde drillings were performed without any technical problem. The overall mean operating time was 82.1 +/- 29.3 min (34.6 +/- 6.4 min for the standard arthroscopy and 11.2 +/- 1.2 min per drill). Twenty-seven of 29 drillings hit the target with a 100% first-pass accuracy. Two complications during drilling (one navigation specific and one navigation independent) were observed. CONCLUSION: The paper describes the promising first clinical applications of a new Fluoro-Free navigation procedure for the retrograde drilling of OCLs determined by arthroscopy. The benefit of that navigated drillings with a high rate of first-pass accuracy and no need for radiation exposure in contrast to standard techniques is highlighted. PMID- 20927508 TI - Simultaneous quantification of ten cytotoxic drugs by a validated LC-ESI-MS/MS method. AB - A liquid chromatography separation with electrospray ionisation and tandem mass spectrometry detection method was developed for the simultaneous quantification of ten commonly handled cytotoxic drugs in a hospital pharmacy. These cytotoxic drugs are cytarabine, gemcitabine, methotrexate, etoposide phosphate, cyclophosphamide, ifosfamide, irinotecan, doxorubicin, epirubicin and vincristine. The chromatographic separation was carried out by RPLC in less than 21 min, applying a gradient elution of water and acetonitrile in the presence of 0.1% formic acid. MS/MS was performed on a triple quadrupole in selected reaction monitoring mode. The analytical method was validated to determine the limit of quantification (LOQ) and quantitative performance: lowest LOQs were between 0.25 and 2 ng mL(-1) for the ten investigated cytotoxic drugs; trueness values (i.e. recovery) were between 85% and 110%, and relative standard deviations for both repeatability and intermediate precision were always inferior to 15%. The multi compound method was successfully applied for the quality control of pharmaceutical formulations and for analyses of spiked samples on potentially contaminated surfaces. PMID- 20927509 TI - Aza-Michael reaction with enone-modified vegetable oils: evidence of the keto enolic equilibrium by NIR chemical imaging and evolving factor analysis. AB - The existence of an enone-dienol tautomerism in enone-containing triglyceride, obtained from high oleic sunflower oil, was detected in an image set captured at 95 degrees C by fixed-size image window-evolving factor analysis. A (1)H NMR spectrum and a UV-Visible spectrum of the enone-containing triglyceride at 25 degrees C and at 95 degrees C were measured to corroborate the presence of the enol form. The presence of this equilibrium explains the different behaviour of the curing reaction between an enone-containing triglyceride and diaminodiphenylmethane, which was evaluated following the spectral evolution of two pixels that differ in the presence or absence of the enol form. As the enol form acts as a inert species in the reaction, it leads to different degree of advance depending on which growing zone is observed. PMID- 20927510 TI - Plasma B-type natriuretic peptides in children with cardiovascular diseases. AB - Natriuretic peptides (NP) are released from the heart in response to pressure and volume overload. The biologic properties of NPs include counterregulation of the rennin-angiotensin-aldosterone pathway and a decrease in sympathetic tone resulting in diuresis, natriuresis, and vasodilation. Natriuretic peptides help to maintain fluid balance and blood pressure in a healthy physiologic range. The B-type natriuretic peptide (BNP) and its N-terminal precursor (NTpBNP) have become important diagnostic biomarkers of cardiovascular diseases (CVDs) in adults. Although many studies suggest that BNP also is a reliable test for diagnosing significant CVDs in children, data are lacking on whether additional use of BNP increases diagnostic accuracy and predicts prognosis. This comprehensive review describes the utility of BNP and NTpBNP for various CVDs of the neonatal and pediatric age groups. Because BNP is not a stand-alone test, it should not replace history, physical examination, or clinical judgment, but it has a clear value in adding details to the whole story for children, thus enabling the front-line physicians to make a diagnosis, especially in the acute care setting. PMID- 20927511 TI - Investigation of supragingival plaque microbiota in different caries status of Chinese preschool children by denaturing gradient gel electrophoresis. AB - This study aimed to detect differences in the richness of total supragingival plaque microbiota as well as the species composition of oral streptococci involved in the different stages of dental caries. Forty-five plaque samples were collected from caries-moderate (CM, 4 <= dmfs <= 6), caries-susceptible (CS, dmfs >= 10), and age-matched caries-free children separately. Total DNA was isolated directly from each sample, and polymerase chain reaction-denaturing gradient gel electrophoresis (PCR-DGGE) analyses using universal and primers specific for oral streptococci were carried out. Using 16S rDNA PCR-DGGE, 34 different species of bacteria were identified in a culture-independent manner and classified into 11 genera according to phylogenetic analysis. Among them, Mitis group streptococci and Campylobacter, which were present in health status, no longer appeared in caries-susceptible samples. In addition, Capnocytophaga, Burkholderia, and Prevotella were found significantly less frequently in the CS group samples (P < 0.05), while there were no significant differences among the prevalence of Neisseria, Leptotrichia, Haemophilus, Mutans group streptococci, Corynebacterium, and Actinomyces in the three groups. Further DGGE analysis of rnpB gene amplicons obtained with oral streptococci species-specific primers showed that a total of 23 species of oral streptococci were identified. Streptococcus sanguinis, Streptococcus mitis, and Streptococcus oralis showed a significantly higher prevalence in healthy children (P < 0.05), while that of Streptococcus mutans and Streptococcus sobrinus did not vary among the three groups. Overall, these results suggest that supragingival plaque microbiota as a whole undergoes a more complicated shift in the caries process. PMID- 20927512 TI - Functional characterization of a new holin-like antibacterial protein coding gene tmp1 from goat skin surface metagenome. AB - We have identified a holin-like gene from a goat skin surface metagenome. The ORF designated tmp1 coding for 34 amino acids shared sequence similarity with putative holin-like toxin genes. To analyze the antibacterial activity of tmp1 encoded protein, this ORF was cloned and expressed in Escherichia coli BL21(DE3). The expressed gene product Tmp1 exhibited antibacterial activity against Gram positive bacteria but not to Gram-negative bacteria. A single transmembrane domain (TMD) was identified within Tmp1 and deletion analysis of the N-terminal region and TMD indicated TMD to be responsible for antibacterial activity. The TMD-dependent antibacterial activity was validated using a synthetic peptide with the amino acid sequence of TMD. Besides antibacterial activity, Tmp1 also complemented the function of holin in a lysis-defective bacteriophage lambda. To broaden the spectrum of antibacterial activity, a mutant library of tmp1 was generated by random mutagenesis. Four mutants with amino acid substitutions at the N-terminus of Tmp1 exhibited increased antibacterial activity against Gram positive and Gram-negative bacteria and were not hemolytic. An improved activity of these mutant proteins is attributed to their increased hydrophobicity. PMID- 20927513 TI - Relationship between the pelvic osteolytic volume on computed tomography and clinical outcome in patients with cementless acetabular components. AB - The purpose of this study was to evaluate the relationship between the pelvic osteolytic volume on computed tomography (CT) and clinical outcome in patients with cementless acetabular components. We reviewed 87 patients (104 hips) who met the following inclusion criteria: (1) there was evidence of pelvic osteolysis on CT at a minium of five years postoperatively, (2) all cups and stems were radiographically stable at the time of CT, (3) the follow-up period after CT was a minimum of two years clinically. The mean pelvic osteolytic volume was 2.3 +/- 6.9 cm(3). The mean Harris hip score (HHS) at CT was 92.3 +/- 7.9 points. Inversely moderate correlation (r = -0.569, P < 0.05) was found between the HHS at CT and pelvic osteolytic volume. In ten cases of hips with acetabular revisions, the mean pelvic osteolytic volume was 16.3 +/- 26.9 cm(3). The mean HHS at CT and HHS at reoperation was 87.6 +/- 9.2 points and 73.4 +/- 8.8 points, respectively, with significant difference (P < 0.05). The area under curve (ROC) analysis showed that the optimal cutoff value of the osteolytic volume was 4.8 cm(3) with 100% each for sensitivity and specificity. We conclude that the amount of pelvic osteolytic volume on CT may be used to guide treatment decision-making in patients with well-fixed cementless acetabular components who show evidence of pelvic osteolysis. PMID- 20927514 TI - Reduction malarplasty using an L-shaped osteotomy through intraoral and sideburns incisions. PMID- 20927515 TI - Update on the split-muscle technique for breast augmentation: prevention and correction of animation distortion and double-bubble deformity. PMID- 20927516 TI - Reduction malarplasty using an L-shaped osteotomy through intraoral and sideburns incisions. AB - The slender, oval-shaped face is considered to be attractive in East Asia. To obtain the ideal contour of the midface, reduction malarplasty has been popularized in oriental countries in recent years. This report describes a surgical technique for reduction of the zygomatic body and arch. After labiobuccal vestibular incisions are made, the anterior zygomatic body and lateral orbital rim are exposed by subperiosteal dissection. Thereafter, an L shaped osteotomy is performed. Two parallel horizontal osteotomies are made in the anterior part of the zygomatic body, and the middle bone segment is removed. The zygomatic arch root is fractured through a small sideburn incision just anterior to the articular tubercle. Finally, the freed zygomatic complex is medially repositioned and fixed with one or two bicortex screws. Operations on 32 patients demonstrated that this technique may be a sound method for malar complex reduction, with the advantages of simple manipulation, stable fixation, and less risk of a drooping face. PMID- 20927517 TI - Juvenile gigantomastia in a 12-year-old girl: a case report. AB - Juvenile gigantomastia is a rare, massive breast enlargement. It appears in adolescence and can affect one or both breasts of otherwise healthy girls. This report describes a case of a bilateral and symmetric gigantomastia in a 12-year old girl. PMID- 20927518 TI - L-specular plasty versus double-round plasty: two new techniques for earlobe split repair. AB - BACKGROUND: Split earlobes can be classified into two groups: congenital and traumatic. The congenital group can be divided into three categories: anterior, posterior with doubled earlobe, and sagittal. The traumatic group can be divided into two categories: complete and incomplete. This report describes and compares two new techniques the authors have developed for split earlobe repair: L specular plasty and double-curve-specular plasty. Both techniques are simple to perform and deliver a good aesthetic result. METHODS: A series of 30 patients with split earlobes underwent surgery from September 2007 to September 2009. All the patients enjoyed good health with no organic pathologies. All the patients had surgery under local anesthesia. The L-specular plasty technique was used to treat 15 patients (13 complete splits, 2 incomplete splits). The remaining 15 patients (13 complete splits, 2 incomplete splits) were treated with the double curve-specular plasty. RESULTS: Skin necrosis was not reported for any of the treated patients. Sutures are completely removed after 2 weeks. The sutures for three patients were removed after 20 days due to slow cicatrization. Repiercing of the ear may occur after 6 months. One patient (8%) experienced a wound infection, treated successfully with systemic antibiotic therapy. Two patients (16%) experienced hypertrophic scars. Only two patients (16%) had recurrence during a mean follow-up period of 13.4 months (range, 6-24 months: September 2007 2009). CONCLUSION: Both double-curve-specular plasty and L-specular plasty are simple, reliable procedures. They both deliver very good aesthetic results thanks to the curve incisions that follow the natural shape of the earlobe. However, the patients treated with double-curve-specular plasty reported greater satisfaction in the outcome of their surgery. PMID- 20927519 TI - Galactorrhea after aesthetic breast augmentation with silicone implants: report of two cases and management of postoperative galactorrhea. AB - Galactorrhea is a rare event after breast augmentation. The physiopathologic bases of galactorrhea depend on the central secretion of prolactin. These physiopathologic bases must be clearly understood for the prevention and treatment of postoperative galactorrhea. This report describes two cases of a postoperative galactorrhea after aesthetic breast augmentation with silicone implants. The clinical appearance closely resembles a postoperative sepsis without hyperthermia. Bacteriologic samples are negative. Endocrinologic examination finds a characteristic hyperprolactinemia. The evolution is favorable under dopaminergic agonists. PMID- 20927520 TI - Environmental impact assessment of sand mining from the small catchment rivers in the southwestern coast of India: a case study. AB - In the past few decades, the demand for construction grade sand is increasing in many parts of the world due to rapid economic development and subsequent growth of building activities. This, in many of the occasions, has resulted in indiscriminate mining of sand from in-stream and floodplain areas leading to severe damages to the river basin environment. The case is rather alarming in the small catchment rivers like those draining the southwestern coast of India due to limited sand resources in their alluvial reaches. Moreover, lack of adequate information on the environmental impact of river sand mining is a major lacuna challenging regulatory efforts in many developing countries. Therefore, a scientific assessment is a pre-requisite in formulating management strategies in the sand mining-hit areas. In this context, a study has been made as a case to address the environmental impact of sand mining from the in-stream and floodplain areas of three important rivers in the southwestern coast of India namely the Chalakudy, Periyar and Muvattupuzha rivers, whose lowlands host one of the fast developing urban-cum-industrial centre, the Kochi city. The study reveals that an amount of 11.527 million ty(-1) of sand (8.764 million ty(-1) of in-stream sand and 2.763 million ty(-1) of floodplain sand) is being mined from the midland and lowland reaches of these rivers for construction of buildings and other infrastructural facilities in Kochi city and its satellite townships. Environmental Impact Assessment (EIA) carried out as a part of this investigation shows that the activities associated with mining and processing of sands have not only affected the health of the river ecosystems but also degraded its overbank areas to a large extent. Considering the degree of degradation caused by sand mining from these rivers, no mining scenario may be opted in the deeper zones of the river channels. Also, a set of suggestions are made for the overall improvement of the rivers and its biophysical environment. PMID- 20927521 TI - Influence of residual stenosis on clinical outcome and restenosis after middle cerebral artery stenting. AB - BACKGROUND: The purpose of this study was to assess whether the residual stenosis has effect on restenosis after stenting for atherosclerotic stenosis in the middle cerebral artery. METHODS: Sixty-seven patients underwent 69 single-stent procedures successfully for atherosclerotic stenosis >=70% in the M1 segment of middle cerebral artery were reviewed retrospectively. All patients were classified into two groups: nonresidual (<=30%) and residual (>30%) stenosis. The influence of residual stenosis immediately after stent placement on clinical outcomes and restenosis at follow-up was analyzed. Restenosis was defined as >=20% stenosis on angiographic follow-up imaging after excluding postoperative residual stenosis. RESULTS: Between groups, it was no difference in the conventional risk factors of cerebrovascular diseases, characteristics of targeted vessels, and types of stent. The residual stenosis had no influence on any stroke or death, but the ipsilateral stroke had a trend in the residual stenosis group. The incidence of restenosis was higher in patients with residual stenosis >30% (17% vs. 45.5%, P = 0.04), and the increase of percent stenosis was 7.9 +/- 11.7 and 17.1 +/- 15.4, respectively (P = 0.03). The correlation coefficient was r = 0.37 (P < 0.01) between the residual stenosis and the increase of percent stenosis. Univariate and multivariate regression analysis showed that residual stenosis >30% was an independent risk factor for restenosis at follow-up (log-rank, Chi-square = 6.09, P = 0.01). CONCLUSIONS: Residual stenosis immediately after stenting for atherosclerotic middle cerebral artery stenosis may be a predictor of clinical outcomes and restenosis at follow-up. PMID- 20927522 TI - The role of interventional radiology in the management of deep venous thrombosis: advanced therapy. AB - Deep vein thrombosis (DVT) is often managed with a health care pathway that funnels patients to anticoagulation therapy alone. This "usual treatment" is designed to stop propagation and embolisation of venous thrombus but not remove it. Surgical thrombectomy was once the only option in severe cases in which limbs were threatened, but thrombus removal is no longer restricted to emergency cases. Interventional radiologists are now using advanced endovascular techniques to achieve thrombus removal in a minimally invasive manner in a very short treatment time, thereby quickly restoring patency, relieving acute symptoms, and potentially limiting the subsequent development of postthrombotic syndrome when followed with anticoagulation and compression regimens. This article provides an overview of the interventions available for treating DVT. One of the newer "single-session" techniques is isolated pharmacomechanical thrombolysis, which is described here in detail with supporting cases. PMID- 20927523 TI - Inhibition of N-linked glycosylation by tunicamycin induces E-cadherin-mediated cell-cell adhesion and inhibits cell proliferation in undifferentiated human colon cancer cells. AB - PURPOSE: Aberrant protein glycosylation and disassembly of E-cadherin-mediated cell-cell adhesion are characteristics of epithelial cancer. However, the relationship between these two events in colorectal cancer remains to be defined. In this study, we analyzed whether N-glycan expression is crucial for the loss of E-cadherin-mediated cell-cell adhesion in human colorectal cancer cells. METHODS: Differentiated Caco-2 and undifferentiated HCT-116 colon cancer cells were used as models of stable and unstable adherens junctions (AJs), respectively. Complex type N-glycans were detected using the lectins E-PHA (Phaseolus vulgaris E.) and L-PHA (Phaseolus vulgaris L.). To study E-cadherin-mediated AJ assembly, we examined the effects of swainsonine, an inhibitor of alpha-mannosidase II, and tunicamycin, a drug that inhibits the biosynthesis of N-glycans, via western blot, immunofluorescence, differential extraction in Triton X-100, and electron microscopy. Cell proliferation and apoptosis were examined by crystal violet staining and flow cytometry, respectively. RESULTS: We observed positive labeling for E-PHA and L-PHA lectins in both cell lines; however, HCT-116 cells had increased E-cadherin-linked complex-type N-glycans. Interestingly, tunicamycin, but not swainsonine, was able to induce functional E-cadherin-mediated cell-cell adhesion in undifferentiated HCT-116 cells, as shown by the increased association of E-cadherin with the actin cytoskeleton. Moreover, in HCT-116 cells, tunicamycin also induced the formation of tight cell-cell contacts, and it inhibited cell proliferation without triggering apoptosis. CONCLUSIONS: Collectively, our results demonstrate for the first time that altered N-glycan expression plays an important role in the loss of AJ stability in undifferentiated colorectal cancer cells and that this loss may be associated with the progression of colorectal cancer. PMID- 20927524 TI - High-performance liquid chromatographic method for the determination of sorafenib in human serum and peritoneal fluid. AB - PURPOSE: Sorafenib is recommended for therapy of advanced hepatocellular carcinoma and renal cell carcinoma. Preclinical data indicate a relation between dose and antitumor efficacy. In clinical trials, adverse events improve after dose reduction suggesting a dose-dependent toxicity. Given dose has a direct impact on the drug serum concentration, but the latter also can be influenced by multiple factors, including interaction and metabolisation. To enable the investigation of concentration-related effects, an easy and sensitive assay for sorafenib drug monitoring is essential. METHODS: A high-performance liquid chromatography (HPLC) analysis involving an extraction with diethyl ether followed by separation on a PinnacleTM DB C18 column and quantitation by UV absorbance at 260 nm was established. Sorafenib concentrations in samples of serum and peritoneal fluid have been determined. RESULTS: The assay was validated for serum samples and is linear over the concentration range of 100-5,000 ng/ml with a determination coefficient of >0.999. The limit of detection is 0.25 ng/ml. The intra- and inter-day coefficients of variation were below 3.03%. Sorafenib recovery in spiked probes of peritoneal fluid was above 85%. Sorafenib concentrations in 44 serum samples and 14 probes of peritoneal fluid have been determined with a mean of 3,328 and 1,380 ng/ml, respectively (standard deviation 2,267 and 659 ng/ml). CONCLUSIONS: A sensitive and selective HPLC method for the determination of sorafenib in human serum was developed and also verified for peritoneal fluid. This method provides a useful tool for pharmacokinetic investigations as well as for therapeutic drug monitoring of sorafenib. PMID- 20927525 TI - Phase II study of a fixed dose-rate infusion of gemcitabine associated with erlotinib in advanced pancreatic cancer. AB - PURPOSE: To evaluate the feasibility, toxicity and efficacy of the combination regimen consisting of gemcitabine-FDR infusion plus erlotinib, in ACP patients. METHODS: Forty-two patients with histologically confirmed, locally advanced or metastatic pancreatic cancer were included in this phase II trial. Main objectives were to assess the efficacy and safety of this regimen. Therapeutic regimen consisted of gemcitabine 1,200 mg/m(2) in 120-min infusion on days 1, 8 and 15, plus erlotinib 100 mg orally once daily. Cycles were repeated every 28 days. RESULTS: A total of 160 courses of gemcitabine-FDR erlotinib were administered (median 3.8 courses per patient). The most common grade 3-4 AEs were neutropenia (21%), thrombocytopenia (10%), skin rash (10%) and asthenia (10%). Complete response was achieved in one patient (2%) and 11 (26%) achieved a partial response. Stable disease and progression disease were observed in 11 patients (26%) and 19 (45%), respectively. Median time to progression was 5 months (95%CI: 3.9-5.8 months) and median overall survival was 8 months (95% CI: 5.1-10.8). One-year survival rate was 35%. CONCLUSIONS: A regimen consisting of gemcitabine-FDR infusion plus erlotinib is active and well tolerated in APC patients. However, the results do not justify the conduct of a Phase III trial. PMID- 20927526 TI - CT predictors of mortality in pathology confirmed ARDS. AB - OBJECTIVES: To identify CT findings that predict mortality in acute respiratory distress syndrome (ARDS) and to identify CT findings that differentiate diffuse alveolar damage (DAD) from DAD with prominent histopathological features of organizing pneumonia (DAD-OP). METHODS: Twenty-eight patients with ARDS (corroborated by open biopsy) and chest CT within 2 weeks of biopsy were included in our study. Differences in CT findings in patients with survivors versus nonsurvivors as well as for DAD versus DAD-OP were compared using Fisher's exact test. RESULTS: Lung involvement of greater than 80%, RA/LA ratio >1, and varicoid traction bronchiectasis were statistically more common in nonsurvivors than in survivors (respective p values of 0.001, 0.008, and 0.038). PA dilation greater than 3 cm and RV/LV ratio greater than 0.9 were also more common in nonsurvivors than in survivors but these factors did not achieve significance. CT findings did not differentiate DAD from DAD-OP. CONCLUSION: Our study suggests that >80% of lung involvement, RA/LA ratio >1, and varicoid bronchiectasis predict mortality in patients with ARDS/DAD. Signs of right-sided heart failure (PA dilation greater than 3 cm and RV/LV ratio greater than 0.9) approached significance. CT findings did not differentiate DAD from DAD-OP. PMID- 20927527 TI - Assessment of tissue perfusion by contrast-enhanced ultrasound. AB - Contrast-enhanced ultrasound (CEUS) with microbubble contrast agents is a new imaging technique for quantifying tissue perfusion. CEUS presents several advantages over other imaging techniques in assessing tissue perfusion, including the use of microbubbles as blood-pool agents, portability, availability and absence of exposure to radiation or nuclear tracers. Dedicated software packages are necessary to quantify the echo-signal intensity and allow the calculation of the degree of tissue contrast enhancement based on the accurate distinction between microbubble backscatter signals and native tissue background. The measurement of organ transit time after microbubble injection and the analysis of tissue reperfusion kinetics represent the two fundamental methods for the assessment of tissue perfusion by CEUS. Transit time measurement has been shown to be feasible and has started to become accepted as a clinical tool, especially in the liver. The loudness of audio signals from spectral Doppler analysis is used to generate time-intensity curves to follow the wash-in and wash-out of the microbubble bolus. Tissue perfusion may be quantified also by analysing the replenishment kinetics of the volume of microbubbles after their destruction in the imaged slice. This allows to obtain semiquantitative parameters related to local tissue perfusion, especially in the heart, brain, and kidneys. PMID- 20927528 TI - Functional inhibition of erectile process in rats by indomethacin. AB - OBJECTIVES: Despite the important role played by prostaglandins in the control of erection, the potential contribution of non-steroidal anti-inflammatory drugs in erectile dysfunction in experimental animals has not been investigated. We examined the effect of the selective COX-2 inhibitor, celexocib, and the non selective COX-inhibitors, indomethacin and diclofenac on erectile process in vivo. METHODS: Erectile responses to electrical stimulation of the cavernous nerve in anesthetized male rats were recorded after single and repeated administration and intracavernosal pressure/mean arterial pressure (ICP/MAP) was calculated. The effect on blood pressure during erection and total plasma nitrite/nitrate level was also investigated. RESULTS: Single-dose administration of indomethacin significantly reduced erectile responses to electrical stimulation at all frequencies tested; 15 mg/kg further reduced ICP/MAP to 0.016 +/- 0.005 compared to 0.064 +/- 0.012 and 0.104 +/- 0.035 for indomethacin (5 mg/kg) and control, respectively at 0.5 Hz. Longer-term treatment with indomethacin completely abolished erectile responses at low frequencies and significantly reduced ICP/MAP at higher frequencies, accompanied by significant reduction in total plasma nitrite/nitrate level. Diclofenac reduced erectile responses only at low frequencies in contrast to celexocib that failed to negatively affect erectile responses. CONCLUSION: Indomethacin, and to a lower extent diclofenac, may adversely affect erectile responses in rats. PMID- 20927529 TI - Observed magnetic resonance imaging changes in pediatric patients treated with stereotactic radiosurgery for intracranial tumors. AB - PURPOSE: This study seeks to characterize magnetic resonance imaging (MRI) changes following stereotactic radiosurgery (SRS) of pediatric brain malignancies. METHODS: Serial MRI evaluations were performed on 21 lesions treated with SRS for either medulloblastoma (n=12), juvenile pilocytic astrocytoma (n=4), ependymoma (n=2), atypical rhabdoid teratoid tumor (n=2), or pineocytoma (n=1). Prescription doses ranged from 14 to 30 Gy in one to five fractions. Tumor response was qualified as complete (CR), partial (PR), stable disease (SD), or progressive disease (PD) according to the RECIST v1.1. Median radiographic follow-up after SRS was 17 months. RESULTS: A total of 80 follow-up MRI scans were reviewed with a median of eight per patient. During serial MRI evaluation, eight lesions met criteria for PD at a median of 6 months. However, of these, three (37%) represented transient tumor edema with two lesions later developing a CR at a median of 15 months and one persisting as SD at 12 months. The remaining five lesions were true local failures. Of the 13 lesions that did not show evidence of PD, a CR was obtained in 11 lesions at a median of 3 months (range, 2-6), and SD was seen in the remaining two tumors at last follow-up. CONCLUSION: Lesion enlargement following SRS for pediatric intracranial tumors is common, and a proportion of patients meeting requirements for PD at early radiographic follow-up may later develop complete resolution of their lesions. Physicians should be aware of these radiographic changes to avoid unwarranted medical and surgical interventions. PMID- 20927530 TI - A novel NF1 gene mutation in an Italian family with neurofibromatosis type 1. AB - PURPOSE: Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder with an estimated incidence of one in 3,500 births. Clinically, NF1 is characterized by cafe-au-lait (CAL) spots, neurofibromas, freckling of the axillary or inguinal region, Lisch nodules, optic nerve glioma, and bone dysplasias. NF1 is caused by inactivating mutations of the 17q11.2-located NF1 gene. We present a clinical and molecular study of an Italian family with NF1. METHODS: The proband, a 10-year-old boy, showed large CAL spots and freckling on the axillary region and plexiform neurofibromas on the right side only. His father (47 years old) showed, in addition to the similar signs, numerous neurofibromas of various sizes on his thorax, abdomen, back, and shoulder. Two additional family members (a brother and a sister of the proband) presented only small CAL spots. The coding exons of NF1 gene were analyzed for mutations by denaturing high-performance liquid chromatography and sequencing in all family members. RESULTS: The mutational analysis of the NF1 gene revealed a novel frameshift insertion mutation in exon 4c (c.654 ins A) in all affected family members. This novel mutation creates a shift on the reading frame starting at codon 218 and leads to the introduction of a premature stop at codon 227. CONCLUSIONS: The segregation of the mutation with the affected phenotype and its absence in the 200 normal chromosomes suggest that it is responsible for the NF1 phenotype. PMID- 20927531 TI - Plasma TM2-PK levels in mycosis fungoides patients. AB - Aerobic glycolysis increases in tumor cells and pyruvate kinase (PK) is one of the key enzymes involved; PK exists in different isoforms in various tissues. Tumor M2-PK (TM2-PK) is one of these isoforms and its expression has been observed in various tumor cells, including lymphocytes, and in lymphoproliferative disorders. The present study aimed to compare plasma levels of TM2-PK and serum levels of two established markers of various lymphoproliferative disorders-lactate dehydrogenase (LDH) and beta-2 microglobulin, and to evaluate the role of TM2-PK in drug monitorization and disease activity in mycosis fungoides (MF) patients. The study included 27 MF patients and 46 healthy controls. Among the MF patients, 18 were stage IA, 6 were stage IB, 1 was stage IIA, and 2 were stage III. Plasma TM2-PK, and serum LDH and beta-2 microglobulin levels in the patients and controls were measured using the ELISA technique, a kinetic method, and a chemiluminescent assay, respectively. Measurements were repeated in the patient group posttreatment. Median levels of TM2-PK, LDH, and beta-2 microglobulin level in the MF patients were 22 U mL-1, 375 U L-1, and 1,831 ng mL-1, respectively. TM2-PK and beta-2 microglobulin levels did not significantly differ between the MF patients and controls; however, LDH levels were significantly higher in the MF patients. TM2-PK levels in 17 of the MF patients that were in remission did not significantly differ from their pre-therapy levels. Based on a cut-off point of 17.5 U mL-1, the sensitivity and specificity of TM2-PK for diagnosing MF were 55.6 and 60.9%, respectively. beta-2 microglobulin was the most sensitive marker for diagnosing MF (63%), while LDH was the most specific marker. Furthermore, the sensitivity of TM2-PK increased when it was analyzed in combination as parallel tests with LDH and beta-2 microglobulin (86%), while the specificity was measured as 32%. In serial analysis, the specificity was increased to 98%, while the sensitivity was 5%. Statistically significant agreement in diagnosing MF was also noted between TM2-PK and LDH levels. TM2-PK may not be a useful marker for MF, especially in early-stage patients, because it proliferates slowly. We think that TM2-PK levels should be investigated in advanced-stage MF or in other types of cutaneous T-cell lymphomas; in particular, in combination with other established markers. PMID- 20927532 TI - Rap1-independent telomere attachment and bouquet formation in mammalian meiosis. AB - Attachment of telomeres to the nuclear envelope (NE) and their clustering in a chromosomal bouquet during meiotic prophase I is an evolutionary conserved event that promotes chromosome pairing and recombination. In fission yeast, bouquet formation fails when the telomeric protein Rap1 is absent or when the telomeric protein Taz1 fails to recruit Rap1 to telomeres. The mammalian Rap1 orthologue is a component of the shelterin complex and localises to telomeres through an interaction with a Taz1-like telomeric DNA binding factor, TRF2. Here, we investigated the role of mammalian Rap1 in meiotic telomere attachment and clustering by analysing spermatogenesis in Rap1-deficient mice. The results establish that the meiotic three-dimensional nuclear architecture and recombination are not affected by the absence of Rap1. Furthermore, Rap1 deficient meiotic telomeres assemble the SUN1 nuclear membrane protein, attach to the NE, and undergo bouquet formation indistinguishable from the wild-type setting. Thus, the role of Rap1 in meiosis is not conserved between fission yeast and mammals, suggesting that mammals have alternative modes for connecting telomeres to SUN proteins on the meiotic nuclear envelope. PMID- 20927533 TI - Deep brain stimulation in the nucleus ventralis intermedius in patients with essential tremor: habituation of tremor suppression. AB - In patients with essential tremor (ET) already treated with chronic deep brain stimulation (DBS) of the nucleus ventralis intermedius (VIM) we investigated whether optimization of stimulation parameters could improve clinical tremor suppression, and whether this putative effect could be sustained over time. Twenty-three ET patients with VIM-DBS participated in the prospective study. All electrode contacts were tested systematically and stimulation parameters were optimized over the course of 2 days. Clinical tremor rating scale (TRS) was videotaped before, directly after the optimization and at a 10 weeks follow-up and evaluated blindly and independently by two clinicians. For stimulation effect optimization we increased the number of active contacts whereas the total charge applied to the tissue was kept constant. TRS hemi-body scores decreased significantly after optimization. At the 10 weeks follow-up, however, the improvement had faded and was no longer significant. The activities of daily living (ADL) remained significantly improved. Systematic optimization of VIM-DBS parameters in ET patients leads to a short term improvement which habituates over time. Our results provide further evidence for a tolerance effect in chronic VIM stimulation thereby suggesting that frequently alternating stimulation protocols should be tested in future studies of ET patients treated with VIM-DBS. PMID- 20927534 TI - Laparoscopic versus open appendectomy--quality of life 7 years after surgery. AB - BACKGROUND: In spite of the widespread use of laparoscopic appendectomy, there is an ongoing debate on the advantages of this method when compared to open appendectomy. In the evaluation of a postoperative procedure, long-term quality of life is essential. PATIENTS AND METHODS: From 1999 to 2001, 493 patients diagnosed with acute appendicitis were operated in a German general district hospital and included in an observational study. In a median postoperative interval of 7 years, these patients were re-evaluated regarding their quality of life after surgery. A Short-Form 36 Health Survey (SF-36) questionnaire was applied to evaluate the general parameters of quality of life after surgery. This questionnaire was supplemented by an additional self-developed module referring to the appendectomy. The primary outcome was the recommendation of the experienced operating procedure to relatives and friends. RESULTS: A total of 243 patients underwent a laparoscopic procedure: 132 patients were re-evaluated (recovery rate 54%). In the open group, 250 patients were operated: 121 patients were re-evaluated (recovery rate 48%). The median interval from operation to evaluation was 7 years in the laparoscopic group and 7.7 years in the open group. For the primary outcome, patients with laparoscopic appendectomy would significantly more often recommend the procedure than patients with the open operation method. For secondary outcomes, the cosmetic results were judged significantly more favourably in the laparoscopic group. The eight scaled scores of the SF-36 questionnaire did not differ significantly between the two groups. Four patients of the open group and nine patients of the laparoscopic group (including one converted procedure) needed a reoperation because of incisional hernia, adhesions and late infections. CONCLUSION: Patients after laparoscopic appendectomy show a higher degree of satisfaction with their body and their scar than patients after open appendectomy. PMID- 20927535 TI - Dysphonia at 12 months corrected age in very low-birth-weight-born children. AB - Preterm newborn infants may suffer laryngeal injuries after multiple intubations and long-term mechanical ventilation. Former studies have focused on acute laryngeal injuries diagnosed by endoscopy, performed within the neonatal period. This retrospective case-control study aims to investigate the prevalence and clinical risk factors for voice disorders in former very low-birth-weight (< 1,500 g) infants (VLBW) at 1-year follow-up examinations. We screened former VLBW infants for presence of dysphonia at the corrected age of 1 year and compared cases with unaffected infants matched by birth weight and gestational age. Of the 843 former VLBW infants, admitted from January 1998 to May 2006, 18 subjects had persistent dysphonia. All cases had a birth weight below 1,000 g. Surgical ligation of a ductus arteriosus had been performed in ten infants. Duration of ventilation and number of intubations were not different between cases and controls, but a documented difficult intubation was a predictor of subsequent dysphonia. The rate of dysphonia at 1 year of life was 6.6% among formerly ventilated infants with birth weights <1,000 g (extremely low-birth-weight infants). Persistent dysphonia has to be added to the list of specific long-term consequences of extremely immature birth and given attention at follow-up examinations. PMID- 20927536 TI - Toll-like receptors in domestic animals. AB - Toll-like receptors are pattern recognition receptors with which hosts recognize pathogen-associated molecular patterns (PAMP). This recognition process is translated rapidly into a meaningful defense reaction. This form of innate host defense is preserved in the animal kingdom: invertebrates heavily depend on it; higher vertebrates also have an adaptive immune system. Both adaptive and innate immune systems are intertwined in that the former also depends on an intact innate recognition and response system. Members of the TLR system cover recognition of parasitic, bacterial or viral germs. Due to the constraints imposed by the necessity to recognize PAMP and to interact with downstream signaling molecules, the TLR system is relatively conserved in evolution. Nevertheless, subtle species differences have been reported for several mammalian TLR members. Examples of this will be given. In all mammalian species investigated, part of the coding sequence is available for the most important TLR members, thus allowing study of expression of these TLR members in various tissues by reverse-transcription polymerase chain reaction in its classical (RT PCR) and quantitative real time RT-PCR (qRT-PCR) form. In some species, the whole coding sequences of the most important or even all TLR members are known. This allows construction of cDNA and transfection of common host cells, thus permitting functional studies. Extensive investigations were devoted to the study of non-synonymous single nucleotide polymorphisms. In a few cases, expression of a given amino acid in the extracellular (ligand-binding) portion of TLR members could be associated with infectious diseases. This will be discussed below. PMID- 20927537 TI - Induced chemical defenses in a freshwater macrophyte suppress herbivore fitness and the growth of associated microbes. AB - The freshwater macrophyte Cabomba caroliniana induces a chemical defense when attacked by either the crayfish Procambrus clarkii or the snail Pomacea canaliculata. Induction by either consumer lowers the palatability of the plant to both consumers. When offered food ad libitum, snails feeding on non-induced C. caroliniana grew 2.6-2.7 times more than those feeding on induced C. caroliniana. Because snails fed less on induced plants, this could be a behavioral effect (reduced feeding), a physiological effect of the induced metabolites on the consumer, or both. To assess these possibilities, we made artificial diets with lipid extracts of induced versus non-induced C. caroliniana and restricted control snails to consuming only as much as treatment snails consumed. Growth measured as shell diameter was significantly lower on the diet containing extract from induced, as opposed to non-induced, plants; change in snail mass was more variable and showed a similar, but non-significant, trend. Thus, snails may reduce feeding on induced plants to avoid suppression of fitness. The induced defenses also suppressed growth of co-occurring microbes that might attack the plant through herbivore-generated feeding scars. When two bacteria and three fungi isolated from C. caroliniana surfaces were cultured with the lipid extract from induced and non-induced C. caroliniana, both extracts inhibited the microbes, but the induced extract was more potent against three of the five potential pathogens. Thus, induced plant defenses can act against both direct consumers and microbes that might invade the plant indirectly through herbivore generated wounds. PMID- 20927538 TI - Does mesh shrinkage in any way depend upon the method of mesh fixation in laparoscopic incisional hernia repair? PMID- 20927539 TI - A comparative study of handsewn versus stapled gastrojejunal anastomosis in laparoscopic Roux-en-Y gastric bypass. AB - BACKGROUND: The two basic techniques available in which to perform the gastrojejunal (GJ) anastomosis during a laparoscopic Roux-en-Y gastric bypass (LRYGBP) are stapled and handsewn. Few outcomes differences have been noted between the two to recommend one as a superior approach. We present our findings in comparison of the two methods. METHODS: This is a retrospective review of all patients who underwent LRYGBP at a single institution during a 3-year period. The two different techniques that were used were a linear stapled and handsewn anastomosis with an anastomotic diameter of 18 mm. The groups were compared for postoperative complications, including stricture, anastomotic leak, and the need for early reoperation. All patients were followed up for a minimum period of 8 months. RESULTS: A total of 222 patients were analyzed after excluding 4 patients: 3 for revisional surgery and 1 for conversion to open. There were 99 patients in the stapled group and 123 in the handsewn group. In both groups, patients were predominantly female. The average age was 42.63 in the stapled group and 44.33 in the handsewn group (P = 0.218). Body mass index was 48.23 in the stapled group and 47.91 in the handsewn group (P = 0.733). Stricture rate in the stapled group was 10.1% (10/99) and 4.1% (5/123) in the handsewn group (P = 0.076). Four patients from the stapled group (4.08%) and six from the handsewn group (4.88%) needed early reoperation. One patient in each group had a GJ anastomotic leak (0.9%). There were no deaths. CONCLUSIONS: The incidence of anastomotic stricture tends to be lower with a handsewn technique with lower operative time. No difference was appreciated in the anastomotic leak or reexploration rate with either technique. PMID- 20927541 TI - Transvaginal laparoscopically assisted endoscopic cholecystectomy: preliminary clinical results for a series of 43 cases in China. AB - BACKGROUND: Transvaginal cholecystectomy has been performed successfully at several research institutions worldwide using natural orifice transluminal endoscopic surgery (NOTES) techniques. However, it is a growing new surgical concept in China. Several technical challenges hinder the safe clinical application of NOTES. This study investigated transvaginal endoscopic cholecystectomy performed with the assistance of a single umbilical trocar and achieved helpful initial clinical experience. METHODS: From May 2009 to April 2010, a total of 43 transvaginal human cholecystectomies were performed. A single umbilical trocar was used for safe access and laparoscopic assistance during the operation. After the gallbladder had been removed through the vagina, the colpotomy was closed with absorbable stitches under direct vision. In addition, Student's t-test was performed for two samples to estimate the superiority of NOTES over a conventional laparoscopic cholecystectomy (LC) operation. RESULTS: The procedure was successfully completed for all the patients. No intra- or post operative complications occurred. The patients recovered promptly after surgery, and all were satisfied with ideal cosmetic outcomes. The postoperative pain, hospital stay, and cost of hospitalization with NOTES were much less than with conventional LC operations. CONCLUSIONS: Although endoscopic instruments specifically designed for NOTES are not available, the addition of an umbilical trocar is an optimal way to allow safe performance of NOTES procedures in an easily reproducible manner. The authors' initial experience demonstrates that this hybrid technique is potentially feasible and effective for reducing postoperative pain and recovery times while improving the cosmetic results of transvaginal cholecystectomy. PMID- 20927542 TI - Synthetic polymer-tissue adhesion using an ultrasonic scalpel. AB - BACKGROUND: Interface phenomena such as encapsulation and formation of dead space around implanted biomaterials lower biomaterial performance. To advance tissue adhesive technology, understanding the interactions between tissue (collagen) and polymer is indispensable. Adhesion between tissue and polymer was studied using an ultrasonically activated scalpel (UAS). METHODS: The Harmonic Scalpel was used as an ultrasonically activated scalpel for polymer and tissue adhesion. A piece of porcine aorta and a polymeric film were layered and placed between the blades of the Harmonic Scalpel. Then the samples were gripped with 20 kgf of force for 1 10 s to adhere the porcine aorta and polymeric films. The adhesion was characterized by macro- and microscopic observation, thermographic analysis, and measurement of bonding strength, static contact angle (SCA), and surface properties. RESULTS: Cellulose, vinylon, polyethylene terephthalate, nylon, and Pellethane could be bonded to the aorta. Bonding was not observed for the polyethylene, polypropylene, polyvinyl chloride, or polytetrafluoroethylene. This suggests that the existence of functional groups such as hydroxyl, carbonyl, carboxyl, and amide groups in the polymer structure are key factors in adhesion. Harmonic Scalpel modification of the polyethylene surface during corona discharge treatment further indicated that the functional groups of the polymers are one of the essential factors for tissue adhesion. The temperatures of adhesion were 90 150 degrees C for the polymers, and the melting temperatures (Tm) were 193-306 degrees C. This suggests that adhesion was formed by the interaction between the melted polymer surface and the tissue collagen. CONCLUSION: Both polar functional groups and adequate thermal characteristics are necessary for polymers to bond with tissues. These findings should be useful for the development of novel polymers that can be bonded to living tissues with UAS treatment, which can be applied for endoscopic surgery. PMID- 20927543 TI - Video-assisted thoracoscopic surgery (VATS) lobectomy using a standardized anterior approach. AB - BACKGROUND: Lobectomy using video-assisted thoracoscopic surgery (VATS) still is a controversial operation despite its many observed benefits. The controversy may be due to difficulties performing the procedure. This study addresses a standardized anterior approach facilitating the operation. METHODS: This report describes 156 VATS lobectomies performed with a uniform anterior three-port technique. The surgeon and the assistant stand on the abdominal side of the patient, and the setup is independent of the lobe to be resected. RESULTS: From 2005 to 2007, 156 VATS lobectomies and 13 conversions (7.7%) were performed with an anterior three-port technique. No mortality occurred among the VATS lobectomies during a 30-day period. The major comorbidity rate was 78%. The comorbidities included former thoracic surgery (9%) or a history of another cancer (22%), indicating potentially difficult surgery and a nonselected population. The majority (92%) of the patients had lung cancer. The major postoperative problem was air leakage, which usually prolongs the tube time and the in-hospital stay, but a "no-touch fissure" technique significantly reduced the median tube time to 4 days and the postoperative hospital stay to 5 days. CONCLUSIONS: This study shows that VATS lobectomies can be performed using a standardized anterior approach with low rates of conversion and morbidity. A "no touch fissure" technique lowers the postoperative tube time, the in-hospital stay, and the number of patients with prolonged air leakage. A uniform anterior approach facilitates VATS lobectomy and makes this advanced procedure more easily adaptable by many surgeons familiar with an open anterior approach. The findings show that VATS lobectomy can be performed safely for a large proportion of lung cancer patients. PMID- 20927544 TI - Transanal endoscopic microsurgery for 135 patients with small nonadvanced low rectal cancer (iT1-iT2, iN0): short- and long-term results. AB - BACKGROUND: Local excision of rectal cancer as an alternative to radical resection for patients with small nonadvanced low rectal cancer (SNALRC) (iT1 iT2, iN0) is debated. This study aimed to analyze the short- and long-term results for a series of 135 patients with SNALRC who underwent local excision by transanal endoscopic microsurgery (TEM). METHODS: According to the study protocol, 135 patients classified by endorectal ultrasound, magnetic resonance imaging (MRI), and computed tomography (CT) imaging as having iT1 iN0 iM0 (n = 51) or iT2 iN0 iM0 (n = 84) low rectal cancer were enrolled in the study. All the patients with iT2 rectal cancer underwent neoadjuvant therapy. The definitive histologic findings showed 24 pT0 patients (17.8%), 66 pT1 patients (48.8%), and 45 pT2 patients (33.4%). RESULTS: Minor complications were observed in 12 patients (8.8%) and major complications in 2 patients (1.5%). During a median follow-up period of 97 months (range, 55-139 months), local recurrences occurred for four patients and distant metastases for two patients. The patients who experienced a recurrence had been preoperatively staged as iT2 and were low or nonresponders to neoadjuvant treatment (ypT2). At the end of the follow-up period, the disease-free survival rates were 100% for the iT1 patients and 93% for the iT2 patients CONCLUSIONS: The long-term results for adequate local excision by TEM with or without neoadjuvant radiochemotherapy in the treatment of SNALRC based on the current study protocol are not inferior to those reported in the literature for radical surgery with total mesorectal excision (TME). PMID- 20927545 TI - Single-incision laparoscopic appendectomy using conventional instruments: an initial experience using a novel technique. AB - BACKGROUND: Laparoscopic appendectomy has gained wide acceptance. This study aimed to evaluate the feasibility, safety, and cosmetic results of a novel technique: single incision laparoscopic (SIL) appendectomy. METHODS: The study enrolled consecutive patients undergoing appendectomy for acute appendicitis. Appendectomy was performed using three trocars and conventional laparoscopic instruments through a single small umbilical incision (length, ~3 cm). The patients received standard pre- and postoperative care and presented for a follow up visit after a mean of 27 days. RESULTS: The study cohort consisted of 26 patients (10 women and 16 men) with an average age of 44 years (range, 13-83 years). Of 26 appendectomies, 22 (85%) were achieved through a single surgical site. The mean SIL appendectomy operative time was 58 min (range, 33-107 min). No operative complications occurred. The average postoperative hospital stay was 1.2 days for nonperforated appendicitis and 2.7 days for perforated appendicitis. At the follow-up visit, no patient showed any evidence of incisional hernia. The operative incisions were minimally visible, and all the individuals reported a highly favorable cosmetic outcome. CONCLUSIONS: The results of the study demonstrated that laparoscopic appendectomy can be achieved through a single umbilical incision using conventional instruments and that this approach is successful, safe, and aesthetic. PMID- 20927546 TI - Safety, efficacy, and cost-effectiveness of common laparoscopic procedures. AB - BACKGROUND: Laparoscopic surgery has been shown to offer superior surgical outcomes for most abdominal surgical procedures. However, there is hardly any evidence on surgical outcomes with patient risk stratification. This study aimed to compare outcomes of common laparoscopic and open surgical procedures for varying illness severity. METHODS: A retrospective analysis of surgical outcomes for six commonly performed surgical procedures including cholecystectomy, appendectomy, reflux surgery, gastric bypass surgery, ventral hernia repair, and colectomy was performed using the University HealthSystem Consortium (UHC) Clinical Database/Resource Manager (CDB/RM). The 3-year discharge data for the six commonly performed laparoscopic surgical procedures were analyzed for outcome measures including observed mortality, overall patient morbidity, intensive care unit (ICU) admissions, 30-day readmissions, length of hospital stay, and hospital costs. RESULTS: In this study, 208,314 patients underwent one of six common surgical procedures by either the open or the laparoscopic approach. Overall, the laparoscopic approach showed significantly lower mortality, reduced morbidity, fewer ICU admissions and 30-day readmissions, shorter hospital stay, and significantly reduced hospital costs for all the procedures. At stratification by illness severity, the laparoscopic group showed better or comparable surgical outcomes across all the illness severity groups. However, the observed mortality was comparable for the minor and moderate severity patients between laparoscopic and open surgery for most procedures. The 30-day readmission rate for major/extreme severity patients was comparable between the two groups for most surgical procedures. CONCLUSIONS: This study demonstrated the superiority of laparoscopy over conventional open surgery across all illness severity risk groups for common surgical procedures. The results in general show that laparoscopic surgery is safe, efficacious, and cost-effective compared with open surgery and suggest that laparoscopic surgery should be the procedure of choice for all common surgical procedures, regardless of illness severity. PMID- 20927547 TI - Video. Laparoscopic dissection of Denonvilliers' fascia and implications for total mesorectal excision for treatment of rectal cancer. AB - AIM: To inspect Denonvilliers' fascia and its relationship with neighboring oncologically and functionally important anatomic structures by laparoscopic approach. METHODS: A total of 112 patients with middle or low rectal cancer were successfully treated by laparoscopic total mesorectal excision (TME). Digital versatile disk (DVD) recordings were retrieved for scrutiny of the whole dissection process of Denonvilliers' fascia and its contiguous anatomic structures. RESULTS: As highlighted in the attached video footage, for nearly all male patients (91%, n = 58), the boundaries of Denonvilliers' fascia could be clearly recognized by laparoscopy. Denonvilliers' fascia, varying in nature from a fragile translucent fibrous layer to a tough leathery membrane, manifests itself as a trapezoidal "apron" covering the glistening fatty tissues of the anterior mesorectum. Anterior dissection in TME can be efficiently continued downwards "in front of" Denonvilliers' fascia. When the prostate is reached, the natural surgical plane halts, and the dissection plane should be shifted to behind this fascia. In contrast, in female patients, Denonvilliers' fascia was much less obvious as a distinct fibrous layer than in male patients. The most appropriate term for the structure in between the rectum and vagina may be rectovaginal septum, in which there is no natural surgical plane, rather than Denonvilliers' fascia. CONCLUSIONS: By laparoscopic approach, the nature of Denonvilliers' fasciae in male and female patients can be better defined and facilitates more precise laparoscopic total mesorectal excision for rectal cancer. PMID- 20927548 TI - Comparative study of balloon and metal olive dilators for endoscopic management of benign anastomotic rectal strictures: clinical and cost-effectiveness outcomes. AB - BACKGROUND: Postoperative anastomotic strictures frequently complicate colorectal resection. Currently, various endoscopic techniques are being employed in their management, but the establishment of an optimal therapeutic strategy is still pending. The purpose of our study is to compare through-the-scope (TTS) balloon dilators versus Eder-Puestow metal olive dilators in the treatment of postoperative benign rectal strictures, considering the clinical outcome and cost effectiveness of each method. METHODS: A total of 39 patients with benign anastomotic rectal stenosis were retrospectively studied. In group A, 15 patients underwent dilation with Eder-Puestow metal olives, while in group B 19 patients were treated by means of TTS balloon dilators. The technical and clinical success of dilation, complications, number of repeated sessions required, disease-free time intervals, and the overall cost of each procedure were evaluated. RESULTS: Dilations were technically successful in all patients. No major complications occurred in either group. The number of dilations needed, rate of stricture recurrence, and duration of stenosis-free time intervals were not statistically significantly different between the two groups. Both methods proved more effective in older patients, given the greater number of dilations required in younger patients of both groups and higher frequency of stricture relapse in younger balloon-dilated patients (median 64.00 years) compared with older ones (median 75.00 years) (p = 0.001). An indisputable advantage of the Eder-Puestow technique, compared with TTS balloon dilators, is the low cost of equipment (median 22.30 compared with 680 , respectively; p < 0.001). CONCLUSION: Endoscopic dilation of postoperative benign rectal strictures is equally effective and safe, especially in older patients, when performed by Eder Puestow bougies or TTS balloon dilators. However, metal olivary tips seem to surpass balloon dilators when considering the obvious economical benefits of the first method. PMID- 20927549 TI - Retention of laparoscopic procedural skills acquired on a virtual-reality surgical trainer. AB - BACKGROUND: Virtual-reality (VR) simulator training has been shown to improve surgical performance in laparoscopic procedures in the operating room. We have, in a randomised controlled trial, demonstrated transferability to real operations. The validity of the LapSim virtual-reality simulator as an assessment tool has been demonstrated in several reports. However, an unanswered question regarding simulator training is the durability, or retention, of skills acquired during simulator training. The aim of the present study is to assess the retention of skills acquired using the LapSim VR simulator, 6 and 18 months after an initial training course. METHODS AND MATERIALS: The investigation was designed as a 6- and 18-month follow-up on a cohort of participants who earlier participated in a skills training programme on the LapSim VR. The follow-up cohort consisted of trainees and senior consultants allocated to two groups: (1) novices (experience < 5 procedures, n = 9) and (2) experts (experience > 200 procedures during the past 3 years, n = 10). Each participant performed ten sessions. Assessment of skills was based on time, economy of movement and the error parameter "bleeding". The novice group were re-tested after 6 and 18 months, whereas the expert group were only retested once, after 6 months. None of the novices performed laparoscopic surgery in the follow-up period. The experts continued their daily work with laparoscopic surgery. RESULTS AND CONCLUSIONS: Novices showed retention of skills after 6 months. After 18 months, novices' laparoscopic skills had returned to the pre-training level. This indicates that laparoscopic skills seemed to deteriorate in the period between 6 and 18 months without training. Experts showed consistent performance over time. This information can be included when planning training curricula in minimal invasive surgery. PMID- 20927550 TI - Management of postoperative nausea and vomiting in patients undergoing laparoscopic cholecystectomy. AB - The common and distressing complications of postoperative nausea and vomiting (PONV) are the main concern of 40-70% of patients undergoing laparoscopic cholecystectomy (LC). The first step in preventing PONV after LC is to reduce the risk factors involving patient characteristics, surgical procedure, anesthetic technique, and postoperative care. Particularly, the use of propofol-based anesthesia can reduce the incidence of PONV after LC. Second, prophylactic antiemetics including antihistamines (dimenhydrinate), phenothiazines (perphenazine), butyrophenones (droperidol), benzamides (metoclopramide), dexamethasone, and serotonin receptor antagonists (ondansetron, granisetron, tropisetron, dolasetron, and ramosetron) are available for preventing PONV after LC. Third, antiemetic therapy combined with a serotonin receptor antagonist (ondansetron, granisetron) and droperidol or dexamethasone is highly effective in the prevention of PONV after LC. Fourth, acupressure at the P6 point is a nonpharmacologic technique that is as effective as ondansetron for preventing PONV after LC. Knowledge regarding the risk factors for PONV and antiemetics is needed for the management of PONV after LC. PMID- 20927551 TI - Video. "No scar" small bowel resection in a survival porcine model using transcolonic NOTES((r)) and transabdominal approach. AB - BACKGROUND: Fundamental techniques and essential tools for performing "no scar" surgery still need to be developed. Our study was designed to evaluate the feasibility of performing small bowel resection by transcolonic NOTES((r)) and transabdominal approach using rigid laparoscopic and flexible endoscopic instruments. METHODS: One non survival and four survival experiments were performed using a porcine model. The endoscope with an overtube was advanced into the peritoneal cavity through the colotomy. Mini-laparoscopic instruments were placed through the abdominal wall under the endoscopic observation. The endoscope was replaced with a rigid linear stapler. The small bowel was identified. The segment of the small bowel was resected by firing the endo stapler, and extracted through the colon. The two limbs of the small bowel were approximated with two stay-sutures. An enterotomy was then created on the antimesenteric sides of each line. A side-to-side anastomosis was performed with another application of the endo stapler. The stapler was withdrawn. The enterotomy was closed by suturing. The colotomy was closed with endoclips and the endoscope was withdrawn. The mini laparoscopic instruments were removed. RESULTS: Small bowel resection was successfully performed in all animals. The surgery time was 70 minutes. There was no mortality or complications. The animals recovered uneventfully, and survived the 2 weeks postprocedure period. They remained healthy, and gained weight. Necropsy was performed 2 weeks after the surgery. On necropsy, evaluation of the abdominal skin revealed no scars. The peritoneal cavity was examined. No signs of infection, bleeding, perforations, and adhesions were noted. Endoscopic examination of the colotomy and anastomosis revealed complete healing that was confirmed by histopathology. CONCLUSIONS: The study has demonstrated the feasibility of small bowel resection using transcolonic NOTES((r)) and transabdominal approach. Simultaneous use of flexible endoscopic and rigid laparoscopic instruments in NOTES((r)) is not only feasible but has significant advantages and greatly facilitates the performance of the operation, yet leaves no scars. PMID- 20927553 TI - Fatal renal failure caused by Cortinarius mushrooms. PMID- 20927556 TI - Pharyngoesophageal diverticulum: a delayed complication of anterior cervical spine surgery. AB - Pharyngoesophageal diverticulum after anterior cervical spine surgery is a rarely reported but potentially life-threatening complication. A case report of pharyngoesophageal diverticulum 7 years after anterior cervical spine surgery is presented. The patient suffered from dysphagia, odynophagia, recurrent fever, weight loss, and also an impressive bulging in the neck with swallowing. After careful examination and preparation, he underwent revision surgery via an open procedure, had the implants removed, pouch excised, and esophagus reconstructed reinforced by a sternohyoid muscle flap as well as an omohyoid muscle flap. The post-operative period was uneventful, and he experienced a satisfactory recovery. At last follow up, 2.5 years post surgery, the patient remained symptom free. Upon review of the literature, only six such previous reports with seven cases were found. Diagnostic tools, possible mechanism, correlative factors and treatment are discussed. This patient was fortunate that although his symptoms developed long after the initial anterior cervical operation and the pouch grew impressively large almost perforating, he still recovered well. It again proves the necessity of long-term X-ray follow up, and also reminds the surgeons to be alert of the possibility of esophageal injury even when the esophageal symptoms are mild and occur long after the initial operation. PMID- 20927554 TI - Preventing chemotherapy-induced hepatitis B reactivation in breast cancer patients: a prospective comparison of prophylactic versus deferred preemptive lamivudine. AB - PURPOSE: Prophylactic lamivudine to prevent chemotherapy-induced hepatitis B virus (HBV) reactivation has been widely adopted in hematological cancer patients. We examined the deferred preemptive strategy, upon rising viremia, in breast cancer (BC) patients based on sensitive serum HBV DNA level monitoring in a non-randomized controlled study. PATIENTS AND METHODS: Baseline virological profiles before cytotoxic chemotherapy were retrospectively analyzed in historical BC and non-BC patients. A prospective cohort study, including 22 early BC patients (Group I) who were hepatitis B surface antigen (HBsAg)+/- and required adjuvant chemotherapy, were enrolled and had deferred preemptive use of lamivudine upon viremic surge. During the study period, another 23 BC patients, who did not participate in the above-mentioned study, received prophylactic use of lamivudine as routine practice (Group 2). Chemotherapy-induced hepatitis events and the lamivudine treatment course were compared. RESULTS: There was no significant difference in the incidence of hepatitis during chemotherapy between these two groups. Patients in Group I had statistically significant shorter duration of lamivudine use during chemotherapy. However, once lamivudine had been initiated, the treatment course is not significantly shorter than those patients given prophylactically. CONCLUSIONS: Deferred preemptive strategy is feasible to control HBV replication and prevent its reactivation in BC patients undergoing chemotherapy. However, it may not be superior to prophylactic strategy and clinically practical. PMID- 20927557 TI - Minimally invasive or open transforaminal lumbar interbody fusion as revision surgery for patients previously treated by open discectomy and decompression of the lumbar spine. AB - Minimally invasive lumbar fusion techniques have been developed in recent 20 years. The goals of these procedures are to reduce approach-related soft tissue injury, postoperative pain, and disability while allowing the surgery to be conducted in an effective manner. There have been no prospective clinical reports published on the comparison of minimally invasive transforaminal lumbar interbody fusion as revision surgery for patients previously treated by open discectomy and decompression or a traditional open approach. A prospective clinical study was performed by evaluating the clinical and radiographic results of minimally invasive transforaminal lumbar interbody fusion as an alternative new technique in the revision surgery for patients previously treated by open procedure. 52 patients (28 M, 24 F) with an average age of 55.7 (31-76) were prospectively evaluated. All patients who had previous discectomy (n = 13), hemilaminectomy (n = 16), laminectomy (n = 12) and facetectomy (n = 11) underwent monosegmental and bisegmental minimally invasive transforaminal lumbar interbody fusion (MiTLIF) (n = 25) or open transforaminal lumbar interbody fusion (OTLIF) (n = 27) by two experienced surgeons at one hospital, from March 2006 to October 2008 (minimum 12 month follow-up). The following data were compared between the two groups: the clinical and radiographic results, operative time, blood loss, X-ray exposure time, postoperative back pain, and complications. Clinical outcome was assessed using the visual analogue scale and the Oswestry disability index (ODI). The operative time and clinical and radiographic results were basically identical in both groups. Comparing with the OTLIF group, the MiTLIF group had significantly less blood loss and less postoperative back pain at the second day postoperatively. The radiation time was significantly longer in the MiTLIF group. Complications included three cases of small dural tear in the MiTLIF group. There were five cases of dural tear and two cases of superficial wound infection in the OTLIF group. One case of nonunion was observed from each group. Minimally invasive TLIF is a safe and effective procedure for treatment of selected revision patients previously treated by open surgery with some potential advantages. However, this technique needs longer X-ray exposure time. PMID- 20927558 TI - Surgical site infection associated with the use of bovine serum albumine glutaraldehyde surgical adhesive (BioGlue) in cranial surgery: a case-control study. AB - PURPOSE: To enhance the water tightness of dura mater closure in cranial surgery, an organic glue called BioGlue was used in our neurosurgical department between January 2006 and June 2007. During this period of time, we noticed an important increase in the surgical site infection (SSI) incidence. We conducted a case control study to identify risk factors for these infections. Our objective was to test the hypothesis that BioGlue was one of the risk factors. METHODS: Cases with infection were defined retrospectively. We included two controls per case. Study data were age, sex, time of year, in stay hospital preoperative time, length of surgery, type of surgery, surgeon, use of BioGlue, and use of duraplasty. We first performed a univariate analysis and then the significant variables were introduced in a logistic regression model. RESULTS: Thirty patients were defined as cases (60 controls). In multivariate analysis, risk factors were young age (p = 0.04), extended operative length (p = 0.02) and the use of BioGlue (p = 0.007). The combined use of BioGlue and Neuropatch appeared to be a significant risk factor for SSI (p = 0.002). CONCLUSIONS: BioGlue seems to increase the risk of SSI for patients who underwent craniotomy, especially when associated with synthetic dural graft. BioGlue triggers an intense inflammatory response, which causes wound breaches allowing bacteria to spread down in the wound, and then creates an ideal environment for bacterial growth. PMID- 20927559 TI - Cardiac 123I-MIBG scintigraphy as an outcome-predicting tool for subthalamic nucleus stimulation in Parkinson's disease. AB - BACKGROUND: 123I-meta-iodobenzylguanidine (MIBG) myocardial scintigraphy is a useful tool for differentiating idiopathic Parkinson's disease (PD) from other parkinsonian syndromes, but its prognostic value in PD has not been established. The objective of this study was to clarify the correlation between cardiac MIBG uptake parameters and the outcome in PD patients subjected to the subthalamic nucleus stimulation. METHOD: We enrolled 31 consecutive PD patients and calculated the heart-to-mediastinum ratio (H/M) and washout rate (WR) based on the activity measured at 15 min (early phase) and 3 h (delayed phase) after the intravenous injection of MIBG (111 MBq). Cardinal motor symptoms and activity of daily living (ADL) were assessed on the Unified Parkinson's Disease Rating Scale (UPDRS) and Schwab and England (S-E) ADL scale, before and 3 months after surgery. FINDINGS: Neither early nor delayed H/M correlated with any of the preoperative subscores on the UPDRS or S-E, nor with postoperative outcome. On the other hand, increased WR was a positive predictor for postoperative improvement rate on S-E in medication-off state (p = 0.00003). Also, WR showed a more faint but significant correlation with preoperative levodopa responsiveness on S-E (p = 0.008). CONCLUSION: Our findings suggest that 123I-MIBG scintigraphy in combination with levodopa-responsiveness evaluation may represent a useful tool for prediction of outcomes in patients subjected to STN stimulation. PMID- 20927560 TI - Venous anastomotic circle, multiple varices and oculomotor palsy--a rare coincidence. AB - Oculomotor nerve palsy due to a venous varix arising from flow anomalies caused by a dural arteriovenous fistula (AVF) is a rare phenomenon. We report a case of surgical third nerve palsy with a rare underlying AVF as the cause and discuss in detail the patho-anatomy and its significance. A tentorial dural AVF mimicking the arterial circle was found with multiple varix formation causing compressive oculomotor palsy. This was treated successfully with OnyxTM injection with a satisfactory angiographic result and complete resolution of symptoms. PMID- 20927561 TI - Reversible encephalopathy induced by cefoperazone: a case report monitored with EEG. AB - In patients with an impaired state of consciousness, EEG is fundamental, a correct neurological work-up. Cephalosporins have been identified as a case of triphasic waves' (TW) reversible encephalopathy. We report a case of an acute reversible encephalopathy with TWs during treatment with cefoperazone. We report the occurrence and regression of a confusional state with TWs encephalopathy at EEG after the administration of cefoperazone for urinary tract infection in a patient admitted for syncope. In conclusion, cefoperazone should be considered as a cause of toxic encephalopathy with EEG TWs, when there is a temporal relationship with its administration; EEG monitoring is useful in the neurological follow-up. PMID- 20927562 TI - Vitamin B12 deficiency associated with symptoms of frontotemporal dementia. AB - We report the case of an elderly patient with cobalamin deficiency who progressively developed cognitive and behavioral symptoms associated with neuropsychiatric disturbances. His neuropsychological profile showed many features suggestive for a frontal-dysexecutive syndrome and was related to a predominant asymmetric (right > left) frontal lobe hypoperfusion. He completely recovered after a treatment with vitamin B12 and follow-up of 7 years showed that his improvement remained stable. Along with the other cases reported in the literature, our case also proves that there are some cases of vitamin B12 deficiency that can manifest with the symptoms of frontotemporal dementia and that they are completely reversible after substitution therapy. PMID- 20927563 TI - A rare Von Hippel-Lindau disease that mimics acute myelitis: case report and review of the literature. AB - Von Hippel-Lindau disease (VHL) comprises a series of complicated clinical manifestations. We hereby report one unique case of VHL with a natural history that mimics acute myelitis. MRI and biopsy in this patient showed multiple solid hemangioblastomas of the central nervous system and kidney. This study further confirmed that VHL is of highly clinical, imaging, and pathological heterogeneity. Diagnosis for VHL should be based on combination of clinical, radiological, pathological, and genetic data. PMID- 20927564 TI - Medical-grade honey enriched with antimicrobial peptides has enhanced activity against antibiotic-resistant pathogens. AB - Honey has potent activity against both antibiotic-sensitive and -resistant bacteria, and is an interesting agent for topical antimicrobial application to wounds. As honey is diluted by wound exudate, rapid bactericidal activity up to high dilution is a prerequisite for its successful application. We investigated the kinetics of the killing of antibiotic-resistant bacteria by RS honey, the source for the production of Revamil(r) medical-grade honey, and we aimed to enhance the rapid bactericidal activity of RS honey by enrichment with its endogenous compounds or the addition of antimicrobial peptides (AMPs). RS honey killed antibiotic-resistant isolates of Pseudomonas aeruginosa, Staphylococcus epidermidis, Enterococcus faecium, and Burkholderia cepacia within 2 h, but lacked such rapid activity against methicillin-resistant S. aureus (MRSA) and extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli. It was not feasible to enhance the rapid activity of RS honey by enrichment with endogenous compounds, but RS honey enriched with 75 MUM of the synthetic peptide Bactericidal Peptide 2 (BP2) showed rapid bactericidal activity against all species tested, including MRSA and ESBL E. coli, at up to 10-20-fold dilution. RS honey enriched with BP2 rapidly killed all bacteria tested and had a broader spectrum of bactericidal activity than either BP2 or honey alone. PMID- 20927565 TI - An unusual cause of hemoptysis: costocervical trunk pseudoaneurysm. PMID- 20927567 TI - Mitochondrial DNA replication and disease: insights from DNA polymerase gamma mutations. AB - DNA polymerase gamma (pol gamma), encoded by POLG, is responsible for replicating human mitochondrial DNA. About 150 mutations in the human POLG have been identified in patients with mitochondrial diseases such as Alpers syndrome, progressive external ophthalmoplegia, and ataxia-neuropathy syndromes. Because many of the mutations are described in single citations with no genotypic family history, it is important to ascertain which mutations cause or contribute to mitochondrial disease. The vast majority of data about POLG mutations has been generated from biochemical characterizations of recombinant pol gamma. However, recently, the study of mitochondrial dysfunction in Saccharomyces cerevisiae and mouse models provides important in vivo evidence for the role of POLG mutations in disease. Also, the published 3D-structure of the human pol gamma assists in explaining some of the biochemical and genetic properties of the mutants. This review summarizes the current evidence that identifies and explains disease causing POLG mutations. PMID- 20927568 TI - Evidence that alpha-lipoic acid inhibits NF-kappaB activation independent of its antioxidant function. AB - OBJECTIVE: alpha-Lipoic acid (LA) exerts beneficial effects in cardiovascular diseases though its antioxidant and/or anti-inflammatory functions. It is postulated that the anti-inflammatory function of LA results from its antioxidant function. In this study we tested whether inhibition of NF-kappaB by LA is dependent on its antioxidant function. METHODS: Human umbilical vein endothelial cells (HUVECs) were treated with tumor necrosis factor-alpha (TNFalpha) in the presence of various antioxidants, including LA, tiron, apocynin, and tempol. The activation of the nuclear factor-kappaB (NF-kappaB) signaling pathway was then analyzed. RESULTS: LA, but not other tested antioxidants, inhibited TNFalpha induced inhibitor-kappaB-alpha (IkappaBalpha) degradation and VCAM-1 and COX2 expression in HUVECs. Although LA activated the phosphatidylinositol-3-kinase (PI3-kinase)/Akt pathway in HUVECs, inhibition of Akt by LY294002 did not affect inhibition of TNFalpha-induced IkappaBalpha degradation by LA. In transient co transfection assays of a constitutively active mutant of IkappaB kinase-2 (IKK2), IKK2(EE), and a NF-kappaB luciferase reporter construct, LA dose-dependently inhibited IKK2(EE)-induced NF-kappaB activation in addition to inhibiting IKK activity in in vitro assays. Consistent with the effect on luciferase expression, LA inhibited IKK2(EE)-induced cyclo-oxygenase-2 (COX2) expression, suggesting that IKK2 inhibition by LA may be a relevant mechanism that explains its anti inflammatory effects. CONCLUSIONS: LA inhibits NF-kappaB activation through antioxidant-independent and probably IKK-dependent mechanisms. PMID- 20927569 TI - Outcome of treatment and parameters influencing recurrence in patients with bisphosphonate-related osteonecrosis of the jaws. AB - PURPOSE: Bisphosphonate-related osteonecrosis of the jaws (BRONJ) is now a well recognised entity which is difficult to manage and often recurs. The aim of this study was to examine the success of resection of the necrotic bone and identify risk factors for recurrence in these patients. METHODS: One hundred and eight patients were evaluated prospectively and investigated at least twice. Multiple logistic regression analysis was used to determine factors independently associated with the dependent variable of recurrence of BRONJ. RESULTS: Factors influencing the development of recurrence of BRONJ were the presence of bacterial bone infection of the necrotic area (P = 0.011), type of treatment (either conservative or surgical, P = 0.001) with a lower recurrence rate for surgically treated patients, extent of surgical treatment with better outcome in larger resections (P < 0.0001), number of debridements performed (P < 0.0001), and the extent of radiographic appearance of osteolysis assessed by dental panoramic tomogram (P = 0.028). CONCLUSIONS: An increased risk for recurrence can be found in cases with bacterial bone infection of the necrotic area, type of conservative or surgical treatment, extent of surgical treatment with better outcome in larger resections, and the number of debridements performed. Microvascular tissue transfer should be considered in selected cases if other options have been exhausted. PMID- 20927570 TI - Stripe-like increase of rCBV beyond the visible border of glioblastomas: site of tumor infiltration growing after neurosurgery. AB - We observed a stripe-like pattern of regional cerebral blood volume (rCBV) increase in a defined region adjacent to the contrast enhancement (CE) on MRI of glioblastomas (GBM) that we defined as the "striate sign" (SS). We hypothesized that the SS marks infiltration of GBM outside the CE volume transforming into future CE tumor in the follow-up. T2*-weighted dynamic susceptibility-weighted CE (DSC)-MRI, and T1 and T2-weighted images (WI) of 16 patients with GBM were retrospectively evaluated in a baseline MRI performed before neurosurgery. In seven of these patients we also performed a (1)H MR spectroscopic imaging ((1)H MRSI). The regions of interest (ROI) delineating the SS were defined on rCBV maps for each patient. ROIs were overlaid on follow-up T1-WI and T2-WI MRI performed 3, 6, and 9 months after neurosurgery. Size and maximum signal intensity (max SI) of de novo CE within the area of the SS were analyzed. Statistical analysis was performed with the Friedman test (P < 0.05). In 15/16 patients de novo CE completely covered the area of the SS within nine months. Normalized max SI of de novo CE of the 3, 6, and 9-months follow-up MR examinations were significantly higher than in the baseline MRI (P < 0.001). Normalized choline was increased within the SS in all patients with de novo CE (n = 6). De-novo CE appeared within the SS in all patients (96% of all slices). This implies that the SS might indicate the site of future CE tumor, which represents the area of tumor growth after neurosurgery. PMID- 20927566 TI - The gap gene network. AB - Gap genes are involved in segment determination during the early development of the fruit fly Drosophila melanogaster as well as in other insects. This review attempts to synthesize the current knowledge of the gap gene network through a comprehensive survey of the experimental literature. I focus on genetic and molecular evidence, which provides us with an almost-complete picture of the regulatory interactions responsible for trunk gap gene expression. I discuss the regulatory mechanisms involved, and highlight the remaining ambiguities and gaps in the evidence. This is followed by a brief discussion of molecular regulatory mechanisms for transcriptional regulation, as well as precision and size regulation provided by the system. Finally, I discuss evidence on the evolution of gap gene expression from species other than Drosophila. My survey concludes that studies of the gap gene system continue to reveal interesting and important new insights into the role of gene regulatory networks in development and evolution. PMID- 20927571 TI - The effect of crystallizing and non-crystallizing cosolutes on succinate buffer crystallization and the consequent pH shift in frozen solutions. AB - PURPOSE: To effectively inhibit succinate buffer crystallization and the consequent pH changes in frozen solutions. METHODS: Using differential scanning calorimetry (DSC) and X-ray diffractometry (XRD), the crystallization behavior of succinate buffer in the presence of either (i) a crystallizing (glycine, mannitol, trehalose) or (ii) a non-crystallizing cosolute (sucrose) was evaluated. Aqueous succinate buffer solutions, 50 or 200 mM, at pH values 4.0 or 6.0 were cooled from room temperature to -25 degrees C at 0.5 degrees C/min. The pH of the solution was measured as a function of temperature using a probe designed to function at low temperatures. The final lyophiles prepared from these solutions were characterized using synchrotron radiation. RESULTS: When the succinic acid solution buffered to pH 4.0, in the absence of a cosolute, was cooled, there was a pronounced shift in the freeze-concentrate pH. Glycine and mannitol, which have a tendency to crystallize in frozen solutions, remained amorphous when the initial pH was 6.0. Under this condition, they also inhibited buffer crystallization and prevented pH change. At pH 4.0 (50 mM initial concentration), glycine and mannitol crystallized and did not prevent pH change in frozen solutions. While sucrose, a non-crystallizing cosolute, did not completely prevent buffer crystallization, the extent of crystallization was reduced. Sucrose decomposition, based on XRD peaks attributable to beta-D glucose, was observed in frozen buffer solutions with an initial pH of 4.0. Trehalose completely inhibited crystallization of the buffer components when the initial pH was 6.0 but not at pH 4.0. At the lower pH, the crystallization of both trehalose dihydrate and buffer components was evident. CONCLUSION: When retained amorphous, sucrose and trehalose effectively inhibited succinate buffer component crystallization and the consequent pH shift. However, when trehalose crystallized or sucrose degraded to yield a crystalline decomposition product, crystallization of buffer was observed. Similarly, glycine and mannitol, two widely used bulking agents, inhibited buffer component crystallization only when retained amorphous. In addition to stabilizing the active pharmaceutical ingredient, lyoprotectants may prevent solution pH shift by inhibiting buffer crystallization. PMID- 20927572 TI - Diagnosis of arthritis through fuzzy inference system. AB - Expert or knowledge-based systems are the most common type of AIM (artificial intelligence in medicine) system in routine clinical use. They contain medical knowledge, usually about a very specifically defined task, and are able to reason with data from individual patients to come up with reasoned conclusion. Although there are many variations, the knowledge within an expert system is typically represented in the form of a set of rules. Arthritis is a chronic disease and about three fourth of the patients are suffering from osteoarthritis and rheumatoid arthritis which are undiagnosed and the delay of detection may cause the severity of the disease at higher risk. Thus, earlier detection of arthritis and treatment of its type of arthritis and related locomotry abnormalities is of vital importance. Thus the work was aimed to design a system for the diagnosis of Arthitis using fuzzy logic controller (FLC) which is, a successful application of Zadeh's fuzzy set theory. It is a potential tool for dealing with uncertainty and imprecision. Thus, the knowledge of a doctor can be modelled using an FLC. The performance of an FLC depends on its knowledge base which consists of a data base and a rule base. It is observed that the performance of an FLC mainly depends on its rule base, and optimizing the membership function distributions stored in the data base is a fine tuning process. PMID- 20927573 TI - Arkansas People Participating in Lead Education (APPLE): results of a lead-safe training program. AB - Lead is still seen as one of the most harmful environmental toxins for young children, with the predominant source being deteriorating lead-based paint. Those at continued risk include those living in homes built before 1978, renovators and remodelers, and especially those with limited access to proper healthcare and diets. Proper training on lead-safe work practices focused on preventing and reducing the spread of lead dust can help reduce lead exposure. Presented in this paper are experiences in delivering lead-safe work practices training in six Arkansas cities, and results from pre- and post- surveys delivered before and immediately after the training. Pre- and post-surveys assess strong and weak areas of training. Participants demonstrated positive shifts in attitude and behavior towards lead-safe work practices following training. However, our research found that more emphasis should be focused on clarifying current lead exposure sources and routes for children. PMID- 20927574 TI - Improving the alcohol retail environment to reduce youth access: a randomized community trial of a best practices toolkit intervention. AB - Underage alcohol use remains a significant public health problem throughout the United States and has important consequences for the health of individuals and communities. The objective of this study was to assess the impact of distributing an alcohol retailer toolkit via direct mail on increasing positive alcohol retailer attitudes towards checking IDs, encouraging retail managers to formalize ID checking procedures with their employees, and promoting consumers to be prepared to show ID when purchasing alcohol. This community randomized study included five matched Massachusetts community pairs. Our analysis sample consisted of 209 retailers (77 intervention; 132 control). In models adjusted for baseline response and matching community and establishment characteristics, intervention communities reported posting, on average, one additional sign or wall decal in their establishments (beta = 0.937, P = 0.0069), and a twofold higher odds of handing out written materials on ID checking to staff (OR: 2.074, 95%CI: 1.003-4.288) compared to control establishments. However, the intervention was not found to have an effect on changing establishment policies, retailer attitudes, or other establishment practices. Intervention retailers perceived all components of the toolkit to be very useful for their establishments, and nearly all reported having shared materials with their employees and customers. These results suggest that some significant changes in alcohol retailer establishment practices can be achieved among motivated owners or managers through the distribution of a toolkit targeting best retailer practices. We do, however, recommend that future program planners consider alternative dissemination and marketing strategies beyond direct mail to encourage greater utilization. PMID- 20927575 TI - Genetic counseling for early-onset familial Alzheimer disease in large Aboriginal kindred from a remote community in British Columbia: unique challenges and possible solutions. AB - A novel, pathogenic presenilin 1 (PS1) mutation has recently been identified in a large Aboriginal kindred living in dispersed communities throughout British Columbia, Canada. Disseminating genetic information and ensuring that appropriate genetic counseling services are provided to all concerned relatives have posed several unique challenges. These challenges include knowledge exchange and continuity of care in a geographically remote and culturally distinct community. To our knowledge, this is the first time a specific genetic counseling approach has been needed for early-onset familial Alzheimer disease (EOFAD) in a North American Aboriginal community. PMID- 20927576 TI - Interacting oscillations in neural control of breathing: modeling and qualitative analysis. AB - In mammalian respiration, late-expiratory (late-E, or pre-inspiratory) oscillations emerge in abdominal motor output with increasing metabolic demands (e.g., during hypercapnia, hypoxia, etc.). These oscillations originate in the retrotrapezoid nucleus/parafacial respiratory group (RTN/pFRG) and couple with the respiratory oscillations generated by the interacting neural populations of the Botzinger (BotC) and pre-Botzinger (pre-BotC) complexes, representing the kernel of the respiratory central pattern generator. Recently, we analyzed experimental data on the generation of late-E oscillations and proposed a large scale computational model that simulates the possible interactions between the BotC/pre-BotC and RTN/pFRG oscillations under different conditions. Here we describe a reduced model that maintains the essential features and architecture of the large-scale model, but relies on simplified activity-based descriptions of neural populations. This simplification allowed us to use methods of dynamical systems theory, such as fast-slow decomposition, bifurcation analysis, and phase plane analysis, to elucidate the mechanisms and dynamics of synchronization between the RTN/pFRG and BotC/pre-BotC oscillations. Three physiologically relevant behaviors have been analyzed: emergence and quantal acceleration of late E oscillations during hypercapnia, transformation of the late-E activity into a biphasic-E activity during hypercapnic hypoxia, and quantal slowing of BotC/pre BotC oscillations with the reduction of pre-BotC excitability. Each behavior is elicited by gradual changes in excitatory drives or other model parameters, reflecting specific changes in metabolic and/or physiological conditions. Our results provide important theoretical insights into interactions between RTN/pFRG and BotC/pre-BotC oscillations and the role of these interactions in the control of breathing under different metabolic conditions. PMID- 20927577 TI - A randomized trial of a group based cognitive behavior therapy program for older adults with epilepsy: the impact on seizure frequency, depression and psychosocial well-being. AB - Few studies have examined the effectiveness of cognitive behavior therapy to manage seizures and improve psychosocial functioning in older adults with epilepsy. This study evaluated the efficacy of a 6 week group CBT program in community dwelling adults with epilepsy who were aged over 60 years. A total of 37 participants were randomly assigned to either a CBT group or a control group. Measures of depression, dysthymia, psychosocial functioning and seizure frequency were completed at pre and post intervention. Seizure frequency was significantly reduced in the CBT group compared to the control group (Cohen's d 0.63). The results suggest that the relationship between seizure frequency and psychological and psychosocial well being in older adults requires further investigation. Although there were no significant between group differences on measures of depression and psychosocial functioning, both the CBT and control groups improved significantly from baseline. PMID- 20927578 TI - Light at night and breast cancer risk: results from a population-based case control study in Connecticut, USA. AB - OBJECTIVE: To investigate the potential association between domestic exposure to light at night (LAN) and the risk of human breast cancer. METHODS: A case-control study of female breast cancer was conducted in Connecticut. A total of 363 incident breast cancer cases and 356 age frequency-matched controls were interviewed using a standardized, structured questionnaire to obtain information on sleeping patterns and bedroom light environment. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by unconditional multivariate logistic regression. RESULTS: A non-significantly increased risk of breast cancer was observed among postmenopausal women for those keeping lights on while sleeping (OR = 1.4, 95% CI 0.7, 2.7), those who reported mainly sleeping in the daytime (OR = 1.4, 95% CI 0.5, 4.3), and those not drawing the curtains/window shades while sleeping at night (OR = 1.2, 95% CI 0.8, 1.9). CONCLUSION: The results from this study suggest a potential increased risk of breast cancer associated with domestic exposure to LAN. Further studies with larger sample size are needed to confirm the results. PMID- 20927579 TI - Anti-angiogenic effects of resveratrol mediated by decreased VEGF and increased TSP1 expression in melanoma-endothelial cell co-culture. AB - Resveratrol, a naturally occurring polyphenol, has been reported to be an anti tumor and chemopreventive agent. Recent data show that it may also exert anti angiogenic effects. We hypothesized that the anti-angiogenic activity of resveratrol may be caused by modulation of tumor cell release of thrombospondin-1 (TSP1) and vascular endothelial growth factor (VEGF) into the extracellular matrix, leading to vascular endothelial cell (VEC) apoptosis. We therefore evaluated the effects of resveratrol on melanoma cell lines co-cultured with vascular endothelial cells in monolayer and in three dimensional spheroids. We found that resveratrol stimulated isolated VEC proliferation, while it caused growth inhibition of VECs grown with melanoma cells in three-dimensional co culture. This effect was associated with increased melanoma cell expression of tumor suppressor protein 53 and matrix protein TSP1, as well as decreased hypoxia driven expression of hypoxia inducible factor-1alpha and inhibition of VEGF production. PMID- 20927582 TI - Mutations in BRCA2 and PALB2 in male breast cancer cases from the United States. AB - Male breast cancer (MBC) is an uncommon disease with a frequency of approximately one in 1000. Due to the rarity of MBC, it is understudied and its etiology is poorly understood. Our objectives are to determine the frequency of pathogenic mutations in BRCA2 and PALB2 in MBC cases and to investigate the correlations between mutation status and cancer phenotypes. Single strand conformation polymorphism analysis, direct sequencing, and multiplex ligation-dependent probe amplification were employed to screen for mutations in the BRCA2 gene, followed by direct sequencing of the PALB2 gene in BRCA2-negative MBC cases. Pathogenic BRCA2 mutations were identified in 18 of the 115 MBC cases, including four of the ten cases (40%) from breast cancer families and 14 of the 105 cases (13%) unselected for family history of breast cancer. The difference in BRCA2-mutation frequencies between cases with and without family history of breast cancer was not statistically significant (P = 0.145), suggesting that family history is not a strong predictor of carrying a mutation in males. We observed a highly significant association of carrying a pathogenic BRCA2 mutation with high tumor grade (P < 0.001) and a weak association with positive lymph nodes (P < 0.02). Of the 97 BRCA2-negative MBC cases, we identified one PALB2 mutation with confirmed pathogenicity and one mutation predicted to be pathogenic, a prevalence of pathogenic PALB2-mutation of 1-2%. Based on our results and previous studies, genetic testing for BRCA2 should be recommended for any diagnosed MBC case, regardless of family history of breast cancer. PMID- 20927583 TI - The non-breast-cancer death rate among breast cancer patients. AB - Non-breast-cancer deaths currently account for almost half of deaths among breast carcinoma patients in the 15 years following diagnosis. Understanding the trends of non-breast-cancer death is vital for calibrating treatment and survival expectations, and for understanding the consequences of potentially toxic therapies. To observe trends over time in non-breast-cancer relative survival-the non-breast-cancer survival rates of breast cancer patients relative to the non breast-cancer survival rates of the population as a whole, matched for gender, race, age, region, and year of diagnosis. Non-breast-cancer relative survival between breast carcinoma patients and the general population was measured using SEER public-use data of patients diagnosed with breast carcinoma between 1973 and 2007. Non-breast-cancer relative survival improved significantly from 1973 to the present. From 1986 onward, the non-breast-cancer survival rate among breast carcinoma patients is equal to, or slightly higher than, matched populations who did not have breast carcinoma. This improvement over time occurred across almost all patient stratifications, including race, age, tumor size, and nodal status. However, patients receiving full mastectomies, and patients not receiving radiotherapy experienced no increase in relative survival. The most dramatic relative survival improvements occurred in patients who received radiation and patients receiving partial mastectomies, and such improvements were seen even after controlling for changes in tumor size over time. Non-breast-cancer relative survival among breast carcinoma patients has improved significantly since 1973; breast cancer patients are currently no more likely to die of other causes than the general population. PMID- 20927584 TI - Physiological studies on the effect of copper nicotinate (Cu-N complex) on the fish, Clarias gariepinus, exposed to mercuric chloride. AB - Female catfish, Clarias gariepinus, were collected from the Nile River at Assiut region, were divided into 7 groups. The first group was left as control, and the second was treated with mercuric chloride (MC) for 3 weeks following by normal water for 1 week. The third, fourth and fifth groups were provided by MC (150 MUg/ l of water). This treatment was continued for 3 weeks. Then, the fish were received CN instead of MC, for 1 week, with 15 and 25 mg CN/100 g wet food. The fifth fish group received diet supplemented with vit E (alpha-tocopherol) (100 mg/kg wet diet), for 1 week, instead of MC treatment. Vitamin E was used as standard antioxidant drug. Following 3 weeks of normal ambient water, the sixth and seventh aquaria received only CN for 1 week, with 15 and 25 mg CN respectively/100 g wet food, respectively. At the end of the experiment, Samples of liver, kidneys (posterior part), gills (right gills) and ovary were excised. The measurement included the oxidative stress parameters: carbonyl protein and total peroxide and the antioxidant enzyme activities superoxide dismutase (SOD), catalase (CAT) and glutathione S-transferase (GST) in all selected organs. MC treatment induced harmful effect in fish, probably due to its enhancing effect on reactive oxygen species (ROS) production in fish organs especially the respiratory and osmoregulatory organs namely gills. The result suggests that this gill damage may exert hypoxic case, anoxia for different organs and some Cu excretion resulting in a magnification of ROS overproduction. Also, the observed oxidative stress in ovary tissue of MC-treated fish may affect fish fertility. The addition of CN in fish diets could protect the fish C. gariepinus against MC induced oxidative damage showing recovery of fish organs. It could suggest that the detoxifying mechanism of action of CN is mainly due to its scavenging activity of free radicals rather than tissue healing. PMID- 20927585 TI - Effects of cocaine-kindling on the expression of NMDA receptors and glutamate levels in mouse brain. AB - In the present study we examined the effects of cocaine seizure kindling on the expression of NMDA receptors and levels of extracellular glutamate in mouse brain. Quantitative autoradiography did not reveal any changes in binding of [3H] MK-801 to NMDA receptors in several brain regions. Likewise, in situ hybridization and Western blotting revealed no alteration in expression of the NMDA receptor subunits, NR1 and NR2B. Basal overflow of glutamate in the ventral hippocampus determined by microdialysis in freely moving animals also did not differ between cocaine-kindled and control groups. Perfusion with the selective excitatory amino acid transporter inhibitor, pyrrolidine-2,4-dicarboxylic acid (tPDC, 0.6 mM), increased glutamate overflow confirming transport inhibition. Importantly, KCl-evoked glutamate overflow under tPDC perfusion was significantly higher in cocaine-kindled mice than in control mice. These data suggest that enhancement of depolarization stimulated glutamate release may be one of the mechanisms underlying the development of increased seizure susceptibility after cocaine kindling. PMID- 20927586 TI - Light effects on mitochondrial photosensitizers in relation to retinal degeneration. AB - The retina captures and converts light between 400-760 nm into electrical signals that are sent to the brain by way of the optic nerve and in the process helps to translate these electrical signals into what is known as vision. The same light that allows vision to occur is nevertheless also potentially toxic to retinal cells in certain situations. The shorter wavelengths of light are known to interact with chromophores in photoreceptors and pigment epithelial cells to cause oxidative stress and severe damage. Indeed it is generally accepted that short wavelength light effects is one cause for loss of photoreceptor function in age-related macular degeneration. Recent studies have demonstrated that light may be a contributing factor for the death of retinal ganglion cells in certain situations. Light as impinging on the retina, especially the short wavelength form, affect mitochondrial chromophores and can result in neurone death. Importantly ganglion cell axons within the eye are laden with mitochondria and unlike the outer retina are not protected from short wavelength light by macular pigments. It has therefore been proposed that when ganglion cell function is already compromised, as in glaucoma, then light impinging on their mitochondria might be a contributor to their eventual demise. PMID- 20927587 TI - Efficacy of eprinomectin against Toxocara vitulorum in calves. AB - This study was made to investigate efficacy of eprinomectin pour-on against to Toxocara vitulorum in calves. In the study, 16 calves naturally infected with T. vitulorum were divided into two groups as treatment (eight calves) and control (eight calves). Eprinomectin (0.5 mg/kg, Eprinex, Merial) was given to treatment group calves, and eggs per gramme were determined in the faeces on the day of pre treatment and the second, third, fourth, fifth, sixth, 14th and 28th days of post treatment. No side effects associated with nervous, respiratory and gastrointestinal systems were observed. In conclusion, eprinomectin was determined to be 100% effective against T. vitulorum. This is the first study to evaluate the efficacy of eprinomectin against a natural T. vitulorum infection in calves. PMID- 20927588 TI - Initial virological response and viral mutation with adefovir dipivoxil added to ongoing Lamivudine therapy in Lamivudine-resistant chronic hepatitis B. AB - BACKGROUND: Although adefovir dipivoxil (ADV) has been used for antiviral treatment of lamivudine (LAM)-resistant chronic hepatitis B (CHB) patients, the long-term efficacy of this treatment is not well understood. Initial virological response (IVR) has been reported to be an important factor in relation to the development of ADV-resistance. AIMS: We therefore examined the factors associated with IVR and ADV mutation in these patients. METHODS: Forty-nine LAM-resistant CHB patients with ADV add-on LAM therapy, 47% of whom were hepatitis B e-antigen (HBeAg)-positive with median treatment duration of 23 months, were enrolled in this study. Patients were classified into IVR and non-IVR groups on the basis of viral suppression status. Mutational analysis of the HBV polymerase/reverse transcriptase (rt) domain was performed by PCR-direct sequencing. RESULTS: Serum HBV DNA was undetectable (<2.6 log10 copies/mL) in 67, 82, and 84% of patients at 24, 48, and 96 weeks, respectively, after ADV add-on LAM therapy. IVR was achieved in 82% of patients, and ALT normalized at week 24 in 90% of IVR and 78% of non-IVR patients. The lower pretreatment HBV DNA level and virus-containing mutations other than double mutation of rtL180M + rtM204V were significantly associated with IVR (P=0.002 and P=0.014, respectively). ADV-resistant mutations in the RT motif, reported previously, were not detected. CONCLUSION: IVR is useful for predicting the antiviral efficacy of ADV and LAM combination therapy in LAM-resistant CHB. PMID- 20927589 TI - Epigenetic silencing of somatostatin in gastric cancer. AB - BACKGROUND: Somatostatin (SST), a primary inhibitor of gastrin-stimulated gastric acid secretion, has potent antitumor and anti-secretory activity in several human cancers. AIMS: This study was performed to investigate the SST gene expression levels and possible epigenetic mechanisms that regulate expression of SST in gastric adenocarcinomas. METHODS: Quantitative real-time (RT)-PCR and quantitative bisulfite pyrosequencing were used to study primary gastric cancer tissue samples and cell lines. RESULTS: Quantitative RT-PCR analysis revealed down-regulation of the SST transcript in 93% of gastric carcinoma samples (30/32), compared with 21 normal samples (P<0.001). Because of the presence of a large CpG island in the SST promoter, we next examined its promoter DNA methylation levels by use of quantitative bisulfite pyrosequencing. The results revealed a significant increase in SST promoter DNA methylation in tumor samples compared with normal samples (P<0.05). Promoter DNA hypermethylation and silencing of SST was also detected in seven gastric cancer cell lines that we tested. To confirm the role of promoter DNA methylation as an epigenetic mechanism regulating SST expression, AGS gastric cancer cells were treated with 5 Aza-dc. This treatment led to reduction of promoter DNA methylation levels of SST accompanied by restoration of its mRNA expression. CONCLUSIONS: Our results indicate that promoter DNA methylation levels play a critical role in regulating SST expression in gastric cancer. This finding provides a foundation for further studies on the role of SST in gastric carcinogenesis and its potential as a biomarker for gastric cancers. PMID- 20927590 TI - Helicobacter pylori VacA reduces the cellular expression of STAT3 and pro survival Bcl-2 family proteins, Bcl-2 and Bcl-XL, leading to apoptosis in gastric epithelial cells. AB - BACKGROUND: Helicobacter pylori vacuolating cytotoxin, VacA, stimulates apoptosis via a mitochondria-dependent pathway. VacA induces apoptosis via activation of the pro-apoptotic B-cell lymphoma (Bcl)-2 family proteins, Bcl-2-associated X protein (Bax) and Bcl-2 homologous antagonist/killer (Bak), while the implication of such pro-survival Bcl-2 family members as Bcl-2 and Bcl-XL in the VacA-induced apoptosis remains unknown. Signal transduction and activator of transcription 3 (STAT3) is a pivotal transcription factor that upregulates Bcl-2 and Bcl-XL. AIMS: This study was conducted to elicit the implication of STAT3 and pro survival Bcl-2 and Bcl-XL in the intrinsic apoptosis. METHODS: Immunoblot and reverse transcriptase real-time polymerase chain reaction (RT-PCR) were employed to assess the cellular expression of STAT3, Bcl-2, and Bcl-XL in response to purified VacA in gastric adenocarcinoma cell lines. VacA-induced apoptosis was quantitated morphologically following knockdown by each specific small interfering RNA (siRNA) or in the presence of pharmacological inhibitors. RESULTS: VacA reduced STAT3, Bcl-2, and Bcl-XL expression in a dose-dependent manner. Knockdown of STAT3, Bcl-2, and Bcl-XL by siRNA induced apoptosis to a similar extent in the case of sufficient VacA inoculation. The VacA-mediated reduction of STAT3 expression was independent of cellular vacuolization, since a vacuolar-type ATPase inhibitor, bafilomycin A1, did not inhibit VacA-induced reduction of STAT3, Bcl-2, and Bcl-XL expression. Instead, a c-JUN NH2-terminal kinase (JNK) inhibitor, SP600125, restored the VacA-induced reduction of STAT3 expression to the basal level. CONCLUSIONS: VacA-induced apoptosis may be, in part, implicated in the reduction of STAT3 linking to the downregulation of Bcl-2 and Bcl-XL, in association with JNK activity. PMID- 20927591 TI - Expression and prognostic significance of CD151, c-Met, and integrin alpha3/alpha6 in pancreatic ductal adenocarcinoma. AB - BACKGROUND: CD151, c-Met, and integrin alpha3/alpha6 are all involved in the hepatocyte growth factor (HGF)/c-Met signal pathway, which plays an important role in the malignant progression of tumors. AIMS: The purpose of this study was to explore the expression and prognostic significance of these proteins in pancreatic ductal adenocarcinoma (PDAC). METHODS: We used immunohistochemical methods to investigate the expression patterns of CD151, c-Met, and integrin alpha3/alpha6proteins in 71 patients with PDAC and in ten samples of normal pancreatic tissue. We also assessed correlations between these proteins and clinicopathological parameters and survival of PDAC patients using various statistical methods. RESULTS: CD151, c-Met, and integrin alpha3/alpha6 were all overexpressed in PDAC. CD151 and c-Met overexpressions were significantly associated with TNM stage (p=0.001 and p=0.038, respectively) and lymph node invasion (p=0.000, p=0.012, respectively). A significant positive linear correlation was found between CD151 and c-Met (r=0.583; p=0.000), integrin alpha3 (r=0.457; p=0.000), and integrin alpha6 (r=0.671; p=0.000). Overexpression of CD151, c-Met, integrin alpha3, or integrin alpha6 was related to poor survival of PDAC patients (p=0.000, p=0.000, p=0.005, and p=0.003, respectively), and CD151 and c-Met were independent factors in prognosis of PDAC. CONCLUSIONS: CD151, c Met, and integrin alpha3/alpha6 were all overexpressed in PDAC. CD151 and c-Met might be new molecular markers to predict the prognosis of PDAC patients. PMID- 20927592 TI - Occult hepatitis B: clinical implications and treatment decisions. AB - First reported in 1978, occult hepatitis B is a term used to describe the presence of hepatitis B virus (HBV) DNA without hepatitis B surface antigenemia. The prevalence of occult HBV is unclear and depends in part on the sensitivity of the hepatitis B surface antigen (HBsAg) and DNA assays used as well as the prevalence of HBV infection in the study population. The origin of occult HBV also remains in question. Several mechanisms have been hypothesized including mutations in the regulatory regions of the HBV genome, persistence of Ig-bound HBV immune complexes, viral interference, and blockage of free HBsAg secretion. Occult HBV has important clinical implications such as transmission through blood transfusion, reactivation in the setting of immunosuppression, and interference with hepatitis C treatment. To date, there is little data pertaining to the treatment of occult HBV outside of the setting of chemotherapy-induced HBV reactivation. PMID- 20927593 TI - Rate and factors affecting treatment uptake of patients with chronic hepatitis C in a tertiary referral hospital. AB - BACKGROUND: Contraindications to interferon and ribavirin for treatment of chronic hepatitis C (CHC) are well recognized, and previous data indicated the consequent suboptimal treatment uptake. AIM: To evaluate the treatment rate of CHC patients in a tertiary referral center in Hong Kong, and to examine the reasons for non-treatment. METHODS: A retrospective review of all referred CHC patients to the outpatient clinic was conducted. Treatment uptake rate was evaluated and patients' sociodemographic, biochemical, and histological data were examined to identify reasons for treatment decision. RESULTS: CHC patients (303) were assessed for antiviral therapy from 2000 to 2009. Of the patients, 138 (45.5%) did not receive antiviral therapy. Reasons for non-treatment were as follows: 31.9% declined treatment, 18.8% had decompensated cirrhosis, 12.3% were considered too elderly, 17.4% had too mild liver disease, 7.2% had psychiatric history, 7.2% had significant comorbidities, and 2.9% had ongoing alcohol or substance abuse. Independent factors associated with non-treatment were older age (adjusted odds ratio [aOR] 1.05, 95% confidence interval [CI] 1.03-1.08, p < 0.001), significant comorbidities (aOR 2.53, 95% CI 1.34-4.78, p = 0.004), psychiatric history (aOR 6.04, 95% CI 2.14-17.02, p < 0.001), mild liver disease (aOR 7.72, 95% CI 3.86-15.44, p < 0.001) and decompensated cirrhosis (aOR 9.42, 95% CI 2.57-34.50, p < 0.001). CONCLUSIONS: Current treatment uptake for CHC patients was suboptimal, as a large proportion of patients were either reluctant for treatment or not suitable for the current antiviral therapy. Multidisciplinary interventions are needed in the short term while alternative antiviral therapy is desired in the long term to overcome barriers to treatment. PMID- 20927594 TI - Automated gastric slow wave cycle partitioning and visualization for high resolution activation time maps. AB - High-resolution (HR) multi-electrode mapping has become an important technique for evaluating gastrointestinal (GI) slow wave (SW) behaviors. However, the application and uptake of HR mapping has been constrained by the complex and laborious task of analyzing the large volumes of retrieved data. Recently, a rapid and reliable method for automatically identifying activation times (ATs) of SWs was presented, offering substantial efficiency gains. To extend the automated data-processing pipeline, novel automated methods are needed for partitioning identified ATs into their propagation cycles, and for visualizing the HR spatiotemporal maps. A novel cycle partitioning algorithm (termed REGROUPS) is presented. REGROUPS employs an iterative REgion GROwing procedure and incorporates a Polynomial-surface-estimate Stabilization step, after initiation by an automated seed selection process. Automated activation map visualization was achieved via an isochronal contour mapping algorithm, augmented by a heuristic 2-step scheme. All automated methods were collectively validated in a series of experimental test cases of normal and abnormal SW propagation, including instances of patchy data quality. The automated pipeline performance was highly comparable to manual analysis, and outperformed a previously proposed partitioning approach. These methods will substantially improve the efficiency of GI HR mapping research. PMID- 20927595 TI - The effect of cumulative length of hospital stay on the antifungal resistance of Candida strains isolated from critically ill surgical patients. AB - Fluconazole is the first line of therapy for the management of candidiasis. However, fluconazole-resistant strains pose an emerging challenge in everyday clinical practice. In this study, we sought to determine whether cumulative length of hospital stay (CLOS) is a predictive factor for the acquisition of non susceptible Candida strains to fluconazole. Thirty-three critically ill emergency surgery patients with 56 Candida isolates were enrolled in this prospective study. We divided our isolates according to their minimum inhibitory concentration (MIC) to fluconazole using 8 mcg/ml as a cutoff. We then compared the two groups with respect to basic demographics, antifungal agents prescribed, number of wide-spectrum antibiotics, duration of central venous catheter placement, elapsed time to positive culture, duration of prior hospital stay, and length of hospital stay. Non-susceptible fluconazole samples belonged to patients with a significantly longer prior hospital stay and a longer CLOS (P = 0.02 and 0.01, respectively). The difference between the 2 groups regarding non-albicans strains was statistically significant (P < 0.001). By fitting a non-parametric receiver-operating characteristics (ROC) curve into our analysis, a CLOS >= 29 days predicted the occurrence of non-susceptible strains with 90% sensitivity and 79.6% specificity (correct classification 81.5%). A CLOS >= 29 days is a strong predictor for the isolation of non-susceptible Candida isolates to fluconazole among critically ill emergency surgery patients. Clinicians should consider the duration of previous hospital stay when deciding on empiric antifungal therapy. PMID- 20927596 TI - Association of goat (Capra hircus) CD4 gene exon 6 polymorphisms with ability of sperm internalizing exogenous DNA. AB - As one of the transport systems on the sperm plasma membrane, CD4 molecule plays a distinct role in the process of sperm/DNA interaction. This makes it possible to explain the mechanism of sperm-mediated gene transfer (SMGT), which at present is still a mystery in this area. In this study, seminal samples of 60 individuals from seven breed bucks were collected to detect the ability of sperm in internalizing exogenous DNA, and genomic DNA from 147 individual blood samples (including 60 bucks referred ahead) were extracted to test the polymorphisms of CD4 genes by using PCR-SSCP technique. Then the correlation between them was evaluated. The results showed that: (1) it was a novel finding that breed dependence of exogenous DNA binding to goat spermatozoa. There was the most significant difference among the buck breeds of sperm in binding exogenous DNA (F((6, 53)) = 4.811, P = 0.001) and in internalizing them into nuclei (F((6, 53)) = 4.587, P = 0.001). The ability of Lezhi Black goat was the lowest (P < 0.01) among the seven breeds. (2) There was no significant correlation between the ability of sperm in internalizing exogenous DNA and each semen quality parameter (P > 0.05). (3) In particular, three single-nucleotide polymorphisms (SNP) were described and there was one SNP (G/A(700)) of CD4 gene that made G234R substitution in the amino acid sequence of CD4 molecule. Nanjiang Yellow goat and Lezhi Black goat had higher hereditary variation compared with other breeds. (4) CD4 polymorphisms were highly associated with the ability of sperm in internalizing exogenous DNA. The SNP of Caprine CD4 gene exon 6 might be an important molecular marker of the ability to internalize exogenous DNA into sperm. PMID- 20927597 TI - Anti-theory in action? Planning for pandemics, triage and ICU or: how not to bite a bullet. AB - Anti-theory is a multi-faceted critique of moral theory which, it appears, is undergoing something of reassessment. In a recent paper Hamalainen discusses the relevance of an anti-theoretical perspective for the activity of applied ethics. This paper explores her view of anti-theory. In particular I examine its relevance for understanding the formal guidance on pandemic flu planning issues by the Department of Health (DoH) in the UK and some subsequent discussions around triage and reverse triage decisions which may be considered by both Primary and Secondary Care Trusts (PCTs and SCTs) (On the division between Primary and Secondary Care Trusts in the UK National Health Service see: http://www.nhs.uk/NHSEngland/thenhs/about/Pages/nhsstructure.aspx [Accessed August 2010]). in setting their own policies and which may face clinicians in the eventuality of a pandemic. Following Hamalainen in contrasting reflective equilibrium with her anti-theory inspired suggestion of an instrumental approach to moral theory in practice I demonstrate how this understanding complements the diversity of our intuitive moral judgements. Consequentially I suggest that this anti-theoretical instrumental approach is in greater accord with the conditions under which such policy planning and decision making is, or will be, made. Furthermore, on the grounds of keeping open the ethical dimensions of medical practice in conditions of uncertainty, i.e. during a pandemic, I suggest that the anti-theoretical instrumental perspective is, ethically, the preferable approach to producing such policies and guidelines. PMID- 20927598 TI - Correlation of pulmonary hypertension severity with metrics of comorbid sleep disordered breathing. AB - PURPOSE: We performed nocturnal polysomnography in patients with pulmonary hypertension (PH) of varying etiologies to determine the association of metrics describing sleep-disordered breathing (SDB) with measures of PH severity. METHODS: Consecutive patients referred for evaluation of dyspnea on exertion and elevated pulmonary arterial pressure >30 mmHg on echocardiography, who underwent right and left heart catheterization and polysomnography, were included. Patients were not pre-selected for symptoms of sleep-disordered breathing. RESULTS: Twenty eight patients including 22 females and six males with a mean age of 55.2 +/- 11.9 years were evaluated. Etiologies of PH were idiopathic (32%) and PH associated with other diseases (68%). Most were World Health Organization (WHO) Functional class II (39%) and III (39%). The group mean pulmonary arterial pressure (mPAP) was 40.9 +/- 15.1 mmHg. Diurnal resting and exercise arterial oxygen saturations (SaO(2)) were 94.9 +/- 3.7% and 88.3 +/- 8.9%. The mean apnea hypopnea index (AHI) was 11.4 +/- 19.8/h; 50% of all patients had an AHI >= 5/h; 30.6 +/- 36.0% of total sleep time was spent with SaO(2) < 90% (T90%); 66% of subjects with an AHI >= 5/h of sleep reported snoring, and 60% noted daytime somnolence; however, only 29% had an Epworth Sleepiness Scale >=10. Right atrial pressure and mPAP were significantly correlated with AHI and T90%. The best predictive model relating PH severity to metrics of SDB was a highly significant association (p = 0.005) between mPAP and a linear combination of AHI and T90%. CONCLUSIONS: SDB comprised of obstructive apneas, hypopneas, and nocturnal hypoxemia is prevalent in PH and cannot be accurately predicted by sleep apnea signs and symptoms or diurnal rest and exercise SaO(2). The association of AHI and T90% with mPAP suggests a potential relationship between the pathophysiology of sleep-disordered breathing and PH. PMID- 20927599 TI - [From "chronic bronchitis"to genetic emphysema]. PMID- 20927600 TI - Journal of General Internal Medicine. From the editor's desk: our paper anniversary. PMID- 20927601 TI - Can technological artefacts be moral agents? AB - In this paper we discuss the hypothesis that, 'moral agency is distributed over both humans and technological artefacts', recently proposed by Peter-Paul Verbeek. We present some arguments for thinking that Verbeek is mistaken. We argue that artefacts such as bridges, word processors, or bombs can never be (part of) moral agents. After having discussed some possible responses, as well as a moderate view proposed by Illies and Meijers, we conclude that technological artefacts are neutral tools that are at most bearers of instrumental value. PMID- 20927602 TI - Short tandem repeat profiling: part of an overall strategy for reducing the frequency of cell misidentification. AB - The role of cell authentication in biomedical science has received considerable attention, especially within the past decade. This quality control attribute is now beginning to be given the emphasis it deserves by granting agencies and by scientific journals. Short tandem repeat (STR) profiling, one of a few DNA profiling technologies now available, is being proposed for routine identification (authentication) of human cell lines, stem cells, and tissues. The advantage of this technique over methods such as isoenzyme analysis, karyotyping, human leukocyte antigen typing, etc., is that STR profiling can establish identity to the individual level, provided that the appropriate number and types of loci are evaluated. To best employ this technology, a standardized protocol and a data-driven, quality-controlled, and publically searchable database will be necessary. This public STR database (currently under development) will enable investigators to rapidly authenticate human-based cultures to the individual from whom the cells were sourced. Use of similar approaches for non-human animal cells will require developing other suitable loci sets. While implementing STR analysis on a more routine basis should significantly reduce the frequency of cell misidentification, additional technologies may be needed as part of an overall authentication paradigm. For instance, isoenzyme analysis, PCR-based DNA amplification, and sequence-based barcoding methods enable rapid confirmation of a cell line's species of origin while screening against cross-contaminations, especially when the cells present are not recognized by the species-specific STR method. Karyotyping may also be needed as a supporting tool during establishment of an STR database. Finally, good cell culture practices must always remain a major component of any effort to reduce the frequency of cell misidentification. PMID- 20927604 TI - Development and characterization of new cell line BPH22 from midgut epithelial cells of Poekilocerus pictus (Fabricius, 1775). AB - Poekilocerus pictus is a painted grasshopper, which feeds on Calotropis sp. containing the cardiac glycosides. A new cell line BPH22 is developed from midgut of P. pictus to study its unique physiology and biochemistry. Initially, the Graces insect medium is used with 10% (v/v) fetal bovine serum. After four passages, the serum quantity was reduced up to 0%.The lag phase in growth curve was 5 d and log phase is up to 10-11 d. The addition of Calotropis extract in Graces medium enhanced the growth of cells. The Calotropis extract with Graces medium altered the morphology of cells of BPH22. The amplification and sequencing of 16S rRNA gene confirmed the origin and purity of the BPH22. PMID- 20927603 TI - The effect of physiological concentrations of sex hormones, insulin, and glucagon on growth of breast and prostate cells supplemented with unmodified human serum. AB - The majority of cell culture studies have assessed the effect of hormones on cancer cell growth using media supplemented with charcoal-treated fetal bovine serum (CTS). We aimed to determine whether using a system more reflective of the human condition by changing the charcoal-treated serum to an untreated pooled human serum (PHS) resulted in the same hormone responses in breast and prostate cell lines. MCF-7 breast cancer, MCF-10A non-transformed breast, and LNCaP prostate cancer cell lines supplemented with PHS were treated with high and low physiological concentrations of six hormones (17beta-estradiol, dehydroepiandosterone (DHEA), dihydrotestosterone (DHT), testosterone, insulin, and glucagon). Cell growth was measured after 72 h of incubation. All hormones stimulated growth of MCF-7 cells (p < 0.05). MCF-10A cell growth was inhibited by DHEA, DHT, and testosterone (p < 0.05), unaffected by 17beta-estradiol and glucagon, and stimulated by insulin (p < 0.05). LNCaP cell growth was stimulated by the highest concentration of DHEA and DHT (p < 0.05) and inhibited by the highest concentration of 17beta-estradiol (p < 0.05), while insulin and testosterone, had no effect. Overall, PHS lowered the magnitude of the effect of hormones on cell growth in comparison to CTS. Due to the presence of all serum constituents, our model represents a more appropriate physiological environment for determining the effect of hormones on cancer cell growth. Further studies are required to determine the mechanisms by which added hormones interact with the constituents of untreated human serum. PMID- 20927605 TI - Convenient gram-scale metabolite synthesis by engineered fission yeast strains expressing functional human P450 systems. AB - The growing need for the characterization of cytochrome P450 (P450) metabolites often necessitates their synthesis up to Gram-scale. This task may in principle be achieved by using various techniques including chemical synthesis, the use of laboratory animals, in vitro P450 systems or microbial biotransformation. However, these approaches are in many instances unfavorable due to low yields, laborious purification, costs of cofactors, or the formation of non-physiologic metabolites. The fission yeast Schizosaccharomyces pombe has previously been shown by others and us to be very well suited for the heterologous expression of human P450s. In this study, we demonstrate whole-cell biotransformation reactions carried out with fission yeast strains that coexpress human cytochrome P450 reductase (CPR) and one of the following P450 isoforms: CYP2B6, CYP2C9, CYP2C19, CYP2D6, or CYP3A4, respectively. These strains could successfully convert their respective standard substrates but showed different responses with respect to incubation pH, the presence of glucose, and temperature, respectively. In addition, the preparative of synthesis of 2.8 g of 4'-hydroxydiclofenac was achieved by whole-cell biotransformation of diclofenac using a CPR-CYP2C9 coexpressing fission yeast strain. PMID- 20927606 TI - Role of vasoactive intestinal peptide in hyperoxia-induced injury of primary type II alveolar epithelial cells. AB - OBJECTIVE: We investigated the effect of VIP on primary type II alveolar epithelial cells (AECIIs) upon the exposure of hyperoxia. METHODS: AECIIs were isolated and purified from premature rats and exposed to air (21% oxygen), hyperoxia(95% oxygen), VIP+air and VIP+hyperoxia, respectively. The proliferation and apoptosis of AECIIs were detected by MTT cell proliferation assay, flow cytometry and western blot. The production of intracellular reactive oxygen species (ROS) was determined by 2 ', 7'-dichloro-dihydrotestosterone fluorescein diacetate (DCFH-DA) molecular probe and the total antioxidant capacity (TAOC) by ultraviolate spectro-photometer. RESULTS: Cell proliferation significantly increased and apoptosis decreased upon the treatment with VIP. In addition, the level of ROS in the hyperoxia+VIP group was significantly lower than in the hyperoxia group, in contrast, TAOC was higher in the hyperoxia+VIP group than that in the hyperoxia group. CONCLUSIONS: VIP exerts a protective role in the hyperoxia-induced oxidative stress damage in AECIIs, which probably attributed to its anti-oxidant and anti-apoptosis property. PMID- 20927607 TI - Phenotype and radiological correlation in patients with growth hormone deficiency. AB - OBJECTIVE: To confirm that MRI findings like hypoplastic anterior pituitary, thin or interrupted pituitary stalk, and ectopic posterior pituitary (EPP) in patients with growth hormone deficiency are a good indicator of the severity of hypopituitarism. METHODS: MR images were obtained for 44 patients (IGHD: CPHD; 30:14) and analyzed to define one or more of the following triad of abnormalities: small/absent anterior pituitary, thin or interrupted pituitary stalk, and EPP, as well as for any other associated anomalies. The findings were correlated with the clinical and biochemical presentation. RESULTS: Pituitary abnormalities were common in both groups (53% with IGHD, 79% with CPHD). Breech delivery, neonatal hypoglycemia, jaundice, micropenis, birth asphyxia occurred more commonly in CPHD compared to IGHD. In patients whose peak growth hormone (GH) level was less than 3 ng/ml (n: 37), 68% had the MR triad; while none of them with GH>3 ng/ml had pituitary abnormality on MRI. CONCLUSIONS: The presence of structural anomalies in the hypothalamic pituitary area in patients with GHD suggests severity of hypopituitarism and MRI of hypothalamic pituitary area may aid in diagnosis of patients with suspected GHD. PMID- 20927608 TI - Intensive medical therapy for asymptomatic carotid artery stenosis. AB - The majority of carotid revascularization procedures are done in patients without recent symptoms of cerebral ischemia (asymptomatic carotid stenosis). In previous studies from the past two decades, the stroke risk associated with asymptomatic carotid stenosis has been estimated to be 2-2.5% per year. Given the relatively benign nature of asymptomatic carotid stenosis, it has been proposed that confining revascularization to a limited, higher-risk subgroup is a sensible strategy. Evidence is accumulating that improved medical therapy has led to a lower risk of stroke in medically treated patients and that ultrasound methods can identify higher-risk patients. These developments are highlighted in this article. PMID- 20927609 TI - Headache in patients with cancer. AB - Contemporary cancer research has led to unparalleled advances in therapeutics and improved survival. Even as treatment options continue to improve, quality of life should remain a priority. Headache drastically impacts the quality of life of patients with cancer and has a wide etiological scope, making diagnosis a challenge. Intracranial mass lesions are only one cause; others include extracranial tumors, paraneoplastic processes, and the consequences of diagnostic and therapeutic interventions used in cancer care. Fortunately, cancer-related headache is treatable, but a sound understanding of the variable etiologies is crucial to appropriate diagnostic evaluation and treatment. In this review, we highlight the important causes of headache in the patient with cancer, and consider the epidemiology, pathophysiology, clinical course, and treatment options for each. PMID- 20927610 TI - Tension type headache in adolescence and childhood: where are we now? AB - Tension type headache (TTH) is a primary headache disorder considered common in children and adolescents. It remains debatable whether TTH and migraine are separate biological entities. This review summarizes the most recent literature of TTH with regards to children and adolescents. Further studies of TTH are needed to develop a biologically based classification system that may be facilitated through understanding changes in the developing brain during childhood and adolescence. PMID- 20927611 TI - An overview of mood disorders in the DSM-5. AB - The process of revising the DSM, which is based on new findings in the literature and experience with the current classification, is initiated every 12-18 years. The process for the revision of DSM-IV to the DSM-5 began in 2006-after a series of meeting proceedings and monographs were published during the previous 3 years with the appointment of diagnostic group chairs by Director Dr. David Kupfer and Vice Director Dr. Darrel Regier. Members were recruited for workgroups to review the existing DSM-IV, to decide what worked well and which areas needed change, to review the available literature and data, and to propose changes based on an appropriate level of evidence in the literature proportional to the significance of the change. At the halfway point in this process, the Mood Disorders Workgroup has made tentative recommendations to be tested in field trials. These recommendations and some of the basis for them are discussed in this review. Final decisions await the data from field trials, possible revisions by the workgroups, and action by the task force. This article describes some of the recommendations made by the Mood Disorders Workgroup at this point in the process. PMID- 20927612 TI - NMR chemical shift assignments of a complex between SUMO-1 and SIM peptide derived from the C-terminus of Daxx. AB - Small Ubiquitin-like MOdifiers (SUMOs) are ubiquitin-like proteins known to covalently modify large number of cellular proteins. The mammalian SUMO family includes four paralogues, SUMO-1 through SUMO-4. Death-associated protein-6, Daxx, is a 740 residue important transcription corepressor known to represses transcriptional potential of several sumolyted transcription factors. Daxx also plays important role in apoptosis. Both terminals of Daxx harbor separate SUMO Interaction Motifs (SIM), which mediate its interaction with SUMO and hence the sumolyted transcription factors. The C-terminal SIM of Daxx preferentially binds SUMO-1. Practically complete (1)H, (13)C and (15)N resonance assignments for the complex between SUMO-1 and 20 residue Daxx C-terminal SIM peptide are reported here. PMID- 20927613 TI - Backbone 1H, 13C, and 15N assignments for the tandem ubiquitin binding domains of signal transducing adapter molecule 1. AB - Signal transducing adapter molecule (STAM) forms the endosomal sorting complex required for transport-0 (ESCRT-0) complex with hepatocyte growth factor regulated substrate (Hrs) to sort the ubiquitinated cargo proteins from the early endosomes to the ESCRT-1 complex. ESCRT-0 complex, STAM and Hrs, contains multiple ubiquitin binding domains, in which STAM has two ubiquitin binding domains, Vps27/Hrs/Stam (VHS) and ubiquitin interacting motif (UIM) at its N terminus. By the cooperation of the multiple ubiquitin binding domains, the ESCRT 0 complex recognizes poly-ubiquitin, especially Lys63-linked ubiquitin. Here, we report the backbone resonance assignments and the secondary structure of the N terminal 191 amino acids of the human STAM1 which includes the VHS domain and UIM. The {(1)H}-(15)N heteronuclear NOE experiments revealed that an unstructured and flexible loop region connects the VHS domain and UIM. Our work provides the basic information for the further NMR investigation of the interaction between STAM1 and poly-ubiquitin. PMID- 20927614 TI - 1H, 15N, and 13C assignments of the N-terminal activation domain of Dictyostelium discoideum Formin C. AB - Dictyostelium discoideum Formin C (ForC) plays an important role in the fruiting body formation during the multicellular stages of the slime mold. Formins are multidomain proteins that are known to regulate the actin cytoskeleton. Here, we report the assignments of the (1)H, (15)N, and (13)C nuclei of the N-terminal activation domain (residues 1-100) of ForC. Chemical shifts have been deposited at the BioMagResBank under the BMRB accession number 17,029. The N-terminal region of the 131 kDa ForC protein is supposed to form a GTPase-binding domain required for activation of the formin. PMID- 20927615 TI - Mechanical circulatory support as a bridge to transplant or for destination therapy. AB - Mechanical circulatory support (MCS) frequently is used to treat medically refractory end-stage heart failure. Initially designed to be a bridge to transplantation, MCS also has proven itself as a durable therapy for patients who are not transplant candidates. As outcomes for patients with MCS have improved, research interest in device development has flourished, with many new device types under investigation. In addition to improvement of MCS devices, investigational work continues to achieve appropriate patient selection and complication management. PMID- 20927616 TI - Antitumor activity of efrapeptins, alone or in combination with 2-deoxyglucose, in breast cancer in vitro and in vivo. AB - Efrapeptins (EF), a family of fungal peptides, inhibit proteasomal enzymatic activities and the in vitro and in vivo growth of HT-29 cells. They are also known inhibitors of F(1)F(0)-ATPase, a mitochondrial enzyme that functions as an Hsp90 co-chaperone. We have previously shown that treatment of cancer cells with EF results in disruption of the Hsp90:F(1)F(0)-ATPase complex and inhibition of Hsp90 chaperone activity. The present study examines the effect of EF on breast cancer growth in vitro and in vivo. As a monotherapy, EF inhibited cell proliferation in vitro with an IC(50) value ranging from 6 nM to 3.4 MUM. Inhibition of Hsp90 chaperone function appeared to be the dominant mechanism of action and the factor determining cellular sensitivity to EF. In vitro inhibition of proteasome became prominent in the absence of adequate levels of Hsp90 and F(1)F(0)-ATPase as in the case of the relatively EF-resistant MDA-MB-231 cell line. In vivo, EF inhibited MCF-7 and MDA-MB-231 xenograft growth with a maximal inhibition of 60% after administration of 0.15 and 0.3 mg/kg EF, respectively. 2 Deoxyglucose (2DG), a known inhibitor of glycolysis, acted synergistically with EF in vitro and antagonistically in vivo. In vitro, the synergistic effect was attributed to a prolonged endoplasmic reticulum (ER) stress. In vivo, the antagonistic effect was ascribed to the downregulation of tumoral and/or stromal F(1)F(0)-ATPase by 2DG. PMID- 20927617 TI - Contribution of nitric oxide to cerebral blood flow regulation under hypoxia in rats. AB - This study was designed to clarify whether nitric oxide (NO) participates in the regulation of local cerebral blood flow (CBF) during hypoxia (inhalation of 15% O(2) in N(2)). The CBF response to hind-paw stimulation (evoked CBF) of Sprague Dawley (SD) rats was measured by laser-Doppler flowmetry. Physiological variables, such as heart rate, mean blood pressure, and PaCO(2) during hypoxia, were identical to those under normoxic conditions. Hypoxia increased the baseline CBF (17.5 +/- 14.3%) and the normalized peak amplitude of evoked CBF (31.1 +/- 18.5%) relative to those during normoxia. When an NOS inhibitor was infused intravenously, these differences were abolished in both the baseline CBF or evoked CBF between normoxic and hypoxic conditions, whereas the heart rate decreased and the mean blood pressure increased during hypoxia in comparison with these during normoxia. The field potential was constant under all experimental conditions. These results suggest that NO plays a major role in the regulation of baseline and evoked CBF during hypoxia. PMID- 20927618 TI - Diethylene glycol in health products sold over-the-counter and imported from Asian countries. AB - Diethylene glycol (DEG), a chemical that has been implicated in multiple medication-associated mass poisonings, can result in renal and neurological toxicity if ingested. Three previous such mass poisonings implicated Chinese manufacturers as the origin of contaminated ingredients. No literature exists on potential DEG or triethylene glycol (TEG), a related compound, contamination of health products imported from Asian countries to the USA. Our primary objective was to quantitatively assess the amount of DEG present in a convenience sampling of these health products. The study's secondary objectives were to: (1) evaluate for, and quantify TEG levels in these samples; (2) compare DEG and TEG levels in these products directly to levels in medications implicated in previous similar mass poisonings; and (3) to estimate DEG dose (in mg/kg) based on the manufacturer's instructions and compare these values to toxic doses from past mass poisonings and the literature. A quantitative assessment of DEG and TEG was performed in a convenience sampling of over-the-counter health products imported from Asian countries. Results were converted to volume to volume (v/v) % and compared with DEG levels in medications implicated in previous mass poisonings. Estimated doses (based on the manufacturer's instructions) of each product with detectable levels of DEG for a 70 kg adult were compared to toxic doses of DEG reported in the literature. Seventeen of 85 (20%) samples were not able to be analyzed for DEG or TEG due to technical reasons. Fifteen of 68 (22%) samples successfully tested had detectable levels of DEG (mean, 18.8 MUg/ml; range, 0.791 110.1 MUg/ml; and volume to volume (v/v) range, 0.00007-0.01%). Two of 68 (3%) samples had TEG levels of 12.8 and 20.2 MUg/ml or 0.0012% and 0.0018% TEG v/v. The product with the highest DEG% by v/v was 810 times less than the product involved in the Panama DEG mass poisoning (8.1%). The lowest reported toxic dose from a past DEG mass poisoning (14 mg/kg) was more than 150 times higher than the highest daily dose estimated in our study (0.09 mg/kg). Sixty-eight of 85 (80%) samples were able to be successfully analyzed for DEG and TEG. DEG and TEG were detectable in 15/68 (22%) and 2/68 (3%) samples, respectively. Based on current standards, these levels probably do not represent an acute public health threat. Additional research focusing on why DEG is found in these products and on the minimum amount of DEG needed to result in toxicity is needed. PMID- 20927619 TI - Effect of phonological and morphological awareness on reading comprehension in Hebrew-speaking adolescents with reading disabilities. AB - This research explored phonological and morphological awareness among Hebrew speaking adolescents with reading disabilities (RD) and its effect on reading comprehension beyond phonological and word-reading abilities. Participants included 39 seventh graders with RD and two matched control groups of normal readers: 40 seventh graders matched for chronological age (CA) and 38 third graders matched for reading age (RA). We assessed phonological awareness, word reading, morphological awareness, and reading comprehension. Findings indicated that the RD group performed similarly to the RA group on phonological awareness but lower on phonological decoding. On the decontextualized morphological task, RD functioned on par with RA, whereas in a contextualized task RD performed above RA but lower than CA. In reading comprehension, RD performed as well as RA. Finally, results indicated that for normal readers contextual morphological awareness uniquely contributed to reading comprehension beyond phonological and word-reading abilities, whereas no such unique contribution emerged for the RD group. The absence of an effect of morphological awareness in predicting reading comprehension was suggested to be related to a different recognition process employed by RD readers which hinder the ability of these readers to use morphosemantic structures. The lexical quality hypothesis was proposed as further support to the findings, suggesting that a low quality of lexical representation in RD students leads to ineffective reading skills and comprehension. Lexical representation is thus critical for both lexical as well as comprehension abilities. PMID- 20927620 TI - Management of portal hypertension in children. AB - Management of portal hypertension in children has evolved over the past several decades. Portal hypertension can result from intrahepatic or extrahepatic causes. Management should be tailored to the child based on the etiology of the portal hypertension and on the functionality of the liver. The most serious complication of portal hypertension is gastroesophageal variceal bleeding, which has a mortality of up to 30%. Initial treatment of bleeding focuses on stabilizing the patient. Further treatment measures may include endoscopic, medical, or surgical interventions as appropriate for the child, depending on the cause of the portal hypertension. beta-Blockers have not been proven to effectively prevent primary or secondary variceal bleeding in children. Sclerotherapy and variceal band ligation can be used to stop active bleeding and can prevent bleeding from occurring. Transjugular intrahepatic portosystemic shunts and surgical shunts may be reserved for those who are not candidates for transplant or have refractory bleeding despite medical or endoscopic treatment. PMID- 20927622 TI - [Abstracts of the 34th Autumn Conference of the DGK and 21st Annual Convention of the Working Group for Cardiac Pacemakers and Arrhythmia. October 7-9, 2010. Nurmberg, Germany]. PMID- 20927621 TI - [Recording cervical and ocular vestibular evoked myogenic potentials: part 1: anatomy, physiology, methods and normal findings]. AB - Vestibular evoked myogenic potentials (VEMP) have gained in clinical significance in recent years, now forming an integral part of neurootological examinations to establish the functional status of the otolith organs. They are sensitive to low frequency acoustic stimuli. When stimulated, receptors in the sacculus and utriculous are activated. By means of reflexive connections, myogenic potentials can be recorded when the relevant muscles are tonically activated. The vestibulocolic (sacculocollic) reflex travels from the otolith organs over the central circuitry to the ipsilateral sternocleidomastoid muscle. Myogenic potentials can be recorded by means of cervical VEMP (cVEMP). The vestibuloocular reflex crosses contralaterally to the extraocular eye muscle. Ocular VEMP (oVEMP) are recorded periocularly, preferably from the inferior oblique muscle. Various stimulation methods are used including air conduction and bone conduction. PMID- 20927623 TI - [Abstracts of the German Pain Congress 2010. Visions and Errors. October 6-9, 2010. Mannheim, Germany]. PMID- 20927624 TI - Seasonal changes of PFOS and PFOA concentrations in Lake Biwa water. AB - A survey on seasonal concentration changes of perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) was performed for surface water in Lake Biwa (14 sites) from February to November in 2009. The concentrations of PFOS and PFOA were 0.8-1.6 and 7.0-10 ng/L in northern basin of Lake Biwa (eight sites), 0.9 1.7 and 8.3-13 ng/L in southern basin of Lake Biwa except Akanoi Bay (four sites), 1.4-2.8 and 9.1-17 ng/L in Akanoi Bay (8C) and 2.4-5.3 and 12-26 ng/L in Akanoi Bay (168), respectively. Seasonal changes were recognized for both of PFOS and PFOA in the two sites of Akanoi Bay but not in the other sites of the southern and northern basins of Lake Biwa. Monthly detailed surveys in the surface water were performed on the changes of PFOS and PFOA concentrations from June in 2009 to May in 2010 and further on the changes of conductivity values. The changes of PFOS and PFOA concentrations were well consistent with those of conductivity values. PMID- 20927625 TI - Bilateral testicular adrenal rests in a boy with congenital adrenal hyperplasia. PMID- 20927626 TI - Internal herniation through the foramen of Winslow during pregnancy: MR findings [corrected]. AB - We present a unique case of jaundice in pregnancy, secondary to common bile duct obstruction by an unusual internal colonic hernia. We also illustrate the benefits of using non-ionizing imaging modalities in the diagnosis and pre operative planning of this rare condition. PMID- 20927628 TI - Curing the plasmid pXO2 from Bacillus anthracis A16 using plasmid incompatibility. AB - Plasmid incompatibility, which has no effect on other plasmids or chromosomal genes, can be used to cure a target plasmid. In this report, we successfully cured the plasmid pXO2 from Bacillus anthracis A16 with a newly constructed, incompatible plasmid pKSV7-oriIV and obtained a new pXO2-cured strain, designated A16PI2. This is the first time that a plasmid was cured from the B. anthracis wild-type strain A16 utilizing this principle, which could be considered as an efficacious method to cure large plasmids. PMID- 20927629 TI - Recanalized umbilical vein as a conduit for mesenterico/porto-Rex bypass for patients with extrahepatic portal vein obstruction. AB - PURPOSE: Mesenterico-left portal vein (meso-Rex) bypass is as an effective modality for restoring intrahepatic portal perfusion in patients with extrahepatic portal vein obstruction. Achieving sufficient patency is difficult with end-to-side anastomosis of a bypass graft to a small or hypoplastic left portal vein in the Rex recessus. Here, we describe the use of a recanalized umbilical vein in the round ligament as a conduit for bypass construction in two patients. METHODS: Case 1 was an 11-year-old boy diagnosed with rupture of the esophageal varices and hypersplenism due to congenital extrahepatic portal hypertension. Because of persistent hypersplenism and thrombocytopenia, he underwent meso-Rex bypassing with a left iliac vein graft interposed between the umbilical vein and the superior mesenteric vein. Case 2 was a neonate with a large hepatic tumor (mesenchymal hamartoma) that developed abdominal compartment syndrome at birth. The tumor was removed by right hepatectomy with excision of the portal vein bifurcation at 3 days of age. Porto-Rex bypassing was accomplished by end-to-end anastomosis between the portal vein trunk and the umbilical vein. RESULTS: Sufficient hepatopetal portal flow through the umbilical vein was achieved in both patients and maintained for over 16 and 13 months, respectively. Although hypersplenism remained in Case 1, intrahepatic portal vein branches gradually widened and the cavernoma in the hepatic hilum disappeared within 2 months. Neither patient had symptoms or signs of portal hypertension at the most recent follow-up. CONCLUSION: Using the umbilical vein as a vein conduit may facilitate construction of a meso/porto-Rex bypass and restore intrahepatic portal vein perfusion in patients with extrahepatic portal vein obstruction. PMID- 20927630 TI - Defects in amphiphysin 2 (BIN1) and triads in several forms of centronuclear myopathies. AB - Myotubular myopathy and centronuclear myopathies (CNM) are congenital myopathies characterized by generalized muscle weakness and mislocalization of muscle fiber nuclei. Genetically distinct forms exist, and mutations in BIN1 were recently identified in autosomal recessive cases (ARCNM). Amphiphysins have been implicated in membrane remodeling in brain and skeletal muscle. Our objective was to decipher the pathogenetic mechanisms underlying different forms of CNM, with a focus on ARCNM cases. In this study, we compare the histopathological features from patients with X-linked, autosomal recessive, and dominant forms, respectively, mutated in myotubularin (MTM1), amphiphysin 2 (BIN1), and dynamin 2 (DNM2). We further characterize the ultrastructural defects in ARCNM muscles. We demonstrate that the two BIN1 isoforms expressed in skeletal muscle possess the phosphoinositide-binding domain and are specifically targeted to the triads close to the DHPR-RYR1 complex. Cardiac isoforms do not contain this domain, suggesting that splicing of BIN1 regulates its specific function in skeletal muscle. Immunofluorescence analyses of muscles from patients with BIN1 mutations reveal aberrations of BIN1 localization and triad organization. These defects are also observed in X-linked and autosomal dominant forms of CNM and in Mtm1 knockout mice. In addition to previously reported implications of BIN1 in cancer as a tumor suppressor, these findings sustain an important role for BIN1 skeletal muscle isoforms in membrane remodeling and organization of the excitation contraction machinery. We propose that aberrant BIN1 localization and defects in triad structure are part of a common pathogenetic mechanism shared between the three forms of centronuclear myopathies. PMID- 20927631 TI - Molecular diagnostics of brain tumors. PMID- 20927633 TI - Immune responses to recombinant Brugia malayi pepsin inhibitor homolog (Bm-33) in patients with human lymphatic filariaisis. AB - Immune responses to recombinant Brugia malayi pepsin inhibitor homolog (rBm-33) were investigated in patients with human lymphatic filariasis (microfilaremics (MF) and chronic pathology (CP)) along with endemic normals (EN). Flow cytometric analysis (24 h) revealed CD4(+) T cell activation in patients (MF and CP) compared to normals (EN), with increased expression of CD69 and diminished levels of CD62L and CD127. This was associated with an elevated expression of CD154 but not CD28 and CTLA4 in CP patients. However, Bm-33-induced cytokine expression profile (IL-1beta, IL-12, IL-8, IFN-gamma, IL-10 and TGF-beta) did not exhibit any significant difference between normals and patients at the same time point. Although CD4(+) T cell activation was observed initially in filarial patients (24 h), lymphoproliferation studies (96 h) suggested diminished proliferation compared to normals, indicating functional inactivation in the former upon prolonged antigen exposure. This indicates that rBm-33 induces an early T cell activation in MF and CP patients followed by a decreased lymphoproliferation that might contribute to immune suppression in these individuals. PMID- 20927632 TI - Disorders of glucose metabolism: post mortem analyses in forensic cases--part II. AB - In continuation to part I, a literature review is presented concerning biochemical problems of forensic post mortem cases of unclear hyperglycaemia or hypoglycaemia. Clinical parameters for this purpose were recently reviewed. Particular attention was paid to the detection of diabetic ketoacidosis, of hyperosmolar coma, insulinoma, insulin-induced or oral diabetic-induced hypoglycaemia. The second part of the review discusses the analytes ketone bodies, synthetic insulins, human insulin, C-peptide, proinsulin and insulin antibodies. Special interest is given to post mortem matrices for those analytes to reference concentrations, stability data, analytic interferences and analytical procedures which should be used in toxicological laboratories willing to detect diabetic metabolism disorders after death. PMID- 20927634 TI - Physiological variability in the deglutition literature: hyoid and laryngeal kinematics. AB - A literature review was conducted on hyoid and/or laryngeal displacement during swallowing in healthy populations according to several inclusion criteria. Anterior and superior displacement measures of both structures from previously published studies were compiled for meta-analysis. Results showed a large degree of variability across studies for each structure and plane of movement. Potential sources of variation were identified, including statistical, methodological, stimulus-related, and participant-related sources. PMID- 20927635 TI - The mutation spectrum of the SLC25A13 gene in Chinese infants with intrahepatic cholestasis and aminoacidemia. AB - BACKGROUND: SLC25A13 gene mutations cause citrin deficiency, which leads to neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). Information on the mutation spectrum of SLC25A13 in the Chinese population is limited. The aim of this study was to explore the mutation spectrum of the SLC25A13 gene in Chinese infants with intrahepatic cholestasis and various forms of aminoacidemia. METHODS: Sequence analyses were performed on 39 infants with intrahepatic cholestasis and various forms of aminoacidemia. Novel mutations were subjected to homology and structural analyses. Western blots were performed when liver specimens available. RESULTS: Genetic testing revealed the presence of SLC25A13 gene mutations (9 heterozygotes, 6 homozygotes and 13 compound heterozygotes) in 28 infants. Subsequent Western blot analysis revealed 22 cases of citrin deficiency, accounting for 56.4% of the 39 patients. Twelve types of mutations, including nine known mutations and three novel mutations, were found. Of the 49 mutated alleles, known ones include 851del4 (26 alleles, 53.1%), 1638ins23 (6 alleles, 12.2%), IVSl6ins3kb (3 alleles, 6.1%), IVS6+5G>A (2 alleles, 4.1%), E601K (2 alleles, 4.1%) and IVS11+1G>A, R184X, R360X and R585H (1 allele each, 2.0%). The three novel mutations were a splice site change (IVS6+1G>A), a deletion mutation (1092_1095delT) and a missense mutation (L85P), each in one allele. CONCLUSIONS: The mutation spectrum of the SLC25A13 gene in a Chinese population of infants with intrahepatic cholestasis with various forms of aminoacidemia was found to be different from that of other population groups in East Asia. The SLC25A13 gene mutation is the most important cause of infantile intrahepatic cholestasis with various forms of aminoacidemia. PMID- 20927637 TI - The emergence of genotypes 3 and 4 hepatitis E virus in swine and humans: a phylogenetic perspective. AB - To investigate whether there is any phylogenetic evidence to support the hypothesis that swine is the natural host of HEV genotypes 3 and 4, Bayesian analysis of 80 full-length genomic sequences of HEV was performed. The results showed that the strains of genotypes 3 and 4 from swine are paraphyletic with regard to strains of human origin, which are thus phylogenetically nested among the swine strains. Recognition of HEV genotypes 3 and 4 as viruses from swine or swine HEV can provide an evolutionary explanation to the observation of cross species infection by genotypes 3 and 4 HEV. PMID- 20927636 TI - High ability to predict the treatment outcome of peginterferon and ribavirin combination therapy based on the reduction in HCV RNA levels at 4 weeks after starting therapy and amino acid substitutions in the hepatitis C virus in patients infected with HCV genotype 1b. AB - BACKGROUND: The ability to predict the outcome of peginterferon (PEG-IFN) and ribavirin combination therapy based on the reduction in hepatitis C virus (HCV) RNA levels at 4 weeks after starting the therapy and amino acid substitutions in HCV was to be confirmed. METHODS: We measured the reduction in HCV RNA levels at 4 weeks after starting the combination therapy, as well as examining amino acid substitutions at residue 70 in the HCV core and within the interferon sensitivity determining region (ISDR) of HCV non-structural protein 5A (NS5A), for 101 patients infected with HCV genotype 1b. The ability of these factors to predict a sustained virologic response (SVR) was analyzed. RESULTS: When a 3 log(10) reduction in HCV RNA levels at 4 weeks after starting therapy was set as the cut off value, an SVR was achieved in 37 of the 46 patients (80.4%) with a >=3 log(10) decrease and in 4 of the 55 patients (7.3%) with a <3 log(10) decrease. All 4 patients who achieved an SVR despite a <3 log(10) reduction in HCV RNA levels at 4 weeks had an arginine at residue 70 in the HCV core and a non-wild type sequence for the ISDR of HCV NS5A. CONCLUSION: A >=3 log(10) reduction in HCV RNA levels at 4 weeks after starting therapy indicates that a patient has a high likelihood of achieving an SVR as a final outcome. Additional information on the amino acid substitutions at residue 70 in the HCV core and within NS5A-ISDR will further increase the ability to predict a clinical response. PMID- 20927638 TI - Two micro-scale protocols for the isolation of DNA from polysaccharide-rich plant tissue. AB - The high polysaccharide content of some plant species hinders the successful isolation of their DNA. As an alternative to the macro-extraction methods previously published for polysaccharide-rich plants, we present two techniques (STE/CTAB and HEPES/CTAB), which are performed in microcentrifuge tubes. These protocols are suitable for small amounts of silica gel-preserved plant tissue such as are commonly available from endangered plants. The critical step to remove polysaccharides was performing initial washes in either STE (0.25 M sucrose, 0.03 M Tris, 0.05 M EDTA) or HEPES (2% beta-mercaptoethanol, 0.2% PVP, 0.1 M HEPES, pH 8.0) buffer. Precipitating the DNA at room temperature with isopropanol also aided in decreasing polysaccharide co-precipitation. Of the two protocols we present the STE/CTAB method has the advantages of being more cost effective and avoiding the use of the hazardous chemical beta-mercaptoethanol. PMID- 20927639 TI - Phase I clinical and pharmacokinetic study of trabectedin and carboplatin in patients with advanced solid tumors. AB - PURPOSE: This study intended to determine the maximum tolerated dose (MTD) and the recommended phase II dose (RD) of trabectedin combined with carboplatin in patients with advanced solid tumors. PATIENTS AND METHODS: Carboplatin-pretreated patients received carboplatin AUC 4 (Group 1), whereas carboplatin-naive patients received carboplatin AUC 5 (Group 2) as a 1-h i.v. infusion followed by trabectedin at dose range from 0.5-1.2 mg/m(2) in the schedule of 3-h/every-3 weeks. Pharmacokinetic (PK) sampling was performed in the first 2 cycles. RESULTS: Forty-four patients were treated and evaluable for safety and dose limiting toxicities (DLTs). In Group 1, at trabectedin 1.0 mg/m(2), cumulative hematological toxicity was found in all patients and 1/10 patients had DLTs. The RD was considered trabectedin 0.8 mg/m(2) combined with carboplatin AUC 4. Although no DLT occurred at this dose level, frequent dose delays (28.6%) and the 4-week cycle re-scheduling (66.7%) were required. In Group 2, DLTs occurred at trabectedin 0.8 mg/m(2) (3/8 patients), 1.0 mg/m(2) (3/10 patients) and 1.2 mg/m(2) (2/2 patients) with cumulative hematological toxicity associated with an important number of transfusions. In this group, neither the MTD nor the RD were established. Promising antitumor activity was found for this carboplatin/trabectedin combination; especially in patients with advanced ovarian cancer and soft tissue sarcoma. No significant PK drug-drug interaction occurred. CONCLUSIONS: This study established a trabectedin dose of 0.8 mg/m(2) combined with carboplatin AUC 4 and given every 4 weeks as the most feasible schedule in carboplatin-pretreated patients. Dose and cycle recommendations for carboplatin naive patients warrant further evaluation. PMID- 20927640 TI - The effect of sampling methods on the apparent constituents of ink from the squid Sepioteuthis australis. AB - Results of experiments conducted on ink recovered from the squid Sepioteuthis australis indicate that there is no epinephrine or protein naturally present in the ink as it would be ejected in vivo. Protein content was effectively zero when ink was syringed from the duct end of the ink sac of freshly killed animals. By contrast, there were proteins in samples collected from dead specimens where ink was collected by a stripping method. From these samples, a single large molecular weight protein was identified as having tyrosinase activity. Digestion of syringed ink did not yield signs of melanin-bound proteins. Analysis of supernatants after centrifugation of squid ink consistently revealed the presence of DOPA, dopamine, and taurine, whereas epinephrine and nor-epinephrine were recorded from what was believed to be contaminated ink. Histological investigations of the ink sac revealed a compartmentalised glandular structure distal to the duct end. Closer observation of the glandular tissue showed that compartments increased in size as they matured and moved further into the lumen. It was concluded that the presence of epinephrine and tyrosinase (or a related protein) in the ink of S. australis could be attributed to rupturing of basal glandular compartments or contamination from other sources during the extraction process. PMID- 20927642 TI - The early years of Title V: extending and improving care for children with special health care needs, 1935-1941. AB - This historical study examines the early years of the federal program of services for children with physical disabilities in the United States (US) during the 1930s, known today as services for Children with Special Health Care Needs (CSHCN). Established as part of the Social Security Act (SSA) of 1935, the Crippled Children Services (CCS) program was one of the first medical programs for children supported by the federal government. Under the SSA, states and territories quickly developed state-level CCS programs during the late 1930s. The US Children's Bureau administered the program for the federal government and helped states to incorporate preventive services and interdisciplinary approaches to service provision into state-level CCS programs. Factors that influenced the implementation of these programs included the availability of matching state funds, the establishment of state programs for crippled children prior to the SSA, and the accessibility of qualified health care professionals and facilities. The early efforts of this federal program on behalf of children with disabilities can be seen in services for CSHCN today. PMID- 20927641 TI - Tomato pathogenesis-related protein genes are expressed in response to Trialeurodes vaporariorum and Bemisia tabaci biotype B feeding. AB - The temporal and spatial expression of tomato wound- and defense-response genes to Bemisia tabaci biotype B (the silverleaf whitefly) and Trialeurodes vaporariorum (the greenhouse whitefly) feeding were characterized. Both species of whiteflies evoked similar changes in tomato gene expression. The levels of RNAs for the methyl jasmonic acid (MeJA)- or ethylene-regulated genes that encode the basic beta-1,3-glucanase (GluB), basic chitinase (Chi9), and Pathogenesis related protein-1 (PR-1) were monitored. GluB and Chi9 RNAs were abundant in infested leaves from the time nymphs initiated feeding (day 5). In addition, GluB RNAs accumulated in apical non-infested leaves. PR-1 RNAs also accumulated after whitefly feeding. In contrast, the ethylene- and salicylic acid (SA)-regulated Chi3 and PR-4 genes had RNAs that accumulated at low levels and GluAC RNAs that were undetectable in whitefly-infested tomato leaves. The changes in Phenylalanine ammonia lyase5 (PAL5) were variable; in some, but not all infestations, PAL5 RNAs increased in response to whitefly feeding. PAL5 RNA levels increased in response to MeJA, ethylene, and abscisic acid, and declined in response to SA. Transcripts from the wound-response genes, leucine aminopeptidase (LapA1) and proteinase inhibitor 2 (pin2), were not detected following whitefly feeding. Furthermore, whitefly infestation of transgenic LapA1:GUS tomato plants showed that whitefly feeding did not activate the LapA1 promoter, although crushing of the leaf lamina increased GUS activity up to 40 fold. These studies indicate that tomato plants perceive B. tabaci and T. vaporariorum in a manner similar to baterical pathogens and distinct from tissue damaging insects. PMID- 20927643 TI - Predictors of obesity in childhood, adolescence, and adulthood in a birth cohort. AB - To determine how characteristics of pregnancy, birth, and early infancy are related to offspring obesity at three critical developmental periods. Mothers were followed through pregnancy and 10-15 years after. Offspring data were obtained through medical record review. Maternal and offspring characteristics were examined to predict obesity in childhood (ages 4-5 years), adolescence (ages 9-14 years), and early adulthood (ages 19-20 years). The original cohort included 802 children born to 795 women. Children who were twins, who had died, or whose mothers had died were excluded (n=25). Medical records of 68.5% of the remaining 777 children documented a height and weight at childhood, adolescence, or early adulthood. Relative risks (RRs) to predict obesity at early adulthood were 12.3 for childhood and 45.1 at adolescence. RRs were also significant to predict obesity at early adulthood between the mother's obesity at prepregnancy (RR=6.4), 4-5 years postpregnancy (RR=6.3), and 10-15 years postpregnancy (RR=6.2). Excluding these variables from the multivariate models and adjusting by gender, birth insurance, and mother's marital status at delivery, the best model to predict obesity at childhood included birth weight, weight gain in infancy, and delivery type. At adolescence, it included maternal pregnancy smoking status, gestational weight gain, and weight gain in infancy, and in early adulthood, included maternal pregnancy smoking status, gestational weight gain, and birth weight. Maternal pregnancy smoking status, gestational weight gain, and weight gain in infancy have long-term effects on offspring. Maternal obesity is the strongest predictor of obesity at all times studied. PMID- 20927644 TI - Epilepsy and Tsc2 haploinsufficiency lead to autistic-like social deficit behaviors in rats. AB - There is a strong association between autism spectrum disorders (ASD), epilepsy and intellectual disability in humans, but the nature of these correlations is unclear. The monogenic disorder Tuberous Sclerosis Complex (TSC) has high rates of ASD, epilepsy and cognitive deficits. Here we used the Tsc2 (+/-) (Eker) rat model of TSC and an experimental epilepsy paradigm to study the causal effect of seizures on learning and memory and social behavior phenotypes. Status epilepticus was induced by kainic acid injection at P7 and P14 in wild-type and Tsc2 (+/-) rats. At the age of 3-6 months, adult rats were assessed in the open field, light/dark box, fear conditioning, Morris water maze, novel object recognition and social interaction tasks. Learning and memory was unimpaired in naive Tsc2 (+/-) rats, and experimental epilepsy did not impair any aspects of learning and memory in either wild-type or Tsc2 (+/-) rats. In contrast, rearing in the open field, novel object exploration and social exploration was reduced in naive Tsc2 (+/-) rats. Seizures induced anxiety and social evade, and reduced social exploration and social contact behavior in wild-type and Tsc2 (+/-) rats. Our study shows that Tsc2 haploinsufficiency and developmental status epilepticus in wild-type and Tsc2 (+/-) rats independently lead to autistic-like social deficit behaviors. The results suggest that the gene mutation may be sufficient to lead to some social deficits, and that seizures have a direct and additive effect to increase the likelihood and range of autistic-like behaviors. PMID- 20927645 TI - Characteristics of petroleum hydrocarbons in surficial sediments from the Songhuajiang River (China): spatial and temporal trends. AB - This paper presents the spatial and temporal characteristics of petroleum hydrocarbons (PH) in surficial sediments from the Songhuajiang River using the method of petroleum chemical fingerprinting. Twenty-four surface sediment samples were collected at 17 sites along the river from upstream to downstream in flood season (August 2005) and icebound season (December 2005) and were analyzed for PH including n-alkanes (C(16)-C(33)), isoprenoid alkanes (pristane and phytane), and unresolved complex mixture (UCM). The concentration of PH varied from 22.64 to 91.45 MUg g( -1) dry sediment. n-alkanes with a carbon number from 16 to 33 were detected in all samples, and the UCM was the dominant composition for PH. The variability of the PH concentration was mostly influenced by external conditions, such as seasonal change and industrial area position, as well as internal sediment physicochemical properties, such as organic carbon and grain size. The concentration of hydrocarbons is higher in flood season than in icebound season and is higher upstream than downstream. The diagnostic ratios of specific hydrocarbons showed that the PH pollution comes from a combination of biogenic and petrogenic sources, and petrogenic input is dominant in icebound season relative to flood season. It also indicates that there is a clear terrigenous input of n-alkanes in flood season. Principal components analysis was used to study the composition and characteristics of PH in Songhuajiang River sediments and to assess the spatial and temporal distribution of their natural and anthropogenic sources. PMID- 20927646 TI - Lentiviral transgenesis in livestock. PMID- 20927647 TI - LXR-alpha genomics programmes neuronal death observed in Alzheimer's disease. AB - Keeping in view the fact that the most pathognomonic feature of Alzheimer's disease is the abnormal processing of neuronal cell membrane amyloid precursor protein accompanied by significantly elevated human serum and CSF levels of 24 hydroxycholesterol recognised widely as the specific endogenous ligand of Liver X receptor (LXR-alpha), the present study was addressed to explore the epigenomic pathway (if any) that connects LXR-alpha activation with the genes recognised to be involved in the regulation of aberrant Abeta production leading to the generation of toxic and inflammatory mediators responsible for neuronal death. The results of such a study revealed that LXR-alpha activation by its specific endogenous or exogenous ligands within neuroblastoma cells resulted in the over expression of PAR-4 gene accompanied by suppression of AATF gene through its inherent capacity to regulate genes coding for SREBP and NF-kappaB. Over expression of PAR-4 gene was accompanied by aberrant Abeta production followed by ROS generation and subsequent death of neuroblastoma cells used in the present study as a cellular model for neurons. Further based upon these results, it was proposed that Abeta-induced heme oxygenase-1 can ensure cholesterol-oxidation to provide endogenous ligands for the sustained activation of neuronal LXR-alpha dependent epigenomic-pathway leading to neuronal death observed in Alzheimer's disease. PMID- 20927649 TI - Treatment of Budd-Chiari syndrome with urokinase following predilation in patients with old inferior vena cava thrombosis. AB - PURPOSE: This study was undertaken to evaluate the safety and feasibility of thrombolytic urokinase treatment after predilation in patients with Budd-Chiari syndrome (BCS) with chronic inferior vena cava (IVC) thrombosis. MATERIALS AND METHODS: Between December 2006 and September 2009, 13 consecutive BCS patients with chronic IVC thrombosis were treated with continuous urokinase infusion after predilation and subsequent (i.e. after thrombus resolution) IVC dilation with a 30-mm dilator. The procedural technical and angiographic, and ultrasonic results, as well as mortality, morbidity and the final clinical outcome, were evaluated immediately after the treatment or at 1 week and 1, 3, 6 and 12 months and then annually thereafter. RESULTS: The immediate and long-term procedural technical outcome was successful in all patients. Follow-up inferior vena cavagrams demonstrated complete resolution of the chronic IVC thrombi and full IVC patency, without occurrence of pulmonary embolism at any time during the study. Colour Doppler ultrasound (US) follow-up for 16.92 months (+/- 12.04) showed full patency of the IVC, without thrombosis, restenosis or reobstruction, in all patients and resolution of all clinical symptoms. All patients were alive at the time of this report. CONCLUSIONS: Our preliminary results indicate that thrombolysis with continuous infusion of urokinase after predilation is a safe and feasible approach for treating BCS patients with chronic IVC thrombosis. PMID- 20927648 TI - Assessing longitudinal quality of life in prostate cancer patients and their spouses: a multilevel modeling approach. AB - PURPOSE: This study aimed at examining the relationship between quality of life (QOL) in prostate cancer (PCa) patients and partners and how baseline demographics, cancer-related factors, and time-varying psychosocial and symptom covariates affect their QOL over time. METHODS: Guided by a modified Stress Coping Model, this study used multilevel modeling to analyze longitudinal data from a randomized clinical trial that tested a family-based intervention to improve QOL in couples managing PCa. Patients and partners from the usual-care control group (N = 134 dyads) independently completed the measurements at baseline, and at 4-, 8-, and 12-month follow-ups. RESULTS: Correlations of QOL between patients and partners over time were small to moderate. Patients' lower education level, partners' older age, higher family income, and localized cancer at baseline were associated with better QOL in couples. Over time, couples' QOL improved as their social support and cancer-related dyadic communication increased and as couples' uncertainty, general symptoms, and patients' prostate cancer-related sexual and hormonal symptoms decreased. CONCLUSIONS: Evidence indicates that couples' QOL during cancer survivorship is affected by multiple contextual factors (e.g., baseline demographics and time-varying psychosocial factors and symptoms). Intervention research is needed to explore comprehensive strategies to improve couples' QOL during the continuum of PCa survivorship. PMID- 20927650 TI - Utility of T2-weighted short-tau inversion recovery (STIR) sequences in cardiac MRI: an overview of clinical applications in ischaemic and non-ischaemic heart disease. AB - T2-weighted short-tau inversion recovery (T2w-STIR) imaging is the best approach for oedema-weighted cardiac magnetic resonance imaging (MRI), as it suppresses the signal from flowing blood and from fat and enhances sensitivity to tissue fluid. The purpose of this pictorial review is to illustrate the clinical use and application of this technique in various ischaemic and non-ischaemic conditions. In ischaemic heart disease, T2w-STIR represents the technique of choice for detecting oedema in patients with acute myocardial infarction (MI), allowing discrimination of acute and chronic injuries. Myocardial haemorrhage may also be depicted as a region of signal abnormality characterised by a central hypointense core with a peripheral hyperintense rim, presumably reflecting the presence of intracellular methaemoglobin within the necrotic area. In the acute setting, elevated T2 relaxation times in association with regional contractile dysfunction but no signs of delayed enhancement may also signify a reversible ischaemic injury without necrosis. In acute myocarditis, the distribution pattern of T2w hyperintensity may be focal in approximately 30% of patients or diffuse in the remaining 70%, and myocardial oedema may be the only marker of disease. Tissue oedema may also be observed in various other conditions, such as primary cardiomyopathies (CMP), storage disease, pulmonary hypertension and cardiac transplant rejection. T2w-STIR represents an appealing and versatile technique that can be applied in a wide variety of ischaemic and non-ischaemic conditions, allowing detection of segmental or global increase of myocardial free water content, reflecting an acute myocardial injury. PMID- 20927651 TI - Prognostic value of CT coronary angiography: focus on obstructive vs. nonobstructive disease and on the presence of left main disease. AB - PURPOSE: The authors investigated the prognostic value of computed tomography coronary angiography (CTCA) for major adverse cardiac events (MACE) in patients with suspected or known coronary artery disease (CAD), with particular focus on left main (LM) disease and obstructive vs. nonobstructive disease. MATERIALS AND METHODS: A total of 727 consecutive patients (485 men, age 62 +/- 11 years) with suspected (514; 70.1%) or known (213; 29.9%) CAD underwent CTCA. Patients were followed up for the occurrence of MACE (i.e. cardiac death, nonfatal myocardial infarction, unstable angina, percutaneous/surgical revascularisation). RESULTS: A total of 117 MACE [five cardiac deaths, 11 acute myocardial infarctions (AMI), five unstable angina, 86 percutaneous coronary interventions, ten coronary artery bypass grafts] occurred during a mean follow-up of 20 months. Severity and extension of CAD was associated with a progressively worse prognosis. The event rate was 0% among patients with normal coronary arteries at CTCA. The presence of LM disease was not associated with a worse prognosis either in patients with no history of CAD or in those with a history of CAD. At multivariate analysis, presence of obstructive CAD and diabetes were the only independent predictors of MACE. CONCLUSIONS: Evaluation of atherosclerotic burden by CTCA provides an independent prognostic value for prediction of MACE. Patients with normal CTCA findings have an excellent prognosis at follow-up. PMID- 20927652 TI - Ultrasonography in lesions of the carotid vessels in HIV positive patients. AB - PURPOSE: This study evaluated with ultrasonography (US) the presence of epiaortic vessel lesions in HIV-positive individuals receiving highly active antiretroviral therapy (HAART) and compared them with naive patients and healthy individuals to highlight the differences among the different vascular damage patterns. MATERIALS AND METHODS: A total of 222 HIV-infected patients receiving HAART, 64 HIV infected patients naive to antiretroviral therapy and 135 HIV-negative control patients underwent US of the carotid vessels. The morphological examination included grey-scale and colour and power Doppler imaging to better characterise lesions and intima media thickness. An automated computerised software package (Q LAB) was used to determine intima media thickness values. Independent risk factors for the development of carotid lesions and, in particular, cholesterolaemia and triglyceridaemia were considered. Atherosclerotic plaques and inflammatory-type lesions were reported. Statistical analysis included the chi-square test, the Fisher exact test for qualitative variables and the Kruskal Wallis test to compare continuous variables. RESULTS: We observed a higher prevalence of carotid lesions in HIV-positive patients receiving HAART compared with HIV-positive naive patients (p<0.0000001) and HIV-negative patients (p<0.0001). Findings consistent with inflammatory-type lesions rather than classic atheroma were depicted only in five patients receiving HAART (0.02%). CONCLUSIONS: Our study confirms a higher prevalence of carotid lesions in HAART treated HIV patients. In agreement with other authors, we identified carotid lesions that were consistent with arteritis rather than with classic atheroma, but the percentage was too small to suggest any robust hypothesis. Further studies are warranted to define the mechanism of onset of carotid lesions in HIV positive individuals. PMID- 20927653 TI - Inflammatory breast carcinoma and locally advanced breast carcinoma: characterisation with MR imaging. AB - PURPOSE: This study was done to identify the typical magnetic resonance (MR) imaging findings of inflammatory breast carcinoma (IBC) in comparison with noninflammatory locally advanced breast carcinoma (LABC). MATERIALS AND METHODS: MR images of 30 patients with IBC (T4d) were compared with those of a cohort of 30 patients with LABC (T3/T4a-c). The age distribution was approximately equal in the two groups. MR images were assessed for the following features: skin thickening (>4 mm), skin oedema, architectural distortion, enhancement pattern (mass-like/non-mass-like), time-signal intensity curve (continuous-persistent type/wash-out type), skin enhancement. Fisher's exact text was used to compare MR imaging appearances of IBC and LABC (significant p value <0.05). RESULTS: Skin involvement and enhancement pattern differed between groups: skin thickening was present in 16/30 IBC (53%) vs 8/30 LABC cases (27%, p=0.06), skin oedema was present in 26/30 IBC (87%) vs 8/30 LABC (27%, p < 0.0001), and skin enhancement in 10/30 IBC (33%) vs 2/30 LABC (7%, p=0.02); non-mass-like enhancement was present in 22/30 IBC (73%) vs 12/30 LABC (40%, p=0.02). CONCLUSIONS: IBC is a distinct clinical and pathological entity resulting in typical MR imaging features. Skin changes (thickening, oedema, enhancement) related to neoplastic involvement of the dermal lymphatics are suggestive of IBC and should prompt a skin biopsy to confirm or rule out the diagnosis. PMID- 20927654 TI - Preoperative imaging assessment of chronic otitis media: what does the otologist need to know? AB - The aim of this paper is to review the role of computed tomography (CT) and magnetic resonance imaging (MRI) in managing chronic otitis media (COM), with special attention to the key information required by the otologist for effective preoperative planning. PMID- 20927655 TI - Quantitative ultrasound of the phalanges and DXA of the lumbar spine and proximal femur in evaluating the risk of osteoporotic vertebral fracture in postmenopausal women. AB - PURPOSE: This study was undertaken to compare the quantitative ultrasound (QUS) parameters of amplitude-dependent speed of sound (AD-SoS) and ultrasound bone profile index (UBPI) of the phalanges with bone mineral density (BMD) of the lumbar spine and proximal hip using dual-energy X-ray absorptiometry (DXA) in discriminating women with vertebral fracture. MATERIALS AND METHODS: A total of 692 postmenopausal Caucasian women were included in the study. The presence of vertebral fracture was evaluated by radiography. AD-SoS and UBPI were measured at the phalangeal metaphysis using a DBM Sonic device. Multiple logistic regression analysis was performed to estimate the odds ratio (OR) for vertebral fractures. The ORs were also adjusted for the significant anthropometric variables of age, weight and height. Furthermore, for QUS parameters, the ORs were also adjusted for lumbar spine and total hip BMD. RESULTS: All measurements obtained with DXA and QUS significantly discriminated between women with and without fractures (p<0.0001). However, the OR was higher for lumbar spine BMD (OR 4.01), AD-SoS (OR 3.81), total hip (OR 3.7) and femoral neck BMD (OR 3.62). CONCLUSIONS: The QUS parameter AD-SoS showed diagnostic sensitivity equal to that of lumbar DXA in discriminating between women with and without osteoporotic vertebral fractures. PMID- 20927656 TI - Atypical femoral neck stress fracture in a marathon runner: a case report and literature review. AB - BACKGROUND: Femoral neck stress fractures are relatively rare and may present as sports-related injuries. The presentation is variable, and prompt diagnosis facilitates the earliest return to pre-morbid functional activity levels. Delayed detection may precipitate femoral non-union or avascular necrosis, resulting in long-term functional deficit. AIMS: We present the case of a basicervical femoral neck stress fracture occurring in a 23-year-old marathon runner. The pathophysiology and practical management issues related to this unusual injury pattern are discussed. CONCLUSION: The growing interest in amateur athletic activities should raise the index of suspicion for stress fractures of the femoral neck in healthy adults with atypical hip pain. Increased levels of patient education and physician awareness can reduce the incidence of long-term morbidity in cases of this unusual sports-related injury. PMID- 20927657 TI - The use of laryngeal mask airway for surgical tracheotomy in a neonate with Pierre Robin syndrome: a case report. PMID- 20927658 TI - Human protein reference database and human proteinpedia as discovery resources for molecular biotechnology. AB - In the recent years, research in molecular biotechnology has transformed from being small scale studies targeted at a single or a small set of molecule(s) into a combination of high throughput discovery platforms and extensive validations. Such a discovery platform provided an unbiased approach which resulted in the identification of several novel genetic and protein biomarkers. High throughput nature of these investigations coupled with higher sensitivity and specificity of Next Generation technologies provided qualitatively and quantitatively richer biological data. These developments have also revolutionized biological research and speed of data generation. However, it is becoming difficult for individual investigators to directly benefit from this data because they are not easily accessible. Data resources became necessary to assimilate, store and disseminate information that could allow future discoveries. We have developed two resources- Human Protein Reference Database (HPRD) and Human Proteinpedia, which integrate knowledge relevant to human proteins. A number of protein features including protein-protein interactions, post-translational modifications, subcellular localization, and tissue expression, which have been studied using different strategies were incorporated in these databases. Human Proteinpedia also provides a portal for community participation to annotate and share proteomic data and uses HPRD as the scaffold for data processing. Proteomic investigators can even share unpublished data in Human Proteinpedia, which provides a meaningful platform for data sharing. As proteomic information reflects a direct view of cellular systems, proteomics is expected to complement other areas of biology such as genomics, transcriptomics, molecular biology, cloning, and classical genetics in understanding the relationships among multiple facets of biological systems. PMID- 20927660 TI - Prognosis after cardiac arrest and hypothermia: a new paradigm. AB - Before the use of hypothermia as a treatment for comatose post-cardiac arrest patients, several prognostic variables were widely accepted as reliable and valid for the prediction of poor outcome. Recent studies using hypothermia have reported on patients with recovery of consciousness in spite of absent or extensor motor responses after 3 days, absent bilateral cortical N20 responses after 24 h, serum neuron-specific enolase levels greater than 33 MUg/L, and early myoclonus status epilepticus. Hypothermia and its associated use of sedative and paralytic agents may delay neurologic recovery and affect the optimal timing of prognostic variables. Recent developments in brain imaging may provide additional objective prognostic information and deserve further study. Pending the results of future validation studies in patients treated with hypothermia, we recommend that irreversible management decisions not be made based on a single prognostic parameter, and, if there is uncertainty, these decisions be delayed for several days to allow for repeated testing. PMID- 20927661 TI - Evaluation of 99(m)Tc-labeled antibiotics for infection detection. AB - One of the fields of research in nuclear medicine is the development of new radiopharmaceuticals for imaging infection and inflammation in humans. For this development, several antimicrobial peptides, antibiotics, antibiotic peptide and chemotactic peptides, etc., have been radiolabeled with different radionuclides (67Ga, 99(m)Tc, 111In, 18F, 131I, etc.) and their imaging potentials studied. Actually, it is very important to distinguish between infection and inflammation. In this respect, radiolabeled antibiotics have advantages because many of the properties of the ideal infection-specific agent through antibiotics localizes in infection site. In this review, only 99(m)Tc-labeled antibiotics are evaluated and discussed. PMID- 20927659 TI - Treatment of myasthenia gravis. AB - Myasthenia gravis (MG) is an antibody-mediated, neuromuscular transmission disorder, which ranges in clinical manifestations of ocular myasthenia that may be visually disabling to myasthenic crisis with patients suffering life threatening respiratory insufficiency. MG also has pathophysiologic subgroups based on presence or absence of acetylcholine receptor or muscle-specific kinase antibodies and presence of thymoma. Cholinesterase inhibitors partially improve weakness, but the vast majority of patients require therapies that moderate the autoimmune attack. Mortality of MG has been reduced over the last century, but adverse effects of treatment compromise patient care and rigorous evidence to guide the clinician are lacking. PMID- 20927662 TI - An electrophysiological study of visual processing in spinocerebellar ataxia type 2 (SCA2). AB - Reports of visual functional impairment in spinocerebellar ataxia type 2 (SCA2) have been studied previously using pattern reversal visually evoked potentials (VEPs) with contradictory results. To provide additional evidence to this area, visual functions were studied using VEPs and event-related potentials (ERPs) in a group of ten patients with genetically verified SCA2. The electrophysiological examination included pattern reversal and motion-onset VEPs as well as visually driven oddball ERPs with an evaluation of a target and a pre-attentive response. In six patients, we found abnormal visual/cognitive processing that differed from normal values in latency, but not in the amplitude of the dominant VEP/ERP peaks. Among the VEPs/ERPs used, the motion-onset VEPs exhibited the highest sensitivity and showed a strong Spearman correlation to SCA2 duration (from r = 0.82 to r = 0.90, p < 0.001) and clinical state assessed by Brief Ataxia Rating Scale (from r = 0.71 (p = 0.022) to r = 0.80 (p < 0.001)). None of the VEP/ERP latencies showed a correlation to the triplet repeats of the SCA2 gene. In three patients, we did not find any visual/cognitive pathology, and one subject showed only a single subtle prolongation of the VEP peak. The observed visual/cognitive deficit was related to the subjects' clinical state and the illness duration, but no relationship to the genetic marker of SCA2 was found. From the VEP/ERP types used, the motion-onset VEPs seems to be the most promising candidate for clinical state monitoring rather than a tool for early diagnostic use. PMID- 20927664 TI - Motor learning in children with neurofibromatosis type I. AB - The aim of this study was to quantify the frequently observed problems in motor control in Neurofibromatosis type 1 (NF1) using three tasks on motor performance and motor learning. A group of 70 children with NF1 was compared to age-matched controls. As expected, NF1 children showed substantial problems in visuo-motor integration (Beery VMI). Prism-induced hand movement adaptation seemed to be mildly affected. However, no significant impairments in the accuracy of simple eye or hand movements were observed. Also, saccadic eye movement adaptation, a cerebellum dependent task, appeared normal. These results suggest that the motor problems of children with NF1 in daily life are unlikely to originate solely from impairments in motor learning. Our findings, therefore, do not support a general dysfunction of the cerebellum in children with NF1. PMID- 20927663 TI - Mechanisms of ethanol-induced death of cerebellar granule cells. AB - Maternal ethanol exposure during pregnancy may cause fetal alcohol spectrum disorders (FASD). FASD is the leading cause of mental retardation. The most deleterious effect of fetal alcohol exposure is inducing neuroapoptosis in the developing brain. Ethanol-induced loss of neurons in the central nervous system underlies many of the behavioral deficits observed in FASD. The cerebellum is one of the brain areas that are most susceptible to ethanol during development. Ethanol exposure causes a loss of both cerebellar Purkinje cells and granule cells. This review focuses on the toxic effect of ethanol on cerebellar granule cells (CGC) and the underlying mechanisms. Both in vitro and in vivo studies indicate that ethanol induces apoptotic death of CGC. The vulnerability of CGC to ethanol-induced death diminishes over time as neurons mature. Several mechanisms for ethanol-induced apoptosis of CGC have been suggested. These include inhibition of N-methyl-D-aspartate receptors, interference with signaling by neurotrophic factors, induction of oxidative stress, modulation of retinoid acid signaling, disturbance of potassium channel currents, thiamine deficiency, and disruption of translational regulation. Cultures of CGC provide an excellent system to investigate cellular/molecular mechanisms of ethanol-induced neurodegeneration and to evaluate interventional strategies. This review will also discuss the approaches leading to neuroprotection against ethanol-induced neuroapoptosis. PMID- 20927665 TI - Effect of vanadium on renal Na+,K+-ATPase activity in diabetic rats: a possible role of leptin. AB - Several researches attempt to protect diabetic patients from the development of nephropathy. Involvement of leptin and renal Na+,K+-ATPase enzyme in diabetic nephropathy (DN) development is a recent field for researches. Vanadium, as a trace element with insulin mimetic effect, may act synergistically with insulin to protect against the development of DN. Sixty male Sprague Dawley rats were divided into six groups: control group (C), vanadium control group (CV), streptozotocin-induced diabetic group (D), insulin-treated diabetic group (DI), vanadium-treated diabetic group (DV), and combined insulin and vanadium-treated diabetic group. Six weeks later, systolic blood pressure (SBP) was measured and retro-orbital blood samples were collected to estimate glycosylated hemoglobin (HbA(1c)), serum sodium (Na+) and creatinine, blood urea nitrogen (BUN) and plasma leptin levels. Preparation of microsomal fraction of renal tissue homogenate for estimation of Na+,K+-ATPase activity was done. The D group showed a significant increase in SBP, HbA(1c), serum Na+, creatinine, and BUN levels and Na+,K+-ATPase activity in microsomal fraction of renal tissue homogenate while plasma leptin level decreased significantly compared with C and CV groups. Both DI and DV groups showed a significant improvement in all the above measured parameters compared with D group while there were no significant changes between the DI and DV groups. Concomitant treatment with insulin and vanadium resulted in a significant improvement in all the measured parameters compared to each alone. Vanadium in combination with insulin ameliorates DN markers and reduces renal Na+,K+-ATPase overactivity in diabetic rats. An effect that may be partially mediated through correction of hypoleptinemia observed in these animals. PMID- 20927668 TI - Measuring the return on our investment. PMID- 20927669 TI - Medical student debt and primary care specialty intentions. AB - BACKGROUND AND OBJECTIVES: This study's purpose was to evaluate the relationship between medical student debt and primary care specialty choice, while examining the potentially confounding effects of family income and race/ethnicity. METHODS: A cross-sectional survey was offered to all students at three medical schools between 2006 and 2008. The survey assessed students' anticipated educational debt and intended specialty choice. The relationship between debt and primary care or non-primary care specialty choice was assessed for all students and also for all students stratified by year in medical school, family income level, and racial/ethnic group. RESULTS: A total of 983 students participated (response rate 64.1%). Students from lower income families and under-represented minority students anticipated more educational debt. There was no relationship between anticipated debt and career plans when participants were analyzed as a whole. However, among students from middle income families, those anticipating more debt were less likely to plan primary care careers. CONCLUSIONS: Confounding factors, including income of family of origin, may mask a relationship between debt and specialty choice in observational studies. This study suggests that medical students from middle income families are sensitive to debt when making career choices. PMID- 20927670 TI - A systematic approach to diabetes mellitus care in underserved populations: improving care of minority and homeless persons. AB - BACKGROUND AND OBJECTIVES: Discrepancy in care of diabetes between racial and ethnic minority groups and Caucasians is well documented in America. System-based practices have been shown to improve quality of care outcomes. We implemented a disease registry and management system proven successful in a suburban practice network in four community health centers to improve diabetes process outcomes. METHODS: Diabetes care measures including HbA1C, LDL, microalbumin testing, and testing for retinopathy were compared for suburban practices and Community Health Center practices within the same health system. A comprehensive systems-based disease management process including a diabetes registry that had been successful with the suburban practices was implemented at the Community Health Centers. Diabetes care measures were followed to determine whether disparity in care could be improved with process-based initiatives. RESULTS: Following implementation of a diabetes registry and system-based disease management process, the percent of Community Health Center patients meeting guidelines improved significantly in all quality measures except the percentage of patients with HbA1C>9%. Despite this improvement, there remained a statistically significant discrepancy in performance between the Community Health Clinics and the suburban practices in most measures including percentage of patients with HbA1C<7%, HbA1C>9%, LDL<130, LDL<100, and percentage of patients with retinopathy screen or microalbumin test within the past year, with the Community Health Centers lagging behind in all comparisons. CONCLUSIONS: A structured systems-based approach to care of minority and at-risk populations utilizing diabetes registries resulted in significant improvement in clinical outcomes and helped to reduce but not eliminate disparities in diabetes outcome measurements between vulnerable and Caucasian populations. PMID- 20927671 TI - The association between the supply of primary care physicians and population health outcomes in Korea. AB - BACKGROUND AND OBJECTIVES: Several studies reported that primary care improves health outcomes for populations. The objective of this study was to examine the relationship between the supply of primary care physicians and population health outcomes in Korea. METHODS: Data were extracted from the 2007 report of the Health Insurance Review, the 2005 report from the Korean National Statistical Office, and the 2008 Korean Community Health Survey. The dependent variables were age-adjusted all-cause and disease-specific mortality rates, and independent variables were the supply of primary care physicians, the ratio of primary care physicians to specialists, the number of beds, socioeconomic factors (unemployment rate, local tax, education), population (population size, proportion of the elderly over age 65), and health behaviors (smoking, exercise, using seat belts rates). We used multivariate linear regression as well as ANOVA and t tests. RESULTS: A higher number of primary care physicians was associated with lower all-cause mortality, cancer mortality, and cardiovascular mortality. However, the ratio of primary care physicians to specialists was not related to all-cause mortality. In addition, the relationship between socioeconomic variables and mortality rates was similar in strength to the relationship between the supply of primary care physicians and mortality rates. Accident mortality, suicide mortality, infection mortality, and perinatal mortality were not related to the supply of primary care physicians. CONCLUSIONS: The supply of primary care physicians is associated with improved health outcomes, especially in chronic diseases and cancer. However, other variables such as the socioeconomic factors and population factors seem to have a more significant influence on these outcomes. PMID- 20927672 TI - Family physicians believe the placebo effect is therapeutic but often use real drugs as placebos. AB - BACKGROUND AND OBJECTIVES: Few national data exist on physicians' use of and beliefs about placebos in routine health care. METHODS: We mailed a 22-question, confidential survey about placebo use and beliefs to a random sample of 1,000 members of the American Academy of Family Physicians. RESULTS: A total of 412 of 970 (43%) eligible physicians responded, and 56% of respondents said they had used a placebo in clinical practice. Forty percent of respondents had used an antibiotic as a placebo, and 11% had used inert substances. The most common reason for prescribing placebos was "after unjustified demand for medication." Eighty-five percent of respondents believed placebos can have both psychological and physical benefits. The majority (61%) recommended a placebo over offering no treatment, while 8% said clinical placebo use should be categorically prohibited. Nearly all respondents believed a number of routine clinical practices promote the placebo effect. CONCLUSIONS: Many US family physicians use placebos and generally believe the placebo effect has both psychological and physical benefits. Physicians recognize the broader application of the placebo effect but they commonly use active medication as placebos. The responses to this survey raise important questions about the appropriate use of placebos and the therapeutic value of the placebo effect in clinical practice. PMID- 20927673 TI - Patient attitudes toward physician use of tablet computers in the exam room. AB - BACKGROUND AND OBJECTIVES: Previous research has examined patients' attitudes toward use of exam room computers by physicians. Our objective was to determine patient attitudes toward physicians' exam room use of new tablet computers. METHODS: A random sample of 96 patients was interviewed immediately following a visit to a physician at an outpatient family medicine clinic at a large academic medical center in central Virginia. We excluded visits to first-year residents. Patients were asked about their attitudes toward technology use in the exam room using a previously validated 16-item structured questionnaire on patient attitudes toward technology use in the exam room. RESULTS: The response rate was 97%. Survey results showed mostly positive patient perceptions of the tablets regardless of age, gender, race, ethnicity, and income. There were differences in attitudes toward privacy (by race and education), use of tablets by the physician (by education and age), depersonalization of the office visit (by race), and speed of medical files overview (by age). CONCLUSIONS: The use of tablet computers by physicians in the examining room is perceived positively by most patients. PMID- 20927674 TI - Does structured audit and feedback improve the accuracy of residents' CPT E&M coding of clinic visits? AB - BACKGROUND AND OBJECTIVES: Family physicians frequently err when applying Current Procedural Terminology (CPT) evaluation and management (E&M) codes to their office visits, but there are few published prospective studies on educational interventions to improve coding. METHODS: Over a 6-year intervention period, 429 resident patient notes from return clinic visits were recoded by a faculty member with coding expertise. Feedback on coding accuracy and annual educational coding workshops were provided to the residents. Coding accuracy was calculated by subtracting residents' code from that of the faculty. Coding accuracy was analyzed cross-sectionally using all available data and longitudinally for 14 residents with data from all 3 years of the residency. RESULTS: Analysis of codings by 68 residents found that residents undercoded their clinic visits by 0.49 levels of service. Higher training year of the resident was associated with more accurate coding. Improvement over time was also found with the longitudinal analysis. However, comparison of 23 residents' coding from before the first feedback and didactic session to codings after starting feedback suggests that these improvements were not due to the intervention. CONCLUSIONS: Residents improved in coding accuracy over time, but our educational intervention may not have been responsible for the improvement. PMID- 20927675 TI - Primary care ride. PMID- 20927676 TI - Spirituality and health's most productive researchers: the role of primary care physicians. PMID- 20927677 TI - Let's break down the barriers. PMID- 20927678 TI - Is it possible to sustain a halt in the decline of medical students' patient centered beliefs? PMID- 20927679 TI - Leadership for change: a vital area for faculty development, continuing education, and resident education. PMID- 20927680 TI - Assessing medical decision making using human patient simulation. AB - BACKGROUND: This pilot study describes an Objective Structured Clinical Examination (OSCE) developed using Human Patient Simulation (HPS). METHODS: Eight residents completed two iterations of this HPS OSCE containing seven stations and utilizing checklists, global ratings, and scoring sheets. RESULTS: The first- and second-year residents scored similarly with mean scores of 64/104 and 62/123, respectively. No statistical difference was noted between the resident scores. CONCLUSIONS: The HPS OSCE is feasible for small groups. A larger study will be needed to determine the effectiveness of this tool for evaluation. PMID- 20927681 TI - Career paths in physicians' postgraduate training - an eight-year follow-up study. AB - QUESTIONS UNDER STUDY: To date, there are hardly any studies on the choice of career path in medical school graduates. The present study aimed to investigate what career paths can be identified in the course of postgraduate training of physicians; what factors have an influence on the choice of a career path; and in what way the career paths are correlated with career-related factors as well as with work-life balance aspirations. METHODS: The data reported originates from five questionnaire surveys of the prospective SwissMedCareer Study, beginning in 2001 (T1, last year of medical school). The study sample consisted of 358 physicians (197 females, 55%; 161 males, 45%) participating at each assessment from T2 (2003, first year of residency) to T5 (2009, seventh year of residency), answering the question: What career do you aspire to have? Furthermore, personal characteristics, chosen specialty, career motivation, mentoring experience, work life balance as well as workload, career success and career satisfaction were assessed. Career paths were analysed with cluster analysis, and differences between clusters analysed with multivariate methods. RESULTS: The cluster analysis revealed four career clusters which discriminated distinctly between each other: (1) career in practice, (2) hospital career, (3) academic career, and (4) changing career goal. From T3 (third year of residency) to T5, respondents in Cluster 1-3 were rather stable in terms of their career path aspirations, while those assigned to Cluster 4 showed a high fluctuation in their career plans. Physicians in Cluster 1 showed high values in extraprofessional concerns and often consider part-time work. Cluster 2 and 3 were characterised by high instrumentality, intrinsic and extrinsic career motivation, career orientation and high career success. No cluster differences were seen in career satisfaction. In Cluster 1 and 4, females were overrepresented. CONCLUSION: Trainees should be supported to stay on the career path that best suits his/her personal and professional profile. Attention should be paid to the subgroup of physicians in Cluster 4 switching from one to another career goal in the course of their postgraduate training. PMID- 20927682 TI - Meniere's disease and the use of proton pump inhibitors. AB - PRINCIPLES: On the basis of previous observations we examined the possibility of a favourable effect of proton pump inhibitors (PPI) on Meniere's disease (MD). A preliminary step was made by retrospectively analysing the number of menieric crisis in group of patients suffering from MD and using PPI for other reasons as compared to a group of menieric subjects who had never used PPI. METHODS: Between January 2001 and December 2006, 42 patients affected by MD were examined in the tertiary referral centre at the University Hospital of Bologna, Italy and in the private office of an ENT specialist in Cassino, Italy. Within the study group, 18 patients had used PPI for various reasons for at least 12 consecutive months, whilst 24 patients had never been prescribed them. We recorded the number of menieric crises reported in the observation period. The mean follow-up period was 21.9 months. Statistical analysis was performed by means of the x2 test and significance was defined when p<0.05. RESULTS: Most of MD patients (72%) using PPI suffered less than one episode of menieric crisis/year. On the other hand patients who had never used a PPI, experienced considerably more episodes only 16.7% having less than one crisis per year. This difference was statistically significant (p<0, 001). CONCLUSIONS: Even taking the limitations of this retrospective study into account the reported data nevertheless strongly suggest a possible role for proton pumps in the pathogenesis of MD. This could lead to interesting developments and contribute to a better definition of MD and the therapeutic possibilities. PMID- 20927683 TI - Association between smoking and presence of mycoplasma pneumoniae in circulating leukocytes. AB - PRINCIPLES: The morbidity and mortality of infectious diseases due to smoking are not widely appreciated by physicians. However, cigarette smoking appears to be a major risk factor for respiratory tract and other systemic infections. Only limited data are available on the association between smoking and Mycoplasma (M) pneumoniae. We raise the question of whether smoking increases the presence of M pneumoniae in circulating leukocytes. Furthermore we have studied whether the combination of smoking and M pneumoniae infection affects circulating levels of inflammatory biomarkers. METHODS: Prevalence of latent M pneumoniae infection was analysed in a total of 122 subjects by polymerase chain reaction. Smoking status was documented at presentation. Circulating levels of c-reactive protein, macrophage chemoattractant protein-1 and complement factor 5a were determined by commercial enzyme linked immuno-sorbent assays. RESULTS: We found a significant association between smoking and latent M pneumoniae infection (p = 0.009). This association remained significant after correction for age, gender and diabetes (OR 3.4; 95% CI 1.3-9.4; p = 0.017). There was no correlation between circulating levels of the inflammatory biomarkers studied and smoking or M pneumoniae infection, respectively. CONCLUSIONS: Our data indicate that smoking is associated with the presence of M pneumoniae in circulating leukocytes. This could contribute to the pro-inflammatory effects of smoking. Despite the low number of subjects included in this study, this is an interesting finding demanding further investigation. PMID- 20927684 TI - Emergency physician intershift handover - can a dINAMO checklist speed it up and improve quality? AB - BACKGROUND: Physician intershift handover has been identified as an area of high risk for adverse events, representing a critical step in patient care transition. Due to frequent shift changes and high patient numbers, emergency departments offer an ideal study setting. AIM OF THE STUDY: At a tertiary care hospital emergency department we aimed to reduce the time needed for patient handover while maintaining or improving quality of information passed between shifts. METHODS: Between 31 March and 20 June 2008 we observed intershift handovers in all non-surgical patients at 8 a.m. between nightshift and dayshift. We collected data on handover characteristics and patient demographics. After the usual clinical rounds following each handover, we asked senior physicians about missing or wrong information and possible implications for patient management. From 31 March to 9 May pre-interventional observation took place. On 13 May the dINAMO checklist with five items and a standardised feedback following each handover was introduced. Post-interventional observation lasted until 20 June. RESULTS: 61 handovers totalling 23.4 hours of observation time covered 1011 patients. The intervention using the dINAMO checklist reduced mean handover time by 26% from 99 +/- 3.3 to 73 +/- 2.8 seconds per individual patient (p <0.0001). This resulted in a reduction of morning handover duration from 30 to 20 minutes. Senior physicians reported insignificant improvement of quality of handover. A significant decline in missing or wrong information from 194 incidents in 496 patients to 78 in 470 patients was recorded. CONCLUSIONS: An intervention consisting of a simple checklist of five items (dINAMO) and an immediate feedback on quality not only contributes to a significant shortening of time needed for physician intershift handover in a university hospital emergency department, but simultaneously helps to improve quality of information and therefore patient management. PMID- 20927686 TI - Intrathecal synthesis of specific antibodies as a marker of herpes simplex encephalitis in patients with negative PCR. AB - BACKGROUND: PCR in the cerebrospinal fluid (CSF) has become the sole method used for the diagnosis of herpes simplex encephalitis (HSE). Nevertheless, PCR results may sometimes be false negative, and in this situation other techniques may be useful. METHODS: 3 patients hospitalised for meningoencephalitis with fever showed a negative result for herpes simplex virus (HSV) PCR in their CSF. We then performed a detection of intrathecal anti-HSV immunoglobulins (IgGs) in the CSF and analysed their level in relation to those in the serum, compared to albumin. RESULTS: We confirmed that IgG synthesis was the direct consequence of an immune system reaction in the 3 patients' CSF. These results were consistent with clinical signs and neurodiagnostic procedures. They prompted us to continue the treatment, which would have been stopped following the negative PCR results. The clinical progression was favourable for all patients. CONCLUSIONS: PCR, which many physicians now consider the gold standard for the detection of HSV, may sometimes yield false negative results, i.e. when performed too early after the disease onset or when the viral load is too low. The method described here, although positive a few days after PCR, may prove helpful in the diagnosis of HSE for patients with negative HSV PCR in the CSF. PMID- 20927685 TI - Liver injury caused by drugs: an update. AB - Although severe idiosyncratic drug-induced liver injury (DILI) is a rare event, it has a large impact on the fate of affected patients and the incriminated drug. Hepatic metabolism of drugs, which occurs in the generation of chemically reactive metabolites in critical amounts, seems to underlie most instances of DILI. Genetic polymorphisms in activating and detoxifying enzymes determine, in part, the extent of cellular stress. A cascade of events, where the pathogenetic relevance of single steps is likely to vary from drug to drug, leads to the disturbance of cellular homeostasis, to mitochondrial dysfunction, to the activation of cell death promoting pathways and the release of drug-modified macromolecules and/or danger signals that initiate an innate and/or adaptive immune response. The patient's response to the initial drug-induced cellular dysfunction determines whether adaptation to the drug-induced cellular stress or DILI in one of its many forms of clinical presentation occurs. Although risk factors for developing DILI have been identified and many pathogenetic mechanisms have been elucidated in model systems, idiosyncratic drug reactions remain unpredictable. PMID- 20927687 TI - [Complex therapeutic procedures, their documentation and the German DRG-system]. PMID- 20927688 TI - [Acute stroke treatment - an update]. AB - An optimised prehospital management is important for acute stroke patients. A structured admittance to a stroke centre increases the rate of thrombolysis four fold. To achieve short door-to-needle-times (< 30 min) a multi-disciplinary approach is necessary. Elderly stroke patients benefit from stroke unit therapy as do the younger patients. Blood pressure management is important during the first 24 hours after thrombolysis. Systolic blood pressures between 140 - 150 mmHg correlate with low bleeding rates. A subgroup analysis of the ECASS III study shows that a broad range of patients can be treated safely and efficiently in the 3 - 4.5 hour time window. Endovascular recanalisation therapy achieves high recanalisation rates. Whether these will be responsible for a significantly better outcome has to be shown in future randomised trials. PMID- 20927689 TI - [Secondary stroke prevention - an update]. AB - Organised secondary prevention is a prerequisite for successful stroke therapy. One of the most relevant factors is elevated blood pressure. It has been shown that long-term blood pressure treatment leads to a significant reduction in mortality of almost 10 % over a 5-year period. Additionally, a large meta analysis in almost 1 million patients confirmed that blood pressure reduction leads to a constant reduction in secondary cerebrovascular events by 40 %, both in primary and secondary prevention. The preventive effect was stronger as the blood pressure reduction increased. Interactions between proton-pump inhibitors and the antiplatelet agent clopidogrel did not receive scientific confirmation. There is no reason to avoid this combination. Patients suffering from atrial fibrillation and stroke should, whenever possible, be treated by oral anticoagulation. In cases in which this treatment is abandoned, the combination of aspirin and clopidogrel offers some marginal benefits over aspirin alone (higher stroke risk reduction, but increase in brain haemorrhages). Dabigatran is a new direct oral thrombin antagonist. It has the advantage compared to the oral vitamin K antagonists that it acts immediately after intake and does not need further regular coagulation test controls. The huge RELY study revealed that dabigatran is safer with the same efficacy in the lower dose, but more effective with the same safety in the higher dose, compared to oral vitamin K antagonists. It will be licensed in 2010. Statins seem to be beneficial for as long as 10 years after a cerebrovascular accident. Carotid stenosis treatment seems to be better done by operation as revealed by the International Carotid Stenosis Stenting study. A patent foramen ovale is a slight risk factor with an OR of 1.1. Therefore, any aggressive treatment options in patients with stroke and pfo seem to be unjustified. PMID- 20927691 TI - [Rightcoding and OPS for the new performance-based reimbursement system of German clinical psychiatry]. PMID- 20927690 TI - [Antiepileptic drug-induced encephalopathy]. AB - The clinical features of an antiepileptic drug-induced encephalopathy (ADE) are confusion, reduction of vigilance, neurological deficits or an increase of the seizure frequency. In the electroencephalogram a general slowing or epileptic discharges are found. Characteristic are non-toxic blood levels of the antiepileptic drugs. So far an ADE was reported under phenytoin, carbamazepine or valproatic acid (valproate) therapy. More seldom, an ADE has been described after the intake of vigabatrine, lamotrigine und topiramate. Potential pathogenic mechanisms of AED are hyperammonemia, intrinsic effects on cerebral receptors, drug interactions, hepatic enzyme interactions, metabolic reasons or paradoxical proconvulsive effects of antiepileptic drugs. The medicamentous therapy consists of an immediate discontinuation of the antiepileptic drug. PMID- 20927693 TI - [Dimensions of the therapeutic alliance from patients' view--development of the "Skala Therapeutische Allianz-Revised STA-R"]. AB - Studies on the dimensionality of the therapeutic alliance had been conducted by Hatcher et al. factor-analyzing three widely used alliance measures (Helping Alliance Questionnaire, Working Alliance Inventory, California Psychotherapy Alliance Scales) and proposing two additional dimensions (on affects and interpersonal aspects). The present study intended to construct an economic German patient questionnaire on the basis of this preliminary work, which represents relevant dimensions of the therapeutic alliance in an economic way. 36 items, purposed by Hatcher et al. were translated into German. They have been examined by confirmative factor analysis (sample 1: N=301 psychotherapy patients). As a result of further factor analysis, the "Skala Therapeutische Allianz - Revised STA-R" was developed. The 17-items questionnaire has 4 scales: "Confident Collaboration", "Bond", "Patient Fear" and "Therapist Interference", which correspond to Hatcher et al. The latter scales have not yet been considered in German questionnaires. A confirmatory factor analysis with sample 2 (N=427 patients) showed a good model fit with these factors, too. Correlations of the therapeutic alliance at the end of the treatment with change in symptom load (SCL 90-R) proved to be significant (rSTA-R, GSI=0.43**). PMID- 20927694 TI - Antiplasmodial constituents from the fruit pericarp of Pentadesma butyracea. AB - Bioassay-guided fractionation of the fruit pericarp of Pentadesma butyracea, using the antiplasmodial test, led to the isolation of a new xanthone, named pentadexanthone (1), together with six known compounds: cratoxylone (2), alpha mangostin (3), 1,3,5-trihydroxy-2-methoxyxanthone (4), garcinone E (5), (-) epicathechin (6), and lupeol (7). The structure of 1 was elucidated by spectroscopic data analysis. An antiplasmodial assay was performed with the isolates, in which compounds 1- 3 and 5 exhibited potent activity in vitro against Plasmodium falciparum chloroquine-resistant strain W2, with IC50 values below 3 uM. PMID- 20927695 TI - A survey of U.K. units and a suggested protocol for free flap reconstruction of the lower limb: follow-up and management in the first postoperative week. AB - A survey was performed of U.K. lower-limb reconstruction services and the protocol for management of free flaps to the lower limb in the first postoperative week. The postoperative period is of vital importance in these patients due to the complex nature of microsurgical tissue transfer. A range of answers were received in response to the questions regarding protocols, with no overall consensus on the postoperative plan for these patients. Patients are being managed differently in different units across the United Kingdom. A protocol that has been used successfully by the senior author is described, and we encourage others without a protocol to adopt this one. PMID- 20927696 TI - Pure muscle transfers can be monitored by use of microdialysis. AB - Most of the methods available for postoperative monitoring of free transfers depend on an accessible skin island. Monitoring of muscle transfers without skin islands represents a challenge. The aim of this study was to describe the experiences after clinical monitoring of free muscle transfers by the use of microdialysis. The charts of 75 free muscle transfers monitored with microdialysis were evaluated with special emphasis on whether or not complications were predicted by the monitoring system. In 16 of the 75 cases, an ischemic trend was seen. In five of these cases, the ischemic trend was reversed without surgical revascularization. In the remaining 11 cases (14.7%), further ischemic trends were seen, and surgical revision with revascularization was needed for transfer salvage. Six of the 11 transfers were subsequently saved. None of the remaining five transfers were lost due to neglected ischemia. The microdialysis system did not exhibit any negative or positive false alarms. No damage to the muscle flap was experienced while performing the monitoring procedures. Microdialysis is a reliable and safe monitoring method for surveillance of free muscle transfers. PMID- 20927697 TI - A critical analysis and discussion of the appropriateness of the schizophrenia consensus remission criteria in clinical pharmaceutical trials. AB - BACKGROUND: The aim of this paper is to apply the proposed consensus remission criteria to an acutely ill inpatient sample at admission and evaluate their adaptability in this patient population and pharmaceutical trials. METHODS: The Remission in Schizophrenia Working Group's consensus criteria were applied to 272 acutely ill schizophrenia patients. Patients were examined using the PANSS, HAMD, UKU and SWN-K total scales at admission as well as the GAF, SOFAS and the Strauss Carpenter Prognostic Scale. Sociodemographic and clinical baseline variables were assessed using a standardized documentation system. RESULTS: 33 patients (12%) fulfilled the symptom severity component of the proposed remission criteria already at baseline. Almost no significant differences were found when comparing patients with achieved and failed symptom severity component that would explain the hospitalization of the patients with achieved criteria despite their apparently mild psychopathological symptoms. The only explainable difference was that patients with an achieved symptom severity component had received significantly more antipsychotics and had suffered from significantly more life events before admission. CONCLUSION: The present results raise the question whether the symptom severity threshold is adequate to identify patients in remission when applied in clinical trials. PMID- 20927700 TI - Bilateral temporal 1 Hz rTMS (repetitive transcranial magnetic stimulation) treatment in a left-handed patient with imperative auditory hallucinations. PMID- 20927698 TI - Zonisamide versus diazepam in the treatment of alcohol withdrawal syndrome. AB - INTRODUCTION: Anticonvulsant drugs have been used in the treatment of alcohol detoxification. The purpose of the present study was to evaluate the efficacy and safety of zonisamide in a sample of patients presenting alcohol withdrawal syndrome. METHOD: In this 3-week, randomized, flexible-dose trial, 40 inpatients with alcohol dependence disorder received zonisamide or diazepam for detoxification. Zonisamide was started at a dose of 400-600 mg/day (week 1), tapering to a minimum dose of 100-300 mg/day (week 3). Diazepam was administered using a similar regimen (from 130-50 mg/day tapering to 5-15 mg/day). Subjects were treated initially (weeks 1 and 2) in an inpatient unit and for the final week in an outpatient facility. During the inpatient period, the Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar) was used to assess the efficacy of each substance. During the outpatient period the Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar), Hamilton Anxiety Rating Scale, Hamilton Depression Rating Scale, and a craving scale were used. RESULTS: All subjects completed the study. During the inpatient period both drugs reduced alcohol withdrawal symptoms, but the decrease was more marked in the zonisamide group. At the end of the study (week 3) participants treated with zonisamide showed lower CIWA-Ar scores than subjects receiving diazepam. Also, individuals in the zonisamide group had less craving for alcohol, less anxiety, and less daytime sedation compared with participants treated with diazepam. CONCLUSION: Zonisamide can be a valuable alternative to benzodiazepines in the prevention of alcohol withdrawal syndrome. PMID- 20927699 TI - Torsade de Pointes episodes under treatment with selective serotonin reuptake inhibitors. PMID- 20927701 TI - Risperidone-induced sialorrhea: dose-related? PMID- 20927711 TI - Switching off angiogenic signalling: creating channelled constructs for adequate oxygen delivery in tissue engineered constructs. AB - A major question in biomimetic tissue engineering is how much of the structure/function of native vasculature needs to be reproduced for effective tissue perfusion. O2 supplied to cells in 3D scaffolds in vitro is initially dependent upon diffusion through the scaffold and cell consumption. Low O2 (3%) enhances specific cell behaviours, but where O2 is critically low (pathological hypoxia) cell survival becomes compromised. We measured real-time O2 in 3D scaffolds and introduced micro-channelled architecture to controllably increase delivery of O2 to cells and switch off the hypoxic response. Simple static micro channelling gives adequate perfusion and can be used to control cell generated hypoxia-induced signalling. PMID- 20927712 TI - Reticulated vitreous carbon: a useful material for cell adhesion and tissue invasion. AB - Diverse carbon materials have been used for tissue engineering and clinical implant applications with varying success. In this study, commercially available reticulated vitreous carbon (RVC) foams were tested in vitro and in vivo for compatibility with primary cell adhesion and tissue repair. Pores sizes were determined as 279 +/- 98 MUm. No hydroxyapatite deposition was detected after immersion of the foams in simulated body fluid. Nonetheless, RVC provided an excellent support for adhesion of mesenchymal stem cells (MSCs) as well as primary chondrocytes without any surface pre-treatment. Live cell quantification revealed neutral behaviour of the material with plastic adhered chondrocytes but moderate cytotoxicity with MSCs. Yet, rabbit implanted foams exhibited good integration in subcutaneous pockets and most importantly, total defect repair in bone. Probably due to the stiffness of the material, incompatibility with cartilage regeneration was found. Interestingly and in contrast to several other carbon materials, we observed a total lack of foreign body reactions. Our results and its outstanding porous interconnectivity and availability within a wide range of pore sizes convert RVC into an attractive candidate for tissue engineering applications in a variety of bone models and for ex vivo cell expansion for regenerative medical applications. PMID- 20927713 TI - Soybean physiology and gene expression during drought. AB - Soybean genotypes MG/BR46 (Conquista) and BR16, drought-tolerant and -sensitive, respectively, were compared in terms of morphophysiological and gene-expression responses to water stress during two stages of development. Gene-expression analysis showed differential responses in Gmdreb1a and Gmpip1b mRNA expression within 30 days of water-deficit initiation in MG/BR46 (Conquista) plants. Within 45 days of initiating stress, Gmp5cs and Gmpip1b had relatively higher expression. Initially, BR16 showed increased expression only for Gmdreb1a, and later (45 days) for Gmp5cs, Gmdefensin and Gmpip1b. Only BR16 presented down regulated expression of genes, such as Gmp5cs and Gmpip1b, 30 days after the onset of moisture stress, and Gmgols after 45 days of stress. The faster perception of water stress in MG/BR46 (Conquista) and the better maintenance of up-regulated gene expression than in the sensitive BR16 genotype imply mechanisms by which the former is better adapted to tolerate moisture deficiency. PMID- 20927714 TI - Genetic variation of Kaempferia (Zingiberaceae) in Thailand based on chloroplast DNA (psbA-trnH and petA-psbJ) sequences. AB - Genetic variation and species authentication of 71 Kaempferia accessions (representing 15 recognized, six new, and four unidentified species) found indigenously in Thailand were examined by determining chloroplast psbA-trnH and partial petA-psbJ spacer sequences. Ten closely related species (Boesenbergia rotunda, Gagnepainia godefroyi, G. thoreliana, Globba substrigosa, Smithatris myanmarensis, S. supraneanae, Scaphochlamys biloba, S. minutiflora, S. rubescens, and Stahlianthus sp) were also included. After sequence alignments, 1010 and 865 bp in length were obtained for the respective chloroplast DNA sequences. Intraspecific sequence variation was not observed in Kaempferia candida, K. angustifolia, K. laotica, K. galanga, K. pardi sp nov., K. bambusetorum sp nov., K. albomaculata sp nov., K. minuta sp nov., Kaempferia sp nov. 1, and G. thoreliana, for which more than one specimen was available. In contrast, intraspecific sequence polymorphisms were observed in various populations of K. fallax, K. filifolia, K. elegans, K. pulchra, K. rotunda, K. marginata, K. parviflora, K. larsenii, K. roscoeana, K. siamensis, and G. godefroyi. A strict consensus tree based on combined psbA-trnH and partial petA-psbJ sequences revealed four major groups of Kaempferia species. We suggest that the genus Kaempferia is a polyphyletic group, as K. candida was distantly related and did not group with other Kaempferia species. Polymorphic sites and indels of psbA trnH and petA-psbJ can be used as DNA barcodes for species diagnosis of most Kaempferia and outgroup species. Nuclear DNA polymorphism should be examined to determine if there has been interspecific hybridization and chloroplast DNA introgression in these taxa. PMID- 20927715 TI - Differential expression of genes in resistant versus susceptible Gyr x Holstein cattle challenged with the tick Rhipicephalus (Boophilus) microplus. AB - The bovine tick Rhipicephalus (Boophilus) microplus causes major losses in cattle production systems in tropical regions. Bos indicus breeds are more resistant to ticks than B. taurus breeds. Resistance genes could be an alternative to control this parasite. We examined the pattern of gene expression of three calcium binding-protein genes: translationally controlled tumor protein 1 (TPT1), allergen Bos d3 (S100A7), calcium channel protein transient receptor potential vanilloid 6 (TRPV6), and the cysteine proteinase inhibitor gene (CST6). These genes were selected from cDNA libraries prepared from skin biopsies taken from resistant and susceptible Gyr x Holstein F2 animals. These biopsies were also used to study the expression level of these genes through real-time PCR analysis. The relative expression levels of the S100A7, TPT1, TRPV6, and CST6 genes were 2.01 +/- 0.6, 1.32 +/- 0.9, 1.53 +/- 1.2, and 2.03 +/- 0.7 times higher in the susceptible group, respectively. Skin lesion tissue from the susceptible animals showed significantly more mRNA transcripts of these genes in comparison with the resistant animals (P = 0.001). However, this hypersensitivity does not seem to protect the susceptible animals against tick infestation. PMID- 20927716 TI - RAPD analysis of selected local Turkish grape cultivars (Vitis vinifera). AB - Turkey is very rich in local grape varieties. The solution to the problem of identifying local cultivars, which is considered an important deficiency for the region, will only be possible when they can be defined with molecular markers. Forty-nine local grapevine cultivars from Sanliurfa (Turkey) were characterized with RAPD markers. Twenty-five decamer primers selected from 60 primers were used in this analysis. A total of 171 bands were obtained with the 25 primers, of which 112 were polymorphic; the level of DNA polymorphism was 65.49% in these local cultivars. Among the selected primers, OPA-18, OPO-07 and P-123 gave the maximum number of polymorphic bands (seven). Genetic relationships among these cultivars were determined with a similarity index and using a dendogram. Among the grape cultivars, the lowest similarity ratio (0.578) was observed among the Kulahi-Kizilbanki cultivars and the highest similarity ratio (0.908) was observed for the Cilorut-Dokulgen combination. The high similarity ratio among the grape cultivars of Sanliurfa Province was also reflected in the dendogram. In general, no relationships were encountered between the genetic identification of the cultivars and their ampelographic properties. PMID- 20927717 TI - Phylogenetic relationships of Malaysian monkeys, Cercopithecidae, based on mitochondrial cytochrome c sequences. AB - Mitochondrial DNA cytochrome c oxidase II (COII) gene sequences of Malaysian Cercopithecidae were examined to ascertain their phylogenetic relationships. Colobinae were represented by the genera Presbytis, Trachypithecus and Nasalis, while the genus Macaca represented Cercopithecinae. DNA amplification and sequencing of the COII gene was performed on 16 samples. Symphalangus syndactylus (Hylobatidae) was used as the outgroup. Data were analyzed using both character (maximum parsimony) and distance (neighbor-joining) methods. Tree topologies indicated that Colobinae and Cercopithecinae have their own distinct monophyletic clade. This result was well supported by bootstrap values and genetic distances derived from the Kimura-2-parameter algorithm. Separation of Macaca nemestrina from M. fascicularis was also well supported by bootstrap values. In addition, tree topologies indicate a good resolution of the Colobinae phylogenetic relationships at the intergeneric level, but with low bootstrap support. The position of Nasalis remained problematic in both trees. Overall, COII is a good gene candidate for portraying the phylogenetic relationships of Malaysian primates at the inter- and intra-subfamily levels. PMID- 20927718 TI - Percutaneous biopsy of anterior mediastinal mass guided by real-time US fused with CT. AB - We report a case of successful fused CT-sonographic imaging-guided percutaneous biopsy of an anterior mediastinal mass, which was visualized poorly with conventional sonography. Real-time sonography fused with CT can be useful for biopsy of anterior mediastinal masses that are not well visualized on conventional sonography. PMID- 20927719 TI - Magnesium sulphate versus phenytoin for eclampsia. AB - BACKGROUND: Eclampsia, the occurrence of a seizure in association with pre eclampsia, remains a rare but serious complication of pregnancy. A number of different anticonvulsants have been used to control eclamptic fits and to prevent further seizures. OBJECTIVES: The objective of this review was to assess the effects of magnesium sulphate compared with phenytoin when used for the care of women with eclampsia. Magnesium sulphate is compared with diazepam and with lytic cocktail in other Cochrane reviews. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 April 2010). SELECTION CRITERIA: Randomised trials comparing magnesium sulphate (intravenous or intramuscular administration) with phenytoin for women with a clinical diagnosis of eclampsia. DATA COLLECTION AND ANALYSIS: Two review authors assessed trial quality and extracted data. MAIN RESULTS: We have included data from seven trials, involving 972 women. One large trial (775 women) was of good quality. Magnesium sulphate was associated with a substantial reduction in the recurrence of seizures, when compared to phenytoin (six trials, 972 women; risk ratio (RR) 0.34, 95% confidence interval (CI) 0.24 to 0.49). The trend in maternal mortality favours magnesium sulphate, but the difference does not reach statistical significance (three trials, 847 women; RR 0.50, 95% CI 0.24 to 1.05). There were reductions in the risk of pneumonia (one trial, RR 0.44, 95% CI 0.24 to 0.79), ventilation (one trial, RR 0.68, 95% CI 0.50 to 0.91) and admission to an intensive care unit (one trial, RR 0.67, 95% CI 0.50 to 0.89) associated with the use of magnesium sulphate rather than phenytoin.For the baby, magnesium sulphate was associated with fewer admissions to a special care baby unit (SCBU) (one trial, 518 babies; RR 0.73, 95% CI 0.58 to 0.91) and fewer babies who died or were in SCBU for more than seven days (one trial, 643 babies; RR 0.77, 95% CI 0.63 to 0.95) than phenytoin. There was no clear difference in perinatal deaths (two trials, 665 babies; (RR 0.85, 95% CI 0.67 to 1.09). AUTHORS' CONCLUSIONS: Magnesium sulphate, rather than phenytoin, for women with eclampsia reduces the risk ratio of recurrence of seizures, probably reduces the risk of maternal death, and improves outcome for the baby. Magnesium sulphate is the drug of choice for women with eclampsia. The use of phenytoin should be abandoned. PMID- 20927720 TI - Antithrombotic drugs for carotid artery dissection. AB - BACKGROUND: Extracranial internal carotid artery dissection (eICAD) is a leading cause of stroke in younger patients. OBJECTIVES: 1. To determine whether, in patients with eICAD, treatment with anticoagulants, antiplatelet agents or control was associated with a better functional outcome. 2. To compare, among patients treated with either anticoagulants or antiplatelet agents, the risk of ischaemic strokes and major bleeding episodes. SEARCH STRATEGY: We searched the Cochrane Stroke Group Trials Register (last searched 3 October 2009). In addition, we performed comprehensive searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 2, 2009), MEDLINE (January 1966 to November 2009) and EMBASE (January 1980 to November 2009), checked all relevant papers for additional eligible studies and contacted authors and researchers in the field. SELECTION CRITERIA: Randomised controlled trials, controlled clinical trials and non-randomised studies (if they reported on outcome stratified by antithrombotic treatment and included at least four patients) of anticoagulants or antiplatelet agents for the treatment of extracranial internal carotid artery dissection. Two review authors independently extracted data. DATA COLLECTION AND ANALYSIS: Primary outcomes were death (all causes) and death or disability. Secondary outcomes were ischaemic stroke, symptomatic intracranial haemorrhage, and major extracranial haemorrhage during the reported follow-up period. The first choice treatment was taken for analyses. MAIN RESULTS: We did not find any completed randomised trials. Comparing antiplatelets with anticoagulants across 36 observational studies (1285 patients), there were no significant differences in the odds of death (Peto odds ratio (Peto OR) 2.02, 95% CI 0.62 to 6.60), or the occurrence of ischaemic stroke (OR 0.63, 95% CI 0.21 to 1.86) (34 studies, 1262 patients). For the outcome of death or disability, there was a non-significant trend in favour of anticoagulants (OR 1.77, 95% CI 0.98 to 3.22; P = 0.06) (26 studies, 463 patients). Symptomatic intracranial haemorrhages (5/627; 0.8%) and major extracranial haemorrhages (7/425; 1.6%) occurred only in the anticoagulation group; however, for both these outcomes, the estimates were imprecise and indicated no significant difference between the two treatment modalities. AUTHORS' CONCLUSIONS: There were no randomised trials comparing either anticoagulants or antiplatelet drugs with control, thus there is no evidence to support their routine use for the treatment of extracranial internal carotid artery dissection. There were also no randomised trials that directly compared anticoagulants with antiplatelet drugs and the reported non-randomised studies did not show any evidence of a significant difference between the two. PMID- 20927721 TI - Alternative versus standard packages of antenatal care for low-risk pregnancy. AB - BACKGROUND: The number of visits for antenatal (prenatal) care developed without evidence of how many visits are necessary. The content of each visit also needs evaluation. OBJECTIVES: To compare the effects of antenatal care programmes with reduced visits for low-risk women with standard care. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (April 2010), reference lists of articles and contacted researchers in the field. SELECTION CRITERIA: Randomised trials comparing a reduced number of antenatal visits, with or without goal-oriented care, with standard care. DATA COLLECTION AND ANALYSIS: Two authors assessed trial quality and extracted data independently. MAIN RESULTS: We included seven trials (more than 60,000 women): four in high-income countries with individual randomisation; three in low- and middle-income countries with cluster randomisation (clinics as the unit of randomisation). The number of visits for standard care varied, with fewer visits in low- and middle- income country trials. In studies in high-income countries, women in the reduced visits groups, on average, attended between 8.2 and 12 times. In low- and middle- income country trials, many women in the reduced visits group attended on fewer than five occasions, although in these trials the content as well as the number of visits was changed, so as to be more 'goal oriented'.Perinatal mortality was increased for those randomised to reduced visits rather than standard care, and this difference was borderline for statistical significance (five trials; risk ratio (RR) 1.14; 95% confidence interval (CI) 1.00 to 1.31). In the subgroup analysis, for high-income countries the number of deaths was small (32/5108), and there was no clear difference between the groups (2 trials; RR 0.90; 95% CI 0.45 to 1.80); for low- and middle income countries perinatal mortality was significantly higher in the reduced visits group (3 trials RR 1.15; 95% CI 1.01 to 1.32). Reduced visits were associated with a reduction in admission to neonatal intensive care that was borderline for significance (RR 0.89; 95% CI 0.79 to 1.02). There were no clear differences between the groups for the other reported clinical outcomes.Women in all settings were less satisfied with the reduced visits schedule and perceived the gap between visits as too long. Reduced visits may be associated with lower costs. AUTHORS' CONCLUSIONS: In settings with limited resources where the number of visits is already low, reduced visits programmes of antenatal care are associated with an increase in perinatal mortality compared to standard care, although admission to neonatal intensive care may be reduced. Women prefer the standard visits schedule. Where the standard number of visits is low, visits should not be reduced without close monitoring of fetal and neonatal outcome. PMID- 20927722 TI - Vaginal misoprostol for cervical ripening and induction of labour. AB - BACKGROUND: Misoprostol (Cytotec, Searle) is a prostaglandin E1 analogue widely used for off-label indications such as induction of abortion and of labour. This is one of a series of reviews of methods of cervical ripening and labour induction using standardised methodology. OBJECTIVES: To determine the effects of vaginal misoprostol for third trimester cervical ripening or induction of labour. SEARCH STRATEGY: The Cochrane Pregnancy and Childbirth Group's Trials Register (November 2008) and bibliographies of relevant papers. We updated this search on 30 April 2010 and added the results to the awaiting classification section. SELECTION CRITERIA: Clinical trials comparing vaginal misoprostol used for third trimester cervical ripening or labour induction with placebo/no treatment or other methods listed above it on a predefined list of labour induction methods. DATA COLLECTION AND ANALYSIS: We developed a strategy to deal with the large volume and complexity of trial data relating to labour induction. This involved a two-stage method of data extraction.We used fixed-effect Mantel-Haenszel meta analysis for combining dichotomous data.If we identified substantial heterogeneity (I2 greater than 50%), we used a random-effects method. MAIN RESULTS: We included 121 trials. The risk of bias must be kept in mind as only 13 trials were double blind.Compared to placebo, misoprostol was associated with reduced failure to achieve vaginal delivery within 24 hours (average relative risk (RR) 0.51, 95% confidence interval (CI) 0.37 to 0.71). Uterine hyperstimulation, without fetal heart rate (FHR) changes, was increased (RR 3.52 95% CI 1.78 to 6.99).Compared with vaginal prostaglandin E2, intracervical prostaglandin E2 and oxytocin, vaginal misoprostol was associated with less epidural analgesia use, fewer failures to achieve vaginal delivery within 24 hours and more uterine hyperstimulation. Compared with vaginal or intracervical prostaglandin E2, oxytocin augmentation was less common with misoprostol and meconium-stained liquor more common.Lower doses of misoprostol compared to higher doses were associated with more need for oxytocin augmentation and less uterine hyperstimulation, with and without FHR changes.We found no information on women's views. AUTHORS' CONCLUSIONS: Vaginal misoprostol in doses above 25 mcg four hourly was more effective than conventional methods of labour induction, but with more uterine hyperstimulation. Lower doses were similar to conventional methods in effectiveness and risks. The authors request information on cases of uterine rupture known to readers. The vaginal route should not be researched further as another Cochrane review has shown that the oral route of administration is preferable to the vaginal route. Professional and governmental bodies should agree guidelines for the use of misoprostol, based on the best available evidence and local circumstances. PMID- 20927723 TI - Hypnotherapy for smoking cessation. AB - BACKGROUND: Hypnotherapy is widely promoted as a method for aiding smoking cessation. It is proposed to act on underlying impulses to weaken the desire to smoke or strengthen the will to stop. OBJECTIVES: To evaluate the efficacy of hypnotherapy for smoking cessation. SEARCH STRATEGY: We searched the Cochrane Tobacco Addiction Group Specialized Register and the databases MEDLINE, EMBASE, AMED, SCI, SSCI using the terms smoking cessation and hypnotherapy or hypnosis. Date of most recent searches July 2010. There were no language restrictions. SELECTION CRITERIA: We considered randomized controlled trials of hypnotherapy which reported smoking cessation rates at least six months after the beginning of treatment. DATA COLLECTION AND ANALYSIS: Three authors independently extracted data on participant characteristics, the type and duration of the hypnotherapy, the nature of the control group, smoking status, method of randomization, and completeness of follow up. They also independently assessed the quality of the included studies.The main outcome measure was abstinence from smoking after at least six months follow up. We used the most rigorous definition of abstinence in each trial, and biochemically validated rates where available. Those lost to follow up were considered to be smoking. We summarised effects as risk ratios (RR). Where possible, we performed meta-analysis using a fixed-effect model. We also noted any adverse events reported. MAIN RESULTS: Eleven studies compared hypnotherapy with 18 different control interventions. There was significant heterogeneity between the results of the individual studies, with conflicting results for the effectiveness of hypnotherapy compared to no treatment, or to advice, or psychological treatment. We did not attempt to calculate pooled risk ratios for the overall effect of hypnotherapy. There was no evidence of a greater effect of hypnotherapy when compared to rapid smoking or psychological treatment. Direct comparisons of hypnotherapy with cessation treatments considered to be effective had confidence intervals that were too wide to infer equivalence. AUTHORS' CONCLUSIONS: We have not shown that hypnotherapy has a greater effect on six-month quit rates than other interventions or no treatment. There is not enough evidence to show whether hypnotherapy could be as effective as counselling treatment. The effects of hypnotherapy on smoking cessation claimed by uncontrolled studies were not confirmed by analysis of randomized controlled trials. PMID- 20927724 TI - Hip protectors for preventing hip fractures in older people. AB - BACKGROUND: Hip fracture in older people usually results from a fall on the hip. Hip protectors have been advocated as a means to reduce the risk of hip fracture. OBJECTIVES: To determine if external hip protectors reduce the incidence of hip fractures in older people following a fall. SEARCH STRATEGY: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (January 2010), The Cochrane Library 2010, Issue 2, MEDLINE (1950 to November 2009), MEDLINE in process (30 December 2009), EMBASE (1988 to 2009 week 52), CINAHL (1982 to February 2009), BioMed Central (January 2010) and reference lists of relevant articles. SELECTION CRITERIA: All randomised or quasi-randomised controlled trials comparing the use of hip protectors with an unprotected control group. DATA COLLECTION AND ANALYSIS: Two authors independently assessed risk of bias and extracted data. We sought additional information from trialists. Data were pooled using fixed-effect or random-effects models as appropriate. MAIN RESULTS: Pooling of data from 13 studies (11,573 participants) conducted in nursing or residential care settings found a marginally significant reduction in hip fracture risk (risk ratio (RR) 0.81, 95% confidence interval (CI) 0.66 to 0.99); statistical significance was lost following exclusion of five studies (3757 participants) assessed at high risk of bias (RR 0.93, 95% CI 0.74 to 1.18).Pooling of data from three trials (5135 community-dwelling participants) showed no evidence of reduction in hip fracture risk (RR 1.14, 95% CI 0.83 to 1.57).There was no evidence of a statistically significant effect on incidence of pelvic or other fractures, or on rate of falls. No important adverse effects of the hip protectors were reported but adherence, particularly in the long term, was poor. AUTHORS' CONCLUSIONS: The effectiveness of the provision of hip protectors in reducing the incidence of hip fracture in older people is still not clearly established, although they may reduce the rate of hip fractures if made available to frail older people in nursing care. It remains unknown from studies identified to date if these findings apply to all types of hip protectors. Some cluster randomised trials have been associated with high risk of bias. Poor acceptance and adherence by older people offered hip protectors have been key factors contributing to the continuing uncertainty. PMID- 20927725 TI - Laparoscopic versus open surgery for suspected appendicitis. AB - BACKGROUND: Laparoscopic surgery for acute appendicitis has been proposed to have advantages over conventional surgery. OBJECTIVES: To compare the diagnostic and therapeutic effects of laparoscopic and conventional 'open' surgery. SEARCH STRATEGY: We searched the Cochrane Library, MEDLINE, EMBASE, LILACS, CNKI, SciSearch, study registries, and the congress proceedings of endoscopic surgical societies. SELECTION CRITERIA: We included randomized clinical trials comparing laparoscopic (LA) versus open appendectomy (OA) in adults or children. Studies comparing immediate OA versus diagnostic laparoscopy (followed by LA or OA if necessary) were separately identified. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial quality. Missing information or data was requested from the authors. We used odds ratios (OR), relative risks (RR), and 95% confidence intervals (CI) for analysis. MAIN RESULTS: We included 67 studies, of which 56 compared LA (with or without diagnostic laparoscopy) vs. OA in adults. Wound infections were less likely after LA than after OA (OR 0.43; CI 0.34 to 0.54), but the incidence of intraabdominal abscesses was increased (OR 1.87; CI 1.19 to 2.93). The duration of surgery was 10 minutes (CI 6 to 15) longer for LA. Pain on day 1 after surgery was reduced after LA by 8 mm (CI 5 to 11 mm) on a 100 mm visual analogue scale. Hospital stay was shortened by 1.1 day (CI 0.7 to 1.5). Return to normal activity, work, and sport occurred earlier after LA than after OA. While the operation costs of LA were significantly higher, the costs outside hospital were reduced. Seven studies on children were included, but the results do not seem to be much different when compared to adults. Diagnostic laparoscopy reduced the risk of a negative appendectomy, but this effect was stronger in fertile women (RR 0.20; CI 0.11 to 0.34) as compared to unselected adults (RR 0.37; CI 0.13 to 1.01). AUTHORS' CONCLUSIONS: In those clinical settings where surgical expertise and equipment are available and affordable, diagnostic laparoscopy and LA (either in combination or separately) seem to have various advantages over OA. Some of the clinical effects of LA, however, are small and of limited clinical relevance. In spite of the mediocre quality of the available research data, we would generally recommend to use laparoscopy and LA in patients with suspected appendicitis unless laparoscopy itself is contraindicated or not feasible. Especially young female, obese, and employed patients seem to benefit from LA. PMID- 20927726 TI - Grommets (ventilation tubes) for hearing loss associated with otitis media with effusion in children. AB - BACKGROUND: Otitis media with effusion (OME; 'glue ear') is common in childhood and surgical treatment with grommets (ventilation tubes) is widespread but controversial. OBJECTIVES: To assess the effectiveness of grommet insertion compared with myringotomy or non-surgical treatment in children with OME. SEARCH STRATEGY: We searched the Cochrane ENT Disorders Group Trials Register, other electronic databases and additional sources for published and unpublished trials (most recent search: 22 March 2010). SELECTION CRITERIA: Randomised controlled trials evaluating the effect of grommets. Outcomes studied included hearing level, duration of middle ear effusion, language and speech development, cognitive development, behaviour and adverse effects. DATA COLLECTION AND ANALYSIS: Data from studies were extracted by two authors and checked by the other authors. MAIN RESULTS: We included 10 trials (1728 participants). Some trials randomised children (grommets versus no grommets), others ears (grommet one ear only). The severity of OME in children varied between trials. Only one 'by child' study (MRC: TARGET) had particularly stringent audiometric entry criteria. No trial was identified that used long-term grommets.Grommets were mainly beneficial in the first six months by which time natural resolution lead to improved hearing in the non-surgically treated children also. Only one high quality trial that randomised children (N = 211) reported results at three months; the mean hearing level was 12 dB better (95% CI 10 to 14 dB) in those treated with grommets as compared to the controls. Meta-analyses of three high quality trials (N = 523) showed a benefit of 4 dB (95% CI 2 to 6 dB) at six to nine months. At 12 and 18 months follow up no differences in mean hearing levels were found.Data from three trials that randomised ears (N = 230 ears) showed similar effects to the trials that randomised children. At four to six months mean hearing level was 10 dB better in the grommet ear (95% CI 5 to 16 dB), and at 7 to 12 months and 18 to 24 months was 6 dB (95% CI 2 to 10 dB) and 5 dB (95% CI 3 to 8 dB) dB better.No effect was found on language or speech development or for behaviour, cognitive or quality of life outcomes.Tympanosclerosis was seen in about a third of ears that received grommets. Otorrhoea was common in infants, but in older children (three to seven years) occurred in < 2% of grommet ears over two years of follow up. AUTHORS' CONCLUSIONS: In children with OME the effect of grommets on hearing, as measured by standard tests, appears small and diminishes after six to nine months by which time natural resolution also leads to improved hearing in the non-surgically treated children. No effect was found on other child outcomes but data on these were sparse. No study has been performed in children with established speech, language, learning or developmental problems so no conclusions can be made regarding treatment of such children. PMID- 20927727 TI - WITHDRAWN: Haemophilus influenzae oral whole cell vaccination for preventing acute exacerbations of chronic bronchitis. AB - BACKGROUND: Acute bronchitis leading to ongoing exacerbations is a serious condition predisposed to by viruses, bacteria or environmental factors. It can be fatal. Antibiotic therapy is not particularly useful. An oral Haemophilus influenzae vaccine has been developed. OBJECTIVES: To assess the effects of an oral, monobacterial whole-cell, killed, nontypeable H. influenzae vaccine in protecting against recurrent acute episodes in chronic bronchitis. SEARCH STRATEGY: In this updated review, we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 1, 2006), MEDLINE (1966 to January Week 4 2006), EMBASE (1990 to September 2005) and ISI Current Contents (2004 to May 2006). SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing the effects of the H. influenzae vaccine on patients with recurrent acute exacerbations of chronic bronchitis were included when there was overt matching of the vaccine and placebo groups on clinical grounds. DATA COLLECTION AND ANALYSIS: Three authors extracted data and assessed trial quality independently from original records and publications for incidence and severity of bronchitis episodes and carriage rate of nontypeable H. influenzae measured in the upper respiratory tract every three months following vaccination. MAIN RESULTS: Six trials were included in the study with a total of 440 participants. The vaccine reduced the incidence of bronchitic episodes at three months after vaccination (rate ratio is 0.69; 95% CI 0.41 to 1.14) and at six months after vaccination (rate ratio 0.82; 95% CI 0.62 to 1.09). If these results been statistically significant, they would have represented a reduction in acute bronchitic attacks for vaccinated individuals of 31% at three months, and 18% at six. The effect had disappeared by nine months. The severity of exacerbations in the treatment group, as measured by requirement to prescribe antibiotics, was likewise reduced by 58% at three months (Peto odds ratio = 0.42; 95% CI 0.16 to 1.13), and by 65% at six months (Peto odds ratio = 0.35; 95% CI 0.16 to 0.75). AUTHORS' CONCLUSIONS: Vaccinating patients with recurrent acute exacerbations of chronic bronchitis in the autumn may reduce the number and severity of exacerbations over the following winter. A large clinical trial is needed. PMID- 20927728 TI - Transfusion thresholds and other strategies for guiding allogeneic red blood cell transfusion. AB - BACKGROUND: Most clinical practice guidelines recommend restrictive red cell transfusion practices, with the goal of minimising exposure to allogeneic blood (from an unrelated donor). The purpose of this review is to compare clinical outcomes in patients randomised to restrictive versus liberal transfusion thresholds (triggers). OBJECTIVES: To examine the evidence for the effect of transfusion thresholds on the use of allogeneic and/or autologous blood, and the evidence for any effect on clinical outcomes. SEARCH STRATEGY: Trials were identified by: computer searches of the Cochrane Central Register of Controlled Trials (the Cochrane Library Issue 3, 2009), OVID MEDLINE (1966 to August 2009), Current Contents (1993 to November 2004), and the Web of Science (2004 to August 2009). References in identified trials and review articles were checked and experts contacted to identify any additional trials. SELECTION CRITERIA: Controlled trials in which patients were randomised to an intervention group or to a control group. Trials were included where intervention groups were assigned on the basis of a clear transfusion 'trigger', described as a haemoglobin (Hb) or haematocrit (Hct) level below which an RBC transfusion was to be administered. DATA COLLECTION AND ANALYSIS: Relative risks of requiring allogeneic blood transfusion, transfused blood volumes and other clinical outcomes were pooled across trials, using a random effects model. The risk of bias was assessed. MAIN RESULTS: Seventeen trials involving a total of 3746 patients were identified. Restrictive transfusion strategies reduced the risk of receiving a red blood cell (RBC) transfusion by a relative 37% (RR=0.63; 95% CI 0.54 to 0.74). This equates to an average absolute risk reduction (ARR) of 33% (95% CI 21% to 45%). The volume of RBCs transfused was reduced on average by 0.75 units (95% CI 0.20 to 1.30 units). However, heterogeneity between trials was statistically significant (P<0.001; I2>=74%) for these outcomes. Restrictive transfusion strategies did not appear to impact on the rate of adverse events compared to liberal transfusion strategies (i.e. mortality, cardiac events, myocardial infarction, stroke, pneumonia and thromboembolism). Restrictive transfusion strategies were associated with a statistically significant reduction in the rates of infection (RR=0.76; 95% CI 0.60 to 0.97). The use of restrictive transfusion strategies did not reduce hospital or intensive care length of stay. AUTHORS' CONCLUSIONS: The existing evidence supports the use of restrictive transfusion triggers in patients who are free of serious cardiac disease. The effects of conservative transfusion triggers on functional status, morbidity and mortality, particularly in patients with cardiac disease, need to be tested in further large clinical trials. In countries with inadequate screening of donor blood, the data may constitute a stronger basis for avoiding transfusion with allogeneic red cells. PMID- 20927729 TI - Sedatives for opiate withdrawal in newborn infants. AB - BACKGROUND: Neonatal abstinence syndrome (NAS) due to opiate withdrawal may result in disruption of the mother-infant relationship, sleep-wake abnormalities, feeding difficulties, weight loss and seizures. Treatments used to ameliorate symptoms and reduce morbidity include opiates, sedatives and non-pharmacological treatments. OBJECTIVES: To assess the effectiveness and safety of using a sedative compared to a non-opiate control for NAS due to withdrawal from opiates, and to determine which type of sedative is most effective and safe. SEARCH STRATEGY: This update included searches of the Cochrane Central Register of Controlled Trials (Issue 1, 2010), MEDLINE 1966 to April 2010 and abstracts of conference proceedings. SELECTION CRITERIA: Trials enrolling infants with NAS born to mothers with an opiate dependence with > 80% follow-up and using random or quasi-random allocation to sedative or control. Control could include another sedative or non-pharmacological treatment. DATA COLLECTION AND ANALYSIS: Each author assessed study quality and extracted data independently. MAIN RESULTS: Seven studies enrolling 385 patients were included. There were substantial methodological concerns for most studies including the use of quasi-random allocation methods and sizeable, largely unexplained differences in reported numbers allocated to each group.One study reported phenobarbitone compared to supportive care alone did not reduce treatment failure or time to regain birthweight, but resulted in a significant reduction in duration of supportive care (MD -162.1 min/day, 95% CI -249.2, -75.1). Comparing phenobarbitone to diazepam, meta-analysis of two studies found phenobarbitone resulted in a significant reduction in treatment failure (typical RR 0.39, 95% CI 0.24, 0.62). Comparing phenobarbitone with chlorpromazine, one study reported no significant difference in treatment failure.In infants treated with an opiate, one study reported addition of clonidine resulted in no significant difference in treatment failure, seizures or mortality. In infants treated with an opiate, one study reported addition of phenobarbitone significantly reduced the proportion of time infants had a high abstinence severity score, duration of hospitalisation and maximal daily dose of opiate. AUTHORS' CONCLUSIONS: Infants with NAS due to opiate withdrawal should receive initial treatment with an opiate. Where a sedative is used, phenobarbitone should be used in preference to diazepam. In infants treated with an opiate, the addition of phenobarbitone or clonidine may reduce withdrawal severity. Further studies are needed to determine the role of sedatives in infants with NAS due to opiate withdrawal and the safety and efficacy of adding phenobarbitone or clonidine in infants treated with an opiate for NAS. PMID- 20927730 TI - Opiate treatment for opiate withdrawal in newborn infants. AB - BACKGROUND: Neonatal abstinence syndrome (NAS) due to opiate withdrawal may result in disruption of the mother-infant relationship, sleep-wake abnormalities, feeding difficulties, weight loss and seizures. OBJECTIVES: To assess the effectiveness and safety of using an opiate compared to a sedative or non pharmacological treatment for treatment of NAS due to withdrawal from opiates. SEARCH STRATEGY: The review was updated in 2010 with additional searches CENTRAL, MEDLINE and EMBASE supplemented by searches of conference abstracts and citation lists of published articles. SELECTION CRITERIA: Randomized or quasi-randomized controlled trials of opiate treatment in infants with NAS born to mothers with opiate dependence. DATA COLLECTION AND ANALYSIS: Each author assessed study quality and extracted data independently. MAIN RESULTS: Nine studies enrolling 645 infants met inclusion criteria. There were substantial methodological concerns in all studies comparing an opiate with a sedative. Two small studies comparing different opiates were of good methodology.Opiate (morphine) versus supportive care (one study): A reduction in time to regain birth weight and duration of supportive care and a significant increase in hospital stay was noted.Opiate versus phenobarbitone (four studies): Meta-analysis found no significant difference in treatment failure. One study reported opiate treatment resulted in a significant reduction in treatment failure in infants of mothers using only opiates. One study reported a significant reduction in days treatment and admission to the nursery for infants receiving morphine. One study reported a reduction in seizures, of borderline statistical significance, with the use of opiate.Opiate versus diazepam (two studies): Meta-analysis found a significant reduction in treatment failure with the use of opiate.Different opiates (six studies): there is insufficient data to determine safety or efficacy of any specific opiate compared to another opiate. AUTHORS' CONCLUSIONS: Opiates compared to supportive care may reduce time to regain birth weight and duration of supportive care but increase duration of hospital stay. When compared to phenobarbitone, opiates may reduce the incidence of seizures but there is no evidence of effect on treatment failure. One study reported a reduction in duration of treatment and nursery admission for infants on morphine. Compared to diazepam, opiates reduce the incidence of treatment failure. A post-hoc analysis generates the hypothesis that initial opiate treatment may be restricted to infants of mothers who used opiates only. In view of the methodologic limitations of the included studies the conclusions of this review should be treated with caution. PMID- 20927731 TI - Interventions for bullous pemphigoid. AB - BACKGROUND: Bullous pemphigoid (BP) is the most common autoimmune blistering disease in the West. Oral steroids are the standard treatment.This is an update of the review published in 2005. OBJECTIVES: To assess treatments for bullous pemphigoid. SEARCH STRATEGY: In August 2010 we updated our searches of the Cochrane Skin Group Specialised Register, the Cochrane Central Register of Controlled Trials (Clinical Trials), MEDLINE, EMBASE, and the Ongoing Trials registers. SELECTION CRITERIA: Randomised controlled trials of treatments for participants with immunofluorescence-confirmed bullous pemphigoid. DATA COLLECTION AND ANALYSIS: At least two authors evaluated the studies for the inclusion criteria, and extracted data independently. MAIN RESULTS: We included 10 randomised controlled trials (with a total of 1049 participants) of moderate to high risk of bias. All studies involved different comparisons, none had a placebo group. In 1 trial plasma exchange plus prednisone gave significantly better disease control at 1 month (0.3 mg/kg: RR 18.78, 95% CI 1.20 to 293.70) than prednisone alone (1.0 mg/kg: RR 1.79, 95% CI 1.11 to 2.90), while another trial showed no difference in disease control at 6 months.No differences in disease control were seen for different doses or formulations of prednisolone (one trial each), for azathioprine plus prednisone compared with prednisone alone (one trial), for prednisolone plus azathioprine compared with prednisolone plus plasma exchange (one trial), for prednisolone plus mycophenolate mofetil or plus azathioprine (one trial), for tetracycline plus nicotinamide compared with prednisolone (one trial). Chinese traditional medicine plus prednisone was not effective in one trial.There were no significant differences in healing in a comparison of a standard regimen of topical steroids (clobetasol) with a milder regimen (RR 1.00, 95% 0.97 to 1.03) in one trial. In another trial, clobetasol showed significantly more disease control than oral prednisolone in people with extensive and moderate disease (RR 1.09, 95% CI 1.02 to 1.17), with significantly reduced mortality and adverse events (RR 1.06, 95% CI 1.00 to 1.12). AUTHORS' CONCLUSIONS: Very potent topical steroids are effective and safe treatments for BP, but their use in extensive disease may be limited by side-effects and practical factors. Milder regimens (using lower doses of steroids) are safe and effective in moderate BP. Starting doses of prednisolone greater than 0.75 mg/kg/day do not give additional benefit, lower doses may be adequate to control disease and reduce the incidence and severity of adverse reactions. The effectiveness of adding plasma exchange, azathioprine or mycophenolate mofetil to corticosteroids, and combination treatment with tetracycline and nicotinamide needs further investigation. PMID- 20927732 TI - Autologous chondrocyte implantation for full thickness articular cartilage defects of the knee. AB - BACKGROUND: Treatments for managing articular cartilage defects of the knee, including drilling and abrasion arthroplasty, are not always effective. When they are, long-term benefits may not be maintained and osteoarthritis may develop. An alternative is autologous chondrocyte implantation (ACI), the surgical implantation of healthy cartilage cells into the damaged areas. OBJECTIVES: To determine the efficacy and safety of ACI in people with full thickness articular cartilage defects of the knee. SEARCH STRATEGY: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (3 December 2008), the Cochrane Central Register of Controlled Trials (The Cochrane Library 2008, Issue 4), MEDLINE (1950 to November Week 3 2008), EMBASE (1980 to Week 48 2008), SPORTDiscus (3 December 2008), the WHO International Clinical Trials Registry Platform (4 December 2008), and Current Controlled Trials (3 December 2008). SELECTION CRITERIA: Randomised and quasi-randomised trials comparing ACI with any other type of treatment (including no treatment or placebo) for symptomatic cartilage defects of the medial or lateral femoral condyle, femoral trochlea or patella. DATA COLLECTION AND ANALYSIS: Review authors selected studies for inclusion independently. We assessed risk of bias based on adequacy of the randomisation and allocation concealment process, potential for selection bias after allocation and level of masking. We did not pool data due to clinical and methodological heterogeneity. MAIN RESULTS: Six heterogeneous trials were identified with 431 participants. Methodological flaws of the included trials included incomplete follow-up and inadequate reporting of outcomes. Three trials compared ACI versus mosaicplasty. One reported statistically significant results in favour of ACI at one year in the numbers of people with 'good' or 'excellent' functional results. Conversely, another trial found significant improvement for the mosaicplasty group when assessed using one functional scoring system at two years, but no statistically significant differences based on two other scoring systems. A third trial found no difference between ACI and mosaicplasty, 10 months on average after the surgery.There was no statistically significant difference in functional outcomes at two years in single trials comparing ACI with microfracture or characterised chondrocyte implantation versus microfracture. The results of the sixth trial comparing matrix-guided ACI versus microfracture were undermined by the severe loss to follow-up. AUTHORS' CONCLUSIONS: There is insufficient evidence to draw conclusions on the use of ACI for treating full thickness articular cartilage defects in the knee. Further good quality randomised controlled trials with long-term functional outcomes are required. PMID- 20927733 TI - WITHDRAWN: Rehabilitation after surgery for flexor tendon injuries in the hand. AB - BACKGROUND: Postoperative rehabilitation of the flexor tendons in the hand consists of a short period of immobilisation while pain and swelling diminish, followed by progressive mobilisation to maximize the range of motion of the affected fingers. By altering the time of immobilisation and the manner of subsequent mobilisation different rehabilitation regimes are created. OBJECTIVES: To determine, with evidence from randomised controlled trials, the optimal rehabilitation strategy after surgery for flexor tendon injuries in the hand. SEARCH STRATEGY: We searched the Cochrane Bone, Joint and Muscle Trauma Group specialised register (November 2002), the Cochrane Central Register of Controlled Trials (The Cochrane Library, issue 4, 2002), MEDLINE (1966 to November 2002), EMBASE (1988 to November 2002), CINAHL (1982 to October 2002), CURRENT CONTENTS (1993 to October 2002), PEDro - The Physiotherapy Evidence Database (http://ptwww.cchs.usyd.edu.au/pedro/ accessed 30/10/2002) and reference lists of articles. SELECTION CRITERIA: All randomised and quasi-randomised controlled trials of interventions for rehabilitation after surgery of flexor tendon injuries in the hand after surgery. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial quality, using a 10 item scale, and extracted data where possible. Additional information was sought from trialists when required. Due to the lack of extractable data and the variety of interventions used, pooling was not attempted. Where possible relative risks and 95 per cent confidence intervals were calculated for dichotomous outcomes, and mean differences and 95 per cent confidence intervals calculated for continuous outcomes. MAIN RESULTS: Six trials, including three reported only in abstracts, with a total of 464 participants were included. Data were not pooled. One trial compared continuous passive motion (CPM) with controlled intermittent passive motion (CIPM) and found a significant difference in mean active motion favouring CPM (WMD 19.00 degrees, 95% CI 15.11 to 22.89). One trial compared a shortened passive flexion/active extension programme with a normal passive flexion/active extension mobilisation programme, and reported (without data) a significant reduction in absence from work of 2.1 weeks in favour of the shortened programme. Other trials compared active flexion with rubber band traction, early controlled active mobilisation with early controlled passive mobilisation and dynamic splintage versus static splintage. No trials found significant differences in overall functioning or complication rate. AUTHORS' CONCLUSIONS: Controlled mobilisation regimens are widely employed in rehabilitation after flexor tendon repair in the hand. This review found insufficient evidence from randomised controlled trials to define the best mobilisation strategy. PMID- 20927734 TI - Different antibiotic treatments for group A streptococcal pharyngitis. AB - BACKGROUND: Antibiotics provide only modest benefit in treating sore throat, although effectiveness increases in participants with positive throat swabs for group A beta-haemolytic streptococci (GABHS). It is unclear which antibiotic is the best choice if antibiotics are indicated. OBJECTIVES: We assessed the comparative efficacy of different antibiotics on clinical outcomes, relapse, complications and adverse events in GABHS tonsillopharyngitis. SEARCH STRATEGY: We searched The Cochrane Library, Cochrane Central Register of Controlled Trials (CENTRAL 2010, Issue 3) which includes the Acute Respiratory Infections Group's Specialised Register, MEDLINE (1966 to July Week 4, 2010) and EMBASE (1974 to August 2010). SELECTION CRITERIA: Randomised, double-blind trials comparing different antibiotics reporting at least one of the following: clinical cure, clinical relapse, complications, adverse events. DATA COLLECTION AND ANALYSIS: Two authors independently screened trials for inclusion and extracted data. MAIN RESULTS: Seventeen trials (5352 participants) were included; 16 compared with penicillin (six with cephalosporins, six with macrolides, three with carbacephem and one with sulfonamides), one trial compared clindamycin and ampicillin. Randomisation reporting, allocation concealment and blinding were poor.There was no difference in symptom resolution between cephalosporins and penicillin (intention-to-treat (ITT) analysis; N = 5; n = 2018; odds ratio for absence of resolution of symptoms (OR) 0.79, 95% confidence interval (CI) 0.55 to 1.12). Clinical relapse was lower with cephalosporins (N = 4; n = 1386; OR 0.55, 95% CI 0.31 to 0.99); overall number needed to treat to benefit (NNTB) 50), but found only in adults (OR 0.42, 95% CI 0.20 to 0.88; NNTB 33). There were no differences between macrolides and penicillin. Carbacephem showed better symptom resolution post-treatment (N = 3; n = 795; OR 0.70, 95% CI 0.49 to 0.99; NNTB 14), but only in children (N = 2; n = 233; OR 0.57, 95% CI 0.33 to 0.99; NNTB 8.3). Children experienced more adverse events with macrolides (N = 1, n = 489; OR 2.33; 95% CI 1.06 to 5.15). AUTHORS' CONCLUSIONS: Evidence is insufficient for clinically meaningful differences between antibiotics for GABHS tonsillopharyngitis. Limited evidence in adults suggests cephalosporins are more effective than penicillin for relapse, but the NNTB is high. Limited evidence in children suggests carbacephem is more effective for symptom resolution. Data on complications are too scarce to draw conclusions. Based on these results and considering the low cost and absence of resistance, penicillin can still be recommended as first choice. PMID- 20927735 TI - Phytomedicines (medicines derived from plants) for sickle cell disease. AB - BACKGROUND: Sickle cell disease (SCD), a common recessively inherited haemoglobin disorder, affects people from sub-Saharan Africa, the Middle East, Mediterranean basin, Indian subcontinent, Caribbeans and South America. It is associated with complications and a reduced life expectancy. Phytomedicines (medicine derived from plants in their original state) encompass many of the plant remedies from traditional healers which the populations most affected would encounter. There has been little systematic appraisal of their benefits. OBJECTIVES: To assess the benefits and risks of phytomedicines in people with SCD of all types, of any age, in any setting. SEARCH STRATEGY: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register and the ISRCTN Register for all publication years; AMED was searched by the previous authors for an earlier version of this review for the period 1985 to August 2003.Dates of most recent searches:Haemoglobinopathies Trials Register: 07 July 2010;ISRCTN: 28 December 2009;AMED: August 2003. SELECTION CRITERIA: Randomised or quasi randomised trials with participants of all ages with SCD, in all settings, comparing the administration of phytomedicines, by any mode to placebo or conventional treatment, including blood transfusion and hydroxyurea. DATA COLLECTION AND ANALYSIS: Both authors independently assessed trial quality and extracted data. MAIN RESULTS: Two trials (182 participants) and two phytomedicines Niprisan((r)) (also known as Nicosan((r))) and Ciklavit((r))) were included. The Phase IIB (pivotal) trial suggests that Niprisan((r)) was effective in reducing episodes of severe painful SCD crisis over a six-month period. It did not affect the risk of severe complications or the level of anaemia. No serious adverse effects were reported. The single trial of Cajanus cajan (Ciklavit((r))) reported a possible benefit to individuals with painful crises, and a possible adverse effect (non-significant) on the level of anaemia. AUTHORS' CONCLUSIONS: While Niprisan((r)) appeared to be safe and effective in reducing severe painful crises over a six-month follow-up period, further trials are required to assess its role in the management of people with SCD and the results of its multicentre trials are awaited. Currently no conclusions can be made regarding the efficacy of Ciklavit((r)). Based on the published results for Niprisan((r)) and in view of the limitations in data collection and analysis of both trials, phytomedicines may have a potential beneficial effect in reducing painful crises in SCD. This needs to be further validated in future trials. More trials are required on the safety and efficacy of phytomedicines in managing SCD. PMID- 20927736 TI - Speed cameras for the prevention of road traffic injuries and deaths. AB - BACKGROUND: It is estimated that by 2020, road traffic crashes will have moved from ninth to third in the world ranking of burden of disease, as measured in disability adjusted life years. The prevention of road traffic injuries is of global public health importance. Measures aimed at reducing traffic speed are considered essential to preventing road injuries; the use of speed cameras is one such measure. OBJECTIVES: To assess whether the use of speed cameras reduces the incidence of speeding, road traffic crashes, injuries and deaths. SEARCH STRATEGY: We searched the following electronic databases covering all available years up to March 2010; the Cochrane Library, MEDLINE (WebSPIRS), EMBASE (WebSPIRS), TRANSPORT, IRRD (International Road Research Documentation), TRANSDOC (European Conference of Ministers of Transport databases), Web of Science (Science and Social Science Citation Index), PsycINFO, CINAHL, EconLit, WHO database, Sociological Abstracts, Dissertation Abstracts, Index to Theses. SELECTION CRITERIA: Randomised controlled trials, interrupted time series and controlled before-after studies that assessed the impact of speed cameras on speeding, road crashes, crashes causing injury and fatalities were eligible for inclusion. DATA COLLECTION AND ANALYSIS: We independently screened studies for inclusion, extracted data, assessed methodological quality, reported study authors' outcomes and where possible, calculated standardised results based on the information available in each study. Due to considerable heterogeneity between and within included studies, a meta-analysis was not appropriate. MAIN RESULTS: Thirty five studies met the inclusion criteria. Compared with controls, the relative reduction in average speed ranged from 1% to 15% and the reduction in proportion of vehicles speeding ranged from 14% to 65%. In the vicinity of camera sites, the pre/post reductions ranged from 8% to 49% for all crashes and 11% to 44% for fatal and serious injury crashes. Compared with controls, the relative improvement in pre/post injury crash proportions ranged from 8% to 50%. AUTHORS' CONCLUSIONS: Despite the methodological limitations and the variability in degree of signal to noise effect, the consistency of reported reductions in speed and crash outcomes across all studies show that speed cameras are a worthwhile intervention for reducing the number of road traffic injuries and deaths. However, whilst the the evidence base clearly demonstrates a positive direction in the effect, an overall magnitude of this effect is currently not deducible due to heterogeneity and lack of methodological rigour. More studies of a scientifically rigorous and homogenous nature are necessary, to provide the answer to the magnitude of effect. PMID- 20927737 TI - Pharmacological interventions for pain in patients with temporomandibular disorders. AB - BACKGROUND: Temporomandibular disorders (TMD) are a group of disorders affecting the temporomandibular joints and the muscles of mastication. TMDs are treated with a wide range of drugs. The extent to which the use of these drugs is based upon evidence is unknown. OBJECTIVES: To assess the effectiveness of pharmacological interventions both alone and in combination with non pharmacological therapy in relieving pain in patients with chronic TMD. SEARCH STRATEGY: Electronic searches of the Cochrane Oral Health Group's Trials Register (2 August 2010), CENTRAL (The Cochrane Library 2010, Issue 3), MEDLINE via OVID (1950 to 2 August 2010), EMBASE via OVID (1980 to 2 August 2010) and CINAHL via EBSCO (1981 to 2 August 2010) were conducted. Reference lists of articles and previous reviews were scanned for relevant articles and authors were contacted for further information where appropriate. SELECTION CRITERIA: Randomised controlled trials (RCTs) in which a pharmacological agent was compared with placebo for the management of pain in patients with TMD. Parenteral routes of administration were excluded. DATA COLLECTION AND ANALYSIS: Duplicate data extraction and assessment of risk of bias in included studies was performed. MAIN RESULTS: Eleven studies were included with a total of 496 participants. The primary outcome of most of the studies was pain. The risk of bias in the included studies was variable. Whilst four studies showed significant pain relief for the active treatment, three were of poor quality. Most adverse effects were mild to moderate in severity. Four studies reported withdrawals due to severe adverse reactions, but insufficient information was provided regarding the trial groups from which the withdrawals occurred. No meta-analysis was conducted due to lack of similarities across the included studies. AUTHORS' CONCLUSIONS: There is insufficient evidence to support or not support the effectiveness of the reported drugs for the management of pain due to TMD. There is a need for high quality RCTs to derive evidence of the effectiveness of pharmacological interventions to treat pain associated with TMD. PMID- 20927738 TI - WITHDRAWN: Self-management education for adults with epilepsy. AB - BACKGROUND: Self-management education has been shown to improve the quality of life of people with chronic illnesses. It has been suggested that self-management education may improve seizure control and other outcomes in people with epilepsy. OBJECTIVES: To review systematically the research literature on the effectiveness of self-management education in improving health outcomes for adults with epilepsy. SEARCH STRATEGY: We searched MEDLINE (Ovid) (1966 to April 2005), EMBASE (Ovid) (1980 to April 2005), CINAHL (Dialog) (1980 to April 2005), PsycINFO (Dialog) (1887 to April 2005), and the Cochrane Epilepsy Group's Specialised Register (April 2005). We also handsearched Epilepsia and conference abstracts and proceedings. Experts in the field were contacted to identify any additional trials. We did not impose any language restriction. We re-ran the searches in February 2007 and added the identified references to the 'Studies awaiting assessment' table. SELECTION CRITERIA: Randomised trials of self management education programmes for adults with epilepsy. DATA COLLECTION AND ANALYSIS: At least two review authors independently assessed the quality of each study and extracted data. MAIN RESULTS: Two trials evaluated the effect of self management education for adults with epilepsy, neither of which assessed as being of high quality. In total, 483 adults with epilepsy were randomised. Both trials showed improvements in seizure frequency and other outcomes, such as knowledge. However, we were not able to estimate a summary effect for seizure frequency due to a lack of data. AUTHORS' CONCLUSIONS: Self-management education programmes, based on increasing understanding through psychosocial methods, may improve knowledge about epilepsy, certain behavioural outcomes, and reduce seizure frequency. It is, however, not clear how effective self-management programmes of epilepsy would be in a more general population of adults with epilepsy, as both trials had higher proportions of people with partial seizures than would be expected in a community sample. PMID- 20927739 TI - WITHDRAWN: Self-management education for children with epilepsy. AB - BACKGROUND: Self-management education has been shown to improve the quality of life of children and young people with chronic illnesses. It has been suggested that self-management education may improve seizure control and other outcomes in children and young people with epilepsy. OBJECTIVES: To review systematically the research literature on the effectiveness of self-management education in improving health outcomes for children and young people with epilepsy. SEARCH STRATEGY: We searched the Cochrane Epilepsy Group's Specialised Register (February 2007), MEDLINE (Ovid) (1966 to February 2007), EMBASE (Ovid) (1980 to February 2007), CINAHL (Dialog) (1980 to February 2007), and PsycINFO (Dialog) (1887 to February 2007). We also handsearched Epilepsia and conference abstracts and proceedings. Experts in the field were contacted to identify any additional trials. No language restriction was imposed. SELECTION CRITERIA: Randomised trials of self-management education programmes for children or young people with epilepsy. DATA COLLECTION AND ANALYSIS: At least two review authors independently assessed the quality of each study and extracted data. MAIN RESULTS: Only one trial involving 167 children was identified that evaluated the effect of a child centred model of training for the self-management of two chronic illnesses, asthma and epilepsy. The trial was not assessed as being of high quality and the methods used to analyse and report the data did not enable us to precisely determine the effect of the intervention. However, improvements were seen in seizure frequency and other outcomes, such as knowledge and behaviour. AUTHORS' CONCLUSIONS: Self-management education programmes that deliver a child-centred model of training, may improve knowledge about epilepsy, certain behavioural outcomes, and reduce seizure frequency in children and young people with epilepsy. However, based on the evidence reviewed, we are not able to determine how effective it is, or what the key components of the programme should be. PMID- 20927740 TI - Glucocorticoids for acute viral bronchiolitis in infants and young children. AB - BACKGROUND: Previous systematic reviews have not shown clear benefit of glucocorticoids for acute viral bronchiolitis, but their use remains considerable. Recent large trials add substantially to current evidence and suggest novel glucocorticoid-including treatment approaches. OBJECTIVES: To review the efficacy and safety of systemic and inhaled glucocorticoids in children with acute viral bronchiolitis. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library 2009, issue 4); MEDLINE (1950 to November 2009); EMBASE (1980 to Week 47 2009); LILACS (1982 to November 2009); Scopus(r) (1823 to November 2009); and IRAN MedEx (1998 to November 2009). SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing short-term systemic or inhaled glucocorticoids versus placebo or another intervention in children < 24 months with acute bronchiolitis (first episode with wheezing). Our primary outcomes were: admissions by days 1 and 7 for outpatient studies; and length of stay (LOS) for inpatient studies. Secondary outcomes included clinical severity parameters, healthcare use, pulmonary function, symptoms, quality of life and harms. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data on study and participant characteristics, interventions and outcomes. We assessed risk of bias and graded strength of evidence. Inpatient and outpatient results were meta-analysed separately using random-effects models. We pre-specified subgroup analyses, including the combined use of protocolised bronchodilators. MAIN RESULTS: We included 17 trials (2596 participants); only two had low overall risk of bias. Baseline severity, glucocorticoid schemes, comparators and outcomes were heterogeneous. Glucocorticoids did not significantly reduce outpatient admissions by days 1 and 7 when compared to placebo (pooled risk ratios (RRs) 0.92; 95% CI 0.78 to 1.08; and 0.86; 95% CI 0.7 to 1.06, respectively). There was no benefit in LOS for inpatients (mean difference -0.18 days; 95% CI -0.39 to 0.04). Unadjusted results from a large factorial low risk of bias RCT found combined high-dose systemic dexamethasone and inhaled epinephrine reduced admissions by day 7 (baseline risk of admission 26%; RR 0.65, 95% CI 0.44 to 0.95; number needed to treat 11, 95% CI 7 to 76), with no differences in short-term adverse effects. No other comparisons showed relevant differences in primary outcomes. AUTHORS' CONCLUSIONS: Current evidence does not support a clinically relevant effect of systemic or inhaled glucocorticoids on admissions or length of hospitalization. Combined dexamethasone and epinephrine may reduce outpatient admissions, but results are exploratory and safety data limited. Future research should further assess the efficacy, harms and applicability of combined therapy. PMID- 20927741 TI - Motorcycle rider training for the prevention of road traffic crashes. AB - BACKGROUND: Riding a motorcycle (a two-wheeled vehicle that is powered by a motor and has no pedals) is associated with a high risk of fatal crashes, particularly in new riders. Motorcycle rider training has therefore been suggested as an important means of reducing the number of crashes, and the severity of injuries. OBJECTIVES: To quantify the effectiveness of pre- and post-licence motorcycle rider training on the reduction of traffic offences, traffic crash involvement, injuries and deaths of motorcycle riders. SEARCH STRATEGY: We searched the Cochrane Injuries Group Specialised Register, CENTRAL (The Cochrane Library 2008, Issue 3), TRANSPORT, MEDLINE, EMBASE, CINAHL, WHOLIS (World Health Organization Library Information System), PsycInfo, LILACS (Latin American and Caribbean Health Sciences), ISI Web of Science: Social Sciences Citation Index (SSCI), ERIC, ZETOC and SIGLE. Database searches covered all available dates up to October 2008. We also checked reference lists of relevant papers and contacted study authors in an effort to identify published, unpublished and ongoing trials related to motorcycle rider training. SELECTION CRITERIA: We included all relevant intervention studies such as randomised and non-randomised controlled trials, interrupted time-series and observational studies such as cohort and case control studies. DATA COLLECTION AND ANALYSIS: Two review authors independently analysed data about the study population, study design and methods, interventions and outcome measures as well as data quality from each included study, and compared the findings. We resolved differences by discussion with a third review author. MAIN RESULTS: We reviewed 23 studies: three randomised trials, two non randomised trials, 14 cohort studies and four case-control studies. Five examined mandatory pre-licence training, 14 assessed non-mandatory training, three of the case-control studies assessed 'any' type of rider training, and one case-control study assessed mandatory pre-licence training and non-mandatory training. The types of assessed rider training varied in duration and content.Most studies suffered from serious methodological weaknesses. Most studies were non-randomised and controlled poorly for confounders. Most studies also suffered from detection bias due to the poor use of outcome measurement tools such as the sole reliance upon police records or self-reported data. Small sample sizes and short follow-up time after training were also common. AUTHORS' CONCLUSIONS: Due to the poor quality of studies identified, we were unable to draw any conclusions about the effectiveness of rider training on crash, injury, or offence rates. The findings suggest that mandatory pre-licence training may be an impediment to completing a motorcycle licensing process, possibly indirectly reducing crashes through a reduction in exposure. It is not clear if training (or what type) reduces the risk of crashes, injuries or offences in motorcyclists, and a best rider training practice can therefore not be recommended. As some type of rider training is likely to be necessary to teach motorcyclists to ride a motorcycle safely, rigorous research is needed. PMID- 20927742 TI - Symphysiotomy for feto-pelvic disproportion. AB - BACKGROUND: Symphysiotomy is an operation in which the fibres of the pubic symphysis are partially divided to allow separation of the joint and thus enlargement of the pelvic dimensions during childbirth. It is performed with local analgesia and does not require an operating theatre nor advanced surgical skills. It may be a lifesaving procedure for the mother or the baby, or both, in several clinical situations. These include: failure to progress in labour when caesarean section is unavailable, unsafe or declined by the mother; and obstructed birth of the aftercoming head of a breech presenting baby. Criticism of the operation because of complications, particularly pelvic instability, and as being a 'second best' option has resulted in its decline or disappearance from use in many countries. Several large observational studies have reported high rates of success, low rates of complications and very low mortality rates. OBJECTIVES: To determine, from the best available evidence, the effectiveness and safety of symphysiotomy versus alternative options for obstructed labour in various clinical situations. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 August 2010), the Cochrane Central Register of Controlled Trials (The Cochrane Library 2010, Issue 3) and PubMed (1966 to 31 August 2010). SELECTION CRITERIA: Randomized trials comparing symphysiotomy with alternative management, or alternative techniques of symphysiotomy, for obstructed labour or obstructed aftercoming head during breech birth. DATA COLLECTION AND ANALYSIS: Planned methods included evaluation of studies against objective quality criteria for inclusion, extraction of data, and analysis of data using risk ratios or mean differences with 95% confidence intervals. The primary outcomes were maternal death or severe morbidity, and perinatal death or severe morbidity. MAIN RESULTS: We found no randomized trials of symphysiotomy. AUTHORS' CONCLUSIONS: Because of controversy surrounding the use of symphysiotomy, and the possibility that it may be a life-saving procedure in certain circumstances, professional and global bodies should provide guidelines for the use (or non-use) of symphysiotomy based on the best available evidence (currently evidence from observational studies). Research is needed to provide robust evidence of the effectiveness and safety of symphysiotomy compared with no symphysiotomy or comparisons of alternative symphysiotomy techniques in clinical situations in which caesarean section is not available; and compared with caesarean section in clinical situations in which the relative risks and benefits are uncertain (for example in women at very high risk of complications from caesarean section). PMID- 20927743 TI - Vitamin A supplementation for postpartum women. AB - BACKGROUND: In vitamin A deficient populations, the amount of vitamin A may be insufficient for maintenance of maternal health and levels in breast milk may be insufficient for breastfeeding infants' needs. OBJECTIVES: To assess the effects of postpartum maternal vitamin A supplementation on maternal and infant health. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 July 2010), LILACS (1982 to July 2010), Web of Science (1945 to July 2010) and Biological Abstracts (1998 to July 2010). SELECTION CRITERIA: Randomised controlled trials evaluating the effects of postpartum maternal vitamin A supplementation. DATA COLLECTION AND ANALYSIS: Two review authors assessed the studies independently. MAIN RESULTS: We included 12 trials at moderate risk of bias, enrolling 25,465 mother-baby pairs and comparing several postpartum doses (200,000-400,000 IU) of vitamin A or 7.8 mg daily beta-carotene, with placebo, iron or no supplement; or higher (400,000 IU) versus lower dose (200,000 IU). The majority of infants in all studies were at least partially breastfed for six months.Maternal: we observed no impact of vitamin A on maternal mortality (two trials of 9,126 women), morbidity (one trial of 50 women) or adverse effects (subset of 786 women in one trial). Vitamin A enhanced serum and breast milk retinol at three months in five trials, but these improvements were generally not sustained.Infant: we observed no significant differences for infant mortality RR 1.14 95% CI 0.84 to 1.57 (five trials (6,170 infants) or morbidity (three trials) except for fewer episodes of fever with vitamin A in one small trial. No significant differences in infant vitamin A status were seen with maternal vitamin A supplementation (five trials).No beneficial effects for maternal or infant health were associated with higher compared to lower doses of vitamin A in two trials. AUTHORS' CONCLUSIONS: The lack of effect on maternal and infant mortality and morbidity, with exception of some improved infant morbidity in one small study, and the improvement in maternal vitamin A status, suggest that maternal postpartum vitamin A supplementation offers limited benefits. PMID- 20927744 TI - Interval debulking surgery for advanced epithelial ovarian cancer. AB - BACKGROUND: Interval debulking surgery (IDS), following induction or neoadjuvant chemotherapy, may have a possible role in treating advanced epithelial ovarian cancer (stage III to IV) where primary debulking surgery is not an option. OBJECTIVES: To assess the effectiveness and complications of IDS for patients with advanced stage epithelial ovarian cancer. SEARCH STRATEGY: We searched the Cochrane Gynaecological Cancer Group's Specialised Register to July 2009, the Cochrane Central Register of Controlled Trials (CENTRAL) Issue 2, 2009, MEDLINE from January 1966 to June week 4 2009, and EMBASE from January 1966 to week 27 2009. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing survival of women with advanced epithelial ovarian cancer, who had IDS performed between cycles of chemotherapy after primary surgery with survival of women who had conventional treatment (primary debulking surgery and adjuvant chemotherapy). DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. Searches for additional information from study authors were attempted. Meta-analysis of overall and progression-free survival (PFS) were performed using random-effects models. MAIN RESULTS: Three RCTs randomising 853 women, of whom 781 were evaluated, met the inclusion criteria. Meta-analysis of three trials for overall survival (OS) found no statistically significant difference between IDS and chemotherapy alone (hazard ratio (HR) = 0.80, 95% confidence interval (CI) 0.61 to 1.06, I(2) = 58%). Subgroup analysis for OS in two trials, where the primary surgery was not performed by gynaecologic oncologists or was less extensive, showed a benefit of IDS: HR = 0.68, 95% CI 0.53 to 0.87, I(2) = 0%). Meta-analysis of two trials for progression-free survival (PFS) found no statistically significant difference between IDS and chemotherapy alone (HR = 0.88, 95% CI 0.57 to 1.33, I(2) = 83%). Rates of toxic reactions to chemotherapy were similar in both arms (risk ratio = 1.19, 95% CI 0.53 to 2.66, I(2) = 0%), but little information was available for other adverse events or quality or life. AUTHORS' CONCLUSIONS: No conclusive evidence was found to determine whether IDS between cycles of chemotherapy would improve or decrease the survival rates of women with advanced ovarian cancer, compared with conventional treatment of primary surgery followed by adjuvant chemotherapy. IDS appeared to yield benefit only in patients whose primary surgery was not performed by gynaecologic oncologists or was less extensive. Data on QoL and adverse events were inconclusive. PMID- 20927745 TI - Finasteride for benign prostatic hyperplasia. AB - BACKGROUND: Benign prostatic hyperplasia (BPH), a non-malignant enlargement of the prostate in aging men, can cause bothersome urinary symptoms (intermittency, weak stream, straining, urgency, frequency, incomplete emptying). Finasteride, a five-alpha reductase inhibitor (5ARI), blocks the conversion of testosterone to dihydrotestosterone, reduces prostate size, and is commonly used to treat symptoms associated with BPH. OBJECTIVES: To compare the clinical effectiveness and harms of finasteride versus placebo and active controls in the treatment of lower urinary tract symptoms (LUTS). SEARCH STRATEGY: We searched The Cochrane Library (which includes CDSR (Cochrane Database of Systematic Reviews), DARE (Database of Abstracts of Reviews of Effects), HTA (Heath Technology Assessments), and CENTRAL (Cochrane Central Register of Controlled Trials, and which includes EMBASE and MEDLINE), LILACS (Latin American and Caribbean Center on Health Sciences Information) and Google Scholar for randomized, controlled trials (RCTs). We also handsearched systematic reviews, references, and clinical practice guidelines. SELECTION CRITERIA: Randomized trials in the English language with placebo and/or active arms with a duration of at least 6 months. DATA COLLECTION AND ANALYSIS: JT extracted the data, which included patient characteristics, outcomes, and harms. Our primary outcome was change in a validated, urinary symptom-scale score, such as the AUA/IPSS. A clinically meaningful change was defined as 4 points. We also categorized outcomes by trial lengths of <= 1 year (short term) and > 1 year (long term). MAIN RESULTS: Finasteride consistently improved urinary symptom scores more than placebo in trials of > 1 year duration, and significantly lowered the risk of BPH progression (acute urinary retention, risk of surgical intervention, >= 4 point increase in the AUASI/IPSS). In comparison to alpha-blocker monotherapy, finasteride was less effective than either doxazosin or terazosin, but equally effective compared to tamsulosin. Both doxazosin and terazosin were significantly more likely than finasteride to improve peak urine flow and nocturia, versus finasteride. Versus tamsulosin, peak urine flow and QoL improved equally well versus finasteride. However, finasteride was associated with a lower risk of surgical intervention compared to doxazosin, but not to terazosin, while finasteride and doxazosin were no different for risk of acute urinary retention. Two small trials reported no difference in urinary symptom scores between finasteride and tamsulosin. Finasteride + doxazosin and doxazosin monotherapy improved urinary symptoms equally well (>= 4 point improvement).For finasteride, there was an increased risk of ejaculation disorder, impotence, and lowered libido, versus placebo. Versus doxazosin, finasteride had a lower risk of asthenia, dizziness, and postural hypotension, and versus terazosin, finasteride had a significant, lower risk of asthenia, dizziness, and postural hypotension. AUTHORS' CONCLUSIONS: Finasteride improves long-term urinary symptoms versus placebo, but is less effective than doxazosin. Long-term combination therapy with alpha blockers (doxazosin, terazosin) improves symptoms significantly better than finasteride monotherapy. Finasteride + doxazosin improves symptoms equally - and clinically - to doxazosin alone. In comparison to doxazosin, finasteride + doxazosin appears to improve urinary symptoms only in men with medium (25 to < 40 mL) or large prostates (>= 40 mL), but not in men with small prostates (25 mL).Comparing short to long-term therapy, finasteride does not improve symptoms significantly better than placebo at the short term, but in the long term it does, although the magnitude of differences was very small (from < 1.0 point to 2.2 points). Doxazosin improves symptoms better than finasteride both short and long term, with the magnitude of differences ~2.0 points and 1.0 point, respectively. Finasteride + doxazosin improves scores versus finasteride alone at both short and long term, with mean differences ~2.0 points for both time points. Finasteride + doxazosin versus doxazosin improves scores equally for short and long term.Drug-related adverse effects for finasteride are rare; nevertheless, men taking finasteride are at increased risk for impotence, erectile dysfunction, decreased libido, and ejaculation disorder, versus placebo. Versus doxazosin, which has higher rates of dizziness, postural hypotension, and asthenia, men taking finasteride are at increased risk for impotence, erectile dysfunction, decreased libido, and ejaculation disorder. Finasteride significantly reduces asthenia, postural hypotension, and dizziness versus terazosin. Finasteride significantly lowers the risk of asthenia, dizziness, ejaculation disorder, and postural hypotension, versus finasteride + terazosin. PMID- 20927746 TI - Chromoscopy versus conventional endoscopy for the detection of polyps in the colon and rectum. AB - BACKGROUND: Although conventional colonoscopy is the most sensitive test available for the investigation of the colorectum for polyps, there are data that raise concerns about its sensitivity. Chromoscopy may be one way of enhancing the ability for colonoscopy to detect polyps particularly diminutive flat lesions that may be otherwise difficult to detect. OBJECTIVES: To determine whether the use of chromoscopy enhances detection of polyps and neoplasia during endoscopic examination of the colon and rectum. SEARCH STRATEGY: MEDLINE, EMBASE and the Cochrane Library databases were searched (April 2010) along with a hand search of abstracts from relevant meetings. Search terms included randomised trials containing combinations of the following: 'chromoscopy' 'colonoscopy' 'dye-spray' 'chromo-endoscopy' 'indigo-carmine' 'magnifying endoscopy'. SELECTION CRITERIA: All prospective randomised trials comparing chromoscopic with conventional endoscopic examination of the lower gastrointestinal tract were included. Patients with inflammatory bowel disease or polyposis syndromes were excluded. DATA COLLECTION AND ANALYSIS: Two reviewers assessed the methodological quality of potentially eligible trials and independently extracted data from the included trials. Outcome measures included the detection of polyps (neoplastic and non neoplastic), the detection of diminutive lesions, the number of patients with multiple neoplastic lesions and the extubation time. MAIN RESULTS: Five trials were included in this update, and although there were some methodological drawbacks and differences in study design, combining the results showed a significant difference in favour of chromoscopy for all detection outcomes. In particular, chromoscopy is likely to yield significantly more patients with at least one neoplastic lesion (OR 1.67 (CI 1.29-2.15)) and significantly more patients with three or more neoplastic lesions (OR 2.55 (CI 1.49-4.36)). Not surprisingly the withdrawal times were significantly slower for the chromoscopy group. AUTHORS' CONCLUSIONS: There appears to be strong evidence that chromoscopy enhances the detection of neoplasia in the colon and rectum. Patients with neoplastic polyps, particularly those with multiple polyps, are at increased risk of developing colorectal cancer. Such lesions, which presumably would be missed with conventional colonoscopy, could contribute to the interval cancer numbers on any surveillance programme. PMID- 20927747 TI - Hand assisted laparoscopic surgery versus conventional laparoscopy for colorectal surgery. AB - BACKGROUND: Laparoscopic surgery for colon disease has been shown to have advantages over the open approach in the perioperative period in terms of shorter hospital stay, decreased analgesic use and a more rapid return of bowel function but provides these benefits at the expense of increased technical difficulty and operative time. Hand assisted surgery which a is a hybrid of open surgery and laparoscopic surgery may offer patients the perioperative advantages of minimally invasive surgery without the technical difficulty and increased operative time associated with the conventional laparoscopic approach. This review compares the benefits and harms of laparoscopic and hand assisted laparoscopic surgery for colon disease. OBJECTIVES: To estimate the perioperative outcomes of hand assisted laparoscopic surgery compared to conventional laparoscopic surgery in adult patients requiring colorectal resections. SEARCH STRATEGY: We searched EMBASE (1980- Feb 2010), Medline (1966- Feb 2010) and the Cochrane Central Register of Controlled Trials (CENTRAL, 2010 issue 1), references of included studies, relevant review articles and conference abstracts. SELECTION CRITERIA: Randomised controlled trials (RCTs) in which adult patients were allocated to either receive hand-assisted laparoscopic surgery or conventional laparoscopic colorectal resection for benign or malignant colorectal disease. Studies were not restricted by language of publication. DATA COLLECTION AND ANALYSIS: Reports of potentially relevant articles were retrieved in full text, and two reviewers independently assessed the eligibility of these studies. Data abstraction was performed independently by two reviewers. Meta-analysis of perioperative outcome measures was carried out using a random effects model. MAIN RESULTS: Three randomised controlled studies met the inclusion criteria (n=189). One study focused exclusively on malignant pathology, the second study focused mostly on benign pathology and the third trial had a mixed variety of pathology with approximately a third representing malignant pathology. Conversion rates were significantly decreased in patients undergoing hand assisted surgery but there was no statistically significant difference in operative time or complication rates when comparing hand assisted surgery to conventional laparoscopy. All studies were associated with methodological limitations. AUTHORS' CONCLUSIONS: Despite the limited number of trials performed, meta-analysis demonstrated a statistically significant decrease in conversion rates among the hand assisted group. There was no difference in operating time or perioperative complication rates. Additional adequately powered and methodologically sound trials are needed to determine if there is a clinically important difference in perioperative outcomes. Due to significant costs associated with the use of hand assist devices, economic analyses are also warranted. PMID- 20927748 TI - Zotepine versus other atypical antipsychotics for schizophrenia. AB - BACKGROUND: In many parts of the world, particularly in industrialised countries, second generation (atypical) antipsychotic drugs have become first line treatment for people suffering from schizophrenia. The question as to whether the effects of various second generation antipsychotic drugs differ is a matter of debate. OBJECTIVES: To evaluate the effects of zotepine compared with other second generation antipsychotic drugs for people suffering from schizophrenia and schizophrenia-like psychoses. SEARCH STRATEGY: We searched the Cochrane Schizophrenia Group Trials Register (November 2009), inspected references of all identified studies for further trials and contacted authors of trials for additional information. SELECTION CRITERIA: We included only randomised clinical controlled trials that compared zotepine with any forms of amisulpride, aripiprazole, clozapine, olanzapine, risperidone, sertindole or ziprasidone in people suffering from only schizophrenia or schizophrenia-like psychoses. DATA COLLECTION AND ANALYSIS: SS and KK extracted data independently. For dichotomous data we calculated relative risks (RR) and their 95% confidence intervals (CI) on an intention-to-treat basis based on a random-effects model. For continuous data, we calculated weighted mean differences (MD) again based on a random-effects model. MAIN RESULTS: We included three studies (total n=289; 2 RCTs zotepine vs clozapine; 1 RCT zotepine vs clozapine vs risperidone (at 4 mg, 8 mg doses) vs remoxipride. All studies were of limited methodological quality. When zotepine was compared with clozapine, it was clozapine that was found to be more effective in terms of global state (n=59, 1 RCT, RR No clinically significant response 8.23 CI 1.14 to 59.17). Mental state scores also favoured clozapine (n=59, 1 RCT, MD average score (BPRS total, high = poor) 6.00 CI 2.17 to 9.83) and there was less use of antiparkinson medication in the clozapine group (n=116, 2 RCTs, RR 20.96 CI 2.89 to 151.90). In the comparison of zotepine and risperidone, mental state scoring found no significant difference between the groups (vs 4 mg: n=40, 1 RCT, MD average endpoint score (BPRS total, high=poor) 1.40 CI -9.82 to 12.62; vs 8 mg: n=40, 1 RCT, MD -1.30 CI -12.95 to 10.35) and use of antiparkinson medication was equivocal (vs 4 mg: n=40, 1 RCT, MD 1.80 CI -0.64 to 4.24; vs 8 mg: n=40, 1 RCT, MD 2.50 CI -0.05 to 5.05). Finally, when zotepine was compared with remoxipride, again no effect was found for mental state (n=58, 1 RCT, MD average endpoint score (BPRS total, high=poor) 5.70 CI -4.13 to 15.53) and there was no significant difference between the two groups in terms of use of antiparkinson medication (n=49, 1 RCT, RR 0.97 CI 0.41 to 2.29).Data on important other outcomes such as other adverse events, service use or satisfaction with care, quality of life were not available. AUTHORS' CONCLUSIONS: The evidence base around zotepine is insufficient to provide firm conclusions on its absolute or relative effects. This is despite it being in use in Austria, France, Germany, Japan and the UK. PMID- 20927749 TI - Unfractionated or low-molecular weight heparin for induction of remission in ulcerative colitis. AB - BACKGROUND: There are a limited number of treatment options for patients with ulcerative colitis (UC). An increased risk of thrombosis in UC coupled with an observation that UC patients being treated with anticoagulant therapy for thrombotic events had an improvement in their bowel symptoms led to trials examining the use of unfractionated heparin (UFH) and low molecular weight heparins (LMWH) in patients with active UC. OBJECTIVES: To review randomized trials examining the efficacy of unfractionated heparin (UFH) or low molecular weight heparins (LMWH) for remission induction in patients with ulcerative colitis. SEARCH STRATEGY: The MEDLINE (PUBMED), and EMBASE databases, The Cochrane Central Register of Controlled Trials, the Cochrane IBD/FBD group specialized trials register, review papers on ulcerative colitis, and references from identified papers were searched up to June 2010 in an effort to identify all randomized trials studying UFH or LMWH use in patients with ulcerative colitis. Abstracts from major gastroenterological meetings were searched to identify research published in abstract form only. SELECTION CRITERIA: Each author independently reviewed potentially relevant trials to determine their eligibility for inclusion based on the criteria identified above. The Cochrane Risk of Bias tool was used to assess study quality. Studies published in abstract form only were included if the authors could be contacted for further information. DATA COLLECTION AND ANALYSIS: A data extraction form was developed and used to extract data from included studies. At least 2 authors independently extracted data. Any disagreements were resolved by consensus. Data were analyzed on an intention-to treat basis. The primary outcome was induction of remission, as defined by the studies. Data were combined for analysis if they assessed the same treatments (UFH or LMWH versus placebo or other therapy). MAIN RESULTS: LMWH administered subcutaneously showed no benefit over placebo for any outcome, including clinical remission, and clinical, endoscopic, or histological improvement. High dose LMWH administered via an extended colon-release tablet demonstrated benefit over placebo for clinical remission (OR 2.73; 95% CI 1.32 to 5.67; P = 0.007), clinical improvement (OR 2.99; 95% CI 1.30 to 6.87; P = 0.01), and endoscopic improvement (OR 2.25; 95%CI 1.01 to 5.01; P = 0.05) but not endoscopic remission or histologic improvement. LMWH was not beneficial when added to standard therapy for clinical remission, clinical improvement, endoscopic remission or endoscopic improvement. LMWH was well-tolerated but provided no significant benefit for quality of life. One study examining UFH versus corticosteroids for the treatment of severe UC demonstrated the inferiority of UFH for clinical improvement. More patients assigned to UFH had rectal hemorrhage as an adverse event. AUTHORS' CONCLUSIONS: There is evidence to suggest that LMWH may be effective for the treatment of active UC. When administered by extended colon-release tablets, LMWH was more effective than placebo for treating outpatients with mild to moderate disease. This benefit needs to be confirmed by further randomized controlled studies. The same benefits were not seen when LMWH was administered subcutaneously at lower doses. There is no evidence to support the use of UFH for the treatment of active UC. A further trial of UFH in patients with mild disease may also be justified. Any benefit found would need to be weighed against a possible increased risk of rectal bleeding in patients with active UC. PMID- 20927750 TI - Traditional Chinese Medicine herbs for stopping bleeding from haemorrhoids. AB - BACKGROUND: Haemorrhoids is a common perianal disease, which often causes haematochezia. Besides a surgical operation or minimally invasive treatment, a variety of traditional Chinese medicinal herbs (TCMHs) have been used to treat bleeding haemorrhoids. OBJECTIVES: To assess the effectiveness of traditional Chinese medicinal herbs for stopping bleeding from haemorrhoids and the adverse effects caused by these herbs. SEARCH STRATEGY: We searched the Cochrane Colorectal Cancer Group Trials Register, Cochrane Central Register of Contolled Trials (CENTRAL) (The Cochrane Library), MEDLINE, EMBASE, CMCD (Chinese Medicine Conference Disc) and CBMD (Chinese Bio-Medicine Disc). SELECTION CRITERIA: All randomised clinical trials (RCTs) of Chinese herbs for bleeding haemorrhoids were included. DATA COLLECTION AND ANALYSIS: Two authors independently extracted the data, which were analysed using RevMan 5.0 software. We estimated the relative risk for dichotomous data and calculated the weighted mean difference for continuous data. MAIN RESULTS: Nine trials involving 1822 patients with bleeding haemorrhoids were identified. The included trials were generally not of high quality and used one TCMH preparation compared with another TCMH preparation (Type I) (five trials) or western medicines (Type II) (four trials). We could not pool the data to perform a meta-analysis as only two of the included trials used the same intervention or comparison.In the nine trials, TCMHs showed a statistically significant difference for the improvement in the general curative effects or total grade of symptoms in six trials (P < 0.05; P < 0.01), of hematochezia in three trials (P < 0.05; P < 0.001), and of inflammation of perianal mucosa in one trial (P < 0.05). The adverse effects reported were not serious and were scarce. AUTHORS' CONCLUSIONS: This review did not provide strong evidence concerning the effectiveness of TCMHs for stopping bleeding from haemorrhoids. Most of the included studies were of low quality and there was a scarcity of eligible trials and numbers of participants. Limited, weak evidence showed that some herbal formulae, when including Radix Sanguisorbae, Radix Rehmanniae, Fructus Sophorae, Radix Angelicae Sinensis, Radix Scutellariae, etc., may alleviate some symptoms caused by haemorrhoids. These include hematochezia, congestive haemorrhoidal cushions and inflammation of perianal mucosa in the short term. Well-designed clinical trials are required urgently before any confident conclusions can be drawn about the value of TCMHs for stopping bleeding from haemorrhoids.At present, the evidence is not enough that clinical practice should be changed immediately on the basis of these results. PMID- 20927751 TI - Methods of cystic duct occlusion during laparoscopic cholecystectomy. AB - BACKGROUND: During laparoscopic cholecystectomy, it is necessary to occlude the cystic duct permanently. Traditionally, this has been performed through the application of non-absorbable metal clips. Use of absorbable materials to occlude the cystic duct has been suggested as an alternative for metal clips for various reasons. OBJECTIVES: To assess the benefits and harms of the different methods of occlusion of cystic duct in patients undergoing laparoscopic cholecystectomy. SEARCH STRATEGY: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Central Register of Controlled Trials in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded until August 2010. SELECTION CRITERIA: We included all randomised clinical trials comparing different methods of occlusion of cystic duct. DATA COLLECTION AND ANALYSIS: We collected the data on the characteristics, methodological quality, bile duct injury, bile leaks, operating time, and incidence of recurrent common bile duct stone from each trial. We analysed the data with both the fixed-effect and the random-effects model using RevMan Analysis. For each outcome we calculated the risk ratio (RR) in the presence of more than one trial for the outcome or mean difference (MD) with 95% confidence intervals (CI) based on intention-to-treat analysis. In the presence of only one trial under a dichotomous outcome, we performed the Fisher's exact test. MAIN RESULTS: Three trials including 255 patients qualified for this review. In two of the trial, a total of 150 patients were randomised to absorbable clips (n = 75) and non-absorbable clips (n = 75). In the third trial, a total of 105 patients were randomised to absorbable ligatures (n = 53) and non-absorbable clips (n = 52). All three trials were of high risk of bias. There was no difference in the morbidity between the groups. There was statistically significant longer operating time (MD 12.00 minutes, 95% CI 1.59 to 22.41) in the absorbable ligature group than non-absorbable clips. The duration and method of follow-up were not adequate to determine the incidence of long-term complications. AUTHORS' CONCLUSIONS: We are unable to determine the benefits and harms of different methods of cystic duct occlusion because of the small sample size, short period of follow-up, and lack of reporting of important outcomes in the included trials. Adequately powered randomised trials with low risk of bias and with long periods of follow-up and assessing all of the important outcomes for patients and professionals are necessary. PMID- 20927752 TI - Droperidol for treatment of nausea and vomiting in palliative care patients. AB - BACKGROUND: Nausea and vomiting are common symptoms in patients with terminal illness and can be very unpleasant and distressing. There are several different types of antiemetic treatments which can be used to control these symptoms. Droperidol is an antipsychotic drug and has been used and studied as an antiemetic in the management of post-operative and chemotherapy nausea and vomiting. OBJECTIVES: To evaluate the efficacy and adverse events (both minor and serious) associated with the use of droperidol for the treatment of nausea and vomiting in palliative care patients. SEARCH STRATEGY: We searched electronic databases including CENTRAL, MEDLINE, EMBASE, CINAHL and AMED, using relevant search terms and synonyms. The basic search strategy was ("droperidol" OR "butyrophenone") AND ("nausea" OR "vomiting"), modified for each database. The search was updated on 2 December 2009. SELECTION CRITERIA: Randomised controlled trials (RCTs) of droperidol for the treatment of nausea or vomiting, or both, for adults receiving palliative care or suffering from an incurable progressive medical condition. DATA COLLECTION AND ANALYSIS: We judged the potential relevance of studies based on their titles and abstracts, and obtained studies which we anticipated might meet the inclusion criteria. We both read these to assess suitability for inclusion. Discrepancies were discussed to achieve consensus. MAIN RESULTS: The search strategy identified 1664 abstracts (and 827 duplicates) of which 23 studies were obtained in full as potentially meeting the inclusion criteria. On review of the full papers, no studies were identified which met the inclusion criteria, therefore, there were no included studies in this review. AUTHORS' CONCLUSIONS: There is insufficient evidence to advise on the use of droperidol for the management of nausea and vomiting in palliative care. Studies of antiemetics in palliative care settings are needed to identify which agents are most effective with a minimum of side effects. PMID- 20927753 TI - Vitamin D supplementation for improving bone mineral density in children. AB - BACKGROUND: Results of randomised controlled trials (RCTs) of vitamin D supplementation to improve bone density in children are inconsistent. OBJECTIVES: To determine the effectiveness of vitamin D supplementation for improving bone mineral density in children, whether any effect varies by sex, age or pubertal stage, the type or dose of vitamin D given or baseline vitamin D status, and if effects persist after cessation of supplementation. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL Issue 3, 2009), MEDLINE (1966 to present), EMBASE (1980 to present), CINAHL (1982 to present), AMED (1985 to present) and ISI Web of Science (1945 to present) on 9 August 2009, and we handsearched key journal conference abstracts. SELECTION CRITERIA: Placebo controlled RCTs of vitamin D supplementation for at least three months in healthy children and adolescents (aged from one month to < 20 years) with bone density outcomes. DATA COLLECTION AND ANALYSIS: Two authors screened references for inclusion, assessed risk of bias, and extracted data. We conducted meta-analyses and calculated standardised mean differences (SMD) of the percent change from baseline in outcomes in treatment and control groups. We performed subgroup analyses by sex, pubertal stage, dose of vitamin D and baseline serum vitamin D and considered these as well as compliance and allocation concealment as possible sources of heterogeneity. MAIN RESULTS: We included six RCTs (343 participants receiving placebo and 541 receiving vitamin D) for meta-analyses. Vitamin D supplementation had no statistically significant effects on total body bone mineral content (BMC), hip bone mineral density (BMD) or forearm BMD. There was a trend to a small effect on lumbar spine BMD (SMD 0.15, 95% CI -0.01 to 0.31, P = 0.07). There were no differences in effects between high and low serum vitamin D studies at any site though there was a trend towards a larger effect with low vitamin D for total body BMC (P = 0.09 for difference). In low serum vitamin D studies, significant effects on total body BMC and lumbar spine BMD were approximately equivalent to a 2.6% and 1.7 % percentage point greater change from baseline in the supplemented group. AUTHORS' CONCLUSIONS: These results do not support vitamin D supplementation to improve bone density in healthy children with normal vitamin D levels, but suggest that supplementation of deficient children may be clinically useful. Further RCTs in deficient children are needed to confirm this. PMID- 20927754 TI - Early versus late pre-intensive care unit admission broad spectrum antibiotics for severe sepsis in adults. AB - BACKGROUND: Severe sepsis and septic shock have recently emerged as particularly acute and lethal challenges amongst critically ill patients presenting to the emergency department (ED). There are no existing data on the current practices of management of patients with severe sepsis comparing early versus late administration of appropriate broad spectrum antibiotics as part of the early goal-directed therapy that is commenced in the first few hours of presentation. OBJECTIVES: To assess the difference in outcomes with early compared to late administration of antibiotics in patients with severe sepsis in the pre-intensive care unit (ICU) admission period. We defined early as within one hour of presentation to the ED. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 1, 2009); MEDLINE (1990 to February 2010); EMBASE (1990 to February 2010); and ISI web of Science (February 2010). We also searched for relevant ongoing trials in specific websites such as www.controlled-trials.com; www.clinicalstudyresults.org; and www.update-software.com. We searched the reference lists of articles. There were no constraints based on language or publication status. SELECTION CRITERIA: We planned to include randomized controlled trials of early versus late broad spectrum antibiotics in adult patients with severe sepsis in the ED, prior to admission to the intensive care unit. DATA COLLECTION AND ANALYSIS: Two authors independently assessed articles for inclusion. MAIN RESULTS: We found no studies that satisfied the inclusion criteria. AUTHORS' CONCLUSIONS: Based on this review we are unable to make a recommendation on the early or late use of broad spectrum antibiotics in adult patients with severe sepsis in the ED pre-ICU admission. There is a need to do large prospective double blinded randomized controlled trials on the efficacy of early (within one hour) versus late broad spectrum antibiotics in adult severe sepsis patients. Since it makes sense to start antibiotics as soon as possible in this group of seriously ill patients, administering such antibiotics earlier as opposed to later is based on anecdotal suboptimal evidence. PMID- 20927755 TI - Antimicrobial agents for treating uncomplicated urinary tract infection in women. AB - BACKGROUND: Acute uncomplicated lower urinary tract infection (UTI) is one of the most common problems for which young women seek medical attention. OBJECTIVES: To compare the efficacy, resistance development and safety of different antimicrobial treatments for acute uncomplicated lower UTI. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), the Cochrane Renal Group's Specialised Register, MEDLINE, EMBASE and bibliographies of included studies. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing different classes of antimicrobials for acute uncomplicated UTI in women were included. The outcomes of interest were symptomatic and bacteriological cure at short and long-term follow-up, resistance development, number of days to symptom resolution, days of work loss, adverse events and complications. DATA COLLECTION AND ANALYSIS: Two authors independently extracted the data and assessed study quality. Statistical analyses were performed using the random effects model and the results expressed as risk ratios (RR) with 95% confidence intervals (CI). MAIN RESULTS: Trimethoprim-sulfamethoxazole (TMP-SMX) was as effective as fluoroquinolones in achieving short-term (RR 1.00, 95% CI 0.97 to 1.03) and long-term (RR 0.99, 95% CI 0.94 to 1.05) symptomatic cure. Beta lactam drugs were as effective as TMP-SMX for short-term (RR 0.95' 95% CI 0.81 to 1.12) and long-term (RR 1.06' 95% CI 0.93 to 1.21) symptomatic cure. Short-term cure for nitrofurantoin was similar to that of TMP-SMX (RR 0.99' 95% CI 0.95 to 1.04) as was long-term symptomatic cure (RR 1.01' 95% CI 0.94 to 1.09).Fluoroquinolones were more effective than beta-lactams (RR 1.22, 95% CI 1.13 to 1.31) for short-term bacteriological cure. Rashes were more frequent in patients treated with TMP-SMX than with nitrofurantoin or fluoroquinolones and in patients treated with beta-lactam drugs compared to fluoroquinolones. Minimal data were available on the emergence of resistant strains during or after antimicrobial treatment. AUTHORS' CONCLUSIONS: No differences were observed between the classes of antimicrobials included in this review for the symptomatic cure of acute uncomplicated UTI. Fluoroquinolones proved more effective than beta lactams for the short-term bacteriological outcome, probably with little clinical significance. Individualised treatment should take into consideration the predictable susceptibility of urinary pathogens in local areas, possible adverse events and resistance development, and patient preference. PMID- 20927756 TI - Effects of communicating DNA-based disease risk estimates on risk-reducing behaviours. AB - BACKGROUND: There are high expectations regarding the potential for the communication of DNA-based disease risk estimates to motivate behaviour change. OBJECTIVES: To assess the effects of communicating DNA-based disease risk estimates on risk-reducing behaviours and motivation to undertake such behaviours. SEARCH STRATEGY: We searched the following databases using keywords and medical subject headings: Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 4 2010), MEDLINE (1950 to April 2010), EMBASE (1980 to April 2010), PsycINFO (1985 to April 2010) using OVID SP, and CINAHL (EBSCO) (1982 to April 2010). We also searched reference lists, conducted forward citation searches of potentially eligible articles and contacted authors of relevant studies for suggestions. There were no language restrictions. Unpublished or in press articles were eligible for inclusion. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials involving adults (aged 18 years and over) in which one group received actual (clinical studies) or imagined (analogue studies) personalised DNA-based disease risk estimates for diseases for which the risk could plausibly be reduced by behavioural change. Eligible studies had to include a primary outcome measure of risk-reducing behaviour or motivation (e.g. intention) to alter such behaviour. DATA COLLECTION AND ANALYSIS: Two review authors searched for studies and independently extracted data. We assessed risk of bias according to the Cochrane Handbook for Systematic Reviews of Interventions. For continuous outcome measures, we report effect sizes as standardised mean differences (SMDs). For dichotomous outcome measures, we report effect sizes as odds ratios (ORs). We obtained pooled effect sizes with 95% confidence intervals (CIs) using the random effects model applied on the scale of standardised differences and log odds ratios. MAIN RESULTS: We examined 5384 abstracts and identified 21 studies as potentially eligible. Following a full text analysis, we included 14 papers reporting results of 7 clinical studies (2 papers report on the same trial) and 6 analogue studies.Of the seven clinical studies, five assessed smoking cessation. Meta-analyses revealed no statistically significant effects on either short-term (less than 6 months) smoking cessation (OR 1.35, 95% CI 0.76 to 2.39, P = 0.31, n = 3 studies) or cessation after six months (OR 1.07, 95% CI 0.64 to 1.78, P = 0.80, n = 4 studies). Two clinical studies assessed diet and found effects that significantly favoured DNA-based risk estimates (OR 2.24, 95% CI 1.17 to 4.27, P = 0.01). No statistically significant effects were found in the two studies assessing physical activity (OR 1.03, 95% CI 0.59 to 1.80, P = 0.92) or the one study assessing medication or vitamin use aimed at reducing disease risks (OR 1.26, 95% CI 0.58 to 2.72, P = 0.56). For the six non-clinical analogue studies, meta-analysis revealed a statistically significant effect of DNA-based risk on intention to change behaviour (SMD 0.16, 95% CI 0.04 to 0.29, P = 0.01).There was no evidence that communicating DNA-based disease risk estimates had any unintended adverse effects. Two studies that assessed fear arousal immediately after the presentation of risk information did, however, report greater fear arousal in the DNA-based disease risk estimate groups compared to comparison groups.The quality of included studies was generally poor. None of the clinical or analogue studies were considered to have a low risk of bias, due to either a lack of clarity in reporting, or where details were reported, evidence of a failure to sufficiently safeguard against the risk of bias. AUTHORS' CONCLUSIONS: Mindful of the weak evidence based on a small number of studies of limited quality, the results of this review suggest that communicating DNA-based disease risk estimates has little or no effect on smoking and physical activity. It may have a small effect on self-reported diet and on intentions to change behaviour. Claims that receiving DNA-based test results motivates people to change their behaviour are not supported by evidence. Larger and better-quality RCTs are needed. PMID- 20927757 TI - Anti-vascular endothelial growth factor for macular edema secondary to central retinal vein occlusion. AB - BACKGROUND: Central retinal vein occlusion (CRVO) is a common retinal vascular disorder in which macular edema (ME) may develop, with a consequent reduction in visual acuity. The visual prognosis in CRVO-ME is poor in a substantial proportion of patients, especially those with the ischemic subtype, and until recently there has been no treatment of proven benefit. Macular grid laser treatment is ineffective, and whilst a few recent randomized controlled trials (RCTs) suggest short-term gains in visual acuity with intravitreal steroids for patients with non-ischemic CRVO-ME, there is no established treatment for ischemic CRVO-ME. Anti-vascular endothelial growth factor (anti-VEGF) agents have been used to treat ME resulting from a variety of causes and may represent a treatment option for CRVO-ME. OBJECTIVES: To investigate the effectiveness and safety of intravitreal anti-VEGF agents in the treatment of CRVO-ME. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2010, Issue 8), MEDLINE (January 1950 to August 2010), EMBASE (January 1980 to August 2010), Latin American and Caribbean Health Sciences Literature Database (LILACS) (January 1982 to August 2010), Cumulative Index to Nursing and Allied Health Literature (CINAHL) (January 1937 to August 2010), OpenSIGLE (January 1950 to August 2010), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com) and ClinicalTrials.gov (www.clinicaltrials.gov). There were no language or date restrictions in the search for trials. The electronic databases were last searched on 10 August 2010. SELECTION CRITERIA: We considered RCTs that compared intravitreal anti-VEGF agents of any dose or duration to sham injection or no treatment. We focused on studies that included individuals of any age or gender with unilateral or bilateral disease and a minimum of six months follow up. Secondarily, we considered non-randomized studies with the same criteria, but did not conduct a separate electronic search for these. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. MAIN RESULTS: We found two RCTs that met the inclusion criteria after independent and duplicate review of the search results. These RCTs utilized different anti-VEGF agents which cannot be assumed to be directly comparable. We, therefore, performed no meta-analysis. Evidence from these trials and from other non-randomized case series is summarized in this review. AUTHORS' CONCLUSIONS: Ranibizumab and pegaptanib sodium have shown promise in the short-term treatment of non-ischemic CRVO-ME. However, effectiveness and safety data from larger RCTs with follow up beyond six months are not yet available. There are no RCT data on anti-VEGF agents in ischemic CRVO-ME. The use of anti-VEGF agents to treat this condition therefore remains experimental. PMID- 20927758 TI - Antibiotic prophylaxis for patients undergoing elective endoscopic retrograde cholangiopancreatography. AB - BACKGROUND: The use of prophylactic antibiotics before endoscopic retrograde cholangiopancreatography (ERCP) is recommended by all major international gastroenterological societies, especially in the presence of an obstructed biliary system. Their use is intended to decrease or eliminate the incidence of complications following the procedure, namely cholangitis, cholecystitis, septicaemia, and pancreatitis. OBJECTIVES: To assess the benefits and harms of antibiotics before elective ERCP in patients without evidence of acute or chronic cholecystitis, or acute or chronic cholangitis, or severe acute pancreatitis. SEARCH STRATEGY: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, and LILACS until March 2010. Relevant medical and surgical international conference proceedings were also searched. SELECTION CRITERIA: Only randomised clinical trials were included in the analyses, irrespective of blinding, language, or publication status. Participants were patients that underwent elective ERCP that were not on antibiotics, without evidence of acute or chronic cholecystitis, cholangitis, or severe acute pancreatitis before the procedure. We compared patients that received prophylactic antibiotics before the procedure with patients that were given placebo or no intervention before the procedure. DATA COLLECTION AND ANALYSIS: The review was conducted according to the recommendations of The Cochrane Collaboration as well as the Cochrane Hepato Biliary Group. Review Manager 5 was used employing fixed-effect and random effects models meta-analyses. MAIN RESULTS: Nine randomised clinical trials (1573 patients) were included in the analyses. The majority of the trials had risks of bias. When all patients providing data for a certain outcome were included, the fixed-effect meta-analyses significantly favoured the use of prophylactic antibiotics in preventing cholangitis (relative risk (RR) 0.54, 95% CI 0.33 to 0.91), septicaemia (RR 0.35, 95% CI 0.11 to 1.11), bacteriaemia (RR 0.50, 95% CI 0.33 to 0.78), and pancreatitis (RR 0.54, 95% CI 0.29 to 1.00). In random-effects meta-analyses, only the effect on bacteriaemia remained significant. Overall mortality was not reduced (RR 1.33, 95% CI 0.32 to 5.44). If one selects patients in whom the ERCP resolved the biliary obstruction at the first procedure, there seem to be no significant benefit in using prophylactic antibiotics to prevent cholangitis (RR 0.98, 95% CI 0.35 to 2.69, only three trials). AUTHORS' CONCLUSIONS: Prophylactic antibiotics reduce bacteriaemia and seem to prevent cholangitis and septicaemia in patients undergoing elective ERCP. In the subgroup of patients with uncomplicated ERCP, the effect of antibiotics may be less evident. Further research is required to determine whether antibiotics can be given during or after an ERCP if it becomes apparent that biliary obstruction cannot be relieved during that procedure. PMID- 20927759 TI - Increased versus stable doses of inhaled corticosteroids for exacerbations of chronic asthma in adults and children. AB - BACKGROUND: Written action plans providing guidance in the early treatment of asthma exacerbations have traditionally advocated doubling of inhaled corticosteroids (ICS) as one of the first steps in treatment. OBJECTIVES: To compare the clinical effectiveness of increasing the dose of ICS versus keeping the usual maintenance dose as part of a patient-initiated action plan at the onset of asthma exacerbations. SEARCH STRATEGY: We searched the Cochrane Airways Group Specialised Register (last search October 2009) which is derived from searches of CENTRAL, MEDLINE, EMBASE and CINAHL, as well as handsearched respiratory journals and meeting abstracts. SELECTION CRITERIA: Randomised controlled trials (RCTs) that compared the strategy of increasing the daily dose of ICS to continuing the same ICS dose in the home management of asthma exacerbations in children or adults with persistent asthma on daily maintenance ICS. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials, assessed quality and extracted data. We contacted authors of RCTs for additional information. MAIN RESULTS: Five RCTs (four parallel-group and one cross-over) involving a total of 1250 patients (28 children and 1222 adults) with mild to moderate asthma were included. The mean daily baseline ICS dose was 555 mg (range 200 mg to 795 mg) and the mean daily ICS dose achieved following increase was 1520 mg (range 1000 mg to 2075 mg), in CFC beclomethasone dipropionate equivalents. Three parallel-group studies in adults (two doubling and one quadrupling; mean achieved daily dose of 1695 mg with a range of 1420 to 2075 mg), involving 1080 patients contributed data to the primary outcome. There was no significant reduction in the need for rescue oral corticosteroids when patients were randomised to the increased ICS compared to stable maintenance dose groups (OR 0.85, 95% CI 0.58 to 1.26). There was no significant difference in the overall risk of non-serious adverse events associated with the increased ICS dose strategy, but the wide confidence interval prevents a firm conclusion. No serious adverse events were reported. AUTHORS' CONCLUSIONS: There is very little evidence from trials in children. In adults with asthma on daily maintenance ICS, a self initiated ICS increase to 1000 to 2000 mcg/day at the onset of an exacerbation is not associated with a statistically significant reduction in the risk of exacerbations requiring rescue oral corticosteroids. More research is needed to assess the effectiveness of increased ICS doses at the onset of asthma exacerbations (particularly in children). PMID- 20927760 TI - Alternative positions for the baby at birth before clamping the umbilical cord. AB - BACKGROUND: The third stage of labour is from birth of the baby until delivery of the placenta. Clamping the umbilical cord is one component of active management of the third stage. Deferring cord clamping allows blood flow between the baby and the placenta to continue; net transfer to the baby is called placental transfusion. If the cord is clamped immediately placental transfusion is restricted. Gravity is one of several factors that may influence the volume and duration of placental transfusion at both vaginal and caesarean births. Hence raising or lowering the baby whilst the cord is intact may influence placental transfusion, which in turn may affect outcome for the baby and the woman. OBJECTIVES: To compare the effects of alternative positions for the baby between birth and cord clamping on outcome for the baby, outcome for the mother and on use of health service resources. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (July 2010). SELECTION CRITERIA: Randomised trials comparing alternative positions for the baby at vaginal and caesarean birth, before clamping of the umbilical cord. DATA COLLECTION AND ANALYSIS: We independently assessed trial eligibility and quality. When necessary, we contacted study authors for additional information. MAIN RESULTS: Thirty-seven studies (7559 mother-infant pairs) were excluded: 33 (7296) because they did not compare alternative positions for the baby before clamping the umbilical cord and four (263) due to quasi-random allocation. No studies met the inclusion criteria. One additional trial is ongoing. AUTHORS' CONCLUSIONS: No randomised trials have assessed the influence of gravity on placental transfusion. Large, well-designed randomised trials are needed to assess whether gravity influences placental transfusion at vaginal and caesarean births and, if so, whether this affects short-term and long-term outcome for the baby and for the mother. PMID- 20927761 TI - Percutaneous vascular interventions for acute ischaemic stroke. AB - BACKGROUND: Most disabling strokes are due to blockage of a large artery in the brain by a blood clot. Prompt removal of the clot with intra-arterial thrombolytic drugs or mechanical devices, or both, can restore blood flow before major brain damage has occurred, leading to improved recovery. However, these so called percutaneous vascular interventions can cause bleeding in the brain. OBJECTIVES: To assess the safety and efficacy of percutaneous vascular interventions in patients with acute ischaemic stroke. SEARCH STRATEGY: We searched the Trials Registers of the Cochrane Stroke Group and Cochrane Peripheral Vascular Diseases Group (last searched May 2010), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Issue 5), MEDLINE (1980 to May 2010), EMBASE (1980 to May 2010) and eight additional databases. We also searched trials registers, screened reference lists, contacted researchers and equipment manufacturers, and handsearched journals and conference proceedings. SELECTION CRITERIA: Randomised, controlled and unconfounded trials of any percutaneous vascular intervention compared with control in patients with definite ischaemic stroke. DATA COLLECTION AND ANALYSIS: Two review authors applied the inclusion criteria, extracted data and assessed trial quality. We obtained both published and unpublished data if available MAIN RESULTS: We included four trials involving 350 patients. Not all trials contributed data to each outcome. The trials tested either intra-arterial urokinase or recombinant pro-urokinase versus an open control. One trial used guidewire-mediated clot disruption in some patients randomised to the intervention group. Most data came from trials that started treatment up to six hours after stroke; one small trial started treatment up to a median of 12.5 hours after stroke. Most data came from trials of middle cerebral artery territory infarction. Compared with non thrombolytic standard medical treatment, the intervention administered up to six hours after ischaemic stroke significantly increased the proportion of patients with favourable outcome (modified Rankin 0 to 2) three months after stroke (relative risk (RR) 1.47, 95% confidence interval (CI) 1.07 to 2.02). The intervention also significantly increased the risk of symptomatic intracranial haemorrhage within 24 hours of treatment (RR 3.85, 95% CI 0.91 to 16.36). There was no significant heterogeneity between the included trials. AUTHORS' CONCLUSIONS: Overall, intervention results in a significant increase in the proportion of patients with a favourable outcome, despite a significant increase in intracranial haemorrhage. Further trials are needed to confirm or refute these findings and, given the cost and practical difficulties, to establish whether percutaneous techniques are feasible and cost effective in wider clinical practice. PMID- 20927762 TI - Oral budesonide for induction of remission in ulcerative colitis. AB - BACKGROUND: Corticosteroids remain one of the most popular medication choices for the induction of remission in ulcerative colitis and Crohn's disease. While corticosteroids may improve symptoms, they do not always result in mucosal healing and have significant adverse effects. Steroids which act topically, with less systemic side-effects may be more desirable. Oral budesonide, a topically acting corticosteroid with extensive first pass hepatic metabolism, is effective in Crohn's disease and in enema formulation for left-sided ulcerative colitis. Data are limited regarding the role of oral budesonide in ulcerative colitis. OBJECTIVES: To systematically review the safety and efficacy of oral budesonide for induction of remission in ulcerative colitis. SEARCH STRATEGY: Electronic searching of the MEDLINE and EMBASE databases was performed. Two authors independently reviewed all identified titles and abstracts. Full text articles of all potentially relevant studies were retrieved. Reference lists of review articles were searched in an attempt to identify additional studies. Abstracts of the major gastroenterology scientific meetings, held over the past 3 years, were hand searched. The ClinicalTrials.gov website as well as the Cochrane Registry of Controlled Trials was searched to identify any ongoing trials. Direct communication with pharmaceutical manufacturers was established to identify any ongoing or unpublished studies. SELECTION CRITERIA: Randomized controlled trials of oral budesonide for the induction of remission in ulcerative colitis, with either a parallel arm or cross-over design, were considered eligible for inclusion. There were no exclusions based on patient age or the type, dose or duration of budesonide therapy. The primary outcome was the induction of clinical remission in ulcerative colitis. Secondary outcomes included clinical, histologic and endoscopic improvement, endoscopic mucosal healing, change in disease activity index scores, adverse events and study withdrawals. DATA COLLECTION AND ANALYSIS: Studies were reviewed for eligibility, data were extracted and quality assessed by 2 independent investigators. It was not possible to perform a meta analysis of the included studies due to significant heterogeneity, with each study comparing budesonide to a different control medication. MAIN RESULTS: Three studies met the inclusion criteria. Oral budesonide was significantly less likely to induce clinical remission than oral mesalamine after 8 weeks of therapy (RR 0.72, 95% CI 0.57 to 0.91). There was no significant benefit of oral budesonide in comparison to placebo for inducing clinical remission after 4 weeks of treatment (RR 1.41, 95% CI 0.59 to 3.39). A small pilot study reported no statistically significant difference in endoscopic remission between budesonide and prednisolone (RR 0.75, 95% CI 0.23 to 2.42). The study was small and not powered to evaluate the impact of budesonide on clinical remission. Suppression of plasma cortisol was significantly more common in prednisolone treated patients (RR 0.02, 95% CI 0.0 to 0.33). Two multicenter studies are ongoing. AUTHORS' CONCLUSIONS: At present, there is no evidence to recommend the clinical use of oral budesonide for the induction of remission in active ulcerative colitis. Mesalamine is superior to budesonide for the treatment of active ulcerative colitis. PMID- 20927763 TI - Telehealthcare for asthma. AB - BACKGROUND: Healthcare systems internationally need to consider new models of care to cater for the increasing numbers of people with asthma. Telehealthcare interventions are increasingly being seen by policymakers as a potential means of delivering asthma care. We defined telehealthcare as being healthcare delivered from a distance, facilitated electronically and involving the exchange of information through the personalised interaction between a healthcare professional using their skills and judgement and the patient providing information. OBJECTIVES: To assess the effectiveness of telehealthcare interventions in people with asthma. SEARCH STRATEGY: We searched in the following databases: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, AMED, and PsycINFO; this was supplemented by handsearching of respiratory journals. We also searched registers of ongoing and unpublished trials. SELECTION CRITERIA: We selected completed randomised controlled trials of telehealthcare initiatives aiming to improve asthma care. DATA COLLECTION AND ANALYSIS: Two review authors independently appraised studies for inclusion and extracted data and performed meta-analyses. We analysed dichotomous variables to produce an odds ratio (OR) and continuous variables to produce a mean difference. MAIN RESULTS: We included 21 trials in this review. The 21 included studies investigated a range of technologies aiming to support the provision of care from a distance. These included: telephone (n = 9); video conferencing (n = 2); Internet (n = 2); other networked communications (n = 6); text Short Messaging Service (n = 1); or a combination of text and Internet (n = 1). Meta-analysis showed that these interventions did not result in clinically important improvements in asthma quality of life (minimum clinically important difference = 0.5): mean difference in Juniper's Asthma Quality of Life Questionnaire (AQLQ) 0.08 (95% CI 0.01 to 0.16). Telehealthcare for asthma resulted in a non-significant increase in the odds of emergency department visits over a 12-month period: OR 1.16 (95% CI 0.52 to 2.58). There was, however, a significant reduction in hospitalisations over a 12-month period: OR 0.21 (95% CI 0.07 to 0.61), the effect being most marked in people with more severe asthma managed predominantly in secondary care settings. AUTHORS' CONCLUSIONS: Telehealthcare interventions are unlikely to result in clinically relevant improvements in health outcomes in those with relatively mild asthma, but they may have a role in those with more severe disease who are at high risk of hospital admission. Further trials evaluating the effectiveness and cost effectiveness of a range of telehealthcare interventions are needed. PMID- 20927764 TI - Oral anti-diabetic agents for women with pre-existing diabetes mellitus/impaired glucose tolerance or previous gestational diabetes mellitus. AB - BACKGROUND: While most guidelines recommend the use of insulin in women whose pregnancies are affected by pre-existing diabetes, oral agents have obvious benefits for patient acceptability and adherence. It is necessary, however, to assess the effects of these anti-diabetic agents on maternal and infant health outcomes. Additionally, women with previous gestational diabetes mellitus are increasingly found to be predisposed to impaired glucose tolerance and, despite the potential need for intervention for these women, there has been little evidence about the use of oral anti-diabetic agents by these women pre conceptionally or during a subsequent pregnancy. OBJECTIVES: To investigate the effect of oral anti-diabetic agents in women with pre-existing diabetes mellitus, impaired glucose tolerance or previous gestational diabetes planning a pregnancy or pregnant women with diabetes mellitus on maternal and infant health.The use of oral antidiabetic agents for management of gestational diabetes in a current pregnancy is evaluated in a separate Cochrane review. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (March 2010). SELECTION CRITERIA: We included randomised and quasi-randomised trials. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial eligibility for inclusion. MAIN RESULTS: We identified 13 trials published as 25 papers using the Cochrane Pregnancy and Childbirth group literature search, and an additional ongoing trial. We have not included any trials in the review. One trial is awaiting assessment and we have excluded twelve trials because they evaluated treatment of women with gestational diabetes or women with polycystic ovary syndrome, were not randomised controlled trials or data were not available. AUTHORS' CONCLUSIONS: Little randomised evidence is available evaluating the use of oral anti-diabetic agents in women with diabetes mellitus, impaired glucose tolerance, previous gestational diabetes mellitus planning a pregnancy or pregnant women with pre-existing diabetes mellitus. Large trials comparing any combination of oral anti-diabetic agent, insulin and dietary and lifestyle advice in these women, reporting on maternal and infant health outcomes, glycaemic control, women's views on the intervention and long-term health outcomes for mother and child, are required to guide clinical practice. PMID- 20927765 TI - Levomepromazine for schizophrenia. AB - BACKGROUND: Levomepromazine is an 'older' typical antipsychotic medication licensed for use in schizophrenia but sparingly prescribed in the United Kingdom. OBJECTIVES: To determine the clinical effects and safety of levomepromazine compared with placebo or antipsychotic medications for schizophrenia and schizophreniform psychoses. SEARCH STRATEGY: We searched the Cochrane Schizophrenia Group's Register (December 2008) which is based on regular searches of, amongst others, BIOSIS, CENTRAL CINAHL, EMBASE, MEDLINE and PsycINFO. References of all identified studies were inspected for further trials. We also contacted relevant pharmaceutical companies for additional information. SELECTION CRITERIA: All randomised trials comparing levomepromazine with placebo or other antipsychotics for schizophrenia and schizophreniform psychoses were included. DATA COLLECTION AND ANALYSIS: Data were extracted independently. For dichotomous outcomes, we calculated relative risk (RR) (random-effects model), 95% confidence intervals (CI) and, where appropriate, number needed to treat (NNT) was calculated. We avoided the use of number needed to harm (NNH), as an alternative we used number needed to treat for an additional beneficial outcome (NNTB) and number needed to treat for an additional harmful outcome (NNTH) to indicate the direction of effect. For continuous outcomes, we calculated weighted mean differences (WMD). MAIN RESULTS: The review currently includes 4 RCTs with 192 participants. For our primary outcome of leaving the study early, levomepromazine was not significantly different compared with other antipsychotics. The levomepromazine arm was significantly better on CGI severity compared with chlorpromazine (n=38, 1 RCT, WMD -0.80 CI -1.51 to -0.09). Risperidone was better for CGI endpoint scores (n=42, 1 RCT, RR 2.33 CI 1.11 to 4.89, NNT 3 CI 2 to 10) compared with levomepromazine. Recipients given levomepromazine had a better BPRS endpoint score (n=38, 1 RCT, WMD -9.00, CI -17.46 to -0.54) and PANSS total score (n=38, 1 RCT, WMD -15.90, CI -30.30 to -1.50) than chlorpromazine. Risperidone recipients noticed a significant difference for the outcome 'at least 20% reduction' on BPRS endpoint score (n=42, 1 RCT, RR 3.33 CI 1.07 to 10.42, NNT 3 CI 2 to 14) compared with levomepromazine. Levomepromazine caused less tremor (n=41, 1 RCT RR 0.12 CI 0.02 to 0.87 NNTB 3 CI 2 to 8), less antiparkinsonian medication administration (n=79, 2 RCTs, RR 0.39 CI 0.17 to 0.90, NNTB 5, CI 2 to 21) compared with haloperidol. Levomepromazine caused less akathisia compared with chlorpromazine, but more hypotension compared with risperidone (n=42, 1 RCT, RR 2.50 CI 1.21 to 5.18, NNTH 3, CI 2 to 7). Dizziness was common with levomepromazine compared with other antipsychotic medications. AUTHORS' CONCLUSIONS: Available data does not enable us to confidently comment on the effectiveness of levomepromazine for schizophrenia. Larger, more robust, studies comparing levomepromazine with other antipsychotics including clozapine are much needed. PMID- 20927768 TI - Drugs for treatment of urinary retention after surgery in adults. AB - BACKGROUND: Post-operative urinary retention, the inability to void following surgery despite a full bladder, is usually transitory but can be prolonged in some cases. It can lead to several complications including urinary tract infection, long term bladder dysfunction and kidney damage leading to chronic kidney disease. Catheterisation, generally regarded as the optimal management method, is associated with risks and so pharmacological treatment of post operative urinary retention that could remove or reduce the need for catheterisation is desirable. OBJECTIVES: To assess the effectiveness of drugs for treatment of post-operative urinary retention either alone or as an adjunct to catheterisation. SEARCH STRATEGY: We searched the Cochrane Incontinence Group Specialised Register (searched 10 February 2010), CENTRAL (2010, Issue 1), MEDLINE (January 1950 to Week 1 January 2010), EMBASE (January 1980 to 2010 Week 5) and the reference lists of relevant articles. SELECTION CRITERIA: Randomised and quasi randomised controlled trials in which at least one arm of the study included a drug treatment for post-operative urinary retention. DATA COLLECTION AND ANALYSIS: Published reports of all potentially eligible studies were evaluated by two reviewers independently. No language or other limitations were applied. Standardised data extraction forms were used by two reviewers independently and cross-checked. Where insufficient data were reported authors were contacted where possible for further information. The risk of bias in eligible trials was assessed independently by two reviewers using the Cochrane risk of bias tool. MAIN RESULTS: Seven studies including 494 participants formed the evidence base for this review. Drug treatments assessed in studies in the review included cholinergic agents, alpha-blockers, sedatives and prostaglandin on their own or in combinations. No statistically significant associations were reported between successful treatment or any other outcome and cholinergic agents, alpha-blockers and sedatives as monotherapies. A statistically significant association between intravesically administered prostaglandin and successful voiding was detected, Risk Ratio 3.07 (95% CI 1.22 to 7.72). A statistically significant association was detected between cholinergic agents combined with sedative and an improved likelihood of spontaneous voiding compared with placebo, Risk Ratio 1.39 (95% CI 1.07 to 1.82). Significant heterogeneity was identified between the two studies in this analysis, however. AUTHORS' CONCLUSIONS: Whilst it may appear that cholinergic agents and intravesically administered prostaglandin offer most promise in the treatment of post-operative urinary retention, the evidence is weak. There is a need for further research into pharmacological alternatives to catheterisation in the treatment of this common surgical complication. PMID- 20927769 TI - Antibiotic adjuvant therapy for pulmonary infection in cystic fibrosis. AB - BACKGROUND: Cystic fibrosis is a multi-system disease characterised by the production of thick secretions causing recurrent pulmonary infection, often with unusual bacteria. This leads to lung destruction and eventually death through respiratory failure. There are no antibiotics in development that exert a new mode of action and many of the current antibiotics are ineffective in eradicating the bacteria once chronic infection is established. Antibiotic adjuvants - therapies that act by rendering the organism more susceptible to attack by antibiotics or the host immune system, by rendering it less virulent or killing it by other means, are urgently needed. OBJECTIVES: To determine if antibiotic adjuvants improve clinical and microbiological outcome of pulmonary infection in people with cystic fibrosis. SEARCH STRATEGY: We searched the Cystic Fibrosis Trials Register which is compiled from database searches, hand searches of appropriate journals and conference proceedings.Date of most recent search: 26 August 2010.We also searched MEDLINE (all years) on 21 July 2010. SELECTION CRITERIA: Randomised controlled trials and quasi-randomised controlled trials of a therapy exerting an antibiotic adjuvant mechanism of action compared to placebo or no therapy for people with cystic fibrosis. DATA COLLECTION AND ANALYSIS: The authors independently assessed and extracted data from identified studies. MAIN RESULTS: We identified eighteen studies of which three are included that examined antibiotic adjuvant therapies, five studies are ongoing. The included studies involve the assessment of beta-carotene, garlic and zinc supplementation. No therapy demonstrated a significant effect upon pulmonary function, pulmonary exacerbations or quality of life. The study of zinc supplementation reports a reduction in the requirement of oral antibiotics but not of intravenous antibiotics, an effect that is difficult to understand. AUTHORS' CONCLUSIONS: We could not identify an antibiotic adjuvant therapy that could be recommended for the treatment of lung infection in those with cystic fibrosis. The emergence of increasingly resistant bacteria makes the reliance on antibiotics alone challenging for cystic fibrosis teams. There is a need to explore alternative strategies, such as the use of adjuvant therapies. Further research is required to provide future therapeutic options. PMID- 20927767 TI - Effects and safety of periconceptional folate supplementation for preventing birth defects. AB - BACKGROUND: It has been reported that neural tube defects can be prevented with periconceptional folic acid supplementation. The effects of different doses, forms and schemes of folate supplementation for the prevention of other birth defects and maternal and infant outcomes are unclear. OBJECTIVES: This review updates and expands a previous Cochrane Review assessing the effects of periconceptional supplementation with folic acid to reduce neural tube defects (NTDs). We examined whether folate supplementation before and during early pregnancy can reduce neural tube and other birth defects (including cleft palate) without causing adverse outcomes for mothers or babies. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (July 2010). Additionally, we searched the international clinical trials registry platform and contacted relevant organisations to identify ongoing and unpublished studies. SELECTION CRITERIA: We included all randomised or quasi-randomised trials evaluating the effect of periconceptional folate supplementation alone, or in combination with other vitamins and minerals, in women independent of age and parity. DATA COLLECTION AND ANALYSIS: We assessed trials for methodological quality using the standard Cochrane criteria. Two authors independently assessed the trials for inclusion, one author extracted data and a second checked for accuracy. MAIN RESULTS: Five trials involving 6105 women (1949 with a history of a pregnancy affected by a NTD and 4156 with no history of NTDs) were included. Overall, the results are consistent in showing a protective effect of daily folic acid supplementation (alone or in combination with other vitamins and minerals) in preventing NTDs compared with no interventions/placebo or vitamins and minerals without folic acid (risk ratio (RR) 0.28, 95% confidence interval (CI) 0.15 to 0.52). Only one study assessed the incidence of NTDs and the effect was not statistically significant (RR 0.08, 95% CI 0.00 to 1.33) although no events were found in the group that received folic acid. Folic acid had a significant protective effect for reoccurrence (RR 0.32, 95% CI 0.17 to 0.60). There is no statistically significant evidence of any effects on prevention of cleft palate, cleft lip, congenital cardiovascular defects, miscarriages or any other birth defects. There were no included trials assessing the effects of this intervention on maternal blood folate or anaemia at term.We found no evidence of short-term side effects. AUTHORS' CONCLUSIONS: Folic acid, alone or in combination with vitamins and minerals, prevents NTDs but does not have a clear effect on other birth defects. PMID- 20927770 TI - Ibuprofen with or without an antiemetic for acute migraine headaches in adults. AB - BACKGROUND: Migraine is a common, disabling condition and a burden for the individual, health services and society. Many sufferers do not seek professional help, relying instead on over-the-counter analgesics. Co-therapy with an antiemetic should help to reduce symptoms commonly associated with migraine headaches. OBJECTIVES: To determine efficacy and tolerability of ibuprofen, alone or in combination with an antiemetic, compared to placebo and other active interventions in the treatment of acute migraine headaches in adults. SEARCH STRATEGY: We searched Cochrane CENTRAL, MEDLINE, EMBASE and the Oxford Pain Relief Database for studies through 22 April 2010. SELECTION CRITERIA: We included randomised, double-blind, placebo- or active-controlled studies using self-administered ibuprofen to treat a migraine headache episode, with at least 10 participants per treatment arm. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. Numbers of participants achieving each outcome were used to calculate relative risk and number needed to treat (NNT) or harm (NNH) compared to placebo or other active treatment. MAIN RESULTS: Nine studies (4373 participants, 5223 attacks) compared ibuprofen with placebo or other active comparators; none combined ibuprofen with a self-administered antiemetic. All studies treated attacks with single doses of medication. For ibuprofen 400 mg versus placebo, NNTs for 2-hour pain-free (26% versus 12% with placebo), 2-hour headache relief (57% versus 25%) and 24-hour sustained headache relief (45% versus 19%) were 7.2, 3.2 and 4.0, respectively. For ibuprofen 200 mg versus placebo, NNTs for 2-hour pain-free (20% versus 10%) and 2-hour headache relief (52% versus 37%) were 9.7 and 6.3, respectively. The higher dose was significantly better for 2-hour headache relief than the lower dose. Soluble formulations of ibuprofen 400 mg were better than standard tablets for 1-hour, but not 2-hour headache relief.Associated symptoms of nausea, vomiting, photophobia and phonophobia and functional disability were reduced within 2 hours, and fewer participants used rescue medication with ibuprofen compared with placebo. Similar numbers of participants experienced adverse events, which were mostly mild and transient.Ibuprofen 400 mg did not differ from rofecoxib 25 mg for 2-hour headache relief, 24-hour headache relief or use of rescue medication. AUTHORS' CONCLUSIONS: Ibuprofen is an effective treatment for acute migraine headaches, providing pain relief in about half of sufferers, but complete relief from pain and associated symptoms for only a minority. NNTs for all efficacy outcomes were better with 400 mg than 200 mg in comparisons with placebo, and soluble formulations provided more rapid relief. Adverse events were mostly mild and transient, occurring at the same rate as with placebo. PMID- 20927766 TI - Intensive case management for severe mental illness. AB - BACKGROUND: Intensive Case Management (ICM) is a community based package of care, aiming to provide long term care for severely mentally ill people who do not require immediate admission. ICM evolved from two original community models of care, Assertive Community Treatment (ACT) and Case Management (CM), where ICM emphasises the importance of small caseload (less than 20) and high intensity input. OBJECTIVES: To assess the effects of Intensive Case Management (caseload <20) in comparison with non-Intensive Case Management (caseload > 20) and with standard community care in people with severe mental illness. To evaluate whether the effect of ICM on hospitalisation depends on its fidelity to the ACT model and on the setting. SEARCH STRATEGY: For the current update of this review we searched the Cochrane Schizophrenia Group Trials Register (February 2009), which is compiled by systematic searches of major databases, hand searches and conference proceedings. SELECTION CRITERIA: All relevant randomised clinical trials focusing on people with severe mental illness, aged 18 to 65 years and treated in the community-care setting, where Intensive Case Management, non Intensive Case Management or standard care were compared. Outcomes such as service use, adverse effects, global state, social functioning, mental state, behaviour, quality of life, satisfaction and costs were sought. DATA COLLECTION AND ANALYSIS: We extracted data independently. For binary outcomes we calculated relative risk (RR) and its 95% confidence interval (CI), on an intention-to-treat basis. For continuous data we estimated mean difference (MD) between groups and its 95% confidence interval (CI). We employed a random-effects model for analyses.We performed a random-effects meta-regression analysis to examine the association of the intervention's fidelity to the ACT model and the rate of hospital use in the setting where the trial was conducted with the treatment effect. MAIN RESULTS: We included 38 trials (7328 participants) in this review. The trials provided data for two comparisons: 1. ICM versus standard care, 2. ICM versus non-ICM.1. ICM versus standard care Twenty-four trials provided data on length of hospitalisation, and results favoured Intensive Case Management (n=3595, 24 RCTs, MD -0.86 CI -1.37 to -0.34). There was a high level of heterogeneity, but this significance still remained when the outlier studies were excluded from the analysis (n=3143, 20 RCTs, MD -0.62 CI -1.00 to -0.23). Nine studies found participants in the ICM group were less likely to be lost to psychiatric services (n=1633, 9 RCTs, RR 0.43 CI 0.30 to 0.61, I2=49%, p=0.05).One global state scale did show an Improvement in global state for those receiving ICM, the GAF scale (n=818, 5 RCTs, MD 3.41 CI 1.66 to 5.16). Results for mental state as measured through various rating scales, however, were equivocal, with no compelling evidence that ICM was really any better than standard care in improving mental state. No differences in mortality between ICM and standard care groups occurred, either due to 'all causes' (n=1456, 9 RCTs, RR 0.84 CI 0.48 to 1.47) or to 'suicide' (n=1456, 9 RCTs, RR 0.68 CI 0.31 to 1.51).Social functioning results varied, no differences were found in terms of contact with the legal system and with employment status, whereas significant improvement in accommodation status was found, as was the incidence of not living independently, which was lower in the ICM group (n=1185, 4 RCTs, RR 0.65 CI 0.49 to 0.88).Quality of life data found no significant difference between groups, but data were weak. CSQ scores showed a greater participant satisfaction in the ICM group (n=423, 2 RCTs, MD 3.23 CI 2.31 to 4.14).2. ICM versus non-ICM The included studies failed to show a significant advantage of ICM in reducing the average length of hospitalisation (n=2220, 21 RCTs, MD -0.08 CI -0.37 to 0.21). They did find ICM to be more advantageous than non-ICM in reducing rate of lost to follow up (n=2195, 9 RCTs, RR 0.72 CI 0.52 to 0.99), although data showed a substantial level of heterogeneity (I2=59%, p=0.01). Overall, no significant differences were found in the effects of ICM compared to non-ICM for broad outcomes such as service use, mortality, social functioning, mental state, behaviour, quality of life, satisfaction and costs.3. Fidelity to ACT Within the meta-regression we found that i. the more ICM is adherent to the ACT model, the better it is at decreasing time in hospital ('organisation fidelity' variable coefficient -0.36 CI -0.66 to -0.07); and ii. the higher the baseline hospital use in the population, the better ICM is at decreasing time in hospital ('baseline hospital use' variable coefficient -0.20 CI -0.32 to -0.10). Combining both these variables within the model, 'organisation fidelity' is no longer significant, but 'baseline hospital use' result is still significantly influencing time in hospital (regression coefficient -0.18 CI -0.29 to -0.07, p=0.0027). AUTHORS' CONCLUSIONS: ICM was found effective in ameliorating many outcomes relevant to people with severe mental illnesses. Compared to standard care ICM was shown to reduce hospitalisation and increase retention in care. It also globally improved social functioning, although ICM's effect on mental state and quality of life remains unclear. ICM is of value at least to people with severe mental illnesses who are in the sub-group of those with a high level of hospitalisation (about 4 days/month in past 2 years) and the intervention should be performed close to the original model.It is not clear, however, what gain ICM provides on top of a less formal non-ICM approach.We do not think that more trials comparing current ICM with standard care or non-ICM are justified, but currently we know of no review comparing non-ICM with standard care and this should be undertaken. PMID- 20927771 TI - Hyperbaric oxygen therapy for treating acute surgical and traumatic wounds. AB - BACKGROUND: Hyperbaric oxygen therapy (HBOT) is used as a treatment for acute wounds (such as those arising from surgery and trauma) however the effects of HBOT on wound healing are unclear. OBJECTIVES: To determine the effects of HBOT on the healing of acute surgical and traumatic wounds. SEARCH STRATEGY: We searched the Cochrane Wounds Group Specialised Register (25 August 2010), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Issue 3), Ovid MEDLINE (1950 to August Week 2 2010 ), Ovid MEDLINE (In Process & Other Non-Indexed Citations August 24, 2010), Ovid EMBASE (1980 to 2010, Week 33) and EBSCO CINAHL (1982 to 20 August 2010). SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing HBOT with other interventions or comparisons between alternative HBOT regimens. DATA COLLECTION AND ANALYSIS: Two review authors conducted selection of trials, risk of bias assessment, data extraction and data synthesis independently. Any disagreements were referred to a third review author. MAIN RESULTS: Three trials involving 219 participants were included. The studies were clinically heterogeneous, therefore a meta-analysis was inappropriate.One trial (48 participants with burn wounds undergoing split skin grafts) compared HBOT with usual care and reported a significantly higher complete graft survival associated with HBOT (95% healthy graft area risk ratio (RR) 3.50; 95% confidence interval (CI) 1.35 to 9.11). A second trial (36 participants with crush injuries) reported significantly more wounds healed with HBOT than with sham HBOT (RR 1.70; 95% CI 1.11 to 2.61) and fewer additional surgical procedures required with HBOT: RR 0.25; 95% CI 0.06 to 1.02 and significantly less tissue necrosis: RR 0.13; 95% CI 0.02 to 0.90). A third trial (135 people undergoing flap grafting) reported no significant differences in complete graft survival with HBOT compared with dexamethasone (RR 1.14; 95% CI 0.95 to 1.38) or heparin (RR 1.21; 95% CI 0.99 to 1.49).Many of the predefined secondary outcomes of the review, including mortality, pain scores, quality of life, patient satisfaction, activities daily living, increase in transcutaneous oxygen pressure (TcpO(2)), amputation, length of hospital stay and costs, were not reported. All three trials were at unclear or high risk of bias. AUTHORS' CONCLUSIONS: There is a lack of high quality, valid research evidence regarding the effects of HBOT on wound healing. Whilst two small trials suggested that HBOT may improve the outcomes of skin grafting and trauma these trials were at risk of bias. Further evaluation by means of high quality RCTs is needed. PMID- 20927772 TI - Cyanoacrylate microbial sealants for skin preparation prior to surgery. AB - BACKGROUND: Surgical site infections are a continuing concern in health care. Microbial sealant is a liquid applied to the skin immediately before surgery. It is thought to contribute to reducing surgical site infections by sealing in the skin flora to prevent contamination and infection of the surgical site. OBJECTIVES: To assess the effects of the preoperative application of microbial sealants (compared with no microbial sealant) on the rates of surgical site infection in people undergoing clean surgery. SEARCH STRATEGY: We searched the Cochrane Wounds Group Specialised Register (searched 10 May 2010), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Issue 2), Ovid MEDLINE (1950 to April Week 3 2010), Ovid MEDLINE - In-Process & Other Non-Indexed Citations (searched 10 May 2010), Ovid EMBASE (1980 to 2010 Week 18) and EBSCO CINAHL (1982 to 10 May 2010). We searched bibliographies and contacted manufacturers of microbial sealants for unpublished studies. There were no restrictions based on language, date or publication status. SELECTION CRITERIA: Randomised controlled trials (RCTs) were eligible for inclusion if they involved people undergoing clean surgery in an operating theatre and compared the use of preoperative microbial sealants with no microbial sealant. DATA COLLECTION AND ANALYSIS: All review authors independently extracted data on the characteristics, risk of bias and outcomes of the eligible trial. MAIN RESULTS: One small trial (177 participants undergoing hernia repair) met the inclusion criteria. There was no statistically significant difference in the rates of surgical site infection (three patients in the control group developed a surgical site infection compared with none in the intervention group; risk ratio (RR) 0.17, 95% CI 0.01 to 3.19, P = 0.23). AUTHORS' CONCLUSIONS: There is currently insufficient evidence as to whether the use of microbial sealants reduces the risk of surgical site infection in people undergoing clean surgery and further rigorous RCTs are required. PMID- 20927773 TI - Surgery for shoulder osteoarthritis. AB - BACKGROUND: Surgical treatment including shoulder arthroplasty is a treatment option for patients with advanced osteoarthritis of the shoulder who have failed conservative treatment. OBJECTIVES: To determine the benefit and harm of surgery in patients with osteoarthritis of the shoulder confirmed on X-ray who do not respond to analgesics and NSAIDs. SEARCH STRATEGY: We searched: The Cochrane Central Register of Controlled Trials (CENTRAL), via The Cochrane Library; OVID MEDLINE; CINAHL (via EBSCOHost); OVID SPORTdiscus; EMBASE; and Science Citation Index (Web of Science). SELECTION CRITERIA: All randomized clinical trials (RCTs) or quasi-randomized trials including adults with osteoarthritis of the shoulder joint (PICO- patients) comparing surgical techniques (total shoulder arthroplasty, hemiarthroplasty, implant types and fixation- intervention) versus placebo or sham surgery, non-surgical modalities, no treatment, or comparison of one type of surgical technique to another (comparison) with patient-reported outcomes (pain, function, quality of life etc.) or revision rates (outcomes). DATA COLLECTION AND ANALYSIS: We reviewed titles and abstracts for inclusion, extracted study and outcomes data and assessed the risk of bias of included studies. For categorical outcomes, we calculated the risk ratio (with 95% confidence interval (CI)) and for continuous outcomes, the mean difference (95% CI). MAIN RESULTS: Seven studies (238 patients) were included for analyses. None of the studies compared shoulder surgery to sham surgery, non-surgical modalities or placebo. Two studies compared hemiarthroplasty to total shoulder arthroplasty; three compared keeled and pegged humeral components; and one each compared navigation surgery to conventional and all-polyethylene to metal-backed implant. Two studies (88 patients) compared hemiarthroplasty to total shoulder arthroplasty. Patients who underwent hemiarthroplasty had statistically significantly worse functional scores on American Shoulder and Elbow Surgeons Shoulder Scale (100 point scale; higher = better) at 24 to 34 month follow-up compared to those who underwent total shoulder arthroplasty (mean difference, 10.05; 95% CI, -18.97 to -1.13; 2 studies, 88 patients), but no statistically significant differences between hemiarthroplasty and TSA were noted for pain scores (mean difference, 7.8; 95% CI, -5.33 to 20.93; 1 study, 41 patients), quality of life on short-form 36 physical component summary (mean difference, 0.80; 95% CI, -6.63 to 8.23; 1 study, 41 patients) and adverse events (Risk ratio, 1.19; 95% CI, 0.37 to 3.81; 1 study, 41 patients), respectively. A non statistically significant trend towards higher revision rate in hemiarthroplasty compared to total shoulder arthroplasty was noted (Risk ratio, 6.18; 95% CI, 0.77 to 49.52; 2 studies, 88 patients; P = 0.09). AUTHORS' CONCLUSIONS: Total shoulder arthroplasty seems to offer an advantage in terms of shoulder function, with no other clinical benefits over hemiarthroplasty. More studies are needed to compare clinical outcomes of surgery using different components and techniques in patients with osteoarthritis of the shoulder. There is a need for studies comparing shoulder surgery to sham, placebo and other non-surgical treatment options. PMID- 20927774 TI - Multidisciplinary care for Guillain-Barre syndrome. AB - BACKGROUND: Guillain-Barre syndrome is a significant cause of new long-term disability, which is thought to be amenable to multidisciplinary care, but the evidence base for its effectiveness is unclear. OBJECTIVES: To assess the effectiveness of multidisciplinary care in adults with Guillain-Barre syndrome, especially the types of approaches that are effective (settings, intensity) and the outcomes that are affected. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group Specialized Register (20 May 2010), The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library 2010, Issue 2), MEDLINE (1966 to May 2010), EMBASE (1980 to May 2010), CINAHL (1982 to May 2010), AMED (1985 to May 2010), PEDro (1982 to May 2010) and LILACS (1982 to May 2010). We checked the bibliographies of papers identified and contacted their authors and known experts in the field seeking published and unpublished trials. SELECTION CRITERIA: Randomised and controlled clinical trials that compared multidisciplinary care in Guillain-Barre syndrome with either routinely available local services or lower levels of intervention, or studies that compared multidisciplinary care in different settings or at different levels of intensity.Studies of 'other designs' (such as observational studies) were included only in the Discussion since such studies could only be of limited contribution to the best evidence synthesis. DATA COLLECTION AND ANALYSIS: We performed a 'best evidence' synthesis based on methodological quality. MAIN RESULTS: No randomised controlled trials or controlled clinical trials were identified. We summarised the results of three observational studies in the Discussion section of this review. AUTHORS' CONCLUSIONS: In the absence of randomised controlled trials or controlled clinical trials, the 'best' evidence to date comes from three 'very low quality' observational studies. These provide some support for improved disability in the short term (less than 6 months) with high intensity inpatient multidisciplinary rehabilitation; and for improved quality of life, as measured by a reduction in handicap (participation). These conclusions are tentative and the gap in current research should not be interpreted as proof that multidisciplinary care is ineffective. Further research is needed into appropriate study designs; outcome measurement; caregiver needs; and the evaluation of optimal settings, type, intensity or frequency and cost effectiveness of multidisciplinary care in the Guillain-Barre syndrome population. PMID- 20927775 TI - Prophylactic gastrojejunostomy for unresectable periampullary carcinoma. AB - BACKGROUND: The role of prophylactic gastrojejunostomy in patients with unresectable periampullary cancer is controversial. OBJECTIVES: To determine whether prophylactic gastrojejunostomy should be performed routinely in patients with unresectable periampullary cancer. SEARCH STRATEGY: We searched the Cochrane Upper Gastrointestinal and Pancreatic Diseases Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, issue 3), MEDLINE, EMBASE and Science Citation Index Expanded until April 2010. SELECTION CRITERIA: We included randomised controlled trials comparing prophylactic gastrojejunostomy versus no gastrojejunostomy in patients with unresectable periampullary cancer (irrespective of language or publication status). DATA COLLECTION AND ANALYSIS: Two authors independently assessed trials for inclusion and independently extracted data. We analysed data with both the fixed-effect and the random-effects models using Review Manager (RevMan). We calculated the hazard ratio (HR), risk ratio (RR), or mean difference (MD) with 95% confidence intervals (CI) based on an intention-to-treat or available case analysis. MAIN RESULTS: We identified two trials (of high risk of bias) involving 152 patients randomised to gastrojejunostomy (80 patients) and no gastrojejunostomy (72 patients). In both trials, patients were found to be unresectable during exploratory laparotomy. Most of the patients also underwent biliary-enteric drainage. There was no evidence of difference in the overall survival (HR 1.02; 95% CI 0.84 to 1.25), peri-operative mortality or morbidity, quality of life, or hospital stay (MD 0.97 days; 95%CI -0.18 to 2.12) between the two groups. The proportion of patients who developed long term gastric outlet obstruction was significantly lower in the prophylactic gastrojejunostomy group (2/80; 2.5%) compared with no gastrojejunostomy group (20/72; 27.8%) (RR 0.10; 95%CI 0.03 to 0.37). The operating time was significantly longer in the gastrojejunostomy group compared with no gastrojejunostomy group (MD 45.00 minutes; 95%CI 21.39 to 68.61). AUTHORS' CONCLUSIONS: Routine prophylactic gastrojejunostomy is indicated in patients with unresectable periampullary cancer undergoing exploratory laparotomy (with or without hepaticojejunostomy). PMID- 20927776 TI - Different classes of antibiotics given to women routinely for preventing infection at caesarean section. AB - BACKGROUND: Caesarean section increases the risk of postpartum infection for women and prophylactic antibiotics have been shown to reduce the incidence; however, there are adverse effects. It is important to identify the most effective class of antibiotics to use and those with the least adverse effects. OBJECTIVES: To determine, from the best available evidence, the balance of benefits and harms between different classes of antibiotic given prophylactically to women undergoing caesarean section. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (April 2010) and reference lists of retrieved papers. SELECTION CRITERIA: We included randomised controlled trials comparing different classes of prophylactic antibiotics given to women undergoing caesarean section. We excluded trials that compared drugs with placebo or drugs within a specific class; these are assessed in other Cochrane Reviews. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the studies for inclusion, assessed risk of bias and carried out data extraction. MAIN RESULTS: We included 29 studies of which 25 provided data on 6367 women. There was a lack of good quality data and important outcomes often included only small numbers of women. This meant we could only conclude that the current evidence shows no overall difference between the different classes of antibiotics in terms of reducing maternal infections after caesarean sections. However, none of the studies looked at outcomes on the baby, nor did they report infections diagnosed after the initial postoperative hospital stay. We were unable to assess what impact, if any, the use of different classes of antibiotics might have on bacterial resistance. AUTHORS' CONCLUSIONS: Based on the best currently available evidence, cephalosporins and penicillins have similar efficacy at caesarean section when considering immediate postoperative infections. We have no data for outcomes on the baby, nor on late infections (up to 30 days) in the mother. Clinicians need to consider bacterial resistance and women's individual circumstances. PMID- 20927777 TI - Tenofovir or zidovudine in three-drug combination therapy with one nucleoside reverse transcriptase inhibitor and one non-nucleoside reverse transcriptase inhibitor for initial treatment of HIV infection in antiretroviral-naive individuals. AB - BACKGROUND: The introduction of highly active antiretroviral therapy (ART) as treatment for HIV infection has greatly improved mortality and morbidity for adults and children living with HIV around the world. Two of the most common medications given in first-line ART are the nucleoside reverse transcriptase inhibitor (NRTI) zidovudine (AZT) and the nucleotide reverse transcriptase inhibitor (NtRTI) tenofovir (TDF). OBJECTIVES: To assess the efficacy, safety, and tolerability of TDF compared with AZT in combination with one NRTI and one non-nucleoside reverse transcriptase inhibitor (NNRTI) as part of first-line ART for HIV-infected people in resource-limited settings SEARCH STRATEGY: Standard Cochrane methods were used to search electronic databases and conference proceedings with relevant search terms without limits to language. SELECTION CRITERIA: Randomised controlled trials of HIV-infected patients aged 5 years and older were included. Primary outcomes of interest included mortality, serious adverse events, virologic response to ART, and adherence/tolerance/retention. Secondary outcomes included immunologic response to ART, development of ART drug resistance, and prevention of sexual transmission of HIV. DATA COLLECTION AND ANALYSIS: Two authors assessed each reference for inclusion and exclusion criteria established a priori. Data were abstracted independently using a standardised abstraction form. MAIN RESULTS: Two randomised controlled trials contributed to this literature, enrolling 586 participants, and found no critical difference between TDF and AZT in regards to serious adverse events or virologic response. The trials did find higher rates of adherence and immunologic response in TDF-containing regimens compared with those containing AZT. The quality of the literature to support this conclusion is moderate to high. Drug resistance was more common for TDF than AZT, but the quality of this literature is low, with only one study reporting this outcome. It should be noted that the two studies compared two different drugs in addition to TDF and AZT; one had lamivudine (3TC) and nevirapine (NVP) and the other had emtricitabine (FTC) and efavirenz (EFV). AUTHORS' CONCLUSIONS: We conclude that for the critical outcomes of virologic response and serious adverse events, initial ART regimens containing TDF are equivalent to those containing AZT. However, TDF is superior to AZT in terms of immunologic response and adherence and less frequent emergence of resistance. How much the other drugs in the regimens contributed to these findings is unclear, and true head-to-head trials are still warranted. The role of each drug in initial ART likely will be driven by their specific toxicities. PMID- 20927779 TI - Fibulin-3 is associated with tumour progression and a poor prognosis in nasopharyngeal carcinomas and inhibits cell migration and invasion via suppressed AKT activity. AB - Nasopharyngeal carcinoma (NPC) is known for its highly metastatic character. Recent advances in diagnosis and treatment have not improved the high mortality rate that is attributable to early metastasis. Although several biomarkers correlate with metastasis and prognosis, the molecular mechanisms of NPC development and progression remain unclear. We demonstrate comprehensively that fibulin-3 is down-regulated in NPC. Loss of fibulin-3 expression is significantly correlated with advanced tumour and lymph node-metastasis stages, and indicates a poor 5-year survival rate. Functionally, fibulin-3 has the ability to suppress cell migration and invasion in NPC cancer cells by decreasing the activity of phospho-AKT. Conversely, its depletion by fibulin-3-mediated siRNAs may elevate phospho-AKT activity and significantly enhance the ability of NPC cancer cells to migrate and invade. Consistent with this negative association between fibulin-3 and phospho-AKT, their expression levels are inversely correlated in NPC specimens by immunohistochemical analysis. Thus, lower fibulin-3 expression is an important indicator of poor survival. It may also contribute to the development of new therapeutic strategies to block the PI3K/AKT pathway in NPC cancer cells. PMID- 20927778 TI - Tumour-infiltrating T-cell subsets, molecular changes in colorectal cancer, and prognosis: cohort study and literature review. AB - The abundance of tumour-infiltrating T-cells has been associated with microsatellite instability (MSI) and a favourable prognosis in colorectal cancer. However, numerous molecular alterations have been associated with clinical outcome, and potentially confounding the biological and prognostic significance of tumour-infiltrating T-cells. We utilized a database of clinically and molecularly-annotated colon and rectal carcinoma cases (N = 768; stage I-IV) in two prospective cohort studies (the Nurses' Health Study and the Health Professionals Follow-up Study) and quantified the densities of CD3(+), CD8(+), CD45RO(+) (PTPRC), and FOXP3(+) cells within neoplastic epithelial areas using an Ariol image analysis system and tissue microarray. We used Cox proportional hazard models to compute the mortality hazard ratio, adjusting for clinical and molecular features including KRAS, BRAF, and PIK3CA mutations, MSI, CIMP, and LINE-1 hypomethylation. The densities of CD8(+), CD45RO(+), and FOXP3(+) cells were significantly associated with patient survival in univariate analyses (P(trend) < 0.007). In the multivariate model, tumour-infiltrating CD45RO(+)-cell density, but not CD3(+), CD8(+) or FOXP3(+)-cell density, was significantly associated with survival (p = 0.0032). In multivariate linear regression analysis, MSI-high (p < 0.0001) and high-level tumour LINE-1 methylation (p = 0.0013) were independently associated with higher CD45RO(+)-cell density. The survival benefit associated with CD45RO(+) cells was independent of MSI and LINE 1 status. In conclusion, tumour-infiltrating CD45RO(+)-cell density is a prognostic biomarker associated with longer survival of colorectal cancer patients, independent of clinical, pathological, and molecular features. In addition, MSI-high and tumour LINE-1 methylation level are independent predictors of CD45RO(+)-cell density. Our data offer a possible mechanism by which MSI confers an improved clinical outcome and support efforts to augment the host immune response in the tumour microenvironment as a strategy of targeted immunotherapy. PMID- 20927780 TI - In reference to Systematic review of the evidence for the etiology of adult sudden sensorineural hearing loss. PMID- 20927781 TI - Hedgehog antagonist GDC-0449 is effective in the treatment of advanced basal cell carcinoma. AB - OBJECTIVES/HYPOTHESIS: To demonstrate the efficacy of the hedgehog pathway inhibitor GDC-0449 in the treatment of advanced basal cell carcinoma. DESIGN STUDY: Case series. METHODS: Three patients treated in a referral center for locally advanced basal cell carcinoma, one with metastases, were referred for treatment in a GDC-0449 phase I clinical trial. The treatment was once per day continuous therapy with oral GDC-0449. RESULTS: Two patients showed complete clinical and radiologic resolution of disease, whereas one patient had significant reduction in tumor burden with radiologic evidence of slowly progressive local disease. Side effects were taste changes, mild to moderate hair loss, and muscle cramps in one patient. CONCLUSIONS: GDC-0449 showed significant inhibitory activity in the treatment of advanced basal cell carcinoma. PMID- 20927782 TI - Percutaneous closure of an aneurysmal patent ductus arteriosus in an adult. AB - We report a case of a 24 year old woman with an aneurysmal patent ductus arteriosus (PDA) that was percutaneously closed using an Amplatzer Vascular Plug II. This is the first report of the successful use of an Amplatzer Vascular Plug II for a PDA, and suggests the feasibility and safety of its utilization in select cases. PMID- 20927783 TI - Predictors for permanent pacing after transcatheter aortic valve implantation. AB - BACKGROUND: Transcatheter aortic valve implantation (TAVI) is a new treatment strategy for patients with symptomatic aortic stenosis who are high risk for traditional surgical aortic valve replacement. The incidence of conduction system abnormalities after the procedure is significant. We examine our experience with CoreValve TAVI focusing on electrocardiographic changes found pre-, peri-, and postintervention. METHODS: During 2007-08 we undertook 33 cases utilizing the CoreValve revalving system (CoreValve, Paris, France). Assessment of ECGs, with particular reference to the PR and QRS duration, was made daily during each patient's hospital stay. RESULTS: Patients were aged 81.7 +/- 6.7 years and the majority were male (57%). Baseline cardiac rhythm was sinus (n = 28, 80%); atrial fibrillation (n = 6, 18%) or ventricular paced (n = 1, 3%). Following CoreValve implantation, prolongation of both the PR interval and QRS duration was seen. Preprocedural PR interval was 193.5 +/- 38.7 ms and QRS interval preprocedure was 115.3 +/- 24.8 ms. PR interval increased after the procedure by 23.5 +/- 23.9 ms and peaked at day 4 with a mean increase of 66.1 +/- 72.7 ms. QRS duration increased by a mean of 30.6 +/- 26.1 ms postprocedure and remained stable thereafter during the remaining hospital stay. The need for PPM insertion was partially predicted by pre-procedural QRS morphology: patients with pre-existing right bundle branch block had an 83% chance of requiring a permanent pacemaker (P < 0.01 OR 28 95%CI 2.4-326.7); those with LBBB had a 33% chance of requiring a pacemaker (P = ns OR 2.3 95%CI 0.2-34.9). Patients undergoing the procedure later in our experience showed a decreased incidence of pacing (P = 0.046 OR 0.36 95% CI 0.07-1.82). Pre-procedural annulus measurements also predicted the requirement for pacing with larger annulus sizes more likely to require a pacemaker (P = 0.044 OR 3.3 95% CI 0.63-17.6). The requirement for pacing was not predicted by age, baseline PR interval or gender. Requirement for pacing overall was 32% with an additional 13% having had a pacemaker inserted prior to the TAVI. CONCLUSION: CoreValve insertion was associated with an increase in PR interval and QRS duration. PR interval continued to rise during admission, peaking on Day 4 post procedure, making a prolonged period of monitoring highly desirable. There was a significant requirement for permanent pacing, which was predicted by pre procedural QRS morphology, annulus measurement, and the learning curve. (c) 2010 Wiley-Liss, Inc. PMID- 20927784 TI - Control of enantioselectivity with flexible biaryl axes: terpene-based alkylzinc catalysts in enantioselective dialkylzinc additions. AB - New enantiopure pyridyl alcohols are efficiently accessible through few synthetic steps from commercially available terpenes, that is, (+)-fenchone, (-)-menthone and (-)-verbenone as well as 2,6-diphenylpyridine. These chelating pyridyl alcohols exhibit flexible pyridyl-phenylene axes, which give rise to P and M conformers. Alkylzincation of the hydroxy groups eliminates equilibria of the conformers and generates alkylzinc complexes with adjusted biaryl axes, as it is demonstrated by NMR studies. These alkylzinc catalysts perform well in the addition of dimethylzinc or diethylzinc to benzaldehyde with yields up to 99% and ee's up to 95%. The adjusted pyridylphenylene conformations in the ligands now control enantioselectivities of the catalysts, which were also analysed by computations at the DFT level. PMID- 20927785 TI - A switch-on fluorescence assay for bacterial beta-lactamases with amyloid fibrils as fluorescence enhancer and visual tool. AB - Herein is described the development of a novel switch-on fluorescence assay for detecting beta-lactamases. The fluorescence assay comprises two components: solid beads coated with a beta-lactam antibiotic, which is linked to an environment sensitive fluorophore (dansylaminothiophenol, DTA), and amyloid fibrils of hen lysozyme (acting as fluorescence enhancer and visual tool). In the presence of the clinically significant TEM-1 beta-lactamase, the DTA-antibiotic complex on the solid beads is hydrolyzed, thus releasing the DTA dye into solution. The DTA dye is only weakly fluorescent in solution but gives strong green fluorescence upon binding to lysozyme fibrils. These strongly fluorescent DTA-bound fibrils can be easily visualized by the naked eye upon illumination of the sample with a simple UV lamp. The fluorescence assay can detect TEM-1 at low concentration (0.01 nM). In contrast, no observable fluorescence appears when the fluorescence assay is performed on samples without the TEM-1 beta-lactamase. PMID- 20927787 TI - Hyperhalogens: discovery of a new class of highly electronegative species. PMID- 20927788 TI - Oxidatively stable, aqueous europium(II) complexes through steric and electronic manipulation of cryptand coordination chemistry. PMID- 20927789 TI - Conformations of gamma-aminobutyric acid (GABA): the role of the n->pi* interaction. PMID- 20927786 TI - Salinosporamide natural products: Potent 20 S proteasome inhibitors as promising cancer chemotherapeutics. AB - Proteasome inhibitors are rapidly evolving as potent treatment options in cancer therapy. One of the most promising drug candidates of this type is salinosporamide A from the bacterium Salinispora tropica. This marine natural product possesses a complex, densely functionalized gamma-lactam-beta-lactone pharmacophore, which is responsible for its irreversible binding to its target, the beta subunit of the 20S proteasome. Salinosporamide A entered phase I clinical trials for the treatment of multiple myeloma only three years after its discovery. The strong biological activity and the challenging structure of this compound have fueled intense academic and industrial research in recent years, which has led to the development of more than ten syntheses, the elucidation of its biosynthetic pathway, and the generation of promising structure-activity relationships and oncological data. Salinosporamide A thus serves as an intriguing example of the successful interplay of modern drug discovery and biomedical research, medicinal chemistry and pharmacology, natural product synthesis and analysis, as well as biosynthesis and bioengineering. PMID- 20927791 TI - Detection of ethylene gas by fluorescence turn-on of a conjugated polymer. PMID- 20927790 TI - Catalytic asymmetric exo'-selective [3+2] cycloaddition of iminoesters with nitroalkenes. PMID- 20927793 TI - A molecular capsule network: guest encapsulation and control of Diels-Alder reactivity. PMID- 20927792 TI - A chiral-anion generator: application to catalytic desilylative kinetic resolution of silyl-protected secondary alcohols. PMID- 20927794 TI - Heteroatom-nucleophile-induced C-C fragmentations: synthesis of allenes and entry to domino reactions. PMID- 20927795 TI - A simple and general platform for generating stereochemically complex polyene frameworks by iterative cross-coupling. PMID- 20927796 TI - Child cancer clusters identified from spatial analysis, and the search for etiologic factors. PMID- 20927798 TI - Drug consumption and air pollution: an overview. AB - PURPOSE: Acute respiratory symptoms are among the health effects of air pollution exposure. Studies over the past decades have linked respiratory drug use (consumption or sales) with changes in air pollution conditions. METHODS: Twenty one studies were analyzed to discuss whether increased levels of air pollution are associated with the use of medications for respiratory diseases. RESULTS: Epidemiological studies agree that variation in the drug use is related to air pollution exposure. In panel studies, although asthmatics are more sensitive to air pollution effects, the increase in drug use was comparable and similar to non asthmatics. Ecological studies confirm a significant association in respiratory drug sales depending on the selected lags (that is the time elapsing between air pollution measurement and the resulting drug use). The results of a meta-analysis of two ecological studies showed an increase in risk for increase in daily mean concentration of some pollutant (10 ug m(-3) ). For Black Smoke RR=1.007 (95% CI 1.004-1.011) for lag 1, and RR=1.008 (95% CI 1.005-1.010) for lag 8. For Nitrogen dioxide, RR=1.008 (95% CI 1.005-1.012) for lag 8 and for Sulfur dioxide, RR=1.005 (95% CI 1.001-1.010) for lag 9. CONCLUSIONS: The analysis of drug use provides useful data for the evaluation of risks which derive from exposure to air pollution. More studies are needed to measure the effects of air pollution on respiratory medication use. Lags of up to 14 days have to be considered and the pollutants to be considered should include particulate matter and ozone. PMID- 20927799 TI - A multifunctional ribonuclease-A-conjugated CdTe quantum dot cluster nanosystem for synchronous cancer imaging and therapy. PMID- 20927800 TI - Sperm morphology in the Malagasy rodents (Muroidea: Nesomyinae). AB - The morphology of the spermatozoon of representative species of the subfamily Nesomyinae (Muroidea: Nesomyidae), a monophyletic group of rodents endemic to Madagascar, was examined by light and electron microscopy to determine the sperm head shape and tail length across the species. Marked interspecific differences were found to occur in both the form of the sperm head and length of the tail. The species that possess a sperm head with an apical hook, which largely contains acrosomal material, generally displayed longer sperm tails, and a species with a spatulate sperm head had the shortest tail. The association between sperm head shape and tail length mirrors that previously found in Eurasian and Australasian murine rodents. Thus, the repeated association between sperm head shape and tail length across these groups of muroid rodents clearly indicates a functional relationship between these two features. A comparison of sperm morphology of the nesomyines to that of related muroid rodents on the mainland of Africa suggests that the possession of an apical hook is the ancestral condition. PMID- 20928827 TI - MRI resolution enhancement: how useful are shifted images obtained by changing the demodulation frequency? AB - Super-resolution reconstruction is a process by which a set of different low resolution images of the same object are used to create an enhanced, higher resolution image of that object. Recently there has been debate amongst researchers whether it is possible to obtain in-plane image enhancement using a set of low resolution magnetic resonance images, acquired by making small, independent changes to the demodulation frequency. We show that shifted low resolution images contain different information that can be used to obtain denser sampling, leading to image enhancement. We conclude this from specific phantom experiments, applying signal processing sampling theory and taking into consideration the relative sampling of the point spread function with respect to the location of signal sources. Furthermore, the maximum achievable resolution for Fourier encoded MRI data at a boundary or object feature is governed by the effective width of the point spread function or the Fourier pixel size determined by the extent of k-space; this is verified experimentally. PMID- 20928828 TI - The role of recollection and familiarity in the functional differentiation of the medial temporal lobes. AB - The components of the medial temporal lobes (MTL) receive different kinds of input. The perirhinal cortex receives primarily object/item information, the parahippocampal cortex receives contextual information, and the hippocampus receives high-level inputs that include object/item, context, and other information. Critically, the perirhinal and parahippocampal cortices have similar cytoarchitectonics, which differ considerably from that of the hippocampus and suggest that these cortices process their inputs differently from the way that the hippocampus processes its inputs. Much evidence indicates that the hippocampus is designed to rapidly bind together pattern-separated representations that support recall/recollection well. In contrast, the newer MTL cortices rapidly create poorly pattern-separated memories that support familiarity well, but recall/recollection very poorly. For over a decade, there has been disagreement about whether recall/recollection is primarily mediated by the hippocampus and familiarity by the evolutionarily newer MTL cortices or whether the MTL mediates these kinds of memory in an integrated, homogeneous fashion. Common misconceptions about familiarity, recollection, item, and associative memory are discussed as are methodological problems with MTL lesion and functional imaging research. The possible confound of familiarity with weaker memory and recollection with stronger memory is discussed and the implications of the Montaldi et al. (2006) functional Magnetic Resonance Imaging (fMRI) study, which matched memory strength between strong familiarity and recollection, finding that only recollection activated the hippocampus, are discussed. A suggestion is made about how the long-running conflict of findings in the human hippocampal lesion literature may be resolved. PMID- 20928829 TI - Microfabricated high-moment micrometer-sized MRI contrast agents. AB - While chemically synthesized superparamagnetic microparticles have enabled much new research based on MRI tracking of magnetically labeled cells, signal-to-noise levels still limit the potential range of applications. Here it is shown how, through top-down microfabrication, contrast agent relaxivity can be increased several-fold, which should extend the sensitivity of such cell-tracking studies. Microfabricated agents can benefit from both higher magnetic moments and higher uniformity than their chemically synthesized counterparts, implying increased label visibility and more quantitative image analyses. To assess the performance of microfabricated micrometer-sized contrast agent particles, analytic models and numerical simulations are developed and tested against new microfabricated agents described in this article, as well as against results of previous imaging studies of traditional chemically synthesized microparticle agents. Experimental data showing signal effects of 500-nm thick, 2-MUm diameter, gold-coated iron and gold coated nickel disks verify the simulations. Additionally, it is suggested that measures of location better than the pixel resolution can be obtained and that these are aided using well-defined contrast agent particles achievable through microfabrication techniques. PMID- 20928830 TI - Microarray analysis of rat hippocampus exposed to excitotoxicity: reversal Na(+)/Ca(2+) exchanger NCX3 is overexpressed in glial cells. AB - Multiple factors are involved in the glutamate-induced excitotoxicity phenomenon, such as overload of ionotropic and metabotropic receptors, excess Ca(2+) influx, nitric oxide synthase activation, oxidative damage due to increase in free radicals, and release of endogenous polyamine, among others. In order to attempt a more integrated approach to address this issue, we established, by microarray analysis, the hippocampus gene expression profiles under glutamate-induced excitotoxicity conditions. Increased gene expression is mainly related to excitotoxicity (CaMKII, glypican 2, GFAP, NCX3, IL-2, and Gmeb2) or with cell damage response (dynactin and Ecel1). Several genes that augmented their expression are related to glutamatergic system modulation, in particular with NMDA receptor modulation and calcium homeostasis (IL-2, CaMKII, acrosin, Gmeb2, hAChE, Slc83a, and SP1 factor). Conversely, among genes that diminished their expression, we found the Syngap 1, which is downregulated by CaMKII, and the MHC II, which is downregulated by glutamate. Changes observed in gene expression induced by monosodium glutamate (MSG) neonatal treatment in the hippocampus are consistent with the activation of the mechanisms that modulate NMDA receptor function as well as with the implementation of plastic response to cell damage and intracellular calcium homeostasis. Regarding this aspect, we report here that NCX3/Slc8a3, a Na(+)/Ca(2+) membrane exchanger, is highly expressed in astrocytes, both in vitro and in vivo, in response to glutamate-induced excitotoxicity. Hence, the results of this analysis present a broad view of the expression profile elicited by MSG neonatal treatment, and lead us to suggest the possible molecular pathways of action and reaction involved under this experimental model of excitotoxicity. PMID- 20928831 TI - Predictive, interactive multiple memory systems. AB - Most lesion studies in animals, and neuropsychological and functional neuroimaging studies in humans, have focused on finding dissociations between the functions of different brain regions, for example in relation to different types of memory. While some of these dissociations can be questioned, particularly in the case of neuroimaging data, we start by assuming a "modal model" in which at least three different memory systems are distinguished: an episodic system (which stores associations between items and spatial/temporal contexts, and which is supported primarily by the hippocampus); a semantic system (which extracts combinations of perceptual features that define items, and which is supported primarily by anterior temporal cortex); and modality-specific perceptual systems (which represent the sensory features extracted from a stimulus, and which are supported by higher sensory cortices). In most situations however, behavior is determined by interactions between these systems. These interactions reflect the flow of information in both "forward" and "backward" directions between memory systems, where backward connections transmit predictions about the current item/features based on the current context/item. Importantly, it is the resulting "prediction error"--the difference between these predictions and the forward transmission of sensory evidence--that drives memory encoding and retrieval. We describe how this "predictive interactive multiple memory systems" (PIMMS) framework can be applied to human neuroimaging data acquired during encoding or retrieval phases of the recognition memory paradigm. Our novel emphasis is thus on associations rather than dissociations between activity measured in key brain regions; in particular, we propose that measuring the functional coupling between brain regions will help understand how these memory systems interact to guide behavior. PMID- 20928832 TI - Estradiol promotes spine growth and synapse formation without affecting pre established networks. AB - Estrogens regulate dendritic spine density, but the mechanism and significance of this effect for brain networks remain unknown. We used repetitive imaging over several days to investigate how 17beta-estradiol affected the turnover and long term behavior of dendritic spines in CA1 cells of hippocampal slice cultures. We find that 17beta-estradiol and serum in the culture medium tightly regulated spine density by promoting an increase in the rate of new spine formation and their transformation into synapses, without affecting spine elimination or stability. New spines formed during a transient 17beta-estradiol application were preferentially eliminated upon removal of the hormone, in contrast with pre existing spines that remained unaffected. Our results reveal that 17beta estradiol transiently regulates the complexity of hippocampal circuits without causing major alterations of pre-existing networks. PMID- 20928833 TI - A unified framework for the functional organization of the medial temporal lobes and the phenomenology of episodic memory. AB - There is currently an intense debate about the nature of recognition memory and about the roles of medial temporal lobe subregions in recognition memory processes. At a larger level, this debate has been about whether it is appropriate to propose unified theories to explain memory at neural, functional, and phenomenological levels of analysis. Here, I review findings from physiology, functional imaging, and lesion studies in humans, monkeys, and rodents relevant to the roles of medial temporal lobe subregions in recognition memory, as well as in short-term memory and perception. The results from these studies are consistent with the idea that there is functional heterogeneity in the medial temporal lobes, although the differences among medial temporal lobe subregions do not precisely correspond to different types of memory tasks, cognitive processes, or states of awareness. Instead, the evidence is consistent with the idea that medial temporal lobe subregions differ in terms of the kind of information they process and represent, and that these regions collectively support episodic memory by binding item and context information. PMID- 20928834 TI - The single place fields of CA3 cells: a two-stage transformation from grid cells. AB - Granule cells of the dentate gyrus (DG) generally have multiple place fields, whereas CA3 cells, which are second order, have only a single place field. Here, we explore the mechanisms by which the high selectivity of CA3 cells is achieved. Previous work showed that the multiple place fields of DG neurons could be quantitatively accounted for by a model based on the number and strength of grid cell inputs and a competitive network interaction in the DG that is mediated by gamma frequency feedback inhibition. We have now built a model of CA3 based on similar principles. CA3 cells receive input from an average of one active DG cell and from 1,400 cortical grid cells. Based on experimental findings, we have assumed a linear interaction of the two pathways. The results show that simulated CA3 cells generally have a single place field, as observed experimentally. Thus, a two-step process based on simple rules (and that can occur without learning) is able to explain how grid cell inputs to the hippocampus give rise to cells having ultimate spatial selectivity. The CA3 processes that produce a single place depend critically on the competitive network processes and do not require the direct cortical inputs to CA3, which are therefore likely to perform some other unknown function. PMID- 20928835 TI - Zinc in the treatment of idiopathic sudden sensorineural hearing loss. AB - OBJECTIVES/HYPOTHESIS: The objective of this study was to investigate whether zinc supplementation can enhance the recovery of idiopathic sudden sensorineural hearing loss (SSNHL). STUDY DESIGN: Prospective, randomized study. METHODS: The 66 SSNHL patients who participated in this study were randomly divided into two groups: 33 were given corticosteroid treatment (control group) and 33 were given oral zinc gluconate plus corticosteroid treatment (zinc group). Serum zinc levels were checked before treatment in both groups and after zinc supplementation in the zinc group. Hearing gain and percentage of recovery were analyzed and compared between the two groups. The correlation between the serum zinc level changes and hearing recovery was also analyzed. RESULTS: A significantly larger hearing gain, an increased percentage of recovery, and an increased rate of successful recovery were seen in the zinc group compared with the control group (all P < .05). There was a significant correlation between serum zinc level changes and posttreatment hearing thresholds by correlation analysis (P < .05), as well as between changes of serum zinc levels and percentage of recovery in the zinc group (P < .05). CONCLUSIONS: Zinc supplementation may enhance the hearing recovery of SSNHL patients. Its antioxidant and anti-inflammatory effects may help reduce the oxidative stress of the cochlea in SSNHL, implying a new direction in the treatment of this disease. PMID- 20928836 TI - Babbling, vegetative function, and language development after cricotracheal resection in aphonic children. AB - OBJECTIVE: To determine the importance of prelinguistic babbling by studying patterns of speech and language development after cricotracheal resection in aphonic children. STUDY DESIGN: Retrospective review of seven previously aphonic children who underwent cricotracheal resection by our pediatric thoracic airway team. The analyzed variables include age, sex, comorbidity, grade of stenosis, length of resected trachea, and communication methods. METHODS: Data regarding the children's pre- and postsurgical communication methods, along with their utilization of speech therapy services, were obtained via speech-language pathology evaluations, clinical observations, and a standardized telephone survey supplemented by parental documentation. Postsurgical voice quality was assessed using the Pediatric Voice Outcomes Survey. RESULTS: All seven subjects underwent tracheostomy prior to 2 months of age when corrected for prematurity. The subjects remained aphonic for the entire duration of cannulation. Following cricotracheal resection, they experienced an initial delay in speech acquisition. Vegetative functions were the first laryngeal sounds to emerge. Initially, the children were only able to produce these sounds reflexively, but they subsequently gained voluntary control over these laryngeal functions. All subjects underwent an identifiable stage of canonical babbling that often occurred concomitantly with vocalizations. This was followed by the emergence of true speech. CONCLUSIONS: The initial delay in speech acquisition observed following decannulation, along with the presence of a postsurgical canonical stage in all study subjects, supports the hypothesis that babbling is necessary for speech and language development. Furthermore, the presence of babbling is universally evident regardless of the age at which speech develops. Finally, there is no demonstrable correlation between preoperative sign language and rate of speech development. PMID- 20928837 TI - Internal pudendal artery stenoses and erectile dysfunction: correlation with angiographic coronary artery disease. AB - OBJECTIVES: To describe the angiographic characteristics of pelvic arterial disease in patients with erectile dysfunction (ED) nonresponsive to phosphodiesterase-5 inhibitors (PDE5i) and suspected coronary artery disease (CAD). BACKGROUND: ED and CAD share common risk factors which can result in endothelial dysfunction, atherosclerosis and flow-limiting stenoses in the coronary and internal pudendal arteries. METHODS: Ten patients undergoing cardiac catheterization with ED and a history of unsatisfactory response to a PDE5i were studied. ED severity was quantified using the International Index of ED scoring system. We performed angiography and quantitative vessel analysis of the coronary arteries, bilateral common and internal iliac arteries, and internal pudendal arteries (IPAs). RESULTS: In this pilot observational study, we found a high correlation between the presence of angiographic CAD and IPA disease. The reference IPA diameters at the point of maximal stenosis were 2.7 +/- 0.4 mm (right IPA) and 2.7 +/- 0.5 mm (left IPA). In the nine patients with IPA disease, the average stenosis severity was 55 +/- 31% (right) and 66% +/- 25% (left), and average lesion length was 12.4 +/- 5.2 mm (right) and 10.0 +/- 3.5 mm (left). Four patients had unilateral IPA total occlusions, three of whom had moderate contralateral disease. The majority of IPA stenoses occurred in the mid to distal IPA and appears amenable to percutaneous revascularization. CONCLUSIONS: This represents the first angiographic report of CAD correlated with IPA disease in patients with ED. Further investigation is required to determine whether the development of macrovascular disease in the IPA causes ED and whether endovascular treatment is safe and effective in this population. PMID- 20928838 TI - Complications associated with left ventricular puncture. AB - OBJECTIVE: To report complications in a consecutive series of patients undergoing percutaneous left ventricular apical puncture (LVAP) and sheath placement for diagnostic or interventional procedures. BACKGROUND: Percutaneous LVAP is only rarely used to provide hemodynamic data in the presence of mechanical prosthetic valves. Recently, LVAP has been used to facilitate complex interventional procedures such as paravalvular leak closures. These frequently necessitate placement of 4-6 F sheaths, rather than smaller needles. Optimal technique and outcomes are largely unknown for this uncommon procedure. METHODS: We retrospectively analyzed 32 patients undergoing LVAP with echocardiographic and fluoroscopic guidance at our institution between 2002 and 2009. These patients were referred to the cardiac catheterization laboratory for hemodynamic assessment to rule out prosthetic dysfunction and or to facilitate paravalvular leak closure. Sheaths ranged from 4 to 6 F were removed at the end of the procedure after reversing any anticoagulation. No specific closure devices were used for hemostasis. Frequency of access site complications associated with LVAP recorded. RESULTS: Apical access site related complications were higher in patients requiring LVAP for intervention than for diagnostic purposes (25% vs. 12.5%). Hemothorax was the most frequent serious complication occurring in 6 (19%) patients and frequently required intervention 5(16%). Three patients had local bleeding with no drop in hemoglobin or need for intervention. CONCLUSIONS: LVAP is associated with a significant incidence of access-related complications. There is a need for safe and reliable methods of closing percutaneous LVAP access sites. PMID- 20928839 TI - Transcatheter closure of perimembranous ventricular septal defect in children: safety and efficiency with symmetric and asymmetric occluders. AB - OBJECTIVES: This study was designed to determine the safety and efficiency of asymmetric and symmetric ventricular septal occluders (AVSDOs and SVSDOs, respectively) for closure perimembranous ventricular septal defect (PMVSD) in children. METHODS: Between January 2003 and December 2007, 142 children with PMVSD were treated with occluders (64 with AVSDOs and 78 with SVSDOs). RESULTS: The defect diameter was 5.3 +/- 1.1 mm in the AVSDO group and 5.4 +/- 1.3 mm in the SVSDO group (P > 0.05). The success rates were similar between two groups [93.8% (AVSDO) vs. 94.9% (SVSDO), P > 0.05]. Two patients in the AVSDO group were switched to the SVSDO group due to residual shunts, and one patient in the SVSDO group was switched due to aortic regurgitation after deployment of the occluder. After procedure, 17 patients [seven with AVSDOs and nine with SVSDOs (P > 0.05)] developed various types of heart block (HB). Among them, 13 patients converted to the normal sinus rhythm. The remaining four cases had not recovered at the end of the study. CONCLUSIONS: Transcatheter closure of PMVSD using both AVSDO and SVSDO was safe and effective. Development of HB was the main complication for both devices. PMID- 20928840 TI - Treatment of an unraveled intracerebral coil. AB - We describe a case of coil unraveling that occurred during stent-assisted cerebral aneurysm embolization. The unraveled coil was stretched and the loose end was fixed in the external carotid artery by the addition of other coils. Herniation of the loose coil end to the distal part of the vessel with potential vessel occlusion was prevented and no immediate or long-term complication was observed. (c) 2010 Wiley-Liss, Inc. PMID- 20928841 TI - Emergency covered stent implantation for rupture of the ascending aorta after balloon angioplasty. AB - An acute rupture of the ascending aorta occurred in a 12-year-old boy after balloon angioplasty and was successfully treated by emergency covered stent implantation during resuscitation and preparation for support with extracorporeal membrane oxygenation. Neuroprotection with sedation, core temperature cooling and mild hyperventilation were undertaken. The boy recovered quickly. There were no neurological sequalae with a good interventional result at discharge and at follow-up after 9 months. PMID- 20928842 TI - Angiographic and intravascular ultrasound follow up of paclitaxel- and sirolimus eluting stent after poststent high-pressure balloon dilation: from the poststent optimal stent expansion trial. AB - OBJECTIVES: The aims of this study were to identify the efficacy of optimal stent expansion (OSE) according to the Multicenter Ultrasound Stenting in Coronaries Study (MUSIC Study) criteria in drug-eluting stent (DES) and compare paclitaxel eluting stent (PES) to sirolimus-eluting stent (SES). BACKGROUND: Although poststent high-pressure balloon dilatation is proposed after bare metal stent implantation according to OSE, defined by the criteria of the MUSIC Study, very little data are available in DES. METHODS: Two hundred fifty patients (M:F = 149:101; age, 61.5 +/- 9.2 years) who underwent 9-month follow-up angiography in the Poststent Optimal Stent Expansion Trial (POET) were included in this study. We assessed angiographic in-stent restenosis (ISR) and neointima volume (NV) using IVUS at 9 months. RESULTS: At 9-month follow up, there were no significant differences in ISR and NV index (NV/stent length, mm(2) ) between patients with and without OSE. However, the rate of ISR and NV index were higher in PES [ISR: 18 (13.7%) and 4 (3.4%), P = 0.004; NV index: 1.02 +/- 0.99 mm(2) and 0.21 +/- 0.37, P < 0.001 in PES and SES]. CONCLUSIONS: OSE according to the MUSIC Study criteria was not related to ISR and NV in the DES era but PES had a significantly higher ISR rate and NV than SES after poststent high-pressure balloon dilatation. PMID- 20928843 TI - Echocardiographically guided catheter closure of arterial ducts in small preterm infants on the neonatal intensive care unit. AB - OBJECTIVE: To describe closure of haemodynamically significant arterial ducts in preterm infants using an echocardiographically guided cardiac catheter technique in selected infants in the neonatal nursery and in preference to cardiac surgery. BACKGROUND: Persistently patent arterial ducts are common in preterm infants and are associated with significant morbidity and mortality. Cardiac catheter techniques continue to improve and occlusion of arterial ducts in preterm infants is becoming technically feasible. Closure of arterial ducts by cardiac catheter techniques would enable selected infants to avoid surgery and a lateral thoracotomy, as well as potentially obviating the need for transfer of sick preterm infants between units for duct closure. METHODS AND RESULTS: This brief report describes placement of coils or Amplatzer duct devices to occlude arterial ducts in small premature infants exclusively under echocardiographic guidance in the Neonatal Intensive Care Unit. CONCLUSIONS: Closing arterial ducts in the neonatal nursery by an echocardiographically guided cardiac catheter technique with minimal morbidity is becoming achievable and is a significant advance in neonatal care. PMID- 20928846 TI - Coriolis coupling and nonadiabaticity in chemical reaction dynamics. AB - The nonadiabatic quantum dynamics and Coriolis coupling effect in chemical reaction have been reviewed, with emphasis on recent progress in using the time dependent wave packet approach to study the Coriolis coupling and nonadiabatic effects, which was done by K. L. Han and his group. Several typical chemical reactions, for example, H+D(2), F+H(2)/D(2)/HD, D(+)+H(2), O+H(2), and He+H(2)(+), have been discussed. One can find that there is a significant role of Coriolis coupling in reaction dynamics for the ion-molecule collisions of D(+)+H(2), Ne+H(2)(+), and He+H(2)(+) in both adiabatic and nonadiabatic context. PMID- 20928844 TI - Social peers rescue autism-relevant sociability deficits in adolescent mice. AB - Behavioral therapies are currently the most effective interventions for treating the diagnostic symptoms of autism. We employed a mouse model of autism to evaluate components of behavioral interventions that improve sociability in mice. BTBR T+tf/J (BTBR) is an inbred mouse strain that exhibits prominent behavioral phenotypes with face validity to all three diagnostic symptom categories of autism, including robust and well-replicated deficits in social approach and reciprocal social interactions. To investigate the role of peer interactions in the development of sociability, BTBR juvenile mice were reared in the same home cage with juvenile mice of a highly social inbred strain, C57BL/6J (B6). Subject mice were tested as young adults for sociability and repetitive behaviors. B6 controls reared with B6 showed their strain-typical high sociability. BTBR controls reared with BTBR showed their strain-typical lack of sociability. In contrast, BTBR reared with B6 as juveniles showed significant sociability as young adults. A 20-day intervention was as effective as a 40-day intervention for improving social approach behavior. High levels of repetitive self-grooming in BTBR were not rescued by peer-rearing with B6, indicating specificity of the intervention to the social domain. These results from a robust mouse model of autism support the interpretation that social enrichment with juvenile peers is a beneficial intervention for improving adult outcome in the social domain. This novel paradigm may prove useful for discovering factors that are essential for effective behavioral treatments, and biological mechanisms underlying effective behavioral interventions. PMID- 20928845 TI - Far visual acuity is unremarkable in autism: do we need to focus on crowding? AB - Although autism presents a unique perceptual phenotype defined in part by atypical (often enhanced) analysis of spatial information, few biologically plausible hypotheses have been advanced to explain its neural underpinnings. One plausible explanation is functional but altered lateral connectivity mediating early or local mechanisms selectively responsive to different stimulus attributes, including spatial frequency and contrast. The goal of the present study was first to assess far visual acuity in autism using Landolt-C optotypes defined by different local stimulus attributes. Second, we investigated whether acuity is differentially affected in autism when target optotypes are simultaneously presented with flanking stimuli at different distances. This typical detrimental "crowding effect" of flanking stimuli on target optotype discrimination is attributed to lateral inhibitory interaction of neurons encoding for visual properties of distracters close to the target. Results failed to demonstrate a between-group difference in acuity to Landolt-C optotypes, whether defined by luminance- or texture-contrast. However, the expected crowding effect at one gap-size opening distance was evidenced for the control group only; a small effect was observed for the autism group at two gap-size opening. These results suggest that although far visual acuity is unremarkable in autism, altered local lateral connectivity within early perceptual areas underlying spatial information processing in autism is atypical. Altered local lateral connectivity in autism might originate from an imbalance in excitatory/inhibitory neural signaling, resulting in changes regarding elementary feature extraction and subsequent downstream visual integration and visuo-spatial analysis. This notion is discussed within the context of characteristic lower- and higher-level perceptual processing in autism. PMID- 20928847 TI - Structural, electronic, bonding, magnetic, and optical properties of bimetallic [Ru(n)Au(m)](0/+) (n + m <= 3) clusters. AB - The structural, electronic, bonding, magnetic, and optical properties of bimetallic [Ru(n)Au(m)](0/+) (n + m <= 3; n, m = 0-3) clusters were computed in the framework of the density functional theory (DFT) and time-dependent DFT (TD DFT) using the full-range PBE0 non local hybrid GGA functional combined with the Def2-QZVPP basis sets. Several low-lying states have been investigated and the stability of the ground state spinomers was estimated with respect to all possible fragmentation schemes. Molecular orbital and population analysis schemes along with computed electronic parameters illustrated the details of the bonding mechanisms in the [Ru(n)Au(m)](0/+) clusters. The TD-DFT computed UV-visible absorption spectra of the bimetallic clusters have been fully analyzed and compared to those of pure gold and ruthenium clusters. Assignments of all principal electronic transitions are given and interpreted in terms of contribution from specific molecular orbital excitations. PMID- 20928848 TI - Time-dependent density functional theory study on excited-state dihydrogen bonding O-H...H-Ge of the dihydrogen-bonded phenol-triethylgermanium complex. AB - Intermolecular dihydrogen bond O-H...H-Ge in the electronically excited state of the dihydrogen-bonded phenol-triethylgermanium (TEGH) complex was studied theoretically using time-dependent density functional theory. Analysis of the frontier molecular orbitals revealed a locally excited S(1) state in which only the phenol moiety is electronically excited. In the predicted infrared spectrum of the dihydrogen-bonded phenol-TEGH complex, the O-H stretching vibrational mode shifts to a lower frequency in the S(1) state in comparison with that in ground state. The Ge-H stretching vibrational mode demonstrates a relatively smaller redshift than the O-H stretching vibrational mode. Upon electronic excitation to the S(1) state, the O-H and Ge-H bonds involved in the dihydrogen bond both get lengthened, whereas the C-O bond is shortened. With an increased binding energy, the calculated H...H distance significantly decreases in the S(1) state. Thus, the intermolecular dihydrogen bond O-H...H-Ge of the dihydrogen-bonded phenol TEGH complex becomes stronger in the electronically excited state than that in the ground state. PMID- 20928849 TI - vmdICE: a plug-in for rapid evaluation of molecular dynamics simulations using VMD. AB - Molecular dynamics (MD) is a powerful in silico method to investigate the interactions between biomolecules. It solves Newton's equations of motion for atoms over a specified period of time and yields a trajectory file, containing the different spatial arrangements of atoms during the simulation. The movements and energies of each single atom are recorded. For evaluating of these simulation trajectories with regard to biomedical implications, several methods are available. Three well-known ones are the root mean square deviation (RMSD), the root mean square fluctuation (RMSF) and solvent accessible surface area (SASA). Herein, we present a novel plug-in for the software "visual molecular dynamics" (VMD) that allows an interactive 3D representation of RMSD, RMSF, and SASA, directly on the molecule. On the one hand, our plug-in is easy to handle for inexperienced users, and on the other hand, it provides a fast and flexible graphical impression of the spatial dynamics of a system for experts in the field. PMID- 20928850 TI - Comparison of aromatic NH...pi, OH...pi, and CH...pi interactions of alanine using MP2, CCSD, and DFT methods. AB - A comparison of the performance of various density functional methods including long-range corrected and dispersion corrected methods [MPW1PW91, B3LYP, B3PW91, B97-D, B1B95, MPWB1K, M06-2X, SVWN5, omegaB97XD, long-range correction (LC) omegaPBE, and CAM-B3LYP using 6-31+G(d,p) basis set] in the study of CH...pi, OH...pi, and NH...pi interactions were done using weak complexes of neutral (A) and cationic (A(+)) forms of alanine with benzene by taking the Moller-Plesset (MP2)/6-31+G(d,p) results as the reference. Further, the binding energies of the neutral alanine-benzene complexes were assessed at coupled cluster (CCSD)/6 31G(d,p) method. Analysis of the molecular geometries and interaction energies at density functional theory (DFT), MP2, CCSD methods and CCSD(T) single point level reveal that MP2 is the best overall performer for noncovalent interactions giving accuracy close to CCSD method. MPWB1K fared better in interaction energy calculations than other DFT methods. In the case of M06-2X, SVWN5, and the dispersion corrected B97-D, the interaction energies are significantly overrated for neutral systems compared to other methods. However, for cationic systems, B97 D yields structures and interaction energies similar to MP2 and MPWB1K methods. Among the long-range corrected methods, LC-omegaPBE and CAM-B3LYP methods show close agreement with MP2 values while omegaB97XD energies are notably higher than MP2 values. PMID- 20928851 TI - Structural stability and phase transition in OsC and RuC. AB - The structural stability and phase transition of osmium and ruthenium carbides (OsC and RuC) were investigated by first principles. Nine structures were considered for each carbide. Zinc blende structure has the lowest energy among the considered structures at ambient conditions for both carbides. For OsC at elevated pressures, the most stable phase is zinc blende structure from 0 to 10 GPa, FeSi from 10 to 32 GPa. In these two structures, Os atom is fourfold coordinated. From 32 to 40 GPa, tungsten carbide (WC) and NiAs are energetically competitive with Os atom sixfold coordinated. NiAs becomes energetically the most stable structure above 40 GPa. For RuC, zinc blende structure is the most stable from 0 to 20 GPa. From 20 to 100 GPa, WC structure is the most stable. PMID- 20928852 TI - TmoleX--a graphical user interface for TURBOMOLE. AB - We herein present the graphical user interface (GUI) TmoleX for the quantum chemical program package TURBOMOLE. TmoleX allows users to execute the complete workflow of a quantum chemical investigation from the initial building of a structure to the visualization of the results in a user friendly graphical front end. The purpose of TmoleX is to make TURBOMOLE easy to use and to provide a high degree of flexibility. Hence, it should be a valuable tool for most users from beginners to experts. The program is developed in Java and runs on Linux, Windows, and Mac platforms. It can be used to run calculations on local desktops as well as on remote computers. PMID- 20928869 TI - Depicting adoptive immunotherapy for prostate cancer in an animal model with magnetic resonance imaging. AB - Genetically modified natural killer (NK) cells that recognize tumor-associated surface antigens have recently shown promise as a novel approach for cancer immunotherapy. To determine NK cell therapy response early, a real-time, noninvasive method to quantify NK cell homing to the tumor is desirable. The purpose of this study was to evaluate if MR imaging could provide a noninvasive, in vivo diagnosis of NK cell accumulation in epithelial cell adhesion molecule (EpCAM)-positive prostate cancers in a rat xenograft model. Genetically engineered NK-92-scFv(MOC31)-zeta cells, which express a chimeric antigen receptor specific to the tumor-associated EpCAM antigen, and nontargeted NK-92 cells were labeled with superparamagnetic particles of iron-oxides (SPIO) ferumoxides. Twelve athymic rats with implanted EpCAM positive DU145 prostate cancers received intravenous injections of 1.5*10(7) SPIO labeled NK-92 and NK-92 scFv(MOC31)-zeta cells. EpCAM-positive prostate cancers demonstrated a progressive and a significant decline in contrast-to-noise-ratio data at 1 and 24 h after injection of SPIO-labeled NK-92-scFv(MOC31)-zeta cells. Conversely, tumor contrast-to-noise-ratio data did not change significantly after injection of SPIO labeled parental NK-92 cells. Histopathology confirmed an accumulation of the genetically engineered NK-92-scFv(MOC31)-zeta cells in prostate cancers. Thus, the presence or absence of a tumor accumulation of therapeutic NK cells can be monitored with cellular MR imaging. EpCAM-directed, SPIO labeled NK-92 scFv(MOC31)-zeta cells accumulate in EpCAM-positive prostate cancers. PMID- 20928868 TI - Automated macrovessel artifact correction in dynamic susceptibility contrast magnetic resonance imaging using independent component analysis. AB - Dynamic susceptibility contrast-MRI is the most commonly used functional MRI based method for studying changes in cerebral perfusion. However, several studies indicated a systematic overestimation of perfusion parameters compared with other imaging modalities related to the high sensitivity of dynamic susceptibility contrast-MRI for blood flow in large vessels. In this study, we therefore suggest an improved, automated, robust, and efficient method allowing for generating hemodynamic parameter maps where signal influence from large vessels is minimized. Based on independent component analysis, this fully automated approach corrects dynamic susceptibility contrast-MRI data without any user interaction, thus making a clinical applicability possible. The accuracy of the proposed method was tested in 10 patients with cerebrovascular disease. Application of our correction algorithm resulted in a significant reduction of the effect of macrovessel signal on hemodynamic parameters like the cerebral blood flow and the cerebral blood volume compared with uncorrected data. As desired, our method specifically corrected for macrovessel artifacts in cortical grey matter tissue, leaving white matter tissue parameters largely unaffected. This may increase sensitivity and reliability of detecting perfusion abnormalities in patient groups, in particular with regard to stroke and other cerebrovascular disorders. PMID- 20928870 TI - The biowaiver procedure: its application to antituberculosis products in the WHO prequalification programme. AB - In 2005, the World Health Organization (WHO) proposed that provided an active pharmaceutical ingredient could meet certain criteria, bioequivalence could be evaluated with a set of laboratory tests, obviating the need for expensive and time-consuming pharmacokinetic studies in humans. The aim of this work was to determine whether this so-called "biowaiver" procedure can be applied to antituberculosis products. Antituberculosis products from the WHO Prequalification Programme, including three ethambutol, two isoniazid and one pyrazinamide product, were investigated. In vitro dissolution data for these products were generated according to the biowaiver method stipulated in the WHO Guidance, and the bioequivalence decision based on these data was compared with that based on the corresponding in vivo pharmacokinetic data. In no case was a "false positive" bioequivalence decision reached using the biowaiver procedure, that is, all products deemed bioequivalent according to the biowaiver methods also proved to be bioequivalent in the corresponding pharmacokinetic study. These findings open the way to a simplified method of ensuring bioequivalence of antituberculosis drug products, thereby improving access to high quality antituberculosis medicines for a greater number of patients. PMID- 20928871 TI - Optimization of formulation variables affecting spray-dried oily core nanocapsules by response surface methodology. AB - The formulation variables required for the production of spray-dried oily core nanocapsules (NCs) with targeted size and drug payload were optimized using a Box Behnken experimental design. These NCs were characterized for size, morphology, encapsulation efficiency (EE%) and drug release kinetics, crystallinity, and density, by dynamic light scattering, electron microscopy, ultraviolet spectrometry, powder X-ray diffraction, and density-gradient centrifugation, respectively. The size of the NCs ranged from 208.6 to 504.4 nm, with EE% from 64.7% to 94.6%. The amounts of oil and surfactant (Pluronic F127) significantly affected size. The amounts of polymer [polylactide (PLA)], oil, and surfactant significantly affected EE%. The optimum formulation parameters were set to be 300 mg of PLA, 0.56 mL of oil, and 239.57 mg of Pluronic F127, which corresponded to size of 284.1 nm and EE% of 95.7%. Morphological analysis and density-gradient centrifugation showed the existence of an oily core and spherical nanostructure with no detectable drug crystals. The NCs had longer sustained drug release than nanosphere control, with a good fit to the Ritger-Peppas model (R(2) > 0.930). Spray-dried oily core NCs were successfully produced, and the Box-Behnken design appears to be an effective tool to predict the size and encapsulation of NCs. PMID- 20928872 TI - A parallel imaging technique using mutual calibration for split-blade diffusion weighted PROPELLER. AB - Split-blade diffusion-weighted periodically rotated overlapping parallel lines with enhanced reconstruction (DW-PROPELLER) was proposed to address the issues associated with diffusion-weighted echo planar imaging such as geometric distortion and difficulty in high-resolution imaging. The major drawbacks with DW PROPELLER are its high SAR (especially at 3T) and violation of the Carr-Purcell Meiboom-Gill condition, which leads to a long scan time and narrow blade. Parallel imaging can reduce scan time and increase blade width; however, it is very challenging to apply standard k-space-based techniques such as GeneRalized Autocalibrating Partially Parallel Acquisitions (GRAPPA) to split-blade DW PROPELLER due to its narrow blade. In this work, a new calibration scheme is proposed for k-space-based parallel imaging method without the need of additional calibration data, which results in a wider, more stable blade. The in vivo results show that this technique is very promising. PMID- 20928873 TI - Bone morphology in response to alendronate as seen by high-resolution computed tomography: Through a glass darkly. PMID- 20928874 TI - The unitary model for estrogen deficiency and the pathogenesis of osteoporosis: is a revision needed? AB - Over a decade ago, we proposed a "unitary" model for the pathogenesis of osteoporosis that identified estrogen deficiency as the predominant cause of both the early, accelerated, and late slow phases of bone loss in postmenopausal women and as a contributing cause of the continuous phase of bone loss in aging men. While this was a plausible model then, new data over the intervening years suggest a need to modify these concepts. Indeed, based largely on rodent studies, a "revisionist" view of the pathogenesis of osteoporosis has been proposed recently that attempts a paradigm shift from the estrogen-centric model to one in which bone loss is largely independent of estrogen deficiency and is driven instead by cell-autonomous age-related factors. However, detailed clinical investigative studies using quantitative computed tomography demonstrate that the onset of cortical bone loss in humans is closely tied to estrogen deficiency; thus the estrogen-centric view is likely correct for cortical bone, which comprises over 80% of the skeleton and is the major structural determinant of fracture risk at most skeletal sites. By contrast, these same studies also demonstrate that trabecular bone loss begins in sex hormone-replete young adults of both sexes. This suggests that a significant proportion of trabecular bone loss is either estrogen-independent or, as suggested by some studies, requires higher levels for its regulation. In this perspective, we critically review these and other findings, leading us to conclude that our original model requires modification but not revision. PMID- 20928875 TI - Reduction of artifacts in T2 -weighted PROPELLER in high-field preclinical imaging. AB - A simple technique is implemented for correction of artifacts arising from nonuniform T(2) -weighting of k-space data in fast spin echo-based PROPELLER (periodically rotated overlapping parallel lines with enhanced reconstruction). An additional blade with no phase-encoding gradients is acquired to generate the scaling factor used for the correction. Results from simulations and phantom experiments, as well as in vivo experiments in free-breathing mice, demonstrate the advantages of the proposed method. This technique is developed specifically for high-field imaging applications where T(2) decay is rapid. PMID- 20928876 TI - High resolution three-dimensional cardiac perfusion imaging using compartment based k-t principal component analysis. AB - Three-dimensional myocardial perfusion imaging requires significant acceleration of data acquisition to achieve whole-heart coverage with adequate spatial and temporal resolution. The present article introduces a compartment-based k-t principal component analysis reconstruction approach, which permits three dimensional perfusion imaging at 10-fold nominal acceleration. Using numerical simulations, it is shown that the compartment-based method results in accurate representations of dynamic signal intensity changes with significant improvements of temporal fidelity in comparison to conventional k-t principal component analysis reconstructions. Comparison of the two methods based on rest and stress three-dimensional perfusion data acquired with 2.3 * 2.3 * 10 mm(3) during a 225 msec acquisition window in patients confirms the findings and demonstrates the potential of compartment-based k-t principal component analysis for highly accelerated three-dimensional perfusion imaging. PMID- 20928877 TI - Ex vivo high resolution magic angle spinning metabolic profiles describe intratumoral histopathological tissue properties in adult human gliomas. AB - In gliomas one can observe distinct histopathological tissue properties, such as viable tumor cells, necrotic tissue or regions where the tumor infiltrates normal brain. A first screening between the different intratumoral histopathological tissue properties would greatly assist in correctly diagnosing and prognosing gliomas. The potential of ex vivo high resolution magic angle spinning spectroscopy in characterizing these properties is analyzed and the biochemical differences between necrosis, high cellularity and border tumor regions in adult human gliomas are investigated. Statistical studies applied on sets of metabolite concentrations and metabolite ratios extracted from 52 high resolution magic angle spinning recordings coming from patients with different grades of glial tumors show a strong correlation between the histopathological tissue properties and the considered metabolic profiles, regardless of the malignancy grade. The results are in agreement with the pathology obtained by the histopathological examination that succeeded the high resolution magic angle spinning measurements. The metabolite concentration set can better differentiate between the considered histopathological tissue properties compared to the ratios. Representative reference tissue models describing the metabolic behavior are extracted for characterizing the intratumoral tissue properties. The proposed metabolic profiles reflect that the metabolites behavior is interconnected, and typical biochemical patterns emerge for each histopathological tissue property. PMID- 20928878 TI - Real-time product switching using a twin catalyst system for the hydrogenation of furfural in supercritical CO2. PMID- 20928879 TI - Antibody detection by using a FRET-based protein conformational switch. PMID- 20928880 TI - Diffusiophoresis of an elongated cylindrical nanoparticle along the axis of a nanopore. AB - The translation of a charged, elongated cylindrical nanoparticle along the axis of a nanopore driven by an imposed axial salt concentration gradient is investigated using a continuum theory, which consists of the ionic mass conservation equations for the ionic concentrations, the Poisson equation for the electric potential in the solution, and the modified Stokes equations for the hydrodynamic field. The diffusiophoretic motion is driven by the induced electrophoresis and chemiphoresis. The former is driven by the generated overall electric field arising from the difference in the ionic diffusivities and the double layer polarization, while the latter is generated by the induced osmotic pressure gradient around the charged particle. The induced diffusiophoretic motion is investigated as functions of the imposed salt concentration gradient, the ratio of the particle's radius to the double layer thickness, the cylinder's aspect ratio (length/radius), the ratio of the nanopore size to the particle size, the surface charge densities of the nanoparticle and the nanopore, and the type of the salt used. The induced diffusiophoretic motion of a nanorod in an uncharged nanopore is mainly governed by the induced electrophoresis, driven by the induced electric field arising from the double layer polarization. The induced particle motion is driven by the induced electroosmotic flow, if the charges of the nanorod and nanopore wall have the same sign. PMID- 20928881 TI - Defeating radiation damping and magnetic field inhomogeneity with spatially encoded noise. AB - A simple NMR experiment capable of providing well resolved spectra under conditions where either radiation damping or static magnetic field inhomogeneity would broaden otherwise high-resolution NMR spectra is introduced. The approach involves using a strong pulsed magnetic field gradient and a selective radio frequency pulse to encode a predetermined noise pattern into the spatial distribution of magnetization. Following readout in a much smaller field gradient, the noise sequence may be deconvolved from the acquired data and a high resolution spectrum is obtained, eliminating the effects of either radiation damping or the static field inhomogeneity. In the presence of field inhomogeneity a field map is also obtained from the same single transient. A quasi-two dimensional version of the experiment eliminates the need for deconvolution and produces improved results with simplified processing, but without requiring a full two-dimensional experiment. Example spectra are shown for both radiation damping and one-dimensional field inhomogeneity with improvement in linewidths of more than a factor of 40. PMID- 20928882 TI - Studies of anti-HIV transcription inhibitor quinolones: identification of potent N1-vinyl derivatives. AB - The 6-desfluoroquinolones (6-DFQs) are anti-HIV agents that target Tat-mediated transcription. This particular mechanism of action makes this class of compounds very attractive for further structural investigations. Identification of the pharmacophore required for inhibition will ultimately result in the design of more selective analogues for use in combination therapy for the treatment of HIV infections. We have focused on the pyridone ring of the quinolone nucleus present in these compounds, designing new modifications to broaden the structure-activity relationship knowledge base. Herein, we present novel and very potent anti-HIV quinolones, most notably those bearing an amino or vinyl group at the N1 position. Attempts were made to determine the structural parameters necessary to impart potent anti-HIV activity to the vinyl derivatives. PMID- 20928883 TI - Long-term MR cell tracking of neural stem cells grafted in immunocompetent versus immunodeficient mice reveals distinct differences in contrast between live and dead cells. AB - Neural stem cell (NSC)-based therapy is actively being pursued in preclinical and clinical disease models. Magnetic resonance imaging (MRI) cell tracking promises to optimize current cell transplantation paradigms, however, it is limited by dilution of contrast agent during cellular proliferation, transfer of label from dying cells to surrounding endogenous host cells, and/or biodegradation of the label. Here, we evaluated the applicability of magnetic resonance imaging for long-term tracking of transplanted neural stem cells labeled with superparamagnetic iron oxide and transfected with the bioluminescence reporter gene luciferase. Mouse neural stem cells were transplanted into immunodeficient, graft-accepting Rag2 mice or immunocompetent, graft-rejecting Balb/c mice. Hypointense voxel signals and bioluminescence were monitored over a period of 93 days. Unexpectedly, in mice that rejected the cells, the hypointense MR signal persisted throughout the entire time-course, whereas in the nonrejecting mice, the contrast cleared at a faster rate. In immunocompetent, graft-rejecting Balb/c mice, infiltrating leukocytes, and microglia were found surrounding dead cells and internalizing superparamagnetic iron oxide clusters. The present results indicate that live cell proliferation and associated label dilution may dominate contrast clearance as compared with cell death and subsequent transfer and retention of superparamagnetic iron oxide within phagocytes and brain interstitium. Thus, interpretation of signal changes during long-term MR cell tracking is complex and requires caution. PMID- 20928884 TI - Enhanced neurochemical profile of the rat brain using in vivo (1)H NMR spectroscopy at 16.4 T. AB - Single voxel magnetic resonance spectroscopy with ultrashort echo time was implemented at 16.4 T to enhance the neurochemical profile of the rat brain in vivo. A TE of 1.7 msec was achieved by sequence optimization and by using short duration asymmetric pulses. Macromolecular signal components were parameterized individually and included in the quantitative analysis, replacing the use of a metabolite-nulled spectrum. Because of the high spectral dispersion, several signals close to the water line could be detected, and adjacent peaks could be resolved. All 20 metabolites detected in this study were quantified with Cramer Rao lower bounds below 20%, implying reliable quantification accuracy. The signal of acetate was detected for the first time in rat brain in vivo with Cramer-Rao lower bounds of 16% and a concentration of 0.52 MUmol/g. The absolute concentrations of most metabolites showed close agreement with values previously measured using in vivo (1)H NMR spectroscopy and in vitro biochemical assay. PMID- 20928885 TI - Serum fibroblast growth factor-23 (FGF-23) and fracture risk in elderly men. AB - A normal mineral metabolism is integral for skeletal development and preservation of bone integrity. Fibroblast growth factor 23 (FGF-23) is a bone-derived circulating factor that decreases serum concentrations of inorganic phosphorous (P(i)) and 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)]. Increased FGF-23 expression is a direct or indirect culprit in several skeletal disorders; however, the relation between FGF-23 and fracture risk remains undetermined. We evaluated the prospective relation between serum intact FGF-23 (measured by a two site monoclonal antibody ELISA) and fracture risk employing the Swedish part of the population-based Osteoporotic Fractures in Men Study (MrOS; n = 2868; mean age 75.4 +/- 3.2 years; median follow-up period 3.35 years). The incidence of at least one validated fracture after baseline was 20.4 per 1000 person-years. FGF 23 was directly related to the overall fracture risk [age-adjusted hazard ratio (HR) per SD increase = 1.20, 95% confidence interval (CI) 1.03-1.40] and vertebral fracture risk (HR = 1.33, 95% CI 1.02-1.75). Spline models revealed a nonlinear relation between FGF-23 and fracture risk, with the strongest relation at FGF-23 levels above 55.7 pg/mL. FGF-23 levels above 55.7 pg/mL also were associated with an increased risk for hip and nonvertebral fractures (HR = 2.30, 95% CI 1.16-4.58, and HR = 1.63, 95% CI 1.01-2.63, respectively). These relations remained essentially unaltered after adjustment for bodymass index (BMI), bone mineral density (BMD), glomerular filtration rate, 25(OH)(2)D(3), parathyroid hormone (PTH), and other fracture risk factors. In conclusion, FGF-23 is a novel predictor of fracture risk in elderly men. PMID- 20928886 TI - Determinants of the mechanical behavior of human lumbar vertebrae after simulated mild fracture. AB - The ability of a vertebra to carry load after an initial deformation and the determinants of this postfracture load-bearing capacity are critical but poorly understood. This study aimed to determine the mechanical behavior of vertebrae after simulated mild fracture and to identify the determinants of this postfracture behavior. Twenty-one human L(3) vertebrae were analyzed for bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA) and for microarchitecture by micro-computed tomography (uCT). Mechanical testing was performed in two phases: initial compression of vertebra to 25% deformity, followed, after 30 minutes of relaxation, by a similar test to failure to determine postfracture behavior. We assessed (1) initial and postfracture mechanical parameters, (2) changes in mechanical parameters, (3) postfracture elastic behavior by recovery of vertebral height after relaxation, and (4) postfracture plastic behavior by residual strength and stiffness. Postfracture failure load and stiffness were 11% +/- 19% and 53% +/- 18% lower than initial values (p = .021 and p < .0001, respectively), with 29% to 69% of the variation in the postfracture mechanical behavior explained by the initial values. Both initial and postfracture mechanical behaviors were significantly correlated with bone mass and microarchitecture. Vertebral deformation recovery averaged 31% +/- 7% and was associated with trabecular and cortical thickness (r = 0.47 and r = 0.64; p = .03 and p = .002, respectively). Residual strength and stiffness were independent of bone mass and initial mechanical behavior but were related to trabecular and cortical microarchitecture (|r| = 0.50 to 0.58; p = .02 to .006). In summary, we found marked variation in the postfracture load-bearing capacity following simulated mild vertebral fractures. Bone microarchitecture, but not bone mass, was associated with postfracture mechanical behavior of vertebrae. PMID- 20928887 TI - Growth hormone mediates pubertal skeletal development independent of hepatic IGF 1 production. AB - Deficiencies in either growth hormone (GH) or insulin-like growth factor 1 (IGF 1) are associated with reductions in bone size during growth in humans and animal models. Liver-specific IGF-1-deficient (LID) mice, which have 75% reductions in serum IGF-1, were created previously to separate the effects of endocrine (serum) IGF-1 from autocrine/paracrine IGF-1. However, LID mice also have two- to threefold increases in GH, and this may contribute to the observed pubertal skeletal phenotype. To clarify the role of GH in skeletal development under conditions of significantly reduced serum IGF-1 levels (but normal tissue IGF-1 levels), we studied the skeletal response of male LID and control mice to GH inhibition by pegvisomant from 4 to 8 weeks of age. Treatment of LID mice with pegvisomant resulted in significant reductions in body weight, femur length (Le), and femur total area (Tt.Ar), as well as further reductions in serum IGF-1 levels by 8 weeks of age, compared with the mean values of vehicle-treated LID mice. Reductions in both Tt.Ar and Le were proportional after treatment with pegvisomant. On the other hand, the relative amount of cortical tissue formed (RCA) in LID mice treated with pegvisomant was significantly less than that in both vehicle-treated LID and control mice, indicating that antagonizing GH action, either directly (through GH receptor signaling inhibition) or indirectly (through further reductions in serum/tissue IGF-1 levels), results in disproportionate reductions in the amount of cortical bone formed. This resulted in bones with significantly reduced mechanical properties (femoral whole-bone stiffness and work to failure were markedly decreased), suggesting that compensatory increases of GH in states of IGF-1 deficiency (LID mice) act to protect against a severe inhibition of bone modeling during growth, which otherwise would result in bones that are too weak for normal and/or extreme loading conditions. PMID- 20928889 TI - The effect of blood inflow and B(1)-field inhomogeneity on measurement of the arterial input function in axial 3D spoiled gradient echo dynamic contrast enhanced MRI. AB - A major potential confound in axial 3D dynamic contrast-enhanced magnetic resonance imaging studies is the blood inflow effect; therefore, the choice of slice location for arterial input function measurement within the imaging volume must be considered carefully. The objective of this study was to use computer simulations, flow phantom, and in vivo studies to describe and understand the effect of blood inflow on the measurement of the arterial input function. All experiments were done at 1.5 T using a typical 3D dynamic contrast-enhanced magnetic resonance imaging sequence, and arterial input functions were extracted for each slice in the imaging volume. We simulated a set of arterial input functions based on the same imaging parameters and accounted for blood inflow and radiofrequency field inhomogeneities. Measured arterial input functions along the vessel length from both in vivo and the flow phantom agreed with simulated arterial input functions and show large overestimations in the arterial input function in the first 30 mm of the vessel, whereas arterial input functions measured more centrally achieve accurate contrast agent concentrations. Use of inflow-affected arterial input functions in tracer kinetic modeling shows potential errors of up to 80% in tissue microvascular parameters. These errors emphasize the importance of careful placement of the arterial input function definition location to avoid the effects of blood inflow. PMID- 20928888 TI - The contribution of chemical exchange to MRI frequency shifts in brain tissue. AB - Recent high-field MRI studies based on resonance frequency contrast have revealed brain structure with unprecedented detail. Although subtle magnetic susceptibility variations caused by iron and myelin seem to be important to this contrast, recent research on protein solutions suggests that chemical exchange between water and macromolecular protons may contribute substantially to the observed gray-white matter frequency contrast. To investigate this, we performed spectroscopic MRI experiments at 14 T on samples of fixed human visual cortex and fresh pig brain. To allow direct observation of any exchange-induced frequency shifts, these samples were soaked in reference chemicals (TSP and dioxane) that are assumed not to be involved in exchange. For both fresh and fixed tissues and with both reference chemicals, substantial negative exchange-induced gray-white matter frequency contrast (-6.3 to -13.5 ppb) was found, whereas intracortical contrast was negligible. The sign of the gray-white matter exchange-induced frequency difference was opposite to the overall gray-white matter frequency difference observed in vivo. This suggests that exchange contributes to, but is not sufficient to explain, the frequency contrast in vivo and tissue susceptibility differences may have a greater contribution than previously thought. The exchange-dependent contribution may report on tissue chemical composition and pH. PMID- 20928890 TI - Estimates of systolic and diastolic myocardial blood flow by dynamic contrast enhanced MRI. AB - Myocardial blood flow varies during the cardiac cycle in response to pulsatile changes in epicardial circulation and cyclical variation in myocardial tension. First-pass assessment of myocardial perfusion by dynamic contrast-enhanced MRI is one of the most challenging applications of MRI because of the spatial and temporal constraints imposed by the cardiac physiology and the nature of dynamic contrast-enhanced MRI signal collection. Here, we describe a dynamic contrast enhanced MRI method for simultaneous assessment of systolic and diastolic myocardial blood flow. The feasibility of this method was demonstrated in a study of 17 healthy volunteers at rest and under adenosine-induced vasodilatory stress. We found that myocardial blood flow was independent of the cardiac phase at rest. However, under adenosine-induced hyperemia, myocardial blood flow and myocardial perfusion reserve were significantly higher in diastole than in systole. Furthermore, the transmural distribution of myocardial blood flow and myocardial perfusion reserve was cardiac phase dependent, with a reversal of the typical subendocardial to subepicardial myocardial blood flow gradient in systole, but not diastole, under stress. The observed difference between systolic and diastolic myocardial blood flow must be taken into account when assessing myocardial blood flow using dynamic contrast-enhanced MRI. Furthermore, targeted assessment of systolic or diastolic perfusion using dynamic contrast-enhanced MRI may provide novel insights into the pathophysiology of ischemic and microvascular heart disease. PMID- 20928891 TI - First-pass contrast-enhanced myocardial perfusion MRI in mice on a 3-T clinical MR scanner. AB - First-pass contrast-enhanced myocardial perfusion MRI in rodents has so far not been possible due to the temporal and spatial resolution requirements. We developed a new first-pass perfusion MR method for rodent imaging on a clinical 3.0-T scanner (Philips Healthcare, Best, The Netherlands) that employed 10-fold k space and time domain undersampling with constrained image reconstruction, using temporal basis sets (k-t principle component analysis) to achieve a spatial resolution of 0.2 * 0.2 * 1.5mm(3) and an acquisition window of 43 msec. The method was successfully tested in five healthy and four infarcted mice (C57BL/6J) at heart rates of 495.1 +/- 45.8 beats/min. Signal-intensity-time profiles showed a percentage myocardial signal increase of 141.3 +/- 38.9% in normal mice, compared with 44.7 +/- 32.4% in infarcted segments. Mean myocardial blood flow by Fermi function for constrained deconvolution in control mice was 7.3 +/- 1.5 mL/g/min, comparable to published literature, with no significant differences between three myocardial segments. In infarcted segments, myocardial blood flow was significantly reduced to 1.2 +/- 0.8 mL/g/min (P < 0.01). This is the first report of first-pass myocardial perfusion MR in a mouse model on a clinical 3-T MR scanner and using a k-t undersampling method. Data were acquired on a 3-T scanner, using an approach similar to clinical acquisition protocols, thus facilitating translation of imaging findings between rodent and human studies. PMID- 20928892 TI - Mouse myocardial first-pass perfusion MR imaging. AB - A first-pass myocardial perfusion sequence for mouse cardiac MRI is presented. A segmented ECG-triggered acquisition combined with parallel imaging acceleration was used to capture the first pass of a Gd-DTPA bolus through the mouse heart with a temporal resolution of 300-400 msec. The method was applied in healthy mice (N = 5) and in mice with permanent occlusion of the left coronary artery (N = 6). Baseline semiquantitative perfusion values of healthy myocardium showed excellent reproducibility. Infarct regions revealed a significant decrease in the semiquantitative myocardial perfusion values (0.05 +/- 0.02) compared to remote myocardium (0.20 +/- 0.04). Myocardial areas of decreased perfusion correlated well to infarct areas identified on the delayed-enhancement scans. This protocol is a valuable addition to the mouse cardiac MRI toolbox for preclinical studies of ischemic heart disease. PMID- 20928893 TI - Diastereomerically pure nucleoside-5'-O-(2-thio-4,4-pentamethylene-1,3,2 oxathiaphospholane)s--substrates for synthesis of P-chiral derivatives of nucleoside-5'-O-phosphorothioates. AB - A method for stereocontrolled chemical synthesis of P-substituted nucleoside 5'-O phosphorothioates has been elaborated. Selected 3'-O-acylated deoxyribonucleoside and 2',3'-O,O-diacylated ribonucleoside-5'-O-(2-thio-4,4-pentamethylene-1,3,2 oxathiaphospholane)s were chromatographically separated into P-diastereomers. Their reaction with anions of phosphorus-containing acids was highly stereoselective (>=90%) and furnished corresponding P-chiral alpha thiodiphosphates and their phosphonate analogs with satisfactory yield. PMID- 20928894 TI - Synthesis of enantiopure trans-N-Boc-3-aminobicyclo[2.2.2]octane-2-carboxylic acids and their bicyclic 1,3-amino alcohol derivatives via the [4+2] cycloaddition of 1,3-cyclohexadiene to a chiral beta-nitroacrylate. AB - The chiral beta-nitroacrylate 2 derived from the (R)- or (S)-4-(3-hydroxy-4,4 dimethyl-2-oxopyrrolidin-1-yl) benzoic acid 1 acts as a reactive dienophile in a diastereoselective Diels-Alder reaction with 1,3-cyclohexadiene. The major cycloadducts have been isolated and transformed into enantiopure trans(2S,3S)- or (2R,3R)-N-Boc-3-aminobicyclic[2,2,2]octane-2-carboxylic acids 5. The trans (2S,3S)- or (2R,3R)-N-Boc 3-(hydoxymethyl)-2-aminobicyclic[2,2,2]octane 6 derivatives were also obtained. PMID- 20928895 TI - A mechanistic approach for the DNA binding of chiral enantiomeric L- and D tryptophan-derived metal complexes of 1,2-DACH: cleavage and antitumor activity. AB - A new chiral series of potential antitumor metal-based complexes 1-3(a and b) of L- and D-tryptophan have been synthesized and thoroughly characterized. Both enantiomers of 1-3 bind DNA noncovalently via phosphate interaction with slight preference of metal center for covalent coordination to nucleobases. The K(b) values of L-enantiomer, however, possess higher propensity for DNA binding in comparison with the D-enantiomeric analogs. The relative trend in K(b) values is as follows: 2(a) > 2(b) > 3(a) > 1(a) > 3(b) > 1(b). These observations together with the findings of circular dichoric and fluorescence studies reveal maximal potential of L-enantiomeric form of copper complex to bind DNA, thereby exerting its therapeutic effect. The complex 2a exhibits a remarkable DNA cleavage activity with pBR322DNA in the presence of different activators such as H(2) O(2) , ascorbic acid, 3-mercaptopropionic acid, and glutathione, suggesting the involvement of active oxygen species for the DNA scission. In vitro anticancer activity of complexes 1-3(a) were screened against 14 different human carcinoma cell lines of different histological origin, and the results reveal that 2a shows significant antitumor activity in comparison with both 1a and 3a and is particularly selective for MIAPACA2 (pancreatic cancer cell line). PMID- 20928896 TI - Determination of optical purity of 3,5-dimethoxybenzoyl-leucine diethylamide by chiral chromatography and 1H and 13C NMR spectroscopy. AB - (R)-N-3,5-dinitrobenzoyl (DNB) leucine derived chiral selector was used as an HPLC chiral stationary phase for the resolution of various racemic amino acids derivatives. In this study, determination of optical purity of an amino acid derivative was performed by chiral high performance liquid chromatography and 1H and 13C NMR spectroscopy by using the DNB leucine derived chiral selector. The accuracy and precision of each optical purity value are calculated and the data are compared to each other. PMID- 20928897 TI - Optical activity and Alfred Werner's coordination chemistry. AB - It is widely accepted, that Pasteur's seminal discovery of the opposite optical activity of ammonium sodium tartrate enantiomorphs in solution gave the spark to organic stereochemistry and led to the development of the tetrahedron model by van't Hoff and Le Bel. The proof that chirality is inherently connected to octahedral coordination chemistry fostered greatly Werner's spatial views of metal complexes and his coordination theory. The actual proof of principle was established via separation of diastereomeric camphor sulfonate salts of racemic metal complexes. PMID- 20928898 TI - Theoretical elucidation on the functional role of pyrrolidine-type ionic liquids in inducing stereoselectivity of the Michael addition of cyclohexanone with trans beta-nitrostyrene. AB - Density functional theory calculations have been carried out to elucidate the stereoselectivity of the Michael addition of cyclohexanone with trans-beta nitrostyrene, induced by a chiral ionic liquid (CIL) pyrrolidine-imidazolium bromide. By comparison of the C-C bond forming processes in the absence and presence of Br(-) anion, we found that intermolecular H-bonds between the imidazolium cation and the nitro group of trans-beta-nitrostyrene and the steric hindrance of the imidazolium cation moiety on the Si-face of enamine dominate the stereoselectivity of the Michael addition. The presence of Br(-) anion obviously reduces the barrier by increasing the polarity of the C4=C5 bond of enamine. The theoretical results rationalize well the early experimental finding, and reveal a valuable clue for the further CIL design with high catalytic efficiency. PMID- 20928899 TI - Conformational studies on chiral rhodium complexes by ECD and VCD spectroscopy. AB - This article reports vibrational circular dichroism (VCD) and electronic circular dichroism (ECD) spectroscopic studies in acetonitrile on the chiral Rh(2)(O-Phe Cbz)(1)(OAc)(3) and Rh(2)(O-Phe-Ac)(1)(OAc)(3) complexes (abbreviated Rh(2)Z(1) and Rh(2)Ac(1) , respectively; Phe, L-phenylalanine; Cbz, benzyloxycarbonyl; Ac, acetyl) supported by theoretical calculations. The ECD spectra of the complexes depend on temperature that indicates the conformational mobility of the chiral ligands. Calculations of the VCD spectra were performed at ab initio (DFT) level of theory using Gaussian 03 [B3LYP functional combined with the LANL2DZ basis set for the dirhodium core and the 6-31G(d) basis set for other atoms]. The population-weighted sums of the computed VCD spectra of the conformers are in excellent agreement with the experimental VCD spectra. The combination of the VCD and ECD spectroscopic methods led us to the structural characterization of the complexes. PMID- 20928900 TI - Enantiomer self-disproportionation and chiral stationary phase based selective chiral separation of organic compounds. AB - In modern chromatography, chiral stationary phase (CSP) and enantiomer self disproportionation (ESD) are new inventions of packing material offer a guarantee for a successful enantiomeric separation. All CSPs were synthesized by chemical bonding of the relevant organic moieties onto a porous parent silica material for the separation of various racemic mixtures whereas achiral silica matrix was used for separation of non-racemic mixtures in ESD. Our present study provides to establish an understanding on the entire enantio-selective profile of amino alcohol based CSP as well as ESD and their precise utilization for high success rates for selective enantiomer separation with its appropriateness. PMID- 20928901 TI - Apple orchard pest control strategies affect bird communities in southeastern France. AB - Birds are regarded as appropriate biological indicators of how changes in agricultural practices affect the environment. They are also involved in the biocontrol of pests. In the present study, we provide an assessment of the impact of pest control strategies on bird communities in apple orchards in southeastern France. We compared the structure (abundance, species richness, and diversity) of breeding bird communities in 15 orchards under conventional or organic pest control over a three-year period (2003-2005). Pest control strategies and their evolution over time were characterized by analyzing farmers' treatment schedules. The landscape surrounding the orchards was characterized using a Geographic Information System. We observed 30 bird species overall. Bird abundance, species richness, and diversity were all affected by pest control strategies, and were highest in organic orchards and lowest in conventional orchards during the three study years. The pest control strategy affected insectivores more than granivores. We further observed a tendency for bird communities in integrated pest management orchards to change over time and become increasingly different from communities in organic orchards, which also corresponded to changes in treatment schedules. These findings indicate that within-orchard bird communities may respond quickly to changes in pesticide use and may, in turn, influence biocontrol of pests by birds. PMID- 20928902 TI - Law, ethics, religion, and clinical translation in the 21st century--a conversation with Il-Hoan Oh. Interview by Majlinda Lako, Alan Trounson and Susan Daher. PMID- 20928903 TI - Comparison of quadriceps inactivation between nerve and muscle stimulation. AB - We evaluated the use of direct muscle stimulation for quantifying quadriceps inactivation at different contraction levels as opposed to conventional twitch interpolation using nerve stimulation. Fourteen healthy volunteers were tested. Paired stimuli were delivered to the femoral nerve or to the quadriceps muscle belly during voluntary contractions ranging from 20% to 100% of maximum, and the amplitude of the superimposed doublet was quantified to investigate inactivation. Superimposed doublet for muscle and nerve stimulation, respectively between the range of 60% to 100% of maximum (e.g., at 100%, muscle stimulation was 14 +/- 5 Nm and nerve stimulation was 15 +/- 6 Nm). Despite higher current doses, muscle stimulation was associated with less discomfort than nerve stimulation (P < 0.05). Collectively, our data suggest that direct muscle stimulation could be used to assess quadriceps inactivation at maximal and quasi-maximal contraction levels as a valid alternative to motor nerve stimulation. PMID- 20928904 TI - Modified C7 neurotization for the treatment of obstetrical brachial plexus palsy. AB - Contralateral C7 transfer is used rarely in infants with obstetrical brachial plexus palsy (OBPP). We aimed to determine the efficacy of contralateral C7 transfer to two different recipient nerves in infants with OBPP. Between 2001 and 2005, 9 infants with brachial plexus root avulsions underwent nerve reconstruction using a modified C7 neurotization technique. In this procedure, the contralateral C7 root was transferred to both the musculocutaneous nerve and the median nerve on the affected side. The strength of the biceps muscles increased to M3 or M4 in 7 patients and to M2 in 2 patients. The median nerve transfers led to regained motor function and strength of wrist and finger flexors with improvement to M3 or M4 in 5 patients. All patients showed notable gains of sensory function. Contralateral C7 transfer to two different recipient nerves is a feasible and efficient approach in infants with OBPP. PMID- 20928905 TI - Confirmation that the specific SSLP microsatellite allele 4qA161 segregates with fascioscapulohumeral muscular dystrophy (FSHD) in a cohort of multiplex and simplex FSHD families. AB - The molecular defect in fascioscapulohumeral muscular dystrophy (FSHD) has proved difficult to explain. Although contraction within a polymorphic tandem repeat located at 4q35.2 is unequivocally associated with disease expression, the specific biological mechanism involved in the phenotype has yet to be resolved. Several studies have demonstrated that a specific 4q35.2-located haplotype (4qA161) is also closely associated with FSHD expression. Therefore, in this study we analyzed the haplotype association in a large cohort of sporadic and familial FSHD families from the UK. In all cases the affected individuals displayed the 4qA161 haplotype. PMID- 20928907 TI - Motor unit properties of biceps brachii during dynamic contractions in chronic stroke patients. AB - The aim of this study was to investigate motor unit (MU) characteristics of the biceps brachii during sinusoidal contractions in chronic stroke patients using high-density surface electromyography. Ten sinusoidal elbow flexion and extension movements were performed both passively and actively by 18 stroke patients and 20 healthy subjects. Motor unit action potentials (MUAPs) were extracted, and their root-mean-square value (RMS(MUAP)) was calculated. RMS(MUAP) was significantly larger in stroke than in healthy subjects. In both groups RMS(MUAP) was smaller during the stretch phase of passive movement than during active movement. The larger MUAPs indicate enlarged MUs, possibly as a result of reinnervation. The lower RMS(MUAP) values during passive stretch than during active movement indicates that the stretch reflex mainly activates smaller MUs, while a larger part of the MU pool can be recruited voluntarily. RMS(MUAP) may have added value for monitoring changes in peripheral MU properties after stroke. PMID- 20928906 TI - Effects of resistance exercise combined with essential amino acid supplementation and energy deficit on markers of skeletal muscle atrophy and regeneration during bed rest and active recovery. AB - Spaceflight and bed rest (BR) lead to muscle atrophy. This study assessed the effect of essential amino acid (EAA) supplementation and resistance training with decreased energy intake on molecular changes in skeletal muscle after 28-day BR and 14-day recovery. Thirty-one men (31-55 years) subjected to an 8 +/- 6% energy deficit were randomized to receive EAA without resistance training (AA, n = 7), or EAA 3 h after (RT, n = 12) or 5 min before (AART, n = 12) resistance training. During BR, myostatin transcript levels increased twofold in the AA group. During recovery, insulin-like growth factor-1 (IGF-1) mRNA increased in all groups, whereas Pax7, MyoD, myogenin, and MRF4 transcripts increased in AA only (all P < 0.05). MAFbx transcripts decreased twofold with AA and RT. Satellite cells did not change during BR or recovery. This suggests that EAA alone is the least protective countermeasure to muscle loss, and several molecular mechanisms are proposed by which exercise attenuates muscle atrophy during BR with energy deficit. PMID- 20928908 TI - Acquired amyloid neuropathy in a Portuguese patient after domino liver transplantation. AB - Familial amyloid polyneuropathy (FAP) is a progressive neuropathy with autonomic dysfunction. Domino liver transplantation (DLT), in which the liver of an FAP patient is transplanted into another patient, is routinely applied to compensate for the shortage of available organs. We report a patient who developed a clinical picture of FAP 9 years after a DLT from an FAP donor. Electrophysiological, neuropathological, and autonomic tests were administered. The patient presented with typical clinical features of FAP. Electrophysiological investigation confirmed a moderate sensorimotor axonal and autonomic neuropathy. Sural nerve biopsy confirmed the presence of amyloid deposits in the endoneurium. Skin biopsy at the ankle showed reduced intraepidermal nerve fiber density. Our report shows that FAP can develop in a recipient of an FAP liver. This suggests that careful longitudinal study is required to evaluate the risk of FAP polyneuropathy in patients who undergo domino liver transplantation. PMID- 20928909 TI - Symmetry of phrenic nerve motor response in amyotrophic lateral sclerosis. AB - To test for interside differences and ipsilateral correlation of compound muscle action potentials (CMAP) from muscles of the cervical region according to El Escorial criteria, we stimulated the phrenic, axillary, and ulnar nerves bilaterally in 67 patients with amyotrophic lateral sclerosis. The diaphragm CMAP was symmetric, but it did not correlate with deltoid or abductor digiti minimi (ADM) CMAPs. The deltoid CMAP in all groups and ADM CMAP in bulbar- and lower limb-onset patients showed significant interside correlation. The ADM CMAP is asymmetric in upper-limb-onset patients. Unilateral stimulation is sufficient to monitor the phrenic nerve response; its degree of CMAP decrease does not correlate with other cervical muscle involvement. PMID- 20928910 TI - Poisson distribution to analyze near-threshold motor evoked potentials. AB - Motor unit action potentials (MUAPs) evoked by repetitive, low-intensity transcranial magnetic stimulation can be modeled as a Poisson process. A mathematical consequence of such a model is that the ratio of the variance to the mean of the amplitudes of motor evoked potentials (MEPs) should provide an estimate of the mean size of the individual MUAPs that summate to generate each MEP. We found that this is, in fact, the case. Our finding thus supports the use of the Poisson distribution to model MEP generation and indicates that this model enables characterization of the motor unit population that contributes to near threshold MEPs. PMID- 20928911 TI - Experience with the Awaji Island modifications to the ALS diagnostic criteria. AB - Amyotrophic lateral sclerosis (ALS) remains a clinical diagnosis without validated biomarkers. To increase diagnostic sensitivity, an expert group modified the Airlie House diagnostic criteria and formulated new recommendations at a meeting on Awaji Island. Our retrospective analysis of patients referred over a 6-month period to the electromyography (EMG) laboratory for suspected motor neuron disease (MND) showed a higher agreement of the Awaji modifications than the Airlie House criteria with the clinical diagnosis of ALS. PMID- 20928912 TI - Multifactorial causes of irritating bladder symptoms in patients with Sjogren's syndrome. AB - AIMS Patients with Sjogren's syndrome (SS) are reported to have an increased severity of irritating bladder symptoms, including urinary frequency and urgency. The mechanism remains unclear. The aim of this study is to elucidate the possible etiologies underlying this problem. METHODS: Data from 23 female patients with SS (15 primary and 8 secondary) who were treated in the urology clinic for chronic, irritating bladder symptoms were studied. Evaluation of each subject is composed of lower urinary tract symptoms (LUTS), bladder diary entries, and urodynamic studies, which also included an ice water test (IWT) to detect the presence of a C-fiber mediated micturition pathway. Interstitial cystitis (IC) was diagnosed with post-hydrodilatation cystoscopic findings of glomerulations and a KCl test. RESULTS: These patients complained predominantly of overactive bladder symptoms (OAB), including frequency (n=20, 87%), nocturia (n=16, 66%), and urgency (n=12, 52%). Based on the aforementioned evaluations, four patients (17%) had polyuria with normal bladder function, nine patients (39%) had detrusor overactivity (DO), seven patients (32%) had bladder hypersensitivity (including two patients (9%) diagnosed with IC), and three patients (13%) had negative findings. Ice water instillation neither elicited novel involuntary contractions, both in those with or without DO. Five of the six patients (83%) with DO versus one of the four patients (25%) without DO responded to antimuscarinic therapy. CONCLUSIONS: Various factors contribute to the irritating bladder symptoms in patients with SS, with DO being predominant. The LUTS developed in patients with SS are not due to any specific single etiology and that each patient must be individually carefully evaluated. PMID- 20928913 TI - Intermittent catheterization with hydrophilic catheters as a treatment of chronic neurogenic urinary retention. AB - AIMS: Neurogenic bladder can be effectively managed with intermittent catheterization (IC) to improve or restore continence, but there is no consensus on which type of catheter is preferred. Hydrophilic catheters were developed to reduce urethral friction, thereby minimizing trauma and sticking, and making them more acceptable to the patient, and easier and safer to use. The objective of this article was to review the literature on the benefits of hydrophilic catheters in patients with neurogenic bladder. METHODS: A large body of experimental and observational evidence, including randomized controlled trials, was identified using PubMed. RESULTS: Compared with plastic catheters that have been manually lubricated with gel, hydrophilic catheters reduce urinary tract infection and microhematuria. Hydrophilic catheters are also associated with high levels of patient satisfaction because they are comfortable to use. CONCLUSIONS: There is a wealth of evidence, including randomized controlled trials, to support the benefits of hydrophilic catheters in terms of safety and quality of life, especially in men with spinal cord injury. More data are required for spina bifida, multiple sclerosis, and in women. Further research is warranted, especially large-scale and long-term robust comparisons of different types of catheter, and in well-defined and stratified populations. PMID- 20928914 TI - Secondary changes in bowel function after successful treatment of voiding symptoms with neuromodulation. AB - AIMS: Expanded indications for neuromodulation are continually being explored. We evaluated secondary changes in bowel function after successful neuromodulation for voiding symptoms. METHODS: Patients in our prospective neuromodulation database study with comorbid irritable bowel syndrome (IBS), constipation and/or diarrhea, or fecal incontinence (FI) at baseline were evaluated. Pre- and 3, 6, and 12 months post-operative measures included Interstitial Cystitis Symptom Index and Problem Index (ICSI-PI), bowel diaries (assessing bowel movement frequency; constipation, diarrhea, and FI episodes), and scaled global response assessments (GRA) ("markedly worse" to "markedly improved" bowel function). RESULTS: Most patients reporting secondary bowel problems (128/199; 64.3%) were female (89%; mean age 56 +/- 15.4 years). Primary voiding complaints were urgency/frequency (U/F) with or without urinary incontinence (n=74), interstitial cystitis/painful bladder syndrome (IC/PBS; n=43), and urinary retention (n=11). Secondary bowel complaints included constipation and/or diarrhea (49%), IBS (27%), and FI (23%). Urinary (ICSI-PI) scores improved after treatment (P<0.0001 for IBS and constipation/diarrhea; P=0.0021 for FI). Bowel diary data only indicated that mean FI episodes/day increased over time (P = 0.0100) in the FI group. Only the 12-month value (1.4 +/- 2.2; n=8) was significantly different from baseline (0.3 +/- 0.5; n = 18). On the GRA, only the IBS group consistently reported bowel function improvement versus worsening at each time point. Many reported no change. CONCLUSIONS: Studies have indicated that neuromodulation improves FI in carefully selected patients. The impact on other bowel conditions, including IBS, is unclear. Since voiding and bowel symptoms often coexist, it is crucial to fully evaluate all potential treatment benefits. PMID- 20928915 TI - Morphological changes in Daphnia galeata induced by a crustacean terpenoid hormone and its analog. AB - Terpenoid hormones in insects (i.e., juvenile hormones) have various effects on physiology, morphology, and behavior, producing a wide range of phenotypic variation. Recent studies have shown that sex determination in cladoceran crustaceans is under the strong control of a major terpenoid hormone of crustaceans, methyl farnesoatote (MF). It can be easily conceived that MF is also a major determinant of other traits in cladocerans. In the present study, morphological changes known as antipredatory responses in a cladoceran Daphnia galeata in response to exposure to MF and a juvenile hormone-mimicking pesticide, fenoxycarb, were investigated. Morphological change was studied using neonates less than 24 h old, exposed either to MF at the concentrations from 1.9 to 30 ug/L, or fenoxycarb at the concentrations from 13 to 200 ng/L, for 6 d. Animals developed a longer helmet at 1.9 ug/L of MF and 25 ng/L of fenoxycarb, and showed a concentration-dependent elongation. However, the tail spine was reduced in size in a concentration-dependent manner. Results of the present study not only give new insight into the mechanisms of inducible defenses in cladocerans, but also provide invaluable information to understand ecological and evolutionary consequences of endocrine disruption through the shift in biological interaction between predator and prey. PMID- 20928916 TI - Extraordinary stability of copper(I)-tetrathiomolybdate complexes: possible implications for aquatic ecosystems. AB - An extraordinary affinity of MoS42- for Cu accounts for Mo-induced Cu deficiency in ruminants (molybdenosis) and offers an approach to treating Wilson's disease in humans. Evidence of thiomolybdates in sulfidic natural waters, and possibly even as metastable traces in oxic natural waters, raises the question of how Cu Mo affinity might affect Cu availability or toxicity in aquatic ecosystems. Stabilities of inorganic Cu-MoS42- complexes are characterized and quantified here for the first time. Two remarkably stable Cu(I) dissolved complexes are identified (T = 23 degrees C +/- 2 degrees C): Cu2(HS)2MoS42- and Cu2S2MoS44-. In addition, the solubility constant for a precipitate (NH4CuMoS4) was measured. Under the extremely reducing conditions in rumen fluids, these complexes will greatly suppress Cu(+) activity, supporting prior conclusions about the mechanism of molybdenosis. In sulfidic natural waters, they help to prevent complete Cu impoverishment, as might otherwise occur by sulfide mineral precipitation. On the other hand, the complexes discovered here are HS--dependent and could not be important in oxic natural waters (with HS- concentrations < 10-9 M) even if metastable, biogenic MoS42- indeed were present as previously conjectured. PMID- 20928917 TI - Environmental risk assessment of three selective serotonin reuptake inhibitors in the aquatic environment: a case study including a cocktail scenario. AB - We present an environmental risk assessment of three selective serotonin reuptake inhibitors (SSRIs; citalopram, sertraline, and fluoxetine) in the aquatic environment based on two case scenarios. Abiotic and biotic degradation experiments and sorption estimates were used to predict environmental concentrations of three SSRIs from the wastewater of two psychiatric hospitals, the primary sector, and wastewater entering and leaving wastewater treatment plants (WWTPs). Assuming a sewage treatment retention time of 8 h, abiotic degradation was low, for all three SSRIs inhibitors, ranging between 0 and 2% for hydrolysis and 0 and 6% for photolysis. The biodegradation was also slow, ranging from 0 to 3% within an 8-h period. In untreated sewage, citalopram (CIT) and sertraline (SER) concentrations may be high enough to exert effects on the aquatic biota (CIT: 0.19-10.3 ug/L; SER: 0.14-17.1 ug/L). Removal of the pharmaceuticals is due primarily to sorption in the WWTP. Sertraline was estimated to have the highest concentrations in the sewage effluents, 4.4 and 19.9 ng/L for the two cases, respectively. In treated wastewater, individual SSRI concentrations are probably too low to exert effects on biota. By using concentration addition, a cocktail exposure scenario was estimated. The predicted concentration in the biota calculated from the cocktail effect was 0.05 and 0.16 nmol/g for the two cases, respectively, and SER was found to give the highest contribution to this cocktail effect. The results indicate that the concentrations in the wastewater effluents are one to two orders of magnitude lower than the concentrations likely to cause an effect in the aquatic biota. PMID- 20928918 TI - Isomer-specific accumulation of perfluorooctane sulfonate in the liver of chicken embryos exposed in ovo to a technical mixture. AB - Prior to its recent phaseout, perfluorooctane sulfonate (PFOS) was produced by electrochemical fluorination processes, which yielded technical mixtures composed of linear isomer (~65-79%) and several branched isomers (~21-35%). Because PFOS can biomagnify in wildlife, birds that occupy higher trophic levels are at increased risk of exposure. We hypothesized that the pharmacokinetic properties of PFOS are isomer-specific in developing chicken (Gallus gallus domesticus) embryos exposed to technical grade PFOS (T-PFOS). In the present study, T-PFOS was composed of 62.7% linear isomer (L-PFOS), and 37.3% branched isomer, including six mono(trifluoromethyl)-branched isomers and four bis(trifluoromethyl)-branched isomers. Concentrations of 0.1, 5, or 100 ug/g of T PFOS were injected into the air cell of chicken eggs prior to incubation. After pipping, compared with T-PFOS, the PFOS isomer profile in embryonic liver tissue for the 0.1 ug/g dose group showed 21% enrichment in the proportion of L-PFOS with a corresponding decrease in the proportion of branched isomers. Not all branched isomers were discriminated against at equal rates. The proportion of two mono(trifluoromethyl)-branched isomers and three bis(trifluoromethyl)-branched isomers decreased to a greater degree than other branched isomers. In contrast, the mono-branched isomer, P6MHpS, was overrepresented in the low-dose group. In the higher dose groups, L-PFOS was still enriched but only by approximately 10%, which indicated a dose-dependent change in isomer composition relative to T-PFOS. These results show that accumulation of PFOS in chicken embryo livers is dependent on the presence and position of branches on the alkyl backbone. This supports the hypothesis that the pharmacokinetics of PFOS are isomer-specific in biota, and may help explain why wildlife PFOS burdens are dominated by L-PFOS relative to T-PFOS mixtures. PMID- 20928919 TI - Pulse-dose application of chelated copper to a river for Didymosphenia geminata control: effects on macroinvertebrates and fish. AB - A 1-h pulse-dose of a chelated Cu formulation (GemexTM; New Zealand) was applied to a river to test efficacy against the invasive mat-forming diatom Didymosphenia geminata (didymo) and to provide information on nontarget species effects that could not be adequately predicted from laboratory and experimental mesocosm studies. Intensive sampling allowed characterization of doses achieved at multiple downstream locations, and concurrent application of rhodamine dye allowed quantification of dispersion, adsorption, and dilution processes. The target dose of 10 to 20 mg Cu/L for 60 min was achieved at least 0.9 km downstream at sites with contrasting levels of didymo mat development. Adsorptive losses of Gemex were 12%/km where didymo was mostly nonvisible and approximately 36%/km where substantial didymo mats were present. At 0.9 km downstream, Cu concentrations peaked at 12 mg/L, and didymo was <5% viable (down from 65-72%) for >=21 d posttreatment. Viability data indicate that elimination of nonvisible infestations is possible and that suppression of early-stage infestations (<=40% cover, <=4.5 mm thick) could be achieved after repeated applications. After a single Gemex application, no significant accumulation of Cu was noted in the sediments six weeks posttreatment, but Cu concentrations remained high in algal mats (109-367 mg/kg dry wt). Long-term effects on the nontarget algal, invertebrate, or fish communities were minimal, although significant localized trout mortalities, not predicted by prior laboratory exposures, occurred on the treatment day. Extended Gemex exposure in low-hardness waters might have caused the mortalities, although changes in chelated Cu speciation also possibly contributed. The present study integrates effects on resident biota with dosage data, including changes in pH, in a natural waterway. PMID- 20928920 TI - mRNA Expression and activity of ion-transporting proteins in gills of the blue crab Callinectes sapidus: effects of waterborne copper. AB - Waterborne Cu effects on the transcription of genes encoding ion-transporting proteins and the activities of these proteins were evaluated in gills of the blue crab Callinectes sapidus acclimated to diluted (20/00) and full (300/00) seawater. Crabs were exposed (96 h) to an environmentally relevant concentration of dissolved Cu (0.78 uM) and had their posterior (osmoregulating) gills dissected for enzymatic and molecular analysis. Endpoints analyzed were the activity of key enzymes involved in crab osmoregulation (sodium-potassium adenosine triphosphatase [Na(+)/K(+)-ATPase], hydrogen adenosine triphosphatase [H(+)-ATPase], and carbonic anhydrase [CA]) and the mRNA expression of genes encoding these enzymes and the sodium-potassium-chloride (Na(+)/K(+)/2Cl-) cotransporter. Copper effects were observed only in crabs acclimated to diluted seawater (hyperosmoregulating crabs) and were associated with an inhibition of the expression of mRNA of genes encoding the Na(+)/K(+)-ATPase and the Na(+)/K(+)/2Cl- cotransporter. However, Cu did not affect Na(+)/K(+)-ATPase activity, indicating that the gene transcription is downregulated before a significant inhibition of the enzyme activity can be observed. This also suggests the existence of a compensatory response of this enzyme to prevent osmoregulatory disturbances after short-term exposure to environmentally relevant Cu concentrations. These findings suggest that Cu is a potential ionoregulatory toxicant in blue crabs C. sapidus acclimated to low salinity. The lack of Cu effect on blue crabs acclimated to full seawater would be due to the reduced ion uptake needed for the regulation of the hemolymph osmotic concentration in full seawater (300/00). Also, this could be explained considering the lower bioavailability of toxic Cu (free ion) associated with the higher ionic content and dissolved organic matter concentration in high salinity (300/00) than in diluted seawater (20/00). PMID- 20928921 TI - An in situ toxicity assay with the local phytoplankton community. AB - The present study describes an approach for toxicity estimates based on the in situ exposure of the local phytoplankton community immobilized in calcium alginate beads. The assay was deployed in an acid mine drainage-impacted system, at a reference site and an impacted site. Abundances and growth rates of major taxonomic groups (green algae, flagellates, diatoms, and cyanobacteria) and of the entire community were measured. The ecological relevance of classical toxicity estimates was evaluated by performing in situ and laboratory assays with the standard species Pseudokirchneriella subcapitata and Chlorella vulgaris. Site waters were tested without and with nutrient enrichment, to discriminate toxic effects from those caused by nutrient limitations. Despite the occurrence of growth-limiting conditions for the local phytoplankton within the alginate matrix, an impact of the mine effluent on the community was detected. The growth of the community and of all taxonomic groups, except for the cyanobacteria, was less at the impacted site than at the reference site, although adding nutrients partially compensated for the effluent detrimental effects. Shifts in the community structure were also provoked by the mine effluent; decreases in the abundance of green algae were paralleled by increases in the abundance of flagellates and diatoms, but mainly of cyanobacteria. Effects on the growth of both standard species of green algae were in conformity with those on the local phytoplankton, probably because the latter was dominated by green algae. Although future improvements regarding the cell immobilization technique should be attempted, the proposed easy and inexpensive approach to assess both the growth and the structure of local phytoplankton communities will allow more environmentally realistic site-specific assessments of water quality. PMID- 20928922 TI - Layer-by-layer self-assembled multi-walled carbon nanotubes/silica microsphere composites as stationary phase for high-performance liquid chromatography. AB - Multi-walled carbon nanotubes (MWCNTs) were layer-by-layer assembled onto silica microspheres to form MWCNTs/SiO(2) composites and were characterized by surface analysis, elemental analysis, and contact angle. The composite was used as a stationary phase in HPLC for the separation of many kinds of aromatic compounds. The separation of polycyclic aromatic hydrocarbons (PAHs) affected by the number of MWCNTs layers on SiO(2) was investigated. Retention times and resolutions of PAHs were affected by the assembled layer of MWCNTs and the type of organic additive in the mobile phase. When the MWCNTs layer increased to 5 (MWCNTs/SiO(2) 5), PAHs can be completely separated. Aromatic compounds with different substituents can be well separated when only water was used as the eluent on the MWCNTs/SiO(2)-5 column. Decreasing the pH of the eluent can increase the retention factors of organic acids. Organic amines can also be separated with acetonitrile as organic additive, which were eluted in the order of the electronic cloud density of their aromatic rings. Comparing the MWCNTs/SiO(2)-5 column with a commercial HPLC column, it was clearly shown that the commercial column exhibited the characteristic of hydrophobicity, and the MWNCTs/SiO(2)-5 column exhibited the characteristic of a large pi-electron system. PMID- 20928923 TI - Carbon nanotubes-assisted polyacrylamide gel electrophoresis for enhanced separation of human serum proteins and application in liverish diagnosis. AB - The application of pore-gradient polyacrylamide gel electrophoresis (PG-PAGE) incorporated with carbon nanotube modified by Triton X-100 and carboxylation so as to improve the separation of human serum proteins is reported. The novel PG PAGE was made by adding water-soluble single-walled carbon nanotubes (CNTs) when preparing the polyacrylamide gel. Significant improvements in separation of complement C3 protein and haptoglobin (Hp) in human serum were achieved. It was estimated that the interactions between the hydrophilic groups on the proteins and the surface of the CNTs result in different adsorption kinetics of complement C3 and Hp subtype on the nanoparticles incorporated in the gel, thus enhancing the separation of the two proteins in serum. This new CNT matrix-assisted PG-PAGE method for enhanced separation of complement C3 and Hp in human serum was successfully applied to distinguish the samples from liverish patients and healthy people. PMID- 20928924 TI - Selectivity issues in targeted metabolomics: Separation of phosphorylated carbohydrate isomers by mixed-mode hydrophilic interaction/weak anion exchange chromatography. AB - Phosphorylated carbohydrates are important intracellular metabolites and thus of prime interest in metabolomics research. Complications in their analysis arise from the existence of structural isomers that do have similar fragmentation patterns in MS/MS and are hard to resolve chromatographically. Herein, we present selective methods for the liquid chromatographic separation of sugar phosphates, such as hexose and pentose phosphates, 2- and 3-phosphoglycerate, dihydroxyacetone phosphate and glyceraldehyde 3-phosphate, as well as glucosamine 1- and 6-phosphate utilizing mixed-mode chromatography with reversed-phase/weak anion-exchangers and a charged aerosol detector. The best results were obtained when the reversed-phase/weak anion-exchanger column was operated under hydrophilic interaction liquid chromatography elution conditions. The effects of various chromatographic parameters were examined and are discussed on the basis of a simple stoichiometric displacement model for explaining ion-exchange processes. Employed acidic conditions have led to the complete separation of alpha- and beta-anomers of glucose 6-phosphate at low temperature. The anomers coeluted in a single peak at elevated temperatures (>40 degrees C) (peak coalescence), while at intermediate temperatures on-column interconversion with a plateau in-between resolved anomer peaks was observed with apparent reaction rate constants between 0.1 and 27.8*10(-4) s(-1). Dynamic HPLC under specified conditions enabled to investigate mutarotation of phosphorylated carbohydrates, their interconversion kinetics, and energy barriers for interconversion. A complex mixture of six hexose phosphate structural isomers could be resolved almost completely. PMID- 20928925 TI - Surface-modified TiO(2) nanoparticles as affinity probes and as matrices for the rapid analysis of phosphopeptides and proteins in MALDI-TOF-MS. AB - We utilized three different types of TiO(2) nanoparticles (NPs) namely TiO(2) dopamine, TiO(2)-CdS and bare TiO(2) NPs as multifunctional nanoprobes for the rapid enrichment of phosphopeptides from tryptic digests of alpha- and beta casein, milk and egg white using a simplified procedure in MALDI-TOF-MS. Surface modified TiO(2) NPs serve as effective matrices for the analysis of peptides (gramicidin D, HW6, leucine-enkephalin and methionine-enkephalin) and proteins (cytochrome c and myoglobin) in MALDI-TOF-MS. In the surface-modified TiO(2) NPs based MALDI mass spectra of these analytes (phosphopetides, peptides and proteins), we found that TiO(2)-dopamine and bare TiO(2) NPs provided an efficient platform for the selective and rapid enrichment of phosphopeptides and TiO(2)-CdS NPs efficiently acted as the matrix for background-free detection of peptides and proteins with improved resolution in MALDI-MS. We found that the upper detectable mass range is 17 000 Da using TiO(2)-CdS NPs as the matrix. The approach is simple and straightforward for the rapid analysis of phosphopeptides, peptides and proteins by MALDI-MS in proteome research. PMID- 20928926 TI - Sol-gel synthesis, characterization and luminescence properties of SrMgAl2 SiO7:Eu2+ as a novel nanocrystalline phosphor. AB - In this research, a new SrMgAl(2) SiO(7):Eu(2+) phosphor was synthesized via the sol-gel method. The phase-forming processes were studied by thermogravimetric differential thermal analysis and X-ray diffraction technique. Scanning electron microscopy showed that there is uniform morphology and microstructure owing to the sol-gel route. Spectrophotometry and colorimetry analyses illustrated that, under short ultraviolet excitation, the main emission peak occurred at 421 nm and also a relatively pure blue color was observed that was ascribed to the 4f(6) 5d(1) ((2) D) -> 4f(7) ((8) S(7/2)) transition of Eu(2+) with color coordination of x = 0.187, y = 0.077. Finally, it was found that the color and phase purity of the synthesized powder increased as calcinations time increased. PMID- 20928927 TI - Muscle dysmorphia symptomatology during a period of religious fasting: a case report. AB - We present a case of muscle dysmorphia in a Muslim male, whose muscle dysmorphia symptomatology markedly escalated during a period of religious fasting, in which abstinence from food and liquid during daylight hours was endorsed. This case represents the first attempt to delineate the relative centrality of eating versus exercise practices in muscle dysmorphia presentations, and suggests that the maintenance of muscle dysmorphia is inclusive of a central eating component, irrespective of exercise status, lending support to the notion of conceptualising muscle dysmorphia within an eating disorder spectrum. Implications and further research are discussed. PMID- 20928928 TI - Cognitive processing of emotions in anorexia nervosa. AB - OBJECTIVE: This study attempts to explore the cognitive processing of emotions in anorexia nervosa (AN), based on the study of emotions felt and the assessment of meta-emotional abilities. METHOD: Eighty patients with AN and a control group of 80 healthy female participants were screened for anxiety, depression and alexithymia and completed an experimental task designed to analyse the emotional experience and meta-emotional abilities. RESULTS: Despite presenting higher levels of alexithymia, participants with AN demonstrated they were able to imagine emotions in hypothetical situations and to identify and label them. The group of patients with AN revealed feeling more intense and internally based negative emotions in comparison with the control group, but this emotional pattern tends to occur in situations associated with food and weight. CONCLUSIONS: Findings on meta-emotional abilities suggested no global deficit in emotional processing, but rather, specific sensitivities pertaining to situations relevant to AN. PMID- 20928930 TI - Managing social difficulties: roles and responsibilities of patients and staff. AB - BACKGROUND: Implementation of guidance on assessment and management of psychosocial and supportive-care problems or needs will be successful only if consideration is given to existing skills, experience and expectations of staff and patients. This study examines the roles and responsibilities of staff, patients and families in relation to management of social difficulties and proposes a pathway for response. METHODS: A qualitative study was performed using staff and patient interviews. Seventeen doctors and 16 nurses were interviewed using patient scenarios and a support service questionnaire. Patients (n = 41) completed a screening questionnaire (the Social Difficulties Inventory) and were interviewed. Interviews were audio-recorded, transcribed and subjected to a Framework analysis. Analysis examined (1) actions taken by staff and patients in response to social difficulties, (2) reasons given for action taken and (3) perceptions of staff and patients of who was responsible for taking action. RESULTS: Staff were confident concerning clinically related issues (i.e. mobility) but more hesitant concerning difficulties related to money, work and family concerns. Patients liked to cope with problems on their own where possible, would have liked information or support from staff but were uncertain how to access this. Results led to development of a hierarchy of interventions in response to detected social difficulties. DISCUSSION: For routine assessment of social difficulties, patients, nurses and doctors will have to work collaboratively, with nurses taking a lead in discussion. For specific clinically related problems doctors would play a more primary role. PMID- 20928931 TI - Fast-track surgery. More comfort, quicker recovery. PMID- 20928929 TI - Psychosocial risk profiles among black male Veterans Administration patients non adherent with colorectal cancer screening. AB - OBJECTIVE: This study identifies unique psychosocial characteristics among African American men that put the men at risk for non-adherence to colorectal cancer (CRC) screening (colonoscopy, sigmoidoscopy, and fecal occult blood tests (FOBT)). Subgroups sharing similar psychosocial characteristics may be targeted with specific intervention strategies aimed at increasing participation in screening, which could lead to increased early detection and decreased morbidity and mortality. METHODS: The male African American veterans in our sample (n = 260) had a mean age of 57.3 (SD = 7.3) years. Our study employs latent class analysis, a quantitative-based, audience segmentation method to identify homogeneous subgroups of African American men with similar psychosocial characteristics related to CRC screening, potentially in need of different health information and intervention strategies. Latent class regression was used to examine the relationships among latent class structure and demographic characteristics. RESULTS: There were four psychosocial risk classes across the three screening tests. A significant subset of men had psychosocial characteristics indicative of willingness to be screened for each test (colonscopy = 21.8%, sigmoidoscopy = 31.5%, and FOBT = 10.8%), although they were currently non-adherent. Men who received a past screening test, had greater than a high school education, or were married were more likely to be represented in a latent class indicative of being prepared for getting colonoscopy or sigmoidoscopy. Sociodemographic variables were unrelated to FOBT latent class structure. CONCLUSIONS: Segmenting our sample of male African American veterans based on psychosocial risk characteristics can inform the development of more precisely targeted interventions for African American men who are non-adherent for CRC screening. PMID- 20928932 TI - Improved iron levels may help chronic heart failure. PMID- 20928933 TI - Ultrasound imaging. Expanding uses for sound therapy. PMID- 20928934 TI - Recently, during the middle of the night, I scared my wife--and myself--when I fainted in the bathroom while urinating. When I saw my doctor about the episode, he said I might have a problem related to urination after a deep sleep. Would you please explain what causes this? PMID- 20928935 TI - Tolerance and B cells are hot topics at ATC. PMID- 20928936 TI - Development of a disposable magnetically levitated centrifugal blood pump (MedTech Dispo) intended for bridge-to-bridge applications--two-week in vivo evaluation. AB - Last year, we reported in vitro pump performance, low hemolytic characteristics, and initial in vivo evaluation of a disposable, magnetically levitated centrifugal blood pump, MedTech Dispo. As the first phase of the two-stage in vivo studies, in this study we have carried out a 2-week in vivo evaluation in calves. Male Holstein calves with body weight of 62.4-92.2 kg were used. Under general anesthesia, a left heart bypass with a MedTech Dispo pump was instituted between the left atrium and the descending aorta via left thoracotomy. Blood contacting surface of the pump was coated with a 2-methacryloyloxyethyl phosphorylcholine polymer. Post-operatively, with activated clotting time controlled at 180-220 s using heparin and bypass flow rate maintained at 50 mL/kg/min, plasma-free hemoglobin (Hb), coagulation, and major organ functions were analyzed for evaluation of biocompatibility. The animals were electively sacrificed at the completion of the 2-week study to evaluate presence of thrombus inside the pump,together with an examination of major organs. To date, we have done 13 MedTech Dispo implantations, of which three went successfully for a 2 week duration. In these three cases, the pump produced a fairly constant flow of 50 mL/Kg/min. Neurological disorders and any symptoms of thromboembolism were not seen. Levels of plasma-free Hb were maintained very low. Major organ functions remained within normal ranges. Autopsy results revealed no thrombus formation inside the pump. In the last six cases, calves suffered from severe pneumonia and they were excluded from the analysis. The MedTech Dispo pump demonstrated sufficient pump performance and biocompatibility to meet requirements for 1-week circulatory support. The second phase (2-month in vivo study) is under way to prove the safety and efficacy of MedTech Dispo for 1-month applications. PMID- 20928937 TI - Hedgehog pathway activation in chronic myeloid leukemia. AB - Chronic Myeloid Leukemia (CML) is a hematopoietic stem cell malignancy that is driven by the oncogenic BCR-ABL fusion protein, and for which treatment with ABL tyrosine kinase inhibitors (TKI) has yielded great success. While this is the case, BCR-ABL leukemic stem cells can persist despite TKI therapy, and efforts have intensified towards determining the molecular pathways that are critical for the maintenance of such cells. Recent studies indicate that aberrant Hedgehog (Hh) signaling plays a crucial role in the survival of the leukemic stem cell population. The Hh pathway displays crucial roles during embryonic development, tissue regeneration and repair in adults. Several mechanisms that lead to the aberrant activation of the Hh pathway have been identified in various cancers. Here we review in detail the discovery that Hh signaling governs the maintenance of the critical leukemia initiating cells or leukemic stem cells (LSCs) in BCR ABL-induced CML as well as discuss investigations on the role of Hh signaling in normal hematopoeisis. As inhibitors that directly target the positive Hh signal transducer Smoothened (SMO) have entered clinical trials, these findings offer a unique opportunity to potentially target the LSC population that is not eliminated with ABL tyrosine kinase inhibition therapy in CML. PMID- 20928938 TI - Does early (CNI) conversion lead to eternal (renal) salvation? PMID- 20928939 TI - A rapid and optimization-free procedure allows the in vivo detection of subtle cell cycle and ploidy alterations in tissues by flow cytometry. AB - Cell cycle alterations are fundamental to many physiological processes but their detection has proven difficult when cells are in the context of a tissue structure. Here we describe an easy, rapid and optimization-free procedure for obtaining high resolution cell cycle profiles from nearly all tissue types derived from mouse, human and sheep. Using a standardized and non-enzymatic procedure that is universally suitable for soft, solid and epithelial tissues alike, we reproducibly obtain cell cycle profiles of highest quality with half peak coefficients of variation below 2.0. We are able to reduce preparation derived debris to almost zero and efficiently exclude doublets, but retain multinucleated cells and apoptotic subG1-fragments. Applying this technique, we determine DNA-indices as small as 1.09 in tumor samples containing large necrotic areas and follow ploidy changes within different sections of individual tumors. Moreover, we examine tissue-specific cell cycle arrest and apoptosis as an in vivo stress response caused by radiation of mice. This method significantly improves the quality of DNA content analysis in tissues and extends the spectrum of applications. It allows assessing changes in ploidy, cell cycle distribution and apoptosis/necrosis in vivo and should be instrumental in all research that involves experimental animal models and/or patient biopsies. PMID- 20928941 TI - Ragging in medical colleges: call for adopting a zero-tolerance policy. PMID- 20928940 TI - Laterally attached kinetochores recruit the checkpoint protein Bub1, but satisfy the spindle checkpoint. AB - Kinetochore attachment to the ends of dynamic microtubules is a conserved feature of mitotic spindle organization that is thought to be critical for proper chromosome segregation. Although kinetochores have been described to transition from lateral to end-on attachments, the phase of lateral attachment has been difficult to study in yeast due to its transient nature. We have previously described a kinetochore mutant, DAM1-765, which exhibits lateral attachments and misregulation of microtubule length. Here we show that the misregulation of microtubule length in DAM1-765 cells occurs despite localization of microtubule associated proteins Bik1, Stu2, Cin8, and Kip3 to microtubules. DAM1-765 kinetochores recruit the spindle checkpoint protein Bub1, however Bub1 localization to DAM1-765 kinetochores is not sufficient to cause a cell cycle arrest. Interestingly, the DAM1-765 mutation rescues the temperature sensitivity of a biorientation-deficient ipl1-321 mutant, and DAM1-765 chromosome loss rates are similar to wild-type cells. The spindle checkpoint in DAM1-765 cells responds properly to unattached kinetochores created by nocodazole treatment and loss of tension caused by a cohesin mutant. Progression of DAM1-765 cells through mitosis therefore suggests that satisfaction of the checkpoint depends more highly on biorientation of sister kinetochores than on achievement of a specific interaction between kinetochores and microtubule plus ends. PMID- 20928942 TI - Nurse practitioners: worth considering in India? PMID- 20928944 TI - Weighing the options. PMID- 20928945 TI - Aids to the investigation of peripheral nerve injuries. Medical Research Council: Nerve Injuries Research Committee. His Majesty's Stationery Office: 1942; pp. 48 (iii) and 74 figures and 7 diagrams; with aids to the examination of the peripheral nervous system. By Michael O'Brien for the Guarantors of Brain. Saunders Elsevier: 2010; pp. [8] 64 and 94 Figures. PMID- 20928946 TI - Intrinsic viscosity of native and single-stranded T7 DNA and its relationship to sedimentation coefficient. AB - The intrinsic viscosity and sedimentation coefficient of native and single stranded T7 DNA have been determined at 250C as a function of ionic strength in neutral and alkaline NaCl. The relationship between [eta] and S0(20,w), is well represented by the Mandelkern-Flory equation over the entire range of conditions between 0.0013 and 1M Na+. An apparent discrepancy between the two methods at moderate to high ionic strengths is probably due to a change in V with ionic strength. It appears that [eta] is a more sensitive and reliable measure of molecular expansion for native DNA,but S0(20,w) is a better index of conformational change in single strands, since [eta] becomes too small to measure conveniently at high ionic strengths. At moderate to high ionic strengths, denaturation leads to a decrease in [eta], although unfolded single strands retain considerable viscosity. At sufficiently low ionic strength, the intrinsic viscosity of the single strands becomes higher than that of native DNA, and the effective volume of a single strand approaches that of the native molecule. PMID- 20928947 TI - Education and Imaging. Gastrointestinal: large antro-duodenal ulcers following hepatic selective internal radiotherapy. PMID- 20928948 TI - Education and Imaging. Gastrointestinal: persistent vomiting after laparoscopic cholecystectomy. PMID- 20928949 TI - Education and Imaging. Hepatobiliary and pancreatic: alveolar echinococcosis mimicking hepatocellular carcinoma. PMID- 20928950 TI - Proceedings of the XVth World Congress on Gestational Trophoblastic Diseases. November 12-15, 2009. Kochi, India. PMID- 20928952 TI - Abstracts of the NASPSPA (North American Society for the Psychology of Sport and Physical Activity) 2010 Conference, June 10-12, 2010. Tucson, Arizona, USA. PMID- 20928951 TI - Proceedings of the 2nd Croatian Congress on Side Effects of Psychotropics. March 11-14, 2010. Rovinj, Croatia. PMID- 20928953 TI - [Abstracts of the 40th Easter/Western Regional Meeting, Japanese Society of Nephrology. 2010. Japan]. PMID- 20928954 TI - [Abstracts of the 72nd Annual Meeting of the Japanese Society of Hematology. September 24-26, 2010. Yokohama, Japan]. PMID- 20928955 TI - [On the 50th birthday of Dr. Jindrich Spinar, CSc., FESC]. PMID- 20928956 TI - Unintended births: patterns by race and ethnicity and relationship type. AB - CONTEXT: Childbearing intentions vary by race and ethnicity and by relationship type. However, few studies have examined whether they differ by race and ethnicity within relationship type. METHODS: Data from the Early Childhood Longitudinal Study were used to examine the childbearing intentions of 9,100 mothers of a cohort of children born in 2001. Multivariate and multinomial regression analyses were conducted to examine whether relationship type (married, cohabiting or neither) helps explain racial and ethnic differences in childbearing intentions and whether associations between race and ethnicity and childbearing intentions vary by relationship type. RESULTS: Blacks were more likely than whites to have had an unintended birth (odds ratio, 2.5); the relationship held among married (2.6), but not unmarried, mothers. For most relationship types, black mothers had higher relative risks than whites of having had an unwanted birth, rather than an intended or a mistimed one. Asian married mothers were more likely than their white counterparts to have had an unwanted, rather than intended, birth (1.9). The odds of an unintended birth were lower among foreign-born Hispanic cohabiting women than among white cohabiting women (0.6), a finding driven by the lower risk of unwanted than of other births among foreign-born Hispanics (0.3-0.5). Few differences were apparent between native born Hispanics and white mothers. CONCLUSIONS: Racial and ethnic differences in childbearing intentions are frequently contingent on relationship context. Differences between whites and blacks are largely attributable to married women. Assessment of childbearing intendedness among Hispanics should take nativity into account. PMID- 20928959 TI - Material and lighting hues of object colour. AB - Observers can easily differentiate between a pigmented stain and the white surface that it lies on. The same applies for a colour shadow cast upon the same surface. Although the difference between these two kinds of colour appearance (referred to as material and lighting hues) is self-evident even for inexperienced observers, it is not one that has been captured by any colour appearance model thus far. We report here on an experiment supplying evidence for the dissociation of these two types of hue in the perceptual space. The stimulus display consisted of two identical sets of Munsell papers illuminated independently by yellow, neutral, and blue lights. Dissimilarities between all the paper/light pairs were ranked by five trichromatic observers, and then analysed by using non-metric multidimensional scaling (MDS). In the MDS output configuration, the Munsell papers lit by the same light made a closed configuration retaining the same order as in the Munsell book. The paper configurations for the yellow and blue lights were displaced transversally and in parallel to each other, with that of the neutral light located in between. The direction of the shift is interpreted as the yellow-blue lighting dimension. We show that the yellow-blue lighting dimension cannot be reduced to that of the reflected light. PMID- 20928958 TI - Medicaid payment for generic drugs: achieving savings and access. AB - Medicaid payment for generic prescription drugs has been a point of contention for the pharmacy industry over the past few years because of reimbursement formula changes contained in the Deficit Reduction Act (DRA) of 2005. The Patient Protection and Affordable Care Act (PPACA) includes provisions to resolve some of these issues. The DRA reduced the maximum amount the federal government would pay state Medicaid programs for generic drugs, and the Centers for Medicare & Medicaid services (CMS) final regulation, to implement the DRA provisions was met with a lawsuit from the pharmacy industry. An injunction by the federal district court, followed by a congressional moratorium, kept CMS from implementing the regulation and kept the pre-DRA formula for the generic drug payment limit in place. PPACA provisions increase maximum federal reimbursement levels for Medicaid generic drugs, but the impact on the pharmacy industry depends on CMS implementation and state policies. This paper examines Medicaid payment for generic drugs, the DRA and PPACA changes to generic drug reimbursement, the concerns of the pharmacy industry, and the potential impact on access. PMID- 20928960 TI - Trimetazidine activates paraoxonase. PMID- 20928961 TI - Effect of combining extended-release carvedilol and lisinopril in hypertension: results of the COSMOS study. PMID- 20928962 TI - Randomised trial of fentanyl anaesthesia in preterm babies undergoing surgery: effects on the stress response. AB - In a randomised controlled trial, preterm babies undergoing ligation of a patent ductus arteriosus were given nitrous oxide and d-tubocurarine, with (n = 8) or without (n = 8) the addition of fentanyl (10 micrograms/kg intravenously) to the anaesthetic regimen. Major hormonal responses to surgery, as indicated by changes in plasma adrenaline, noradrenaline, glucagon, aldosterone, corticosterone, 11 deoxycorticosterone, and 11-deoxycortisol levels, in the insulin/glucagon, molar ratio, and in blood glucose, lactate, and pyruvate concentrations were significantly greater in the non-fentanyl than in the fentanyl group. The urinary 3-methylhistidine/creatinine ratios were significantly greater in the non fentanyl group on the second and third postoperative days. Compared with the fentanyl group, the non-fentanyl group had circulatory and metabolic complications postoperatively. The findings indicate that preterm babies mount a substantial stress response to surgery under anaesthesia with nitrous oxide and curare and that prevention of this response by fentanyl anaesthesia may be associated with an improved postoperative outcome. PMID- 20928963 TI - VALO light curing unit. PMID- 20928964 TI - Penicillin VK. PMID- 20928965 TI - They giveth; they taketh away. AB - As the government tries to help employers with healthcare costs under the reform law, a study reveals workers are being forced to pay more for their coverage-a whopping 14% more this year, and a budget-busting 47% over the past five years. "It's the first time that I can remember seeing employers shifting all the costs to workers," said Drew Altman, president and CEO of the Kaiser Family Foundation. PMID- 20928966 TI - Blues eye green. Some 20 plans eligible for reinsurance program. PMID- 20928967 TI - Uneasy in the Big Easy. Removed hospital board members sue mayor. PMID- 20928968 TI - Hospitable hospitals. Winning entries in annual Design Awards keep focus on the patients experience. PMID- 20928969 TI - Largest for-profit hospital chains. Ranked by 2009 operating revenue (in millions) from most recent CMS Medicare hospital cost report. PMID- 20928970 TI - The 2006-2010 National Survey of Family Growth: sample design and analysis of a continuous survey. AB - OBJECTIVE: The National Survey of Family Growth (NSFG) collects data on pregnancy, childbearing, men's and women's health, and parenting from a national sample of women and men 15-44 years of age in the United States. This report describes the sample design for the NSFG's new continuous design and the effects of that design on weighting and variance estimation procedures. A working knowledge of this information is important for researchers who wish to use the data. Two data files are being released--the first covering 2.5 years (30 months) of data collection and the second after all data have been collected. This report is being released with the first data file. A later report in this Series will include specific results of the weighting, imputation, and variance estimation. METHODS: The NSFG's new design is based on an independent, national probability sample of women and men 15-44 years of age. Fieldwork was carried out by the University of Michigan's Institute for Social Research (ISR) under a contract with the National Center for Health Statistics (NCHS). In-person, face-to-face interviews were conducted by professional female interviewers using laptop computers. RESULTS: Analysis of NSFG data requires the use of sampling weights and estimation of sampling errors that account for the complex sample design and estimation features of the survey. Sampling weights are provided on the data files. The rate of missing data in the survey is generally low. However, missing data were imputed for about 600 key variables (called "recodes") that are used for most analyses of the survey. Imputation was accomplished using a multiple regression procedure with software called IVEware, available from the University of Michigan website. PMID- 20928971 TI - Antibiotics. NDM-1 how dangerous is the mutation? PMID- 20928972 TI - This really sucks. PMID- 20928974 TI - X-ray vision. How safe are airports' new low-radiation scanners? PMID- 20928973 TI - The womb. Your mother. Yourself. PMID- 20928975 TI - ["Investigacion Clinica": 50 years disseminating biomedical research]. AB - INVESTIGACION CLINICA was founded by the initiative of Americo Negrette, who became its first editor, and it has been published uninterruptedly since July 1960, with a quarterly frequency. The first issues consisted mainly of a collection of reviews of seminars held at the now called Instituto de Investigaciones Clinicas "Dr. Americo Negrette", Facultad de Medicina, Universidad del Zulia, its publisher. Very soon, original research results from this institution were included in the novel journal. In the 60's, papers on results obtained during the outbreaks of Venezuelan Equine Encephalitis present in the area, were prominent. Originally, the journal published 3-4 papers, but due to the increased number of contributions, in 2001, its format changed from 1/16 to 1/8, and now each number includes 11 original articles. Currently, INVESTIGACION CLINICA publishes 44 papers a year, in Spanish or English on different biomedical topics, from contributors all around the world. Progressively it has been included in different renowned indexes, such as PubMed/MEDLINE, Science Citation Index Expanded, Excerpta Medica, Tropical Diseases Bulletin, Copernicus, Scopus, Periodica, and several others. Besides, it can be found in open access through www.Scielo.org.ve, www.freemedicaljournals.com and in our new Web page: https://sites. google.com/site/revistainvestigacionesclinicas/home. Most papers published in INVESTIGACION CLINICA have been cited in the regional or foreign literature accumulating more than 1200 citations by now. For this particular issue, to celebrate the 50th anniversary of INVESTIGACION CLINICA, we have invited some of our more recent referees or authors to contribute with Reviews in their respective areas of expertise. PMID- 20928976 TI - [Fifty years studying hiperlipidemias: the case of familial combined hyperlipidemia]. AB - Familial combined hyperlipidemia (FCHL) is the most frequent primary dyslipidemia. Its manifestations include hypercholesterolemia, hypertriglyceridemia or the combination of both abnormalities. In spite of its high frequency, the proper diagnosis is rarely done. For this purpose, the measurement of a lipid profile is required in at least three first-degree relatives. A critical review of the current literature in this field is presented in this paper. Prospective studies have confirmed the atherogenicity of the disease. It is possible to identify the FCHL causal genes with the current methodology because it is an oligogenic disease. Based on the use of new technologies, several loci that regulate apolipoprotein B concentrations have been identified. In addition it was demostrated that variations of the activity or the expression of various nuclear factors (USF1, TCF7L2, HNF4alfa) have a major role in the pathophysiology of FCHL. These nuclear factors regulate the expression of multiple genes involved in the metabolism of lipids or carbohydrates. PMID- 20928977 TI - [Immune tolerance at 50 years from the Nobel Prize in Medicine and Physiology: a perspective as a mechanism of immune response against pathogens]. AB - The immune system has the capability of protection against infectious disease which is accomplished by an enormous repertoire of receptors specifically reactive to foreign antigens, but it is tolerant to self-antigens, establishing biological identity. The ability to discriminate between self and non-self is a central property of the immune system, by using complex network of cellular and molecular mechanisms in order to prevent autoimmunity; this function is called immune tolerance. Thus, the Interaction between immune system and antigens is required for the generation of tolerance and it is critical in different physiological and pathological conditions in order to limit the damage to self tissues. Since Medawar description, who showed that the tolerance is an acquired property playing a central role in the homeostasis, several mechanism has been proposed to explain it. It is accepted today that an important group of antigen specific cells called regulatory T cell, both natural and induced, are critical as a unifying mechanism to maintain self-tolerance. These suppressor lymphocyte subpopulations had shown to play an important role not only by controlling autoimmune disease but also in the pathogenesis of many chronic infectious diseases, either manipulated by the microorganism to escape from the immune system, or induced by the host to reduce inflammatory damage. This review has the intention of updating about modern concepts in immune tolerance mechanisms, with special emphasis played by Treg cell in the tolerance which is unquestionable induced during the course of chronic infections diseases. PMID- 20928978 TI - [Human papilloma virus and cervical cancer. An historical review on the development of research on cancer of the cervix uteri in Venezuela]. AB - The history on the relationship of VPH infection and cervical cancer was examined. Findings were initially reported in Maracaibo(1971), later in Mexico(1973) and thereafter several studies on the ultrastructure and immunohistochemistry of VPH infection and its role on cervical cancer were described. The ultrastructural findings of viral particles of HPV and their proteins, as well as their role in the incorporation of the viral genome to the human cervical cells were also described. Glycoproteins on the surface of cervical cells were reviewed and their importance on HPV infection was related to p16, blood group antigens and early genetic changes in the cell cycle with loss of heterozigocity, all of which, stimulated by the high risk HPV infection lead to cervical cancer. PMID- 20928979 TI - [Mind-body connection, parapsychological phenomena and spiritual healing. A review]. AB - Evidence regarding the influence of the mind on the body is abundant. Several mind-body healing procedures are currently being used, among them hypnosis, biofeedback, meditation, visualizations, management of emotions and prayer. Since the Big Bang, we are entangled with everything. This interaction would let individuals to communicate with the minds and bodies of others. The field of parapsychological research has provided a lot of information about significant events, including apparitions, communications with the dead, near-death experiences and out of the body experiences. It looks apparently evident, that consciousness can persist in the absence of brain function. According to the model that assumes that it is consciousness and not matter, the base of everything that exists, what survives after death is the "quantum monad" or spirit. It is said that spiritual cures are practiced by discarnate physicians who diagnose and prescribe conventional treatments, but very often they use unknown procedures based on the management of energy fields that are currently being studied by many physicists. Representative examples of the practice of spiritual medicine were the mediums Ze Arigo, George Chapman, Barbara Guerrero (Pachita) and presently the Brazilian medium John of God. Case reports of paranormal phenomena observed and studied by honest and serious scientists are very important for the advancement of parapsychology, because it has not been clearly established which approach, the qualitative or the quantitative, is more useful for the development of this field. PMID- 20928980 TI - [Amebiasis: implications of the recognition of Entamoeba dispar and the identification of Entamoeba moshkovskii in humans]. AB - The history of Entamoeba histolytica is very confuse and shows several wrong concepts about the parasite and its relationship with the host. The poor correlation between the prevalence of asymptomatic and symptomatic amebiasis originated the proposal of three explicative hypothesis, among them was the concept of Brumpt that E. histolytica comprised two morphologically identical species, E. dysenteriae and E. dispar. The application of modern molecular techniques irrefutably proved that E. histolytica was really a complex of two species, confirming the concept of Brumpt almost 7 decades later. Recent studies have identified in humans E. moshkovskii, morphologically indistinguishable from E. histolytica and E. dispar, a great genetic diversity within each of these species, and heterogeneity in virulence among E. histolytica strains. The redescription of E. dispar, and the recovery of E. moshkovskii from humans have had a major impact in our understanding of E. histolytica and amebiasis with important clinical and epidemiologic implications. This has led to the need of a reevaluation of the infection in terms of prevalence and morbidity in the global population and to study the geographic distribution, prevalence, and transmission pattern of E. histolytica strains in order to detect those with epidemiologic relevance and predict the risk of amebic disease in a population. PMID- 20928981 TI - [Role of the receptor for advanced glycation end products (RAGE) in inflammation]. AB - The receptor for advanced glycation end products (RAGE) is a transmembrane protein on the cellular surface that recognizes tridimensional molecules, instead of aminoacid sequences, making this molecule capable of interacting with diverse ligands. RAGE represents an important factor in innate immunity against pathogens, but it also interacts with endogenous ligands, resulting in chronic inflammation. RAGE signaling has been implicated in multiple human illnesses, including diabetes, atherosclerosis, arthritis, Alzheimer's disease, atherosclerosis and aging associated diseases. In addition to advanced glycation end products (AGE), RAGE has other important ligands such as: high mobility group box 1 protein (HMGB1, also termed amphoterin), the group of calcium binding cellular factors S100 (also termed calgranulin), amiloid beta peptides and Mac-1, a beta-2 integrin (CD1lb/CD18). Ligation of RAGE on the cellular surface triggers a series of cellular signaling events, including the activation and translocation to the nucleus of transcription factor NF-kappaB, leading to the production of pro-inflammatory cytokines, chemokines, adhesion molecules and oxidative stress and causing inflammation. More recent work has revealed the role of RAGE in inflammatory cell recruitment and extravasation of leukocytes across the endothelial barrier with further inflammatory events. Recent therapeutic strategies show that RAGE is an important target to treat RAGE activation associated diseases. PMID- 20928982 TI - [Fifty years of clinical use of warfarin]. AB - Warfarin is the most utilized oral anticoagulant for the long term prophylaxes of thrombosis. Its use has been increased as new clinical conditions, capable of leading to thrombosis, have been detected. Due to the special characteristics of warfarin, such as the variability of doses for each individual, the narrow margin between adequate and inadequate doses, interaction with multiple pharmaceutical products, interference of its action by vitamin K present in the diet and the possibility of hemorrhagic complications or thrombotic recurrence, this drug requires a very careful dosage and strict laboratory and clinical monitoring. Despite being in the market for more than de fifty years and its many disadvantages, warfarin has not been substituted for the new oral anticoagulants. In 1999, warfarin was positioned eleventh on the list of the most used medicines in the world. PMID- 20928983 TI - Early pregnancy failure: factors affecting successful medical treatment. AB - BACKGROUND: The results of medical treatment for early pregnancy failure are conflicting. OBJECTIVES: To determine whether gestational sac volume measurement as well as other variables can predict the success rate of medical treatment for early pregnancy failure. METHODS: The study group comprised 81 women diagnosed with missed abortion or anembryonic pregnancy who consented to medical treatment. Demographic data were collected and beta-human chorionic gonadotropin level was documented. Crown-rump length and the sac volume were measured using transvaginal ultrasound. TVU was performed 12-24 hours after intravaginal administration of 800 micro g misoprostol. If the thickness of the uterine cavity was less than 30 mm, the women were discharged. If the sac was still intact or the thickness of the uterine cavity exceeded 30 mm, they were offered an additional dosage of intravaginal misoprostol or surgical uterine evacuation. RESULTS: Medical treatment successfully terminated 32 pregnancies (39.5%), 30 after one dose of misoprostol and 2 after two doses (group A); 49 underwent surgical evacuation (group B), 47 following one dose of misoprostol and 2 following two doses. There were no significant differences between the groups in age and gestational week. Gestational sac volume did not differ between groups A and B (10.03 and 11.98 ml respectively, P = 0.283). Parity (0.87 and 1.43, P = 0.015), previous pregnancies (2.38 and 2.88, P = 0.037), and betahCG concentration (6961 and 28,748 mlU, P = 0.013) differed significantly between the groups. CONCLUSIONS: Gestational sac volume is not a predictor of successful medical treatment for early pregnancy failure. Previous pregnancies and deliveries and higher betahCG concentration negatively affect the success rate of medical treatment. PMID- 20928984 TI - Fast track evaluation of patients with acute chest pain: experience in a large scale chest pain unit in Israel. AB - BACKGROUND: Many patients present to the emergency department with chest pain. While in most of them chest pain represents a benign complaint, in some patients it underlies a life-threatening illness. OBJECTIVES: To assess the routine evaluation of patients presenting to the ED with acute chest pain by means of a cardiologist-based chest pain unit using different noninvasive imaging modalities. METHODS: We evaluated the records of 1055 consecutive patients who presented to the ED with complaints of chest pain and were admitted to the CPU. After an observation period and according to the decision of the attending cardiologist, patients underwent myocardial perfusion scintigraphy, multidetector computed tomography, or stress echocardiography. RESULTS: The CPU attending cardiologist did not prescribe non-invasive evaluation for 108 of the 1055 patients, who were either admitted (58 patients) or discharged (50 patients) after an observation period. Of those remaining, 444 patients underwent MDCT, 445 MPS, and 58 stress echocardiography. Altogether, 907 patients (86%) were discharged from the CPU. During an average period of 236 +/- 223 days, 25 patients (3.1%) were readmitted due to chest pain of suspected cardiac origin, and only 8 patients (0.9%) suffered a major adverse cardiovascular event. CONCLUSIONS: Utilization of the CPU enabled a rapid and thorough evaluation of the patients' primary complaint, thereby reducing hospitalization costs and occupancy on the one hand and avoiding misdiagnosis in discharged patients on the other. PMID- 20928985 TI - Measurement of electrical resistance of dermal-visceral zones as a diagnostic tool for gynecologic disorders. AB - BACKGROUND: Non-invasive screening tests may allow early diagnosis and prompt treatment, thereby potentially reducing morbidity and mortality and reducing costs for the community. This may be especially important for gynecologic pathologies that are difficult to promptly diagnose, such as endometriosis or ovarian cancer. OBJECTIVES: To evaluate the reliability of measuring skin resistance using the Medex Test for screening and diagnosis of gynecologic pathologies in a blinded single-center study. METHODS: We enrolled 150 patients: 59 with a functional disorder and 91 with an organic disease. Measurements were carried out in all patients and the results were analyzed separately by a second physician who was blinded to the patients' diagnosis. RESULTS: A high correlation was found between the clinical diagnosis and the results of the measurement of electrical skin resistance, with a specificity of 76.3% (45/59) for functional disorders and a sensitivity of 85.7% (78/91) for organic disorders, positive predictive value of 84.8% (78/92) and negative predictive value 77.6% (45/58). The kappa value for the results was 0.622, representing a value much better than expected randomly. CONCLUSIONS: The Medex Test has a good specificity and a high sensitivity for the diagnosis of gynecologic disorders. Further prospective studies are needed to validate these preliminary findings. PMID- 20928986 TI - Influenza vaccination coverage determinants among employees of the Nazareth Hospital in Israel. AB - BACKGROUND: Health care workers bear the risk of both contracting influenza from patients and transmitting it to them. Although influenza vaccine is the most effective and safest public health measure against influenza and its complications, and despite recommendations that HCWs be vaccinated, influenza vaccination coverage among them remains low. OBJECTIVES: To characterize influenza vaccination coverage and its determinants among employees in an Arab hospital in Israel. METHODS: An anonymous self-administered questionnaire was distributed among employees involved in patient care in the winter of 2004-2005 at Nazareth Hospital in Israel. The questionnaire included items related to health demographic characteristics, health behaviors and attitudes, knowledge and attitude concerning influenza vaccination, and whether the respondent had received the flu shot during the previous winter or any other winter. RESULTS: The overall rate of questionnaire return was 66%; 256 employees participated in the study. The immunization coverage rate was 16.4%, similar to that reported for other hospitals in Israel. Logistic regression analysis demonstrated that influenza vaccination coverage was significantly and solely associated with the presence of chronic illness and influenza vaccination. CONCLUSIONS: Influenza vaccination coverage among Nazareth Hospital health care workers was low. They did not view themselves as different from the general population with regard to vaccination. Three years after the study, an intervention program was launched with the aim of increasing knowledge on the efficacy and safety of the vaccine; it stressed the importance of vaccinating HCWs and administering the vaccine at the workplace. The program led to a 50% increase in vaccination coverage. PMID- 20928987 TI - Efficacy of multiple micronutrient supplementations on child health: study design and baseline characteristics. AB - BACKGROUND: The rates of anemia in children in southern Israel are high despite the current prevention strategy. A daily dose of "Sprinkles" (SuppleForte, Heinz, Canada), a micronutrient home supplementation, was proven effective for the treatment of anemia worldwide. OBJECTIVES: To assess the efficacy of Sprinkles, a novel supplementation formulation, in the primary prevention of anemia in infants who have free access to health care services. METHODS: A two-arm open-labeled cluster randomized controlled clinical trial was performed in 6 month old Bedouin and Jewish infants. The Sprinkles arm received sachets with iron, vitamins A and C, folic acid and zinc, and the control arm received standard treatment (liquid iron and vitamins A and D). The infants were from families attending Mother and Child Health clinics during 2005-2007. Intervention and follow-up were conducted for babies aged 6-12 months. Health outcomes (hematologic and nutritional indicators, growth parameters, morbidity rates) were evaluated at 12 and 18 months. RESULTS: The final study population numbered 621 infants (328 Bedouin and 293 Jewish); of the parents approached 88.5% agreed to participate. Hemoglobin > 11 g/dl was found in 55% of Bedouin and 40% of Jewish infants (P < 0.01). Bedouin infants had significantly lower serum concentration of iron, folic acid and zinc. All background, hematologic and micronutrient indicators were similar in the two study arms except for a slightly but not clinically significant difference in hemoglobin and hematocrit levels in Bedouins. CONCLUSIONS: Our findings indicate the need to improve the micronutrient status of infants living in the Negev. A cluster randomized trial in MCH clinics is a feasible option. PMID- 20928988 TI - Peritonitis in a pediatric dialysis unit: local profile and implications. AB - BACKGROUND: Peritonitis is a major complication of chronic peritoneal dialysis therapy. It is recommended that each center monitor infection rates in order to define the local microbiological profile and implement an appropriate empiric antibiotic regimen. OBJECTIVES: To analyze the microbiologic profile of peritonitis in our pediatric dialysis unit and identify local predisposing factors. METHODS: In this retrospective study we reviewed the files of children treated with chronic PD during the 10 year period 1997-2007. RESULTS: Eighty peritonitis episodes were recorded in 29 children (20 male, 9 female) aged 0.1 18.5 years (median 11.75) treated with peritoneal dialysis for 6-69 months (median 19) for a total of 578 patient-months. The annual peritonitis rate was 1.66/patient. The main pathogens were coagulase-negative Staphyloccocus (32.5%) and Pseudomonas spp. (16%), which were also cultured in most cases (64-69%) from the exit site during the 3 months preceding peritonitis. No peritonitis occurred in 31% of the patients (median age 12.5 years). All patients less than 5 years old had at least one peritonitis episode. Contaminating conditions (gastrostomy, enuresis, diaper use), found in 44% of the study group, and first infection within 6 months from starting PD were significantly associated with an increased peritonitis rate (P = 0.01, P = 0.009, respectively). Recurrent peritonitis led to a switch to hemodialysis in 18% of patients. There were no deaths. CONCLUSIONS: The risk factors for peritonitis in our study were: first infection within less than 6 months from starting treatment, Pseudomonas exit-site colonization, and contaminating conditions (gastrostomies, diaper use, enuresis). These susceptible subgroups as well as very young age (< 5 years) at starting PD should be especially targeted during training of caregivers and follow-up to prevent later complications. PMID- 20928989 TI - Breast cancer HER2 equivocal cases: is there an alternative to FISH testing? A pilot study using two different antibodies sequentially. AB - BACKGROUND: HER2 is an important prognostic and predictive marker in invasive breast cancer. It is currently assessed by immunohistochemistry for protein over expression and by fluorescence in situ hybridization for gene amplification. The immunohistochemistry-equivocal cases (2+) are currently retested by FISH to determine eligibility for trastuzumab treatment. Retesting by FISH significantly raises the cost of patient management and sometimes delays treatment. The 4B5 is a new, FDA-approved, rabbit monoclonal antibody for HER2 testing. OBJECTIVES: To examine the reliability of 4B5 IHC HER2 testing in cases found by CB11 IHC to be HER2 status equivocal. METHODS: Twenty-eight invasive breast cancer cases, with an equivocal HER2 status by CB11 IHC, were retested by the 4B5 antibody as well as by FISH analysis. The scoring was performed using the same guidelines as HercepTest and was correlated with the FISH ratio. RESULTS: Of the original 28 CB11 clone designated equivocal cases, 14 (50%) showed negative HER2 staining using the 4B5 clone (HercepTest score 0 and 1+). Five cases (18%) proved to be positive (HercepTest score 3+) and 9 cases (32%) remained equivocal (HercepTest score 2+). The corresponding FISH ratio results showed that all 4B5 negative cases were negative by FISH testing, with a negative predictive value of 100%; 4 of 5 of the 4B5-positive cases were positive by FISH testing, with a positive predictive value of 80%. One 4B5-positive case was borderline-high (2.2 ratio) by FISH. The correlation between 4B5 IHC and FISH was statistically significant (P = 0.0013) by chi-square test. CONCLUSIONS: Sequential testing by 4B5 IHC could greatly reduce the need for FISH testing in cases considered HER2 equivocal by CB11 IHC. PMID- 20928990 TI - Routine chest X-ray on hospital admission: does it contribute to diagnosis or treatment? AB - BACKGROUND: In many hospitals a routine chest X-ray is performed on admission. There are, however, scant data regarding its usefulness in contemporary patient populations. METHODS: We studied consecutive patients admitted during a 2 month period to a single department of medicine, where hospital policy mandates performing an admission CXR. Two senior clinicians not involved in the care of these patients assessed the discharge summaries for a clinical indication to perform CXR on admission, as well as its contribution to patient management (major positive, major negative, minor positive, or no contribution). RESULTS: There were 675 patients whose mean age was 64.5 +/- 17.2 years. In 19.6% (130 cases) CXR was not performed. Of the 545 CXRs done, 260 (48%) were normal. In only 128 (23.5%) did the admission CXR make a major positive contribution to diagnosis or treatment. In 61 (11.2%) it provided a minor positive contribution and in 153 (28.1%) a major negative contribution. In 184 patients (33.8%) the CXR did not affect either diagnosis or management. It made a major positive contribution to management in patients for whom there was an indication for performing the X-ray (odds ratio 10.3, P < 0.0005) and in those with a relevant finding on physical examination (OR 1.63, P = 0.110). For the 329 patients who had neither a clinical indication for performing a CXR nor an abnormal chest examination the admission CXR contributed to patient management in only 12 cases (3.6%). CONCLUSIONS: A routine admission CXR has a significant impact on patient management only in those patients in whom there are relevant findings on physical examination or a clear clinical indication for performing the test. There is no need to routinely order CXR on admission to hospital. PMID- 20928991 TI - Splenic infarction: an update on William Osler's observations. AB - BACKGROUND: Osler taught that splenic infarction presents with left upper abdominal quadrant pain, tenderness and swelling accompanied by a peritoneal friction rub. Splenic infarction is classically associated with bacterial endocarditis and sickle cell disease. OBJECTIVES: To describe the contemporary experience of splenic infarction. METHODS: We conducted a chart review of inpatients diagnosed with splenic infarction in a Jerusalem hospital between 1990 and 2003. RESULTS: We identified 26 cases with a mean age of 52 years. Common causes were hematologic malignancy (six cases) and intracardiac thrombus (five cases). Only three cases were associated with bacterial endocarditis. In 21 cases the splenic infarction brought a previously undiagnosed underlying disease to attention. Only half the subjects complained of localized left-sided abdominal pain, 36% had left-sided abdominal tenderness; 31% had no signs or symptoms localized to the splenic area, 36% had fever, 56% had leukocytosis and 71% had elevated lactate dehydrogenase levels. One splenectomy was performed and all patients survived to discharge. A post hoc analysis demonstrated that single infarcts were more likely to be associated with fever (20% vs. 63%, p < 0.05) and leukocytosis (75% vs. 33%, P = 0.06) CONCLUSIONS: The clinical presentation of splenic infarction in the modern era differs greatly from the classical teaching, regarding etiology, signs and symptoms. In patients with unexplained splenic infarction, investigation frequently uncovers a new underlying diagnosis. PMID- 20928992 TI - Attitudes of emergency department staff toward family presence during resuscitation. AB - BACKGROUND: While family presence during resuscitation has been researched extensively in the international and especially American medical literature, in Israel this subject has rarely been researched. Because such policies have become common practice in many countries, it is important to investigate the attitudes of health care staff in Israeli emergency departments to better understand the potential implication of adopting such policies. OBJECTIVES: To examine the attitudes of the physicians and nurses in the ED of Soroka Medical Center to FPDR. METHODS: The methods we used were both qualitative (partly structured open interviews of 10 ED staff members from various medical professions) and quantitative (an anonymous questionnaire that collected sociodemographic, professional, and attitude data). RESULTS: The qualitative and quantitative results showed that most staff members opposed FPDR. The main reasons for objecting to FPDR were concern about family criticism, the added pressure that would be put on the staff members, fear of lawsuits, fear of hurting the feelings of the families, and the danger of losing one's "objectivity" while treating patients. Physicians objected more strongly to FPDR than did nurses. CONCLUSIONS: More research is needed on FPDR in Israel, including an examination of its medical, ethical, legal and logistic aspects. In addition to the views of the medical staff, the attitudes of patients and their families should also be examined. PMID- 20928993 TI - Is chloramphenicol making a comeback? AB - BACKGROUND: Due to increasing antimicrobial resistance there has been renewed interest in old drugs that have fallen into disuse because of toxic side effects. OBJECTIVES: To evaluate the susceptibility profile, in our hospital, of Enterobacteriaceae and Streptococcus pneumoniae isolates to chloramphenicol and to compare them with the susceptibility to amoxicillin-clavulanate. METHODS: All isolates of Enterobacteriaceae and S. pneumoniae recovered in our lab during a one year period were tested for susceptibility to chloramphenicol and amoxicillin clavulanate or penicillin, respectively. RESULTS: Of 413 Enterobacteriaceae isolates, 182 (44.1%) were resistant to amoxicillin-clavulanate, but only 76 (18.4%) were resistant to chloramphenicol. Of 189 isolates of S. pneumoniae, 4 (2.1%) were highly resistant to penicillin and 73 (38.8%) were partially resistant, while only 2 (1.1%) were resistant to chloramphenicol. None of the 24 S. pneumoniae isolates causing invasive diseases exhibited resistance to chloramphenicol CONCLUSIONS: In an era of increasing resistance to many antibiotic preparations, chloramphenicol might have a role in the treatment of intraabdominal and respiratory tract infections. PMID- 20928994 TI - Misoprostol for early pregnancy failure. PMID- 20928995 TI - The chest pain unit: doing it right or overdoing it? PMID- 20928996 TI - Patent foramen ovale: when the innocent bystander becomes a medical threat. PMID- 20928997 TI - Right-to-Left shunting due to a patent foramen ovate during right ventricular infarction. PMID- 20928998 TI - Mitral valve abscess due to infective endocarditis detected by computed tomography. PMID- 20928999 TI - Microaneurysms in the diabetic human heart. PMID- 20929000 TI - Celiac disease in Pakistan: challenges and opportunities. PMID- 20929001 TI - Adolescent knowledge and awareness about AIDS/HIV and factors affecting them in Bangladesh. AB - BACKGROUND: Adolescents are more vulnerable than adults of unplanned pregnancies, sexually transmitted diseases and HIV/AIDS. Among the adolescents, girls are more vulnerable to STDs including HIV/AIDS. Their knowledge about different diseases is very poor. This paper investigated adolescent's knowledge about sexually transmitted diseases including HIV/AIDS, its mode of transmission and ways of its prevention. METHODS: Cross sectional study design was adopted for this study. A multistage cluster sampling technique was used to select the sample. Data on 3362 female adolescents irrespective of their marital status was analyzed. RESULTS: The study found that a large proportion of adolescents were not aware about sexually transmitted diseases and AIDS. More than half (54.8%) of the adolescents ever heard about AIDS respectively. On an average, about one tenth of them had better knowledge on AIDS in terms of mode of transmission and prevention. The multivariate logistic regression analysis revealed that adolescent age, years of schooling and knowledge on STDs appeared to be important predictors of the awareness about AIDS (p < 0.05). CONCLUSIONS: Useful and fruitful media campaigns to educate the adolescents regarding the health consequences of STDs including HIV/AIDS and integrated approach is strongly suggested for creating knowledge and awareness to control the spread of HIV and AIDS among young people in Bangladesh. PMID- 20929002 TI - Gynaecomastia: management in a developing country. AB - BACKGROUND: Gynaecomastia is a benign enlargement of male breast. It is common in the general population, resulting from various pathophysiological mechanisms. The aim of this study was to describe the presentation and outcome of treatment for gynaecomastia at a University Hospital in Pakistan. METHODS: A three year retrospective study was carried out of one hundred men with gynaecomastia. Patients were evaluated in detail clinically and by appropriate investigations. They were counselled and kept on hormonal therapy for three months. Surgery was considered for patients with long standing gynaecomastia, failed medical therapy and for cosmetic reasons. Post operative complications and patient's satisfaction was assessed. RESULTS: Most (90%) cases were idiopathic. Other causes were liver cirrhosis in 4 cases, testicular tumour in two, thyrotoxicosis in one and drug induced (use of cimetidine and Kushta) in two. Carcinoma of the breast was diagnosed in one patient. Most of the patients had bilateral, non tender lump in the breast. Three cases of idiopathic gynaecomastia resolved on danazol. Eighty eight cases underwent surgical treatment. The mean age of patients who underwent surgery (n = 88) was 30.5 +/- 9.59 years. Most of the patients belonged to 21-30 years age group. Major indications for surgery were failure of medical treatment (45.5%) and cosmetic reasons (34.0%). Mean operating time for subcutaneous mastectomy was 42.2 +/- 3.70 (36-48) minutes. Mean hospital stay after subcutaneous mastectomy was 5.2 +/- 2.44 (2-10) days. The only postoperative complication noted was wound infection (24%). Seventy-two (81.8%) were satisfied with the results of their surgical treatment. CONCLUSION: Gynaecomastia is the common condition affecting male breasts and most common cause of gynaecomastia is idiopathic. Secondary gynaecomastia may regress in size by treating the primary cause. Idiopathic gynaecomastia do not respond to danazol so they needed surgical treatment. Subcutaneous mastectomy through a periareolar skin incision is a valid procedure for treatment for gynaecomastia and provides satisfactory cosmetic results. PMID- 20929003 TI - Characteristics of infertile patients with ovulatory dysfunction and their relation to body mass index. AB - BACKGROUND: Ovulatory dysfunction is a group of disorders with variable clinical presentations occasionally having serious long-term adverse effects. It accounts for 30% of female fertility problems. Evidence suggests an association between an individual's weight and disorders of ovulation. The objective of our study was to describe the clinical and hormonal profile of subfertile women with ovulatory dysfunction in relation to their body mass index (BMI). METHODS: This prospective, descriptive study was carried out in Mother and Child Health Centre, PIMS, Islamabad and Railway hospital, Rawalpindi from April 2001 to March 2007. One hundred & thirty eight infertile patients with ovulatory dysfunction were included. The clinical data including BMI of each patient was recorded in addition to reports of investigations comprised of cervical smear, pelvic ultrasound and hormonal profile. RESULTS: Primary infertility was found in 61% while secondary in 39% of the patients. The mean age was 29 years and mean duration of infertility was 6 years. Menstrual pattern was normal in 56.5%. BMI was normal in 30.4% while most patients were overweight and obese. Prolonged cycles, history of systemic endocrine disorders, abnormal vaginal discharge, hirsutism, polycystic ovarian morphology and hormonal abnormalities were more frequent in patients with increased BMI. During the study period, 21.7% of the women conceived. CONCLUSION: Infertile patients with ovulatory dysfunction present more frequently with primary infertility. They usually have higher than required BMI. Oligomenorrhoea amenorrhoea, hirsutism and hormonal abnormalities are more frequent in overweight than infertile patients with ovulatory dysfunction having a normal BMI. PMID- 20929004 TI - Nutritional iron deficiency in women of child bearing age--what to do? AB - BACKGROUND: Iron deficiency is the most common aetiology of anaemia worldwide and has several risk factors. Although iron deficiency anaemia (IDA) can occur at any age, women from reproductive age group are particularly vulnerable to develop IDA due to increased nutritional demand during pregnancy. Objective was to determine the frequency and nutritional risk factor of iron deficiency anaemia in women of child bearing age. This descriptive, cross sectional study was conducted from October 2005 to March 2006 at the Department of Medicine, Ward-5, and out patients department of Jinnah Postgraduate Medical Centre, Karachi. METHOD: Two hundred non-pregnant females of child bearing age were included in the study; 100 with no previous pregnancy and remaining 100 with at least one prior history of pregnancy. All the relevant information, i.e., demographic and socioeconomic was collected through a questionnaire. RESULTS: Two hundred patients with signs and symptoms of anaemia were recruited. Out of them 89 patients were found to be having iron deficiency anaemia in various age groups. Results also showed that dietary habit of patients was one of the causative factors leading to iron deficiency anaemia. CONCLUSION: To overcome iron deficiency anaemia a thorough and comprehensive strategy is required, i.e., educating the subjects to consume food rich in iron, community based program, monitoring severely anaemic cases and their treatment. PMID- 20929005 TI - Effect of race, gender and age on thyroid and thyroid stimulating hormone levels in North West Frontier Province, Pakistan. AB - BACKGROUND: Thyroid is one of the ductless endocrine gland, which is located immediately below the larynx on either side of and anterior to the trachea. The principal hormones of thyroid gland are thyroxine (T4) and triiodothyronine (T3). The current study was carried out to investigate the impact of race, gender and area on the levels of Thyroxine (T4), Triiodothyronine (T3) and Thyroid Stimulating Hormone (TSH) in normal healthy individuals. METHODS: Serum levels of T4, T3 and TSH in 498 normal healthy individuals belonging to different districts of North West Frontier Province, Pakistan, were examined. Serum T4 and T3 were analysed by Radio Immuno Assay (RIA) method whereas TSH was estimated by Immunoradiometric assay (IRMA) method. RESULTS: Levels of T4, T3 and TSH ranged from 53 to 167 etamol/L, 0.6 to 3.1 etamol/L and 0.3-4.8 microIU/L respectively. The levels of these hormones show significant change from the reference values that are used in clinical laboratories as well as in Institute of Radiotherapy and Nuclear Medicine (IRNUM), Peshawar, Pakistan. CONCLUSION: It is concluded that the age, gender, race and area, all have an appreciable effect on the levels T4, T3 and TSH. PMID- 20929006 TI - Surgical ligation of patent ductus arteriosus in a noncardiac surgical centre. AB - BACKGROUND: Surgery for Patent Ductus Arteriosus (PDA) is usually performed in specialized cardiac centres with either open surgery or percutaneous embolisation using different materials and devices. This involves high cost of treatment especially for those poor patients who have grown up to several years of age without seeking any treatment for their disease. The objective of this study is to evaluate the safety of surgery for PDA in a non cardiac paediatric surgical setup. METHODS: A total of 89 patients of 8 months to 12 years (mean 3 years) age were operated over a period of 13 years (from 1993 to 2006). Fifty-five cases were females and 34 were males. Investigations included x-ray chest, ECG and echocardiography. All patients with PDA were included in the study except those who had other associated cardiac anomaly and those who had a calcified ductus. The ductus was dissected out and ligated with non-absorbable suture (Silk No. 1 or 2). The patients were discharged by the 5th postoperative day. RESULTS: In majority of the patients the recovery was smooth and uneventful. Eight patients had minor complications which were treated conservatively. There were 3 mortalities in this series; 2 patients were over 10 years of age and had calcified ductus. They died during surgery due to primary haemorrhage and 1 died after 24 hours in the intensive care unit. All patients were reviewed at 1 week, 1 month, 3 months and 1 year after surgery. In majority, the typical machinery murmur disappeared immediately or a soft systolic murmur persisted for up to 4 weeks and then disappeared. CONCLUSION: With proper patient selection, the procedure can safely be performed in a paediatric surgical setup with facilities for cardiac monitoring. The surgeon needs to receive some additional training in the cardiac institution for safe surgery on these children. This will significantly reduce the cost with minimal complications especially for those poor patients who cannot afford the modern procedures due to monitory constraints. Children older than 10 years are not suitable for open surgery because of calcification of the duct. PMID- 20929007 TI - Vesico-vaginal fistula: interposition flap, a key to success. AB - BACKGROUND: Vesico-vaginal Fistula (VVF) is an abnormal communication between bladder and vagina that causes continuous discharge of urine in to vaginal vault. The objective of this study is to describe current trends of aetiology and repair of Vesico-vaginal Fistulae. This is a Descriptive Study, conducted at Armed Forces Institute of Urology, Rawalpindi and Combined Military Hospital, Kharian between May 2001 and May 2007. METHODS: All patients diagnosed as cases of vesico vaginal fistulae were included in the study. Their demographic profile and repair success was determined. RESULTS: A total of 86 patients were included in the study. The mean age of the patients was 35.5 years (range 25-46). Total abdominal hysterectomy was the most common cause (53% of the cases) followed by obstetric causes (43.92% of the cases). Success rate of the surgery in the study was 97.5%. CONCLUSION: The common causes of vesico-vaginal fistula in this study were total abdominal hysterectomy and obstetric causes. The success rate was high, yet the attempt should be made to prevent this socially distressing condition. PMID- 20929008 TI - Frequency and clinical outcome in conduction defects in acute myocardial infarction. AB - BACKGROUND: Conduction defects complicating acute myocardial infarction (MI) are frequent and associated with increased mortality and complications. Common conduction defects after acute MI are atrioventricular nodal blocks (1st, 2nd and 3rd degree) and intraventricular conduction defects (right or left bundle branch blocks and hemiblocks). In myocardial infarction occlusion of coronary arteries at different levels affects the conduction system of heart leading to various types of blocks. Conduction defects usually reflect extensive damage to the myocardium. METHODS: In this descriptive case series with non-probability purposive sampling, 345 cases of acute ST elevation myocardial Infarction were studied at Armed Forces Institute of Cardiology/National Institute of Heart Disease, Rawalpindi from May 2007 to May 2008. ECG was continuously observed in CCU and daily ECGs were done. Conduction defects whether transient or persistent were recorded in pre-designed proforma in addition to other clinical features and associated complications during hospital stay. RESULTS: Out of 345 patients, 251 (72.8%) patients received thrombolytic therapy and 61 (17.6%) developed various types of conduction defects (Group A) and 284 had no significant conduction defects (Group B). Isolated complete atrioventricular block (AVB) at the node level occurred in 28 patients (8.1%) mainly in inferior MI. Bundle branches Blocks occurred in 32 (9.2%) patients mostly in Anterior MI. One patient (0.6%) had complete heart block at bundle branch level. All patients with complete atrioventricular block reverted to sinus rhythm except one who required permanent pacemaker. Mortality rate and clinical complications were higher in group A as compared to group B. CONCLUSION: Conduction defects are common even in this thrombolytic era. Patients with conduction defects are at high risk of inhospital complications and mortality. They need close monitoring and optimum clinical care to reduce mortality and morbidity. PMID- 20929009 TI - Efficacy of immunoassay chromatography test for hepatitis-C antibodies detection. AB - OBJECTIVE: To asses the efficacy of commercially available tests device method for anti HCV detection. METHODS: Total 2000 blood samples for detection of anti HCV were screened initially by immunochromatographic method. Those found positive on initial screening were re-tested by ELISA method at the Biochemistry Laboratory of the Pakistan Medical Research Council, Fatima Jinnah Medical College, Lahore. RESULTS: Out of a total of 2,000 blood samples, 177 were found to be initially reactive/positive for anti-HCV with immunochromatographic method. When these reactive/positive samples were retested for confirmation with ELISA, 47 blood samples were found to have tested falsely positive for anti-HCV. Overall 2.35% of blood samples were found to be tested false positive for anti-HCV by immunochromatographic device method. CONCLUSIONS: Immunochromatographic device method test is rapid and simple, which can be used in setting with limited facility when rapid testing is required. However it should not be used as sole criteria for diagnosis but should serve the purpose of initial screening only. Further research is required to establish the reliability of such devices for their specificity and sensitivity. PMID- 20929010 TI - Evaluation of insulin-like growth factor-1 and insulinlike growth factor binding protein-3 in diagnosis of growth hormone deficiency in short-stature children. AB - BACKGROUND: Growth Hormone Deficiency (GHD) is conventionally diagnosed and confirmed by diminished peak Growth Hormone (GH) levels to provocative testing. Serum Insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) are under the influence of GH and reflect the spontaneous endogenous GH secretion. Owing to the absence of a circadian rhythm, it is possible to take individual measurements of IGF-1 and IGFBP-3 at any time of the day for evaluation of GH status instead of subjecting the individual to cumbersome provocative tests. Objectives of this study were to compare IGF-1 and IGFBP-3 assays with Exercise and L-Dopa stimulation tests in the diagnosis of growth hormone deficiency in short stature children using ITT as gold standard. METHODS: This validation study was conducted at Department of Chemical Pathology and Endocrinology, AFIP, Rawalpindi, from November 2005 to October 2006. Fifty two short stature children were included in the study. Basal samples for GH levels and simultaneous IGF-1 and IGFBP-3 measurements were obtained and afterwards all children were subjected to sequential exercise and L-Dopa stimulation tests. Insulin Tolerance Test (ITT) was performed one week later with all the necessary precautionary measures. On the basis of ITT results, children were divided into two groups, i.e., 31 growth hormone deficient and 21 Normal Variant Short Stature (NVSS). RESULTS: The diagnostic value of exercise stimulation test remained highest with sensitivity 90.3%, specificity 76.0%, Positive Predictive Value (PPV) 84.84%, Negative Predictive Value (NPV) 84.2% and accuracy 84.6%. The conventional L-Dopa stimulation had sensitivity 96.7%, specificity 38.0%, PPV 69.7%, NPV 88.8 % and accuracy 73.0%. The serum IGF-1 and IGFBP-3 levels were positively correlated with post ITT peak GH levels (r = 0.527, r = 0.464 respectively, both p < 0.001). The diagnostic value of IGF-1 had sensitivity 83.87%, specificity 76.2%, PPV 83.87%, NPV 76.2% and accuracy 80.76%. The diagnostic value of IGFBP-3 had sensitivity 54.83%, specificity 90.47%, PPV 89.47%, NPV 57.57% and accuracy 69.23%. With combined use of IGF-1 and IGFBP-3 diagnostic value had sensitivity 69.35%, specificity 83.33% PPV 86%, NPV 64.81% and accuracy 75%. CONCLUSION: Growth Hormones provocative tests still remain the most useful investigations for the diagnosis of GHD. Measurements of IGF-1 and IGFBP-3 have shown comparable diagnostic performance with growth hormone stimulation tests and are valuable for patients' convenience and ease of performance and can be useful in the initial workup of short stature. PMID- 20929011 TI - Baseline leukocyte count and acute coronary syndrome: predictor of adverse cardiac events, long and short-term mortality and association with traditional risk factors, cardiac biomarkers and C-reactive protein. AB - BACKGROUND: The elevated WBC count has been accepted as part of healing response following myocardial infarction as well as a predictor of adverse cardiovascular events. The study was designed to find out correlation between WBC count and coronary risk factors, cardiac biomarkers, C-reactive protein (CRP), incidence of adverse cardiac events and mortality in patients of ACS in Pakistan. METHODS: One hundred and thirty-three patients of ACS were stratified according to WBC categories, WBC1 (< 7000/mm3), WBC2 (7100-10,000/mm3) and WBC3 (> 10,000/mm3). The WBCs were counted on admission by Sysmex cell counter, CRP by immunoturbidimetric method, and CK-MB and Trop-I by enzyme immunoassay. Adverse cardiac events and mortality were recorded for 12 months of follow up period. RESULTS: Long-term mortality in patients with ACS was 6.4% in WBC1, 18.2% in WBC2 and 40.9% in WBC3 categories, while short term mortality was 2.6%, 3.0% and 18.2% in WBC1, WBC2, and WBC3 categories respectively. Relative to patients in lower 2 WBC categories, patients in the highest category were 7 times more likely to die during 30 days (HR 7.83, p = 0.017) and more than 9 times during the total follow up period (HR 9.42, p < 0.001). Cox regression analysis showed WBC3 a strong independent predictor of mortality (HR 6.36, p = 0.016). WBC count showed a positive correlation with coronary risk factors, cardiac biomarkers and CRP. CONCLUSION: WBC count is a strong independent predictor of mortality in patients with ACS and has positive correlation with coronary risk factors, cardiac biomarkers and CRP. PMID- 20929012 TI - Frequency of osteoporosis in patients with cirrhosis due to hepatitis B and hepatitis C: a study of 100 cases. AB - BACKGROUND: Osteoporosis is the disease of bone that affected King David of Israel 3000 years ago. This condition is no longer considered to be due to aging alone and is increasingly recognised as a major health concern and accounts for about 1.5 million fractures annually in United States. Objective of this study was to see the frequency of osteoporosis in patients with cirrhosis due to Hepatitis B and C, and any correlation between the Bone Mineral Density (BMD) and duration and stage of the liver disease. METHODS: The study was conducted in the Department of Gastroenterology, Postgraduate Medical Institute, Hayatabad Medical Complex, Peshawar, from January 2008 to December 2008. All patients from the OPD or Ward fulfilling the criteria and consenting were included. Physical examination, with special emphasis on any signs of chronic liver disease was performed. Full blood count, platelet count, prothrombin time and INR, liver function tests including serum albumin, and renal function tests were done on all patients. Viral serology was checked for those patients who were either newly diagnosed as cirrhotic or were cirrhotic but not screened for viral markers. Abdominal sonogram was recorded on all patients. The Child's score was calculated for each patient using the clinical and lab parameters. The BMD was calculated for all patients using computer based ultrasound probe. Calcaneum was used for evaluation of BMD. The information collected was entered on structured data collection sheets and was analysed using SPSS version 11. RESULTS: Osteoporosis was found in 26% of subject and osteopenia in 42%, while 32% had BMD in the normal range. The mean T score was -1.483 (+/- 1.29). The mean duration of liver disease was 3.77 (+/- 1.56) year. Majority of the patients (81%) were in Child's Class C, followed by Class B and A (16% and 3% respectively). Fifty-nine percent of the patients were males with a mean age of 37.65 years, while 41% were females with mean age of 37.76 years. CONCLUSION: Osteoporosis is a common finding in patients with cirrhosis due to Hepatitis B and C. Osteoporosis is more frequent in patients with long duration of liver disease but there is no significant correlation between the aetiology or severity of liver disease and osteoporosis. PMID- 20929013 TI - In vitro ciprofloxacin resistance patterns of gram-positive bacteria isolated from clinical specimens in a teaching hospital in Saudi Arabia. AB - BACKGROUND: Over the last few decades the ever-increasing level of bacterial resistance to antimicrobials has been a cause of worldwide concern. Fluoroquinolones, particularly ciprofloxacin has been used indiscriminately for both gram-positive and gram-negative bacterial infections. The increased use of ciprofloxacin has led to a progressive loss of bacterial susceptibility to this antibiotic. Therefore it is necessary to have update knowledge of resistance pattern of bacteria to this antibiotic so that alternate appropriate antibiotics can be used for ciprofloxacin-resistant bacterial infections. OBJECTIVE: To evaluate the trends of ciprofloxacin resistance pattern in commonly isolated gram positive bacteria over time in a Saudi Arabian teaching hospital. METHODS: A retrospective analysis was carried out for ciprofloxacin susceptibility patterns of 5534 isolates of gram-positive bacteria isolated from clinical specimens submitted to microbiology laboratories at King Fahd Hospital of the University (KFHU), Al-Khobar, Saudi Arabia during the period from January 2002 to August 2005. RESULTS: Increase in ciprofloxacin resistance rates with some fluctuations, among these isolates, were observed. For Staphylococcus aureus, it varied from 4.62, 1.83, 7.01 and 3.98%, methicillin resistant Staphylococcus aureus (MRSA) 97.92, 97.75, 87.01 and 88.26%, Streptococcus pyogenes 5.35, 4.47, 14.44 and 3.53% during the years 2002, 2003, 2004 and 2005 respectively. Cirprofloxacin resistance during the years 2002, 2004 and 2005 for other isolates was as follows: Streptococcus pneumoniae, 30.23, 23.02 and 26.47%; enterococcus group D, 43.05, 20.68 and 57.03% and non-enterococcus group D, 62.96, 76.92 and 87.50% respectively. CONCLUSION: Ciprofloxacin resistance in gram-positive bacterial clinical isolates particularly Staphylococcus aureus, methicillin resistant Staphylococcus aureus (MRSA) enterococcus group D, and non-enterococcus group D, has greatly increased and ciprofloxacin no more remains the drug of choice for these infections. PMID- 20929014 TI - Frequency of external hernias in Ayub Teaching Hospital Abbottabad. AB - BACKGROUND: Hernia is a protrusion of a viscous or a part of a viscous through an abnormal opening in wall of its containing cavity. Different external hernias present differently and ultimate treatment is surgical, which is most commonly performed elective operation in the world. The objectives were to know the age and gender wise frequency of external hernias in Ayub Teaching Hospital, Abbottabad. This retrospective study was conducted at the surgical units of Ayub Teaching Hospital from June 2004 to June 2005. METHODS: Records of all cases of hernias operated in Ayub Teaching Hospital during June 2004 to June 2005 were retrieved from the operation registers of the entire three surgical units available at the operation theatres. The data was collected on a proforma and was analysed by SPSS-16. RESULTS: Of the 1063 cases, 982 (92.38%) were male and 81 (7.62%) were female. Right Inguinal Hernia (RIH) was the most frequent as expected, i.e., 44.12%, followed by Left Inguinal Hernias (LIH) 18.72%. Least common hernias were femoral hernias with a frequency of 0.85%. CONCLUSION: It is concluded that 85% hernias occur in the groin, with 12% incisional and only 3% hernias occur elsewhere. To reduce the rate of complications, health education is the most important intervention. For future health planning maintenance of disease register can not be over emphasised. PMID- 20929015 TI - Relationship of white blood cell counts, haemoglobin and ESR with IHD. AB - OBJECTIVES: To find any association of white blood cells, haemoglobin and ESR with ischemic heart disease in high risk native population. METHODOLOGY: The study included 93 male patients with Ischemic heart disease, between 40 and 60 years of age; 96 age and gender matched subjects. All study participants were non diabetics. Complete blood cells count, haemoglobin and ESR levels were compared between the patient and control groups. RESULTS: Total leukocyte counts along with neutrophils were significantly higher in the test group compared to the control population (p < 0.001) and lymphocytes were significantly lower (p < 0.001) in the patient group as compared to the control group. Haemoglobin levels were significantly lower (p < 0.001) and ESR was higher (p = 0.030) in the patient group as compared to the control group. CONCLUSION: Although, our findings of the study variables extend previous reports, the prevalence and prognostic importance of theses variables in IHD should be assessed in future experimental studies. These parameters could be important in public health because they are routinely measured by clinicians and may be helpful to predict the risk of future and secondary ischemic events in a high risk population. PMID- 20929016 TI - Relation of hypertension with body mass index and age in male and female population of Peshawar, Pakistan. AB - BACKGROUND: Hypertension, a condition developed as a result of high blood pressure is strongly correlated with body mass index (BMI). Obesity was noted to be a single best predictor of hypertension incidence, and was regarded as a major controllable contributor to hypertension. Overweight and obesity is conveniently determined from BMI. Present study was conducted in Khyber Medical College (KMC) Peshawar to investigate the relation of hypertension with BMI and age. The objective of the present investigation is to establish a relationship between hypertension and BMI in male and female population of Peshawar with consideration of age. METHODS: This study was conducted at KMC, Peshawar during 2008-2009. A total of 1006 adult male and female volunteers were the subject of present research and were categorised in terms of their ages. BMI was determined from weight and height; the subjects were grouped as normal, overweight and obese. Hypertension was determined from the measure of blood pressure. RESULTS: The results show a consistence relation between BMI and hypertension within age groups in both male and females. The figures exhibited a relation of age with BMI and hypertension in both males and females subjects. CONCLUSION: The results showed a higher trend of hypertension with increasing BMI. In young females it was noted that with a shift from normal BMI the incidence of hypertension was very high. PMID- 20929017 TI - Effect of chronic treatment with a cyclooxygenase inhibitor on reproductive parameters in male rat. AB - BACKGROUND: Indomethacin is a member of non-steroidal anti-inflammatory drugs (NSAIDs) commonly used for treatment of gout, arthritis, and other inflammatory conditions. It has been shown to inhibit ovarian prostaglandins synthesis in mammals, birds, fish and reptiles. However, the effects of its chronic administration on male reproductive functions remain largely unknown. Using rat as a model, we studied the effect of chronic treatment with indomethacin on the male reproductive system. METHODS: Testosterone was measured in the serum, testicular tissue, and testicular interstitial fluid by radioimmunoassay. Moreover, we also studied the direct effect of indomethacin in vitro on luteinizing hormone stimulated testosterone secretion from the Leydig cells isolated from various treatment groups. RESULTS: Indomethacin treatment for 50 days caused a significant but reversible decrease in prostate weight, epididymal sperm reserves and sperm motility score compared with control rats (p < 0.05). In vitro stimulation of Leydig cells isolated from treated rat's testes with luteinizing hormone (250 microIU) produced significantly reduced testosterone compared with cells from control groups (p < 0.05). Furthermore, stimulatory effect of luteinizing hormone on the control Leydig cells was significantly reduced when these cells were challenged with luteinizing hormone in the presence of indomethacin, (p < 0.05). Testosterone concentration in the testicular tissue and testicular interstitial fluid reduced after indomethacin treatment (p < 0.05). CONCLUSION: Due to its significant inhibition of key reproductive hormones, indomethacin effectively inhibits reproductive functions if used on a long-term basis. In his study, we have identified potential risks in the long term use ofcyclooxygenase inhibitors. PMID- 20929018 TI - The frequency of old world cutaneous leishmaniasis in skin ulcers in Peshawar. AB - BACKGROUND: Old World Cutaneous Leishmaniasis (OWCL) is a preventable skin infection that leads to morbidity and social isolation. It is spreading rapidly. The sore of OWCL may be a non-ulcerative red papule, nodule or a large mutilating ulcer. The ulcer is typically painless and can leave a disfiguring scar. METHODS: This was a descriptive study. The diagnosis of OWCL was established by finding LD bodies in skin smear preparation. RESULTS: This study identified 1680 cutaneous leishmaniasis in 1767 skin ulcers. Children (n = 924) were infected more than other age groups (n = 756). There were typical skin sore of OWCL in 1512 cases while 168 patients had atypical presentation. The ulcers were painless in 1603 patients. History of insect bite was present in 1366 cases, thorn prick in 156 patients, religious visit to endemic areas in 256 patients, and 4 patients had post surgical non healing wound. Lesions with 4 to 6 months of age had a maximum yield of LD bodies. There were 498 patients from different areas of Peshawar; 688 cases from leishmania endemic belt of FATA while 89 patients came from other urban and rural areas of NWFP. CONCLUSIONS: There is a tremendous increase in cases of OWCL and the disease became endemic in many regions of Pakistan. The bordering areas along Afghanistan have constituted an endemic belt that had invaded the neighboring urban and rural areas. Several chronic non healing ulcers had been diagnosed as OWCL. Many cases have been detected in Peshawar. People need education about the nature of the diseases and the efficacy of personal protective measures. Spray with suitable insecticides is required in all residential areas. PMID- 20929019 TI - Changing pattern of fabricated injuries in Larkana region. AB - BACKGROUND: Man has been egotist by nature and from Ancient time man has been endeavouring to bring under power other human beings. With the passage of time and growth of civilization this trend has been increased. Now there are more dangerous ways of violence and torture in use for twisting and turning people around. Inflection of fabricated injuries is one of the ways for fulfilment of his lust. Incidence of fabricated injuries is related with crime rate in any society, and this practice is carried out through out the world. Fabricated Injury is a major problem which forensic expert/causality medical officer face during their duty. Very little literature is available regarding study of fabricated injuries and no authentic criteria has so for been developed for labelling an injury as fabricated one. METHODOLOGY: The present study is about 130 challenged medico-legal cases in Larkana Division which were studied in special medical board held in the Department of Urology Chandka Medical College Larkana. Out of 130 cases 50 were proved to be fabricated. RESULTS: The total number of challenged cases was 130, out of these 50 (38.46%) cases were of fabricated injuries. Out of 50 fabricated cases, 46 (92%) were males and 4 (8%) were female, thus the male to female ratio was approximately 11:1. Maximum cases (25) were from Larkana District, 15 cases were from Shikarpur and 10 cases from Jacobabad. The majority of fabricated injuries from Larkana District were nose injuries as out of 25 fabricated injuries from Larkana district 10 were nasal injuries, while from district Jacobabad and Shikarpur there was no nasal fabricated injury. CONCLUSION: Most of the fabricated injuries are caused on accessible part of the body like arms, legs, abdomen, chest etc. The pattern of fabricated injuries is changing in Larkana District as out of 25 fabricated injuries in this district 10 were nasal injuries while in District Jacobabad and Shikarpur there was no nasal fabricated injury. PMID- 20929020 TI - Maternal serum levels of adiponectin in preeclampsia. AB - BACKGROUND: The results of the serum levels of adiponectin in preeclamptic patients are conflicting. OBJECTIVE: The aim of the present study was to assess serum levels of adiponectin in women with preeclampsia compared with healthy pregnant women. METHODS: A cross-sectional study was designed. The case group consisted of women with preeclampsia (n = 30). The control group consisted of 30 matched normal pregnant women. Serum levels of adiponectin were assessed using enzyme-linked immunosorbent assay method. RESULTS: Serum levels of adiponectin were significantly higher in the preeclamptic group than those in the normal control group. In the preeclamptic patients serum levels of adiponectin showed a significant negative correlation with body mass index while no correlation was found in the normal pregnant women. In women with preeclampsia, levels of adiponectin were decreased significantly in the overweight women compared with normal weight women, while in the control group no significant difference was observed. CONCLUSION: In conclusion, elevation of adiponectin levels might be a physiological feedback response to minimize endothelial dysfunction in preeclamptic patients. PMID- 20929021 TI - Prevalence of microalbuminuria with relation to glycemic control in type-2 diabetic patients in Karachi. AB - BACKGROUND: Diabetes is one of the most common endocrine disorders characterized by hyperglycaemia. Diabetic nephropathy is a consequence of long standing diabetes. The prevalence of microalbuminuria predicts progression to diabetic nephropathy. The present study was conducted to determine the prevalence of microalbuminuria in relation to duration of diabetes, BMI, Serum Creatinine and HbA1c in an ethnic group of Type 2 diabetes mellitus residing in Karachi. METHODS: This cross-sectional descriptive study was carried out in a community diabetic centre, located at Garden East Karachi from July to December 2007. One hundred known Type 2 diabetic patients with age 30-70 years were included in the study. Informed consent and a structured questionnaire of each patient were recorded. Fasting venous blood and morning urine sample was collected for analysis of creatinine, HbA1c and microalbuminuria respectively. Statistical analysis was done using SPSS version 13.0. Pearson correlation was applied to observe association of microalbuminuria with different parameters. All p-values < 0.05 were considered as statistically significant. RESULTS: Microalbuminuria had a highly significant correlation with duration of diabetes, serum creatinine (p < 0.001), HbA1c (p < 0.05) and BMI (p < 0.024). A strong correlation exists between age and serum creatinine (r = 0.73). CONCLUSION: The present study found an early onset of microalbuminuria in the selected community which could be due to poor glycaemic control (high HbA1c > 7%) or heredity factors. Screening for microalbuminuria and HbAlc test should be done in both newly and already diagnosed Type 2 diabetic patients as an early marker of renal dysfunction and glycaemic control. PMID- 20929022 TI - Carcinoma cheek: regional pattern and management. AB - BACKGROUND: Oral cancer varies globally and regionally, and is closely linked with geographical, social, economical, biological, ethnic, dietary and environmental factors. In western countries it accounts for about 2-5% while in the south-east Asia for about 40% of all cancers. In Pakistan it is second commonest tumour after bronchogenic carcinoma in males and breast carcinoma in females. The objectives of this study were to find out the pattern of carcinoma cheek in our region, its etiological associations, management and prognosis. This study was conducted in the Otolaryngology and Head and Neck Surgery Department of Civil Hospital, Karachi from April 1995 to December 1998. It was prospective study. METHODS: Forty-five cases of primary carcinoma cheek were diagnosed and investigations including OPG and CT scan were carried out along with other required investigations to evaluate the extension of tumour, bony erosion and metastasis. TNM staging was done. All patients were treated surgically, sent for post-operative radiotherapy or chemoradiation and followed up for 3 years. RESULT: Among 45 cases of oral cancer, 28 were females and 17 were males. Common presenting symptom was growth or ulcer. It was more common in 41-50 years of age. Squamous cell carcinoma (SCC) was found in 95.5% of the cases. Most of the patients 31 (68%) were in T4 stage. Surgical excision was done in all cases with reconstructuion in 23 cases and neck dissection in 39 cases. In the follow up for 3 years, 30 patient remained disease free. CONCLUSION: Carcinoma cheek is a common entity in our region and now it is seen in relatively younger patients. Oral cancer is a self preventable disease. What is required is to develop awareness of oral hygiene and discourage the habit of social carcinogens use. Early diagnosis and treatment offers better chance of cure whereas advance disease has a poor prognosis. PMID- 20929023 TI - Vitamin B12 deficiency--a major cause of megaloblastic anaemia in patients attending a tertiary care hospital. AB - BACKGROUND: Folate and vitamin B12 deficiencies have been known to cause megaloblastic anaemia. Since the deficiencies of these two vitamins are very common in Pakistani population, it would be imperative to investigate their role in causing megaloblastic anaemia. The objective of this study was to find out the contribution of folate and vitamin B12 deficiencies in causing megaloblastic anaemia in our patient population. METHODS: In this retrospective cohort study, clinical records of 220 patients (101 females and 119 males with an age range of 1-80 years) who presented themselves with macrocytic anaemia at the Aga Khan University Hospital were collected. Data pertaining to complete blood count and serum levels of folate and vitamin B12 were analysed. RESULTS: The mean haemoglobin (Hb) level was 6.8 +/- 0.2 gm/dl. Sixty-nine percent of the patients had severe anaemia (Hb < 8 gm/dl). Mean +/- SEM values of haemoglobin, serum folate and serum B12 were not significantly different between males and females (Hb 6.4 +/- 0.3 gm/dl vs 6.3 +/- 0.3 gm/dl; folate 6.9 +/- 0.8 etag/ml vs 7.8 +/- 1 etag/ml; B12 259 +/- 65 rhog/ml vs 225 +/- 45 rhog/ml, respectively). Linear regression analysis showed that serum folate was inversely related with the mean corpuscular volume (MCV, p = 0.04). Spearman's correlation analysis indicated an inverse mild association between MCV and serum folate (correlation coefficient = 0.18). Folate deficiency was 43.4%, while vitamin B12 deficiency was 78.5% in these patients. Seventy-one percent of folate-deficient patients had vitamin B12 deficiency as well, while 26.1% of patients with B12 deficiency had a co occurrence of folate deficiency. CONCLUSION: Vitamin B12 deficiency appears to be the major factor leading to megaloblastic anaemia in our study population. Inadequate dietary intake, over-cooking of our food and poor absorption might be contributing to high prevalence of vitamin B12 deficiency in this population. PMID- 20929024 TI - Outcome of balloon pulmonic valvuloplasty with 18 months follow up. AB - OBJECTIVE: To determine the immediate and intermediate term outcome of balloon pulmonic valvuloplasty by echocardiography. METHODS: This study was conducted in the Department of Cardiology Postgraduate Medical Institute Lady Reading Hospital (LRH), Peshawar from July 1999 to January 2003. Patients with severe pulmonic valve stenosis who underwent balloon pulmonic valvuloplasty during this period were included in the study. Forty Patients fulfilling the study inclusion criteria were followed up to 18 months by two dimensional and Doppler echocardiographic examinations at 6 months interval. Patients with dysplastic valve leaflets or for whom 18 months follow up data was not available were excluded from the study. Echocardiographic data was collected prospectively. Echocardiographic hemodynamic data was analysed initially and at all three follow up visits, using descriptive statistics and paired t-test. RESULTS: Total 64 balloon pulmonic valvuloplasty procedures were performed during this period. Forty patients fulfilled the study inclusion criteria and the remaining 24 patients were excluded from the study. Mean age of the patients was 13.05 +/- 8.22 years, ranging from 1-33 years. Pre-peak pulmonic valve gradient reduced from 100.9 +/- 29.20 mmHg to 31.38 +/- 15.99 mmHg (p < 0.0001) immediately after balloon pulmonic valvuloplasty. Pulmonic valve gradient at day 1 (31.38 +/- 15.99) reduced significantly at 18 months (18.88 +/- 10.24) (p < 0.0001). Complication encountered during the procedure was transient ventricular tachycardia or multiple premature ventricular contractions. CONCLUSION: Balloon pulmonic valvuloplasty is safe and effective in reducing pulmonic valve gradient acutely and the benefit persists till 18 months. Further fall in pulmonic valve gradient is seen in intermediate term follow up. PMID- 20929025 TI - Determinants and pattern of health care services utilisation in post graduate students. AB - BACKGROUND: The health care utilisation of a population is dependent on their health seeking behaviour which is determined by their physical, political, socio economic and socio-cultural aspects. OBJECTIVES: This particular study is conducted to identify the determinants and the patterns of health services utilisation by the postgraduate students of Allama Iqbal Open University in Pakistan. It was a cross-sectional study and conducted from December 2008 to April 2009 in Allama Iqbal Open University Islamabad. METHODS: A non-probability convenience sampling was done in post graduate students who were enrolled for Masters Degree at Allama Iqbal Open University Islamabad. Data was collected on a self administered, pre-tested questionnaire to identify the pattern of utilisation of health care services by this educated class. Data was labelled and entered in SPSS version 16. Chi-square test is applied as a test of significance with fixing the p value at 0.05 as significant. RESULTS: Only 129 students 32 males, 97 females) out of 250 responded to the questionnaire with the response rate of only 51.6%. The sociodemographic profile of the participants shows that 71 (55%) belong to age group 20-29 years, followed by 43 (33.3%) in age group 30 39 years. The marital status of the participants had a significant association with selection of health care services (p = 0.04). Twenty-four (75%) of the males and 67 (65%) of the females were using private sector facilities. Age, marital status and income of the study subjects had significant association with selection of the provider with p values of 0.000, 0.047 and 0.051 respectively. CONCLUSION: The health care system in Pakistan comprises the public as well as private health facilities. In Pakistan vast majority of doctors resides in urban area and attracts the educated class towards private sector. Utilisation of public health care facility is not the main priority of the educated class of the country. Government officials should pay attention to make it more convenient for general public. PMID- 20929026 TI - Correlation of plasma endothelin-1 levels with pulmonary hypertension after inhaled nitric oxide therapy. AB - BACKGROUND: Variable response to inhaled nitric oxide (iNO) therapy in patients with mitral stenosis (MS) having pulmonary hypertension (PH) has been documented in early studies. The objectives of this study were to measure plasma Endothelin 1 (ET-1) levels in those patients and to correlate them with pulmonary vascular indices after iNO therapy. It was Quesi-experimental study. METHODS: Thirty patients with mitral or mixed mitral and aortic valve disease with severe pulmonary hypertension and enrolled for valve replacement surgery were included. Before the replacement, baseline pulmonary vascular indices and cardiac output were recorded. After the surgery, 10-20 ppm iNO was administered for 1 hour and all the parameters were again recorded. Patients were grouped into responders and non responders on the basis of % reduction in Pulmonary Vascular Resistance (PVR) after iNO therapy. Plasma ET-1 levels were measured in both groups by ELISA before and after the iNO therapy. Paired sample t-test was used to compare mean values for significance. The correlations between variables were then calculated by using Pearson's coefficient. RESULTS: The plasma ET-1 levels were very high in all patients. They reduced in responders after iNO therapy; non-responders paradoxically showed significant increase in the levels of ET-1 after iNO therapy. Moreover, a positive correlation was observed in plasma ET-1 levels and post operative levels of PVR. CONCLUSION: The correlation of changes in PVR and plasma ET-1 levels in responders suggests that high plasma ET-1 is a key mediator of poor response in PH secondary to MS, after iNO therapy. PMID- 20929027 TI - Consanguinity among the risk factors for underweight in children under five: a study from rural Sindh. AB - BACKGROUND: Malnutrition is a common problem, especially in developing countries. Of the 11 million children under 5 who die each year in the developing countries mainly from preventable causes, the death of about 54% are either directly or indirectly attributable to malnutrition. The objectives of this study were to assess the prevalence and associated factors for underweight in rural Sindh. METHODS: A cross-sectional survey was conducted in Jhangara Town, located in District Dadu, Sindh. Eight hundred children under 5 years of age were enrolled. A questionnaire was used to elicit required information and anthropometric measurements were made. RESULTS: The overall prevalence for underweight was 54.3% in the study population, which was higher than the prevalence reported by PDHS 1990-91. In multivariate analysis, various factors for underweight were consanguinity (OR = 1.5, 95% CI = 1.08-2.07), low birth weight (parents' perspective) (OR = 1.6, 95% CI = 1.08-2.16) and lack of breast-feeding (OR = 2.7, 95% CI = 1.19-6.17). CONCLUSION: Effective strategies to discourage consanguineous marriages between first cousins are required. Promoting breast feeding is another factor that should be incorporated while designing control strategies to reduce morbidity and mortality due to malnutrition in children (< 5 years). PMID- 20929028 TI - Intermediate and long-term outcome of patients after device closure of ASD with special reference to complications. AB - BACKGROUND: Device closure of Secundum atrial septal defect (ASD) is an accepted mode of treatment in selected patients with a suitable defect. The major initial concern over the long-term outcome has been erosions and more recently development of aortic regurgitation. Objective was to assess the intermediate and long term outcome of patients with device closure of ASD with special reference to complications. METHODS: Two hundred and four patients with significant Secundum ASD, 16 months to 55 years (median 8 years) were considered for transcatheter closure with the Amplatzer septal occluder from October 1999 to April 2009 with follow up examinations at 1, 3, 6, and 12 months and thereafter at yearly interval. RESULTS: Device closure of ASD was done successfully in 202/204 patients. The immediate (first 24-hour) major complications included device embolization (n = 4), pericardial effusion (n = 1) and 2:1 heart block (n = 1). At a mean follow up of 4.9 years (90 days to 9.6 years, median 5.3 years) complete closure was documented in all patients. Two patients (1%) had developed mild aortic regurgitation. Atrial fibrillation occurred in 3 adult patients (1.5%) at a mean of 2 weeks post procedure with complete recovery within 6 months. There were no late embolizations, erosions or thromboembolic events on long-term follow up. CONCLUSIONS: Device closure of Secundum ASD using Amplatzer septal occluder is safe and effective in intermediate and long-term follow up with extremely low mortality rate. The risk of development of aortic regurgitation or atrial fibrillation is also very low. PMID- 20929029 TI - Echocardiographic profile of rheumatic heart disease at a tertiary cardiac centre. AB - BACKGROUND: Rheumatic Heart Disease (RHD) continues to be a major public health problem in developing countries like Pakistan. Objective of this cross sectional analytical study was to analyze the severity of valvular lesions on echocardiography in patients pre-diagnosed with RHD. METHODS: The transthoracic echocardiographic records of RHD patients from 2004 to 2008 were retrospectively reviewed for type and degree of valvular involvement according to AHA/ACC guidelines. RESULTS: A total of 13,414 patients [7,219 Males (53.8%), 6,195 Females (46.2%)] ranging from 11 to 90 years with a mean age of 42.33 +/- 18.976 were studied. On echocardiography, 7,500 (56%) had mitral regurgitation (8.8% severe MR), 6,449 (48.2%) had tricuspid regurgitation (7.1% severe TR) and 5,550 (41.4%) had aortic regurgitation (4.8% severe AR). MS was detected in 2,729 (20.3%) patients (15.3% severe MS), AS in 102 (0.8%) and TS in 31 (0.2%) patients. Mixed mitral valve disease was seen in 3,185 (23.7%), mixed aortic valve disease in 222 (1.7%) and mixed tricuspid valve disease in 47 (0.4%) patients. All three valves were involved in 2,826 (21.06%) patients, combination of mitral and aortic valves in 3,103 (23.13%), mitral and tricuspid in 3,784 (28.2%), and mitral only in 3,701 (27.59%) patients. There was some mitral valve abnormality in all patients. CONCLUSION: Mitral valve was most commonly affected, while regurgitant lesions were more common than stenotic lesions, and most severe in younger patients. All valvular lesions had almost an equal distribution among the sexes, except aortic regurgitation, which was more common in females. Therefore, echocardiography should be done routinely for patients with RHD, focusing on younger population, to facilitate diagnosis and definitive treatment before complications set in. PMID- 20929030 TI - Aetiological considerations of acquired aplastic anaemia. AB - BACKGROUND: Acquired aplastic anaemia is one of the important causes of pancytopenia. This study was conducted to observe the mode of presentation of acquired aplastic anaemia and to find out its possible etiological factors. METHODS: It is a hospital based descriptive study of 100 patients of acquired aplastic anaemia. RESULTS: Out of 100 patients 60 were male and 40 female. Majority (44%) of the patients were between 12-20 years of age. Patient presented with variable symptoms majority (40%) with fever. Most of the patients had haemoglobin levels between 4-6 gm/dl. (53%). Seventy percent of the cases had no obvious cause, while in 30% some known causative factors were found. Chloramphenicol was found to be the most common causative drug. Mortality was 35%. Thirty patients were partially treated and 15 were lost to follow up. Twenty patients showed improvement with treatment. CONCLUSIONS: Acquired aplastic anaemia is common among males and more prevalent in younger age group. It is idiopathic in 70% cases while 30% had some cause. It has very high mortality. Doctors need to keep in mind this fatal condition in patients presenting with anaemia and should properly investigate before prescribing antibiotics and haematinics. PMID- 20929031 TI - Outcome of labour in nullipara at term with unengaged vertex. AB - BACKGROUND: Primigravidas with unengaged foetal head at term should be regarded as high risk cases. It is seen that nuglliparous women with the floating foetal head demonstrate higher rates of caesarean section than those with dipping or engaged head in early labour. These cases should be regarded as high risk and identified early and should be referred to a tertiary care centre where good facilities for operative delivery are available. The present study was undertaken to determine the outcome of labour in nulliparous women with unengaged head and compare it with those who present with engaged head at term as a case control study. The objective of the study was to enumerate the outcome of labour in nulliparous women presenting with unengaged head at term and compare it with those who present with engaged head in early active labour. METHODS: It was a case control study, completed in 11 months, conducted in Department of Obstetrics and Gynaecology, Sir Ganga Ram Hospital, Lahore. 300 women were selected by convenience sampling. 150 nulliparous women who presented with unengaged head in early active labour were taken as cases, out which 2 women left against medical advice with their medical records so data was missing leaving 148 patients in this group. While 150 nulliparous women who presented with engaged head were taken as controls. RESULTS: C-section rates was significantly found to be more in unengaged group being 16.89%, compared with 5.33% in engaged group (p = 0.000). Most of C-sections were carried out due to failed progress of labour (48%). Patients with unengaged foetal head had significantly lower APGAR scores at 1 (p < 0.002) and 5 min (0.003) and higher mean birth weights (p = 0.002).Cases also had significantly longer 1st (p = 0.0001) and 2nd stage (p = 0.004) of labour. CONCLUSION: Engaged vertex at the onset of active labour is associated with a lower risk of caesarean delivery in nulliparous women. Patients with unengaged vertex are at higher risk for caesarean delivery due to arrest disorders. In addition to the higher caesarean rate patients with unengaged vertex are at risk of having lower foetal APGAR scores and higher mean birth weights of newborns. PMID- 20929032 TI - Surgical site infection in lumbar surgeries, pre and postoperative antibiotics and length of stay: a case study. AB - BACKGROUND: Postoperative wound infection also called as surgical site infection (SSI), is a trouble some complication of lumbar spine surgeries and they can be associated with serious morbidities, mortalities and increase resource utilization. With the improvement in diagnostic modalities, proper surgical techniques, antibiotic therapy and postoperative care, infectious complications can result in various compromises afterwards. The objective was to study the relation of surgical site infection in clean lumbar surgeries with the doses of antibiotics. This Retrospective study was conducted at Shifa International Hospital, from January 2006 to March 2008. METHODS: Hundred post operated cases of lumber disc prolapse, lumbar stenosis or both studied retrospectively by tracing their operated data from hospital record section for the development of surgical site infection (SSI). The patients were divided into three groups depending upon whether they received single, three or more than three doses of antibiotics respectively. Complete data analyses and cross tabulation done with SPSS version 16. RESULT: Of 100 cases, only 6% had superficial surgical site infection; only 1 case with co morbidity of hypertension was detected. Twenty-one cases had single dose of antibiotic (Group-I), 59 cases had 3 doses (Group-II) and 20 cases received multiple doses (Group-III). There was no infection in Group I. Only one patient in Group-II and 5 patients in Group-III developed superficial SSI. While 4 in Group-II, 3 in Group-III, and none of Group-I had > 6 days length of stay (LOS). CONCLUSION: The dose of antibiotic directly correlates with the surgical site infection in clean lumbar surgeries. When compared with multiple doses of antibiotics a single preoperative shot of antibiotic is equally effective for patients with SSI. PMID- 20929033 TI - Effect of glycaemic status on left ventricular diastolic function in normotensive type 2 diabetic patients. AB - BACKGROUND: Diabetes is associated with Left ventricular diastolic and systolic dysfunction known as diabetic cardiomyopathy. Echocardiography is helpful for the detection of diastolic dysfunction and Echocardiographic screening for asymptomatic diabetic cardiomyopathy should be performed in all asymptomatic diabetic subjects. Identification of diabetic cardiomyopathy should result in the initiation of therapies to prevent the progression of diabetic cardiomyopathy. The objectives of this Descriptive case series was to determine the effect of glycaemic status on left ventricular diastolic function in normotesive type 2 diabetic patients. METHODS: This study was performed at Cardiology department, PGMI Lady Reading Hospital, Peshawar from March 2007 to September 2007. Sixty normotesive type 2 diabetic patients were enrolled, 20 well control, 20 moderately control and 20 poorly control (Group-3). Main outcome measures was Left ventricular diastolic function determined by Echocardiography. RESULTS: Out of 60 patients there were 32 (53.3%) males and 28 (46.7%) females. Mean E/A ratio in Group 1 was 1.38 +/- 0.29, in Group 2 was 1.16 +/- 0.39 and in Group 3 was 0.60 +/- 0.15 (p < 0.05). IVRT in Group-1 was 91 +/- 7.87 mSec, in Group-2 was 100 +/- 7.83 mSec and in Group-3 was 109 +/- 6.45 mSec (p < 0.05). DT in Group 1 was 207.2 +/- 12.6 mSec, in Group 2 was 218 +/- 11.3 mSec and in Group 3 was 229.7 +/- 9.52 mSec (p < 0.05). Mean Em at mitral annulus in Group-1 was 0.14 +/- 0.04 m/Sec, in Group-2 was 0.11 +/- 0.04 m/Sec and in Group-3 was 0.10 +/- 0.03 m/Sec (p = 0.002). Left ventricular diastolic dysfunction was documented in 4 (25%) patients in Group-1, 9 (45%) patients in Group-2 and 16 (80%) patients in Group-3 (p < 0.05). There was Strong correlation between HbA1c level and diastolic indexes (p < 0.05). CONCLUSION: Diastolic dysfunction is more frequent in poorly controlled diabetic patients and its severity is correlated with glycaemic control. PMID- 20929034 TI - Association of lipoprotein-alpha with obesity in children and adolescents in district Swat. AB - BACKGROUND: Studies have demonstrated that atherosclerosis has its silent beginning during childhood. Coronary artery disease, particularly when it presents early in adult life has been observed to have a familial tendency. Lipoprotein-alpha [Lp-alpha], has a strong genetic association and raised levels when combined with obesity increase the risk of premature coronary heart disease. Thus in adults, has emerged the possibility of preventing or delaying the coronary artery disease when appropriate measures are applied early in life. In our study, we assessed the prevalence of overweight and obesity and its association with Lp-alpha in the child population of district Swat. METHODS: The study was carried out in Saidu Teaching Hospital and Biochemistry Department, Saidu Medical College, Swat, from May to July 2007. Both boys and girls between 10-20 years of age were included. The prevalence of obesity was detected in 200 subjects by using body mass index. One hundred subjects were selected to compare the anthropometric and cardiovascular parameters of obese subjects with control group. Lp-alpha was measured in children of both the groups. RESULTS: The prevalence of obesity in adolescent boys was 6.7% and that in adolescent girls was 10%. The prevalence was higher in female subjects, compared to male subjects. Obese subjects had significantly higher weight, body mass index, blood pressure values and Lp-alpha levels as compared to control group. CONCLUSION: Lipoprotein alpha level is higher in obese children and adolescents than in non-obese. PMID- 20929035 TI - Assessment of amniotic fluid index in normal pregnancy at a tertiary care hospital setting. AB - BACKGROUND: Ultrasound assessment of amniotic fluid has important implication in obstetrics care and it has become an integral and important component of pregnancy assessment. Changes in amniotic fluid volume are associated with adverse outcome. Excess volume is associated with foetal anomalies and aneuploidy and less volume is associated with Intra Uterine Growth Retardation, renal anomalies in the second trimester. The objective of this study was to establish a normative scale of Amniotic Fluid Index (AFI) throughout gestation in uncomplicated singleton pregnancies, and to identify the lower and upper limits for each gestational week. METHOD: A prospective cross-sectional study conducted in a private tertiary care Hospital from Jan 2004 to April 2005. Amniotic fluid index was calculated in 400 women attending the antenatal clinic. The gestational age of these women range from 20-40 weeks. Women with foetal anomalies, Pregnancy Induced Hypertension, Diabetes Mellitus and other maternal complication were excluded from study. The median, mean, 5th, 50th, and 95th percentile were calculated for each gestation and these values are compared with other studies. RESULTS: The amniotic fluid index observations from regression equation curve were stratified in week-specific normative curves. The mean of preterm was significantly greater than mean of term gestation (p < 0.05). Our median reached peak at 27th week of gestation another peak at 30-31 week. The values then begin a gradual fall to 40 weeks gestation. CONCLUSION: Gestational age specific values of AFI were established, showing significant trends of changes in the amniotic fluid volume with gestation. PMID- 20929036 TI - Hydatid cysts of the brain. AB - BACKGROUND: Brain involvement with hydatid disease occurs in 1-2% of all Echinococcus granulosus infections. Cerebral hydatid cysts are usually supratentorial, whereas infratentorial lesions are quite rare. Objective of the study was to determine the clinical presentation and surgical outcome of cranial hydatidosis. METHODS: This retrospective study was performed in the department of neurosurgery LRH Peshawar from December 2000 to Oct 2007. Twenty one cases with intracranial hydatidosis were operated. The patients were either admitted through OPD or referred from other units. CT and/or MRI were the imaging modalities to reach the diagnosis in addition to serological and haematological tests. Surgery was the only treatment option used. Pericystic hydraulic method was the technique used for the excision of the hydatid cyst of brain. RESULTS: There were 9 males and 12 females with male to female ratio of 1:1.3. All patients belonged to paediatric age group with age range of 3-14 years and mean age of 7.42 +/- 3.2 years. Headache, vomiting, papilloedema were present in all the patients while seizures were the present in 16 patients. The lesion was removed surgically by adopting pericystic hydraulic method during craniotomy in all cases. There was no intra-operative morbidity except that the cyst ruptured in one case. No postoperative complications were noted and there was no mortality. CONCLUSION: Hydatid cyst of the brain presents clinically as intracranial space occupying lesion and is more common in children. Surgery is the treatment option with affordable morbidity and low mortality. PMID- 20929037 TI - Electrical storms and their prognostic implications. AB - BACKGROUND: Prevention of sudden cardiac death has always been a challenge for electrophysiologists and to date, automatic implantable cardiovertor defibrillator (AICD) is found to be the only remedy. This device delivers an intracardiac shock whenever it senses a fatal ventricular arrhythmia in order to achieve sinus rhythm. If the delivery of these intracardiac shocks becomes frequent, the situation is declared as an electrical storm. This article deals with the frequency, precipitating factors and prevention of electrical storms. METHODS: One hundred and ten episodes of electrical storms (a total of 668 shocks) were retrospectively analysed in 25 recipients of automatic implantable cardioverter defibrillators. ECG, echocardiography, serum electrolytes, urea and creatinine were done for all the patients, and they were hospitalized for a minimum of 24 hours. RESULTS: During the 3 year study period, all the 25 patients with an implantable cardiovertor defibrillator, on an average, received one shock per two years. However, 12 out of these 25 patients (50%) had more than two shocks within 24 hours. Most of these patients with electrical storms were having active ischemia, electrolytes imbalances or renal failure. CONCLUSION: Electrical storms are common in patients with coronary artery disease with impaired left ventricular functions. Ischemia, electrolytes imbalances and renal failure predispose to the electrical storms. Electrical Storms are predictors of poor prognosis. PMID- 20929038 TI - Attitude and knowledge of medical students of Isra University about dysmenorrhoea and its treatment. AB - BACKGROUND: Dysmenorrhoea is the term for painful menstruation. It is a common gynaecological complaint among female adolescent. The objective of this study was to assess attitude and knowledge about treatment of dysmenorrhoea among medical students of Isra University. METHODS: This study was conducted at Isra University Hyderabad. Non-probability, convenient random selection from MBBS student was done. Participants included were 18-25 years of ages, irrespective of marital status. Girls with irregular menstrual cycles, primary or secondary amenorrhea were excluded from the study. Pre-designed questionnaire was filled by the students. RESULTS: A total of 197 female medical students were recruited, dysmenorrhoea was reported in 76%, of these 62.43% had primary and 13.19% had secondary dysmenorrhoea. Majority 89 (59.70%) of the girls had mild G1 to moderate 48 (32.21%) G2 dysmenorrhoea and twelve 8.05% were with sever dysmenorrhoea. The most common symptoms observed were abdominal cramps 94 (63%), irritability 91 (61.07%), headache 41 (24.5%) and vomiting 34 (22.8%). Different attitudes of students were assessed, that 40.6% of subjects can not do their routine work and 19.3% remain absent from education place. Only 69.5% students were using commercial pads, 67% girls were not taking bath and 92.4% were not doing exercise during menstruation, only 15 (7.6%) were doing exercise from the study population. Simple analgesic was the most known drug to 49.7% of participants for relief of dysmenorrhoea pain. CONCLUSION: Dysmenorrhoea is a common problem among young girls, and it significantly affects their class attendance, academic performance and routine work. Even being medical students, strong cultural believes were observed regarding menstrual cycle. Attitudinal changes are necessary to develop, educational strategies, appropriate use of medications and consultation with physician, to empower these young girls regarding healthy life-style. PMID- 20929039 TI - Comparison of gender performance on an intelligence test among medical students. AB - BACKGROUND: Since the Government of Pakistan abolished the gender based system of admission to medical colleges, all colleges have seen a huge influx of female medical students, reaching up to 70-80% of all students in some colleges. This trend is still persisting about 15 years after the decision. The objectives of the current study were to assess if there is any significant difference between male and female medical students in scores on a structured, standard, robust test of intellectual ability. Exact venue of the research is withheld for confidentiality. The study was carried out in 2003-2005. METHODS: A cross sectional, comparative study with sample size of 150 students, 75 male and 75 female students. Participants signed a consent form, were assessed on Raven's Standard Progressive Matrices (SPM), and data was analysed using SPSS-12. RESULTS: On the SPM test, the male students as a group, scored higher than the female students as a group, the difference was small but statistically significant (p = 0.015). CONCLUSION: Performance on the SPM inclines in favour of the male gender group. More research needs to be carried out into the other possible factors that could explain the gender disparity in medical colleges in Pakistan. PMID- 20929040 TI - Attitude of teaching faculty towards statistics at a medical university in Karachi, Pakistan. AB - BACKGROUND: Statistics is mainly used in biological research to verify the clinicians and researchers findings and feelings, and gives scientific validity for their inferences. In Pakistan, the educational curriculum is developed in such a way that the students who are interested in entering in the field of biological sciences do not study mathematics after grade 10. Therefore, due to their fragile background of mathematical skills, the Pakistani medical professionals feel that they do not have adequate base to understand the basic concepts of statistical techniques when they try to use it in their research or read a scientific article. The aim of the study was to assess the attitude of medical faculty towards statistics. METHODS: A questionnaire containing 42 close ended and 4 open-ended questions, related to the attitude and knowledge of statistics, was distributed among the teaching faculty of Dow University of Health Sciences (DUHS). One hundred and sixty-seven filled questionnaires were returned from 374 faculty members (response rate 44.7%). RESULTS: Forty-three percent of the respondents claimed that they had 'introductive' level of statistics courses, 63% of the respondents strongly agreed that a good researcher must have some training in statistics, 82% of the faculty was in favour (strongly agreed or agreed) that statistics was really useful for research. Only 17% correctly stated that statistics is the science of uncertainty. Half of the respondents accepted that they have problem of writing the statistical section of the article. 64% of the subjects indicated that statistical teaching methods were the main reasons for the impression of its difficulties. 53% of the faculty indicated that the co-authorship of the statistician should depend upon his/her contribution in the study. Gender did not show any significant difference among the responses. However, senior faculty showed higher level of the importance for the use of statistics and difficulties of writing result section of articles as compared to junior faculty. CONCLUSION: The study showed a low level of knowledge, but high level of the awareness for the use of statistical techniques in research and exhibited a good level of motivation for further training. PMID- 20929041 TI - Individual differences and stress-performance relationship. AB - BACKGROUND: Medicine is a high risk profession. Infectious diseases, dealing with difficult patients, accidents on the job, and other hazards have shortened the careers of many practitioners. The extent to which they experience stress turns into poor performance in terms of quality of patient care. Personality traits are often thought to affect the stress that a person perceives. Specific types of personalities seem to be more susceptible to the effects of stress than others. Job performance is associated with different levels of stress. The purpose of the present study was to investigate any effect of job stress on job performance and effect of personality type on the stress-performance relationship. METHODS: All 55 house officers enrolled at Ayub Teaching Hospital at the time of study were included in the study. Primary data was gathered through questionnaire designed to address personality type and to gathered information about job stress and performance. Individual semi-structured interviews and observations were used to collect information in order to find out how the work patterns have been influenced by environmental factors. The data obtained through questionnaire was analysed using the statistical methods including descriptive statistics, Spearman's correlation and multiple regression. RESULTS: The results indicated that Type A individuals tend to experience more stress than Type B, however no major statistical differences were found. Type A individuals performed slightly better than Type B. CONCLUSION: Identification of house officers' personality traits will be helpful in assessing stress and designing different stress coping strategies to reduce their level of stress and improve their performance. The correlation between job stress and job performance among house officers with Type A personality characteristics is high. PMID- 20929042 TI - Fracture penis with complete urethral disruption during intercourse. AB - We present a rare case of fracture penis with complete urethral disruption in a 38 years old male. This resulted in an erect penis during sexual intercourse. He presented with diffuse and tense swelling of the penis along with acute urinary retention and distended urinary bladder. Emergency exploration revealed complete urethral disruption with tears in both corpus cavernosa. Evacuation of haematoma, repair of corpora and primary urethral repair was performed. Post-operative recovery was smooth and the patient developed satisfactory erectile and voiding function. PMID- 20929043 TI - Epidermoid inclusion cyst of the perineum--a rare case report in a 50 years old male. AB - A 50 year old male presented with a history of mid line painless swelling in the perineum for last 4 years. The patient's only concern was a perineal swelling which was gradually increasing in size. Clinical examination mimics subcutaneous lipoma with soft lobulated surface with positive slip sign. The base line investigations were within normal limits. Complete surgical excision of the cyst performed. Histopathology confirmed epidermal inclusion cyst with no evidence of malignancy. Patient discharged on next day. The follow-up visits were un remarkable. Perineal epidermal inclusion cyst is a rare entity and only few cases have been reported. PMID- 20929044 TI - Post hysterectomy spontaneous rupture of spleen. AB - Spontaneous rupture of spleen is a rare entity in the world of obstetrics and gynaecology. The obstetricians-gynaecologist has to confront with ruptured spleen sometimes in their practice. Ruptured spleen is not uncommon in trauma and some surgical procedures in upper abdomen. Splenic rupture after hysterectomy is exceedingly rare occurrence. However it should be considered as part of diagnostic workup in any unstable post hysterectomy subject with high degree of suspicion along with other differential diagnosis. Early reorganisation of this potentially life-threatening complication is very important for the wellbeing of patient and carries medico legal significance as well. We are reporting fourth case of spontaneous rupture spleen after abdominal hysterectomy found in the literature along with literature review and update on the topic regarding its diagnostic criteria. PMID- 20929045 TI - Calculation of LD50 values from the method of Miller and Tainter, 1944. PMID- 20929046 TI - Environmental pollution and experimental pharmacological approaches. Preface. PMID- 20929047 TI - Idiopathic environmental intolerances (IEI): from molecular epidemiology to molecular medicine. AB - Inherited or acquired impairment of xenobiotics metabolism is a postulated mechanism underlying environment-associated pathologies such as multiple chemical sensitivity, fibromyalgia, chronic fatigue syndrome, dental amalgam disease, and others, also collectively named idiopathic environmental intolerances (IEI). In view of the poor current knowledge of their etiology and pathogenesis, and the absence of recognised genetic and metabolic markers of the diseases. They are often considered "medically unexplained syndromes",. These disabling conditions share the features of polysymptomatic multi-organ syndromes, considered by part of the medical community to be aberrant responses triggered by exposure to low dose organic and inorganic chemicals and metals, in concentrations far below average reference levels admitted for environmental toxicants. A genetic predisposition to altered biotransformation of environmental chemicals, drugs, and metals, and of endogenous low-molecular weight metabolites, caused by polymorphisms of genes coding for xenobiotic metabolizing enzymes, their receptors and transcription factors appears to be involved in the susceptibility to these environment-associated pathologies, along with epigenetic factors. Free radical/antioxidant homeostasis may also be heavily implicated, indirectly by affecting the regulation of xenobiotic metabolizing enzymes, and directly by causing increased levels of oxidative products, implicated in the chronic damage of cells and tissues, which is in part correlated with clinical symptoms. More systematic studies of molecular epidemiology, toxico- and pharmaco-genomics, elucidating the mechanisms of regulation, expression, induction, and activity of antioxidant/detoxifying enzymes, and the possible role of inflammatory mediators, promise a better understanding of this pathologically increased sensitivity to low-level chemical stimuli, and a solid basis for effective individualized antioxidant- and/or chelator-based treatments. PMID- 20929048 TI - Developmental exposure to lead and late life abnormalities of nervous system. AB - Role of developmental exposure to environmental agents in altering the disease process is well known. Exposure to chemical agents at critical periods of development may cause some permanent changes in the functioning of various vital systems including the nervous system in the organisms. It is not surprising to see an extensive response due to exposure to chemical agents early in life as the organ systems are more vulnerable to chemical insults during developmental stages. In some cases the response to low level environmental insults may not be obvious until adult or old age. Results from several studies have shown such latency in response to the nervous system leading to neurodegeneration in old age. Studies conducted in murine and primate models provided ample evidence for the association of developmental exposure to low levels of heavy metal lead (Pb) and Alzheimer's disease-like pathology during senescence. It is not clear about the reasons behind such response; however, the contribution of epigenetic mechanisms could explain the role of early events in life in inducing the late life abnormalities of nervous system. It is possible that environmental agents epigenetically modulate the gene regulation to persist the response silent for a long period of time and to result pathological outcomes significantly later in life. This article will summarize the association of early life exposure to environmental agents and late-life abnormalities with an emphasis on developmental exposure to Pb and neurodegeneration in old age. PMID- 20929049 TI - Pharmacological agents in the prophylaxis/treatment of organophosphorous pesticide intoxication. AB - Organophosphorus pesticide poisoning causes tens of thousands of deaths each year across the world. Poisoning includes acute cholinergic crisis as a result of AChE inhibition, intermediate syndrome (IMS) due to neuromuscular necrosis and organophosphate-induced delayed neuropathy (OPIDN) due to inhibition of neuropathy target esterase (NTE). Standard treatment for acute poisoning involves administration of intravenous atropine, oxime 2-PAM to counter AChE inhibition and diazepam for CNS protection. However clinical trials showed ineffectiveness of the standard therapy regimen. Although new oximes that can reactivate both peripheral and cerebral AChE and other prophylactic agents such as human serum butyrylcholinesterase (Hu BChE), sodium bicarbonate, huperzine A (a reversible ChE inhibitor) with imidazenil (a GABAA receptor modulator) have been proved effective in animal models, systematic clinical trials in patients are warranted. For IMS which is non-responsive to standard therapy, supportive therapy specifically artificial respiration followed by recovery is indicated. For OPIDN which has a different target (NTE) than AChE, standard therapy is ineffective. However neuroprotective drugs such as corticosteroids proved partially effective. Pretreatment with protease inhibitor PMSF has been shown to protect the aging of NTE and prevent the development of delayed symptoms in hens. Since the biology of NTE is being explored, new pharmacological agents should be developed in future. OP pesticide poisoning is a serious condition that needs rapid diagnosis and treatment. Since respiratory failure is the major reason for mortality, artificial respiration, careful monitoring, appropriate treatment and early recognition of OP pesticide poisoning may decrease the mortality rate among these patients. PMID- 20929050 TI - Association of functionally important polymorphisms in cytochrome P450s with squamous cell carcinoma of head and neck. AB - Head and neck squamous cell carcinoma (HNSCC), a common malignancy that possibly involves a combination of exposure to the carcinogens and inherited genetic differences in the enzymes catalyzing their metabolism. Alcohol and tobacco consumption are the primary environmental risk factors, while polymorphism in various biotransformation enzymes such as cytochrome P450s (CYPs) and glutathione S-transferases, (GSTs) has been implicated as the major genetic risk factors for the development of HNSCC. The functionally important polymorphisms in these CYPs (1AI*2A, 1A1*2C, 1B1*2, 2E1*5B, 2E1*6, 2C19*2, 2D6*4, 2D6*10) and GSTs (GSTM1 null or GSTT1-null) were found to be significantly associated with HNSCC risk. Significant differences in the distribution of certain haplotypes of CYPs have also been reported and prevalence of certain genotype combinations of CYPs and GSTS in cases has indicated the importance of gene-gene interactions in HNSCC risk. Alcohol or tobacco use (smoking and chewing) were also found to interact synergistically with variant genotypes of these CYPs and GSTS in significantly enhancing HNSCC risk. This increase in risk associated with the variant genotypes with tobacco or alcohol use have further demonstrated the importance of gene environment interactions in determining the susceptibility to HNSCC. PMID- 20929051 TI - Arsenic and fluoride: two major ground water pollutants. AB - Increasing human activities have modified the global cycle of heavy metals, non metals and metalloids. Both arsenic and fluoride are ubiquitous in the environment. Thousands of people are suffering from the toxic effects of arsenicals and fluorides in many countries all over the world. These two elements are recognized worldwide as the most serious inorganic contaminants in drinking water. Many studies have reported as regards to simple fluorosis and arsenicosis, but the knowledge of the joint action of these two elements is lacking and the results derived from previous studies were inconclusive. Contradictory results were reported in experimental studies in which different joint actions such as independent, synergistic and antagonistic effects were observed. This indicates that interaction mechanism of these two elements is considerable complicated and requires extensive studies. When two different types of toxicants are simultaneously going inside a human body they may function independently or can act as synergistic or antagonistic to one another. Thus there is an urge to resolve the question that how arsenic and fluoride act in condition of concomitant exposure. Although there have been reports in literature of individual toxicity of arsenic and fluoride however, there is very little known about the effects following the combined exposure to these toxicants. This review focused on recent developments in the research on the condition of individual exposure to arsenic and fluoride along with the recent updates of their combined exposure to better understand the joint action of these two toxicants. PMID- 20929052 TI - Resistance to heavy metal toxicity in organisms under chronic exposure. AB - The rate of changes of heavy metal ions concentrations in the organism or biological system will determine the choice of strategy of realization of heavy metal ions effect and, consequently, the biological effect itself. Which of the possible strategies will dominate, depend on the rate of changes of concentration of heavy metal ions in biological systems, functional activity of organism at the moment of metal action and on metals chemical properties. Keeping this view, the present review deals with the concept of time-based alterations of concentration of heavy metal ions (TACMI) in biological systems. On the basis of TACMI concept formation of organism resistance to metal ions action could be explained. In the event of slow increase of its concentration in organism, it produces induction of metallothioneins, other stress-proteins and relative changes in the whole metabolic system. This, first of all, results in formation of new specific epigenotypes, which provide higher resistance (hormesis effect) not only to metal ions that induced this effect, but also to such stress-factors as high temperature (at least, for micro-algae cells). PMID- 20929053 TI - Cellular and molecular mechanisms of dichlorvos neurotoxicity: cholinergic, nonchlolinergic, cell signaling, gene expression and therapeutic aspects. AB - Inappropriate use of toxic chemicals is common in developing countries, where it leads to excessive exposure and high risks of unintentional poisoning. Risks are particularly high with the pesticides used in agriculture, poor rural populations live and work in close proximity to these compounds and often store these compounds in and around their homes. It is estimated that most of the death from pesticide poisoning occur in developing countries. Organophosphate insecticides have been extensively used in agriculture in developing countries. Dichlorvos is a synthetic insecticide and belongs to a family of chemically related organophosphate pesticides (OP). Toxicity of dichlorvos has been documented in accidental human poisoning, epidemiological studies, and animal models. In this review, molecular mechanisms of dichlorvos neurotoxicity have been described. Usage, biotransformation, environmental levels, general population and occupational exposure, effects on cell signaling receptors, mitochondrial metabolism, oxidative stress and gene expression of dichlorvos have been reviewed. Assessment of acute and chronic exposures as well as neurotoxicity risk for lifetime exposures to dichlorvos have also been considered. In addition special emphasis has been given to describe, the role of dichlorvos in the chronic neurotoxicity and its molecular targets that ultimately lead to neurodegeneration. PMID- 20929054 TI - Effects of diesel exhaust, heavy metals and pesticides on various organ systems: possible mechanisms and strategies for prevention and treatment. AB - Environmental pollutants have a significant impact on the ecosystem and disrupt balance between environment, human and non-human components that result in deleterious effects to all forms of life. Identifying environmental factors for potential imbalance are extremely crucial for devising strategies for combating such toxic dysregulation. Automobile exhaust (in air), heavy metals (in food and water) and pesticides (in air, food, soil and water) are the most common environmental pollutants and their short and long-term exposures can cause hazardous effects in humans leading to systemic disorders involving lungs, kidney and immune systems. Mechanisms involved in genesis of such toxic effects have revealed complex, interactive pathways. Strategies for the protection of homeostasis and health, viz., general preventive measures, nutritional supplements and herbal agents have been described, to counter these pollutants induced damaging effects on various body systems. PMID- 20929055 TI - Altered glucose homeostasis in response to aluminium phosphide induced cellular oxygen deficit in rat. AB - The present study was designed to analyze the effect of acute aluminium phosphide (ALP) (10 mg/kg body wt.) exposure on the glucose homeostasis in rat liver and brain. ALP has been implicated in the inhibition of cytochrome oxidase causing reduced oxygen uptake and decreased ATP synthesis eventually resulting in cellular energy crisis. A significant decrease in plasma glucose levels in the ALP treated rats has been observed. Therefore, decreased ATP levels coupled with hypoglycemia may further intensify the cellular energy deficits. In order to meet the sudden increase in the local energy demand, the brain tissue utilizes its stored energy in the form of glycogen breakdown as observed by a decrease in the glycogen levels in both liver and brain which was accompanied by a marked increase in the activity of glycogen phosphorylase in both the tissues. The glycolytic rate was found to be enhanced in brain tissue as evident by increased activities of hexokinase and phosphofructokinase enzymes, but decreased in liver of ALP treated rats. Lactate levels were increased in plasma and brain, but decreased in liver of ALP treated rats. Pyruvate levels increased in the plasma and liver, but no change was observed in the brain tissue. ALP did not cause any change in the gluconeogenic enzymes like glucose-6-phosphatase and fructose-1,6 bisphophatase in brain, but a significant increase was observed in the liver. Results of the study showed that ALP induced cellular energy deficit leads to compromised energy status of liver and brain coupled with substantial alterations in glucose homeostasis. However, the activity of glucose-6-phosphate dehydrogenase decreased significantly in both the tissues. PMID- 20929056 TI - Cyanide-induced changes in the levels of neurotransmitters in discrete brain regions of rats and their response to oral treatment with alpha-ketoglutarate. AB - Cyanide is a potential suicidal, homicidal and chemical warfare agent. It produces histotoxic hypoxia following inhibition of cytochrome c oxidase, a terminal respiratory chain enzyme. The profound metabolic changes lead to neurotoxicity including alterations in the levels of neurotransmitters. The present study addressed the effect of acute exposure of lethal and sub-lethal doses of potassium cyanide (KCN; 0.75 or 2.0 LD50; po) on the levels of neurotransmitters in discrete brain regions of rats and its response to treatment with alpha-ketoglutarate (alpha-KG; 0.5 g/kg; po; -10 min) alone or with sodium thiosulphate (STS; 1.0 g/kg; ip; -15 min). KCN significantly decreased norepinephrine, dopamine and 5-hydroxytryptamine levels in different brain regions which were resolved by alpha-KG and/or STS. Corpus striatum and hippocampus were more sensitive as compared to cerebral cortex and hypothalamus. alpha-KG, a potential cyanide antidote alone or with STS showed neuroprotective effects against cyanide. PMID- 20929057 TI - Microsomal Ca2+ flux modulation as an indicator of heavy metal toxicity. AB - Inositol 1,4,5-trisphosphatee (IP3), an intracellular messenger, releases Ca2+ from microsomes. Ca2+ plays a major role in regulating various cellular events like neural transmission and regulation of hormones and growth factors. Aluminum (Al), lead (Pb) and mercury (Hg) were reported to alter Ca(2+)-regulated events thereby causing neurotoxicity. Hence, an attempt was made characterize IP3 mediated Ca2+ release from rat brain microsomes under the influence of Al, Pb and Hg. Different concentrations of metals were tested over a designated time scale and their effects on IP3 mediated Ca2+ release from microsomes were monitored using Fura-2 technique. All the three metals inhibited IP3 mediated Ca2+ release, Pb being more potent. The order of potency of these three metals was Pb>Hg>Al. Except for Al, both Hg and Pb independently released Ca2+ from microsomes. Re uptake of Ca2+ into microsomes was inhibited by all the three metals, Pb being more potent. Microsomal Ca(2+)-ATPase activity was also inhibited by all the three metals. These results suggest that neurotoxicity exerted by Al, Pb and Hg may be due to the interference of these metals with IP3 mediated calcium release and also interfering with the microsomal Ca2+ sequestration mechanism. Differential effects of heavy metal induced changes in Ca2+ flux can be used as an index of relative toxicity. PMID- 20929058 TI - Acute and sub-acute toxicity of an insect pheromone, N-heneicosane and combination with insect growth regulator, diflubenzuron, for establishing no observed adverse effect level (NOAEL). AB - Aedes aegypti mosquito is one of the most notorious vectors of dangerous diseases like dengue hemorrhagic fever and chikangunya. One method of control of the vectors is by the use of semiochemicals or pheromones. The pheromone n heneicosane (C21) has been proved to be effective in attracting the female Aedes aegypti to lay eggs in the treated water and the growth of the larva is controlled by insect growth regulator diflubenzuron (DB). This study was planned to assess the safety of C21 alone and the combination with DB. Acute toxicity tests were carried out using two doses, viz., 1600 and 3200 mg/kg and two routes of exposure oral and intra-peritoneal. Dermal toxicity test was carried out in both male and female rats at the dose of 3200 mg/kg. Primary skin irritation test was carried out in rabbits. Sub-acute (90 days) dermal toxicity studies in male and female rats at the dose of 1 and 2 mg/kg via the per-cutaneous route were also studied. Sub-acute (90 days) toxicity test through the oral route was carried out, at doses 125, 250 and 500 mg/kg in male and female rats. The calculated LD50 by ip route and dermal route was more than 5 g/kg in mouse and rats of both the sexes. In the primary skin irritation test no significant changes were noted. In the sub-acute toxicity studies even 500 mg/kg dose was not able to produce toxic response in rats when they were dosed daily for 90 days. The established no observed adverse effect level (NOAEL) was more than 500 mg/kg. PMID- 20929059 TI - Prophylactic efficacy of combination of DRDE-07 and its analogues with amifostine against sulphur mustard induced systemic toxicity. AB - Sulphur mustard, [bis (2-chloroethyl)] sulphide (SM), is a bifunctional alkylating agent. SM forms sulphonium ion in the body which alkylates DNA and several other macromolecules, and induces oxidative stress. Although several antidotes have been screened for the treatment of systemic toxicity of SM in experimental animals none of them are recommended so far. In the search for more effective and less toxic antidotes, various combinations were tried against SM induced toxicity and skin lesions. SM exposed through percutaneous route was used to evaluate the prophylactic efficacy of various combinations. Low dose of DRDE 07 (S-2(2-aminoethylamino) ethyl phenyl sulphide), DRDE-30 [S-2(2-aminoethyl amino) ethyl propyl sulphide], DRDE-35 [S-2(2-aminoethyl amino) ethyl butyl sulphide] with amifostine combinations, were given orally 30 min prior to SM exposure. Significant depletion was observed in body weight, organ body weight index and hepatic GSH and GSSG content in mice after SM exposure. Pretreatment with low dose of different combinations of DRDE-07, DRDE-30 and DRDE-35 with amifostine could recover biochemical alterations and histopathological changes caused by SM exposures. PMID- 20929060 TI - Sub-chronic arsenic exposure aggravates nephrotoxicity in experimental diabetic rats. AB - The present experiment was planned to study nephrotoxicity in experimental diabetic rats under sub-chronic exposure to arsenic. Alloxan induced diabetic and control rats were exposed to sodium arsenite (0 and 5.5 mg/kg, orally) for 30 days. More pronounced nephrotoxic effects were noted in arsenic exposed diabetic group as evidenced by increased blood urea nitrogen, serum creatinine and relative kidney weight and decreased level of reduced glutathione and glutathione peroxidase activity compared to non arsenic exposed diabetic group. Increased level of lipid peroxidation, protein oxidation, superoxide dismutase and catalase activities under diabetic condition remained unchanged in arsenic exposed diabetic group compared to unexposed diabetic group. PMID- 20929061 TI - Creating patient service excellence. PMID- 20929062 TI - John Black: Renaissance man. PMID- 20929063 TI - [Warfarin therapy and hemarthrosis]. AB - Bleeding in patients on oral anticoagulant treatment is not uncommon, but hemarthrosis has been described only in few patients. This is a case report of a patient on warfarin due to recurrent venous and arterial thromboembolism, with congenital thrombophilia and Behcet's disease. This report presents knee hemarthrosis during warfarin therapy, reviews the literature and discusses this issue. PMID- 20929064 TI - [Thrombophilia and thrombosis in children--lessons from cerebral sinus vein thrombosis registry of a tertiary center]. AB - BACKGROUND: Pediatric thrombosis is a rare event, and its pathophysiology is often associated with the presence of thrombophilic risk factors as welt as acute comorbid conditions. Sinus venous thrombosis [SVT] in childhood is a serious disease with reported annual incidence of 0.67 per 100,000 children. The etiology and pathophysiology of SVT in the pediatric population is stilt poorty understood, and the role of thrombophilic risk factors remains to be elucidated. METHODS: In our single tertiary center registry the authors documented all new acute cases of radiologically confirmed SVT from 1996 to 2008. Children were consecutively referred for thrombophilia work-up. Anticoagulant therapy was applied according to treating physicians' decision and all cases were prospectively followed for a median of 5 years. RESULTS: Our patient group included 15 males and 8 females whose median age was 2.9 years. Comorbid systemic illness was present in patients at diagnosis. Thrombophilia results were similar in comparison to pediatric controls previously collected at the said medical center. Short term anticoagulation was immediately initiated in most cases, and neurologic outcome was good. Neither clinical presentation nor acute-phase treatment decisions were affected by the presence of thrombophilic risk factors in the specified study group. Nevertheless, since SVT is a rare multifactorial disorder, imaging studies are recommended in sick "high-risk" children for better diagnosis and early initiation of anticoagulant treatment. Despite the presence of comorbid conditions in most cases, thrombophilia work-up is recommended to determine treatment length and assess potential further future risks. PMID- 20929065 TI - [Prevention of venous thromboembolism--what have we learned and how well are we doing?]. AB - INTRODUCTION: In recent years, awareness regarding thromboprophylactic treatment for hospitalized patients at risk has grown significantly. Large trials incorporating thousands of patients published in recent years have proved that prophylactic treatment is effective and reduces the rates of hospital-acquired venous thromboembolism. PATIENTS AND METHODS: Two cross-sectional studies held in medical and general surgery wards have found that, similar to other medical centers worldwide, hospitalized patients are older, have many medical problems, and suffer from reduced mobility. These risk factors exist in approximately half of the patients in medical wards and should lead to prophylactic therapy, however only 22% of such high risk patients actually received treatment. In non-operated general surgery patients, the rate of prophylaxis use is even lower. In patients after surgery, the rate of use is higher but not optimal. Although in a survey most of the directors in medical and surgical wards claimed that prophylaxis is an important issue, and that they support prophylaxis regimens, the rate of prophylaxis was generally low and unsatisfying. CONCLUSION: Patients hospitalized at medical and surgical wards are at risk of acquiring venous thromboembolism, however rates of prophylaxis are low. Methods to improve prophylaxis rates should be adopted. PMID- 20929066 TI - [Aortic atheroma and splenic emboli]. AB - The association between atheroma of the thoracic aorta and systemic embolization to the brain and other organs was discovered in the early 1990s in concordance with the improvement in the trans-esophageal echocardiography technique. The optimal treatment for secondary prevention of recurrent emboli is controversial, since the results of several studies differ and even contradict one another. In this article, the authors describe a man with splenic infarct, originating from a mobile descending aortic plaque. The cLinical approach for prevention of recurrent emboli is discussed, including the surgical and medical treatment options, and the literature on that subject is reviewed. Due to the absence of guidelines for optimal treatment in these cases and the Lack of conclusive randomized trials, the chosen treatment should be individualized, based on the characteristics of the plaque and other risk factors of each patient. PMID- 20929067 TI - [Von Willebrand disease: diagnostic and treatment dilemmas]. AB - Von Willebrand disease (VWD) is the most common hereditary bleeding disorder, characterized by skin and mucosaL bleeding in most of the cases. In the Western world, the approximate number of bleeding VWD patients is 6.9 to 17 million. The disease is represented by several types with specific treatment for each type. Diagnosis can be troublesome and, therefore, n order to prevent bleeding complications, a professional clinical/laboratory team is required. PMID- 20929068 TI - [Megakaryocyte development and platelet production in normal and disease states]. AB - Megakaryocytopoiesis involves the commitment of hematopoietic stem cell, the proliferation and terminal differentiation of the megakaryocytic progenitors and maturation to platelet producing megakaryocytes (MK). MKs align adjacent to bone marrow vascular endothelial cells, and form proplatelets. Platelets are released, or sheared from the MK directly into the circulation from the tips of proplatelets which protrude into the vascular lumen. The regulation of megakaryocytopoiesis is mediated through multiple hematopoietic growth factors, chemokines and cellular interactions via signal transduction pathways and integrated transcription factors. The primary physiological growth factor that regulates megakaryocytopoiesis and platelet production is thrombopoietin. Circulating Levels of thrombopoietin (TPO) induce concentration-dependent proliferation and maturation of MK progenitors by binding to the c-Mpl receptor and signaling induction. Increased concentration of free TPO resulting from decreased platelet turnover rates enables the compensatory response of marrow MKs to drive amplified platelet production. C-MpL signaling is orchestrated by a complex cascade of signaling molecules inducing the action of specific transcription factors to drive MK proliferation and maturation. Newly developed thrombopoietic agents operating via c-Mpl receptor have now been proven useful in supporting platelet production in thrombocytopenic states. In this article, the authors review the regulation of megakaryocytopoiesis and platelet production in normal and disease states, and new approaches of thrombopoietic therapy. PMID- 20929069 TI - [Inherited bleeding disorders common in Jews]. AB - Four inherited disorders of hemostasis have been identified in Jews with a relatively high frequency: Factor XI deficiency, factor VII deficiency, combined factor V and VIII deficiency and GLanzmann thrombasthenia. During the past decades, the bleeding manifestations of these disorders, the diagnosis, the molecular-genetic basis and therapy have been discerned. Furthermore, the prevalence of the respective mutant genes have been delineated in various Jewish Communities. Each one of the disorders can serve as a model enabling better understanding of the pathophysioLogy of the coagulation systems. On the basis of data obtained from the research of Glanzmann thrombasthenia, several widely used drugs have been developed as effective antithrombotic agents. PMID- 20929070 TI - [Fat embolism syndrome following injuries and limb fractures]. AB - Fat embolism syndrome is a clinical entity characterized by varying degrees of cerebral dysfunction, pulmonary changes and petechial rash that usually develop within 24-48 hours in a small percentage of victims after trauma and Long bone fractures. Deterioration can occur within a few hours Leading to unconsciousness or acute respiratory insufficiency, similar to adult respiratory distress syndrome (ARDS). The pathophysiology is still not clearly understood and there are two theories--the mechanical and biochemical cascade of events. It seems that the most significant diagnostic sign is hypoxemia with relatively normaL values of PaCO2 leading to development of radiographic "snow-like appearance" of the Lungs, resulting from the typical interstitial lung edema. Treatment consists of early fracture fixation, volume replacement, respiratory support and analgesia carefully managed since some of the patients may develop acute respiratory distress. The role of steroids and other drugs is still under debate. The vast majority of patients may heal without any complications, while 5%-10% of the patients may develop some neurological complications manifesting as behavior disturbances. The aim of this review is to update the clinical and pathophysiological aspects of fat embolism syndrome and to describe the various aspects of prevention and treatment. PMID- 20929071 TI - [Effect of iron deficiency and iron deficiency anemia in the first two years of life on cognitive and mental development during childhood]. AB - INTRODUCTION: The prevalence of iron deficiency anemia among infants and children over the world ranges between 2%-22.5%. Iron is essential for intact development of the body, and especiaLLy for the development of the central nervous system in the first two years of Life. OBJECTIVES: To examine, through a review of the literature, if there is any relation between iron deficiency and iron deficiency anemia (IDA), and cognitive and mental development in the first two years of life. METHODS: A review of 10 longitudinal and clinical trials from the last 16 years, in which this correlation was examined. RESULTS: According to recent studies, the relation between iron deficiency and iron deficiency anemia to cognitive and mental development in childhood is stiLL unclear. Followup studies found poorer cognitive scores on measures of mental and cognitive functioning in the long run. Intervention trials in which iron supplementation was administered to infants with IDA, found an improvement in Language and mental deveLopmental test scores. However, micronutrient intervention, or zinc and iron combined or alone, did not improve performance on mental tests. The studies differed in the characteristics of the study population, definition of exposure, type of treatment and confounders. CONCLUSIONS: It is difficult to assess a causal relationship between iron deficiency and iron deficiency anemia, and cognitive and mental development in childhood, mainly due to methodoLogical and ethical reasons. However, most studies from recent years support a negative association. The Ministry of Health in israel recommends iron as a preventive action for iron deficiency in infants. PMID- 20929072 TI - [Splenic metastases from female genital tract malignancies]. AB - Splenic metastases are rare. Usually, they are part of a disseminated disease and located on the splenic capsule. Common sources are breast cancer, lung cancer and malignant melanoma. SoLitary splenic metastases are rare, usuaLLy located in the splenic parenchyma and metastasizing via the hematogenous route. Splenic metastases from ovarian carcinoma are usuaLly part of a disseminated disease, located on the splenic capsule and metastasize via the peritoneum. Splenic metastases from endometriaL carcinoma are usuaLLy solitary, Located in the splenic parenchyma and metastasize via the hematogenous route. Splenic metastases from cervical carcinoma are divided equally between metastases as part of a disseminated disease and soLitary metastases. Less than 100 cases of solitary splenic metastases have been reported with half of them being metastases from female genital tract malignancies: 30--ovarian carcinoma; 11--endometriaL carcinoma; 8--cervical carcinoma; and 1--tubal carcinoma. Few cases have been reported of splenic rupture because of metastases from choriocarcinoma. Splenic metastases as part of a disseminated disease are associated with poor prognosis, and splenectomy--apart from cases in which it might assist in achieving optimaL debulking--is not effective. Solitary splenic metastases represent a more moderate disease and the treatment of choice is splenectomy. SoLitary splenic metastases may be detected after an interval from the diagnosis of the primary disease. Hence, patients who had been treated for female genital tract malignancy, even if they are asymptomatic, need a long-term follow-up, including serial imaging studies of the spleen. PMID- 20929073 TI - [Breaking the bad news--effective communication with children]. PMID- 20929074 TI - The red reflex examination in neonates: an efficient tool for early diagnosis of congenital ocular diseases. AB - BACKGROUND: The American Academy of Pediatrics recently published recommendations for the red reflex assessment in the newborn period to detect and treat ocular disorders as early as possible, and to prevent lifelong visual impairment and even save lives. The test is technically simple to perform, non-invasive, requires minimal equipment and can detect a variety of ocular pathologies including cataracts and retinal abnormalities. No specific national guidelines exist on this issue. OBJECTIVES: To document the implementation of red reflex examination in routine neonatal care and present the findings. METHODS: Our clinical experience following inclusion of the red reflex test into the newborn physical examination in a single center was reviewed. In addition, an electronic mail questionnaire was sent to all neonatology departments in Israel regarding performance of the red reflex test. RESULTS: During 2007-2008, five infants were identified with congenital cataracts at days 2-6 of life prior to discharge from hospital. Surgery was performed in one infant at age 2 months and all infants underwent a thorough follow-up. The incidence of congenital cataract in our center was 1:2300. Less than half the neonatology departments have endorsed the AAP recommendation and perform the red reflex test routinely. CONCLUSIONS: Abnormal red reflex test after delivery enables a rapid ophthalmologic diagnosis, intervention and close followup. We recommend that red reflex screening be performed as part of the newborn physical examination; if abnormal, an urgent ophthalmologic referral should be made. PMID- 20929075 TI - A costly covenant: ritual circumcision and urinary tract infection. AB - BACKGROUND: Ritual circumcision in neonates may cause a urinary tract infection within 2 weeks of the procedure. OBJECTIVES: To evaluate the prevalence of urinary tract infection among Jewish male circumcised neonates < or = 28 days old) evaluated for fever in the emergency room. METHODS: All available medical records of neonates presenting to the pediatric emergency room for evaluation of fever over a 10 year period were reviewed. Data included gender, ethnic background, age (in days) on presentation to the emergency room, age (in days) when circumcision was performed (in males > or = 8 days of age), and results of urine, blood and cerebrospinal fluid cultures. Families of males older than 8 days of age who had a UTI were contacted by telephone to verify the circumcision status when the infant presented to the ER, to ascertain whether the circumcision had been performed ritually by a mohel* or by a physician, and, if not recorded in the chart, to verify the day of life on which circumcision was performed. RESULTS: Among neonates older than 8 days of age, 60 (24.7%) of the 243 febrile Jewish males had a UTI, as compared to 12 (8.4%) of 143 females (P < 0.0001). In 39 of 54 male neonates (72%) for whom circumcision was performed ritually on the eighth day of life, UTI occurred within 9 days of the circumcision. For females, there was no such clustering of UTI cases in the second week of life, nor during any other time period. CONCLUSIONS: Febrile male neonates who have undergone ritual circumcision have a high prevalence of UTI and must be evaluated and treated accordingly. PMID- 20929076 TI - Prevalence of celiac disease in an adult Jewish population in Israel. AB - BACKGROUND: In the last decade the frequency of celiac disease diagnosis has increased in adults. OBJECTIVES: To determine disease prevalence (including silent and potential disease) in this population group. METHODS: We performed serologic screening of celiac disease in a representative and homogenous sample of a young adult general population in Israel, namely, 18 year old military conscripts, in 2003. Serologic screening was performed on serum samples randomly obtained from 850 healthy recruits (male/female = 1.1). Immunoglobulin A anti tissue transglutaminase was determined by enzyme-linked immunosorbent assay. In cases of IgA deficiency, lgG anti-endomysial antibodies were determined. A small intestinal biopsy was offered to all patients with positive serology. RESULTS: The prevalence of overt CD diagnosed prior to recruitment was 0.12% (0.1% in men and 0.14% in women). The overall prevalence based on positive serology was 1.1%. Six of nine subjects with positive serology agreed to undergo endoscopy and intestinal biopsies. In all cases, biopsies were compatible with celiac disease (five biopsies were graded as Marsh 3a and one as Marsh 3b). One subject previously reporting irritable bowel-like symptoms was diagnosed with overt atypical CD. The prevalence of overt CD diagnosed by screening was 0.12%. The ratio, of overt to silent CD was 1:8. No cases of potential CD were encountered. CONCLUSIONS: Our findings suggest that CD is highly prevalent in the young adult population in Israel. Serologic screening for CD is a reliable and simple method for diagnosing this disease before symptoms or complications develop. PMID- 20929077 TI - Preoperative staging using transrectal ultrasound in high and low rectal cancer. AB - BACKGROUND: An accurate preoperative definition of tumor and lymph node status is needed for reaching the correct decision regarding rectal cancer treatment. Transrectal ultrasonography is the most commonly used diagnostic modality for the local staging of rectal cancer. OBJECTIVES: To determine the accuracy of TRUS in the staging of rectal cancer. METHODS: We conducted a retrospective study on 95 patients evaluated by TRUS. The rectum was subdivided into two parts (lower and upper). RESULTS: Sixty patients underwent radical surgery. Of these, 34 received no preoperative chemo-irradiation owing to microT1, was suggested to patients with adenocarcinoma that proved to be microT3). The overall accuracy rate was 80% for T stage. Overstaging was found in 13.3% and understaging in 6.7%. The N-stage was correctly assessed in 70%. The overall accuracy rate for tumors was 73.9% in the lower part and 90.9% in the upper. A trend towards a lower accuracy rate for low-lying tumors compared to high-located rectal tumors was found (P = 0.532), which did not reach statistical significance. CONCLUSIONS: TRUS gave better results for T1 and T3 stage rectal tumors but was inaccurate for stage T2, indicating the possible need for local excision in order to base the final treatment for T2 tumors on pathologic staging. PMID- 20929078 TI - Characterization and clinical outcomes of drug-eluting in-stent restenosis. AB - BACKGROUND: The best therapeutic alternative for patients suffering from in-stent restenosis after drug-eluting stent implantation remains to be elucidated. OBJECTIVE: To characterize the pattern, treatment and outcomes of DES-related in stent restenosis in patients treated at our institution. METHODS: We determined the incidence and major adverse clinical events in 71 consecutive patients with DES failure among 2473 patients who were treated with 2548 drug-eluting stents between 2004 and 2007. We analyzed the clinical data, procedural parameters and clinical outcomes. RESULTS: The type and number of stents implanted were as follows: Cypher (n = 1808), Endeavor (421) and Taxus (319); of these, 53 (2.9%), 10 (2.4%), and 8 (2.5%) patients respectively presented with restenosis. The mean time to restenosis was 11.3 +/- 9.9 months. Patients' mean age was 65 +/- 11 years; 75% were male, and 68% had diabetes mellitus. Unstable angina was the clinical presentation in 52 (73%). At 6 months, 3 patients had developed myocardial infarction (4.2%), repeat restenosis at follow-up was diagnosed in 8 patients (11.3%), the overall major adverse clinical events rate was 18.3% (13 patients), and 2 patients died (2.8%). CONCLUSIONS: Drug-eluting stent-related restenosis is relatively infrequent but remains a clinical challenge. It occurs more frequently in complex lesion subsets, but the overall intermediate-term prognosis is tolerable. PMID- 20929079 TI - Age-related immunoglobulin G seroprevalence of human parvovirus B-19 in Israeli children. AB - BACKGROUND: Human parvovirus B19 is a global and common infectious pathogen in humans, particularly in children. OBJECTIVES: To assess the immunoglobulin G3 seroprevalence of B19 in children in Israel. METHODS: Overall, 128 previously healthy children (1.5-17 years old) hospitalized for various diseases other than acute human parvovirus B19 infection were assessed for IgG to the virus by enzyme linked immunosorbent assay. RESULTS: The IgG seroprevalence increased from 22% in children aged 1.5-9 years to 52% in older children (P = 0.001). CONCLUSIONS: Our data suggest that most acute parvovirus B19 infections in Israel occur in the early school years, and that by 18 years of age 50% of Israeli children have been infected by the virus. PMID- 20929080 TI - The endless differential diagnosis of acute obstructive renal failure: unusual challenges for the sharp-sighted clinician. AB - Obstruction of urine outflow can result from mechanical blockade as well as from functional defects. In adults, urinary tract obstruction is due mainly to acquired defects, such as pelvic tumors, calculi, and urethral stricture. In childhood it is mostly due to congenital malformations. In this article we present two rare cases of acute obstructive renal failure that presented with hydronephrosis. These cases underline the wide range of causes that may lead to this clinical feature. PMID- 20929081 TI - A pertussis outbreak among daycare children in Northern Israel: who gets sick? AB - BACKGROUND: An outbreak of pertussis occurred in a daycare center with 87.5% vaccination coverage. OBJECTIVES: To assess the effectiveness of the acellular pertussis vaccine and prevention of pertussis after chemoprophylaxis with azithromycin. METHODS: We studied 31 daycare children aged 3-5.5 years exposed to a child with pertussis. Nasopharyngeal swabs were obtained for Bordetella pertussis culture and polymerase chain reaction initially, and at days 21 and 60 of follow-up, in cases exhibiting symptoms. RESULTS: Of the 31 daycare children 6 (19%) tested positive for 8. pertussis by PCR, 4 of whom had not been vaccinated against the disease. Of the two vaccinated children who contracted pertussis, one had milder symptoms and the other was asymptomatic. The incidence of pertussis was significantly lower in the vaccinated group (2/27) than in the unvaccinated group (4/4) (P = 0.000), with efficacy of the vaccine calculated to be 92.5%. Azithromycin chemoprophylaxis was taken only by 14 of the 25 exposed children (56%). On day 21 follow-up, there was no further laboratory-diagnosed B. pertussis cases in any of the exposed children, regardless of whether or not chemoprophylaxis was taken. CONCLUSIONS: Based o the children's clinical manifestations and PCR findings a pertussis outbreak had occurred in the daycare center studied. Our findings support the importance of pertussis vaccination since all the unvaccinated children in the daycare center contracted the infection. PMID- 20929082 TI - Neurologic evaluations in normal-tension glaucoma workups: are they worth the effort? AB - BACKGROUND: Normal-tension glaucoma is a chronic progressive optic neuropathy of unknown etiology. Neuro-imaging workup in these patients is controversial. OBJECTIVES: To determine the value of routine neurologic and neuro-ophthalmologic evaluations in patients with NTG. METHODS: We conducted a retrospective review of all patients diagnosed with NTG in our institution between 2001 and 2006. Neurologic and neuro-ophthalmologic data were evaluated. RESULTS: Sixty-eight patients were considered suitable for the study 135 males, 33 females; age range 43-90 years). Neurologic and neuro-ophthalmologic findings were normal in all of them. The computed tomography brain scan was normal in 88% and duplex carotid Doppler scan was normal in 92%. CONCLUSIONS: Pathologic findings in neurologic and neuro-ophthalmologic assessments were uncommon in NTG. Therefore, contrary to earlier suggestions, neurologic and neuro-ophthalmologlc evaluations in typical normal-tension glaucoma patients appear to have no added value. PMID- 20929083 TI - Prognostic significance of HER-2/neu expression in patients with ductal carcinoma in situ. AB - BACKGROUND: The prognostic significance of biologic markers in women with ductal carcinoma in situ is not fully understood. HER2/neu is a marker of prognostic significance that is routinely assessed in invasive cancer but its correlation with clinical outcome in DCIS is still obscure. OBJECTIVES: To evaluate the significance of HER-2/neu expression as a prognostic marker in DCIS. METHODS: Clinical and pathologic data from 84 patients treated for DCIS were analyzed. HER 2/neu expression was determined by immunohistochemical staining. Histopathologic parameters (nuclear grade, histologic subtype, necrosis, calcifications, margins) were reviewed by an experienced pathologist. Local recurrence and/or metastatic spread were used as endpoints to determine the prognostic significance of HER 2/neu expression. RESULTS: With a median follow-up of 94.8 months, nine recurrences were reported. Neither univariate nor multivariate analysis showed a significant correlation between HER-2/neu expression and disease recurrence or the time to disease recurrence. Although HER-2/neu expression demonstrated a significant association with high nuclear grade (P < 0.0001) and comedo subtype (P < 0.0001), there was no correlation between these histologic features and recurrence rate. The correlation between high nuclear grade and disease recurrence approached statistical significance (P = 0.07). CONCLUSIONS: No significant association was found between HER-2/neu expression in DCIS and disease recurrence. However, HER-2/neu correlated with negative markers such as nuclear grading and comedo necrosis, and its role should therefore be investigated in larger studies. PMID- 20929084 TI - The Israel National Immunization Registry. AB - Immunization coverage is a major health indicator. In Israel, routine childhood immunizations are provided at community public well-baby clinics. Immunization monitoring is an important cornerstone of a national health policy; however data obtained through sampling carries the risk of under-representation of certain population strata, particularly high risk groups. Despite high national average immunization coverage, specific subpopulations are under-immunized, as highlighted by outbreaks of vaccine-preventable diseases. The mean national immunization coverage at age 2 years (2006 data) was: DTaP-IPV-Hib4 (all 93%), HBV3 (96%), MMR1 (94%), HAV1 (90%). These reports are based on a 17% population based sampIe in some districts and on cumulative reports in others. A national immunization registry requires data completeness, protection of confidentiality, compulsory reporting by providers, and links to other computerized health records. It should provide individual immunization data from infancy to adulthood and be accessible to both providers and consumers. In 2008 the Israel Ministry of Health launched a national immunization registry based on immunization reporting from well-baby clinics using a web-based computerized system. As of January 2010,120 well-baby clinics are connected to the nascent registry, which includes the records of some 50,000 children. The implementation of a comprehensive national immunization registry augurs well for the prospect of evidence-based assessment of the health status of children in Israel. PMID- 20929085 TI - Red reflex examination in neonates: the need for early screening. PMID- 20929086 TI - Ritual circumcision and urinary tract infection in Israel. PMID- 20929087 TI - An additional piece in the Israeli celiac disease puzzle. PMID- 20929089 TI - Mucosal small bowel metastasis from uterine leiomyosarcoma. PMID- 20929090 TI - Symptomatic spinal hemangioma in pregnancy. PMID- 20929088 TI - Molecular adsorbent recycling system therapy in the treatment of acute valproic acid intoxication. PMID- 20929091 TI - Overestimation by a hand-held glucometer of blood glucose level due to icodextrin. PMID- 20929092 TI - Should we operate on occult hip fractures? PMID- 20929093 TI - Metastasis of cervical carcinoma to the distal biliary system. PMID- 20929094 TI - One man's opinion. PMID- 20929095 TI - The green orthodontist. PMID- 20929096 TI - Clinical tips for improving 2D lingual treatment. PMID- 20929097 TI - Long-term stability of Class II correction with the Twin Force Bite Corrector. PMID- 20929098 TI - Surgical-Invisalign treatment of a patient with Class III malocclusion and multiple missing teeth. PMID- 20929099 TI - The Micro-Implant Pearl. PMID- 20929100 TI - The readers' corner. PMID- 20929101 TI - Glass ionomer cement hooks for stabilizing lingual retainer wires. PMID- 20929102 TI - Courage and character, leaders and legends: an interview with Sir Roy Calne, FRS. Interview by Linda Ohler. PMID- 20929103 TI - Proper analysis and interpretation of the stability of levothyroxine sodium 0.4 microg/mL in 0.9% sodium chloride injection. PMID- 20929104 TI - Methadone maintenance therapy in liver transplantation. AB - Cirrhosis due to chronic infection with hepatitis C virus remains by far the most common reason for liver transplantation in North America. Currently, parenteral use of street drugs is the most common means of acquiring hepatitis C. Methadone maintenance therapy is an accepted form of treatment for chronic opiate (eg, heroin) addiction and, not surprisingly, a significant proportion of methadone treated patients have chronic hepatitis C. The feasibility of liver transplant candidacy in hepatitis patients who require methadone maintenance therapy is controversial, and some transplant centers require patients to withdraw from such therapy in order for the transplant process to move forward. Thus stable patients with end-stage cirrhosis who are receiving methadone maintenance are left in a most difficult situation: discontinue methadone and accept the side effects of withdrawal with the risk of recidivism to use of street opiates, an absolute contraindication for transplantation, or continue methadone therapy and risk exclusion from the transplant process. The issue of methadone replacement therapy in end-stage cirrhosis and the posttransplant literature on the subject are explored in this paper. PMID- 20929105 TI - Impact of a chronic kidney disease clinic on preemptive kidney transplantation and transplant wait times. AB - BACKGROUND: Despite the known benefits of preemptive kidney transplantation, its rate of use remains low. OBJECTIVE: To determine whether focused, comprehensive education provided at a clinic for patients with chronic kidney disease would improve the rate of preemptive transplantation and transplant wait times. METHODS: A retrospective cohort study design was used. The rate of preemptive transplantation and transplant wait times were compared between patients with end stage renal disease who had been followed in a chronic kidney disease clinic for more than 3 months and patients with end-stage kidney disease who had not been followed for chronic kidney disease care during the same period. RESULTS: More African Americans than others had initiated dialysis without having had previous care for chronic kidney disease. The rate of preemptive transplantation was 24% for patients followed in the clinic. For those patients without living donor options, mean transplant referral time was significantly different between patients followed at the clinic and patients who were not: 234 (SD, 392) days before dialysis was started versus 161 (SD, 525) days after dialysis was started (P = .01). CONCLUSION: A chronic kidney disease clinic can influence rates of preemptive kidney transplantation and transplantation referral times. PMID- 20929106 TI - Fatigue and sleep quality before and after liver transplantation. AB - CONTEXT: Recent publications suggest that fatigue and sleep disturbance are problems in patients with chronic liver disease and in liver transplant recipients. OBJECTIVES: To characterize the severity and nature of fatigue and sleep quality before and after liver transplantation, to examine the relationship between fatigue/ sleep quality and quality of life, and to identify their multivariate correlates. DESIGN, SETTINGS, AND PARTICIPANTS: Cross-sectional survey administered to 110 patients before and 95 patients after liver transplantation at 2 transplant centers. MAIN OUTCOME MEASURES: Fatigue and sleep quality. RESULTS: Most pretransplant (86%) and posttransplant (76%) patients experienced high fatigue severity. Correlates of pretransplant fatigue severity were being female (odds ratio [OR] = 0.22, P = .04), higher body mass index (OR = 1.07, P = .04), higher mood disturbance (OR = 1.05, P = .02), and poor sleep quality (OR = 0.26, P = .02). Correlates of posttransplant fatigue severity were use of sleep medications in the past month (OR = 0.51, P = .02) and higher mood disturbance (OR = 1.06, P = .004). Seventy-three percent of pretransplant and 77% of posttransplant patients were classified as having poor sleep quality. Higher body mass index (OR = 1.06, P = .05), sleep medications (OR = 0.43, P = .03), and more mood disturbance (OR = 1.04, P = .007) were predictive of poor sleep quality in pretransplant patients, whereas higher body mass index (OR = 1.07, P = .04) and more anxious mood (OR = 1.28, P = .03) were predictive of poor sleep quality in posttransplant patients. CONCLUSION: A very high proportion of both pretransplant and posttransplant patients experience clinically severe fatigue levels. Prospective research is necessary to identify causal mechanisms of these disorders and to evaluate strategies to reduce fatigue severity and improve sleep quality. PMID- 20929107 TI - Multiorgan transplant program in a nonacademic center: organizational structure and outcomes. AB - Given the complexity of solid organ transplantation, it is reasonable to believe that numerous factors are at play in achieving the enviable outcomes reported. The aim of this study is to examine the role of an organizational structure in maintaining the outcomes of a multiorgan transplant program at a nonacademic center. A retrospective analysis of 2378 solid organ transplants at Nazih Zuhdi Transplant Institute between March 1985 and December 2008 was performed. The 1 year and 3-year patient and graft survival rates, rate of retransplantation, and median length of hospital stay were compared with US national data released by the Scientific Registry of Transplant Recipients in January 2009. The 1-year patient survival rates were 87.5% for heart, 95.1% for kidney, 75.8% for lung, 89.6% for liver, and 100.0% for pancreas. The 3-year patient survival rates were 73.5% for heart, 89.7% for kidney, 57.8% for lung, 87.7% for liver, and 100.0% for pancreas. A well-structured transplant program along with competent medical, administrative, and ancillary support can achieve comparable patient and graft survival rates independent of volume. PMID- 20929108 TI - Why families decline donation: the perspective of organ procurement coordinators. AB - CONTEXT: Current knowledge regarding the barriers to organ donation relies on 3 data sources: potential donor families, hospital staff, and members of the general public. The current study complements these findings by interviewing organ procurement coordinators about their experiences during the familial consent process. OBJECTIVE: To characterize organ procurement coordinators' reports of barriers to obtaining familial consent for donation. DESIGN: Structured, face-to-face interviews. PARTICIPANTS: One hundred and two organ procurement coordinators recruited from a national sample of 16 organ procurement organizations. MAIN OUTCOME MEASURE: Interviews were content analyzed to describe coordinators' experiences with families who decline donation. Manifest coding was used to determine the frequency with which particular barriers were identified by coordinators. Coordinators' reports of barriers were compared with organizational conversion rates to determine which barriers were associated with performance as an organization. RESULTS: Organ procurement coordinators revealed 16 distinct barriers in 4 overlying categories: concerns regarding decedents' wishes, structural barriers to donation, unsupportive belief systems, and lack of public education. Three reported barriers could be used to differentiate between high- and low-performance organizations: (1) familial concerns over bodily disfigurement, (2) failure of families to understand brain death, and (3) families' cultural/racial background. CONCLUSION: These results supplement existing reports of barriers to donation and are discussed in terms of shaping future public education efforts and request processes to improve conversion rates. PMID- 20929109 TI - Roles of sex and ethnicity in procurement coordinator--family communication during the organ donation discussion. AB - CONTEXT: Interpersonal relations with health care providers influence families' decisions to consent to solid-organ donation. However, previous research has been based on retrospective interviews with donation-eligible families and has not directly examined the interpersonal interactions between families and organ procurement coordinators. OBJECTIVE: To increase understanding of the interpersonal interaction between procurement coordinators and families during the organ donation discussion, with special attention to the influence of the sex and race of the procurement coordinator and the race of the potential donor's family. DESIGN: A descriptive study in which standardized patients portrayed family members interacting with actual procurement coordinators in simulated donation request scenarios. SETTING AND PARTICIPANTS: Thirty-three videotaped interactions between standardized patients and 17 procurement coordinators involving 2 different scenarios depicting deceased donation were evaluated. MAIN OUTCOME MEASURES: Video recordings were rated by independent coders. Coders completed the Impact Message Inventory-Form C, the Participatory Style of Physician Scale, and the Siminoff Communication and Content and Affect Program Global Observer Ratings scale. RESULTS AND CONCLUSIONS: African American procurement coordinators, particularly African American women, were rated as more controlling and work-oriented than white procurement coordinators. Male procurement coordinators were more affiliative with the white family than the African American family, whereas female procurement coordinators were slightly less affiliative with the white family. African American procurement coordinators expressed more positive affect when interacting with the African American family than the white family, whereas the opposite was true for white procurement coordinators. Research is needed to cross-validate these exploratory findings and further examine cultural mistrust between procurement coordinators and families of ethnic minorities, especially given the negative attitudes of many minorities toward donation. PMID- 20929110 TI - Hypotension after reperfusion in liver transplantation: histidine-tryptophan ketoglutarate versus University of Wisconsin solution. AB - BACKGROUND: The greatest hemodynamic instability during orthotopic liver transplantation occurs at graft reperfusion. Many factors have been implicated. PURPOSE: To compare hemodynamic changes after reperfusion in grafted livers preserved with histidine-tryptophan-ketoglutarate (HTK) solution versus grafted livers preserved with University of Wisconsin (UW) solution. METHODS: In this prospective study, we randomly divided 89 patients who underwent deceased donor liver transplantation into 2 groups: the UW group and the HTK group. The HTK group was further divided into 2 subgroups: flushed and not flushed before reperfusion. The patients were monitored with hemodynamic and metabolic parameters at 3 times: after the skin incision, 5 minutes before reperfusion, and 5 minutes after reperfusion. RESULTS: Hemodynamic parameters in the UW group had not changed significantly at 5 minutes before reperfusion or 5 minutes after reperfusion (P = .45), and the incidence of hypotension after reperfusion in the UW group was 20%. In both HTK groups, the mean arterial pressure 5 minutes after reperfusion was significantly lower than at 5 minutes before reperfusion (P = .002); the incidence of hypotension after reperfusion in the nonflushed HTK group was 83.3% and in the flushed HTK group, 65.5%. CONCLUSIONS: The incidence of hypotension after reperfusion is greater if HTK solution rather than UW solution is used. Flushing of grafted livers preserved with HTK solution might eliminate some vasoactive substances found in HTK solution. PMID- 20929111 TI - Differential lung ventilation during adult donor care. AB - Differential lung ventilation may be required when one lung is injured or affected more than the other lung following, for example, aspiration, crush injury, or selective pneumonia, or if lung rupture results in formation of a bronchopleural fistula. Unilateral lung failure causes increased ventilation perfusion mismatching that often leads to severe hypoxemia. Treatment may include careful attention to ventilator parameters to avoid overdistention of the less affected lung or lateral decubitus positioning of the donor with the less affected lung down (gravitationally dependent position). Under extreme conditions, use of a specialized double-lumen endotracheal tube and separate ventilators with individualized parameters for each lung is required to provide adequate oxygenation and ventilation for organ preservation. PMID- 20929112 TI - Airway pressure release ventilation during adult donor care. AB - Airway pressure release ventilation is most commonly used during donor care to treat hypoxemia and to avoid high peak airway pressure. The traditional concept of cyclic inhalation/exhalation is replaced by a continuous positive airway inflation interspersed by brief episodes in which the positive pressure is reduced. The variables, Pressure-high, Pressure-low, Time-high, and Time-low, are manipulated to ensure adequate donor oxygenation and carbon dioxide removal. Organ procurement coordinators may find this method of mechanical ventilation in place when donor care is assumed or initiate it as a useful tool in providing donor support. PMID- 20929113 TI - Organ transplantation in Egypt. AB - Concern has increasingly been expressed about the growing number of reports of medical personnel participating in the transplantation of human organs or tissues taken from the bodies of executed prisoners, handicapped patients, or poor persons who have agreed to part with their organs for commercial purposes. Such behavior has been universally considered as ethically and morally reprehensible, yet in some parts of the world the practice continues to flourish. The concept of justice demands that every person have an equal right to life, and to protect this right, society has an obligation to ensure that every person has equal access to medical care. Regrettably, the Egyptian system does not legally recognize brain death and continues to allow the buying and selling of organs. For more than 30 years in Egypt, the ability to pay has determined who receives an organ and economic need has determined who will be the donor. As transplant professionals, it is important that we advocate on behalf of all patients, potential recipients, and donors and for those who are left out and not likely to receive a donor organ in an economically based system. Current issues associated with this debate are reviewed and recommendations about how to address them in Egypt are discussed. PMID- 20929114 TI - Significant alterations in reported clinical practice associated with increased oversight of organ transplant center performance. AB - In the past several years, emphasis on quality metrics in the field of organ transplantation has increased significantly, largely because of the new conditions of participation issued by the Centers for Medicare and Medicaid Services. These regulations directly associate patients' outcomes and measured performance of centers with the distribution of public funding to institutions. Moreover, insurers and marketing ventures have used publicly available outcomes data from transplant centers for business decision making and advertisement purposes. We gave a 10-question survey to attendees of the Transplant Management Forum at the 2009 meeting of the United Network for Organ Sharing to ascertain how centers have responded to the increased oversight of performance. Of 63 responses, 55% indicated a low or near low performance rating at their center in the past 3 years. Respondents from low-performing centers were significantly more likely to indicate increased selection criteria for candidates (81% vs 38%, P = .001) and donors (77% vs 31%, P < .001) as well as alterations in clinical protocols (84% vs 52%, P = .007). Among respondents indicating lost insurance contracts (31%), these differences were also highly significant. Based on respondents' perceptions, outcomes of performance evaluations are associated with significant changes in clinical practice at transplant centers. The transplant community and policy makers should practice vigilance that performance evaluations and regulatory oversight do not inadvertently lead to diminished access to care among viable candidates or decreased transplant volume. PMID- 20929115 TI - Humoral rejection after pediatric heart transplantation: a case report. AB - Humoral rejection was observed 2 years after heart transplantation in a 10-year old African American girl with sickle cell disease. Hemodynamic compromise developed, and the patient started treatment with extracorporeal membrane oxygenation within 24 hours of admission. With cellular rejection initially believed to be the cause, administration of thymoglobulin and high-dose steroids was initiated. Human leukocyte antigen antibody analysis revealed high titers of donor-specific class I and II antibodies. Aggressive treatment for antibody mediated rejection was started with plasmapheresis and administration of intravenous immune globulin and rituximab. The patient displayed clinical signs of infection and was treated with antimicrobial, antiviral, and antifungal agents. Computed tomography of the chest suggested asperigillous infection. The patient underwent a left upper lobectomy. The patient recovered and has done well, now 4 years after having received the heart transplant. Antibody-mediated rejection should be considered early in heart transplant patients presenting with hemodynamic compromise and may respond to aggressive antibody and B cell-directed therapy. Vigilance for secondary infections, especially during treatment for rejection, is crucial. PMID- 20929117 TI - Intel's cultural anthropologist. PMID- 20929116 TI - Probing transplant and living donor candidates about their participation in organ vending. AB - The selling of human organs for transplant is illegal in the United States and in most countries; however, such transactions still occur. Transplant hospitals and their personnel have multiple ethical duties, including (1) protecting the safety of their living donors and transplant recipients and (2) protecting the integrity of living donation and transplantation as clinical practices. To date, few psychosocial screening tools exist that pertain specifically to a person's risk or intent of pursuing organ vending (buying or selling). This article presents a series of transplant ethics case consultations that spawned the creation of a set of behavioral prompts for teams to probe with regard to organ vending when screening candidates about their suitability for participation as living donors or transplant recipients. PMID- 20929118 TI - The algorithm of love. PMID- 20929119 TI - [Problems and intervention strategies of Chinese medicine on assisted reproductive technology]. PMID- 20929120 TI - [Effect of cuichan zhunsheng decoction for promoting cervical ripening in late pregnancy]. AB - OBJECTIVE: To observe the effect of Cuichan Zhunsheng Decoction (CZD) on the cervical ripening factors in late pregnancy. METHODS: Ninety women with full-term pregnant ready for labor inducing were equally assigned to 3 groups. The treated group was orally treated with CZD, the control group was with pitocin by adding 1 U into 500 mL of 5% glucose for intravenous dripping in 6 h, and the placebo group was orally treated with simulator of CZD as placebo, with the medication lasted for 3 days. Changes of cervical length and width, and neck tube diameter were measured by vaginal B-ultrasonography to estimate the degree of cervical maturation referring to the clinical Bishop scale; meanwhile, changes in blood levels of prostaglandin E2alpha(PGE2alpha), interleukin-8 (IL-8) and endothelin-1 (ET-1) were measured. RESULTS: The total effective rate on cervical ripening was 96.7% in the treated group, which was significantly superior to those in the control group (83.3%) and the placebo group (26.7%, P < 0.05). The blood levels of PGE2alpha, IL-8, and ET-1 after treatment in the treated group were significantly higher than those in the placebo group (P < 0.05), and levels of PGE2alpha and IL-8 were higher in the control group than in the placebo group (P < 0.05). CONCLUSION: CZD can promote the cervical ripening through raising blood levels of PGE2alpha, IL-8 and ET-1, altering the structure of cervical tissue to reduce the cervical tension, which could increase the maturation of cervix, induce delivery sign, so as to elevate the vaginal delivery rate and reduce the percentage of caesarean birth. PMID- 20929121 TI - [Clinical observation on effect of shenqi guchong recipe in treating peri menopausal anovulatory dysfunctional uterine bleeding]. AB - OBJECTIVE: To investigate the effect and hemostatic mechanism of Shenqi Guchong Recipe (SGR) in treating peri-menopausal anovulatory dysfunctional uterine bleeding (ADUB) of qi deficiency blood stasis syndrome type (QDBS). METHODS: Patients of ADUB-QDBS were assigned to two groups, the 47 patients in the treated group administering orally with SGR and the 31 in the control group treated with Kunning Oral Liquid. The hemostatic effect, and the changes before and after treatment of 6-ketoprostaglandin 1alpha (6-K-PGF1 alpha), thromboxane B2(TXB2), T lymphocyte subsets (CD3 and CD8, CD4/CD8 ratio) in menstrual blood, and serum calcium level in patients were observed. RESULTS: The hemostatic effect in the treated group [85.1% (40/47)] was better than that in the control group [51.6% (16/31)], significant difference was shown between groups (P < 0.05). Changes of 6-K-PGF1 alpha TXB2, and 6-K-PGF1 alph/TXB2 ratio in the treated group were significant after treatment and showed significant difference as compared with those in the control group (P < 0.05 or P < 0.01). Meantime, serum Ca2+ level was increased and parameters of T-lymphocyte subsets improved significantly in the treated group (P < 0.05 or P < 0.01), also statistically different to those in the control group (P < 0.05). CONCLUSION: SGR shows obvious hemostatic effect in treating patients with ADUB of QDBS type, and the mechanism may be related to its actions for improving microcirculation, enhancing immune function, and improving uterine local micro-environment, etc. PMID- 20929122 TI - [Prelimary exploration on Chinese medicine syndrome type distribution in patients with polycystic ovary syndrome]. AB - OBJECTIVE: To explore the Chinese medicine syndrome type distribution in patients with polycystic ovary syndrome (PCOS) and its relationship with sexual hormones. METHODS: Chinese medicine syndrome types of 212 PCOS patients were differentiated and sorted by adopting fuzzy mean C clustering method, and their relationship with the indices of sexual hormones detected on the 3rd to 5th day of menstrual cycle was analyzed, with the values got from 20 healthy women for controls. RESULTS: Intermingling syndromes were commonly seen in PCOS patients. Shen deficiency syndrome (presented in 64 patients) and Gan-qi stagnancy syndrome (61 patients) were the dominance, accounting for 30.2% and 28.8% respectively, significantly higher than that of other syndromes (P < 0.05), which were Pi deficiency syndrome (41 patients, 19.3%), phlegm-dampness syndrome (33 patients, 15.6%) and blood stasis syndrome (13 patients, 6.1%). Levels of estradiol (E2), testosterone (T), luteinzing hormone (LH), dehydroiso-androsterone (DHEA-S) and prolactin (PRL) were higher, while the level of sexual hormone binding protein (SHBG) was lower in PCOS patients than those in control, follicular stimulating hormone (FSH) level in patients of Shen-deficiency syndrome and phlegm-dampness syndrome was high than that in control (P < 0.05 and P < 0.01). However, no significant differences were found in comparing the various sexual endocrinal indices between patients with different syndrome types (P > 0.05). Besides, the level of PRL was positively correlated with LH and E2 levels in patients. CONCLUSION: Chinese medicine syndromes presented in patients with PCOS are mostly intermingling, Shen-deficiency and Gan-stagnancy are the basic syndromes, and there is some correlation between syndrome type and sexual hormone levels. PMID- 20929123 TI - [Clinical study on treatment of acute radiation oral mucositis of yin deficiency induced inner heat syndrome by nourishing yin and clearing heat method]. AB - OBJECTIVE: To observe the clinical effect of Chinese medicine for nourishing yin and clearing heat therapy (CM therapy) in treating nasopharyngeal carcinoma (NPC) patients with yin deficiency-induced inner heat syndrome, and suffered from acute radiation oral mucositis. METHODS: Sixty patients with NPC fitting to the inclusion criteria and undergoing initial dose radiotherapy were assigned to two groups. The 31 patients in the treatment group received CM therapy, and the 29 in the control group were treated with standard Western medical therapy. The condition of oral mucosa and epidermal growth factor (EGF) content in saliva of patients during the therapeutic period were observed, meanwhile the quality of life (QOL) of patients was estimated with the quality of life questionnaire-core 30 (QLQ-C30) issued by European Organization for Research and Treatment of Cancer (EORTC). RESULTS: Acute radiation oral mucositis occurred in all patients, but the severity in the treatment group was milder than that in the control group (P < 0.01). Salivary EGF content decreased along with the increasing radiation dosage, it decreased significantly when 40 Gy radiated and down to the minimum when 70 Gy radiated, but the decrement in the treatment group was less than that in the control group (P < 0.01). Comparison of QOL by QLQ-C30 scale showed that after radiotherapy the global health status in the treatment group was superior to the control group (P < 0.01). CONCLUSION: Chinese medicine for nourishing yin and clearing heat therapy could actually postpone the occurrence of acute radiation oral mucositis, lessen the adverse reaction of radiotherapy and improve patient's QOL, show a favorable effect in prevention and treatment, and has definite application value for clinical spreading. PMID- 20929125 TI - [Comparative study on the methods of Chinese medicine and Western medicine therapeutic evaluation for advanced non-small cell lung cancer]. AB - OBJECTIVE: To compare the differences and characteristics in Chinese medicine (CM) and Western medicine therapeutic evaluation methods in the application of advanced non-small cell lung cancer. METHODS: A total of 200 cases of advanced non-small cell lung cancer from 3 subcenters were enrolled the study and assigned to two groups, 104 in the CM group treated with CM injection combined with treatment based on syndrome differentiation, 96 in the chemotherapy group treated with the international chemothearapy scheme, both the course of treatment was 6 weeks. Their short-term therapeutic effects were observed by the "clinic efficacy appraisal standard of therapy for advanced lung cancer with CM" simultaneously and by the follow-up Western medical solid tumor's effect evaluation criterion, including clinical symptoms, tumor body, Karnorfsky score, body weight and immune function evaluation. RESULTS: According to WHO solid tumor's effect evaluation criterion, the efficacy of the chemotherapy group was much better than that of the CM group (P < 0.01). While, according to the "clinic efficacy appraisal standard of therapy for advanced lung cancer with CM", the efficacy of the CM group was better than that of the chemotherapy group without statistical difference (P = 0.05), however, there was a very strong trend of appearing difference. There was difference inult o the results of the two evaluation methods. CONCLUSION: Compared with WHO solid tumor's effect evaluation criterion, "the clinic efficacy appraisal standard of therapy for advanced lung cancer with CM" can reflect more features and advantages of CM for cancer treatment, having value for further study. PMID- 20929124 TI - [Effects of astragalus on cardiac function and serum tumor necrosis factor-alpha level in patients with chronic heart failure]. AB - OBJECTIVE: To explore the effects of Astragalus on cardiac function and serum tumor necrosis factor-alpha (TNF-alpha) level in patients with chronic heart failure (CHF). METHODS: Forty-five patients of Xin-qi deficiency or Xin-yang deficiency types were assigned to the Chinese medicine (CM) group and the Western medicine (WM) group by a randomizing digital table. Standard treatment for correcting heart failure, including digoxin, diuretics, etc. was administered to both groups, but to the CM group oral medication of Astragalus granule was given additionally at the dosage of 2.25 g twice a day, the treatment for both was continued for two weeks. NYHA cardiac functional grading, serum TNF-alpha level, left ventricular ejection fraction (LVEF) and walk distance in 6 min (WD) were measured before and after treatment, and a correlation analysis was carried out. RESULTS: After therapy, the level of TNF-alpha in the two groups decreased (P < 0.05) and it was lower in the CM group [(54.77 +/- 9.34) microg/L] than in the WM group [(62.10 +/- 9.94) microg/L] (P < 0.05); LVEF in the two groups increased (P < 0.05) and it was higher in the CM group [(64.45 +/- 12.47)%] than that in the WM group [(56.03 +/- 13.33)%] (P < 0.05); both groups' WD increased (P < 0.05) and it was longer in the CM group [(446.97 +/- 68.82) m] than in the WM group [(345.40 +/- 63.62) m] (P < 0.05); the improvement of cardiac functional grading in the CM group was outstriper than the WM group (P < 0.05). The improvement in cardiac function was negatively correlated with TNF-alpha level. CONCLUSION: Astragalus can alleviate the calcium overload-induced myocardial damage and improve both systolic and diastolic functions of heart in patients with CHF. PMID- 20929126 TI - [Effect of combined therapy with Chinese drug and narrow broad ultraviolet B on Bcl-2, caspase-3 and survivin in skin lesion with psoriasis vulgaris]. AB - OBJECTIVE: To reveal the possible role of combined therapy with Chinese drug and narrow broad ultraviolet B (NB-UVB) on keratinocytes apoptosis in skin lesion of psoriasis vulgaris (PV). METHODS: Skin samples were taken from 20 healthy subjects and 30 PV patients before and after they received the combined therapy for 8 weeks. SP immunohistochemical method was used to detect the expressions of Bcl-2, Caspase-3 and survivin in the samples. RESULTS: As compared with those in the normal skin, expression of Bcl-2 in PV skin was significantly lower (7.50 +/- 2.01 vs. 12.65 +/- 2.83), while expression of Caspase-3 (21.73 +/- 3.70 vs. 8.55 +/- 2.16), and survivin (23.90 +/- 2.82 vs. 7.06 +/- 1.96) were higher (all P < 0.01). After treatment, in skin of PV, Bcl-2 expression increased to 13.63 +/- 2.14, Caspase-3 and survivin decreased to 11.70 +/- 2.44 and 12.46 +/- 1.80, respectively (all P < 0.01), showing a normalizing trend. Moreover, patients' psoriasis area and severity index (PASI) score decreased from 14.24 +/- 3.42 before treatment to 3.52 +/- 1.07 after treatment (P < 0.01). CONCLUSION: The curing effect of the combined therapy with Chinese drug and NB-UVB in treating PV is possibly realized by way of regulating Bcl-2, Caspase-3 and survivin expressions to adjust keratinocyte apoptosis. PMID- 20929127 TI - [Effect of bushen recipe on the immune effector molecules of natural killer cells in patients with chronic hepatitis B]. AB - OBJECTIVE: To investigate the immunoregulation mechanism of Bushen Recipe (BSR) in patients with chronic hepatitis B (CHB) of Gan-Shen yin-deficiency and lingering damp-heat syndrome (GSS). METHODS: Thirty-five patients with positive HBV DNA and abnormal alanine transaminase (ALT) level were assigned to the treatment group (22 patients) and the control group (13 patients), they were treated with BSR and alpha-2b interferon for 6 months respectively. Blood levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL) and HBV DNA were measured before and after treatment. And the expressions of immune effector molecules of nature killer (NK) cell, including perforin (PF), granzyme B (GrB), granulysin (GNLY), tumor necrosis factor-alpha (TNF-alpha) and gamma-interferon (gamma-IFN), were detected using flow cytometry. RESULTS: Levels of ALT and AST declined significantly in both groups after treatment (P < 0.05 or P < 0.01), showing insignificant difference between them. And the expressions (%) of PF and GNLY in the treatment group reduced significantly after treatment, from 69.62 +/- 27.58 to 34.86 +/- 31.60 for PF and from 64.54 +/- 25.96 to 25.72 +/- 24.98 for GNLY (both P < 0.05). In the treatment group and the control group, as compared with before treatment, the total scores of Chinese medicine symptoms were significantly declined after treatment (P < 0.01), and the total scores of Chinese medicine symtoms in the treatment group was significantly lower than that of the control group (P < 0.05). As compared with the total effective rate of Chinese medicine syndromes in the control group after treatment, that in the treatment group was significantly increased (P < 0.05). CONCLUSION: The mechanism of BSR in immuneregulating on patients with CHB of GSS is by way of declining the expressions of relative immune effector molecules to promote the recovery of the damaged liver. PMID- 20929128 TI - [Perioperative intervention of tetramethylpyrazine on free skin flap transplantation]. AB - OBJECTIVE: To study the impacts of tetramethylpyrazine (TMP) intervention on hemorheology and blood coagulation before and after free skin flap transplantation, in order to provide new clues of applying Chinese drugs for activating blood circulation and removing stasis in microsurgery. METHODS: Sixty patients undergoing free skin flap transplantation were randomly and equally assigned to two groups, the treatment group administered with tetramethylpyrazine, the control group with low molecular dextran, both were treated for 7 days. The survival rate of transplanted flap, hemorrheologic parameters and four blood coagulation associated indices (prothrombin time, thrombin time, activated prothrombin time and fibrinogen) were detected before and after treatment. RESULTS: Comparisons of clinical efficacy and hemorrheologic indices showed no significant difference between the two groups (P > 0.05), but TMP showed less impacts on the four blood coagulation associated indices at the 24, 48 and 72 h after operation (P < 0.05). CONCLUSION: TMP could prevent blood vessel crisis after free skin flap transplantation, so it is valuable in microsurgical clinical application. PMID- 20929129 TI - [Effect of ru'ai shuhou recipe on immune response in HER2/neu tranagenic mice undergoing breast cancer carcinogenesis process]. AB - OBJECTIVE: To explore the immune response induced by HER2/neu oncogene in the breast cancer (BC) carcinogenesis process and the immunological mechanism of Ru'ai Shuhou Recipe (RSR) in the prevention and treatment of BC. METHODS: HER2/neu transgenic spontaneous breast tumor model mice were fed with RSR from 5 weeks old, the occurrence of breast tumor in them was observed, and the changes of T cell-mediated immune response and associated cytokines were detected during the carcinogenesis process, i. e., when mice aged between 15 and 25 weeks. RESULTS: RSR showed significant effects in postponing and reducing the carcinogenesis of primary breast tumor, up-regulating the amount of T cell in splenic lymphocyte in tumor-bearing mice, promoting the proliferation of T lymphocyte, and inducing the secretion of cytokines such as interleukin-2, interleukin-12 and interferon-y. CONCLUSIONS: A serial immune response reveals in the carcinogenesis process. The immunologic function of HER-2/neu transgenic mice is significantly different to that of the same strain non-transgenic mice. Effect of RSR in preventing and postponing breast cancer carcinogenesis is possibly realized through enhancing the anti-tumor immune response of transgenic mice themselves. PMID- 20929130 TI - [Study on the apoptosis inducing effect of pseudolaric acid B on cervical carcinoma cell line HeLa cells]. AB - OBJECTIVE: To investigate the biological effect and mechanism of action of pseudolaric acid B (PAB) on the cultured human HeLa cells in vitro. METHODS: MTT and flow cytometric assays were used to detect the cells proliferation inhibitory rate and apoptosis of HeLa cell in exposure to PAB; the morphological changes of apoptosis were observed with electron microscope; and the expressions of p53/bcl 2/bax mRNA were detected by RT-PCR. RESULTS: (1) HeLa cell proliferation was inhibited by PAB in a dose-dependent manner, the IC50 being about 10 micromol/L; (2) flow cytometry showed that the distribution of HeLa cell cycle was changed time-dependently by 10 micromol/L PAB-treatment, showing decrease of G0/G1 phase cell percentage and increase of G2/M phase cell percentage; (3) the bax mRNA expression elevated and bcl-2 protein expression decreased markedly after being treated by 10 micromol/L PAB for 12 h, 24 h, and 48 h; while the expression of p53 mRNA could not be detected. CONCLUSION: PAB can inhibit the proliferation and induce the apoptosis of Hela cells in vitro, and its molecular mechanism may be associated with up-regulating bax mRNA expression and down-regulating bcl-2 mRNA expression. PMID- 20929131 TI - [Inhibitory effect of matrine on proliferation of human ovary malignant teratoma cell line PA-1 in vitro]. AB - OBJECTIVE: To study the effect of matrine (MAT) on the proliferation of human ovary malignant teratoma cell line PA-1 in vitro. METHODS: PA-1 cells allocated in different groups were treated with different concentrations (0.25 mg/mL, 0.5 mg/mL and 1.0 mg/mL) of MAT. The inhibitory effect of MAT and its dose- and time effect relationship were detected with MTT; the apoptosis rate and cell cycle were evaluated by flow cytometry; and the changes of bcl-2/bax mRNA expression in cells were measured using semi-quantitative RT-PCR. RESULTS: After being exposed to MAT, the PA-1 cell proliferation was decreased in a concentration- and time dependent manner; cell apoptosis rate raised as the increasing concentration of MAT and acting time; cells retarded at G1 phase in the cell cycle dose dependently; and the bcl-2/bax mRNA expression in cells dawn-regulated significantly. CONCLUSION: MAT can dose- and time-dependently inhibit the proliferation of PA-1 cell by reducing bcl-2/bax mRNA ratio to produce a G1 phase arresting in cell cycle. PMID- 20929132 TI - [Effect of ethanol extract from Matbuhi Aftimun on blood lipide level in rat hyperilpldemla model]. AB - OBJECTIVE: To investigate the acute toxicity, lipid reducing effect and mechanism of action of ethanol extracts of Matbuhi Aftimun (E-MA), a classic prescription of Uighur medicine, on hyperlipidemia rat model. METHODS: The LD50 or maximum tolerance of rats to E-MA was determined by simplified probit method. Hyperlipidemia rat model was established in SD rats by feeding high lipid emulsion, then E-MA at different dosages (0.80 g/kg, 1.60 g/kg and 3.20 g/kg) was given orally to them. The effects of E-MA on model rats' serum lipids, including total cholesterol (TC), low density lipoprotein-cholesterol (LDL-C), high density lipoprotein-cholesterol (HDL-C), triglyceride (TG), were observed. And its effects on malondialdehydec (MDA) content, superoxide dismutase (SOD), glutathione peroxidase (GSH-PX), total lipase, including lipoprotein lipase (LPL) and hepato-lipase (HL) activities in the liver homogenate were assayed. RESULTS: The maximum tolerance of rats to E-MA was 64 g (crude drug)/kg. Compared with the hyperlipidemia model rat, the blood TC level was lower (P < 0.05 or P < 0.01), and the MDA content in the liver homogenate was higher in model rat after E-MA treatment (at all the three specified dosages, P < 0.01), but no significant difference was found in comparisons of serum levels of LDL-C, HDL-C and TG (P > 0.05), also on the levels of SOD, GSH-PX and total lipase in the liver homogenate (P > 0.05). CONCLUSION: E-MA shows a serum TC reducing effect on hyperlipidemia rat model with low toxicity in mice. PMID- 20929133 TI - [Effect of dureping injection on T-cells function and their function in killing FM1 infected Mphi in vitro]. AB - OBJECTIVE: To investigate the effect of Dureping Injection (DRP) on the T-cells function of mice and the function of T-cells in killing MF infected by influenza virus subtype A mice-lung adaptive strain FM1 in vitro. METHODS: Number of splenic normal and FM1 infected T-cells in mice were measured by MTT and double antibody sandwich ELISA, after being treated with DRP at different concentrations (2.1, 8.5 and 17.0 microg/mL), and the effect of DRP on interferon-gamma (IFN gamma) and interleukin-10 (IL-10) production as well as on splenic T-cell killing FM1 infected Mphi/Ana-1 function were detected. RESULTS: DRP inhibited the multiplication of normal spleen T cells induced by concanavalin A in vitro, suppressed Th2 cell factor IL-10 production, and maintained Th1 cell factor IFN-y at a definite level, moreover, it directly enhanced the power of T-cells in killing FM1 infected Mphi (P < 0.05, P < 0.01). CONCLUSION: DRP could act on mice T-cells to enhance the immune response for antiinfluenza viral FM1 in vitro. PMID- 20929134 TI - [Effects of Lignum Sappen on growth and metastases of Lewis lung carcinoma at different phases in C57BL/6 mice]. AB - OBJECTIVE: To observe the effects of Lignum Sappan (LS) on the growth and metastases of transplanted Lewis lung carcinoma (LLC) in mice and investigate its partial mechanism of action. METHODS: C57BL/6 mice were established in LLC model and divided into six groups in random: Group A was untreated; Group B was treated by chemotherapy (CM) only; Groups C-F were treated respectively with low-dose LS, high-dose LS, CM + low-dose LS and CM + high-dose LS, via intragastric administration for 21 successive days. Mice were sacrificed in batches at different time points (d 7, d 14 and d 21) to observe the tumor inhibition rate and the metastases suppressing rate was measured dynamically. Meantime, the CD44 expression in tumor cells was measured by flow cytometry and serum P-selectin concentration was measured by ELISA assay. RESULTS: Tumor weight in all treated groups, except Group C, was lower than that in Group A at the three time points (P < 0.05, P < 0.01), and that was lower in Group F than in Group B at the corresponding time points (P < 0.05, P < 0.01). Comparisons of CD44+ in tumor cells showed that as compared with Group A, on d 7, it was lower in Groups B and D (P < 0.01); on d 14, it was lower in Group E (P < 0.01) and Group F (P < 0.05); and on d 21, it was lower in Groups E and F (P < 0.01). As for the concentration of P-selectin, the intergroup comparisons showed that it was lower in Groups B-F on d 7 and in Group F on d 21 than that in Group A (P < 0.05 or P < 0.01), but showed insignificant difference in comparing the Group A with all the treated Groups on d 14 (P > 0.05). CONCLUSION: LS and CM +LS could inhibit the growth and metastases of LLC, and shows inhibition on CD44 expression in tumor cells and P selectin level in serum, which may be one of the mechanisms of LS in suppressing tumor metastasis. PMID- 20929135 TI - [Effect and mechanism of action of qingkailing on learning and memory capacity of SAMP8 mouse]. AB - OBJECTIVE: To investigate the influence of Qingkailing (QKL) on learning and memory abilities, global neurotransmitter and phosphatidylinositol 3 kinase/protein kinase B (PI3K/AKT) signaling pathway of senescence accelerated mouse-prone/8 (SAMP8) mice with Alzheimer's dementia (AD). METHODS: SAMP mice were modeled and divided into the model group, the QKL group and the doneppezil hydrochloride group, all treated for 90 days. And a control group was set up with senescence accelerated mouse-resistance/1 (SAMR1) mice. Morris water maze was used to test the learning and memory abilities of mice; contents of acetylcholine (Ach) and monoamine neurotransmitters in brain were measured by HPLC; levels of Grb2-associated binder-1 (Gab1), AKT and phospho-serine/threonine protein kinase B (PAKT473) were evaluated by Western-blot. RESULTS: Compared with the control group, in the model group, the average escape latency detected by hidden platform trial and reverse trial on the 3rd day was higher (P < 0.01); levels of Ach, 5 hydroxytryptamine (5-HT) and Gab1 were lower (P < 0.01, P < 0.05 and P < 0.01), respectively. As compared with the model group, the escape latency (within the 2nd to 5th day) decreased (P < 0.01), levels of Ach and 5-HT increased (P < 0.05), and Gab1 protein expression increased (P < 0.01) in the QKL treated group after treatment, in addition, the level of phosphorylated AKT protein significantly increased (P < 0.05). CONCLUSION: QKL could improve the learning and memory ability of AD model mice, which is probably related to its function in increasing cerebral Ach, 5-HT and activating PI3K/AKT pathway. PMID- 20929136 TI - [Effects of changwelqing on nuclear translocation of Y-box binding protein-1 and expression of P-glycoprotein in human colon cancer cell line with drug-resistance induced by vincristine]. AB - OBJECTIVE: To evaluate the effects and molecular mechanism of action of Changweiqing (CWQ) in reversing multidrug resistance by observing its impacts on nuclear translocation of Y-box binding protein-1 (YB-1), multi-drug resistance gene (MDR1) expression and P-glycoprotein (P-gp) expression in human colon cancer cell line HCT8/V with drug-resistance induced by vincristine. METHODS: Cultured HCT8/V cells were exposed to the CWQ-containing rat serum prepared by drug perfusion. YB-1 expressions in cell plasma and nuclei were examined by Western blot; the binding activity of YB-1 to MDR1 gene promoter sequences was detected by electrophoretic mobility shift assay (EMSA); the mRNA transcription levels of MDR1, YB-1 and multi-resistance related protein (MRP) were examined by RT-PCR; the expression of P-gp on cell membrane was determined by flow cytometry. Results Along with the increasing drug's concentration of CWQ-containing serum from 1.25% up to 2.5% and 5%, the expressions of YB-1 decreased in HCT8/V cell nuclear and increased in cytoplasm gradually; the binding activity of YB-1 to MDR1 gene promoter weakened (P < 0.01), MDR1 mRNA expression and fluorescence intensity of P-gp on cell membrane attenuated (P < 0.05 or P < 0.01), while YB-1 and MRP mRNA unchanged (P > 0.05). CONCLUSION: CWQ could reverse the drug-resistance of colon cancer cells by influencing nuclear translocation of YB-1 and reducing the expression of MDR1/P-gp. PMID- 20929137 TI - [Effects of panax quinquefolius saponin of stem and leaf on glucose-lipid metabolism and insulin signal transduction in insulin resistant model adipocytes]. AB - OBJECTIVE: To observe the effects of panax quinquefolius saponin (PQS) of stem and leaf on glucose-lipid metabolism and insulin signal transduction in the insulin resistant model of adipocytes. METHODS: The insulin resistant model of differentiated 3T3-L1 adipocytes was established in vitro with free fatty acid. After induction of insulin resistance, cells were treated with metformin or PQS for 2 days. The glucose consumption in culture fluid was detected by glucose oxidase method; the effects of PQS on the lipolysis induced by tumor necrosis factor (TNF-alpha) was observed using colorimetry; and the phospholation of signal proteins was detected by Western-blot. RESULTS: The amount of glucose consumption (mmol/L) in the model group (5.250 +/- 2. 671) was significantly lower than that in the normal control group (14.133 +/- 1.305, P < 0.01), it increased in the meformin treated group (11.807 +/- 1.358), and the groups treated with high-, middle- and low-dose PQS dose-dependently (10.784 +/- 2.373, 10.217 +/- 1.237 and 9.984 +/- 2.006, respectively), significantly higher than that in the model group (P < 0.01). Upon TNF-alpha treatment, the concentration of free fatty acid (FFA) (nmol/ microg) in culture medium was 2.479 +/- 0.597, predominantly higher than that in the control group (1.320 +/- 0.538, P < 0.01), while it was 1.210 +/- 0.566 in the metformin group, 1.105 +/- 0.631 in high-dose PQS group, 1.108 +/- 0.260 in the middle-dose PQS group, 1.201 +/- 0.593 in the low-dose PQS group, all were lower than that in the TNF-alpha group (P < 0.05 or P < 0.01), and a dose-dependent tendency of PQS's action was seen. The tyrosine phosphorylation of insulin receptor and IRS-1 as well as Ser473 phosphorylation of PKB were lower in the model group than in the control group; they were insignificantly changed in the low-dose PQS group, but did show significant difference in comparing with those in the high-and middle-dose PQS groups or metformin group. CONCLUSION: PQS can accelerate the glucose utilization and depress the lipolysis in adipocytes induced by TNF-alpha, which may be correlated with its promoting insulin signal transduction and improving insulin resistance in adipocytes. PMID- 20929138 TI - [Number needed to treat (NNT), an index for clinical therapeutic efficacy assessment--its significance and application]. AB - Number needed to treat (NNT) is a simple and effective index for clinical therapeutic effect assessment worldwide accepted in recent years. By calculation of absolute risk reduction (ARR) of classified variables, it made the effect estimate reflect objectively the therapeutic effect of an intervention. However, clinical application of this index was introduced rarely in Chinese literature. With the examples from some published clinical reports, the calculation of NNT and its 95% confidence interval were demonstrated in this paper, and its application was illustrated by some relevant terms explanation and Meta-analysis methods introduction. PMID- 20929139 TI - [A literature review on the conceptual framework of sub-health]. AB - OBJECTIVE: To further articulate the conceptual framework of sub-health by way of literature review. METHODS: Published papers and relevant literature about sub health were collected, the representative publishing about theoretical exploration and practical surveys were focused for analyzing and assessing the category of sub-health, investigative objects, assessing tools, conceptual framework, diagnostic criteria and its operability, foundation support, etc. RESULTS: Sub-health conditions were categorized into three kinds in most documents, namely, the somatic, the mental and the social adaptative sub-health, and the relevant symptoms were classified into three levels. However, contents regarding the homogeneous issues, such as meaning and definition of sub-health, its diagnostic criteria and operability, in different documents were discrepant. CONCLUSION: Discrepancy exists between the theoretical and practical studies of sub-health. And detailed description is needed to articulate the problems respectively on specific and non-specific sub-health. The perspicuity of conceptual framework is the basis of sub-health researches. The authors recommended that to form the framework the four-level hierarchic structure should be adopted; in developing the assessing tool for sub-health diagnosis, besides the basic assessment on concrete conditions, the differential evaluation on the belonging of overall manifestations, subjective complain or objective symptom, should also be paid attention to. PMID- 20929140 TI - [Clinical observation on application of Bushen Tiaozhou method in in vitro fertilization-embryo transfer]. PMID- 20929141 TI - [Clinical effect of xianling gubao capsule combined with baofukang suppository in treating atrophic vaginitis]. PMID- 20929142 TI - [Effect of anti-thymocyte globulin combined with Chinese medicine drugs for shen nourishing in treating acute aplastic anemia]. PMID- 20929143 TI - [Clinical observation on treatment of knee osteoarthritis by wangbi tablet]. PMID- 20929144 TI - [Effect of auxiliary Chinese medicine drug therapy via percutaneous medication in treating 78 patients with infantile pneumonia]. PMID- 20929145 TI - [Application of four kinds of education mode in teaching integrative medical pediatrics]. PMID- 20929146 TI - [On English translation of Chinese medicine--from the perspective of polysystem translation theory]. PMID- 20929147 TI - [Molecular mechanism of malignant hematological tumor cell apoptosis induction by active components of traditional Chinese herbs]. PMID- 20929148 TI - Does charity also begin at home? PMID- 20929149 TI - Prevention of iatrogenic inferior alveolar nerve injuries in relation to dental procedures. AB - This article aims to review current hypotheses on the aetiology and prevention of inferior alveolar nerve (IAN) injuries in relation to dental procedures. The inferior alveolar nerve can be damaged during many dental procedures, including administration of local anaesthetic, implant bed preparation and placement, endodontics, third molar surgery and other surgical interventions. Damage to sensory nerves can result in anaesthesia, paraesthesia, pain, or a combination of the three. Pain is common in inferior alveolar nerve injuries, resulting in significant functional problems. The significant disability associated with these nerve injuries may also result in increasing numbers of medico-legal claims. Many of these iatrogenic nerve injuries can be avoided with careful patient assessment and planning. Furthermore, if the injury occurs there are emerging strategies that may facilitate recovery. The emphasis of this review is on how we may prevent these injuries and facilitate resolution in the early post surgical phase. CLINICAL RELEVANCE: It is imperative that dental practitioners are aware of the significant disability associated with iatrogenic nerve injuries and have an awareness of risk factors relating to inferior alveolar nerve injury. By understanding the risk factors and modification of intervention as a result, more of these injuries will be prevented. PMID- 20929150 TI - Dentinogenesis imperfecta--clinical presentation and management. AB - Dentinogenesis imperfecta (DI) is a hereditary condition which affects the development of dentine in both the primary and permanent dentitions. Three types of DI have been described in the literature. The presentation of DI is variable, depending on the type and severity of the disease. Early intervention in the treatment of a patient with DI is extremely important both for psycho-social and for functional reasons. This paper attempts to describe the clinical presentation and management of DI, and explores its association with certain medical conditions. CLINICAL RELEVANCE: Recognition of DI is important, so that correct treatment principles may be instituted. PMID- 20929151 TI - Cone beam computed tomography (CBCT) in endodontics. AB - Cone beam computed tomography (CBCT) is an extra-oral imaging system which produces 3-dimensional scans of the maxillofacial skeleton. It is useful in overcoming the limitations of conventional radiography. CBCT is a valuable aid in providing additional information for diagnosis and enabling more predictable management of complex endodontic problems compared to using intra-oral radiographs alone. CLINICAL RELEVANCE: There are potential indications for the use of CBCT in diagnosis and treatment planning. PMID- 20929152 TI - Bite size oral health promotion. AB - Improving health is part of the Government's wider public health agenda and central to this theme is the requirement to help patients make informed healthy choices. The aim of the article is to review the basis of oral health promotion in primary dental care, explain why it is necessary and to give some practical tips on behaviour change in practice. CLINICAL RELEVANCE: Understanding and relating well to your patients can make oral health promotion more successful, with communication skills being paramount in achieving this goal, along with the creation of a supportive health-orientated practice environment. PMID- 20929153 TI - Antimicrobial irrigants in endodontic therapy: 1. Root canal disinfection. AB - This paper highlights the importance of root canal disinfection. It discusses the different endodontic irrigants available and comments on how these can be used most effectively. CLINICAL RELEVANCE: Eliminating bacteria from the root canal system is an essential stage in endodontic therapy. Practitioners should be adequately informed and skilled in this vital aspect of endodontics. PMID- 20929154 TI - An osteosarcoma, presenting as a loose maxillary bridge, with pain and swelling. AB - An osteosarcoma (OS) is the second most common primary bone malignancy, yet rarely presents in the jaws. This paper describes the progress of a patient, with osteosarcoma of the jaw (OSJ), from the initial presentation at the dental surgery, through to diagnosis and treatment. CLINICAL RELEVANCE: This paper reminds the dental practitioner to be wary of any unusual presentation or clinical picture. It emphasizes the benefit of a prompt and appropriate referral. PMID- 20929155 TI - Neurofibromatosis-1 and the provision of dental care. AB - The general features of Neurofibromatosis-1 are outlined and the oral and maxillofacial features described. Two case reports of patients treated in the Department of Sedation and Special Care Dentistry at King's College London Dental Institute are presented, and the dental management of patients with Neurofibromatosis discussed. CLINICAL RELEVANCE: Neurofibromatosis-1 is a neurocutaneous genetic disease with a prevalence of one in 4000-5000. Dentists may be presented with these patients in their surgery and this article will help them to understand the condition and explain how to manage these patients. PMID- 20929156 TI - Physical signs for the general dental practitioner. Case 76. Deep vein thrombosis and cellulitis. PMID- 20929157 TI - Apects of human disease. Human disease. 56. Sjogren's syndrome. PMID- 20929158 TI - A Tennessee nurse reflects on walking Capitol Hill. PMID- 20929159 TI - Perception is everything. PMID- 20929160 TI - Being there: policymaking and nurses. PMID- 20929161 TI - Heart disease. Are you a type-D personality? PMID- 20929162 TI - The cost of happiness. A new study from a nobel-winning psychologist prices it out at about $75,000 a year. PMID- 20929163 TI - Hope for the best, prepare for the worst. PMID- 20929164 TI - Tales from the front. Physicians share their stories of bringing relief to disaster victims. PMID- 20929165 TI - How to protect yourself when you share care duty. PMID- 20929166 TI - What do we really know about consumer-driven health plans? AB - ABOUT CDHPs: Employers began offering consumer-driven health plans (CDHPs) in 2001 when a handful started offering health reimbursement arrangements (HRAs). They then started offering health savings account (HSA)-eligible plans after the Medicare Prescription Drug, Improvement, and Modernization Act of 2003 included a provision to allow individuals with certain high-deductible health plans to contribute to an HSA. This report summarizes what is known about CDHPs, which include both HRAs and HSAs. OFFER RATES: Surveys show that employers offering a CDHP increased from less than 5 percent in 2005 to between 12-15 percent by 2009. Growth in offer rates can be seen across all firm sizes. Recently, the percentage of small firms that offered a CDHP declined while larger firms continued to add a CDHP as an option. ENROLLMENT: Overall, 19.1 million, or 11 percent of individuals with private insurance, were enrolled in a CDHP in 2009. More recent data suggest that by 2010, 10 million people were in an HSA-eligible plan. PREMIUMS: Generally, premiums for CDHPs were lower than premiums for non-CDHPs. A number of studies have tried to explain the differences in premiums. One found savings ranged from 15.5 percent to a low of -4.7 percent, with average savings of 4.8 percent. However, the study found that most of the savings was due to younger, healthier workers choosing CDHPs and concluded that once typical risk- and benefit-adjustment factors were taken into account, CDHPs saved only 1.5 percent. There is strong evidence that initially CDHP enrollees will be healthier than non-CDHP enrollees, but that over time the CDHP population has a significantly higher illness burden. IMPACT OF CDHPS ON PREVENTIVE SERVICES: The studies agree that use of preventive services did not change (upward or downward) as a result of the CDHP. IMPACT OF CDHPS ON MEDICATION ADHERENCE: The studies found that overall use of brand-name prescription drugs fell and, while there was some offset from increased use of generic drugs, some enrollees stopped their use of prescription drugs. CDHP enrollees increased their use of the mail-order pharmacy option. Overall use of prescription drugs among CDHP enrollees with certain chronic conditions fell, or did not increase when enrollees met their deductible. One study found that the financial incentives of the plan are not sufficient in driving behavior, and that educational outreach also matters. NEED FOR FURTHER RESEARCH: Despite the growing body of evidence on the effect of CDHPs on cost and quality, there are many unanswered questions about these plans. Most of the research to date has focused on HRA-based plans. Little systematic research has been conducted on HSA-eligible enrollees. The differences between these plans are significant enough to warrant separate analyses. Also, most of the research to date has ignored the impact of the account on the use of services and on spending. Individuals may use health care services differently depending on how much money is being contributed to the account, especially relative to the deductible, amounts rolled over, and portability of the account. PMID- 20929167 TI - Phlebotomy in Japan. PMID- 20929168 TI - Flu 2010-2011 roundtable: Influenza insights from executive experts in the medical laboratory marketplace. PMID- 20929169 TI - The essential nature of comprehensive respiratory viral testing. PMID- 20929170 TI - Fused quartz, the uncompromising lab ware. PMID- 20929171 TI - Hospital lauds its point-of-care testing success. PMID- 20929172 TI - Can out-of-network labs waive coinsurance? PMID- 20929173 TI - Diary of the "mad" med-lab techs. PMID- 20929174 TI - Survey says: check the box. PMID- 20929175 TI - Keeping transfusion blood safe. PMID- 20929176 TI - Survey reveals realities of blood-collection cost-saving measures. PMID- 20929177 TI - Trends in blood collection and transfusion. PMID- 20929178 TI - Need phobics: stuck on not getting stuck. PMID- 20929179 TI - FDA scrutinizes LDTs. PMID- 20929180 TI - Rothmann offers fertility solutions for semen analysis. PMID- 20929181 TI - Pressure, the nervous system and ion channels: are humans too complicated? PMID- 20929182 TI - Hyperbaric pressure effects on voltage-dependent Ca+2 channels: relevance to HPNS. AB - Known and unpublished data regarding hyperbaric pressure (HP) effects on voltage dependent-Ca2+ channels (VDCCs) were reviewed in an attempt to elucidate their role in the development of high-pressure neurological syndrome (HPNS). Most postulated effects from studies performed in the last two decades (e.g., depressed maximal current) rely on indirect findings, derived from extracellular [Ca2+] manipulation or by observing Ca(2+)-dependent processes. More recent experiments have tried to directly measure Ca2+ currents under high pressure conditions, some of which are potentially challenging previous indirect findings on one hand, but support findings from work done on neuronal behavior on the other. Additional support for some of the recent findings is provided by computer simulation of pressure effects on a spinal motor neuron activity. HP effect on different types of VDCCs seems to be selective - i.e., HP may suppress, facilitate or not change their activity. Thus, the specific distribution of the various types of the channels in each synaptic terminal or throughout the neuron will determine their function and will influence the neuronal network behavior under HP. Further research is needed in order to fully understand the HPNS etiology. PMID- 20929183 TI - Advanced instrumentation for research in diving and hyperbaric medicine. AB - Improving the safety of diving and increasing knowledge about the adaptation of the human body to underwater and hyperbaric environment require specifically developed underwater instrumentation for physiological measurements. In fact, none of the routine clinical devices for health control is suitable for in-water and/or under-pressure operation. The present paper addresses novel technological acquisitions and the development of three dedicated devices: * an underwater data logger for recording O2 saturation (reflective pulsoxymetry), two-channel ECG, depth and temperature; * an underwater blood pressure meter based on the oscillometric method; and * an underwater echography system. Moreover, examples of recordings are presented and discussed. PMID- 20929184 TI - Bidirectional influences of acetazolamide on central nervous system oxygen toxicity of rats. AB - Central nervous system oxygen toxicity, which occurs during diving and hyperbaric oxygen treatment, can lead to very dangerous situations, and it is of great importance to explore its mechanisms. We have speculated that cerebral blood flow plays a pivotal role in its occurrence. Except for acting as an anticonvulsant in clinical applications, acetazolamide is also a vasodilator used in both clinical and laboratory settings. In this study, when acetazolamide from 5 to 500 ug/kg body weight was administered by intracerebroventricular injection, the latency of central nervous system oxygen toxicity detected by electroencephalogram recording in rats subjected to hyperbaric oxygen at 6 atmospheres absolute was prolonged significantly. On the contrary, when the dose of intracerebroventricular injection achieved 5,000 ug/kg body weight, acetazolamide shortened the latency significantly. Intraperitoneal injection of acetazolamide more than 7.5 mg/kg body weight also shortened the latency significantly. Results also showed both intracerebroventricular injection of acetazolamide at a dose of 5,000 ug/kg body weight and intraperitoneal injection at dose of 7.5 mg/kg body weight inhibited the activity of carbonic anhydrase and increased the cerebral blood flow significantly, which helped aggravate oxidation damage and resulted in increased MDA and impaired glutathione peroxidase in brain tissue. But intracerebroventricular injection of acetazolamide at 5 ug/kg body weight had no effect on MDA and glutathione peroxidase, though it inhibited the activity of carbonic anhydrase. These observations indicated acetazolamide covers bidirectional influences on central nervous system oxygen toxicity. Within local brain tissue, especially neurons, it could exert its anticonvulsive effect on the central nervous system at low doses. On the other hand, under high doses, it would display its convulsive-hastening effect through increasing cerebral blood flow to aggravate the oxidation state of brain tissues and exacerbate central nervous system oxygen toxicity when subjected to hyperbaric oxygen. Blood flow of brain plays a pivotal role in central nervous system oxygen toxicity. PMID- 20929185 TI - Dysbaric osteonecrosis in recreational divers: a study using magnetic resonance imaging. AB - OBJECTIVE: We set out to identify whether magnetic resonance imaging (MRI) would identify evidence of dysbaric osteonecrosis (DON) in a group of experienced recreational scuba divers. DESIGN: Local British Sub Aqua Club divers of at least Trainee Dive Leader grade were offered MRI scans (T1 and TIRM sequences) of hips, femora and shoulders. Anonymous images were interpreted separately by two radiologists, and cases not considered unequivocally normal were discussed for consensus opinion. RESULTS: Of 26 divers imaged, five merited discussion. Four of these were considered to show unrelated normal variants or incidental findings. Only one case (abnormalities in the right humerus and left femur) could have possibly represented osteonecrotic lesions. After obtaining plain radiographs and more detailed clinical and dive history, these lesions were considered "indeterminate" but probably not DON by both reviewers and after taking further specialist musculoskeletal MRI opinion. CONCLUSION: This study found no evidence that DON is a significant risk in recreational scuba diving and as such concurs with prevailing current opinion. PMID- 20929186 TI - Hyperbaric oxygen therapy and neurological disease. PMID- 20929188 TI - Coverage wars. As reform takes effect, insurers drop child-only policies and threaten more cuts. AB - As the first provisions of the healthcare reform law kick in, insurers are signaling they'll simply abandon business lines that are troublesome, such as child-only policies. America's Health Insurance Plans defends the moves as necessary in the wake of additional, mandated benefits. AHIP's "math doesn't make sense," says J. James Rohack, left, immediate past president of the American Medical Association. PMID- 20929187 TI - Age-related macular degeneration and hyperbaric oxygen. PMID- 20929189 TI - PHA's next chapter. PMID- 20929190 TI - At the starting line. As the first payment years are set to commence under the federal EHR subsidy program, providers find themselves at different stages of readiness. PMID- 20929191 TI - Proton pros and cons. Some cite dearth of studies on effectiveness; others see therapy's unique value. PMID- 20929192 TI - Largest group practices. Ranked by number of full-time-equivalent physicians, based on MGMA data as of September 2010. PMID- 20929193 TI - Reading the public mind. PMID- 20929194 TI - Competing on talent analytics. AB - Do investments in your employees actually affect workforce performance? Who are your top performers? How can you empower and motivate other employees to excel? Leading-edge companies such as Google, Best Buy, Procter & Gamble, and Sysco use sophisticated data-collection technology and analysis to answer these questions, leveraging a range of analytics to improve the way they attract and retain talent, connect their employee data to business performance, differentiate themselves from competitors, and more. The authors present the six key ways in which companies track, analyze, and use data about their people-ranging from a simple baseline of metrics to monitor the organization's overall health to custom modeling for predicting future head count depending on various "what if" scenarios. They go on to show that companies competing on talent analytics manage data and technology at an enterprise level, support what analytical leaders do, choose realistic targets for analysis, and hire analysts with strong interpersonal skills as well as broad expertise. PMID- 20929195 TI - Build the co-creative enterprise. AB - These days more companies are inviting customers to help them design products. Now a few are taking things further and including their other stakeholders- employees, suppliers, distributors, and even regulators--in "co-creation" efforts, too. By focusing on improving the experiences of everyone involved, such firms are achieving breakthrough insights, lower costs, new revenues, and new business models. Consider how this worked at France's La Poste, which wanted to expand package delivery and banking services in light of a decline in its mail business. La Poste had three obstacles: unmotivated union tellers, customers disgruntled by long waits, and frustrated local managers, who felt caught in between. The company set some high-level goals and invited all three groups to decide how to reach them together. To get tellers' buy-in, La Poste gave them a say in their schedules. In workshops, the groups figured out when each office should be open and how its space should be configured. THE RESULTS: a 50% decrease in waiting time, a jump in satisfaction for customers, soaring job satisfaction among tellers, and significant growth in package delivery and banking, despite the recession. PMID- 20929196 TI - Effect of cationic polyacrylamide adsorption kinetics and ionic strength on precipitated calcium carbonate flocculation. AB - The effect of polymer adsorption kinetics and ionic strength on the dynamics of particle flocculation was quantified using a model system consisting of precipitated calcium carbonate (PCC) and cationic polyacrylamide (CPAM) at a low shear rate. All early flocculations detectable by a photodispersion analyzer (PDA) happened in nonequilibrium polymer adsorption regimes. We observed discrepancies in flocculation rates with the surface coverage theory, which is based on a simple monolayer adsorption model, in both early and late flocculation stages. For instance, the same amount of adsorbed CPAM reached at different polymer doses demonstrated different flocculating capabilities. This highlighted the importance of polymer adsorption kinetics upon flocculation. The transient conformation of the adsorbed CPAM during the kinetic process sometimes even superceded the adsorbed amount in the determination of PCC flocculation. Both antagonistic and synergetic effects of increased ionic strength on the CPAM induced PCC aggregation were observed during early flocculation. However, late stage PCC flocculation shared some similarities, irrespective of polymer dose and ionic strength. Despite the decreased amount of adsorbed polymer from the increased ionic strength, the combination of CPAM and salt, at certain concentrations, demonstrated a synergy to promote PCC aggregation more efficiently than the same amount of the respective components. PMID- 20929198 TI - Surface instabilities in ultrathin, cross-linked poly(N-isopropylacrylamide) coatings. AB - Near-the-surface instabilities with a cusplike morphology were observed in ultrathin photo-cross-linked poly(N-isopropylacrylamide) coatings upon swelling in water. The characteristic wavelength of the instability was approximately 25 times the dry thickness and scaled linearly with coating thickness between 30 and 1200 nm. Above 1200 nm, slippage of the coating along the confining substrate led to reticulated patterns with a much larger wavelength. To help interpret the origin of the instability, the coatings were also exposed to a solvent slightly worse than water (acetone) and a solvent slightly better than water (isopropanol). In all cases, the characteristic wavelength scaled linearly with respect to the swelling induced by each solvent. Both water and isopropanol produced well-defined cusps or folds in the gel surface, while acetone produced semiordered blisters that grew into one another. The features produced in acetone may be a consequence of swelling being close to the threshold value for the loss of planar stability. Through the use of a first-order linear perturbation of the Flory-Rehner model, it is shown that the emergence of a characteristic wavelength is consistent with an inhomogeneous distribution of solvent that results from diffusion of solvent into a dry coating. PMID- 20929197 TI - Biomimetic total synthesis of meiogynin A, an inhibitor of Bcl-xL and Bak interaction. AB - A short, convergent, and selective synthesis of meiogynin A, an inhibitor of the antiapoptotic protein Bcl-xL, has been performed. This synthesis, based on a biomimetic approach, allowed the determination of its absolute configuration. Three isomers of meiogynin A have also been elaborated. One of these was found to be three times more potent than the natural compound. PMID- 20929199 TI - Thiolated dextran-coated gold nanorods for photothermal ablation of inflammatory macrophages. AB - Thiolated dextran-coated gold nanorods (DEX-GNRs) were synthesized for targeted delivery to inflammatory macrophages and their photothermal ablation under near infrared (NIR) light irradiation. Successful synthesis of DEX-GNRs was achieved using thiolated dextran, generated by applying mercaptopropionic acid to transform a hydroxyl group of dextran into a thiol group which has strong binding affinity with surfaces of GNRs. We confirmed both the existence of a thiol group in the functionalized dextran using Ellman's reagent in a thiol group assay and the characteristic band of DEX-GNRs using FT-IR spectrum. Furthermore, a cellular uptake study revealed that dextran showed a superior ability to bind the GNRs surface against macrophages compared to those of PEGylated GNRs with various molecular weights of polyethyleneglycol (PEG). Consequently, an in vitro photothermal irradiation experiment using NIR light indicated that DEX-GNRs exhibited a significant cell-killing efficacy, even with a lower concentration of Au and a low-power light source. PMID- 20929200 TI - Synthesis of 2',4'-propylene-bridged (carba-ENA) thymidine and its analogues: the engineering of electrostatic and steric effects at the bottom of the minor groove for nuclease and thermodynamic stabilities and elicitation of RNase H. AB - 2',4'-Propylene-bridged thymidine (carba-ENA-T) and five 8'-Me/NH(2)/OH modified carba-ENA-T analogues have been prepared through intramolecular radical addition to C?N of the tethered oxime-ether. These carba-ENA nucleosides have been subsequently incorporated into 15mer oligodeoxynucleotides (AON), and their affinity toward cDNA and RNA, nuclease resistance, and RNase H recruitment capability have been investigated in comparison with those of the native and ENA counterparts. These carba-ENAs modified AONs are highly RNA-selective since all of them led to slight thermal stabilization effect for the AON:RNA duplex, but quite large destabilization effect for the AON:DNA duplex. It was found that different C8' substituents (at the bottom of the minor groove) on carba-ENA-T only led to rather small variation of thermal stability of the AON:RNA duplexes. We, however, observed that the parent carba-ENA-T modified AONs exhibited higher nucleolytic stability than those of the ENA-T modified counterparts. The nucleolytic stability of carba-ENA-T modified AONs can be further modulated by C8' substituent to variable extents depending on not only the chemical nature but also the stereochemical orientation of the C8' substituents: Thus, (1) 8'S-Me on carba-ENA increases the nucleolytic stability but 8'R-Me leads to a decreased effect; (2) 8'R-OH on carba-ENA had little, if any, effect on nuclease resistance but 8'S-OH resulted in significantly decreased nucleolytic stability; and (3) 8' NH(2) substituted carba-ENA leads to obvious loss in the nuclease resistance. The RNA strand in all of the carba-ENA derivatives modified AON:RNA hybrid duplexes can be digested by RNase H1 with high efficiency, even at twice the rate of those of the native and ENA modified counterpart. PMID- 20929201 TI - A concise and convergent synthesis of PA-824. AB - An efficient four-step synthesis of PA-824, a promising antituberculosis drug candidate, has been developed. This concise approach offers significant improvements over the synthetic route currently used for large-scale production. PMID- 20929202 TI - Synthesis of a tetracyclic G?C scaffold for the assembly of rosette nanotubes with 1.7 nm inner diameter. AB - The synthesis of a tetracyclic self-complementary molecule 4 for self-assembly into rosette nanotubes is presented. This new heterocycle has a core structure containing two pyrido[2,3-d]pyrimidine molecules fused together and features the Watson-Crick hydrogen bond donor-acceptor arrays of both guanine (G) and cytosine (C). Current methods to synthesize pyrido[2,3-d]pyrimidines require harsh conditions and long reaction times and result usually in low product yields. This is particularly problematic for the direct incorporation of functional groups that cannot withstand these conditions. Here, we present an efficient approach to access the multifunctional pyrido[2,3-d]pyrimidine intermediate 2 under relatively mild conditions using three regioselective S(N)Ar reactions at C2, C4, and C7 on the trichloro compound 1. The electron-withdrawing group and amino functionalities on 2 are then used as a handle to install the third and fourth rings of 4 using a Friedlander-type condensation followed by mixed urea synthesis and cyclization. PMID- 20929203 TI - Size-dependent infrared phonon modes and ferroelectric phase transition in BiFeO3 nanoparticles. AB - One emergent property of ferroelectric nanoparticles is the sized-induced structural distortion to a high-symmetry paraelectric phase at small particle sizes. Finite length scale effects can thus be advantageously employed to elucidate ferroelectric transition mechanisms. In this work, we combine infrared spectroscopy with group theory and lattice dynamics calculations to reveal the displacive nature of the ferroelectric transition in BiFeO3, a room temperature multiferroic. Systematic intensity and frequency trends in selected vibrational modes show that the paraelectric phase is Pm3m and the lowest frequency A1 feature is the soft mode that drives the first order transition. Finite length scale effects are also evident in the electronic structure with a red-shifted band gap in nanoscale BiFeO3 compared with that of the rhombohedral film, a result that can impact the development of ferroelectric photovoltaics and oxide based electronics. Taken together, these findings demonstrate the foundational importance of size effects for enhancing the rich functionality and broad utility of transition metal oxides. PMID- 20929204 TI - Local nanoscale heating modulates single-asperity friction. AB - We demonstrate measurement and control of single-asperity friction by using cantilever probes featuring an in situ solid-state heater. The heater temperature was varied between 25 and 650 degrees C (tip temperatures from 25 +/- 2 to 120 +/- 20 degrees C). Heating caused friction to increase by a factor of 4 in air at ~ 30% relative humidity, but in dry nitrogen friction decreased by ~ 40%. Higher velocity reduced friction in ambient with no effect in dry nitrogen. These trends are attributed to thermally assisted formation of capillary bridges between the tip and substrate in air, and thermally assisted sliding in dry nitrogen. Real-time friction measurements while modulating the tip temperature revealed an energy barrier for capillary condensation of 0.40 +/- 0.04 eV but with slower kinetics compared to isothermal measurements that we attribute to the distinct thermal environment that occurs when heating in real time. Controlling the presence of this nanoscale capillary and the associated control of friction and adhesion offers new opportunities for tip-based nanomanufacturing. PMID- 20929205 TI - Evans-Tishchenko coupling of heteroaryl aldehydes. AB - The low-temperature Evans-Tishchenko coupling of a range of functionalized heteroaryl aldehydes with beta-hydroxy ketones in the presence of a Sm(III) catalyst has been achieved with high yields (90-99%) and good to excellent diastereoselectivity (90:10 -> 95:5 dr). However, at room temperature a retro aldol aldol-Tishchenko reaction was found to compete with the desired Evans Tishchenko reaction. Identification of these byproducts has allowed the corresponding aldol-Tishchenko reaction to be optimized for several heteroaryl aldehydes. PMID- 20929206 TI - Layer-by-layer electrostatic-assembly: magnetic-field assisted ordering of organic molecules. AB - During the layer-by-layer (LbL) electrostatic assembly process, we orient organic molecules (nickel phthalocyanine) by an external magnetic field. Orientation of the magnetic moment of the molecules in a monolayer is immobilized by depositing a monolayer of a suitable polycation. Due to the orientation of magnetic moments, the electrostatic adsorption process becomes enhanced in subsequent layers. By cycling the deposition sequence layer after layer, we have achieved highly ordered and closely packed LbL films of the molecules with their magnetic moments oriented perpendicular to the substrate. Nonmagnetic copper phthalocyanine expectedly showed neither a magnetic-field assisted alignment nor an enhanced adsorption in LbL film deposition process. PMID- 20929207 TI - Nanometals induce stress and alter thyroid hormone action in amphibia at or below North American water quality guidelines. AB - Nanometals are manufactured to particle sizes with diameters in the nanometer range and are included in a variety of consumer and health products. There is a lack of information regarding potential effects of these materials on aquatic organisms. Amphibians are regarded as environmental sentinels and demonstrate an exquisite sensitivity to thyroid hormone action, a hormone that is essential for human health. This present study assessed the effect of exposure to nanometals on stress and thyroid hormone signaling in frog tissue using a cultured tail fin biopsy (C-fin) assay derived from Rana catesbeiana tadpoles. The C-fin assay maintains tissue complexity and biological replication while multiple chemical responses can be assessed from the same individual. We tested the ability of nanosilver (0.06 MUg/L-5.5 mg/L), quantum dots (0.25 MUg/L-22 mg/L), and nanozinc oxide (0.19-10 mg/L) to alter gene expression in the presence or absence of 3,3',5'-triiodothyronine (T(3)) using quantitative real-time polymerase chain reaction. Results were compared to exposure to micrometer-silver, silver nitrate, and micrometer-cadmium telluride. Nanosilver (>=2.75 mg/L) and quantum dots (>=0.22 mg/L) altered the expression of transcripts linked to T(3)- and stress mediated pathways, while nanozinc oxide had no effect. Lower concentrations of nanosilver (0.6 to 550 MUg/L) perturbed T(3)-mediated signaling while not inducing cell stress. The observed effects were orders of magnitude below acute toxicity levels and occurred at or below the current North American water quality guidelines for metals, underscoring the need for evaluating nanoparticles separately from their constituent chemicals. PMID- 20929208 TI - Regioselective palladium-catalyzed arylation of 4-chloropyrazoles. AB - A highly regioselective Pd-catalyzed arylation of N-methylpyrazoles with aryl bromides is described. This transformation was studied extensively via automated reaction screening. A Design of Experiments (DoE) approach for optimizing the critical parameters was applied, resulting in excellent conditions for preparing selectively 5-arylpyrazoles in moderate to excellent yields under mild conditions. PMID- 20929209 TI - One-pot conditional self-assembly of multicopper metallacycles. AB - The self-assembly of supramolecular metallacycles via the coordination-driven directional bonding approach can be modified to produce some unexpected structural variations. The combination of a flexible ligand-capped dinuclear transition-metal acceptor like [Cu(2)(dppm)(2)(NCMe)(2)]X(2) (1X(2); dppm = Ph(2)PCH(2)PPh(2); X(-) = BF(4)(-), PF(6)(-), or BPh(4)(-)) with monodentate bidentate donors like 2-, 3-, and 4-pyridylcarboxylates produced oligomeric compounds [{Cu(2)(dppm)(2)}(MU-(2-PyCO(2)))](2)X(2) (2X(2)), [{Cu(2)(dppm)(2)}(MU (3-PyCO(2)))](2)X(2) (3X(2)), and [{Cu(2)(dppm)(2)}(MU-(4-PyCO(2)))](4)X(4) (4X(4)), respectively, as the thermodynamically stable products in one-pot reactions. However, the modified self-assembly is still subject to steric hindrance. The reaction of complex 1(BF(4))(2) with 6-Me-3-PyCO(2)H did not produce a polygonal dimeric metallacycle but a simple dinuclear complex, [Cu(2)(dppm)(2)(6-Me-3-PyCO(2))](BF(4)) (5(BF(4))). The crystal structures of complexes 2(PF(6))(2), 3(PF(6))(2), 4(BF(4))(4), and 5(BF(4)) were determined using X-ray diffraction. PMID- 20929210 TI - Phase behavior of an extended surfactant in water and a detailed characterization of the concentrated phases. AB - The formation of microemulsions with triglycerides at ambient conditions can be improved by increasing the surfactant-water and surfactant-oil interactions. Therefore, extended surfactants were developed, which contain hydrophilic/lipophilic linkers. They have the ability to stretch further into the oil and water phase and enhance the solubility of oil in water. In this work, the phase behavior of a chosen extended surfactant (C(12-14)-PO(16)-EO(2)-SO(4)Na, X AES) in H(2)O/D(2)O at high surfactant concentrations (30-100 wt %) and at temperatures between 0 and 90 degrees C is studied for the first time. The lyotropic liquid crystals formed were determined by optical microscopy, small angle X-ray scattering (SAXS), and (2)H and (23)Na NMR, and a detailed phase diagram of the concentrated area is given. The obtained mesophases are a hexagonal phase (H(1)), at low temperatures and small concentrations, a lamellar phase (L(alpha)) at high temperatures or concentrations, a bicontinuous cubic phase (V(2)) as well as a reverse hexagonal phase (H(2)). To our knowledge, this is the first surfactant that forms both H(1) and H(2) phases without the addition of a third compound. From the (2)H NMR quadrupole splittings of D(2)O, we have examined water binding in the L(alpha) and the H(2) phases. There is no marked difference in the bound water between the two phases. Where sufficient water is present, the number of bound water molecules per X-AES is estimated to be ca. 18 with only small changes at different temperatures. Similar results were obtained from the (23)Na NMR data, which again showed little difference in the ion binding between the L(alpha) and the H(2) phases. The X-ray diffraction data show that X AES has a much smaller average length in the L(alpha) phase compared to the all trans length than in the case for conventional surfactants. At very high surfactant concentrations an inverse isotropic solution (L(2)), containing a small fraction of solid particles, is formed. This isotropic solution is clearly identified and the size of the reversed micelles was determined using (1)H NMR measurements. Furthermore, the solid particles within the L(2) phase and the neat surfactant were analyzed. The observed results were compared to common conventional surfactants (e.g., sodium dodecyl sulfate, sodium lauryl ether sulfate, and sodium dodecyl-p-benzene sulfonate), and the influence of the hydrophilic/lipophilic linkers on the phase behavior was discussed. PMID- 20929211 TI - Investigation of DNA condensing properties of amphiphilic triblock cationic polymers by atomic force microscopy. AB - Introduction of nucleic acids into cells is an important biotechnology research field which also holds great promise for therapeutic applications. One of the key steps in the gene delivery process is compaction of DNA into nanometric particles. The study of DNA condensing properties of three linear cationic triblock copolymers poly(ethylenimine-b-propylene glycol-b-ethylenimine), namely, LPEI(50)-PPG(36)-LPEI(50), LPEI(19)-PPG(36)-LPEI(19), and LPEI(14)-PPG(68) LPEI(14), indicates that proper DNA condensation is driven by both the charge and the size of the respective cationic hydrophilic linear polyethylenimine (LPEI) and neutral hydrophobic poly(propylene glycol) (PPG) parts. Atomic force microscopy was used to investigate the interactions of the triblock copolymers with plasmid DNA at the single molecule level and to enlighten the mechanism involved in DNA condensation. PMID- 20929212 TI - Functional importance of tyrosine 294 and the catalytic selectivity for the bis Fe(IV) state of MauG revealed by replacement of this axial heme ligand with histidine . AB - The diheme enzyme MauG catalyzes the posttranslational modification of a precursor protein of methylamine dehydrogenase (preMADH) to complete the biosynthesis of its protein-derived tryptophan tryptophylquinone (TTQ) cofactor. It catalyzes three sequential two-electron oxidation reactions which proceed through a high-valent bis-Fe(IV) redox state. Tyr294, the unusual distal axial ligand of one c-type heme, was mutated to His, and the crystal structure of Y294H MauG in complex with preMADH reveals that this heme now has His-His axial ligation. Y294H MauG is able to interact with preMADH and participate in interprotein electron transfer, but it is unable to catalyze the TTQ biosynthesis reactions that require the bis-Fe(IV) state. This mutation affects not only the redox properties of the six-coordinate heme but also the redox and CO-binding properties of the five-coordinate heme, despite the 21 A separation of the heme iron centers. This highlights the communication between the hemes which in wild type MauG behave as a single diheme unit. Spectroscopic data suggest that Y294H MauG can stabilize a high-valent redox state equivalent to Fe(V), but it appears to be an Fe(IV)?O/pi radical at the five-coordinate heme rather than the bis Fe(IV) state. This compound I-like intermediate does not catalyze TTQ biosynthesis, demonstrating that the bis-Fe(IV) state, which is stabilized by Tyr294, is specifically required for this reaction. The TTQ biosynthetic reactions catalyzed by wild-type MauG do not occur via direct contact with the Fe(IV)?O heme but via long-range electron transfer through the six-coordinate heme. Thus, a critical feature of the bis-Fe(IV) species may be that it shortens the electron transfer distance from preMADH to a high-valent heme iron. PMID- 20929213 TI - Asymmetric total synthesis of ent-cyclooroidin. AB - An enantiospecific total synthesis of the pyrrole-imidazole natural product cyclooroidin from histidine is described. The key N1-C9 bond is constructed through an intramolecular SN2-type of reaction of a chloro ester. Subsequent imidazole azidation at the 2-position, pyrrole bromination, azide reduction, and deprotection leads to the completion of the synthesis. PMID- 20929214 TI - Direct enantioselective Bronsted acid catalyzed N-acyliminium cyclization cascades of tryptamines and ketoacids. AB - A direct enantio- and diastereoselective N-acyliminium cyclization cascade through chiral phosphoric acid catalyzed condensation of tryptamines with gamma- and delta-ketoacid derivatives to provide architecturally complex heterocycles has been developed. The reaction is technically simple to perform, atom efficient, and broad in scope. Employing 10 mol % of (R)-BINOL derived chiral phosphoric acids in refluxing toluene allowed the polycyclic product materials to be generated in good yields (53-99%) and moderate to high enantioselectivities (68-98% ee). PMID- 20929215 TI - Photo-reversible liquid crystal alignment using azobenzene-based self-assembled monolayers: comparison of the bare monolayer and liquid crystal reorientation dynamics. AB - Photosensitive surfaces treated to have in-plane structural anisotropy by illumination with polarized light can be used to orient liquid crystals (LCs). Here we report a detailed study of the dynamic behavior of this process at both short and long times, comparing the ordering induced in the bare active surface with that of the LC in contact with the surface using a high-sensitivity polarimeter that enables detailed characterization of the anisotropy of the active surface. The experiments were carried out using self-assembled monolayers (SAMs) made from dimethylaminoazobenzene covalently bonded to a glass surface through a triethoxysilane terminus. This surface gives planar alignment of the liquid crystal director with an azimuthal orientation that can be controlled by the polarization of actinic light. We find a remarkable long-term collective interaction between the orientationally ordered SAM and the director field of the LC: while an azobenzene based SAM in contact with an isotropic gas or liquid relaxes to an azimuthally isotropic state in the absence of light due to thermal fluctuations, an orientationally written SAM in contact with LC in the absence of light can maintain the LC director twist permanently, that is, the SAM is capable of providing azimuthal anchoring to the LC even in the presence of a torque about the surface normal. We find that the short-time, transient LC reorientation is limited by the weak azimuthal anchoring strength of the SAM and by the LC viscosity. PMID- 20929216 TI - HOCO radical chemistry. AB - Free radicals are important species in atmospheric chemistry, combustion, plasma environments, interstellar clouds, and biochemistry. Therefore, researchers would like to understand the formation mechanism, structure, stability, reactivity, spectroscopy, and dynamics of these chemical species. However, due to the presence of one or more unpaired electrons, radicals are often very reactive and have short lifetimes, which makes it difficult to conduct experiments. The HOCO radical appears in the atmosphere as well as in combustion environments and plays an important role in the conversion of CO to CO(2). Through the interplay between theoretical and experimental investigations, researchers have only recently understood the chemical role of the HOCO radical. In this Account, we systematically describe the current state of knowledge of the HOCO radical based on recent theoretical and experimental studies. This radical's two stable conformers, trans- and cis-HOCO, have been identified by high-level ab initio calculations and experimental spectroscopy. trans-HOCO is more stable by approximately 1.8 kcal/mol. The heat of formation of HOCO (298 K) was determined to be -43.0 +/- 0.5 kcal/mol, giving a potential well depth of 30.1 +/- 0.5 kcal/mol relative to the asymptote of the reactants OH + CO. The HOCO radical is very reactive. In most reactions between the HOCO radical and atoms, the HOCO radical acts as a hydrogen donor to reaction partners. Generally, the hydrogen is transferred through the formation of an association intermediate, which then proceeds through a molecular elimination step to produce the reaction products. The reaction rates of HOCO with some small radicals fall in the range of 10(-11) 10(-10) cm(3) molecule(-1) s(-1). These results clearly illustrate important features in the reactivity of the HOCO radical with other molecules. PMID- 20929217 TI - Dissolution and dissolved state of cytochrome C in a neat, hydrophilic ionic liquid. AB - The dissolution and dissolved molecular state of cytochrome c were investigated in the room temperature ionic liquid ethylmethylimidazolium ethylsulfate, [EMIM][EtSO4], by viscometry, optical and vibrational spectroscopies, and peroxidase activity. In dilute mixtures, viscometry demonstrated true molecular dissolution of cytochrome c in the ionic liquid and uncovered a molecular size larger than that in aqueous buffer, suggesting altered solvation or slight denaturation. The protein's heme unit absorbs light outside the spectral range masked by [EMIM], enabling conformational assessments by UV-visible and circular dichroism spectroscopies. Adding trends from fluorescence and Fourier transform infrared spectroscopy, unchanged secondary but perturbed tertiary structures were determined, consistent with the appreciable peroxidase activity measured. Different than in aqueous buffers, denaturation is not accompanied by aggregation. Results are relevant to the proposed application of ionic liquids as media for room temperature preservation of biomacromolecules. PMID- 20929218 TI - Partitioning of ssRNA molecules between preformed monolithic HII liquid crystalline phases of lipids and supernatant isotropic phases. AB - The interaction of nucleic acids with the nanoarchitectures formed by lipidic systems is a new area of research that may offer insights into the functioning of genetic materials in vivo. Here we report that ssRNA has a strong preference to reside in isotropic solution rather than in inverse hexagonal (HII) liquid crystalline phases. This is in contrast to dsDNA, which becomes localized in the pores of the HII phase. The RNA that does associate with the external surfaces of the HII phase appears to form an accretion layer, tens of molecules thick, but this layer still allows the transcription of dsDNA that resides within the pores of the phase. PMID- 20929219 TI - Solution-phase synthesis of heteroatom-substituted carbon scaffolds for hydrogen storage. AB - This paper reports a bottom-up solution-phase process for the preparation of pristine and heteroatom (boron, phosphorus, or nitrogen)-substituted carbon scaffolds that show good surface areas and enhanced hydrogen adsorption capacities and binding energies. The synthesis method involves heating chlorine containing small organic molecules with metallic sodium at reflux in high-boiling solvents. For heteroatom incorporation, heteroatomic electrophiles are added to the reaction mixture. Under the reaction conditions, micrometer-sized graphitic sheets assembled by 3-5 nm-sized domains of graphene nanoflakes are formed, and when they are heteroatom-substituted, the heteroatoms are uniformly distributed. The substituted carbon scaffolds enriched with heteroatoms (boron ~7.3%, phosphorus ~8.1%, and nitrogen ~28.1%) had surface areas as high as 900 m(2) g( 1) and enhanced reversible hydrogen physisorption capacities relative to pristine carbon scaffolds or common carbonaceous materials. In addition, the binding energies of the substituted carbon scaffolds, as measured by adsorption isotherms, were 8.6, 8.3, and 5.6 kJ mol(-1) for the boron-, phosphorus-, and nitrogen-enriched carbon scaffolds, respectively. PMID- 20929221 TI - Spin-dependent electron-phonon interaction in SmFeAsO by low-temperature Raman spectroscopy. AB - The interplay between spin dynamics and lattice vibration has been suggested as an important part of the puzzle of high-temperature superconductivity. Here, we report the strong interaction between spin fluctuation and phonon in SmFeAsO, a parent compound of the iron arsenide family of superconductors, revealed by low temperature Raman spectroscopy. Anomalous zone-boundary-phonon Raman scattering from spin superstructure was observed at temperatures below the antiferromagnetic ordering point, which offers compelling evidence on spin-dependent electron phonon coupling in pnictides. PMID- 20929220 TI - Two-step adsorption on jungle-gym-type porous coordination polymers: dependence on hydrogen-bonding capability of adsorbates, ligand-substituent effect, and temperature. AB - A preliminary study of isopropanol (IPA) adsorption/desorption isotherms on a jungle-gym-type porous coordination polymer, [Zn(2)(bdc)(2)(dabco)](n) (1, H(2)bdc = 1,4-benzenedicarboxylic acid, dabco =1,4-diazabicyclo[2.2.2]octane), showed unambiguous two-step profiles via a highly shrunk intermediate framework. The results of adsorption measurements on 1, using probing gas molecules of alcohol (MeOH and EtOH) for the size effect and Me(2)CO for the influence of hydrogen bonding, show that alcohol adsorption isotherms are gradual two-step profiles, whereas the Me(2)CO isotherm is a typical type-I isotherm, indicating that a two-step adsorption/desorption is involved with hydrogen bonds. To further clarify these characteristic adsorption/desorption behaviors, selecting nitroterephthalate (bdc-NO(2)), bromoterephthalate (bdc-Br), and 2,5 dichloroterephthalate (bdc-Cl(2)) as substituted dicarboxylate ligands, isomorphous jungle-gym-type porous coordination polymers, {[Zn(2)(bdc NO(2))(2)(dabco)].solvents}(n) (2 ? solvents), {[Zn(2)(bdc Br)(2)(dabco)].solvents}(n) (3 ? solvents), and {[Zn(2)(bdc Cl(2))(2)(dabco)].solvents}(n) (4 ? solvents), were synthesized and characterized by single-crystal X-ray analyses. Thermal gravimetry, X-ray powder diffraction, and N(2) adsorption at 77 K measurements reveal that [Zn(2)(bdc NO(2))(2)(dabco)](n) (2), [Zn(2)(bdc-Br)(2)(dabco)](n) (3), and [Zn(2)(bdc Cl(2))(2)(dabco)](n) (4) maintain their frameworks without guest molecules with Brunauer-Emmett-Teller (BET) surface areas of 1568 (2), 1292 (3), and 1216 (4) m(2) g(-1). As found in results of MeOH, EtOH, IPA, and Me(2)CO adsorption/desorption on 2-4, only MeOH adsorption on 2 shows an obvious two-step profile. Considering the substituent effects and adsorbate sizes, the hydrogen bonds, which are triggers for two-step adsorption, are formed between adsorbates and carboxylate groups at the corners in the pores, inducing wide pores to become narrow pores. Interestingly, such a two-step MeOH adsorption on 2 depends on the temperature, attributed to the small free-energy difference (DeltaF(host)) between the two guest-free forms, wide and narrow pores. PMID- 20929222 TI - Highly efficient metal-free growth of nitrogen-doped single-walled carbon nanotubes on plasma-etched substrates for oxygen reduction. AB - We have for the first time developed a simple plasma-etching technology to effectively generate metal-free particle catalysts for efficient metal-free growth of undoped and/or nitrogen-doped single-walled carbon nanotubes (CNTs). Compared with undoped CNTs, the newly produced metal-free nitrogen-containing CNTs were demonstrated to show relatively good electrocatalytic activity and long term stability toward oxygen reduction reaction (ORR) in an acidic medium. Owing to the highly generic nature of the plasma etching technique, the methodology developed in this study can be applied to many other substrates for efficient growth of metal-free CNTs for various applications, ranging from energy related to electronic and to biomedical systems. PMID- 20929223 TI - 'Living' controlled in situ gelling systems: thiol-disulfide exchange method toward tailor-made biodegradable hydrogels. AB - A 'living' controlled hydrogel formation method was first reported to create loose and compact in situ biodegradable hydrogels. The method executed under mild reaction conditions can conveniently tailor the hydrogel properties, and it has the potential to develop into a powerful tool for the design, synthesis, and self assembly of novel tailor-made biomaterials and drug delivery systems. PMID- 20929224 TI - Allylic C-H acetoxylation with a 4,5-diazafluorenone-ligated palladium catalyst: a ligand-based strategy to achieve aerobic catalytic turnover. AB - Pd-catalyzed C-H oxidation reactions often require the use of oxidants other than O(2). Here we demonstrate a ligand-based strategy to replace benzoquinone with O(2) as the stoichiometric oxidant in Pd-catalyzed allylic C-H acetoxylation. Use of 4,5-diazafluorenone (1) as an ancillary ligand for Pd(OAc)(2) enables terminal alkenes to be converted to linear allylic acetoxylation products in good yields and selectivity under 1 atm O(2). Mechanistic studies have revealed that 1 facilitates C-O reductive elimination from a pi-allyl-Pd(II) intermediate, thereby eliminating the requirement for benzoquinone in this key catalytic step. PMID- 20929225 TI - Hydrogen-atom abstraction from Ni(I) phosphido and amido complexes gives phosphinidene and imide ligands. AB - Hydrogen-atom abstraction from M-E(H) to generate M?E-containing complexes (E = PR, NR) is not well studied because only a few complexes are known to undergo such reactions. Hydrogen-atom abstraction from nickel(I) phosphide and amide complexes led to the corresponding phosphinidene and imide compounds. These reactions are unparalleled in the organometallic chemistry of nickel and feature an unusual example of a transition-metal phosphinidene synthesized by hydrogen atom abstraction. PMID- 20929226 TI - Bioconjugation of ultrabright semiconducting polymer dots for specific cellular targeting. AB - Semiconducting polymer dots (Pdots) represent a new class of ultrabright fluorescent probes for biological imaging. They exhibit several important characteristics for experimentally demanding in vitro and in vivo fluorescence studies, such as their high brightness, fast emission rate, excellent photostability, nonblinking, and nontoxic feature. However, controlling the surface chemistry and bioconjugation of Pdots has been a challenging problem that prevented their widespread applications in biological studies. Here, we report a facile yet powerful conjugation method that overcomes this challenge. Our strategy for Pdot functionalization is based on entrapping heterogeneous polymer chains into a single dot, driven by hydrophobic interactions during nanoparticle formation. A small amount of amphiphilic polymer bearing functional groups is co condensed with the majority of semiconducting polymers to modify and functionalize the nanoparticle surface for subsequent covalent conjugation to biomolecules, such as streptavidin and immunoglobulin G (IgG). The Pdot bioconjugates can effectively and specifically label cellular targets, such as cell surface marker in human breast cancer cells, without any detectable nonspecific binding. Single-particle imaging, cellular imaging, and flow cytometry experiments indicate a much higher fluorescence brightness of Pdots compared to those of Alexa dye and quantum dot probes. The successful bioconjugation of these ultrabright nanoparticles presents a novel opportunity to apply versatile semiconducting polymers to various fluorescence measurements in modern biology and biomedicine. PMID- 20929227 TI - Thermochemistry of ammonium nitrate, NH4NO3, in the gas phase. AB - Hildenbrand and co-workers have shown recently that the vapor above solid ammonium nitrate includes molecules of NH4NO3, not only NH3 and HNO3 as previously believed. Their measurements led to thermochemical values that imply an enthalpy change of D298 = 98 +/- 9 kJ mol-1 for the gas-phase dissociation of ammonium nitrate into NH3 and HNO3. Using updated spectroscopic information for the partition function leads to the revised value of D298 = 78 +/- 21 kJ mol-1 (accompanying paper in this journal, Hildenbrand, D. L., Lau, K. H., and Chandra, D. J. Phys. Chem. B 2010, DOI: 10.1021/jp105773q). In contrast, high-level ab initio calculations, detailed in the present report, predict a dissociation enthalpy half as large as the original result, 50 +/- 3 kJ mol-1. These are frozen-core CCSD(T) calculations extrapolated to the limiting basis set aug-cc pVinfinityZ using an anharmonic vibrational partition function and a variational treatment of the NH3 rotor. The corresponding enthalpy of formation is Delta(f)H298 degrees (NH4NO3,g) = -230.6 +/- 3 kJ mol-1. The origin of the disagreement with experiment remains unexplained. PMID- 20929228 TI - Synthesis, structure, and dynamic properties of hybrid organic-inorganic rotaxanes. AB - The synthesis and characterization of a series of hybrid organic-inorganic [2]rotaxanes is described. The ring components are heterometallic octa- ([Cr(7)MF(8)(O(2)C(t)Bu)(16)]; M = Co, Ni, Fe, Mn, Cu, Zn, and Cd) nuclear cages in which the metal centers are bridged by fluoride and pivalate ((t)BuCO(2)(-)) anions; the thread components feature dialkylammonium units that template the formation of the heterometallic rings about the axle to form the interlocked structures in up to 92% yield in conventional macrocyclization or one-pot 'stoppering-plus-macrocyclization' strategies. The presence in the reaction mixture of additives (secondary or tertiary amines or quaternary ammonium salts), and the nature of the stoppering groups (3,5-(t)Bu(2)C(6)H(3)CO(2)- or (t)BuCONH ), can have a significant effect on the rotaxane yield. The X-ray crystal structures of 11 different [2]rotaxanes, a pseudorotaxane, and a two-station molecular shuttle show two distinct types of intercomponent hydrogen bond motifs between the ammonium groups of the organic thread and the fluoride groups of the inorganic ring. The different hydrogen bonding motifs account for the very different rates of dynamics observed for the heterometallic ring on the thread (shuttling slow; rotation fast). PMID- 20929230 TI - Effects of concentration prior to cold-stabilization on anthocyanin stability in concord grape juice. AB - The color of Concord grape juice produced by concentration before cold stabilization and detartration (direct-to-concentrate, DTC) was compared to juice produced via cold-stabilization prior to concentration (standard concentrate, SC) and evaluated by several metrics. Using the Boulton copigmentation assay, the majority of the absorbance at 520 nm in bottled SC juice (72%) was due to monomeric anthocyanins. Following reconstitution, DTC juice had a 63% greater absorbance at 520 nm than SC juice. A significant loss of anthocyanins was observed using a paired t test during cold-stabilization of single-strength juice during SC processing (mean loss: 79 mg/L as cyanidin-3-glucoside, 23% of total anthocyanins), while no significant loss of anthocyanins or change in other color metrics was observed during cold-stabilization of DTC concentrate. The concentration of anthocyanins in the SC bitartrate crystals was 0.80% w/w compared to 0.13% w/w in the DTC bitartrate crystals. Between DTC and SC, no difference in copigmentation was observed in cold-stabilized concentrate or reconstituted juice, indicating that the increased stability of anthocyanins could not be credited to greater copigmentation in DTC during detartration. HPLC analyses indicated that anthocyanin species with higher pKh and thus proportionally greater flavylium ion concentration at juice pH are preferentially lost during SC processing. The proportional changes in color metrics during shelf life stability testing (0-16 weeks, 2-30 degrees C) were not significantly different between SC and DTC juices. PMID- 20929229 TI - A hot oxidant, 3-NO2Y122 radical, unmasks conformational gating in ribonucleotide reductase. AB - Escherichia coli ribonucleotide reductase is an alpha2beta2 complex that catalyzes the conversion of nucleotides to deoxynucleotides and requires a diferric-tyrosyl radical (Y(*)) cofactor to initiate catalysis. The initiation process requires long-range proton-coupled electron transfer (PCET) over 35 A between the two subunits by a specific pathway (Y(122)(*)->W(48)->Y(356) within beta to Y(731)->Y(730)->C(439) within alpha). The rate-limiting step in nucleotide reduction is the conformational gating of the PCET process, which masks the chemistry of radical propagation. 3-Nitrotyrosine (NO(2)Y) has recently been incorporated site-specifically in place of Y(122) in beta2. The protein as isolated contained a diferric cluster but no nitrotyrosyl radical (NO(2)Y(*)) and was inactive. In the present paper we show that incubation of apo-Y(122)NO(2)Y beta2 with Fe(2+) and O(2) generates a diferric-NO(2)Y(*) that has a half-life of 40 s at 25 degrees C. Sequential mixing experiments, in which the cofactor is assembled to 1.2 NO(2)Y(*)/beta2 and then mixed with alpha2, CDP, and ATP, have been analyzed by stopped-flow absorption spectroscopy, rapid freeze quench EPR spectroscopy, and rapid chemical quench methods. These studies have, for the first time, unmasked the conformational gating. They reveal that the NO(2)Y(*) is reduced to the nitrotyrosinate with biphasic kinetics (283 and 67 s(-1)), that dCDP is produced at 107 s(-1), and that a new Y(*) is produced at 97 s(-1). Studies with pathway mutants suggest that the new Y(*) is predominantly located at 356 in beta2. In consideration of these data and the crystal structure of Y(122)NO(2)Y-beta2, a mechanism for PCET uncoupling in NO(2)Y(*)-RNR is proposed. PMID- 20929231 TI - Effect of different enological practices on skin and seed proanthocyanidins in three varietal wines. AB - Proanthocyanidins are important for wine quality since they participate in astringency, bitterness and color. Given the localization of proanthocyanidins in the berry (skin and seeds), different methods have been developed that help to modulate the release of these phenolic compounds. In this study, the effect of two low prefermentative temperature techniques (cold soak and must freezing with dry ice) and the use of macerating enzymes has been studied during the vinification of three different varietal wines (Monastrell, Syrah and Cabernet Sauvignon) to assess their influence on wine proanthocyanidin concentration and composition. Syrah wines showed the lowest proanthocyanidin content, together with the lowest mDP and the highest percentage of galloylation in its proanthocyanidins. Monastrell and Cabernet Sauvignon wines showed similar proanthocyanidin concentration. The application of the low temperature prefermentative maceration (cold soak) was the most effective treatment, increasing the proanthocyanidin concentration in Monastrell and Cabernet Sauvignon wines although neither of the treatments had any effect on Syrah wines. As regards the effect of the different treatments on the proanthocyanidin composition, the results seem to indicate that the observed increases were mainly due to an increase in seed proanthocyanidins, even in the case of cold soak treatments, which occur in the absence of ethanol, suggesting that ethanol is not so crucial in the extraction of seed proanthocyanidins. PMID- 20929232 TI - Identification of prenyl ethyl ether as a source of metallic, solvent-like off flavor in hazelnut. AB - In a large batch of ground hazelnuts, a metallic, solvent-like off-note was detected. In this investigation, the volatiles from the batch showing off-notes were compared to a batch without off-notes. On the basis of gas chromatography (GC) sniffing and instrumental analysis, a terpenoid compound, prenyl ethyl ether, was identified as a key contributor to the off-note. The compound was quantified, and its contribution to the metallic, solvent-like off-flavor was confirmed by spiking experiments and sensory evaluation. Analytical and sensory experiments found that the off-note was still present in hazelnut cakes. Fat oxidation did not contribute to the off-flavor. Analysis of market products demonstrated the correlation between the identified terpenoid and the off-flavor. It is assumed that fungi are involved in off-flavor formation. PMID- 20929233 TI - Synthesis, fungicidal activity, and structure-activity relationship of 2-oxo- and 2-hydroxycycloalkylsulfonamides. AB - To explore new potential fungicides, a series of novel compounds, including 11 2 oxocycloalkylsulfonamide (3) and 21 2-hydroxycycloalkylsulfonamide (4) derivatives, were synthesized and their structures were confirmed by (1)H nuclear magnetic resonance (NMR), infrared (IR), and elemental analysis. The results of the bioassay showed that the compounds 3 and 4 possessed excellent fungicidal activity against Botrytis cinerea Pers. both in vitro and in vivo. The fungicidal activity of the compounds with 7- or 8-membered rings is better than those with 5 , 6-, or 12-membered rings. According to the results of the mycelium growth rate test, the EC50 values of the compounds 3C, 4C, 3D, and 4D were 0.80, 0.85, 1.22, and 1.09 MUg/mL, respectively, and similar to or better than commercial fungicide procymidone. The bioassay results of spore germination indicated that most of the compounds exhibited obvious inhibitory effects against B. cinerea and the inhibition rates of 2-oxocycloalkylsulfonamides were higher than 2 hydroxycycloalkylsulfonamides, among them. The EC50 values of compounds 3A, 3B17, 3E, and 4A were 4.21, 4.21 3.24, and 5.29 MUg/mL, respectively. Those compounds containing 5- or 6-membered rings showed better activity than those containing 7 , 8-, or 12-membered rings. Furthermore, the results of the pot culture test showed that almost all of the compounds had effective control activity in vivo and 2-hydroxycycloalkylsulfonamides were obviously superior to 2 oxocycloalkylsulfonamides. The compounds 3E, 4C and 4D presented higher control efficacy than procymidone and pyrimethanil against gray mold disease on cucumber plants. PMID- 20929234 TI - Characterization of graininess formed in all beef tallow-based shortening. AB - A batch of all beef tallow (BT)-based model shortening (divided into six rectangular block samples) was stored under temperature fluctuation cycles of 5 20 degrees C until granular crystals were observed. The lipid composition, thermal properties, and polymorphism of the granular crystals and their surrounding materials were evaluated. Furthermore, the isothermal crystallization behavior of two parts noted above was also examined by pulsed nuclear magnetic resonance (pNMR), rheology, and polarized light microscopy (PLM). The changes of nanostructure including the aggregation of high-melting triacylglycerols (TAGs) and transformation into the most stable beta polymorph occurred in granular crystals compared with surrounding materials. Concomitantly, a slower crystallization rate with a simultaneous increase in crystal growth led to the formation of large crystals and further aggregated to larger granular crystals when the size ultimately exceeded the sensory threshold. PMID- 20929236 TI - Effects of grape pomace antioxidant extract on oxidative stress and inflammation in diet induced obese mice. AB - Norton grape is one of the most important wine grapes in Southern and Midwestern states and generates massive pomace byproducts. The objective of this study is to characterize the antioxidant compounds and activity in Norton grape pomace extract (GPE) and further assess the potential health promoting properties of Norton GPE using an animal disease model. The total phenolic content and anthocyanins in Norton GPE were 475.4 mg of gallic acid equiv/g and 156.9 mg of cyanidin 3-glucoside equiv/g, respectively. Catechin and epicatechin in GPE were 28.6 and 24.5 mg/g, respectively. Other major antioxidants in GPE included quercetin (1.6 mg/g), trans-resveratrol (60 MUg/g), gallic acid (867.2 MUg/g), coutaric acid (511.8 MUg/g), p-hydroxybenzoic acid (408.3 MUg/g), and protocatechuic acid (371.5 MUg/g). The antioxidant activity of GPE was evaluated by oxygen radical absorbance capacity (ORAC) and was 4133 MUmol of Trolox equiv/g. Male diet-induced obese (DIO) mice were randomly divided to three treatment groups (n = 12): a normal diet (ND group), a high fat diet (HF group), and the high fat diet supplemented with GPE (HFGPE group). After 12-week treatment, mice in the high fat diet groups gained 29% more weight than the ND group. The GPE supplementation (estimated 250 mg/kg bw/d) lowered plasma C reactive protein levels by 15.5% in the high fat diet fed mice (P < 0.05), suggesting a potential anti-inflammatory effect by dietary GPE. However, dietary GPE did not improve oxidative stress in DIO mice as determined by plasma ORAC, glutathione peroxidase, and liver lipid peroxidation. The results showed that GPE contained significant antioxidants and dietary GPE exerted an anti-inflammatory effect in diet induced obesity. PMID- 20929235 TI - Potential physiological functions of acceptor products of dextransucrase with cellobiose as an inhibitor of mutansucrase and fungal cell synthase. AB - A series of oligosaccharides (cellobio-oligosaccharides) ranging from degrees of polymer 3 to 6 were synthesized by Leuconostoc mesenteroides B-512 FMCM in the presence of cellobiose. The major oligosaccharides were the trisaccharides, alpha D-glucopyranosyl-(1 -> 2)-beta-D-glucopyranosyl-(1 -> 4)-D-glucopyranose and alpha-D-glucopyranosyl-(1 -> 6)-beta-D-glucopyranosyl-(1 -> 4)-D-glucopyranose. These cellobio-oligosaccharides were inhibitory on mutansucrase, an enzyme that causes dental caries. They were also found to be effective antifungal agents against Aspergillus terreus acting by inhibiting beta-(1 -> 3)-glucan synthase, which is required for fungal cell wall formation. PMID- 20929237 TI - The Fowler-Nordheim plot behavior and mechanism of field electron emission from ZnO tetrapod structures. AB - Field emission measurements of current-voltage characteristics are reported for tetrapod structures of ZnO. The nonlinear Fowler-Nordheim (FN) plot is analyzed according to a model of calculation based on saturation of conduction band current and predominance of valence band current at high-field values. The simulated FN plot exhibits similar features to those observed experimentally. The model of calculation suggests that the slope variation of the FN plot, in the high-field and low-field regions, does not depend on the magnitude of saturation. Instead, it is a characteristic of the energy band structure and voltage-to barrier-field conversion factor of the emitting material. PMID- 20929238 TI - Holographically directed assembly of polymer nanocomposites. AB - Layered polymer/nanoparticle composites have been created through the one-step two-beam interference lithographic exposure of a dispersion of 25 and 50 nm silica particles within a photopolymerizable mixture at a wavelength of 532 nm. The polymerizable mixture is composed of pentaerythritol triacrylate (monomer), 1 vinyl-2-pyrrolidinone (monomer), and photoinitiator. In the areas of constructive interference, the monomer begins to polymerize via a free-radical process and concurrently the nanoparticles move into the regions of destructive interference. The effects of exposure time, power density, nanoparticle size, and periodicity on the final nanocomposite structure were measured with transmission electron microscopy to determine the mechanism for particle segregation. Diffraction from the sample was monitored as well, though its magnitude was not a good predictor of nanostructure in this relatively low index contrast system. Exposure time did not have a strong effect on the final structure. The best nanoparticle sequestration was observed at reduced laser power density, smaller interferogram periodicity, and decreased nanoparticle size, indicating that particle segregation is dominated by diffusion-limited nanoparticle transport directed by a matrix containing a gradient of polymerization kinetics. PMID- 20929239 TI - An ultraclean tip-wear reduction scheme for ultrahigh density scanning probe based data storage. AB - Probe-based memory devices using ferroelectric media have the potential to achieve ultrahigh data-storage densities under high write-read speeds. However, the high-speed scanning operations over a device lifetime of 5-10 years, which corresponds to a probe tip sliding distance of 5-10 km, can cause the probe tip to mechanically wear, critically affecting its write-read resolution. Here, we show that the long distance tip-wear endurance issue can be resolved by introducing a thin water layer at the tip-media interface-thin enough to form a liquid crystal. By modulating the force at the tip-surface contact, this water crystal layer can act as a viscoelastic material which reduces the stress level on atomic bonds taking part in the wear process. Under our optimized environment, a platinum-iridium probe tip can retain its write-read resolution over 5 km of sliding at a 5 mm/s velocity on a smooth ferroelectric film. We also demonstrate a 3.6 Tbit/inch(2) storage density over a 1 * 1 MUm(2) area, which is the highest density ever written on ferroelectric films over such a large area. PMID- 20929240 TI - Field electron emission characteristics and physical mechanism of individual single-layer graphene. AB - Due to its difficulty, experimental measurement of field emission from a single layer graphene has not been reported, although field emission from a two dimensional (2D) regime has been an attractive topic. The open surface and sharp edge of graphene are beneficial for field electron emission. A 2D geometrical effect, such as massless Dirac fermion, can lead to new mechanisms in field emission. Here, we report our findings from in situ field electron emission characterization on an individual singe-layer graphene and the understanding of the related mechanism. The measurement of field emission from the edges was done using a microanode probe equipped in a scanning electron microscope. We show that repeatable stable field emission current can be obtained after a careful conditioning process. This enables us to examine experimentally the typical features of the field emission from a 2D regime. We plot current versus applied field data, respectively, in ln(I/E(3/2)) ~ 1/E and ln(I/E(3)) ~ 1/E(2) coordinates, which have recently been proposed for field emission from graphene in high- and low-field regimes. It is observed that the plots all exhibit an upward bending feature, revealing that the field emission processes undergo from a low- to high-field transition. We discuss with theoretical analysis the physical mechanism responsible for the new phenomena. PMID- 20929241 TI - Nickel-assisted healing of defective graphene. AB - The healing of graphene grown from a metallic substrate is investigated using tight-binding Monte Carlo simulations. At temperatures (ranging from 1000 to 2500 K), an isolated graphene sheet can anneal a large number of defects suggesting that their healings are thermally activated. We show that in the presence of a nickel substrate we obtain a perfect graphene layer. The nickel-carbon chemical bonds keep breaking and reforming around defected carbon zones, providing a direct interaction, necessary for the healing. Thus, the action of Ni atoms is found to play a key role in the reconstruction of the graphene sheet by annealing defects. PMID- 20929242 TI - pH-Sensitive breathing of clay within the polyelectrolyte matrix. AB - Stimuli-responsive organic-inorganic hybrid spheres were synthesized by coating the colloidal polystyrene spheres with polyelectrolyte-protected aminoclay, Mg phyllo(organo)silicate layers in a layer-by-layer method. The clay layers are sandwiched between the polyelectrolyte layers. The aminoclay swells in water due to protonation of amino groups, and the degree of swelling depends on the pH of the medium. As a result, the hybrid spheres undergo a size change up to 60% as the pH is changed from 9 to 4. The stimuli-responsive property of the hybrid spheres was used for the release of ibuprofen and eosin at different pH. PMID- 20929243 TI - Dispersion in the SERS enhancement with silver nanocube dimers. AB - The SERS phenomenon was studied using a large set of silver nanocube dimers programmed to self-assemble in preset locations of a patterned substrate. This SERS substrate made it possible to demonstrate the dependence of the SERS enhancement on the geometry of the silver nanocube dimers and to quantify the dispersion in the SERS enhancement obtained in an ensemble of dimers. In addition to the effects of the gap distance of the dimer and the orientation of the dimer axis relative to the laser polarization on SERS enhancement, the data reveal an interesting dependence of the site-to-site variations of the enhancement on the relative orientation of the nanocubes in the dimer. We observed the highest heterogeneity in the SERS signal intensity with face-to-face dimers and a more robust SERS enhancement with face-to-edge dimers. Numerical calculations indicate that the plasmon resonance frequencies of face-to-face dimers shift considerably with small changes in gap distance. The resonance frequency shifts make it less likely for many of the dimers to satisfy the matching condition between the photon frequencies and the plasmon resonance frequency, offering an explanation for the large site-to-site variations in SERS signal intensity. These results indicate that plasmonic nanostructure designs for SERS substrates for real-world applications should be selected not only to maximize the signal enhancement potential but also to minimize the heterogeneity of the substrate with respect to signal enhancement. The latter criterion poses new challenges to experimentalists and theorists alike. PMID- 20929244 TI - A natively unfolded betagamma-crystallin domain from Hahella chejuensis. AB - To date, very few betagamma-crystallins have been identified and structurally characterized. Several of them have been shown to bind Ca(2+) and thereby enhance their stability without any significant change in structure. Although Ca(2+) induced conformational changes have been reported in two putative betagamma crystallins from Caulobacter crescentus and Yersinia pestis, they are shown to be partially unstructured, and whether they acquire a betagamma-crystallin fold is not known. We describe here a betagamma-crystallin domain, hahellin, its Ca(2+) binding properties and NMR structure. Unlike any other betagamma-crystallin, hahellin is characterized as a pre-molten globule (PMG) type of natively unfolded protein domain. It undergoes drastic conformational change and acquires a typical betagamma-crystallin fold upon Ca(2+) binding and hence acts as a Ca(2+) regulated conformational switch. However, it does not bind Mg(2+). The intrinsically disordered Ca(2+)-free state and the close structural similarity of Ca(2+)-bound hahellin to a microbial betagamma-crystallin homologue, Protein S, which shows Ca(2+)-dependent stress response, make it a potential candidate for the cellular functions. This study indicates the presence of a new class of natively unfolded betagamma-crystallins and therefore the commencement of the possible functional roles of such proteins in this superfamily. PMID- 20929245 TI - Graphene on metallic substrates: suppression of the Kohn Anomalies in the phonon dispersion. AB - The phonon dispersion of graphene is known to display two strong Kohn Anomalies (kinks) in the highest optical branch (HOB) at the high-symmetry points Gamma and K [ Piscanec , S. ; et al. Phys. Rev. Lett. 2004 , 93 , 185503 ]. The phonon slope around the Kohn anomalies is related to the electron-phonon-coupling (EPC) with the graphene pi bands. We show that this EPC, which has strong impact, for example, on Raman scattering and electron transport, can be strongly modified due to interaction with a metallic substrate. For graphene grown on a Ni(111) surface, a total suppression of the Kohn anomaly occurs; the HOB around Gamma and K becomes completely flat. This is due to the strong hybridization of the graphene pi-bands with the nickel d bands that lifts the linear crossing of the pi bands at K. In addition, the out-of-plane modes are also found to be strongly affected by the binding to the substrate. For other metallic substrates, where the distance between the graphene sheet and the substrate is larger, hybridization is much less pronounced and the Kohn anomaly is only weakly perturbed. From experimental phonon dispersions, one can therefore draw conclusions about the interaction strength between graphene and its different substrates. PMID- 20929246 TI - Electric field control of spin rotation in bilayer graphene. AB - The manipulation of the electron spin degree of freedom is at the core of the spintronics paradigm, which offers the perspective of reduced power consumption, enabled by the decoupling of information processing from net charge transfer. Spintronics also offers the possibility of devising hybrid devices able to perform logic, communication, and storage operations. Graphene, with its potentially long spin-coherence length, is a promising material for spin-encoded information transport. However, the small spin-orbit interaction is also a limitation for the design of conventional devices based on the canonical Datta Das spin field-effect transistors. An alternative solution can be found in magnetic doping of graphene or, as discussed in the present work, in exploiting the proximity effect between graphene and ferromagnetic oxides (FOs). Graphene in proximity to FO experiences an exchange proximity interaction, that acts as an effective Zeeman field for electrons in graphene, inducing a spin precession around the magnetization axis of the FO. Here we show that in an appropriately designed double-gate field-effect transistor, with a bilayer graphene channel and FO used as a gate dielectric, spin-precession of carriers can be turned ON and OFF with the application of a differential voltage to the gates. This feature is directly probed in the spin-resolved conductance of the bilayer. PMID- 20929247 TI - Label-free voltammetric detection using individually addressable oligonucleotide microelectrode arrays. AB - The utility and performance of label-free, oligonucleotide probes for reagentless detection of dilute target analytes was examined using a voltammetric transduction principle in an array format. Multistep, solid-state fabrication yielded preproduction arrays of 16 individually addressable, 30 MUm diameter microelectrodes in a 30 mm * 6.5 mm * 0.5 mm dipstick disposable device. The specificity of 16 nucleotide (nt) 2'-O-methylribonucleic acid and 22 nt DNA backbone probes bound through Mg(2+)-phosphonate bridges to polypyrrole films on the microelectrodes were studied using microbial target RNAs of various lengths. Probe-specific interactions with Escherichia coli O157 H7 23S rRNA (2907 nt) and Candida albicans 18S rRNA (1788 nt) were detected at 65 and 58 fmol/mL, respectively, in volumes as low as 0.5 mL. Specificity studies showed that, for a given probe, "nontarget" transcripts can contribute to changes in the voltammetric detection signal, though with responses that never exceed 70% of the detection signal acquired for specifically designed complementary targets. These results statistically validate the use of the voltammetric microelectrode array for obtaining a "yes-no" answer on complementary specific binding. The study also identifies challenges and pitfalls for the selection strategies of oligonucleotide probes. PMID- 20929249 TI - Water-soluble MnO nanocolloid for a molecular T1 MR imaging: a facile one-pot synthesis, in vivo T1 MR images, and account for relaxivities. AB - A facile one-pot synthesis of a water-soluble MnO nanocolloid (i.e., D-glucuronic acid-coated MnO nanoparticle) is presented. The MnO nanoparticle in the MnO nanocolloid was coated with a biocompatible and hydrophilic D-glucuronic acid, and its particle diameter was nearly monodisperse and ranged from 2 to 3 nm. The average hydrodynamic diameter of the MnO nanocolloid was estimated to be 5 nm. The MnO nanoparticle was nearly paramagnetic down to T=3 K. The MnO nanocolloid showed a high longitudinal water proton relaxivity of r1=7.02 s(-1) mM(-1) with the r2/r1 ratio of 6.83 due to five unpaired S-state electrons of Mn(II) ion (S=5/2) as well as a high surface to volume ratio of the MnO nanoparticle. High contrast in vivo T1 MR images were obtained for various organs, showing the capability of the MnO nanocolloid as a sensitive T1 MRI contrast agent. The suggested three key-parameters which control the r1 and r2 relaxivities of nanocolloids (i.e., the S value of a metal ion, the spin structure, and the surface to volume ratio of a nanoparticle) successfully accounted for the observed r1 and r2 relaxivities of the MnO nanocolloid. PMID- 20929250 TI - Synthesis, crystal structure, quantum chemical calculations, DNA interactions, and antimicrobial activity of [Ag(2-amino-3-methylpyridine)(2)]NO(3) and [Ag(pyridine-2-carboxaldoxime)NO(3)]. AB - [Ag(2-amino-3-methylpyridine)(2)]NO(3) (1) and [Ag(pyridine-2 carboxaldoxime)NO(3)] (2) were prepared from corresponding ligands and AgNO(3) in water/ethanol solutions, and the products were characterized by IR, elemental analysis, NMR, and TGA. The X-ray crystal structures of the two compounds show that the geometry around the silver(I) ion is bent for complex 1 with nitrate as an anion and trigonal planar for complex 2 with nitrate coordinated. ESI-MS results of solutions of 2 indicate the independent existence in solution of the [Ag(pyridine-2-carboxaldoxime)](+) ion. The geometries of the complexes are well described by DFT calculations using the ZORA relativistic approach. The compounds were tested against 14 different clinically isolated and four ATCC standard bacteria and yeasts and also compared with 17 commonly used antibiotics. Both 1 and 2 exhibited considerable activity against S. lutea , M. lutea , and S. aureus and against the yeast Candida albicans , while 2-amino-3-methylpyridine is slightly active and pyridine-2-carboxaldoxime shows no antimicrobial activity. In addition, the interaction of these metal complexes with DNA was investigated. Both 1 and 2 bind to DNA and reduce its electrophoretic mobility with different patterns of migration, while the ligands themselves induce no change. PMID- 20929251 TI - X-ray-induced lysis of the Fe-CO bond in carbonmonoxy-myoglobin. AB - By using X-ray absorption near edge structure (XANES) spectroscopy, we show that under prolonged exposure to Synchrotron X-rays, at T < 10 K, the Fe-heme in carbonmonoxy-myoglobin (MbCO) undergoes a slow two-state transition process. The final spectrum is nearly identical to that of the classical photoproduct (Mb*CO) obtained by UV-visible light illumination at 15 K. By increasing the temperature, the starting spectrum of MbCO is recovered at T > 100 K, demonstrating that the process is reversible and no damage occurred at the heme site in the time course of the experiment. Thus, the overall X-ray-induced process at low temperature is identical to the well-known (light-induced) photolysis of CO-hemeproteins. PMID- 20929252 TI - Ozonation of oil sands process-affected water accelerates microbial bioremediation. AB - Ozonation can degrade toxic naphthenic acids (NAs) in oil sands process-affected water (OSPW), but even after extensive treatment a residual NA fraction remains. Here we hypothesized that mild ozonation would selectively oxidize the most biopersistent NA fraction, thereby accelerating subsequent NA biodegradation and toxicity removal by indigenous microbes. OSPW was ozonated to achieve approximately 50% and 75% NA degradation, and the major ozonation byproducts included oxidized NAs (i.e., hydroxy- or keto-NAs). However, oxidized NAs are already present in untreated OSPW and were shown to be formed during the microbial biodegradation of NAs. Ozonation alone did not affect OSPW toxicity, based on Microtox; however, there was a significant acceleration of toxicity removal in ozonated OSPW following inoculation with native microbes. Furthermore, all residual NAs biodegraded significantly faster in ozonated OSPW. The opposite trend was found for ozonated commercial NAs, which are known to contain no significant biopersistent fraction. Thus, we suggest that ozonation preferentially degraded the most biopersistent OSPW NA fraction, and that ozonation is complementary to the biodegradation capacity of microbial populations in OSPW. The toxicity of ozonated OSPW to higher organisms needs to be assessed, but there is promise that this technique could be applied to accelerate the bioremediation of large volumes of OSPW in Northern Alberta, Canada. PMID- 20929253 TI - Identification and inhibitory properties of multifunctional peptides from pea protein hydrolysate. AB - Pea protein isolate was hydrolyzed with alcalase, and the hydrolysate passed through a 1 kDa cutoff ultrafiltration membrane. The permeate was freeze-dried and fractionated on a cationic solid-phase extraction (SPE) column. All fractions were tested for their inhibitory activities against angiotensin-converting enzyme (ACE), renin, and calmodulin-dependent phosphodiesterase 1 (CaMPDE). With the exception of the first eluted fraction, inhibitory properties of the SPE fractions against CaMPDE (but not ACE and renin) were directly related to cationic character (residence time on the column). However, the fraction that eluted with 1% ammonium hydroxide (SPE 1%) had the highest peptide yield and was subsequently fractionated using two consecutive rounds of reversed-phase high performance liquid chromatography to obtain three peaks with major peptides identified as IR, KF, and EF by ultra performance liquid chromatography-tandem mass spectrometry. The three dipeptides showed weak inhibitory properties toward CaMPDE but strong inhibitions (IC50 values <25 mM) of ACE and renin. In general, the peptides had higher potency against ACE than against renin. It is indicated from our results that these peptides may be used as potential ingredients to formulate multifunctional food products and nutraceuticals. PMID- 20929254 TI - Transepithelial transport and metabolism of new lipophilic ether derivatives of hydroxytyrosol by enterocyte-like Caco-2/TC7 cells. AB - Intestinal transport and metabolism of a series of ether derivatives of the natural antioxidant hydroxytyrosol with differing alkyl chain lengths (methyl, ethyl, propyl, and butyl) were evaluated at 1, 2, and 4 h using a two-compartment transwell system containing human enterocyte (differentiated Caco-2/TC7) monolayers, which simulates the small intestinal barrier. All four ether derivatives were transferred across the enterocyte monolayers with Papp(apical basolateral) values between 32.6 and 43.5 cm/s * 10(-6). One hour after apical loading, the predominant forms of the compounds on the basolateral side were unmodified molecules. Glucuronides and methylated metabolites were also present in both the apical and basolateral compartments, with conjugated metabolites preferentially transported to the basolateral side. The rate of metabolism increased according to the lipohilicity of the ether derivative (butyl > propyl > ethyl > methyl). In conclusion, hydroxytyrosyl ethers are rapidly absorbed across, and partially metabolized by, Caco-2/TC7 cell monolayers, in keeping with their lipophilic nature. PMID- 20929255 TI - Oral bioaccessibility of polycyclic aromatic hydrocarbons (PAHs) through fish consumption, based on an in vitro digestion model. AB - An in vitro gastrointestinal digestion model was used to evaluate bioaccessibility of PAHs in 20 fish species collected from Hong Kong markets. The average bioaccessibilities of PAHs were 24.3 and 31.1%, respectively, in gastric and intestinal conditions. When bioaccessibility was taken into consideration, the values of potency equivalent concentrations (PEC) decreased from 0.53 to 0.18 ng g(-1) for freshwater fish and from 1.43 to 0.35 ng g(-1) for marine fish. This indicated that bioaccessibility should be taken into account for health risk assessment with regard to PAH contamination in fish. The relative accumulation ratios (R(nn)) of PAH congeners were significantly correlated with their physicochemical parameters and their corresponding concentrations reported in subcutaneous fats of Hong Kong residents. The data suggest that R(nn) values calculated in the present study could effectively reflect the accumulations of PAHs in the human body. PMID- 20929256 TI - Rational design, synthesis, and evaluation of new selective inhibitors of microbial class II (zinc dependent) fructose bis-phosphate aldolases. AB - We report the synthesis and biochemical evaluation of several selective inhibitors of class II (zinc dependent) fructose bis-phosphate aldolases (Fba). The products were designed as transition-state analogues of the catalyzed reaction, structurally related to the substrate fructose bis-phosphate (or sedoheptulose bis-phosphate) and based on an N-substituted hydroxamic acid, as a chelator of the zinc ion present in active site. The compounds synthesized were tested on class II Fbas from various pathogenic microorganisms and, by comparison, on a mammalian class I Fba. The best inhibitor shows K(i) against class II Fbas from various pathogens in the nM range, with very high selectivity (up to 10(5)). Structural analyses of inhibitors in complex with aldolases rationalize and corroborate the enzymatic kinetics results. These inhibitors represent lead compounds for the preparation of new synthetic antibiotics, notably for tuberculosis prophylaxis. PMID- 20929257 TI - Quo vadis, virtual screening? A comprehensive survey of prospective applications. PMID- 20929258 TI - Psiguadials A and B, two novel meroterpenoids with unusual skeletons from the leaves of Psidium guajava. AB - Psiguadials A (1) and B (2), two novel sesquiterpenoid-diphenylmethane meroterpenoids with unusual skeletons, along with a pair of known epimers, psidial A (3) and guajadial (4), were isolated from the leaves of Psidium guajava. Their structures with absolute configurations were elucidated by means of NMR, X-ray diffraction, and quantum chemical CD calculation. Compounds 1, 2, and 4 exhibited potent inhibitory effects on the growth of human hepatoma cells. PMID- 20929259 TI - Coordination properties of ionic liquid-mediated chromium(II) and copper(II) chlorides and their complexes with glucose. AB - The structural and coordination properties of complexes formed upon the interaction of copper(II) and chromium(II) chlorides with dialkylimidazolium chloride (RMIm(+)Cl(-)) ionic liquids and glucose are studied by a combination of density functional theory (DFT) calculations and X-ray absorption spectroscopy (XAS). In the absence of the carbohydrate substrate, isolated mononuclear four coordinated MeCl(4)(2-) species (Me = Cu, Cr) dominate in the ionic liquid solution. The organic part of the ionic liquid does not directly interact with the metal centers. The interactions between the RMIm(+) cations and the anionic metal chloride complexes are limited to hydrogen bonding with the basic Cl(-) ligands and the overall electrostatic stabilization of the anionic metal complexes. Exchange of Cl(-) ligands by a hydroxyl group of glucose is only favorable for CrCl(4)(2-). For Cu(2+) complexes, the formation of hydrogen bonded complexes between CuCl(4)(2-) and glucose is preferred. No preference for the coordination of metal chloride species to specific hydroxyl group of the carbohydrate is found. The formation of binuclear metal chloride complexes is also considered. The reactivity and selectivity patterns of the Lewis acid catalyzed reactions of glucose are discussed in the framework of the obtained results. PMID- 20929260 TI - Ruthenium-catalyzed tertiary amine formation from nitroarenes and alcohols. AB - A highly selective ruthenium-catalyzed C-N bond formation was developed by using the hydrogen-borrowing strategy. Various tertiary amines were obtained efficiently from nitroarenes and primary alcohols. The reaction tolerates a wide range of functionalities. A tentative mechanism was proposed for this direct amination reaction of alcohols with nitroarenes. PMID- 20929261 TI - Mammea E/BB, an isoprenylated dihydroxycoumarin protonophore that potently uncouples mitochondrial electron transport, disrupts hypoxic signaling in tumor cells. AB - The mammea-type coumarin mammea E/BB (1) was found to inhibit both hypoxia induced and iron chelator-induced hypoxia-inducible factor-1 (HIF-1) activation in human breast tumor T47D cells with IC(50) values of 0.96 and 0.89 MUM, respectively. Compound 1 suppressed the hypoxic induction of secreted VEGF protein (T47D cells) and inhibited cell viability/proliferation in four human tumor cell lines. Compound 1 (at 5 and 20 MUM) inhibited human breast tumor MDA MB-231 cell migration. While the mechanisms that underlie their biological activities have remained unknown, prenylated mammea coumarins have been shown to be cytotoxic to human tumor cells, suppress tumor growth in animal models, and display a wide variety of antimicrobial effects. Mechanistic studies revealed that 1 appears to exert an assemblage of cellular effects by functioning as an anionic protonophore that potently uncouples mitochondrial electron transport and disrupts mitochondrial signaling in human tumor cell lines. PMID- 20929262 TI - Degradation of ozone-refractory organic phosphates in wastewater by ozone and ozone/hydrogen peroxide (peroxone): the role of ozone consumption by dissolved organic matter. AB - Ozonation is very effective in eliminating micropollutants that react fast with ozone (k > 10(3) M(-1) s(-1)), but there are also ozone-refractory (k < 10 M(-1) s(-1)) micropollutants such as X-ray contrast media, organic phosphates, and others. Yet, they are degraded upon ozonation to some extent, and this is due to (*)OH radicals generated in the reaction of ozone with organic matter in wastewater (DOM, determined as DOC). The elimination of tri-n-butyl phosphate (TnBP) and tris-2-chloroisopropyl phosphate (TCPP), added to wastewater in trace amounts, was studied as a function of the ozone dose and found to follow first order kinetics. TnBP and TCPP concentrations are halved at ozone to DOC ratios of ~0.25 and ~1.0, respectively. The (*)OH rate constant of TCPP was estimated at (7 +/- 2) * 10(8) M(-1) s(-1) by pulse radiolysis. Addition of 1 mg H(2)O(2)/L for increasing the (*)OH yield had very little effect. This is due to the low rate of reaction of H(2)O(2) with ozone at wastewater conditions (pH 8) that competes unfavorably with the reaction of ozone with wastewater DOC. Simulations based on the reported (Nothe et al., ES&T 2009, 43, 5990-5995) (*)OH yield (13%) and (*)OH scavenger capacity of wastewater (3.2 * 10(4) (mgC/L)(-1) s(-1)) confirm the experimental data. Based on a typically applied molar ratio of ozone and H(2)O(2) of 2, the contribution of H(2)O(2) addition on the (*)OH yield is shown to become important only at high ozone doses. PMID- 20929264 TI - Cu(I)-catalyzed carboxylative coupling of terminal alkynes, allylic chlorides, and CO2. AB - A highly selective synthesis of a variety of functionalized allylic 2-alkynoates was realized via the carboxylative coupling of terminal alkynes, allylic chlorides, and CO(2) catalyzed by the N-heterocyclic carbene copper(I) complex (IPr)CuCl. The catalyst can be easily recovered without any loss in activity and product selectivity. PMID- 20929266 TI - Bioresponsive small molecule polyamines as noncytotoxic alternative to polyethylenimine. AB - Nonviral gene therapy continues to require novel synthetic vectors to deliver therapeutic nucleic acids effectively and safely. The majority of synthetic nonviral vectors employed in clinical trials to date have been cationic liposomes; however, cationic polymers are attracting increasing attention. One of the few cationic polymers to enter clinical trials has been polyethylenimine (PEI); however, doubts remain over its cytotoxicity, and in addition it displays lower levels of transfection than viral systems. Herein, we report on the development of a series of small molecule analogues of PEI that are bioresponsive to the presence of pDNA, forming poly(disulfide)s that are capable of efficacious transfection with no associated toxicity. The most effective small molecule developed, a cyclic disulfide based upon a spermine backbone, is shown to form very well-defined polyplexes (100-200 nm in diameter) that mediate murine lung transfection in vivo to within an order of magnitude of in vivo jetPEI, and at the same time display a much improved cytotoxicity profile. PMID- 20929265 TI - Serine side chain-linked peptidomimetic conjugates of cyclic HPMPC and HPMPA: synthesis and interaction with hPEPT1. AB - Cidofovir (HPMPC), a broad spectrum antiviral agent, cannot be administered orally due to ionization of its phosphonic acid group at physiological pH. One prodrug approach involves conversion to the cyclic form (cHPMPC, 1) and esterification by the side chain hydroxyl group of a peptidomimetic serine. Transport studies in a rat model have shown enhanced levels of total cidofovir species in the plasma after oral dosing with L-Val-L-Ser-OMe cHPMPC, 2a. To explore the possibility that 2a and its three L/D stereoisomers 2b-d undergo active transport mediated by the peptide-specific intestinal transporter PEPT1, we performed radiotracer uptake and electrophysiology experiments applying the two-electrode voltage clamp technique in Xenopus laevis oocytes overexpressing human PEPT1 (hPEPT1, SLC15A1). 2a-d did not induce inward currents, indicating that they are not transported, but the stereoisomers with an L-configuration at the N-terminal valine (2a and 2b) potently inhibited transport of the hPEPT1 substrate glycylsarcosine (Gly-Sar). A "reversed" dipeptide conjugate, L-Ser-L Ala-OiPr cHPMPC (4), also did not exhibit detectable transport, but completely abolished the Gly-Sar signal, suggesting that affinity of the transporter for these prodrugs is not impaired by a proximate linkage to the drug in the N terminal amino acid of the dipeptide. Single amino acid conjugates of cHPMPC (3a and 3b) or cHPMPA (5, 6a and 6b) were not transported and only weakly inhibited Gly-Sar transport. The known hPEPT1 prodrug substrate valacyclovir (7) and its L Val-L-Val dipeptide analogue (8) were used to verify coupled transport by the oocyte model. The results indicate that the previously observed enhanced oral bioavailability of 2a relative to the parent drug is unlikely to be due to active transport by hPEPT1. Syntheses of the novel compounds 2b-d and 3-6 are described, including a convenient solid-phase method to prepare 5, 6a and 6b. PMID- 20929267 TI - Metabolic detoxication pathways for sterigmatocystin in primary tracheal epithelial cells. AB - Human health effects of inhaled mycotoxins remain poorly documented, despite the large amounts present in bioaerosols. Among these mycotoxins, sterigmatocystin is one of the most prevalent. Our aim was to study the metabolism and cellular consequences of sterigmatocystin once it is in contact with the airway epithelium. Metabolites were analyzed first in vitro, using recombinant P450 1A1, 1A2, 2A6, 2A13, and 3A4 enzymes, and subsequently in porcine tracheal epithelial cell (PTEC) primary cultures at an air-liquid interface. Expressed enzymes and PTECs were exposed to sterigmatocystin, uniformly enriched with (13)C to confirm the relationship between sterigmatocystin and metabolites. Induction of the expression of xenobiotic-metabolizing enzymes upon sterigmatocystin exposure was examined by real-time quantitative real-time polymerase chain reaction. Incubation of 50 MUM sterigmatocystin with recombinant P450 1A1 led to the formation of three metabolites: monohydroxy-sterigmatocystin (M1), dihydroxy sterigmatocystin (M2), and one glutathione adduct (M3), the latter after the formation of a transient epoxide. Recombinant P450 1A2 also led to M1 and M3. P450 3A4 led to only M3. In PTEC, 1 MUM sterigmatocystin metabolism resulted in a glucuro conjugate (M4) mainly excreted at the basal side of cells. If PTEC were treated with beta-naphthoflavone prior to sterigmatocystin incubation, two other products were detected, i.e., a sulfo conjugate (M5) and a glucoro conjugate (M6) of hydroxy-sterigmatocystin. Exposure of PTEC for 24 h to 1 MUM sterigmatocystin induced an 18-fold increase in the mRNA levels of P450 1A1, without significantly induced 7-ethoxyresorufin O-deethylation activity. These data suggest that sterigmatocystin is mainly detoxified and is unable to produce significant amounts of reactive epoxide metabolites in respiratory cells. However, sterigmatocystin increases the P450 1A1 mRNA levels with unknown long-term consequences. These in vitro results obtained in the porcine pulmonary tract need to be confirmed in human epithelial cells. PMID- 20929268 TI - Mechanistic insight into direct arylations with ruthenium(II) carboxylate catalysts. AB - Mechanistic studies revealed ruthenium-catalyzed direct arylations to proceed through reversible C-H bond activation and subsequent rate-limiting oxidative addition with aryl halides, which led to the development of widely applicable well-defined ruthenium(II) carboxylate catalysts. PMID- 20929269 TI - Synthesis of 6- and 7-membered cyclic enaminones: scope and mechanism. AB - Six- and seven-membered cyclic enaminones can be prepared using common, environmentally benign reagents. Amino acids are used as synthetic precursors allowing diversification and the incorporation of chirality. The key reaction in this multistep process involves deprotection of Boc-amino ynones and subsequent treatment with methanolic K(2)CO(3) to induce cyclization. A beta-amino elimination side reaction was identified in a few labile substrates that led to either loss of stereochemical purity or degradation. This process can be mitigated in specific cases using mild deprotection conditions. NMR and deuterium labeling experiments provided valuable insight into the workings and limitations of this reaction. Although disguised as a 6-endo-dig cyclization, the reagents employed in the transformation play a direct role in bond-making and bond breaking, thus changing the mode of addition to a 6-endo-trig cyclization. This method can be used to construct an array of monocyclic and bicyclic scaffolds, many of which are found in well-known natural products (e.g., indolizidine, quinolizidine, and Stemona alkaloids). PMID- 20929270 TI - Kinetic analysis of a naturally occurring bioremediation enzyme: dehaloperoxidase hemoglobin from Amphitrite ornata. AB - The temperature dependence of the rate constant for substrate oxidation by the dehaloperoxidase-hemoglobin (DHP) of Amphitrite ornata has been measured from 278 to 308 K. The rate constant is observed to increase over this range by approximately a factor of 2 for each 10 degrees C temperature increment. An analysis of the initial rates using a phenomenological approach that expresses the peroxidase ping-pong mechanism in the form of the Michaelis-Menten equation leads to an interpretation of the effects in terms of the fundamental rate constants. The analysis of kinetic data considers a combination of diffusion rate constants for substrate and H(2)O(2), elementary steps involving activation and heterolysis of the O-O bond of H(2)O(2), and two electron transfers from the substrate to the iron. To complete the analysis from the perspective of turnover of substrate into product, density function theory (DFT) calculations were used to address the fate of phenoxy radical intermediates. The analysis suggests a dominant role for diffusion in the kinetics of DHP. PMID- 20929271 TI - Micropatterned polyvinyl butyral membrane for acid-base diodes. AB - Until now, polyvinyl alcohol (PVA) gel cylinders have been used in electrolyte diodes as a connecting element between the acidic and alkaline reservoirs. In this paper, a new connecting element is reported: a breath figure templated polyvinyl butyral (PVB) membrane prepared with dip-coating from a dichloromethane solution of the polymer in a humid atmosphere. The procedure gives a 1.5-2 MUm thick membrane with a hexagonal pattern, the average characteristic length of which is 1 MUm. After an acidic etching, it was found to be a good connecting element. The voltage-current characteristics and dynamic properties of PVA and PVB were measured and compared. The PVB membrane has a faster response to voltage changes than the PVA gel, but in both cases, there was a slow drift in the current that prevented it from reaching a steady state. Reproducible characteristics can be obtained, however, after the current reaches a well defined quasi-steady state. PMID- 20929272 TI - Revised thermochemistry of gaseous ammonium nitrate, NH4NO3(g). AB - In an earlier paper (Hildenbrand, D. L., Lau, K. H., and Chandra, D. J. Phys. Chem. B 2010, 114, 330.), we detected the presence of NH4NO3(g) in the vapor over the solid nitrate and evaluated its partial pressure along with those of HNO3 and NH3. The molecular constants of the gaseous nitrate were estimated in the absence of experimental values in an attempt to derive its enthalpies of sublimation and formation. After publication, we became aware of the sought molecular data, evaluated primarily from high-level theoretical calculations, and revised the analysis to yield Delta(f)H298 degrees (NH4NO3(g)) = -61.8 +/- 5 kcal mol-1. PMID- 20929273 TI - Time-resolved spectroscopic measurements of shock-wave induced decomposition in cyclotrimethylene trinitramine (RDX) crystals: anisotropic response. AB - Plate impact experiments on the (210), (100), and (111) planes were performed to examine the role of crystalline anisotropy on the shock-induced decomposition of cyclotrimethylenetrinitramine (RDX) crystals. Time-resolved emission spectroscopy was used to probe the decomposition of single crystals shocked to peak stresses ranging between 7 and 20 GPa. Emission produced by decomposition intermediates was analyzed in terms of induction time to emission, emission intensity, and the emission spectra shapes as a function of stress and time. Utilizing these features, we found that the shock-induced decomposition of RDX crystals exhibits considerable anisotropy. Crystals shocked on the (210) and (100) planes were more sensitive to decomposition than crystals shocked on the (111) plane. The possible sources of the observed anisotropy are discussed with regard to the inelastic deformation mechanisms of shocked RDX. Our results suggest that, despite the anisotropy observed for shock initiation, decomposition pathways for all three orientations are similar. PMID- 20929274 TI - Concise and enantioselective total synthesis of 15-deoxy-Delta-(12,14) prostaglandin J(2). AB - The concise and enantioselective synthesis of 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) has been accomplished in 11 steps from a known alcohol. The key step of the synthesis involves an asymmetric Rh-catalyzed cycloisomerization of ene-ynone, followed by an olefin isomerization. PMID- 20929275 TI - Early childhood caries among Hutterite preschool children in Manitoba, Canada. AB - INTRODUCTION: This study investigated the prevalence of early childhood caries (ECC) among Hutterite preschool children from different colonies in southwestern Manitoba, Canada. METHODS: Following informed consent from the child's parent, children under 72 months of age underwent a dental screening examination. Approval was granted by the University of Manitoba's Health Research Ethics Board. RESULTS: A total of 66 children with a mean age of 40.1 +/- 20.1 months participated. The prevalence of ECC was 53%, while the mean decayed, extracted and filled teeth (deft) score was 2.8 +/- 4.0 (range 0-20). A total of 42.4% had severe ECC (S-ECC). There was no difference in prevalence among the 6 participating colonies. Only 15 children had already been to the dentist, with the majority of these visits due to decay or dental pain. Of those, the mean age for a first visit was 2.7 +/- 0.6 years. Children with ECC were determined to be significantly older than those who were caries-free (p<.0001). Early childhood caries and higher caries rates were associated with lower maternal ratings of their child's dental health. Both ECC and increased deft scores were significantly associated with the number of children in the home. CONCLUSIONS: This is the first study to report the prevalence of primary tooth decay in Hutterite children. Rates were comparable with other Canadian data for rural dwelling children. Effective and culturally appropriate prevention and health promotion activities are warranted, including fluoride varnish and early dental visits. PMID- 20929276 TI - Cationic nanosystems for the delivery of small interfering ribonucleic acid therapeutics: a focus on toxicogenomics. AB - IMPORTANCE OF THE FIELD: siRNAs may serve as novel nanomedicines for sequence specific gene silencing in the clinic. However, delivering siRNA to targeted tissue or cells remains a challenge. An appropriate delivery nanosystem such as cationic polymers or liposomes is required for effective gene silencing with siRNA in vivo but the available drug delivery vectors are not all biologically inert. AREAS COVERED IN THIS REVIEW: A combination of highly focused and comprehensive literature searches to identify any relevant reports using Medline (from 1950 to 7 April 2010) through the OVID system. WHAT THE READER WILL GAIN: Using cationic delivery nanosystems as examples, this review article highlights the importance of undertaking toxicogenomics studies - the application of transcription profiling to toxicology - to acquire gene expression signatures of siRNA delivery systems so as to determine and/or predict their impact on gene silencing activity and specificity. Such nanotoxicological information will be important for the optimal selection of siRNA-delivery system combinations in the many proposed clinical applications of RNA interference. TAKE HOME MESSAGE: Cationic delivery nanosystems can elicit multiple gene expression changes in cells that may contribute to the 'off-target' effects of siRNAs and/or modulate their pharmacological activity. Thus, selection of delivery systems for siRNA applications should be based on both their delivery enhancing capability and toxicogenomics. PMID- 20929277 TI - Interleukin-1beta, C-x-C motif ligand 10, and interferon-gamma serum levels in mixed cryoglobulinemia with or without autoimmune thyroiditis. AB - The aim of this study was to evaluate serum levels of interleukin-1beta (IL 1beta), chemokine (C-X-C motif) ligand 10 (CXCL10), and interferon-gamma (IFN gamma) in a series of patients with "mixed cryoglobulinemia and hepatitis C virus chronic infection" (MC + HCV) in the presence or absence of autoimmune thyroiditis (AT) and to relate them to the clinical phenotype of these patients. Serum IL-1beta, IFN-gamma, and CXCL10 were assayed in 30 patients with MC + HCV without AT, in 30 patients with MC + HCV and AT, and in 30 sex- and age-matched controls. Cryoglobulinemic patients showed significantly higher mean IL-1beta and CXCL10 levels than controls (P < 0.01). Moreover, CXCL10 was significantly increased in patients with AT patients with respect to those without AT (P < 0.01). Serum IFN-gamma levels were not significantly higher in MC + HCV patients than in controls. In conclusion, our study demonstrates significantly high serum levels of IL-1beta in patients with MC + HCV with and without AT compared with healthy controls. Further, significantly high serum levels of CXCL10 in patients with MC + HCV compared with healthy controls were confirmed, overall in the presence of AT. Moreover, a pathophysiological association between high circulating levels of IL-1beta and CXCL10 has been suggested. A possible therapeutic role of the anti-IL-1 receptor antagonist (Anakirna) in MC remains to be evaluated. PMID- 20929278 TI - Molecular characterization and antiviral analyses of porcine type III interferons. AB - Type III interferons (IFNs) are a family of recently identified antiviral cytokines. One to 3 paralogs have been identified in several species; however, little information is available about type III IFNs in pigs. We have identified 2 porcine type III IFNs, Sus scrofa IFN-lambda1 (SsIFN-lambda1) and SsIFN-lambda3, and determined their tissue expression profile and antiviral activities. Open reading frames of SsIFN-lambda1 and SsIFN-lambda3 are 576 and 588 bp, encoding 191 and 195 amino acid preproteins, respectively. In healthy pigs, SsIFN-lambda3 was primarily expressed in mesenteric lymph nodes and intestine, whereas expression of SsIFN-lambda1 was found in all tested tissues and was high in mesenteric lymph nodes, intestine, and liver. Porcine cells treated with the viral mimic, dsRNA, robustly increased SsIFN-lambda3 expression, with epithelial cells generally displaying the greatest response. Conversely, dsRNA-induced mRNA expressions of SsIFN-lambda1, SsIFN-alpha1, and SsIFN-beta were relatively weaker and delayed compared with SsIFN-lambda3. SsIFN-lambda1 and SsIFN-lambda3 peptides exerted similar but lower antiviral potency than SsIFN-alpha1 and SsIFN-beta against a porcine arterivirus and an adenovirus. These findings indicate that pigs have 2 type III IFN paralogs, which have antiviral activity and may serve as targets for modulation of the porcine host-pathogen interaction. PMID- 20929279 TI - Nucleoside reverse transcriptase inhibitor toxicity and mitochondrial DNA. AB - IMPORTANCE OF THE FIELD: HIV/AIDS is a worldwide epidemic. While there remains no cure for the HIV-1 infection, nucleoside reverse transcriptase inhibitors (NRTIs) have helped transform the HIV-1 infection from a lethal disease into a chronic illness. Though NRTIs inhibit HIV-1 replication, they exhibit side effects in human tissues that appear to result from NRTI inhibition of human mitochondrial polymerase gamma (pol gamma). AREAS COVERED IN THIS REVIEW: this review discusses the current knowledge of NRTI-induced toxicity, specifically the inhibition of pol gamma and the mitochondrial toxicity from incorporation of NRTIs into mitochondrial DNA. Details are discussed about general mechanisms of NRTI toxicity and how specific tissue toxicities in mitochondria relate to clinical manifestation. WHAT THE READER WILL GAIN: a detailed knowledge of the mitochondrial toxicity resulting from NRTI-inclusive therapies and related tissue toxicities are provided. This review presents both the molecular effects of NRTI usage on mitochondrial genetic homeostasis and energy metabolism as well as the clinical manifestations associated with NRTI toxicities. TAKE HOME MESSAGE: NRTIs remain a critical component of current HIV-1 treatment regimens. Future NRTIs should provide higher specificity for HIV-RT and lower incorporation by pol gamma to minimize mitochondrial toxicity. Alternatively, therapeutic interventions to prevent or alleviate mitochondrial toxicity should be addressed. PMID- 20929280 TI - Xenopus laevis as a novel model to study long bone critical-size defect repair by growth factor-mediated regeneration. AB - We used the tarsus of an adult Xenopus laevis frog as an in vivo load-bearing model to study the regeneration of critical-size defects (CSD) in long bones. We found the CSD for this bone to be about 35% of the tarsus length. To promote regeneration, we implanted biocompatible 1,6 hexanediol diacrylate scaffolds soaked with bone morphogenetic proteins-4 and vascular endothelial growth factors. In contrast to studies that use scaffolds as templates for bone formation, we used scaffolds as a growth factor delivery vehicle to promote cartilage-to-bone regeneration. Defects in control frogs were filled with scaffolds lacking growth factors. The limbs were harvested at a series of time points ranging from 3 weeks to 6 months after implantation and evaluated using micro-computed tomography and histology. In frogs treated with growth factor loaded scaffolds, we observed a cartilage-to-bone regeneration in the skeletal defect. Five out of eight defects were completely filled with cartilage by 6 weeks. Blood vessels had invaded the cartilage, and bone was beginning to form in ossifying centers. By 3 months, these processes were well advanced, and extensive ossification was observed in 6-month samples. In contrast, the defects in control frogs showed only formation of fibrous scar tissue. This study demonstrates the utility of a Xenopus model system for tissue engineering research and that the normal in vivo mechanism of endochondral bone development and fracture repair can be mimicked in the repair of CSD with scaffolds used as growth factor delivery mechanisms. PMID- 20929281 TI - Vascularization of the dermal support enhances wound re-epithelialization by in situ delivery of epidermal keratinocytes. AB - Despite significant advances in management of severe wounds such as burns and chronic ulcers, autologous split-thickness skin grafts are still the gold standard of care. The main problems with this approach include pain and discomfort associated with harvesting autologous tissue, limited availability of donor sites, and the need for multiple surgeries. Although tissue engineering has great potential to provide alternative approaches for tissue regeneration, several problems have hampered progress in translating technological advances to clinical reality. Specifically, engineering of skin substitutes requires long culture times and delayed vascularization after implantation compromises graft survival. To address these issues we developed a novel two-prong strategy for tissue regeneration in vivo: (1) vascularization of acellular dermal scaffolds by infiltration of angiogenic factors; and (2) generation of stratified epidermis by in situ delivery of epidermal keratinocytes onto the prevascularized dermal support. Using athymic mouse as a model system, we found that incorporation of angiogenic factors within acellular human dermis enhanced the density and diameter of infiltrating host blood vessels. Increased vascularization correlated with enhanced proliferation and stratification of the neoepidermis originating from the fibrin-keratinocyte cell suspension. This strategy promoted tissue regeneration in vivo with no need for engineering skin substitutes; therefore, it may be useful for treatment of major wounds when skin donor sites are scarce and rapid wound coverage is required. PMID- 20929282 TI - Synergistic angiogenesis promoting effects of extracellular matrix scaffolds and adipose-derived stem cells during wound repair. AB - Slow vascularization rate is considered one of the main drawbacks of scaffolds used in wound healing. Several efforts, including cellular and acellular technologies, have been made to induce vascular growth in scaffolds. However, thus far, there is no established technology for inducing vascular growth. The aim of this study was to promote the vascularization capacities of scaffolds by seeding adipose-derived stem cells (ADSCs) on them and to compare the vascularization capacities of different scaffolds seeded with ADSCs. Two kinds of extracellular matrix scaffolds (small intestinal submucosa [SIS] and acellular dermal matrix [ADM]) and a kind of composite scaffold (collagen-chondroitin sulfate-hyaluronic acid [Co-CS-HA]) were selected. Subcutaneous implantation analysis showed that the vascularization capacity of SIS and ADM was greater than that of Co-CS-HA. ADSCs seeded in SIS and ADM secreted greater amounts of vascular endothelial growth factor than those seeded in Co-CS-HA. In a murine skin injury model, ADSC-seeded scaffolds enhanced the angiogenesis and wound healing rate compared with the nonseeded scaffolds. Moreover, ADSC-SIS and ADSC ADM had greater vascularization capacity than that of ADSC-Co-CS-HA. Taken together, these results suggest that ADSCs could be used as a cell source to promote the vascularization capacities of scaffolds. The vascularization capacities of ADSC-seeded scaffolds were influenced by both the vascularization capacities of the scaffolds themselves and their effects on the angiogenic potential of ADSCs; the combination of extracellular matrix scaffolds and ADSCs exhibited synergistic angiogenesis promoting effects. PMID- 20929284 TI - Optimization of an in vitro three-dimensional microenvironment to reprogram synovium-derived stem cells for cartilage tissue engineering. AB - Adult stem cells gradually lose their stemness when plated in monolayer culture after isolation from their in vivo niche. In this study, we hypothesized that the in vitro microenvironment can be optimized by modulating oxygen tension and mitotic signal in a tissue-specific extracellular matrix (ECM) deposited by synovium-derived stem cells (SDSCs) to rejuvenate expanded SDSC proliferation and chondrogenic potential. Passage 3 SDSCs were plated on either SDSC-derived ECM or plastic flask and incubated in either hypoxia (5% O(2)) or normoxia (21% O(2)) with or without the supplementation of 10 ng/mL of basic fibroblast growth factor 2 (FGF-2) for 7 days, followed by pellet culture in a serum-free chondrogenic medium for 14 days. Our data showed that, compared with the mitotic effect of FGF 2 on SDSCs, ECM expansion greatly enhanced SDSC proliferation while retaining SDSC stem cell characteristics. More importantly, ECM pretreatment yielded SDSC pellets with a comparable chondrogenic index to FGF-2 pretreatment, both of which were much higher than SDSC expansion on plastic flask alone. FGF-2 pretreatment led to the highest glycosaminoglycans and DNA content; intriguingly, it also contributed to the highest expression level of hypertrophic marker genes. Surprisingly, the hypertrophic marker genes could be downregulated if the pretreatment was combined with hypoxia or ECM. The combination of hypoxia, FGF-2, and SDSC-derived ECM contributed to the highest cell number in SDSC expansion. Our study indicates that the three-dimensional microenvironment for ex vivo expansion can be optimized to provide high-quality stem cells for stem cell-based cartilage defect repair. PMID- 20929285 TI - The porcine limbal epithelial stem cell niche as a new model for the study of transplanted tissue-engineered human limbal epithelial cells. AB - Transparency of the human cornea is dependent upon the integrity of its epithelium and hence a population of limbal epithelial stem cells (LESCs). We have previously shown that LESCs reside in limbal epithelial crypts at the periphery of the human cornea. In this study the anatomy and functionality of the porcine limbus was evaluated for the first time as a novel model of the human limbus. Scanning electron microscopy, confocal microscopy, and histology revealed common structures in the porcine and human limbus in terms of the location and topography of palisades of Vogt and limbal epithelial crypts. Epithelial cells harvested from crypt regions achieved higher colony forming efficiency than cultures established from the noncrypt regions and central cornea. Also, expression of the putative SC markers p63alpha and integrin beta1 brightness was higher in the basal layer of the crypt regions, as shown by immunocytochemistry. De-epithelialized porcine corneas were used as an in vitro organ culture model to study the fate of transplanted human epithelium cultured from the limbus. Multilayered epithelium was observed after ~1 week. Subsequently, wounds were inflicted on the central corneal epithelium. The wounded tissue healed within 5-7 days, and multilayering of the central corneal epithelium was re-established. The transplanted epithelia were repeatedly wounded at least four times and the wounds healed by 1 week. Putative SC marker expression of the transplanted epithelia was confirmed using immunohistochemistry. These results demonstrate that the porcine limbus shares features with the human limbus and as such provides a suitable model for the study of cultured limbal epithelial cell transplantation. These data have significant clinical value as this model can provide information on LESC fate post-transplantation and their ability to respond to injury, which is not possible to study in patients. PMID- 20929283 TI - Direct comparisons of the morphology, migration, cell adhesions, and actin cytoskeleton of fibroblasts in four different three-dimensional extracellular matrices. AB - Interactions between cells and the extracellular matrix are at the core of tissue engineering and biology. However, most studies of these interactions have used traditional two-dimensional (2D) tissue culture, which is less physiological than three-dimensional (3D) tissue culture. In this study, we compared cell behavior in four types of commonly used extracellular matrix under 2D and 3D conditions. Specifically, we quantified parameters of cell adhesion and migration by human foreskin fibroblasts in cell-derived matrix or hydrogels of collagen type I, fibrin, or basement membrane extract (BME). Fibroblasts in 3D were more spindle shaped with fewer lateral protrusions and substantially reduced actin stress fibers than on 2D matrices; cells failed to spread in 3D BME. Cell-matrix adhesion structures were detected in all matrices. Although the shapes of these cell adhesions differed, the total area per cell occupied by cell-matrix adhesions in 2D and 3D was nearly identical. Fibroblasts migrated most rapidly in cell-derived 3D matrix and collagen and migrated minimally in BME, with highest migration directionality in cell-derived matrix. This identification of quantitative differences in cellular responses to different matrix composition and dimensionality should help guide the development of customized 3D tissue culture and matrix scaffolds for tissue engineering. PMID- 20929286 TI - Engineered three-dimensional liver mimics recapitulate critical rat-specific bile acid pathways. AB - A critical hepatic function is the maintenance of optimal bile acid (BA) compositions to achieve cholesterol homeostasis. BAs are rarely quantified to assess hepatic phenotype in vitro since existing analytical techniques have inadequate resolution. We report a detailed investigation into the biosynthesis and homeostasis of eight primary rat BAs in conventional in vitro hepatocyte cultures and in an engineered liver mimic. The three-dimensional (3D) liver mimic was assembled with layers of primary rat hepatocytes and liver sinusoidal endothelial cells. A high-pressure liquid chromatography and mass spectrometry technique was developed with a detection limit of 1 ng/mL for each BA, which is significantly lower than previous approaches. Over a 2-week culture, only 3D liver mimics exhibited the ratio of conjugated cholic acid to chenodeoxycholic acid that has been observed in vivo. This ratio, an important marker of BA homeostasis, was significantly higher in stable collagen sandwich cultures indicating significant deviation from physiological behavior. The biosynthesis of tauro-beta-muricholic acid, a key primary rat BA, doubled only in the engineered liver mimics while decreasing in the other systems. These trends demonstrate that the 3D liver mimics provide a unique platform to study hepatic metabolism. PMID- 20929287 TI - Tubular perfusion system for the long-term dynamic culture of human mesenchymal stem cells. AB - In vitro culture techniques must be improved to increase the feasibility of cell based tissue engineering strategies. To enhance nutrient transport we have developed a novel bioreactor, the tubular perfusion system (TPS), to culture human mesenchymal stem cells (hMSCs) in three-dimensional scaffolds. This system utilizes an elegant design to create a more effective environment for cell culture. In our design, hMSCs in the TPS bioreactor are encapsulated in alginate beads that are tightly packed in a tubular growth chamber. The medium is perfused by a peristaltic pump through the growth chamber and around the tightly packed scaffolds enhancing nutrient transfer while exposing the cells to shear stress. Results demonstrate that bioreactor culture supports early osteoblastic differentiation of hMSCs as shown by alkaline phosphatase gene expression. After 14 and 28 days of culture significant increases in the gene expression levels of osteocalcin, osteopontin, and bone morphogenetic protein-2 were observed with bioreactor culture, and expression of these markers was shown to increase with media flow rate. These results demonstrate the TPS bioreactor as an effective means to culture hMSCs and provide insight to the effect of long-term shear stresses on differentiating hMSCs. PMID- 20929288 TI - Organ-specific tubular and collagen-based composite scaffolds. AB - The body contains a number of organs characterized by a tubular shape. In this study, we explored several methodologies for the construction of collagenous tubular scaffolds and films with defined (ultra)structure, length, diameter, orientation, and molecular composition. Standardization of molding, casting, freezing, and lyophilizing techniques using inexpensive materials and methods resulted in controllable fabrication of a wide variety of tubular and tissue specific tubular scaffolds and films. Analysis included immunohistochemical and (ultra)structural examination. Handling and suturability were found adequate for tissue engineering applications. PMID- 20929291 TI - Systemic monoclonal antibody therapy (daclizumab) in the treatment of cicatrizing conjunctivitis in stevens-johnson syndrome, refractory to conventional therapy. AB - PURPOSE: At least one-year follow-up of a case series of young Stevens-Johnson syndrome (SJS) patients with cicatrizing ocular surface disease and recurrent inflammation (SJS-RI) treated with systemic humanized monoclonal antibody (daclizumab). METHODS: Five patients (median age 16 yr; range 8-34 yr) with SJS, with recurrent inflammation refractory to conventional immunotherapy, were enrolled in a prospective non-randomized case series study. Inclusion criteria were patients with SJS and ocular cicatrizing inflammatory disease with severe visual impairment, using topical or systemic anti-inflammatory and/or immunomodulatory drugs without clinical improvement resulting in persistent inflammation (SJS-RI). Treatment with Daclizumab 1 mg/Kg (intravenous) was scheduled in three cycles. First cycle with concomitant immunotherapy: a total of 5 doses, with 14 days interval between them (total of this cycle: 10 weeks). Second cycle: interval was increased to 3 weeks; the patients received 2 doses (the second cycle had a total of 6 weeks). Third cycle: maintenance phase with 4 weeks interval between each application, until at least 12 months of the total follow up. After the first cycle (5th dose), the patients were kept with preservative-free lubricants and systemic doxycycline. RESULTS: Control of ocular inflammation was observed at a median of 8 weeks (range 6-10 weeks) in all patients, with relapses in two patients at 20-36 weeks. Relapses were controlled with topical steroids at a median of 10 days, and within 2 weeks the steroids were tapered for both patients. CONCLUSION: In this small case series, daclizumab demonstrated to play a beneficial role in the control of the inflammatory process of the recurrent inflammation in SJS, refractory to conventional immunomodulatory therapy. PMID- 20929292 TI - Vascular basement membrane thickening in diabetic retinopathy. AB - Vascular basement membrane (BM) thickening is a fundamental structural alteration of small blood vessels in diabetes. Over two decades of research has established hyperglycemia as the primary causal factor mediating this alteration. Various high glucose-induced mechanisms have been investigated and excess synthesis of BM components has been identified as a major contributing factor to BM thickening. Although BM thickening has been long hailed as the histological hallmark of diabetic microangiopathy, the consequences of BM thickening on the functionality of target organs of diabetes remain elusive even today. This review presents an overview of our current understanding of the BM structure and function, and focuses on how capillary BM thickening develops, its effect on retinal vascular function, and potential strategies for preventing the development of BM thickening in diabetic retinopathy. PMID- 20929293 TI - Is nail fold capillaroscopy useful in normotensive and primary open angle glaucoma? A pilot study. AB - PURPOSE: Vascular dysregulation is deemed a significant risk factor in glaucoma occurrence and progression. Capillaroscopy of the blood vessels on the finger nail-fold is a method that can provide information regarding the state of the vascular system at the capillary level. The aim of this pilot study was to determine whether there are significant differences in the morphological characteristics of the peripheral blood vessels in normotensive glaucoma and primary open angle glaucoma. MATERIALS AND METHODS: An ophthalmological and capillaroscopic examination was conducted on 30 normotensive glaucoma patients and 30 primary open angle glaucoma patients. The capillaroscopic characteristics described were as follows: capillary row density, capillary diameter, number of spirally formed capillaries, permeability of the loop, and loop resistance. RESULTS: Statistically, significantly more intensively spiraled capillaries were found in normotensive glaucoma patients (chi(2) test, p < 0.05). CONCLUSIONS: Results confirm the thesis that vascular factors play a significant role in the pathogenesis of the glaucoma, especially in cases where the level of intraocular pressure cannot be deemed responsible for the present damage of the optical nerve. Despite the newer, technologically more developed methods for diagnostics and monitoring glaucoma, it is often not easy to establish the right diagnosis and determine further the course of the illness, since the role the intraocular pressure (IOP) plays compared to the role of vascular factors is unknown; hence, capillaroscopy as a complementary diagnostic procedure can be of help. PMID- 20929294 TI - Preoperative multidetector row computed tomography for evaluation and assessment of resection criteria in patients with pancreatic masses. AB - BACKGROUND: preoperative assessment of pancreatic masses is still challenging as regards the characterization and assessment of irresectability. The opportunities of modern multidetector computed tomography (MDCT) with image postprocessing can be expected to enhance the diagnostic performance if accurate criteria are elaborated. PURPOSE: to estimate the accuracy of MDCT and multiplanar image reconstructions with the use of standardized imaging criteria for preoperative evaluation of pancreatic masses with respect to irresectability. MATERIAL AND METHODS: a total of 105 consecutive patients who underwent exploratory laparoscopy or pancreatic resection and had preoperative 3-phase MDCT (4-64 rows) were enrolled retrospectively. First, transverse sections and secondly additional 3Ds were reviewed by two independent blinded observers (O1/O2). Preoperative imaging findings were correlated with intraoperative and histopathologic results. RESULTS: among all 105 patients, 70 malignant pancreatic tumors and 35 benign pancreatic diseases were found (accuracy of 93% for O1 and 91% for O2). For arterial tumor invasion, receiver operator characteristic (ROC) analysis (values averaged from the results of O1 and O2) revealed an area under the curve (AUC) of 0.931 for transverse sections and 0.986 for 3Ds. Regarding irresectability, positive predictive values were 97% (with 3Ds, 97%) for O1/O2; negative predictive values were 84% (with 3Ds, 89%) for O1 and 86% (with 3Ds, 91%) for O2. CONCLUSION: MDCT with 3Ds was highly accurate for evaluation and assessment of irresectability criteria in patients with pancreatic masses. However, due to the limited specificity regarding arterial tumor infiltration, the indication for surgical exploration should be made generously in case of inconclusive findings. PMID- 20929295 TI - CT, MR, (18)F-FDG PET/CT, and their combined use for the assessment of mandibular invasion by squamous cell carcinomas of the oral cavity. AB - BACKGROUND: a reliable assessment of mandibular invasion is crucial for treatment planning to obtain both radical tumor resection and good functional results. PURPOSE: to retrospectively compare the diagnostic value of three different imaging methods - computed tomography (CT), magnetic resonance (MR) imaging, (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT - and their combined use for detection of mandibular invasion by squamous cell carcinoma (SCC) of the oral cavity. MATERIAL AND METHODS: forty-six patients (39 men and 7 women; mean age, 59.4 years) suspected of having mandibular invasion by SCC of the oral cavity underwent CT, MR, and PET/CT within 2 weeks before surgery. First, each study was reviewed separately for the presence of mandibular invasion by tumors. Then, the value of combined images was assessed based on a confidence rating score for each modality assigned by observers. These results were verified with histopathologic findings. RESULTS: HIstopathologic examination revealed mandibular invasion in 12 of 46 SCCs. The sensitivity, specificity, and accuracy were 41.7%, 100%, and 84.8% for CT; 58.3%, 97.1%, and 87.0% for MR; and 58.3%, 97.1%, and 87.0% for PET/CT, respectively. The comparison of these modalities showed no statistically significant difference among them (P > 0.05). The combination of CT, MR, and PET/CT improved sensitivity (83.3%), without loss of specificity (100%) and accuracy (95.7%), although the difference failed to reach statistical significance (P > 0.05). CONCLUSION: the combined analysis of CT, MR, and PET/CT can improve sensitivity in the detection of mandibular invasion by SCC of the oral cavity. PMID- 20929296 TI - Grey matter volume changes over the whole brain in amyotrophic lateral sclerosis: A voxel-wise meta-analysis of voxel based morphometry studies. AB - Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with selected both upper and lower motor neuron involvement. Although some inconsistent results exist, both pathological studies and many structural neuroimaging studies have revealed brain volume changes in ALS. To provide an objective overview of structural changes in ALS, a voxel-wise meta-analysis was performed in published voxel based morphometry (VBM) studies. A systematic search of VBM studies was applied in ALS. Five studies met the inclusion criteria, comprising 84 ALS patients and 81 normal controls. A voxel-wise meta-analysis was performed on the retrieved VBM studies using signed differential mapping. Descriptive analysis showed that 25% of ALS patients had right precentral gyrus atrophy (2373 voxels). Group analysis demonstrated regional grey matter loss over the whole brain in the right precentral gyrus (p = 7.96 * 10(-4)). Sensitivity analysis showed good sensitivity (157 voxels). In conclusion, right precentral grey matter atrophy was a common finding and prominent feature of brain structural changes in ALS. PMID- 20929301 TI - Electronic medical records: unintended consequences of a duplicitous default setting. PMID- 20929300 TI - Moving toward elimination of healthcare-associated infections: a call to action. PMID- 20929302 TI - Extrinsic contamination of liquid soap with various gram-negative bacteria in a hospital in Turkey. PMID- 20929303 TI - Hydrogen peroxide vapor is not the same as aerosolized hydrogen peroxide. PMID- 20929304 TI - High clonal diversity of Staphylococcus aureus isolates in nasal swab samples of medical students in Turkey. PMID- 20929305 TI - Rifampin plus metronidazole for Clostridium difficile infection. PMID- 20929307 TI - Morphological changes in varicocele veins: ultrastructural study. AB - BACKGROUND: Varicocele consists of dilatation of the pampiniform venous plexus and the internal spermatic veins. It is present in 15% of male population and is a common cause of male infertility. OBJECTIVE: To describe the normal structure of the internal spermatic vein and the morphological changes in grade 3 varicocele. METHODS: The authors dissected and analyzed a 2- to 3-cm tract of the pampiniform venous plexus of 20 patients undergoing varicocelectomy for left varicocele and of 10 consecutive patients undergoing surgery for left inguinal hernia. The histological examination was performed with hematoxylin-eosin and Masson trichrome stains. The ultrastructural evaluation was done using both scanning and transmission electron microscopy. RESULTS: Compared with normal internal spermatic veins, varicocele veins showed narrowing and/or obliteration of the lumens, destruction of the endothelial cells, invagination of the intima, and deposition of collagen bundles in the media (light microscopy). The ultrastructural changes in varicocele veins included elongation of the endothelial cells with features of cellular damage, loss of the internal elastic lamina, and the appearance of ghost bodies and degenerative vacuoles in the subendothelial layer. CONCLUSIONS: The authors believe this is the first report analyzing ultrastructual changes in normal human internal spermatic vein samples and in varicocele. The underlying molecular mechanisms of these changes await further studies. PMID- 20929308 TI - Electron microscopy in end stage renal disease: a case of Fabry's disease. AB - Fabry's disease is an X-linked error of metabolism with deficiency of the enzyme α-glycosidase A, and glycosphingolipid accumulation in multiple tissues. Patients may be asymptomatic and present with advanced disease. We report a case of a 38 year old white male who presented with end stage renal disease of unknown etiology. He received a living-related donor kidney transplant (mother), but lost the graft after 10 years to multiple episodes of rejection. Review of the native renal biopsy with added ultrastructural studies established the diagnosis of Fabry's disease. Evaluation of renal biopsies showing advanced chronic injury should include electron microscopic studies, which may reveal characteristic diagnostic features, as seen in this case of Fabry's disease. Identification of hereditary disorders involving the kidney is important for appropriate treatment and prevention of disease recurrence. Potential living related donors should be screened for genetic involvement. PMID- 20929309 TI - Biochemical and ultrastructural correlations of calreticulin and thioredoxin expression in breast mucinous carcinoma and infiltrating ductal carcinoma non special type. AB - Mucinous infiltrating invasive ductal adenocarcinoma consists of 2-4% invasive breast cancer, but is a very interesting type due to its macroscopic similarity to non-special-type (NST) ductal carcinoma. The macroscopic similarity of mucinous and infiltrating ductal carcinoma NST adenocarcinomas consists of a loose and edematous stroma, which is often seen in portions of NST carcinoma and may mimic the mucin pools of mucinous carcinoma. In this study the authors examined the ultrastructural differences between mucinous carcinoma and infiltrating ductal carcinoma NST. They also examined the protein expression of the tissues by 2D electrophoresis due to their belief that from the results of these two levels it is possible to understand the changes that take place both in the ultrastructural and biochemical levels in these two types of breast cancer. The ultrastructural results from mucinous carcinoma have shown many changes in cytoplasmic organelles in comparison to normal samples, depending on the grade and the number of metastatic lymph nodes. At the 2D elecrophoresis level the authors studied two interesting polypeptides, calreticulin and thioredoxin. Both of these proteins were found in patterns of fibroadenoma, mucinous carcinoma, and NST carcinoma, but with different quantitative expression among them. In the future the quantitative differences of these two proteins may provide specific tumor markers for these two types of carcinoma. PMID- 20929310 TI - Effect of mailed feedback on drug prescribing profiles in general practice: a seven-year longitudinal study in Storstrom County, Denmark. AB - BACKGROUND: Whether written feedback on drug prescribing in general practice affects prescribing habits is controversial. Most short-term studies showed no effect. However, the issue has not been tested in long-term studies involving the local general practitioner community. AIMS OF THE STUDY: To assess whether prescribing levels in general practice are affected by long-term, unsolicited, systematically repeated, mailed feedback. METHODS: Each of the 94 general practices in Storstrom County, Denmark, received semi-annual, mailed feedback about their prescribing volumes and costs within 13 major drug groups, in relation to the levels for all the other 93 practices over a 7-year period in a project initiated by the local general practitioner association. Data on the number of defined daily doses (DDDs) prescribed per 1000 listed patients in each practice per 6-months, and practice characteristics, were obtained from the Pharmaceutical Database at the County Health Department. RESULTS: There was a large variation in drug prescribing volume between practices, but little within practice variation over time. After adjustments for the influence of practice size and other potential outcome-affecting variables, there was no evidence of a general change of prescribing volume over time, no change among practices with a high or a low prescribing level, and no significant change within the various drug groups. CONCLUSIONS: We found no significant effects on prescribing levels of mailed feedback, even when repeated semi-annually during 7 years and initiated by the local general practitioner community. PMID- 20929311 TI - Enzymes, embryos, and ancestors. AB - In the 1950s, cellular regulatory mechanisms were newly recognized; with Arthur Pardee I investigated the initial enzyme of pyrimidine biosynthesis, which he discovered is controlled by feedback inhibition. The protein proved unusual in having separate but interacting sites for substrates and regulators. Howard Schachman and I dissociated the protein into different subunits, one binding regulators and one substrates. The enzyme became an early prime example of allostery. In developmental biology I studied the egg of the frog, Xenopus laevis, characterizing early processes of axis formation. My excellent students and I described cortical rotation, a 30° movement of the egg's cortex over tracks of parallel microtubules anchored to the underlying cytoplasmic core, and we perturbed it to alter Spemann's organizer and effect spectacular phenotypes. The entire sequence of events has been elucidated by others at the molecular level, making Xenopus a prime example of vertebrate axis formation. Marc Kirschner, Christopher Lowe, and I then compared hemichordate (half-chordate) and chordate early development. Despite anatomical-physiological differences, these groups share numerous steps of axis formation, ones that were probably already in use in their pre-Cambrian ancestor. I've thoroughly enjoyed exploring these areas during a 50-year period of great advances in biological sciences by the worldwide research community. PMID- 20929312 TI - Modulation of host cell function by Legionella pneumophila type IV effectors. AB - Macrophages and protozoa ingest bacteria by phagocytosis and destroy these microbes using a conserved pathway that mediates fusion of the phagosome with lysosomes. To survive within phagocytic host cells, bacterial pathogens have evolved a variety of strategies to avoid fusion with lysosomes. A virulence strategy used by the intracellular pathogen Legionella pneumophila is to manipulate host cellular processes using bacterial proteins that are delivered into the cytosolic compartment of the host cell by a specialized secretion system called Dot/Icm. The proteins delivered by the Dot/Icm system target host factors that play evolutionarily conserved roles in controlling membrane transport in eukaryotic cells, which enables L. pneumophila to create an endoplasmic reticulum like vacuole that supports intracellular replication in both protozoan and mammalian host cells. This review focuses on intracellular trafficking of L. pneumophila and describes how bacterial proteins contribute to modulation of host processes required for survival within host cells. PMID- 20929313 TI - A new wave of cellular imaging. AB - Fluorescence imaging methods that push or break the diffraction limit of resolution (approximately 200 nm) have grown explosively. These super-resolution nanoscopy techniques include: stimulated emission depletion (STED), Pointillism microscopy [(fluorescence) photoactivation localization microscopy/stochastic optical reconstruction microscopy, or (F)PALM/STORM], structured illumination, total internal reflection fluorescence microscopy (TIRFM), and those that combine multiple modalities. Each affords unique strengths in lateral and axial resolution, speed, sensitivity, and fluorophore compatibility. We examine the optical principles and design of these new instruments and their ability to see more detail with greater sensitivity--down to single molecules with tens of nanometers resolution. Nanoscopes have revealed transient intermediate states of organelles and molecules in living cells and have led to new discoveries but also biological controversies. We highlight common unifying principles behind nanoscopy such as the conversion of a subset of probes between states (ground or excited) and the use of scanning (ordered or stochastic). We emphasize major advances, biological applications, and promising new developments. PMID- 20929314 TI - Functioning and disability in traumatic brain injury. AB - PURPOSE: To describe functioning and disability in patients with traumatic brain injury (TBI) according to the model endorsed by the International Classification of Functioning Disability and Health (ICF). METHODS: Adult patients with acquired TBI were consecutively enrolled. The Functional Independence Measure (FIM), the WHO Disability Assessment Schedule II (WHO-DAS II) and the ICF checklist were administered in individual sessions. Descriptive analyses were performed to report on FIM and WHO-DAS II scores. ICF categories reported as a problem by more than 20% of patients were described in detail. RESULTS: One hundred patients (66 males, mean age 36.1) were enrolled. Mean WHO-DAS II score was 16.8, mean FIM was 116.5 and 87 ICF categories were selected: 27 Body Functions (mainly mental and movement-related) and Structures, 43 Activities and Participation (mainly connected with mobility) and 17 Environmental Factors. Negligible difference between capacity and performance qualifiers was observed. CONCLUSIONS: The ICF can be successfully implemented in clinical and rehabilitation of patients with TBI, because it enables to describe the variety of problems they encounter: ICF derived data provide a holistic view of disability and enable the impact of service interventions on functioning and participation, and enable clinicians to tailor intervention according to patient's actual needs. PMID- 20929315 TI - Statin use and need for therapy in chronic lymphocytic leukemia. PMID- 20929316 TI - Correlation between IDH2 mutations and disease status in acute myeloid leukemia. PMID- 20929317 TI - Numb chin syndrome as the initial manifestation of acute megakaryoblastic leukemia. PMID- 20929318 TI - Clinicopathologic features of primary lymphoma in soft tissue. AB - By reviewing 3725 lymphomas diagnosed in our institution from 1999 to 2010, we found eight cases (0.21%) of primary lymphoma in soft tissue with comprehensive histologic and immunohistochemical studies. Of the eight cases of primary lymphoma in soft tissue, two patients were male and six were female. The mean age was 54.8 years with range from 23 to 76 years. The greatest diameter of tumor ranged from 1.3 to 20 cm with an average diameter of 7.5 cm. Six cases were diffuse large B-cell lymphoma (DLBCL), subclassified as three DLBCL non-germinal center B-cell phenotype, one DLBCL germinal center B-cell phenotype, and two (Epstein-Barr Virus) EBV-positive DLBCL of the elderly; one case was anaplastic large cell lymphoma, ALK-positive; and one case was peripheral T cell lymphoma, not otherwise specified. Follow-up was available for four patients. One patient who refused further therapy died of the disease at 2 months after diagnosis. The other three patients with follow-up were alive without recurrence and metastatic disease at 9, 36, and 48 months, respectively, after excisional biopsy combined with appropriate chemotherapy and/or radiation therapy. PMID- 20929319 TI - Impact of genomic aberrations including chromosome 1 abnormalities on the outcome of patients with relapsed or refractory multiple myeloma treated with lenalidomide and dexamethasone. AB - Previous literature suggests that cytogenetics may be used for risk-adapted therapy in patients with relapsed/refractory multiple myeloma (MM) treated with lenalidomide and dexamethasone. However, the significance of each abnormality is still unclear, and chromosome 1 abnormalities have yet to be studied in this population. We therefore evaluated genetic risk factors including chromosome 1q gain and 1p loss by cIg-FISH in 143 patients with relapsed/refractory MM treated with lenalidomide and dexamethasone, and correlated the genomic aberrations with patient clinical outcomes. Patients had a median of two (range 1-7) previous therapies in this cohort. A total of 119 out of 143 (83%) patients had an objective response, with median time to progression (TTP) and overall survival (OS) of 11 and 28 months, respectively. Patients with del(1p21) or del(17p) (p53) deletions had a significantly shorter TTP. OS was shorter in patients with 1p21 or 17p deletions, but did not reach statistical significance. Prior bortezomib or thalidomide treatment was associated with shorter TTP and OS. Multivariate analysis identified del(17p), del(1p21), and prior bortezomib or thalidomide therapy as independent risk factors for shorter TTP. Our data suggest that chromosome 17p and 1p21 deletions adversely impact the outcome of lenalidomide and dexamethasone treated patients with relapsed/refractory MM. Improved therapeutic strategies are required for these patients. PMID- 20929320 TI - Complete remission following treatment with bortezomib, doxorubicin, dexamethasone and autologous stem cell transplant in patient with immunoglobulin E multiple myeloma. PMID- 20929321 TI - Immunoglobulin heavy chain V-D-J gene rearrangement and mutational status in Uruguayan patients with chronic lymphocytic leukemia. AB - B-cell chronic lymphocytic leukemia (CLL) is characterized by the accumulation of long-lived circulating clonal leukemic B-cells, although the etiopathogenesis remains unclear. The incidence of CLL is variable in different regions around the world. While it is the most frequent chronic leukemia in Western countries, it has a low incidence in Asia. In this work we have investigated the immunoglobulin heavy chain gene rearrangements and mutational status in 80 Uruguayan patients with CLL, and compared these results with those obtained in other geographic regions. Our results demonstrate that Uruguayan patients with CLL display an IGHV gene usage which resembles that observed in Mediterranean countries and exhibits certain differences compared with Brazilian and Asian series, as expected, considering the ethnic basis of the Uruguayan population. This suggests that genetic influences could be important in the development and etiopathogenesis of CLL, but larger studies are necessary to substantiate this possibility. PMID- 20929322 TI - Long-term outcome of childhood acute myeloid leukemia in a developing country: experience from a children's hospital in China. AB - Data on childhood acute myeloid leukemia (AML) in developing countries are limited. Herein we report the outcome of childhood AML treated with modified NPCLC-AML97 in our institution from 1997 to 2005. One hundred and eighty-five children with newly diagnosed AML were admitted. The 7-year overall survival (OS) and event free survival (EFS) rates for the whole cohort were 33.1 +/- 4.1% and 31.2 +/- 3.7%, respectively. Sixty patients (32.4%) refused chemotherapy and 123 were eligible for protocol evaluation. Among eligible patients, 111 (90.2%) achieved complete remission (CR). The estimated 7-year OS and EFS rates were 50.2 +/- 5.5% and 46.9 +/- 5.1%, respectively. APL was more curable than non-APL (7 year EFS: 63.5 +/- 7.9% vs. 35.9 +/- 6.3%, p = 0.005). Thirty-one patients (25.2%) relapsed, but no central nervous system leukemia was observed. Although the cure rate of childhood AML in China was low, the treatment outcome for patients who could adhere to the treatment protocol was satisfactory. PMID- 20929323 TI - Immunohistochemical expression profile and prognosis in patients with diffuse large B-cell lymphoma with or without human immunodeficiency virus infection. AB - Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma subtype in non immunosuppressed and in human immunodeficiency virus (HIV)-positive patients. The prognosis of DLBCL with germinal center (GC) phenotype is better than that of the non-germinal center (non-GC) phenotype by immunohistochemical expression profile (IHC) in some studies but not in others. The frequency and the prognosis of these phenotypic subtypes in DLBCL related to HIV infection is not well known. The objectives of this study were to characterize the IHC by tissue microarray in 98 patients with DLBCL, 34 of whom were HIV-positive, and to evaluate their prognosis. Patients with HIV-related DLBCL with a non-GC pattern had poorer prognosis than patients with non-HIV-related DLBCL with the same pattern, but this difference disappeared when we considered only patients receiving HAART. PMID- 20929324 TI - Audit of fluoroquinolone prophylaxis against chemotherapy-induced febrile neutropenia in a hospital with highly prevalent fluoroquinolone resistance. PMID- 20929325 TI - A case of Kaposi sarcoma-associated herpesvirus/human herpesvirus 8-unrelated but Epstein-Barr virus-positive primary effusion lymphoma-like lymphoma in the setting of human immunodeficiency virus and hepatitis C virus infection. PMID- 20929326 TI - Y-box binding protein-1 expression in diffuse large B-cell lymphoma: an impact on prognosis in the rituximab era. AB - The expression of YB-1 has been reported to predict poor clinical outcome in many human malignancies, including hematopoietic malignancies. In this study, we investigated the correlations between YB-1 expression and the clinicopathological features of patients with diffuse large B-cell lymphoma (DLBCL) in a single institution. The expression of YB-1 was analyzed in 168 cases by immunohistochemistry. Fifteen out of 168 cases (8.9%) showed cytoplasmic expression of YB-1. The expression of YB-1 was significantly associated with 5 year overall survival (OS) (p = 0.023). Rituximab plus CHOP therapy (n = 94) improved the 5-year survival rate in both YB-1-positive and -negative patients. In conclusion, the data presented in this report provide evidence that the cytoplasmic expression of YB-1 is a poor prognosis factor in DLBCL treated with CHOP therapy, whereas rituximab improves the survival of both YB-1-positive and negative patients with DLBCL. PMID- 20929327 TI - IDH2 mutations in patients with acute myeloid leukemia: missense p.R140 mutations are linked to disease status. PMID- 20929329 TI - Bortezomib, cyclophosphamide, and dexamethasone: highly effective for rapid reversal of myeloma-associated hyperammonemic encephalopathy. PMID- 20929328 TI - Decitabine in myelodysplastic syndromes and chronic myelomonocytic leukemia: Argentinian/South Korean multi-institutional clinical experience. AB - This multicenter, open-label study evaluated the efficacy and safety of decitabine in patients from Argentina and South Korea with myelodysplastic syndromes or chronic myelomonocytic leukemia. Of 106 patients who received decitabine 20 mg/m(2) intravenously over 1 h once daily for 5 days in 4-week cycles, 99 patients were evaluable after receiving at least two cycles. The overall improvement rate was 35% (19% complete response +4% marrow complete response +4% partial response +8% hematologic improvement). Overall survival at 2 years was 71%. Treatment-related adverse events included febrile neutropenia, thrombocytopenia and bleeding, asthenia, fatigue, and eosinophilia. After complete response (CR), three patients received an allogeneic stem cell transplant. Four patients who relapsed after CR responded to decitabine retreatment. Acute myelogenous leukemia developed during follow-up in 21% of patients. Decitabine in a 5-day outpatient administration schedule was effective and well tolerated in typical clinical practice settings in South America and Asia. PMID- 20929330 TI - Extensive analysis of the T315I substitution and detection of additional ABL mutations in progenitors and primitive stem cell compartment in a patient with tyrosine kinase inhibitor-resistant chronic myeloid leukemia. AB - Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of chronic myeloid leukemia (CML). However, resistance is occasionally observed, mainly due to mutations within the BCR-ABL kinase domain. The T315I substitution confers complete resistance to all TKIs commonly used in clinical practice. To date, the hierarchical level of stem cells in which this mutation initially appears has not been studied. The aim of this study was to evaluate the behavior of T315I mutated cells and to study the presence of potential additional mutations in progenitors and stem cells from a patient with CML. A comprehensive analysis of BCR-ABL(315I) mRNA expressing cells in mononuclear cells, in CD34+ cell populations, and in their primitive long-term culture-initiating cell (LTC-IC) derived progenitors was performed. We show that the T315I substitution arises in primitive Ph1 stem cells without altering their myeloid and erythroid terminal differentiation potential. Leukemic cells expressing a T315I mutated BCR-ABL display a progressive decline in LTC-IC assays as described for non-mutated CML cells at diagnosis. Finally, in our experiments, additional non-315 ABL mutations were identified in hematopoietic stem cell colonies. This observation is suggestive of genetic instability affecting CML progenitors. PMID- 20929331 TI - Rituximab-induced life-threatening coagulopathy occurring in a patient with Waldenstrom macroglobulinemia treated with fludarabine, cyclophosphamide, and rituximab combination. PMID- 20929332 TI - Ocular adnexal mucosa-associated lymphoid tissue lymphomas: more clues but still a puzzle. PMID- 20929333 TI - Proteomic profile of a therapy related acute myeloid leukemia following brain tumor. PMID- 20929334 TI - T-cell large granular lymphocytic leukemia with pleomorphic nuclei and colonic infiltration with chronic diarrhea. PMID- 20929335 TI - Hypomethylating agents in acute lymphoblastic leukemia: untapped potential? PMID- 20929336 TI - A review of multifunctional nanoemulsion systems to overcome oral and CNS drug delivery barriers. AB - The oral and central nervous systems (CNS) present a unique set of barriers to the delivery of important diagnostic and therapeutic agents. Extensive research over the past few years has enabled a better understanding of these physical and biological barriers based on tight cellular junctions and expression of active transporters and metabolizing enzymes at the luminal surfaces of the gastrointestinal (GI) tract and the blood-brain barrier (BBB). This review focuses on the recent understanding of transport across the GI tract and BBB and the development of nanotechnology-based delivery strategies that can enhance bioavailability of drugs. Multifunctional lipid nanosystems, such as oil-in-water nanoemulsions, that integrate enhancement in permeability, tissue and cell targeting, imaging, and therapeutic functions are especially promising. Based on strategic choice of edible oils, surfactants and additional surface modifiers, and different types of payloads, rationale design of multifunctional nanoemulsions can serve as a safe and effective delivery vehicle across oral and CNS barriers. PMID- 20929337 TI - Intracellular uptake, transport, and processing of gold nanostructures. AB - The emerging field of nanomedicine requires better understanding of the interface between nanotechnology and medicine. Better knowledge of the nano-bio interface will lead to better tools for diagnostic imaging and therapy. In this review, recent progress in understanding of how size, shape, and surface properties of nanoparticles (NPs) affect intracellular fate of NPs is discussed. Gold nanostructures are used as a model system in this regard since their physical and chemical properties can be easily manipulated. The NP-uptake is dependent on the physiochemical properties, and once in the cell, most of the NPs are trafficked via an endo-lysosomal path followed by a receptor-mediated endocytosis process at the cell membrane. Within the size range of 2-100 nm, Gold nanoparticles (GNPs) of diameter 50 nm demonstrate the highest uptake. Cellular uptake studies of gold nanorods (GNRs) show that there is a decrease in uptake as the aspect ratio of GNRs increases. Theoretical models support the size- and shape-dependent NP uptake. The intracellular transport of targeted NPs is faster than untargeted NPs. The surface ligand and charge of NPs play a bigger role in their uptake, transport, and organelle distribution. Exocytosis of NPs is dependent on size and shape as well; however, the trend is different compared to endocytosis. GNPs are now being incorporated into polymer and lipid based NPs to build multifunctional devices. A multifunctional platform based on gold nanostructures, with multimodal imaging, targeting, and therapeutics; hold the possibility of promising directions in medical research. PMID- 20929338 TI - Nanoparticles: crossing barriers and membrane interactions. PMID- 20929339 TI - Multifunctionality of lipid-core micelles for drug delivery and tumour targeting. AB - Phospholipid micelles have proven to be the versatile pharmaceutical nanocarrier of choice for the delivery of poorly soluble chemotherapeutics for cancer therapy using various treatment modalities. Phospholipid micelles are typically expected to increase the accumulation of the loaded drugs in tumour tissues by taking advantage of the enhanced permeability and retention effect and by ligand mediated active targeting. Furthermore, by tailoring the composition of the micelles, it is possible to enhance the intracellular delivery of the cargo. This review highlights the important advancements in our laboratory with polyethyleneglycol phosphatidylethanolamine (PEG-PE)-based micellar drug delivery systems for improvement of the therapeutic efficacy of poorly soluble anticancer drugs. PMID- 20929340 TI - Functioning and disability in multiple sclerosis. AB - PURPOSE: To describe functioning and disability in patients with multiple sclerosis (MS) according to the model endorsed by the International Classification of Functioning Disability and Health (ICF). METHODS: Adult patients with MS were consecutively enrolled. The Expanded Disability Status Scale (EDSS), the WHO Disability Assessment Schedule II (WHO-DAS II) and the ICF checklist were administered in individual sessions. Descriptive analyses were performed to report on EDSS and WHO-DAS II scores. ICF categories reported as a problem by more than 20% of patients were described in detail. RESULTS: One hundred patients (70 females, mean age 41.7), 73 with relapsing-remitting MS were enrolled. Mean WHO-DAS II score was 10.6 and 58 ICF categories were selected: 23 Body Functions and Structures, 21 Activities and Participation and 14 Environmental Factors. CONCLUSIONS: The ICF can be successfully implemented in clinical and rehabilitation of patients with MS, because it enables to describe its multiple facets. Little differences between capacity and performance in ICF categories connected with activities of daily living, and presence of technical aids and other environmental factors are reported. On the contrary, in categories related to relationships, performance was worse than capacity thus revealing attitudinal barriers. PMID- 20929344 TI - Short communication: quantitative proteomic plasma profiling reveals activation of host defense to oxidative stress in chronic SIV and methamphetamine comorbidity. AB - The double epidemic of substance abuse and HIV infection is a multifaceted problem To investigate mechanistic clues to the effects of substance abuse on infected individuals we preformed quantitative proteomic profiling of plasma in a methamphetamine treated nonhuman primate model for AIDS. A nontargeted quantitative approach identified extracellular superoxide dismutase to be significantly upregulated by SIV and methamphetamine treatment, and targeted studies revealed an increase in expression in the antioxidant glutathione S transferase, thus pointing to a compensatory response to increased oxidative stress in methamphetamine-treated animals. PMID- 20929345 TI - HIV type 1 alters mesenchymal stem cell differentiation potential and cell phenotype ex vivo. AB - An increased incidence of bone and lipid toxicities is associated with HIV-1 infection and its treatment. Mesenchymal stem cells (MSCs) are multipotent cells that can differentiate into both osteoblasts (OB) and adipocytes (AC). We hypothesize that the interaction of MSC and HIV-1 underlie these toxicities. Serum was collected from uninfected control and HIV-infected, antiviral-naive patients. Sera were divided into three groups: HIV-negative sera (n = 5), HIV positive low viral load (LVL) (VL range 120; 4000, n = 5) or high viral load (HVL) (VL range 100,000; 500,000, n = 5). MSCs were exposed to these sera (5%) in an adipogenic/osteogenic condition and in nondifferentiating conditions in acute and chronic exposure models. Markers of adipogenesis/osteogenesis were examined in both MSCs induced to differentiated and nondifferentiating cells. Sera from HVL HIV-1-infected individuals induced a clear proadipogenic phenotype, as evidenced by an increase in adipocyte formation and the induction of increased expression of adipogenic markers including LPL and PPARgamma. Both CD4 receptor blockade and treatment with the antiretroviral AZT attenuated these proadipogenic effects, suggesting that an infection event may underlie the observed phenomena. Finally, inhibition of COUP TF-1 by HIV-1 TAT was identified as a potential molecular mechanism for these effects. These results suggest that HIV-1 directly interacts with and may infect MSCs resulting in alterations of their differentiation potential, findings that significantly enhance our understanding of HIV-1-associated bone and fat toxicities. PMID- 20929341 TI - n-3 fatty acids and cardiovascular events after myocardial infarction. AB - BACKGROUND: Results from prospective cohort studies and randomized, controlled trials have provided evidence of a protective effect of n-3 fatty acids against cardiovascular diseases. We examined the effect of the marine n-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and of the plant derived alpha-linolenic acid (ALA) on the rate of cardiovascular events among patients who have had a myocardial infarction. METHODS: In a multicenter, double blind, placebo-controlled trial, we randomly assigned 4837 patients, 60 through 80 years of age (78% men), who had had a myocardial infarction and were receiving state-of-the-art antihypertensive, antithrombotic, and lipid-modifying therapy to receive for 40 months one of four trial margarines: a margarine supplemented with a combination of EPA and DHA (with a targeted additional daily intake of 400 mg of EPA-DHA), a margarine supplemented with ALA (with a targeted additional daily intake of 2 g of ALA), a margarine supplemented with EPA-DHA and ALA, or a placebo margarine. The primary end point was the rate of major cardiovascular events, which comprised fatal and nonfatal cardiovascular events and cardiac interventions. Data were analyzed according to the intention-to-treat principle, with the use of Cox proportional-hazards models. RESULTS: The patients consumed, on average, 18.8 g of margarine per day, which resulted in additional intakes of 226 mg of EPA combined with 150 mg of DHA, 1.9 g of ALA, or both, in the active treatment groups. During the follow-up period, a major cardiovascular event occurred in 671 patients (13.9%). Neither EPA-DHA nor ALA reduced this primary end point (hazard ratio with EPA-DHA, 1.01; 95% confidence interval [CI], 0.87 to 1.17; P=0.93; hazard ratio with ALA, 0.91; 95% CI, 0.78 to 1.05; P=0.20). In the prespecified subgroup of women, ALA, as compared with placebo and EPA-DHA alone, was associated with a reduction in the rate of major cardiovascular events that approached significance (hazard ratio, 0.73; 95% CI, 0.51 to 1.03; P=0.07). The rate of adverse events did not differ significantly among the study groups. CONCLUSIONS: Low-dose supplementation with EPA-DHA or ALA did not significantly reduce the rate of major cardiovascular events among patients who had had a myocardial infarction and who were receiving state-of-the-art antihypertensive, antithrombotic, and lipid-modifying therapy. (Funded by the Netherlands Heart Foundation and others; ClinicalTrials.gov number, NCT00127452.). PMID- 20929346 TI - Short communication: intermediate prevalence of HIV type 1 primary antiretroviral resistance in Ceara State, Northeast Brazil. AB - Brazil is a large developing country where almost all FDA-licensed antiretrovirals are made available to more than 200,000 individuals under antiretroviral treatment. General primary HIV-1 resistance in Brazil is assumed to be low, but data are scarce, especially in the Northeast region. To evaluate the prevalence of primary HIV-1 antiretroviral resistance in the state of Ceara, Brazil, a cross-sectional prospective study of antiretroviral-naive HIV-1 infected individuals was performed between May 2008 and May 2009. Genomic sequences of reverse transcriptase and protease regions of the pol gene of HIV-1 using PCR products were obtained. Mutations related to resistance to NRTI, NNRTI, and PI were evaluated according to the WHO mutation list for primary resistance surveillance, which excludes common polymorphisms. Seventy-four individuals were evaluated (50% male) with a median age 30 years; 55.4% were men who have sex with men. Median CD4(+) T lymphocyte counts were 418 and 960 cells/mm(3) and the median viral loads were 4.41 and 4.46 log(10) RNA copies/ml for individuals older and younger that 18 years, respectively. Twenty-seven percent of patients were symptomatic. Five patients (6.8%) were recently infected, as detected by the BED test. The mutations 41L, 67N, 215D, 219Q, 101E, and 103N in the RT and 32I, 46I, 54V, 82T, and 90M, in the PR were identified in 9.5% of samples, more frequently in HIV subtype B (85.1%). A significant level of primary HIV resistance was detected in urban Northeast Brazil, a region geographically distant from the more highly populated and wealthier areas of Southeast Brazil, and this emphasizes the need for monitoring resistance in the studied area. PMID- 20929347 TI - Detection of a Rare HIV Type 1 Strain CRF16_A2D in Bangladesh. AB - Circulating recombinant form (CRF) 16_A2D is a rare HIV strain among the most recently identified subsubtype A2. Samples taken from an HIV-seropositive married couple who attended a voluntary counseling and testing unit in Dhaka, Bangladesh showed two rare CRF16_A2D isolates. Further genetic analyses targeting three HIV genes (gag, pol, and env) showed that the two isolates from the couple were closely related making it likely that one of them acquired the virus and transferred it to the other. The husband admitted that he had contact with sex workers and both wife and husband had never traveled outside the country. This indicates that the husband might have acquired the virus from sex workers and that this rare strain is already circulating in the country. Detecting unusual isolates is important to determine the true diversity of HIV strains in the country. Monitoring of such strains will help in identifying transmission patterns and possible interventions to prevent the spread of HIV infection. PMID- 20929348 TI - Diversity of HIV type 1 long terminal repeat (LTR) sequences following mother-to child transmission in North India. AB - We genetically characterized the extent of variation in HIV-1 LTR sequences from 11 mother-to-child transmission (MTCT) pairs from HIV-1-infected individuals from North India. Nine pairs were found to be infected with subtype C virus whereas two pairs were infected with subtype B virus. They harbored the characteristic three and two NF-kappaB sites, respectively. The analysis of intrasubtype divergence between B and C revealed greater diversity with subtype B LTR sequences than subtype C (p < 0.005). Significant evolutionary divergence of subtype C and subtype B was found in NFAT-III (p < 0.000001), NFAT-II (p < 0.0001), and USF (p < 0.005) transcription factor binding sites (TFBS). NF-kappaB I, Sp I and II, Ets-I, AP-I and II, and TATA Box TFBS were highly conserved in both the subtypes. An alternate secondary structure of Tar was detected in the VT5 sample due to the point mutation from G to C (position +21) and T to C (position +38). PMID- 20929349 TI - Frequency of primary resistance to antiretroviral drugs and genetic variability of HIV-1 among infected pregnant women recently diagnosed in Luanda-Angola. AB - The determination of the prevalence of primary resistance to antiretroviral therapy in different places of the world is of extreme importance in molecular epidemiology monitoring, and it can guide the initial patient therapy in a given geographical area. The frequency of drug resistance mutations (DRM) and the genetic variability of HIV-1 isolates from newly diagnosed HIV-infected pregnant women attending the antenatal clinics of the Lucrecia Paim and Augusto N'Gangula maternities, Luanda-Angola, were determined. Thirty five out of 57 samples (61.4%) were sequenced and one mutation associated with resistance to nucleoside reverse transcriptase inhibitors was detected. Additionally, two mutations associated with resistance to non-nucleoside reverse transcriptase inhibitors were also detected. No primary mutations associated with protease inhibitors (PI) were found. Subtypes A1, C, D, F1, G, H, CRF 13, CRF 37, and other mosaics were detected. PMID- 20929350 TI - Genotypic characterization of HIV type 1 in Jamaica. AB - This study seeks to analyze nearly full-length viral genomes for distinct genetic characteristics that are unique to local or regional strains and to identify regions that have high variability or are highly conserved. Nearly full length sequences of seven HIV-1 samples were obtained to ascertain the circulating subtype diversity in the HIV-1 epidemic in Jamaica as well as conduct detailed sequence analysis. The phylogenetic analysis of the seven sequences showed all the sequences clustering with HIV-1 pure B subtype references. The predicted amino acid sequenced in the V3 loop for the Jamaican samples showed that six samples contained the characteristic conserved tetrapeptide motif GPGR. One occurrence in isolate 09JM.PF09WX displayed a GQGP tetrameric motif similar to that found in a Korean B strain. All seven isolates (100%) were R5 viruses for preferential cofactor usage. These samples were collected from individuals who had tested positive for 1-5 years and were drug naive. The results suggested that the viruses were isolated from patients in the nonprogressive stage of disease. These are early stages in the assessment and the patient should be monitored to predict the progression of the disease and when HAART should begin. PMID- 20929351 TI - Seroprevalence and molecular epidemiology of HTLV-1 isolates from HIV-1 co infected women in Feira de Santana, Bahia, Brazil. AB - HTLV-1/HIV-1 co-infection is associated with severe clinical manifestations, marked immunodeficiency, and opportunistic pathogenic infections, as well as risk behavior. Salvador, the capital of the State of Bahia, Brazil, has the highest HTLV-1 prevalence (1.74%) found in Brazil. Few studies exist which describe this co-infection found in Salvador and its surrounding areas, much less investigate how these viruses circulate or assess the relationship between them. To describe the epidemiological and molecular features of HTLV in HIV co-infected women. To investigate the prevalence of HTLV/HIV co-infection in surrounding areas, as well as the molecular epidemiology of HTLV, a cross sectional study was carried out involving 107 women infected with HIV-1 from the STD/HIV/AIDS Reference Center located in the neighboring City of Feira de Santana. Patient samples were submitted to ELISA, and HTLV infection was confirmed using Western Blot and Polymerase Chain Reaction (PCR). Phylogenetic analysis using Neighbor-Joining (NJ) and Maximum Likelihood (ML) was performed on HTLV LTR sequences in order to gain further insights about molecular epidemiology and the origins of this virus in Bahia. Four out of five reactive samples were confirmed to be infected with HTLV-1, and one with HTLV-2. The seroprevalence of HTLV among HIV-1 co-infected women was 4.7%. Phylogenetic analysis of the LTR region from four HTLV-1 sequences showed that all isolates were clustered into the main Latin American group within the Transcontinental subgroup of the Cosmopolitan subtype. The HTLV 2 sequence was classified as the HTLV-2c subtype. It was also observed that four HTLV/HIV-1 co-infected women exhibited risk behavior with two having parenteral exposure, while another two were sex workers. This article describes the characteristics of co-infected patients. This co-infection is known to be severe and further studies should be conducted to confirm the suggestion that HTLV-1 is spreading from Salvador to surrounding areas. PMID- 20929352 TI - Measles in the United States during the postelimination era. AB - BACKGROUND: Measles affected entire birth cohorts in the prevaccine era but was declared eliminated in the United States in 2000 because of a successful measles vaccination program. METHODS: We reviewed US surveillance data on confirmed measles cases reported to the Centers for Disease Control and Prevention and data on national measles-mumps-rubella (MMR) vaccination coverage during postelimination years 2001-2008. RESULTS: During 2001-2008, a total of 557 confirmed cases of measles (annual median no. of cases, 56) and 38 outbreaks (annual median no. of outbreaks, 4) were reported in the United States; 232 (42%) of the cases were imported from 44 countries, including European countries. Among case-patients who were US residents, the highest incidences of measles were among infants 6-11 months of age and children 12-15 months of age (3.5 and 2.6 cases/1 million person-years, respectively). From 2001 through 2008, national 1-dose MMR vaccine coverage among children 19-35 months of age ranged from 91% to 93%. From 2001 through 2008, a total of 285 US-resident case-patients (65%) were considered to have preventable measles (ie, the patients were eligible for vaccination but unvaccinated). During 2004-2008, a total of 68% of vaccine-eligible US-resident case-patients claimed exemptions for personal beliefs. CONCLUSIONS: The United States maintained measles elimination from 2001 through 2008 because of sustained high vaccination coverage. Challenges to maintaining elimination include large outbreaks of measles in highly traveled developed countries, frequent international travel, and clusters of US residents who remain unvaccinated because of personal belief exemptions. PMID- 20929353 TI - A novel histological grading scheme for placental malaria applied in areas of high and low malaria transmission. AB - BACKGROUND: Plasmodium falciparum-infected erythrocytes sequester in the placenta and elicit an inflammatory response that is harmful to both fetus and mother. Histologic measurements during placental malaria might provide surrogate end points for interventional trials, but existing histologic schemes capture limited complexity and are not consistently used among study sites. METHODS: Using frozen section histologic evaluation in Tanzania (high-transmission area), we established a novel grading scheme to separately quantify inflammation and pigment deposition during placental malaria (n = 102). To generalize this method, formalin-fixed, paraffin-embedded placental samples from Karen women in Thailand (low-transmission area) were selected from among women with documented antenatal parasitemia who were near term (n = 18). RESULTS: In the Tanzanian cohort, the inflammation and pigment-deposition scores were independently associated with birth weight, and the inflammation score was associated with chemokine levels. In the smaller cohort from Thailand, both inflammation and pigment scores were associated with birth weight, and the pigment score had an inverse trend with the number of antenatal clinic visits. CONCLUSIONS: This semiquantitative pathological grading scheme is simple to implement and captures information that is associated with outcomes in Asia and Africa; therefore, it should facilitate the comparison and standardization of results among clinical trials across areas of differing endemicity. PMID- 20929354 TI - A 2009 varicella outbreak in a Connecticut residential facility for adults with intellectual disability. AB - We investigated a varicella outbreak in a residential facility for adults with intellectual disabilities. A case of varicella was defined as a generalized maculopapular rash that developed in a facility resident or employee. Immunoglobulin M testing was conducted on serologic samples, and polymerase chain reaction testing was performed on environmental and skin lesion samples. Eleven cases were identified among 70 residents and 2 among ~145 staff. An unrecognized case of herpes zoster was the likely source. Case patients first entered any residential facility at a younger age than non-case residents (9.5 vs 15.0 years; P < .01). Varicella zoster virus DNA was detected 2 months after the outbreak in environmental samples obtained from case patients' residences. This outbreak exemplifies the potential for at-risk pockets of varicella-susceptible adults, especially among those who have lived in residential facilities from a young age. Evidence of immunity should be verified for all adults and healthcare staff in similar residential settings. PMID- 20929355 TI - Human haploid cells differentiated from meiotic competent clonal germ cell lines that originated from embryonic stem cells. AB - Early germ-like cells (GLCs) derived from human embryonic stem cells (hESCs) have presented new opportunities to study germ cell differentiation in vitro. However, differentiation conditions that facilitate the formation of haploid cells from the derived GLCs have eluded the field. The inability to propagate GLCs in culture is a further limitation, resulting in inconsistent rederivations of GLCs from hESCs with relatively few GLCs in these heterogeneous populations. Here we found in vitro conditions that enrich for DDX4/POU5F1+ GLCs (~60%) and that has enabled continual propagation for >50 passages without loss of phenotype. Clonal isolation of single GLCs from these mixed cultures generated 3 GLC (>90% DDX4/POU5F1+) and 2 hESC (<0.1% DDX4+) lines that could be continually expanded without loss of phenotype. Differentiation of clonal GLC lines in serum resulted in expression of postmeiotic markers and >11% were haploid, ~5-fold higher than previous studies. The robust clonal meiotic competent and incompetent GLC lines will be used to understand the factors controlling human germ cell meiosis and postmeiotic maturation. PMID- 20929356 TI - Transfusion-transmitted malaria in countries where malaria is endemic: a review of the literature from sub-Saharan Africa. AB - Although international policies recommend that blood for transfusion should be screened for transfusion-transmitted infections, malaria screening is not performed in most malaria-endemic countries in sub-Saharan Africa. Our literature review identified 17 relevant studies from the period 1980-2009 and indicated that the median prevalence of malaria among 33,029 blood donors was 10.2% (range, 0.7% in Kenya to 55.0% in Nigeria). Malaria screening methods, including microscopy (used in 16 of 17 studies), are either insensitive or impractical for donor screening in resource-poor countries. Even if a suitable screening method were available, rejection of malaria-positive donors would jeopardize the blood supply. Only 1 study established the prevalence of parasitemia among transfusion recipients. This review highlights the need for more evidence about the clinical impact of transfusion-transmitted malaria to justify the policy of screening for blood for malaria in areas of endemicity and for a critical analysis of the feasibility of implementing such a policy and its effect on blood supply. PMID- 20929358 TI - Maximizing infection prevention in the next decade: defining the unacceptable. AB - An important role of public health agencies is to define the unacceptable. This concept has particular relevance for healthcare-associated infections. Evidence indicates that, with focused efforts, these once-formidable infections can be greatly reduced in number, leading to a 'new normal' for healthcare-associated infections as rare, unacceptable events. PMID- 20929357 TI - Malaria and transfusion: a neglected subject coming back to the forefront. PMID- 20929359 TI - Infection prevention research in Europe: recent advances and future priorities. AB - During the past 2 decades, Europe has made substantial progress in the prevention and control of hospital-acquired infections and antimicrobial resistance (e.g., through multicenter trials, international surveillance networks, and hand hygiene initiatives). This short overview highlights recent advances and future priorities in infection prevention research, including methodological challenges to be addressed. PMID- 20929360 TI - Implementation science: how to jump-start infection prevention. AB - Implementing evidence‐based infection prevention practices is challenging. Implementation science, which is the study of methods promoting the uptake of evidence into practice, addresses the gap between theory and practice. Just as healthcare epidemiology has emerged as a paradigm for patient safety, infection prevention may serve as a clinical model for implementation researchers. PMID- 20929361 TI - The past, present, and future of healthcare-associated infection prevention in pediatrics: multidrug-resistant organisms. AB - Multidrug resistant organisms (MDROs) and healthcare‐associated infections (HAIs) are associated with increased lengths of hospital stay, increased costs, and increased mortality. We explore the scope of MDRO HAIs in children, current MDRO HAI prevention practices and data to support these practices, and we propose research topics targeting MDRO HAI prevention in children. PMID- 20929362 TI - The past, present, and future of healthcare-associated infection prevention in pediatrics: viral respiratory infections. AB - Viral respiratory infections pose a significant challenge to pediatric infection prevention programs. We explore issues regarding the prevention of viral respiratory infections by discussing transmission of influenza A virus, isolation of infected patients, and hospital programs for influenza vaccination. PMID- 20929363 TI - The past, present, and future of healthcare-associated infection prevention in pediatrics: catheter-associated bloodstream infections. AB - Central line–associated bloodstream infections cause morbidity and mortality in children. We explore the evidence for prevention of central line–associated bloodstream infections in children, assess current practices, and propose research topics to improve prevention strategies. PMID- 20929364 TI - Global epidemiology of Clostridium difficile infection in 2010. AB - The past decade has been characterized by an epidemic of Clostridium difficile infection in North America and Europe that threatens to extend to the rest of the world. The epidemic is due in part to the emergence of a previously rare and now more lethal C. difficile strain variously named group BI, ribotype 027, and North American pulsed‐field gel electrophoresis type 1. PMID- 20929365 TI - Detection of Clostridium difficile infection. AB - There has been a recent surge of interest in Clostridium difficile infection, which reflects an impressive increase in the number and severity of these infections. This review addresses some of the newer methods for detection of C. difficile infection at the bedside and in the laboratory. Particularly important are the new rapid diagnostic tests that detect toxigenic C. difficile using polymerase chain reaction and the combination tests that, either simultaneously or sequentially, screen for C. difficile and test for toxins A and B. It is expected that these new testing methods will largely supplant the enzyme immunoassays for toxins, which are used by most laboratories, departments, and divisions. The present goal is to combine clinical, laboratory, and animal research related to C. difficile that reflects issues that are considered to be major contemporary challenges. Among this work is the pursuit of studies of immune mechanisms to better control this disease. PMID- 20929367 TI - Critical gaps in knowledge of the epidemiology and pathophysiology of healthcare associated infections. AB - The past decade has witnessed an intense interest in healthcare‐associated infections as well as increases in legislation and reporting requirements aimed at decreasing the number of these costly infections. In the next decade, healthcare epidemiology must address major gaps in understanding of the epidemiology and pathogenesis of healthcare‐associated infections and in knowledge of the efficacy of interventions for healthcare‐associated infections and the efficacy in implementing such interventions. PMID- 20929366 TI - Prevention of healthcare-associated Clostridium difficile infection: what works? AB - Prevention of Clostridium difficile infection has become extremely important because of increases in its incidence and severity. Unfortunately, efforts at C. difficile infection prevention are hampered by lack of data to support optimal prevention methods, especially for endemic C. difficile infection. Studies are needed to define the optimal prevention practices and to investigate novel prevention methods. PMID- 20929368 TI - Prevention of methicillin-resistant Staphylococcus aureus infection: is Europe winning the fight? AB - Methicillin‐resistant Staphylococcus aureus (MRSA) is a common cause of disease across Europe, except for Scandinavian countries and the Netherlands. Recently, MRSA incidence has decreased in many European countries following national interventions, including structural and regulatory changes in health care, promotion of hand hygiene, antibiotic stewardship, and targeted screening, isolation, and decolonization of hospitalized carriers of MRSA. PMID- 20929369 TI - Immunotherapies for Staphylococcus aureus: current challenges and future prospects. AB - Development of an effective vaccine against Staphylococcus aureus would provide great potential public health benefit. We present a brief overview of the current knowledge in this field, with emphasis on present challenges and lessons learned, together with a summary of vaccines and immunoglobulin preparations currently under investigation. PMID- 20929370 TI - Methicillin-resistant Staphylococcus aureus and the media. AB - How the media communicate and how the scientific community influences the media are important factors to consider in the public health response to emerging pathogens, including methicillin-resistant Staphylococcus aureus. Social representation theory suggests that the media link "the threatening" to commonplace "anchor representations" which can serve to educate or to create fear. PMID- 20929371 TI - Current epidemiology of multidrug-resistant gram-negative bacilli in the United States. AB - Gram‐negative bacilli are an important cause of infection in healthcare and community settings. Antimicrobial resistance, including resistance to multiple antimicrobial classes, is an ongoing problem among gram‐negative bacilli. This synopsis reviews the incidence of multidrug resistance among gram‐negative bacilli in the United States and describes emerging issues in their epidemiology. PMID- 20929372 TI - The antibiotic development pipeline for multidrug-resistant gram-negative bacilli: current and future landscapes. AB - Development of antibiotics to treat infections caused by multidrug‐resistant gram‐negative bacilli has lagged significantly behind development of antibiotics to treat infections with gram‐positive pathogens. Although a few promising drugs have entered early clinical development, more must be done to preserve the utility of currently available antibiotics and to ensure a pipeline of efficacious, safe antibacterials. PMID- 20929373 TI - The burden of healthcare-associated infections in European long-term care facilities. AB - Since 2006, several projects have been initiated in Europe to describe the distribution and characteristics of infection control programs in long‐term care facilities and to quantify the burden of infections, antimicrobial resistance, and antimicrobial use in long‐term care facilities. This article summarizes the results and activities that are underway. PMID- 20929374 TI - Pandemic preparedness: implementation of infection prevention emergency plans. AB - The H1N1 influenza pandemic provided a real‐world test of hospital disaster plans. Challenges to hospitals included inconsistent use of isolation precautions; changing and conflicting guidelines; lack of available supplies, including N95 respirators and medications; and overwhelming amounts of information that required sifting. Further research is needed regarding pandemic planning. PMID- 20929375 TI - Opportunists and opportunities: the 2010 SHEA Lecture. AB - My experience as a hospital epidemiologist at the National Institutes of Health Clinical Center has underscored the importance of aggressively managing infection with opportunistic pathogens and of taking advantage of opportunities as they arise (most often as crises). I review selected aspects of my career and use these as examples of the opportunists and opportunities now facing healthcare epidemiology. PMID- 20929376 TI - Progress and challenges in implementing the research on ESKAPE pathogens. AB - The ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) are responsible for a substantial percentage of nosocomial infections in the modern hospital and represent the vast majority of isolates whose resistance to antimicrobial agents presents serious therapeutic dilemmas for physicians. Over the years, improved molecular biology techniques have led to detailed information about individual resistance mechanisms in all these pathogens. However, there remains a lack of compelling data on the interplay between resistance mechanisms and between the bacteria themselves. In addition, data on the impact of clinical interventions to decrease the prevalence of resistance are also lacking. The difficulty in identifying novel antimicrobial agents with reliable activity against these pathogens argues for an augmentation of research in the basic and population science of resistance, as well as careful studies to identify optimal strategies for infection control and antimicrobial use. PMID- 20929377 TI - Influential outbreaks of healthcare-associated infections in the past decade. AB - Outbreaks of healthcare‐associated infections have long played a critical role in both identification and mitigation of emerging challenges in health care. This article describes some of the most influential outbreaks of healthcare‐associated infections in the past decade that serve as excellent illustrations of this point. PMID- 20929378 TI - Healthcare epidemiology: past and future. AB - Healthcare epidemiology is a robust and adaptable profession with the noble mission of protecting patients and their healthcare providers from infectious diseases and other threats. Change is the constant that links the successes of our field in each decade of our history. Although it is not possible to predict what specific challenges the next decade will bring, the themes of the Sixth Decennial International Conference in 2020 are likely to reflect the most prominent drivers of change that are affecting our profession, including globalization, sustainability, and consumer empowerment. PMID- 20929381 TI - Prevention of nosocomial pneumonia in the intensive care unit: beyond the use of bundles. AB - BACKGROUND: The occurrence of nosocomial pneumonia (NP) in the hospital setting is especially problematic, as it is associated with a greater risk of in-hospital death, longer stays on mechanical ventilation and in the intensive care unit (ICU), more need for tracheostomy, and significantly higher medical care costs. METHODS: Review of the pertinent English-language literature. RESULTS: The adverse effect of NP on healthcare outcomes has increased pressure on clinicians and hospital systems to prevent this infection. This brief review provides an overview of the current approaches to the prevention of NP, focusing primarily on ventilator-associated pneumonia (VAP). CONCLUSION: Clinicians working in ICUs should consider the following recommendations: (1) Develop a VAP prevention bundle based on evidence-based guidelines; (2) monitor the rates of VAP prior to and during implementation of the program; (3) make adjustments according to VAP occurrence; and (4) integrate VAP prevention with other quality improvement programs. PMID- 20929380 TI - Pilot controlled trial of mindfulness meditation and education for dementia caregivers. AB - OBJECTIVES: The objectives of this study were to evaluate whether a mindfulness meditation intervention may be effective in caregivers of close relatives with dementia and to help refine the protocol for future larger trials. DESIGN: The design was a pilot randomized trial to evaluate the effectiveness of a mindfulness meditation intervention adapted from the Mindfulness-Based Cognitive Therapy program in relation to two comparison groups: an education class based on Powerful Tools for Caregivers serving as an active control group and a respite only group serving as a pragmatic control. SETTINGS/LOCATION: This study was conducted at the Oregon Health & Science University, Portland, OR. SUBJECTS: The subjects were community-dwelling caregivers aged 45-85 years of close relatives with dementia. INTERVENTIONS: The two active interventions lasted 7 weeks, and consisted of one 90-minute session per week along with at-home implementation of knowledge learned. The respite-only condition provided the same duration of respite care that was needed for the active interventions. OUTCOME MEASURES: Subjects were assessed prior to randomization and again after completing classes at 8 weeks. The primary outcome measure was a self-rated measure of caregiver stress, the Revised Memory and Behavior Problems Checklist (RMBPC). Secondary outcome measures included mood, fatigue, self-efficacy, mindfulness, salivary cortisols, cytokines, and cognitive function. We also evaluated self-rated stress in the subjects' own environment, expectancy of improvement, and credibility of the interventions. RESULTS: There were 31 caregivers randomized and 28 completers. There was a significant effect on RMBPC by group covarying for baseline RMBPC, with both active interventions showing improvement compared with the respite-only group. Most of the secondary outcome measures were not significantly affected by the interventions. There was an intervention effect on the caregiver self-efficacy measure and on cognitive measures. Although mindfulness was not impacted by the intervention, there were significant correlations between mindfulness and self-rated mood and stress scores. CONCLUSIONS: Both mindfulness and education interventions decreased the self rated caregiver stress compared to the respite-only control. PMID- 20929382 TI - Transperitoneal laparoendoscopic single-site pyeloplasty: initial experiences. AB - PURPOSE: The purpose of this study was to present our initial clinical experience with laparoendoscopic single-site surgery (LESS) for ureteropelvic junction (UPJ) obstruction. PATIENTS AND METHODS: Between May and October 2009, 14 consecutive patients underwent LESS-pyeloplasty (LESS-P) by the same surgeon at our institution. All patients underwent single port transperitoneal Anderson-Hynes laparoscopic dismembered pyeloplasty using the single incision laparoendoscopic surgery port, inserted through a transumbilical incision. Ultrasonography, intravenous urography (IVU) or diuretic renal scan was performed at the third month and semiannually thereafter. Patients were examined clinically every 3 to 6 months, depending on the symptoms. Radiographic success was defined as improvement of hydronephrosis with a patent UPJ on IVU, or improved drainage on diuretic renal scan. RESULTS: Anterior crossing vessels, high insertion, and severe adhesion were found in seven (50%), five (35.7%), and two (14.3%) cases, respectively. The mean operating-room time, which includes cystoscopy with retrograde ureteral catheterization and open-end stent placement, was 204.5 minutes (range 160-300 min), and the mean estimated blood loss, including urine, was 102 mL (range 80-170 mL). Mean hospital stay was 2 days (range 1-3 d). Wound infection occurred in one patient. The mean follow-up period was 6.2 months (range, 3-8 mos). The success rate was 100%. CONCLUSION: With the advent of the single port and laparoscopic instrument technology, the LESS-P, as minimally invasive surgery, would take the place of the standard laparoscopic pyeloplasty, and it may be a new choice for the management of UPJ obstruction. PMID- 20929384 TI - HIV transmission patterns among The Netherlands, Suriname, and The Netherlands Antilles: a molecular epidemiological study. AB - We aimed to study patterns of HIV transmission among Suriname, The Netherlands Antilles, and The Netherlands. Fragments of env, gag, and pol genes of 55 HIV infected Surinamese, Antillean, and Dutch heterosexuals living in The Netherlands and 72 HIV-infected heterosexuals living in Suriname and the Antilles were amplified and sequenced. We included 145 pol sequences of HIV-infected Surinamese, Antillean, and Dutch heterosexuals living in The Netherlands from an observational cohort. All sequences were phylogenetically analyzed by neighbor joining. Additionally, HIV-1 mobility among ethnic groups was estimated. A phylogenetic tree of all pol sequences showed two Surinamese and three Antillean clusters of related strains, but no clustering between ethnic groups. Clusters included sequences of individuals living in Suriname and the Antilles as well as those who have migrated to The Netherlands. Similar clustering patterns were observed in env and gag. Analysis of HIV mobility among ethnic groups showed significantly lower migration between groups than expected under the hypothesis of panmixis, apart from higher HIV migration between Antilleans in The Netherlands and all other groups. Our study shows that HIV transmission mainly occurs within the ethnic group. This suggests that cultural factors could have a larger impact on HIV mobility than geographic distance. PMID- 20929385 TI - Molecular analysis of human T cell lymphotropic virus type 1 and 2 (HTLV-1/2) seroindeterminate blood donors from Northeast Iran: evidence of proviral tax, env, and gag sequences. AB - Human T cell lymphotropic virus type 1 and 2 (HTLV-1/2) Western blot indeterminate results are a problem for blood banks in endemic areas. To determine the prevalence of HTLV-1/2 infection among indeterminate donors, we analyzed 130 cases from Mashhad, an HTLV-1/2 endemic area in Northeast Iran. The most frequent Western blot bands were GD21 alone (37.2%) followed by rgp46-2 alone (32.1%). We further tested 40 available DNA samples of these cases by PCR for viral sequences, tax, gag, and pol, and found five cases (12.5%) to be positive for two or three HTLV-1 genes. There were no significant age, sex, and blood group differences between PCR-positive and PCR-negative cases. Among PCR positive individuals, the most prevalent Western blot bands were variable combinations of rgp46-1, GD21, and gp21. The mean of the optical density (OD) of the enzyme-linked immunosorbent assay (ELISA) test was significantly higher in PCR-positive individuals. The frequency of the rgp46-1 band was also significantly higher in PCR-positive cases compared to PCR-negative ones. In conclusion, the majority of HTLV-indeterminate donors lack the HTLV provirus and therefore are not considered infected. However, in some cases with higher ODs in the ELISA test and seroreactivity to env proteins, rgp46-1 and GD21 in particular may be indicative of infection and need further evaluation by molecular methods. PMID- 20929386 TI - Photodynamic therapy as consolidation treatment for primary cutaneous adenoid cystic carcinoma: a case report. AB - OBJECTIVE: The purpose of this case report was to evaluate the efficacy of photodynamic therapy (PDT) for a patient with primary cutaneous adenoid cystic carcinoma (PCACC). MATERIALS AND METHODS: A 53-year-old female patient presented with a lesion at the pre-auricular area. After performing a local resection along a margin of 0.5 cm beyond the surrounding tissue, PCACC was clearly revealed based on the histological features and the exclusion of differentiation of other metastasis in the skin. The patient was then treated repetitively with 5 aminolevulinic acid (ALA)-PDT. After the final PDT treatment, the control pathological biopsy at the same location demonstrated no tumor cell in the specimen. RESULTS: The 40-month follow-up diagnosis showed no evidence of recurrence or metastasis observed on the treated area. CONCLUSION: ALA-PDT was a safe and effective therapy for obtaining good cosmetic results and reducing recurrence in this case report. PMID- 20929387 TI - Effects from exposure to dental amalgam on systemic mercury levels in patients and dental school students. AB - OBJECTIVES: The purpose of this study was to evaluate the systemic mercury levels in urine of patients and dental school students caused by exposure to silver amalgam. It is currently believed that occupational exposure shows the highest rate of potential for poisoning by mercury. Dental professionals are part of that quota, introducing concerns regarding the handling of dental amalgam. MATERIALS AND METHODS: The study comprised 40 urine samples from 20 subjects, which were divided into four sampling groups: G1A (n = 10) composed of students before their first occupational contact; G1B (n = 10) composed of the same G1 students after their first contact; G2A (n = 10) composed of patients who needed to have dental restorations before amalgam removal; and G2B (n = 10) composed of patients who needed to have dental restoration after amalgam removal. Cold-vapor atomic absorption spectrophotometry (CVAAS) was used as the evaluation method. RESULTS: A statistically significant difference was found among dependent groups 1 and 2 (p = 0.0038), whereas mercury levels increased considerably after the first occupational contact of all subjects. CONCLUSIONS: Occupational exposure to dental amalgam poses a potential risk of increasing systemic mercury levels, although urine mercury levels in all the sample participants were below the limits of biologic tolerance. PMID- 20929388 TI - Raman spectroscopy validation of DIAGNOdent-assisted fluorescence readings on tibial fractures treated with laser phototherapy, BMPs, guided bone regeneration, and miniplates. AB - OBJECTIVES: We aimed to assess through Raman spectroscopy and fluorescence the levels of calcium hydroxyapatite (CHA) and lipids and proteins in complete fractures treated with internal rigid fixation (IRF) treated or not with laser phototherapy (LPT) and associated or not with bone morphogenetic proteins (BMPs) and guided bone regeneration (GBR). BACKGROUND: Fractures have different etiologies and treatments and may be associated with bone losses. LPT has been shown to improve bone healing. METHODS: Tibial fractures were created on 15 animals and divided into five groups. LPT started immediately after surgery, repeated at 48-h intervals. Animal death occurred after 30 days. RESULTS: Raman spectroscopy and fluorescence were performed at the surface. Fluorescence data of group IRF + LPT + Biomaterial showed similar readings to those of the group IRF no bone loss. Significant differences were seen between groups IRF + LPT + Biomaterial and IRF + LPT; IRF + LPT + Biomaterial; and IRF + Biomaterial; and between IRF + LPT + Biomaterial and IRF. CH groups of lipids and proteins readings showed decreased levels of organic components in subjects treated with the association of LPT, biomaterial, and GBR. Pearson correlation showed that fluorescence readings of both CHA and CH groups of lipids and proteins correlated negatively with the Raman data. CONCLUSIONS: The use of both methods indicates that the use of the biomaterials associated with infrared LPT resulted in a more advanced and higher quality of bone repair in fractures treated with miniplates and that the DIAGNOdent may be used to perform optical biopsy on bone. PMID- 20929389 TI - A feasible procedure in dental practice: the treatment of oral dysplastic hyperkeratotic lesions of the oral cavity with the CO2 laser. AB - OBJECTIVES: The aim of this work is to report some cases of surgical removal of hyperkeratotic lesions of the oral cavity with the CO(2) laser. BACKGROUND: Hyperkeratosis is an abnormal thickening of the stratum corneum caused by increased deposition of keratin, and its histopathologic features show wide variations. These changes are significant because they determine different biologic behavior. Several techniques are used to treat these lesions, including scalpel incision, electrosurgery, cryosurgery, photodynamic therapy, and some drugs. The use of surgical lasers has been proposed as an effective way of treating such lesions safely. The CO(2) laser is the most used laser on the oral cavity because of its affinity for water and high absorption by the oral mucosa. Several benefits of the use of the CO(2) laser are reported in the literature in regard to surgical procedures carried out on the oral cavity. PATIENTS AND METHODS: All patients had histopathologic diagnosis of hyperkeratosis and mild epithelial dysplasia and were routinely prepared for surgery under local anesthesia. The surgical procedures were carried out by using a CO(2) laser (Sharplan 20 C; Laser Industries, Tel Aviv, Israel, lambda10,600 nm, phi~2 mm, CW/RSP). The beam was focused to delimit each lesion, and then lesions were excised, and the removed specimens were sent for histopathology. At the end of the surgery, the beam was used in a defocused manner to promote better hemostasis. Neither sutures nor dressings were used after the surgery. No medication but mouthwashes was prescribed to all patients in the postoperative period. CONCLUSIONS: The use of the CO(2) laser does not reduce the risk of relapses of the lesion, but it is an easy-to-use technique and results in both a quick surgical procedure and trouble-free postoperative period and may be safely used in dental practice. PMID- 20929390 TI - Effect of nucleoside and nucleotide analog reverse transcriptase inhibitors on cell-mediated immune functions. AB - Nucleoside analog reverse transcriptase inhibitors (NRTIs) constitute the most commonly used drugs in antiretroviral therapy. NRTIs differ with respect to their host cell toxicity. We compared the in vitro effect of zidovudine (AZT; 2 MUg/ml), lamivudine (3TC; 5 MUg/ml), stavudine (d4T; 1 MUg/ml), and tenofovir (TFV; 1 MUg/ml) on Candida cell-mediated immunity (CMI) of peripheral blood mononuclear cells (PBMCs). The concentrations of the active derivative AZT triphosphate were 4-fold higher in Candida-stimulated compared with unstimulated PBMCs (p = 0.01), but those of 3TC-triphosphate and TFV-diphosphate did not differ significantly. AZT treatment decreased proliferation of unstimulated and Candida-stimulated PBMCs and IFN-gamma ELISPOT responses; 3TC decreased proliferation of unstimulated PBMCs only; d4T and TFV decreased proliferation of Candida-stimulated PBMCs only. AZT, but not the other NRTIs, increased unstimulated PBMC apoptosis measured by caspase 3 activity. All NRTIs increased annexin-V-measured apoptosis of Candida-stimulated PBMCs. The effect of d4T on apoptosis of Candida-stimulated PBMCs strongly correlated with its inhibitory effect on mitochondrial DNA synthesis (r2 = 0.94; p = 0.007). The other NRTIs did not significantly decrease the mitochondrial:nuclear DNA ratios in Candida stimulated or unstimulated cultures, suggesting that other mechanisms mediated their effect on apoptosis and CMI. In conclusion, AZT had the most pronounced inhibitory effect on CMI. Further studies are warranted to determine the clinical significance of this observation. PMID- 20929391 TI - Short communication: contribution of the immunovirological state and traditional cardiovascular risk factors to low HDL-cholesterol in HIV patients. AB - The prevalence of low HDL-C levels in an HIV population and its related factors was investigated. We undertook a multicenter, cross-sectional study of all HIV patients on regular follow-up in five hospitals (Southern Spain). A physical examination and fasting laboratory analysis were performed and a questionnaire about cardiovascular risk factors was provided. One thousand and seventy-two patients were included, 43.8% of whom had low HDL-C levels. The prevalence of low HDL-C was higher among patients diagnosed with AIDS, those not on antiretroviral therapy, those with a detectable HIV viral load, those with CD4 cell counts <=350 cells/MUl, smokers, and those with hypertriglyceridemia. For patients on antiretroviral therapy, the prevalence of low HDL-C was higher for those on protease inhibitors than those taking nonnucleoside reverse transcriptase inhibitors. In the multivariate analysis, low HDL-C levels were associated with tobacco use (OR 1.37, 95% CI 1.04-1.8; p = 0.04), hypertriglyceridemia (OR 2.94, 95% CI 2.2-3.8; p < 0.00001), CD4 cells count <=350 cells/MUl (OR 1.74, 95% CI 1.2-2.3; p < 0.0001), and a detectable HIV viral load (OR 1.85, 95% CI 1.3-2.5; p < 0.0001). The immunological and virological conditions, in addition to traditional cardiovascular risk factors such as tobacco use and hypertriglyceridemia, affect HDL-C levels in HIV-infected patients. For patients on antiretroviral therapy, the use of protease inhibitors is associated with a higher probability of low levels of HDL-C. Although it is not clear if the higher HDL-C levels associated with antiretroviral use are surrogates for decreased cardiovascular disease risk, this may be another reason to start antiretroviral therapy earlier. PMID- 20929392 TI - Short communication: no evidence of HTLV-3 and HTLV-4 infection in New York State subjects at risk for retroviral infection. AB - The primate T-cell lymphoma viruses (PTLV) are divided into six distinct species. The biology and epidemiology of PTLV-1 and PTLV-2 are very well understood. However, that of PTLV-3, 4, 5, and 6 are not. Recently, in Cameroon, three and one humans were shown to be infected with HTLV-3 and HTLV-4, respectively. We undertook a study to ascertain whether any of these two retroviruses were present in the peripheral blood mononuclear cell DNA of New York State subjects deemed at risk for PTLV infection. Samples were analyzed by PTLV-3 and PTLV-4 specific PCR assays from the following human and simian subject types: African-American medical clinic patients; HTLV EIA+, WB indeterminate blood donors; intravenous drug users; patients with leukemia, lymphoma, myelopathy, polymyositis, or AIDS; and African chimpanzees. None of the 1200 subjects was positive for HTLV-3 or 4. The data indicate that, at the time of sample collection, no evidence exists for the dissemination of HTLV-3 or 4 to New York State. Continued epidemiological studies are warranted to explore the worldwide prevalence rates and dissemination patterns of HTLV-3 and 4 infections, and their possible disease associations. PMID- 20929394 TI - Estimating the extent of underreporting of mortality among HIV-infected individuals in Rio de Janeiro, Brazil. AB - Non-HIV-related causes of death have been increasing after the introduction of highly active antiretroviral therapy. Underlying and contributing causes of death were assessed in respect to the presence/absence of HIV/AIDS among HIV infected/AIDS patients in Rio de Janeiro, Brazil. Demographic variables (age, gender, ethnicity, and schooling) and CD4 cell counts closest to death were assessed through logistic regression models comparing those who did not have with those who had HIV/AIDS mentioned on the death certificate. The linkage with the two cohorts identified 1249 records, of which 370 (29.6%) did not have HIV/AIDS listed on any field of the death certificate [77 (20.8%) attributed to undefined and 72 (19.5%) to external causes]. After excluding external causes, 25.3% still did not have HIV/AIDS listed on the death certificate. Multiple logistic regression analysis showed that age >40 years (OR = 2.09; 95%CI = 1.49-2.93; p < 0.001) and CD4 cell count closest to the date of death (OR = 1.15; 95% CI = 1.07 1.23; p < 0.001 for 100 cell increase) were associated with an increased probability of not having HIV/AIDS mentioned on the death certificate, when external causes were excluded. Mortality among HIV-infected individuals is underreported in the Rio de Janeiro Mortality Registry, particularly among older individuals and those with higher CD4 counts. Physicians should be aware of the changing patterns of mortality among HIV individuals, and public health officials should regularly perform linkages between all-cause mortality and available HIV infected patients databases, such as AIDS registries and large cohort studies. PMID- 20929393 TI - Outcomes of patients on dual-boosted PI regimens: experience of the Swiss HIV cohort study. AB - Dual-boosted protease inhibitors (DBPI) are an option for salvage therapy for HIV 1 resistant patients. Patients receiving a DBPI in the Swiss HIV Cohort Study between January1996 and March 2007 were studied. Outcomes of interest were viral suppression at 24 weeks. 295 patients (72.5%) were on DBPI for over 6 months. The median duration was 2.2 years. Of 287 patients who had HIV-RNA >400 copies/ml at the start of the regimen, 184 (64.1%) were ever suppressed while on DBPI and 156 (54.4%) were suppressed within 24 weeks. The median time to suppression was 101 days (95% confidence interval 90-125 days). The median number of past regimens was 6 (IQR, 3-8). The main reasons for discontinuing the regimen were patient's wish (48.3%), treatment failure (22.5%), and toxicity (15.8%). Acquisition of HIV through intravenous drug use and the use of lopinavir in combination with saquinavir or atazanavir were associated with an increased likelihood of suppression within 6 months. Patients on DBPI are heavily treatment experienced. Viral suppression within 6 months was achieved in more than half of the patients. There may be a place for DBPI regimens in settings where more expensive alternates are not available. PMID- 20929395 TI - Tenofovir (TDF)-selected or abacavir (ABC)-selected low-frequency HIV type 1 subpopulations during failure with persistent viremia as detected by ultradeep pyrosequencing. AB - Detection of drug resistance is critical for determining antiretroviral treatment options. Ultradeep pyrosequencing (UDPS; 454 Life Sciences) is capable of detecting virus variant subpopulations with much greater sensitivity than population sequencing, which typically has a detection limit around 20%. UDPS of the HIV-1 reverse transcriptase (RT) (amino acids 56-120) was performed to detect the key mutations K65R and L74V associated with tenofovir and abacavir use. Plasma specimens from subjects with persistent rebound viremia following suppression on tenofovir (n = 8) or abacavir (n = 9)-based therapy were studied. Samples from a subject treated with zidovudine/lamivudine/efavirenz with a similar loss of virologic response served as a control. HIV-1 plasma RNA was >=3.68 log(10) copies/ml at all time points sequenced. The median number of UDPS sequences analyzed/time point was 33,246. Among the eight tenofovir-treated subjects, three showed high-frequency (>20%) RT K65R at the time of failure, whereas one showed low-frequency (<20%) L74V; no low-frequency K65R was detected in these subjects. Among the nine abacavir-treated subjects, three showed low frequency K65R; no L74V was detected in these patients. No K65R or L74V was detected in the samples from the control subject. At failure, other RT mutations were detected, including low-frequency NNRTI-resistant species detected at >=1 time point in nine subjects; the key NNRTI mutation K103N, however, was always observed at >20% frequency. Although UDPS is useful in the detection of low frequency subpopulations with transmitted resistance in antiviral-naive patients, it may have less utility in treatment-experienced patients with persistent viremia on therapy. PMID- 20929396 TI - Microsporidiosis and Cryptosporidiosis in HIV/AIDS Patients in St. Petersburg, Russia: Serological identification of microsporidia and Cryptosporidium parvum in sera samples from HIV/AIDS patients. AB - To determine seroprevalence of the opportunistic organisms Cryptosporidium parvum and microsporidia (Encephalitozoon cuniculi, E. intestinalis, E. hellem, and Enterocytozoon bieneusi) in Russian HIV/AIDS patients, we evaluated 46 sera from HIV/AIDS patients from the S.P. Botkin Clinical Infectious Diseases Hospital, St. Petersburg, Russia. Five (10.9%) sera were seropositive for E. cuniculi and 19 (41.3%) were positive for C. parvum by ELISA. By IFAT, 6 (13.0%) sera were seropositive for E. bieneusi, 4 (8.7%) for E. intestinalis, and 9 (19.6%) for E. hellem. This study is the first report to estimate the prevalence of infection with Cryptosporidium and microsporidia among Russian HIV/AIDS patients. PMID- 20929397 TI - Cervicovaginal shedding of HIV type 1 is related to genital tract inflammation independent of changes in vaginal microbiota. AB - We examined the relationship of proinflammatory vaginal cytokines and secretory leukocyte protease inhibitor (SLPI) with genital HIV-1 shedding after controlling for genital coinfections. Fifty-seven HIV-1-infected women in Seattle, WA (n = 38) and Rochester, NY (n = 19) were followed every 3-4 months for a total of 391 visits. At each visit, plasma and cervicovaginal lavage (CVL) were tested for HIV 1 RNA using qPCR. Vaginal samples were tested for bacterial vaginosis, yeast, hydrogen peroxide-producing Lactobacillus colonization, Trichomonas vaginalis, Neisseria gonorrhea, Chlamydia trachomatis, CMV, and HSV shedding. CVL interleukins (IL)-1beta, IL-6, IL-8, and SLPI were measured using ELISA. Linear regression with generalized estimating equations examined effects of cytokine concentrations on CVL HIV-1 RNA, adjusted for plasma HIV RNA, and measured coinfections. CVL IL-1beta and IL-8 were significantly associated with CVL HIV-1 RNA. This persisted after adjusting for plasma HIV-1 RNA. Higher levels of IL 1beta were associated with higher concentrations of HIV-1 RNA in CVL (beta = 0.25, 95% CI 0.09, 0.42), as were higher levels of IL-8 (beta = 0.34, 95% CI 0.17, 0.50). Adjusting for the presence of the coinfections described, this relationship was attenuated for IL-1beta (beta = 0.16; 95% CI -0.01, 0.33) but still significant for IL-8 (beta = 0.29; 95% CI 0.13, 0.45). The proinflammatory cytokines IL-1beta and IL-8 are associated with higher cervicovaginal HIV-1 RNA concentrations, even after controlling for plasma viral load and vaginal microbial cofactors. This association suggests that there may be additional, noninfectious causes of inflammation that increase cervicovaginal HIV-1 shedding. PMID- 20929398 TI - Enhanced DNA binding of 9-omega-amino alkyl ether analogs from the plant alkaloid berberine. AB - To understand the structure-activity relationship of isoquinoline alkaloids, absorption, fluorescence, circular dichroism, and thermodynamics were employed to study the interaction of five C-9-omega-amino alkyl ether analogs from the plant alkaloid berberine with double-stranded calf thymus DNA. The C-9 derivatization resulted in dramatic enhancements in the fluorescence emission of these compounds. The most remarkable changes in the spectral and binding properties were in the BC4 and BC5 derivatives. Interactions of these analogs, which have an additional recognition motif with DNA, were evaluated through different spectroscopic and calorimetric titration experiments. The analogs remarkably enhanced the DNA binding affinity and the same was directly dependent on the alkyl chain length. The analog with six alkyl chains enhanced the DNA binding affinity by about 33 times compared with berberine. The binding became more entropically driven with increasing chain length. These results may be of potential use in the design of berberine derivatives and understanding of the structure-activity relationship for improved therapeutic applications. PMID- 20929399 TI - Lysyl oxidase 473 G>A polymorphism and breast cancer susceptibility in Chinese Han population. AB - Lysyl oxidase (LOX) is an extracellular enzyme critical for the cross-linking of collagens and elastin. The LOX gene has also been shown to inhibit the transforming activity of Ras oncogene signaling. Recently, a single-nucleotide polymorphism (SNP) of LOX G473A (rs1800449) has been demonstrated to be associated with increased risk of breast cancer in African American women. In this hospital-based case-control study, the association of LOX polymorphism with breast cancer susceptibility in Chinese Han population was investigated. In total, 238 female patients with breast cancer and 234 age-matched healthy controls recruited were genotyped. We found a significant difference in the frequency of the LOX G473A genotype between the breast cancer and control groups. Individuals with GA genotype showed a 2.79-fold (95% confidence interval = 1.87 4.16) increased risk of breast cancer compared with subjects carrying GG genotype (p < 0.001). Further statistical analysis revealed that this polymorphism was an independent parameter with regard to other variables that are significantly associated with breast cancer, that is, age, menopausal status, estrogen exposure interval, expression status of estrogen receptor, and progesterone receptor. These findings suggest that the LOX 473 GA genotype is independently associated with increased risk of breast cancer in Chinese female population. PMID- 20929400 TI - New priorities in the robotic exploration of Mars: the case for in situ search for extant life. PMID- 20929402 TI - Stridor due to an unsuspected parathyroid cyst in a thirty-two-year-old woman with goiter. PMID- 20929403 TI - Tumor size and age predict the risk of malignancy in Hurthle cell neoplasm of the thyroid and can therefore guide the extent of initial thyroid surgery. AB - BACKGROUND: The majority of patients having a diagnosis of Hurthle cell neoplasm (HCN) on fine-needle aspiration (FNA) of a thyroid nodule have a diagnostic thyroid lobectomy to make the final diagnosis. If the nodule is malignant, they require a completion thyroidectomy. The objective of this study was to devise a simple clinical scheme capable of predicting malignancy in patients with cytologic diagnosis of HCN and, therefore, guide the extent of initial thyroid surgery. METHODS: A total of 57 patients who underwent thyroid surgery after an FNA diagnosis of HCN were retrospectively studied. The patients were examined for clinical features, preoperative imaging studies, and pathology reports. The risk of malignancy was calculated using a multiple logistic regression model. RESULTS: The overall rate of malignancy in patients with HCN was 46% (26/57). The predictors of malignancy based on multiple logistic regression analysis were tumor size >1.5 cm (odds ratio [95% confidence interval] = 8.0 [1.9-33.4]) and patient age >45 years (odds ratio [95% confidence interval] = 2.3 [0.6-8.6]). In patients with nodules larger than 1.5 cm, the predicted probability of malignancy was greater in patients over 45 years than in younger patients (65% for >45 years vs. 44% for <=45 years). In patients with a nodule 1.5 cm or less, the probability of malignancy was relatively low and not significantly different between the two age categories (18% for >45 years vs. 10% for <=45 years). CONCLUSIONS: This study suggests that tumor size and age can be integrated into decision making for patients with an FNA diagnosis of HCN to facilitate patient selection for surgical referral and, particularly, to determine in which patients a thyroidectomy rather than a lobectomy should be the initial surgery. PMID- 20929404 TI - Metastatic colon carcinoma in a preexisting thyroid nodule. PMID- 20929405 TI - Percutaneous laser ablation of cold benign thyroid nodules: a 3-year follow-up study in 122 patients. AB - BACKGROUND: Percutaneous laser ablation (PLA) is a proposed therapeutic procedure for the management of benign thyroid nodules. However, long-term results are unknown. The aim of this study was to evaluate retrospectively the safety and effects of PLA treatment in patients with benign nonfunctioning thyroid nodules in a 3-year follow-up. METHODS: One hundred twenty-two patients (95 women and 27 men; age 52.2 +/- 12.3 years) with benign cold thyroid solitary nodules or a dominant nodule within a normo-functioning multinodular goiter (volume range: 2.6 86.4 mL) underwent thermal Nd:YAG laser ablation of thyroid nodular tissue by 1-4 optical fibers positioned into the tissue by 21-gauge needles under ultrasound real-time assistance. The setting was an interventional suite and outpatient endocrine clinics in a community hospital in Italy. Nodule volume, ablation volume, side effects, serum thyroid-stimulating hormone (TSH), free triiodothyronine, free thyroxine (fT4), thyroglobulin (Tg), anti-Tg, anti thyroperoxidase antibodies, symptoms, and cosmetic signs were recorded. RESULTS: Data are mean +/- standard deviation. Energy delivered was 8522 +/- 5365 J with an output power of 3.1 +/- 0.5 W. Three years after PLA, nodule volume decreased from 23.1 +/- 21.3 to 12.5 +/- 18.8 mL (-47.8% +/- 33.1% of initial volume, p <= 0.001). At day 1, TSH and fT4 values significantly changed (time 0 vs. day 1: TSH = 1.16 +/- 1.06 vs. 0.62 +/- 0.81 MUU/mL, p <= 0.001; fT4 = 11.68 +/- 1.88 vs. 13.20 +/- 3.32 pg/mL, p <= 0.01) and normalized within 1 month. No change in free triiodothyronine, thyroperoxidase antibodies, and Tg antibodies values was observed. Symptoms improved in 89 patients (73.0%), were unchanged in 28 (22.9%), and worsened in 5 (4.1%). Cosmetic signs improved in 87 patients (71.3%), were unchanged in 29 (23.8%), and worsened in 6 (4.9%). In 11 patients (9%), nodules regrew above baseline. Two patients (1.6%) experienced delayed (12-24 hours) laryngeal dysfunction with vocal cord motility recovery after 6-10 weeks. Two patients (1.6%) became hypothyroid and two patients (1.6%) hyperthyroid after PLA. CONCLUSIONS: After 3 years, the PLA technique achieved shrinkage of about 50% of the initial volume in a wide size range of benign cold thyroid nodules, with an improvement in local symptoms and signs. Side effects and failures were few although not negligible. PLA may be a new option for the management of benign cold thyroid nodules. Long-term controlled studies are required to establish the eligibility of patients for routine PLA. PMID- 20929406 TI - Thyroid dysfunction caused by second-generation tyrosine kinase inhibitors in Philadelphia chromosome-positive chronic myeloid leukemia. AB - BACKGROUND: Thyroid dysfunction is a well-known adverse effect of first generation tyrosine kinase inhibitors (TKIs), like sunitinib. The aim of this study was to investigate the effect of second-generation TKIs on thyroid function. METHODS: We retrospectively assessed the effect of the first-generation TKI imatinib and the second-generation TKI nilotinib and dasatinib on thyroid function tests in 73 Philadelphia chromosome-positive (Ph-positive) chronic myeloid leukemia patients. RESULTS: Overall, 33 of 73 (45%) had one or more thyroid function test abnormalities during follow-up. Hypothyroidism or hyperthyroidism were found in 18 of 73 (25%) and 21 of 73 (29%) cases after a median of 6 and 22 weeks, respectively. In most patients (29 of 39, 74%) thyroid dysfunction was transient without clinical symptoms. Therapy of hypo /hyperthyroidism was required in three patients. Thyroid dysfunction never resulted in the discontinuation of TKI therapy. Under treatment with imatinib, nilotinib, and dasatinib, thyroid abnormalities were detected in 25%, 55%, and 70%, respectively. Four of 55 patients (7%) treated with nilotinib had evidence for an autoimmune thyroiditis (antibody positive in 3 of 4 patients) with an episode of hyperthyroidism preceding hypothyroidism. CONCLUSIONS: Thyroid dysfunction is a common adverse event with second-generation TKI therapy in patients with Ph-positive chronic myeloid leukemia. Although the mechanism is still unclear, the high frequency of thyroid abnormalities, including autoimmune thyroiditis, warrants regular and long-term monitoring of thyroid function in these patients. PMID- 20929408 TI - Healthcare utilization in women diagnosed with hypoactive sexual desire disorder: interim baseline results from the HSDD Registry for Women. AB - OBJECTIVE: To investigate treatment seeking and utilization of women diagnosed with hypoactive sexual desire disorder (HSDD) in the clinical setting. METHODS: We used interim baseline data from the ongoing HSDD Registry for Women (n = 724, enrolled at 27 clinical sites across the United States in 2008-2009). The recent diagnosis of generalized, acquired HSDD was confirmed by clinician's administration of the validated diagnostic Decreased Sexual Desire Screener. Treatment-seeking behavior was categorized as formal (discussion with a healthcare provider or use of off-label prescription treatment for HSDD) or informal/none (over-the-counter products, anonymous media, or no help seeking). RESULTS: Over half (n = 386, 53%) of these women with clinically diagnosed HSDD had not sought formal healthcare for their decreased sexual desire problem. Among formal healthcare seekers, 36% remained untreated, whereas 64% received some form of treatment. The most common treatments reported were nonprescription lubricants or arousal creams (36%) and off-label prescription medications (20%). Women were more likely to have sought formal help if they were married/cohabiting, were postmenopausal, had private health insurance, had > 5 current prescription medications, had depression symptoms, had a longer duration of sexual desire problems, or reported that the partner relationship or sense of femininity/sexual self was threatened by HSDD. CONCLUSIONS: In these women with HSDD, less than half had sought healthcare, but of those who had sought healthcare, almost two thirds received some form of treatment. Regardless of treatment-seeking behavior, most women had a strong desire to "feel like a normal person again" regarding sexuality, which was the most common motivating factor for treatment seeking. PMID- 20929407 TI - Subclinical nonautoimmune hyperthyroidism in a family segregates with a thyrotropin receptor mutation with weakly increased constitutive activity. AB - BACKGROUND: Subclinical hyperthyroidism is usually associated with Graves' disease or toxic nodular goiter. Here we report a family with hereditary subclinical hyperthyroidism caused by a constitutively activating germline mutation of the thyrotropin receptor (TSHR) gene. METHODS: The proband was a 64 year-old Japanese woman who presented with a thyroid nodule and was found to be euthyroid with a suppressed serum TSH. The nodule was not hot. Although antibodies to thyroid peroxidase and thyroglobulin antibodies were present, TSHR antibodies were not detected by TSH-binding inhibition or by bioassay. Two of her middle-aged sons, but not her daughter, also had subclinical hyperthyroidism without TSHR antibodies. Without therapy, the clinical condition of the affected individuals remained unchanged over 3 years without development of overt hyperthyroidism. RESULTS: A novel heterozygous TSHR point mutation causing a glutamic acid to lysine substitution at codon 575 (E575K) in the second extracellular loop was detected in the three family members with subclinical hyperthyroidism, but was absent in her one daughter with normal thyroid function. In vitro functional studies of the E575K TSHR mutation demonstrated a weak, but significant, increase in constitutive activation of the cAMP pathway. CONCLUSION: Although hereditary nonautoimmune overt hyperthyroidism is very rare, TSHR activating mutations as a cause of subclinical hyperthyroidism may be more common and should be considered in the differential diagnosis, especially if familial. PMID- 20929409 TI - Application of ice cold irrigation during vascular pedicle control of robot assisted radical prostatectomy: EnSeal instrument cooling to reduce collateral thermal tissue damage. AB - BACKGROUND AND PURPOSE: Energy-based hemostasis of the prostatic vascular pedicles (PVP) during robot-assisted radical prostatectomy (RARP) may cause collateral thermal injury to adjacent neural tissue and has been shown to negatively impact sexual function recovery. The unique engineering design of the EnSeal((r)) (Ethicon, Cincinnati, OH) has been demonstrated to limit collateral thermal tissue damage to <1.0 mm. Use of tissue and instrument cooling before and during device activation may potentially further reduce thermal spread. As such, we sought to evaluate the collateral tissue effects of EnSeal with or without cold saline irrigation (CSI) during PVP control. PATIENTS AND METHODS: The EnSeal Trio device was used for PVP control in 20 consecutive men undergoing bilateral, non-nerve-sparing RARP. Ipsilateral vascular pedicles were randomly selected to EnSeal plus CSI (<4 degrees C) application to the tissue before and during device activation or EnSeal alone. The primary end point was the distance of thermal injury from the inked margin using both hematoxylin and eosin (H&E) and terminal transferase uridyl nick end-labeling (TUNEL) apoptosis staining. A mean of three measurements was taken for each pedicle. Pathologic analysis was performed by a single, blinded uropathologist. RESULTS: Mean distance of thermal injury from the inked margin using H&E staining was 0.31 mm (range 0.15-0.40 mm) and 0.98 mm (range 0.7-1.2 mm) for the EnSeal plus CSI and EnSeal alone, respectively (P < 0.0001). TUNEL staining also demonstrated lateral tissue damage of 0.39 mm (range 0.2-0.5 mm) and 1.12 mm (range 0.9-1.3 mm), respectively (P < 0.001). No complications related to hemostasis or postoperative bleeding were observed in the study. CONCLUSIONS: The hemostatic properties of EnSeal work effectively when submerged in CSI. Adjacent thermal tissue damage is significantly minimized with the addition of CSI. This may have a beneficial impact on nerve preservation and sexual function outcomes after RARP. PMID- 20929410 TI - Conversion from pure laparoscopy to hand-assisted laparoscopy for control of bleeding in renal surgery: an attractive alternative to open conversion. AB - PURPOSE: To assess the safety and efficacy of conversion from pure laparoscopy to hand-assisted laparoscopy to control mild-to-moderate bleeding during renal surgery. PATIENTS AND METHODS: Between August 2006 and August 2008, we performed 94 laparoscopic nephrectomies (44 partial and 50 radical). A total of three radical nephrectomies were converted from pure to hand-assisted laparoscopy for control of bleeding. The first patient was a 44-year-old man with a 14-cm cystic renal mass. The second patient was a 52-year-old man with a 3.8-cm renal mass, and the third patient was an 86-year-old woman with a 7-cm renal mass. RESULTS: In all three procedures, the indication for conversion was bleeding from the renal hilum or the kidney parenchyma during dissection. The bleeding was difficult to control using pure laparoscopy, and therefore a hand port was inserted. Time for conversion and placement of the hand port averaged less than 7 minutes. Total estimated blood loss for the three patients was 800 mL, 2000 mL, and 650 mL, respectively. One patient needed a transfusion with three units of packed red blood cells. The postoperative course was uneventful in all patients, except for one patient who had prolonged ileus and stayed in the hospital for 6 days. The remaining two patients were discharged on postoperative days 2 and 3. CONCLUSIONS: Conversion from pure to hand-assisted laparoscopy for bleeding control is feasible and effective. It adds minimal morbidity while maximizing cosmesis, and it should be considered as an alternative to open conversion in cases of mild-to-moderate bleeding. PMID- 20929411 TI - Right-sided transperitoneal hand-assisted laparoscopic donor nephrectomy: is there an issue with the renal vessels? AB - OBJECTIVE: Short right renal vessels might complicate kidney transplantation, thus causing traction and difficulties during anastomosis. Single-center prospective comparison of right- and left-sided transperitoneal hand-assisted laparoscopic donor nephrectomy (HALDN) is presented. PATIENTS AND METHODS: Eighty two living kidney donors underwent HALDN between 2003 and 2008. Right-sided HALDN was performed in 46 living kidney donors. The operative technique of right-sided HALDN was modified to obtain the maximum length of right renal vessels. Outcome data in donors including quality of life as well as graft outcome in recipients were prospectively collected. RESULTS: All procedures were laparoscopically completed with no conversion. Mean operative time was 127 minutes (vs. 138 minutes in left HALDN, p = 0.08). The mean warm ischemia time was 41 seconds (vs. 39 seconds in left HALDN, p = 0.23). There was no renal artery or vein thrombosis in any of the grafts. Mean blood loss was 81 mL (vs. 92 mL in left HALDN, p = 0.09). Hospital discharge was on an average of 3.6 days postoperative. Delayed graft function occurred in two recipients: one in the left group and the other in the right group. One-year graft survival rate was 95% in the left group versus 96.9% in the right group (p = 0.08). Further, no statistically significant difference in serum levels of creatinine was seen between the groups 1 year after the transplantation. CONCLUSIONS: Right HALDN is technically safe and feasible and results in convenient extension of right renal vessels to full length with no increased incidence of vascular thrombosis. PMID- 20929412 TI - Percutaneous cystolithotripsy using self-retaining laparoscopic trocar for management of large bladder stones. AB - BACKGROUND AND PURPOSE: Percutaneous endoscopic management of bladder stones is not new. The ideal technique to establish suprapubic access, however, is still not justified. In this study, we used the 12-mm self-retaining laparoscopic trocar for access during management of large bladder stones. PATIENTS AND METHODS: With the patient in the lithotomy position, a 12-mm self-retaining laparoscopic trocar was inserted in a full bladder under cystoscopic visual control. A 28F nephroscope was used to fragment the stone using ultrasound and pneumoclast lithotriptors. After stone treatment, the trocar was left in place, and transurethral resection of the prostate (TURP) was completed when indicated. Both urethral and suprapubic catheters were left at the end of the procedure. Clinical examination, urinalysis, and ultrasonographic examination were routinely performed during follow-up visits. RESULTS: The mean stone size was 4.07 + 0.20 cm (2.8-6 cm). The average time for stone fragmentation was 32.78 + 2.16 minutes (range 8-53 min). A concomitant TURP was performed in 12 patients. The mean hospital stay was 2.56 + 0.15 days (range 1-4 days). All patients were stone free, and a total of six complications occurred, including extravasation, one patient; hematuria, two patients; and fever, three patients. All were treated conservatively. The mean follow-up time was 15.65 + 1.51 months (range 9-36 mos). CONCLUSIONS: Suprapubic percutaneous cystolithotripsy is a safe, minimally invasive alternative for management of large bladder stones. The use of a self retaining trocar facilitates access and allows use of a large nephroscope for rapid fragmentation and extraction of the stone fragments. The presence of specific trocars for suprapubic access into the urinary bladder will encourage more transvesical end-laparoscopic procedures. PMID- 20929413 TI - Recent FDA approvals and changes. PMID- 20929414 TI - First automated molecular test for assessing HBV treatment approved. PMID- 20929415 TI - Association of physical activity level and stroke outcomes in men and women: a meta-analysis. AB - OBJECTIVE: The protective effect of physical activity (PA) on risk of stroke remains controversial as a result of lack of insight into the sources of heterogeneity between studies. We performed a comprehensive meta-analysis of studies to (1) quantify the association between PA level and risk of stroke outcomes and (2) test the hypothesis that the association of PA level with stroke outcomes will be similar between men and women. The outcome measures are stroke incidence, stroke mortality, or both. METHODS: Cohort studies were identified by searching MEDLINE and EMBASE (from 1986 to 2005) and meta-analysis conducted according to meta-analysis of Observational Studies in Epidemiology (MOOSE) group recommendations. Data were reported as pooled relative risk (RR) and 95% confidence intervals (CI) using random-effects models to assess the association of stroke outcomes with PA level. Heterogeneity was investigated, and sensitivity analysis was performed. Stratified analysis by gender was performed. RESULTS: Of 992 articles, 13 satisfied all eligibility criteria and were studied. Compared with low PA, moderate PA caused an 11% reduction in risk of stroke outcome (RR = 0.89, 95% CI 0.86-0.93, p < 0.01) and high PA a 19% reduction (RR = 0.81, CI 0.77 0.84, p < 0.01). Among the men, results showed a 12% reduction in risk associated with moderate PA (RR = 0.88, CI 0.82-0.94, p < 0.01) and 19% reduction for high PA (RR = 0.81, CI 0.75-0.87, p < 0.01). Among the women, results showed a 24% reduction in risk for high PA (RR = 0.76, CI 0.64-.89, p < 0.01). There was, however, no significant risk reduction associated with a moderate PA level in women. CONCLUSIONS: Increased PA level appears beneficial in reduction of risk of stroke and related outcomes. However, higher levels of PA may be required in women to achieve as significant a risk reduction as in men. An exercise regimen tailored to women to improve related physiological mechanisms will likely be beneficial. PMID- 20929416 TI - "something we'd rather not talk about": findings from CDC exploratory research on sexually transmitted disease communication with girls and women. AB - BACKGROUND: Chlamydia is a leading cause of pelvic inflammatory disease (PID), which can lead to ectopic pregnancy, chronic pelvic pain, and infertility. Annual Chlamydia screening is recommended for all sexually active women aged <= 25 years, yet only about 40% of eligible women are screened each year in the United States. To promote Chlamydia screening for the prevention of infertility, the Centers for Disease Control and Prevention (CDC) is developing direct-to-consumer efforts for sexually active young women and key influencers. To inform this effort, CDC sought to explore girls'/women's understandings of sexually transmitted disease (STD) and Chlamydia testing and STD communications and information sources. METHODS: Two waves of one-on-one interviews (n = 125) were conducted in 10 metropolitan areas with African American, Caucasian, and Latina females, aged 15-25 years. RESULTS: Most participants were not knowledgeable about Chlamydia or its screening; their discussions about it suggested low levels of perceived susceptibility or relevance to Chlamydia and screening. STDs are rarely discussed in home or social settings or with partners or close friends; yet young women may turn to interpersonal sources if concerned about an STD. Providers are the primary and preferred source of STD information for girls and women, although missed opportunities for engaging young women in STD/sexual health discussions were identified in clinical and other settings. CONCLUSIONS: Providers, family members, friends, and partners may serve as important intermediaries for reaching young women and encouraging STD/Chlamydia screening. Resources are identified that could be leveraged and/or developed to facilitate such interactions. PMID- 20929418 TI - Congenital anomalies in newborns of women with type 1 diabetes: nationwide population-based study in Norway, 1999-2004. AB - OBJECTIVE: To estimate the risk of congenital anomalies in offspring of women with type 1 diabetes in Norway during recent years. DESIGN: Nationwide population based study using the Medical Birth Registry of Norway and the Norwegian type 1 Diabetes Registry. SETTING: All birth clinics in Norway. PARTICIPANTS: All births in Norway during 1999-2004 (N = 350,961), of which 1,583 were births by a mother registered with pregestational type 1 diabetes. MAIN OUTCOME MEASURE: Congenital anomalies, excluding minor anomalies according to the EUROCAT system. RESULTS: Anomalies were registered in 5.7% of offspring of women with type 1 diabetes, and in 2.9% among the background population (odds ratio 2.1, 95% CI: 1.7-2.6). Cardiovascular anomalies were registered in 3.2% in the diabetes group and 0.94% in the background population (odds ratio 3.5, 95% CI: 2.7-4.7). Results were similar when restricted to women identified with type 1 diabetes through the Diabetes Registry. CONCLUSIONS: Women in Norway with type 1 diabetes experience a significantly higher risk of congenital anomalies in their babies compared with the background population. PMID- 20929419 TI - Functioning and disability in persons with low back pain. AB - PURPOSE: To demonstrate the feasibility and usefulness of using the ICF framework to investigate functioning and disability in persons with low back pain (LBP) and to study the extent to which the capacity level for various domains of functioning is different from the performance level. METHOD: The study was part of the MHADIE project and reports baseline data collected in 118 patients with LBP using the ICF Core Sets for LBP. The statistical analysis consisted of descriptive statistics. RESULTS: A total of 76 ICF categories reached the 20% threshold: 20 body functions, 8 structures, 28 activities and participation and 20 environmental factors. The percentage of persons having problems in capacity is always higher than the percentage of persons having problems in performance. CONCLUSIONS: This study shows the potential value of the capacity-performance distinction, both as a conceptual and practical tool that can enhance clinical treatment and intervention planning and as a method to capture the impact of the environment on the lived experience of people suffering from LBP. What is needed are longitudinal investigations that are able to identify and track the patterns that such conditions exhibit and further enhance the effectiveness of treatment strategies. PMID- 20929420 TI - Overtreatment of cruciate ligament injuries. PMID- 20929422 TI - Developing a tool for evaluating community-based rehabilitation in Uganda. AB - PURPOSE: The overall purpose of this study is to use the conceptual criteria of the 'Joint Position Statement (JPS)' (see http://www.ilo.org/public/english/employment/skills/download/jointpaper.pdf )on Community-based rehabilitation (CBR), together with the data collected from a CBR programme in Uganda (Tororo) to generate a prototype CBR evaluation tool. METHOD: A case study approach is used to examine the Tororo CBR programme. Project documentation was examined to generate base line data which was used to inform sampling for interviews and focus group discussions. These were conducted with a wide range of stakeholders. The interview and focus group data are recorded, translated, transcribed and imported into a computer-assisted analysis programme, NVivo. The data was analysed in two stages: (i) data led development of themes (ii) allocation of the generated themes to the conceptual structure of the 'JPS'. A third stage uses the data to generate an outcome measurement tool for evaluating CBR programmes. RESULTS: Fifty different themes were identified during the analysis and used to construct a questionnaire framed around the concepts of the 'JPS'. In addition, the questionnaire reflected the words and phrases used by participants. The outcome is a short and feasible tool for evaluating CBR programmes. CONCLUSION: The 'JPS' has been used as a framework for the analysis of qualitative data to generate the basis of a prototype evaluative questionnaire which can now be piloted, amended and then used for the evaluation of other CBR programmes. PMID- 20929423 TI - Successful endoscopic therapy of postoperative duodenal fistula by lipiodol injection: a new therapeutic approach. AB - Postoperative upper gastrointestinal fistulas or anastomotic leaks with peritonitis are rare but serious clinical conditions. Due to severe fluid and electrolyte imbalance and risk of development of sepsis implementation of efficient and timely management is crucial. Various endoscopic interventions have been performed to date for postoperative upper gastrointestinal fistulas. We herein describe a new therapeutical approach involving lipiodol injection, which we performed to treat a patient who had unsuccessfully undergone surgery for a posttraumatic duodenal fistula. The fistula was then successfully managed by endoscopic lipiodol injection. We present this case due to its interesting nature of a postsurgical duodenal fistula without evident fistula tract, and a successful therapy by a new approach, lipiodol injection. We conclude that this new method offers an option for patients with high operation risk or for those with failed surgery, and this new method may decrease morbidity, mortality and the time required for the closure of duodenal fistulas. PMID- 20929424 TI - Colonic perforation after stent placement for malignant colorectal obstruction- causes and contributing factors. AB - Self-expanding metal stents (SEMS) are used to manage malignant colorectal obstruction. Colonic perforation is the most worrisome complication from colonic stenting. We reviewed causes and contributing factors of perforation with colonic stent placement in patients with malignant colorectal obstruction. Articles from both English and foreign language publications were identified from Medline. Data were collected on causes, timing, treatment and mortality related to perforation. A total of 2287 patients from 82 articles were included in this analysis, which showed an overall perforation rate of 4.9%. Perforation rates for palliation and bridge to surgery (BTS) were not significantly different (4.8% vs. 5.4%, p = 0.66); over 80% occurred within 30 days of stent placement (half during or within one day of the procedure). The mortality rate related to perforation was 0.8% per stented patient, but the mortality of patients experiencing perforation was 16.2%. There was no significant difference (p = 0.78) in the mortality rates between the palliation and the BTS group and concomitant chemotherapy, steroids, and radiotherapy are risk factors of perforation. The overall perforation related mortality is far less than that of patients undergoing emergency surgery for bowel obstruction. PMID- 20929425 TI - The impact of consumer involvement on satisfaction with and use of assistive technology. AB - PURPOSE: This exploratory study examined the relationships between consumers' involvement in the pre-purchase decision-making process, their perceptions of feeling informed, and their degree of being satisfied with and use of assistive technology (AT). Does consumer information and participation in decision-making process lead to improved satisfaction and use of AT? METHOD: A link to an project specific web-based survey, sent to several online disability forums and independent living centres, resulted in a sample of 145 individuals with a range of disabilities, who used a range of AT and were geographically dispersed. RESULTS: There is a significant relationship between being feeling informed and being satisfied with an AT device (F(13,278) = 27.79, p = 0.000). Feeling that personal needs were not assessed led to lower satisfaction (beta = -0.15, p < 0.07), while feeling informed resulted from a number of different factors. Lack of consumer involvement in the pre-purchase decision-making process led to somewhat greater rates of abandonment in some categories of AT (some with small n's). CONCLUSIONS: Talking with other users, auditioning the device and searching the Internet are important ways for consumers to gather information. When consumers feel informed, they are more likely to be satisfied with the AT and retain it. PMID- 20929426 TI - Anti-inflammatory activity of ethylacetate fraction of Cliona celata. AB - We evaluated the ability of the ethylacetate fraction of marine sponge, Cliona celata (ECC), harvested from Korean seaside to regulate the expression of inducible nitric oxide synthase (iNOS) in lipopolysaccharide (LPS)-stimulated murine macrophage-like RAW264.7 cells. ECC dose-dependently inhibited both the expression of iNOS protein and mRNA, resulting in decreased production of nitric oxide (NO), with an IC(50) of 80.5 MUg/mL. To investigate action mechanism by which ECC inhibits NO production and iNOS expression, we examined the activation of IkappaB in LPS-stimulated RAW264.7 cells. ECC clearly inhibited translocation of nuclear factor-kappaB (NF-kappaB) p65 subunits from cytosol to nucleus, which correlated with its inhibitory effects on IkappaB-alpha phosphorylation and degradation. Furthermore, ECC potently suppressed both the reporter gene expression and DNA-binding activity of NF-kappaB, which was associated with decreased p65 protein levels in the nucleus. Here, we show for the first time that ECC inhibits NF-kappaB activation through the inhibition of IkappaB degradation. PMID- 20929428 TI - Paeoniflorin: a monomer from traditional Chinese medical herb ameliorates Schistosoma japonicum egg-induced hepatic fibrosis in mice. AB - Treatment of liver fibrosis associated with Schistosoma japonicum ova-induced granulomas remains a challenging proposition. There is a close relationship between high levels of interleukin-13 (IL-13) and the development of severe schistosome fibrosis. In contrast, IL-13 receptor (R) alpha2 has an effective role in attenuation of profibrosis. Several Chinese herbs have significant beneficial effects in liver disease. Accordingly, the purpose of the present study was to investigate the therapeutic effect of Paeoniflorin (PAE) on liver fibrosis. A mouse model for liver fibrosis was established, using infection with S. japonicum cercariae via the skin. Liver tissue was used to examine the effect of PAE on hydroxyproline, collagen I and III, and IL-13 and IL-13Ralpha2. The results showed that PAE has significant suppressive effect on the increase of both hepatic hydroxyproline and collagen I and III, which are the main components of extracellular matrix (ECM). Meanwhile, PAE not only inhibits IL-13 production, it also elevates IL-13Ralpha2 in PAE-pretreated groups compared with controls. These results suggested that PAE can improve liver fibrosis due to S. japonicum infection. The effect of PAE appears to depend on a decrease of IL-13 and an increase of IL-13Ralpha2. PMID- 20929429 TI - Effects and mechanisms of action of ionophorous antibiotics valinomycin and salinomycin-Na on Babesia gibsoni in vitro. AB - Valinomycin and salinomycin-Na, 2 ionophorous antibiotics, exhibited in vitro antibabesial activities against Babesia gibsoni that infected normal canine erythrocytes containing low potassium (LK) and high sodium concentrations, i.e., LK erythrocytes, which completely lack Na,K-ATPase activity. The level of parasitemia of B. gibsoni was significantly decreased when the parasites were incubated in culture medium containing either 10(-1) ng/ml valinomycin or 10(2) ng/ml salinomycin-Na for 24 hr. Four-hour incubation in the culture medium containing 5 MUg/ml salinomycin-Na led to the destruction of most parasites. In contrast, when the parasites infected canine erythrocytes containing high potassium (HK) and low sodium concentrations, i.e., HK erythrocytes, the in vitro antibabesial activities of both ionophorous antibiotics seemed to be weakened, apparently due to the protection by the host cells. Therefore, differential influences of ionophorous antibiotics on LK and HK erythrocytes were observed. In LK erythrocytes, the intracellular concentrations of potassium, sodium, and adenosine triphosphate (ATP) were not modified, and hemolysis was not observed after incubation in the medium containing each ionophorous antibiotic. These results suggested that these ionophorous antibiotics did not affect cells without Na,K-ATPase, and directly affected B. gibsoni. In HK erythrocytes, the ionophorous antibiotics increased the intracellular sodium concentration, and decreased the intracellular potassium and ATP concentrations, causing obvious hemolysis. Additionally, the decrease of the intracellular ATP concentration and the hemolysis in HK erythrocytes caused by valinomycin disappeared when the activity of Na,K-ATPase was inhibited by ouabain. These results indicate that modification of the intracellular cation concentrations by the ionophorous antibiotics led to the activation of Na,K-ATPase and increased consumption of intracellular ATP, and that the depletion of intracellular ATP resulted in hemolysis in HK erythrocytes. Moreover, the antibabesial activity of valinomycin disappeared when B. gibsoni in LK erythrocytes were incubated in culture media containing high potassium concentrations. This showed that the intracellular cation concentration in the parasites was not modified in those media and would remain the same. PMID- 20929430 TI - A novel CYP2A26 identified in cynomolgus monkey liver metabolizes coumarin. AB - A novel cytochrome P450 (CYP), CYP2A26, was identified and characterized in cynomolgus monkey, one of the animal species used in preclinical studies. Deduced amino acid sequences of CYP2A26 cDNA showed high sequence identities (91-95%) with cynomolgus monkey CYP2A23 and CYP2A24, and human CYP2A6 and CYP2A13. Phylogenetic analysis showed that macaque CYP2As (CYP2A26, CYP2A23, and CYP2A24) were most closely clustered with human CYP2As, unlike CYP2As of dog, rat, and mouse (other species also used in drug metabolism). Quantitative polymerase chain reaction analysis showed that CYP2A26 mRNA, along with CYP2A23 and CYP2A24 mRNAs, was expressed predominantly in the liver, where CYP2A proteins were also detected by immunoblotting. Drug-metabolizing assays using the CYP2A26 protein heterologously expressed in Escherichia coli indicated that CYP2A26 catalyzed coumarin 7-hydroxylation with its apparent K(m) lower than that of CYP2A24, but similar to those of CYP2A6 and CYP2A23. These results suggest an evolutionary closeness and functional similarity of cynomolgus monkey CYP2A26 (together with CYP2A23 and CYP2A24) to human CYP2A6, and its functional role as a drug metabolizing enzyme in the liver. PMID- 20929431 TI - Reviewing radiographic images with patients: results of a trial on patient preferences, understanding, and satisfaction. AB - PURPOSE: To evaluate patient preferences, understanding, and satisfaction regarding visual review of radiographic images during counseling. PATIENTS AND METHODS: 101 urologic patients who presented for counseling where images impacted decision making were randomized into group A, shown their images, and group B, shown a diagram. Both completed a satisfaction survey blinded to the study's purpose. A second unblinded survey evaluated patient comprehension of and preferences regarding images. Comparison of intervention and control groups for differences in satisfaction and analysis of patient self-reported preferences and understanding regarding radiographic images was performed. RESULTS: Group A had higher satisfaction scores but did not reach statistical significance. Both groups reported comprehension of images (100%, 97.9%), improvement in understanding of their condition and treatment because of viewing images (98%, 95.8%), and felt images should be shown to all patients (92%, 89.6%). Multivariate analysis identified female sex to independently predict greater understanding of images and belief that all patients should be shown their images. CONCLUSIONS: Almost all patients reported comprehension of images, improvement in understanding because of review of images, and preference for being shown images. Female patients expressed greater understanding and preference for all patients to be shown their images. Review of radiographic images represents a potentially useful additional modality for patient counseling whose usefulness for improving satisfaction will need to be confirmed in further studies. PMID- 20929432 TI - All trans retinoic acid and cancer. AB - All-trans retinoic acid (ATRA) is an active metabolite of vitamin A under the family retinoid. Retinoids, through their cognate nuclear receptors, exert potent effects on cell growth, differentiation and apoptosis, and have significant promise for cancer therapy and chemoprevention. Differentiation therapy with ATRA has marked a major advance and become the first choice drug in the treatment of acute promyelocytic leukemia (APL). Conversions of 13-cis-retinoic acid and 9-cis retinoic acid to all-trans-retinoic acid is very rapid. Currently, two distinct families of retinoid responsive nuclear receptors have been identified and characterized: retinoic acid receptors (RARs) and retinoid receptors (RXRs), each of which include three isoforms, alpha,beta,and gamma. ATRA is being increasingly included in anti-tumour therapeutical schemes for the treatment of various tumoral diseases such as Kaposi's sarcoma, head and neck squamous cell carcinoma, ovarian carcinoma, bladder cancer, neuroblastoma and has shown antiangiogenic effects in several systems, inhibiting proliferation in vascular smooth muscle cells (VSMCs) and anti-inflammatory in rheumatoid arthritis. This review helps to understand in details about the ATRA and its role on cancer and it is predicted that modulating the activity of ATRA will soon provide novel prevention and treatment approaches for the cancer patients. PMID- 20929433 TI - Evaluation of second-look transurethral resection in restaging of patients with nonmuscle-invasive bladder cancer. AB - PURPOSE: Evaluation of second-look transurethral resection (TUR) in avoidance of staging errors, and determination of risk factors of upstaging in patients with nonmuscle invasive bladder cancer. PATIENTS AND METHODS: An analytic prospective cohort study included 91 patients with stage T(1) and T(a) bladder cancer. All patients underwent second-look TUR within 2 to 6 weeks after the initial resection. Histopathologic findings of the second TUR of bladder tumor (TURBT) were compared with those of the initial one. RESULTS: Specimens obtained during the second TURBT showed no tumor in 38 (41.7%) patients; 22 (24.2%) patients had residual cancer of the same stage, 9 (14.8%) patients of PT(1) had a lower stage, and 22 (24.2%) had a higher stage. Upstaging had changed treatment strategy in 22 (24.2%) cases. Appearance, size, grade, and stage of the tumor at the initial resection are all considered independent risk factors for upstaging detected at second-look TURBT. CONCLUSIONS: Second TURBT is a valuable procedure for accurate staging of nonmuscle-invasive bladder cancer. It changed the treatment strategy of a significant proportion of our patients. Second TURBT is indicated in T(1), high grade, large size (>3 cm), and nodular tumors because of the significant risk of detecting muscle-invasive disease. PMID- 20929434 TI - Epirubicin-encapsulated long-circulating thermosensitive liposome improves pharmacokinetics and antitumor therapeutic efficacy in animals. AB - In the present work, a long-circulating epirubicin hydrochloride (EPI)-containing thermosensitive liposome aiming at antitumor therapy, DPPC/MSPC/DSPG/DSPE mPEG(2000) (EPI-LTSL), was developed and evaluated. Nonthermosensitive and traditional liposomes, HSPC/cholesterol/DSPG/DSPE-mPEG(2000) (EPI-NTSL) and HSPC/cholesterol (EPI-LIP), were also prepared at the same time for comparison. Temperature-dependent EPI release from loaded liposomes in vitro was characterized by the fluorescence method. Different liposome preparations were administered in rats by intravenous injection at the same dosage of 12 mg.kg(-1). EPI and internal standard daunorubicin hydrochloride (DAU) were analyzed by high performance liquid chromatography and verified by LC tandem mass spectrometry. In the pharmacodynamics study, the EPI-LTSL was combined with local hyperthermia for target-specific delivery to the anesthetized and tumor-bearing mice. According to the in vitro results, more than 90% of loaded EPI was released from MSPC containing liposome (EPI-LTSL) within 4 minutes at 43 degrees C, while at 37 degrees C, less than 5% was released beyond 60 minutes. However, less than 5% of drug was released at 43 degrees C for the other two liposomes without MSPC (EPI NTSL and EPI-LIP). The results of the pharmacokinetics study in rats showed that not only the circulation time of EPI was prolonged significantly, but also the concentration in vivo was promoted for EPI-LTSL, compared to EPI-NTSL and EPI solution. The mean tumor inhibitory rate for EPI-LTSL, EPI-NTSL, and EPI-solution were 61.1, 39.6, and 43.1%, respectively. PMID- 20929435 TI - Improving quality of life in hypertension management using a fixed-dose combination of olmesartan and amlodipine in primary care. AB - OBJECTIVES: To assess quality of life (QoL) in unselected patients in primary care treated with a fixed-dose combination of olmesartan and amlodipine. Research design and methods. Multicenter, noninterventional, noncontrolled observational study in 8241 patients seen by 2187 physicians over 12 - 18 weeks. MAIN OUTCOME MEASURES: Changes in QoL were assessed by using the Short Form 12 (SF-12) questionnaire completed by 5434 patients (65.9%) at baseline and 4924 patients (59.8%) at the follow-up visit. RESULTS: Patients had a mean age of 62.8 +/- 11.8 years (48.1% female), mean blood pressure [BP] at baseline was 161.8 +/- 16.6/93.6 +/- 10.2 mmHg and 74.8% had at least one co-morbid risk factor or condition. All 12 items of the SF-12 improved over the observational period (p < 0.0001) as did the physical (46.8 vs 40.4; p < 0.0001) and mental summary scores (52.4 vs 47.5; p < 0.0001). Correlations of changes in systolic and diastolic BP, pulse pressure and heart rate with scores were significant, although weak (maximum -0.2055 for physical health and changes in systolic blood pressure). CONCLUSIONS: The fixed-dose combination of olmesartan and amlodipine significantly improves QoL in an unselected population of patients in primary care practice. This might translate into improved patient compliance and improved long-term antihypertensive efficacy. PMID- 20929436 TI - Food-borne parasites and the relevant therapeutic targets. PMID- 20929437 TI - Concerns and hopes for stem cell therapy in cardiology: focus on endothelial progenitor cells. AB - The crucial role played by the endothelium in cardiovascular disorders has been repetitively recognised. Endothelium injury has been implicated in atherosclerosis, thrombosis, hypertension and other cardiovascular diseases. Recently, however, research has undertaken a new avenue. As mature endothelial cells posses limited regenerative capacities, the interest has been switched to the circulating endothelial progenitor cells (EPCs). Indeed, the scientific community has made progress in understanding the role of EPCs in the maintenance of endothelial integrity and function as well as post natal neovascularisation. It has been suggested that these cells are able to home in the site of heart injury / damage and that they might take part in angiogenesis, giving hope for new treatment opportunities. There is evidence that reduced availability of EPCs or impairment of their function is associated with more severe CV disease and to comorbid risk factors. Different current drug regimes are able to influence bone marrow production and release of EPCs and several growth factors are considered for possible useful new therapeutic approaches. Thus, many studies into the potential use of EPCs in the clinical setting have recently been conducted with conflicting results. The goal of this review article is to discuss current therapies to regenerate new vessels and therefore to enhance myocardial function. The article overviews the search strategy and the pathophysiological aspects behind this therapy, consider the target currently under investigation and set the stage for new ideas. PMID- 20929438 TI - Characterization of the xenobiotic response of Caenorhabditis elegans to the anthelmintic drug albendazole and the identification of novel drug glucoside metabolites. AB - Knowledge of how anthelmintics are metabolized and excreted in nematodes is an integral part of understanding the factors that determine their potency, spectrum of activity and for investigating mechanisms of resistance. Although there is remarkably little information on these processes in nematodes, it is often suggested that they are of minimal importance for the major anthelmintic drugs. Consequently, we have investigated how the model nematode Caenorhabditis elegans responds to and metabolizes albendazole, one of the most important anthelmintic drugs for human and animal use. Using a mutant strain lacking the beta-tubulin drug target to minimize generalized stress responses, we show that the transcriptional response is dominated by genes encoding XMEs (xenobiotic metabolizing enzymes), particularly cytochrome P450s and UGTs (UDP-glucuronosyl transferases). The most highly induced genes are predominantly expressed in the worm intestine, supporting their role in drug metabolism. HPLC-MS/MS revealed the production of two novel glucoside metabolites in C. elegans identifying a major difference in the biotransformation of this drug between nematodes and mammals. This is the first demonstration of metabolism of a therapeutic anthelmintic in C. elegans and provides a framework for its use to functionally investigate nematode anthelmintic metabolism. PMID- 20929439 TI - Erythropoietin and the heart: facts and perspectives. AB - EPO (erythropoietin) has long been identified as a primary regulator of erythropoiesis. Subsequently, EPO has been recognized as playing a role in a broad variety of processes in cardiovascular pathophysiology. In particular, the tight interactions of EPO with the nitric oxide pathway, apoptosis, ischaemia, cell proliferation and platelet activation appear of great interest. Although enhanced EPO synthesis is viewed as an appropriate compensatory mechanism in the cardio-renal syndrome, which features CHF (congestive heart failure) and CRF (chronic renal failure), maladaptative excessive EPO synthesis in the advanced stages of these diseases appears to be predictive of higher mortality. Clinical trials based on the use of EPO in both heart and renal failure have so far produced contradictory results, whereas treatment targeted to restore low Hb levels appears rational and is supported by regulatory authorities. New areas for therapeutic use of EPO, such as acute coronary syndromes, are under investigation, and they are discussed in the present review together with other clinical applications in cardiovascular diseases. The revisited concept of a potential use of endogenous EPO levels as a predictor of CHF severity, as well as in the monitoring of responses to treatment, deserves appropriate investigation, as this may identify EPO as a useful biomarker in the clinical management of cardiovascular diseases. PMID- 20929440 TI - The circadian clock and metabolism. AB - Mammals have developed an endogenous circadian clock located in the SCN (suprachiasmatic nuclei) of the anterior hypothalamus that responds to the environmental light-dark cycle. Human homoeostatic systems have adapted to daily changes in a way that the body anticipates the sleep and activity periods. Similar clocks have been found in peripheral tissues, such as the liver, intestine and adipose tissue. Recently it has been found that the circadian clock regulates cellular and physiological functions in addition to the expression and/or activity of enzymes and hormones involved in metabolism. In turn, key metabolic enzymes and transcription activators interact with and affect the core clock mechanism. Animals with mutations in clock genes that disrupt cellular rhythmicity have provided evidence to the relationship between the circadian clock and metabolic homoeostasis. The present review will summarize recent findings concerning the relationship between metabolism and circadian rhythms. PMID- 20929441 TI - Optimization of antioxidant potential of Aspergillus terreus through different statistical approaches. AB - A three-step optimization strategy, which includes a one-factor-at-a-time classical method and different statistical approaches [Plackett-Burman design and RSM (response surface methodology)], were applied to optimize the antioxidant potential of Aspergillus terreus. Antioxidant activity was assayed by different procedures and compared with TPC (total phenolic content). Primarily, different carbon and nitrogen sources were screened by classical methods, which revealed sucrose and NaNO3 to be the most suitable. The significance of the components of Czapek Dox's medium with respect to antioxidant activity was evaluated with the Plackett-Burman design, which supported sucrose and NaNO3 to be the most significant. In a second step, sucrose and NaNO3 along with temperature were further taken as three variables for RSM to study their interaction. Response surface analysis showed 4% sucrose, 0.1% NaNO3 and an incubation temperature of 30 degrees C to be the optimal conditions. Under these conditions, the antioxidant potential assayed through the different procedures was 88.1, 74.9 and 70.2% scavenging effect for DPPH (1,1-diphenyl-2-picryl hydrazyl) radical, ferrous ion and nitric oxide ion respectively. The reducing power showed an absorbance of 2.0 with 71.5% activity for the FRAP (ferric reducing antioxidant power) assay. TPC under different physio-chemical conditions and antioxidant potential under various assay procedures correlated positively. PMID- 20929442 TI - Mycobacterium tuberculosis WhiB1 is an essential DNA-binding protein with a nitric oxide-sensitive iron-sulfur cluster. AB - Mycobacterium tuberculosis is a major pathogen that has the ability to establish, and emerge from, a persistent state. Wbl family proteins are associated with developmental processes in actinomycetes, and M. tuberculosis has seven such proteins. In the present study it is shown that the M. tuberculosis H37Rv whiB1 gene is essential. The WhiB1 protein possesses a [4Fe-4S]2+ cluster that is stable in air but reacts rapidly with eight equivalents of nitric oxide to yield two dinuclear dinitrosyl-iron thiol complexes. The [4Fe-4S] form of WhiB1 did not bind whiB1 promoter DNA, but the reduced and oxidized apo-WhiB1, and nitric oxide treated holo-WhiB1 did bind to DNA. Mycobacterium smegmatis RNA polymerase induced transcription of whiB1 in vitro; however, in the presence of apo-WhiB1, transcription was severely inhibited, irrespective of the presence or absence of the CRP (cAMP receptor protein) Rv3676, which is known to activate whiB1 expression. Footprinting suggested that autorepression of whiB1 is achieved by apo-WhiB1 binding at a region that overlaps the core promoter elements. A model incorporating regulation of whiB1 expression in response to nitric oxide and cAMP is discussed with implications for sensing two important signals in establishing M. tuberculosis infections. PMID- 20929443 TI - Enhanced expression of pro-inflammatory mediators and liver X-receptor-regulated lipogenic genes in non-alcoholic fatty liver disease and hepatitis C. AB - NAFLD (non-alcoholic fatty liver disease) is one of the most frequent chronic liver diseases worldwide. The metabolic factors associated with NAFLD are also determinants of liver disease progression in chronic HCV (hepatitis C virus) infection. It has been reported that, besides inducing hepatic fatty acid biosynthesis, LXR (liver X receptor) regulates a set of inflammatory genes. We aimed to evaluate the hepatic expression of LXRalpha and its lipogenic and inflammatory targets in 43 patients with NAFLD, 44 with chronic HCV infection and in 22 with histologically normal liver. Real-time PCR and Western blot analysis were used to determine hepatic expression levels of LXRalpha and related lipogenic and inflammatory mediators in the study population. We found that the LXRalpha gene and its lipogenic targets PPAR-gamma (peroxisome-proliferator activated receptor-gamma), SREBP (sterol-regulatory-element-binding protein)-1c, SREBP-2 and FAS (fatty acid synthase) were overexpressed in the liver of NAFLD and HCV patients who had steatosis. Moreover, up-regulation of inflammatory genes, such as TNF (tumour necrosis factor)-alpha, IL (interleukin)-6, OPN (osteopontin), iNOS (inducible NO synthase), COX (cyclo-oxygenase)-2 and SOCS (suppressors of cytokine signalling)-3, was observed in NAFLD and HCV patients. Interestingly, TNF-alpha, IL-6 and osteopontin gene expression was lower in patients with steatohepatitis than in those with steatosis. In conclusion, hepatic expression of LXRalpha and its related lipogenic and inflammatory genes is abnormally increased in NAFLD and HCV patients with steatosis, suggesting a potential role of LXRalpha in the pathogenesis of hepatic steatosis in these chronic liver diseases. PMID- 20929459 TI - Improvement of ecdysone receptor gene switch for applications in plants: Locusta migratoria retinoid X receptor (LmRXR) mutagenesis and optimization of translation start site. AB - Gene switches have potential applications for the regulation of transgene expression in plants and animals. Recently, we have developed a two-hybrid ecdysone receptor (EcR) gene switch using chimera 9 [CH9, a chimera between helices 1-8 of Homo sapiens retinoid X receptor (HsRXR) and helices 9-12 of Locusta migratoria RXR (LmRXR)] as a partner for Choristoneura fumiferana EcR (CfEcR). As CH9 includes a region of human RXR, public acceptance of this gene switch for use in genetically modified crops may be an issue. The current studies were conducted to identify an LmRXR mutant that could replace CH9 as a partner for CfEcR. The amino acid identity between LmRXR and HsRXR is fairly high. However, there are a few amino acid residues that are different between these two proteins. LmRXR mutants were produced by changing the amino acids in the helices 1-8 that are different between LmRXR and HsRXR to HsRXR residues. Screening of these mutants in tobacco protoplasts identified a triple mutant, A62S:T81H:V123I (SHILmRXR), that performed as well as CH9. The performance of the EcR gene switch was further improved by optimizing the translational start site (Kozak sequence, AACAATGG) of the transgene. The EcR gene switch containing SHILmRXR and the modified translation start site supported very low background activity in the absence of a ligand and a higher induced activity in the presence of a ligand in tobacco protoplasts, as well as Arabidopsis thaliana transgenic plants. At 16-80 nm methoxyfenozide, the induction of luciferase activity was better than that observed with the CfEcR:CH9 switch. PMID- 20929460 TI - The Mycobacterium tuberculosis ORF Rv0654 encodes a carotenoid oxygenase mediating central and excentric cleavage of conventional and aromatic carotenoids. AB - Mycobacterium tuberculosis, the causative agent of tuberculosis, is assumed to lack carotenoids, which are widespread pigments fulfilling important functions as radical scavengers and as a source of apocarotenoids. In mammals, the synthesis of apocarotenoids, including retinoic acid, is initiated by the beta-carotene cleavage oxygenases I and II catalyzing either a central or an excentric cleavage of beta-carotene, respectively. The M. tuberculosis ORF Rv0654 codes for a putative carotenoid oxygenase conserved in other mycobacteria. In the present study, we investigated the corresponding enzyme, here named M. tuberculosis carotenoid cleavage oxygenase (MtCCO). Using heterologously expressed and purified protein, we show that MtCCO converts several carotenoids and apocarotenoids in vitro. Moreover, the identification of the products suggests that, in contrast to other carotenoid oxygenases, MtCCO cleaves the central C15 C15' and an excentric double bond at the C13-C14 position, leading to retinal (C(20)), beta-apo-14'-carotenal (C(22)) and beta-apo-13-carotenone (C(18)) from beta-carotene, as well as the corresponding hydroxylated products from zeaxanthin and lutein. Moreover, the enzyme cleaves also 3,3'-dihydroxy-isorenieratene representing aromatic carotenoids synthesized by other mycobacteria. Quantification of the products from different substrates indicates that the preference for each of the cleavage positions is determined by the hydroxylation and the nature of the ionone ring. The data obtained in the present study reveal MtCCO to be a novel carotenoid oxygenase and indicate that M. tuberculosis may utilize carotenoids from host cells and interfere with their retinoid metabolism. PMID- 20929444 TI - Decoding the intrinsic mechanism that prohibits ALIX interaction with ESCRT and viral proteins. AB - The adaptor protein ALIX [ALG-2 (apoptosis-linked-gene-2 product)-interacting protein X] links retroviruses to ESCRT (endosomal sorting complex required for transport) machinery during retroviral budding. This function of ALIX requires its interaction with the ESCRT-III component CHMP4 (charged multivesicular body protein 4) at the N-terminal Bro1 domain and retroviral Gag proteins at the middle V domain. Since cytoplasmic or recombinant ALIX is unable to interact with CHMP4 or retroviral Gag proteins under non-denaturing conditions, we constructed ALIX truncations and mutations to define the intrinsic mechanism through which ALIX interactions with these partner proteins are prohibited. Our results demonstrate that an intramolecular interaction between Patch 2 in the Bro1 domain and the TSG101 (tumour susceptibility gene 101 protein)-docking site in the proline-rich domain locks ALIX into a closed conformation that renders ALIX unable to interact with CHMP4 and retroviral Gag proteins. Relieving the intramolecular interaction of ALIX, by ectopically expressing a binding partner for one of the intramolecular interaction sites or by deleting one of these sites, promotes ALIX interaction with these partner proteins and facilitates ALIX association with the membrane. Ectopic expression of a GFP (green fluorescent protein)-ALIX mutant with a constitutively open conformation, but not the wild type protein, increases EIAV (equine infectious anaemia virus) budding from HEK (human embryonic kidney)-293 cells. These findings predict that relieving the autoinhibitory intramolecular interaction of ALIX is a critical step for ALIX to participate in retroviral budding. PMID- 20929461 TI - Physician consultation, multidisciplinary care, and 1-year mortality in Medicare recipients hospitalized with hip and lower extremity injuries. AB - OBJECTIVE: To determine whether routine surgeon consultation with medicine specialists and multidisciplinary care conferences-potentially modifiable hospital characteristics-are associated with lower 1-year mortality in older adults with hip and lower extremity injuries. DESIGN: Retrospective cohort study. SETTING: Oregon hospitals. PARTICIPANTS: Two thousand five hundred thirty-eight Medicare recipients aged 67 and older hospitalized in Oregon hospitals in 2002 with hip or lower extremity injuries. MEASUREMENTS: Demographic, injury, comorbidity, and survival information were gathered from Medicare records for 2000 to 2003. All Oregon hospitals with a qualifying case were surveyed using a structured telephone interview to collect information about routine surgeon consultations and multidisciplinary care conferences for older adult orthopedic patients. Multivariable generalized estimating equation models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between hospital characteristics and mortality. RESULTS: After adjusting for age, injury severity, comorbid conditions, trauma center status, and hospital annual volume of patients with hip fracture, the relative odds of dying in the year after injury for inpatients treated in settings with routine surgeon consultation with medical staff was 0.69 (95% CI 0.57-0.83) compared with patients not treated in such settings. Inpatient treatment in settings with routine multidisciplinary care conferences did not significantly affect the relative odds of dying in the year after injury (OR=1.06, 95% CI=0.89-1.26). CONCLUSION: Routine consultation by attending orthopedic surgeons with medicine or primary care specialists for Medicare inpatients is associated with better survival 1 year after injury. PMID- 20929462 TI - Prognostic effect of exercise capacity on mortality in older adults with diabetes mellitus. AB - OBJECTIVES: To investigate the prognostic effect of exercise capacity in older individuals with diabetes mellitus. DESIGN: Retrospective data review in a clinic based cohort. SETTING: Veterans Affairs Medical Centers in Washington, District of Columbia, and Palo Alto, California. PARTICIPANTS: Two thousand eight hundred sixty-seven men aged 50 to 87 with type 2 diabetes mellitus. MEASUREMENTS: Exercise tolerance testing with fitness categories based on peak metabolic equivalents of task (METs) achieved adjusted for age. All-cause mortality in age groups 50 to 65 (Group 1; n=1,658) and older than 65 (Group 2; n=1,209) was analyzed using adjusted Cox proportional hazards models. RESULTS: After a mean +/ standard deviation follow-up period of 7.8 +/- 5.1 years, there were 324 deaths in Group 1 (20%) and 464 in Group 2 (38%). For each 1-MET increase in exercise capacity, mortality was 18% lower for the entire cohort (hazard ratio (HR)=0.82, 95% confidence interval (CI)=0.79-0.86), 23% lower for Group 1 (HR=0.77, 95% CI=0.73-0.82), and 16% lower for Group 2 (HR=0.84, 95% CI=0.8-0.89). When fitness categories were considered, the mortality risk was 30% to 80% lower for those who achieved more than 4 METs in both age groups. CONCLUSION: Augmented exercise capacity is associated with lower risk of mortality in people with type 2 diabetes mellitus aged 50 to 65 as well as in those older than 65. Thus, physical fitness, as represented by exercise capacity, lowers mortality risk in people with diabetes mellitus irrespective of age. These findings suggest that healthcare providers should be cognizant of the level of exercise capacity in individual patients and encourage a physically active lifestyle regardless of age. PMID- 20929463 TI - Morbidity and physical functioning in old age: differences according to living area. AB - OBJECTIVES: To describe differences in morbidity and functional status according to living area. DESIGN: Community-based survey. SETTING: A community-based prospective cohort, the Kungsholmen-Nordanstig Project. PARTICIPANTS: Adults aged 75 and older living in an urban area of central Stockholm (n=1,222) and in the rural community of Nordanstig in northern Sweden (n=919). MEASUREMENTS: Physicians clinically examined all participants using the same standardized protocols in both living areas; trained nurses directly assessed disability. RESULTS: Cardiovascular disease was the most common disorder in both living areas (39.9% in the urban area and 45.2% in the rural area). There were great area differences in the prevalence of stroke (7.4% and 14.0%), diabetes mellitus 6.3% and 16.1%), and Parkinson's disease (1.0% and 3.7%). It was more common to have two or more diseases than no diseases in the rural area than in the urban area (odds ratio=1.9, 95% confidence interval=1.4-2.4). Significant living area differences (urban vs rural) in population attributable risk (PAR) was found for disability due to stroke (5.6 vs 32.2), diabetes mellitus (1.2 vs 6.1), fractures (1.4 vs 10.7), and hearing impairment (8.7 vs 22.0). CONCLUSION: Differences were found in disability, morbidity, and disease patterns according to living area. The rural elderly population was more disabled and had more diseases than the urban elderly population, despite being slightly younger than the urban cohort. There were significant area differences in the PAR of how specific chronic conditions influenced the risk of disability. PMID- 20929464 TI - Sisters in motion: a randomized controlled trial of a faith-based physical activity intervention. AB - OBJECTIVES: To evaluate a faith-based intervention (Sisters in Motion) intended to increase walking in older, sedentary African-American women. DESIGN: Randomized controlled trial using within-church randomization. SETTING: Three Los Angeles churches. PARTICIPANTS: Sixty-two African-American women aged 60 and older who reported being active less than 30 minutes three times per week and walked less than 35,000 steps per week as measured using a baseline pedometer reading. INTERVENTION: Intervention participants received a multicomponent curriculum including scripture readings, prayer, goal-setting, a community resource guide, and walking competitions. Intervention and control participants both participated in physical activity sessions. MEASUREMENTS: The primary outcome was change in weekly steps walked as measured using the pedometer. Secondary outcomes included change in systolic blood pressure (SBP). Outcomes were assessed at baseline and 6 months after the intervention. RESULTS: Eighty five percent of participants attended at least six of eight sessions. Intervention participants averaged 12,727 steps per week at baseline, compared with 13,089 steps in controls. Mean baseline SBP was 156 mmHg for intervention participants and 147 mmHg for controls (P=.10). At 6 months, intervention participants had increased their weekly steps by 9,883 on average, compared with an increase of 2,426 for controls (P=.02); SBP decreased on average by 12.5 mmHg in intervention participants and only 1.5 mmHg in controls (P=.007). CONCLUSION: The Sisters in Motion intervention led to an increase in walking and a decrease in SBP at 6 months. This is the first randomized controlled trial of a faith based physical activity program to increase physical activity in older African American women and represents an attractive approach to stimulate lifestyle change in this population. PMID- 20929465 TI - Sleep disturbances and adverse driving events in a predominantly male cohort of active older drivers. AB - OBJECTIVES: To evaluate the association between sleep disturbances and adverse driving events in active older drivers. DESIGN: Longitudinal. SETTING: Clinic and community sites in greater New Haven, Connecticut. PARTICIPANTS: Four hundred thirty older persons (mean age 78.5, 84.9% male) who drove at least once a week. MEASUREMENTS: Baseline measures included self-reported driving patterns and sleep questionnaires (Insomnia Severity Index (ISI), Epworth Sleepiness Scale (ESS), and Sleep Apnea Clinical Score (SACS)). The primary outcome was an adverse driving event based on self-report and driving records and categorized as a crash or traffic infraction (composite I) or as a crash, traffic infraction, near crash, or getting lost (composite II). RESULTS: Participants reported driving a median of 17.0 miles per day, with 96.7% (416/430) driving daily or every other day. Although 26.0% (112/430) had insomnia (ISI>=8), 19.3% (83/430) had daytime drowsiness (ESS>=10), and 19.9% (84/422) had high sleep apnea risk (SACS>15), the median scores for the ISI, ESS, and SACS were normal at 3.0, 6.0, and 8.0, respectively, and only 5.1% reported drowsy driving. Over a period of up to 2 years, 24.9% (104/418) and 51.4% (215/418) of participants had a composite I and II driving event, respectively. In unadjusted and adjusted multivariable models, insomnia, daytime drowsiness, and high sleep apnea risk were not associated with a composite I or II driving event. CONCLUSION: In a predominantly male cohort of active older drivers, sleep disturbances were mild and not associated with adverse driving events. Accordingly, and because older persons are known to self regulate driving practices, future studies should evaluate whether sleep disturbances are more important as a mechanism that underlies driving cessation rather than compromising driving safety. PMID- 20929466 TI - Receipt of influenza and pneumonia vaccinations: the dual disparity of rural minorities. AB - OBJECTIVES: To examine the receipt of age-appropriate influenza and pneumococcal polysaccharide vaccinations (PPV), with particular attention to rural minority persons. DESIGN: Data were drawn from the 2005 Behavioral Risk Factor Surveillance System. The dependent variables were self-reported receipt of annual influenza immunizations in adults aged 50 and older (n=177,417) or lifetime pneumococcal immunizations in adults aged 65 and older (n=81,762). The main independent variables were residence and race. MEASUREMENTS: All data are self reported. Multivariate analysis controlled for selected personal and county-level characteristics. Analyses were conducted in 2009/10. RESULTS: Forty-two percent of adults aged 50 and older reported an influenza vaccination; 31.1% of rural African Americans reported an influenza vaccination, and 64.6% reported a PPV. White and African-American rural residents reported lower vaccination rates. Adjusted analysis indicated an interaction between race and rurality. White rural residents were more likely to be vaccinated than other whites, whereas rural African Americans were less likely to be vaccinated than urban African Americans. CONCLUSION: This study confirms previous findings while finding an interactive effect between rurality and race. The results indicated the importance of provider availability to delivery. Alternative delivery methods may be an effective solution to improve delivery rates. PMID- 20929467 TI - Home-based leg-strengthening exercise improves function 1 year after hip fracture: a randomized controlled study. AB - OBJECTIVES: To compare the effectiveness of a short-term leg-strengthening exercise program with that of attentional control on improving strength, walking abilities, and function 1 year after hip fracture. DESIGN: Randomized controlled pilot study. SETTING: Patients' homes. PARTICIPANTS: Community-dwelling older adults (n=26) 6 months after hip fracture at baseline. INTERVENTION: Exercise and control participants received interventions from physical therapists twice a week for 10 weeks. The exercise group received high-intensity leg-strengthening exercises. The control group received transcutaneous electrical nerve stimulation and mental imagery. MEASUREMENTS: Isometric force production of lower extremity muscles, usual and fast gait speed, 6-minute walk (6-MW) distance, modified Physical Performance Test (mPPT), and Medical Outcomes Study 36-item Short Form Survey (SF-36) physical function. RESULTS: The primary endpoint was 1 year after fracture. Isometric force production (P=.006), usual (P=.02) and fast (P=.03) gait speed, 6-MW distance (P=.005), and mPPT score (P<.001) were improved 1 year after fracture with exercise. Effect sizes were 0.79 for strength, 0.81 for mPPT score, 0.56 for gait speed, 0.49 for 6-MW, and 0.30 for SF-36 score. More patients in the exercise group made meaningful changes in gait speed and 6-MW distance than control patients (chi-square P=.004). CONCLUSION: A 10-week home based progressive resistance exercise program was sufficient to achieve moderate to large effects on physical performance and quality of life and may offer an alternative intervention mode for patients with hip fracture who are unable to leave home by 6 months after the fracture. The effects were maintained at 3 months after completion of the training program. PMID- 20929468 TI - Effect of new disability subtype on 3-year mortality in Chinese older adults. AB - OBJECTIVES: To examine a new method of classifying disability subtypes by combining self-reported and performance-based tools to predict mortality in older Chinese adults. DESIGN: Prospective cohort study. SETTING: Community-dwelling older adults. PARTICIPANTS: Sixteen thousand twenty Chinese adults aged 65 and older from the Chinese Longitudinal Healthy Longevity Survey (CLHLS). MEASUREMENTS: Self-reported activities of daily living (ADLs) and physical performance (PP) tests (chair standing, lifting a book from floor, turning 360 degrees ) cross-classified to create mutually exclusive disability subtypes: subtype 0 (no limitations in PP or ADLs), subtype 1 (limitations in PP, no limitations in ADLs), subtype 2 (no limitations in PP, limitations in ADLs), and subtype 3 (limitations in PP and ADLs). Outcome was mortality over 3 years. RESULTS: Cox proportional hazard models, controlling for sociodemographic variables, living situation, healthcare access, social support, health status, and life-style, showed that older adults without any limitations in ADLs or PP had significantly lower mortality risk than those with other disability subtypes and that there was a graded pattern of greater mortality according to subtype 1 (hazard ratio (HR)=1.31, 95% confidence interval (CI)=1.20-1.42), 2 (HR=1.39, 95% CI=1.23-1.59), and 3 (HR=1.88, 95% CI=1.72-2.05). When compared with the average survival curve in the cohort, subtypes of isolated performance deficits or self reported disability did not substantially discriminate risks of death over 3 years. CONCLUSION: Combined use of self-reported and PP tools is necessary when screening for mutually exclusive disability subtypes that confer significantly higher or lower mortality risks on a population of older adults. PMID- 20929469 TI - Health status of older Asian Americans in California. AB - Given the paucity of research on differences between older adults representing the many Asian-American subcategories, the present study explored physical and mental health status in five subcategories of Asian Americans aged 60 and older: Chinese, Japanese, Korean, Vietnamese, and Filipino. Data were drawn from the 2007 California Health Interview Survey (CHIS). Background characteristics and physical and mental health conditions were compared, with results showing differences cross the five subcategories of older Asian Americans. Specific patterns were identified in chronic diseases, disease comorbidity, and disability rates. Vietnamese and Filipinos tended to have poorer physical health than Chinese, Japanese, and Koreans. The poorest self-rated health and the highest disability rate were found in the older Vietnamese. Filipinos also exhibited the greatest number of chronic diseases, including the highest rates of asthma, high blood pressure, and heart disease. Although Koreans had the fewest self-reported chronic diseases and the least evidence of disease comorbidity, they also had the highest psychological distress. The lowest psychological distress was found in older Japanese. Findings suggest that generalizing findings from one particular Asian category or from an aggregate Asian category may be problematic and may not reflect an accurate picture of the burden of health in specific Asian categories. Being aware of these differences in background and health characteristics may help providers to better serve older Asian clients. PMID- 20929470 TI - Racial and ethnic disparities in indicators of physical health status: do they still exist throughout late life? AB - Physical health problems become more common as people age and are associated with a great deal of disability. Although racial and ethnic disparities have been reported in physical health, little is known about whether these disparities remain in the latest part of older adulthood. Accordingly, the current study sought to examine racial and ethnic differences in the physical health status of three age groups of older adults, using the 2005 and 2007 California Health Interview Survey. The sample for the current study included 40,631 individuals aged 55 and older: 33,488 non-Hispanic whites, 1,858 blacks, 2,872 Asians and Pacific Islanders, and 2,412 Latinos. Respondents were compared with regard to three indicators of physical health: four chronic health conditions, difficulties with activities of daily living, and self-rated health. Analyses were conducted with and without adjustment for sex, marital status, education, English-language proficiency, nativity, and insurance status. Results revealed that, in general, racial and ethnic disparities existed for physical health in late adulthood, with differences less pronounced for Asians and Pacific Islanders and Latinos aged 75 and older after multivariable adjustment. Disparities between blacks and non Hispanic whites and disparities across all racial and ethnic minorities in self rated health still existed. These findings suggest that, to reduce racial and ethnic disparities, clinicians need to address specific sociodemographic and lifestyle factors related to racial and ethnic differences in health before these conditions are manifested in late adulthood. PMID- 20929471 TI - Screening in frail older people: an ounce of prevention or a pound of trouble? AB - Screening for subclinical disease has provided benefit to many asymptomatic patients, especially those who are relatively young and otherwise healthy. However, frail older people do not always profit from such maneuvers, for several reasons. First, older individuals usually have less physiological reserve and greater comorbidity and resultant polypharmacy than their younger counterparts. As such, they may tolerate the invasive interventions called for after a positive screening test less easily. In addition, shorter natural life expectancy shifts the focus to quality of life improvement after screening tests rather than simply offering a promise of "more years." Lack of education and cognitive decline may also interfere with the older person's ability to give truly informed consent to these maneuvers. Thus, on the whole, in this rapidly growing subpopulation, screening programs may tilt the balance toward the likelihood of causing more harm than good. For many frail older patients, an individualized approach to screening is recommended, adjusted to comorbidity, life expectancy, and patient preference. One size does not fit all. PMID- 20929472 TI - Outcomes of hip fracture: do medical doctors matter? PMID- 20929473 TI - Integrating aging into geriatric practice: an emerging orientation for health care. PMID- 20929474 TI - Midodrine hydrochloride is safe and effective in older people with neurocardiogenic syncope. PMID- 20929475 TI - Prevalence of metabolic syndrome in an elderly Chinese population: a community based cross-sectional study. PMID- 20929477 TI - Age and time spent in the emergency department of an urban teaching hospital in Italy. PMID- 20929476 TI - Feasibility of cranberry capsule administration and clean-catch urine collection in long-term care residents. PMID- 20929478 TI - Comprehensive geriatric assessment in the emergency department. PMID- 20929479 TI - Prevalence and predictors of fatigue in middle-aged and older adults: evidence from the health and retirement study. PMID- 20929480 TI - Tube feeding can be discontinued by taking dopamine agonists and angiotensin converting enzyme inhibitors in the advanced stages of dementia. PMID- 20929481 TI - Severe human rhinovirus outbreak associated with fatalities in a long-term care facility in Ontario, Canada. PMID- 20929482 TI - Effect of malnutrition on executive function in older Egyptians in geriatric homes. PMID- 20929483 TI - A giant intra-abdominal mass in a 68-year-old woman. PMID- 20929484 TI - Early physician follow-up after hospitalization for heart failure is also relevant. PMID- 20929485 TI - An atypical case of giant cell arteritis (Horton's disease) associated with facial swelling, confusion, and pericarditis in an elderly woman. PMID- 20929486 TI - Moderate resistance training program can reduce triglycerides in elderly women: a randomized controlled trial. PMID- 20929487 TI - Allopurinol-induced drug reaction with eosinophilia and systemic symptoms syndrome with recurrence. PMID- 20929488 TI - Association between anorexia of aging and disability in older community-dwelling Mexicans. PMID- 20929489 TI - Association between renal function and cognitive performance in elderly community dwelling men without dementia. PMID- 20929490 TI - Measures for enhancing the mobility of older people with dementia in Japan: should it be a matter of self-help? PMID- 20929491 TI - Medical students' longitudinal and cross-sectional attitudes toward and knowledge of geriatrics at the University of New Mexico School of Medicine. PMID- 20929492 TI - HIV and the body: a review of multidisciplinary management. AB - The increase in the life expectancy achieved following the introduction of more effective antiretroviral therapy (ART) in recent years now means that the HIV infected population are for the first time being exposed to the age-related diseases that affect the general population. Nevertheless, the prevalence of these diseases (which include cardiovascular disease, dyslipidaemia, glucose intolerance and diabetes) is higher, and their onset earlier in the HIV population, probably due to the complex interplay between HIV infection, coinfection with hepatitis B and C, and ART. As a result, HIV physicians are now required to adopt a new approach to the management of HIV, which involves screening and regular monitoring of all HIV-infected individuals for the presence of comorbidities and prompt referral to other clinical specialties when required. If this challenge to patient management is to be overcome, it is clear that educating physicians in the diagnosis and treatment of age-associated comorbidities is essential, either through ongoing programmes such as the HIV and the Body initiative, an overarching independent medical education programme established in 2007 and overseen by an independent Steering Committee, organized and funded by Gilead, and/or through internal training. To assist in this process, this article provides an overview of common comorbidities affecting HIV infected persons and provides practical guidance on their management. PMID- 20929493 TI - A meta-ethnographic synthesis of women's experience of breastfeeding. AB - Despite considerable evidence and effort, breastfeeding duration rates in resource-rich countries such as Australia remain below World Health Organization recommendations. The literature on the experience of breastfeeding indicates that women construct and experience breastfeeding differently depending upon their own personal circumstances and the culture within which they live. Breastfeeding has also been described as a deeply personal experience, which can be associated with 'moral' decision-making. The aim of this synthesis was to better understand the social phenomenon of breastfeeding by making the hidden obvious. Using a meta ethnographic approach, we analysed the findings from 17 qualitative studies exploring women's experience of breastfeeding. Commonly used metaphors, ideas and phrases across the national and international qualitative studies were identified. Two overarching themes emerged. Breastfeeding was described in terms of 'expectation' and 'reality', while the emotional aspects of breastfeeding were expressed in 'connected' or 'disconnected' terms. The prevalence of health professionals and public health discourses in the language women use to describe their experience, and the subsequent impact of this on maternal confidence and self-assessment of breastfeeding are discussed. This synthesis provides insight into some of the subtle ways health professionals can build maternal confidence and improve the experience of early mothering. PMID- 20929494 TI - The Infant Feeding Intentions scale demonstrates construct validity and comparability in quantifying maternal breastfeeding intentions across multiple ethnic groups. AB - Research tools that are comparable across ethnic groups are needed in order to understand sociodemographic disparities in breastfeeding rates. The Infant Feeding Intentions (IFI) scale provides a quantitative measure of maternal breastfeeding intentions. IFI score ranges from 0 (no intention to breastfeed) to 16 (very strong intentions to fully breastfeed for 6 months). The objective of this study was to examine intra- and inter-ethnic validity of the IFI scale. The IFI scale was administered to 218 white non-Hispanic, 75 African-American, 80 English-speaking Hispanic, 62 Spanish-speaking Hispanic and 64 Asian expectant primiparae. Participants were asked their planned duration of providing breast milk as the sole source of milk (full breastfeeding). The IFI scale was examined for intra-ethnic internal consistency and construct validity and for inter-ethnic comparability. For all five ethnic categories, principal component analysis separated the scale into the same two factors: intention to initiate breastfeeding and intention to continue full breastfeeding. Across ethnic categories, the range in Cronbach's alpha was 0.70-0.85 for the initiation factor and 0.90-0.93 for the continuation factor. Within each ethnic category, IFI score increased as planned duration of full breastfeeding increased (P < 0.0001 for all). Within the planned duration categories of <1, 1-3, 3-6 and >=6 months, the median IFI score by ethnic category ranged from (low-high) 5-8, 9-10, 12-14 and 16-16, respectively. The IFI scale provides a valid measure of breastfeeding intentions in diverse populations of English- and Spanish-speaking primiparae, and may be a useful tool when researching disparities in breastfeeding practices. PMID- 20929495 TI - Breastfeeding support - the importance of self-efficacy for low-income women. AB - Breastfeeding is a key determinant in promoting public health and reducing health inequality. Low-income women have a significantly lower level of breastfeeding. Midwives in the UK have been encouraged to implement the World Health Organization/United Nations Children's Fund's Ten Steps to Successful Breastfeeding, but to date, there has been no evaluation of the impact of the training initiative on the breastfeeding behaviours of low-income women. As part of a wider study, this qualitative component was designed to answer the question what are the views and experiences of low-income women (defined by Jarman scores) in relation to their breastfeeding support received in the post-natal period? A sample of seven women was interviewed. The in-depth interviews were analysed using a qualitative, thematic approach based on the self-efficacy theory. The four themes that emerged from the data were the following: breastfeeding related to the woman's self-confidence, the social environment in which the woman lived, knowledge of breastfeeding and the influence of maternity services on breastfeeding outcomes. These themes were interpreted in relation to the self-efficacy theory. The findings suggest that the components that inform self-efficacy are consistent with the themes from the data, suggesting that midwives and other health professionals should take the psychosocial aspects of breastfeeding support into account. As this important feature of breastfeeding support is not explicitly part of the current Ten Steps to Successful Breastfeeding, we suggest that further research and debate could inform expansion of these minimum standards to include the psychosocial aspects. PMID- 20929496 TI - Breastfeeding practice in mothers with eating disorders. AB - The purpose of this study was to compare the prevalence of breastfeeding in women with anorexia nervosa, bulimia nervosa, binge eating disorder and eating disorders not otherwise specified - purging subtype, with mothers with no eating disorders during the first 6 months after birth. The study is based on the Norwegian Mother and Child Cohort Study conducted at the Norwegian Institute of Public Health. Questionnaire-based information on eating disorder diagnoses and breastfeeding in 39 355 women was used to estimate the risk of cessation of breastfeeding with Cox proportional hazards regression. Almost all women (98%) initially breastfeed their infants, with no statistically significant difference between the eating disorders subgroups and women with no eating disorders. However, the risk of early cessation before 6 months post-partum increased for all subgroups of mothers with eating disorders, compared with mothers with no eating disorders. After adjusting for maternal body mass index, age, education, birthweight and pre-term birth, only mothers with anorexia nervosa [hazard ratios (HR), 2.35; 95% confidence interval (CI) 1.22-4.53] and eating disorder not otherwise specified-purging subtype (HR, 1.95; 95% CI 1.08-3.53) had increased risk for cessation of breastfeeding There were no differences in the risk of cessation of exclusive breastfeeding. These results show that some eating disorders may influence mothers' early feeding practices and indicate that additional support may be necessary to assist women with anorexia nervosa in maintaining breastfeeding. PMID- 20929497 TI - Acceptability and feasibility of infant-feeding options: experiences of HIV infected mothers in the World Health Organization Kesho Bora mother-to-child transmission prevention (PMTCT) trial in Burkina Faso. AB - In Burkina Faso, prolonged breastfeeding with introduction of ritual fluids from birth is a deep-seated norm. We explored HIV-infected mothers' views and experiences of the acceptability and feasibility of the World Health Organization's recommended infant-feeding options within a mother-to-child transmission prevention trial. A qualitative study was conducted on 17 formula feeding and 19 breastfeeding mothers, from a larger cohort of 51 eligible HIV infected women, consenting to participate in separate focus group discussions in early post-partum. Mothers opted for breastfeeding essentially out of fear of family rejection. Most of them were afraid of denigration for disrespecting tradition if they formula-fed or being suspected of HIV infection. Achieving exclusive breastfeeding remained a difficult challenge as they engaged in a continuous struggle with close elders to avoid fluid feeding. Additional stress and fatigue were fed by their perception of a high transmission risk through breast milk. Exclusive formula-feeding seemed easier to implement, especially as formula was provided free of charge. Formula-feeding mothers more frequently had a supportive partner, a strong personality and lived in better socio-economic conditions than breastfeeding mothers (76% had education and electricity supply vs. 42%, respectively). Exclusive breastfeeding for the first 6 months remains the most appropriate option for many HIV-infected mothers in sub-Saharan Africa. Its acceptability and feasibility urgently need to be improved by promoting it as the best feeding option for all infants. Other crucial interventions are the promotion of voluntary counselling and testing for couples, and greater partner involvement in infant-feeding counselling. PMID- 20929498 TI - The role of parents' romantic relationship warmth and hostility in child feeding practices and children's eating behaviours. AB - This research examined the associations between parents' reports of the quality of their romantic relationships with their partner/spouse, their feeding interactions with their children, and their children's eating behaviours. One hundred and fifty-six married/cohabiting mothers of young children completed self report measures of their romantic relationship quality, child feeding practices and children's eating behaviours. Reports of a less warm, more hostile romantic relationship were associated with children's less adaptive eating behaviours. More hostile relationship quality was also related to greater restriction of their children's food intake. The quality of parents' romantic relationships is associated with parental feeding practices and children's eating behaviours. Further work should examine the emotional tone of mealtimes in order to discover whether this may be the mechanism of the relationship. PMID- 20929499 TI - Effects of a lifestyle modification trial among phenotypically obese metabolically normal and phenotypically obese metabolically abnormal adolescents in comparison with phenotypically normal metabolically obese adolescents. AB - This study aimed to assess the effects of a 2-month lifestyle modification trial on cardio-metabolic abnormalities and C-reactive protein (CRP) among obese adolescents with metabolic syndrome [phenotypically obese metabolically abnormal (POMA)] and obese adolescents without a cardio-metabolic disorder [phenotypically obese metabolically normal (POMN)], as well as in normal-weight adolescents with at least one cardio-metabolic disorder [phenotypically normal metabolically obese (PNMO)]. The study comprised 360 adolescents assigned in three groups of equal number of POMN, POMA and PNMO. They were enrolled in a trial consisting of aerobic activity classes, diet and behaviour modification, and were recalled after 6 months. Overall, 94.7% of participants completed the 2-month trial, and 87.3% of them returned after 6 months. The mean CRP was not significantly different between the POMA and PNMO groups, but was higher than in the POMN group. After the trial, body mass index (BMI) and waist circumference (WC) decreased in obese participants, and the mean body fat mass decreased in all groups. At 2 months, the mean total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG) and CRP decreased in the POMA and PNMO groups. After 2 and 6 months, the decrease in mean TC, LDL-C, TG, CRP and systolic blood pressure was greater in the POMA than in the POMN group. The magnitude of decrease in CRP correlated with that of BMI, WC, fat mass, TG, TC and LDL-C. Lifestyle modification programmes for primordial/primary prevention of chronic diseases would be beneficial at the population level and should not be limited to obese children. PMID- 20929501 TI - What is the evidence base for the randomized controlled trial? PMID- 20929500 TI - The post-partum mid-upper arm circumference of adolescents is reduced by pregnancy in rural Nepal. AB - The purpose of this study was to examine whether changes in the mid-upper arm circumference (MUAC) in pregnancy and early post-partum varied by maternal age. The MUAC of 3359 nulliparous pregnant women <=25 years of age in rural Nepal was measured in early pregnancy and at 3 months post-delivery of a live-born infant. Regression was used to model the change in MUAC and prevalence of MUAC < 20 cm by maternal age, adjusted for confounders. A total of 5.2% of the pregnant women were under 16 years of age. The prevalence of MUAC measurements <20 cm was 11.3% in early pregnancy and did not differ by maternal age. The prevalence of low MUAC was 17.7% at post-partum, but those <16 years of age had a significantly higher prevalence of low post-partum MUAC [odds ratio: 2.47, 95% confidence interval (CI) 1.49, 4.10] compared with women 20-25 years of age, adjusted for maternal literacy, caste, meat consumption in early pregnancy and timing of measurements. All women reduced their MUAC from early pregnancy through post-partum. The adjusted loss of the MUAC among those under 16 years of age was 0.97 cm (95% CI: 1.33, -0.60), compared with 0.40 cm (95% CI: -0.70, -0.10) among women 20-25 years of age. In an energy-restricted environment, girls under 16 years contributed to a half centimetre more loss of MUAC than older women of the same parity. Such a loss of fat, muscle or both may put younger women and their breastfed offspring at greater risk of other adverse health and nutritional outcomes. PMID- 20929504 TI - Intensified multifactorial treatment of patients with Type 2 diabetes: what can be achieved and does it pay off? AB - By influencing the standards of diabetes care and treatment guidelines throughout the world, the results of recent long-term risk factor interventions in Type 2 diabetes (T2D) have likely contributed to the improved health outcomes and induced a decline in mortality in people with T2D. Although we have a need for even more evidence to support early, individualized, and intensive management of all known modifiable risk factors, we have now reached an era in T2D care where the critical challenges appear to be to translate the insights, knowledge and benefits to patients in the community setting. Current surveys show slow progress in achieving treatment goals and in the use of recommended drugs and adjustments of lifestyle for the prevention of vascular complications in diabetes. The resistance and barriers among medical professionals and patients likely have multiple causes. The present review focuses on experiences from multifactorial interventions in high-risk patients with T2D where it is possible to markedly improve their prognosis. PMID- 20929505 TI - Effects of systolic and diastolic blood pressures on incident coronary heart disease and all-cause death in Chinese women with Type 2 diabetes: the Hong Kong Diabetes Registry. AB - BACKGROUND: Elevated blood pressure (BP) is an important risk factor for the development of coronary heart disease (CHD), although the threshold above which the risk increases has not been clearly defined. The aim of the present study was to examine the full-range association between BP and CHD. METHODS: A prospective cohort of 3861 Chinese women with Type 2 diabetes mellitus (T2DM) was followed for a median of 5.61 years. Restricted cubic spline analysis was used to examine the relationship between BP and CHD. RESULTS: Subjects who developed CHD were older, more likely to be smokers, had a significantly longer duration of diabetes, higher systolic BP (SBP), glycated hemoglobin, albuminuria, low-density lipoprotein-cholesterol, and triglycerides, and lower estimated glomerular filtration rate and high-density lipoprotein-cholesterol. Mortality was higher in those who developed CHD compared with those who did not, with all-cause death in 30.2% and 7.8% of patients, respectively. Over 21,641 and 22 049 person-years follow up, 4.4% of patients (n = 169) developed CHD and 8.8% (n = 340) died, respectively. The relative risk of SBP for CHD was constant up to 120 mmHg, after which it started to rise: from 130 mmHg, each 10-mmHg increase in SBP was associated with a 1.13-fold increased risk of CHD. CONCLUSIONS: We identified 130 mmHg as the threshold of SBP for increased risk of CHD in Chinese female patients with T2DM. It appears that 67-77 mmHg is the optimal range for diastolic BP, within which the risk of CHD is lowest. PMID- 20929506 TI - Cinnamic acid, from the bark of Cinnamomum cassia, regulates glucose transport via activation of GLUT4 on L6 myotubes in a phosphatidylinositol 3-kinase independent manner. AB - BACKGROUND: Cinnamomum cassia (Family: Lauraceae) is an Ayurvedic medicinal plant used traditionally for the treatment of a number of diseases, including diabetes. The hypoglycemic effect of this plant has been established in vivo. However, the effects of cinnamic acid, isolated from C. cassia, on the insulin signaling cascade in an in vitro model have not been elucidated. Hence, the aim of the present study was to evaluate the anti-diabetic effect of cinnamic acid on glucose transport by L6 myotubes. METHODS: The mechanism of action of cinnamic acid was determined using specific targets in the insulin signaling pathway, including protein tyrosine phosphatase (PTP) 1B, phosphatidylinositol 3-kinase (PI3-K) and the glucose transporter GLUT4. After differentiation of myoblast to myotubes, the cells were serum deprived for 5 h and then treated with 1 ng/mL cinnamic acid and 50 MUmol/L rosiglitazone for 18 h and 100 nmol/L insulin for 20 min for gene expression studies. RESULTS: Expression of GLUT4 mRNA was increased following treatment of L6 myotubes with 1 ng/mL cinnamic acid. Furthermore, cinnamic acid inhibited PTP1B activity (by 96.5%), but had no significant effect on PI3-K activity. CONCLUSION: On the basis of the results of the present study, we postulate that cinnamic acid isolated from the hydro-alcoholic extract of Cinnamomum cassia activates glucose transport by a PI3-K-independent pathway. However, the detailed mechanism of action requires further analysis. PMID- 20929507 TI - Mild and severe forms of tuberculosis in diabetic and non-diabetic patients. AB - BACKGROUND: The aim of the present study was to compare the frequency of pleural tuberculosis in patients with and without diabetes mellitus (DM). METHODS: Three hundred consecutive patients who were smear positive for pulmonary tuberculosis or isolated pleural tuberculosis were enrolled in the study. Patients' age and smoking status (pack-years) were recorded. Patients were divided into two groups: those with and without DM. RESULTS: All patients enrolled in the study were male. Mean (+/- SD) patient age was 42.4 +/- 15.9 years. Of the 300 patients in the study, 48 had DM. There was no significant difference in the distribution of pulmonary tuberculosis and isolated pleural tuberculosis between patients with and without DM (P > 0.05). However, there was a significant difference in mean pack-years of smoking between patients with pulmonary tuberculosis and those with isolated pleural tuberculosis for all patients; patients with isolated pleural tuberculosis had a significantly lower number of pack-years of smoking (P < 0.05). CONCLUSION: Severe pulmonary involvement in DM patients may be due to smoking status. PMID- 20929508 TI - Relevance of insulin-like growth factor 2 in the etiopathophysiology of diabetic nephropathy: possible roles of phosphatase and tensin homolog on chromosome 10 and secreted protein acidic and rich in cysteine as regulators of repair. AB - BACKGROUND: Diabetic nephropathy (DN) is a devastating complication of diabetes, the exact molecular pathophysiology of which is not well established. Hyperglycemia increases insulin-like growth factors (IGFs), especially IGF2, which acts via the IGF1 receptor present on renal cells. Elevated glucose levels damage the kidney, which is repaired by modulators such as secreted protein acidic and rich in cysteine (SPARC). Hence, it was hypothesized that IGF2 and SPARC may have an important role in the etiology of DN. METHODS: Human renal biopsies, histopathologically categorized as normal, early Type 2 diabetes mellitus (T2DM), or established DN, were analyzed for the localization and expression of IGF2, its negative regulator phosphatase and tensin homolog on chromosome 10 (PTEN), and SPARC. RESULTS: Expression of IGF2, PTEN, and SPARC was increased in renal biopsies from T2DM patients compared with normal samples. Although IGF2 protein was increased in biopsies from DN patients, PTEN and SPARC levels were decreased. Real-time reverse transcription-polymerase chain reaction indicated that transcript levels of IGF2 and PTEN were greater than those of beta actin in all human renal biopsy samples. CONCLUSION: The results suggest the following molecular etiopathophysiology of DN: (i) hyperglycemia upregulates IGF2, which initiates PTEN, a regulator of IGF2 signaling; (ii) loss of this IGF2 PTEN feedback loop causes changes that are characteristic of DN; and (iii) lowered expression of the repair modulator SPARC results in the development and/or progression of DN. Hence, targeting relevant modulators, such as like IGF2, PTEN, and SPARC, may be important in the management of DN. PMID- 20929509 TI - Serum retinol-binding protein 4 is associated with insulin secretion in Chinese people with normal glucose tolerance. AB - BACKGROUND: Serum levels of retinol-binding protein 4 (RBP4) are associated with insulin resistance and type 2 diabetes mellitus (T2DM) and may impact on beta cell function. Thus, the present study investigated the relationship between serum RBP4 and insulin secretion in Chinese people with and without T2DM. METHODS: A 75 g oral glucose tolerance test was administered to all 867 subjects and serum RBP4 concentrations were determined. Insulin secretion was assessed by DeltaI/DeltaG (increment in plasma insulin concentration/plasma glucose concentration 30 min after the oral administration of 75 g glucose) and the total area under the curve for insulin over 180 min (AUC-I). Magnetic resonance imaging was used to measure visceral fat area (VFA) at L4-L5; subjects with VFA >=80 cm(2) were considered to have visceral obesity (VO). RESULTS: Serum RBP4 concentrations were significantly higher in subjects with VO than without, regardless of the presence of T2DM. In addition, in the entire group with normal glucose tolerance (NGT), serum RBP4 was positively correlated with DeltaI/DeltaG (r = 0.152; P < 0.01) and AUC-I (r = 0.218; P < 0.01) after adjustment for gender. The correlation between RBP4 and DeltaI/DeltaG (r = 0.162; P < 0.05) and AUC-I (r = 0.195; P < 0.01) remained in NGT non-VO subjects. No correlation was found between serum RBP4 and DeltaI/DeltaG or AUC-I in T2DM patients. Stepwise multiple regression analysis showed that serum RBP4 is an independent factor that contributes to DeltaI/DeltaG (beta = 0.176) and AUC-I (beta = 0.204) in NGT non VO subjects. CONCLUSIONS: Serum RBP4 is correlated with glucose-stimulated insulin secretion in NGT non-VO subjects, but not in NGT VO subjects and T2DM patients. PMID- 20929510 TI - Leading the way: guidance to quality scientific reporting. PMID- 20929511 TI - Expression of concern. PMID- 20929513 TI - Ischemic priapism and implant surgery with sharp corporal fibrosis excision. AB - INTRODUCTION: Prolonged ischemic priapism is commonly associated with severe erectile dysfunction. Subsequent implant surgery is complicated by fibrosis of corporal tissue. AIM: In this article we review clinical practice methods for safe and effective use of intracavernosal injection therapy as well as management of erectile dysfunction that may result from inappropriate priapism treatment. METHODS: A case report is presented followed by a review of literature addressing surgical techniques for penile prosthesis implantation in the setting of corporal fibrosis. MAIN OUTCOME MEASURES: Review of literature and discussion of best practice management. RESULTS: Erectile dysfunction should be clearly distinguished from premature ejaculation. Careful training and monitoring of patients using penile self-injection therapy is essential for preventing episodes of priapism. Local injection clinics that are primarily motivated by financial considerations threaten the safe management of men with sexual dysfunction. Development of corporal fibrosis occurs during prolonged ischemic priapism and is duration-dependent. Implant surgeons should be familiar with maneuvers to address fibrotic corporal tissue. PMID- 20929516 TI - Responses to the proposed DSM-V changes. PMID- 20929517 TI - The DSM diagnostic criteria for Hypoactive Sexual Desire Disorder in men. AB - INTRODUCTION: Hypoactive Sexual Desire Disorder (HSDD) is one of two sexual desire disorders in the Diagnostic and Statistical Manual of Mental Disorders (DSM) and is defined by two criteria: A-"persistently or recurrently deficient (or absent) sexual fantasies and desire for sexual activity" and B-"marked distress or interpersonal difficulty." AIM: This paper reviews the prevalence and correlates of low desire in men and qualitative and quantitative research on the experience of sexual desire in men and women. METHODS: A literature search of Medline, PudMed, and PsychInfo was used to identify any publication on low desire in men. MAIN OUTCOME MEASURE: The strength of empirical findings was used as a basis for making proposed revisions to the diagnostic criteria for HSDD in men. RESULTS: The dilemma of whether desire and arousal can be reliably differentiated in men is discussed, and parallels to the literature in women are drawn. Finally, I consider three options for the diagnosis of low desire in men for DSM-5. Option 1 proposes that the DSM-IV-TR name and criteria are preserved for men in DSM-5. Option 2 proposes that the recently proposed criteria for Sexual Interest/Arousal Disorder in women are also adopted for men, which would result in one gender neutral category. Option 3 proposes that the criteria for Sexual Interest/Arousal Disorder also be applied to men, with a minor modification to one criterion (i.e., that absent or reduced genital and/or nongenital physical changes not be included as a criterion); this diagnosis would then be applied only to men. CONCLUSIONS: The evidence supporting each of these proposals is presented and critiqued. It is concluded that the proposal for DSM-5 should be made on the basis of field testing of new criteria. PMID- 20929518 TI - Highlights from the history of sexual medicine. AB - INTRODUCTION: Today, we have a clear concept of sexual medicine and how to define this medical discipline. But historically, the unification of sexuality and medicine was not a given condition. Medicine was mainly focused on human reproduction and how to prevent and treat sexually transmitted diseases. Hardly any other aspect would have met the interest of medical doctors for centuries. METHODS: Historical review that can only highlight developments and milestones of sexual medicine and is not intended to be encyclopedic. RESULTS: Perhaps, the first true medicalization of sexuality was the dreadful anti-masturbation campaign led by doctors, beginning with Tissot, since the middle of the 18th century. In the 2nd half of the 19th century, first pioneers like the physician Paolo Mantagazza were systematically addressing issues related to human sexuality. This highly developing scientific field and medical community were destroyed after 1933 by the political influence of the national socialists in Europe. After World War II, a new era started with the works of Alfred Kinsey and other sexologists mainly in the United States of America. CONCLUSIONS: The term sexual medicine was established around 1970, most likely in Europe, and subsequently resulted in a new worldwide academic and clinical speciality. PMID- 20929519 TI - Predicting delay in presentation in men with Peyronie's disease. AB - INTRODUCTION: Many men with Peyronie's disease (PD) delay presentation to a urologist. The reasons for this are unclear. AIM: To define the differences in men who present early compared to those presenting in a delayed fashion and to determine predictors of delayed presentation. METHODS: A retrospective analysis of all patients presenting for the first medical evaluation of PD. All patients underwent a standard history and physical examination and had a standardized deformity assessment. Demographic and PD parameters were recorded. MAIN OUTCOME MEASURES: Statistical comparison was used to define factors that were different between early and delayed presenters and multivariable analysis was used to define predictors of presentation >12 months. RESULTS: 482 patients were analyzed, 61% presenting <=12 months, 39% >12 months. Mean patient age was 52 +/- 13 years and mean duration of PD was 17 +/- 30 months. Mean measured curvature was 42 degrees +/- 19 degrees . Multivariable analysis revealed that delayed presentation patients were significantly more likely to be older (odds ratio [OR] = 4.0), to be in long-term relationships (OR = 3.6), to have dorsal curvature (OR = 2.5), to have curvature <45 degrees (OR = 3.3), to be heterosexual (OR = 2.0), and to have simple deformity (OR = 1.5). CONCLUSIONS: One-third of men with PD presented in a delayed fashion and they tended to be older, to be in long-term relationships, to have dorsal curvature, or to have simple deformity. PMID- 20929520 TI - A letter to the editor on the article by Burri et al. PMID- 20929523 TI - Penile prostheses for the treatment for erectile dysfunction. PMID- 20929524 TI - Automatic, context-specific generation of Gene Ontology slims. AB - BACKGROUND: The use of ontologies to control vocabulary and structure annotation has added value to genome-scale data, and contributed to the capture and re-use of knowledge across research domains. Gene Ontology (GO) is widely used to capture detailed expert knowledge in genomic-scale datasets and as a consequence has grown to contain many terms, making it unwieldy for many applications. To increase its ease of manipulation and efficiency of use, subsets called GO slims are often created by collapsing terms upward into more general, high-level terms relevant to a particular context. Creation of a GO slim currently requires manipulation and editing of GO by an expert (or community) familiar with both the ontology and the biological context. Decisions about which terms to include are necessarily subjective, and the creation process itself and subsequent curation are time-consuming and largely manual. RESULTS: Here we present an objective framework for generating customised ontology slims for specific annotated datasets, exploiting information latent in the structure of the ontology graph and in the annotation data. This framework combines ontology engineering approaches, and a data-driven algorithm that draws on graph and information theory. We illustrate this method by application to GO, generating GO slims at different information thresholds, characterising their depth of semantics and demonstrating the resulting gains in statistical power. CONCLUSIONS: Our GO slim creation pipeline is available for use in conjunction with any GO-annotated dataset, and creates dataset-specific, objectively defined slims. This method is fast and scalable for application to other biomedical ontologies. PMID- 20929525 TI - Activated mammalian target of rapamycin is a potential therapeutic target in gastric cancer. AB - BACKGROUND: The mammalian target of rapamycin (mTOR) plays a key role in cellular growth and homeostasis. The purpose of our present study is to investigate the expression of activated mTOR (p-mTOR) in gastric cancer patients, their prognostic significance and the inhibition effect of RAD001 on tumor growth and to determine whether targeted inhibition of mTOR could be a potential therapeutic strategy for gastric cancer. METHODS: The expression of p-mTOR was detected in specimens of 181 gastric cancers who underwent radical resection (R0) by immunohistochemistry. The correlation of p-mTOR expression to clinicopathologic features and survival of gastric cancer was studied. We also determined the inhibition effect of RAD001 on tumor growth using BGC823 and AGS human gastric cancer cell lines. RESULTS: Immunostaining for p-mTOR was positive in 93 of 181 (51.4%) gastric cancers, closely correlated with lymph node status and pTNM stage. Patients with p-mTOR positive showed significantly shorter disease-free survival (DFS) and overall survival (OS) rates than those with p-mTOR-negative tumors in univariable analyses, and there was a trend toward a correlation between p-mTOR expression and survival in multivariable analyses. RAD001 markedly inhibited dose-dependently proliferation of human gastric carcinoma cells by down regulating expression of p70s6k, p-p70s6k, C-myc, CyclinD1 and Bcl-2, up regulating expression of P53. CONCLUSIONS: In gastric cancer, p-mTOR is a potential therapeutic target and RAD001 was a promising treatment agent with inducing cell cycle arrest and apoptosis by down-regulating expression of C-myc, CyclinD1 and Bcl-2, up-regulating expression of P53. PMID- 20929526 TI - Epigenetic modifications as key regulators of Waldenstrom's Macroglobulinemia biology. AB - Waldenstrom's Macroglobulinemia is a low-grade B-cell lymphoma characterized by the presence of lymphoplasmacytic cells in the bone marrow and a monoclonal immunoglobulin M in the circulation. Recent evidences support the hypothesis that epigenetic modifications lead to Waldesntrom cell proliferation and therefore play a crucial role in the pathogenesis of this disease. Indeed, while cytogenetic and gene expression analysis have demonstrated minimal changes; microRNA aberrations and modification in the histone acetylation status of primary Waldenstrom Macroglobulinemia tumor cells have been described. These findings provide a better understanding of the underlying molecular changes that lead to the initiation and progression of this disease. PMID- 20929527 TI - Imperforate anus with a rectovestibular fistula and pseudotail: a case report. AB - INTRODUCTION: Human tails and pseudotails are rare sacrococcygeal lesions that are associated with a wide variety of anomalies and syndromes. Anorectal malformations are also relatively uncommon congenital defects that often occur in conjunction with syndromes or other congenital abnormalities. The anomalies associated with both disorders determine the timing and approach to surgical correction. We present an unusual case of a patient with both imperforate anus and a pseudotail in the absence of a syndrome or other associated anomalies and we emphasize the necessity of a thorough preoperative evaluation. CASE PRESENTATION: A Caucasian girl was born at term after an uncomplicated pregnancy and was noted at birth to have a skin-covered posterior midline mass and imperforate anus with a fistula to the vaginal vestibule. Ultrasound and magnetic resonance imaging revealed a predominately fatty lesion without presacral extension and ruled out associated spinal and cord abnormalities. The patient underwent diversion with colostomy and a mucous fistula in the newborn period as a fistulogram demonstrated a long fistulous tract to normal rectum and it was anticipated that anoplasty and resection of the mass would require extensive posterior dissection. The sacrococcygeal mass was removed during posterior sagittal anorectoplasty at the age of six weeks which was determined to be a pseudotail because of the composition of brown fat and cartilage. The patient is now 14 months old with normal bowel function after a colostomy takedown. CONCLUSION: A comprehensive preoperative assessment and thoughtful operative plan were necessary in this unusual case because of the extensive differential diagnosis for sacrococcygeal masses in the newborn and the frequency of anomalies and syndromes associated with tail variants and imperforate anus. The pediatricians and neonatologists who initially evaluate such patients and the surgeons who correct these disorders must be aware of the potential pitfalls in their management. PMID- 20929528 TI - Expression analysis of flavonoid biosynthesis genes during Arabidopsis thaliana silique and seed development with a primary focus on the proanthocyanidin biosynthetic pathway. AB - BACKGROUND: The coordinated activity of different flavonoid biosynthesis genes in Arabidopsis thaliana results in tissue-specific accumulation of flavonols, anthocyanins and proanthocyanidins (PAs). These compounds possess diverse functions in plants including light-attenuation and oxidative stress protection. Flavonoids accumulate in a stimulus- and/or development-dependent manner in specific parts of the plant. PAs accumulate in the seed coat (testa). FINDINGS: We describe the biological material and the preparation of total RNA for the AtGenExpress developmental silique and seed series. AtGenExpress ATH1 GeneChip expression data from the different stages were reanalyzed and verified using quantitative real time PCR (qPCR). We observed organ-specific transcript accumulation of specific flavonoid biosynthetic genes consistent with previously published data and our PA compound accumulation data. In addition, we investigated the regulation of PA accumulation in developing A. thaliana seeds by correlating gene expression patterns of specific flavonoid biosynthesis genes with different seed embryonic developmental stages and organs and present two useful marker genes for isolated valve and replum organs, as well as one seed specific marker. CONCLUSIONS: Potential caveats of array-based expression data are discussed based on comparisons with qPCR data. Results from ATH1 microarray and qPCR experiments revealed a shift in gene activity from general flavonoid biosynthesis at early stages of seed development to PA synthesis at late (mature) stages of embryogenesis. The examined PA accumulation-associated genes, including biosynthetic and regulatory genes, were found to be exclusively expressed in immature seeds. Accumulation of PAs initiates at the early heart stage of silique and seed development. Our findings provide new insights for further studies targeting the PA pathway in seeds. PMID- 20929529 TI - Cardiovascular risk profile: cross-sectional analysis of motivational determinants, physical fitness and physical activity. AB - BACKGROUND: Cardiovascular risk factors are associated with physical fitness and, to a lesser extent, physical activity. Lifestyle interventions directed at enhancing physical fitness in order to decrease the risk of cardiovascular diseases should be extended. To enable the development of effective lifestyle interventions for people with cardiovascular risk factors, we investigated motivational, social-cognitive determinants derived from the Theory of Planned Behavior (TPB) and other relevant social psychological theories, next to physical activity and physical fitness. METHODS: In the cross-sectional Utrecht Police Lifestyle Intervention Fitness and Training (UP-LIFT) study, 1298 employees (aged 18 to 62) were asked to complete online questionnaires regarding social-cognitive variables and physical activity. Cardiovascular risk factors and physical fitness (peak VO2) were measured. RESULTS: For people with one or more cardiovascular risk factors (78.7% of the total population), social-cognitive variables accounted for 39% (p < .001) of the variance in the intention to engage in physical activity for 60 minutes every day. Important correlates of intention to engage in physical activity were attitude (beta = .225, p < .001), self-efficacy (beta = .271, p < .001), descriptive norm (beta = .172, p < .001) and barriers (beta = -.169, p < .01). Social-cognitive variables accounted for 52% (p < .001) of the variance in physical active behaviour (being physical active for 60 minutes every day). The intention to engage in physical activity (beta = .469, p < .001) and self-efficacy (beta = .243, p < .001) were, in turn, important correlates of physical active behavior.In addition to the prediction of intention to engage in physical activity and physical active behavior, we explored the impact of the intensity of physical activity. The intensity of physical activity was only significantly related to physical active behavior (beta = .253, p < .01, R2 = .06, p < .001). An important goal of our study was to investigate the relationship between physical fitness, the intensity of physical activity and social-cognitive variables. Physical fitness (R2 = .23, p < .001) was positively associated with physical active behavior (beta = .180, p < .01), self-efficacy (beta = .180, p < .01) and the intensity of physical activity (beta = .238, p < .01).For people with one or more cardiovascular risk factors, 39.9% had positive intentions to engage in physical activity and were also physically active, and 10.5% had a low intentions but were physically active. 37.7% had low intentions and were physically inactive, and about 11.9% had high intentions but were physically inactive. CONCLUSIONS: This study contributes to our ability to optimize cardiovascular risk profiles by demonstrating an important association between physical fitness and social-cognitive variables. Physical fitness can be predicted by physical active behavior as well as by self-efficacy and the intensity of physical activity, and the latter by physical active behavior.Physical active behavior can be predicted by intention, self-efficacy, descriptive norms and barriers. Intention to engage in physical activity by attitude, self-efficacy, descriptive norms and barriers. An important input for lifestyle changes for people with one or more cardiovascular risk factors was that for ca. 40% of the population the intention to engage in physical activity was in line with their actual physical active behavior. PMID- 20929530 TI - Production of haploids and doubled haploids in oil palm. AB - BACKGROUND: Oil palm is the world's most productive oil-food crop despite yielding well below its theoretical maximum. This maximum could be approached with the introduction of elite F1 varieties. The development of such elite lines has thus far been prevented by difficulties in generating homozygous parental types for F1 generation. RESULTS: Here we present the first high-throughput screen to identify spontaneously-formed haploid (H) and doubled haploid (DH) palms. We secured over 1,000 Hs and one DH from genetically diverse material and derived further DH/mixoploid palms from Hs using colchicine. We demonstrated viability of pollen from H plants and expect to generate 100% homogeneous F1 seed from intercrosses between DH/mixoploids once they develop female inflorescences. CONCLUSIONS: This study has generated genetically diverse H/DH palms from which parental clones can be selected in sufficient numbers to enable the commercial scale breeding of F1 varieties. The anticipated step increase in productivity may help to relieve pressure to extend palm cultivation, and limit further expansion into biodiverse rainforest. PMID- 20929531 TI - Successful treatment of Fusarium solani ecthyma gangrenosum in a patient affected by leukocyte adhesion deficiency type 1 with granulocytes transfusions. AB - BACKGROUND: Ecthyma gangrenosum (EG) manifests as a skin lesion affecting patients suffering extreme neutropenia and is commonly associated with Pseudomonas aeruginosa in immunocompromised patients. Leukocyte adhesion deficiency I (LAD I) which count among primary immunodeficiency syndromes of the innate immunity, is an autosomal recessive disorder characterized in its severe phenotype by a complete defect in CD18 expression on neutrophils, delayed cord separation, chronic skin ulcers mainly due to recurrent bacterial and fungal infections, leucocytosis with high numbers of circulating neutrophils and an accumulation of abnormally low number of neutrophils at sites of infection. CASE PRESENTATION: We report at our knowledge the first case of a child affected by LAD-1, who experienced during her disease course a multi-bacterial and fungal EG lesion caused by fusarium solani. Despite targeted antibiotics and anti-fungi therapy, the lesion extended for as long as 18 months and only massive granulocytes pockets transfusions in association with G-CSF had the capacity to cure this lesion. CONCLUSION: We propose that granulocytes pockets transfusions will be beneficial to heal EG especially in severely immunocompromised patients. PMID- 20929533 TI - The parenting attitudes and the stress of mothers predict the asthmatic severity of their children: a prospective study. AB - OBJECTIVE: To examine relationships between a mother's stress-related conditions and parenting attitudes and their children's asthmatic status. METHODS: 274 mothers of an asthmatic child 2 to 12 years old completed a questionnaire including questions about their chronic stress/coping behaviors (the "Stress Inventory"), parenting attitudes (the "Ta-ken Diagnostic Test for Parent-Child Relationship, Parent Form"), and their children's disease status. One year later, a follow-up questionnaire was mailed to the mothers that included questions on the child's disease status. RESULTS: 223 mothers (81%) responded to the follow-up survey. After controlling for non-psychosocial factors including disease severity at baseline, multiple linear regression analysis followed by multiple logistic regression analysis found chronic irritation/anger and emotional suppression to be aggravating factors for children aged < 7 years; for children aged 7 and over, the mothers' egocentric behavior was a mitigating factor while interference was an aggravating factor. CONCLUSIONS: Different types of parental stress/coping behaviors and parenting styles may differently predict their children's asthmatic status, and such associations may change as children grow. PMID- 20929532 TI - Nutritional and herbal supplements for anxiety and anxiety-related disorders: systematic review. AB - BACKGROUND: Over the past several decades, complementary and alternative medications have increasingly become a part of everyday treatment. With the rising cost of prescription medications and their production of unwanted side effects, patients are exploring herbal and other natural remedies for the management and treatment of psychological conditions. Psychological disorders are one of the most frequent conditions seen by clinicians, and often require a long term regimen of prescription medications. Approximately 6.8 million Americans suffer from generalized anxiety disorder. Many also suffer from the spectrum of behavioural and physical side effects that often accompany its treatment. It is not surprising that there is universal interest in finding effective natural anxiolytic (anti-anxiety) treatments with a lower risk of adverse effects or withdrawal. METHODS: An electronic and manual search was performed through MEDLINE/PubMed and EBSCO. Articles were not discriminated by date of publication. Available clinical studies published in English that used human participants and examined the anxiolytic potential of dietary and herbal supplements were included. Data were extracted and compiled into tables that included the study design, sample population, intervention, control, length of treatment, outcomes, direction of evidence, and reported adverse events. RESULTS: A total of 24 studies that investigated five different CAM monotherapies and eight different combination treatments and involved 2619 participants met the inclusion criteria and were analyzed. There were 21 randomized controlled trials and three open label, uncontrolled observational studies. Most studies involved patients who had been diagnosed with either an anxiety disorder or depression (n = 1786). However, eight studies used healthy volunteers (n = 877) who had normal levels of anxiety, were undergoing surgery, tested at the upper limit of the normal range of a trait anxiety scale, had adverse premenstrual symptoms or were peri-menopausal, reported anxiety and insomnia, or had one month or more of elevated generalized anxiety. Heterogeneity and the small number of studies for each supplement or combination therapy prevented a formal meta-analysis. Of the randomized controlled trials reviewed, 71% (15 out of 21) showed a positive direction of evidence. Any reported side effects were mild to moderate. CONCLUSIONS: Based on the available evidence, it appears that nutritional and herbal supplementation is an effective method for treating anxiety and anxiety-related conditions without the risk of serious side effects. There is the possibility that any positive effects seen could be due to a placebo effect, which may have a significant psychological impact on participants with mental disorders. However, based on this systematic review, strong evidence exists for the use of herbal supplements containing extracts of passionflower or kava and combinations of L-lysine and L arginine as treatments for anxiety symptoms and disorders. Magnesium-containing supplements and other herbal combinations may hold promise, but more research is needed before these products can be recommended to patients. St. John's wort monotherapy has insufficient evidence for use as an effective anxiolytic treatment. PMID- 20929534 TI - Rheumatoid arthritis patients receive less frequent acute reperfusion and secondary prevention therapy after myocardial infarction compared with the general population. AB - INTRODUCTION: The 30-day case-fatality rate after acute myocardial infarction (MI) for rheumatoid arthritis (RA) patients is twice that of the general population. This study compared the frequency and timeliness of early reperfusion therapy and treatment with secondary prevention medications after acute MI in RA patients and controls. METHODS: We performed a structured medical chart review of RA patients and matched controls who had been admitted with acute MI to one of three hospitals in Victoria, Australia, between 1995 and 2005. The administration and timing of acute reperfusion therapy and in-hospital treatment with secondary prevention medications were compared between the two groups. Acute reperfusion was defined as thrombolysis or percutaneous coronary intervention (PCI) within 12 hours of the first symptom of MI. RESULTS: The medical charts of 90 RA patients and 90 matched controls were reviewed. The RA patients were significantly less likely to receive acute reperfusion compared with the controls (16% versus 37%: odds ratio (OR), 0.27; 95% confidence interval (CI), 0.10 to 0.64)), and this difference persisted after adjusting for type of MI, clinical setting of MI, and prior MI (OR, 0.2; 95% CI, 0.05 to 0.6). The RA patients also received less frequent in-hospital treatment with beta blockers (71% versus 83%; OR, 0.42; 95% CI, 0.18 to 0.96) and lipid-lowering agents (40% versus 70%; OR, 0.21; 95% CI, 0.09 to 0.46). CONCLUSIONS: RA patients who experience acute MI receive acute reperfusion and secondary prevention medications less frequently than do controls. This may contribute to higher case-fatality rates after MI in RA patients. PMID- 20929535 TI - The modulation of auditory novelty processing by working memory load in school age children and adults: a combined behavioral and event-related potential study. AB - BACKGROUND: We investigated the processing of task-irrelevant and unexpected novel sounds and its modulation by working-memory load in children aged 9-10 and in adults. Environmental sounds (novels) were embedded amongst frequently presented standard sounds in an auditory-visual distraction paradigm. Each sound was followed by a visual target. In two conditions, participants evaluated the position of a visual stimulus (0-back, low load) or compared the position of the current stimulus with the one two trials before (2-back, high load). Processing of novel sounds were measured with reaction times, hit rates and the auditory event-related brain potentials (ERPs) Mismatch Negativity (MMN), P3a, Reorienting Negativity (RON) and visual P3b. RESULTS: In both memory load conditions novels impaired task performance in adults whereas they improved performance in children. Auditory ERPs reflect age-related differences in the time-window of the MMN as children showed a positive ERP deflection to novels whereas adults lack an MMN. The attention switch towards the task irrelevant novel (reflected by P3a) was comparable between the age groups. Adults showed more efficient reallocation of attention (reflected by RON) under load condition than children. Finally, the P3b elicited by the visual target stimuli was reduced in both age groups when the preceding sound was a novel. CONCLUSION: Our results give new insights in the development of novelty processing as they (1) reveal that task-irrelevant novel sounds can result in contrary effects on the performance in a visual primary task in children and adults, (2) show a positive ERP deflection to novels rather than an MMN in children, and (3) reveal effects of auditory novels on visual target processing. PMID- 20929536 TI - Rheumatoid synovial fluid interleukin-17-producing CD4 T cells have abundant tumor necrosis factor-alpha co-expression, but little interleukin-22 and interleukin-23R expression. AB - INTRODUCTION: Th17 cells have been implicated in the pathogenesis of rheumatoid arthritis (RA). The aim of this study was to systematically analyse the phenotype, cytokine profile and frequency of interleukin-17 (IL-17) producing CD4 positive T cells in mononuclear cells isolated from peripheral blood, synovial fluid and synovial tissue of RA patients with established disease, and to correlate cell frequencies with disease activity. METHODS: Flow cytometry was used to analyse the phenotype and cytokine production of mononuclear cells isolated from peripheral blood (PBMC) (n = 44), synovial fluid (SFMC) (n = 14) and synovium (SVMC) (n = 10) of RA patients and PBMC of healthy controls (n = 13). RESULTS: The frequency of IL-17-producing CD4 T cells was elevated in RA SFMC compared with RA PBMC (P = 0.04). However, the frequency of this population in RA SVMC was comparable to that in paired RA PBMC. The percentage of IL-17 producing CD4 T cells coexpressing tumor necrosis factor alpha (TNFalpha) was significantly increased in SFMC (P = 0.0068). The frequency of IFNgamma-producing CD4 T cells was also significantly higher in SFMC than paired PBMC (P = 0.042). The majority of IL-17-producing CD4 T cells coexpressed IFNgamma. IL-17-producing CD4 T cells in RA PBMC and SFMC exhibited very little IL-22 or IL-23R coexpression. CONCLUSIONS: These findings demonstrate a modest enrichment of IL 17-producing CD4 T cells in RA SFMC compared to PBMC. Th17 cells in SFMC produce more TNFalpha than their PBMC counterparts, but are not a significant source of IL-22 and do not express IL-23R. However, the percentage of CD4 T cells which produce IL-17 in the rheumatoid joint is low, suggesting that other cells may be alternative sources of IL-17 within the joints of RA patients. PMID- 20929539 TI - Simultaneous detection and differentiation by multiplex real time RT-PCR of highly pathogenic avian influenza subtype H5N1 classic (clade 2.2.1 proper) and escape mutant (clade 2.2.1 variant) lineages in Egypt. AB - BACKGROUND: The endemic status of highly pathogenic avian influenza virus (HPAIV) of subtype H5N1 in Egypt continues to devastate the local poultry industry and poses a permanent threat for human health. Several genetically and antigenically distinct H5N1 lineages co-circulate in Egypt: Strains of clade 2.2.1 proper replicate mainly in backyard birds causing the bulk of human infections, while a variant lineage within 2.2.1 (2.2.1 v) appears to be perpetuated mainly in commercial poultry farms in Egypt. Viruses of the 2.2.1 v lineage represent drift variants escaping from conventional vaccine-induced immunity and some of these strains also escaped detection by commercial real time reverse transcriptase PCR (RT-qPCR) protocols due to mismatches in the primers/probe binding sites. RESULTS: We developed therefore a versatile, sensitive and lineage-specific multiplex RT-qPCR for detection and typing of H5N1 viruses in Egypt. Analytical characterization was carried out using 50 Egyptian HPAIV H5N1 strains isolated since 2006 and 45 other avian influenza viruses (AIV). A detection limit of 400 cRNA copies per ml sample matrix was found. Higher diagnostic sensitivity of the multiplex assay in comparison to other generic H5 or M-gene based RT-qPCR assays were found by examination of 63 swab samples from experimentally infected chickens and 50 AIV-positive swab samples from different host species in the field in Egypt. CONCLUSIONS: The new multiplex RT-qPCR assay could be useful for rapid high-throughput monitoring for the presence of HPAIV H5N1 in commercial poultry in Egypt. It may also aid in prospective epidemiological studies to further delineate and better control spread of HPAIV H5N1 in Egypt. PMID- 20929538 TI - Cardiovascular magnetic resonance at 3.0 T: current state of the art. AB - There are advantages to conducting cardiovascular magnetic resonance (CMR) studies at a field strength of 3.0 Telsa, including the increase in bulk magnetization, the increase in frequency separation of off-resonance spins, and the increase in T1 of many tissues. However, there are significant challenges to routinely performing CMR at 3.0 T, including the reduction in main magnetic field homogeneity, the increase in RF power deposition, and the increase in susceptibility-based artifacts.In this review, we outline the underlying physical effects that occur when imaging at higher fields, examine the practical results these effects have on the CMR applications, and examine methods used to compensate for these effects. Specifically, we will review cine imaging, MR coronary angiography, myocardial perfusion imaging, late gadolinium enhancement, and vascular wall imaging. PMID- 20929540 TI - Prediction of global left ventricular functional recovery in patients with heart failure undergoing surgical revascularisation, based on late gadolinium enhancement cardiovascular magnetic resonance. AB - BACKGROUND: The new gold standard for myocardial viability assessment is late gadolinium enhancement-cardiovascular magnetic resonance (LGE-CMR); this technique has demonstrated that the transmural extent of scar predicts segmental functional recovery. We now asked how the number of viable and number of viable+normal, segments predicted recovery of global left ventricular (LV) function in patients undergoing CABG. Finally, we examined which segmental transmural threshold of scarring best predicted global LV recovery. METHODS AND RESULTS: Fifty patients with reduced LV ejection fraction (EF) referred for CABG were recruited, and 33 included in this analysis. Patients underwent CMR to assess LV function and viability pre-operatively at 6 days and 6 months. Mean LVEF 38% +/- 11, which improved to 43% +/- 12 after surgery. 21/33 patients improved EF by >=3% (EF before 38% +/- 13, after 47% +/- 13), 12/33 did not (EF before 39% +/- 6, after 37% +/- 8). The only independent predictor for global functional recovery after revascularisation was the number of viable+normal segments: Based on a segmental transmural viability cutoff of <50%, ROC analysis demonstrated >=10 viable+normal segments predicted >=3% improvement in LVEF with a sensitivity of 95% and specificity of 75% (AUC = 0.9, p < 0.001). Transmural viability cutoffs of <25 and <75% and a cutoff of >=4 viable segments were less useful predictors of global LV recovery. CONCLUSIONS: Based on a 50% transmural viability cutoff, patients with >=10 viable+normal segments improve global LV function post revascularisation, while patients with fewer such segments do not. LGE-CMR is a simple and powerful tool for identifying which patients with impaired LV function will benefit from CABG. TRIAL REGISTRATION: Research Ethics Committee Unique Identifier: NRES:05/Q1603/42. The study is listed on the Current Controlled Trials Registry: ISRCTN41388968.URL: http://www.controlled-trials.com. PMID- 20929541 TI - Expression and function of human hemokinin-1 in human and guinea pig airways. AB - BACKGROUND: Human hemokinin-1 (hHK-1) and endokinins are peptides of the tachykinin family encoded by the TAC4 gene. TAC4 and hHK-1 expression as well as effects of hHK-1 in the lung and airways remain however unknown and were explored in this study. METHODS: RT-PCR analysis was performed on human bronchi to assess expression of tachykinin and tachykinin receptors genes. Enzyme immunoassay was used to quantify hHK-1, and effects of hHK-1 and endokinins on contraction of human and guinea pig airways were then evaluated, as well as the role of hHK-1 on cytokines production by human lung parenchyma or bronchi explants and by lung macrophages. RESULTS: In human bronchi, expression of the genes that encode for hHK-1, tachykinin NK1-and NK2-receptors was demonstrated. hHK-1 protein was found in supernatants from explants of human bronchi, lung parenchyma and lung macrophages. Exogenous hHK-1 caused a contractile response in human bronchi mainly through the activation of NK2-receptors, which blockade unmasked a NK1 receptor involvement, subject to a rapid desensitization. In the guinea pig trachea, hHK-1 caused a concentration-dependant contraction mainly mediated through the activation of NK1-receptors. Endokinin A/B exerted similar effects to hHK-1 on both human bronchi and guinea pig trachea, whereas endokinins C and D were inactive. hHK-1 had no impact on the production of cytokines by explants of human bronchi or lung parenchyma, or by human lung macrophages. CONCLUSIONS: We demonstrate endogenous expression of TAC4 in human bronchi, the encoded peptide hHK-1 being expressed and involved in contraction of human and guinea pig airways. PMID- 20929542 TI - Differential interleukin-6/Stat3 signaling as a function of cellular context mediates Ras-induced transformation. AB - INTRODUCTION: Tyrosine phosphorylated signal transducer and activator of transcription 3 (pStat3) is present in numerous cancers and is required for mediating tumorigenesis. Autocrine and paracrine interleukin (IL)-6 signaling is the principal mechanism by which Stat3 is persistently phosphorylated in epithelial tumors including breast, lung, colon and gastric cancer. The Ras oncogene mediates cellular transformation without evidence of pStat3 in cultured cells. Recently, however non-tyrosine phosphorylated Stat3 was shown to have a transcriptional activating function, a role in mitochondrial function and to mediate cell migration.. Here we examined the role of Stat3 in Ras mediated transformation. METHODS: Ha-rasV12 transformed mammary epithelial cells (MCF10A) cells were transduced with a Stat3shRNA, IL-6shRNA and/or treated with inhibitors of Janus kinases (JAKs) to examine the role of the IL-6 signaling pathway in Ras mediated invasion and tumorigenesis. RESULTS: Cellular migration, invasion, anchorage independent growth and tumorigenesis were largely abrogated in the Stat3-reduced cells compared to control cells. Analysis of MCF10A-Ras tumors revealed high levels of pStat3 and interleukin-6. Tumors derived from transgenic MMTV-K-Ras mice were also found to express pStat3 and IL-6. MCF10A-Ras cells, when grown in a three-dimensional Matrigel culture system revealed the appearance of the junctional protein E-Cadherin as a consequence of reducing Stat3 levels or inhibiting Stat3 activity. Decreasing IL-6 levels in the MCF10A-Ras cells abrogated tumorigenesis and reduced cell migration. By isolating Ras-expressing primary tumors and serially passaging these cells in two-dimensional culture led to a decrease in IL-6 and pStat3 levels with the reappearance of E-Cadherin. CONCLUSIONS: The cellular and environmental context can lead to differential IL 6/pStat3 signaling and a dependency on this cytokine and transcription factor for migration, invasion and tumorigenesis. PMID- 20929543 TI - Multi-analyte profiling of ten cytokines in South African HIV-infected patients with Immune Reconstitution Inflammatory Syndrome (IRIS). AB - BACKGROUND: Immune reconstitution inflammatory syndrome (IRIS) is an important complication of HAART in sub-Saharan Africa, where opportunistic infections (OIs) including mycobacteria and cryptococcus are common. The immune system's role in HIV infected patients is complex with cytokine expression strongly influencing HIV infection and replication. METHODS: We determined the expression patterns of 10 cytokines by Luminex multi-analyte profiling in 17 IRIS nested case-control pairs participating in a prospective South African cohort initiating anti retroviral therapy. RESULTS: Interferon-gamma (IFN-gamma) expression was significantly elevated in IRIS cases compared to controls (median 9.88 pg/ml versus 2.68 pg/ml, respectively, P = 0.0057), while other cytokines displayed non significant differences in expression. Significant correlation was observed between IL-6, IL-10, and IFN-gamma expression in the IRIS patients. CONCLUSIONS: Significantly increased expression levels of IFN-gamma suggest that this cytokine possibly plays a role in IRIS pathology and is a potential diagnostic marker. PMID- 20929544 TI - Emergency intraosseous access in a helicopter emergency medical service: a retrospective study. AB - BACKGROUND: Intraosseous access (IO) is a method for providing vascular access in out-of-hospital resuscitation of critically ill and injured patients when traditional intravenous access is difficult or impossible. Different intraosseous techniques have been used by our Helicopter Emergency Medical Services (HEMS) since 2003. Few articles document IO use by HEMS physicians. The aim of this study was to evaluate the use of intraosseous access in pre-hospital emergency situations handled by our HEMS. METHODS: We reviewed all medical records from the period May 2003 to April 2010, and compared three different techniques: Bone Injection Gun (B.I.G(r) - Waismed), manual bone marrow aspiration needle (Inter V - Medical Device Technologies) and EZ-IO(r) (Vidacare), used on both adults and paediatric patients. RESULTS: During this seven-year period, 78 insertion attempts were made on 70 patients. Overall success rates were 50% using the manual needle, 55% using the Bone Injection Gun, and 96% using the EZ-IO(r). Rates of success on first attempt were significantly higher using the EZ-IO(r) compared to the manual needle/Bone Injection Gun (p < 0.01/p < 0.001). Fifteen failures were due to insertion-related problems (19.2%), with four technical problems (5.1%) and three extravasations (3.8%) being the most frequent causes. Intraosseous access was primarily used in connection with 53 patients in cardiac arrest (75.7%), including traumatic arrest, drowning and SIDS. Other diagnoses were seven patients with multi-trauma (10.0%), five with seizures/epilepsy (7.1%), three with respiratory failure (4.3%) and two others (2.9%). Nearly one third of all insertions (n = 22) were made in patients younger than two years. No cases of osteomyelitis or other serious complications were documented on the follow-up. CONCLUSIONS: Newer intraosseous techniques may enable faster and more reliable vascular access, and this can lower the threshold for intraosseous access on both adult and paediatric patients in critical situations. We believe that all emergency services that handle critically ill or injured paediatric and adult patients should be familiar with intraosseous techniques. PMID- 20929545 TI - Genetic modification of Bluetongue virus by uptake of "synthetic" genome segments. AB - Since 1998, several serotypes of Bluetongue virus (BTV) have invaded several southern European countries. In 2006, the unknown BTV serotype 8 (BTV8/net06) unexpectedly invaded North-West Europe and has resulted in the largest BT outbreak ever recorded. More recently, in 2008 BTV serotype 6 was reported in The Netherlands and Germany. This virus, BTV6/net08, is closely related to modified live vaccine virus serotype 6, except for genome segment S10. This genome segment is closer related to that of vaccine virus serotype 2, and therefore BTV6/net08 is considered as a result of reassortment. Research on orbiviruses has been hampered by the lack of a genetic modification method. Recently, reverse genetics has been developed for BTV based on ten in vitro synthesized genomic RNAs. Here, we describe a targeted single-gene modification system for BTV based on the uptake of a single in vitro synthesized viral positive-stranded RNA. cDNAs corresponding to BTV8/net06 genome segments S7 and S10 were obtained by gene synthesis and cloned downstream of the T7 RNA-polymerase promoter and upstream of a unique site for a restriction enzyme at the 3'-terminus for run-off transcription. Monolayers of BSR cells were infected by BTV6/net08, and subsequently transfected with purified in vitro synthesized, capped positive stranded S7 or S10 RNA from BTV8/net06 origin. "Synthetic" reassortants were rescued by endpoint dilutions, and identified by serotype-specific PCR-assays for segment 2, and serogroup-specific PCRs followed by restriction enzyme analysis or sequencing for S7 and S10 segments. The targeted single-gene modification system can also be used to study functions of viral proteins by uptake of mutated genome segments. This method is also useful to generate mutant orbiviruses for other serogroups of the genus Orbivirus for which reverse genetics has not been developed yet. PMID- 20929546 TI - Phagocytosis and LPS alter the maturation state of beta-amyloid precursor protein and induce different Abeta peptide release signatures in human mononuclear phagocytes. AB - BACKGROUND: The classic neuritic beta-amyloid plaque of Alzheimer's disease (AD) is typically associated with activated microglia and neuroinflammation. Similarly, cerebrovascular beta-amyloid (Abeta) deposits are surrounded by perivascular macrophages. Both observations indicate a contribution of the mononuclear phagocyte system to the development of beta-amyloid. METHODS: Human CD14-positive mononuclear phagocytes were isolated from EDTA-anticoagulated blood by magnetic activated cell sorting. After a cultivation period of 72 hours in serum-free medium we assessed the protein levels of amyloid precursor protein (APP) as well as the patterns and the amounts of released Abeta peptides by ELISA or one-dimensional and two-dimensional urea-based SDS-PAGE followed by western immunoblotting. RESULTS: We observed strong and significant increases in Abeta peptide release upon phagocytosis of acetylated low density lipoprotein (acLDL) or polystyrene beads and also after activation of the CD14/TLR4 pathway by stimulation with LPS. The proportion of released N-terminally truncated Abeta variants was increased after stimulation with polystyrene beads and acLDL but not after stimulation with LPS. Furthermore, strong shifts in the proportions of single Abeta1-40 and Abeta2-40 variants were detected resulting in a stimulus specific Abeta signature. The increased release of Abeta peptides was accompanied by elevated levels of full length APP in the cells. The maturation state of APP was correlated with the release of N-terminally truncated Abeta peptides. CONCLUSIONS: These findings indicate that mononuclear phagocytes potentially contribute to the various N-truncated Abeta variants found in AD beta-amyloid plaques, especially under neuroinflammatory conditions. PMID- 20929548 TI - The role of non-governmental organisations in the management of separated and unaccompanied children, following disasters in Iran. AB - BACKGROUND: Following disasters, separated and unaccompanied children are among the most vulnerable, therefore international organisations have formed guidelines regarding the management of these children. Guidelines include recommendations for identifying and registering children, tracing family members, reunification and arrangements for interim and durable care. There is a lack of experiential evidence on how these principles are put into practice at operational levels, and whether existing policies were useful. There is a particular lack of empirical evidence from the disaster prone country of Iran. The aim of this study was to describe the role of Non- Governmental Organisations (NGOs) in the management of separated and unaccompanied children, following disasters in Iran in order to plan for and provision of future disasters. FINDINGS: The Iranian Red Crescent Organisation, Committee Emdad Imam Khomeini (a national organisation unique to Iran that is protected by the government and supported by public contributions) and Behzisti (the government welfare organisation in Iran) are the main figures involved in the management of separated and unaccompanied children, following disasters in Iran. NGOs are rarely responsible for caring for unaccompanied children, however they provide valuable support including financial assistance, arrangement of educational and extra-curricular activities and psychosocial support. Following the initial chaos after the Bam earthquake, international guidelines on separated and unaccompanied children were largely followed. CONCLUSIONS: Systems for managing separated and unaccompanied children following disasters in Iran, involving NGOs, are emerging. However, most are yet to be formalised. PMID- 20929547 TI - Genome-wide analysis of host-chromosome binding sites for Epstein-Barr Virus Nuclear Antigen 1 (EBNA1). AB - The Epstein-Barr Virus (EBV) Nuclear Antigen 1 (EBNA1) protein is required for the establishment of EBV latent infection in proliferating B-lymphocytes. EBNA1 is a multifunctional DNA-binding protein that stimulates DNA replication at the viral origin of plasmid replication (OriP), regulates transcription of viral and cellular genes, and tethers the viral episome to the cellular chromosome. EBNA1 also provides a survival function to B-lymphocytes, potentially through its ability to alter cellular gene expression. To better understand these various functions of EBNA1, we performed a genome-wide analysis of the viral and cellular DNA sites associated with EBNA1 protein in a latently infected Burkitt lymphoma B cell line. Chromatin-immunoprecipitation (ChIP) combined with massively parallel deep-sequencing (ChIP-Seq) was used to identify cellular sites bound by EBNA1. Sites identified by ChIP-Seq were validated by conventional real-time PCR, and ChIP-Seq provided quantitative, high-resolution detection of the known EBNA1 binding sites on the EBV genome at OriP and Qp. We identified at least one cluster of unusually high-affinity EBNA1 binding sites on chromosome 11, between the divergent FAM55 D and FAM55B genes. A consensus for all cellular EBNA1 binding sites is distinct from those derived from the known viral binding sites, suggesting that some of these sites are indirectly bound by EBNA1. EBNA1 also bound close to the transcriptional start sites of a large number of cellular genes, including HDAC3, CDC7, and MAP3K1, which we show are positively regulated by EBNA1. EBNA1 binding sites were enriched in some repetitive elements, especially LINE 1 retrotransposons, and had weak correlations with histone modifications and ORC binding. We conclude that EBNA1 can interact with a large number of cellular genes and chromosomal loci in latently infected cells, but that these sites are likely to represent a complex ensemble of direct and indirect EBNA1 binding sites. PMID- 20929550 TI - The Rg1 allele as a valuable tool for genetic transformation of the tomato 'Micro Tom' model system. AB - BACKGROUND: The cultivar Micro-Tom (MT) is regarded as a model system for tomato genetics due to its short life cycle and miniature size. However, efforts to improve tomato genetic transformation have led to protocols dependent on the costly hormone zeatin, combined with an excessive number of steps. RESULTS: Here we report the development of a MT near-isogenic genotype harboring the allele Rg1 (MT-Rg1), which greatly improves tomato in vitro regeneration. Regeneration was further improved in MT by including a two-day incubation of cotyledonary explants onto medium containing 0.4 MUM 1-naphthaleneacetic acid (NAA) before cytokinin treatment. Both strategies allowed the use of 5 MUM 6-benzylaminopurine (BAP), a cytokinin 100 times less expensive than zeatin. The use of MT-Rg1 and NAA pre incubation, followed by BAP regeneration, resulted in high transformation frequencies (near 40%), in a shorter protocol with fewer steps, spanning approximately 40 days from Agrobacterium infection to transgenic plant acclimatization. CONCLUSIONS: The genetic resource and the protocol presented here represent invaluable tools for routine gene expression manipulation and high throughput functional genomics by insertional mutagenesis in tomato. PMID- 20929549 TI - Possible association of norepinephrine transporter -3081(A/T) polymorphism with methylphenidate response in attention deficit hyperactivity disorder. AB - BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a heritable disorder characterized by symptoms of inattention and/or hyperactivity/impulsivity. Methylphenidate (MPH) has been shown to block the norepinephrine transporter (NET), and genetic investigations have demonstrated that the norepinephrine transporter gene (SLC6A2) is associated with ADHD. The aims of this study were to examine the association of the SLC6A2 -3081(A/T) and G1287A polymorphisms with MPH response in ADHD. METHODS: This study enrolled 112 children and adolescents with ADHD. A response criterion was defined based on the Clinical Global Impression-Improvement (CGI-I) score, and the ADHD Rating Scale IV (ARS) score was also assessed at baseline and 8 weeks after MPH treatment. RESULTS: We found that the subjects who had the T allele as one of the alleles (A/T or T/T genotypes) at the -3081(A/T) polymorphism showed a better response to MPH treatment than those with the A/A genotype as measured by the CGI-I. We also found a trend towards a difference in the change of the total ARS scores and hyperactivity/impulsivity subscores between subjects with and without the T allele. No significant association was found between the genotypes of the SLC6A2 G1287A polymorphism and response to ADHD treatment. CONCLUSION: Our findings provide evidence for the involvement of the -3081(A/T) polymorphism of SLC6A2 in the modulation of the effectiveness of MPH treatment in ADHD. PMID- 20929551 TI - Mucins in neoplastic spectrum of colorectal polyps: can they provide predictions? AB - BACKGROUND: The significance of expression of different mucins in succession of malignant transformation of colorectal polyps is not determined yet. The aim of the present study was to determine the pattern of expression of MUC1, MUC2, MUC5AC and MUC6 in colorectal polyps and to evaluate the applicability of using mucin expression in predicting the extent of malignant transformation in colorectal polyps. METHODS: A total of 454 polyp specimens comprising 36 hyperplastic polyps, 15 serrated adenomas, 258 tubular adenomas, 114 tubulovillous adenomas, and 31 villous adenomas were included in this study, and were immunostained for MUC1, MUC2, MUC5AC and MUC6 by using mucin specific antibodies. RESULTS: MUC1 and MUC6 were absent in all hyperplastic polyps and their expression was higher in serrated and traditional adenomas. Only 5 cases including 2 serrated adenomas, 1 tubulovillous adenoma, and 2 villous adenomas stained negative for MUC2. The highest expression of MUC5AC was observed in serrated adenomas followed by tubular adenomas. Binary logistic regression analysis indicated that positive staining for MUC1, and MUC6, and negative staining for MUC2 would increase the risk of invasion to mucosa or the muscularis mucosae in colorectal polyps. Ordinal regression analysis demonstrated a positive association between the level of staining for MUC1 and risk of being of high configuration/grade in colorectal polyps. CONCLUSIONS: MUC1, MUC2, MUC5AC, and MUC6 have the potential to be used as predictors of malignant transformation and invasion to mucosa or the muscularis mucosae in colorectal polyps. The most reliable predictions can be achieved by determining the level of expression of MUC1. PMID- 20929552 TI - Efficacy of labral repair, biceps tenodesis, and diagnostic arthroscopy for SLAP lesions of the shoulder: a randomised controlled trial. AB - BACKGROUND: Surgery for type II SLAP (superior labral anterior posterior) lesions of the shoulder is a promising but unproven treatment. The procedures include labral repair or biceps tenodesis. Retrospective cohort studies have suggested that the benefits of tenodesis include pain relief and improved function, and higher patient satisfaction, which was reported in a prospective non-randomised study. There have been no completed randomised controlled trials of surgery for type II SLAP lesions. The aims of this participant and observer blinded randomised placebo-controlled trial are to compare the short-term (6 months) and long-term (2 years) efficacy of labral repair, biceps tenodesis, and placebo (diagnostic arthroscopy) for alleviating pain and improving function for type II SLAP lesions. METHODS/DESIGN: A double-blind randomised controlled trial are performed using 120 patients, aged 18 to 60 years, with a history for type II SLAP lesions and clinical signs suggesting type II SLAP lesion, which were documented by MR arthrography and arthroscopy. Exclusion criteria include patients who have previously undergone operations for SLAP lesions or recurrent shoulder dislocations, and ruptures of the rotator cuff or biceps tendon. Outcomes will be assessed at baseline, three, six, 12, and 24 months. Primary outcome measures will be the clinical Rowe Score (1988-version) and the Western Ontario Instability Index (WOSI) at six and 24 months. Secondary outcome measures will include the Shoulder Instability Questionnaire (SIQ), the generic EuroQol (EQ-5 D and EQ-VAS), return to work and previous sports activity, complications, and the number of reoperations. DISCUSSION: The results of this trial will be of international importance and the results will be translatable into clinical practice. TRIAL REGISTRATION: [ClinicalTrials.gov NCT00586742]. PMID- 20929553 TI - Analysis of mtDNA sequence variants in colorectal adenomatous polyps. AB - Colorectal tumors mostly arise from sporadic adenomatous polyps. Polyps are defined as a mass of cells that protrudes into the lumen of the colon. Adenomatous polyps are benign neoplasms that, by definition display some characteristics of dysplasia. It has been shown that polyps were benign tumors which may undergo malignant transformation. Adenomatous polyps have been classified into three histologic types; tubular, tubulovillous, and villous with increasing malignant potential. The ability to differentially diagnose these colorectal adenomatous polyps is important for therapeutic intervention. To date, little efforts have been directed to identifying genetic changes involved in adenomatous polyps. This study was designed to examine the relevance of mitochondrial genome alterations in the three adenomatous polyps. Using high resolution restriction endonucleases and PCR-based sequencing, fifty-seven primary fresh frozen tissues of adenomatous polyps (37 tumors and 20 matched surrounding normal tissues) obtained from the southern regional Cooperative Human Tissue Network (CHTN) and Grady Memorial Hospital at Atlanta were screened with three mtDNA regional primer pairs that spanned 5.9 kbp. Results from our data analyses revealed the presence of forty-four variants in some of these mitochondrial genes that the primers spanned; COX I, II, III, ATP 6, 8, CYT b, ND 5, 6 and tRNAs. Based on the MITODAT database as a sequence reference, 25 of the 44 (57%) variants observed were unreported. Notably, a heteroplasmic variant C8515G/T in the MT-ATP 8 gene and a germline variant 8327delA in the tRNAlys was observed in all the tissue samples of the three adenomatous polyps in comparison to the referenced database sequence. A germline variant G9055A in the MT-ATP 6 gene had a frequency of 100% (17/17) in tubular and 57% (13/23) in villous adenomas; no corresponding variant was in tubulovillous adenomas. Furthermore, A9006G variant at MT-ATP 6 gene was observed at frequency of 57% (13/23) in villous adenomas only. Interestingly, variants A9006G and G9055A were absent in the villous tissue samples that were clinicopathological designated as "polyvillous adenomas". Our current data provide a basis for continued investigation of certain mtDNA variants as predictors of the three adenomatous polyps in a larger number of clinicopathological specimens. PMID- 20929554 TI - Differential regulation of p53 function by the N-terminal DeltaNp53 and Delta113p53 isoforms in zebrafish embryos. AB - BACKGROUND: The p53 protein family coordinates stress responses of cells and organisms. Alternative promoter usage and/or splicing of p53 mRNA gives rise to at least nine mammalian p53 proteins with distinct N- and C-termini which are differentially expressed in normal and malignant cells. The human N-terminal p53 variants contain either the full-length (FL), or a truncated (DeltaN/Delta40) or no transactivation domain (Delta133) altogether. The functional consequences of coexpression of the different p53 isoforms are poorly defined. Here we investigated functional aspects of the zebrafish DeltaNp53 ortholog in the context of FLp53 and the zebrafish Delta133p53 ortholog (Delta113p53) coexpressed in the developing embryo. RESULTS: We cloned the zebrafish DeltaNp53 isoform and determined that ionizing radiation increased expression of steady-state DeltaNp53 and Delta113p53 mRNA levels in zebrafish embryos. Ectopic DeltaNp53 expression by mRNA injection caused hypoplasia and malformation of the head, eyes and somites, yet partially counteracted lethal effects caused by concomitant expression of FLp53. FLp53 expression was required for developmental aberrations caused by DeltaNp53 and for DeltaNp53-dependent expression of the cyclin-dependent kinase inhibitor 1A (CDKN1A, p21, Cip1, WAF1). Knockdown of p21 expression markedly reduced the severity of developmental malformations associated with DeltaNp53 overexpression. By contrast, forced Delta113p53 expression had little effect on DeltaNp53-dependent embryonal phenotypes. These functional attributes were shared between zebrafish and human DeltaNp53 orthologs ectopically expressed in zebrafish embryos. All 3 zebrafish isoforms could be coimmunoprecipitated with each other after transfection into Saos2 cells. CONCLUSIONS: Both alternative N terminal p53 isoforms were expressed in developing zebrafish in response to cell stress and antagonized lethal effects of FLp53 to different degrees. However, in contrast to Delta113p53, forced DeltaNp53 expression itself led to developmental defects which depended, in part, on p21 transactivation. In contrast to FLp53, the developmental abnormalities caused by DeltaNp53 were not counteracted by concomitant expression of Delta113p53. PMID- 20929555 TI - Increasing walking in patients with intermittent claudication: protocol for a randomised controlled trial. AB - BACKGROUND: People with intermittent claudication are at increased risk of death from heart attack and stroke compared to matched controls. Surgery for intermittent claudication is for symptom management and does not reduce the risk of cardiovascular morbidity and mortality. Increasing physical activity can reduce claudication symptoms and may improve cardiovascular health. This paper presents the pilot study protocol for a randomised controlled trial to test whether a brief psychological intervention leads to increased physical activity, improvement in quality of life, and a reduction in the demand for surgery, for patients with intermittent claudication. METHODS/DESIGN: We aim to recruit 60 patients newly diagnosed with intermittent claudication, who will be randomised into two groups. The control group will receive usual care, and the treatment group will receive usual care and a brief 2-session psychological intervention to modify illness and walking beliefs and develop a walking action plan. The primary outcome will be walking, measured by pedometer. Secondary outcomes will include quality of life and uptake of surgery for symptom management. Participants will be followed up after (a) 4 months, (b) 1 year and (c) 2 years. DISCUSSION: This study will assess the acceptability and efficacy of a brief psychological intervention to increase walking in patients with intermittent claudication, both in terms of the initiation, and maintenance of behaviour change. This is a pilot study, and the results will inform the design of a larger multi-centre trial. TRIAL REGISTRATION: Current Controlled Trials ISRCTN28051878. PMID- 20929556 TI - Patient-orientated longitudinal study of multiple sclerosis in south west England (The South West Impact of Multiple Sclerosis Project, SWIMS) 1: protocol and baseline characteristics of cohort. AB - BACKGROUND: There is a need for greater understanding of the impact of multiple sclerosis (MS) from the perspective of individuals with the condition. The South West Impact of MS Project (SWIMS) has been designed to improve understanding of disease impact using a patient-centred approach. The purpose is to (1) develop improved measurement instruments for clinical trials, (2) evaluate longitudinal performance of a variety of patient-reported outcome measures, (3) develop prognostic predictors for use in individualising drug treatment for patients, particularly early on in the disease course. METHODS: This is a patient-centred, prospective, longitudinal study of multiple sclerosis and clinically isolated syndrome (CIS) in south west England. The study area comprises two counties with a population of approximately 1.7 million and an estimated 1,800 cases of MS. Self-completion questionnaires are administered to participants every six months (for people with MS) or 12 months (CIS). Here we present descriptive statistics of the baseline data provided by 967 participants with MS. RESULTS: Seventy-five percent of those approached consented to participate. The male:female ratio was 1.00:3.01 (n = 967). Average (standard deviation) age at time of entry to SWIMS was 51.6 (11.5) years (n = 961) and median (interquartile range) time since first symptom was 13.3 (6.8 to 24.5) years (n = 934). Fatigue was the most commonly reported symptom, with 80% of participants experiencing fatigue at baseline. Although medication use for symptom control was common, there was little evidence of effectiveness, particularly for fatigue. Nineteen percent of participants were unable to classify their subtype of MS. When patient-reported subtype was compared to neurologist assessment for a sample of participants (n = 396), agreement in disease sub-type was achieved in 63% of cases. There were 836 relapses, reported by 931 participants, in the twelve months prior to baseline. Twenty-three percent of the relapsing-remitting group and 12% of the total sample were receiving disease-modifying therapy at baseline. CONCLUSIONS: Demographics of this sample were similar to published data for the UK. Overall, the results broadly reflect clinical experience in confirming high symptom prevalence, with relatively little complete symptom relief. Participants often had difficulty in defining MS relapses and their own MS type. PMID- 20929557 TI - Screening for bovine leukocyte adhesion deficiency, deficiency of uridine monophosphate synthase, complex vertebral malformation, bovine citrullinaemia, and factor XI deficiency in Holstein cows reared in Turkey. AB - BACKGROUND: Bovine leukocyte adhesion deficiency (BLAD), deficiency of uridine monophosphate synthase (DUMPS), complex vertebral malformation (CVM), bovine citrullinaemia (BC) and factor XI deficiency (FXID) are autosomal recessive hereditary disorders, which have had significant economic impact on dairy cattle breeding worldwide. In this study, 350 Holstein cows reared in Turkey were screened for BLAD, DUMPS, CVM, BC and FXID genotypes to obtain an indication on the importance of these defects in Turkish Holsteins. METHODS: Genomic DNA was obtained from blood and the amplicons of BLAD, DUMPS, CVM, BC and FXID were obtained by using PCR. PCR products were digested with TaqI, AvaI and AvaII restriction enzymes for BLAD, DUMPS, and BC, respectively. These digested products and PCR product of FXID were analyzed by agarose gel electrophoresis stained with ethidium bromide. CVM genotypes were detected by DNA sequencing. Additionally, all genotypes were confirmed by DNA sequencing to determine whether there was a mutant allele or not. RESULTS: Fourteen BLAD, twelve CVM and four FXID carriers were found among the 350 Holstein cows examined, while carriers of DUMPS and BC were not detected. The mutant allele frequencies were calculated as 0.02, 0.017, and 0.006 for BLAD, CVM and FXID, respectively with corresponding carrier prevalence of 4.0% (BLAD), 3.4% (CVM) and 1.2% (FXID). CONCLUSION: This study demonstrates that carriers of BLAD, CVM and FXID are present in the Turkish Holstein population, although at a low frequency. The actual number of clinical cases is unknown, but sporadic cases may appear. As artificial insemination is widely used in dairy cattle breeding, carriers of BLAD, CVM and FXID are likely present within the population of breeding sires. It is recommended to screen breeding sires for these defective genes in order to avoid an unwanted spread within the population. PMID- 20929558 TI - Association of FcgammaRIIa R131H polymorphism with idiopathic pulmonary fibrosis severity and progression. AB - BACKGROUND: A significant genetic component has been described for idiopathic pulmonary fibrosis (IPF). The R131H (rs1801274) polymorphism of the IgG receptor FcgammaRIIa determines receptor affinity for IgG subclasses and is associated with several chronic inflammatory diseases. We investigated whether this polymorphism is associated with IPF susceptibility or progression. METHODS: In a case-control study, we compared the distribution of FcgammaRIIa R131H genotypes in 142 patients with IPF and in 218 controls using allele-specific PCR amplification. RESULTS: No differences in the frequency of FcgammaRIIa genotypes were evident between IPF patients and control subjects. However, significantly impaired pulmonary function at diagnosis was observed in HH compared to RR homozygotes, with evidence of more severe restriction (reduced forced vital capacity (FVC)) and lower diffusing capacity for carbon monoxide (DLCO). Similarly, increased frequency of the H131 allele was observed in patients with severe disease (DLCO < 40% predicted) (0.53 vs. 0.38; p = 0.03). Furthermore, the H131 allele was associated with progressive pulmonary fibrosis as determined by > 10% drop in FVC and/or > 15% fall in DLCO at 12 months after baseline (0.48 vs. 0.33; p = 0.023). CONCLUSIONS: These findings support an association between the FcgammaRIIa R131H polymorphism and IPF severity and progression, supporting the involvement of immunological mechanisms in IPF pathogenesis. PMID- 20929560 TI - The assessment of population exposure to chlorination by-products: a study on the influence of the water distribution system. AB - BACKGROUND: The relationship between chlorination by-products (CBPs) in drinking water and human health outcomes has been investigated in many epidemiological studies. In these studies, population exposure assessment to CBPs in drinking water is generally based on available CBP data (e.g., from regulatory monitoring, sampling campaigns specific to study area). Since trihalomethanes (THMs) and haloacetic acids (HAAs) are the most documented CBP classes in drinking water, they are generally used as indicators of CBP exposure. METHODS: In this paper, different approaches to spatially assign available THM and HAA concentrations in drinking water for population exposure assessment purposes are investigated. Six approaches integrating different considerations for spatial variability of CBP occurrence within different distribution systems are compared. For this purpose, a robust CBP database (i.e., high number of sampling locations selected according to system characteristics) corresponding to nine distribution systems was generated. RESULTS AND CONCLUSION: The results demonstrate the high impact of the structure of the distribution system (e.g., presence of intermediary water infrastructures such as re-chlorination stations or reservoirs) and the spatial variability of CBPs in the assigned levels for exposure assessment. Recommendations for improving the exposure assessment to CBPs in epidemiological studies using available CBP data from water utilities are also presented. PMID- 20929559 TI - Changes in deceleration capacity of heart rate and heart rate variability induced by ambient air pollution in individuals with coronary artery disease. AB - BACKGROUND AND OBJECTIVE: Exposure to ambient particles has been shown to be responsible for cardiovascular effects, especially in elderly with cardiovascular disease. The study assessed the association between deceleration capacity (DC) as well as heart rate variability (HRV) and ambient particulate matter (PM) in patients with coronary artery disease (CAD). METHODS: A prospective study with up to 12 repeated measurements was conducted in Erfurt, Germany, between October 2000 and April 2001 in 56 patients with physician-diagnosed ischemic heart disease, stable angina pectoris or prior myocardial infarction at an age of at least 50 years. Twenty-minute ECG recordings were obtained every two weeks and 24 hour ECG recordings every four weeks. Exposure to PM (size range from 10 nm to 2.5 MUm), and elemental (EC) and organic (OC) carbon was measured. Additive mixed models were used to analyze the association between PM and ECG recordings. RESULTS: The short-term recordings showed decrements in the high-frequency component of HRV as well as in RMSSD (root-mean-square of successive differences of NN intervals) in association with increments in EC and OC 0-23 hours prior to the recordings. The long-term recordings revealed decreased RMSSD and pNN50 (% of adjacent NN intervals that differed more than 50 ms) in association with EC and OC 24-47 hours prior to the recordings. In addition, highly significant effects were found for DC which decreased in association with PM2.5, EC and OC concurrent with the ECG recordings as well as with a lag of up to 47 hours. CONCLUSIONS: The analysis showed significant effects of ambient particulate air pollution on DC and HRV parameters reflecting parasympathetic modulation of the heart in patients with CAD. An air pollution-related decrease in parasympathetic tone as well as impaired heart rate deceleration capacity may contribute to an increased risk for cardiac morbidity and sudden cardiac death in vulnerable populations. PMID- 20929561 TI - From pharmaco-therapy to pharmaco-prevention: trends in prescribing to older adults in Ontario, Canada, 1997-2006. AB - BACKGROUND: The developed world is undergoing a demographic transition with greater numbers of older adults and higher rates of chronic disease. Most elder care is now provided by primary care physicians, who prescribe the majority of medications taken by these patients. Despite these significant trends, little is known about population-level prescribing patterns to primary care patients aged 65+. METHODS: We conducted a population-based retrospective cohort study to examine 10-year prescribing trends among family physicians providing care to patients aged 65+ in Ontario, Canada. RESULTS: Both crude number of prescription claims and prescription rates (i.e., claims per person) increased dramatically over the 10-year study period. The greatest change was in prescribing patterns for females aged 85+. Dramatic increases were observed in the prescribing of preventive medications, such as those to prevent osteoporosis (+2,347%) and lipid lowering agents (+697%). And lastly, the number of unique classes of medications prescribed to older persons has increased, with the proportion of older patients prescribed more than 10 classes of medications almost tripling during the study period. CONCLUSIONS: Prescribing to older adults by family physicians increased substantially during the study period. This raises important concerns regarding quality of care, patient safety, and cost sustainability. It is evident that further research is urgently needed on the health outcomes (both beneficial and harmful) associated with these dramatic increases in prescribing rates. PMID- 20929562 TI - Comparative biochemical analysis of recombinant reverse transcriptase enzymes of HIV-1 subtype B and subtype C. AB - BACKGROUND: HIV-1 subtype C infections account for over half of global HIV infections, yet the vast focus of HIV-1 research has been on subtype B viruses which represent less than 12% of the global pandemic. Since HIV-1 reverse transcriptase (RT) is a major target of antiviral therapy, and since differential drug resistance pathways have been observed among different HIV subtypes, it is important to study and compare the enzymatic activities of HIV-1 RT derived from each of subtypes B and C as well as to determine the susceptibilities of these enzymes to various RT inhibitors in biochemical assays. METHODS: Recombinant subtype B and C HIV-1 RTs in heterodimeric form were purified from Escherichia coli and enzyme activities were compared in cell-free assays. The efficiency of ( ) ssDNA synthesis was measured using gel-based assays with HIV-1 PBS RNA template and tRNA3(Lys) as primer. Processivity was assayed under single-cycle conditions using both homopolymeric and heteropolymeric RNA templates. Intrinsic RNase H activity was compared using 5'-end labeled RNA template annealed to 3'-end recessed DNA primer in a time course study in the presence and absence of a heparin trap. A mis-incorporation assay was used to assess the fidelity of the two RT enzymes. Drug susceptibility assays were performed both in cell-free assays using recombinant enzymes and in cell culture phenotyping assays. RESULTS: The comparative biochemical analyses of recombinant subtype B and subtype C HIV-1 reverse transcriptase indicate that the two enzymes are very similar biochemically in efficiency of tRNA-primed (-) ssDNA synthesis, processivity, fidelity and RNase H activity, and that both enzymes show similar susceptibilities to commonly used NRTIs and NNRTIs. Cell culture phenotyping assays confirmed these results. CONCLUSIONS: Overall enzyme activity and drug susceptibility of HIV-1 subtype C RT are comparable to those of subtype B RT. The use of RT inhibitors (RTIs) against these two HIV-1 enzymes should have comparable effects. PMID- 20929563 TI - Scoring function to predict solubility mutagenesis. AB - BACKGROUND: Mutagenesis is commonly used to engineer proteins with desirable properties not present in the wild type (WT) protein, such as increased or decreased stability, reactivity, or solubility. Experimentalists often have to choose a small subset of mutations from a large number of candidates to obtain the desired change, and computational techniques are invaluable to make the choices. While several such methods have been proposed to predict stability and reactivity mutagenesis, solubility has not received much attention. RESULTS: We use concepts from computational geometry to define a three body scoring function that predicts the change in protein solubility due to mutations. The scoring function captures both sequence and structure information. By exploring the literature, we have assembled a substantial database of 137 single- and multiple point solubility mutations. Our database is the largest such collection with structural information known so far. We optimize the scoring function using linear programming (LP) methods to derive its weights based on training. Starting with default values of 1, we find weights in the range [0,2] so that predictions of increase or decrease in solubility are optimized. We compare the LP method to the standard machine learning techniques of support vector machines (SVM) and the Lasso. Using statistics for leave-one-out (LOO), 10-fold, and 3-fold cross validations (CV) for training and prediction, we demonstrate that the LP method performs the best overall. For the LOOCV, the LP method has an overall accuracy of 81%. AVAILABILITY: Executables of programs, tables of weights, and datasets of mutants are available from the following web page: http://www.wsu.edu/~kbala/OptSolMut.html. PMID- 20929565 TI - Gastrointestinal complaints in shift-working and day-working nurses in Iran. AB - BACKGROUND: There is evidence in the scientific literature of the adverse physiological and psychological effects of shift work. The work of nurses in hospitals is connected with shift and night work. Several publications have described gastrointestinal disturbances in shift workers. The aim of this study was to compare the frequency of gastrointestinal (GI) complaints of nurses on a rotating shift with that of nurses on a regular day shift. METHODS: The study involved 160 nurses (133 working in shifts and at night and 27 working on day shifts) in the Shahid Beheshti Hospital in Kashan, Iran. These nurses answered a Gastrointestinal Symptom Questionnaire regarding the presence of gastrointestinal symptoms (including heartburn, regurgitation, constipation, diarrhea and bloating). Positive responses required frequent symptom occurrence in the past 4 weeks. Significance of group differences was assessed by chi-square and Fisher exact tests. RESULTS: Prevalence of GI symptoms was significantly higher (p = 0.009) in rotating-shift nurses (81.9%) than in day-shift nurses (59.2%). Irregular meal consumption (p = 0.01) and GI medications (p = 0.002) were all significantly higher among the rotating shift nurses. In both groups, regurgitation was the most common symptom. CONCLUSION: Nurses on rotating shifts in Iran experience more GI disturbances than do nurses on day shifts. PMID- 20929564 TI - An optimized protocol for microarray validation by quantitative PCR using amplified amino allyl labeled RNA. AB - BACKGROUND: Validation of microarrays data by quantitative real-time PCR (qPCR) is often limited by the low amount of available RNA. This raised the possibility to perform validation experiments on the amplified amino allyl labeled RNA (AA aRNA) leftover from microarrays. To test this possibility, we used an ongoing study of our laboratory aiming at identifying new biomarkers of graft rejection by the transcriptomic analysis of blood cells from brain-dead organ donors. RESULTS: qPCR for ACTB performed on AA-aRNA from 15 donors provided Cq values 8 cycles higher than when original RNA was used (P < 0.001), suggesting a strong inhibition of qPCR performed on AA-aRNA. When expression levels of 5 other genes were measured in AA-aRNA generated from a universal reference RNA, qPCR sensitivity and efficiency were decreased. This prevented the quantification of one low-abundant gene, which was readily quantified in un-amplified and un labeled RNA. To overcome this limitation, we modified the reverse transcription (RT) protocol that generates cDNA from AA-aRNA as follows: addition of a denaturation step and 2-min incubation at room temperature to improve random primers annealing, a transcription initiation step to improve RT, and a final treatment with RNase H to degrade remaining RNA. Tested on universal reference AA aRNA, these modifications provided a gain of 3.4 Cq (average from 5 genes, P < 0.001) and an increase of qPCR efficiency (from -1.96 to -2.88; P = 0.02). They also allowed for the detection of a low-abundant gene that was previously undetectable. Tested on AA-aRNA from 15 brain-dead organ donors, RT optimization provided a gain of 2.7 cycles (average from 7 genes, P = 0.004). Finally, qPCR results significantly correlated with microarrays. CONCLUSION: We present here an optimized RT protocol for validation of microarrays by qPCR from AA-aRNA. This is particularly valuable in experiments where limited amount of RNA is available. PMID- 20929566 TI - Improving educational achievement and anaemia of school children: design of a cluster randomised trial of school-based malaria prevention and enhanced literacy instruction in Kenya. AB - BACKGROUND: Improving the health of school-aged children can yield substantial benefits for cognitive development and educational achievement. However, there is limited experimental evidence on the benefits of school-based malaria prevention or how health interventions interact with other efforts to improve education quality. This study aims to evaluate the impact of school-based malaria prevention and enhanced literacy instruction on the health and educational achievement of school children in Kenya. DESIGN: A factorial, cluster randomised trial is being implemented in 101 government primary schools on the coast of Kenya. The interventions are (i) intermittent screening and treatment of malaria in schools by public health workers and (ii) training workshops and support for teachers to promote explicit and systematic literacy instruction. Schools are randomised to one of four groups: receiving either (i) the malaria intervention alone; (ii) the literacy intervention alone; (iii) both interventions combined; or (iv) control group where neither intervention is implemented. Children from classes 1 and 5 are randomly selected and followed up for 24 months. The primary outcomes are educational achievement and anaemia, the hypothesised mediating variables through which education is affected. Secondary outcomes include malaria parasitaemia, school attendance and school performance. A nested process evaluation, using semi-structured interviews, focus group discussion and a stakeholder analysis will investigate the community acceptability, feasibility and cost-effectiveness of the interventions. DISCUSSION: Across Africa, governments are committed to improve health and education of school-aged children, but seek clear policy and technical guidance as to the optimal approach to address malaria and improved literacy. This evaluation will be one of the first to simultaneously evaluate the impact of health and education interventions in the improvement of educational achievement. Reflection is made on the practical issues encountered in conducting research in schools in Africa. TRIAL REGISTRATION: National Institutes of Health NCT00878007. PMID- 20929567 TI - A novel model of common Toll-like receptor 4- and injury-induced transcriptional themes in human leukocytes. AB - INTRODUCTION: An endotoxin challenge, sepsis, and injury/trauma, trigger significant changes in human peripheral blood leukocytes (PBL) gene expression. In this study, we have sought to test the hypothesis that the Toll-like receptor 4 (TLR4) induced transcription patterns elicited in humans exposed to in vivo endotoxin would parallel gene expression patterns observed in trauma patients with initial non-infectious injury. In addition, we sought to identify functional modules that are commonly affected by these two insults of differing magnitude and duration. METHODS: PBL were obtained from seven adult human subject experimental groups. The groups included a group of healthy, hospitalized volunteers (n = 15), that comprised four study groups of subjects challenged with intravenous endotoxin, without or with cortisol, and two serial samplings of trauma patients (n = 5). The PBL were analyzed for gene expression using a 8,793 probe microarray platform (Gene Chip(r) Focus, Affymetrix). The expression of a subset of genes was determined using qPCR. RESULTS: We describe sequential selection criteria of gene expression data that identifies 445 genes that are significantly differentially expressed (both P <= 0.05 and > 1.2 fold-change) in PBL derived from human subjects during the peak of systemic inflammatory responses induced by in vivo endotoxin, as well as in PBL obtained from trauma patients at 1 to 12 days after admission. We identified two functional modules that are commonly represented by this analysis. The first module includes more than 50 suppressed genes that encode ribosomal proteins or translation regulators. The second module includes up-regulated genes encoding key enzymes associated with glycolysis. Finally, we show that several circadian clock genes are also suppressed in PBL of surgical ICU patients. CONCLUSIONS: We identified a group of > 400 genes that exhibit similar expression trends in PBL derived from either endotoxin-challenged subjects or trauma patients. The suppressed translational and circadian clock modules, and the upregulated glycolytic module, constitute a robust and long lasting PBL gene expression signature that may provide a tool for monitoring systemic inflammation and injury. PMID- 20929568 TI - Mechanisms of transcriptional regulation and prognostic significance of activated leukocyte cell adhesion molecule in cancer. AB - BACKGROUND: Activated leukocyte cell adhesion molecule (ALCAM) is implicated in the prognosis of multiple cancers with low level expression associated with metastasis and early death in breast cancer. Despite this significance, mechanisms that regulate ALCAM gene expression and ALCAM's role in adhesion of pre-metastatic circulating tumor cells have not been defined. We studied ALCAM expression in 20 tumor cell lines by real-time PCR, western blot and immunochemistry. Epigenetic alterations of the ALCAM promoter were assessed using methylation-specific PCR and bisulfite sequencing. ALCAM's role in adhesion of tumor cells to the vascular wall was studied in isolated perfused lungs. RESULTS: A common site for transcription initiation of the ALCAM gene was identified and the ALCAM promoter sequenced. The promoter contains multiple cis-active elements including a functional p65 NF-kappaB motif, and it harbors an extensive array of CpG residues highly methylated exclusively in ALCAM-negative tumor cells. These CpG residues were modestly demethylated after 5-aza-2-deoxycytidine treatment. Restoration of high-level ALCAM expression using an ALCAM cDNA increased clustering of MDA-MB-435 tumor cells perfused through the pulmonary vasculature of ventilated rat lungs. Anti-ALCAM antibodies reduced the number of intravascular tumor cell clusters. CONCLUSION: Our data suggests that loss of ALCAM expression, due in part to DNA methylation of extensive segments of the promoter, significantly impairs the ability of circulating tumor cells to adhere to each other, and may therefore promote metastasis. These findings offer insight into the mechanisms for down-regulation of ALCAM gene expression in tumor cells, and for the positive prognostic value of high-level ALCAM in breast cancer. PMID- 20929570 TI - Parent-child interactions and objectively measured child physical activity: a cross-sectional study. AB - BACKGROUND: Parents influence their children's behaviors directly through specific parenting practices and indirectly through their parenting style. Some practices such as logistical and emotional support have been shown to be positively associated with child physical activity (PA) levels, while for others (e.g. monitoring) the relationship is not clear. The objectives of this study were to determine the relationship between parent's PA-related practices, general parenting style, and children's PA level. METHODS: During the spring of 2007 a diverse group of 99 parent-child dyads (29% White, 49% Black, 22% Hispanic; 89% mothers) living in low-income rural areas of the US participated in a cross sectional study. Using validated questionnaires, parents self-reported their parenting style (authoritative, authoritarian, permissive, and uninvolved) and activity-related parenting practices. Height and weight were measured for each dyad and parents reported demographic information. Child PA was measured objectively through accelerometers and expressed as absolute counts and minutes engaged in intensity-specific activity. RESULTS: Seventy-six children had valid accelerometer data. Children engaged in 113.4 +/- 37.0 min. of moderate-vigorous physical activity (MVPA) per day. Children of permissive parents accumulated more minutes of MVPA than those of uninvolved parents (127.5 vs. 97.1, p < 0.05), while parents who provided above average levels of support had children who participated in more minutes of MVPA (114.2 vs. 98.3, p = 0.03). While controlling for known covariates, an uninvolved parenting style was the only parenting behavior associated with child physical activity. Parenting style moderated the association between two parenting practices - reinforcement and monitoring - and child physical activity. Specifically, post-hoc analyses revealed that for the permissive parenting style group, higher levels of parental reinforcement or monitoring were associated with higher levels of child physical activity. CONCLUSIONS: This work extends the current literature by demonstrating the potential moderating role of parenting style on the relationship between activity-related parenting practices and children's objectively measured physical activity, while controlling for known covariates. Future studies in this area are warranted and, if confirmed, may help to identify the mechanism by which parents influence their child's physical activity behavior. PMID- 20929571 TI - Developing measures on the perceptions of the built environment for physical activity: a confirmatory analysis. AB - BACKGROUND: Minimal validity evidence exists for scales assessing the built environment for physical activity. The purpose of this study was to assess the test-retest reliability and invariance of a three-factor model (Neighborhood Characteristics, Safety/Crime, and Access to Physical Activity Facilities) across gender, race, geographic location, and level of physical activity. METHODS: To assess measurement invariance, a random sample of 1,534 adults living in North Carolina or Mississippi completed a computer assisted telephone interview that included items examining perceptions of the neighborhood for physical activity. Construct level test-retest reliability data were collected from a purposeful sample of 106 participants who were administered the questionnaire twice, approximately two weeks apart. Fit indices, Cronbach's alpha, Mokken H and Spearman correlation coefficients (SCC) were used to evaluate configural and co/variance invarianc,e and intraclass correlation coefficients (ICC) were used to assess reliability. RESULTS: Construct test-retest reliability was strong (ICC 0.90 to 0.93). SCC for Neighborhood Characteristics and Crime/Safety were weak with Access (0.21 and 0.25), but strong between Crime/Safety and Neighborhood Characteristics (0.62). Acceptable fit and evidence of measurement invariance was found for gender, race (African American and White), geographic location, and level of physical activity. Fit indices consistently approached or were greater than 0.90 for goodness of fit index, normed fit index, and comparative fit index which is evidence of configural invariance. There was weak support of variance and covariance invariance for all groups that was indicative of factorial validity. CONCLUSIONS: Support of the validity and reliability of the three factor model across groups expands the possibilities for analysis to include latent variable modeling, and suggests these built environment constructs may be used in other settings and populations. PMID- 20929569 TI - Signaling network of dendritic cells in response to pathogens: a community-input supported knowledgebase. AB - BACKGROUND: Dendritic cells are antigen-presenting cells that play an essential role in linking the innate and adaptive immune systems. Much research has focused on the signaling pathways triggered upon infection of dendritic cells by various pathogens. The high level of activity in the field makes it desirable to have a pathway-based resource to access the information in the literature. Current pathway diagrams lack either comprehensiveness, or an open-access editorial interface. Hence, there is a need for a dependable, expertly curated knowledgebase that integrates this information into a map of signaling networks. DESCRIPTION: We have built a detailed diagram of the dendritic cell signaling network, with the goal of providing researchers with a valuable resource and a facile method for community input. Network construction has relied on comprehensive review of the literature and regular updates. The diagram includes detailed depictions of pathways activated downstream of different pathogen recognition receptors such as Toll-like receptors, retinoic acid-inducible gene-I like receptors, C-type lectin receptors and nucleotide-binding oligomerization domain-like receptors. Initially assembled using CellDesigner software, it provides an annotated graphical representation of interactions stored in Systems Biology Mark-up Language. The network, which comprises 249 nodes and 213 edges, has been web-published through the Biological Pathway Publisher software suite. Nodes are annotated with PubMed references and gene-related information, and linked to a public wiki, providing a discussion forum for updates and corrections. To gain more insight into regulatory patterns of dendritic cell signaling, we analyzed the network using graph-theory methods: bifan, feedforward and multi-input convergence motifs were enriched. This emphasis on activating control mechanisms is consonant with a network that subserves persistent and coordinated responses to pathogen detection. CONCLUSIONS: This map represents a navigable aid for presenting a consensus view of the current knowledge on dendritic cell signaling that can be continuously improved through contributions of research community experts. Because the map is available in a machine readable format, it can be edited and may assist researchers in data analysis. Furthermore, the availability of a comprehensive knowledgebase might help further research in this area such as vaccine development. The dendritic cell signaling knowledgebase is accessible at http://tsb.mssm.edu/pathwayPublisher/DC_pathway/DC_pathway_index.html. PMID- 20929573 TI - Biting behaviour of Simulium damnosum complex and Onchocerca volvulus infection along the Osun River, Southwest Nigeria. AB - BACKGROUND: Studies on biting behaviours and infectivity status of insect vectors are pre-requisites in understanding the epidemiology of the vector- borne diseases and planning effective control measures. A longitudinal study was carried out to investigate the transmission index of Simulium damnosum complex species along Osun River, South Western Nigeria. Adult flies were collected on human attractants from 07:00 to 18:00 hours for two consecutive days from February 2008 to June 2009 at three communities: Osun Eleja, Osun Ogbere and Osun Budepo. The infectivity rate was determined by dissection and Polymerase Chain Reaction amplification (PCR) of 0-150 genes of Onchocerca parasite using the pool screening technique. RESULTS: The results indicated that the majority of the flies collected at the three sampling points were nulliparous as they accounted for 53.90%, 57.86% and 59.58% of the flies dissected at Osun Budepo, Osun Ogbere and Osun Eleja, respectively. The parous rate was higher during the dry season than the wet season but the difference was not statistically significant (p < 0.05). The biting activity of the parous flies showed two peaks at Osun Budepo and three peaks at Osun Eleja and Osun Ogbere. Of the 1,472 flies dissected and 1,235 flies screened by molecular method, none was infected with Onchocerca parasite at the three sampling points however the annual biting rates at the three communities were higher than 1,000 considered as tolerable value for a person living in an onchocerciasis zone by Word Health Organization. CONCLUSION: The study has provided the baseline data for further study on onchocerciasis transmission dynamics and the need to intercept man- simuliid vector contact at the study area. PMID- 20929572 TI - Lineage divergence detected in the malaria vector Anopheles marajoara (Diptera: Culicidae) in Amazonian Brazil. AB - BACKGROUND: Cryptic species complexes are common among anophelines. Previous phylogenetic analysis based on the complete mtDNA COI gene sequences detected paraphyly in the Neotropical malaria vector Anopheles marajoara. The "Folmer region" detects a single taxon using a 3% divergence threshold. METHODS: To test the paraphyletic hypothesis and examine the utility of the Folmer region, genealogical trees based on a concatenated (white + 3' COI sequences) dataset and pairwise differentiation of COI fragments were examined. The population structure and demographic history were based on partial COI sequences for 294 individuals from 14 localities in Amazonian Brazil. 109 individuals from 12 localities were sequenced for the nDNA white gene, and 57 individuals from 11 localities were sequenced for the ribosomal DNA (rDNA) internal transcribed spacer 2 (ITS2). RESULTS: Distinct A. marajoara lineages were detected by combined genealogical analysis and were also supported among COI haplotypes using a median joining network and AMOVA, with time since divergence during the Pleistocene (<100,000 ya). COI sequences at the 3' end were more variable, demonstrating significant pairwise differentiation (3.82%) compared to the more moderate 2.92% detected by the Folmer region. Lineage 1 was present in all localities, whereas lineage 2 was restricted mainly to the west. Mismatch distributions for both lineages were bimodal, likely due to multiple colonization events and spatial expansion (~798 81,045 ya). There appears to be gene flow within, not between lineages, and a partial barrier was detected near Rio Jari in Amapa state, separating western and eastern populations. In contrast, both nDNA data sets (white gene sequences with or without the retention of the 4th intron, and ITS2 sequences and length) detected a single A. marajoara lineage. CONCLUSIONS: Strong support for combined data with significant differentiation detected in the COI and absent in the nDNA suggest that the divergence is recent, and detectable only by the faster evolving mtDNA. A within subgenus threshold of >2% may be more appropriate among sister taxa in cryptic anopheline complexes than the standard 3%. Differences in demographic history and climatic changes may have contributed to mtDNA lineage divergence in A. marajoara. PMID- 20929574 TI - Chronic immobilisation stress ameliorates clinical score and neuroinflammation in a MOG-induced EAE in Dark Agouti rats: mechanisms implicated. AB - BACKGROUND: Multiple sclerosis (MS) is the endpoint of a complex and still poorly understood process which results in inflammation, demyelination and axonal and neuronal degeneration. Since the first description of MS, psychological stress has been suggested to be one of the trigger factors in the onset and/or relapse of symptoms. However, data from animal models of MS, such as experimental autoimmune encephalomyelitis (EAE) are inconsistent and the effect of stress on EAE onset and severity depends on duration and time of application of the stress protocol and the underlying mechanisms. METHODS: Dark Agouti rats were inoculated with MOG/CFA to induce EAE, and an immobilisation stress protocol with two different durations (12 and 21 days, starting at the moment of MOG-inoculation) was applied in order to analyse the effect of stress on disease onset and neuroinflammation. RESULTS: Twelve days of stress exposure increased EAE clinical score in Dark Agouti rats. In addition, these animals presented higher levels of MMP-9 and proinflammatory PGE2 in spinal cord. In contrast, animals chronically exposed to stress (21 days) showed a significantly lower incidence of EAE clinical signs and reduced myelin loss, leukocyte infiltration and accumulation of inflammatory/oxidative mediators in spinal cord. Interestingly, chronically stressed animals showed a parallel increase in levels of the anti-inflammatory prostaglandin 15d-PGJ2, the main endogenous agonist of PPARgamma. CONCLUSIONS: Our results demonstrate that, depending on duration, stress exposure elicits opposite effects on PGE2/15d-PGJ2 ratios in spinal cord of EAE-induced Dark Agouti rats. Further studies are needed to elucidate if these changes in prostaglandin balance are sufficient to mediate the differences in clinical score and inflammation here reported, and to establish the potential utility of pharmacological intervention in MS directed toward anti-inflammatory pathways. PMID- 20929577 TI - Is distortion of the bioprosthesis ring a risk factor for early calcification? AB - BACKGROUND: As the population ages, bioprosthesis are increasingly being used in cardiac valve replacement. Pericardial bioprosthesis combine an excellent hemodynamic performance with low thrombogenicity, but valve failure associated with calcification remains a concern with these valves. We describe distortion of the bioprosthesis ring as a risk factor for early calcification. METHODS: A total of 510 patients over the age of 70 years underwent isolated aortic valve replacement with the Mitroflow (A12) pericardial bioprosthesis. Thirty two patients (6,2%) have undergone a second aortic valve replacement due to structural valve dysfunction resulting from valve calcification. In all patients a chest radiography and coronary angiography was performed before reoperation. A 64 Multidetector Computed Tomography (MDCT) with retrospective ECG gating study was performed in four patients to evaluate the aortic bioprosthesis. RESULTS: Chest radiography showed in all patients an irregular bioprosthesis ring. At preoperative coronary angiography a distorted bioprosthesis ring was detected in all patients. Macroscopic findings of the explanted bioprostheses included extensive calcification in all specimens. CONCLUSION: There was a possible relationship between early bioprosthetic calcification and radiologic distortion of the bioprosthesis ring. PMID- 20929575 TI - Genome analysis and comparative genomics of a Giardia intestinalis assemblage E isolate. AB - BACKGROUND: Giardia intestinalis is a protozoan parasite that causes diarrhea in a wide range of mammalian species. To further understand the genetic diversity between the Giardia intestinalis species, we have performed genome sequencing and analysis of a wild-type Giardia intestinalis sample from the assemblage E group, isolated from a pig. RESULTS: We identified 5012 protein coding genes, the majority of which are conserved compared to the previously sequenced genomes of the WB and GS strains in terms of microsynteny and sequence identity. Despite this, there is an unexpectedly large number of chromosomal rearrangements and several smaller structural changes that are present in all chromosomes. Novel members of the VSP, NEK Kinase and HCMP gene families were identified, which may reveal possible mechanisms for host specificity and new avenues for antigenic variation. We used comparative genomics of the three diverse Giardia intestinalis isolates P15, GS and WB to define a core proteome for this species complex and to identify lineage-specific genes. Extensive analyses of polymorphisms in the core proteome of Giardia revealed differential rates of divergence among cellular processes. CONCLUSIONS: Our results indicate that despite a well conserved core of genes there is significant genome variation between Giardia isolates, both in terms of gene content, gene polymorphisms, structural chromosomal variations and surface molecule repertoires. This study improves the annotation of the Giardia genomes and enables the identification of functionally important variation. PMID- 20929576 TI - Comparison of thromboelastometry with procalcitonin, interleukin 6, and C reactive protein as diagnostic tests for severe sepsis in critically ill adults. AB - INTRODUCTION: Established biomarkers for the diagnosis of sepsis are procalcitonin, interleukin 6, and C-reactive protein. Although sepsis evokes changes of coagulation and fibrinolysis, it is unknown whether thromboelastometry can detect these alterations. We investigated whether thromboelastometry variables are suitable as biomarkers for severe sepsis in critically ill adults. METHODS: In the observational cohort study, blood samples were obtained from patients on the day of diagnosis of severe sepsis (n = 56) and from postoperative patients (n = 52), and clotting time, clot formation time, maximum clot firmness, alpha angle, and lysis index were measured with thromboelastometry. In addition, procalcitonin, interleukin 6, and C-reactive protein levels were determined. For comparison of biomarkers, receiver operating characteristic (ROC) curves were used, and the optimal cut-offs and odds ratios were calculated. RESULTS: In comparison with postoperative controls, patients with sepsis showed an increase in lysis index (97% +/- 0.3 versus 92 +/- 0.5; P < 0.001; mean and SEM) and procalcitonin (2.5 ng/ml +/- 0.5 versus 30.6 +/- 8.7; P < 0.001). Clot-formation time, alpha angle, maximum clot firmness, as well as interleukin 6 and C-reactive protein concentrations were not different between groups; clotting time was slightly prolonged. ROC analysis demonstrated an area under the curve (AUC) of 0.901 (CI 0.838-0.964) for the lysis index, and 0.756 (CI 0.666-0.846) for procalcitonin. The calculated cut-off for the lysis index was > 96.5%, resulting in a sensitivity of 84.2%, and a specificity of 94.2%, with an odds ratio of 85.3 (CI 21.7-334.5). CONCLUSIONS: The thromboelastometry lysis index proved to be a more reliable biomarker of severe sepsis in critically ill adults than were procalcitonin, interleukin 6, and C-reactive protein. The results also demonstrate that early involvement of the hemostatic system is a common event in severe sepsis. PMID- 20929578 TI - Aberrant host immune response induced by highly virulent PRRSV identified by digital gene expression tag profiling. AB - BACKGROUND: There was a large scale outbreak of the highly pathogenic porcine reproductive and respiratory syndrome (PRRS) in China and Vietnam during 2006 and 2007 that resulted in unusually high morbidity and mortality among pigs of all ages. The mechanisms underlying the molecular pathogenesis of the highly virulent PRRS virus (H-PRRSV) remains unknown. Therefore, the relationship between pulmonary gene expression profiles after H-PRRSV infection and infection pathology were analyzed in this study using high-throughput deep sequencing and histopathology. RESULTS: H-PRRSV infection resulted in severe lung pathology. The results indicate that aberrant host innate immune responses to H-PRRSV and induction of an anti-apoptotic state could be responsible for the aggressive replication and dissemination of H-PRRSV. Prolific rapid replication of H-PRRSV could have triggered aberrant sustained expression of pro-inflammatory cytokines and chemokines leading to a markedly robust inflammatory response compounded by significant cell death and increased oxidative damage. The end result was severe tissue damage and high pathogenicity. CONCLUSIONS: The systems analysis utilized in this study provides a comprehensive basis for better understanding the pathogenesis of H-PRRSV. Furthermore, it allows the genetic components involved in H-PRRSV resistance/susceptibility in swine populations to be identified. PMID- 20929579 TI - Epigenetic regulation of CpG promoter methylation in invasive prostate cancer cells. AB - BACKGROUND: Recently, much attention has been focused on gaining a better understanding of the different populations of cells within a tumor and their contribution to cancer progression. One of the most commonly used methods to isolate a more aggressive sub-population of cells utilizes cell sorting based on expression of certain cell adhesion molecules. A recently established method we developed is to isolate these more aggressive cells based on their properties of increased invasive ability. These more invasive cells have been previously characterized as tumor initiating cells (TICs) that have a stem-like genomic signature and express a number of stem cell genes including Oct3/4 and Nanog and are more tumorigenic compared to their 'non-invasive' counterpart. They also have a profile reminiscent of cells undergoing a classic pattern of epithelial to mesenchymal transition or EMT. Using this model of invasion, we sought to investigate which genes are under epigenetic control in this rare population of cells. Epigenetic modifications, specifically DNA methylation, are key events regulating the process of normal human development. To determine the specific methylation pattern in these invasive prostate cells, and if any developmental genes were being differentially regulated, we analyzed differences in global CpG promoter methylation. RESULTS: Differentially methylated genes were determined and select genes were chosen for additional analyses. The non-receptor tyrosine kinase BMX and transcription factor SOX1 were found to play a significant role in invasion. Ingenuity pathway analysis revealed the methylated gene list frequently displayed genes from the IL-6/STAT3 pathway. Cells which have decreased levels of the targets BMX and SOX1 also display loss of STAT3 activity. Finally, using Oncomine, it was determined that more aggressive metastatic prostate cancers in humans also have higher levels of both Stat3 and Sox1. CONCLUSIONS: Using this method we can begin to understand which genes are epigenetically regulated in the invasive population compared to the bulk tumor cells. These aggressive sub populations of cells may be linked to the cancer stem cell hypothesis, making their patterns of epigenetic regulation very attractive for biomarker analysis. PMID- 20929581 TI - Bi-directional gene set enrichment and canonical correlation analysis identify key diet-sensitive pathways and biomarkers of metabolic syndrome. AB - BACKGROUND: Currently, a number of bioinformatics methods are available to generate appropriate lists of genes from a microarray experiment. While these lists represent an accurate primary analysis of the data, fewer options exist to contextualise those lists. The development and validation of such methods is crucial to the wider application of microarray technology in the clinical setting. Two key challenges in clinical bioinformatics involve appropriate statistical modelling of dynamic transcriptomic changes, and extraction of clinically relevant meaning from very large datasets. RESULTS: Here, we apply an approach to gene set enrichment analysis that allows for detection of bi directional enrichment within a gene set. Furthermore, we apply canonical correlation analysis and Fisher's exact test, using plasma marker data with known clinical relevance to aid identification of the most important gene and pathway changes in our transcriptomic dataset. After a 28-day dietary intervention with high-CLA beef, a range of plasma markers indicated a marked improvement in the metabolic health of genetically obese mice. Tissue transcriptomic profiles indicated that the effects were most dramatic in liver (1270 genes significantly changed; p < 0.05), followed by muscle (601 genes) and adipose (16 genes). Results from modified GSEA showed that the high-CLA beef diet affected diverse biological processes across the three tissues, and that the majority of pathway changes reached significance only with the bi-directional test. Combining the liver tissue microarray results with plasma marker data revealed 110 CLA sensitive genes showing strong canonical correlation with one or more plasma markers of metabolic health, and 9 significantly overrepresented pathways among this set; each of these pathways was also significantly changed by the high-CLA diet. Closer inspection of two of these pathways--selenoamino acid metabolism and steroid biosynthesis--illustrated clear diet-sensitive changes in constituent genes, as well as strong correlations between gene expression and plasma markers of metabolic syndrome independent of the dietary effect. CONCLUSION: Bi directional gene set enrichment analysis more accurately reflects dynamic regulatory behaviour in biochemical pathways, and as such highlighted biologically relevant changes that were not detected using a traditional approach. In such cases where transcriptomic response to treatment is exceptionally large, canonical correlation analysis in conjunction with Fisher's exact test highlights the subset of pathways showing strongest correlation with the clinical markers of interest. In this case, we have identified selenoamino acid metabolism and steroid biosynthesis as key pathways mediating the observed relationship between metabolic health and high-CLA beef. These results indicate that this type of analysis has the potential to generate novel transcriptome based biomarkers of disease. PMID- 20929582 TI - The chondroitin/dermatan sulfate synthesizing and modifying enzymes in laryngeal cancer: expressional and epigenetic studies. AB - BACKGROUND: Significant biochemical changes are observed in glycosaminoglycans in squamous cell laryngeal carcinoma. The most characteristics are in chondroitin/dermatan sulfate fine structure and proportion, which might be due to differential expression of the enzymes involved in their biosynthesis. The aim of the present work was the investigation in expressional and epigenetic level of the enzymes involved in chondroitin/dermatan sulfate biosynthesis in laryngeal cancer. METHODS: Tissues subjected to total RNA and DNA isolation, and protein extraction. The techniques used in this study were RT-PCR analysis, western blotting and methylation specific PCR. RESULTS: We identified that many enzymes were expressed in the cancerous specimens intensively. Dermatan sulfate epimerase was expressed exclusively in the cancerous parts and in minor amounts in healthy tissues; in the macroscopically normal samples it was not detected. Furthermore, chondroitin synthase I and chondroitin polymerizing factor were strongly expressed in the cancerous parts compared to the corresponding normal tissues. Sulfotransferases, like chondroitin 6 sulfotransferase 3, were highly expressed mainly in healthy specimens. CONCLUSIONS: The study of the various chondroitin/dermatan synthesizing enzymes revealed that they were differentially expressed in cancer, in human laryngeal cartilage, leading to specific chondroitin/dermatan structures which contributed to proteoglycan formation with specific features. The expression of the examined enzymes correlated with the glycosaminoglycan profile observed in previous studies. PMID- 20929583 TI - The impact of CdSe/ZnS Quantum Dots in cells of Medicago sativa in suspension culture. AB - BACKGROUND: Nanotechnology has the potential to provide agriculture with new tools that may be used in the rapid detection and molecular treatment of diseases and enhancement of plant ability to absorb nutrients, among others. Data on nanoparticle toxicity in plants is largely heterogeneous with a diversity of physicochemical parameters reported, which difficult generalizations. Here a cell biology approach was used to evaluate the impact of Quantum Dots (QDs) nanocrystals on plant cells, including their effect on cell growth, cell viability, oxidative stress and ROS accumulation, besides their cytomobility. RESULTS: A plant cell suspension culture of Medicago sativa was settled for the assessment of the impact of the addition of mercaptopropanoic acid coated CdSe/ZnS QDs. Cell growth was significantly reduced when 100 mM of mercaptopropanoic acid -QDs was added during the exponential growth phase, with less than 50% of the cells viable 72 hours after mercaptopropanoic acid -QDs addition. They were up taken by Medicago sativa cells and accumulated in the cytoplasm and nucleus as revealed by optical thin confocal imaging. As part of the cellular response to internalization, Medicago sativa cells were found to increase the production of Reactive Oxygen Species (ROS) in a dose and time dependent manner. Using the fluorescent dye H2DCFDA it was observable that mercaptopropanoic acid-QDs concentrations between 5-180 nM led to a progressive and linear increase of ROS accumulation. CONCLUSIONS: Our results showed that the extent of mercaptopropanoic acid coated CdSe/ZnS QDs cytotoxicity in plant cells is dependent upon a number of factors including QDs properties, dose and the environmental conditions of administration and that, for Medicago sativa cells, a safe range of 1-5 nM should not be exceeded for biological applications. PMID- 20929580 TI - Mitochondrial genome evolution in fire ants (Hymenoptera: Formicidae). AB - BACKGROUND: Complete mitochondrial genome sequences have become important tools for the study of genome architecture, phylogeny, and molecular evolution. Despite the rapid increase in available mitogenomes, the taxonomic sampling often poorly reflects phylogenetic diversity and is often also biased to represent deeper (family-level) evolutionary relationships. RESULTS: We present the first fully sequenced ant (Hymenoptera: Formicidae) mitochondrial genomes. We sampled four mitogenomes from three species of fire ants, genus Solenopsis, which represent various evolutionary depths. Overall, ant mitogenomes appear to be typical of hymenopteran mitogenomes, displaying a general A+T-bias. The Solenopsis mitogenomes are slightly more compact than other hymentoperan mitogenomes (~15.5 kb), retaining all protein coding genes, ribosomal, and transfer RNAs. We also present evidence of recombination between the mitogenomes of the two conspecific Solenopsis mitogenomes. Finally, we discuss potential ways to improve the estimation of phylogenies using complete mitochondrial genome sequences. CONCLUSIONS: The ant mitogenome presents an important addition to the continued efforts in studying hymenopteran mitogenome architecture, evolution, and phylogenetics. We provide further evidence that the sampling across many taxonomic levels (including conspecifics and congeners) is useful and important to gain detailed insights into mitogenome evolution. We also discuss ways that may help improve the use of mitogenomes in phylogenetic analyses by accounting for non-stationary and non-homogeneous evolution among branches. PMID- 20929584 TI - Trial Protocol: randomised controlled trial of the effects of very low calorie diet, modest dietary restriction, and sequential behavioural programme on hunger, urges to smoke, abstinence and weight gain in overweight smokers stopping smoking. AB - BACKGROUND: Weight gain accompanies smoking cessation, but dieting during quitting is controversial as hunger may increase urges to smoke. This is a feasibility trial for the investigation of a very low calorie diet (VLCD), individual modest energy restriction, and usual advice on hunger, ketosis, urges to smoke, abstinence and weight gain in overweight smokers trying to quit. METHODS: This is a 3 armed, unblinded, randomized controlled trial in overweight (BMI > 25 kg/m2), daily smokers (CO > 10 ppm); with at least 30 participants in each group. Each group receives identical behavioural support and NRT patches (25 mg(8 weeks),15 mg(2 weeks),10 mg(2 weeks)). The VLCD group receive a 429-559 kcal/day liquid formula beginning 1 week before quitting and continuing for 4 weeks afterwards. The modest energy restricted group (termed individual dietary and activity planning(IDAP)) engage in goal-setting and receive an energy prescription based on individual basal metabolic rate(BMR) aiming for daily reduction of 600 kcal. The control group receive usual dietary advice that accompanies smoking cessation i.e. avoiding feeling hungry but eating healthy snacks. After this, the VLCD participants receive IDAP to provide support for changing eating habits in the longer term; the IDAP group continues receiving this support. The control group receive IDAP 8 weeks after quitting. This allows us to compare IDAP following a successful quit attempt with dieting concurrently during quitting. It also aims to prevent attrition in the unblinded, control group by meeting their need for weight management. Follow-up occurs at 6 and 12 months.Outcome measures include participant acceptability, measured qualitatively by semi-structured interviewing and quantitatively by recruitment and attrition rates. Feasibility of running the trial within primary care is measured by interview and questionnaire of the treatment providers. Adherence to the VLCD is verified by the presence of urinary ketones measured weekly. Daily urges to smoke, hunger and withdrawal are measured using the Mood and Physical Symptoms Scale-Combined (MPSS-C) and a Hunger Craving Score (HCS). 24 hour, 7 day point prevalence and 4-week prolonged abstinence (Russell Standard) is confirmed by CO < 10 ppm. Weight, waist and hip circumference and percentage body fat are measured at each visit. TRIAL REGISTRATION: Current controlled trials ISRCTN83865809. PMID- 20929585 TI - The biochemical aftermath of anti-amyloid immunotherapy. AB - BACKGROUND: Active and passive immunotherapy in both amyloid-beta precursor protein (APP) transgenic mice and Alzheimer's Disease (AD) patients have resulted in remarkable reductions in amyloid plaque accumulation, although the degree of amyloid regression has been highly variable. Nine individuals with a clinical diagnosis of AD dementia were actively immunized with the Abeta peptide 1-42 (AN 1792) and subjected to detailed postmortem biochemical analyses. These patients were compared to 6 non-immunized AD cases and 5 non-demented control (NDC) cases. RESULTS: All patients were assessed for the presence of AD pathology including amyloid plaques, neurofibrillary tangles and vascular amyloidosis. This effort revealed that two immunotherapy recipients had dementia as a consequence of diseases other than AD. Direct neuropathological examination consistently demonstrated small to extensive areas in which amyloid plaques apparently were disrupted. Characterization of Abeta species remnants by ELISA suggested that total Abeta levels may have been reduced, although because the amounts of Abeta peptides among treated individuals were extremely variable, those data must be regarded as tentative. Chromatographic analysis and Western blots revealed abundant dimeric Abeta peptides. SELDI-TOF mass spectrometry demonstrated a substantive number of Abeta-related peptides, some of them with elongated C terminal sequences. Pro-inflammatory TNF-alpha levels were significantly increased in the gray matter of immunized AD cases compared to the NDC and non immunized AD groups. CONCLUSIONS: Immunotherapy responses were characterized by extreme variability. Considering the broad range of biological variation that characterizes aging and complicates the recognition of reliable AD biomarkers, such disparities will make the interpretation of outcomes derived from epidemiologic and therapeutic investigations challenging. Although in some cases the apparent removal of amyloid plaques by AN-1792 was impressive, proportionate alterations in the clinical progression of AD were not evident. The fact that plaque elimination did not alter the trajectory of decline into dementia suggests the likelihood that these deposits alone are not the underlying cause of dementia. PMID- 20929586 TI - A novel envelope mediated post entry restriction of murine leukaemia virus in human cells is Ref1/TRIM5alpha independent. AB - BACKGROUND: 'Intrinsic' resistance to retroviral infection was first recognised with the Friend virus susceptibility gene (Fv1), which determines susceptibility to murine leukaemia virus (MLV) infection in different murine species. Similarly, the tripartite motif (TRIM) family of proteins determine lentiviral restriction in a primate host-species specific manner. For example rhesus TRIM5alpha (rhTRIM5alpha) can potently restrict HIV-1 infection while human TRIM5alpha (huTRIM5alpha) only has a mild effect on SIVmac and HIV-1 infectivity (Lv1). Human TRIM5alpha is able to restrict MLV-N virus replication, but is ineffective against MLV-B or MLV-NB virus infection. Lv2 restriction of some HIV-2 viruses is seen in human cells. Like Lv1, Lv2 is a post-entry restriction factor, whose viral determinants have been mapped to the viral capsid (CA). Unlike Lv1, however, Lv2 is determined by envelope (Env) in addition to CA. Here we present evidence of a novel Env determined post entry restriction to infection in human cells of pseudotyped MLV-B and MLV-NB cores. RESULTS: We generated retroviral vectors pseudotyped with various gamma and lentiviral Envs on MLV-B and -NB CAs containing a green fluorescent protein (GFP) reporter. Flow cytometry was used to determine transduction efficiencies in NP2/CD4/CXCR4 (glioma cell line stably transduced with the HIV receptors) and HeLa/CD4 cell lines. The HeLa/CD4 cell line restricted both MLV CAs in an Env dependent manner, compared to NP2/CD4/CXCR4 cells. Quantitative polymerase chain reaction (QT-PCR) analysis of reverse transcription (RT) transcripts demonstrates that this restriction occurs at a post entry and RT level. siRNA knockdown of huTRIM5alpha ruled out a direct role for this cellular component in mediating this restriction. We describe a previously unobserved Env determined restriction of MLV-B and MLV-NB CAs in HeLa/CD4 cells when pseudotyped with HIV-2 and RD114 Envs, but not gibbon ape leukaemia virus (GALV), HIV-1 or Amphotrophic (Ampho) Envs. CONCLUSIONS: Our data further demonstrate the variability of Env and CA mediated susceptibility to post entry host cell restriction. We discuss the relevance of these findings in light of the growing evidence supporting the complexities involved in innate host immunity to retroviral infection. PMID- 20929587 TI - Parental influences on child physical activity and screen viewing time: a population based study. AB - BACKGROUND: Parents can influence their children's physical activity participation and screen time.This study examined the relative significance of perceived parental barriers and self-efficacy in relation to children's physical activity participation and screen time viewing. The associations between these factors and the behaviours were analysed. METHODS: Cross-sectional population survey in New South Wales, Australia of parents of pre-school (N = 764), younger (Kindergarten, Grades 2 and 4; N = 1557) and older children (Grades 6, 8 and 10; N = 1665). Parents reported barriers and self-efficacy to influence their child's physical activity and screen time behaviours in a range of circumstances. Differences were examined by child's sex and age group, household income, maternal education and location of residence. The duration of physical activity and screen viewing was measured by parental report for pre-school and younger children and self-report for older children. Associations between parental factors and children's organised, non-organised and total activity and screen time were analysed. RESULTS: Cost, lack of opportunities for participation and transport problems were the barriers most often reported, particularly by low income parents and those in rural areas. The number of barriers was inversely related to children's time spent in organised activity, but not their non organised activity. Higher parental self-efficacy was positively associated with organised physical activity in the younger and older children's groups and the non-organised activity of older children. School-age children (younger and older groups) were less likely to meet physical activity guidelines when parents reported >=4 barriers (OR 3.76, 95% CI 1.25-11.34 and OR 3.72, 95% CI 1.71-8.11 respectively). Low parental self-efficacy was also associated with the likelihood of children exceeding screen time guidelines for each age group (pre-school OR 0.62, 95% CI 0.43-0.87; young children OR 0.56, 95% CI 0.39-0.80; and older children OR 0.57, 95% CI 0.43-0.74). CONCLUSION: Parental barriers are associated with the time that children spend in both active and sedentary pursuits. These findings highlight family, economic and environmental factors that should be addressed in programs to promote child physical activity and tackle sedentary behaviour. PMID- 20929588 TI - Plasmodium ovale infection in Malaysia: first imported case. AB - BACKGROUND: Plasmodium ovale infection is rarely reported in Malaysia. This is the first imported case of P. ovale infection in Malaysia which was initially misdiagnosed as Plasmodium vivax. METHODS: Peripheral blood sample was first examined by Giemsa-stained microscopy examination and further confirmed using a patented in-house multiplex PCR followed by sequencing. RESULTS AND DISCUSSION: Initial results from peripheral blood smear examination diagnosed P. vivax infection. However further analysis using a patented in-house multiplex PCR followed by sequencing confirmed the presence of P. ovale. Given that Anopheles maculatus and Anopheles dirus, vectors of P. ovale are found in Malaysia, this finding has significant implication on Malaysia's public health sector. CONCLUSIONS: The current finding should serve as an alert to epidemiologists, clinicians and laboratory technicians in the possibility of finding P. ovale in Malaysia. P. ovale should be considered in the differential diagnosis of imported malaria cases in Malaysia due to the exponential increase in the number of visitors from P. ovale endemic regions and the long latent period of P. ovale. It is also timely that conventional diagnosis of malaria via microscopy should be coupled with more advanced molecular tools for effective diagnosis. PMID- 20929589 TI - What are the beliefs, attitudes and practices of front-line staff in long-term care (LTC) facilities related to osteoporosis awareness, management and fracture prevention? AB - BACKGROUND: Compared to the general elderly population, those institutionalized in LTC facilities have the highest prevalence of osteoporosis and subsequently have higher incidences of vertebral and hip fractures. The goal of this study is to determine how well nurses at LTC facilities are educated to properly administer bisphosphonates. A secondary question assessed was the nurse's and PSW's attitudes and beliefs regarding the role and benefits of vitamin D for LTC patients. METHODS: Eight LTC facilities in Hamilton were surveyed, and all nurses were offered a survey. A total 57 registered nurses were surveyed. A 21 item questionnaire was developed to assess existing management practices and specific osteoporosis knowledge areas. RESULTS: The questionnaire assessed the nurse's and personal support worker's (PSWs) education on how to properly administer bisphosphonates by having them select all applicable responses from a list of options. These options included administering the drug before, after or with meals, given with or separate from other medications, given with juice, given with or without water, given with the patient sitting up, or finally given with the patient supine. Only 52% of the nurses and 8.7% of PSWs administered the drug properly, where they selected the options: (given before meals, given with water, given separate from all other medications, and given in a sitting up position). If at least one incorrect option was selected, then it was scored as an inappropriate administration. Bisphosphonates were given before meals by 85% of nurses, given with water by 90%, given separately from other medication by 71%, and was administered in an upright position by 79%. Only 52% of the nurses and 8.7% of PSWs surveyed were administering the drug properly. Regarding the secondary question, of the 57 nurses surveyed, 68% strongly felt their patients should be prescribed vitamin D supplements. Of the 124 PSWs who completed the survey, 44.4% strongly felt their patients should be prescribed vitamin D supplementation. CONCLUSION: Bisphosphonates are quite effective in increasing the bone mineral density of LTC patients, and may reduce fracture rates, but it is only effective if properly administered. In our study, proper administration of bisphosphonate therapy was less than optimal. In summary, although the education of health providers has improved since the mid-1990's, this area still requires further attention and the subject of future quality assurance research. PMID- 20929590 TI - Declining in efficacy of a three-day combination regimen of mefloquine-artesunate in a multi-drug resistance area along the Thai-Myanmar border. AB - BACKGROUND: Declining in clinical efficacy of artesunate-mefloquine combination has been documented in areas along the eastern border (Thai-Cambodian) of Thailand. In the present study, the clinical efficacy of the three-day combination regimen of artesunate-mefloquine as first-line treatment for acute uncomplicated falciparum malaria in Thailand was monitored in an area along the western border (Thai-Myanmar) of the country. METHODS: A total of 150 Burmese patients (85 males and 65 females) aged between 16 and 50 years who were attending the Mae Tao clinic, Mae-Sot, Tak Province, and presenting with symptomatic acute uncomplicated Plasmodium falciparum malaria were included into the study. Patients were treated initially (day 0) with 4 mg/kg body weight artesunate and 15 mg/kg body weight mefloquine. The dose regimen on day 2 was 4 mg/kg body weight artesunate and 10 mg/kg body weight mefloquine. On day 3, artesunate at the dose of 4 mg/kg body weight was given with 0.6 mg/kg body weight primaquine. Whole blood mefloquine and plasma artesunate and dihydroartemisinin (active plasma metabolite of artesunate) concentrations following treatment were determined by high performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometry (LCMS), respectively. RESULTS: Thirty-four cases had recrudescence during days 7 and 42. Five and 5 cases, respectively had reinfection with P. falciparum and reappearance of Plasmodium vivax in their peripheral blood during follow-up. The Kaplan-Meier estimate of the 42-and 28-day efficacy rates of this combination regimen were 72.58% (95% CI: 63.20-79.07%) and 83.06 (95% CI 76.14-94.40%), respectively. Parasite clearance time (PCT) and fever clearance time (FCT) were significantly prolonged in patients with treatment failure compared with those with sensitive response [median (95% CI) values for PCT 32.0 (20.0-48.0) vs 24.0 (14.0-32.0) hr and FCT 30.0 (22.0-42.0) vs 26.0 (18.0-36.0) hr; p < 0.005]. Whole blood mefloquine concentrations on days 1, 7 and 14 in patients with sensitive and recrudescence response were comparable. Although plasma concentration of dihydroartemisinin at 1 hour of treatment was significantly lower in patients with recrudescence compared with sensitive response [mean (95% CI) 456 (215-875) vs 525 (452-599) ng/ml; p < 0.001], the proportion of patients with recrudescence who had relatively low (compared with the lower limit of 95% CI defined in the sensitive group) was significantly smaller than that of the sensitive group. CONCLUSIONS: Although pharmacokinetic (ethnic-related) factors including resistance of P. falciparum to mefloquine contribute to some treatment failure following treatment with a three-day combination regimen of artesunate-mefloquine, results suggest that artesunate resistance may be emerging at the Thai-Myanmar border. PMID- 20929591 TI - Unique genome-wide transcriptome profiles of chicken macrophages exposed to Salmonella-derived endotoxin. AB - BACKGROUND: Macrophages play essential roles in both innate and adaptive immune responses. Bacteria require endotoxin, a complex lipopolysaccharide, for outer membrane permeability and the host interprets endotoxin as a signal to initiate an innate immune response. The focus of this study is kinetic and global transcriptional analysis of the chicken macrophage response to in vitro stimulation with endotoxin from Salmonella typhimurium-798. RESULTS: The 38535 probeset Affymetrix GeneChip Chicken Genome array was used to profile transcriptional response to endotoxin 1, 2, 4, and 8 hours post stimulation (hps). Using a maximum FDR (False Discovery Rate) of 0.05 to declare genes as differentially expressed (DE), we found 13, 33, 1761 and 61 DE genes between endotoxin-stimulated versus non-stimulated cells at 1, 2, 4 and 8 hps, respectively. QPCR demonstrated that endotoxin exposure significantly affected the mRNA expression of IL1B, IL6, IL8, and TLR15, but not IL10 and IFNG in HD 11 cells. Ingenuity Pathway Analysis showed that 10% of the total DE genes were involved in inflammatory response. Three, 9.7, 96.8, and 11.8% of the total DE inflammatory response genes were significantly differentially expressed with endotoxin stimulation at 1, 2, 4 and 8 hps, respectively. The NFKBIA, IL1B, IL8 and CCL4 genes were consistently induced at all times after endotoxin treatment. NLRC5 (CARD domain containing, NOD-like receptor family, RCJMB04_18i2), an intracellular receptor, was induced in HD11 cells treated with endotoxin. CONCLUSIONS: As above using an in vitro model of chicken response to endotoxin, our data revealed the kinetics of gene networks involved in host response to endotoxin and extend the known complexity of networks in chicken immune response to Gram-negative bacteria such as Salmonella. The induction of NFKBIA, IL1B, IL8, CCL4 genes is a consistent signature of host response to endotoxin over time. We make the first report of induction of a NOD-like receptor family member in response to Salmonella endotoxin in chicken macrophages. PMID- 20929592 TI - Effectiveness of tocotrienol-rich fraction combined with tamoxifen in the management of women with early breast cancer: a pilot clinical trial. AB - INTRODUCTION: Basic research has indicated that tocotrienols have potent antiproliferative and proapoptotic effects that would be expected to reduce the effect of breast cancer. METHODS: We conducted a double-blinded, placebo controlled pilot trial to test the effectiveness of adjuvant tocotrienol therapy in combination with tamoxifen for five years in women with early breast cancer. Two-hundred-forty women, aged between 40-60 years, with either tumor node metastases (TNM) Stage I or II breast cancer and estrogen receptor (ER) positive tumors were non-randomly assigned to two groups. The intervention group received tocotrienol rich fraction (TRF) plus tamoxifen whilst the control group received placebo plus tamoxifen, for five years. RESULTS: During the five years of study, 8 patients died due to breast cancer while 36 patients developed local or systemic recurrence. Five-year breast cancer specific survival was 98.3% (95% confidence interval (CI): 95.9% to 100%) in the intervention group and 95%, (95% CI: 91.1% to 98.9%) in the control group, while 5-years disease free survival was 86.7% (95% CI: 80.6% to 92.8%) and 83.3% (95% CI: 76.6% to 90.0%), respectively. Risk of mortality due to breast cancer was 60% (HR: 0.40; 95% CI: 0.08 to 2.05) lower in the intervention group versus the controls following adjustment for age, ethnicity, stage and lymph node status but this was not statistically significant. Adjuvant TRF therapy was not associated with breast cancer recurrence (HR: 0.84; 95% CI: 0.43-1.65). CONCLUSIONS: From the current study, there seems to be no association between adjuvant tocotrienol therapy and breast cancer specific survival in women with early breast cancer. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01157026. PMID- 20929594 TI - Translational research in oncology: key bottlenecks and new paradigms. AB - Translational research is about transforming progress in basic research into products that benefit patients. Here I discuss some of the key obstacles to effective translational research in oncology that have previously received limited attention. Basic research often does not go far enough for straightforward clinical translation, and long-term, high-risk endeavours to fill these key gaps have not been adequately addressed either by industry or by the culture of investigator-initiated research. These key gaps include the identification of causative oncogenic mutations and new approaches to regulating currently undruggable targets such as tumour suppressor genes. Even where an inhibitor of a key target has been identified, new approaches to clinical development are needed. The current approach of treating broad populations of patients based primarily on primary cancer site is not well suited to the development of molecularly targeted drugs. Although developing drugs with predictive diagnostics makes drug development more complex, it can improve the success rate of development, as well as provide benefit to patients and the economics of healthcare. I review here some prospective Phase III designs that have been developed for transition from the era of correlative science to one of reliable predictive and personalised oncology. PMID- 20929593 TI - The longitudinal association of common susceptibility variants for type 2 diabetes and obesity with fasting glucose level and BMI. AB - BACKGROUND: Variation in the effects of genetic variants on physiological traits over time or with age may alter the trajectories of these traits. However, few studies have investigated this possibility for variants associated with type 2 diabetes or obesity, and these show little consensus. We aimed to characterise the possible longitudinal associations of common diabetes-susceptibility variants in the KCNJ11, PPARG, TCF7L2, IGF2BP2, CDKAL1, SLC30A8 and HHEX gene loci, with fasting glucose level; and of an obesity-associated variant in the FTO gene, with body mass index (BMI). METHODS: The study analysed data from the Busselton Health Study (n = 4,554). Cross-sectional association analyses included family data and used the total association test. Longitudinal association analyses of unrelated participant data (n = 2,864) used linear mixed-effects models. RESULTS: In cross sectional analyses, we observed associations of the T allele at the IGF2BP2 single nucleotide polymorphism (SNP) rs4402960 with raised fasting glucose (p = 0.045), and the A allele at the FTO SNP rs9939609 with raised BMI (p = 0.003). Longitudinal analyses showed no significant associations between SNPs and changes in fasting glucose or BMI in the same individuals, either over mean follow-up times of 18.7 and 21.8 years respectively, or with age during adulthood. CONCLUSIONS: There was no indication that the effects of common type 2 diabetes variants on fasting glucose varied with age during adulthood or over time. PMID- 20929595 TI - Metabolic imprinting, programming and epigenetics - a review of present priorities and future opportunities. AB - Metabolic programming and metabolic imprinting describe early life events, which impact upon on later physiological outcomes. Despite the increasing numbers of papers and studies, the distinction between metabolic programming and metabolic imprinting remains confusing. The former can be defined as a dynamic process whose effects are dependent upon a critical window(s) while the latter can be more strictly associated with imprinting at the genomic level. The clinical end points associated with these phenomena can sometimes be mechanistically explicable in terms of gene expression mediated by epigenetics. The predictivity of outcomes depends on determining if there is causality or association in the context of both early dietary exposure and future health parameters. The use of biomarkers is a key aspect of determining the predictability of later outcome, and the strengths of particular types of biomarkers need to be determined. It has become clear that several important health endpoints are impacted upon by metabolic programming/imprinting. These include the link between perinatal nutrition, nutritional epigenetics and programming at an early developmental stage and its link to a range of future health risks such as CVD and diabetes. In some cases, the evidence base remains patchy and associative, while in others, a more direct causality between early nutrition and later health is clear. In addition, it is also essential to acknowledge the communication to consumers, industry, health care providers, policy-making bodies as well as to the scientific community. In this way, both programming and, eventually, reprogramming can become effective tools to improve health through dietary intervention at specific developmental points. PMID- 20929596 TI - New-onset asthma among soldiers serving in Iraq and Afghanistan. AB - Since June 4, 2004, asthma diagnosed and symptomatic after the age of 12 years has been an exclusion criterion for military enlistment unless exempted via medical waiver. The Department of Defense determined that 13% of U.S. Army Medic visits in Iraq are for new-onset acute respiratory illness; case reports of veterans with asthma that began in Iraq and Afghanistan War zones have surfaced. This prompted our study to determine whether new asthma is diagnosed more frequently among Iraq/Afghanistan War troops versus stateside-based troops. Retrospective review of asthma diagnoses among computerized charts for military personnel discharged from active duty and examined between March 1, 2004 and May 1, 2007, at the Veterans Affairs Medical Center (VAMC), Northport, NY, classified soldiers by (1) deployment status-whether they were stationed in Iraq/Afghanistan for a 1-year tour of duty or stationed in the United States, and (2) VA diagnosis of asthma per International Classification of Disease codes. Associations between deployment and asthma statuses were evaluated/stratified by gender/age group. Eligibility criteria entailed (1) residence in Long Island, (2) aged 18-45 years, and (3) both U.S. military service and discharge dates between March 1, 2004 and May 1, 2007. Out of 6233 patients who served between 2004 and 2007 and were followed at the Northport VAMC, 290 new-onset/prevalent asthma cases were identified. Deployment to Iraq was associated with a significantly higher risk of asthma compared with stateside soldiers (6.6% versus 4.3%; with a crude odds ratio, 1.58; 95% CI, 1.18, 2.11). These associations persist when stratified by gender and age group. Deployment to Iraq and Afghanistan is associated with new onset asthma. Etiologic studies, surveillance, incidence, epidemiology, and assessing response to therapy are recommended. PMID- 20929597 TI - Comprehensive use of environmental control practices among adults with asthma. AB - Asthma is a common chronic illness among adults. National guidelines recommend comprehensive implementation of environmental control practices (ECP) for asthma management. The purpose of this study was to examine the association between preventive asthma care and comprehensive ECP use among adults with asthma. We used data from the Four-State National Asthma Survey, including 3727 adults with asthma. Comprehensive management was defined as implementing at least five of eight ECP: (1) air filter, (2) dehumidifier, (3) mattress cover, (4) pillow cover, (5) no pets, (6) no smoking, (7) no carpets, and (8) washing sheets in hot water. We examined the association between comprehensive implementation of ECP and receipt of preventive asthma care, as measured by number of routine asthma visits in the prior year and physician advice to modify the environment. Overall, 13.3% (95% confidence interval [CI], 11.8-14.8%) of participants reported comprehensive ECP use. The most frequently implemented ECP were no smoking (80%), no pets (54%), and washing sheets in hot water (43%). Comprehensive ECP use was associated with having received physician advice (odds ratio [OR], 2.3; 95% CI, 1.6-3.4) and increased number of routine asthma visits (1-2 visits: OR, 2.4, and 95% CI, 1.5-4.0; 3-4 visits: OR, 2.4, and 95% CI, 1.3-4.5; 5 or more visits: OR, 3.4, and 95% CI, 1.9-6.4). Receipt of preventive asthma care is associated with comprehensive implementation of ECP. Further research is needed to determine the factors mediating these associations to develop more effective asthma counseling. PMID- 20929598 TI - Comparable effect of a leukotriene receptor antagonist and long-acting beta2 adrenergic agonist in cough variant asthma. AB - Cough variant asthma (CVA) is a common cause of chronic persistent cough, in which allergic airway inflammation may play a role. Although current guidelines recommend bronchodilators and anti-inflammatory drugs for the treatment, comparison of the efficacy of these medications has not been investigated. This study was designed to evaluate the effectiveness of pranlukast, a leukotriene receptor antagonist, and salmeterol, a long-acting beta2-adrenergic agonist, in the treatment of CVA. The study was a randomized, controlled, parallel-group, multicenter trial. After a 4-week run-in period, 49 patients with newly diagnosed CVA were assigned to receive oral pranlukast (225 mg, b.i.d.) or inhaled salmeterol (100 MUg, b.i.d.) for 4 weeks. Primary outcome measure was cough symptom and secondary outcome measures were pulmonary function and eosinophilic airway inflammation. Treatment with pranlukast and salmeterol each decreased cough symptom scores, where the changes from baseline values were significantly greater in the pranlukast group than in the salmeterol group. Forced expiratory volume in 1 second and peak expiratory flow (PEF) increased in the two treatment groups with the same magnitudes, but significant decreases in diurnal variation of PEF and eosinophil counts and eosinophil cationic protein contents in the peripheral blood and induced sputum were observed only in the pranlukast group. In view of antitussive and anti-inflammatory actions, the leukotriene receptor antagonist pranlukast seems to be more effective than the long-acting beta2 adrenergic agonist salmeterol in the treatment of CVA. PMID- 20929599 TI - Both bronchial and alveolar exhaled nitric oxide are reduced with extrafine beclomethasone dipropionate in asthma. AB - Exhaled nitric oxide (NO) is a noninvasive marker of airway inflammation. Beclomethasone dipropionate (BDP) is the only inhaled corticosteroid (ICS) available as both extrafine and nonextrafine hydrofluoroalkane (HFA) pressurized metered-dose inhaler (pMDI) formulation. The present study was designed to evaluate whether the different patterns of lung deposition of two HFA BDP formulations are associated with a different effect on bronchial and alveolar NO. This was a prospective double-blind, randomized, controlled, crossover study. After a 2-week placebo run-in period without ICSs, asthmatic patients were randomized to extrafine BDP, 100 MUg, b.i.d. or nonextrafine BDP, 250 MUg, b.i.d. for two 2-week periods separated by a 2-week washout period. Fourteen patients (5 men) with a mean age 37 years and mean baseline forced expiratory volume in 1 second (FEV1) of 83% of predicted were analyzed. Exhaled bronchial NO was significantly (p < 0.001) reduced in both treatment groups when compared with the last week of run-in period, whereas alveolar NO was significantly (p < 0.001) reduced only with extrafine BDP. Moreover, extrafine BDP was superior to nonextrafine BDP in both parameters (p < 0.05). Extrafine but not nonextrafine BDP HFA formulation lowers both bronchial and alveolar exhaled NO in asthmatic patients. ICS distribution throughout the whole bronchial tree could be important in patients who do not gain optimal control of inflammation with conventional nonextrafine ICS. PMID- 20929600 TI - Beta(2)-adrenergic receptor haplotype/polymorphisms and asthma susceptibility and clinical phenotype in a Chinese Han population. AB - Association and linkage studies of beta2-adrenergic receptor (beta2AR) polymorphisms in relation to the expression of asthmatic phenotypes and immune regulatory mechanisms have shown inconsistent results. This study was designed to analyze the relationship of particular combinations of single nucleotide polymorphisms (SNPs) or haplotypes of the beta2AR gene with bronchial asthma, bronchodilator response, and total IgE. By direct DNA sequencing, five SNPs (in positions -47, -20, 46, 79, and 252) of beta2AR gene were determined and combined with haplotypes in 201 asthmatic patients and 276 normal controls recruited from the Chinese Han population. Significantly higher bronchodilator response was observed in patients with homozygotic genotype 46A/A (13.40 +/- 3.48%), compared with those with homo-46G/G (7.25 +/- 3.11%) and heterozygotes 46A/G (7.39 +/- 3.14%), respectively (p < 0.0001). There was also a significant difference in bronchodilator response when beta2AR haplotypes were analyzed (p = 0.003). From two common SNPs at positions 46A/G and 79C/G, we had determined three haplotypes that constructed six haplotype pairs. Comparison of the mean delta forced expiratory volume in 1 second (FEV1) values for the six haplotype pairs showed significant difference. Subjects homozygous for 46A/79C (Arg16/Gln27) had the highest deltaFEV1 (13.40 +/- 3.48%) and those with 46G/79C (Gly16/Gln27) homozygote had the lowest (6.43 +/- 0.55%). The two SNP haplotype pairs were significantly associated with delta FEV1 (p < 0.0001). Significantly higher total IgE levels were found in patients with homozygotic carriers of 79C genotypes (p = 0.022) and homozygotic haplotype -47 T/-20 T/46 A/79 C/252 G (p < 0.0001). These results indicate that the manifestation of asthma might be affected by either an individual beta2AR SNPs or beta2AR haplotype. PMID- 20929601 TI - Allergic and mixed rhinitis: Epidemiology and natural history. AB - Allergic rhinitis (AR) is a prevalent chronic respiratory problem in the United States associated with significant comorbidities and health care costs. Recent surveys suggest that mixed rhinitis (MR), which refers to patients with nonallergic AR (NAR) and AR, is a specific rhinitis subtype that may represent between 50 and 70% of all AR patients although the true prevalence of these conditions has not been confirmed. It is important to make a clear distinction between these chronic rhinitis (CR) phenotypes as symptom triggers; response to treatment and prevalence of comorbidities such as sinusitis may be significantly different. Incorporating patient centric questionnaires that can reliably characterize AR, MR, and NAR phenotypes will improve our ability to further investigate the natural history/epidemiology, mechanisms, and development of novel therapies for NAR-related CR subtypes. PMID- 20929602 TI - Allergic rhinitis: Pathophysiology. AB - The inflammatory response in the nasal mucosa in subjects with allergic rhinitis challenged intranasally with an allergen includes an immediate IgE-mediated mast cell response as well as a late-phase response characterized by recruitment of eosinophils, basophils, and T cells expressing Th2 cytokines including IL-4, a switch factor for IgE synthesis, and IL-5, an eosinophil growth factor. Recent advances have suggested that additional pathways may contribute to the pathophysiology of allergic rhinitis including local synthesis of IgE in the nasal mucosa, the epithelial expression of cytokines that regulate Th2 cytokine responses (i.e., thymic stromal lymphopoietin, IL-25, and IL-33), and the activation of histamine receptors other than H1 and H2 such as H4-histamine receptors. This review focuses on briefly reviewing well-established pathways in the pathophysiology of allergic rhinitis and then updating knowledge on recent advances in the pathophysiology of allergic rhinitis. The review references information obtained from original articles published and available online on PubMed. In vitro and in vivo studies indicate that B cells in nasal mucosa can be induced to express IgE. Preclinical studies show an important role for epithelial derived cytokines (thymic stromal lymphopoietin, IL-25, and IL-33) in regulating Th2 responses at mucosal surfaces, and for H4-histamine receptors in mediating itching. In addition, regulatory T cells may play an important role in mediating active tolerance to allergens. An improved understanding of the pathophysiology of allergic rhinitis may provide important insight into novel therapeutic targets. PMID- 20929603 TI - Allergic rhinitis: Direct and indirect costs. AB - Allergic rhinitis is one of the most common conditions affecting both children and adults. Along with the burden of the disease and decrease in quality of life associated with allergic rhinitis, there are high costs related to the disorder. Costs due to allergic rhinitis can be divided into two categories: direct costs that are related to monies spent on the course of managing the disease and indirect costs that are due to missing work and decreased productivity due to the illness. There are also the costs associated with the comorbidities of allergic rhinitis, such as sinusitis and asthma, which are classified as "hidden" direct costs. Management of allergic rhinitis involves allergen avoidance, proper pharmacologic therapies, and allergen immunotherapy. These treatments add to the direct cost of the condition and need to be evaluated to determine their cost effectiveness in the control of the patient's nasal allergies. This article reviews the latest data on cost issues in allergic rhinitis and information of cost-effectiveness of treatments for this condition. PMID- 20929604 TI - Pet dander and difficult-to-control asthma: The burden of illness. AB - There is evidence that allergy to common indoor pets, particularly cats and dogs, is closely associated with symptomatic asthma in the United States. Because the presence of pets in a home is a potentially modifiable factor, it is important to consider how much asthma morbidity and health care cost might be alleviated by the removal of pets from the homes of all persons with pet-allergic asthma. The percentage of pet-associated excess asthma morbidity was estimated as a proportion of all asthma-related health care costs for the United States. PMID- 20929606 TI - The role of food allergy in atopic dermatitis. AB - Atopic dermatitis (AD) affects ~10% of children. Food allergy is a known provoking cause of AD in a subset of affected children. A literature search of PubMed and Medline was conducted to review the epidemiology and pathophysiology of AD, with special focus on the role of food allergy in the development of AD, its management, and its long-term preventive strategies. A literature search of PubMed and Medline was conducted. Food allergens readily provoke AD in ~35% of patients, as proven through double-blind placebo-controlled food challenge studies. Milk, egg, wheat, soy, and peanut account for 75% of the cases of food induced AD. However, the positive predictive values of the parental history, skin prick tests, or serum tests for detecting food-specific IgE are low, making these unsuitable for use as single diagnostic modalities. Therefore, the use of a food challenge test is very helpful in objectively confirming the history or positive tests. Elimination diets are often helpful in challenge-proven cases, but care must be taken to evaluate the nutritional status of the child. There are few effective long-term strategies to prevent the development of food allergen induced AD. Early onset of AD has been shown to be a risk factor for the development of other allergic diseases, including other food allergy/sensitization, as part of the atopic march. Treatment of other causes of AD, such as barrier dysfunction and cutaneous infection, are of equal importance to food allergen avoidance. Food allergy is an important provoking cause of AD, but it is only relevant in ~35% of affected individuals. PMID- 20929605 TI - Pet dander and difficult-to-control asthma: Therapeutic options. AB - The prevalence of sensitization to cat and dog allergens is high in the general population and poses a challenge to the physician managing allergic asthma. Adequate allergen avoidance is difficult to achieve because of the physical characteristics of airborne animal allergens and patient noncompliance. Allergen specific high-dose subcutaneous immunotherapy has shown benefit in cat-allergic patients with asthma and rhinoconjunctivitis, whereas the data for dog-allergic patients are not as convincing. Alternative immunotherapy approaches including the sublingual route or allergen-derived peptide-based immunotherapy remain experimental. Pharmacotherapy of pet-allergic asthmatic patients requires a stepwise approach following established asthma management guidelines. In addition to short-acting beta-agonists and inhaled corticosteroids, prophylactic antihistamines before anticipated pet exposure, the use of intranasal steroids, and the use of leukotriene antagonists may also be considered as adjunctive therapy in pet-allergic patients with asthma and/or allergic rhinitis. Omalizumab appears to have particular efficacy in pet allergen-induced asthma. Novel therapies such as Fcgamma-Fel d 1 chimeric proteins still have to be evaluated in the human setting. PMID- 20929607 TI - Current treatment of hereditary angioedema: An update on clinical studies. AB - Hereditary angioedema (HAE) is a rare, potentially life-threatening disease that manifests as recurrent episodes of nonpruritic swelling that may affect the extremities, face, genitalia, gastrointestinal tract, and/or larynx. HAE is the result of a deficiency of functional C1-esterase inhibitor (C1-INH), a key regulator of the complement, coagulation, and kallikrein-kinin cascades. In HAE patients, overactivation of the kallikrein-kinin cascade results in excessive release of bradykinin, the mediator of the pain and swelling that is characteristic of HAE. Historically, treatment options for HAE have been limited, but newly approved and emerging therapies, such as C1-INH replacement products, a plasma kallikrein inhibitor, and a bradykinin B2-receptor antagonist, appear to provide safe and effective relief for a significant proportion of patients with HAE. Because they may have therapeutic and practical advantages over existing HAE therapies, the new agents have the potential to improve the overall management of patients with HAE. This article reviews the results from recent clinical trials of these drugs and considers their role in clinical practice. PMID- 20929608 TI - The humanistic burden of hereditary angioedema: Impact on health-related quality of life, productivity, and depression. AB - Hereditary angioedema (HAE) is a rare, autosomal dominant disorder characterized by recurrent acute attacks of swelling of the larynx, abdomen, and periphery. This study was designed to assess the humanistic burden of illness associated with HAE. HAE burden was assessed via a web-based survey of patients that solicited information on attack characterization, treatment, side effects, pain, and functional and emotional burden of disease management. In addition to HAE specific sections, the survey used three standardized instruments to compare HAE patient data to normative (healthy) and chronic disease populations: the 12-Item Short Form (SF-12) Health Survey, the Work Productivity and Activity Impairment General Health (WPAI-GH) questionnaire, and the Hamilton Depression Inventory Short Form (HDI-SF). A total of 457 HAE patients responded to the survey (response rate, ~19%). Patients reported significantly poorer health-related quality of life versus population norms, based on the SF-12 Physical Component Summary (mean, 43.7 versus 49.6; p < 0.001) and Mental Component Summary (mean, 42.6 versus 49.4; p < 0.001). HAE patients also had higher mean HDI-SF scores than population norms (8.1 +/- 6.5 versus 3.1 +/- 3.0; p < 0.001), with 42.5% of HAE patients scoring >8.5, indicative of depressive symptomatology. Productivity was also markedly impaired in all WPAI-GH categories, including 34% overall work impairment. Because of their most recent HAE attack, workers lost a mean of 3.3 days; students lost a mean of 1.9 days. HAE results in considerable humanistic burden to patients across physical and mental health domains; negatively impacts education, career, and work productivity; and compounds the substantial economic burdens that are reported separately. PMID- 20929609 TI - Effect of addition of salmeterol versus doubling the dose of fluticasone propionate on specific airway resistance in children with asthma. AB - Based primarily on extrapolation from adult studies, current pediatric asthma guidelines advise the addition of long-acting beta2-agonists for children symptomatic on low/moderate-dose inhaled corticosteroids before increasing the corticosteroid dose. This study was designed to compare the effect of combination salmeterol/fluticasone propionate (SFC) with doubling the dose of fluticasone propionate (FP) on specific airway resistance (sR(aw)) in moderate/severe persistent asthmatic children. A double-blind, randomized, controlled study was performed; children with asthma (4-11 years old; sR(aw) > 1.3 kPa.s) were randomized after a 2-week run-in (FP, 100 MUg, b.i.d.) to either SFC (50 MUg/100 MUg b.i.d.) or FP (200 MUg b.i.d.) via Diskus (GlaxoSmithKline, Stockley Park, U.K.) for 6 weeks. Lung function (sR(aw)-plethysmography and forced expiratory volume in 1 second [FEV1]) was measured before run-in, at randomization, after 3 weeks, at the end of 6-week treatment, and after 48-hour washout. Symptom scores and rescue medication use were recorded throughout. Thirty-five children entered run-in and 24 were randomized (mean age, 7.3 +/- 2.2 years; 50% boys). All children showed an improvement in sR(aw). After adjusting for age, gender, and baseline sR(aw,) children receiving SFC had a significantly greater improvement in sR(aw) compared with those receiving FP (adjusted means ratio [95% confidence interval {CI}], 0.81 [0.68-0.97]; p = 0.021). There was a significant interaction between treatment and gender (sR(aw), adjusted geometric mean [95% CI ]kPa.s, SFC versus FP: boys, 1.25 [1.10-1.41] [n = 7] versus 1.87 [1.61-2.17] [n = 5]; girls, 1.29 [1.10-1.52] [n = 5] versus 1.29 [1.13-1.47] [n = 7]; p = 0.008). There were no differences in FEV1, symptoms, or rescue medication use between the groups. Addition of salmeterol provides greater improvement in sR(aw) than doubling the dose of FP in children with moderate/severe persistent asthma. PMID- 20929610 TI - Reevaluation of pollen quantitation by an automatic pollen counter. AB - Accurate and detailed pollen monitoring is useful for selection of medication and for allergen avoidance in patients with allergic rhinitis. Burkard and Durham pollen samplers are commonly used, but are labor and time intensive. In contrast, automatic pollen counters allow simple real-time pollen counting; however, these instruments have difficulty in distinguishing pollen from small nonpollen airborne particles. Misidentification and underestimation rates for an automatic pollen counter were examined to improve the accuracy of the pollen count. The characteristics of the automatic pollen counter were determined in a chamber study with exposure to cedar pollens or soil grains. The cedar pollen counts were monitored in 2006 and 2007, and compared with those from a Durham sampler. The pollen counts from the automatic counter showed a good correlation (r > 0.7) with those from the Durham sampler when pollen dispersal was high, but a poor correlation (r < 0.5) when pollen dispersal was low. The new correction method, which took into account the misidentification and underestimation, improved this correlation to r > 0.7 during the pollen season. The accuracy of automatic pollen counting can be improved using a correction to include rates of underestimation and misidentification in a particular geographical area. PMID- 20929611 TI - Acquired angioedema: Autoantibody associations and C1q utility as a diagnostic tool. AB - Acquired Angioedema (AAE) is a rare condition classified into two subtypes: Type I, which is associated with lymphoproliferative disorders, and Type II, which is linked with autoantibodies against C1-esterase inhibitor (C1-INH). Unlike Type I AAE, Type II has no correlation with lymphoproliferative disorders. We report the evaluation of angioedema that was associated with an underlying lymphoproliferative disorder for the purpose of discussing the relationship between C1q and a diagnosis of AAE. A literature review was completed for the purpose of assessing the diagnostic value of C1q when used in the workup of AAE. A PubMed/Web of Science search (1976-2010) produced 78 references (yielding 167 individual cases of AAE) using terminology "AAE." The case described a patient with a depressed C1q (<3.5 mg/dL), decreased C4 (<3 mg/dL), decreased C1 inhibitor (1 mg/dL), decreased functional C1-INH (12%), and decreased total complement (<10 U/mL). Autoantibodies against C1-INH (free and bound respectively) were normal (12.4% and 10.1% of the standard of deviation). Using the above figures and data collected from the literature search, we tabulated 168 individual cases of AAE. Of the 168 cases, C1q was drawn in 104 cases, and 64 cases have no information regarding C1q. There are 10 cases where the C1q was documented as normal. With these values, a correlation between C1q and a diagnosis of AAE was assessed: A decreased C1q correlated with a diagnosis of AAE approximately 56%-94% of the time. C1q is a useful tool when working up a case of AAE. PMID- 20929612 TI - [Chagas disease and the transfusional safety in Mexico]. AB - The World Health Organization considers to the American trypanosomiasis a disease with priority attention that cause 45 000 deaths annually. We are celebrating a century of the disease description and the identification of etiologic agent and the transmitter. The universal screen strategy had diminished the risk of transmission by blood transfusion. In this number, Novelo Garza ET AL. described the national prevalence in Mexico through a screen test that led us watch the first geographical image of the disease in the country. PMID- 20929613 TI - [Survival pronostic factors in Mexican patients with multiforme glioblastoma]. AB - OBJECTIVE: To study the pre- and transoperative factors that influence patients' survival with GM. METHODS: Clinical and pathological records of all confirmed cases of GM diagnosed between 2000 and 2006 were included. Postoperative survival was divided in less or more than 8 months. chi2 test was used. RESULTS: One hundred and twenty patients (45 women and 75 men) were studied. Age range was from 7 to 85 years, 3.3% were 16 years old or younger and 12.5% were 70 years old or older. Headache was the most frequent complain, 40 patients developed hemiparesia and 6 had parestesias. Predominance of white matter hemispheric lesions was observed: right hemispheric tumors 65 (54%), left lesions 30 (25%) and bilateral tumors 7%. Histologically, 1.6% of GM had a sarcomatous component; 35% of patients survived less than 8 months. A difference between patients survival was the preoperative Karnofsky Performance Scale Score and the degree of cerebral edema during the surgical procedure. CONCLUSIONS: Pre-operative Karnofsky evaluation and edema during the surgical procedure were significant prognostic factors for survival. PMID- 20929614 TI - [Perception of benefits, limit and social assistance on the elderly to accomplish physical activity]. AB - BACKGROUND: Worldwide older adult (OA) population will grow from 10% to 22% between the year 2000 and 2050. In Mexico 8.2 millions are OA, which represents a worry for the governmental institutions because affect the social participation. OBJECTIVE: to understand the perceived benefits, barriers and social support for physical activity (PA) in OA in a gerontology unit. METHODS: We used a qualitative approach with semi structured interviews in depth. Fifteen OA from both sexes were included. Microanalysis line by line was conducted to get at open and axial encoding. Health Belief Model was used as theoretical and interpretative framework. RESULTS: Categories and subcategories analysis allowed us to understand the benefits perceived, barriers and social support for PA. The OA perceived that PA benefits their health. However emotional and social factors limit the acquisition of behavior perception. CONCLUSIONS: Health and recreation were the main reason for PA. The OA developed autonomy that impacts on the acquisition of an emotional attitude and confidence. PA retards the expression of functional deficiency and prevents the onset or exacerbation of chronic degenerative diseases. PMID- 20929615 TI - [Validation of an instrument to measure life quality in breast cancer patients]. AB - BACKGROUND: There are no reliable and valid instruments in Mexico for breast cancer patients. Our objective was to measure reliability and validity of a Spanish version of the FACT-B (Functional Assessment of Cancer Therapy-Breast) questionnaire in Mexican population. METHODS: The translation of the questionnaire was reviewed and minor changes were made. The instrument was applied to 142 patients recently diagnosed with breast cancer. It was applied to 105 for the second time, and to 75 for the third time. An analysis of item discrimination was made. The questionnaire's reliability was determined by Cronbach's alpha. Concurrent validity was determined by an analysis of correlations between the instrument's scales and EORTC's QLQ C-30 y BR-23 scales. RESULTS: The five FACT-B subscales were reliable, their alpha coefficients varied between 0.65 and 0.82. The entire scale obtained a value of 0.87. The correlation analysis between FACT-B and EORTC QLQ C-30 subscales indicated that the same construct was being evaluated. CONCLUSIONS: FACT-B is a valid, reliable and sensitive instrument to measuring quality life in Mexican breast cancer patients. PMID- 20929616 TI - [Detection of Trypanosoma cruzi in blood donors]. AB - BACKGROUND: The American trypanosomiasis is the second parasitic disease in importance after paludism and one of the main mechanism of transmission is a blood transfusion. Our objective was to measure the effect the Tripanosoma Cruzi screening test in blood banks in the Mexican Institute of Social Security. METHODS: Information was obtained from each unit of blood collected. The Tripanosoma cruzi prevalence was calculated only in samples with double reactivity in the blood banks. RESULTS: Of 71 blood banks, only 26 had been doing T. Cruzi screen; after implementation of integrated services 55 are doing the screening. There were 935 donors with double reactivity to the T. Cruzi test from 230,074 samples. The national prevalence was 0.406%. The seroprevalence was 0.013% to 3.118%. CONCLUSIONS: The screening of the T. cruzi improved the detection and increased the safety and the prevention of its transmission by blood transfusion. PMID- 20929617 TI - [Catheter-associated bloodstream infections. Review of five-year surveillance among hospitalized patients]. AB - BACKGROUND: Catheter related infections (CRI) and bloodstream infection (BSI) associated to central venous catheter (CVC) is cause of frequent hospital acquired infection (HAI) and a major reason of morbidity and mortality among patients and it is itself an indicator of quality health care. OBJECTIVE: To determine the incidence of CRI and BSI and to identify the hospital areas where they occurred over a five-year period. METHODS: A prospective study from 2004 to 2008 in a population of hospitalized patients who required the use of CVC was made. The HAI team detected the appearance of CRI during a daily routine surveillance. RESULTS: During the period of observation, 176 BSI were detected, accounting for 11 % of all HAI, and represented the third place in frequency. Incidence rate for 1000 catheter-days varied from 2.7 in 2006 to 5.4 in 2008; 57 % of these BSI were detected in the intensive care units. Candida spp. accounted as the more frequently isolated microorganism with predominance of C. parapsilosis. CONCLUSIONS: Our results and the incidence rate found in our study occurred within rates established in other studies. PMID- 20929618 TI - [Incidence and trends of neuroblastoma in Mexican children attending at Instituto Mexicano del Seguro Social]. AB - BACKGROUND: Neuroblastoma (NB) is the principal tumor of the sympathetic nervous system in children. OBJECTIVE: to describe the epidemiological and clinical characteristics of Mexican children with NB. METHODS: A population-based, prolective study, with data obtained from the Childhood Cancer Registry of the Instituto Mexicano del Seguro Social. The frequencies and incidence of the variables of the study were obtained by age and sex. The trend was calculated with the annual percentage of change. RESULTS: Of a total of 2758 children with cancer, 72 (2.6%) were identified in the Group IV, according to the International Classification of Childhood Cancer. The average incidence for NB was 3.8, the highest incidence was found in Guerrero. NB was highest in the group under one year of age (18.5). The male/female ratio was 1.1 and there was no trend toward an increase. Stages III and IV were presented in 88% of the cases. There was no association between the stages, the age at the TD, or the histological pattern. CONCLUSIONS: It is possible that the low incidence of NB in Mexican children is due to the difficulty in early diagnosis due the majority of the cases was diagnosed in the advanced stages. PMID- 20929619 TI - [The teaching of clinical medicine and surgery at the end of the Colonial Period]. AB - There were three schools of medicine in Mexico at the beginning of the Independence time where the doctors and surgeons could learn. In the Faculty of Medicine of the University of Mexico, the most ancient and traditional, the humoral model balance based on medieval knowledge and scholastic method was the rule. At the end of the XVIII century, the Nueva Espana enrollment in the Illustration movement, this led to an opening period and development of the scientific world. Botany was incorporated to curriculum in medicine school and the students could through the courses of the Surgery College approached to new medical theories and other teaching model without restrictions. PMID- 20929620 TI - [Epidemics and disease during the Revolution Period in Mexico]. AB - The health condition in Mexico was bad around de beginning of the revolutionary period. The movement of troops led the development of epidemics like yellow fever, typhus, smallpox, and influenza that were enhance with natural disasters and hunger in whole country, from cost to cost and in the north big cities like Monterrey, Guadalajara and Saltillo. Doctor Liceaga conducted a well planned campaign against yellow fever eradicating water stagnant deposits in order to combat the vector transmission, the Aedes aegypti, mosquito with satisfactory results. The first smallpox epidemic in the XX Century in Mexico was in 1916. The Mexican physicians used the smallpox vaccine against this epidemic. An American physician named Howard Taylor Ricketts arrived to Mexico for studying the typhus transmission. Accidentally he had been infected and finally, he died from typhus. Definitively, the epidemics predominate along de revolutionary period in Mexico. PMID- 20929621 TI - [Mexican consensus on Gaucher's disease]. AB - The lysosomal storage diseases (LSD) are a group of entities with a meaningful organic affectation profile and important morbidity-mortality rates, which considerably affect the patients' quality of life. At present, new LSD are regularly described because their physiopathological mechanism is recognized and they are susceptible to be treated with enzyme replacement therapy. During 2009, a cross-disciplinary group of Mexican experts on the Gaucher's disease gathered to develop diagnosis and treatment guidelines. This document presents the approach and recommendations of Mexican experts, according to the demography, resources, and epidemiologic reality in Mexico, a country with over 100 million inhabitants. PMID- 20929622 TI - [Schizophrenia: a public health problem of substantial size in the Mexican population]. PMID- 20929623 TI - [Epilepsy and remission in primary care level]. AB - OBJECTIVE: To identify the epilepsy remission period in a primary care unit. METHODS: There were 330 patients with diagnosis of epilepsy in remission according to the international criteria treated in a Primary Care Unit of the Instituto Mexicano del Seguro Social, Xalapa, Veracruz; There were 216 patients who were controlled (without epilepsy crisis) 150 of them were interviewed with a structure instrument designed for this purpose. RESULTS: The history of epilepsy was from five to nine years (49%). Partial crisis was identified in 54%. The age of diagnosis was established in 44% between one to ten years. The patients received drug treatment during a period of three to eight years in 51% of them. The monotherapy was used in 51% of the cases. CONCLUSIONS: Remission of epilepsy crisis can be obtained in most patients with two years drug treatment. However, we can not talk about definitive cure. PMID- 20929624 TI - [Anatomical vascular variations in renal allograft and the consequences in kidney transplantation]. AB - OBJECTIVE: To determine if the anatomical vascular variations of the renal allograft affect kidney function after a transplant surgery. METHODS: Patients that received kidney transplantation in a period of six years were included. The anatomical vascular variations of the allograft, techniques for reconstruction, outcomes in kidney function and surgical vascular complications were investigated and a comparison between the group with multiple renal arteries (MRA) and the group with a single (SRA) renal artery was performed. RESULTS: In a period of six years 477 kidney transplants were performed; 22.8% (109) presented MRA of the allograft. In these patients, an anastomosis for two, three, or four arteries was performed. Fifteen percent (72) presented multiple veins. The mean serum creatinine at day seven and three years later were 1.32 and 1.43 mg/dL respectively for the group with MRA; for the group with SRA 1.2 and 1.38 mg/dL respectively. Vascular surgical complications occurred in 2.48% (4) in the group with MRA and in 1.2% (2) in the group with SRA. CONCLUSIONS: There is no difference in kidney function and incidence of surgical vascular complications between both groups. PMID- 20929625 TI - [Cost of health care in children with haemophilia]. AB - OBJECTIVE: To determine the cost of health care in hemophilic children. METHODS: A study of costs analysis of children under 16 years with haemophilia type A and B with different severity grade in one year period was performed. Sociodemographic and clinical data were included. The costs of: 1) ambulatory care, 2) use of emergency services, 3) hospital stay, 4) drugs, 5) antihaemophilic treatment, 6) laboratory and 7) image studies were estimated. We obtained costs for each patient during a year with micro costs technique. RESULTS: We found 52 children (92.3% with haemophilia type A). Mean Age was 9.1 years. A half of them started treatment at the age of one year old, with 7.4 years of following. They had 6.7 average visits per year and 13 emergency hospitalization; haemartrosis was the main cause of hospitalization. Five children had more than 40 hospitalization and 27 cases with 1.9 hospitalization. The hospital average stay was 7.4 days. Total annual cost was 116,000 pesos. Higher cost was for the anti hemophilic factor with 73 052 pesos. CONCLUSIONS: The cost was similar to others Latin American studies and lower than in developed countries, however, factor replacement therapy accounts for most of the costs. PMID- 20929626 TI - [A case of the calcifying epithelial odontogenic tumor (Pindborg's tumor). Reported and literature review]. AB - The calcifying epithelial odontogenic tumor known as Pindborg's tumor, is a rare odontogenic neoplasm of the jaws. One of their characteristics is the cortical expansion and the relationship with a non erupted tooth. Since the original description in 1955, only 200 cases approximately have been described in the world literature. This article reviews the literature and describes a case of patient who presented calcifying epithelial odontogenic tumor in the jaw undergoing surgical excision treatment with an evolution without complications. PMID- 20929627 TI - [A right sided colon volvulus with necrosis in a young patient. A case reported]. AB - BACKGROUND: Colon volvulus (CV) is the twisting or rotation of an intestinal segment over the mesenterium, which causes occlusion and vascular compromise. It is a frequent disease in individuals over 65 years-old. We report a young patient with right CV and necrosis. CLINICAL CASE: A 17 year-old male with clinical findings of acute abdomen presented in the emergency room. During the surgical procedure, a right sided was found, CV with ileocecal valve and caecum ischemia and right colon necrosis with mesenteric vessels thrombosis. The case presented begun with sudden abdominal pain, with intestinal occlusion data, and widespread peritoneal rebound tenderles which suggested an intestinal occlusion. A simple abdomen Rx showed prominent right side colon distention with air levels in small bowel and a "coffee bean" image, suggestive of CVA hemicolectomy with termino lateral ileocolic anastomosis was performed. CONCLUSIONS: Right-sided CV is considered as congenital in origin. They corresponded to 21% of cases in Mexico, with an average age of presentation at 62 years. The CV represents 10% of the causes of large bowel obstruction in Mexico. This is the first case in young people reported in Mexican literature. PMID- 20929628 TI - [Myxedema coma. A case reported]. AB - Myxedema coma is a life-threatening condition; it is a complication of untreated hypothyroidism and an endocrine emergency. Most patients are elderly women with a previous history of long-standing hypothyroidism which presents during the winter. The myxedema coma has an insidious onset and it is very rare; its recognition can be quite difficult. Once suspected, treatment can be lifesaving and should be start promptly in anticipation of confirmation of the diagnosis by laboratory test. The mortality rate is high. I presented a case of an old woman with myxedema coma with an undiagnosed hypothyroidism, with altered mental status, normal temperature, pneumonia, hyponatremia and high level of creatine phosphokinase, who presented in the emergency room. PMID- 20929630 TI - [A comparative study between two academic working environments in residents of family medicine]. AB - OBJECTIVE: To compare the satisfaction level in the academic working environments (AWE) between the residents of two training primary care units. METHODS: Observational, transversal and comparative study. A previously constructed and validated instrument was applied, it included 30 items that evaluated the AWE with the following indicators: support, satisfaction, participation and respect; the reliability index's instrument was high (Cronbach's alpha is 0.88). The statistical analysis was made with the Mann-Whitney U test, and chi2 test for proportions. RESULTS: Regarding the AWE, 4.28% of the residents obtained a really inappropriate environment; 8.57% very appropriate and 14% inappropriate environment. However the 72% was between intermediate environments. No statistical significant difference was found between the three measurements. CONCLUSIONS: Our results are consistent with other national studies results where the "respect" indicator was the one with higher rank. The environment along with "participation," and "support," creates a favorable relationship among residents, teachers and the staff. However, the "imposition" and "rigidity" produces a decrease in the collective participation. PMID- 20929629 TI - [Academic performance and problem-based learning acceptance in medical students]. AB - OBJECTIVE: To measure the acceptance of problem based learning (PBL), to find out if they consider that spending extra-time is worthy, how they perceive their own learning, and how it correlated with other learning parameters. METHODS: After exposure to PBL during one semester, a cross sectional survey based on Likert type scale was conducted to measure the students' opinion about PBL acceptance and perception of their own learning. The sample was 268 (65%) females and 143 (35%) males from the 3rd semester of the medical school. The Spearman's correlation was used for analysis. RESULTS: PBL was considered to be useful or very useful for their learning to 89% of the students. The PBL used longer time working after the classroom activities. The extra-time spent in the course was considered worthy by 77%. Perception of their own learning correlated with the marks that they obtained (rho=0.202, p<0.0001), and with the acceptance of PBL (rho=0.291, p<0.0001). CONCLUSIONS: Students' acceptance of PBL was corroborated. Perception of a better learning correlated with higher marks and, with better acceptance of PBL and with the perception that the additional time spent was worth while. PMID- 20929631 TI - [The preoperative and postoperative changes of T lymphocyte subsets and TNF in patients with locally advanced lung cancer.]. AB - BACKGROUND: To study the immunologic significance of surgical resection for patients with locally advanced lung cancer. METHODS: The levels of the subsets of the peripheral blood T lymphocytes (CD3 , CD4 , CD8) and the serum tumor necrosis factor (TNF) were detected in 15 patients with locally advanced lung cancer before operation and on the 10th day and the 17th after operation by indirect immunofluorescence technique and enzyme linked immunosorbent assay (ELISA) respectively. RESULTS: (1)The subsets of T lymphocytes in patients with lung cancer were remarkably abnormal before operation. The CD3 score and CD4/ CD8 ratio in the cancer cases were significantly lower than those in the abnormal adults ( P < 0. 05) , but the CD8 and level of serum TNF significantly higher than those in the control group ( P < 0. 05) . (2)The CD3 score and CD4/ CD8 ratio on the 17th postoperative day were significantly higher than those before operation in the cancer patients ( P < 0. 05) , but the CD8 significantly lower than that before operation ( P < 0. 05) . The level of serum TNF on the 17th postoperative day was significantly lower than that before operation ( P < 0. 05) too. CONCLUSIONS: (1)The cellular immunobalance of the patients could be recovered by surgical treatment. (2)From the immunologic point of view , the surgical resection for locally advanced lung cancer shows active significance. PMID- 20929632 TI - [The clinicopathologic significance of expression of mtp53, p16 and Bcl-2 protein in lung cancer.]. AB - BACKGROUND: To explore the relationship between abnormal expression of mtp53 , p16 and Bcl-2 protein and oncogenesis and development of lung cancer. METHODS: Expression of mtp53 , p16 and Bcl-2 protein was detected in 114 lung cancer tissues by immunohistochemistry , and 14 normal lung tissues as control. RESULTS: Over-expression of mtp53 protein was not related to pathological type and histological grade of lung cancer ( P > 0. 05) ,but correlated with lymph node status ( P < 0. 05) . Positive expression of p16 was closely related to histological grade of lung cancer and lymph node metatasis ( P < 0. 05) ,but not to pathological type ( P > 0. 05) . The positive rate of Bcl-2 protein expression in SCLC was significantly higher than that in NSCLC ( P < 0. 05) . CONCLUSIONS: mtp53 , p16 and Bcl-2 genes may play important roles in the oncogenesis and development of lung cancer. PMID- 20929633 TI - [A study on the correlation between P-selectin and lung cancer.]. AB - BACKGROUND: To investigate the role of P-selectin in metastasis of lung cancer. METHODS: Expression of P-selectin were examined in 48 primary lung cancer specimens by the microware enhanced immunohistochemical staining method (SP) using a rat monoclonal antibody against human P-selectin , with 18 cases of adjacent non-cancerous tissue as control. RESULTS: The positive rate of P selectin expression in adenocarcinoma was significantly higher than those of squamous cell carcinoma and adjacent non-cancerous tissues ( P < 0. 01) . In adenocarcinoma , the expression of P-selectin in stage III and IV was significantly higher than that of stage I and II ( P < 0. 01) .But there were no significant correlation between the expression of P-selectin and differentiation grade of tumor , lymph node metastasis , size of the primary tumor. CONCLUSIONS: P-selectin might be associated with vascular metastasis in adenocarcinoma. PMID- 20929634 TI - [Investigation on differential diagnostic value of multi-index detection of pleural effusion.]. AB - BACKGROUND: To study the roles of adenosine deaminase (ADA) , interferon gamma ( IFN-gamma) and carcinoembryonic antigen(CEA) for diagnosis of tuberculous and neoplastic pleural effusion. METHODS: ADA , IFN-gamma and CEA activity in the serum and pleural fluid were detected in 67 patients with pleural effusion by the method of Guisti , a solid-phase enzyme-immunoassay employing the multiple antibody sandwich principle , and radioimmunoassay respectively. RESULTS: The mean ADA and IFN-gamma concentration in the tuberculous pleural effusion differed significantly from those in the neoplastic pleural effusion ( P < 0. 001) . The mean CEA concentration in the serum and pleural fluid with the neoplastic pleural effusion differed from those with the tuberculous pleural effusion ( P < 0. 05) . The sensitivity of ADA (with a diagnostic threshold of 40 U/L) and IFN gamma(threshold of 140 pg/ mL) for tuberculosis was 88 % and 96 % respectively , the specificity was 85. 71 % and 97. 62 % , and diagnostic index was 73. 71 % and 93. 62 %. Using the ADA (with below 40 U/L) and IFN-gamma (below 140 pg/mL) and CEA (above 15mug/L) , we achieved a specificity of 95. 95 %for diagnosis of neoplastic pleural effusion. CONCLUSIONS: ADA , IFN-gamma and CEA are useful parameters in differential diagnosis of tuberculous and neoplastic pleural effusion. PMID- 20929635 TI - [Study on expression of disaccharide residue and its significance in lung cancer tissues.]. AB - BACKGROUND: To study the expression of disaccharide residu (D-Galactose-beta (1v3)-N-Acetyl- galactosamine) in lung cancer. METHODS: Surgical dissected samples from 109 cases of lung cancer and 87 cases of lung benign diseases were fixed in 4 % formaldehyde and embeded in parafin. Disaccharide residue was examined by galactose oxidase-Schiff's method. RESULTS: The positive rate of bronchial submucous glands from patients with lung cancer was 71. 76 %(61/ 85) , and the positive rate of bronchial submucous gland from patients with benign pulmonary diseases was 71. 83 %(51/ 71) . There was no significant difference between two groups (Chi-Square = 0. 0026 , P > 0. 9) . Among 94 cases of lung cancer tissues , the positive rate of adenocarcinoma was 36. 11 %(13/ 36) , and the other lung cancer were negative reaction. CONCLUSIONS: The study showed that disaccharide residue was expressed in submucous glands of bronchial submuca in both patients with pulmonary benign or malignant diseases , and only expressed in partial adenocarcinoma tissues among the pulmonary carcinoma. It has not enough evidence to differentiate benign from malignant diseases of lung. PMID- 20929636 TI - [Combination chemotherapy with gemcitabine plus cisplatin in the treatment of advanced non-small cell lung cancer.]. AB - BACKGROUND: To determine the clinical activity and toxicity of a novel combination chemotherapy with gemcitabine and cisplatin in the treatment of non small cell lung cancer (NSCLC) . METHODS: We chose 12 previously untreated patients with NSCLC in stages III (41. 7 %) and IV (58. 3 %) . Gemcitabine was given on day 1 , 8 and 15 at a dose of 1 000 mg/m(2) and cisplatin at a dose of 100 mg/m(2) on day 1. The chemotherapy was repeated every 28 days. RESULTS: Eleven patients were evaluable for response. Six patients (54. 5 %) achieved partial response. The overall response rate was 54. 5 %. The main toxicity was hematological : neutropenia and thrombocytopenia at WHO-CTC grade III-IV occured in 33. 3 % and 41. 7 % of the patients respectively. The non-hematological toxicity was mild and tolerable. Only 15. 2 % of total patients were dose-reduced or omitted due to toxicity. Within follow-up 3 patients were still alive and 8 died. The median overall survival period was 8 months. CONCLUSIONS: This regimen of gemcitabine and cisplatin is effective and well-tolerated in the treatment of NSCLC , especially in the elderly patients. The clinical symptoms relieve and the living quality improves significantly. PMID- 20929637 TI - [Comparison between carboplatin and cisplatin plus etoposide and carboplatin plus etoposide in the treatment of small cell lung cancer.]. AB - BACKGROUND: To evaluate the effect and toxicity of combination chemotherapy with carboplatin and cisplatin plus etoposide (CPE regimen) and carboplatin plus etoposide (CE regimen) in the treatment of small cell lung cancer (SCLC) . METHODS: Thirty-two patients with SCLC were treated with CPE and CE regimens , and each regimen had 16 cases respectively. There were 10 retreated cases in CPE group and 7 retreated cases in CE group. RESULTS: The total response rate (CR + PR) was 81. 3 %(13/ 16) in CPE group , and 87. 5 %(14/ 16) in CE group ( P > 0. 05) respectively. The response rate of the retreated cases in CPE group was 60 %(6/ 10) , and 42. 9 %(3/ 7) in CE group ( P < 0. 05) . The bone marrow suppression rate was 71. 9 % in CPE group and 93. 8 % in CE group ( P < 0. 05) . There were no significant differences between other toxicity in both groups ( P > 0. 05) . CONCLUSIONS: The therapeutic effect of CPE regimen in SCLC is similar to that of CE regimen , but the bone marrow suppression rate of CPE regimen is less severe than that of CE regimen. The therapeutic effect of CPE regimen is better than that of CE regimen for the retreated cases. PMID- 20929638 TI - [Evaluation of the curative effect of combination chemotherapy with cisplatin plus radiotherapy in patients with advanced non-small cell lung cancer.]. AB - BACKGROUND: To evaluate the curative effect of combination chemotherapy with cisplatin plus radiotherapy for advanced non-small cell lung cancer. METHODS: Fifty-eight patients with advanced non-small cell lung cancer were treated by combination chemotherapy with cisplatin plus radiotherapy as study group , and another 29 patients given radiotherapy only as control group. RESULTS: CR , CR + PR and PD in the study group were 55. 2 %(32/58) , 65. 5 %(38/ 58) , 8. 6 %(5/ 58) , and 24. 1 %(7/ 29) , 31. 0 %(9/ 29) , 44. 8 %(13/ 29) in the control group respectively. There were remarkable differences between the two groups ( P < 0. 01) . The 1 , 2 and 3 year survival rates in study group were significantly higher than those of control group ( P < 0. 01) . CONCLUSIONS: Combination chemotherapy with cisplatin plus radiotherapy is helpful to improving curative effects and survival rates in patients with advanced non-small cell lung cancer , and it should be spread in clinical practice. PMID- 20929639 TI - [Determination of 5-FU in serumand tissues after nebulization in patients with lung cancer.]. AB - BACKGROUND: To observe the distribution of 5-FU in serum and respiratory system after nebulization in patients with lung cancer. METHODS: Ten patients with lung cancer were given 40 ml of 1. 25 % 5-FU by nebulization twice every day. At the same time , other 10 patients with lung cancer , chosen as control group , were given 0. 75g of 5-FU intravenously once every day. The concentration of 5-FU in serum and respiratory systemwas determined by chromatography. RESULTS: The highest concentration of serum 5-FU was (4. 59 +/-1. 77)mg/L in nebulization group and (10. 46 +/-1. 46)mg/L in control group respectively ( P < 0. 001) . Compared with the control group , the 5-FU concentration for nebulization group was remarkably higher in main bronchi ( P < 0. 05) . The 5-FU concentration in peripheral lung and hilar lymph nodes and tumor tissue had no significant difference for both groups ( P > 0. 05) . CONCLUSIONS: The 5-FU concentration was significantly higher in respiratory system and lower in serum by nebulization than by injection. Nebulization can lessen the toxic reaction and offer a safe and effective route for chemotherapy. PMID- 20929640 TI - [High-dose endobronchial radiation therapy under fiberoptic bronchoscope for malignant airway obstruction.]. AB - BACKGROUND: To assess the effect of endobronchial radiation guided by fiberoptic bronchoscope for malignant airway obstruction. METHODS: Sixty-five patients with lung cancer and malignant airway obstruction were investigated. After routine bronchoscopic examination , the brachytherapy catheter was inserted through biopsy channel and the tip was fixed onto the obstructing malignancies. Then radiotherapy was performed with 192 Ir at a dose of 628 Gy distributed among 225 points. The treatment was rendered weekly in a sequence of 3 weeks as one course. The chest X-ray and bronchoscopic assessment were made 1 and 4 week after finishing radiation therapy. RESULTS: X-ray assessment :CR ,PR and MR were 23. 08 %(15 cases) ,43. 08 %(28 cases) and 18. 46 %(12 cases) respectively , with 84. 62 %of total effective rate (CR + PR +MR) . Bronchoscopic assessment : CR , PR and MR were 38. 46 %(25 cases) , 43. 08 (28 cases) and 13. 85 %(9 cases) respectively , with 95. 38 % of total effective rate. CONCLUSIONS: The endobronchial radiation guided by fiberoptic bronchoscope has better reopening effect and less complications for malignant airway obstruction in the patients with lung cancer. PMID- 20929641 TI - [The role of thoracoscopy in diagnosis and management of malignant pleural effusions.]. AB - BACKGROUND: To assess the value of thoracoscopy in malignant pleural effusions. METHODS: Fifteen patients with pleural effusions of unknown causes were examined by thoracoscope and were treated by intrapleural spraying with talcum powder suspension and cisplatin under thoracoscopy. RESULTS: All patients were proved as malignant cases through lung biopsy. The overall diagnostic rate was 100 %. Fourteen cases obtained complete pleurodesis and the persistent success rate was 93. 3 %. CONCLUSIONS: Thoracoscopy is a simple , safe , reliable , and practical method in the diagnosis of pleural effusions , and talc pleurodesis is an effective management for controlling malignant pleural effusions. PMID- 20929642 TI - [Surgical treatment in patients with primary bronchogenic carcinoma involving the chest wall.]. AB - BACKGROUND: To sum up experience of surgical treatment for patients with bronchogenic carcinoma involving the chest wall. METHODS: Thirty-five patients with bronchogenic carcinoma invading chest wall underwent surgical treatment. Extra pleural-pulmonary resection for group one ( n = 16) and en bloc resection of chest wall-pulmonary for group two ( n = 19) were performed. RESULTS: There was no operative mortality. The 3 and 5 year survival rates in group one were 38. 5 % and 18. 2 % , and 41. 2 % and 35. 7 % in group two respectively. In patients with N(0) disease , 3 and 5 year survival rates were 63. 2 %(12/ 19) and 42. 9 %(6/ 14) respectively , but there was only one patient with N(1-2) disease surviving for over 5 years. CONCLUSIONS: The operation types and lymph node status play important roles in the prognosis after operation. Reconstruction of chest wall defect could be successful with 2-0 Prolene suture and covering with muscles of chest and back. PMID- 20929643 TI - [Bronchial sleeve resection , carinal resection and reconstruction in the treatment of central lung cancer.]. AB - BACKGROUND: To review the advantages of bronchial sleeve resection , carinal resection and reconstruction in the treatment of central lung cancer. METHODS: We summarized 23 cases of central lung cancer treated with this method in our hospital from 1989 to 1997 and discussed the surgical effect. RESULTS: The incidence of complications was 34. 8 %(8/ 23) . Three cases of them had bronchial bleeding and two cases had pulmonary infection. The overall 1 , 3 and 5 year survival rate was 91. 3 %(21/ 23) , 68. 7 %(11/ 16) , and 45. 5 %(5/ 11) respectively. All patients were given post-operative chemotherapy and/ or radiotherapy. Two cases occured atelectasis complicated with infection , which resulted in ventilation disturbance. CONCLUSIONS: The results suggest that bronchial sleeve resection , carinal resection and reconstruction in the treatment of patients with central lung cancer can not only maximize preservation of functional pulmonary parenchyma , but also resect the tumor thoroughly. This method may be spread out for its lower mortality and less complications with the improvement of the anesthetic technology. PMID- 20929644 TI - Onychomadesis outbreak linked to hand, foot, and mouth disease, Spain, July 2008. AB - In July 2008 an onychomadesis outbreak in a nursery setting was reported in Saragossa (Spain). Some of the cases had previously suffered from hand, foot and mouth disease (HFMD). In order to study the outbreak and to determine the relation between the two diseases, two epidemiological studies were conducted: a descriptive study focused on cases and a retrospective cohort study. Samples from stool, pharynx and nails were obtained from cases for microbiological analysis. During the study period, 27 children fulfilled the case definition. The average age was 1.8 years. A case shed on average four nails (minimum one maximum twelve). Twenty-four of the 27 cases had previously presented with HFMD which started an average of 40 days before the onset of onychomadesis (relative risk: 14). Unidentified non-polio enterovirus (n=10), coxsackie B1 (n=4) and coxsackie B2 virus (n=3) were isolated in 28 specimens obtained from 14 cases. The analysis showed a strong association between HMFD and onychomadesis. Microbiological results have not been conclusive; consequently more studies are necessary to determine the causal agent of infectious onychomadesis. PMID- 20929645 TI - Community outbreak of group B meningococcal disease in southwest France--December 2008 to September 2009. AB - Between December 2008 and September 2009, 11 cases of invasive meningococcal disease (IMD) group B were reported in a 20 km diameter area in the Departement Landes, France. Two of them presented with purpura fulminans and one of them died. The strain responsible for this community outbreak was of the clonal complex ST-269.The incidence rate for IMD group B was 3 per 100,000 inhabitants in Landes from week 40 in 2008 to week 40 in 2009; it was the highest in France during that period. The number of cases observed was significantly higher than expected, especially in young adults (standardised incidence ratio: 23.5, p<0.001). A nightclub located in the 20 km diameter area was a possible place of transmission and a prophylaxis recommended for the staff members helped in decreasing the transmission. However, several cases notified later suggested that the bacteria circulated during several months through healthy carriers in the community. This situation prompted increased surveillance of IMD in Landes and medical practitioners were asked to remain vigilant because of the possible emergence of new cases within the following months. PMID- 20929646 TI - Hepatitis A outbreak in an Orthodox Jewish community in London, July 2010. AB - A cluster of hepatitis A cases in the Orthodox Jewish community in London, United Kingdom in July 2010 has triggered extensive contact tracing and vaccination. Two primary cases imported from a common source in Israel and three secondary cases have resulted in immunisation of over 900 contacts to date. Rapid response by local public health, primary care services and a dedicated community health team, and active hepatitis A vaccination rather than immunoglobulin treatment were used to avert a larger outbreak. PMID- 20929647 TI - Quantifying benefits and risks of vaccinating Australian children aged six months to four years with trivalent inactivated seasonal influenza vaccine in 2010. AB - Australian and New Zealand health authorities identified seasonal trivalent inactivated influenza vaccines manufactured by CSL Biotherapies as the probable cause of increased febrile convulsions in children under five within 24 hours of vaccination and recommended against their use in this age group. We quantified the benefit-risk profile of the CSL vaccines using the number needed to vaccinate and suggest they might have caused two to three hospital admissions due to febrile convulsions for every hospital admission due to influenza prevented. PMID- 20929648 TI - Onychomadesis and hand, foot and mouth disease--is there a connection? PMID- 20929650 TI - European Medicines Agency updates on the review of Pandemrix and reports of narcolepsy. PMID- 20929651 TI - Risk factors for disease severity among hospitalised patients with 2009 pandemic influenza A (H1N1) in Spain, April - December 2009. AB - We describe the clinical and epidemiological characteristics of patients hospitalised with confirmed 2009 pandemic influenza A(H1N1) in Spain from April to December 2009 and the risk factors associated with a worse outcome (admission to an intensive care unit or death) in adults. Case-based epidemiological information was collected as part of the national strategy for the surveillance of severe cases. Of 3,025 patients, 852 were admitted to an intensive care unit and overall, 200 died. The median patient age was 38 years (range: 0-94). A total of 662 (26%) patients had no underlying risk conditions. Antiviral therapy was initiated within 48 hours after symptom onset in only 35.2% (n=711); the median length of time before treatment was four days. In a multivariate analysis, the start of antiviral therapy more than 48 hours after symptom onset (odds ratio (OR) 2.39; 95% confidence interval (CI): 1.79 to 3.2), morbid obesity (OR: 2.01; 95% CI 1.38 to 2.94), cardiovascular disease (OR: 1.79; 95% CI: 1.2 to 2.67) and chronic obstructive pulmonary disease (OR: 1.51; 95% CI: 1.03 to 2.2) were significantly associated with a worse outcome in adults. PMID- 20929652 TI - Public health advice based on routine mumps surveillance in England and Wales. AB - In view of the increase in the number of mumps cases in 2009 and of the reports of mumps outbreaks in 2010, we report on the most recently available mumps surveillance data in England and Wales. PMID- 20929653 TI - Fatal and mild primary dengue virus infections imported to Norway from Africa and south-east Asia, 2008-2010. AB - Between 2008 and 2010, eight cases of viraemic dengue fever in travellers were diagnosed in Norway. They had returned from Eritrea, Thailand and Indonesia. All cases were primary dengue infections, seven non-complicated dengue fever and one dengue shock syndrome with a fatal outcome. Four patients were infected with dengue virus serotype 1, one with type 2 and three with type 3. Two cases from Thailand, the fatal case and the two imported from Eritrea were infected with type 1. PMID- 20929654 TI - Dengue virus infection in travellers returning from Benin to France, July - August, 2010. PMID- 20929655 TI - Hepatitis C virus infection in HIV-infected men who have sex with men: sustained rising incidence in Antwerp, Belgium, 2001-2009. AB - During the last decade, outbreaks of acute hepatitis C virus (HCV) infection have been reported among human immunodeficiency virus (HIV)-infected men who have sex with men (MSM) in several European countries. To study this emerging infection in MSM in Antwerp, Belgium, we reviewed all cases of newly acquired HCV infection in HIV-positive MSM followed from 2001 to 2009 at the HIV/sexually transmitted infection (STI)reference clinic of the Institute of Tropical Medicine in Antwerp. Newly acquired HCV infection was considered as certain or probable according to local definitions. During the study period, 69 episodes of newly acquired HCV infection (40 certain and 29 probable) were diagnosed in 67 HIV-infected MSM. In only 10 episodes (14%) were the patients symptomatic. The annual incidence of HCV infection in our population of HIV-infected MSM rose steadily from 0.2% in 2001 to 1.51% in 2008, and then peaked to 2.9% in 2009. For 60 episodes (87%), another STI (mainly syphilis and lymphogranuloma venereum) had been diagnosed within the six months before the diagnosis of HCV infection. All but one patient with available genotyping (n=54) were found to be infected with the difficult to-treat HCV genotypes 1 or 4. Our results therefore demonstrate the rising incidence of HCV infection in HIV-positive MSM in Antwerp, since 2001, which reached an alarming level in 2009. Targeted awareness campaigns and routine screening are urgently needed to limit further HCV spread and its expected long-term consequences. PMID- 20929656 TI - Decrease in number of genital chlamydia cases in Norrbotten, Sweden, October - November 2009: an indirect effect of pandemic influenza A(H1N1)? AB - A sudden reduction in the number of reported genital chlamydia cases was observed in Norrbotten County, Sweden, during October to November 2009. After exploring other possibilities, such as a reduction in the number of chlamydia tests analysed or a new Chlamydia trachomatis variant that had been undetected in standard laboratory tests, it was found likely that the decrease was an indirect effect of the 2009 influenza A(H1N1) pandemic due to reduced social interactions among young adults. PMID- 20929657 TI - Outbreak of Legionnaires' disease in a nursing home, Slovenia, August 2010: preliminary report. AB - We report an outbreak of Legionnaires' disease ina nursing home in Slovenia in August 2010 affecting 15 of 234 residents. To date, Legionnaires' disease has been confirmed in four patients. Further serum analyses and genotyping of isolates are ongoing. The building's water distribution system with dead end sections has been identified as the probable source of infection. PMID- 20929658 TI - The Hajj: communicable and non-communicable health hazards and current guidance for pilgrims. AB - The Hajj has become the epicenter of mass migration of millions of Muslims of enormous ethnic diversity. No other mass gathering can compare, either in scale or in regularity. Communicable disease outbreaks of various infectious diseases have been reported repeatedly, during and following the Hajj. The Hajj 2010 starts in the first week of November 2010 and this report is a timely reminder that many infectious diseases can be avoided or averted by adopting appropriate prophylactic measures. PMID- 20929660 TI - [Mitochondrial dynamics: from geometry to function]. PMID- 20929659 TI - First two autochthonous dengue virus infections in metropolitan France, September 2010. AB - In September 2010, two cases of autochthonous dengue fever were diagnosed in metropolitan France for the first time. The cases occurring in Nice, southeast France, where Aedes albopictus is established, are evidence of dengue virus circulation in this area. This local transmission of dengue calls for further enhanced surveillance, active case finding and vector control measures to reduce the spread of the virus and the risk of an epidemic. PMID- 20929661 TI - [Caspase activation precedes and leads to neurodegeneration in a murine model of Alzheimer's disease]. PMID- 20929662 TI - [Spikelets contribute to place cell firing during spatial exploration]. PMID- 20929663 TI - [Nuclear reprogramming and pluripotency: the case of epiblast stem cells]. PMID- 20929664 TI - [Role of TGF-beta in a model of abdominal aortic aneurysm in mice]. PMID- 20929665 TI - [PICs (PW1+ interstitial cells), a new muscle stem cell population]. PMID- 20929666 TI - [GRK6, a new therapeutic approach to alleviate L-dopa-induced dyskinesia]. PMID- 20929667 TI - [Leptin, a new therapeutic agent for treatment of diabetes?]. PMID- 20929668 TI - [The Japanese and us]. PMID- 20929669 TI - [You are what you eat: the sushi factor in the Japanese gut microbiota]. PMID- 20929670 TI - [When p53 mutants engage in trafficking!]. PMID- 20929672 TI - [Mitochondrial morphology and dynamics: actors, mechanisms and functions]. AB - Mitochondria are dynamic organelles that continuously move, fuse and divide. Their overall morphology, ranging from a filamentous network to a collection of isolated dots, is determined by fusion-fission equilibrium, which depends on the cellular and physiological context. The machineries of fusion and fission, that are conserved throughout evolution, include three large GTPases of the dynamin superfamily: Dnm1/DRP1 - involved in fission - as well as Fzo1/MFN and Mgm1/OPA1 required for fusion. While the activities, mecanisms and regulations of mitochondrial fusion and fission machineries continue to be unravelled, the relevance of mitochondrial dynamics is witnessed by their impact on organelle functions, cell survival and cell differenciation, their requirement for embryonic development and their involvement in neurological diseases. PMID- 20929673 TI - [Mitochondrial dynamics during apoptosis]. AB - Mitochondria exist as dynamic networks that often change shape and subcellular distribution. The morphology of mitochondria within a cell is controlled by precisely regulated rates of organelle fusion and fission. Several reports have described dramatic alterations in mitochondrial morphology during the early stages of apoptosis: a fragmentation of the network and the cristae remodeling. However, whether this mitochondrial fragmentation is a required step for apoptosis is highly debated. In this review the recent progress in understanding the mechanisms governing mitochondrial morphology during apoptosis and the latest advances connecting the regulation of mitochondrial morphology with apoptosis are discussed. PMID- 20929674 TI - [From yeast to neurodegenerative diseases: ten years of exploration of mitochondrial dynamic disorders]. AB - Ten years ago, OPA1 was identified as the major gene responsible for hereditary optic nerve degeneration, evidencing the first defect in mitochondrial network dynamics as the princeps pathophysiological mechanism in a mitochondriopathy. Later, alterations in other genes involved in mitochondrial fusion or fission, such as MFN2, DRP1 and GDAP1, were also associated with inherited neurological diseases, mainly affecting peripheral nerves. More recently, altered mitochondrial plasticity was also demonstrated in common age-related neurodegenerative disorders, as Alzheimer and Parkinson diseases, thus substantiating the critical role of mitochondrial dynamics in neurons as a key element governing the efficiency of oxidative respiration and its distribution along the axons. PMID- 20929675 TI - [Charcot-Marie-Tooth (CMT) disease: an update]. AB - Charcot-Marie-Tooth (CMT) <> is the generic name given to a group of genetic disorders characterized by a relatively isolated dysfunction of peripheral nerves, with combined motor and sensory impairment. These CMT syndromes are the most frequent genetically-determined peripheral neuropathies, with a global prevalence between 4.7 and 36/100,000. Their clinical phenotype is predominantly motor, with a grossly symmetrical distal amyotrophy involving both lower and upper limbs. Mode of inheritance is variable: autosomal dominant, autosomal recessive or X-linked. Apparently sporadic forms can be a difficult diagnosis and they must be considered in all patients with a chronic polyneuropathy which is not clearly of acquired origin. During the last two decades, the identification of more than 25 genes mutated in CMT syndromes has complicated the classification of these disorders. Knowledge of the function of some of these genes has improved our understanding of the pathogenesis of myelinic or axonal dysfunction in CMT, but for some others their function remains elusive or unknown. PMID- 20929676 TI - [An overview of pluripotent stem cell lines]. AB - More than 20 years ago, the finding of a population of cells with the ability of self-renewal and differentiation inside teratocarcinomas (embryonic carcinoma cells) would allow their direct derivation from preimplantation embryos (embryonic stem cells, ESC). The phenomenal pluripotency properties of those cells and the therapeutical potential of their human counterparts triggered a massive interest from the scientific community. The research on the field of pluripotent stem cells improved a lot and many ES-like pluripotent stem cells of several embryonic and adult sources were described. Next step has been the reprogramming of terminally differentiated cells into embryonic cells, with the aim to produce patient-specific stem cells. The recent breakthrough has been the in vitro reprogramming of adult cells into ES cell-like cells named induced pluripotent stem cells (iPSC), using four transcription factors (Oct4, Sox2, Klf4, c-Myc). Even though some challenges remain, we are now one step closer to the eventuality to use these cells for clinical purposes. In this review we propose to analyse the several pluripotent stem cells existing today. PMID- 20929677 TI - [Rendu-Osler disease: clinical and molecular update]. AB - The Rendu-Osler disease, also called Hereditary Hemorrhagic Telangiectasia (HHT) affects 1 in -5-8000 people. A french epidemiological study pointed out that it was particularly high in the Haut-Jura mountains in France. This pathology is characterized by frequent nosebleeds, mucocutaneous and visceral telangiectasia and hereditary autosomal-dominant trait. The mucocutaneous telangiectasia are hemorrhagic while the visceral telangiectasia, less frequent, lead to arteriovenous fistula in the lungs, the liver and the brain. HHT disease-causing genes (ENG, ACVRL1 and MADH4) encode proteins that modulate TGFbeta superfamilly signaling in vascular endothelial cells. The recent discovery that BMP9 acts as the specific ligand of the receptor ALK1 and endoglin as its co-receptor shows that this signaling pathway is involved in the maturation phase of angiogenesis. Mice heterozygous for endoglin or ALK1 defects reproduce the HHT phenotype and further support the involvement of endothelial hyper proliferation in the pathogenesis of the disease. The medical management of patients remains mainly symptomatic, however the angiogenic trait of this disease should allow us to consider in the future new -therapeutic approaches using anti-angiogenic drugs. PMID- 20929678 TI - [Infection of semen-producing organs by HIV and role in virus dissemination]. AB - Despite semen being the main vector of human immunodeficiency virus (HIV) dissemination worldwide, the origin of the virus in this bodily fluid remains unknown. Of particular significance is the persistence of virus release in the semen of a subset of HIV-infected men under antiretroviral therapy, who otherwise show an undetectable blood viral load. It is therefore considered critical to identify the sources of virus shedding in semen for the more efficient control of HIV transmission. Our recent findings indicate HIV infection of several semen producing organs, including the testis (which represents a pharmacological sanctuary for several antiretroviral drugs). This reinforces phylogenetic observations suggesting that the free viral particles and infected cells contaminating semen are produced within the male genital tract. The fact that HIV replicates within the male genital organs raises several questions: Is one or several of the male genital tract organs responsible for the persistence of HIV in semen despite efficient antiviral therapies? What is the nature of HIV interactions with spermatozoa and testicular germ cells? Recent results established that semen from HIV negative men modifies HIV infectivity: does the seminal fluid from HIV+ men enhance or inhibit the efficiency of HIV sexual transmission? PMID- 20929679 TI - [Hepatitis C virus subverts pattern recognition receptors-mediated control of adaptative immunity orchestrated by dendritic cells]. AB - Chronic hepatitis C virus (HCV) is a liver-borne infectious disease that remains a major global health threat. The mechanisms whereby HCV evades the host's immune defences and establishes persistent infection remain elusive; but they likely require a complex and coordinated interruption of the interplay between innate and adaptive immune actors. This review discusses the concept that HCV evades the host's immune response to its components partly because of its ability to inactivate the major orchestrator of the adaptive immune response - the DCs. It argues that DCs constitute an immunologically relevant cellular viral host actively targeted by HCV. This targeting disrupts TRIF- and IPS-1-dependent but not MyD88-coupled pathogen recognition receptors (PRR) sensing pathways in these infected cells to foil the networks by which innate immunity to HCV is translated into virus-specific adaptive immune-mediated host resistance. Thus, as a culprit, this cell-specific and numerically restrained DC defect offers a promising field of investigation in which to study and understand the HCV-restricted nature of the deficit in cellular immunity in persistently infected -individuals who have otherwise normal immune functions to unrelated pathogens. In this model, protective immunity is contingent on proper processing and delivery of danger signals by DCs presenting HCV antigens. PMID- 20929681 TI - [Forward - representation in life sciences: how technical evolution influenced our vision of life, from organism to single cell and molecule]. PMID- 20929680 TI - [Age-dependent oxidative stress: toward an irreversible failure in endothelial maintenance]. AB - In order to maintain cellular homeostasis against endogenous and exogenous aggressions, different cellular mechanisms of defence, maintenance and repair are continuously activated throughout life. Hormesis, a concept based on the fact that mild stresses protect cells against subsequent stresses, amplifies the efficacy of the cellular mechanisms of defence and repair. Ageing, senescence and ultimately death, result from the exhaustion of these mechanisms maintaining cellular functions. One of the major sources of vascular endothelial damage is oxidative stress. The age-dependent shift in the redox environment towards pro oxidation contributes to a progressive compensatory remodelling of the endothelium, an accumulation of damages, and its dysfunction, the premises for atherosclerosis. We propose that in agreement with the concept of hormesis, a moderate exposure during endothelial maturation to mild physiological oxidative stressors determines -vascular longevity. PMID- 20929682 TI - [For an epigenetic approach of the biological representations]. PMID- 20929685 TI - Dynamic obstruction of inferior vena cava flow caused by right-sided diaphragmatic elevation. PMID- 20929684 TI - Uncertainties associated with quantifying climate change impacts on human health: a case study for diarrhea. AB - BACKGROUND: Climate change is expected to have large impacts on health at low latitudes where droughts and malnutrition, diarrhea, and malaria are projected to increase. OBJECTIVES: The main objective of this study was to indicate a method to assess a range of plausible health impacts of climate change while handling uncertainties in a unambiguous manner. We illustrate this method by quantifying the impacts of projected regional warming on diarrhea in this century. METHODS: We combined a range of linear regression coefficients to compute projections of future climate change-induced increases in diarrhea using the results from five empirical studies and a 19-member climate model ensemble for which future greenhouse gas emissions were prescribed. Six geographical regions were analyzed. RESULTS: The model ensemble projected temperature increases of up to 4 degrees C over land in the tropics and subtropics by the end of this century. The associated mean projected increases of relative risk of diarrhea in the six study regions were 8-11% (with SDs of 3-5%) by 2010-2039 and 22-29% (SDs of 9-12%) by 2070-2099. CONCLUSIONS: Even our most conservative estimates indicate substantial impacts from climate change on the incidence of diarrhea. Nevertheless, our main conclusion is that large uncertainties are associated with future projections of diarrhea and climate change. We believe that these uncertainties can be attributed primarily to the sparsity of empirical climate-health data. Our results therefore highlight the need for empirical data in the cross section between climate and human health. PMID- 20929686 TI - A bullet in the heart: an incremental value of three-dimensional echocardiography. PMID- 20929687 TI - Intrapericardial paraganglioma. PMID- 20929688 TI - Calcified ball-like left ventricular thrombus embolized during echocardiography follow-up. PMID- 20929689 TI - [Ventricular tachycardia related to diverticulum of right ventricular outflow tract]. PMID- 20929690 TI - Thrombus entrapped in a patent foramen ovale presenting with acute pulmonary embolism. PMID- 20929691 TI - Successful surgical repair of mitral and tricuspid valves regurgitation associated with Behcet's disease. PMID- 20929692 TI - [Our peer-review practice and strategies to improve journal scientific performance]. PMID- 20929693 TI - [The levels of the leptin and adiponectin according to body mass index and their relationship with oxidative parameters]. AB - OBJECTIVE: Obesity is an important risk factor of atherosclerosis and its prevalence in humans is increasing. Recent studies suggest that the leptin and adiponectin play important roles in obesity, and they are associated with complications of obesity. However, the mechanism of effects has not been outstandingly established. In this study, we studied leptin and adiponectin levels according to body mass index (BMI) and their relationship with oxidative parameters. METHODS: A total of 87 healthy individuals with BMI <=35 kg/m2 (n=29, Group 1), BMI=25-35 kg/m2 (n=29, Group 2) and BMI =25 kg/m2 (n=29, Group 3) were included in the cross-sectional observational study. Leptin, adiponectin levels, total antioxidant capacity (TAC) and total oxidant status (TOS) were measured. Oxidative stress index (OSI) was calculated using TAC and TOS values. Statistical analyses were performed using Chi-Square, Mann-Whitney U, one-way ANOVA, Kruskal Wallis, Pearson correlation and multiple regression analyses tests. RESULTS: Age and gender ratio were similar in the groups. The TAC level was the lowest in group 3 and the highest in group 1. The TOS level was higher in groups 2 and 3 than in group 1 (p =0.05 for both). OSI levels were similar in groups 2 and 3, and it was significantly different from the group 1 (p=0.05). The trend for leptin levels was decreasing and for antiponectin levels was increasing from group 1 to group 3. Except for other parameters, levels of leptin were independently related to the TOS (b=-1.123, 95% CI =-12.734-0.255, p=0.040), OSI (b=1.689, 95% CI=1.105-12.481, p=0.018) and waist circumference (b=-0.592, 95% CI= -0.630-0.134, p=0.003). Adiponectin had no significant relation with these parameters. CONCLUSION: Findings of the present study reveal that leptin decreased and adiponectin increased with BMI in healthy people. These data support that these changes may be responsible in the increased TOS and OSI levels. PMID- 20929694 TI - [Mechanisms underlying obesity associated oxidative stress: the role of leptin and adiponectin]. PMID- 20929695 TI - The influence of alpha-adducin gene polymorphism on response of blood pressure to exercise in patients with hypertension. AB - OBJECTIVE: Clinical studies have indicated that an excessive response of blood pressure (BP) to exercise predicts risk of cardiovascular mortality. Although the mechanism responsible for the excessive BP response to exercise has not been revealed, there are some plausible mechanisms linking with underlying structural abnormalities in the cardiovascular system. Carriers of the Trp460 allele of the alpha-adducin Gly460Trp polymorphism have an increased risk of hypertension. The aim of the present study was to examine the influence of alpha-adducin gene polymorphism on response of BP to exercise in patients with hypertension. METHODS: The cross-sectional observational study consisted of 49 hypertensive patients (29 women and 20 men; mean age, 53.1+/-8.8 years). All participants underwent a multistage exercise treadmill test according to the Bruce protocol. Arterial BPs were compared at rest, peak exercise and end of the recovery phase. Patients were classified according to their alpha-adducin gene polymorphisms; Gly460Gly homozygotes - Group 1 (n=28) and Trp460Trp homozygotes and Gly460Trp heterozygotes - Group 2 (n=21). Statistical analysis was performed using Chi square, unpaired t, Mann-Whitney U and ANCOVA tests. RESULTS: Mean exercise duration and mean exercise capacity in metabolic equivalents were not different between Group 1 and 2. The major finding of the study was that systolic BP responses at peak exercise and recovery period (3. min) were significantly higher (p=0.036) in hypertensive patients carrying at least one Trp460 allele of the alpha-adducin gene. CONCLUSION: Our results suggest that genetic variants that alter renal function and/or vasoreactivity are logical candidates to explain some of the individual variability in the BP response to exercise. PMID- 20929696 TI - An important role for VCAM-1, but not for ICAM-1 in restenosis following coronary stent implantation. AB - OBJECTIVE: In this study, we evaluated the possibility that, levels of circulating adhesion molecules following direct stent implantation may be a marker of restenosis. METHODS: This prospective, observational study investigated levels of circulating intercellular (ICAM-1), and vascular cell (VCAM-1) adhesion molecules in 15 patients with stable angina pectoris before and after coronary stent implantation for single vessel-single lesion disease in proximal left anterior descending artery. All patients received bare-metal stents. Patients underwent repeat coronary angiography for detection of restenosis at 6 month. Continuous data between patients with and without restenosis were compared using Mann-Whitney U test. Repeated measurements were compared using Wilcoxon T test. Categorical data were compared using Chi-square statistics. RESULTS: Baseline ICAM-1 and VCAM-1 concentrations before percutaneous coronary intervention (PCI) were 4.89+/-2.28 and 46.35+/-22.96 ng/ml respectively. Levels of ICAM and VCAM increased nonsignificantly 24 hours after PCI (5.01+/-2.35 ng/ml and 52.57+/ 19.40 ng/ml, respectively). Six patients (40%) developed restenosis within 6 months. Mean stent length, mean stent diameter, and mean dilatation pressure were comparable in patient groups with and without restenosis. Levels of plasma VCAM-1 measured before and after PCI did not change significantly in patients without restenosis. However, these levels increased significantly in the group of restenosis. At 6 months, patients who developed restenosis, had higher VCAM-1 levels, as compared to baseline values (from 45.1+/-21.0 to 57.2+/-14.3 ng/ml, p=0.05). Plasma levels of pre and post PCI ICAM-1 did not differ significantly between groups with and without restenosis. CONCLUSION: These results suggest a more dominant role for VCAM-1, but not for ICAM-1 in development of restenosis following coronary stent implantation. PMID- 20929697 TI - Relation of homocysteine levels with patency and flow rate of infarct-related artery in patients receiving fibrinolytic therapy. AB - OBJECTIVE: Elevated homocysteine levels induce a hypercoagulable state and make the clot more resistant to fibrinolysis. In this prospective observational study, we investigated the influence of homocysteine levels on infarct-related artery (IRA) patency and flow as determined with regard to thrombolysis in myocardial infraction (TIMI) flow grade and corrected TIMI frame count (CTFC). METHODS: Sixty-one patients who received fibrinolytic therapy for a first ST elevation myocardial infarction (STEMI) within 12 hours of chest pain were included. Coronary angiography was performed according to the Judkins technique within 72 hours after fibrinolytic therapy. Total plasma homocysteine level was determined by the high-performance liquid chromatography method with fluorescence detection. Statistical analysis was performed using Chi-square, Student's t and Pearson correlation tests. Logistic regression analysis was used to determine the predictors of IRA occlusion. RESULTS: Of the 61 patients, 22 (36.1%) had an occluded IRA (group 1), 39 (63.9%) had a patent IRA (group 2). Mean plasma homocysteine levels were found to be significantly higher in the group 1 compared to the group 2 (18.5+/-9.6 umol/L vs 14.3+/-5 umol/L, p=0.04). In addition, we found a significant positive correlation between CTFC and plasma homocysteine levels (r=0.415; p=0.01). In multiple logistic regression analysis, high levels of plasma homocysteine (OR=1.2; 95% CI 1.1-1.25; p=0.03) and being a non-smoker (OR=5.9; 95% CI 1.1-31.6; p=0.03) were found to be significant independent predictors of having an occluded IRA. CONCLUSION: There is an inverse relation between plasma homocysteine levels and IRA patency and flow in patients receiving fibrinolytic therapy for STEMI. PMID- 20929698 TI - Acute phase reactants in patients with coronary slow flow phenomenon. AB - OBJECTIVE: In this study, we sought to investigate the serum levels of high sensitivity C-reactive protein (Hs-CRP), N-terminal pro-brain natriuretic peptide (NT proBNP), erythrocyte sedimentation rate, leukocyte, thyroid hormone and fibrinogen levels in patients with coronary slow flow phenomenon (CSFP). METHODS: A total of 82 patients with angiographically proven normal coronary arteries and slow coronary flow in all three coronary vessels (45 males and 37 females, mean age 59+/-11 years) and 34 patients with normal coronary arteries and normal coronary flow (19 males and 15 females, mean age 56+/-10 years) with similar risk profiles were included in this cross-sectional observational study. Coronary flow rates of all patients and control subjects were documented by Thrombolysis In Myocardial Infarction (TIMI) frame count, serum level of Hs-CRP, NT proBNP, sedimentation, leukocyte, free triiodothyronine (FT3), free thyroxine (FT4), thyroid stimulating hormone (TSH) and fibrinogen levels were measured. Statistical analysis was performed using t test for independent samples, Chi square test and Pearson correlation analysis. RESULTS: Hs-CRP (0.88+/-0.86 vs 0.36+/-0.35 mg/L, p=0.001) and NT proBNP (117.83+/-163.2 vs 47.33+/-30.6 ng/ml, p=0.01) were found to be significantly higher in patients with coronary slow flow compared with normal control group. There were no significant differences regarding thyroid hormones, fibrinogen, sedimentation rate and leukocyte count between two groups. The mean TIMI frame counts were positively correlated (r=0.454, p=0.001 and r=0.554, p=0.001, respectively) with plasma Hs-CRP levels and NT-proBNP levels. CONCLUSION: Hs-CRP and NT proBNP are significantly higher in patients with coronary slow flow compared with normal control group. Their increased levels are positively correlated with TIMI frame count. PMID- 20929699 TI - C-reactive protein in unstable angina pectoris and its relation to coronary angiographic severity and diffusion scores of coronary lesions. AB - OBJECTIVE: We aimed to assess the relationship between C-reactive protein (CRP) and the severity and diffusion of coronary artery lesions in patients with unstable angina pectoris (UAP) and the independent association of CRP with this clinical situation. METHODS: This cross-sectional, observational study included 50 patients. Classification by Braunwald was used for UAP. The severity and diffusion of angiographic coronary disease were graded according to Reardon's modified scoring system. Plasma CRP levels were quantified by immunoturbidimetry. Nonparametric tests were used for comparison of CRP and other risk factors, and logistic regression analysis for evaluation of independent association between CRP and unstable angina pectoris. RESULTS: The severity score was 46+/-18 points in class IIB1 UAP, 36+/-20 points in class IIB2 and 53+/-18 points in class IIIB2 (p=0.017, class IIIB2 vs IIB2). Respectively, CRP levels were 6.6 mg/L, 3.8 mg/L and 4.8 mg/L (p=0.371, class IIB1 vs IIB2 vs IIIB2). Lesions with diffusion score 4 revealed higher CRP values than lesions with diffusion score 1 (11.1 mg/L vs 3.1 mg/L, p=0.048). Adjusting age, sex and smoking, assessment of partial correlation analysis showed a positive, moderately powerful and significant association between CRP levels and the severity and diffusion scores of the coronary lesions (r=0.30; p=0.034 and r=0.31; p=0.030, respectively) in the whole study group. Multiple logistic regression analysis showed no appreciable independent association between CRP and UAP (OR: 1.63, 95%CI: 0.90-5.63, p=0.093). CONCLUSION: Although, CRP was correlated with the severity and diffusion of angiographic coronary disease in patients with UAP, there was no independent association between CRP and clinical severity of UAP. PMID- 20929700 TI - Influence of statin therapy on circadian variation of acute myocardial infarction. AB - OBJECTIVE: Strong evidence has suggested that there is a circadian periodicity of acute coronary event. Beta-blockers, aspirin and angiotensin-converting enzyme inhibitors decrease the rate of acute myocardial infarction (AMI) and blunt the peak incidence in the morning. However, such effect has not been evaluated for statins. Accordingly, the present study aimed to evaluate the influence of statin therapy on circadian variation of AMI. METHODS: This retrospective study consisted of 451 consecutive patients with acute ST segment elevation AMI. The patients were divided into two group based on prior statin usage. In statistical analysis t test, Chi-square test and Mann Whitney U test were used for comparison of groups. We used harmonic regression models to evaluate the circadian variation of onset of MI symptoms in patients receiving statin and patients not receiving statin. RESULTS: In all study participants, the highest incidence of AMI was between 6.00 and 12.00; the odds ratio was 1.34 (95% CI 1.20 to 1.46, p=0.001). In the non-statin group, the highest incidence of AMI occurred between 0:00 A.M. and 06.00. There was still a peak incidence between 6.00 A.M. and noon in the statin therapy receiving group; the odds ratio was 1.61 (95% CI 1.34 to 1.80, p=0.001). Accordingly, there was no statistical difference between the statin and non-statin groups regarding circadian variation of AMI. Prior usage of statin did not blunt the peak incidence of AMI in the morning. CONCLUSION: Prior usage of statin does not seem to play a role in the circadian periodicity of AMI. PMID- 20929702 TI - Evaluation of congenital heart diseases and thyroid abnormalities in children with Down syndrome. AB - OBJECTIVE: Congenital heart disease (CHD) associated with thyroid disease has been reported in Down syndrome (DS). The purpose of this work was to assess abnormalities of the thyroid in relation to the frequency and type of CHD on admission among children with DS. METHODS: This retrospective study included 187 children with DS between August 1993- December 2005. Karyotype analysis, thyroid function tests and echocardiographic studies were performed in all children with DS. If necessary, hemodynamic study by catheterization was carried out. Thyrotropin releasing hormone (TRH) stimulation test was performed in having elevated thyroid stimulating hormone (TSH) level. Statistical analyses were performed using Chi-square, "t" test for independent samples or Mann-Whitney U test. RESULTS: It was found that 136 (72.73%) patients with DS had CHD. The age difference at the time of admission was statistically significant for these two groups (p=0.001) in children with /without CHD. There were 12 (11.88%) patients with congenital hypothyroidism and DS, of whom 11 had CHD. There were statistically significant differences in the levels of TSH and total thyroxine (tT4) between congenital and subclinical hypothyroid and euthyroid groups (p=0.001 for TSH and p= 0.001 for tT4). But, there was no significant relationship between having any kind of CHD and levels of TSH and tT4. CONCLUSION: Our data suggest that all patients with DS should be evaluated with careful physical and echocardiographic examination on admission. In addition, congenital or subclinical hypothyroidism should also be kept in mind in children with DS and monitored accordingly. PMID- 20929701 TI - Can D-dimer testing help emergency department physicians to detect acute aortic dissections? AB - OBJECTIVE: To determine the diagnostic accuracy of D-dimer testing for detection of acute aortic dissection. METHODS: This study is a retrospective chart review of patients who had been evaluated with suspicion of acute aortic dissection. All patients' D-dimer levels were determined prior to their further work up in the emergency department. The study was conducted in a tertiary care center between February 2006-August 2008. The D-dimer assay used was the immunoturbidimetric assay, with a normal range up to 0.246 ug/ml. Statistical analysis was accomplished using Chi-square test, Student's t-test and a receiver-operating characteristics (ROC) curve analysis. RESULTS: Ninety-nine patients were included in the study, 30 patients were diagnosed as having acute aortic dissection and 69 patients were evaluated in non-acute aortic dissection group. In comparison of the two groups, positive D-dimer results were found to be significantly higher in acute aortic dissection group than in non-acute aortic dissection group (p=0.001). Sensitivity of the D-dimer test in detection of acute aortic dissection was found as 96.6% and the negative predictive value of the test was 97.3%. Specificity and positive predictive value of the D-dimer test were 52.2% and 46.8%, respectively. The area under the ROC curve yielded an acceptable certainty for excluding acute aortic dissection on base of negative results (AUC: 0.764; CI 95%: 0.674-0.855; p=0.001). CONCLUSION: D-dimer testing is helpful for emergency physicians in detection of patients with suspected acute aortic dissection in the emergency department. PMID- 20929703 TI - The relation between blood and tissue magnesium levels and development of atrial fibrillation after coronary artery bypass surgery. AB - OBJECTIVE: Atrial fibrillation (AF) is a common complication of cardiovascular surgery and its mechanisms are not well understood. The aim of our study was a prospective investigation of the relationship between AF development and tissue or blood magnesium levels. METHODS: This prospective observational study evaluated 20 patients undergoing elective initial coronary artery bypass graft (CABG) surgery. Right atrial appendage and skeletal muscle samples were obtained for tissue magnesium level analysis before, during (at 60th minute) and 30 minutes after cardiopulmonary bypass (CPB) with simultaneous blood samples. Daily measurements of blood Mg levels and continuous monitoring for AF were performed for 7 postoperative days. Statistical analyses were performed using ANOVA, independent samples t and Chi-square tests. RESULTS: AF developed in 5 out of 20 patients during postoperative period (25%). Patients with or without AF did not differ in terms of tissue and blood magnesium levels during and early after CPB and during 7 days after the operation. Blood magnesium levels were significantly higher in the whole study population on postoperative days 3 through 7 (day 3 - 1.13+/-0.11 mmol/L; day 4-, 1.18+/-0.07 mmol/L; day 5-1.15+/-0.10 mmol/L; day 6 1.17+/-0.08 mmol/L; and day 7, 1.22+/-0.08 mmol/L) compared to day 1 and day 2 (day 1-0.96+/-0.13 mmol/L and day 2-1.02+/-0.12 mmol/L; p=0.002 for all comparisons). CONCLUSION: Although patients with and without AF did not significantly differ with regard to blood and tissue magnesium levels, the coincidence of an early postoperative reduction in magnesium levels in all patients and occurrence of all AF incidences at this time period suggests a potential association deserving further investigation. PMID- 20929704 TI - [Left ventricular mass regression after aortic valve replacement]. AB - OBJECTIVE: Our objective was to evaluate the degree of change in left ventricular mass index (LVMI) regression after aortic valve replacement (AVR) using three different valves. METHODS: Group 1 (n=17) included patients with bioprosthesis (Medtronic Hancock 2), Group 2 (n=21) included patients with mono-leaflet mechanical valve (Medtronic Hall), and Group 3 (n=17) included patients with bi leaflet mechanical valve (St Jude). The mean ages of Group 1, 2 and 3 patients were 70.8+/-9.1, 61.6+/-13.7 and 56.2+/-18.3 years, respectively. In this observational study, patients were followed-up after surgery and left ventricular wall thickness and valvular functions were evaluated with echocardiography. The findings were compared with preoperative values. Statistical analyses were performed using one-way variance analysis (ANOVA), Kruskal -Wallis, and Chi square tests. RESULTS: Statistically significant difference was observed among the three groups with respect to age (p=0.015). LVMI regressed in all groups; Group 1 from 232.74+/-53.36 g/m2 (preoperative) to 174.64+/-46.33 g/m2 (postoperative) (p=0.0001), Group 2-from 198.49+/-40.53 g/m2 to 167.04+/-33.9 g/m2 (p=0.0001), and Group 3-228.77+/-47.87 g/m2 to 185.44+/-37.76 g/m2 (p=0.0001). No statistically significant difference was observed among the groups with respect to LVMI regression (p=0.054, p=0.363). CONCLUSION: Mid-term results of AVR with three different aortic valve prosthesis revealed that all groups showed a similar regression of left ventricular mass. However, we advocate that long-term results of an increased number of patients should be evaluated for assessment in depth. PMID- 20929705 TI - [Efficacy of long-term oral monotherapy and additional effect of inhaled iloprost in patients with severe idiopathic pulmonary arterial hypertension]. PMID- 20929706 TI - Two cases of coronary vasospasm induced by 5-fluorouracil. PMID- 20929707 TI - Transcatheter closure of congenital coronary arteriovenous fistula using detachable balloon technique. PMID- 20929708 TI - Acute rheumatic carditis associated with Schoenlein-Henoch vasculitis. PMID- 20929709 TI - [Brachial artery intima-media thickness/ The relation of intima-media thickness with endothelial function and left ventricular mass index]. PMID- 20929710 TI - Supranuclear ophthalmoplegia in Powassan encephalitis. PMID- 20929711 TI - Infantile-onset saccade initiation delay in a child with a thin intercollicular commissure. PMID- 20929714 TI - Larry Meskin: a man of his time with vision beyond his time. PMID- 20929713 TI - Impact of predatory threat on fear extinction in Lewis rats. AB - Humans with post-traumatic stress disorder (PTSD) are deficient at extinguishing conditioned fear responses. A study of identical twins concluded that this extinction deficit does not predate trauma but develops as a result of trauma. The present study tested whether the Lewis rat model of PTSD reproduces these features of the human syndrome. Lewis rats were subjected to classical auditory fear conditioning before or after exposure to a predatory threat that mimics a type of traumatic stress that leads to PTSD in humans. Exploratory behavior on the elevated plus maze 1 wk after predatory threat exposure was used to distinguish resilient vs. PTSD-like rats. Properties of extinction varied depending on whether fear conditioning and extinction occurred before or after predatory threat. When fear conditioning was carried out after predatory threat, PTSD-like rats showed a marked extinction deficit compared with resilient rats. In contrast, no differences were seen between resilient and PTSD-like rats when fear conditioning and extinction occurred prior to predatory threat. These findings in Lewis rats closely match the results seen in humans with PTSD, thereby suggesting that studies comparing neuronal interactions in resilient vs. at-risk Lewis rats might shed light on the causes and pathophysiology of human PTSD. PMID- 20929716 TI - Accuracy of 3D reconstructions based on cone beam computed tomography. AB - Three-dimensional imaging of teeth will increase its impact in clinical practice if reconstructions are metrically accurate. We hypothesized that, with cone beam computed tomography (CBCT) data, three-dimensional images of teeth can be reconstructed with the same accuracy and precision as with in vitro micro computed tomography (micro-CT) data acquisition, the current reference standard. We used a sample of CBCT and micro-CT data taken of tooth germs. Volumes obtained with CBCT and micro-CT devices were statistically similar (n = 120, Passing Bablok regression). Geometric deviations between CBCT and micro-CT three dimensional surface reconstructions did not show any areas of important and systematic errors. Future investigations with the use of larger samples may also demonstrate that CBCT data will be helpful for a more in-depth study of other aspects of dental morphology--for example, assessing tooth development. With sufficient accuracy for clinical situations, potential future medical applications of such measurements with CBCT are envisaged. PMID- 20929715 TI - Altered ion-responsive gene expression in Mmp20 null mice. AB - During enamel maturation, hydroxyapatite crystallites expand in volume, releasing protons that acidify the developing enamel. This acidity is neutralized by the buffering activity of carbonic anhydrases and ion transporters. Less hydroxyapatite forms in matrix metalloproteinase-20 null (Mmp20(-/-)) mouse incisors, because enamel thickness is reduced by approximately 50%. We therefore asked if ion regulation was altered in Mmp20(-/-) mouse enamel. Staining of wild type and Mmp20(-/-) incisors with pH indicators demonstrated that wild-type mice had pronounced changes in enamel pH as development progressed. These pH changes were greatly attenuated in Mmp20(-/-) mice. Expression of 4 ion-regulatory genes (Atp2b4, Slc4a2, Car6, Cftr) was significantly decreased in enamel organs from Mmp20(-/-) mice. Notably, expression of secreted carbonic anhydrase (Car6) was reduced to almost undetectable levels in the null enamel organ. In contrast, Odam and Klk4 expression was unaffected. We concluded that a feedback mechanism regulates ion-responsive gene expression during enamel development. PMID- 20929717 TI - Bell's palsy: the answer to the riddle of Leonardo da Vinci's 'Mona Lisa'. AB - The smile of the famed portrait 'The Mona Lisa' has perplexed both art historians and researchers for the past 500 years. There has been a multitude of theories expounded to explain the nature of the model's enigmatic smile. The origin of the model's wry smile can be demonstrated through a careful analysis of both documented facts concerning the portrait--some gathered only recently through the use of modern technology--and a knowledge of the clinical presentation of Bell's palsy. Bell's palsy is more prevalent in women who are either pregnant or who have recently given birth. This paper postulates that the smile of the portrait's model was due to Leonardo da Vinci's anatomically precise representation of a new mother affected by Bell's palsy subsequent to her recent pregnancy. PMID- 20929718 TI - Enamel-smear compromises bonding by mild self-etch adhesives. AB - In light of the increased popularity of less acidic, so-called 'ultra-mild' self etch adhesives, adhesion to enamel is becoming more critical. It is hypothesized that this compromised enamel bonding should, to a certain extent, be attributed to interference of bur debris smeared across enamel during cavity preparation. High-resolution transmission electron microscopy revealed that the enamel smear layer differed not only in thickness, but also in crystal density and size, depending on the surface-preparation method used. Lab-demineralization of sections clearly disclosed that resin-infiltration of an ultra-mild self-etch adhesive progressed preferentially along micro-cracks that were abundantly present at and underneath the bur-cut enamel surface. The surface-preparation method significantly affected the nature of the smear layer and the interaction with the ultra-mild adhesive, being more uniform and dense for a lab-SiC-prepared surface vs. a clinically relevant bur-prepared surface. PMID- 20929719 TI - Differentiating dental pulp cells via RGD-dendrimer conjugates. AB - Traumatic dental injuries are often irreversible, underscoring the need for therapies that protect dental pulp cells and enhance their regeneration. We hypothesized that generation 5 poly amido amine (PAMAM) dendrimers (G5), functionalized with fluorescein isothiocyanate (FL) and alphaVbeta3-specific, cyclic arginine-glycine-aspartic acid (RGD) peptides, will bind to dental pulp cells (DPCs) and modulate their differentiation. Dental pulp cells and mouse odontoblast-like cells (MDPC-23) (+/-) treated with G5-FL-RGD were analyzed via Western blot, RT-PCR, and quantitative PCR. Transcription of dental differentiation markers was as follows: Dentin matrix protein (DMP-1), dentin sialoprotein (DSPP), and matrix extracellular phosphoglycoprotein (MEPE) as well as vascular endothelial growth factor (VEGF) all increased via the JNK pathway. Long-term G5-RGD treatment of dental pulp cells resulted in enhanced mineralization as examined via Von Kossa assay, suggesting that PAMAM dendrimers conjugated to cyclic RGD peptides can increase the odontogenic potential of these cells. PMID- 20929720 TI - Fluoride's effects on the formation of teeth and bones, and the influence of genetics. AB - Fluorides are present in the environment. Excessive systemic exposure to fluorides can lead to disturbances of bone homeostasis (skeletal fluorosis) and enamel development (dental/enamel fluorosis). The severity of dental fluorosis is also dependent upon fluoride dose and the timing and duration of fluoride exposure. Fluoride's actions on bone cells predominate as anabolic effects both in vitro and in vivo. More recently, fluoride has been shown to induce osteoclastogenesis in mice. Fluorides appear to mediate their actions through the MAPK signaling pathway and can lead to changes in gene expression, cell stress, and cell death. Different strains of inbred mice demonstrate differential physiological responses to ingested fluoride. Genetic studies in mice are capable of identifying and characterizing fluoride-responsive genetic variations. Ultimately, this can lead to the identification of at-risk human populations who are susceptible to the unwanted or potentially adverse effects of fluoride action and to the elucidation of fundamental mechanisms by which fluoride affects biomineralization. PMID- 20929721 TI - Stem cell-calcium phosphate constructs for bone engineering. AB - While human bone-marrow-derived mesenchymal stem cells (hBMSCs) have been investigated, human umbilical cord mesenchymal stem cells (hUCMSCs) are a relatively new cell source. Little has been reported on hUCMSC encapsulation in scaffolds for bone tissue engineering. The objective of this study was to encapsulate hBMSCs and hUCMSCs in calcium phosphate cement (CPC) scaffolds for dental, craniofacial, and orthopedic applications. Stem-cell-encapsulating CPC construct with chitosan and fiber reinforcement reached the strength of cancellous bone, which was much stronger than previous injectable carriers for cell delivery. hUCMSCs and hBMSCs inside the constructs showed excellent viability and osteo-differentiation. The encapsulated hUCMSCs synthesized nearly three-fold more bone minerals than the hBMSCs in vitro. Hence, stem-cell encapsulating CPC-chitosan-fiber construct may be promising for dental and orthopedic applications. This study indicated that the hUCMSCs were a potent alternative to the gold-standard hBMSCs, which may have a broad impact on regenerative medicine and dental tissue engineering. PMID- 20929722 TI - Potential of the Tannerella forsythia S-layer to delay the immune response. AB - The periodontal pathogen Tannerella forsythia possesses a glycosylated S-layer as an outermost cell decoration. While the S-layer provides a selection advantage to the bacterium in the natural habitat, its virulence potential remains to be investigated. In the present study, the immune responses of human macrophages and gingival fibroblasts upon stimulation with wild-type T. forsythia and an S-layer deficient mutant were investigated. The mRNA expression levels of the pro inflammatory mediators IL-1beta, TNF-alpha, and IL-8 were analyzed by qPCR, and the production of the corresponding cytokines was investigated by ELISA. The S layer-deficient T. forsythia mutant induced significantly higher levels of pro inflammatory mediators compared with wild-type T. forsythia, especially at the early phase of response. Analysis of these data suggests that the S-layer of T. forsythia is an important virulence factor that attenuates the host immune response to this pathogen by evading the bacterium's recognition by the innate immune system. ABBREVIATIONS: DMSO, dimethylsulfoxide; FBS, fetal bovine serum; GAPDH, glycerinaldehyde-3-phosphate-dehydrogenase; HGFs, human gingival fibroblasts; LPS, lipopolysaccharide; MEM, minimal essential medium; MTT, 3,4,5 dimethylthiazol-2-yl-2,5-diphenyl tetrazolium bromide; OD, optical density; PBS, phosphate-buffered saline; qPCR, quantitative polymerase chain-reaction; SD, standard deviation; Tannerella forsythia ATCC 43037, Tf wt; Tannerella forsythia ATCC 43037 S-layer mutant, Tf DeltatfsAB. PMID- 20929723 TI - APF and dentifrice effect on root dentin demineralization and biofilm. AB - Because dentin is more caries-susceptible than enamel, its demineralization may be more influenced by additional fluoride (F). We hypothesized that a combination of professional F, applied as acidulated phosphate F (APF), and use of 1100-ppm-F dentifrice would provide additional protection for dentin compared with 1100-ppm F alone. Twelve adult volunteers wore palatal appliances containing root dentin slabs, which were subjected, during 4 experimental phases of 7 days each, to biofilm accumulation and sucrose exposure 8x/day. The volunteers were randomly assigned to the following treatments: placebo dentifrice (PD), 1100-ppm-F dentifrice (FD), APF + PD, and APF+FD. APF gel (1.23% F) was applied to the slabs once at the beginning of the experimental phase, and the dentifrices were used 3x/day. APF and FD increased F concentration in biofilm fluid and reduced root dentin demineralization, presenting an additive effect. Analysis of the data suggests that the combination of APF gel application and daily regular use of 1100-ppm-F dentifrice may provide additional protection against root caries compared with the dentifrice alone. PMID- 20929724 TI - Physiopathology of dental rickets in vitamin D receptor-ablated mice. AB - 1alpha25(OH)(2)vitaminD(3) and its nuclear receptor, VDR, are essential for normal tooth development. However, the relative contributions of the direct vs. indirect effects of vitamin D action on odontogenesis are unclear. The aim of this study was to discriminate among the specific roles of 1alpha25(OH)(2) vitaminD(3), calcemia/phosphatemia, and the maternal environment in mouse VDR null mutants. Microradiographic, histological, and molecular analyses were conducted on adult mice under hypocalcemic/hypophosphatemic vs. normocalcemic/normophosphatemic conditions, and pups of first- (VDR-/- born to VDR+/- dams) vs. second-generation (VDR-/- born to VDR-/- dams) mice. In VDR-/- mice, crown morphogenesis was affected exclusively in second-generation pups. In first-generation adult VDR-/- mice, both enamel and dentin were affected, and pathologic features of root resorption in both apical and cervical regions were observed. Nutritional calcium and phosphate normalization completely rescued the root resorption and partially rescued the dentin and enamel phenotypes (altered cell differentiation and matrix protein expression). Analysis of these data illustrates the co-existence of different pathways of vitamin D action in tooth differentiation and biomineralization. These targeted and cumulative effects would generate the diverse and wide spectrum of dental rickets phenotypes. PMID- 20929725 TI - Evidence for a collective intelligence factor in the performance of human groups. AB - Psychologists have repeatedly shown that a single statistical factor--often called "general intelligence"--emerges from the correlations among people's performance on a wide variety of cognitive tasks. But no one has systematically examined whether a similar kind of "collective intelligence" exists for groups of people. In two studies with 699 people, working in groups of two to five, we find converging evidence of a general collective intelligence factor that explains a group's performance on a wide variety of tasks. This "c factor" is not strongly correlated with the average or maximum individual intelligence of group members but is correlated with the average social sensitivity of group members, the equality in distribution of conversational turn-taking, and the proportion of females in the group. PMID- 20929727 TI - Gamma-secretase gene mutations in familial acne inversa. AB - Acne inversa (AI), also known as hidradenitis suppurativa, is a chronic, recurrent, inflammatory disease of hair follicles that often runs in families. We studied six Chinese families with features of AI as well as additional skin lesions on back, face, nape, and waist and found independent loss-of-function mutations in PSENEN, PSEN1, or NCSTN, the genes encoding essential components of the gamma-secretase multiprotein complex. Our results identify the gamma secretase component genes as the culprits for a subset of familial AI, implicate the gamma-secretase-Notch pathway in the molecular pathogenesis of AI, and demonstrate that familial AI can be an allelic disorder of early-onset familial Alzheimer's disease. PMID- 20929726 TI - Structures of the CXCR4 chemokine GPCR with small-molecule and cyclic peptide antagonists. AB - Chemokine receptors are critical regulators of cell migration in the context of immune surveillance, inflammation, and development. The G protein-coupled chemokine receptor CXCR4 is specifically implicated in cancer metastasis and HIV 1 infection. Here we report five independent crystal structures of CXCR4 bound to an antagonist small molecule IT1t and a cyclic peptide CVX15 at 2.5 to 3.2 angstrom resolution. All structures reveal a consistent homodimer with an interface including helices V and VI that may be involved in regulating signaling. The location and shape of the ligand-binding sites differ from other G protein-coupled receptors and are closer to the extracellular surface. These structures provide new clues about the interactions between CXCR4 and its natural ligand CXCL12, and with the HIV-1 glycoprotein gp120. PMID- 20929728 TI - Mcl-1 is essential for germinal center formation and B cell memory. AB - Lymphocyte survival during immune responses is controlled by the relative expression of pro- and anti-apoptotic molecules, regulating the magnitude, quality, and duration of the response. We investigated the consequences of deleting genes encoding the anti-apoptotic molecules Mcl1 and Bcl2l1 (Bcl-x(L)) from B cells using an inducible system synchronized with expression of activation induced cytidine deaminase (Aicda) after immunization. This revealed Mcl1 and not Bcl2l1 to be indispensable for the formation and persistence of germinal centers (GCs). Limiting Mcl1 expression reduced the magnitude of the GC response with an equivalent, but not greater, effect on memory B cell formation and no effect on persistence. Our results identify Mcl1 as the main anti-apoptotic regulator of activated B cell survival and suggest distinct mechanisms controlling survival of GC and memory B cells. PMID- 20929729 TI - Zooming in on microscopic flow by remotely detected MRI. AB - Magnetic resonance imaging (MRI) can elucidate the interior structure of an optically opaque object in unparalleled detail but is ultimately limited by the need to enclose the object within a detection coil; acquiring the image with increasingly smaller pixels reduces the sensitivity, because each pixel occupies a proportionately smaller fraction of the detector's volume. We developed a technique that overcomes this limitation by means of remotely detected MRI. Images of fluids flowing in channel assemblies are encoded into the phase and intensity of the constituent molecules' nuclear magnetic resonance signals and then decoded by a volume-matched detector after the fluids flow out of the sample. In combination with compressive sampling, we thus obtain microscopic images of flow and velocity distributions ~10(6) times faster than is possible with conventional MRI on this hardware. Our results illustrate the facile integration of MRI with microfluidic assays and suggest generalizations to other systems involving microscopic flow. PMID- 20929730 TI - Channel-mediated tonic GABA release from glia. AB - Synaptic inhibition is based on both tonic and phasic release of the inhibitory transmitter gamma-aminobutyric acid (GABA). Although phasic GABA release arises from Ca(2+)-dependent exocytosis from neurons, the mechanism of tonic GABA release is unclear. Here we report that tonic inhibition in the cerebellum is due to GABA being released from glial cells by permeation through the Bestrophin 1 (Best1) anion channel. We demonstrate that GABA directly permeates through Best1 to yield GABA release and that tonic inhibition is eliminated by silencing of Best1. Glial cells express both GABA and Best1, and selective expression of Best1 in glial cells, after preventing general expression of Best1, fully rescues tonic inhibition. Our results identify a molecular mechanism for tonic inhibition and establish a role for interactions between glia and neurons in mediating tonic inhibition. PMID- 20929731 TI - Lineage relationship analysis of RORgammat+ innate lymphoid cells. AB - Lymphoid tissue-inducer (LTi) cells initiate the development of lymphoid tissues through the activation of local stromal cells in a process similar to inflammation. LTi cells express the nuclear hormone receptor RORgammat, which also directs the expression of the proinflammatory cytokine interleukin-17 in T cells. We show here that LTi cells are part of a larger family of proinflammatory RORgammat(+) innate lymphoid cells (ILCs) that differentiate from distinct fetal liver RORgammat(+) precursors. The fate of RORgammat(+) ILCs is determined by mouse age, and after birth, favors the generation of cells involved in intestinal homeostasis and defense. Contrary to RORgammat(+) T cells, however, RORgammat(+) ILCs develop in the absence of microbiota. Our study indicates that RORgammat(+) ILCs evolve to preempt intestinal colonization by microbial symbionts. PMID- 20929732 TI - Particle acceleration on megaparsec scales in a merging galaxy cluster. AB - Galaxy clusters form through a sequence of mergers of smaller galaxy clusters and groups. Models of diffusive shock acceleration suggest that in shocks that occur during cluster mergers, particles are accelerated to relativistic energies, similar to conditions within supernova remnants. In the presence of magnetic fields, these particles emit synchrotron radiation and may form so-called radio relics. We detected a radio relic that displays highly aligned magnetic fields, a strong spectral index gradient, and a narrow relic width, giving a measure of the magnetic field in an unexplored site of the universe. Our observations show that diffusive shock acceleration also operates on scales much larger than in supernova remnants and that shocks in galaxy clusters are capable of producing extremely energetic cosmic rays. PMID- 20929733 TI - Intestinal stem cell replacement follows a pattern of neutral drift. AB - With the capacity for rapid self-renewal and regeneration, the intestinal epithelium is stereotypical of stem cell-supported tissues. Yet the pattern of stem cell turnover remains in question. Applying analytical methods from population dynamics and statistical physics to an inducible genetic labeling system, we showed that clone size distributions conform to a distinctive scaling behavior at short times. This result demonstrates that intestinal stem cells form an equipotent population in which the loss of a stem cell is compensated by the multiplication of a neighbor, leading to neutral drift dynamics in which clones expand and contract at random until they either take over the crypt or they are lost. Combined with long-term clonal fate data, we show that the rate of stem cell replacement is comparable to the cell division rate, implying that neutral drift and symmetrical cell divisions are central to stem cell homeostasis. PMID- 20929734 TI - Magnitude of the 2010 Gulf of Mexico oil leak. AB - To fully understand the environmental and ecological impacts of the Deepwater Horizon disaster, an accurate estimate of the total oil released is required. We used optical plume velocimetry to estimate the velocity of fluids issuing from the damaged well both before and after the collapsed riser pipe was removed. We then calculated the volumetric flow rate under a range of assumptions. With a liquid oil fraction of 0.4, we estimated that the average flow rate from 22 April 2010 to 3 June 2010 was 5.6 * 10(4) +/- 21% barrels/day (1.0 * 10(-1) meter(3)/second), excluding secondary leaks. After the riser was removed, the flow was 6.8 * 10(4) +/- 19% barrels/day (1.2 * 10(-1) meters(3)/second). Taking into account the oil collected at the seafloor, this suggests that 4.4 * 10(6) +/ 20% barrels of oil (7.0 * 10(5) meters(3)) was released into the ocean. PMID- 20929735 TI - Polarized myosin produces unequal-size daughters during asymmetric cell division. AB - Asymmetric positioning of the mitotic spindle before cytokinesis can produce different-sized daughter cells that have distinct fates. Here, we found an asymmetric division in the Caenorhabditis elegans Q neuroblast lineage that began with a centered spindle but generated different-sized daughters, the smaller (anterior) of which underwent apoptosis. During this division, more myosin II accumulated anteriorly, suggesting that asymmetric contractile forces might produce different-sized daughters. Indeed, partial inactivation of anterior myosin by chromophore-assisted laser inactivation created a more symmetric division and allowed the survival and differentiation of the anterior daughter. Thus, the balance of myosin activity on the two sides of a dividing cell can govern the size and fate of the daughters. PMID- 20929737 TI - Fossil evidence for evolution of the shape and color of penguin feathers. AB - Penguin feathers are highly modified in form and function, but there have been no fossils to inform their evolution. A giant penguin with feathers was recovered from the late Eocene (~36 million years ago) of Peru. The fossil reveals that key feathering features, including undifferentiated primary wing feathers and broad body contour feather shafts, evolved early in the penguin lineage. Analyses of fossilized color-imparting melanosomes reveal that their dimensions were similar to those of non-penguin avian taxa and that the feathering may have been predominantly gray and reddish-brown. In contrast, the dark black-brown color of extant penguin feathers is generated by large, ellipsoidal melanosomes previously unknown for birds. The nanostructure of penguin feathers was thus modified after earlier macrostructural modifications of feather shape linked to aquatic flight. PMID- 20929738 TI - Prepare and inspire. PMID- 20929736 TI - Structure of a eukaryotic CLC transporter defines an intermediate state in the transport cycle. AB - CLC proteins transport chloride (Cl(-)) ions across cell membranes to control the electrical potential of muscle cells, transfer electrolytes across epithelia, and control the pH and electrolyte composition of intracellular organelles. Some members of this protein family are Cl(-) ion channels, whereas others are secondary active transporters that exchange Cl(-) ions and protons (H(+)) with a 2:1 stoichiometry. We have determined the structure of a eukaryotic CLC transporter at 3.5 angstrom resolution. Cytoplasmic cystathionine beta-synthase (CBS) domains are strategically positioned to regulate the ion-transport pathway, and many disease-causing mutations in human CLCs reside on the CBS-transmembrane interface. Comparison with prokaryotic CLC shows that a gating glutamate residue changes conformation and suggests a basis for 2:1 Cl(-)/H(+) exchange and a simple mechanistic connection between CLC channels and transporters. PMID- 20929739 TI - Nobel Prizes. Honor for test tube baby pioneer. PMID- 20929740 TI - Nobel Prizes. Still in its infancy, two-dimensional crystal claims prize. PMID- 20929741 TI - Biomedical ethics. Guatemala study from 1940s reflects a 'dark chapter' in medicine. PMID- 20929742 TI - Newsmaker interview: Kim Heung-Kwang and Park Chan-Mo. Will Korea's computer savvy crown prince embrace reform? Interview by Richard Stone. PMID- 20929743 TI - Cellular reprogramming. New technique RiPS open stem cell field. PMID- 20929744 TI - Court battle. What's next for stem cell research? PMID- 20929746 TI - Scientific exchanges. A chill in China-Japan academic relations. PMID- 20929745 TI - Brain research. Neuroscientists grapple with their field's big questions. PMID- 20929748 TI - Interview: Stephen Lekson. Giving back the bones. Interview by Keith Kloor. PMID- 20929749 TI - Science and native rights. Grave disputes. PMID- 20929750 TI - Science and native rights. Walking in two worlds. PMID- 20929751 TI - Science and native rights. A world of graves. PMID- 20929752 TI - Science and native rights. A tale of two skeletons. PMID- 20929753 TI - Interview: Ernie LaPointe. Honoring his ancestor by studying his DNA. Interview by John Travis. PMID- 20929754 TI - Science and native rights. In search of Sitting Bull. PMID- 20929755 TI - AIDS funds: undervalued. PMID- 20929756 TI - AIDS funds: promised. PMID- 20929757 TI - AIDS funds: benefits. PMID- 20929758 TI - AIDS funds: prevention. PMID- 20929759 TI - AIDS funds: Rwanda. PMID- 20929760 TI - Comment on "Climate, critters, and cetaceans: Cenozoic drivers of the evolution of modern whales". AB - Marx and Uhen (Reports, 19 February 2010, p. 993) suggested that correlated diversity changes in the fossil record of whales and diatoms reflects secular evolutionary signals of underlying ecological drivers. We question the meaning of this association and outline avenues for more complete testing of correlations between productivity and marine consumers through geologic time. PMID- 20929761 TI - Science and regulation. Regulating direct-to-consumer personal genome testing. PMID- 20929763 TI - Physics. Looking at how things slip. PMID- 20929762 TI - Molecular biology. Surfing chromosomes (and Survivin). PMID- 20929764 TI - Plant science. Saving the bilayer. PMID- 20929765 TI - Microbiology. Interacting parasites. PMID- 20929766 TI - Chemistry. Inorganic nanoparticles as protein mimics. PMID- 20929767 TI - Plant science. Communal benefits of transgenic corn. PMID- 20929768 TI - The evolution and future of Earth's nitrogen cycle. AB - Atmospheric reactions and slow geological processes controlled Earth's earliest nitrogen cycle, and by ~2.7 billion years ago, a linked suite of microbial processes evolved to form the modern nitrogen cycle with robust natural feedbacks and controls. Over the past century, however, the development of new agricultural practices to satisfy a growing global demand for food has drastically disrupted the nitrogen cycle. This has led to extensive eutrophication of fresh waters and coastal zones as well as increased inventories of the potent greenhouse gas nitrous oxide (N(2)O). Microbial processes will ultimately restore balance to the nitrogen cycle, but the damage done by humans to the nitrogen economy of the planet will persist for decades, possibly centuries, if active intervention and careful management strategies are not initiated. PMID- 20929769 TI - Bacteria use type IV pili to walk upright and detach from surfaces. AB - Bacterial biofilms are structured multicellular communities involved in a broad range of infections. Knowing how free-swimming bacteria adapt their motility mechanisms near surfaces is crucial for understanding the transition between planktonic and biofilm phenotypes. By translating microscopy movies into searchable databases of bacterial behavior, we identified fundamental type IV pili-driven mechanisms for Pseudomonas aeruginosa surface motility involved in distinct foraging strategies. Bacteria stood upright and "walked" with trajectories optimized for two-dimensional surface exploration. Vertical orientation facilitated surface detachment and could influence biofilm morphology. PMID- 20929770 TI - Nanophase transition metal oxides show large thermodynamically driven shifts in oxidation-reduction equilibria. AB - Knowing the thermodynamic stability of transition metal oxide nanoparticles is important for understanding and controlling their role in a variety of industrial and environmental systems. Using calorimetric data on surface energies for cobalt, iron, manganese, and nickel oxide systems, we show that surface energy strongly influences their redox equilibria and phase stability. Spinels (M(3)O(4)) commonly have lower surface energies than metals (M), rocksalt oxides (MO), and trivalent oxides (M(2)O(3)) of the same metal; thus, the contraction of the stability field of the divalent oxide and expansion of the spinel field appear to be general phenomena. Using tabulated thermodynamic data for bulk phases to calculate redox phase equilibria at the nanoscale can lead to errors of several orders of magnitude in oxygen fugacity and of 100 to 200 kelvin in temperature. PMID- 20929771 TI - The dynamics of the onset of frictional slip. AB - The way in which a frictional interface fails is critical to our fundamental understanding of failure processes in fields ranging from engineering to the study of earthquakes. Frictional motion is initiated by rupture fronts that propagate within the thin interface that separates two sheared bodies. By measuring the shear and normal stresses along the interface, together with the subsequent rapid real-contact-area dynamics, we find that the ratio of shear stress to normal stress can locally far exceed the static-friction coefficient without precipitating slip. Moreover, different modes of rupture selected by the system correspond to distinct regimes of the local stress ratio. These results indicate the key role of nonuniformity to frictional stability and dynamics with implications for the prediction, selection, and arrest of different modes of earthquakes. PMID- 20929772 TI - Block copolymer self-assembly-directed single-crystal homo- and heteroepitaxial nanostructures. AB - Epitaxy is a widely used method to grow high-quality crystals. One of the key challenges in the field of inorganic solids is the development of epitaxial single-crystal nanostructures. We describe their formation from block copolymer self-assembly-directed nanoporous templates on single-crystal Si backfilled with Si or NiSi through a laser-induced transient melt process. Depending on thickness, template removal leaves either an array of nanopillars or porous nanostructures behind. For stoichiometric NiSi deposition, the template pores provide confinement, enabling heteroepitaxial growth. Irradiation through a mask provides access to hierarchically structured materials. These results on etchable and non-etchable materials suggest a general strategy for growing epitaxial single-crystal nanostructured thin films for fundamental studies and a wide variety of applications, including energy conversion and storage. PMID- 20929773 TI - An oxidative enzyme boosting the enzymatic conversion of recalcitrant polysaccharides. AB - Efficient enzymatic conversion of crystalline polysaccharides is crucial for an economically and environmentally sustainable bioeconomy but remains unfavorably inefficient. We describe an enzyme that acts on the surface of crystalline chitin, where it introduces chain breaks and generates oxidized chain ends, thus promoting further degradation by chitinases. This enzymatic activity was discovered and further characterized by using mass spectrometry and chromatographic separation methods to detect oxidized products generated in the absence or presence of H(2)(18)O or (18)O(2). There are strong indications that similar enzymes exist that work on cellulose. Our findings not only demonstrate the existence of a hitherto unknown enzyme activity but also provide new avenues toward more efficient enzymatic conversion of biomass. PMID- 20929774 TI - Areawide suppression of European corn borer with Bt maize reaps savings to non-Bt maize growers. AB - Transgenic maize engineered to express insecticidal proteins from the bacterium Bacillus thuringiensis (Bt) has become widely adopted in U.S. agriculture. In 2009, Bt maize was planted on more than 22.2 million hectares, constituting 63% of the U.S. crop. Using statistical analysis of per capita growth rate estimates, we found that areawide suppression of the primary pest Ostrinia nubilalis (European corn borer) is associated with Bt maize use. Cumulative benefits over 14 years are an estimated $3.2 billion for maize growers in Illinois, Minnesota, and Wisconsin, with more than $2.4 billion of this total accruing to non-Bt maize growers. Comparable estimates for Iowa and Nebraska are $3.6 billion in total, with $1.9 billion for non-Bt maize growers. These results affirm theoretical predictions of pest population suppression and highlight economic incentives for growers to maintain non-Bt maize refugia for sustainable insect resistance management. PMID- 20929777 TI - The future of Russian science. PMID- 20929776 TI - Species interactions in a parasite community drive infection risk in a wildlife population. AB - Most hosts, including humans, are simultaneously or sequentially infected with several parasites. A key question is whether patterns of coinfection arise because infection by one parasite species affects susceptibility to others or because of inherent differences between hosts. We used time-series data from individual hosts in natural populations to analyze patterns of infection risk for a microparasite community, detecting large positive and negative effects of other infections. Patterns remain once variations in host susceptibility and exposure are accounted for. Indeed, effects are typically of greater magnitude, and explain more variation in infection risk, than the effects associated with host and environmental factors more commonly considered in disease studies. We highlight the danger of mistaken inference when considering parasite species in isolation rather than parasite communities. PMID- 20929775 TI - Two histone marks establish the inner centromere and chromosome bi-orientation. AB - For proper partitioning of chromosomes in mitosis, the chromosomal passenger complex (CPC) including Aurora B and survivin must be localized at the center of paired kinetochores, at the site called the inner centromere. It is largely unknown what defines the inner centromere and how the CPC is targeted to this site. Here, we show that the phosphorylation of histone H3-threonine 3 (H3-pT3) mediated by Haspin cooperates with Bub1-mediated histone 2A-serine 121 (H2A-S121) phosphorylation in targeting the CPC to the inner centromere in fission yeast and human cells. H3-pT3 promotes nucleosome binding of survivin, whereas phosphorylated H2A-S121 facilitates the binding of shugoshin, the centromeric CPC adaptor. Haspin colocalizes with cohesin by associating with Pds5, whereas Bub1 localizes at kinetochores. Thus, the inner centromere is defined by intersection of two histone kinases. PMID- 20929778 TI - U.S. graduate education. Academy rankings tell you a lot, but not who's No. 1 in any field. PMID- 20929779 TI - Infectious diseases. Rival teams identify a virus behind deaths in central China. PMID- 20929781 TI - Psychology. Social savvy boosts the collective intelligence of groups. PMID- 20929782 TI - Science policy. India's vision: from scientific pipsqueak to powerhouse. PMID- 20929783 TI - Conservation. Filling gaps in global biodiversity estimates. PMID- 20929784 TI - Newsmaker interview: Ian Poiner. Counting the ocean's creatures, great and small. Interview by Dennis Normile. PMID- 20929785 TI - Growing prospects for life on Mars divide astrobiologists. PMID- 20929786 TI - Archaeology. Archaeologists see big promise in going molecular. PMID- 20929787 TI - IEEE International Conference on Computational Intelligence and Games. Killer bots are getting human. PMID- 20929788 TI - IEEE International Conference on Computational Intelligence and Games. Game miners grapple with massive data. PMID- 20929789 TI - IEEE International Conference on Computational Intelligence and Games. Smarts for serious games. PMID- 20929791 TI - Perennial questions of hydrology and climate. PMID- 20929792 TI - HIV/AIDS: use existing funds effectively. PMID- 20929793 TI - A positive review for PLoS ONE. PMID- 20929794 TI - Comment on "The human K-complex represents an isolated cortical down-state". AB - Cash et al. (Reports, 22 May 2009, p. 1084) argue that the human K-complex, a defining characteristic of slow-wave sleep, is a unipolar electroencephalogram (EEG) wave reflecting a simple neuronal hyperpolarizing event. We disagree with this conclusion and point to several confounding aspects of the study. PMID- 20929795 TI - Education. Complex systems view of educational policy research. PMID- 20929796 TI - Medicine. Neutrophils find smoke attractive. PMID- 20929797 TI - Archaeology. When humans arrived in the New Guinea Highlands. PMID- 20929798 TI - Cell biology. How to STIMulate calcium channels. PMID- 20929799 TI - Chemistry. A balancing act for Taxol precursor pathways in E. coli. PMID- 20929800 TI - Genetics. Mosaicism--switch or spectrum? PMID- 20929801 TI - Astronomy. A dance of extrasolar planets. PMID- 20929802 TI - Retrospective. George C. Williams (1926-2010). PMID- 20929803 TI - High frequency of horizontal gene transfer in the oceans. AB - Oceanic bacteria perform many environmental functions, including biogeochemical cycling of many elements, metabolizing of greenhouse gases, functioning in oceanic food webs (microbial loop), and producing valuable natural products and viruses. We demonstrate that the widespread capability of marine bacteria to participate in horizontal gene transfer (HGT) in coastal and oceanic environments may be the result of gene transfer agents (GTAs), viral-like particles produced by alpha-Proteobacteria. We documented GTA-mediated gene transfer frequencies a thousand to a hundred million times higher than prior estimates of HGT in the oceans, with as high as 47% of the culturable natural microbial community confirmed as gene recipients. These findings suggest a plausible mechanism by which marine bacteria acquire novel traits, thus ensuring resilience in the face of environmental change. PMID- 20929804 TI - Multiple exciton collection in a sensitized photovoltaic system. AB - Multiple exciton generation, the creation of two electron-hole pairs from one high-energy photon, is well established in bulk semiconductors, but assessments of the efficiency of this effect remain controversial in quantum-confined systems like semiconductor nanocrystals. We used a photoelectrochemical system composed of PbS nanocrystals chemically bound to TiO(2) single crystals to demonstrate the collection of photocurrents with quantum yields greater than one electron per photon. The strong electronic coupling and favorable energy level alignment between PbS nanocrystals and bulk TiO(2) facilitate extraction of multiple excitons more quickly than they recombine, as well as collection of hot electrons from higher quantum dot excited states. Our results have implications for increasing the efficiency of photovoltaic devices by avoiding losses resulting from the thermalization of photogenerated carriers. PMID- 20929805 TI - Allosteric supramolecular triple-layer catalysts. AB - Allosteric regulation of organometallic catalysts could allow for greater control over reactions. We report an allosteric supramolecular structure in which a monometallic catalytic site has been buried in the middle layer of a triple-layer complex. Small molecules and elemental anions can open and close this complex and reversibly expose and conceal the catalytic center. The ring-opening polymerization of epsilon-caprolactone can be turned on by the in situ opening of the triple-layer complex and then completely turned off by reforming it through the abstraction of Cl(-), the allosteric effector agent, without appreciable loss of catalytic activity. This process can regulate the molecular weights of the resulting polymers. PMID- 20929807 TI - Reactivity of the gold/water interface during selective oxidation catalysis. AB - The selective oxidation of alcohols in aqueous phase over supported metal catalysts is facilitated by high-pH conditions. We have studied the mechanism of ethanol and glycerol oxidation to acids over various supported gold and platinum catalysts. Labeling experiments with (18)O(2) and H(2)(18)O demonstrate that oxygen atoms originating from hydroxide ions instead of molecular oxygen are incorporated into the alcohol during the oxidation reaction. Density functional theory calculations suggest that the reaction path involves both solution mediated and metal-catalyzed elementary steps. Molecular oxygen is proposed to participate in the catalytic cycle not by dissociation to atomic oxygen but by regenerating hydroxide ions formed via the catalytic decomposition of a peroxide intermediate. PMID- 20929806 TI - Isoprenoid pathway optimization for Taxol precursor overproduction in Escherichia coli. AB - Taxol (paclitaxel) is a potent anticancer drug first isolated from the Taxus brevifolia Pacific yew tree. Currently, cost-efficient production of Taxol and its analogs remains limited. Here, we report a multivariate-modular approach to metabolic-pathway engineering that succeeded in increasing titers of taxadiene- the first committed Taxol intermediate--approximately 1 gram per liter (~15,000 fold) in an engineered Escherichia coli strain. Our approach partitioned the taxadiene metabolic pathway into two modules: a native upstream methylerythritol phosphate (MEP) pathway forming isopentenyl pyrophosphate and a heterologous downstream terpenoid-forming pathway. Systematic multivariate search identified conditions that optimally balance the two pathway modules so as to maximize the taxadiene production with minimal accumulation of indole, which is an inhibitory compound found here. We also engineered the next step in Taxol biosynthesis, a P450-mediated 5alpha-oxidation of taxadiene to taxadien-5alpha-ol. More broadly, the modular pathway engineering approach helped to unlock the potential of the MEP pathway for the engineered production of terpenoid natural products. PMID- 20929808 TI - Human adaptation and plant use in highland New Guinea 49,000 to 44,000 years ago. AB - After their emergence by 200,000 years before the present in Africa, modern humans colonized the globe, reaching Australia and New Guinea by 40,000 to 50,000 years ago. Understanding how humans lived and adapted to the range of environments in these areas has been difficult because well-preserved settlements are scarce. Data from the New Guinea Highlands (at an elevation of ~2000 meters) demonstrate the exploitation of the endemic nut Pandanus and yams in archaeological sites dated to 49,000 to 36,000 years ago, which are among the oldest human sites in this region. The sites also contain stone tools thought to be used to remove trees, which suggests that the early inhabitants cleared forest patches to promote the growth of useful plants. PMID- 20929809 TI - Identifying the driver of pulsating aurora. AB - Pulsating aurora, a spectacular emission that appears as blinking of the upper atmosphere in the polar regions, is known to be excited by modulated, downward streaming electrons. Despite its distinctive feature, identifying the driver of the electron precipitation has been a long-standing problem. Using coordinated satellite and ground-based all-sky imager observations from the THEMIS mission, we provide direct evidence that a naturally occurring electromagnetic wave, lower band chorus, can drive pulsating aurora. Because the waves at a given equatorial location in space correlate with a single pulsating auroral patch in the upper atmosphere, our findings can also be used to constrain magnetic field models with much higher accuracy than has previously been possible. PMID- 20929810 TI - Sequencing of Culex quinquefasciatus establishes a platform for mosquito comparative genomics. AB - Culex quinquefasciatus (the southern house mosquito) is an important mosquito vector of viruses such as West Nile virus and St. Louis encephalitis virus, as well as of nematodes that cause lymphatic filariasis. C. quinquefasciatus is one species within the Culex pipiens species complex and can be found throughout tropical and temperate climates of the world. The ability of C. quinquefasciatus to take blood meals from birds, livestock, and humans contributes to its ability to vector pathogens between species. Here, we describe the genomic sequence of C. quinquefasciatus: Its repertoire of 18,883 protein-coding genes is 22% larger than that of Aedes aegypti and 52% larger than that of Anopheles gambiae with multiple gene-family expansions, including olfactory and gustatory receptors, salivary gland genes, and genes associated with xenobiotic detoxification. PMID- 20929811 TI - Pathogenomics of Culex quinquefasciatus and meta-analysis of infection responses to diverse pathogens. AB - The mosquito Culex quinquefasciatus poses a substantial threat to human and veterinary health as a primary vector of West Nile virus (WNV), the filarial worm Wuchereria bancrofti, and an avian malaria parasite. Comparative phylogenomics revealed an expanded canonical C. quinquefasciatus immune gene repertoire compared with those of Aedes aegypti and Anopheles gambiae. Transcriptomic analysis of C. quinquefasciatus genes responsive to WNV, W. bancrofti, and non native bacteria facilitated an unprecedented meta-analysis of 25 vector-pathogen interactions involving arboviruses, filarial worms, bacteria, and malaria parasites, revealing common and distinct responses to these pathogen types in three mosquito genera. Our findings provide support for the hypothesis that mosquito-borne pathogens have evolved to evade innate immune responses in three vector mosquito species of major medical importance. PMID- 20929812 TI - The CRAC channel activator STIM1 binds and inhibits L-type voltage-gated calcium channels. AB - Voltage- and store-operated calcium (Ca(2+)) channels are the major routes of Ca(2+) entry in mammalian cells, but little is known about how cells coordinate the activity of these channels to generate coherent calcium signals. We found that STIM1 (stromal interaction molecule 1), the main activator of store-operated Ca(2+) channels, directly suppresses depolarization-induced opening of the voltage-gated Ca(2+) channel Ca(V)1.2. STIM1 binds to the C terminus of Ca(V)1.2 through its Ca(2+) release-activated Ca(2+) activation domain, acutely inhibits gating, and causes long-term internalization of the channel from the membrane. This establishes a previously unknown function for STIM1 and provides a molecular mechanism to explain the reciprocal regulation of these two channels in cells. PMID- 20929813 TI - The calcium store sensor, STIM1, reciprocally controls Orai and CaV1.2 channels. AB - Calcium signals, pivotal in controlling cell function, can be generated by calcium entry channels activated by plasma membrane depolarization or depletion of internal calcium stores. We reveal a regulatory link between these two channel subtypes mediated by the ubiquitous calcium-sensing STIM proteins. STIM1 activation by store depletion or mutational modification strongly suppresses voltage-operated calcium (Ca(V)1.2) channels while activating store-operated Orai channels. Both actions are mediated by the short STIM-Orai activating region (SOAR) of STIM1. STIM1 interacts with Ca(V)1.2 channels and localizes within discrete endoplasmic reticulum/plasma membrane junctions containing both Ca(V)1.2 and Orai1 channels. Hence, STIM1 interacts with and reciprocally controls two major calcium channels hitherto thought to operate independently. Such coordinated control of the widely expressed Ca(V)1.2 and Orai channels has major implications for Ca(2+) signal generation in excitable and nonexcitable cells. PMID- 20929814 TI - Science for physicians. PMID- 20929815 TI - Science in U.S. schools. A way to heal science education, but is there the political will? PMID- 20929816 TI - Scientific misconduct. Misconduct by postdocs leads to retraction of papers. PMID- 20929817 TI - Scientific publishing. Genomics researchers upset by rivals' publicity. PMID- 20929818 TI - Parasitology. Origin of most deadly human malaria comes out of the mist. PMID- 20929819 TI - Animal research. Long-fought compromise reached on European animal rules. PMID- 20929820 TI - Animal-rights activism. A tricky balance between activists' and researchers' rights. PMID- 20929821 TI - Astronomy. New type of cosmic dust tells of galaxy's violent history. PMID- 20929822 TI - Genetic resources. Parlous times for seed banks spell trouble for Australian agriculture. PMID- 20929823 TI - Conservation ecology. Home, home outside the range? PMID- 20929824 TI - Immunology. Mouse studies challenge rare immune cell's powers. PMID- 20929825 TI - Fisheries. Behind the eco-label, a debate over Antarctic toothfish. PMID- 20929826 TI - Science standards: value the teachers. PMID- 20929827 TI - Science standards: averages deceive. PMID- 20929828 TI - A recount of tropical tree species. PMID- 20929829 TI - Retraction. PMID- 20929830 TI - Education framework needs better foundation. PMID- 20929831 TI - Astronomy. More supernova surprises. PMID- 20929832 TI - Botany. The rise of sunflowers. PMID- 20929833 TI - Genetics. A bit of Texas in Florida. PMID- 20929834 TI - Genetics. Exposing a DUX tale. PMID- 20929835 TI - Physics. STM ready for the time domain. PMID- 20929836 TI - Developmental biology. Branching takes nerve. PMID- 20929837 TI - Neuroscience. Dendrites do it in sequences. PMID- 20929838 TI - SPORE series winner. Immunology for clinicians: a "Trojan Horse" approach. PMID- 20929839 TI - Reaction-diffusion model as a framework for understanding biological pattern formation. AB - The Turing, or reaction-diffusion (RD), model is one of the best-known theoretical models used to explain self-regulated pattern formation in the developing animal embryo. Although its real-world relevance was long debated, a number of compelling examples have gradually alleviated much of the skepticism surrounding the model. The RD model can generate a wide variety of spatial patterns, and mathematical studies have revealed the kinds of interactions required for each, giving this model the potential for application as an experimental working hypothesis in a wide variety of morphological phenomena. In this review, we describe the essence of this theory for experimental biologists unfamiliar with the model, using examples from experimental studies in which the RD model is effectively incorporated. PMID- 20929840 TI - Eocene Patagonia fossils of the daisy family. AB - Fossil capitula and pollen grains of Asteraceae from the Eocene of Patagonia, southern Argentina, exhibit morphological features recognized today in taxa, such as Mutisioideae and Carduoideae, that are phylogenetically close to the root of the asteracean tree. This fossil supports the hypothesis of a South American origin of Asteraceae and an Eocene age of divergence and suggests that an ancestral stock of Asteraceae may have formed part of a geoflora developed in southern Gondwana before the establishment of effective dispersal barriers within this landmass. PMID- 20929841 TI - The ubiquity of micrometer-sized dust grains in the dense interstellar medium. AB - Cold molecular clouds are the birthplaces of stars and planets, where dense cores of gas collapse to form protostars. The dust mixed in these clouds is thought to be made of grains of an average size of 0.1 micrometer. We report the widespread detection of the coreshine effect as a direct sign of the existence of grown, micrometer-sized dust grains. This effect is seen in half of the cores we have analyzed in our survey, spanning all Galactic longitudes, and is dominated by changes in the internal properties and local environment of the cores, implying that the coreshine effect can be used to constrain fundamental core properties such as the three-dimensional density structure and ages and also the grain characteristics themselves. PMID- 20929842 TI - Measurement of fast electron spin relaxation times with atomic resolution. AB - Single spins in solid-state systems are often considered prime candidates for the storage of quantum information, and their interaction with the environment the main limiting factor for the realization of such schemes. The lifetime of an excited spin state is a sensitive measure of this interaction, but extending the spatial resolution of spin relaxation measurements to the atomic scale has been a challenge. We show how a scanning tunneling microscope can measure electron spin relaxation times of individual atoms adsorbed on a surface using an all electronic pump-probe measurement scheme. The spin relaxation times of individual Fe-Cu dimers were found to vary between 50 and 250 nanoseconds. Our method can in principle be generalized to monitor the temporal evolution of other dynamical systems. PMID- 20929843 TI - Optical clocks and relativity. AB - Observers in relative motion or at different gravitational potentials measure disparate clock rates. These predictions of relativity have previously been observed with atomic clocks at high velocities and with large changes in elevation. We observed time dilation from relative speeds of less than 10 meters per second by comparing two optical atomic clocks connected by a 75-meter length of optical fiber. We can now also detect time dilation due to a change in height near Earth's surface of less than 1 meter. This technique may be extended to the field of geodesy, with applications in geophysics and hydrology as well as in space-based tests of fundamental physics. PMID- 20929844 TI - Alkali-stabilized Pt-OHx species catalyze low-temperature water-gas shift reactions. AB - We report that alkali ions (sodium or potassium) added in small amounts activate platinum adsorbed on alumina or silica for the low-temperature water-gas shift (WGS) reaction (H(2)O + CO -> H(2) + CO(2)) used for producing H(2). The alkali ion-associated surface OH groups are activated by CO at low temperatures (~100 degrees C) in the presence of atomically dispersed platinum. Both experimental evidence and density functional theory calculations suggest that a partially oxidized Pt-alkali-O(x)(OH)(y) species is the active site for the low-temperature Pt-catalyzed WGS reaction. These findings are useful for the design of highly active and stable WGS catalysts that contain only trace amounts of a precious metal without the need for a reducible oxide support such as ceria. PMID- 20929845 TI - Graphene double-layer capacitor with ac line-filtering performance. AB - Electric double-layer capacitors (DLCs) can have high storage capacity, but their porous electrodes cause them to perform like resistors in filter circuits that remove ripple from rectified direct current. We have demonstrated efficient filtering of 120-hertz current with DLCs with electrodes made from vertically oriented graphene nanosheets grown directly on metal current collectors. This design minimized electronic and ionic resistances and produced capacitors with RC time constants of less than 200 microseconds, in contrast with ~1 second for typical DLCs. Graphene nanosheets have a preponderance of exposed edge planes that greatly increases charge storage as compared with that of designs that rely on basal plane surfaces. Capacitors constructed with these electrodes could be smaller than the low-voltage aluminum electrolyte capacitors that are typically used in electronic devices. PMID- 20929846 TI - Slip systems in MgSiO3 post-perovskite: implications for D'' anisotropy. AB - Understanding deformation of mineral phases in the lowermost mantle is important for interpreting seismic anisotropy in Earth's interior. Recently, there has been considerable controversy regarding deformation-induced slip in MgSiO(3) post perovskite. Here, we observe that (001) lattice planes are oriented at high angles to the compression direction immediately after transformation and before deformation. Upon compression from 148 gigapascals (GPa) to 185 GPa, this preferred orientation more than doubles in strength, implying slip on (001) lattice planes. This contrasts with a previous experiment that recorded preferred orientation likely generated during the phase transformation rather than deformation. If we use our results to model deformation and anisotropy development in the D'' region of the lower mantle, shear-wave splitting (characterized by fast horizontally polarized shear waves) is consistent with seismic observations. PMID- 20929847 TI - Genetic restoration of the Florida panther. AB - The rediscovery of remnant Florida panthers (Puma concolor coryi) in southern Florida swamplands prompted a program to protect and stabilize the population. In 1995, conservation managers translocated eight female pumas (P. c. stanleyana) from Texas to increase depleted genetic diversity, improve population numbers, and reverse indications of inbreeding depression. We have assessed the demographic, population-genetic, and biomedical consequences of this restoration experiment and show that panther numbers increased threefold, genetic heterozygosity doubled, survival and fitness measures improved, and inbreeding correlates declined significantly. Although these results are encouraging, continued habitat loss, persistent inbreeding, infectious agents, and possible habitat saturation pose new dilemmas. This intensive management program illustrates the challenges of maintaining populations of large predators worldwide. PMID- 20929848 TI - Parasympathetic innervation maintains epithelial progenitor cells during salivary organogenesis. AB - The maintenance of a progenitor cell population as a reservoir of undifferentiated cells is required for organ development and regeneration. However, the mechanisms by which epithelial progenitor cells are maintained during organogenesis are poorly understood. We report that removal of the parasympathetic ganglion in mouse explant organ culture decreased the number and morphogenesis of keratin 5-positive epithelial progenitor cells. These effects were rescued with an acetylcholine analog. We demonstrate that acetylcholine signaling, via the muscarinic M1 receptor and epidermal growth factor receptor, increased epithelial morphogenesis and proliferation of the keratin 5-positive progenitor cells. Parasympathetic innervation maintained the epithelial progenitor cell population in an undifferentiated state, which was required for organogenesis. This mechanism for epithelial progenitor cell maintenance may be targeted for organ repair or regeneration. PMID- 20929849 TI - Olfactory plasticity is regulated by pheromonal signaling in Caenorhabditis elegans. AB - Population density-dependent dispersal is a well-characterized strategy of animal behavior in which dispersal rate increases when population density is higher. Caenorhabditis elegans shows positive chemotaxis to a set of odorants, but the chemotaxis switches from attraction to dispersal after prolonged exposure to the odorants. We show here that this plasticity of olfactory behavior is dependent on population density and that this regulation is mediated by pheromonal signaling. We show that a peptide, suppressor of NEP-2 (SNET-1), negatively regulates olfactory plasticity and that its expression is down-regulated by the pheromone. NEP-2, a homolog of the extracellular peptidase neprilysin, antagonizes SNET-1, and this function is essential for olfactory plasticity. These results suggest that population density information is transmitted through the external pheromone and endogenous peptide signaling to modulate chemotactic behavior. PMID- 20929850 TI - A general mechanism for network-dosage compensation in gene circuits. AB - Coping with variations in network dosage is crucial for maintaining optimal function in gene networks. We explored how network structure facilitates network level dosage compensation. By using the yeast galactose network as a model, we combinatorially deleted one of the two copies of its four regulatory genes and found that network activity was robust to the change in network dosage. A mathematical analysis revealed that a two-component genetic circuit with elements of opposite regulatory activity (activator and inhibitor) constitutes a minimal requirement for network-dosage invariance. Specific interaction topologies and a one-to-one interaction stoichiometry between the activating and inhibiting agents were additional essential elements facilitating dosage invariance. This mechanism of network-dosage invariance could represent a general design for gene network structure in cells. PMID- 20929851 TI - Stability of the regulatory T cell lineage in vivo. AB - Tissue maintenance and homeostasis can be achieved through the replacement of dying cells by differentiating precursors or self-renewal of terminally differentiated cells or relies heavily on cellular longevity in poorly regenerating tissues. Regulatory T cells (T(reg) cells) represent an actively dividing cell population with critical function in suppression of lethal immune mediated inflammation. The plasticity of T(reg) cells has been actively debated because it could factor importantly in protective immunity or autoimmunity. By using inducible labeling and tracking of T(reg) cell fate in vivo, or transfers of highly purified T(reg) cells, we have demonstrated notable stability of this cell population under physiologic and inflammatory conditions. Our results suggest that self-renewal of mature T(reg) cells serves as a major mechanism of maintenance of the T(reg) cell lineage in adult mice. PMID- 20929852 TI - The promoting role of a tumour-secreted chemorepellent in self-metastatic tumour progression. AB - It has been proposed that cancer cells, in particular glioma tumour cells, secrete a chemorepellent factor that guides cell migration away from the tumour, facilitating migration and invasion. We present a hybrid continuous-discrete mathematical model of tumour growth and the chemotropism phenomenon to show that such a chemorepellent factor can also act as a promoter of self-metastases, a mechanism for tumour expansion we have previously shown can explain several essential kinetic dependencies of tumour growth. A sufficient criterion for this expansion was found to be the passive migration of peripheral cancer stem and non stem cells away from the main tumour mass, where migrating cancer stem cells form new clusters. We show here how the introduction of an active repellent trait serves to accelerate peripheral migration and thus, by the self-metastases principle, accelerate tumour growth. These results provide a mechanistic basis for the proposal that chemorepellent action in gliomas may underlie their rapid growth. PMID- 20929853 TI - Beyond the neglect of psychological consequences: post-traumatic stress disorder increases the non-fatal burden of injury by more than 50%. AB - BACKGROUND: Psychological consequences such as post-traumatic stress disorder (PTSD) are currently neglected in burden-of-injury calculations. AIM: To assess the disease burden of PTSD due to unintentional injury and compare this health loss with physical injury consequences. METHODS: From literature sources, the prevalence of PTSD at four follow-up periods (<3 months, 3-6 months, 7-12 months and >12 months) was estimated. The uncertainty of the estimated PTSD prevalence was modelled by a Bayesian approach. The prevalence rates were then linked to national data on unintentional injury, disability weights and duration to estimate the incidence and disability-adjusted life years (DALY) resulting from PTSD in addition to physical injury consequences. RESULTS: The data suggest that PTSD prevalence among injury victims decreases over time. The average PTSD prevalence at <3 months follow-up was 21% (90% credibility interval (CI) 17% to 24%) for patients presenting at the emergency department and 30% (90% CI 27% to 33%) for patients who were hospitalised, tapering down after 12 months to 4% (90% CI 3% to 5%) and 6% (90% CI 4% to 10%), respectively. These estimates translate into 191,000 (90% CI 161,000 to 222,000) cases of PTSD per year in the Dutch population (1.2%) due to unintentional injury. Including PTSD increases the non fatal burden of disease of unintentional injuries by 53% (from 116,000 to 178,000 DALYs (90% CI 150,000 to 217,000)). CONCLUSIONS: Ignoring PTSD in burden-of injury studies results in a considerable underestimation of the burden of injury. This may affect resource allocation and the identification of important prevention priorities. PMID- 20929854 TI - Changes in the state-level distribution of primary and secondary syphilis in the USA, 1985-2007. AB - OBJECTIVES: To examine changes over time in the distribution of primary and secondary syphilis cases across states, using Lorenz curves and Gini coefficients. METHODS: For each year from 1985 to 2007, the Gini coefficient for the state-level distribution of male and female syphilis cases was calculated. The Gini coefficient can range from 0 (indicating equality in syphilis rates across states) to 1 (indicating complete inequality such that all syphilis cases occur in one state). RESULTS: The Gini coefficients for men are notably lower (indicating more equality in the distribution of syphilis across states) in recent years (in which men who have sex with men (MSM) account for most syphilis cases) than in the heterosexual epidemic of the late 1980s and early 1990s. Although syphilis rates in men were similar in 1995 and 2007 (6.7 and 6.6 per 100,000, respectively), the Gini coefficient for male syphilis decreased from 0.523 in 1995 to 0.333 in 2007. For syphilis in women, Gini coefficients have not shown the same degree of decline. CONCLUSIONS: The spread of MSM syphilis cases to urban areas across the nation is likely to be a main cause of the decreased concentration of male syphilis cases across states from 1995 to 2007. PMID- 20929855 TI - Modelling HIV epidemics in the antiretroviral era: the UNAIDS Estimation and Projection package 2009. AB - OBJECTIVE: The UNAIDS Estimation and Projection Package (EPP) is a tool for country-level estimation and short-term projection of HIV/AIDS epidemics based on fitting observed HIV surveillance data on prevalence. This paper describes the adaptations made in EPP 2009, the latest version of this tool, as new issues have arisen in the global response, in particular the global expansion of antiretroviral therapy (ART). RESULTS: By December 2008 over 4 million people globally were receiving ART, substantially improving their survival. EPP 2009 required modifications to correctly adjust for the effects of ART on incidence and the resulting increases in HIV prevalence in populations with high ART coverage. Because changing incidence is a better indicator of program impact, the 2009 series of UNAIDS tools also focuses on calculating incidence alongside prevalence. Other changes made in EPP 2009 include: an improved procedure, incremental mixture importance sampling, for efficiently generating more accurate uncertainty estimates; provisions to vary the urban/rural population ratios in generalised epidemics over time; introduction of a modified epidemic model that accommodates behaviour change in low incidence settings; and improved procedures for calibrating models. This paper describes these changes in detail, and discusses anticipated future changes in the next version of EPP. PMID- 20929856 TI - Identification of interacting hot spots in the beta3 integrin stalk using comprehensive interface design. AB - Protein-protein interfaces are usually large and complementary surfaces, but specific side chains, representing energetic "hot spots," often contribute disproportionately to binding free energy. We used a computational method, comprehensive interface design, to identify hot spots in the interface between the stalk regions of the beta3 and the complementary alphaIIb and alphav integrin subunits. Using the Rosetta alanine-scanning and design algorithms to predict destabilizing, stabilizing, and neutral mutations in the beta3 region extending from residues Lys(532) through Gly(690), we predicted eight alanine mutations that would destabilize the alphaIIbbeta3 interface as well as nine predicted to destabilize the alphavbeta3 interface, by at least 0.3 kcal/mol. The mutations were widely and unevenly distributed, with four between residues 552 and 563 and five between 590 and 610, but none between 565 and 589, and 611 and 655. Further, mutations destabilizing the alphavbeta3 and alphaIIbbeta3 interfaces were not identical. The predictions were then tested by introducing selected mutations into the full-length integrins expressed in Chinese hamster ovary cells. Five mutations predicted to destabilize alphaIIb and beta3 caused fibrinogen binding to alphaIIbbeta3, whereas three of four predicted to be neutral or stabilizing did not. Conversely, a mutation predicted to destabilize alphavbeta3, but not alphaIIbbeta3 (D552A), caused osteopontin binding to alphavbeta3, but not fibrinogen binding to alphaIIbbeta3. These results indicate that stability of the distal stalk interface is involved in constraining integrins in stable, inactive conformations. Further, they demonstrate the ability of comprehensive interface design to identify functionally significant integrin mutations. PMID- 20929857 TI - Novel anti-carbohydrate antibodies reveal the cooperative function of sulfated N- and O-glycans in lymphocyte homing. AB - Cell surface glycans play pivotal roles in immune cell trafficking and immunity. Here we present an efficient method for generating anti-carbohydrate monoclonal antibodies (mAbs) using gene-targeted mice and describe critical glycans in lymphocyte homing. We immunized sulfotransferase GlcNAc6ST-1 and GlcNAc6ST-2 doubly deficient mice with sulfotransferase-overexpressing Chinese hamster ovary cells and generated two mAbs, termed S1 and S2. Both S1 and S2 bound high endothelial venules (HEVs) in the lymphoid organs of humans and wild-type mice, but not in those of doubly deficient mice. Glycan array analysis indicated that both S1 and S2 specifically bound 6-sulfo sialyl Lewis X and its defucosylated structure. Interestingly, S2 inhibited lymphocyte homing to peripheral lymph nodes by 95%, whereas S1 inhibited it by only 25%. S2 also significantly inhibited contact hypersensitivity responses and L-selectin-dependent leukocyte adhesion to HEVs. Immunohistochemical and Western blot analyses indicated that S1 preferentially bound sulfated O-glycans, whereas S2 bound both sulfated N- and O glycans in HEVs. Furthermore, S2 strongly inhibited the N-glycan-dependent residual lymphocyte homing in mutant mice lacking sulfated O-glycans, indicating the importance of both sulfated N- and O-glycans in lymphocyte homing. Thus, the two mAbs generated by a novel method revealed the cooperative function of sulfated N- and O-glycans in lymphocyte homing and immune surveillance. PMID- 20929858 TI - Both thioredoxin 2 and glutaredoxin 2 contribute to the reduction of the mitochondrial 2-Cys peroxiredoxin Prx3. AB - The proteins from the thioredoxin family are crucial actors in redox signaling and the cellular response to oxidative stress. The major intracellular source for oxygen radicals are the components of the respiratory chain in mitochondria. Here, we show that the mitochondrial 2-Cys peroxiredoxin (Prx3) is not only substrate for thioredoxin 2 (Trx2), but can also be reduced by glutaredoxin 2 (Grx2) via the dithiol reaction mechanism. Grx2 reduces Prx3 exhibiting catalytic constants (K(m), 23.8 MUmol.liter(-1); V(max), 1.2 MUmol.(mg.min)(-1)) similar to Trx2 (K(m), 11.2 MUmol.liter(-1); V(max), 1.1 MUmol.(mg.min)(-1)). The reduction of the catalytic disulfide of the atypical 2-Cys Prx5 is limited to the Trx system. Silencing the expression of either Trx2 or Grx2 in HeLa cells using specific siRNAs did not change the monomer:dimer ratio of Prx3 detected by a specific 2-Cys Prx redox blot. Only combined silencing of the expression of both proteins led to an accumulation of oxidized protein. We further demonstrate that the distribution of Prx3 in different mouse tissues is either linked to the distribution of Trx2 or Grx2. These results introduce Grx2 as a novel electron donor for Prx3, providing further insights into pivotal cellular redox signaling mechanisms. PMID- 20929859 TI - Generation and selection of novel fully human monoclonal antibodies that neutralize Dickkopf-1 (DKK1) inhibitory function in vitro and increase bone mass in vivo. AB - Wnt/LRP5 signaling is a central regulatory component of bone formative and resorptive activities, and the pathway inhibitor DKK1 is a suppressor of bone formation and bone mass accrual in mice. In addition, augmented DKK1 levels are associated with high bone turnover in diverse low bone mass states in rodent models and disease etiologies in human. However, examination of the precise role of DKK1 in the normal skeleton and in higher species requires the development of refined DKK1-specific pharmacological tools. Here, we report the strategy resulting in isolation of a panel of fully human anti-DKK1 antibodies applicable to studies interrogating the roles of mouse, rhesus, and human DKK1. Selected anti-DKK1 antibodies bind primate and human DKK-1 with picomolar affinities yet do not appreciably bind to DKK2 or DKK4. Epitopes mapped within the DKK1 C terminal domain necessary for interaction with LRP5/6 and consequently effectively neutralized DKK1 function in vitro. When introduced into naive normal growing female mice, IgGs significantly improved trabecular bone volume and structure and increased both trabecular and cortical bone mineral densities in a dose-related fashion. Furthermore, fully human DKK1-IgG displayed favorable pharmacokinetic parameters in non-human primates. In summary, we demonstrate here a rate-limiting function of physiologic DKK1 levels in the regulation of bone mass in intact female mice, amendable to specific pharmacologic neutralization by newly identified DKK1-IgGs. Importantly the fully human IgGs display a profile of attributes that recommends their testing in higher species and their use in evaluating DKK1 function in relevant disease models. PMID- 20929860 TI - Perturbed amelogenin secondary structure leads to uncontrolled aggregation in amelogenesis imperfecta mutant proteins. AB - Mutations in amelogenin sequence result in defective enamel, and the diverse group of genetically altered conditions is collectively known as amelogenesis imperfecta (AI). Despite numerous studies, the detailed molecular mechanism of defective enamel formation is still unknown. In this study, we have examined the biophysical properties of a recombinant murine amelogenin (rM180) and two point mutations identified from human DNA sequences in two cases of AI (T21I and P41T). At pH 5.8 and 25 degrees C, wild type (WT) rM180 and mutant P41T existed as monomers, and mutant T21I formed lower order oligomers. CD, dynamic light scattering, and fluorescence studies indicated that rM180 and P41T can be classified as a premolten globule-like subclass protein at 25 degrees C. Thermal denaturation and refolding monitored by CD ellipticity at 224 nm indicated the presence of a strong hysteresis in mutants compared with WT. Variable temperature tryptophan fluorescence and dynamic light scattering studies showed that WT transformed to a partially folded conformation upon heating and remained stable. The partially folded conformation formed by P41T, however, readily converted into a heterogeneous population of aggregates. T21I existed in an oligomeric state at room temperature and, upon heating, rapidly formed large aggregates over a very narrow temperature range. Thermal denaturation and refolding studies indicated that the mutants are less stable and exhibit poor refolding ability compared with WT rM180. Our results suggest that alterations in self-assembly of amelogenin are a consequence of destabilization of the intrinsic disorder. Therefore, we propose that, like a number of other human diseases, AI appears to be due to the destabilization of the secondary structure as a result of amelogenin mutations. PMID- 20929861 TI - Proliferating cell nuclear antigen-dependent rapid recruitment of Cdt1 and CRL4Cdt2 at DNA-damaged sites after UV irradiation in HeLa cells. AB - The licensing factor Cdt1 is degraded by CRL4(Cdt2) ubiquitin ligase dependent on proliferating cell nuclear antigen (PCNA) during S phase and when DNA damage is induced in G(1) phase. Association of both Cdt2 and PCNA with chromatin was observed in S phase and after UV irradiation. Here we used a micropore UV irradiation assay to examine Cdt2 accumulation at cyclobutane pyrimidine dimer containing DNA-damaged sites in the process of Cdt1 degradation in HeLa cells. Cdt2, present in the nucleus throughout the cell cycle, accumulated rapidly at damaged DNA sites during G(1) phase. The recruitment of Cdt2 is dependent on prior PCNA chromatin binding because Cdt2 association was prevented when PCNA was silenced. Cdt1 was also recruited to damaged sites soon after UV irradiation through its PIP-box. As Cdt1 was degraded, the Cdt2 signal at damaged sites was reduced, but PCNA, cyclobutane pyrimidine dimer, and XPA (xeroderma pigmentosum, complementation group A) signals remained at the same levels. These findings suggest that Cdt1 degradation following UV irradiation occurs rapidly at damaged sites due to PCNA chromatin loading and the recruitment of Cdt1 and CRL4(Cdt2), before DNA damage repair is completed. PMID- 20929862 TI - RGD-independent cell adhesion via a tissue transglutaminase-fibronectin matrix promotes fibronectin fibril deposition and requires syndecan-4/2 alpha5beta1 integrin co-signaling. AB - Fibronectin (FN) deposition mediated by fibroblasts is an important process in matrix remodeling and wound healing. By monitoring the deposition of soluble biotinylated FN, we show that the stress-induced TG-FN matrix, a matrix complex of tissue transglutaminase (TG2) with its high affinity binding partner FN, can increase both exogenous and cellular FN deposition and also restore it when cell adhesion is interrupted via the presence of RGD-containing peptides. This mechanism does not require the transamidase activity of TG2 but is activated through an RGD-independent adhesion process requiring a heterocomplex of TG2 and FN and is mediated by a syndecan-4 and beta1 integrin co-signaling pathway. By using alpha5 null cells, beta1 integrin functional blocking antibody, and a alpha5beta1 integrin targeting peptide A5-1, we demonstrate that the alpha5 and beta1 integrins are essential for TG-FN to compensate RGD-induced loss of cell adhesion and FN deposition. The importance of syndecan-2 in this process was shown using targeting siRNAs, which abolished the compensation effect of TG-FN on the RGD-induced loss of cell adhesion, resulting in disruption of actin skeleton formation and FN deposition. Unlike syndecan-4, syndecan-2 does not interact directly with TG2 but acts as a downstream effector in regulating actin cytoskeleton organization through the ROCK pathway. We demonstrate that PKCalpha is likely to be the important link between syndecan-4 and syndecan-2 signaling and that TG2 is the functional component of the TG-FN heterocomplex in mediating cell adhesion via its direct interaction with heparan sulfate chains. PMID- 20929863 TI - Interactions of STAP-2 with Brk and STAT3 participate in cell growth of human breast cancer cells. AB - STAP-2 (signal transducing adaptor protein-2) is a recently identified adaptor protein that contains pleckstrin homology (PH) and Src homology 2-like domains, as well as a STAT3-binding motif in its C-terminal region. STAP-2 is also a substrate of breast tumor kinase (Brk). In breast cancers, Brk expression is deregulated and promotes STAT3-dependent cell proliferation. In the present study, manipulated STAP-2 expression demonstrated essential roles of STAP-2 in Brk-mediated STAT3 activation. STAP-2 interacts with both Brk and STAT3. In addition, small interfering RNA-mediated reduction of endogenous STAP-2 expression strongly decreased Brk-mediated STAT3 activation in T47D breast cancer cells. The PH domain of STAP-2 is involved in multiple steps: the binding between Brk and STAP-2, the activation and tyrosine phosphorylation of STAT3, and the activation of Brk. Notably, a STAP-2 PH-Brk fusion protein exhibited robust kinase activity and increased activation and tyrosine phosphorylation of STAT3. Finally, STAP-2 knockdown in T47D cells induced a significant decrease of proliferation, as strong as that of Brk or STAT3 knockdown. Taken together, our findings are likely to inform the development of a novel therapeutic strategy, as well as the determination of novel prognostic values, in breast carcinomas. PMID- 20929864 TI - Dna2 exhibits a unique strand end-dependent helicase function. AB - Dna2 endonuclease/helicase participates in eukaryotic DNA transactions including cleavage of long flaps generated during Okazaki fragment processing. Its unusual substrate interaction consists of recognition and binding of the flap base, then threading over the 5'-end of the flap, and cleaving periodically to produce a terminal product ~5 nt in length. Blocking the 5'-end prevents cleavage. The Dna2 ATP-driven 5' to 3' DNA helicase function promotes motion of Dna2 on the flap, presumably aiding its nuclease function. Here we demonstrate using two different nuclease-dead Dna2 mutants that on substrates simulating Okazaki fragments, Dna2 must thread onto an unblocked 5' flap to display helicase activity. This requirement is maintained on substrates with single-stranded regions thousands of nucleotides in length. To our knowledge this is the first description of a eukaryotic helicase that cannot load onto its tracking strand internally but instead must enter from the end. Biologically, the loading requirement likely helps the helicase to coordinate with the Dna2 nuclease function to prevent creation of undesirably long flaps during DNA transactions. PMID- 20929865 TI - Structural analysis of the conserved ubiquitin-binding motifs (UBMs) of the translesion polymerase iota in complex with ubiquitin. AB - Ubiquitin-binding domains (UBDs) provide specificity to the ubiquitin system, which is also involved in translesion synthesis (TLS) in eukaryotic cells. Upon DNA damage, the UBDs (UBM domains) of polymerase iota (Pol iota) interact with ubiquitinated proliferating cell nuclear antigen to regulate the interchange between processive DNA polymerases and TLS. We report a biophysical analysis and solution structures of the two conserved UBM domains located in the C-terminal tail of murine Pol iota in complex with ubiquitin. The 35-amino acid core folds into a helix-turn-helix motif, which belongs to a novel domain fold. Similar to other UBDs, UBMs bind to ubiquitin on the hydrophobic surface delineated by Leu 8, Ile-44, and Val-70, however, slightly shifted toward the C terminus. In addition, UBMs also use electrostatic interactions to stabilize binding. NMR and fluorescence spectroscopy measurements revealed that UBMs bind monoubiquitin, and Lys-63- but not Lys-48-linked chains. Importantly, these biophysical data are supported by functional studies. Indeed, yeast cells expressing ubiquitin mutants specifically defective for UBM binding are viable but sensitive to DNA damaging conditions that require TLS for repair. PMID- 20929866 TI - Separate and combined biochemical activities of the subunits of a naturally split reverse gyrase. AB - Reverse gyrase reanneals denatured DNA and induces positive supercoils in DNA, an activity that is critical for life at very high temperatures. Positive supercoiling occurs by a poorly understood mechanism involving the coordination of a topoisomerase domain and a helicase-like domain. In the parasitic archaeon Nanoarchaeum equitans, these domains occur as separate subunits. We express the subunits, and characterize them both in isolation and as a heterodimer. Each subunit tightly associates and interacts with the other. The topoisomerase subunit enhances the catalytic specificity of the DNA-dependent ATPase activity of the helicase-like subunit, and the helicase-like subunit inhibits the relaxation activity of the topoisomerase subunit while promoting positive supercoiling. DNA binding preference for both single- and double-stranded DNA is partitioned between the subunits. Based on a sensitive topological shift assay, the binding preference of helicase-like subunit for underwound DNA is modulated by its binding with ATP cofactor. These results provide new insight into the mechanism of positive supercoil induction by reverse gyrase. PMID- 20929867 TI - Local sequence targeting in the AID/APOBEC family differentially impacts retroviral restriction and antibody diversification. AB - Nucleic acid cytidine deaminases of the activation-induced deaminase (AID)/APOBEC family are critical players in active and innate immune responses, playing roles as target-directed, purposeful mutators. AID specifically deaminates the host immunoglobulin (Ig) locus to evolve antibody specificity, whereas its close relative, APOBEC3G (A3G), lethally mutates the genomes of retroviral pathogens such as HIV. Understanding the basis for the target-specific action of these enzymes is essential, as mistargeting poses significant risks, potentially promoting oncogenesis (AID) or fostering drug resistance (A3G). AID prefers to deaminate cytosine in WRC (W = A/T, R = A/G) motifs, whereas A3G favors deamination of CCC motifs. This specificity is largely dictated by a single, divergent protein loop in the enzyme family that recognizes the DNA sequence. Through grafting of this substrate-recognition loop, we have created enzyme variants of A3G and AID with altered local targeting to directly evaluate the role of sequence specificity on immune function. We find that grafted loops placed in the A3G scaffold all produced efficient restriction of HIV but that foreign loops in the AID scaffold compromised hypermutation and class switch recombination. Local targeting, therefore, appears alterable for innate defense against retroviruses by A3G but important for adaptive antibody maturation catalyzed by AID. Notably, AID targeting within the Ig locus is proportionally correlated to its in vitro ability to target WRC sequences rather than non-WRC sequences. Although other mechanisms may also contribute, our results suggest that local sequence targeting by AID/APOBEC3 enzymes represents an elegant example of co-evolution of enzyme specificity with its target DNA sequence. PMID- 20929868 TI - DBASS3 and DBASS5: databases of aberrant 3'- and 5'-splice sites. AB - DBASS3 and DBASS5 provide comprehensive repositories of new exon boundaries that were induced by pathogenic mutations in human disease genes. Aberrant 5'- and 3' splice sites were activated either by mutations in the consensus sequences of natural exon-intron junctions (cryptic sites) or elsewhere ('de novo' sites). DBASS3 and DBASS5 currently contain approximately 900 records of cryptic and de novo 3'- and 5'-splice sites that were produced by over a thousand different mutations in approximately 360 genes. DBASS3 and DBASS5 data can be searched by disease phenotype, gene, mutation, location of aberrant splice sites in introns and exons and their distance from authentic counterparts, by bibliographic references and by the splice-site strength estimated with several prediction algorithms. The user can also retrieve reference sequences of both aberrant and authentic splice sites with the underlying mutation. These data will facilitate identification of introns or exons frequently involved in aberrant splicing, mutation analysis of human disease genes and study of germline or somatic mutations that impair RNA processing. Finally, this resource will be useful for fine-tuning splice-site prediction algorithms, better definition of auxiliary splicing signals and design of new reporter assays. DBASS3 and DBASS5 are freely available at http://www.dbass.org.uk/. PMID- 20929869 TI - genenames.org: the HGNC resources in 2011. AB - The HUGO Gene Nomenclature Committee (HGNC) aims to assign a unique gene symbol and name to every human gene. The HGNC database currently contains almost 30,000 approved gene symbols, over 19,000 of which represent protein-coding genes. The public website, www.genenames.org, displays all approved nomenclature within Symbol Reports that contain data curated by HGNC editors and links to related genomic, phenotypic and proteomic information. Here we describe improvements to our resources, including a new Quick Gene Search, a new List Search, an integrated HGNC BioMart and a new Statistics and Downloads facility. PMID- 20929871 TI - TADB: a web-based resource for Type 2 toxin-antitoxin loci in bacteria and archaea. AB - TADB (http://bioinfo-mml.sjtu.edu.cn/TADB/) is an integrated database that provides comprehensive information about Type 2 toxin-antitoxin (TA) loci, genetic features that are richly distributed throughout bacterial and archaeal genomes. Two-gene and much less frequently three-gene Type 2 TA loci code for cognate partners that have been hypothesized or demonstrated to play key roles in stress response, bacterial physiology and stabilization of horizontally acquired genetic elements. TADB offers a unique compilation of both predicted and experimentally supported Type 2 TA loci-relevant data and currently contains 10,753 Type 2 TA gene pairs identified within 1240 prokaryotic genomes, and details of over 240 directly relevant scientific publications. A broad range of similarity search, sequence alignment, genome context browser and phylogenetic tools are readily accessible via TADB. We propose that TADB will facilitate efficient, multi-disciplinary and innovative exploration of the bacteria and archaea Type 2 TA space, better defining presently recognized TA-related phenomena and potentially even leading to yet-to-be envisaged frontiers. The TADB database, envisaged as a one-stop shop for Type 2 TA-related research, will be maintained, updated and improved regularly to ensure its ongoing maximum utility to the research community. PMID- 20929870 TI - Functional regulation of FEN1 nuclease and its link to cancer. AB - Flap endonuclease-1 (FEN1) is a member of the Rad2 structure-specific nuclease family. FEN1 possesses FEN, 5'-exonuclease and gap-endonuclease activities. The multiple nuclease activities of FEN1 allow it to participate in numerous DNA metabolic pathways, including Okazaki fragment maturation, stalled replication fork rescue, telomere maintenance, long-patch base excision repair and apoptotic DNA fragmentation. Here, we summarize the distinct roles of the different nuclease activities of FEN1 in these pathways. Recent biochemical and genetic studies indicate that FEN1 interacts with more than 30 proteins and undergoes post-translational modifications. We discuss how FEN1 is regulated via these mechanisms. Moreover, FEN1 interacts with five distinct groups of DNA metabolic proteins, allowing the nuclease to be recruited to a specific DNA metabolic complex, such as the DNA replication machinery for RNA primer removal or the DNA degradosome for apoptotic DNA fragmentation. Some FEN1 interaction partners also stimulate FEN1 nuclease activities to further ensure efficient action in processing of different DNA structures. Post-translational modifications, on the other hand, may be critical to regulate protein-protein interactions and cellular localizations of FEN1. Lastly, we also review the biological significance of FEN1 as a tumor suppressor, with an emphasis on studies of human mutations and mouse models. PMID- 20929872 TI - BSDB: the biomolecule stretching database. AB - We describe the Biomolecule Stretching Data Base that has been recently set up at http://www.ifpan.edu.pl/BSDB/. It provides information about mechanostability of proteins. Its core is based on simulations of stretching of 17 134 proteins within a structure-based model. The primary information is about the heights of the maximal force peaks, the force-displacement patterns, and the sequencing of the contact-rupturing events. We also summarize the possible types of the mechanical clamps, i.e. the motifs which are responsible for a protein's resistance to stretching. PMID- 20929873 TI - Amplification of a plasmid bearing a mammalian replication initiation region in chromosomal and extrachromosomal contexts. AB - Amplified genes in cancer cells reside on extrachromosomal double minutes (DMs) or chromosomal homogeneously staining regions (HSRs). We used a plasmid bearing a mammalian replication initiation region to model gene amplification. Recombination junctions in the amplified region were comprehensively identified and sequenced. The junctions consisted of truncated direct repeats (type 1) or inverted repeats (type 2) with or without spacing. All of these junctions were frequently detected in HSRs, whereas there were few type 1 or a unique type 2 flanked by a short inverted repeat in DMs. The junction sequences suggested a model in which the inverted repeats were generated by sister chromatid fusion. We were consistently able to detect anaphase chromatin bridges connected by the plasmid repeat, which were severed in the middle during mitosis. De novo HSR generation was observed in live cells, and each HSR was lengthened more rapidly than expected from the classical breakage/fusion/bridge model. Importantly, we found massive DNA synthesis at the broken anaphase bridge during the G1 to S phase, which could explain the rapid lengthening of the HSR. This mechanism may not operate in acentric DMs, where most of the junctions are eliminated and only those junctions produced through stable intermediates remain. PMID- 20929874 TI - Optimizing the noise versus bias trade-off for Illumina whole genome expression BeadChips. AB - Five strategies for pre-processing intensities from Illumina expression BeadChips are assessed from the point of view of precision and bias. The strategies include a popular variance stabilizing transformation and model-based background corrections that either use or ignore the control probes. Four calibration data sets are used to evaluate precision, bias and false discovery rate (FDR). The original algorithms are shown to have operating characteristics that are not easily comparable. Some tend to minimize noise while others minimize bias. Each original algorithm is shown to have an innate intensity offset, by which unlogged intensities are bounded away from zero, and the size of this offset determines its position on the noise-bias spectrum. By adding extra offsets, a continuum of related algorithms with different noise-bias trade-offs is generated, allowing direct comparison of the performance of the strategies on equivalent terms. Adding a positive offset is shown to decrease the FDR of each original algorithm. The potential of each strategy to generate an algorithm with an optimal noise bias trade-off is explored by finding the offset that minimizes its FDR. The use of control probes as part of the background correction and normalization strategy is shown to achieve the lowest FDR for a given bias. PMID- 20929875 TI - The IKMC web portal: a central point of entry to data and resources from the International Knockout Mouse Consortium. AB - The International Knockout Mouse Consortium (IKMC) aims to mutate all protein coding genes in the mouse using a combination of gene targeting and gene trapping in mouse embryonic stem (ES) cells and to make the generated resources readily available to the research community. The IKMC database and web portal (www.knockoutmouse.org) serves as the central public web site for IKMC data and facilitates the coordination and prioritization of work within the consortium. Researchers can access up-to-date information on IKMC knockout vectors, ES cells and mice for specific genes, and follow links to the respective repositories from which corresponding IKMC products can be ordered. Researchers can also use the web site to nominate genes for targeting, or to indicate that targeting of a gene should receive high priority. The IKMC database provides data to, and features extensive interconnections with, other community databases. PMID- 20929876 TI - Pseudomonas Genome Database: improved comparative analysis and population genomics capability for Pseudomonas genomes. AB - Pseudomonas is a metabolically-diverse genus of bacteria known for its flexibility and leading free living to pathogenic lifestyles in a wide range of hosts. The Pseudomonas Genome Database (http://www.pseudomonas.com) integrates completely-sequenced Pseudomonas genome sequences and their annotations with genome-scale, high-precision computational predictions and manually curated annotation updates. The latest release implements an ability to view sequence polymorphisms in P. aeruginosa PAO1 versus other reference strains, incomplete genomes and single gene sequences. This aids analysis of phenotypic variation between closely related isolates and strains, as well as wider population genomics and evolutionary studies. The wide range of tools for comparing Pseudomonas annotations and sequences now includes a strain-specific access point for viewing high precision computational predictions including updated, more accurate, protein subcellular localization and genomic island predictions. Views link to genome-scale experimental data as well as comparative genomics analyses that incorporate robust genera-geared methods for predicting and clustering orthologs. These analyses can be exploited for identifying putative essential and core Pseudomonas genes or identifying large-scale evolutionary events. The Pseudomonas Genome Database aims to provide a continually updated, high quality source of genome annotations, specifically tailored for Pseudomonas researchers, but using an approach that may be implemented for other genera-level research communities. PMID- 20929877 TI - MiRNA-miRNA synergistic network: construction via co-regulating functional modules and disease miRNA topological features. AB - Synergistic regulations among multiple microRNAs (miRNAs) are important to understand the mechanisms of complex post-transcriptional regulations in humans. Complex diseases are affected by several miRNAs rather than a single miRNA. So, it is a challenge to identify miRNA synergism and thereby further determine miRNA functions at a system-wide level and investigate disease miRNA features in the miRNA-miRNA synergistic network from a new view. Here, we constructed a miRNA miRNA functional synergistic network (MFSN) via co-regulating functional modules that have three features: common targets of corresponding miRNA pairs, enriched in the same gene ontology category and close proximity in the protein interaction network. Predicted miRNA synergism is validated by significantly high co expression of functional modules and significantly negative regulation to functional modules. We found that the MFSN exhibits a scale free, small world and modular architecture. Furthermore, the topological features of disease miRNAs in the MFSN are distinct from non-disease miRNAs. They have more synergism, indicating their higher complexity of functions and are the global central cores of the MFSN. In addition, miRNAs associated with the same disease are close to each other. The structure of the MFSN and the features of disease miRNAs are validated to be robust using different miRNA target data sets. PMID- 20929880 TI - Integrating tools for breast cancer risk assessment, risk reduction, and early detection. PMID- 20929878 TI - Advanced computational algorithms for microbial community analysis using massive 16S rRNA sequence data. AB - With the aid of next-generation sequencing technology, researchers can now obtain millions of microbial signature sequences for diverse applications ranging from human epidemiological studies to global ocean surveys. The development of advanced computational strategies to maximally extract pertinent information from massive nucleotide data has become a major focus of the bioinformatics community. Here, we describe a novel analytical strategy including discriminant and topology analyses that enables researchers to deeply investigate the hidden world of microbial communities, far beyond basic microbial diversity estimation. We demonstrate the utility of our approach through a computational study performed on a previously published massive human gut 16S rRNA data set. The application of discriminant and topology analyses enabled us to derive quantitative disease associated microbial signatures and describe microbial community structure in far more detail than previously achievable. Our approach provides rigorous statistical tools for sequence-based studies aimed at elucidating associations between known or unknown organisms and a variety of physiological or environmental conditions. PMID- 20929881 TI - Mammographic density and risk of second breast cancer after ductal carcinoma in situ. AB - BACKGROUND: We examined whether mammographic density predicts risk of second breast cancers among patients with ductal carcinoma in situ (DCIS). METHODS: The study included DCIS patients diagnosed during 1990 to 1997 and treated with breast-conserving surgery at Kaiser Permanente Northern California. Medical records were reviewed for clinical factors and subsequent breast cancers (DCIS and invasive). Ipsilateral mammograms from the index DCIS were assessed for density without knowledge of subsequent cancer status. Cox regression modeling was used to examine the association between mammographic density and risk of breast cancer events. RESULTS: Of the 935 eligible DCIS patients, 164 (18%) had a subsequent ipsilateral breast cancer, and 59 (6%) had a new primary cancer in the contralateral breast during follow-up (median, 103 mo). Those with the greatest total area of density (upper 20% of values) were at increased risk for invasive disease in either breast [hazard ratio (HR), 2.1; 95% confidence interval (95% CI), 1.2-3.8] or any cancer (DCIS or invasive) in the ipsilateral (HR, 1.7; 95% CI, 1.0-2.9) or contralateral (HR, 3.0; 95% CI, 1.3-6.9) breast compared with those with the smallest area of density (bottom 20%). HRs for these same end points comparing those in the highest with those in the lowest American College of Radiology Breast Imaging Reporting and Data System category were 1.6 (95% CI, 0.7-3.6), 1.3 (95% CI, 0.7-2.6), and 5.0 (95% CI, 1.4-17.9), respectively. There was a suggestion of increasing risk of contralateral, but not ipsilateral, cancer with increasing percent density. CONCLUSIONS: Women with mammographically dense breasts may be at higher risk of subsequent breast cancer, especially in the contralateral breast. IMPACT: Information about mammographic density may help with DCIS treatment decisions. PMID- 20929882 TI - Fecal DNA for noninvasive diagnosis of colorectal cancer in immunochemical fecal occult blood test-positive individuals. AB - BACKGROUND: We aimed to define the potential of the fecal DNA assay as an alternative or in addition to the currently used immunochemical fecal occult blood test (iFOBT) for the early diagnosis of colorectal cancer. METHODS: A total of 560 individuals aged 50 to 69 years with a positive iFOBT were recruited from an Italian FOBT regional screening program. Twenty-six were diagnosed with adenocarcinoma, 264 with high-risk adenoma, and 54 with low-risk adenoma, whereas 216 subjects did not have premalignant or malignant lesions. Fecal DNA integrity was analyzed blindly by the fluorescence long DNA (FL-DNA) test. RESULTS: iFOBT and FL-DNA were largely independent variables (rs = 0.036, P = 0.42), with values ranging from 101 to 5,826 ng/mL and from 0 to 515 ng, respectively. Median values of both variables were significantly higher in cancer patients than in patients with noncancerous lesions or in healthy individuals. Moreover, iFOBT and FL-DNA values were individually associated with a number of pathologic parameters. Sequential use of the diagnostic iFOBT and FL-DNA methods showed that fecal DNA provided more accurate diagnostic information and was able to identify subgroups at different risk of cancer in iFOBT-positive individuals. CONCLUSIONS: A combined approach based on FL-DNA and iFOBT evaluation could help to better identify colorectal cancers and to determine a patient's risk of harboring a preneoplastic or neoplastic lesion. Further evaluation in a screening setting is needed to confirm this hypothesis. IMPACT: Fecal DNA could be a useful tool to better predict cancer risk in FOBT-positive individuals. PMID- 20929883 TI - Dietary factors and risk of chronic lymphocytic leukemia and small lymphocytic lymphoma: a pooled analysis of two prospective studies. AB - BACKGROUND: Other than male sex, family history, advanced age, and race, risk factors for chronic lymphocytic leukemia and small lymphocytic lymphoma (CLL/SLL) are unknown. Very few studies have investigated diet in relation to these leukemias, and no consistent associations are known. METHODS: Using two large prospective population-based studies, we evaluated the relationship between diet and CLL/SLL risk. Among 525,982 men and women free of cancer at enrollment, we identified 1,129 incident CLL/SLL cases during 11.2 years of follow-up. RESULTS: We found no associations between total fat, saturated fat, fiber, red meat, processed meat, fruit, or vegetable intake and risk of CLL/SLL. We noted a suggestive positive association between body mass index and CLL/SLL (hazard ratio, 1.30; 95% confidence interval, 0.99-1.36). CONCLUSION: We did not find any associations between food or nutrient intake and CLL/SLL. IMPACT: Our large prospective study indicates that diet may not play a role in CLL/SLL development. PMID- 20929885 TI - Indoor tanning and risk of melanoma: a case-control study in a highly exposed population - letter. PMID- 20929886 TI - Doctors and managers: radical thinking required. PMID- 20929887 TI - Acupuncture - a treatment to die for? PMID- 20929888 TI - Pandemic H1N1 influenza at the 2009 Hajj: understanding the unexpectedly low H1N1 burden. PMID- 20929889 TI - The need for an NHS Staff College. PMID- 20929890 TI - British psychiatry and its discontents. AB - Psychiatry in the UK is currently faced with serious difficulties arising from failure in recruiting British doctors and a high rate of early retirement from the specialty. To diagnose the underlying causes, account must be taken of government policies affecting the NHS in general and mental health services in particular. The latter include an excessive run-down of acute hospital beds, as well as projects aimed at changing the clinical role of psychiatrists and promoting mass treatment of milder mental disorders by non-medical personnel. Psychiatrists have reacted to these developments with anger and dismay, but have as yet reached no consensus with regard to either causal factors or appropriate response. Their uncertainty reflects the need for a firmer grasp of the historical background. Modern British psychiatry was effectively created and moulded as an integral part of the NHS. It flourished as long as the public service framework remained intact, but has suffered a decline since the whole structure began to buckle under the pressure of sustained political assaults. A clearer understanding of this vital connection would help to raise psychiatrists' morale and encourage them to establish common ground with medical colleagues and other healthcare professionals. PMID- 20929892 TI - An epidemiologist's journey from typhus to thalidomide, and from the Soviet Union to Seveso. PMID- 20929891 TI - The effect on mortality of antipyretics in the treatment of influenza infection: systematic review and meta-analysis. AB - OBJECTIVE: To determine whether antipyretic treatment for influenza infection influences the risk of mortality in animal models and humans. DESIGN: A systematic search of Medline, Embase and the Cochrane Register of Controlled Trials was undertaken to identify randomized placebo-controlled trials of antipyretic use in influenza infection in animal models or humans that reported mortality. A quantitative meta-analysis of the risk of death using Peto's one step odds ratio with calculation of the pooled risk of death and standard evaluation of heterogeneity was undertaken. SETTING: Not applicable. PARTICIPANTS: Not applicable. MAIN OUTCOME MEASURES: Risk of mortality associated with antipyretic use in influenza infection. RESULTS: Eight studies from three publications met the inclusion criteria. No human studies were identified. The risk of mortality was increased by antipyretic use in influenza-infected animals with a fixed effects pooled odds ratio of 1.34 (95% CI 1.04-1.73). An increased risk was observed with aspirin, paracetamol and diclofenac. CONCLUSION: In animal models, treatment with antipyretics for influenza infection increases the risk of mortality. There are no randomized placebo-controlled trials of antipyretic use in influenza infection in humans that reported data on mortality and a paucity of clinical data by which to assess their efficacy. We suggest that randomized placebo-controlled trials of antipyretic use in human influenza infection are urgently required, and that these are sufficiently powered to investigate a potential effect on mortality. PMID- 20929893 TI - Scarless surgery: a warning for shortcut history-taking. PMID- 20929895 TI - A comparative analysis of leaf shape of wheat, barley and maize using an empirical shape model. AB - BACKGROUND AND AIMS: The phenotypes of grasses show differences depending on growth conditions and ontogenetic stage. Understanding these responses and finding suitable mathematical formalizations are an essential part of the development of plant and crop models. Usually, a marked change in architecture between juvenile and adult plants is observed, where dimension and shape of leaves are likely to change. In this paper, the plasticity of leaf shape is analysed according to growth conditions and ontogeny. METHODS: Leaf shape of Triticum aestivum, Hordeum vulgare and Zea mays cultivars grown under varying conditions was measured using digital image processing. An empirical leaf shape model was fitted to measured shape data of single leaves. Obtained values of model parameters were used to analyse the patterns in leaf shape. KEY RESULTS: The model was able to delineate leaf shape of all studied species. The model error was small. Differences in leaf shape between juvenile and adult leaves in T. aestivum and H. vulgare were observed. Varying growth conditions impacted leaf dimensions but did not impact leaf shape of the respective species. CONCLUSIONS: Leaf shape of the studied T. aestivum and H. vulgare cultivars was remarkably stable for a comparable ontogenetic stage (leaf rank), but differed between stages. Along with other aspects of grass architecture, leaf shape changed during the transition from juvenile to adult growth phase. Model-based analysis of leaf shape is a method to investigate these differences. Presented results can be integrated into architectural models of plant development to delineate leaf shape for different species, cultivars and environmental conditions. PMID- 20929896 TI - Massively parallel sequencing and analysis of expressed sequence tags in a successful invasive plant. AB - BACKGROUND: Invasive species pose a significant threat to global economies, agriculture and biodiversity. Despite progress towards understanding the ecological factors associated with plant invasions, limited genomic resources have made it difficult to elucidate the evolutionary and genetic factors responsible for invasiveness. This study presents the first expressed sequence tag (EST) collection for Senecio madagascariensis, a globally invasive plant species. METHODS: We used pyrosequencing of one normalized and two subtractive libraries, derived from one native and one invasive population, to generate an EST collection. ESTs were assembled into contigs, annotated by BLAST comparison with the NCBI non-redundant protein database and assigned gene ontology (GO) terms from the Plant GO Slim ontologies. KEY RESULTS: Assembly of the 221,746 sequence reads resulted in 12,442 contigs. Over 50 % (6183) of 12,442 contigs showed significant homology to proteins in the NCBI database, representing approx. 4800 independent transcripts. The molecular transducer GO term was significantly over-represented in the native (South African) subtractive library compared with the invasive (Australian) library. Based on NCBI BLAST hits and literature searches, 40 % of the molecular transducer genes identified in the South African subtractive library are likely to be involved in response to biotic stimuli, such as fungal, bacterial and viral pathogens. CONCLUSIONS: This EST collection is the first representation of the S. madagascariensis transcriptome and provides an important resource for the discovery of candidate genes associated with plant invasiveness. The over-representation of molecular transducer genes associated with defence responses in the native subtractive library provides preliminary support for aspects of the enemy release and evolution of increased competitive ability hypotheses in this successful invasive. This study highlights the contribution of next-generation sequencing to better understanding the molecular mechanisms underlying ecological hypotheses that are important in successful plant invasions. PMID- 20929897 TI - Auxin transport in maize roots in response to localized nitrate supply. AB - background and aims: Roots typically respond to localized nitrate by enhancing lateral-root growth. Polar auxin transport has important roles in lateral-root formation and growth; however, it is a matter of debate whether or how auxin plays a role in the localized response of lateral roots to nitrate. METHODS: Treating maize (Zea mays) in a split-root system, auxin levels were quantified directly and polar transport was assayed by the movement of [(3)H]IAA. The effects of exogenous auxin and polar auxin transport inhibitors were also examined. KEY RESULTS: Auxin levels in roots decreased more in the nitrate-fed compartment than in the nitrate-free compartment and nitrate treatment appeared to inhibit shoot-to-root auxin transport. However, exogenous application of IAA only partially reduced the stimulatory effect of localized nitrate, and auxin level in the roots was similarly reduced by local applications of ammonium that did not stimulate lateral-root growth. CONCLUSIONS: It is concluded that local applications of nitrate reduced shoot-to-root auxin transport and decreased auxin concentration in roots to a level more suitable for lateral-root growth. However, alteration of root auxin level alone is not sufficient to stimulate lateral-root growth. PMID- 20929898 TI - The effects of salinity and osmotic stress on barley germination rate: sodium as an osmotic regulator. AB - BACKGROUND AND AIMS: Seed germination is negatively affected by salinity, which is thought to be due to both osmotic and ion-toxicity effects. We hypothesize that salt is absorbed by seeds, allowing them to generate additional osmotic potential, and to germinate in conditions under which they would otherwise not be able to germinate. METHODS: Seeds of barley, Hordeum vulgare, were germinated in the presence of either pure water or one of five iso-osmotic solutions of polyethylene-glycol (PEG) or NaCl at 5, 12, 20 or 27 degrees C. Germination time courses were recorded and germination indices were calculated. Dry mass, water content and sodium concentration of germinating and non-germinating seeds in the NaCl treatments at 12 degrees C were measured. Fifty supplemental seeds were used to evaluate the changes in seed properties with time. KEY RESULTS: Seeds incubated in saline conditions were able to germinate at lower osmotic potentials than those incubated in iso-osmotic PEG solutions and generally germinated faster. A positive correlation existed between external salinity and seed salt content in the saline-incubated seeds. Water content and sodium concentration increased with time for seeds incubated in NaCl. At higher temperatures, germination percentage and dry mass decreased whereas germination index and sodium concentration increased. CONCLUSIONS: The results suggest that barley seeds can take up sodium, allowing them to generate additional osmotic potential, absorb more water and germinate more rapidly in environments of lower water potential. This may have ecological implications, allowing halophytic species and varieties to out-compete glycophytes in saline soils. PMID- 20929899 TI - The infection processes of Sclerotinia sclerotiorum in cotyledon tissue of a resistant and a susceptible genotype of Brassica napus. AB - BACKGROUND AND AIMS: Sclerotinia sclerotiorum can attack >400 plant species worldwide. Very few studies have investigated host-pathogen interactions at the plant surface and cellular level in resistant genotypes of oilseed rape/canola (Brassica napus). METHODS: Infection processes of S. sclerotiorum were examined on two B. napus genotypes, one resistant cultivar 'Charlton' and one susceptible 'RQ001-02M2' by light and scanning electron microscopy from 2 h to 8 d post inoculation (dpi). KEY RESULTS: The resistant 'Charlton' impeded fungal growth at 1, 2 and 3 dpi, suppressed formation of appresoria and infection cushions, caused extrusion of protoplast from hyphal cells and produced a hypersensitive reaction. At 8 dpi, whilst in 'Charlton' pathogen invasion was mainly confined to the upper epidermis, in the susceptible 'RQ001-02M2', colonization up to the spongy mesophyll cells was evident. Calcium oxalate crystals were found in the upper epidermis and in palisade cells in susceptible 'RQ001-02M2' at 6 dpi, and throughout leaf tissues at 8 dpi. In resistant 'Charlton', crystals were not observed at 6 dpi, whereas at 8 dpi they were mainly confined to the upper epidermis. Starch deposits were also more prevalent in 'RQ001-02M2'. CONCLUSIONS: This study demonstrates for the first time at the cellular level that resistance to S. sclerotiorum in B. napus is a result of retardation of pathogen development, both on the plant surface and within host tissues. The resistance mechanisms identified in this study will be useful for engineering disease resistant genotypes and for developing markers for screening for resistance against this pathogen. PMID- 20929900 TI - Molecular phylogenetics of Ruscaceae sensu lato and related families (Asparagales) based on plastid and nuclear DNA sequences. AB - BACKGROUND: Previous phylogenetics studies of Asparagales, although extensive and generally well supported, have left several sets of taxa unclearly placed and have not addressed all relationships within certain clades thoroughly (some clades were relatively sparsely sampled). One of the most important of these is sampling within and placement of Nolinoideae (Ruscaceae s.l.) of Asparagaceae sensu Angiosperm Phylogeny Group (APG) III, which subfamily includes taxa previously referred to Convallariaceae, Dracaenaaceae, Eriospermaceae, Nolinaceae and Ruscaceae. METHODS: A phylogenetic analysis of a combined data set for 126 taxa of Ruscaceae s.l. and related groups in Asparagales based on three nuclear and plastid DNA coding genes, 18S rDNA (1796 bp), rbcL (1338 bp) and matK (1668 bp), representing a total of approx. 4.8 kb is presented. Parsimony and Bayesian inference analyses were conducted to elucidate relationships of Ruscaceae s.l. and related groups, and parsimony bootstrap analysis was performed to assess support of clades. KEY RESULTS: The combination of the three genes results in the most highly resolved and strongly supported topology yet obtained for Asparagales including Ruscaceae s.l. Asparagales relationships are nearly congruent with previous combined gene analyses, which were reflected in the APG III classification. Parsimony and Bayesian analyses yield identical relationships except for some slight variation among the core asparagoid families, which nevertheless form a strongly supported group in both types of analyses. In core asparagoids, five major clades are identified: (1) Alliaceae s.l. (sensu APG III, Amarylidaceae-Agapanthaceae-Alliaceae); (2) Asparagaceae-Laxmanniaceae-Ruscaceae s.l.; (3) Themidaceae; (4) Hyacinthaceae; (5) Anemarrhenaceae-Behniaceae Herreriaceae-Agavaceae (clades 2-5 collectively Asparagaceae s.l. sensu APG III). The position of Aphyllanthes is labile, but it is sister to Themidaceae in the combined maximum-parsimony tree and sister to Anemarrhenaceae in the Bayesian analysis. The highly supported clade of Xanthorrhoeaceae s.l. (sensu APG III, including Asphodelaceae and Hemerocallidaceae) is sister to the core asparagoids. Ruscaceae s.l. are a well-supported group. Asparagaceae s.s. are sister to Ruscaceae s.l., even though the clade of the two families is weakly supported; Laxmanniaceae are strongly supported as sister to Ruscaceae s.l. and Asparagaceae. Ruscaceae s.l. include six principal clades that often reflect previously named groups: (1) tribe Polygonateae (excluding Disporopsis); (2) tribe Ophiopogoneae; (3) tribe Convallarieae (excluding Theropogon); (4) Ruscaceae s.s. + Dracaenaceae + Theropogon + Disporopsis + Comospermum; (5) Nolinaceae, (6) Eriospermum. CONCLUSIONS: The analyses here were largely conducted with new data collected for the same loci as in previous studies, but in this case from different species/DNA accessions and greater sampling in many cases than in previously published analyses; nonetheless, the results largely mirror those of previously conducted studies. This demonstrates the robustness of these results and answers questions often raised about reproducibility of DNA results, given the often sparse sampling of taxa in some studies, particularly the earliest ones. The results also provide a clear set of patterns on which to base a new classification of the subfamilies of Asparagaceae s.l., particularly Ruscaceae s.l. (= Nolinoideae of Asparagaceae s.l.), and examine other putatively important characters of Asparagales. PMID- 20929903 TI - Cycling for transport and public health: a systematic review of the effect of the environment on cycling. AB - BACKGROUND: Active transport policies are being developed across Europe designed to have health and environmental benefits. There is little evidence of impact on physical activity of active transport strategies which modify the built environment. Cycling represents one virtually carbon-neutral form of transport that can help to address declining levels of exercise. METHODS: A systematic literature review of experimental or observational studies that objectively evaluated the effect of the built environment on cycling. RESULTS: A total of 21 studies met the inclusion criteria, all of which were observational studies. Eleven studies identified objectively measured environmental factors with a significant positive association with cycling. The environmental factors identified as being positively associated with cycling included presence of dedicated cycle routes or paths, separation of cycling from other traffic, high population density, short trip distance, proximity of a cycle path or green space and for children projects promoting 'safe routes to school'. Negative environmental factors were perceived and objective traffic danger, long trip distance, steep inclines and distance from cycle paths. Of the seven studies which focused primarily on the impact of cycle routes, four demonstrated a statistically significant positive association. CONCLUSION: Although the study identified environmental factors with positive and negative associations with cycling behaviour, many other types of environmental policies and interventions have yet to be rigorously evaluated. Policies promoting cycle lane construction appear promising but the socio-demographic distribution of their effects on physical activity is unclear. The wider impact of active transport policies on health and inequalities across Europe must be explored. PMID- 20929904 TI - Direct health costs of environmental tobacco smoke exposure and indirect health benefits due to smoking ban introduction. AB - BACKGROUND: Introducing comprehensive smoke-free policies to public places is expected to reduce health costs. This includes prevented health damages by avoiding environmental tobacco smoke (ETS) exposure as well as indirect health benefits from reduced tobacco consumption. METHODS: The aim of this study was to estimate direct health costs of ETS exposure in public places and indirect health benefits from reduced tobacco consumption. We calculated attributable hospital days and years of life lost (YLL), based on the observed passive smoking and disease rates in Switzerland. The exposure-response associations of all relevant health outcomes were derived by meta-analysis from prospective cohort studies in order to calculate the direct health costs. To assess the indirect health benefits, a meta-analysis of smoking ban studies on hospital admissions for acute myocardial infarction was conducted. RESULTS: ETS exposure in public places in Switzerland causes 32,000 preventable hospital days (95% CI: 10,000-61,000), 3000 YLL (95% CI: 1000-5000), corresponding to health costs of 330 Mio CHF. The number of hospital days for ischaemic heart disease attributable to passive smoking is much larger if derived from smoking ban studies (41,000) than from prospective cohort studies (3200), resulting in additional health costs of 89 Mio CHF, which are attributed to the indirect health benefits of a smoking ban introduction. CONCLUSION: The example of smoking ban studies on ischaemic heart disease hospitalization rates suggests that total health costs that can be prevented with smoking bans are considerably larger than the costs arising from the direct health impact of ETS exposure in public places. PMID- 20929905 TI - Education in child neurology: the role of the International Child Neurology Association (ICNA). AB - Recent progress in pediatric neurosciences has greatly increased the divide between the possibilities for diagnosis and intervention among developed countries and resource-poor countries, where child neurologists suffer from the lack of adequate training, the absence of a network with professionals around the world, and the shortage of infrastructure. The International Child Neurology Association (ICNA) is the only child neurology association that can deal with these important issues and promote the reduction of this gap. In this article, the author reviews the role played by ICNA in the past 2 decades in supporting education worldwide, in offering teaching seminars and visits by senior members, and in addressing the needs of the global community of child neurologists. The challenges and success of ICNA in the promotion of educational resources and recommendations for the future are discussed. PMID- 20929901 TI - Prospective analysis of DNA damage and repair markers of lung cancer risk from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. AB - Mutagen challenge and DNA repair assays have been used in case-control studies for nearly three decades to assess human cancer risk. The findings still engender controversy because blood was drawn after cancer diagnosis so the results may be biased, a type called 'reverse causation'. We therefore used Epstein-Barr virus transformed lymphoblastoid cell lines established from prospectively collected peripheral blood samples to evaluate lung cancer risk in relation to three DNA repair assays: alkaline Comet assay, host cell reactivation (HCR) assay with the mutagen benzo[a]pyrene diol epoxide and the bleomycin mutagen sensitivity assay. Cases (n = 117) were diagnosed with lung cancer between 0.3 and 6 years after blood collection and controls (n = 117) were frequency matched on calendar year and age at blood collection, gender and smoking history; all races were included. Case and control status was unknown to laboratory investigators. In unconditional logistic regression analyses, statistically significantly increased lung cancer odds ratios (OR(adjusted)) were observed for bleomycin mutagen sensitivity as quartiles of chromatid breaks/cell [relative to the lowest quartile, OR = 1.2, 95% confidence interval (CI): 0.5-2.5; OR = 1.4, 95% CI: 0.7-3.1; OR = 2.1, 95% CI: 1.0-4.4, respectively, P(trend) = 0.04]. The magnitude of the association between the bleomycin assay and lung cancer risk was modest compared with those reported in previous lung cancer studies but was strengthened when we included only incident cases diagnosed more than a year after blood collection (P(trend) = 0.02), supporting the notion the assay may be a measure of cancer susceptibility. The Comet and HCR assays were unrelated to lung cancer risk. PMID- 20929906 TI - Evaluation of white matter changes in agyria-pachygyria complex using diffusion tensor imaging. AB - Associated abnormalities of the white matter in patients with agyria-pachygyria complex have rarely been investigated using new imaging modalities like diffusion tensor imaging. The present study evaluated the white matter changes of 9 children with agyria-pachygyria complex using diffusion tensor imaging. Regions of interest were placed in 17 white matter tracts. Compared with normal controls, the axial diffusivity of the genu of the corpus callosum, corticospinal tract, and fornix in patients with agyria-pachygyria complex was decreased. In the subcortical white matter without changes in T2-weighted image, there were significant decreases in fractional anisotropy and axial diffusivity and increases in radial diffusivity, indicating significant alterations of the white matter. Since axial diffusivity and radial diffusivity reflect changes in the axon and myelin, respectively, the findings here indicate disturbance in both axonal and myelin development in agyria-pachygyria complex. PMID- 20929907 TI - Risperidone use in autism spectrum disorders: a retrospective review of a clinic referred patient population. AB - Risperidone is widely used in children with autism spectrum disorders for behavioral modification. In this study, the authors aimed to (1) describe a clinic-referred sample of patients with an autism spectrum disorder on risperidone, (2) identify differences between the success and nonsuccess groups, and (3) describe our experience with young children (< age 5 years) on risperidone. Eighty patients were initiated on risperidone. Indications included aggression (66%), impulsivity (14%), and stereotypies (4%). Sixty-six percent met criteria for success at 6 months and 53% at 1 year. Sixty-seven percent of the nonsuccess group reported side effects, compared to 47% of the success group. Weight gain was the most common side effect in both groups, followed by somnolence. Somnolence was the most robust predictor of nonsuccess. In our clinic referred sample, the short-term success rate of risperidone was more than 50%, and side effects limited its use. Although weight gain was common, somnolence more significantly influenced treatment discontinuation. PMID- 20929909 TI - Botulinum toxin a injections to the upper limbs in children with cerebral palsy: duration of effect. AB - We report our experience on the duration of effectiveness of botulinum toxin A injections to the upper extremities of children with cerebral palsy. A retrospective chart review was conducted on 30 consecutive patients (mean age, 9.9 +/- 5.0 years) with spastic hemiparesis and quadriparesis. They received 1 to 5 treatments, totaling 56 treatments for the entire cohort. The injected muscles were the pronator teres (50/56), flexor carpi radialis (39/56), biceps (38/56), flexor carpi ulnaris (35/56), opponens (21/56), and adductor pollicis (17/56). Children were assessed for muscle tone and classified according to the Manual Ability Classification System before and after treatment. Functional improvement was apparent after 42 of 56 treatments, and muscle tone decreased significantly (P < .001). The mean duration of the effect was 7.0 +/- 3.0 months. We conclude that the effect of botulinum toxin A to the upper limbs is retained for longer periods of time than those reported for lower limbs. PMID- 20929908 TI - Muscle volume estimation by magnetic resonance imaging in spinal muscular atrophy. AB - Thigh muscle volume was assessed using magnetic resonance imaging in 16 subjects with spinal muscular atrophy. Scans were successful for 14 of 16 subjects (1 type 1, 6 type 2, and 7 type 3) as young as 5.7 years. Muscle volume with normal and abnormal signal was measured using blinded, semiautomated analysis of reconstructed data. Results were compared with segmental lean mass estimated by dual-energy X-ray absorptiometry and correlated with clinical and electrophysiological measures of disease severity. Muscle volume was reduced with abnormal signal quality. Test-retest reliability (r = .99) and correlation with dual-energy X-ray absorptiometry (r = .91) were excellent. Type 2 subjects had lower volume (3.5 +/- 1.6 vs 6.3 +/- 2.8 mL/cm height; P = .06) and higher percentage of muscle with abnormal signal (68% +/- 20% vs 47% +/- 27%; P = .14) than type 3. Reproducibility, tolerability, and strong correlation with clinical measures make magnetic resonance imaging a candidate biomarker for clinical research. PMID- 20929910 TI - Body mass index of children with attention-deficit/hyperactivity disorder. AB - An association between overweight and attention-deficit/hyperactivity disorder (ADHD) in children was previously suggested. We examined the prevalence of overweight, anthropometric changes, and the effect of methylphenidate treatment in 275 children with ADHD without neurological comorbidities and in controls. Data were extracted from medical charts, for up to 17 months of follow-up. Height, weight, body mass index, and their z scores did not differ between the ADHD and control groups. Prevalence of overweight and obesity was lower in the ADHD group compared with controls (19% vs 35%, P = .02, and 7% vs 16%, P = .05, respectively). During a follow-up of up to 17 months, no significant changes in height or body mass index z scores were found, including in a subgroup of overweight children. We conclude that compared with local controls, children with ADHD have rates of overweight and obesity that are lower, but that are similar to national estimates. Methylphenidate treatment did not significantly affect height, weight, or overweight status. PMID- 20929911 TI - PyETV: a PyMOL evolutionary trace viewer to analyze functional site predictions in protein complexes. AB - SUMMARY: PyETV is a PyMOL plugin for viewing, analyzing and manipulating predictions of evolutionarily important residues and sites in protein structures and their complexes. It seamlessly captures the output of the Evolutionary Trace server, namely ranked importance of residues, for multiple chains of a complex. It then yields a high resolution graphical interface showing their distribution and clustering throughout a quaternary structure, including at interfaces. Together with other tools in the popular PyMOL viewer, PyETV thus provides a novel tool to integrate evolutionary forces into the design of experiments targeting the most functionally relevant sites of a protein. AVAILABILITY: The PyETV module is written in Python. Installation instructions and video demonstrations may be found at the URL http://mammoth.bcm.tmc.edu/traceview/HelpDocs/PyETVHelp/pyInstructions.html. CONTACT: lichtarge@bcm.tmc.edu. PMID- 20929912 TI - Pathway Activity Profiling (PAPi): from the metabolite profile to the metabolic pathway activity. AB - MOTIVATION: Metabolomics is one of the most recent omics-technologies and uses robust analytical techniques to screen low molecular mass metabolites in biological samples. It has evolved very quickly during the last decade. However, metabolomics datasets are considered highly complex when used to relate metabolite levels to metabolic pathway activity. Despite recent developments in bioinformatics, which have improved the quality of metabolomics data, there is still no straightforward method capable of correlating metabolite level to the activity of different metabolic pathways operating within the cells. Thus, this kind of analysis still depends on extremely laborious and time-consuming processes. RESULTS: Here, we present a new algorithm Pathway Activity Profiling (PAPi) with which we are able to compare metabolic pathway activities from metabolite profiles. The applicability and potential of PAPi was demonstrated using a previously published data from the yeast Saccharomyces cerevisiae. PAPi was able to support the biological interpretations of the previously published observations and, in addition, generated new hypotheses in a straightforward manner. However, PAPi is time consuming to perform manually. Thus, we also present here a new R-software package (PAPi) which implements the PAPi algorithm and facilitates its usage to quickly compare metabolic pathways activities between different experimental conditions. Using the identified metabolites and their respective abundances as input, the PAPi package calculates pathways' Activity Scores, which represents the potential metabolic pathways activities and allows their comparison between conditions. PAPi also performs principal components analysis and analysis of variance or t-test to investigate differences in activity level between experimental conditions. In addition, PAPi generates comparative graphs highlighting up- and down-regulated pathway activity. AVAILABILITY: These datasets are available in http://www.4shared.com/file/hTWyndYU/extra.html and http://www.4shared.com/file/VbQIIDeu/intra.html. PAPi package is available in: http://www.4shared.com/file/s0uIYWIg/PAPi_10.html CONTACT: s.villas boas@auckland.ac.nz SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 20929913 TI - R3D Align: global pairwise alignment of RNA 3D structures using local superpositions. AB - MOTIVATION: Comparing 3D structures of homologous RNA molecules yields information about sequence and structural variability. To compare large RNA 3D structures, accurate automatic comparison tools are needed. In this article, we introduce a new algorithm and web server to align large homologous RNA structures nucleotide by nucleotide using local superpositions that accommodate the flexibility of RNA molecules. Local alignments are merged to form a global alignment by employing a maximum clique algorithm on a specially defined graph that we call the 'local alignment' graph. RESULTS: The algorithm is implemented in a program suite and web server called 'R3D Align'. The R3D Align alignment of homologous 3D structures of 5S, 16S and 23S rRNA was compared to a high-quality hand alignment. A full comparison of the 16S alignment with the other state-of the-art methods is also provided. The R3D Align program suite includes new diagnostic tools for the structural evaluation of RNA alignments. The R3D Align alignments were compared to those produced by other programs and were found to be the most accurate, in comparison with a high quality hand-crafted alignment and in conjunction with a series of other diagnostics presented. The number of aligned base pairs as well as measures of geometric similarity are used to evaluate the accuracy of the alignments. AVAILABILITY: R3D Align is freely available through a web server http://rna.bgsu.edu/R3DAlign. The MATLAB source code of the program suite is also freely available for download at that location. PMID- 20929914 TI - Cloning and characterization of a new polyol transporter (HbPLT2) in Hevea brasiliensis. AB - Quebrachitol is a cyclic polyol and, along with sucrose, is one of the main sugars in Hevea latex. However, in contrast to sucrose, the mechanism and regulation of quebrachitol absorption is still unknown. Screening a latex-derived cDNA library using polyol transporter-specific probes, two full-length cDNAs were isolated, and named HbPLT1 and HbPLT2 (for Hevea brasiliensis polyol transporter 1 and 2, respectively). Their respective sequences exhibited close similarity with the previously cloned acyclic sugar polyol transporters, and shared the main features of the major facilitative superfamily. The functional activity of one of the cDNAs was determined by using an HbPLT2-complemented yeast strain. These strains displayed a marginal absorption of cyclic (inositol) and acyclic (mannitol and sorbitol) polyol but no absorption of sucrose, hexose and glycerol. Active absorption for xylitol was detected, and was competitively inhibited by quebrachitol. HbPLT1 and HbPLT2 expression patterns varied in response to different stimuli. Bark treatment with ethylene resulted in an early and significant up-regulation of HbPLT2 transcripts in laticifers as well as in inner bark cells, when compared with HbPLT1. Other treatments, especially mechanical wounding, strongly induced HbPLT2 transcripts. These data were consistent with the presence of ethylene and a wound-responsive regulatory cis-element on the sequence of the HbPLT2 promoter. All these findings together with those recently obtained for sucrose transporters and aquaporins are discussed in relation to the different roles for quebrachitol in Hevea brasiliensis. PMID- 20929915 TI - A randomized controlled trial comparing intravenous ferric carboxymaltose with oral iron for treatment of iron deficiency anaemia of non-dialysis-dependent chronic kidney disease patients. AB - BACKGROUND: Iron deficiency is a common cause of anaemia and hyporesponsiveness to erythropoiesis-stimulating agents (ESAs) in non-dialysis-dependent chronic kidney disease (ND-CKD) patients. Current intravenous iron agents cannot be administered in a single high dose because of adverse effects. Ferric carboxymaltose, a non-dextran parenteral iron preparation, can be rapidly administered in high doses. METHODS: This open-label trial randomized 255 subjects with glomerular filtration rates <= 45 mL/min/1.73 m(2), haemoglobin <= 11 g/dL, transferrin saturation <= 25%, ferritin <= 300 ng/mL, and stable ESA dose to either intravenous ferric carboxymaltose 1000 mg over 15 min (with up to two additional doses of 500 mg at 2-week intervals) or oral ferrous sulphate 325 mg thrice daily for a total of 195 mg elemental iron daily for 56 days. RESULTS: In the modified intent-to-treat population, the proportion of subjects achieving a haemoglobin increase >= 1 g/dL at any time was 60.4% with ferric carboxymaltose and 34.7% with oral iron (P < 0.001). At Day 42, mean increase in haemoglobin was 0.95 +/- 1.12 vs 0.50 +/- 1.23 g/dL (P = 0.005), mean increase in ferritin was 432 +/- 189 ng/mL vs 18 +/- 45 ng/mL (P < 0.001) and mean increase in transferrin saturation was 13.6 +/- 11.9% vs 6.1 +/- 8.1% (P < 0.001). Treatment-related adverse events were significantly fewer with ferric carboxymaltose than with oral iron (2.7% and 26.2%, respectively; P < 0.0001). CONCLUSIONS: We conclude that 1000 mg ferric carboxymaltose can be rapidly administered, is more effective and is better tolerated than oral iron for treatment of iron deficiency in ND-CKD patients. PMID- 20929916 TI - Effects of synbiotic treatment on serum level of p-cresol in haemodialysis patients: a preliminary study. AB - BACKGROUND: para-Cresol, which is present in the blood mainly as p-cresyl sulphate, is a protein-bound uraemic toxin that is produced in the intestine by certain intestinal bacteria, and its production is affected by various intestinal environmental factors. Patients with end-stage renal disease who are undergoing haemodialysis (HD) often have defective bowel function leading to abnormal defecation. Since treatment with synbiotics (SYN), which are a combination of probiotics and prebiotics, is reported to improve bowel habit, we examined the effects of SYN on the serum p-cresol level in HD patients. METHODS: Nine HD patients received SYN (Lactobacillus casei strain Shirota and Bifidobacterium breve strain Yakult as probiotics and galacto-oligosaccharides as prebiotics) three times a day for 2 weeks. The duration of the study was 4 weeks (2 weeks of pretreatment observation and 2 weeks of treatment). The subjects were asked to complete a questionnaire about their bowel habits (defecation frequency, stool quantity, stool form and ease of defecation) during the study period. Serum p cresol levels before and after SYN treatment were determined. RESULTS: According to the questionnaire conducted during the pretreatment observation period, HD patients with a high serum p-cresol level tended to have hard stools with difficulty in defecation. With SYN treatment, stool quantity increased significantly and hard, muddy or soft stools tended to be replaced by normal ones. The serum p-cresol level also decreased significantly. CONCLUSIONS: It was found that uraemic toxin, p-cresol, was associated with constipation and that SYN treatment resulted in normalization of bowel habits and a decrease of serum p cresol levels in HD patients. Therefore, SYN treatment may be anticipated to reduce the toxic effect of p-cresol in HD patients. PMID- 20929917 TI - Countries should consider legalising cannabis in light of futility of bans. PMID- 20929918 TI - Prohibition of cannabis. PMID- 20929919 TI - Most OECD countries could save money by improving clinical guidelines and negotiating better drug prices. PMID- 20929921 TI - Apgar score and risk of cerebral palsy. PMID- 20929920 TI - Association of cerebral palsy with Apgar score in low and normal birthweight infants: population based cohort study. AB - OBJECTIVES: To assess the association of Apgar score 5 minutes after birth with cerebral palsy in both normal weight and low birthweight children, and also the association with the cerebral palsy subdiagnoses of quadriplegia, diplegia, and hemiplegia. DESIGN: Population based cohort study. SETTING: The Medical Birth Registry of Norway was used to identify all babies born between 1986 and 1995. These data were linked to the Norwegian Registry of Cerebral Palsy in Children born 1986-95, which was established on the basis of discharge diagnoses at all paediatric departments in Norway. POPULATION: All singletons without malformations born in Norway during 1986-95 and who survived the first year of life (n=543 064). MAIN OUTCOME MEASURE: Cerebral palsy diagnosed before the age of 5 years. RESULTS: 988 children (1.8 in 1000) were diagnosed with cerebral palsy before the age of 5 years. In total, 11% (39/369) of the children with Apgar score of less than 3 at birth were diagnosed with cerebral palsy, compared with only 0.1% (162/179 515) of the children with Apgar score of 10 (odds ratio (OR) 53, 95% CI 35 to 80 after adjustment for birth weight). In children with a birth weight of 2500 g or more, those with an Apgar score of less than 4 were much more likely to have cerebral palsy than those who had an Apgar score of more than 8 (OR 125, 95% confidence interval 91 to 170). The corresponding OR in children weighing less than 1500 g was 5 (95% CI 2 to 9). Among children with Apgar score of less than 4, 10-17% in all birthweight groups developed cerebral palsy. Low Apgar score was strongly associated with each of the three subgroups of spastic cerebral palsy, although the association was strongest for quadriplegia (adjusted OR 137 for Apgar score <4 v Apgar score >8, 95% CI 77 to 244). CONCLUSIONS: Low Apgar score was strongly associated with cerebral palsy. This association was high in children with normal birth weight and modest in children with low birth weight. The strength of the association differed between subgroups of spastic cerebral palsy. Given that Apgar score is a measure of vitality shortly after birth, our findings suggest that the causes of cerebral palsy are closely linked to factors that reduce infant vitality. PMID- 20929922 TI - Psychiatrists are concerned by rise in patients subject to compulsory mental health treatment. PMID- 20929924 TI - Asc1, a WD-repeat protein, is required for hyphal development and virulence in Candida albicans. AB - Candida albicans is a human pathogenic fungus which can undergo a morphological transition from yeast to hyphae in response to a variety of environmental stimuli. We analyzed a C. albicans Asc1 (Absence of growth Suppressor of Cyp1) protein which is entirely composed of seven repeats of the WD domain, and is conserved from fungi to metazoan. Deleting the ASC1 in C. albicans led to a profound defect in hyphal development under hypha-inducing conditions examined. Furthermore, deletion of the ASC1 attenuated virulence of C. albicans in a mouse model of systemic infection. These data strongly suggested that the conserved WD repeat protein Asc1 is required for morphogenesis and pathogenesis of C. albicans. PMID- 20929925 TI - Copy number increase of aurora kinase A in colorectal cancers: a correlation with tumor progression. AB - The centrosome-associated kinase aurora A (AURKA) is involved in genetic instability and is over-expressed in several human carcinomas including colorectal cancer (CRC). The choromosome locus of AURKA, 20q13, is frequently amplified in CRC, and the functional impact of such regions needs to be extensively investigated in large amount of clinical samples. Case-matched tissues of colorectal adenocarcinomas and adjacent normal epithelium (n= 134) were included in this study. Quantitative PCR was carried out to examine the copy number and mRNA level of AURKA in CRC. Our results showed that copy number gains of AUKRA were detected in a relative high percentage of CRC samples (32.4%, 43 of 134). There was a positive correlation between copy number increase of AURKA and tumor progression. And copy number gains of AURKA also showed a positive correlation with mRNA over-expression in CRC. However, the expression level of AURKA mRNA was also enhanced in the group of CRC samples with unaltered copy numbers. These findings indicated that sporadic colorectal cancers exhibit different mechanisms of aurora A regulation and this may impact the efficacy of aurora-targeted therapies. PMID- 20929926 TI - Electrical stimulation inhibits neointimal hyperplasia after abdominal aorta balloon injury through the PTEN/p27Kip1 pathway. AB - Electric fields (EFs) exert biological effects on promoting wound healing by facilitating cell division, cell proliferation, and cell directional migration toward the wound. In this study, we examined the inhibitory effect of direct current (DC) EFs on the formation of neointimal hyperplasia and the possible mechanism in an abdominal aorta balloon injury rabbit model. Sixty rabbits were divided into normal, control, and experimental groups. After establishment of the abdominal aorta balloon injury model, electrodes were implanted into the bilateral psoas major muscle in control and experimental groups. Only the experimental group received electric stimulation (EFs applied at 3 or 4 V/cm for 30 min/day) for 1, 2, and 4 weeks, respectively. Neointimal hyperplasia of the abdominal aorta and proliferation of vascular smooth muscle cells (VSMCs) were measured. Expressions of collagen, p27(Kip1), and phosphatase and tensin homolog deleted on chromosome 10 (PTEN) were detected. Results showed that the ratio of the tunica intima area to the tunica media area, the expression of type-I collagen in the neointimal, and the proliferating cell nuclear antigen index in experimental groups were significantly less than those in control groups 2 weeks post-operation (P< 0.01). Expressions of p27(Kip1) and PTEN were increased in experimental groups compared with control groups (P< 0.01). In conclusion, our results suggested that the application of DC EFs could inhibit neointimal hyperplasia and reduce collagen expression after abdominal aorta balloon injury. This was probably induced by upregulation of PTEN/p27(Kip1) expression, thereby inhibiting VSMC proliferation. PMID- 20929927 TI - Zinc induces unfolding and aggregation of dimeric arginine kinase by trapping reversible unfolding intermediate. AB - Arginine kinase plays an important role in the cellular energy metabolism of invertebrates. Dimeric arginine kinase (dAK) is unique in some marine invertebrates. The effects of Zn2(+) on the unfolding and aggregation of dAK from the sea cucumber Stichopus japonicus were investigated. Our results indicated that Zn2(+) caused dAK inactivation accompanied by conformational unfolding, the exposure of hydrophobic surface, and aggregation. Kinetic studies showed the inactivation and unfolding of dAK followed biphasic kinetic courses. Zn2(+) can affect unfolding and refolding of dAK by trapping the reversible intermediate. Our study provides important information regarding the effect of Zn2(+) on metabolic enzymes in marine invertebrates. PMID- 20929928 TI - Mitochondrially localized EGFR is independent of its endocytosis and associates with cell viability. AB - The molecular mechanism underlying epidermal growth factor receptor (EGFR) localization in mitochondria remains largely unknown. Using immune electron microscopy, we validated that EGFR could be localized on either the outer or the inner membrane of mitochondria. Mutant receptor lacked amino acids 646-660 was flawed in migration onto the organelles, whereas the mutated receptor with a defective endocytosis showed a greater capability of moving onto mitochondria upon stimulation of epidermal growth factor (EGF). Gefitinib, an inhibitor of EGFR kinase, inhibited the receptor endocytosis after short time of treatment, yet, only reduced cell viability as well as the amount of mitochondrial EGFR after longer time of exposure. Moreover, the content of mitochondrial EGFR transfer was decreased when the cells were exposed to the apoptotic inducer etoposide. EGF-induced programmed cell death usually coincided with a decline in mitochondrial EGFR. These data indicated that the mitochondrial-localized EGFR is independent of its internalization and may be correlated with cell survival and participate in the ligand-induced programmed cell death. PMID- 20929929 TI - A 2-week prognostic prediction model for terminal cancer patients in a palliative care unit at a Japanese general hospital. AB - OBJECTIVE: We aimed to develop a prognostic prediction model for 2-week survival among patients with terminal cancer in a palliative care unit (PCU). METHODS: A prospective cohort study was conducted on terminal cancer patients in the PCU for 11 months at a general hospital in Tokyo, Japan. We collected data regarding demographics, treatment history, performance status, symptoms, and laboratory results. Patients who survived more than 2 weeks were labeled 'long survivors' and those who died within 2 weeks were grouped as 'short survivors'. Stepwise logistic regression model was constructed for the model development and bootstrapping was used for the internal model validation. RESULTS: In 158 subjects whose data were available for the analysis, 109 (69%) subjects were categorized as long survivors and 49 (31%) subjects as short survivors. A prognostic prediction model with a total score of 8 points was constructed as follows: 2 points each for anorexia, dyspnea, and edema; 1 point each for blood urea nitrogen >25 mg/dl and platelets <260,000/mm(3). Area under the receiver operating characteristic (ROC) curve of this model was 83.2% (95% CI: 75.3 91.0%). Bootstrapped validation beta coefficients of the predictors were similar to the original cohort beta coefficients. CONCLUSION: Our prognostic prediction model for estimating 14-day survival for patients with terminal cancer on the PCU ward included five clinical predictors that are readily available in the clinical setting and showed a relatively high accuracy. External validation is needed to confirm the model's generalizability. PMID- 20929930 TI - The outcomes of palliative care day services: a systematic review. AB - This systematic review evaluates the evidence underpinning the provision of palliative day care services (PDS) to determine whether such services have a measurable effect on attendees' wellbeing. The majority of studies reviewed were qualitative and elicited individual perceptions of the benefits PDS. Although it was difficult to determine the quality of many studies, it would appear that attendance at PDS had a positive impact on attendees' quality of life. Fewer studies utilized validated outcome measures to determine the effect of PDS on attendees' wellbeing and small sample sizes combined with high attrition rates influenced the significance of some the results. However little quantitative evidence was offered to prove that PDS had an impact on attendees' quality of life or wellbeing. The review concludes that dying people find attending PDS a valuable experience that allows them to engage with others and to be supported in a restorative environment. However, further well-powered empirical studies are required to provide quality evidence to determine whether or not attendance at PDS does indeed have a positive impact on the wellbeing of attendees. PMID- 20929931 TI - Hip adduction and abduction strength profiles in elite soccer players: implications for clinical evaluation of hip adductor muscle recovery after injury. AB - BACKGROUND: An ipsilateral hip adduction/abduction strength ratio of more than 90%, and hip adduction strength equal to that of the contralateral side have been suggested to clinically represent adequate strength recovery of hip adduction strength in athletes after groin injury. However, to what extent side-to-side symmetry in isometric hip adduction and abduction strength can be assumed in soccer players remains uncertain. PURPOSE: To compare isometric hip adduction and abduction strength on the dominant and nondominant side in injury-free soccer players. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: One hundred elite soccer players were included. Maximal unilateral isometric hip adduction and abduction strength on the dominant and nondominant side were measured with a handheld dynamometer, using a reliable test procedure. RESULTS: The dominant side was stronger than the nondominant side for both isometric hip adduction (2.45 +/- 0.54 vs 2.37 +/- 0.48 Nm/kg, P = .02) and hip abduction (2.35 +/- 0.33 vs 2.25 +/- 0.31 Nm/kg, P < .001), corresponding to a 3% and 4% difference, respectively. Isometric hip adduction was greater than isometric hip abduction for both the dominant (2.44 +/- 0.53 vs 2.35 +/- 0.33 Nm/kg, P = .04) and nondominant (2.37 +/- 0.48 vs 2.26 +/- 0.33 Nm/kg, P = .03) side. Isometric hip adduction/abduction ratio was not different between the dominant (1.04 +/- 0.18) and nondominant (1.06 +/- 0.17, P = .40) side. A post hoc analysis showed that isometric hip adduction/abduction ratio was significantly lower in players with groin pain during hip adduction testing compared with players with a pain free test (0.80 +/- 0.14, P < .001) CONCLUSION: The marginal difference between the dominant and the nondominant side is within the measurement variation of the test procedure, and contralateral isometric hip adduction strength can therefore be used as a simple clinical reference point of full recovery of hip adduction muscle strength in soccer players. Furthermore, it is suggested that the ipsilateral hip adduction/abduction strength ratio is used as a guideline for evaluating hip adduction strength recovery in soccer players with bilateral groin problems. PMID- 20929932 TI - Outcome of ulnar collateral ligament reconstruction of the elbow in 1281 athletes: Results in 743 athletes with minimum 2-year follow-up. AB - BACKGROUND: The anterior bundle of the ulnar collateral ligament (UCL) is the primary anatomical structure providing elbow stability in overhead sports, particularly baseball. Injury to the UCL in overhead athletes often leads to symptomatic valgus instability that requires surgical treatment. HYPOTHESIS: Ulnar collateral ligament reconstruction with a free tendon graft, known as Tommy John surgery, will allow return to the same competitive level of sports participation in the majority of athletes. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Ulnar collateral reconstruction (1266) or repair (15) was performed in 1281 patients over a 19-year period (1988-2006) using a modification of the Jobe technique. Data were collected prospectively and patients were surveyed retrospectively with a telephone questionnaire to determine outcomes and return to performance at a minimum of 2 years after surgery. RESULTS: Nine hundred forty-two patients were available for a minimum 2-year follow-up (average, 38.4 months; range, 24-130 months). Seven hundred forty-three patients (79%) were contacted for follow-up evaluation and/or completed a questionnaire at an average of 37 months postoperatively. Six hundred seventeen patients (83%) returned to the previous level of competition or higher, including 610 (83%) after reconstruction. The average time from surgery to the initiation of throwing was 4.4 months (range, 2.8-12 months) and the average time to full competition was 11.6 months (range, 3-72 months) after reconstruction. Complications occurred in 148 patients (20%), including 16% considered minor and 4% considered major. CONCLUSION: Ulnar collateral ligament reconstruction with subcutaneous ulnar nerve transposition was found to be effective in correcting valgus elbow instability in the overhead athlete and allowed most athletes (83%) to return to previous or higher level of competition in less than 1 year. PMID- 20929933 TI - Anterior laxity, slippage, and recovery of function in the first year after tibialis allograft anterior cruciate ligament reconstruction. AB - BACKGROUND: The increase in anterior laxity and slippage is greater with metal interference screw fixation of a hamstring anterior cruciate ligament (ACL) graft than a bone-patellar tendon-bone graft. HYPOTHESIS: When slippage-resistant fixation is used with a soft tissue graft, early recovery of function does not result in a clinically important increase in anterior laxity and slippage STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Nineteen subjects were treated with a single-tunnel, single-looped, tibialis allograft with slippage resistant, cortical fixation. An examiner, different from the treating surgeon, used stereophotogrammetric analysis to compute the increase in anterior laxity at a 150 N anterior force and slippage between the day of surgery and each monthly follow-up interval, and determined recovery of function and motion. RESULTS: Anterior laxity did not increase between the day of surgery and 1 year (P = .23). Total slippage plateaued after 1 month, but increased 1.5 mm between the day of surgery and 1 month (P < .05). Extension and flexion plateaued after 2 months (P < .0001 and P < .02, respectively); activity level (Tegner score) plateaued after 3 months (P < .05), function (Lysholm score) plateaued after 4 months (P < .002), and subjective satisfaction (International Knee Documentation Committee score) plateaued after 6 months (P < .02). CONCLUSION: Early recovery of function after ACL reconstruction with a soft tissue allograft did not result in a clinically important increase in anterior laxity and slippage at 1 year. We believe the avoidance of an increase in anterior laxity was related to the use of a transtibial technique designed to place the femoral and tibial tunnels without roof and posterior cruciate ligament impingement, the use of cortical fixation devices designed to resist slippage, the use of an aseptically harvested fresh frozen tibialis allograft that was not irradiated or chemically processed, and the use of a self-administered rehabilitation program designed to encourage an early return of motion and function. PMID- 20929934 TI - Medial patellofemoral ligament reconstruction fixed with a cylindrical bone plug and a grafted semitendinosus tendon at the original femoral site for recurrent patellar dislocation. AB - BACKGROUND: The medial patellofemoral ligament (MPFL) is the most important factor for stabilizing the patella and preventing lateral patellar dislocation. Medial patellofemoral ligament reconstruction is an accepted surgical technique to restore patellofemoral stability after lateral patellar dislocation. The authors recently developed a new anatomical MPFL reconstruction method using a cylindrical bone plug and grafted semitendinosus tendon at the anatomical femoral attachment site to mimic the native MPFL. This study evaluated the new technique for stabilizing recurrent patellar dislocation. HYPOTHESIS: This new MPFL reconstruction technique will improve knee symptoms and function with excellent clinical results. STUDY DESIGN: Case series; Level of evidence, 4. METHOD: Thirty one knees were evaluated from 29 cases of recurrent patellar dislocation that were surgically treated using the anatomical MPFL reconstruction technique. The average patient age was 22.2 years (range, 12-34 years); postsurgery follow-up was 2 to 5 years (average, 3.2 years). The patients were clinically evaluated based on the Kujala score, range of motion, and signs of apprehension. The Merchant view was used to measure congruence and tilting angles. RESULTS: Of the 31 knees, 30 showed good clinical results after surgery, while 1 patient showed remaining signs of apprehension. The Kujala score improved from an average of 64 points (range, 35-70) initially to an average of 94.5 points (range, 79-100) at the final follow-up. Range of motion improved for all patients, with an average knee extension of 0 degrees +/- 2 degrees and knee flexion of 145 degrees +/- 3 degrees at final follow-up. No patellar redislocation was reported. Radiological assessment indicated significant improvement to the congruence angle from 13 degrees +/- 4 degrees before surgery to -5 degrees +/- 5 degrees at the final follow-up, while the tilting angle went from 8 degrees +/- 7 degrees before surgery to 7 degrees +/- 4 degrees at the final follow-up. CONCLUSION: This study demonstrated excellent results using the new procedure for recurrent dislocation of the patella, with instability in only 1 of 31 knees (3.2%). PMID- 20929935 TI - In vivo positioning analysis of medial patellofemoral ligament reconstruction. AB - BACKGROUND: Several techniques have been described for reconstruction of the medial patellofemoral ligament (MPFL). The anatomical insertion of the MPFL has been defined; however, there are no reports describing the accuracy of femoral graft positioning assessed postoperatively. PURPOSE: To analyze our femoral tunnel positioning for MPFL reconstruction in correlation with our clinical results. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: The authors reported a prospective series of 29 MPFL reconstructions with a minimum follow-up of 24 months. The tunnel positioning analysis was performed using plain radiographs and magnetic resonance imaging at 1-year follow-up. RESULTS: Twenty nine femoral tunnels were analyzed; 20 femoral tunnels (69%) were considered to be in good position on plain radiographs. On magnetic resonance imaging, the authors found 19 femoral tunnels (65%) in a proper location, 5 (17.5%) in a high position, and 5 in an anterior and/or high position. CONCLUSION: The study highlights the difficulty of reproducible MPFL reconstruction. The surgical procedure continues to be improved and finding a reliable technique to anatomically place the graft remains challenging. Verifying femoral tunnel placement radiographically may be recommended during surgery. PMID- 20929936 TI - A proximal strengthening program improves pain, function, and biomechanics in women with patellofemoral pain syndrome. AB - BACKGROUND: It is hypothesized that patients with patellofemoral pain syndrome (PFPS) have hip and core muscle weakness leading to dynamic malalignment of the lower extremity. Thus, hip strengthening is a common PFPS treatment approach. PURPOSE: To determine changes in hip strength, core endurance, lower extremity biomechanics, and patient outcomes after proximally focused rehabilitation for PFPS patients. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Nineteen women (age, 22.68 +/- 7.19 years; height, 1.64 +/- 0.07 m; mass, 60.2 +/- 7.35 kg) with PFPS participated in an 8-week program to strengthen the hip and core muscles and improve dynamic malalignment. Paired t tests were used to compare the dependent variables between prerehabilitation and postrehabilitation. The dependent variables were pain; functional ability; isometric hip abduction and external rotation strength; anterior, lateral, and posterior core endurance; joint range of motion (ROM; rearfoot eversion, knee abduction and internal rotation, and hip adduction and internal rotation); and peak internal joint moments (rearfoot inversion, knee abduction, and hip abduction and external rotation) during the stance phase of running. RESULTS: Significant improvements in pain, functional ability, lateral core endurance, hip abduction, and hip external rotation strength were observed. There was also a significant reduction in the knee abduction moment during running, although there were no significant changes in joint ROM. CONCLUSION: An 8-week rehabilitation program focusing on strengthening and improving neuromuscular control of the hip and core musculature produces positive patient outcomes, improves hip and core muscle strength, and reduces the knee abduction moment, which is associated with developing PFPS. PMID- 20929937 TI - Medial versus lateral supraspinatus tendon properties: implications for double row rotator cuff repair. AB - BACKGROUND: Rotator cuff repair retear rates range from 25% to 90%, necessitating methods to improve repair strength. Although numerous laboratory studies have compared single-row with double-row fixation properties, little is known regarding regional (ie, medial vs lateral) suture retention properties in intact and torn tendons. HYPOTHESIS: A torn supraspinatus tendon will have reduced suture retention properties on the lateral aspect of the tendon compared with the more medial musculotendinous junction. STUDY DESIGN: Controlled laboratory study. METHODS: Human supraspinatus tendons (torn and intact) were randomly assigned for suture retention mechanical testing, ultrastructural collagen fibril analysis, or histologic testing after suture pullout testing. For biomechanical evaluation, sutures were placed either at the musculotendinous junction (medial) or 10 mm from the free margin (lateral), and tendons were elongated to failure. Collagen fibril assessments were performed using transmission electron microscopy. RESULTS: Intact tendons showed no regional differences with respect to suture retention properties. In contrast, among torn tendons, the medial region exhibited significantly higher stiffness and work values relative to the lateral region. For the lateral region, work to 10-mm displacement (1592 +/- 261 N-mm) and maximum load (265 +/- 44 N) for intact tendons were significantly higher (P < .05) than that of torn tendons (1086 +/- 388 N-mm and 177 +/- 71 N, respectively). For medial suture placement, maximum load, stiffness, and work of intact and torn tendons were similar (P > .05). Regression analyses for the intact and torn groups revealed generally low correlations between donor age and the 3 biomechanical indices. For both intact and torn tendons, the mean fibril diameter and area density were greater in the medial region relative to the lateral (P <= .05). In the lateral tendon, but not the medial region, torn specimens showed a significantly lower fibril area fraction (48.3% +/- 3.8%) than intact specimens (56.7% +/- 3.6%, P < .05). CONCLUSION: Superior pullout resistance of medially placed sutures may provide a strain shielding effect for the lateral row after double-row repair. Larger diameter collagen fibrils as well as greater fibril area fraction in the medial supraspinatus tendon may provide greater resistance to suture migration. CLINICAL RELEVANCE: While clinical factors such as musculotendinous integrity warrant strong consideration for surgical decision making, the present ultrastructural and biomechanical results appear to provide a scientific rationale for double-row rotator cuff repair where sutures are placed more medially at the muscle-tendon junction. PMID- 20929938 TI - Apophyseolysis of the greater trochanter through excessive sports: a case report. PMID- 20929939 TI - A conceptual model of HIV disclosure in casual sexual encounters among men who have sex with men. AB - HIV/AIDS continues to disproportionately impact men who have sex with men (MSM). Advances in highly active antiretroviral therapies (HAART) have successfully helped HIV-infected individuals lead longer, healthier, and presumably more sexually active lives. Consequently, secondary prevention approaches aimed at reducing the rate of HIV transmission have raised important questions about the role of sexual communication, namely HIV disclosure, as a primary target for intervention. This paper proposes a conceptual model of HIV disclosure in casual sexual encounters among MSM informed by Goffman's work on stigma and based on existing empirical research. The article concludes with an agenda for research based in this integrative model. PMID- 20929940 TI - Factors from the transtheoretical model differentiating between solar water disinfection (SODIS) user groups. AB - Solar water disinfection (SODIS) is a sustainable household water treatment technique that could prevent millions of deaths caused by diarrhoea. The behaviour change process necessary to move from drinking raw water to drinking SODIS is analysed with the Transtheoretical Model of Change (TTM). User groups and psychological factors that differentiate between types of users are identified. Results of a 1.5 year longitudinal study in Zimbabwe reveal distinguishing factors between groups, from which it can be deduced that they drive the development of user groups. Implications are drawn for campaigns with the aim of bringing all user types to a regular use. PMID- 20929941 TI - Using mixed methods to design a web-based behavioural intervention to reduce transmission of colds and flu. AB - This mixed methods study informed the development of our web-based intervention to reduce the risk of transmission of respiratory infections. Two qualitative studies examined 28 users' responses to website materials, and elicited additional beliefs. A questionnaire study (N = 129) tested key intervention assumptions: that hand-washing is considered the most feasible preventive behaviour; behavioural determinants were related to behavioural intentions; beliefs related to hand-washing intentions and behaviour. Thematic analysis of the qualitative data revealed important issues, such as the belief that catching minor infections is beneficial to the immune system. The questionnaire results confirmed our assumptions, including hand-washing as the appropriate target behaviour. PMID- 20929942 TI - Personality pathology comorbidity in adult females with eating disorders. AB - Personality pathology is examined in 100 female in-patients diagnosed with eating disorders. The Eating Disorder Inventory-II and the NEO-PI-R were self administered and personality pathology was assessed using a structured interview. Clinicians additionally evaluated patients' global functioning. The results indicated sizeable personality disorder comorbidity, and two dimensions of personality pathology, for example, an internalizing and an externalizing factor, could be identified. Patients' global functioning was primarily associated with dimensions of personality pathology, but not with eating disorder symptoms. Assessment and therapeutic interventions should focus on this co-occurring pathology in order to improve patients' functioning. PMID- 20929943 TI - Depression may mediate the relationship between sense of coherence and quality of life in lung cancer patients. AB - Lung cancer patients generally experience high levels of physical and psychological distress and decreased quality of life (QOL). Sense of coherence (SOC) has been conceptualized as a personality orientation reflecting the degree to which an individual perceives their world as comprehensible, manageable and meaningful. The present study investigated the associations of SOC with QOL in lung cancer. It also examined potential psychological mediators by which SOC may exert its influences on QOL. Fifty-six participants with non-small cell lung cancer were administered self-report assessments of SOC, QOL and psychological distress. Results revealed that SOC was positively associated with QOL and this relationship may be mediated by depressive symptoms. The current study supports the notion that SOC may be a protective factor with regard to psychological adjustment and QOL in cancer survivors. PMID- 20929944 TI - The role of identity in adjustment among survivors of oesophageal cancer. AB - The study sought to contextualize the physical, social and emotional adjustments that are faced by oesophageal cancer patients following surgery. Semi-structured interviews were conducted with five survivors, guided by the principles of Interpretative Phenomenological Analysis (IPA). Participants' accounts encompassed descriptions of personal, social and medical relationships, illness and treatment experiences, eating behaviours, and spiritual and religious perspectives, representing myriad challenges to the self-concept. Surviving patients may have a role in addressing patient expectations about eating. The importance of attempts to nurture and maintain a sense of self should be recognized by those providing care. PMID- 20929945 TI - Better to bend than to break: coping strategies utilized by substance-abusing homeless youth. AB - This study investigated the relationship between coping styles and problem behaviors among a sample of substance-abusing homeless youth. Homeless youth (n = 268) were recruited through the only drop-in center in Albuquerque, New Mexico. Results revealed that youth with higher task-oriented coping reported less delinquent behaviors while those with higher emotion-oriented coping reported higher levels of anxiety/ depression and higher delinquency. Contrary to expectations, youth utilizing higher avoidance-oriented coping skills showed fewer HIV risk behaviors, fewer anxiety/depressive symptoms, and less frequent alcohol use. Findings emphasize the need to examine coping strategies in the context that individuals are situated. PMID- 20929946 TI - Young adults' images of abstaining and drinking: prototype dimensions, correlates and assessment methods. AB - This research investigated contents of actor and abstainer prototypes with regard to young adults' social drinking combining quantitative and qualitative approaches (adjective ratings, N = 300; open answers, N = 90). Exploratory and confirmatory factor analyses yielded two factors (sociability/hedonism, responsibility) in both prototypes, confirmed by qualitative data. Given the importance for intention and willingness to drink alcohol, interventions should focus on the factor 'sociability/hedonism' of the actor and the abstainer prototype to reduce heavy drinking; addressing 'responsibility' may be ineffective. Participants' evaluations appeared to be less prone to mean tendencies subsequent to open answers compared with adjective scales. PMID- 20929947 TI - Transforming your life: an environmental modification approach to weight loss. AB - This investigation compared a traditional behavioral weight loss program with a weight loss intervention emphasizing environmental modification and habit formation and disruption. Fifty-four overweight and obese adults (BMI >= 27 kg/m2 were randomly assigned to either a 14-week LEARN or TYL intervention. Forty-two participants completed the six-month follow-up assessment. Treatment outcomes between LEARN and TYL participants were equivalent. During the six-month no treatment follow-up period, participants evidenced a 3.3 lb (SD = 9.2) weight gain. The TYL intervention appears to represent an attractive option for individuals seeking an alternative to the traditional behavioral approach to weight loss. PMID- 20929948 TI - Endothelin receptor type A expression defines a distinct cardiac subdomain within the heart field and is later implicated in chamber myocardium formation. AB - The avian and mammalian heart originates from two distinct embryonic regions: an early differentiating first heart field and a dorsomedially located second heart field. It remains largely unknown when and how these subdivisions of the heart field divide into regions with different fates. Here, we identify in the mouse a subpopulation of the first (crescent-forming) field marked by endothelin receptor type A (Ednra) gene expression, which contributes to chamber myocardium through a unique type of cell behavior. Ednra-lacZ/EGFP-expressing cells arise in the ventrocaudal inflow region of the early linear heart tube, converge to the midline, move anteriorly along the outer curvature and give rise to chamber myocardium mainly of the left ventricle and both atria. This movement was confirmed by fluorescent dye-labeling and transplantation experiments. The Ednra lacZ/EGFP-expressing subpopulation is characterized by the presence of Tbx5 expressing cells. Ednra-null embryonic hearts often demonstrate hypoplasia of the ventricular wall, low mitotic activity and decreased Tbx5 expression with reciprocal expansion of Tbx2 expression. Conversely, endothelin 1 stimulates ERK phosphorylation and Tbx5 expression in the early embryonic heart. These results indicate that early Ednra expression defines a subdomain of the first heart field contributing to chamber formation, in which endothelin 1/Ednra signaling is involved. The present finding provides an insight into how subpopulations within the crescent-forming (first) heart field contribute to the coordination of heart morphogenesis through spatiotemporally defined cell movements. PMID- 20929949 TI - Novel modes of localization and function of nanos in the wasp Nasonia. AB - Abdominal patterning in Drosophila requires the function of nanos (nos) to prevent translation of hunchback (hb) mRNA in the posterior of the embryo. nos function is restricted to the posterior by the translational repression of mRNA that is not incorporated into the posteriorly localized germ plasm during oogenesis. The wasp Nasonia vitripennis (Nv) undergoes a long germ mode of development very similar to Drosophila, although the molecular patterning mechanisms employed in these two organisms have diverged significantly, reflecting the independent evolution of this mode of development. Here, we report that although Nv nanos (Nv-nos) has a conserved function in embryonic patterning through translational repression of hb, the timing and mechanisms of this repression are significantly delayed in the wasp compared with the fly. This delay in Nv-nos function appears to be related to the dynamic behavior of the germ plasm in Nasonia, as well as to the maternal provision of Nv-Hb protein during oogenesis. Unlike in flies, there appears to be two functional populations of Nv-nos mRNA: one that is concentrated in the oosome and is taken up into the pole cells before evidence of Nv-hb repression is observed; another that forms a gradient at the posterior and plays a role in Nv-hb translational repression. Altogether, our results show that, although the embryonic patterning function of nos orthologs is broadly conserved, the mechanisms employed to achieve this function are distinct. PMID- 20929950 TI - Mechanics of head fold formation: investigating tissue-level forces during early development. AB - During its earliest stages, the avian embryo is approximately planar. Through a complex series of folds, this flat geometry is transformed into the intricate three-dimensional structure of the developing organism. Formation of the head fold (HF) is the first step in this cascading sequence of out-of-plane tissue folds. The HF establishes the anterior extent of the embryo and initiates heart, foregut and brain development. Here, we use a combination of computational modeling and experiments to determine the physical forces that drive HF formation. Using chick embryos cultured ex ovo, we measured: (1) changes in tissue morphology in living embryos using optical coherence tomography (OCT); (2) morphogenetic strains (deformations) through the tracking of tissue labels; and (3) regional tissue stresses using changes in the geometry of circular wounds punched through the blastoderm. To determine the physical mechanisms that generate the HF, we created a three-dimensional computational model of the early embryo, consisting of pseudoelastic plates representing the blastoderm and vitelline membrane. Based on previous experimental findings, we simulated the following morphogenetic mechanisms: (1) convergent extension in the neural plate (NP); (2) cell wedging along the anterior NP border; and (3) autonomous in-plane deformations outside the NP. Our numerical predictions agree relatively well with the observed morphology, as well as with our measured stress and strain distributions. The model also predicts the abnormal tissue geometries produced when development is mechanically perturbed. Taken together, the results suggest that the proposed morphogenetic mechanisms provide the main tissue-level forces that drive HF formation. PMID- 20929951 TI - Immunomodulatory impact of a synbiotic in T(h)1 and T(h)2 models of infection. AB - BACKGROUND AND METHODS: The immunomodulatory activity of a synbiotic combination containing three bacterial strains (Lactobacillus helveticus R0052, Bifidobacterium longum subsp. infantis R0033 and Bifidobacterium bifidum R0071) and short-chain fructooligosaccharide was examined in two distinct infectious rat models. In the T(h)1 model, Wistar rats were administered the synbiotic combination for 2 weeks prior to challenge with a single oral dose of enterotoxigenic Escherichia coli or vehicle. In the T(h)2 model, pretreated rats were challenged with a single subcutaneous dose of hook worm, Nippostrongylus brasiliensis. Blood samples were collected 3 hours or 4 days postchallenge and serum levels of pro- and anti-inflammatory cytokines were measured. RESULTS: Significant reductions in pro-inflammatory cytokines interleukin (IL)-1alpha, IL 1beta, IL-6, and tumour necrosis factor (TNF)-alpha were observed in both models suggesting a single, unifying mode of action on an upstream regulator. The N. brasiliensis study also compared the effect of the individual strains to synbiotic. For most of cytokines the combination appeared to average the effect of the individual strains with the exception of IL-4 and IL-10 where there was apparent synergy for the combination. Furthermore, the cytokine response varied by strain. CONCLUSIONS: It was concluded that this synbiotic combination of these three microbes could be beneficial in both T(h)1 and T(h)2 diseases. PMID- 20929952 TI - Growth of Pseudomonas putida F1 on styrene requires increased catechol-2,3 dioxygenase activity, not a new hydrolase. AB - Pseudomonas putida F1 cannot grow on styrene despite being able to degrade it through the toluene degradation (tod) pathway. Previous work had suggested that this was because TodF, the meta-fission product (MFP) hydrolase, was unable to metabolize the styrene MFP 2-hydroxy-6-vinylhexa-2,4-dienoate. Here we demonstrate via kinetic and growth analyses that the substrate specificity of TodF is not the limiting factor preventing F1 from growing on styrene. Rather, we found that the metabolite 3-vinylcatechol accumulated during styrene metabolism and that micromolar concentrations of this intermediate inactivated TodE, the catechol-2,3-dioxygenase (C23O) responsible for its cleavage. Analysis of cells growing on styrene suggested that inactivation of TodE and the subsequent accumulation of 3-vinylcatechol resulted in toxicity and cell death. We found that simply overexpressing TodE on a plasmid (pTodE) was all that was necessary to allow F1 to grow on styrene. Similar results were also obtained by expressing a related C23O, DmpB from Pseudomonas sp. CF600, in tandem with its plant-like ferredoxin, DmpQ (pDmpQB). Further analysis revealed that the ability of F1 (pDmpQB) and F1 (pTodE) to grow on styrene correlated with increased C23O activity as well as resistance of the enzyme to 3-vinylcatechol-mediated inactivation. Although TodE inactivation by 3-halocatechols has been studied before, to our knowledge, this is the first published report demonstrating inactivation by a 3-vinylcatechol. Given the ubiquity of catechol intermediates in aromatic hydrocarbon metabolism, our results further demonstrate the importance of C23O inactivation as a determinant of growth substrate specificity. PMID- 20929953 TI - Flexible metabolism in Metarhizium anisopliae and Beauveria bassiana: role of the glyoxylate cycle during insect pathogenesis. AB - Insect pathogenic fungi such as Metarhizium anisopliae and Beauveria bassiana have an increasing role in the control of agricultural insect pests and vectors of human diseases. Many of the virulence factors are well studied but less is known of the metabolism of these fungi during the course of insect infection or saprobic growth. Here, we assessed enzyme activity and gene expression in the central carbon metabolic pathway, including isocitrate dehydrogenase, aconitase, citrate synthase, malate synthase (MLS) and isocitrate lyase (ICL), with particular attention to the glyoxylate cycle when M. anisopliae and B. bassiana were grown under various conditions. We observed that ICL and MLS, glyoxylate cycle intermediates, were upregulated during growth on 2-carbon compounds (acetate and ethanol) as well as in insect haemolymph. We fused the promoter of the M. anisopliae ICL gene (Ma-icl) to a marker gene (mCherry) and showed that Ma icl was upregulated when M. anisopliae was grown in the presence of acetate. Furthermore, Ma-icl was upregulated when fungi were engulfed by insect haemocytes as well as during appressorium formation. Addition of the ICL inhibitor 3 nitroproprionate delayed conidial germination and inhibited appressorium formation. These results show that these insect pathogenic fungi have a flexible metabolism that includes the glyoxylate cycle as an integral part of germination, pathogenesis and saprobic growth. PMID- 20929954 TI - Microbial communication and virulence: lessons from evolutionary theory. AB - At the heart of tackling the huge challenge posed by infectious micro-organisms is the overwhelming need to understand their nature. A major question is, why do some species of bacteria rapidly kill their host whilst others are relatively benign? For example, Yersinia pestis, the causative organism of plague, is a highly virulent human pathogen whilst the closely related Yersinia pseudotuberculosis causes a much less severe disease. Using molecular techniques such as mutating certain genes, microbiologists have made significant advances over recent decades in elucidating the mechanisms that govern the production of virulence factors involved in causing disease in many bacterial species. There are also evolutionary and ecological factors which will influence virulence. Many of these ideas have arisen through the development of evolutionary theory and yet there is strikingly little empirical evidence testing them. By applying both mechanistic and adaptive approaches to microbial behaviours we can begin to address questions such as, what factors influence cooperation and the evolution of virulence in microbes and can we exploit these factors to develop new antimicrobial strategies? PMID- 20929955 TI - Evidence for a non-replicative intracellular stage of nontypable Haemophilus influenzae in epithelial cells. AB - Nontypable Haemophilus influenzae (NTHi) is a Gram-negative, non-capsulated human bacterial pathogen, a major cause of a repertoire of respiratory infections, and intimately associated with persistent lung bacterial colonization in patients suffering from chronic obstructive pulmonary disease (COPD). Despite its medical relevance, relatively little is known about its mechanisms of pathogenicity. In this study, we found that NTHi invades the airway epithelium by a distinct mechanism, requiring microtubule assembly, lipid rafts integrity, and activation of phosphatidylinositol 3-kinase (PI3K) signalling. We found that the majority of intracellular bacteria are located inside an acidic subcellular compartment, in a metabolically active and non-proliferative state. This NTHi-containing vacuole (NTHi-CV) is endowed with late endosome features, co-localizing with LysoTracker, lamp-1, lamp-2, CD63 and Rab7. The NTHi-CV does not acquire Golgi- or autophagy related markers. These observations were extended to immortalized and primary human airway epithelial cells. By using NTHi clinical isolates expressing different amounts of phosphocholine (PCho), a major modification of NTHi lipooligosaccharide, on their surfaces, and an isogenic lic1BC mutant strain lacking PCho, we showed that PCho is not responsible for NTHi intracellular location. In sum, this study indicates that NTHi can survive inside airway epithelial cells. PMID- 20929956 TI - Evolution of the capsular gene locus of Streptococcus pneumoniae serogroup 6. AB - Streptococcus pneumoniae expressing serogroup 6 capsules frequently causes pneumococcal infections and the evolutionary origins of the serogroup 6 strains have been extensively studied. However, these studies were performed when serogroup 6 had only two known members (serotypes 6A and 6B) and before the two new members (serotypes 6C and 6D) expressing wciN(beta) were found. We have therefore reinvestigated the evolutionary origins of serogroup 6 by examining the profiles of the capsule gene loci and the multilocus sequence types (MLSTs) of many serogroup 6 isolates from several continents. We confirmed that there are two classes of cps locus sequences for serogroup 6 isolates. In our study, class 2 cps sequences were limited to a few serotype 6B isolates. Neighbour-joining analysis of cps sequence profiles showed a distinct clade for 6C and moderately distinct clades for class 1 6A and 6B sequences. The serotype 6D cps profile was found within the class 1 6B clade, suggesting that it was created by recombination between 6C and 6B cps loci. Interestingly, all 6C isolates also had a unique wzy allele with a 6 bp deletion. This suggests that serotype switching to 6C involves the transfer of a large (>4 kb) gene segment that includes both the wciN(beta) allele and the 'short' wzy allele. The MLST studies of serotype 6C isolates suggest that the 6C cps locus is incorporated into many different pneumococcal genomic backgrounds but that, interestingly, 6C cps may have preferentially entered strains of the same genomic backgrounds as those of serotype 6A. PMID- 20929957 TI - Gene expression under low-oxygen conditions in the cyanobacterium Synechocystis sp. PCC 6803 demonstrates Hik31-dependent and -independent responses. AB - We have investigated the response of the cyanobacterium Synechocystis sp. PCC 6803 during growth at very low O2 concentration (bubbled with 99.9 % N(2)/0.1 % CO2). Significant transcriptional changes upon low-O2 incubation included upregulation of a cluster of genes that contained psbA1 and an operon that includes a gene encoding the two-component regulatory histidine kinase, Hik31. This regulatory cluster is of particular interest, since there are virtually identical copies on both the chromosome and plasmid pSYSX. We used a knockout mutant lacking the chromosomal copy of hik31 and studied differential transcription during the aerobic-low-O2 transition in this DeltaHik31 strain and the wild-type. We observed two distinct responses to this transition, one Hik31 dependent, the other Hik31 independent. The Hik31-independent responses included the psbA1 induction and genes involved in chlorophyll biosynthesis. In addition, there were changes in a number of genes that may be involved in assembling or stabilizing photosystem (PS)II, and the hox operon and the LexA-like protein (Sll1626) were upregulated during low-O2 growth. This family of responses mostly focused on PSII and overall redox control. There was also a large set of genes that responded differently in the absence of the chromosomal Hik31. In the vast majority of these cases, Hik31 functioned as a repressor and transcription was enhanced when Hik31 was deleted. Genes in this category encoded both core and peripheral proteins for PSI and PSII, the main phycobilisome proteins, chaperones, the ATP synthase cluster and virtually all of the ribosomal proteins. These findings, coupled with the fact that DeltaHik31 grew better than the wild type under low-O2 conditions, suggested that Hik31 helps to regulate growth and overall cellular homeostasis. We detected changes in the transcription of other regulatory genes that may compensate for the loss of Hik31. We conclude that Hik31 regulates an important series of genes that relate to energy production and growth and that help to determine how Synechocystis responds to changes in O2 conditions. PMID- 20929958 TI - Longitudinal study of prepregnancy cardiometabolic risk factors and subsequent risk of gestational diabetes mellitus: The CARDIA study. AB - This study examined prepregnancy cardiometabolic risk factors and gestational diabetes mellitus (GDM) in subsequent pregnancies. The authors selected 1,164 women without diabetes before pregnancy who delivered 1,809 livebirths between 5 consecutive examinations from 1985 to 2006 in the Coronary Artery Risk Development in Young Adults (CARDIA) Study. The authors measured prepregnancy cardiometabolic risk factors and performed multivariate repeated-measures logistic regression to compute the odds of GDM adjusted for race, age, parity, birth order, and other covariates. Impaired fasting glucose (100-125 vs. <90 mg/dL), elevated fasting insulin (>15-20 and >20 vs. <10 MUU/mL), and low levels of high-density lipoprotein cholesterol (<40 vs. >50 mg/dL) before pregnancy were directly associated with GDM: The odds ratios = 4.74 (95% confidence interval (CI): 2.14, 10.51) for fasting glucose, 2.19 (95% CI: 1.15, 4.17) for middle insulin levels and 2.36 (95% CI: 1.20, 4.63) for highest insulin levels, and 3.07 (95% CI: 1.62, 5.84) for low levels of high-density lipoprotein cholesterol among women with a negative family history of diabetes; all P < 0.01. Among overweight women, 26.7% with 1 or more cardiometabolic risk factors developed GDM versus 7.4% with none. Metabolic impairment exists before GDM pregnancy in nondiabetic women. Interconceptual metabolic screening could be included in routine health assessments to identify high-risk women for GDM in a subsequent pregnancy and to potentially minimize fetal exposure to metabolic abnormalities that program future disease. PMID- 20929959 TI - Adolescents' emotional reactions to parental cancer: effect on emotional and behavioral problems. AB - OBJECTIVES: We examined adolescents' emotional reactions to parental cancer and explored relationships between emotional reactions and adolescents' emotional/behavioral problems. METHODS: Two studies were performed: retrospective and prospective. A total of 221 adolescents (105 sons) of 138 patients (retrospective) and 70 adolescents (31 sons) of 70 patients (prospective) participated. Adolescents reported on cancer-specific uncertainty, loneliness, helplessness and positive emotions (Situation-Specific Emotional Reactions Questionnaire), and filled in the Youth Self-Report once retrospectively during the period of 1-5 year(s) after diagnosis and three times prospectively during the first year (4 months post-diagnosis, 6 and 12 months after T1). RESULTS: Emotional reactions were similar between pro- and retrospective studies. Prospectively, uncertainty and helplessness decreased over time. Uncertainty and loneliness related significantly to adolescents' dysfunction (prospective and retrospective). Relationships between emotions and functioning were stronger and more often significant for daughters. Prospectively, adolescents' post-diagnosis emotional reactions were largely unrelated to later functioning. CONCLUSIONS: Uncertainty and loneliness related to adolescents' emotional and behavioral problems. Daughters' emotions seem more strongly related to functioning than sons'. PMID- 20929960 TI - Loss of striatal type 1 cannabinoid receptors is a key pathogenic factor in Huntington's disease. AB - Endocannabinoids act as neuromodulatory and neuroprotective cues by engaging type 1 cannabinoid receptors. These receptors are highly abundant in the basal ganglia and play a pivotal role in the control of motor behaviour. An early downregulation of type 1 cannabinoid receptors has been documented in the basal ganglia of patients with Huntington's disease and animal models. However, the pathophysiological impact of this loss of receptors in Huntington's disease is as yet unknown. Here, we generated a double-mutant mouse model that expresses human mutant huntingtin exon 1 in a type 1 cannabinoid receptor-null background, and found that receptor deletion aggravates the symptoms, neuropathology and molecular pathology of the disease. Moreover, pharmacological administration of the cannabinoid Delta(9)-tetrahydrocannabinol to mice expressing human mutant huntingtin exon 1 exerted a therapeutic effect and ameliorated those parameters. Experiments conducted in striatal cells show that the mutant huntingtin-dependent downregulation of the receptors involves the control of the type 1 cannabinoid receptor gene promoter by repressor element 1 silencing transcription factor and sensitizes cells to excitotoxic damage. We also provide in vitro and in vivo evidence that supports type 1 cannabinoid receptor control of striatal brain derived neurotrophic factor expression and the decrease in brain-derived neurotrophic factor levels concomitant with type 1 cannabinoid receptor loss, which may contribute significantly to striatal damage in Huntington's disease. Altogether, these results support the notion that downregulation of type 1 cannabinoid receptors is a key pathogenic event in Huntington's disease, and suggest that activation of these receptors in patients with Huntington's disease may attenuate disease progression. PMID- 20929961 TI - Riboflavin-responsive oxidative phosphorylation complex I deficiency caused by defective ACAD9: new function for an old gene. AB - Mitochondrial complex I deficiency is the most common oxidative phosphorylation defect. Mutations have been detected in mitochondrial and nuclear genes, but the genetics of many patients remain unresolved and new genes are probably involved. In a consanguineous family, patients presented easy fatigability, exercise intolerance and lactic acidosis in blood from early childhood. In muscle, subsarcolemmal mitochondrial proliferation and a severe complex I deficiency were observed. Exercise intolerance and complex I activity was improved by a supplement of riboflavin at high dosage. Homozygosity mapping revealed a candidate region on chromosome three containing six mitochondria-related genes. Four genes were screened for mutations and a homozygous substitution was identified in ACAD9 (c.1594 C>T), changing the highly conserved arginine-532 into tryptophan. This mutation was absent in 188 ethnically matched controls. Protein modelling suggested a functional effect due to the loss of a stabilizing hydrogen bond in an alpha-helix and a local flexibility change. To test whether the ACAD9 mutation caused the complex I deficiency, we transduced fibroblasts of patients with wild-type and mutant ACAD9. Wild-type, but not mutant, ACAD9 restored complex I activity. An unrelated patient with the same phenotype was compound heterozygous for c.380 G>A and c.1405 C>T, changing arginine-127 into glutamine and arginine-469 into tryptophan, respectively. These amino acids were highly conserved and the substitutions were not present in controls, making them very probably pathogenic. Our data support a new function for ACAD9 in complex I function, making this gene an important new candidate for patients with complex I deficiency, which could be improved by riboflavin treatment. PMID- 20929962 TI - GPR56-related bilateral frontoparietal polymicrogyria: further evidence for an overlap with the cobblestone complex. AB - GPR56 mutations cause an autosomal recessive polymicrogyria syndrome that has distinctive radiological features combining bilateral frontoparietal polymicrogyria, white matter abnormalities and cerebellar hypoplasia. Recent investigations of a GPR56 knockout mouse model suggest that bilateral bifrontoparietal polymicrogyria shares some features of the cobblestone brain malformation and demonstrate that loss of GPR56 leads to a dysregulation of the maintenance of the pial basement membrane integrity in the forebrain and the rostral cerebellum. In light of these findings and other data in the literature, this study aimed to refine the clinical features with the first description of a foetopathological case and to define the range of cobblestone-like features in GPR56 bilateral bifrontoparietal polymicrogyria in a sample of 14 patients. We identified homozygous GPR56 mutations in 14 patients from eight consanguineous families with typical bilateral bifrontoparietal polymicrogyria and in one foetal case, out of 30 patients with bifrontoparietal polymicrogyria referred for molecular screening. The foetal case, which was terminated at 35 weeks of gestation in view of suspicion of Walker Warburg syndrome, showed a cobblestone like lissencephaly with a succession of normal, polymicrogyric and 'cobblestone like' cortex with ectopic neuronal overmigration, agenesis of the cerebellar vermis and hypoplastic cerebellar hemispheres with additional neuronal overmigration in the pons and the cerebellar cortex. The 14 patients with GPR56 mutations (median 8.25 years, range 1.5-33 years) were phenotypically homogeneous with a distinctive clinical course characterized by pseudomyopathic behaviour at onset that subsequently evolved into severe mental and motor retardation. Generalized seizures (12/14) occurred later with onset ranging from 2.5 to 10 years with consistent electroencephalogram findings of predominantly anterior bursts of low amplitude alpha-like activity. Neuroimaging demonstrated a common phenotype with bilateral frontoparietally predominant polymicrogyria (13/13), cerebellar dysplasia with cysts mainly affecting the superior vermis (11/13) and patchy to diffuse myelination abnormalities (13/13). Additionally, the white matter abnormalities showed a peculiar evolution from severe hypomyelination at 4 months to patchy lesions later in childhood. Taken as a whole, these observations collectively demonstrate that GPR56 bilateral bifrontoparietal polymicrogyria combines all the features of a cobblestone-like lissencephaly and also suggest that GRP56-related defects produce a phenotypic continuum ranging from bilateral bifrontoparietal polymicrogyria to cobblestone-like lissencephaly. PMID- 20929963 TI - Survival after organ preserving treatment for T4a laryngeal squamous cell carcinoma. PMID- 20929964 TI - Long-term effects of anastrozole on bone mineral density: 7-year results from the ATAC trial. AB - BACKGROUND: This 'Arimidex', Tamoxifen, Alone or in Combination (ATAC) trial sub study examined the effects of anastrozole and tamoxifen on bone mineral density (BMD) following 5 years of treatment. PATIENTS AND METHODS: Lumbar spine and total hip BMD were assessed at years 6 and 7 in a total of 71 eligible patients. In total, 50 patients had evaluable data. RESULTS: Following anastrozole treatment, the lumbar spine median BMD increased by 2.35% (P=0.04) and 4.02% (P=0.0004) at years 6 and 7, while total hip median BMD increased by 0.71% (P=0.3) and 0.5% (P=0.8). After tamoxifen treatment, lumbar spine median BMD decreased by 0.79% (P=0.2) and 0.30% (P=0.9) at years 6 and 7, while total hip median BMD decreased by 2.09% (P=0.0003) and 2.52% (P=0.0002). Patients with a normal BMD or who were osteopenic at 5 years did not become osteoporotic. CONCLUSIONS: Anastrozole treatment-related bone loss did not continue into the off-treatment follow-up period. The recovery in lumbar spine BMD and absence of further loss at the hip is consistent with the reduction in the annual rate of fracture observed after treatment cessation in the main ATAC trial. PMID- 20929965 TI - Chemotherapy in elderly small-cell lung cancer patients: yes we can, but should we do it? AB - BACKGROUND: Twenty percent of all newly diagnosed patients with small-cell lung cancer (SCLC) are >75 years. Elderly patients may show more toxicity due to co morbidity. We evaluated motives for adherence to treatment guidelines, completion of treatment and toxicity. PATIENTS AND METHODS: Population-based data from patients aged >=75 years and diagnosed with SCLC in 1997-2004 in The Netherlands were used (368 limited disease and 577 extensive disease). Additional data on co morbidity (Adult Co-morbidity Evaluation 27), World Health Organisation performance status (PS), treatment, motive for no chemotherapy, adaptations and underlying motive and grade 3 or 4 toxicity were gathered from the medical records. RESULTS: Forty-eight percent did not receive chemotherapy. The most common motives were refusal by the patient or family, short life expectancy or a combination of high age, co-morbidity and poor PS. Although only relatively fit elderly were selected for chemotherapy, 60%-75% developed serious toxicity, and two-thirds of all patients could not complete the full chemotherapy. CONCLUSIONS: We hypothesise that a better selection by proper geriatric assessments is needed to achieve a more favourable balance between benefit and harm. PMID- 20929966 TI - Corollary discharge, hallucinations, and dreaming. PMID- 20929967 TI - On identifying magnocellular and parvocellular responses on the basis of contrast response functions. AB - It has been proposed that magnocellular and parvocellular sensitivity in schizophrenic individuals can be assessed using steady-state visually evoked potentials (VEPs) to either low-contrast stimuli or stimuli whose contrast is modulated around a high contrast "pedestal" (Green MF, Butler PD, Chen Y, et al. Schizophr Bull. 2009;35:163-181). This suggestion faces 2 difficulties: (1) To use low-contrast stimuli to activate the magnocellular system is inconsistent with lesion studies that have shown that under many conditions, the parvocellular system responds to the lowest contrasts and (2) To rely on contrast-response relationships to identify magnocellular and parvocellular responses is difficult because other neurons exist in the visual system that have contrast-response relationships similar to those of magnocellular and parvocellular cells. PMID- 20929968 TI - Progressive structural brain changes during development of psychosis. AB - BACKGROUND: Ultra-high risk (UHR) for psychosis has been associated with widespread structural brain changes in young adults. The onset of these changes and their subsequent progression over time are not well understood. METHODS: Rate of brain change over time was investigated in 43 adolescents at UHR for psychosis compared with 30 healthy controls. Brain volumes (total brain, gray matter, white matter [WM], cerebellum, and ventricles), cortical thickness, and voxel-based morphometry were measured at baseline and at follow-up (2 y after baseline) and compared between UHR individuals and controls. Post hoc analyses were done for UHR individuals who became psychotic (N = 8) and those who did not (N = 35). RESULTS: UHR individuals showed a smaller increase in cerebral WM over time than controls and more cortical thinning in the left middle temporal gyrus. Post hoc, a more pronounced decrease over time in total brain and WM volume was found for UHR individuals who became psychotic relative to controls and a greater decrease in total brain volume than individuals who were not psychotic. Furthermore, UHR individuals with subsequent psychosis displayed more thinning than controls in widespread areas in the left anterior cingulate, precuneus, and temporo-parieto occipital area. Volume loss in the individuals who developed psychosis could not be attributed to medication use. CONCLUSION: The development of psychosis during adolescence is associated with progressive structural brain changes around the time of onset. These changes cannot be attributed to (antipsychotic) medication use and are therefore likely to reflect a pathophysiological process related to clinical manifestation of psychosis. PMID- 20929969 TI - Toward new approaches to psychotic disorders: the NIMH Research Domain Criteria project. PMID- 20929970 TI - An evaluation of the strengths and weaknesses of a register of newly diagnosed rheumatoid arthritis, 1986-2010. AB - OBJECTIVES: To evaluate the strengths and weaknesses of a register of management and outcomes of recently diagnosed RA, and allow comparisons between rheumatology centres on good clinical practice and guidelines. METHODS: A register of newly diagnosed RA was initiated in 1986 in nine different regions of England, later expanded to UK-wide membership in 2002. Standardized data collection includes disease activity, function, radiological damage, therapy, hospitalizations, major comorbidity and mortality. A centralized database generates individual reports and comparative data for each centre yearly. Aims have been compared with actual achievements and any changes over 25 years. RESULTS: Thirty rheumatology centres have recruited 2866 patients. Study outputs have included peer-reviewed scientific publications and contributions to the recent National Audit Office report on RA. Referral times into secondary care have changed little over 25 years, but time to initiation of drug therapies has decreased. Delays between publication of clinical trial evidence and management guidelines and their implementation in normal clinical practice are illustrated by relatively infrequent use of combination therapies at diagnosis. Consecutive case recruitment, centre participation and follow-up were reportedly compromised by local funding issues. Centre participants report a benefit from feedback of actual clinical practice compared with recommended standards of care. CONCLUSIONS: Most of the original objectives have been achieved. Cohort studies based predominantly in District General Hospitals provide unique insights into the natural history and impact of RA, its management, the translation of research findings into clinical practice and provide participating centres with important clinical governance and professional development opportunities. PMID- 20929971 TI - Health-related quality of life and continuation rate on first-line anti-tumour necrosis factor therapy among rheumatoid arthritis patients from the Australian Rheumatology Association Database. AB - OBJECTIVES: To describe changes in health-related quality of life (HRQoL) up to 60 months after commencing anti-TNF therapy for RA patients enrolled in the Australian Rheumatology Association Database (ARAD), and to determine the continuation rate and predictors of discontinuation of first-line anti-TNF therapy. METHODS: Responses to the HAQ, Assessment of Quality of Life, Medical Outcomes Study Short Form-36 (SF-36) and European Quality of Life-5 Dimensions (EQ-5D) were extracted from ARAD for patients commencing anti-TNF therapy and analysed in 6-monthly intervals from the start date. Predictors of discontinuation of therapy were assessed using Cox regression. RESULTS: Since September 2001, 2601 RA patients have enrolled in ARAD; 1801 have used anti-TNF therapy. Before starting the therapy, all HRQoL scores were below the population norms, but showed improvements in the first 6 months. From 12 to 60 months, HRQoL remained stable but below population means. Data to 60 months were available for 106 patients; 47% were still on first-line therapy at 5 years, all were using concurrent DMARDs and 55% were using concurrent prednisolone. Predictors of discontinuation of therapy were poorer HRQoL scores, a more recent therapy start date, concurrent prednisolone use and self-reported severe infection. Older patients and those with longer symptom duration were more likely to remain on therapy. CONCLUSIONS: In routine practice, HRQoL scores improve rapidly within 6 months of starting anti-TNFs and then remain stable for up to 60 months. Almost half remain on first-line therapy. PMID- 20929972 TI - Meta-analysis of systemic lupus erythematosus and the risk of cervical neoplasia. AB - OBJECTIVE: Individuals with SLE have a heightened risk of developing atypical cervical smears or cervical cancer. Many studies have investigated the association between SLE and cervical neoplasia risk. However, the risk for SLE associated with cervical neoplasia risk is unclear. The present meta-analysis clarified the risk of cervical neoplasia in patients with SLE. METHODS: A systematic review of English-language studies was conducted. Data on the risk of cervical neoplasia risk in patients with SLE were pooled using case-control models. Replication studies that tested the association between SLE and cervical neoplasia risk were reviewed for meta-analysis. The meta-analysis procedure was used to pool odds ratios (ORs) with 95% CIs to evaluate the association. RESULTS: Seven replication studies fulfilled the selection criteria for inclusion in the meta-analysis. Homogeneity was confirmed across the replication studies. The common OR was 4.17 (95% CI 3.03, 5.74; P < 0.00001) for the study. The association was confirmed when individuals with SLE have an increased susceptibility to cervical neoplasia risk. CONCLUSION: This meta-analysis demonstrates the positive association between SLE and cervical neoplasia risk. Individuals with SLE have a heightened risk of developing cervical cancer. PMID- 20929973 TI - The dynamics of implicit skill consolidation in young and elderly adults. AB - OBJECTIVES: Implicit skill learning underlies not only motor but also cognitive and social skills; it is therefore an important aspect of life from infancy to old age. We studied aging effects on the time course of implicit skill consolidation. METHODS: Young and elderly adults performed a probabilistic implicit sequence-learning task before and after a 12-, a 24-hr, and a 1-week interval. The task enabled us to separate the components of skill learning and consolidation: (a) general skill and (b) sequence-specific learning (SSL). RESULTS: We found improvement of general skill for the young adults in all delay conditions. The elderly adults also showed enhancement after the 12-hr period, revealing brain plasticity similar to young adults. This improvement disappeared in the 24-hr and the 1-week delay conditions. Regarding SSL, no improvement was found in either age group and at either consolidation intervals. In contrast, sequences-specific knowledge decreased in the elderly group independently of the delay. DISCUSSION: These results draw attention to the fact that consolidation is not a single process, rather there are multiple mechanisms that are differentially affected by time course and by aging. PMID- 20929974 TI - Smelling chemosensory signals of males in anxious versus nonanxious condition increases state anxiety of female subjects. AB - The hypothesis of this experiment was that humans in an anxious state compared with a nonanxious state are able to increase anxiety levels in other humans via their body odors. Specifically, we hypothesized that male chemosensory anxiety signals compared with neutral chemosignals increase state anxiety of female subjects. Thirteen male subjects participated in 2 different sweat donation sessions: chemosignals were collected during participation in a high rope course (anxiety condition) and in an ergometer workout (neutral condition). State and trait anxiety were evaluated in 20 female odor recipients using Spielberger's state-trait anxiety inventory in a double-blind design. Comparison of state anxiety of odor donors between control and anxiety condition differed significantly indicating that our model of anxiety induction successfully led to the expected change in emotion. Comparison of state anxiety of odor recipients showed a trend toward higher state anxiety in the anxiety condition compared with the neutral condition after 5 min of odor exposure. After 20 min of odor exposure, state anxiety of female subjects was significantly higher during the perception of sweat collected during the anxiety condition in comparison with the perception of sweat collected during the neutral condition. This experiment gives evidence that male anxiety chemosignals compared with neutral chemosignals are capable of inducing an increased state anxiety in female subjects. PMID- 20929976 TI - Direct recruitment of insulin receptor and ERK signaling cascade to insulin inducible gene loci. AB - OBJECTIVE: Insulin receptor (IR) translocates to the nucleus, but its recruitment to gene loci has not been demonstrated. Here, we tested the hypothesis that IR and its downstream mitogenic transducers are corecruited to two prototypic insulin-inducible genes: early growth response 1 (egr-1), involved in mitogenic response, and glucokinase (Gck), encoding a key metabolic enzyme. RESEARCH DESIGN AND METHODS: We used RNA and chromatin from insulin-treated rat hepatic tumor cell line expressing human insulin receptor (HTC-IR) and livers from lean and insulin-resistant ob/ob glucose-fed mice in quantitative RT-PCR and chromatin immunoprecipitation studies to determine gene expression levels and associated recruitment of RNA polymerase II (Pol II), insulin receptor, and cognate signaling proteins to gene loci, respectively. RESULTS: Insulin-induced egr-1 mRNA in HTC-IR cells was associated with corecruitment of IR signaling cascade (IR, SOS, Grb2, B-Raf, MEK, and ERK) to this gene. Recruitment profiles of phosphorylated IR, B-Raf, MEK, and Erk along egr-1 transcribed region were similar to those of elongating Pol II. Glucose-feeding increased Gck mRNA expression in livers of lean but not ob/ob mice. In lean mice, there was glucose feeding-induced recruitment of IR and its transducers to Gck gene synchronized with elongating Pol II. In sharp contrast, in glucose-fed ob/ob mice, the Gck recruitment patterns of active MEK/Erk, IR, and Pol II were asynchronous. CONCLUSIONS: IR and its signal transducers recruited to genes coupled to elongating Pol II may play a role in maintaining productive mRNA synthesis of target genes. These studies suggest a possibility that impaired Pol II processivity along genes bearing aberrant levels of IR/signal transducers is a previously unrecognized facet of insulin resistance. PMID- 20929977 TI - Mitochondrial biogenesis and peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) deacetylation by physical activity: intact adipocytokine signaling is required. AB - OBJECTIVE Transcriptional peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) plays a key role in mitochondrial biogenesis and energy metabolism and is suggested to be involved in the exercise-induced increase in mitochondrial content. PGC-1alpha activity is regulated by posttranslational modifications, among them acetylation or phosphorylation. Accordingly, the deacetylase SIRT1 and the kinase AMPK increase PGC-1alpha activity. RESEARCH DESIGN AND METHODS We tested whether chronic treadmill exercise or a single exercise session modifies PGC-1alpha activation and mitochondrial biogenesis differentially in obese ob/ob mice with dysregulated adiponectin/leptin-mediated AMPK activation compared with C57BL/6J wild-type mice. RESULTS Exercise training (12 weeks) induced adiponectin and lowered plasma insulin and glucose, suggesting improved insulin sensitivity in wild-type mice. It enhanced mitochondrial biogenesis in red gastrocnemius muscle, as indicated by increased mRNA expression of transcriptional regulators and primary mitochondrial transcripts, increased mtDNA content, and citrate synthase activity. Parallel to this, we observed AMPK activation, PGC-1alpha deacetylation, and SIRT1 induction in trained wild-type mice. Although none of these exercise-induced changes were detected in ob/ob mice, comparable effects on mitochondrial respiration were observed. A single exercise session resulted in comparable changes in wild-type mice. These changes remained detectable 6 h after the exercise session but had disappeared after 24 h. Treatment of C2C12 myoblasts with leptin or adiponectin resulted in increased AMPK phosphorylation and PGC-1alpha deacetylation. CONCLUSIONS Chronic exercise induces mitochondrial biogenesis in wild-type mice, which may require intact AMPK activation by adipocytokines and involve SIRT1 dependent PGC-1alpha deacetylation. Trained ob/ob mice appear to have partially adapted to reduced mitochondrial biogenesis by AMPK/SIRT1/PGC-1alpha-independent mechanisms without mtDNA replication. PMID- 20929978 TI - Heart failure reversal by ventricular unloading in patients with chronic cardiomyopathy: criteria for weaning from ventricular assist devices. AB - AIMS: Unloading-promoted reversal of heart failure (HF) allows long-term transplant-free outcome after ventricular assist device (VAD) removal. However, because few patients with chronic cardiomyopathy (CCM) were weaned from VADs (the majority only recently), the reliability of criteria used for weaning decisions to predict long-term post-weaning success is barely known. After 15 years of weaning experience, we assessed this issue. METHODS AND RESULTS: In 47 patients with CCM as the underlying cause for HF, who were part of a total of 90 patients weaned from bridge-to-transplant-designed VADs since 1995, we analysed data on cardiac morphology and function collected before VAD implantation, echocardiographic parameters recorded during 'off-pump' trials, duration of HF before implantation, and stability of recovery before and early after VAD removal. Post-weaning 5 year freedom from HF recurrence reached 66%. Only five patients (10.6%) died due to HF recurrence or weaning-related complications. Pre explantation off-pump left ventricular ejection fraction (LVEF) of >=50 and >=45% revealed predictive values for cardiac stability lasting >=5 years after VAD removal of 91.7 and 79.1%, respectively. With each unit of LVEF reduction, the risk of HF recurrence became 1.5 times higher. The predictive value of LVEF >=45% also became >90% if additional parameters like pre-explantation LV size and geometry, stability of unloading-induced cardiac improvement before VAD removal, and HF duration before VAD implantation were also considered. Definite cut-off values for certain parameters (including tissue-Doppler-derived LV wall motion velocity) allowed formulation of weaning criteria with high predictability for post-weaning stability, also in patients with incomplete cardiac recovery. CONCLUSIONS: Ventricular assist device removal in CCM patients is feasible and can be successful even after incomplete cardiac recovery. Parameters of pre explantation cardiac function, LV size and geometry, their stability during final off-pump trials, and HF duration allow detection of patients with the potential to remain stable for >5 post-weaning years. PMID- 20929979 TI - Predictors of morbidity and mortality in contemporary Fontan patients: results from a multicenter study including cardiopulmonary exercise testing in 321 patients. AB - AIMS: previous studies have established an association between exercise intolerance and increased morbidity and mortality in congenital heart disease patients. We aimed to clarify if exercise intolerance is associated with poor outcome in Fontan patients and to identify risk factors for mortality, transplantation, and cardiac-related hospitalization. METHODS AND RESULTS: a total of 321 Fontan patients (57% male, mean age 20.9 +/- 8.6 years) who underwent cardiopulmonary exercise testing (CPET) at four major European centres between 1997 and 2008 were included. During a median follow-up of 21 months, 22 patients died and 6 patients underwent cardiac transplantation (8.7%), resulting in an estimated 5-year transplant-free survival of 86%. Parameters of CPET were strongly related to increased risk of hospitalization, but-with the exception of heart rate reserve-unrelated to risk of death or transplantation. In contrast, patients with clinically relevant arrhythmia had a 6.0-fold increased risk of death or transplantation (P < 0.001). Furthermore, patients with atriopulmonary/ ventricular Fontan had a 3.7-fold increased risk of death or transplantation compared with total cavopulmonary connection patients (P= 0.009). The combination of clinically relevant arrhythmia, atriopulmonary/-ventricular Fontan, and signs of symptomatic or decompensated heart failure was associated with a particularly poor outcome (3-year mortality 25%). CONCLUSION: on short-term follow-up, most parameters of CPET are associated with increased risk of hospitalization but not death or transplantation in contemporary Fontan patients. Only decreased heart rate reserve and a history of clinically relevant arrhythmia, atriopulmonary/ ventricular Fontan, and/or heart failure requiring diuretic therapy are associated with poor prognosis, potentially identifying patients requiring medical and/or surgical attention. PMID- 20929975 TI - Malformation syndromes caused by disorders of cholesterol synthesis. AB - Cholesterol homeostasis is critical for normal growth and development. In addition to being a major membrane lipid, cholesterol has multiple biological functions. These roles include being a precursor molecule for the synthesis of steroid hormones, neuroactive steroids, oxysterols, and bile acids. Cholesterol is also essential for the proper maturation and signaling of hedgehog proteins, and thus cholesterol is critical for embryonic development. After birth, most tissues can obtain cholesterol from either endogenous synthesis or exogenous dietary sources, but prior to birth, the human fetal tissues are dependent on endogenous synthesis. Due to the blood-brain barrier, brain tissue cannot utilize dietary or peripherally produced cholesterol. Generally, inborn errors of cholesterol synthesis lead to both a deficiency of cholesterol and increased levels of potentially bioactive or toxic precursor sterols. Over the past couple of decades, a number of human malformation syndromes have been shown to be due to inborn errors of cholesterol synthesis. Herein, we will review clinical and basic science aspects of Smith-Lemli-Opitz syndrome, desmosterolosis, lathosterolosis, HEM dysplasia, X-linked dominant chondrodysplasia punctata, Congenital Hemidysplasia with Ichthyosiform erythroderma and Limb Defects Syndrome, sterol-C 4 methyloxidase-like deficiency, and Antley-Bixler syndrome. PMID- 20929980 TI - Paradoxical pulmonary embolism. PMID- 20929981 TI - Substrate ablation of ventricular tachycardia in structural heart disease: a new dimension? PMID- 20929982 TI - Subtotal aortic occlusion due to dehiscence of a supracoronary graft 10 years after surgery for acute type A dissection. PMID- 20929983 TI - Sleep apnoea and malignant ventricular arrhythmias in heart failure. PMID- 20929984 TI - Mycotoxin citrinin induced cell cycle G2/M arrest and numerical chromosomal aberration associated with disruption of microtubule formation in human cells. AB - As a nephrotoxic mycotoxin, citrinin (CTN) contaminates various foodstuffs and animal feed commodities. In the present study, the effects of CTN on cell cycle arrest and microtubule formation were investigated by applying human embryonic kidney (HEK293) cells as a model. Exposure of HEK293 cells to CTN resulted in an arrest of cell cycle G2/M in a concentration-dependent increase. Administrating CTN elevated the expression levels of p53 and p21 proteins, yet attenuated the signals of phosphorylated cell division cycle 2 (cdc2). Furthermore, treating HEK293 with CTN increased both the value of mitotic index and the population of cells recognized by antibody mitotic protein monoclonal 2, suggesting that arrest of CTN-induced cell cycle occurred mainly during the mitotic phase. With the assistance of immunocytostaining of alpha-tubulin, CTN was found to disrupt the stable microtubule skeleton during the interphase of cell cycle and also interfere with the mitotic spindle integrity during mitosis. Additionally, for either in vivo or in vitro assays, CTN effectively inhibited tubulin polymerization in a concentration-dependent manner. When human peripheral blood mononuclear cells were exposed to CTN, the percentage of cells with numerical chromosome changes was increased by 4.3-fold over that of vehicle-treated group. Results of this study suggest that CTN-activated G2/M arrest primarily arises from the inhibition of tubulin polymerization and associated mitotic spindle formation. Additionally, disruption of microtubule organization by CTN also contributes to the induction of numerical chromosome aberration in human cells. PMID- 20929985 TI - ASK1 overexpression accelerates paraquat-induced autophagy via endoplasmic reticulum stress. AB - Apoptosis signal-regulating kinase 1 (ASK1) is activated by various types of stress, including, endoplasmic reticulum (ER) stress. ER stress-induced ASK1 activation could play an important role both in neuronal apoptosis and an autophagic response in the pathogenesis of several neurodegenerative diseases, including Parkinson's disease. The mechanism by which ASK1 executes apoptosis and/or autophagy under ER stress is still unclear. We have addressed this question using SH-SY5Y cells overexpressing wild-type (WT) ASK1. We show an important autophagic response and an acceleration of the paraquat (PQ)-induced autophagy with hallmarks as accumulation of autophagic vacuoles, activation of beclin-1, accumulation of LC3 II, p62 degradation, and mammalian target of rapamycin dephosphorylation. Inhibition of autophagy caused an exacerbation of the apoptosis induced by WT ASK1 overexpression with or without PQ. These data support the idea that the autophagic response could have a protector role. We found also an increase in the phosphorylation of the proteins such as IRE1 and eIF2alpha in response to both the overexpression of WT ASK1 and pesticide exposure. These data suggest that the WT ASK1 overexpression-induced autophagy is an event that occurs in parallel with ER stress activation. The importance of ER stress in the autophagy induced by ASK1 and/or PQ was confirmed with salubrinal, a selective inhibitor of eIF2alpha dephosphorylation. In conclusion, we report that PQ induces an early ER stress response that is correlated with the activation of autophagy as a protective response, which is accelerated in cells that overexpress WT ASK1. However, when the toxic stimuli remain, the cell eventually succumbs to apoptosis. PMID- 20929986 TI - Physicochemical characterization and ecotoxicological assessment of CeO2 nanoparticles using two aquatic microorganisms. AB - The physicochemical properties of nanoparticles determine their interaction with living organisms. Four different cerium oxide nanoparticles, including commercial materials, were characterized and compared with a micron-sized ceria. The formation of aggregates as well as zeta-potential, surface area, and chemical composition were determined. The formation of primary particle aggregates was a slow process that led to different particle sizes depending on the composition of the medium. In this paper, we describe the toxicity of cerium oxide for the self luminescent cyanobacterial recombinant strain Anabaena CPB4337 and the green alga Pseudokirchneriella subcapitata. The toxicity for Anabaena exposed to nanoparticles in pure water for 24 h ranged from 0.27 to 6.3 mg/l; P. subcapitata EC(50) (yielded effective concentration of nanoparticles that inhibits the cellular function of interest by 50%) values in the 2.4-29.6 mg/l range. Images of both organisms showed membrane disruption and highly damaged cells. Free cerium was highly toxic for both organisms, but the negligible amount found dissolved in the nanoparticle suspensions could not explain the observed toxic effect of nanoceria on the aquatic organisms; the dissolution of zinc could contribute to the toxicity of bulk material but could not explain the toxic effect of nanoceria either. We found no evidence of nanoparticle uptake by cells, but our observations suggested that their toxic mode of action required direct contact between nanoparticles and cells; in the case of the cyanobacterium, cells completely coated by layers of ceria nanoparticles were observed. Cell damage most probably took place by cell wall and membrane disruption; further research is needed to find out whether the oxidative activity of ceria could be responsible. PMID- 20929987 TI - Role of PTH1R internalization in osteoblasts and bone mass using a phosphorylation-deficient knock-in mouse model. AB - Phosphorylation, internalization, and desensitization of G protein-coupled receptors, such as the parathyroid hormone (PTH) and PTH-related peptide (PTHrP) receptor (PTH1R), are well characterized and known to regulate the cellular responsiveness in vitro. However, the role of PTH1R receptor phosphorylation in bone formation and osteoblast functions has not yet been elucidated. In previous studies, we demonstrated impaired internalization and sustained cAMP stimulation of a phosphorylation-deficient (pd) PTH1R in vitro, and exaggerated cAMP and calcemic responses to s.c. PTH infusion in pdPTH1R knock-in mouse model. In this study, we examined the impact of impaired PTH1R phosphorylation on the skeletal phenotype of mice maintained on normal, low, and high calcium diets. The low calcium diet moderately reduced (P<0.05) bone volume and trabecular number, and increased trabecular spacing in both wild-type (WT) and pd mice. The effects, however, seem to be less pronounced in the female pd compared to WT mice. In primary calvarial osteoblasts isolated from 2-week-old pd or WT mice, PTH and PTHrP decreased phosphorylated extracellular signal-regulated kinases 1/2 (pERK1/2), a member of mitogen-activated protein kinase, and cyclin D1, a G1/S phase cyclin, in vitro. In contrast to WT osteoblasts, down-regulation of cyclin D1 was sustained for longer periods of time in osteoblasts isolated from the pd mice. Our results suggest that adaptive responses of intracellular signaling pathways in the pd mice may be important for maintaining bone homeostasis. PMID- 20929988 TI - Effect of adding pharmacists to primary care teams on blood pressure control in patients with type 2 diabetes: a randomized controlled trial. AB - OBJECTIVE: To evaluate the effect of adding pharmacists to primary care teams on the management of hypertension and other cardiovascular risk factors in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: We conducted a randomized controlled trial with blinded ascertainment of outcomes within primary care clinics in Edmonton, Canada. Pharmacists performed medication assessments and limited history and physical examinations and provided guideline-concordant recommendations to optimize medication management. Follow-up contact was completed as necessary. Control patients received usual care. The primary outcome was a >=10% decrease in systolic blood pressure at 1 year. RESULTS: A total of 260 patients were enrolled, 57% were women, the mean age was 59 years, diabetes duration was 6 years, and blood pressure was 129/74 mmHg. Forty-eight of 131 (37%) intervention patients and 30 of 129 (23%) control patients achieved the primary outcome (odds ratio 1.9 [95% CI 1.1-3.3]; P = 0.02). Among 153 patients with inadequately controlled hypertension at baseline, intervention patients (n = 82) were significantly more likely than control patients (n = 71) to achieve the primary outcome (41 [50%] vs. 20 [28%]; 2.6 [1.3-5.0]; P = 0.007) and recommended blood pressure targets (44 [54%] vs. 21 [30%]; 2.8 [1.4-5.4]; P = 0.003). The 10 year risk of cardiovascular disease, based on changes to the UK Prospective Diabetes Study Risk Engine, were predicted to decrease by 3% for intervention patients and 1% for control patients (P = 0.005). CONCLUSIONS: Significantly more patients with type 2 diabetes achieved better blood pressure control when pharmacists were added to primary care teams, which suggests that pharmacists can make important contributions to the primary care of these patients. PMID- 20929989 TI - Five-year outcomes in high-risk participants in the Detection of Ischemia in Asymptomatic Diabetics (DIAD) study: a post hoc analysis. AB - OBJECTIVE: To estimate baseline cardiovascular risk of 1,123 participants in the Detection of Ischemia in Asymptomatic Diabetics (DIAD) study and to assess cardiac event rates and the effect of screening on outcomes in these higher-risk participants. RESEARCH DESIGN AND METHODS: Baseline cardiovascular risk was assessed using four established methods: Framingham score, UK Prospective Diabetes Study (UKPDS) risk engine, criteria of the French-Speaking Association for the Study of Diabetes and Metabolic Diseases, and the presence or absence of metabolic syndrome. Cardiac events (cardiac death or nonfatal myocardial infarction) were assessed during the 4.8-year follow-up in participants with intermediate/high cardiovascular risk. RESULTS: By various risk-stratification approaches, 53-75% of participants were defined as having intermediate or high cardiovascular risk. The prevalence of inducible ischemia on screening in these individuals ranged from 21 to 24%, similar to lower-risk participants (19-23%). Cardiac event rates were greater in intermediate-/high-risk versus low-risk groups, but this was only significant for the UKPDS risk engine (4.2 vs. 1.2%, P = 0.002). The annual cardiac event rate was <1% in all risk groups, except in the high-risk UKPDS group (~2% per year). In intermediate-/high-risk participants randomized to screening versus no screening, 4.8-year cardiac event rates were similar (2.5-4.8% vs. 3.1-3.7%). CONCLUSIONS: A substantial portion of the DIAD population was defined as having intermediate/high baseline cardiovascular risk. Nevertheless, their annual cardiac event rate was low and not altered by routine screening for inducible ischemia. PMID- 20929990 TI - Pharmacological treatment of the pathogenetic defects in type 2 diabetes: the randomized multicenter South Danish Diabetes Study. AB - OBJECTIVE: To determine the effect of treatment with insulin aspart compared with NPH insulin, together with metformin/placebo and rosiglitazone/placebo. The hypothesis was that combined correction of major pathogenetic defects in type 2 diabetes would result in optimal glycemic control. RESEARCH DESIGN AND METHODS: This study was a 2-year investigator-driven randomized partly placebo-controlled multicenter trial in 371 patients with type 2 diabetes on at least oral antiglycemic treatment. Patients were assigned to one of eight treatment groups in a factorial design with insulin aspart at mealtimes versus NPH insulin once daily at bedtime, metformin twice daily versus placebo, and rosiglitazone twice daily versus placebo. The main outcome measurement was change in A1C. RESULTS: A1C decreased more in patients treated with insulin aspart compared with NPH ( 0.41 +/- 0.10%, P < 0.001). Metformin decreased A1C compared with placebo (-0.60 +/- 0.10%, P < 0.001), as did rosiglitazone (-0.55 +/- 0.10%, P < 0.001). Triple therapy (rosiglitazone, metformin, and any insulin) resulted in a greater reduction in A1C than rosiglitazone plus insulin (-0.50 +/- 0.14%, P < 0.001) and metformin plus insulin (-0.45 +/- 0.14%, P < 0.001). Aspart was associated with a higher increase in body weight (1.6 +/- 0.6 kg, P < 0.01) and higher incidence of mild daytime hypoglycemia (4.9 +/- 7.5 vs. 1.7 +/- 5.4 number/person/year, P < 0.001) compared with NPH. CONCLUSIONS: Insulin treatment of postprandial hyperglycemia results in lower A1C than treatment of fasting hyperglycemia, at the expense of higher body weight and hypoglycemic episodes. However, insulin therapy has to be combined with treatment of both peripheral and liver insulin resistance to normalize blood glucose, and in this case, the insulin regimen is less important. PMID- 20929991 TI - Fetuin-A levels are increased in patients with type 2 diabetes and peripheral arterial disease. AB - OBJECTIVE: Low levels of fetuin-A, a systemic calcification inhibitor, are linked to mortality in patients on dialysis. In contrast, elevated fetuin-A is associated with cardiovascular events in non-renal patients. We investigated fetuin-A in patients with type 2 diabetes and peripheral arterial disease (PAD). RESEARCH DESIGN AND METHODS: We studied fetuin-A in 76 patients with PAD and normal glucose metabolism (NGM-PAD) and in 129 patients with PAD and type 2 diabetes (type 2 diabetes-PAD). Additionally, 40 patients with diabetes without any complications (type 2 diabetes-non-PAD) were examined. RESULTS: Type 2 diabetes-PAD subjects (399 +/- 155 MUg/ml) had significantly higher fetuin-A levels than type 2 diabetes-non-PAD subjects (247 +/- 42; P < 0.001). In NGM-PAD subjects (376 +/- 144), fetuin-A was significantly higher than in type 2 diabetes non-PAD subjects (P < 0.001). Type 2 diabetes-PAD patients with mediasclerosis had lower fetuin-A than subjects without (P < 0.03). Regression analysis in type 2 diabetes-PAD subjects revealed that glycated A1C (P < 0.001) and mediasclerosis (P = 0.004) were the strongest predictors of fetuin-A. Multivariate regression revealed that a 1-SD increase in fetuin-A was associated with an odds ratio (OR) of 2.1 (95% CI 1.1-3.3; P < 0.001) for the prevalence of PAD and an OR of 1.4 (1.0-1.7, P = 0.039) for the prevalence of myocardial infarction. CONCLUSIONS: In contrast to previous findings, fetuin-A was higher in type 2 diabetes-PAD patients than in type 2 diabetes-non-PAD patients. In NGM-PAD patients, fetuin-A was also higher than in type 2 diabetes-non-PAD patients. In type 2 diabetes-PAD patients, fetuin-A was inversely associated with mediasclerosis-the calcification process pathognomonic for diabetic PAD. This association persisted in multivariate regression, which is in line with the calcification inhibition in coronary heart or renal disease. PMID- 20929992 TI - Association of depressive symptoms with impaired glucose regulation, screen detected, and previously known type 2 diabetes: findings from the Finnish D2D Survey. AB - OBJECTIVE: To study the association between impaired glucose regulation (IGR), screen-detected type 2 diabetes, and previously known diabetes and depressive symptoms. RESEARCH DESIGN AND METHODS: Altogether, 2,712 participants from three hospital districts in Finland attended a health examination. Cutoff scores >=10 and >=16 in the 21-item Beck Depression Inventory (BDI-21) were used for depressive symptoms. The participants were defined as having known diabetes if they reported diabetes. An oral glucose tolerance test was used to detect normal glucose regulation (NGR), impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and screen-detected diabetes. The participants were defined as having IGR if they had IFG or IGT. RESULTS: Prevalence of depressive symptoms, defined as a BDI-21 cutoff score >=10, was 14.4% for those with NGR, 13.7% for those with IGR, 14.8% for those with screen-detected diabetes, and 26.4% for those with previously known diabetes. The corresponding prevalences for a cutoff score >=16 were 3.4, 3.4, 4.2, and 7.5%, respectively. Compared with NGR and adjusted for demographic, lifestyle, and biological factors, the odds ratios for IGR, screen-detected diabetes, and previously known diabetes were 0.91 (95% CI 0.69-1.20), 0.70 (0.45-1.08), and 1.35 (0.84-2.15), respectively, for a cutoff score >=10. For a cutoff score >=16, the corresponding odds ratios were 1.05 (0.62-1.76), 0.87 (0.40-1.90), and 1.56 (0.69-3.50), respectively. CONCLUSIONS: Participants with diagnosed diabetes had a higher prevalence of depressive symptoms than participants with NGR, IGR, and previously unknown diabetes. When potential confounding factors were included in the analysis, previously known diabetes was not significantly associated with depressive symptoms. PMID- 20929993 TI - Human enterovirus RNA in monthly fecal samples and islet autoimmunity in Norwegian children with high genetic risk for type 1 diabetes: the MIDIA study. AB - OBJECTIVE: To test whether the frequency of human enterovirus RNA in fecal samples collected monthly from early infancy was associated with development of multiple islet autoantibodies in children with the highest risk HLA genotype. RESEARCH DESIGN AND METHODS: Individuals carrying the HLA DRB1*0401-DQA1*03 DQB1*0302/DRB1*03-DQA1*05-DQB1*02 genotype were identified at birth and followed with monthly stool samples from age 3 to 35 months. Blood samples taken at age 3, 6, 9, and 12 months and then annually were tested for autoantibodies to insulin, GAD 65 and IA-2. Among 911 children, 27 developed positivity for two or more islet autoantibodies in two or more consecutive samples (case subjects). Two control subjects per case subject were matched by follow-up time, date of birth, and county of residence. Stool samples were analyzed for enterovirus with a semiquantitative real-time RT-PCR. RESULTS: The frequency of human enterovirus RNA in stool samples from case subjects before seroconversion (43 of 339, 12.7%) did not differ from the frequency in control subjects (94 of 692, 13.6%) (P = 0.97). Results remained essentially unchanged after adjustment for potential confounders, restriction to various time windows before seroconversion, or infections in the 1st year of life or after inclusion of samples collected after seroconversion. There was no difference in the average quantity of enterovirus RNA or in the frequency of repeatedly positive samples. The estimated relative risk for islet autoimmunity per enterovirus RNA-positive sample during follow-up (nested case-control analysis) was 1.12 (95% CI 0.66-1.91). CONCLUSIONS: There was no support for the hypothesis that fecal shedding of enteroviral RNA is a major predictor of advanced islet autoimmunity. PMID- 20929994 TI - Glutathione synthesis is diminished in patients with uncontrolled diabetes and restored by dietary supplementation with cysteine and glycine. AB - OBJECTIVE: Sustained hyperglycemia is associated with low cellular levels of the antioxidant glutathione (GSH), which leads to tissue damage attributed to oxidative stress. We tested the hypothesis that diminished GSH in adult patients with uncontrolled type 2 diabetes is attributed to decreased synthesis and measured the effect of dietary supplementation with its precursors cysteine and glycine on GSH synthesis rate and oxidative stress. RESEARCH DESIGN AND METHODS: We infused 12 diabetic patients and 12 nondiabetic control subjects with [2H2] glycine to measure GSH synthesis. We also measured intracellular GSH concentrations, reactive oxygen metabolites, and lipid peroxides. Diabetic patients were restudied after 2 weeks of dietary supplementation with the GSH precursors cysteine and glycine. RESULTS: Compared with control subjects, diabetic subjects had significantly higher fasting glucose (5.0 +/- 0.1 vs. 10.7 +/- 0.5 mmol/l; P < 0.001), lower erythrocyte concentrations of glycine (514.7 +/ 33.1 vs. 403.2 +/- 18.2 MUmol/l; P < 0.01), and cysteine (25.2 +/- 1.5 vs. 17.8 +/- 1.5 MUmol/l; P < 0.01); lower concentrations of GSH (6.75 +/- 0.47 vs. 1.65 +/- 0.16 MUmol/g Hb; P < 0.001); diminished fractional (79.21 +/- 5.75 vs. 44.86 +/- 2.87%/day; P < 0.001) and absolute (5.26 +/- 0.61 vs. 0.74 +/- 0.10 MUmol/g Hb/day; P < 0.001) GSH synthesis rates; and higher reactive oxygen metabolites (286 +/- 10 vs. 403 +/- 11 Carratelli units [UCarr]; P < 0.001) and lipid peroxides (2.6 +/- 0.4 vs. 10.8 +/- 1.2 pg/ml; P < 0.001). Following dietary supplementation in diabetic subjects, GSH synthesis and concentrations increased significantly and plasma oxidative stress and lipid peroxides decreased significantly. CONCLUSIONS: Patients with uncontrolled type 2 diabetes have severely deficient synthesis of glutathione attributed to limited precursor availability. Dietary supplementation with GSH precursor amino acids can restore GSH synthesis and lower oxidative stress and oxidant damage in the face of persistent hyperglycemia. PMID- 20929995 TI - Risk of cardiovascular disease events in patients with type 2 diabetes prescribed the glucagon-like peptide 1 (GLP-1) receptor agonist exenatide twice daily or other glucose-lowering therapies: a retrospective analysis of the LifeLink database. AB - OBJECTIVE: To test the hypothesis that exenatide twice daily reduces the relative incidence of cardiovascular disease (CVD) events among patients with type 2 diabetes compared with other glucose-lowering agent(s). RESEARCH DESIGN AND METHODS: A retrospective database analysis was performed of the LifeLink database of medical and pharmaceutical insurance claims for June 2005 through March 2009. Patients with no history in the preceding 9 months of myocardial infarction, ischemic stroke, or coronary revascularization procedure were assigned to the exenatide-initiated or non-exenatide-initiated cohorts based on the first new prescription filled and reassigned if exenatide was prescribed or discontinued. Incident CVD events (myocardial infarction, ischemic stroke, or coronary revascularization procedure) were identified by ICD-9-CM diagnosis codes. Patient outcomes were adjusted for differences in clinical and demographic characteristics and compared using propensity score-weighted discrete time survival analysis with time-varying exposure to exenatide. RESULTS: A total of 39,275 patients with type 2 diabetes were treated with exenatide twice daily, and 381,218 patients were treated with other glucose-lowering therapies. Patients who initiated exenatide were more likely to have prior ischemic heart disease, obesity, hyperlipidemia, hypertension, and/or other comorbidities at baseline. Exenatide-treated patients were less likely to have a CVD event than non exenatide-treated patients (hazard ratio 0.81; 95% CI 0.68-0.95; P = 0.01) and lower rates of CVD-related hospitalization (0.88; 0.79-0.98; P = 0.02) and all cause hospitalization (0.94; 0.91-0.97; P < 0.001). CONCLUSIONS: Exenatide twice daily treatment was associated with a lower risk of CVD events and hospitalizations than treatment with other glucose-lowering therapies. PMID- 20929996 TI - Repeated episodes of hypoglycemia as a potential aggravating factor for preclinical atherosclerosis in subjects with type 1 diabetes. AB - OBJECTIVE: To evaluate through early preclinical atherosclerosis assessment whether repeated episodes of hypoglycemia represent an aggravating factor for macrovascular disease in type 1 diabetes. RESEARCH DESIGN AND METHODS: After sample-size calculation, a case-control study of 25 patients with type 1 diabetes and repeated severe/nonsevere hypoglycemia (H-group) compared with 20 age- and sex-matched type 1 diabetes control subjects (C-group) was designed. Assessment of preclinical atherosclerosis consisted of flow-mediated brachial dilatation (FMD) and carotid and femoral intima-media thickness (IMT) studies. To consider hypoglycemia awareness, two different questionnaires and symptomatic response to an acute induction to hypoglycemia were used. Evaluation of the glycemic profile was obtained from continuous glucose monitoring. Endothelial function/inflammation markers were measured in euglycemia/hypoglycemia. A multivariate linear regression analysis was performed to test whether repeated hypoglycemia was independently associated with atherosclerosis. RESULTS: H-group subjects displayed hypoglycemia unawareness and presented a higher percentage of continuous glucose values and area under the curve <70 mg/dl compared with the C group (14.2 +/- 8.9 vs. 6.3 +/- 7.1%, P < 0.02 and 2.4 +/- 1.8 vs. 0.6 +/- 1.0 mg/dl/day, P < 0.01). The percentage of maximal FMD was lower in the H-group than in the C-group (6.52 +/- 2.92 vs. 8.62 +/- 3.13%, P < 0.05). A significantly higher IMT was observed at both carotid and femoral sites in the H-group (carotid 0.53 +/- 0.09 vs. 0.47 +/- 0.08 mm, P < 0.05 and femoral 0.51 +/- 0.17 vs. 0.39 +/- 0.09 mm, P < 0.05). Baseline inflammation and endothelial function markers were higher in the H-group (leukocytes 7.0 +/- 1.8 vs. 5.6 +/- 1.4 * 103/ml, von Willebrand factor 119 +/- 29 vs. 93 +/- 26%, fibrinogen 2.82 +/- 0.64 vs. 2.29 +/ 0.44 g/l, and soluble intercellular adhesion molecule-1 408 +/- 224 vs. 296 +/- 95 ng/ml; P < 0.05 for all). CONCLUSIONS: In addition to the induction of hypoglycemia unawareness and an increased risk for severe hypoglycemia, repeated hypoglycemia could be related to and considered an aggravating factor for preclinical atherosclerosis in type 1 diabetes. The precise mechanisms explaining this association remain to be clarified. PMID- 20929997 TI - Osteoprotegerin and mortality in type 2 diabetic patients. AB - OBJECTIVE: Plasma osteoprotegerin (OPG) is an emerging strong and independent predictor of cardiovascular disease (CVD) in high-risk populations. OPG is a bone related glycopeptide produced by vascular smooth muscle cells, and increased plasma OPG levels may reflect arterial vascular damage. We aimed to investigate the prognostic value of OPG in relation to all-cause and cardiovascular mortality in a cohort of type 2 diabetic patients. RESEARCH DESIGN AND METHODS: In a prospective observational follow-up study, 283 type 2 diabetic patients (172 men; aged 53.9 +/- 8.8 years) were followed for a median of 16.8 years (range 0.2 23.0). Baseline plasma OPG concentrations were determined by immunoassay. RESULTS: During follow-up, 193 (68%) patients died. High versus low levels of OPG predicted all-cause mortality (covariate-adjusted for urinary albumin excretion rate [UAER], estimated glomerular filtration rate, and conventional risk factors); hazard ratio (HR) 1.81 [95% CI 1.21-2.69]. The all-cause predictive effect of OPG was independent of NH(2)-terminal pro-brain natriuretic peptide (NT proBNP) and was also useful within groups divided according to level of UAER. In total, 103 (73%) patients died because of CVD. High and medium versus low levels of OPG predicted cardiovascular mortality (unadjusted HR 1.86 [95% CI 1.07-3.23] and 3.51 [2.10-5.85], respectively). However, after adjustment for the covariates, HRs were no longer significant. CONCLUSIONS: Elevated plasma OPG is a strong predictor of all-cause mortality in type 2 diabetic patients. The effect of OPG on all-cause mortality was independent of conventional cardiovascular risk factors, UAER, and NT-proBNP levels. PMID- 20929998 TI - Reduction in the incidence of type 2 diabetes with the Mediterranean diet: results of the PREDIMED-Reus nutrition intervention randomized trial. AB - OBJECTIVE: To test the effects of two Mediterranean diet (MedDiet) interventions versus a low-fat diet on incidence of diabetes. RESEARCH DESIGN AND METHODS: This was a three-arm randomized trial in 418 nondiabetic subjects aged 55-80 years recruited in one center (PREDIMED-Reus, northeastern Spain) of the Prevencion con Dieta Mediterranea [PREDIMED] study, a large nutrition intervention trial for primary cardiovascular prevention in individuals at high cardiovascular risk. Participants were randomly assigned to education on a low-fat diet (control group) or to one of two MedDiets, supplemented with either free virgin olive oil (1 liter/week) or nuts (30 g/day). Diets were ad libitum, and no advice on physical activity was given. The main outcome was diabetes incidence diagnosed by the 2009 American Diabetes Association criteria. RESULTS: After a median follow up of 4.0 years, diabetes incidence was 10.1% (95% CI 5.1-15.1), 11.0% (5.9 16.1), and 17.9% (11.4-24.4) in the MedDiet with olive oil group, the MedDiet with nuts group, and the control group, respectively. Multivariable adjusted hazard ratios of diabetes were 0.49 (0.25-0.97) and 0.48 (0.24-0.96) in the MedDiet supplemented with olive oil and nuts groups, respectively, compared with the control group. When the two MedDiet groups were pooled and compared with the control group, diabetes incidence was reduced by 52% (27-86). In all study arms, increased adherence to the MedDiet was inversely associated with diabetes incidence. Diabetes risk reduction occurred in the absence of significant changes in body weight or physical activity. CONCLUSIONS: MedDiets without calorie restriction seem to be effective in the prevention of diabetes in subjects at high cardiovascular risk. PMID- 20929999 TI - Improving epinephrine responses in hypoglycemia unawareness with real-time continuous glucose monitoring in adolescents with type 1 diabetes. AB - OBJECTIVE: To determine whether real-time continuous glucose monitoring (CGM) with preset alarms at specific glucose levels would prove a useful tool to achieve avoidance of hypoglycemia and improve the counterregulatory response to hypoglycemia in adolescents with type 1 diabetes with hypoglycemia unawareness. RESEARCH DESIGN AND METHODS: Adolescents with type 1 diabetes with hypoglycemia unawareness underwent hyperinsulinemic hypoglycemic clamp studies at baseline to determine their counterregulatory hormone responses to hypoglycemia. Subjects were then randomized to either standard therapy or real-time CGM for 4 weeks. The clamp study was then repeated. RESULTS: The epinephrine response during hypoglycemia after the intervention was greater in the CGM group than in the standard therapy group. CONCLUSIONS: A greater epinephrine response during hypoglycemia suggests that real-time CGM is a useful clinical tool to improve hypoglycemia unawareness in adolescents with type 1 diabetes. PMID- 20930000 TI - Relationship between right ventricular volumes measured by cardiac magnetic resonance imaging and prognosis in patients with chronic heart failure. AB - AIMS: The aim of this study was to investigate the prognostic impact of right ventricular (RV) size in patients with chronic heart failure. METHODS AND RESULTS: Normal volunteers (n = 80) and patients (n = 380) with left ventricular (LV) ejection fraction <45% on echocardiography and on optimal treatment for heart failure underwent cardiac magnetic resonance imaging with measurement of LV and RV volumes, mass and ejection fraction. The mean and the standard deviation (SD) of the RV end-systolic volume index in normal subjects were used to define the normal range as: mean RV end-systolic volume index +2 SD. Patients with dilated RV (>2 SD beyond the mean) (25%) had more frequent evidence of fluid overload in clinical examination and greater LV dimensions (P < 0.0001). During follow-up (median 45, interquartile range: 28-66 months), 37% of patients with and 24% without RV dilation died (log-rank test = 8.4; P = 0.004). In a multivariable Cox regression model, including 13 other clinical variables, RV (HR: 1.08/10 mL/m(2), 95% CI: 1.00-1.18, P = 0.044), but not LV, end-systolic volume index predicted a worse outcome. CONCLUSION: Twenty-five per cent of patients with heart failure due to LV systolic dysfunction have a dilated right ventricle. Greater RV dimensions predict mortality in patients with chronic heart failure. Treatments aimed at preserving or enhancing RV structure and function, possibly by unloading the RV by reducing pulmonary vascular resistance or left atrial pressure, should be investigated. PMID- 20930001 TI - Absence of obesity paradox in patients with chronic heart failure and diabetes mellitus: a propensity-matched study. AB - AIMS: Obesity is paradoxically associated with survival benefit in patients with chronic heart failure (HF). However, obesity complicates the management of diabetes mellitus (DM), which is common in HF. Yet, little is known about the impact of obesity in HF patients with DM. Therefore, we examined the association between obesity and outcomes in propensity-matched cohorts of HF patient with and without DM. METHODS AND RESULTS: Of the 7788 participants with chronic mild to moderate HF in the Digitalis Investigation Group trial, 7379 were non-cachectic [body mass index (BMI) >= 20 kg/m2] at baseline. Of these, 2153 (29%) had DM, of whom 798 (37%) were obese (BMI >= 30 kg/m2). Of the 5226 patients without DM, 1162 (22%) were obese. Propensity scores for obesity were used to separately assemble 636 pairs of obese and non-obese patients with DM and 770 pairs of obese and non-obese patients without DM, who were balanced on 32 baseline characteristics. Among matched patients with DM, all-cause mortality occurred in 38 and 39% of obese and non-obese patients, respectively [hazard ratio (HR) when obesity was compared with no obesity 0.99; 95% confidence interval (CI) 0.80 1.22; P = 0.915]. Among matched patients without DM, all-cause mortality occurred in 23 and 27% obese and non-obese patients, respectively (HR associated with obesity 0.77; 95% CI 0.61-0.97; P = 0.025). CONCLUSION: In patients with chronic mild to moderate HF and DM, obesity confers no paradoxical survival benefit. Whether intentional weight loss may improve outcomes in these patients needs to be investigated in future prospective studies. PMID- 20930002 TI - The value of dynamic radiographs in diagnosing painful vertebrae in osteoporotic compression fractures. AB - BACKGROUND AND PURPOSE: Many authors have reported the increase in vertebral body height after vertebroplasty; if the fractured vertebrae are mobile, we should be able to demonstrate their mobility in radiographs. The purpose of this study was to discover the diagnostic value of dynamic radiographs and the percentage of mobile vertebrae in painful VCFs. MATERIALS AND METHODS: From September 2005 to September 2008, 105 patients underwent surgery to treat 144 painful osteoporotic VCFs. The indications for surgery were severe pain and MR imaging-confirmed active edematous lesions. Preoperative sitting lateral radiographs of the fractured vertebrae were compared with supine cross-table (with a bolster beneath) lateral radiographs to determine the presence or absence of dynamic mobility. Kyphotic angle and anterior vertebral body height were measured. RESULTS: The patients' ages ranged from 62 to 90 years. There were 19 men and 86 women. The total number of mobile VCFs was 126 (87.5%). One hundred four (99%) patients had at least 1 mobile VCF. The average anterior vertebral height in sitting lateral radiographs was 13.53 +/- 6.80 mm and increased to 22.01 +/- 6.13 mm in supine cross-table with bolster lateral radiographs. The average vertebral body height increase was 8.48 +/- 5.36 mm. CONCLUSIONS: Dynamic (sitting and supine with bolster) radiographs can be valuable in diagnosing painful vertebrae in VCFs. The sensitivity was 0.88 in this study. PMID- 20930003 TI - Abnormal microstructure of the atrophic thalamus in preterm survivors with periventricular leukomalacia. AB - BACKGROUND AND PURPOSE: The neuroanatomic substrate of cognitive deficits in long term survivors of prematurity with PVL is poorly understood. The thalamus is critically involved in cognition via extensive interconnections with the cerebral cortex. We hypothesized that the thalamus is atrophic (reduced in volume) in childhood survivors of prematurity with neuroimaging evidence of PVL and that the atrophy is associated with selective microstructural abnormalities within its subdivisions. MATERIALS AND METHODS: We performed quantitative volumetric and DTI measurements of the thalamus in 17 children with neuroimaging evidence of PVL (mean postconceptional age, 5.6 +/- 4.0 years) who were born prematurely and compared these with 74 term control children (5.7 +/- 3.4 years). RESULTS: The major findings were the following: 1) a significant reduction in the overall volume of the thalamus in patients with PVL compared with controls (P < .0001), which also correlated with the severity of PVL (P = .001); 2) significantly decreased FA (P = .003) and increased lambda(?) (P = .02) in the thalamus overall and increased axial, radial, and mean diffusivities in the pulvinar (P < .03), suggesting injury to afferent and efferent myelinated axons; and 3) a positive correlation of pulvinar abnormalities with those of the parieto-occipital white matter in periventricular leukomalacia, suggesting that the pulvinar abnormalities reflect secondary effects of damaged interconnections between the pulvinar and parieto-occipital cortices in the cognitive visual network. CONCLUSIONS: There are volumetric and microstructural abnormalities of the thalamus in preterm children with PVL, very likely reflecting neuronal loss and myelinated axonal injury. The selective microstructural damage in the pulvinar very likely contributes to abnormal cognitive visual processing known to occur in such survivors. PMID- 20930004 TI - Maximal flow at functional residual capacity in healthy children from birth to 7 years, and beyond. AB - BACKGROUND: Reference values for maximal expiratory flows throughout childhood have been developed for each age group, but it remains a challenge to find a single outcome measure that can be tracked from birth to childhood. We believe that maximal flow at functional residual capacity (FRC) (VmaxFRC) may be a good candidate. The aim of this article was to explore the possible use of VmaxFRC as a continuous measure in healthy infants and children of preschool age. METHODS: Original spirometric data from healthy infants and preschool children in previously published studies from four centers around the world were reanalyzed (N = 242; ages 0-7 years). In preschool children, VmaxFRC was extracted by reanalysis of available records. Multiple regression analysis was applied to find the best correlation between VmaxFRC and height, weight, and/or age. VmaxFRC values were also compared with previously published data from healthy populations of similar ages. RESULTS: VmaxFRC highly correlated with height from infancy to childhood: Ln{VmaxFRC [L/s]} = -11.99 + (2.561 * Ln{Length[cm]}), where Ln is natural logarithm; r = 0.90; SE = 0.355; P < .0001. Adding weight but not age improved the correlation slightly (r = 0.91). VmaxFRC values were not affected by sex, maneuver modality (passive or voluntary), body posture, or degree of sedation. We found very good agreement between our calculated VmaxFRC values and the extrapolated VmaxFRC values from reference data of similar and older populations. CONCLUSIONS: VmaxFRC can be easily extracted from spirometry and can potentially serve as a continuous spirometric parameter for describing maximal flow at low lung volumes. Further studies are needed to confirm VmaxFRC values in a wider age range in health and disease. PMID- 20930005 TI - Early and long-term validation of an algorithm assessing fitness for surgery in patients with postoperative FEV1 and diffusing capacity of the lung for carbon monoxide < 40%. AB - BACKGROUND: There is evidence in the literature that the incidence of pulmonary complications and mortality is fair enough in patients with lower pulmonary function than conventionally accepted. In this article, we validate in patients with low baseline lung function (ie, FEV(1) or diffusing capacity of the lung for carbon monoxide [DLCO] < 80%) an algorithm to evaluate anatomic lung surgery in patients with low predicted postoperative lung function (ie, either FEV(1) postoperative estimated [ppo] or DLCO-ppo < 40% or both between 30% and 40% predicted) if peak oxygen uptake (VO(2)peak)-ppo > 10 mL/kg/min. METHODS: We prospectively studied 126 consecutive patients evaluated for anatomic resection of lung tumors by thoracotomy. RESULTS: Ninety-two patients were operated on: age 67 (8 SD) years; FEV(1) 63 (14)% pp; DLCO 71 (19)% pp; VO(2)peak 71 (19)% predicted; and 2-year Kaplan-Meier conditional probability of survival (CPS) 0.62 (0.06). Thirty-day perioperative mortality was 6.4%. Thirty-four patients were not functionally fit, or rejected the procedure: age 69 (8) years; FEV(1) 58 (16)% predicted; DLCO 67 (26)% predicted; VO(2)peak 66 (16)% predicted. In this group, 2-year CPS was 0.18 (0.08), P < .01. Subgroups A (FEV(1)-ppo and DLCO-ppo > 40% predicted) and B (either FEV(1)-ppo or DLCO-ppo < 40% predicted or both between 30% and 40% predicted) were comparable in terms of perioperative morbidity; however, they were different in terms of 30-day mortality (A, 1/53 [1.9%]; B, 5/37 [13.5%]; P = .047; relative risk, 7.2; 95% CI 1.1-27.7). The survival functions of both subgroups were significantly different (P < .01) from nonsurgical subjects. CONCLUSIONS: Adherence to the proposed algorithm results in a reasonable preoperative mortality in patients with low preoperative lung function. Although perioperative mortality is significantly higher when predicted postoperative lung function is low, 2-year survival of patients is better than if such patients had not undergone surgery. PMID- 20930006 TI - Rapid pleurodesis for malignant pleural effusions: a pilot study. AB - BACKGROUND: Malignant pleural effusions (MPEs) affect > 150,000 people each year in the United States. Current palliative options include pleurodesis and placement of an indwelling catheter, each with its own associated benefits. This study was conducted to determine the safety, efficacy, and feasibility of a rapid pleurodesis protocol by combining medical thoracoscopy with talc pleurodesis and simultaneous placement of a tunneled pleural catheter (TPC) in patients with symptomatic MPE. METHODS: Patients with recurrent, symptomatic MPEs underwent medical thoracoscopy with placement of a TPC and talc poudrage. The TPC was drained per protocol until the output was < 150 mL/d on two consecutive drainage attempts and then removed. Patients were followed for up to 6 months. RESULTS: Between October 2005 and September 2009, 30 patients underwent the procedure. The median duration of hospitalization following the procedure was 1.79 days. All patients showed an improvement in dyspnea and quality of life. Pleurodesis was successful in 92% of patients, and the TPC was removed at a median of 7.54 days. Complications included fever (two patients), the need for TPC replacement (one patient), and empyema (one patient). CONCLUSION: Rapid pleurodesis can be achieved safely by combining medical thoracoscopy and talc poudrage with simultaneous TPC placement. Both hospital length of stay and duration of TPC use can be reduced significantly as compared with historical controls of either procedure alone. Future randomized trials are needed to confirm these results. PMID- 20930007 TI - Community-acquired respiratory coinfection in critically ill patients with pandemic 2009 influenza A(H1N1) virus. AB - BACKGROUND: Little is known about the impact of community-acquired respiratory coinfection in patients with pandemic 2009 influenza A(H1N1) virus infection. METHODS: This was a prospective, observational, multicenter study conducted in 148 Spanish ICUs. RESULTS: Severe respiratory syndrome was present in 645 ICU patients. Coinfection occurred in 113 (17.5%) of patients. Streptococcus pneumoniae (in 62 patients [54.8%]) was identified as the most prevalent bacteria. Patients with coinfection at ICU admission were older (47.5+/-15.7 vs 43.8+/-14.2 years, P<.05) and presented a higher APACHE (Acute Physiology and Chronic Health Evaluation) II score (16.1+/-7.3 vs 13.3+/-7.1, P<.05) and Sequential Organ Failure Assessment (SOFA) score (7.0+/-3.8 vs 5.2+/-3.5, P<.05). No differences in comorbidities were observed. Patients who had coinfection required vasopressors (63.7% vs 39.3%, P<.05) and invasive mechanical ventilation (69% vs 58.5%, P<.05) more frequently. ICU length of stay was 3 days longer in patients who had coinfection than in patients who did not (11 [interquartile range, 5-23] vs 8 [interquartile range 4-17], P=.01). Coinfection was associated with increased ICU mortality (26.2% vs 15.5%; OR, 1.94; 95% CI, 1.21-3.09), but Cox regression analysis adjusted by potential confounders did not confirm a significant association between coinfection and ICU mortality. CONCLUSIONS: During the 2009 pandemics, the role played by bacterial coinfection in bringing patients to the ICU was not clear, S pneumoniae being the most common pathogen. This work provides clear evidence that bacterial coinfection is a contributor to increased consumption of health resources by critical patients infected with the virus and is the virus that causes critical illness in the vast majority of cases. PMID- 20930008 TI - Monitoring asthma control in children with allergies by soft computing of lung function and exhaled nitric oxide. AB - BACKGROUND: Asthma control is emphasized by new guidelines but remains poor in many children. Evaluation of control relies on subjective patient recall and may be overestimated by health-care professionals. This study assessed the value of spirometry and fractional exhaled nitric oxide (FeNO) measurements, used alone or in combination, in models developed by a machine learning approach in the objective classification of asthma control according to Global Initiative for Asthma guidelines and tested the model in a second group of children with asthma. METHODS: Fifty-three children with persistent atopic asthma underwent two to six evaluations of asthma control, including spirometry and FeNO. Soft computing evaluation was performed by means of artificial neural networks and principal component analysis. The model was then tested in a cross-sectional study in an additional 77 children with allergic asthma. RESULTS: The machine learning method was not able to distinguish different levels of control using either spirometry or FeNO values alone. However, their use in combination modeled by soft computing was able to discriminate levels of asthma control. In particular, the model is able to recognize all children with uncontrolled asthma and correctly identify 99.0% of children with totally controlled asthma. In the cross-sectional study, the model prospectively identified correctly all the uncontrolled children and 79.6% of the controlled children. CONCLUSIONS: Soft computing analysis of spirometry and FeNO allows objective categorization of asthma control status. PMID- 20930009 TI - Twenty-two years' experience with childhood-onset SLE in a developing country: are outcomes similar to developed countries? AB - INTRODUCTION: The outcome of systemic lupus erythematosus (SLE) has dramatically improved since the introduction of corticosteroids; however, although many regimens of treatment have been supplemented, the mortality has not improved further. OBJECTIVE: To describe the severity and outcome in patients diagnosed with SLE aged <=18 years in a group of Thai children, compare gender and age differences, and our outcomes with those from developed countries. METHODS: The authors retrospectively reviewed the files of patients aged <=18 years diagnosed with SLE admitted to Songklanagarind University Hospital in southern Thailand, for the period 1985-2007. Patient survival rates were calculated. RESULTS: There were 213 SLE patients, 41 males and 172 females, average age 11.6+/-2.6 years, with a median follow-up of 3.6 years. Outcomes were alive (109), lost to follow up (22), referred (31) or deceased (51). Of the patients who were alive, 23 were not on any treatment, 59 were on prednisolone alone while 27 were on prednisolone plus some other immunosuppressive drug. Total survival rates were 88%, 76% and 64% at 2, 5 and 10 years, respectively. Males had significantly worse survival than females at 2 and 5 years (78% vs 91% and 58% vs 80%, respectively, p=0.018). There were no differences in mortality between age groups. The 5-year survival rates in the periods 1985-1993, 1994-2000 and 2001-2007 were not significantly different. CONCLUSION: This retrospective study of patients with SLE in southern Thailand showed different outcomes compared to some studies and similar survival rates and treatment status to other studies, with one-fourth of surviving patients being free of medication. PMID- 20930010 TI - Bronchoalveolar lavage in children with cystic fibrosis: how many lobes should be sampled? AB - BACKGROUND: The European Respiratory Society guidance on bronchoalveolar lavage (BAL) in children was published in 2000. It recommended taking one BAL specimen from the most affected lobe or from the right middle lobe in diffuse disease. In 2007, the European Respiratory Society modified the recommendations for children with cystic fibrosis (CF), suggesting two BAL specimens (right middle lobe and the lingula or the most affected lobe). OBJECTIVE: To determine if BAL samples from one or two lobes give the full picture of lower airway infection in children with CF. DESIGN, SETTING AND PATIENTS: A retrospective review of all paediatric patients with CF who underwent flexible bronchoscopy between May 2007 and May 2009 was undertaken. MAIN OUTCOME MEASURES: As BAL specimens from all six lobes were collected, the BAL results were reviewed to identify if positive cultures would have been missed if only one lobe (right middle or most affected) or two lobes (right middle plus the lingula or most affected) had been sampled. RESULTS: The results of 39 bronchoscopic procedures in 31 children were reviewed. The BAL samples were taken from 6 lobes in all 39 procedures. Had only one lobe been used, 26 positive cultures (14 organisms) would have been missed in 11 patients. Had two lobes been used, 12 positive cultures (8 organisms) would have been missed in 7 patients. CONCLUSION: A single-lobe BAL is insufficient in assessing patients with CF for lower airway infection. Even when BAL specimens are taken from two lobes, a number of infections may be missed. PMID- 20930011 TI - When the mother is a child: the impact of child marriage on the health and human rights of girls. PMID- 20930012 TI - Treatment of severe childhood constipation with restorative proctocolectomy: the surgeon's view. PMID- 20930013 TI - Pubertal development in daughters of women with pre-eclampsia. AB - OBJECTIVE: To compare clinical signs of puberty onset in daughters of pre eclampsia and normotensive pregnancies. DESIGN: Population based follow-up study. METHODS: In a cohort of 120 daughters of pre-eclampsia pregnancies and 203 daughters of pregnancies without pre-eclampsia, pubic hair growth and breast development were assessed at 11, 12 and 13 years of age by Tanner scores and by self-assessment. RESULTS: Compared to the normotensive group, pubic hair growth (pubarche) more often preceded breast development (thelarche) (risk ratio (RR) 2.3, 95% CI 1.3 to 4.1) and thelarche less often preceded pubarche (RR 0.8, 95% CI 0.7 to 1.0) in daughters of pre-eclampsia pregnancies. Adjustment for birth weight and body mass index in early adolescence did not substantially influence these results, but increasing severity of pre-eclampsia strengthened the differences. CONCLUSIONS: Pubarche tends to precede thelarche in daughters of pre eclampsia pregnancies compared to daughters of normotensive pregnancies. This may reflect a stronger androgenic influence in daughters of pre-eclampsia pregnancies at the beginning of puberty. PMID- 20930014 TI - Managing anorexia nervosa. AB - Clinical confidence and coordinated multidisciplinary care can influence the course of anorexia nervosa in children and adolescents. Sicker and younger patients with anorexia nervosa often present first to a paediatrician, requiring early recognition and appropriate management. Paediatric knowledge and skills are also needed to manage the impact of eating disorders on growth and development. This review provides practical guidance on the management of anorexia nervosa for paediatricians, in the areas of assessment, acute management and re-feeding, and long-term monitoring. In the absence of a strong evidence base for some of these recommendations, local protocols based on best practice guidelines can reduce anxiety, increase cooperation and reduce risk. PMID- 20930015 TI - Seizure relapse following medication withdrawal in childhood epilepsy. PMID- 20930016 TI - Comparison of 6-min walk test distance and cardiopulmonary exercise test performance in children with pulmonary hypertension. AB - OBJECTIVE: To assess the relationship between 6-min walk test (6MWT) distance and variables of cardiopulmonary exercise testing (CPET) in children with pulmonary arterial hypertension (PAH). DESIGN: Retrospective study. SETTING: Tertiary hospital. PATIENTS: Children with PAH. INTERVENTIONS: CPETs and 6MWTs. MAIN OUTCOME MEASURES: Correlations between variables of CPET and 6MWT distance. RESULTS: 41 exercise studies were included: 15 in children with idiopathic PAH (mean age 13.0+/-3.0 years; 9 female), 18 in children with PAH associated with congenital heart disease (age 14.8+/-2.8 years; 7 female) and 8 in children with Eisenmenger syndrome (age 11.8+/-2.9 years; 4 female). All underwent a CPET and 6MWT. Peak oxygen consumption (pVO(2)) and 6MWT distance were reduced to 31.5+/ 12.2% and 47.7+/-16.7% of the predicted value, respectively (p<0.0001 for both). pVO(2) and oxygen consumption at anaerobic threshold showed correlation with 6MWT distance (r=0.49; p=0.001 and r=0.40, p=0.01, respectively), while an inverse correlation was found between measures of ventilatory efficiency (eg, VE/VCO(2)) at anaerobic threshold and 6MWT distance (r=-0.43; p=0.005). There was a significant linear relationship between pVO(2) and 6MWT up to a distance of 300 m, with the 6MWT distance accounting for 71% of the variation in pVO(2) but there was hardly any association when the 6MWT distance was >300 m. CONCLUSIONS: The 6MWT reflects maximal exercise capacity in patients with a 6MWT distance below 300 m. A CPET should therefore be considered as a complimentary test in children with an exercise tolerance above this threshold. These findings may have implications for assessing response to drug therapy and for consideration as an end point in future PAH trials. PMID- 20930017 TI - Routine educational outcome measures in health studies: Key Stage 1 in the ORACLE Children Study follow-up of randomised trial cohorts. AB - OBJECTIVES: Statutory educational attainment measures are rarely used as health study outcomes, but Key Stage 1 (KS1) data formed secondary outcomes in the long term follow-up to age 7 years of the ORACLE II trial of antibiotic use in preterm babies. This paper describes the approach, compares different approaches to analysis of the KS1 data and compares use of summary KS1 (level) data with use of individual question scores. PARTICIPANTS: 3394 children born to women in the ORACLE Children Study and resident in England at age 7. METHODS: Analysis of educational achievement measured by national end of KS1 data (KS1) using Poisson regression modelling and anchoring of the KS1 data using external standards. RESULTS: KS1 summary level data were obtained for 3239 (95%) eligible children; raw individual question scores were obtained for 1899 (54%). Use of individual question scores where available did not change the conclusion of no evidence of treatment effects based on summary KS1 outcome data. CONCLUSIONS: When accessible for medical research purposes, routinely collected educational outcome data may have advantages of low cost and standardised definition. Here, summary scores lead to similar conclusions to raw (individual question) scores and so are attractive and cost-effective alternatives. PMID- 20930018 TI - Diplopia as a presenting symptom in a gastric gastrointestinal stromal tumor. AB - Gastrointestinal stromal tumors are the most common mesenchymal neoplasm of the gastrointestinal tract. Distant metastasis of gastrotintestinal stromal tumors occurs in ~50% of the cases and is usually found in the liver and peritoneum. We present a patient with diplopia which was due to a metastatic gastrointestinal stromal tumor of the clivus. Transsphenoidal resection of the tumor was performed and post-operative treatment with oral imatinib mesylate was done. One month after the surgery, treatment was started with imatinib and the patient's diplopia improved within 15 days. Follow-up computed tomography was taken 2 months after the initiation of oral imatinib, and the size of the main gastric mass has decreased. To our knowledge, this is an extremely rare case of gastrointestinal stromal tumor with metastasis to the clivus with diplopia as the presenting symptom. We report our clinical findings along with a review of the relevant literature. PMID- 20930020 TI - Antenatal testing and the subsequent birth of a child with Down syndrome: a phenomenological study of parents' experiences. AB - The objective was to gain a deeper insight into the lived experiences of parents during antenatal testing for Down syndrome and the subsequent birth of their baby. A phenomenological research inquiry used unstructured interviews and thematic framework analysis. Conversations between parents and midwives about Down syndrome, when they occurred, were brief, functional and had a biomedical problem orientation. Antenatal screening failed to meet parents' expectations of better preparation for birth. After birth, children's 'differentness' rather than health needs was the main focus of care interventions. The inquiry revealed the 'invisibility' of the potential child with Down syndrome. Professionals in maternity care services must be equipped with appropriate knowledge about Down syndrome in order to better support parents. Such preparation must include a balanced view of the future of the child, consistent with the principle of reproductive autonomy. Appropriate support after birth is also essential in helping parents to adapt to their new situation. PMID- 20930021 TI - The adult day care workforce in England at a time of policy change: implications for learning disability support services. AB - More people will receive personal budgets to pay for social care services in England. Such people may or may not continue using services such as adult day care centres. Many day centres are under threat of closure. These trends will affect those working in adult day care. This article examines the profile of this workforce, using recent NMDS-SC data and applying multinomial statistical modelling. We identified nearly 6000 adult day care workers, over half supporting adults with learning disability. The results of the analysis show significant variations between the adult day care, residential care and domiciliary workforces. At the personal level, day care workers are significantly older and less ethnically diverse than other workers. They tend to have been working in the sector for longer, and their work patterns are more stable. The findings are discussed within the context of policy changes affecting learning disabilities and social care workforce strategies. PMID- 20930022 TI - Developing a person-centred support service for families caring for children with severe learning disabilities in rural and urban areas. AB - The article describes an innovative, person-centred service provided to families who had a child or teenager with severe learning (intellectual) disabilities. It was delivered in three areas within Northern Ireland: two urban and one rural. The service promoted the social inclusion of young people in volunteer-run community activities, based around a person-centred plan developed with the child's family. A three-year formative evaluation of the service was undertaken (2006-2008) via interviews and focus groups with parents (N = 48), young people (N = 19), volunteers (N = 7), community workers (N = 4) and referring social services staff (N = 14). The service was successfully implemented in all three areas. In particular, it helped parents to clarify their individual support needs and engaged their child in ordinary community activities. The distinctive features of the service and the changed ethos it represents are discussed. PMID- 20930023 TI - Focus groups with people with learning disabilities. AB - Focus groups are a widely accepted method in qualitative research. While there is a burgeoning literature on the methodology of focus groups, using focus groups with people with learning disabilities has received less attention so far. The article serves two purposes: (1) to review the current literature on focus groups in learning disability research and (2) to sketch four aspects that may impact on the usefulness of the focus group method with respondents with learning disabilities. Some comments on the role of focus groups in qualitative research start the article before we outline the emancipatory and participatory context of research with people with learning disabilities. PMID- 20930024 TI - Assessing motivation for work in people with developmental disabilities. AB - Factors that might influence motivation for work have been neglected in previous investigations in the process of people with intellectual disabilities finding employment. This article describes the development of The Work Readiness Scale which was largely adapted from The Readiness to Change Questionnaire. A structured interview was conducted with 69 participants who had developmental and intellectual disabilities while at the supported employment agency or vocational training centre in a large city in England. A subgroup of 43 individuals completed the questionnaire again about two weeks later. A member of staff who knew the person well was asked to independently rate the motivational level of the individual. The questionnaire seems to have reasonable psychometric properties and may have utility in assessing individuals for work and designing appropriate training to find work. PMID- 20930025 TI - An unusual syncope cause in the ED: favism. AB - Favism is an acute hemolytic syndrome occurring in glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals after the consumption of fava beans. The highest incidence is in boys aged 2-6 years. We report a 56-year-old man presented to the emergency department (ED) with recurrent syncope attacks due to favism. In our knowledge, this is the first report of favism-caused syncope in an adult patient without a G6PD deficiency diagnosis in the past and diagnosed in ED. PMID- 20930026 TI - Protective role of Vernonia cinerea L. against gamma radiation--induced immunosupression and oxidative stress in mice. AB - The radioprotective effect of Vernonia cinerea extract was studied in balb/c mice. Whole-body irradiation of gamma-rays (6 Gy) given to animals reduced the white blood cell count, bone marrow cellularity and alpha-esterase positive cells in control animals, which were elevated by the administration of V. cinerea extract (20 mg/kg body weight [b.wt.], intraperitoneally [i.p.]). The elevated levels of serum enzymes alkaline phosphatase (ALP), glutamate pyruvate transferases (GPT) and lipid peroxidation (LPO) after irradiation were also reduced with V. cineria extract administration. V. cinerea treatment also significantly enhanced the animal's antioxidant status by enhancing the activities superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and reduced glutathione (GSH) level in irradiated animals. Histopathological analysis of liver and small intestine also suggests that V. cinerea could reduce the tissue damages induced by radiation. The level of pro inflammatory cytokines such as interleukin 1beta (IL-1beta), tumour necrosis factor alpha (TNF-alpha) and C-reactive protein (CRP) elevated after irradiation, which were significantly reduced by V. cinerea extract administration. On the other hand, the extract stimulated the production of other cytokines such as granulocyte monocyte-colony stimulating factor (GM-CSF) and interferon-gamma (IFN gamma) in animals exposed to radiation. Agarose gel electrophoresis of DNA isolated from bone marrow of control animals showed heavy DNA damage, but a reduced DNA damage was seen in animals treated with V. cinerea extract. Administration of V. cinerea did not compromise the anti-neoplastic efficiency of radiation. In fact, there was a synergistic action of radiation and V. cinerea in reducing the solid tumours in mice. Methanolic extract of V. cinerea given i.p. showed a significant radioprotective activity without compromising the radiotherapeutic efficacy of radiation, indicating its possible use as an adjuvant during radiotherapy. PMID- 20930027 TI - Acute toxicity and synergism of binary mixtures of antifouling biocides with heavy metals to embryos of sea urchin Glyptocidaris crenularis. AB - Acute toxicity and synergism of four antifouling biocides (Irgarol 1051, dichlofluanid, tolylfluanid and Sea-Nine 211) and five heavy metals (Ni, Pb, Zn, Cd and Cu) are investigated using the sea urchin embryos of Glyptocidaris crenularis (G. crenularis) at six typical developmental stages, that is, 2-cell, 4-cell, 8-cell, blastula, gastrula and 4-arm pluteus. Our results show that the toxicity of the four biocides is in an order of Sea-Nine 211 > tolylfluanid > dichlofluanid > Irgarol 1051 and their -log EC(50) values at all stages are strongly linearly correlated with the 1-octanol/water partition coefficient (log P) values (correlation coefficients R > 0.72) indicating the importance of hydrophobicity for the embryonic toxicity. For the five heavy metals, the EC(50) ranges from 0.36 to 30.78 MUM and the toxicity follows an order of Cu > Pb > Zn > Cd >Ni. The significant correlation (R > 0.79) between the -log EC50 and the bioconcentration factor (log BCF) values of metals also indicate that the bioaccumulation property of metals contributes to their aquatic toxicity. In addition, the joint effects of the biocides with the heavy metals in embryonic development are assessed by using a concentration addition model. Synergistic effects are observed in almost all 25 mixtures, showing that Cu yields the strongest while Ni the weakest synergistic toxic effects on the embryos development. PMID- 20930028 TI - 2-(3-Methoxyphenyl)-6, 7-methylenedioxoquinolin-4-one, a novel synthetic compound, inhibited migration and invasion in TSGH8301 human bladder cancer cells. AB - Matrix metalloproteinases (MMPs) play an important role in the invasion, metastasis and angiogenesis of cancer cells. Many agents have been shown to inhibit the cancer cell migration and invasion by suppression of MMPs. 2-(3 Methoxyphenyl)-6,7-methylenedioxoquinolin-4-one (MMEQ) is a derivative compound synthesized from quinolin and the purpose of this study is to determine whether or not cell migration would be reduced in human bladder cancer TSGH8301 cells after MMEQ treatment. Wound healing assay and boyden chamber assay were used in cell migration and invasion determinations. Cell migration and invasion inhibited by MMEQ exerted an inhibitory effect on the sevenless homolog-1 (SOS-1), protein kinase c (PKC), extracellular signal-regulated kinase (ERK) and Rho A for causing the inhibitions of MMP-2 and -9, and then followed by the inhibitions of invasion and migration. MMEQ also affected FAK, PI3K or inhibited growth factor receptor bound protein 2 (GRB2), nuclear factor kappaB (NF-kappaB), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) for cell proliferation inhibition. Therefore, MMEQ may serve as a drug in the prevention of tumor metastasis of bladder cancer in the future. PMID- 20930029 TI - Protective effect of Cassia fistula fruit extract against bromobenzene-induced liver injury in mice. AB - In the present study, hepatoprotective effect of Cassia fistula fruit extract was investigated in mice. Animals were divided into six groups receiving normal saline (1), bromobenzene (460 mg/kg) alone (2) and together with increasing doses (200, 400, 600, 800 mg/kg) of a crude hydro-alcoholic extract of Cassia fistula fruit (3-6, respectively). All administrations were carried out orally, daily, for 10 days. On the 11th day, animals were sacrificed. Serum activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) and gamma glutamyl transpeptidase (gammaGT) were determined; serum levels of direct and total bilirubin were measured; furthermore, livers were prepared for histological examination. Our results showed that bromobenzene treatment alone elicited a significant increase in activities of AST, ALT, ALP (but not gammaGT), and it significantly elevated the levels of direct and total bilirubin. Co-treatment with Cassia fistula fruit extract, however, significantly and dose-dependently decreased the above-mentioned enzyme activities (with exception of gammaGT) and bilirubin levels, producing a recovery to the naive state. The protective effect of Cassia fistula fruit extract against liver injury evoked by bromobenzene was confirmed by histological examination as well. In conclusion, the Cassia fistula fruit extract has significant hepatoprotective effect in our murine model. PMID- 20930030 TI - SMG6 interacts with the exon junction complex via two conserved EJC-binding motifs (EBMs) required for nonsense-mediated mRNA decay. AB - Nonsense-mediated mRNA decay (NMD) is a quality control mechanism that detects and degrades mRNAs containing premature stop codons (PTCs). In vertebrates, PTCs trigger efficient NMD when located upstream of an exon junction complex (EJC). Degradation of PTC-containing mRNAs requires the endonucleolytic activity of SMG6, a conserved NMD factor; nevertheless, the precise role for the EJC in NMD and how the SMG6 endonuclease is recruited to NMD targets have been unclear. Here we show that SMG6 interacts directly with the EJC via two conserved EJC-binding motifs (EBMs). We further show that the SMG6-EJC interaction is required for NMD. Our results reveal an unprecedented role for the EJC in recruiting the SMG6 endonuclease to NMD targets. More generally, our findings identify the EBM as a protein motif present in a handful of proteins, and suggest that EJCs establish multiple and mutually exclusive interactions with various protein partners, providing a plausible explanation for the myriad functions performed by this complex in post-transcriptional mRNA regulation. PMID- 20930031 TI - Monoclonal free light chains can be found in heavy chain diseases. AB - Heavy chain diseases (HCDs) are rare B-cell lymphoproliferative neoplasias characterized by the production of a monoclonal component consisting of a truncated monoclonal Ig heavy chain without the associated light chain. Among them, patients with gamma-HCD are so rare that no more than 150 cases can be found in the literature. In this paper, we report one additional case: an 83-year old man with a gamma-HCD, in whom a kappa light chain component was detected in the serum by using the serum free light-chain assessment and in addition monoclonal kappa cytoplasmic expression was detected in bone marrow plasma cells by flow cytometric analysis. In the work-up of the patient, the underlying anatomopathological lymphoproliferative disease corresponded to a lymphoplasmacytic lymphoma, as it is stated in the current World Health Organization classification (2008), with both lymphadenopathic and bone marrow infiltration. As in other cases, several autoimmune manifestations (antiphospholipidic syndrome and immune thrombocytopenia) were present during the course of the disease in this patient. This case report illustrates a new case of gamma-HCD, in which serum free light-chain analysis and flow cytometry represented a valuable tool for diagnosis, a finding that could be very important for the future management of these patients. PMID- 20930032 TI - Effect of recipient-derived cells on the progression of familial amyloidotic polyneuropathy after liver transplantation: a retrospective study. AB - BACKGROUND: Some familial amyloidotic polyneuropathy (FAP) patients show the post transplant progression of the clinical symptoms. Although the presence of recipient-derived cells in transplanted livers has been reported, no studies investigating the functional significance of this post-transplant chimerism in transplanted FAP patients were performed. The aims of this study were to evaluate amyloidogenic transthyretin (ATTR) production of recipient-derived cells and the relationship between the protein from recipient-derived cells and the progression of FAP symptoms after liver transplantation (LT). METHODS: Seven FAP ATTR Val30Met patients who underwent LT were included in this study. In one male patient with sex-mismatched donor, fluorescence in situ hybridization (FISH) method was performed on a liver biopsy sample using DNA probes for visualizing X and Y chromosomes to detect the recipient-derived cells. In three patients including the FISH-analysed patient, ATTR mRNA expression in transplanted livers was evaluated by the polymerase chain reaction (PCR)-restriction fragment length polymorphism method and realtime quantitative reverse transcription-PCR. In five of the seven patients, ATTR in serum protein expression was measured by mass spectrometry. RESULTS: One FAP patient has 3.1% recipient-derived cells in the transplanted liver. The ATTR mRNA was not expressed in any of the three transplanted livers. The ATTR was not detected in any sera of the sampled patients. CONCLUSION: Although the FAP patient had recipient-derived cells in the transplanted liver, the recipient-derived cells did not contribute to the production of ATTR in our specific case. The effect of recipient-derived cells on the post-transplant progression of FAP symptoms may be negligible. PMID- 20930033 TI - The measurement, definition, aetiology and clinical consequences of neonatal transient hypothyroxinaemia. AB - This review focuses on neonatal transient hypothyroxinaemia, a condition characterized by temporary postnatal reductions in concentrations of Total T4 or Free T4, with normal or low concentrations of thyroid stimulating hormone (TSH). There is neither an agreed quantitative definition, nor an agreed mode of measurement for the condition. Transient hypothyroxinaemia is not routinely monitored yet it is thought to affect about 50% of preterm infants; it was thought to be without long-term sequelae but observational studies indicate that neurodevelopment may be compromised. The aetiology of transient hypothyroxinaemia is complex. There are significant contributions from the withdrawal of maternal placental thyroxine transfer, hypothalamic-pituitary-thyroid immaturity, developmental constraints on the synthesis and peripheral metabolism of iodothyronines and iodine deficiency. It is not possible to distinguish clinically, or from laboratory measurements, whether transient hypothyroxinaemia is an independent condition or simply a consequence of non-thyroidal illness and/or drug usage. An answer to this question is important because studies of thyroid hormone replacement have been instigated, with mixed results. Until the aetiology of transient hypothyroxinaemia is better understood it would seem prudent not to routinely supplement preterm infants with thyroid hormones. Iodine deficiency, non-thyroidal illness and drug usage are the most modifiable risk factors for transient hypothyroxinaemia and are the clear choices for attempts at reducing its incidence. We suggest that transient hypothyroxinaemia in preterm infants is defined as a normal or low TSH concentration in conjunction with a concentration of Total T4, that is <=10th percentile of cord Total T4 of the equivalent gestational age had the infant remained in utero. PMID- 20930034 TI - Structure, assembly and homeostatic regulation of the 26S proteasome. AB - The 26S proteasome is the major protease responsible for degradation of regulatory and abnormal proteins in the cell. Proteasomal degradation controls many cellular processes including, but not limited to, cell cycle control, transcription, DNA repair, apoptosis, quality control and antigen presentation. To elucidate how the proteasome is regulated is crucial to our understanding of the molecular details of proteasomal degradation and its functions in diverse biological pathways. In this article, I will highlight recent advances in understanding the proteasome structure and assembly and the regulation of proteasome gene expression. The implications of these new developments in cancer therapy will also be discussed. PMID- 20930035 TI - Combining phylogenomics and fossils in higher-level squamate reptile phylogeny: molecular data change the placement of fossil taxa. AB - Molecular data offer great potential to resolve the phylogeny of living taxa but can molecular data improve our understanding of relationships of fossil taxa? Simulations suggest that this is possible, but few empirical examples have demonstrated the ability of molecular data to change the placement of fossil taxa. We offer such an example here. We analyze the placement of snakes among squamate reptiles, combining published morphological data (363 characters) and new DNA sequence data (15,794 characters, 22 nuclear loci) for 45 living and 19 fossil taxa. We find several intriguing results. First, some fossil taxa undergo major changes in their phylogenetic position when molecular data are added. Second, most fossil taxa are placed with strong support in the expected clades by the combined data Bayesian analyses, despite each having >98% missing cells and despite recent suggestions that extensive missing data are problematic for Bayesian phylogenetics. Third, morphological data can change the placement of living taxa in combined analyses, even when there is an overwhelming majority of molecular characters. Finally, we find strong but apparently misleading signal in the morphological data, seemingly associated with a burrowing lifestyle in snakes, amphisbaenians, and dibamids. Overall, our results suggest promise for an integrated and comprehensive Tree of Life by combining molecular and morphological data for living and fossil taxa. PMID- 20930036 TI - What changes in survival rates tell us about us health care. AB - Many advocates of US health reform point to the nation's relatively low life expectancy rankings as evidence that the health care system is performing poorly. Others say that poor US health outcomes are largely due not to health care but to high rates of smoking, obesity, traffic fatalities, and homicides. We used cross national data on the fifteen-year survival of men and women over three decades to examine the validity of these arguments. We found that the risk profiles of Americans generally improved relative to those for citizens of many other nations, but Americans' relative fifteen-year survival has nevertheless been declining. For example, by 2005, fifteen-year survival rates for forty-five-year old US white women were lower than in twelve comparison countries with populations of at least seven million and per capita gross domestic product (GDP) of at least 60 percent of US per capita GDP in 1975. The findings undercut critics who might argue that the US health care system is not in need of major changes. PMID- 20930040 TI - Can a community-based 'smoke-free homes' intervention persuade families to apply smoking restrictions at homes? AB - BACKGROUND: Children are commonly exposed to second-hand smoke (SHS). The aim of this study is to evaluate the feasibility, acceptability and outcome of Smoke Free Homes (SFH), a community-based intervention; and assess potential evaluation methods. METHODS: SFH, designed to encourage families to implement smoking restrictions at home, was delivered over a period of 6 months through schools, healthcare settings and community events in Beeston, South Leeds, UK. It was evaluated using baseline and post-implementation surveys, focus group discussions and promise forms follow-up. RESULTS: We surveyed 318 households before, and 217 households after, the intervention. The proportion of all surveyed households reporting being completely smoke free significantly increased from 35% [95% confidence interval (CI) 30, 40] at baseline to 68% (95% CI: 61, 74) 6 months post-implementation (P < 0.0001). Ninety per cent of people, followed-up by telephone 3 months after signing SFH promise form, said they were still keeping their promise. Focus group discussions with children and parents conveyed acceptability of the intervention, in particular, the schools element, where children are encouraged to discuss the concept of SFH with the adults in their households. CONCLUSIONS: Our study shows that SFH can be implemented effectively and has the potential to improve children's health through preventing exposure to SHS in the home. PMID- 20930037 TI - Uncovering the human methyltransferasome. AB - We present a comprehensive analysis of the human methyltransferasome. Primary sequences, predicted secondary structures, and solved crystal structures of known methyltransferases were analyzed by hidden Markov models, Fisher-based statistical matrices, and fold recognition prediction-based threading algorithms to create a model, or profile, of each methyltransferase superfamily. These profiles were used to scan the human proteome database and detect novel methyltransferases. 208 proteins in the human genome are now identified as known or putative methyltransferases, including 38 proteins that were not annotated previously. To date, 30% of these proteins have been linked to disease states. Possible substrates of methylation for all of the SET domain and SPOUT methyltransferases as well as 100 of the 131 seven-beta-strand methyltransferases were surmised from sequence similarity clusters based on alignments of the substrate-specific domains. PMID- 20930041 TI - Targeting RET receptor tyrosine kinase activation in cancer. AB - After ligand binding induces dimerization, the RET receptor tyrosine kinase activates multiple signal transduction pathways. Constitutively activating mutations and chromosomal rearrangements are the primary oncogenic event in a significant number of medullary thyroid cancers (MTC) and papillary thyroid cancers (PTC), respectively. When specific germline mutations in RET are identified early, prophylactic thyroidectomy can be timed to remove at-risk tissue in patients with multiple endocrine neoplasia 2 (MEN2) syndromes who would otherwise develop MTC. Conventional therapy for progressive metastatic MTC is limited. Small-molecule tyrosine kinase inhibitors can target multiple kinases at nanomolar concentrations, including RET, and have shown efficacy against a variety of malignancies. Initial clinical evidence suggests that several of these inhibitors, including sorafenib, vandetanib, motesanib, sunitinib, and XL-184, may have some benefit in treating progressive MTC. Although initial success seen in these trials seems to be modest, it represents a major breakthrough in the treatment of patients with widespread metastatic MTC. PMID- 20930042 TI - Prognostic significance of RNA-dependent protein kinase on non-small cell lung cancer patients. AB - PURPOSE: The role of RNA-dependent protein kinase (PKR) in antiviral defense mechanisms and in cellular differentiation, growth, and apoptosis is well known, but the role of PKR in human lung cancer remains poorly understood. To explore the role of PKR in human lung cancer, we evaluated the expression of PKR in tissue microarray (TMA) specimens from both non-small cell lung cancer (NSCLC) and normal human bronchial epithelium tissue. EXPERIMENTAL DESIGN: TMA samples (TMA-1) from 231 lung cancers were stained with PKR antibody and validated on TMA 2 from 224 lung cancers. Immunohistochemical expression score was quantified by three pathologists independently. Survival probability was computed by the Kaplan Meier method. RESULTS: The NSCLC cells showed lower levels of PKR expression than normal bronchial epithelium cells did. We also found a significant association between lower levels of PKR expression and lymph node metastasis. We found that loss of PKR expression is correlated with a more aggressive behavior, and that a high PKR expression predicts a subgroup of patients with a favorable outcome. Univariate and multivariate Cox proportional hazards regression models showed that a lower level of PKR expression was significantly associated with shorter survival in NSCLC patients. We further validated and confirmed PKR to be a powerful prognostic factor in TMA-2 lung cancer (hazard ratio, 0.22; P < 0.0001). CONCLUSIONS: Our findings first indicate that PKR expression is an independent prognostic variable in NSCLC patients. PMID- 20930043 TI - Tigecycline activity: low resistance rates but problematic disc breakpoints revealed by a multicentre sentinel survey in the UK. AB - OBJECTIVES: A multicentre surveillance of tigecycline activity against relevant pathogens in the UK. METHODS: Forty-three representative UK hospitals were each asked to test 150 consecutive, clinically significant isolates from hospitalized patients, excluding those from urine or faeces. The sentinel laboratories tested all these isolates against a panel of antibiotics by the BSAC disc method and a selection of isolates were retested centrally by the BSAC agar dilution method. RESULTS: The isolates collected comprised Staphylococcus aureus (39.9%), Escherichia coli (13.3%), streptococci (11.9%), enterococci (6.3%), Klebsiella (6.1%), coagulase-negative staphylococci (6.1%), Enterobacter spp. (3.9%), Proteus spp. (2.2%) and other Gram-negative species (10.3%). The laboratories' disc susceptibility testing found that 4% of isolates were resistant to tigecycline, using the zone breakpoints in place at that time. However, centralized retesting by agar dilution showed that many of these 'resistant' isolates were susceptible, with resistance only confirmed in a range of Gram negative isolates and one S. aureus. These findings reduced the estimated resistance rate to 2.4%, or to 0.8% if Proteus spp. were ignored as intrinsically resistant to tigecycline. Sixty-two percent of the isolates found resistant by the disc method but susceptible by agar dilution had zones of inhibition within experimental error (4 mm) of the published breakpoints. CONCLUSIONS: Tigecycline resistance was rare in isolates causing clinically significant infections in the UK and was overestimated ~2-fold by the BSAC disc method. Adjustment of the breakpoints might overcome this problem but at the risk of increasing the false susceptibility rate. The best advice is to perform dilution tests, e.g. by gradient strip test on isolates with borderline results, especially in severe infection and when tigecycline use is intended. PMID- 20930044 TI - Prevalence and impact of a chronic total occlusion in a non-infarct-related artery on long-term mortality in diabetic patients with ST elevation myocardial infarction. AB - BACKGROUND: Recently, a chronic total occlusion (CTO) in a non-infarct-related artery (non-IRA) and not multivessel disease (MVD) alone was identified as an independent predictor of mortality after ST elevation myocardial infarction (STEMI). Patients with diabetes mellitus (DM) constitute a patient group with a high prevalence of MVD and high mortality after STEMI. The prevalence of CTO in a non-IRA was studied and its impact on long-term mortality in STEMI patients with DM was investigated. METHODS: Between 1997 and 2007 4506 patients with STEMI were admitted and treated with primary percutaneous coronary intervention (PCI). Patients with DM were identified. The patients were categorised as having single vessel disease (SVD), MVD without CTO and CTO based on the angiogram before PCI. RESULTS: A total of 539 patients (12%) had DM. MVD with or without a CTO was present in 33% of non-diabetic patients and in 51% of diabetic patients. The prevalence of a CTO in a non-IRA was 21% in STEMI patients with DM and 12% in STEMI patients without DM (p<0.01). Kaplan-Meier estimates for 5-year mortality in STEMI patients with DM were 25%, 21% and 47% in patients with SVD, MVD without a CTO and MVD with a CTO in a non-IRA, respectively. A CTO in a non-IRA was an independent predictor of 5-year mortality (HR 2.2, 95% CI 1.3 to 3.5, p<0.01). CONCLUSION: The prevalence of a CTO in a non-IRA was increased in STEMI patients with DM. The presence of a CTO in a non-IRA was a strong and independent predictor of 5-year mortality. These results suggest that, particularly in the high-risk subgroup of STEMI patients with DM, MVD has prognostic implications only if a concurrent CTO is present. PMID- 20930045 TI - Prolonged right ventricular post-systolic isovolumic period in pulmonary arterial hypertension is not a reflection of diastolic dysfunction. AB - BACKGROUND: In pulmonary arterial hypertension (PAH) a prolonged time interval between pulmonary valve closure and tricuspid valve opening is found. This period is interpreted as prolonged right ventricular (RV) relaxation, and thus a reflection of diastolic dysfunction. This concept recently has been questioned, since it was shown that RV contraction continues after pulmonary valve closure causing a post-systolic contraction period. OBJECTIVES: To investigate in PAH whether the increased RV post-systolic isovolumic period is caused by either an additional post-systolic contraction period, or an increased relaxation period (diastolic dysfunction). METHODS: 23 patients with PAH (mean pulmonary arterial pressure 54 +/- 12 mm Hg), and 18 healthy subjects were studied using cardiac MRI. In a RV two-chamber view, times of pulmonary valve closure (T(PVC)) and tricuspid valve opening (T(TVO)) were measured, defining the total post-systolic isovolumic period. Time to peak of RV free wall contraction (T(peak)RV) was determined with myocardial tagging. Post-systolic contraction and relaxation periods were defined as the time intervals between T(PVC) and T(peak)RV and between T(peak)RV and T(TVO), respectively. These periods were normalised to an RR interval. RESULTS: The total post-systolic isovolumic period was longer in patients than in healthy subjects (0.15 +/- 0.04 vs 0.04 +/- 0.02, p < 0.001), but the relaxation period was not different (0.06 +/- 0.02 vs 0.05 +/- 0.02, p = 0.09). The post-systolic contraction period in patients was strongly related to the total post-systolic isovolumic period (y = 0.98x-0.05; r = 0.89, p < 0.001), and was associated with disease severity. CONCLUSION: In PAH, the prolonged post systolic isovolumic period is caused by an additional post-systolic contraction period, rather than by an increased relaxation period. PMID- 20930047 TI - Molecular biology and clinical management of arrhythmogenic right ventricular cardiomyopathy/dysplasia. AB - In the last two decades the extraordinary advances in molecular biology of arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) have provided significant insights into our understanding of the disease aetiology by showing that it is a genetic disorder of the cardiac desmosomes and that interactions between mechanical disruption of cell-cell adhesion and defects of desmosomal mediated intracellular signalling are likely to be involved in the pathogenesis of the ARVC/D phenotype. The discovery of the causative genes for ARVC/D offers the possibility of identifying genetically-affected individuals before potentially malignant clinical phenotype occurs. Moreover, the evaluation of abnormal localisation of desmosomal proteins by immunohistochemical analysis on endomyocardial biopsy samples represents a promising test for ARVC/D diagnosis. Early detection of ARVC/D and preventive therapy of young individuals at highest risk of experiencing sudden cardiac death may be improved by molecular genetic screening within affected families and may alter the clinical management of patients. At present, however, the clinical use of genotyping is limited by the incomplete knowledge of causative mutations and the complex genetic background of the disease, which accounts for the incomplete penetrance and the marked variability of the phenotype expression. This review addresses the advances in the molecular biology of ARVC/D, with particular reference to the genetic basis of the disease, and how these advances have impacted on understanding the disease pathogenesis, on diagnosis and in establishing management strategies. PMID- 20930046 TI - Changes in anxiety and depression over 2 years in medically stable patients after myocardial infarction and their spouses in the Home Automatic External Defibrillator Trial (HAT): a longitudinal observational study. AB - OBJECTIVE: To compare the long-term effects of cardiopulmonary resuscitation (CPR) training and CPR/automatic external defibrillator (AED) training on anxiety and depression of patients who were medically stable after myocardial infarction (MI) and of their spouses/companions. DESIGN: Longitudinal. PARTICIPANTS: Post-MI patients (N=460) and their spouses/companions from the Home Automatic External Defibrillator Trial. MAIN OUTCOME MEASURES: Depression (Beck Depression Inventory II scores) and anxiety (State Trait Anxiety Inventory scores). RESULTS: At study entry, 25% of the patients and 15% of their spouses were depressed and 21% of the patients and 19% of the spouses were anxious. The prevalence of depression and anxiety did not change over time in the patients or their spouses. Average depression and anxiety decreased for patients but not for spouses. An intervention group did not contribute significantly to these changes. Psychological distress, indicated by depression or anxiety of the spouse or the patient, occurred in 191 couples. Among psychologically distressed patients (N=128), depression and anxiety decreased over time; the intervention group did not contribute to these changes. The reduction in anxiety among male patients was greater than in female patients (p=0.012, 95% CI 0.002 to 0.018). Among psychologically distressed spouses (N=118), depression decreased over time independently of the intervention. Changes in spouse anxiety depended on the intervention group (p=0.012, 95% CI 0.001 to 0.012); anxiety decreased significantly in the CPR and remained high in the CPR/AED group. CONCLUSION: There was no evidence that home AEDs caused psychological distress among patients. Even among those who were psychologically distressed when they were assigned to receive either CPR training or CPR/AEDs, home AEDs did not influence changes in patients' depression or anxiety or spouses' depression in comparison with CPR training. Among psychologically distressed spouses, AEDs may keep anxiety higher than it would be otherwise. Interventions to reduce anxiety of spouses who are psychologically distressed may be indicated when their partners receive an AED. PMID- 20930048 TI - Transcription factor Nrf2 regulates SHP and lipogenic gene expression in hepatic lipid metabolism. AB - Nuclear factor erythroid-2 related factor 2 (Nrf2) plays a pivotal role in cytoprotection against both endogenous and exogenous stresses. Here, we establish a novel molecular link between Nrf2, nuclear receptor small heterodimer partner (SHP; NROB2), lipogenic genes, and hepatic lipid homeostasis. Deletion of Nrf2 (Nrf2-(/)-) in mice resulted in a reduced liver weight, a decrease in fatty acid content of hepatic triacylglycerol, as well as concomitant increases in the levels of serum VLDL-triglyceride (TG), HDL cholesterol, and ketone bodies at 6 mo of age. Liver weight and hepatic TG content were consistently lower in Nrf2 (/)- mice upon a high-fat challenge. This phenotype was accompanied by downregulation of genes in lipid synthesis and uptake and upregulation of genes in lipid oxidation in older Nrf2-(/)- mice. Interestingly, SHP expression was induced with age in Nrf2(+/+) mice but decreased by Nrf2 deficiency. Forced expression and activation of Nrf2 by Nrf2 activators consistently induced SHP expression, and Nrf2 was identified as a novel activator of the SHP gene transcription. We also identified PPAR-gamma, Fas, Scd1, and Srebp-1 as direct targets of Nrf2 activation. These findings provide evidence for a role of Nrf2 in the modulation of hepatic lipid homeostasis through transcriptional activation of SHP and lipogenic gene expression. PMID- 20930049 TI - The steroid glycoside H.g.-12 from Hoodia gordonii activates the human bitter receptor TAS2R14 and induces CCK release from HuTu-80 cells. AB - Steroid glycosides extracted from the succulent plant Hoodia gordonii are suggested to have appetite-suppressant effects both in animals and humans. Yet, the mechanisms underlying the putative satiety action of Hoodia steroid glycosides are not fully understood. We found that H.g.-12, a steroid glycoside purified from H. gordonii extract, initiated cholecystokinin (CCK) secretion both ex vivo in rat intestine and in vitro in the human enteroendocrine (EC) cell line HuTu-80. CCK is known to exert central effects on appetite suppression via the vagus nerve which afferents terminate in the gut wall. Recent data show that G protein-coupled receptors signaling bitter taste (T2Rs) are expressed in both rodent and human gastrointestinal tract. It was further demonstrated that bitter sensing is functional in mouse STC-1 EC cells and leads to CCK secretion via increased intracellular Ca2(+) concentrations. Based on the bitter taste of H. gordonii purified extracts, we assessed whether H.g.-12 could activate human bitter receptors. The steroid glycoside activated selectively TAS2R7 and TAS2R14, both heterologously expressed in HEK 293 cells. Removing an essential structural feature from the steroid glycoside inhibited H.g.-12-induced Ca2(+) increase in TAS2R14-expressing HEK cells and abolished H.g.-12-induced CCK secretion from human EC cells. Similarly, a nonspecific bitter receptor antagonist abolished H.g.-12-induced CCK secretion in HuTu-80 cells. These results point to a potential route of action by which components of Hoodia might influence appetite control. Our data also provide additional evidence that bitter taste-sensing mechanisms are coupled to hormone release from EC cells in the intestine. Moreover, we identified a natural agonist of TAS2R7 and TAS2R14 for further studies on the role of bitter receptors in satiety control and food intake. PMID- 20930050 TI - The first year of practice: an investigation of the professional learning and development of promising novice physical therapists. AB - BACKGROUND: The goal in studying expertise is not merely to describe ways in which experts excel but also to understand how experts develop in order to better facilitate the development of novices. The study of novice progression helps us to understand what successful versus unsuccessful learning looks like. This understanding is critical, as autonomous practice places increased demands for advanced clinical judgments and the ability to assume professional responsibilities. OBJECTIVES: The purpose of this study was to explore the experiences, learning, and development of promising novice therapists throughout their first year of practice in the United States. DESIGN AND METHODS: A longitudinal, multiple-site qualitative case study method was used for within case and across-case analysis. A purposive sample of 11 promising new graduates from 4 physical therapist education programs participated. Investigators followed the graduates throughout their first year of practice. Data sources included: (1) semistructured interviews conducted at baseline and every 3 months thereafter for 1 year, (2) reflective journals completed at regular intervals, and (3) review of academic and clinical education records and resumes. RESULTS: Four themes emerged: (1) the clinical environment influenced the novice physical therapists' performance, (2) participants learned through experience and social interaction and learning was primarily directed toward self, (3) growing confidence was directly related to developing communication skills, and (4) therapists were engaged in professional identity formation and role transitions. CONCLUSIONS: The findings suggest there are common experiences and themes that emerge as novice physical therapists develop. Although research has been conducted on expertise in physical therapy, few longitudinal investigations have explored the development of therapists across transitions from graduate to novice to expert practitioner. This study explored and described the learning and development of graduates during their first year of practice. PMID- 20930051 TI - Determinants of social participation--with friends and others who are not family members--for youths with cerebral palsy. AB - BACKGROUND: Social participation provides youths with opportunities to develop their self-concept, friendships, and meaning in life. Youths with cerebral palsy (CP) have been reported to participate more in home-based leisure activities and to have fewer social experiences with friends and others than youths without disabilities. OBJECTIVE: The objective of this study was to identify youth, family, and service determinants of the participation of youths with CP in leisure activities with friends and others who are not family members. DESIGN: The study design was a cross-sectional analysis. METHODS: The participants were 209 youths who were 13 to 21 years old (52% male), had CP, and were classified in Gross Motor Function Classification System (GMFCS) levels I to V as well as their parents. The participants were recruited from 7 children's hospitals in 6 different states. Youths completed the Children's Assessment of Participation and Enjoyment in structured interviews. Parents completed the Coping Inventory, Pediatric Outcomes Data Collection Instrument, Family Environment Scale, Measure of Processes of Care, and demographic and service questionnaires. Researchers determined GMFCS levels. A sequential multiple regression analysis was used to determine the youth, family, and service variables that predicted participation with friends and with others who were not family members. RESULTS: Sports and physical function, communication or speech problems, educational program, and the extent to which the desired community recreational activities were obtained explained 45.8% of the variance in the number of activities engaged in with friends. A higher level of parental education explained 6.3% of the variance in the number of activities engaged in with others who were not family members. Limitations The youths' activity preferences and intensity of participation were not examined. CONCLUSIONS: /b> Youth and service characteristics were determinants of participation with friends but not others who were not family members. The findings have implications for the role of physical therapists in promoting sports and physical and communication abilities and enhancing community opportunities to optimize the social participation of youths with CP. PMID- 20930052 TI - Molecular characterization and antimicrobial susceptibility of extended-spectrum {beta}-lactamase-producing Enterobacteriaceae isolates at a tertiary-care centre in Monterrey, Mexico. AB - Our objective was to analyse phenotypic and genetic data of extended-spectrum beta-lactamase (ESBL)-producing Klebsiella pneumoniae, Enterobacter cloacae, Escherichia coli and Serratia marcescens that cause infections in our hospital. Over a 3 year period, 342 randomly selected clinical Enterobacteriaceae isolates were tested for ESBL production and evaluated for the presence of the beta lactamase genes bla(SHV), bla(TEM,) bla(CTX-M) and bla(TLA-1). The antibiotic susceptibilities of these isolates were also determined, and the clonality of the isolates was assessed by PFGE. Based on our analyses, 33/92 (35.9 %) K. pneumoniae, 31/87 (35.6 %) Enterobacter cloacae, 24/80 (30 %) E. coli and 17/83 (20.5 %) S. marcescens were identified as ESBL producers. The presence of TEM, SHV or CTX ESBL types was detected in 99/105 (94 %) of the isolates. TLA-1 was not detected in any of the 105 isolates. The dominant ESBL types were bla(SHV-5) (n=33), bla(SHV12) (n=31) and bla(CTX-M-15) (n=30). The predominant ESBL identified in E. coli and Enterobacter cloacae isolates was CTX-M-15, whereas in K. pneumoniae and S. marcescens the predominant types were SHV-12 and SHV-5, respectively. PFGE genotyping revealed two main genetic patterns in the K. pneumoniae isolates, types SHV-12 and TEM-1+SHV-5. An outbreak caused by Enterobacter cloacae SHV-5+CTX-M-15 was detected. In contrast, most ESBL producing isolates of E. coli and S. marcescens did not have similar PFGE banding patterns and thus were not genetically similar. Enterobacteriaceae are a concern in our hospital, especially K. pneumoniae and Enterobacter cloacae. Our results confirm that the CTX-M-15 ESBL type has spread rapidly in the hospital, and thus requires careful monitoring. PMID- 20930053 TI - Selection and application of peptide mimotopes of MPT64 protein in Mycobacterium tuberculosis. AB - Antibody responses can be useful markers of tuberculosis (TB) infection, especially in the screening of extra-pulmonary TB. MPT64 is an important antigen in Mycobacterium tuberculosis (MTB) infection and is used in serological diagnosis. However, large variability in the diagnostic accuracy of MPT64 as a serological tool has limited its application. Phage-displayed random peptide libraries have emerged as a powerful technique to select peptides (epitopes) or mimotopes that may serve as surrogate diagnostic markers in serological tests. In the present study, this method was employed to identify mimotopes of the MPT64 protein of MTB by screening a linear heptapeptide library with rabbit antibodies raised against MPT64 protein. Two antigenic mimotopes (M2 and M6) resembling B cell epitopes of MPT64 were identified that bound the affinity purified anti MPT64 polyclonal antibodies and competed with MPT64 for antibody binding. From the results of sequence alignment and a structure modelling figure of MPT64, the sequence of the 2nd to 5th amino acids (DSML) of M2 was totally consistent with the sequence of the 224th to 227th amino acids of MPT64 and the peptide is located on the surface of the space structure of MPT64, suggesting that it might be a linear epitope of MPT64. The recognition of both phage-displayed and synthetic peptides of M2 by the anti-MPT64 polyclonal antibodies also supported this. Although no recurring sequence and no analogue to MPT64 of M6 were found for sequence alignment, the recognition of both phage-displayed and synthetic peptides of M6 by the anti-MPT64 polyclonal antibodies indicated that it might be a mimotope of a conformational epitope of MPT64. According to the results of the reactivity of human sera with synthetic M2 and M6 peptides and MPT64, M2 showed a significantly higher AUC and sensitivity than M6 and MPT64, especially for the sera from sputum-negative TB patients, suggesting that the M2 mimotope may be useful in serological diagnostic testing for TB. PMID- 20930054 TI - Deep divergences of human gene trees and models of human origins. AB - Two competing hypotheses are at the forefront of the debate on modern human origins. In the first scenario, known as the recent Out-of-Africa hypothesis, modern humans arose in Africa about 100,000-200,000 years ago and spread throughout the world by replacing the local archaic human populations. By contrast, the second hypothesis posits substantial gene flow between archaic and emerging modern humans. In the last two decades, the young time estimates- between 100,000 and 200,000 years--of the most recent common ancestors for the mitochondrion and the Y chromosome provided evidence in favor of a recent African origin of modern humans. However, the presence of very old lineages for autosomal and X-linked genes has often been claimed to be incompatible with a simple, single origin of modern humans. Through the analysis of a public DNA sequence database, we find, similar to previous estimates, that the common ancestors of autosomal and X-linked genes are indeed very old, living, on average, respectively, 1,500,000 and 1,000,000 years ago. However, contrary to previous conclusions, we find that these deep gene genealogies are consistent with the Out of-Africa scenario provided that the ancestral effective population size was approximately 14,000 individuals. We show that an ancient bottleneck in the Middle Pleistocene, possibly arising from an ancestral structured population, can reconcile the contradictory findings from the mitochondrion on the one hand, with the autosomes and the X chromosome on the other hand. PMID- 20930055 TI - Germline SMARCB1 mutation and somatic NF2 mutations in familial multiple meningiomas. AB - BACKGROUND: Multiple meningiomas occur in <10% of meningioma patients. Their development may be caused by the presence of a predisposing germline mutation in the neurofibromatosis type 2 (NF2) gene. The predisposing gene in patients with non-NF2 associated multiple meningiomas remains to be identified. Recently, SMARCB1 was reported to be a potential predisposing gene for multiple meningiomas in a family with schwannomatosis and multiple meningiomas. However, involvement of this gene in the development of the meningiomas was not demonstrated. RESULTS: Five affected members of a large family with multiple meningiomas were investigated for the presence of mutations in SMARCB1 and NF2. A missense mutation was identified in exon 2 of SMARCB1 as the causative germline mutation predisposing to multiple meningiomas; furthermore, it was demonstrated that, in accordance with the two-hit hypothesis for tumourigenesis, the mutant allele was retained and the wild-type allele lost in all four investigated meningiomas. In addition, independent somatically acquired NF2 mutations were identified in two meningiomas of one patient with concomitant losses of the wild-type NF2 allele. CONCLUSION: It is concluded that, analogous to the genetic events in a subset of schwannomatosis associated schwannomas, a four-hit mechanism of tumour suppressor gene inactivation, involving SMARCB1 and NF2, might be operative in familial multiple meningiomas associated meningiomas. PMID- 20930056 TI - Multiexon deletions account for 15% of congenital myasthenic syndromes with RAPSN mutations after negative DNA sequencing. AB - Congenital myasthenic syndromes (CMS) are a heterogeneous group of genetic disorders that give rise to a defect in neuromuscular transmission. We described here three patients with a characteristic phenotype of recessive CMS and presenting mutation in the gene encoding rapsyn (RAPSN). Familial analysis showed that one allelic mutation failed to be detected by direct sequencing. An allelic quantification on patient's DNA identified three novel multi-exon deletions of RAPSN. These three genomic rearrangements in RAPSN represent 15% of our CMS patients with RAPSN mutations and we emphasize that single-nucleotide polymorphism markers and a gene dosage method should be performed in addition to DNA direct sequencing analysis particularly when there is a genetic counselling issue. PMID- 20930057 TI - Secondhand tobacco smoke exposure in selected public places (PM2.5 and air nicotine) and non-smoking employees (hair nicotine) in Ghana. AB - BACKGROUND: Secondhand tobacco smoke (SHS) exposure is a global public health problem. Ghana currently has no legislation to prevent smoking in public places. To provide data on SHS levels in hospitality venues in Ghana the authors measured (1) airborne particulate matter <2.5 MUm (PM(2.5)) and nicotine concentrations and (2) hair nicotine concentrations in non-smoking employees. Quantifying SHS exposure will provide evidence needed to develop tobacco control legislation. METHOD: PM(2.5) was measured for 30 min in 75 smoking and 13 non-smoking venues. Air nicotine concentrations were measured for 7 days in 8 smoking and 2 non smoking venues. Additionally, 63 non-smoking employees provided hair samples for nicotine analysis. RESULT: Compared to non-smoking venues, smoking venues had markedly elevated PM(2.5) (median 553 [IQR 259-1038] vs 16.0 [14.0-17.0]MUg/m(3)) and air nicotine (1.83 [0.91-4.25] vs 0.03 [0.02-0.04]MUg/m(3)) concentrations. Hair nicotine concentrations were also higher in non-smoking employees working in smoking venues (median 2.49 [0.46-6.84] ng/mg) compared to those working in non smoking venues (median 0.16 [0.08-0.79]ng/mg). Hair nicotine concentrations correlated with self-reported hours of SHS exposure (r=0.35), indoor air PM(2.5) concentrations (r=0.47) and air nicotine concentrations (r=0.63). CONCLUSION: SHS levels were unacceptably high in public places in Ghana where smoking is allowed, despite a relatively low-smoking prevalence in the country. This is one of the first studies to ascertain SHS and hair nicotine in Africa. Levels were comparable to those measured in American, Asian and European countries without or before smoking bans. Implementing a comprehensive smoke-free legislation that protects workers and customers from exposure to secondhand smoke is urgently needed in Ghana. PMID- 20930058 TI - Major tobacco companies have technology to reduce carcinogen levels but do not apply it to popular smokeless tobacco products. PMID- 20930059 TI - Swedish Match marketing on YouTube. PMID- 20930060 TI - Electronic cigarettes: a new 'tobacco' industry? PMID- 20930061 TI - The effect of GH replacement therapy on different fat compartments: a whole-body magnetic resonance imaging study. AB - OBJECTIVE: Patients with GH deficiency (GHD) are insulin resistant with an increase in visceral fat mass (FM). Whether this holds true when sedentary control subjects (CS) are matched for waist has not been documented. GH replacement therapy (GHRT) results in a decrease in FM. Whether the decrease in FM is mainly related to a reduction in visceral FM remains to be proven. The aim was to separately assess visceral and subcutaneous FM in relation to insulin resistance (IR) in GHD patients before and after GHRT and in sedentary CS. METHODS: Ten patients with GHD were investigated before and 6 months after GHRT. Sedentary CS matched for age, gender, body mass index, and waist were assessed. Exercise capacity was measured as VO(2max) using an incremental work load on a treadmill. Visceral and subcutaneous FM were measured using whole-body magnetic resonance imaging and IR by the homeostasis model assessment of IR (HOMA-IR) index. RESULTS: GHD patients had a non-significantly lower VO(2max) but did not have increased subcutaneous and visceral FM compared with CS. GHRT resulted in a similar relative decrease in subcutaneous and visceral FM. Compared with CS, GHD patients showed a lower HOMA-IR. GHRT tended to increase HOMA-IR. CONCLUSION: Matching for waist and separate assessment of visceral and subcutaneous FM may be critical in the evaluation of body composition and IR in GHD patients before and after GHRT. PMID- 20930062 TI - Association of thyroid function with estimated glomerular filtration rate in a population-based study: the HUNT study. AB - OBJECTIVE: Low thyroid function may be associated with reduced glomerular filtration rate (GFR). We therefore studied the association of thyroid function with estimated GFR (eGFR) in a population-based study. DESIGN: A cross-sectional, population-based study of 29 480 individuals above 40 years of age, without previously known thyroid disease. METHODS: We calculated geometric mean eGFR and odds ratio (OR) of chronic kidney disease (CKD; eGFR <60 ml/min per 1.73 m(2)) according to categories of thyroid function, using people with TSH in the lower third of the reference range (0.50-1.4 mU/l) as the comparison group. RESULTS: TSH within the reference range (0.50-3.5 mU/l) was negatively associated with eGFR (P for trend <0.001). Compared with people with TSH in the lower third of the reference range (83.0 ml/min per 1.73 m(2)), eGFR was lower in people with TSH in the middle (81.6 ml/min per 1.73 m(2)) and highest third (80.3 ml/min per 1.73 m(2)) of the reference range, and in people with subclinical (79.3 ml/min per 1.73 m(2), P<0.001) or overt hypothyroidism (76.5 ml/min per 1.73 m(2), P<0.001). The prevalence of CKD was higher in people with TSH in the middle (OR 1.20, 95% confidence interval (CI) 1.07-1.35) or highest third (OR 1.31, 95% CI 1.13-1.52) of the reference range, compared with people in the reference group. Also, CKD was more common in people with subclinical (OR 1.63, 95% CI 1.38-1.93) or overt (OR 1.98, 95% CI 1.22-3.20) hypothyroidism. CONCLUSIONS: These findings suggest that low thyroid function, also within the clinically normal range, is associated with reduced GFR. PMID- 20930063 TI - Impairment of insulin receptor signal transduction in placentas of intra-uterine growth-restricted newborns and its relationship with fetal growth. AB - OBJECTIVE: Intra-uterine growth restriction (IUGR) is related to a higher incidence of type 2 diabetes mellitus. We previously reported reduced adiponectin and increased interleukin 6 (IL6) concentrations in IUGR placentas, which are features of insulin resistance. We aimed to investigate placental insulin receptor (IR) function and activation in human placenta and subsequently the relationships of insulin signalling peptides with placental protein content in IL6, insulin, resistin and adiponectin, and with parameters of fetal growth. DESIGN AND METHODS: Whole villous tissue was collected from 18 IUGR and 24 appropriate for gestational age (AGA) placentas of comparable gestational age. Insulin signalling peptides, suppressors of cytokine signalling-2 (SOCS2), insulin, adiponectin, resistin, and IL6 concentrations were determined by using western immunoblotting or specific research kits. RESULTS: The amount of total IR was similar in both groups but activated IR significantly higher in IUGR. Total IR substrate-1 (IRS1) was increased in IUGR, whereas total IRS2 and activated IRS1 were similar. AKT content was reduced and activated AKT was undetectable in IUGR placentas. c-Jun N-terminal kinase content was reduced in IUGR. Total and activated ERK1/2 was similar in IUGR and AGA groups, and total SOCS2 was increased in IUGR. IL6 lysate concentrations correlated with AKT content and activated IR. Correlations were found also with adiponectin and resistin. SOCS2 correlated negatively with all growth parameters at birth. CONCLUSIONS: IR was more activated in placentas of IUGR compared with AGA; however, signal transduction downstream of the receptor was impaired. The increase in activated IR could be in favour of a compensatory mechanism to increase insulin sensitivity. Close relationships of insulin action in placenta with fetal growth were shown. PMID- 20930064 TI - Back to school: why the speech-language pathologist belongs in the classroom. PMID- 20930065 TI - An emerging role for SPAK in NCC, NKCC, and blood pressure regulation. PMID- 20930066 TI - Epigenetic histone methylation modulates fibrotic gene expression. AB - TGF-beta1-induced expression of extracellular matrix (ECM) genes plays a major role in the development of chronic renal diseases such as diabetic nephropathy. Although many key transcription factors are known, mechanisms involving the nuclear chromatin that modulate ECM gene expression remain unclear. Here, we examined the role of epigenetic chromatin marks such as histone H3 lysine methylation (H3Kme) in TGF-beta1-induced gene expression in rat mesangial cells under normal and high-glucose (HG) conditions. TGF-beta1 increased the expression of the ECM-associated genes connective tissue growth factor, collagen alpha1[Iota], and plasminogen activator inhibitor-1. Increased levels of chromatin marks associated with active genes (H3K4me1, H3K4me2, and H3K4me3), and decreased levels of repressive marks (H3K9me2 and H3K9me3) at these gene promoters accompanied these changes in expression. TGF-beta1 also increased expression of the H3K4 methyltransferase SET7/9 and recruitment to these promoters. SET7/9 gene silencing with siRNAs significantly attenuated TGF-beta1 induced ECM gene expression. Furthermore, a TGF-beta1 antibody not only blocked HG-induced ECM gene expression but also reversed HG-induced changes in promoter H3Kme levels and SET7/9 occupancy. Taken together, these results show the functional role of epigenetic chromatin histone H3Kme in TGF-beta1-mediated ECM gene expression in mesangial cells under normal and HG conditions. Pharmacologic and other therapies that reverse these modifications could have potential renoprotective effects for diabetic nephropathy. PMID- 20930067 TI - The chemokine CXCL12 regulates monocyte-macrophage differentiation and RUNX3 expression. AB - Monocytes are versatile cells that can express different functional programs in response to microenvironmental signals. We show that primary blood monocytes secrete the CXCL12 chemokine, and express the CXCR4 and CXCR7 receptors, leading to an autocrine/paracrine loop that contribute to shape monocyte differentiation to a distinct type of macrophages, with an enhanced expression of CD4, CD14, and CD163, or dendritic cells, with a reduced functional ability to stimulate antigen specific T-lymphocyte responses. The in vivo relevance of CXCL12 production by mononuclear phagocytes was studied in metastatic melanoma tissues by a thoroughly immunofluorescence phenotyping of CXCL12(high) expressing cells, which were CD45(+), coexpressed the macrophage antigens CD68, CD163, and CD209 and constituted the 60%-90% of tumor-associated macrophages. Microarray analysis of primary monocytes revealed that the vascular endothelial growth factor and the angiogenic chemokine CCL1 mRNA levels were up-regulated in response to CXCL12, leading to enhanced expression of both proteins. In addition, we found that CXCL12 autocrine/paracrine signaling down-regulates the expression of the transcription factor RUNX3 and contributes to maintain the long-term CD4 and CD14 expression in monocytes/macrophages. Together, these results suggest that autocrine CXCL12 production modulates differentiation of monocytes toward a distinct program with proangiogenic and immunosuppressive functions. PMID- 20930068 TI - Distinct molecular mechanisms responsible for bortezomib-induced death of therapy resistant versus -sensitive B-NHL cells. AB - Resistance to currently available therapies is a major impediment to the successful treatment of hematological malignancies. Here, we used a model of therapy-resistant B-cell non Hodgkin lymphoma (B-NHL) developed in our laboratory along with primary B-NHL cells to study basic mechanisms of bortezomib activity. In resistant cells and a subset of primary B-NHLs, bortezomib treatment led to stabilization of Bak and subsequent Bak-dependent activation of apoptosis. In contrast to sensitive cells that die strictly by apoptosis, bortezomib was capable of killing resistant cells through activation of apoptosis or caspase independent mechanism(s) when caspases were pharmacologically inhibited. Our data demonstrate that bortezomib is capable of killing B-NHL cells via multiple mechanisms, regardless of their basal apoptotic potential, and contributes to growing evidence that proteasome inhibitors can act via modulation of B-cell lymphoma 2 (Bcl-2) family proteins. The capacity of bortezomib to act independently of the intrinsic apoptotic threshold of a given B-NHL cell suggests that bortezomib-based therapies could potentially overcome resistance and result in relevant clinical activity in a relapsed/refractory setting. PMID- 20930069 TI - IL-6 in human cytomegalovirus secretome promotes angiogenesis and survival of endothelial cells through the stimulation of survivin. AB - Human cytomegalovirus (HCMV) is linked to the acceleration of vascular diseases such as atherosclerosis and transplant vasculopathy. One of the hallmarks of these diseases is angiogenesis (AG) and neovessel formation. Endothelial cells (ECs) are an integral part of AG and are sites of HCMV persistence. AG requires multiple synchronous processes that include EC proliferation, migration, and vessel stabilization. Virus-free supernatant (secretome) from HCMV-infected ECs induces AG. To identify factor(s) involved in this process, we performed a human cytokine array. Several cytokines were significantly induced in the HCMV secretomes including interleukin-6 (IL-6), granulocyte macrophage colony stimulating factor, and IL-8/CXCL8. Using in vitro AG assays, neutralization of IL-6 significantly reduced neovessel formation. Addition of the HCMV secretome to preformed vessels extended neovessel survival, but this effect was blocked by neutralization of IL-6. In these cells, IL-6 prevented apoptosis by blocking caspase-3 and -7 activation through the induction of survivin. Neutralization of IL-6 receptor on ECs abolished the ability of HCMV secretome to increase survivin expression and activated effector caspases. Moreover, survivin shRNA expression induced rapid regression of tubule capillary networks in ECs stimulated with HCMV secretome and activated effector caspases. These observations may explain how CMV accelerates vascular disease despite limited infection in tissues. PMID- 20930070 TI - Antiviral drug resistance of human cytomegalovirus. AB - The study of human cytomegalovirus (HCMV) antiviral drug resistance has enhanced knowledge of the virological targets and the mechanisms of antiviral activity. The currently approved drugs, ganciclovir (GCV), foscarnet (FOS), and cidofovir (CDV), target the viral DNA polymerase. GCV anabolism also requires phosphorylation by the virus-encoded UL97 kinase. GCV resistance mutations have been identified in both genes, while FOS and CDV mutations occur only in the DNA polymerase gene. Confirmation of resistance mutations requires phenotypic analysis; however, phenotypic assays are too time-consuming for diagnostic purposes. Genotypic assays based on sequencing provide more rapid results but are dependent on prior validation by phenotypic methods. Reports from many laboratories have produced an evolving list of confirmed resistance mutations, although differences in interpretation have led to some confusion. Recombinant phenotyping methods performed in a few research laboratories have resolved some of the conflicting results. Treatment options for drug-resistant HCMV infections are complex and have not been subjected to controlled clinical trials, although consensus guidelines have been proposed. This review summarizes the virological and clinical data pertaining to HCMV antiviral drug resistance. PMID- 20930071 TI - Helicobacter pylori and gastric cancer: factors that modulate disease risk. AB - Helicobacter pylori is a gastric pathogen that colonizes approximately 50% of the world's population. Infection with H. pylori causes chronic inflammation and significantly increases the risk of developing duodenal and gastric ulcer disease and gastric cancer. Infection with H. pylori is the strongest known risk factor for gastric cancer, which is the second leading cause of cancer-related deaths worldwide. Once H. pylori colonizes the gastric environment, it persists for the lifetime of the host, suggesting that the host immune response is ineffective in clearing this bacterium. In this review, we discuss the host immune response and examine other host factors that increase the pathogenic potential of this bacterium, including host polymorphisms, alterations to the apical-junctional complex, and the effects of environmental factors. In addition to host effects and responses, H. pylori strains are genetically diverse. We discuss the main virulence determinants in H. pylori strains and the correlation between these and the diverse clinical outcomes following H. pylori infection. Since H. pylori inhibits the gastric epithelium of half of the world, it is crucial that we continue to gain understanding of host and microbial factors that increase the risk of developing more severe clinical outcomes. PMID- 20930073 TI - Perspectives on clinical and preclinical testing of new tuberculosis vaccines. AB - This review hopes to improve the selection of new tuberculosis (TB) vaccines by providing several perspectives on the immunization of humans, mice, guinea pigs, rabbits, and monkeys which have not usually been considered. (i) In human TB vaccine trials, the low rate of healing of Mycobacterium bovis BCG lesions (used as the control group) would distinguish individuals who might be helped by vaccination from the 95% who do not need it and would make these trials more conclusive. (ii) The rabbit immune response to Mycobacterium tuberculosis is much more effective in arresting tuberculosis than those of other laboratory animals, so pulmonary tubercle counting in rabbits should be included in all preclinical TB vaccine testing. (iii) Both delayed-type hypersensitivity (DTH) and cell mediated immunity (CMI) are necessary to control the growth of M. tuberculosis. The testing of new TB vaccines in mice or in guinea pigs may not detect important antigens needed for human immunization. Mice respond poorly to tuberculin-like antigens that cause DTH. Guinea pigs respond poorly to antigens that cause CMI. Rabbits and humans respond well to both DTH and CMI antigens. Since monkeys are very susceptible to M. tuberculosis, they may not be as useful as rabbits for preclinical vaccine evaluation. (iv) Critical antigens (possibly ESAT-6 or CFP 10) might increase the immunity of the host to a greater extent than that produced by a natural M. tuberculosis infection and therefore would be useful in both prophylaxis and immunotherapy. Such critical antigens would increase the host's ability to neutralize key components of M. tuberculosis that enable it to survive in both laboratory animals and humans. PMID- 20930072 TI - Infections of people with complement deficiencies and patients who have undergone splenectomy. AB - The complement system comprises several fluid-phase and membrane-associated proteins. Under physiological conditions, activation of the fluid-phase components of complement is maintained under tight control and complement activation occurs primarily on surfaces recognized as "nonself" in an attempt to minimize damage to bystander host cells. Membrane complement components act to limit complement activation on host cells or to facilitate uptake of antigens or microbes "tagged" with complement fragments. While this review focuses on the role of complement in infectious diseases, work over the past couple of decades has defined several important functions of complement distinct from that of combating infections. Activation of complement in the fluid phase can occur through the classical, lectin, or alternative pathway. Deficiencies of components of the classical pathway lead to the development of autoimmune disorders and predispose individuals to recurrent respiratory infections and infections caused by encapsulated organisms, including Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae. While no individual with complete mannan-binding lectin (MBL) deficiency has been identified, low MBL levels have been linked to predisposition to, or severity of, several diseases. It appears that MBL may play an important role in children, who have a relatively immature adaptive immune response. C3 is the point at which all complement pathways converge, and complete deficiency of C3 invariably leads to severe infections, including those caused by meningococci and pneumococci. Deficiencies of the alternative and terminal complement pathways result in an almost exclusive predisposition to invasive meningococcal disease. The spleen plays an important role in antigen processing and the production of antibodies. Splenic macrophages are critical in clearing opsonized encapsulated bacteria (such as pneumococci, meningococci, and Escherichia coli) and intraerythrocytic parasites such as those causing malaria and babesiosis, which explains the fulminant nature of these infections in persons with anatomic or functional asplenia. Paramount to the management of patients with complement deficiencies and asplenia is educating patients about their predisposition to infection and the importance of preventive immunizations and seeking prompt medical attention. PMID- 20930075 TI - Role of bacteria in oncogenesis. AB - Although scientific knowledge in viral oncology has exploded in the 20th century, the role of bacteria as mediators of oncogenesis has been less well elucidated. Understanding bacterial carcinogenesis has become increasingly important as a possible means of cancer prevention. This review summarizes clinical, epidemiological, and experimental evidence as well as possible mechanisms of bacterial induction of or protection from malignancy. PMID- 20930078 TI - Impressions of the myeloma landscape. PMID- 20930079 TI - PTEN: not just a tumor suppressor. PMID- 20930076 TI - Penetration of drugs through the blood-cerebrospinal fluid/blood-brain barrier for treatment of central nervous system infections. AB - The entry of anti-infectives into the central nervous system (CNS) depends on the compartment studied, molecular size, electric charge, lipophilicity, plasma protein binding, affinity to active transport systems at the blood-brain/blood cerebrospinal fluid (CSF) barrier, and host factors such as meningeal inflammation and CSF flow. Since concentrations in microdialysates and abscesses are not frequently available for humans, this review focuses on drug CSF concentrations. The ideal compound to treat CNS infections is of small molecular size, is moderately lipophilic, has a low level of plasma protein binding, has a volume of distribution of around 1 liter/kg, and is not a strong ligand of an efflux pump at the blood-brain or blood-CSF barrier. When several equally active compounds are available, a drug which comes close to these physicochemical and pharmacokinetic properties should be preferred. Several anti-infectives (e.g., isoniazid, pyrazinamide, linezolid, metronidazole, fluconazole, and some fluoroquinolones) reach a CSF-to-serum ratio of the areas under the curves close to 1.0 and, therefore, are extremely valuable for the treatment of CNS infections. In many cases, however, pharmacokinetics have to be balanced against in vitro activity. Direct injection of drugs, which do not readily penetrate into the CNS, into the ventricular or lumbar CSF is indicated when other effective therapeutic options are unavailable. PMID- 20930080 TI - Iron, bone, and marrow. PMID- 20930074 TI - Importance of nonenteric protozoan infections in immunocompromised people. AB - There are many neglected nonenteric protozoa able to cause serious morbidity and mortality in humans, particularly in the developing world. Diseases caused by certain protozoa are often more severe in the presence of HIV. While information regarding neglected tropical diseases caused by trypanosomatids and Plasmodium is abundant, these protozoa are often not a first consideration in Western countries where they are not endemic. As such, diagnostics may not be available in these regions. Due to global travel and immigration, this has become an increasing problem. Inversely, in certain parts of the world (particularly sub-Saharan Africa), the HIV problem is so severe that diseases like microsporidiosis and toxoplasmosis are common. In Western countries, due to the availability of highly active antiretroviral therapy (HAART), these diseases are infrequently encountered. While free-living amoebae are rarely encountered in a clinical setting, when infections do occur, they are often fatal. Rapid diagnosis and treatment are essential to the survival of patients infected with these organisms. This paper reviews information on the diagnosis and treatment of nonenteric protozoal diseases in immunocompromised people, with a focus on patients infected with HIV. The nonenteric microsporidia, some trypanosomatids, Toxoplasma spp., Neospora spp., some free-living amoebae, Plasmodium spp., and Babesia spp. are discussed. PMID- 20930081 TI - "Capping": necessary for graduation. PMID- 20930082 TI - Donor selection for AML: do the KIR. PMID- 20930083 TI - Sex-related efficiency in NSG mouse engraftment. PMID- 20930084 TI - Dasatinib induces complete remission in a patient with primary cerebral involvement of B-cell chronic lymphocytic leukemia failing chemotherapy. PMID- 20930085 TI - Gemtuzumab ozogamicin: is there room for salvage? PMID- 20930086 TI - Autologous mesenchymal stromal cells and kidney transplantation: a pilot study of safety and clinical feasibility. AB - BACKGROUND AND OBJECTIVES: Mesenchymal stromal cells (MSCs) abrogate alloimmune response in vitro, suggesting a novel cell-based approach in transplantation. Moving this concept toward clinical application in organ transplantation should be critically assessed. DESIGN, SETTING, PARTICIPANTS & MEASUREMENTS: A safety and clinical feasibility study (ClinicalTrials.gov, NCT00752479) of autologous MSC infusion was conducted in two recipients of kidneys from living-related donors. Patients were given T cell-depleting induction therapy and maintenance immunosuppression with cyclosporine and mycophenolate mofetil. On day 7 posttransplant, MSCs were administered intravenously. Clinical and immunomonitoring of MSC-treated patients was performed up to day 360 postsurgery. RESULTS: Serum creatinine levels increased 7 to 14 days after cell infusion in both MSC-treated patients. A graft biopsy in patient 2 excluded acute graft rejection, but showed a focal inflammatory infiltrate, mostly granulocytes. In patient 1 protocol biopsy at 1-year posttransplant showed a normal graft. Both MSC-treated patients are in good health with stable graft function. A progressive increase of the percentage of CD4+CD25highFoxP3+CD127- Treg and a marked inhibition of memory CD45RO+RA-CD8+ T cell expansion were observed posttransplant. Patient T cells showed a profound reduction of CD8+ T cell activity. CONCLUSIONS: Findings from this study in the two patients show that MSC infusion in kidney transplant recipients is feasible, allows enlargement of Treg in the peripheral blood, and controls memory CD8+ T cell function. Future clinical trials with MSCs to look with the greatest care for unwanted side effects is advised. PMID- 20930088 TI - CMS 2728: what good is it? PMID- 20930087 TI - Vascular risk factors and cognitive impairment in chronic kidney disease: the Chronic Renal Insufficiency Cohort (CRIC) study. AB - BACKGROUND AND OBJECTIVES: Cognitive impairment is common among persons with chronic kidney disease, but the extent to which nontraditional vascular risk factors mediate this association is unclear. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted cross-sectional analyses of baseline data collected from adults with chronic kidney disease participating in the Chronic Renal Insufficiency Cohort study. Cognitive impairment was defined as a Modified Mini Mental State Exam score>1 SD below the mean score. RESULTS: Among 3591 participants, the mean age was 58.2+/-11.0 years, and the mean estimated GFR (eGFR) was 43.4+/-13.5 ml/min per 1.73 m2. Cognitive impairment was present in 13%. After adjustment for demographic characteristics, prevalent vascular disease (stroke, coronary artery disease, and peripheral arterial disease) and traditional vascular risk factors (diabetes, hypertension, smoking, and elevated cholesterol), an eGFR<30 ml/min per 1.73 m2 was associated with a 47% increased odds of cognitive impairment (odds ratio 1.47, 95% confidence interval 1.05, 2.05) relative to those with an eGFR 45 to 59 ml/min per 1.73 m2. This association was attenuated and no longer significant after adjustment for hemoglobin concentration. While other nontraditional vascular risk factors including C-reactive protein, homocysteine, serum albumin, and albuminuria were correlated with cognitive impairment in unadjusted analyses, they were not significantly associated with cognitive impairment after adjustment for eGFR and other confounders. CONCLUSIONS: The prevalence of cognitive impairment was higher among those with lower eGFR, independent of traditional vascular risk factors. This association may be explained in part by anemia. PMID- 20930089 TI - Successful models of interventional nephrology at academic medical centers. AB - The foundation of endovascular procedures by nephrologists was laid in the private practice arena. Because of political issues such as training, credentialing, space and equipment expenses, and co-management concerns surrounding the performance of dialysis-access procedures, the majority of these programs provided care in an outpatient vascular access center. On the basis of the improvement of patient care demonstrated by these centers, several nephrology programs at academic medical centers have also embraced this approach. In addition to providing interventional care on an outpatient basis, academic medical centers have taken a step further to expand collaboration with other specialties with similar expertise (such as with interventional radiologists and cardiologists) to enhance patient care and research. The enthusiastic initiative, cooperative, and mutually collaborative efforts used by academic medical centers have resulted in the successful establishment of interventional nephrology programs. This article describes various models of interventional nephrology programs at academic medical centers across the United States. PMID- 20930090 TI - Copeptin, a surrogate marker of vasopressin, is associated with disease severity in autosomal dominant polycystic kidney disease. AB - BACKGROUND AND OBJECTIVES: Experimental studies suggest a detrimental role for vasopressin in the pathogenesis of autosomal dominant polycystic kidney disease (ADPKD). However, it is unknown whether endogenous vasopressin concentration is associated with disease severity in patients with ADPKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Plasma copeptin concentration (a marker of endogenous vasopressin levels) was measured in 102 ADPKD patients (diagnosis based on Ravine criteria) by an immunoassay. Plasma and urinary osmolarity were also measured. To assess disease severity, GFR and effective renal blood flow were measured by continuous infusion of 125I-iothalamate and 131I-hippuran, total renal volume by magnetic resonance imaging, and 24-hour urinary albumin excretion by nephelometry. RESULTS: In these ADPKD patients, copeptin was associated with the various markers of disease severity in ADPKD (positively with total renal volume [R=0.47] and albuminuria [R=0.39] and negatively with GFR [R=-0.58] and effective renal blood flow [R=-0.52], all P<0.001). These associations were independent of age, gender, and use of diuretics. Copeptin was furthermore associated with plasma osmolarity (P<0.001) but not with 24-hour urinary volume, 24-hour urinary osmolarity or fractional urea excretion (P=0.7, 0.9, and 0.3, respectively). CONCLUSIONS: On cross-sectional analysis, copeptin is associated with disease severity in ADPKD patients, supporting the results of experimental studies that suggest that vasopressin antagonists have a renoprotective effect in ADPKD and offering a good prospect for clinical studies with these agents. PMID- 20930077 TI - Melanized fungi in human disease. AB - Melanized or dematiaceous fungi are associated with a wide variety of infectious syndromes, including chromoblastomycosis, mycetoma, and phaeohyphomycosis. [corrected]. Many are soil organisms and are generally distributed worldwide, though certain species appear to have restricted geographic ranges. Though they are uncommon causes of disease, melanized fungi have been increasingly recognized as important pathogens, with most reports occurring in the past 20 years. The spectrum of diseases with which they are associated has also broadened and includes allergic disease, superficial and deep local infections, pneumonia, brain abscess, and disseminated infection. For some infections in immunocompetent individuals, such as allergic fungal sinusitis and brain abscess, they are among the most common etiologic fungi. Melanin is a likely virulence factor for these fungi. Diagnosis relies on careful microscopic and pathological examination, as well as clinical assessment of the patient, as these fungi are often considered contaminants. Therapy varies depending upon the clinical syndrome. Local infection may be cured with excision alone, while systemic disease is often refractory to therapy. Triazoles such as voriconazole, posaconazole, and itraconazole have the most consistent in vitro activity. Further studies are needed to better understand the pathogenesis and optimal treatment of these uncommon infections. PMID- 20930091 TI - Large artery calcification on dialysis patients is located in the intima and related to atherosclerosis. AB - BACKGROUND AND OBJECTIVES: Vascular calcification (VC) has a significant effect in cardiovascular diseases on dialysis patients. However, VC is assessed with x ray-based techniques, which do not inform about calcium localization (intima, media, atherosclerosis-related). The aim of this work is to study VC and its related factors using arterial ultrasound to report the exact location of calcium. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This was an observational, cross-sectional, case-control study that included 232 patients in dialysis and 208 age- and sex-matched controls with normal kidney function. Demographic data and laboratory values were collated. Carotid, femoral, and brachial ultrasounds were performed to assess VC and atherosclerosis burden using a standardized protocol. RESULTS: Cardiovascular risk factors were predominantly found in controls, although the burden of atherosclerosis was higher in the dialysis group. VC was significantly more prevalent in the group of patients on dialysis than control subjects, and in both groups the most prevalent pattern of VC was linear calcification located in the intima of the artery wall. Age and undergoing dialysis (with or without previous cardiovascular diseases) were positively and significantly associated with linear calcification. Conversely, the absence of atherosclerosis and low levels of C-reactive protein and phosphorus significantly impeded the development of linear calcification. CONCLUSIONS: VC in large, conduit arteries is more prevalent in patients on dialysis than controls and is predominantly located in a linear fashion in the intima of the arteries. PMID- 20930092 TI - Life stage and sex specificity in relationships between the built and socioeconomic environments and physical activity. AB - BACKGROUND: In the largely cross-sectional literature, built environment characteristics such as walkability and recreation centres are variably related to physical activity. Subgroup-specific effects could help explain inconsistent findings, yet few studies have compared built environment associations by key characteristics such as sex or life stage. METHODS: Using data from the National Longitudinal Study of Adolescent Health (wave I 1994-5, wave III 2001-2; n=12 701) and a linked geographic information system, cross-sectional relationships between moderate to vigorous physical activity (MVPA) bouts and built and socioeconomic environment measures were estimated. Negative binomial generalised estimating equation regression modelled MVPA as a function of log-transformed environment measures, controlling for individual sociodemographics and testing for interactions with sex and life stage (waves I and III, when respondents were adolescents and young adults, respectively). RESULTS: Higher landscape diversity (coefficient 0.040; 95% CI 0.019 to 0.062) and lower crime (coefficient -0.047; 95% CI -0.071 to -0.022) were related to greater weekly MVPA regardless of sex or life stage. Higher street connectivity was marginally related to lower MVPA (coefficient -0.176; 95% CI -0.357 to 0.005) in females but not males. Pay facilities and public facilities per 10 000 population and median household income were unrelated to MVPA. CONCLUSIONS: Similar relationships between higher MVPA and higher landscape diversity and lower crime rate across sex and life stage suggest that application of these environment features may benefit broad populations. Sex-specific associations for street connectivity may partly account for the variation in findings across studies and have implications for targeting physical activity promotion strategies. PMID- 20930093 TI - Effects of mannose-binding lectin polymorphisms on irinotecan-induced febrile neutropenia. AB - OBJECTIVE: Mannose-binding lectin (MBL) is important in the innate immune response. MBL2 gene polymorphisms affect MBL expression, and genotypes yielding low MBL levels have been associated with an elevated risk for infections in hematological cancer patients undergoing chemotherapy. However, these reported associations are inconsistent, and data on patients with solid tumors are lacking. Here, we investigated the effects of MBL2 genotypes on irinotecan induced febrile neutropenia in patients with solid tumors. PATIENTS AND METHODS: Irinotecan-treated patients were genotyped for the MBL2 gene. Two promoter (-550 H/L and -221 X/Y) and three exon polymorphisms (52 A/D, 54 A/B, and 57 A/C) were determined, together with known risk factors for irinotecan-induced toxicity. Neutropenia and febrile neutropenia were recorded during the first course. RESULTS: Of the 133 patients, 28% experienced severe neutropenia and 10% experienced febrile neutropenia. No associations were found between exon polymorphisms and febrile neutropenia. However, patients with the H/H promoter genotype, associated with high MBL levels, experienced significantly more febrile neutropenia than patients with the H/L and L/L genotypes (20% versus 13% versus 5%). Moreover, patients with the HYA haplotype encountered significantly more febrile neutropenia than patients without this high MBL-producing haplotype (16% versus 4%). In the subgroup with wild-type exon polymorphisms (A/A), patients with the high MBL promoter phenotype had the highest incidence of febrile neutropenia, regardless of known risk factors. CONCLUSION: Patients with high MBL2 promoter genotypes and haplotypes seem more at risk for developing febrile neutropenia. If confirmed, these preliminary findings may contribute to more individualized approaches of irinotecan treatment. PMID- 20930094 TI - Age and axillary lymph node ratio in postmenopausal women with T1-T2 node positive breast cancer. AB - PURPOSE: The purpose of this article was to examine the relationship between age and lymph node ratio (LNR, number of positive nodes divided by number of examined nodes), and to determine their effects on breast cancer (BC) and overall mortality. METHODS: Women aged >=50 years, diagnosed in 1988-1997 with a unilateral histologically confirmed T1-T2 node positive surgically treated primary nonmetastatic BC, were selected from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER). Generalized Additive Models for Location Scale and Shape (GAMLSS) were used to evaluate the age-LNR relationship. Cumulative incidence functions and multivariate competing risks analysis based on model selection by the Bayesian Information Criterion (BIC) were used to examine the effect of age and LNR on mortality. Low LNR was defined as <=0.20, mid-LNR 0.21-0.65, and high LNR >0.65. RESULTS: GAMLSS showed a nonlinear LNR-age relationship, increasing from mean LNR 0.26-0.28 at age 50-70 years to 0.30 at 80 years and 0.40 at 90 years. Compared with a 9.8% [95% confidence interval (CI) 8.8%-10.8%] risk of BC death at 5 years in women aged 50 59 years with low LNR, the risk in women >=80 years with low LNR was 12.6% [95% CI 10.1%-15.0%], mid-LNR 18.1% [13.9%-22.1%], high LNR 29.8% [22.7%-36.1%]. Five years overall risk of death increased from 40.8% [37.5%-43.9%] by low LNR to 67.4% [61.4%-72.4%] by high LNR. The overall mortality hazard ratio for age >=80 years with high LNR was 7.49 [6.54-8.59], as compared with women aged 50-59 years with low LNR. CONCLUSION: High LNR combined with older age was associated with a threefold increased risk of BC death and a sevenfold increased hazard ratio of overall mortality. PMID- 20930095 TI - Obesity and the risk for a hematological malignancy: leukemia, lymphoma, or myeloma. AB - The aggregate of epidemiological studies indicates a significantly elevated risk for cancer in people with a high body mass index (BMI); a "dose-response" effect exists with increasing risk as BMI increases from the normal to overweight to obese categories. Successful sustained weight loss decreases future risk. The relationship of being overweight to the risk for leukemia in the aggregate has been supported in several large cohort studies and two meta-analyses of cohort and case-control studies. One meta-analysis found an elevated risk for each of the four major subtypes of leukemia. A significant association between the risk for non-Hodgkin's lymphoma and elevated BMI was supported by a meta-analysis of 13 cohort and nine case-control studies. The risk for diffuse large B-cell lymphoma may be especially significant. A high BMI increases the risk for myeloma, as judged by a meta-analysis of 11 cohort and four case-control studies. The biological relationship of obesity to the risk for cancer (biological plausibility) is unresolved. The two major causal final pathways could be "inductive" or "selective." The metabolic, endocrinologic, immunologic, and inflammatory-like changes resulting from obesity may increase the cell mutation rate, dysregulate gene function, disturb DNA repair, or induce epigenetic changes, favoring the induction of neoplastic transformation (inductive). Alternatively, obesity may create an environment in which pre-existing clones that are dormant are permitted (selected) to emerge. PMID- 20930096 TI - New results will change the paradigm for phase I trials and drug approval. PMID- 20930097 TI - Prognosis and outcome of small (<=1 cm), node-negative breast cancer on the basis of hormonal and HER-2 status. AB - Long-term outcomes and hence the role of adjuvant therapy in patients with small (<=1 cm), node-negative breast cancer remain unclear. This study's objective was to evaluate whether human epidermal growth factor receptor (HER)-2 status is an independent, poor prognostic marker in patients with these tumors and to identify a subgroup of patients with these small tumors who might benefit from adjuvant systemic therapy. All patients with a diagnosis of a node-negative breast tumor measuring <=1 cm and available HER-2 test results between January 1, 2001, and December 31, 2005, at the three Mayo Clinic sites were identified. Clinicopathologic data were compared in three groups: HER-2(-), HER-2(+), and triple-negative (TN) tumors. Of the 421 tumors identified, 364 (86.5%) were HER 2(-), 28 (6.7%) were HER-2(+), and 29 (6.9%) were TN. The median follow-up time was 1,015 days (range, 1-2,549 days). Groups were balanced in terms of patient age and tumor histology. Eleven patients with HER-2(-) tumors (3.0%), seven with HER-2(+) tumors (25.0%), and eight with TN tumors (27.6%) received adjuvant chemotherapy. Follow-up data were available for 357, 28, and 28 patients in the three groups, respectively. Death rates in the three groups were 6.4% (23 of 357) (one recurrence-related death), 0% (0 of 28), and 7.1% (2 of 28) (one recurrence related death), respectively. During follow-up, the tumor recurred in nine patients: four were HER-2(-) tumors (1.1%), two were HER-2(+) tumors (7.1%), and three were TN tumors (10.7%). Patients with small, node-negative breast tumors have an excellent prognosis, but HER-2(+) and TN tumors appear to have a higher recurrence rate, warranting consideration for broad use and optimization of systemic adjuvant treatments. PMID- 20930098 TI - Maintenance and consolidation therapy in patients with unresectable stage III/IV non-small cell lung cancer. AB - Globally, lung cancer is the leading cause of cancer-related mortality. Current chemotherapy combinations for the first-line treatment of advanced disease (stage IIIB with malignant pleural effusion/stage IV) and chemoradiotherapy regimens for the treatment of unresectable locally advanced disease (stage IIIA and IIIB without malignant pleural effusion) appear to have reached an efficacy plateau. The addition of new compounds including targeted agents to standard first-line cytotoxic doublets, administered concurrently and/or as maintenance therapy in patients who have not experienced disease progression after such treatment, has been shown to improve efficacy beyond this plateau in patients with advanced disease. However, to date, such approaches have been less successful in the treatment of patients with unresectable locally advanced stage III disease. The purpose of this review is to summarize the data from recent randomized phase III studies involving agents administered as maintenance or consolidation therapy in the treatment of unresectable stage III/IV non-small cell lung cancer (NSCLC). A possible alternative approach to the use of cytotoxic or molecularly targeted agents in this setting is the administration of therapeutic anticancer vaccines, which are designed to stimulate a host immunological response against the tumor. Current data in relation to the potential of vaccine therapy for NSCLC are therefore also reviewed, with a particular focus on belagenpumatucel-L and L BLP25 vaccines, which are currently undergoing phase III evaluation as maintenance therapies in patients with unresectable stage III/IV NSCLC who have tumor control following first-line therapy. PMID- 20930099 TI - Hepatitis B reactivation and rituximab in the oncology practice. AB - Rituximab use in hematology and oncology practice has significantly and positively improved the clinical outcomes in patients with a wide variety of B cell lymphoproliferative disorders. However, emerging data reveal that there is a risk of viral hepatitis B reactivation in some patients treated with rituximab. Many of these cases result in treatment delays, inferior oncologic outcomes, increased morbidity, and more rarely fulminant hepatic decompensation and death. Indeed, the rituximab package insert and many clinical practice guidelines have been modified to reflect these concerns. The true incidence and mechanism of reactivation are still being elucidated. This article focuses on the current evidence that supports these recently revised clinical recommendations along with a review of the risk factors for reactivation, suggested monitoring, and preventative interventions. PMID- 20930100 TI - Is increasing physical activity necessary to diminish fatigue during cancer treatment? Comparing cognitive behavior therapy and a brief nursing intervention with usual care in a multicenter randomized controlled trial. AB - BACKGROUND: Two interventions for fatigue were given during curative cancer treatment. The aim of this multicenter randomized controlled trial (RCT) with three conditions was to demonstrate the efficacy and to determine the contribution of physical activity. METHODS: Recruited from seven hospitals, 220 patients with various malignancies participated in a RCT. The brief nursing intervention (BNI) consisted of two 1-hour sessions, 3 months apart, given by 12 trained nurses, focusing only on physical activity. Cognitive behavior therapy (CBT) consisted of up to ten 1-hour sessions, within 6 months, provided by two therapists, focusing on physical activity and psychosocial elements. The control group received only usual care (UC). Assessments took place before and at least 2 months after cancer treatment, when patients had recovered from acute fatigue. Fatigue was the primary outcome. Efficacy was tested using analyses of covariance. A nonparametric bootstrap approach was used to test whether the effect on fatigue was mediated by physical activity. RESULTS: The CBT group was significantly less fatigued than the UC group. Between the BNI and the UC groups, no significant difference was found in fatigue. The mediation hypothesis was rejected. DISCUSSION: CBT given during curative cancer treatment proved to be an effective intervention to reduce fatigue at least 2 months after cancer treatment. The BNI was not effective. Contrary to what was expected, physical activity did not mediate the effect of CBT on fatigue. Thus, the reduction in fatigue elicited by CBT was realized without a lasting increase in physical activity. PMID- 20930101 TI - Endometrial carcinoma: a review of chemotherapy, drug resistance, and the search for new agents. AB - Adenocarcinoma of the endometrium represents the most common gynecologic malignancy in developed countries. Although early-stage cancers are effectively treated surgically, commonly without adjuvant therapy, the treatment of high-risk and advanced disease is more complex. Chemotherapy has evolved into an important modality in high-risk early-stage and advanced-stage disease, and in recurrent endometrial cancer. Taxane-based therapy consistently demonstrates the highest response rates in the first-line and salvage settings of endometrial cancer. Unfortunately, response to chemotherapy is modest and strategies are needed to predict chemotherapy-responsive and chemotherapy-resistant populations. Chemotherapy resistance mediated by overexpression of drug efflux pump proteins and mutations in beta-tubulin isoforms in both primary and recurrent disease represent unique treatment challenges and highlight the need for new agents that are less susceptible to these known resistance pathways. Epothilone B analogs are novel cytotoxic agents with activity in solid tumors, including advanced/recurrent endometrial carcinoma, and may have unique properties that can overcome resistance in some settings. These agents alone and in combination represent a new therapeutic opportunity in endometrial carcinoma. PMID- 20930102 TI - Future scenarios for the treatment of advanced non-small cell lung cancer: focus on taxane-containing regimens. AB - Despite recent progress in the development of new molecularly targeted agents, the chemotherapy regimens considered standard at the end of the last century- that is, two-drug combinations consisting of either cisplatin or carboplatin plus a third-generation agent (docetaxel, paclitaxel, gemcitabine, or vinorelbine)- remain the primary treatment option for advanced non-small cell lung cancer (NSCLC) patients. Most recently, the existing standard of care has been amended to reflect the significant survival advantage of cisplatin-pemetrexed over cisplatin-gemcitabine as first-line treatment of nonsquamous NSCLC. The addition of a biological drug (bevacizumab, cetuximab) or the use of a single-agent epidermal growth factor receptor inhibitor may further improve outcomes in selected patients. It has become increasingly clear, primarily through recent meta-analyses, that although the therapeutic equivalence of any combination of a platinum agent plus either gemcitabine, vinorelbine, docetaxel, or paclitaxel has been long accepted, each regimen has different side effects and therapeutic outcomes that allow clinicians to select the most appropriate treatment for chemotherapy-naive patients with stage IIIB/IV NSCLC. In this review, we evaluate the available evidence and explore the role and importance of various modern chemotherapy regimens, with the aim of optimizing treatment selection and combination with biological agents. Emphasis is placed on the role of taxanes (docetaxel versus paclitaxel) in this changing landscape. PMID- 20930103 TI - Tolerability, efficacy, and safety of pegylated liposomal Doxorubicin in combination with Carboplatin versus gemcitabine-Carboplatin for the treatment of platinum-sensitive recurrent ovarian cancer: a systematic review. AB - OBJECTIVE: To compare the tolerability, efficacy, and safety profiles of pegylated liposomal doxorubicin in combination with carboplatin (PLD-Carbo) with those of gemcitabine-carboplatin (Gem-Carbo) for the treatment of patients with platinum-sensitive recurrent ovarian cancer (PSROC) by reviewing the published literature. METHODS: Using the PubMed database, a systematic review of peer reviewed literature published between January 2000 and September 2009 was undertaken to identify studies related to the treatment of patients with PSROC with PLD-Carbo or Gem-Carbo. Studies reporting either response rate, progression free survival (PFS), and/or overall survival (OS) were included. Treatment regimens, efficacy endpoints, and safety profiles were compared between the two combination therapies. RESULTS: Ten studies evaluating 608 patients (PLD-Carbo: 5 studies, 278 patients; Gem-Carbo: 5 studies, 330 patients) were identified. The mean planned doses were: PLD, 34.8 mg/m(2) and Gem, 993 mg/m(2). The dose intensity reported in Gem trials was lower (75% of the planned dose) than the dose intensity reported in PLD trials (93.7% of the planned dose), suggesting better tolerability for the PLD-Carbo regimen. Among patients receiving PLD Carbo, 60.2% achieved a response (complete, 27.0%; partial, 33.2%), versus 51.4% of patients treated with Gem-Carbo (complete, 19.2%; partial, 32.2%). The median PFS times were 10.6 months and 8.9 months in the PLD-Carbo and the Gem-Carbo populations, respectively. The median OS was longer for the PLD-Carbo regimen (27.1 months) than for the Gem-Carbo regimen (19.7 months). The hematological safety profiles were comparable in the two groups, although grade III or IV anemia (PLD-Carbo, 13.6%; Gem-Carbo, 24.5%) and neutropenia (PLD-Carbo, 45.5%; Gem-Carbo, 62.9%) were more common in patients receiving Gem-Carbo. CONCLUSION: Results from this systematic analysis of peer-reviewed literature suggest that PLD-Carbo therapy is a rational alternative to Gem-Carbo for the treatment of patients with PSROC. PMID- 20930104 TI - Spermatocytic seminoma with neuroectodermal differentiation and sertoli cell tumor in a dog. AB - Two distinct nodules developed in a cryptorchid testis of an 8-year-old male West Highland White Terrier. One nodule was a Sertoli cell tumor. The other was a spermatocytic seminoma with focal primitive neuroectodermal differentiation: formation of Homer-Wright rosettes and perivascular pseudorosettes, with immunoreactivity for S-100 protein, neuron-specific enolase, synaptophysin, neurofilament-68 kDa, microtubule-associated protein 2, and vimentin. The dog was alive and healthy 2 years after castration. PMID- 20930105 TI - Direct inoculation of Mycobacterium avium subspecies Paratuberculosis into ileocecal Peyer's patches results in colonization of the intestine in a calf model. AB - The objective of this study was to develop an intestinal model of Mycobacterium avium subspecies paratuberculosis (Map) infection in the calf for evaluation of mucosal pathology and local and systemic immunologic responses. Map was inoculated into Peyer's patches of young calves using a right flank surgical approach in standing calves to exteriorize the ileocecal junction. Inoculum doses ranging from 10(3) to 10(9) colony-forming units of strain K10 Map were injected through the serosal surface into Peyer's patches of the distal ileum near the ileocecal valve. Fecal samples were collected for culture from each calf weekly until termination of the study. Calves were necropsied at 7, 30, 60, and 90 days after infection, when inoculation sites, lymph nodes, spleen, and peripheral blood were collected for evaluation. Ileocecal lymph nodes were consistently colonized by Map in the 10(5) to 10(9) groups. The ileocecal valve was also colonized in 10(7) and 10(9) groups. This correlated with fecal culture results as infected calves intermittently shed Map in their feces throughout the study. Granulomatous lesions with giant cells and acid-fast bacilli at the ileocecal junction, ileocecal lymph nodes, and lamina propria of high-dose animals (10(7) and 10(9)) were identified from each time point. Flow cytometry was used to detect antigen-specific production of interferon-gamma and interleukin-4 locally (ileocecal lymph node) and systemically (peripheral blood mononuclear cells), which defined distinct immunologic profiles in low-dose and high-dose calves. This study demonstrates intestinal Map infection via Peyer's patch inoculation, a novel model with many shared features of natural Map infection. PMID- 20930106 TI - Histopathologic changes of the ear in canine models of mucopolysaccharidosis types I and VII. AB - Mucopolysaccharidosis (MPS) types I and VII are inborn errors of metabolism caused by mutation of enzymes involved in glycosaminoglycan catabolism, which leads to intralysosomal accumulation of glycosaminoglycans. In children, severe forms of MPS I and VII are characterized by somatic and neurologic manifestations, including a poorly understood hearing loss. The purpose of this study is to describe the age-related histopathologic changes of the ear in spontaneous canine models of MPS I and VII. Pathologic changes in the ear were assessed in MPS I and VII dogs ranging from 1.6 to 9.3 months of age. Paraffin embedded sections of the whole ear and Epon-embedded semithin sections of the cochlea were examined. The following lesions were blindly scored in the middle and inner ear: inflammation, cells vacuolization, thickening of osseous and membranous structures, perivascular vacuolated macrophages infiltration, and bone resorption. All dogs had lysosomal storage within cells of tympanic membrane, ossicles, tympanic bone and mucosa, cochlear bone, spiral ligament, limbus, and stria vascularis. The MPS I dogs mainly had progressive cochlear lesions. The MPS VII dogs had severe and early middle ear lesions, including chronic otitis media and bone resorption. The MPS I dog only partially recapitulates the pathology seen in humans; specifically, the dog model lacks inflammatory middle ear disease. In contrast, the MPS VII dog has severe inflammatory middle ear disease similar to that reported in the human. In conclusion, the canine MPS VII model appears to be a good model to study MPS VII-related deafness. PMID- 20930107 TI - T-lymphocyte predominance in lesions of canine coccidioidomycosis. AB - Coccidioidomycosis is a systemic fungal infection endemic to the southwestern United States. Although cell-mediated immunity is considered critical in control of the infection, little is known of the cellular population in naturally occurring lesions. To characterize the lymphocytic infiltration, archived formalin-fixed, paraffin-embedded tissues (subcutis, pericardium/heart, lung, bone, and synovium) from 18 dogs with coccidioidomycosis were studied with immunohistochemistry for CD3 and CD79a. In nearly all lesions, T lymphocytes were more numerous than B lymphocytes and were distributed throughout the lesion with concentration in the periphery of granulomas, whereas B lymphocytes were mostly confined to the periphery of granulomas. The predominance of T lymphocytes in lesions of canine coccidioidomycosis was independent of the tissue evaluated, the number of intralesional organisms, and the nature or severity of the inflammatory response. PMID- 20930108 TI - The clinical presentation and histopathologic-immunohistochemical classification of histiocytic sarcomas in the Flat Coated Retriever. AB - The Flat Coated Retriever is a breed at risk of development of histiocytic sarcoma (HS), but in contrast to the disseminated form of disease recognized in the Bernese Mountain Dog, most reports of HS in Flat Coated Retrievers describe a localized lesion affecting the musculature or fascia of limbs. The purpose of this study was to review data and material received though an ongoing Flat Coated Retriever tumor survey to better define the presentation of HS in the breed and to determine the utility of subclassification of tumors arising at different sites by histology and immunohistologic phenotyping. Data on 180 dogs bearing HS like tumors were available for review, which showed that although the majority (101 lesions, 57%) were primary limb lesions, 47 dogs (26%) had visceral, mainly splenic lesions with no peripheral primary tumor. A detailed histologic and immunohistologic review of 20 limb tumors and 20 splenic tumors showed that 2 distinct phenotypic subtypes could be identified: a histiocytic subtype, most prevalent in the splenic tumors, and a histiocytic-spindle-pleomorphic subtype, mainly seen in the limb tumors. Despite their variable morphology, all tumors expressed major histocompatibility complex class II and the leukocyte antigen CD18, but only those tumors in the spleen consistently expressed CD11d. The majority of tumors also contained a mild to moderate infiltrate of T lymphocytes. PMID- 20930109 TI - Copper transporter 2 regulates endocytosis and controls tumor growth and sensitivity to cisplatin in vivo. AB - Copper transporter 2 (CTR2) is one of the four copper transporters in mammalian cells that influence the cellular pharmacology of cisplatin and carboplatin. CTR2 was knocked down using a short hairpin RNA interference. Robust expression of CTR2 was observed in parental tumors grown in vivo, whereas no staining was found in the tumors formed from cells in which CTR2 had been knocked down. Knockdown of CTR2 reduced growth rate by 5.8-fold, increased the frequency of apoptotic cells, and decreased the vascular density, but it did not change copper content. Knockdown of CTR2 increased the tumor accumulation of cis diamminedichloroplatinum(II) [cisplatin (cDDP)] by 9.1-fold and greatly increased its therapeutic efficacy. Because altered endocytosis has been implicated in cDDP resistance, uptake of dextran was used to quantify the rate of macropinocytosis. Knockdown of CTR2 increased dextran uptake 2.5-fold without reducing exocytosis. Inhibition of macropinocytosis with either amiloride or wortmannin blocked the increase in macropinocytosis mediated by CTR2 knockdown. Stimulation of macropinocytosis by platelet-derived growth factor coordinately increased dextran and cDDP uptake. Knockdown of CTR2 was associated with activation of the Rac1 and cdc42 GTPases that control macropinocytosis but not activation of the phosphoinositide-3 kinase pathway. We conclude that CTR2 is required for optimal tumor growth and that it is an unusually strong regulator of cisplatin accumulation and cytotoxicity. CTR2 regulates the transport of cDDP in part through control of the rate of macropinocytosis via activation of Rac1 and cdc42. Selective knockdown of CTR2 in tumors offers a strategy for enhancing the efficacy of cDDP. PMID- 20930110 TI - A novel pentamethoxyflavone down-regulates tumor cell survival and proliferative and angiogenic gene products through inhibition of IkappaB kinase activation and sensitizes tumor cells to apoptosis by cytokines and chemotherapeutic agents. AB - Most anticancer drugs have their origin in traditional medicinal plants. We describe here a flavone, 5,3'-dihydroxy-3,6,7,8,4'-pentamethoxyflavone (PMF), from the leaves of the Thai plant Gardenia obtusifolia, that has anti inflammatory and anticancer potential. Because the nuclear factor-kappaB (NF kappaB) pathway is linked to inflammation and tumorigenesis, we investigated the effect of PMF on this pathway. We found that PMF suppressed NF-kappaB activation induced by inflammatory agents, tumor promoters, and carcinogens. This suppression was not specific to the cell type. Although PMF did not directly modify the ability of NF-kappaB proteins to bind to DNA, it inhibited IkappaBalpha (inhibitory subunit of NF-kappaB) kinase, leading to suppression of phosphorylation and degradation of IkappaBalpha, and suppressed consequent p65 nuclear translocation, thus abrogating NF-kappaB-dependent reporter gene expression. Suppression of the NF-kappaB cell signaling pathway by the flavone led to the inhibition of expression of NF-kappaB-regulated gene products that mediate inflammation (cyclooxygenase-2), survival (XIAP, survivin, Bcl-xL, and cFLIP), proliferation (cyclin D1), invasion (matrix metalloproteinase-9), and angiogenesis (vascular endothelial growth factor). Suppression of antiapoptotic gene products by PMF correlated with the enhancement of apoptosis induced by tumor necrosis factor-alpha and the chemotherapeutic agents cisplatin, paclitaxel, and 5-flurouracil. Overall, our results indicate that PMF suppresses the activation of NF-kappaB and NF-kappaB-regulated gene expression, leading to the enhancement of apoptosis. This is the first report to demonstrate that this novel flavone has anti-inflammatory and anticancer effects by targeting the IKK complex. PMID- 20930113 TI - Zona occludens proteins modulate podosome formation and function. AB - Podosomes are highly dynamic structures that are involved in cell adhesion and extracellular matrix remodeling. They present as intracellular columns composed of an actin-rich core region and a surrounding ring-like structure containing focal adhesion proteins, actin binders as well as cell signaling molecules. A key player in podosome biogenesis is the scaffolding protein cortactin, which is thought to control actin assembly at the core region. We show that the zona occludens protein 1 (ZO-1), a pivotal tight junction protein and known binding partner of cortactin, is a component of podosomes. In the smooth muscle cell line A7r5, phorbol ester treatment induced a rapid relocation of ZO-1 from the cell cortex and cytosolic pools toward newly formed podosomes. Podosomal localization was also observed for the known ZO-1-binding proteins l-afadin, alpha-catenin, and phospho-connexin 43. Truncation studies revealed that the actin-binding domain but not the association with cortactin is necessary for ZO-1 recruitment to podosomes. Moreover, impaired ZO-1 expression leads to significantly reduced podosome formation and concomitant decreased matrix degradation at podosomes. Our findings demonstrate that besides their known function in tight junction assembly and intercellular communication, zona occludens proteins and their binding partners may play a novel role in podosome formation and associated function, thus regulating cell adhesion and matrix remodeling. PMID- 20930114 TI - Manipulating the permeation of charged compounds through the MscL nanovalve. AB - MscL is a bacterial mechanosensor that serves as a biological emergency release valve, releasing cytoplasmic solutes to the environment on osmotic downshock. Previous studies have recognized that this channel has properties that make it ideal for use as a triggered nanovalve for vesicular-based targeted drug-release devices. One can even change the modality of the sensor. Briefly, the introduction of charges into the MscL pore lumen gates the channel in the absence of membrane tension; thus, by inserting compounds that acquire a charge on exposure to an alternative stimulus, such as light or pH, into the pore of the channel, controllable nanoswitches that detect these alternative modalities have been engineered. However, a charge in the pore lumen could not only encourage actuation of the nanopore but also have a significant influence on the permeation of large charged compounds, which would thus have important implications for the efficiency of drug-release devices. In this study, we used in vivo and electrophysiological approaches to demonstrate that the introduction of a charge into pore lumen of MscL does indeed influence the permeation of charged molecules. These effects were more drastic for larger compounds and, surprisingly, were related to the orientation of the MscL channel in the membrane. PMID- 20930115 TI - Annexin-1 signals mitogen-stimulated breast tumor cell proliferation by activation of the formyl peptide receptors (FPRs) 1 and 2. AB - The role of the calcium- and phospholipid-binding protein annexin I (ANXA1) in cell cycle regulation has been investigated in estrogen receptor (ER)-positive MCF-7 and ER-negative MDA-MB-231 breast tumor cell lines. In MCF-7 cells, ANXA1 targeting small interfering RNA (siRNA) reduced ANXA1 mRNA and protein levels and attenuated cell proliferation induced by FCS, estradiol, or epidermal growth factor. Well-characterized agonists for the known ANXA1 receptor, FPR2, including the ANXA1 N-terminal proteolytic product ANXA1(2-26), lipoxin A(4) (LXA(4)), and the synthetic peptide, Trp-Lys-Tyr-Met-Val-D-Met (WKYMVm), stimulated proliferation of MCF-7 and MDA-MB-231 cells that was attenuated by incubation with FPR2 antagonists WRW(4) (1 MUM) or Boc2 (100 nM) or by siRNA against FPR2. FCS-induced mitogenic responses were attenuated by each of the FPR antagonists and by siRNA against FPR2 and, to a lesser extent, FPR1. LXA(4) increased phosphorylation of Akt, p70(S6K) but not ERK1/2. Increases in cyclin D1 protein induced by FCS or LXA(4) were blocked by the PI3 kinase inhibitor, LY294002, and attenuated by FPR2 antagonism using Boc2. In invasive breast cancer, immunohistochemistry revealed the presence of ANXA1 and its receptor, FPR2, in both tumor epithelium and stromal cells. These observations suggest a novel signaling role for ANXA1 in mitogen-activated proliferation of breast tumor epithelial cells that is mediated via activation of FPR1 and FPR2. PMID- 20930116 TI - Tocochromanols: rancid lipids, seed longevity, and beyond. PMID- 20930117 TI - Signaling by olfactory receptor neurons near threshold. AB - An important contributing factor for the high sensitivity of sensory systems is the exquisite sensitivity of the sensory receptor cells. We report here the signaling threshold of the olfactory receptor neuron (ORN). We first obtained a best estimate of the size of the physiological electrical response successfully triggered by a single odorant-binding event on a frog ORN, which was ~0.034 pA and had an associated transduction domain spanning only a tiny fraction of the length of an ORN cilium. We also estimated the receptor-current threshold for an ORN to fire action potentials in response to an odorant pulse, which was ~1.2 pA. Thus, it takes about 35 odorant-binding events successfully triggering transduction during a brief odorant pulse in order for an ORN to signal to the brain. PMID- 20930118 TI - Mitochondrial Lon protease regulates mitochondrial DNA copy number and transcription by selective degradation of mitochondrial transcription factor A (TFAM). AB - Lon is the major protease in the mitochondrial matrix in eukaryotes, and is well conserved among species. Although a role for Lon in mitochondrial biogenesis has been proposed, the mechanistic basis is unclear. Here, we demonstrate a role for Lon in mtDNA metabolism. An RNA interference (RNAi) construct was designed that reduces Lon to less than 10% of its normal level in Drosophila Schneider cells. RNAi knockdown of Lon results in increased abundance of mitochondrial transcription factor A (TFAM) and mtDNA copy number. In a corollary manner, overexpression of Lon reduces TFAM levels and mtDNA copy number. Notably, induction of mtDNA depletion in Lon knockdown cells does not result in degradation of TFAM, thereby causing a dramatic increase in the TFAMmtDNA ratio. The increased TFAMmtDNA ratio in turn causes inhibition of mitochondrial transcription. We conclude that Lon regulates mitochondrial transcription by stabilizing the mitochondrial TFAMmtDNA ratio via selective degradation of TFAM. PMID- 20930119 TI - Isolation of circulating tumor cells using a microvortex-generating herringbone chip. AB - Rare circulating tumor cells (CTCs) present in the bloodstream of patients with cancer provide a potentially accessible source for detection, characterization, and monitoring of nonhematological cancers. We previously demonstrated the effectiveness of a microfluidic device, the CTC-Chip, in capturing these epithelial cell adhesion molecule (EpCAM)-expressing cells using antibody-coated microposts. Here, we describe a high-throughput microfluidic mixing device, the herringbone-chip, or "HB-Chip," which provides an enhanced platform for CTC isolation. The HB-Chip design applies passive mixing of blood cells through the generation of microvortices to significantly increase the number of interactions between target CTCs and the antibody-coated chip surface. Efficient cell capture was validated using defined numbers of cancer cells spiked into control blood, and clinical utility was demonstrated in specimens from patients with prostate cancer. CTCs were detected in 14 of 15 (93%) patients with metastatic disease (median = 63 CTCs/mL, mean = 386 +/- 238 CTCs/mL), and the tumor-specific TMPRSS2 ERG translocation was readily identified following RNA isolation and RT-PCR analysis. The use of transparent materials allowed for imaging of the captured CTCs using standard clinical histopathological stains, in addition to immunofluorescence-conjugated antibodies. In a subset of patient samples, the low shear design of the HB-Chip revealed microclusters of CTCs, previously unappreciated tumor cell aggregates that may contribute to the hematogenous dissemination of cancer. PMID- 20930120 TI - Roles and interactions among protease-activated receptors and P2ry12 in hemostasis and thrombosis. AB - Toward understanding their redundancies and interactions in hemostasis and thrombosis, we examined the roles of thrombin receptors (protease-activated receptors, PARs) and the ADP receptor P2RY12 (purinergic receptor P2Y G protein coupled 12) in human and mouse platelets ex vivo and in mouse models. Par3(-/-) and Par4(+/-) mouse platelets showed partially decreased responses to thrombin, resembling those in PAR1 antagonist-treated human platelets. P2ry12(+/-) mouse platelets showed partially decreased responses to ADP, resembling those in clopidogrel-treated human platelets. Par3(-/-) mice showed nearly complete protection against carotid artery thrombosis caused by low FeCl(3) injury. Par4(+/-) and P2ry12(+/-) mice showed partial protection. Increasing FeCl(3) injury abolished such protection; combining partial attenuation of thrombin and ADP signaling, as in Par3(-/-):P2ry12(+/-) mice, restored it. Par4(-/-) mice, which lack platelet thrombin responses, showed still better protection. Our data suggest that (i) the level of thrombin driving platelet activation and carotid thrombosis was low at low levels of arterial injury and increased along with the contribution of thrombin-independent pathways of platelet activation with increasing levels of injury; (ii) although P2ry12 acts downstream of PARs to amplify platelet responses to thrombin ex vivo, P2ry12 functioned in thrombin/PAR independent pathways in our in vivo models; and (iii) P2ry12 signaling was more important than PAR signaling in hemostasis models; the converse was noted for arterial thrombosis models. These results make predictions being tested by ongoing human trials and suggest hypotheses for new antithrombotic strategies. PMID- 20930121 TI - Geography and Indonesian oil-palm expansion. PMID- 20930122 TI - Silencing of hsa-miR-124 by EVI1 in cell lines and patients with acute myeloid leukemia. PMID- 20930123 TI - Drug efflux transporter multidrug resistance-associated protein 5 affects sensitivity of pancreatic cancer cell lines to the nucleoside anticancer drug 5 fluorouracil. AB - Pancreatic adenocarcinoma is one of the malignancies that is highly resistant to therapy and among the leading causes of cancer-related death. Several factors may influence pancreatic cancer resistance, and expression of ATP-binding cassette transport proteins is one of the major mechanisms of drug resistance. Members of this family's C-branch, also referred to as multidrug resistance-associated proteins (MRPs), might be of particular interest because they are able to efflux nucleoside analogs used in the treatment of pancreatic cancer. Expression of MRP1, MRP3, MRP4, and MRP5 in human pancreas and pancreatic carcinoma has been reported. However, contributions of MRPs to chemoresistance of pancreatic cancer are not fully understood. MRP5 mRNA expression in pancreatic adenocarcinoma cell lines correlated significantly with cellular sensitivity to 5-fluorouracil (5-FU) (r = 0.738, p < 0.05). Long-term treatment with 5-FU increased expression of MRP5 by 2.4-fold and was associated with significant drug resistance [IC(50) values for control and 5-fluorouracil (5-FU)-resistant Patu-T cell lines were 11.3 +/- 5.3 and 33.2 +/- 6.9 MUM, respectively (p < 0.05)]. Consequently, overexpression of MRP5 in Colo-357 cells resulted in significantly reduced accumulation of 5-FU related radioactivity and 5-FU cytotoxicity. Knockdown of MRP5 significantly increased cellular cytotoxicity of 5-FU to Patu-02 cells and enhanced accumulation of radioactivity related to 5-FU and its metabolites. Our results suggest that MRP5 is expressed and functionally active and contributes to variable sensitivities of pancreatic adenocarcinoma cell lines to 5-FU. Further investigations using models that resemble human pancreas tumors are necessary to prove a causative relation between expression and activity of MRP5 and tumor resistance to 5-FU. PMID- 20930124 TI - Distribution of myogenic progenitor cells and myonuclei is altered in women with vs. those without chronically painful trapezius muscle. AB - It is hypothesized that repeated recruitment of low-threshold motor units is an underlying cause of chronic pain in trapezius myalgia. This study investigated the distribution of satellite cells (SCs), myonuclei, and macrophages in muscle biopsies from the trapezius muscle of 42 women performing repetitive manual work, diagnosed with trapezius myalgia (MYA; 44 +/- 8 yr; mean +/- SD) and 20 matched healthy controls (CON; 45 +/- 9 yr). Our hypothesis was that muscle of MYA, in particular type I fibers, would demonstrate higher numbers of SCs, myonuclei, and macrophages compared with CON. SCs were identified on muscle cross sections by combined immunohistochemical staining for Pax7, type I myosin, and laminin, allowing the number of SCs associated with type I and II fibers to be determined. We observed a pattern of SC distribution in MYA previously only reported for individuals above 70 yr of age. Compared with CON, MYA demonstrated 19% more SCs per fiber associated with type I fibers (MYA 0.098 +/- 0.039 vs. CON 0.079 +/- 0.031; P < 0.05) and 40% fewer SCs associated with type II fibers (MYA 0.047 +/- 0.017 vs. CON 0.066 +/- 0.035; P < 0.05). The finding of similar numbers of macrophages between the two groups was not in line with our hypothesis and suggests that the elevated SC content of MYA was not due to heightened inflammatory cell contents, but rather to provide new myonuclei. The findings of greater numbers of SCs in type I fibers of muscle subjected to repeated low intensity work support our hypothesis and provide new insight into stimuli capable of regulating SC content. PMID- 20930125 TI - A transcriptional map of the impact of endurance exercise training on skeletal muscle phenotype. AB - The molecular pathways that are activated and contribute to physiological remodeling of skeletal muscle in response to endurance exercise have not been fully characterized. We previously reported that ~800 gene transcripts are regulated following 6 wk of supervised endurance training in young sedentary males, referred to as the training-responsive transcriptome (TRT) (Timmons JA et al. J Appl Physiol 108: 1487-1496, 2010). Here we utilized this database together with data on biological variation in muscle adaptation to aerobic endurance training in both humans and a novel out-bred rodent model to study the potential regulatory molecules that coordinate this complex network of genes. We identified three DNA sequences representing RUNX1, SOX9, and PAX3 transcription factor binding sites as overrepresented in the TRT. In turn, miRNA profiling indicated that several miRNAs targeting RUNX1, SOX9, and PAX3 were downregulated by endurance training. The TRT was then examined by contrasting subjects who demonstrated the least vs. the greatest improvement in aerobic capacity (low vs. high responders), and at least 100 of the 800 TRT genes were differentially regulated, thus suggesting regulation of these genes may be important for improving aerobic capacity. In high responders, proangiogenic and tissue developmental networks emerged as key candidates for coordinating tissue aerobic adaptation. Beyond RNA-level validation there were several DNA variants that associated with maximal aerobic capacity (Vo(2max)) trainability in the HERITAGE Family Study but these did not pass conservative Bonferroni adjustment. In addition, in a rat model selected across 10 generations for high aerobic training responsiveness, we found that both the TRT and a homologous subset of the human high responder genes were regulated to a greater degree in high responder rodent skeletal muscle. This analysis provides a comprehensive map of the transcriptomic features important for aerobic exercise-induced improvements in maximal oxygen consumption. PMID- 20930126 TI - Reversible blunting of arousal from sleep in response to intermittent hypoxia in the developing rat. AB - Arousal is an important survival mechanism when infants are confronted with hypoxia during sleep. Many sudden infant death syndrome (SIDS) infants are exposed to repeated episodes of hypoxia before death and have impaired arousal mechanisms. We hypothesized that repeated exposures to hypoxia would cause a progressive blunting of arousal, and that a reversal of this process would occur if the hypoxia was terminated at the time of arousal. P5 (postnatal age of 5 days), P15, and P25 rat pups were exposed to either eight trials of hypoxia (3 min 5% O(2) alternating with room air) (group A), or three hypoxia trials as in group A, followed by five trials in which hypoxia was terminated at arousal (group B). In both groups A and B, latency increased over the first four trials of hypoxia, but reversed in group B animals during trials 5-8. Progressive arousal blunting was more pronounced in the older pups. The effects of intermittent hypoxia on heart rate also depended on age. In the older pups, heart rate increased with each hypoxia exposure. In the P5 pups, however, heart rate decreased during hypoxia and did not return to baseline between exposures, resulting in a progressive fall of baseline values over successive hypoxia exposures. In the group B animals, heart rate changes during trials 1-4 also reversed during trials 5-8. We conclude that exposure to repeated episodes of hypoxia can cause progressive blunting of arousal, which is reversible by altering the exposure times to hypoxia and the period of recovery between hypoxia exposures. PMID- 20930128 TI - Increased training loads do not magnify cancellous bone gains with rodent jump resistance exercise. AB - This study sought to elucidate the effects of a low- and high-load jump resistance exercise (RE) training protocol on cancellous bone of the proximal tibia metaphysis (PTM) and femoral neck (FN). Sprague-Dawley rats (male, 6 mo old) were randomly assigned to high-load RE (HRE; n = 16), low-load RE (LRE; n = 15), or sedentary cage control (CC; n = 11) groups. Animals in the HRE and LRE groups performed 15 sessions of jump RE during 5 wk of training. PTM cancellous volumetric bone mineral density (vBMD), assessed by in vivo peripheral quantitative computed tomography scans, significantly increased in both exercise groups (+9%; P < 0.001), resulting in part from 130% (HRE; P = 0.003) and 213% (LRE; P < 0.0001) greater bone formation (measured by standard histomorphometry) vs. CC. Additionally, mineralizing surface (%MS/BS) and mineral apposition rate were higher (50-90%) in HRE and LRE animals compared with controls. PTM bone microarchitecture was enhanced with LRE, resulting in greater trabecular thickness (P = 0.03) and bone volume fraction (BV/TV; P = 0.04) vs. CC. Resorption surface was reduced by nearly 50% in both exercise paradigms. Increased PTM bone mass in the LRE group translated into a 161% greater elastic modulus (P = 0.04) vs. CC. LRE and HRE increased FN vBMD (10%; P < 0.0001) and bone mineral content (~ 20%; P < 0.0001) and resulted in significantly greater FN strength vs. CC. For the vast majority of variables, there was no difference in the cancellous bone response between the two exercise groups, although LRE resulted in significantly greater body mass accrual and bone formation response. These results suggest that jumping at minimal resistance provides a similar anabolic stimulus to cancellous bone as jumping at loads exceeding body mass. PMID- 20930127 TI - Exercise mitigates the stunting effect of cold temperature on limb elongation in mice by increasing solute delivery to the growth plate. AB - Ambient temperature and physical activity modulate bone elongation in mammals, but mechanisms underlying this plasticity are a century-old enigma. Longitudinal bone growth occurs in cartilaginous plates, which receive nutritional support via delivery of solutes from the vasculature. We tested the hypothesis that chronic exercise and warm temperature promote bone lengthening by increasing solute delivery to the growth plate, measured in real time using in vivo multiphoton microscopy. We housed 68 weanling female mice at cold (16 degrees C) or warm (25 degrees C) temperatures and allowed some groups voluntary access to a running wheel. We show that exercise mitigates the stunting effect of cold temperature on limb elongation after 11 days of wheel running. All runners had significantly lengthened limbs, regardless of temperature, while nonrunning mice had shorter limbs that correlated with housing temperature. Tail length was impacted only by temperature, indicating that the exercise effect was localized to limb bones and was not a systemic endocrine reaction. In vivo multiphoton imaging of fluoresceinated tracers revealed enhanced solute delivery to tibial growth plates in wheel-running mice, measured under anesthesia at rest. There was a minimal effect of rearing temperature on solute delivery when measured at an intermediate room temperature (20 degrees C), suggesting that a lasting increase in solute delivery is an important factor in exercise-mediated limb lengthening but may not play a role in temperature-mediated limb lengthening. These results are relevant to the study of skeletal evolution in mammals from varying environments and have the potential to fundamentally advance our understanding of bone elongation processes. PMID- 20930129 TI - Vertical distribution of specific ventilation in normal supine humans measured by oxygen-enhanced proton MRI. AB - Specific ventilation (SV) is the ratio of fresh gas entering a lung region divided by its end-expiratory volume. To quantify the vertical (gravitationally dependent) gradient of SV in eight healthy supine subjects, we implemented a novel proton magnetic resonance imaging (MRI) method. Oxygen is used as a contrast agent, which in solution changes the longitudinal relaxation time (T1) in lung tissue. Thus alterations in the MR signal resulting from the regional rise in O(2) concentration following a sudden change in inspired O(2) reflect SV lung units with higher SV reach a new equilibrium faster than those with lower SV. We acquired T1-weighted inversion recovery images of a sagittal slice of the supine right lung with a 1.5-T MRI system. Images were voluntarily respiratory gated at functional residual capacity; 20 images were acquired with the subject breathing air and 20 breathing 100% O(2), and this cycle was repeated five times. Expired tidal volume was measured simultaneously. The SV maps presented an average spatial fractal dimension of 1.13 +/- 0.03. There was a vertical gradient in SV of 0.029 +/- 0.012 cm(-1), with SV being highest in the dependent lung. Dividing the lung vertically into thirds showed a statistically significant difference in SV, with SV of 0.42 +/- 0.14 (mean +/- SD), 0.29 +/- 0.10, and 0.24 +/- 0.08 in the dependent, intermediate, and nondependent regions, respectively (all differences, P < 0.05). This vertical gradient in SV is consistent with the known gravitationally induced deformation of the lung resulting in greater lung expansion in the dependent lung with inspiration. This SV imaging technique can be used to quantify regional SV in the lung with proton MRI. PMID- 20930131 TI - Falsely decreased human chorionic gonadotropin (hCG) results due to increased concentrations of the free beta subunit and the beta core fragment in quantitative hCG assays. AB - BACKGROUND: Earlier studies have shown that increased concentrations of certain human chorionic gonadotropin (hCG) variants can cause false-negative results in some qualitative hCG devices. The objective of this study was to determine if increased concentrations of hCGbeta and hCGbeta core fragment (hCGbetacf) cause falsely decreased results on 9 commercially available quantitative hCG assays. METHODS: Several concentrations of purified hCGbeta and hCGbetacf were added to 2 sets of 6 serum samples with and without a fixed concentration of intact hCG. We examined 9 widely used immunoassays to measure immunoreactive hCG. Falsely decreased results were defined as those in which the measured hCG concentration was <=50% of expected. RESULTS: High concentrations of hCGbeta (>=240 000 pmol/L) produced falsely decreased hCG measurements in 2 assays known to detect this variant. Similarly, high concentrations of hCGbetacf (>=63 000 pmol/L) produced falsely decreased hCG measurements in 3 assays that do not detect purified hCGbetacf. Two assays were identified that detected both hCGbeta and hCGbetacf, and neither produced falsely decreased results in the presence of high concentrations of these variants. CONCLUSIONS: Extremely high concentrations of hCG variants can cause falsely decreased results in certain quantitative hCG assays. Of the 9 assays examined, none exhibited falsely decreased results in the presence of hCGbeta concentrations typically associated with hCGbeta-producing malignancies. Two assays exhibited decreased (>50%) hCG results in the presence of hCGbetacf concentrations found during normal pregnancy. PMID- 20930130 TI - Plasma microRNA-122 as a biomarker for viral-, alcohol-, and chemical-related hepatic diseases. AB - BACKGROUND: The liver is frequently subject to insult because of viral infection, alcohol abuse, or toxic chemical exposure. Extensive research has been conducted to identify blood markers that can better discern liver damage, but little progress has been achieved in clinical practice. Recently, circulating microRNAs (miRNAs) have been reported as potential biomarkers for the noninvasive diagnosis of cancer. In this study, we investigated whether plasma miRNAs have diagnostic utility in identifying liver disease. METHODS: The study was divided into 2 phases: marker selection by real-time quantitative PCR analysis of a small set of plasma samples, and marker validation with a large set of plasma samples from 83 patients with chronic hepatitis B viral infections, 15 patients with skeletal muscle disease, and 40 healthy controls. Two mouse model systems, d-galactosamine and alcohol-induced liver injury, were also developed to evaluate whether differences in miRNA concentration were associated with various liver diseases. RESULTS: Among the miRNA candidates identified, miR-122 presented a disease severity-dependent change in plasma concentration in the patients and animal models. Compared with an increase in aminotransferase activity in the blood, the change in miR-122 concentration appeared earlier. Furthermore, this change was more specific for liver injury than for other organ damage and was more reliable, because the change was correlated with liver histologic stage. CONCLUSIONS: Our findings suggest that circulating miR-122 has potential as a novel, predictive, and reliable blood marker for viral-, alcohol-, and chemical-induced liver injury. PMID- 20930132 TI - Targeting African American nonsmokers to motivate smokers to quit: a qualitative inquiry. AB - African Americans bear a disproportionate health burden from smoking but are less likely than other populations to engage in cessation treatment. Intervening on adult nonsmokers residing with a smoker might represent an innovative approach to motivate smokers to engage in smoking behavior change. Twelve focus groups were conducted with African American smokers (four groups, n = 27), nonsmokers (four groups, n = 26) and pairs of cohabitating smokers and nonsmokers (four groups, n = 22) to assess attitudes and/or beliefs regarding engaging a nonsmoker in the home in smoking behavior change efforts. Participants ( N = 75) were middle-aged (45.1 +/-3.7 years) females (68.0%) with 11.8 +/-1.5 years of education. Smokers smoked 14.9 +/-11.3 cigarettes per day, made 3.0 +/-4.4 quit attempts in the past year, and are interested in receiving cessation assistance from a nonsmoker in their home. African American nonsmokers living with a smoker may be an appropriate target group to motivate smoking behavior change in the smoker. Suggestions for future research considerations are provided. PMID- 20930133 TI - Social integration and health behavioral change in San Luis, Honduras. AB - This study explores the effects of social integration on behavioral change in the course of an intensive, community-based public health intervention. The intervention trained volunteers and mobilized local organizations to promote 16 key family health practices in rural San Luis, Honduras, during 2004 to 2006. A mixed methods approach is used. Standard household sample surveys were performed in 22 villages before and after the intervention. Eight villages were then resurveyed. A household survey, focus groups, and key informant interviews measured health behaviors and several social structural and psychosocial variables. The villages were then ranked on their mean behavioral and social integration scores. The quantitative and qualitative rankings were in close agreement (Kendall's coefficient of concordance = .707, p < .001). Behaviors changed most markedly in the villages where respondents participated in local organizations, observed that others performed those behaviors, and depended on their neighbors for support. The results show that social integration conditions health behavioral change. Health interventions can be made more effective by analyzing these features a priori. PMID- 20930134 TI - Cross-cultural validation of the preventive health model for colorectal cancer screening: an Australian study. AB - We investigated whether the five-factor structure of the Preventive Health Model for colorectal cancer screening, developed in the United States, has validity in Australia. We also tested extending the model with the addition of the factor Self-Efficacy to Screen using Fecal Occult Blood Test (SESFOBT). Randomly selected men and women aged between 50 and 76 years (n = 414) responded to a survey. Confirmatory factor analyses indicated that the U.S. model provided adequate fit for the group as a whole and for men and women separately, thereby demonstrating cross-cultural validity for measuring factors influencing the decision to screen. The inclusion of SESFOBT in the model resulted in a comparable, but less parsimonious, fit. However, self-efficacy is a demonstrated mediator of intention and action, and it is argued that the addition of SESFOBT as a sixth factor may have utility for the design of strategies to increase actual uptake of FOBT. PMID- 20930135 TI - The role of leadership and management in six southern public health partnerships: a study of member involvement and satisfaction. AB - Research has led to greater understanding of what is needed to create and sustain well-functioning public health partnerships. However, a partnership's ability to foster an environment that encourages broad member involvement in discussions, decision making, and activities has received scant empirical attention. This study examined the relationship between partnership members' perceptions of how well leadership and management facilitated their involvement, and their satisfaction with their role and influence within the partnership. Data came from 60 individuals who participated in two waves of a quantitative process evaluation of six southern interorganizational partnerships, formed as part of a national pilot project to increase cervical and breast cancer screening rates. Results suggested that environments fostering broad partner involvement were associated with measures of member satisfaction, controlling for other partnership characteristics. Findings indicated that facilitation of member involvement deserves increased consideration from researchers and practitioners as an indicator of the quality of partnership functioning. PMID- 20930136 TI - Microtubule +TIPs at a glance. PMID- 20930137 TI - Kinesins at a glance. PMID- 20930138 TI - Tubulin depolymerization may be an ancient biological motor. AB - The motions of mitotic chromosomes are complex and show considerable variety across species. A wealth of evidence supports the idea that microtubule-dependent motor enzymes contribute to this variation and are important both for spindle formation and for the accurate completion of chromosome segregation. Motors that walk towards the spindle pole are, however, dispensable for at least some poleward movements of chromosomes in yeasts, suggesting that depolymerizing spindle microtubules can generate mitotic forces in vivo. Tubulin protofilaments that flare outward in association with microtubule shortening may be the origin of such forces, because they can move objects that are appropriately attached to a microtubule wall. For example, some kinetochore-associated proteins can couple experimental objects, such as microspheres, to shortening microtubules in vitro, moving them over many micrometers. Here, we review recent evidence about such phenomena, highlighting the force-generation mechanisms and different coupling strategies. We also consider bending filaments of the tubulin-like protein FtsZ, which form rings girding bacteria at their sites of cytokinesis. Mechanical similarities between these force-generation systems suggest a deep phylogenetic relationship between tubulin depolymerization in eukaryotic mitosis and FtsZ mediated ring contraction in bacteria. PMID- 20930139 TI - Towards a quantitative understanding of mitotic spindle assembly and mechanics. AB - The 'simple' view of the mitotic spindle is that it self-assembles as a result of microtubules (MTs) randomly searching for chromosomes, after which the spindle length is maintained by a balance of outward tension exerted by molecular motors on the MTs connecting centrosomes and chromosomes, and compression generated by other motors on the MTs connecting the spindle poles. This picture is being challenged now by mounting evidence indicating that spindle assembly and maintenance rely on much more complex interconnected networks of microtubules, molecular motors, chromosomes and regulatory proteins. From an engineering point of view, three design principles of this molecular machine are especially important: the spindle assembles quickly, it assembles accurately, and it is mechanically robust--yet malleable. How is this design achieved with randomly interacting and impermanent molecular parts? Here, we review recent interdisciplinary studies that have started to shed light on this question. We discuss cooperative mechanisms of spindle self-assembly, error correction and maintenance of its mechanical properties, speculate on analogy between spindle and lamellipodial dynamics, and highlight the role of quantitative approaches in understanding the mitotic spindle design. PMID- 20930141 TI - Snail1 suppresses TGF-beta-induced apoptosis and is sufficient to trigger EMT in hepatocytes. AB - Although TGF-beta suppresses early stages of tumour development, it later contributes to tumour progression when cells become resistant to its suppressive effects. In addition to circumventing TGF-beta-induced growth arrest and apoptosis, malignant tumour cells become capable of undergoing epithelial-to mesenchymal transition (EMT), favouring invasion and metastasis. Therefore, defining the mechanisms that allow cancer cells to escape from the suppressive effects of TGF-beta is fundamental to understand tumour progression and to design specific therapies. Here, we have examined the role of Snail1 as a suppressor of TGF-beta-induced apoptosis in murine non-transformed hepatocytes, rat and human hepatocarcinoma cell lines and transgenic mice. We show that Snail1 confers resistance to TGF-beta-induced cell death and that it is sufficient to induce EMT in adult hepatocytes, cells otherwise refractory to this transition upon exposure to TGF-beta. Furthermore, we show that Snail1 silencing prevents EMT and restores the cell death response induced by TGF-beta. As Snail1 is a known target of TGF beta signalling, our data indicate that Snail1 might transduce the tumour promoting effects of TGF-beta, namely the EMT concomitant with the resistance to cell death. PMID- 20930142 TI - PtdIns(3,4,5)P3 is a regulator of myosin-X localization and filopodia formation. AB - Phosphatidylinositol (3,4,5)-trisphosphate [PtdIns(3,4,5)P3] is a key regulator of cell signaling that acts by recruiting proteins to the cell membrane, such as at the leading edge during cell migration. Here, we show that PtdIns (3,4,5)P3 plays a central role in filopodia formation via the binding of myosin-X (Myo10), a potent promoter of filopodia. We found that the second pleckstrin homology domain (Myo10-PH2) of Myo10 specifically binds to PtdIns(3,4,5)P3, and that disruption of this binding led to impairment of filopodia and partial re localization of Myo10 to microtubule-associated Rab7-positive endosomal vesicles. Given that the localization of Myo10 was dynamically restored to filopodia upon reinstatement of PtdIns(3,4,5)P3-binding, our results indicate that PtdIns(3,4,5)P3 binding to the Myo10-PH2 domain is involved in Myo10 trafficking and regulation of filopodia dynamics. PMID- 20930140 TI - Post-translational modifications of microtubules. AB - Microtubules--polymers of tubulin--perform essential functions, including regulation of cell shape, intracellular transport and cell motility. How microtubules are adapted to perform multiple diverse functions is not well understood. Post-translational modifications of tubulin subunits diversify the outer and luminal surfaces of microtubules and provide a potential mechanism for their functional specialization. Recent identification of a number of tubulin modifying and -demodifying enzymes has revealed key roles of tubulin modifications in the regulation of motors and factors that affect the organization and dynamics of microtubules. PMID- 20930143 TI - Coactivation of the CLOCK-BMAL1 complex by CBP mediates resetting of the circadian clock. AB - The transcription factor CLOCK-BMAL1 is a core component of the molecular clock machinery that drives circadian gene expression and physiology in mammals. Recently, we reported that this heterodimeric transcription factor functions as a signaling molecule in response to the resetting stimuli via the Ca2+-dependent protein kinase C pathway. Here, we demonstrate that the CREB-binding protein (CBP) plays a key role in rapid activation of the CLOCK-BMAL1 heterodimer that leads to phase resetting of the circadian clock. Under physiological conditions, a bimolecular fluorescence complementation (BiFC) assay revealed that CLOCK and BMAL1 dimerize in the cytoplasm and subsequently translocate into the nucleus in response to serum stimuli (mean time duration was 29.2 minutes and mean velocity 0.7 MUm/minute). Concomitantly, BMAL1 rapidly recruited CBP on Per1 promoter E box, but not p300 (a functional analog of CBP), in the discrete nuclear foci. However, recruitment of CBP by cAMP/Ca2+ response element-binding (CREB) protein on CRE was not markedly increased upon delivery of the resetting stimuli. Furthermore, overexpression of CBP greatly potentiated the CLOCK-BMAL1-mediated Per1 transcription, and this effect was completely abolished by site-directed mutation of E-box elements, but not by the mutation of CRE in the Per1 promoter. Furthermore, molecular knockdown of CBP severely dampened circadian oscillation of clock gene expression triggered by the resetting stimuli. These findings suggest that CBP recruitment by BMAL1 mediates acute transactivation of CLOCK BMAL1, thereby inducing immediate-early Per1 transcription and phase resetting of the circadian clock. PMID- 20930144 TI - ATF3, an adaptive-response gene, enhances TGF{beta} signaling and cancer initiating cell features in breast cancer cells. AB - The activating transcription factor 3 (ATF3) gene is induced by a variety of signals, including many of those encountered by cancer cells. We present evidence that ATF3 is induced by TGFbeta in the MCF10CA1a breast cancer cells and plays an integral role for TGFbeta to upregulate its target genes snail, slug and twist, and to enhance cell motility. Furthermore, ATF3 upregulates the expression of the TGFb gene itself, forming a positive-feedback loop for TGFbeta signaling. Functionally, ectopic expression of ATF3 leads to morphological changes and alterations of markers consistent with epithelial-to-mesenchymal transition (EMT). It also leads to features associated with breast-cancer-initiating cells: increased CD24(low)-CD44(high) population of cells, mammosphere formation and tumorigenesis. Conversely, knockdown of ATF3 reduces EMT, CD24(low)-CD44(high) cells and mammosphere formation. Importantly, knocking down twist, a downstream target, reduces the ability of ATF3 to enhance mammosphere formation, indicating the functional significance of twist in ATF3 action. To our knowledge, this is the first report demonstrating the ability of ATF3 to enhance breast cancer initiating cell features and to feedback on TGFbeta. Because ATF3 is an adaptive response gene and is induced by various stromal signals, these findings have significant implications for how the tumor microenvironment might affect cancer development. PMID- 20930146 TI - Neuronal connexin-36 can functionally replace connexin-45 in mouse retina but not in the developing heart. AB - The gap junction protein connexin-45 (Cx45) is expressed in the conduction system of the heart and in certain neurons of the retina and brain. General and cardiomyocyte-directed deficiencies of Cx45 in mice lead to lethality on embryonic day 10.5 as a result of cardiovascular defects. Neuron-directed deletion of Cx45 leads to defects in transmission of visual signals. Connexin-36 (Cx36) is co-expressed with Cx45 in certain types of retinal interneurons. To determine whether these two connexins have similar functions and whether Cx36 can compensate for Cx45, we generated knock-in mice in which DNA encoding Cx45 was replaced with that encoding Cx36. Neuron-directed replacement of Cx45 with Cx36 resulted in viable animals. Electroretinographic and neurotransmitter coupling analyses demonstrated functional compensation in the retina. By contrast, general and cardiomyocyte-directed gene replacement led to lethality on embryonic day 11.5. Mutant embryos displayed defects in cardiac morphogenesis and conduction. Thus, functional compensation of Cx45 by Cx36 did not occur during embryonic heart development. These data suggest that Cx45 and Cx36 have similar functions in the retina, whereas Cx45 fulfills special functions in the developing heart that cannot be compensated by Cx36. PMID- 20930145 TI - Ets1 blocks terminal differentiation of keratinocytes and induces expression of matrix metalloproteases and innate immune mediators. AB - The transcription factor Ets1 is normally expressed in the proliferative layer of stratified epithelium, but expression of Ets1 is significantly upregulated in squamous cell carcinomas. How elevated levels of Ets1 impact tumor initiation and progression is not well understood. To determine the biological consequences of overexpression of Ets1, we developed a transgenic mouse model that allows induction of Ets1 expression in keratinocytes of stratified epithelium in a regulatable fashion. Induction of Ets1 during embryonic development results in a dramatic alteration in epidermal structure and function by suppressing the expression of multiple stratum corneum constituents, while at the same time inducing expression of EGF ligands, AP1 transcription factors and matrix metalloproteases. Interestingly, expression of certain immune-related genes, including defensins, chemokines and cytokines was increased as well, suggesting a possible role for immune dysregulation in the promotion of squamous dysplasia. Experiments using cultured mouse keratinocytes indicate that Ets1 can induce expression of some of these mediators in a cell-intrinsic fashion. Collectively, our data reveal that elevated expression of Ets1 has a much broader array of pro tumorigenic effects on epithelial cells than previously appreciated. PMID- 20930147 TI - Role of PECAM-1 in arteriogenesis and specification of preexisting collaterals. AB - RATIONALE: Hemodynamic forces caused by the altered blood flow in response to an occlusion lead to the induction of collateral remodeling and arteriogenesis. Previous work showed that platelet endothelial cell adhesion molecule (PECAM)-1 is a component of a mechanosensory complex that mediates endothelial cell responses to shear stress. OBJECTIVE: We hypothesized that PECAM-1 plays an important role in arteriogenesis and collateral remodeling. METHODS AND RESULTS: PECAM-1 knockout (KO) and wild-type littermates underwent femoral artery ligation. Surprisingly, tissue perfusion and collateral-dependent blood flow were significantly increased in the KO mice immediately after surgery. Histology confirmed larger caliber of preexisting collaterals in the KO mice. Additionally, KO mice showed blunted recovery of perfusion from hindlimb ischemia and reduced collateral remodeling, because of deficits in shear stress-induced signaling, including activation of the nuclear factor kappaB pathway and inflammatory cell accumulation. Partial recovery was associated with normal responses to circumferential wall tension in the absence of PECAM-1, as evidenced by the upregulation of ephrin B2 and monocyte chemoattractant protein-1, which are 2 stretch-induced regulators of arteriogenesis, both in vitro and in vivo. CONCLUSIONS: Our findings suggest a novel role for PECAM-1 in arteriogenesis and collateral remodeling. Furthermore, we identify PECAM-1 as the first molecule that determines preexisting collateral diameter. PMID- 20930149 TI - The neuropeptide catestatin acts as a novel angiogenic cytokine via a basic fibroblast growth factor-dependent mechanism. AB - RATIONALE: The neuropeptide catestatin is an endogenous nicotinic cholinergic antagonist that acts as a pleiotropic hormone. OBJECTIVE: Catestatin shares several functions with angiogenic factors. We therefore reasoned that catestatin induces growth of new blood vessels. METHODS AND RESULTS: Catestatin induced migration, proliferation, and antiapoptosis in endothelial cells and exerted capillary tube formation in vitro in a Matrigel assay, and such effects were mediated via G protein, mitogen-activated protein kinase, and Akt. Catestatin induced endothelial cell functions are further mediated by basic fibroblast growth factor, as shown by blockade of effects by a neutralizing fibroblast growth factor antibody. Furthermore, catestatin released basic fibroblast growth factor from endothelial cells and stimulated fibroblast growth factor signaling. In addition to its function on endothelial cells, catestatin also exerted effects on endothelial progenitor cells and vascular smooth muscle cells. In vivo, catestatin induced angiogenesis in the mouse cornea neovascularization assay and increased blood perfusion and number of capillaries in the hindlimb ischemia model. In addition to angiogenesis, catestatin increased density of arterioles/arteries and incorporation of endothelial progenitor cells in the hindlimb ischemia model, indicating induction of arteriogenesis and postnatal vasculogenesis. CONCLUSION: We conclude that catestatin acts as a novel angiogenic cytokine via a basic fibroblast growth factor-dependent mechanism. PMID- 20930148 TI - Angiotensin-converting enzyme inhibition prevents the release of monocytes from their splenic reservoir in mice with myocardial infarction. AB - RATIONALE: Monocytes recruited to ischemic myocardium originate from a reservoir in the spleen, and the release from their splenic niche relies on angiotensin (Ang) II signaling. OBJECTIVE: Because monocytes are centrally involved in tissue repair after ischemia, we hypothesized that early angiotensin-converting enzyme (ACE) inhibitor therapy impacts healing after myocardial infarction partly via effects on monocyte traffic. METHODS AND RESULTS: In a mouse model of permanent coronary ligation, enalapril arrested the release of monocytes from the splenic reservoir and consequently reduced their recruitment into the healing infarct by 45%, as quantified by flow cytometry of digested infarcts. Time-lapse intravital microscopy revealed that enalapril reduces monocyte motility in the spleen. In vitro migration assays and Western blotting showed that this was caused by reduced signaling through the Ang II type 1 receptor. We then studied the long term consequences of blocked splenic monocyte release in atherosclerotic apolipoprotein (apo)E(-/-) mice, in which infarct healing is impaired because of excessive inflammation in the cardiac wound. Enalapril improved histologic healing biomarkers and reduced inflammation in infarcts measured by FMT-CT (fluorescence molecular tomography in conjunction with x-ray computed tomography) of proteolytic activity. ACE inhibition improved MRI-derived ejection fraction by 14% on day 21, despite initially comparable infarct size. In apoE(-/-) mice, ischemia/reperfusion injury resulted in larger infarct size and enhanced monocyte recruitment and was reversible by enalapril treatment. Splenectomy reproduced antiinflammatory effects of enalapril. CONCLUSION: This study suggests that benefits of early ACE inhibition after myocardial infarction can partially be attributed to its potent antiinflammatory impact on the splenic monocyte reservoir. PMID- 20930150 TI - Predictors of hospital readmission after stroke: a systematic review. AB - BACKGROUND AND PURPOSE: Risk-standardized hospital readmission rates are used as publicly reported measures reflecting quality of care. Valid risk-standardized models adjust for differences in patient-level factors across hospitals. We conducted a systematic review of peer-reviewed literature to identify models that compare hospital-level poststroke readmission rates, evaluate patient-level risk scores predicting readmission, or describe patient and process-of-care predictors of readmission after stroke. METHODS: Relevant studies in English published from January 1989 to July 2010 were identified using MEDLINE, PubMed, Scopus, PsycINFO, and all Ovid Evidence-Based Medicine Reviews. Authors of eligible publications reported readmission within 1 year after stroke hospitalization and identified >= 1 predictors of readmission in risk-adjusted statistical models. Publications were excluded if they lacked primary data or quantitative outcomes, reported only composite outcomes, or had < 100 patients. RESULTS: Of 374 identified publications, 16 met the inclusion criteria for this review. No model was specifically designed to compare risk-adjusted readmission rates at the hospital level or calculate scores predicting a patient's risk of readmission. The studies providing multivariable models of patient-level and/or process-of care factors associated with readmission varied in stroke definitions, data sources, outcomes (all-cause and/or stroke-related readmission), durations of follow-up, and model covariates. Few characteristics were consistently associated with readmission. CONCLUSIONS: This review identified no risk-standardized models for comparing hospital readmission performance or predicting readmission risk after stroke. Patient-level and system-level factors associated with readmission were inconsistent across studies. The current literature provides little guidance for the development of risk-standardized models suitable for the public reporting of hospital-level stroke readmission performance. PMID- 20930152 TI - The Acute STroke Registry and Analysis of Lausanne (ASTRAL): design and baseline analysis of an ischemic stroke registry including acute multimodal imaging. AB - BACKGROUND AND PURPOSE: Stroke registries are valuable tools for obtaining information about stroke epidemiology and management. The Acute STroke Registry and Analysis of Lausanne (ASTRAL) prospectively collects epidemiological, clinical, laboratory and multimodal brain imaging data of acute ischemic stroke patients in the Centre Hospitalier Universitaire Vaudois (CHUV). Here, we provide design and methods used to create ASTRAL and present baseline data of our patients (2003 to 2008). METHODS: All consecutive patients admitted to CHUV between January 1, 2003 and December 31, 2008 with acute ischemic stroke within 24 hours of symptom onset were included in ASTRAL. Patients arriving beyond 24 hours, with transient ischemic attack, intracerebral hemorrhage, subarachnoidal hemorrhage, or cerebral sinus venous thrombosis, were excluded. Recurrent ischemic strokes were registered as new events. RESULTS: Between 2003 and 2008, 1633 patients and 1742 events were registered in ASTRAL. There was a preponderance of males, even in the elderly. Cardioembolic stroke was the most frequent type of stroke. Most strokes were of minor severity (National Institute of Health Stroke Scale [NIHSS] score <= 4 in 40.8% of patients). Cardioembolic stroke and dissections presented with the most severe clinical picture. There was a significant number of patients with unknown onset stroke, including wake-up stroke (n=568, 33.1%). Median time from last-well time to hospital arrival was 142 minutes for known onset and 759 minutes for unknown-onset stroke. The rate of intravenous or intraarterial thrombolysis between 2003 and 2008 increased from 10.8% to 20.8% in patients admitted within 24 hours of last-well time. Acute brain imaging was performed in 1695 patients (97.3%) within 24 hours. In 1358 patients (78%) who underwent acute computed tomography angiography, 717 patients (52.8%) had significant abnormalities. Of the 1068 supratentorial stroke patients who underwent acute perfusion computed tomography (61.3%), focal hypoperfusion was demonstrated in 786 patients (73.6%). CONCLUSIONS: This hospital-based prospective registry of consecutive acute ischemic strokes incorporates demographic, clinical, metabolic, acute perfusion, and arterial imaging. It is characterized by a high proportion of minor and unknown-onset strokes, short onset-to-admission time for known-onset patients, rapidly increasing thrombolysis rates, and significant vascular and perfusion imaging abnormalities in the majority of patients. PMID- 20930153 TI - Local is better than general anesthesia during endovascular acute stroke interventions. PMID- 20930154 TI - General or local anesthesia during endovascular procedures: sailing quiet in the darkness or fast under a daylight storm. PMID- 20930151 TI - Discarding heparins as treatment for progressive stroke in Sweden 2001 to 2008. AB - BACKGROUND AND PURPOSE: High-dose heparin has been used extensively to treat patients with progressive ischemic stroke, but the scientific support is poor and the current stroke guidelines advise against its use. We studied how heparin treatment for progressive stroke has been discarded in Sweden. METHODS: All 78 hospitals in Sweden that admit acute stroke patients participate in Riks-Stroke, the Swedish Stroke Register. During 2001 to 2008, information on the use of high dose heparin was available for 155,344 patients with acute ischemic stroke. The determinants as to region, patient characteristics, and stroke service settings were analyzed. RESULTS: Use of heparin for progressive stroke declined from 7.5% (2001) to 1.6% (2008) of all patients with ischemic stroke. The marked regional differences present in 2001 were reduced over time. The use of heparin declined at a similar rate in all types of hospital settings, in stroke units vs nonstroke units, and in neurological vs medical wards. Independent predictors of use of heparin included younger age, first-ever stroke, independence in activities of daily living before stroke, atrial fibrillation, no aspirin treatment, and lowered consciousness on admission. CONCLUSIONS: There is no immediate, stepwise effect of new scientific information and national guidelines on clinical practice. Rather, the phasing out of heparin has followed a linear course over several years, with less variation between hospitals. We speculate that open comparisons between hospitals in a national stroke register may have helped to reduce the variations in clinical practice. PMID- 20930155 TI - Detection of intracranial in-stent restenosis using quantitative magnetic resonance angiography. AB - BACKGROUND AND PURPOSE: In-stent restenosis (ISR) after angioplasty/stenting for intracranial stenosis has been reported in up to 25% to 30% of patients. Detection and monitoring of ISR relies primarily on serial catheter angiography, because noninvasive imaging methods are typically hampered by stent-related artifact. We examined the value of serial vessel flow measurements using quantitative magnetic resonance angiography (QMRA) in detection of ISR. MATERIAL AND METHODS: Records of patients undergoing stenting for intracranial symptomatic stenosis >50% between 2005 and 2009 were retrospectively reviewed. Angiographic images were graded by a blinded neurointerventionalist for stenosis pretreatment, immediately after treatment, and during follow-up. Flow in the affected vessel measured by QMRA was recorded; > 25% reduction in flow was considered indicative of an adverse change. Clinical data regarding neurological outcome were also collected. RESULTS: Twenty-eight patients underwent stenting during the time interval studied. Of these, 12 patients (mean age, 55.5 years; 8 female) had contemporaneous angiography and QMRA and were analyzed. Median follow-up was 9 months. Six patients (50%) demonstrated angiographic restenosis 2 to 12 months after treatment; all had an analogous decrease in flow in the vessel of interest. Of 3 patients with more severe flow decrement (> 50%), 2 experienced stroke. None of the patients without angiographic ISR demonstrated a flow decrease on QMRA. CONCLUSIONS: In this preliminary series, flow decrease on QMRA is highly predictive of angiographic ISR. Additionally, the degree of flow decrement correlates with symptomatic ISR. QMRA may provide a useful noninvasive tool for serial monitoring after intracranial stenting. PMID- 20930156 TI - General is better than local anesthesia during endovascular procedures. PMID- 20930157 TI - An epidemiological study of stroke hospitalizations in Maputo, Mozambique: a high burden of disease in a resource-poor country. AB - BACKGROUND AND PURPOSE: Already a major cause of death and disability in high income countries, the burden of stroke in sub-Saharan Africa is also expected to be high. However, specific stroke data are scarce from resource-poor countries. We studied the incidence, characteristics, and short-term consequences of hospitalizations for stroke in Maputo, Mozambique. METHODS: Over 12 months, comprehensive data from all local patients admitted to any hospital in Maputo with a new stroke event were prospectively captured according to the World Health Organization's STEPwise approach to stroke surveillance program. Disability levels (pre- and posthospital discharge) and short-term case-fatality (in hospital and 28 days) were also studied. RESULTS: Overall, 651 new stroke events (mean age 59.1 +/- 13.2 years and 53% men) were captured by the registry with 601 confirmed by CT scan (83.4%) or necropsy (8.9%). Crude and adjusted (world reference population) annual incidence rates of stroke were 148.7 per 100,000 and 260.1 per 100,000 aged >= 25 years, respectively. Of these, 531 (81.6%) represented a first-ever stroke event comprising 254 ischemic (42.0%) and 217 (36.1%) an intracerebral hemorrhage. Before admission, 561 patients (86.2%) had hypertension and 271 (41.6%) had symptoms for > 24 hours. In-hospital and 28-day case-fatality were 33.3% and 49.6% (72.3% for hemorrhagic stroke), respectively. From almost no preadmission disability, 64.4% of 370 survivors at 28 days had moderate-to-severe disability. CONCLUSIONS: The burden of disease associated with stroke is high in Maputo, emphasizing the importance of primary prevention and improvement of the standards of care in a developing country under epidemiological transition. PMID- 20930158 TI - Cerebral autoregulation in stroke: a review of transcranial Doppler studies. AB - BACKGROUND AND PURPOSE: Cerebral autoregulation may become impaired after stroke. To provide a review of the nature and extent of any autoregulation impairment after stroke and its course over time, a technique allowing repeated bedside measurements with good temporal resolution is required. Transcranial Doppler (TCD) in combination with continuous blood pressure measurements allows noninvasive continuous bedside investigation with high temporal resolution of the dynamic and the steady-state components of cerebral autoregulation. Therefore, this review focuses on all TCD studies on cerebral autoregulation in the setting of documented ischemic stroke. METHODS: PubMed and EMBASE were searched for studies of stroke, autoregulation, and TCD. Studies were either acute phase (<96 hours after index stroke) or chronic phase (>96 hours after index stroke) autoregulation studies. Quality of studies was studied in a standardized fashion. RESULTS: Twenty-three studies met the inclusion criteria. General agreement existed on cerebral autoregulation being impaired, even after minor stroke. Bilateral impairment of autoregulation was documented, particularly after lacunar stroke. Studies showed progressive deterioration of cerebral autoregulation in the first 5 days after stroke and recovery over the next 3 months. Impaired cerebral autoregulation as assessed by TCD was related to neurological deterioration, the necessity for decompressive surgery, and poor outcome. Synthesis of the data of various studies was, however, limited by studies not meeting key methodological criteria for observational studies. CONCLUSIONS: TCD in combination with continuous blood pressure measurement offers a method with a high temporal resolution feasible for bedside evaluation of cerebral autoregulation in the stroke unit. TCD studies have shown impairment of cerebral autoregulation in various subtypes of ischemic stroke. To improve the synthesis of data from various research groups, there is urgent need for standardization of methodology of TCD studies in cerebral autoregulation. PMID- 20930160 TI - Stroke risk and antithrombotic strategies in atrial fibrillation. AB - BACKGROUND AND PURPOSE: Although the stroke rate associated with atrial fibrillation has declined over the last 10 years, the emerging atrial fibrillation epidemic threatens to increase the incidence of cardioembolic stroke. Summary of Review-Oral anticoagulants are superior antithrombotic agents but are underused due to fear of bleeding and uncertainty about which patients will benefit. Individualized decisions on antithrombotic therapy require balancing the competing risks of thromboembolism and bleeding. The CHADS2 (Congestive heart failure, Hypertension, Age > 75 years, and Diabetes mellitus, and 2 points for prior Stroke/transient ischemic attack) score and other schemes provide an estimate of thromboembolic risk; however, the external validity of these estimates in the context of well-controlled risk factors, or a hypercoagulable state, is uncertain. Moreover, it is very difficult to estimate bleeding risk. Recent studies highlight the need for meticulous international normalized ratio control to achieve optimal outcomes hampered by the high bleeding risk during oral anticoagulant inception and other limitations of warfarin. Dabigatran is at least as efficacious as warfarin in preventing stroke and systemic embolism for patients in whom the risk of thromboembolism outweighs bleeding risk. In addition, the results of ongoing trials evaluating alternative anticoagulants such as oral anti-Xa agents are awaited. In this review, we discuss emerging therapies including available and completed trials of direct antithrombins and anti-Xa agents, including ximelagatran, idraparinaux, and dabigatran; and new device therapies including left atrial appendage occlusion devices. CONCLUSIONS: In light of these promising new therapies, it is likely that atrial fibrillation thromboembolism guidelines will need to be rewritten and frequently updated. PMID- 20930159 TI - Tumor necrosis factor-alpha enhances microvascular tone and reduces blood flow in the cochlea via enhanced sphingosine-1-phosphate signaling. AB - BACKGROUND AND PURPOSE: We sought to demonstrate that tumor necrosis factor (TNF) alpha, via sphingosine-1-phosphate signaling, has the potential to alter cochlear blood flow and thus, cause ischemic hearing loss. METHODS: We performed intravital fluorescence microscopy to measure blood flow and capillary diameter in anesthetized guinea pigs. To measure capillary diameter ex vivo, capillary beds from the gerbil spiral ligament were isolated from the cochlear lateral wall and maintained in an organ bath. Isolated gerbil spiral modiolar arteries, maintained and transfected in organ culture, were used to measure calcium sensitivity (calcium-tone relationship). In a clinical study, a total of 12 adult patients presenting with typical symptoms of sudden hearing loss who were not responsive or only partially responsive to prednisolone treatment were identified and selected for etanercept treatment. Etanercept (25 mg s.c.) was self administered twice a week for 12 weeks. RESULTS: TNF-alpha induced a proconstrictive state throughout the cochlear microvasculature, which reduced capillary diameter and cochlear blood flow in vivo. In vitro isolated preparations of the spiral modiolar artery and spiral ligament capillaries confirmed these observations. Antagonizing sphingosine-1-phosphate receptor 2 subtype signaling (by 1 MUmol/L JTE013) attenuated the effects of TNF-alpha in all models. TNF-alpha activated sphingosine kinase 1 (Sk1) and induced its translocation to the smooth muscle cell membrane. Expression of a dominant negative Sk1 mutant (Sk1(G82D)) eliminated both baseline spiral modiolar artery calcium sensitivity and TNF-alpha effects, whereas a nonphosphorylatable Sk1 mutant (Sk1(S225A)) blocked the effects of TNF-alpha only. A small group of etanercept-treated, hearing loss patients recovered according to a 1-phase exponential decay (half-life=1.56 +/- 0.20 weeks), which matched the kinetics predicted for a vascular origin. CONCLUSIONS: TNF-alpha indeed reduces cochlear blood flow via activation of vascular sphingosine-1-phosphate signaling. This integrates hearing loss into the family of ischemic microvascular pathologies, with implications for risk stratification, diagnosis, and treatment. PMID- 20930161 TI - Unfractionated or low-molecular weight heparin for the treatment of cerebral venous thrombosis. AB - BACKGROUND AND PURPOSE: There is no consensus whether to use unfractionated heparin or low-molecular weight heparin for the treatment of cerebral venous thrombosis. We examined the effect on clinical outcome of each type of heparin. METHODS: A nonrandomized comparison of a prospective cohort study (the International Study on Cerebral Vein and Dural Sinus Thrombosis) of 624 patients with cerebral venous thrombosis. Patients not treated with heparin (n = 107) and those who sequentially received both types of heparin (n = 99) were excluded from the primary analysis. The latter were included in a secondary analysis, allocated according to the type of heparin given first. The primary end point was functional independency at 6 months (modified Rankin scale score <= 2). Secondary end points were complete recovery (modified Rankin scale score 0 to 1), mortality, and new intracranial hemorrhages. RESULTS: A total of 119 patients received low-molecular weight heparin (28%) and 302 received unfractionated heparin (72%). Significantly more patients treated with low-molecular weight heparin were functionally independent after 6 months, both in univariate analysis (odds ratio, 2.1; CI, 1.0 to 4.2) and after adjustment for prognostic factors and imbalances (odds ratio, 2.4; CI, 1.0 to 5.7). In the secondary analysis, there was a similar, nonsignificant trend (odds ratio, 1.7; CI, 0.80 to 3.6). Low molecular weight heparin was associated with less new intracerebral hemorrhages (adjusted odds ratio, 0.29; CI, 0.07 to 1.3), especially in patients with intracerebral lesions at baseline (adjusted odds ratio, 0.19; CI, 0.04 to 0.99). There was no difference in complete recovery and mortality. CONCLUSIONS: This nonrandomized study in patients with cerebral venous thrombosis suggests a better efficacy and safety of low-molecular weight heparin over unfractionated heparin. Low-molecular weight heparin seems preferable above unfractionated heparin for the initial treatment of cerebral venous thrombosis. PMID- 20930162 TI - Relative energy index to detect malignant microemboli. PMID- 20930163 TI - Intravenous alteplase for stroke in those older than 80 years old. AB - BACKGROUND AND PURPOSE: Risks and benefits of intravenous thrombolysis for patients with stroke > 80 years of age are unclear. We examined outcomes and symptomatic intracerebral hemorrhage rates in <= 80- and > 80-year-old patients in the Safe Implementation of Treatment in Stroke International Stroke Thrombolysis Register. METHODS: We compared mortality and independence (modified Rankin Scale 0 to 2) at 3 months and symptomatic intracerebral hemorrhage (per Safe Implementation of Treatment in Stroke >= 4-point deterioration in National Institutes of Health Stroke Scale within 36 hours and Type 2 parenchymal hemorrhage and per National Institute of Neurological Disorders and Stroke [any increase in National Institutes of Health Stroke Scale and any hemorrhage]) of 1831 patients > 80 years of age with 19 411 patients <= 80 years of age compliant with other European licensing criteria. RESULTS: The > 80-year-old group (median, 83 years) had more severe strokes (median National Institutes of Health Stroke Scale 14 versus 12), lower levels of prestroke independence (modified Rankin Scale 0 to 1, 82% versus 93%), and a larger proportion of females (59% versus 39%) compared with the younger group (68 years). Symptomatic intracerebral hemorrhage was not significantly increased after adjustment for other risk factors in those >80 years of age compared with those <= 80 years of age (per Safe Implementation of Treatment in Stroke 1.8% versus 1.7%, P = 0.70, adjusted OR, 0.90, 95% CI, 0.73 to 1.09; P = 0.28; per National Institute of Neurological Disorders and Stroke 9.5% versus 7.8%, P < 0.005, adjusted OR, 0.96, 95% CI, 0.87 to 1.06, P = 0.42). The patients >80 years of age had a higher mortality rate (30% versus 12%; P < 0.005; adjusted OR, 1.53; 95% CI, 1.43 to 1.65; P < 0.005) and reduced independence (35% versus 57%; P < 0.005; adjusted OR, 0.73; 95% CI, 0.68 to 0.78; P < 0.005). CONCLUSIONS: Selected patients with acute ischemic stroke > 80 years of age otherwise fulfilling the intravenous alteplase license criteria have a similar rate of symptomatic intracerebral hemorrhage compared with younger patients and are appropriate candidates for thrombolysis. The higher mortality and the poorer functional outcome are consistent with the overall worse prognosis seen in the natural history of this age group. PMID- 20930164 TI - Impact of microalbuminuria on incident stroke: a meta-analysis. AB - BACKGROUND AND PURPOSE: Microalbuminuria, a marker of both kidney disease and endothelial dysfunction, may be associated with global vascular risk, but the nature and magnitude of the link between microalbuminuria and incident stroke has not been clearly defined. The purpose of this study was to assess the consistency and strength of the association of microalbuminuria with risk of stroke in prospective studies using meta-analysis. METHODS: We conducted a systematic search of electronic databases and bibliographies for studies reporting a multivariate-adjusted estimate, represented as relative risk with 95% CI, of the association between microalbuminuria and stroke risk. Studies were excluded if a majority of study participants had established kidney disease or pre-eclampsia. Estimates were combined using a random-effect model. RESULTS: We identified 12 studies, with a total of 48 596 participants and 1263 stroke events. Overall, presence of microalbuminuria was associated with greater stroke risk (relative risk, 1.92; 95% CI, 1.61 to 2.28; P < 0.001) after adjustment for established cardiovascular risk factors. There was evidence of significant heterogeneity in the magnitude of the association across studies (P for heterogeneity < 0.001, I2 = 68%), which was partially explained by differences in study population, microalbuminuria definition, and different microalbuminuria-related risk among stroke subtypes. However, in stratified analyses, microalbuminuria was associated with increased risk of subsequent stroke in all subgroups (general population, diabetics, those with known stroke). CONCLUSIONS: Microalbuminuria is strongly and independently associated with incident stroke risk. Future studies should explore whether microalbuminuria is just a risk marker or a modifiable risk factor for stroke. PMID- 20930165 TI - Aspirin in Alzheimer's disease: increased risk of intracerebral hemorrhage: cause for concern? AB - BACKGROUND AND PURPOSE: In a randomized controlled trial in Alzheimer's disease (AD), we found a higher number of intracerebral hemorrhages (ICHs) in patients randomized to aspirin treatment. Here, we evaluate the literature on the risk of ICH as a complication in patients with AD treated with aspirin. METHODS: Systematic review and comparison of the occurrence of events over time between the aspirin and control group in each trial using Cox regression analysis. Estimated hazard ratios (HRs) were combined in a pooled HR. RESULTS: Two randomized controlled trials on aspirin for AD were found. In the Evaluation of Vascular Care in Alzheimer's Disease (EVA) trial (conducted in our center), 4.6% of patients in the group receiving a multicomponent treatment that included aspirin had an ICH (3/65; 95% confidence interval [CI], 1.0 to 12.9) versus 0% in the control group (0/58; 95% CI, 0 to 6.2). In the Aspirin in Alzheimer's Disease (AD2000) trial, these proportions were, respectively, 2.6% (4/156; 95% CI, 0.7 to 6.4) and 0% (0/154; 95% CI, 0 to 2.4). The pooled proportion of ICHs in the aspirin group is 3.2% (7/221; 95% CI, 1.3 to 6.4) versus 0% in the control group (0/212; 95% CI, 0 to 1.7). The pooled HR for an ICH in AD patients using aspirin is 7.63 (95% CI, 0.72 to 81.00; P=0.09). CONCLUSIONS: Although the number of cases in both trials is small, our findings suggest that aspirin use in AD might pose an increased risk of ICH, whereas it has no effect on cognition. If there is an unequivocal cardiovascular indication for aspirin, it should not be withheld in AD patients. PMID- 20930166 TI - Intra-arterial thrombolysis within 3 hours: where is the evidence? PMID- 20930167 TI - n-3 Fatty acids decrease arterial low-density lipoprotein cholesterol delivery and lipoprotein lipase levels in insulin-resistant mice. AB - OBJECTIVE: To determine whether n-3 fatty acids (n-3) influence arterial cholesterol delivery and lipoprotein lipase (LpL) levels in insulin-resistant mice. METHODS AND RESULTS: Insulin resistance contributes to risk of cardiovascular disease. It was previously reported that saturated fat (SAT) diets increased, but n-3 diets decreased, arterial low-density lipoprotein (LDL) cholesterol deposition from LDL total and selective uptake; this was associated with increased or decreased arterial LpL, respectively. Insulin receptor transgenic knockout mice (L1) were fed a chow, SAT, or n-3 diet for 12 weeks. Double-fluorescent boron dipyrromethene (BODIPY)-cholesteryl ester (CE) and Alexa dye-labeled human LDL were injected to separately trace LDL-CE and LDL apolipoprotein B whole particle uptake. In contrast to SAT, n-3 diets markedly reduced all plasma lipids, ameliorating progression of insulin resistance. As opposed to SAT, n-3 reduced arterial LDL uptake, CE deposition, and selective uptake. Disparate patterns of CE deposition between diets were comparable with arterial LpL distribution; SAT induced high LpL levels throughout aortic media; LpL was limited only to intima in n-3-fed mice. CONCLUSIONS: n-3 diets diminish arterial LDL-cholesterol deposition in mice with insulin resistance, and this is associated with changes in arterial LpL levels and distribution. PMID- 20930168 TI - Alcohol inhibits smooth muscle cell proliferation via regulation of the Notch signaling pathway. AB - OBJECTIVE: To determine the role of Notch signaling in mediating alcohol's inhibition of smooth muscle cell (SMC) proliferation. METHODS AND RESULTS: Treatment of human coronary artery SMCs with ethanol (EtOH) decreased Notch 1 mRNA and Notch 1 intracellular domain protein levels, in the absence of any effect on Notch 3. EtOH treatment also decreased C-promoter binding factor-1 (CBF 1)/recombination signal-binding protein (RBP)-jk promoter activity and Notch target gene (hairy related transcription factor [HRT-1] or HRT-2) expression. These effects were concomitant with an inhibitory effect of EtOH on SMC proliferation. Overexpression of constitutively active Notch 1 intracellular domain or human hairy related transcription factor-1 (hHRT-1) prevented the EtOH induced inhibition of SMC proliferation. In vivo, Notch 1 and HRT-1 mRNA expression was increased after ligation-induced carotid artery remodeling. The vessel remodeling response was inhibited in mice that received "moderate" amounts of alcohol by gavage daily; intimal-medial thickening was markedly reduced, and medial and neointimal SMC proliferating cell nuclear antigen expression was decreased. Moreover, Notch 1 and HRT-1 expression, induced after ligation injury, was inhibited by moderate alcohol consumption. CONCLUSIONS: EtOH inhibits Notch signaling and, subsequently, SMC proliferation, in vitro and in vivo. The modulation of Notch signaling in SMCs by EtOH may be relevant to the cardiovascular protective effects of moderate alcohol consumption purported by epidemiological studies. PMID- 20930169 TI - The I{kappa}B kinase inhibitor nuclear factor-{kappa}B essential modulator binding domain peptide for inhibition of injury-induced neointimal formation. AB - OBJECTIVE: The activation of nuclear factor-kappaB (NF-kappaB) is a crucial step in the arterial wall's response to injury. The identification and characterization of the NF-kappaB essential modulator-binding domain (NBD) peptide, which can block the activation of the IkappaB kinase complex, have provided an opportunity to selectively abrogate the inflammation-induced activation of NF-kappaB. The aim of the present study was to evaluate the effect of the NBD peptide on neointimal formation. METHODS AND RESULTS: In the rat carotid artery balloon angioplasty model, local treatment with the NBD peptide (300 MUg/site) significantly reduced the number of proliferating cells at day 7 (by 40%; P<0.01) and reduced injury-induced neointimal formation (by 50%; P<0.01) at day 14. These effects were associated with a significant reduction of NF kappaB activation and monocyte chemotactic protein-1 expression in the carotid arteries of rats treated with the peptide. In addition, the NBD peptide (0.01 to 1 MUmol/L) reduced rat smooth muscle cell proliferation, migration, and invasion in vitro. Similar results were observed in apolipoprotein E(-/-) mice in which the NBD peptide (150 MUg/site) reduced wire-induced neointimal formation at day 28 (by 47%; P<0.01). CONCLUSIONS: The NBD peptide reduces neointimal formation and smooth muscle cell proliferation/migration, both effects associated with the inhibition of NF-kappaB activation. PMID- 20930170 TI - Oral administration of an active form of vitamin D3 (calcitriol) decreases atherosclerosis in mice by inducing regulatory T cells and immature dendritic cells with tolerogenic functions. AB - OBJECTIVE: To determine whether the administration of an active form of vitamin D(3) (calcitriol) could prevent atherosclerosis through anti-inflammatory actions. METHODS AND RESULTS: Recent clinical studies have shown that lack of vitamin D(3) is a risk factor for cardiovascular events. Oral calcitriol administration decreased atherosclerotic lesions, macrophage accumulation, and CD4(+) T-cell infiltration at the aortic sinus, when compared with the corresponding observations in control mice. We observed a significant increase in Foxp3(+) regulatory T cells and a decrease in CD80(+)CD86(+) dendritic cells (DCs) in the mesenteric lymph nodes, spleen, and atherosclerotic lesions in oral calcitriol-treated mice in association with increased interleukin 10 and decreased interleukin 12 mRNA expression. CD11c(+) DCs from the calcitriol group showed reduced proliferative activity of T lymphocytes, suggesting the suppression of DC maturation. Neutralization of CD25 in vivo revealed that calcitriol inhibited atherosclerosis mainly in a regulatory T cell-dependent manner but also partly because of a decrease in DC maturation. CONCLUSIONS: Oral calcitriol treatment could prevent the development of atherosclerosis by changing the function or differentiation of DCs and regulatory T cells. These findings suggest that intestinal and systemic immune modulation by calcitriol may be a potentially valuable therapeutic approach against atherosclerosis. PMID- 20930171 TI - Hypoxia and upregulation of hypoxia-inducible factor 1{alpha} stimulate venous thrombus recanalization. AB - OBJECTIVE: Angiogenic factors are expressed within thrombus during resolution, but the primary stimulus for neovascularization is unknown. Our aims were to determine whether (1) hypoxia and hypoxia-inducible factor 1alpha (HIF1alpha) are induced in resolving thrombus, (2) this stimulates angiogenic factor production, and (3) upregulating HIF1alpha enhances thrombus resolution and vein recanalization. METHODS AND RESULTS: Oxygen tension in the thrombus was negatively correlated with HIF1alpha levels (Spearman correlation [RS] = -0.77, P<0.0001), whereas HIF1alpha levels positively correlated with vascular endothelial growth factor (VEGF) expression (Pearson correlation [R] = 0.85, P<0.0005), during resolution in a murine model. HIF1alpha (P<0.005), VEGF (P<0.005), and VEGF receptor 1 (VEGFR1) (P<0.05) expression was 2-fold greater in the thrombus of mice treated with the prolyl hydroxylase domain inhibitor L mimosine compared with controls. The levels of 13 other HIF1-mediated angiogenic factors were also increased. Thrombus weight (P<0.001) and volume (P<0.05) were reduced by a third in l-mimosine-treated mice compared with controls, whereas vein recanalization (P<0.005) and thrombus neovascularization (P<0.001) were 2 fold greater, and this was associated with increased inflammatory cell content. CONCLUSIONS: Hypoxia and HIF1alpha are induced in the naturally resolving thrombus and correlate with increased angiogenic factor expression. Upregulation of HIF1alpha enhances thrombus resolution and vein recanalization. HIF1alpha may represent a novel target for treatments that promote resolution and recanalization and reduce the incidence of post-thrombotic syndrome. PMID- 20930172 TI - Activation of protease-activated receptors 3 and 4 accelerates tissue factor induced thrombin generation on the surface of vascular smooth muscle cells. AB - OBJECTIVE: To determine factors regulating human aortic smooth muscle cells (HASMC) supported tissue factor-induced thrombin generation. METHODS AND RESULTS: The addition of nonlipidated tissue factor and Ca(2+) to HASMCs maintained in reptilase-treated platelet-poor plasma resulted in the robust formation of thrombin after a lag phase of approximately 6 minutes. Pretreatment with low concentrations of alpha-thrombin before the addition of tissue factor and Ca(2+) accelerated the rate of thrombin generation (time to reach half of peak thrombin was reduced by [mean +/- SD] 42.0 +/- 2.2%; P<0.05) but had no effect on the amount of peak thrombin generated. Protease-activated receptor (PAR) 3 activating peptides (APs) or PAR-4 APs accelerated thrombin generation without affecting peak thrombin levels (time to half of peak thrombin decreased by 17.4 +/- 5.6% and 21.7 +/- 3.5%; P<0.05 with PAR-3 AP and PAR-4 AP, respectively). The addition of PAR-3 AP and PAR-4 AP together had an additive effect, with a reduction in time to half of peak thrombin of 43.9 +/- 4.0%. PAR-3 AP or PAR-4 AP enhanced tissue factor-induced factor Xa production and phosphatidylserine exposure on the surface of HASMCs. PAR-1 activation had no effect on thrombin generation, factor Xa production, or phosphatidylserine exposure. CONCLUSIONS: Low concentrations of alpha-thrombin accelerate tissue factor-induced thrombin generation on the surface of HASMCs, and this effect is mediated by PAR-3 and PAR-4. PMID- 20930173 TI - CD4+CD25+Foxp3+ regulatory T cells protect the proinflammatory activation of human umbilical vein endothelial cells. AB - OBJECTIVE: To investigate the role of CD4(+)CD25(+)forkhead box P 3 (Foxp3)(+) T regulatory cells (Tregs) in protecting the activation and function of human umbilical vein endothelial cells (HUVECs) induced by proinflammatory stimulus and the mechanisms of it. METHODS AND RESULTS: ECs play a major role in atherogenic initiation, changing their quiescence into activated phenotypes to support every phase of the inflammatory process. HUVECs were incubated alone, with Tregs or CD4(+)CD25(-) T cells in the presence of anti-CD3 monoclonal antibodies for 48 hours, and then were stimulated with or without oxidized low-density lipoprotein/lipopolysaccharide for an additional 24 hours. Tregs are able to induce alternative expression of immune phenotypic markers of activated HUVECs by down modulating CD86 and to inhibit the adhesion molecule, such as vascular cell adhesion molecule-1 (VCAM-1) and proinflammatory cytokine (eg, monocyte chemoattractant protein-1 and interleukin 6), response of HUVECs to oxidized low density lipoprotein/lipopolysaccharide. Moreover, Tregs downregulate proinflammatory factor nuclear factor-kappaB activation and induce resistance to suppression of anti-inflammatory factor Kruppellike factor 2 in HUVECs induced by a proinflammatory stimulus. Mechanism studies reveal that Treg-mediated suppression of HUVEC proinflammatory cytokines and adhesion molecule expression impaired by oxidized low-density lipoprotein/lipopolysaccharide require cell contact by cytotoxic T-lymphocyte antigen-4 and CD86 and by soluble factors (mainly interleukin 10 and transforming growth factor [TGF]-beta). CONCLUSIONS: Tregs may exert their protective effects against atherogenesis in part through inducing an immune-inhibitory phenotype of ECs involving cytotoxic T-lymphocyte antigen-4-dependent cell-to-cell contact and also requiring soluble factors (mainly interleukin 10 and TGF-beta). PMID- 20930174 TI - Psychometric testing of the Gordon Facial Muscle Weakness Assessment Tool. AB - School nurses may be the first health professionals to assess the onset of facial paralysis/muscle weakness in school-age children. The purpose of this study was to test the psychometric properties of the Gordon Facial Muscle Weakness Assessment Tool (GFMWT) developed by Gordon. Data were collected in two phases. In Phase 1, 4 content experts independently rated each of the 22 items on the GFMWT for content relevance. The ratings were used to generate Item and Scale Content Validity Index (CVI) scores. In Phase 2, school nurses (N = 74) attending a state conference independently rated referral urgency on a set of 10 clinical scenarios using the GFMWT. The GFMWT had an item and scale CVI of 1.0. Overall, the interrater reliability was .602 (p < .001). When used by school nurses, the GFMWT was shown to be both a reliable and a valid tool to assess facial muscle weakness in school-age children. PMID- 20930176 TI - Uptake of prenatal HIV testing in Hai Phong Province, Vietnam. AB - The objective of the study is to describe the uptake of prenatal HIV testing among Vietnamese women. Exit interviews were conducted among 300 women who had delivered at Hai Phong obstetrical hospital. Information about socioeconomic characteristics and HIV testing was obtained through structured questionnaire interviews. It was found that 45% of the women were tested for HIV before the end of 34 weeks of gestation, 5% in 35 to 40 weeks of gestation, and 55% at labor. Low educational levels, being a farmer or worker, having a low income, and living close to the hospital were associated with being tested at labor. When adjusting for possible confounders, however, living more than 15 km from the hospital was the only factor, which remained significantly associated with HIV testing during labor (odds ratio = 2.15; confidence interval = 1.14-4.04). The results suggest that many Vietnamese women are not tested for HIV during prenatal care and that a relationship exists between distance to the hospital and lack of HIV testing during pregnancy. PMID- 20930177 TI - The Bahasa Melayu version of the Nursing Stress Scale among nurses: a reliability study in Malaysia. AB - The Nursing Stress Scale (NSS) has been shown to be a valid and reliable instrument to assess occupational stressors among nurses. The NSS, which was previously used in the English version, was translated and back-translated into Bahasa Melayu. This study was conducted to assess the reliability of the Bahasa Melayu version of the NSS among nurses for future studies in this country. The reliability of the NSS was assessed after its readministration to 30 nurses with a 2-week interval. The Spearman coefficient was calculated to assess its stability. The internal consistency was measured through 4 measures: Cronbach's alpha, Spearman-Brown, Guttman split-half, and standardized item alpha coefficients. The total response rate was 70%. Test-retest reliability showed remarkable stability (Spearman's rho exceeded .70). All 4 measures of internal consistency among items indicated a satisfactory level (coefficients in the range of .68 to .87). In conclusion, the Bahasa Melayu version of the NSS is a reliable and useful instrument for measuring the possible stressors at the workplace among nurses. PMID- 20930179 TI - Trauma-related symptoms in neglected preschoolers and affective quality of mother child communication. AB - This study (a) assessed whether child neglect is associated with posttraumatic stress disorder (PTSD) and dissociative symptoms in the preschool period and (b) examined the role of quality of mother-child affective communication in the development of trauma-related symptoms among neglected children. Participants were 33 neglected and 72 non-neglected preschoolers (mean age = 60 months). Neglected children were recruited from the Child Protection Agencies. Neglected and non-neglected children victims of other form of abuse were excluded from the study. Trauma symptoms were evaluated through mother and preschool teacher reports. Quality of mother-child affective communication was assessed in a lab visit during an unstructured task. According to teachers, neglected children displayed more PTSD and dissociative symptoms than non-neglected children. Quality of mother-child communication was lower in neglected dyads. Mother-child affective communication predicted teacher-reported child trauma symptomatology, over and above child neglect. Discussion focuses on the traumatic nature of child neglect and the underlying parent-child relational processes. PMID- 20930180 TI - No follow-up after positive newborn screening: medical neglect? AB - The current study examined medical professionals' behaviors related to reporting medical neglect when a family is noncompliant with follow-up services after a positive newborn screening result. Pediatric medical professionals within an urban medical campus were provided with five case vignettes in relation to different diseases. Medical professionals rated the severity of family noncompliance with follow-up services and indicated whether they would report suspected medical neglect to Child Protective Services (CPS). Physicians were more likely to report medical neglect than the other mandated reporters in the study. Logistic regression analyses found that medical professionals' perceptions of the severity of family noncompliance with services were significantly predictive of decisions to report medical neglect. Respondent gender and the method by which families were notified of screening results also significantly affected reporting behaviors in certain instances. Although all vignettes included information that met legal statutes for reporting neglect, medical professionals indicated that they would only report neglect 40-61% of the time across vignettes. Continued investigation of the rationale behind medical professionals' decision-making process and training protocols designed to improve mandated reporter knowledge and reporting behaviors are needed to further reduce bias and improve objectivity when considering ethical and professional obligations to report medical neglect. PMID- 20930181 TI - Child maltreatment and women's adult sexual risk behavior: childhood sexual abuse as a unique risk factor. AB - This study investigated (a) whether childhood sexual abuse (CSA) was uniquely associated with adult sexual risk behavior, after controlling for other types of childhood maltreatment and (b) whether there were additive or interactive effects of different types of maltreatment on adult sexual risk behavior. Participants were 414 women (M age = 28 years) attending a publicly funded STD clinic. All women completed a computerized survey assessing childhood maltreatment (sexual, physical, psychological abuse, and neglect) and sexual risk behavior. Analyses showed that sexual abuse, physical abuse, psychological abuse, and neglect were associated with adult sexual risk behavior. Multivariate analyses that controlled for all other forms of child maltreatment showed that only CSA was uniquely associated with adult sexual risk behavior (i.e., percentage of episodes of unprotected sex in the past 3 months and number of lifetime partners). The authors found little support for an additive or an interactive model of the effects of different types of childhood maltreatment on adult sexual risk behavior; CSA alone was the best predictor of adult sexual risk behavior. Sexual risk reduction interventions are needed for women who were sexually abused as children. Continued research on the effects of multitype maltreatment on adult sexual risk behavior is needed. PMID- 20930185 TI - Ten steps in training volunteer support group facilitators. AB - Caregiver support groups are often led by volunteer lay leaders who might have personal experiences with Alzheimer's disease. This article offers 10 steps in what to consider and how to conduct training for these lay leaders so that the success of the support groups can be maximized. Steps include helping trainees understand their own feelings and the feelings of their group members as well as teaching about the stages that groups typically experience from beginning to termination and the role of the leader at each stage. PMID- 20930186 TI - Effects of prescribed medications on cognition and behavior in frontotemporal lobar degeneration. AB - A retrospective chart review of 21 patients meeting core clinical criteria for behavioral or aphasic variants of frontotemporal lobar degeneration (FTLD) was conducted. Data recorded included Folstein Mini-Mental State Examination (MMSE) scores, medications prescribed, and subjective reports of behavioral symptoms from each visit. Behaviors were graded on a scale from 1 to 3 and totaled for each visit. Changes in MMSE and behavior scores between visits 1 month and 6 months apart where a new medication was started were analyzed using a paired t test and were compared between medication classes using an unpaired t test. Acetylcholinesterase inhibitors (AChEIs) were associated with a decrease in MMSE scores by 1.6 (P = .02) and an increase in total behavior scores by 1.0 (P = .03). Mean MMSE and behavior scores were statistically more improved by selective serotonin reuptake inhibitors than AChEIs (P = .04). This data suggest a potential worsening of objective measures of cognitive and behavioral symptoms in FTLD with AChEI treatment. PMID- 20930187 TI - The generation effect in patients with mild cognitive impairment. AB - The generation effect (GE) has been proven as an effective technique to improve learning and memory in healthy and clinical populations. However, it has not been found with meaningless materials such as pseudowords. Several hypotheses postulate the participation of semantic memory in the information-generating process. There is indeed a clear decrease in the effect in patients with serious semantic memory disorders, such as Alzheimer's disease (AD) but, if this is correct, other patients whose memory disorders are not so serious, such as mild cognitive impairment (MCI), should show GE to some extent. To test this hypothesis, we examined 54 participants (18 healthy adults, 18 patients with AD, and 18 with MCI) in a task involving reading and completion of phrases. Results show a decreased (although obvious) GE in patients with MCI. Likewise, results indicate that greater semantic damage will lead to poorer performance with less familiar stimuli or low-frequency words. PMID- 20930189 TI - An examination of the predictive validity of the risk matrix 2000 in England and wales. AB - This study examined the predictive validity of an actuarial risk-assessment tool with convicted sexual offenders in England and Wales. A modified version of the RM2000/s scale and the RM2000 v and c scales (Thornton et al., 2003) were examined for accuracy in predicting proven sexual violent, nonsexual violent, and combined sexual and/or nonsexual violent reoffending in a sample of sexual offenders who had either started a community sentence or been released from prison into the community by March 2007. Rates of proven reoffending were examined at 2 years for the majority of the sample (n = 4,946), and 4 years ( n = 578) for those for whom these data were available. The predictive validity of the RM2000 scales was also explored for different subgroups of sexual offenders to assess the robustness of the tool. Both the modified RM2000/s and the complete v and c scales effectively classified offenders into distinct risk categories that differed significantly in rates of proven sexual and/or nonsexual violent reoffending. Survival analyses on the RM2000/s and v scales (N = 9,284) indicated that the higher risk groups offended more quickly and at a higher rate than lower risk groups. The relative predictive validity of the RM2000/s, v, and c, as calculated using Receiver Operating Characteristics (ROC) analyses, were moderate (.68) for RM2000/s and large for both the RM2000/c (.73) and RM2000/v (.80), at the 2-year follow-up. RM2000/s was moderately accurate in predicting relative risk of proven sexual reoffending for a variety of subgroups of sexual offenders. PMID- 20930190 TI - Men with ED also report changes in orgasmic sensations. PMID- 20930191 TI - Genetic regulation of prostate development. AB - Prostatic development is a dynamic process in which basic mechanisms of epithelial outgrowth and epithelial-mesenchymal interaction are initiated by androgens and androgen receptor signaling. Even in adulthood, the prostate's function remains tightly regulated by androgens--without them, pathologic diseases, including hyperplastic and malignant growth that together plague nearly 50% of aging males, do not occur. Unraveling the etiology of these pathologic processes is a complex and important goal. In fact, many insights into these processes have come from an intimate understanding of the complex signaling networks that regulate physiologic prostatic growth in development. This review aims to highlight important key molecules such as Nkx3.1, sonic hedgehog, and Sry box 9, as well as key signaling pathways including the fibroblast growth factor and wingless pathways. These molecules and pathways are critical for prostate development with both known and postulated roles in prostatic pathology. PMID- 20930193 TI - Development of bovine fetal testis tissue after ectopic xenografting in mice. AB - Testis tissue xenografting represents a versatile model to study testis biology, and to preserve fertility in immature animals. To evaluate whether bovine fetal testes can mature when grafted into mouse hosts, small fragments of testes from midgestation (125 to 145 days of gestation) bovine fetuses were grafted ectopically into immunodeficient castrated male mice. At grafting, donor tissue displayed the typical seminiferous cords composed of gonocytes and primitive Sertoli cells. At 5 or 10 months after grafting, weight of the seminal vesicles in recipient mice was indicative of production of bioactive testosterone by xenografts. Xenografts showed similar development regardless of donor age. At 5 months, tubule formation occurred but germ cell differentiation had not proceeded beyond the spermatogonia stage. At 10 months, an increase in tubule size was evident and pachytene spermatocytes were observed as the most advanced type of germ cells in the xenografts of 2 donors. The number of tubules with germ cells was reduced in xenografts compared to donor tissue, but at 10 months the number of germ cells per tubule was higher than in donors. Germ cell proliferation was similar in donor tissue and xenografts. However, Sertoli cells showed a higher proliferation rate in xenografts collected at 5 months than in donor fetal testes and xenografts collected at 10 months. Sertoli cells in xenografts showed a progressive but incomplete loss of expression of Mullerian inhibiting substance and weak androgen receptor expression, indicating an incomplete Sertoli cell maturation. In conclusion, fetal testis tissue developed partially, qualitatively similar to pubertal testes in situ. PMID- 20930192 TI - Genetically induced estrogen receptor alpha mRNA (Esr1) overexpression does not adversely affect fertility or penile development in male mice. AB - Previously, we reported that estrogen receptor alpha mRNA (Esr1) or protein (ESR1) overexpression resulting from neonatal exposure to estrogens in rats was associated with infertility and maldeveloped penis characterized by reduced length and weight and abnormal accumulation of fat cells. The objective of this study was to determine if mutant male mice overexpressing Esr1 are naturally infertile or have reduced fertility and/or develop abnormal penis. The fertility parameters, including fertility and fecundity indices, numbers of days from the day of cohabitation to the day of delivery, and numbers of pups per female, were not altered from controls as a result of Esr1 overexpression. Likewise, penile morphology, including the length, weight, and diameter and os penis development, was not altered from controls. Conversely, weights of the seminal vesicles and bulbospongiosus and levator ani (BS/LA) muscles were significantly (P < .05) lower as compared with controls; however, the weight of the testis, the morphology of the testis and epididymis, and the plasma and testicular testosterone concentration were not different from controls. Hence, genetically induced Esr1 overexpression alone, without an exogenous estrogen exposure during the neonatal period, is unable to adversely affect the development of the penis as well as other male reproductive organs, except for limited, but significant, reductions in weights of the seminal vesicles and BS/LA muscles. PMID- 20930195 TI - Thoracic surgery and lung transplantation: Thoracic Surgery Assembly contribution to the celebration of 20 years of the ERS. PMID- 20930194 TI - Distribution of alpha- and delta-tocopherols in seminal plasma and sperm fractions of men with normal and abnormal semen parameters. AB - The aim of this study was to investigate the presence of the different isoforms of tocopherol (T) in seminal plasma (P) and in the sperm fractions of individuals with abnormal (group 1) and normal (group 2) sperm parameters; the relationships between these isoforms and conventional sperm parameters were also explored. Two vitamin E homologues, alpha-T and delta-T, were identified in the semen of all participants. Although alpha-T and delta-T concentrations were similar in the semen of the 2 groups, group 1 showed a lower alpha-T ratio (S/P) (0.90 vs. 1.20, P < .001) and delta-T ratio (0.86 vs 1.13, P = .007) than group 2. In addition, both T ratios were correlated with the percentage of viable cells, detected by eosin staining. These results suggested that alpha-T and delta-T are not homogeneously distributed in the semen fractions; in normal semen they are more concentrated in the sperm membrane, whereas in abnormal semen the damaged sperm cells may release both Ts in the plasma. To verify whether sperm membrane breakage could alter alpha-T and delta-T distribution between the seminal plasma and the spermatozoa, normal sperm samples were sonicated; after sonication a consistent sperm plasma membrane fragmentation, highlighted by transmission electron microscopy, and a concomitant release of alpha-T and delta-T were observed. In conclusion, the Ts coupled directly with the sperm membrane seem to play the main protective role in the semen, and the release of alpha-T and delta T in the P fraction is probably an index of lower antioxidant power and sperm quality. PMID- 20930196 TI - Slaying the CVD dragon with steroids. PMID- 20930197 TI - Do bacteria have a role in asthma development? PMID- 20930198 TI - Use of cluster analysis to define COPD phenotypes. PMID- 20930199 TI - Extensively drug-resistant tuberculosis: back to the future. PMID- 20930200 TI - European Curriculum Recommendations for Training in Paediatric Respiratory Medicine: one step further. PMID- 20930201 TI - Comorbidities of asthma during childhood: possibly important, yet poorly studied. AB - Asthma in adults is associated with comorbidities such as obesity, gastro oesophageal reflux, dysfunctional breathing and mental disorders. Herein, we provide an overview of the current state of evidence on these comorbidities in childhood asthma. The prevalence, known mechanisms and possible treatment options for each comorbid condition will be discussed. Obesity is an increasing health problem in children, but its relationship with asthma remains unclear. Allergic rhinitis is a very common comorbidity in asthma, both in children and in adults, but its effect on childhood asthma severity has not been studied. The prevalence and treatment options of dysfunctional breathing, a known comorbidity in adult asthma, have not yet been studied in paediatric asthma. Food allergies appear to cause more severe reactions in patients with asthma. Depressive disorders are more prevalent in childhood asthma than in healthy children, but seem to be poorly recognised and treated in children. Although gastro-oesophageal reflux is commonly thought to be a comorbid disease complicating asthma, it remains uncertain whether treatment improves asthma control. In conclusion, knowledge of asthma comorbidities in childhood is sparse. Further studies are urgently needed to identify the prevalence, and, more importantly, the effects of these comorbidities and their treatment on the degree of asthma control in children. PMID- 20930202 TI - Using a whole-blood interferon-{gamma} assay to improve diagnosis of tuberculous pleural effusion. PMID- 20930203 TI - Endogenous and nitrovasodilator-induced release of NO in the airways of end-stage cystic fibrosis patients. PMID- 20930204 TI - A role for ITPA variants in the clinical course of pulmonary Langerhans' cell histiocytosis? PMID- 20930205 TI - Quadriceps myostatin expression in COPD. PMID- 20930206 TI - Exposure at high altitude and exercise altered membrane diffusion capacity of the lung. PMID- 20930207 TI - Exhaled nitric oxide and COPD. PMID- 20930208 TI - New concepts for expressing forced expiratory volume in 1 s: conclusions need nuances. PMID- 20930209 TI - Pirfenidone in idiopathic pulmonary fibrosis. PMID- 20930211 TI - Improved functional recovery after facial nerve reconstruction by temporary denervation of the contralateral mimic musculature with botulinum toxin in rats. AB - BACKGROUND: Even optimal nerve reconstruction after facial nerve damage leads to defective reinnervation because of misdirected axonal sprouting and polyinnervation of the end plates of the facial muscles. OBJECTIVE: The authors studied whether temporary chemical denervation of the contralateral nonlesioned hemiface with botulinum toxin (BTX) would increase regeneration of the lesioned buccal branch of the facial nerve and improve functional recovery of the whisker pad. METHODS: The experiments were performed in 65 adult rats distributed in 4 interventions: (1) buccal-buccal nerve anastomosis (BBA), (2) BBA plus ipsilateral injection of BTX into the whisker pad, (3) BBA plus contralateral BTX injection, or (4) BTX injection without any surgery. Sequential preoperative and postoperative retrograde fluorescence tracing at 4 weeks after surgery quantified the accuracy of reinnervation. Functional recovery was measured by biometrical image analysis of whisking behavior at 12 weeks after surgery. RESULTS: After BTX injection without any surgery, muscle paralysis was transient, and the animals restored normal nerve terminals and normal vibrissal function at 8 weeks after treatment. After BBA and ipsilateral or contralateral BTX injection, the degree of correct reinnervation increased significantly to 61% in comparison to 27% after BBA without any other intervention. Enhanced correct reinnervation was accompanied by a significant improvement of whisking after contralateral but not after ipsilateral injection of BTX. CONCLUSIONS: These results provide evidence that transient contralateral muscle paralysis helps improve the morphological and functional regeneration after facial nerve repair. PMID- 20930213 TI - A high-throughput, homogeneous, fluorescence polarization assay for inhibitors of hedgehog protein autoprocessing. AB - Hedgehog (Hh) signaling plays an important role in embryonic patterning and adult stem cell renewal but has recently been found also to be involved in certain stem cell cancers. One of the first steps in Hh signaling is the autoprocessing of Hh protein, in which the C-terminal domain (Hh-C) catalyzes a cholesterol-dependent autocleavage reaction that leads to the production of the cholesterol ester of the N-terminal Hh domain (Hh-N), thereby yielding a signaling molecule that activates the Hh pathway by binding to the Patched receptor. This article describes an in vitro, homogeneous assay system that measures changes in fluorescence polarization that accompany the cholesterol-dependent autocleavage of Hh protein. The assay system makes use of a modified Hh protein in which Hh-N, which is not essential for autocleavage, is replaced by a 25-residue peptide containing a tetracysteine motif, complexed with a bisarsenical fluorophore. The assay is quite robust and easily adapted to high-throughput screening in 384-well plates with Z' factors above 0.8. It has been used to screen the National Institutes of Health Clinical Collection, which has led to the identification of 2 compounds that inhibit the cholesterol-dependent autocleavage of Hh protein at micromolar concentrations. PMID- 20930212 TI - Bilateral and unilateral arm training improve motor function through differing neuroplastic mechanisms: a single-blinded randomized controlled trial. AB - BACKGROUND AND PURPOSE: This randomized controlled trial tests the efficacy of bilateral arm training with rhythmic auditory cueing (BATRAC) versus dose-matched therapeutic exercises (DMTEs) on upper-extremity (UE) function in stroke survivors and uses functional magnetic resonance imaging (fMRI) to examine effects on cortical reorganization. METHODS: A total of 111 adults with chronic UE paresis were randomized to 6 weeks (3*/week) of BATRAC or DMTE. Primary end points of UE assessments of Fugl-Meyer UE Test (FM) and modified Wolf Motor Function Test Time (WT) were performed 6 weeks prior to and at baseline, after training, and 4 months later. Pretraining and posttraining, fMRI for UE movement was evaluated in 17 BATRAC and 21 DMTE participants. RESULTS: The improvements in UE function (BATRAC: FM Delta = 1.1 + 0.5, P = .03; WT Delta = -2.6 + 0.8, P < .00; DMTE: FM Delta = 1.9 + 0.4, P < .00; WT Delta = -1.6 + 0.7; P = .04) were comparable between groups and retained after 4 months. Satisfaction was higher after BATRAC than DMTE (P = .003). BATRAC led to significantly higher increase in activation in ipsilesional precentral, anterior cingulate and postcentral gyri, and supplementary motor area and contralesional superior frontal gyrus (P < .05). Activation change in the latter was correlated with improvement in the WMFT (P = .01). CONCLUSIONS: BATRAC is not superior to DMTE, but both rehabilitation programs durably improve motor function for individuals with chronic UE hemiparesis and with varied deficit severity. Adaptations in brain activation are greater after BATRAC than DMTE, suggesting that given similar benefits to motor function, these therapies operate through different mechanisms. PMID- 20930214 TI - A homogeneous, high-throughput fluorescence anisotropy-based DNA supercoiling assay. AB - The degree of supercoiling of DNA is vital for cellular processes, such as replication and transcription. DNA topology is controlled by the action of DNA topoisomerase enzymes. Topoisomerases, because of their importance in cellular replication, are the targets of several anticancer and antibacterial drugs. In the search for new drugs targeting topoisomerases, a biochemical assay compatible with automated high-throughput screening (HTS) would be valuable. Gel electrophoresis is the standard method for measuring changes in the extent of supercoiling of plasmid DNA when acted upon by topoisomerases, but this is a low throughput and laborious method. A medium-throughput method was described previously that quantitatively distinguishes relaxed and supercoiled plasmids by the difference in their abilities to form triplex structures with an immobilized oligonucleotide. In this article, the authors describe a homogeneous supercoiling assay based on triplex formation in which the oligonucleotide strand is labeled with a fluorescent dye and the readout is fluorescence anisotropy. The new assay requires no immobilization, filtration, or plate washing steps and is therefore well suited to HTS for inhibitors of topoisomerases. The utility of this assay is demonstrated with relaxation of supercoiled plasmid by Escherichia coli topoisomerase I, supercoiling of relaxed plasmid by E. coli DNA gyrase, and inhibition of gyrase by fluoroquinolones and nalidixic acid. PMID- 20930215 TI - Development of a high-throughput screen for inhibitors of Epstein-Barr virus EBNA1. AB - Latent infection with Epstein-Barr virus (EBV) is a carcinogenic cofactor in several lymphoid and epithelial cell malignancies. At present, there are no small molecule inhibitors that specifically target EBV latent infection or latency associated oncoproteins. EBNA1 is an EBV-encoded sequence-specific DNA binding protein that is consistently expressed in EBV-associated tumors and required for stable maintenance of the viral genome in proliferating cells. EBNA1 is also thought to provide cell survival function in latently infected cells. In this work, the authors describe the development of a biochemical high-throughput screening (HTS) method using a homogeneous fluorescence polarization (FP) assay monitoring EBNA1 binding to its cognate DNA binding site. An FP-based counterscreen was developed using another EBV-encoded DNA binding protein, Zta, and its cognate DNA binding site. The authors demonstrate that EBNA1 binding to a fluorescent-labeled DNA probe provides a robust assay with a Z factor consistently greater than 0.6. A pilot screen of a small-molecule library of ~14,000 compounds identified 3 structurally related molecules that selectively inhibit EBNA1 but not Zta. All 3 compounds had activity in a cell-based assay specific for the disruption of EBNA1 transcription repression function. One of the compounds was effective in reducing EBV genome copy number in Raji Burkitt lymphoma cells. These experiments provide a proof of concept that small-molecule inhibitors of EBNA1 can be identified by biochemical HTS of compound libraries. Further screening in conjunction with medicinal chemistry optimization may provide a selective inhibitor of EBNA1 and EBV latent infection. PMID- 20930216 TI - An automated high-content assay for tumor cell migration through 3-dimensional matrices. AB - High-content tumor cell migration assays in 3-dimensional (3D) extracellular matrix are a powerful tool for modeling and understanding the biology of this critical step in the process of metastasis. Currently available methods offer very limited throughput and are not amenable to studies of comparative pharmacology or small-scale screening. The authors present an automated approach to high-content tumor cell migration assays. A standard screening-sized plate with an array of microchannels was designed and constructed from common thermoplastics. After filling the channels with 3D matrix, cells were placed at one end of the channel, and migration into the channel was monitored via an imaging system. All liquid-handling steps were performed by standard liquid handling robotics. Tumor cell migration in the channel was truly 3D and correlated with metastatic potential. The information-rich data from these assays were used to rank the potency of compounds inhibiting migration through 3D collagen as well as to gain additional insights into the compounds' activities related to cell health. This approach is compatible with a variety of multiparametric, morphological, and/or kinetic readouts. PMID- 20930217 TI - A high-throughput analysis method to detect regions of interest and quantify zebrafish embryo images. AB - Zebrafish is widely used to understand neural development and model various neurodegenerative diseases. Zebrafish embryos are optically transparent, have a short development period, and can be kept alive in microplates for days, making them amenable to high-throughput microscopic imaging. As a result of high throughput experiments, a large number of images can be generated in a single experiment, posing a challenge to researchers to analyze them efficiently and quantitatively. In this work, we develop an image processing focused on detecting and quantifying pigments in zebrafish embryos. The algorithm automatically detects a region of interest (ROI) enclosing an area around the pigments and then segment the pigments for quantification. In this process, the algorithm identifies the head and torso at first, and then finds the boundaries corresponding to the back and abdomen by taking advantage of a priori information about the anatomy of zebrafish embryos. The method is robust in terms that it can detect and quantify pigments even when the embryos have different orientations and curvatures. We used real data to demonstrate the performance of the method to extract phenotypic information from zebrafish embryo images and compared its results with manual analysis for verification. PMID- 20930218 TI - The missing men: high risk of disease in men of Mexican origin. AB - The present study sought to determine gender- and age-specific prevalences of chronic diseases in an urban Mexican American border community. The Cameron County Hispanic Cohort (CCHC; n = 2,000) was selected using a multistaged cluster design. Sociodemographics, anthropometric measures, and blood samples were collected on each participant. More women were obese (55.1%) than men (44.8%). Men had significantly higher rates of diabetes (20.4% for men vs. 15.8% for women, p < .05) and undiagnosed diabetes (6.2% for men vs. 2.4% for women, p < .01); the prevalence of diabetes rose steeply between the ages of 40 and 49 years. Men were significantly more likely to have serum cholesterol levels of 200 mg/dL and elevated low-density lipoprotein levels (22.6% vs. 26.1%, p < .01). Mexican American males in the U.S./Mexico border region have a high prevalence of obesity in younger men and higher overall rates of diabetes, including undiagnosed diabetes, and significantly higher serum cholesterol levels than women. PMID- 20930219 TI - Breast milk expression and maintenance in mothers of very low birth weight infants: supports and barriers. AB - The study objective was to identify patterns of factors that supported or hindered initiation of breast milk expression and maintenance of breast milk production after the birth of a very low birth weight (VLBW) infant in a sample of US women with varied prenatal infant feeding intentions. In-depth interviews were conducted 1 to 6 months after delivery in 32 women who initiated breast milk expression after encouragement from hospital staff. Pregnancy complications, anxiety regarding their infant's health, and lack of privacy interfered with initiation of milk expression. After hospital discharge, using manual or small electric breast pumps, travel to the neonatal intensive care unit, return to work, and difficulty with time management interfered with maintenance of breast milk production. Family support, positive attitudes toward pumping, and anticipation of breastfeeding supported maintenance of breast milk production. From these data emerge points of intervention where additional support could improve mothers' experiences and increase duration of breast milk feeding. PMID- 20930220 TI - The role of enrichment programs in strengthening the academic Pipeline to dental education. AB - Academic enrichment programs can be essential to efforts by dental schools to recruit and enroll underrepresented minority students (URM). Many summer academic enrichment programs provide additional preparation and support to URM students in the sciences. They often address barriers to student achievement such as unevenness in academic preparation, less rigorous educational background, family influence on preparation aspiration and success, unease in a new setting, and lack of professional role models. To be successful, these programs must address both the academic and social complexities of URM students and often require a range of programs to meet the specific needs of different student groups. PMID- 20930221 TI - Reflections on the dental Pipeline program's efforts regarding underrepresented minority dental students. PMID- 20930222 TI - Suggestions for further reading. PMID- 20930223 TI - Infrastructure for a community-based dental education program: students and clinics. AB - The infrastructure of a community-based dental education program is important to its success. Thorough preparation of students for the community experience and careful selection of community clinical sites are indispensable. Student training in cultural competence, early community exposure, third-year clinical training, assignment of students to rotations, transportation, and housing all need careful attention. When selecting sites for the community rotation, it is important to have detailed site criteria or a wish list, a memorandum of understanding, and awareness of legal liability issues. PMID- 20930224 TI - Management of experiences in community-based dental education. AB - The successful management of community-based service-learning relies on developing and maintaining community partnerships that meet both the educational mission of the dental school and the service mission of the community clinic. The partnership enhances the dental curriculum by introducing students to a wide variety of practice models, patient populations, and perspectives on health care delivery systems. The partnership enhances the service mission of the community sites by providing them with a university affiliation, a window into the state-of the-art techniques that students bring with them from the dental school, and a pool of future graduates who may choose to practice in that clinic setting. This "win-win" scenario is not automatic, but rather relies on carefully matching, maintaining, and evaluating the service-learning partnerships. This article describes the development and implementation of the community-based service learning curriculum in the College of Dentistry, University of Illinois at Chicago. PMID- 20930225 TI - Financial impact of community-based dental education. AB - The financial impact of community-based dental education on dental school and community clinic budgets is a major issue. The evidence suggests that community experiences for dental students of fifty or more days, if effectively managed, can increase school net revenues due to the following factors: 1) the community rotations increase student productivity, approximating the loss of dental school clinical income; 2) the reallocation of unused clinical resources at the dental school reduces student clinic deficits; 3) schools and federally qualified health centers (FQHCs) that share surplus student patient revenues generate additional net income; and 4) enrollment of more students without additional new facilities and faculty increases total school tuition revenues. For FQHC dental clinics, student rotations increase the number of patients treated and may generate surplus revenues. Community-based dental education also provides schools and clinics important non-financial advantages. PMID- 20930226 TI - The impact of community-based dental education on students. AB - Community-based dental education (CBDE) shifts a substantial portion of dental clinical education from dental school clinics to mainly public health settings. For dental students to learn effectively in community settings they need preparatory education in cultural awareness, communication skills, and the social and behavioral sciences. The effective integration of CBDE into a dental curriculum requires reflective components, evaluation, and highly organized community-based experiences. This chapter reviews organizational principles and specific strategies to ensure that CBDE is conducted in a fashion that enables student learning and community oral health service. CBDE has substantial potential for affecting the values and behaviors of dental students relative to health care access for underserved populations and for attracting diverse students to dental education. CBDE also provides dentistry with an opportunity to guide dental faculty and student values and orientation towards public service, engagement, ethics, and the health of the public. PMID- 20930227 TI - Preface: about the dental Pipeline program. PMID- 20930228 TI - The experiences of community dental clinic directors with dental students and dental school collaborations. PMID- 20930229 TI - Reflections on the dental Pipeline program's efforts regarding community-based dental education. AB - Although many changes are being made, many are still needed in educating future dental professionals about prevention programs, ethics, professionalism, communication, cultural competence, and access to care. It is not yet clear if producing more dentists will put these professionals into underserved areas where they are needed, with the skills they need. The achievements of the Pipeline, Profession, and Practice: Community-Based Dental Education program schools in increasing the amount of time students spend in community-based education and service-learning programs result from a widespread, national effort to meet this challenge. This article is a personal reflection and review of these programs, considering what has been learned and still needs to be learned about student educational impact and quality, faculty issues, program management, infrastructure and logistics, and financial impact, with suggestions for future study that can help dental schools design the most effective programs. PMID- 20930230 TI - Underrepresented minority dental student recruitment and enrollment programs: an overview from the dental Pipeline program. AB - By now, all dental schools should understand the need to increase the enrollment of underrepresented minority (URM) students. While there has been a major increase in the number of Hispanic/Latino, African American/Black, and Native American applicants to dental schools over the past decade, there has not been a major percent increase in the enrollment of URM students except in the schools participating in the Pipeline, Profession, and Practice: Community-Based Dental Education program, which have far exceeded the percent increase in enrollment of URM students in other U.S. dental schools during Phase I of the program (2002 07). Assuming that all dental schools wish to improve the diversity of their student bodies, chapters 9-12 of this report--for which this chapter serves as an introduction--provide strategies learned from the Pipeline schools to increase the applications and enrollment of URM students. Some of the changes that the Pipeline schools put into place were the result of two focus group studies of college and dental students of color. These studies provided guidance on some of the barriers and challenges students of color face when considering dentistry as a career. New accreditation standards make it clear that the field of dentistry expects dental schools to re-energize their commitment to diversity. PMID- 20930231 TI - Pipeline program. Foreword. PMID- 20930232 TI - Components of effective outreach and recruitment programs for underrepresented minority and low-income dental students. AB - Dental schools in the Pipeline, Profession, and Practice: Community-Based Dental Education program that increased the number of underrepresented minority (URM) and low-income (LI) students in their predoctoral programs used focused approaches in their outreach, recruitment, and retention initiatives. Various combinations of approaches were used by the fifteen schools that received funding during Phase I of the program, which spanned 2003 to 2007. URM enrollment in the Pipeline schools increased from 184 students in 2003 to 246 in 2007. These enrollment numbers represent 16 and 20 percent of the first-year class in the Pipeline schools in 2003 and 2007, respectively. If the historically minority serving institutions--Howard University College of Dentistry and Meharry Medical College School of Dentistry--are removed from these totals, the numbers changed from 100 in 2003 to 144 in 2007, representing 10 and 13 percent of the first-year classes. This chapter describes the approaches used by the fifteen Pipeline schools to increase the number of URM and LI students recruited to and enrolled in their predoctoral programs. It describes the internal infrastructural and organizational approaches these dental schools used to increase awareness about oral health careers among URM and LI students and to recruit applicants from these populations to their educational programs. The effective partnerships and collaborations these dental schools established with each other and external stakeholders to bolster their career outreach and recruitment efforts and some of the informal efforts that supported increased diversity are also examined. PMID- 20930233 TI - Effective admissions practices to achieve greater student diversity in dental schools. AB - In this chapter we describe the institutional and policy-level strategies that dental schools in the Pipeline, Profession, and Practice: Community-Based Dental Education program used to modify their admissions practices to increase the diversity of their student bodies. Schools developed and used clear statements recognizing the value of diversity. They incorporated recent U.S. Supreme Court rulings regarding educational diversity into their revised admissions practices; these rulings cited diversity as both a "compelling interest" and its use in only "narrowly tailored" circumstances. We make a case for admissions decisions based on a comprehensive evaluation that balances the quantitative and qualitative qualities of a candidate. It refutes the practice of overreliance on standardized tests by detailing the whole-file review process to measure merit and professional promise. Also described is a range of noncognitive variables (e.g., leadership, ability to sustain academic achievement with competing priorities, volunteerism, communication, social background, and disadvantaged status) that schools can take into consideration in admissions decisions. Admissions committees can tie this comprehensive review of candidates into the case for promoting cross-cultural understanding and enhanced competence to provide care to patients from diverse backgrounds. In addition, the chapter reviews the challenges schools face in developing admissions policies and procedures that reflect the university's mission for diversity. It addresses the importance of a diverse composition of the admissions committee. It also describes how tailored workshops and technical assistance for admissions committees can help schools improve their student diversity and how admissions committees can engage in a process of periodic review of their diversity objectives in relationship to the school's mission. PMID- 20930234 TI - Organization and management of community-based dental education programs: an overview from the dental Pipeline program. AB - Disparities in access to dental care are a major problem in the United States. Effectively run community-based dental education programs can make a significant contribution to reducing access disparities and at the same time enrich the educational experiences of dental students and residents. For complex historical reasons, dental schools did not base their clinical training programs in community hospitals and clinics like the other health professions. Now, because of trends in school finances, changes in societal values, and limitations in current educational experiences, schools are increasing the time students spend in community clinics. This is likely to continue. The chapters in the first section of the report on the Pipeline, Profession, and Practice: Community-Based Dental Education program--for which this chapter serves as an introduction provide detailed information on the operation of community-based education programs. PMID- 20930235 TI - The role of the dental school environment in promoting greater student diversity. AB - This chapter describes the strategies implemented by one dental school during the past decade to establish an environment that supports a culture of diversity. The school audited its initial diversity milieu, authored a strategic plan for diversity, fully participated in university-wide diversity initiatives, and created an administrative infrastructure for underrepresented minority (URM) student support. Mentoring and counseling programs were established for URM students, and a schoolwide diversity committee was formed to make cultural competence a high priority for all students, faculty, and staff. URM faculty members were recruited and retained through a minority faculty development program. Student professional organizations were established and supported by mentoring partnerships with members of the corresponding organizations in the practicing community. The school's diversity culture is continuously evaluated and nurtured within the context of evolving human interactions in society, dental education, and dental practice. PMID- 20930237 TI - Assessment of tobacco dependence curricula in U.S. dental hygiene programs. AB - Tobacco dependence education (TDE) continues to be a vital component of dental hygiene curricula-made even more important by the fact that tobacco cessation in adults in the United States has stagnated over the past ten years. This study was undertaken to assess the salient characteristics of TDE in U.S. dental hygiene programs. A fifty-one question survey was mailed to the program directors of all 283 accredited dental hygiene programs during the 2007-08 school year (this number does not include the programs in Illinois, which were excluded since they had participated in a previous study). A total of 187 schools returned the survey for a return rate of 66 percent. Curricular content, minutes spent on each topic, existing level of clinical competence measured, expected level of clinical competence, and resources used were assessed. Respondents reported an average of 6.7 hours spent on all identified components of tobacco education. While 77 percent of respondents reported formally assessing whether a student asked if a patient used tobacco, only 26 percent indicated having a formal competency utilizing all of the U.S. Public Health Service's Clinical Practice Guideline 5 As and 5 Rs. In contrast, 72 percent of program directors reported expecting their graduates to be competent in a moderate intervention that included all 5 As. Though there is a clear commitment to TDE among dental hygiene programs in the United States, we recommend training to a more intensive level of TDE in order to facilitate broader adoption of comprehensive, evidence-based guidelines. PMID- 20930238 TI - Fourth-year dental students' perceived barriers to providing tobacco intervention services. AB - In order to facilitate effective tobacco cessation services within dental school clinics, it is necessary to understand the perceived barriers encountered by dental students while providing these services. The aim of this study was to identify which factors fourth-year dental students perceive to be associated with barriers to providing tobacco intervention services. A written survey was developed and completed by incoming fourth-year dental students (a convenience sample of seventy students) at the University of Iowa College of Dentistry in 2008. The survey assessed the perceived barriers to providing tobacco intervention services and related factors. Descriptive, bivariate, and linear regression analyses were conducted. The response rate was 97 percent. The most frequently reported barriers were patients' resistance to tobacco intervention services (96 percent), inadequate time available for tobacco intervention services (96 percent), and forgetting to give tobacco intervention advice (91 percent). The following variables were significantly (p<0.05) related to greater perceived barriers in providing tobacco intervention services: lower "adequacy of tobacco intervention curriculum coverage of specific topics covered over the previous three years" and greater "perceived importance of incorporating objective structured clinical examination teaching method for learning tobacco intervention." Students probably could benefit from additional didactic training, but most important may be enhanced clinical experiences and faculty reinforcement to facilitate effective practical student learning and adaptation for future delivery of intervention services in private practice settings. PMID- 20930236 TI - Consortium for oral health-related informatics: improving dental research, education, and treatment. AB - Advances in informatics, particularly the implementation of electronic health records (EHR), in dentistry have facilitated the exchange of information. The majority of dental schools in North America use the same EHR system, providing an unprecedented opportunity to integrate these data into a repository that can be used for oral health education and research. In 2007, fourteen dental schools formed the Consortium for Oral Health-Related Informatics (COHRI). Since its inception, COHRI has established structural and operational processes, governance and bylaws, and a number of work groups organized in two divisions: one focused on research (data standardization, integration, and analysis), and one focused on education (performance evaluations, virtual standardized patients, and objective structured clinical examinations). To date, COHRI (which now includes twenty dental schools) has been successful in developing a data repository, pilot testing data integration, and sharing EHR enhancements among the group. This consortium has collaborated on standardizing medical and dental histories, developing diagnostic terminology, and promoting the utilization of informatics in dental education. The consortium is in the process of assembling the largest oral health database ever created. This will be an invaluable resource for research and provide a foundation for evidence-based dentistry for years to come. PMID- 20930239 TI - Preparing the dental workforce for oral disease prevention in an aging population. AB - The growing proportion of older adults in the U.S. population, as well as escalating dental expenditures, is leading to major changes in the demands on oral health care delivery. Researchers over the years have clearly demonstrated the shortcomings of traditional restorative treatment and the cycle of repeat interventional care. Oral health care professionals are constantly seeking advances in technology, protocols, methodologies, and materials to meet the needs of the growing, diverse older population. Early stages of oral diseases such as caries and periodontal disease are vigorous, preventable, and reversible. Assessment of social, systemic, and oral risk factors that emphasize patient counseling to facilitate risk reduction, along with individualized evidence-based disease prevention planning, is more cost-effective than traditional restorative treatment and will improve overall outcome. The purposes of this article are to briefly describe current issues and challenges related to oral health promotion for older adults and to examine strategies for disease prevention and health promotion in health and dental care settings. PMID- 20930240 TI - The influence of industry on dental education. AB - Academic dental institutions face the growing challenge of securing the resources needed to develop a curriculum that incorporates current innovation and technology to ensure that students' learning experiences are relevant to current dental practice. As a result, university-industry relationships are becoming increasingly common in academe. While these relationships facilitate curriculum relevance, they also expose students to external market forces. The purpose of this study was to explore the influence of industry on dental education using a qualitative research study design. Analysis of semistructured interviews with thirteen Dalhousie University dental faculty members revealed two primary themes that suggest a tension between the traditional hierarchical organizational structures guiding curriculum (i.e., authoritarianism) and industry's quest for profit (i.e., entrepreneurialism). Additional themes demonstrate a belief that industry directly influences students' knowledge and understanding of evidence as well as their experience with both the formal and informal curricula. Industry's presence in academe is a concern. Dental educators, as stewards of the profession, must be nimble in brokering industry's presence without compromising the integrity of both the educational program and the teaching institution as a whole. PMID- 20930241 TI - A content analysis of dental education research as reported in two journals. AB - Little systematic information has been collected about the nature and types of studies published in dental education journals. The goals of this study were to conduct a content analysis of articles published in dental education journals in two recent years, describe the type of research published, identify possible gaps, and propose future agendas. A content analysis of articles published in two leading dental education journals was performed for the years 2003 and 2008 with 253 articles reviewed. Most articles were descriptive and observational in nature. Curriculum was the most common topic of study addressed. The mean number of authors per article increased slightly over time, and authors held mostly a combination of D.D.S. and M.S. degrees or Ph.D. degrees. A review of the literature was present and critically discussed in almost three-quarters of the articles studied. One-third of the articles mentioned ethics review or approval. Most of the studies were conducted in North America, followed by Europe. About one-third of the articles reported a source of funding. A plea is made for more systematic studies of the effectiveness of instructional and curricular innovations and more clarification studies to better understand why certain initiatives or interventions work or not. PMID- 20930242 TI - Application of basic science to clinical problems: traditional vs. hybrid problem based learning. AB - It is widely acknowledged that clinical problem-solving is a key skill for dental practitioners. The aim of this study was to determine if students in a hybrid problem-based learning curriculum (h-PBL) were better at integrating basic science knowledge with clinical cases than students in a traditional, lecture based curriculum (TC). The performance of TC students (n=40) was compared to that of h-PBL students (n=31). Participants read two clinical scenarios and answered a series of questions regarding each. To control for differences in ability, Dental Admission Test (DAT) Academic Average scores and predental grade point averages (GPAs) were compared, and an ANCOVA was used to adjust for the significant differences in DAT (t-test, p=0.002). Results showed that h-PBL students were better at applying basic science knowledge to a clinical case (ANCOVA, p=0.022) based on overall scores on one case. TC students' overall scores were better than h-PBL students on a separate case; however, it was not statistically significant (p=0.107). The h-PBL students also demonstrated greater skills in the areas of hypothesis generation (Mann-Whitney U, p=0.016) and communication (p=0.006). Basic science comprehension (p=0.01) and neurology (p<0.001) were two areas in which the TC students did score significantly higher than h-PBL students. PMID- 20930243 TI - Comparison of clinical productivity of senior dental students in a dental school teaching clinic versus community externship rotations. AB - The aim of this study was to report on the clinical and monetary productivity of fourth-year dental students at community-based clinical sites and school-based clinics at the Harvard School of Dental Medicine (HSDM). This study included forty-seven students from the graduating classes of 2006, 2007, and 2008. These fourth-year students were required to spend twelve weeks at one of several participating community health centers throughout Massachusetts and New Hampshire. Students also treated their patient pool in the teaching practice at HSDM in the fourth year. The most common sixty American Dental Association procedure codes were compared, and variables were created by grouping them by specialty or type of service. HSDM dental students completed 8,365 procedures at an externship site during their community experience. An average of 178 procedures was completed per student, and mean revenue of $17,486 was produced. In comparison, the same students completed 3,640 procedures during an equal amount of time spent (normalized for this study) at the school teaching practice clinic, where each student completed an average of seventy-seven procedures and generated $16,802 in revenue. The results of this study show that fourth-year dental students at the community health centers, working under the supervision of adjunct faculty, completed more than double the number of procedures they did in the HSDM teaching practice clinic. However, the revenue generated was very similar at the two sites. In addition, the types of procedures performed by students at externship sites were simpler than the complex and specialized procedures performed at the HSDM clinic, which include fixed and removable prosthetics, periodontal surgery, and implantology. PMID- 20930244 TI - Introducing and evaluating MorphoDent, a Web-based learning program in dental morphology. AB - MorphoDent, a computer-assisted learning program designed to teach the anatomy of the adult dentition, was introduced into the curriculum of dentistry at the University of Saarland in Homburg, Germany. Thirty-six second-year students of the School of Dentistry were introduced to morphoDent alongside the traditional lectures of dental anatomy. Questionnaires that evaluated the students' perceptions of virtual learning as well as aspects of the functionality of the program educational objectives were developed and distributed to the students. Online tests were performed and compared with a traditional examination. All questionnaires were returned. A wide variety of aspects dealing the pedagogic implications of e-learning were evaluated by the students, with the overall result being that students are aware of the needed hardware and technical skills and expect the quality of their studies to improve by implementation of e learning. All sophomores except one felt that morphoDent had helped them in learning dental morphology and reported enjoying the virtual anatomical examination. One-third reported technical difficulties in operating the program. The average exam score was 2.53 (SD: 0.66) for the traditional and 2.23 (SD: 0.59) for the online dental anatomy test. Students expressed their positive attitude towards e-learning in general and indicated that the use of photorealistic 3D models of human teeth supported the process of individual learning of dental anatomy. The online test could be rated as a good option for students' self-performance rating. PMID- 20930245 TI - Alternative careers in pediatric dentistry: a survey of pediatric dental residents. AB - Pediatric dentistry has enjoyed growing popularity in recent years, yet there remains a need for leadership in academe, research, and public health. In November 2008, the first Maternal and Child Health Bureau-sponsored regional Leadership in Pediatric Dentistry convocation was held at the Columbia University College of Dental Medicine. Seventy-two pediatric dentistry trainees from thirteen programs in the New York City area participated in interactive presentations and exercises. Of the sixty- seven participants who completed a pre event survey, 93 percent stated they would likely or very likely pursue careers that involved, at least in part, private practice, 55 percent in care of children in Medicaid, 51 percent academics, 36 percent dental public health, and 12 percent research. Barriers related to finances, competence, or work environment/location were perceived by 83 percent for careers involving research, 73 percent for dental public health, 66 percent for providing care to children in Medicaid, 46 percent for academics, and 9 percent for private practice. Results of a pair of pre-event and post-event surveys completed by sixty-three attendees showed no change in reported likelihood to pursue a career alternative except for an increase in the likelihood of working in a practice that accepts Medicaid. The challenge before dental educators is to provide consistent and meaningful opportunities throughout training that encourage residents to consider all career options and to discover how their individual interests mesh with their clinical learning. PMID- 20930246 TI - Evaluation of a U.K. community-based clinical teaching/outreach program by former dental students two and five years after graduation. AB - Over the past few years, community-based clinical teaching/outreach teaching programs have been established in many dental schools in the United Kingdom. One such program was developed by Cardiff University at the local St. David's Hospital in 2002. Students visit this unit throughout their dental school program -as an assistant/observer initially, but gaining a significant amount of clinical operating experience within the unit during their final year of studies. While contemporaneous feedback from current dental students at this and other programs has been positive, very little information exists on the impact of this form of training on the subsequent clinical careers and working practices of qualified dentists. In autumn 2009, a postal questionnaire was distributed to dentists who graduated from the School of Dentistry at Cardiff in 2004 (n=41) and 2007 (n=51). Fifty-eight responses were returned, for a response rate of 63 percent: 2004 (66 percent), 2007 (61 percent). Forty-seven respondents (81 percent) reported that their learning experience at the St. David's outreach teaching program had been of significant assistance in their professional development in their subsequent clinical careers. Positive features of the program included the availability of a suitably trained dental nurse for all procedures (n=26, 45 percent), ready access to helpful/approachable teaching staff (n=24, 41 percent), and a good working atmosphere (n=23, 40 percent). Overwhelmingly, former dental students reported that the educational experiences they gained were positive and have had a beneficial effect on their subsequent clinical careers. Further development of community-based clinical teaching/outreach training as part of dental school training programs is encouraged. PMID- 20930247 TI - Mobile phone hygiene: potential risks posed by use in the clinics of an Indian dental school. AB - The objectives of this cross-sectional study were to determine the level and type of bacterial contamination of the mobile phones of dental personnel involved in direct patient care and to determine the usefulness of cleaning with 70 percent isopropyl alcohol for decontamination. Dental faculty and trainees in an Indian dental school were asked to participate in a study in which a questionnaire concerning patterns of mobile phone use and disinfection was administered. Swabs from mobile phones of the participants were taken using moist sterile swabs and plated on blood agar plates. The bacteria isolated were identified by biochemical tests. Eighteen percent of the participants (n=9) reported using their phones while attending patients. Nearly 64 percent (n=32) used their mobiles for checking time, and 64 percent (n=42) reported never cleaning their phones. In total, fifty mobile phones were cultured for microorganisms: 98 percent (n=49) were culture-positive, and 34 percent (n=17) grew potentially pathogenic bacteria. There was significant reduction in the mean number of colony-forming units after decontamination with alcohol (p<0.001). The bacterial load was reduced by around 87 percent. The results of this study show that mobile phones may act as an important source of nosocomial pathogens in the dental setting. Therefore, it is important for dental school administrators to encourage higher compliance with hand-washing practices and routine surface disinfection through framing of strict protocols to reduce the chances of occurrence of nosocomial infections. PMID- 20930248 TI - Jordanian dental students' knowledge and attitudes in regard to child physical abuse. AB - The aim of this study was to investigate Jordanian dental students' educational experience, attitudes, and knowledge regarding child physical abuse. Data were collected from a self-administered questionnaire completed by 441 undergraduate and postgraduate dental students in both dental schools in Jordan. Descriptive statistics were used to report responses to each question. The chi-square test was used to analyze the relationship between students' responses and level of education; the difference was considered significant if the probability of the difference was less than 5 percent. Results indicated major lack of knowledge of social indicators, signs of physical abuse, and reporting procedure among all respondents with no significant difference between postgraduate and undergraduate students. Most students indicated that their dental school was the main source of information on this topic; however, more postgraduates reported benefit from extracurricular sources. We conclude that dental students in Jordan are not sufficiently prepared to undergo their role in protection of children from abuse. Dental curricula in both dental schools include information on the topic of child abuse; however, the content should be expanded to better prepare the students. PMID- 20930249 TI - Key concepts in a rights-based approach to health. From the publisher. PMID- 20930250 TI - Our place in the world: Conceptualizing obligations beyond borders in human rights-based approaches to health. AB - The case of Haiti's devastating earthquake and the reactions it has elicited sharply illustrate an array of seemingly dichotomous ways of understanding obligations of "international assistance and cooperation," which are taken up by authors in this issue. First, there is a tension between dealing with immediate humanitarian needs and addressing underlying structural causes. Second, there is the related dichotomy between compassion/charity and the accountability for legal obligations that a human rights approach to health and development demands. Third, within a framework for accountability, there is a tension between an ahistorical understanding of international responsibility - based purely on the self-evident need of fellow human beings - and a contextually-rooted accountability. Finally, the situation of Haiti begs the question of whether we can address immense human suffering in the world through a strongly statist model or whether we require a more cosmopolitan understanding of ethical and legal obligations across borders. Drawing on the Critical Concepts articles in this issue, this essay briefly explores some of these tensions, and the potential contributions and limitations of applying a human rights framework to advance global health. PMID- 20930251 TI - Informed consent: Enforcing pharmaceutical companies' obligations abroad. AB - The past several years have seen an evolution in the obligations of pharmaceutical companies conducting clinical trials abroad. Key players, such as international human rights organizations, multinational pharmaceutical companies, the United States government and courts, and the media, have played a significant role in defining these obligations. This article examines how such obligations have developed through the lens of past, present, and future recommendations for informed consent protections. In doing so, this article suggests that, no matter how robust obligations appear, they will continue to fall short of providing meaningful protection until they are accompanied by a substantive enforcement mechanism that holds multinational pharmaceutical companies accountable for their conduct. Issues of national sovereignty, particularly in the United States, will continue to prevent meaningful enforcement by an international tribunal or through one universally adopted code of ethics. This article argues that, rather than continuing to pursue an untenable international approach, the Alien Torts Statute (ATS) offers a viable enforcement mechanism, at least for US-based pharmaceutical companies. Recent federal appellate court precedent interpreting the ATS provides the mechanism for granting victims redress and enforcing accountability of sponsors (usually pharmaceutical companies and research and academic institutions) for informed consent misconduct. Substantive human rights protections are vital in order to ensure that every person can realize the "right to health." This article concludes that by building on the federal appellate court's ATS analysis, which grants foreign trial participants the right to pursue claims of human rights violations in US courts, a mechanism can be created for enforcing not only substantive informed consent, but also human rights protections. PMID- 20930252 TI - Taking up Daniels' challenge: The case for global health justice. AB - In "Just Health", Norman Daniels makes a strong argument for obligations of mutual assistance to fulfill the right to health at the national level and challenges readers to develop arguments supporting obligations of mutual assistance at the global level. In this paper, we argue that there is global responsibility for global health and that there are obligations of justice (beyond charity) to help fulfill (not merely respect or even protect) the right to health in other countries; these we call obligations of global health justice. We show how international human rights law affirms obligations of global health justice - beyond national obligations and beyond obligations of charity - and assert that the human rights approach provides guidance on delineating the relationship between national and global responsibility for fulfilling the core obligations that arise from socioeconomic human rights and addressing global health inequities. We further argue that new ways of providing international assistance, originating from the global HIV/AIDS response, demonstrate the feasibility of improving health outcomes through exogenous efforts and that obligations of global health justice thus carry much weight: the weight of lives not saved. The global response to the HIV/AIDS pandemic has led to the emergence of a new international health assistance paradigm, and the Global Fund to fight AIDS, Tuberculosis and Malaria is, we suggest, an embryonic form of this new paradigm. We conclude that agreements on several common parameters delineating global and national responsibility for global health can advance the movement towards a global institution for the distribution of health-related goods. PMID- 20930253 TI - Making health an imperative of foreign policy: The value of a human rights approach. AB - Health is increasingly seen as relevant to foreign policy; nevertheless, it remains subordinate to other interests. In particular, the interests of security and economics are often presented as more critical than health. This is due to a failure to sufficiently recognize the legal obligations that states have undertaken to ensure the human right to health. This article argues that health should be an imperative of foreign policy, equally valid, and prioritized in resource allocation. We suggest application of the human rights approach with attention to the legal duty of cooperation and the necessity of ensuring broad participation. We suggest that the human rights approach to health can contribute to achieving this result and is compatible with, and beneficial to, other foreign policy concerns. Finally, we conclude that the human rights approach to health requires that health be an imperative in foreign policymaking processes. PMID- 20930254 TI - International obligations through collective rights: Moving from foreign health assistance to global health governance. AB - This article analyzes the growing chasm between international power and state responsibility in health rights, proposing an international legal framework for collective rights - rights that can reform international institutions and empower developing states to realize the determinants of health structured by global forces. With longstanding recognition that many developing state governments cannot realize the health of their peoples without international cooperation, scholars have increasingly sought to codify international obligations under the purview of an evolving human right to health, applying this rights-based approach as a foundational framework for reducing global health inequalities through foreign assistance. Yet the inherent limitations of the individual human rights framework stymie the right to health in impacting the global institutions that are most crucial for realizing underlying determinants of health through the strengthening of primary health care systems. Whereas the right to health has been advanced as an individual right to be realized by a state duty-bearer, the authors find that this limited, atomized right has proven insufficient to create accountability for international obligations in global health policy, enabling the deterioration of primary health care systems that lack the ability to address an expanding set of public health claims. For rights scholars to advance disease protection and health promotion through national primary health care systems - creating the international legal obligations necessary to spur development supportive of the public's health - the authors conclude that scholars must look beyond the individual right to health to create collective international legal obligations commensurate with a public health-centered approach to primary health care. Through the development and implementation of these collective health rights, states can address interconnected determinants of health within and across countries, obligating the international community to scale-up primary health care systems in the developing world and thereby reduce public health inequities through global health governance. PMID- 20930255 TI - International assistance and cooperation for access to essential medicines. AB - Access to essential medicines is a critical problem that plagues many developing countries. With a daunting number of domestic constraints - technologically, economically, and otherwise - developing countries are faced with a steep uphill battle to meet the human rights obligation of providing essential medicines immediately. To meet these challenges, the international human rights obligations of international assistance and cooperation can play a key role to help developing countries fulfill the need for access to essential medicines. This article seeks to highlight and expand upon the current understanding of international assistance and cooperation for access to essential medicines through a review of obligations identified in international human rights law and a synthesis of official guidance provided on the matter. PMID- 20930256 TI - Allies unknown: Social accountability and legal empowerment. AB - This essay suggests that two strands of social action which have hitherto developed separately - legal empowerment and social accountability - ought to learn from one another. Legal empowerment efforts grow out of the tradition of legal aid for the poor; they assist citizens in seeking remedies to breaches of rights. Social accountability interventions employ information and participation to demand fairer, more effective public services. The two approaches share a focus on the interface between communities and local institutions. The legal empowerment approach includes, in addition, the pursuit of redress from the wider network of state authority. The essay suggests that social accountability interventions should couple local community pressure with legal empowerment strategies for seeking remedies from the broader institutional landscape. Legal empowerment programs, for their part, often under-emphasize injustices related to essential public services such as health and education, perhaps in part because they tend to wait for communities and individuals to raise problems. Instead, legal empowerment programs should learn from social accountability practitioners' use of aggregate data as a catalyst for community action. Legal empowerment organizations would also benefit from adopting the attention to empirical impact evaluation that has characterized experimentation in social accountability. PMID- 20930257 TI - Holding the World Bank accountable for leakage of funds from Africa's health sector. AB - This article explores the accountability of international financial institutions (IFIs), such as the World Bank, for human rights violations related to the massive leakage of funds from sub-Saharan Africa's health sector. The article begins by summarizing the quantitative results of Public Expenditure Tracking Surveys performed in six African countries, all showing disturbingly high levels of leakage in the health sector. It then addresses the inadequacy of good governance and anticorruption programs in remedying this problem. After explaining how the World Bank's Inspection Panel may serve as an accountability mechanism for addressing the leakage of funds, discussing violations of specific Bank policies and procedures that would support a claim related to leakage and examining the relevance of human rights concerns to such as claim, the article explores some of the Panel's limitations and the positive steps taken to address these concerns. PMID- 20930258 TI - A one-time-only combination: Emergency medicine exports and the TRIPS agreement under Canada's access to medicines regime. AB - In 2008, a Canadian generic pharmaceutical firm, Apotex Inc. (Apotex), shipped 7 million doses of antiretroviral drugs to Rwanda for the treatment of HIV/AIDS. While this event may be seen as a positive outcome of international patent changes that facilitate the fulfillment of health as a human right, the fact that there has been only one shipment of medication in response to these changes highlights the difficulties with both the Canadian legislation and with the international decisions that it implements. The shipment was authorized under Canada's Access to Medicines Regime (CAMR), which implements the World Trade Organization (WTO) General Council Decision (the Decision), made in 2003, to permit someone other than the patent holder to manufacture a lower-cost version of a patented drug or medical device for export to developing countries that do not have the capacity to manufacture such products. The Decision requires that the developing country announce its intention to use this mechanism, to specify the expected quantity of drugs to be supplied, and to issue a compulsory license for the drugs. The requirement of notification in particular may render developing countries vulnerable to pressure from pharmaceutical firms. Neither the mechanism created by the Decision nor Canadian legislation implementing it have facilitated the export of generic medicines to developing countries. To date, the Canadian shipment is the only one to have occurred using the WTO mechanism. PMID- 20930259 TI - Partnership, sex, and marginalization: Moving the Global Fund sexual orientation and gender identities agenda. AB - After almost three decades of work to address HIV and AIDS, resources are still failing to adequately address the needs of the most affected and marginalized groups in many societies. In recognition of this ongoing failure, the Global Fund to Fight AIDS, Tuberculosis and Malaria (the Global Fund) has approved a sexual orientation and gender identities (SOGI) Strategy. The Strategy is designed to help its investments more effectively reach men who have sex with men; transgender populations; male, female, and transgender sex workers; and women who have sex with women. The Global Fund financing model is unique and based on ideas of broad partnership. It emphasizes the importance of country-ownership while ensuring that work is appropriately targeted, evidence-based, and rooted in principles of human rights. The classic international development tension of pursuing a rights-based agenda, while also supporting strong country ownership, has moved the Global Fund into a more substantive technical, advocacy, and policy arena, resulting in the creation of the SOGI Strategy, which emphasizes the needs of marginalized groups. A strong commitment to participation and consultation was crucial during the development stages of the Strategy. Now, as the Strategy goes live, it is clear that progress will only be achieved through continued and strengthened partnership. The diverse partners - in particular the governments and other stakeholders in recipient countries that helped develop the Strategy - must now commit to stronger collaboration on this agenda and must demonstrate bold leadership in overcoming the considerable technical and political challenges of implementation that lie ahead. PMID- 20930260 TI - Essential surgery: Integral to the right to health. AB - In a rights-based approach to health, the provision of essential surgical services is not a luxury, but a critical component of the "highest attainable standard of health." Yet while access to select basic health care interventions has increasingly been discussed as part of the human right to health, essential surgical services have generally not been part of this discussion. This is despite the substantial global burden of surgical conditions in low- and middle income countries, extreme global disparities in access to surgical care, and the fact that relatively simple, cost-effective, and curative surgical procedures can avert disability and premature death from many life-threatening emergencies and other conditions. Many barriers, both supply and demand-related, such as constraints in human resources, infrastructure, and access to care, have limited the ability of health systems to deliver surgical services. In this paper, the authors share their experience - as a group of surgeons, anesthesiologists, emergency physicians, and public health experts working with colleagues in varied resource-constrained settings to provide basic surgical care - in addressing the challenge of realizing the right to surgery in resource-poor settings. We argue that essential surgical care should be included in the basic human right to health, and that the current emphasis on "vertical" disease-specific models of health service delivery should be broadened to include systems needed to provide surgical services. We outline the global burden of surgical conditions, discuss the public health importance of surgery, identify the most significant global disparities in access to surgical care, and provide economic arguments for surgical delivery. PMID- 20930261 TI - Cellular senescence controls fibrosis in wound healing. AB - Mammalian wound healing involves the rapid synthesis and deposition of extracellular matrix (ECM) to maintain tissue integrity during repair. This process must be tightly controlled, as its deregulation may result in fibrosis, scarring, and loss of tissue function. Recent studies have uncovered an efficient and parsimonious mechanism for rendering fibrogenesis self-limiting in wound healing: in such diverse organs as the liver and skin, the myofibroblasts that initially proliferate and produce ECM are themselves eventually driven into senescence, blocking their further proliferation and converting them into matrix degrading cells. Myofibroblast senescence in skin wounds is triggered by a dynamically expressed matricellular protein, CCN1/CYR61, which acts through integrin-mediated induction of oxidative stress. We propose that the onset of myofibroblast senescence is a programmed wound healing response that functions as a self-limiting mechanism for fibrogenesis, and this process may be regulated by the ECM microenvironment through the expression of CCN1/CYR61. PMID- 20930264 TI - A gene expression pattern in blood for the early detection of Alzheimer's disease. AB - A whole genome screen was performed using oligonucleotide microarray analysis on blood from a large clinical cohort of Alzheimer's disease (AD) patients and control subjects as clinical sample. Blood samples for total RNA extraction were collected in PAXgene tubes, and gene expression analysis performed on the AB1700 Whole Genome Survey Microarrays. When comparing the gene expression of 94 AD patients and 94 cognitive healthy controls, a Jackknife gene selection based method and Partial Least Square Regression (PLSR) was used to develop a disease classifier algorithm, which gives a test score indicating the presence (positive) or absence (negative) of AD. This algorithm, based on 1239 probes, was validated in an independent test set of 63 subjects comprising 31 AD patients, 25 age matched cognitively healthy controls, and 7 young controls. This algorithm correctly predicted the class of 55/63 (accuracy 87%), including 26/31 AD samples (sensitivity 84%) and 29/32 controls (specificity 91%). The positive likelihood ratio was 8.9 and the area under the receiver operating characteristic curve (ROC AUC) was 0.94. Furthermore, the algorithm also discriminated AD from Parkinson's disease in 24/27 patients (accuracy 89%). We have identified and validated a gene expression signature in blood that classifies AD patients and cognitively healthy controls with high accuracy and show that alterations specific for AD can be detected distant from the primary site of the disease. PMID- 20930262 TI - Trichostatin A accentuates doxorubicin-induced hypertrophy in cardiac myocytes. AB - Histone deacetylase inhibitors represent a new class of anticancer therapeutics and the expectation is that they will be most effective when used in combination with conventional cancer therapies, such as the anthracycline, doxorubicin. The dose-limiting side effect of doxorubicin is severe cardiotoxicity and evaluation of the effects of combinations of the anthracycline with histone deacetylase inhibitors in relevant models is important. We used a well-established in vitro model of doxorubicin-induced hypertrophy to examine the effects of the prototypical histone deacetylase inhibitor, Trichostatin A. Our findings indicate that doxorubicin modulates the expression of the hypertrophy-associated genes, ventricular myosin light chain-2, the alpha isoform of myosin heavy chain and atrial natriuretic peptide, an effect which is augmented by Trichostatin A. Furthermore, we show that Trichostatin A amplifies doxorubicin-induced DNA double strand breaks, as assessed by gammaH2AX formation. More generally, our findings highlight the importance of investigating potential side effects that may be associated with emerging combination therapies for cancer. PMID- 20930265 TI - A novel blood test for the early detection of Alzheimer's disease. AB - Despite a variety of testing approaches, it is often difficult to make an accurate diagnosis of Alzheimer's disease (AD), especially at an early stage of the disease. Diagnosis is based on clinical criteria as well as exclusion of other causes of dementia but a definitive diagnosis can only be made at autopsy. We have investigated the diagnostic value of a 96-gene expression array for detection of early AD. Gene expression analysis was performed on blood RNA from a cohort of 203 probable AD and 209 cognitively healthy age matched controls. A disease classification algorithm was developed on samples from 208 individuals (AD = 103; controls = 105) and was validated in two steps using an independent initial test set (n = 74; AD = 32; controls = 42) and another second test set (n = 130; AD = 68; controls = 62). In the initial analysis, diagnostic accuracy was 71.6 +/- 10.3%, with sensitivity 71.9 +/- 15.6% and specificity 71.4 +/- 13.7%. Essentially the same level of agreement was achieved in the two independent test sets. High agreement (24/30; 80%) between algorithm prediction and subjects with available cerebrospinal fluid biomarker was found. Assuming a clinical accuracy of 80%, calculations indicate that the agreement with underlying true pathology is in the range 85%-90%. These findings suggest that the gene expression blood test can aid in the diagnosis of mild to moderate AD, but further studies are needed to confirm these findings. PMID- 20930266 TI - Mapping the altered patterns of cerebellar resting-state function in longitudinal amnestic mild cognitive impairment patients. AB - The cerebellum is known to be a relatively well preserved structure, but subtle alterations may occur early in the evolution of Alzheimer's disease (AD). Amnestic mild cognitive impairment (aMCI) patients appear to be particularly vulnerable to AD. However, little is currently known whether altered patterns of cerebellar function occur in aMCI patients. 26 aMCI patients and 18 well-matched healthy controls underwent a baseline resting-state functional magnetic resonance imaging (fMRI) scan. After a mean follow-up period of 20 months, the subjects who successfully completed baseline fMRI scans underwent a further follow-up scan, while spontaneous activation and functional connectivity of the cerebellum were explored by using resting-state fMRI. Compared to controls, increased amplitude of low frequency fluctuation of the posterior cerebellar lobe may contribute to the underlying mechanisms affected, while greater decreased functional connections to the posterior cerebellar lobe were identified in the longitudinal study of aMCI patients. This suggests that abnormal functional connectivity of the cerebellum may offer a more sensitive and possibly preferred index of functional disturbance than regional activity measures in aMCI patients. The cerebellum may be partly related to the underlying mechanisms of aMCI, and it could help guide subsequent investigations designed to specify the precise functional role of cerebellum in aMCI patients. PMID- 20930267 TI - Secretase-independent and RhoGTPase/PAK/ERK-dependent regulation of cytoskeleton dynamics in astrocytes by NSAIDs and derivatives. AB - Profens like ibuprofen, R-flurbiprofen, or CHF5074 are being considered for the treatment of Alzheimer's disease because epidemiological data indicates that non steroidal anti-inflammatory drugs are protective against neurodegeneration. Rho GTPases are small G proteins, including RhoA, Cdc42, and Rac1, which control cytoskeleton dynamics. Because ibuprofen promotes axon growth via RhoA in neurons, we examined whether profens modulate astrocyte plasticity via Rho GTPases. We report that ibuprofen (100-500 MUM), R-flurbiprofen (100-500 MUM), and CHF5074 (10-30 MUM) caused a concentration-dependent stellation of astrocytes in primary cultures, associated with the reorganization of GFAP and actin filaments. The stellation was independent of COX2, alpha-, beta- or gamma secretase as judged by the lack of effect of inhibitors of these enzymes. RhoA, PAK, and Cdc42, but not Rac1, accounted for the profen-mediated stellation, as concluded from the joint analyses of activities and reversal experiments with adenoviral or pharmacological manipulations. Ibuprofen accelerated migration in a scratch-wound assay, while R-flurbiprofen had no effect and CHF5074 caused deceleration. Cell polarity regulation by Cdc42 and ERK1/2 may underlie the paradoxical effects of profens on migration. We conclude that profens regulate cytoskeleton dynamics in astrocytes via Rho-GTPases, PAK, and ERK1/2. Since migration is a hallmark of astrocyte response during inflammation we propose that, in addition to (or instead of) lowering amyloid-beta42 via secretases, ibuprofen and its derivatives may prevent Alzheimer's disease instead of AD by modulating astrocyte reactivity through Rho-GTPase/PAK/ERK-dependent signaling. PMID- 20930269 TI - Intra-familial clinical heterogeneity due to FTLD-U with TDP-43 proteinopathy caused by a novel deletion in progranulin gene (PGRN). AB - Frontotemporal dementia (FTD) is one of the commonest forms of early-onset dementia, accounting for up to 20% of all dementia patients. Recently, it has been shown that mutations in progranulin gene (PGRN) cause many familial cases of FTD. Members of a family affected by FTD spectrum disorders were ascertained in Poland and Canada. Clinical, radiological, molecular, genetic, and pathological studies were performed. A sequencing analysis of PGRN exons 1-13 was performed in the proband. Genotyping of the identified PGRN mutation and pathological analysis was carried out in the proband's brother. The onset of symptoms of FTD in the proband included bradykinesia, apathy, and somnolence followed by changes in personality, cognitive deficits, and psychotic features. The proband's clinical diagnosis was FTD and parkinsonism (FTDP). DNA sequence analysis of PGRN revealed a novel, heterozygous mutation in exon 11 (g.2988_2989delCA, P439_R440fsX6). The mutation introduced a premature stop codon at position 444. The proband's brother with the same mutation had a different course first presenting as progressive non fluent aphasia, and later evolving symptoms of behavioral variant of FTD. He also developed parkinsonism late in the disease course evolving into corticobasal syndrome. Pathological analysis in the brother revealed Frontotemporal Lobar Degeneration-Ubiquitin (FTLD-U)/TDP-43 positive pathology. The novel PGRN mutation is a disease-causing mutation and is associated with substantial intra familial clinical heterogeneity. Although presenting features were different, rapid and substantial deterioration in the disease course was observed in both family members. PMID- 20930270 TI - Neuroprotective and neurorescue effects of a novel polymeric nanoparticle formulation of curcumin (NanoCurcTM) in the neuronal cell culture and animal model: implications for Alzheimer's disease. AB - Alzheimer's disease (AD) is characterized by deposition of amyloid-beta (Abeta) plaques within the brain parenchyma followed by synaptic loss and neuronal death. Deposited Abeta reacts with activated microglia to produce reactive oxygen species (ROS) and cytochemokines, which lead to severe neuroinflammation. Curcumin is a yellow polyphenol compound found in turmeric, a widely used culinary ingredient that possesses anti-inflammatory and anti-cancer properties and may show efficacy as a potential therapeutic agent in several neuro inflammatory diseases including AD. However, poor aqueous solubility and sub optimal systemic absorption from the gastrointestinal tract may represent factors contributing to its failure in clinical trials. To increase curcumin's bioavailability, a polymeric nanoparticle encapsulated curcumin (NanoCurcTM) was formulated which is completely water soluble. NanoCurcTM treatment protects neuronally differentiated human SK-N-SH cells from ROS (H2O2) mediated insults. NanoCurcTM also rescues differentiated human SK-N-SH cells, which were previously insulted with H2O2. In vivo, intraperitoneal (IP) NanoCurcTM injection at a dose of 25mg/kg twice daily in athymic mice resulted in significant curcumin levels in the brain (0.32 MUg/g). Biochemical study of NanoCurcTM-treated athymic mice revealed decreased levels of H2O2 as well as caspase 3 and caspase 7 activities in the brain, accompanied by increased glutathione (GSH) concentrations. Increased free to oxidized glutathione (GSH:GSSH) ratio in athymic mice brain versus controls also indicated a favorable redox intracellular environment. Taken together, these results suggest that NanoCurcTM represents an optimized formulation worthy of assessing the therapeutic value of curcumin in AD. PMID- 20930271 TI - A novel progranulin mutation causing frontotemporal lobar degeneration with heterogeneous phenotypic expression. AB - Frontotemporal lobar degeneration (FTLD) is a neurodegenerative disorder characterized by behavioural disturbances and cognitive decline. Here we describe an Italian family with FTLD showing remarkable phenotypic heterogeneity. Based on low plasma levels of progranulin, we analyzed the progranulin gene (GRN) in two patients with early onset and found the novel frame-shift mutation T278SfsX7. mRNA analysis confirmed the null effect of the mutation. The patients were homozygous for H1 MAPT haplotype, a disease modifier factor that can account for early age at onset. Being predictive for GRN null mutations, plasma progranulin dosage should be included in diagnostic work-up of dementia. PMID- 20930272 TI - Oxidative balance in Alzheimer's disease: relationship to APOE, Braak tangle stage, and the concentrations of soluble and insoluble amyloid-beta. AB - Oxidative damage is greater in brain tissue from patients with Alzheimer's disease (AD) than age-matched controls. The timing of this damage in relation to other pathogenic processes in AD remains unclear. We have examined the relationship of lipid peroxidation (thiobarbituric acid-reactive substances; TBARS) and antioxidant capacity (Trolox-equivalent) to APOE status, Braak tangle stage, amyloid-beta (Abeta) plaque load, and the concentration of soluble and insoluble forms of Abeta, post-synaptic and dendritic spine proteins PSD95 and drebrin, beta-secretase and Abeta-degrading enzymes neprilysin (NEP), insulin degrading enzyme (IDE), and angiotensin-converting enzyme (ACE), in frontal, temporal, and parietal cortex from AD and control brains. Antioxidant capacity was significantly elevated in AD and directly related to disease severity as indicated by Braak tangle stage and the amount of insoluble Abeta. APOE epsilon4 was associated with increased antioxidant capacity in AD but not controls. In contrast, apart from a reduction in TBARS in Braak stages III-IV in frontal cortex, this measure of oxidative damage did not change significantly with any indicator of disease severity. It was, however, higher in APOE epsilon4-positive than epsilon4-negative AD patients and correlated with beta-secretase activity. Neither antioxidant capacity nor oxidative damage was related to the level of PSD95 or drebin or the activity of NEP, IDE, or ACE. Antioxidant capacity in AD is closely related to the level of insoluble Abeta and increases with pathological progression of the disease. Increased beta-secretase activity associated with oxidative stress is likely to contribute to the accumulation of Abeta and this, in turn, to induce antioxidant capacity. PMID- 20930273 TI - Linkage to the 8p21.1 region Including the CLU gene in age at onset stratified alzheimer's disease families. AB - Two powerful genome-wide association studies have recently reported significant association between sporadic late-onset Alzheimer's disease (AD) and markers at the CLU locus in chromosome 8p. In this study, we have stratified our previously analyzed 109 Swedish AD families according to range in age at onset and performed whole-genome linkage analysis and subsequent fine-mapping in 8p21. The subgroup analyzed in the fine-mapping consisted of 28 families with AD, having a within family onset-range not exceeding 8 years and an age at onset between 49 <= 70 years. A maximum non-parametric linkage peak (LOD = 3.5) was found between markers D8S1809 and 236c6-1. Intriguingly this linked 9.5cM region contains clusterin (CLU), which is one of the two top susceptibility genes for AD. Our finding may be a reflection of linkage to the CLU susceptibility gene, in the same way as familial AD has previously been linked to the APOE locus. PMID- 20930268 TI - Heritability of different forms of memory in the Late Onset Alzheimer's Disease Family Study. AB - The study aim was to estimate the genetic contribution to individual differences in different forms of memory in a large family-based group of older adults. As part of the Late Onset Alzheimer's Disease Family Study, 899 persons (277 with Alzheimer's disease, 622 unaffected) from 325 families completed a battery of memory tests from which previously established composite measures of episodic memory, semantic memory, and working memory were derived. Heritability in these measures was estimated using the maximum likelihood variance component method, controlling for age, gender, and education. In analyses of unaffected family members, the adjusted heritability estimates were 0.62 for episodic memory, 0.49 for semantic memory, and 0.72 for working memory, where a heritability estimate of 1 indicates that genetic factors explain all of the phenotypic variance and a heritability of 0 indicates that genetic factors explain none. Adjustment for APOE genotype had little effect on these estimates. When analyses included affected and unaffected family members, adjusted heritability estimates were lower (0.47 for episodic memory, 0.32 for semantic memory, 0.42 for working memory). Adjusting for APOE slightly reduced the estimate for episodic memory (0.40) but had no effect on the remaining estimates. The results indicate that memory functions are under strong genetic influence in older persons with and without AD, and are only partly attributable to APOE. This suggests that genetic analyses of memory endophenotypes may help to identify genetic variants associated with AD. PMID- 20930274 TI - Proteome-based plasma markers of brain amyloid-beta deposition in non-demented older individuals. AB - Blood-based markers reflecting core pathological features of Alzheimer's disease (AD) in pre-symptomatic individuals are likely to accelerate the development of disease-modifying treatments. Our aim was to discover plasma proteins associated with brain amyloid-beta (Abeta) burden in non-demented older individuals. We performed discovery-phase experiments using two dimensional gel electrophoresis (2DGE) and mass spectrometry-based proteomic analysis of plasma in combination with 11C-PiB PET imaging of the brain in samples collected 10 years prior to the PET scans. Confirmatory studies used ELISA assays in a separate set of blood samples obtained within a year of the PET scans. We observed that a panel of 18 2DGE plasma protein spots effectively discriminated between individuals with high and low brain Abeta. Mass spectrometry identified these proteins, many of which have established roles in Abeta clearance, including a strong signal from apolipoprotein-E (ApoE). In validation-phase studies, we observed a strong association between plasma ApoE concentration and Abeta burden in the medial temporal lobe. Targeted voxel-based analysis localized this association to the hippocampus and entorhinal cortex. APOE epsilon4 carriers also showed greater Abeta levels in several brain regions relative to epsilon4 non-carriers. These results suggest that both peripheral concentration of ApoE protein and APOE genotype are related to early neuropathological changes in brain regions vulnerable to AD pathology even in the non-demented elderly. Our strategy combining proteomics with in vivo brain amyloid imaging holds promise for the discovery of biologically relevant peripheral markers in those at risk for AD. PMID- 20930275 TI - Accumulation of insoluble amyloid-beta in down's syndrome is associated with increased BACE-1 and neprilysin activities. AB - We previously reported age- and Alzheimer's disease (AD)-related increases in the activities of beta-secretase (BACE-1) and Abeta-degrading enzymes including neprilysin (NEP) and angiotensin-converting enzyme (ACE) in the frontal cortex. We suggested that these increases were secondary to the accumulation of insoluble amyloid-beta (Abeta) and a decline in soluble Abeta. We have further tested this hypothesis by examination of frontal cortex obtained postmortem from individuals with Down's syndrome (DS), in whom AD-like neuropathological changes occur in association with early-onset dementia. We measured total soluble and insoluble (guanidine-extractable) Abeta, BACE-1 activity, and the concentrations and activities of NEP and ACE in two independent DS cohorts: an initial, Bristol cohort (9 DS cases, 8 controls matched for age-at-death) and a validation Newcastle cohort (20 DS, 18 controls with a wider spectrum of age-at-death). In both cohorts the level of insoluble (but not soluble) Abeta was significantly higher in DS than controls and was comparable to previously measured levels in AD. NEP protein concentration and activity were significantly increased in DS; a trend towards increased BACE-1 activity was observed in DS but did not reach statistical significance. Both NEP and BACE-1 correlated with the level of insoluble Abeta. The concentration of ACE in DS was elevated in the pilot cohort only and ACE activity was unchanged. These findings provide strong support that BACE-1 and NEP activities, but not ACE, increase in response to the accumulation of insoluble Abeta within the brain. PMID- 20930276 TI - PLA2G3, a gene involved in oxidative stress induced death, is associated with Alzheimer's disease. AB - Oxidative stress, which plays a critical role in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD), is intimately linked to aging, the best established risk factor for AD. Studies in neuronal cells subjected to oxidative stress, mimicking such stress in AD brains, are therefore of great interest. PLA2G3 is the most overexpressed gene in a human neuronal model of oxidative stress induced by the free radical-generating xanthine/xanthine oxidase (X-XOD) system, which provokes apoptotic cell death. In this work, we describe that PLA2G3 gene silencing produced a marked inhibition of X-XOD induced cell death, and that PLA2G3 polymorphisms are associated with AD in a Spanish case-control sample. The capacity to respond to oxidative stress may therefore modulate the risk of AD, and PLA2G3 is a potential target to regulate neuronal damage induced by free radicals. PMID- 20930277 TI - Endolysosome mechanisms associated with Alzheimer's disease-like pathology in rabbits ingesting cholesterol-enriched diet. AB - Alzheimer's disease (AD) is characterized clinically by progressive disturbances in memory, judgment, reasoning, and olfaction, and pathologically by loss of synaptic integrity, extracellular accumulations of amyloid-beta (Abeta) containing plaques, and intraneuronal tangles composed of hyperphosphorylated tau. Endolysosome dysfunction is one of the earliest pathological features of AD and cholesterol, a known risk factor for sporadic AD, is up-taken into neurons via receptor-mediated endocytosis. Accordingly, we determined the extent to which endolysosome dysfunction is associated with pathological features observed in rabbits fed cholesterol-enriched diet; a well-characterized model of sporadic AD. Olfactory bulbs were taken from rabbits fed for 12 weeks a diet enriched with 2% cholesterol and endolysosome morphology and function as well as AD-like pathology were investigated using enzyme activity measurements, immunoblotting and immunostaining techniques. In olfactory bulbs of rabbits fed cholesterol-enriched diet, we observed enlarged endolysosomes containing increased accumulations of ApoB containing cholesterol and increased accumulations of synaptophysin, Abeta, and phosphorylated tau. The cholesterol-enriched diet also significantly decreased specific enzyme activities of the endolysosome enzymes acid phosphatase and cathepsin D. Decreased synaptic area was present in olfactory bulbs of cholesterol-fed rabbits as indicated by significant decreases in protein expression levels of the synaptic area marker protein synaptophysin. Our results suggest strongly that elevated circulating cholesterol plays an important role in the pathogenesis of AD, and that alterations in endolysosome structure and function are associated with cholesterol diet-induced AD-like pathology. PMID- 20930278 TI - Phytic acid as a potential treatment for alzheimer's pathology: evidence from animal and in vitro models. AB - Alzheimer's disease (AD) causes progressive, age-dependent cortical and hippocampal dysfunction leading to abnormal intellectual capacity and memory. We propose a novel protective treatment for AD pathology with phytic acid (inositol hexakisphosphate), a phytochemical found in food grains and a key signaling molecule in mammalian cells. We evaluated the protective and beneficial effects of phytic acid against amyloid-beta (Abeta) pathology in MC65 cells and the Tg2576 mouse model. In MC65 cells, 48-72-hour treatment with phytic acid provided complete protection against amyloid precursor protein-C-terminal fragment-induced cytotoxicity by attenuating levels of increased intracellular calcium, hydrogen peroxide, superoxide, Abeta oligomers, and moderately upregulated the expression of autophagy (beclin-1) protein. In a tolerance paradigm, wild type mice were treated with 2% phytic acid in drinking water for 70 days. Phytic acid was well tolerated. Ceruloplasmin activity, brain copper and iron levels, and brain superoxide dismutase and ATP levels were unaffected by the treatment. There was a significant increase in brain levels of cytochrome oxidase and a decrease in lipid peroxidation with phytic acid administration. In a treatment paradigm, 12 month old Tg2576 and wild type mice were treated with 2% phytic acid or vehicle for 6 months. Brain levels of copper, iron, and zinc were unaffected. The effects of phytic acid were modest on the expression of AbetaPP trafficking-associated protein AP180, autophagy-associated proteins (beclin-1, LC3B), sirtuin 1, the ratio of phosphorylated AMP-activated protein kinase (PAMPK) to AMPK, soluble Abeta1-40, and insoluble Abeta1-42. These results suggest that phytic acid may provide a viable treatment option for AD. PMID- 20930279 TI - Phenserine efficacy in Alzheimer's disease. AB - To gather preliminary evidence in Alzheimer's disease (AD) for the efficacy of phenserine, a non-competitive acetylcholinesterase inhibitor that has independent modulatory effects on amyloid-beta generation, a 12-week comparison of patients receiving phenserine (10 and 15 mg BID) or placebo was conducted under double blind conditions. Patients who completed 12 weeks of the double-blind before others were continued in the double-blind to determine longer-term treatment effects. At 12 weeks, mean ADAS-cog (AD assessment scale-cognitive) changes from baseline were -2.5 and -1.9 for high-dose phenserine (n=83) and placebo (n=81) groups, respectively, a non-statistically significant improvement for the high dose phenserine group relative to placebo. CIBIC+ (clinician's interview based impression of change + caregiver's input) values for the high-dose and placebo groups were similar at 12 weeks. For patients who received more than 12 weeks of therapy, the ADAS-cog changes were -3.18 and -0.66 for the high-dose phenserine (n=52) and placebo (n=63) groups, respectively, a difference achieving statistical significance (p=0.0286). After 12 weeks, CIBIC+ values were 3.59 and 3.95 for the high-dose (n=54) and placebo (n=66) groups respectively (p=0.0568). These results from this short-term study are consistent with phenserine potentially benefiting mild to moderate Alzheimer's disease symptomatically but do not address possible amyloid metabolic mediated effects on disease processes in AD. PMID- 20930280 TI - Ghrelin ameliorates cognitive dysfunction and neurodegeneration in intrahippocampal amyloid-beta1-42 oligomer-injected mice. AB - Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by cognitive deficits, neuroinflammation, and loss of neurons. Recently, it has been shown that ghrelin, a 28 amino acid peptide hormone produced from the stomach and hypothalamus, has been reported as a potential therapeutic agent for several neurological disorders, including Parkinson's disease (PD), stroke, epilepsy, multiple sclerosis, and spinal cord injury. Here we determined the effects of ghrelin on memory impairments and neuropathological changes in an AD mouse model induced by intrahippocampal injection of amyloid beta oligomers (AbetaO). We report that ghrelin: 1) rescues memory deficits in mice injected with AbetaO in the hippocampus; 2) decreases AbetaO-induced microgliosis in hippocampus; 3) attenuates hippocampal neuronal loss mediated by AbetaO; 4) prevents AbetaO-associated synaptic degeneration including cholinergic fiber loss. Taken together, our findings demonstrate that ghrelin can ameliorate AbetaO-induced cognitive impairment associated with neuroinflammation and neuronal loss. These results suggest that ghrelin may be a promising therapeutic agent for the treatment of AD. PMID- 20930281 TI - Impaired visual recognition memory in amnestic mild cognitive impairment is associated with mesiotemporal metabolic changes on magnetic resonance spectroscopic imaging. AB - In the early stages of Alzheimer's disease (AD), neurofibrillary tangles develop in the mesial temporal lobe (MTL), first in the anterior subhippocampal (perirhinal/entorhinal) cortex and then in the hippocampal formation. This region plays a key role in visualrecognition memory (VRM). VRM has been reported to be impaired in patients with amnestic mild cognitive impairment (aMCI). The aim of the present study was to determine if an impairment of VRM is associated with metabolic changes in the MTL using magnetic resonance spectroscopic imaging and if evaluating VRM can contribute to the early diagnosis of AD. 28 patients with aMCI and 28 controls underwent a full neuropsychological assessment including an evaluation of VRM using the DMS48. NAA/mIno ratios, reduced in patients with AD and associated with the severity of pathological changes, were determined in the MTL. aMCI-patients were further divided into two subgroups according to their VRM performance. aMCI-patients showed decreased NAA/mIno levels in the right hippocampus compared with controls. aMCI-patients with impaired VRM showed decreased NAA/mIno ratios in the MTL bilaterally, including a region that sampled the left anterior subhippocampal cortex, compared to controls. No changes were found in aMCI patients with normal VRM. Performance on the DMS48 correlated with NAA/mIno levels in the anterior MTL. Clinical 6-year follow-up data (available for 78.6% of the aMCI-patients) indicates that impaired performance on the DMS48 could predict conversion to AD with a sensitivity and specificity of 81.8%. These findings provide further evidence that impaired VRM, as a hallmark of MTL dysfunction, may contribute to the early diagnosis of AD. PMID- 20930282 TI - CSF levels of heart fatty acid binding protein are altered during early phases of Alzheimer's disease. AB - Heart fatty acid binding protein (HFABP) has been proposed as a putative marker for dementia disorders. To evaluate the value of this protein as an early marker of Alzheimer's disease (AD), we analyzed HFABP level and the classical biomarkers amyloid-beta (Abeta)1-42, total tau (t-tau), and phosphorylated tau (p-tau) in cerebrospinal fluid (CSF) of patients with mild cognitive impairment (MCI) followed up for four years (n=41), AD (n=32), and subjects with other neurological diseases without dementia (OND, n=25). HFABP levels were higher in AD patients and in MCI converting to AD (MCI-AD) with respect to OND and to cognitively stable MCI patients (MCI-MCI). The receiver operator characteristics analysis for HFABP alone showed a sensitivity of 87% and a specificity of 81% for AD versus OND (area under the curve, AUC=0.83); sensitivity and specificity were 46% and 94%, respectively, when comparing MCI-MCI versus MCI-AD. CSF HFABP levels showed a strong positive correlation with both t-tau and p-tau. Interestingly, the ratio between HFABP and Abeta1-42 improved the performance in distinguishing AD from OND (sensitivity: 90%; specificity 82%, AUC=0.89), and gave the best accuracy in discriminating MCI-AD from MCI-MCI (sensitivity: 80%; specificity 100%, AUC=0.90). Survival analysis by means of Kaplan-Meier curve showed a significantly higher proportion of MCI patients converting to AD in the group with higher values of HFABP/Abeta1-42 ratio (cut-off=0.7). A significant correlation between HFABP/Abeta1-42 ratio and MMSE annual decrease rate was also documented (p<0.0001). HFABP /Abeta1-42 ratio might be a useful predictor of conversion in MCI patients. PMID- 20930283 TI - Peri-operative risk management in patients with Alzheimer's disease. AB - The aim of this review is to identify an evidence-based perioperative management for patients affected by Alzheimer's disease (AD) that are scheduled to undergo surgery. This will minimize the negative effects of anesthesia and postoperative sedation and correct those perioperative variables possibly responsible for a decline in cognitive status and a worsening of AD. We here gather evidence on the importance of correct preoperative assessment regarding cognitive and functional status and the presence of preoperative delirium. The potential role of anesthesia, surgery, and postoperative analgosedation as risk factors for development of delirium are herein outlined. Finally, pain assessment instruments, as well as principles of management strategies for postoperative delirium in subjects with AD, are suggested. PMID- 20930284 TI - MAPT isoforms: differential transcriptional profiles related to 3R and 4R splice variants. AB - Tau aggregation in neurofibrillary tangles is a pathological hallmark in tauopathies including Alzheimer's disease (AD). The predominant aggregation of certain MAPT (tau gene) isoforms, either the 4-repeat (4R tau) or the 3-repeat (3R tau) isoform has been widely described in tauopathies. Alterations of the 4R tau to 3R tau ratio may be a key for tau-related neurodegeneration. To study the biological consequences in expression between tau splicing isoforms 4R and 3R, we analyzed the main neurobiological effects of inclusion of the repeat region coded by exon 10 in MAPT. We compared the transcriptional profiles of the 4R tau isoforms to 3R tau isoforms using whole-genome gene expression profiling microarrays using human neuroblastoma SH-SY5Y cell lines overexpressing either human 4R tau or 3R tau isoforms. We identified 68 transcripts that differed significantly (at p < 0.001) between 4R and 3R isoforms as conditioned on a second variant, the so-called 2N inclusion. We extended these findings in a 2 * 2 ANOVA to examine interaction effects of these variants. Transcripts involved in embryonic development were downregulated when exon 10 was present, while transcripts related to outgrowth of neurites were generally upregulated. An important pathway implicated in AD also differed between the 3R and 4R cell lines, Wnt signaling. These studies demonstrate expression differences between MAPT isoforms 4R tau and 3R tau due to the inclusion/exclusion of the repeat region coded for by exon 10. Our data add to complex findings on the role of 3R/4R in normal and abnormal neuronal function and highlight several molecular mechanisms that might drive neurodegeneration, or perhaps, set the stage for it. PMID- 20930285 TI - Anesthetics and Alzheimer's disease. Editorial. PMID- 20930286 TI - BACE1 mRNA expression in Alzheimer's disease postmortem brain tissue. AB - beta-site AbetaPP cleaving enzyme 1 (BACE1) catalyses the rate-limiting step for production of amyloid-beta (Abeta) peptides, involved in the pathological cascade underlying Alzheimer's disease (AD). Elevated BACE1 protein levels and activity have been reported in AD postmortem brains. Our study explored whether this was due to elevated BACE1 mRNA expression. RNA was prepared from five brain regions in three study groups: controls, individuals with AD, and another neurodegenerative disease group affected by either Parkinson's disease (PD) or dementia with Lewy bodies (DLB). BACE1 mRNA levels were measured using quantitative realtime PCR (qPCR) and analyzed by qbasePLUS using validated stably expressed reference genes. Expression of glial and neuronal markers (glial fibrillary acidic protein (GFAP) and neuron-specific enolase (NSE), respectively) were also analyzed to quantify the changing activities of these cell populations in the tissue. BACE1 mRNA levels were significantly elevated in medial temporal and superior parietal gyri, compared to the PD/DLB and/or control groups. Superior frontal gryus BACE1 mRNA levels were significantly increased in the PD/DLB group, compared to AD and control groups. For the AD group, BACE1 mRNA changes were analyzed in the context of the reduced NSE mRNA, and strongly increased GFAP mRNA levels apparent as AD progressed (indicated by Braak stage). This analysis suggested that increased BACE1 mRNA expression in remaining neuronal cells may contribute to the increased BACE1 protein levels and activity found in brain regions affected by AD. PMID- 20930287 TI - Grouping and trajectories of neuropsychiatric symptoms in patients with Alzheimer's disease. Part II: two-year patient trajectories. AB - Behavioral and psychological symptoms of dementia (BPSD) are characterized by fluctuations in their frequency and severity as well as by differences in the concurrent presentation of different symptoms. The goal of the current study was to identify groups of patients with Alzheimer's disease (AD) that had similar trajectories in the expression of BPSD. Over a 24-month period, an observational study was conducted using a population of ambulatory patients with AD of mild or moderate severity. The Neuropsychiatric Inventory (NPI) was administered every 6 months to the patient's caregiver. To classify patients according to changes in the frequency and severity of BPSD, growth mixture models were fitted to the applied to the grouping of NPI subscales in the following three categories: psychotic syndrome (hallucinations and delusions), affective syndrome (depression, anxiety, irritability, and agitation), and behavioral syndrome (disinhibition, euphoria, apathy, and aberrant motor behavior). The sample population consisted of 491 patients (70.9% women) that had an average age of 75.2 years (SD=6.6). Different trajectory patterns were identified based on differences in changes over the time in the frequency (stable, increasing, decreasing, or fluctuating in course) and severity (low, moderate, or elevated severity) for psychotic syndrome, emotional syndrome, and behavior syndrome. Patients with AD display a high degree of variability in the evolutionary course of BPSD. It is possible to identify groups of patients with similar evolutionary trajectories in terms of changes in the frequency and severity of BPSD. PMID- 20930288 TI - Cortical changes in incipient Alzheimer's disease. AB - Mild cognitive impairment (MCI) is defined by memory impairment with no impact on daily activities. 10 to 15% of MCI convert to Alzheimer's disease (AD) per year. While structural changes in the cortex of AD patients have been extensively investigated, fewer studies analyzed changes in the years preceding conversion. 46 MCI patients and 20 healthy controls underwent structural 1.0T-weighted high resolution MR scans at baseline and after 1.4 (SD 0.3) years. All subjects were assessed yearly for up to 4 years with a comprehensive neuropsychological battery. Sixteen of the 46 patients converted to AD (cMCI) while 30 remained stable (sMCI). An accurate voxel-based statistical mesh-model technique (cortical pattern matching) with a related region-of-interest analysis based on networks defined from a Brodmann area atlas (BAs) were used to map gray matter changes over time. At baseline, cMCI patients had 10 to 30% less cortical gray matter volume than healthy controls in regions known to be affected by AD pathology (entorhinal, temporoparietal, posterior cingulate, and orbitofrontal cortex, p=0.0001). Over time, cMCI patients lost more gray matter than sMCI in all brain areas but mainly in the olfactory and in the polysynaptic hippocampal network (more than 8% gray matter loss, p<0.024). sMCI patients had 10 to 20% less volume than controls in the posterior cingulate and orbitofrontal cortex (p<0.008) although their progression over time was significantly slower than cMCI. AD patients in the MCI stage show greater gray matter loss in the olfactory and polysynaptic hippocampal network. These findings are in line with neuropathological knowledge. PMID- 20930289 TI - Grouping and trajectories of the neuropsychiatric symptoms in patients with Alzheimer's disease, part I: symptom clusters. AB - Behavioral and psychological symptoms of dementia (BPSD) are frequently observed in Alzheimer's disease (AD) and affect more than 80% of patients over the course of AD. The goal of this study was to establish a model for grouping the symptoms of BPSD into clinical syndromes. Over a 24-month period, an observational study was conducted using a population of ambulatory patients with AD of mild to moderate severity. The Neuropsychiatric Inventory (NPI) was administered to the patients' caregivers every 6 months. BPSD were grouped using exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) of the NPI scores of each assessment. The sample population consisted of 491 patients (70.9% women) with an average age of 75.2 years (SD=6.6). The five EFA suggested that there was a stable three-factor structure. According to the results of the EFA, three models of symptom grouping were adjusted using CFA methodology. The CFA model that satisfactorily grouped the NPI scores into three factors included a psychotic syndrome (hallucinations, delusions), an affective syndrome (depression, anxiety, irritability, agitation) and a behavior syndrome (euphoria, disinhibition, apathy, aberrant motor behavior). Based on our findings, we propose a model for grouping the BDSD in which there are core nuclear syndromes (psychotic and affective) as well as an unspecified behavior syndrome comprising satellite symptoms that may be related to the presence of the nuclear syndromes. PMID- 20930290 TI - Mild cognitive impairment is associated with mild parkinsonian signs in a door-to door study. AB - Mild cognitive impairment (MCI) and healthy aging have been shown to be associated with mild parkinsonian signs (MPS). We performed a door-to-door observational and follow-up study amongst consenting residents of Wadi Ara Arab villages in northern Israel aged >=65 years (n=687) to examine whether MPS represent a risk factor for MCI and/or conversion from MCI to Alzheimer's disease (AD). In Phase 1, 223 cognitively normal (CN) and 173 MCI subjects were assessed by interview for medical history, neurological examination, motor part of the Unified Parkinson Disease Rating Scale (mUPDRS) (divided into item-clusters: axial, limb bradykinesia, tremor and rigidity) and cognitive tests. MCI subjects (n=111) were re-evaluated in Phase 2 for conversion to AD at least one year after initial assessment. MCI subjects had a higher frequency of axial dysfunction (8.7% vs. 1.3%) and limb bradykinesia (10.4% vs. 1.3%) than CN subjects (p<0.001, both). Stepwise logistic regression analysis estimating the probability of MCI vs. CN revealed higher mUPDRS (OR =1.19, 95% CI, 1.05 to 1.35, p=0.006) and higher limb bradykinesia scores (OR=1.75, 95% CI, 1.2 to 2.56, p=0.003) and not age as explanatory variables. Presence of MPS did not predict conversion to AD after adjustment for age and time-interval. These results suggest that axial and bradykinetic parkinsonian signs represent risk factors for MCI but MPS may not predict conversion from MCI to AD. PMID- 20930291 TI - Intensity of recreational physical activity throughout life and later life cognitive functioning in women. AB - Long-term physical activity may affect risk of cognitive impairment but few studies have examined later life cognition in relation to intensity of life-long physical activity. We examined the associations between the intensity of long term recreational physical activity and neuropsychological functioning in 90 healthy postmenopausal women on tests found to be useful in the early identification of dementia. Information was collected about their participation in strenuous and moderate activities between high school and menopause. Summary measures of long-term strenuous and moderate activity were constructed for each participant. All analyses were adjusted for relevant covariates. The six linear regression analyses showed significant positive associations between moderate activity and Wechsler Adult Intelligence Scale Revised (WAIS-R), Digit Span backward, WAIS-R Digit Symbol, and Trail Making Test Part B. Significant negative relationships were found between strenuous activity and Rey Auditory Verbal Learning Test delayed verbal recall, Complex Figure Test delayed visual memory, WAIS-R Digit Span backward, category fluency, and WAIS-R Digit Symbol. The associations found in the present study suggest that while moderate activity may be protective, long-term strenuous activity before menopause may lower cognitive performance later in life. These results support further investigation of the effects of life-long exercise intensity on cognition in later life. PMID- 20930292 TI - Information and communication technology systems to improve quality of life and safety of Alzheimer's disease patients: a multicenter international survey. AB - Within the frame of the European Commission funded Smart Home for Elderly People (HOPE) Project, relatives/caregivers of 223 Alzheimer's Disease (AD) patients were recruited in Italy, Spain, and Greece for a multicenter international survey on the potential role of Information and Communication Technology system (ICT systems) for AD patients. A five-minute video on HOPE ICT-systems was shown, and all relatives/caregivers completed a 13-item questionnaire that evaluated the potential role of: A) ICT-systems in improving quality of life, care, and safety; B) devices for monitoring personal movements, medication use, and ambient environmental conditions; C) devices to improve communication, home-based rehabilitation, and reduction of specific risks; and D) possible agreement in using ICT-systems by AD patients. Relatives/caregivers reported that ICT-systems could be very useful to improve: A) quality of life (66.4%), care (56.1%), and safety (87.0%); B) monitoring bed rest and movements (80.7%), medication use (87.4%), and ambient environmental conditions (85.2%); and C) emergency communication (83.4%). Relatives/caregivers reported that ICT-systems could be significantly more useful for AD patients aged 75-84 than patients aged <75 or >=85 years (p < 0.0001) and with moderate than mild or severe dementia (p < 0.0001). Relatives/caregivers aged >=50 years and with low educational level considered ICT-systems more useful than relatives/caregivers aged <50 years (p < 0.0001) and with high educational level (p < 0.0001). In conclusion, relatives/caregivers considered that the HOPE ICT-system could be useful to improve the management of AD patients. PMID- 20930293 TI - The Alzheimer's questionnaire: a proof of concept study for a new informant-based dementia assessment. AB - The aim of this pilot study is to determine the feasibility and clinical utility of a brief, informant-based screening questionnaire for Alzheimer's disease (AD) that can be administered in a primary care setting. The Alzheimer's Questionnaire (AQ) was administered to the informants of 188 patients in 3 dementia clinics (50 cognitively normal, 69 mild cognitive impairment (MCI), 69 AD). Total score for the AQ is based upon the sum of clinical symptom items in which the informant responds as being present. Clinical symptoms which are known to be highly predictive of the clinical AD diagnosis are given greater weight in the total AQ score. The mean time of administration of the AQ was 2.6 +/- 0.6 minutes. Sensitivity and specificity were found to be high for detecting both AD (98.55, 96.00) and MCI (86.96, 94.00) with ROC curves yielding AUC values of 0.99 and 0.95, respectively. This pilot study indicates that the AQ is a brief, sensitive measure for detecting both MCI and AD and could be easily implemented in a primary care setting. PMID- 20930294 TI - Redox proteomics analysis of brains from subjects with amnestic mild cognitive impairment compared to brains from subjects with preclinical Alzheimer's disease: insights into memory loss in MCI. AB - Alzheimer's disease (AD) is a central nervous system disorder pathologically characterized by senile plaques, neurofibrillary tangles, and synapse loss. A small percentage of individuals with normal antemortem psychometric scores, after adjustments for age and education, meet the neuropathological criteria for amnestic mild cognitive impairment (MCI) or AD; these individuals have been termed 'preclinical' or 'asymptomatic' AD (PCAD). In this study, we employed the immunochemical slot-blot method and two-dimensional gel-based redox proteomics to observe differences in protein levels and oxidative modifications between groups with equal levels of AD pathology who differ in regards to clinical symptoms of memory impairment. Results of global oxidative stress measurements revealed significantly higher levels of protein carbonyls in the MCI inferior parietal lobule (IPL) relative to PCAD (and controls), despite equal levels of neuropathology. Proteomics analysis of the IPL revealed differences in protein levels and specific carbonylation that are consistent with preservation of memory in PCAD and apparent memory decline in MCI. Our data suggest that marked changes occur at the protein level in MCI that may cause or reflect memory loss and other AD symptoms. PMID- 20930295 TI - Ultrafiltrate of blood plasma modulates amyloid-beta aggregation. AB - Several neurodegenerative diseases, including Alzheimer's disease (AD), have etiology connected to abnormal protein self association. Copper-induced striking differences in amyloid-beta40 aggregation, distinct from spontaneous self association, prompted us to study whether amyloid-beta40 aggregation could be applied to differentiate between platelet poor plasma ultrafiltrates obtained from AD and control samples. We report, based on 20 AD and 18 age-matched controls, a significant difference in the concentration of short fibers induced by ultrafiltrated plasma from AD compared to control samples. The observed effect was independent of copper and other EDTA chelatable ions. PMID- 20930296 TI - One-carbon metabolism alteration affects brain proteome profile in a mouse model of Alzheimer's disease. AB - Late Onset Alzheimer's Disease (LOAD) can be associated to high homocysteine level and alteration of one-carbon metabolism. We previously demonstrated in the TgCRND8 mice strain, over-expressing human amyloid-beta protein precursor, that B vitamin deficiency causes alteration of one-carbon metabolism, together with unbalance of S-adenosylmethionine/S-adenosylhomocysteine levels, and is associated with AD like hallmarks as increased amyloid-beta plaque deposition, hyperhomocysteinemia, and oxidative stress. The same model of nutritional deficit was used here to study the variation of the brain protein expression profile associated to B vitamin deficiency. A group of proteins mainly involved in neuronal plasticity and mitochondrial functions was identified as modulated by one-carbon metabolism. These findings are consistent with increasing data about the pivotal role of mitochondrial abnormalities in AD patho-physiology. The identified proteins might represent new potential biomarkers of LOAD to be further investigated. PMID- 20930297 TI - Free copper distinguishes mild cognitive impairment subjects from healthy elderly individuals. AB - In patients affected by Alzheimer's disease (AD), serum copper not bound to ceruloplasmin ('free' copper) appears elevated, slightly but significantly enough to distinguish AD patients from healthy elderly subjects. In this paper we tested the hypothesis that this is also the case for individuals affected by mild cognitive impairment (MCI). A sample of 83 MCI subjects were compared with 100 elderly control subjects in terms of levels of serum copper, free copper, ceruloplasmin, apolipoprotein E4 genotype (APOE4), iron, transferrin, and total antioxidant capacity (TRAP). The groups were also compared in terms of demographic and cardiovascular risk factors. The comparison with an additional group of 105 mild to moderate AD patients was also evaluated. The possible effects of copper dysfunction on cognitive decline were evaluated by multinomial logistic regression analysis. A linear regression model was applied to define the role of metals and antioxidant dysfunction in explaining Mini-Mental Status Examination (MMSE) variations. APOE4 and free copper differentiated the MCI group from the healthy control group. The probability of acquiring MCI increased by about 24% for each free copper unit (MUmol/L) increment. APOE4 and free copper differentiated the MCI group also from the AD group. APOE4 and free copper appeared associated to MMSE worsening, as did age and gender. These results suggest that free copper can help in discriminating MCI subjects from healthy controls, but not on an individual basis. PMID- 20930298 TI - Shape abnormalities of the striatum in Alzheimer's disease. AB - Postmortem studies show pathological changes in the striatum in Alzheimer's disease (AD). Here, we examine the surface of the striatum in AD and assess whether changes of the surface are associated with impaired cognitive functioning. The shape of the striatum (n. accumbens, caudate nucleus, and putamen) was compared between 35 AD patients and 35 individuals without cognitive impairment. The striatum was automatically segmented from 3D T1 magnetic resonance images and automatic shape modeling tools (Growing Adaptive Meshes) were applied for morphometrical analysis. Repeated permutation tests were used to identify locations of consistent shape deformities of the striatal surface in AD. Linear regression models, corrected for age, gender, educational level, head size, and total brain parenchymal volume were used to assess the relation between cognitive performance and local surface deformities. In AD patients, differences of shape were observed on the medial head of the caudate nucleus and on the ventral lateral putamen, but not on the accumbens. The head of the caudate nucleus and ventral lateral putamen are characterized by extensive connections with the orbitofrontal and medial temporal cortices. Severity of cognitive impairment was associated with the degree of deformity of the surfaces of the accumbens, rostral medial caudate nucleus, and ventral lateral putamen. These findings provide evidence for the hypothesis that in AD primarily associative and limbic cerebral networks are affected. PMID- 20930299 TI - Prion protein is reduced in aging and in sporadic but not in familial Alzheimer's disease. AB - The cellular form of the prion protein (PrPC) has been shown to inhibit the production of amyloid-beta which is critically involved in the pathogenesis of Alzheimer's disease (AD). We examined the expression of PrPC by immunoblot analysis in the hippocampus and temporal cortex in sporadic AD, familial AD, and appropriate age-matched controls, and in an aging series (age 20 to 88 years) of brains. PrPC was reduced by 53% (p=0.032) in the hippocampus in sporadic AD as compared to the age-matched controls. No such reduction in PrPC was seen in familial AD. PrPC was reduced in the hippocampus with aging (rs=0.03). The reduction in PrPC in sporadic but not familial AD suggests that reduced PrPC expression reflects a primary mechanism of disease and is not merely a secondary consequence of other AD-associated changes. The reduction of PrPC in the brain with aging suggests that age-related decreases in PrPC may contribute to the increased incidence of AD in older people. PMID- 20930300 TI - A multi-center randomized proof-of-concept clinical trial applying [18F]FDG-PET for evaluation of metabolic therapy with rosiglitazone XR in mild to moderate Alzheimer's disease. AB - Here we report the first multi-center clinical trial in Alzheimer's disease (AD) using fluorodeoxyglucose positron emission tomography ([18F]FDG-PET) measures of brain glucose metabolism as the primary outcome. We contrasted effects of 12 months treatment with the PPARgamma agonist Rosiglitazone XR versus placebo in 80 mild to moderate AD patients. Secondary objectives included testing for reduction in the progression of brain atrophy and improvement in cognition. Active treatment was associated with a sustained but not statistically significant trend from the first month for higher mean values in Kiindex and CMRgluindex, novel quantitative indices related to the combined forward rate constant for [18F]FDG uptake and to the rate of cerebral glucose utilization, respectively. However, neither these nor another analytical approach recently validated using data from the Alzheimer's Disease Neuroimaging Initiative indicated that active treatment decreased the progression of decline in brain glucose metabolism. Rates of brain atrophy were similar between active and placebo groups and measures of cognition also did not suggest clear group differences. Our study demonstrates the feasibility of using [18F]FDG-PET as part of a multi-center therapeutics trial. It suggests that Rosiglitazone is associated with an early increase in whole brain glucose metabolism, but not with any biological or clinical evidence for slowing progression over a 1 year follow up in the symptomatic stages of AD. PMID- 20930301 TI - The effect of MAPT H1 and APOE epsilon4 on transition from mild cognitive impairment to dementia. AB - Microtubule-associated protein tau (MAPT) and apolipoprotein E (APOE) are involved in the pathogenic mechanisms of Alzheimer's disease (AD). We prospectively followed three longitudinal independent samples (total n=319) with amnestic mild cognitive impairment (MCI) and analyzed whether MAPT H1/H2 haplotypes and APOE epsilon4 polymorphisms accelerated the rate of progression from MCI to dementia. At the end of the study, 172 subjects remained cognitively stable, whereas 147 progressed to dementia. APOE epsilon4 and MAPT H1/H1 were independently associated with an increased rate of progression to dementia in the combined sample. Cox regression models of the combined MCI sample showed that MAPT H1/H1 carriers had an increased rate of progression to dementia compared with non carriers (Hazard Ratio =1.45; 95% CI=1.04-2.02; p=0.028) and time-to progression was shortened by 1.37 years. APOE epsilon4 allele also accelerated progression to dementia (Hazard Ratio=1.47; 95% CI= 1.06-2.04; p=0.020) and reduced the time-to-progression by 0.87 years. Additionally, MAPT H1/H1 genotype and APOE epsilon4 allele had an additive effect in progression to dementia, increasing progression rate to dementia (Hazard Ratio=2.24, 95% CI =1.40-3.58; p=0.001) and shortening time-to-progression to dementia by 2.92 years. Similar results were obtained when only considering progression to AD-type dementia. Our results suggest that both MAPT H1/H1 genotype and APOE epsilon4 allele lead to a more rapid progression to dementia among MCI subjects, probably mediating an increased rate of amyloid-beta and tau brain deposition. PMID- 20930302 TI - Hydrogen sulfide protects amyloid-beta induced cell toxicity in microglia. AB - Alzheimer's disease (AD) is pathologically characterized by the accumulation of senile plaques, containing activated microglia and amyloid-beta peptides (Abeta). We found that aggregated Abeta1-40 peptide (25 MUM, 24 h) significantly decreased viability of BV-2 microglial cells. This was concentration-dependently attenuated by NaHS (a hydrogen sulfide (H2S) donor, 25-500 MUM). NaHS also significantly attenuated Abeta-induced LDH release and the up-regulation of protein expression of growth arrest DNA damage (GADD 153). These data suggest that H2S may attenuate Abeta-induced cell toxicity and cell cycle re-entry. Pretreatment with NaHS also suppressed the release of nitric oxide and the upregulation of inducible nitric oxide synthase. These effects were attenuated by exogenous application of NaHS or stimulation of endogenous generation of H2S with S-adenosyl-L-methionine, a cystathionine beta synthase activator. NaHS also decreased the releases of TNF alpha and suppressed the up-regulation of protein expression of cyclooxygenase 2, which were mimicked by blockade of p38 and JNK-MAPK. In addition, Abeta induced loss of mitochondrial member potential (DeltaPsim) and activation of p38-, JNK-, and ERK-MAPKs. Application of NaHS attenuated these effects but failed to affect the activation of ERK. In conclusion, we demonstrated for the first time that H2S may protect cell against Abeta-induced cell injury by inhibition of inflammation, promotion of cell growth and preservation of mitochondrial function in a p38- and JNK-MAPK dependent manner. Our results suggest that H2S may have potential therapeutic value for treatment of AD. PMID- 20930303 TI - Higher cathepsin B levels in plasma in Alzheimer's disease compared to healthy controls. AB - Cathepsin B is suggested to be involved in amyloid-beta (Abeta) processing and Alzheimer's disease (AD). Studies of cathepsin B levels in plasma and cerebrospinal fluid (CSF) have not been previously performed. We examined cathepsin B levels in plasma and CSF samples in persons with AD, mild cognitive impairment (MCI), and healthy controls in order to test the hypothesis that cathepsin B levels can discriminate persons with AD or MCI from healthy controls. Cathepsin B, Cystatin C, Abeta1-40 and Abeta1-42, total tau, phosphorylated tau, and albumin levels in plasma and CSF were analyzed by ELISA (Cathepsin B) turbidimetry (cystatin C), xMAP Luminex technology (Abeta1-40 and Abeta1-42 and tau), and Cobas C501 analyzer (albumin) in persons with AD (n=101), MCI (n=84), and healthy control subjects (n=28). Plasma cathepsin B levels were higher in persons with AD compared to healthy controls, both in unadjusted models and in multivariable models adjusting for age, gender, APOE genotype, cystatin C, and albumin levels: Odds ratio (OR) for AD per 1 SD of plasma cathepsin B; 2.04, 95% confidence interval (CI); 1.01-4.14, p= 0.05. There was no difference between diagnostic groups in cathepsin B levels in CSF: OR for AD per 1 SD of CSF cathepsin B; 0.93, 95% CI; 0.37-2.30, p= 0.87. Plasma cathepsin B levels were higher in persons with AD compared to healthy controls whereas there was no difference between diagnostic groups in cathepsin B levels in CSF. Further investigation of cathepsin B as a predictor of AD is warranted. PMID- 20930304 TI - Assessment of non-viral amyloid-beta DNA vaccines on amyloid-beta reduction and safety in rhesus monkeys. AB - We recently demonstrated that newly developed non-viral amyloid-beta (Abeta) DNA vaccines are safe and effective in reducing Abeta burdens in the brains of Alzheimer's disease (AD) model mice. The present study was undertaken to examine whether DNA vaccines effectively and safely reduce Abeta deposition in the brain of rhesus monkeys. For this purpose, DNA vaccines or empty vector at a dose of 3 mg were injected intramuscularly on a biweekly basis into rhesus monkeys (15-18 years old). Before and during vaccination, blood was drawn once a month and used for hematological and biochemical examinations. Six months after the first vaccination, it was demonstrated that anti-Abeta antibodies in plasma of vaccinated monkeys were significantly elevated than that of control monkeys. Immunohistochemical examinations revealed that DNA vaccination reduced the Abeta burden to approximately 50% of that found in control monkeys (p=0.026). There was neither inflammation nor microhemorrhage in the brain and no significant changes in cytokine and chemokine levels in the blood throughout the observation period. Taken together, DNA vaccination to monkeys is safe and effective in Abeta reduction and provides useful information for performing preclinical and clinical trials. PMID- 20930305 TI - Impact of executive dysfunction on verbal memory performance in patients with Alzheimer's disease. AB - It is currently accepted that there is a subset of patients diagnosed with Alzheimer's disease (AD) who show executive functioning (EF) impairments even in the earlier stages. These patients have been shown to present distinct psychiatric, behavioral, occupational, and even histopathological profiles. We assessed thirty patients with AD on two tasks of verbal memory (Logical Memory - LM, and the Rey Auditory-Verbal Learning Task - RAVLT), as well as classical tests of EF. AD patients were classified into either a spared EF (SEF) group if they showed impaired performance (z < -1.5 SD) in none or only one of the executive tests, or into an impaired EF (IEF) group if they showed impaired performance on two or more tasks of EF. Their performance was compared with fourteen healthy controls. SEF showed significantly more years of education than IEF, but the groups did not differ significantly on age, gender, mood symptoms, or performance on general screening tests or attentional tasks. With education as a covariate, both AD groups differed from controls on all measures of memory, but a significant difference was found between SEF and IEF patients only on the recognition phases of both logical memory (p < 0.01) and RAVLT (p = 0.02). Recognition scores significantly correlated with performance on executive tasks. Early AD patients who preserve their EF seem to have an advantage in their ability to recognize information that has been previously presented over patients with impaired EF. Such advantage seems to be strongly associated with executive performance. PMID- 20930306 TI - Reactivity of cortical alpha rhythms to eye opening in mild cognitive impairment and Alzheimer's disease: an EEG study. AB - Cortical sources of resting eyes-closed alpha rhythms are typically abnormal in mild cognitive impairment (MCI) and Alzheimer's disease (AD) subjects. Here we tested the hypothesis of a progressive impairment of cortical alpha reactivity to eye-opening across amnesic MCI and mild AD subjects, reflecting another aspect of the impairment of cortical neural synchronization. Resting electroencephalography (EEG) data were recorded in 36 normal elderly subjects (Nold), 91 amnesic MCI, and 31 mild AD subjects during eyes-closed and -open conditions. EEG sources were estimated by LORETA software. In the eye-closed condition, posterior alpha 1 (8 10.5 Hz) sources were lower in MCI and AD than Nold subjects. The opposite was true for occipital delta sources (2-4 Hz). Reactivity to the eyes-open condition showed posterior alpha 1 and alpha 2 (10.5-13 Hz) sources was high in the Nold, intermediate in the MCI, and low in the AD subjects. Furthermore, occipital alpha 1 reactivity across MCI and AD subjects was correlated to the cognitive impairment as revealed by Mini-Mental State Examination score. In conclusion, at least at group level, the continuum across amnesic MCI and mild AD status is related to an impaired reactivity of cortical neuronal synchronization to eyes opening at alpha rhythms. PMID- 20930307 TI - Enhanced expression of the voltage-dependent anion channel 1 (VDAC1) in Alzheimer's disease transgenic mice: an insight into the pathogenic effects of amyloid-beta. AB - The mitochondrial voltage-dependent anion channel 1 (VDAC1) is involved in the release of apoptotic proteins with possible relevance in Alzheimer's disease (AD) neuropathology. Through proteomic analysis followed by Western blotting and immunohistochemical techniques, we have found that VDAC1 is overexpressed in the hippocampus from amyloidogenic AD transgenic mice models. VDAC1 was also overexpressed in postmortem brain tissue from AD patients at an advanced stage of the disease. Interestingly, amyloid-beta (Abeta) soluble oligomers were able to induce upregulation of VDAC1 in a human neuroblastoma cell line, further supporting a correlation between Abeta levels and VDAC1 expression. In hippocampal extracts from transgenic mice, a significant increase was observed in the levels of VDAC1 phosphorylated at an epitope that is susceptible to phosphorylation by glycogen synthase kinase-3beta, whose activity was also increased. The levels of hexokinase I (HXKI), which interacts with VDAC1 and affects its function, were decreased in mitochondrial samples from AD models. Since phospho-VDAC and reduced HXKI levels favors a VDAC1 conformational state more prone to the release proapoptotic factors, regulation of the function of this channel may be a promising therapeutic approach to combat AD. PMID- 20930308 TI - Postoperative cognitive dysfunction: toward the Alzheimer's disease pathomechanism hypothesis. AB - Alzheimer's disease (AD), a chronic and progressive deterioration of memory and other cognitive domains, is the most common form of dementia. Because of related health and social impact, there is growing interest in assessing potential relationship between anesthesia and the onset and progression of chronic neurodegenerative disorders, including AD. Currently, preclinical and clinical research is addressed to identify underlying pathomechanisms, patient risk factors, and the use of the least provocative drugs and techniques, to minimize the incidence of chronic neurodegenerative disorders. Preclinical studies are providing an increasing body of evidences on some of the mechanisms that link anesthetics to neuronal programmed cell death (apoptosis) and accumulation of misfolded proteins in the aging brain. Therefore, risk factors and pathomechanisms of chronic neurodegenerative disorders, including AD, and persistent postoperative-postanesthesia cognitive dysfunction may overlap. PMID- 20930309 TI - Evaluation of intrathecal serum amyloid P (SAP) and C-reactive protein (CRP) synthesis in Alzheimer's disease with the use of index values. AB - Serum amyloid P (SAP) and C-reactive protein (CRP) are proteins involved in innate immunity. The expression of SAP and CRP is increased in Alzheimer's disease (AD) brain tissue, compared to healthy controls. Although both proteins are found in cerebrospinal fluid (CSF), their origin is unclear. We investigated if increased local production of SAP and CRP in AD brain results in higher levels in CSF with the use of index values. To study this, SAP, CRP, and albumin levels were determined in CSF and serum samples of 30 control (65 +/- 11 years; 57% female) and 140 AD subjects (65 +/- 9 years; 53% female). To correct for inter individual differences in protein diffusion from blood to CSF, quotients (Q =CSF/serum) of SAP, CRP, and albumin and index values (Qprotein/Qalb) were calculated. The results showed no significant differences in SAP and CRP index values between control and AD subjects, although eight percent of individual AD patients showed evidence of intrathecal SAP or CRP production using the Reiber hyperbolic model. Interestingly, the SAP index value was much lower than expected, based on its molecular size. In conclusion, these data suggest that local production of SAP and CRP in the AD brain does not substantially contribute to the CSF levels. PMID- 20930310 TI - Higher serum sTNFR1 level predicts conversion from mild cognitive impairment to Alzheimer's disease. AB - The activation of inflammatory cascades has been consistently demonstrated in the pathophysiology of Alzheimer's disease (AD). Among several putative neuroinflammatory mechanisms, the tumor necrosis factor alpha (TNF-alpha) signaling system has a central role in this process. Recent evidence indicates that the abnormal production of inflammatory factors may accompany the progression from mild cognitive impairment (MCI) to dementia. We aimed to examine serum levels of TNF-alpha and its soluble receptors (sTNFR1 and sTNFR2) in patients with MCI and AD as compared to cognitively unimpaired elderly subjects. We further aimed to investigate whether abnormal levels of these cytokines predict the progression from MCI to AD upon follow-up. We utilized cross sectional determination of serum levels of TNF-alpha, sTNFR1, and sTNFR2 (ELISA method) in a test group comprising 167 older adults (31 AD, 72 MCI, and 64 healthy controls), and longitudinal reassessment of clinical status after 18.9 +/ 10.0 months. At baseline, there were no statistically significant differences in serum TNF-alpha, sTNFR1, and sTNFR2 between patients with MCI and AD as compared to controls. Nevertheless, patients with MCI who progressed to AD had significantly higher serum sTNFR1 levels as opposed to patients who retained the diagnosis of MCI upon follow-up (p = 0.03). Cox regression analysis showed that high serum sTNFR1 levels predicted the conversion from MCI to AD (p = 0.003), whereas no significant differences were found with respect to serum levels of TNF alpha and sTNFR2. Abnormal activation of TNF-alpha signaling system, represented by increased expression of sTNFR1, is associated with a higher risk of progression from MCI to AD. PMID- 20930311 TI - Unusual risk factors for cognitive decline. AB - The evaluation and management of patients with cognitive decline pose many diagnostic and therapeutic challenges. While most cognitive disorders need a standard screening for common reversible causes, the diagnosis of 'not so usual' causes are delayed and often missed. It is important to be aware of such clinical scenarios, especially since a lot of these are reversible. Many coexisting metabolic, nutritional, endocrinal, toxic, and infectious causes mask the subtle and progressive cognitive changes that become apparent with stress and in the post operative period, often after a major surgery. Many more metabolic, nutritional, endocrinal, toxic, post operative, autoimmune, cerebrovascular, genetic, infectious, and hemorheological factors are now emerging as unusual causes. This review deals with the recognition and evaluation of these unusual causes of cognitive decline. PMID- 20930312 TI - Chromatin-modifying agents increase transcription of CYP46A1, a key player in brain cholesterol elimination. AB - The major mechanism of brain cholesterol elimination is the conversion of cholesterol into 24S-hydroxycholesterol by CYP46A1, a neuron-specific cytochrome P450. Since increasing evidence suggests that upregulation of CYP46A1 may be relevant for the treatment of Alzheimer's disease, we aim to identify the molecular mechanisms involved in CYP46A1 transcription. Our previous studies demonstrated the role of Sp transcription factors in basal expression and histone deacetylase (HDAC) inhibitor-dependent derepression of CYP46A1. Here, we show that the demethylating agent 5'-Aza-2'-deoxycytidine (DAC) is a CYP46A1 inducer and that pre-treatment with DAC causes a marked synergistic activation of CYP46A1 transcription by trichostatin A. Surprisingly, bisulfite sequencing analysis revealed that the CYP46A1 core promoter is completely unmethylated in both human brain and non-neuronal human tissues where CYP46A1 is not expressed. Therefore, we have investigated Sp expression levels by western blot and real-time PCR, and their binding patterns to the CYP46A1 promoter, by electrophoretic mobility shift assay and chromatin immunoprecipitation assays, after DAC treatment. Our results showed that DAC decreases not only Sp1 and Sp3 protein levels, but also the binding activity of Sp3 to the +1 region of the CYP46A1 locus. Concomitantly, HDAC1 and HDAC2 were also significantly dissociated from the promoter. In conclusion, DAC induces CYP46A1 gene expression, in a DNA methylation-independent mechanism, decreasing Sp3/HDAC binding to the proximal promoter. Furthermore, by affecting the expression of the Sp3 transcription factor in neuronal cells, DAC might affect not only brain cholesterol metabolism, but also the expression of many other neuronal genes. PMID- 20930313 TI - In vivo detection of amyloid plaques in the mouse brain using the near-infrared fluorescence probe THK-265. AB - Noninvasive detection of amyloid-beta (Abeta) deposits in the brain would be beneficial for an early and presymptomatic diagnosis of Alzheimer's disease (AD). We developed THK-265 as a candidate near-infrared fluorescence (NIRF) probe for the in vivo detection of amyloid deposits in the brain. The maximal emission wavelength of THK-265 was greater than 650nm and it showed high quantum yield and molar absorption coefficients. A fluorescence binding assay showed its high binding affinity to Abeta fibrils (Kd = 97 nM). THK-265 clearly stained amyloid plaques in AD neocortical brain sections and showed a moderate log p value (1.8). After intravenous administration of THK-265 in amyloid-beta protein precursor (AbetaPP) transgenic mice, amyloid deposits in the brain were clearly labeled with THK-265. Furthermore, in vivo NIRF imaging demonstrated significantly higher fluorescence intensity in the brains of AbetaPP transgenic mice than in those of wild-type mice. As THK-265 showed profound hyperchromic effect upon binding to Abeta fibrils, good discrimination between AbetaPP transgenic and wild-type mice was demonstrated even early after THK-265 administration. Furthermore, the fluorescence intensity of THK-265 correlated with amyloid plaque burden in the brains of AbetaPP transgenic mice. These findings strongly support the usefulness of THK-265 as an NIRF imaging probe for the noninvasive measurement of brain amyloid load. PMID- 20930314 TI - CERAD neuropsychological battery total score in multinational mild cognitive impairment and control populations: the AddNeuroMed study. AB - An important focus in Alzheimer's disease (AD) research is the development of methods for early diagnosis. Despite progress with some other biomarkers, sensitive and specific neuropsychological measures for identifying subjects in the prodromal phase of AD remain the most promising early diagnostic tool. We evaluated the value of the composite score for the Consortium to Establish a Registry for Alzheimer's disease Neuropsychological Battery (CERAD-NB) in Europeans with mild cognitive impairment (MCI) and in control populations. Baseline clinical data were analyzed from 223 healthy elderly and 224 subjects with MCI from the prospective AddNeuroMed study carried out in Finland, France, Greece, Italy, Poland, and the United Kingdom. The total score for CERAD-NB was calculated by the subtest addition method. The CERAD total score, adjusted for age, gender, education, and country, clearly differentiated the control and MCI groups (p < 0.001). The optimal between-groups cut-off point for the CERAD total score derived from ROC analysis yielded 81.5% sensitivity and 75.4% specificity (AUC = 0.848, p < 0.001). The CERAD total score was superior to the Mini-Mental Status Examination, or any single CERAD subtest in discriminating between the control and MCI groups. While the overall level of the CERAD total score varied between the different countries, it remained accurate in differentiating controls and MCI subjects within each country. We conclude that the CERAD total score is an accurate measure for detecting mild cognitive impairment, but implementing specific cut-off points needs to be based upon country specific normative data. PMID- 20930315 TI - Prediction of all-cause dementia using neuropsychological tests within 10 and 5 years of diagnosis in a community-based sample. AB - While neuropsychological tests have been identified for the early prediction of Alzheimer's disease, this has not been established for prediction of all-cause dementia. This would be helpful for clinicians concerned about the risk of progression to dementia in patients who may present with a variety of medical and neurological conditions. We wanted to determine whether neuropsychological tests could accurately predict incident dementia within 10 and five years of diagnosis in a community-based sample. The Canadian Study of Health and Aging was conducted in three waves over a 10-year period (1991-2002). We studied 1472 non-demented participants who completed neuropsychological testing in 1991 and received a diagnostic assessment for dementia in 2001 (n = 284). We also studied 1231 non demented participants who completed neuropsychological testing in 1996 and received a diagnostic assessment in 2001 (n = 634). Diagnosticians were blinded to performance on the predictive tests. Age, education, and sex were included as covariates in all regression analysis. Ten-year prediction: 2 tests, Rey Auditory Verbal Learning Test (RAVLT) short delayed verbal recall and Wechsler Adult Intelligence Test Revised (WAIS-R) Digit Symbol, were significant predictors of dementia (sensitivity = 78%, specificity = 72%, positive likelihood ratio = 2.81). Five-year prediction: 4 tests, Wechsler Memory Scale Information, RAVLT short delayed verbal recall, animal fluency, and WAIS-R Digit Symbol, significantly predicted incident dementia (sensitivity = 75%, specificity = 74%, positive likelihood ratio = 2.90). Regression models were supported with bootstrapping estimates. Neuropsychological tests can accurately predict progression to all-cause dementia within 10 years of diagnosis in a large community-based sample of non-demented participants. PMID- 20930317 TI - Anesthetics and Alzheimer's disease: background and research. Preface. PMID- 20930316 TI - Olfactory deficits and amyloid-beta burden in Alzheimer's disease, mild cognitive impairment, and healthy aging: a PiB PET study. AB - Olfactory deficits and increased amyloid-beta (Abeta) burden are observed in people with amnestic mild cognitive impairment (aMCI); both factors may be predictive of Alzheimer's disease (AD). We explored whether olfactory identification is related to in vivo measures of Abeta burden using Pittsburgh Compound B (PiB) PET. Nineteen control, 24 aMCI, and 20 AD participants completed an olfactory identification task and underwent PiB PET scanning. Control participants performed better on olfactory identification and showed lower PiB binding than aMCI patients. There was a significant correlation between both factors when pooling all groups together but not when considering each group separately. In addition, the olfactory identification score did not differ between aMCI participants who were PiB-positive and those who were PiB-negative. We conclude that AD-related olfactory identification deficits are not directly related to Abeta burden. PMID- 20930318 TI - Papers from the 5th Scientific Meeting on Cartilage Engineering, February 2010, Nancy, France. Foreword. PMID- 20930319 TI - Regulatory enablers and regulatory challenges for the development of tissue engineered products in the EU. AB - The EU Regulation on Advanced Therapy Medicinal Products (ATMP) bridges a regulatory gap and is expected to act as an enabler for the regenerative medicine sector in the EU by setting a centralised and harmonised regulatory framework for tissue-engineered products. Some of its key features are a workable and comprehensive scope, a new committee allowing for a pooling of expertise and tailored yet flexible requirements meant to keep pace with technology development. However, while providing a much needed regulatory framework, the new regulation still has potential shortfalls with regard to facilitating the research and commercialisation of tissue-engineered products in the future. PMID- 20930320 TI - Introduction to tissue engineering and application for cartilage engineering. AB - Tissue engineering is a multidisciplinary field that applies the principles of engineering, life sciences, cell and molecular biology toward the development of biological substitutes that restore, maintain, and improve tissue function. In Western Countries, tissues or cells management for clinical uses is a medical activity governed by different laws. Three general components are involved in tissue engineering: (1) reparative cells that can form a functional matrix; (2) an appropriate scaffold for transplantation and support; and (3) bioreactive molecules, such as cytokines and growth factors that will support and choreograph formation of the desired tissue. These three components may be used individually or in combination to regenerate organs or tissues. Thus the growing development of tissue engineering needs to solve four main problems: cells, engineering development, grafting and safety studies. PMID- 20930321 TI - Genetic modification of mesenchymal stem cells for cartilage repair. AB - Reproduction of a native, functional architecture in articular cartilage defects is a major problem in orthopaedic surgery. The elaboration of workable options to heal damaged cartilage might necessitate to involve cellular, molecular and environmental components to allow for the formation of an adequate and stable repair tissue in sites of injury. Strategies based on the transfer of candidate sequences to progenitor cells offer powerful tools to achieve this goal. The aim of this report is to provide an overview of the most recent therapeutic approaches developed in experimental orthopaedic research. PMID- 20930322 TI - Chondrogenic potential of bone marrow- and adipose tissue-derived adult human mesenchymal stem cells. AB - Regarding cartilage repair, tissue engineering is currently focusing on the use of adult mesenchymal stem cells (MSC) as an alternative to autologous chondrocytes. The potential of stem cells from various tissues to differentiate towards the chondrogenic phenotype has been investigated and it appears that the most common and studied sources are bone marrow (BM) and adipose tissue (AT) for historical and easy access reasons. In addition to three dimensional environment, the presence of member(s) of the transforming growth factor (TGF-beta family and low oxygen tension have been reported to promote the in vitro differentiation of MSCs. Our work aimed at characterizing and comparing the degree of chondrogenic differentiation of MSCs isolated from BM and AT cultured in the same conditions. We also further aimed at and at determining whether hypoxia (2% oxygen) could affect the chondrogenic potential of AT-MSCs. Cells were first expanded in the presence of FGF-2, then harvested and centrifuged to allow formation of cell pellets, which were cultured in the presence of TGF-beta3 and/or Bone Morphogenetic Protein-2 (BMP-2) and with 2 or 20% oxygen tension, for 24 days. Markers of the chondrocyte (COL2A1, AGC1, Sox9) and hypertrophic chondrocyte (COL10A1, MMP-13) were monitored by real-time PCR and/or by immunohistological staining. Our data show that BMP-2/TGF-beta3 combination is the best culture condition to induce the chondrocyte phenotype in pellet cultures of BM and AT MSCs. Particularly, a switch in the expression of the pre-chondrogenic type IIA form to the cartilage-specific type IIB form of COL2A1 was observed. A parallel increase in gene expression of COL10A1 and MMP-13 was also recorded. However when AT-MSCs were cultured in hypoxia, the expression of markers of hypertrophic chondrocytes decreased when BMP-2/TGF-beta3 were present in the medium. Thus it seems that hypoxia participates to the control of AT-MSCs chondrogenesis. Altogether, these cellular model systems will help us to investigate further the potential of different adult stem cells for cartilage engineering. PMID- 20930323 TI - Cartilage tissue engineering: From hydrogel to mesenchymal stem cells. AB - Articular cartilage does not repair itself spontaneously. To promote its repair, the transfer of stem cells from adipose tissue (ATSC) using an injectable self setting cellulosic-hydrogel (Si-HPMC) appears promising. In this context, the objective of this work was to investigate the influence of in vitro chondrogenic differentiation of ATSC on the in vivo cartilage formation when combined with Si HPMC. In a first set of experiments, we characterized ATSC for their ability to proliferate, self renew and express typical mesenchymal stem cell surface markers. Then, the potential of ATSC to differentiate towards the chondrogenic lineage and the optimal culture conditions to drive this differentiation were evaluated. Real-time RT-PCR and histological analysis for sulphated glycosaminoglycans and type II collagen revealed that 3-dimensional culture and hypoxic condition favored ATSC chondrogenesis regarding mRNA expression level and the corresponding proteins production. In order to assess the phenotypic stability of chondrogenically-differentiated ATSC, real-time RT-PCR for specific terminal chondrogenic markers and alkaline phosphatase activity assay were performed. In addition to promote chondrogenesis, our culture conditions seem to prevent the terminal differentiation of ATSC. Histological examination of ATSC/Si HPMC implants suggested that the in vitro chondrogenic pre-commitment of ATSC in monolayer is sufficient to obtain cartilaginous tissue in vivo. PMID- 20930324 TI - Original approach for cartilage tissue engineering with mesenchymal stem cells. AB - Cartilage tissue engineering gives the ability to product adaptable neocartilage to lesion with autologous cells. Our work aimed to develop a stratified scaffold with a simple and progressive spraying build-up to mimic articular cartilage environment. An Alginate/Hyaluronic Acid (Alg/HA) hydrogel seeded with human Mesenchymal Stem Cells (hMSC) was construct by spray. First, cells repartition and actin organization were study with confocal microscopy. Then, we analyzed cells viability and finally, metabolic activity. Our results indicated a homogenous cells repartition in the hydrogel and a pericellular actin repartition. After 3 days of culture, we observed about 52% of viable cells in the scaffold. Then, from day 7 until the end of culture (D28), the proportion of living cells and their metabolic activity increased, what indicates that culture conditions are not harmful for the cells. We report here that sprayed method allowed to product a scaffold with hMSCs that confer a favorable environment for neocartilage construction: 3D conformation and ability of cells to increase their metabolic activity, therefore with few impact on hMSCs. PMID- 20930325 TI - Expression of chondrogenic genes by undifferentiated vs. differentiated human mesenchymal stem cells using array technology. AB - This study investigated the gene expression profile of human mesenchymal stem cells seeded in collagen sponge for 28 days in three different mediums: (1) basal medium as control containing ITS alone, (2) ITS+TGF-beta1 alone or (3) ITS 1% supplemented sequentially by TGF-beta1 (D3-D14) followed by BMP-2 (D15-D28). Differential expression of 84 genes implicated in chondrogenic and osteogenic differentiation of MSCs was analyzed at D28 by real-time RT-PCR array technology. TGF-beta1 alone down-regulated two genes, CD36 and cathepsin K. Sixteen genes were significantly up-regulated, notably type 2 and type 10 collagens, COMP and Sox9. The sequential combination of TGF-beta1 and BMP-2 produced a similar profile with prominent expression of type 2 collagen and the alkaline phosphatase gene. Interestingly, in this in vitro condition, RUNX2 was not up-regulated, suggesting that the sequential combination of TGF-beta1/BMP2 enhances the hypertrophic chondrogenic profile without turning towards the osteoblastic pathway. PMID- 20930326 TI - Innovative TCSPC-SHG microscopy imaging to monitor matrix collagen neo synthetized in bioscaffolds. AB - We propose an innovative invasiveless technique in the field of nonlinear optical imaging to facilitate monitoring of cell/scaffold combinations for tissue repair. By using a near infrared (NIR) femtosecond excitation, we were able to introduce a new index based on decay time response for fluorescence (F) and Second Harmonic Generation (SHG) obtained with Time Correlated Single Photon Counting (TCSPC) microscopy to monitor structural information on the state of the matrix collagen. Some human Mesenchymal Stem Cells (hMSCs) seeded in 3D scaffolds were tested with different culture times (from D7 to D56) to analyze the effect of Tumor Growth Factor beta 1 (TGF-beta1) on type-2 collagen expression in the matrix. After 14 days in the presence of TGF-beta1, our results showed an increase in the expression of type-2 collagen synthesized by hMSCs, and a change in collagen conformation, as an indication of its ability to be detected as a harmonophore by TCSPC-SHG without the need for an exogenous probe. PMID- 20930327 TI - New trends in MRI of cartilage: Advances and limitations in small animal studies. AB - Due to the actual interest for bioengineering in the osteoarthritis (OA) healing context, researchers need accurate qualitative and quantitative methodologies to evaluate in vivo the integration and functionality of their cartilage-like biomaterials. As in clinical diagnostic strategies, advances in Magnetic Resonance Imaging (MRI) seem promising for non-vulnerant assessments of articular cartilage bio-architecture and morphology in small animal models. These experimental models are commonly used to monitor the physiopathology of OA and to evaluate therapeutic responses mediated by chondroprotective drugs or tissue engineering. Nowadays, the application of MR protocols to in vivo small animal cartilage imaging is achievable with the development of high magnetic fields and the adaptation of methodologies to reach the required spatial resolution and contrast. The purpose of this article is to summarize these current MRI strategies used for in vivo small animal articular cartilage assessments. PMID- 20930328 TI - Evaluation of a rat knee mono-arthritis using microPET. AB - AIM: Assessing the activity of synovitis, which is characterized by an increase in cell metabolism, is important for the prediction of future articular destruction in clinical and preclinical studies. To evaluate the correlation between 18F-FDG accumulation and arthritis pathology during its establishment, we used microPET to evaluted 18F-FDG accumulation in vivo during rat Mycobacterium wall-induced knee arthritis. METHODS: 18F-FDG PET images of arthritic rats were acquired on days 1, 2, 3 and 7 after arthritis induction. The subjects (n=2/time) were subsequently subjected to macro-autoradiography, and 18F-FDG accumulation was compared with histological findings. RESULTS: 18F-FDG PET images depicted swollen joints, and 18F-FDG accumulation increased with the progression of arthritis. Histologically, increased 18F-FDG accumulation correlated with the pannus rather than the infiltration of inflammatory cells around the joints. CONCLUSION: 18F-FDG accumulation in arthritis reflects proliferating pannus and inflammatory activity enhanced by inflammatory cytokines. 18F-FDG microPET should be effective for quantifying the inflammatory activity of arthritis and/or its therapeutic response. PMID- 20930329 TI - Post-translational proteolytic events influence LRP-1 functions. AB - The low-density lipoprotein receptor-related protein (LRP-1) is a membrane receptor displaying both endocytic scavenging and signaling functions. In this review, we briefly present post-translational proteolytic processes targeting this receptor and speculate on their possible influence on LRP-1 biological functions. PMID- 20930330 TI - Inorganic phosphate (Pi) modulates the expression of key regulatory proteins of the inorganic pyrophosphate (PPi) metabolism in TGF-beta1-stimulated chondrocytes. AB - The balance between extracellular inorganic phosphate (ePi) and extracellular inorganic pyrophosphate (ePPi) is controlled by four membrane proteins: the transporters ANK (exporting PPi outside the cells) and PiT-1 (importing ePi into the cells), and the enzymes PC-1 (generating ePPi from nucleotides) and Tissue Non-specific Alkaline Phosphatase (TNAP, hydrolyzing ePPi into ePi). TGF-beta1 was shown to stimulate ANK and PC-1 expression in articular chondrocytes, and subsequent ePPi level, as well as to increase ePi uptake by inducing PiT-1 expression in a chondrogenic cell line. Thus, we investigated the ability of ePi to modulate the effect of TGF-beta1 on the regulatory proteins of the ePi/ePPi balance in chondrocytes. In the pathophysiological range of 0.01-1 mM, ePi was inactive by itself but potentiated the stimulatory effects of TGF-beta1 on ANK, PC-1 or PiT-1 mRNA (RT-qPCR) and protein (Western blot) levels. PC-1 activity was also increased by TGF-beta1 and further potentiated by ePi supplementation. TNAP mRNA and activity became undetectable in response to TGF-beta1. These data suggest that ePi could increase ePPi level by changing the control of ANK and PC 1 expression by TGF-beta1, further highlighting an adaptative regulation of the Pi/PPi balance to prevent basic calcium phosphate deposition into the joints. PMID- 20930331 TI - Polyelectrolyte multilayer films: A sponge for insulin? AB - Considering restrictive diabetes treatments, new insulin administration strategies constitute a huge medical challenge. This study aimed at developing a new support for insulin reservoirs, using polyelectrolyte multilayer films (PEM films), and thus studying this hormone release in a progressive manner. At first, insulin was loaded in (PDADMAC-PAA)n films, by immerging them for various periods of time (2, 14 and 24 h) in a solution containing this protein. Confocal laser scanning microscopy (CLSM) revealed that insulin-FITC could diffuse inside the film with a bigger concentration in the upper part of the film (after 2 and 14 h in contact with the polypeptide solution), and then in the whole film (after 24 h) from a solution at pH=4.3 (below insulin's isolelectric point). Environmental scanning electron microscopy (ESEM) and CLSM showed that the film swells upon insulin loading. We finally investigated the insulin release by ATR-FTIR spectroscopy. It revealed that a loaded (PDADMAC-PAA)15 film, immerged in distilled water, showed no measurable insulin release. In contrast, a slow unloading was observed in the presence of a NaCl 0.15 M solution (salinity close to physiological serum). This study could open the route for a new way of insulin delivery. PMID- 20930332 TI - Are FoxO transcription factors implicated in osteoarthritis? Influence of Diacerhein. AB - The FoxO family of Forkhead transcription factors functions at the interface of tumor suppression, energy metabolism and organismal longevity. FoxO factors are key downstream targets of insulin, growth factor, nutrient and oxidative stress stimuli that coordinate a wide-range of cellular outputs. These transcription factors could participate in the regulation of different phenomena found in the osteoarthritis pathology, like apoptosis, chondrocyte proliferation, cell dedifferentiation or resistance to oxidative stress. Moreover, we found recently that FoxO transcription factors could be involved on Diacerhein mode of action, a drug that reduces the IL-1beta deleterious effects on osteoarthritis cartilage through inhibition of the expression of degrading enzymes. It could explain the downregulated proliferation and the increased p27 expression observed on human osteoarthritic chondrocytes in the presence of Diacerhein. PMID- 20930333 TI - Evaluation of intra-articular delivery of hyaluronic acid functionalized biopolymeric nanoparticles in healthy rat knees. AB - The aim of this study is to evaluate the toxicity of nanoparticles of poly(D,L lactic acid) (PLA) or poly(D,L-lactic-co-glycolic acid) (PLGA) covered by chemically esterified amphiphilic hyaluronate (HA) which will be used for intra articular injection as a drug carrier for the treatment of arthritis (RA) and/or osteoarthritis (OA). PLA and PLGA are FDA approved polymers that are already used for the preparation of nano or microparticles. HA is a natural polysaccharide already present in the articulations known to interact with the CD44 receptors of the cells (especially chondrocytes). Therefore, we can envisage that the HA covering can improve the interactions between the cells and the nanoparticles, leading to better targeting or biodistribution. The knee of healthy male rats was injected one to two times weekly, with various concentrations of nanoparticles encapsulating Dextran-FITC. The synovial membranes and the patellae were collected aseptically and histologically analyzed to assess the effects and localization of the nanocapsules in the knee joint. We did not observe significant modifications in the synovial membranes (weak hyperplasia) or patellae integrity after local administration of nanodevices into the rats. While we found some nanoparticles in the synovial membrane, none were detected in the patellae. Moreover, the histological observations for patellae were confirmed by radiosulfate intake, which depicted no decrease in proteoglycans biosynthesis in nanoparticles treated animals. Concerning the safety towards synovial membranes, we also had a look at the inflammatory response after injections of nanoparticles covered by amphiphilic HA or polyvinyl alcohol (PVA) by monitoring the mRNA expression levels of some specific early cytokines (IL-1beta and TNF-alpha). Once again, no differences were observed between the control rats and the rats treated with nanoparticles. Considering these preliminary results obtained in healthy rats, we can establish that neither the amphiphilic HA-covered PLGA nanoparticles nor their degradation products induce major modifications of articular tissues functions, while injected into the knee of healthy rats. These results should be confirmed in OA or RA rat models, in order to confirm that nanoparticles do not worsen already altered (degenerative or inflamed) articular tissues. Once confirmed, such tuneable nanoparticles could be proposed as a safe drug delivery system for the treatment of articular disease, allowing a wide range of encapsulating molecules. PMID- 20930334 TI - Ethical guidelines deciding the authorship. PMID- 20930335 TI - Trends in the epidemiology of oral squamous cell carcinoma in Western UP: an institutional study. AB - OBJECTIVE: The purpose of the study was to identify trends in incidence rates of oral squamous cell carcinoma (OSCC) at specific anatomic sites or within specific age or sex groups in the Western Uttar Pradesh population. MATERIALS AND METHODS: The study covers the period from January 2004 through April 2009. OSCC cases were retrospectively analysed for site, age, gender and habits and the findings were formulated to chart the trends in Western U.P. RESULTS: The study revealed a male to female ratio of 2.2:1 with the largest number of OSCCs developing in the fourth and fifth decades of life. Overall, the most common site was the buccal mucosa (63.75%), followed by retromolar area (15%), floor of the mouth (11.25%), lateral border of the tongue (3.75%), labial mucosa (3.75%), and palate (2.5%). Smokeless tobacco habit was more prevalent than smoking tobacco in both men as well as women. Karl - Pearson's correlation coefficient was calculated to find the degree of association between the two variables i.e. between gender to buccal mucosa and gender to smokeless and smoking tobacco habits, which were found to be positively correlated with respect to the age. CONCLUSION: Oral cancer is an important cause of morbidity and mortality worldwide with an incidence rate that varies widely by geographic location. Even within one geographic location, the incidence varies among groups categorized by age, sex, site or habit. PMID- 20930336 TI - Matrix metalloproteinase-1 expression in oral submucous fibrosis: an immunohistochemical study. AB - CONTEXT: Oral submucous fibrosis (OSF) is a form of pathological fibrosis affecting the oral mucosa. There is compelling evidence to implicate the habitual chewing of areca nut with the development of OSF. Because collagens are the major structural components of connective tissues, including oral submucosa, the composition of collagen within each tissue needs to be precisely regulated to maintain tissue integrity. Arecoline stimulates fibroblasts to increase the production of collagen by 150%. AIM: As the role of collagenase is implicated in cleaving the collagen under physical conditions, this study was carried out to evaluate the role of collagenase-1 (matrix metalloproteinase [MMP]-1) in a pathologic condition like OSF. SETTINGS AND DESIGN: A total of 40 patients were included in the study, comprising of 30 OSF as Group 1 and 10 normal buccal mucosa tissue as Group 2. MATERIALS AND METHODS: Both the groups were stained for MMP-1 by the immunohistochemical method using the streptavidin HRP-biotin labeling technique. MMP-1 expression intensity in the epithelium and connective tissue was decreased in Group 1 when compared to Group 2. STATISTICAL ANALYSIS USED: Chi-square test of association was used to determine the difference in the expression of MMP-1 between OSF and normal buccal mucosa and among different histological gradings of OSF. RESULTS: The results were statistically significant. However, there was no statistically significant difference between the expression of MMP-1 among different histological grades of OSF in Group 1. PMID- 20930337 TI - Evaluation of the C-reactive protein serum levels in periodontitis patients with or without atherosclerosis. AB - BACKGROUND: Several studies suggested an association between periodontal disease and cardiovascular disease (CVD). C- reactive protein is elevated in periodontitis patients and has been found to be a predictor of increased risk for cardiovascular disease. Since, CRP is known to play a role in pathogenesis of atherosclerosis, the present study was undertaken to evaluate the serum levels of CRP in periodontitis patients with or without atherosclerosis. MATERIALS AND METHODS: A total of 45 patients, 15 chronic periodontitis patients with atherosclerosis (Group A), 15 chronic periodontitis patients with no history of any systemic disease (Group B), and 15 clinically healthy individuals with no history of periodontal or systemic disease (Group C) within age range of 30 to 55 years were selected for the study. PI, PBI, PPD, CAL and radiographic marginal alveolar bone level were assessed in all the three groups. CRP levels were assessed with 'Turbi-latex' kit using turbidimetric analysis. RESULTS: The mean CAL recorded was 4.9mm in group A, 4.6mm in group B and 1.9 mm in group C. The mean radiographic marginal bone level was 45 to 50% in group A, 45 to 50% in group B and 90 to 95% in group C. Mean serum C-reactive protein level was significantly higher in group A (8.9 mg/l), as compared to group B (4.9 mg/l) as well as group C (0.9 mg/l). CONCLUSION: Within the limits of this study it was concluded that periodontitis may add to the inflammatory burden of the individual and may result in increased risk of atherosclerosis based on serum C-reactive protein concentrations. PMID- 20930338 TI - Effect of carbonated drink on excisional palatal wound healing: a study on Wistar rats. AB - BACKGROUND: Millions of people worldwide consume carbonated drinks every day. The effects of these drinks on hard tissues in the mouth have been proved beyond doubt. Only a little has been done so far to assess the effects of carbonated drinks on oral soft tissues. This study was an attempt to assess the effect of carbonated drinks on oral wound healing. MATERIALS AND METHODS: Twenty female Wistar rats were considered for the study. A circular wound was created on the palate and the animals were divided into two groups (experimental and control group). The experimental group animals were fed with a commercially available carbonated drink instead of water, and two animals from each group were euthanized at 3, 7, 14 and 21 days. Wound site was assessed morphometrically and histologically. RESULTS: There was a marked difference in the healing pattern between the experimental group and control group animals. Control group animals showed a normal healing pattern with formation of a fibrous connective tissue at the end of 21 days. In the experimental group, healing was delayed and disrupted. The wound site showed a definite palatal perforation in experimental group animals after 14 days, but osteoclasts were not noticed in the histological sections. CONCLUSION: Consumption of carbonated drinks can disrupt oral wound healing. Results suggest that the bone changes seen in experimental group samples are not mediated by osteoclasts, and acidity of the carbonated drinks could be one of the reasons for these changes. PMID- 20930339 TI - Antifungal efficacy of Punica granatum, Acacia nilotica, Cuminum cyminum and Foeniculum vulgare on Candida albicans: an in vitro study. AB - BACKGROUND: The establishment and maintenance of oral microbiota is related not only to interbacterial coaggregations but also to interactions of these bacteria with yeasts. Hence, it is important for agents used in the treatment of oral diseases to have antifungal properties for effective therapy. OBJECTIVE: The main purpose of this study was to evaluate the in vitro antifungal efficacy of Punica granatum, Acacia nilotica, Cuminum cyminum and Foeniculum vulgare on Candida albicans. MATERIALS AND METHODS: The pomegranate peel is separated, dried and powdered. Fennel, cumin and acacia bark obtained from the tree are powdered. Candida is inoculated at 37C and seeded on Sabourauds agar medium. Sterilized filter papers saturated with 30 MUl of the extracts are placed on the seeded plates and inoculated at 24 and 48 h. Zones of inhibition on all four sides are measured around the filter paper with a vernier caliper. The experiments were repeated on four plates, with four samples of each extract on one plate for all of the extracts. RESULTS: All the above-mentioned ingredients showed antifungal property, with Punica granatum showing the highest inhibition of Candida albicans with a mean zone of inhibition of 22 mm. P-values <0.05 were obtained for Punica granatum when compared with the other extracts. CONCLUSION: The results showed the potential use of these products as cheap and convenient adjuvants to pharmaceutical antifungal products. PMID- 20930340 TI - Mucocele--a study of 36 cases. AB - BACKGROUND: Mucocele is one of the most common benign soft tissue tumor present in the oral cavity. They are of two types - one is extravasation and second one is retention type but the majority are extravasation type. AIMS: The objective is to determine various factors related to mucocele such as role of trauma due to nearby teeth, recurrence, duration, and to find out whether there is any role of psychological stress which initiates trauma like lip or cheek biting. MATERIALS AND METHODS: 36 cases of mucocele diagnosed at the Department of the Oral Pathology, Govt. Dental College and Hospital, Ahmedabad, between 2004 and 2008 were reviewed. The clinical data were recorded and histopathologic diagnosis was made. STATISTICAL ANALYSIS USED: Data analysis tool, Microsoft Office Excel 2007. RESULTS: A diagnosis of mucocele was established in 36 cases with male-to-female ratio of 1.77:1. Most common type was extravasation in 30 (83.33%) cases. The peak age of occurrence was between 1st and 3rd decade. Lateral side of the lower labial mucosa was the most affected site in 34 (94.44%) cases. The history of trauma appeared the major etiological factor seen in 28 (77.77%) cases. CONCLUSION: We conclude that there was male predominance and they were more affected in 2nd and 3rd decade. The lateral side of lower labial mucosa was the commonest site and the trauma due to teeth or lip biting was the major etiological factor for the occurrence of the mucocele. The article highlights role of psychological stress in occurrence of mucocele. The reader should understand the importance of histopathology examination and should try to control the psychological stress in such mucocele patients. PMID- 20930341 TI - The use of ozonated water and 0.2% chlorhexidine in the treatment of periodontitis patients: a clinical and microbiologic study. AB - BACKGROUND: The development of periodontal disease has been thought to be associated with several restricted members of the oral anaerobic species, such as black-pigmented Porphyromonas species and Actinobacillus actinomycetemcomitans (Aa), in the subgingival environment. Apart from bacteria, certain viruses and fungi that are associated with periodontal disease are also present in the subgingival plaque . MATERIALS AND METHODS: A randomized, double-blind, crossover split-mouth design was performed. A total of 16 patients suffering from generalized chronic periodontitis were selected for the study. The study period of 18 days was divided into two time-intervals, i.e. baseline (0 days) to 7 th day, with a washout period of 4 days followed by a second time interval of 7 days. The use of ozone and chlorhexidine gluconate (CHX) irrigation was randomized. Both the patient and the clinician evaluating the clinical parameters were blinded regarding the type of irrigation used. RESULTS: The interpretation of clinical and microbial data is from baseline to 7 th day. A higher percentage of plaque index (12%), gingival index (29%) and bleeding index (26%) reduction was observed using ozone irrigation as compared to chlorhexidine. The percentile reduction of Aa (25%) using ozone was appreciable as compared to no change in Aa occurrence using chlorhexidine. By using O 3 and chlorhexidine, there was no antibacterial effect on Porphyromonas gingivalis (Pg) and Tannerella forsythensis. The antifungal effect of ozone from baseline (37%) to 7 th day (12.5%) was pronounced during the study period, unlike CHX, which did not demonstrate any antifungal effect. CONCLUSION: Ozone may be considered as an alternative management strategy due to its powerful ability to inactivate microorganisms. Also, there is growing evidence that ozone can be employed as a useful therapeutic agent in both dentistry and medicine. PMID- 20930342 TI - Titanium implants: a removal torque study in osteopenic rabbits. AB - CONTEXT: Osteoporosis is a skeletal disorder characterized by low bone mass and microarchitectural deterioration of bone tissue. It may affect the craniomaxillofacial complex and result in less bone-implant contact. AIMS: The objective of this study was to measure the endosseous integration of titanium implants using the removal torque test in low-mineral density experimental animal models. MATERIALS AND METHODS: Thirty female New Zealand white rabbits were divided into two groups: control (n=14), sham-operated; and test (n=16), ovariectomized. All animals received 2.2 mm Chi 4.0 mm titanium implants in the right tibia, 120 days after ovariectomy or sham surgery. Animals were killed at 7 and 14 weeks of postimplant insertion, when implants were removed by reverse torque rotation using a digital torque meter. Statistical analysis used was Student's t-test. RESULTS AND CONCLUSION: At the 7-week period, the mean torque values for the control and test groups were 11.6 Ncm and 10.4 Ncm, respectively, with no statistical significance. Implant removal torque analysis showed statistically lower values (P < 0.05) for the test group at the 14-week period (control=16.7 Ncm and test=9.7 Ncm). The results of this study indicate that hormonal privacy compromise implants biomechanical performance. PMID- 20930343 TI - A microbiological evaluation of the use of denture cleansers in combination with an oral rinse in complete denture patients. AB - BACKGROUND AND AIM: Patients with complete dentures more occasionally neglect their denture and oral health by improper maintenance of dentures, resulting in bad oral and denture hygiene. This may lead to a host of multiple local and systemic problems such as stomatitis, bacterial and fungal infections, reservoirs for distant infections, denture stains and bad breath. Most denture wearers maintain their dentures with simple manual cleansing methods, which are not adequate to effectively sanitize the reservoir of microorganisms inhabiting the denture surfaces. The aim of this study was to compare the efficacy of the use of a denture cleanser and compare it with an adjunct use of chlorhexidine mouth rinse along with the denture cleanser and possibly suggest it as a suitable protocol. MATERIALS AND METHODS: Two groups of complete denture patients were selected for the study. The total number of patients in each group was 12 and the total period of the study was 21 days. Three sets of microbiological samples were collected from each patient: before the start of the study, on day 8 and on day 21 of the study. The first sample was collected after an initial washover period (7 days) with plain water before the start of the study and the second set after 1 week of study initiation, where group-1 followed protocol-I (denture cleanser only) and group-2 followed protocol-II (denture cleanser and mouth rinse). A second washout period of 7 days followed and a crossover of the protocol was performed for the groups and followed for 1 week. Then, a third set of samples were collected. The colony-forming units were calculated for each patient for each sample and statistically analyzed. Friedman test for non-parametric analysis was employed for the comparison within the groups and a Mann-Whitney test was used for the statistical comparison between the groups. RESULTS: There was a definite reduction in the bacterial numbers and a significant statistical difference after administering the protocols in both the groups (P < 0.001). However, there was little significance on comparing the samples between the groups (P=0.026) in the initial study period, and there was no statistical significance when comparing the groups after the crossover (P=0.140). CONCLUSION: The use of denture cleansers definitely reduced the microbial numbers as compared to plain manual cleansing methods in complete dentures. Although there was a substantial decrease in the bacterial colonies after the use of the mouthwash, it was not statistically significant. PMID- 20930344 TI - Evaluation of the antimicrobial activity of various concentrations of Tulsi (Ocimum sanctum) extract against Streptococcus mutans: an in vitro study. AB - AIM: To determine if Tulsi (Ocimum sanctum) extract has an antimicrobial activity against Streptococcus mutans and to determine which concentration of Tulsi (Ocimum sanctum) extract among the 15 concentrations investigated has the maximum antimicrobial activity. SETTING AND DESIGN: Experimental design, in vitro study, Lab setting. MATERIALS AND METHODS: Ethanolic extract of Tulsi was prepared by the cold extraction method. The extract was then diluted with an inert solvent, dimethyl formamide, to obtain 15 different concentrations (0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 6%, 7% 8%, 9%, 10%) of the extract. 0.2% chlorhexidine was used as a positive control and dimethyl formamide was used as a negative control. The extract, along with the controls, was then subjected to microbiological investigation to determine which concentration among the 15 different concentrations of the extract gave a wider inhibition zone against Streptococcus mutans. The zones of inhibition were measured in millimeters using a vernier caliper. RESULTS: At the 4% concentration of Tulsi extract, a zone of inhibition of 22 mm was obtained. This was the widest zone of inhibition observed among all the 15 different concentrations of Tulsi that were investigated. CONCLUSION: Tulsi extract demonstrated an antimicrobial property against Streptococcus mutans. PMID- 20930345 TI - Folic acid in cleft lip, alveolus and palate prevention: awareness among dental professionals. AB - OBJECTIVES: To determine the awareness amongst dental students, practitioners and maxillofacial surgeons the role of folic acid in the prevention of CLAP and its clinical use. MATERIALS AND METHODS: Questionnaire based study involving a sample base of 1100, comprising of dental students, practitioners and specialist maxillofacial surgeons. RESULTS: hundred percent of the sample population were aware of CLAP disorders, of which 9.5 % believed that CLAP could be prevented. 3.8 % of the population were able to correlate folic acid to CLAP while a negligible 0.03 % could provide the dosage. CONCLUSION: Educating healthcare providers and, in turn, the prospective parents on benefits folic acid would not only help in reducing the incidence of CLAP but also significantly influence the economics of the patients afflicted with CLAP disorders. PMID- 20930346 TI - ABO blood groups and Rhesus factor: an exploring link to periodontal diseases. AB - BACKGROUND: The presence or absence of blood group antigens has been associated with various diseases, with antigens also acting as receptors for infectious agents. Scanty literature is available in assessing the relative liability of blood group phenotypes to periodontal diseases. This research was conducted to determine the association of the ABO blood group and Rhesus (Rh) factor to periodontal diseases to assess whether they could be the predictors of periodontal diseases. MATERIALS AND METHODS: A total of 1,220 subjects aged between 20 and 55 years were selected on a random basis. The study populations were segregated into three groups according to Ramfjord's periodontal disease index: Healthy, Gingivitis and Periodontitis. Blood samples were collected to identify the ABO blood groups and the Rh factor by the slide method. RESULTS: Blood group A showed a significantly higher percentage in the gingivitis group and blood group O showed a higher percentage in the periodontitis group. The blood group AB showed the least percentage of periodontal diseases. The distribution of Rh factor in all groups showed a significantly higher distribution of Rh-positive. CONCLUSION: The genetic factors may alter the oral ecology and the process of periodontal disease. These data are suggestive of a broad correlation between periodontal diseases and blood groups, which may act as risk predictors for periodontal diseases. This will make it possible to better understand the risk factors of diseases of the periodontal tissues and to predict the effective methods of prevention and treatment of periodontal diseases. PMID- 20930347 TI - A radiographic correlation between systemic disorders and pulp stones. AB - AIM: The purpose of this study was to determine the correlation between pulp stones and cardiovascular disorders, Type II diabetes mellitus, autoimmune disorders and dental wear defects. This study also aims to evaluate the frequency of pulp stone in population of Dakshina Kannada district (Karnataka, India) and to determine association of pulp stones in different sexes, tooth type, dental arches and sides. PATIENTS AND METHODS: A total of 1432 teeth of five groups were examined, comprising of patients with C.V.S. disorders; Type II diabetes mellitus, autoimmune disorders, dental wear defects and control group. Teeth were examined under 2Chi magnification on radio visiograph (RVG) and conventional intra-oral periapical radiograph. The presence or absence of pulp stones were recorded. STATISTICAL ANALYSIS USED: Chi-square analysis was used to compare the frequency of occurrence of pulp stones between sexes, tooth type, dental arches and sides. RESULTS: Pulp stones were found in 134 (9.35%) of 1432 teeth detected. Significantly, higher numbers of pulp stones were recorded in patients with cardiovascular disorder (15.86%) than other groups. The occurrence of pulp stones were significantly higher in molars (18.29%) than premolars (6.6%) and in maxillary arch (12.36%) than in mandibular arch (5.95%). No significant difference was found between sexes and sides. CONCLUSION: Positive correlation was found between systemic disorder and pulp stones. Cardiovascular patients had maximum number of pulp stones followed by dental-wear defects and least number of pulp stones were evident in control group. PMID- 20930348 TI - An evaluation of the mechanical properties of Type III and Type IV gypsum mixed with two disinfectant solutions. AB - BACKGROUND AND OBJECTIVES: This in-vitro study was conducted to evaluate the strength and properties of Type III and Type IV gypsum mixed with disinfectant solutions. MATERIALS AND METHODS: Type III and Type IV gypsum were used for the study. Three different mixing solutions namely waterqueous solutions of 0.525% sodium hypochlorite and 2% glutaraldehyde were used. Gypsum materials were subjected to further modification by adding a mixture of 1.0% gum arabic and 0.132% calcium hydroxide before mixing with the disinfectant solutions, at two different liquid/powder (L/P) ratios for each. Both, the unmodified and the modified gypsum were tested for compressive and tensile strength after one hour and one week from the start of the mix. The crystalline configuration of the fracture fragments of the unmodified and modified set gypsum were studied under the scanning electron microscope. RESULTS: The disinfectant solutions reduced the strength of both Type III and Type IV gypsum. Water showed higher-strength, which was followed by 0.525% sodium hypochlorite and 2% glutaraldehyde. The modified Type III and Type IV gypsum with reduced L/P ratio also showed strength values less than that of the control groups. INTERPRETATION AND CONCLUSION: Chemical disinfectants reduced the strength of gypsum when used as water substitutes. Gum Arabic and calcium hydroxide additives permitted lower L/P ratio, however, there was still excess water retained in the set gypsum that lowered the strength values of Type III and Type IV gypsum. Hence, further reduction of L/P ratio may increase the properties of the modified Type III and Type IV gypsum. PMID- 20930349 TI - Chitosan-based polyherbal toothpaste: as novel oral hygiene product. AB - OBJECTIVE: The objective of the present work was to develop chitosan-based polyherbal toothpaste and evaluate its plaque-reducing potential and efficacy in reduction of dental pathogens. MATERIALS AND METHODS: Antimicrobial activity of herbal extracts against dental pathogens were performed by using disk diffusion method. The pharmaceutical evaluation of toothpaste was carried out as per the US Government Tooth Paste Specifications. A 4-week clinical study was conducted in patients with oro-dental problems to evaluate the plaque removing efficacy of chitosan-based polyherbal toothpaste with commercially available chlorhexidine gluconate (0.2% w/v) mouthwash as positive control. Total microbial count was carried out to determine the percentage decrease in the oral bacterial count over the period of treatment. RESULT: Herbal extracts were found to possess satisfactory antimicrobial activity against most of the dental pathogens. Chitosan-containing polyherbal toothpaste significantly reduces the plaque index by 70.47% and bacterial count by 85.29%, and thus fulfills the majority of esthetic and medicinal requirements of oral hygiene products. CONCLUSION: Chitosan-based polyherbal toothpaste proves itself as a promising novel oral hygiene product as compared with currently available oral hygiene products. A further study to confirm the exact mechanism and active constituents behind antiplaque and antimicrobial activity of chitosan-based polyherbal toothpaste and its efficacy in large number of patient population is on high demand. PMID- 20930350 TI - Histopathologic changes in soft tissue associated with radiographically normal impacted third molars. AB - BACKGROUND: The incidence of impacted or embedded third molars accounts for approximately 98%. Since 1948, there are studies reporting pathological changes in an asymptomatic dental follicle. Controversy still exists for removal of asmptomatic impacted teeth. Hence, this study was performed to histologically evaluate soft tissue pathosis in the pericoronal tissues of impacted third molars with pericoronal radiolucency measuring up to 2.5 mm on orthopantomographs. MATERIALS AND METHODS: Forty-one asymptomatic impacted third molars with follicular space of up to 2.5 mm on radiographs were included. The disimpacted teeth and the follicular tissues were obtained for histological examination. RESULTS: Age of the patients ranged from 14 to 25 years. Of 41 tissues evaluated, histopathological reports of 18 follicles were suggestive of dentigerous cyst, two follicles showed odontogenic keratocyst, one follicle each of calcifying epithelial odontogenic cyst, ameloblastoma-like proliferation, odontogenic myxoma and odontogenic fibroma. CONCLUSION: This study showed 58.5% of asymptomatic cases with definite pathological changes. Hence, thorough clinical and radiographic examination should be carried out for all impacted third molars and the dental follicular tissue should be submitted for histopathological evaluation. PMID- 20930351 TI - Influence of the processing technique on the flexural fatigue strength of denture base resins: an in vitro investigation. AB - BACKGROUND: Though acrylic resins possess many desirable properties, denture fracture due to flexural fatigue or impact failure is a common problem. One major factor influencing the flexural fatigue strength of denture base resins is the processing technique used. AIM: To measure the flexural fatigue strength of denture base resins polymerized using short and long curing cycles using water bath, pressure cooker, and microwave polymerization techniques. MATERIALS AND METHODS: Flexural fatigue strength of 60 samples (n=10) were measured using a cyclic 3-point loading method on a dynamic universal testing machine. Data were analyzed using a Student 't' test. RESULTS: Comparative evaluation using Student's 't' test of mean flexural fatigue strength of samples processed by water bath processing (660.6) and the microwave technique (893.6) showed statistically significant (P < 0.01) result with microwave processing being higher. Comparison of water bath (660.6) and pressure cooker (740.6) processing and microwave (893.6) and pressure cooker (740.6) processing using Student's 't' test was not statistically significant (P > 0.05). In the intra-group analysis, it was found that there was statistically significant difference in samples processed using the short and long curing cycle, the latter being better in all groups, P-values being < 0.05, < 0.001, and < 0.001 for water bath, microwave, and pressure cooker polymerization techniques, respectively. CONCLUSION: The polymerization procedure plays an important role in influencing the flexural fatigue strength of denture base resins, and the microwave long curing processing technique produced denture bases with highest flexural fatigue strength. PMID- 20930352 TI - E-cadherin and CD1a expression in gingival epithelium in periodontal health, disease and post-treatment. AB - BACKGROUND: Epithelial integrity is important for maintenance of periodontal health. It is not fully known if non-surgical periodontal therapy is capable of recreating the epithelial barrier in its functional state. PATIENTS AND METHODS: Sixty-five patients (31 males and 34 females) were included in the study. They were divided into group A (healthy gingiva 16 patients), group B (gingivitis 17 patients), group C (periodontitis 17 patients), and group D (post-treatment 15 patients). Gingival samples were collected and immunohistochemical study was done using E-cadherin and CD1a antibody. Statistical analysis was done using analysis of variance (ANOVA), followed by Tukey-Kramer multiple comparison test for CD1a and Tukey's highly significant difference (HSD) test for E-cadherin. RESULT: There was a statistically significant difference (P < 0.001) in the expression of E-cadherin between healthy (1.846+/-0.555), gingivitis (1.100+/-0.994), and periodontitis group (0.700+/-0.483). Similarly, there was a statistically significant difference (P < 0.001) in the expression of CD1a between healthy (75.70+/-3.09), gingivitis (42.53+/-3.09), and periodontitis group (29.07+/ 3.08). However, the expression of E-cadherin (1.242+/-0.653) and CD1a in post treatment samples (52.18+/-2.90) was lower with no statistically significant difference when compared to health. DISCUSSION: The significant reduction in E cadherin and CD1a levels in periodontal disease when compared to health could possibly be a result of invasion by the periodontopathogens and its subsequent sequel. Although, the post-treatment samples showed significant improvement when compared to disease, the reduction in E-cadherin and CD1a levels when compared to gingival health suggests that the epithelial barrier was not yet fully established in its functional state. PMID- 20930353 TI - Masseter muscle thickness in different skeletal morphology: an ultrasonographic study. AB - BACKGROUND: The thickness of the masseter muscle during relaxation and contraction states was measured by ultrasonography. Subjects were classified according to their sagittal skeletal relationships. The association between muscle thickness and facial morphology was studied. CONTEXT: Masseter muscle thickness influences the skeletal patterns. AIM: To measure and compare the thickness of the masseter muscle in individuals with skeletal class I occlusion and skeletal class II malocclusions and to correlate its relationship with craniofacial morphology. SETTINGS AND DESIGN: The study was conducted in a hospital setup and was designed to study the thickness of the masseter muscle in different skeletal morphologies. MATERIALS AND METHODS: Seventy two individuals between the ages of 18 and 25 years were divided into Group I, Group IIA and Group IIB according to their skeletal relationships. Masseter muscle thickness was measured by ultrasonography. Eight linear and six angular cephalometric measurements were assessed. STATISTICAL ANALYSIS USED: Analysis of variance and Pearson's correlation analysis. RESULTS: There was a statistically significant difference in muscle thickness between subjects of different skeletal patterns. Significant positive correlation between masseter muscle thickness and posterior total face height, jarabak ratio, ramus height, mandibular length and significant negative correlations with mandibular plane angle, gonial angle and PP-MP angle were observed. CONCLUSION: This study indicates the strong association between the masseter muscle and skeletal morphology. PMID- 20930354 TI - Efficacy and acceptability of 0.074% diclofenac-containing mouthwash after periodontal surgery: a clinical study. AB - BACKGROUND: The systemic use of non-steroidal anti-inflammatory drugs are associated with various side-effects like hepatotoxicity, blood dyscrasias, nephrotoxicity and gastric irritability. Among these, gastric irritability is the most common and the most important one, which should be taken care of. Therefore, it may be preferable to use a local formulation such as a mouthwash to treat the inflammatory conditions of the oral cavity. AIM: To determine the efficacy and acceptability of 0.074% diclofenac mouthwash in relieving pain and inflammation of post-periodontal surgery patients. MATERIALS AND METHODS: The study was designed as a double-blind, placebo-controlled clinical trial. Twenty chronic periodontitis patients who were scheduled for full-mouth periodontal flap surgery were randomized to receive either diclofenac mouthwash or placebo to rinse with 15 ml of solution daily for a period of 7 days. Modified gingival index (Lobene 1986) was used to verify gingival inflammation and visual analog scale was used to assess pain. After the baseline measurements for all the parameters were recorded, spontaneous pain and burning were evaluated daily while redness and edema were recorded on the 3 rd and 7 th day from the day of treatment. RESULTS: Data obtained were analyzed statistically using paired " t" test for intragroup comparison and unpaired " t"-test for intergroup comparison. Spontaneous pain was significantly reduced by diclofenac mouthwash. Other parameters, i.e. gingival inflammation and swelling, had not shown significant reduction in scores in either group, although the reduction was higher in the test group. CONCLUSION: The new 0.074% diclofenac mouthwash is an effective and tolerable medicinal product for post-surgical symptomatic relief. PMID- 20930355 TI - Transforming growth factor-beta-1 polymorphisms are infrequent but exist at selected loci in oral submucous fibrosis. AB - BACKGROUND: Oral submucous fibrosis (OSF) may be considered a collagen metabolic disorder resulting from areca-nut alkaloid exposure and individual variation in collagen metabolism. Due to the complexity of OSF pathogenesis, it is important to elucidate independent and interactive effects of polymorphisms of collagen related genes on OSF risk. MATERIALS AND METHODS: This study is focused on seven polymorphisms (SNPs) of transforming growth factor-beta-1 (TGF-beta-1) gene in patients with oral submucous fibrosis (OSF), belonging to south Indian ethnic extraction. The mean age at presentation was 43.9 years, range 23-72 years (n=50, M:F ratio, 2.6:1). DNA samples from 50 subjects of the same ethnic group and comparable demographic features who have had practiced the habit of areca-chewing of almost equal duration, but remained free of disease constituted the controls. All DNA samples were collected progressively and purified from peripheral blood employing standard protocols and tested for SNPs. They included two polymorphisms in the promoter region (C-509T and G-800A), three polymorphisms in exon-1 (Arg25Pro(G915C), Leu10Pro(T869C), Glu47Gly(A979G) and two in 5 cUTR regions (C >T(rs13306708) and G->A (rs9282871). The extracted DNA samples along with the primers underwent PCR amplification and the genotypic and allelic frequencies were calculated. All calculations were performed using the SPSS software. The PCR products were purified and subsequently sequenced using Flour STM multi-imager system (Biorad). The sequenced data were analyzed using the BioEdit sequence analysis software. RESULTS: Out of the seven polymorphisms analyzed, six such as two in the promoter region, three in exon-1 and one in 5cUTR were found to have a " P" value above 0.05 and hence were not significant. The C->T transition (rs13306708) in the 5cUTR region recorded a " P" value of 0.03 on comparison and hence was found to be significant. The allelic frequencies for this C->T transition in patients were 68.7% C and 31.2% T (27CC, 15CT, 8TT) and that in controls were 89.5% C and 10.4% T (42CC, 6CT, 2TT). CONCLUSIONS: The polymorphism in 5cUTR C-T in TGF beta 1 gene has a significant association with OSF, being a prime determinant in the pro-angiogenic pathway which has got direct bearing with the pathophysiology of the disease. The proximity of this polymorphism to the transcription site and the associated risk involved is discussed. PMID- 20930356 TI - Histological and radiographic evaluation of the muscle tissue of rats after implantation of bone morphogenic protein (rhBMP-2) in a scaffold of inorganic bone and after stimulation with low-power laser light. AB - OBJECTIVE: The present study histologically and radiologically evaluates the muscle tissue of rats after implantation of bone morphogenic protein (rhBMP-2) in a natural inorganic bone mineral scaffold from a bull calf femur and irradiation with low-power light laser. MATERIALS AND METHODS: The right and left hind limbs of 16 rats were shaved and an incision was made in the muscle on the face corresponding to the median portion of the tibia, into which rhBMP-2 in a scaffold of inorganic bone was implanted. Two groups of limbs were formed: control (G1) and laser irradiation (G2). G2 received diode laser light applied in the direction of the implant, at a dose of 8 J/cm2 for three minutes. On the 7th, 21st, 40th and 112th days after implantation, hind limbs of 4 animals were radiographed and their implants removed together with the surrounding tissue for study under the microscope. The histological results were graded as 0=absence, 1=slight presence, 2=representative and 3=very representative, with regard to the following events: formation of osteoid structure, acute inflammation, chronic inflammation, fibrin deposition, neovascularization, foreign-body granuloma and fibrosis. RESULTS: There were no statistically significant differences in these events at each evaluation times, between the two groups (P > 0.05; Mann-Whitney test). Nevertheless, it could be concluded that the natural inorganic bone matrix with rhBMP-2, from the femur of a bull calf, is a biocompatible combination. CONCLUSIONS: Under these conditions, the inductive capacity of rhBMP-2 for cell differentiation was inhibited. There was a slight acceleration in tissue healing in the group that received irradiation with low-power laser light. PMID- 20930357 TI - Infinite to finite: an overview of finite element analysis. AB - The method of finite elements was developed at perfectly right times; growing computer capacities, growing human skills and industry demands for ever faster and cost effective product development providing unlimited possibilities for the researching community. This paper reviews the basic concept, current status, advances, advantages, limitations and applications of finite element method (FEM) in restorative dentistry and endodontics. Finite element method is able to reveal the otherwise inaccessible stress distribution within the tooth-restoration complex and it has proven to be a useful tool in the thinking process for the understanding of tooth biomechanics and the biomimetic approach in restorative dentistry. Further improvement of the non-linear FEM solutions should be encouraged to widen the range of applications in dental and oral health science. PMID- 20930358 TI - Status of surface treatment in endosseous implant: a literary overview. AB - The attachment of cells to titanium surfaces is an important phenomenon in the area of clinical implant dentistry. A major consideration in designing implants has been to produce surfaces that promote desirable responses in the cells and tissues. To achieve these requirements, the titanium implant surface can be modified in various ways. This review mainly focuses on the surface topography of dental implants currently in use, emphasizing the association of reported variables with biological outcome. PMID- 20930359 TI - Cowden syndrome. AB - Cowden syndrome or multiple hamartoma syndrome is an autosomal dominant condition with variable expressions that result mainly from mutation in the PTEN gene on arm 10q. It is characterized by multiple hamartomatous neoplasms of the skin, oral mucosa, gastrointestinal tract, bones, CNS, eyes, and genitourinary tract. Mucocutaneous features include trichilemmomas, oral mucosal papillomatosis, acral keratosis, and palmoplantar keratosis. Here we present a case of Cowden syndrome in a 14-year-old female patient with the chief complaint of multiple oral papillomatous lesions. PMID- 20930360 TI - Spiral CT diagnosis and endodontic management of an anatomically variant palatal root with two canals in a maxillary first molar. AB - This case report presents the endodontic management of an anatomically variant palatal root with 2 canals (Vertucci type II) in a maxillary first molar, which was confirmed with the help of spiral computed tomography (SCT). This serves to remind clinicians that such anatomic variations should be taken into account during the endodontic treatment of maxillary molars and highlights the invaluable aid of the SCT in accurate diagnosis and in negotiating the complex morphologic variations in root canals, thus enabling successful endodontic management. PMID- 20930361 TI - Toothbrush injury in an adult. AB - Tooth brushing is an oral hygiene measure. Keeping the toothbrush in the mouth and doing other works with both arms may lead to injury of the oral tissues. We hereby report a case of severe injury to the oral mucosal tissues caused by the toothbrush, which was treated surgically. PMID- 20930362 TI - Metastatic lung malignancy to mandibular gingiva. AB - Metastatic tumors of oral cavity are uncommon and may occur in oral soft tissues or jaw bones. Because of their rarity, metastasis to oral cavity are challenging to diagnose and difficult to treat. They often have vague symptoms that mimic dental infections. These lesions generally show poorly differentiated histopathologic picture and have poor prognosis. We reported a case of a 40-year old male patient of metastatic lesion to the oral cavity and brain with primary tumor, diagnosed as an undifferentiated epithelial malignancy of lung. PMID- 20930363 TI - Modified measuring compass as an intraoral paralleling device. AB - This article describes a simple technique of useful modification of measuring compass, procured from a school compass box, to make an intraoral paralleling device. This device is useful in examining parallelism of tooth or implant abutment preparations for a common path of placement in fixed dental prostheses. It can be used to examine the parallelism of guiding planes in removable partial denture patients as well. PMID- 20930364 TI - Restoration of the maxillary anterior tooth using immediate implantation with simultaneous ridge augmentation. AB - Atrophy is most severe during the first month of post-extraction in the anterior maxilla with the degree of horizontal bone resorption being nearly twice as high as that of vertical bone resorption. The loss of the buccal alveolar plate following tooth extraction may lead to palatal implant positioning of the implants. Thus, immediate or early implant placement in the extraction socket has been suggested, because it would reduce the time period and the number of surgical intervention and yield higher patient satisfaction compared with delayed placed implants. However, placement of an implant immediately after tooth extraction may result in a gap between the occlusal portion of the implant and the surrounding alveolar bone crest. In this case report, an implant-supported restoration which is in harmony with the surrounding hard and soft tissue was created by the immediate implant placement with ridge augmentation in anterior region with high satisfaction from the patient. PMID- 20930365 TI - Schwannoma of the tongue: an unusual presentation in a child. AB - Schwannomas are benign tumors of nerve sheath and quite uncommon in the oral cavity. In contrast to the earlier reports in the literature, a confounding case of a lingual schwannoma presenting as a symptomatic and exophytic growth on the ventral surface of the tongue in a 12-year-old boy is discussed here. PMID- 20930366 TI - Gingival plasma cell granuloma. AB - Plasma cell granuloma is a rare reactive lesion composed of polyclonal plasma cells. It manifests primarily in the lungs, but may occur in various other anatomic locations like the oral cavity. Intraoral plasma cell granulomas involving the tongue, lip, oral mucosa and gingiva have been reported in the past. This case presents a 54-year-old female with chronic periodontitis and mandibular anterior gingival overgrowth treated by Phase I therapy (scaling and root planing) and excisional biopsy. Histological examination revealed inflammatory cell infiltrate containing sheets of plasma cells. Immunohistochemistry for kappa and lambda light chains showed a polyclonal staining pattern confirming a diagnosis of plasma cell granuloma. This case highlights the need to biopsy for unusual lesions to rule out potential neoplasms. PMID- 20930367 TI - Why tooth carving? PMID- 20930368 TI - Invited comment: " letter to the editor on tooth morphology". PMID- 20930369 TI - Computational study of the three-dimensional structure of N-acetyltransferase 2 acetyl coenzyme a complex. AB - N-Acetyltransferase 2 (NAT2) is one of the most important polymorphic drug metabolizing enzymes and plays a significant role in individual differences of drug efficacies and/or side effects. Coenzyme A (CoA) is a cofactor in the experimentally determined crystal structure of NAT2, although the acetyl source of acetylation reactions catalyzed by NAT is not CoA, but rather acetyl CoA. In this study, the three-dimensional structure of NAT2, including acetyl CoA, was calculated using molecular dynamics simulation. By substituting acetyl CoA for CoA the amino acid residue Gly286, which is known to transform into a glutamate residue by NAT2*7A and NAT2*7B, comes close to the cofactor binding site. In addition, the binding pocket around the sulfur atom of acetyl CoA expanded in the NAT2-acetyl CoA complex. PMID- 20930370 TI - Berberine-induced apoptosis in human glioblastoma T98G cells is mediated by endoplasmic reticulum stress accompanying reactive oxygen species and mitochondrial dysfunction. AB - Berberine has a wide range of biochemical and pharmacologic effects, including antitumor activity, but the mechanisms involved in berberine-induced apoptosis remain unclear. The purpose of the present study was to investigate the changes in oxidative stress and endoplasmic reticulum (ER)-related molecules, which are closely associated with cell death-signaling transduction pathways, in human glioblastoma T98G cells treated with berberine. Berberine significantly decreased the cell viability of T98G cells in a dose-dependent manner. Berberine increased the production of reactive oxygen species (ROS) and level of intracellular Ca(2+). Berberine induced ER stress as evidenced by the detection of ER stress associated molecules such as phosphorylated protein kinase-like ER kinase, eukaryotic translation initiation factor-2alpha, glucose-regulated protein 78/immunoglobulin heavy chain-binding protein, and CCAAT/enhancer-binding protein (C/EBP)-homologous protein/growth arrest and DNA damage-inducible gene 153, which was associated with the activation of caspase-3. Furthermore, the administration of the antioxidants, N-acetylcysteine and glutathione, reversed berberine-induced apoptosis. Berberine also markedly enhanced apoptosis in T98G cells through the induction of a higher ratio of Bax/Bcl-2 proteins, disruption of the mitochondrial membrane potential, activation of caspase-9 and -3, and cleavage of the poly(ADP-ribose) polymerase (PARP). The inhibition of ER stress using salubrinal led to an increased the level of Bcl-2, whereas the level of Bax, cleavage of procaspase-9 and -3, and PARP were decreased when compared with cells treated with berberine alone, indicating that berberine-induced apoptosis is associated with mitochondrial dysfunction. These results demonstrate that berberine induces apoptosis via ER stress through the elevation of ROS and mitochondrial-dependent pathway in human glioblastoma T98G cells. PMID- 20930371 TI - Bi-functional induction of the quinone reductase and cytochrome P450 1A1 by youngiasides via Nrf2-ARE and AhR-XRE pathways. AB - Many phytochemicals are known to exert cancer chemopreventive activity by eliminating chemical carcinogens or toxic xenobiotics through the action of detoxification enzymes. In this study, we investigated the cancer chemopreventive effects of youngiasides isolated from Crepidiastrum denticulatum. These youngiasides significantly induced quinone reductase (QR) activity in mouse hepatoma Hepa-1c1c7 cells, and showed a relatively high chemoprevention index (CI; divided IC(50) value with CD value). The youngiasides also significantly induced transcriptional activation of QR in Hepa-QR-secreted alkaline phosphatase (SEAP) cells, which is a stable cell line containing the intact promoter region of QR. In order to determine if upregulation of QR by the youngiasides was mediated through a mono-functional or bi-functional mechanism, we examined the nuclear factor-E2 p45-related factor 2(Nrf2)-antioxidant response element (ARE) and aryl hydrocarbon receptor (AhR)-xenobiotic response element (XRE) pathways, which are two major pathways, involved in regulation of Phase I and/or Phase II detoxification enzymes. The youngiasides increased the cytochrome P450 1A1 (CYP1A1) mRNA and protein levels in human colorectal cancer Caco-2 cells and also increased the QR mRNA and protein levels in Caco-2 cells through ARE and XRE activation which resulted from translocation of Nrf2 and AhR into the nucleus. These results suggest that regulation of QR by the youngiasides was due to bi functional induction through the Nrf2-ARE and AhR-XRE pathways. Thus, these youngiasides as bi-functional inducers of QR have potential as cancer chemopreventive agents. PMID- 20930372 TI - The effect of different species aminopeptidase N structure on the activity screening of aminopeptidase N inhibitor. AB - Aminopeptidase N (APN) is a transmembrane metallopeptidase, which participates in the tumor progress such as proliferation, attachment, angiogenesis and tumor invasion. All of this makes APN as a good chemical therapeutic anti-tumor target. In the present study, we got a novel compound 16l which markedly inhibited the enzyme activity of porcine APN, and the inhibition constant, K(i), of 16l are similar to the positive medicine Bestatin determined using porcine APN. However, when tested using human tumor cells, 16l couldn't effectively inhibit the enzyme activity, cell viability, cell migration and invasion. Computer aided drug design verified that because of the difference in structure, the binding pattern of 16l in the active site of homo sapien and porcine APN was different. The compound 16l could effectively inhibit the enzyme activity of porcine APN, but not homo sapien APN located on the surface of tumor cells. Therefore, the activity screening of APN inhibitor using aminopeptidase N from porcine should be only preliminary determination. The real activity screening should be determined using homo sapien aminopeptidase N. PMID- 20930373 TI - Doxorubicin induces apoptosis in H9c2 cardiomyocytes: role of overexpressed eukaryotic translation initiation factor 5A. AB - The cardiotoxicity of doxorubicin limits its clinical use in the treatment of a variety of solid tumors and malignant hematologic disease. Although the mechanism by which it causes cardiac injury is not yet known, apoptosis has been regarded as one of mechanisms underlying the cardiotoxic effects of doxorubicin. Eukaryotic translation initiation factor 5A (eIF5A) is a ubiquitously expressed multifunctional protein that interacts with a range of ligands and is implicated in cell signaling. However, there has been no direct evidence for the critical involvement of eIF5A in doxorubicin-induced apoptosis. Overexpression of eIF5A induced by doxorubicin in cardiomyocyte leads to growth perturbation along with initiation of apoptosis. Overexpression of eIF5A results in a gradual increase in reactive oxygen species (ROS) generation. This mitochondrial dysfunction is due to a gradual increase in ROS generation in eIF5A-overexpressing H9c2 cells. Along with ROS generation, increased Ca(2+) influx in mitochondria leads to loss of the mitochondrial transmembrane potential, release of cytochrome-c, and caspase activation. However, small interfering RNA (siRNA)-mediated suppression of eIF5A results in inhibition of apoptosis. Interestingly, upon overexpression of eIF5A induced by doxorubicin, cell apoptosis was shown to be significantly inhibited when cells were treated with SB202190 (p38 mitogen-activated protein kinase inhibitor) and SP600125 (anti-c-Jun N-terminal kinase inhibitor) for 18 h. The reduction in oxidant generation and reduction in the apoptotic cell population were the results of the disruption of eIF5A expression, corroborating the hypothesis that excess ROS generation with overexpression of eIF5A induced by doxorubicin leads to apoptosis due to the accumulation of eIF5A. PMID- 20930374 TI - Establishment of an efficient fermentation system of gamma-aminobutyric acid by a lactic acid bacterium, Enterococcus avium G-15, isolated from carrot leaves. AB - In the present study, we successfully isolated a carrot leaf-derived lactic acid bacterium that produces gamma-aminobutyric acid (GABA) from monosodium L glutamate (L-MSG) at a hyper conversion rate. The GABA-producing bacterium, identified as Enterococcus (E.) avium G-15, produced 115.7+/-6.4 g/l GABA at a conversion rate of 86.0+/-5.0% from the added L-MSG under the optimum culture condition by a continuous L-MSG feeding method using a jar-fermentor, suggesting that the bacterium displays a great potential ability for the commercial-level fermentation production of GABA. Using the reverse transcription polymerase chain reaction (RT-PCR) method, we analyzed the expression of genes for the GABA transporter and glutamate decarboxylase, designated gadT and gadG, respectively, which were cloned from the E. avium G-15 chromosome. Both genes were expressed even without the added L-MSG, but their expression was enhanced by the addition of L-MSG. PMID- 20930375 TI - Enzymic synthesis of gastrodin through microbial transformation and purification of gastrodin biosynthesis enzyme. AB - Gastrodin, a major bioactive component of a famous Chinese herb Gastrodia elata B1., has diverse pharmaceutical functions. It is usually obtained by extraction from a plant or through chemical synthesis. However, traditional extraction from Gastrodia elata B1. is time and money consuming, while chemical synthesis is a complicated procedure and always leads to very serious environmental pollution. Thus it is urgent to explore a new gastrodin source which is more economical and environmental. The present study reports a novel approach to the production of gastrodin through biosynthesis and microbial transformation. Rhizopus chinensis SAITO AS3.1165 was screened from about 50 fungal and bacterial strains and found capable of biotransforming p-hydroxybenzaldehyde into gastrodin for use in gastrodin production. A series of purification steps including (NH(4))(2)SO(4) precipitation, ion exchange chromatography and gel filtration column chromatography was successfully used for purification of the gastrodin biosynthesis enzyme (GBE). The purity of GBE was above 95% and its molecular weight was about 63.2 kDa. We further characterized GBE's function condition, and found that the optimal temperature was 50 degrees C and the optimum pH 6.0. The enzyme was stable at a temperature lower than 50 degrees C and a pH between 6.0 and 9.0. The result indicated that gastrodin could be successfully synthesized by microbial transformation, providing a new approach for gastrodin production. PMID- 20930376 TI - alpha-Solanine inhibits human melanoma cell migration and invasion by reducing matrix metalloproteinase-2/9 activities. AB - alpha-Solanine, a naturally occurring steroidal glycoalkaloid in potato sprouts, was found to possess anti-carcinogenic properties, such as inhibiting proliferation and inducing apoptosis of tumor cells. However, the effect of alpha solanine on cancer metastasis remains unclear. In the present study, we examined the effect of alpha-solanine on metastasis in vitro. Data demonstrated that alpha solanine inhibited proliferation of human melanoma cell line A2058 in a dose dependent manner. When treated with non-toxic doses of alpha-solanine, cell migration and invasion were markedly suppressed. Furthermore, alpha-solanine reduced the activity of matrix metalloproteinase-2 (MMP-2) and MMP-9, which are involved in the migration and invasion of cancer cells. Our biochemical assays indicated that alpha-solanine potently suppressed the phosphorylation of c-Jun N terminal kinase (JNK), phosphatidylinositide-3 kinase (PI3K) and Akt, while it did not affect phosphorylation of extracellular signal regulating kinase (ERK). In addition, alpha-solanine significantly decreased the nuclear level of nuclear factor kappa B (NF-kappaB), suggesting that alpha-solanine inhibited NF-kappaB activity. Taken together, the results suggested that alpha-solanine inhibited migration and invasion of A2058 cells by reducing MMP-2/9 activities. It also inhibited JNK and PI3K/Akt signaling pathways as well as NF-kappaB activity. These findings reveal new therapeutic potential for alpha-solanine in anti metastatic therapy. PMID- 20930377 TI - Gender differences in vascular reactivity of aortas from streptozotocin-induced diabetic mice. AB - The aim of the present study was to assess gender differences in diabetes-related vascular reactivity in murine aortas. Diabetes is a risk factor for ischemic heart disease, cerebral ischemia, and atherosclerosis, conditions in which endothelial dysfunction plays a pathogenetic role. We examined vascular responses in aortas isolated from streptozotocin (STZ)-induced type 1 diabetic mice and age matched control mice, and looked for gender differences in the diabetes-induced changes in these responses. For each gender, the plasma adiponectin levels were lower in diabetic mice than in the controls, and they were significantly higher in females than in males. The acetylcholine (ACh)-induced endothelium-dependent relaxation of aortic rings was impaired (vs. that in the age-matched controls) in diabetic male mice, but not in diabetic female mice. The sodium nitroprusside induced endothelium-independent aortic relaxation was not altered by diabetes in either male or female mice. The norepinephrine-induced aortic contraction was enhanced (vs. that in the control group) in diabetic female mice, but not in diabetic male mice, whereas in the presence of N(G)-nitro-L-arginine neither gender exhibited a significant diabetes-induced change in this contraction. The clonidine-induced and insulin-induced endothelium-dependent aortic relaxations were impaired only in the diabetic female group (vs. the age-matched controls). These results suggest that: a) in male diabetic mice, which exhibited low adiponectin levels, these were impairments of both the aortic relaxation and nitric oxide (NO) production induced by ACh, whereas b) in female diabetic mice, there were impairments of the aortic relaxations induced by both insulin and clonidine. PMID- 20930378 TI - Potent modification of inducible CYP1A1 expression by flavonoids. AB - The present study examined modifications of beta-naphthoflavone (beta-NF)-induced cytochrome P450 1A1 (CYP1A1) expression by flavonoids in mouse hepatocytes in primary culture. Some flavonoids (apigenin, chrysin, flavone, flavanone, galangin, luteolin, and naringenin) by themselves induced CYP1A1 mRNA expression, especially flavone which was even more effective than beta-NF. The effect on beta NF-induced CYP1A1 mRNA expression was varied, namely additive, suppressive, or both. An additive effect was observed after combined treatment with flavanone, naringenin, and chrysin, whereas kaempferol, myricetin, and quercetin decreased CYP1A1 levels. Apigenin, chrysin, galangin, luteolin, and morin synergistically enhanced beta-NF-induced CYP1A1 expression at 24 h, but considerably suppressed it at 9 h. The structure-activity relationship of flavonoids affecting CYP1A1 expression as inducers or inhibitors is discussed. The present observations suggest the need to reveal the mechanism by which CYP1A1 expression is modified by flavonoids for risk assessment, since CYP1A1 activates environmental carcinogenic polycyclic hydrocarbons and flavonoids are major constituents in food. PMID- 20930379 TI - Synthesis and biological properties of benzo-annulated rutaecarpines. AB - A series of benzo-annulated rutaecarpines were prepared from anthranilic acid and 3-aminonaphthalene-2-carboxylic acid by Fischer indole synthesis as key reaction. Cytotoxicity was somewhat increased by the introduction of benzo-annulation, which was not directly related to the inhibitory activity against topoisomerases (topo) I and II. Benzo-annulation on ring A led to significant increase of inhibitory activity against topo II while annulations on ring E increased inhibitory activity against topo I. PMID- 20930380 TI - Effect of TJN-331 on anti-Thy1 nephritis in rats via inhibition of transforming growth factor-beta1 production. AB - This study was performed to examine the effects of the antifibrotic agents TJN 331 and tranilast on mesangial expansion in a rat model of anti-Thy1 nephritis. We first investigated the effects of TJN-331 and tranilast on mesangial expansion induced by anti-Thy1 serum in rats, and determined the counts of glomerular cells and proliferative cell nuclear antigen (PCNA)-positive cells. The effects of TJN 331 and tranilast on production of transforming growth factor-beta1 (TGF-beta1) by isolated glomeruli incubated for 48 h were then examined. The TGF-beta1 staining score, the number of TGF-beta1-positive cells and the TGF-beta1 receptor positive area in the anti-Thy1 nephritis model were also measured using immunohistochemistry. TJN-331 administered from day 1 (the day after anti-Thy1 serum injection) blocked an increase in mesangial matrix accumulation on days 4 and 8, compared to untreated anti-Thy1 nephritic rats. TJN-331 also inhibited both the increase in the number of glomerular cells on day 8 and the decrease in this cell count on day 2 observed in untreated nephritic rats, and TJN-331 and tranilast inhibited an increase in PCNA-positive cells in the glomerular cross section on days 4 and 8. Both TJN-331 and tranilast inhibited increases in the TGF-beta1 protein content from nephritic glomeruli, the TGF-beta1-positive area, and the number of TGF-beta1-positive cells/cross section in anti-Thy1 nephritic glomeruli. These results suggest that TJN-331 and tranilast prevent expansion of the mesangial area by suppression of TGF-beta1 secretion from inflamed glomeruli. PMID- 20930381 TI - Isofraxidin, a coumarin component from Acanthopanax senticosus, inhibits matrix metalloproteinase-7 expression and cell invasion of human hepatoma cells. AB - 7-Hydroxy-6,8-dimethoxy-2H-1-benzopyran-2-one (isofraxidin) is a major coumarin component isolated from the stem bark of Acanthopanax senticosus, a widely used Chinese medicinal herb. We investigated isofraxidin in its anti-tumor effects on human hepatoma cell lines HuH-7 and HepG2. Isofraxidin significantly inhibited hepatoma cell invasion, without affecting cell attachment or growth. Expression of 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced matrix metalloproteinase-7 (MMP-7) in hepatoma cells was inhibited by isofraxidin at the both mRNA and protein levels. This inhibition tended to be greater in cells inoculated at low density than in those at high density. Isofraxidin showed an inhibitory effect on the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) in hepatoma cells, whereas activator protein-1 (AP-1) DNA binding activity, nuclear factor-kappa B (NF-kappaB) nuclear translocation, and inhibitory kappa B (IkappaB) degradation were affected very little. These results indicate that isofraxidin inhibits expression of MMP-7 and in vitro cell invasion at a non toxic level through inhibiting ERK1/2 phosphorylation in hepatoma cell lines, which suggest isofraxidin might become an effective agent for suppressing hepatoma cell invasion. PMID- 20930382 TI - Molecular phylogenetic analysis of Phyllanthus species in Thailand and the application of polymerase chain reaction-restriction fragment length polymorphism for Phyllanthus amarus identification. AB - The genus Phyllanthus (Phyllanthaceae) is distributed in tropical and subtropical regions, and its members are widely used as medicinal plants in many countries. We analyzed the nucleotide sequences of the internal transcribed spacers of ribosomal DNA of 56 plant samples covering 23 Phyllanthus species collected from various habitats in Thailand. Based on the sequence alignment, we constructed phylogenetic trees of all Phyllanthus species distributed in Thailand. Furthermore, a simple protocol to discriminate three important medicinal Phyllanthus species, P. amarus, P. debilis, and P. urinaria, was developed using a Polymerase Chain Reaction-Restriction Fragment Length Polymorphism method and successfully applied to the crude drug samples obtained in Thai markets. PMID- 20930383 TI - Anti-hepatitis B virus activities of cinobufacini and its active components bufalin and cinobufagin in HepG2.2.15 cells. AB - Cinobufacini (Huachansu) is a Chinese medicine prepared from the skin of Bufo bufo gargarizans Cantor (Bufonidae), which has long been used in traditional Chinese medicine (TCM). The aim of present study was to examine the anti hepatitis B virus (HBV) activities of cinobufacini and its active components bufalin and cinobufagin in the human HBV-transfected cell line HepG2.2.15. The hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg), and hepatitis B core-related antigen (HBcrAg) concentrations in cell culture medium were determined by chemiluminescent enzyme immunoassay after HepG2.2.15 cells were respectively treated with different concentrations of cinobufacini, bufalin, and cinobufagin for 3 or 6 d. HBV DNA and mRNA were determined using transcription mediated amplification and real-time polymerase chain reaction (PCR), respectively. On d 3, cinobufacini at a concentration of 1 ug/ml had no activity against HBV virological markers. However, on d 6, cinobufacini at 1 ug/ml effectively inhibited the secretion of HBsAg, HBeAg, and HBcrAg by 29.58, 32.87, and 42.52%. It was more potent than the positive control lamivudine (100 ug/ml). Bufalin and cinobufagin slightly inhibited HBV antigen secretion. Treatment with cinobufacini, bufalin, or cinobufagin had no anti-HBV effect on DNA in cell culture medium. Consistent with the HBV antigen reduction, HBV mRNA expression was markedly inhibited in comparison to the control when HepG2.2.15 cells were treated with cinobufacini, bufalin, or cinobufagin. Results suggested that cinobufacini had more potent activity against HBV antigen secretion than its components bufalin and cinobufagin and this inhibitory role was attributed to the specific inhibition of HBV mRNA expression. PMID- 20930384 TI - Palmatine attenuates osteoclast differentiation and function through inhibition of receptor activator of nuclear factor-kappab ligand expression in osteoblast cells. AB - Osteoclasts are the only cell type capable of resorbing mineralized bone, and they act under the control of numerous cytokines produced by supporting cells such as osteoblasts and stromal cells. Among cytokines, receptor activator of nuclear factor-kappaB ligand (RANKL) was found to be a key osteoclastogenetic molecule that directly binds to its cognate receptor, RANK, on osteoclast precursor cells. In turn, RANKL, which is an essential factor for differentiation and activation of osteoclasts, is one of the major targets of anti-resorptive agents. In this study, we found that palmatine, an isoquinoline alkaloid originally isolated from Coptis chinensis, had an inhibitory effect on osteoclast differentiation and function in vitro. Palmatine inhibited osteoclast formation in the co-culture system with mouse bone marrow cells (BMC) and osteoblasts in the presence of 10 nM 1alpha,25-(OH)(2)D(3). Palmatine did not affect osteoclast formation induced by RANKL in the BMC cultures. Reverse-transcription polymerase chain reaction (RT-PCR) analysis showed that palmatine significantly inhibited the expression of 1alpha,25-(OH)(2)D(3)-induced expression of RANKL mRNAs in stromal cells without loss of cell viability. Moreover, palmatine suppressed resorption pit formation by mature osteoclasts on dentin slices and induced disruption of actin ring formation in mature osteoclasts with an impact on cell viability. Taken together, these results suggest that palmatine attenuates osteoclast differentiation through inhibition of RANKL expression in osteoblast cells, and its inhibitory effect on bone resorption is due to its disruptive effect on actin rings in mature osteoclasts. Therefore, palmatine might be an ideal candidate as an anti-resorptive agent for the prevention and treatment of bone disorders such as osteoporosis. PMID- 20930385 TI - Matrine inhibits proliferation and induces apoptosis of pancreatic cancer cells in vitro and in vivo. AB - Matrine, an alkaloid extracted from a Chinese herb, Sophora flavescens AIT., has exhibited anti-proliferative and pro-apoptotic abilities against various types of cancer cells. This study aims to investigate its anti-cancer activity and underlying mechanisms in human pancreatic cancer cells in vitro and in vivo. Human BxPC-3 and PANC-1 pancreatic cancer cells, and human HL-7702 liver cells were incubated with matrine at different concentrations. Cell viability was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and cell apoptosis, by flow cytometry. Subcutaneous BxPC-3 xenograft tumors were established in nude BALB/c mice, and matrine was intraperitoneally (i.p.) administered. The tumors were monitored and harvested. Tumor sections were immunostained with an anti-Ki-67 antibody (Ab) to examine cell proliferation, or stained with terminal deoxynucleotidyl transferase mediated deoxyuridine triphosphate (dUTP) nick-end labeling (TUNEL) to evaluate in situ cell apoptosis. The expression of proliferating cell nuclear antigen (PCNA) and several apoptosis related proteins in cells and tumor tissues were evaluated by Western blot analysis. In in vitro assays, matrine inhibited cell viability by downregulating the expression of PCNA, and induced cell apoptosis by reducing the ratio of Bcl 2/Bax, upregulating Fas, and increasing activation of caspases-8,-3 and -9, in a dose-dependent manner. Administration of matrine inhibited tumor growth in a dose dependent manner, and regulated tumoral gene expression consistent with the in vitro results. But matrine had no significant effects on the viability of HL-7702 cells or the bodyweight of mice compared to controls. These results indicate matrine may be a potential and promising agent of natural resource to treat pancreatic cancer. PMID- 20930386 TI - Fluorescence polarization analysis for revealing molecular mechanism of nucleotide-dependent phospholipid membrane binding of MinD adenosine 5' triphosphate, adenosine triphosphatase. AB - Membrane binding of Walker type adenosine 5'-triphosphate, adenosine triphosphatase (ATPase), MinD, is a key step in regulating the site of cell division in Escherichia coli. Two lysine residues (K11, K16) in the Walker A motif of MinD have been suggested to be essential for both membrane binding and ATPase activity, but the relationship between the membrane binding of MinD and its ATPase activity is still unclear. To reveal the role of K11 and K16 in MinD membrane interaction and ATP-binding, we compared the functionality of wild-type MinD (WT) and two MinD mutants that lack ATPase activity, where alanine was substituted for lysine at positions 11 and 16 (K11A, K16A), using liposomes and fluorescent-labeled ATP. The ATP dissociation constant (K(d)) of wild-type MinD was 4.9 uM. Unexpectedly, the K(d) values of the two lysine mutants were almost the same as that of wild type, indicating that ATP can bind to MinD mutants, even though these mutants showed no ATPase activity and membrane binding ability. Our results presumed that K11 and K16 residues might play an important role in dimmer formation of MinD, but not ATP binding step, for recruiting to membrane. PMID- 20930387 TI - Association of the A-1438G polymorphism in serotonin 2A receptor in migraine with aura among Japanese patients. AB - We investigated the possible association of serotonin (5-HT) 2A receptor gene A 1438G polymorphism in Japanese patients with migraine. Genotyping of 5-HT(2A) A 1438G polymorphism was performed by polymerase chain reaction-restriction fragment length polymorphism in patients with migraine (male 17 : 3 with aura and 14 without aura, female 65 : 17 with aura and 48 without aura) and controls (male 31, female 84). The distribution of 5-HT(2A) A-1438G genotype frequency between migraine patients and controls did not differ. These results suggest that the A 1438G polymorphism of the 5-HT(2A) receptor gene is not a direct risk factor for migraine; however, the incidence of the A/A genotype between migraine with aura (MA) and without aura (MO) was significantly different. The 5-HT(2A) A-1438G polymorphism may be involved in determining the subtypes of migraine in Japanese. PMID- 20930388 TI - Involvement of Kv4.1 K(+) channels in gastric cancer cell proliferation. AB - Voltage-gated potassium (Kv) channels are expressed not only in excitable cells but also in non-excitable cells such as epithelial cells. Recent studies have demonstrated that several subtypes of Kv channels are expressed in epithelial tumor cells, including human gastric cancer cells, and are associated with cell proliferation. In the present study, we examined the expression of Kv4.1 in human gastric cancer cell lines and the effects of suppressed expression of Kv4.1 on cell proliferation and cell cycle distribution. We found that Kv4.1 mRNA and protein are expressed in the human gastric cancer cell lines MKN-45 and SNU-638. Moreover, Kv4.1-targeted small interference RNA (siRNA) treatment inhibited gastric cancer cell proliferation. Flow cytometric analysis revealed that suppressed expression of Kv4.1 induced a G1-S transition block of cell cycle progression. These results reveal that Kv4.1 plays a role in the proliferation of the human gastric cancer cell lines MKN-45 and SNU-638 and can be considered as a therapeutic target for human gastric cancer. PMID- 20930389 TI - Human trial of liposomal lactoferrin supplementation for periodontal disease. AB - New approaches to periodontal health have been in strong demand in addition to conventional local plaque control. In this study, liposomal bovine lactoferrin (L bLF) was orally administered to subjects with periodontal disease to investigate whether it could be a useful treatment. L-bLF composed of soy phosphatidylcholine was given as a supplement for four weeks in tablet form (180 mg bLF/d) to twelve subjects with multiple sites of more than 3 mm probing depth (PD). PD, bleeding on probing (BOP), gingival crevicular fluid (GCF) volume and the levels of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, and monocyte chemoattractant protein-1 (MCP-1) in GCF were evaluated for 51 sites with more than 4 mm PD in five subjects. Blood samples of all subjects were collected 0, 2 and 4 weeks after supplementation. Isolated peripheral blood mononuclear cells (PBMCs) were incubated for 24 h with or without lipopolysaccharide (LPS) (100 ng/ml) from Porphyromonas gingivalis, and TNF-alpha, IL-1beta, IL-6 and MCP-1 in the culture media were measured. Toll-like receptor 2 (TLR2) and TLR4 mRNA expressions of isolated PBMCs were also quantitatively analyzed using real-time reverse transcription-polymerase chain reaction (RT-PCR). The PD was significantly reduced by L-bLF supplementation, but the BOP and GCF volume were not significantly changed. The MCP-1 level in GCF was significantly reduced, while levels of other cytokines were not changed. Four-week L-bLF supplementation also showed significant decreases of LPS-induced cytokine production from PBMCs. Relative gene expressions of TLR2 and TLR4 did not change. These results suggest that L-bLF supplementation can be effective in the treatment of periodontal disease, although prospective controlled large-scale studies are required. PMID- 20930390 TI - Comparative study of skin permeation profiles between brand and generic tulobuterol patches. AB - Tulobuterol patches are long-acting bronchodilators for percutaneous absorption including the beta(2)-adrenoreceptor agonist tulobuterol, as a main ingredient, used for long-term management of pediatric asthma. Since patients who have pediatric asthma often also have atopic dermatitis in which the skin barrier is impaired, we compared the skin penetration profiles of the brand and generic patches using a skin barrier-impaired rat model. Skin penetration was significantly (p<0.001) higher in the generic patches compared with the brand patch, suggesting that it is important to understand the pharmaceutical properties of available products by giving careful consideration not only to the patient's asthma control but also to their skin condition before using tulobuterol patches. PMID- 20930391 TI - Preparation and characterization of laminin-derived peptide AG73-coated liposomes as a selective gene delivery tool. AB - Targeted gene delivery to cancer cells is considered as a promising strategy for cancer therapy. Since, several targeting ligands have been studied for cancer gene therapy, such as transferrin, folate, anisamide, RGD-peptide, and antibodies. We have focused on AG73 peptide, which is derived from the globular domain of the laminin alpha1 chain. AG73 peptide is known as a ligand for syndecans, one of the major heparin sulfate-containing transmembrane proteoglycans. Syndecan-2 is highly expressed in various cancer cells and plays a role in angiogenesis. In this study, we prepared AG73-labeled polyethyleneglycol modified liposomes (AG73-PEG liposomes) for gene delivery tool to syndecan-2 overexpressing cancer cells, and assessed the characterization of AG73-PEG liposomes. We confirmed the conjugation of AG73 peptide to PEG liposomes by reverse-phase high-performance liquid chromatography analysis. Electron microscopy analysis showed that monodiseperse AG73-labeled lipsomes were prepared. We also assessed the gene transfection efficiency of AG73-PEG liposomes in syndecan-2 overexpressing cancer cells or syndecan-2 less expressing cancer cells. As a result, AG73-mediated liposomal gene transfection efficiency was increased by 100-fold in syndecan-2 overexpressing cancer cells compared to syndecan-2 less expressing cancer cells. These results suggested that AG73-PEG liposomes were successfully prepared from a point of view of the modification of AG73 peptide to PEG-liposomes and the particle size of liposomes, which presented nano size. Furthermore, our results suggest that AG73-PEG liposomes can be a useful targeted gene delivery vehicle for syndecan-2 overexpressing cancer cells. PMID- 20930392 TI - Development of responsive lanthanide-based magnetic resonance imaging and luminescent probes for biological applications. AB - Lanthanide complexes have unique chemical characteristics compared with typical organic complexes, and have recently attracted much interest because of the expanding need for new bioanalytical sensors. For example, magnetic resonance imaging (MRI) permits noninvasive three-dimensional imaging inside opaque organisms, and gadolinium ion (Gd(3+)) complexes have become important tools as MRI contrast agents. However, most of them are nonspecific, and report solely on anatomy. Therefore, responsive MRI contrast agents, so-called "smart" MRI contrast agents whose ability to relax water protons is greatly enhanced by recognition of a particular biomolecule, have great potential for elucidating biological phenomena. On the other hand, lanthanide complexes such as europium (Eu(3+)) and terbium (Tb(3+)) complexes have excellent luminescence properties for biological applications, i.e., long luminescence lifetime of the order of milliseconds and a large Stoke's shift of >200 nm. Their long-lived luminescence is especially suitable for time-resolved measurements, because the interference from short-lived background fluorescence and scattered light rapidly decays to a negligible level after a pulse of excitation light is applied, and the emitted light can be collected after an appropriate delay time. These luminescent lanthanide complexes have already found commercial use as highly sensitive luminescent probes in heterogeneous and homogeneous assays. This paper reviews our research on the design and synthesis of responsive lanthanide-based MRI and luminescent probes for advanced bioimaging. PMID- 20930393 TI - The relationship between the drug concentration profiles in plasma and the drug doses in the colon. AB - After the dosing of an extended-release (ER) formulation, compounds may exist in solutions at various concentrations in the colon because the drugs are released at various speeds from the ER dosage form. The aim of this study was to investigate the relationship between the drug concentration profiles in plasma and the drug doses in the colon. Several drug solutions of different concentrations were directly administered into the ascending colon of dogs using a lubricated endoscope, and the effects of the drug dose on colonic absorption were estimated. As a result, dose-dependency of colonic absorption varied from compound to compound. Although the relative bioavailability of colonic administration of diclofenac, metformin and cevimeline compared to oral administration was similar regardless of the drug doses in the colon, colonic absorption of diltiazem varied according to the doses. From the results of the co administration of verapamil and fexofenadine, it was clear that diltiazem underwent extensive hepatic and gastrointestinal first-pass metabolism, resulting in a low area under the curves (AUC) at a low drug dose. During the design of oral ER delivery systems, a colonic absorption study of candidate compounds should be carried out at several solutions of different drug concentrations and assessed carefully. PMID- 20930394 TI - Effects of pathological conditions on ocular pharmacokinetics of antimicrobial drugs. AB - A diffusion model of ocular pharmacokinetics was used to estimate the effects of pathological conditions on ocular pharmacokinetics. In vivo rabbit data after topical instillation of ciprofloxacin and ofloxacin were compared with the simulated concentrations in the aqueous and vitreous humors. The barrier capacity of the surrounding membranes such as the retina/choroid/sclera (RCS) membrane and the cornea was characterized by dimensionless Sherwood number derived by the pseudo-steady state approach (PSSA). We assumed the barrier capacity decreased by inflammation; when the barrier capacity of the RCS membrane and the cornea was assumed to be one-tenth for the RCS membrane and a half for the cornea respectively, the in vivo data agreed with the simulated profile without contradiction. The drug concentration gradient simulated in the vitreous body near the RCS membrane was more significant in the inflamed eyes than in the normal eyes, suggesting that the elimination of the drugs from the RCS membrane was enhanced by inflammation. The present diffusion model can better describe the ocular pharmacokinetics in both normal and diseased conditions. PMID- 20930395 TI - Synthesis, characterization, antioxidant activities, and DNA-binding studies of (E)-N'-[1-(pyridin-2-yl)ethylidene]isonicotinohydrazide and its Pr(III) and Nd(III) complexes. AB - A new ligand, (E)-N'-[1-(pyridin-2-yl)ethylidene]isonicotinohydrazide (HL), was prepared by condensation of 2-acetylpyridine and isonicotinohydrazide in ethanol. Its two lanthanide(III) complexes, [Nd(III)(L)(2)(NO(3))(CH(3)OH)(2)].CH(3)CH(2)OH (1), and [Pr(III)(L)(2)(NO(3))(CH(3)OH)(2)].CH(3)CH(2)OH (2), have been synthesized and characterized on the basis of element analyses, molar conductivities and IR spectra. The structure of complex 2 has been confirmed by X-ray diffraction. In addition, the DNA-binding properties of the two complexes have been investigated by electronic absorption spectroscopy, fluorescence spectroscopy, circular dichroic (CD) spectroscopy and viscosity measurements. The experimental results suggest that the two complexes bind to DNA via a groove binding mode, and the binding affinity of complex 2 is higher than that of complex 1. Furthermore, the antioxidant activities (superoxide and hydroxyl radical) of the ligand and its metal complexes were determined by spectrophotometry methods in vitro. These complexes were found to possess potent antioxidant activity and be superior to standard antioxidant like mannitol. PMID- 20930396 TI - Preparation and characterization of hydroxypropyl-beta-cyclodextrin inclusion complex of eugenol: differential pulse voltammetry and (1)H-NMR. AB - The objective of present investigation was to improve the solubility of Eugenol by preparing the inclusion complex of Eugenol with hydroxypropyl-beta cyclodextrin (Hp-beta-CD) and characterize the prepared complex by using NMR and differential pulse voltammetry (DPV). Phase solubility curve was plotted using Hp beta-CD in ranging from 0-40 mM of Hp-beta-CD and found to be linear. Therefore, inclusion complex was prepared in equimolar ratio of Eugenol and Hp-beta-CD by lyophilization method. Fourier transform infrared spectroscopy (FT-IR), (1)H-NMR and DPV were performed for Eugenol, Hp-beta-CD and prepared inclusion complex of Eugenol. 2D (two dimensional) NMR was also performed for prepared inclusion complex. The proton of phenol moiety of Eugenol experienced a pronounced chemical shift variation in (1)H-NMR. The positive sign of the variation for proton in (1)H-NMR indicated that the proton was located near to an oxygen atom in the Hp beta-CD cavity and its magnitude showed a strong interaction between -OH proton of Eugenol and Hp-beta-CD. 2D NMR confirms the interaction between phenolic group and hydrogen atoms of Hp-beta-CD. A well defined anodic peak current corresponding to oxidation of Eugenol in non-encapsulated and Hp-beta-CD-Eugenol inclusion complex in phosphate buffer (pH 6.8) was obtained at about 0.35 V and 0.40 V, respectively. The positive shift in oxidation potential indicated the formation of complex via hydrophobic interactions. The oxidant power of Eugenol was retained in complex form as indicated by DPV results. Thus, its oxidation dependent pharmacological property such as antimicrobial activity is not affected after complexation with Hp-beta-CD. Thus, (1)H-NMR, 2D-NMR and DPV techniques can be used as valuable tools to determine the mechanism of complexation and state of electrochemical active drug in inclusion complex. PMID- 20930397 TI - Synthesis of 2-oxo/thioxooctahydroquinazolin-5-one derivatives and their evaluation as anticancer agents. AB - An environment friendly method for the synthesis of 2 oxo/thioxooctahydroquinazolin-5-one derivatives has been devised using Ceric ammonium nitrate (CAN) as catalyst and polyethylene glycol (PEG) as solvent. The cytotoxic effect of these compounds was studied on U87 human glioma cells, compounds 4c, 4d and 4e are found to exhibit excellent activity at a concentration as low as 0.06 ug/ml. PMID- 20930398 TI - Synthesis, cytotoxicity and pro-apoptosis of novel benzoisoindolin hydrazones as anticancer agents. AB - A series of benzoisoindolin hydrazones as analogues of natural lignan diphyllin were synthesized and the structures of these compounds were established by (1)H NMR, (13)C-NMR, Mass and high resolution (HR)-MS. The compounds were evaluated for in vitro cytotoxicity against KB, A549 and HCT-116 cancer cell lines by 3 (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Compound 4 possessed the highest growth inhibitory effect. Significant apoptosis of HCT 116 cells treated with compound 4 was observed by Hoechst33342-propidium iodide (PI) and acridine orange (AO)-ethidium bromide (EB) staining assay. Western blot analysis disclosed that compound 4 induced apoptosis via the mitochondrial pathway accompanied by an increased expression of Bax and a decreased expression of Bcl-2. PMID- 20930399 TI - Synthesis of new 1,2,4-triazole[3,4-b][1,3,4]thiadiazoles bearing pyrazole as potent antimicrobial agents. AB - A new series of 6-(aryl/heteryl)-3-(5-methyl-1-phenyl-1H-4 pyrazolyl)[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles (7a-j) has been synthesized by the reaction of 4-amino-5-(5-methyl-1-phenyl-1H-4-pyrazolyl)-4H-1,2,4-triazol 3-yl-hydrosulfide (6) with POCl(3) and the corresponding aryl/heteryl carboxylic acid, in ethanol at reflux temperature for 12 h. All the synthesized compounds were tested for in vitro activities against certain strains of bacteria such as Staphylococcus aureus, Bacillus subtilis, Escherichia coli and fungi such as Aspergillus niger, Aspergillus nodulans, Alternaria alternate. Compounds having 4 chlorophenyl (7d), 4-aminophenyl (7f), 4-nitrophenyl (7h) and 3-pyridyl (7i) substituents at 6-position of thiadiazole ring, showed marked inhibition of bacterial and fungal growth nearly equal to the standards. The other new compounds also showed appreciable activity against the test bacteria and fungi. PMID- 20930400 TI - Formulation and physicochemical characterization of imwitor 308 based self microemulsifying drug delivery systems. AB - Self Microemulsifying Drug Delivery Systems (SMEDDS) are a novel alternative to the conventional transdermal delivery systems. SMEDDS are water-free systems, made up of oils and surfactants that can readily form a microemulsion upon dilution within an aqueous medium. Before SMEDDS can be used as a drug delivery system it is necessary to investigate the internal microstructure of the resulting microemulsion. Novel Imwitor 308 based SMEDDS were prepared and investigated. Phase behaviour of the comprising components was investigated through the construction of pseudoternary phase diagrams. The formed systems were characterized using visual inspection, measurement of electrical conductivity, viscosity and droplet size. Amongst the pseudoternary systems investigated, IPM/Cremophor EL (50% w/w)/Imwitor (50% w/w) and Myritol 318/Tween 85 (64% w/w)/ Transcutol P (20% w/w)/Imwitor (16% w/w) possessed the largest microemulsion area. Electrical conductivity and viscosity studies depict structural transitions from w/o microemulsion to bicontinuous or o/w microemulsion around 20-35% water. This was further supported by the droplet size and Fourier transform (FT)-IR measurements. The FT-IR data suggests that below the percolation threshold (psi(C)) the water molecules are mainly bounded to the surfactant head group (bound water). Above this value, water molecule move to the outer phase of the microemulsion mainly interacting with each other though hydrogen bounding (free water). It was also found that pseudoternary systems with water content of less than 30% were stable at 32 degrees C. Such systems may form stable microemulsion upon contact with the skin. Absorption of water may also result in a supersaturated solution with enhanced transdermal flux. PMID- 20930401 TI - Isolation of four new flavonoids from Melicope triphylla. AB - Four new flavonoids, 3,5-dihydroxy-7,8-dimethoxy-3',4'-methylenedioxyflavone (1), 3,5-dihydroxy-7-methoxy-3',4'-methylenedioxyflavone (2), 3,5-dihydroxy-7 isopentenyloxy-8-methoxy-3',4'-methylenedioxyflavone (3) and 5-hydroxy-3 isopentenyloxy-7-methoxy-3',4'-methylenedioxyflavone (4), were isolated from the leaves of Melicope triphylla. In addition, two known flavonoids were detected including 5-hydroxy-3,7-dimethoxy-3',4'-methylenedioxyflavone (5) and 5-hydroxy-7 isopentenyloxy-3,8-dimethoxy-3',4'-methylenedioxyflavone (6). The structures of the new compounds were established by spectroscopic methods. PMID- 20930402 TI - Schefflerins A-G, new triterpene glucosides from the leaves of Schefflera arboricola. AB - From the 1-BuOH-soluble fraction of a MeOH extract of leaves of Schefflera arboricola, collected in Okinawa, six new lupane glucosides, named schefflerins A F (1-6) and one new dammarane glucoside, named schefflerin G (7), were isolated together with three known compounds, citroside A (8), and oleanane saponins, oleanolic acid (9) and echinocystic acid (10) 3-O-alpha-L-rhamnopyranosyl(1->4') O-beta-D-glucuronopynosides. Their structures were elucidated through a combination of spectroscopic analyses and the structure of schefflerin F (6) was determined by X-ray crystallographic method using SPring-8 synchrotron radiation. PMID- 20930403 TI - Rhodium-catalyzed organothio exchange reaction of alpha-organothioketones with disulfides. AB - RhH(PPh(3))(4) and 1,2-bis(diphenylphosphino)ethane (dppe) catalyzed the organothio exchange reaction of alpha-organothioketones and organic disulfides. The reaction was affected by the structure of the substrate: alpha-phenylthio and alpha-alkylthio aryl ketones reacted effectively with diaryl and dialkyl disulfides; alpha-phenylthio dialkyl ketones reacted with diaryl disulfides but not with dialkyl disulfides; diaryl disulfides with electron-donating p substituents were more reactive than those with electron-withdrawing p substituents. PMID- 20930404 TI - Kojic acid derivatives as histamine H(3) receptor ligands. AB - The histamine H(3) receptor (H(3)R) is a promising target in the development of new compounds for the treatment of mainly centrally occurring diseases. However, emerging novel therapeutic concepts have been introduced and some indications in the H(3)R field, e.g. migraine, pain or allergic rhinitis, might take advantage of peripherally acting ligands. In this work, kojic acid-derived structural elements were inserted into a well established H(3)R antagonist/inverse agonist scaffold to investigate the bioisosteric potential of gamma-pyranones with respect to the different moieties of the H(3)R pharmacophore. The most affine compounds showed receptor binding in the low nanomolar concentration range. Evaluation and comparison of kojic acid-containing ligands and their corresponding phenyl analogues (3-7) revealed that the newly integrated scaffold greatly influences chemical properties (S Log P, topological polar surface area (tPSA)) and hence, potentially modifies the pharmacokinetic profile of the different derivatives. Benzyl-1-(4-(3-(piperidin-1-yl)propoxy)phenyl)methanamine ligands 3 and 4 belong to the centrally acting diamine-based class of H(3)R antagonist/inverse agonist, whereas kojic acid analogues 6 and 7 might act peripherally. The latter compounds state promising lead structures in the development of H(3)R ligands with a modified profile of action. PMID- 20930405 TI - Carotenoids and related polyenes, part 12. First total synthesis and absolute configuration of 3'-deoxycapsanthin and 3,4-didehydroxy-3'-deoxycapsanthin. AB - The synthesis of 3'-deoxycapsanthin (1) and 3,4-didehydroxy-3'-deoxycapsanthin (2), carotenoids of paprika, has been achieved by employing Lewis acid-promoted regio- and stereoselective rearrangement of the C(15)-epoxy dienal 5a. The absolute stereochemistry of the newly formed C-5 chiral center of rearrangement product 6a was determined to be (R) from its alternative synthesis derived from (+)-(R)-camphonanic acid (11). PMID- 20930406 TI - Calculating critical relative humidity from solubility according to Pitzer ion interaction model. AB - The solubility and the critical relative humidity (H(cr)) of 14 drugs and inorganic salts were determined, the relationship between the H(cr) and the solubility was explored theoretically, and the H(cr) was calculated in the light of Raoult's law and Pitzer ion interaction model from their solubility. The results indicate that the H(cr) values calculated by Raoult's law in high humidity (H(cr)>80%) and by Pitzer ion interaction model in low humidity (H(cr)<80%) are comparable to the measured ones. PMID- 20930407 TI - Chemical constituents in the leaves of Vateria indica. AB - Comprehensive re-investigation of the chemical constituents in the leaves of Vateria indica (Dipterocarpaceae) resulted in the isolation of a novel resveratrol dimeric dimer having a C(2)-symmetric structure, vateriaphenol F (1), and two new O-glucosides of resveratrol oligomers, vateriosides A (2) (resveratrol dimer) and B (4) (resveratrol tetramer), along with a new natural compound (3) and 33 known compounds including 26 resveratrol derivatives. The absolute structures were elucidated by spectroscopic analysis, including two dimensional NMR and circular dichroism (CD) spectra. PMID- 20930408 TI - Structures of novel norstilbene dimer, longusone A, and three new stilbene dimers, longusols A, B, and C, with antiallergic and radical scavenging activities from Egyptian natural medicine Cyperus longus. AB - The methanolic extract of the whole plant of Cyperus longus originating in Egypt was found to show antiallergic effect on ear passive cutaneous anaphylaxis reactions in mice. By bioassay-guided separation, 11 stilbenes and stilbene dimers including a novel norstilbene dimer, longusone A, and three new stilbene dimers, longusols A, B, and C, were isolated. Their structures were elucidated on the basis of chemical and physicochemical evidence. Among the isolates, longusol B (IC(50)=96 uM), luteolin (3.0 uM), resveratrol (17 uM), piceatannol (24 uM), and cassigarols E (84 uM) and G (84 uM) were found to inhibit the release of beta hexosaminidase, as a marker of antigen-induced degranulations, in rat basophilic leukemia (RBL-2H3) cells. In addition, the methanolic extract and the constituents showed 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity (SC(50)=22 ug/ml and 2.8-29 uM, respectively). PMID- 20930409 TI - Conformational analysis of beta-1,2-linked mannobiose to mannoheptaose, specific antigen of pathogenic yeast Candida albicans. AB - Candida albicans contains characteristic beta-1,2-linked oligomannosyl moieties in the cell wall mannan. Reduction of the reducing termini of these oligosaccharides by NaBH(4) causes a significant downfield shift in the NMR signals for the second and third mannose units and upfield shift of the fourth mannose unit. To show the correlation between the shift in the NMR signals and the conformations of the beta-1,2-linked mannooligosaccharides, we performed molecular mechanics calculations. Six energy minima of the beta-1,2-linked mannobiose were found in the relaxed map computed using the AMBER force field. Five of the six energy minima could also be generated by a simulated annealing from a 900 K molecular dynamics. Similarly, the solution conformation of the beta 1,2-linked mannotriose to mannoheptaose was identified by the high temperature simulated annealing. In the mannotetraose, the nonreducing terminal mannose unit was located near the reducing terminal one and formed a folded conformation. This result suggests that a mannose unit affects the H-1 chemical shifts of not only the second mannose unit, but also the third and fourth mannose units. PMID- 20930410 TI - A novel cyclopentene derivative and a polyhydroxylated steroid from a South China Sea gorgonian Menella sp. AB - A chemical investigation on a South China Sea gorgonian, Menella sp. resulted in the isolation and elucidation of menellin A (1), a highly oxygenated racemate with C(8) skeleton, and a polyhydroxylated steroid, menellsteroid C (2), along with eight known compounds (3-10). The structures of the new compounds were elucidated by means of MS, 1D and 2D NMR spectra, and the relative stereochemistry of 1 was determined by X-ray single-crystal diffraction analysis. In addition, compound 7 was isolated as a new natural product. Compounds 1-3 and 7 were selected to test the anti-inflammatory inhibition against lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW264.7 macrophages. 1 and 3 exhibited modest inhibitory effects with IC(50) of 71.3, 33.9 uM, respectively, compared to the positive control aminoguanidine (IC(50) 25.0 uM). PMID- 20930411 TI - Two new flavan-flavanones from Sarcandra hainanensis. AB - Chemical study of the whole plants of Sarcandra hainanensis yielded two new biflavonoids with a flavan-flavanone skeleton, sarcandrone C (1), D (2) and 6 known compounds (3-8). Structures were elucidated on the basis of NMR spectroscopic methods. PMID- 20930412 TI - Reinvestigation of the absolute stereochemistry of megastigmane glucoside, icariside B(5). AB - Icariside B(5) is one of the widely distributed megastigmane glucosides among plant sources. The absolute structure of icariside B(5) was reinvestigated by chemical conversion from the related compound and the application of the modified Mosher's method. As a result, the structure of icariside B(5) was revised to be (6S,9S)-6,9-dihydroxymegastigman-4-en-3-one 9-O-beta-D-glucopyranoside. PMID- 20930413 TI - Iridoid and acyclic monoterpene glycosides, kankanosides L, M, N, O, and P from Cistanche tubulosa. AB - Three iridoid glycosides, kankanosides L, M, and N, and two acyclic monoterpene glycosides, kankanosides O and P, were isolated from fresh stems of Cistanche tubulosa (Orobanchaceae) together with eight iridoid glycosides, five acyclic monoterpene glycosides, three phenylpropanoid glycosides, and four lignan glycosides. Their structures were elucidated on the basis of chemical and physicochemical evidence. PMID- 20930414 TI - A new monoterpenoid glycoside from Myrica esculenta and the inhibition of angiotensin I-converting enzyme. AB - One new monoterpenoid glycoside, myresculoside (1), and eleven known compounds, were isolated from methanol extract of Myrica esculenta leaves by repeated column chromatography. The effects of these compounds on angiotensin I-converting enzyme (ACE) inhibition were investigated. Compounds 3 and 4 showed the most potent ACE inhibition with rates of 29.97% and 25.63% at concentration of 100 uM, respectively. Compounds 5, 6, and 11 showed weak activity with inhibitory rates of 0.07-1.41% at concentration of 100 uM. PMID- 20930415 TI - Nucleophilic addition to 2,3-disubstituted butanal derivatives and their application to natural product synthesis. AB - The reaction of 2,3-anti-2-tert-butyldimethylsiloxy-3-substituted butanal derivative [anti-B, (+/-)-10 and (+/-)-16] derived from trans-(2,3)-epoxy butanoate (1) with carbon nucleophiles [alpha-furyl anion, acetate anion, and indium (In)-assisted allyl anion] has been investigated to give selectively the anti-, anti-adduct D. This anti-stereoselection could be explained by the Felkin Anh transition state model. Thus obtained anti-, anti-adducts (+/-)-17 and (+/-) 38 were formally converted to natural products, (+/-)-asperlin (2) and (+/-) olivose (4), respectively. The major anti-, anti-adduct (+/-)-26 was converted to (+/-)-digitoxose (3), while the minor anti-, syn-adduct (+/-)-27 was also converted to (+/-)-olivose (4). The reaction of (+/-)-10 with tert-butyl acetate anion gave predominantly afforded the anti-, anti-adduct (+/-)-23, which was converted to (+/-)-1,5-dideoxyhexitol (25). Alternately, the reaction of 2,3-syn 2-tert-butyldimethylsiloxy-3-p-methoxyphenoxy butanal derivative [syn-B, (+/-) 14] derived from trans-(2,3)-epoxy butanoate (1) with carbon nucleophile (In assisted allyl anion) afforded a ca. 1 : 1 mixture of the syn-, anti-adduct E [(+/-)-32 or (+/-)-34] and syn-, syn-adduct F [(+/-)-33 or (+/-)-35]. After separation of this mixture, (+/-)-34 and (+/-)-35 were separately converted to (+/-)-oliose (5) and (+/-)-boivinose (6), respectively. PMID- 20930416 TI - Sterically congested, "roofed" beta-iminodisulfides as new chiral ligands for palladium-catalyzed, asymmetric allylic alkylation. AB - The preparation of a new class of "roofed" beta-iminodisulfides from sterically congested, conformationally rigid chiral 2-thiazolidinones is described. A functional survey of palladium-catalyzed asymmetric allylic alkylation of 1,3 diphenyl-2-propenyl acetate with dimethyl malonate proved that symmetrical "roofed" beta-iminodisulfides are efficient chiral ligands, showing enantioselectivity opposite that associated with chiral "roofed" beta iminothioether ligands. PMID- 20930417 TI - Pharmacogenetics of CYP1A2, novel polymorphisms and haplotypes in three distinct Asian populations. AB - CYP1A2 play an important role in the metabolism of many carcinogens and clinically important drugs. CYP1A2 activity has been found to be influenced by the presence of polymorphic variants which were reported to display wide interethnic variation. This study investigates the frequency distribution and linkage disequilibrium patterns of CYP1A2 genetic polymorphisms, and characterize their haplotype structures in three healthy Asian populations in Singapore (Chinese, Malay, and Indian). The entire CYP1A2 gene was screened in 126 healthy subjects from all three ethnic groups (N=42 each). A total of 25 polymorphisms was identified, of which nine were novel. The polymorphisms, -2467delT and 163C>A were detected at high frequencies in all Asian ethnic groups. Significant interethnic differences were observed in the genotypic frequency distribution of IVS2-99G>A (P<0.01) and 1548C>T (P=0.05) across the three ethnic groups while 163C>A (P=0.02) was found to differ between Chinese and Malays. Haplotype analyses revealed four to six major haplotypes in each ethnic population which accounted for more than 60% of the cumulative haplotype frequencies. Future studies should be done to investigate the functional roles of these haplotypes. PMID- 20930418 TI - Genetic polymorphisms of FCGRT encoding FcRn in a Japanese population and their functional analysis. AB - Neonatal Fc receptor (FcRn) plays an important role in regulating IgG homeostasis in the body. Changes in FcRn expression levels or activity caused by genetic polymorphisms of FCGRT, which encodes FcRn, may lead to interindividual differences in pharmacokinetics of therapeutic antibodies. In this study, we sequenced the 5'-flanking region, all exons and their flanking regions of FCGRT from 126 Japanese subjects. Thirty-three genetic variations, including 17 novel ones, were found. Of these, two novel non-synonymous variations, 629G>A (R210Q) and 889T>A (S297T), were found as heterozygous variations. We next assessed the functional significance of the two novel non-synonymous variations by expressing wild-type and variant proteins in HeLa cells. Both variant proteins showed similar intracellular localization as well as antibody recycling efficiencies. These results suggested that at least no common functional polymorphic site with amino acid change was present in the FCGRT of our Japanese population. PMID- 20930419 TI - Pharmacokinetic and pharmacodynamic variation associated with VKORC1 and CYP2C9 polymorphisms in Thai patients taking warfarin. AB - We investigated the influence of genetic polymorphisms of CYP2C9 and VKORC1 genotypes on the pharmacokinetics and pharmacodynamics of warfarin and established an equation for predicting the maintenance dose of warfarin in the Thai population using genetic and non-genetic factors. The CYP2C9*2, CYP2C9*3, VKORC1 C1173T and VKORC1 G-1639A genotypes were detected by realtime PCR using fluorogenic hybridization probes. The associations between genetic and demographic factors with respect to warfarin dosage were analyzed. CYP2C9 polymorphisms affect warfarin metabolism as shown by a significant difference in warfarin clearance, whereas VKORC1 genotypes cause a significant difference in warfarin sensitivity index (INR:Cp). The mean weekly warfarin dose was significantly different among different VKORC1 and CYP2C9 genotypes. Patients with the VKORC1 BB haplotype and CYP2C9*1/*1 required about twice the warfarin dose compared to those with the VKORC1 AA haplotype and CYP2C9*1/*1. Using stepwise multiple linear regression, clinical factors (age and weight) and genetic factors (CYP2C9 and VKORC1) could explain about 53.8% of the variance of the warfarin maintenance dose. CYP2C9 and VKORC1 genotypes played an important role in the inter-individual variation in warfarin maintenance dose in a Thai population. PMID- 20930420 TI - Induction of hepatic cytochrome P450s by the herbal medicine Sophora flavescens extract in rats: impact on the elimination of theophylline. AB - The roots of Sophora flavescens (Sf) have been widely used as a herbal medicine for the treatment of diarrhea, gastrointestinal hemorrhage, and eczema. Cytochrome P450 (P450) forms including CYP1A2, CYP2B, CYP2E1, and CYP3A participate in the oxidative metabolism of theophylline, which is an important bronchodilation agent with a narrow therapeutic index. To assess the interaction of Sf with theophylline, the effects of Sf extract on theophylline-metabolizing P450s and on the pharmacokinetic profile of theophylline were investigated in male Sprague-Dawley rats. Oral treatment of rats with the Sf extract caused dose dependent increases of liver microsomal oxidation activities toward 7 ethoxyresorufin, 7-pentoxyresorufin, and nifedipine. However, nitrosodimethylamine N-demethylation activity was not affected. The ingestion of Sf extract stimulated theophylline 8-oxidation and N-demethylation activities. The increases of oxidative activities were in consensus with the elevation of the protein levels of CYP1A2, CYP2B1/2, CYP2C11, and CYP3A. Sf-treatment increased the clearance of theophylline and decreased the area under the concentration-time curve (AUC) and the area under the moment curve (AUMC). These results demonstrate that Sf reduces blood theophylline concentration through facilitating the elimination of theophylline. In patients taking Sf, possible P450 induction induced drug interaction should be noted to decrease the risk of therapeutic failure or adverse effects resulting from the use of additional therapeutic agents. PMID- 20930421 TI - Garlic flavonoids and organosulfur compounds: impact on the hepatic pharmacokinetics of saquinavir and darunavir. AB - The therapeutic efficacy of saquinavir and darunavir is affected by the presence of xenobiotics (such as garlic compounds) capable of modifying transporter-enzyme interplay. To ascertain the mechanism of interactions between antiretroviral drugs and garlic supplements and to identify the garlic constituents responsible, the hepatic pharmacokinetics of two antiretroviral drugs was investigated in the presence of garlic phytochemicals and aged garlic extract. For this purpose, rat liver slices and isolated rat hepatocytes were used. Aged garlic extract significantly inhibited saquinavir efflux from rat hepatocytes, while the efflux of darunavir significantly increased. Phytochemicals inducing distribution changes of saquinavir and darunavir were most probably flavonoids and lipophilic organosulfur compounds, respectively. All tested phytochemicals (except S-allyl L cysteine) and aged garlic extract inhibited CYP3A4 metabolism of both drugs and modulated hepatic distribution of the corresponding saquinavir and darunavir metabolites. The competition between saquinavir and garlic constituent(s) for the same binding site on the efflux transporter and the positive cooperative effect between darunavir and garlic phytochemical(s), which bind to separate binding places on transporter, are the most probable mechanisms explaining the plasma profile changes, which could occur in vivo during concomitant consumption of antiretrovirals and garlic supplements. PMID- 20930422 TI - In vitro evaluation of cytochrome P450 and glucuronidation activities in hepatocytes isolated from liver-humanized mice. AB - Cryopreserved human (h-) hepatocytes are currently regarded as the best in vitro model for predicting human intrinsic clearance of xenobiotics. Although fresh h hepatocytes have greater plating efficiency on dishes and greater metabolic activities than cryopreserved cells, performing reproducible studies using fresh hepatocytes from the same donor and having an "on demand" supply of fresh hepatocytes are not possible. In this study, cryopreserved h-hepatocytes were transplanted into albumin enhancer/promoter-driven, urokinase-type plasminogen activator, transgenic/severe combined immunodeficient (uPA/SCID) mice to produce chimeric mice, the livers of which were largely replaced with h-hepatocytes. We determined whether the chimeric mouse could serve as a novel source of fresh h hepatocytes for in vitro studies. h-Hepatocytes were isolated from chimeric mice (chimeric hepatocytes), and cytochrome P450 (P450) activities were determined. Compared with cryopreserved cells, the P450 (1A2, 2C9, 2C19, 2D6, 2E1, 3A) activities of fresh chimeric hepatocytes were similar or greater. Moreover, ketoprofen was more actively metabolized through glucuronide conjugates by fresh chimeric hepatocytes than by cryopreserved cells. We conclude that chimeric mice may be a useful tool for supplying fresh h-hepatocytes on demand that provide high and stable phase I enzyme and glucuronidation activities. PMID- 20930423 TI - Metabolism of parabens (4-hydroxybenzoic acid esters) by hepatic esterases and UDP-glucuronosyltransferases in man. AB - Parabens (alkyl esters of 4-hydroxybenzoic acid) are widely used as preservatives in drugs, cosmetic products, and foodstuffs. Safety concerns have recently increased due to the potential health risks associated to exposure to large amounts of these substances. Biotransformation of parabens mainly includes hydrolysis of the ester bond and glucuronidation reactions. The hydrolysis and glucuronidation of a series of six parabens differing by the nature of the alkyl group were investigated in human liver microsomes and plasma, and the major human UDP-glucuronosyltransferase (UGT) isoforms involved in the reaction were identified. Methyl- and ethylparaben were stable in human plasma, with 95% of the initial concentration remaining after 24 h. On the other hand, propyl-, butyl- and benzylparaben concentrations decreased by 50% under similar conditions. In contrast, rapid hydrolysis was measured with human liver microsomes depending on the alkyl chain length, with t(1/2) varying from 22 min for methylparaben to 87 min for butylparaben. All parabens were actively glucuronidated by liver microsomes, in comparison to 4-hydroxybenzoic acid. They were mainly substrates of human recombinant UGT1A1, UGT1A8, UGT1A9, UGT2B7, UGT2B15 and UGT2B17. In conclusion, the parabens were readily metabolized in human liver through esterase hydrolysis and glucuronidation by several UGT isoforms. These results suggest that these parabens do not accumulate in human tissue. PMID- 20930424 TI - Hypertonicity enhances GABA uptake by cultured rat retinal capillary endothelial cells. AB - We have reported previously that taurine transporter (TauT) mediates gamma aminobutyric acid (GABA) as a substrate in a conditionally immortalized rat retinal capillary endothelial cell line (TR-iBRB2 cells). This study investigates how TauT-mediated GABA transport is regulated in TR-iBRB2 cells under hypertonic conditions. [3H]GABA uptake by TR-iBRB2 cells exposed to 12 h- to 24 h-hypertonic culture medium was significantly greater than that of isotonic culture medium. [3H]GABA uptake by TR-iBRB2 cells was Na(+)-, Cl(-)-, and concentration-dependent with a Michaelis-Menten (K(m)) constant of 3.5 mM under isotonic conditions and K(m) of 0.324 and 5.48 mM under hypertonic conditions. Under hypertonic conditions, [3H]GABA uptake by TR-iBRB2 cells was more potently inhibited by substrates of TauT, such as taurine and beta-alanine, than those of GABA transporters such as GABA, nipecotic acid, and betaine. These results suggest that an unknown high-affinity GABA transport process and TauT-mediated GABA transport are enhanced under hypertonic conditions. In conclusion, hypertonicity enhances GABA uptake by cultured rat retinal capillary endothelial cells. PMID- 20930425 TI - Functional characterization of genetic polymorphisms identified in the promoter region of the xanthine oxidase gene. AB - Xanthine oxidase (XO) catalyzes the oxidation of endogenous and exogenous purines and pyrimidines. In the present study, we investigated polymorphisms in the promoter region of the XO gene. Sequence variations in the 5'-flanking region were screened using denaturing high-performance liquid chromatography (DHPLC) on DNA samples from 196 unrelated Japanese individuals. Thirteen polymorphisms were identified and 13 haplotypes were classified by haplotype analysis. The promoter activities of these polymorphisms were measured by luciferase assay in the human hepatoma cell lines HepG2 and Huh-7. Transcriptional activity was significantly lower in cell lines transfected with the reporter construct containing 5-kb upstream fragments with -1756T than in those with wild-type -1756C. Our results indicate that genetic variation in the promoter region of XO may determine interindividual differences in XO gene expression. PMID- 20930426 TI - Electromechanical activation time in the prediction of discharge outcomes in patients hospitalized with acute heart failure syndrome. AB - OBJECTIVE: Left ventricular systolic time intervals, including pre-ejection period (PEP), ejection time (ET), and their ratio (PEP/ET), is determined by systolic and diastolic function and ventriculo-arterial coupling. We investigated the usefulness of the electromechanical activation time [(EMAT) PEP minus isovolumic contraction time] in the prediction of cardiac mortality or re hospitalization for heart failure in patients with the acute heart failure syndrome (AHFS). PATIENTS AND METHODS: A total of 45 patients (71.9+/-16.1 years old) hospitalized for AHFS were enrolled. Systolic time intervals and EMAT normalized by cardiac cycle length (%) were measured separately by separate automated acoustic devices. All parameters were assessed within 24 hours of admission, before discharge, and 2 weeks after discharge. RESULTS: During a mean follow-up of 242+/-156 days, 20 patients (44%) incurred adverse cardiovascular events including 18 re-hospitalizations for heart failure and 2 cardiovascular deaths. Using uni-variate Cox regression analysis, at admission %EMAT and %PEP, pre-discharge %EMAT, and post-discharge %EMAT significantly predicted post discharge cardiovascular events with hazard ratios and 95% confidence intervals of 1.75 (1.13-2.70), 1.67 (1.02-2.70), 1.87 (1.10-3.17) and 2.50 (1.58-3.97) per 1-SD increment, respectively. The predictions remained significant after adjustment for age, sex, left ventricular ejection fraction, E/E' by Doppler echocardiography, and serum N-terminal pro-brain natriuretic peptide. CONCLUSION: EMAT measured during the hospitalization course is useful in the prediction of cardiovascular outcomes in patients with AHFS independent of left ventricular ejection fraction, E/E', and serum N-terminal pro-brain natriuretic peptide. PMID- 20930427 TI - A NADH dehydrogenase ubiquinone flavoprotein is decreased in patients with dilated cardiomyopathy. AB - BACKGROUND: It is known that patients with myocarditis of unknown etiology and with dilated cardiomyopathy show a high incidence of serum autoantibodies (M7) directed against mitochondrial flavoproteins. The tissue concentration of mitochondrial flavoproteins in the myocardium obtained from patients with dilated cardiomyopathy (DCM) was examined to further investigate the immunopathological mechanism of cardiomyopathy. METHODS AND RESULTS: Myocardial tissue specimens were obtained from patients who underwent cardiac catheterization and a subendomyocardial biopsy for the diagnosis of cardiomyopathy. All samples were analyzed by Western blotting. NADH dehydrogenase ubiquinone flavoprotein (NDUFV1) production in the myocardium decreased significantly with DCM, in comparison to fumarate hydratase and flavoprotein SDHA. There was a significant negative correlation between the left ventricular end-diastolic dimension and NDUFV1 production (R(2)=0.291, p value<0.05). CONCLUSION: NDUFV1 may be involved in the pathogenesis of DCM. A defect of mitochondrial NDUFV1 may reduce complex I, which produces most of the superoxide, which is then scavenged by the mitochondrial enzyme Mn-superoxide dismutase to produce H(2)O(2). Exploring the nature of the candidate protein found in the myocardium in this study will provide further insight into the immunological mechanism of DCM. PMID- 20930428 TI - Positive effect of baclofen on body weight reduction in obese subjects: a pilot study. AB - BACKGROUND AND OBJECTIVE: We previously reported that baclofen, a GABA(B) agonist, reduces body weight in obese mice. In this clinical study, we examined the possibility that baclofen might serve as an effective therapeutic agent for obesity in humans. METHODS: Seven women and three men ranging from 25-51 years of age and 31.3-41.0 kg/m(2) body mass index were included in the study. Baclofen, which was started at a dose of 15 mg/day and increased to 30 mg/day in 10 days, was administered for 12 weeks. RESULTS: Administration of baclofen for 12 weeks significantly decreased both body weight (baseline: 93.30 +/- 9.80 kg, 12 weeks: 91.70 +/- 10.30 kg) and waist circumference (baseline: 107.9 +/- 9.0 cm, 12 weeks: 105.6 +/- 10.0 cm). Serum leptin levels, which possibly reflect the amount of adipose stores, were also decreased significantly by the treatment. On the other hand, there were no significant changes in the blood pressure or metabolism of glucose and lipid. No adverse effects were observed. CONCLUSION: Although the anti-obesity effects of baclofen in the present study were mild, this pilot study suggests the possibility that baclofen might serve as a new anti-obesity drug in humans. PMID- 20930429 TI - Meta-analysis of Tripterygium wilfordii Hook F in the immunosuppressive treatment of IgA nephropathy. AB - OBJECTIVE: Numerous Chinese patients with IgA nephropathy (IgAN) have benefited from Tripterygium wilfordii Hook F (TwHF) from two decades ago. However, to date there is no systematic evaluation of this remedy for IgAN. METHODS: We conducted a meta-analysis of all eligible randomized clinical trials (RCTs) to assess the effect of TwHF on IgAN for the first time. In August 2009 a systematic search was performed among eight electronic databases. Review Manager (RevMan) version 5.0 was used. RESULTS: (i) Four eligible RCTs with 188 participants were included; (ii) The validities of included RCTs were generally acceptable; (iii) TwHF brought about a favorable increase in complete remission (CR) (RR 1.53, 95%CI 1.09 to 2.16, I(2)=12%) and total remission (TR) (RR 1.27, 95%CI 1.08 to 1.48, I(2)=0%) compared with non-TwHF treatment; and this result was further confirmed by intention-to-treat analysis; (iv) Exploiting subgroup meta-analysis, TwHF led to significantly greater improvements of IgAN with non-nephrotic proteinuria with regard to the increase of CR (RR 1.80, 95%CI 1.21 to 2.68, I(2)=0%) and TR (RR 1.32, 95%CI 1.11 to 1.57, I(2)=0%), and decrease of urinary proteinuria excretion (UPE) (MD -467.41 mg/24h, 95%CI -633.99 to -300.82, I(2)=0%). Meanwhile, the renal function was well preserved (MD -2.66 umol/L, 95%CI -9.26 to 3.94, I(2)=0%). Conclusion Although the results of this meta-analysis should be interpreted with caution and warrant further investigation, TwHF was certainly a valuable and promising immunosuppressive remedy for IgAN, which was in accordance with the accruing evidence from numerous large clinical and experimental studies. PMID- 20930430 TI - Low serum acylated ghrelin levels are associated with the development of cardiovascular disease in hemodialysis patients. AB - BACKGROUND: Ghrelin has a protective effect on endothelial cells. Endothelial cell dysfunction is associated with cardiovascular disease (CVD) and CVD remains the leading cause of morbidity in hemodialysis (HD) patients. Acylated ghrelin (A Ghr) is the functional form of ghrelin, so we hypothesized that A-Ghr is associated with the occurrence of CVD in HD patients. METHODS: We conducted a prospective cohort study in 412 HD patients. The cohort was sub-grouped into low and high A-Ghr groups according to the median A-Ghr level of 4.88 pg/mL. The association between the low/high A-Ghr groups and the incidence of CVD were analyzed. RESULTS: The HD patients in a low A-Ghr group had a greater risk of incidental CVD than those in a high A-Ghr ghrelin. This association remained significant after the adjustment for possible confounding factors, including age, gender, HD duration, BMI, diabetes, albumin, nPCR and Charlson's comorbidity index score. CONCLUSION: It appears that a low serum A-Ghr level is associated with the development of CVD in HD patients. PMID- 20930431 TI - Risedronate therapy for the prevention of steroid-induced osteoporosis in patients with minimal-change nephrotic syndrome. AB - BACKGROUND: Minimal-change nephrotic syndrome (MCNS) is treated by the administration of prednisolone (PSL) at high doses. Steroid-induced osteoporosis is a serious adverse effect of this drug. METHODS: Patients with MCNS were randomly assigned to two groups, the risedronate (2.5 mg/day) + alfacalcidol (0.25 ug/day) group (n=20) and the alfacalcidol (0.25 ug/day)-alone group (n=20). All the patients had received PSL and the clinical characteristics were compared between the two groups at baseline and at 12 months. RESULTS: A significant decrease of the mean bone mineral density (BMD) of the lumbar spine from 0.710+/ 0.162 (g/cm(2)) to 0.588+/-0.125 was observed in the alfacalcidol-alone group (p=0.02), while no such decrease of the bone mineral density was found in the risedronate + alfacalcidol group (0.663+/-0.169 at baseline and 0.626+/-0.129 at 12 months). No significant differences in the results of other biochemical tests performed at the baseline and at 12 months were observed between the two groups. The likelihood of development of steroid-induced osteoporosis was influenced by the cumulative dose of PSL, the mean BMD at the baseline, occurrence of disease relapse, and risedronate therapy. CONCLUSION: Risedronate appears to be effective in preventing steroid-induced osteoporosis. It is necessary to use bisphosphonates to maintain the BMD in patients with MCNS receiving prolonged steroid therapy. PMID- 20930432 TI - Improved assessment of aortic calcification in Japanese patients undergoing maintenance hemodialysis. AB - OBJECTIVE: Vascular calcification is a feature of arteriosclerosis and in hemodialysis (HD) patients it may be severe, even at a relatively young age, and is closely related to the overall prognosis. We used the aortic calcification area index (ACAI), derived from the aortic calcification index (ACI), to evaluate and analyze the risk factors for abdominal aortic calcification in HD patients. PATIENTS AND METHODS: Subjects comprised 137 patients on maintenance HD. ACAI was measured on abdominal plain computed tomography: 10 slices of the abdominal aorta were obtained at 1-cm intervals from the bifurcation of the common iliac artery and the area of the aortic cross-section and calcification was measured using image software. The calcification area was divided by the cross-sectional area and expressed as a percentage (%). The mean value for the 10 slices was also calculated. Patients were divided into 2 groups according to ACAI being lower or higher than the mean value and the risk factors in each group were compared by multivariate analysis. Results Group comparison showed significant differences in age, systolic blood pressure, serum calcium, and lipoprotein(a). On multiple regression analysis, age, systolic blood pressure, and serum calcium were independent risk factors. On logistic regression analysis, age, duration of dialysis, systolic blood pressure, and serum calcium were independent risk factors. CONCLUSION: Risk factors for abdominal aortic calcification in HD patients include age, systolic blood pressure, and serum calcium, according to ACAI evaluation. The ACAI was accurate and useful for evaluating abdominal calcification. PMID- 20930433 TI - Noninvasive ventilation in patients with acute exacerbation of pulmonary tuberculosis sequelae. AB - BACKGROUND: The efficacy of noninvasive ventilation (NIV) in acute exacerbation of pulmonary tuberculosis sequelae has not been fully studied. METHODS: We retrospectively reviewed 58 patients with acute exacerbation of pulmonary tuberculosis sequelae who were admitted to Tosei General Hospital and treated with NIV over a 9-year period. RESULTS: The 58 patients (mean age: 76.2+/-8.0) consisted of 39 males and 19 females. Arterial blood gas analysis on admission showed a mean pH of 7.28+/-0.07 and a mean PaCO(2) of 72.6+/-14.2 mmHg. After the start of NIV, significant improvement occurred in pH, to 7.32+/-0.06 after 2 h and 7.36+/-0.06 after 24 h, and in PaCO(2), to 66.4+/-11.2 mmHg after 2 h and 61.6+/-11.3 mmHg after 24 h. The success rate in weaning from NIV was 86.2%. There were statistically significant differences in pH, body mass index (BMI), blood leukocyte count and serum potassium between patients successfully and unsuccessfully weaned from NIV. CONCLUSION: We conclude that patients with acute exacerbation of pulmonary tuberculosis sequelae can be treated successfully with NIV. Lower pH, BMI, and serum potassium, and higher blood leukocyte count are related to NIV failure. PMID- 20930434 TI - Resting energy expenditure and substrate metabolism in Chinese patients with acute or chronic hepatitis B or liver cirrhosis. AB - OBJECTIVE: Patients with liver disease usually have an imbalanced nutrient and energy metabolism that leads to malnutrition and seriously affects their prognosis. Therefore, it is of great clinical interest to understand the resting energy expenditure (REE) and oxidation rates of glucose, fat, and protein in these patients. METHODS: A total of 315 patients with liver diseases caused by hepatitis B virus were categorized into three groups: 20 acute hepatitis patients, 142 chronic hepatitis patients and 153 liver cirrhosis patients. The REE and the oxidation rates of glucose, fat and protein were assessed by indirect heat measurement. Energy intake data were also collected which were compared with the REE results. RESULTS: The REE per kg (REE/kg) were 27.34 +/- 5.46 kJ/kg, 21.67 +/- 5.01 kJ/kg and 19.07 +/- 4.45 kJ/kg in acute, chronic hepatitis and liver cirrhosis patients (p=0.000), respectively. Respiratory quotient (RQ) tended to be lower in patients with chronic hepatitis and liver cirrhosis than that in acute hepatitis patients (p=0.023). Energy, protein and carbohydrate intakes were lower in liver cirrhosis patients. CONCLUSION: These data demonstrated that Chinese patients with chronic hepatitis B and liver cirrhosis had lower energy expenditure and abnormal substrate metabolism. Patients with chronic hepatitis and cirrhosis had a higher protein oxidation rate and a lower carbohydrate oxidation rate compared with acute hepatitis patients. PMID- 20930435 TI - Association between airflow obstruction and the metabolic syndrome or its components in Japanese men. AB - BACKGROUND: The aim of this cross-sectional study was to investigate the association between airflow obstruction and the metabolic syndrome (MS) or its components in Japanese men. METHODS: The study included 7,189 male subjects, aged 45-88 years, who underwent spirometric lung function tests at a medical check-up. The spirometric criteria for diagnosis of airflow obstruction were forced expiratory volume in 1 second (FEV(1))/forced vital capacity (FVC) <70%. The severity of airflow obstruction was defined according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guideline. RESULTS: The prevalence of airflow obstruction was 9.0% and the frequency of MS was 25.6%. In logistic regression models adjusting for age, body mass index, smoking, and alcohol, the risk of MS was higher in subjects with airflow obstruction of GOLD stage II-IV compared to those with normal lung function [odds radio (OR), 1.33; 95% confidence interval (95% CI), 1.01-1.76)]. Of the MS components, waist circumference (OR, 1.76; 95% CI, 1.24-2.50) and blood pressure (OR, 1.37; 95% CI, 1.08-1.74) were associated with airflow obstruction of GOLD stage II-IV, after controlling for potential confounders. CONCLUSION: Airflow obstruction of GOLD stage II-IV might be associated with MS, waist circumference and blood pressure components in Japanese men. PMID- 20930436 TI - Gastritis associated with Epstein-Barr virus infection. AB - Infectious mononucleosis is a self-limiting clinical syndrome caused by primary Epstein-Barr virus (EBV) infection. EBV-associated gastritis, however, has rarely been documented. We report a case of a 17-year-old woman who presented with fever, sore throat, and epigastric pain. Upper endoscopy revealed diffuse granular mucosae and elevated lesions in the stomach. Histologically, the biopsied mucosa was infiltrated by numerous atypical lymphocytes. From clinical, histopathologic, immunohistochemical, and in situ hybridization analyses, we diagnosed EBV-associated gastritis. Her symptoms spontaneously resolved, and follow-up endoscopy revealed improvement and no atypical lymphocytes. To prevent misdiagnosis and unnecessary treatment, the possibility of EBV-associated gastritis should be considered. PMID- 20930437 TI - Paroxysmal atrial fibrillation due to bronchogenic cyst. AB - A 62-year-old man presented newly developed tachyarrhythmia diagnosed as paroxysmal atrial fibrillation (PAF) and was treated with flecainide and enalapril. He underwent a whole-body F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) scan for cancer screening. The FDG-PET images showed a FDG non-avid lesion in the mid mediastinum. He was referred to our hospital for further examination under suspicion of a cardiac tumor in the left atrium. A chest computed tomography scan and magnetic resonance imaging revealed a bronchogenic cyst just under the carina and also compressed left atrium and pulmonary vein from its cranial portion. The cyst was completely excised. After the operation, PAF was stopped and sinus rhythm was preserved. PAF was thought to be due to compression by the bronchogenic cyst. PMID- 20930438 TI - Acute disseminated encephalomyelitis associated with meningitis due to Mycobacterium intracellulare. AB - A 73-year-old woman was admitted to our hospital because of persistent fever, headache and fatigue for several weeks. On admission, she was diagnosed as having meningitis due to Mycobacterium intracellulare (M. intracellulare) detected in her cerebrospinal fluid (CSF) by polymerase chain reaction. Even though anti tuberculous therapy improved her CSF findings, her condition was not restored. Brain MRI showed multifocal and asymmetrical increases in T2 signals involving white matter and cortical gray-white junction of cerebral hemispheres, cerebellum and brainstem. Based on the progression of clinical symptoms and radiological features, we diagnosed her illness as acute disseminated encephalomyelitis (ADEM) associated with meningitis due to M. intracellulare. Steroid therapy dramatically improved her condition. This is the first report of ADEM following meningitis due to M. intracellulare in a non-immunocompromized host. PMID- 20930439 TI - A case of juvenile acromegaly that was initially diagnosed as severe congestive heart failure from acromegaly-induced dilated cardiomyopathy. AB - Acromegaly is characterized by chronic hypersecretion of growth hormone (GH) and is associated with increased mortality rate because of the potential complications such as cardiovascular disease, respiratory disease, or malignancy, which are probably caused by the long-term exposure of tissues to excess GH, for at least 10 years, before diagnosis and treatment. A 22-year-old man with a 2 month history of fatigue was admitted to our hospital because of chest discomfort, dyspnea, and pitting edema of the lower limbs experienced over a 1 month period. On admission, his height and body weight were 186 cm and 138.5 kg, respectively, with a BMI of 39.8 kg/m(2). He showed acromegalic features and elevated serum GH and IGF-1 levels, which were 11.5 ng/mL and 960 ng/mL, respectively. There was no GH suppression in the 75-g oral glucose tolerance test. Pituitary magnetic resonance imaging (MRI) revealed microadenoma. Chest X ray revealed cardiomegaly, and echocardiogram showed dilated left ventricular (LV) cavity and diffuse hypokinesis with extremely decreased ejection fraction (EF). He was diagnosed as having acromegaly with congestive heart failure from diastolic cardiomyopathy. After the successful transsphenoidal resection of the pituitary adenoma, the level of GH was normalized. However, the cardiac dysfunction did not show any improvement even after the administration of beta blockers, angiotensin-converting enzyme inhibitor (ACE-I), or diuretics. The patient was re-hospitalized, and he died of cardiac failure at the age of 25 years. Patients with acromegaly have been reported to have about 30% higher mortality rate, and cardiovascular disease accounts for 60% of the deaths. We report a case of a patient with juvenile acromegaly who was diagnosed with severe cardiac failure at the time of diagnosis and failed to recover cardiac function even after the successful resection of the pituitary adenoma. Immediate diagnosis and treatment are required for better control of acromegalic cardiomyopathy. PMID- 20930440 TI - Glucose-responsive insulinoma in a patient with postprandial hypoglycemia in the morning. AB - We report the case of an obese 79-year-old woman who experienced postprandial hypoglycemia in the morning. The serum immunoreactive insulin (IRI) and C-peptide levels responded in parallel with her serum glucose level during a 75-g oral glucose tolerance test. A prolonged fast test lowered her serum glucose level to 30 mg/dL, but serum IRI was not fully suppressed. Abdominal computed tomography revealed a tumor in the uncinate process of the pancreas. The tumor was histologically diagnosed as benign insulinoma after surgery. Therefore, glucose responsive insulinoma as well as reactive hypoglycemia should be considered in patients who exhibit postprandial hypoglycemia. PMID- 20930441 TI - A case of AL amyloidosis with renal rupture. AB - We report a 59-year-old woman with AL amyloidosis who presented with massive bleeding from the right kidney, in whom emergency surgery proved to be life saving. The patient had been diagnosed as having AL amyloidosis 16 years previously. After 5 years, hemodialysis had been initiated. In 2007, a large right-sided perinephric, intracapsular hematoma was detected. Right nephrectomy was performed and the patient recovered with no sequelae. Histopathological examination revealed a greater degree of amyloid deposition in the resected kidney than that at the time of diagnosis. Amyloid angiopathy may promote bleeding. PMID- 20930442 TI - A rare masquerader of lung cancer: nonsecretory multiple myeloma with plasmacytoma of bone presenting as acute kidney injury. AB - Multiple myeloma (MM) is a neoplasm of B cell lineage characterized by excessive proliferation of abnormal plasma cells which produce immunglobulins. If a monoclonal spike is not found in serum or urine but the patient has clinical findings and bone marrow plasma cell infiltration suggestive of MM, then the patient may have a rare subtype known as nonsecretory multiple myeloma (NSMM). Here, we describe a rare case of NSMM with plasmacytoma of bone who presented with severe hypercalcemia, acute kidney injury and a large thoracal mass on chest X-ray masquerading as lung cancer. PMID- 20930443 TI - Birt-Hogg-Dube syndrome with multiple cysts and recurrent pneumothorax: pathological findings. AB - A 39-year-old woman presented with right-sided pneumothorax. Partial lung resection was done via thoracoscopy. Five years later, left-sided pneumothorax occurred, and she underwent thoracoscopy again. However, air leakage continued, and pleurodesis was performed. Although she had no skin eruptions or renal tumors, Birt-Hogg-Dube (BHD) syndrome was suggested by radiographic findings. BHD gene analysis was performed, which revealed the BHD gene mutation. Reevaluation of pathological findings showed elastic fibers in the alveolar walls with fine granular changes and accumulation of macrophages. BHD syndrome should be considered in patients presenting with multiple pulmonary cysts with or without skin eruption, or kidney tumor. PMID- 20930444 TI - Upper lobe-dominant pulmonary fibrosis showing deposits of hard metal component in the fibrotic lesions. AB - We present a 54-year-old man employed in the field of hard metal manufacturing who complained of progressive dyspnea and weight loss. His chest radiograph showed bilateral fibrosis predominantly distributed in the upper lobes with bilateral pleural effusions, and a strong reduction in lung volume. Lung histopathology showed apical cap-like fibrosis but no giant cell interstitial pneumonia. Electron probe microanalysis detected tungsten deposits in the fibrotic region: we therefore considered this to be a case of hard metal disease. Hard metal disease should be considered as one possibility in the differential diagnosis of upper lobe-dominant pulmonary fibrosis. PMID- 20930445 TI - Mediastinal follicular lymphoma diagnosed with multidirectional analysis using tissue samples obtained by EBUS-TBNA. AB - Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has been developed as a useful tool for the diagnosis of diseases adjacent to the airway to be used in place of open surgery or mediastinoscopy. In this report, we present a 46-year-old man with a solid tumor in the mediastinum. Since no other pathological sites were identified, EBUS-TBNA was employed for tumor sampling. Sufficient tissue specimens were collected and the diagnosis of follicular lymphoma was established based on the combination of immunohistochemistry, flow cytometry and FISH analysis. This report demonstrates the advantage of EBUS-TBNA even for the diagnosis of hematological disease. PMID- 20930446 TI - A case of afebrile miliary tuberculosis that progressed from tuberculous spondylitis with iliopsoas abscess. AB - We present a case of a 78-year-old woman who visited our hospital for chronic atrial fibrillation. She consulted an orthopedic surgeon for lumbar pain in August 2009 and has been followed up for osteoporosis. However, her lumbar pain became exacerbated. In December 2009, clinical examination revealed that the pain was caused by tuberculous spondylitis and iliopsoas abscess. Diffuse miliary shadow, which was undetected earlier, was noted on chest roentgenogram; she was diagnosed with miliary tuberculosis. Lumbar pain is common in elderly individuals and should be regarded as one of the tuberculosis symptoms, considering its atypical course in elderly patients. PMID- 20930447 TI - Successful treatment of refractory enteropathy-associated T-cell lymphoma using high-dose chemotherapy and autologous stem cell transplantation. AB - A 65-year-old woman presented with a 6-month history of abdominal pain and watery diarrhea. Type II enteropathy-associated T-cell lymphoma (EATL) was diagnosed based on the clinical presentation and pathological examination of the tumor. The patient received combination chemotherapy but did not achieve remission. Subsequently, high-dose therapy (HDT) and autologous stem cell transplantation (ASCT) were performed. After these therapies, she achieved complete remission, which has been sustained for 18 months. Although the role of HDT-ASCT for EATL is still controversial, the clinical course of this patient suggests that ASCT can improve the prognosis in some patients with EATL. PMID- 20930448 TI - Efficacy of rituximab monotherapy for an elderly hemodialysis patient with primary cardiac lymphoma. AB - We report a case of primary cardiac lymphoma (PCL) occurring in a 76-year-old man during maintenance hemodialysis. Chest computed tomography (CT) revealed a tumor with pericardial effusion in the left ventricular posterior wall. Cytological examination of the pericardial fluid revealed monotonous lymphoid cells positive for B-cell markers, and clonal immunoglobulin heavy chain gene rearrangement was detected, indicating B-cell lymphoma. Rituximab monotherapy was administered biweekly at the therapeutic level on hemodialysis. The follow-up chest CT showed tumor disappearance with pericardial fluid after two courses of therapy. Rituximab monotherapy was effective for an elderly hemodialysis patient with PCL. PMID- 20930449 TI - Expression of various glutamate receptors including N-methyl-D-aspartate receptor (NMDAR) in an ovarian teratoma removed from a young woman with anti-NMDAR encephalitis. AB - A 21-year-old woman developed psychiatric symptoms, progressive unresponsiveness, generalized seizures, severe dyskinesia, marked fluctuation of blood pressure, and hypersalivation after a flu-like episode. Anti-glutamate receptor (GluR)epsilon2 and anti-N-methyl-D-aspartate receptor (NMDAR) antibodies were positive in both her serum and CSF. After she recovered five months later she underwent surgery to remove a right ovarian teratoma. Immunohistochemical examinations of her teratoma disclosed abundant expression of various GluRs including NR2B subunit of NMDAR, GluR1, and GluR2/3. These immunoreactivities of GluRs were seen not only in small areas of neural tissue identified as anti-glial fibrillary acidic protein (GFAP)-immunoreactive areas but also in other large areas of undifferentiated neuroepithelial tissue without GFAP immunoreactivity. Our findings strongly support the recent idea that neural elements in ovarian teratoma play an important role in the production of antibodies to NMDARs in anti NMDAR encephalitis. Additionally, the study of control ovaries clearly showed NR2B-related immunoreactivity in the cytoplasm of oocytes, indicating that the normal ovary itself has expression of NMDARs. This finding might provide a clue to understand the pathogenesis of this disease in female patients without ovarian teratoma. PMID- 20930450 TI - Intestinal angina due to atherosclerosis in a 45-year-old systemic lupus erythematosus patient. AB - We report a patient with systemic lupus erythematosus (SLE) who developed progressive emaciation and postprandial abdominal pain with a 27-year history of corticosteroid treatment. The patient was diagnosed as having intestinal angina based on computed tomography that showed severe stenosis of the superior mesenteric artery (SMA) in addition to complete occlusion of the celiac and inferior mesenteric arteries. Histopathology of the SMA and abdominal aorta showed atherosclerosis with no vasculitis or thrombus formation. Intestinal angina should actively be considered as a possible cause of recurrent abdominal pain in SLE patients, particularly in those with a long history of disease. PMID- 20930451 TI - Three cases of fungemia in HIV-infected patients diagnosed through the use of mycobacterial blood culture bottles. AB - We treated three cases of fungemia in HIV-infected patients. These cases were caused by Candida albicans, Cryptococcus neoformans, and Penicillium marneffei, respectively, and all were diagnosed through the use of mycobacterial blood culture bottles. Although the detection of the etiologic agents of fungal infection is difficult, it has been shown that blood culture media for mycobacteria are more effective for the detection of fungemia than media for aerobes and anaerobes. Some reports have shown that Bactec Myco/F lytic bottles were useful for the diagnosis of fungemia in clinical samples. Here, we report the successful use of BacT MB bottles. PMID- 20930452 TI - Cytomegalovirus in the kidney allograft. PMID- 20930453 TI - Cutaneous vasculitis following influenza vaccination. PMID- 20930454 TI - Spontaneous perinephric hemorrhage from a hemorrhagic renal cyst. PMID- 20930455 TI - Telmisartan and obesity. PMID- 20930457 TI - Improvement of the embryonic stem cell test endpoint analysis by use of field potential detection. AB - The embryonic stem cell test (EST) is a validated in vitro method to assess the embryotoxic potential of compounds and is a promising tool for drug screening. EST requires microscopic observation of beating cardiomyocytes differentiated from embryonic stem cells as a toxicological endpoint. However, this process is time-consuming and lacks throughput performance. To improve the analysis, we introduced an electrophysiological method with a microelectrode array system for the evaluation of differentiated cardiomyocytes. Embryotoxic (valproic acid, verapamil, and 5-fluorouracil) and non-embryotoxic (penicillin G, d-camphor, and isoniazid) compounds were assessed with the system. Mouse embryonic stem cells were differentiated into cardiomyocytes and treated with each compound during the differentiation process. The embryotoxicity of each compound was then assessed by measuring the field potentials of differentiated cardiomyocytes using the microelectrode array system, as well as by microscopic evaluation. All the embryotoxic compounds dose-dependently inhibited the field potential formation and the myocardial beating of differentiated cells, while the non-embryotoxic compounds did not affect either endpoint. The detection capabilities of the two assay methods were similar. These results indicated that the field potential measurements can be used as an alternative endpoint of EST. Moreover, the field potential can be measured automatically, introducing a high throughput performance compared to the conventional microscopic observation. We therefore concluded that the endpoint analysis with the microelectrode array system improves the original EST and can be useful for the assessment of the embryotoxic potential of compounds. PMID- 20930458 TI - Cell proliferative activity in the kidney of young growing rat analyzed using flash and cumulative labeling with bromodeoxyuridine. AB - We examined the cell proliferation activity of kidney in young growing rats using flash and cumulative labeling with bromodeoxyuridine (BrdU). Rats were subjected to the study at the age of 6 weeks, and cumulative labeling was carried out for periods of 7 to 28 days. BrdU-positive cells were observed after flash labeling and were increased by cumulative labeling. The positive epithelia were mainly distributed in the cortex and the outer stripe of the outer medulla and were scarce in the inner stripe of the outer medulla and inner medulla throughout all labeling periods. In the tubular epithelium, the majority of positive cells were found in the proximal tubule. In the proximal tubule, positive epithelia were abundant in the medullary rays and in the outer stripe of the outer medulla. In the intermediate tubule to collecting duct, positive epithelia were rare. In the renal corpuscle, positive nuclei were mainly found in the endothelial cells and the mesangial cells and were scarce in the parietal cells of the Bowman's capsule. BrdU-positive nuclei were not observed in podocytes. These results indicate that renal tubules actively grow relative to epithelial proliferation, and that the endothelial cells, the mesangial cells and the parietal cells in the renal corpuscle also proliferate at the age of 6 to 10 weeks in rats. For assessment of renal toxicity using young growing rats, not only the morphologic and physiologic features unique to the kidney but also the growing process of the kidney should be taken into account. PMID- 20930459 TI - Relationships between plasma and tissue transaminase activities in rats maintained under different feeding conditions. AB - In order to verify the nutritional aspect of alterations of the plasma and tissue transaminase activities, rats were fed 4 hr per day for 35 days (the spaced-fed (SF) rats) and the time course of the alterations in plasma and tissue transaminase activity was compared with those in the ad libitum fed (ALF) rats. Plasma transaminase activities were stable throughout the experiment period in the ALF rats. In the SF rats there were alterations in the plasma alanine aminotransferase (ALT) activities, the direction of which was different between the early phase and late phase of the experiment period; plasma ALT activities decreased in the early phase and gradually increased in the late phase. Plasma aspartate aminotransferase (AST) activities were stable in the SF rats throughout the experiment period as well as the ALF rats. The decreases in plasma ALT activities in the early phase were considered to be related to decreases in ALT activities in the small intestinal mucosa (SI mucosa). On the other hand, the increases in plasma ALT activities in the late phase were considered to be related to increases in ALT activities in the liver. Multiple regression analyses (MRAs) revealed that plasma ALT activities in the SF rats could be estimated by the ALT activities in the SI mucosa and liver. From these results, the alterations of the plasma ALT activities in the SF rats could be explained by those in the SI mucosa and liver under the conditions in our study. PMID- 20930460 TI - Induction of pulmonary fibrosis by methotrexate treatment in mice lung in vivo and in vitro. AB - Methotrexate (MTX) has been used as the first-line disease-modifying antirheumatic drug (DMARD) in patients with early progressive rheumatoid arthritis (RA). Several severe side effects such as myelosuppression, hepato-, nephro-, and pulmonary toxicities have been reported. However, the pathogenic mechanism of MTX-induced pulmonary fibrosis is still unknown. Here, we evaluated the morphological and biological changes of the pulmonary fibrosis in mice treated with MTX. Three, four and five weeks after consecutive administration of MTX (3 mg/kg/day), hydroxyproline content in the lung tissues increased significantly to about 2 times higher that of the control level. This result closely reflected to the results of hematoxylin and eosin (HE) and Azan stains. Immunohistochemical analysis revealed that MTX treatment resulted in a decrease of alveolar epithelial cells and an increase of fibroblast cells in the mouse lung tissues. When we examined the effects of MTX on primary mouse alveolar epithelial cell (MAEC) and mouse lung fibroblast (MLF) survival in vitro, the efficiency of MTX-induced cytotoxicity and apoptosis in MAEC was more sensitive than MLF cells. Thus, our results indicate that the administration of MTX by an oral route could induce a fibrotic response with cell dysfunction of the alveolar epithelium by which MTX-induced apoptosis. Our results thus suggest that MTX could induce alveolar epithelial cell injury and resulted in the loss of integrity of the alveolar-capillary barrier basement membranes followed by the recruitment and proliferation of myofibroblasts with the deposition of collagens. PMID- 20930461 TI - Protective effect of Etlingera elatior (torch ginger) extract on lead acetate- induced hepatotoxicity in rats. AB - Lead is known to disrupt the biological systems by altering the molecular interactions, cell signaling, and cellular function. Exposure to even low levels of lead may have potential hazardous effects on brain, liver, kidneys and testes. The efficacy of Etlingera elatior (torch ginger) to protect hepatotoxicity induced by lead acetate was evaluated experimentally in male Sprague - Dawley rats. Rats were exposed to lead acetate in drinking water (500 ppm) for 21 days and the effects of concurrent treatment with extract of E. elatior on hepatic lipid hydroperoxides (LPO), protein carbonyl content (PCC), total antioxidants (TA), superoxide dismutase (SOD), glutathione peroxidase (GPX) and glutathione S- Transferase (GST) levels and histopathological changes in liver were evaluated. There was a significant decrease in TA and other antioxidant enzymes (p < 0.05) and increase in LPO and PCC (p < 0.05) with lead acetate ingestion. Concurrent treatment with E. elatior extract significantly reduced the LPO and PCC (p < 0.05) in serum and increased the antioxidant enzyme levels (p < 0.05) in the liver. Significant histopathological changes were seen in hepatic tissue with chronic lead ingestion. Treatment with E. elatior significantly reduced these lead-induced changes in hepatic architecture. E. elatior has also reduced the blood lead levels (BLL). Thus, there has been extensive biochemical and structural alterations indicative of liver toxicity with exposure to lead and E. elatior treatment significantly reduced these oxidative damage. Our results suggest that E. elatior has a powerful antioxidant effect against lead-induced hepatotoxicity. PMID- 20930462 TI - Circadian modulation of hepatic transcriptome in transgenic rats expressing human growth hormone. AB - The secretory profile of growth hormone (GH) is sexually dimorphic in rats. In male transgenic (TG) rats expressing human GH (hGH) that we generated, the circulating levels of both hGH and endogenous GH are flattened with no male-type pulsatility. To elucidate the regulatory role of episodic GH profile on the liver, the hepatic transcriptome of male TG rats at the middle of the light and dark phases was characterized by genome-wide analyses as compared with that of male wild-type (WT) rats. Transcripts commonly up- or down-regulated regardless of the lighting conditions in TG rats were mainly enriched in the metabolism of xenobiotics. In TG rats, the gene expression profile was functionally feminized, verifying that the sexually dimorphic profile of GH rather than genetic sexuality is a stronger sex-determining factor on the hepatic transcriptome. The common transcripts which fluctuated during the day in both TG and WT rats were enriched in circadian rhythm signaling, and physiological rhythmicity was considered to be finely interconnected with liver metabolism via sexually dimorphic GH secretion. In contrast, some genes were differentially regulated in TG rats at only one of two time points measured, and others were fluctuated daily in only one genotype. In particular, some genes involved in the GH signaling pathway were included, suggesting the signal transduction is circadian-modulated depending upon the GH profile. Our transcriptome analyses clarified the regulatory role of episodic GH profile on the liver and strengthen the functional link between sexually dimorphic GH secretion, liver metabolism, and its circadian regulation. PMID- 20930463 TI - Accurate detection of drug-induced delayed ventricular repolarization with a suitable correction formula in Langendorff guinea pig heart. AB - The aims of this study were to determine a suitable method to correct the ventricular repolarization period against the RR interval in isolated perfused Langendorff guinea pig heart and to clarify the reliability of this model using several drugs. QT and RR intervals from an electrocardiogram and the epicardial monophasic action potential duration (MAP(90)) were measured. Two drugs clinically known to be QT-prolonging (E-4031, moxifloxacin) and two known to be non-QT-prolonging (verapamil, zatebradine) were used for the study. To determine a method of correcting the ventricular repolarization period against RR interval, heart rates were slowed with 0.3 uM zatebradine, a specific bradycardiac agent, and then accelerated with atrial pacing to obtain a wide range of MAP(90)/RR relationships. An exponential rate-correction model elicited the most appropriate algorithm for the relationship among the four models tested. Based on linear regression analysis, the exponential showed superior dissociation of corrected MAP(90)s against RR intervals than generic Bazett's and Fridericia's formulae. E 4031 and moxifloxacin prolonged the corrected QT (QTc) intervals and MAP(90) under atrial pacing at a cycle length of 0.25 sec (MAP(90(pacing))) dose dependently; verapamil and zatebradine failed to prolong them, indicating that the reliability of this model was excellent. MAP(90(pacing)) prolongation by moxifloxacin, the positive compound in the clinical "Thorough QT/QTc Study", was seen at around QTc-prolonging concentrations in clinic, suggesting that the sensitivity would be appropriate for QT evaluation. We therefore concluded that the isolated guinea pig heart model is sufficiently sensitive and useful for assessing the potential QT prolongation of drugs. PMID- 20930464 TI - Enhancement of immediate allergic reactions by trichloroethylene ingestion via drinking water in mice. AB - The prevalence of allergic disorders is increasing in industrial areas and countries. Recent reports suggest that some environmental pollutants are related to the increase in allergic diseases, and we reported that trichloroethylene (TCE) is a candidate chemical for causing the increase of allergic diseases, as TCE ingestion is associated with allergic reaction enhancement. TCE is widely used in many industries, and it is commonly detected as an environmental contaminant. This study aimed to clarify the immunotoxicity of TCE in detail. BALB/c mice were treated with TCE dissolved in drinking water for 2 and 4 weeks, and the mice were immunized with ovalbumin (OVA)/aluminum hydroxide (alum) twice. On the final day of the TCE exposure period, we measured the active cutaneous anaphylaxis (ACA) reaction and the antigen- specific IgE level in serum as well as the histamine level at the allergic reaction site and assayed the proliferation rates of splenocytes collected from the animals. The ACA reaction was enhanced by TCE ingestion. The OVA specific IgE level in mice was enhanced by TCE exposure for 4 weeks. The proliferation rate of the splenocytes was enhanced by TCE ingestion for 2 and 4 weeks. The enhancement of the ACA reaction by TCE ingestion via drinking water may be related to the increase in splenocyte proliferation. On the other hand, it may be weakly related to antigen-specific IgE production. PMID- 20930466 TI - Early changes to oxidative stress levels following exposure to formaldehyde in ICR mice. AB - Formaldehyde (FA) is a commonly used chemical in everyday life and can react with many molecules in the human body. Although toxicity has been reported, exposure to FA has also been shown to have beneficial effects or no effect at all. In the present study, we examined the effect of FA inhalation on oxidative stress and inflammation in mice. Male adult ICR mice were exposed FA in gaseous form (0.1 ppm), and blood, urine, brain, lung and liver were obtained for 24 hr. Levels of 8-hydroxy-2'-deoxyguanosine (8OHdG) and NO(3)(-) were then determined by HPLC. A second group of mice were injected with 5 mg/kg lipopolysaccharide (LPS) after 24 hr of FA (3 ppm) inhalation and blood and organs were assayed for NO(3)(-) level and SOD activity. After exposure to a low dose of FA (0.1 ppm), the 8OHdG/dG ratio significantly increased in plasma. However, the ratio in urine and organs significantly decreased during 24 hr of FA exposure. The NO(3)(-) levels mirrored the 8OHdG/dG ratio. After 24 hr exposure to a high dose of FA (3 ppm), NO(3)(-) levels in plasma and liver were significantly lower than in control mice exposed to air only. The SOD activity of blood and urine were conversely increased in FA exposed animals. In the present study, we suggest that inhalation of FA at low doses influences the oxidative stress response in a tissue-specific manner. The FA may partially alleviate in some tissues like preconditioning in oxidative stress. PMID- 20930465 TI - Enhancing effects of carbon tetrachloride on in vivo mutagenicity in the liver of mice fed 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx). AB - Chronic stimulus subsequent to cell injury plays an important role in cancer development, but the precise mechanisms remain unknown partly because appropriate animal models are lacking. In the present study, the effects of hepatotoxicant carbon tetrachloride (CCl(4)) on in vivo mutagenicity were investigated using gpt delta mice with or without p53. Female B6C3F(1) p53-proficient or -deficient gpt delta mice were given a diet containing 300 ppm of 2-amino-3,8 dimethylimidazo[4,5-f]quinoxaline (MeIQx) for 13 weeks, concurrently with intraperitoneal injection of 1 ml/kg CCl(4) solution once a week. Mutant frequencies of gpt and red/gam in p53-proficient mice fed MeIQx were both significantly elevated by CCl(4)co-treatment. Enhancing effects of CCl(4) treatment were also noted in p53-deficient mice. In the mutation spectra analysis of gpt mutant colonies, G:C to T:A transversions were predominantly observed regardless of CCl(4) injection, and clonal expansion of gpt colonies were increased in the co-treated group as compared with MeIQx alone group. The present data showing no significant changes in mRNA expression levels of CYP1A2 and GSTa4 between MeIQx-treated groups with and without CCl(4). In the Western blotting analysis, CYP1A2 protein levels were significantly decreased in the co-treated group as compared to MeIQx alone group, and GSTalpha protein levels were not changed among any groups. It is suggested that the mutant frequency by co treatment with CCl(4) might result from some factors other than p53 or MeIQx metabolism/excretion. Thus, our data clearly demonstrate that this model could be a powerful tool for identifying the mechanisms underlying combinatorial effects on carcinogenesis. PMID- 20930467 TI - Effects of co-treatment of dextran sulfate sodium and MeIQx on genotoxicity and possible carcinogenicity in the colon of p53-deficient mice. AB - To investigate the effects of dextran sulfate sodium (DSS) and/or 2-amino-3,8 dimethylimidazo[4,5-f]quinoxaline (MeIQx) on in vivo genotoxicity in the colon, male C57BL/6 p53 (+/+), p53 (+/-) or p53 (-/-) gpt delta mice were twice given 1 week treatment with DSS, 2 weeks apart, and then sacrificed after 2 and 14 weeks. Although colon length was significantly shortened after DSS treatment in all genotypes at each time point, no significant difference in gpt mutant frequency (MF) and tumorigenicity was found between DSS and control groups regardless of genotype. Then, male B6C3F(1) p53 (+/+) or p53 (+/-) gpt delta mice were given DSS as described above and/or fed 300 ppm MeIQx for 7 weeks. Colon length was significantly shortened with DSS in either genotype at weeks 7 and 26, but no effects of co-treatment with MeIQx or p53 deficiency were evident. MeIQx showed a tendency to increase gpt MF in the colon of mice with either genotype, but co treatment with DSS did not affect these increments. Appreciable incidences of colonic aberrant crypt foci (ACFs) were reported in DSS as well as co-treatment groups of each genotype. Colonic adenomas were observed in co-treatment groups of both genotypes as well as the DSS-only group of p53 (+/+). No effects of the combination of DSS and MeIQx on colon pre- and neoplastic lesions were reported. Our results indicate that MeIQx may take more than 7 weeks to induce genotoxicity in the colon and that the co-treatment of mice did not enhance colon tumorigenicity even in p53-deficient mice. PMID- 20930468 TI - Testosterone-lowering activity of canola and hydrogenated soybean oil in the stroke-prone spontaneously hypertensive rat. AB - Canola and some other types of oil unusually shorten the survival of stroke-prone spontaneously hypertensive rats (SHRSP), compared with soybean oil, perilla oil and animal fats. Since differential effects of canola and soybean oil on steroid hormone metabolism were suggested by a preliminary DNA microarray analysis as a reason for this, the steroid hormone levels in the serum and tissues of SHRSP fed different oils were investigated. The testosterone levels in the serum and the testes were found to be significantly lower in the canola oil group than in the soybean oil group, while no significant differences were detected in the corticosterone and estradiol levels in tissues. In a second experiment, it was found that hydrogenated soybean oil, with a survival-shortening activity comparable to that of canola oil, also decreased the testosterone level in testes to a similar degree. The testosterone-lowering activity of canola and hydrogenated soybean oil observed in SHRSP was considered in relation to other factors possibly affecting the physiology of SHRSP. PMID- 20930469 TI - Prenatal exposure to titanium dioxide nanoparticles increases dopamine levels in the prefrontal cortex and neostriatum of mice. AB - Titanium dioxide (TiO(2)) nanoparticles are widely used in cosmetics, sunscreen and as a photocatalyst. However, little is known about the biological effect of TiO(2) nanoparticles in humans and other animals. Here, we investigated whether prenatal exposure to TiO(2) nanoparticles impacted the central nervous system in mice. We measured the levels of dopamine (DA) and its metabolites in several regions of the brain in mice using high performance liquid chromatography (HPLC). HPLC analysis showed that DA and its metabolites were increased in the prefrontal cortex and the neostriatum following prenatal exposure to TiO(2) nanoparticles. The present study highlights the possibility that maternal exposure to TiO(2) nanoparticles might influence the development of the central dopaminergic system in offspring. PMID- 20930470 TI - Testicular spermiation failure in rats exposed prenatally to 3,3',4,4',5 pentachlorobiphenyl. AB - Testicular spermatogenesis was studied in 7-, 10-, 13- and 17-week-old Sprague Dawley rats whose dams had been administered intragastrically with 2.5, 25, or 250 ng of 3,3',4,4',5-pentachlorobiphenyl (PCB126) or vehicle on days 13-19 of gestation. The 250 ng groups among the 7-, 10- and 13-week-old offspring showed significant inhibition of mature spermatid release (spermiation), but 17-week-old offspring did not show this. These alterations were not observed in other PCB126 and vehicle groups, and no germ cell or Sertoli cell degeneration were observed in any group. Spermiation failure at puberty appeared in those rats born to dams exposed 250 ng/kg PCB126 on days 13-19 of gestation was reversible change that recovered at adulthood. Because the serum testosterone, luteinizing hormone and follicle-stimulating hormone concentrations were similar in the PCB126 and vehicle groups, a direct endocrine cause for the observed effects was unlikely. PMID- 20930471 TI - Neurotoxic action of inorganic mercury injected in the intraventricular space of mouse cerebrum. AB - To examine the neurotoxic action of inorganic mercury, HgCl(2) was injected in the intraventricular space of a mouse brain as a mimic for an Hg(0) vapor-exposed model, and the Hg distribution in the brain and behavioral changes were compared with those of Hg(0)-exposed mice. Although no difference was found in the Hg accumulation and its localization in the brains of two model mice at 3 weeks after Hg treatment, the turnover rate of the brain Hg in the Hg(0)-exposed mice was higher than in the Hg(II)-injected mouse. Despite a similar Hg level in the cerebrum at 3 weeks, behavioral alterations, hyper-activity in an open field test and shortening of latency in a passive avoidance test, were significant only in Hg(II)-injected mice. Considered together with the differences in the turnover rate and the effectiveness of neurotoxic action of the brain Hg, the microenvironment of Hg, such as biomolecules with which Hg interacts, might not be the same in both model mice. Inorganic Hg-induced neurotoxic action could be observed with a minimum dose of Hg(II) without any effects on the other organs, such as the kidney and lung. The present study demonstrated that intraventricular injection of HgCl(2) might be a convenient method to study the neurotoxic action of inorganic Hg, and, at least partly, to represent an animal model of Hg(0) vapor exposure. PMID- 20930472 TI - Changes in blood parameters in pregnant Japanese White rabbits. AB - Changes in blood parameters, especially those related to blood coagulations, were examined on gestational days (GDs) 6, 18 and 28 in Japanese White rabbits. As compared with the non-pregnant group, the following changes were observed in the pregnant group. For blood coagulation-related parameters, fibrinogen, platelets and antithrombin time III (ATIII) was significantly increased on GD 18 and/or GD 28, and activated partial thromboplastin time (APTT) was significantly prolonged on GDs 18 and 28. For the other hematological and blood chemical parameters, hemoglobin and hematocrit values were significantly decreased on GDs 18 and 28. Reticulocyte counts significantly and prominently increased on GD 18 and then decreased to significantly lower levels than those in the non-pregnant group on GD 28. Eosinophils and basophil showed significant decreases on GD 18 and/or GD 28. The serum progesterone concentration reached its highest level on GD 18. Total protein (TP), albumin, alkaline phosphatase (ALP), alanine aminotransferase (ALT), cholesterol, calcium, glucose and blood urea nitrogen were significantly decreased on GD 18 and/or GD 28. These results were almost similar to those in the pregnant New Zealand White rabbits (Mizoguchi et al., 2010). PMID- 20930473 TI - beta3-adrenoceptor-mediated increased circulating transaminase levels in mice treated with its agonist BRL 37344. AB - Treatment with the selective beta(3)-adrenoceptor agonist BRL 37344 increased circulating levels of alanine transaminase (ALT) and aspartate transaminase (AST) in mice without causing hepatocellular injury. To clarify whether this was a beta(3)-adrenoceptor-mediated effect, the inhibitory effect of the selective beta(3)-adrenoceptor antagonist SR 59230A on the increase in circulating transaminase levels induced by BRL 37344 was examined. A single intraperitoneal dose of BRL 37344 alone initially increased insulin and non-esterified fatty acid (NEFA) dose-proportionally at 0.5 hr post-dose, findings considered attributable to beta(3)-adrenoceptor-stimulating effects. Levels of the gluconeogenic precursors pyruvate (PA) and lactate (LA) were increased corresponding to the change in insulin. Thereafter, glucose (GLU) level was decreased at 4 and 8 hr post-dose, suggesting disruption of glucose homeostasis. In association with these changes in glucose metabolism, transaminase levels were increased maximally at 4 hr post-dose. The transaminase changes were not accompanied by increases in circulating levels of other hepatocellular enzymes, including guanine deaminase (GUA), glutamate dehydrogenase (GLDH), and lactate dehydrogenase (LDH), or any morphological hepatocellular injury. Intraperitoneal pre-treatment with SR 59230A partly inhibited the effects of BRL 37344 alone, indicating that the increase in levels of circulating ALT by BRL 37344 was attributable to a beta(3)-adrenoceptor stimulating effect. In conclusion, the beta(3)-adrenoceptor agonist BRL 37344 was shown to increase circulating transaminase levels in mice accompanied with dynamic changes in glucose metabolism. These findings suggest the possibility that circulating transaminase levels are increased as pharmacological effects of drugs disrupting glucose metabolism, and that hepatotoxic markers should be selected considering these effects to distinguish between acceptable pharmacology and toxicity. PMID- 20930474 TI - A repeated dose 28-day oral toxicity study of extract from cultured Lentinula edodes mycelia in Wistar rats. AB - To evaluate the toxicological safety of extract from cultured Lentinula edodes mycelia (L.E.M.), repeated doses (2,000 mg/kg/day) were administered to male and female Wistar rats for 28 days. No mortality or abnormality in the general status or appearance was observed in rats administered L.E.M extract. Body weight and food consumption decreased slightly, particularly in the case of male rats, although the degree of decrease was not as prominent toward the end of administration. Examination of hematology, serum biochemistry, absolute and relative organ weights, autopsy and histopathology revealed only a few statistically significant differences between the treatment and control groups; these differences suggested no clinically significant changes related to toxicity. Consequently, the no observed adverse effect level (NOAEL) of L.E.M. extract was considered to be more than 2,000 mg/kg/day under the conditions of the present study. PMID- 20930475 TI - [Measurements of the ascending velocity of CO2 arc welding fume plumes]. PMID- 20930476 TI - [On the occasion of retirement from Graduate School of Pharmaceutical Sciences, Hokkaido University]. AB - I have devoted my life to NMR research for nearly 40 years since I graduated from Tokyo University. Owing to innovative technical developments such as introduction of superconductive magnets into NMR, and development of FT-NMR and two dimensional NMR, I have spent an interesting and inspired research life. When I look back on my life, I found myself starting from structural chemistry and doing research from the beginning of and all the way to the maturation of structural biology. I have been enjoying scientific challenges with my students and collaborators and I am proud that many young scientists grew up in my laboratory. PMID- 20930477 TI - [Dopaminergic neuroprotection and reconstruction of neural network tiara]. AB - Parkinson's disease (PD) is an age-related neurodegenerative disorder in whose brain massive loss of dopaminergic neurons and formation of Lewy bodies occur in the substantia nigra (SN). L-Dihydroxyphenylamine (L-DOPA) substitution is still considered the gold standard of antiparkinsonian drug therapy. However, there has been little information available on neuroprotective and regenerative therapies. Recently, we have found that pramipexole and talipexole (D(2)/D(3)-dopaminergic agonists) inhibit dopaminergic neurotoxin-induced production of reactive oxygen species and apoptotic cell death. In addition, treatment with these drugs induces enhancement of anti-apoptotic Bcl-2 expression and inhibition of alpha-synuclein aggregation. Interestingly, recent study suggests that pramipexole treatment delays the progression of early PD symptom. On the other hand, we investigated the transplantation strategy for PD by assessing whether double-transplants of mouse embryonic stem (ES) cell-derived neurons in the striatum (ST) and SN, or subthalamic nucleus (STN), induce functional recovery in rat hemi-parkinsonian model. The study indicates that both the involvement of ST as a place of transplantation and the number of ES cell-derived neurons are essential factors for efficacy on PD animal model. Interestingly, an invertebrate planarian can regenerate complete organs, including a well-organized central nervous system (brain), within about 7 days. The regeneration process of the planarian dopaminergic neural network (tiara) may be divided into five steps: 1) anterior blastema formation, 2) brain rudiment formation, 3) brain pattern formation, 4) the formation of dopaminergic tiara, and 5) functional recovery of dopaminergic motor regulation, with several kinds of genes and molecular cascades acting at each step. PMID- 20930478 TI - [Study on natural products for drug development]. AB - The ubiquitin-proteasome system (UPS) plays a major role in selective protein degradation and regulates various cellular events. Approval of bortezomib for the treatment of multiple myeloma validated the proteasome as an anticancer target. In order to find drug candidates targeting the ubiquitin-dependent protein degradation, we paid an attention to inhibitors against three enzymes, ubiquitin activating enzyme (E1), ubiquitin-conjugating enzyme (E2), and ubiquitin-protein ligase (E3), which are required for polyubiquitination of proteins and prerequisite to proteasome-mediated protein degradation. We succeeded in isolating various compounds with three distinct inhibitory activities against an E1 enzyme reaction, Ubc13 (E2)-Uev1A interaction, and p53-HDM2 (E3) interaction as well as the proteasome inhibitors. We also isolated new alkaloids, notoamides, from a marine-derived Aspergillus sp. Among them, notoamide B and stephacidin A contain a bicyclo[2.2.2]diazaoctane ring in their structures. We proposed this ring is constructed from notoamide E by the intramolecular Diels-Alder (IMDA) reaction. Recently, the isolation of the antipodes of notoamides from the terrestrial Aspergillus has been reported. We propose that each enantiomer is generated by a distinct face-selective IMDA. PMID- 20930479 TI - [Highly emissive pyrene-based fluorophores and highly sensitive fluorescent sensors using pyrene emission switching]. AB - In this review, I report highly emissive pyrene-based fluorophores and highly sensitive fluorescent sensors using pyrene emission switching. Alkynylpyrene derivatives show fruitful photophysical properties, as compared with pyrene itself: longer absorption and emission wavelengths and high fluorescence quantum yields in the presence of O(2). Alkynylpyrene-based fluorescent probes allow the highly sensitive detection of biomolecules such as proteins. Additionally, a rotaxane-based fluorophore, consisting of an alkynylpyrene derivative and two cyclodextrins, is highly stable upon irradiation with a UV/vis illuminator. On the other hand, I and my colleagues have developed a variety of fluorescent sensors using pyrene emission switching. One of them is DNA probes in which two pyrenes are connected both at 3' and 5' ends of a single-stranded oligonucleotide. Emission switching occurs from excimer to monomer when the probes hybridized with target DNAs. The DNA probes met antibody structures to produce the following fluorescent sensors. The sensors consist of three functional regions, crown ether (or cyclodextrin), DNA, and pyrene as guest binding, dimerizing, and sensing sites, respectively. These sensors can detect potassium cation, porphyrin, unsaturated fatty acid by pyrene monomer-excimer switching. PMID- 20930480 TI - [Three-dimensional structure of membrane protein stomatin and function of stomatin-specific protease]. AB - Stomatin is a major integral membrane protein of human erythrocytes, the absence of which is associated with a form of hemolytic anemia known as hereditary stomatocytosis. It is reported that stomatin regulates the gating of acid-sensing ion channels in mammalian neurons. However, the function of stomatin is not fully understood. In the genomic sequence of the hyperthermophilic archaeon Pyrococcus horikoshii, the putative operon-forming genes PH1511 and PH1510 encode stomatin and its partner protein, respectively. The N-terminal region of PH1510p (1510-N) is a serine protease, and specifically cleaves the C-terminal hydrophobic region of stomatin PH1511p. We have determined the first crystal structure of the core domain of stomatin PH1511p (residues 56-234, designated as PhSto(CD)). This review focuses on the three-dimensional structure of PhSto(CD), and discusses the function of stomatin and its specific protease 1510-N. PhSto(CD) forms a novel homotrimeric structure. Three alpha/beta domains form a triangle of about 50 A on each side, and three alpha-helical segments about 60 A in length extend from the apexes of the triangle. The alpha/beta domain of PhSto(CD) is partly similar in structure to the band-7 domain of mouse flotillin-2. While the alpha/beta domain is relatively rigid, the alpha-helical segment shows a conformational flexibility, adapting to the neighboring environment. One alpha-helical segment forms an anti-parallel coiled-coil with another alpha-helical segment from a symmetry-related molecule. The alpha-helical segment shows a heptad repeat pattern, and mainly hydrophobic residues form a coiled-coil interface. The coiled coil fold observed in the crystal probably contributes to the self-association. PMID- 20930481 TI - [Visualization of amyloid formation processes on cell membranes: gangliosides as key molecules for the onset of amyloidosis]. AB - Deposition of insoluble amyloid fibrils in tissues is a common hallmark of a wide range of human diseases referred to as amyloidoses, including Alzheimer's disease, type II diabetes mellitus. The amyloid deposits cause cell dysfunction, death, and subsequently severe impairment in tissues. Elucidation of amyloid formation mechanisms is essential for prevention of the onset and development of amyloidoses. Accumulated experimental evidence demonstrates that membrane lipids enhance the fibril formation of amyloidogenic proteins. Our group demonstrated that amyloid formation by amyloid beta-protein (Abeta) was facilitated by gangliosides in lipid raft-like model membranes. Phosphatidylserine and phosphatidylglycerol were also reported to trigger fibril formation by human islet amyloid polypeptide (hIAPP). However, it is not verified whether the proposed lipid-protein interactions can occur on plasma membranes of live cells. The author developed a method for visualizing amyloid fibrils on live cell membranes and investigated the roles of gangliosides and cholesterol in lipid rafts for amyloid formation. Congo red, an amyloid-specific dye, was found to be a promising compound for staining amyloids in live cells. Abeta was accumulated on cholesterol-dependent ganglioside-rich domains in PC12 neuronal cells in a time- and concentration-dependent manner, leading to cell death. Nerve growth factor-induced differentiation of PC12 cells increased both gangliosides and cholesterol and thereby greatly potentiated the accumulation and cytotoxic effect of Abeta. Amyloid formation by hIAPP was also facilitated by gangliosides in lipid rafts. Membrane lipid compositions, in this case, gangliosides in lipid rafts, actually caused striking change in amyloid formation on cell membranes. PMID- 20930482 TI - [Beneficial effect of galantamine on sensory information-processing deficits]. AB - Clinical studies show that galantamine, a weak acetylcholine (ACh) esterase inhibitor and allosteric potentiator of nicotinic ACh receptors (nAChRs), improves negative and cognitive symptoms in schizophrenia, while donepezil, a potent ACh esterase inhibitor, does not. We have recently found that galantamine, but not donepezil, reversed isolation rearing-induced deficits of prepulse inhibition (PPI), sensory information-processing deficits, in mice. In addition, we unexpectedly found that the galantamine-induced improvements in PPI deficits were prevented by the muscarinic ACh receptor (mAChR) antagonists scopolamine and telenzepine (preferential for M(1) subtype), but not by the nAChR antagonists. Galantamine, like donepezil, increased extracellular ACh levels in the prefrontal cortex. However, donepezil, unlike galantamine, inhibited M(1)-mAChR-mediated Ca(2+) signal in human neuroblastoma SH-SY5Y. These results suggest that galantamine improves isolation rearing-induced PPI deficits via an activation of mAChRs and the difference in the effect on the PPI deficits between galantamine and donepezil is due to that in their action on M(1)-mAChRs. The possible mechanisms for the beneficial effect of galantamine are discussed in a model of isolation rearing-induced PPI deficits. PMID- 20930483 TI - [Development of tissue pressure-mediated transfection method aimed at organ specific gene expression control]. AB - A mechanism-based logical approach is a mainstream of current novel drug therapy development in the context of these trends and, therefore, the elucidation of gene function and the molecular level mechanism analysis of diseases at an individual level in mammals are essential in addition to that in cultured cells. In vivo gene transfection techniques are also indispensable for these purposes as well as the evaluation of gene therapy and nucleic acid-based therapy approaches and clinical applications during the process of development of novel drug therapies. Various recombinant virus and synthetic carrier-mediated transfection methods have been reported, however, above all, naked plasmid DNA transfection without virus vectors, synthetic carriers and special physical devices has attracted much attention, because of its advantages including convenience of preparation and handling and lack of toxicity associated with the transfection agents. In this review, I collect the information of these naked plasmid DNA transfection methods involving tissue pressure-mediated transfection from the comprehensive view point including side effects. Additively, the key physiological phenomena affecting transgene expression, especially activation of transcriptional factors, are reviewed. Combined with conventional approach based with biodistribution control, regulation of physiological change in transfected cells will provide spatial- and temporal-controlled transgene expression at various organs, which leads us to elucidate mechanism of diseases and to develop novel drug therapy in near future. PMID- 20930484 TI - [Development of selective determination methods for quinones with fluorescence and chemiluminescence detection and their application to environmental and biological samples]. AB - Quinones are compounds that have various characteristics such as a biological electron transporter, an industrial product and a harmful environmental pollutant. Therefore, an effective determination method for quinones is required in many fields. This review describes the development of sensitive and selective determination methods for quinones based on some detection principles and their application to analyses in environmental, pharmaceutical and biological samples. Firstly, a fluorescence method was developed based on fluorogenic derivatization of quinones and applied to environmental analysis. Secondly, a luminol chemiluminescence method was developed based on generation of reactive oxygen species through the redox cycle of quinone and applied to pharmaceutical analysis. Thirdly, a photo-induced chemiluminescence method was developed based on formation of reactive oxygen species and fluorophore or chemiluminescence enhancer by the photoreaction of quinones and applied to biological and environmental analyses. PMID- 20930485 TI - Pharmacologically active metabolites of currently marketed drugs: potential resources for new drug discovery and development. AB - Biotransformation is the major clearance mechanism of therapeutic agents from the body. Biotransformation is known not only to facilitate the elimination of drugs by changing the molecular structure to more hydrophilic, but also lead to pharmacological inactivation of therapeutic compounds. However, in some cases, the biotransformation of drugs can lead to the generation of pharmacologically active metabolites, responsible for the pharmacological actions. This review provides an update of the kinds of pharmacologically active metabolites and some of their individual pharmacological and pharmacokinetic aspects, and describes their importance as resources for drug discovery and development. PMID- 20930486 TI - [Synthesis of a strain molecule, 1-azabicyclo [1.1.0] butane]. AB - 1-Azabicyclo [1.1.0] butane (ABB) bearing the highly strained bicyclic structure, which is synthetically useful for the preparation of 3-substituted azetidines, was obtained by the cyclization of 2,3-dibromopropylamine hydrobromide derived from inexpensive allylamine only with organolithium compounds and lithium amides. When other bases were employed, such as potassium, sodium, and magnesium species, the reaction yielded almost no ABB. It was speculated that a lithium cation played an important role in the cyclization. Thus, we proposed that this reaction proceeded by the consecutive cyclization to aziridines via the SN2 process involving the activation of the C-Br bond based on the intermolecular Br...Li(+) coordination, as a result of studies of reaction mechanisms. PMID- 20930487 TI - Acceptable incremental cost effectiveness ratio for use of new drugs, cases in statin therapies. AB - As it is an urgent issue to contain increasing healthcare expenditures, unlimited reimbursement of pharmaceuticals continues to be controversial. The objective of this study is to identify acceptable incremental cost effectiveness ratios between new and conventional therapies. Clinical study data for five statin therapies were used to indicate treatment effectiveness and incremental costs were indicated by price premiums at price listing. The incremental cost effectiveness ratios to pravastatin were 0 yen/patient with response, 1,475.1 yen/patient with response, 3,033.3 yen/patient with response, and 3,032.4 yen/patient with response. By conducting further analyses in various pharmaceuticals and categorizing acceptable incremental cost effectiveness ratios based on the disease severity and expected level of improvement in disease condition, drug prices that reflect the value of new pharmaceuticals and that are reasonable to be reimbursed can be suggested. PMID- 20930488 TI - Preparation, characterization and evaluation of docetaxel-loaded, folate conjugated PEG-liposomes. AB - For the purpose of enhancing the anticancer potency of docetaxel, a novel excipient, cholesterol-PEG-folate (alpha-(3.beta) cholest-5-en-3-omega-folic acid poly (oxy-1, 2-ethanediyl)), was synthesized and used for the preparation of liposomes (folate-conjugated PEG-liposomes). The in vitro release properties, in vitro cytotoxicity, in vivo pharmacokinetics and distribution, as well as in vivo potency of the liposomes were evaluated. These liposomes were able to control the release of the loaded drug. Docetaxel-loaded, folate-conjugated PEG-liposomes were more cytotoxic to MCF-7 cells than ordinary PEG-liposomes. The pharmacokinetic parameters of folate-conjugated PEG-liposomes were studied in rats. Compared to docetaxel solution, the folate-conjugated PEG-liposomes enhanced the t(1/2) of docetaxel by 6.74-fold. The biodistributions of docetaxel in the heart, brain and kidneys decreased when delivered in liposomes. The folate conjugated PEG-liposomes could significantly enhance tumor accumulation of docetaxel and antitumor activity in tumor-bearing mice (p<0.05). The precent results indicate that these folate-conjugated PEG-liposomes might enhance the potency while preventing the side effects of docetaxel. PMID- 20930489 TI - [Clinical evaluation of drug information provided by the pharmacists in the intensive care unit]. AB - Pharmacists working in the intensive care unit (ICU) in Saiseikai Yokohamashi Tobu Hospital are mainly responsible for managing the stock of drugs, providing drug information to other medical staff, educating them for rational drug therapy, and providing pharmaceutical care to the patients. In order to evaluate the contribution to the rational drug therapy, we investigated the acceptance rate of the drug information that the pharmacists in the ICU provided to the physicians from February to May in 2009. The number of cases in which drug information was provided by the pharmacists to the physicians during the period was 288. It was suggested that more than half of the information could optimize the drug dosage regimens and correct the inadequate prescriptions. Furthermore, 98.9% of the information provided by pharmacists was accepted by physicians. We questioned 5 intensivists to evaluate the information with a 5 point scale (maximum score was 4, minimum score was 0) and then the average of score was 3.3. In addition, their evaluation of the information about optimizing the drug dosage regimens marked the highest point (over 3.5). Meanwhile, providing drug information which led the physicians to correct the inadequate prescriptions contributed to reduce the cost of the drug therapy by 900000 yen during the period. As a result, it was suggested that the intensivists highly appreciated the information offered by the pharmacists and the information contributed to enhance high-quality drug therapy. Additionally, the economic impact was identified through the cost reduction in drug therapy. PMID- 20930490 TI - Light-induced deterioration test of carboplatin under clinical settings. AB - Chemotherapeutic drug dosages are calculated precisely based on the patient's height, body weight, and renal function, etc. To ensure safe and favorable outcomes of treatment, dosing solutions are prepared by appropriate mixing of the drug solutions based on such calculations. The package inserts for many injectable preparations include a warning for storing the product "shielded from light." However, there are no reports of stability assessment of a mixed product against light exposure or the residual amount of active ingredient in the dosing solution during or at the end of treatment. We evaluated the stability of carboplatin from the time of mixing of the dosing solution until the end of drug infusion in a clinical-like setting. With 4-hour exposure to outdoor scattered light, the dosing solution began to show discoloration by 1 hour, becoming dark yellow by 4 hours, with reduction of the percent residual carboplatin to about 23%. To identify the optimal light-shielding shade, the dosing solution was shielded from outdoor scattered light with 1 of 3 protective covers: aluminum foil, yellow plastic shade, and brown plastic shade. The yellow plastic shade prevented any changes of the appearance of the dosing solution during the 4-hour exposure period. The percent residual carboplatin, determined by HPLC, in the dosing solution shielded with a yellow plastic shade was about 85.2% at 2 hours and 78.6% at 4 hours. Thus carboplatin dosing solution should be completely shielded from light until infusion is completed. PMID- 20930491 TI - Side chain orientation of the amino acid substituted by a cysteine residue is important for successful crosslinking of galectin to its glycoprotein ligand using a photoactivatable sulfhydryl reagent. AB - We have employed a combination of cysteine mutagenesis and chemical crosslinking using a photoactivatable sulfhydryl reagent, benzophenone-4-maleimide, to obtain a covalent complex between human galectin-1 and a model glycoprotein ligand, asialofetuin. We previously obtained a crosslinked product when Lys(28) of the cysteine-less form of human galectin-1 was mutated to cysteine. To investigate whether substituting either of the two flanking amino acid residues in the same beta-strand, Ala(27) and Ser(29), to cysteine could result in crosslinking to the bound asialofetuin, two cysteine-containing mutants were generated. Although both the mutants adsorbed to asialofetuin-agarose and were eluted with 0.1 M lactose, confirming their ability to interact with asialofetuin, these mutants did not crosslink to the bound glycoprotein ligand following treatment with benzophenone 4-maleimide. Therefore the orientation of the side chain of the introduced cysteine residue apparently plays an important role in the crosslinking reaction. PMID- 20930492 TI - [Survey on the attitudes of pregnant and lactating women about the use of drugs]. AB - The purposes of this survey were to determine the attitudes and the extent of anxiety of pregnant and lactating women about drug use, and to research priority issues for pharmacists' intervention. Postpartum lactating women and mothers with children in a Growing Care Unit (GCU) in hospitals certified as Baby Friendly Hospital (BFH) were surveyed. The questions included the images the respondents had of drugs before pregnancy, the extent of anxiety about drug use, and ways to relieve it. The highest number of respondents (49.1%) did not want to use drugs often before pregnancy, but said "physician-prescribed drugs are fine". 24.5% had no negative images, and they "take drugs when necessary without worrying". An additional 14.2% did not like drugs, and "avoid them whenever possible", followed by 9.4% who did not want to use drugs, but were willing to take health food and other over-the-counter items. The respondents reported that the extent of anxiety about drug use was 79.3% during pregnancy, which was higher than 71.7% during lactation. It was not influenced by birth experience and age. "The images of drugs before pregnancy" and "the extent to which the anxiety was relieved during pregnancy" were extracted as factors related to the extent of anxiety, verifying that negative images of drugs and low degrees of relief from anxiety raise the anxiety of pregnant women. The above shows that pharmacists need to understand the anxiety of pregnant and lactating women about drug use, and the images they had of drugs before pregnancy, thereby they are expected to work actively to determine and relieve the anxiety. PMID- 20930493 TI - [Microarray analysis of the effects of serum-free medium on gene expression changes in human mesenchymal stem cells during the in vitro culture]. AB - We examined the effects of serum-free medium on the gene expression changes in human mesenchymal stem cells (hMSCs) during the in vitro culture using a DNA microarray analysis. In this study, we cultured hMSCs with two kinds of medium; 1) MSCGM (contain 10% fetal bovine serum) or 2) STK2 (serum-free medium developed for mesechymal stem cells multiplication), and compared hMSCs proliferation, cell morphology, and gene expression changes until 50 days culture. Expression analysis was performed with Affymetrix GeneChip Human Genome U133 Plus 2.0 Array. hMSC proliferation was significantly higher in STK2 medium than in MSCGM medium. The cell morphology of hMSC cultured with STK2 was not significantly changed in 50 days culture. The gene expression changes in hMSCs during the in vitro culture were significantly higher in STK2 than in MSCGM. After 50 days culture, 1991 genes were significantly changed the expression levels compared with 3 days in STK2 but not MSCGM. The expressions of genes related to cell cycle, cancer, proliferation, and cell growth were significantly changed by STK2 for 50 days culture. It was also changed by STK2 that the expressions of genes related to the signaling pathways contain various growth factors, such as IGF-1, FGF, TGF-beta, EGF, proliferation, and cell cycle. These results suggest that STK2 may be useful to obtain an enough number of hMSC cells for tissue engineered medical devices in short-term, however, it should be recognized that STK2 would alter the expressions of genes related to a variety of signaling pathways in hMSC if the culture period would be extended to obtain a large number of cells. PMID- 20930495 TI - N-terminal pro-brain natriuretic peptide in newly diagnosed acromegaly. AB - INTRODUCTION AND AIM: The mechanisms of acromegalic cardiomyopathy are not clearly understood. Brain natriuretic peptide (BNP) and N-terminal fragment of its pro-hormone (NT-proBNP) are released by the cardiac ventricles and increase in heart failure. In the present study, we aimed to evaluate serum NT-proBNP levels in acromegalic patients and determine a relationship between NT-proBNP levels and echocardiographic parameters. SUBJECTS AND METHODS: Twenty-two newly diagnosed acromegalic patients [mean age 38.85 +/- 11.06 yr; body mass index (BMI): 28.51 +/- 3.48 kg/m2] and 26 age- and BMI-matched healthy control subjects (mean age 32.9 +/- 12.6 yr; BMI: 26.2 +/- 5.3 kg/m2) were included in the study. Standard oral glucose tolerance test (OGTT) was performed. Serum NT-proBNP and GH were measured at the beginning of the OGTT (0 min). Body fat analyses were measured by bioelectrical impedance. Echocardiography was used in cardiac evaluations. RESULTS: The mean NT-proBNP level in the acromegalic group was not significantly different from the control subjects (55.89 +/- 46.64 pg/ml in acromegaly vs 28.76 +/- 22.13 pg/ml in control subjects). There were no correlations between the serum NTproBNP, GH, and IGF-I levels. Echocardiography revealed significantly increased left ventricular end-diastolic diameter (p=0.008), interventricular septum thickness (p=0.009), left atrium (p=0.029), and right ventricle diameter (p=0.027) in the acromegalic group. CONCLUSION: NT proBNP levels were found to be slightly higher in acromegalic patients as an indicator of heart failure, but the increase was not statistically significant. Although these cardiac structural changes in newly diagnosed acromegalic patients are present, the normal level of NT-proBNP shows that NT-proBNP may not be a good indicator in acromegaly. PMID- 20930496 TI - Search for genetic mutations in cytological samples from thyroid nodules as a diagnostic tool: reality, hope or myth? PMID- 20930497 TI - Growth hormone/insulin-like growth factor I axis in neurodegenerative diseases. AB - Neurodegenerative diseases (ND) are a group of heterogeneous disorders characterized by unknown etiology, subtle onset, and progressive involvement of neuronal systems leading to degeneration and dysfunction. They represent a challenge for basic science and clinical medicine because of increasing prevalence, social cost, complex biochemistry and pathology, and lack of mechanism-based treatments. Endocrine modifications may accompany the progression of ND, due to the intimate connections between central nervous and endocrine systems. Reported data on endocrine changes in different ND have often been non conclusive or conflicting. GH/IGF-I axis is involved in the regulation of brain growth, development, and metabolism. Dysfunctions in GH/IGF-I axis in most of ND are therefore reviewed. Whether GH deficiency, when present, may act as a contributory factor in the pathogenesis of these diseases, or might represent a consequence of it is presently unknown. A thorough effort in investigating every possible involvement of GH/IGF-I axis is warranted, in the light of future possible therapeutic strategies. PMID- 20930498 TI - Medical therapy of acromegaly in Turkey. AB - Acromegaly is associated with multiple co-morbidities and risk of premature mortality. Mortality rate of acromegalic patients is similar to that of the general population when normal GH levels are achieved. Surgery is the mainstay of acromegaly but when surgery fails to achieve disease control, or when surgery is impossible or contraindicated, patients are offered medical therapy and/or radiotherapy. Current medical therapy modalities were revised in this short review. PMID- 20930499 TI - Efficiency and applicability of comprehensive geriatric assessment in the emergency department: a systematic review. AB - BACKGROUND AND AIMS: Comprehensive geriatric assessment (CGA) may benefit frail or chronically ill patients in the emergency department (ED), but take too much time to be performed routinely in ED. An alternative approach is to use first a screening tool to detect high-risk patients and then perform CGA in these patients only. This systematic review focuses on the use and value of CGA in ED for evaluation of older patients and its influence on adverse outcomes. This approach is compared with an alternative one using existing screening tools, validated in ED, to detect high-risk patients needing subsequent CGA. This review ends by suggesting a short assessment of CGA to be used in ED and ways to improve home discharge management from ED. METHODS: A systematic English Medline literature search was conducted in December 2009, with no date limit with the following Medical Subject Heading (MeSH) terms: "Frail Elderly", "Health Services for Aged", "Community Health Nursing", "Emergency Service, Hospital", "Geriatric Assessment", "Patient Discharge", "Risk Assessment" and "Triage". RESULTS: We selected 8 studies on CGA efficiency and 14 on screening tools. CGA in ED is efficient for decreasing functional decline, ED readmission and possibly nursing home admission in high-risk patients. As CGA takes too much time to be performed routinely in ED, validated screening tools can be applied to detect high-risk patients who will benefit most from CGA. CONCLUSIONS: The selected studies demonstrated that screening of high-risk patients is more efficient than age based screening, and that CGA performed in ED, followed by appropriate interventions, improves outcomes. PMID- 20930500 TI - Relationship between whole body oxygen consumption and skeletal muscle glucose metabolism during walking in older adults: FDG PET study. AB - BACKGROUND AND AIMS: The purpose of this study was to determine the relationship between whole body energy metabolism measured as oxygen consumption (VO2) and local muscle activity measured by positron emission tomography (PET) and [18F]fluorodeoxyglucose (FDG). METHODS: Ten community- dwelling older women (73 83 yrs) had FDG PET and VO2 measured while walking at a comfortable speed. RESULTS: A significant positive correlation was found between VO2 and FDG uptake in the biceps femoris (r=0.83), gluteus minimus (r=0.67), gluteus medius (r=0.77) and pelvis section muscles (r=0.76). The subjects who showed high FDG uptake in the hip muscle group had significantly higher VO2 while walking, compared with subjects without high FDG uptake in the hip muscles. CONCLUSIONS: These results indicate that FDG PET provides an index which reflects whole body energy metabolism during walking, and revealed that excess muscle activity in the hip muscles during walking plays a key role in increasing VO2 in older adults. PMID- 20930501 TI - Forecasting dengue vaccine demand in disease endemic and non-endemic countries. AB - BACKGROUND: A dengue vaccine in large-scale clinical trials could be licensed in several years. We estimated the potential vaccine demand for different introduction strategies in 54 dengue-endemic countries and for travelers from non endemic countries to enable vaccine producers and public health agencies to better prepare for timely utilization of the vaccine. RESULTS: Under our assumptions, 2.4-3.5 billion dengue vaccine doses would be needed in the first five years after introduction with >75% delivered in the public sector. Among 20 potential 'early-adopter' countries, an estimated 0.9-1.4 billion doses would be needed for the same introduction approach. For the private sector, covering 10% of children and 30% of adults an estimated 443-664 million doses would be required. In non-endemic countries, travelers could use an estimated 59-89 million vaccine doses, although the present product profile would make it unlikely to be able to administer vaccine in a timely manner. METHODS: Calculations were based on 2015-2020 population projections for endemic countries in Asia and the Americas with populations >100,000. For dengue-endemic countries we assumed country-wide routine 12-23 month-old vaccination and catch-up vaccination among 2-14 year-old children employing a 2 or 3-dose schedule. Assumptions on expected vaccination coverage were based on country-specific public, private and travelers' sectors immunization performance. CONCLUSIONS: Our results project an upper-limit estimate of vaccine demand, with actual demand depending on country priorities, cost and product profile. Given the potential for a dengue vaccine, policymakers in endemic and nonendemic countries should consider appropriate implementation strategies in advance of licensure. PMID- 20930502 TI - The role of p53 in nutrients levels. PMID- 20930503 TI - A screen for deubiquitinating enzymes involved in the G2/M checkpoint identifies USP50 as a regulator of HSP90-dependent Wee1 stability. AB - Tight regulation of cell cycle progression is essential for the maintenance of genomic integrity in response to DNA injury. The aim of this study was to identify new deubiquitinating enzymes (DUBs) involved in the regulation of the G2/M checkpoint. By using an siRNA-based screen to identify DUBs with an inherent ability to enhance a CDC25B-dependent G2/M checkpoint bypass, we have identified 11 candidates whose invalidation compromises checkpoint stringency. We subsequently focused our attention on one of these, the previously uncharacterized USP50. Using a TAP-tag approach associated to mass spectrometry, in addition to a yeast-two-hybrid screen, we identified HSP90 as a major interacting partner for USP50. We also demonstrate USP50 depletion causes a loss in accumulation of the HSP90 client Wee1, which is an essential component of the G2/M cell cycle arrest. Finally, we show that in response to DNA damaging agents, USP50 accumulates in the nucleus. We propose that USP50 may act through a HSP90 dependent mechanism to counteract CDC25B mitotic inducing activity and prevent Wee1 degradation, thereby repressing entry into mitosis following activation of the DNA damage checkpoint. PMID- 20930504 TI - Anticancer function of polyinosinic-polycytidylic acid. AB - Polyinosinic-polycytidylic acid (polyi:c) is a synthetic analog of double stranded RNA and an agonist of toll-like receptor (TLR) 3 and retinoic acid inducible gene I (RIG-I)-like receptors (RLRs), including RIG-I and melanoma differentiation-associated gene 5 (MDA5). The effect of polyi:c on tumor immunotherapy has been well explored for several decades. The accumulated evidence suggests that polyi:c could be used as a vaccine adjuvant to enhance innate and adaptive immune responses, and to alter the tumor microenvironment. Recent studies have also shown that activation of TLR3 and RLR signaling by polyi:c can directly trigger apoptosis in some cancer cells. This review focuses on polyi:c-induced signaling pathways and the applications of polyi:c in cancer treatment. PMID- 20930505 TI - Cyclin E and histone H3 levels are regulated by 5-fluorouracil in a DNA mismatch repair-dependent manner. AB - Several studies indicate that the DNA mismatch repair (MMR) system may trigger cytotoxicity upon 5-fluorouracil (5-FU) recognition, but signaling pathways regulated by MMR in response to 5-FU are unknown. We hypothesize that recognition of 5-FU in DNA by MMR proteins trigger specific signaling cascades that results in slowing of the cell cycle and cell death. Whole human genome cDNA microarrays were used to examine relative signaling responses induced in MMR-proficient cells after 5-FU (5 MUM) treatment for 24 hours. Analysis revealed 43 pathways differentially affected by 5-FU compared to control (P 1.4-fold) and downregulated cdc25C, cyclins B1 and B2, histone H2A, H2B, and H3 (< -1.4-fold) over control. Cell cycle analysis revealed a G1/S arrest by 5-FU that was congruent with increased cyclin E and decreased cdc25C protein expression. Importantly, with knockdown of hMLH1 and hMSH2, we observed that decreased histone H3 expression by 5-FU was dependent on hMLH1. Additionally, 5-FU treatment dramatically decreased levels of several histone H3 modifications. Our data suggest that 5-FU induces a G1/S arrest by regulating cyclin E and cdc25C expression, and MMR recognition of 5-FU in DNA may modulate cyclin E to affect the cell cycle. Furthermore, MMR recognition of 5-FU reduces histone H3 levels that could be related to DNA access by proteins and/or cell death during the G1/S phase of the cell cycle. PMID- 20930506 TI - A new layer of regulation is required to silence the DNA damage checkpoint. PMID- 20930507 TI - Additional proof for the importance of Eco1 for DNA double strand break repair. PMID- 20930508 TI - Incapacitating CtBP to kill cancer. PMID- 20930509 TI - Carbon-iron magnetic nanoparticles for agronomic use in plants: promising but still a long way to go. AB - In the recent years, multiple ways of interaction between the fields of nanotechnology and biology have been opened, mainly in the biomedical research, with the development of tools for diagnosis and controlled delivery of substances. (1,2) On the other hand, in the field of plant biology, the interaction between both disciplines has been less frequent. Most of the published work on this field has focus in the environmental impact of nanoparticles on crop growth and development; (3,4) and also on the bio production of nanoparticles using plant extracts (reviewed in (5) , as an example see also (6,7,8)). Much less attention has taken other possible aspects of the interrelationship between nanotechnology and plant biology, such as the development of nanodevices for controlled delivery of drugs or different kind of substances, (9,10) in a similar way to that already developed in the medical research. PMID- 20930511 TI - Price as a double-edged sword in the golden era of vaccines. AB - As a child, I reluctantly submitted to routine vaccinations at my pediatrician's office, much as my own patients do today. PMID- 20930510 TI - Damage-specific modification of PCNA. AB - Okazaki fragment processing is an integral part of DNA replication. For a long time, we assumed that the maturation of these small RNA-primed DNA fragments did not necessarily have to occur during S phase, but could be postponed to late in S phase after the bulk of DNA synthesis had been completed. This view was primarily based on the arrest phenotype of temperature-sensitive DNA ligase I mutants in yeast, which accumulated with an almost fully duplicated set of chromosomes. However, many temperature-sensitive alleles can be leaky and the re-evaluation of DNA ligase I-deficient cells has offered new and unexpected insights into how cells keep track of lagging strand synthesis. It turns out that if Okazaki fragment joining goes awry, cells have their own alarm system in the form of ubiquitin that is conjugated to the replication clamp PCNA. Although this modification results in mono- and poly-ubiquitination of PCNA, it is genetically distinct from the known post-replicative repair mark at lysine 164. In this Extra View, we discuss the possibility that eukaryotic cells utilize different enzymatic pathways and ubiquitin attachment sites on PCNA to alert the replication machinery to the accumulation of single-stranded gaps or nicks behind the fork. PMID- 20930512 TI - A sliding scale: the many faces of Ctf7/Eco1 cohesion establishment factor in DNA repair. PMID- 20930513 TI - Biological and clinical relevance of quantitative global methylation of repetitive DNA sequences in chronic lymphocytic leukemia. AB - Global DNA hypomethylation affecting repeat sequences has been reported in different cancer types. Herein, we investigated the methylation levels of repetitive DNA elements in chronic lymphocytic leukemia (CLL), their correlation with the major cytogenetic and molecular features, and clinical relevance in predicting therapy-free survival (TFS). A quantitative bisulfite-PCR Pyrosequencing method was used to evaluate methylation of Alu, long interspersed nuclear elements-1 (LINE-1) and satellite-alpha (SAT-alpha) sequences in 77 untreated early-stage (Binet A) CLL patients. Peripheral B-cells from 7 healthy donors were used as controls. Methylation levels (median %5mC) were lower in B CLLs compared with controls (21.4 vs. 25.9; 66.8 vs. 85.7; 84.0, vs. 88.2 for Alu, LINE-1 and SAT-alpha, respectively) (p < 0.001). Among CLL patients, a significant association was observed with 17p13.1 deletion (16.8 vs. 22.4; 51.2 vs. 68.5; 52.6 vs. 85.0, for Alu, LINE-1 and SAT-alpha) but not with other major genetic lesions, IgVH mutation status, CD38 or ZAP-70 expression. Follow-up analyses showed that lower SAT-alpha methylation levels appeared to be an independent prognostic marker significantly associated with shorter TFS. Our study extended previous limited evidences in methylation of repetitive sequences in CLL suggesting an important biological and clinical relevance in the disease. PMID- 20930514 TI - Unsuccessful high dose IL-2 therapy followed immediately by near continuous low dose temozolomide can result in rapid durable complete and near-complete remissions in metastatic melanoma. AB - Metastatic melanoma remains a disease with a very poor prognosis. High dose Interleukin-2 (HD IL-2) and temozolomide (TMZ) are both approved treatments for this malignancy but response rates remain poor. HD IL-2 is the only approved therapy that has been shown to induce durable complete responses albeit in a very small percentage of patients. The combination of TMZ followed by HD IL-2 as biochemotherapy has been studied previously but did not improve responses over what had been observed for HD IL-2 alone. In our clinical practice, we noted surprising rapid and dramatic responses to TMZ when given as therapy at 75 mg/m2 for 21 days per one month cycles in 6/9 (67%) sequentially treated patients who had just completed a full course of HD IL-2 and either had failed to respond (11%) or frankly progressed (89%). The TMZ therapy began on average within 6 weeks of stopping the IL-2. All responding patients had complete or near complete responses (CR and nearCR) to TMZ. The responses became evident rapidly, typically within 1 or 2 cycles of TMZ. Three patients remain alive and completely disease free, two are off of all therapy to date. Two patients recurred after initial CR and nearCR. One patient died from an acute myocardial infarction while in a CR. One patient had prolonged stable disease and 2 patients progressed. These were much better responses than what is typically observed for single agent TMZ; indeed, durable CR to TMZ that persists off therapy is an unrecognized phenomenon to our knowledge. TMZ is an oral atypical alkylating agent that in addition to having cytotoxic activity against melanoma has also been shown to decrease the T regulatory population of lymphocytes (T-regs). We hypothesize that the TMZ may be synergistic with HD IL-2 in a sequence-specific fashion by allowing the immune activation induced by the HD IL-2 to proceed without negative feedback applied by the T-reg population of cells whose major function is to inhibit an exuberant immune response. This postulated mechanism would result in the sequence-specific activity noted in our patients. Of interest, 3/6 responding patients and 1/3 stable/ non-responding patients also exhibited persistent polyarthralgias that began on TMZ suggesting the induction of autoimmunity which may be related to anti-melanoma effects. The durable CRs that persist after the cessation of treatment suggest that this sequence-specific combination should be studied further, ideally in a prospective trial of repeated courses of HD IL-2 followed strategically by continuous TMZ. PMID- 20930515 TI - Anti-TNFalpha domain antibody construct CEP-37247: Full antibody functionality at half the size. AB - We report preclinical data for CEP-37247, the first human framework domain antibody construct to enter the clinic. At approximately 11 - 13kDa, domain antibodies or dAbs are the smallest antibody domain able to demonstrate the antigen-recognition function of an antibody, e.g. high selectivity and affinity for target antigen. CEP-37247 is a bivalent anti-tumor necrosis factor (TNF)alpha domain antibody protein construct combining the antigen-recognition function of a dAb with the pharmacological advantages of an antibody Fc region. As a homodimer, with each chain comprising VL dAb, truncated CH1, hinge, CH2 and CH3 domains, CEP 37247 has a molecular mass of approximately 78kDa, which is about half the size of a conventional IgG molecule. Surface plasmon resonance data demonstrate that CEP-37247 possesses high selectivity and affinity for TNFalpha. CEP-37247 is a potent neutralizer of TNFalpha activity in vitro in the L929 TNF-mediated cytotoxicity assay. In a human TNFalpha-over-expressing mouse model of polyarthritis, CEP-37247 prevents development of disease, and is at least as effective as the marketed product etanercept. Fc functionality is intact - CEP 37247 is capable of mediating antibody-dependent cell-mediated cytotoxicity and has a circulating half-life of approximately 4.5 days in cynomolgus macaques. Given the favorable properties outlined above, and its high expression levels (approaching 7 g/L) in a CHOK1 based-expression system, CEP-37247 is progressing into the clinic, where other potential advantages such as enhanced efficacy due to improved tissue distribution, and beneficial immunogenicity profile, will be evaluated. PMID- 20930516 TI - E. coli 6S RNA: a universal transcriptional regulator within the centre of growth adaptation. AB - Bacterial 6S RNA has been shown to bind with high affinity to sigma(70) containing RNA polymerase, suppressing sigma(70)-dependent transcription during stationary phase, when 6S RNA concentrations are highest. We recently reported a genome-wide transcriptional comparison of wild-type and 6S RNA deficient E. coli strains. Contrary to the expected sigma(70)- and stationary phase-specific regulatory effect of 6S RNA it turned out that mRNA levels derived from many alternative sigma factors, including sigma(38) or sigma(32), were affected during exponential and stationary growth. Among the most noticeably down-regulated genes at stationary growth are ribosomal proteins and factors involved in translation. In addition, a striking number of mRNA levels coding for enzymes involved in the purine metabolism, for transporters and stress regulators are altered both during log- and stationary phase. During the study we discovered a link between 6S RNA and the general stress alarmone ppGpp, which has a higher basal level in cells deficient in 6S RNA. This finding points to a functional interrelation of 6S RNA and the global network of stress and growth adaptation. PMID- 20930517 TI - How calmodulin binding transcription activators (CAMTAs) mediate auxin responses. AB - Phenotypic plasticity is an adaptive feature of all organisms, which, in land plants, entails changes in orientation of growth (tropism), patterns of development, organ architecture, timing of developmental processes, and resource allocation. However, little is known about the molecular components that integrate exogenous environmental cues with internal hormonal signaling pathways. This addendum describes a role for calcium-regulated calmodulin-binding transcription 1 (CAMTA1) in auxin signaling and stress responses. We discuss possible mechanisms that may underlie this role of CAMTA1, and speculate on the more general roles of CAMTAs in auxin responses and phenotypic plasticity. PMID- 20930518 TI - Re-examining the role of ABA as the primary long-distance signal produced by water-stressed roots. AB - The role of ABA as the primary long-distance signal produced by water-stressed roots and transported to stomata continues to be challenged. We have recently reported that expression of ABA biosynthetic genes in roots only increases in the later stage of water stress. Our results support the hypothesis that in early water stress, increased levels of ABA in xylem sap are due to leaf biosynthesis and translocation to roots and from there to xylem. If so, other xylem-borne chemicals may be the primary stress signal(s) inducing ABA biosynthesis in leaves. We found that apart from ABA, sulfate was the only xylem-borne chemical that consistently showed higher concentrations from early to later water stress. We also found increased expression of a sulfate transporter gene in roots from early water stress onwards. Moreover, using bioassays we found an interactive effect of ABA and sulfate in decreasing maize transpiration rate, as compared to ABA alone. While ABA is undoubtedly the key mediator of water stress responses such as stomatal closure, it may not be the primary signal produced by roots perceiving water stress. PMID- 20930519 TI - Allosteric inhibition of BCR-ABL. AB - Impaired regulation of kinase activity can lead to a variety of diseases, including cancer. Inhibition of kinase activity has, therefore, been considered an attractive anti-cancer therapeutic strategy. The success of targeted therapy with kinase inhibitors has been well documented with BCR-ABL, where imatinib specifically inhibits kinase activity with impressive pharmacological responses in chronic myelogenous leukemia (CML). However, the success of kinase inhibitors as cancer therapeutics is being challenged clinically by the emergence of acquired resistance. Most kinase inhibitors available today are ATP-competitive. There have been efforts to develop kinase inhibitors with new modes of action. In this review, we highlight the development of 'allosteric kinase inhibitors' that inhibit kinase activity by binding to a site remote from the active site of the kinase. We focus on recent efforts directed towards BCR-ABL, for which, significant progress has been made to develop allosteric inhibitors with promising therapeutic activity, especially in the context of overcoming clinically acquired resistance mutations to the first generation of ATP competitive kinase inhibitors. PMID- 20930520 TI - Long noncoding RNA in genome regulation: prospects and mechanisms. AB - Long noncoding RNAs (lncRNAs) are pervasively transcribed and critical regulators of the epigenome[1, 2]. These long, polyadenylated RNAs do not code for proteins, but function directly as RNAs, recruiting chromatin modifiers to mediate transcriptional changes in processes ranging from X-inactivation (XIST) to imprinting (H19)[3]. The recent discovery that lncRNA HOTAIR can link chromatin changes to cancer metastasis[4] furthers the relevance of lncRNAs to human disease. Here, we discuss lncRNAs as regulatory modules and explore the implications for disease pathogenesis. Although large-scale analyses of mammalian transcriptomes have revealed that more than 50% of transcripts have no protein coding potential[2, 5, 6], the functions of these putative transcripts are largely unknown. A subset of these noncoding transcripts are termed long noncoding RNAs (lncRNAs), based on an arbitrary minimum length of 200 nucleotides. LncRNAs are roughly classified based on their position relative to protein-coding genes: intergenic (between genes), intragenic/intronic (within genes), and antisense[2]. Initial efforts to characterize these molecules demonstrated that they function in cis, regulating their immediate genomic neighbors. Examples include AIR, XIST, and Kcnq1ot (reviewed in [1, 7, 8]), which recruit chromatin modifying complexes to silence adjacent sites. The scope of lncRNAs in gene regulation was advanced with the finding that lncRNA HOTAIR exhibited trans regulatory capacities. HOTAIR is transcribed at the intersection of opposing chromatin domains in the HOXC locus, but targets Polycomb Repressive Complex 2 (PRC2) to silence 40 kilobases of HOXD[9], a locus involved in developmental patterning. A subsequent study revealed that HOTAIR is overexpressed in approximately one quarter of human breast cancers, directing PRC2 to approximately 800 ectopic sites in the genome, which leads to histone H3 lysine 27 trimethylation and changes in gene expression[4]. The impacts of lncRNA mediated chromatin changes are noteworthy: not only did HOTAIR drive metastasis in a mouse model, but HOTAIR expression in human breast cancer was found to be an independent prognostic marker for death and metastasis[4]. The fact that HOTAIR drives chromatin reprogramming genome-wide suggests that long-range regulation by lncRNAs may be a widespread mechanism. This is supported by a study showing that > 20% of tested lncRNAs are bound by PRC2 and other chromatin modifiers[10]. Furthermore, this is an underestimate of the total RNAs involved in chromatin modification, as PRC2 target genes also transcribe smaller 50-200 nt RNAs that interact with SUZ12 to mediate gene repression[11]. These findings provoke questions regarding the initial triggers for HOTAIR overexpression and whether understanding of lncRNA mechanics may have clinical relevance. PMID- 20930522 TI - Fibronectin 1 is a potential biomarker for radioresistance in head and neck squamous cell carcinoma. AB - Radiotherapy remains the backbone of head and neck cancer therapy but response is sometimes impeded by tumor radioresistance. Identifying predictive biomarkers of radiotherapy response is a crucial step towards personalized therapy. The aim of this study was to explore gene expression data in search of biomarkers predictive of the response to radiotherapy in head and neck squamous cell carcinoma (HNSCC). Microarray analysis was performed on five cell lines with various intrinsic radiosensitivity, selected from a panel of 29 HNSCC cell lines. The bioinformatics approach included Gene Ontology (GO) enrichment profiling and Ingenuity Pathway Analysis (IPA). The GO-analysis detected 16 deregulated categories from which development, receptor activity, and extracellular region represented the largest groups. Fourteen hub genes (CEBPA, CEBPB, CTNNB1, FN1, MYC, MYCN, PLAU, SDC4, SERPINE1, SP1, TAF4B, THBS1, TP53 and VLDLR) were identified from the IPA network analysis. The hub genes in the highest ranked network, (FN1, SERPINE1, THBS1 and VLDLR) were further subjected to qPCR analysis in the complete panel of 29 cell lines. Of these genes, high FN1 expression associated to high intrinsic radiosensitivity (p=0.047). In conclusion, gene ontologies and hub genes of importance for intrinsic radiosensitivity were defined. The overall results suggest that FN1 should be explored as a potential novel biomarker for radioresistance. PMID- 20930521 TI - Making sense of ubiquitin ligases that regulate p53. AB - The functions of p53 most highly associated with the well-studied tumor suppressor are its abilities to induce cell cycle arrest and apoptosis in response to cellular stresses. Recent progress underscores that p53 is a multi functional protein with activities that range beyond tumor suppression to normal homeostasis, metabolism, fertility and differentiation. A unifying theme of these studies is that p53 is first and foremost a transcription factor; and control of p53 protein stability determines its ability to carry out this task. There are an expanding number of E3-ubiquitin ligase proteins that target p53 for ubiquitin tagging and protein degradation. This review discusses these many effectors of p53 protein degradation, and our task is to provide some level of understanding as to their differences and their similarities. Further, we propose how some degree of specialization may be assigned to the E3-ligases, in their navigation toward a common goal of regulating p53 protein levels, and emphasize that better understanding of the mechanisms involved in E3-ligase functions is needed to further their potential as therapeutic targets. PMID- 20930523 TI - HDAC1 in axonal degeneration: A matter of subcellular localization. AB - Multiple sclerosis (MS) is a disease characterized by inflammatory demyelination and a strong neurodegenerative component. Axonal damage is characteristically detected in MS brains, although the pathogenic mechanisms are not clearly understood. Here, we discuss the importance of HDAC1 localization as one of the potential mechanisms initiating damage in demyelinating conditions. We suggest the occurrence of a two-stage mechanism of damage. The first event is a calcium dependent HDAC1 nuclear export in a CRM1-dependent manner and the second event is the interruption of mitochondrial transport resulting from the cytoplasmic localization of HDAC1. In the cytosol of neurons challenged by cytokines and excitatory aminoacids, HDAC1 formed complexes with motor-protein and microtubules and this resulted in blockade of axonal transport and release of cargo from motor proteins. We suggest that these findings might be the framework for future studies and for the development of novel therapeutic targets for axonal damage in demyelinating conditions. PMID- 20930524 TI - Ectopic expression of RhoBTB2 inhibits migration and invasion of human breast cancer cells. AB - RhoBTB2, or Deleted in Breast Cancer 2 (DBC2), identified as a candidate tumor suppressor gene for breast cancer and other human malignancies, is an atypical member of a novel gene family encoding small GTPases. In this study, we found that ectopic expression of RhoBTB2 inhibits the migration and invasion of the human metastatic breast cancer cell lines MDA-MB-231 and MDA-MB-435 in a dose dependent manner. Western blotting analysis revealed that ectopic expression of RhoBTB2 induces a significant increase in the breast cancer metastasis suppressor, BRMS1. siRNA suppression of BRMS1 expression markedly reversed the inhibitory effects of RhoBTB2 on the migration and invasion abilities of both cell lines. Ezrin is a member of the ezrin-radixin-moesin cytoskeleton-associated protein family and is a key signaling molecule that regulates cancer migration and invasion. Western blotting analysis demonstrated that ectopic expression of RhoBTB2 results in decreased phosphorylation of ezrin and Akt2 in both MDA-MB-231 and MDA-MB-435 cells. Therefore, we conclude that up-regulation of the breast cancer metastasis suppressor BRMS1 and down-regulation of the phosphorylation of the cancer metastasis-related gene, ezrin, contributed to RhoBTB2-induced inhibition of metastatic breast carcinoma cell migration and invasion. Our findings suggest that understanding RhoBTB2-mediated migration and suppression of invasion is critical to the development of new therapies designed to prevent and treat patients with breast cancer metastasis. PMID- 20930526 TI - Sporadic human cases of swine-origin influenza before 2009 share the Sa epitope. PMID- 20930525 TI - New insights into the regulation of greening and carbon-nitrogen balance by sugar metabolism through a plastidic invertase. AB - Since the photosynthetic apparatus of plants contains a massive amount of nitrogen, the regulation of its development by sugar signals is important to the maintenance of the carbon-nitrogen balance. Recently, we isolated a new Arabidopsis mutant, sicy (sugar-inducible cotyledon yellow)-192, whose cotyledons were prevented from greening by treatment with sucrose. On treatment with sucrose, the expression of photosynthesis- and nitrogen assimilation-related genes was respectively weaker and stronger in the mutant seedlings than the wild type seedlings. In the mutants, the gene encoding plastidic alkaline/neutral (A/N) invertase (INV-E) was point-mutated at codon 294, with Tyr substituted for Cys (C294Y). These findings provide new insights into the regulation of greening and carbon-nitrogen balance by sugar metabolism through INV-E in plastids. In this addendum, we describe the phenotypes of sicy-192 on treatment with sucrose in more detail, and propose a possible relationship among sugar metabolism through INV-E, plastid-to-nucleus retrograde signaling, and ethylene, a plant hormone, in the regulation of plant development and metabolism. PMID- 20930527 TI - Biosynthesis of anther cuticle and pollen exine in rice. AB - The lipidic structures, anther cuticle (outer anther surface) and pollen exine (outer pollen wall), play a key protective role for the male gametophyte and pollen grain development. We recently identified ancient cytochrome P450 family member CYP704B2 in rice, and proposed a common fatty acid omega-hydroxylation pathway for synthesizing anther cuticle and pollen exine during plant male reproductive development. Furthermore, we propose developmental model of pollen exine formation and discuss key genes required for pollen exine synthesis in the important crop plant rice. PMID- 20930530 TI - HPV vaccine protects against pre-cancerous growths. PMID- 20930528 TI - A conserved G1 regulatory circuit promotes asynchronous behavior of nuclei sharing a common cytoplasm. AB - Synthesis and accumulation of conserved cell cycle regulators such as cyclins are thought to promote G1/S and G2/M transitions in most eukaryotes. When cells at different stages of the cell cycle are fused to form heterokaryons, the shared complement of regulators in the cytoplasm induces the nuclei to become synchronized. However, multinucleate fungi often display asynchronous nuclear division cycles, even though the nuclei inhabit a shared cytoplasm. Similarly, checkpoints can induce nuclear asynchrony in multinucleate cells by arresting only the nucleus that receives damage. The cell biological basis for nuclear autonomy in a common cytoplasm is not known. Here we show that in the filamentous fungus Ashbya gossypii, sister nuclei born from one mitosis immediately lose synchrony in the subsequent G1 interval. A conserved G1 transcriptional regulatory circuit involving the Rb-analogue Whi5p promotes the asynchronous behavior yet Whi5 protein is uniformly distributed among nuclei throughout the cell cycle. The homologous Whi5p circuit in S. cerevisiae employs positive feedback to promote robust and coherent entry into the cell cycle. We propose that positive feedback in this same circuit generates timing variability in a multinucleate cell. These unexpected findings indicate that a regulatory program whose products (mRNA transcripts) are translated in a common cytoplasm can nevertheless promote variability in the individual behavior of sister nuclei. PMID- 20930531 TI - One vaccine for a range of cancers. PMID- 20930529 TI - NANOG promoter methylation and expression correlation during normal and malignant human germ cell development. AB - Testicular germ cell tumors are the most frequent malignant tumors in young Caucasian males, with increasing incidence. The actual model of tumorigenesis is based on the theory that a block in maturation of fetal germ cells lead to formation of the intratubular germ cell neoplasia unclassified. Early fetal germ cells and undifferentiated germ cell tumors express pluripotency markers such as the transcription factor NANOG. It has been demonstrated, that epigenetic modifications such as promoter DNA-methylation is able to silence gene expression in normal and cancer cells. Here we show, that OCT3/4-SOX2 mediated expression of NANOG can be silenced by methylation of promoter CpG-sites. We found that global methylation of DNA decreased from fetal spermatogonia to mature sperm. In contrast, CpGs in the NANOG promoter were found hypomethylated in spermatogonia and hypermethylated in sperm. This selective repression might reflect the cells need to suppress pluripotency in order to prevent malignant transformation. Finally, methylation of CpGs in the NANOG promoter in germ cell tumors and derived cell lines correlated to differentiation state. PMID- 20930532 TI - Vaccine to combat chronic stress. PMID- 20930533 TI - Pertussis outbreak in California. PMID- 20930534 TI - Seasonal flu vaccines on the way. PMID- 20930535 TI - Computer-aided design of live viral vaccine. PMID- 20930536 TI - HIV vaccine research: Hope for renaissance. PMID- 20930538 TI - 2010 albert B. Sabin gold medal award. PMID- 20930537 TI - Questions for biotechs: genocea biosciences. PMID- 20930539 TI - The role of jasmonic acid and ethylene crosstalk in direct defense of Nicotiana attenuata plants against chewing herbivores. AB - We examined performance of herbivores on plants lacking either jasmonate (JA, asLOX3) or ethylene (ET, mETR1) signaling, or both (mETR1asLOX3). Plant defenses against Manduca sexta caterpillars were strongly impaired in JA-deficient asLOX3 plants; however, making asLOX3 plants ethylene insensitive did not further increase the performance of the larvae on a mETR1asLOX3 genetic cross. This result demonstrates the dominant role of JA over ET in the regulation of plant defenses against herbivores. However, ET-insensitivity combined with otherwise normal levels of JA in mETR1 plants promoted faster caterpillar growth, which correlated with reduced accumulation of the alkaloidal direct defense nicotine in mETR1 compared to WT plants. Our data points to an important accessory function of ET in the activation of JA-regulated plant defenses against herbivores at the level of alkaloid biosynthesis in the roots and/or accumulation in the leaves. PMID- 20930540 TI - Therapeutic implications of autophagy-mediated cell survival in gastrointestinal stromal tumor after treatment with imatinib mesylate. PMID- 20930541 TI - In the beginning: Generating neural crest cell diversity. AB - Neural crest cells (NCCs) are migratory cells that delaminate from the neural tube early in development and then disseminate throughout the embryo to give rise to a wide variety of cell types that are key to the vertebrate body plan. During their journey from the neural tube to their peripheral targets, NCCs progressively differentiate, raising the question when the fate of an individual NCC is sealed. One hypothesis suggests that the fate of a NCC is specified by target-derived signals emanating from the environment they migrate through, while another hypothesis proposes that NCCs are already specified to differentiate along select lineages at the time they are born in the neural tube, with environmental signals helping them to realize their prespecified fate potential. Alternatively, both mechanisms may cooperate to drive NCC diversity. This review highlights recent advances in our understanding of prespecification during trunk NCC development. PMID- 20930543 TI - Hypoxia induced upregulation and function of the thiamine transporter, SLC19A3 in a breast cancer cell line. AB - Adaptive responses within hypoxic tumor microenvironments require the altered expression of Solute Carrier (SLC) transporters to maintain nutrient uptake in support of cellular metabolism and biosynthesis. Using a real time PCR array strategy to further characterize changes in transporter expression within a chronic hypoxia breast cancer cell line model (BT474), we have found a 31 fold increase in the expression of the thiamine transporter, SLC19A3. Thus, further investigations into the expression changes of the thiamine transporters, SLC19A2 and SLC19A3, and the role of hypoxia inducible factor-1 alpha (HIF-1alpha) regulating their expression were conducted. Chronic culturing of BT474 cells in 1% O2 up to 142 days consistently demonstrated a high level of SLC19A3 expression with a mean of approximately 40 fold with no change in SLC19A2. A corresponding 2 fold increase in thiamine uptake over 15 min was measured in chronic hypoxic BT474 cells compared to normoxia. Acute 1% O2 exposure of BT474 cells up to 72 h demonstrated a 7.5 fold increase in SLC19A3 expression. The chemical hypoxia mimetic deferoxamine, resulted in an approximately 70 fold increase in SLC19A3 expression. Stable shRNA knockdown of HIF-1alpha reduced hypoxia mediated SLC19A3 up-regulation by approximately 3 fold compared to scrambled construct. In conclusion, SLC19A3 transporter expression was observed to be up-regulated under acute, chronic and DFO induced hypoxia. The attenuated increase in SLC19A3 expression after HIF-1alpha knockdown suggests a role for HIF-1alpha mediated pathways regulating SLC19A3 gene expression. PMID- 20930542 TI - Ubiquitin becomes ubiquitous in cancer: emerging roles of ubiquitin ligases and deubiquitinases in tumorigenesis and as therapeutic targets. AB - By virtue of its ability to regulate both protein turnover and non-proteolytic signalling functions, ubiquitin protein conjugation has been implicated in the control of multiple cellular processes, including protein localization, cell cycle control, transcription regulation, DNA damage repair, and endocytosis. Ubiquitin metabolism enzymes have been identified as either oncogenes or tumor suppressors in a variety of cancers. Given that ubiquitin metabolism is governed by enzymes--E1, E2, E3, E4, deubiquitinases (DUBs), and the proteasome- the system as a whole is ripe for target and drug discovery in cancer. Of the ubiquitin/proteasome system components, the E3's and DUBs can recognize substrates with the most specificity, and are thus of key interest as drug targets in cancer. This review examines the molecular role in cancer, relevant substrates, and potential for pharmacologic development, of E3's and DUBs that have been associated thus far with human malignancies as oncogenes or tumor suppressors. PMID- 20930544 TI - Therapeutic targeting of C-terminal binding protein in human cancer. AB - The CtBP transcriptional corepressors promote cancer cell survival and migration/invasion. CtBP senses cellular metabolism via a regulatory dehydrogenase domain, and is antagonized by p14/p19(ARF) tumor suppressors. The CtBP dehydrogenase substrate 4-methylthio-2-oxobutyric acid (MTOB) can act as a CtBP inhibitor at high concentrations, and is cytotoxic to cancer cells. MTOB induced apoptosis was p53-independent, correlated with the derepression of the proapoptotic CtBP repression target Bik, and was rescued by CtBP overexpression or Bik silencing. MTOB did not induce apoptosis in mouse embryonic fibroblasts (MEFs), but was increasingly cytotoxic to immortalized and transformed MEFs, suggesting that CtBP inhibition may provide a suitable therapeutic index for cancer therapy. In human colon cancer cell peritoneal xenografts, MTOB treatment decreased tumor burden and induced tumor cell apoptosis. To verify the potential utility of CtBP as a therapeutic target in human cancer, the expression of CtBP and its negative regulator ARF was studied in a series of resected human colon adenocarcinomas. CtBP and ARF levels were inversely-correlated, with elevated CtBP levels (compared with adjacent normal tissue) observed in greater than 60% of specimens, with ARF absent in nearly all specimens exhibiting elevated CtBP levels. Targeting CtBP may represent a useful therapeutic strategy in human malignancies. PMID- 20930546 TI - Global DNA methylation levels in girls with and without a family history of breast cancer. AB - Lower levels of global DNA methylation in white blood cell (WBC) DNA have been associated with adult cancers. It is unknown whether individuals with a family history of cancer also have lower levels of global DNA methylation early in life. We examined global DNA methylation in WBC (measured in three repetitive elements, LINE1, Sat2 and Alu, by MethyLight and in LINE1 by pyrosequencing) in 51 girls ages 6-17. Compared to girls without a family history of breast cancer, methylation levels were lower for all assays in girls with a family history of breast cancer, and statistically significantly lower for Alu and LINE1 pyrosequencing. After adjusting for age, body mass index (BMI), and Tanner stage, only methylation in Alu was associated with family history of breast cancer. If these findings are replicated in larger studies, they suggest that lower levels of global WBC DNA methylation observed later in life in adults with cancer may also be present early in life in children with a family history of cancer. PMID- 20930545 TI - The various roles of ubiquitin in Wnt pathway regulation. AB - Wnt signaling mediates key developmental and homeostatic processes including stem cell maintenance, growth and cell fate specification, cell polarity and migration. Inappropriate activation of Wnt signaling is linked to a range of human disorders, most notably cancer and neurodegenerative diseases. In the Wnt/beta-catenin cascade, signaling events converge on the regulation of ubiquitin-mediated degradation of the crucial transcriptional regulator beta catenin. The emerging mechanisms by which ubiquitin modification of proteins controls cellular pathways comprise both proteolytic and nonproteolytic functions. In nonproteolytic functions, ubiquitin acts as a signaling device in the control of protein activity, subcellular localization and complex formation. Here, we review and discuss recent developments that implicate ubiquitin-mediated mechanisms at multiple steps of Wnt pathway activation. PMID- 20930547 TI - DNA methylation of IGF2, GNASAS, INSIGF and LEP and being born small for gestational age. AB - Being born small for gestational age (SGA), a proxy for intrauterine growth restriction (IUGR), and prenatal famine exposure are both associated with a greater risk of metabolic disease. Both associations have been hypothesized to involve epigenetic mechanisms. We investigated whether prenatal growth restriction early in pregnancy was associated with changes in DNA methylation at loci that were previously shown to be sensitive to early gestational famine exposure. We compared 38 individuals born preterm (< 32 weeks) and with a birth weight too low for their gestational age (-1SDS) and a normal postnatal growth (> 1SDS at 3 months post term; AGA). The SGA individuals were not only lighter at birth, but also had a smaller length (P=3.3x10 (-13) ) and head circumference at birth (P=4.1x10 (-13) ). The DNA methylation levels of IGF2, GNASAS, INSIGF and LEP were 48.5%, 47.5%, 79.4% and 25.7% respectively. This was not significantly different between SGA and AGA individuals. Risk factors for being born SGA, including preeclampsia and maternal smoking, were also not associated with DNA methylation at these loci. Growth restriction early in development is not associated with DNA methylation at loci shown to be affected by prenatal famine exposure. Our and previous results by others indicate that prenatal growth restriction and famine exposure may be associated with different epigenetic changes or non epigenetic mechanisms that may lead to similar later health outcomes. PMID- 20930548 TI - Integrin alphaIIbbeta3: a novel effector of Galpha13. AB - Under physiological conditions, circulating platelets are discoid in shape. On these platelets, the fibrinogen receptor (integrin alphaIIbbeta3) is in a low affinity state, unable to bind soluble fibrinogen (Fg). Activation by agonists such as ADP and thrombin leads to a change in the conformation of the integrin alphaIIbbeta3 through a process known as inside-out signaling. This enables the integrin to bind soluble Fg, which initiates a cascade of events referred to as outside-in signaling. Outside-in signaling control processes such as platelet spreading and clot retraction by regulating small G-proteins such as RhoA, Rac and cdc42. PMID- 20930549 TI - Using peripheral blood mRNA signature to distinguish between breast cancer and benign breast disease in non-conclusive mammography patients. AB - Due to the small volume and high density of breast tissue in Asian women, particularly younger women, mammographic diagnosis is sometimes non-conclusive, with a Breast Imaging Reporting and Data System (BI-RADS) result of 0. No alternative based on blood biomarkers has yet succeeded in discriminating between patients with breast cancer (BC) and those with benign breast disease (BBD) among BI-RADS 0 patients. In our study, 84 BC and 94 BBD patients with mammographic results and confirmed pathologic information were enrolled and categorized into two groups, namely, 79 BC and 73 BBD patients with BI-RADS 1-5 and 5 BC and 21 BBD patients with BI-RADS 0. RNA extracted from peripheral blood samples collected in PAXgene (TM) tubes was analyzed after NuGEN WT-Ovation (TM) RNA amplification using Affymetrix GeneChip. PMID- 20930550 TI - STAT3 transcriptional factor activated by reactive oxygen species induces IL6 in starvation-induced autophagy of cancer cells. AB - Autophagy is one of the survival processes of cancer cells, especially in stressful conditions such as starvation, hypoxia and chemotherapeutic agents. However, its roles in tumor survival have not yet been fully elucidated. Here, we found for the first time that JAK2/STAT3 was activated in HeLa cells when they were starved or treated with rapamycin. STAT3 activation was associated with autophagic processes, because it was completely inhibited by 3-methyladenine, partially inhibited by knockdown of molecules associated with autophagic processes and blocked by antioxidants, DPI, a Nox inhibitor and knockdown of p22 phox, indicating that ROS generated by Nox that was activated during autophagic processes activated JAK2/STAT3 pathway. Activated STAT3 directly bound to IL6 promoter and increased IL6 mRNA and protein secretion. Finally, the conditioned media, which included IL6, from starved HeLa cells promoted cancer cell survival in both normal and starved conditions, confirmed by clonogenic, proliferation and cell death assays. These data together indicate that the autophagic process in cancer cells can contribute to their survival by JAk2/STAT3 activation and subsequent secretion of growth factors. PMID- 20930551 TI - Prognostic signatures, cancer metastasis and MYC. PMID- 20930552 TI - Plant-produced microbial vaccines: Alexander V. Karasev, editor: Current topics in microbiology and immunology 2009; v. 332. PMID- 20930553 TI - Maternal protein restriction during pregnancy induces CCAAT/enhancer-binding protein (C/EBPbeta) expression through the regulation of histone modification at its promoter region in female offspring rat skeletal muscle. AB - Maternal nutrition during pregnancy is an important intrauterine environmental factor that can cause persistent alterations of the offspring genome and is associated with potential disease risk later in life. In the present study, we investigated the impact of a maternal low protein diet (LP) on the expression of the transcription factor CCAAT/enhancer-binding protein (C/EBPbeta) in offspring skeletal muscle. C/EBPbeta belongs to a family of transcription factors that regulates the expression of genes involved in energy homeostasis and muscle development. We investigated C/EBPbeta transcriptional regulation from an epigenetic aspect. We observed sex-dependent differences in C/EBPbeta expression in offspring skeletal muscle subjected to a maternal protein-restricted diet. In female offspring skeletal muscle, both C/EBPbeta mRNA and protein levels were increased by maternal protein restriction. However, C/EBPbeta expression was not altered in other tissues or male offspring. Analysis of transcriptional and epigenetic regulation showed acetylated histone 3 and acetylated histone 4 at significantly increased levels at the C/EBPbeta promoter region in female LP pup's muscle. Phosphoenolpyruvate carboxykinase (PEPCK) gene transcription was also up-regulated in female LP pups through the increased binding of C/EBPbeta at its promoter. The induction of C/EBPbeta expression in female offspring skeletal muscle by maternal protein restriction during pregnancy may indicate C/EBPbeta involvement in signaling response in energy metabolism to a low maternal protein diet. PMID- 20930554 TI - Auxins upregulate nif and fix genes. AB - In a recent publication we analyzed the global effects triggered by IAA overproduction in S. meliloti RD64 under free-living conditions by comparing the gene expression pattern of wild type 1021 with that of RD64 and 1021 treated with IAA and other four chemically or functionally related molecules. Among the genes differentially expressed in RD64 and IAA-treated 1021 cells we found two genes of pho operon, phoT and phoC. Based on this finding we examined the mechanisms for mineral P solubilization in RD64 and the potential ability of this strain to improve Medicago growth under P-starved conditions. Here, we further analyze the expression profiles obtained in microarray analysis and evaluate the specificity and the extent of overlap between all treatments. Venn diagrams indicated that IAA- and 2,4-D-regulated genes were closely related. Furthermore, most differentially expressed genes from pSymA were induced in 1021 cells treated with 2,4-D, ICA, IND and Trp as compared to the untreated 1021 cells. RT-PCR analysis was employed to analyze the differential expression patterns of nitrogen fixation genes under free-living and symbiotic conditions. Under symbiotic condition, the relative expression levels of nif and fix genes were significantly induced in Mt- RD64 plants and in Mt-1021 plants treated with IAA and 2,4-D whereas they were unchanged or repressed in Mt-1021 plants treated with the other selected compounds when compared to the untreated Mt-1021 plants. PMID- 20930555 TI - Metrics for antibody therapeutics development. AB - A wide variety of full-size monoclonal antibodies (mAbs) and therapeutics derived from alternative antibody formats can be produced through genetic and biological engineering techniques. These molecules are now filling the preclinical and clinical pipelines of every major pharmaceutical company and many biotechnology firms. Metrics for the development of antibody therapeutics, including averages for the number of candidates entering clinical study and development phase lengths for mAbs approved in the United States, were derived from analysis of a dataset of over 600 therapeutic mAbs that entered clinical study sponsored, at least in part, by commercial firms. The results presented provide an overview of the field and context for the evaluation of on-going and prospective mAb development programs. The expansion of therapeutic antibody use through supplemental marketing approvals and the increase in the study of therapeutics derived from alternative antibody formats are discussed. PMID- 20930556 TI - Identification of small molecules enhancing autophagic function from drug network analysis. AB - Enhancing autophagy is a potentially effective strategy for the treatment of several human disorders. Therefore, there is a great effort in developing drugs modulating autophagy, and various approaches have been taken towards this goal. Gene expression has been considered an important biomarker for drug activity for prediction of drug mode of action. However, the lack of efficient method of analysis has hampered recognition of drug mode of action based on the analysis of gene expression profiles. A novel and robust tool for prediction of drug mode of action and drug repositioning overcomes the limitations of previously available methods. This novel tool is based on a data set of expression profiles derived from a large number of drugs integrated into a "drug network" constructed by comparing the transcriptional responses induced in human cell lines. Automatic analysis of the topology of the drug network makes it possible to classify compounds and to predict unreported effects of well-known drugs. Using this tool, it was possible to identify fasudil as a new enhancer of autophagy. PMID- 20930557 TI - Role of histone deacetylases HDA6 and HDA19 in ABA and abiotic stress response. AB - Our recent study revealed the involvement of the Arabidopsis histone deacetylase HDA6 in modulating ABA and salt stress responses. In this report, we further investigated the role of HDA19 in ABA and salt stress responses. The Arabidopsis HDA19 T-DNA insertion mutant, hda19-1, displayed a phenotype that was hypersensitive to ABA and salt stress. Compared with wild-type plants, the expression of ABA responsive genes, ABI1, ABI2, KAT1, KAT2, and RD29B, was decreased in hda19-1 plants when treated with ABA. Our study indicates that HDA6 and HDA19 may play a redundant role in modulating seed germination and salt stress response, as well as ABA- and salt stress-induced gene expression in Arabidopsis. PMID- 20930558 TI - A member of a new plant gene family encoding a meprin and TRAF homology (MATH) domain-containing protein is involved in restriction of long distance movement of plant viruses. AB - Restriction of long distance movement of several potyviruses in Arabidopsis thaliana is controlled by at least three dominant restricted TEV movement (RTM) genes, named RTM1, RTM2 and RTM3 and acts as a non conventional resistance. RTM1 encodes a protein belonging to the jacalin family and RTM2 encodes a protein which has similarities to small heat shock proteins. The recent cloning of RTM3 which encodes a protein belonging to an unknown protein family of 29 members which has a meprin and TRAF homology (MATH) domain in its N-terminal region and a coiled-coil (CC) domain at its C-terminal end is an important breakthrough for a better understanding of this resistance process. Not only the third gene involved in this resistance has been identified and has allowed revealing a new gene family in plant but the discovery that the RTM3 protein interacts directly with RTM1 strongly suggests that the RTM proteins form a multimeric complex. However, these data also highlight striking similarities of the RTM resistance with the well known R-gene mediated resistance. PMID- 20930559 TI - A new approach to estimate vaccine efficacy based on immunogenicity data applied to influenza vaccines administered by the intradermal or intramuscular routes. AB - BACKGROUND: Despite their pivotal role in the assessment of influenza vaccines, limited attempts have been made to use haemagglutination inhibition (HI) titers for predicting vaccine efficacy against laboratory-confirmed influenza. We present here the second step of a two-step approach allowing performing such predictions and use it to compare a new trivalent inactivated influenza vaccine administered by the intradermal (ID) route (INTANZA(r) /IDFlu(r)) with the vaccine administered by the classical intramuscular (IM) route. METHODS: The first step corresponding to the estimation of the level of protection against laboratory-confirmed influenza that can be linked to each HI titer, referred to as the HI protection curve, was achieved by using a meta-analytical approach based on published information. Vaccine efficacy and differences in vaccine efficacy are predicted in a second step using this HI protection curve alongside the results of two randomized clinical trials providing comparative information on the immunogenicity of trivalent inactivated influenza vaccines administered ID or IM in 3503 & 1645 elderly participants, respectively. RESULTS: Pooling all available immunogenicity data, the predicted vaccine efficacy was 63.3% [CI: 58.1; 68.7] for ID route and 54.4% [CI: 49.4; 59.2] for IM route. The corresponding relative increase in efficacy that is of 16.5% [CI: 12.7; 20.1]. Predicted vaccine efficacies decreased with age for both vaccines, but the decrease was less marked by ID route: the relative increase in efficacy for subjects aged 70 years and above is of 18.0% [CI:12;24]. CONCLUSION: The analysis performed confirmed that the superior immune response provided by the vaccine using the ID route should translate into a higher vaccine efficacy against laboratory-confirmed influenza. PMID- 20930560 TI - Neural crest cells and motor axons in avians: Common and distinct migratory molecules. AB - It has long been thought that the same molecules guide both trunk neural crest cells and motor axons as these cell types grow and extend to their target regions in developing embryos. There are common territories that are navigated by these cell types: both cells grow through the rostral portion of the somitic sclerotomes and avoid the caudal half of the sclerotomes. However, these cell types seem to use different molecules to guide them to their target regions. In this review, I will talk about the common and distinct methods of migration taken by trunk neural crest cells and motor axons as they grow and populate their target regions through chick embryos at the level of the trunk. PMID- 20930561 TI - The Bcl-2-Beclin 1 interaction in (-)-gossypol-induced autophagy versus apoptosis in prostate cancer cells. AB - Bcl-2 is a key dual regulator of autophagy and apoptosis, but how the level of Bcl-2 influences the cellular decision between autophagy and apoptosis is unclear. The natural BH3-mimetic (-)-gossypol preferentially induces autophagy in androgen-independent (AI) prostate cancer cells that have high levels of Bcl-2 and are resistant to apoptosis, whereas apoptosis is preferentially induced in androgen-dependent or -independent cells with low Bcl-2. (-)-Gossypol induces autophagy via blocking Bcl-2-Beclin 1 interaction at the endoplasmic reticulum (ER), together with downregulating Bcl-2, upregulating Beclin 1 and activating the autophagic pathway. Furthermore, (-)-gossypol-induced autophagy is Beclin 1- and Atg5-dependent. These results provide new insights into the mode of cell death induced by Bcl-2 inhibitors, which could facilitate the rational design of clinical trials by selecting patients who are most likely to benefit from the Bcl 2-targeted molecular therapy. PMID- 20930562 TI - Factors affecting Varicella vaccine uptake among children 1-17 years old in the Haifa District in 2007. AB - The Israeli National Vaccination Program (INVP) is aimed mainly at the pediatric age group. Till 2008 the program did not include routine administration of vaccine against Varicella (chickenpox). For the past 7 years, however, vaccine against Varicella has been available to the public and subsidized through the health maintenance organizations (HMOs). On the eve of probable introduction of the Varicella Zoster Vaccine (VZ-V) into the INVP a study was conducted to examine factors postulated to be of importance in vaccination uptake. These factors can be assessed while the vaccine is only administered through active choice, as opposed to administration by default as part of INVP. The study group comprised the communities in the District of Haifa. The aim of the study was to assess vaccination rates and contributing factors in the decision to vaccinate or not vaccinate against VZ. The study showed that uptake of VZ-V was in correlation with: 1. Population group (i.e. religious denomination)--Jews were more likely to vaccinate (OR=3.88). 2. Level of education--parents with higher level of education were more likely to vaccinate. (OR=1.91). 3. Level of religious observance--non-observant parents were more likely to vaccinate (OR=2.7) 4. Complementary insurance (reimbursement of cost)--parents with complementary insurance were more likely to vaccinate (OR=3.41). 5. A physician's recommendation to vaccinate--when a physician recommendation was given for vaccination the likelihood of vaccination was increased (OR=2.94). PMID- 20930563 TI - Pandemic influenza A 2009 (H1N1) vaccination in high risk children with chronic renal diseases: acceptance and perceptions. AB - We aimed to evaluate the acceptance of pandemic influenza A 2009 vaccination in our high risk children with chronic renal diseases. A total of 64 children/parents of pediatric nephrology department were approached to fill in a standardised questionnaire on influenza immunization profile. The H1N1 vaccination rates were 57.1% for transplant recipients, 61.5% for patients on peritoneal dialysis (PD), 36.4% for patients with various stages of chronic renal disease (CRD) and 26.7% for patients with glomerulonephritis (GN) on immunosuppressive therapy. Children on renal transplantation or PD had a fourfold higher rate of being vaccinated than children with GN (p=0.04). Causes of denying vaccination included fear of adverse effects (48.9%), lack of sufficient data on the new vaccine (31.9%) and others (19.2%). Patients being vaccinated were all urged by their pediatric nephrologist (100%), while patients not vaccinated were negatively influenced by media (41.4%), friends (24.1%), pediatrician (20.7%) and others (13.8%). Regarding parents education, higher level was associated with increased rate of children vaccination (p=0.04). It seems that patients with severe renal disease had better compliance with vaccination. The pediatric nephrologists had the most significant positive influence in contrast to the media which had the most negative influence. PMID- 20930565 TI - Dried influenza vaccines: over the counter vaccines. AB - Since last year influenza pandemic has struck again after 40 years, this is the right moment to discuss the different available formulation options for influenza vaccine. Looking back to the last 4 decades, most vaccines are still formulated as liquid solution. These vaccines have shown a poor stability profile and are limited in their potential route of administration. An ideal solution to these problems can be to convert vaccines into a dry and stable powder formulation. Recently, drying and delivery technologies have shown promising results regarding the vaccine stability. Therefore, in future we can envisage a stable dry influenza vaccine. Also with regard to the route of administration developments are accelerating and the potential of non-invasive administration has been demonstrated. PMID- 20930564 TI - Proteomic consequences of expression and pathological conversion of the prion protein in inducible neuroblastoma N2a cells. AB - Neurodegenerative diseases are often associated with misfolding and deposition of specific proteins in the nervous system. The prion protein, which is associated with transmissible spongiform encephalopathies (TSEs), is one of them. The normal function of the cellular form of the prion protein (PrP(C)) is mediated through specific signal transduction pathways and is linked to resistance to oxidative stress, neuronal outgrowth and cell survival. In TSEs, PrP(C) is converted into an abnormally folded isoform, called PrP(Sc), that may impair the normal function of the protein and/or generate toxic aggregates. To investigate these molecular events we performed a two-dimensional gel electrophoresis comparison of neuroblastoma N2a cells expressing different amounts of PrP(C) and eventually infected with the 22L prion strain. Mass spectrometry and peptide mass fingerprint analysis identified a series of proteins with modified expression. They included the chaperones Grp78/BiP, protein disulfide-isomerase A6, Grp75 and Hsp60 which had an opposite expression upon PrPC expression and PrP(Sc) production. The detection of these proteins was coherent with the idea that protein misfolding plays an important role in TSEs. Other proteins, such as calreticulin, tubulin, vimentin or the laminin receptor had their expression modified in infected cells, which was reminiscent of previous results. Altogether our data provide molecular information linking PrP expression and misfolding, which could be the basis of further therapeutic and pathophysiological research in this field. PMID- 20930566 TI - BROTHER OF FT AND TFL1 (BFT), a member of the FT/TFL1 family, shows distinct pattern of expression during the vegetative growth of Arabidopsis. AB - Transition to the flowering stage is precisely controlled by a few classes of regulatory molecules. BROTHER OF FT AND TFL1 (BFT) is a member of FLOWERING LOCUS T (FT)/TERMINAL FLOWER 1 (TFL1) family, an important class of flower development regulators with unidentified biochemical function. BFT has a TFL1-like activity and plays a role in axillary inflorescence development. To elucidate the expression pattern of BFT, we analyzed the subcellular localization and conditional expression of BFT in this study. We generated 35S::BFT:GFP plants to investigate the subcellular localization of BFT protein. 35S::BFT:GFP plants showed late flowering, similarly as did 35S::BFT plants. BFT:GFP fusion protein was localized in the nucleus and the plasma membrane, which was different from the localization pattern of FT and TFL1. BFT expression was induced by abiotic stress conditions. ABA, drought, and osmotic stress treatments induced BFT expression, whereas cold, salt, and heat stress conditions did not, suggesting that BFT plays a role in regulating flowering time and inflorescence structure under drought conditions. The induction pattern of BFT was different from those of other FT/TFL1 family genes. Our studies indicated that BFT showed a distinct expression pattern from its homologous genes during the vegetative growth in Arabidopsis. PMID- 20930567 TI - Seeds of Arabidopsis plants expressing dominant-negative AtSKD1 under control of the GL2 promoter show a transparent testa phenotype and a mucilage defect. AB - We have recently shown that overexpression of dominant-negative AtSKD1 versions under control of the trichome and non-root-hair-cell specific GL2 promoter (GL2pro) blocks trafficking of soluble cargo to the vacuole, resulting in its fragmentation and ultimately cell death. GL2pro is also active in the Arabidopsis seeds. When we inspected seeds of the dominant-negative AtSKD1 variants we found two phenotypes. The seeds display a transparent testa phenotype caused by a lack of proanthocyanidin (PA) and do not possess seed coat mucilage. Both phenotypes could be connected by cell death induced by the overexpression of dominant negative AtSKD1. PMID- 20930568 TI - Significance of light-induced hook exaggeration as reinforced by the concomitant anatomical change of germinating tomato seeds. AB - Progression of the apical hook of tomato, Solanum lycopersicum, exaggerated by phytochrome mediation at the early germination stage is followed in detail macroscopically and anatomically, and its proposed significance, i.e. survival by securing the seed coat release in the field, is reinforced by new findings. Furthermore, after self-release or artificial removal of the seed coat and the endosperm, no hook exaggeration occurs any more. Similar light-induced hook exaggeration (LIHE) is also found in carrot, parsley, and Cryptotaenia japonica, which share some seed characteristics with tomato. These findings also support the above-stated significance. PMID- 20930569 TI - A new view on development of a Staphylococcus aureus vaccine: insights from mice and men. PMID- 20930572 TI - Current Opinion in Neurology. Current world literature. PMID- 20930576 TI - Retinopathy of prematurity. PMID- 20930570 TI - In vivo imaging of autophagy in a mouse stroke model. AB - Recent studies have suggested that autophagy is involved in a neural death pathway following cerebral ischemia. In vivo detection of autophagy could be important for evaluating ischemic neural cell damage for human stroke patients. Using novel green fluorescent protein (GFP)-fused microtubule-associated protein 1 light chain 3 (LC3) transgenic (Tg) mice, in vivo imaging of autophagy was performed at 1, 3 and 6 d after 60 min transient middle cerebral artery occlusion (tMCAO). Ex vivo imaging of autophagy, testing of the autophagy inhibitor 3 methyladenine (3-MA), estern blot analysis, immunohistochemistry, terminal deoxynucleotidyl transferase-mediated dUTP-digoxigenin nick end labeling (TUNEL) and fluorescent analyses were performed on brain sections following tMCAO. In vivo fluorescent signals were detected above the ischemic hemisphere through the skull bone at 1, 3 and 6 d after tMCAO, with a peak at 1 d. Similar results were obtained with ex vivo fluorescence imaging. western blot analysis revealed maximum LC3-I and LC3-II expression at 1 d after tMCAO and fluorescence immunohistochemistry demonstrated that GFP-LC3-positive cells were primarily neuronal, not astroglial or microglial, cells. The number of GFP-LC3/TUNEL double positive cells was greater in the periischemic area than in the core. These results provided evidence of in vivo autophagy detection, with a peak at 1 d, in a live animal model following cerebral ischemia. This novel technique could be valuable for monitoring autophagic processes in vivo in live stroke patients, as well as for clarifying the detailed role of autophagy in the ischemic brain, as well as in other neurological diseases. PMID- 20930577 TI - Periocular infantile hemangioma. PMID- 20930578 TI - Ophthalmologic manifestations of systemic disease. PMID- 20930579 TI - Inherited retinal degenerations. PMID- 20930580 TI - Primary infantile glaucoma. PMID- 20930581 TI - Update on pediatric lacrimal disorders. PMID- 20930582 TI - Pediatric uveitis. PMID- 20930583 TI - Update on myopia and myopic progression in children. PMID- 20930584 TI - Pediatric excimer refractive surgery. PMID- 20930585 TI - Update on pediatric cataracts and cataract surgery. PMID- 20930586 TI - Choosing IOL power in pediatric cataract surgery. PMID- 20930587 TI - Strabismus surgery complications. PMID- 20930588 TI - Pediatric eye disease in Tanzania. PMID- 20930589 TI - Pediatric ophthalmologic infectious diseases in the developing world. PMID- 20930592 TI - Cooperative cardioprotection through adenosine A1 and A2A receptor agonism in ischemia-reperfused isolated mouse heart. AB - Recent reports have shown that adenosine A1 receptor-mediated cardioprotection requires concomitant A2 receptor activation, but no study thus far has shown that this phenomenon occurs using A1 agonists at reperfusion. Thus, we compared adenosine A2A receptor knockout (A2AKO) and wild-type mouse hearts (n = 9-11) subjected to global ischemia (30 minutes) and reperfusion (60 minutes) in the presence and absence of the A1 agonist N-cyclopentlyadenosine (CPA). We also determined the effects of selective antagonists at A2A and A2B receptors on CPA induced protection. In wild-type hearts, CPA (100 nM) significantly (P < 0.05) improved contractility (52.7 +/- 6.2% versus 23.9 +/- 4.9% of preischemia), left ventricular developed pressure, end diastolic pressure; reduced infarct size (7.9 +/- 1.7% versus 23.9 +/- 6.6% area at risk); decreased lactate dehydrogenase efflux; and increased ERK1/2 phosphorylation at 60 minutes of reperfusion. Adenosine A2A (ZM241385, 50 nM) and A2B (MRS1754, 100 nM) receptor antagonists abolished CPA-mediated cardioprotection in wild-type groups as did the A1 receptor antagonist DPCPX (P < 0.05). In A2AKO hearts, CPA did not improve functional parameters and protective signaling with the exception of end diastolic pressure. In this model, using a clinically relevant mode of pharmacologic intervention, pERK 1/2-dependent A1-mediated cardioprotection requires a cooperative activation of A2 receptors, presumably through endogenous adenosine. PMID- 20930593 TI - The first clinical pilot study of intravenous adrenomedullin administration in patients with acute myocardial infarction. AB - Adrenomedullin (AM) is a 52-amino-acid vasodilator peptide that was originally isolated from human pheochromocytoma. In the previous experimental study with rat ischemia/reperfusion model, AM reduced infarct size and inhibited myocyte apoptosis. AM also suppressed the production of oxygen-free radicals. The present study was designed to evaluate the feasibility of intravenous administration of AM in patients with acute myocardial infarction. We studied 10 patients with first acute myocardial infarction [male to female ratio: 9 to 1, age: 65 +/- 9 (mean +/- SD) years, peak creatine phosphokinase level: 4215 +/- 1933 (SD) U/L], who were hospitalized within 12 hours of symptom onset. Proceeding reperfusion therapy, AM infusion was initiated and continued at concentration of 0.0125-0.025 MUg.kg.min for 12 hours. Follow-up coronary angiography and left ventriculography were performed at 3 months. Cardiac magnetic resonance was examined at 1 month and 3 months after AM therapy. During infusion of AM, hemodynamics kept stable except 2 patients. Wall motion index in the infarct area at 3 months was significantly improved compared with that at baseline, and infarct size evaluated by cardiac magnetic resonance was significantly decreased at 3 months. In conclusion, intravenous administration of AM, which possesses a variety of potential cardiovascular protective actions, can be adjunctive to percutaneous coronary intervention. PMID- 20930591 TI - 20-hydroxyeicosatetraeonic acid: a new target for the treatment of hypertension. AB - Arachidonic acid is metabolized by enzymes of the CYP4A and 4F families to 20 hydroxyeicosatetraeonic acid (20-HETE), which plays an important role in the regulation of renal function, vascular tone, and the long-term control of arterial pressure. In the vasculature, 20-HETE is a potent vasoconstrictor, and upregulation of the production of this compound contributes to the elevation in oxidative stress and endothelial dysfunction and the increase in peripheral vascular resistance associated with some forms of hypertension. In kidney, 20 HETE inhibits Na transport in the proximal tubule and thick ascending loop of Henle, and deficiencies in the renal formation of 20-HETE contributes to sodium retention and development of some salt-sensitive forms of hypertension. 20-HETE also has renoprotective actions and opposes the effects of transforming growth factor beta to promote proteinuria and renal end organ damage in hypertension. Several new inhibitors of the synthesis of 20-HETE and 20-HETE agonists and antagonists have recently been developed. These compounds along with peroxisome proliferator-activated receptor-alpha agonists that induce the renal formation of 20-HETE seem to have promise as antihypertensive agents. This review summarizes the rationale for the development of drugs that target the 20-HETE pathway for the treatment of hypertension and associated cardiovascular complications. PMID- 20930594 TI - Increased cardiac risk in concomitant methadone and diazepam treatment: pharmacodynamic interactions in cardiac ion channels. AB - Methadone, a synthetic opioid for treatment of chronic pain and withdrawal from opioid dependence, has been linked to QT prolongation, potentially fatal torsades de pointes, and sudden cardiac death. Concomitant use of diazepam or other benzodiazepines in methadone maintenance treatment can increase the risk of sudden death. Therefore, we determined the effects of methadone and diazepam singly and in combination on cardiac action potentials (APs) and on the major ion channels responsible for cardiac repolarization. Using patch clamp recording in human stem cell-derived cardiomyocytes and stably transfected mammalian cells, we found that methadone produced concentration-dependent AP prolongation and ion channel block at low micromolar concentrations: hERG (IC50 = 1.7 MUM), hNav1.5 (11.2 MUM tonic block; 5.5 MUM phasic block), and hCav1.2 (26.7 MUM tonic block; 7.7 MUM phasic block). Methadone was less potent in hKv4.3/hKChIP2.2 (IC50 = 39.0 MUM) and hKvLQT1/hminK (53.3 MUM). In contrast, diazepam blocked channels only at much higher concentrations and had no effect on AP duration at 1 MUM. However, coadministration of 1-MUM diazepam with methadone caused a statistically significant increase in AP duration and a 4-fold attenuation of hNav1.5 block (IC50 values were 44.2 MUM and 26.6 MUM, respectively, for tonic and phasic block), with no significant effect on methadone-induced block of hERG, hCav1.2, hKv4.3/hKChIP2.2, and hKvLQT1/hminK channels. Thus, although diazepam alone does not prolong the QT interval, the relief of methadone-induced Na channel block may leave hERG K channel block uncompensated, thereby increasing cardiac risk. PMID- 20930595 TI - Inhibition of atherosclerotic lesion development in the ApoE-/- mouse by a novel beta-oxa polyunsaturated fatty acid. AB - Recent findings that a novel polyunsaturated fatty acid, beta-oxa 23:4n-6, inhibits adhesion molecule expression on vascular endothelial cells and leukocyte adhesion led us to examine its ability to inhibit the development of atherosclerosis in the apoE-deficient (apoE) mouse. The mice were kept on normal chow or a high-fat/high-cholesterol diet for various periods and treated with either vehicle or beta-oxa 23:4n-6 by the intraperitoneal route. The hearts and aortae were isolated and lesion development at the aortic root was determined. Morphometric assessment revealed that lesion development was a function of compensatory aortic enlargement, suggesting that measurement of plaque size per se is the appropriate assessment of lesion size. Using this criterion, we found that atherosclerosis development was reduced in response to beta-oxa 23:4n-6, plaque size by 74% and aortic cross-sectional area by 62%, under an optimized regime. The number of foam cells per unit tissue area in the lesions of beta-oxa 23:4n-6-treated mice was significantly reduced by 37.5%. The blood levels of beta oxa23:4n-6 in these mice exceeded the concentrations previously found to inhibit adhesion molecule expression in cultured endothelial cells. These data show that beta-oxa23:4n-6 protects against experimental atherosclerosis, most likely by reducing the number of infiltrating monocytes. PMID- 20930596 TI - Apparent desaturation on pulse oximetry because of hemoglobinopathy. AB - Hemoglobinopathies are an uncommon cause of cyanosis and low oxygen saturation on pulse oximetry. However, when they do occur, they can present a complex clinical scenario for the emergency physician. We report the index case of a previously undescribed hemoglobinopathy that presented to the pediatric emergency department. The evaluation and management of the cyanotic/hypoxic child and review of hemoglobinopathies are presented here. PMID- 20930597 TI - Multiple ecthyma gangrenosum in a healthy infant with community-acquired Pseudomonas aeruginosa sepsis. AB - We report the case of a previously healthy 8-month-old infant girl with Pseudomonas aeruginosa sepsis who presented to a pediatric emergency department with multiple ecthyma gangrenosum. Skin manifestations are uncommon in Pseudomonas infection. Ecthyma gangrenosum is a rare, distinct skin disorder associated with potentially fatal underlying Pseudomonas sepsis. Although typically occurring in immunocompromised or neutropenic patients, it can occasionally affect otherwise healthy children. This case demonstrates the critical importance of the pediatrician's identification of ecthyma gangrenosum to give directed antipseudomonal therapy. PMID- 20930598 TI - Respiratory alkalosis and metabolic acidosis in a child treated with sulthiame. AB - OBJECTIVES: To report on severe acid-base disturbance in a child with symptomatic epilepsy treated with sulthiame. RESULTS: A 9.5-year-old boy with chronic generalized tonic-clonic seizures was treated with carbamazepine and valproic acid. Because of poor seizure control, sulthiame was added to the treatment. Two months later, he presented at the emergency department with severe weakness, headache, dizziness, dyspnea, anorexia, and confusional state. Arterial blood gas analysis showed mixed respiratory alkalosis with high anion gap metabolic acidosis. Sulthiame-induced acid-base disturbance was suspected. The drug was withheld for the first 24 hours and then restarted at a reduced dosage. The arterial blood gases gradually normalized, the confusion disappeared, and the patient was discharged home.Three months later, 4 weeks after an increase in sulthiame dosage, the patient was once again admitted with the same clinical picture. Improvement was noted after the drug dosage was reduced. CONCLUSIONS: This is the first report of mixed respiratory alkalosis and metabolic acidosis in a child treated with sulthiame. Monitoring of the acid-base status should be considered in patients treated with sulthiame. PMID- 20930599 TI - Prolonged delirium after quetiapine overdose. AB - Quetiapine is an atypical antipsychotic agent increasingly used to treat schizophrenia and bipolar disorder in pediatric patients. Few published data exist concerning quetiapine's effects in therapeutic settings or short-term overdose in pediatric and adolescent populations. In this report, we describe a 15-year-old adolescent girl who experienced continued delirium 5 days after an overdose of quetiapine, trazodone, and clonidine. The patient initially presented with sedation and stable vital signs. After 3 days of gradual improvement, she experienced episodes of delirium coinciding with an increase in resting heart rate. On the basis of suspicion for quetiapine-associated antimuscarinic effects, the patient was administered intravenously with physostigmine on the fifth day after ingestion. Treatment resulted in a brief resolution of symptoms. Serum quetiapine levels measured 1 day and 5 days after ingestion were 3400 and 4800 ng/mL, respectively. The use of physostigmine and interpretation of serum levels are discussed further. PMID- 20930601 TI - Haemophilus influenzae type B meningitis in a previously healthy child. AB - Vaccines have proven successful in virtually eradicating certain infectious diseases that typically attack the pediatric population. Since 1988, when the conjugate vaccine was introduced, the incidence of invasive Haemophilus influenzae type B disease was reduced dramatically. However, immunization rates have decreased in certain parts of the country because of a combination of vaccine shortage and widespread parental perception that vaccines are harmful. We present the case of a previous healthy child, who ultimately succumbed to H. influenzae type B meningitis where multiple factors were likely responsible for his acquisition of the disease. PMID- 20930600 TI - An uncommon late complication of appendicitis. AB - A 10-year-old boy presented with a 2.5-week history of right leg pain and limp. A right flank mass was noted by a parent on the day of presentation. The child's past medical history was remarkable for perforated appendicitis treated with an interval laparoscopic appendectomy 2 years before this presentation. Abdominal and pelvic computed tomography revealed a retroperitoneal mass with calcifications, suggestive of a retained appendicolith with abscess formation. This case illustrates the importance of considering very late complications of appendicitis in patients presenting with fever and abdominal or flank pain or masses. PMID- 20930602 TI - Facial nerve palsy: etiology and approach to diagnosis and treatment. AB - Facial nerve palsy has a broad differential diagnosis and possible psychological and anatomical consequences. A thorough investigation must be performed to determine the cause of the palsy and to direct treatment. If no cause can be found, therapy with prednisone with or without an antiviral medication can be considered and begun as early as possible after onset of symptoms. Resolution and time to recovery vary with etiology, but overall prognosis is good. PMID- 20930605 TI - Pediatric emergency medicine: legal briefs. PMID- 20930606 TI - ECGs in the ED. PMID- 20930604 TI - Priorities for pediatric prehospital research. AB - Up to 3 million US children are cared for by emergency medical services (EMSs) annually. Limited research exists on pediatric prehospital care. The Pediatric Emergency Care Applied Research Network (PECARN) mission is to perform high quality research for children, including prehospital research. Our objective was to develop a pediatric-specific prehospital research agenda. METHODS: Representatives from all 4 PECARN nodes and from EMS agency partners participated in a 3-step process. First, participants ranked potential research priorities and suggested others. Second, participants reranked the list in order of importance and scored each priority using a modified Hanlon method (prevalence, seriousness, and practicality of each research area were assessed). Finally, the revised priority list was presented at a PECARN EMS summit, and consensus was sought. RESULTS: Forty-two representatives participated, including PECARN representatives, EMS agency leaders, and nationally recognized prehospital researchers. Consensus was reached on the priority ranking. The prioritization processes resulted in 2 ranked lists: 15 clinical topics and 5 EMS system topics. The top 10 clinical priorities included (1) airway management, (2) respiratory distress, (3) trauma, (4) asthma, (5) head trauma, (6) shock, (7) pain, (8) seizures, (9) respiratory arrest, and (10) C-spine immobilization. The 5 EMS system topics identify methods to improve prehospital care on the system level. CONCLUSIONS: PECARN has identified high-priority EMS research topics for children using a consensus-derived method. These research priorities include novel EMS system topics. The PECARN EMS pediatric research priority list will help focus future pediatric prehospital research both within and outside the network. PMID- 20930607 TI - Cervical neurofibroma in a child without neurofibromatosis. PMID- 20930608 TI - Birth of a new publication in pediatric emergency medicine. PMID- 20930609 TI - Transverse fracture of the distal femoral metadiaphysis. PMID- 20930611 TI - Effect of anesthetic technique on serum vascular endothelial growth factor C and transforming growth factor beta in women undergoing anesthesia and surgery for breast cancer. AB - BACKGROUND: In breast cancer, vascular endothelial growth factor C, transforming growth factor beta, placental growth factor, and fibroblast growth factor (acidic and basic) promote angiogenesis and metastases. We tested the hypothesis that a propofol-paravertebral anesthetic (PPA) technique would attenuate postoperative changes in these angiogenic factors to a greater extent than balanced general anesthesia (GA) and morphine analgesia in women undergoing surgery for primary breast cancer. METHOD: Forty women with primary breast cancer undergoing surgical excision were randomized to receive either standard GA or PPA technique. Venous blood was sampled before and at 24 h after surgery and serum analyzed. The primary endpoint was a preoperative versus postoperative change in vascular endothelial growth factor C and transforming growth factor beta concentrations. RESULTS: Using a visual analog scale (median [25-75% interquartile range]), PPA patients (1 [0-2]) had less pain at 2 h (P = 0.02) than did GA patients (3 [2 5]). The mean postoperative change in vascular endothelial growth factor C concentrations among GA patients was 733 versus 27 pg/ml for PPA patients (difference, 706 [97.5% CI, 280-1,130] pg/ml, P = 0.001). In contrast, the mean postoperative change in transforming growth factor beta concentration among GA patients was -163 versus 146 pg/ml for PPA patients (difference, 309 [97.5% CI, 474 to -143] pg/ml, P = 0.005). Concentrations of placental growth factor and fibroblast growth factor, both acidic and basic, were undetectable in serum. CONCLUSION: Anesthetic technique influences serum concentrations of factors associated with angiogenesis in primary breast cancer surgery. PMID- 20930612 TI - Intrathecal injection of hepatocyte growth factor gene-modified marrow stromal cells attenuates neurologic injury induced by transient spinal cord ischemia in rabbits. AB - BACKGROUND: Our previous studies showed that transfer of hepatocyte growth factor (HGF) gene or transplantation of marrow stromal cells (MSCs) remarkably attenuated neurologic injuries after spinal cord ischemia. We sought to investigate a novel neuroprotective strategy of transplantation of human HGF gene modified MSCs on ischemic spinal cords. METHODS: Human HGF gene was transferred into MSCs in vitro. The HGF gene-modified MSCs were transplanted by means of intrathecal injection. Two days later, spinal cord ischemia was induced by occlusion of the infrarenal aorta with a balloon catheter for 40 or 50 min. Hind limb motor function was assessed during a 14-day recovery period with Tarlov criteria, and then histologic examination was performed. RESULTS: Human HGF was detected in the cerebrospinal fluid from 2 to 16 days after transplantation of HGF gene-modified MSCs. Compared with the controls, transplantation of HGF gene modified MSCs or MSCs alone significantly improved the Tarlov scores 1, 2, 7, and 14 days after spinal cord ischemia of 40 or 50 min (P < 0.01, respectively) and increased the number of intact motor neurons in the lumbar spinal cord (P < 0.01, respectively). When the ischemic period was extended to 50 min, the Tarlov scores and the number of intact motor neurons of rabbits transplanted with HGF gene modified MSCs were markedly higher than those of the rabbits transplanted with MSCs only (P < 0.05, respectively). CONCLUSIONS: Transplantation of HGF gene modified MSCs induces powerful neuroprotection on spinal cords against ischemia reperfusion injury and is more therapeutically efficient than transplantation of MSCs only. PMID- 20930613 TI - Hydroxyethyl starch 6% (130/0.4) ameliorates acute lung injury in swine hemorrhagic shock. AB - BACKGROUND: Traumatic hemorrhage induces acute lung injury. The aim of this study was to assess whether lactated Ringer's solution or 6% hydroxyethyl starch 130/0.4 would have different effects on acute lung injury following hemorrhagic shock. METHODS: Twenty healthy pigs (19 +/- 2 kg) were subjected to hemorrhage and were randomly allocated to two groups: Group A (10 pigs) who received lactated Ringer's solution and Group B (10 pigs) who received hydroxyethyl starch 130/0.4. Hemodynamic response and serum lactate were measured at predetermined phases. Four hours after fluid resuscitation animals were euthanized. Lungs were harvested, and tissue samples were collected. Focal thickening of the alveolar membranes, vascular congestion, number of activated neutrophils, alveolar edema, interstitial neutrophil infiltration, intraalveolar infiltration, and alveolar hemorrhage were assessed. Each feature was given a score from 0 to 3 (0 = absence, 3 = severe). The wet/dry ratio was also calculated, and with the use of Evans blue dye extravasation method, capillary permeability was assessed. RESULTS: The total histology score of Group A differed significantly from that of Group B, being significantly lower in Group B animals P = 0.048. The wet/dry weight ratio was significantly higher in the lactated Ringer's group (median [range]) (Group A, 5.1 [0.5]; Group B, 4.9 [0.3]; P = 0.009). The Evans blue dye extravasation method was utilized to study the lung capillary permeability. The animals in Group B showed a marked reduction in microvascular capillary permeability compared with the animals in Group A (Group A, 58.5 [21] mg/g; Group B, 51.5 [14] mg/g; P = 0.017). CONCLUSIONS: Our study indicates that resuscitation after hemorrhagic shock with hydroxyethyl starch 130/0.4 led to less lung edema and less microvascular permeability in this swine model. PMID- 20930614 TI - A robust immunohistochemical assay for detecting PTEN expression in human tumors. AB - Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a negative regulator of the phosphoinositol-3-kinase (PI3K)/AKT signaling pathway that controls cell cycle progression, growth and inhibition of apoptosis. Loss of PTEN protein expression has been associated with tumorigenesis, cancer progression and drug resistance, but conflicting results exist which may be due in part to difficulties inherent in PTEN immunohistochemistry (IHC). We sought a robust PTEN IHC assay. Human tumor cell lines with PTEN status verified by copy number analysis were formalin fixed and paraffin embedded for use as positive and negative controls. PTEN antibodies were optimized on tumor cell lines. Five optimized antibodies were analyzed on 10 molecularly characterized endometrial carcinoma samples. Four antibodies (CST, Millipore, Abcam, Novus) stained 3/10 positive and 7/10 negative, however, all but CST exhibited nonspecific nucleolar staining of negative controls. One antibody (Dako) stained 5/10 positive and 5/10 negative but with areas (<=10%) of positivity. The 4 samples predicted to be negative by sequencing were negative with the CST antibody, however, one was positive with Dako; as a result we chose the CST antibody for our assay. The assay was validated on an automated platform using 50 formalin fixed and paraffin embedded colon, lung, prostate and breast adenocarcinoma cases. Tumor cell lines served as external controls; endothelial cells and peripheral nerves served as internal positive controls. Dichotomous scoring achieved 100% concordance between three independent pathologists. This reproducible PTEN assay (PREZEON) has been implemented in a CLIA certified laboratory. PMID- 20930615 TI - Immunohistochemistry of breast tumor markers on archived bouin-fixed paraffin embedded tissues. AB - Neutral-buffered formalin is the most commonly used tissue fixative in pathology laboratory. Among other fixatives, Bouin's solution has been used in several laboratories and is still in use for particular tissues. In this project, we determine if we can study breast clinical markers on archived Bouin-fixed tissue samples with immunohistochemistry (IHC) protocols optimized for tissue fixed in neutral-buffered formalin. To evaluate the concordance of IHC results between formalin-fixed and Bouin-fixed tissues, we calculated the concordance percentage and the kappa statistic of 12 clinical IHC markers quantified by an automated system on breast cancer tissues fixed in neutral-buffered formalin and their corresponding tissues fixed in Bouin's solution. When positivity threshold of immunostaining was setup at >=10% for both fixation conditions, we observed a concordance percentage of 83.9% (kappa=0.65). However, when positivity threshold of immunostaining was lowered to 3% to 4% for Bouin-fixed tissues, concordance percentage was then of 96.8% (kappa=0.92). Our data demonstrate that we can study IHC markers on archived Bouin-fixed tissue from patients with long clinical follow-up using IHC protocols optimized for formalin-fixed tissues after an adjustment of the positivity threshold of immunostaining quantified by an automated system. PMID- 20930616 TI - HER2 testing in breast carcinoma: very low concordance rate between reference and local laboratories in Brazil. AB - Breast cancer accounts for approximately one quarter of all cancers in females. HER2 gene amplification or HER2 protein overexpression, detected in about 20% of breast carcinomas, predicts a more aggressive clinical course and determines eligibility for targeted therapy with trastuzumab. HER2 testing has become an essential part of the clinical evaluation of all breast carcinoma patients, and accurate HER2 results are critical in identifying patients who may be benefited from targeted therapy. This study investigated the concordance in the results of HER2 immunohistochemistry assays performed in 500 invasive breast carcinomas between a reference laboratory and 149 local laboratories from all geographic regions of Brazil. Our results showed an overall poor concordance (171 of 500 cases, 34.2%) regarding HER2 results between local and reference laboratories, which may be related to the low-volume load of HER2 assays, inexperience with HER2 scoring system, and/or technical issues related to immunohistochemistry in local laboratories. Standardization of HER2 testing with rigorous quality control measures by local laboratories is highly recommended to avoid erroneous treatment of breast cancer patients. PMID- 20930617 TI - Increased urothelial cell detection in the primary bladder smooth muscle cell cultures with dual MACS/qRT-PCR approach. AB - Bladder tissue has been regenerated in humans with neurogenic bladder using an implant produced from autologous urothelial (UC) and smooth muscle cells (SMC) expanded from bladder biopsies seeded onto a biodegradable synthetic scaffold. As the majority of bladder cancers are urothelial carcinomas (aka, transitional cell carcinoma), this 2-cell type autologous sourcing strategy presents significant challenges to product development. Entire bladders have been regenerated in cystectomized animals using a single-cell-type sourcing strategy: implants were seeded with bladder-derived SMC-only. Applying the bladder SMC-only sourcing strategy to produce clinical implants for bladder replacement or urinary diversion in bladder cancer patients requires methods for screening SMC cultures for the presence of potentially cancerous UC cells to provide evidence of SMC culture purity before seeding the scaffold. In this report, we show a 10-fold to 100-fold improvement in the sensitivity of qualitative and quantitative reverse transcription PCR (qRT-PCR)-based assays for detecting UC positive for Cytokeratin 5 (CK5) in mixed SMC/UC cultures when the cell population was first subjected to magnetic activated cell sorting to enrich for cells expressing the epithelial cell adhesion molecule (known as EPCAM or CD326), a marker known to be present in normal UC and upregulated in the cancerous UC. PMID- 20930618 TI - Thrombogenic potential of Innovia polymer valves versus Carpentier-Edwards Perimount Magna aortic bioprosthetic valves. AB - Trileaflet polymeric prosthetic aortic valves (AVs) produce hemodynamic characteristics akin to the natural AV and may be most suitable for applications such as transcatheter implantation and mechanical circulatory support (MCS) devices. Their success has not yet been realized due to problems of calcification, durability, and thrombosis. We address the latter by comparing the platelet activation rates (PARs) of an improved polymer valve design (Innovia LLC) made from poly(styrene-block-isobutylene-block-styrene) (SIBS) with the commercially available Carpentier-Edwards Perimount Magna Aortic Bioprosthetic Valve. We used our modified prothrombinase platelet activity state (PAS) assay and flow cytometry methods to measure platelet activation of a pair of 19 mm valves mounted inside a pulsatile Berlin left ventricular assist device (LVAD). The PAR of the polymer valve measured with the PAS assay was fivefold lower than that of the tissue valve (p = 0.005) and fourfold lower with flow cytometry measurements (p = 0.007). In vitro hydrodynamic tests showed clinically similar performance of the Innovia and Magna valves. These results demonstrate a significant improvement in thrombogenic performance of the polymer valve compared with our previous study of the former valve design and encourage further development of SIBS for use in heart valve prostheses. PMID- 20930619 TI - Monitoring of brain function in anesthesia and intensive care. AB - PURPOSE OF REVIEW: Despite its obvious importance, the brain is inconsistently the focus of monitoring in anesthesia and intensive care settings. However, there are multiple modalities available to address cerebral monitoring that when acted upon, may improve perioperative outcomes. This review addresses the various brain monitoring options that can be integrated in anesthetic and intensive care practice in order to optimize perioperative outcomes. RECENT FINDINGS: Although numerous monitoring modalities are available, the level of evidence supporting each application is somewhat limited with few of the available monitors having been subjected to large-scale randomized trials. Despite this, they each may have a potential role to play in providing information that can be integrated to optimize care. SUMMARY: Using a comprehensive cerebral monitoring strategy may optimize outcomes in anesthetic and intensive care. PMID- 20930620 TI - Is it time to re-evaluate the routines about stopping/keeping platelet inhibitors in conjunction to ambulatory surgery? AB - PURPOSE OF REVIEW: To assess the influence of antiplatelet drugs (APDs) in outpatients' perioperative care and to propose up-to-date management of those patients. RECENT FINDINGS: Evidence is spreading on the risk of adverse cardiovascular events (ACEs) when APD therapy is discontinued, specifically in patients with coronary stents. Conversely, maintaining such treatments throughout the operative period appears usually safe. Bridging with low-molecular-weight heparins poorly protects against ACEs. In outpatients, major surgical bleeding is rare, but sometimes a minor hemorrhage may jeopardize the success of a surgical procedure. Despite the paucity of properly sized randomized trials in this setting, recommendations have been issued by scientific societies and can be used as guidelines. Variability in APD efficiency is now better appraised, and research on versatile bedside testing of platelet function is active. New drugs are expected to be launched in the near future, all this aiming at improving individualized drug dosage and therefore both safety and efficiency of APD therapies. SUMMARY: In surgical patients APD therapy should be maintained in all situations in which the risk of surgical bleeding is low, which is usually the case in the ambulatory setting. In clearly identified cases in which bleeding might threaten either the patient's life or the success of the surgical procedure in patients at high risk of ACE, the discontinuation protocol must be established in conjunction with the cardiologist and the APD therapy resumed as soon as possible. Bridging with low-molecular-weight heparins is not recommended. PMID- 20930621 TI - Anaesthesia for the elderly outpatient: preoperative assessment and evaluation, anaesthetic technique and postoperative pain management. AB - PURPOSE OF REVIEW: Epidemiological data show a continuous expansion of elderly population, associated with an increased demand for surgical treatments by older patients. Geriatric anaesthesia is emerging as a new subspecialty. Outpatient anaesthesia for elderly patients requires greater specific knowledge and skills. Given the high economic and social pressure, anaesthetists will be requested to treat an increasing number of elderly as outpatients. RECENT FINDINGS: Functional status as a criterion for preoperative assessment of older patients has been introduced in the last years. In comparison to inpatient, outpatient setting seems to reduce the risk of postoperative cognitive disorders after surgery. Heart failure has shown to be an important risk factor of perioperative complication and death in the elderly; when more than mild, it contraindicates day surgery. Drug-eluting stents, which require a double antiaggregative therapy for 12 months after positioning, formally exclude patients from day surgery for that period. Sedation as a part of Monitored Anaesthesia Care (MAC) has shown to be potentially dangerous, due to increased risk of hypoxic complications and increased likelihood of cognitive disturbances. Effective postoperative pain treatment after geriatric day surgery requires careful pain assessment and drug titration. In the future, the development of telematic communication systems will extend indications. SUMMARY: Recent findings contribute to a better comprehension of the most important specificities of elderly patients undergoing day surgery and provide basic elements for a safe perioperative management in the outpatient setting. PMID- 20930622 TI - Patient safety during anaesthesia: incorporation of the WHO safe surgery guidelines into clinical practice. AB - PURPOSE OF REVIEW: WHO makes clear recommendations on how to improve patient safety during surgical procedures by using the WHO Surgical Safety Checklist. We will review the scientific basis of these recommendations and the practical problems encountered during introduction. RECENT FINDINGS: Perioperative severe complications and death are a major health issue in both developed and developing countries. Nearly half of these complications can be avoided. The systematic use of checklists and structured preprocedural and postprocedural briefings like a time-out procedure reduces perioperative morbidity and mortality. A broader use of checklists to cover the whole surgical pathway gives additional benefit, further reducing perioperative morbidity and mortality.Introducing patient safety procedures can be met with some resistance from healthcare workers and is helped by an organization-wide safety policy and a systematic approach. SUMMARY: There is sufficient scientific evidence to make the use of checklists and structured perioperative briefings and debriefings mandatory for the broad spectrum of operative procedures. PMID- 20930623 TI - Conflicts and communication gaps in the intensive care unit. AB - PURPOSE OF REVIEW: Conflicts occur frequently in the ICU. Research on ICU conflicts is an emerging field, with only few recent studies being available on intrateam and team-family conflicts. Research on communication in the ICU is developing at a faster pace. RECENT FINDINGS: Recent findings come from one multinational epidemiological survey on intrateam conflicts and one qualitative study on the causes and consequences of conflicts. Advances in research on communication with families in the ICU have improved our understanding of team family and intrateam conflicts, thus suggesting targets for improvement. SUMMARY: Data about ICU conflicts depend on conflict definition, study designs (qualitative versus quantitative), patient case-mix, and detection bias. Conflicts perceived by caregivers are frequent and consist mainly in intrateam conflicts. The two main sources of conflicts in the ICU are end-of-life decisions and communication issues. Conflicts negatively impact patient safety, patient/family-centered care, and team welfare and cohesion. They generate staff burnout and increase healthcare costs. Further qualitative studies rooted in social-science theories about workplace conflicts are needed to better understand the typology of ICU conflicts (sources and consequences) and to address complex ICU conflicts that involve systems as opposed to people. Conflict prevention and resolution are complex issues requiring multimodal interventions. Clinical research in this field is insufficiently developed, and no guidelines are available so far. Prevention strategies need to be developed along two axes: improved understanding of family experience, preferences, and values, as well as evidence-based communication may reduce team-family conflicts and organizational measures including restoring leadership, multidisciplinary teamwork, and improved communication within the team may prevent intrateam conflicts in the ICU. PMID- 20930624 TI - Critical incident monitoring in paediatric and adult critical care: from reporting to improved patient outcomes? AB - PURPOSE OF REVIEW: Critical incident reporting alone does not necessarily improve patient safety or even patient outcomes. Substantial improvement has been made by focusing on the further two steps of critical incident monitoring, that is, the analysis of critical incidents and implementation of system changes. The system approach to patient safety had an impact on the view about the patient's role in safety. This review aims to analyse recent advances in the technique of reporting, the analysis of reported incidents, and the implementation of actual system improvements. It also explores how families should be approached about safety issues. RECENT FINDINGS: It is essential to make as many critical incidents as possible known to the intensive care team. Several factors have been shown to increase the reporting rate: anonymity, regular feedback about the errors reported, and the existence of a safety climate. Risk scoring of critical incident reports and root cause analysis may help in the analysis of incidents. Research suggests that patients can be successfully involved in safety. SUMMARY: A persisting high number of reported incidents is anticipated and regarded as continuing good safety culture. However, only the implementation of system changes, based on incident reports, and also involving the expertise of patients and their families, has the potential to improve patient outcome. Hard outcome criteria, such as standardized mortality ratio, have not yet been shown to improve as a result of critical incident monitoring. PMID- 20930625 TI - Management of pelvic fractures. AB - PURPOSE OF REVIEW: The management of patients with pelvic fractures can be demanding. Severe pelvic fractures pose a great challenge for physicians and can greatly contribute to significant patient morbidity and mortality. The purpose of this review is to highlight recent, positive changes in the management of patients with pelvic fractures. RECENT FINDINGS: The current status of pelvic fracture management is presented, including a recently proposed algorithm for management, an evaluation of roles of angioembolization and preperitoneal packing. Additionally, the approach of bilateral internal iliac artery ligation as a salvage procedure is reviewed, and the outcome of acute (<24 h) pelvic fracture operative fixation. Regardless of the strategy adopted, a multidisciplinary approach is required for the proper management of hemodynamically unstable patients with pelvic fractures. SUMMARY: The key elements in managing patients with pelvic fractures are swift and adequate resuscitation, reversal of shock and acidosis, and rapid control of hemorrhage to facilitate survival of these patients. Multimodality therapies including external pelvic stabilization, angioembolization and preperitoneal pelvic packing are useful adjuncts that require appropriately trained and immediately available personnel. A multidisciplinary approach has been shown to be beneficial for patient outcomes. PMID- 20930626 TI - Kidney injury molecule-1. AB - PURPOSE OF REVIEW: To review the new findings about the physiological roles of kidney injury molecule-1 (KIM-1) and the rapidly expanding evidence for this molecule as a promising biomarker in preclinical kidney toxicity evaluation and various human kidney diseases. RECENT FINDINGS: KIM-1 has attracted increasing interest because of its possible pathophysiological role in modulating tubular damage and repair. There is rapidly accumulating evidence from both animal models and clinical studies that urinary KIM-1 is a sensitive and specific urinary biomarker for various forms of nephrotoxic injury, cardiac surgery-induced kidney injury, transplant rejection, and chronic kidney diseases. SUMMARY: KIM-1 mediates epithelial phagocytosis in the injured kidney converting the proximal epithelial cell into a phagocyte, with potentially important pathophysiological implications for modulation of the immune response and repair process after injury. KIM-1 serves as a highly sensitive and specific urinary biomarker for kidney injury and may also be a therapeutic target for various kidney diseases. PMID- 20930627 TI - Urinary glutathione S-transferases in the pathogenesis and diagnostic evaluation of acute kidney injury following cardiac surgery: a critical review. AB - PURPOSE OF REVIEW: A focused review of the nature, source, physiological role and rapidly expanding evidence for glutathione S-transferase (GST) subtypes pi and alpha as biomarkers of acute kidney injury (AKI) in patients undergoing cardiac surgery. Expanded insights into the site-specific expression of the GSTs in defined parts of the nephron during renal damage are presented, with particular emphasis on the pathogenesis of cardiac surgery and cardiopulmonary bypass (CPB) associated AKI and the role of GSTs in oxygen radical disposal. RECENT FINDINGS: Recent developments have highlighted a potential role of urinary alpha-GST and pi GST in the diagnostic evaluation of cardiac surgery-associated AKI. Both urinary alpha-GST and pi-GST are detected in the postoperative period. pi-GST performed best at predicting AKI severity at the time of the initial diagnosis of AKI. alpha-GST was able to predict the future development of both stage 1 and stage 3 AKI. SUMMARY: The current data from a small number of patients suggest a potential role of urinary GSTs in the clinical diagnostic evaluation of AKI following cardiac surgery. The performance of the GSTs for the early diagnosis of AKI needs to be validated in larger multicentre studies and in other patient populations at increased risk of AKI (e.g. patients with acute transplant rejection, septic patients). Comparison with other emerging AKI biomarkers is required to continue the development of pi-GST and alpha-GST. Finally, additional studies examining the pathophysiological role of the GSTs in minimizing oxygen free radical exposure in the renal tubules during CPB may shed further light into their role as promising biomarkers of cardiac surgery-associated AKI. PMID- 20930628 TI - Indoleamine 2,3-dioxygenase and immune tolerance in ovarian cancer. AB - PURPOSE OF REVIEW: Ovarian cancer is the leading cause of cancer death among gynecologic malignancies despite significant advances in cytoreductive surgery and chemotherapy, and novel therapeutic approaches are urgently needed. Immunotherapy is one of these strategies; however, its clinical applications have shown limited efficacy. This may be attributed to tumor-induced immune tolerance, and much attention has been paid to overcoming these immune resistance mechanisms. This review focuses on the immunoregulatory enzyme indoleamine 2,3 dioxygenase (IDO) and shows the role of IDO and its clinical potential in ovarian cancer. RECENT FINDINGS: IDO suppresses the proliferation of effector T cells or natural killer cells and their killer functions. In ovarian cancer, high IDO expression in tumor cells was correlated with a reduced number of tumor infiltrating lymphocytes. The IDO expression was also correlated with advanced surgical stage and impaired survival. Preclinical studies in mice demonstrated that oral administration of IDO inhibitors suppressed peritoneal dissemination and potentiated the antitumor efficacy of chemotherapeutic agents. SUMMARY: IDO induces immune tolerance and promotes ovarian cancer progression. Tumoral IDO expression is correlated with impaired clinical outcome. IDO inhibition may therefore be a promising strategy to restore host antitumor immunity and to enhance the antitumor potential of current chemotherapy or immunotherapy for advanced ovarian cancer. PMID- 20930629 TI - Pregnancy and spinal problems. AB - PURPOSE OF REVIEW: To review recent publications in spinal problems during pregnancy, diagnosis, and management. RECENT FINDINGS: Pregnancy-related low back pain (LBP) is the most common problem which can occur during pregnancy. Among the various factors of pregnancy-related LBP, previous LBP and LBP during menstruation seem to be significant risk factors of pregnancy-related LBP. Patient counseling and wearing of a nonelastic pelvic belt are effective for the control of pelvic girdle pain. Lumbar pain can be treated with exercise such as water gymnastics during the second and third trimesters. Although rare, pregnancy can cause osteoporotic compression fractures and symptoms in spinal tumors, especially in vertebral hemangiomas. Lumbar disc herniation is the most common spinal disorder during pregnancy and can cause permanent neurologic deficit in pregnant women. Most cases can be treated by conservative management, but operation can also be safely performed maintaining a healthy pregnancy. SUMMARY: Recent concern about spinal problems in pregnancy is still pregnancy-related LBP. The further studies about its prevalence, risk factors, and treatment will be expected to continue. In both general spinal diseases and pregnancy-induced spinal diseases, there is no significant difference in treatment between pregnant women and ordinary people. Therefore, if consideration of possible spinal problems, exact diagnosis and adequate treatment are performed, good prognosis may be enough achieved in pregnant women. PMID- 20930630 TI - Obstetric outcome after early placental complications. AB - PURPOSE OF REVIEW: To evaluate the impact of early pregnancy complications involving placentation and early placental development on adverse obstetric outcome in ongoing and subsequent pregnancies. RECENT FINDINGS: We found an increased risk of adverse outcome (odds ratio >2.0) in ongoing pregnancies of preterm delivery (PTD), very preterm delivery (VPTD), placental abruption, small for gestational age (SGA), low birth weight (LBW) and very LBW (VLBW) after a threatened miscarriage episode; pregnancy-induced hypertension, preeclampsia, placental abruption, PTD, SGA and low 5-min Apgar score following the detection of an intrauterine haematoma; and VPTD, VLBW and perinatal death after a vanishing twin phenomenon. In subsequent pregnancies, the risk of perinatal death was increased (odds ratio >2.0) after a single miscarriage, the risk of VPTD after two or more miscarriages, the risk of placenta previa, premature preterm rupture of membranes, PTD, VPTD and LBW after recurrent miscarriage and the risk of VPTD after two or more terminations of pregnancy. SUMMARY: Our analysis of the literature review indicates a link between early pregnancy complications involving the placenta and subsequent adverse obstetric and perinatal outcomes. Some of these associations are based on limited or small uncontrolled studies. Larger population-based prospective controlled studies have recently been published confirming most of these findings. This suggests that the early detection of these risk factors could improve the screening of women at high risk of specific obstetric complications in ongoing and subsequent pregnancies. PMID- 20930631 TI - Improving research, policy and practice to promote paternal involvement in pregnancy outcomes: the roles of obstetricians-gynecologists. AB - PURPOSE OF REVIEW: To review current research, policy, and practice on paternal involvement in pregnancy outcomes and suggest recommendations to improve paternal involvement in pregnancy and childbirth. RECENT FINDINGS: Although much has been written about fathers' influence on child health and development, little is known about the expectant father's role in pregnancy and childbirth. Recent studies have demonstrated the importance of paternal involvement during pregnancy, but more research is needed to identify specific contributions expectant fathers make and their impact on reducing infant mortality and associated risk factors during pregnancy and childbirth. SUMMARY: Obstetricians-gynecologists can play a greater role in promoting research, policy and practice to improve paternal involvement in pregnancy and childbirth. PMID- 20930632 TI - Contemporary management of migrainous disorders in pregnancy. AB - PURPOSE OF REVIEW: Migraine is a frequent event among women of reproductive age. It is difficult to predict the course and severity of disease that migraineurs will endure during pregnancy. Treatment is often compromised during pregnancy because of concerns regarding pharmacotherapy and fetal well being. RECENT FINDINGS: The majority of women with migraine during pregnancy will not require ongoing pharmacotherapy or prophylaxis. Nonpharmacologic strategies should be the first-line treatment of migraines. For severe migraines, recent cohort studies documenting the use of triptans for treatment during pregnancy have shown no increase in adverse pregnancy and fetal outcomes above the average rate. High dose valproate is the only antiepileptic drug available for migraine prophylaxis that has been shown to cause long-term cognitive effects in infants exposed during gestation. Congenital syndromes have been described for most of the older antiepileptic drugs but less so for many of the newer drugs. These newer medications appear to have improved safety profiles for use in pregnancy but there is still information lacking from larger patient cohorts and longitudinal studies of neurodevelopmental outcomes. There is also evidence to support use of beta-blockers and calcium-channel blockers for migraine prevention during pregnancy. SUMMARY: For those patients who develop debilitating migraine or whose migraines interfere with activities of daily living, there are several options for treatment and headache prevention that have a low likelihood of compromising fetal well being. PMID- 20930633 TI - A review of obstetric anesthesia in the new millennium: where we are and where is it heading? AB - PURPOSE OF REVIEW: The present article is an update on the state-of-the-art practice of obstetric anesthesia in the new millennium. It explores a number of important issues in this relatively new and still evolving subspecialty of anesthesiology. RECENT FINDINGS: Obstetric anesthesia is a subspecialty of anesthesiology dedicated to peripartum, perioperative pain and anesthetic management of women during pregnancy and the puerperium. In the new millennium an obstetric anesthesiologist has become an essential member of the peripartum care team, who closely works with the obstetrician, perinatologist, midwife, neonatologist, and labor and delivery nurse to ensure the highest quality care for the pregnant woman and her child. SUMMARY: Changes in maternal-fetal and neonatal medicine and obstetric anesthesia have been developing rapidly during the recent years and will continue to do so in the years to come. Obstetric anesthesia is art and science combined. An obstetric anesthesiologist is concerned simultaneously with the lives of at least two patients - the mother and her child. Exchange of information and communication skills in the ever changing environment of labor and delivery is essential for perfect outcome, which is always expected when providing passage for the mother and her baby from the antepartum to postpartum period. PMID- 20930634 TI - State of the art on the research for biomarkers allowing individual, tailor-made minimization of immunosuppression. AB - PURPOSE OF REVIEW: In order to avoid toxic side effects by long-term immunosuppressive treatment, transplant research therefore focuses on new strategies to either induce tolerance or allow partial or complete immunosuppressive weaning whenever possible. This can be only safely achieved when guided by biomarkers reflecting the individual immune reactivity. Here we summarize the recent efforts to identify biomarkers and functional assays which allow an individualized minimization or complete weaning of immunosuppression in stable or 'operational' tolerant transplant patients, respectively. RECENT FINDINGS: Data obtained by two main collaborative networks, 'RISET' and 'Immune Tolerance Network' have provided a better characterization of operational tolerant kidney patients. In both studies an increased numbers of B cells and a B cell-associated peripheral gene signature were discovered. Long-term observation of tolerant liver transplant patients undergoing immunosuppressive minimization highlight the importance of surveillance or protocol biopsies. Additionally, functional assays such as IFN-gamma ELISPOT or urine markers have been shown to predict long-term graft outcome. SUMMARY: With the recent findings we have gained a better understanding of operational tolerant patients and have identified biomarkers and assays which will be very helpful when guiding partial or complete immunosuppressive minimization. For the future, collaborative efforts are needed to design and perform prospective multicenter trials to validate the identified biomarkers across different laboratories and laboratory platforms. PMID- 20930635 TI - Cell therapy approaches aiming at minimization of immunosuppression in solid organ transplantation. AB - PURPOSE OF REVIEW: Cell transplantation or administration of cellular products has escaped preclinical experimental status and will be integrated as a substantial component of future individualized treatment modalities for a broad scope of medical fields, including transplantation tolerance, cancer immunotherapies and auto-immune diseases. RECENT FINDINGS: Renal allograft tolerance has been successfully demonstrated using bone marrow transplantation with nonmyeloablative conditioning to induce transient hematopoietic chimerism, hereby exemplifying the immunomodulatory potential of living cells to reprogram an existing immune system to recognize and accept nonself major histocompatibility antigens expressed on the allogeneic donor organ. Strong efforts are currently undertaken to circumvent the necessity of hematopoietic chimerism induction by harnessing peripheral regulatory mechanisms. Potential candidate cell populations that bear immunomodulating and regulatory properties comprise regulatory T cells, dendritic cells and deactivated macrophages as well as stem cells of various origins, currently tested in different clinical transplantation tolerance trials. SUMMARY: Although transplantation tolerance is still on its way to be reliably accomplished in clinical settings, use of well specified and functionally characterized cellular therapeutics with regulatory properties is now entering the field of personalized medicine for transplanted patients to benefit from minimization protocols and less severe side affects related to conventional immunosuppressive drug treatment. PMID- 20930636 TI - Carbapenem-resistant Enterobacteriaceae and Acinetobacter baumannii: assessing their impact on organ transplantation. AB - PURPOSE OF REVIEW: This review highlights the impact of carbapenem-resistant Enterobacteriaceae and carbapenem-resistant Acinetobacter baumannii on patients who have undergone organ transplantation and explores both available and potential agents to treat infections caused by these multidrug-resistant (MDR) pathogens. RECENT FINDINGS: Few antimicrobials exist to treat carbapenem resistant Gram-negative infections, and resistance to salvage therapies is escalating. Organ transplantation appears to be a risk factor for infections with Klebsiella pneumoniae carbapenemase-producing Enterobacteriaceae. Isolation of these MDR bacteria is increasing and may be associated with allograft failure and mortality. In the majority of cases, aminoglycosides, polymyxins, and tigecycline have been employed to treat these infections. Anecdotal successes exist but these antibiotics may be unreliable. Few novel agents are in development. SUMMARY: Bacterial infections remain a leading cause of posttransplantation morbidity and mortality. Carbapenem resistance is a significant threat to allograft and patient survival. With few antimicrobials being developed, transplant centers may be forced to make decisions regarding surveillance, empiric antimicrobial regimens, and transplant candidacy in the setting of carriage of MDR pathogens. There is an urgent need for collaborative studies to address the clinical impact of these infections on transplantation. PMID- 20930637 TI - Targeting B cells in sensitized kidney transplant patients: state of the art and future perspectives. AB - PURPOSE OF REVIEW: In sensitized kidney transplant recipients, whose number is continuously growing, the negative impact of antibody-mediated rejection is being increasingly recognized. The purpose of this review is to summarize the state of knowledge about the mechanisms of alloantibody production. We will also report the most recent clinical results of current immunosuppressive protocols - either preventive or curative - in this population. RECENT FINDINGS: Even if progress in access to transplantation and short-term graft survival has been made in sensitized patients using therapeutic strategies targeting both alloantibodies (plasmapheresis and/or intravenous globulins) and B cells (CD20 antibodies), antibody-mediated rejection remains a critical issue frequently compromising renal function and middle-term graft survival. The partial efficacy of such strategies and the presence in sensitized patients of both peripheral memory B cells and bone marrow plasma cells capable of alloantibody synthesis in vitro suggest that, in vivo, alloantibody production most likely involves both cell types, not equally targeted by CD20 antibody-based therapies. SUMMARY: The need for improved strategies of prevention/treatment of antibody-mediated rejection, have led, based on the actual understanding of alloantibody synthesis, to the use of drugs targeting plasma cells, that is proteasome inhibitors. Preliminary results are contrasted and highlight the necessity for controlled studies in the field of antihumoral therapies. PMID- 20930638 TI - How the development of new biological agents may help minimize immunosuppression in kidney transplantation: the impact of belatacept. AB - PURPOSE OF REVIEW: The purpose of this review is to discuss the use of belatacept as part of an immunosuppression regimen in renal transplant recipients to avoid the renal and nonrenal toxicities associated with calcineurin inhibitors (CNIs). RECENT FINDINGS: Current immunosuppression protocols utilize CNIs that are associated with renal and cardiovascular/metabolic toxicities. Belatacept, a selective costimulation blocker, is designed to provide effective immunosuppression while avoiding the toxicities associated with CNIs. Phase III trial data have demonstrated that belatacept is noninferior to cyclosporine in 1 year patient and allograft survival. Two-year data demonstrate up to a 17 ml/min/1.73 m improvement in mean measured glomerular filtration rate in belatacept-treated versus cyclosporine-treated patients. Belatacept-treated patients had better blood pressure control and lipid profiles compared to cyclosporine-treated patients. There were more cases of posttransplant lymphoproliferative disease in belatacept-treated patients, especially in Epstein Barr virus-negative recipients or patients treated with lymphocyte-depleting agents. In a conversion trial from a CNI to belatacept, the mean increase in renal function was 7.0 and 2.1 ml/min/1.73 m in the belatacept and cyclosporine groups, respectively. SUMMARY: Belatacept provides effective immunosuppression while avoiding or minimizing the untoward side effects seen with CNIs. Conversion from a CNI to belatacept posttransplantation appears to be safe and effective and results in improved renal allograft function. Data suggest that belatacept use may eventually lead to improved long-term allograft survival and decrease the overall long-term mortality by improving the cardiovascular and metabolic profile of renal transplant recipients. PMID- 20930639 TI - T-cell therapy for cytomegalovirus infection. AB - PURPOSE OF REVIEW: Human cytomegalovirus (CMV) reactivation and disease remains one of the major complications after allogeneic haemopoietic stem cell transplantation. Cell-mediated immunity is essential in counteracting CMV infection as evident by detection of high frequencies of CMV-specific CD8 and CD4 lymphocytes among the healthy CMV-seropositive individuals. Adoptive transfer of CMV-specific T cells to speed up reconstitution of CMV-specific immunity potentially offers clinical protection and reduces drug toxicities as well as outgrowth of drug-resistant strains from prolonged antiviral therapy. RECENT FINDINGS: Different strategies to generate CMV-specific T cell have been explored. Similarly, vast diversities in term of cell dose and composition of the cellular product have been infused into small cohorts of patients. To date, a number of phase I/II clinical trials have demonstrated the feasibility of adoptive transferred CMV-specific T cells as prophylaxis, pre-emptive or therapeutic measure. In general, all these strategies showed variable degrees of efficacy without obvious adverse event particularly with regard to the induction of graft-versus-host disease. SUMMARY: In this review, we would like to give a comprehensive synopsis regarding therapeutic application of CMV-specific T cells in fighting CMV infection. PMID- 20930641 TI - Complicated peptic ulcer disease in three patients with familial dysautonomia. AB - Familial dysautonomia (FD) is an autosomal recessive disorder characterized by autonomic and sensory neuropathy. Owing to pervasive dysfunction, the disease has protean clinical manifestations, affecting the ocular, gastrointestinal, pulmonary, orthopedic, vasomotor, and neurologic systems. The gastrointestinal perturbations, including dysphagia, gastroesophageal dysmotility, gastroesophageal reflux, and vomiting crises, are among the earliest signs. Here, we present the first 3 instances of gastric ulcers in patients with FD and discuss their common presenting features and the special management that was required. PMID- 20930640 TI - Changes in inflammatory and coagulation biomarkers: a randomized comparison of immediate versus deferred antiretroviral therapy in patients with HIV infection. AB - OBJECTIVES: Among a subgroup of participants in the Strategies for Management of Antiretroviral Therapy (SMART) Trial that were naive to antiretroviral therapy (ART) or off ART (6 months or longer) at study entry, risk of AIDS and serious non-AIDS events were increased for participants who deferred ART compared with those randomized to (re)initiate ART immediately. Our objective was to determine whether ART initiation in this group reduced markers of inflammation and coagulation that have been associated with increased mortality risk in SMART. Changes in these biomarkers have been described after stopping ART, but not after starting ART in SMART. METHODS: Stored specimens for 254 participants (126 drug conservation [DC] and 128 viral suppression [VS]) who were naive to ART or off ART (6 months or longer) were analyzed for interleukin-6, high sensitivity C reactive protein, and D-dimer at baseline and Months 2 and 6. RESULTS: At Month 6, 62% of the VS group had HIV RNA less than 400 copies/mL and median CD4 count was 190 cells/mm3 higher than for the DC group (590 versus 400 cells/mm3). Compared with DC, the VS group had 32% (95% confidence interval, 19%-43%) lower D dimer levels at Month 6 (P < 0.001); differences were not significant for high sensitivity C-reactive protein or interleukin-6 levels. CONCLUSIONS: In this randomized comparison of immediate versus delayed ART initiation, D-dimer, but not interleukin-6 and high sensitivity C-reactive protein, declined significantly after starting ART. Further studies are needed to determine whether improvements in D-dimer are associated with reduced risk of clinical disease and whether adjunct treatments used in combination with ART can reduce inflammation among individuals with HIV infection. PMID- 20930642 TI - Clinical management and case reports for the treatment of hepatocellular carcinoma with sorafenib. AB - Hepatocellular carcinoma (HCC) is one of the most common solid organ malignancies worldwide, and its incidence is rising in industrialized nations. Sorafenib, an oral multikinase inhibitor, is effective for the treatment of advanced HCC, and is the only systemic drug indicated for the treatment of unresectable HCC. Patients with HCC often have cirrhosis due to viral infection, chronic alcohol consumption, or other causes of liver damage, resulting in reduced liver function of variable severity. Because of the heterogeneity of HCC cases, physicians must consider the benefits and risks associated with sorafenib treatment on a patient by-patient basis. California Pacific Medical Center (PMC) has established a clinical protocol, discussed here, for treatment of HCC with sorafenib, and for management of treatment-associated adverse effects. In addition, 3 case reports are presented as examples of the use of sorafenib in patient populations not represented in the phase 3 trials: as an adjuvant treatment after a surgical procedure and as effective treatment for stabilizing recurrent and metastatic HCC. PMID- 20930643 TI - Seizures during pegylated interferon and ribavirin therapy for chronic Hepatitis C: observations from the WIN-R trial. AB - BACKGROUND: Seizures are reported as an uncommon side effect of interferon therapy. AIM: To determine the frequency and presentation of seizures occurring during pegylated interferon-alpha (PEG-IFNalpha) and ribavirin therapy for chronic hepatitis C. METHODS: Patients were identified using data from the WIN-R trial database, a US multicenter study comparing fixed (800 mg) versus weight based (800 to 1400 mg) daily dosing of ribavirin in combination with PEG-IFNalpha 2b (1.5 MUg/kg/wk). RESULTS: Of the 4913 enrolled patients, 8 (0.16%) had a seizure. Three patients had a grand mal seizure and the seizure type was unknown in 5 patients. At the time of seizure, 6 patients were taking antidepressants (including 3 on bupropion), 1 was hyponatremic, and 1 had consumed a significant amount of alcohol. One patient had a history of seizures. Neuroimaging and electroencephalographic studies were negative. Antiepileptic medications were continued in the patient with a history of seizures and initiated in 1 patient. PEG-IFNalpha-2b plus ribavirin therapy was continued in 2 patients following seizure and neither experienced a recurrent seizure. CONCLUSIONS: Seizures occur infrequently in patients receiving PEG-IFNalpha-2b plus ribavirin, and appear to be associated with other risk factors including antidepressant use. PMID- 20930644 TI - Airway platelet activation is associated with airway eosinophilic inflammation in asthma. AB - BACKGROUND: Allergic asthma is characterized by airway inflammation associated with recruitment and activation of eosinophils. In mice, allergen exposure induces platelet migration to the airways that is necessary for eosinophil recruitment and activation. We therefore hypothesized that in the airways of human subjects with asthma, platelet activation would be positively associated with eosinophil activation and platelet and eosinophil activation would both be associated with clinical asthma characteristics. METHODS: Nasal wash levels of P selectin (a measure of platelet activation) and eosinophil cationic protein (ECP) (a measure of eosinophil activation) were compared with each other and with clinical asthma characteristics in a cross-sectional study of urban children and adolescents (age range, 6-20 years) with asthma. RESULTS: Regression analysis revealed a significantly positive association between log10 P-selectin levels and log10 ECP levels (beta = 0.50 ng/mL [95% confidence interval, 0.05-0.94 ng/mL]; P = 0.029). Additionally, ECP was significantly and negatively associated with 2 asthma-related quality of life measurements, and P-selectin was associated with one of these. CONCLUSIONS: Our study shows the first significant association between platelet and eosinophil activation in airways of human subjects with asthma. These data provide a first step toward delineating what seems to be an important role for platelets in airway eosinophilia. PMID- 20930645 TI - "Senobi" stretch ameliorates asthma symptoms by restoring autonomic nervous system balance. AB - The number of asthmatic patients is increasing in Japan. It is conceivable that changes in lifestyle (eg, lack of exercise and high-energy diet) may be associated with this phenomenon. The resulting factor seems to be altered activity of autonomic nervous system of these patients. When this activity was estimated by the measurement of heart rate variability, asthmatic patients (n = 11) showed a tendency for parasympathetic nerve dominance in comparison with healthy controls (n = 10). We recommend the patients engage in the "Senobi" stretch exercise, which involves stretching the arms and body upward while standing. After 1 month of regularly performing this exercise, most patients showed a decrease in the frequency of asthma rescue medication use. They also showed a recovery of forced expiratory volume in 1 second. These results suggest that the Senobi stretch is a useful exercise for asthmatic patients to perform to achieve a desirable improvement in symptoms. PMID- 20930647 TI - Progressive postoperative visual loss in idiopathic intracranial hypertension with extremely elevated ICP. PMID- 20930646 TI - Procalcitonin, C-reactive protein, and cell counts in the diagnosis of parapneumonic pleural effusions. AB - BACKGROUND AND OBJECTIVE: Pleural effusion is relatively common in pneumonia. Because traditional methods for its diagnosis are not always effective, there is a need for new biomarkers to make its differential diagnosis easier. METHODS: A total of 233 patients with pleural effusion were admitted to our hospital between 2005 and 2008. Total and differential leukocyte counts, along with blood and pleural fluid procalcitonin and C-reactive protein (CRP) were performed on all of them. The patients were classified into 5 groups depending on the cause of their effusion: (1) parapneumonic, n = 28; (2) tuberculous, n = 49; (3) neoplastic, n = 57; (4) miscellaneous, n = 46; and (5) transudates, n = 53. RESULTS: Procalcitonin levels were higher in the pleural fluid of the parapneumonic group (PAR, 0.15 ng/mL) compared with those of the rest of the groups, but statistically significant differences were only observed with the miscellaneous and tuberculous groups (P < 0.001). Levels of CRP were also higher in the PAR (0.67 mg/L) compared with those of the rest of the groups, with statistically significant differences observed (P < 0.001-0.004) in all of them. The parameter with the largest area under the receiver operator characteristics curve was the product of the total neutrophil count and the CRP in the pleural fluid, in which an area of 0.836 had a sensitivity of 64.3% and a specificity of 93.4%. CONCLUSIONS: Determination of procalcitonin and CRP, in the pleural fluid and blood, does not seem to provide great value to the diagnosis of PAR. However, calculating the product of the total neutrophil count and the CRP may be useful in the diagnosis of these effusions because increased values have a high specificity and predictive values. PMID- 20930648 TI - Multiplex reverse transcription-polymerase chain reaction as diagnostic molecular screening of 4 common fusion chimeric genes in Taiwanese children with acute lymphoblastic leukemia. AB - BACKGROUND: The classification of B-lineage acute lymphoblastic leukemia (ALL) by specific chromosomal translocations has prognostic implications for risk-directed therapy. Reverse transcription-polymerase chain reaction (RT-PCR) assay is a useful tool for detecting fusion transcripts from common chromosomal translocations of ALL cells. METHODS: Multiplex RT-PCR and nested-PCR assays were used to detect ALL-type BCR-ABL1 transcripts of the t(9;22), TCF-PBX1 transcripts of t(1;19), the MLL-AF4 transcripts of t(4;11), and 2 variants of ETV6-RUNX1 of the cryptic t(12;21) in 148 leukemic samples upon diagnosis. The patients received risk-directed protocols of the Taiwan Pediatric Oncology Group-ALL-2002 that consisted of multiple chemotherapeutic agents of different intensities. Event-free survival (EFS) and overall survival (OS) rates were analyzed for genetic abnormalities detected by multiplex PCR and conventional cytogenetic analysis by the Kaplan-Meier method, and compared with the Mantel-Haenszel test. The Cox proportional hazards model was implemented to identify independent prognostic factors for EFS and OS. RESULTS: In this cohort of Taiwanese children, the relative frequencies of the 4 translocations of B-lineage ALL were 8% with ALL-type t(9;22)/BCR-ABL1, 4% with (1;19)/TCF-PBX1, 2% with t(4;11)/MLL-AF4, and 17.6% with t(12;21)/ETV6-RUNX1. Patients with t(12;21)/ETV6-RUNX1 fusion, hyperdiploidy, and t(1;19)/TCF-PBX1 fusion had the most favorable outcomes, whereas those with the t(9;22)/BCR-ABL1 fusion or t(4;11) and other MLL gene rearrangement had poor prognosis (P<0.001 for EFS and OS). BCR-ABL1, MLL gene rearrangement, and very high-risk group were independent prognostic factors after Cox regression analysis. CONCLUSIONS: The biological factors of leukemia cells are associated with treatment outcomes in childhood ALL. Multiplex RT-PCR assay is an efficient and sensitive diagnostic tool that may improve the ability to accurately and rapidly risk-stratify children with ALL. PMID- 20930650 TI - Burkitt lymphoma with pancreatic involvement. AB - A 10-year-old boy was referred to our clinic for tonsillectomy and was found to have a large mass within his oropharynx. Intraoperative biopsies confirmed Burkitt lymphoma. Further imaging and biopsy revealed pancreatic involvement. He was treated with multiagent chemotherapy. He remains disease-free 6 years later. Review of the literature demonstrates other cases of non-Hodgkin lymphoma with pancreatic involvement with good outcomes. Pancreatic involvement is a relatively rare occurrence in childhood lymphoma. PMID- 20930649 TI - Childhood acute lymphoblastic leukemia in Turkey: factors influencing treatment and outcome: a single center experience. AB - There is limited data about the long-term treatment outcome and prognosis of childhood acute lymphoblastic leukemia (ALL) in developing countries. Our study was designed to assess survival data and identify risk factors. Data of 142 children with ALL who were treated with a modified BFM 95 protocol between 1997 and 2007 were evaluated. The median age was 4.3 years. Complete remission (CR) rate after induction phase was 93.5%; with 2.1% induction-related mortality and 0.7% having resistance disease. Of complete responders, 67.1% are in continuous CR with a median follow-up of 63 months (range: 24 to 153 mo). Treatment-related mortality was 17.7% and the total rate of treatment abandonment was 3.5%. The probability of event-free survival was 67.3% (95% confidence interval 59.3-75.3) at 4 years and 63.2% (95% confidence interval 54.4-72.0) at 8 years. This report examines children with ALL treated with a modified ALL-BFM 95 protocol in a tertiary care center in Turkey with adequate follow up and demonstrates the need for improvements especially for patients with unfavorable risk group and strategies to reduce deaths from infection in CR to keep pace with cure rates in developed countries. PMID- 20930651 TI - Growth in children with acute lymphoblastic leukemia during treatment. AB - Obesity is increasingly prevalent in affluent societies and portends considerable morbidity. This is especially true in children with acute lymphoblastic leukemia (ALL) in whom the metabolic syndrome may begin during therapy, demanding clarification of the trajectory of weight gain so that effective interventions may be developed. In this retrospective study of body mass index from a single institution over a 20-year period, almost 15% of children with ALL were at risk of overweight or frankly overweight (body mass index >85th centile) at diagnosis. This proportion increased steadily, reaching 40% at the end of treatment. Strategies to limit weight gain will have to be instituted early in the management of children with ALL, and will probably have to be maintained throughout and after the completion of active treatment. PMID- 20930652 TI - Iron polymaltose versus ferrous gluconate in the prevention of iron deficiency anemia of infancy. AB - We prospectively compared the efficacy and safety of iron deficiency anemia prophylaxis with iron gluconate (IG) or iron polymaltose complex (IPC) in healthy infants attending a community pediatric center. Participants were randomly assigned to receive one of the test drugs from age 4 to 6 months to age 12 months. Parents/guardians were given extensive information on iron-rich diets and anemia prevention. Main outcome measures were blood levels of hemoglobin, hematocrit, mean corpuscular volume, red blood cell distribution width, and serum iron, ferritin, and transferrin, in addition to adverse effects. One hundred five children completed the study: 53 in the IG group and 52 in the IPC group Mean hemoglobin levels at study end were significantly higher in the IG group (12.04+/ 0.09 g/dL vs. 11.68+/-0.11, P<0.014). A hemoglobin level <11 g/dL was detected in 3 infants of the IG group, and in 10 infants of the IPC group (P<0.04). Adverse effects (spitting, vomiting, diarrhea, constipation, discolored teeth) were significantly more common in the IG group (47% vs. 25%, P>0.025). In conclusion, both oral IG and IPC prevent iron deficiency anemia in infants. Iron gluconate seems to be more effective but less tolerable. PMID- 20930653 TI - Gamma knife surgery of vestibular schwannomas: volumetric dosimetry correlations to hearing loss suggest stria vascularis devascularization as the mechanism of early hearing loss. AB - OBJECTIVE: Determine which variables are correlated with early hearing changes after gamma knife surgery of vestibular schwannomas (VSs). STUDY DESIGN: Prospective clinical study of hearing outcomes, radiation dosimetry, conformity, and tumor size of all sporadic unilateral VS patients treated between June 2000 and July 2009. SETTING: Tertiary referral center. PATIENTS: : Fifty-nine VS patients with at least 6 months of follow-up data were studied. INTERVENTIONS: Audiometry and imaging were performed to determine auditory thresholds, speech discrimination, and tumor size. Radiation doses to 5 volumes were measured. MAIN OUTCOME MEASURES: Pretreatment and posttreatment comparisons were performed with regard to change in tumor size; radiation dose to specific volumes including the internal auditory canal, cochlea, basal turn of the cochlea, and modiolus; and conformity of the treatment. RESULTS: The mean follow-up was 63.76 months (standard deviation, +/-29.02 mo; range, 9-109 mo). The median follow-up was 65.5 months. A statistically significant association between maximum radiation dose to the cochlea volume and 3-frequency pure-tone average in patients starting with 50 dB or lesser PTA3 was demonstrated using linear regression analysis. CONCLUSION: Longitudinal changes in hearing occur over time, with the largest changes seen in the first 12 months after treatment. With our study outcomes as basis, limiting the dose of radiation to the cochlea to no more than 4 Gy would likely reduce vascular injury to the stria vascularis and improve hearing outcomes. Shielding the cochlea during the treatment planning process would be one mechanism to accomplish this goal. PMID- 20930654 TI - The floating mass transducer on the round window versus attachment to an ossicular replacement prosthesis. AB - HYPOTHESIS: The Vibrant Soundbridge floating mass transducer (FMT) is part of a commercially available implantable hearing device in which the FMT can be placed in the round window (RW) niche or attached to a partial (V-PORP) or total ossicular replacement prosthesis (V-TORP) contacting the stapes head or footplate. The goal is to provide efficient transfer of sound vibration into the cochlea. The hypothesis is that the FMT location on the prosthesis is superior to the RW location. BACKGROUND: No direct comparisons of the 3 FMT sites have been performed using the same measurement location. METHODS: A new measurement method called the third window method was used in eleven fresh human temporal bones to compare the sites. A small hole was made into the scala tympani of the temporal bones preserving the endosteum. A reflective target was placed on the third window endosteum and displacement of the cochlear fluid was measured using a Polytec HLV-1000 laser Doppler vibrometer. The input to the FMT at all locations was a constant 316 millivolts (mV); the frequency range was 0.5 to 8.0 kHz. RESULTS: The V-PORP and V-TORP FMT locations both provided statistically significant better performance above 1.0 kHz than the RW site but not below that frequency. The V-PORP and V-TORP responses were similar at all test frequencies. CONCLUSION: In this temporal bone model, the FMT provided better higher frequency performance when attached to a PORP or TORP than in the RW niche. PMID- 20930655 TI - The role of facial palsy in staging squamous cell carcinoma of the temporal bone and external auditory canal: a comparative survival analysis. AB - OBJECTIVES: The role for facial palsy in the Pittsburgh staging system for squamous cell carcinoma (SCC) of the external auditory canal (EAC) is unclear. The objective of this study was to conduct a systematic review of published studies to determine the impact of facial palsy on survival outcomes. DATA SOURCES: A search of MEDLINE, EMBASE, Cochrane Central Register of Clinical Trials, Cochrane, clinicaltrials.gov, and the National Guideline Clearinghouse databases was supplemented by hand searching. STUDY SELECTION: Articles selected for final analysis had individual subject data on staging and/or facial nerve function, outcome, and follow-up period. DATA EXTRACTION: Data extracted included demographics, type and stage of cancer, survival, and facial nerve status. DATA SYNTHESIS: Of 3,046 citations identified by a systematic literature search, 21 case series including 348 subjects with SCC of the EAC met criteria for analysis. The overall and disease-specific survival for subjects with facial palsy were significantly worse than subjects without facial palsy, regardless of stage (p = 0.006 and p = 0.002, respectively). The overall survival outcome for subjects with facial palsy was significantly worse than subjects with stage PITT-2000 T3 designated cancer (p = 0.027) and demonstrated no statistically significant difference from stage PITT-2000 T4-designated cancer (p = 0.897). CONCLUSION: This pooled-data survival analysis for SCC of the EAC demonstrates that facial nerve involvement is associated with a poor outcome and that the survival outcomes for subjects with facial palsy more closely parallel the survival curves of advanced stage T4 disease. Disease with facial palsy should be classified as stage T4, in accordance with the PITT-2000 system. PMID- 20930656 TI - Selective retinal therapy with microsecond exposures using a continuous line scanning laser. AB - PURPOSE: To evaluate the safety, selectivity, and healing of retinal lesions created using a continuous line scanning laser. METHODS: A 532-nm Nd:YAG laser (PASCAL) with retinal beam diameters of 40 MUm and 66 MUm was applied to 60 eyes of 30 Dutch-belted rabbits. Retinal exposure duration varied from 15 MUs to 60 MUs. Lesions were acutely assessed by ophthalmoscopy and fluorescein angiography. Retinal pigment epithelial (RPE) flatmounts were evaluated with live-dead fluorescent assay. Histological analysis was performed at 7 time points from 1 hour to 2 months. RESULTS: The ratios of the threshold of rupture and of ophthalmoscopic visibility to fluorescein angiography visibility (measures of safety and selectivity) increased with decreasing duration and beam diameter. Fluorescein angiography and live-dead fluorescent assay yielded similar thresholds of RPE damage. Above the ophthalmoscopic visibility threshold, histology showed focal RPE damage and photoreceptor loss at 1 day, without inner retinal effects. By 1 week, photoreceptor and RPE continuity was restored. By 1 month, photoreceptors appeared normal. CONCLUSION: : Retinal therapy with a fast scanning continuous laser achieves selective targeting of the RPE and, at higher power, of the photoreceptors without permanent scarring or inner retinal damage. Continuous scanning laser can treat large retinal areas within standard eye fixation time. PMID- 20930657 TI - CABG for patients on hemodialysis: comments at present. PMID- 20930658 TI - Surgical remodeling of the left ventricle in heart failure. PMID- 20930659 TI - The in vitro effects of iloprost with other vasodilators on the human internal thoracic artery. AB - PURPOSE: We aimed (a) to analyze the effects of iloprost as a vasodilator on the human internal thoracic artery (ITA) and (b) to compare these effects with the effects of other vasodilators now being used in the clinic. METHODS: Following transfer into only Krebs solution or into Krebs solution containing papaverine or iloprost, human ITA strips were then incubated only in Krebs or in Krebs with vasodilators that are generally used in clinical practice, such as diltiazem or glyceryl trinitrate. Cumulative concentration-contraction curves for noradrenaline (NA) and KCl were then established for these strips. Student's t test and one-way analysis of variance followed by Tukey-Kramer tests were used to compare differences between groups. A p <0.05 was used to indicate significance. RESULTS: Among the transfer solutions, papaverine (6.50 +/- 0.20) and iloprost (7.33 +/- 0.13) were significantly more potent than Krebs (8.46 +/- 0.75, p <0.001 and p <0.05) with regard to preventive effect on precontracted ITA with NA. Iloprost significantly relaxed the NA-induced precontracted ITA strips in the Krebs, papaverine, and iloprost groups. Diltiazem significantly relaxed the precontracted ITA with KCl in all storage groups. CONCLUSION: Iloprost may also prevent perioperative ITA spasm, but should be tested in the clinical setting. PMID- 20930660 TI - Postoperative serum C-reactive protein levels in non-small cell lung cancer patients. AB - PURPOSE: The significance of the postoperative serum C-reactive protein (CRP) level as a prognosis indicator was evaluated in patients with non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: A total of 276 patients who had undergone a curative resection of NSCLC were retrospectively reviewed. RESULTS: The overall and disease-specific survival rates in the postoperative CRP/high group (>= 0.5 mg/dL at 30 days postoperation: n = 130) were significantly lower than those in the postoperative CRP/low group (< 0.5 mg/dL at 30 days postoperation: n = 146). However, based on a multivariate analysis, the postoperative CRP level was not among the unfavorable indicators regarding survival. The patients were divided into two groups, namely, the preoperative CRP/low group (n = 231) and the CRP/high group (n = 45). The proportion of the postoperative CRP/low group (60.2%) in the preoperative CRP/low group was significantly lower than that in the preoperative CRP/low group (15.6%; p <0.0001). No significant difference was observed in the disease-specific survival rates in the postoperative CRP/high group and the postoperative CRP/low group in either the preoperative high/group or low/group. CONCLUSIONS: The overall and disease-specific survival rates in the postoperative CRP/high group were significantly lower than that in the postoperative CRP/low group. This difference may be associated with the relationship between the pre- and postoperative CRP levels. PMID- 20930661 TI - Electron beam cine CT-based evaluation of left atrial function after the maze procedure for mitral valve regurgitation. AB - OBJECTIVE: There has been little investigation of whether atrial function is equally restored by surgery in patients with mitral regurgitation (MR) and atrial fibrillation (AF) compared to patients in sinus rhythm (SR). PATIENTS AND METHODS: We evaluated left atrium (LA) volume-time curves obtained from electron beam tomography. The study involved 33 patients who had surgical treatment for MR with or without AF and 11 control patients. RESULTS: (1) In patients with SR, LA volume decreased significantly along with a resolution of early regurgitation postoperatively, and the reserve function was well maintained. The LA booster pump function was also well maintained before and after surgery. (2) In patients with AF that resolved after maze surgery, the LA volume was larger than that of the sinus group immediately after surgery, and it did not improve in postoperative periods. These patients had a lower reserve function and a much lower booster pump function despite restoration of SR. CONCLUSIONS: The maze procedure is suggested to be unlikely to achieve restoration of atrial function in patients with MR accompanied by AF, even if SR returns postoperatively. Because patients with SR demonstrated the same LA function as the control postoperatively, surgical indication should be considered for patients with severe MR while their atrial function and SR are maintained. PMID- 20930662 TI - The influence of previous percutaneous coronary intervention in patients undergoing off-pump coronary artery bypass grafting. AB - BACKGROUND: The aim of the present study was to compare the early outcomes of patients undergoing off-pump coronary artery bypass grafting (OPCAB) with and without previous percutaneous coronary intervention (PCI). PATIENTS AND METHODS: We retrospectively reviewed the records of 545 patients who underwent first-time isolated OPCAB from September 2004 to June 2007. Overall, 154 had previous PCIs, including 99 with stents. The number of diseased vessels was higher in patients without a PCI than in those with a PCI (2.8 vs. 2.7; p = 0.0311). Postoperative angiography was performed to assess the graft patency in 430 patients (78.9%). RESULTS: The number of anastomoses per patient was lower in PCI patients than in non-PCI patients (3.8 vs. 4.2; p = 0.0066). The operative mortality rates did not differ between these groups (0% vs. 1.8%; p = 0.1995); neither did the major morbidity rates. Similar results were obtained for the comparison of patients with stents and patients without PCIs. There was no significant difference in the graft patency rates between PCI patients and non-PCI patients (97.1% vs. 97.9%; p = 0.4976). CONCLUSIONS: A previous PCI is not a predictor of early morbidity or mortality in patients undergoing OPCAB. Furthermore, the graft patency is not affected by a previous PCI. PMID- 20930663 TI - Effect of cryopreservation on cell proliferation and immunogenicity of transplanted human heart cells. AB - BACKGROUND: Cell preservation is essential for successful cell transplantation and/or tissue engineering. We examined the effects of cryopreservation on the transplantation of human heart cells. METHODS: Cells isolated from human atrial tissues were cultured for 15 days (control group), cryopreserved for 1 week, and rapidly thawed and cultured for 15 days. Proliferation was compared among control and cryopreserved cells or tissues by constructing growth curves. Growth factors, cytokines, biochemical features, and cell cycle phase were measured immediately before and after cryopreservation, and immunogenicity was evaluated from growth curves generated from heart cells after 7 days in mixed-lymphocyte culture. Control or cryopreserved cells were transplanted into rat connective tissues and evaluated histologically 2 weeks later. RESULTS: Cryopreserved cells proliferated more effectively than control cells. Levels of basic fibroblast growth factor and transforming growth factor-beta1 were significantly higher, and those of interleukin (IL)-6 and IL-8 were significantly lower after cryopreservation. Fewer peripheral blood lymphocytes were produced in cryopreserved cells than in noncryopreserved cells, and the cell cycle phase of cryopreserved heart cells shifted primarily to G2 + M from G1 + G0. Noncryopreserved and cryopreserved cells both survived in connective tissue. CONCLUSION: Human atrial cells can be cultured, cryopreserved, and transplanted. Cryopreservation might increase the proliferation of human cells and tissues and also reduce the immunogenicity of heart cells. PMID- 20930664 TI - Locally infiltrative glomus tumor of the bronchus: a case report. AB - We report a glomus tumor of the bronchus that showed invasion of the neural area and extrabronchial extension without significant histological malignancy. The patient was a male in his late 30s with the chief complaint being hemosputum. CT revealed a nodal shadow 15 mm in diameter in the right bronchus intermedius. An irregularly protruding lesion on the tumor surface was observed by bronchoscopy immediately under the second carina in the right truncus intermedius, but could not be diagnosed because of bleeding. Sleeve lobectomy of the right upper lobe was performed, since carcinoid tumor was suspected in open chest biopsy and intraoperative frozen section diagnosis. A solid growth of spherical and cubic uniform cells with a clear eosinophilic cytoplasm and spherical nuclei was observed. Immunohistochemistry was positive for alpha-smooth muscle actin and type IV collagen, weakly positive for synaptophysin, and negative for keratin, neural cell adhesion molecule, chromogranin A, desmin, CD34, and S100, leading to a diagnosis of glomus tumor. Neuroinvasion and extrabronchial tumor extension were observed, but an atypical cytology, bleeding, or necrosis was found histologically. This is the first description of infiltrative glomus tumor of the bronchus. PMID- 20930665 TI - Resection of a chondrosarcoma arising in the right first rib: a case report. AB - Primary chest wall tumors are relatively rare, and in individual cases the biological properties and onset site of the tumor must be considered before surgery, and the chest wall defect must be reconstructed. The case of a patient with a chondrosarcoma arising in the right first rib who underwent resection and reconstruction is reported. The patient was a 56-year-old man with a 6 * 7 cm tumor in the anterior chest wall side of the right first rib; biopsy confirmed a grade I chondrosarcoma. During surgery, a safe surgical field was prepared by severing the clavicle inside the periosteum and resecting the tumor with the anterior side of the first and second ribs. The chest wall defect measured about 10 cm, and reconstruction was performed, using the greater pectoral muscle and a polypropylene mesh as covers. In the treatment of chondrosarcoma, chemotherapy and radiotherapy are less effective, and appropriate surgery is needed. In the present patient it was useful to prepare a safe surgical field for resecting the first rib tumor by severing the clavicle and then reconstructing the chest wall, using the greater pectoral muscle and a polypropylene mesh. PMID- 20930666 TI - Pulmonary apical mass, the so-called pulmonary apical cap, in a 43-year-old woman. AB - A 43-year-old woman had a pulmonary tumor detected by a computed tomographic (CT) scan during follow-up for breast cancer 15 years previously. The tumor showed a solid mass measuring 42 * 32 * 12 mm in extensive contact with the pleura of the apex of the left upper lobe. The edge of the tumor was relatively well-defined with an irregular shape, and a bubblelike area was seen within it. The longitudinal slice high-resolution CT findings showed a flat and thick mass, and its inferior border was distinct and horizontal. The pathological findings by a thoracoscopic lung biopsy showed a localized pulmonary fibrosis of the apex, a so called pulmonary apical cap (PAC). With the recent advances in CT scan technology, the detection of PACs is very likely to increase, and they must be differentiated from superior sulcus tumors. PMID- 20930667 TI - Off-pump coronary bypass via left thoracotomy resulting from sternoclavicular arthritis. AB - We report a case of coronary artery bypass grafting through the left thoracotomy in a patient who suffered from sternoclavicular joint infection with methicillin resistance Staphylococcus aureus. We performed off-pump coronary bypass surgery, using the left internal thoracic artery to the left anterior descending coronary artery and a saphenous vein graft from the aorta to the circumflex artery, with a successful outcome. This approach seems to be safe and effective for coronary bypass grafting in situations where median sternotomy is not favorable, as in the described patient. PMID- 20930668 TI - Delayed closure of postinfarction ventricular septal rupture. AB - We present the case of a patient with postinfarction ventricular septal rupture (VSR) who underwent delayed repair using a modified infarction exclusion technique. The patient was taken to the operating room 21 days after the first incidence of acute myocardial infarction because the intra-aortic balloon pump maintained a stable circulatory condition without cardiogenic shock. In our procedure, a Dacron patch was sutured to the healthy endocardium to exclude the infarcted septum, and the VSR was subsequently closed with another Dacron patch. After three years of postoperation, the patient's condition remains normal with good ventricular kinesis and no residual shunt. We describe herein a novel procedure for repairing postinfarction VSR by using two Dacron patches. PMID- 20930669 TI - Efficacy of a heparin-coated closed circuit for intractable bleeding in adult cardiac surgery. AB - Hemostatic procedures and control of blood pressure concomitant with rapid transfusion of blood products aimed at recovery of coagulability are necessary for intractable bleeding during cardiac surgery. However, when the bleeding is massive and hemostasis is prolonged for several hours, operative maneuvers such as manual compression of the heart can affect hemodynamics, decrease cardiac output, and elevate atrial and venous pressure, with consequent hepatic, renal, and pulmonary dysfunction over time. Herein we present three cases of potentially fatal bleeding during open-heart surgery, in which we used a heparin-coated closed circuit for circulatory support after standard cardiopulmonary bypass. We achieved stable hemodynamics following surgical hemostatic maneuvers and avoided the postoperative multiple organ failure by using a cardiopulmonary support system. PMID- 20930670 TI - Three surgical cases of isolated tricuspid valve infective endocarditis. AB - Tricuspid valve infective endocarditis (TVIE) is rare in Japan, though many reports of it in intravenous drug users are found in other countries. We experienced 3 surgical cases of isolated TVIE in 2 nonintravenous drug users and 1 intravenous user, and we presented successful results. The surgical options for TVIE are vegetectomy and valvulectomy, valve repair, and valve replacement, which are controversial in regard to hemodynamic consequences in right-sided low pressure system and long-term prognosis. We report the 3 surgical cases of isolated TVIE. PMID- 20930671 TI - A presumed mechanism of mitral regurgitation after left ventriculoplasty. AB - After isolated left ventriculoplasty, the mechanism of mitral regurgitation (MR) remains unclear. A 68-year-old male with ischemic cardiomyopathy presented with a new onset of severe MR after left ventriculoplasty without a mitral procedure. He needed a second operation for heart failure because of the MR. We speculate about its mechanism and express caution about the procedure. PMID- 20930672 TI - Aortic valve destruction and pseudoaneurysm of the sinus of Valsalva associated with infective endocarditis. AB - We report the successful surgical treatment of a case of aortic valve destruction and pseudoaneurysm of the sinus of Valsalva associated with infective endocarditis (IE) in an 80-year-old woman. Multidetector-row computed tomography revealed an abnormal cavity in the left posterior aortic root. We had made the diagnosis of the aortic valve destruction and saccular pseudoaneurysm of the sinus of Valsalva associated with IE. Aortic valve replacement and patch plasty of the left sinus of Valsalva was performed successfully. A histopathologic examination of the resected aortic valve leaflet revealed inflammatory changes consistent with IE. We describe the surgical technique used in this rare case of pseudoaneurysm of the sinus of Valsalva resulting from IE. PMID- 20930673 TI - Resecting an unresectable tumor? PMID- 20930674 TI - Additional lung-protective perfusion techniques during cardiopulmonary bypass. AB - Postoperative cardiopulmonary bypass (CPB)-induced lung dysfunction still remains as a serious complication that could lead to life-threatening problems. CPB is associated with a whole-body inflammatory response. The contact of blood components with the artificial surface of the bypass circuit causes activation of complements, upregulation of cytokines and adhesion molecules, and induction of oxygen-free radicals. The pathogenic consequences are adhesions of complement activated neutrophils to endothelial cells, neutrophil migration into the extravascular spaces, and free-radical mediated pulmonary damage. Injured endothelial cells are vulnerable to the cytokine-mediated inflammatory cascade. Moreover, CPB renders the lung being at risk for ischemic insults because lung perfusion is maintained solely by the bronchial arterial system. Postischemic reperfusion of the lung upregulates adhesion molecules and enhances neutrophil endothelial cell adhesion and extravascular neutrophil sequestration, thereby aggravating further structural and functional abnormalities of pulmonary endothelial cells. Thus the systemic inflammatory response and ischemia reperfusion during CPB constitute a vicious network in the pathogenesis of CPB derived lung injury. Accordingly, it is postulated that additional pulmonary perfusion could alleviate CPB-induced lung damage. This review article summarizes recent literature on the mechanisms involved in lung dysfunction after CPB, and it also summarizes current reports on lung-protective perfusion techniques. PMID- 20930675 TI - Evaluation of prognosis in patients with respiratory failure requiring venovenous extracorporeal membrane oxygenation (ECMO). AB - PURPOSE: In this study, we analyzed the respiratory status and the prognosis of patients, including adults with acute respiratory failure requiring venovenous extracorporeal membrane oxygenation (VV ECMO) to maintain respiratory status. We then evaluated the differences between patients who could be removed from VV ECMO and those who could not. PATIENTS AND METHODS: From January 2003 to December 2008, eleven patients in our hospital required VV ECMO for severe acute respiratory failure. All 11 had severe acute respiratory distress syndrome. The age of the patients was 52 +/- 24 (range; 8-86) years, and the male/female ratio was 8/3. The acute physiology and chronic health evaluation II (APACHE II) score, ECMO flow, and respiratory parameters, such as PaO2/FiO2 (P/F ratio), pulmonary compliance, and Lung Injury Score (LIS) before and after the introduction of ECMO, were compared among patients in whom ECMO could or could not be removed. RESULTS: ECMO could be removed from six patients (55%, group A), but in five (45%, group B) could not. The duration of ECMO support was significantly shorter in group A than in group B (111 +/- 68 hr vs. 380 +/- 233 hr, p = 0.011). The pre ECMO ventilator time was shorter in group A than in group B. Significant differences were found between the two groups in the P/F ratio and LIS from pre ECMO introduction to 72 hours after. ECMO flow in group A could be weaned for 48 hours after introduction, significantly different compared with group B. CONCLUSION: The early introduction of ECMO may be desirable if the causes of respiratory failure are recoverable. It is presumed that VV ECMO removal will be difficult if the ECMO flow cannot be weaned within 48 hours after ECMO introduction in patients with severe respiratory failure. PMID- 20930676 TI - Does patient-prosthesis mismatch affect long-term results after mitral valve replacement? AB - BACKGROUND: Recently, some articles about patient-prosthesis mismatch (PPM) of the mitral valve have been published. However, the outcome of PPM of the mitral valve remains controversial. The objective of this study was to determine the impact of mitral valve PPM on clinical results after mitral valve replacement (MVR). METHODS AND RESULTS: Eighty-four patients underwent MVR from 1992 to 2005. They were divided into a PPM group and a non-PPM group. Preoperative, perioperative, and postoperative variables were analyzed retrospectively. The indexed effective orifice area (IEOA) was provided by postoperative echocardiography and body surface area. PPM was defined as an IEOA of 1.2 cm2/m2 or less, and 25 patients had PPM. Thirty-day mortality was 0% in both groups. Postoperative pulmonary artery pressure and residual mitral valve pressure gradient had no significant differences. There was no significant difference in freedom from recurrence of heart failure or from cardiac death between the two groups. CONCLUSION: The present study revealed that PPM does not affect the short or long-term outcome after MVR. But the clinical result when the definition of PPM is made more severe, such as IEOA of 1.0 cm2/m2 or less, was not examined. Further research is required to establish the allowable range of IEOA. PMID- 20930677 TI - Results and treatment strategy for patients undergoing emergent coronary artery bypass grafting. AB - BACKGROUND: Emergent coronary artery bypass grafting (CABG) remains a high-risk procedure in cardiac surgery. Therefore we performed this study to evaluate its current results. METHODS: From 2001 to 2007, fifty-seven patients with an acute coronary syndrome underwent an isolated CABG procedure emergently. Data were collected retrospectively from the patients' charts. RESULTS: The mean age of the patients, 45 males (79%) and 12 females (21%), was 64.5 +/- 11.5 years. Operations were performed on 40 patients (70%) with cardiopulmonary bypass (CPB) and cardioplegic cardiac arrest and on 6 without CPB. Eleven patients (11%) underwent on-pump beating heart procedures (19%). The operating times (minutes) were duration of surgery 215.2 +/- 64.2; duration of CPB 116.9 +/- 51.5; and X clamp time 57.3 +/- 19.9. The mean number of grafts per patient was 2.95 +/- 0.97. Postoperative durations of mechanical ventilation (hours), Intensive Care Unit stay (days), and normal ward stay (days) were 45.8 +/- 75.3, 8.9 +/- 23.1, and 9.6 +/- 8.0, respectively. The total number of complications was 57, and postoperative confusion (29.8%), revision for bleeding (22.8%), and renal insufficiency (21%) occurred most frequently. Seven of the 57 patients died: 5 succumbed to multiorgan failures, 1 to cardiac decompensation, and 1 to bleeding complications. CONCLUSION: Emergent CABG is associated with an enhanced perioperative risk, and further developments are absolutely necessary to improve its results. PMID- 20930678 TI - The value of angiogenic therapy with intramyocardial administration of basic fibroblast growth factor to treat severe coronary artery disease. AB - BACKGROUND: Basic fibroblast growth factor (bFGF) was administered intramyocardially together with CABG to induce myocardial neovascularizaton and collateral growth in patients with ungraftable coronary arteries. Coronary angiographic and myocardial scintigraphic findings revealed that the effects of CABG were potentially confounding. METHODS AND RESULTS: Patients in the bFGF group (n = 16) underwent angiogenic therapy using bFGF for ungraftable territory, and incomplete revascularization (IR) patients (n = 22) underwent only CABG. The magnitude of collateral development was assessed by the Rentrop score and collateral connection (CC) grade. Rentrop scores tended to increase among patients in the bFGF group (before vs. after surgery, 1.9 +/- 1.2 vs. 2.3 +/- 1.2, p = 0.05), but not in the IR group. The CC grade significantly increased among patients in the bFGF group (before vs. after surgery, 1.0 +/- 0.9 vs. 1.4 +/- 0.5, p <0.05), but not in the IR group. Myocardial perfusion in territories injected with bFGF improved in 13 patients (81%) of the bFGF group, and also in the nonbypassed territory in 4 IR patients (25%) (p <0.05). CONCLUSION: Angiogenic therapy with bFGF induced collateral development and improved myocardial perfusion in territories injected with bFGF. PMID- 20930679 TI - Aortic valve replacement by ministernotomy in redo patients with previous left internal mammary artery patent grafts. AB - OBJECTIVE: Aortic valve surgery with a patent left internal mammary artery (LIMA) on the left anterior descending (LAD) coronary artery is challenging in terms of myocardial protection and graft injury. Minimally invasive techniques may require minimal dissection of adhesions and may eventually decrease the risk of injuries. METHODS: Since 1997, more than 1000 ministernotomies have been performed by our surgical unit. Of these, 16 patients (14 males, 2 females, mean age: 68.7 years) had a patent LIMA graft on LAD. Fourteen underwent native aortic valve replacement, and in 2 a previously implanted prosthesis was replaced. A miniresternotomy was performed using either a "J" (15 patients) or a "reversed-T" method (1 patient). RESULTS: Cardiopulmonary bypass (CPB) was achieved by either femoral vein (12 patients) or right atrium (4 patients); arterial inflow was achieved either by ascending aorta (12 patients) or by femoral artery (4 patients). Mean CPB time was 119.7 +/- 38.1 minutes (range: 50-235). Mean cooling body temperature was 27.4 degrees C. Antegrade cold crystalloid cardioplegia was delivered to all the patients. Mean aortic cross-clamp time was 72 +/- 20 minutes (range: 45-125). No damage to LIMA occurred in any of the patients. No intra- or perioperative myocardial infarction (MI) occurred. Neither a conversion to full sternotomy nor a reoperation for bleeding was needed. Mean postoperative bleeding was 426 +/- 474 ml (range: 120-1950). A blood transfusion was necessary in 7 patients. Mean postoperative ICU stay was 1.6 +/- 1.1 days. Mean postoperative hospital stay was 7.5 +/- 2.6 days. Postoperative course was totally uneventful in 10 patients (58.8%). Follow-up was complete for a total of 928 patient/months (range: 11-124), and there were four late deaths, two of which were related to cardiac problems. Nine of the 12 survivors are in NYHA CLASS I . II. Prosthesis related morbidity did not occur either early or late during follow-up. CONCLUSIONS: This experience may represent the feasibility of an alternative surgical approach to a standard full-length median sternotomy in patients with previous coronary revascularization and with a patent LIMA on the LAD, requiring new surgery on the aortic valve. PMID- 20930680 TI - Necessity of lung resection in neglected cases of pulmonary hydatidosis. AB - In pulmonary hydatid disease, lung resection is not a desirable treatment. Two young boys, aged 9 and 15, presented at our institution, the 9-year-old with a destroyed lung as the result of a delayed diagnosis of a giant cyst; the second with a massive hemoptysis as the result of preoperative albendazole use. Both children underwent a lobectomy for the treatment of pulmonary hydatidosis. Delayed diagnosis and use of albendazole, respectively, were considered the causes necessitating lung resection in these cases of giant and complicated pulmonary hydatid disease. PMID- 20930681 TI - A resected case of pulmonary carcinosarcoma. AB - The patient was a 78-year-old man with a history of smoking 5 or 6 cigarettes per day for 40 years. A chest X-ray taken during a medical checkup demonstrated a mass shadow in the right lower lung field. The patient was diagnosed with squamous cell carcinoma by bronchoscopic brushing cytology. A right lower lobectomy and a lymph node dissection were performed under a diagnosis of squamous cell carcinoma of the lung (cT2N0M0, stage IB). Gross examination of the resected specimen demonstrated an ovoid, irregularly bordered, yellowish-white tumor, 8 cm in diameter, containing a necrotic cavity. Histopathological examination showed diffuse proliferation of spindle-shaped tumor cells intermingled with areas of well-differentiated squamous cell carcinoma with definite keratinization. Areas of cartilage and bone were observed in the spindle cell components of the tumor. These findings led to a diagnosis of carcinosarcoma (pT2N0M0, stage IB). The patient developed multiple intrapulmonary metastases 5 months after surgery and died of respiratory failure 10 months later. Herein we report a rare surgical case of lung carcinosarcoma. PMID- 20930682 TI - Progressive growth of primary synovial sarcoma of the lung. AB - An 80-year-old male was admitted because of a giant mass in the left lower lobe of the lung on a routine chest X-ray. Chest computed tomography verified this to be a well-defined heterogeneous mass as described with no associated lymphadenopathy. FDG-PET depicted moderately marginal FDG uptake. The patient underwent a left lower lobectomy and lymphadenectomy. Grossly, the tumor measured 60 * 50 mm and was uniformly filled with a pure white, pudding-like friable substance. No lymph node metastasis was observed microscopically. Histologically, the tumor showed a dense proliferation of rounded or spindled malignant cells with a frequent mitotic activity and an increased nuclear-to-cytoplasmic ratio. The immunohistochemical staining was positive for vimentin, negative for cytokeratin, keratin-wide, EMA, CD34. A SYT-SSX2 fusion gene transcript was detected as a result of RT-PCR analysis. Because of these results, the tumor was diagnosed as a monophasic synovial sarcoma. PMID- 20930683 TI - Management of descending mediastinal infections with an unusual cause: a report of 3 cases. AB - Mediastinal infections are a life-threatening and distinctly rare event, especially when they are caused by a dental abscess or by a foreign body that has not perforated the esophagus. We evaluated how best to treat descending mediastinal infections occurring from an unusual cause. We report 3 female patients with mediastinal infections: two aged 45 and 80 years, each with a dental abscess, and one 62 with a foreign-body injury of the retropharyngeal wall. A retropharyngeal abscess and descending necrotizing mediastinitis developed in two of these patients. The mediastinal abscess was detected by computed tomographic scanning. All patients were successfully treated by drainage of their abscesses via cervicotomy or thoracotomy. A mediastinal abscess can be a serious complication. Mediastinitis is associated with a high mortality rate if the diagnosis is not quickly established and adequate therapy is not provided. In this report, we discuss the management and possible pathophysiological mechanisms of descending mediastinal infections that have an unusual cause. Clinicians should be aware of the possibility of descending mediastinal infections in patients with a retropharyngeal abscess or a dental abscess associated with persistent signs, such as fever. Imaging modalities must be used as soon as possible to enable early diagnosis. Aggressive treatment includes surgical drainage, and medical management in an intensive care unit may prevent a catastrophic outcome. PMID- 20930684 TI - Congenital systemic and coronary-to-pulmonary artery fistulas. AB - Congenital systemic-to-pulmonary artery fistulas are very rare, with the exception of congenital heart disease and pulmonary sequestration. We describe the first reported case of left internal mammary and bronchial artery to pulmonary artery fistulas associated with bilateral coronary arteries to pulmonary artery fistulas. PMID- 20930685 TI - Successful surgical treatment of tricuspid valve endocarditis associated with vertebral osteomyelitis. AB - Right-sided endocarditis is relatively rare and can occasionally be complicated by vertebral osteomyelitis (VO). We describe successful treatment, including valve repair for tricuspid endocarditis associated with VO. A 77-year-old man presented with back pain and high fever. Magnetic resonance imaging demonstrated VO. Despite 2 months of intravenous antibiotics, the infectious signs persisted and both legs became edematous. Enterococcus faecalis was isolated from blood cultures, and echocardiography showed severe tricuspid regurgitation with large vegetations attached to the anterior leaflet (AL). A series of echocardiographic assessments revealed that the antibiotic therapy did not affect the tricuspid lesions. In surgery, the infection was extended to some chordae and over half of the AL was resected. The AL was repaired with autologous pericardium and artificial chordae. Antibiotic therapy was continued for 2 months after surgery, and the infections did not reoccur. Follow-up echocardiography showed mild regurgitation of the tricuspid valve. The patient remains free from endocarditis at 2 years after surgery. PMID- 20930686 TI - Redo an aortic valve replacement for bioprosthetic valve destruction in a patient developing Streptococcus bacteremia three years after the initial operation. AB - A 66-year-old man with a bioprosthetic aortic valve developed Streptococcus bacteremia and was treated with antibiotics. He responded well to this therapy, and no evidence of bioprosthetic valve endocarditis (BVE) was detected at this time. One-and-a-half years after the antibiotic therapy for bacteremia, the patient was referred to our department with a diagnosis of acute cardiac failure. Transthoracic echocardiography revealed torn bioprosthetic valve leaflets with severe aortic regurgitation. A redo aortic valve replacement was undertaken, followed by antibiotic therapy for 6 weeks after the surgery. A histopathological examination of the surgically resected valve suggested a healed infective BVE. No recurrence of bacteremia has been noted since the reoperation. PMID- 20930687 TI - Surgical treatment of aortic valve papillary fibroelastoma with neurofibromatosis (von Recklinghausen's disease). AB - A 69-year-old man with a medical history of neurofibromatosis was transferred to our hospital for the treatment of an aortic valve mass. His workup identified an aortic valve papillary fibroelastoma based on the absence of signs of infection, thrombus in the left atrium, and valvular destruction or abnormal valvular function. A tumor was excised under cardiopulmonary bypass. The pathology of the mass was a papillary fibroelastoma. Neurofibromatosis with cardiac tumor is extremely rare. This is the first report of a case of papillary fibroelastoma associated with neurofibromatosis. PMID- 20930688 TI - Total arch replacement with associated anomaly of the left vertebral artery. AB - We describe total arch replacement after ascending aortic replacement for acute type II dissecting aneurysm with associated anomaly of the left vertebral artery. A female patient was recommended at 10 years of age after the initial operation because of an enlargement of the distal ascending aorta. Magnetic resonance angiography revealed an isolated left vertebral artery that arises distal to the left subclavian artery. Total arch replacement was proceeding using selective cerebral perfusion. The isolated artery was reconstructed with a saphenous vein graft interposed between the native left vertebral artery and the side of the graft branch anastomosed to the left subclavian artery. The patient recovered uneventfully after extensive surgical replacement of the thoracic aorta and remains asymptomatic at 1 year after the procedure. To prevent possible neurological complications, we find it critical to assess vascularization in this region prior to conducting surgical procedure. Careful examination and correct identification of the vessels are essential to avoid major complications. PMID- 20930689 TI - Selective digestive decontamination to prevent pneumonia after esophageal surgery. PMID- 20930690 TI - Alternative approaches for redo aortic arch surgery. PMID- 20930691 TI - The role of transcription factor FoxO1 in the pathogenesis of acne vulgaris and the mode of isotretinoin action. AB - It is the purpose of this review to demonstrate that oral isotretinoin treatment restores all major pathogenetic factors of acne vulgaris by upregulation of the nuclear transcription factor FoxO1, which will be shown to be the major target of retinoid action. Nuclear FoxO1 deficiency is the result of increased growth factor signaling with activated phosphoinositol-3-kinase (PI3K) and Akt kinase during growth hormone signaling of puberty and increased insulin/IGF-1 signaling due to consumption of insulinotropic milk/dairy products as well as hyperglycemic carbohydrates of Western diet. Nuclear FoxO1 deficiency increases androgen receptor transactivation and modifies the activity of important nuclear receptors and key genes involved in pilosebaceous keratinocyte proliferation, sebaceous lipogenesis and expression of perifollicular inflammatory cytokines. Isotretinoin induced upregulation of nuclear FoxO1 is proposed to be responsible for the mode of action of isotretinoin on all major pathogenetic factors in acne. Acne pathogenesis can be explained at the genomic level of transcriptional regulation. All major events in acne pathogenesis as well as all major effects of isotretinoin treatment appear to be related to modifications of the PI3K/Akt/FoxO1 signaling pathway, the well-known oncogenic pathway. These insights extend our understanding of FoxO1-mediated retinoid action in acne and other hyperproliferative skin diseases, cancer chemoprevention and cutaneous immune regulation. Understanding FoxO's pivotal regulatory role in acne allows the development of novel treatment strategies and dietary interventions in acne which focus on the restoration of growth factor- and diet-induced imbalances of nuclear FoxO protein levels. PMID- 20930692 TI - Cost-effectiveness analysis of topical treatments for actinic keratosis in the perspective of the Italian health care system. AB - Actinic keratosis (AK) is the most common cutaneous malignant neoplasm and its prevalence continues to increase. According to the most recent findings, AK is currently considered the initial stage, in situ, of squamous cell carcinoma. Field-directed therapies for AKs are the preferred treatment since they have the advantage to clear the clinically visible lesions and also subclinical lesions within the cancerous field. We assessed the cost-effectiveness of topical treatments for AKs including 3% diclofenac in 2.5% hyaluronic acid (HA) gel, imiquimod 5% cream and photodynamic therapy with methyl aminolevulinate (MAL-PDT) in the perspective of the Italian Health Care System (SSN). We used a decision tree analytical approach and efficacy data were drawn from published clinical trials. Cost was evaluated from the SSN perspective during a time horizon of 3 months. A responder was defined as a patient with all lesions clinically cleared and showing an excellent cosmetic result. Based on the applied model, the cost per complete responder was calculated. Diclofenac 3% in HA was less expensive (Euro 256) than MAL-PDT (Euro 320) and imiquimod (Euro 342). Effectiveness was similar and better for diclofenac 3% in HA and MAL-PDT (0.813%) in comparison to 0.734% of imiquimod, respectively. The one-way and probabilistic sensitivity analyses confirmed the results of base case scenario. Based on this cost effectiveness model, diclofenac 3% in HA can be considered the treatment of choice for AK lesions and surrounding field under a pharmacoeconomic point of view. PMID- 20930693 TI - What's new in skin resurfacing and rejuvenation? AB - Skin resurfacing and rejuvenation techniques have experienced significant advances in the last few decades, and new devices are continuously being introduced into the marketplace. The large number of available modalities such as fractional lasers, radiofrequency systems, microdermabrasion, laser-assisted lipolysis, and ultrasound provides practitioners with a wide array of choices to address the needs of cosmetic patients. Many of the newer technologies, such as devices that integrate a fractional delivery system, provide excellent results with few adverse side effects. However, proper perioperative management is essential to achieving the desired effects. Furthermore, practitioners must be fluent with the operation and expected complications of these new technologies. While there are many overlapping treatment indications for each of the devices mentioned above, some modalities offer distinct advantages making proper patient selection essential. In certain cases, utilizing various combinations of mechanical, optic, acoustic, and electrical energies may be necessary to achieve the desired outcomes. This review discusses the application of new and existing skin rejuvenation techniques to clinical practice. A particular emphasis is placed on the use of fractional, radiofrequency, microdermabrasion, laser assisted lipolysis, and ultrasound devices. PMID- 20930694 TI - Molecular patterns in melanoma and therapeutic targets. AB - Malignant melanoma is one of the most lethal cancers whose treatment options are limited once it has metastasized. Recent advances in molecular technology have improved our understanding of the underlying mechanisms of melanoma pathogenesis. In this article, we highlight several pathways that have been implicated in melanoma-genesis. While a cure is not yet within grasp, the picture on the horizon is less hazy and the next decade promises to yield exciting new therapeutic discoveries. PMID- 20930695 TI - Melanocyte photobiology, ultraviolet radiation and melanoma. AB - Of all the organs of the human body, the skin is most commonly affected by malignancy, and ultraviolet radiation has long been implicated as the primary mutagenic exposure leading to the development of many cutaneous cancers. However, as research in this field has continued, it has become clear that the effect of ultraviolet radiation on the skin is quite complex. Distinct cell types within the skin exhibit differing responses to ultraviolet radiation, and even within the same cell type, divergent effects may be observed; depending on the dose or wavelength of the radiation, or the maturational state of the affected cell, unique responses can be elicited. Melanocytes form a minor component of the outermost layer of skin, but they have an enormous impact on not only the appearance of the skin, but also the ability of the skin to withstand exposure to ultraviolet radiation. In addition, melanocytes give rise to melanoma, one of the most deadly types of skin cancer. Clearly, it is critical that we achieve a better understanding of the effect of ultraviolet radiation on melanocytes, and that we clarify its role in the oncogenesis of melanoma. Although the picture is far from complete, the mechanisms by which melanocytes respond to ultraviolet radiation are beginning to be elucidated, and, as these pathways emerge, they offer new targets for chemopreventive and chemotherapeutic intervention. PMID- 20930696 TI - The use of photodynamic therapy in dermatology. AB - In dermatology, topical photodynamic therapy (PDT) is a well established treatment modality which has mainly shown to be effective for dermato-oncologic conditions like actinic keratosis, Bowen's disease, in-situ squamous cell carcinoma and superficial basal cell carcinoma. However, a therapeutical benefit of PDT is also evident for inflammatory dermatoses like localized scleroderma, acne vulgaris and granuloma annulare as well as for aesthetic indications like photo aged skin or sebaceous gland hyperplasia. Recent work has been focused on the development and evaluation of topical photosensitizers like the hem precursor 5-aminolevulinic acid or its methyl ester inducing photosensitizing porphyrins. These drugs do not induce strong generalized cutaneous photosensitization like the systemically applied porphyrins or their derivatives. For dermatological purposes incoherent lamps or LED arrays can be used for light activation. Depending on the applied light dose and the concentration of the photosensitizer either cytotoxic effects resulting in tumor destruction or immunomodulatory effects improving the inflammatory conditions occur. Treating superficial oncologic lesions (tumor thickness < 2-3 mm) cure rates achieved by PDT are equal to the cure rates of the respective standard therapeutic procedure. The benefits of PDT are the low level of invasiveness and the excellent cosmetic results after treatment. PMID- 20930697 TI - Photoprotection in moisturizers and daily-care products. AB - During usual daily activities, an appropriate protection against solar UV exposure should prevent clinical, cellular and molecular changes potentially leading to photoaging. In skin areas regularly exposed to sun, UV-damage is superimposed to tissue degeneration resulting from chronological aging. It is, therefore, important to know if moisturizers and daily-care products containing UVA absorbers combined with UVB ones are able to prevent these skin damages. This review will summarize clinical studies evaluating this topic. These studies demonstrate that broad-spectrum protection in moisturizers or daily-care products can prevent the "silent" sub-erythemal cumulative effects of UVR from inadvertent sun exposure. PMID- 20930698 TI - Skin substitutes in dermatosurgery. AB - Skin substitutes are a growing market since technical advancements have allowed a substantial progress in treating extensive defects of the skin. A variety of skin substitutes with different properties and thus resulting different indications is offered on the market. Important benefits of skin substitutes are their ready availability in almost any quantity and the predictable product properties concerning implantation, incorporation, resorption and long-term outcome. Although, most skin substitutes still need skin grafts at a later date which is disadvantageous. Nevertheless dermal substitutes have reduced the need for thick skin grafts allowing the donor site and the patient to heal faster with fewer surgeries. The use of skin substitutes in dermatologic surgery is widespread and new fields of application are emerging. The variety of artificial skin has definitely changed the reconstructive ladder helping to cover larger defects with less time and effort which is an important issue especially in elderly and multimorbid patients. In the last years a growing number of studies in the literature report the use of artificial skin substitutes to secure a rapid reconstruction with reliable cosmetic and functional results after oncological resections. Furthermore, skin substitutes are used to cover chronic wounds like diabetic foot ulcers or venous leg ulcers to promote healing. Congenital diseases like giant hairy nevi, aplasia cutis congenital or epidermolysis bullosa are conditions in children where skin substitutes play a role. But even in tissue augmentation or in cosmetic surgery skin substitutes come into vogue. The latest advance are cultured autologous or allogenic substitutes some even in combination with alloplastic material. Besides of medical questions that arise from the use of these materials in reconstructive surgery legal and economic aspects have to be taken into account. This article is giving an overview over the most common skin substitutes and their use in dermatosurgery. PMID- 20930699 TI - What's new in cosmetic procedures. AB - Innovative technology and product advancements in cosmetic procedures have been developing at a rapid pace. Advances in neuromodulators and fillers as well as new technology in skin tightening, body contouring and skin resurfacing have been profound over the past few years. This article will discuss the most current and promising cosmetic procedures available today as well as those soon to be available. PMID- 20930700 TI - Sporotrichosis: an update. AB - Sporotrichosis is the most frequent and worldwide distributed subcutaneous mycoses. The aim of this article is to review the most recent aspects of sporotrichosis about its epidemiology, etiologic agents, mycologic characteristics, clinical features, diagnosis and treatment. The causative agents of sporotrichosis belong to five well defined species of dimorphic fungi of the called Sporothrix schenckii complex. Sporotrichosis and its etiologic agents have specific endemic areas, but it is possible to find epidemics of the disease in practically every continent, the entrance via is cutaneous due to the inoculation of the fungi into the skin after a traumatism and less frequent due to respiratory way. Clinical manifestations are widely variable, with important involvement of the skin and the superficial lymphatic system, but also with affection of the mucosa and some organs like lungs, bones and joints. Nowadays sporotrichosis is considered a true zoonosis with important changes related to the endemic areas and the ecologic features of the causative pathogens. The therapy of choice is the potassium iodide (KI), but other alternatives are itraconazole, terbinafine, thermotherapy and in severe cases amphotericin B. The importance of the recognition of the clinical manifestations of the disease in some non-endemic areas helps to challenge the diagnosis and give an accurate therapy. PMID- 20930701 TI - Advances in pemphigus research, signaling, and acantholysis. AB - Pemphigus is a family of human autoimmune blistering diseases in which pathogenic autoantibodies induce blistering in skin and mucosa. The mechanisms by which pemphigus autoantibodies induce disease in the skin is under active investigation. A large number of cellular events induced in the target keratinocytes by pemphigus IgG have been described and suggest that pemphigus IgG binding to desmogleins trigger a complicated cascade of intracellular signaling and regulatory events. Targeting these intracellular events may prove useful therapeutically. PMID- 20930702 TI - The actual management of pemphigus. AB - Pemphigus is usually treated with systemic prednisone in combination with adjuvant immunosuppressants. Though the mortality associated with pemphigus has been reduced with the use of systemic corticosteroids, the iatrogenic complications have warranted the development of newer therapies. This review discusses the different treatments, therapies and procedures. PMID- 20930703 TI - Prevalence of doctor-diagnosed arthritis and arthritis-attributable activity limitation --- United States, 2007-2009. AB - Arthritis is a large and growing public health problem in the United States, resulting in costs of $128 billion annually, and continues to be the most common cause of disability. With the aging of the U.S. population, even assuming that the prevalence of obesity and other risk factors remain unchanged, the prevalence of doctor-diagnosed arthritis and arthritis-attributable activity limitation (AAAL) is expected to increase significantly by 2030. To update previous U.S. estimates of doctor-diagnosed arthritis and AAAL, CDC analyzed National Health Interview Survey (NHIS) data from 2007--2009. This report summarizes the results of that analysis, which found that 22.2% (49.9 million) of adults aged >=18 years had self-reported doctor-diagnosed arthritis, and 9.4% (21.1 million or 42.4% of those with arthritis) had AAAL. Among persons who are obese, an age-adjusted 33.8% of women and 25.2% of men reported doctor-diagnosed arthritis. Arthritis and AAAL represent a major public health problem in the United States that can be addressed, at least in part, by implementing proven obesity prevention strategies and increasing availability of effective physical activity programs and self management education courses in local communities. PMID- 20930704 TI - Seasonal influenza vaccination coverage among children aged 6 months-18 years --- eight immunization information system sentinel sites, United States, 2009-10 influenza season. AB - Annual influenza vaccination was first recommended for children aged 6-23 months and 2-4 years by the Advisory Committee on Immunization Practices (ACIP) in 2004 and 2006, respectively. In August 2008, ACIP expanded its seasonal influenza vaccination recommendations to also include all children aged 5-18 years no later than the 2009-10 season. To update previous estimates of seasonal influenza vaccination coverage among children aged 6 months-18 years, CDC analyzed data from the eight immunization information system (IIS) sentinel sites for the 2009 10 influenza season. Vaccination coverage with influenza A (H1N1) 2009 monovalent vaccine is not included in this report. Average (unweighted) vaccination coverage with >=1 seasonal influenza vaccine doses was 26.3%, a 5.5 percentage point increase from the 2008-09 season (20.8%). Increases varied by age group, ranging from almost no increase among children aged 6-23 months (55.2% during the 2008-09 season to 55.7% during the 2009-10 season) to notable increases among children aged 2--4 years (from 33.0% to 38.4%), 5-12 years (19.0% to 27.1%), and 13-18 years (10.9% to 15.3%). Full vaccination coverage was low during the 2009-10 season, ranging from 34.7% among children aged 6-23 months to 15.3% among children aged 13-18 years. These findings highlight the need to identify varied strategies and venues for delivering influenza vaccine to different age groups of children to increase vaccination coverage. PMID- 20930705 TI - Influenza activity --- United States and worldwide, June 13-September 25, 2010. AB - From June 13 to September 25, 2010, the United States experienced low levels of influenza activity. During this period, typical seasonal patterns of influenza activity occurred in the Southern Hemisphere; in addition, influenza activity was observed in the tropical regions, with a mix of 2009 influenza A (H1N1), influenza A (H3N2), and influenza B viruses cocirculating. This report summarizes influenza activity in the United States and worldwide since the update published on July 30, 2010. PMID- 20930706 TI - Vital signs: binge drinking among high school students and adults --- United States, 2009. AB - BACKGROUND: Binge drinking was responsible for more than half of the estimated 79,000 deaths and two thirds of the estimated 2.3 million years of potential life lost as a result of excessive drinking each year in the United States during 2001 2005. METHODS: CDC analyzed data from the 2009 Behavioral Risk Factor Surveillance System (BRFSS) on the prevalence of binge drinking (defined as consuming four or more alcoholic drinks per occasion for women and five or more for men during the past 30 days) among U.S. adults aged >=18 years who responded to the BRFSS survey by landline or cellular telephone. Data also were analyzed from the 2009 National Youth Risk Behavior Survey (YRBS) on the prevalence of current alcohol use (consuming at least one alcoholic drink during the 30 days before the survey), and binge drinking (consuming five or more alcoholic drinks within a couple of hours during the 30 days before the survey) among U.S. high school students, and on the prevalence of binge drinking among high school students who reported current alcohol use. RESULTS: Among U.S. adults, the prevalence of reported binge drinking was 15.2% among landline respondents. Binge drinking was more common among men (20.7%), persons aged 18-24 years (25.6%) and 25-34 years (22.5%), whites (16.0%), and persons with annual household incomes of $75,000 or more (19.3%). Among cellular telephone respondents, the overall prevalence of binge drinking (20.6%) was higher than among landline respondents, although the demographic patterns of binge drinking were similar. Prevalence among high school students was 41.8% for current alcohol use, 24.2% for binge drinking, and 60.9% for binge drinking among students who reported current alcohol use. CONCLUSIONS: Binge drinking is common among U.S. adults, particularly those with higher household incomes, and among high school students. Binge drinking estimates for adults were higher in the cellular telephone sample than in the landline sample. Most youths who reported current alcohol use also reported binge drinking. IMPLICATIONS FOR PUBLIC HEALTH PRACTICE: Binge drinking is a serious problem among adults and youths that can be reduced by implementation of evidence-based interventions. PMID- 20930707 TI - Adiponectin and hypertension. AB - Adipose tissue secretes a variety of bioactive molecules, also known as adipocytokines or adipokines. Obesity, in particular, visceral fat accumulation, is implicated in the dysregulated secretion of adipocytokines, which can contribute to the development of metabolic syndrome and cardiovascular diseases. Adiponectin is an adipocytokine that is exclusively secreted from adipose tissue, but its plasma levels are reduced in obese subjects, especially those with visceral fat accumulation. Adiponectin has a variety of protective properties against obesity-linked complications, such as hypertension, metabolic dysfunction, atherosclerosis, and ischemic heart disease. Adiponectin exerts the beneficial effects on vascular disorders by directly affecting components of vascular tissue. This review will discuss clinical and experimental findings that examine the role of adiponectin in regulation of hypertension and vascular function. PMID- 20930708 TI - Circadian rhythms in blood pressure regulation and optimization of hypertension treatment with ACE inhibitor and ARB medications. AB - Specific features of the 24 h-blood pressure (BP) pattern are linked to the progressive injury of target tissues and risk of cardiac and cerebrovascular events. Studies have consistently shown an association between blunted asleep BP decline and increased incidence of fatal and nonfatal cardiovascular events. Thus, there is growing interest in how to achieve better BP control during nighttime sleep in addition to during daytime activity, according to the particular requirements of each hypertension patient. One approach takes into consideration the endogenous circadian rhythm-determinants of the 24-h BP pattern, especially, the prominent day-night variation of the renin-angiotensin aldosterone system, which activates during nighttime sleep. A series of clinical studies have demonstrated a different effect of the angiotensin-converting enzyme (ACE) inhibitors benazepril, captopril, enalapril, lisinopril, perindopril, quinapril, ramipril, spirapril, and trandolapril when routinely ingested in the morning vs. the evening. In most cases, the evening schedule exerts a more marked effect on the asleep than awake BP means. Similarly, a once-daily evening, in comparison to morning, ingestion schedule of the angiotensin receptor blockers (ARBs) irbesartan, olmesartan, telmisartan, and valsartan exerts greater therapeutic effect on asleep BP, plus significant increase in the sleep-time relative BP decline, with normalization of the circadian BP profile toward a more dipping pattern, independent of drug terminal half-life. Chronotherapy, the timing of treatment to body rhythms, is a cost-effective means of both individualizing and optimizing the treatment of hypertension through normalization of the 24-h BP level and profile, and it may constitute an effective option to reduce cardiovascular risk. PMID- 20930712 TI - Systemic effects of white adipose tissue dysregulation and obesity-related inflammation. PMID- 20930711 TI - Pregravid obesity associates with increased maternal endotoxemia and metabolic inflammation. AB - Obese pregnant women develop severe insulin resistance and enhanced systemic and placental inflammation, suggesting associated modifications of endocrine and immune functions. Activation of innate immunity by endotoxins/lipopolysaccharides (LPS) has been proposed as a mechanism for enhancing metabolic alterations in disorders with insulin resistance. The aim of this study was to characterize the immune responses developed by the adipose tissue (AT) and their potential links to maternal endotoxemia in pregnancy with obesity. Blood and subcutaneous abdominal AT were obtained from 120 lean and obese women (term pregnancy) recruited at delivery. Gene expression was assessed in AT and stromal vascular cells isolated from a subset of 24 subjects from the same cohort. Doubling of plasma endotoxin concentrations indicated subclinical endotoxemia in obese compared with lean women. This was associated with significant increase in systemic C-reactive protein and interleukin-6 (IL-6) but not tumor necrosis factor-alpha (TNF-alpha) concentrations. AT inflammation was characterized by accumulation of CD68(+) macrophages with a threefold increased gene expression of the macrophage markers CD68, EMR1, and CD14. Gene expression for cytokines IL-6, TNF-alpha, IL-8, and monocyte chemotactic protein-1 (MCP1) and for LPS-sensing CD14, toll-like receptor 4 (TLR4), translocating chain-associated membrane protein 2 was 2.5-5-fold higher in stromal cells of obese compared to lean. LPS treated cultured stromal cells of obese women expressed a 5-16-fold stimulation of the same cytokines upregulated in vivo. Our data demonstrate that subclinical endotoxemia is associated with systemic and AT inflammation in obese pregnant women. Recognition of bacterial pathogens may contribute to the combined dysfunction of innate immunity and the metabolic systems in AT. PMID- 20930713 TI - Associations of SNPs in ADIPOQ and subclinical cardiovascular disease in the multi-ethnic study of atherosclerosis (MESA). AB - Circulating adiponectin is associated with both clinical and subclinical cardiovascular disease (CVD). Variants of the adiponectin gene (ADIPOQ) are associated with clinical CVD, but little is known about associations with subclinical CVD. We studied the association of 11 ADIPOQ single-nucleotide polymorphisms (SNPs) with common and internal carotid intima media thickness (cIMT), presence of coronary artery calcification (CAC), and CAC scores (in those with CAC) in 2,847 participants in the Multi-Ethnic Study of Atherosclerosis (MESA). Participants were white (n = 712), African American (n = 712), Chinese (n = 718), and Hispanic (n = 705). All models were adjusted for age, sex, and field site, and stratified by race/ethnic group. African Americans with genotypes AG/GG of rs2241767 had 36% greater (95% confidence interval (CI; 16%, 59%), P = 0.0001) CAC prevalence; they also had a larger common cIMT (P = 0.0043). Also in African Americans, genotypes AG/AA of rs1063537 were associated with a 35% (95% CI (14%, 59%), P = 0.0005) greater CAC prevalence. Hispanics with the AA genotype of rs11711353 had a 37% (95% CI (14%, 66%), P = 0.0011), greater CAC prevalence compared to those with the GG genotype. Additional adjustment for ancestry in African-American and Hispanic participants did not change the results. No single SNP was associated with subclinical CVD phenotypes in Chinese or white participants. There appears to be an association between ADIPOQ SNPs and subclinical CVD in African Americans and Hispanics. Replication as well as assessment of other ADIPOQ SNPs is warranted. PMID- 20930714 TI - Water turnover assessment in overweight adolescents. AB - Adequate intake (AI) standards for water in adolescents range between 2.4-3.3 l/day for males and 2.1-2.3 l/day for females, independent of obesity status. Water intakes and excretions of this population are not well documented. The purposes of this study were to assess water turnover, inputs, and outputs in overweight adolescents, compare these parameters between males and females, and evaluate the reproducibility of water turnover. Eighteen girls (BMI 31.7 +/- 4 kg/m(2); mean +/- s.d.) and nine boys (BMI 26.3 +/- 3 kg/m(2)) aged 12-15 years completed two 3-week metabolic balance trials. Rate of water turnover (rH(2)O) was measured by tracking the decline of deuterated water from the body over 14 days. Water inputs (diet*, ad libitum(#), metabolic(#)) and outputs (urine*, feces*, insensible(#)) were assessed (*measured, #estimated). rH(2)O was lower (P = 0.002) in girls vs. boys (3,742 +/- 536 vs. 4,537 +/- 623 g/day). Per kg body weight, rH(2)O was 28% lower in girls vs. boys (46 +/- 7 vs. 64 +/- 9 g.kg( 1).day(-1)). Water input from food and beverages provided and metabolic production were 44 and 28% lower, respectively, in girls vs. boys. Urine and insensible water losses were 21 and 17% lower in girls vs. boys. BMI was positively associated with water turnover in both sexes (girls P = 0.037; boys P = 0.014). The intraclass correlation of rH(2)O between trials was 0.981 (P < 0.001). In conclusion, these overweight adolescents consumed water well in excess of sex-specific AI standards. The lower rH(2)O in girls compared to boys is consistent with adult females and males. PMID- 20930715 TI - Overexpression of constitutively active PKG-I protects female, but not male mice from diet-induced obesity. AB - Cyclic guanosine monophosphate (cGMP)-dependent protein kinase I (PKG-I) is a multifunctional protein. The direct effects of PKG-I activation on energy homeostasis and obesity development are not well understood. Herein, we generated transgenic mice with expression of the constitutively active PKG-I in adipose tissue as well as in other tissues. Male and female PKG-I overexpressing mice were fed a low-fat (LF) or high-fat (HF) diet for 16 weeks. HF-fed female PKG-I transgenic mice had decreased body weight gain, lower percentage of body fat, and improved glucose tolerance compared to HF-fed wild-type (WT) controls. In contrast, male transgenic PKG-I mice were not resistant to the development of HF diet-induced obesity, and exhibited similar levels of adiposity and glucose intolerance as HF-fed WT controls. Furthermore, we found that HF-fed female transgenic PKG-I mice had increased energy expenditure and cold-induced adaptive thermogenesis compared to HF-fed WT controls, which was associated with increased expression of uncoupling protein-1 (UCP1) in brown adipose tissue (BAT). In addition, the rates of lipolysis in white adipose tissue (WAT) were also increased in female transgenic PKG-I mice compared to WT controls due to increased phosphorylation of hormone-sensitive lipase (HSL). However, in male mice, adaptive thermogenesis or WAT lipolysis was similar between transgenic PKG I mice and WT controls. Together, these data demonstrate sex differences in effects of PKG-I activation on the regulation of adipose tissue function and its contribution to diet induced obesity. PMID- 20930717 TI - D2 Thr92Ala and PPARgamma2 Pro12Ala polymorphisms interact in the modulation of insulin resistance in type 2 diabetic patients. AB - Type 2 deiodinase (D2) converts T4 into its active metabolite T3, an essential step in thyroid metabolism. A Thr92Ala polymorphism in the gene encoding D2 has been inconsistently associated with insulin resistance (IR). Recently, it was reported that the D2 Thr92Ala (rs225014) and the peroxisome proliferator activated receptor (PPAR) gamma2 Pro12Ala (rs1801282) polymorphisms interact in the modulation of metabolic syndrome in nondiabetic subjects. Here, we investigated the effect of both polymorphisms, isolated or in combination, on IR in patients with type 2 diabetes mellitus (DM2). The D2 Thr92Ala and PPARgamma2 Pro12Ala polymorphisms were genotyped in 721 DM2 patients. IR was evaluated using the homeostasis model assessment-IR (HOMA(IR)) index in a subgroup of 246 DM2 subjects. The frequencies of D2 Ala92 and PPARgamma2 Ala12 variants were 0.390 and 0.074, respectively. Patients carrying D2 Ala/Ala genotype had a higher fasting plasma insulin and HOMA(IR) index as compared to patients carrying Thr/Ala or Thr/Thr genotypes (P = 0.022 and P = 0.001, respectively). A significant synergistic effect was observed between D2 Thr92Ala and PPARgamma2 Pro12Ala polymorphisms on HOMA(IR) index, with carriers of both D2 Ala/Ala genotype and PPARgamma2 Ala12 allele showing the highest HOMA(IR) values, after adjusting for age, gender, BMI, and use of medication for DM2 (P = 0.010). In conclusion, DM2 patients harboring both D2 Ala/Ala genotype and PPARgamma2 Ala12 allele seem to present more severe IR than those with other D2/PPARgamma2 genotype combinations. These findings suggest that these polymorphisms interact in the IR modulation, which may constitute a potential therapeutic target. PMID- 20930716 TI - Lifestyle and socioeconomic-status modify the effects of ADRB2 and NOS3 on adiposity in European-American and African-American adolescents. AB - The aim of the study is to investigate the influence of and interaction between lifestyle behaviors (diet and physical activity (PA)) and single-nucleotide polymorphisms (SNPs) in obesity-candidate genes (ADRB2, APOB and NOS3) on general and central adiposity. Six-hundred-and-twenty-one European-American (EA) and African-American (AA) youths aged 13-19 years were classified by ethnicity (49% AA), gender (45% male), and socioeconomic status (SES). PA and dietary intake with up to seven 24-h recalls were reported for all subjects. Percent body fat (%BF) was measured by dual-energy X-ray absorptiometry, visceral adipose tissue (VAT), and subcutaneous abdominal adipose tissue (SAAT) by magnetic resonance imaging. Reported energy intake (EI) and vigorous PA (VPA) were negative predictors of %BF and SAAT. Carriers of the NOS3 Asp298 allele had higher %BF only in the presence of an adverse environment (low SES). Compared to the most common NOS3 haplotype, homozygotes for haplotype A-non4r-Asp had 6.1% higher %BF. Significant interactions were revealed between the ADRB2 Arg16Gly SNP and VPA on VAT, SAAT and waist circumference (WC) such that Gly16 homozygotes may benefit less from increased VPA to reduce their weight. Genetic susceptibility to increased general and central adiposity is dependent on several factors, such as SES and vigorous exercise. Improved understanding of the joint effect of genes and lifestyle on adiposity will offer new insights into obesity and may provide new avenues for personalized prevention and treatment. PMID- 20930718 TI - Identifying patterns of eating and physical activity in children: a latent class analysis of obesity risk. AB - We used latent class analysis (LCA) to identify heterogeneous subgroups with respect to behavioral obesity risk factors in a sample of 4th grade children (n = 997) residing in Southern California. Multiple dimensions assessing physical activity, eating and sedentary behavior, and weight perceptions were explored. A set of 11 latent class indicators were used in the analysis. The final model yielded a five-class solution: "High-sedentary, high-fat/high-sugar (HF/HS) snacks, not weight conscious," "dieting without exercise, weight conscious," "high-sedentary, HF/HS snacks, weight conscious," "active, healthy eating," and "low healthy, snack food, inactive, not weight conscious." The results suggested distinct subtypes of children with respect to obesity-related risk behaviors. Ethnicity, gender, and a socioeconomic status proxy variable significantly predicted the above latent classes. Overweight or obese weight status was determined based on the Centers for Disease Control and Prevention BMI (kg/m2) for-age-and-sex percentile (overweight, 85th percentile <= BMI < 95th percentile; obese, 95th percentile <= BMI). The identified latent subgroup membership, in turn, was associated with the children's weight categories. The results suggest that intervention programs could be refined or targeted based on children's characteristics to promote effective pediatric obesity interventions. PMID- 20930719 TI - Critical comparisons. PMID- 20930720 TI - Pooled studies can raise misleading alarm bells, regulators say. PMID- 20930721 TI - 'Pay-for-delay' decision may be left to lawmakers. PMID- 20930722 TI - Sugar treatment doesn't pacify those concerned about preemies. PMID- 20930723 TI - Talkin' 'bout my (third) generation. PMID- 20930724 TI - Fluctuating baseline pain implicated in failure of clinical trials. PMID- 20930725 TI - Sequencing of superbugs seen as key to combating their spread. PMID- 20930726 TI - Genomics uncovers microbe resistance. PMID- 20930727 TI - Targeting hotspots of transmission promises to reduce malaria. PMID- 20930728 TI - Companies hope to bring DNA storage in from the cold. PMID- 20930729 TI - As pediatric trials go global, some worry who really benefits. PMID- 20930731 TI - Following Europe's lead, Congress moves to ban ape research. PMID- 20930732 TI - Call for renewed focus on rare mutations grows more common. PMID- 20930733 TI - In season, atmospheric conditions can drive disease. PMID- 20930734 TI - A disease--or gene--by any other name would cause a stink. PMID- 20930736 TI - Straight talk with...Jules Hirsch. Interview by Roxanne Palmer. PMID- 20930737 TI - Nothing to sneeze at. PMID- 20930738 TI - A timeline of histamine and its receptors. PMID- 20930739 TI - Sunshine biomedicine. PMID- 20930740 TI - Advocates deserve room at the decision-making table. PMID- 20930742 TI - Stem cells on the move. PMID- 20930743 TI - High glucose, no cry. PMID- 20930744 TI - A sweet path toward tolerance in the gut. PMID- 20930746 TI - A small kiss of death for cancer. PMID- 20930745 TI - Good and bad lipids in the lung. PMID- 20930747 TI - The persistence of memory. PMID- 20930748 TI - Peering into the aftermath: The inhospitable host? PMID- 20930751 TI - How to win a Lasker? Take a close look at Bathers and Bulls. PMID- 20930749 TI - Peering into the aftermath: JAKi rips STAT3 in cancer. PMID- 20930752 TI - A historical perspective on leptin. PMID- 20930753 TI - A tale of two hormones. PMID- 20930755 TI - Thalassemia: the long road from the bedside through the laboratory to the community. PMID- 20930754 TI - Vascular endothelial growth factor and age-related macular degeneration: from basic science to therapy. PMID- 20930756 TI - The wider dental team. PMID- 20930757 TI - Out of the bottle. PMID- 20930758 TI - NCAS continues. PMID- 20930759 TI - A reasoned approach. PMID- 20930760 TI - Masochistic pleasure. PMID- 20930761 TI - Redeploying resources. PMID- 20930773 TI - Why dentists should take a greater interest in sex and gender. AB - This brief review highlights the lack of evidence relating to sex and gender differences in oral health as well as the widespread conceptual confusion and conflation that often underlies them. A broader biomedical understanding of these issues will offer a valuable framework within which differences in oral health between women and men can be further explored. This in turn would facilitate the development of the evidence base necessary to optimise the efficacy of dental practice in meeting the needs of both women and men patients. PMID- 20930774 TI - Risk management in clinical practice. Part 6b. Identifying and avoiding medico legal risks in removable dentures. AB - The most likely cause of complaint with prosthodontics is a denture that in some way fails to be accepted. A denture that does not perform as the patient expects can give rise to great disappointment and anger. The problem is that acceptance of a denture is not just a technical issue. Success depends on the individual's ability to tolerate and adapt to the denture. It is therefore essential to make the right assessment for the patient from the outset. This includes discovering the patient's priorities and establishing realistic expectations. With the aim of assisting the dental profession in identifying and avoiding medico-legal risks in removable dentures, this article sets out a systematic, diagnostic and collaborative approach to complete and partial denture assessment and treatment. PMID- 20930779 TI - Summary of: an audit improves the quality of water within the dental unit water lines of general dental practices across the East of England. PMID- 20930795 TI - Stem-cell laws in China fall short. PMID- 20930796 TI - Transgenic harvest. PMID- 20930797 TI - Garage biology. PMID- 20930798 TI - Scientists need a shorter path to research freedom. PMID- 20930810 TI - The spread of postdoc unions. PMID- 20930811 TI - Baby boom bags Nobel prize. PMID- 20930812 TI - Graphene speeds pair to Stockholm win. PMID- 20930813 TI - Plan for addiction institute splits NIH. PMID- 20930814 TI - NASA privacy case goes to highest court. PMID- 20930815 TI - A shocking discovery. PMID- 20930816 TI - Epigenome effort makes its mark. PMID- 20930819 TI - Earth science: Weighing the world. PMID- 20930817 TI - Safety authority rebuts conflict claim. PMID- 20930820 TI - Garage biotech: Life hackers. PMID- 20930821 TI - Altruism researchers must cooperate. PMID- 20930826 TI - Call for a return to rigour in models. PMID- 20930827 TI - Better living through physics. PMID- 20930828 TI - Ground truth is the test that counts. PMID- 20930829 TI - Inclusive fitness is just bookkeeping. PMID- 20930830 TI - Surface science: Seeing the spin through. PMID- 20930831 TI - Medical microbiology: A toxin contest. PMID- 20930832 TI - Nanofluidics: Tiny electrostatic traps. PMID- 20930833 TI - DNA repair: A protein giant in its entirety. PMID- 20930834 TI - Atmospheric physics: Solar surprise? PMID- 20930835 TI - Mycology: Spores ride a cooperative wind. PMID- 20930837 TI - Vision: Neurons show their true colours. PMID- 20930838 TI - Functional connectivity in the retina at the resolution of photoreceptors. AB - To understand a neural circuit requires knowledge of its connectivity. Here we report measurements of functional connectivity between the input and ouput layers of the macaque retina at single-cell resolution and the implications of these for colour vision. Multi-electrode technology was used to record simultaneously from complete populations of the retinal ganglion cell types (midget, parasol and small bistratified) that transmit high-resolution visual signals to the brain. Fine-grained visual stimulation was used to identify the location, type and strength of the functional input of each cone photoreceptor to each ganglion cell. The populations of ON and OFF midget and parasol cells each sampled the complete population of long- and middle-wavelength-sensitive cones. However, only OFF midget cells frequently received strong input from short-wavelength-sensitive cones. ON and OFF midget cells showed a small non-random tendency to selectively sample from either long- or middle-wavelength-sensitive cones to a degree not explained by clumping in the cone mosaic. These measurements reveal computations in a neural circuit at the elementary resolution of individual neurons. PMID- 20930839 TI - High star formation rates as the origin of turbulence in early and modern disk galaxies. AB - Observations of star formation and kinematics in early galaxies at high spatial and spectral resolution have shown that two-thirds are massive rotating disk galaxies, with the remainder being less massive non-rotating objects. The line-of sight-averaged velocity dispersions are typically five times higher than in today's disk galaxies. This suggests that gravitationally unstable, gas-rich disks in the early Universe are fuelled by cold, dense accreting gas flowing along cosmic filaments and penetrating hot galactic gas halos. These accreting flows, however, have not been observed, and cosmic accretion cannot power the observed level of turbulence. Here we report observations of a sample of rare, high-velocity-dispersion disk galaxies in the nearby Universe where cold accretion is unlikely to drive their high star formation rates. We find that their velocity dispersions are correlated with their star formation rates, but not their masses or gas fractions, which suggests that star formation is the energetic driver of galaxy disk turbulence at all cosmic epochs. PMID- 20930840 TI - Geometry-induced electrostatic trapping of nanometric objects in a fluid. AB - The ability to trap an object-whether a single atom or a macroscopic entity affects fields as diverse as quantum optics, soft condensed-matter physics, biophysics and clinical medicine. Many sophisticated methodologies have been developed to counter the randomizing effect of Brownian motion in solution, but stable trapping of nanometre-sized objects remains challenging. Optical tweezers are widely used traps, but require sufficiently polarizable objects and thus are unable to manipulate small macromolecules. Confinement of single molecules has been achieved using electrokinetic feedback guided by tracking of a fluorescent label, but photophysical constraints limit the trap stiffness and lifetime. Here we show that a fluidic slit with appropriately tailored topography has a spatially modulated electrostatic potential that can trap and levitate charged objects in solution for up to several hours. We illustrate this principle with gold particles, polymer beads and lipid vesicles with diameters of tens of nanometres, which are all trapped without external intervention and independently of their mass and dielectric function. The stiffness and stability of our electrostatic trap is easily tuned by adjusting the system geometry and the ionic strength of the solution, and it lends itself to integration with other manipulation mechanisms. We anticipate that these features will allow its use for contact-free confinement of single proteins and macromolecules, and the sorting and fractionation of nanometre-sized objects or their assembly into high-density arrays. PMID- 20930841 TI - An influence of solar spectral variations on radiative forcing of climate. AB - The thermal structure and composition of the atmosphere is determined fundamentally by the incoming solar irradiance. Radiation at ultraviolet wavelengths dissociates atmospheric molecules, initiating chains of chemical reactions-specifically those producing stratospheric ozone-and providing the major source of heating for the middle atmosphere, while radiation at visible and near-infrared wavelengths mainly reaches and warms the lower atmosphere and the Earth's surface. Thus the spectral composition of solar radiation is crucial in determining atmospheric structure, as well as surface temperature, and it follows that the response of the atmosphere to variations in solar irradiance depends on the spectrum. Daily measurements of the solar spectrum between 0.2 um and 2.4 um, made by the Spectral Irradiance Monitor (SIM) instrument on the Solar Radiation and Climate Experiment (SORCE) satellite since April 2004, have revealed that over this declining phase of the solar cycle there was a four to six times larger decline in ultraviolet than would have been predicted on the basis of our previous understanding. This reduction was partially compensated in the total solar output by an increase in radiation at visible wavelengths. Here we show that these spectral changes appear to have led to a significant decline from 2004 to 2007 in stratospheric ozone below an altitude of 45 km, with an increase above this altitude. Our results, simulated with a radiative-photochemical model, are consistent with contemporaneous measurements of ozone from the Aura-MLS satellite, although the short time period makes precise attribution to solar effects difficult. We also show, using the SIM data, that solar radiative forcing of surface climate is out of phase with solar activity. Currently there is insufficient observational evidence to validate the spectral variations observed by SIM, or to fully characterize other solar cycles, but our findings raise the possibility that the effects of solar variability on temperature throughout the atmosphere may be contrary to current expectations. PMID- 20930842 TI - Melting above the anhydrous solidus controls the location of volcanic arcs. AB - Segregation of magma from the mantle in subduction zones is one of the principal mechanisms for chemical differentiation of the Earth. Fundamental aspects of this system, in particular the processes by which melt forms and travels to the Earth's surface, remain obscure. Systematics in the location of volcanic arcs, the surface expression of this melting, are widely considered to be a clue to processes taking place at depth, but many mutually incompatible interpretations of this clue exist (for example, see refs 1-6). We discriminate between those interpretations by the use of a simple scaling argument derived from a realistic mathematical model of heat transfer in subduction zones. The locations of the arcs cannot be explained by the release of fluids in reactions taking place near the top of the slab. Instead, the sharpness of the volcanic fronts, together with the systematics of their locations, requires that arcs must be located above the place where the boundary defined by the anhydrous solidus makes its closest approach to the trench. We show that heat carried by magma rising from this region is sufficient to modify the thermal structure of the wedge and determine the pathway through which both wet and dry melts reach the surface. PMID- 20930843 TI - Global metabolic impacts of recent climate warming. AB - Documented shifts in geographical ranges, seasonal phenology, community interactions, genetics and extinctions have been attributed to recent global warming. Many such biotic shifts have been detected at mid- to high latitudes in the Northern Hemisphere-a latitudinal pattern that is expected because warming is fastest in these regions. In contrast, shifts in tropical regions are expected to be less marked because warming is less pronounced there. However, biotic impacts of warming are mediated through physiology, and metabolic rate, which is a fundamental measure of physiological activity and ecological impact, increases exponentially rather than linearly with temperature in ectotherms. Therefore, tropical ectotherms (with warm baseline temperatures) should experience larger absolute shifts in metabolic rate than the magnitude of tropical temperature change itself would suggest, but the impact of climate warming on metabolic rate has never been quantified on a global scale. Here we show that estimated changes in terrestrial metabolic rates in the tropics are large, are equivalent in magnitude to those in the north temperate-zone regions, and are in fact far greater than those in the Arctic, even though tropical temperature change has been relatively small. Because of temperature's nonlinear effects on metabolism, tropical organisms, which constitute much of Earth's biodiversity, should be profoundly affected by recent and projected climate warming. PMID- 20930845 TI - Maternal phosphatidylinositol 3-kinase signalling is crucial for embryonic genome activation and preimplantation embryogenesis. AB - Maternal effect factors derived from oocytes are important for sustaining early embryonic development before the major wave of embryonic genome activation (EGA). In this study, we report a two-cell-stage arrest of embryos lacking maternal 3 phosphoinositide-dependent protein kinase 1 as a result of suppressed EGA. Concurrent deletion of maternal Pten completely rescued the suppressed EGA and embryonic progression through restored AKT signalling, which fully restored the fertility of double-mutant females. Our study identifies maternal phosphatidylinositol 3-kinase signalling as a new maternal effect factor that regulates EGA and preimplantation embryogenesis in mice. PMID- 20930846 TI - MAPK signalling in cellular metabolism: stress or wellness? AB - Mitogen-activated protein kinase (MAPK) signalling occurs in response to almost any change in the extracellular or intracellular milieu that affects the metabolism of the cell, organ or the entire organism. MAPK-dependent signal transduction is required for physiological metabolic adaptation, but inappropriate MAPK signalling contributes to the development of several interdependent pathological traits, collectively known as metabolic syndrome. Metabolic syndrome leads to life-threatening clinical consequences, such as type 2 diabetes. This Review provides an overview of the MAPK-signalling mechanisms that underly basic cellular metabolism, discussing their link to disease. PMID- 20930847 TI - Trichoplein/mitostatin regulates endoplasmic reticulum-mitochondria juxtaposition. AB - Trichoplein/mitostatin (TpMs) is a keratin-binding protein that partly colocalizes with mitochondria and is often downregulated in epithelial cancers, but its function remains unclear. In this study, we report that TpMs regulates the tethering between mitochondria and endoplasmic reticulum (ER) in a Mitofusin 2 (Mfn2)-dependent manner. Subcellular fractionation and immunostaining show that TpMs is present at the interface between mitochondria and ER. The expression of TpMs leads to mitochondrial fragmentation and loosens tethering with ER, whereas its silencing has opposite effects. Functionally, the reduced tethering by TpMs inhibits apoptosis by Ca(2+)-dependent stimuli that require ER-mitochondria juxtaposition. Biochemical and genetic evidence support a model in which TpMs requires Mfn2 to modulate mitochondrial shape and tethering. Thus, TpMs is a new regulator of mitochondria-ER juxtaposition. PMID- 20930848 TI - The history of p53. A perfect example of the drawbacks of scientific paradigms. PMID- 20930850 TI - Short-chain fatty acids induced autophagy serves as an adaptive strategy for retarding mitochondria-mediated apoptotic cell death. AB - Short-chain fatty acids (SCFAs) are the major by-products of bacterial fermentation of undigested dietary fibers in the large intestine. SCFAs, mostly propionate and butyrate, inhibit proliferation and induce apoptosis in colon cancer cells, but clinical trials had mixed results regarding the anti-tumor activities of SCFAs. Herein we demonstrate that propionate and butyrate induced autophagy in human colon cancer cells to dampen apoptosis whereas inhibition of autophagy potentiated SCFA induced apoptosis. Colon cancer cells, after propionate treatment, exhibited extensive characteristics of autophagic proteolysis: increased LC3-I to LC3-II conversion, acidic vesicular organelle development, and reduced p62/SQSTM1 expression. Propionate-induced autophagy was associated with decreased mTOR activity and enhanced AMP kinase activity. The elevated AMPKalpha phosphorylation was associated with cellular ATP depletion and overproduction of reactive oxygen species due to mitochondrial dysfunction involving the induction of MPT and loss of Deltapsi. In this context, mitochondria biogenesis was initiated to recover cellular energy homeostasis. Importantly, when autophagy was prevented either pharmacologically (3-MA or chloroquine) or genetically (knockdown of ATG5 or ATG7), the colon cancer cells became sensitized toward propionate-induced apoptosis through activation of caspase-7 and caspase-3. The observations indicate that propionate-triggered autophagy serves as an adaptive strategy for retarding mitochondria-mediated apoptotic cell death, whereas application of an autophagy inhibitor (Chloroquine) is expected to enhance the therapeutic efficacy of SCFAs in inducing colon tumor cell apoptosis. PMID- 20930849 TI - Cyclin-dependent kinase 9-cyclin K functions in the replication stress response. AB - Cyclin-dependent kinase 9 (CDK9) is a well-characterized subunit of the positive transcription elongation factor b complex in which it regulates transcription elongation in cooperation with cyclin T. However, CDK9 also forms a complex with cyclin K, the function of which is less clear. Using a synthetic lethal RNA interference screen in human cells, we identified CDK9 as a component of the replication stress response. Loss of CDK9 activity causes an increase in spontaneous levels of DNA damage signalling in replicating cells and a decreased ability to recover from a transient replication arrest. This activity is restricted to CDK9-cyclin K complexes and is independent of CDK9-cyclin T complex. CDK9 accumulates on chromatin in response to replication stress and limits the amount of single-stranded DNA in cells under stress. Furthermore, we show that CDK9 and cyclin K interact with ataxia telangiectasia and Rad3-related protein and other checkpoint signalling proteins. These results reveal an unexpectedly direct role for CDK9-cyclin K in checkpoint pathways that maintain genome integrity in response to replication stress. PMID- 20930851 TI - Cyclophilin A release as a biomarker of necrotic cell death. PMID- 20930852 TI - Central serous chorioretinopathy: an update on pathogenesis and treatment. AB - Central serous chorioretinopathy (CSC) is a chorioretinal disease, incompletely understood with systemic associations, a multifactorial aetiology, and a complex pathogenesis. Increased permeability from the choriocapillaris leads to focal or diffuse dysfunction of the retinal pigment epithelium causing a detachment of the neurosensory retina. CSC has been described in patients with endogenously high levels of corticosteroids as well as in patients with hypercortisolism due to the treatment of ocular or systemic diseases. It is therefore the only 'inflammatory' choroiditis, not proven to be associated with infection that is precipitated or worsened by glucocorticoids. Foveal attenuation, chronic macular oedema, and damage of the foveal photoreceptor layer have been reported as causes of visual loss in CSC. Photoreceptor atrophy in the fovea, despite successful retinal reattachment, typically occurs after a duration of symptoms of approximately 4 months. Treatment should therefore be considered after 3 months if there is angiographic evidence of ongoing foveal leakage in recurrent chronic CSC or in a single CSC episode accompanied by signs of chronic CSC alterations. Based on results of trials conducted so far, it appears that photodynamic therapy with verteporfin is effective and safer than argon laser treatment and should be considered as the treatment of choice, whereas micropulse diode laser photocoagulation seems to be an effective alternative. Glucocorticoid inhibitors are an interesting alternative treatment. Clinical trials are ongoing to test their efficacy. In addition, it is important, where possible, to discontinue any corticosteroid treatment. The possible association of CSC with stress should also be discussed with patients. PMID- 20930853 TI - Glaucoma surgery: trainee outcomes and implications for future training: southeast Scotland. AB - AIM: Postoperative outcome of trainee glaucoma surgery compared with glaucoma specialist consultant surgery. Survey of Scottish consultant ophthalmologists' views on trainee surgery. METHOD: Retrospective analysis of 128 trainee and 176 consultant trabeculectomies, with minimum postoperative follow-up of 2 years. Prospective postal survey of 80 Scottish consultant ophthalmologists. RESULTS: Trainees operated mainly on cases of chronic open angle glaucoma, while consultants operated on significantly more complicated glaucomas (P=0.0004). Trainee cases had more bleb leaks (P=0.01), hypotony (P=0.05), early (P=0.01) and late (P=0.03) return to theatre, and bleb interventions (P=0.01). Trainee mitomycin trabeculectomies were associated with higher rates of return to theatre (P=0.002), and cataract extraction within the first postoperative year (P=0.002). Trainee cases of pseudoexfoliation had more early complications (P=0.024), and trainee cases of low tension required more bleb interventions (P=0.05). There was no significant difference (P>0.05) between average intra-ocular pressure control (IOP) at postoperative visit year 1 between consultant (14.3 mm Hg) and trainee (13.9 mm Hg) cases. More than 50% of the 80 Scottish ophthalmology consultants surveyed, indicated that glaucoma surgery training requirements should be retained. CONCLUSIONS: Trainee trabeculectomy cases showed significantly higher rates of early complications, return to theatres, and bleb interventions compared with consultant cases. Satisfactory IOP control was achieved in both groups at postoperative year 1. Trainee cases require careful preoperative selection, avoiding complicated glaucomas including pseudoexfoliation and low tension, and those that require mitomycin. The majority of Scottish consultants wish to retain glaucoma surgery within the remit of generic training. PMID- 20930854 TI - Longitudinal changes in refractive error of children with infantile esotropia. AB - AIM: the aim of this study was to quantify changes in refractive status over time in children with infantile esotropia (ET) and to analyse a number of clinical factors associated with infantile ET to determine how they may affect emmetropisation. METHODS: longitudinal cycloplegic refraction data were collected for 5-12 years from 143 consecutive children enroled in a prospective study of infantile ET by 6 months of age. Changes in refractive error with age were summarised with descriptive statistics and the influence of amblyopia, undercorrection of hypermetropia, accommodation, and binocular factors on emmetropisation were evaluated by analysis of variance and t-tests. RESULTS: most had low to moderate hypermetropia on the initial visit (55% had <+3.00 D). Although the initial refractive error is similar to normative data, the rapid decrease in hypermetropia that characterises normal development during the first 9 months of life is absent in children with infantile ET. After 9 months of age, children with infantile ET follow a developmental course, which is similar to the normative course; there is little change in hypermetropia during years 1-7, followed by a decline of approximately -0.5 D/year beginning at age 8 years. None of the clinical factors examined had a statistically significant effect on the course of refractive changes with age. CONCLUSION: children with infantile ET exhibit a different pattern of refractive development than that seen in normative cohorts. The long-term changes in refraction observed in children with infantile ET suggest that there is a need for long-term clinical follow-up of these children. PMID- 20930855 TI - Spontaneous sub-conjunctival haemorrhage in patients using long-term topical corticosteroids. AB - PURPOSE: to investigate the observed high prevalence of spontaneous sub conjunctival haemorrhage (SCH) in patients using long-term topical steroid treatment. PATIENTS AND METHODS: a cross sectional survey of the occurrence of SCH was carried out in 248 patients using steroid eye drops and in a comparison group of 113 patients using topical glaucoma medication. RESULTS: twenty-four patients with uveitis (10% of total) experienced single or recurrent SCH. Of these 71% used prednisolone acetate 1% (compared with 75% for those unaffected). None of 113 glaucoma patients were affected. CONCLUSIONS: the long-term use of topical steroid for chronic uveitis substantially increases the prevalence of spontaneous or minimal-trauma SCH. Steroid-induced vascular fragility is the likely cause. PMID- 20930856 TI - Intraocular filarial infection. PMID- 20930857 TI - Intravitreal Ranibizumab in the treatment of choroidal neovascularisation secondary to ocular toxocariasis in a 13-year-old boy. PMID- 20930858 TI - Morning glory with serous macular detachment responds to oral acetazolamide. PMID- 20930859 TI - Diagnostic accuracy of nerve fibre layer, macular thickness and optic disc measurements made with the RTVue-100 optical coherence tomograph to detect glaucoma. AB - PURPOSE: To evaluate the diagnostic accuracy of retinal nerve fibre layer thickness (RNFLT), ganglion cell complex (GCC), and optic disc measurements made with the RTVue-100 Fourier-domain optical coherence tomography (OCT) to detect glaucoma in a Caucasian referral population. METHODS: One randomly selected eye of 286 Caucasian patients (93 healthy, 36 ocular hypertensive, 46 preperimetric glaucoma, and 111 perimetric glaucoma eyes) was evaluated. RESULTS: Using the software-provided classification, for the total population sensitivity did not exceed 73.6% for the optic nerve head parameters, and 62.7% for the other parameters. Specificity was high (94.6-100%) for most RNFLT and GCC parameters, but low (72.0-76.3%) for the optic disc parameters. Positive predictive value varied between 98.1 and 100% for the main RNFLT parameters, 92.6 and 100% for the 16 RNFLT sectors, 92.4 and 99.0% for the GCC parameters, but did not exceed 86.3% for any of the optic disc parameters. Positive likelihood ratio (PLR) was higher than 10 for average, inferior and superior RNFLT (25.5 to infinite), 12 of the 16 RNFLT sectors (12.6 to infinite), and three of the four GCC parameters (40.0 to 48.6). No optic disc parameter had a PLR higher than 3.0. CONCLUSIONS: RNFLT and GCC parameters of the RTVue-100 Fourier-domain OCT showed moderate sensitive but high specificity, positive predictive value and PLR for detection of glaucoma. The optic disc parameters had lower diagnostic accuracy than the RNFLT and GCC parameters. PMID- 20930861 TI - Modified polyethyleneimine with histidine-lysine short peptides as gene carrier. AB - There are several strategies that can be utilized to improve transfection efficiency while reducing the cytotoxicity of polyethyleneimine (PEI) as a promising non-viral gene delivery vector. In this study, we evaluated the potential use of lysine-histidine (KH) peptides in modifying the PEI 10 kDa structure and enhancing its efficiency while maintaining low toxicity of PEI. PEI 10 kDa was modified with 6-bromohexanoic acid (alkyl) to increase its lipophilicity. Then, ethylenediamine (EDA) was attached to the carboxylic groups of PEI-hexanoate to restore the primary amines of PEI. Subsequently, six different KH short peptides were conjugated to PEIs and evaluated for the effect of the KH sequence on vector transfection efficiency and cytotoxicity. The transfection efficiency of PEI-peptides complexed with a luciferase reporter gene (pRLCMV) in Neuro-2A murine neuroblastoma cells showed that the PEI conjugated to KHHHKKHHHK peptide had a significantly higher rate of gene transfection efficiency in comparison with other KH peptides. This peptide was conjugated to PEI-alkyl and PEI-alkyl-EDA and significant improvement in efficiency with minimal cytotoxicity was observed. The results obtained suggest that the sequence and content of KH peptides will have a significant impact on the transfection efficiency of modified PEI 10 kDa. PMID- 20930860 TI - Development of an oncolytic herpes simplex virus using a tumor-specific HIF responsive promoter. AB - We exploited the differential activation of hypoxia-inducible factor (HIF) dependent gene expression in tumors versus normal tissue for the design of a targeted oncolytic herpes simplex virus type-1 (HSV-1). A gene that is essential for viral replication, infected cell polypeptide 4 (ICP4), was placed under the regulation of an HIF-responsive promoter and then introduced into the thymidine kinase locus (U(L)23) of HSV d120, which contains partial deletions in the two endogenous ICP4 genes. Recombinant HIF-HSV was isolated and their derivation from d120 was verified by expression of a truncated, non-functional form of ICP4 protein. Disruption of the U(L)23 locus was confirmed by loss of thymidine kinase expression and resistance to acyclovir. Unexpectedly, HIF-HSV expressed ICP4 and induced tumor cell lysis at similar levels under normoxia and hypoxia. The lack of HIF-dependent ICP4 transgene expression by HIF-HSV was due to two factors that have not previously been reported-reversion of the ICP4 gene region to its wild type configuration and increased HIF-transcriptional activity under normoxia when cells were infected with any strain of HSV-1. The findings that an oncolytic HSV 1 is genetically unstable and can activate a tumor-related promoter in a non specific manner have important implications for any proposed use of this virus in cancer therapy. PMID- 20930862 TI - Prostate cancer: A closer look at the initial results from the REDUCE trial. PMID- 20930864 TI - Surgery: Does laparoscopic adrenalectomy have a role in suspected ACC? PMID- 20930863 TI - Prostate cancer: Patient-reported functional outcomes with radiation therapy. PMID- 20930865 TI - Incontinence: Evaluation of a midurethral single incision sling. PMID- 20930866 TI - Health policy: All-or-none compliance is the best determinant of quality of care. PMID- 20930867 TI - MRI for men undergoing active surveillance or with rising PSA and negative biopsies. AB - The role of imaging in treatment decision-making for patients with prostate cancer is to characterize the cancer already diagnosed on biopsy, to determine tumor location, to assess tumor volume, and to exclude more-extensive disease. MRI is currently the most established imaging modality for this purpose, with the highest sensitivity and specificity for detection and staging of prostate tumors. The development and wider adoption of active surveillance and focal treatment approaches would also benefit from accurate localization of cancer. As such, 3 T MRI and multiparametric approaches are being developed as tools for the localization and staging of prostate cancer. Men wishing to commence or remain on active surveillance might benefit by having larger cancers identified before embarking on this management strategy. MRI might have its greatest role in patients where there is a discrepancy between PSA and biopsy results suggesting a potential missed prostate tumor. PMID- 20930869 TI - [Iron deficiency anemia in Southeastern Asia]. PMID- 20930870 TI - [Competence and authorization]. PMID- 20930868 TI - Management of overactive bladder. AB - Many people are affected by urinary urgency, which can be highly bothersome. Urgency is the cornerstone symptom of overactive bladder (OAB), commonly occurring in conjunction with urinary frequency and nocturia. Once other medical causes of similar symptoms have been excluded, first-line OAB management comprises fluid intake advice and bladder training, supplemented by antimuscarinic drugs if necessary. Urodynamic confirmation of the diagnosis is required for OAB patients whose symptoms are refractory to first-line interventions. If patients are severely bothered by OAB despite optimization of medical treatment, they may proceed to invasive treatments, including neuromodulation, enterocystoplasty, detrusor myectomy, or urinary diversion. Our burgeoning understanding of the complex cellular, neural and integrative physiology of the bladder offers new insights into the causative mechanisms of OAB, and reasons why patients sometimes fail to respond to treatment. Study of sensory information pathways in the lower urinary tract has led to identification of the urothelium, afferent nerves and interstitial cells as key cellular elements in OAB. In-depth knowledge of the hierarchy of central nervous system control is lacking, but functional imaging is beginning to elucidate the challenges that lie ahead. New treatments under investigation include botulinum neurotoxin-A injection, oral beta(3)-adrenergic agonists, and novel modalities for nerve stimulation. The subjective nature of urinary urgency, the lack of animal models and the multifactorial pathophysiology of OAB present significant challenges to effective clinical management. PMID- 20930871 TI - [Sex without borders?]. PMID- 20930872 TI - [Soft tissue injuries following low speed collisions]. PMID- 20930874 TI - [Placing medical historical events in time]. PMID- 20930875 TI - [The power of unclear citations]. PMID- 20930876 TI - [What happened with influenza A(H1N1) serology?]. PMID- 20930877 TI - [Cryopreservation of ovarian tissue is used too seldom!]. PMID- 20930878 TI - [Unwanted sexual experiences and health complaints among adolescents]. AB - BACKGROUND: Strong indicators support a causal relationship between sexual assaults and impaired emotional health. The aim of this study was to investigate the prevalence of unwanted sexual experiences among adolescents and potential associations between such experiences and other health problems. MATERIAL AND METHODS: The study is based on a survey among senior high school students in Forde in 2001. Linear regression analyses were used to examine the association between negative sexual experiences and emotional and somatic impairment. RESULTS: 837 students participated, representing 93 % of the student mass. 7.5 % of the girls and 1.4 % of the boys had experienced a sexual assault. Students with such experiences reported earlier sexual debut and more alcohol intoxication in association with their sexual debut than students without negative experiences. They also had more depression, anxiety and somatic complaints than students without a sexual debut (beta values 0.15-0.18, p < 0.001 in the multivariable analyses). The associations were partly mediated by reduced parental support and lack of self-confidence. INTERPRETATION: Health impairment is associated with earlier unwanted sexual experiences. The study indicates that such experiences may be prevented by consumption of less alcohol in association with the sexual debut, sexual debut at a higher age, and that the health consequences can be alleviated by parental support and the promotion of self confidence. PMID- 20930879 TI - [Age limit for authorization and licensing of doctors]. AB - BACKGROUND: As outlined in the Norwegian Act relating to medical practitioners (of 1980), doctors practising in Norway loose their authorization automatically at age 75, but have the possibility of applying for a continued license. Such a regulation is rather unique from an international point of view. We have investigated doctors' attitude towards this regulation. MATERIAL AND METHOD: The article is based on two postal questionnaire surveys; one sent to 1400 practising doctors in 2006 and one sent to 900 retired doctors in 2007. RESULTS: 69% (969/1400) of the practising and 92 % (829/900) of the retired doctors responded. 80 % (772/969) of the practising and 34 % (284/829) of the retired doctors agreed with the requirement to apply for an extended licence at age 75. 25 % (97/389) of the respondents over 74 years had retained their license at the time of the investigation. INTERPRETATION: Most doctors under age 70 accept automatic discontinuation of authorization at age 75, but support of the regulation decreases with increasing age. PMID- 20930880 TI - [Mechanisms for pain inhibiton in the central nervous system]. AB - BACKGROUND: Several endogenous factors regulate the perception of pain. Understanding of pain-alleviating mechanisms is increasing, which is useful both for doctors who treat pain-ridden patients and for researchers interested in the physiology of pain. This article provides an overview of such mechanisms. MATERIAL AND METHODS: This review article is based on literature identified through a non-systematic search in PubMed. RESULTS: Endogenous pain-alleviating mechanisms are mainly controlled by different parts of the reticular substance, and are normally activated by painful stimulation. Expectation of pain reduction (placebo analgesic effect), painful stimulation in other sites and high blood pressure are examples of factors which may increase the body's endogenous pain alleviating mechanisms. Opioid-sensitive cells in the brain stem are important for endogenous pain alleviation. Reduced endogenous pain alleviation is found in a number of painful conditions, but it has not been clarified whether reduced endogenous pain inhibition is a cause of or a result of chronic pain. INTERPRETATION: Strengthening of the body's own mechanisms for pain alleviation is possible and potentially useful in treatment of pain-ridden patients. PMID- 20930881 TI - [Addictive drugs prescription practice among general practitioners]. AB - BACKGROUND: Rogaland A-senter, Norway has investigated prescription and cessation of benzodiazepine and minor opiates among GPs, and examined their need for external help to deal with this issue. MATERIAL AND METHODS: A questionnaire, to be completed anonymously, was sent to all GPs in Rogaland county in spring 2008. RESULTS: 44% (134) of GPs responded to the survey. All GPs who responded had patients who seemed to use (based on renewal frequency of prescriptions) benzodiazepines or minor opiates on a daily basis. 94% (126) of GPs had patients for whom they doubted the treatment's usefulness. 99% (132) of GPs had attempted cessation, but their patients often lacked motivation. 70% of GPs responded that external help would be useful, both for patients (treatment possibilities) and themselves (guidance, support and knowledge). INTERPRETATION: The results indicate that treatment of patients using benzodiazepine and minor opiates requires a closer cooperation between different levels of health services (primary and specialist). PMID- 20930882 TI - [Sexual dysfunction induced by antidepressants]. AB - Sexual dysfunction is often concurrent with depressive disorders. Antidepressants may induce or augment sexual dysfunction as an adverse effect. About 40% of all patients treated with selective serotonin reuptake inhibitors, or other serotonergic agents, report such effects. If sexual dysfunction is not adequately dealt with it may contribute to noncompliance and thus compromise treatment. For the norepinephrine and dopamine reuptake inhibitor bupropion, the incidence of sexual adverse effects is equal to that for placebo. Additional treatment with bupropion, or switching to mirtazapin or bupropion, may be effective. Studies in men have documented positive effects of concomitant treatment with sildenafil or tadalafil. PMID- 20930883 TI - [Does rhinovirus inhibit influenza A(H1N1) pandemic?]. PMID- 20930884 TI - [Right-sided aortic arch]. PMID- 20930885 TI - [Jungle Nirvana]. PMID- 20930887 TI - Driving disease emergence: will land-use changes beat climate change to the punch? PMID- 20930888 TI - Classification of 'healthier' and 'less healthy' supermarket foods by two Australasian nutrient profiling models. AB - AIM: To determine whether a modified version of the Heart Foundation Tick (MHFT) nutrient profiling model appropriately classifies supermarket foods to endorse its use for identifying 'healthier' products eligible for promotion in a supermarket intervention trial. METHODS: Top-selling products (n=550) were selected from an existing supermarket nutrient composition database. Percentage of products classified as 'healthier' by the MHFT and a modified comparator model (Food Standards Australia New Zealand; MFSANZ) were calculated. Percentage agreement, consistency (kappa statistic), and average nutrient values were assessed overall, and across seven food groups. RESULTS: The MHFT model categorised 16% fewer products as 'healthier' than the MFSANZ model. Agreement and consistency between models were 72% and kappa=0.46 (P=0.00), respectively. For both models, 'healthier' products were on average lower in energy, protein, saturated fat, sugar, and sodium than their 'less healthy' counterparts. CONCLUSION: The MHFT nutrient profiling model categorised regularly purchased supermarket foods similarly to the MFSANZ model, and both appear to distinguish appropriately between 'healthier' and 'less healthy' options. Therefore, both models have the potential to appropriately identify 'healthier' foods for promotion and positively influence food choices. PMID- 20930889 TI - Human myiasis in New Zealand: imported and indigenously-acquired cases: the species of concern and clinical aspects. AB - Reports of myiasis in humans in New Zealand are somewhat rare, and little attention has been paid to this issue in the local medical literature. A number of Diptera (fly) families present in New Zealand have been associated with cases of human myiasis: Calliphoridae (7 species), Fanniidae (2 species), Muscidae (3 species), Oestridae (4 species), Phoridae (3 species), Psychodidae (1 species), Sarcophagidae (2 species), Stratiomyidae (1 species) and Syrphidae (1 species). Despite these numbers, there have only been 6 published records and we obtained further 16 unpublished reports of myiasis acquired in New Zealand. Records of imported myiasis in humans are also rare, with only 2 published and 6 unpublished cases obtained. As many medical practitioners are unaware of myiasis or encounter it rarely, we provide a brief discussion of the clinical features and treatment. PMID- 20930890 TI - An outbreak of Salmonella typhimurium phage type 1 associated with watermelon in Gisborne, January 2009. AB - AIM: To investigate an increase in Salmonella typhimurium phage type 1 (STM1) cases identified in the Gisborne region (eastern North Island, New Zealand) in January 2009. METHODS: Initial investigations found that ham and watermelon were both consumed by a high proportion of cases. A case control study was conducted to determine if there was an association between cases of STM1 in Gisborne and consumption of ham or watermelon. Environmental investigations were conducted and included testing of ham and watermelon samples, as well as trace back of suppliers of these foods. RESULTS: The case control study included 15 cases and 40 controls and found that cases were seven times more likely to have eaten watermelon compared with controls (p=0.026). Cases were one and a half times more likely to have eaten ham compared with controls (p=0.620). Pulsed field gel electrophoresis analysis determined that cases were caused by indistinguishable STM1 isolates. Salmonella was not recovered from any food samples. Trace back found watermelons were purchased from roadside stalls and came from one grower. CONCLUSIONS: This outbreak was associated with watermelon consumption from a grower in the Gisborne region. The outbreak was most likely controlled by the implementation of chlorine washing of watermelons at the grower's pack house. PMID- 20930891 TI - Prevalence of sexually transmitted infections in men who have sex with men presenting to Auckland Sexual Health Service. AB - AIM: Reported incidence of HIV infection and infectious syphilis in New Zealand has been increasing in recent years in men who have sex with men (MSM) but there is no recent published data about prevalence of other sexually transmitted infections (STIs) in this group. Therefore we decided to collect data on prevalent STIs and possible risk factors in a sample of MSM presenting to Auckland Sexual Health Service (ASHS). METHOD: All MSM presenting to ASHS during the study period were eligible for enrollment. Data on demographics, sexual behaviour, use of recreational drugs and STI diagnoses was collected and entered into a data collection form after verbal consent was obtained. RESULTS: Eighty seven men participated in the survey. A third of the men were symptomatic (n=26) and 44% (n=38) were diagnosed with a new STI including 2 with infectious syphilis and 3 with HIV. The Internet (65%) was the most common method used for meeting sex partners (n=55) and 46% of men (n=37) reported use of recreational drugs within the previous 6 months. Sixty percent (n=52) of men reported more than 5 sexual partners within the previous 6 months and 52% were engaging in concurrent sexual partnerships with both casual and regular partners(n=45). Participants were more likely to use condoms for insertive and receptive anal sex with casual than with regular partners (p=0.0004, p=0.005), however a history of consistent condom use did not rule out diagnosis with a new STI or HIV. CONCLUSION: There was a high prevalence of STIs (44%) in this sample of MSM presenting to a sexual health clinic. Many were presenting with problems rather than attending for routine screening. Possible explanations for the high STI rate include high rates of concurrent sexual partnerships (52%), lower rates of consistent condom use within relationships and use of recreational drugs. Internet use was a common method for meeting sex partners and offers future potential for health promotion interventions for MSM. STI screening should be regularly offered to sexually active MSM regardless of whether they report consistent condom use. PMID- 20930892 TI - Land-use change and emerging public health risks in New Zealand: assessing Giardia risks. AB - Agriculture is key to New Zealand's economy with land-use conversions in response to market forces occurring regularly, like that of recent dairy intensification throughout the country. However, land-use conversion can occasionally result in unexpected and significant consequences for public health that need to be accurately estimated and subsequently managed accordingly. For example, dairy cattle have high Giardia prevalence in New Zealand and identical strains from infected humans and cattle located in the same geographical region have recently been reported. Thus, the high rates of human infections in New Zealand compared to similar socioeconomic countries caused by the waterborne pathogen Giardia are particularly concerning given the increasing dairy cattle populations on the landscape. However, the ability of traditional, evidence-based, epidemiological approaches to detect such causal relationships between land-use and Giardia infections is limited given the many possible indirect links between the two, in turn highlighting the need to develop appropriate risk assessment techniques. As such, the general requirements for and development of risk assessment frameworks to evaluate the likelihood of public health risks from waterborne pathogens are introduced and explored using Giardia in New Zealand as an example. Specifically, the importance of recent advances in Giardia-based knowledge, the incorporation of such data into existing risk assessment frameworks and the influence of remaining research gaps are each discussed for expanding currently available risk assessment tools. Not surprisingly, the availability of appropriate risk assessment tools for agencies responsible for public health and environmental management would ensure the public health risks for Giardia resulting from land use change could be quantified holistically and strategies subsequently developed through active agency communication to minimise such risks. PMID- 20930893 TI - Anti-NMDA-receptor autoimmune encephalitis without neoplasm: a rare condition? PMID- 20930894 TI - Atypical gastric ulcer with characteristic eschar appearance. AB - Cocaine is a known potent vasoconstrictor known to cause various complications ranging from nasal septum perforations to myocardial ischemia. Many gastrointestinal effects of cocaine are reported, including bowel ischemia and gangrene. The knowledge on endoscopic appearance of cocaine-induced gastric ulcers is limited, mainly due to presentation of patients with frank perforations. We report a case of 48 year old male, a non-smoker but chronic substance abuser, who presented with abdominal pain, mainly epigastric with radiation to the back. Abdominal CT scan was normal, and endoscopy showing a single chronic non-bleeding ulcer at the incisura. The ulcer due to large sized, round in shape with irregular borders and thick eschar appearance is characteristic of cocaine-induced ulcer. It is important for physicians to remain cognisant of gastrointestinal complications of cocaine, recognise these ulcers endoscopically and prevent perforations in these subsets of patients. PMID- 20930895 TI - Medical image. Kidney solitaire: pearls to share. PMID- 20930896 TI - Medical image. Delayed puberty--an occult systemic cause. PMID- 20930897 TI - Defendants of the Cartwright Inquiry are unable to provide a description of 'adequate care' for cervical carcinoma in situ. PMID- 20930898 TI - Clare Matheson protests too much. PMID- 20930899 TI - Clare Matheson's inaccurate reporting. PMID- 20930900 TI - A farsighted energy strategy would benefit health in New Zealand. PMID- 20930902 TI - Response to letters by Paul and Bunkle. PMID- 20930901 TI - The doctor's dilemma. PMID- 20930903 TI - A particular relationship: part 2. PMID- 20930904 TI - The New Zealand Medical Journal, Thomson Reuters ISI, and the impact factor. PMID- 20930905 TI - Net-based information on varicose vein treatments: a tangled web. AB - AIMS: 30-40% of individuals will be affected by varicose veins during their lifetime. Many will contemplate treatment and will access the (Inter)net for information. The aim of this study is to determine whether New Zealand-based websites are an accurate source of information for the public. METHODS: Inclusion criteria were New Zealand based websites that contained information on varicose vein treatments. These websites were identified using the search-engines Google and Yahoo. The first 60 websites from each were evaluated and subdivided into 4 groups based on web-site ownership: (1) Vein clinic/hospital; (2) Appearance medicine; (3) Online stores; (4) Health editorials; and (5) Medical resources. RESULTS: 46 of the 120 websites satisfied the inclusion criteria. 18 websites (39%) explained what varicose veins were. Information about treatment options was most comprehensive in the "Vein clinic/hospital" group. The "Appearance medicine" group mostly contained information on outpatient interventional therapies. "Health editorial" sites had lifestyle modification options. All the online herbal/health stores mentioned herbal treatment options. CONCLUSION: Few websites fully informed patients about treatment options while some simply advertised non evidence based treatments. This study suggests that the Internet is not a reliable source of information and does not accurately inform patients about varicose veins and the treatment options. PMID- 20930906 TI - Development of the Rural Immersion Programme for 5th-year medical students at the University Of Otago. AB - AIMS: To report the development of the first Rural Medical Immersion Programme (RMIP) of the University of Otago in New Zealand. METHOD: We review medical education trends and challenges for educating New Zealand's doctors and recruiting them to careers in rural practice. We describe key features of the RMIP developed in response to these challenges. RESULTS: Medical education is evolving from discipline and hospital-based teaching to using more integrated, community-based teaching. The RMIP aims to immerse 5th-year medical students in an integrated, patient-centred, community-based, parallel learning environment where learners' experiences in primary, secondary, and tertiary settings are always based on patient care. Government funding for the RMIP pilot was granted in November 2006 and the first 6 students started in the programme in 2007. Experiences of the programme from 2007-2009 are reported. CONCLUSION: The RMIP remains true to the principles underpinning its establishment and has to date delivered successful medical education outcomes for the first 18 students of the 2007 and 2008 cohorts. We cannot yet assess its role in future recruitment to rural medical careers. PMID- 20930907 TI - Completing an intercalated research degree during medical undergraduate training: barriers, benefits and postgraduate career profiles. AB - AIM: To undertake a comprehensive evaluation of the intercalated research degree at the School of Medicine, University of Auckland, New Zealand and to ascertain the career profiles of Auckland medical graduates who completed the intercalated degree programme. METHOD: A questionnaire was devised and mailed to all Auckland MBChB graduates (1972-2005) who completed an intercalated research degree during the undergraduate medical course. RESULTS: Among 50 graduates who met the inclusion criteria (mean of 1.5 per annum), 30 (60%) completed the questionnaire. An interest in a career in research and academic medicine was the most commonly cited reason for undertaking an intercalated degree. Eighty percent of respondents encountered some problems during the intercalated year, with the most common reported being loss of contact with friends in the medical course. The satisfaction associated with an intercalated degree was generally high, with 90% giving an affirmative response to the statement that 'it was a worthwhile endeavour.' However, a majority of respondents were reluctant to do the intercalated degree again if given time over as a medical student in the current environment (33% affirmative versus 43% negative). Only one respondent was in general practice, whereas 73% of the respondents were either consultants or trainees in other specialties. Ninety percent of the respondents had been involved with research since graduation and 33% already possessed a higher research degree, such as MD or PhD. CONCLUSIONS: Despite the extremely low uptake rate of the intercalated degree option, the graduates who took the intercalated degree option were generally satisfied with their experience. However, although the majority of respondents reported that the intercalated degree was worthwhile and 90% had also completed further research since graduation, 43% would be reluctant to pursue an intercalated degree in the current environment. PMID- 20930908 TI - Medical students' attitudes towards research and a career in research: an Auckland, New Zealand study. AB - AIM: To determine the attitudes towards research and research careers among students at a New Zealand medical school. METHODS: A questionnaire was devised and distributed during compulsory lecture sessions to all medical students enrolled at the School of Medicine, University of Auckland during the 2007 academic year. RESULTS: Among the 756 students enrolled for the 2007 academic year, 558 responded, with an overall response rate of 74%. Twenty-five percent of students had participated in some form of research activity during medical school, with summer studentships being the most common type of research experience. Seventy percent of all students surveyed expressed interest in participating in research during medical school. Although 68% of respondents were aware of the intercalated research degree option at the School of Medicine, only 8.6% expressed interest in undertaking this option. The most common reasons for not pursuing an intercalated degree option were lack of interest in this format of research experience (46%), social reasons (29%), and financial reasons (27%). There was no widespread support from the students for having research training as a compulsory part of medical school curriculum. With respect to long-term career plan, 35% of respondents planned to be involved in research throughout their medical career, and 22% were interested in pursuing higher degrees (MD or PhD) following graduation. However, more students rated lifestyle (84% affirmative) and earning potential (43% affirmative) as more important factors than opportunity for research (23% affirmative) when choosing a career specialty. CONCLUSIONS: The New Zealand medical students sampled reported a significant interest in research, with a majority of the students planning to participate in extracurricular research activities during medical school, and many hoping to be involved in research throughout their medical careers. However, only a small number of students were interested in pursuing research through an intercalated undergraduate degree option. Ultimately, the opportunity for research was deemed to be a less important consideration when choosing a specialty, compared to lifestyle and earning potential. PMID- 20930909 TI - Using the asthma control test to improve asthma outcomes. AB - There is a major gap between what can be achieved with modern asthma management and what is currently being achieved. One of the main reasons for this is a lack of recognition of asthma control and the requirement for more effective treatment it is only through identifying those patients with uncontrolled asthma that appropriate treatment will be prescribed. In part, the difficulty in the assessment of control relates to the lack of a clear therapeutic target in asthma. This contrasts with other chronic diseases such as hypertension or diabetes where treatment is prescribed in order to achieve a definite therapeutic target. One approach to this difficulty is to develop a simple test which is a screening tool to identify patients with poorly controlled asthma. The Asthma Control Test (ACT) has been developed and validated for this purpose. It involves patients completing a simple written questionnaire of 5 questions, from which a score (out of 25) is obtained. It has been shown that the ACT is a simple, quick and accurate tool for assessing asthma control and it has been shown to be responsive to changes in asthma control over time. It can easily be incorporated into the routine assessment of patients with asthma and enable busy healthcare professionals to more easily identify patients whose asthma control can be improved, enabling changes to their management to be made and thereby improve outcomes. PMID- 20930910 TI - Dr Nathan Tucker's Asthma Specific--a treatment for asthma preceding inhaled steroids and beta-agonists. AB - We present the case of an 83-year-old woman who was diagnosed with bronchial asthma in 1929 and had been treated in her childhood with "Dr Nathan Tucker Asthma Specific", a cocaine-based aerosolised asthma treatment. PMID- 20930911 TI - Zolendronate associated inflammatory orbital disease. AB - Bisphosphonate infusions are associated with adverse events in approximately a third of patients. Ocular complications are rare and even more so, inflammatory orbital disease. Bisphosphonate-induced orbital inflammation is not a well recognised complication and there have been only a few published case reports of this. We present a case of orbital inflammatory disease associated with zolendronate infusion. PMID- 20930912 TI - Medical image: A case of five fingers and a murmur. PMID- 20930913 TI - Carotid endarterectomy: a Southern North Island regional consensus statement. AB - AIMS: The aim of this project was to employ interdepartmental and cross district health board collaboration to reach a regional consensus on the management of patients who may benefit from carotid endarterectomy. METHODS: All regional stroke physicians, neurologists, and vascular surgeons met to review relevant literature and local audits and to discuss best management strategies suited to the region. RESULTS: A consensus statement was agreed upon and is presented here along with a summary of the supporting scientific evidence. DISCUSSION: Regional interdisciplinary collaboration proved an effective way to reach a carotid endarterectomy management consensus across a wider geographical area that is served by a single vascular surgery department. This approach could serve as a model for other regional initiatives. PMID- 20930914 TI - NZMJ's impact factor. PMID- 20930915 TI - Response to Ron Paterson's editorial on the Cartwright legacy. PMID- 20930916 TI - Revisiting the Cartwright report. PMID- 20930917 TI - Correcting an error but inadequate treatment of cervical cancer still occurred. PMID- 20930918 TI - Confusion surrounding the unfortunate experiment. PMID- 20930919 TI - A particular relationship: part 3. PMID- 20930920 TI - GP training. PMID- 20930921 TI - Hydrophobic Proteome Analysis of Triple Negative and Hormone-Receptor-Positive Her2-Negative Breast Cancer by Mass Spectrometer. AB - INTRODUCTION: It is widely believed that discovery of specific, sensitive, and reliable tumor biomarkers can improve the treatment of cancer. Currently, there are no obvious targets that can be used in treating triple-negative breast cancer (TNBC). METHODS: To better understand TNBC and find potential biomarkers for targeted treatment, we combined a novel hydrophobic fractionation protocol with mass spectrometry LTQ-orbitrap to explore and compare the hydrophobic sub proteome of TNBC with another subtype of breast cancer, hormone-receptor-positive Her2-negative breast cancer (non-TNBC). RESULTS: Hydrophobic sub-proteome of breast cancer is rich in membrane proteins. Hundreds of proteins with various defined key cellular functions were identified from TNBC and non-TNBC tumors. In this study, protein profiles of TNBC and non-TNBC were systematically examined, compared, and validated. We have found that nine keratins are down-regulated and several heat shock proteins are up-regulated in TNBC tissues. Our study may provide insights of molecules that are responsible for the aggressiveness of TNBC. CONCLUSION: The initial results obtained using a combination of hydrophobic fractionation and nano-LC mass spectrometry analysis of these proteins appear promising in the discovery of potential cancer biomarkers and bio-signatures. When sufficiently refined, this approach may prove useful in improving breast cancer treatment. PMID- 20930922 TI - Novel In Situ Collection of Tumor Interstitial Fluid from a Head and Neck Squamous Carcinoma Reveals a Unique Proteome with Diagnostic Potential. AB - INTRODUCTION: Tumors lack normal drainage of secreted fluids and consequently build up tumor interstitial fluid (TIF). Unlike other bodily fluids, TIF likely contains a high proportion of tumor-specific proteins with potential as biomarkers. METHODS: Here, we evaluated a novel technique using a unique ultrafiltration catheter for in situ collection of TIF and used it to generate the first catalog of TIF proteins from a head and neck squamous cell carcinoma (HNSCC). To maximize proteomic coverage, TIF was immunodepleted for high abundance proteins and digested with trypsin, and peptides were fractionated in three dimensions prior to mass spectrometry. RESULTS: We identified 525 proteins with high confidence. The HNSCC TIF proteome was distinct compared to proteomes of other bodily fluids. It contained a relatively high proportion of proteins annotated by Gene Ontology as "extracellular" compared to other secreted fluid and cellular proteomes, indicating minimal cell lysis from our in situ collection technique. Several proteins identified are putative biomarkers of HNSCC, supporting our catalog's value as a source of potential biomarkers. CONCLUSIONS: In all, we demonstrate a reliable new technique for in situ TIF collection and provide the first HNSCC TIF protein catalog with value as a guide for others seeking to develop tumor biomarkers. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s12014-010-9050-3) contains supplementary material, which is available to authorized users. PMID- 20930923 TI - Explaining Underrepresentation: A Theory of Precluded Interest. AB - What processes best explain women's underrepresentation in science, math, and engineering fields in the U.S.? Do they also explain men's underrepresentation in the humanities? Two survey studies across two U.S. West Coast universities (N = 62; N = 614) addressed these questions in the context of two fields: one male dominated (computer science) and the other female-dominated (English). Among a set of social predictors-including perceived similarity to the people in the field, social identity threats, and expectations of success-the best mediator of women's lower interest in computer science and men's lower interest in English was perceived similarity. Thus, changing students' social perceptions of how they relate to those in the field may help to diversify academic fields. PMID- 20930924 TI - Measuring Negative and Positive Thoughts in Children: An Adaptation of the Children's Automatic Thoughts Scale (CATS). AB - The aim of this study is to describe the factor structure and psychometric properties of an extended version of the Children's Automatic Thoughts Scale (CATS), the CATS-Negative/Positive (CATS-N/P). The CATS was originally designed to assess negative self-statements in children and adolescents. However, positive thoughts also play a major role in childhood disorders such as anxiety and depression. Therefore, positive self-statements were added to the CATS. The CATS N/P was administered to a community sample of 554 children aged 8-18 years. The results of a confirmatory factor analysis revealed that the positive self statements formed a separate and psychometrically sound factor. Internal and short-term test-retest reliability was good. Boys reported more hostile and positive thoughts than girls; and younger children reported more negative thoughts concerning physical threat, social threat, and failure than older children. In conclusion, the results of the current study support the use of the CATS-N/P for the measurement of positive and negative thoughts in children. The application of the CATS-N/P can facilitate further research on cognitive factors in different childhood disorders. PMID- 20930925 TI - The Relationship Between Homework Compliance and Therapy Outcomes: An Updated Meta-Analysis. AB - The current study was an updated meta-analysis of manuscripts since the year 2000 examining the effects of homework compliance on treatment outcome. A total of 23 studies encompassing 2,183 subjects were included. Results indicated a significant relationship between homework compliance and treatment outcome suggesting a small to medium effect (r = .26; 95% CI = .19-.33). Moderator analyses were conducted to determine the differential effect size of homework on treatment outcome by target symptoms (e.g., depression; anxiety), source of homework rating (e.g., client; therapist), timing of homework rating (e.g., retroactive vs. contemporaneous), and type of homework rating (e.g., Likert; total homeworks completed). Results indicated that effect sizes were robust across target symptoms, but differed by source of homework rating, timing of homework rating, and type of homework rating. Specifically, studies utilizing combined client and therapist ratings of compliance had significantly higher mean effect size relative to those using therapist only assessments and those using objective assessments. Further, studies that rated the percentage of homeworks completed had a significantly lower mean effect size compared to studies using Likert ratings, and retroactive assessments had higher effect size than contemporaneous assessments. PMID- 20930926 TI - An efficient gene deletion procedure for the mushroom-forming basidiomycete Schizophyllum commune. AB - Gene deletion in Schizophyllum commune is hampered by a low incidence of homologous integration. As a consequence, extensive screening is required to identify a transformant with the desired genotype. To alleviate this and to facilitate the assembly of deletion plasmids, vector pDelcas was constructed. This construct has a set of restriction sites, which allows for directional cloning of the flanking sequences at both sides of a nourseothricin resistance cassette. Moreover, it contains a phleomycin resistance cassette elsewhere in the plasmid, which is used to screen for transformants with an ectopic integration of the pDelcas derivative. The use of pDelcas derivatives in combination with an improved PCR screening protocol permitted the efficient identification of S. commune deletion strains. This procedure may also function in other basidiomycetes. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11274-010-0356-0) contains supplementary material, which is available to authorized users. PMID- 20930927 TI - Health-related quality of life in adolescents and young adults with high functioning autism-spectrum disorder. AB - AIM: Over the last years, health-related quality of life (HRQOL) has emerged as an important measure not only in somatic medicine but also in psychiatry. To date, there are only few reports on HRQOL in patients with autism-spectrum disorder (ASD). This study aimed at studying HRQOL in ASD patients with an IQ >70, using a self-report HRQOL questionnaire with cross-cultural validity. METHODS: In this cross-sectional study, twenty-six male adolescents and young adults with the diagnosis of Asperger Syndrome, high functioning autism and atypical autism were evaluated, using the German version of the WHOQOL-BREF HRQOL questionnaire. RESULTS: Mean WHOQOL-BREF global scores were 60.6 (SD +/-26.1), mean WHOQOL-BREF subscale scores were 70.1 (SD +/-19.1) for the domain "physical health", 61.5 (SD +/-21.9) for the domain "psychological health", 53.8 (SD +/ 23.5) for the domain "social relationships" and 67.9 (SD +/-17.4) for the domain "environment". Compared to a reference population of healthy controls, our sample scored significantly lower in three of four WHOQOL-BREF domains. In comparison to a reference sample of individuals with schizophrenia spectrum disorder (SSD), HRQOL of our sample was significantly better in all domains except for the "social relations" domain. There was a significant association between HRQOL and the Vineland Adaptive Behavior Scales domain "daily living skills", but not with age, IQ, or ADOS-G summary scores. CONCLUSION: Overall self-reported HRQOL in patients with high functioning ASD seems to be lower than in healthy individuals, but better than in patients with SSD. Also, higher HRQOL was associated with better daily living skills. This interrelationship should especially be accounted for in the design and application of treatment programmes for individuals with ASD, as it is of importance for the level of self-perceived HRQOL. PMID- 20930928 TI - Psychodynamic mechanism and weight reduction in obesity group therapy - first observations with different attachment styles. AB - OBJECTIVES: Successful long-term results are extremely rare in non-surgical obesity treatment. Interactional difficulties with the attending physicians and the limited compliance of obese patients are a frequently described dilemma in repeated psychotherapeutic group treatment attempts. The type of relationship initiation and the attachment behavior probably play a central role in this connection but have not yet been systematically investigated. METHODS: This paper focuses on the attachment styles of obese subjects and their effects on psychodynamic group therapy within the context of a weight-reduction program. RESULTS: The attachment styles are characterized in 107 pre-obese and obese patients, and their effects on patients and therapists in group therapy are described. CONCLUSION: The paper surveys the motivational situation, clinical pictures, and repeated group topics. PMID- 20930929 TI - A case of gastric polyposis in antral area of stomach following prolonged proton pump therapy. AB - We describe the clinical scenario of a young male with history of non ulcer dyspepsia who had endoscopic evidence of gastric polyposis in antral area. The polyps disappeared four months after proton pump inhibitors were stopped. Proton pump inhibitors have been linked to gastric fundal polyposis and not antral gland polyposis. This is the first report originating from an Asian country describing antral gland polyposis (AGPs) in a patient on long-term PPI therapy with no evidence of Helicobacter pylori. A case report with brief review is presented. PMID- 20930930 TI - Epithelioid finger-sarcoma in an 11 year old girl--a case report. AB - Malignant tumors of pediatric hand are very rare. This case report describes an epithelioid sarcoma at the finger of an 11 year old girl and discusses general treatment options in this rare patient population. PMID- 20930932 TI - New approach to breast tumor detection based on fluorescence x-ray analysis. AB - A new technical approach to breast-tumor detection is proposed. The technique is based on fluorescence x-ray analysis, and can identify a miniature malignant tumor within the breast. The primary beam intensity needed in fluorescence x-ray analysis is on a lower order of magnitude than that used in mammography. Thus, the newly-proposed technique would enable detection of a still tiny breast cancer while dramatically lowering the radiation dose. Field-emission x-ray sources might be a key for translating this concept into a medical technique. PMID- 20930931 TI - Role of the complement components C5 and C3a in a mouse model of myocardial ischemia and reperfusion injury. AB - OBJECTIVE: Ischemic heart disease is the leading cause of death worldwide. The complement system plays a major role in inflammation and tissue injury following myocardial ischemia and reperfusion (MI/R) injury. Systemic C5 inhibition in clinical studies has resulted in mixed results and the role of earlier complement components (e.g., C3a), upstream from C5 cleavage, has not been elucidated for MI/R injury. Therefore, we evaluated the role of C5 or C3a in a mouse model of MI/R injury. METHODS: We performed experimental MI/R with 30 min of ischemia and 4 hr of reperfusion in 8-12 wk old C57BL/6 (WT) mice. Systemic C5 or C3a inhibition was performed with an anti-C5 monoclonal antibody (BB5.1) 30 min prior to reperfusion or with a C3a receptor antagonist (C3aRA). Since the C3aRA induces neutropenia that resolves within 120 min, we administered C3aRA at two different time points in two separate groups: 30 min prior to reperfusion within the neutropenic time frame and 120 min prior to reperfusion, when the neutropenia had resolved, but C3aRA remained active. Following MI/R, cardiac function was assessed via echocardiography, serum troponin I concentrations were measured as an index of myocardial cell death and myocardial inflammation was determined via myocardial polymorphonuclear leukocyte (PMN) infiltration. RESULTS: In wild type mice, MI/R significantly decrease myocardial ejection fraction and increased serum troponin I levels and myocardial PMN infiltration compared to sham-operated animals. Systemic C5 inhibition, 30 min prior to reperfusion, significantly protected mice from MI/R injury, confirming an important role for C5 in murine MI/R injury.Treatment with the C3aRA, 30 min prior to reperfusion (i.e., within the neutropenic time frame), protected mice significantly from MI/R related injury. In contrast, administration of the C3aRA 120 min prior to reperfusion, when the neutropenia had resolved, but C3aRA remained active, did not prevent MI/R injury. CONCLUSIONS: These results confirm an important role for C5 cleavage in murine MI/R injury. At the same time, they suggest a minimal role for C3a, since neutropenia rather than C3a receptor antagonism appears to be responsible for C3aRA related amelioration in MI/R injury. While C5 inhibition in the clinical setting of MI/R does not appear to be therapeutic, our results raise the possibility that inhibition of either C5a or C5b-9 may be more advantageous than inhibition of C3a or complete inhibition of C5 in humans. PMID- 20930933 TI - Microfluidic device for robust generation of two-component liquid-in-air slugs with individually controlled composition. AB - Using liquid slugs as microreactors and microvessels enable precise control over the conditions of their contents on short-time scales for a wide variety of applications. Particularly for screening applications, there is a need for control of slug parameters such as size and composition. We describe a new microfluidic approach for creating slugs in air, each comprising a size and composition that can be selected individually for each slug. Two-component slugs are formed by first metering the desired volume of each reagent, merging the two volumes into an end-to-end slug, and propelling the slug to induce mixing. Volume control is achieved by a novel mechanism: two closed chambers on the chip are initially filled with air, and a valve in each is briefly opened to admit one of the reagents. The pressure of each reagent can be individually selected and determines the amount of air compression, and thus the amount of liquid that is admitted into each chamber. We describe the theory of operation, characterize the slug generation chip, and demonstrate the creation of slugs of different compositions. The use of microvalves in this approach enables robust operation with different liquids, and also enables one to work with extremely small samples, even down to a few slug volumes. The latter is important for applications involving precious reagents such as optimizing the reaction conditions for radiolabeling biological molecules as tracers for positron emission tomography. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10404-010-0617-0) contains supplementary material, which is available to authorized users. PMID- 20930934 TI - Alteration of microRNAs regulated by c-Myc in Burkitt lymphoma. AB - BACKGROUND: Burkitt lymphoma (BL) is an aggressive B-cell lymphoma, with a characteristic clinical presentation, morphology and immunophenotype. Over the past years, the typical translocation t(8;14) and its variants have been considered the molecular hallmark of this tumor. However, BL cases with no detectable MYC rearrangement have been identified. Intriguingly, these cases express MYC at levels comparable with cases carrying the translocation. In normal cells c-Myc expression is tightly regulated through a complex feedback loop mechanism. In cancer, MYC is often dysregulated, commonly due to genomic abnormalities. It has recently emerged that this phenomenon may rely on an alteration of post-transcriptional regulation mediated by microRNAs (miRNAs), whose functional alterations are associated with neoplastic transformation. It is also emerging that c-Myc modulates miRNA expression, revealing an intriguing crosstalk between c-Myc and miRNAs. PRINCIPAL FINDINGS: Here, we investigated the expression of miRNAs possibly regulated by c-Myc in BL cases positive or negative for the translocation. A common trend of miRNA expression, with the exception of hsa-miR-9*, was observed in all of the cases. Intriguingly, down-regulation of this miRNA seems to specifically identify a particular subset of BL cases, lacking MYC translocation. Here, we provided evidence that hsa-miR-9-1 gene is heavily methylated in those cases. Finally, we showed that hsa-miR-9* is able to modulate E2F1 and c-Myc expression. CONCLUSIONS: Particularly, this study identifies hsa-miR-9* as potentially relevant for malignant transformation in BL cases with no detectable MYC translocation. Deregulation of hsa-miR-9* may therefore be useful as a diagnostic tool, suggesting it as a promising novel candidate for tumor cell marker. PMID- 20930939 TI - Ganglioside metabolism in a transgenic mouse model of Alzheimer's disease: expression of Chol-1alpha antigens in the brain. AB - The accumulation of Abeta (amyloid beta-protein) is one of the major pathological hallmarks in AD (Alzheimer's disease). Gangliosides, sialic acid-containing glycosphingolipids enriched in the nervous system and frequently used as biomarkers associated with the biochemical pathology of neurological disorders, have been suggested to be involved in the initial aggregation of Abeta. In the present study, we have examined ganglioside metabolism in the brain of a double Tg (transgenic) mouse model of AD that co-expresses mouse/human chimaeric APP (amyloid precursor protein) with the Swedish mutation and human presenilin-1 with a deletion of exon 9. Although accumulation of Abeta was confirmed in the double Tg mouse brains and sera, no statistically significant change was detected in the concentration and composition of major ganglio-N-tetraosyl-series gangliosides in the double-Tg brain. Most interestingly, Chol-1alpha antigens (cholinergic neuron specific gangliosides), such as GT1aalpha and GQ1balpha, which are minor species in the brain, were found to be increased in the double-Tg mouse brain. We interpret that the occurrence of these gangliosides may represent evidence for generation of cholinergic neurons in the AD brain, as a result of compensatory neurogenesis activated by the presence of Abeta. PMID- 20930941 TI - Feasibility of Using Modified Adaptive Conjoint Analysis Importance Questions. AB - PURPOSE: Prior practical experience in conducting ACA surveys has demonstrated that many subjects have difficulty understanding the "importance" questions. The objective of this study was to develop a modified version of ACA's importance questions. METHODS: Modified ACA importance questions composed of two tasks were developed and tested in a pilot study of patients with knee pain. In the first, respondents were presented with the list of attributes and asked to choose which they consider to be the most important. In the second, they were asked to rate the importance of the remaining attributes relative to the most important one on an 11-point numeric rating scale. Consecutive patients, followed at a hospital based Bone and Joint Clinic with knee pain, were randomized to complete the original or modified version of the ACA survey. The two versions were identical except for the importance questions. The ACA survey included six attributes: pain, energy, route of administration, stomach upset, bleeding ulcer and cost. Each attribute contained three levels, all of which had a natural order except for route of administration. As this was a pilot study, we present descriptive statistics only. RESULTS: 49 patients were recruited; 24 completed the original version and 25 completed the modified version. Subjects felt that bar graphs illustrating the relative importances were more accurate for the modified version of ACA. The proportion of subjects for which the most important attribute chosen on a card sorting task matched that generated by ACA was greater for the modified compare to original version (48% vs 29%). The proportion of subjects for which the treatment option chosen on a card sorting task matched that predicted by ACA was also greater for the modified compare to original version (80% versus 75%). Subjects used a greater number of points to rate the importance of attributes on the modified version of ACA (3.4 +/- 0.9) compared to the original version (2.7 +/- 1.0). CONCLUSIONS: The modified version of the ACA importance questions appears to perform as well or better then the original version. Use of a simplified set of ACA importance questions is a reasonable alternative for investigators interested in using ACA as a decision support tool in clinical practice. PMID- 20930942 TI - Anticancer Drug-Phospholipid Conjugate for Enhancement of Intracellular Drug Delivery. AB - Tumor specific delivery of anti-cancer drugs is one of the major challenges faced by drug development processes. In this study, we prepared a doxorubicin (DOX) conjugated liposome (DCL) by incorporating the newly synthesized DSPE-PEG2000-DOX (DPD) into liposomes as a lipid component and tested its anti-tumor activity in vivo. DPD was synthesized by coupling DOX to DSPE-PEG2000-COOH via amide linkage and the chemical structure of resulting DPD was confirmed by (1)H-NMR analysis. DCL having liposome size of 130 nm was prepared through thin film cast-hydration method. DCL was found to have significantly higher cellular uptake than conventional liposomes as confirmed by flow cytometry analysis. Anti-tumor activity of DCL against murine B16F10 melanoma tumor-bearing mice revealed that DCL inhibits tumor growth more efficiently than the conventional liposomes, presumably attributed to DOX mediated endocytosis process. PMID- 20930940 TI - Variation in the biological properties of HIV-1 R5 envelopes: implications of envelope structure, transmission and pathogenesis. AB - HIV-1 R5 viruses predominantly use CCR5 as a coreceptor to infect CD4(+) T cells and macrophages. While R5 viruses generally infect CD4(+) T cells, research over the past few years has demonstrated that they vary extensively in their capacity to infect macrophages. Thus, R5 variants that are highly macrophage tropic have been detected in late disease and are prominent in brain tissue of subjects with neurological complications. Other R5 variants that are less sensitive to CCR5 antagonists and use CCR5 differently have also been identified in late disease. These latter variants have faster replication kinetics and may contribute to CD4 T-cell depletion. In addition, R5 viruses are highly variable in many other properties, including sensitivity to neutralizing antibodies and inhibitors that block HIV-1 entry into cells. Here, we review what is currently known about how HIV-1 R5 viruses vary in cell tropism and other properties, and discuss the implications of this variation on transmission, pathogenesis, therapy and vaccines. PMID- 20930944 TI - Two-Dimensional Modeling of Nanomechanical Strains in Healthy and Diseased Single Cells During Microfluidic Stress Applications. AB - Investigations in cellular and molecular engineering have explored the impact of nanotechnology and the potential for monitoring and control of human diseases. In a recent analysis, the dynamic fluid-induced stresses were characterized during microfluidic applications of an instrument with nanometer and picoNewton resolution as developed for single-cell biomechanics (Kohles, S. S., Neve, N., Zimmerman, J. D., and Tretheway, D. C., 2009, "Stress Analysis of Microfluidic Environments Designed for Isolated Biological Cell Investigations," ASME J. Biomech. Eng., 131(12), p. 121006). The results described the limited stress levels available in laminar, creeping-flow environments, as well as the qualitative cellular strain response to such stress applications. In this study, we present a two-dimensional computational model exploring the physical application of normal and shear stress profiles (with 0.1, 1.0, and 10.0 Pa peak amplitudes) potentially available within uniform and extensional flow states. The corresponding cellular strains and strain patterns were determined within cells modeled with healthy and diseased mechanical properties (5.0-0.1 kPa moduli, respectively). Strain energy density results integrated over the volume of the planar section indicated a strong mechanical sensitivity involving cells with disease-like properties. In addition, ex vivo microfluidic environments creating in vivo stress states would require freestream flow velocities of 2-7 mm/s. Knowledge of the nanomechanical stresses-strains necessary to illicit a biologic response in the cytoskeleton and cellular membrane will ultimately lead to refined mechanotransduction relationships. PMID- 20930943 TI - Biomedical Nanomagnetics: A Spin Through Possibilities in Imaging, Diagnostics, and Therapy. AB - Biomedical nanomagnetics is a multidisciplinary area of research in science, engineering and medicine with broad applications in imaging, diagnostics and therapy. Recent developments offer exciting possibilities in personalized medicine provided a truly integrated approach, combining chemistry, materials science, physics, engineering, biology and medicine, is implemented. Emphasizing this perspective, here we address important issues for the rapid development of the field, i.e., magnetic behavior at the nanoscale with emphasis on the relaxation dynamics, synthesis and surface functionalization of nanoparticles and core-shell structures, biocompatibility and toxicity studies, biological constraints and opportunities, and in vivo and in vitro applications. Specifically, we discuss targeted drug delivery and triggered release, novel contrast agents for magnetic resonance imaging, cancer therapy using magnetic fluid hyperthermia, in vitro diagnostics and the emerging magnetic particle imaging technique, that is quantitative and sensitive enough to compete with established imaging methods. In addition, the physics of self-assembly, which is fundamental to both biology and the future development of nanoscience, is illustrated with magnetic nanoparticles. It is shown that various competing energies associated with self-assembly converge on the nanometer length scale and different assemblies can be tailored by varying particle size and size distribution. Throughout this paper, while we discuss our recent research in the broad context of the multidisciplinary literature, we hope to bridge the gap between related work in physics/chemistry/engineering and biology/medicine and, at the same time, present the essential concepts in the individual disciplines. This approach is essential as biomedical nanomagnetics moves into the next phase of innovative translational research with emphasis on development of quantitative in vivo imaging, targeted and triggered drug release, and image guided therapy including validation of delivery and therapy response. PMID- 20930945 TI - Design of a dynamic model of genes with multiple autonomous regulatory modules by evolutionary computations. AB - A new approach to design a dynamic model of genes with multiple autonomous regulatory modules by evolutionary computations is proposed. The approach is based on Genetic Algorithms (GA), with new crossover operators especially designed for these purposes. The new operators use local homology between parental strings to preserve building blocks found by the algorithm. The approach exploits the subbasin-portal architecture of the fitness functions suitable for this kind of evolutionary modeling. This architecture is significant for Royal Road class fitness functions. Two real-life Systems Biology problems with such fitness functions are implemented here: evolution of the bacterial promoter rrnPl and of the enhancer of the Drosophila even-skipped gene. The effectiveness of the approach compared to standard GA is demonstrated on several benchmark and real life tasks. PMID- 20930947 TI - Identification of novel cellular targets for therapeutic intervention against Ebola virus infection by siRNA screening. AB - While much progress has been made in developing drugs against a few prominent viruses such as HIV, few examples exist for emerging infectious agents. In some cases broad spectrum anti-viral drugs, such as ribavirin, are effective, but for some groups of viruses, these show little efficacy in animal models. Traditional methods focus on screening small molecule libraries to identify drugs that target virus factors, with the intention that side-effects to the host can be minimized. However, this greatly limits potential drug targets and virus genes can rapidly mutate to avoid drug action. Recent advances in siRNA gene targeting technologies have provided a powerful tool to specifically target and suppress the expression of cell genes. Since viruses are completely dependent upon host cell proteins for propagation, siRNA screening promises to reveal novel cell proteins and signaling pathways that may be viable targets for drug therapy regimens. Here we used an siRNA screening approach to identify gene products that play critical roles in Ebola virus infection. By gene cluster analysis, proteins in phosphatidylinositol 3-kinase and calcium/calmodulin kinase related networks were identified as important for Zaire Ebola virus infection and prioritized for further evaluation. Key roles of each were confirmed by testing available drugs specific for members of each pathway. Interestingly, both sets of proteins are also important in cancer and subject to intense investigation. Thus development of new drugs against these cancer targets may also prove useful in combating Ebola virus. PMID- 20930948 TI - Parenting by lying. AB - The present set of studies identifies the phenomenon of 'parenting by lying', in which parents lie to their children as a means of influencing their emotional states and behaviour. In Study 1, undergraduates (n = 127) reported that their parents had lied to them while maintaining a concurrent emphasis on the importance of honesty. In Study 2 (n = 127), parents reported lying to their children and considered doing so to be acceptable under some circumstances, even though they also reported teaching their children that lying is unacceptable. As compared to European American parents, Asian American parents tended to hold a more favourable view of lying to children for the purpose of promoting behavioural compliance. PMID- 20930946 TI - Over-expression of CKS1B activates both MEK/ERK and JAK/STAT3 signaling pathways and promotes myeloma cell drug-resistance. AB - Here we demonstrate the crucial role of CKS1B in multiple myeloma (MM) progression and define CKS1B-mediated SKP2/p27(Kip1)-independent down-stream signaling pathways. Forced-expression of CKS1B in MM cells increased cell multidrug-resistance. CKS1B activates STAT3 and MEK/ERK pathways. In contrast, SKP2 knockdown or p27(Kip1) over-expression resulted in activation of the STAT3 and MEK/ERK pathways. Further investigations showed that BCL2 is a downstream target of MEK/ERK signaling. Stimulation of STAT3 and MEK/ERK signaling pathways partially abrogated CKS1B knockdown induced MM cell death and growth inhibition. Targeting STAT3 and MEK/ERK signaling pathways by specific inhibitors induced significant MM cell death and growth inhibition in CKS1B-overexpressing MM cells and their combinations resulted in synergy. Thus, our findings provide a rationale for targeting STAT3 and MEK/ERK/BCL2 signaling in aggressive CKS1B overexpressing MM. PMID- 20930949 TI - Religious and Spiritual Dimensions of the Vietnamese Dementia Caregiving Experience. AB - This paper focuses on the role of religion and spirituality in dementia caregiving among Vietnamese refugee families. In-depth qualitative interviews were conducted with nine Vietnamese caregivers of persons with dementia, then tape-recorded, transcribed, and analyzed for emergent themes. Caregivers related their spirituality/religion to three aspects of caregiving: (1) their own suffering, (2) their motivations for providing care, and (3) their understanding of the nature of the illness. Key terms or idioms were used to articulate spiritual/religious dimensions of the caregivers' experience, which included sacrifice, compassion, karma, blessings, grace and peace of mind. In their narratives, the caregivers often combined multiple strands of different religions and/or spiritualities: Animism, Buddhism, Taoism, Confucianism and Catholicism. Case studies are presented to illustrate the relationship between religion/spirituality and the domains of caregiving. These findings have relevance for psychotherapeutic interventions with ethnically diverse populations. PMID- 20930950 TI - The Fragility of Healing. AB - This article explores a paradox-the simultaneous cultivation and suppression of "healing dramas" by pediatric rehabilitation therapists. Dramatic moments are defined as ones in which the routine exercises and treatment activities of therapeutic practice are transformed into narrative plots. These improvisational plots involve multiple characters, risks, suspense, and above all, a heightened sense that something is at stake. Experience itself becomes the focus of attention for the patient. Based upon ethnographic research in Chicago and Los Angeles, this article offers an anatomy of two such moments, investigating not only how healing dramas are constructed between patients and healers but how and why institutional discourses and practices invite their abandonment. PMID- 20930951 TI - Seeing The World Through Rose-colored Glasses? Neglect of Consensus Information in Young Children's Personality Judgments. AB - The present study examined the use of consensus information in early childhood. Ninety-six three- to six-year-olds watched a demonstration that depicted the positive or negative behavior of one or several actors toward a recipient (low vs. high consensus, respectively). Subsequently, participants made behavioral predictions and personality judgments about the actors and recipients. Participants viewed all story characters favorably and were reluctant to assign blame for negative outcomes, although the appropriate use of consensus information increased with age for behavioral predictions. These findings suggest that there is a positivity bias in young children's personality judgments even in the face of explicit contradictory behavioral evidence. Children's early 'theory of personality' is apparently driven by a baseline assumption that people are nice. PMID- 20930952 TI - A Method for Identifying Small-Molecule Aggregators Using Photonic Crystal Biosensor Microplates. AB - Small molecules identified through high-throughput screens are an essential element in pharmaceutical discovery programs. It is now recognized that a substantial fraction of small molecules exhibit aggregating behavior leading to false positive results in many screening assays, typically due to nonspecific attachment to target proteins. Therefore, the ability to efficiently identify compounds within a screening library that aggregate can streamline the screening process by eliminating unsuitable molecules from further consideration. In this work, we show that photonic crystal (PC) optical biosensor microplate technology can be used to identify and quantify small-molecule aggregation. A group of aggregators and nonaggregators were tested using the PC technology, and measurements were compared with those gathered by three alternative methods: dynamic light scattering (DLS), an alpha-chymotrypsin colorimetric assay, and scanning electron microscopy (SEM). The PC biosensor measurements of aggregation were confirmed by visual observation using SEM, and were in general agreement with the alpha-chymotrypsin assay. DLS measurements, in contrast, demonstrated inconsistent readings for many compounds that are found to form aggregates in shapes, very different from the classical spherical particles assumed in DLS modeling. As a label-free detection method, the PC biosensor aggregation assay is simple to implement and provides a quantitative direct measurement of the mass density of material adsorbed to the transducer surface, whereas the microplate based sensor format enables compatibility with high-throughput automated liquid handling methods used in pharmaceutical screening. PMID- 20930953 TI - Configurational asymmetry in vernier offset detection. AB - Two psychophysical experiments were conducted at the horizontal and vertical orientations respectively, demonstrating substantial main effect of configuration, but no effect of offset direction on vernier acuity. In Experiment 1, a pair of horizontal bars were arranged side by side with a large gap between them. The observers were, on average, significantly better at discriminating a vertical offset if the right-hand bar was below the left-hand bar than vice versa, regardless of which bar they experienced as displaced and which as constant. A similar asymmetry was evident in Experiment 2 where observers judged horizontal offset for a pair of vertically oriented bars, where one was placed above the other. In this case average performance was better if the upper bar was on the right of the lower bar rather than on its left. There were large individual variations in the asymmetrical trend, but the effect could not be explained by subjective response bias. Furthermore, vernier acuity improved significantly and the asymmetry decreased more or less as a function of training. The average asymmetrical trend was consistent across training days and across two orientations, which indicates that the processing of line vernier stimuli is possibly configuration-specific in the cardinal orientation. PMID- 20930954 TI - Frontocerebellar Connectivity: Climbing through the Inferior Olive. PMID- 20930955 TI - AV Interval Optimization - A Step Towards Physiological Pacing in Patients with Normal Left Ventricular Function. PMID- 20930956 TI - Utilization of Electrocardiographic P-wave Duration for AV Interval Optimization in Dual-Chamber Pacemakers. AB - BACKGROUND: Empiric programming of the atrio-ventricular (AV) delay is commonly performed during pacemaker implantation. Transmitral flow assessment by Doppler echocardiography can be used to find the optimal AV delay by Ritter's method, but this cannot easily be performed during pacemaker implantation. We sought to determine a non-invasive surrogate for this assessment. Since electrocardiographic P-wave duration estimates atrial activation time, we hypothesized this measurement may provide a more appropriate basis for programming AV intervals. METHODS: A total of 19 patients were examined at the time of dual chamber pacemaker implantation, 13 (68%) being male with a mean age of 77. Each patient had the optimal AV interval determined by Ritter's method. The P-wave duration was measured independently on electrocardiograms using MUSE(r) Cardiology Information System (version 7.1.1). The relationship between P wave duration and the optimal AV interval was analyzed. RESULTS: The P-wave duration and optimal AV delay were related by a correlation coefficient of 0.815 and a correction factor of 1.26. The mean BMI was 27. The presence of hypertension, atrial fibrillation, and valvular heart disease was 13 (68%), 3 (16%), and 2 (11%) respectively. Mean echocardiographic parameters included an ejection fraction of 58%, left atrial index of 32 ml/m(2), and diastolic dysfunction grade 1 (out of 4). CONCLUSIONS: In patients with dual chamber pacemakers in AV sequentially paced mode and normal EF, electrocardiographic P wave duration correlates to the optimal AV delay by Ritter's method by a factor of 1.26. PMID- 20930957 TI - Cryoballoon ablation for paroxysmal atrial fibrillation in septuagenarians: a prospective study. AB - AIMS: To evaluate the effects of pulmonary vein isolation (PVI) in terms of feasibility, safety and success rate on a midterm follow-up period in septuagenarians undergoing ablation with the Arctic Front Cryoballoon for atrial fibrillation (AF). METHODS AND RESULTS: We prospectively enrolled 21 patients aged 70 years or older (14 male; age 73 +/- 2.5 years) elected to circumferential PVI with the 28mm cryoballoon for symptomatic drug resistant paroxysmal AF. A total number of 82 pulmonary veins (PV) were evidenced. Successful isolation could be obtained in all 82 (100%) PV ostia at the end of procedure. No major complication occurred during procedure. At a mean follow-up of 11.5 +/- 4.7 months following ablation, 62% of patients did not present recurrence of atrial arrhythmias. CONCLUSION: Cryoballoon ablation may be feasible and safe in older patients. Moreover a large proportion of the latter did not present AF recurrence during follow-up. PMID- 20930958 TI - Brugada syndrome: Controversies in Risk stratification and Management. AB - In the 18 years since the first description of Brugada Syndrome in a small series of cardiac arrest survivors it has become evident that there is a marked spectrum in phenotype and prognosis. An internal cardiac defibrillator (ICD) is the only established therapy but is associated with significant morbidity. A number of registries have published their data, but risk stratification, particularly in asymptomatic patients, remains controversial. This article summarises the evidence to enable the clinician to make informed management decisions on an individual basis. PMID- 20930960 TI - Uncommon presentation of a common tachycardia. AB - We describe a patient with an implanted pacemaker for impaired AV conduction who presented with an incessant tachycardia. EP study showed that the tachycardia was atrioventricular nodal reentrant tachycardia (AVNRT) with repeated spontaneous initiation because of poor or absent antegrade fast pathway conduction. Slow pathway ablation was successful in terminating the tachycardia and making it non inducible. PMID- 20930959 TI - A review of the mechanisms of ventricular arrhythmia in brugada syndrome. AB - Brugada syndrome (BrS) is characterised by the triad of coved ST elevation, lethal ventricular arrhythmia in an apparently structurally normal heart. The precise mechanisms responsible for the coved ST elevation and ventricular arrhythmias in this disease have been debated since its initial description in 1992. Indeed the recent recognition of early repolarisation J wave disorders linked to primary VF broadens the mechanistic importance of BrS in sudden cardiac death. It may lie on a spectrum of early repolarisation pathology which is becoming increasingly recognised as a marker of premature cardiovascular death. Mechanistically, abnormalities of both depolarisation and repolarisation in the right ventricular outflow tract, and heterogeneities of conduction between the endocardium and epicardium have been implicated in the electrographic manifestations of BrS and arrhythmogenesis.The initial belief of BrS as a single autosomal dominant ion channel disorder has been challenged. It has become apparent that sodium channel mutations only account for a maximum of 30% of cases and structural myocardial abnormalities have now been described in what was previously thought to be a purely functional condition. It is highly probable that BrS is an umbrella diagnosis for a number of conduction and repolarisation abnormalities which manifest as this syndrome and the coved ST elevation represents the final common pathway of both ion channel and structural derangements. This review will discuss the issues surrounding the mechanisms of lethal arrhythmia in BrS and summarise both basic science and clinical research findings. PMID- 20930961 TI - The lightning heart: a case report and brief review of the cardiovascular complications of lightning injury. AB - Lightning strike is a rare natural phenomenon, which carries a risk of dramatic medical complications to multiple organ systems and a high risk of fatality. The known complications include but are not limited to: myocardial infarction, arrhythmia, cardiac contusion, stroke, cutaneous burns, respiratory disorders, neurological disorders, acute kidney injury and death. We report a case of a healthy young man who suffered a lightning injury and discuss the cardiovascular complications of lightning injury, ranging from ECG changes to death. The patient in our case, a 27-year old previously healthy male, developed a syndrome of rhabdomyolysis and symptomatic cardiogenic pulmonary edema. Electrocardiographic findings included transient T-wave inversions, late transition shift and long QT. His clinical condition improved with supportive measures.Early recognition of lightning injury syndromes and anticipation of complications may help us improve outcomes for these patients. Evaluation of patients having experienced a lightning injury should include a minimum of a detailed history and physical examination, 12-lead ECG and drawing of baseline troponins. Prolonged electrocardiographical monitoring (for monitoring of ventricular arrhythmias) and assessment for signs and symptoms of hemodynamic compromise may be warranted. PMID- 20930962 TI - What's new in Emergencies, Trauma, and Shock? Developing predictor models for infectious diseases. PMID- 20930963 TI - Developing a clinically relevant classification to predict mortality in severe leptospirosis. AB - BACKGROUND: Severe leptospirosis requires critical care and has a high mortality. We reviewed the literature to identify factors predicting mortality, and such predictors were classified according to the predisposition, infection, response, organ dysfunction (PIRO) concept, which is a risk stratification model used in severe sepsis. MATERIAL AND METHODS: PUBMED was searched for all articles (English), with the key word leptospirosis in any field, within the last 20 years. Data were collected from 45 relevant papers and grouped into each component of the PIRO model. RESULTS: THE FOLLOWING CORRELATED WITH INCREASED MORTALITY: predisposition - increasing age and chronic alcoholism; infection - leptospiraemic burden; response - hemodynamic disturbances, leukocytosis; organ dysfunction - multiple organ dysfunction syndrome, pulmonary involvement and acute renal failure. CONCLUSIONS: Further research is needed to identify the role of infecting serovars, clinical signs, inflammatory markers, cytokines and evidence of hepatic dysfunction as prognostic indicators. It is hoped that this paper will be an initiative to create a staging system for severity of leptospirosis based on the PIRO model with an added component for treatment related predictors. PMID- 20930964 TI - Acute febrile encephalopathy in adults from Northwest India. AB - BACKGROUND: Acute onset fever with altered mentation is a common problem encountered by the physician practicing in tropical countries. Central nervous system (CNS) infections are the most common cause resulting in fever with altered mentation in children. AIM: In this study, we have tried to analyze the cause of encephalopathy following short febrile illness in adults presenting to a tertiary care center in Northwestern part of India. SETTING AND DESIGN: A prospective observational study carried out in a tertiary care center in the Northwestern India over a period of 1 year. MATERIAL AND METHODS: A total of 127 patients with fever of less than 2 weeks duration along with alteration in mentation were studied prospectively over a period of 12 months. The demographic variables were recorded in detail. In addition to routine investigations, cerebrospinal fluid analysis, noncontrast- and contrast-enhanced computed tomography, along with magnetic resonance imaging were performed in all the subjects. STATISTICAL ANALYSIS: The results were analyzed using SPSS statistical software. The values were expressed as mean with standard deviation for contiguous variable as percentage for the others. RESULTS AND CONCLUSION: Out of these, 70% had primary CNS infection as the etiology. A total of 33% patients had meningitis, 29.9% had evidence of meningoencephalitis, and 12.7% were diagnosed as sepsis-associated encephalopathy. These were followed by cerebral malaria, leptospirosis, and brain abscess as the cause of febrile encephalopathy in adults. Among the noninfectious causes, acute disseminated encephalomyelitis, cortical venous thrombosis, and neuroleptic malignant syndrome were documented in 2.36% each. In 11% of the patients, the final diagnosis could not be made in spite of the extensive investigations. Our study demonstrates that acute febrile encephalopathy in adults is a heterogeneous syndrome with primary CNS infections being the commonest etiology. PMID- 20930965 TI - Reviewing the blood ordering schedule for elective orthopedic surgeries at a level one trauma care center. AB - BACKGROUND: Patients undergoing elective orthopedic surgeries often incur excess blood loss necessitating transfusion. The preoperative placement of blood requests frequently overshoots the actual need resulting in unnecessary crossmatching. AIMS: Our primary goal was to audit the blood utilization in elective orthopedic surgeries in our hospital over a 1-year period and recommend a blood ordering schedule. MATERIALS AND METHODS: A retrospective analysis of patients who underwent elective orthopedic surgeries over a period of 1 year was done. The data collected include patients' age, sex, type of surgical procedure, pre- and postoperative hemoglobin (Hb) levels, number of units crossmatched, returned, transfused, crossmatch to transfusion ratio (C:T), transfusion indices, estimated blood loss for each surgical procedure, and the actual and predicted fall in Hb. We propose a blood ordering schedule based on surgical blood ordering equation. RESULTS AND CONCLUSIONS: A total of 487 patients with a median age of 37+/-17 years (mean +/- standard deviation) were evaluated. One thousand three hundred and seventy-seven units of blood were crossmatched and only 564 units were transfused to 260 patients. Fifty-nine percent of the units crossmatched were not transfused. Six of the 12 elective procedures had a C:T ratio higher than 2.5. Ten of the 12 procedures (83.3%) had a low transfusion index (TI < 0.5). The calculated red blood cell units were less than 0.5 in 5 of the 12 elective procedures, and hence we recommend a group and save policy for these procedures. Blood ordering schedule based on patient and surgical variables would provide an efficient way of blood utilization and management of resources. PMID- 20930966 TI - Comparing the efficacy and safety of two regimens of sequential systemic corticosteroids in the treatment of acute exacerbation of bronchial asthma. AB - BACKGROUND: Corticosteroids are commonly used in the management of acute asthma. However, studies comparing various steroids in the management of acute asthma are lacking. OBJECTIVE: To compare the efficacy and safety of two treatment regimens intravenous (IV) methylprednisolone (MP) followed by oral MP and IV hydrocortisone (HC) followed by oral prednisolone in acute bronchial asthma patients. MATERIALS AND METHODS: This was a randomized, prospective study performed in the emergency department (ED) of a tertiary care hospital in North India. A total of 94 patients with acute asthma were randomly allocated to either of the two treatment groups: Group A (n = 49) or Group B (n = 45). Patients in Group A were administered HC 200 mg IV 6-hourly until discharge from the ED, followed by oral prednisolone 0.75 mg/kg daily for 2 weeks. Patients in Group B were administered MP 125 mg IV bolus, followed by 40 mg MP IV 6-hourly until discharge, and then oral MP 0.6 mg/kg daily for 2 weeks. All clinical variables, peak expiratory flow (PEF) and forced expiratory volume in one second (FEV(1)) were assessed at baseline, at 1, 3 and 6 h and at every 6 h thereafter until discharge from the ED. The patients were followed-up after 2 weeks of discharge. The response to treatment was assessed by clinical and spirometric evaluation. Independent t-tests and chi-square tests were used to compare the two treatment regimens. RESULTS: The baseline characteristics were comparable in the two groups. There was a significant improvement in PEF and FEV(1) within the groups at 2 weeks of treatment when compared to the baseline. At 2 weeks of follow-up, Group B showed significant improvement over Group A in PEF (P < 0.0001), FEV(1) (P < 0.0001) and asthma score (P = 0.034). There was a significant increase in the blood sugar value at 2 weeks in both the groups. However, the increase was greater in Group A as compared to Group B (P < 0.0001). CONCLUSION: This study suggests that in acute asthma patients, IV MP followed by oral MP is a more efficacious and safer treatment regimen than IV HC followed by oral prednisolone. PMID- 20930967 TI - Using inverted autogenous veins to substitute arteries in a canine model. AB - AIMS: Rapid harvesting of autogenous graft over a wire is an optional way in trauma surgery and it places the inverted conduit so that its adventitial layer is within the lumen of the graft. Our aim of this study was to compare the patency of inverted autogenous graft vs noninverted graft in dogs. SETTINGS AND DESIGN: Experimental animal models. MATERIALS AND METHODS: In this experimental study, 12 dogs were anesthetized and 10 cm of the external jugular vein was excised. The vein was equally divided into two 5-cm sections. One section was inverted and the other was left intact. Afterward, 5 cm of both the femoral arteries were removed and the right (inverted) and the left (not inverted) arteries were grafted, respectively. The patency of the arteries was evaluated by Color Doppler ultrasonography immediately postoperation and up to 6 months thereafter. STATISTICAL ANALYSIS: Data were analyzed with Fisher's exact test using SPSS version 15. P value below 0.05 was significant. RESULTS: None of the 12 inverted vein grafts were patent at 3(rd) to 14(th) days follow-up with Doppler ultrasonography. All of them were completely obstructed by thrombosis. However, 11 (92%) of the noninverted vein grafts were patent both at 3 and 6 months follow-up. One of the noninverted grafts was almost completely obstructed with thrombosis (90%) and the other 2 were incompletely obstructed with intimal thickening. CONCLUSIONS: Despite many favorable results in the previous studies with regard to excellent patency of inverted vein graft, our results were disappointing and we recommend using the graft in the right direction and taking care to preserve the intima intact. PMID- 20930968 TI - Better outcome after pediatric resuscitation is still a dilemma. AB - Pediatric cardiac arrest is not a single problem. Although most episodes of pediatric cardiac arrest occur as complications and progression of respiratory failure and shock. Sudden cardiac arrest may result from abrupt and unexpected arrhythmias. With a better-tailored therapy, we can optimize the outcome. In the hospital, cardiac arrest often develops as a progression of respiratory failure and shock. Typically half or more of pediatric victims of in-hospital arrest have pre-existing respiratory failure and one-third or more have shock, although these figures vary somewhat among reporting hospitals. When in-hospital respiratory arrest or failure is treated before the development of cardiac arrest, survival ranges from 60% to 97%. Bradyarrthmia, asystole or pulseless electric activity (PEA) were recorded as an initial rhythm in half or more of the recent reports of in-hospital cardiac arrest, with survival to hospital discharge ranging from 22% to 40%. Data allowing characterization of out of hospital pediatric arrest are limited, although existing data support the long-held belief that as with hospitalized children, cardiac arrest most often occurs as a progression of respiratory failure or shock to cardiac arrest with bradyasystole rhythm. Although VF (Ventricular fibrillation, is a very rapid, uncoordinated, ineffective series of contractions throughout the lower chambers of the heart. Unless stopped, these chaotic impulses are fatal) and VT (Ventricular tachycardia is a rapid heartbeat that originates in one of the ventricles of the heart. To be classified as tachycardia, the heart rate is usually at least 100 beats per minute) are not common out-of-cardiac arrest in children, they are more likely to be present with sudden, witnessed collapse, particularly among adolescents. Pre hospital care till the late 1980s was mainly concerned with adult care, and the initial focus for pediatric resuscitation was provision of oxygen and ventilation, with initial rhythm at the time of emergency medical services arrival being infrequently recorded. In the 1987 series, pre-hospital pediatric cardiac arrest demonstrated asystole in 80%, PEA in 10.5% and VF or VT in 9.6%. Only 29% arrests were witnessed, however, and death in many victims was caused by sudden infant death syndrome. PMID- 20930969 TI - Emergency diagnosis and management of pediatric arrhythmias. AB - True emergencies due to unstable arrhythmias in children are rare, as most rhythm disturbances in this age group are well-tolerated. However, presentation to an emergency department with symptoms of palpitations, fatigue and/or syncope is much more common. Sinus tachycardia is by far the most commonly reported arrhythmia, followed by supraventricular tachycardia. Emergency physicians should be prepared for diagnosis and to acutely manage various types of arrhythmias seen in children, to assess the need for further diagnostic testing, and to determine whether cardiology evaluation and follow-up are needed. This article is intended to provide diagnostic and management guidelines of the most common types of arrhythmias seen in children with structurally normal hearts as well as those associated with congenital heart disease and cardiomyopathies. PMID- 20930970 TI - Defibrillation in children. AB - Defibrillation is the only effective treatment for ventricular fibrillation (VF). Optimal methods for defibrillation in children are derived and extrapolated from adult data. VF occurs as the initial rhythm in 8-20% of pediatric cardiac arrests. This has fostered a new interest in determining the optimal technique for pediatric defibrillation. This review will provide a brief background of the history of defibrillation and a review of the current literature on pediatric defibrillation. The literature search was performed through PubMed, using the MeSH headings of cardiopulmonary resuscitation, defibrillation and electric countershock. The authors' personal bibliographic files were also searched. Only published articles were chosen. The recommended energy dose has been 2 J/kg for 30 years, but recent reports may indicate that higher dosages may be more effective and safe. In 2005, the European Resuscitation Council recommended 4 J/kg as the initial dose, without escalation for subsequent shocks. Automated external defibrillators are increasingly used for pediatric cardiac arrest, and available reports indicate high success rates. Additional research on pediatric defibrillation is critical in order to be able to provide an equivalent standard of care for children in cardiac arrest and improve outcomes. PMID- 20930971 TI - Cardiac arrest in children. AB - Major advances in the field of pediatric cardiac arrest (CA) were made during the last decade, starting with the publication of pediatric Utstein guidelines, the 2005 recommendations by the International Liaison Committee on Resuscitation, and culminating in multicenter collaborations. The epidemiology and pathophysiology of in-hospital and out-of-hospital CA are now well described. Four phases of CA are described and the term "post-cardiac arrest syndrome" has been proposed, along with treatment goals for each of its four phases: immediate post-arrest, early post-arrest, intermediate and recovery phase. Hypothermia is recommended to be considered as a therapy for post-CA syndrome in comatose patients after CA, and large multicenter prospective studies are underway. We reviewed landmark articles related to pediatric CA published during the last decade. We present the current knowledge of epidemiology, pathophysiology and treatment of CA relevant to pre-hospital and acute care health practitioners. PMID- 20930972 TI - Out-of-hospital cardiac arrests in children. AB - Prehospital pediatric cardiac arrest is a rare event compared with adult cardiac arrest. Despite the recent advancements in postresuscitation care improving the outcome of adult patients, similar evidence is lacking in pediatric victims of cardiac arrest. In this brief article, the current data on pediatric cardiac arrest occurring in the prehospital setting are reviewed. The annual incidence of pediatric out-of-hospital cardiac arrest is approximately 8-10 cases per 100,000 persons. The outcome is generally poor, as only 2-9.6% of patients survive to hospital discharge. The neurologic outcome of survivors is good in 24-31% of patients. Current evidence is insufficient to strongly support or refute the use of mild therapeutic hypothermia during the postresuscitation phase in pediatric patients. The application of a goal-directed treatment protocol for pediatric cardiac arrest and postresuscitation syndrome needs to be evaluated. PMID- 20930973 TI - Hypothermia and pediatric cardiac arrest. AB - The survival outcome following pediatric cardiac arrest still remains poor. Survival to hospital discharge ranges anywhere from 0 to 38% when considering both out-of-hospital and in-hospital arrests, with up to 50% of the survivors having neurologic injury. The use of mild induced hypothermia has not been definitively proven to improve outcomes following pediatric cardiac arrest. This may be due to the lack of consensus regarding target temperature, best method of cooling, optimal duration of cooling and identifying the patient population who will receive the greatest benefit. We review the current applications of induced hypothermia in pediatric patients following cardiac arrest after searching the current literature through Pubmed and Ovid journal databases. We put forth compiled recommendations/guidelines for initiating hypothermia therapy, its maintenance, associated monitoring and suggested adjunctive therapies to produce favorable neurologic and survival outcomes. PMID- 20930975 TI - An unusual presentation of an atypical hangman's fracture. PMID- 20930974 TI - Bedside emergency cardiac ultrasound in children. AB - Bedside emergency ultrasound has rapidly developed over the past several years and has now become part of the standard of care for several applications. While it has only recently been applied to critically ill pediatric patients, several of the well-established adult indications may be applied to pediatric patients. One of the most important and life-saving applications is bedside echocardiography. While bedside emergency ultrasonography does not serve to replace formal comprehensive studies, it serves as an extension of the physical examination. It is especially useful as a rapid and effective tool in the diagnosis of pericardial effusions, tamponade and in distinguishing potentially reversible causes of pulseless electrical activity from asystole. Most recently, left ventricular function and inferior vena cava measurements have proven helpful in the assessment of undifferentiated hypotension and shock in adults and children. Future research remains to be carried out in determining the efficacy of bedside ultrasonography in pediatric-specific pathology such as congenital heart disease. This article serves as a comprehensive review of the adult literature and a review of the recent applications in the pediatric emergency department. It also highlights the techniques of bedside ultrasonography with examples of normal and pathologic images. PMID- 20930976 TI - A nosy fish. PMID- 20930977 TI - Near-fatal subdural empyema complicating a rapidly progressive orbital cellulites. PMID- 20930978 TI - Hyperreactio luteinalis with preeclampsia. AB - Hyperreactio luteinalis (HL) is a condition associated with bilateral and, in rare cases, unilateral ovarian enlargement due to theca lutein cysts. HL is a benign condition, usually found incidentally at cesarean section, which can appear anaplastic and lead to unnecessary ovarian resection. A 24-year-old woman with 35 weeks of gestation attended with bilaterally enlarged ovaries. She had preeclampsia and preterm contractions. Due to breech presentation of baby and nulliparity and possible severe preeclampsia, she delivered by cesarean section. The ovaries had an anaplastic appearance and a biopsy was taken during cesarean section. Pathology revealed multiple benign theca lutein cysts. There are 51 reported cases of HL associated with a normal pregnancy in the literature. It is estimated that approximately 60% of the cases of HL is not associated with trophoblastic disease and occurs with normal singleton pregnancy. Only three of them were found to be associated with preeclampsia and this is the fourth case. HL may help explain the underlying cause of preeclampsia in these cases. There are multiple benign ovarian lesions in HL, which can mimic ovarian neoplasms. Accordingly, it is important to exclude these from the differential diagnosis via a wedge biopsy and frozen section to avoid unnecessary surgical excision. PMID- 20930979 TI - Strangulation injury from indigenous rocking cradle. AB - Indigenously made rocking cradle is frequently used in rural India. We report strangulation from an indigenously made rocking cradle in an 11-month-old female child. The unique mode of injury and its mechanism have been discussed. Strangulation is an important cause of homicidal and suicidal injury in adults but in children it is usually accidental leading to death due to asphyxia as a result of partial hanging. In western countries, it is the third most common cause of accidental childhood deaths, 17% of them being due to ropes and cords. It ranks fourth amongst the causes of unintentional injury in children less than 1 year of age following roadside accidents, drowning and burns. However, in India, strangulation injury is under reported although indigenous rocking cradles are very commonly used in rural India, and they are even more dangerous than the cribs and adult beds as there are no safety mechanisms therein. We report a case of accidental strangulation following suspension from an indigenously made rocking cradle. The unique mode of injury has prompted us to report this case. PMID- 20930980 TI - A newborn with cardiomegaly. AB - An infant with Down's syndrome was noted to have hypoxemia and tachypnea at birth. The clinical examination, electrocardiogram (ECG) and the chest X-ray findings suggested a specific diagnosis that is not usually associated with Down's syndrome. Despite the extremely rare association of Ebstein's anomaly with Down's syndrome, this diagnosis was highly suspected from the initial evaluation. An echocardiogram confirmed the diagnosis of Ebstein's anomaly in this neonate. So far, only about seven cases of Ebstein's anomaly associated with Down's syndrome have been reported in the literature. This case is discussed for its rarity; it also highlights the importance of clinical examination and initial investigations that had suggested the diagnosis well prior to that of the echocardiogram. PMID- 20930981 TI - Postcoital vaginoperitoneal fistula after hysterectomy for gynecological malignancy. AB - A true incidence of postcoital fistula is not known as it is seldom suspected. It presents as acute pneumoperitoneum with signs and symptoms same as that of perforation of a hollow viscus. A 38-year-old parous woman presented with postcoital fistula 10 weeks after panhysterectomy for carcinoma ovary stage IIIc. Pneumoperitoneum was detected, with large amount of gas under the diaphragm on radiograph of the abdomen. A breach was found in the vaginal vault. All other causes of fistula were excluded. Fistula healed spontaneously on follow-up. PMID- 20930982 TI - Fatal spontaneous rectus sheath hematoma in a patient with cirrhosis. AB - Rectus sheath hematoma (RSH) is an uncommon and often misdiagnosed condition. This well-described entity is typically self-limited. In rare cases, the condition may be fatal. We report a case of a patient with cirrhosis who died of progressive RSH and its subsequent complications. PMID- 20930983 TI - Traumatic hemorrhage of occult phaeochromocytoma in a patient with septic shock. AB - Phaeochromocytoma can have a variety of presentations; however, traumatic hemorrhage into a phaeochromocytoma is a very rare presentation. Diagnosing and managing a critically ill, septic patient with a Phaeochromocytoma can be very challenging. We report a case of 53 years old man with a previously undiagnosed Phaeochromocytoma, who presented initially with bowel perforation following an assault. Following a laparotomy for bowel resection and anastomosis, whilst on the intensive care unit, he developed paroxysmal severe hypertension overlying septic shock. Phaeochromocytoma was confirmed using a computed tomography scan and urinary assay of metanephrine and catecholamines. We managed the haemodynamic instability using labetalol and noradrenaline infusions. As his septic state improved he was convention therapy and following control of his symptoms over the next few weeks, he underwent an uncomplicated right sided adrenalectomy. He made a full recovery. PMID- 20930984 TI - Fatal dialysis disequilibrium syndrome: A tale of two patients. AB - Dialysis disequilibrium syndrome (DDS) is a central nervous system disorder, which occurs during hemodialysis (HD) or within 24 h following the first HD. DDS commonly occurs in patients suffering from end-stage renal failure undergoing HD for the first time. In a critically ill patient suffering from severe sepsis or septic shock, the combined effects of post-HD brain edema and changes in the brain due to septic encephalopathy, may become amplified leading to DDS. Here we report 2 cases with acute renal failure (ARF), undergoing HD for more than a week and being ventilated and who developed DDS. DDS might have contributed to the sudden deterioration and death in these septic patients. The first case was a 31 year-old male, involved in a motor vehicle accident and had a severe abdominal injury. Underwent laparotomy and hemostasis was achieved. On day 4, the patient developed hemorrhagic shock associated with ARF, which prompted daily HD. On day 8, he went into septic shock. On day 16, 1 h after his daily HD, he became unresponsive and his pupils became dilated and fixed and he expired 2 days later. The second case was a young male who suffered severe abdominal and chest injury after a fall from a height. He developed ARF on day 3 and required HD. On day 9, he had septic shock. Three days later, during his daily HD, he became unconscious and his pupils were not reacting to light and the patient died on day 12. CONCLUSION: In patients with severe sepsis/septic shock, DDS may occur even after repeated sessions of HD. The acute care physicians, intensivists, and nephrologists should be aware of the risks of DDS. PMID- 20930985 TI - Asymptomatic diaphragmatic rupture with retroperitoneal opening as a result of blunt trauma. AB - Blunt traumas of the abdomen and thorax are important clinical problems in pediatric ages. Severity of trauma may not always be compatible with the patients' clinical situation. A 2-year-old male child was admitted to our emergency clinic as a result of tractor crash accident. Physical examination of the child was normal. The abdominal and thoracic ultrasonography (USG) examination performed in the emergency clinic was normal. In thoracic computed tomography (CT) scan of the patient, there was irregularity of the right diaphragmatic contour that was described as micro perforation-rupture (the free air was just in the perihepatic and retroperitoneal area, which was not passing through the abdomen). The patient was followed-up for 1 week in the hospital with a diagnosis of retroperitoneal diaphragmatic rupture. It is not appropriate to decide the severity of trauma in childhood on the basis of clinical findings. Although severe trauma and sustaining radiological examinations, the patients' clinical pictures may be surprisingly normal, as in our patient. In such cases, there may not be any clinical symptom. CT scan examination must be preferred to USG for both primary diagnosis and follow-up of these patients. According to the current literature, there is no reported case with retroperitoneal rupture of the diaphragm. PMID- 20930986 TI - A case of renal artery thrombosis with renal infarction. AB - Renal artery thrombosis is a rare, but serious and often misdiagnosed, condition. Emergency physicians and other physicians need to consider this diagnosis in unexplained flank pain, especially in patients with risk factors for this disease. In this case report, the authors review a case of renal infarction caused by renal artery thrombosis in a patient with risk factors for thrombosis but no previous history of thromboembolism. A review of scholarly articles was performed and the case is discussed in the context of the current knowledge of this condition. Common presenting symptoms, features of the history and risk factors will all be discussed herein. Diagnostic evaluation of flank pain in the setting of the suspicion of renal infarction will be discussed, including the modalities of high-resolution computed tomography, renal angiography, scintography and ultrasound. Acute management and prognosis will also be discussed. PMID- 20930987 TI - Post exercise ice water immersion: Is it a form of active recovery? AB - Ice water immersion and contrast temperature water immersion therapy post exercise is fast becoming a common practice among athletes involved in a variety of sports. Several mechanisms have been put forth to explain the rationale for its use. However, there is still a lack of evidence from a sufficiently large scale trial to support the routine practice and formal incorporation into certain sporting guidelines. We describe here two athletes who applied the therapy post exercise and presented to the Emergency Department with delayed onset muscle pain. PMID- 20930988 TI - Anticholinergic delirium following Datura stramonium ingestion: Implications for the Internet age. AB - Recreational use of Datura to deliberately induce an anticholinergic delirium is not uncommon. We present a case of Datura intoxication in a young adult who learned about the recreational use of Datura on the Internet and subsequently purchased Datura stramonium seeds from an online vendor. Using the Google search engine, we conducted searches for "Datura," "jimson weed" and "Datura seeds" and reviewed the first 200 search results for each search term. We found 16 websites recommending the recreational use of Datura, 12 vendors selling seeds of genus Datura and one website that both promoted the recreational use of Datura and also sold Datura stramonium leaves. The promotion of recreational use of Datura on the Internet represents a danger to public health and the ability to purchase Datura seeds from Internet vendors may increase the prevalence of Datura abuse. PMID- 20930989 TI - Successful removal of an impacted metallic arrowhead penetrating up to the brainstem. AB - A case of impacted metallic arrowhead in the brain through an unusual route of the neck and behind the external carotid artery to the base of the skull up to the brainstem is reported. Review of the literature reveals no previous reports of this type of injury. A 35-year-old man was admitted to the hospital after 36 h of injury, being fully conscious and with partial facial palsy. The arrowhead was successfully removed by exploration of the entry wound, without any neurovascular complications. The patient not only survived the operation but was also discharged in an improved neurological condition. PMID- 20930990 TI - Acute idiopathic gastric necrosis, perforation and shock. PMID- 20930991 TI - Maxillomandibular impalement due to a gardening hoe strike to the face. PMID- 20930992 TI - Heterotopic pregnancy: A diagnosis we should suspect more often. PMID- 20930993 TI - A case of quadriplegia with gastric perforation. PMID- 20930994 TI - Double-lumen endobronchial tube in the emergency management of massive hemoptysis. PMID- 20930995 TI - Surgical field fire and skin burns caused by alcohol-based skin preparation. PMID- 20930996 TI - Collapse of left lung after endotracheal intubation: Is it always due to misplacement of tube? PMID- 20930997 TI - Bedside sonography to diagnose bladder trauma in the emergency department. PMID- 20930998 TI - Traumatic diaphragmatic rupture with delayed gastric incarceration. PMID- 20930999 TI - Cardiac tamponade mimicking septic shock diagnosed by early echocardiography. PMID- 20931000 TI - Shock: A presentation of enteric fever. PMID- 20931001 TI - Foreign body of the rectum: An unusual case. PMID- 20931002 TI - Unusual malignant cause of adult intussusception: Stromal tumor of the small bowel. PMID- 20931003 TI - Paradoxical reaction to midazolam reversed with flumazenil. PMID- 20931004 TI - Management of acute ischemic stroke. PMID- 20931005 TI - Chest pain in young people: Is cannabis a risk factor? PMID- 20931006 TI - Role of clinical parameters and early noncontrast magnetic resonance imaging scan of brain in prediction of final neurologic outcome of hanging victims. PMID- 20931007 TI - Author's Reply. PMID- 20931008 TI - Authors's reply. PMID- 20931009 TI - An in-flight respiratory emergency and survival in the sky. PMID- 20931010 TI - Posterior dislocation of elbow with brachial artery injury. PMID- 20931011 TI - Commenting on biomarkers for differentiating between SIRS and sepsis. PMID- 20931012 TI - Oral systemic therapy: Not all "win-win". PMID- 20931013 TI - Comparison of vinorelbine with cisplatin in concomitant chemoradiotherapy in head and neck carcinoma. AB - AIM: Head and neck cancer is one of the most commonly occurring malignancies in the world. In India, the most commonly occurring head and neck cancers are those of the oral cavity and the pharynx. The majority of these cancers present with stage III/IV disease. Surgery and radiation therapy are the main treatment modalities. Concomitant chemoradiation is being investigated with the goal of improved local control that translates into improved survival. In this background, we have started this prospective randomized trial to ascertain the dose, schedule and sequence of therapy and to note whether Vinorelbine as radiosensitizer is equally effective as Cisplatin, comparing compliance, local control and toxicity. PATIENTS AND METHODS: Forty patients of advanced head and neck cancer were randomized into two arms. Arm A received weekly injection Cisplatin 40mg/m(2) along with radiation. Arm B received weekly injection of Vinorelbine 6mg/m(2) along with radiation. Radiotherapy was delivered at a dose of 6,600-7,000 Gy in conventional fractionation in a telecobalt machine. RESULTS: The complete response (CR) rate was higher in arm B (90%) than in arm A (70%). Major toxicities included neutropenia, anemia, mucositis and nausea. CONCLUSION: Concomitant chemoradiation with Vinorelbine produced more CR than chemoradiation with Cisplatin in advanced head and neck cancer. Toxicities were more in the Cisplatin arm, but they were manageable. Although a majority of the study was performed using Cisplatin as the radiosensitizer, Vinorelbine can be recommended as radiosensitizer in advanced head and neck malignancy. PMID- 20931015 TI - An unusual case of primary osteosarcoma of the rib in an adult. AB - Primary osteosarcomas are one of the most common malignant bone tumors principally affecting the long bones in children and adolescents. An unusual case of a primary osteoblastic osteosarcoma of the rib in a 42-year-old male is presented here. The patient underwent a wide excision of the tumor and chest wall reconstruction. Although clinically unsuspected in this unusual site, the classic microscopic feature of a ramifying osteoid matrix amidst the tumor cells was diagnostic of an osteosarcoma. PMID- 20931014 TI - NEO adjuvant chemotherapy in breast cancer: What have we learned so far? AB - Neoadjuvant chemotherapy (NACT) in breast cancer has undergone continuous evolution over the last few decades to establish its role in the combined modality management of these tumors. The process of evolution is still far from over. Many questions are still lurking in the minds of oncologists treating breast cancer. This review analyzes the evidence from metaanlyses, major multiinstitutional prospective trials, retrospective institutional series and systematic reviews in breast cancer to determine the current standards and controversies in NACT. The most effective drugs, their advantages, issues and controversies in delivery as well as the criteria for response are reviewed. A summary of evidence-based consensus is presented and unresolved aspects are discussed. PMID- 20931016 TI - Endometrial stromal sarcoma. AB - Endometrial stromal sarcoma (ESS) is a rare malignant tumor of the endometrium, occurring in the age group of 40-50 years. This is a case of low-grade ESS presenting as rapid enlargement of a fibroid uterus. Because of her secondary infertility, she was planned for myomectomy. However, due to the high degree of suspicion of a sarcomatous change in the fibroid, in view of rapid enlargement of uterus within the last 4 months, we planned for a preoperative endometrial aspiration. It showed low-grade ESS, which was later confirmed by histopathology examination of total hysterectomy specimen. As surgery was the main treatment for ESS, because of the proper preoperative diagnosis, we could plan the treatment accordingly. Despite the rarity of the tumor, one has to consider the possibility of ESS in cases with presentation of rapid enlargement of a fibroid uterus. PMID- 20931017 TI - Intra-abdominal desmoplastic small round cell tumor: Presentation of four cases and review of the literature. AB - Desmoplastic small round cell tumor (DSRCT) of the abdomen is a recently identified aggressive neoplasm. Very few cases have been reported in the literature. Thus, the treatment guidelines are yet to be defined. The role of chemotherapy, radiotherapy and surgery is evolving. We treated four cases of DSRCT involving the abdomen using combination chemotherapy and/or tumor cytoreductive surgery. There were two men and two women. The chemotherapy drugs consisted of cisplatin, adriamycin, etoposide, ifosphamide, vincristine and cyclophsophamide. All patients achieved meaningful partial response to chemotherapy, which maintained for 6-9 months. There were very minimal chemotherapy-related complications. At the time of reporting, the median survival time was 15 months. Thus, DSRCT is an aggressive intra-abdominal tumor with excellent chemoresponsiveness, but relapse is frequent. PMID- 20931018 TI - Multiple cystic swelling: Initial presentation of multiple myeloma. AB - Multiple myeloma, a disease allied to malignancy of reticuloendothelial cells, is not an uncommon condition. However, the diagnosis is often made quite late because the disease has multiple modes of presentation. We are reporting a case of multiple myeloma in a 55-year-old male who presented with multiple cystic swellings on the chest. PMID- 20931019 TI - Virilizing adrenal carcinoma in a 3-year-old boy: A rarity. AB - A 3-year-old boy presented with iso-sexual precocious puberty for 18 months. Radiological images revealed left suprarenal mass and hormonal profile showed markedly increased testosterone and dehydroepiandrosterone-sulfate. The child underwent open adrenalectomy and histopathology revealed adrenocortical carcinoma. At 3 months follow-up, the child is doing well. PMID- 20931020 TI - Secondary acute myeloid leukemia after successful treatment for osteosarcoma. AB - Secondary acute myeloid leukemia (sAML) is a rare complication following chemotherapy for osteogenic sarcoma. However, the exact offending drug is difficult to prove as there is no consistent data. It usually develops 2 years after completion of therapy. We report a case of sAML that developed within 8 months of completing the treatment. The patient was treated with cisplatin, doxorubicin and high-dose methotreaxate followed by surgery (amputation). Eight months after completion of therapy, while on follow-up, he presented with leukocytosis and thrombocytopenia and confirmed to have AML. PMID- 20931021 TI - Florid plasmacytosis in a case of acute myeloid leukemia: A diagnostic dilemma. AB - The association of acute myeloid leukemia (AML) with plasmacytosis is a known, although rare event. There are very few case reports documenting an increase in the number of plasma cells at the time of AML diagnosis. Here, we present the case of a 65-year-old male diagnosed as acute myelomonocytic leukemia with exuberant plasmacytosis, which posed a difficulty in diagnosis. Paracrine interleukin-6 production by leukemic blast cells is thought to contribute to this associated reactive plasma cell proliferation. PMID- 20931022 TI - Lymphoma in HIV patients: Varied presentations. AB - Although lymphomas have been reported in patients with acquired immunodeficiency syndrome, it has rarely been reported from the Indian subcontinent. We present three human immunodeficiency virus-infected patients (two adults and one child) who had non-Hodgkin's lymphoma - plasmablastic variety, Hodgkin's lymphoma - nodular sclerosis type II and B cell lymphoma, respectively. PMID- 20931023 TI - From the Editor's desk. PMID- 20931024 TI - RNTCP and tuberculosis control - High time to act. PMID- 20931025 TI - Why do tuberculosis suspects bypass local services to attend tuberculosis sanatorium? AB - BACKGROUND: The Government Hospital of Thoracic Medicine (GHTM), Tambaram, in Kanchipuram district (formerly known as tuberculosis [TB] sanatorium), Tamil Nadu, draws patients from all over India although RNTCP services have been in place country-wide for a number of years. OBJECTIVE: To document the reasons for patients with chest symptoms attending GHTM, Tambaram. MATERIALS AND METHODS: In a prospective observational study, on a simple random sample basis, TB suspects attending the out-patient department of GHTM during the period January-March, 2006, were interviewed using a semi-structured interview schedule. Information on demographic, socio-economic characteristics and reasons for attending GHTM for health care was collected. RESULTS: A total of 2,023 respondents attended GHTM during the study period; 56% were males, 67% were aged <45 years, 63% were literates and the average annual family income was Rs 25,000. Multiple reasons for attending GHTM were given: popularity of the centre (82%), perceived availability of good treatment (52%), referral by earlier treated patients (36%), expectation of specialized care (22%), referred by treating physicians (13%), and came for inpatient care (11%). CONCLUSION: Despite the availability of local RNTCP health services, many patients with chest symptoms made use of GHTM services due to the reputation of the former "TB sanatorium" in the community. The findings suggest that there is a need to improve community awareness of the availability of free diagnostic and treatment facilities locally under RNTCP. PMID- 20931026 TI - Outcomes of category III and I in immunocompetent patients of tuberculous lymphadenopathy treated in revised national tuberculosis control programme. AB - BACKGROUND: Retrospective observation analysis to evaluate the outcome of six month treatment regimen, CAT-III and CAT-I, for all patients diagnosed with tubercular lymphadenopathy at M.G.M. Medical College and M.Y. Hospital, Indore, India from January 2006 to December 2008. MATERIALS AND METHODS: Out of 3158 cases of tuberculosis, there were 337 (10.67%) lymphnode cases; 31 (9.19%) HIV positive and 11(3.26 %) defaulters were excluded from the study. Of the remaining 295 cases of lymphadenopathy enrolled, 240 were on CAT-III and 55 cases of complicated lymphadenopathy were on CAT-I. All patients were followed for six months, to monitor response and complications. Patients with abscess formation or sinus formation underwent aspiration, AFB smear and culture sensitivity. In patients with persistent lymphadenopathy, repeat FNAC of the gland and in cases of hard lymphnode excision biopsy was done before receiving re-treatment regimen category -II or reserved drugs. RESULT: Out of 295 patients, 212 (71.86%) responded to treatment, however, 83 (28.14%) did not show response at the end of treatment. Of the 83 patients, 54 (65.06%) responded to re-treatment regimen CAT II, while 29 (34.93%) were found to be drug resistant and were given second line anti tubercular drugs. In the follow-up at six months and later after the end of treatment, 11 (5.18%) relapse was seen. CONCLUSION: In our study, success rate of currently recommended regimens, category III and I under the revised national tuberculosis control programme in tubercular lymphadenopathy was 71.86%; with 28.34% of patients requiring re-treatment regimen. This requires a lager study involving more number of patients to prove adequacy of regimen. PMID- 20931027 TI - Utility of fiberoptic bronchoscopy in diagnosis of various lung conditions: Our experience at rural medical college. AB - AIM: To evaluate the utility of fiberoptic bronchoscopy in order to find out the etiology in various lung conditions. MATERIALS AND METHODS: Fiberoptic bronchoscopy was performed in 120 adult patients who had persistent opacities on chest radiography in the form of collapse, consolidation, hilar mass and cavity with proper antibiotic course of 1 to 3 months. Bronchoscopic aspirates, brushing and biopsy (as and when required) were taken. Patient with known lung cancer, sputum positive pulmonary TB, recent myocardial infarction, allergic diseases and blood dyscrasias were excluded. RESULTS: Fiberoptic bronchoscopy was diagnostic in 90 (75%) patients. Bacterial pneumonias were found in 32 (26.66%), malignancy in 28(23.33%), pulmonary TB in 20 (16.66%), fungal pneumonia in 6(5%) and foreign bodies in 4(3.33%) patients. In 30(25%) patients no specific diagnosis was made. CONCLUSION: We conclude that fiberoptic bronchoscopy was found to be extremely useful in finding specific etiology of various lung diseases. PMID- 20931028 TI - Study of bronchoalveolar lavage in clinically and radiologically suspected cases of pulmonary tuberculosis. AB - CONTEXT: About 30 to 50 % of pulmonary tuberculosis patients have sputum report negative for acid fast bacilli or present with no expectoration. A lot of research is going on to find methods to establish early and accurate diagnosis of pulmonary tuberculosis (PTB) as institutions of early treatment can have significant effects on morbidity and mortality of patients and also the development of MDR-TB. Samples other than sputum play an important role in the diagnosis of disease in such patients. AIMS: To assess the significance of bronchoalveolar lavage samples and fiberoptic bronchoscopy (FOB) in the early diagnosis of occult sputum smear negative pulmonary tuberculosis. SETTINGS AND DESIGN: Study was conducted in a tertiary care hospital. FOB was performed in patients with three consecutive sputum smear negative acid fast bacilli to obtain bronchoalveolar lavage (BAL) samples. Written informed consent was obtained from these patients. MATERIALS AND METHODS: BAL samples were subjected to Z-N staining and culture on L-J slopes for acid fast bacilli. Sputum samples from the same patients were also cultured. RESULTS: BAL samples were positive in 82.2% of sputum smear negative samples. Culture positivity of BAL samples was 90.9% as compared to sputum culture positivity which was 26.4%. Overall diagnosis could be established in 86.6% of patients with the help of fiber optic bronchoscopy. CONCLUSIONS: BAL samples are very useful in early sputum smear negative pulmonary tuberculosis and FOB can play an important role in diagnosis of lower respiratory tract infections with minimal complications in hands of an expert. PMID- 20931029 TI - Non-invasive ventilation for acute exacerbation of COPD with very high PaCO(2): A randomized controlled trial. AB - OBJECTIVE: To assess the role of non-invasive positive pressure ventilation (NIPPV) for management of Indian patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). MATERIALS AND METHODS: Forty patients (mean age 57.6 +/- 10.8 years; M:F 31:9) with AECOPD with pH <7.35, admitted to the intensive care unit were included. Patients were randomized to receive NIPPV (N, n = 20) with conventional therapy or conventional therapy (C, n = 20) alone at admission. NIPPV was given through the nasal mask. Incidence of need of endotracheal intubation (ETI) was the primary efficacy variable. Hospital mortality, duration of hospital stay and change in clinical and blood gas parameters were the secondary outcome variables. RESULTS: Mean pH at baseline for N and C groups were similar (7.23 +/- 0.07) whereas PaCO(2) was 85.4 +/- 14.8 and 81.1 +/- 11.6 mm of Hg, respectively. At one hour, patients in N group had greater improvement in pH (P = 0.017) as well as PaCO(2) (P = 0.04) which corroborated with clinical improvement. Whereas need of ETI was reduced in patients who received NIPPV (3/20 vs 12/20, P = 0.003), in-hospital mortality was similar (3/20 and 2/20, P = NS). The mean duration of hospital stay was significantly shorter in N group (9.4 +/- 4.3 days) as compared to C group (17.8 +/- 2.6 days); P = 0.001. CONCLUSIONS: In patients with AECOPD, NIPPV leads to rapid improvement in blood gas parameters and reduces the need for ETI. PMID- 20931030 TI - Lung cancer in the Kashmir valley. AB - BACKGROUND: Lung cancer has been found to be the second commonest cancer according to a hospital-based data from Kashmir, India. However, no incidence studies are available. OBJECTIVE: To ascertain the incidence of lung cancer in Kashmir. MATERIALS AND METHODS: All newly histologically diagnosed cases of lung cancer seen in various hospital and private laboratories of the Kashmir valley were registered over a period of two years (January 1, 2004 to December 31, 2005). Also included were patients attending the various oncological service areas of the institute and those diagnosed from any other laboratory outside the state. The incidence rate was calculated using the January 2005 population as the reference population estimated using the census-based projected populations. RESULTS: Four hundred and sixty-two incident cases of lung cancer were seen during the study period. The crude incidence rate, age standardized (world) and truncated age adjusted (40-69 years, world) incidence rates for lung cancer per 100 000 population were 4.01, 6.48 and 15.28 respectively (males 6.55, 10.09 and 23.94 respectively and females 1.19, 2.14 and 4.65). The age adjusted rates for males in district Srinagar was 19.34 per 100 000. One hundred and fifty nine (69.8%) of the 221 had a history of Hukkah smoking. CONCLUSIONS: Even though Kashmir as a whole is a low incidence area for lung cancer (ASR of < 15), Srinagar district has the highest incidence of lung cancer among the males in Kashmir. The data presented is assumed to be the closest approximation to a population-based data registry and the geographical incidence maps of ICMR need appropriate updating. PMID- 20931031 TI - Evaluation of serum immunoglobulin E levels in bronchial asthma. AB - BACKGROUND: Immunoglobulin E and associated cellular responses are responsible for allergic airway diseases. A hypersensitivity reaction initiated by immunologic mechanisms, mediated by IgE antibodies occurs in allergic asthma AIM: To estimate and compare serum IgE levels in mild, moderate, and severe asthmatics and in normal subjects and to obtain a mathematical model describing the relationship between serum IgE levels and severity of asthma. MATERIALS AND METHODS: A stratified sample of 60 patients within age group of 18-60 years and 31 male and 29 female asthmatic patients and 13 healthy controls within 18-60 years were included in this study and classified according to GINA classification. Serum IgE levels were estimated by using ELISA kit. RESULTS: Mean IgE levels ranged from 151.95 IU/ml in normal subjects to 1045.32 IU/ml in severe asthmatics. The model developed was 27% efficient. CONCLUSION: Serum Immunoglobulin E levels were high in asthmatics as compared to normal subjects. On an average, the levels increased as the severity of asthma increased. However, there was no statistically significant correlation since the variability in each level of asthma was very large. PMID- 20931032 TI - Treatment of asthma: Identification of the practice behavior and the deviation from the guideline recommendations. AB - BACKGROUND: Despite an exponential development of the understanding of the disease with availability of good therapy and feasibility of good control along with availability of globally accepted guidelines, there remains a significant gap between the guidelines and prevailing practice behavior for treating asthma all over the globe. This perhaps stands as the single most deterrent factor for good asthma care worldwide. The objective of the study is to analyze the asthma prescriptions to find out the available status of the practice behaviour and the deviations from the guideline in asthma practice. MATERIALS AND METHODS: The asthma prescriptions of the referred patients presenting to the OPD services of the IPCR, Kolkata were photocopied and collected. They were further analyzed based on the available information upon a format being prepared on four major areas as qualifications, clinical recording habit, practice of evaluating patients, and treatment habit that stands apparent from the prescribed medications. The doctors were divided into three categories as a) MBBS, b) MD/DNB (medicine and respiratory medicine), and c) DM (non respiratory sub-specialities) and statistical analysis has been performed comparing the three groups as per the performance in the four pre-decided areas. RESULTS: All the groups fall short of any guideline or text of asthma care in all the areas involved. CONCLUSION: The practice behaviour of our doctors for asthma care appears deficient in several areas and seems far from guideline recommendations. This needs further evaluation and adoption of appropriate interventions. PMID- 20931033 TI - Pulmonary function test in healthy school children of 8 to 14 years age in south Gujarat region, India. AB - OBJECTIVE: To obtain reference values for FEV(1), FVC, FEV(1)% and PEFR among children aged 8-14 years in south Gujarat region of India. MATERIALS AND METHODS: This cross-sectional study was conducted among 655 normal healthy school children (408 boys and 247 girls) of Surat city aged 8 to 14 years studying in V to VII standard during November 2007 to April 2008. Height, weight, body surface area were measured. All included children were tested in a sitting position with the head straight after taking written consent from parents. Spirometry was done using the spirometer "Spirolab II" MIR 010. Spirometer used in the study facilitates the total valuation of lung function including forced vital capacity (FVC), forced expiratory volume in one second (FEV(1)), forced expiratory volume ratio in one second (FEV(1)%) and peak expiratory flow rate (PEFR). RESULTS: FVC, FEV(1) and PEFR were found to be statistically significant in the study groups. For FVC and FEV(1), highest correlation was found with age in girls and height in boys. For FEV(1)%, significant negative correlation was found with age and height in both sexes, but positive correlation was found with surface area. Similarly, PEFR showed highest correlation with surface area in boys and girls. CONCLUSION: Variables such as FVC, FEV(1) and PEFR show good positive correlation with height, age and body surface area in both sexes. There is a need to have regional values for the prediction of normal spirometric parameters in a country like India with considerable diversity. PMID- 20931034 TI - Nosocomial pneumonia in critically ill patients. AB - The care of critically ill patients in the intensive care unit (ICU) is a primary component of modern medicine. ICUs create potential for recovery in patients who otherwise may not have survived. However, they may suffer from problems associated with of nosocomial infections. Nosocomial infections are those which manifest in patients 48 hours after admission to hospital. Nosocomial infections are directly related to diagnostic, interventional or therapeutic procedures a patient undergoes in hospital, and are also influenced by the bacteriological flora prevailing within a particular unit or hospital. Urinary tract infections are the most frequent nosocomial infection, accounting for more than 40% of all nosocomial infections. Critical care units increasingly use high technology medicine for patient care, hemodynamic monitoring, ventilator support, hemodialysis, parenteral nutrition, and a large battery of powerful drugs, particularly antibiotics to counter infection. It is indeed a paradox that the use of high-tech medicine has brought in its wake the dangerous and all too frequent complication of nosocomial infections. PMID- 20931035 TI - Three cases of ARDS: An emerging complication of Plasmodium vivax malaria. AB - Plasmodium (P.) vivax malaria is rarely associated with severe complications like acute respiratory distress syndrome (ARDS). We report three cases of ARDS, which occurred as a complication of vivax malaria, from the city of Kolkata. A middle aged man who developed ARDS along with hepatic and renal dysfunction on the day 7 after completion of antimalarial treatment; a 36-year-old man who developed ARDS on the day 5 after completion of antimalarial treatment and a 15-year-old boy who developed ARDS on day 2, before starting anti-malarial drug. In all cases, vivax malaria was diagnosed by peripheral blood film (PBF) examination. Associated falciparum infection was excluded by repeated PBF examination, and by negative P. falciparum malaria antigen tests. In all cases, ARDS was diagnosed by the presence of hypoxia with PaO(2) / FiO(2) ratio < 200 and bilateral pulmonary infiltration, and by excluding cardiac disease by echocardiography. All cases typically had dramatic onset of ARDS, and required immediate (within hour of onset of dyspnea) institution of mechanical ventilation with high positive end expiratory pressure. All three cases recovered completely, and early ventilator support was life-saving. PMID- 20931036 TI - Non-small cell lung carcinoma presenting as carcinomatous meningitis. AB - Meningeal carcinomatosis is a diffuse infiltration of leptomeninges and sub arachnoid space by malignant cells metastasizing from systemic cancer. Primary bronchogenic carcinoma presenting as carcinomatous meningitis is a very rare occurrence in clinical practice, often occurring during the treatment course of the underlying malignancy. We present this rare presentation in a young non smoker male. PMID- 20931037 TI - Diagnostic role of magnetic resonance angiography in Swyer James syndrome: Case series of two cases. AB - Swyer James syndrome is a rare syndrome which occurs due to viral illness in early childhood. The post infective obliterative bronchiolitis results in arrest of lung growth and alveolarization with reduced vascularity resulting in classical radiological features. We describe two cases of patients fulfilling all the criteria of the syndrome - 1) Unilateral hyperlucent small lung in chest radiograph with air trapping on expiration, small ipsilateral hila and pulmonary artery. 2) Diffuse decrease in attenuation of lung parenchyma with bronchiectasis and reduction in vascularity. 3) Unilateral pruned tree appearance on angiography (MRA). The clinical presentation was recurrent chest infection in a child and infrequent bouts of hemoptysis in a middle aged female. The study demonstrates the role of magnetic resonance angiography in diagnosing the condition. PMID- 20931038 TI - It's easy to miss complicated hydatid cyst of lung. AB - A 60-year-old female presented with pneumonitis of right lower zone. CT scan revealed mass like lesion with multiple air pockets. FNAC and ultrasound confirmed the diagnosis as isolated active pulmonary hydatid cyst, which is not common finding in adult population. PMID- 20931039 TI - Primary adenoid cystic carcinoma of trachea presenting as midline neck swelling and mimicking thyroid tumor: A case report and review of literature. AB - We report an extremely rare case of primary adenoid cystic carcinoma (ACC) trachea presenting as midline swelling neck and mimicking thyroid tumor. A 44 year-old female presented with painless midline swelling neck without any respiratory complaints, hoarseness of voice or dysphagia etc. Fine needle aspiration cytology (FNAC) from swelling reveal features of papillary carcinoma thyroid. Subsequently the operative findings, bronchoscopy and histological diagnosis of excised mass, along with review of FNAC, revealed features of ACC of trachea with exra tracheal extension anteriorly into the soft tissue neck, without actual invasion of the thyroid gland. The world literature on extension of an ACC arising in the laryngotracheal complex to thyroid or soft tissue neck and clinical manifestation as a thyroid nodule or mass is reviewed. The cytological differential diagnosis of ACC and CT findings are also briefly discussed. PMID- 20931040 TI - Laser resection of endobronchial hamartoma via fiberoptic bronchoscopy. AB - Endobronchial hamartoma is a rare benign tumor of lung that may present with symptoms of airway obstruction with wheezing, stridor, recurrent pneumonia or atelectasis. We report a case of a patient with endobronchial hamartoma, recurrent pneumonia, who presented to us with sputum smear and culture positive pulmonary tuberculosis. He was treated with antitubercular treatment and endobronchial hamartoma was resected completely by diode laser through fiberoptic bronchoscope. PMID- 20931041 TI - Silicosis with bilateral spontaneous pneumothorax. AB - Presentation with simultaneous bilateral pneumothorax is uncommon and usually in the context of secondary spontaneous pneumothorax. The association of pneumothorax and silicosis is infrequent and most cases are unilateral. Bilateral pneumothorax in silicosis is very rare with just a few reports in medical literature. PMID- 20931042 TI - Cleidocranial dysplasia. AB - Cleidocranial dysplasia is a rare autosomal dominant condition with generalized dysplasia of bone, characterized by delayed closer of cranial sutures, hypoplastic or aplastic clavicles, short stature, dental abnormalities and a variety of other skeletal abnormalities. We present a seven-year-old female child presenting with classical features of cleidocranial dysplasia. PMID- 20931043 TI - Late recurrence of malignant melanoma presenting with hemoptysis. AB - After a disease-free period of 10 years, a surgically treated case of cutaneous malignant melanoma is usually not followed up further and there is a tendency to assume that the disease is cured. Late recurrence (after 10 years) of cutaneous malignant melanoma, though infrequent, has been documented well in Western countries. In our country, the malignant melanoma is still considered uncommon and there is no data regarding its late recurrence. We report a case of pulmonary malignant melanoma as a late metastatic manifestation of primary plantar malignant melanoma in a 61-year-old man who presented with hemoptysis; metastatic malignant melanoma of the lung occurred 12 years after resection of primary malignant melanoma of sole of the right foot. PMID- 20931044 TI - Erythema nodosum: Atypical presentation of common disease. AB - Tuberculosis is a very common disease often presenting in an uncommon form. High level of suspicion is required to diagnose it, thereby preventing its morbidity and mortality. We present a case of young female with multiple tuberculo-protein hypersensitivity reactions without any evidence of active tuberculosis in the body. PMID- 20931045 TI - Benign fibrous histiocytoma of larynx: A rare cause of acute airway obstruction. AB - Fibrous histiocytoma of larynx is a rare entity. We herein present a 35-year-old femaleof benign fibrous histiocytoma oflarynx with severe airway obstruction that requiring urgent endotracheal intubation followed by tracheostomy. We also report the good long-term survival of this case after such a critical condition. PMID- 20931046 TI - Diagnosis of three cases of endobronchial tuberculosis presenting as unresolved pneumonia, following fiberoptic bronchoscopic biopsy. AB - Nowadays, endobronchial tuberculosis is of rare occurrence. This article presents three such cases. All of them presented as unresolved pneumonia with collapse consolidation in chest X-ray. All the three patients were sputum smear negative for acid fast bacilli. Diagnosis was possible only with fiberoptic bronchoscopy and bronchial biopsy. PMID- 20931047 TI - Periodontitis: A risk factor to respiratory diseases. PMID- 20931048 TI - Chilaiditi sign. PMID- 20931050 TI - Maternal deaths drop by one-third from 1990 to 2008: a United Nations analysis. PMID- 20931051 TI - National and global responsibilities for health. PMID- 20931052 TI - Implications of the adelaide statement on health in all policies. PMID- 20931053 TI - Life-saving learning around the drinking pot. PMID- 20931054 TI - New Zealand cuts health spending to control costs. PMID- 20931055 TI - Sierra Leone's long recovery from the scars of war. PMID- 20931057 TI - Retrospective comparative evaluation of the lasting impact of a community-based primary health care programme on under-5 mortality in villages around Jamkhed, India. AB - OBJECTIVE: To conduct the first rigorous evaluation of the long-term effect of the Comprehensive Rural Health Project on childhood mortality in rural Maharashtra. METHODS: Background information and full birth histories were collected by conducting household surveys and interviewing women. Control villages resembling project villages in terms of population size were randomly selected from an area enclosed by two ellipses centred around, but not including, the project area. An equal number of villages and approximately equal numbers of households and women were randomly sampled from both areas. Cox models with robust standard errors were used to compare the hazard of death among children under 5 years of age in project and control villages. FINDINGS: The hazard of death was reduced by 30% (95% confidence interval, CI: 6% to 48%) after the neonatal period in the project villages compared with control villages after adjustment for caste and religion of subjects and for availability of irrigation in the villages. During the neonatal period there was an increase of 3% in the hazard of death, but it was not statistically significant (95% CI: -18% to 29%). CONCLUSION: Our methods provide useful tools for evaluating long-running community-based primary health care programmes. Our findings add to the growing debate on the long-term sustainability of community-based interventions designed to reduce child mortality. PMID- 20931058 TI - Common perinatal mental disorders in northern Viet Nam: community prevalence and health care use. AB - OBJECTIVE: To establish the prevalence of common perinatal mental disorders their determinants, and their association with preventive health care use among women in one rural and one urban province in northern Viet Nam. METHODS: We conducted a cross-sectional survey of cohorts of pregnant women and mothers of infants recruited systematically in 10 randomly-selected communes. The women participated in psychiatrist-administered structured clinical interviews and separate structured interviews to assess sociodemographic factors, reproductive health, the intimate partner relationship, family violence and the use of preventive and psychiatric health care. Associations between these variables and perinatal mental disorders were explored through univariate analyses and multivariable logistic regression. FINDINGS: Among women eligible for the study (392), 364 (93%) were recruited. Of these, 29.9% (95% confidence interval, CI: 25.20-34.70) were diagnosed with a common perinatal mental disorder (CPMD). The frequency of such disorders during pregnancy and in the postpartum period was the same. Their prevalence was higher among women in rural provinces (odds ratio, OR: 2.17; 95% CI: 1.19-3.93); exposed to intimate partner violence (OR: 2.11; 95% CI: 1.12 3.96); fearful of other family members (OR: 3.36; 95% CI: 1.05-10.71) or exposed to coincidental life adversity (OR: 4.40; 95% CI: 2.44-7.93). Fewer women with a CPMD used iron supplements than women without a CPMD, but the results were not statistically significant (P = 0.05). None of the women studied had ever received mental health care. CONCLUSION: Perinatal depression and anxiety are prevalent in women in northern Viet Nam. These conditions are predominantly determined by social factors, including rural residence, poverty and exposure to family violence. At present the needs of women with common perinatal mental disorders are unrecognized and not attended to and their participation in essential antenatal preventive care appears to be compromised. PMID- 20931059 TI - Declining child mortality in northern Malawi despite high rates of infection with HIV. AB - OBJECTIVE: To determine whether routine surveys, such as the Demographic and Health Surveys (DHS), have underestimated child mortality in Malawi. METHODS: Rates and causes of child mortality were obtained from a continuous-registration demographic surveillance system (DSS) in Malawi for a population of 32 000. After initial census, births and deaths were reported by village informants and updated monthly by project enumerators. Cause of death was established by verbal autopsy whenever possible. The likely impact of human immunodeficiency virus (HIV) infection on child mortality was also estimated from antenatal clinic surveillance data. Overall and age-specific mortality rates were compared with those from the 2004 Malawi DHS. FINDINGS: Between August 2002 and February 2006, 38 617 person-years of observation were recorded for 20 388 children aged < 15 years. There were 342 deaths. Re-census data, follow-up visits at 12 months of age and the ratio of stillbirths to neonatal deaths suggested that death registration by the DSS was nearly complete. Infant mortality was 52.7 per 1000 live births, under-5 mortality was 84.8 per 1000 and under-15 mortality was 99.1 per 1000. One-fifth of deaths by age 15 were attributable to HIV infection. Child mortality rates estimated with the DSS were approximately 30% lower than those from national estimates as determined by routine surveys. CONCLUSION: The fact that child mortality rates based on the DSS were relatively low in the study population is encouraging and suggests that the low mortality rates estimated nationally are an accurate reflection of decreasing rates. PMID- 20931060 TI - Effectiveness of zinc supplementation plus oral rehydration salts for diarrhoea in infants aged less than 6 months in Haryana state, India. AB - OBJECTIVE: To determine if educating caregivers in providing zinc supplements to infants < 6 months old with acute diarrhoea is effective in treating diarrhoea and preventing acute lower respiratory infections (ALRIs), and whether it leads to a decrease in the use of oral rehydration salts (ORS). METHODS: In this retrospective subgroup analysis of infants aged < 6 months, six clusters were randomly assigned to intervention or control sites. Care providers were trained to give zinc and ORS to children with acute diarrhoea at intervention sites, and only ORS at control sites. Surveys were conducted at 3 and 6 months to assess outcomes. Differences between intervention and control sites in episodes of diarrhoea and ALRI in the preceding 24 hours or 14 days and of hospitalizations in the preceding 3 months were analysed by logistic regression. FINDINGS: Compared with control sites, intervention sites had lower rates of acute diarrhoea in the preceding 14 days at 3 months (odds ratio, OR: 0.60; 95% confidence interval, CI: 0.43-0.84) and 6 months (OR: 0.72; 95% CI: 0.54-0.94); lower rates of acute diarrhoea in the preceding 24 hours at 3 months (0.66; 95% CI: 0.50-0.87) and of ALRI in the preceding 24 hours at 6 months (OR: 0.59; 95% CI: 0.37-0.93); and lower rates of hospitalization at 6 months for all causes (OR: 0.40; 95% CI: 0.34-0.49), diarrhoea (OR: 0.34; 0.18-0.63) and pasli chalna or pneumonia (OR: 0.36; 95% CI: 0.24-0.55). CONCLUSION: Educating caregivers in zinc supplementation and providing zinc to infants < 6 months old can reduce diarrhoea and ALRI. More studies are needed to confirm these findings as these data are from a subgroup analysis. PMID- 20931061 TI - Measuring and correcting biased child mortality statistics in countries with generalized epidemics of HIV infection. AB - OBJECTIVE: Under Millennium Development Goal 4, countries are required to reduce child mortality by two-thirds between 1990 and 2015. In countries with generalized epidemics of human immunodeficiency virus (HIV) infection, standard statistics based on fertility history may misrepresent progress towards this target owing to the correlation between deaths among mothers and early childhood deaths from acquired immunodeficiency syndrome. METHODS: To empirically estimate this bias, child mortality data and fertility history, including births to deceased women, were collected through prospective household surveys in eastern Zimbabwe during 1998-2005. A mathematical model was then used to investigate the determinants and temporal dynamics of the bias, first in Zimbabwe and then in other countries with different background mortality rates and HIV-related epidemic profiles. FINDINGS: According to the empirical data, standard cross sectional survey statistics underestimated true infant and under-5 mortality by 6.7% and 9.8%, respectively. These estimates were in agreement with the output from the model, in which the bias varied according to the magnitude and stage of the epidemic of HIV infection and background mortality rates. The bias was greater the longer the period elapsed before the survey and in later stages of the epidemic. Bias could substantially distort the measured effect of interventions to reduce non-HIV-related mortality and of programmes to prevent mother-to-child transmission, especially when trends are based on data from a single survey. CONCLUSION: The correlation between the HIV-related deaths of mothers and their children can bias survey estimates of early child mortality. A mathematical model with a user-friendly interface is available to correct for this bias when measuring progress towards Millennium Development Goal 4 in countries with generalized epidemics of HIV infection. PMID- 20931062 TI - Trends in smoking and quitting in China from 1993 to 2003: National Health Service Survey data. AB - OBJECTIVE: China has about 350 million smokers, more commonly men. Using data from National Health Service Surveys conducted in 1993, 1998 and 2003, we (i) estimated trends in smoking prevalence and cessation according to sociodemographic variables and (ii) analysed cessation rates, quitting intentions, reasons for quitting and reasons for relapsing. METHODS: Data were collected from approximately 57 000 households and 200 000 individuals in each survey year. Household members > 15 years of age were interviewed about their smoking habits, quitting intentions and attitudes towards smoking. We present descriptive data stratified by age, sex, income level and rural versus urban residence. FINDINGS: In China, current smoking in those > 15 years old declined 60-49% in men and 5-3.2% in women over 1993-2003. The decline was more marked in urban areas. However, heavy smoking (>= 20 cigarettes daily) increased substantially overall and doubled in men. The average age of uptake also dropped by about 3 years. In 2003, 7.9% of smokers reported intending to quit, and 6% of people who had ever smoked reported having quit. Of former smokers, 40.6% quit because of illness, 26.9% to prevent disease and 10.9% for financial reasons. CONCLUSION: Smoking prevalence declined in China over the study period, perhaps due to the combined effect of smoking cessation, reduced uptake in women and selective mortality among men over 40 years of age. However, heavy smoking increased. People in China rarely quit or intend to quit smoking, except at older ages. Further tobacco control efforts are urgently needed, especially in rural areas. PMID- 20931063 TI - Context counts: training health workers in and for rural and remote areas. AB - Access to well trained and motivated health workers is the major rural health issue. Without local access, it is unlikely that people in rural and remote communities will be able to achieve the Millennium Development Goals. Studies in many countries have shown that the three factors most strongly associated with entering rural practice are: (i) a rural background; (ii) positive clinical and educational experiences in rural settings as part of undergraduate medical education; and (iii) targeted training for rural practice at the postgraduate level. This paper presents evidence for policy initiatives involving the training of medical students from, in and for rural and remote areas. We give examples of medical schools in different regions of the world that are using an evidence based and context-driven educational approach to producing skilled and motivated health workers. We demonstrate how context influences the design and implementation of different rural education programmes. Successful programmes have overcome major obstacles including negative assumptions and attitudes, and limitations of human, physical, educational and financial resources. Training rural health workers in the rural setting is likely to result in greatly improved recruitment and retention of skilled health-care providers in rural underserved areas with consequent improvement in access to health care for the local communities. PMID- 20931064 TI - The formulation and implementation of a national helmet law: a case study from Viet Nam. AB - PROBLEM: Road traffic injuries are a leading cause of death and disability in Viet Nam. In 2008, official data reported 11 243 deaths and 7771 serious injuries on the roads, of which an estimated 60% of fatalities occur in motorcycle riders and passengers. In recognition of this problem, Viet Nam has had partial motorcycle helmet legislation since 1995. However, for a variety of reasons, implementation and enforcement have been limited. APPROACH: On 15 December 2007, Viet Nam's first comprehensive mandatory helmet law came into effect, covering all riders and passengers on all roads nationwide. Penalties increased ten-fold and cohorts of police were mobilized for enforcement. LOCAL SETTING: The Viet Nam national helmet legislation was developed and implemented by the National Traffic Safety Committee. RELEVANT CHANGES: Despite past barriers to enforcement, increased policing in 2008 led to 680 000 infringements being issued for non helmet wearing. While changes in helmet wearing were not nationally observed, significant increases were documented in selected provinces in the first six months of the law's introduction. In Da Nang, helmet wearing increased from 27 to 99%. In the first three months after the law took effect, surveillance data from 20 urban and rural hospitals, found the risk of road traffic head injuries and deaths decreased by 16% and 18% respectively. LESSONS LEARNT: Political leadership, intensive advanced public education and stringent enforcement have contributed to the successful implementation of the new law. Through continual monitoring of the legislation, loopholes detrimental to the effectiveness of the law have been identified and addressed. PMID- 20931065 TI - Expansion of antiretroviral treatment to rural health centre level by a mobile service in Mumbwa district, Zambia. AB - PROBLEM: Despite the Government's effort to expand services to district level, it is still hard for people living with HIV to access antiretroviral treatment (ART) in rural Zambia. Strong demands for expanding ART services at the rural health centre level face challenges of resource shortages. APPROACH: The Mumbwa district health management team introduced mobile ART services using human resources and technical support from district hospitals, and community involvement at four rural health centres in the first quarter of 2007. This paper discusses the uptake of the mobile ART services in rural Mumbwa. LOCAL SETTING: Mumbwa is a rural district with an area of 23 000 km2 and a population of 167 000. Before the introduction of mobile services, ART services were provided only at Mumbwa District Hospital. RELEVANT CHANGES: The mobile services improved accessibility to ART, especially for clients in better functional status, i.e. still able to work. In addition, these mobile services may reduce the number of cases "lost to follow-up". This might be due to the closer involvement of the community and the better support offered by these services to rural clients. LESSONS LEARNT: These mobile ART services helped expand services to rural health facilities where resources are limited, bringing them as close as possible to where clients live. PMID- 20931066 TI - A standardized health information system for refugee settings: rationale, challenges and the way forward. PMID- 20931067 TI - Suicide research and prevention in developing countries in Asia and the Pacific. PMID- 20931069 TI - Pharmacognosy and technology. PMID- 20931070 TI - Protective effects of bioactive phytochemicals from Mentha piperita with multiple health potentials. AB - Mentha piperita essential oil was bactericidal in order of E. coli> S. aureus > Pseudomonas aeruginosa > S. faecalis > Klebsiella pneumoniae. The oil with total phenolics of 89.43 +/- 0.58 ug GAE/mg had 63.82 +/- 0.05% DPPH inhibition activity with an IC (50) = 3.9 ug/ml. Lipid peroxidation inhibition was comparable to BHT and BHA. A 127% hike was noted in serum ferric-reducing antioxidant power. There was 38.3% decrease in WBCs count, while platelet count showed increased levels of 214.12%. Significant decrease in uric acid level and cholesterol/HDL and LDL/HDL ratios were recorded. The volatile oil displayed high cytotoxic action toward the human tumor cell line. The results of this study deserve attention with regard to antioxidative and possible anti-neoplastic chemotherapy that form a basis for future research. The essential oil of mint may be exploited as a natural source of bioactive phytopchemicals bearing antimicrobial and antioxidant potentials that could be supplemented for both nutritional purposes and preservation of foods. PMID- 20931071 TI - A validated high performance liquid chromatography method for the analysis of thymol and carvacrol in Thymus vulgaris L. volatile oil. AB - Thymus vulgaris L. (Lamiaceae) is a well-known medicinal plant that contains important compounds such as thymol and carvacrol and it has been used in many pharmaceutical dosage forms. Thymol and carvacrol in essential oils are often quantified by gas chromatography (GC) technique but in this work, a validated and reliable high performance liquid chromatography (HPLC) method has been developed for the analysis of these two components in T. vulgaris essential oil. The essential oil of the plant was analyzed by HPLC and GC techniques. The HPLC system consisted of ACE C(18) column and an isocratic acetonitrile:water (50:50) as the mobile phase which was kept at a flow rate of 1 ml/min. The method was validated for selectivity, linearity (r(2) > 0.997 for both thymol and carvacrol), precision (intra-day 0.8-1.9, 1.7-2.6; and inter-day 3.5-4.5, 3.6 4.7) and recovery (97.7%, 97.6%) for thymol and carvacrol, respectively. The limits of detection (LODs) and limits of quantization (LOQs) were calculated to be 2.8, 0.6 ug/ml and 8.6, 1.8 ug/ml for thymol and carvacrol, respectively. The GC system consisted of flame ionization detector (FID) and CP-SIL 8 column. The concentrations of thymol and carvacrol in essential oil obtained by HPLC (41.2%, 4.3%) and GC (40.7%, 4.2%) were compared by statistical methods and they showed good agreement. PMID- 20931072 TI - Screening of molluscicidal strain against Oncomelania hupensis from the rhizosphere of medicinal plant Phytolacca acinosa Roxb. AB - The research aimed to screen and exploit molluscicidal microorganisms against Oncomelania hupensis, from the rhizosphere of medicinal plant, Phytolacca acinosa Roxb., and one strain named as SL-30 was obtained with excellent molluscicidal activity. The freeze-dried powder of exocellular broth (EXB) of SL-30 could kill 100% of snails at a concentration of 48 mg/l for a submerged period of 24 h, with stabile molluscicidal activity at a temperature lower than 60 degrees C; furthermore, it could be gradually degraded after exposure to illumination for 15 days. The freeze-dried powder of SL-30's EXB was safe to fresh fish and shrimp, even at a concentration beyond LC(90) of 24-h exposure period. The glycogen and total protein content of soft tissues of snails decreased after treating with SL 30's EXB, and glycogen content's decreasing rate had a linear relationship with molluscicidal activity. Finally, phylogenetic analysis based on ITS sequence showed that strain SL-30 had a higher similarity to Aspergillus fumigatus with bootstrap value 98%; accordingly, it was identified as a species of Aspergillus. PMID- 20931073 TI - Toxicity evaluation of Xanthorrhoea johnsonii leaf methanolic extract using the Artemia franciscana bioassay. AB - The toxicity of Xanthorrhoea johnsonii methanolic leaf extract was investigated using the Artemia franciscana nauplii bioassay. At 24 h, the extract produced an EC(50) of 361.0 +/- 41.8 MUg/ml, indicating that it was substantially more toxic than the pesticide Mevinphos (1346.2 +/- 80.1 MUg/ml) and approximately 4 fold less toxic than potassium dichromate (87.1 +/- 5.2 MUg/ml). Whilst potassium dichromate LC(50) values remained constant across the 72-h test period, these values decreased for the extract and Mevinphos to similar values (199.8 +/- 60.5 and 114 +/- 12.8 MUg/ml, respectively), indicating their similar level of efficacy. Noteworthy was the apparent anesthetic effect of X. johnsonii leaf extract. Although the extract initially appeared to kill the A. franciscana nauplii, they were seen to temporarily recover by 48 h only to die by 72 h. PMID- 20931074 TI - Antimicrobial and antifungal properties of the essential oil and methanol extracts of Eucalyptus largiflorens and Eucalyptus intertexta. AB - This study was conducted to evaluate the in vitro antimicrobial properties of essential oil, its major component, 1,8-cineole, and extracts of two Eucalyptus species, Eucalyptus intertexta and Eucalyptus largiflorens. Minimum inhibitory concentration (MIC) of the extracts was calculated by broth dilution method and the zone of inhibition was studied by agar disk diffusion method. Gentamicin (10 ug/disk) and rifampin (5 ug/disk) were used as reference controls for antibacterial studies and nystatin (100 ug/disk) for antifungal studies. The results of MIC study revealed that the essential oil has a stronger activity and broader spectrum than those of methanol extracts. It is interesting to point out that the oils had even greater potential of antimicrobial activities than those of 1,8-cineole as their main component. PMID- 20931075 TI - Cytotoxicity of hydro-alcoholic extracts of Cucurbitapepo and Solanum nigrum on HepG2 and CT26 cancer cell lines. AB - Plants are used worldwide for the treatment of diseases, and novel drugs continue to be developed through research from plants. There are more than 20,000 species of plants used in traditional medicines, and these are all potential reservoirs for new drugs. Cucurbitapepo has been used in traditional folk medicine to treat cold and alleviate ache. Previous pharmacological tests have shown that it possesses antiviral, anti-inflammatory, and analgesic effects. Also, Solanum nigrum has been used as a diuretic and an antipyretic agent and it has also been used to cure inflammation, edema, mastitis and hepatic cancer. In this investigation, cytotoxicity of specific concentrations of hydro-alcoholic extracts of C. pepo and S. nigrum was studied on normal [Chinese hamster ovarian cells (CHO) and rat fibroblast] and cancer (HepG2 and CT26) cell lines. The cytotoxic effects and IC(50) of the extracts on the selected cell lines were studied followed by colonogenic assay method. The results showed that IC(50) of S. nigrum extract was significantly lower than that of the C. pepo extract on all four cell lines (P < 0.05). On the other hand, IC(50) of S. nigrum extract was significantly higher than the extract of Taxus baccata and Cisplatin, herbal and chemical control positive anticancer compounds, respectively, on all four cell lines (P < 0.05). As a result, it is concluded that the extract of S. nigrum has almost similar cytotoxicity to the extract of T. baccata on cancer cells. PMID- 20931076 TI - Production of podophyllotoxin in Linum linearifolium in vitro cultures. AB - For the first time, callus and suspension cultures of Linum linearifolium were initiated. Podophyllotoxin (PTOX), a strong antitumor precursor, was isolated from the calli and suspension, as a main lignan besides smaller amount of 6 methoxypodophyllotoxin (6MPTOX). L. linearifolium is now the third Linum species of section Syllinum, with PTOX as the main lignan. The amounts of lignans, especially PTOX, found in L. linearifolium cell cultures are quite high within the studied Linum species until now. The antiproliferative effects of extracts were tested in a panel of human tumor cell lines, using the MTT [3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide]-dye reduction assay. The lignan mixtures caused concentration-dependent inhibition of malignant cell proliferation and showed moderate cytotoxic activity. The results clearly demonstrate that the lignan mixture of L. linearifolium exerts inhibitory effects against malignant cells. PMID- 20931077 TI - Evaluation of the hypoglycemic and hypolipidemic effects of an ethylacetate fraction of Artocarpus heterophyllus (jak) leaves in streptozotocin-induced diabetic rats. AB - Aqueous extracts of mature leaves of Artocarpus heterophyllus (jak) are used by traditional medical practitioners in Sri Lanka and India for the treatment of diabetes. This study was conducted to investigate the hypoglycemic and hypolipidemic effects of an ethylacetate (EA) fraction of the mature leaves of A. heterophyllus in a streptozotocin (STZ) induced diabetic rat model. In normoglycemic rats, administration of a single dose (20 mg/kg) of the EA fraction resulted in a significant (P < 0.05) reduction in the fasting blood glucose concentration and a significant improvement in glucose tolerance (P < 0.05), compared to the controls. In STZ-induced diabetic rats, chronic administration of the EA fraction of A. heterophyllus leaves daily for 5 weeks resulted in a significant lowering of serum glucose, cholesterol and triglyceride (TG) levels. Compared to control diabetic rats, the extract-treated rats had 39% less serum glucose, 23% lower serum total cholesterol and 40% lower serum TG levels and 11% higher body weight at the end of the fifth week. The percentage reductions in the serum parameters mediated by the test fraction were comparable with those produced by glibenclamide (0.6 mg/kg), the reference drug used in this study. It can be concluded that the EA fraction of A. heterophyllus leaves contains one or more hypoglycemic and hypolipidemic principles which have the potential to be developed further for the treatment of diabetes specifically associated with a hyperlipidemic state. PMID- 20931079 TI - Total phenolic, anthocyanin contents and antioxidant capacity of selected elderberry (Sambucus canadensis L.) accessions. AB - Fourteen purple-black American elderberry accessions (Sambucus canadensis L.) obtained from various sites in midwestern USA and then grown at a single Ohio production site in USA were analyzed for their total phenolic (TP) and total monomeric anthocyanin (TMA) contents and for their antioxidant capacity by the ferric reducing antioxidant power (FRAP) and DPPH radical scavenging assays. Total phenolic and anthocyanin contents were measured using the Folin-Ciocalteu reagent and the pH differential methods, respectively. Overall, the phytonutrient contents and antioxidant capacity of our elderberry accessions were similar to those typically reported for black raspberries, blackberries and other dark fleshed small fruits. Variability among accessions was greatest for TMA content (CV 37.5%); individuals ranged nearly threefold from 1308 to 4004 MUg cy3-GE/g on a fresh weight basis. Variation among accessions was also evident for TP, FRAP and DPPH values (CV 14.4, 21.7 and 26.8%, respectively). TP and TMA values were very highly correlated (r = 0.93), although individuals differed in the estimated proportion of total phenolics attributable to anthocyanins. Both TP and TMA also highly correlated to antioxidant capacity values (r = 0.70-0.85). Within this limited study of 14 accessions, variability for phytonutrient content and antioxidant capacity suggested the employment of wild germplasm within an elderberry improvement program to incorporate an array of superior horticultural, post-harvest or processing traits into new or existing cultivars with superior phytonutrient profiles. PMID- 20931078 TI - Preservation on calcium homeostasis is involved in mitochondrial protection of Limonium sinense against liver damage in mice. AB - Mechanisms underlying the mitochondrial protection of Limonium sinense extracts (LSE) was studied in lipopolysaccharide and D-galactosamine (LPS/D-GalN) intoxicated mice. It was found that increased activities of serum aspartate aminotransferase and alanine aminotransferase induced by LPS/D-GalN were significantly inhibited by pretreatment with LSE. The obvious disruption of membrane potential, intramitochondrial Ca (2+) overload and suppression in mitochondrial Ca (2+) -ATPase activity induced by LPS/D-GalN were significantly blocked by pretreatment with LSE. It was concluded that mechanisms underlying protection of LSE against liver mitochondria damage might be related to the preservation on mitochondrial Ca (2+) homeostasis through the preservation on mitochondrial Ca (2+) -ATPase activity. PMID- 20931080 TI - Antimicrobial activity of Bauhinia tomentosa and Bauhinia vahlii roots. AB - The hexane, ethylacetate and methanol extracts from Bauhinia tomentosa and Bauhinia vahlii roots were tested for their antimicrobial activity against Gram positive bacteria (four strains), Gram-negative bacteria (three strains) and three fungi strains using microdilution methods, for the determination of minimal inhibition concentration (MIC) and the minimal microbicidal concentration (MMC). The MIC values of hexane extracts of B. tomentosa and B. vahlii roots were more than 250 ug/ml. The MIC values of ethylacetate and methanol extracts of B. tomentosa roots varied from 7.81 to 31.25 ug/ml and 31.25 to 62.50 ug/ml, respectively. The MIC values of ethylacetate and methanol extracts of B. vahlii roots varied from 15.63 to 62.5 ug/ml and 62.5 to 250 ug/ml, respectively. MMC values obtained are two times greater than the corresponding MIC values. The activities of ethylacetate extracts are attributed to the presence of flavonoids and that of methanol extracts are attributed to the presence of tannins. PMID- 20931081 TI - Essential oil constituents of Illicium griffithii and its antimicrobial activity. AB - The essential oil of the fruit of Illicium griffithii Hook f. et Thoms. was extracted using Clevenger's apparatus. Forty-one compounds were characterized by gas chromatography-mass spectroscopy (GC-MS). 4-Methyl-6-(2-propenyl)-1,3 benzodioxole was characterized as the major constituent, followed by linalool amongst the volatile constituents. The essential oil was found to be effective against Aspergillus niger, Penicillium spp. and Saccharomyces cerevisiae and possessed considerable activity against Staphylococcus aureus and was inactive against Klebsiella pnemoniae, Pseudomonas aureginosae, Proteus vulgaris and Escherichia coli. PMID- 20931082 TI - Phytochemical investigation and antimicrobial activity of Psidium guajava L. leaves. AB - Psidium guajava L. leaves were subjected to extraction, fractionation and isolation of the flavonoidal compounds. Five flavonoidal compounds were isolated which are quercetin, quercetin-3-O-alpha-L-arabinofuranoside, quercetin-3-O-beta D-arabinopyranoside, quercetin-3-O-beta-D-glucoside and quercetin-3-O-beta-D galactoside. Quercetin-3-O-beta-D-arabinopyranoside was isolated for the first time from the leaves. Fractions together with the isolates were tested for their antimicrobial activity. The antimicrobial studies showed good activities for the extracts and the isolated compounds. PMID- 20931083 TI - Effect of Phlomis persica on glucose levels and hepatic enzymatic antioxidants in streptozotocin-induced diabetic rats. AB - Methanol extract of the aerial parts of Phlomis persica Boiss. (Lamiaceae) (PPE) was studied to evaluate the effects of antidiabetic potential, by measuring fasting blood glucose, insulin, total antioxidant power (TAP), using ferric reducing antioxidant power (FRAP), lipid peroxidation (using thiobarbituric acid reactive substances, TBARS), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) on streptozotocin-induced diabetes in rats. Male Wistar rats were randomly divided into five groups of six animals each. Oral administration of PPE at doses of 100 and 200 mg/kg once a day for 10 days resulted in a significant reduction in fasting blood glucose and an increase in serum insulin levels, in comparison with diabetic control group. It also prevented diabetes-induced loss in body weight. Hepatic TAP increased and TBARS decreased following PPE treatments. The extract at 100 and 200 mg/kg increased the activity of hepatic SOD, CAT, and GPx in diabetic rats. It is concluded that PPE has antidiabetic potential that is comparable with glibenclamide. In conclusion, the results of the present study show positive effects of P. persica on experimental diabetes and thus the antidiabetic effect of PPE is related to its potential to inhibit hepatocellular oxidative stress. PMID- 20931084 TI - Cissus quadrangularis L. extract attenuates chronic ulcer by possible involvement of polyamines and proliferating cell nuclear antigen. AB - The present study was designed to investigate whether Cissus quandrangularis extract (CQE) had healing effects on gastric ulcer, through modulation of polyamines and proliferating cell nuclear antigen (PCNA) in rats. Administration of acetic acid (AA) was accompanied by reduced PCNA which was determined by immunohistochemical staining, (3)H-thymidine incorporation using liquid scintillation spectrometry, mitochondrial marker enzymes, polyamine contents and transforming growth factor-alpha (TGF-alpha) expression in gastric mucosa of rats. Administration of CQE after the application of AA to the stomach enhanced the reduction of ulcer area in a dose-dependent manner which was confirmed by histoarchitecture. Moreover, CQE significantly increased the (3)H-thymidine incorporation and the levels of polyamines such as putrescine, spermine and spermidine in ulcerated rats. In addition, the extract offers gastroprotection in the ulcerated area by increased expression of TGF-alpha and also reversed the changes in the gastric mucosa of ulcerated rats with significant elevation in mitochondrial tricarboxylic acid (TCA) cycle enzymes and PCNA levels. Based on these results, the healing effect of CQE on AA induced gastric mucosal injury in rats may be attributed to its growth promoting and cytoprotective actions, possibly involving an increase in tissue polyamine contents and cell proliferation. PMID- 20931085 TI - Ultrasound-assisted extraction of alantolactone and isoalantolactone from Inula helenium roots. AB - This work deals with ultrasound-assisted extraction (UAE) of alantolactone and isoalantolactone from the roots of Inula helenium L., a well-known medicinal plant. The effects of ethanol concentration, extraction time, temperature and number of extraction steps on the extraction yields of both sesquiterpene lactones were investigated. Gas chromatographic (GC) method was used for simultaneous determination of their contents in the corresponding extracts. A comparison with classical extraction methods [maceration, infusion and micro steam distillation-extraction (MSDE)] showed that the amounts of alantolactone and isoalantolactone achieved by UAE with 70 and 96% EtOH for 30 min at room temperature were higher or almost equal to those obtained by maceration for 24 hours. PMID- 20931086 TI - Correlation between antioxidant effect mechanisms and polyphenol content of Rosa canina. AB - Rosa canina L. is a member of Rosaceae family, which is well-known for its high phenolic contents. These compounds are known to possess antioxidant, antimutagenic and anticarcinogenic effects. However, they have yet to pass controlled clinical trials for efficacy, and their potential for prooxidant activity is an understudied field of research. In order to estimate the correlations between phenolic contents and antioxidant/proxidant effect mechanisms, different concentrations of R. canina fruit extracts were examined in this study. R. canina showed antioxidant activities at all concentrations with respect to the reducing power, hydrogen peroxide scavenging activity and superoxide anion radical scavenging (O2(?-)) activity assays, whereas a negative correlation was observed with the metal ion chelating activity and free radical scavenging activity [1,1-diphenyl-2-picryl-hydrazil (DPPH) % inhibition] assays at higher concentrations with the phenolic content of R. canina. These results suggest that R. canina may act not only as an antioxidant, but also as a prooxidant with the effects depending on its concentrations. PMID- 20931087 TI - Antimicrobial activity of extracts from Tamarindus indica L. leaves. AB - Tamarindus indica L. leaves are reported worldwide as antibacterial and antifungal agents; however, this observation is not completely accurate in the case of Cuba. In this article, decoctions from fresh and sun dried leaves, as well as fluid extracts prepared with 30 and 70% ethanol-water and the pure essential oil from tamarind leaves were microbiologically tested against Bacillus subtilis, Enterococcus faecalis, Staphylococcus aureus, Escherichia coli, Salmonella typhimurium, Pseudomona aeruginosa and Candida albicans. Aqueous and fluid extracts were previously characterized by spectrophotometric determination of their total phenols and flavonoids, while the essential oil was chemically evaluated by gas chromatography/mass spectroscopy (GC/MS). Experimental data suggest phenols as active compounds against B. subtilis cultures, but not against other microorganisms. On the other hand, the essential oil exhibited a good antimicrobial spectrum when pure, but its relative low concentrations in common folk preparations do not allow for any good activity in these extracts. PMID- 20931088 TI - Phenolic content and antioxidant activity of Pereskia grandifolia Haw. (Cactaceae) extracts. AB - The leaves of Pereskia grandifolia Haw. (Cactaceae), commonly known as "Jarum Tujuh Bilah" in Malaysia, have been traditionally used as natural remedy in folk medicine by the locals. In the present study, the antioxidant potential of P. grandifolia crude methanol and its fractionated extracts (hexane, ethyl acetate and water) have been investigated, employing three different established testing systems, such as scavenging activity on 1,1-diphenyl-2-picrylhydrazyl (DPPH) radicals, reducing power assay and beta-carotene method. The total phenolic content of the P. grandifolia extracts was also assessed by the Folin Ciocalteau's method. The ethyl acetate extract showed significantly the highest total phenolic content, DPPH scavenging ability and antioxidant activity in beta carotene bleaching assay while the hexane extract possessed significantly strongest reducing power. The data obtained in these testing systems clearly establish the antioxidant potency of P. grandifolia. As such, this is the first report on the antioxidant activities of P. grandifolia. PMID- 20931089 TI - Isolation and functional expression of a novel lipase gene isolated directly from oil-contaminated soil. AB - A lipase gene SR1 encoding an extracellular lipase was isolated from oil contaminated soil and expressed in Escherichia coli. The gene contained a 1845-bp reading frame and encoded a 615-amino-acid lipase protein. The mature part of the lipase was expressed with an N-terminal histidine tag in E. coli BL21, purified and characterized biochemically. The results showed that the purified lipase combines the properties of Pseudomonas chlororaphis and other Serratia lipases characterized so far. Its optimum pH and temperature for hydrolysis activity was pH 5.5-8.0 and 37 degrees C respectively. The enzyme showed high preference for short chain substrates (556.3+/-2.8 U/ug for C10 fatty acid oil) and surprisingly it also displayed high activity for long-chain fatty acid. The deduced lipase SR1 protein is probably from Serratia, and is organized as a prepro-protein and belongs to the GXSXG lipase family. PMID- 20931090 TI - Salivary aldehyde dehydrogenase - temporal and population variability, correlations with drinking and smoking habits and activity towards aldehydes contained in food. AB - Fluorimetric method based on oxidation of the fluorogenic 6-methoxy-2 naphthaldehyde was applied to evaluate temporal and population variability of the specific activity of salivary aldehyde dehydrogenase (ALDH) and the degree of its inactivation in healthy human population. Analyzed was also its dependence on drinking and smoking habits, coffee consumption, and its sensitivity to N acetylcysteine. Both the specific activity of salivary ALDH and the degree of its inactivation were highly variable during the day, with the highest activities recorded in the morning hours. The activities were also highly variable both intra- and interpersonally, and negatively correlated with age, and this correlation was stronger for the subgroup of volunteers declaring abstinence from alcohol and tobacco. Moderately positive correlations of salivary ALDH specific activity with alcohol consumption and tobacco smoking were also recorded (r(s) ~0.27; p=0.004 and r(s) =0.30; p=0.001, respectively). Moderate coffee consumption correlated positively with the inactivation of salivary ALDH, particularly in the subgroup of non-drinking and non-smoking volunteers. It was found that mechanical stimulation of the saliva flow increases the specific activity of salivary ALDH. The specific activity of the salivary ALDH was strongly and positively correlated with that of superoxide dismutase, and somewhat less with salivary peroxidase. The antioxidant-containing drug N acetylcysteine increased activity of salivary ALDH presumably by preventing its inactivation in the oral cavity. Some food-related aldehydes, mainly cinnamic aldehyde and anisaldehyde, were excellent substrates of the salivary ALDH3A1 enzyme, while alkenals, particularly those with short chain, were characterized by lower affinity towards this enzyme but high catalytic constants. The protective role of salivary ALDH against aldehydes in food and those found in the cigarette smoke is discussed, as well as its participation in diminishing the effects of alcohol- and smoking-related oxidative stress. PMID- 20931091 TI - Benefits and expected outcomes of the Pan-Canadian Data Definitions and Quality Indicators projects. PMID- 20931092 TI - Regional variations in not treating diagnosed hypertension in Canada. AB - BACKGROUND: Improvements in the diagnosis and treatment of hypertension have been documented in Canada following implementation of a national program to improve hypertension management. OBJECTIVE: To determine whether there are regional variations in not treating diagnosed hypertension with drugs in Canada. METHODS: Using data from the Canadian Community Health Survey (CCHS) cycle 3.1 (2005), regional variation in drug treatment of diagnosed hypertension was examined. Also, national drug data from the Intercontinental Medical Statistics CompuScript database were analyzed to determine regional trends in total antihypertensive prescriptions in the period before and following the CCHS cycle 3.1. RESULTS: The overall rate of untreated hypertension among those diagnosed with hypertension in Canada was 12.7%. The highest untreated rate among those diagnosed with hypertension was in the Northern region (29.2%) and the lowest was in the Atlantic region (8.8%). Alberta (16.5%) and British Columbia (BC) (15.4%) also had higher untreated rates, while Ontario (13.2%) was similar to Canada overall. Younger age, single/never married status, larger household size, lack of access to a family physician and daily smoking were all associated with a higher likelihood of not receiving antihypertensive treatment. Adjusting for demographic characteristics, diagnosed hypertensive patients in Alberta (adjusted OR 1.35 [95% CI 1.14 to 1.61]) and BC (adjusted OR 1.64 [95% CI 1.40 to 1.91]) were more likely to be untreated than those in Ontario. The largest overall percentage increase in total antihypertensive prescriptions following the CCHS (ie, 2006) occurred in BC and Ontario. In Alberta, it remained almost unchanged and declined in Manitoba. CONCLUSIONS: Among adult Canadians diagnosed with hypertension, there were regional variations in the likelihood of not receiving antihypertensive therapy. Further research is required to understand the reasons for these variations to regionally target interventions and improve hypertension management in Canada. PMID- 20931093 TI - Management of hypertension: Regional variations in a greatly improved landscape. PMID- 20931094 TI - Novel characteristics of a trafficking-defective G572R-hERG channel linked to hereditary long QT syndrome. AB - BACKGROUND: The congenital long QT syndrome is a heterogeneous genetic disease associated with delayed cardiac repolarization, prolonged QT intervals, the development of ventricular arrhythmias and sudden death. Type 2 congenital long QT syndrome (LQT2) results from KCNH2 or hERG gene mutations. hERG encodes the K(v)11.1 alpha subunit of the rapidly activating delayed rectifier K(+) current in the heart. Studies of mutant hERG channels indicate that most LQT2 missense mutations generate trafficking-deficient K(v)11.1 channels. OBJECTIVE: To identify the mechanism underlying G572R-hERG by using molecular and electrophysiological analyses. METHODS AND RESULTS: To elucidate the electrophysiological properties of the G572R-hERG mutant channels, mutant hERG subunits were heterologously expressed in HEK293 cells alone or in combination with wild-type (WT)-hERG subunits. Patch-clamp techniques were used to record currents, and double immunofluorescence protein tagging and Western blotting were performed to examine the cellular trafficking of mutant subunits. When expressed alone, G572R-hERG subunits were not present in the cell membrane and did not produce detectable currents. When coexpressed with WT-hERG subunits, G572R-hERG decreased current density and altered gating properties of the WT-hERG channel. CONCLUSION: The hERG-associated missense mutation G572R, like most LQT2 missense mutations, generates a trafficking-deficient phenotype. Furthermore, G572R-hERG causes a loss of function in hERG by a strong dominant negative effect on the WT hERG channel. PMID- 20931095 TI - Cardiac remodeling in a rat model of diet-induced obesity. AB - The mechanisms by which diet-induced obesity cause remodeling and cardiac dysfunction are still unknown. Interstitial collagen and myocardial ultrastructure are important in the development of left ventricular hypertrophy, and are essential to the adaptive and maladaptive changes associated with obesity. Thus, the accumulation of collagen and ultrastructural damage may contribute to cardiac dysfunction in obesity. The purpose of the present study was to investigate cardiac function in a rat model of diet-induced obesity and to test the hypothesis that cardiac dysfunction induced by obesity is related to myocardial collagen deposition and ultrastructural damage. Thirty-day-old male Wistar rats were fed standard (control [C]) and hypercaloric diets (obese [Ob]) for 15 weeks. Cardiac function was evaluated by echocardiogram and isolated left ventricle papillary muscle. Cardiac morphology was assessed by histology and electron microscopy. Compared with C rats, Ob rats had increased body fat, systolic blood pressure and area under the curve for glucose, leptin and insulin plasma concentrations. Echocardiographic indexes indicated that Ob rats had increased left ventricular mass, increased systolic stress and depressed systolic function. Analysis of the isolated papillary muscle was consistent with higher myocardial stiffness in Ob compared with C rats. The Ob rats had an increase in myocardial collagen and marked ultrastructural changes compared with C rats. Obesity promotes pathological cardiac remodeling with systolic dysfunction and an increase in myocardial stiffness, which, in turn, is probably related to afterload elevation and cardiac fibrosis. Obesity also causes damage to myocardial ultrastructure, but its effect on myocardial function needs to be further clarified. PMID- 20931096 TI - Safety and effectiveness of enoxaparin following fibrinolytic therapy: Results of the Acute Myocardial Infarction (AMI)-QUEBEC registry. AB - BACKGROUND: Previous randomized controlled trials and meta-analyses demonstrated the superior efficacy of enoxaparin (ENOX) over unfractionated heparin (UFH) in patients with ST segment elevation myocardial infarction (STEMI). The external validity of randomized controlled trials may be limited by selective inclusion of patients who are younger and healthier than the 'real-life' population. OBJECTIVE: To evaluate the safety and effectiveness of ENOX compared with UFH in unselected STEMI patients. METHODS: The safety and effectiveness of ENOX and UFH were compared in STEMI patients who received fibrinolytic therapy at 17 Quebec hospitals in 2003. RESULTS: A total of 498 STEMI patients received systemic anticoagulation, with ENOX and UFH administered in 114 and 384 patients, respectively. There were no differences in baseline characteristics between the two patient groups. The rates of in-hospital major adverse cardiac or cerebral events were 11.4% in the ENOX group compared with 14.0% in the UFH group (P=0.51). In-hospital death or nonfatal reinfarction occurred in 7.9% of patients who received ENOX compared with 9.9% of patients who received UFH (P=0.52). Major bleeding occurred in 4.4% of patients who received ENOX versus 6.0% in patients who received UFH (P=0.51). INTERPRETATION: There was no significant difference in the rates of in-hospital adverse events in the ENOX group compared with the UFH group, when used in the real-life context. Larger observational studies may further confirm the safety, effectiveness and optimal duration of the administration of ENOX in unselected STEMI patients treated with fibrinolysis. PMID- 20931097 TI - Referrals in acute coronary events for CARdiac catheterization: The RACE CAR trial. AB - BACKGROUND: Women with acute coronary syndromes have lower rates of cardiac catheterization (CC) than men. OBJECTIVE: To determine whether sex/gender, age, risk level and patient preference influence physician decision making to refer patients for CC. METHODS: Twelve clinical scenarios controlling for sex/gender, age (55 or 75 years of age), Thrombolysis in Myocardial Infarction risk score (low, moderate or high) and patient preference for CC (agreeable or refused/no preference expressed) were designed. Scenarios were administered to specialists across Canada using a web-based computerized survey instrument. Questions were standardized using a five-point Likert scale ranging from 1 (very unlikely to benefit from CC) to 5 (very likely to benefit from CC). Outcomes were assessed using a two-tailed mixed linear regression model. RESULTS: Of 237 scenarios, physicians rated men as more likely to benefit from CC than women (mean [+/- SE] 4.44+/-0.07 versus 4.25+/-0.07, P=0.03), adjusted for age, risk and patient preference. Low-risk men were perceived to benefit more than low-risk women (4.20+/-0.13 versus 3.54+/-0.14, P<0.01), and low-risk younger patients were perceived to benefit more than low-risk older patients (4.52+/-0.17 versus 3.22+/ 0.16, P<0.01). Regardless of risk, patients who agreed to CC were perceived as more likely to benefit from CC than patients who were disagreeable or made no comment at all (5.0+/-0.23, 3.67+/-0.21, 2.95+/-0.14, respectively, P<0.01). CONCLUSION: Canadian specialists' decisions to refer patients for CC appear to be influenced by sex/gender, age and patient preference in clinical scenarios in which cardiac risk is held constant. Future investigation of possible age and sex/gender biases as proxies for risk is warranted. PMID- 20931098 TI - One-year costs associated with cardiovascular disease in Canada: Insights from the REduction of Atherothrombosis for Continued Health (REACH) registry. AB - BACKGROUND AND OBJECTIVES: To provide a contemporary estimate of the economic burden of atherothrombosis in Canada, annual cardiovascular-related hospitalizations, medication use and associated costs across the entire spectrum of atherothrombotic disease were examined. METHODS: The REduction of Atherothrombosis for Continued Health (REACH) registry enrolled 1964 Canadian outpatients with coronary artery disease, cerebrovascular disease or peripheral arterial disease (PAD), or three or more cardiovascular risk factors. Baseline data on cardiovascular risk factors and associated medication use, and one-year follow-up data on cardiovascular events, hospitalizations, procedures and medication use were collected. Annual hospitalization and medication costs (Canadian dollars) were derived and compared among patients according to the presence of established atherothrombotic disease at baseline, specific arterial beds affected and the number of affected arterial beds. RESULTS: Average annualized medication costs were $1,683, $1,523 and $1,776 for patients with zero, one, and two or three symptomatic arterial beds, respectively. Average annual hospitalization costs increased significantly with the number of beds affected ($380, $1,403 and $3,465, respectively; P<0.0001 for overall linear trend). Mean hospitalization costs for patients with any coronary artery disease, any cerebrovascular disease and any PAD were $1,743, $1,823 and $4,677, respectively. After adjusting for other clinical factors, PAD at baseline was independently associated with a significant increase in hospitalization costs. CONCLUSION: Costs associated with vascular-related hospitalizations and interventions for Canadian patients increased with the number of affected arterial beds, and were particularly high for patients with PAD and/or polyvascular disease. These contemporary data provide insight into the economic burden associated with atherothrombotic disease in Canada, and highlight the need for increased preventive strategies to lessen the burden for patients and society. PMID- 20931099 TI - Administrative data have high variation in validity for recording heart failure. AB - BACKGROUND: Many studies have relied on administrative data to identify patients with heart failure (HF). OBJECTIVE: To systematically review studies that assessed the validity of administrative data for recording HF. METHODS: English peer-reviewed articles (1990 to 2008) validating International Classification of Diseases (ICD)-8, -9 and -10 codes from administrative data were included. An expert panel determined which ICD codes should be included to define HF. Frequencies of ICD codes for HF were calculated using up to the 16 diagnostic coding fields available in the Canadian hospital discharge abstract during fiscal years 2000/2001 and 2005/2006. RESULTS: Between 1992 and 2008, more than 70 different ICD codes for defining HF were used in 25 published studies. Twenty-one studies validated hospital discharge abstract data; three studies validated physician claims and two studies validated ambulatory care data. Eighteen studies reported sensitivity (range 29% to 89%). Specificity and negative predictive value were greater than 70% across 17 studies. Nineteen studies reported positive predictive values (range 12% to 100%). Ten studies reported kappa values (range 0.39 to 0.84). For Canadian hospital discharge data, ICD-9 and -10 codes 428 and I50 identified HF in 5.50% and 4.80% of discharge records, respectively. Additional HF-related ICD-9 and -10 codes did not impact HF prevalence. CONCLUSION: The ICD-9 and -10 codes 428 and I50 were the most commonly used to define HF in hospital discharge data. Validity of administrative data in recording HF varied across the studies and data sources that were assessed. PMID- 20931100 TI - Increasing the doses of both diuretics and angiotensin receptor blockers is beneficial in subjects with uncontrolled systolic hypertension. AB - BACKGROUND: Blood pressure (BP) control is frequently difficult to achieve in patients with predominantly elevated systolic BP. Consequently, these patients frequently require combination therapy including a thiazide diuretic such as hydrochlorothiazide (HCTZ) and an agent blocking the renin-angiotensin aldosterone system. Current clinical practice usually limits the daily dose of HCTZ to 25 mg. This often leads to the necessity of using additional antihypertensive agents to control BP in a high proportion of patients. OBJECTIVES: To compare the efficacy of two doses of losartan (LOS)/HCTZ combinations in patients with uncontrolled ambulatory systolic hypertension after six weeks of treatment with LOS 100 mg/HCTZ 25 mg (LOS100/HCTZ25). METHODS: Following a two- to four-week washout period, subjects with a mean clinic sitting systolic BP of 160 mmHg or higher and a mean ambulatory daytime systolic BP (MDSBP) of 135 mmHg or higher on LOS100/HCTZ25 (n=105; 33 women and 72 men) were randomly assigned to receive LOS 150 mg/HCTZ 25 mg (group 1; n=53) or LOS 150 mg/HCTZ 37.5 mg (LOS150/HCTZ37.5, group 2; n=52). The primary end point was the difference in MDSBP reductions. RESULTS: At the end of the six-week treatment period, the respective additional decreases in MDSBP were 1.2 mmHg (P=0.335) on LOS 150 mg/HCTZ 25 mg and 5.6 mmHg (P<0.0001) on LOS150/HCTZ37.5 (difference of 4.4 mmHg; P=0.011). Daytime systolic ambulatory BP goal (lower than 130 mmHg) achievement tended to be higher (25% versus 17%; P=0.313) with LOS150/HCTZ37.5, while it was significantly higher (65% versus 43%; P=0.024) for mean daytime diastolic BP (lower than 80 mmHg). No deleterious metabolic changes were observed. CONCLUSIONS: In patients with uncontrolled systolic ambulatory hypertension receiving LOS100/HCTZ25, increasing both HCTZ and LOS dosages simultaneously to LOS150/HCTZ37.5 may be an effective strategy that does not affect metabolic parameters. PMID- 20931101 TI - Interprovincial spoke-to-hub transport using the Impella Recover LP 5.0 left ventricular assist device as a bridge to long-term circulatory support. AB - Current hospital administrative practices categorize health care centres in a network of 'spokes' (primary care centres) and 'hubs' (tertiary care centres). For the treatment of cardiogenic shock, long-term left ventricular assist devices (LVADs) and transplant therapies are only used at a few hub centres nationwide and are, thus, only available to patients living in close proximity to these centres. The relatively lower technical requirements of the Impella Recover LP 5.0 LVAD (ABIOMED Inc, USA) translate into greater use by spoke centres for the short-term treatment of cardiogenic shock, and facilitate appropriate stabilization and subsequent transportation to a suitable hub centre. Based on a review of the literature, the present report describes the first case demonstrating successful use of the Impella Recover LP 5.0 LVAD, implanted under local anesthetic, for the purposes of interprovincial spoke-to-hub transport in a bridge-to-bridge-to-transplant procedure. By providing an economical and technically straightforward alternative to traditional extracorporeal membrane oxygenation, the present case demonstrates that less invasive LVADs are valuable to the spoke-and-hub model for delivery of specialized cardiac care. PMID- 20931102 TI - Cardiovascular complications of Salmonella enteritidis infection. AB - Salmonella has the ability to adhere to damaged endothelium, predisposing individuals to complications rarely seen with other Gram-negative organisms. Potential complications include endocarditis, infected atheroma or aneurysms, myocarditis and pericarditis. The present report describes two cases of Salmonella enteritidis-associated cardiovascular disease. Patient 1 is a young adult who presented with myopericarditis complicated by recurrent cardiac arrests following return from a tropical climate. This patient was successfully treated with a 14-day course of ciprofloxacin. Patient 2 is an elderly man who developed a pseudoaneurysm of the ascending aorta complicating S enteritidis bacteremia, and died of this complication. Recognition of potential complications of salmonellosis, especially in individuals with risk factors, is paramount in correctly diagnosing and managing these patients. PMID- 20931103 TI - Robotic coronary artery bypass for aberrant right coronary artery stenosis. AB - Anomalous coronary arteries that course between the aorta and pulmonary artery are subject to compressive forces and can manifest angina, myocardial infarction and sudden death. The current report presents a young, female patient who presented with a short duration of severe, rapidly progressive angina despite optimal medical therapy. Combined computed tomography and myocardial perfusion scanning identified an anomalous dominant right coronary artery that appeared kinked at its origin between the aorta and main pulmonary artery. A robot assisted right internal thoracic artery to right coronary artery bypass was performed, which was confirmed to be widely patent (FitzGibbon grade A) on routine intraoperative angiography. The procedure completely resolved the patient's angina symptoms. PMID- 20931104 TI - An unusual presentation of left ventricular free wall rupture. AB - Left ventricular free wall rupture (LVFWR) is one of the most lethal complications following myocardial infarction. It accounts for approximately 12% to 21% of all in-hospital deaths following myocardial infarction. The majority of patients die shortly after LVFWR from instantaneous pericardial tamponade and hemodynamic collapse. However, up to one-third of cases are subacute in nature, allowing limited time for emergent surgical repair to prevent sudden death. A high index of suspicion and timely use of diagnostic tests are important in recognizing cases. The present report describes the case of a 69-year-old man who initially presented with acute pericardial tamponade and was subsequently diagnosed with LVFWR in the operating room as the cause of his hemopericardium. The pathology, diagnosis and management of LVFWR are reviewed. PMID- 20931105 TI - Synthesis and characterization of nanogels of poly(N-isopropylacrylamide) by a combination of light and small-angle X-ray scattering. AB - Thermo-responsive crosslinked nanogels of N-isopropylacrylamide (NIPAM) were synthesized by emulsion polymerization and the size was varied using different concentrations of surfactant (sodium dodecyl sulfate, SDS) in the polymerization process. The collapse behavior of the nanogels at the lower critical solution temperature at around 32 degrees C was investigated by dynamic light scattering, and by combined static light scattering (SLS) and small-angle X-ray scattering (SAXS). The combined data from SLS and SAXS were analyzed by a model for the nanogels which at intermediate temperatures included a central core and a more diffuse outer layer describing pending polymer chains with a low degree of cross linking. In the expanded state, the particles were modeled with a single component with a broad graded surface. In the collapsed state the nanogels were modeled as homogeneous and relatively compact particles. The amount of surfactant used had a profound effect on the final size of the nanogels owing to the phenomenon of colloidal stabilization of the emulsion droplets during polymerization. The combination of SLS and SAXS as applied to the nanogels is an attractive method for particle characterization as it spans a very large range of scattering vector from q = 0.0004 to 0.22 A(-1). PMID- 20931106 TI - Anti-aggregation of gold nanoparticle-based colorimetric sensor for glutathione with excellent selectivity and sensitivity. AB - For the widely used Au nanoparticles (AuNPs)-based colorimetric probe, AuNPs generally change from the dispersion to the aggregation state and corresponding colors turn from red to blue concomitantly. In previous studies, there are few probes based on the anti-aggregation of AuNPs though anti-aggregation of AuNPs is preferable to aggregation to achieve higher selectivity. In this manuscript, a fast and simple but sensitive and selective sensor suitable for on-site and real time detection of glutathione (GSH) has been developed based on the anti aggregation of AuNPs. The sensor has a LOD of 8 nM and excellent selectivity toward GSH by a factor of 200-fold or more relative to natural amino acids as well as homocysteine (Hcys) and glutathione disulfide (GSSG). The dynamic range of the sensor can be tuned simply by adjusting the amount of aggregation agent used. PMID- 20931107 TI - Diatoms: self assembled silica nanostructures, and templates for bio/chemical sensors and biomimetic membranes. AB - In this review we highlight recent advances in the understanding of biosilica production, biomodification of diatom frustules and their subsequent applications in bio/chemical sensors, and as a model membrane for filtration and separation. PMID- 20931109 TI - Borylnitrenes: electrophilic reactive intermediates with high reactivity towards C-H bonds. AB - Borylnitrenes (catBN 3a and pinBN 3b; cat = catecholato, pin = pinacolato) are reactive intermediates that show high tendency towards insertion into the C-H bonds of unactivated hydrocarbons. The present article summarizes the matrix isolation investigations that were aimed at identifying, characterizing and investigating the chemical behaviour of 3a by spectroscopic means, and of the experiments in solution and in the gas phase that were performed with 3b. Comparison with the reactivity reported for difluorovinylidene 1a in solid argon indicates that 3a shows by and large similar reactivity, but only after photochemical excitation. The derivative 3b inserts into the C-H bonds of hydrocarbon solvents in high yields and thus allows the formation of primary amines, secondary amines, or amides from "unreactive" hydrocarbons. It can also be used for generation of methylamine or methylamide from methane in the gas phase at room temperature. Remaining challenges in the chemistry of borylnitrenes are briefly summarized. PMID- 20931108 TI - "Click" synthesis of small molecule-peptide conjugates for organelle-specific delivery and inhibition of lysosomal cysteine proteases. AB - A click chemistry approach for the synthesis of small molecule inhibitor-peptide conjugates to achieve organelle-specific delivery has been developed. Biological testing showed that the inhibitor-Tat conjugate was successfully delivered to the lysosomes, leading to potent inhibition of lysosomal cysteine proteases in cultured cells. PMID- 20931110 TI - Tracking infrared signatures of drugs in cancer cells by Fourier transform microspectroscopy. AB - Aimed at developing accurate, reliable and cost-saving analytical techniques for drugs screening we evaluated the potential of Fourier Transform (FT) InfraRed (IR) microspectroscopy (microFTIR) as a quantitative pre-diagnostic approach for the rapid identification of IR signatures of drugs targeting specific molecular pathways causing Chronic Myeloid Leukemia (CML). To obtain reproducible FTIR absorbance spectra at the necessary spatial resolution we optimized sample preparation and acquisition parameters on a single channel Mercury-Cadmium Telluride (MCT) detector in the spectral interval of frequencies from 4000 to 800 cm(-1). Single K562 cells were illuminated by Synchrotron Radiation (SR) and a number of ~15 K562 cells spread in monolayer were illuminated by a conventional IR source (Globar), respectively. Combining IR spectral data with the results of complementary biochemical investigations carried out in samples by different analytical methods we identified and cross-validated IR signatures of drugs targeting the oncogenic protein BCR/ABL and its associated abnormal tyrosine kinase activity in K562 cell line. Unsupervised pattern recognition performed by Hierarchical Cluster Analysis (HCA) clustered the spectra of single K562 cells in two distinct groups roughly corresponding to living and to apoptotic cells, respectively. The corresponding IR spectral profiles were assumed to represent drug-resistant and drug-sensitive cells. Significant variations with increasing percentages of apoptotic cells were observed after the treatment of K562 cells with drugs that directly or indirectly target BCR/ABL. In conclusion, we suggest that microFTIR associated with multivariate data analysis may be useful to assess drug compounds in ex vivo cancer cell models and possibly peripheral blast cells from CML patients. PMID- 20931111 TI - Depuration kinetics of paralytic shellfish toxins in Mytilus galloprovincialis exposed to Gymnodinium catenatum: laboratory and field experiments. AB - The kinetics of paralytic shellfish toxins in Mytilus galloprovincialis, previously exposed to Gymnodinium catenatum, was studied under depuration laboratory conditions and over a declining bloom of the dinoflagellate in the field. The variation of the levels observed throughout the laboratory experiment was characterized by a fast depuration of B1, C1 + 2, dcSTX and dcGTX2 + 3, possibly due to the gut evacuation of unassimilated toxins or microalgae cells, or loss during digestive mechanisms. Subsequent enhancements were observed for all compounds with emphasis to dcSTX and dcGTX2 + 3, pointing to biotransformation of the assimilated toxins. Then levels decreased gradually. A first-order depuration kinetic model fitted well to the decrease of B1, C1 + 2 and dcGTX2 + 3 concentrations, but not for dcSTX. Mussels exposed to a declining bloom of Gymnodinium catenatum exhibited a loss of toxins following the same pattern. Despite the low abundance of this dinoflagellate, a similar kinetic model was applied to the field data. The depuration rate of dcGTX2 + 3 in the field experiment (0.153 +/- 0.03 day(-1)) significantly exceeded the value calculated in the laboratory (0.053 +/- 0.01 day(-1)), while smaller differences were obtained for B1 (0.071 +/- 0.02 and 0.048 +/- 0.01 day(-1)) and similar values for C1 + 2 (0.082 +/- 0.03 and 0.080 +/- 0.03 day(-1)). The slower depuration rate of dcGTX2 + 3 in the heavily contaminated mussels at the laboratory may be related to a more effective contribution of C1 + 2 biotransformation. PMID- 20931112 TI - Evaluation of the potential of Raman microspectroscopy for prediction of chemotherapeutic response to cisplatin in lung adenocarcinoma. AB - The study of the interaction of anticancer drugs with mammalian cells in vitro is important to elucidate the mechanisms of action of the drug on its biological targets. In this context, Raman spectroscopy is a potential candidate for high throughput, non-invasive analysis. To explore this potential, the interaction of cis-diamminedichloroplatinum(II) (cisplatin) with a human lung adenocarcinoma cell line (A549) was investigated using Raman microspectroscopy. The results were correlated with parallel measurements from the MTT cytotoxicity assay, which yielded an IC(50) value of 1.2 +/- 0.2 uM. To further confirm the spectral results, Raman spectra were also acquired from DNA extracted from A549 cells exposed to cisplatin and from unexposed controls. Partial least squares (PLS) multivariate regression and PLS Jackknifing were employed to highlight spectral regions which varied in a statistically significant manner with exposure to cisplatin and with the resultant changes in cellular physiology measured by the MTT assay. The results demonstrate the potential of the cellular Raman spectrum to non-invasively elucidate spectral changes that have their origin either in the biochemical interaction of external agents with the cell or its physiological response, allowing the prediction of the cellular response and the identification of the origin of the chemotherapeutic response at a molecular level in the cell. PMID- 20931113 TI - Model catalysts of supported Au nanoparticles and mass-selected clusters. AB - In surface science, much effort has gone into obtaining a deeper understanding of the size-selectivity of nanocatalysts. In this article, electronic and chemical properties of various model catalysts consisting of Au are reported. Au supported by oxide surfaces becomes inert towards chemisorption and oxidation as the particle size became smaller than a critical size (2-3 nm). The inertness of these small Au nanoparticles is due to the electron-deficient nature of smaller Au nanoparticles, which is a result of metal-substrate charge transfer. Properties of Au clusters smaller than ~20 atoms were shown to be non-scalable, i.e., every atom can drastically change the chemical properties of the clusters. Moreover, clusters with the same size can show dissimilar properties on various substrates. These recent endeavours show that the activity of a catalyst can be tuned by varying the substrate or by varying the cluster size on an atom-by-atom basis. PMID- 20931114 TI - Ion association and solvation behavior of tetraalkylammonium iodides in binary mixtures of dichloromethane + N,N-dimethylformamide probed by a conductometric study. AB - Precise measurements on electrical conductances of tetraalkylammonium iodides, R(4)NI (R = n-butyl to n-heptyl), in different mass% (0-100) of dichloromethane (DCM) + N,N-dimethylformamide (DMF) at 298.15 K have been performed. Limiting molar conductances (Lambda(0)), association constants (K(A)) and co-sphere diameter (R) for ion-pair formation in the mixed solvent mixtures have been evaluated using the Fuoss conductance-concentration equation. However, the deviation of the conductometric curves (Lambda versus ?c) from linearity for the electrolytes in 100 mass% of DCM indicated triple ion formation, and therefore corresponding conductance data have been analyzed by the Fuoss-Kraus theory of triple ions. Limiting ionic molar conductances lambda have been calculated by the reference electrolyte method along with a numerical evaluation of ion pair and triple ion formation constants (K(P)~K(A) and K(T)). The results have been interpreted in terms of ion-solvent interactions and structural changes in the mixed solvents. PMID- 20931115 TI - Electrostatic attraction between a hydrophilic solid and a bubble. AB - The contact between fine hydrophilic alpha-Al(2)O(3) particles and nitrogen bubbles was studied as a function of solution composition in single bubble capture experiments, where the bubble collection efficiency was measured. The surface charges of both bubble and particle were controlled by varying the electrolyte concentration and pH of the solution. In all experiments the bubbles were negatively charged while the alpha-Al(2)O(3) particles were either negatively (above pH of the isoelectric point, pH(IEP)) or positively (below pH(IEP)) charged. The collection efficiency was found to be strongly influenced by the surface charge of the particles. The maximum collection efficiency occurred when the bubble and particle were oppositely charged (at low pH values) and at low salt concentration, i.e. when a long range attractive electrostatic interaction is present. In the case where both bubble and particle were of the same charge, the collection efficiency was near to zero within experimental error and was not influenced by either salt concentration or pH. This is the first experimental proof of the concept of 'contactless flotation', first proposed by Derjaguin and Dukhin in 1960, with far reaching implications from minerals processing to biology. PMID- 20931116 TI - Implications of citrate concentration during the seeded growth synthesis of gold nanoparticles. AB - Increasing the citrate concentration during the seeded growth synthesis of gold nanoparticles yields materials with decreased aspect ratios and increased defect densities. The stability of these nanoparticles is attributed to variations in their overall Gibb's free energy. PMID- 20931117 TI - Stability and transformation mechanism of weddellite nanocrystals studied by X ray diffraction and infrared spectroscopy. AB - This study is focused on the stability of weddellite, the dihydrate phase of calcium oxalate [CaC(2)O(4).(2 + x)H(2)O], mainly detected in kidney stones and in oxalate films found on the surfaces of several ancient monuments. Its occurrence is a critical issue since, at environmental conditions, weddellite is unstable and quickly changes into whewellite, the monohydrate phase of calcium oxalate (CaC(2)O(4).H(2)O). New single crystal X-ray diffraction experiments have been carried out, which confirm the structural model of weddellite previously published. Synthesised nanocrystals of weddellite have been kept under different hygrometric conditions in order to study, by X-ray powder diffraction, the influence of humidity on their stability. Moreover, the mechanism of transformation of weddellite nanocrystals has been investigated by infrared spectroscopy using D(2)O as a structural probe. PMID- 20931118 TI - Predicting water uptake in poly(perfluorosulfonic acids) using force field simulation methods. AB - Free energy perturbation methods were applied to predict water contents in hydrated poly(perfluorosulfonic acids) (PPFSA). The simulations were based on the TEAM force field which was derived from quantum mechanical data calculated for small molecules using density functional theory (DFT) and thermodynamic data of molecular liquids and crystal. The equilibrium water contents in three PPFSA polymers (Nafion-117, Nafion-115 and Hyflon) were predicted by evaluating excess chemical potentials of water in hydrated polymers and in pure water. High level of precision measured by average uncertainty of ca. 0.1 kcal mol(-1), and accuracy in terms of deviation from experimental data by ca. 0.2 kcal mol(-1) were obtained in the predicted excess chemical potentials. The predicted amounts of water uptake agree well with experimental values. In addition, the equilibrium and dynamic properties of hydrated Nafion-117 were calculated and the results agree well with the existing experimental and computational data. The entropy and enthalpy contributions in the calculated excess chemical potentials are analyzed and the results are consistent with intuition. A linear correlation between the entropies and enthalpies is identified for the systems studied, which indicates that just increasing the interaction energies between water and host materials does not guarantee enhancement of the water uptake. PMID- 20931119 TI - Insertion of indigo molecules in the sepiolite structure as evidenced by 1H-29Si heteronuclear correlation spectroscopy. AB - Despite the numerous studies of the famous indigo-based pigment Maya Blue, there are still many questions regarding the elucidation of its structure. Here, two dimensional (2D) (1)H-(29)Si heteronuclear correlation (HETCOR) spectroscopy with frequency-switched Lee-Goldburg (FSLG) homonuclear decoupling is applied to sepiolite and sepiolite-indigo complexes. Owing to the high resolution in the (1)H dimension of the 2D (1)H-(29)Si HETCOR spectrum obtained by FSLG homonuclear decoupling, the assignment of the (29)Si cross-polarization magic-angle spinning (CPMAS) spectrum of sepiolite is clearly confirmed. Moreover, 2D (1)H-(29)Si FSLG HETCOR spectroscopy gives the first direct evidence that some indigo molecules are inserted in the sepiolite structure whereas no interaction between indigo and the external side surface (silanol groups) is observed in the (29)Si CPMAS spectra. These results are consistent with the fact that indigo molecules interact with water coordinated to magnesium and suggest that Maya Blue made from sepiolite is not a surface complex. PMID- 20931120 TI - Ionic physisorption on bubbles induced by pulsed ultra-sound. AB - Ion flotation processes involve the use of bubbles in order to separate ionic species from a mixed solution. Due to bubble interfaces we may assume null curvature at the molecular scale, where selective ion adsorption might be more easily investigated than with liquid-liquid extraction. In contrast to a classical flotation set-up, where bubbles are introduced via a glass frit, we use here a controlled sono-device generating cavitation bubbles which are initially absolutely clean. Moreover we have a faster process with a smaller device. The liquid phase resulting from the coalescence of the overflowing foam is enriched in some ions versus the initial brine. We show here that this effect follows the Hofmeister series and can be attributed to a weak adsorption of hydrated ions at the surfactant-water interface. The selectivity of alkali metals physisorbed at interfaces is analysed through the concentrations of competing ions remaining in solution by inductively coupled plasma optical emission spectrometry. Cationic selectivity, which is independent of the method for obtaining a foam, is discussed via the Gibbs free energy difference for bulk to hydrated surfactant monolayer. Relative values of effective adsorption energies are determined versus sodium ions taken as reference and correspond to 1-3% of the total hydration free energy. PMID- 20931121 TI - The influence of pi-pi-stacking on the light-harvesting properties of perylene bisimide antennas that are covalently linked to a [60]fullerene. AB - A flexible organic triad consisting of two perylene bisimide antennas covalently linked to a [60]fullerene by flexible spacers has been synthesized and studied by electrochemistry, steady-state and time-resolved spectroscopy. We found that pi pi-stacking of the two antenna subunits has considerable impact on the photophysics of the system and leads to a reduction of the effective light harvesting efficiency of the assembly. This finding is important for light harvesting in flexible materials based on the dye antenna-fullerene concept. PMID- 20931122 TI - Characteristics and transport of organochlorine pesticides in urban environment: air, dust, rain, canopy throughfall, and runoff. AB - Characteristics and transport of organochlorine pesticides (OCPs) in urban multiple environments, including air, dust, rain, canopy throughfall, and runoff water, are explored in this study. Hexachlorocyclohexanes (HCHs) dominated in both air and rain water, and dichlorodiphenyltrichloroethane (DDT) related substances showed a higher affinity to dust. Relatively high concentrations of DDT and dichlorodiphenyldichloroethylene (DDE) in air, rain and dust imply that technical DDT in the environment has been degrading, and there may be unknown local or regional emission sources that contain DDTs in the study area. Source identification showed that DDTs in Beijing urban environments with a fresh signature may originate from the atmospheric transport from remote areas. The ratio of alpha-/gamma-HCH in dust, rain, canopy throughfall and runoff were close to 1, indicating the possible use of lindane. OCPs in runoff were transported from various sources including rain, dust, and canopy throughfall. In runoff, DDTs and hexachlorobenzene (HCB) were mainly transported from dust, and HCHs were mainly from rain and canopy throughfall. PMID- 20931123 TI - Three-dimensional surface microfluidics enabled by spatiotemporal control of elastic fluidic interface. AB - As an emerging alternative to the conventional counterpart, surface microfluidics incorporates both intrinsic resistive solid-liquid and elastic frictionless gas liquid interfaces, leading to unique flow-pressure characteristics. Furthermore, the open-surface microfluidic platforms can be fabricated on a monolithic substrate with high wettability contrast by the previously reported one-step lithographic process of a photosensitive superhydrophobic nanocomposite material, which permits flexible fluidic operations and direct surface modifications. In the paper, we first present three-dimensional microfluidic manipulations utilizing the unconventional gas-liquid interfaces of surface microfluidics, outlined by the micropatterned wetting boundaries (also known as the triple lines). In contrast to the primary linear (resistive) nature of the conventional closed-channel microfluidics, the distinct elastic interface of surface microfluidics enables remarkable three-dimensional (deformable) and time dependent (capacitive) operations of the flow. Specifically, spatiotemporal dependence of microflow patterns on the planar fluidic surfaces has been theoretically analyzed and experimentally characterized. Utilizing the unconventional interface-enabled flow-pressure relationship, novel surface fluidic operations, including microflow regulation and flow-controlled switching, have been demonstrated and fully investigated. Furthermore, three-dimensional surface microfluidic networks together with analog-to-digital stereo-flow activations have been established, in which miniature capillary bridges form fluidic connections between two independent surface microfluidic circuits. PMID- 20931124 TI - Rapid and efficient screening of Alzheimer's disease beta-amyloid inhibitors using label-free gold nanoparticles. AB - Herein we report that a visual, label-free gold nanoparticle-based assay for rapid and efficient screening of Alzheimer's disease beta-amyloid inhibitors. PMID- 20931125 TI - The impact of erbium incorporation on the structure and photophysics of silicon germanium nanowires. AB - In this paper, we report multi-step processes for the fabrication of Er3+-doped SiGe nanowires (NWs) and characterization of their emissive properties. Three different alloyed architectures are obtained by altering the deposition sequences of Si and Er3+ on a Ge core NW, each involving a fixed concentration of these three elements. The deposition of Si onto the Ge NW core, followed by an Er3+ rich layer on the outermost surface, permits facile formation of a SiGe alloy given the lack of an erbium diffusion barrier; yet clustering of the erbium centers on the NW surface produces the weakest emitter. For nanowires prepared by co-depositing Si and Er3+ on top of the Ge core, the presence of impurity Er3+ ions greatly reduces the alloying rate of Si and Ge such that less Si can diffuse into the Ge core. For this structure, the reduction of Er-Er interactions by a polycrystalline Si shell results in the strongest emission at 1540 nm. If an Er3+ layer is inserted between the Ge and Si layers (a sandwich structure), it is found that Er3+ ions diffuse preferentially into the SiGe core instead of the silicon-rich shell, with a correspondingly weaker luminescence intensity. A combination of high resolution transmission electron microscopy, energy dispersive X-ray mapping, micro-Raman spectroscopy, and photoluminescence spectroscopy are employed to derive these conclusions. PMID- 20931126 TI - Nanoscale patterning controls inorganic-membrane interface structure. AB - The ability to non-destructively integrate inorganic structures into or through biological membranes is essential to realizing full bio-inorganic integration, including arrayed on-chip patch-clamps, drug delivery, and biosensors. Here we explore the role of nanoscale patterning on the strength of biomembrane-inorganic interfaces. AFM measurements show that inorganic probes functionalized with hydrophobic bands with thicknesses complimentary to the hydrophobic lipid bilayer core exhibit strong attachment in the bilayer. As hydrophobic band thickness increases to 2-3 times the bilayer core the interfacial strength decreases, comparable to homogeneously hydrophobic probes. Analytical calculations and molecular dynamics simulations predict a transition between a 'fused' interface and a 'T-junction' that matches the experimental results, showing lipid disorder and defect formation for thicker bands. These results show that matching biological length scales leads to more intimate bio-inorganic junctions, enabling rational design of non-destructive membrane interfaces. PMID- 20931127 TI - Modification of bone-like apatite nanoparticle size and growth kinetics by alizarin red S. AB - The formation of nanocrystals in biomineralization such as in bone occurs under the influence of organic molecules. Prompted by this fact, the effect of alizarin red S, a dye used in in vivo bone labeling methods, on bone-like carbonated apatite nanocrystal formation was investigated as a function of alizarin red S additive concentration. The obtained nanoparticles were investigated by powder X ray diffraction (XRD), FTIR as well thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) while the kinetics of nanoparticle formation was investigated by in situ pH and synchrotron XRD measurements. Increasing alizarin red S concentration lead to amorphous particles over a threshold concentration and to smaller crystallites in a dose-dependent fashion. Alizarin red S induced a macroscopic lattice strain that scaled linearly with the alizarin red S concentration; this effect is reminiscent of that seen in biogenic calcium carbonates. TGA showed that the amorphous particles contained significantly more water than the crystalline samples and the DSC data showed that crystallization occurs after loss of most of the included organic material. The in situ studies showed that the formation of apatite goes via the very rapid formation of an amorphous precursor that after a certain nucleation time crystallizes into apatite. This nucleation time increased exponentially with alizarin red S concentration showing that this additive strongly stabilizes the amorphous precursor phase. PMID- 20931128 TI - Studies in catalytic C-H amination involving nitrene C-H insertion. AB - Stereoselective catalytic intermolecular C-H amination of complex molecules is reported. Site-selective functionalizations occur with very good yields up to 91% and excellent d.e.s up to 99%. However, the precise nature of the nitrene C-H insertion remains a matter of debate despite several physical organic experiments. PMID- 20931129 TI - Importance of palladium-carbon bond energies in direct arylation of polyfluorinated benzenes. AB - Fagnou et al. reported direct arylation reactions that use palladium catalysts to couple Ar(1)-X to Ar(2)-H with the aid of a coordinated base. These reactions are particularly favourable for polyfluorinated arenes Ar(2)-H (see S. I. Gorelsky, D. Lapointe and K. Fagnou, J. Am. Chem. Soc. 2008, 130, 10848). In this paper, we show by means of a DFT analysis how the energetics and activation energies vary with fluorine substitution and examine the structures of intermediates and transition states. The reactant is modelled by Pd(OAc)(Ph)(PMe(3))(DMA) (DMA = dimethylacetamide). The sequence consists of (a) replacement of DMA by arene, (b) Concerted Deprotonation Metallation (CMD), (c) decoordination of AcOH, (d) reductive elimination of biaryl. Many of the variations are dominated by the number of fluorine substituents ortho to the C-H bond and fall into three groups labelled accordingly: Set0Fo, Set1Fo, and Set2Fo. In the first step a coordinated solvent is replaced by the arene. The arenes of Set0Fo and Set1Fo coordinate in a conventional eta(2)-CH=CH mode, whereas the arenes of Set2Fo coordinate in an eta(1)-CH mode assisted by an OH-C hydrogen bond from the coordinated acetate. Both the energy barriers to CMD and the product energies fall into the three typical sets with the highest barrier and highest product energy being for Set0Fo. They correlate more satisfactorily with the variations in Pd-C bond energies than with the C-H acidities. The barriers to reductive elimination from Pd(Ph)(Ar(F))(PMe(3))(AcOH) increase systematically from Set0Fo to Set2Fo as the Pd-C bond becomes stronger in a regular fashion from Set0Fo to Set2Fo. Again there is a strong correlation between the energy barriers to reductive elimination and the Pd-C bond energies. It is found overall that the key aspects of the reactions are: (a) the lowering of the energy of the CMD step by the ortho fluorine substituents, (b) the regioselective activation of C-H bonds ortho to fluorine which is also determined at the CMD step, (c) the decoordination of AcOH, which maintains the transition state for reductive elimination at low Gibbs free energy. The presence of fluorine increases the effectiveness of the reaction in the sense of points a and b via the increasing strength of the palladium carbon bond. PMID- 20931130 TI - Solvent-free aromatic C-H functionalisation/halogenation reactions. AB - The solvent-free, palladium-catalysed reaction of anilides with CuCl(2) in the presence or absence of copper acetate yields ortho-chlorinated anilides in good to excellent yields, even on a large scale (100 mmol). By contrast, the equivalent reactions with copper bromide, either solvent free or in 1,2 dichloroethane, in the presence or absence of palladium, under air or inert conditions, gave the products of simple electrophilic bromination. Mechanistic studies highlighted the involvement of palladacyclic intermediates, one of which was characterised crystallographically, which undergo subsequent reaction with copper(II) chloride to yield the chlorinated anilide products. PMID- 20931131 TI - Measurement of the cellular deacetylase activity of SIRT1 on p53 via LanthaScreen(r) technology. AB - Upon genomic insult, the tumor suppressor p53 is phosphorylated and acetylated at specific serine and lysine residues, increasing its stability and transactivation function. Deacetylases, including the type III histone deacetylase SIRT1, remove acetyl groups from p53 and counterbalance acetyltransferase activity during a DNA damage response. This report describes a series of high-throughput LanthaScreen(r) time-resolved Forster resonance energy transfer (TR-FRET) immunoassays for detection of intracellular p53 phosphorylation of Ser15 and acetylation of Lys382 upon treatment with DNA damage agents, such as etoposide. These assays were used to measure the deacetylase activity of SIRT1 and/or Type I/II Histone deacetylases (HDACs). First, BacMam-mediated overexpression of SIRT1 resulted in dose-dependent deacetylation of GFP-p53 following etoposide treatment of U-2 OS cells, confirming that GFP-p53 serves as a SIRT1 substrate in this assay format. Further, overexpression of the acetyltransferase p300 via BacMam increased the acetylation of GFP-p53 at Lys382. Next, siRNA-mediated knockdown of SIRT1 resulted in increased GFP-p53 acetylation, indicating that endogenous SIRT1 activity can also be measured in U-2 OS cells. Consistent with these results, GFP p53 acetylation was also increased upon treatment of cells with a small-molecule inhibitor of SIRT1, EX-527. The effect of this compound was dramatically increased when used in combination with chemotherapeutic drug and/or the HDAC inhibitor Trichostatin A, confirming a proposed synergistic mechanism of p53 deacetylation by SIRT1 and Type I/II HDACs. Taken together, the cellular assays described here can be used as high-throughput alternatives to traditional immunoassays such as western blotting for identifying pharmacological modulators of specific p53-modifying enzymes. PMID- 20931132 TI - Mechanistic understanding of Pyrococcus horikoshii Dph2, a [4Fe-4S] enzyme required for diphthamide biosynthesis. AB - Diphthamide, the target of diphtheria toxin, is a unique posttranslational modification on eukaryotic and archaeal translation elongation factor 2 (EF2). The proposed biosynthesis of diphthamide involves three steps and we have recently found that in Pyrococcus horikoshii (P. horikoshii), the first step uses an S-adenosyl-L-methionine (SAM)-dependent [4Fe-4S] enzyme, PhDph2, to catalyze the formation of a C-C bond. Crystal structure shows that PhDph2 is a homodimer and each monomer contains three conserved cysteine residues that can bind a [4Fe 4S] cluster. In the reduced state, the [4Fe-4S] cluster can provide one electron to reductively cleave the bound SAM molecule. However, different from classical radical SAM family of enzymes, biochemical evidence suggest that a 3-amino-3 carboxypropyl radical is generated in PhDph2. Here we present evidence supporting that the 3-amino-3-carboxypropyl radical does not undergo hydrogen abstraction reaction, which is observed for the deoxyadenosyl radical in classical radical SAM enzymes. Instead, the 3-amino-3-carboxypropyl radical is added to the imidazole ring in the pathway towards the formation of the product. Furthermore, our data suggest that the chemistry requires only one [4Fe-4S] cluster to be present in the PhDph2 dimer. PMID- 20931133 TI - Effect of intracellular photosensitized singlet oxygen production on the electrophysiological properties of cultured rat hippocampal neurons. AB - Whole-cell patch-clamp recordings from single cultured mammalian neurons have been used to provide insight into early membrane-dependent events that result upon the intracellular photosensitized production of singlet molecular oxygen, O(2)(a(1)Delta(g)). The singlet oxygen sensitizers used, pyropheophorbide a (PPa) and protoporphyrin IX (PpIX), locate mainly in cell membranes and mitochondria, respectively. Irradiation of these sensitizers altered both passive and dynamic electrophysiological properties of the neurons in a dose-dependent manner, though the response threshold was much lower with PPa than with PpIX. In particular, notable decreases were observed in the rising and falling rates of action potentials and, at higher light fluences, plateau potentials consistent with activation of Ca(2+) channels also developed. The data suggest that singlet oxygen production specifically influences Na(+), K(+) and Ca(2+) ionophores in the cell membrane. Upon terminating sensitizer irradiation, responses evoked by PPa stabilized immediately whereas those evoked by PpIX continued to develop. These data are consistent with a spatially-resolved sphere of intracellular singlet oxygen activity. While the response to PPa irradiation appears to be membrane specific, the response to PpIX irradiation appears to be systemic and possibly part of a cascade of apoptotic events. These results should contribute to a better understanding of membrane-dependent events pertinent to cell death mediated by singlet oxygen. PMID- 20931134 TI - Effective photoinactivation of Gram-positive and Gram-negative bacterial strains using an HIV-1 Tat peptide-porphyrin conjugate. AB - Given that cell-penetrating peptides (CPP) are cationic and often amphipathic, similar to membrane-active antimicrobial peptides, it may be possible to use CPP conjugation to improve the delivery of photosensitisers for antimicrobial photodynamic therapy (antimicrobial PDT). We investigated the possibility of using a Tat peptide to deliver the photosensitiser, tetrakis(phenyl)porphyrin (TPP) and kill bacteria. The Tat peptide is a positively-charged mammalian cell penetrating peptide with potent antimicrobial activity but no haemolytic activity. Fluorescence spectroscopy revealed that the bioconjugate can bind to and/or be incorporated into all bacterial species tested. All species were susceptible to the Tat-porphyrin, with the bactericidal effect being dependent on both the concentration and the light dose. Using the highest light dose, treatment with the Tat-porphyrin achieved reductions of 6.6 log(10) and 6.37 log(10) in the viable counts of Staphylococcus aureus and Streptococcus pyogenes, and reductions of 5.74 log(10) and 6.6 log(10) in the viable counts of Pseudomonas aeruginosa and Escherichia coli. Moreover, the Tat moiety appears to confer antimicrobial properties to the conjugate, particularly for the Gram positive strains, based on the observation of dark toxicity using 1 MUM of Tat porphyrin. Finally, the conjugate induced membrane destabilization by synergistic action of the peptide and PDT, resulting in carboxyfluorescein leakage from bacterial membrane-mimicking liposomes. These findings demonstrate that the use of CPP to deliver a photosensitiser is an effective way of improving the uptake and the treatment efficacy of antimicrobial PDT. PMID- 20931135 TI - Photosensitized addition of isopropanol to furanones in a 365 nm UV-LED microchip. AB - The DMBP-sensitized addition of isopropanol to furanones was studied in a novel LED-driven microchip reactor. Complete conversions were achieved after just 2.5 to 5 min of irradiation with 6 * 365 nm high-power LEDs. The results were compared to analogous experiments using a conventional batch reactor. PMID- 20931136 TI - Mass spectrometry provides accurate and sensitive quantitation of A2E. AB - Orange autofluorescence from lipofuscin in the lysosomes of the retinal pigment epithelium (RPE) is a hallmark of aging in the eye. One of the major components of lipofuscin is A2E, the levels of which increase with age and in pathologic conditions, such as Stargardt disease or age-related macular degeneration. In vitro studies have suggested that A2E is highly phototoxic and, more specifically, that A2E and its oxidized derivatives contribute to RPE damage and subsequent photoreceptor cell death. To date, absorption spectroscopy has been the primary method to identify and quantitate A2E. Here, a new mass spectrometric method was developed for the specific detection of low levels of A2E and compared to a traditional method of analysis. The new mass spectrometric method allows the detection and quantitation of approximately 10,000-fold less A2E than absorption spectroscopy and the detection and quantitation of low levels of oxidized A2E, with localization of the oxidation sites. This study suggests that identification and quantitation of A2E from tissue extracts by chromatographic absorption spectroscopy overestimates the amount of A2E. This mass spectrometric approach makes it possible to detect low levels of A2E and its oxidized metabolites with greater accuracy than traditional methods, thereby facilitating a more exact analysis of bis-retinoids in animal models of inherited retinal degeneration as well as in normal and diseased human eyes. PMID- 20931137 TI - Phototoxicity of Hoechst 33342 in time-lapse fluorescence microscopy. AB - Dyes that bind to DNA, such as Hoechst 33342, are commonly used to visualize chromatin in live cells by fluorescence microscopy. A caveat is that the probes themselves should not perturb cellular responses and under normal conditions the dyes are generally non-toxic. However, researchers are increasingly using computerized time-lapse microscopy (CTLM), where cells stained with fluorescent dyes are often imaged frequently over a period of several days, to follow cellular responses in real time. Little is currently known about possible toxicity of fluorescent DNA dyes under CTLM conditions. In this study we demonstrate that the common live-cell DNA stain Hoechst 33342 can cause apoptosis under CTLM conditions. Although toxicity is evident at long times in the absence of imaging at high dye concentrations, phototoxicity from repeated excitation of the dye in the imaging process is dominant. We show that phototoxicity is a function of the product of light fluence and dye concentration, irrespective of irradiance, frequency and total number of scans. Thus, phototoxicity can be prevented by a combination of dye concentration and imaging procedure that is below this threshold. These quantitative data can be used as a guide to others performing time-lapse microscopy studies with this common live-cell DNA stain and serves as a caution for researchers when using other fluorescent stains under CTLM conditions. PMID- 20931138 TI - Structural divergence and functional versatility of the rhodopsin superfamily. AB - Seven-transmembrane-helix retinylidene proteins, which constitute the rhodopsin superfamily, have been discovered in diverse species, including Archaea, Eubacteria, fungi, algae and animals. Some members of this super-family were specialized to function as light-driven proton pumps, light-driven chloride pumps, photoisomerases, or light-gated ion channels, where the photochemical reactions are self-completed without interactions with other proteins. Other members evolved to acquire the ability to modulate soluble cytoplasmic or membrane-embedded signal transducers. During the last decade, high-resolution crystal structures were reported for ten members of the rhodopsin superfamily; viz., four proton pumps, two chloride pumps, two microbial photosensors and two visual pigments. Comparison of these structures provides us with a hint to elucidate the common structural motif that is utilized to stabilize their tertiary structures as well as unique architectures that are relevant to specific functions. PMID- 20931140 TI - The effect of tetramethylammonium ion on the voltammetric behavior of polycyclic aromatic hydrocarbons: computations explain a long-standing anomaly. AB - Cyclic voltammograms of several polycyclic aromatic hydrocarbons (PAH's) in highly purified N,N-dimethylformamide are known to exhibit two reversible reduction waves. To a good approximation, the potential of the first wave is independent of the nature of the supporting electrolyte, but the potential of the second wave is highly dependent upon the nature of the electrolyte. The spacing DeltaE degrees between the first and second waves increases as the size of the cation of the electrolyte is increased from Et(4)N(+) through Pr(4)N(+) to Bu(4)N(+). This is typically interpreted as due to decreasing strength of ion pairing between the cation and the dianion of the PAH with increasing size of the electrolyte cation. However, it has been known for many years that Me(4)N(+) exhibits anomalous behavior: even though Me(4)N(+) is much smaller than Et(4)N(+), DeltaE degrees is greater with Me(4)N(+) than with Et(4)N(+) for anthracene and in fact greater than any of the larger electrolytes with perylene. It is now shown that this behavior arises out of the fact that Me(4)N(+) ion is present in solution as a tetrasolvate [Me(4)N(+)/(DMF)(4)]. The PAH dianion (Ar( 2)) reacts with Me(4)N(+)/(DMF)(4) to displace a molecule of DMF and produce the species Me(4)N(+)/(DMF)(3)/Ar(-2). The computed pairing association constant K(ion-pairing) for the anthracene species is 35 M(-1), compared with a value of 50,000 M(-1) for association of the bare Me(4)N(+) ion with the dianion; the corresponding values for perylene are computed to be 4400 and 3.5 M(-1), respectively. PMID- 20931139 TI - UVB-Induced p21 degradation promotes apoptosis of human keratinocytes. AB - Skin cancer is the most common cancer in the United States. Ultraviolet B (UVB) radiation in sunlight is the major environmental factor causing skin cancer. p21, a p53-inducible protein, plays an important role in cell cycle, DNA repair, and apoptosis. Here we have investigated the effect of UVB radiation on p21 and its molecular mechanisms and function in human HaCaT keratinocytes, which we used as a premalignant cellular model because normal skin harbors numerous clones of p53 mutated keratinocytes. We found that in human HaCaT keratinocytes UVB induces rapid p21 down-regulation via a proteasomal degradation mechanism. In p53 defective HaCaT cells, the p21 protein levels remain decreased at a later time post-UVB, but in normal human and mouse epidermal keratinocytes with wild-type p53 the p21 levels are initially reduced but later increase post-UVB. These findings indicate that loss of p53 function leads to sustained p21 down regulation in response to UVB damage. Degradation of p21 following UVB radiation does not require ATR, ATM, or both, because either the ATR/ATM inhibitor caffeine or siRNA knockdown of ATR, ATM, or both failed to reverse p21 degradation. However, inhibiting MDM2 or GSK3beta partially reduced UVB-induced p21 degradation, while inhibiting both enzymes completely prevented it. Restoring the p21 protein levels in UVB-irradiated keratinocytes reduced apoptosis. Although at the molecular level increasing p21 expression has no effect on the protein levels of the Bcl-2 family members, it enhances the activation of AKT, a critical survival pathway to protect cells from apoptosis. Our results suggest a distinct mechanism of p21 degradation in keratinocytes by UVB, and this p21 degradation may significantly enhance UVB-induced apoptosis of premalignant keratinocytes with a p53 defect to eliminate damaged cells and therefore prevent skin cancer development. PMID- 20931141 TI - Vibrational properties of the trinuclear spin crossover complex [Fe3(4-(2' hydroxy-ethyl)-1,2,4-triazole)6(H2O)6](CF3SO3)6: a nuclear inelastic scattering, IR, Raman and DFT study. AB - The vibrational properties of the trimeric iron complex [Fe(3)(4-(2'-hydroxy ethyl)-1,2,4-triazole)(6)(H(2)O)(6)](CF(3)SO(3))(6) which serves as a model of the 1D iron coordination polymers based on 1,2,4-triazoles have been investigated by nuclear inelastic scattering of synchrotron radiation (NIS), as well as by Raman and infrared (IR) spectroscopy. The system reveals a soft spin crossover involving only the central iron atom with its FeN(6) core, while the terminal FeN(3)O(3) units show no spin transition. The NIS spectra of the central low-spin isomer exhibit a number of marker bands in the 350-450 cm(-1) region which have not been detected in the Raman spectra. The density functional theory (DFT) calculations allowed the assignment of these bands to Fe-N bending and stretching modes. A characteristic high-spin marker mode has been identified and discriminated from the iron-ligand modes of the terminal iron atoms. This characteristic central Fe-N mode has been observed experimentally at 245 cm(-1) and theoretically at 255 cm(-1). Contrary to mononuclear centrosymmetric Fe complexes, some of the symmetric vibrations of the trimeric complex involving iron movements are observed by NIS. Furthermore the DFT calculations displayed the importance of the coulombic repulsion between metal ions for the geometry and stability of a given spin isomer. PMID- 20931142 TI - Enhancement of antimicrobial activity by synthetic ion channel synergy. AB - Hydraphile synthetic ion channels were found to enhance the cytotoxicity to E. coli and B. subtilis of erythromycin, kanamycin, rifampicin, and tetracycline when co-administered with the antibiotic at sublethal concentrations of channel. PMID- 20931143 TI - Artificial frustule prepared through a single-templating approach. AB - An "artificial frustule" was prepared through a single-templating approach, where the self-assembled architecture undergoes a transition from cocoons with pore channels parallel to the surface, to hollow spheres with perpendicular pore channels. PMID- 20931144 TI - Modulation of intramolecular heterodimer-induced fluorescence quenching of tricarbocyanine dye for the development of fluorescent sensor. AB - Various approaches have been used to modulate the fluorescence changes of sensors in the presence of target analytes, including intramolecular interaction between fluorophores or between fluorophore and other molecular species, like resonance energy transfer (RET). Here, we focus on fluorescence quenching by intramolecular heterodimer complex formation, which can be modulated over a shorter distance range than RET. We synthesized several conjugates of tricarbocyanine, which is a near-infrared fluorophore, with several quencher candidates via flexible short linker structure, and examined their fluorescence properties. Of our synthesized compounds, the dabcyl group proved to be the best quencher via heterodimer complex formation. The fluorescence of tricarbocyanine-dabcyl conjugates in aqueous media was almost completely quenched, and there was a dramatic fluorescence enhancement when heterodimer formation was blocked. These results suggested a design approach to develop fluorescence sensors for probing proximity relationships and structural transitions. PMID- 20931147 TI - Polyelectrolyte and carbon nanotube multilayers made from ionic liquid solutions. AB - The inevitable contact of substrates with water during the traditional practice of layer-by-layer assembly (LBL) creates problems for multiple potential applications of LBL films in electronics. To resolve this issue, we demonstrate here the possibility of a LBL process using ionic liquids (ILs), which potentially eliminates corrosion and hydration processes related to aqueous media and opens additional possibilities in structural control of LBL films. ILs are also considered to be one of the best "green" processing solvents, and hence, are advantageous in respect to traditional organic solvents. Poly(ethyleneimine) (PEI) and poly(sodium styrenesulfonate) (PSS) were dispersed in a hydrophilic IL and successfully deposited in the LBL fashion. To produce electroactive thin films with significance to electronics, a similar process was realized for PSS modified single-walled carbon nanotubes (SWNT-PSS) and poly(vinyl alcohol) (PVA). Characterization of the coating using standard spectroscopy and microscopy techniques typical of the multilayer field indicated that there are both similarities and differences in the structure and properties of LBL films build from ILs and aqueous solutions. The films exhibited electrical conductivity of 10(2) S m(-1) with transparency as high as 98% for visible light, which is comparable to similar parameters for many carbon nanotube and graphene films prepared by both aqueous LBL and other methods. PMID- 20931151 TI - [Care of thyroid carcinoma in pregnancy: Thyroglobulin content]. PMID- 20931150 TI - Advanced inoperable type B3 thymoma: monitoring of a novel therapeutic approach with radio-chemotherapy and sorafenib by FDG-PET and CT. PMID- 20931152 TI - Obesity in school-aged children: Interpretation of the Body Mass Index in a sample of children and adolescents in Rome. AB - OBJECTIVES: To evaluate overweight and obesity in a sample of children of school age in the city of Rome (Italy). MATERIALS AND METHODS: A sample of 18.299 school children (9.531 males and 8.768 females) aged between 3 and 15 years was studied. Height and weight have been measured in order to calculate the BMI. The percentile distribution of BMI has been determined and then subdivided according to the categories proposed by Cole. The analysis has been done using the program "Statistica" produced by StatSoft, Italia. RESULTS: The prevalence of overweight exceeded 20% in all age groups with the exception of the two extremes 3 years old and 15 years old in which the prevalence was 11.8% and 15.4% respectively. Children between 5 and 10 years old have the highest rates of obesity. The prevalence of obesity was highest in females between 4 and 8 years, while for the males it was 8 to 15 years. However the difference in the prevalence between males and females was statistically significantly different only in ages 9 and 10. CONCLUSIONS: The prevalence of overweight rises to a peak at age 9, reaching 30%, but declines at older ages. The prevalence of obesity peaks at an earlier age reaching between 12% and 15% at ages 5-8 years. The prevalence of obesity declines as the children get older. PMID- 20931153 TI - First clinical case of effective medical treatment of the vitreoretinal traction with recovery of the visual acuity. AB - This case-report evaluates the effectiveness of the medical treatment on vitreomacular traction through the use of palmitoylethanolamide (PEA), orally administered. Our 69 year-old patient reported a significant eyesight reduction, metamorphopsia and photopsia. He underwent the following investigations, before and after medical treatment: visual acuity evaluation, dilated fundus examination, OCT. The treatment consisted of the administration of two tablets of PEA per day over 7 days. We observed that, while the visual acuity in the right eye was 2/10 compared to the initial 11/10, the dilated fundus examination highlighted a foveal hole. Moreover, the OCT confirmed the presence of a vitreomacular traction due to the incomplete posterior vitreous detachment. At the end of the treatment with PEA, the visual acuity was equal to 8/10 and the OCT showed a disappearance of the hyperreflective streak with recovery of the physiological retinal and foveal profile. The therapy was eventually carried on for 10 more days with a final visual acuity of 10/10. In conclusion, PEA orally administered, beyond a rare possibility of a spontaneous resolution of the vitreomacular traction, probably contributed, by anti inflammatory action, to the vitreolysis and thus to the disappearance of the vitreomacular traction and foveal hole with a subsequent recovery of the eyesight and of the metamorphopsia. PMID- 20931154 TI - Duloxetine versus venlafaxine in the treatment of unipolar and bipolar depression. AB - OBJECTIVES: Both duloxetine and venlafaxine are efficacious in treating patients with Major Depressive Disorder (MDD), even though the advantages in treatment patients with bipolar disorder is unclear. This study aimed to evaluate the efficacy of duloxetine vs venlafaxine in the acute treatment of unipolar and bipolar depression. MATERIALS AND METHODS: The study was a non randomized controlled trial. The participants were 62 consecutive outpatients (41 men; 21 women) affected by unipolar and bipolar depression treated either with duloxetine and venlafaxine. RESULTS: More patients treated with duloxetine had a positive response to treatment and remission both for depression (HAMD17 response: 90.3% vs 0.0%; p < .001; HAM-D17 remission: 48.4% vs 0.0%; p < .001), and anxiety (HAM A response: 90.3% vs 6.5%; p < .001; HAM-A remission: 71.0% vs 6.5%; p < .001) than controls. Patients treated with duloxetine were also more likely to show a decrease in HAM-D17 suicidality (100% vs 45.2%; p less than .001) and an increase in the quality of life (SF-36 percentage of improvement: 6.35 [SD=9.66 vs -2.58 [9.98]; p less than .001) than controls. CONCLUSIONS: Duloxetine is more effective in reducing anxiety and suicidal ideation. Both treatments were safe and tolerated, and both may be successfully used in unipolar and bipolar depression. PMID- 20931155 TI - [Psychopathology, quality of life and social functioning in dialysis treatment and kidney transplantation patients]. AB - OBJECTIVES: Psychiatric evaluation of organ transplant candidates is now routinely proposed also in Italy. This study purposed to assess the psychological status in patients on hemo-dialysis, peritoneal dialysis and renal transplantation; moreover other purpose is to investigate the possible differences among the three groups. MATERIALS AND METHODS: 157 subjects were consecutively enrolled, to the service of U.O. Trapianti d'Organo of San Salvatore Hospital in L'Aquila (Italy), between October 2007 and August 2009; 127 were in dialysis (80.9%), of which 101 were in hemodialysis (64.3%) (HD group) and 26 in peritoneal dialysis (16.6%) (PD group) and 30 (19.1%) Kidney transplant (PT group). The subjects were examined with clinical evaluation and through the following psychometric instruments: HAM-D, HAM-A, Jalowiec Coping Scale, STAI-Y1, STAI-Y2, DISS, SF-36. RESULTS: 30% out of our sample showed the presence of some psychopathological signs and symptoms, especially depression and anxiety. At HAM D there were no differences between HD group (6.73; DS + 5.58) and PD group (5.27, DS + 5.63); the mean value at HAM-D in PT group was 4.4 (DS + 3.16) (p < 0.05). At HAM-A there were no differences between three groups. The HD group showed an higher value at STAI-Y1 (38.61; DS + 10.64) than PD (34.95; DS + 6.75) and PT (33.89; DS + 6.14) groups (p < 0.05). The quality of life (physical role, general health, vitality and role emotional) was lower in HD and PD groups, higher in group PT. The HD e PD groups showed a higher level of disability than PT group (p < 0.05). All subjects used "positive: coping styles. CONCLUSIONS: We consider essential to investigate the issues observed in this study, with the need to integrate psychosocial and functional needs assessment within a course of diagnosis and treatment for people who are undergoing dialysis procedures, or after waiting for a transplantation. Dialysis affects the quality of life, leading to limitations in activities and high level of disability. The PT group showed better quality of life and less impairment in functioning in the investigated areas. If the impact of psychological and/or psychiatric aid remains difficult to appraise, these results emphasize the impact of psychological status and the appropriateness of psychosocial support intervention on patients facing the transplant process or in dialysis treatments. PMID- 20931156 TI - Pain assessment in fibromyalgia and rheumatoid arthritis: influence of physical activity and illness perception. AB - OBJECTIVE: Pain visual analog scales (VAS) have been validated for clinical use in fibromyalgia (FM) and rheumatoid arthritis (RA) patients. There are potential limitations, however, not only considering their use as a continuous measurement, but also with regard to the influence of personal illness perceptions, habitual physical activity and other life-style features. The aim of the study was to ascertain whether different illness perception, physical activity and clinical and laboratory characteristics can predict the severity of perceived pain assessed by VAS. MATERIALS AND METHODS: This is an observational comparative study of forty consecutive out-patients, 20 of them with fibromyalgia and 20 with rheumatoid arthritis, treated by medical and physical therapy. Patients were assessed also by Pain VAS, Health Assessment Questionnaire (HAQ) disability index, Ritchie index, Baecke questionnaire for physical activity, Illness Perception Questionnaire (IPQr) and SF36. RESULTS: Pain VAS is explained differently by some of the studied variables: in the total group HAQ and Ritchie index explain 29.8% of the variance; in the RA patients number of joints with pain and Ritchie index explain 52.7% of the variance; in FM patients total SF36 score and IPQr personal control dimension explains 44.7% of the variance. No definite role of anxiety and/or depression was found as predictor of perceived pain and disability. CONCLUSION: Pain perception and complaint are explained by belief in FM patients: This seems to suggest the need for a more articulated cognitive approach; addressing both diagnostic and therapeutic interventions to anxiety/depression issues is not supported by our results. PMID- 20931157 TI - Impact of a metabolic stone clinic on management of patients with cystinuria: 5 years follow-up. AB - PURPOSE: Cystinuric patients develop new stones and exhibit stone growth despite conservative measures and often require surgical intervention. There have been reports of better outcome both in surgical intervention rates and compliance when patients were referred to dedicated metabolic stone clinics. We wish to report our experience in the running of a metabolic stone disease clinic and to compare our intervention rates to the pre-metabolic stone clinic period in our department. PATIENTS AND METHODS: We reviewed retrospectively our cystinuria patients' database between the years of 1992 and 2008. Patients were divided into two groups. Group A patients (n=28) were treated before the introduction of a dedicated stone clinic (years 1992-2002) and group B patients (n=28) after the establishment of the metabolic stone clinic but every group B patient had a minimum follow up of 5 years. 21 patients were common between the two groups. Main therapy included hyperdiuresis and alkalization. Parameters recorded included the number of clinic visits, whether the patients were stone free or asymptomatic at the time of our review and the nature and frequency of surgical intervention. RESULTS: A total number of 145 procedures were carried out in group A including 89 ESWL, 27 PCNL, 24 ureteroscopy retrograde lithotripsies and 5 open procedures. In group B, a total of 54 procedures were carried out and included 6 ESWL, 5 PCNL and 43 ureteroscopy laser lithotripsies. The average number of surgical interventions per patient per year was 0.74 and 0.34 in group A and B respectively. The number of clinic attendances increased in group B to 279 from 188 in group A. Stone free rates were 46% for group A and 50% for group B patients but all group B patients were asymptomatic at the time of our review. CONCLUSIONS: The introduction of a dedicated cystinuria clinic halved the intervention rate in this complicated group of patients. The majority of surgical procedures shifted towards ureteroscopies (both as inpatients and as day case procedures). We believe that cystine stone patients should be managed in a devoted metabolic stone clinic. With this approach, compliance is better achieved and surgical intervention is less, resulting in better clinical outcome, and less burden both for the patient and the urological services. PMID- 20931158 TI - Laparoscopic deroofing of hepatic cysts: The most effective treatment option. AB - OBJECTIVES: With advances in laparoscopic surgery, laparoscopic deroofing has gained wide acceptance in the surgical community to treat symptomatic non parasitic hepatic cysts. Published non-surgical data still favour aspiration and sclerotherapy as treatment in these cases, though morbidity is higher and recurrence rates are not acceptable. We reviewed all patients that had been treated by laparoscopic deroofing in our department over a period of 6 years in order to find out if the surgical approach should be considered the standard treatment. MATERIALS AND METHODS: Over a 6 year period, 34 laparoscopic deroofings were performed in 21 patients with symptomatic cysts. Patients underwent laparoscopy followed by radical deroofing using an Ultracision device. RESULTS: All cases were completed laparoscopically, no intraoperative adverse events were recorded. Mean operation time was 101 +/- 22.7 min. The mean size of treated cysts was 9.7 +/- 2.18 cm. Follow up showed only one symptomatic recurrence (3.3%) two months after surgery. CONCLUSION: Laparoscopic deroofing of hepatic cysts is a safe and effective treatment option. Recurrence rates are unprecedentedly low. Our data suggest that the risk of operation is justified and that the method is superior to sclerotherapy. PMID- 20931159 TI - An interesting case of Multiple Endocrine Neoplasia Type 2A. AB - We report the case of a 37-year-old Chinese man who came with a history of bilateral adrenalectomy and was admitted for recurrent phaeochromocytoma. Further investigations of an incidental finding of persistently raised carcinoembryonic antigen (CEA), fi rst observed four years ago, revealed medullary thyroid carcinoma (MTC). As such, a provisional diagnosis of Multiple Endocrine Neoplasia 2A (MEN 2A) was made. In this case, it seemed like the long-standing elevation of CEA was ignored until it was noted in a post-clinical discussion among several physicians. The present case illustrates the significance of considering a single abnormal biochemical test in an asymptomatic patient and also discusses the importance of life-long follow-up of a patient with a history of phaeochromocytoma. PMID- 20931160 TI - Unduly extensive mandibular insertion of temporalis muscle: A case report. AB - PURPOSE: Anomalous extensive attachment of temporalis muscle covering the mandibular incisure is rarely reported in literature. Such variations of temporalis muscle are of immense significance in operative procedures of maxillo facial region, utilization of temporalis muscle fl ap and accurate interpretation of radiographs. MATERIALS AND METHODS: Dissection of the head and neck region during the course of undergraduate teaching programme revealed unduly extensive attachment of temporalis muscle fibres in the left side in an adult Indian male cadaver. The temporal and infra-temporal regions were carefully dissected to delineate the temporalis muscle with special emphasis on the branches of maxillary artery and mandibular nerve. The morphological details of the temporalis muscle were recorded and appropriate photographs taken. RESULTS: The mandibular notch was 3.1 cm wide. The extra fleshy fibres of the temporalis muscle completely occupied the mandibular notch and further descended for insertion onto the coronoid process, and external and internal surfaces of the ramus of mandible. The masseteric nerves and vessels pierced the anomalous fibres of temporalis muscle in the mandibular notch. CONCLUSION: The present study highlights the morphological details of an unduly extensive attachment of temporalis muscle and discusses its importance in reconstructive procedures of maxillo-facial region. Detailed information of the variations of temporalis muscle is also important in accurate interpretation of modern imaging procedures. PMID- 20931161 TI - Wound healing in diabetes mellitus: traditional treatment modalities. AB - The healing of wound is a complex process which requires the interactions of different cells and extracellular molecules. The normal wound healing process can be divided into four overlapping phases i.e. haemostasis, inflammation, proliferation and remodeling. In diseased condition like diabetes mellitus, the wound healing process is grossly impaired, resulting in chronic wounds which fail to heal. In the past decades, several researchers have tested various traditional medicines obtained from the plants for their wound healing properties. Such traditional plants are Aloe vera, Calotropis procera, Portulaca oleracea, Acalypha langiana, Plagiochasma appendiculatum and Momordica charantia. Perhaps one of the most popular and easily available plant is Momordica charantia (bitter gourd). The present article presents an extensive review on the impaired wound healing process in diabetes mellitus and highlights the use of traditional medicines in diabetic wounds. PMID- 20931162 TI - Clinical trials with mentally disabled subjects: ethical issues in national and international documents. AB - This article summarises the key ethical considerations involved in performing clinical trials involving persons who cannot conscious, free and informed consensus. Criteria are considered, which are drawn from ethical codes, declarations, treaties, conventions, regulations and other documents and published by national, international, and supranational institutions and authorities. The article focuses on the evolution of attitudes regarding the evolution of participation of incapacitate people in clinical research--from their almost complete exclusion in the mid-twentieth century, partly because of serious historical violations of human rights, to a gradually acceptance that these "vulnerable" people could be involved in trials, provided that certain conditions were met. In particular, the problem of including incapacitated people in clinical trials during emergencies is also addressed. PMID- 20931163 TI - [Pulmonary rehabilitation: pathophysiology, indications, and clinical efficacy]. AB - Pulmonary rehabilitation (PR) is a non pharmacologic treatment of demonstrated efficacy indicated for symptomatic patients with chronic lung diseases. In the pulmonary rehabilitation programs (PRPs), exercise training is a cornerstone component, recommended for improving muscle function. Its aim is to address the disability, intended as the reduction in functional performance and quality of life, derived from muscle deconditioning caused by physical inactivity due to chronic breathlessness, fatigue, and impairment of daily activities claimed by patients with chronic pulmonary diseases. Other components of PRPs are educational, psychosocial and nutritional interventions. Moreover, any PRP should include an outcome assessment, needed for an objective evaluation of program effectiveness, and of patient progress through the time. Although its pivotal role is now accepted worldwide, this was not the prevailing thought during the 1980's and the 1990's, when the pathophysiologic rationale of PR was still not demonstrated, condemning it to be an ancillary treatment to add to standard COPD treatment. The following ascent of PR was mainly due to the number of studies providing its effectiveness, overcoming skepticism and convincing physicians and institutions about its efficacy. Today PR clearly improves exercise tolerance, dyspnea, and quality of life, but despite such demonstration, it is mostly overlooked by health professionals, and only about 2% of patients with COPD undergo to PRPs. A proper consideration of the capability of PR is warranted to ensure optimal management of COPD when the disease causes symptoms and a decrease in physical capacity. PMID- 20931164 TI - Microscopic colitis: a concise review. AB - Microscopic colitis is an increasingly common cause of chronic watery diarrhoea, and often a causes of abdominal pain of unknown origins. The increase of interest for this clinical entity is due to a misdiagnosis of any symptoms that have been frequently attributed to diarrhea-predominant irritable bowel syndrome, often for many years before diagnosis. Presumably, most estimates of incidence and prevalence understate the true frequency of microscopic colitis for this reason. The aim of this paper is to evaluate the importance of microscopic colitis as cause of chronic non bloody diarrhoea, on the basis of literature review. These kind of colitis are characterized by normal colonic mucosa at endoscopy or barium enema but with increased inflammation in colonic biopsies. Microscopic colitis consists of two main subtypes, collagenous colitis and lymphocytic colitis, distinguished by the presence of absence of a thickened subepithelial collagen band. Several models of pathogenesis has been proposed but no convincing mechanism has been identified, although is difficult to characterize this clinical entity as an independent phenomenon or a simple manifestation or related factors active to induce microscopic changing in the colonic mucosa. A rational approach to therapy does not exist and was conduct with several types of drugs after the exclusion of other causes, commonly characterized by this symptoms and the definitive histological assessment in the biopsies specimens. In the majority of cases this condition tends to follow a self-limited course but potentially can assume the characteristics of relapsing course with the necessity to a chronic therapy. Several long-term follow-up studies excluded a possible progression to neoplastic malignancies of microscopic colitis. PMID- 20931165 TI - Efficacy and safety of duloxetine in fibromyalgia. AB - Fibromyalgia is a chronic disorder of uncertain aetiology, more common in women than in man, characterized by widespread pain, muscle tenderness and decreased pain threshold to pressure and other stimuli. The pathophysiology of fibromyalgia is still unknown, but some evidences suggest that abnormalities in central monoaminergic transmission might play an important role. These abnormalities include dysfunction in both serotonin (5-HT) and norepinephrine (NE) systems. In addition, fibromyalgia frequently presents in comorbidity with depression and anxiety disorders. On these basis antidepressants are the most widely studied drugs and, probably the most effective therapy of fibromyalgia. Until now amitriptyline, a tricyclic antidepressant, was considered the most effective, with some evidence of efficacy for other antidepressant such as the SSRI fluoxetine and sertraline. Here we review the efficacy and safety of duloxetine, a SNRI antidepressant, in the management of fibromyalgia. PMID- 20931166 TI - Informed consent. AB - Informed consent (IC) in clinical experimentation is a process by which a subject voluntarily and freely confirms his/her willingness to participate in a trial, after having been informed of all involved aspects. IC is a concept enough recent within medical tradition. Unquestionably, Nuremberg trials (1945-1947) influenced thought about consent in Medicine. When the idea of IC evolved, discussion for appropriate guidelines moved increasingly from a narrow focus on the physician's/researcher's obligation. IC shall be obtained in writing and documented before a subject is enrolled into clinical investigation. , Particularly in the case of medical devices, it is necessary an adequate information to the patient on possible incidents occurring following placing of devices. PMID- 20931167 TI - Observational protocol. AB - An observational study (OS) is a non-interventional/non-experimental survey. In the OSs, the investigator observes and evaluates results of ongoing medical care without 'controlling' the therapy beyond normal medical practice. An OS is aimed: 1. to the evaluation of the safety profile of any medical procedure (drug, device, surgical procedure, radiotherapy, diagnostics, etc.) under the normal conditions of use and on great numbers of patients, 2. for close examinations on the effectiveness in the clinical practice, 3. for the verification of the prescriptive appropriateness and 4. for pharmacoeconomic evaluations. For their characteristics OPs don't involve additional risks for the patients to which the best conditions of clinical assistance are offered. Consequently they do not need further or different ethical procedures/ requirements in comparison to the experimental clinical studies Particularly it is necessary to avoid that an interventional trial could be introduced as an OP. PMID- 20931168 TI - Diversity of Mesozoic semionotiform fishes and the origin of gars (Lepisosteidae). AB - Gars (Lepisosteidae) are ray-finned fishes with controversial relationships to other actinopterygian lineages. When fossil taxa are considered, gars are grouped with Mesozoic macrosemiids and 'semionotids' in the Semionotiformes, but the intra-relationships within this order are still elusive. Here, the evolutionary history of gars is reinvestigated using a set of well-preserved extinct semionotiform taxa in a phylogenetic analysis. Results indicate that the gar lineage roots in a clade of Late Jurassic-Cretaceous semionotiform fishes. The closest relatives to gars were plant-eating and detritivorous freshwater fishes. The occurrence of semionotiform remains in Early and early Late Cretaceous continental deposits worldwide possibly reflects an important radiation of this group, comparable to the present-day diversification of cypriniforms. Other Late Triassic to Early Cretaceous semionotiform taxa are gathered in a single clade with weakly supported internal nodes, pointing out the necessity to better understand the osteology of these fishes. PMID- 20931169 TI - [Somatoform disorders and functional somatic syndromes]. AB - Somatoform symptoms occur in the absence of clear organic pathology. Typically, such symptoms are long-lasting and disabling. Somatoform symptoms and disorders are highly prevalent in primary care. The course of somatoform disorders is mostly chronic, and remission rates are low. Multiple factors influence the development and perpetuation of somatoform disorders. Currently, there is strong debate about the classification of somatoform disorders, and it is very likely that there will be significant changes in the classification of somatoform disorders in the upcoming DSM-V. With regard to the psychotherapeutic treatment of somatoform disorders, there is empirical evidence for the efficacy of cognitive-behavioral as well as psychodynamic-interpersonal strategies. Pharmacotherapy plays a minor role, but it can be useful mainly in cases of comorbid depression or anxiety. PMID- 20931170 TI - Multiplex single nucleotide polymorphism (SNP) assay for detection of soybean mosaic virus resistance genes in soybean. AB - Soybean mosaic virus (SMV) is one of the most destructive viral diseases in soybean (Glycine max). Three independent loci for SMV resistance have been identified in soybean germplasm. The use of genetic resistance is the most effective method of controlling this disease. Marker assisted selection (MAS) has become very important and useful in the effort of selecting genes for SMV resistance. Single nucleotide polymorphism (SNP), because of its abundance and high-throughput potential, is a powerful tool in genome mapping, association studies, diversity analysis, and tagging of important genes in plant genomics. In this study, a 10 SNPs plus one insert/deletion (InDel) multiplex assay was developed for SMV resistance: two SNPs were developed from the candidate gene 3gG2 at Rsv1 locus, two SNPs selected from the clone N11PF linked to Rsv1, one 'BARC' SNP screened from soybean chromosome 13 [linkage group (LG) F] near Rsv1, two 'BARC' SNPs from probe A519 linked to Rsv3, one 'BARC' SNP from chromosome 14 (LG B2) near Rsv3, and two 'BARC' SNPs from chromosome 2 (LG D1b) near Rsv4, plus one InDel marker from expressed sequence tag (EST) AW307114 linked to Rsv4. This 11 SNP/InDel multiplex assay showed polymorphism among 47 diverse soybean germplasm, indicating this assay can be used to investigate the mode of inheritance in a SMV resistant soybean line carrying Rsv1, Rsv3, and/or Rsv4 through a segregating population with phenotypic data, and to select a specific gene or pyramid two or three genes for SMV resistance through MAS in soybean breeding program. The presence of two SMV resistance genes (Rsv1 and Rsv3) in J05 soybean was confirmed by the SNP assay. PMID- 20931171 TI - Coordination in phenanthrene biodegradation: pyruvate as microbial demarcation. AB - The principle involved in the phenanthrene degradation is regarded as the key to unlock the mechanisms governing the pathway of other polycyclic aromatic hydrocarbons. Past studies have made some pathway proposals via metabolite analysis. In this study, two dominating species (phn01 and phn02) were isolated from oil contaminated soil and were used in lab-scale experiment of phenanthrene degradation. The GC/MS results revealed the metabolites of pyruvate, phthalate, 1 hydroxy-2-naphthaldehyde and 9-phenanthrol at retention time of 12.01, 15.34, 16.82 and 18.16 min, respectively. A new proposal of pathway was derived. Selective degradation indicated the relationship of coordination between these two species, one of which was mainly responsible for pyruvate production and the other for pyruvate consumption. Pyruvate played a role of microbial demarcation which might be closely associated with invoking signal for microbial community during biodegradation. PMID- 20931172 TI - Sudden cadmium increases in the digestive gland of scallop, Nodipecten nodosus L., farmed in the tropics. AB - Cadmium bioaccumulation in Nodipecten nodosus reared on a marine farm in a tropical bay was measured in muscle tissue and the digestive glands in animals ranging from 6 to 16 months. No bioaccumulation tendencies regarding Cd concentration were observed in muscle tissue (below 1 MUg g-1), while in the digestive gland concentrations remained below 5 MUg g-1 until the organisms reached 10 months, and reached levels above 10 MUg g-1 from 12 months onwards (reaching 27 MUg g-1). This is the same bioaccumulation pattern noted in animals transplanted to a different Cd exposure. Allometry and environmental factors cannot explain this sudden increase. PMID- 20931173 TI - Transobturator adjustable tape for severe stress urinary incontinence and stress urinary incontinence with voiding dysfunction. AB - INTRODUCTION AND HYPOTHESIS: This prospective multicenter study was conducted to evaluate the efficacy and safety of an adjustable mid-urethral sling (MUS) using transobturator adjustable tape (TOA) in women with severe stress urinary incontinence or combined stress urinary incontinence (SUI) and voiding dysfunction (VD). METHODS: One day after placement of TOA, the tension was adjusted. Six months after surgery, changes in several questionnaires and uroflowmetry (UFM) parameters were evaluated. RESULTS: Among the 65 women enrolled in the study, 27 (41.5%) required postoperative tension readjustments. At 6 months, the complete cure rate of SUI was 84.4%, and patient satisfaction with the operation was 86.2%. There was improvement in the total scores on several questionnaires. There were no significant changes in postoperative UFM parameters. CONCLUSION: Our results support the use of TOA as an effective modality for the treatment of SUI in women at risk for persistent postoperative SUI or obstructive symptoms. PMID- 20931174 TI - Characterization of toxins from the broad-banded water snake Helicops angulatus (Linnaeus, 1758): isolation of a cysteine-rich secretory protein, Helicopsin. AB - Helicops angulatus (broad-banded water snake) according to recent proposals is presently cited in the family Dipsadidae, subfamily Xenodontinae, forming the tribe Hydropsini along with the genera Hydrops and Pseudoeryx. The current work characterizes the proteolytic and neurotoxic activities of H. angulatus crude toxins from salivary excretion (SE) and describes the isolation and identification of a cysteine-rich secretory protein (CRISP) called helicopsin. The SE lethal dose (LD50) was 5.3 mg/kg; however, the SE did not contain hemorrhagic activity. Helicopsin was purified using activity-guided, Superose 12 10/300 GL molecular exclusion, Mono Q10 ion exchange, and Protein Pak 60 molecular exclusion. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) showed a highly purified band of approximately 20 kDa. The minimal lethal dose for helicopsin was 0.4 mg/kg. Liquid chromatography mass spectrometry (LC-MS/MS) analysis identified 2 unique peptides MEWYPEAAANAER and YTQIVWYK, representing a protein sequence (deleted homology) belonging to cysteine-rich secretory proteins, which are conserved in snake venoms (CRISPs). CRISPs are a large family of cysteine-rich secretory proteins found in various organisms and participate in diverse biological processes. Helicopsin exhibited robust neurotoxic activity as evidenced by immediate death (~8 min) due to respiratory paralysis in NIH mice. These observations for helicopsin purified from H. angulatus provide further evidence of the extensive distribution of highly potent neurotoxins in the Colubroidea superfamily of snakes than previously described. PMID- 20931175 TI - New developments in quantitative polymerase chain reaction applied to control the quality of heparins. AB - Heparin is a widely used intravenous anticoagulant comprised of a very complex mixture of glucosaminoglycan chains, mainly derived from porcine intestinal mucosa. Recent contamination of heparin with oversulfated (OS) chondroitin sulfate resulted in a significant number of deaths, triggering a rapid revision of product monographs and the introduction of new analytical methods to limit as far as possible the chances of another occurrence of such a phenomenon. The distribution of heparin-processing units across the globe prevents their complete fool-proof auditing. Therefore, the implementation of additional orthogonal analytical techniques for quality control (QC) of heparin batches is highly important. We perform routine quantitative polymerase chain reaction (Q-PCR) release tests to confirm the quality of all crude heparin batches received by sanofi-aventis. The routine test used provides information on the animal species of origin as requested by the US Pharmacopoeia (USP) and European Pharmacopoiea monographs. Here, we demonstrate that the Q-PCR test is inhibited by OS glycosaminoglycans at concentrations as low as 0.5% (w/w versus heparin) and can be used as an additional safeguard to monitor levels of potentially harmful contaminants without any increased workload. In response to a request from the USP, we also describe the development of a Q-PCR method for monitoring nucleotidic impurities in pure heparin, which is able to detect amplifiable DNA at concentrations lower than 0.1 ng DNA per milligram of heparin. This increased sensitivity makes this modified Q-PCR method a potential candidate for inclusion as a QC requirement in future monographs. PMID- 20931176 TI - Unilateral NMR, 13C CPMAS NMR spectroscopy and micro-analytical techniques for studying the materials and state of conservation of an ancient Egyptian wooden sarcophagus. AB - A multi-technique approach was employed to study a decorated Egyptian wooden sarcophagus (XXV-XXVI dynasty, Third Intermediate Period), belonging to the Museo del Vicino Oriente of the Sapienza University of Rome. Portable non-invasive unilateral NMR was applied to evaluate the conservation state of the sarcophagus. Moreover, using unilateral NMR, a non-invasive analytical protocol was established to detect the presence of organic substances on the surface and/or embedded in the wooden matrix. This protocol allowed for an educated sampling campaign aimed at further investigating the state of degradation of the wood and the presence of organic substances by (13)C cross polarization magic angle spinning (CPMAS) NMR spectroscopy. The composition of the painted layer was analysed by optical microscopy (OM), scanning electron microscopy-energy dispersive spectroscopy (SEM-EDS), Raman and surface enhanced (resonance) Raman spectroscopy (SERS/SERRS), infrared and GC-MS techniques, evidencing original components such as clay minerals, Egyptian green, indigo, natural gums, and also highlighting restoration pigments and alteration compounds. The identification of the wood, of great value for the reconstruction of the history of the artwork, was achieved by means of optical microscopy. PMID- 20931177 TI - Where does an object trigger an action? An investigation about affordances in space. AB - A series of experiments provide evidence that affordances rely not only on the mutual appropriateness of the features of an object and the abilities of an individual, but also on the fact that those features fall within her own reachable space, thus being really ready-to-her-own-hand. We used a spatial alignment effect paradigm and systematically examined this effect when the visually presented object was located either within or outside the peripersonal space of the participants, both from a metric (Experiment 1) and from a functional point of view (Experiment 2). We found that objectual features evoke actions only when the object is presented within the portion of the peripersonal space that is effectively reachable by the participants. Experiments 3 and 4 ruled out that our results could be merely accounted for by differences in the visual salience of the presented objects. Our data suggest that the power of an object to automatically trigger an action is strictly linked to the effective possibility that an individual has to interact with it. PMID- 20931178 TI - Extending Fitts' Law to three-dimensional obstacle-avoidance movements: support for the posture-based motion planning model. AB - According to Fitts' Law, the time (MT) to move to a target is a linear function of the logarithm of the ratio between the target's distance and width. Although Fitts' Law accurately predicts MTs for direct movements, it does not accurately predict MTs for indirect movements, as when an obstacle intrudes on the direct movement path. To address this limitation, Jax et al. (2007) added an obstacle intrusion term to Fitts' Law. They accurately predicted MTs around obstacles in two-dimensional (2-D) workspaces, but their model had one more parameter than Fitts' Law did and was merely descriptive. In this study, we addressed these concerns by turning to the mechanistic, posture-based (PB) movement planning model. The PB-based model accounted for almost as much MT variance in a 3-D movement task as the model of Jax et al., with only two parameters, the same number of parameters as in Fitts' Law. PMID- 20931179 TI - Structure-activity relationships on the odor detectability of homologous carboxylic acids by humans. AB - We measured concentration detection functions for the odor detectability of the homologs: formic, acetic, butyric, hexanoic, and octanoic acids. Subjects (14 <= n <= 18) comprised young (19-37 years), healthy, nonsmoker, and normosmic participants from both genders. Vapors were delivered by air dilution olfactometry, using a three-alternative forced-choice procedure against carbon filtered air, and an ascending concentration approach. Delivered concentrations were established by gas chromatography (flame ionization detector) in parallel with testing. Group and individual olfactory functions were modeled by a sigmoid (logistic) equation from which two parameters are calculated: C, the odor detection threshold (ODT) and D, the steepness of the function. Thresholds declined with carbon chain length along formic, acetic, and butyric acid where they reached a minimum (ODTs = 514, 5.2, and 0.26 ppb by volume, respectively). Then, they increased for hexanoic (1.0 ppb) and octanoic (0.86 ppb) acid. Odor thresholds and interindividual differences in olfactory acuity among these young, normosmic participants were lower than traditionally thought and reported. No significant effects of gender on odor detectability were observed. The finding of an optimum molecular size for odor potency along homologs confirms a prediction made by a model of ODTs based on a solvation equation. We discuss the mechanistic implications of this model for the process of olfactory detection. PMID- 20931180 TI - Effects of instructed focus and task difficulty on concurrent walking and cognitive task performance in healthy young adults. AB - Dual task paradigms can be used to examine the interactions between cognition and the control of posture and gait. Measuring and interpreting changes in dual task performance is challenging, however, because many factors can influence performance. This study examined the effects of instructed focus and walking task difficulty, and the interaction between these factors, on dual task performance in healthy young adults. Fifteen participants performed a cognitive task while walking with either a usual base or a narrow base of support. Participants were instructed to focus on either the cognitive task or walking. Trade-offs both within and between tasks were assessed using the modified attention allocation index and the performance operating characteristic. Instructed focus influenced both the cognitive task and walking. Performance on the cognitive task was faster with instructions to focus on the cognitive task, and walking was faster (and more accurate in the narrow-base condition) with instructions to focus on walking. Walking task difficulty did not affect cognitive performance but did affect walking, with faster walking in the usual-base versus narrow-base condition. There was evidence of an interaction, with greater effects of instructed focus on the cognitive task during usual versus narrow-base walking. These results support the idea that the ability to flexibly shift attention allocation and task performance in response to instructions depends on the difficulty of the postural control task. The modified attention allocation index and the performance operating characteristic were instrumental in fully characterizing trade-offs between and within tasks in order to understand dual task performance changes. A clearer understanding of the factors that affect dual task walking and the interactions between these factors has important implications for the assessment of dual task performance in both clinical and research settings. PMID- 20931181 TI - Phase dependence of transport-aperture coordination variability reveals control strategy of reach-to-grasp movements. AB - Based on an assumption of movement control optimality in reach-to-grasp movements, we have recently developed a mathematical model of transport-aperture coordination (TAC), according to which the hand-target distance is a function of hand velocity and acceleration, aperture magnitude, and aperture velocity and acceleration (Rand et al. in Exp Brain Res 188:263-274, 2008). Reach-to-grasp movements were performed by young adults under four different reaching speeds and two different transport distances. The residual error magnitude of fitting the above model to data across different trials and subjects was minimal for the aperture-closure phase, but relatively much greater for the aperture-opening phase, indicating considerable difference in TAC variability between those phases. This study's goal is to identify the main reasons for that difference and obtain insights into the control strategy of reach-to-grasp movements. TAC variability within the aperture-opening phase of a single trial was found minimal, indicating that TAC variability between trials was not due to execution noise, but rather a result of inter-trial and inter-subject variability of motor plan. At the same time, the dependence of the extent of trial-to-trial variability of TAC in that phase on the speed of hand transport was sharply inconsistent with the concept of speed-accuracy trade-off: the lower the speed, the larger the variability. Conversely, the dependence of the extent of TAC variability in the aperture-closure phase on hand transport speed was consistent with that concept. Taking into account recent evidence that the cost of neural information processing is substantial for movement planning, the dependence of TAC variability in the aperture-opening phase on task performance conditions suggests that it is not the movement time that the CNS saves in that phase, but the cost of neuro-computational resources and metabolic energy required for TAC regulation in that phase. Thus, the CNS performs a trade-off between that cost and TAC regulation accuracy. It is further discussed that such trade-off is possible because, due to a special control law that governs optimal switching from aperture opening to aperture closure, the inter-trial variability of the end of aperture opening does not affect the high accuracy of TAC regulation in the subsequent aperture-closure phase. PMID- 20931182 TI - Biophysical properties of human medulloblastoma cells. AB - Medulloblastoma is a pediatric high-grade cerebellar malignancy derived from neuronal precursors. Although electrophysiologic characteristics of cerebellar granule neurons at all stages of cell development have been well described, such characterization has not been reported for medulloblastoma. In this study we attempt to characterize important electrophysiologic features of medulloblastoma that may distinguish it from the surrounding cerebellum. Using patient-derived cell lines and tumor tissues, we show that medulloblastoma cells have no inward Na+ current or transient K+ current involved in action potential generation and propagation, typically seen in granule neurons. Expression and function of calcium-activated, large-conductance K+ channels are diminished in medulloblastoma, judged by electrophysiology and Western analysis. The resting membrane potential of medulloblastoma cells in culture is quite depolarized compared to granule neurons. Interestingly, medulloblastoma cells express small, fast-inactivating calcium currents consistent with T-type calcium channels, but these channels are activated only from hyperpolarized potentials, which are unlikely to occur. Additionally, a background acid-sensitive K+ current is present with features characteristic of TASK1 or TASK3 channels, such as inhibition by ruthenium red. Western analysis confirms expression of TASK1 and TASK3. In describing the electrophysiologic characteristics of medulloblastoma, one can see features that resemble other high-grade malignancies as opposed to normal cerebellar granule neurons. This supports the notion that the malignant phenotype of medulloblastoma is characterized by unique changes in ion channel expression. PMID- 20931183 TI - Primary angioplasty for a subtype of symptomatic middle cerebral artery stenosis. AB - INTRODUCTION: The purpose of this study was to assess the long-term efficacy of middle cerebral artery revascularisation by primary balloon angioplasty for the prevention of stroke in a certain subtype of patients. METHOD: A retrospective study was performed to evaluate 33 patients with symptomatic middle cerebral artery stenoses who underwent primary balloon angioplasty; the selection criteria were: greater than 70% stenosis measured by digital subtraction angiography, lesions equal to or shorter than 5 mm, lesions near or across a bifurcation, and lesions with very tortuous proximal vessels that increase the risk of stenting. All patients were available for follow-up ranging from 6 to 60 months. The technical success rate, periprocedural complications, and long-term outcome were retrospectively reviewed. RESULT: The mean stenosis degree was reduced from 87.12 +/- 7.40 to 23.03 +/- 9.84 after angioplasty. The periprocedural complication rate was 18.18% (six dissections without an ischemic event). Two patients had strokes in the territory of the angioplasty at 6 and 32 months after angioplasty, and the stroke-free survival at 5 years was 90.04% (mean survival time, 56.42 +/- 2.43 months; 95% CI, 51.66-61.19 months). CONCLUSION: These results suggest that this treatment is safe and could provide a durable clinical result at long-term follow-up in this subtype of patients, but the high rate of dissection remains a major technical drawback. PMID- 20931184 TI - Comparative genomics of marine mussels (Mytilus spp.) gender associated mtDNA: rapidly evolving atp8. AB - The unusual mode of mitochondrial DNA inheritance, with two separate: maternal (F) and paternal (M) lineages, gives unique opportunities to study the evolution of the mitochondrial genome. This system was first discovered in the marine mussels Mytilus. The three related species: Mytilus edulis, Mytilus galloprovincialis and Mytilus trossulus form a complex in which the divergence of M and F lineages pre-dates the speciation. The complete mitochondrial genomes of both lineages were known for all species except Pacific M. trossulus. Here we report, for the first time, the complete sequences of both mitochondrial genomes of Pacific M. trossulus, filling the gap. While the reported M and F genomes are highly diverged (26%), they have similar organisation. The only difference is the translocation of one tRNA gene into the long, mosaic control region of the F genome. Consistent presence of an ORF which most likely represents the atp8 gene was confirmed in both genomes. The predicted protein has characteristics expected of the functional atp8 even though the M and F versions are markedly different in length. Comparative analysis involving all three species led to the conclusion that the cause of a faster evolution of atp8 and Mytilus mtDNA in general is most likely the Compensation-Draft Feedback process coupled with relatively relaxed selection in the M lineage. Thus, we postulate that the adaptive changes may have played a role in the emergence of highly diverged, barely recognizable atp8 in Mytilus mussels. PMID- 20931186 TI - The impact of acetate metabolism on yeast fermentative performance and wine quality: reduction of volatile acidity of grape musts and wines. AB - Acetic acid is the main component of the volatile acidity of grape musts and wines. It can be formed as a by-product of alcoholic fermentation or as a product of the metabolism of acetic and lactic acid bacteria, which can metabolize residual sugars to increase volatile acidity. Acetic acid has a negative impact on yeast fermentative performance and affects the quality of certain types of wine when present above a given concentration. In this mini-review, we present an overview of fermentation conditions and grape-must composition favoring acetic acid formation, as well the metabolic pathways leading to its formation and degradation by yeast. The negative effect of acetic acid on the fermentative performance of Saccharomyces cerevisiae will also be covered, including its role as a physiological inducer of apoptosis. Finally, currently available wine deacidification processes and new proposed solutions based on zymological deacidification by select S. cerevisiae strains will be discussed. PMID- 20931187 TI - Microbial fuel cells for energy self-sufficient domestic wastewater treatment-a review and discussion from energetic consideration. AB - As the microbial fuel cell (MFC) technology is getting nearer to practical applications such as wastewater treatment, it is crucial to consider the different aspects that will make this technology viable in the future. In this paper, we provide information about the specifications of an energy self sufficient MFC system as a basis to extrapolate on the potential benefits and limits of a future MFC-based wastewater treatment plant. We particularly emphasize on the importance of two crucial parameters that characterize an MFC: its electromotive force (E (emf)) and its internal resistance (R (int)). A numerical projection using state-of-art values (E (emf) = 0.8 V and R (int) = 5 Omega) emphasized on the difficulty at this moment to reach self-sufficiency using a reasonable number of MFCs at the laboratory scale. We found that a realistic number of MFCs to provide enough voltage (=5 V) at a sufficient current (=0.8 A) to power a pump requiring 4 W would be of 13 MFCs in series and 10 stacks of MFCs in parallel, resulting in a total number of 130 MFCs. That would result in a treatment capacity of 144 L of domestic wastewater (0.5 g-COD L(-1)) per day. The total MFC system would be characterized by an internal resistance of 6.5 Omega. PMID- 20931188 TI - US imaging of the musculocutaneous nerve. AB - PURPOSE: To describe the potential value of high-resolution sonography for evaluation of the musculocutaneous nerve (MCN). MATERIALS AND METHODS: The normal anatomy of the MCN was evaluated on three cadaveric limbs and correlated with the US images obtained in 15 healthy subjects. Seven consecutive patients with MCN neuropathy were then evaluated with sonography using 17.5 and 12.5-MHz broadband linear array transducers. All patients had abnormal nerve conduction studies and underwent correlative MR imaging on a 1.5-T system. RESULTS: One-to-one comparison between cadaveric specimens and sonographic images showed that the MCN can be reliably identified from the axilla through the elbow, including the lateral antebrachial cutaneous (LAbC) nerve. In the patients group with MCN neuropathy, sonography allowed detection of a wide spectrum of abnormalities. In 5/7 cases, a spindle neuroma was depicted in continuity with the nerve. In one case, US identified focal swelling of the nerve and in another case US was negative. The neuroma was hyperintense on T2-weighted sequences in 75% of cases. In one patient, the nerve showed Gd-enhancement on fat-suppressed T1-weighted sequences. The nerve was never detected on unenhanced T1-scans. Owing to its small-size and out-of-plane course, the MCN may be more reliably depicted with sonography rather than with MR imaging. CONCLUSIONS: US is promising for evaluating traumatic injuries of the MCN. By providing unique information on the entire course of the nerve, US can be used as a valuable complement of clinical and electrophysiologic findings. PMID- 20931185 TI - Laser capture microdissection and metagenomic analysis of intact mucosa associated microbial communities of human colon. AB - Metagenomic analysis of colonic mucosa-associated microbes has been complicated by technical challenges that disrupt or alter community structure and function. In the present study, we determined the feasibility of laser capture microdissection (LCM) of intact regional human colonic mucosa-associated microbes followed by phi29 multiple displacement amplification (MDA) and massively parallel sequencing for metagenomic analysis. Samples were obtained from the healthy human subject without bowel preparation and frozen sections immediately prepared. Regional mucosa-associated microbes were successfully dissected using LCM with minimal contamination by host cells, their DNA extracted and subjected to phi29 MDA with a high fidelity, prior to shotgun sequencing using the GS-FLX DNA sequencer. Metagenomic analysis of approximately 67 million base pairs of DNA sequences from two samples revealed that the metabolic functional profiles in mucosa-associated microbes were as diverse as those reported in feces, specifically the representation of functional genes associated with carbohydrate, protein, and nucleic acid utilization. In summary, these studies demonstrate the feasibility of the approach to study the structure and metagenomic profiles of human intestinal mucosa-associated microbial communities at small spatial scales. PMID- 20931189 TI - CT-guided corticosteroid injection for solitary eosinophilic granuloma of the spine. AB - OBJECTIVE: To evaluate the clinical and imaging outcome of patients with symptomatic eosinophilic granuloma of the spine treated with CT-guided intralesional methylprednisolone injection after biopsy. MATERIALS AND METHODS: Patients (n =19) with symptomatic solitary eosinophilic granuloma of the spine treated by CT-guided intralesional methylprednisolone injection were retrospectively studied. There were 12 males and seven females with a mean age of 17 years (range, 3-43 years). The mean follow-up was 6 years (median, 4 years; range, 0.5-19 years). Spinal location included the cervical (two patients), thoracic (seven patients), lumbar spine (eight patients), and the sacrum (two patients). Vertebra plana was observed in two patients. All patients had biopsies before treatment. RESULTS: Complete resolution of pain and healing of the lesion was observed in 17 patients (89.5%); none of these patients had recurrence at the latest examination. Reconstitution of the T1 and L1 vertebra plana was observed in both patients. Two patients initially diagnosed and treated for a solitary eosinophilic granuloma had constant pain after the procedure; in these patients, 6 and 12 months after the procedure, respectively, imaging showed multifocal disease and systemic therapy was administered. Complications related to the procedure were not observed. General anesthesia was administered in two patients because of intolerable pain during the procedure. CONCLUSIONS: In view of the benign clinical course of eosinophilic granuloma, in patients with symptomatic lesions, CT-guided intralesional corticosteroid injection is a safe and effective outpatient treatment with a low complication rate. PMID- 20931190 TI - Three tesla magnetic resonance imaging of the anterior cruciate ligament of the knee: can we differentiate complete from partial tears? AB - PURPOSE: To determine the ability of 3.0T magnetic resonance (MR) imaging to identify partial tears of the anterior cruciate ligament (ACL) and to allow distinction of complete from partial ACL tears. MATERIALS AND METHODS: One hundred seventy-two patients were prospectively studied by 3.0T MR imaging and arthroscopy in our institution. MR images were interpreted in consensus by two experienced reviewers, and the ACL was diagnosed as being normal, partially torn, or completely torn. Diagnostic accuracy of 3.0T MR for the detection of both complete and partial tears of the ACL was calculated using arthroscopy as the standard of reference. RESULTS: There were 132 patients with an intact ACL, 17 had a partial, and 23 had a complete tear of the ACL seen at arthroscopy. Sensitivity, specificity, and accuracy of 3.0T MR for complete ACL tears were 83, 99, and 97%, respectively, and, for partial ACL tears, 77, 97, and 95%, respectively. Five of 40 ACL lesions (13%) could not correctly be identified as complete or partial ACL tears. CONCLUSION: MR imaging at 3.0T represents a highly accurate method for identifying tears of the ACL. However, differentiation between complete and partial ACL tears and identification of partial tears of this ligament remains difficult, even at 3.0T. PMID- 20931191 TI - Percutaneous selective myoablation in plastic surgery. AB - A new technique in aesthetic plastic surgery termed "myoablation" is described. Thermal energy is applied via the percutaneous route for ablation of selected facial muscles to modify the facial dynamics. Myoablation was found to be useful in ameliorating noticeable frown wrinkles caused by muscular hyperactivity. A series of 30 patients underwent myoablation as the sole procedure with encouraging results. In 80% of the cases, good to excellent aesthetic results were achieved. This report presents the electrophysiologic bases, technique, animal experiments, and initial clinical experience of myoablation. PMID- 20931192 TI - Reduction mammaplasty using the free-nipple-graft vertical technique for severe breast hypertrophy: improved outcomes with the superior dermaglandular flap. AB - BACKGROUND: Management of severe mammary hypertrophy is a challenge. The limitations of most dermal pedicle techniques include insufficient breast projection with severe hypertrophy. The authors have designed a free-nipple-graft vertical technique with a superior demaglandular flap to provide acceptable breast projection and an attractive, smooth breast contour for patients with severe hypertrophy and gigantomastia who are not suitable for pedicle breast reduction techniques. METHODS: Reduction was performed for 24 patients with severe mammary hypertrophy between 2003 and 2009. This study evaluated patient age, cup size, mean distances from sternal notch to nipple and from nipple to inframammary fold, amount of resection, complications, and postoperative breast shape. RESULTS: All 24 patients were followed regularly to 1 year postoperatively. The inclusion criteria for the reported technique specified gigantomastia larger than 1,000 g per side, grade 4 breast ptosis, and increased sternal notch-to-nipple distance. The mean distance from the sternal notch to the nipple was 48.5 cm, and the mean distance from the nipple to the inframammary fold was 19.5 cm. The new nipple was positioned at a mean of 23.5 cm. The tissue excised per breast was 1,670 g. All the patients had long-lasting, pronounced nipple and adequate breast mound projection with attractive, smooth breast contours. CONCLUSION: A free-nipple graft with a superior dermaglandular flap yields a conical breast with adequate projection and fullness. Parenchyma sutures to the pectoral fascia provide long lasting results. Plastic surgeons experienced in superior pedicle breast reduction can adopt this technique easily. PMID- 20931193 TI - The high-superior-tension technique: evolution of lipoabdominoplasty. AB - Because abdominoplasty is associated with complications such as seroma and necrosis as well as epigastric bulging and a suprapubic scar located too high, the demand for this procedure is not as high as it otherwise might be. However, although these negative effects were common many years ago, their incidence has decreased dramatically with modern abdominoplastic techniques. One approach using a combination of abdominoplasty and liposuction or lipoabdominoplasty has resolved many of the problems faced with earlier techniques, offering aesthetically pleasing results and excellent reliability. The keys to successful lipoabdominoplasty, first developed as the high-superior-tension technique, are extensive liposuction, preservation of lymphatic trunks, preaponeurotic epigastric dissection, major muscle fascia plication, two high-tension paraumbilical sutures, hypogastric tension sutures, and closure of the dead spaces. The most recent updates to this technique are described in this article. PMID- 20931194 TI - The usefulness of a threat and disturbance categorization developed for Queensland wetlands to environmental management, monitoring, and evaluation. AB - There is no comprehensive system of describing threats and disturbances currently used in Australia, despite the widespread impacts of human activities on natural ecosystems. Yet a detailed categorization would facilitate the collation of threatening process information into information systems; enable standardized collection and availability of data; and enable comparative analyses of ecosystem condition between stakeholders, agencies, states, and nations, particularly for environmental reporting and evaluation mechanisms such as State of the Environment. As part of the Queensland Wetlands Programme (QWP), a threat and disturbance framework was developed, focused on the pressure and impacts components of the DPSIR (driver-pressure-state-impacts-response) framework. A wetland inventory database was developed also that included a detailed threat and disturbance categorization using the QWP framework. The categorization encompasses a broad range of anthropogenic and natural processes, and is hierarchical to accommodate varying levels of detail or knowledge. By incorporating detailed qualitative and quantitative information, a comprehensive threats and disturbances categorization can contribute to conceptual or spatially explicit knowledge and management assessments. The application of the framework and categorization to several threatening processes is demonstrated, and its relationship to current natural resource condition indicators is discussed. Threat evaluation is an essential component of ecological assessment and environmental management, and a standardized categorization enables consistency in attributing processes, impacts and their short- to long-term consequences. Such a systematic framework and categorization demonstrates the importance and usefulness of comprehensive approaches, and this approach can be readily adapted to management, monitoring and evaluation of other target ecosystems and biota. PMID- 20931195 TI - Comparison of early and late complications after various bariatric procedures: incidence and treatment during 15 years at a single institution. AB - BACKGROUND: Bariatric procedures are effective in the life-long treatment of clinically severe obesity, but they are technically demanding and have known complications. The present study presents mortality and morbidity with different procedures from the prospective 15-year bariatric database of the University Hospital of Patras in Greece. METHODS: From June 1994 through December 2008, 1,162 morbidly obese patients underwent various bariatric procedures at our institution (35 vertical banded gastroplasties, 151 laparoscopic sleeve gastrectomies, 90 open and 137 laparoscopic Roux-en-Y gastric bypasses, 699 biliopancreatic diversions with long limbs, and 50 reoperations). Postoperative metabolic deficiencies and causes of early and late morbidity for various bariatric procedures were compared by using the z-test for the comparison of proportions. Logistic regression analysis was used to model the occurrence of early and late death and complications. RESULTS: Total mortality was 1.81% (early 0.6%, intermediate 0.26%, late 0.95%). No significant predictors for early death were found, but age (odds ratio (OR), 1.077; 95% confidence interval (CI), 1.024 1.133; P = 0.004) and BMI (OR, 1.156; 95% CI, 1.023-1.306; P = 0.02) were predictors for late death. Early and late morbidity were 8% and 27.71%, respectively. The total leakage incidence was 1.98% and was significantly higher (P < 0.05) after reoperation. Fifteen of the 23 leaks were successfully treated conservatively. Most late complications were incisional hernias (18.85%)--almost all after open procedures. Hypoalbuminemia incidence was significantly higher after biliopancreatic diversion with long limbs (3.58%) and reoperation (8%). CONCLUSIONS: Bariatric procedures, even in specialized centers, may have serious complications because of their technical complexity in a high-risk population. Almost all can be managed successfully. PMID- 20931196 TI - Closure of the cystic duct during laparoscopic cholecystectomy in children using the LigaSure Vessel Sealing System. AB - BACKGROUND: The goal of the present study was to evaluate the efficacy of the LigaSure(TM) Vessel Sealing System (LVSS) when used for cystic duct closure during laparoscopic cholecystectomy in children and adolescents. METHODS: The laparoscopic cholecystectomy was performed beginning with visualization of Calot's triangle, and dissection of Calot's triangle was achieved using a monopolar cautery device. Once the cystic duct was exposed, sealing was performed proximally and distally, and the cystic duct was divided midway using the LVSS. The procedure was completed in the standard fashion. RESULTS: The closure of the cystic duct was performed in seven cases of simultaneous cholecystectomy and splenectomy and in 15 cases of microlaparoscopic cholecystectomy. The patients' ages ranged from 7 to 21 years (average = 14.5 years), and body weight ranged from 42 to 83 kg (average = 58 kg). There was no bile leakage noted, and the closure of the cystic duct was sufficient in all cases. We noted one case of common bile duct obstruction on postoperative day 1. In this case, an exploration of the biliary tree was performed by laparotomy. No direct injury to the common bile duct was found during exploration, but thermal changes were detected in the surrounding tissues as a result of transmitted thermal energy caused by bipolar cautery device. CONCLUSION: The closure of the cystic duct using the LVSS is feasible and effective in laparoscopic cholecystectomy in children. However, it is important to keep a safe distance from other intra-abdominal structures when using thermal energy devices to prevent thermal collateral damage. PMID- 20931197 TI - Wound infection after excision and primary midline closure for pilonidal disease: risk factor analysis to improve patient selection. AB - BACKGROUND: Excision and primary midline closure for pilonidal disease (PD) is a simple procedure; however, it is frequently complicated by infection and prolonged healing. The aim of this study was to analyze risk factors for surgical site infection (SSI) in this context. METHODS: All consecutive patients undergoing excision and primary closure for PD from January 2002 through October 2008 were retrospectively assessed. The end points were SSI, as defined by the Center for Disease Control, and time to healing. Univariable and multivariable risk factor analyses were performed. RESULTS: One hundred thirty-one patients were included [97 men (74%), median age = 24 (range 15-66) years]. SSI occurred in 41 (31%) patients. Median time to healing was 20 days (range 12-76) in patients without SSI and 62 days (range 20-176) in patients with SSI (P < 0.0001). In univariable and multivariable analyses, smoking [OR = 2.6 (95% CI 1.02, 6.8), P = 0.046] and lack of antibiotic prophylaxis [OR = 5.6 (95% CI 2.5, 14.3), P = 0.001] were significant predictors for SSI. Adjusted for SSI, age over 25 was a significant predictor of prolonged healing. CONCLUSION: This study suggests that the rate of SSI after excision and primary closure of PD is higher in smokers and could be reduced by antibiotic prophylaxis. SSI significantly prolongs healing time, particularly in patients over 25 years. PMID- 20931198 TI - A novel approach for sentinel lymph node identification using fluorescence imaging and image overlay navigation surgery in patients with breast cancer. AB - BACKGROUND: We reported a novel technique of sentinel lymph node (SLN) identification using fluorescence imaging of indocyanine green injection. Furthermore, to obtain safe and accurate identification of SLN during surgery, we introduce the image overlay navigation surgery and evaluate its efficacy. METHODS: This study enrolled 50 patients with a tumors <2 cm in diameter. Initially, we obtained three-dimensional (3-D) imaging from multidetector-row computed tomography (MD-CT) by volume rendering. It was projected on the patient's operative field with the clear visualization of lymph node (LN) through projector. Then, the dye of indocyanine green (ICG) was injected subdermally in the areola. Subcutaneous lymphatic channels draining from the areola to the axilla were visible by fluorescence imaging immediately. Lymphatic flow was reached after LN revealed on 3-D imaging. After incising the axillary skin on the point of LN mapping, SLN was then dissected under the guidance of fluorescence imaging with adequate adjustment of sensitivity and 3-D imaging. RESULTS: Lymphatic channels and SLN were successfully identified by Photodynamic eye (PDE) in all patients. And the sites of skin incision also were identical with the LN being demonstrated by 3-D imaging in all patients. The mean number of SLN was 3.7. The image overlay navigation surgery was visually easy to identify the location of SLN from the axillary skin. There were no intra- or postoperative complications associated with SLN identification. CONCLUSIONS: This combined navigations of fluorescence and 3-D imaging revealed more easy and effective to detect SLN intraoperatively than fluorescence imaging alone. PMID- 20931199 TI - Risk adjustment as basis for rational benchmarking: the example of colon carcinoma. AB - BACKGROUND: The results of resection of colorectal carcinoma can vary greatly from one hospital to another. However, this does not necessarily reflect differences in the quality of treatment. The purpose of this study was to compare various tools for the risk-adjusted assessment of treatment results after resection of colorectal carcinoma within the context of hospital benchmarking. METHODS: On the basis of a data pool provided by a multicentric observation study of patients with colon cancer, the postoperative in-hospital mortality rates at two high-volume hospitals ("A" and "B") were compared. After univariate comparison, risk-adjusted comparison of postoperative mortality was performed by logistic regression analysis (LReA), propensity-score analysis (PScA), and the CR POSSUM score. Postoperative complications were compared by LReA and PScA. RESULTS: Although postoperative mortality differed significantly (P = 0.041) in univariate comparison of hospitals A and B (2.9% vs. 6.4%), no significant difference was found by LReA or PScA. Similarly, the observed mortality at these did not differ significantly from the mortality estimated by the CR-POSSUM score (hospital A, 2.9%/4.9%, P = 0.298; hospital B, 6.4%/6.5%, P = 1.000). Significant differences were seen in risk-adjusted comparison of most postoperative complications (by both LReA and PScA), but there were no differences in the rates of relaparotomy or anastomotic leakage that required surgery. CONCLUSIONS: For the hard outcome variable "postoperative mortality," none of the three risk adjustment procedures showed any difference between the hospitals. The CR-POSSUM score can be regarded as the most practicable tool for risk-adjusted comparison of the outcome of colon-carcinoma resection in clinical benchmarking. PMID- 20931200 TI - Recommended nomenclature for five mammalian carboxylesterase gene families: human, mouse, and rat genes and proteins. AB - Mammalian carboxylesterase (CES or Ces) genes encode enzymes that participate in xenobiotic, drug, and lipid metabolism in the body and are members of at least five gene families. Tandem duplications have added more genes for some families, particularly for mouse and rat genomes, which has caused confusion in naming rodent Ces genes. This article describes a new nomenclature system for human, mouse, and rat carboxylesterase genes that identifies homolog gene families and allocates a unique name for each gene. The guidelines of human, mouse, and rat gene nomenclature committees were followed and "CES" (human) and "Ces" (mouse and rat) root symbols were used followed by the family number (e.g., human CES1). Where multiple genes were identified for a family or where a clash occurred with an existing gene name, a letter was added (e.g., human CES4A; mouse and rat Ces1a) that reflected gene relatedness among rodent species (e.g., mouse and rat Ces1a). Pseudogenes were named by adding "P" and a number to the human gene name (e.g., human CES1P1) or by using a new letter followed by ps for mouse and rat Ces pseudogenes (e.g., Ces2d-ps). Gene transcript isoforms were named by adding the GenBank accession ID to the gene symbol (e.g., human CES1_AB119995 or mouse Ces1e_BC019208). This nomenclature improves our understanding of human, mouse, and rat CES/Ces gene families and facilitates research into the structure, function, and evolution of these gene families. It also serves as a model for naming CES genes from other mammalian species. PMID- 20931201 TI - A phylogenetic approach to test for evidence of parental conflict or gene duplications associated with protein-encoding imprinted orthologous genes in placental mammals. AB - There are multiple theories on the evolution of genomic imprinting. We investigated whether the molecular evolution of true orthologs of known imprinted genes provides support for theories based on gene duplication or parental conflicts (where mediated by amino-acid changes). Our analysis of 34 orthologous genes demonstrates that the vast majority of mammalian imprinted genes have not undergone any subsequent significant gene duplication within placental species, suggesting that selection pressures against gene duplication events could be operating for imprinted loci. As antagonistic co-evolution between imprinted genes can regulate offspring growth, proteins mediating this interaction could be subject to rapid evolution via positive selection. Supporting this, we detect evidence of site specific positive selection for the imprinted genes OSBPL5 (and GNASXL), and detect lineage-specific positive selection for 14 imprinted genes where it is known that the gene is imprinted in a specific lineage, namely for: PLAGL1, IGF2, SLC22A18, OSBPL5, DCN, DLK1, RASGRF1, IGF2R, IMPACT, GRB10, NAPIL4, UBE3A, GATM and GABRG3. However, there is an overall lack of concordance between the known imprinting status of each gene (i.e. whether the gene is imprinted or biallelically expressed in a particular mammalian lineage) and positive selection. While only a small number of orthologs of imprinted loci display evidence of positive selection, we observe that the majority of orthologs of imprinted loci display high levels of micro-synteny conservation and have undergone very few cis- or trans-duplications in placental mammalian lineages. PMID- 20931202 TI - [Tuberculosis-associated posterior uveitis]. AB - The commercially available interferon gamma release assays T-SPOT.TB and QuantiFERON-TB Gold/QuantiFERON-TB Gold In-Tube may be important, besides the direct detection with culturing, PCR or the Mantoux skin test, for the diagnosis of tuberculosis as a possible cause of uveitis. It is important to know the limitations of these tests to get a fast and reliable diagnosis which may necessitate initiation of causative treatment of the tuberculosis to prevent further damage to the eye and to avoid multi-drug resistant tuberculosis strains. PMID- 20931203 TI - [Documentation of ophthalmological findings in contact lens wearers: software based symbol library of the Efron grading scale]. AB - BACKGROUND: To prevent complications through the use of contact lenses the efforts spent on documentation will have to be increased to meet the demands of quality management. How can ophthalmologists benefit from the use of software based graphical documentation? METHODS: To make a standardized documentation of contact lens complications possible a software module with a graphically intuitive visualization scheme of the Efron grading scale was developed. The Efron grading scale defines 16 different classes of findings scaled to 5 grades. RESULTS: The software module shows a schematic view of the eye which allows an easy sectoral assignment of all 16 Efron findings. The designated sector can simply be marked with a mouse click. A subsequently appearing context menu offers all 16 Efron findings together with the corresponding 5 grades. Finally the chosen Efron grade is graphically visualized in the corresponding sector. CONCLUSION: The software module supplies a feasible way for high quality documentation in the clinical routine with illustrative visualization. The practical application of software tools to assist clinical documentation can help to meet the challenges of quality management in contact lens utilization. PMID- 20931204 TI - Cognitive and social functioning in children and adolescents after the removal of craniopharyngioma. AB - PURPOSE: The aim of this study is to assess cognitive, emotional and social functioning in children and adolescents after the removal of craniopharyngioma. METHODS: Twenty-seven children operated for craniopharyngioma and their parents participated in the study. Cognitive functions were assessed with WISC-R/WAIS-R PL and Rey-Osterrieth Complex Figure Test. Parents completed Achenbach's Child Behaviour Checklist (CBCL) questionnaires on problems in functioning and psychopathological symptoms and took part in an interview on children coping in everyday life. RESULTS: Eighty-two percent of patients were diagnosed with an average level of intellectual functioning. No child received results indicating mental disability. In half of the children, effectiveness of visual memory was reduced, despite normal visual-spatial abilities. The results in the CBCL scale indicated more frequent presence of psychopathological symptoms-especially social problems, depression, anxiety and withdrawal. The most frequent problems in children's everyday functioning included inability to control emotions, difficulties in learning, unsatisfactory peer relationships, and unattractive appearance resulting from hormonal disorders (short height and obesity). One third of parents also reported problems with pathological appetite in their children. CONCLUSIONS: Despite normal intellectual abilities and relatively good physical condition, children after removal of craniopharyngioma experience many difficulties in everyday life regarding social relationships, emotion control and learning. The analogy between the above-mentioned symptoms and symptoms observed in patients after infantile damage in the frontal area leads to an observation that, apart from endocrine disorders, damage to the frontal lobe caused by the growth of tumour and operational intervention is of crucial importance to the further development of children with craniopharyngioma. PMID- 20931205 TI - Carboplatin and ototoxicity: hearing loss rates among survivors of childhood medulloblastoma. AB - PURPOSE: Patients with medulloblastoma are exposed to ototoxic treatments including radiation therapy and platinum chemotherapy. The favorable toxicity profile of carboplatin led us to substitute this chemotherapeutic agent for cisplatin in the HIT-1991, HIT-MED-1999, and HIT-2000 chemotherapy protocols. We retrospectively investigated its consequences in terms of overall survival and ototoxicity rates. METHODS: Twenty-four medulloblastoma patients were treated according to HIT protocols with carboplatin substitution between April 1999 and June 2006. Nineteen (79%) patients had adequate baseline and post-treatment audiological data. Mean age at diagnosis was 9.3 (range 3.5-18.9) years with a mean follow-up time of 30.8 (8.1-111.3) months. Patients received a mean carboplatin cumulative dose of 2,131 (830-4312) mg/m(2). RESULTS: Twenty-three patients were alive at the time of assessment. Hearing loss greater than 20 dB was observed in two (10.5%) of 19 patients. Both had grade 2 ototoxicity according to Brock's scale. There were no significant differences between the patients' baseline and post-treatment audiograms at any frequency. The observed hearing loss was significantly correlated to younger age at diagnosis and cumulative carboplatin dose (p<0.05). CONCLUSIONS: The encouraging overall survival and low hearing loss rates in this medulloblastoma patient cohort suggest that protocols containing carboplatin may offer a viable alternative to standard cisplatin protocols and warrant further investigation. PMID- 20931206 TI - Intracranial tumors in infants: a single institution experience of 22 patients. AB - OBJECTIVES: The prognosis in infants with brain tumors has hitherto been very poor. The purpose of the study was to collect and analyze information regarding the clinical presentation, diagnosis, and management of these patients and to assess the eventual prognosis regarding survival and response to treatment. MATERIALS AND METHODS: This study retrospectively reviewed the records of 22 infants with brain tumors at our institution between November 1995 and October 2009. Their medical records were retrieved for age at diagnosis, presenting features, location, histology, surgical procedures, adjuvant treatment, recurrence, and survival. RESULTS: The patients included 18 boys and four girls. The median age at diagnosis was 3 months with a range of antenatal diagnosis at 36 weeks of gestation up to 11.9 months. The group included four patients with definite congenital tumors presented in the perinatal period. The common presenting signs included increased head circumference, seizure, and vomiting. Over half of the tumors were histologically benign; however, medulloblastoma/primitive neuroectodermal tumor is the most frequent tumor type, accounting for six patients. Surgical resection was attempted in 18 patients, and three of them died in early postoperative period. Cerebrospinal fluid diversion was required in 11 patients, and seven of these patients needed VP shunting. Four patients received adjuvant chemotherapy, but one of them subsequently received salvage radiotherapy. CONCLUSION: Because of the expandability of the skull, brain tumors in infants may have protean manifestations. Although pathology categorization was quite a variable in our study, three quarters have tangibly survived after current therapeutic modalities. PMID- 20931208 TI - Clinicopathological characteristics and survival analysis of primary duodenal cancers: a 14-year experience in a tertiary centre in South China. AB - BACKGROUND: Primary duodenal cancer (PDC) is rare and few studies have addressed it adequately, especially in China. The present study is to evaluate the clinicopathological features and prognosis of PDC in Chinese patients. PATIENTS AND METHODS: All the consecutive cases confirmed as PDC by histopathological analysis in The First Affiliated Hospital of Sun Yat-sen University between 1995 and 2008 were included. Clinicopathological details were retrospectively analysed and prognostic factors influencing survival were evaluated. RESULTS: The patient cohort included 53 men and 38 women, accounting for only 0.02% of all in-patients during this period. Esophagogastroduodenoscopy and gastrointestinal barium radiography were mainstay diagnostic tests for PDC; they detected 88.6% and 83.3% of the tumours, respectively. Tumours mainly occurred in the descending portion of the duodenum (67.0%). Abdominal pain was the most frequent symptom (56.0%). Histologically, adenocarcinoma was the most common type (74.7%). The overall 1-, 3- and 5-year survival rates were 62.6%, 43.7% and 33.1%, respectively. Patients survived longer in the curative surgery group (median survival time of 45 months) than those in the palliative group (6 months) (P < 0.001). Nodal metastasis and positive resection margin had a significant negative impact on survival in patients undergoing potentially curative surgery in a univariate and multivariate model (P < 0.05). CONCLUSION: Patients with PDC are rare and lack specific presentations. Esophagogastroduodenoscopy and gastrointestinal barium radiography are effective in screening this rare tumour. Nodal metastasis and positive resection margins are associated with a poor prognosis. A curative surgery that achieves complete resection with negative margin should be pursued. PMID- 20931211 TI - Pregnancy and postpartum specifics in women with schizophrenia: a meta-study. AB - OBJECTIVE: This meta-study intends to elucidate schizophrenia-pregnancy inferences. METHODS: A total of 63 quasi-randomized, case-control, linkage studies on outcomes of singleton pregnancies in women with schizophrenia are identified through PubMed, ACOG, and SCOPUS. A sample of 216 pregnant and puerperal women with schizophrenia, allocated from studies of level I-IIA evidence, is compared with a sample of 487 births to unaffected women. Calculations use births as unit of analysis. Poisson regression model is used in exchangeable correlation structure. RESULTS: Older age (2.13), excessive smoking (1.85) and less antenatal care (1.92) in women with schizophrenia determine high risk for prematurity (2.08), including miscarriages (2.04) and preterm birth (1.98). Neonates to mothers with schizophrenia are profiled with twice likelihood of low Apgar scores (2.22), intrauterine growth retardation (2.16), and congenital defects (2.1). Poor maternal-fetal attachment and preoccupation about fetus are related to negative symptoms of schizophrenia (-0.518), length of antipsychotic treatment (-0.304) and are not associated with maternal age (0.216). Postpartum period is eventful with psychotic relapse (7.86), and parenting difficulties (11.2). CONCLUSIONS: After adjusting for age, parity, unhealthy behaviors, length of antipsychotic treatment, and maternal-fetal attachment, maternal schizophrenia remains predictive to prematurity and postpartum psychosis. PMID- 20931210 TI - Hakim Esmail Jorjani (1042-1137 AD: ): Persian physician and jurist. AB - The great 11th-12th century Persian physician Seyed Esmail Jorjani (known as Hakim Jorjani) is known for his 750,000 word encyclopedia of medicine, the Treasure of King Khwarazm, which has been ranked along with Avicenna's Canon and the works of Haly Abbas. Translations of this work provide modern readers with a detailed insight into medical practice in medieval Persia. Parts of the Treasure are devoted to guidance about midwifery and perinatal care. In this article we present translations of excerpts from this part of the work. PMID- 20931209 TI - The plasminogen activator inhibitor system in colon cancer cell lines is influenced by the CO2 pneumoperitoneum. AB - PURPOSE: Laparoscopic surgery in the treatment of colon carcinoma causes pH value alterations as well as changes in fibrinolytic activity. This results in enhanced proliferation of colon carcinoma cells in vitro and also in enhanced growth of liver metastasis when compared to isobaric (gasless) laparoscopy in vivo. So far, the direct influence of CO(2) pneumoperitoneum on the invasiveness and metastatic capabilities of colon cancer cells remains unclear. We therefore evaluated transcripts of the uPA system. METHODS: The influence of CO(2) pneumoperitoneum on the gene expression of plasminogen activator inhibitor-1 (PAI-1), urokinase type plasminogen activator (uPA), and tissue-type plasminogen activator (tPA) was investigated in colon carcinoma cell lines (HT116, SW48, and WiDr) and mesothelial cells employing a pneumoperitoneum chamber in vitro. Quantitative gene expression data were collected using real-time RT-PCR and statistical analysis was performed by means of analysis of variance and Bonferroni correction. RESULTS: The expression of uPA and PAI-1 was increased in colon carcinoma cell lines when cultivated at pH 6.1, a value corresponding to intraabdominal pH values during CO(2) insufflation. Elevated PAI-1 mRNA levels were also observed when CO(2) was simultaneously applied with a pressure of 10 mmHg. In contrast, there were no significant changes in mesothelial cells in the investigated parameter. CONCLUSION: The conditions of CO(2) pneumoperitoneum cause changes in the expression of genes controlling the fibrinolytic activity. The increase of PAI-1 and uPA can contribute to the enhancement of metastasis and invasive potential of tumour cells. Therefore, changes in the conditions of laparoscopy may well optimise laparoscopic therapy in colon cancer. PMID- 20931212 TI - Pelvic mass-like florid cystic endosalpingiosis of the uterus: a case report and a review of literature. AB - INTRODUCTION: Endosalpingiosis is a disorder of Mullerian system characterized by benign glands lined by tubal type epithelium and involves the peritoneum, subperitoneal tissues, and retroperitoneal lymph nodes. Endosalpingiosis is almost an incidental finding on microscopic examination. Seldom it appears as a cyst and it can be confused clinically for an ovarian tumor. DESIGN: A case report and a systematic review about pelvic mass-like florid endosalpingiosis of the uterus from PUB MED database were performed. PATIENT(S): We describe a case report of a 50-year-old woman with a pedunculated uterine neoformation, for which the preoperative exams could be compatible with an adnexal mass. Twelve patients with similar clinical history were discussed in the review. TREATMENT: Laparoscopy with radical exeresis was performed. RESULTS: Microscopic exam revealed florid cystic endosalpingiosis of the uterus. CONCLUSIONS: Endosalpingiosis is a rare mullerian disorder and the main problem is that the symptomatology is not specific and it may be initially misinterpreted. In relation to the papillary aspect of the lesion and focal calcifications, the histological differential diagnosis could include serous adenocarcinoma, but the lack of cellular stratification in absence of mitotic activity, and the presence of slight nuclear atypia contradict the diagnosis of carcinoma. The differential diagnosis for endosalpingiosis also includes multiple peritoneal inclusion cysts (benign cystic mesothelioma). The aim of this case report has not been only to describe the rarity of this pathology, but it contributes to consider endosalpingiosis as a possible diagnostic hypothesis for which may be indicated a conservative surgical treatment. PMID- 20931213 TI - Anti-Yo positive dorsal root ganglionopathy. PMID- 20931214 TI - A survey of the role of virtual surgery simulators in ophthalmic graduate medical education. PMID- 20931215 TI - Primary intravitreal ranibizumab for adult-onset foveomacular vitelliform dystrophy. AB - AIM: To evaluate the efficacy of intravitreal injections of ranibizumab in adult onset foveomacular vitelliform dystrophy (AOFVD). METHODS: Six female patients were misdiagnosed in the office as occult choroidal neovascularization due to AMD, and scheduled for 3-monthly intravitreal injections of ranibizumab. One month after the third injection, all patients underwent further examinations consisting of visual acuity, optical coherence tomography, Indocyanine Green angiography, electrophysiological tests (electroretinogram and electrooculogram), and an exhaustive familial history of macular diseases. Cases were followed-up every 6 weeks since the formal diagnose of AOFVD was evidenced. RESULTS: The mean BCVA improved from 0.36 +/- 0.1 at baseline to 0.56 +/- 0.1 (p = 0.038). No significant change was evidence in the SD-OCT thickness analysis. Metamorphopsia disappeared completely in all cases after the first injection. No familial history was evidenced. CONCLUSIONS: Ranibizumab intravitreal injections are effective in the short-term BCVA improvement in patients with AOFVD. PMID- 20931216 TI - Sliding macular fold following retinal detachment surgery. AB - BACKGROUND: Retinal folds (RF) following retinal detachment (RD) surgery are infrequent complications and their management is controversial. Spontaneous resolution of RF has been reported. METHODS: An observational case report of a surgical complication of RD surgery was done. The progressive migration of a postoperative macular fold away from the center of the fovea was documented by optical coherence tomography (OCT) and retinography. RESULTS: A macular fold was detected following 23G vitrectomy with liquid perfluorocarbon injection, photocoagulation, and SF6 injection to treat a bullous rhegmatogenous retinal detachment. In the following year, visual acuity remained stable at 20/25 while the macular fold migrated 1 mm away from the center of the fovea. CONCLUSIONS: A conservative approach may be appropriate in cases of macular fold following retinal detachment surgery, provided that good visual acuity is present and OCT shows a trend towards migration of the macular fold. PMID- 20931217 TI - Influence of alcohol consumption on incidence and severity of open-globe eye injuries in adults. AB - AIM: To investigate the influence of alcohol consumption on the occurrence of open-globe injuries in adults. METHODS: A retrospective study was made of 100 consecutive patients (81 male, 19 female) with open-globe injuries. Of these patients, 18 exhibited alcohol intoxication (group Ai), and 82 exhibited no alcohol intoxication (group nAi). Investigated parameters were best-corrected visual acuity at day of admission and last examination (logMAR), type of injury according to BETT-classification, extraocular injuries, cause of injury, time and setting of injury, in relation to alcohol consumption and tested for statistical significance with Fisher's exact test or the Mann-Whitney U test, respectively. RESULTS: In group Ai, 83.3% of the patients were male, and in group nAi, 80.5%. Mean logMAR at day of admission was 1.06 +/- 0.63 (20/250) in group Ai and 1.08 +/- 0.59 (20/250) in group nAi. At last examination, mean logMAR in group Ai was 1.11 +/- 0.59 (20/250), in group nAi 0.75 +/- 0.60 (20/125). This difference was statistically significant (p = 0.02). In group Ai, significantly more ruptures according to BETT classification occurred (p = 0.05). In group Ai, significantly more additional extraocular injuries occurred compared to group nAi (38.9% versus 6.1%; p = 0.0009). In group Ai, the cause of injury was significantly more often glass (44.4% versus 2.4%; p = 0.0000), in group nAi the injury was more often directly or indirectly caused by tools (74.4% versus 33.3%; p = 0.001). In group Ai, the injury was significantly more often inflicted by others (50.0% versus 9.8%; p = 0.0003). The settings in which the injuries occurred were significantly more often the street in group Ai (44.4% versus 6.1%; p = 0.0002), in group nAi the garden or tool shed (31.7% versus 5.6%; p = 0.02) or the workplace (34.2 % versus 11.1 %; p = 0.04). In group Ai, the injuries occurred significantly more often at night (p = 0.0001) and on weekends (p = 0.0000). CONCLUSIONS: Open-globe eye injuries under alcohol intoxication are more often caused by a third party and have a worse prognosis. Open-globe injuries under alcohol intoxication occur in a different spatio-temporal setting and exhibit a more severe type of injury. Risk behavior combined with alcohol consumption therefore seems to be an independent factor for the incidence of open-globe eye injuries. PMID- 20931218 TI - Effect of submaximal isometric wrist extension training on grip strength. AB - Gripping force is produced by co-contraction of forearm flexors and extensors. Activation of extensors is important for stabilizing the wrist during gripping. However, forearm muscle function is complicated and the neurophysiological mechanism responsible for the gain in gripping force is unclear. Therefore, the purpose of this study was to investigate whether increasing forearm extensor activation with isometric wrist extension training has an effect on gripping force. Thirteen healthy subjects participated in this study. Maximal voluntary contraction of gripping was measured using a piezosensor (MVC(grip)) and EMG of forearm muscles at every wrist angle (from 70 degrees flexion to 80 degrees extension with 10 degrees intervals) were measured simultaneously at baseline, 4 weeks, and 8 weeks after training. Training consisted of 30 repetitions equal to 70% MVC of isometric wrist extension for 8 weeks (5/week) on the right side. Gripping force was measured on both sides using a grip dynamometer without wrist angle restriction. Gripping force, EMG, maximal wrist extension force, and wrist angle-gripping force curve were investigated after training. After training, maximal wrist extension force increased significantly. Gripping force on the trained side also increased significantly. The training changed wrist angle at peak of MVC(grip). EMG activation of forearm extensors increased and that of flexors decreased during gripping. These results suggest that wrist extension training leads to an increase in gripping force and changes the balance of EMG activation between forearm flexors and extensors during gripping. Therefore, this training method should be useful as a therapeutic strategy for increasing grip strength. PMID- 20931219 TI - Modulation of circulating purines and pyrimidines by physical exercise in the horse. AB - This study was designed to examine the influence of sub-maximal exercise on purine and pyrimidine catabolism in horses. Ten horses were initially trained for 12 weeks at the end of which they underwent a standardized exercise test (SET); venous blood samples were taken at rest, 5 and 30 min after the SET. Six untrained healthy horses, from which a blood withdrawal was taken at rest, were used as the control group. Samples were analyzed by HPLC for the simultaneous determination of uric acid, uridine, beta-pseudouridine and creatinine in plasma. Glucose and lactate were measured in blood. Trained horses had basal uridine levels significantly lower than sedentary horses. The SET caused significant increase in plasma uric acid, uridine, beta-pseudouridine and creatinine. Following the SET, a significant negative correlation was found between plasma uridine and glucose, whilst a significant positive correlation was observed between plasma uric acid and creatinine. These results indicate that increase in energy demand during exercise in the horse causes not only the degradation of purine but also of pyrimidine compounds, the latter possibly exerting a control on glucose uptake as also demonstrated in human beings. PMID- 20931220 TI - Effects of plyometric training on both active and passive parts of the plantarflexors series elastic component stiffness of muscle-tendon complex. AB - The aims of this study were to determine the effects of plyometric training on both active and passive parts of the series elastic component (SEC) stiffness, and on geometrical parameters [i.e., muscle architecture, muscle and tendon cross sectional area (CSA)] of the plantarflexors muscle-tendon complex to assess possible specific adaptations of the elastic properties. Nineteen subjects were randomly divided into a trained group and a control group. Active and passive components of the SEC stiffness were determined using a fast stretch during submaximal voluntary isometric plantarflexor activity. Geometrical parameters of the triceps surae muscles and the Achilles tendon were determined using ultrasonography. A significant increase in the passive component of the SEC stiffness was found (p < 0.05). In contrast, a significant decrease in the active part of the SEC stiffness was observed (p < 0.05). No significant changes in plantarflexor muscles CSA, architecture and Achilles tendon CSA were seen (p > 0.05). Thus, plyometric training led to specific adaptations within each part of the SEC. Theses adaptations could increase both the efficiency of the energy storage-recoil process and muscular tension transmission leading to an increase in jump performances. PMID- 20931221 TI - Are the parameters of VO2, heart rate and muscle deoxygenation kinetics affected by serial moderate-intensity exercise transitions in a single day? AB - This study compared the parameter estimates of pulmonary oxygen uptake (VO(2p)), heart rate (HR) and muscle deoxygenation (Delta[HHb]) kinetics when several moderate-intensity exercise transitions (MODs) were performed during a single visit versus several MODs performed during separate visits. Nine subjects (24 +/- 5 years, mean +/- SD) each completed two successive cycling MODs on six occasions (1-6A and 1-6B) from 20 W to a work rate corresponding to 80% estimated lactate threshold with 6 min recovery at 20 W. During one visit, subjects completed two series of three MODs (6A-F), separated by 20 min rest. VO(2p) time constants (tauVO(2p); 27 +/- 10 s, 25 +/- 12 s, 25 +/- 11 s) were similar (p > 0.05) for MODs 1-6A, 1-6B and 6A-F, respectively. tauVO(2p) had reproducibility 95% confidence intervals (CI(95)) of 8.3, 8.2, 4.7, 4.9 and 4.7 s when comparing single (1A vs. 2A), the average of two (1-2A vs. 3-4A), three (1-3A vs. 4-6A), four (1-2AB vs. 3-4AB) and six (1-3AB vs. 4-6AB) MODs, respectively. The effective Delta[HHb] response time (tau'Delta[HHb]) was unaffected across conditions (1-6A: 19 +/- 2 s, 1-6B: 19 +/- 3 s, 6A-F: 17 +/- 4 s) with reproducibility CI(95) of 5.3, 4.5, 3.1, 2.9 and 3.3 s when a single, two, three, four and six MODs were compared, respectively. tauHR was reduced in MODs 6A-F compared to 1-6A and 1-6B (23 +/- 5 s, 25 +/- 5 s, 27 +/- 6 s, respectively). This study showed that parameter estimates of VO(2p), HR and Delta[HHb] kinetics are largely unaffected by data collection sequence, and the day-to-day reproducibility of tauVO(2p) and tau'Delta[HHb] estimates, as determined by the CI(95), was appreciably improved by averaging of at least three MODs. PMID- 20931222 TI - Brassinolide-improved development of Brassica napus microspore-derived embryos is associated with increased activities of purine and pyrimidine salvage pathways. AB - Cellular brassinolide (BL) levels regulate the development of Brassica napus microspore-derived embryos (MDEs). Synthesis and degradation of nucleotides were measured on developing MDEs treated with BL or brassinazole (BrZ), a biosynthetic inhibitor of BL. Purine metabolism was investigated by following the metabolic fate of (14)C-labelled adenine and adenosine, substrates of the salvage pathway, and inosine, an intermediate of both salvage and degradation pathways. For pyrimidine, orotic acid, uridine and uracil were employed as markers for the de novo (orotic acid), salvage (uridine and uracil), and degradation (uracil) pathways. Our results indicate that utilization of adenine, adenosine, and uridine for nucleotides and nucleic acids increased significantly in BL-treated embryos at day 15 and remained high throughout the culture period. These metabolic changes were ascribed to the activities of the respective salvage enzymes: adenine phosphoribosyltransferase (EC 2.4.2.7), adenosine kinase (EC 2.7.1.20), and uridine kinase (EC 2.7.1.48), which were induced by BL applications. The BL promotion of salvage synthesis was accompanied by a reduction in the activities of the degradation pathways, suggesting the presence of competitive anabolic and catabolic mechanisms utilizing the labelled precursors. In BrZ-treated embryos, with depleted BL levels, the salvage activity of both purine and pyrimidine nucleotides was reduced and this was associated to structural abnormalities and poor embryonic performance. In these embryos, the activities of major salvage enzymes were consistently lower to those measured in their control (untreated) counterparts. PMID- 20931224 TI - Temporal and spatial diversities of the immunolabeling of mannan and xylan polysaccharides in differentiating earlywood ray cells and pits of Cryptomeria japonica. AB - Wood is composed of various types of cells and each type of cell has different structural and functional properties. However, the temporal and spatial diversities of cell wall components in the cell wall between different cell types are rarely understood. To extend our understanding of distributional diversities of cell wall components among cells, we investigated the immunolabeling of mannans (O-acetyl-galactoglucomannans, GGMs) and xylans (arabino-4-O methylglucuronoxylans, AGXs) in ray cells and pits. The labeling of GGMs and AGXs was temporally different in ray cells. GGM labeling began to be detected in ray cells at early stages of S(1) formation in tracheids, whereas AGX labeling began to be detected in ray cells at the S(2) formation stage in tracheids. The occurrence of GGM and AGX labeling in ray cells was also temporally different from that of tracheids. AGX labeling began to be detected much later in ray cells than in tracheids. GGM labeling also began to be detected in ray cells either slightly earlier or later than in tracheids. In pits, GGM labeling was detected in bordered and cross-field pit membranes at early stages of pit formation, but not observed in mature pits, indicating that enzymes capable of GGM degradation may be involved in pit membrane formation. In contrast to GGMs, AGXs were not detected in pit membranes during the entire developmental process of bordered and cross-field pits. AGXs showed structural and depositional variations in pit borders depending on the developmental stage of bordered and cross-field pits. PMID- 20931223 TI - Molecular characterization of a miraculin-like gene differentially expressed during coffee development and coffee leaf miner infestation. AB - The characterization of a coffee gene encoding a protein similar to miraculin like proteins, which are members of the plant Kunitz serine trypsin inhibitor (STI) family of proteinase inhibitors (PIs), is described. PIs are important proteins in plant defence against insects and in the regulation of proteolysis during plant development. This gene has high identity with the Richadella dulcifica taste-modifying protein miraculin and with the tomato protein LeMir; and was named as CoMir (Coffea miraculin). Structural protein modelling indicated that CoMir had structural similarities with the Kunitz STI proteins, but suggested specific folding structures. CoMir was up-regulated after coffee leaf miner (Leucoptera coffella) oviposition in resistant plants of a progeny derived from crosses between C. racemosa (resistant) and C. arabica (susceptible). Interestingly, this gene was down-regulated during coffee leaf miner herbivory in susceptible plants. CoMir expression was up-regulated after abscisic acid application and wounding stress and was prominent during the early stages of flower and fruit development. In situ hybridization revealed that CoMir transcripts accumulated in the anther tissues that display programmed cell death (tapetum, endothecium and stomium) and in the metaxylem vessels of the petals, stigma and leaves. In addition, the recombinant protein CoMir shows inhibitory activity against trypsin. According to the present results CoMir may act in proteolytic regulation during coffee development and in the defence against L. coffeella. The similarity of CoMir with other Kunitz STI proteins and the role of CoMir in plant development and plant stress are discussed. PMID- 20931225 TI - Vacuolated cell pattern of pancreatobiliary adenocarcinoma: a clinicopathological analysis of 24 cases of a poorly recognized distinctive morphologic variant important in the differential diagnosis. AB - Pancreatic ductal adenocarcinoma (PDCA) is characterized by well-defined tubular units in the vast majority of the cases; however, variations in this theme do occur. It is important to recognize the morphologic spectrum of PDCA to avoid misdiagnosis especially in small specimens and also in metastatic foci. Here, we document a morphologic variant of PDCA that is characterized by a distinctive pattern of infiltrating cribriform nests in a distinctive "microcystic" or "secretory" pattern. Twenty-four cases of PDCA have been identified in a review of 505 cases diagnosed with PDCA. Histologically, this pattern was characterized by infiltrating nests of tumor cells with large vacuoles and "signet-ring" like appearance imparting a cribriform growth pattern. The vacuoles were one to five cells in size, often merging to form multilocular spaces separated by a thin rim of cell membrane. Many of these spaces contained CA19.9 positive granular secretory material. The nuclei were often pushed to the periphery and compressed in a pattern resembling adipocytes, although the nuclei were often densely hyperchromatic and displayed significant atypia. Especially in biopsies from the peripancreatic fat and peritoneum, these neoplastic cells had been misdiagnosed as degenerating adipocytes, and in the lymph nodes, they had been misinterpreted as lipogranulomas. Clinical findings of the patients were similar to that of conventional PDCA, except higher incidence of history of smoking (83% vs. 60%; p=0.034). In conclusion, vacuolated cell adenocarcinoma is a distinct morphologic variant of PDCA, and the presence of this peculiar pattern in a metastatic site, although not specific, should raise the suspicion of a PDCA. PMID- 20931226 TI - Inhaled corticosteroids in childhood asthma: the story continues. AB - Inhaled corticosteroids (ICS) are the most effective anti-inflammatory drugs for the treatment of persistent asthma in children. Treatment with ICS decreases asthma mortality and morbidity, reduces symptoms, improves lung function, reduces bronchial hyperresponsiveness and reduces the number of exacerbations. The efficacy of ICS in preschool wheezing is controversial. A recent task force from the European Respiratory Society on preschool wheeze defined two different phenotypes: episodic viral wheeze, wheeze that occurs only during respiratory viral infections, and multiple-trigger wheeze, where wheeze also occurs in between viral episodes. Treatment with ICS appears to be more efficacious in the latter phenotype. Small particle ICS may offer a potential benefit in preschool children because of the favourable spray characteristics. However, the efficacy of small particle ICS in preschool children has not yet been evaluated in prospective clinical trials. The use of ICS in school children with asthma is safe with regard to systemic side effects on the hypothalamic-pituitary-adrenal axis, growth and bone metabolism, when used in low to medium doses. Although safety data in wheezing preschoolers is limited, the data are reassuring. Also for this age group, adverse events tend to be minimal when the ICS is used in appropriate doses. PMID- 20931227 TI - Two siblings with triple A syndrome and novel mutation presenting as hereditary polyneuropathy. AB - The clinical and molecular data on triple A syndrome in two siblings (girl 3.5 years and boy 5.5 years at presentation) with early onset of neurological dysfunction are described. Both patients showed delayed developmental milestones and neurological dysfunctions (motor and sensory demyelinating neuropathy, marked hyperreflexia, calves hypothrophy, pes cavus, gait disturbance) in early childhood, when erroneously diagnosed with hereditary polyneuropathy, most likely Charcot-Marie-Tooth disease. After a severe adrenal crisis in the younger sister at the age of 3 years, the older brother aged 5.5 years was also evaluated and latent adrenal insufficiency was discovered. As both of the siblings had alacrima, hyperkeratosis of palms, cutis anserina, and nasal speech, diagnosis of triple A syndrome was considered. Sequencing of the AAAS gene detected a compound heterozygous mutation consisting of a novel mutation p.Ser296Tyr (c.887C>A) in exon 9 and a previously described p.Ser263Pro (c.787T>C) missense mutation in exon 8 in both siblings. In conclusion, triple A syndrome should be considered in patients presenting with early neurological dysfunction and developmental delay. Alacrima as the earliest and most consistent clinical sign should be investigated by Schirmer test. Patients should be regularly tested for adrenal dysfunction to prevent life-threatening adrenal crises. PMID- 20931229 TI - Adenovirus infection mimics the cerebellitis caused by rotavirus infection. PMID- 20931230 TI - Sperm rates of 7q11.23, 15q11q13 and 22q11.2 deletions and duplications: a FISH approach. AB - Genomic disorders are human diseases caused by meiotic chromosomal rearrangements of unstable regions flanked by Low Copy Repeats (LCRs). LCRs act as substrates for Non-Allelic Homologous Recombination (NAHR) leading to deletions and duplications. The aim of this study was to assess the basal frequency of deletions and duplications of the 7q11.23, 15q11-q13 and 22q11.2 regions in spermatozoa from control donors to check differences in the susceptibility to generate anomalies and to assess the contribution of intra- and inter-chromatid NAHR events. Semen samples from ten control donors were processed by FISH. A customized combination of probes was used to discriminate among normal, deleted and duplicated sperm genotypes. A minimum of 10,000 sperm were assessed per sample and region. There were no differences in the mean frequency of deletions and duplications (del + dup) among the 7q11.23, 15q11-q13 and 22q11.2 regions (frequency +/- SEM, 0.37 +/- 0.02; 0.46 +/- 0.07 and 0.27 +/- 0.07%, respectively) (P = 0.122). Nevertheless, hierarchical cluster analysis reveals interindividual differences suggesting that particular haplotypes could be the main source of variability in NAHR rates. The mean frequency of deletions was not different from the mean frequency of duplications in the 7q11.23 (P = 0.202) and 15q11-q13 (P = 0.609) regions, indicating a predominant inter-chromatid NAHR. By contrast, in the 22q11.2 region the frequency of deletions slightly exceed duplications (P = 0.032), although at the individual level any donor showed differences. Altogether, our results support the inter-chromatid NAHR as the predominant mechanism involved in the generation of sperm deletions and duplications. PMID- 20931232 TI - Relative importance of top-down and bottom-up forces in food webs of Sarracenia pitcher communities at a northern and a southern site. AB - The relative importance of resources (bottom-up forces) and natural enemies (top down forces) for regulating food web dynamics has been debated, and both forces have been found to be critical for determining food web structure. How the relative importance of top-down and bottom-up forces varies between sites with different abiotic conditions is not well understood. Using the pitcher plant inquiline community as a model system, I examine how the relative importance of top-down and bottom-up effects differs between two disparate sites. Resources (ant carcasses) and top predators (mosquito larvae) were manipulated in two identical 4 * 4 factorial press experiments, conducted at two geographically distant sites (Michigan and Florida) within the range of the purple pitcher plant, Sarracenia purpurea, and the aquatic community that resides in its leaves. Overall, top predators reduced the density of prey populations while additional resources bolstered them, and the relative importance of top-down and bottom-up forces varied between sites and for different trophic levels. Specifically, top down effects on protozoa were stronger in Florida than in Michigan, while the opposite pattern was found for rotifers. These findings experimentally demonstrate that the strength of predator-prey interactions, even those involving the same species, vary across space. While only two sites are compared in this study, I hypothesize that site differences in temperature, which influences metabolic rate, may be responsible for variation in consumer-resource interactions. These findings warrant further investigation into the specific factors that modify the relative importance of top-down and bottom-up effects. PMID- 20931231 TI - Partial correlation network analyses to detect altered gene interactions in human disease: using preeclampsia as a model. AB - Differences in gene expression between cases and controls have been identified for a number of human diseases. However, the underlying mechanisms of transcriptional regulation remain largely unknown. Beyond comparisons of absolute or relative expression levels, disease states may be associated with alterations in the observed correlational patterns among sets of genes. Here we use partial correlation networks aiming to compare the transcriptional co-regulation for 222 genes that are differentially expressed in decidual tissues between preeclampsia (PE) cases and non-PE controls. Partial correlation coefficients (PCCs) have been calculated in cases (N = 37) and controls (N = 58) separately. For all PCCs, we tested if they were significant non-zero in the cases and controls separately. In addition, to examine if a given PCC is different between the cases and controls, we tested if the difference between two PCCs were significant non-zero. In the group with PE cases, only five PCCs were significant (FDR p value <= 0.05), of which none were significantly different from the PCCs in the controls. However, in the controls we identified a total of 56 statistically significant PCCs (FDR p value <= 0.05), of which 31 were also significantly different (FDR p value <= 0.05) from the PCCs in the PE cases. The identified partial correlation networks included genes that are potentially relevant for developing PE, including both known susceptibility genes (EGFL7, HES1) and novel candidate genes (CFH, NADSYN1, DBP, FIGLA). Our results might suggest that disturbed interactions, or higher order relationships between these genes play an important role in developing the disease. PMID- 20931233 TI - Density affects mating mode and large male mating advantage in a fiddler crab. AB - Fiddler crabs show two different mating modes: either females search and crabs mate underground in male burrows, or males search and crabs mate on the surface near female burrows. We explored the relationship between crab density, body size, the searching behavior of both sexes, and the occurrence of both mating modes in the fiddler crab Uca uruguayensis. We found that crabs change their mating mode depending on their size and crab density. Crabs mated mostly on the surface at low densities, and underground at high densities. The proportion of wandering receptive females but not courting males accounted for the variation in mating modes. This suggests that whether crabs mate underground (or on the surface) is determined by the presence (or absence) of searching females. We found that the change in the mating mode affected the level of assortative mating; males mating underground were bigger than those mating on the surface, suggesting active female choice. Given that fiddler crabs experience multiple reproductive cycles, they are prone to showing behavioral plasticity in their mating strategy whenever the payoffs of using different mating modes differ between reproductive events. Our results suggest that the incorporation of different levels of environmental variability may be important in theoretical models aimed at improving our understanding of the evolution of alternative mating tactics and strategies. PMID- 20931234 TI - Defensive effects of extrafloral nectaries in quaking aspen differ with scale. AB - The effects of plant defenses on herbivory can differ among spatial scales. This may be particularly common with indirect defenses, such as extrafloral nectaries (EFNs), that attract predatory arthropods and are dependent on predator distribution, abundance, and behavior. We tested the defensive effects of EFNs in quaking aspen (Populus tremuloides Michx.) against damage by a specialist herbivore, the aspen leaf miner (Phyllocnistis populiella Cham.), at the scale of individual leaves and entire ramets (i.e., stems). Experiments excluding crawling arthropods revealed that the effects of aspen EFNs differed at the leaf and ramet scales. Crawling predators caused similar reductions in the percent leaf area mined on individual leaves with and without EFNs. However, the extent to which crawling predators increased leaf miner mortality and, consequently, reduced mining damage increased with EFN expression at the ramet scale. Thus, aspen EFNs provided a diffuse defense, reducing damage to leaves across a ramet regardless of leaf-scale EFN expression. We detected lower leaf miner damage and survival unassociated with crawling predators on EFN-bearing leaves, suggesting that direct defenses (e.g., chemical defenses) were stronger on leaves with than without EFNs. Greater direct defenses on EFN-bearing leaves may reduce the probability of losing these leaves and thus weakening ramet-scale EFN defense. Aspen growth was not related to EFN expression or the presence of crawling predators over the course of a single season. Different effects of aspen EFNs at the leaf and ramet scales suggest that future studies may benefit from examining indirect defenses simultaneously at multiple scales. PMID- 20931235 TI - Geographic host use variability and host range evolutionary dynamics in the phytophagous insect Apagomerella versicolor (Cerambycidae). AB - The high diversity of phytophagous insects has been explained by the tendency of the group towards specialization; however, generalism may be advantageous in some environments. The cerambycid Apagomerella versicolor exhibits intraspecific geographical variation in host use. In northern Argentina it is highly specialized on the herb Pluchea sagittalis (Asteraceae), while in central and southern areas it uses seven Asteraceae species. To study host species geographical variation from ecological and evolutionary perspectives, we investigated field host availability and use across a wide latitudinal range, and performed laboratory studies on insect oviposition preference and larval performance and mitochondrial DNA (mtDNA) variation in a phylogeographical framework. Geographic variation in host use was unrelated to host availability but was highly associated with laboratory oviposition preference, larval performance, and mtDNA variation. Genetic studies revealed three geographic races of A. versicolor with gene flow restriction and recent geographic expansion. Trophic generalism and oligophagy within A. versicolor seem to have evolved as adaptations to seasonal and spatial unavailability of the preferred host P. sagittalis in cooler areas of the species' geographic range. No single genotype is successful in all environments; specialization may be advantageous in environments with uniform temporal and spatial host availability, while being a trophic generalist may provide an adaptive advantage in host-constrained environments. PMID- 20931236 TI - Process performance of parallel bioreactors for batch cultivation of Streptomyces tendae. AB - Batch cultivations of the nikkomycin Z producer Streptomyces tendae were performed in three different parallel bioreactor systems (milliliter-scale stirred-tank reactors, shake flasks and shaken microtiter plate) in comparison to a standard liter-scale stirred-tank reactor as reference. Similar dry cell weight concentrations were measured as function of process time in stirred-tank reactors and shake flasks, whereas only poor growth was observed in the shaken microtiter plate. In contrast, the nikkomycin Z production differed significantly between the stirred and shaken bioreactors. The measured product concentrations and product formation kinetics were almost the same in the stirred-tank bioreactors of different scale. Much less nikkomycin Z was formed in the shake flasks and MTP cultivations, most probably due to oxygen limitations. To investigate the non Newtonian shear-thinning behavior of the culture broth in small-scale bioreactors, a new and simple method was applied to estimate the rheological behavior. The apparent viscosities were found to be very similar in the stirred tank bioreactors, whereas the apparent viscosity was up to two times increased in the shake flask cultivations due to a lower average shear rate of this reactor system. These data illustrate that different engineering characteristics of parallel bioreactors applied for process development can have major implications for scale-up of bioprocesses with non-Newtonian viscous culture broths. PMID- 20931237 TI - Clinical factors predicting bacteremia in low-risk febrile neutropenia after anti cancer chemotherapy. AB - PURPOSE: Bacteremia is an important clinical condition in febrile neutropenia that can cause clinical failure of antimicrobial therapy. The purpose of this study was to investigate the clinical factors predictive of bacteremia in low risk febrile neutropenia at initial patient evaluation. METHODS: We performed a retrospective cohort study in a university hospital in Seoul, Korea, between May 1995 and May 2007. Patients who met the criteria of low-risk febrile neutropenia at the time of visit to emergency department after anti-cancer chemotherapy were included in the analysis. RESULTS: During the study period, 102 episodes of bacteremia were documented among the 993 episodes of low-risk febrile neutropenia. Single gram-negative bacteremia was most frequent. In multivariate regression analysis, initial body temperature >=39 degrees C, initial hypotension, presence of clinical sites of infection, presence of central venous catheter, initial absolute neutrophil count <50/mm(3), and the CRP >=10 mg/dL were statistically significant predictors for bacteremia. A scoring system using these variables was derived and the likelihood of bacteremia was well correlated with the score points with AUC under ROC curve of 0.785. Patients with low score points had low rate of bacteremia, thus, would be candidates for outpatient-based or oral antibiotic therapy. CONCLUSIONS: We identified major clinical factors that can predict bacteremia in low-risk febrile neutropenia. PMID- 20931238 TI - Intermediate segment degeneration after noncontiguous anterior cervical fusion. AB - BACKGROUND: Studies suggest that the annual incidence of symptomatic adjacent segment disease is 2-3%. Because biomechanical studies have shown increased stress at levels adjacent to a fusion mass, some surgeons have advocated including the normal level in the fusion construct in patients presenting with noncontiguous cervical spondylosis requiring surgical intervention. Our objective was to evaluate the incidence of adjacent segment disease (ASD) in intermediate segments in noncontiguous anterior cervical fusion. METHOD: We reviewed patients who underwent noncontiguous anterior cervical arthrodesis between 1985 and 2007. The primary outcome was the presence of symptomatic degeneration at the intermediate segment in noncontiguous fusions. Secondary outcomes were visual analog scale (VAS) scores and overall neurologic outcome. RESULTS: Seventeen cases of noncontiguous anterior cervical fusion were included. None had symptomatic ASD at the intervening level during mean follow-up of 26 months. Thirteen of 17 patients demonstrated postoperative neurological improvement; four had no change. Overall symptomatic outcome was judged as significantly improved, moderately improved, and unchanged in 11, two, and four patients, respectively. A mean five-point improvement in the VAS score was seen at 3-month follow-up, with continued improvement at 24 months. Among the 37 levels fused, three levels in two patients showed evidence of pseudarthrosis, one of which remained asymptomatic during the follow-up period. CONCLUSIONS: We observed neurological and clinical overall improvement in our series of patients after noncontiguous fusions without evidence of increased degeneration requiring treatment at the intermediate segment. We believe this technique is safe and effective without increased postoperative or long-term morbidity. PMID- 20931239 TI - Clinicopathological study on chronic encapsulated expanding hematoma associated with incompletely obliterated AVM after stereotactic radiosurgery. AB - BACKGROUND: Chronic encapsulated expanding hematoma is a rare, but highly morbid, severe complication after stereotactic radiosurgery for intracerebral arteriovenous malformations (AVMs). The aim of this study was to clarify the clinical features and possible mechanisms of formation and expansion of this type of hematoma based on histopathological findings. METHODS: The patients were comprised of three males and one female. Three of these patients had AVMs in the basal ganglia, while the remaining one in the frontal lobe. RESULTS: Cerebral angiograms performed 6 months to 11 years after radiosurgery demonstrated major, but incomplete, obliteration of the nidi. Each patient developed localized enhancing mass lesions at 2, 3, 5, and 11 years after radiosurgery. The lesions expanded slowly, but progressively over time in association with marked perifocal edema. The perifocal edema disappeared immediately after removal of the hematoma; their neurological symptoms improved partially or completely. Histopathologically, the hematomas were well-encapsulated and the capsule walls uniformly consisted of an outer fibrocollagenous layer and an inner granulation layer. Immunohistochemistry revealed vascular endothelial growth factor (VEGF) expression in the endothelium of newly formed blood vessels and myofibroblasts in the hematoma capsule inner layer. Myofibroblasts also expressed VEGFR-1. CONCLUSIONS: The activation of VEGF pathway may lead to neovascularization in the granulation layer of the hematoma capsule that serves as a continual source of bleeding and perifocal edema. Thus, radical resection of the capsule and residual nidus is strongly recommended for the management of both bleeding and edema. PMID- 20931240 TI - Arachnoid cysts of the middle cranial fossa accompanied by subdural effusions- experience with 60 consecutive cases. AB - BACKGROUND: Subdural effusions (SDEs) can complicate arachnoid cysts of the middle cranial fossa (ACMFs). While there is a consensus that at least in adults asymptomatic ACMFs should not be operated, those with concomitant subdural and/or intracystic effusions are clinically apparent in the majority of cases and should be surgically treated. But it remains unclear, which surgical procedure is best. METHODS: Since 1980, 60 out of 343 patients with an ACMF presented with accompanying SDEs. Four categories of SDEs were differentiated radiologically. This collective was controlled in a follow-up study up to 60 months after conservative or operative treatment by clinical and radiological means. RESULTS: In 54 of the 60 patients, we saw an indication for surgical treatment. Twenty nine patients received a burr hole, 13 cases were treated by craniotomy, seven by endoscopical means, three patients underwent shunting and two combined procedures. Six patients were treated conservatively. An excellent final clinical outcome was observed in 55 cases. While craniotomy succeeded best to reduce the cyst volume in postoperative CT, the final clinical outcome did not differ significantly compared with burr hole trepanation. CONCLUSIONS: Patients with small effusions can be treated conservatively in selected cases. Based on our experience, we prefer a differentiated therapy. As first procedure, burr hole and subdural drainage were performed, leaving the cyst alone, seeming sufficient for the majority of cases. Craniotomy or endoscopical means should be reserved as treatment of choice for special cases, depending on category and acuteness of SDE and size/localisation of the ACMF. PMID- 20931241 TI - Multidisciplinary management of giant functional petrous bone paraganglioma. AB - Giant and functional paragangliomas of the skull base are rare. Their endocrinological and surgical management is challenging. We report the case of an aggressive giant noradrenalin-secreting paraganglioma of the right temporal bone. Three procedures of embolisation were performed. The second one was complicated by a hypertensive crisis due to catecholamine release. The tumour was resected via a widened transcochlear approach. Tumour residue was treated by gamma knife radiosurgery, without additional growth at the last follow-up. This case illustrates the interest of multidisciplinary management of giant skull base paragangliomas. PMID- 20931242 TI - NIR-labeled nanoparticles engineered for brain targeting: in vivo optical imaging application and fluorescent microscopy evidences. AB - The presence of the blood-brain barrier (BBB) makes extremely difficult to develop efficacious strategies for targeting contrast agents and delivering drugs inside the Central Nervous System (CNS). To overcome this drawback, several kinds of CNS-targeted nanoparticles (NPs) have been developed. In particular, we proposed poly-lactide-co-glycolide (PLGA) NPs engineered with a simil-opioid glycopeptide (g7), which have already proved to be a promising tool for achieving a successful brain targeting after i.v. administration in rats. In order to obtain CNS-targeted NPs to use for in vivo imaging, we synthesized and administrated in mice PLGA NPs with double coverage: near-infrared (NIR) probe (DY-675) and g7. The optical imaging clearly showed a brain localization of these novel NPs. Thus, a novel kind of NIR-labeled NPs were obtained, providing a new, in vivo detectable nanotechnology tool. Besides, the confocal and fluorescence microscopy evidences allowed to further confirm the ability of g7 to promote not only the rat, but also the mouse BBB crossing. PMID- 20931243 TI - Combination of intracortically administered VEGF and environmental enrichment enhances brain protection in developing rats. AB - Postnatal development of the visual cortex is modulated by experience, especially during the critical period. In rats, a stable neuronal population is only acquired after this relatively prolonged period. Vascular endothelial growth factor (VEGF) is the most important angiogenic factor and also has strong neuroprotective, neurotrophic and neurogenic properties. Similar effects have been described for rearing in enriched environments. Our aim is to investigate the vascular and neuronal effects of combining VEGF infusion and environmental enrichment on the visual cortex during the initial days of the critical period. Results showed that a small percentage of Cleaved Caspase-3 positive cells colocalized with neuronal markers. The lesion produced by the cannula implantation resulted in decreased vascular, neuronal and Caspase-3 positive cell densities. Rearing under enriched environment was unable to reverse these effects in any group, whereas VEGF infusion alone partially corrected those effects. A higher effectiveness was reached by combining both the procedures, the most effective combination being when enriched-environment rearing was introduced only after minipump implantation. In addition to the angiogenic effect of VEGF, applied strategies also had synergic neuroprotective effects, and the combination of the two strategies had more remarkable effects than those achieved by each strategy applied individually. PMID- 20931244 TI - Association of polymorphisms in genes involved in the dopaminergic pathway with blood pressure and uric acid levels in Chinese females. AB - Since the high degree of heritability of physiological traits was demonstrated by twin and adoption studies, contemporary researchers in the fields of clinical medicine, behavioral science, and genetics have acknowledged the crucial role of genetic factors in human physiology. The study described herein explores the association between physiological parameters and the dopaminergic system using molecular genetic techniques. A total of 558 Taiwanese female volunteers, ranging from 16 to 17 years, were recruited. Single nucleotide polymorphisms in genes involved in the dopaminergic pathway were selected for analysis. Systolic blood pressure and diastolic blood pressure were associated significantly with the catechol-O-methyltransferase (COMT) Val158Met polymorphism and the dopamine beta hydroxylase (DBH) C1021T polymorphism. Furthermore, plasma uric acid was associated significantly with the COMT Val158Met polymorphism. Our study suggests the possible involvement of genetic polymorphisms in COMT and DBH in the regulation of blood pressure and plasma uric acid. PMID- 20931245 TI - Comparative EEG mapping studies in Huntington's disease patients and controls. AB - Huntington's disease (HD) is a devastating neurodegenerative disorder with prominent motor and cognitive decline. Previous studies with small sample sizes and methodological limitations have described abnormal electroencephalograms (EEG) in this cohort. The aim of the present study was to investigate objectively and quantitatively the neurophysiological basis of the disease in HD patients as compared to normal controls, utilizing EEG mapping. In 55 HD patients and 55 healthy controls, a 3-min vigilance-controlled EEG (V-EEG) was recorded during midmorning hours. Evaluation of 36 EEG variables was carried out by spectral analysis and visualized by EEG mapping techniques. To elucidate drug interference, the analysis was performed for the total group, unmedicated patients only and between treated and untreated patients. Statistical overall analysis by the omnibus significance test demonstrated significant (p < 0.01 and p < 0.05) EEG differences between HD patients and controls. Subsequent univariate analysis revealed a general decrease in total power and absolute alpha and beta power, an increase in delta/theta power, and a slowing of the centroids of delta/theta, beta and total power. The slowing of the EEG in HD reflects a disturbed brain function in the sense of a vigilance decrement, electrophysiologically characterized by inhibited cortical areas (increased delta/theta power) and a lack of normal routine and excitatory activity (decreased alpha and beta power). The results are similar to those found in other dementing disorders. Medication did not affect the overall interpretation of the quantitative EEG analysis, but certain differences might be due to drug interaction, predominantly with antipsychotics. Spearman rank correlations revealed significant correlations between EEG mapping and cognitive and motor impairment in HD patients. PMID- 20931246 TI - Expression of heat shock protein (HSP 72 kDa) during acute methamphetamine intoxication depends on brain hyperthermia: neurotoxicity or neuroprotection? AB - In the present study, light and electron microscopy were used to examine heat shock protein (HSP 72 kD) expression during acute methamphetamine (METH) intoxication in rats and evaluate its relationships with brain temperature and alterations in a number of other histochemical and morphological parameters. Freely moving rats received METH at the same dose (9 mg/kg, sc) but at different ambient temperatures (23 and 29 degrees C), showing a wide range of brain temperature elevations (37.6-42.5 degrees C); brains were taken for histochemical and morphological evaluations at peak of brain temperature increase. We found that acute METH intoxication induces massive and wide-spread HSP expression in neural and glial cells examined in detail in the cortex, hippocampus, thalamus, and hypothalamus. In each of these structures, the number of HSP-positive cells tightly correlated with brain temperature elevation. The changes in HSP immunoreactivity were also tightly related to alterations in permeability of the blood-brain barrier, acute glial activation, and brain edema assessed by albumin and GFAP immunoreactivity and measuring tissue water content, respectively. While robust and generalized HSP production normally appears to be the part of an adaptive brain response associated with METH-induced metabolic activation, activation of this protective mechanism has its natural limits and could not counteract the damaging effects of oxidative stress, high temperature, and edema- the leading factors of METH-induced neurotoxicity. PMID- 20931249 TI - Molecular identification of human enteroviruses in children with neurological infections from the central region of Argentina. AB - In the central area of Argentina, epidemiological and molecular characteristics of human enterovirus infections are still unknown. RT-nested PCR of the highly conserved 5'NCR was used to detect enteroviruses in 168 samples of cerebrospinal fluid from hospitalized patients with suspected infection of the central nervous system (2007-2008), and 13 (7.7%) were positive. Molecular typing was performed by sequencing of the 3'-half VP1 region. Echovirus 30 was the predominant type detected, followed by coxsackie viruses A9 and B4. All echovirus 30 strains of 2007 clustered in lineage H, whereas the echovirus 30 isolate obtained in 2008 was more distantly related, possibly representing a new lineage. PMID- 20931248 TI - Proanthocyanidin-rich fraction from Croton celtidifolius Baill confers neuroprotection in the intranasal 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine rat model of Parkinson's disease. AB - We have recently demonstrated that rodents treated intranasally with 1-methyl-4 phenyl-1,2,3,6-tetrahydropyridine (MPTP) suffered impairments in olfactory, cognitive and motor functions associated with time-dependent disruption of dopaminergic neurotransmission in different brain structures conceivably analogous to those observed during different stages of Parkinson's disease (PD). On the other hand, the proanthocyanidin-rich fraction (PRF) obtained from the bark of Croton celtidifolius Baill (Euphorbiaceae), a tree frequently found in the Atlantic forest in south Brazil, has been described to have several neurobiological activities including antioxidant and anti-inflammatory properties, which may be of interest in the treatment of PD. The present data indicated that the pretreatment with PRF (10 mg/kg, i.p.) during five consecutive days was able to prevent mitochondrial complex-I inhibition in the striatum and olfactory bulb, as well as a decrease of the enzyme tyrosine hydroxylase expression in the olfactory bulb and substantia nigra of rats infused with a single intranasal administration of MPTP (1 mg/nostril). Moreover, pretreatment with PRF was found to attenuate the short-term social memory deficits, depressive like behavior and reduction of locomotor activity observed at different periods after intranasal MPTP administration in rats. Altogether, the present findings provide strong evidence that PRF from C. celtidifolius may represent a promising therapeutic tool in PD, thus being able to prevent both motor and non-motor early symptoms of PD, together with its neuroprotective potential. PMID- 20931250 TI - Identification of a novel astrovirus in a domestic pig in Hungary. AB - The family Astroviridae consists of two genera, Avastrovirus and Mamastrovirus, whose members are associated with gastroenteritis in avian and mammalian hosts, respectively. We serendipitously identified a novel porcine astrovirus in a fecal specimen from a domestic pig (Sus scrofa domestica) in Hungary. Sequencing of a fragment indicated that it was an ORF1b/ORF2/3'UTR sequence, and it has been submitted to the database as porcine astrovirus type 2 (PAstV-2/Hungary/2007) with accession number GU562296. Its unique sequence characteristics and its phylogenetic position suggest that PAstV-2 could be an important link between previously reported astroviruses and that a genetically divergent lineage of astroviruses exist in piglets. PMID- 20931247 TI - Transgenic animal models of neurodegeneration based on human genetic studies. AB - The identification of genes linked to neurodegenerative diseases such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD) and Parkinson's disease (PD) has led to the development of animal models for studying mechanism and evaluating potential therapies. None of the transgenic models developed based on disease-associated genes have been able to fully recapitulate the behavioral and pathological features of the corresponding disease. However, there has been enormous progress made in identifying potential therapeutic targets and understanding some of the common mechanisms of neurodegeneration. In this review, we will discuss transgenic animal models for AD, ALS, HD and PD that are based on human genetic studies. All of the diseases discussed have active or complete clinical trials for experimental treatments that benefited from transgenic models of the disease. PMID- 20931251 TI - Phylogenetic analysis of pandemic 2009 influenza A virus circulating in the South American region: genetic relationships and vaccine strain match. AB - The first influenza pandemic of this century was declared in April of 2009, with the emergence of a novel H1N1 influenza A virus strain (H1N1pdm). Understanding the evolution of H1N1pdm strains within the South American region is essential for studying global diversification, emergence and resistance, as well as determining vaccine efficacy. In order to gain insight into these matters, phylogenetic analysis was performed using 29 hemagglutinin (HA) gene sequences from H1N1pdm strains isolated in South America. The results of these studies revealed that clade 7 was the dominant H1N1pdm lineage in South America. None of the strains isolated in South America clustered together with the 2010 H1 vaccine strain. Amino acid substitutions P100S, S220T and I338V were found in almost all HAs of South American H1N1pdm strains. PMID- 20931252 TI - A 13-year clinical evaluation of two three-step etch-and-rinse adhesives in non carious class-V lesions. AB - This 13-year randomized clinical trial compared the clinical effectiveness of two three-step etch-and-rinse adhesives in combination with a hybrid, stiffer composite versus a micro-filled, more flexible composite. The influence of composite stiffness on the clinical performance of one of the adhesives was assessed as well. One hundred and forty-two non-carious cervical lesions were restored with composites with contrasting stiffness. Seventy-one patients randomly received two cervical restorations placed following two out of three adhesive procedures: (1) the three-step etch-and-rinse adhesive Permaquick applied with the stiff micro-hybrid composite Amelogen Hybrid (PMQ-H, Ultradent), (2) Permaquick applied with the more flexible micro-filled Amelogen Microfill (PMQ-M, Ultradent), or (3) the "gold-standard" three-step etch-and-rinse adhesive Optibond FL applied with the micro-hybrid composite Prodigy (OFL-P, Kerr). The restorations were evaluated after 6 months, 1, 2, 3, 5, 7, and 13 years of clinical service regarding their retention, marginal integrity and discoloration, caries occurrence, preservation of tooth vitality, and post-operative sensitivity. Retention loss, severe marginal defects, and/or discoloration that needed intervention (repair or replacement) and the occurrence of caries were considered as clinical failures. The recall rate at 13 years was 77%. Bond degradation after 13 years was mainly characterized by a further increase in the presence of small but clinically acceptable marginal defects and superficial marginal discoloration. Twelve percent of the OFL-P restorations were clinically unacceptable. In the PMQ group, 22% of the PMQ-M restorations and 26% of the PMQ H restorations needed repair or replacement. Regarding the clinical failure rate, Optibond FL scored significantly better than Permaquick (McNemar; p = 0.015). No statistically significant differences were found between the micro-filled and the hybrid composite for each of the parameters evaluated (McNemar, p > 0.05). After 13 years of clinical functioning, the clinical effectiveness of the three adhesive/composite combinations remained highly acceptable. PMID- 20931253 TI - Emotional symptoms from kindergarten to middle childhood: associations with self- and other-oriented social skills. AB - The study investigated the interactive impact of different dimensions of social skills on children's emotional symptoms. We differentiate between self-oriented social skills which focus on considering own goals and needs in social interactions (assertiveness, social participation) and other-oriented social skills which focus on considering other's goals and needs (pro-social and cooperative behavior). 167 children participated in the study at the ages of 5, 6, and 9 years. A multi-informant approach (parents, teacher, and child) was employed to assess children's psychopathology. Teachers rated children's social skills. The study demonstrated the importance of deficits in self-oriented social skills for the development of emotional symptoms. Low levels of assertiveness predicted later emotional symptoms. In children with low levels of pro-social behavior, high assertiveness protected from emotional problems. In contrast, high levels of pro-social behavior emerged as a risk factor for later emotional symptoms, especially when is goes along with low levels of social participation. PMID- 20931254 TI - Microbial diversity of supra- and subgingival biofilms on freshly colonized titanium implant abutments in the human mouth. AB - Supra- and subgingival biofilm formation is considered to be mainly responsible for early implant failure caused by inflammations of periimplant tissues. Nevertheless, little is known about the complex microbial diversity and interindividual similarities around dental implants. An atraumatic assessment was made of the diversity of microbial communities around titanium implants by single strand conformation polymorphism (SSCP) analysis of the 16S rRNA gene amplicons as well as subsequent sequence analysis. Samples of adherent supra- and subgingival periimplant biofilms were collected from ten patients. Additionally, samples of sulcusfluid were taken at titanium implant abutments and remaining teeth. The bacteria in the samples were characterized by SSCP and sequence analysis. A high diversity of bacteria varying between patients and within one patient at different locations was found. Bacteria characteristic for sulcusfluid and supra- and subgingival biofilm communities were identified. Sulcusfluid of the abutments showed higher abundance of Streptococcus species than from residual teeth. Prevotella and Rothia species frequently reported from the oral cavity were not detected at the abutments suggesting a role as late colonizers. Different niches in the human mouth are characterized by specific groups of bacteria. Implant abutments are a very valuable approach to study dental biofilm development in vivo. PMID- 20931255 TI - The effectiveness of local anesthetics in preventing postoperative adhesions in rat models. AB - BACKGROUND: Intra-abdominal adhesions are fibrous bands that develop after abdominal surgery or inflammation and cause significant surgical morbidity and mortality. In this study, the effectiveness of lidocaine, prilocaine and bupivacaine in preventing experimental intra-abdominal adhesions in rats was studied. METHODS: After obtaining the approval of our local institutional review board, 50 female Wistar-Albino rats weighing 250-320 g underwent laparotomy via a standard 5-cm midline incision under intramuscular anesthesia with ketamine (40 mg/kg) and xylazine (10 mg/kg). The cecal serosa and adjacent abdominal wall were superficially injured using sterile gauze. The laparotomy incision was closed after irrigation of the peritoneal cavity with the following: 5 ml saline in Group II, (the sham group), 7 mg/kg prilocaine in Group III, 3 mg/kg lidocaine in Group IV or 2 mg/kg bupivacaine in Group V. No irrigation was performed in Group I rats (the control group). After laparotomy closure, all rats were allowed to wake spontaneously. Two weeks after the initial experimental procedure, all rats underwent a second laparotomy, and adhesions were scored using the Linsky scale. RESULTS: The adhesion quantity and quality were comparable among all groups (P > 0.05); however, adhesion severity scores were significantly lower in the prilocaine and bupivacaine groups vs. the other groups (P < 0.05). CONCLUSIONS: Prilocaine and bupivacaine were found to decrease the severity of intra peritoneal adhesions. PMID- 20931256 TI - Characteristics and disease severity of healthcare-associated pneumonia among patients in a hospital in Kitakyushu, Japan. AB - Healthcare-associated pneumonia (HCAP) is a newly identified condition, and epidemiologic studies in Japan are still limited. We retrospectively observed patients with HCAP and community-acquired pneumonia (CAP) who were hospitalized between December 2004 and March 2005, and compared their disease characteristics. A total of 34 patients (14 with HCAP and 20 with CAP) were evaluated. Of the patients with HCAP, seven (50%) were hospitalized for at least 2 days in the preceding 90 days and five (35.7%) resided in a nursing home or extended care facility. Compared with patients with CAP, patients with HCAP were older, had more complications, including central nerve diseases, had greater disease severity, but lower serum albumin level. More methicillin-resistant Staphylococcus aureus, Pseudomonas spp., and anaerobes were isolated from patients with HCAP than from those with CAP. Conversely, more Streptococcus pneumoniae was detected and more penicillin was used in patients with CAP. This study provides additional evidence that HCAP should be distinguished from CAP and suggests the pathogenesis and therapeutic strategy for HCAP may be similar to those for hospital-acquired pneumonia. PMID- 20931257 TI - Erratum to: NCL-CD30 staining of epithelial cells in the basal germinative layer of the epidermis and epithelial buds during foetal skin development. PMID- 20931258 TI - Surgical wound infection, tuboovarian abscess, and sepsis caused by Edwardsiella tarda: case reports and literature review. AB - Edwardsiella tarda is a freshwater pathogen that may cause mild to invasive infections with high mortality in humans. We describe two patients with serious E. tarda infections. The first patient was a woman with a tuboovarian abscess (TOA) and bilateral salpingitis requiring surgical resection and drainage. Her hospital course was complicated by a postoperative wound infection. TOA fluid as well as surgical wound culture revealed pure growth of E. tarda resistant to several antibiotics. The second patient was a man with a bloodstream E. tarda infection and cholangitis who recently traveled to Ecuador. He presented with hypoxia and further workup revealed choledocholithiasis and common bile duct benign polyps. Both patients made a full recovery. PMID- 20931259 TI - Mediastinitis as a complication of central venous catheterization. PMID- 20931260 TI - Current approaches to exploit actinomycetes as a source of novel natural products. AB - For decades, microbial natural products have been one of the major sources of novel drugs for pharmaceutical companies, and today all evidence suggests that novel molecules with potential therapeutic applications are still waiting to be discovered from these natural sources, especially from actinomycetes. Any appropriate exploitation of the chemical diversity of these microbial sources relies on proper understanding of their biological diversity and other related key factors that maximize the possibility of successful identification of novel molecules. Without doubt, the discovery of platensimycin has shown that microbial natural products can continue to deliver novel scaffolds if appropriate tools are put in place to reveal them in a cost-effective manner. Whereas today innovative technologies involving exploitation of uncultivated environmental diversity, together with chemical biology and in silico approaches, are seeing rapid development in natural products research, maximization of the chances of exploiting chemical diversity from microbial collections is still essential for novel drug discovery. This work provides an overview of the integrated approaches developed at the former Basic Research Center of Merck Sharp and Dohme in Spain to exploit the diversity and biosynthetic potential of actinomycetes, and includes some examples of those that were successfully applied to the discovery of novel antibiotics. PMID- 20931261 TI - Improving the Clostridium acetobutylicum butanol fermentation by engineering the strain for co-production of riboflavin. AB - Solvent-producing clostridia are well known for their capacity to use a wide variety of renewable biomass and agricultural waste materials for biobutanol production. To investigate the possibility of co-production of a high value chemical during biobutanol production, the Clostridium acetobutylicum riboflavin operon ribGBAH was over-expressed in C. acetobutylicum on Escherichia coli Clostridium shuttle vector pJIR750. Constructs that either maintained the original C. acetobutylicum translational start codon or modified the start codons of ribG and ribB from TTG to ATG were designed. Riboflavin was successfully produced in both E. coli and C. acetobutylicum using these plasmids, and riboflavin could accumulate up to 27 mg/l in Clostridium culture. Furthermore, the C. acetobutylicum purine pathway was modified by over-expression of the Clostridium purF gene, which encodes the enzyme PRPP amidotransferase. The function of the plasmid pJaF bearing C. acetobutylicum purF was verified by its ability to complement an E. coli purF mutation. However, co-production of riboflavin with biobutanol by use of the purF over-expression plasmid was not improved under the experimental conditions examined. Further rational mutation of the purF gene was conducted by replacement of amino acid codons D302 V and K325Q to make it similar to the feedback-resistant enzymes of other species. However, the co-expression of ribGBAH and purFC in C. acetobutylicum also did not improve riboflavin production. By buffering the culture pH, C. acetobutylicum ATCC 824(pJpGN) could accumulate more than 70 mg/l riboflavin while producing 190 mM butanol in static cultures. Riboflavin production was shown to exert no effect on solvent production at these levels. PMID- 20931262 TI - Adding a combination of hydroxycitrate and lipoic acid (METABLOCTM) to chemotherapy improves effectiveness against tumor development: experimental results and case report. AB - Altered metabolism of cancer first highlighted by Otto Warburg has a long history. Although ignored for a considerable amount of time, it is now receiving substantial attention. We recently published results obtained with a combination of two drugs, lipoic acid and hydroxycitrate, targeting metabolic enzymes particularly affected in cancer: ATP citrate lyase and pyruvate dehydrogenase kinase. This treatment was as efficient as chemotherapy in the three mouse cancer models that were tested. In this work, we asked if our drug combination could be used in conjunction with standard cytotoxic chemotherapy, in particular cisplatin, to improve basic protocol efficacy. A combination of lipoic acid and hydroxycitrate was administered to mice implanted with syngeneic cancer cells, LL/2 lung carcinoma and MBT-2 bladder carcinoma, concommitantly with classical chemotherapy (cisplatin or methotrexate). We demonstrate that the triple combination lipoic acid + hydroxycitrate + cisplatin or methotrexate is more efficient than cisplatin or methotrexate used individually or the combination of lipoic acid and hydroxycitrate administered alone. Of particular note are the results obtained in the treatment of an 80 year-old female who presented with ductal adenocarcinoma of the pancreas accompanied by liver metastases. A treatment course using gemcitabine plus alpha-lipoic acid and hydroxycitrate gave highly promising results. The in vivo data, coupled with the case study results, suggest a possible advantage in using a treatment targeted at cancer metabolism in association with classical chemotherapy. PMID- 20931263 TI - Cytomegalovirus retinitis after low-dose intravitreous triamcinolone acetonide in an immunocompetent patient: a warning for the widespread use of intravitreous corticosteroids. AB - We report the case of an immunocompetent 78-year-old woman who developed cytomegalovirus (CMV) retinitis after a single intravitreous injection of triamcinolone acetonide (IVTA). Review of medical records. The patient with macular edema secondary to branch retinal vein occlusion developed peripheral retinitis with hemorrhagic and inflammatory vascular sheathing 3 months after IVTA. A presumptive diagnosis of viral retinitis was confirmed by polymerase chain reaction (PCR) of the aqueous humor tap. The PCR test was positive for CMV DNA. The patient slowly responded to intravenous ganciclovir and oral valganciclovir. After therapeutic vitrectomy for intercurrent vitreous hemorrhage, and while still under treatment, the retinitis resolved completely with final visual acuity of 20/25. CMV retinitis can occur after local immunosuppression with IVTA in an immunocompetent patient with no other systemic risk factors. PMID- 20931264 TI - Automated protein resonance assignments of magic angle spinning solid-state NMR spectra of beta1 immunoglobulin binding domain of protein G (GB1). AB - Magic-angle spinning solid-state NMR (MAS SSNMR) represents a fast developing experimental technique with great potential to provide structural and dynamics information for proteins not amenable to other methods. However, few automated analysis tools are currently available for MAS SSNMR. We present a methodology for automating protein resonance assignments of MAS SSNMR spectral data and its application to experimental peak lists of the beta1 immunoglobulin binding domain of protein G (GB1) derived from a uniformly 13C- and 15N-labeled sample. This application to the 56 amino acid GB1 produced an overall 84.1% assignment of the N, CO, CA, and CB resonances with no errors using peak lists from NCACX 3D, CANcoCA 3D, and CANCOCX 4D experiments. This proof of concept demonstrates the tractability of this problem. PMID- 20931265 TI - Cell cycle arrest in cultured neuroblastoma cells exposed to a bis(thiosemicarbazonato) metal complex. AB - Brain tumors such as neuroblastomas and gliomas are often refractory to current treatments. Development of metal-based drugs may offer an alternative approach due to the ability to deliver radionuclides or cytotoxic metals to the tumor. Previous studies have shown that diacetyl-bis(N(4)-methylthiosemicarbazonato) copper(II) (Cu(II)(atsm)) can selectively target hypoxic tumors and this feature has been utilized for development of imaging and radiotherapy. However, we have recently shown that glyoxal-bis(N(4)-methylthiosemicarbazonato)-copper(II) (Cu(II)(gtsm)) can target the brain in animal models of neurodegeneration. Unlike Cu(II)(atsm), Cu(II)(gtsm) is able to release Cu intracellularly under normoxic conditions. Glyoxal-bis(thiosemicarbazones) have reported anticancer effects but little is known about the cellular mechanisms involved. Therefore, in this study, we used protein microarray analysis to investigate the effect of Cu(II)(gtsm) on neuroblastoma cell growth in vitro. Treatment of the human neuroblastoma cell line BE(2)-M17, resulted in cell cycle arrest as assessed by fluorescent activated cell sorting (FACS) analysis. Rapidly arrested growth was not associated with onset of apoptosis. Instead, protein microarray analysis revealed that Cu(II)(gtsm) rapidly and potently reduced cyclin D1 expression, while increasing Kip2 expression. Other changes observed were decreased Cdk7 expression and activation of CHK2. These changes may be associated with the cell cycle arrest. We also observed a potent decrease of total and phosphorylated insulin like growth factor receptor (IGF-IR) by Cu(II)(gtsm) which is associated with modulation of cyclin D1 expression. Our studies reveal important insights into the potential anticancer activity of Cu(II)(gtsm). Further studies are needed to examine the therapeutic potential of Cu(II)(gtsm) and other bis(thiosemicarbazonato) metal complexes as metallo-drugs for treatment of systemic or brain tumors. PMID- 20931266 TI - Delivery of an angiogenic gene into ischemic muscle by novel bubble liposomes followed by ultrasound exposure. AB - PURPOSE: To develop a safe and efficient gene delivery system into skeletal muscle using the combination of Bubble liposomes (BL) and ultrasound (US) exposure, and to assess the feasibility and the effectiveness of BL for angiogenic gene delivery in clinical use. METHODS: A solution of luciferase expressing plasmid DNA (pDNA) and BL was injected into the tibialis (TA) muscle, and US was immediately applied to the injection site. The transfection efficiency was estimated by a luciferase assay. The ischemic hindlimb was also treated with BL and US-mediated intramuscular gene transfer of bFGF-expressing plasmid DNA. Capillary vessels were assessed using immunostaining. The blood flow was determined using a laser Doppler blood flow meter. RESULTS: Highly efficient gene transfer could be achieved in the muscle transfected with BLs, and US mediated the gene transfer. Capillary vessels were enhanced in the treatment groups with this gene transfer method. The blood flow in the treated groups with this gene transfer method quickly recovered compared to other treatment groups (non treated, bFGF alone, or bFGF+US). CONCLUSION: The gene transfer system into skeletal muscle using the combination of BL and US exposure could be an effective means for angiogenic gene therapy in limb ischemia. PMID- 20931267 TI - Tissue distribution and expression of paraoxonases and chemokines in mouse: the ubiquitous and joint localisation suggest a systemic and coordinated role. AB - A vicious cycle between oxidation and inflammation leads to complications in a growing number of disease states. Knowledge on tissue distribution of chemokines, mediators of inflammatory response, and paraoxonases, with antioxidant and anti inflammatory actions, may be relevant. Using immunohistochemistry and quantitative real-time PCR we have investigated the distribution of PON1, 2 and 3, CCL2, 7, 8 and 12 and the chemokine receptor CCR2 protein and mRNA in 23 tissues from C57BL/6J mice. As expected, PON1, 2 and 3, CCL2, 7, 8 and 12 and CCR2 proteins were present in the vast majority of tissues investigated. Surprisingly, mRNA for these proteins was also expressed in most of these tissues suggesting local production and the ability to respond in situ to inflammatory stimuli. The wide distribution and expression of mRNA for paraoxonases and CC chemokines suggest a systemic, probably coordinated, role in the overall inflammatory response. PMID- 20931268 TI - Synthesis, characterization, DNA binding properties, fluorescence studies and toxic activity of cobalt(III) and ruthenium(II) polypyridyl complexes. AB - The new ligand 4-(isopropylbenzaldehyde)imidazo[4,5-f ][1,10]phenanthroline (ippip) and its complexes [Ru(phen)(2)(ippip)](2+)(1),[Co(phen)(2)(ippip)](3+)(2),[Ru(bpy)(2)(ippip)](2+)(3 ,[Co(bpy)(2)(ippip)](3+)(4)(bpy=2,2-bipyridine) and (phen=1,10-phenanthroline) were synthesized and characterized by ES(+)-MS, (1)H and (13)C NMR. The DNA binding properties of the four complexes were investigated by different spectrophotometric methods and viscosity measurements. The results suggest that complexes bind to calf thymus DNA (CT-DNA) through intercalation. When irradiated at 365 nm, the complexes promote the photocleavage of pBR322 DNA, and complex 1 cleaves DNA more effectively than 2, 3, 4 complexes under comparable experimental conditions. Furthermore, photocleavage studies reveal that singlet oxygen ((1)O(2)) plays a significant role in the photocleavage. PMID- 20931269 TI - Gd3+ sensitized enhanced green luminescence in Gd:Tb(Sal)3Phen complex in PVA. AB - Ternary and tertiary complexes of Tb(Sal)(3)Phen and Gd:Tb(Sal)(3)Phen were synthesized and characterized in PVA polymer. The structural properties of these systems were evaluated on the basis of NMR and FT-IR techniques. The absorption, excitation and emissive properties of the Tb(3+) ion were improved when coordinated with Sal and Phen ligands. Photoluminescence properties of the complexes in solution, crystals and dispersed in PVA film were explored in steady state and in time domain. Selective excitations (487, 355, 310 and 266 nm) of Tb(3+), Sal and Gd(3+) ions reveal an intramolecular energy transfer process. The emission of Gd:Tb(Sal)(3)Phen complex in PVA indicates the contribution of Gd(3+) ion to enhance the emission intensity of Tb(3+) ion. On the basis of these investigations, photophysics was widely discussed in terms of energy transfer and encapsulation effect. PMID- 20931270 TI - Divergent models of diabetes among American Indian elders. AB - The purpose of this study was to examine belief systems about diabetes in American Indian elders, and the effects of culture on care-seeking, adherence, and diabetes self-care. Health belief theory predicts that care-seeking and medical adherence are a function of culturally mediated beliefs that result in behaviors that effect health status. In order to elicit cultural meanings of diabetes, in-depth interviews were conducted with an intensity sample of 30 American Indian diabetic elders (55+). Two models of diabetes were identified, divergent in terms of 1) health behaviors, and 2) cultural identification. One model was characterized by delayed care-seeking, and a non-valuing of adherence to diabetes self-care. Non-adherence to medical recommendations was perceived as being socially desirable, because adherence placed the elder outside their peer group. The second model was characterized by early care-seeking and improved adherence to diabetes self-care. These divergent models of diabetes, in which care-seeking, diabetes self-care, and adherence vary as a function of cultural immersion, has implications for health education and disease management and may contribute substantially to health disparities. PMID- 20931271 TI - Hypersexual disorder: just more muddled thinking. PMID- 20931272 TI - Successful tocilizumab treatment in a patient with adult-onset Still's disease complicated by chronic active hepatitis B and amyloid A amyloidosis. AB - We report successful tocilizumab (TCZ) use in a patient with adult-onset Still's disease (AOSD) complicated by chronic hepatitis B (CHB) and AA amyloidosis (AAA). Treatments with corticosteroid and various types of immunosuppressants were unsuccessful. Aggravation of CHB ensued, and entecavir was started. Normalisation of liver function and hepatitis B virus (HBV) DNA were confirmed. TCZ was then started. His arthritis and AAA improved dramatically. TCZ is an excellent treatment for refractory AOSD and is feasible in an HBV-infected patient. PMID- 20931273 TI - A patient with intravascular lymphoma presenting with cerebral infarction and a high serum MPO-ANCA level. AB - A 74-year-old woman presented with multiple brain infarctions, an inflammatory reaction, and a high serum titer (414 U/ml) of myeloperoxidase-specific antineutrophil cytoplasmic antibody (MPO-ANCA) with no hematological abnormalities. After the inflammation and ANCA titers were resolved with steroid therapy for suspected microscopic polyangiitis, hemophagocytic syndrome developed. Biopsies revealed non-Hodgkin's intravascular lymphoma (IVL). The flare of IVL with negative serum ANCA suggested that the initial high serum MPO ANCA had not originated from tumor cells. PMID- 20931274 TI - Cytogenetic abnormalities in 1162 couples with recurrent miscarriages in southern region of India: report and review. AB - PURPOSE: The purpose of the present study was to investigate the contribution of chromosomal anomalies and the frequency of a particular type of aberration in couples with recurrent miscarriages. METHODS: A total of 1,162 couples with recurrent miscarriages were analyzed using G-banding and Fluorescence in situ hybridization where ever necessary. RESULTS: Chromosomal anomalies were detected in 78 cases. This study describes majority of the cases with balanced reciprocal translocations. Among the abnormal karyotypes we also report for the first time three unique translocations involving (3;14), (18;22) and (X;22) chromosomes which were confirmed by molecular cytogenetic methods. CONCLUSIONS: The review of literature and the overall incidence of the abnormalities suggest that chromosomal analysis in couples with recurrent miscarriages should be taken up by all the practioners at all levels. This not only helps to check the cytological abnormalities but also helps to correlate the recurrent abnormalities in a given population. Thus establishing and correlating the environmental and genetic condition of that particular phenotype and genotype. PMID- 20931275 TI - The role of maternal and child ADHD symptoms in shaping interpersonal relationships. AB - The current study investigated the influence of maternal ADHD symptoms on: (a) mothers' own social functioning; (b) their child's social functioning; and (c) parent-child interactions following a lab-based playgroup involving children and their peers. Participants were 103 biological mothers of children ages 6-10. Approximately half of the children had ADHD, and the remainder were comparison youth. After statistical control of children's ADHD diagnostic status and mothers' educational attainment, mothers' own inattentive ADHD symptoms predicted poorer self-reported social skills. Children with ADHD were reported to have more social problems by parents and teachers, as well as received fewer positive sociometric nominations from playgroup peers relative to children without ADHD. After control of child ADHD status, higher maternal inattention and hyperactivity/impulsivity each predicted children having more parent-reported social problems; maternal inattention predicted children receiving more negative sociometric nominations from playgroup peers. There were interactions between maternal ADHD symptoms and children's ADHD diagnostic status in predicting some child behaviors and parent-child relationship measures. Specifically, maternal inattention was associated with decreased prosocial behavior for children without ADHD, but did not influence the prosocial behavior of children with ADHD. Maternal inattention was associated with mothers' decreased corrective feedback and, at a trend level, decreased irritability toward their children with ADHD, but there was no relationship between maternal inattention and maternal behaviors for children without ADHD. A similar pattern was observed for maternal hyperactivity/impulsivity and mothers' observed irritability towards their children. Treatment implications of findings are discussed. PMID- 20931276 TI - Ductal carcinoma in situ: trends in treatment over time in the US. AB - To describe therapy and changes in therapy over time for women diagnosed with ductal carcinoma in situ (DCIS) and treated in the community setting. Women aged 20 or older diagnosed with DCIS in this study were sampled from the population based Surveillance, Epidemiology and End Results Program. A total of 770, 1055, 480, and 404 women with DCIS were selected in 1991, 1995, 2000, or 2005, respectively. Most women do not have nodal sampling, but between 2000 and 2005 there was an increase in the use of sentinel node biopsy, 9 and 22%, respectively. Of the DCIS patients, 80% had no or unknown HER-2 assays, 12% were postitive, 7% negative, and 1% equivocal. After adjusting for tumor size, age, race, marital status, and insurance there has been a decrease in mastectomy since 1991. Of women with DCIS 36% were given tamoxifen in 2000; in 2005 this decreased to about 21%. However, in 2005 we see the use of aromatase inhibitors in nearly 4% of patients. HER-2 testing is increasingly performed for women with DCIS. Despite positive HER-2 tests no women received trastuzumab as of 2005. Despite the lack of clinical trials evidence, aromatase inhibitors are being prescribed for women with DCIS. PMID- 20931277 TI - Invasive ductal breast cancer associated polymyositis causing respiratory failure. AB - Polymyositis (PM) is a very rare paraneoplastic syndrome in association with breast cancer, here we present a breast cancer patient with a sudden onset of respiratory failure caused by PM. A 47-year-old woman, with a history of a lump in her right breast for 3 months, weakness and anorexia for about 1 month, suddenly presented with respiratory failure and elevated muscle enzymes. Muscle biopsy revealed myositis and breast biopsy was consistent with invasive ductal breast cancer. Decreases of muscle enzyme levels were observed after corticosteroid therapy and the lumpectomy, but the patient died from respiratory failure. A case of respiratory failure caused by breast cancer associated polymyositis was presented. This case server to remind that breast cancer patients with muscle weakness or muscle enzyme elevation may be involved with PM. PMID- 20931278 TI - QSAR study of C allosteric binding site of HCV NS5B polymerase inhibitors by support vector machine. AB - Multiple linear regressions (MLR) and support vector machine (SVM) were used to develop quantitative structure-activity relationship (QSAR) models of novel Hepatitis C virus (HCV) NS5B polymerase inhibitors. Various kinds of molecular descriptors were calculated to represent the molecular structures of compounds, such as chemical, topological, geometrical, and quantum descriptors. Principal component analysis (PCA) was used to select the training set. A variable selection method utilizing a genetic algorithm (GA) was employed to select from the large pool of calculated descriptors, an optimal subset of descriptors which have significant contribution to the overall inhibitory activity. The models were validated using Leave-One-Out (LOO) and Leave-Group-Out (LGO) crossvalidation, and Y-randomization test. Results demonstrated the SVM model offers powerful prediction capabilities. PMID- 20931279 TI - Ultrasonic assisted Fischer glycosylation: generating diversity for glycochemistry. AB - In this study ultrasound has been utilised for the Fischer glycosylation using free sugars and sulphuric acid immobilized on silica as catalyst. N-acetyl-D glucosamine, N-acetyl-D-galactosamine, D-glucose, D-galactose, D-mannose, L fucose, and lactose were glycosylated with propargyl alcohol or 2-azidoethanol affording the corresponding glycosides, with the production of the alpha glycopyranoside as the dominant product. Remarkable acceleration of the glycosylation reactions (15 min-2 h compared to several hours) over reported procedures together with good yields were always observed. PMID- 20931280 TI - First computational chemistry multi-target model for anti-Alzheimer, anti parasitic, anti-fungi, and anti-bacterial activity of GSK-3 inhibitors in vitro, in vivo, and in different cellular lines. AB - In the work described here, we developed the first multi-target quantitative structure-activity relationship (QSAR) model able to predict the results of 42 different experimental tests for GSK-3 inhibitors with heterogeneous structural patterns. GSK-3beta inhibitors are interesting candidates for developing anti Alzheimer compounds. GSK-3beta are also of interest as anti-parasitic compounds active against Plasmodium falciparum, Trypanosoma brucei, and Leishmania donovani; the causative agents for Malaria, African Trypanosomiasis and Leishmaniosis. The MARCH-INSIDE technique was used to quickly calculate total and local polarizability, n-octanol/water partition coefficients, refractivity, van der Waals area and electronegativity values to 4,508 active/non-active compounds as well as the average values of these indexes for active compounds in 42 different biological assays. Both the individual molecular descriptors and the average values for each test were used as input for a linear discriminant analysis (LDA). We discovered a classification function which used in training series correctly classifies 873 out of 1,218 GSK-3 cases of inhibitors (97.4%) and 2,140 out of 2,163 cases of non-active compounds (86.1%) in the 42 different tests. In addition, the model correctly classifies 285 out of 406 GSK-3 inhibitors (96.3%) and 710 out of 721 cases of non-active compounds (85.4%) in external validation series. The result is important because, for the first time, we can use a single equation to predict the results of heterogeneous series of organic compounds in 42 different experimental tests instead of developing, validating, and using 42 different QSAR models. Lastly, a double ordinate Cartesian plot of cross-validated residuals (first ordinate), standard residuals (second ordinate), and leverages (abscissa) defined the domain of applicability of the model as a squared area within +/- 2 band for residuals and a leverage threshold of h = 0.0044. PMID- 20931281 TI - Gitelman syndrome due to p.A204T mutation in CLCNKB gene. AB - A 45-year-old woman presented with phenotypical features suggestive of Gitelman syndrome (adult age at diagnosis, normal-low blood pressure, hypokalaemia, metabolic alkalosis, hypomagnesaemia, and hypocalciuria). Mutational analysis revealed no significant abnormality in SLC12A3 gene, but homozygous p.A204T mutation was found in the CLCNKB gene. This is a founder effect mutation described in Spanish patients with classic and atypical Bartter syndrome. This report confirms previous descriptions and expands the clinical spectrum of this mutation. PMID- 20931282 TI - The long-term outcomes and unmet needs of a cohort of former long-stay patients in Melbourne, Australia. AB - Former long-stay patients with psychotic disorders have significant unmet needs. This study assessed the long-term outcomes for the original cohort of 18 residents of the Footbridge Community Care Unit (CCU), a residential psychiatric rehabilitation unit at St Vincent's Mental Health Melbourne. A review of case records and interviews were conducted for each member of the cohort 8 years after admission to the CCU. Members of the cohort were living in a variety of settings after discharge from the CCU. Despite significant gains during the period of residential rehabilitation in the CCU after hospital discharge, by the time of follow-up individuals were in general leading restricted lives characterised by a lack of stable residential and social supports. Most reported positively on the support provided in the CCU although later experiences of moving repeatedly from one setting to another were adverse. Five key unmet needs were identified: promotion of independence; stability in accommodation; stability in social networks; consistency of care; and addressing the theme of loss. A longitudinal perspective in management that focuses on stability in residential care is required for long-stay patients. PMID- 20931283 TI - Subclinical intestinal inflammation in siblings of children with Crohn's disease. AB - BACKGROUND: Intestinal permeability and altered inflammatory responses, along with genetic and environmental factors, likely contribute to the pathogenesis of Crohn's disease. AIMS: This study aimed to assess the presence and prevalence of subclinical intestinal inflammation among apparently healthy, first-degree relatives of pediatric patients with Crohn's disease, using non-invasive fecal markers. METHODS: Stool samples were collected from 13 patients with Crohn's disease, 36 siblings and 41 parents. S100A12 levels were measured using an in house ELISA assay and calprotectin levels were determined using the PhiCal test, with levels compared to normal healthy population controls. RESULTS: Fecal S100A12 levels in siblings (median, 14 mg/kg; 95% confidence interval [CI], 9-32 mg/kg) and patients (71 mg/kg; CI 4-286 mg/kg) differed significantly from pediatric controls (1 mg/kg; CI 1-5 mg/kg; p < 0.001). In contrast, fecal calprotectin levels in siblings (22 mg/kg; CI 15-31 mg/kg) were lower than that of pediatric controls (31 mg/kg; CI 19-52 mg/kg; p = 0.03). Fecal markers were not elevated in parents compared to adult controls. CONCLUSIONS: This study provides further evidence of subclinical intestinal inflammation amongst first degree relatives of patients with Crohn's disease. The presence of sub-clinical gut inflammation may be a risk factor for the subsequent development of Crohn's disease. PMID- 20931284 TI - Altered gut flora are associated with septic complications and death in critically ill patients with systemic inflammatory response syndrome. AB - BACKGROUND: Gut under severe insult is considered to have an important role in promoting infection and multiple organ dysfunction syndrome from the viewpoint of altered intestinal epithelium, immune system and commensal bacteria. There are few reports, however, about the relationship between gut flora and septic complications. METHODS: We analyzed gut flora in patients with systemic inflammatory response syndrome (SIRS) and evaluated key bacteria and their cutoff values for infectious complications and mortality by using classification and regression trees (CART). Eighty-one SIRS patients with a serum C-reactive protein level higher than 10 mg/dL treated in the intensive care unit (ICU) for more than 2 days were included for the study. We quantitatively evaluated nine types of bacteria in fecal samples by plate or tube technique. Two hundred seventy-one samples were analyzed using CART and logistic regression. RESULTS: The dominant factors for complication of enteritis were the minimum number of total obligate anaerobes and the maximum number of Staphylococcus and Enterococcus. The dominant factors for complication of bacteremia were the minimum numbers of total obligate anaerobes and total facultative anaerobes. The dominant factors for mortality were the numbers of total obligate anaerobes and total facultative anaerobes and age. CONCLUSIONS: A decrease in total obligate anaerobes and an increase in pathogenic bacteria in the gut are associated with septic complications and mortality in patients with SIRS. The altered gut flora may be a potential prognostic marker in SIRS patients. PMID- 20931285 TI - Prevalence and impact of hepatic steatosis on the response to antiviral therapy in Saudi patients with genotypes 1 and 4 chronic hepatitis C. AB - BACKGROUND: Hepatic steatosis in hepatitis C virus (HCV)-infected patients has been shown to enhance the progression of liver fibrosis and decrease the response to antiviral therapy. AIMS: We aimed to determine the role of HCV genotype 4 (HCV G4) in the prevalence of hepatic steatosis, its impact on antiviral therapy, and its associations and predictive factors in comparison to HCV-G1-infected patients. METHODS: Treatment-naive HCV patients who were started on pegylated interferon a-2b plus ribavirin therapy in two centers in Saudi Arabia were included. The severity of steatosis was assessed using the METAVIR and NAS (non alcoholic fatty liver disease [NAFLD] activity score) scoring systems. Sustained virological response (SVR) was studied in relation to the degree of steatosis. Associations between steatosis and multiple demographic, laboratory, and virological factors were examined. HCV-G1 and HCV-G4 patients were compared. RESULTS: A total of 116 patients (HCV-G4 85 [73.3%]; HCV-G1 31 [26.7%]) were included. The mean age was 50.4+/-10.7 years and 56.9% were males. In terms of steatosis grading using the NAS scoring system, 50% had steatosis grade 0, 26.7% grade 1, 14.7% grade 2, and 8.6% grade 3, while the overall staging of steatosis revealed that 43.1% had mild steatosis, 42.2% moderate, and 14.7% severe. Gamma glutamyl transpeptidase (GGT), platelet count, body mass index (BMI), cholesterol level, presence of hyperlipidemia, liver histology stage, and grade were significantly correlated with hepatic steatosis in one or more of the statistical analyses. Twenty-two out of 55 patients (40.0%) had an SVR in the mild steatosis group, compared to 52.7% in the moderate group and 7.3% in the severe group (P=0.03). The HCV genotype did not correlate with steatosis or SVR. CONCLUSION: Our study confirms the high prevalence of steatosis in HCV-G4 and HCV-G1 patients, but with no difference in the grade or score of steatosis between the two genotypes. The grade of steatosis correlates with GGT, platelet count, and BMI, while the NAS score of steatosis correlates with response to antiviral therapy. PMID- 20931286 TI - Problematic situations associated with dating experiences and relationships among urban African American adolescents: a qualitative study. AB - This qualitative study focused on the identification of problem situations associated with adolescent dating experiences and relationships, including those that placed youth at risk for dating violence perpetration or victimization. Interviews were conducted with 44 African American middle and high school students in an urban school system. Qualitative analysis identified 18 individual themes representing six categories of problem situations: (a) approach and initiation; (b) conflict, conflict resolution, and break-ups; (c) communication, connection, and emotion; (d) aggression and victimization; (e) the role of others; and (f) media and technology. Identification of these problem situation themes has important implications for developing and evaluating prevention efforts designed to foster healthy adolescent dating relationships. PMID- 20931287 TI - Relationship of myocardial mechanics and regional volume change in patients with left ventricular systolic dysfunction. AB - The contraction and rotation of left ventricular (LV) segments in a synchronous fashion is vital for cardiac pump function. However, no data exist regarding the relationship of LV segmental mechanics and regional volume change in patients with LV systolic dysfunction. Thirty-two patients with EF < 50% and fifty-two normal subjects were enrolled. The radius strain and rotation were assessed in six segments at three short axis views using speckle tracking imaging. The mean and standard deviation (SD) of the strain peak time index (SPTI%) and the rotation peak time index (RPTI%) for each view were calculated as representing myocardial segmental synchrony. The mean and the SD of the 4-D mini-volume time index (VMTI, %) from 16 regions were calculated as representing regional volume change using real-time three-dimensional echocardiography (RT-3DE). The SD for each time index was averaged as the systolic dyssynchrony index (SDI) in both groups. The differences of the SPTI and the RPTI to the VMTI (T(sv) and T(rv)) were calculated as dyssynchrony between myocardial segmental mechanics and regional volume change. The time interval of the RPTI between apical and basal rotation (T(abrot)) was also calculated. The relationship of T(sv), T(rv) and T(abrot) to LV ejection fraction (EF) was then analyzed. In patients with LV systolic dysfunction, both peak strain and peak rotation occurred later than the regional minimum volume (55.3 +/- 11.1% vs. 45.9 + 5.5%; 50.4 +/- 8.7% vs. 45.9 +/- 5.5% (both P < 0.05) as compared with normal subjects (41.1 +/- 6.6% vs. 40.3 +/- 3.8%; 44.1 +/- 7.5% vs. 40.3 +/- 3.8%). The SDI in each time index is also significantly wider than in normal subjects (P < 0.001). In addition, there was a negative correlation between T(sv), T(rv) and T(abrot) with EF, respectively (P < 0.05). In patients with abnormal LV systolic function the rotation occurs significantly later than regional volume change as compared with normal subjects. There is a negative correlation between this time delay and LVEF. Thus, the relationship of myocardial segmental change and regional volume change could provide insight into intraventricular dyssynchrony in patients with LV systolic dysfunction. PMID- 20931288 TI - Impact of CT attenuation correction on the viability pattern assessed by 99mTc tetrofosmin SPECT/ 18F-FDG PET. AB - SPECT myocardial perfusion imaging (MPI) is commonly used for comprehensive interpretation of metabolic PET FDG imaging in ischemic dysfunctional myocardium. We evaluated the difference in scan interpretation introduced by CT attenuation correction (CTAC) of SPECT MPI in patients undergoing viability characterization by (99m)Tc SPECT MPI/PET FDG. In 46 consecutive patients (mean age 64, range 36 83 years) with dysfunctional myocardium, we analyzed viability from combined SPECT MPI and PET FDG scanning without attenuation correction (NC) and with CTAC for SPECT MPI. FDG uptake was classified in groups of percent uptake using the segment with maximum tracer in SPECT perfusion uptake as reference. Viability patterns were categorized as normal, mismatch, mild match and scar by relative comparison of SPECT and PET. Applying CTAC introduced a different reference segment for the normalization of PET FDG study in 57% of cases. As a result, the flow-metabolism pattern changed in 28% of segments, yielding a normal, mismatch, mild match and scar pattern in 462, 150, 123, and 47 segments with NC and 553, 86, 108, and 35 with CTAC, respectively (P = 0.001). Thus, by introducing CTAC for SPECT MPI 25% of segments originally classified as scar were reclassified and the number of normal segments increased by 20%. Introducing CTAC decreased by 54% the number of patients with possible indication for revascularization, from 26/46 to 12/46 (P < 0.001). Different interpretation of myocardial viability can be observed when using CTAC instead of NC SPECT MPI as reference for PET FDG scans. PMID- 20931289 TI - ASCI 2010 contrast media guideline for cardiac imaging: a report of the Asian Society of Cardiovascular Imaging cardiac computed tomography and cardiac magnetic resonance imaging guideline working group. AB - The use of contrast media for cardiac imaging becomes increasing as the widespread of cardiac CT and cardiac MR. A radiologist needs to carefully consider the indication and the injection protocol of contrast media to be used as well as the possibility of adverse effect. There are several guidelines for contrast media in western countries. However, these are focusing the adverse effect of contrast media. The Asian Society of Cardiovascular Imaging, the only society dedicated to cardiovascular imaging in Asia, formed a Working Group and created a guideline, which summarizes the integrated knowledge of contrast media for cardiac imaging. In cardiac imaging, coronary artery evaluation is feasible by non-contrast MR angiography, which can be an alternative examination in high risk patients for the use of iodine contrast media. Furthermore, the body habitus of Asian patients is usually smaller than that of their western counterparts. This necessitates modifications in the injection protocol and in the formula for calculation of estimated glomerular filtration rate. This guideline provided fundamental information for the use of contrast media for Asian patients in cardiac imaging. PMID- 20931290 TI - HLA genes in Amerindian immigrants to Madrid (Spain): epidemiology and a virtual transplantation waiting list: Amerindians in Madrid (Spain). AB - Amerindians immigrated to Madrid (Spain) region are about 10% of the present day population. Amerindians are believed to be the first American inhabitants, before Na-Dene speakers, Aleuts and Eskimo. They may initially have arrived to America from Siberia and also from other parts of Pacific Sea (South Asia, Polynesia and Australia). Nowadays, they populate America from Canada to Tierra del Fuego (South America tip South). Most Amerindian immigrants to Madrid have come from Andean Countries in the last 10 years (mainly Ecuador, Bolivia, Peru and Colombia). They show an HLA profile with "quasi-specific alleles", which makes them different to the rest of the World. In the present work, we have aimed to determine the immigrants HLA profile in order to establish a virtual transplantation waiting list which may be useful for their therapeutic transplants, particularly bone marrow transplantation. This would be carried out together with Amerindian immigrants to other parts of Spain and with their own countries in order to build up transplantation programs. Specific epidemiology programs on HLA linked disease will also be established. Immigrant volunteer unrelated blood donors contributed to the present study. HLA typing was performed by standard methods and their HLA profile obtained and obtained and compared with 15,108 HLA chromosomes from the rest of the World, including Spaniards. The immigrants showed a typical Amerindian profile similar to isolated Amerindian ethnic groups and altogether different to other World inhabitants (including Spaniards). These are the first bases to set up transplantation and epidemiology studies in collaboration with their original population in America. Finally, the HLA profile found in these Amerindians does not indicate their American specific original area, as it is expected from previous studies, i.e.: they do not relate more with Andean than with other Amerindians in Neighbour Joining dendrograms or correspondence analyses. PMID- 20931291 TI - A natural process of cirrhosis resolution and deceleration of liver regeneration after thioacetamide withdrawal in a rat model. AB - Characteristics of thioacetamide (TAA)-induced liver cirrhosis in rat was observed for 120 days after TAA withdrawal as part of the radiobiological study of partial liver irradiation on TAA-induced cirrhotic rats. The natural process focused on cirrhosis and regeneration was recorded as a baseline condition for the interpretation of the outcome of the partial liver irradiation study. Cirrhosis in rats was successfully induced by drinking 0.03% TAA water orally for 29 weeks with a modeling rate of 96%. After establishment of the cirrhosis model, the rats were observed for 120 days upon TAA withdrawal to investigate the dynamic changes of cirrhosis and regeneration. The following characteristics were observed: (1) Histological changes; (2) Liver functions; (3) Cirrhosis: trichrome stain, quantification of hydroxyproline in hydrolysed liver tissue and TGF-beta1; (4) Liver regeneration: liver index, hepatocyte mitotic index (MI), hepatocyte proliferation index (PI) by flow cytometry, PCNA labeling index (LI) by IHC and expression of PCNA mRNA; and (5) Growth factors: serum HGF, VEGF, TGF-alpha, and IL-6. After TAA withdrawal, gradual improvement in liver functions was noted with decreases of ALT, AST, and ALP, and increase of PA. The resolution of cirrhosis was evident by histological improvement with attenuation of collagen fiber and decrease of TGF-beta1 IHC index, and also decrease of trichrome stain and hydroxyproline content. However, cirrhosis was still existed on 120 days after TAA withdrawal. Significant deceleration of liver regeneration was demonstrated with TAA withdrawal, evidenced by decrease of MI and PI, reduced expression of PCNA mRNA and PCNA LI. In conclusion, upon TAA withdrawal hepatic cirrhosis was continuously resolved, but persisted up to 120 days, and liver regeneration was significantly decelerated. PMID- 20931292 TI - Congenital hyperinsulinism due to mutations in HNF4A and HADH. AB - Mutations in the HADH and HNF4A genes are rare causes of diazoxide responsive congenital hyperinsulinism (CHI). This chapter details the phenotype known to be associated with mutations in these genes. Additionally, the authors give a brief overview of the role of these genes in glucose physiology and the possible mechanisms of CHI in patients with mutations in these genes. PMID- 20931293 TI - On the inference of large phylogenies with long branches: how long is too long? AB - The accurate reconstruction of phylogenies from short molecular sequences is an important problem in computational biology. Recent work has highlighted deep connections between sequence-length requirements for high-probability phylogeny reconstruction and the related problem of the estimation of ancestral sequences. In Daskalakis et al. (in Probab. Theory Relat. Fields 2010), building on the work of Mossel (Trans. Am. Math. Soc. 356(6):2379-2404, 2004), a tight sequence-length requirement was obtained for the simple CFN model of substitution, that is, the case of a two-state symmetric rate matrix Q. In particular the required sequence length for high-probability reconstruction was shown to undergo a sharp transition (from O(log n) to poly(n), where n is the number of leaves) at the "critical" branch length g (ML)(Q) (if it exists) of the ancestral reconstruction problem defined roughly as follows: below g (ML)(Q) the sequence at the root can be accurately estimated from sequences at the leaves on deep trees, whereas above g (ML)(Q) information decays exponentially quickly down the tree.Here, we consider a more general evolutionary model, the GTR model, where the q*q rate matrix Q is reversible with q>=2. For this model, recent results of Roch (Preprint, 2009) show that the tree can be accurately reconstructed with sequences of length O(log (n)) when the branch lengths are below g (Lin)(Q), known as the Kesten-Stigum (KS) bound, up to which ancestral sequences can be accurately estimated using simple linear estimators. Although for the CFN model g (ML)(Q)=g (Lin)(Q) (in other words, linear ancestral estimators are in some sense best possible), it is known that for the more general GTR models one has g (ML)(Q)>=g (Lin)(Q) with a strict inequality in many cases. Here, we show that this phenomenon also holds for phylogenetic reconstruction by exhibiting a family of symmetric models Q and a phylogenetic reconstruction algorithm which recovers the tree from O(log n)-length sequences for some branch lengths in the range (g (Lin)(Q),g (ML)(Q)). Second, we prove that phylogenetic reconstruction under GTR models requires a polynomial sequence-length for branch lengths above g (ML)(Q). PMID- 20931294 TI - Patient navigation to increase mammography screening among inner city women. AB - BACKGROUND: Lower mammography screening rates among minority and low income women contribute to increased morbidity and mortality from breast cancer. OBJECTIVE: To evaluate the effect of a patient navigation intervention on adherence rates to biennial screening mammography among women engaged in primary care at an inner city academic medical center. DESIGN: Quality improvement intervention with a concurrent control group, conducted from February to November of 2008. STUDY SUBJECTS: All women in a hospital-based primary care practice aged 51-70 years. Subjects were randomized at the level of their primary care provider, such that half of the patients in the practice received the intervention, while the other half received usual care. INTERVENTIONS: Intervention subjects whose last mammogram was >18 months prior received a combination of telephone calls and reminder letters from patient navigators trained to identify barriers to care. Navigators were integrated into primary care teams and interacted directly with patients, providers, and radiology to coordinate care. Navigators utilized an electronic report to track subjects. Adherence rates to biennial mammography were assessed in intervention and control groups at baseline and post-intervention. KEY RESULTS: A total of 3,895 women were randomized to intervention (n = 1,817) and control (n = 2,078) groups. Mean age was 60, 71% were racial/ethnic minorities, 23% were non-English speaking, and 63% had public or no health insurance. At baseline, there was no difference in mammography adherence between the control and intervention groups (78%, respectively, p = 0.55). After the 9 month intervention, mammogram adherence was higher in the intervention group compared with the control group (87% vs. 76%, respectively, p < 0.001). Except among Hispanic women who demonstrated high rates in both the intervention and control groups (85% and 83%, respectively), all racial/ethnic and insurance groups demonstrated higher adherence in the intervention group. CONCLUSIONS: Patient navigation improves biennial mammography rates for inner city, low income, minority populations. PMID- 20931295 TI - On the logic of restrictive recognition of peptide by the T-cell antigen receptor. AB - This essay provides an analysis of the inadequacy of the current view of restrictive recognition of peptide by the T-cell antigen receptor. A competing model is developed, and the experimental evidence for the prevailing model is reinterpreted in the new framework. The goal is to contrast the two models with respect to their consistency, coverage of the data, explanatory power, and predictability. PMID- 20931297 TI - Clozapine associated cardiomyopathy: a cluster of 3 cases. PMID- 20931296 TI - Inhibition of axonal transport caused by tert-butyl hydroperoxide in cultured mouse dorsal root ganglion neurons. AB - Reactive oxygen species (ROS) are capable of affecting neuronal cell function and structure. Here, we investigated the direct effects of hydrogen peroxide (H(2)O(2)), one of the ROS, on axonal transport in cultured mouse dorsal root ganglion neurons using video-enhanced microscopy. Treatment of neurons with the H(2)O(2) donor tert-butyl hydroperoxide (TBHP; 10 nM-1 mM) inhibited anterograde and retrograde movement of organelles in a time- and concentration-dependent manner. Mitochondria and lysosomes were clearly swollen by TBHP at 100 MUM and 1 mM in association with complete and irreversible cessation of axonal transport. In contrast, cytoskeletal structures were apparently unchanged even at the highest TBHP concentration (1 mM). Lipid peroxides, detected by swallow-tailed perylene derivative fluorescence, were produced by TBHP in plasma membranes and more highly in organelle membranes. The TBHP-induced inhibition of axonal transport, lipid peroxide production, and organelle swelling were blocked by pretreatment with alpha-tocopherol (vitamin E, 1 mM). These results suggest that H(2)O(2) inhibited axonal transport via lipid peroxidation along with degenerative changes in organelles. PMID- 20931298 TI - Bleeding ileal varices: a rare cause of chronic anemia in liver cirrhosis. PMID- 20931299 TI - A double-blind, placebo-controlled, randomized phase III trial of chemotherapy plus epigenetic therapy with hydralazine valproate for advanced cervical cancer. Preliminary results. AB - The reversing of epigenetic aberrations using the inhibitors of DNA methylation and histone deacetylases may have therapeutic value in cervical cancer. This is a randomized phase III, placebo-controlled study of hydralazine and valproate (HV) added to cisplatin topotecan in advanced cervical cancer. Patients received hydralazine at 182 mg for rapid, or 83 mg for slow acetylators, and valproate at 30 mg/kg, beginning a week before chemotherapy and continued until disease progression. Response, toxicity, and PFS were evaluated, and 36 patients (17 CT + HV and 19 CT + PLA) were included. The median number of cycles was 6. There were four PRs to CT + HV and one in CT + PLA. Stable disease in five (29%) and six (32%) patients, respectively, whereas eight (47%) and 12 (63%) showed progression (P = 0.27). At a median follow-up time of 7 months (1-22), the median PFS is 6 months for CT + PLA and 10 months for CT + HV (P = 0.0384, two tailed). Although preliminary, this study represents the first randomized clinical trial to demonstrate a significant advantage in progression-free survival for epigenetic therapy over one of the current standard combination chemotherapy in cervical cancer. Molecular correlates with response and survival from this trial are pending to analyze. PMID- 20931300 TI - Prognostic factors and outcome of resected patients with gastrointestinal stromal tumors of small intestine. AB - We document the clinical behavior of gastrointestinal stromal tumors (GISTs) of the small intestine and identify predictors for long-term disease-free survival (DFS) for small intestine GIST patients. From December 2001 to 2008, 114 consecutive patients with mesenchymal tumors involving the small intestine were enrolled. There were 54 male and 60 female (50.6%) patients. After a median follow-up period of 36 months (ranging from 12 to 96 months), recurrence was noted in 19 patients (16.7%) with a median time of 20 months (ranging from 7 to 50 months). There were 12 patients (10.5%) who died of GISTs with a median time from recurrence to death of 14 months (ranging from 8 to 22 months). Univariate analysis by log-rank test indicated that tumor size and mitotic activity were statistically significant for DFS (P = 0.001 and 0.036, respectively). Tumor size was the only significant predictive factor for DFS according to multivariate analysis (P = 0.006). Small tumor size, indicating low risk, predicted more favorable DFS of small intestine GIST patients who underwent curative resection. PMID- 20931301 TI - Pandemic H1N1 2009 in neonates. PMID- 20931302 TI - Isolated ventricular septal rupture caused by non-penetrating trauma to the chest. AB - Cardiac injury following blunt trauma is an important cause of morbidity and mortality and is often unsuspected. Isolated chamber rupture and valvular injury are infrequent but recognized consequences of non-penetrating trauma. The diagnosis is generally based on clinical and ECG findings and is further confirmed on echocardiography. This report describes imaging findings of isolated ventricular septal rupture as seen on MDCT. PMID- 20931303 TI - Hemophagocytic syndrome in a child with brucellosis. AB - The authors report case of a two and half years old female child presented with fever for one month with hepatosplenomegaly. Though the child had been symptomatic for a prolonged period, she did not appear very unwell at presentation. However, after admission there was sudden rapid deterioration of her clinical status. Investigations revealed hemophagocytosis with brucella infection. PMID- 20931304 TI - 1H, 15N chemical shift assignments of the imino groups in the base pairs of Escherichia coli tRNA(Leu) (CAG). AB - tRNA molecules are the adaptors in ribosome-based protein biosynthesis and are stabilized by Mg(2+). However, the detailed mechanism for the Mg(2+) mediated stability is not fully understood. To study the effects of Mg(2+) on conformational flexibility of Escherichia coli tRNA(Leu) (CAG) at millisecond timescale, we applied NMR spectroscopic approach to measure proton exchange rates of imino groups in the presence of different concentration of Mg(2+) and correlated them with the corresponding aminoacylation activity of tRNA(Leu). Here, we report the first part of the above mentioned study, the (1)H, (15)N chemical shift assignments of the imino groups in all base pairs of Escherichia coli tRNA(Leu) (CAG) based on 2D (1)H-(15)N TROSY, 2D NOESY and 3D NOESY-HMQC experiments. This work laid the foundation for the NMR study of tRNA(Leu) (BMRB deposits with accession number 17078). PMID- 20931305 TI - The potential of FDG-PET/CT for detecting prostate cancer in patients with an elevated serum PSA level. AB - PURPOSE: The aim of this study is to evaluate the potential and limitation of FDG PET/CT for detecting prostate cancer in subjects with an elevated serum prostate specific antigen (PSA) level. Although [18F]-2-fluoro-2-deoxyglucose positron emission tomography (FDG-PET) has limited value in detecting prostate cancer, the potential of PET/CT has not been precisely evaluated, since positron emission tomography/computed tomography (PET/CT) provides accurate localization of functional findings obtained by PET. METHODS: Subjects with an increasing PSA level suggestive of prostate cancer were enrolled in this study. FDG-PET/CT was performed prior to prostate biopsy and the findings were compared with the pathological results. RESULTS: Fifty subjects with an elevated serum PSA level took part in this study. The sensitivity, specificity and positive predictive value (PPV) of FDG-PET/CT in the prostate were 51.9% (27/52 areas), 75.7% (112/148 areas) and 42.9% (27/63 areas), respectively; those in the peripheral zone were 73.3% (22/30 areas), 64.3% (45/70 areas) and 46.8% (22/47 areas), respectively; and those in the central gland were 22.7% (5/22 areas), 85.9% (67/78 areas) and 31.3% (5/16 areas), respectively. The estimated cut-off values according to the highest odds ratio (OR) were age of 70 years [OR: 7.00, 95% confidence interval (CI): 1.89-25.93] and a PSA value of 12.0 ng/ml (OR: 10.77, 95% CI: 2.78-41.74). The FDG-PET/CT could potentially detect cancer with 80.0% sensitivity and 87.0% PPV in cases with a Gleason score of 7 or greater. CONCLUSION: FDG-PET/CT was appropriate for detecting peripheral zone prostate cancer in patients at more than an intermediate risk. PMID- 20931306 TI - Predictors of abnormal heart rate response to dipyridamole in patients undergoing myocardial perfusion SPECT. AB - OBJECTIVE: To identify predictors of abnormal HR response to dipyridamole (DIP) in patients undergoing myocardial perfusion SPECT (MPS). BACKGROUND: Patients with a reduced heart rate (HR) response to DIP have higher cardiac mortality, but the mechanism is unknown. METHODS: We studied 432 patients who underwent dual isotope gated MPS. DIP (0.56 mg/kg) was infused over 4 min, and Tc-99m tetrofosmin was injected 3 min after the end of the infusion. MPS was semiquantitatively interpreted. Left ventricular ejection fraction (LVEF) and volumes were automatically calculated. The population was categorized into quartiles according to HR ratio, and characteristics in each quartile were compared. Logistic regression analysis was performed to identify predictors of abnormal HR response, using the lowest quartile as the independent variable. RESULTS: Patients with abnormal HR response were more frequently without chest pain, with a history of chronic renal failure and taking digoxin. Baseline HR was higher and had fewer symptoms during stress. The stress and rest perfusion defects were greater, but reversibility was not; in addition, LVEF was lower. Multivariable logistic regression analysis demonstrated that the independent predictors of abnormal HR response were baseline HR and low LVEF. CONCLUSIONS: LV dysfunction is an independent predictor of abnormal HR response to DIP, and the association between low LVEF and low HR ratio may explain the link between abnormal HR ratio and increased mortality. PMID- 20931307 TI - Enteric micro-particles for targeted oral drug delivery. AB - This work is focused on production of enteric-coated micro-particles for oral administration, using a water-in-oil-in-water solvent evaporation technique. The active agent theophylline was first encapsulated in cellulose acetate phthalate (CAP), a pH-sensitive well-known polymer, which is insoluble in acid media but dissolves at neutral pH (above pH 6). In this first step, CAP was chosen with the aim optimizing the preparation and characterization methods. The desired release pattern has been obtained (low release at low pH, higher release at neutral pH) but in presence of a low encapsulation efficiency. Then, the CAP was replaced by a novel-synthesized pH-sensitive poly(methyl methacrylate-acrylic acid) copolymer, poly(MMA-AA). In this second step, the role of two process parameters was investigated, i.e., the percentage of emulsion stabilizer (polyvinyl alcohol, PVA) and the stirring power for the double emulsion on the encapsulation efficiency. The encapsulation efficiency was found to increase with PVA percentage and to decrease with the stirring power. By increasing the PVA content and by decreasing the stirring power, a high stable double emulsion was obtained, and this explains the increase in encapsulation efficiency found. PMID- 20931308 TI - Revisions of extensive acetabular defects with impaction grafting and a cement cup. AB - BACKGROUND: Loosening of acetabular components often leads to bony defects. Management of extensive acetabular bone loss in hip revision arthroplasty can be a tremendous challenge. QUESTIONS/PURPOSES: We asked whether a reconstruction with impacted bone grafts will provide a durable and pain-free function in extensive acetabular defects. We specifically determined the (1) survival rates with the end point of revision for any reason, aseptic revision, and radiographic loosening; (2) visual analog scale (VAS) pain score, Harris hip score (HHS), and the Oxford Hip Questionnaire score (OHQS); (3) number of repeat revisions; (4) complications; and (5) radiographic loosening, wear, and radiolucencies. PATIENTS AND METHODS: We retrospectively followed 25 patients (27 hips) with extensive acetabular defects. No patient was lost to followup. Two patients died during followup. Minimum followup was 3 years (mean, 8.8 years; range, 3-14.1 years). RESULTS: Three patients (three hips) underwent repeat revision surgery and another two patients (two hips) had radiographically loose hips. The 10-year survival rate was 88% (95% confidence interval, 74.2%-100%) with the end point acetabular revision for any reason and 95% (95% confidence interval, 86.0%-100%) with the end point acetabular revision for aseptic loosening. The mean HHSs were 55 points before surgery and 72 points postoperatively. CONCLUSIONS: Acetabular reconstruction with impaction bone grafting and a cemented cup is a reliable technique with a 10-year survival rate of 88% in patients with extensive acetabular deficiencies. LEVEL OF EVIDENCE: Level IV, case series. See the Guidelines for Authors for a complete description of levels of evidence. PMID- 20931310 TI - Remote at-home detection and monitoring of functional chronotropic incompetence in heart failure patients. AB - Chronotropic incompetence (CI) is common in heart failure (HF) patients and is associated with worsening outcome. Detecting and tracking functional CI during activities of daily living could provide insight into its contribution to HF symptoms and facilitate effective HF patient management. HF patients (n = 180, NYHA Class III/IV, ejection fraction (EF) <=40%) were enrolled in a multi-center prospective monitoring study and had an external multi-sensor system applied to the chest and replaced weekly during a 90-day study. Medical information was collected at baseline and study close. Heart rate, respiration, activity, and body fluid data from the system were transmitted at regular intervals and used for offline analysis. Patients were primarily male (70%), with 61 +/- 13 years mean age, 25 +/- 5 kg/m(2) BMI, and 28 +/- 7% EF. By correlating age-adjusted activity level and heart rate adaptation with a proprietary algorithm, functional CI was detected in 45% and ruled out in 29% of patients under conditions of daily living. In the remaining patients (26%), functional CI assessment was indeterminate due to insufficient age-adjusted activity level. Functional CI and No-CI groups were not significantly different in terms of baseline demographics, characteristics or HF outcome over the study period. beta-blocker use was 16% in the CI group and 82% in the no-CI group (p < 0.001), and therefore, could not explain the manifestation of functional CI. This proof-of-concept study suggests that a chronotropic response that may be functionally debilitating during activities of daily living in HF patients can be detected and tracked in a point of-care telemonitoring approach using a non-invasive, adherent device. PMID- 20931309 TI - Exercise interventions for cancer survivors: a meta-analysis of quality of life outcomes. AB - BACKGROUND: Exercise improves quality of life (QOL) in cancer survivors, although characteristics of efficacious exercise interventions for this population have not been identified. PURPOSE: The present meta-analysis examines the efficacy of exercise interventions in improving QOL in cancer survivors, as well as features that may moderate such effects. METHOD: Studies were identified and coded, and QOL effect sizes were calculated and analyzed for trends. RESULTS: Overall, exercise interventions increased QOL, but this tendency depended to some extent on exercise and patient features. Although several features were associated with effect sizes, models revealed that interventions were particularly successful if they targeted more intense aerobic exercise and addressed women. These tendencies emerged over longer periods of time and were more prominent in studies with higher methodological quality. CONCLUSION: Appropriately designed exercise interventions enhance QOL for cancer survivors and this pattern is especially evident for women. Limitations are discussed. PMID- 20931311 TI - Review article: Renal support in critical illness. AB - PURPOSE: This review provides a focused and comprehensive update on established and emerging evidence in acute renal replacement therapy (RRT) for critically ill patients with acute kidney injury (AKI). PRINCIPAL FINDINGS: There have been considerable technological innovations in the methods and techniques for provision of extracorporeal RRT in critical illness. These have greatly expanded our capability to provide both renal and non-renal life-sustaining organ support for critically ill patients. Recent data suggest earlier initiation of RRT in AKI may confer an advantage for survival and renal recovery. Two large trials have recently shown no added benefit to augmented RRT dose delivery in AKI. Observational data have also suggested that fluid accumulation in critically ill patients with AKI is associated with worse clinical outcome. However, several fundamental clinical questions remain to be answered, including issues regarding the time to ideally initiate/discontinue RRT, the role of high-volume hemofiltration or other blood purification techniques in sepsis, and extracorporeal support for combined liver-kidney failure. Extracorporeal support with RRT in sepsis, rhabdomyolysis, and liver failure are discussed, along with strategies for drug dosing and management of RRT in sodium disorders. CONCLUSIONS: We anticipate that this field will continue to expand to promote research and innovation, hopefully for the benefit of sick critically ill patients. PMID- 20931312 TI - [Review article: Acute kidney injury in critical illness]. AB - PURPOSE: This review provides a focused and comprehensive update on emerging evidence related to acute kidney injury (AKI). PRINCIPAL FINDINGS: Acute kidney injury is a significant clinical problem that increasingly complicates the course of hospitalization and portends worse clinical outcome for sick hospitalized patients. The recent introduction of consensus criteria for the diagnosis of AKI (i.e., RIFLE/AKIN classification) have greatly improved our capacity not only to standardize the diagnosis and classification of severity of AKI, but also to facilitate conducting comparative epidemiologic studies in an effort to better understand the burden of adult and pediatric AKI and its syndromes (i.e., septic, cardio-renal, hepato-renal). The characterization of several novel AKI-specific biomarkers (i.e., neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, and interleukin-18) is extending our understanding of the pathophysiology of AKI. Moreover, these biomarkers appear to have clinical relevance for early detection and they provide prognostic value. These innovations are aiding in the design of epidemiologic surveys and randomized trials of therapeutic interventions. Strategies for prevention and conservative management of AKI across a range of clinical settings are discussed, including sepsis, hepato-renal syndrome, cardio-renal syndrome, rhabdomyolysis and in the perioperative setting. CONCLUSIONS: Acute kidney injury is an escalating clinical problem in hospitalized patients. Recent advances in AKI have improved knowledge of its pathogenesis, diagnosis, and prognosis; however, considerable research effort is needed. There are still relatively few interventions proven to alter the natural history of established AKI in hospitalized settings, and its development foretells less favourable outcomes. PMID- 20931313 TI - [Conjonctival human myiasis by Oestrus ovis in southern Tunisia]. AB - Conjunctival myiasis is the most frequent expression of ocular myiasis. It results from infestation of the conjunctiva by the larval form of flies. We report 11 cases of conjunctival myiasis to encourage ophthalmologists to be aware of the diagnosis of external ophthalmomyiasis, its complications, and its treatment. Most of the cases occurred amongst males during summer and autumn. Symptoms are related to the foreign body with a sudden evolution. We diagnosed this affection by direct observation of the larva on conjunctiva. The number of larvae ranged from 2 to 30. The larvae were identified as first-instars of Oestrus ovis. The treatment was performed by removal of the larvae which resulted in rapid improvement. In conclusion, early diagnosis and management are important in preventing complications of internal ophthalmomyiasis. PMID- 20931314 TI - [Editorial on the main topic posterior cruciate ligament]. PMID- 20931315 TI - [Refixation of tibial bony avulsions of the posterior cruciate ligament with a hook plate]. AB - OBJECTIVE: Posteromedial approach to the knee. Exact reduction and fixation of avulsed tibial attachment of posterior cruciate ligament with small-fragment plate. INDICATIONS: Avulsed tibial attachment of posterior cruciate ligament. CONTRAINDICATIONS: Ligamentous rupture of the posterior cruciate ligament. Local soft-tissue problems. SURGICAL TECHNIQUE: Posteromedial approach with mobilization and retraction of the medial gastrocnemius muscle. Subperiosteal detachment of the popliteal muscle. Identification of fracture site. Longitudinal incision of the posterior capsule of the knee. Debridement of the fracture site, reposition and stabilization with small-fragment plate. POSTOPERATIVE MANAGEMENT: Partial weight bearing with 15 kg for 6 weeks, limitation of knee flexion to 90 degrees for 6 weeks. A special joint orthesis is not necessary. The use of an EMT unit is recommended to prevent muscular atrophy. RESULTS: Six patients (four female, two male) with avulsed tibial attachment of posterior cruciate ligament were treated using the posteromedial approach. PMID- 20931316 TI - [Arthroscopic reconstruction of the anterolateral bundle of the posterior cruciate ligament in single-bundle technique with autologous hamstring grafts]. AB - OBJECTIVE: Restoration of the function of the posterior cruciate ligament (PCL). INDICATIONS: Chronic posterior instability with posterior tibial translation of >10 mm. CONTRAINDICATIONS: Fixed posterior drawer, local infections at the knee joint, local soft-tissue damage, poor compliance of the patient. SURGICAL TECHNIQUE: Surgery starts with arthroscopic examination of the knee joint and therapy of associated injuries (meniscus and cartilage injuries). Harvesting of the semitendinosus and gracilis tendons is performed via a 3 cm long skin incision 1 cm distally and medially of the tibial tuberosity. The tendons are folded to a four- or five-stranded graft with a minimum length of 10 cm. The femoral tunnel for the graft is drilled via a deep anterolateral portal under arthroscopic control. For drilling of the tibial tunnel, a posteromedial portal is needed. The tibial insertion of the PCL is debrided with a shaver and a specific raspatory. For tibial tunnel placement, a specific closed aimer is used and a Kirschner wire is placed in the center of the tibial insertion. This Kirschner wire is overdrilled using a cannulated drill with a diameter according to the graft size. After femoral fixation, the graft is tensioned in 90 degrees flexion with 80 N. At the femoral and tibial side, a hybrid fixation is performed with a button (flipp tack) and a resorbable interference screw. If there are any signs of posterolateral instability, a posterolateral corner reconstruction is performed before tensioning and fixation of the PCL graft. POSTOPERATIVE MANAGEMENT: For 6 weeks, the knee is immobilized in extension with a posterior tibial support (PTS) brace (Medi, Bayreuth, Germany). Passive range of motion exercises should be performed in prone position (first 2 weeks 0-0-30 degrees , 3rd to 4th week 0-0-60 degrees , 5th to 6th week 0-0-90 degrees ). After the first 6 weeks, a movable brace is needed at daytime. At nighttime, the patient has to wear the PTS brace. RESULTS: Between 2003 and 2006, a PCL reconstruction in singlebundle technique was performed in 58 patients. In 42 cases, a simultaneous reconstruction of the posterolateral corner was done. The Lysholm Score improved from 62.2 to 88.4 points, the Tegner Activity Score from 3.3 to 5.4 points. PMID- 20931317 TI - [Modified Larson technique for posterolateral corner reconstruction of the knee]. AB - OBJECTIVE: Posterolateral soft-tissue reconstruction to restore knee kinematics in isolated or combined posterolateral instabilities. INDICATIONS: Isolated or multiligament knee injuries with posterolateral insufficiency (popliteus tendon, lateral collateral ligament [LCL], popliteofibular ligament). CONTRAINDICATIONS: Arthrofibrosis. Severe varus deformity. Fixed posterior drawer. Doubts about compliance. SURGICAL TECHNIQUE: Graft harvest of semitendinosus tendon. In cases with multiligament reconstruction or associated posterior cruciate ligament (PCL) reconstruction contralateral graft harvest. Suture at 24 cm with baseball stitches using biodegradable material. Two-incision technique: one over the fibular head, one over the lateral epicondyle. Dissection along the biceps femoris to identify and free the peroneal nerve. Kirschner wire-guided creation of a 4.5-mm tunnel through the fibular head. Longitudinal incision of tensor fasciae latae and Kirschner wire drilling at the insertion of the LCL and the politeus tendon. Isometric testing. Overdrilling with an appropriately sized drill (6-7 mm, depth 40 mm). Graft passage through the fibular head and underneath biceps muscle and tensor fasciae latae into the femoral tunnel. Fixation with a biodegradable interference screw at 70 degrees knee flexion in slight internal rotation. POSTOPERATIVE MANAGEMENT: Defensive rehabilitation due to associated PCL reconstruction using a Posterior Tibial Support (PTS) brace for 6 weeks (day and night). PCL brace with limited range of motion for the next 6 weeks and PTS brace at night. Rehabilitation in a prone position. RESULTS: 42 patients (10/2003-10/2006) with posterolateral reconstruction according to Larson. All patients received combined PCL and posterolateral reconstruction. No intraoperative complications, one patient with hematoma in the popliteal fossa (conservative treatment), two patients with hematoma following contralateral graft harvest. At followup after 2.6 years, 40 patients were enrolled showing high improvement according to IKDC (International Knee Documentation Committee) and Lysholm Scores. PMID- 20931318 TI - [Double-bundle technique--anatomic reconstruction of the posterior cruciate ligament]. AB - OBJECTIVE: To improve the posterior translational stability of the knee joint by anatomic reconstruction of the posterior cruciate ligament in double-bundle technique. The functional bundles are reconstructed by native grafts from semitendinosus and gracilis muscles. The grafts are fixed with bioabsorbable screws in aperture technique. INDICATIONS: Symptomatic tears of the posterior cruciate ligament (classification by Harner) or chronic posterior or posterolateral instabilities; combined instabilities may need extended operative procedure. CONTRAINDICATIONS: Open growth plate. Fixed posterior drawer position. Nonjustifiable operative risks. Decline of the operation by the patient. Noncompliance. SURGICAL TECHNIQUE: Graft harvest of the semitendinosus and gracilis tendons via a 3-cm skin incision parallel to pes anserinus. Preparation, multilooping and arming of the tendons with sutures, arthroscopy, resection of the stump of the posterior cruciate ligament and clearing of its origin and insertion (using an additional posteromedial portal). Tunnel placement by means of aiming devices in the following order: femoral anterolateral, femoral posteromedial, and tibial (by accurate protection of the popliteal structures). Passing in the bundles, fixation in biomechanical functional positions in the following order: posteromedial bundle femoral (90 degrees flexion), tibial (extension 0 degrees ), and anterolateral bundle femoral (90 degrees flexion) with bioabsorbable interference screws. POSTOPERATIVE MANAGEMENT: 6 weeks PTS orthesis for 24 h/7 days with partial weight bearing (20 kg). Increased weight bearing from 7th postoperative week with PCL support orthesis during daytime and PTS orthesis during nighttime for further 6 weeks. Return to sports after 6 months at the earliest, no contact sports and competition for at least 9 months. RESULTS: First studies show positive results after reconstruction of the posterior cruciate ligament in double-bundle technique. A comparison with the single-bundle technique with a sufficient number of cases has not been published yet. PMID- 20931320 TI - Percutaneous Gigli saw osteotomy. AB - OBJECTIVE: To perform minimally invasive periosteum-preserving osteotomy using a Gigli saw. INDICATIONS: Lengthening and deformity correction of any long bone. CONTRAINDICATIONS: Local sepsis or very poor soft-tissue condition at the desired site of osteotomy. SURGICAL TECHNIQUE: The desired site is selected, and two 1-2 cm long longitudinal incisions opposite to each other are made. After subperiosteal dissection, two curved Kocher forceps are passed. The Gigli saw is held with one of them and then taken out from the opposite site with the help of the other forceps. Osteotomy is performed with back and forth reciprocal movements, taking care of the soft-tissue sleeve surrounding the osteotomy site. RESULTS: Since 1980, the authors have performed thousands of procedures using this technique without facing any serious problems. Therefore, it is recommended as a valid alternative to other osteotomy techniques. PMID- 20931319 TI - [Computer-assisted surgery-(CAS-)guided correction arthrodesis of the subtalar joint]. AB - OBJECTIVE: Restoration of a stable and plantigrade foot in deformities at the hindfoot and concomitant degenerative changes at the subtalar joint. INDICATIONS: Deformities at the hindfoot and concomitant degenerative changes at the subtalar joint. CONTRAINDICATIONS: Active local infection or relevant vascular insufficiency. SURGICAL TECHNIQUE: Prone position and posterolateral approach to the subtalar joint. Placement of dynamic reference bases in talus and calcaneus through stab incisions. Two-dimensional image acquisition for navigation. Definition of the axes of talus and calcaneus, and of the extent of correction. Exposure of the subtalar joint and removal of remaining cartilage. Computer- assisted surgery-(CAS-)guided correction and transfixation of the corrected position with two 2.5-mm Kirschner wires. Transplantation of autologous cancellous and cortical bone, if necessary. Three-dimensional (3-D) image acquisition for analysis of the accuracy of the correction and planning of the drillings for the screws. CAS-guided drilling and insertion of the screws. 3-D image acquisition for analysis of the accuracy of the correction implant position. Wound closure in layers. POSTOPERATIVE MANAGEMENT: 15 kg partial weight bearing in an orthosis (e.g. Vacuped TM, OPED Inc., Valley, Germany) for 6 weeks, followed by full weight bearing in a stable standard shoe. RESULTS: From September 1, 2006 to August 31, 2008, 26 correction arthrodeses were performed. The accuracy was assessed by intraoperative 3-D imaging. All achieved angles/translations were within a maximum deviation of 2 degrees /2 mm when compared to the planned correction. Complications that were associated with CAS were not observed. In all 25 cases that completed 2-year follow-up, timely fusion was registered. PMID- 20931321 TI - [Minimally invasive anterolateral approach for total hip replacement (OCM technique)]. AB - OBJECTIVE: Hip replacement with reduction of operative trauma. Thereby earlier mobilization and faster rehabilitation time compared with conventional techniques. No restrictions with regard to exposure of femur and acetabulum. INDICATIONS: Primary total hip arthroplasty. With experience also applicable in revisions. CONTRAINDICATIONS: None. SURGICAL TECHNIQUE: Patient in lateral position with fixed pelvis. Leg support for the leg being operated and modified leg support for the contralateral side on the operating table. Special retractors and instruments are advisable. Skin incision over the anterior portion of the greater trochanter slightly curved then over the muscular interval between gluteus medius and tensor fasciae latae. Fascia incision. Preparation of anterolateral muscular interval. Exposure and incision of capsule. Leg positioning for neck osteotomy in external rotation and hyperextension. For preparation of acetabulum leg again on support. Preparation of acetabulum and cup implantation. For femoral preparation leg in external rotation, hyperextension, and adduction. Capsular release nearby greater trochanter. Capsular release and stem implantation. Repositioning. Capsule and wound closure. POSTOPERATIVE MANAGEMENT: Early mobilization. Physical therapy and lymph drainage. Loading of the leg according to tolerance; if patient is pain-free, full weight bearing allowed. Thrombosis prophylaxis for at least 3 weeks postoperatively. RESULTS: Currently, the experience comprises over 3,500 patients operated on using the minimally invasive anterolateral approach since March 2003. Restrictions regarding indications are not known. In experienced hands, the technique can even be used for revision surgery. The clinical results show significant differences with improved clinical results as compared to patients after standard approaches, especially in terms of skin-to-skin time, blood loss, use of analgesics, rehabilitation time, and functional outcome. The accuracy of implant placement is not compromised. After a fundamental learning curve, there is no evidence of increased complications. PMID- 20931322 TI - [Cup & cone reamers for arthrodesis of the first metatarsophalangeal joint]. AB - THE PROBLEM: Individual optimized positioning of arthrodesis of the first metatarsophalangeal joint (fusion of MTP1 joint) as well as presumable shortage of the first ray using precalculated osteotomies often unpredictable. THE SOLUTION: Preparation of accurately fitting broad contact surfaces for MTP1 joint fusion with maximum flexibility of intraoperative decision-making for an optimized position. ADVANTAGES OF THE INSTRUMENTS: Semi-open or open systems of motor powered Cup & Cone reamers allow removal of remaining cartilage intended for MTP1 joint fusion with checkable shortage of the first ray, creation of exactly congruent concave-convex surfaces for an optimized position of MTP1 joint fusion. SURGICAL TECHNIQUE: Medial longitudinal incision for exposure of MTP1 joint. Removal of osteoarthrophytes, cartilage, and sclerotic bone from the first metatarsal head and the base of proximal phalanx, using a motorized Cup & Cone reamer set over axially directed guide wires to cancellous bone. Provisional positioning of the fragments in an optimized position. Clinical and fluoroscopic control. Definite internal fixation using a plantar lag screw and superelastic bone staples or a locking-plate system. PERSONAL EXPERIENCE: Allows the surgeon to prepare congruent and broad metatarsal and phalangeal cancellous bone surfaces for an optimized position of MTP1 joint fusion. Reamer-induced thermal damage and osteonecrosis were not encountered. PMID- 20931323 TI - [The pedicled groin flap for defect closure of the hand]. AB - OBJECTIVE: Soft-tissue defect closure of the volar and dorsal aspect of the hand and lower arm with a maximum defect size of 10 * 25 cm. INDICATIONS: Soft-tissue defects of the entire palm and dorsum of the hand and lower arm with a maximum defect size of 10 * 25 cm. CONTRAINDICATIONS: Polytraumatized patients presenting with concomitant life-threatening injuries. In these cases one should perform the definite defect closure secondary after cardiovascular stabilization. Scars and vascular injury at the donor site. Lack of vascularity and necrosis of implantation site. Poorly vascularized recipient site (e.g. after radiation) Infection and necrosis at the donor and/or recipient site. Prior operations of the groin with impairment of the vasculature. Noncompliant patient. SURGICAL TECHNIQUE: Landmarks are the femoral artery, inguinal ligament, anterior superior iliac spine, and sartorius muscle. The superior and inferior border of the flap should be orientated parallel to the inguinal ligament. The longitudinal axis of the flap is parallel to the superficial circumflex iliac artery, which is partially located superior to the inguinal ligament. One third of the flap is located superior, and two thirds inferior, to the inguinal ligament. Flap dissection starts at the lateral border without including the fascia. Identification of the lateral border of the sartorius muscle, incision of its fascia and inclusion of the fascia into flap dissection in order to preserve the vessel. If a long flap pedicle is favored, flap dissection is continued to the source of the superficial circumflex iliac artery. Primary closure of the donor site and, finally, inset of the flap. A tubed pedicle protects the vessels and simplifies the ischemic preconditioning during the postoperative phase. According to the flap size, the donor site closure is either primary or split-thickness skin grafting is necessary at the lateral aspect of the donor site. The mean duration of the procedure is 120 min in a teaching hospital (own data). POSTOPERATIVE MANAGEMENT: The patient should be mobilized as early as possible. Dressings and flap monitoring should be performed daily. Ischemic preconditioning by applying a tourniquet starts after 10-14 days. The ischemic period is increased continuously from 3 * 5 min/d in the beginning to 3 * 1 h/d before flap dissection. Flap dissection of the pedicle is performed after 3 weeks. The residual donor site is closed, while the distal pedicle is left untrimmed and closed secondarily a few days later to allow for sufficient venous drainage. Finally, defect closure can be completed after demarcation of the pedicle. RESULTS: In a 3-year period, defect closure with a pedicled groin flap was performed in 14 patients. Indications for this procedure were the following: thumb reconstruction for lengthening and defect closure after amputation and burn injury, soft-tissue reconstruction of the dorsum of the hand after decollement and infection, soft-tissue reconstruction of the distal part of the lower arm, wrist and palm after complex and combined trauma, and plastic reconstructive preservation of multiple fingers with subsequent phalangealization and syndactyly release, respectively. In all patients, complete soft-tissue coverage and flap survival could be achieved. The functional and aesthetic result was satisfactory in all cases. PMID- 20931325 TI - Childhood adversity and hallucinations: a community-based study using the National Comorbidity Survey Replication. AB - OBJECTIVE: Numerous studies of both clinical and large-scale population based samples have demonstrated that adverse childhood events are risk factors for subsequent psychosis. This study assessed the relationships between adverse childhood events and auditory and visual hallucinatory experiences. METHOD: The study analysed data from the National Comorbidity Survey Replication conducted in the US that assessed (all before age 16) rape, sexual assault and physical assault. Psychosis symptomatology was represented by lifetime experience of auditory and visual hallucinations. Control variables included gender, age, urbanity, ethnicity, marital status, education, employment status, alcohol dependence and drug dependence. RESULTS: All three adverse events were significantly related to both types of hallucinations. Those who had been raped as children were 3.3 times more likely to have experienced visual hallucinations and 3.5 times more likely to have experienced auditory hallucinations compared to those who had not been raped in childhood. Both rape and physical assault significantly predicted visual and auditory hallucinations. A significant dose response relationship was also found. CONCLUSIONS: Previous findings indicating that adverse events in childhood may be causally related to subsequent psychosis are supported. The psychological and biological mechanisms underlying the relationship are already the subject of investigation. Repeated recommendations concerning routine enquiry about adverse experiences in childhood in order to facilitate comprehensive formulations and appropriate treatment, also receive support from these findings. PMID- 20931326 TI - Psychopathology and subjective burden amongst primary caregivers of people with mental illness in South-Western Nigeria. AB - BACKGROUND: Most mentally ill persons reside with family members in sub-Saharan Africa with the primary caregiver having to cater for the patients' needs. The burden of this care giving may be associated with psychopathology in the carer. AIMS: To examine the rate and correlates of psychopathology and subjective burden amongst primary caregivers of people with mental illness in South-Western Nigeria. METHOD: Adult psychiatric outpatients (n = 338) from three centres were assessed for clinical and functioning status, while their adult primary caregivers (n = 338) were assessed for psychopathology (using the General Health Questionnaire-GHQ-12) and level of burden (using the Zarit's caregiver burden scale-ZCBS). RESULTS: The mean caregivers' GHQ-12 score was 3.11 (SD 2.57) and mean ZBCS score was 42.85 (SD = 19.31) with a significant correlation between the two (r = 0.638, P < 0.001). 118 (34.9%) caregivers had significant psychopathology and 205 (60.7%) had significant (moderate/severe) burden. The independent associate of psychopathology was poor patient functioning either measured objectively (OR 6.43, 95% CI 3.12-13.29) or subjectively perceived by the carers (OR 6.28, 95% CI 2.46-17.94). Caregivers burden was independently associated with patients' poor functioning (OR 5.97, 95% CI 2.56-15.45), caregivers' being employed (OR 5.40, 95% CI 3.02-9.64) and being male (OR 2.62, 95% CI 1.50-4.59). CONCLUSION: With the high level of psychopathology and burden amongst caregivers in this region, clinicians should be sensitive and review them periodically and to pick up signs of psychopathology which may necessitate attention. Caregivers should be encouraged to meet regularly to share their experiences and ventilate their emotions. PMID- 20931327 TI - Environmental factors associated with adolescent antisocial behavior in a poor urban community in Brazil. AB - BACKGROUND: Investigating risk factors for anti-social behavior (ASB) is particularly relevant in a poor urban and violent community of a developing country where homicide is the primary cause of death among 15-24-year olds. OBJECTIVES: To identify individual and environmental factors associated with ASB in adolescents from an urban poor community in the outskirts of Sao Paulo City, Brazil. METHOD: This cross-sectional study was based on a probabilistic sample of clusters that included all eligible households (women aged 15-49 years with a son or daughter <18 years of age). One mother-child pair was randomly selected per household (n = 813; response rate: 82.4%). This study is focused on the age group 11-17 years (n = 248). ASB was identified by externalizing scores in the clinical range on the Child Behavior Checklist and/or the Youth Self Report. Potential correlates included individual, maternal, paternal, and familial characteristics. Backward logistic regression analysis identified independent correlates and significant interactions. FINDINGS: Youths with high ASB scores were more likely to be victims of severe physical punishment and have an absent father/substitute. Maternal anxiety/depression was a risk factor only among older adolescents (15-17 years), while the presence of internalizing problems was a risk factor only among younger adolescents (11-14 years). Having a non-working mother increased the risk for ASB only among low-income adolescents. CONCLUSION: The recognition that certain environmental factors may have harmful effects on adolescents' mental health, and the identification of more vulnerable groups can contribute to the development of effective strategies for prevention and treatment of ASB. PMID- 20931328 TI - Disruption of opioid-induced placebo responses by activation of cholecystokinin type-2 receptors. AB - RATIONALE: Placebos are known to induce analgesia through the activation of MU opioid receptors in some circumstances, such as after morphine pre-conditioning, an effect that is blocked by opioid antagonists. OBJECTIVES: On the basis of the anti-opioid action of cholecystokinin, here we tested whether the activation of the cholecystokinin type-2 receptors abolishes opioid-induced placebo responses. METHODS: The activation of the cholecystokinin type-2 receptors was performed by means of the agonist pentagastrin, and placebo responses were obtained after morphine pre-conditioning in an experimental human model of pain (tourniquet technique). RESULTS: Opioid-induced placebo responses were completely disrupted by pentagastrin administration. In addition, a high correlation between the response to morphine and the response to placebo was found, and this correlation was completely abolished by pentagastrin. CONCLUSION: These results show that the cholecystokinin-2 receptor agonist, pentagastrin, has the same effect as the MU opioid receptor antagonist, naloxone, on placebo analgesia induced by morphine pre-conditioning, which suggests that the balance between cholecystokinergic and opioidergic systems is crucial in placebo responsiveness in pain. These findings also suggest that cholecystokinin type-2 receptor hyperactivity might be present in placebo non-responders. PMID- 20931329 TI - The CYP2C8 inhibitor gemfibrozil does not affect the pharmacokinetics of zafirlukast. AB - PURPOSE: Gemfibrozil, a strong inhibitor of cytochrome P450 (CYP) 2C8 in vivo, was recently found to markedly increase the plasma concentrations of montelukast in humans. Like montelukast, zafirlukast is a substrate of CYP2C9 and CYP3A4 and a potent inhibitor of CYP2C8 in vitro. To investigate the contribution of CYP2C8 to the metabolism of zafirlukast in vivo, we studied the effect of gemfibrozil on the pharmacokinetics of zafirlukast. METHODS: Ten healthy subjects in a randomized cross-over study took gemfibrozil 600 mg or placebo twice daily for 5 days, and on day 3, a single oral dose of 20 mg zafirlukast. The plasma concentrations of zafirlukast were measured for 72 h postdose. RESULTS: The mean total area under the plasma concentration-time curve of zafirlukast during the gemfibrozil phase was 102% (geometric mean ratio; 95% confidence interval 89 116%) of that during the placebo phase. Furthermore, there were no statistically significant differences in the peak plasma concentration, time of peak concentration, or elimination half-life of zafirlukast between the phases. CONCLUSIONS: Gemfibrozil has no effect on the pharmacokinetics of zafirlukast, indicating that CYP2C8 does not play a significant role in the elimination of zafirlukast. PMID- 20931331 TI - Vigabatrin-associated diffusion MRI abnormalities in tuberous sclerosis. PMID- 20931330 TI - Do CYP3A and ABCB1 genotypes influence the plasma concentration and clinical outcome of donepezil treatment? AB - PURPOSE: The aim of our study was to evaluate the impact of CYP3A4, CYP3A5, and ABCB1 polymorphisms on donepezil disposition and clinical outcome. METHODS: Fifty four Italian patients diagnosed with probable mild to moderate Alzheimer's disease, treated with donepezil (37 patients 5 mg/day, 17 patients 10 mg/day) were genotyped for CYP3A4 (*1B, *3, and *4), CYP3A5 (*2, *3, and *6) and ABCB1 (3435C>T, 2677G>T/A, and 1236C>T) polymorphisms. All patients were evaluated for the degree of cognitive impairment with Mini Mental State Examination (MMSE) screening test at baseline (before treatment) and after at least 3 months of donepezil treatment at stable dose, when the drug plasma levels were measured. RESULTS: Three patients carried one detrimental CYP3A4 allelic variant, and 12 carried one functional CYP3A5*1 allele. No statistically significant association was found between CYP3A4 or CYP3A5 genotypes and plasma donepezil concentrations, or between genotypes and clinical response (as measured by change in MMSE score). Nine ABCB1 haplotypes were observed, the most common being 1236C/2677G/3435C (46%) and 1236T/2677T/3435T (41%). Patients homozygous for the T/T/T haplotype had slightly though not significantly lower plasma donepezil concentration-to dose ratios than those carrying other genotypes [median (95% CI) 0.18 (0.13-0.45) vs. 0.31 (0.30-0.44) mg/l/mg/kg, respectively]. These patients also showed a slightly better clinical response (as measured by change in MMSE score) than the other genotype groups [median (95% CI) 0 (-1.3 to 3.3) vs. -1.0 (-2.1 to 0.0), respectively]. CONCLUSIONS: Our data suggest that the CYP3A4 and CYP3A5 polymorphisms are unlikely to influence donepezil metabolism and/or clinical outcome. On the other hand, the ABCB1 polymorphisms may play a role in donepezil disposition and clinical outcome. PMID- 20931332 TI - Computed tomographic features of two cases of acute gastric anisakiasis. AB - Little is known about the detailed computed tomography (CT) features of acute gastric anisakiasis. Our two cases showed transiently swollen gastric folds comprised of the remarkably thickened contrast little-enhanced submucosal layer with little-thickened contrast-enhanced mucosal and muscular-serosal layers on multi-detector row CT. When CT demonstrates the swollen gastric folds in acute abdomen, acute gastric anisakiasis should be included in the differential diagnosis. PMID- 20931334 TI - MIRO1 influences the morphology and intracellular distribution of mitochondria during embryonic cell division in Arabidopsis. AB - Regulating the morphology and intracellular distribution of mitochondria is essential for embryo development in animals. However, the importance of such regulation is not clearly defined in plants. The evolutionarily conserved Miro proteins are known to be involved in the regulation of mitochondrial morphology and motility. We previously demonstrated that MIRO1, an Arabidopsis thaliana orthologue of the Miro protein, is required for embryogenesis. An insertional mutation in the MIRO1 gene causes arrest of embryonic cell division, leading to abortion of the embryo at an early stage. Here we investigated the role of MIRO1 in the regulation of mitochondrial behaviour in egg cells and early-stage embryos using GFP-labeled mitochondria. Two-photon laser scanning microscopy revealed that, in miro1 mutant egg cells, mitochondria are abnormally enlarged, although egg cell formation is nearly unaffected. After fertilization and subsequent zygotic cell division, the homozygous miro1 mutant two-celled embryo contained a significantly reduced number of mitochondria in its apical cell compared with the wild type, suggesting that the miro1 mutation inhibits proper intracellular distribution of mitochondria, leading to an arrest of embryonic cell division. Our findings suggest that proper mitochondrial morphology and intracellular distribution are maintained by MIRO1 and are vital for embryonic cell division. PMID- 20931335 TI - Interval-counting neurons in the anuran auditory midbrain: factors underlying diversity of interval tuning. AB - In anurans, the temporal patterning of sound pulses is the primary information used for differentiating between spectrally similar calls. One class of midbrain neurons, referred to as 'interval-counting' cells, appears to be particularly important for discriminating among calls that differ in pulse repetition rate (PRR). These cells only respond after several pulses are presented with appropriate interpulse intervals. Here we show that the range of selectivity and sharpness of interval tuning vary considerably across neurons. Whole-cell recordings revealed that neurons showing temporally summating excitatory postsynaptic potentials (EPSPs) with little or no inhibition or activity dependent enhancement of excitation exhibited low-pass or band-pass tuning to slow PRRs. Neurons that showed inhibition and rate-dependent enhancement of excitation, however, were band-pass or high-pass to intermediate or fast PRRs. Surprisingly, across cells, interval tuning based on membrane depolarization and spike rate measures were not significantly correlated. Neurons that lacked inhibition showed the greatest disparities between these two measures of interval tuning. Cells that showed broad membrane potential-based tuning, for example, varied considerably in their spike rate-based tuning; narrow spike rate-based tuning resulted from 'thresholding' processes, whereby only the largest depolarizations triggered spikes. The potential constraints associated with generating interval tuning in this manner are discussed. PMID- 20931336 TI - Multi-model inference of adult and childhood leukaemia excess relative risks based on the Japanese A-bomb survivors mortality data (1950-2000). AB - Some relatively new issues that augment the usual practice of ignoring model uncertainty, when making inference about parameters of a specific model, are brought to the attention of the radiation protection community here. Nine recently published leukaemia risk models, developed with the Japanese A-bomb epidemiological mortality data, have been included in a model-averaging procedure so that the main conclusions do not depend on just one type of model or statistical test. The models have been centred here at various adult and young ages at exposure, for some short times since exposure, in order to obtain specially computed childhood Excess Relative Risks (ERR) with uncertainties that account for correlations in the fitted parameters associated with the ERR dose response. The model-averaged ERR at 1 Sv was not found to be statistically significant for attained ages of 7 and 12 years but was statistically significant for attained ages of 17, 22 and 55 years. Consequently, such risks when applied to other situations, such as children in the vicinity of nuclear installations or in estimates of the proportion of childhood leukaemia incidence attributable to background radiation (i.e. low doses for young ages and short times since exposure), are only of very limited value, with uncertainty ranges that include zero risk. For example, assuming a total radiation dose to a 5-year-old child of 10 mSv and applying the model-averaged risk at 10 mSv for a 7-year-old exposed at 2 years of age would result in an ERR=0.33, 95% CI: -0.51 to 1.22. One model (United Nations scientific committee on the effects of atomic radiation report. Volume 1. Annex A: epidemiological studies of radiation and cancer, United Nations, New York, 2006) weighted model-averaged risks of leukaemia most strongly by half of the total unity weighting and is recommended for application in future leukaemia risk assessments that continue to ignore model uncertainty. However, on the basis of the analysis presented here, it is generally recommended to take model uncertainty into account in future risk analyses. PMID- 20931337 TI - Whole-body to tissue concentration ratios for use in biota dose assessments for animals. AB - Environmental monitoring programs often measure contaminant concentrations in animal tissues consumed by humans (e.g., muscle). By comparison, demonstration of the protection of biota from the potential effects of radionuclides involves a comparison of whole-body doses to radiological dose benchmarks. Consequently, methods for deriving whole-body concentration ratios based on tissue-specific data are required to make best use of the available information. This paper provides a series of look-up tables with whole-body:tissue-specific concentration ratios for non-human biota. Focus was placed on relatively broad animal categories (including molluscs, crustaceans, freshwater fishes, marine fishes, amphibians, reptiles, birds and mammals) and commonly measured tissues (specifically, bone, muscle, liver and kidney). Depending upon organism, whole body to tissue concentration ratios were derived for between 12 and 47 elements. The whole-body to tissue concentration ratios can be used to estimate whole-body concentrations from tissue-specific measurements. However, we recommend that any given whole-body to tissue concentration ratio should not be used if the value falls between 0.75 and 1.5. Instead, a value of one should be assumed. PMID- 20931338 TI - Extra cellular matrix remodelling after heterotopic rat heart transplantation: gene expression profiling and involvement of ED-A+ fibronectin, alpha-smooth muscle actin and B+ tenascin-C in chronic cardiac allograft rejection. AB - Chronic cardiac rejection is represented by cardiac allograft vasculopathy (CAV) and cardiac interstitial fibrosis (CIF) known to cause severe complications. These processes are accompanied by remarkable changes in the cardiac extra cellular matrix (cECM). The aim of our study was to analyse the cECM remodelling in chronic rejection and to elucidate a potential role of ED-A domain containing fibronectin (ED-A(+) Fn), alpha smooth muscle actin (ASMA) and B domain containing tenascin-C (B(+) Tn-C). A model of chronic rejection after heterotopic rat heart transplantation was used. Allografts, recipient and control hearts were subjected to histological assessment of rejection grade, to real-time PCR based analysis of 84 genes of ECM and adhesion molecules and to immunofluorescence labelling procedures, including ED-A(+) Fn, ASMA and B(+) Tn-C antibodies. Histological analysis revealed different grades of chronic rejection. By gene expression analysis, a relevant up-regulation of the majority of ECM genes in association with chronic rejection could be shown. For 8 genes, there was a relevant up-regulation in allografts as well as in the corresponding recipient hearts. Association of ASMA positive cells with the grade of chronic rejection could be proven. In CAV and also in CIF there were extensive co-depositions of ED A(+) Fn, ASMA and B(+) Tn-C. In conclusion, chronic cardiac allograft rejection is associated with a cECM remodelling. ASMA protein deposition in CAV, and CIF is a valuable marker to detect chronic rejection. Interactions of VSMCs and Fibro /Myofibroblasts with ED-A(+) Fn and B(+) Tn-C might functionally contribute to the development of chronic cardiac rejection. PMID- 20931339 TI - Autophagy in myocardium of murine hearts subjected to ischemia followed by reperfusion. AB - Autophagy in myocardium has been thought to be cardioprotective, but its extent after transient or prolonged myocardial ischemia remains unclear. Accordingly, we characterized its magnitude in myocardium of murine hearts subjected to ischemia with or without reperfusion. Ten-week-old transgenic GFP-LC3 mice and C57Bl6 mice were subjected to coronary ligation for 1 or 4 h followed by 24 h of reperfusion (1HTL, 4HTL) or to 24 h of persistent ligation (24HPL). Their hearts were analyzed by fluorescence microscopy, electron microscopy, and by Western blotting. Fluorescent GFP-LC3 dots indicative of autophagy were absent in infarct zones and reduced markedly in the peri-infarct zones compared with dots in sham controls (p <= 0.05). The LC3-II/LC3-I ratio indicative of autophagy did not increase in LV homogenates from hearts following ischemia. Phosphorylation of ribosomal protein S6 increased in LV homogenates in hearts from mice subjected to 4HTL and 24HPL (p <= 0.05). Virtually no autophagic cells recognizable by electron microscopy were evident in infarct or peri-infarct zones. Autophagy is virtually absent within 24 h in the center of zones of infarction and is decreased significantly in the peri-infarct zones compared with that in normal hearts. PMID- 20931340 TI - Characterisation of the epitope for a herpes simplex virus glycoprotein B specific monoclonal antibody with high protective capacity. AB - Monoclonal antibody (MAb) 2c, specific for glycoprotein B of herpes simplex virus (HSV), had been shown to mediate clearance of infection from the mucous membranes of mice, thereby completely inhibiting mucocutaneous inflammation and lethality, even in mice depleted of both CD4(+) and CD8(+) cells. Additionally, ganglionic infection was highly restricted. In vitro, MAb 2c exhibits a potent complement independent neutralising activity against HSV type 1 and 2, completely inhibits the viral cell-to-cell spread as well as the syncytium formation induced by syncytial HSV strains (Eis-Hubinger et al. in Intervirology 32:351-360, 1991; Eis Hubinger et al. in J Gen Virol 74:379-385, 1993). Here, we describe the mapping of the epitope for MAb 2c. The antibody was found to recognise a discontinuous epitope comprised of the HSV type 1 glycoprotein B residues 299 to 305 and one or more additional discontinuous regions that can be mimicked by the sequence FEDF. Identification of the epitope was confirmed by loss of antibody binding to mutated glycoprotein B with replacement of the epitopic key residues, expressed in COS-1 cells. Similarly, MAb 2c was not able to neutralise HSV mutants with altered key residues, and MAb 2c was ineffective in mice inoculated with such mutants. Interestingly, identification and fine-mapping of the discontinuous epitope was not achieved by binding studies with truncated glycoprotein B variants expressed in COS cells but by peptide scanning with synthetic overlapping peptides and peptide key motif analysis. Reactivity of MAb 2c was immensely increased towards a peptide composed of the glycoprotein B residues 299 to 305, a glycine linker, and a C-terminal FEDF motif. If it could be demonstrated that antibodies of the specificity and bioactivity of MAb 2c can be induced by the epitope or a peptide mimicking the epitope, strategies for active immunisation might be conceivable. PMID- 20931341 TI - Effects of TGF-beta1 on the proliferation and differentiation of human periodontal ligament cells and a human periodontal ligament stem/progenitor cell line. AB - Periodontal ligament (PDL) is a specialized connective tissue that influences the lifespan of the tooth. Transforming growth factor-beta1 (TGF-beta1) is a multifunctional cytokine, but little is known about the effects of TGF-beta1 on PDL cells. Our aim has been to demonstrate the expression of TGF-beta1 in rat PDL tissues and to evaluate its effects on the proliferation and gene expression in human PDL cells (HPLCs) and a human PDL stem/progenitor cell line, line 1-11, that we have recently developed. The expression of TGF-beta1 in the entire PDL tissue was confirmed immunohistochemically, and both HPLCs and cell line 1-11 expressed mRNA from the TGF-beta1, TGF-beta type I receptor, and TGF-beta type II receptor genes. Although exogenous TGF-beta1 stimulated the proliferation of HPLCs, it did not upregulate the expression of alpha-smooth muscle actin (alpha SMA), type I collagen (Col I), or fibrillin-1 (FBN1) mRNA or of alpha-SMA protein in HPLCs, whereas expression for these genes was attenuated by an anti-TGF-beta1 neutralizing antibody. In contrast, exogenous TGF-beta1 reduced the proliferation of cell line 1-11, although it upregulated the expression of alpha-SMA, Col I, and FBN1 mRNA and of alpha-SMA protein in this cell line. In addition, interleukin-1 beta stimulation significantly reduced the expression of TGF-beta1 mRNA and protein in HPLCs. Thus, TGF-beta1 seems to play an important role in inducing fibroblastic differentiation of PDL stem/progenitor cells and in maintaining the PDL apparatus under physiological conditions. PMID- 20931342 TI - Clinical significance of bile cytology via an endoscopic nasobiliary drainage tube for pathological diagnosis of malignant biliary strictures. AB - BACKGROUND/PURPOSE: In patients in whom there is a suspicion of malignant biliary strictures, bile cytology via an endoscopic nasobiliary drainage tube (ENBD cytology) is often performed, in addition to aspirated bile cytology, brush cytology, and forceps biopsy, during the initial endoscopic retrograde cholangiopancreatography (ERCP). We aimed to reveal the significance of ENBD cytology for the pathological diagnosis of malignant biliary strictures. METHODS: We studied 214 patients with malignant biliary strictures. We performed aspirated bile cytology, brush cytology, and forceps biopsy in 93, 130, and 114 patients, respectively. ENBD cytology was performed one or more times in 79 patients. We examined the sensitivity of each sampling method, and analyzed the utility of ENBD cytology. RESULTS: The sensitivities of each sample acquisition method were as follows: 30% (28/93) for aspirated bile cytology, 48% (62/130) for brush cytology, 41% (47/114) for forceps biopsy, and 24% (19/79) for ENBD cytology. In 19 patients who showed positive ENBD cytology, other methods were performed in 11. Aspirated bile cytology, brush cytology, and forceps biopsy, were performed in 7, 5, and 6 patients, and the results were negative in 3 (43%), 2 (40%), and 1 (17%) patient, respectively. Three patients showed positive results only on ENBD cytology. CONCLUSIONS: Although the sensitivity of ENBD cytology was inferior to that of the other methods used, ENBD cytology may contribute to the improvement of the total diagnostic sensitivity for malignancy. PMID- 20931344 TI - Reduced expression of intestinal N-acetylglutamate synthase in suckling piglets: a novel molecular mechanism for arginine as a nutritionally essential amino acid for neonates. AB - The objective of this study was to determine developmental changes in mRNA and protein levels for N-acetylglutamate synthase (NAGS; a key enzyme in synthesis of citrulline and arginine from glutamine/glutamate and proline) in the small intestine of suckling piglets. The porcine NAGS gene was cloned using the real time polymerase-chain reaction (RT-PCR) method. The porcine NAGS gene encoded 368 amino acid residues and had a high degree of sequence similarity to the "conserved domain" of human and mouse NAGS genes. The porcine NAGS gene was expressed in E. coli BL21 and a polyclonal antibody against the porcine NAGS protein was developed. Real-time RT-PCR and western-blot analyses were performed to quantify NAGS mRNA and protein, respectively, in the jejunum and ileum of 1- to 28-day-old pigs. Results indicated that intestinal NAGS mRNA levels were lower in 7- to 28-day-old than in 1-day-old pigs. Immunochemical analysis revealed that NAGS protein was localized in enterocytes of the gut. Notably, intestinal NAGS protein abundance declined progressively during the 28-day suckling period. The postnatal decrease in NAGS protein levels was consistent with the previous report of reduced NAGS enzymatic activity as well as reduced synthesis of citrulline and arginine in the small intestine of 7- to 28-day-old pigs. Collectively, these results suggest that intestinal NAGS expression is regulated primarily at the post-transcriptional level. The findings also provide a new molecular basis to explain that endogenous synthesis of arginine is impaired in sow-reared piglets and arginine is a nutritionally essential amino acid for the neonates. PMID- 20931343 TI - Superoxide dismutase type 1 in monocytes of chronic kidney disease patients. AB - We analyzed proteomic profiles in monocytes of chronic kidney disease (CKD) patients and healthy control subjects. Two-dimensional electrophoresis (2-DE) and silver staining indicated differences in protein pattern. Among the analyzed proteins, superoxide dismutase type 1 (SOD1), which was identified both by MS/MS mass-spectrometry and immunoblotting, was reduced in kidney disease. We characterized SOD1 protein amount, using quantitative in-cell Western assay and immunostaining of 2-DE gel blots, and SOD1 gene expression, using quantitative real-time polymerase chain reaction (PCR), in 98 chronic hemodialysis (HD) and 211 CKD patients, and 34 control subjects. Furthermore, we showed that different SOD1 protein species exist in human monocytes. SOD1 protein amount was significantly lower in HD (normalized SOD1 protein, 27.2 +/- 2.8) compared to CKD patients (34.3 +/- 2.8), or control subjects (48.0 +/- 8.6; mean +/- SEM; P < 0.05). Analysis of SOD1 immunostaining showed significantly more SOD1 protein in control subjects compared to patients with CKD or HD (P < 0.0001, analysis of main immunoreactive protein spot). SOD1 gene expression was significantly higher in HD (normalized SOD1 gene expression, 17.8 +/- 2.3) compared to CKD patients (9.0 +/- 0.7), or control subjects (5.5 +/- 1.0; P < 0.0001). An increased SOD1 gene expression may indicate increased protein degradation in patients with CKD and compensatory increase of SOD1 gene expression. Taken together, we show reduced SOD1 protein amount in monocytes of CKD, most pronounced in HD patients, accompanied by increased SOD1 gene expression. PMID- 20931345 TI - Liver autoantibodies in patients with scleroderma. AB - Association between autoimmune liver diseases and scleroderma has been described. The purpose of this study was to study the prevalence of antimithocondrial antibody (AMA), antismooth muscle antibodies (SMA), and liver-kidney-microsomal (LKM-1) autoantibody in a cohort of 63 scleroderma patients and 100 healthy controls. The autoantibodies AMA, SMA, and LKM were determined by indirect immunofluorescence. Patients' charts were reviewed for demographic data, scleroderma form, and clinical and anti-nuclear antibody profile, aiming a comparison between patients with and without liver autoantibodies. Nine patients (14.3%) were positive for at least one of the liver autoantibodies; only one patient had both AMA and SMA positive. Antibody SMA was positive in 6.4% (4/63) patients; AMA was present in 9.52% (6/63) of them; none were positive to LKM-1. In the control group just one patient (1%) was SMA positive; the other autoantibodies were negative. There is an increased prevalence of liver autoantibodies in patients with scleroderma than in control population. These patients should be carefully followed for liver dysfunction. PMID- 20931346 TI - The effects of strength and endurance training in patients with rheumatoid arthritis. AB - Patients with rheumatoid arthritis (RA) suffer from muscle loss, causing reduced muscle strength and endurance. The current study aimed to: (1) evaluate the effects of combined strength and endurance training (CT) on disease activity and functional ability in patients with RA and (2) investigate the benefits of a 6 month supervised CT program on muscle strength, cardio-respiratory fitness, and body composition of RA patients. Forty patients with RA, aged 41-73 years, were recruited for the current study. Twenty of these patients (19 females, one male) were randomly assigned to a 6-month supervised CT program; 20 patients (17 females, three males) served as controls. Within the CT program, strength training consisted of sets of weight bearing exercises for all major muscle groups. In addition to strength training, systematic endurance training was performed on a cycle ergometer two times per week. For RA patients involved in CT, disease activity (p = 0.06) and pain (p = 0.05) were reduced after the 6 month training period while general health (p = 0.04) and functional ability (p = 0.06) improved. Cardio-respiratory endurance was found to have improved significantly (by 10%) after 6 months of CT (p < 0.001). The overall strength of patients undertaking CT increased by an average of 14%. Lean body mass increased, and the percentage of body fat was found to decrease significantly (p < 0.05). A combination of strength and endurance training resulted in considerable improvements in RA patients' muscle strength and cardio-respiratory endurance, accompanied by positive changes in body composition and functional ability. Long term training appears to be effective in reducing disease activity and associated pain and was found to have no deleterious effects. PMID- 20931347 TI - Neurogenic inflammation: a study of rat trigeminal ganglion. AB - Calcitonin gene-related peptide (CGRP) is linked to neurogenic inflammation and to migraine. Activation of the trigeminovascular system plays a prominent role during migraine attacks with the release of CGRP. The trigeminal ganglion (TG) contains three main cell types: neurons, satellite glial cells (SGC) and Schwann cells; the first two have before been studied in vitro separately. Culture of rat TG provides a method to induce inflammation and the possibility to evaluate the different cell types in the TG simultaneously. We investigated expression levels of various inflammatory cytokines on mRNA level using RT-PCR arrays and qRT-PCR; furthermore expression at protein level was studied using immunohistochemistry. We report that (1) organ culture of the TG is possible with preserved morphology, (2) organ culture is associated with enhanced expression of cytokines and mitogen activated protein kinases (MAPKs) primarily in neurons, (3) CGRP can induce expression of some cytokines and (4) cytokine expression is still upregulated following MAPK pathway inhibition by MEK inhibitor U0126 and pp38 inhibitor SB202192, but the cytokine expression is abolished when co-incubating with the JNK inhibitor SP600125. This method may be of value to examine local TG inflammation, putatively involved in the pathophysiology of some forms of primary headaches. PMID- 20931349 TI - Marginal Structural Models: unbiased estimation for longitudinal studies. AB - INTRODUCTION: In this article, we introduce Marginal Structural Models, which yield unbiased estimates of causal effects of exposures in the presence of time varying confounding variables that also act as mediators. OBJECTIVES: We describe estimation via inverse probability weighting; estimation may also be accomplished by g-computation (Robins in Latent Variable Modeling and Applications to Causality, Springer, New York, pp 69-117, 1997; van der Wal et al. in Stat Med 28:2325-2337, 2009) or targeted maximum likelihood (Rosenblum and van der Laan in Int J Biostat 6, 2010). CONCLUSIONS: When both time-varying confounding and mediation are present in a longitudinal setting data, Marginal Structural Models are a useful tool that provides unbiased estimates. PMID- 20931350 TI - Heterologous expression of human interleukin-6 in Streptomyces lividans TK24 using novel secretory expression vectors. AB - Streptomyces is an attractive host for heterologous protein secretion. To further optimize its expression capacity, better expression vectors will be helpful. Here, based on pSGL1, a high copy number plasmid present in Streptomyces globisporus C-1027, we constructed a series of novel E. coli-Streptomyces shuttle expression vectors pIMB2-4. These vectors, which are compatible with pIJ-derived vectors, contain the strong promoter ermE*p and signal sequence SP (MelC1) of the first ORF of melanin operon in S. antibiotics (pIMB2), SP (CagA) of C-1027 apoprotein in S. globisporus C-1027 (pIMB3 and pIMB4). Using these vectors, human interleukin-6 (IL-6) could successfully be expressed and secreted using S. lividans TK24 as host. Furthermore, replacement of a rare leucine codon TTA with CTG in SP (CagA) enhanced IL-6 production. PMID- 20931351 TI - Specific inhibition of the halogenase for radicicol biosynthesis by bromide at the transcriptional level in Pochonia chlamydosporia. AB - Pochonia chlamydosporia produces radicicol (1), a potent antifungal and anticancer product. NaBr, but not NaF, NaCl or NaI, inhibited the biosynthesis of 1 in P. chlamydosporia in a dose-dependent manner, accompanied by the formation chlorine-lacking monocillins II-V (2-5), indicating that the dedicated halogenase, Rdc2 had been inhibited. RT-PCR analysis confirmed that transcription of rdc2 was selectively inhibited by Br(-), whereas the putative P450 epoxidase gene, rdc4, was not affected. PMID- 20931348 TI - Are the current IHS guidelines for migraine drug trials being followed? AB - In 2000, the Clinical Trials Subcommittee of the International Headache Society (IHS) published the second edition of its guidelines for controlled trials of drugs in migraine. The purpose of this publication was to improve the quality of such trials by increasing the awareness amongst investigators of the methodological issues specific to this particular illness. Until now the adherence to these guidelines has not been systematically assessed. We reviewed all published controlled trials of drugs in migraine from 2002 to 2008. Eligible trials were scored for compliance with the IHS guidelines by using grading scales based on the most essential recommendations of the guidelines. The primary efficacy measure of each trial was also recorded. A total of 145 trials of acute treatment and 52 trials of prophylactic treatment were eligible for review. Of the randomized, double-blind trials, acute trials scored an average of 4.7 out of 7 while prophylactic trials scored an average of 5.6 out of 9 for compliance. Thirty-one percent of acute trials and 72% of prophylactic trials used the recommended primary efficacy measure. Fourteen percent of the reviewed trials were either not randomized or not double-blinded. Adherence to international guidelines like these of IHS is important to ensure that only high-quality trials are performed, and to provide the consensus that is required for meta analyses. The primary efficacy measure for trials of acute treatment should be "pain free" and not "headache relief". Open-label or non-randomized trials generally have no place in the study of migraine drugs. PMID- 20931352 TI - A loop-controlled rrnB P1 promoter for high-level expression of heterologous proteins in Escherichia coli. AB - An effective protein expression system was constructed in Escherichia coli utilizing the rRNA rrnB P1 promoter and the regulatory element of the lac operon (lacO). To regulate the transcriptional activity of the rrnB P1 promoter, we designed two lacO sites with an intervening loop structure; expression was verified by measuring the levels of the beta-1,4-glucanase gene, cel5G. Basal expression from the looped promoter construct was reduced by 92% when compared to expression from the T7 promoter. We also found that the host cell type had a significant effect on the regulation of the rrnB P1 promoter: E. coli DH5alpha and DH10B had high expression levels, whereas the expression in BL21(DE3) was more stringent. PMID- 20931353 TI - Production of human metabolites of the anti-cancer drug flutamide via biotransformation in Cunninghamella species. AB - Fungi belonging to the genus Cunninghamella have enzymes similar to those employed by mammals for the detoxification of xenobiotics, thus they are useful as models of mammalian drug metabolism, and as a source for drug metabolites. We report the transformation of the anti-cancer drug flutamide in Cunninghamella sp. The most predominant phase I metabolites present in the plasma of humans, 2 hydroxyflutamide and 4-nitro-3-(trifluoromethyl)aniline, were also produced in Cunninghamella cultures. Other phase I and phase II metabolites were also detected using a combination of HPLC, GC-MS and (19)F-NMR. PMID- 20931354 TI - Fatty acylation enhances cellular localization of dansylated phenylalanines. AB - Two series of fluorescent molecules were synthesized by acylation of dansyl ethylenediamine and phenylalanine dansyl ethylenediamine with one of either acetyl (C(2)), hexanyl (C(6)), cyclohexanecarbonyl (C(7)), myristyl (C(14)), or palmityl (C(16)) groups and examined for entry and localization in Chinese Hamster Ovary (CHO) cells in tissue culture. Gross total fluorescence retention and cellular microscopic fluorescence patterns were analyzed. In both series, molecules with myristyl or palmityl groups entered cells. Only in the phenylalanine series did hexyl and cyclohexanecarbonyl modification enable entry. Consistent with a mechanism of passive diffusion, entry of compounds into cells was neither energy dependent nor endocytosis linked. Acylated molecules were observed to localize in cytoplasm and not enter nuclei or associate with lipophilic plasma membranes. PMID- 20931356 TI - PER2 variation is associated with diurnal preference in a Korean young population. AB - The PER2 gene has been reported to influence diurnal preference. In this study, we have attempted to characterize the associations between the PER2 gene polymorphisms and diurnal preference in a population of healthy young subjects, controlling for the social and environmental confounding factors. Subjects were 299 students in a college, carefully selected to be mentally and physically healthy. All subjects completed the 13-item composite scale for morningness (CSM). PER2 gene polymorphisms were genotyped by PCR-based methods. Genotype and allele carrier status of a PER2 G3853A polymorphism (rs934945) were associated with CSM scores. Carriers of the 3853G allele showed significantly higher CSM scores (P = 0.004, P = 0.009, and P = 0.001; total, morningness, and activity plan, respectively). There were no significant differences on CSM scores among genotypes and allele status of PER2 rs2304672. This result indicates that rs934945 of PER2 may be associated with diurnal preference in a Korean healthy population. PMID- 20931355 TI - Genetic counseling considerations in the evaluation of families for Lynch syndrome--a review. AB - Lynch syndrome is the most common hereditary colorectal cancer syndrome and the most common cause of hereditary endometrial cancer. Identifying and evaluating families for Lynch syndrome is increasing in complexity due to the recognition that: family history-based clinical criteria lack sensitivity and specificity; genetic testing for Lynch syndrome continues to evolve as understanding of the molecular mechanisms underlying it evolves; and the Lynch syndrome phenotype encompasses multiple organ systems and demonstrates overlap with other hereditary cancer syndromes. This document is a summary of considerations when evaluating individuals and families for Lynch syndrome, including information on cancer risks, diagnostic criteria, tumor and genetic testing strategies, and the management of individuals with this condition. PMID- 20931358 TI - Polymorphism in exons of the myostatin gene and its relationship with body weight traits in the Bian chicken. AB - In our research, single nucleotide polymorphisms (SNPs) of exon regions of the myostatin gene were detected by PCR-SSCP in the Bian chicken and three reference chicken populations (Jinghai, Youxi, and Arbor Acre). Four novel SNPs (G2283A, C7552T, C7638T, and T7661A) were detected. The findings from the least square means showed that Bian chickens with EE and DE genotypes had significantly higher body weight, at 6-18 weeks of age, than those of the DD genotype (P < 0.05). The results suggest that the mutation G2283A, detected in exon 1, has potential as a genetic marker for body weight traits in the Bian chicken. PMID- 20931357 TI - Lack of association of the N-acetyltransferase NAT1*10 allele with prostate cancer incidence, grade, or stage among smokers in Finland. AB - Genetic variations in xenobiotic metabolizing genes can influence susceptibility to many environmentally induced cancers. Inheritance of the N-acetyltransferase 1 allele (NAT1*10), linked with increased metabolic activation of pro-carcinogens, is associated with an increased susceptibility to many cancers in which cigarette or meat-derived carcinogens have been implicated in their etiology. The role of NAT1*10 in prostate cancer is under studied. Although cigarette smoking is not considered a risk factor for prostate cancer, a recent review suggests it may play a role in disease progression. Consequently, we examined the association of NAT1*10 with prostate cancer risk, grade, and stage among 400 Finnish male smokers using a case-control study design. Following genotyping of 206 patients and 196 healthy controls, our results do not support the role of NAT1*10 in relation to prostate cancer risk (OR = 1.28; 95% CI, 0.66-2.47), aggressive disease (OR = 0.58; 95% CI, 0.13-2.67), or advanced disease (OR = 1.19; 95% CI, 0.49-2.91). PMID- 20931359 TI - Diagnosing infections: a qualitative view on prescription decisions in general practice over time. AB - OBJECTIVE: Antibiotics may frequently be prescribed on the basis of vague diagnoses, possibly resulting in unnecessary antimicrobial resistance. Our aim is to map general practitioners' (GPs') decision-making for common infections, exploring their diagnostic basis for antibiotic prescriptions. SETTING: General practice in Iceland. METHOD: Ten in-depth qualitative interviews with, and three observations of, GPs in 1995. Diagnostic issues extracted and analysed. In 2006, eight GPs commented on analysis and updated (email/telephone). MAIN OUTCOME MEASURE: Diagnostic variability and reasons for prescribing antibiotics, consistency or changes over time. RESULTS: Wide variations were uncovered in diagnostic procedures, although each GP remained consistent through time. Some GPs had developed "rules-of-thumb". They often balanced risks against issues like money, time, need for the workforce (perceived importance of the patient's job), client's need for job/earnings (perceived ability to afford a sick day) and doctor-patient relationship (risk of refusal adversely affecting the relationship). Perceptions of risk varied from focusing on resistance development to focusing on possible harm from untreated infections, also ranging between considering both to worrying about neither. Changes over time were not prominent but included increased point-of-care testing and the perception by GPs that patients were increasingly willing to "wait and see". CONCLUSIONS: Large variability and individuality characterized the GPs' diagnostic procedures, contrasted by consistency through time. If modification of diagnostic routines is needed, provision of "scientific facts" and technological aids is insufficient. A prerequisite for changing practice is GPs' acceptance of accuracy of information and of reliability, applicability, and relevance of technology, for physician and/or patient. PMID- 20931360 TI - Free will and mental disorder: exploring the relationship. AB - A link between mental disorder and freedom is clearly present in the introduction of the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). It mentions "an important loss of freedom" as one of the possible defining features of mental disorder. Meanwhile, it remains unclear how "an important loss of freedom" should be understood. In order to get a clearer view on the relationship between mental disorder and (a loss of) freedom, in this article, I will explore the link between mental disorder and free will. I examine two domains in which a connection between mental disorder and free will is present: the philosophy of free will and forensic psychiatry. As it turns out, philosophers of free will frequently refer to mental disorders as conditions that compromise free will and reduce moral responsibility. In addition, in forensic psychiatry, the rationale for the assessment of criminal responsibility is often explained by referring to the fact that mental disorders can compromise free will. Yet, in both domains, it remains unclear in what way free will is compromised by mental disorders. Based on the philosophical debate, I discuss three senses of free will and explore their relevance to mental disorders. I conclude that in order to further clarify the relationship between free will and mental disorder, the accounts of people who have actually experienced the impact of a mental disorder should be included in future research. PMID- 20931361 TI - Complete fully automatic model-based segmentation of normal and pathological lymph nodes in CT data. AB - PURPOSE: Exact and reproducible knowledge regarding the position, size, and type of the lymph nodes is often needed for tumor computer-aided diagnosis, treatment planning, and follow-up. An automatic segmentation method for CT data was developed that can identify and delineate normal as well as pathologically altered lymph nodes to satisfy this requirement. METHODS: A semi-automatic lymph node segmentation method was developed using a 3D Stable Mass-Spring Model (SMSM), based on parallel simulation of the shape model on CT scan images. The models are started across the whole dataset at all potential lymph node positions but will only adapt to the data where a lymph node is found. The node positions can be determined by an evaluation of the model's quality of fit. RESULTS: Systematically chosen lymph nodes in 5 CT datasets, including enlarged, necrotic, fuzzy-bounded, and deformed lymph nodes, were used to evaluate the segmentation algorithm performance. A test set of 29 lymph nodes taken from 4 typical lymph node regions were included. All lymph nodes were detected automatically, while an additional 31% false-positive (n = 9) candidates were detected. The average calculation time was 2 min per dataset. The segmentation accuracy was comparable to the inter-observer variance of human experts. CONCLUSIONS: Clinically relevant lymph nodes were detected within a few minutes and provided sufficient accuracy to demonstrate the feasibility of a new segmentation method. The test data were diverse, and the robust results suggest potential applicability to many kinds of lymph node abnormalities, except for extremely degenerated lymph nodes. PMID- 20931362 TI - Serial MRI changes in comatose cardiac arrest patients. AB - BACKGROUND: Neuroimaging may prove useful in identifying cardiac arrest patients destined for a poor recovery, as certain patterns have been associated with a poor outcome. However, MRI changes evolve temporally and spatially, which may lead to misinterpretation and misclassification of patients. METHODS: Eight comatose patients following cardiac arrest underwent diffusion-weighted imaging (DWI) at two time points, and one patient underwent DWI at three time points. Each of the prespecified areas of each study were read as either "normal" or "abnormal" by two stroke neurologists. Neurological examinations, including GCS scores, were recorded on days 0, 1, 3, and 7. Outcomes were determined by the modified Rankin Scale (mRS), with poor outcome defined as mRS score >=4 at 6 months. RESULTS: In the acute (<24 h) period, two patients exhibited changes on DWI and FLAIR in the cerebellum and basal ganglia. In the early subacute period (days 1-5), cortical abnormalities predominated, with a shift to more white matter changes in the late subacute period (days 6-12). We observed more widespread imaging abnormalities in patients with poor outcomes, and partial or full resolution of DWI abnormalities in the two patients with good outcomes. CONCLUSIONS: MRI patterns after global hypoxic-ischemic injury follow a characteristic pattern with variable acute changes in the cortex, basal ganglia, and cerebellum, followed by predominantly cortical and white matter changes in the early and late subacute periods. Diffuse, persistent widespread changes on MRI may help to predict poor outcome. PMID- 20931363 TI - The genetics of obesity. AB - Obesity is a result of excess body fat accumulation. This excess is associated with adverse health effects such as CVD, type 2 diabetes, and cancer. The development of obesity has an evident environmental contribution, but as shown by heritability estimates of 40% to 70%, a genetic susceptibility component is also needed. Progress in understanding the etiology has been slow, with findings largely restricted to monogenic, severe forms of obesity. However, technological and analytical advances have enabled detection of more than 20 obesity susceptibility loci. These contain genes suggested to be involved in the regulation of food intake through action in the central nervous system as well as in adipocyte function. These results provide plausible biological pathways that may, in the future, be targeted as part of treatment or prevention strategies. Although the proportion of heritability explained by these genes is small, their detection heralds a new phase in understanding the etiology of common obesity. PMID- 20931365 TI - Broadening the perspective when assessing evidence on boosted protease inhibitor based regimens for initial antiretroviral therapy. AB - Several national and international guidelines recommend the use of antiretroviral therapy containing a protease inhibitor (PI) with ritonavir (RTV) boosting for human immunodeficiency virus (HIV)-infected treatment-naive patients. RTV-boosted PIs such as lopinavir (LPV/r), atazanavir (ATV + RTV), darunavir (DRV + RTV), fosamprenavir (FPV + RTV), and saquinavir (SQV + RTV) are usually recommended in regimens for initial therapy. The guideline recommendations are generally based on the clinical efficacy of the regimens. A broadened perspective of assessing the evidence related to selection of a PI for optimal first-line therapy might consider additional factors for evaluation, such as effectiveness in actual clinical practice and cost-effectiveness of individual drugs in formulating recommendations. Among the guideline-recommended PIs, LPV/r is one of the earliest PIs approved, has been a well-recognized boosted PI for treatment-naive patients in all guidelines, and demonstrates the most evidence on long-term clinical and economic effectiveness. Studies have shown its efficacy in various controlled and real-world settings in different populations, the relationship of adherence to virologic efficacy, and the implications of resistance when used in sequence with other PI regimens. In the absence of published evidence for other guideline-recommended PIs that will greatly facilitate a fully transparent, comparative effectiveness evaluation, the cumulative evidence from this broader perspective indicates all PIs should not be viewed as equally safe and effective across all patients for initial therapy, nor should any single PI within the class be considered preferred for all treatment-naive patients. PMID- 20931364 TI - Interleukin-33 in asthma: how big of a role does it play? AB - In complex disorders such as asthma and allergic disease, the goal for developing disease-modifying biotherapeutics is to find a target that is a central instigator of immunologic activity. Interleukin (IL)-33 seems to be such a molecule, as it is one of the earliest-released signaling molecules following epithelial damage and can orchestrate the recruitment and activation of the cells responsible for disease. Unregulated IL-33 activity leads to activation of T helper type 2 cells, mast cells, dendritic cells, eosinophils, and basophils, ultimately leading to increased expression of cytokines and chemokines that define the disease. As such, IL-33 is an attractive candidate for therapeutic intervention with the goal of ameliorating disease. This review focuses on the role of IL-33 in promoting and maintaining the asthma phenotype. PMID- 20931366 TI - Effects of benzalkonium chloride-preserved, polyquad-preserved, and sofZia preserved topical glaucoma medications on human ocular epithelial cells. AB - INTRODUCTION|: To investigate potentially adverse effects of different topical glaucoma medications and preservatives on cultured ocular epithelial cells. METHODS|: Confluent cultures of human corneal (10.014 pRSV-T) and conjunctival cells (1-5c-4) were assayed with 100 MUL of different glaucoma medications for 25 minutes at 37 degrees C and 5% CO2. We also tested the preservative sofZia(r) (Alcon Laboratories, Fort Worth, TX, USA), as well as a range of concentrations of the preservative benzalkonium chloride (BAK; 0.001% to 0.050%). Balanced salt solution was used as the "live" control and a solution containing 70% methanol and 0.2% saponin was used as a "dead" control. The LIVE/DEAD viability/cytotoxicity kit (Invitrogen, Carlsbad, CA, USA) was used to determine the percentage of dead and live cells via ethidium homodimer and calcein fluorescence, respectively. RESULTS|: The toxicity of the prostaglandin analogs latanoprost, tafluprost and travoprost preserved with BAK was similar to the toxicity observed in their respective BAK concentrations. The prostaglandin analog travoprost (0.004%) preserved with the oxidizing preservative sofZia had much greater corneal and conjunctival cell survival than travoprost preserved with BAK. Travoprost (0.004%) containing polyquad also performed statistically better than its BAK-preserved formulation. CONCLUSION|: Ocular surface side effects have previously been demonstrated with chronic, long-term exposure to intraocular pressure-lowering medications containing the common preservative BAK. BAK alone has significant in-vitro cytotoxicity to cultured ocular epithelial cells. Substitution of BAK with polyquad or sofZia resulted in significantly higher percentages of live conjunctival and corneal cells. Further studies are needed to understand the- clinical implications of these findings. PMID- 20931367 TI - The styrene metabolite, phenylglyoxylic acid, induces striatal-motor toxicity in the rat: influence of dose escalation/reduction over time. AB - Exposure to the industrial solvent, styrene, induces locomotor and cognitive dysfunction in rats, and parkinsonian-like manifestations in man. The antipsychotic, haloperidol (HP), well known to induce striatal toxicity in man and animals, and styrene share a common metabolic pathway yielding p-fluoro phenylglyoxylic acid and phenylglyoxylic acid (PGA), respectively. Using an exposure period of 30 days and the vacous chewing movement (VCM) model as an expression of striatal-motor toxicity, we found that incremental PGA dosing (220 400 mg/kg) significantly increased VCMs up to day 25, but decreased to control levels shortly after reaching maximum dose. However, a diminishing dose of PGA (400-200 mg/kg) did not evoke an immediate worsening of VCMs but precipitated a significant increase in VCMs following dosage reduction to 200 mg/kg on day 22. PGA exposure, therefore, compromises striatal-motor function that is especially sensitive to changes in exposure dose. Longer alternating dose exposure studies are needed to establish whether motor dysfunction is progressive in severity or longevity. These findings are of significance for the environmental toxicology of styrene in the chemical industry. PMID- 20931368 TI - Analysis of high-throughput sequencing data. AB - Next-generation sequencing has revolutionized biology by exponentially increasing sequencing output while dramatically lowering costs. High-throughput sequence data with shorter reads has opened up new applications such as whole genome resequencing, indel and SNP detection, transcriptome sequencing, etc. Several tools are available for the analysis of high-throughput sequencing data. In this chapter, we describe the use of an ultrafast alignment program, Bowtie, to align short-read sequence (SRS) data against the Arabidopsis reference genome. The alignment files generated from Bowtie will be used to identify SNPs and indels using Maq. PMID- 20931369 TI - Identification of plant microRNAs using expressed sequence tag analysis. AB - microRNAs (miRNAs) are a new class of small endogenous noncoding regulatory RNAs, which play an important function in plant growth, development, phase change, and response to environmental stress. Identifying miRNAs is the first step for investigating miRNA-mediated gene regulation and miRNA function. In this chapter, we describe a comprehensive comparative genomics-based expressed sequence tag (EST) analysis for identifying miRNAs from a wide range of plant species. EST analysis is based on the conservation of miRNA sequences and the stem-loop hairpin secondary structures of miRNAs. In this method, potential miRNAs will first be identified by EST analysis followed by confirmation using TaqMan((r)) MicroRNA qRT-PCR. This method is simple and reliable with high efficiency. This method has also been widely adopted by many scientists around the world and several hundreds of miRNAs have been identified in many plant species using this method. PMID- 20931370 TI - Microarray data analysis. AB - Gene expression profiling has revolutionized functional genomics research by providing a quick handle on all the transcriptional changes that occur in the cell in response to internal or external perturbations or developmental programs. Microarrays have become the most popular technology for recording gene expression profiles. This chapter describes all the necessary steps for analyzing Affymetrix microarray data using the open-source statistical tools (R and bioconductor). The reader is walked through all the basic steps of data analysis: reading raw data, assessing quality, preprocessing/normalization, discovery of differentially expressed genes, comparison of gene lists, functional enrichment analysis, and saving results to files for future reference. Some familiarity with computer is assumed. This chapter is self-contained with installation instructions for R and bioconductor packages along with links to downloadable data and code for reproducing the examples. PMID- 20931371 TI - Setting up reverse transcription quantitative-PCR experiments. AB - Quantitative real-time PCR (qRT-PCR), in conjunction with reverse transcriptase, has been used for the systematic measurement of plant physiological changes in gene expression. In the present paper, we describe a qRT-PCR protocol that illustrates the essential technical steps required to generate quantitative data that are reliable and reproducible. To demonstrate the methods used, we evaluated the expression stability of five [actin (ACT), actin1 (ACT1), beta-glyceraldehyde 3-phosphate dehydrogenase (GAPDH), cyclophilin (CYC), and elongation factor 1alpha (EF-1alpha)] frequently used housekeeping genes in rice. The expression stability of the five selected housekeeping genes varied considerably in different tissues (seedlings, vegetative and reproductive stages) in a given stress condition. The analysis allowed us to choose a set of two candidates (ACT1 and EF-1alpha) that showed more uniform expression and are also suitable for the validation of weakly expressed genes (>=0.5 fold), identified through microarray analysis. PMID- 20931372 TI - Virus-induced gene silencing in nicotiana benthamiana and other plant species. AB - Virus-induced gene silencing (VIGS) is an efficient tool for high throughput reverse genetic screens. VIGS engages the endogenous RNA-silencing machinery of the plant host, and can yield an 85-95% reduction of target transcripts. Gene silencing is rapid, target-specific, and does not require the creation of stable transformants. The technique has been used successfully in numerous Solanaceae species as well as in Arabidopsis, maize, and rice. Here we describe a protocol for conducting a VIGS screen in Nicotiana benthamiana using Tobacco Rattle Virus (TRV) based silencing vectors. This protocol can readily be adapted to many other model plant species. PMID- 20931373 TI - Agroinoculation and agroinfiltration: simple tools for complex gene function analyses. AB - Agroinoculation, first developed as a simple tool to study plant-virus interactions, is a popular method of choice for functional gene analysis of viral genomes. With the explosive growth of genomic information and the development of advanced vectors to dissect plant gene function, this reliable method of viral gene delivery in plants, has been recruited and morphed into a technique popularly known as agroinfiltration. This technique was developed to examine the effects of transient gene expression, with applications ranging from studies of plant-pathogen interactions, abiotic stresses, a variety of transient expression assays to study protein localization, and protein-protein interactions. We present a brief overview of literature which document both these applications, and then provide simple agroinoculation and agroinfiltration methods being used in our laboratory for functional gene analysis, as well as for fast-forward and reverse genetic screens using virus-induced gene silencing (VIGS). PMID- 20931374 TI - Full-length cDNA overexpressor gene hunting system (FOX hunting system). AB - Full-length cDNAs (fl-cDNAs) are important resources for the characterization of gene function, since they contain all the information required for the production of functional RNAs and proteins. Large sets of fl-cDNA clones have been collected from several plant species and have become available for functional genomic analysis. We have developed a system for the identification of gene function by screening for transgenic plants ectopically expressing fl-cDNAs and named it the FOX (fl-cDNA overexpressor gene) hunting system. This system can be applied to almost all plant species without prior knowledge of their genome sequences because only fl-cDNAs are required. For utilization of the FOX hunting system, Agrobacterium libraries and Arabidopsis seeds carrying rice and Arabidopsis fl cDNAs are available. Here, we will describe the procedure followed in the FOX hunting system from the generation of expression vectors carrying fl-cDNAs to the confirmation of phenotype in retransformed plants. PMID- 20931375 TI - Activation tagging with En/Spm-I /dSpm transposons in Arabidopsis. AB - Activation tagging is a powerful strategy to find new gene functions, especially from genes that are redundant or show lethal knock-out phenotypes. It has been applied using T-DNA or transposons. En/Spm-I/dSpm engineered transposons are efficient Activation tags in Arabidopsis. An immobilized transposase source and an enhancer-bearing non-autonomous element are used in combination with positive and negative selectable markers to generate a population of single or low copy, stable insertions. This method describes the steps required to select the best parental lines, generate a population of stable insertions, and gene identification. PMID- 20931376 TI - Activation tagging and insertional mutagenesis in barley. AB - The process of activation tagging in plants involves the random distribution of plant regulatory sequences throughout the genome. The insertion of a regulatory sequence in the vicinity of an endogenous gene can alter the transcriptional pattern of this gene resulting in a mutant phenotype that arises from excess functional gene product. Activation tagging has been undertaken extensively in a number of dicot plants and also in rice. This has been achieved primarily by high throughput plant transformation using T-DNA sequences that encode regulatory elements. Apart from rice, most cereals do not have a suitably efficient transformation system for high-throughput transformation. In this article, we detail an activation tagging system in barley that exploits the mobility of the maize Ac/Ds transposable element system to distribute a highly expressed promoter throughout the barley genome. The advantage of this approach in this species is that a relatively small number of primary transgenics are required to generate an activation tagging population. Insertion of this transposable element into genes can also generate insertional inactivation mutants enabling both gene overexpression and gene knockout mutants to be identified in the same population. PMID- 20931377 TI - Methods for rice phenomics studies. AB - With the completion of the rice genome sequencing project, the next major challenge is the large-scale determination of gene function. A systematic phenotypic profiling of mutant collections will provide major insights into gene functions important for crop growth or production. Thus, detailed phenomics analysis is the key to functional genomics. Currently, the two major types of rice mutant collections are insertional mutants and chemical or irradiation induced mutants. Here we describe how to manipulate a rice mutant population, including conducting phenomics studies and the subsequent propagation and seed storage. We list the phenotypes screened and also describe how to collect data systematically for a database of the qualitative and quantitative phenotypic traits. Thus, data on mutant lines, phenotypes, and segregation rate for all kinds of mutant populations, as well as integration sites for insertional mutant populations, would be searchable, and the collection would be a good resource for rice functional genomics study. PMID- 20931378 TI - Development of an efficient inverse PCR method for isolating gene tags from T-DNA insertional mutants in rice. AB - The central goal of current genomics research in plants, as in other organisms, is to elucidate the functions of every gene. Insertional mutagenesis using known DNA sequences such as T-DNA is a powerful tool in functional genomics. Development of efficient methods for isolating the genomic sequences flanking insertion elements accelerates the systematic cataloging of insertional mutants, and thus allows functions to be assigned to uncharacterized genes via reverse genetic approaches. In our current study, we report a rapid and efficient inverse PCR (iPCR) method for the isolation of gene tags in T-DNA mutant lines of rice (Oryza sativa), a model monocot plant. PMID- 20931379 TI - Transposon insertional mutagenesis in rice. AB - Insertion mutants offer one of the direct ways to relate a gene to its function by employing forward or reverse genetics approaches. Both T-DNA and transposon insertional mutants are being produced in several crops, including rice, the first cereal with its complete genome sequenced. Transposons have several advantages over T-DNA including the ability to produce multiple independent insertion lines from individual starter lines, as well as producing revertants by remobilization. With our new gene constructs, and a two-component transposon iAc/Ds mutagenesis protocol, we have improved both gene trapping and screening efficiencies in rice. PMID- 20931380 TI - Reverse genetics in medicago truncatula using Tnt1 insertion mutants. AB - Medicago truncatula has been chosen as one of the two model species for legume molecular genetics and functional genomics studies. With the imminent completion of M. truncatula genome sequencing, availability of large-scale mutant populations becomes a priority. Over the last 5 years, nearly 12,000 insertion lines, which represent approximately 300,000 insertions, have been generated at the Samuel Roberts Noble Foundation using the tobacco retrotransposon Tnt1. Individual genomic DNA was isolated from each insertion line and pooled into four levels with the super-pool containing 500 lines. Using Tnt1-specific and gene specific primers, a PCR-based efficient reverse screening strategy has been developed. Amplified PCR products are purified and sequenced to identify the exact insertion locations. Overall, approximately 90% of genes screened were found to have one or more Tnt1 insertions. Therefore, this PCR-based reverse screening is a rapid way of identifying knock-out mutants for specific genes in Tnt1-tagged population of M. truncatula. In addition to the DNA pool screening, a web-based database with more than 13,000 flanking sequence tags (FSTs) has also been set up. One can search the database to find an insertion line for the gene of interest. PMID- 20931381 TI - Screening Arabidopsis genotypes for drought stress resistance. AB - A high throughput drought screen is described for Arabidopsis that is based on a gravimetric method to monitor and control water content of the soil. To screen for plant growth under mild drought conditions, 30% of field capacity can be used, which is equal to 2 g H(2)O/g dry soil. The screen allows the testing of a large number of plants of different sizes to the same level of soil water. Therefore, response to drought of different genotypes can be compared. This method can be used for knockout or overexpression genotypes, which are evaluated for their drought response in terms of their growth measured by change in biomass. PMID- 20931382 TI - Protein tagging for chromatin immunoprecipitation from Arabidopsis. AB - A powerful method to identify binding sites in target genes is chromatin immunoprecipitation (ChIP), which allows the purification of in vivo formed complexes of a DNA-binding protein and associated DNA. Briefly, the method involves the fixation of plant tissue and the isolation of the total protein-DNA mixture, followed by an immunoprecipitation step with an antibody directed against the protein of interest and, subsequently, the DNA can be purified. Finally, the DNA can be analyzed by PCR for the enrichment of specific regions. A drawback of ChIP is that for each protein another antibody is needed. To overcome this, a generic strategy is possible using tags fused to the protein of interest. In this case, only antibody is needed against the tag. This protocol describes the tagging of proteins and how to perform ChIP. PMID- 20931383 TI - Yeast one-hybrid screens for detection of transcription factor DNA interactions. AB - The yeast one-hybrid system is widely recognized as a valuable and straightforward technique to study interactions between transcription factors and DNA. By means of one-hybrid screens, transcription factors or other DNA-binding proteins, expressed from cDNA expression libraries, can be identified due to the interactions with a DNA sequence-of-interest that is linked to a reporter gene, such as the yeast HIS3 gene. Usually, the library is constructed in an E. coli yeast shuttle vector designed for production of hybrid proteins consisting of a library protein and the trans-activating domain (AD) from the yeast GAL4 transcription factor. Here, we describe an optimized system of vectors for one hybrid screenings together with detailed step-wise protocols, an elaborate trouble-shooting guide and many technical tips to conduct successful screenings. This system and other yeast genetic selection procedures derived from one-hybrid methodology proved highly useful to help understanding the regulatory networks controlling expression of the genome. PMID- 20931384 TI - Plant metabolomics by GC-MS and differential analysis. AB - Metabolomics is a new genomics approach that aims at measuring all or a subset of metabolites in the cell. Several approaches to plant metabolomics are currently used in plant research. These include targeted analysis, metabolite profiling, and metabolic fingerprinting. Metabolic fingerprinting, unlike metabolite profiling, does not aim at separating or identifying all the metabolites present in the sample, but rather generates a fingerprint that characterizes a specific metabolic state of the plant system under investigation. This chapter describes the implementation of metabolic fingerprinting approach using gas chromatography coupled to mass spectrometry (GC-MS) and discriminant function analysis combined with genetic algorithm (GA-DFA). This approach enables the identification of specific metabolites that are biologically relevant, and which may go undetected if direct infusion-based fingerprinting approaches were used due to the sample complexity and matrix suppression effects. PMID- 20931385 TI - Gramene database: a hub for comparative plant genomics. AB - The rich collection of known genetic information and the recent completion of rice genome sequencing project provided the cereal plant researchers a useful tool to investigate the roles of genes and genomic organization that contribute to numerous agronomic traits. Gramene ( http://www.gramene.org ) is a unique database where users are allowed to query and explore the power of genomic colinearity and comparative genomics for genetic and genomic studies on plant genomes. Gramene presents a wholesome perspective by assimilating data from a broad range of publicly available data sources for cereals like rice, sorghum, maize, wild rice, wheat, oats, barley, and other agronomically important crop plants such as poplar and grape, and the model plant Arabidopsis. As part of the process, it preserves the original data, but also reanalyzes for integration into several knowledge domains of maps, markers, genes, proteins, pathways, phenotypes, including Quantitative Trait Loci (QTL) and genetic diversity/natural variation. This allows researchers to use this information resource to decipher the known and predicted interactions between the components of biological systems, and how these interactions regulate plant development. Using examples from rice, this article describes how the database can be helpful to researchers representing an array of knowledge domains ranging from plant biology, plant breeding, molecular biology, genomics, biochemistry, genetics, bioinformatics, and phylogenomics. PMID- 20931386 TI - MicroRNA biogenesis and cancer. AB - MicroRNAs are short non-coding RNA molecules that are involved in diverse physiological and developmental processes by controlling the gene expression of target mRNAs. They play important roles in almost all kinds of cancer where they modulate key processes during tumorigenesis such as metastasis, apoptosis, proliferation, or angiogenesis. Depending on the mRNA targets they regulate, they can act as oncogenes or as tumor suppressor genes. Multiple links between microRNA biogenesis and cancer highlight its significance for tumor diseases. However, mechanisms of their own regulation on the transcriptional and posttranscriptional level in health and disease are only beginning to emerge. Here, we review the microRNA-processing pathway as well as recent insights into posttranscriptional regulation of microRNA expression. PMID- 20931387 TI - Computational identification of miRNAs involved in cancer. AB - Changes in the structure and/or the expression of protein-coding genes were thought to be the major cause of cancer for many decades. However, the recent discovery of non-coding RNA (ncRNA) transcripts suggests that the molecular biology of cancer is far more complex. MicroRNAs (miRNAs) are key players of the family of ncRNAs and they have been under extensive investigation because of their involvement in carcinogenesis, often taking up roles of tumor suppressors or oncogenes. Owing to the slow nature of experimental identification of miRNA genes, computational procedures have been applied as a valuable complement to cloning. Numerous computational tools, implemented to recognize the characteristic features of miRNA biogenesis, have resulted in the prediction of multiple novel miRNA genes. Computational approaches provide valuable clues as to which are the dominant features that characterize these regulatory units and furthermore act by narrowing down the search space making experimental verification faster and significantly cheaper. Moreover, in combination with large-scale, high-throughput methods, such as deep sequencing and tilling arrays, computational methods have aided in the discovery of putative molecular signatures of miRNA deregulation in human tumors. This chapter focuses on existing computational methods for identifying miRNA genes, provides an overview of the methodology undertaken by these tools, and underlies their contribution toward unraveling the role of miRNAs in cancer. PMID- 20931388 TI - The principles of MiRNA-masking antisense oligonucleotides technology. AB - MiRNA-masking antisense oligonucleotides technology (miR-mask) is an anti microRNA antisense oligodeoxyribonucleotide (AMO) approach of a different sort. A standard miR-mask is single-stranded 2'-O-methyl-modified oligoribonucleotide (or other chemically modified) that is a 22-nt antisense to a protein-coding mRNA as a target for an endogenous miRNA of interest. Instead of binding to the target miRNA like an AMO, an miR-mask does not directly interact with its target miRNA but binds to the binding site of that miRNA in the 3' UTR of the target mRNA by fully complementary mechanism. In this way, the miR-mask covers up the access of its target miRNA to the binding site so as to derepress its target gene (mRNA) via blocking the action of its target miRNA. The anti-miRNA action of an miR-mask is gene-specific because it is designed to be fully complementary to the target mRNA sequence of an miRNA. The anti-miRNA action of an miR-mask is miRNA-specific as well because it is designed to target the binding site of that particular miRNA. The miR-mask approach is a valuable supplement to the AMO technique; while AMO is indispensable for studying the overall function of an miRNA, the miR-mask might be more appropriate for studying the specific outcome of regulation of the target gene by the miRNA. This technology was first established by my research group in 2007 (Xiao et al., J Cell Physiol 212:285-292; Wang et al., J Mol Med 86:772-783, 2008) and a similar approach with the same concept was subsequently reported by Schier's laboratory (Choi et al., Science 318:271-274, 2007). PMID- 20931389 TI - The concept of multiple-target anti-miRNA antisense oligonucleotide technology. AB - The multiple-target AMO technology or MT-AMO technology is an innovative strategy, which confers on a single AMO fragment the capability of targeting multiple miRNAs. This modified AMO is single-stranded 2'-O-methyl-modified oligoribonucleotides carrying multiple AMO units, which are engineered into a single unit and are able to simultaneously silence multiple-target miRNAs or multiple miRNA seed families. Studies suggest that the MT-AMO is an improved approach for miRNA target finding and miRNA function validation; it not only enhances the effectiveness of targeting miRNAs but also confers diversity of actions. It has been successfully used to identify target genes and cellular function of several oncogenic miRNAs and of the muscle-specific miRNAs (Lu et al., Nucleic Acids Res 37:e24-e33, 2009). This novel strategy may find its broad application as a useful tool in miRNA research for exploring biological processes involving multiple miRNAs and multiple genes, and the potential as an miRNA therapy for human disease such as cancer and cardiac disorders. This technology was developed by my research laboratory in collaboration with Yang's group (Lu et al., Nucleic Acids Res 37:e24-e33, 2009), and it is similar but distinct from the miRNA Sponge technology developed by Sharp's laboratory in 2007 (Ebert et al., Nat Methods 4:721-726, 2007) and modified by Gentner et al. (Nat Methods 6:63-66, 2009). PMID- 20931390 TI - Modulation of microRNAs for potential cancer therapeutics. AB - MicroRNA (miRNA) is a nonprotein coding small RNA molecule that negatively regulates gene expression by degradation of mRNA or suppression of mRNA translation. MiRNA plays important roles in physiological processes such as cellular development, differentiation, proliferation, apoptosis, and stem cell self-renewal. Studies show that the deregulation of miRNA expression is closely associated with tumorigenicity, invasion, and metastasis. The functionality of miRNAs may act as oncogenes or tumor suppressors during tumor initiation and progression. miRNomes in almost all types of cancers started to develop the regulatory network of miRNA::mRNA interaction in the view of systems biology. Experimental evidence demonstrates that the modulation of specific miRNA alterations in cancer cells using miRNA replacement or anti-miRNA technologies can restore miRNA activities and repair the gene regulatory network and signaling pathways, in turn, reverse the phenotype of cancerous cells. Numerous animal studies for miRNA-based therapy offer the hope of targeting miRNAs as alternative cancer treatment. Developing the small molecules to interfere with miRNAs could be of great pharmaceutical interest in the future. Interestingly, specific miRNA is capable of reprogramming the cancer cells into a pluriopotent embryonic stem cell-like state (mirPS), which could be induced into tissue-specific mature cell types. This chapter will present the various strategies of modulation of miRNAs in vitro and in vivo. PMID- 20931391 TI - Detection of microRNAs in cultured cells and paraffin-embedded tissue specimens by in situ hybridization. AB - Determination of gene expression is essential for understanding the role of a given gene in normal cell growth or disease processes. Recently, newly described microRNAs have been shown to play a key role in the regulation of gene expression; in particular, deregulation of microRNAs is often associated with a variety of human disorders including cancer. Although microRNAs are small RNA molecules with about 20-23 nucleotides in length and detection of their expression is believed to be challenging, with the introduction of modified nucleotides such as locked nucleic acid, the specificity and sensitivity of detection have been greatly improved. There are many methods developed for microRNA detection, but our focus in this chapter is on in situ hybridization (ISH) detection of microRNAs. We have successfully used ISH to detect several microRNAs in paraffin-embedded tumor specimens or cells-cultured in vitro. PMID- 20931392 TI - MicroRNA Northern blotting, precursor cloning, and Ago2-improved RNA interference. AB - Aberrant expression of microRNAs (miRNAs) and processing defects in their biogenesis pathway are a widespread phenomenon in tumors, conveying great importance to the analysis of miRNA expression, regulation, and biogenesis to gain knowledge about their role in cancer. Besides Drosha and Dicer, Argonaute proteins are key players in miRNA processing. In addition to their role as components of the RNA-induced silencing complex (RISC) executing target silencing, Argonautes mediate posttranscriptional regulation of miRNA maturation by creating an additional intermediate processing step, the Ago2-cleaved precursor miRNA (ac-pre-miRNA), and enhancing the production or stability of mature miRNAs. Here, we describe the detection of miRNA levels by Northern blotting and the identification of the 3' end of miRNAs by precursor cloning to accentuate two of the many roles of Argonaute proteins. In addition, we describe a method to optimize RNAi experiments by increasing the efficacy and specificity of target silencing via Ago2 cotransfection. PMID- 20931393 TI - miRNA profiling on high-throughput OpenArrayTM system. AB - Micro RNA (miRNAs) are a class of 17-25 nucleotides noncoding RNAs that have been shown to have critical functions in a wide variety of biological processes. Measuring quantity of miRNAs in tissues of different physiological and pathological conditions is an important first step to investigate the functions of miRNAs. To this date, the number of identified miRNA consists of around 850 different species, and more sequence-predicted miRNA genes are awaiting experimental confirmation. The need for high-throughput technologies allowing to profile all known miRNAs with power similar to microarray and precision/specificity of qPCR is evident. The example of such system based on high-density array of nanoliter PCR assays is described here. Functionally equivalent to a microtiter plate, a single OpenArrayTM nanoplate makes possible to do up to 3,072 real-time PCRs at a single experiment. Methods for miRNA profiling using the dual-label probe chemistry (Taqman((r))) are outlined in this chapter, and experimental data illustrating system performance are provided. PMID- 20931394 TI - Silicon nanowire biosensor for ultrasensitive and label-free direct detection of miRNAs. AB - MicroRNA (miRNA), a large and growing class of 18-24-nucleotide long, noncoding RNA molecules in all known animal and plant genomes, is a key player in gene regulation. The functions of miRNA are yet to be understood with respect to how and where it is produced and the changes within an organism associated with variations in miRNA expression level. The expression profiles serve as molecular diagnostics for diseases and new targets in drug discovery. Consequently, highly sensitive and selective detection of miRNA is playing a significant role in understanding miRNA functions. Existing major methods of detecting miRNA are dependent on hybridization, in which a target miRNA molecule is hybridized to a complementary probe molecule. Recently developed detection methods introduce nanomaterials to the hybridized duplex to enhance the sensitivity. However, all of them are indirect, involving labeling or conjugating process. To overcome the above-mentioned issues, we have demonstrated a highly sensitive and label-free direct detection method for miRNA by using peptide nucleic acids (PNAs) functionalized silicon nanowires (SiNWs) biosensor. The sensor is capable of detecting target miRNA as low as 1 fM (10(-15) M), as well as identifying fully matched versus mismatched miRNA sequences. More importantly, the SiNW biosensor enables miRNA detection in total RNA extracted from HeLa cells. The developed detection method shows potential applications in label-free, early detection of miRNA as a biomarker in cancer diagnostics with very high sensitivity and good specificity. PMID- 20931395 TI - High-throughput and reliable protocols for animal microRNA library cloning. AB - MicroRNAs are short single-stranded RNA molecules (18-25 nucleotides). Because of their ability to silence gene expressions, they can be used to diagnose and treat tumors. Experimental construction of microRNA libraries was the most important step to identify microRNAs from animal tissues. Although there are many commercial kits with special protocols to construct microRNA libraries, this chapter provides the most reliable, high-throughput, and affordable protocols for microRNA library construction. The high-throughput capability of our protocols came from a double concentration (3 and 15%, thickness 1.5 mm) polyacrylamide gel electrophoresis (PAGE), which could directly extract microRNA-size RNAs from up to 400 MUg total RNA (enough for two microRNA libraries). The reliability of our protocols was assured by a third PAGE, which selected PCR products of microRNA size RNAs ligated with 5' and 3' linkers by a miRCatTM kit. Also, a MathCAD program was provided to automatically search short RNAs inserted between 5' and 3' linkers from thousands of sequencing text files. PMID- 20931396 TI - MicroRNA regulation of growth factor receptor signaling in human cancer cells. AB - Aberrant expression of the epidermal growth factor receptor (EGFR) and/or human epidermal growth factor receptor 2 (HER2) is a feature of many human tumors and is associated with disease progression, treatment resistance, and poor prognosis. Protein kinase B/Akt, an important downstream effector of these receptor tyrosine kinases, induces signaling pathways that control cancer cell proliferation, invasion, angiogenesis, and apoptosis resistance. MicroRNAs (miRNAs), small noncoding RNAs that bind to the 3'-untranslated region of target mRNAs, are now recognized to play key roles in the regulation of gene expression, particularly in tumor development and metastasis. We have shown that miRNA-7 (miR-7) and miRNA 331-3p (miR-331-3p) directly regulate expression of EGFR and HER2, respectively, in glioblastoma and prostate cancer cell lines. As a consequence, miR-7 and miR 331-3p reduce Akt activity and thus have the capacity to regulate a signaling pathway critical to the development and progression of glioblastoma and prostate cancer. This chapter provides a detailed approach outlining how to confirm that a putative target of a miRNA is a direct target, and subsequent assessment of downstream signaling mediators. PMID- 20931397 TI - Epigenetic regulation of microRNA expression in cancer. AB - Epigenetic gene regulation is important in human cancer. Both functional and observational data implicate alterations of histone modifications, DNA promoter methylation, and non-coding RNA expression in carcinogenic roles. We sought to explore the role of aberrant DNA hypermethylation in the regulation of microRNA (miR) expression in human cancer. From human genome databases we calculated that 13 and 28% of human miR genes are located within 3 and 10 kb of a CpG island, respectively. To identify miRs that are regulated by epigenetic mechanisms in cancer, we performed expression profiling prior to and following treatment of cell lines with 5-azacytidine. We used oligonucleotide microarrays to determine miR expression. For miRs whose expression changed following 5-azacytidine treatment, we sequenced the adjacent CpG island and promoter using bisulphite treated DNA. Here, we describe these methods to enable other researchers to use this approach. PMID- 20931398 TI - In vitro functional study of miR-126 in leukemia. AB - MicroRNAs (miRNAs, miRs) are postulated to be important regulators in various cancers, including leukemia. In a large-scale miRNA expression profiling analysis of 435 human miRNAs in 52 acute myeloid leukemia (AML) samples, we found that miR 126 and its minor counterpart in biogenesis, namely, miR-126*, were specifically aberrantly overexpressed in core binding factor (CBF) AMLs including both t(8;21)/AML1-ETO and inv(16)/CBFB-MYH11 samples. Our in vitro gain- and loss-of function experiments showed that forced expression of miR-126 inhibited apoptosis and increased the viability of AML cells, whereas the opposite effect was observed when endogenous expression of miR-126 was knocked down. In addition, through in vitro colony-forming/replating assays, we demonstrated that forced expression of miR-126 enhanced proliferation and colony-forming/replating capacity of mouse normal bone marrow progenitor cells alone and particularly, in cooperation with AML1-ETO, a fusion gene resulting from t(8;21). Thus, our data shows that miR-126 may play a critical role in the development of CBF leukemias. In the present chapter, the materials and protocols for the study of miR-126 in leukemia are described. PMID- 20931399 TI - Prediction of the biological effect of polymorphisms within microRNA binding sites. AB - MicroRNAs (miRNAs) are negative gene regulators acting at the 3'UTR level, modulating the translation of cancer-related genes. Single-nucleotide polymorphisms (SNPs) within the 3'UTRs could impact the miRNA-dependent gene regulation either by weakening or by reinforcing the binding sites. Thus, the alteration of the normal regulation of a given gene could affect the individual's risk of cancer. Therefore, it is helpful to develop a tool enabling the researchers to predict which of the many SNPs could really impact the regulation of a target gene. At present, there are several available databases and algorithms able to predict potential binding sites in the 3'UTR of genes. However, each algorithm gives different predictions and none of them gives, for each polymorphism, a direct measurement of the biological impact. We propose an approach allowing the assignment to each polymorphism a ranking of its biological impact. The method is based on a simple elaboration of predictions from preexisting well-established algorithms. As an example, we show the application of this approach to 140 genes candidate for colorectal cancer (CRC). These genes were identified following a genome-wide sequencing of 20,857 transcripts from 18,191 genes in 11 CRC specimens and were found somatically mutated and thought to be crucial for the development of cancer. PMID- 20931400 TI - The guideline of the design and validation of MiRNA mimics. AB - The miRNA mimic technology (miR-Mimic) is an innovative approach for gene silencing. This approach is to generate nonnatural double-stranded miRNA-like RNA fragments. Such an RNA fragment is designed to have its 5'-end bearing a partially complementary motif to the selected sequence in the 3'UTR unique to the target gene. Once introduced into cells, this RNA fragment, mimicking an endogenous miRNA, can bind specifically to its target gene and produce posttranscriptional repression, more specifically translational inhibition, of the gene. Unlike endogenous miRNAs, miR-Mimics act in a gene-specific fashion. The miR-Mimic approach belongs to the "miRNA-targeting" and "miRNA-gain-of function" strategy and is primarily used as an exogenous tool to study gene function by targeting mRNA through miRNA-like actions in mammalian cells. The technology was developed by my research group (Department of Medicine, Montreal Heart Institute, University of Montreal) in 2007 (Xiao, et al. J Cell Physiol 212:285-292, 2007; Xiao et al. Nat Cell Biol, in review). PMID- 20931401 TI - Analysis of targets and functions coregulated by microRNAs. AB - MicroRNAs (miRNAs) are small, nonprotein-coding RNAs that negatively regulate their mRNA target genes in a sequence-specific manner. While their specific impact on biological processes and cellular functions remain largely unknown, dysregulated miRNAs have been implicated in numerous diseases, including cancers. Several large-scale profiling studies using tissue samples have revealed a consistent yet complex pattern of miRNA dysregulation in human cancer. In particular, global alteration of multiple miRNAs is common in human tumorigenesis. Systemic analysis of pathways and functions coregulated by these dysregulated miRNAs is a crucial step to understand the role of miRNAs in tumorigenesis. This chapter provides an integrated pipeline to identify cellular pathways and functions specifically regulated by multiple dysregulated miRNAs. Protocols described in this chapter include (1) miRNA target prediction using TargetScan algorithm, (2) data compilation to identify target genes coregulated by multiple miRNAs, and (3) pathway enrichment analysis of coregulated targets using MetaCore pathway and network database. PMID- 20931402 TI - Utilization of SSCprofiler to predict a new miRNA gene. AB - Experimental identification provides a valuable yet slow and expensive method for predicting novel miRNA genes. With the advent of computational procedures, it is now possible to capture characteristic features of miRNA biogenesis in an in silico model, resulting thereafter in the fast and inexpensive prediction of multiple novel miRNA gene candidates. These computational tools provide valuable clues to experimentalists, allowing them to narrow down their search space, making experimental verification less time consuming and less costly. Furthermore, the computational model itself can provide biological information as to which are the dominant features that characterize these regulatory units. Moreover, large-scale, high-throughput techniques, such as deep sequencing and tiling arrays, require computational methods to analyze this vast amount of data. Computational miRNA gene prediction tools are often used in synergy with high throughput methods, aiding in the discovery of putative miRNA genes. This chapter focuses on a recently developed computational tool (SSCprofiler) for identifying miRNA genes and provides an overview of the methodology undertaken by this tool, and defines a stepwise guideline on how to utilize SSCprofiler to predict novel miRNAs in the human genome. PMID- 20931403 TI - MicroRNA profiling using fluorescence-labeled beads: data acquisition and processing. AB - The discovery of small regulatory RNA molecules during the last years has changed our understanding of many biological and pathological processes. The most prominent and best analyzed class of these small regulatory noncoding RNAs is composed of the microRNAs. The analysis of microRNA expression patterns is now widely used in biology and pathology employing a range of methodologies. However, procedures for data processing and calculations are far from standardized and differ considerably between published studies. This makes comparisons and meta analyses still quite difficult. In this chapter, we describe a modified method for normalization and processing of raw data obtained if utilizing fluorescence labeled bead technology from Luminex. Inc. PMID- 20931404 TI - Schizophrenia, language and evolution (or the schizophrenias as logopathies). AB - Ever since the distinction between praecox dementia and manic-depressive illness made by Kraepelin in 1899, many changes have occurred in the way these conditions and especially their boundaries are conceived. The clearest example is the extraordinary increase in the diagnoses of bipolar disease with respect to those of schizophrenia. But there have also been important changes within each one of these categories. In the first case, the separation of schizo- affective and cycloid psychoses, and in the second, the distinction between mono and bipolar disease. Then there is the description of innumerable forms of monopolar depression1 or, on the contrary, the postulation of the existence of only one endogenous-melancholic syndrome by Tellenbach, an idea which is shall come up again, although from another methodological perspective, in the concept of major depression of DSM III. The present author thinks that this state of nosological confusion has to do, on one hand, with the improper combination of descriptive and etiological criteria,and on the other, with the application of categorical criteria to complex realities, without an organic basis supporting them.The present author proposes a logopathies/thymopathies dichotomy. The first would include all forms of schizophrenia,paraphrenias and paranoias. The second would correspond to the affective disorders and also to a great part of the so called "anxiety disorders". In this first part he develops the subject of the logopathies, trying to demonstrate the legitimacy of the concept upon the basis of three fundamental arguments: (i) Alteration of the thought/language as a nucleus of schizophrenic suffering. (ii) Schizophrenia is a constitutive element of the human condition. And (iii)Schizophrenia appears as a perturbation of Verstehen (understanding),as described by Heidegger in Being and Time as one of the ways Dasein (human being) is present in the world, together with Befindlichkeit (attunement or state-of mind),which is precisely what would be altered in thymopathies. PMID- 20931405 TI - Topiramate in the treatment of alcohol dependence: a meta-analysis. AB - Several controlled clinical trials have studied the efficacy of topiramate in the treatment of alcoholism. In this paper, we have performed a meta-analysis of those trials in which topiramate was compared with placebo and then we reviewed its efficacy in trials in which it was compared with other drugs. METHOD: A quantitative synthesis of data was per-formed using inverse variance weighting in a random effects model. RESULTS: Based on three placebo-controlled trials, topiramate is more efficacious than placebo in reducing the percentage of heavy drinking days (23.2%, 95% confidence interval [CI]: 15.7 to 34.4), increasing the number of days of abstinence (mean difference: 2.9 days, 95% CI: 2.5 to 3.3),and lowering the logarithm of g-GT levels (mean difference:0.075 95% CI: 0.048 to 0.118). Two trials suggested that topiramate is also more efficacious than naltrexone, and one open-label study reported better results for disulfiram than for topiramate. CONCLUSION: Topiramate can be used in alcohol dependence. Adverse effects such as paresthesia or insomnia should be taken into account when prescribing topiramate.Its optimal dosage requires further research. PMID- 20931406 TI - Observational, open-label, prospective multicenter study of sexual function in patients starting treatment with aripiprazole. AB - INTRODUCTION: Treatment with neuroleptics may be associated with secondary sexual dysfunction. Studies of sexual dysfunction induced by antipsychotic are important to establish the effectiveness of these agents in patients taking chronic treatments. The main objective of this study was to evaluate prospectively whether a 3 month course ofaripiprazole produces changes in the sexual function of patients with schizophrenia. METHODS: The efficacy analysis was performed in the intention-to-treat population (41 patients) and the per protocol population (36 patients). The safety analysis was based on the total sample (42 patients). RESULTS: The incidence of sexual dysfunction after 3 months of treatment with aripiprazole was zero both in patients who switched therapy due to lack of efficacy and in those taking aripiprazole as a first antipsychotic. Aripiprazole led to an improvement in the symptoms of psychosis (score on the BPRS) and lower scores on the SALSEX questionnaire.The most remarkable improvement was in delayed eyaculation/orgasm. CONCLUSION: During the 3 months of treatment, we observed an overall improvement in sexual performance, with a quicker recovery in men than in women, although recovery was similar in both at the end of treatment. PMID- 20931407 TI - Neurobiological bases of quetiapine antidepresant effect in the bipolar disorder. AB - Bipolar disorder is considered an important public health problem in the world. The depressive phase is the most important in terms of frequency, duration, and impairment of the quality of life. Common treatment of bipolar depression usually includes antidepressants, mood stabilizers and antipsychotics in different combinations, despite not having a specific indication for that. Quetiapine is the first drug in Europe that has obtained a specific indication for the treatment of bipolar depression, due to a pharmacologic profile that makes it to act on the three neurotransmitter systems involved in bipolar depression neurobiology. Regarding the dopaminergic pathway, quetiapine leads to an increasing of prefrontal dopamine release by antagonism of5-HT2A receptors, partial agonist of 5-HT1A and antagonism of a2 adrenoceptors. Quetiapine also enhances the serotoninergic transmission by increasing the density of receptors5 HT1A in the prefrontal cortex and by antagonism of 5-HT2A receptors and a2 adrenoceptors. On the other hand, norquetiapine, the main active metabolite of quetiapine, actsas a 5-HT2C antagonist and is a potent inhibitor of norepinephrine transporter (NET). NET inhibition leads to an increase of noerpinephrine in the synapse, and together with the increase of prefrontal dopamine and serotonin, could explain the antidepressive effect demonstrated by quetiapine in several clinical trials. Quetiapine's action on glutamatergicand GABAergic receptors represents an interesting object of research, together with a potential neuroprotective effect that have already been observed in animal models. PMID- 20931408 TI - Adaptation of the wisconsin scales of psychosis proneness to Spanish. AB - INTRODUCTION: Nowadays the study of vulnerability to psychosis and early intervention is an area of great clinical impact and research. The aim of this study was to adapt the Wisconsin Scales of Vulnerability to Psychosis from English to Spanish. A set of five scales (Magical Ideation, Perceptual Aberration, Physical Anhedonia, Revised Social Anhedonia and Ambivalence) assess schizotypal traits in the general population and the possible risk of developing disorders embedded in the psychotic spectrum. Additionally, this tool contains a scale of Hypomaniac Personality to detect risk of affective spectrum psychosis. METHODOLOGY: The Wisconsin Scales of Vulnerability to Psychosis have been adapted following the back-translation method. The scales were translated to an original Spanish version, which was then translated again into English in order to assess the conceptual and semantic overlap with the original items. RESULTS: All the items were back-translated and evaluated in respect to the original ones by an expert in the scales, and all of them were rated with a perfect equivalence (Type A) or satisfactory (Type B). CONCLUSIONS: The Spanish version of the Wisconsin Scales of Vulnerability to Psychosis shows good equivalence with the English one, thus allowing to measure affective and schizotypal traits in samples of Spanish speaking individuals properly. Future studies should test the reliability and validity of these scales in our environment. PMID- 20931409 TI - The axial diagnostic and sensitive-to-change for depression index: diagnostic utility and use in studies of therapeutic evaluation. AB - INTRODUCTION: The authors develop a new rating scale for to measure its sensibility to the change of the intensity of the depressive symptoms under the effects of antidepressants drugs, and for to analyze the predictive validity of its total score. Designate it: The Axial Diagnostic and Sensitive-to-Change for Depression Index (ADSCDI). For this, use only seven nuclear items for the depression diagnosis (mood, interest, impulse/drive, pleasure, energy, daily job and different quality) without vegetative symptoms or anxious. METHODOLOGY: The authors interview to 111 psychiatric outpatients attended consecutively in a Mental Health Center. Sixty were fulfilling the criteria for depressive episode of the ICD-10 and fifty and one were forming part of the group of control: psychiatric outpatients not depressed. They use for this a protocol of collection of data that contains the ADSCDI, where the patients indicate how are found on a Visual Analogical Scale in the one which quantify their answers in each item, the Hamilton Rating Scale for Depression of 17 articles (HRSD-17) and an Global Clinical Impression scale (GCI). Each depressed patient receipt the antidepressant treatment that better were adjusted to his clinical profile according to the psychiatrist that was trying to him. The depressed patients were evaluated a second time after thirty days of treatment. RESULTS: All the items of the ADSCDI perceive a change statistically significant in the intensity of the depressive symptoms (p=0.00). The total score of the ADSCDI, also, at same level of statistical significance that the total scores of the HRSD-17 and of the GCI p=0.000). The ADSCDI interrelates high and significatively with the HRSD-17 as with the GCI (r=0.77 and r=0.73 respectively; p=0.00). Equally makes it with the average of the "proportion of improvement" that evaluates, with the one evaluated by the HRSD-17 and the GCI (r=0.74 and r=0.68 respectively; p=0.000). A cut-off of 39 offers the best predictive values for the ADSCDI respect to the clinical and the ICD-10 criteria for depression. With a sensibility of 0.97, a specificity of 0.76 (of 0.88 with psychiatric patients free of symptoms), a total probability of guessing right of 93% and a kappa reliability of 0.74. The results improve when the ADSCDI is used as external criterion. For this new operative diagnostic criteria (ADCD), a cut-off of 40 offers a sensibility of 1.00, a specificity of 0.96 a probability of guessing right of 99% and a kappa reliability of 0.96. CONCLUSIONS: The ADSCDI offers sufficient concurrent validity with the HRSD-17 and the GCI. It can be considered a sensitive instrument to the change, with the advantage of containing, only, items that have shown be frequent, discriminant and predictives. The ADSCDI also is a good instrument to establish diagnostic of depression in the system ADCD/ADSCDI or in the ICD-10 one. PMID- 20931410 TI - Emergency psychiatric condition, mental illness behavior and lunar cycles: is there a real or an imaginary association? AB - There is a fairly widespread belief regarding the influence of the moon phases on the psychological behavior in humans. This relationship could be more pronounced among patients with mental disorders. OBJECTIVE: To study the possible association between the incidence of psychiatric emergencies and moon phases and between the behaviors of psychiatric patients and moon phases. METHODS: Daily series of cases seen in psychiatric emergencies were established according to the condition, typical behaviors manifested and treatments received by patients admitted to the short-term in-patient psychiatric unit, and the brightness of the moon, from 11-1-2006 to 10-31-2007. The possible association between the first two with the second was examined by making cross-correlations in the tuning fork of delays from 0 to 7 days. RESULTS: No association appeared between moon phases and characteristics of psychiatric emergencies. In hospitalized patients, a correlation was observed between the moon phases and the bed occupancy rate, which was direct, weak but significant, decreasing until the third day after admission (0.20, 0.18, 0.16 and 0.11), while hypnotic medication intake increased with moon brightness moon until the second day after, also declining and significantly weakness (0.22, 0.19 and 0.15). CONCLUSIONS: The only empirical relationship of the moon phases with psychiatric behavior of the mentally ill in our sample was manifested as an increase in the incidence of cases and greater disruption of sleep patterns. PMID- 20931411 TI - Attitudes of the family toward the mentally ill patient? AB - INTRODUCTION: In this article the attitudes towards mental illness in those families who have mentally ill members is presented in order to compare them with those found 25 years before in a similar research. METHODOLOGY: In order to carry out the survey we used Struening and Cohen's Opinion about Mental Illness (OMI) questionnaire. adapted for use in Spain by Ylla and Guimon (1979). The population studied were the families associations of the mentally ill persons suffering from sychotic and affective disturbance. alcoholism and Alzheimer's dementia; the control group was made up of a number of Civil Servants and another section of health care workers. The samples were collected at random among the associated members. For the study we undertook a factorial analysis of the answers. RESULTS: The first five factors contain the greater part of the accumulated variation. that is to say 34.2%. 19 factors explain the whole 100% of the variation. The five principle factors are: (i) Mental hygiene (14% of the variation). (ii) therapeutic negativism (7% of the variation). (iii) Social reinsertion (4.87% of the variation). which was also similar to the following factor. (iv) social rehabilitation. and (v) authoritarism (3.62% of the variation). CONCLUSION: The extensive knowledge of these illnesses and a close relationship with those who are ill could be the cause of the large and diverse opinions and that some attitudes are more complex nowadays. According to these five principle factors we can see that the controls are appreciably less authoritarian and restrictive than that of the families of these ill people and that the attitudes vary depending on the age. profession and diagnosis of the illness. PMID- 20931412 TI - Mothers' Adult Attachment Interview ratings predict preschool children's IQ following domestic violence exposure. AB - This study examined links between mothers' Adult Attachment Interview ratings (AAI; Main, Goldwyn, & Hesse, 2003) and their preschool children's IQ among 70 families who had experienced domestic violence. As predicted, children displayed significantly stronger verbal and perceptual-organizational abilities when their mothers exhibited more secure, i.e. coherent, states of mind regarding attachment. Mothers' coherence of mind on the AAI explained 18% of the variance in children's Verbal IQ and 12% of the variance in children's Performance IQ, after controlling for maternal education. Mothers' attachment security also was related to children's total IQ score, but this association was accounted for by effects on children's Verbal IQ. Children whose mothers were rated as unclassifiable on the AAI and those whose mothers were unresolved/insecure had lower IQ scores. Although mothers who appeared more secure on the AAI were more sensitively responsive toward their children, mediational analyses suggested that there was a direct link between mothers' security and children's IQ that was not explained by sensitive parenting. This suggests that clinical interventions for children exposed to domestic violence should include helping their mothers achieve coherent ways of thinking about their own childhood experiences, including past trauma. PMID- 20931413 TI - Finnish mother's and father's attachment representations during child's first year predict psychosocial adjustment in preadolescence. AB - The aim of the longitudinal study was to examine, for the first time in a Nordic country, whether autonomous parenting in infancy affects psychosocial adjustment in preadolescence. Attachment representations of mothers and fathers were investigated with the Adult Attachment Interview in a community sample of two parent Finnish families. Most mothers and fathers were classified as autonomous, a finding which is in line with normative Western distributions. Moreover, the ratio of dismissing versus preoccupied adults was similar to Western norms. Demographic characteristics such as family structure and years of education differentiated autonomous from non-autonomous mothers. In preadolescence, the children who had experienced at least one autonomous parent were more empathic and had fewer problems in social relationships and thought processes compared to children of two non-autonomous parents. The findings suggest that autonomous parenting has long-term parent gender specific influences on children's psychosocial adjustment. PMID- 20931414 TI - Growing up in foster families or institutions: attachment representation and psychological adjustment of young adults. AB - This study considers whether type of placement (foster care versus institutional care) is related to patterns of attachment representation and the quality of psychological adjustment in a sample of 48 young adults, who grew up either in foster care or in institutions. The subjects were interviewed using the Adult Attachment Interview (George, Kaplan, & Main, 1996, [2001]) and their psychological adjustment was assessed by using the Brief Symptom Inventory (Derogatis, 1993; German version by Franke, 2000). The results show significantly more positive effects of foster care when compared with institutional upbringing. These findings support the possibility of a beneficial effect of an alternative stable (foster) family relationship for children's psychological development. Implications for assessing placement options for children following severe traumatization are discussed. PMID- 20931415 TI - Reflective functioning in mothers with drug use disorders: implications for dyadic interactions with infants and toddlers. AB - In this study, we examined maternal reflective functioning as a bi-dimensional construct in a sample of 47 mothers with drug use disorders caring for infants and toddlers. We first tested a two-factor solution with scale items from the Parent Development Interview and confirmed the presence of two related but distinct dimensions: self-mentalization and child-mentalization. We then tested predictions that (a) self-mentalization would be associated with overall quality of maternal caregiving and that (b) child-mentalization would be associated with (i) maternal contingent behavior and (ii) child communication. Results partially supported hypotheses (a) and (bii). Unexpectedly, self-mentalization alone was associated with maternal contingent behavior. Findings suggest that self mentalization may be a critical first step in improving mother-child relations involving mothers with drug use disorders. Implications for theory and practice are discussed. PMID- 20931416 TI - Assessment of the potential suitability of selected commercially available enzymes for cleaning-in-place (CIP) in the dairy industry. AB - The potential suitability of 10 commercial protease and lipase products for cleaning-in-place (CIP) application in the dairy industry was investigated on a laboratory scale. Assessment was based primarily on the ability of the enzymes to remove an experimentally generated milk fouling deposit from stainless steel (SS) panels. Three protease products were identified as being most suitable for this application on the basis of their cleaning performance at 40 degrees C, which was comparable to that of the commonly used cleaning agent, 1% NaOH at 60 degrees C. This was judged by quantification of residual organic matter and protein on the SS surface after cleaning and analysis by laser scanning confocal microscopy (LSCM). Enzyme activity was removed/inactivated under conditions simulating those normally undertaken after cleaning (rinsing with water, acid circulation, sanitation). Preliminary process-scale studies strongly suggest that enzyme-based CIP achieves satisfactory cleaning at an industrial scale. Cost analysis indicates that replacing caustic-based cleaning procedures with biodegradable enzymes operating at lower temperatures would be economically viable. Additional potential benefits include decreased energy and water consumption, improved safety, reduced waste generation, greater compatibility with wastewater treatment processes and a reduction in the environmental impact of the cleaning process. PMID- 20931417 TI - Levels of synthetic antioxidants (ethoxyquin, butylated hydroxytoluene and butylated hydroxyanisole) in fish feed and commercially farmed fish. AB - Several synthetic antioxidants are authorized for use as feed additives in the European Union. Ethoxyquin (EQ) and butylated hydroxytoluene (BHT) are generally added to fish meal and fish oil, respectively, to limit lipid oxidation. The study was conducted to examine the concentrations of EQ, BHT and butylated hydroxyanisole (BHA) in several commercially important species of farmed fish, namely Atlantic salmon, halibut and cod and rainbow trout, as well as concentrations in fish feed. The highest levels of BHT, EQ and BHA were found in farmed Atlantic salmon fillets, and were 7.60, 0.17 and 0.07 mg kg(-1), respectively. The lowest concentrations of the synthetic antioxidants found were in cod. The concentration of the oxidation product ethoxyquin dimer (EQDM) was more than ten-fold higher than the concentration of parent EQ in Atlantic salmon halibut and rainbow trout, whereas this dimer was not detected in cod fillets. The theoretical consumer exposure to the synthetic antioxidants EQ, BHA and BHT from the consumption of farmed fish was calculated. The contribution of EQ from a single portion (300 g) of skinned fillets of the different species of farmed fish would contribute at most 15% of the acceptable daily intake (ADI) for a 60 kg adult. The consumption of farmed fish would not contribute measurably to the intake of BHA; however, a 300 g portion of farmed Atlantic salmon would contribute up to 75% of the ADI for BHT. PMID- 20931418 TI - Comparison of the migration of melamine from melamine-formaldehyde plastics ('melaware') into various food simulants and foods themselves. AB - A variety of melaware articles were tested for the migration of melamine into the food simulant 3% w/v acetic acid as a benchmark, and into other food simulants, beverages and foods for comparison. The results indicate that the acidity of the food simulant plays a role in promoting migration, but not by as much as might have been anticipated, since 3% acetic acid gave migration values about double those obtained using water under the same time and temperature test conditions. In contrast, migration into the fatty food simulant olive oil was not detectable and at least 20-fold lower than with the aqueous food simulants. This was expected given the solubility properties of melamine and the characteristics of the melaware plastic. Migration levels into hot acidic beverages (apple juice, tomato juice, red-fruit tea and black coffee) were rather similar to the acetic acid simulant when the same time and temperature test conditions are used, e.g. 2 h at 70 degrees C. However, migration levels into foods that were placed hot into melaware articles and then allowed to cool on standing were much lower (6-14 times lower) than if pre-heated food was placed into the articles and then maintained (artificially) at that high temperature in the same way that a controlled time-temperature test using simulants would be conducted. This very strong influence of time and especially temperature was manifest in the effects seen of microwave heating of food or beverage in the melaware articles. Here, despite the short duration of hot contact, migration levels were similar to simulants used for longer periods, e.g. 70 degrees C for 2 h. This is rationalized in terms of the peak temperature achieved on microwave heating, which may exceed 70 degrees C, counterbalancing the shorter time period held hot. There was also evidence that when using melaware utensils in boiling liquids, as for stovetop use of spatulas, the boiling action of circulating food/simulant can have an additional effect in promoting surface erosion, increasing the plastic decomposition and so elevating the melamine release. PMID- 20931419 TI - Investigating the nature and time-course of the modality shift effect between vision and touch. AB - It is well known that stimuli grab attention to their location, but do they also grab attention to their sensory modality? The modality shift effect (MSE), the observation that responding to a stimulus leads to reaction time benefits for subsequent stimuli in the same modality, suggests that this may be the case. If noninformative cue stimuli, which do not require a response, also lead to benefits for their modality, this would suggest that the effect is automatic. We investigated the time-course of the visuotactile MSE and the difference between the effects of cues and targets. In Experiment 1, when visual and tactile tasks and stimulus locations were matched, uninformative cues did not lead to reaction time benefits for targets in the same modality. However, the modality of the previous target led to a significant MSE. Only stimuli that require a response, therefore, appear to lead to reaction time benefits for their modality. In Experiment 2, increasing attention to the cue stimuli attenuated the effect of the previous target, but the cues still did not lead to a MSE. In Experiment 3, a MSE was demonstrated between successive targets, and this effect decreased with increasing intertrial intervals. Overall, these studies demonstrate how cue- and target-induced effects interact and suggest that modalities do not automatically capture attention as locations do; rather, the MSE is more similar to other task repetition effects. PMID- 20931420 TI - Immunohistochemical analysis of Ki-67, p53 and Bcl-2 expression related to histological features in gastroesophageal reflux disease. AB - BACKGROUND/AIMS: The endoscopic and histologic findings of gastroesophageal reflux disease are usually indistinct. The current study was designed to define accurately the histology in gastroesophageal reflux disease and to develop a hypothesis that reflux produces immunohistochemical changes. METHODS: The study was based on the examination of endoscopic esophageal biopsy specimens obtained from 20 patients with evidence of reflux with 24-hour pH-meter monitoring and from 20 control subjects without clinical or endoscopic reflux. The pathogenesis of reflux esophagitis was discussed by comparing the histopathologic changes with determined Ki-67, p53 and Bcl-2 immunoreactivity. RESULTS: In this study, the presence of esophagitis was determined endoscopically in only 55% of the patients with gastroesophageal reflux disease, while microscopic esophagitis was detected in 60% of them. No correlation was found between presence of endoscopic esophagitis and microscopic esophagitis in the patients with gastroesophageal reflux disease. There was a significant difference between control cases and the patients according to histological parameters, which included basal activity (p=0.006), height of papillae (p=0.006), intraepithelial neutrophils (p=0.000), intraepithelial eosinophils (p=0.006), congestion (p=0.001), and dilated intercellular spaces (p=0.006). Immunohistochemically, there was a significant difference in the expression of p53 and Ki-67 between the three study groups (patients with/without microscopic esophagitis, controls) (p<0.05). However, there was no difference in Bcl-2 between the patients with reflux and control cases. CONCLUSIONS: In this study, we considered that microscopic esophagitis does not always accompany reflux, and the lack of reliable diagnostic histologic criteria is still a serious problem for pathologists. Immunohistochemically, an increase in cell proliferative activity and p53 protein accumulation to repair oxidative DNA damage related to reflux were observed. However, the close Bcl-2 immunoreactivity in all groups that was indicated by a weak positivity suggests that the inhibition of apoptosis may not be involved in reflux esophagitis. PMID- 20931421 TI - Sequential therapy for Helicobacter pylori eradication. AB - BACKGROUND AND AIMS: The success of Helicobacter pylori eradication using triple eradication therapy declines over time. In this prospective study, we have compared a group of naive H. pylori-positive patients receiving sequential therapy with our previously published naive H. pylori-positive control group who received ranitidine bismuth citrate-clarithromycin-amoxicillin eradication treatment. Moreover, the eradication success of these two treatment protocols was compared with that of recent standard triple eradication treatment results for the naive patients in our country and western communities. METHODS: We performed invasive tests for H. pylori in naive patients who underwent gastroduodenoscopy in the Endoscopy Unit, Ankara University, Faculty of Medicine, and patients who were diagnosed as H. pylori-positive by these tests were rechecked by the same invasive tests one month after the completion of eradication treatment. The group receiving sequential therapy was given pantoprazole + amoxicillin during the first seven days and pantoprazole + metronidazole + tetracycline during the second seven days. These patients were compared with the H. pylori-positive naive control group patients, who were given ranitidine bismuth citrate + clarithromycin + amoxicillin. The patients in whom eradication was achieved in the 4th week with sequential therapy were reevaluated one year later regarding the success of eradication with the H. pylori stool antigen test. RESULTS: The average age of the 108 patients who received the sequential therapy was 45.2+/ 12.5 years. The average age of the 75 patients who received ranitidine bismuth citrate treatment was 41.2+/-12.6 years. Six (5%) patients in the consecutive treatment group developed deterioration in taste in the mouth and 10 (9%) developed diarrhea. However, no side effects severe enough to require discontinuation of the treatments were observed in either treatment group. The results of the invasive tests were evaluated by the end of the first month, and revealed an eradication rate of 88% in the sequential treatment group versus 95% in the ranitidine bismuth citrate treatment group. Sixty-eight of 94 patients in whom eradication was achieved by sequential therapy were reevaluated with H. pylori stool antigen test in one year, and eradication was found to persist in 52 (77%) of these 68 patients. CONCLUSIONS: High rates of eradication were achieved in both groups in the 4th week evaluation. It was observed at the follow-up performed one year later that the eradication achieved with sequential therapy persisted in 77% of the patients treated. PMID- 20931423 TI - Effectiveness of different treatment regimens in helicobacter pylori eradication: ten-year experience of a single institution. AB - AIM: We aimed to report the outcomes of different H. pylori eradication regimens used in our institution over the last 10 years. METHOD: Retrospectively, H. pylori-positive patients who were referred for upper gastrointestinal endoscopy with dyspeptic symptoms and who started eradication treatment and returned for a follow-up visit were included in the study. Subjects were allocated into six groups according to their treatment regimens as follows: Group 1) Proton pump inhibitor, clarithromycin and amoxicillin for 2 weeks; Group 2) Colloidal bismuth subcitrate, metronidazole and tetracycline for 2 weeks; Group 3) ranitidine bismuth citrate, clarithromycin and amoxicillin for 2 weeks; Group 4) Proton pump inhibitor, colloidal bismuth subcitrate, clarithromycin and amoxicillin for 2 weeks; Group 5) Proton pump inhibitor, tetracycline and amoxicillin for 2 weeks; and Group 6) Proton pump inhibitor and amoxicillin for 5 days, followed consecutively by Proton pump inhibitor, clarithromycin and metronidazole for 5 days. A follow-up visit to determine eradication was scheduled a minimum of 6 weeks after completion of the treatment. RESULTS: In this study, 400 patients were included. Eradication rates were 74.7%, 92.3%, 81.2%, 81.5%, 70.5%, and 66.6% in Groups 1-6, respectively. CONCLUSION: In Group 1, the eradication rate was lower than 80%. In Groups 34, the eradication rate increased to over 80%. The colloidal bismuth subcitrate, metronidazole and tetracycline regimen (Group 2) was the most successful, with a rate of 92.3%. The eradication rate in the consecutive regimen group (Group 6) did not reach the recommended level (higher than 80-85%). PMID- 20931422 TI - Efficacy of probiotics in Helicobacter pylori eradication therapy. AB - BACKGROUND/AIMS: Triple therapy with a proton pump inhibitor, amoxicillin and clarithromycin in Helicobacter pylori eradication is widely accepted, but this combination fails in a considerable number of cases. Our aim was to evaluate whether probiotic-containing yogurt affects the success of eradication. The second aim was to investigate the efficacy of probiotics in the prevention of the side effects related to eradication therapy. METHODS: A total of 76 histopathologically proven H. pylori-positive patients enrolled in this study were randomized into two groups. The following regimens were recommended: Group A: pantoprazole (40 mg, b.i.d.), amoxicillin (1000 mg b.i.d.), clarithromycin (500 mg b.i.d.), and 125 ml of probiotic-containing yogurt (Bifidobacterium DN 173 010-1010 cfu/g) before breakfast for 14 days; and Group B: pantoprazole (40 mg, b.i.d.), amoxicillin (1000 mg b.i.d.) and clarithromycin (500 mg b.i.d.) for 14 days. Subjects were asked to report any side effects of therapy during the treatment period. H. pylori status was rechecked four weeks after the completion of the eradication therapy by 13C-urea breath test. RESULTS: H. pylori eradication was achieved in 25 of the 38 patients in Group A (66%) and in 20 of the 38 patients (53%) in Group B. Although the success rate was higher in Group A than in Group B, the difference was not significant (p=0.350). The addition of probiotics to the triple therapy significantly lessened the frequency of stomatitis and constipation (p=0.037 and p=0.046, respectively). CONCLUSIONS: The addition of probiotic-containing yogurt to the triple therapy did not increase the H. pylori eradication rates for the evaluated dosage and model; however, it decreased the frequency of stomatitis and constipation. PMID- 20931424 TI - beta-Catenin-independent noncanonical Wnt pathway might be induced in gastric cancers. AB - BACKGROUND/AIMS: Abnormal Wnt signaling is often observed in human cancers. Wnt5a is a representative Wnt ligand that can activate both beta-catenin-dependent canonical and beta-catenin-independent noncanonical Wnt pathways. However, the role of Wnt5a in carcinogenesis is controversial. This study was designed to understand whether Wnt5a in the Wnt pathway and its key downstream molecules such as MMP-7 and beta-catenin are involved in gastric cancers. METHODS: We analyzed the expressions of Wnt5a, MMP-7 and beta-catenin genes in 40 primary gastric normal and tumor biopsies by RT-PCR and the subcellular localization of beta catenin by immunohistochemistry. RESULTS: Our results showed a specific combination of genes expressed significantly in the gastric tumor tissues: 65% of the tumor samples containing non-nuclear beta-catenin were Wnt5a-positive, 42.5% were MMP-7-positive, and 35% of the samples involved both. Interestingly, normal samples did not show any relevant coexpression of Wnt5a and MMP-7 in the beta catenin-containing samples. CONCLUSIONS: These results suggest that the noncanonical Wnt pathway might be critically important in gastric carcinogenesis. PMID- 20931425 TI - Seroprevalence of autoimmune thyroiditis and celiac disease in children with insulin-dependent diabetes mellitus in the Thrace region of Turkey. AB - BACKGROUND/AIMS: We aimed to estimate the seroprevalence of celiac disease, a gluten-sensitive enteropathy, and autoimmune thyroiditis in children with insulin dependent diabetes mellitus in the Thrace region of Turkey. METHODS: The population studied consisted of 33 children with insulin-dependent diabetes mellitus and 41 healthy children with demographic features similar to the study subjects. Free triiodothyronine, free thyroxine, thyroid-stimulating hormone, anti-thyroid peroxidase antibody, anti-thyroglobulin antibody, IgA, anti endomysium IgA, and anti-gliadin IgA were measured in all cases and controls. RESULTS: The serum levels of free triiodothyronine and free thyroxine were within the normal range in all cases. However, in one patient who had anti-thyroid peroxidase and antithyroglobulin antibodies, the thyroid-stimulating hormone level was high despite a normal free triiodothyronine and free thyroxine value. Ultrasonographic findings confirmed thyroiditis in this patient. Anti-thyroid peroxidase antibodies, anti-thyroglobulin antibodies, anti-endomysium IgA and anti-gliadin IgA were detected in 15.4%, 6%, 9.1% and 3% of the diabetic cases, respectively. None of these antibodies was detected in the control group. In the diabetic group, the seroprevalences of the antithyroid peroxidase antibodies and the anti-endomysium IgA were statistically higher than in the control group (p<0.05). CONCLUSIONS: Children with insulin-dependent diabetes mellitus in our region should undergo periodic screenings for autoimmune thyroiditis and celiac disease. PMID- 20931426 TI - The effects of oral liquid and intravenous glutamine on bowel adaptation in a rabbit short bowel syndrome model. AB - BACKGROUND/AIMS: The aim of this study was to examine whether liquid glutamine given to rabbits after resection is as effective as intravenous (i.v.) glutamine and to study the positive effects of glutamine on mucosal atrophy that occurs after bowel resection. METHODS: Thirty rabbits with an average weight of 2500 g were used. On the third day, 30 rabbits were divided into three groups as follows: Group I (controls): bowel resection + oral total parenteral nutrition, Group II (oral liquid L-glutamine): Bowel resection + oral total parenteral nutrition + oral liquid L-glutamine, and Group III (i.v. L-glutamine): bowel resection + oral total parenteral nutrition + i.v. L-glutamine. On the postoperative 7th day, all subjects were sacrificed to examine intestinal adaptation indicators. RESULTS: There was an increase in average villus height and crypt depth in Group III compared to the other groups (p=0.0001). In Group II, the villus height and crypt depth increased more than in Group I, but the difference was less significant (p=0.038). There was no significant difference between groups in terms of average goblet cell proliferation. CONCLUSIONS: In our experimental study, it was observed that the orally given L-glutamine liquid in the rabbit intestinal adaptation model prevented mucosal atrophy after 50% bowel resection and even increased mucosa mass. However, i.v. glutamine led to similar and even better results. Neither route of glutamine administration was determined to have an effect on goblet cell proliferation. PMID- 20931427 TI - Anti-allergic effects of probiotic Dahi through modulation of the gut immune system. AB - BACKGROUND/AIMS: The alarming increase in allergy in the last few decades demands the development of new anti-allergic prevention strategies, and consumption of functional foods (i.e. probiotic Dahi, which has already been proven to enhance immunity by modulation of the gut mucosal immune system) may be one of them. In the present study, we evaluated anti-allergic effects of a Dahi (yogurt) containing probiotic Lactobacillus acidophilus, L. casei and normal Dahi culture Lactococcus lactis biovar diacetylactis (named probiotic Dahi) on ovalbumin induced allergy in mice. METHODS: Allergy was induced by injecting (i.p.) ovalbumin at 0 and 14 days. Animals were fed with standard diet (control), milk, control Dahi or probiotic Dahi for 21 days. Total and ovalbumin-specific IgE, cytokines and lymphocyte proliferation index were examined after 7, 14 and 21 days. RESULTS: Feeding of probiotic Dahi completely suppressed the elevation of total and ovalbumin-specific IgE in the serum of ovalbumin-injected mice. Similarly, splenocytes collected from mice fed with probiotic Dahi entirely lost the total and ovalbumin-specific IgE production property during in-vitro culture. Production of T helper (Th)-1 cell-specific cytokines, i.e. interferon -gamma and interleukin (IL)-2, increased, while Th2-specific cytokines, i.e. IL-4 and IL-6, decreased in the supernatant of cultured splenocytes collected from mice fed with probiotic Dahi compared to the other groups. Moreover, ovalbumin-stimulated lymphocyte proliferation was strongly suppressed by feeding of probiotic Dahi in comparison to milk and control Dahi. CONCLUSIONS: Results of the present study indicate that probiotic Dahi suppressed ovalbumin-induced allergic consequences characterized by decreasing levels of total and ovalbumin-specific IgE and lymphocyte proliferation and skewed ovalbumin-induced Th2-specific immune response towards Th1-specific response. PMID- 20931428 TI - Is the prevalence of intestinal metaplasia at the squamocolumnar junction different in patients with progressive systemic sclerosis? AB - BACKGROUND/AIMS: Gastroesophageal reflux disease is seen frequently in patients with progressive systemic sclerosis. The aim of the present study was to determine the prevalence of intestinal metaplasia-squamocolumnar junction in patients with progressive systemic sclerosis and to investigate the association with gastroesophageal reflux disease. METHODS: Thirty-one patients with progressive systemic sclerosis (Group A), 58 patients with gastroesophageal reflux disease--without progressive systemic sclerosis (Group B) and 36 patients without progressive systemic sclerosis or gastroesophageal reflux disease (Group C) were prospectively enrolled into this study. Biopsies were taken from the antrum, body, squamocolumnar junction (Z-line), and from the esophagus (3 cm above the Z-line). All biopsies were independently evaluated by two pathologists who were unaware of the diagnosis. RESULTS: We found that grade C-D esophagitis, esophageal stricture and Barrett's esophagus were statistically significantly higher in Group A (p<0.05). Intestinal metaplasia at squamocolumnar junction was detected in 31% of Group A, in 32% of Group B and in 29% of Group C patients (p>0.05), and prevalence of Helicobacter pylori was 61%, 67% and 38% in Groups A, B and C, respectively. Prevalence of Helicobacter pylori was similar in Group B and Group A, and significantly higher in Group B than Group C. Within each group, no significant relationship was detected between intestinal metaplasia at squamocolumnar junction and gender, age, smoking, alcohol consumption, body mass index, gastric atrophy, and prevalence of Helicobacter pylori. CONCLUSIONS: Patients with progressive systemic sclerosis have a higher tendency to the more severe forms and complications of gastroesophageal reflux disease including Barrett's esophagus than in those without progressive systemic sclerosis. However, there was no difference in the prevalence of intestinal metaplasia at squamocolumnar junction between groups, and it can be pointed out that intestinal metaplasia at squamocolumnar junction might not be related with gastroesophageal reflux disease. PMID- 20931429 TI - Short-term outcomes after surgery for colorectal cancer in Turkish patients aged 70 and above. AB - BACKGROUND/AIMS: We aimed to evaluate the impact of age on short-term surgical outcomes and to investigate the risk factors for postoperative mortality in 660 Turkish colorectal cancer patients. METHODS: Between January 2002 and January 2007, 660 consecutive patients who were operated for colorectal cancer at our institution were enrolled in this study. The patients were divided into two groups as: a younger group (<70 years) and an older group (>=70 years). Patient data were recorded prospectively with the use of specially designed forms. Variables and short-term patient results were compared. RESULTS: American Society of Anesthesiologists (ASA) scores were significantly higher and albumin levels were lower in the older group compared with the younger group (p<0.05). Morbidity and mortality rates were 16.8% (83/494) and 2.6% (13/494) in the younger group and 22.9% (38/166) and 3.0% (5/166) in the older group, respectively. These differences in rates were not statistically significant. ASA score (ASA 4) and non-resective procedures were found to be independent risk factors for mortality. CONCLUSIONS: Age should not be regarded as a reason for limited surgery. Elderly patients should undergo the same standard surgical approach as younger patients. The patient's general state of health is more effective on postoperative mortality. PMID- 20931430 TI - Protective role of Urtica dioica L. (Urticaceae) extract on hepatocytes morphometric changes in STZ diabetic Wistar rats. AB - BACKGROUND/AIMS: The present investigation was carried out to evaluate the protective effect of the hydroalcoholic extract of Urtica dioica leaves on the quantitative morphometric changes in the liver of streptozotocin-induced diabetic rats. METHODS: Thirty male Wistar rats were divided into control (G1), diabetic (G2), diabetic + Urtica dioica (G3) groups. The control group received only sham injections of intraperitoneal saline; the diabetic group received intraperitoneal saline for 5 days followed by streptozotocin (80 mg/kg) on the 6th day; and the diabetic + Urtica dioica group received 100 mg/kg Urtica dioica intraperitoneal (7) injections for 5 days and streptozotocin injection on the 6th day. After five weeks, the animals were sacrificed and whole livers removed. Liver specimens were used for quantitative morphometric analysis after hematoxylin and eosin staining. All data were statistically analyzed by one-way ANOVA and expressed as the mean with standard error of means. RESULTS: In the G3 (diabetic + Urtica diocia) group, the mean surface area of hepatocytes in the periportal zone (Z1) was greater than in G2 (diabetic) and G1 (control) groups, but this difference was not significant. No alteration was observed in the surface area of hepatocytes in the perivenous zone (Z3) in the diabetic + Urtica dioica (G3) group compared to the diabetic (G2) group. The mean nuclear area of hepatocytes of the rats in the diabetic + Urtica dioica (G3) group was higher in Z1 and lower in Z3 than that of rats in the diabetic (G2) group. The mean diameter of hepatocyte nuclei in the diabetic + Urtica dioica (G3) group was lower than that of diabetic (G2) and control (G1) groups in both Z1 and Z3. CONCLUSIONS: This study revealed that the administration of extract of Urtica dioica leaves before induction of diabetic with streptozotocin has a protective effect on the morphometric alterations of hepatocytes in the periportal and perivenous zones of the liver lobule in rats. PMID- 20931431 TI - Fulminant hepatic failure and serum phosphorus levels in children from the western part of Turkey. AB - BACKGROUND/AIMS: Clinical and laboratory predictors of recovery in children with fulminant hepatic failure are limited. Recently, hypophosphatemia has been reported as a laboratory indicator of recovering liver function in children with fulminant hepatic failure . We aimed to determine the incidence of hypophosphatemia and its association with clinical outcome in children in our center with fulminant hepatic failure. METHODS: We analyzed 21 children who had been diagnosed with fulminant hepatic failure. Laboratory findings were recorded from admission date until the patient spontaneously recovered, underwent orthotopic liver transplantation or died. RESULTS: Eight patients (38%) died, 6 (28.6%) underwent orthotopic liver transplantation, and 7 (33.3%) recovered without orthotopic liver transplantation. We identified hypophosphatemia in 57.1% of children with fulminant hepatic failure. Serum phosphorus levels were significantly lower in patients who recovered than in the orthotopic liver transplantation+death group. The presence of encephalopathy was determined at a much lower rate in the recovery group than in the orthotopic liver transplantation+death group. Serum phosphorus concentration >=2.9 mg/dl and presence of encephalopathy were identified as independent risk factors for mortality. CONCLUSIONS: Hypophosphatemia can be identified as a marker of recovery in children with fulminant hepatic failure. Presence of encephalopathy and a serum phosphorus level >=2.9 mg/dl appear to indicate a poor prognosis in children with fulminant hepatic failure. PMID- 20931433 TI - Utilization of impedance cardiography in noninvasive assessment of hemodynamic status in cirrhotic patients. AB - BACKGROUND/AIMS: This study aimed to assess hemodynamic alterations noninvasively using a dedicated device Task Force(r) Monitor providing various hemodynamic data utilizing impedance cardiography and beat-to-beat blood pressure analysis via a vascular unloading unit. METHODS: Forty-seven patients with cirrhosis awaiting hepatic transplantation and 26 healthy volunteers matched for age and gender were enrolled. Basic hemodynamic status of these patients (following temporary interruption of any drugs affecting the cardiovascular system) was evaluated noninvasively by Task Force(r) Monitor with patients in the supine position. RESULTS: Mean age of the patients was 46 years and 74.5% were male. The etiology of cirrhosis was viral hepatitis in 59.5% and alcoholic cirrhosis in 19.1% of cases, whereas 17% had cryptogenic cirrhosis. 38.3%, 25.5%, and 36.1% of the patients were stratified into groups A, B and C according to the Child-Pugh classification, respectively. Heart rate, cardiac output and cardiac index were significantly higher in patients with cirrhosis compared to the control group. However, diastolic blood pressure, total peripheral resistance and total peripheral resistance index were significantly lower in the cirrhosis group. This situation representing a hyperdynamic circulatory state became more prominent in conjunction with advanced disease severity. CONCLUSIONS: The present study demonstrates that the Task Force(r) Monitor device is capable of delineating the hyperdynamic circulatory state in cirrhotic patients and satisfactorily indicates differences between controls and patients at diverse levels of severity. Regarding potential applications in clinical practice and research, noninvasive hemodynamic monitoring by Task Force(r) Monitor may be a reliable and reasonable alternative tool to invasive procedures. PMID- 20931432 TI - MR angiography of esophageal mural veins in portal hypertension: a correlation with endoscopic grades of esophageal varices. AB - BACKGROUND/AIMS: The esophageal mural veins are important for providing blood to the esophageal submucosal varices. The purpose of this study was to investigate any correlation between the diameters of esophageal mural veins as observed on routine contrast-enhanced magnetic resonance angiography and the endoscopic grades of esophageal varices in patients with portal hypertension. METHODS: The images of 57 patients with portal hypertension in whom magnetic resonance portography was performed were evaluated retrospectively. The correlation between the diameter of the esophageal mural veins and the endoscopic grade of the esophageal varices was investigated with Spearman's correlation test. This test was also used to assess the correlation between the grade of esophageal varices and the diameters of the paraesophageal veins. A p value less than 0.05 was considered to be statistically significant. RESULTS: A positive correlation was determined between the diameter of mural veins and the endoscopic grade of the esophageal varices (p=0.022; r=0.363). There was no correlation, however, between the endoscopic grade of the esophageal varices and the diameter of the paraesophageal veins. CONCLUSIONS: A correlation exists between the diameters of the esophageal mural veins and the endoscopic grades of the esophageal varices. Magnetic resonance angiography may give information about the status of the esophageal varices in portal hypertensive patients. PMID- 20931434 TI - Effects of a long-acting somatostatin analogue, lanreotide, on bile duct ligation induced liver fibrosis in rats. AB - BACKGROUND/AIMS: Somatostatin receptors have been shown on hepatic stellate cells, and somatostatin infusion has been shown to inhibit hepatic stellate cells activation. We aimed to test the effects of a long-acting somatostatin analogue, lanreotide, on bile duct ligation-induced liver fibrosis in rats. METHODS: Thirty seven Wistar rats were divided into 5 groups as follows: Group 1, bile duct ligation+lanreotide; Group 2, bile duct ligation; Group 3, sham+lanreotide; Group 4, sham; and Group 5, control group. Lanreotide-autogel (20 mg/kg/month) or saline in intraperitoneal doses was administered. Serum biochemical parameters, liver collagen level, and oxidative stress and histological parameters were determined after 28 days. RESULTS: The tissue collagen level, biochemical parameters (AST, ALT, bilirubins, alkaline phosphatase, gamma-glutamyl transpeptidase) and oxidative stress parameters (malondialdehyde, luminal, lucigenin) in the bile duct ligation groups were higher than in the sham-operated and control groups (p<0.001 for all). Lanreotide improved malondialdehyde and glutathione levels in the bile duct ligation+lanreotide group. In histopathological examination, bile duct ligation groups showed stage-3 liver fibrosis, while all the controls were normal. Lanreotide did not improve the liver fibrosis histologically or biochemically. CONCLUSIONS: A monthly active somatostatin analogue, lanreotide, improved malondialdehyde and glutathione; however, it was not able to improve bile duct ligation-induced liver fibrosis in rats. Although lanreotide is a long-acting medication, it did not show anti fibrotic effects in the model. PMID- 20931435 TI - Double Dieulafoy's lesions of the stomach in a patient with chronic renal failure on long-term hemodialysis. AB - Dieulafoy's lesions are an uncommon cause of major gastrointestinal hemorrhage; they occur after rupture of an exposed submucosal artery. Despite widespread awareness of this entity, the lesion remains a diagnostic challenge because of its small size and hidden location. Dieulafoy's lesions may be associated with immunosuppression, hemodynamic disorders and the vascular compromise that occurs after long-term hemodialysis. However, there are no data comparing the incidence of Dieulafoy's lesions in patients with chronic renal failure to that in controls. Dieulafoy's lesions have been reported in patients with chronic renal failure, but are extremely rare. Furthermore, there are no prior reports on double lesions in the stomach. This is the first report of simultaneous double Dieulafoy's lesions of the stomach diagnosed after the seventh upper gastrointestinal endoscopy and massive transfusions in a 70-year-old woman with chronic renal failure on long-term hemodialysis. These lesions were successfully treated by successive endoscopic band ligations. PMID- 20931436 TI - Gastroscopic removal of a migrated adjustable gastric band: a case report. AB - Laparoscopic gastric banding is a popular method for treating morbid obesity. Band migration is a well-known late complication and the treatment is usually reoperation. In this case report, we show that a band penetrating the gastric wall can be treated by gastroscopic operation with the Gastric Band Cutter device without complication. It seems that this technique is simpler than reoperation and is beneficial even when the intraluminal migration is partial. PMID- 20931438 TI - Mitochondrial neurogastrointestinal encephalomyopathy: case report. AB - Mitochondrial neurogastrointestinal encephalomyopathy is an autosomal recessive multisystem disorder caused by thymidine phosphorylase deficiency. The disease is characterized clinically by ptosis, progressive external ophthalmoparesis, severe gastrointestinal dysmotility, peripheral neuropathy, leukoencephalopathy, and mitochondrial abnormalities. Herein, we describe a patient with mitochondrial neurogastrointestinal encephalomyopathy who presented intestinal pseudoobstruction. PMID- 20931437 TI - Coexistence of gastric cancer and gastrointestinal stromal tumor: report of two cases. AB - Gastrointestinal stromal tumors and adenocancers are distinct neoplasms originating from different cell layers. Though adenocancers constitute the most common type of gastric tumors, synchronous development of a gastrointestinal stromal tumor is extremely rare. Case 1: A 63-year-old male patient underwent a radical total gastrectomy with D2 lymphadenectomy and Rouxen-Y reconstruction. Histopathologic and immunohistochemical examination of the specimen disclosed an advanced stage, intestinal type adenocancer intermixing with a distinct lesion of gastrointestinal stromal tumor. The early postoperative course was uneventful; however, recurrence was seen and he survived only 13 months. Case 2: A 60-year old male patient underwent a distal subtotal gastrectomy with D2 lymphadenectomy, and reconstruction was provided with Billroth 2 procedure. Intraoperatively, a 0.5 cm vegetating lesion was detected on the gastric body and resected. Histopathologic and immunohistochemical examination disclosed an intestinal type adenocancer, and the incidental lesion was reported as gastrointestinal stromal tumor. His postoperative course was uneventful, and the patient is free of disease after one year. The conditions under which the synchronous tumors develop away from each other or collide are vague. Currently, the stage of the adenocancer and the size and mitotic manner of the gastrointestinal stromal tumors are the leading prognostic factors. PMID- 20931439 TI - Inflammatory pseudotumor of the liver diagnosed by needle biopsy: report of three cases (one with neuroendocrine tumor of the rectum and lung). AB - Inflammatory pseudotumor of the liver is a rare disorder that can histologically and radiologically resemble malignant neoplasms. The prognosis of the patients with hepatic inflammatory pseudotumor is usually good with conservative therapy. Most of the reported cases are diagnosed in the surgical resection specimens; only very few reported cases have been diagnosed by needle biopsy. We report three additional cases of inflammatory pseudotumor of the liver diagnosed by liver biopsy. Two of these cases were treated successfully with antibiotics. The other case, who was resistant to medical treatment, had coexisting neuroendocrine neoplasms of the rectum and the lung. Since her general condition did not allow an extensive surgery, the mass of the liver could not be resected and she died approximately five months after she was voluntarily discharged from the hospital. Many of the inflammatory pseudotumor of the liver are found to be associated with variable neoplasms, but to our knowledge, the latter case is the first case of inflammatory pseudotumor associated with a neuroendocrine tumor. PMID- 20931440 TI - A case of gynecomastia due to entecavir. AB - Hepatitis B is an important health problem all over the world as well as in our country. Entecavir is a nucleoside analog used in the treatment of chronic hepatitis B. We present a case of a 55-year-old male patient who developed unilateral gynecomastia while under treatment with entecavir. Physical examination was unremarkable except for minimal hepatomegaly. Laboratory examination revealed: HbsAg: positive, HBeAg: negative, anti-HBe: positive, HBV DNA: 800,000 copies/ml, total anti-HDV: negative, and alanine aminotransferase: 105 U/L (normal range: 0-41). The treatment was started with pegylated interferon. During the follow-up, transaminases did not regress and HBV DNA was found to still be highly positive at the sixth month evaluation. Pegylated interferon treatment was stopped and entecavir was started at a dose of 0.5 mg/day. Six months after the initiation of entecavir treatment, the patient presented with a painful swelling in the right breast. On physical examination, there was painful gynecomastia on the right side, which was confirmed with mammography and ultrasound of the breast tissue. The patient was not taking any drug that may have caused gynecomastia. Hormonal status of the patient was normal. Laboratory values were normal. We considered that this unilateral gynecomastia might be an adverse effect of entecavir. Since the patient had a rapid viral and biochemical response to entecavir, the drug was continued under close follow-up and there was no further progression of the gynecomastia. PMID- 20931441 TI - Splenic hydatic cyst as a cause of sinistral portal hypertension and isolated gastric variceal bleeding. AB - A 60-year-old male, living in a rural area, presented with recurrent upper gastrointestinal bleeding. Isolated fundal varices were seen on endoscopy. A lesion similar to cyst hydatid was seen in the spleen on abdominal ultrasonography and computerized tomography scanning. Also, sinistral (left sided) portal hypertension and collaterals were seen due to the compression of the splenic vein by the cyst. Indirect hemagglutination antibody test for Echinococcus granulosus was positive. By screening, no other cyst was found in any other site of the body. The patient underwent open abdominal surgery, and the anterior wall of the cyst was resected partially; within it were multiple daughter cysts and hydatid fluid. After decontamination of the daughter cysts and hydatid fluid, germinative membrane omentoplasty was performed with a part of the omentum. However, the patient suffered from recurrent gastrointestinal bleeding postoperatively and he was re-evaluated. Later, splenectomy was performed in order to relieve left-sided portal hypertension. The patient did not experience further bleeding and gastric varices disappeared following splenectomy. PMID- 20931442 TI - Esophageal melanocytosis. PMID- 20931443 TI - Stomach full of ingested foreign bodies: more than a "metallic taste". PMID- 20931444 TI - A case of Behcet's disease with multiple colon perforations. PMID- 20931445 TI - A case of severe acute hepatitis due to oral intake of firecrackers. PMID- 20931446 TI - Unusal presentation of liver dysfunction in the later stages of pregnancy. PMID- 20931447 TI - A rare cause of cholangitis: Fasciola hepatica. PMID- 20931448 TI - A rare cause of acute abdomen in children: an intrabiliary rupture of hydatid cyst. PMID- 20931449 TI - ALA-induced porphyrin accumulation in medulloblastoma and its use for fluorescence-guided surgery. PMID- 20931450 TI - Postcolonic polypectomy pancreatitis. PMID- 20931451 TI - Endoscopic retrograde cholangiopancreatography (ERCP) for intradiverticular papilla: endoclip-assisted biliary cannulation. PMID- 20931452 TI - Transnasal flexible bronchoscopic implantation of a nickel titanium (NiTi) bronchial occlusive device for a bronchobiliary fistula. PMID- 20931453 TI - Chronic pancreatitis and cholangitis caused by absence of the duodenal papilla. PMID- 20931454 TI - All that is red is not blood! PMID- 20931455 TI - Gastric inflammatory myofibroblastic tumor masquerading as a pancreatic cystic neoplasm. PMID- 20931456 TI - Lipiodol as a marker for hepatocellular carcinoma migrating into the bile duct. PMID- 20931457 TI - Panendoscopic characterization of Peutz-Jeghers syndrome. PMID- 20931458 TI - Early mucinous colorectal adenocarcinoma--mucosal type. PMID- 20931459 TI - Endoscopic removal of a large rectal foreign body using a large balloon dilator: report of a case and description of the technique. PMID- 20931460 TI - An unusual cause of hemosuccus pancreaticus diagnosed by endoscopic ultrasonography: splenic arterial fistula due to a pancreatic stent (with video). PMID- 20931461 TI - Endoscopic removal of the Padlock-G clip. PMID- 20931462 TI - Pseudomelanosis ilei associated with ingestion of oral iron therapy. PMID- 20931463 TI - Endoscopic retrieval of a migrated esophageal stent in the cecum. PMID- 20931464 TI - Microcystic reticular schwannoma of the colon. PMID- 20931465 TI - Regurgitation of a mass into the mouth: a fibrovascular polyp of the esophagus. PMID- 20931466 TI - Cholangiocarcinoma metastasis to the esophagus. PMID- 20931467 TI - Esophageal lesions herald widely metastatic disease. PMID- 20931468 TI - Endoscopic removal of migrating silastic band after vertical banding gastroplasty. PMID- 20931469 TI - Endoscopic diagnosis of secondary rectal teratoma in a young woman with constipation and positive fecal occult blood test. PMID- 20931470 TI - Endoscopic ultrasound (EUS)-guided ethanol injection in hepatic metastatic carcinoma: a case report. PMID- 20931471 TI - Suture material in the common bile duct causing recurrent post-cholecystectomy pain. PMID- 20931473 TI - Early oncocytic adenocarcinoma of the transverse colon. PMID- 20931472 TI - Iodine-125 biliary stent for palliative treatment of locally advanced gallbladder cancer. PMID- 20931474 TI - Pancreatic head mass of unusual etiology: multiple myeloma diagnosed by endoscopic ultrasound-guided fine needle aspiration. PMID- 20931475 TI - Primary lymphoma of the common bile duct presenting with acute pancreatitis and cholangitis. PMID- 20931476 TI - Massive pneumoperitoneum after argon plasma coagulation. PMID- 20931477 TI - Removal of a migrated covered metallic stent through an esophageal stricture, with multiple endoloops. PMID- 20931478 TI - Endoscopic hemostasis through gastrostomy. PMID- 20931479 TI - No prolonged effect of Ankaferd Blood Stopper on chronic radiation proctitis. PMID- 20931480 TI - Gastric penetration of epicardial pacemaker leads 8 years after cardiac surgery. PMID- 20931481 TI - [Outpatient if possible, outreaching if necessary]. PMID- 20931482 TI - [Rehabilitation research in the Netherlands; research review and synthesis of recent findings]. AB - BACKGROUND: Interventions aimed at encouraging people with severe mental illnesses (including drug addiction) to participate in social activities are on the increase. Over the last few years the Netherlands has increased its research into the effectiveness of these interventions. However, there are considerable gaps in our knowledge and the research results need to be synthesised. AIM: To synthesise the information collected in recent years concerning the results of these rehabilitation programmes and interventions. METHOD: We performed a systematic review of research databases, focusing on Dutch research (2000 to 2007). With regard to the interventions, we evaluated whether an ideal 'knowledge cycle' had been established (i.e. problem exploration, intervention development, evaluation, systematic implementation and wider dissemination). RESULTS: We found 29 studies of interventions that aimed primarily at societal participation by people with severe mental illness; 23 of these studies were complete. According to a longitudinal comparative controlled study, the most effective interventions were the Boston psychiatric rehabilitation approach, individual placement and support and 'guided peer support'. However, the required 'knowledge cycle' as specified in the Method section, had not been completed in the case of any of the interventions. CONCLUSION: Both the range and the quality of research info the effectiveness of rehabilitation programmes have improved tremendously. In the Netherlands over the last decade, in order to complete the above-mentioned knowledge cycle, a new research agenda needs to be established. We propose some items for this agenda. PMID- 20931484 TI - [Loss of sense and meaning, a neglected topic in psychiatry]. AB - Inherent in human existence is one's need to give sense to one's life. It is this need that drives life forward. In this paper the terms 'giving sense' and 'giving meaning' are used more or less interchangeably. A life acquires meaning when goals are set and attempts are made to achieve them. Giving meaning to one's existence often involves engaging in altruistic activity. The need to give sense to one's life can be felt to be 'self generated' or metaphysically inspired, in other words inspired by a supernatural authority. Sense-deficiency is a mental condition which is barely recognised in psychiatry and hardly ever treated. Thorough research is needed to find the causes and the appropriate treatment and, in particular, to discover to what extent the spiritual domain is able to perform therapeutic functions. A discussion of certain aspects of this domain should be given a definitive place in the curriculum of trainee psychiatrists. PMID- 20931483 TI - [The cenesthesiopathies]. AB - BACKGROUND: Up till a century ago the classic concepts of cenesthesis and cenesthesiopathy played a major role in the conceptualisation of aberrant somatosensory sensations and disturbances in the sensation of physical existence. Although these concepts are considered obsolete by a number of authors, the conceptual work of the German psychiatrist Gert Huber and the results of modern neuroimaging studies point to the need for a re-evaluation of the concepts cenesthesis and cenesthesiopathy. METHOD: Background information was obtained from PubMed, Embase and the medical historical literature. By way of illustration, two cases are presented: the first is a female patient with a strongly diminished sense of physical existence (hypocenesthesiopathy) and the second is a male patient with such pronounced somatosensory sensations that he believed he was being transformed into a werewolf (hypercenesthesiopathy, clinical lycanthropy). RESULTS: On the basis of the literature and the two case studies, it is shown that the concepts of cenesthesis and cenesthesiopathy may be helpful in the conceptualisation of disorders of the sensation of bodily existence brought about by aberrant somatosensory sensations. CONCLUSION: In the cases of peculiar and unexplained physical symptoms, the cenesthesiopathies should be part of the differential diagnosis. Particularly if patients have longlasting, medication-resistant forms of cenesthesiopathy, it is strongly recommended that such patients undergo neuroimaging and are given an EEG so that treatable somatic conditions can either be demonstrated or ruled out. PMID- 20931485 TI - [Update of the multidisciplinary guidelines for anxiety and depression]. AB - The multidisciplinary guidelines for depression, panic disorder and post traumatic stress disorder have been revised. They incorporate some important changes: algorithms are now based on the severity of the disorders, a 'stepped care' approach is promoted, so-called basic interventions are required for each algorithm and so-called first-step interventions are advocated for mild disorders. Antidepressants are no longer indicated for mild disorders. PMID- 20931486 TI - [Sleep disturbances in Smith-Magenis syndrome: treatment with melatonin and beta adrenergic antagonists]. AB - Smith-Magenis syndrome is a generic disorder, characterised by physical, neurological and behavioural features and caused by a 17p11.2 deletion. Patients with this syndrome typically display an inversion of the sleep-wake cycle. In this article we describe clinical developments in a two-year-old girl with Smith Magenis syndrome whose sleep problems were successfully treated with melatonin and beta-adrenergic blockers. We also mention relevant data obtained in our literature search. PMID- 20931487 TI - [Reaction on 'Myocarditis and cardiomyopathy underestimated complications resulting from clozapine therapy']. PMID- 20931488 TI - [Reaction on 'Protocol for complementary and alternative medicine within the Dutch mental health services']. PMID- 20931489 TI - [Reaction on 'Conscience development: a review of theory and research']. PMID- 20931490 TI - Endo180 and MT1-MMP are involved in the phagocytosis of collagen scaffolds by macrophages and is regulated by interferon-gamma. AB - Subcutaneously implanted disks of hexamethylenediisocyanate or glutaraldehyde cross-linked sheep collagen (referred to as HDSC and GDSC, respectively) in mice show large differences in degradation rate. Although comparable numbers of macrophages are seen in HDSC and GDSC, phagocytosis of collagen by macrophages occurred only in GDSC. The molecular mechanisms involved in the phagocytosis of collagen by macrophages are essentially unknown. Immunofluorescence and RT-PCR showed that Endo180 was expressed in GDSC only. TissueFaxs showed that Endo180 co localized with MT1-MMP on F4/80 positive cells, which is likely responsible for the phagocytosis in GDSC. RT-PCR further showed that Endo180 expression correlated with high levels of IFN-gamma mRNA. In vitro, IFN-gamma induced the expression Endo180 and MT1-MMP in murine macrophages cultured on collagen type I (although too high levels of IFN-gamma dampened the expression of Endo180 and MT1 MMP). Moreover, the expression of Endo180 and MT1-MMP induced by IFN-gamma can be inhibited through IL-10. The differences in microenvironment between GDSC and HDSC (high IFN-gamma and low IL-10 levels in GDSC, low IFN-gamma and high IL-10 levels in HDSC) provide an explanation why phagocytosis of collagen by macrophages is only seen in GDSC. In summary, we show for the first time that the IFN-gamma dependent co-expression of Endo180 and MT1-MMP on macrophages coincides with collagen phagocytosis, thus providing evidence that the mechanism of collagen phagocytosis operating in the foreign body reaction by macrophages is comparable with the mechanism of intracellular collagen degradation by fibroblasts seen under physiological conditions. PMID- 20931491 TI - Ecto-mesenchymal stem cells from dental pulp are committed to differentiate into active melanocytes. AB - Dental pulp stem cells (DPSCs) are multipotent stem cells derived from neural crest and mesenchyme and have the capacity to differentiate into multiple cell lineages. It has already been demonstrated that DPSCs differentiate into melanocyte-like cells but only when cultivated in a specific melanocyte differentiating medium. In this study we have shown, for the first time, that DPSCs are capable of spontaneously differentiating into mature melanocytes, which display molecular and ultrastructural features of full development, including the expression of melanocyte specific markers and the presence of melanosomes up to the terminal stage of maturation. We have also compared the differentiating features of DPSCs grown in different culture conditions, following the timing of differentiation at molecular and cytochemical levels and found that in all culture conditions full development of these cells was obtained, although at different times. The spontaneous differentiating potential of these cells strongly suggests their possible applications in regenerative medicine. PMID- 20931492 TI - [Dementia 1: Definition/ causes/strategy of diagnostic assessment]. PMID- 20931494 TI - [What is your diagnosis? Pneumatosis intestinalis coli]. PMID- 20931495 TI - [Chronic venous insufficiency in postthrombotic syndrome and varicose veins]. AB - Venous disorders have a high prevalence and require approximately 1% of health budgets of industrialized countries. The postthrombotic syndrome (PTS) is defined by subjective symptoms and morphologic trophical skin changes following deep venous thrombosis. Prevention of venous thromboembolism in risk situations, easy availability of diagnostic tools (D-dimers, colour-coded duplex sonography) and early detection of deep venous thrombosis, as well as immediate therapeutic anticoagulation along with leg compression during the acute phase and over a two year period of time significantly reduce the incidence of PTS. Chronic venous insufficiency (CVI) includes trophical skin and soft tissue pathologies of the lower leg due to venous hypertension in the distal venous system of the lower extremity. Roughly, two main causes can be distinguished. (A) Deep venous insufficiency (A1 in postthrombotic syndrome; A2 in primary deep venous insufficiency) and (B) superficial venous reflux, usually varicose veins. Compression therapy, surgical ablation of superficial venous reflux, and tangential ablation with split skin graft (shave treatment) of refractory venous ulcers are the mainstays in the treatment of CVI. PMID- 20931496 TI - [Interventional closure of persistent foramen ovale in patients after crytogenic stroke]. AB - A persistent foramen ovale can be a possible cause of paradoxical cerebral embolism. Thranscatheter closure by transcatheter technique has a high success rate and is a recurrence prevention measure. This paper reviews of patent foramen ovale anatomy, pathophysiology, and clinical impact and discusses current therapeutic options. PMID- 20931497 TI - [Commentary from the viewpoint of an advocate. "Breast cancer mortality in organized mammography screening in Denmark--a comparative Study"]. PMID- 20931498 TI - [Critical comment. "Breast cancer mortality in organized mammography screening in Denmark--a comparative Study"]. PMID- 20931499 TI - [Hoarseness]. PMID- 20931500 TI - [Tiredness, hyperpigmentation, weight loss, nausea and vomiting. Polyglandular autoimmune syndrome (PAS) type 2]. AB - In this patient with tiredness, hyperpigmentation, weight loss, nausea and vomiting, chronic primary adrenal insufficiency (M. Addison) was diagnosed based on the clinical features, the typical electrolyte abnormalities and the reduced morning cortisol together with increased adrenocorticotropic hormone. The detection of autoantibodies against adrenal tissue and 21-hydroxylase revealed an auto-immune adrenalitis as the cause. The additional primary hypothyroidism (with positive thyreoperoxidase-anti-bodies, anti-TPO-antibodies) and the coeliac disease argued for a polyglandular autoimmune syndrome type 2. Treatment with hydrocortisone and with mineralocorticoid and thyroxine later on showed a rapid improvement of clinical symptoms. In patients with Morbus Addison, a screening for associated endocrine disorders is warranted. PMID- 20931501 TI - [Breast cancer mortality in organised mammography screening in Denmark]. PMID- 20931502 TI - [Timely care after an abnormal mammogram among low-income women in a public breast cancer screening program]. PMID- 20931505 TI - [The physician's art column. Tea Makipaas: World of Plenty (2008)]. PMID- 20931506 TI - [The physician's literature puzzle. Roland Barthes (Diary of Grief)]. PMID- 20931507 TI - Adverse event monitoring of artemesinin combination therapy in Nigeria: the challenges and limitations of the study. AB - Artemesinin combination therapies (ACTs) are first line antimalarial drugs in malaria endemic regions of the world as recommended by the World Health Organization. ACTs are relatively new in Nigeria and there is little experience with their use. The pharmacovigilance of ACT drugs has been advocated in African countries so as to establish their safety in the African population. There is an on-going adverse event monitoring of the ACT drugs in Nigeria and a preliminary result has been published by the National Agency for Food and Drug Administration and Control. This commentary aims to discuss the challenges and limitations of the on-going pharmacovigilance of ACT drugs in Nigeria and proffer useful suggestions on how to overcome the problems. PMID- 20931508 TI - Left ventricular diastolic function in a predialysis patient population. AB - BACKGROUND: Diastolic dysfunction is common in chronic kidney disease (CKD) accounting for 40%-66% of cardiovascular complications. OBJECTIVE: To determine the prevalence of and factors associated with left ventricular diastolic dysfunction (LVDD) in adult Nigerians with CKD at presentation and to compare findings with those of hypertensive patients with normal renal function. METHODS: Eighty-six consecutive patients with CKD were studied, comprising 43 hypertensives and 43 age- and sex-matched healthy subjects as controls. Clinical, laboratory, and echocardiographic variables were measured. RESULTS: Left ventricular diastolic dysfunction was present in 62.8% of CKD patients, 79.1% of hypertensive patients and 25.6% of normal controls (p<0.001). There was a positive correlation between left ventricular diastolic function (LVDF) and systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), severity of SBP, severity of DBP in CKD patients but not in hypertensive patients. There was a negative correlation between LVDF and age in CKD patients and hypertensive patients. Linear multiple regression analysis showed age as the only predictor of LVDD. CONCLUSION: There is a high prevalence of diastolic dysfunction in CKD patients at first presentation to a nephrologist in Nigeria. PMID- 20931509 TI - Surgical anatomy of the vertebrobasilar territory and posterior circle of Willis. AB - BACKGROUND: In the present era of microscopic and neuroendoscopic procedures, the surgical anatomy of the skull base vessels has gained increased significance. The pattern of the vertebrobasilar arterial complex and the posterior circle of Willis (COW) in Nigerians has not been previously reported despite various variants of these complexes existing in different populations. OBJECTIVE: To review and document the size, distribution and anomalies of the vertebrobasilar territory and posterior COW pattern in a Nigerian set of brains. METHODS: The target population for this study was a group of Nigerian adults 18 years and above. Specimens from patients with an ante-mortem or post-mortem evidence of meningitis or atherosclerosis were excluded. The size, distribution and anomalies of the vertebrobasilar artery, its branches, and the posterior COW were defined in 50 brains. RESULTS: The male: female ratio was 1.9:1 and a mean age of 44 years. Statistical analysis showed significant differences between the sizes of posterior inferior cerebellar arteries and anterior inferior cerebellar arteries (Student's t=-30.189; p-value= 0.000). Fifty-six percent of the brains had no anomalies. Thirty anomalies were noted in posterior COW compared with six in the vertebrobasilar territory. There were no aneurysms in all the specimens studied. CONCLUSION: Anomalies in the region of the posterior COW are commoner than the vertebrobasilar territory and the region of the posterior communicating artery is the most common site of anomalies in the posterior COW territory. These variations should be taken into account during skull base and carotid surgeries, and cerebral angiography. PMID- 20931510 TI - Urinary tract infections in children with primary nephrotic syndrome and acute glomerulonephritis. AB - BACKGROUND: The occurrence of urinary tract infection (UTI) in children with nephrotic syndrome (NS) has been widely reported by various workers, but not much has been documented about its occurrence among children with acute glomerulonephritis (AGN). Hence, the level of susceptibility to UTI by both diseases has not been compared. OBJECTIVE: To determine and compare the prevalence of UTI in children newly diagnosed of AGN or NS. METHODS: Urinary microscopy, culture and sensitivity of all children admitted with a diagnosis of NS and AGN between 1996-2004 were reviewed. Children with NS who had a relapse or were commenced on steroids, cytotoxic agents or antibiotics before admission were excluded from the study. RESULTS: A total of 35 and 32 children diagnosed of AGN and NS respectively met the study criteria. Urinary tract infection occurred in three (9%) children with AGN and one (3%) of the children with NS. The organisms isolated among the AGN patients included Coliforms, Klebsiella, and Staphylococcus aureus while Coliform was isolated in the only NS patient with UTI. CONCLUSION: There is a low prevalence of UTI in children newly diagnosed of AGN and NS. PMID- 20931511 TI - The role of echocardiography in the management of stroke. AB - BACKGROUND: Echocardiography is increasingly being used as a screening test to identify sources of cardiogenic embolism in patients with ischemic stroke or transient ischaemic attack (TIA). However, no consensus exists presently on the utilization of this imaging facility in individuals with stroke. OBJECTIVE: To evaluate the yield of transthoracic echocardiography in patients with ischaemic stroke with a view to providing guidance in its use in clinical management of stroke. METHODS: One hundred and twenty-six consecutive stroke patients with 90 controls were recruited prospectively. Patients were examined echocardiographically for evidence of intramural thrombus, congenital defects, valvular heart disease, wall motion abnormalities and intra-cardiac masses using two-dimensional, m-Mode and Doppler facilities. RESULTS: Potential cardiac source of emboli (CSE) was identified in 23.0% of the stroke patients. Those who had CSE identified aged 53.0(20.8) years were younger (p=0.0001) than those who did not have CSE, 57.2 (13.5) years. Five (4.0%) patients had rheumatic valvular heart disease with demonstrable clots in the left atrium. On the other hand, four(3.2%) patients had RHD without thrombi seen. Two patients had biventricular thrombi. One of these patients had giant clots within the ventricles and multiple freely mobile thrombi in right ventricle without obvious cardiac structural defect. CONCLUSION: Young stroke or transient ischaemic attacks patients who have clinical signs suggesting the heart as the potential CSE should have low threshold for echocardiography. However, there is a need for rationalisation of request for echocardiography where such clinical signs are absent. PMID- 20931512 TI - Liver enzymes and trace elements in the acute phase of sickle cell anaemia. AB - BACKGROUND: Trace elements are required for the performance of numerous functions of immune cells. It is not clear whether levels of trace elements are elevated and whether there is a relationship between the levels of liver enzymes and trace elements in patients with sickle cell anaemia in crisis. OBJECTIVE: To compare the plasma levels of liver enzymes and trace elements in non sickle cell anaemia (NSCA), sickle cell anaemia subjects in the steady state (SCASS) and sickle cell anaemia patients in crisis (SCAC). METHODS: Haematological parameters, liver enzymes and trace elements were determined in 20 NSCA subjects, 20 SCASS subjects and 18 SCAC subjects. Variables studied included aspartate aminotransferase (AST) , alanine aminotransaminase (ALT), alkaline phosphatase (ALP), and the trace elements copper, zinc, and manganese. RESULTS: Levels of liver enzymes were higher in the SCAC subjects than in the NSCA or SCASS subjects (p<0.001). Plasma Cu++, Zn++ and Mn++ were also higher in the SCAC subjects than in the NSCA or SCASS subjects (p<0.001). Correlationships were high and strong between AST and ALT (r=+0.7; p=0.03), AST and ALP (r=+0.9; p=0.001), Zn++ and Fe++ (r=+0.9; p=0.001) in SCAC. CONCLUSION: During crisis in sickle cell anaemia, liver enzymes, as well as the trace elements of Cu++, Zn++ and Mn++ are increased; levels of aspartate aminotransaminase are strongly correlated with those of ALT and ALP. Levels of liver enzymes do not appear to be related to those of the trace elements in painful sickle cell crisis. PMID- 20931513 TI - Mortality pattern within twenty-four hours of emergency paediatric admission in a resource-poor nation health facility. AB - BACKGROUND: Mortality among emergency paediatric admissions within the first 24 hours is high in resource- poor nations. Measures to reduce the childhood mortality rate can only be effectively planned and implemented when the causes and magnitude of this problem are well defined. OBJECTIVE: To determine the mortality pattern among emergency paediatric admissions within the first 24 hours in a health facility in Nigeria. METHODS: The clinical state and progress of post neonatal patients who presented alive and were admitted into the emergency paediatric room of the University of Ilorin Teaching Hospital, Ilorin, Nigeria were monitored over a period of six months. The monitoring included records of diagnosis and outcome of management. RESULTS: A total of 606 children were admitted during the period of study out of which 51(8.4%) died. Twenty-nine (57%) of the deaths occurred within the first 24 hours of admission comprising 15 (51.7%) males and 14 (48.3%) females giving M:F ratio of about of 1:1. Majority of the deaths were among patients who reported late to the hospital. Loss of consciousness was a strong risk factor for mortality within 24 hours of admission. The highest mortality within the first 24 hours of admission was recorded among patients with malaria (89.0%) followed by protein energy malnutrition. CONCLUSION: Majority of deaths among emergency paediatric admission occur within the first 24 hours of admission and are associated with clinical conditions such as malaria and protein-energy malnutrition for which sustained intervention strategies must be developed. PMID- 20931514 TI - Diagnostic accuracy of fine needle aspiration cytology of palpable breast masses in Benin City, Nigeria. AB - BACKGROUND: Beast cancer is the commonest malignancy afflicting women. It accounts for 18.4% of all female cancers worldwide. OBJECTIVE: To determine the diagnostic accuracy of fine needle aspiration cytology (FNAC) of palpable breast masses at a Nigerian University Teaching Hospital.. METHODS: Fine Needle Aspiration Cytology was done on all consecutive cases of palpable breast masses referred from the surgical outpatient clinic of the University of Benin Teaching Hospital between January 2005 and March 2006. Comparison was made with subsequent histological diagnoses in order to ascertain the diagnostic accuracy of the procedure. RESULTS: One hundred and three fine needle aspirates of breast masses were performed during the study period. Subsequent biopsies were done on 43 of these cases yielding a biopsy rate of 41.8%. The absolute and complete sensitivities of this study were 84.6% and 97.4% respectively. The full specificity was 64% while the specificity for biopsy cases was 75%. The positive predictive value for malignancies was 100% with a false positive rate of 0%; however the false negative rate was 2.6% with a suspicious rate of 9.7%. The inadequacy rate was 19.4%. CONCLUSION: These results show that FNAC of palpable breast masses in UBTH is an accurate procedure with results comparable to those from other centres and well above the minimum standards recommended internationally. It is, therefore, recommended that FNAC be done on all palpable breast masses. PMID- 20931515 TI - Paediatric tuberculosis at the national teaching hospital CNHU-HKM of Cotonou, Benin: a retrospective study. AB - BACKGROIUND: Tuberculosis (TB) is a public health problem. Knowing its patterns could help address it more efficiently. OBJECTIVE: To determine the hospital incidence, presentation, management, and outcome of TB in our setting. METHODS: We conducted a chart review of children with TB during a five-year period at the University Hospital CNHU-HKM, Cotonou, Benin. RESULTS: Hospital prevalence of TB among hospitalised children was 0.2%. The mean age was six years, with a male:female ratio of 1.4:1. The common clinical features were: cough (78.1%), long standing fever (81.2%), growth retardation (65.6%), pulmonary consolidation (53.1%) and hepatosplenomegaly (34.4%). The skin tuberculin test was positive in only 40.6% of cases. Co-infection with HIV was present in 51.8% of cases. Mycobacterium tuberculosis could be identified in only 21.8% of cases. Twenty-six (81.2%) pulmonary tuberculosis (PTB) cases were diagnosed, eight (25%) of which were associated with extra pulmonary TB. Six (18.7%) presumed isolated extra PTB were also diagnosed. Eight-month treatment regimen was used in most patients, with mortality rate of 9.3%. CONCLUSION: Although TB hospital prevalence seems low in our setting, management needs to be improved according to guidelines. PMID- 20931516 TI - Superficial fungal infections seen at a tertiary health centre: clinical and mycological studies. AB - BACKGROUND: Superficial fungal infections are common in the tropics, partly due to the climate, relatively poor hygiene, and lifestyle of the people. OBJECTIVE: To determine the clinical forms and aetiological agents of superficial fungal infections as seen among skin cases in the north- central part of Nigeria. METHODS: All consecutive new patients seen at the skin clinic of the General Out patient Department of the Federal Medical Centre, Bida from July 2006 to December 2007 were included in this prospective study. Participants were examined for superficial fungal lesions. Samples of skin scrapings for microbiological investigations were obtained from suspicious lesions. RESULTS: A total of 381 patients attended the Skin Clinic during the period of study. Superficial fungal infections constituted 89(23.4%) of all skin cases seen. The commonest clinical type of fungal infection was Tinea corporis, followed by Tinea unguium. Male to female ratio of clinical lesions was 1: 1.5. A total of 41 samples grew fungal organisms on Sabouraud Dextrose Agar culture, of which dermatophytes were the isolates in 22(53.7%), while non-dermatophytes accounted for the rest. Seven species of dermatophytes, dominated by Trichophyton spp. 15 (68.2%), followed by Microsporum gypseum 4(18.2%), and Epidermophyton floccosum 3(13.6%) were the main isolates. The most commonly recovered species were T. mentagrophytes (36.4%). CONCLUSION: These data show the continued predominance of dermatophytes as the principal pathogen in superficial fungal infection. Trichophyton spp. is the predominant class of which T. mentagrophyte is the most prevalent. PMID- 20931517 TI - Familial hypophosphataemic rickets affecting a father and his two daughters: a case report. AB - BACKGROUND: Hypophosphataemic rickets (HR) is a rare cause of short stature associated with limb deformities. OBJECTIVE: To report the clinical and laboratory features of HR in two siblings and their father. METHODS: Following the diagnosis of HR in a 4-year-old girl, her siblings and parents were screened using clinical, laboratory, and radiological parameters. RESULTS: Short stature, lower limb deformities, frontal bossing and hypophosphataemia were present in all three patients. Serum alkaline phosphatase (ALP) was markedly elevated in both siblings who were aged two and 11 years but only minimally raised in their 43 year-old father. While spontaneous mutation is the presumed aetiology in the father, X linked dominant inheritance is the likely cause in both daughters. CONCLUSIONS: Hypophosphataemic rickets should be considered in the differential diagnosis of short stature associated with limb deformities regardless of a family history of HR. Serum ALP may not be remarkably elevated when the diagnosis is made in adulthood. PMID- 20931518 TI - Haemophilus meningitis in an African neonate: time for active surveillance and institution of appropriate control measure. AB - BACKGROUND: Childhood routine immunization in Nigeria, like most developing nations, do not include vaccination against Haemophilus influenzae type b (Hib) infection. This is probably because infection with Hib is uncommon in children younger than two months due to passive acquisition of maternal antibodies which protects newborn till about four to six months of life. OBJECTIVE: To illustrate a case of neonatal meningitis caused by Haemophilus influenzae and to highlight its other peculiarities. METHODS: A 22-day old baby presented with excessive crying, refusal of feed, progressive abdominal distension, fever and vomiting. Besides clinical assessment, body fluids were cultured. RESULTS: The baby had tachypnoea (90 bpm), tachycardia (182 bpm), and tympanitic and hypoactive abdomen. The musculoskeletal and central nervous systems appeared clinically normal. Haemophilus influenzae was isolated by culture from the cerebrospinal fluid. The baby responded well to treatment with ceftriaxone and gentamycin. Neurological examination has remained normal after discharge for up to three months at follow-up visit. CONCLUSION: There is the need to provide serological and molecular facilities for typing Nigerian Haemophilus infulenzae strain(s) to enhance the development of appropriate vaccine that will be most suitable for prevention of infection due to this organism in Nigeria. However, presently available Haemophilus influenzae vaccine needs to be listed in the National Programme for Immunization (NPI) for the control of infections associated with this organism especially in childhood. PMID- 20931519 TI - Medicine turned poison for children in Nigeria. PMID- 20931520 TI - [Analysis of the phenotype-genotype relationship of Hb Constant Spring]. AB - OBJECTIVE: To analyze the genotype-phenotype correlations in the Hb Constant Spring (HbCS) carriers, and to investigate the effect of HbCS on hematologic parameters. METHODS: Complete blood cell count and hemoglobin electrophoresis analyses were performed in 125 HbCS cases. The alpha-and beta-thalassemia mutations were determined by reverse dot-blotting and Gap-PCR. RESULTS: The presence of the SEA deletion or Hb Quong Sze (HbQS) with HbCS leads to HbH-CS disease. There was significant difference between HbH-CS and alphaCSalpha/-alpha, HbH-CS and alphaCSalpha/alphaalpha in the hematological parameters. The genotype of alphaCSalpha/-alpha or alphaalpha/alphaCSalpha had slight effect on hematological parameters. When the Hb Constant Spring mutation co-existed with heterozygous beta-thalassemia, the hematological characteristics of beta thalassemia was presented. Only 57.6% of carriers with HbCS were detected by hemoglobin electrophoresis. CONCLUSION: The cases with co-existence of HbCS trait and other alpha-thalassemia trait, or beta-thalassemia trait, showed variation in their red blood cell parameters. For such compound heterozygotes for HbCS and other alpha- or beta-thalassaemia mutations, which were usually misdiagnosed in clinical screening by hemoglobin electrophoresis, accurate diagnose can be made by molecular diagnosis. PMID- 20931521 TI - [Effect of bone morphogenetic protein 4 on glioma stem cell proliferation and apoptosis in vitro]. AB - OBJECTIVE: To investigate the role of bone morphogenetic protein 4 (BMP4) on the proliferation and apoptosis in glioma stem cells. METHODS: Stem cells were isolated from a human glioma cell line U87 by using vincristine and characterized by immunofluorescence assay. Proliferation and apoptosis were determined by soft agar colony assay and flow cytometry; Cyclin D1, Bcl-2 and Bax were detected by Western blot analysis. RESULTS: BMP4 inhibited cell proliferation and promoted apoptosis in U87 glioma stem cells. Moreover, Bcl-2 and Cyclin D1 expression were decreased by BMP4, while Bax level was elevated. CONCLUSION: BMP4 can inhibit U87 glioma stem cells proliferation through downregulating Cyclin D1 level, and promote apoptosis through induction of Bax expression and inhibition of Bcl-2 level. It suggests that BMP4 plays an important role in human glioma stem cell biology. PMID- 20931522 TI - [Founder effect of two families with TGFBI related Thiel-Behnke corneal dystrophy]. AB - OBJECTIVE: To investigate the transforming growth factor beta induced (TGFBI; BIGH3) gene mutation and founder effect of two large Chinese families clinically diagnosed as Thiel-Behnke corneal dystrophy. METHODS: Fifteen members including 13 affected and 2 healthy in family A, 14 members including 6 affected and 8 healthy in family B, as well as 20 other unrelated healthy individuals were tested for TGFBI gene mutation. Haplotype analysis and clinical examination were also carried out in the two families. RESULTS: In exon 12 of the TGFBI gene, 1664G to A change was detected in all the patients, which leads to an amino acid replacement of arginine with glutamine (p.Arg555Gln). Members of the two families share some similar haplotypes. CONCLUSION: Genetic analysis is helpful in the diagnosis of corneal dystrophy. The two families may come from a same ancestor. PMID- 20931523 TI - [Mutation analysis of the GLUD1 gene in patients with glutamate dehydrogenase congenital hyperinsulinism]. AB - OBJECTIVE: To investigate the glutamate dehydrogenase 1 (GLUD1) gene mutation of three patients diagnosed as glutamate dehydrogenase congenital hyperinsulinism (GDH-HI). METHODS: Three patients diagnosed as GDH-HI and their parents were involved in the study. PCR-DNA direct sequencing was used to analyze the exons 6,7,10,11 and 12 of the GLUD1 gene. RESULTS: In the first case, an R269H heterozygous mutation was found in the GLUD1 gene, with autosomal dominant inheritance. In the second case, there was a de novo S445L heterozygous mutation of the GLUD1 gene. No mutation was detected in the third case. CONCLUSION: In Chinese, R269H, S445L heterozygous mutation of the GLUD1 gene can lead to GDH-HI. Genetic analysis is necessary in making genetic diagnosis of congenital hyperinsulinsm. PMID- 20931524 TI - [A new mutation in the GJB1 gene of a Chinese family with Charcot-Marie-Tooth disease associated with vocal cord paresis]. AB - OBJECTIVE: To report an X-linked dominant Charcot-Marie-Tooth disease (CMTX) Chinese family with vocal cord paresis and to identify the mutation of gap junction protein beta 1 gene (GJB1). METHODS: Part of the family members with dysphagia, dysphonia and lethal respiratory failure were studied through flexible laryngoscope, clinical, brain MRI and electrophysiological examinations. After excluding large fragment tandem duplication containing peripheral myelin protein 22 gene (PMP22), direct sequencing was performed to analyze the mutation of the GJB1 gene in 5 patients including the proband, 5 unaffected family members and 50 unrelated healthy individuals. RESULTS: Eight members spanning 3 generations in this family were affected with CMTX characterized by progressive atrophy and weakness of the anterior tibial and peroneal muscles, especially in the proband. Vocal cord paresis was observed through flexible laryngoscope in total of 4 affected members with dysarthria and dysphagia, 2 of them died of severe respiratory failure due to complete bilateral vocal cord involvement. Normal brain MRI was observed in the proband. The electrophysiological data showed predominant demyelization involving the motor and sensory nerves in the proband. DNA sequencing revealed a de novo c.186 C>G missense mutation in exon 2 of the GJB1 gene, the mutation cosegregated with phenotype. CONCLUSION: Respiratory failure associated with vocal cord involvement may be a rare and severe symptom in CMTX. The present report provides further evidence for clinical and genetic heterogeneity in the X-linked Charcot-Marie-Tooth disease. PMID- 20931525 TI - [Polynucleotide repeat expansion of nine spinocerebellar ataxia subtypes and dentatorubral-pallidoluysian atrophy in healthy Chinese Han population]. AB - OBJECTIVE: To assist the establishment of platform and provide the reference standard for mutation detection in spinocerebellar ataxia (SCA) subtypes 1, 2, 3, 6, 7, 8, 10, 12, 17 and dentatorubral-pallidoluysian atrophy (DRPLA) in Chinese Han population. METHODS: The nucleotide repeat numbers of the 9 SCA subtypes and DRPLA were detected using fluorescence-PCR and capillary gel electrophoresis technique in 300 healthy Chinese Han individuals. RESULTS: Among the 300 healthy controls, the range of the CAG trinucleotide repeat number was 17 to 35 in SCA1, 14-28 in SCA2, 13-41 in SCA3/MJD, 4-16 in SCA6, 5-17 in SCA7, 5-21 in SCA12, 23 41 in SCA17, and 12-33 in DRPLA; and the range of CTA/CTG trinucleotide repeat number on SCA8 locus was 12-43 and the range of ATTCT pentanucleotide repeat number on SCA10 locus was 9-32. Of which, the 12 CTA/CTG repeats of SCA8, 9 ATTCT repeats of SCA10, 23 CAG repeats of SCA17 were the shortest normal repeat number, while the 41 CAG repeats of SCA3/MJD, 32 CAG repeats of SCA10 were the largest normal number that have not been reported. CONCLUSION: The normal ranges of polynucleotide repeats of different subtypes of SCA vary with geographical areas and ethnicities. It might be associated with the genetic and ethnic backgrounds. This is the first normal reference standard of polynucleotide repeat number of these ten SCA subtypes in Chinese Han. PMID- 20931526 TI - [Association of the ABCG1 gene polymorphism with the susceptibility and severity of coronary atherosclerotic disease]. AB - OBJECTIVE: To investigate the association of the ATP-binding cassette sub-family G member 1 (ABCG1) gene polymorphisms with coronary atherosclerotic disease (CAD) in Chinese Han population. METHODS: A population based case-control association study was carried out in 541 patients with CAD and 649 healthy controls from Chinese Han population. Two single nucleotide polymorphisms (SNPs) of the ABCG1 gene were genotyped using polymerase chain reaction-restriction fragment length polymorphism. Logistic regression was used to compare the genotypic and allelic frequency difference. RESULTS: The frequency of allele C of rs225374 was significantly higher in the CAD patients than that in the healthy controls (OR=1.186, 95%CI: 1.009-1.394, P=0.039), while the difference was also significant in the male subgroup (OR=1.236, 95%CI: 1.014-1.506, P=0.036). A statistically higher frequency of rs1044317 allele A was found in the CAD patients in comparison to the healthy controls (OR=1.187, 95%CI: 1.009-1.397, P=0.039). In case-only association study, rs225374 showed significant association in the high Gensini score group compared with the low Gensini score group (OR=1.303, 95%CI: 1.024-1.657, P=0.031). CONCLUSION: The two SNPs of the ABCG1 gene might be associated with the susceptibility and severity of CAD in Chinese Han population. PMID- 20931527 TI - [A novel GATA4 mutation leading to congenital ventricular septal defect]. AB - OBJECTIVE: To identify the GATA4 gene mutation of congenital ventricular septal defect (VSD) and study the molecular mechanism of a novel mutation. METHODS: The clinical data and blood samples from 185 unrelated subjects with congenital VSD were collected and evaluated together with 200 healthy individuals. The coding exons and the flanking intron regions of the GATA4 gene were amplified by PCR and sequenced using the di-deoxynucleotide chain termination approach. The GATA4 gene was cloned and the corresponding mutant was acquired by site directed mutagenesis. The recombinant plasmid expressing GATA4 and the reporter vector expressing enhanced green fluorescence protein (EGFP) driven by the promoter of atrial natrium peptide (ANP) gene were transfected into HeLa cells with Lipofectamine. The effect of mutated GATA4 gene on the transcriptional activity of encoded transcriptional factor was analyzed by reverse transcription (RT)-PCR. RESULTS: A novel heterozygous missense GATA4 mutation, c.191G>A was identified in 1 VSD patient. The mutation leads to glycine to glutamic acid change at amino acid residue 64 (G64E) in the GATA4 protein. Functional analysis showed that GATA4 G64E mutation decreased the transcriptional activity of GATA4 transcriptional factor. CONCLUSION: A novel heterozygous missense GATA4 mutation, G64E, was identified in 1 VSD patient. The mutation might cause VSD by impairing the transcriptional activity of GATA4 transcriptional factor. PMID- 20931528 TI - [Progress in research on susceptibility gene mapping of Tic disorder]. AB - Tic disorder (TD) is a chronic neuropsychiatric disorder with childhood onset. Previous research has demonstrated that genetic factors play an important role in the pathogenesis of TD, and TD is a complex disease affected by multiple genes. Many susceptibility genes have been identified and the relationship between these genes and the etiology of TD was investigated in the past few years. These researches have yielded large valuable information as well as provided a reference for understanding the pathogenesis and further research of this disease. In this paper we reviewed the recent progress in the study on the susceptibility gene mapping of TD. PMID- 20931529 TI - [Molecular genetics of autoimmune diabetes]. AB - Autoimmune diabetes is a T cell-mediated disease characterized by the autoimmune destruction of pancreatic beta-cells and insulin deficiency. It is related to multiple genes. The IDDM1 locus, which lies within the human leukocyte antigen (HLA) and the IDDM2 locus, which is located to the insulin gene region, are two major genetic contributors of susceptibility. Many other loci conferring susceptibility to autoimmune diabetes are being discovered, including PTPN22, CTLA4, IL2RA and IFIH1. In this article, these loci and their possible immunologic mechanisms involved in the pathogenesis of this disease will be reviewed. PMID- 20931530 TI - [Identification of a cryptic 1p36.3 microdeletion in a patient with Prader-Willi like syndrome features]. AB - OBJECTIVE: To determine the karyotype of a patient with Prader-Willi-like syndrome features. METHODS: Chromosomal high resolution banding was carried out to analyze the karyotype of the patient, and methylation-specific PCR was used to analyze the imprinting region of chromosome 15. Subtelomeric region was screened by multiplex ligation-dependent probe amplification (MLPA), and fluorescent in situ hybridization (FISH) and real-time quantitative PCR were further performed to identify the deleted region. RESULTS: No abnormality was discovered by high resolution karyotype analysis and methylation-specific PCR studies. MLPA analysis showed that the patient had a deletion of 1p subtelomeric area, which was confirmed by FISH analysis. The deleted region was shown within a 4.2 Mb in the distal 1p by 3 BAC FISH probes of 1p36 combined with real-time PCR technique. Family pedigree investigation showed the chromosome abnormality was de novo. Therefore, partial monosomy 1p36 was likely responsible for the mental retardation of the patient. CONCLUSION: Molecular cytogenetic techniques should be performed to those patients with Prader-Willi-like syndrome features, to determine their karyotypes. PMID- 20931531 TI - [Establishment of the multiplex quantitative ligase chain reaction for detecting mutations of deafness genes]. AB - OBJECTIVE: To establish a low-cost, convenient and accurate multiplex quantitative ligase chain reaction (MQ-LCR) technique to detect the five common mutations in Chinese patients with deafness. METHODS: Primers and probes for 5 common mutations of deafness genes, i.e., GJB2 gene 235delC and 299-300delAT, mtDNA A1555G, SLC26A4 gene IVS7-2 A>G and 2168A>G, were designed and synthesized. The technique for those mutations was established, and the reliability of the technique was tested in 98 patients with impaired hearing and 30 children with normal hearing, who were randomly selected from the ENT in Children's Hospital of Fudan University. The subjects were detected by MQ-LCR and direct DNA sequencing of PCR products, following a double-blind approach. Finally the results from the two methods were compared. RESULTS: The results revealed 48 cases carried two mutations, 31 cases carried heterozygous mutations in the 98 deaf children, and 3 had heterozygous mutation in 30 normal controls. These results were consistent with that from DNA sequencing. No false positive and false negative result was obtained. CONCLUSION: The MQ-LCR technique established in this study is of low cost, convenience, accuracy, high sensitivity and high specificity. It is suitable for large-scale detection and preventive diagnosis of mutations in deafness. PMID- 20931532 TI - [Association of the Pro1770Leu polymorphism in CYP5A1 gene with myocardial infarction in Uigur population of Xinjiang]. AB - OBJECTIVE: To investigate the association between the polymorphism of the thromboxane synthase gene and Uigur patients with myocardial infarction (MI) in Xinjiang. METHODS: Three hundred and fifteen patients with MI and 218 healthy control subjects were detected by polymerase chain reaction and restriction fragment length polymorphism. The serum thromboxane B2 (TXB2) in all subjects was detected with radioimmunoassay kit. RESULTS: The genotype distributions of the MI group and control group were in Hardy-Weinberg equilibrium (Chi square=0.375,0.029, P>0.05). The frequencies of CC and TC were 0.933 and 0.067 in MI group while they were 0.977 and 0.023 in controls. There was significant difference in frequencies of the TC genotype and T allele but no difference in frequencies of CC genotype between controls and MI cases. There was significant difference in serum TXB2 level between the MI and control group (P<0.05), and between individuals of the TC and CC genotypes (P<0.05). The serum TXB2 level in the MI cases with TC genotype was increased compared with that of other genotypes (P<0.05). CONCLUSION: The TC genotype and T allele of thromboxane synthase gene might be risk factors of MI in Uigur population in Xinjiang, which might result from the increased serum TXB2 level. PMID- 20931533 TI - [Association of HER2 genetic heterogeneity with clinicopathological characteristics in breast cancer]. AB - OBJECTIVE: To introduce the College of American Pathologists/American College of Medical Genetics Cytogenetics Resource Committee criteria for genetic heterogeneity (GH) in HER2 testing, and investigate the clinicopathological significance of HER2 genetic heterogeneity in invasive breast cancer. METHODS: The clinical parameters of 100 cases of invasive breast carcinomas were collected. HER2 expression level and HER2 gene copy number in formalin-fixed and paraffin embedded tumor samples were detected by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), and the relationship between HER2 gene GH and clinicopathological characteristics were analyzed. RESULTS: Among the 100 patients, HER2 gene GH was observed in 20 (20%) cases. When the number of HER2 amplified cells was more than 25%, the frequencies of FISH positive were higher than those cases with less than 25% HER2 amplified cells. The results showed that HER2 gene GH was associated with the degree of HER2 protein expression (P=0.004), and ER expression (P=0.002). CONCLUSION: HER2 gene GH may be correlated with the HER2 protein IHC 1+/2+, and ER expression in breast carcinoma. It is important for doctors to avoid ignoring or only counting FISH positive cells leading to incorrect diagnosis for these patients. PMID- 20931534 TI - [Association of the C1155547T polymorphism in WNK4 gene with essential hypertension in Xinjiang Kazakhs]. AB - OBJECTIVE: To investigate whether the WNK lysine deficient protein kinase 4 (WNK4) gene C1155547T polymorphism is associated with essential hypertension (EH) in Xinjiang Kazakhs and to assess the effect of the interaction between this polymorphism and environment factors on EH. METHODS: The study covered 556 hypertension patients and 341 normotensive controls. The C1155547T was determined by Taqman probe real-time PCR method. Some biochemical index such as glucose, triglyceride and total cholesterol were also measured. All of these results were analyzed with Logistic regression analysis. Additive model was applied to assess the effect of interaction between the WNK4 gene C1155547T polymorphism and environment factors on hypertension. RESULTS: The C1155547T polymorphism was consistent with Hardy-Weinberg equilibrium in both the case and control groups. There was significant difference in the genotype frequencies (P=0.003). The T allele frequency was significantly higher in the patient group (P=0.002). Logistic regression analysis revealed that the age, body mass index (BMI), total cholesterol as well as the CT+TT genotype frequency conferred increased risks for EH. Positive interaction between the C1155547T polymorphism and gender, BMI, glucose was observed. The ORs were 3.85 (95%CI:1.23-12.04), 5.91 (95%CI:1.99 17.57) and 8.77 (95%CI:1.04-73.93), respectively. CONCLUSION: The result suggested that the exon 7 C1155547T polymorphism in WNK4 gene might be associated with EH in Xinjiang Kazakhs, the T allele might be the risk factor of essential hypertension. There were interactive effects between the WNK4 gene C1155547T polymorphism and gender, BMI and glucose. PMID- 20931535 TI - [PPARGC1A gene Thr394Thr G/A polymorphism and its association with type 2 diabetes mellitus and insulin resistance in a Chinese population]. AB - OBJECTIVE: To examine the association of the Thr394Thr polymorphism of PPARGC1A gene with type 2 diabetes (T2DM), insulin resistance (IR) and other metabolic disorders in a Chinese population. METHODS: Three hundred and seven subjects including 151 T2DM patients and 156 normal glucose tolerant controls (NC) were enrolled in this study. The Thr394Thr G/A polymorphism was genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Glucose, insulin, lipids levels were determined in all subjects. Body mass index (BMI), waist circumferences, index of homeostasis model assessment-insulin resistance (HOMA-IR) and blood pressure were also measured. RESULTS: The diabetic subjects had higher levels of BMI, waist circumferences, blood systolic pressure, triglycerides and lower levels of high density lipoprotein-cholesterol (HDL-C) compared with those of control subjects (P<0.05). About 43.7% (66/151) of the T2DM subjects had the AG genotype, while 37.2% (58/156) in the NC group. The frequency of the A allele was 0.225 in T2DM, and 0.186 in the NC subjects. There were no significant differences either in genotype or allelic distribution of G/A polymorphism between the two groups. In the T2DM group, subjects with AA and GA genotypes had significantly higher levels of HOMA-IR, waist circumferences and lower levels of HDL-C (P<0.05) than those carrying GG genotype. HOMA-IR in subjects with AA and AG were significantly higher than those with GG genotype in both groups. CONCLUSION: The A allele of the Thr394Thr (G-->A) polymorphism of the PPARGC1A gene was associated with insulin resistance, and may be related to central obesity and decreased HDL-C levels in Chinese population. The relationship between this polymorphism and T2DM needs further investigation. PMID- 20931536 TI - [Mutation analysis of PTPN11 gene in Noonan syndrome]. AB - OBJECTIVE: To investigate the mutations in protein tyrosine phosphatase, nonreceptor-type 11 (PTPN11) gene in patients with Noonan syndrome (NS). METHODS: Three sporadic patients with NS were studied. Genomic DNAs were extracted from peripheral blood leukocytes. All 15 coding exons and their flanking intronic boundaries of the PTPN11 gene were amplified by polymerase chain reaction and followed by direct sequencing. DNAs from parents were sequenced in the corresponding region when the mutation was detected in their affected child. The identified mutation was screened in 100 healthy individuals for exclusion of polymorphism by restriction endonuclease digestion of the PCR products. Protein conservation analysis was performed among 10 species using an online ClustalW tool. RESULTS: Direct DNA sequence analysis identified a heterozygous 181G to A change in exon 3 of the PTPN11 gene in one patient, which resulted in the substitution of an aspartic acid residue by an asparagine at codon 61. The mutation was absent in his parents and 100 controls, and is located in a highly conserved amino acid site. No mutation in the coding region of PTPN11 gene was observed in the other two patients. CONCLUSION: The p.D61N mutation was reported previously in Caucasians and is a de-novo mutation in this patient. Our study further confirmed that the p.D61N is a pathogenic mutation for NS and consistent with the clinical diagnosis. Additional genes may be involved in the other two patients with NS, indicating high genetic heterogeneity of this disease. PMID- 20931537 TI - [Analysis of ring chromosome 9 syndrome with fluorescence in situ hybridization]. AB - OBJECTIVE: To investigate the mechanism of the ring chromosome 9 formation by cytogenetic analysis of one case affected with ring chromosome 9 syndrome. METHODS: Routine chromosome GTG-binding analysis and dual-color fluorescence in situ hybridization (FISH) with TelVision 9p and 9q probes were applied to characterize the case. RESULTS: The G-binding revealed that the patient had ring chromosome 9 with the following karyotype: 45,X, 9/46,XX,r(9)(p24q34)/46,XX,r(9;9)(p24q34;p24q34)[4/92/4]. The dual-color FISH analysis with TelVision 9p and TelVision 9q probes failed to detect a hybridization signal on the ring chromosome in the case, which indicated that at least 115 kb were deleted on the terminal 9p and 95 kb were deleted on the terminal 9q. Comparing to the cases reported in the literatures, our patient shared some common features of the 9p- and 9q- syndrome. CONCLUSION: The clinical features of patients with identical r(9) breakpoints present variable phenotypes. The possible cause might be the submicroscopic variation in the deletion breakpoints, variation in the ring stability, the modification of the expression of the deleted by the individual's genetic background, or the effect of changes in the fetal environment. The haploinsufficiency of genes located in the deleted regions may play critical roles in the patient phenotype as well. PMID- 20931538 TI - [Application of fluorescence in situ hybridization technique in diagnosis of variant Ph chromosome translocation and Ph-negative chronic myelocytic leukemia]. AB - OBJECTIVE: To explore the value of fluorescence in situ hybridization (FISH) technique in diagnosis of variant Ph chromosome translocation (VT) and Ph chromosome-negative chronic myelocytic leukemia (CML). METHODS: Nine CML patients with VT and 2 Ph chromosome-negative CML patients confirmed by R banding were assayed with dual color-dual fusion BCR/ABL probe by FISH. RESULTS: The 9 patients with VT involved chromosomes 1, 3, 5, 12, 13, 15, 17 and 21 besides chromosomes 9 and 22, and some of them showed recurrent aberrations; FISH results were positive and the signal feature was 2R2G1Y. The 2 Ph-negative CML patients had normal karyotypes; FISH was positive and the signal feature was 1R1G2Y and 1R1G1Y respectively. CONCLUSION: FISH can provide better diagnosis for CML with VT and Ph-negative CML. Abnormal karyotype and marker gene changes can be assessed based on the signal feature of the positive cell. So FISH is a complementary method to banding technique in diagnosis of CML. PMID- 20931539 TI - [Investigation of the molecular changes in patients with multiple myeloma by fluorescence in situ hybridization]. AB - OBJECTIVE: To investigate the incidence and prognosis of 1q21 amplification, 13q14 deletion, TP53 gene deletion and IgH translocation in patients with multiple myeloma (MM). METHODS: Interphase fluorescence in situ hybridization (I FISH) with four different specific probes for the regions containing 1q21, 13q14.3 (D13S319), 14q32 and TP53 gene were performed in 43 MM patients. RESULTS: Among the 43 MM patients, 1q21 amplification was observed in 28 (65.1%) cases, 13q14 deletion in 30 (69.7%) cases, TP53 gene deletion in 8 (18.6%) cases, and IgH translocation in 29 (67.4%) cases. The mortality of MM patients with 1q21 amplification, 13q14 deletion or TP53 gene deletion was higher than those without them. CONCLUSION: There is high frequency of 1q21 amplification, 13q14 deletion, TP53 gene deletion and IgH translocation in multiple myeloma, and 1q21 amplification, 13q14 deletion and TP53 gene deletion are poor prognosis factors for MM patients. PMID- 20931540 TI - [22q11 microdeletion test in patients with congenital heart defects by quantitative fluorescent PCR]. AB - OBJECTIVE: To establish an assay for screening chromosome 22q11 microdeletion efficiently, and apply it for detecting del22q11 in patients with non-syndromic congenital heart defects (CHD). METHODS: Seventy nine patients with non-syndromic CHD and 84 normal controls were genotyped for 8 short tandem repeat (STR) markers located in 22q11 region, by using quantitative fluorescence polymerase chain reaction (QF-PCR). RESULTS: The average heterozygosity of the STR markers in patients and controls was 0.76 and 0.79, respectively. One patient with Tetralogy of Fallot (TOF) from the 79 CHD cases (1.3%) was found to have a deletion within chromosome 22q11.2, which was confirmed by multiplex ligation-dependent probe amplification (MLPA). CONCLUSION: The QF-PCR assay developed in this study was a reliable and an efficient alterative approach to screen for 22q11 microdeletion in clinical diagnosis and genetic counseling. PMID- 20931541 TI - [The c.3463C>T mutation of the ADAR1 gene in patients with dyschromatosis symmetrical hereditaria]. AB - OBJECTIVE: To analyze the mutation of the adenosine deaminase acting on RNA 1 (ADAR1) gene in a pedigree with dyschromatosis symmetrical hereditaria (DSH). METHODS: Mutation analysis of the ADAR1 gene was carried out by PCR and direct DNA sequencing in the DSH family, as well as in 50 unrelated healthy controls. RESULTS: A missense mutation of c.3463C>T, which results in p.R1155W in the ADAR1 protein, was found in the 2 patients, but was absent in the 2 healthy members in the family and 50 unrelated individuals. CONCLUSION: A missense mutation of c.3463C>T in the ADAR1 gene was detected in the DSH family, which is likely responsible for the pathogenesis of the disease. PMID- 20931542 TI - [Association of IVS10+12G>A polymorphism in hMSH2 gene with colorectal cancer in Chinese]. AB - OBJECTIVE: To investigate the association of the single-nucleotide polymorphism (SNP) IVS10+12 G>A in hMSH2 gene with colorectal cancer in a Chinese population of Jiangsu province. METHODS: A case-control study to investigate whether this SNP affects the risk of developing colorectal cancer was conducted. Subjects included 108 colorectal cancer patients and 180 healthy individuals. Peripheral white blood cell DNA was obtained from all subjects. The hMSH2 gene IVS10+12 G>A was genotyped using a PCR-based DHPLC, the existence of IVS10+12 G>A was verified by DNA sequencing. RESULTS: The allele frequency of the IVS10+12 G>A in the hMSH2 gene in the healthy individuals was 51.7%. There was significant difference in the frequency of the IVS10+12 G>A between patients and healthy controls (P<0.05), and between familial patients and healthy controls (P<0.05). There was also significant difference of the frequency of the IVS10+12 G>A between patients younger than 50 years, and patients with high consumption of fried food and pickled vegetable and healthy controls respectively (P<0.05). CONCLUSION: This SNP may be associated with colorectal cancers in Chinese. Further investigation with larger sample size is needed. PMID- 20931543 TI - [Study of nine single nucleotide polymorphism loci of human HIF1A gene in three Tibetan groups]. AB - OBJECTIVE: To investigate the effect of hypoxia environment induced by altitude on hypoxia inducible factor 1alpha (HIF1A) gene. METHODS: Nine single nucleotide polymorphism (SNP) loci of the HIF1A gene from three Tibetan groups (Tibet, Qinghai Province and Yunnan Province) were genotyped using PCR-restriction fragment length polymorphism (PCR-RFLP) method. RESULTS: For non-synonymous mutation SNP site, there was no significant difference among the three Tibetan groups, except for SNP rs11549465 between Tibet Tibetan and Yunnan Tibetan, as well as between Qinghai Tibetan and Yunnan Tibetan. Frequencies of genotypes and alleles in rs4899056, rs1957757, rs10873142 and rs3783752 had significant differences between Tibet Tibetan and Yunnan Tibetan, and between Qinghai Tibetan and Yunnan Tibetan (all P<0.05). We also observed that the difference was negatively correlated with the altitude. CONCLUSION: The results suggested that the HIF1A gene might be under hypoxic selection induced by high altitude in the three groups. PMID- 20931544 TI - [Radical prostatectomy: local recurrence and persistence of disease. Is it possible to hypothesize any responsibility of the surgeon?]. AB - Radical prostatectomy (RP) represents the most frequently chosen therapeutic option for treating newly diagnosed localized prostate cancer. Cancer recurrence after surgery is linked to biologic variables. But are these the only ones that must be considered to give an explanation of a possible local or distal recurrence, or can it also admit the possibility that an incorrectly conducted surgery has a negative role in the unfavorable evolution after PR? Prostate cancer recurrence, as a matter of fact, is related also to surgical technique. The PR, by definition is a surgical, potentially complicated act. Surgery outcomes depend on a whole series of factors: the surgeon's ability, and the way the surgical procedure is conducted, play an essential role. Here we evaluate the role of biological and surgical factors on biochemical recurrence. PMID- 20931545 TI - [Interstitial cystitis: minimal diagnostic criteria]. AB - Any article reporting on Interstitial Cystitis (IC) will list numerous investigations. This paper presents a review of the minimum investigations needed and their significance for the initial evaluation and diagnosis of patients with Interstitial Cystitis. To optimize patient?s early diagnosis and disease monitoring, a comprehensive algorithm for the diagnosis of IC has been proposed. The paper defines interstitial cystitis (IC) as a disease of the urinary bladder diagnosed by at least one of the following 3 requirements: 1) endoscopic criteria (cystoscopy findings); 2) pathologic criteria of bladder biopsy; and 3) clinical criteria including pain and lower urinary tract symptoms evaluation. Furthermore, the exclusion of confusable diseases is mandatory in all cases. These are recommendations, mostly based on expert opinions and literature review. Where possible, a level of recommendation was developed according to a 3-grade scale: mandatory (grade 1), recommended (grade 2), and optional (grade 3). By using a stepwise approach and an evidence-based thought process, the diagnosis of IC is made easier and reliable. PMID- 20931546 TI - [Safety and tolerability of local treatment with Iloprost in patients with Peyronie's disease. A phase 1 pilot study and proposal of a new symptom questionnaire]. AB - PURPOSE: Intralesional therapy is a less invasive method for the treatment of Peyronie's disease. The objective of this study was to evaluate safety and tolerability of intralesional injections of Iloprost (I2 Prostacyclin analogue) for its property to suppress in fibroblasts CTFG (Connective tissue growth factor) production, which acts in concert with TGF-beta to stimulate the fibrotic process. METHODS: Nineteen patients with Peyronie's disease were preliminarily evaluated by considering the degree of penile curvature, plaque size and local and systemic symptoms. Each patient then received weekly intralesional injections of 200 ng of Iloprost in 1 ml of normal saline for 4-5 weeks. If tolerated, the single dose increased weekly to the maximum of 400 ng (2 mL). RESULTS: The treatment has shown that all patients seem to well tolerate a 200 ng Iloprost dose; 7 of them reached a 300 ng dose and 6 tolerate a 400 ng dose without showing side effects. There was no placebo control group in this study. To evaluate the efficacy of the treatment, the absence of objective parameters (except for the auto-photograph of penis in erection) led us to develop a subjective questionnaire that was given to all patients to assess sexual function, pain reduction, ecc. CONCLUSIONS: Due to the relatively small size of the sample, the efficacy evaluation has been restricted to check the questionnaire reliability. Iloprost is well tolerated to a dose of 400 ng in the local treatment of Peyronie's disease. PMID- 20931547 TI - Analysis of the results obtained with a new phytotherapeutic association for LUTS versus control. [corrected]. AB - INTRODUCTION: Benign prostatic hypertrophy (BPH) is a common disease whose frequency has risen throughout the world in concomitance with the increase in life expectancy. BPH causes voiding disturbances known by the acronym LUTS (lower urinary tract symptoms), which heavily influence the quality of life in the elderly. The treatment for LUTS is mainly divided into medical and surgical, the latter usually represented by prostate ablation. Medical therapy includes synthetic molecules that interfere with the hormonal control of BPH or act on the bladder neck tonus, as well as natural remedies based on plant extracts from Serenoa Repens and/or Urtica Dioica. MATERIAL AND METHODS: Two groups of patients who were candidates for surgery for BPH-induced LUTS, were randomly recruited in a six-month trial aimed at comparing outcome of treatment with a new combination of plants extracts (Pluvio(r)), which differs from the previous ones in that it also contains avocado and soya oil, as well as a high dose of Urtica Dioica, with no therapy. Age, IPSS score, maximal uroflow, prostate volume, PSA, free-to-total PSA ratio, post voiding residual urine and number of nocturia episodes were recorded and statistically evaluated using a NCSS 60(r) program. RESULT: A marked benefit in terms of quality of life, measured by IPSS score, uroflow, residual urine and nocturia, was observed in the treated group compared to controls. PSA and prostate volume were not significantly affected. No noteworthy adverse events were observed. CONCLUSIONS: The new phytotherapeutic combination evaluated in the present study would seem to be highly effective for the treatment of LUTS in BPH patients and does not have negative side effects. Its use could therefore be strongly advocated in this setting. PMID- 20931548 TI - [Treatment of acute iatrogenic cystitis secondary to bladder chemo-immuno instillation or pelvic radiotherapy]. AB - The onset of cystitis during intravesical chemo-immunotherapy for the treatment of non-muscle invasive transitional cell bladder tumor, or after pelvic radiotherapy mainly for prostate cancer, is a frequent clinical situation, not easily manageable due to the lack of responsiveness to symptomatic drugs, often resulting in discontinuation of cancer treatment in many cases.?The similarity of symptoms with those of the painful bladder syndrome, otherwise called interstitial cystitis, has led us to use the same treatment with intravesical sodium hyaluronate in order to obtain an improvement of symptomatology. We therefore performed a prospective study on 55 consecutive male symptomatic patients, aged from 54 to 81 years: 11 after radiotherapy, 17 after BCG and 27 after Mitomicyn C bladder instillations ,12 of whom in combination with bladder hyperthermia.?All subjects underwent bladder instillations with sodium hyaluronate 40 mg in 50 mL weekly for 8 to 24 weeks depending on the time needed to the resolution of the symptoms.?During the first 4 weeks 32 mg of dexamethasone were also instilled intravesically, mixed with hyaluronate, in order to obtain a stronger anti-inflammatory activity due also to its higher capacity of penetration in the bladder mucosa. The symptoms intensity was evaluated through a Visual Analogue Score (VAS) of the discomfort and pain perceived from 0 to 10, and bladder capacity was recorded with micturition diary before and after the treatment.?After 16 weeks VAS improved in every case of chemical cystitis from an initial mean value of 8.6 to a final mean value of 1(with 3 as a maximum value recorded). The difference was highly significant (p <0.001). Bladder capacity increased in all cases of chemical cystitis from a mean value of 56 to 276 mL with a highly significant improvement (p <0.001) and in all cases of post-actinic cystitis from a mean bladder capacity of 89 to a final mean value of 239 mL, with a significant improvement (p= 0.05). We did not observe any side effect due to our treatment. Therefore, we can conclude that bladder instillation with sodium hyaluronate for at least 8 weeks and dexamethasone in the first 4 weeks can solve the symptoms of iatrogenic cystitis secondary to chemo-immunotherapy or pelvic radiotherapy, without incurring in side effects. To our knowledge this treatment has never been published before in scientific medical literature. PMID- 20931549 TI - [Wunderlich syndrome. Clinical and therapeutic aspects of a long-term experience]. AB - INTRODUCTION: Wunderlich's syndrome is defined as a clinical manifestation secondary to sudden spontaneous rupture of renal parenchyma in the absence of injury, resulting in hemoretroperitoneum. This syndrome may occur in patients with benign or malignant neoplasm of the kidney, arterial venous fistulae, immunovasculitis and other phlogosis of the kidney. MATERIALS AND METHODS: We present 19 cases of acute spontaneous hemoretroperitoneum or Wunderlich's syndrome diagnosed from 1996 to 2009, related to the following conditions: 7 renal carcinomas, 4 angiomyolipomas, 2 adrenal hemorrhages, 1 bleeding polycystic kidney, 2 hemorrhagic renal cysts and three cases of immunovasculitis. Overall, 6 patients were treated with acetylsalicylic acid and 4 with dicumarolics for cardiovascular disease, while 13 patients were suffering from hypertension? RESULTS: In 19 cases there was no mortality and the following treatment was performed: 11 nephrectomy, 4 partial nephrectomy, 2 adrenalectomy, 2 selective embolization of intrarenal branches as single treatment, while in three other cases, the embolization was carried out from a surgical procedure, conservative (partial nephrectomy) in one case, ablative (nephrectomy) in two other cases. CONCLUSIONS: The spontaneous hemoretroperitoneum is a rare syndrome associated with acute kidney disease often unknown to the patient and only in selected cases with small hematoma; it is possible to perform arteriography with selective embolization of branches avoiding renal access surgery. So far, it is unknown to which extent anti-platelet and anticoagulant drug treatment contributes to this syndrome but, in our experience, they have increased the morbidity of the clinical condition. PMID- 20931550 TI - [Conservative treatment of persistent calyceal fistula after tumor excision. Case report and clinical remarks]. AB - BACKGROUND: Nowadays, ultrasounds allow to discover accidentally a large number of renal small tumors. So, radical nephrectomy, which years ago was considered as the gold standard, is rarely required. Today, nephron sparing surgery is often prescribed for renal masses smaller than 4 cm. Its most frequent complication is calyceal fistula. It can be prevented exploring carefully the surgical surface, and suturing any opening. It can heal over within a few days or some weeks, so it can be a trouble for both the patient and the surgeon. A complete urinary drainage, obtained with an ureteral stent and an open bladder catheter, helps heal. Recently, it has become common practice to spread synthetic or biological tissue sealants over the surgical surface, to improve hemostasis. These surgical glues have also been used to repair calyceal openings, with conflicting results. METHODS: We performed left renal tumor excision (3.5 x 3 cm) in a 72-years-old man, during temporary renal artery occlusion with surface hypothermia. We placed intraoperatively an ureteral stent. The visual examination of the surgical cavity did not reveal any calyceal opening. We electrocauterized it and stuffed it with FloSeal. Surgical edges were free from illness. After 5 days urinary leakage from the drainage tube increased. Pyelography showed a calyceal fistula. A further stent was placed, with no results. Bladder catheter was kept open for about 2 months. Urinary leakage stopped 34 days after surgery. RESULTS: Urinary leakage increased when the catheter was removed, and stopped only after many days of complete urinary drainage. CONCLUSIONS: The conservative treatment of a calyceal fistula must be considered a still effective therapy, also in difficult cases, provided that a complete and long-lasting urinary drainage is carried out. PMID- 20931551 TI - Different clinical presentations of pelvic ectopic kidneys: report of two cases and review of the literature. AB - Pelvic kidney is the most common type of renal ectopia. These abnormally positioned kidneys are often clinically asymptomatic. However, they are prone to urinary infection, stone formation and trauma. Admitted patients often complain of lower abdominal pain and urinary infection. Pelvic kidneys may also lead to misdiagnosis when it is associated with hydronephrosis or large cystic structures. Thus, it is rather difficult to pinpoint the origin of the problem. We reported here different clinical presentations of our two patients with pelvic kidneys. PMID- 20931552 TI - [Hydronephrosis caused by inferior vena cava penetration by a mobin-uddin filter]. AB - The inferior vena cava (IVC) filter placement represents an excellent protection from significant pulmonary embolism in at-risk patients. Perforation of the wall of the IVC by components of caval filters is a recognized complication. We report a case of asymptomatic hydronephrosis caused by transcaval penetration of a Mobin Uddin filter. PMID- 20931553 TI - Does timing of biochemistry in first-trimester aneuploidy risk assessment affect the gestational age at prenatal diagnosis and pregnancy termination? AB - OBJECTIVE: To determine the relationship between the timing of chemistry and timing of prenatal diagnosis and pregnancy termination in pregnancies with chromosomal abnormalities. METHOD: Singleton pregnancies with chromosomal abnormalities from 2005 to 2009 were identified. Records were reviewed to identify timing of chemistry, nuchal translucency (NT), prenatal diagnosis and pregnancy termination. Mann-Whitney U and Fisher's exact test were used for statistical analysis. RESULTS: A total of 110 pregnancies were included. Seventy eight had biochemistry performed at the time of NT and 32 had biochemistry a median of 9 days prior. Aneuploidy risks were similar between the two groups. Although the timing of NT was similar, those having biochemistry before NT had prenatal diagnosis and pregnancy termination at significantly earlier gestational ages. Those with early biochemistry were more likely to have chorionic villus sampling (CVS) (69% vs 37%; p = 0.003) compared to those who had biochemistry at the time of NT. CONCLUSION: There was a strong correlation between the timing of biochemistry and prenatal diagnosis and pregnancy termination. PMID- 20931554 TI - Mutation analysis and characterization of alternative splice variants of the Wilson disease gene ATP7B. AB - Wilson disease is a copper metabolism disorder caused by mutations in ATP7B, a copper-transporting adenosine triphosphatase. A molecular diagnosis was performed on 135 patients with Wilson disease in Taiwan. We identified 36 different mutations, eight of which were novel: five missense mutations (Ser986Phe, Ile1348Asn, Gly1355Asp, Met1392Lys, and Ala1445Pro), one deletion (2810delT) in the coding region, and two nucleotide substitutions (-133A->C and -215A->T) in the promoter region. These mutations were not observed in 100 control subjects and reduced the activity of the mutated protein by at least 50% when compared with wild-type ATP7B. In addition to exon 8, our data indicate another mutation hotspot in exon 12 where 9.62% of all mutations occurred. An alternative splice variant of ATP7B lacking exon 12 was observed in one patient who had a homozygous 2810delT mutation and very mild clinical symptoms. Clinical examination and functional characterization of alternative splice variants of ATP7B lacking exon 12 showed that they retained 80% of their biological activity. The 2810delT mutation increased the expression of these variants, which may have explained the mild symptoms in the patient with the 2810delT mutation. We also discovered that treating liver cancer cells with a Na(+)/H(+) exchanger inhibitor, 5-(N-ethyl-N isopropyl)-amiloride, significantly enhanced the expression of the alternative splice variant of ATP7B lacking exon 12. CONCLUSION: This study suggests a novel therapeutic strategy for patients with mutations in exon 12. PMID- 20931555 TI - Hyponatremia in patients treated with terlipressin for severe gastrointestinal bleeding due to portal hypertension. AB - Terlipressin is frequently used in acute variceal bleeding due to its powerful effect on vasopressin V1 receptors. Although terlipressin is also a partial agonist of renal vasopressin V2 receptors, its effects on serum sodium concentration have not been specifically investigated. To examine the effects of terlipressin on serum sodium concentration in patients with acute portal hypertensive bleeding, 58 consecutive patients with severe portal-hypertensive bleeding treated with terlipressin were investigated. In the whole population, serum sodium decreased from 134.9 +/- 6.6 mEq/L to 130.5 +/- 7.7 mEq/L (P = 0.002). Thirty-nine patients (67%) had a decrease in serum sodium >= 5 mEq/L during treatment: in 18 patients (31%), between 5 and 10 mEq/L and in 21 patients (36%), greater than 10 mEq/L. In this latter group, serum sodium decreased from 137.2 +/- 5 to 120.5 +/- 5 mEq/L (P < 0.001). In multivariate analysis, the reduction in serum sodium was related to baseline serum sodium and Model for End Stage Liver Disease (MELD) score; patients with low MELD and normal or near normal baseline serum sodium had the highest risk of hyponatremia. Serum sodium returned to baseline values in most patients shortly after cessation of therapy. Three of the 21 patients with marked reduction in serum sodium developed neurological manifestations, including osmotic demyelination syndrome in one patient due to a rapid recovery of serum sodium (serum sodium in these three patients decreased from 135, 130, and 136 to 117, 114, and 109 mEq/L, respectively). CONCLUSION: An acute reduction in serum sodium concentration is common during treatment with terlipressin for severe portal-hypertensive bleeding. It develops rapidly after start of therapy, may be severe in some patients and is associated with neurological complications, and is usually reversible after terlipressin withdrawal. PMID- 20931556 TI - Kinetics of hepatitis B surface antigen decline during 3 years of telbivudine treatment in hepatitis B e antigen-positive patients. AB - The impact of prolonged direct antiviral therapy on hepatitis B surface antigen (HBsAg) levels in patients with chronic hepatitis B is poorly understood. We quantitatively assessed serum HBsAg levels during 3 years of telbivudine treatment, as well as their relationship with virologic and biochemical characteristics in 162 hepatitis B e antigen-positive patients who maintained undetectable serum hepatitis B virus (HBV) DNA long-term. Telbivudine treatment progressively reduced serum HBsAg levels (mean +/- SD) from baseline (3.8 +/- 0.6 log10 IU/mL) to treatment week 24 (3.4 +/- 0.7 log10 IU/mL), treatment year 1 (3.3 +/- 0.8 log10 IU/mL), and treatment year 3 (3.0 +/- 1.4 log10 IU/mL) (P <0.0001). In this patient population, HBsAg loss was observed in nine (6%) of 162 patients through year 3. During the first year of treatment, three patterns of HBsAg decline were observed: rapid (>= 1 log10 IU/mL) in 32 patients, slow (0-1 log10 IU/mL) in 74 patients, and steady levels in 56 patients. These findings were associated with different likelihoods of HBsAg loss during long-term telbivudine therapy. Eight of 32 patients with rapid HBsAg decline versus none of 56 patients with steady HBsAg levels achieved HBsAg loss at year 3 (P = 0.0024). HBV genotype was a significant determinant for HBsAg kinetics, with the fastest decline in genotype A patients. In patients with subsequent HBsAg loss, viral antigens were already undetectable in liver biopsy samples after 1 year of treatment. This was associated with markedly enhanced antiviral T cell reactivity. CONCLUSION: In patients who have effective suppression of viral replication during telbivudine treatment, a rapid decline in serum HBsAg levels during the first year may identify those with a greater likelihood of achieving HBsAg clearance. PMID- 20931557 TI - Inhibition of hepatitis C virus replication using adeno-associated virus vector delivery of an exogenous anti-hepatitis C virus microRNA cluster. AB - RNA interference (RNAi) is being evaluated as an alternative therapeutic strategy for hepatitis C virus (HCV) infection. The use of viral vectors encoding short hairpin RNAs (shRNAs) has been the most common strategy employed to provide sustained expression of RNAi effectors. However, overexpression and incomplete processing of shRNAs has led to saturation of the endogenous miRNA pathway, resulting in toxicity. The use of endogenous microRNAs (miRNAs) as scaffolds for short interfering (siRNAs) may avoid these problems, and miRNA clusters can be engineered to express multiple RNAi effectors, a feature that may prevent RNAi resistant HCV mutant generation. We exploited the endogenous miRNA-17-92 cluster to generate a polycistronic primary miRNA that is processed into five mature miRNAs that target different regions of the HCV genome. All five anti-HCV miRNAs were active, achieving up to 97% inhibition of Renilla luciferase (RLuc) HCV reporter plasmids. Self-complementary recombinant adeno-associated virus (scAAV) vectors were chosen for therapeutic delivery of the miRNA cluster. Expression of the miRNAs from scAAV inhibited the replication of cell culture-propagated HCV (HCVcc) by 98%, and resulted in up to 93% gene silencing of RLuc-HCV reporter plasmids in mouse liver. No hepatocellular toxicity was observed at scAAV doses as high as 5 * 10(11) vector genomes per mouse, a dose that is approximately five fold higher than doses of scAAV-shRNA vectors that others have shown previously to be toxic in mouse liver. CONCLUSION: We have demonstrated that exogenous anti HCV miRNAs induce gene silencing, and when expressed from scAAV vectors inhibit the replication of HCVcc without inducing toxicity. The combination of an AAV vector delivery system and exploitation of the endogenous RNAi pathway is a potentially viable alternative to current HCV treatment regimens. PMID- 20931558 TI - Interleukin-6 is an important mediator for mitochondrial DNA repair after alcoholic liver injury in mice. AB - We investigated the hypothesis that a prominent effect of chronic ethanol consumption is mitochondrial DNA (mtDNA) injury and compared this injury in IL-6 knockout (KO) and wild-type (WT) mice. Ethanol feeding for 4 weeks resulted in steatosis and oxidative mtDNA damage (8-OHdG) in both IL-6KO and WT mice. However, the WT mice were able to repair the injury by increased production of mtDNA repair enzymes (OGG-1, Neil 1) and check point (p21, p53) proteins and avoid the mtDNA mutations. By contrast the IL-6 KO mice were unable to repair mtDNA resulting in deletions and diminished transcription of the mtDNA encoded protein cytochrome c oxidase subunit-I (COI). The mitochondrial injury was reflected by decreased membrane potential, reduced levels of ATP, and apoptosis inducing factor (AIF)-induced apoptosis. CONCLUSION: IL-6 plays a critical role in allowing the liver to recover from significant mtDNA oxidation caused by alcohol. The data suggests that IL-6 activates mtDNA repair enzymes and induces cell cycle arrest allowing time for mtDNA repair. PMID- 20931560 TI - Application of the 2010 American Association for the study of liver diseases criteria of remission to a cohort of Italian patients with autoimmune hepatitis. PMID- 20931559 TI - IL28B genotype is associated with differential expression of intrahepatic interferon-stimulated genes in patients with chronic hepatitis C. AB - Genetic variation in the IL28B (interleukin 28B; interferon lambda 3) region has been associated with sustained virological response (SVR) rates in patients with chronic hepatitis C (CHC) who were treated with peginterferon-alpha and ribavirin. We hypothesized that IL28B polymorphism is associated with intrahepatic expression of interferon-stimulated genes (ISGs), known to influence treatment outcome. IL28B genotyping (rs12979860) and whole-genome RNA expression were performed using liver biopsies from 61 North American patients with CHC. After correction for multiple testing (false discovery rate < 0.10), 164 transcripts were found to be differentially expressed by IL28B-type. The interferon signaling pathway was the most enriched canonical pathway differentially expressed by IL28B-type (P < 10(-5)), with most genes showing higher expression in livers of individuals carrying the poor-response IL28B-type. In 25 patients for which treatment response data were available, IL28B-type was associated with SVR (P = 0.0054). ISG expression was also associated with SVR; however, this was not independent of IL28B-type. Analysis of miR-122 expression in liver biopsies showed reduced miR-122 levels associated with poorer treatment outcome, independently of IL28B-type. No association was observed between IL28B type and levels of liver IL28B or IL28A messenger RNA expression. IL28B protein sequence variants associated with rs12979860 were therefore investigated in vitro: no differences in ISG induction or inhibition of HCV replication were observed in Huh7.5 cells. CONCLUSION: The good response IL28B variant was strongly associated with lower level ISG expression. The results suggest that IL28B genotype may explain the relationship between hepatic ISG expression and HCV treatment outcome, and this is independent of miR-122 expression. IL28B-type was not associated with intrahepatic IL28B messenger RNA expression in vivo. Further investigation of the precise molecular mechanism(s) by which IL28B genetic variation influences HCV outcomes is warranted. PMID- 20931561 TI - Tuning the threshold voltage in organic thin-film transistors by local channel doping using photoreactive interfacial layers. PMID- 20931562 TI - Superstrong low-resistant carbon nanotube-carbide-metal nanocontacts. PMID- 20931563 TI - In vivo viscoelastic properties of the brain in normal pressure hydrocephalus. AB - Nearly half a century after the first report of normal pressure hydrocephalus (NPH), the pathophysiological cause of the disease still remains unclear. Several theories about the cause and development of NPH emphasize disease-related alterations of the mechanical properties of the brain. MR elastography (MRE) uniquely allows the measurement of viscoelastic constants of the living brain without intervention. In this study, 20 patients (mean age, 69.1 years; nine men, 11 women) with idiopathic (n = 15) and secondary (n = 5) NPH were examined by cerebral multifrequency MRE and compared with 25 healthy volunteers (mean age, 62.1 years; 10 men, 15 women). Viscoelastic constants related to the stiffness (u) and micromechanical connectivity (alpha) of brain tissue were derived from the dynamics of storage and loss moduli within the experimentally achieved frequency range of 25-62.5 Hz. In patients with NPH, both storage and loss moduli decreased, corresponding to a softening of brain tissue of about 20% compared with healthy volunteers (p < 0.001). This loss of rigidity was accompanied by a decreasing alpha parameter (9%, p < 0.001), indicating an alteration in the microstructural connectivity of brain tissue during NPH. This disease-related decrease in viscoelastic constants was even more pronounced in the periventricular region of the brain. The results demonstrate distinct tissue degradation associated with NPH. Further studies are required to investigate the source of mechanical tissue damage as a potential cause of NPH-related ventricular expansions and clinical symptoms. PMID- 20931564 TI - On the mechanism of ruthenium-catalyzed formation of hydrogen from alcohols: a DFT study. AB - The mechanism of the ruthenium-catalyzed dehydrogenation of methanol has been investigated by using three DFT-based methods. Three pathways were considered in which the ruthenium catalyst was ligated by either two or three phosphine ligands. Dispersion interactions, which are not described by the popular B3LYP functional, were taken into account by using the dispersion-corrected B3LYP-D and M06 density functionals. These interactions were found to be important in the description of reaction steps that involved ligand/substrate/product association with or dissociation from the catalyst. In line with experimental results, the resting state of the catalyst was predicted to be a ruthenium trihydride complex. It is shown that the dehydrogenation reaction preferentially proceeds through pathways in which the catalyst is ligated by two phosphine ligands. The catalytic cycle of the dehydrogenation process involves an intermolecular proton transfer from the methanol substrate to the catalyst followed by the release of dihydrogen. Rate-determining beta-hydride elimination from the resulting methoxide species then regenerates the resting state of the catalyst and completes the catalytic cycle. The overall free-energy barriers of 29.6-31.4 kcal mol(-1) predicted by the three density functionals are in good agreement with the experimentally observed reaction rate of 6 h(-1) at 423 K. PMID- 20931565 TI - Competitive and selective Csp3-Br versus Csp2-Br bond activation in palladium catalysed Suzuki cross-coupling: an experimental and theoretical study of the role of phosphine ligands. AB - Phosphine ligands have been demonstrated to have an effect on reactivity and selectivity in the competitive intramolecular palladium-catalysed Suzuki-Miyaura coupling of dibromo sulfoxide 1a possessing two different hybridised electrophilic carbons. It was found that the bromine bond to the sp(3)-hybridised carbon is selectively replaced in the presence of unhindered phosphines such as PPh(3) or xantphos. The use of hindered phosphine ligands such as P(o-tol)(3) and P(1-naphthyl)(3) reversed the selectivity, conducting the cross-coupling at the Csp(2)-Br. Identical trends were observed in external competition experiments carried out with bromomethyl sulfoxide and different substituted bromoarenes. DFT and DFT/MM calculations showed that the selectivity observed is mainly due to the different facility of the ligands to dissociate. Bisphosphine catalysts favour coupling at the sp(3) carbon, whereas monophosphine catalysts prefer the sp(2) carbon. PMID- 20931566 TI - Titanosilicate beads with hierarchical porosity: synthesis and application as epoxidation catalysts. AB - Porous titanosilicate beads with a diameter of 0.5-1.5 mm (TiSil-HPB-60) were synthesized from a preformed titanosilicate solution with a porous anion-exchange resin as template. The bead format of this material enables its straightforward separation from the reaction mixture in its application as a liquid-phase heterogeneous catalyst. The material displays hierarchical porosity (micro/mesopores) and incipient TS-1 structure building units. The titanium species are predominantly located in tetrahedral framework positions. TiSil-HPB 60 is a highly active catalyst for the epoxidation of cyclohexene with t-butyl hydroperoxide (TBHP) and aqueous H(2)O(2). With both oxidants, TiSil-HPB-60 gave higher epoxide yields than Ti-MCM-41 and TS-1. The improved catalytic performance of TiSil-HPB-60 is mainly ascribed to the large mesopores favoring the diffusion of reagents and products to and from the titanium active sites. The epoxide yield and selectivity could be further improved by silylation of the titanosilicate beads. Importantly, TiSil-HPB-60 is a stable catalyst immune to titanium leaching, and can be easily recovered and reused in successive catalytic cycles without significant loss of activity. Moreover, TiSil-HPB-60 is active and selective in the epoxidation of a wide range of bulky alkenes. PMID- 20931568 TI - Structural topology and chemical bonding in Laves phases. PMID- 20931567 TI - Hybrid-increased radical-scavenging activity of resveratrol derivatives by incorporating a chroman moiety of vitamin E. PMID- 20931569 TI - Positive contrast technique for the detection and quantification of superparamagnetic iron oxide nanoparticles in MRI. AB - In vivo detection and quantification of cells labeled with superparamagnetic iron oxide (SPIO) nanoparticles has been attracting increasing attention. In particular, positive contrast methods, such as susceptibility gradient mapping (SGM) and phase gradient mapping (PGM), have been proposed for the improved detection of SPIO nanoparticles. In this study, a different implementation of the PGM method is introduced; it calculates the phase gradient in the image space using a fast Fourier transform without the need for phase unwrapping. We first compared positive contrast generation between the PGM and SGM methods, which estimates the susceptibility gradient in k space through echo shift measurements. Next, PGM was applied to quantify SPIO concentrations by fitting the resulting phase gradient maps to those of a theoretical model. MR experiments were conducted using a 3-T magnet scanner to acquire two datasets: the first was acquired from a gelatin phantom with three SPIO-doped vials of different concentrations, and the second was obtained in vivo from a nude rat with SPIO labeled C6 glioma cells implanted in the flanks. The sensitivity of the PGM and SGM methods was compared using various factors, including different SPIO concentrations, TEs and signal-to-noise ratios. Based on the theoretical model of an infinite cylinder, the results demonstrated that, without loss of spatial resolution, the PGM method presents positive contrast maps with a higher sensitivity than SGM at medium and low SPIO concentrations, whereas SGM is more sensitive than PGM at longer TEs. The quantification of SPIO concentrations using the phantom dataset was also reported. On the basis of the same infinite cylinder model, it was shown that the PGM method provides an accurate estimation of SPIO concentration. PMID- 20931571 TI - Sb2S3 with various nanostructures: controllable synthesis, formation mechanism, and electrochemical performance toward lithium storage. AB - The size- and shape-controlled synthesis of Sb(2)S(3) nanostructures has been successfully realized by a facile hydrothermal route. A range of dimensional nanostructures, such as one-dimensional nanorods, two-dimensional nanowire bundles, three dimensional sheaf-like superstructures, dumbbell-shaped superstructures, and urchin-like microspheres, could be obtained through introducing different organic complex reagents or ionic liquids to the reaction system. The formation mechanisms of various Sb(2)S(3) nanostructures have been rationally proposed based on the crystal structure and the nature of the complex reagents and the ionic liquid. The effects of experimental parameters on the final product are also discussed in detail. In addition, electrochemical measurements demonstrate that the as-synthesized Sb(2)S(3) nanostructures have higher initial Li intercalation capacity and excellent cyclic performances, which indicates that the as-synthesized Sb(2)S(3) nanostructures could have potential applications in commercial batteries. PMID- 20931570 TI - In vivo diffusion tensor MRI of the mouse retina: a noninvasive visualization of tissue organization. AB - Diffusion tensor MRI (DTI) is a method for the noninvasive assessment of cellular organization and integrity in vivo. In this study, in vivo DTI was performed to demonstrate its ability to reflect photoreceptor cell alignment in adult C57BL/6 wild-type mice. Age-matched retinal degeneration 1 (rd1) mice were employed as a negative control, i.e. loss of the photoreceptor cell layer. In wild-type mice, DTI-estimated cell alignment suggests that the MR-detected outer retinal layer comprises cells aligning perpendicular to the retinal surface, consistent with the known organization of photoreceptor cells. The MR-detected outer retinal layer exhibits a lower apparent diffusion coefficient and higher fractional anisotropy than the other two MR-detected retinal layers (p < 0.05 for all comparisons). In rd1 mice, the remaining MR-detected retinal layer exhibits different cell alignment, apparent diffusion coefficient and fractional anisotropy from that of the MR-detected outer retinal layer in wild-type mice (p < 0.05 for all comparisons), reflecting the degeneration of photoreceptor cells in rd1 mouse retina. Overall, our findings suggest that in vivo DTI assessment of mouse retina with normal physiology or degenerative pathology is feasible. PMID- 20931572 TI - Metal-molecule-metal junctions in Langmuir-Blodgett films using a new linker: trimethylsilane. AB - Herein trimethylsilane (TMS) is demonstrated to be an efficient binding group suitable for construction of metal-molecule-metal (M-mol-M') junctions, in which one of the metal contacts is an atomically flat gold surface and the other a scanning tunnelling microscopy (STM) tip. The molecular component of the M-mol-M' devices is an oligomeric phenylene ethynylene (OPE) derivative Me(3)Si C=C{C(6)H(4)C=C}(2)C(6)H(4)NH(2), featuring both Me(3)SiC=C and NH(2) metal contacting groups. This compound can be assembled into Langmuir-Blodgett (LB) films on Au--substrates by surface binding through the amine groups. Alternatively, low coverage (sub-monolayer) films are formed by adsorption from solution. In the case of condensed monolayers top electrical contacts are formed to STM tips through the TMS end group. In low coverage films, single molecular bridges can be formed between the gold surface and a gold STM tip. The similarity in the I-V response of a one-layer LB film and the single molecule conductance experiments reveals several points of critical importance to the design of molecular components for use in the construction of M-mol-M' junctions. Firstly, the presence of neighbouring pi systems does not have a significant effect on the conductance of the M-mol-M' junction. Secondly, in the STM configuration, intermolecular electron hopping does not significantly enhance the junction transport characteristics. Thirdly, the symmetric behaviour of the I-V curves obtained, despite the different metal-molecule contacts, indicates that the molecule is simply an amphiphilic electron-donating wire and not a molecular diode with strong rectifying characteristics. Finally, the conductance values obtained from the amine/TMS-contacted OPE described here are of the same order of magnitude as thiol anchored OPEs, making them attractive alternatives to the more conventionally used thiol-contacting chemistry for OPE molecular wires. PMID- 20931573 TI - Oxidative spirocyclization of phenolic sulfonamides: scope and applications. AB - A full account of the oxidative dearomatization of para- and ortho-phenolic sulfonamides is provided together with an overview of the chemistry of the products and their elaboration to building blocks for spirocyclic alkaloids. A concise total synthesis of putative lepadiformine complements the discussion. PMID- 20931574 TI - On/off switching of perylene tetracarboxylic bisimide luminescence by means of substitution at the N-position by electron-rich mono-, di-, and trimethoxybenzenes. AB - A series of perylene tetracarboxylic bisimides, substituted at the N-position with methoxyphenyl groups, have been synthesized together with model compounds and their photophysical properties have been investigated by means of steady state and time-resolved spectroscopic techniques. The luminescence properties of the examined compounds vary remarkably with the substitution pattern, with emission quantum yields ranging from 1 to 10(-2)-10(-3). The observed quenching of the luminescence is assigned to a photoinduced electron transfer (PET) from the electron-rich methoxybenzene unit to the perylene bisimide moiety. The radical anion of perylene bisimide has been detected by transient-absorption spectroscopy. The results could satisfactorily be explained by taking into consideration the redox potentials of the partners and the electron-releasing ability of each methoxy group in relation to its position with respect to N. Quantum-chemical calculations were also performed. PMID- 20931575 TI - Weapons in disguise--activating mechanisms and protecting group chemistry in nature. AB - Bioactive natural products often possess uniquely functionalized structures with unusual modes of action; however, the natural product itself is not always the active species. We discuss molecules that draw on protecting group chemistry or else require activation to unmask reactive centers, illustrating that nature is not only a source of complex structures but also a guide for elegant chemical transformations which provides ingenious chemical solutions for drug delivery. PMID- 20931576 TI - New iridium catalysts for the efficient alkylation of anilines by alcohols under mild conditions. AB - The synthesis of eight new iridium complexes containing anionic P,N ligands is described. These complexes have been investigated as catalysts for amine alkylation reactions, resulting in a highly active catalyst for the selective monoalkylation of anilines with primary alcohols, under mild reaction conditions. Nearly quantitative conversion was observed at 70 degrees C with a catalyst loading as low as 0.05 mol% iridium. PMID- 20931577 TI - Activation and deactivation by temperature: behavior of Ph2PN(iPr)P(Ph)N(iPr)H in the presence of alkylaluminum compounds relevant to catalytic selective ethene trimerization. AB - Coordination, deprotonation, rearrangement, and cleavage of Ph(2)PN(iPr)P(Ph)N(iPr)H (1) by trialkylaluminum compounds R(3)Al (R=Me, Et) are reported that are relevant to the selective ethene trimerization system consisting of the ligand 1, CrCl(3)(THF)(3) and Et(3)Al that produces 1-hexene in more than 90% yield and highest purity. With increasing temperature and residence time first the formation of an adduct [Ph(2)PN(iPr)P(Ph)N(iPr)H][AlR(3)] (2), second the aluminum amide [Ph(2)PN(iPr)P(Ph)(AlR(3))N(iPr)][AlR(2)] (3) and third its rearrangement to the cyclic compound [N(iPr)P(Ph)P(Ph(2))N(iPr)][AlR(2)] (4) were observed. The cleavage of 3 by an excess of R(3)Al into an amidophosphane and an iminophosphane could be the reason for its rearrangement to complex 4, as well as to the cyclic dimer [R(2)AlN(iPr)P(Ph)(2)](2) (5). The chemistry of ligand 1 in the presence of alkylaluminum compounds gives hints on possible activation and deactivation mechanisms of 1 in trimerization catalysis. PMID- 20931578 TI - The development of a general strategy for the synthesis of tyramine-based natural products by using continuous flow techniques. PMID- 20931579 TI - Direct three-dimensional imaging of the buried interfaces between water and superhydrophobic surfaces. PMID- 20931581 TI - The next generation of advanced spectroscopy: surface enhanced Raman scattering from metal nanoparticles. PMID- 20931580 TI - Prins-type macrocyclizations as an efficient ring-closing strategy in natural product synthesis. AB - Prins-type macrocyclizations have recently emerged as a successful strategy in the synthesis of polyketide-derived natural products. This reaction provides a concise and selective means to form tetrahydropyran-containing macrocyclic rings of varying size. A high degree of functionality within the macrocycle is tolerated and the yields for these transformations are typically good to excellent. Since the initial report of a Prins macrocyclization reaction in 1979, examples of this approach did not re-emerge until 2008. However, the use of this method in natural product synthesis has rapidly gained momentum in the synthetic community, with multiple examples of this macrocyclization tactic reported in the recent literature. PMID- 20931582 TI - Nanoparticle-mediated delivery of bleomycin. PMID- 20931583 TI - Temporary restraints to overcome steric obstacles: an efficient strategy for the synthesis of mycalamide B. PMID- 20931584 TI - Hydridoboranes as modifiers for single-site organochromium catalysts: from low- to ultrahigh-molecular-weight polyethylene. PMID- 20931585 TI - Enantioselective intramolecular aza-Michael additions of indoles catalyzed by chiral phosphoric acids. PMID- 20931586 TI - Insights into the dealumination of zeolite HY revealed by sensitivity-enhanced 27Al DQ-MAS NMR spectroscopy at high field. PMID- 20931587 TI - Core-protected platinum monolayer shell high-stability electrocatalysts for fuel cell cathodes. PMID- 20931588 TI - Organocatalytic asymmetric sulfa-michael/michael addition reactions: a strategy for the synthesis of highly substituted chromans with a quaternary stereocenter. PMID- 20931589 TI - Regioselective nickel-catalyzed reductive couplings of enones and allenes. PMID- 20931590 TI - Dehydrosilylation of ArNHSiH3 with ytterbium(II) amide: formation of a dimeric ytterbium(II) silanimine complex. PMID- 20931591 TI - Probing enzyme promiscuity of SGNH hydrolases. AB - Several hydrolases of the SGNH superfamily, including the lipase SrLip from Streptomyces rimosus (Q93MW7), the acyl-CoA thioesterase I TesA from Pseudomonas aeruginosa (Q9HZY8) and the two lipolytic enzymes EstA (from P. aeruginosa, O33407) and EstP (from Pseudomonas putida, Q88QS0), were examined for promiscuity. These enzymes were tested against four chemically different classes of a total of 34 substrates known to be hydrolysed by esterases, thioesterases, lipases, phospholipases, Tweenases and proteases. Furthermore, they were also analysed with respect to their amino acid sequences and structural homology, and their phylogenetic relationship was determined. The Pseudomonas esterases EstA and EstP each have an N-terminal domain with catalytic activity together with a C terminal autotransporter domain, and so the hybrid enzymes EstA(N)-EstP(C) and EstP(N)-EstA(C) were constructed by swapping the corresponding N- and C-terminal domains, and their hydrolytic activities were compared. Interestingly, substrate specificity and kinetic measurements indicated a significant influence of the autotransporter domains on the catalytic activities of these enzymes in solution. TesA, EstA and EstP were shown to function as esterases with different affinities and catalytic efficacies towards p-nitrophenyl butyrate. Of all the enzymes tested, only SrLip revealed lipase, phospholipase, esterase, thioesterase and Tweenase activities. PMID- 20931592 TI - Probing functional groups at the gas-aerosol interface using heterogeneous titration reactions: a tool for predicting aerosol health effects? AB - The complex chemical and physical nature of combustion and secondary organic aerosols (SOAs) in general precludes the complete characterization of both bulk and interfacial components. The bulk composition reveals the history of the growth process and therefore the source region, whereas the interface controls- to a large extent--the interaction with gases, biological membranes, and solid supports. We summarize the development of a soft interrogation technique, using heterogeneous chemistry, for the interfacial functional groups of selected probe gases [N(CH(3))(3), NH(2)OH, CF(3)COOH, HCl, O(3), NO(2)] of different reactivity. The technique reveals the identity and density of surface functional groups. Examples include acidic and basic sites, olefinic and polycyclic aromatic hydrocarbon (PAH) sites, and partially and completely oxidized surface sites. We report on the surface composition and oxidation states of laboratory-generated aerosols and of aerosols sampled in several bus depots. In the latter case, the biomarker 8-hydroxy-2'-deoxyguanosine, signaling oxidative stress caused by aerosol exposure, was isolated. The increase in biomarker levels over a working day is correlated with the surface density N(i)(O3) of olefinic and/or PAH sites obtained from O(3) uptakes as well as with the initial uptake coefficient, gamma(0), of five probe gases used in the field. This correlation with gamma(0) suggests the idea of competing pathways occurring at the interface of the aerosol particles between the generation of reactive oxygen species (ROS) responsible for oxidative stress and cellular antioxidants. PMID- 20931593 TI - Prescriptions from general practitioners and in hospital physicians requiring pharmacists' interventions. AB - PURPOSE: To study prescribing errors requiring pharmacists' interventions and to evaluate the potential clinical significance of the errors and omissions detected. METHODS: The pharmacists at ten community pharmacies and two out patient hospital pharmacies recorded prescribing errors and corresponding interventions using a modified version of a previously developed registration scheme. Prescription errors with potential clinical significance were scored according to a modified version of Safety Assessment Code (SAC)-score RESULTS: During the study period 85,475 prescriptions were dispensed. A total of 2385 prescribing errors were detected on 2226 (2.6%) prescriptions. The proportion of prescriptions with errors and omissions was more than four times higher on prescriptions from hospital physicians (7.1%) than on prescriptions from general practitioners (1.5%). The information on the majority (62.2%) of the prescriptions with inaccuracies had to be clarified before the drug could be dispensed. About 1/4 of the errors and omissions were of potential importance for the drug therapy. An expert panel of physicians and pharmacists judged 85% of these errors and omissions to be clinically significant. Individual physicians and pharmacists judged the clinical importance of the detected prescribing errors somewhat differently. CONCLUSIONS: Pharmacists intervened on 2.6% of prescriptions, and the majority of the potentially clinically significant prescribing errors were judged as significant to the patient's drug therapy and safety. PMID- 20931596 TI - Editorial: Biocommodities for day-to-day life. PMID- 20931598 TI - Enhanced cell viability and cell adhesion using low conductivity medium for negative dielectrophoretic cell patterning. AB - Negative dielectrophoretic (n-DEP) cell manipulation is an efficient way to pattern human liver cells on micro-electrode arrays. Maintaining cell viability is an important objective for this approach. This study investigates the effect of low conductivity medium and the optimally designed microchip on cell viability and cell adhesion. To explore the influence of conductivity on cell viability and cell adhesion, we have used earlier reported dielectrophoresis (DEP) buffer with a conductivity of 10.2 mS/m and three formulated media with conductivity of 9.02 (M1), 8.14 (M2), 9.55 (M3) mS/m. The earlier reported isotonic sucrose/dextrose buffer (DEP buffer) used for DEP manipulation has the drawback of poor cell adhesion and cell viability. A microchip prototype with well-defined positioning of titanium electrode arrays was designed and fabricated on a glass substrate. The gap between the radial electrodes was accurately determined to achieve good cell patterning performance. Parameters such as dimension of positioning electrode, amplitude, and frequency of voltage signal were investigated to optimize the performance of the microchip. PMID- 20931599 TI - Apolipoprotein A-I(Milano) anion exchange chromatography: Self association and adsorption equilibrium. AB - The self-associative properties of apolipoprotein A-I(Milano) (apoA-I(M)) were investigated in relationship to its anion exchange behavior on Q-Sepharose-HP with and without the addition of urea as a denaturant. Self-association was dependent on protein and urea concentration and both influenced interactions of the protein with the chromatographic surface. In the absence of urea, apoA-I(M) was highly associated and existed primarily as a mixture of homodimer, tetramer and hexamer forms. Under these conditions, since the binding strength was greater for the oligomer forms, broad, asymmetrical peaks were obtained in both isocratic and gradient elution. Adding urea depressed self-association and caused unfolding. This resulted in sharper peaks but also decreased the binding strength. Thus, under these conditions chromatographic elution occurred at lower salt concentrations. The adsorption isotherms obtained at high protein loadings were also influenced by self-association and by the varying binding strength of the differently associated and unfolded forms. The isotherms were thus dependent on protein, urea, and salt concentration. Maximum binding capacity was obtained in the absence of urea, where adsorption of oligomers was shown to be dominant. Adding urea reduced the apparent binding capacity and weakened the apparent binding strength. A steric mass action model accounting for competitive binding of the multiple associated forms was used to successfully describe the equilibrium binding behavior using parameters determined from isocratic elution and isotherm experiments. PMID- 20931600 TI - Apolipoprotein A-I(Milano) anion exchange chromatography: mass transfer and adsorption kinetics. AB - The mass transfer and adsorption kinetics of self-associating apolipoprotein A I(Milano) (apoA-I(M)) was investigated for the two anion exchangers Q-Sepharose HP and Macro-Prep-HQ. At high salt where no protein binding occurs and without urea, mass transfer was controlled by hindered pore diffusion of multiple associated forms for both materials. Adding urea suppressed self-association, but resulted in higher viscosity and caused unfolding. As a consequence, the effective diffusivity decreased as urea was added and was greater for the larger pore Macro-Prep-HQ resin. At low salt, under strong binding conditions, the adsorption kinetics followed a more complex mechanism. In this case, the kinetics was very slow for both stationary phases up to 2 M urea. However, at higher urea concentrations, the adsorption kinetics for the smaller pore Q-Sepharose-HP matrix became much faster, suggesting a transition from pore- to surface dominated diffusion. Microscopic observations confirmed that different transport mechanisms were in play below and above 2 M urea, which marked the approximate boundary above which self-association was suppressed and unfolding occurred. The net result was enhanced uptake kinetics at high urea concentrations (e.g., 4 M) where protein unfolding is thought to lead to a more flexible structure that can reptate along the pore surface. Although the observed enhancement was dependent on the pore size and, thus, the surface area of the resin, it was not limited to apoA-I(M). BSA showed a similar trend as a function of urea when its disulfide bonds were reduced. PMID- 20931601 TI - Metabolism of green tea catechins by the human small intestine. AB - Numerous studies have shown that green tea polyphenols can be degraded in the colon, and there is abundant knowledge about the metabolites of these substances that appear in urine and plasma after green tea ingestion. However, there is very little information on the extent and nature of intestinal degradation of green tea catechins in humans. Therefore, the aim of this study was to examine in detail the microbial metabolism and chemical stability of these polyphenols in the small intestine using a well-established ex vivo model. For this purpose, fresh ileostomy fluids from two probands were incubated for 24 h under anaerobic conditions with (+)-catechin (C), (-)-epicatechin (EC), (-)-epicatechin 3-O gallate (ECG), (-)-epigallocatechin (EGC), (-)-epigallocatchin 3-O-gallate (EGCG) and gallic acid (GA). After lyophilisation and extraction, metabolites were separated, identified and quantified by high performance liquid chromatography photodiode array detection (HPLC-DAD) and HPLC-ESI-tandem mass spectrometry. Two metabolites of EC and C (3', 4', 5'-trihydroxyphenyl-gamma-valerolactone and 3', 4'-dihydroxyphenyl-gamma-valerolactone) were identified. In addition, 3', 4', 5' trihydroxyphenyl-gamma-valerolactone was detected as a metabolite of EGC, and (after 24-h incubation) pyrogallol as a degradation product of GA. Cleavage of the GA esters of EGCG and ECG was also observed, with variations dependent on the sources (probands) of the ileal fluids, which differed substantially microbiotically. The results provide new information about the degradation of green tea catechins in the gastrointestinal tract, notably that microbiota dependent liberation of GA esters may occur before these compounds reach the colon. PMID- 20931602 TI - Biosurfactant production and growth kinetics of bacteria in a designer marine medium: improved physiochemical properties. AB - A combinatorial screening strategy was adopted for the development of a suitable medium for enhanced biosurfactant production by a marine strain. As a result, a modified marine medium (MMM) was developed, which contained urea and strontium chloride besides other salts important for the growth of marine bacteria. This medium supported growth, evident from a higher maximum growth rate value of 0.42 h(-1) and an enhanced biosurfactant production of 2.58 g/L. The critical micelle concentration (CMC) was determined for the biosurfactants obtained from all tested media combinations. The biosurfactant produced with this medium was stable at high temperature (100 degrees C), a wide range of pH (5-11) and salt concentration of 5-35%. The emulsifying activity and stability of the biosurfactant obtained using MMM was better than the biosurfactant obtained using conventional media. This biosurfactant with improved physiochemical properties is suitable for a wide range of applications in industry and for marine environmental cleaning. PMID- 20931603 TI - CHO-K1 host cells adapted to growth in glutamine-free medium by FACS-assisted evolution. AB - During the process of recombinant cell line optimisation for production of biopharmaceuticals, multiple cellular properties like robustness against stress, the attainment of high cell concentrations and maintenance of high viability must be considered to maximize protein yield. To improve growth and viability, glutamine is supplemented as an alternative energy source for rapidly dividing cells that oxidize glucose inefficiently. However, the resulting by-product ammonia is toxic at high concentrations and has a negative impact on protein glycosylation, a major quality-determining parameter of biopharmaceuticals. In this work, the CHO-K1 cell line was adapted to a chemically defined medium and suspension growth within 3 weeks. Subsequently, the glutamine concentration was stepwise reduced from 8 to 4 and 2 mM. After each reduction, both the final cell concentration in the batch and the viability decreased. To force a rapid evolution of cells to achieve high final cell concentrations, cells were seeded at high densities (10(7) cells/mL) and surviving cells were sorted by FACS or MACS when viability declined to 10% (typically after 24 h). Sorted cells were grown in batch until viability declined to 10% and viable cells recovered again. The final sorted population was able to reach comparable or even better viable cell concentrations and showed a significantly improved viability compared to their ancestors. The 2 mM glutamine-adapted cell line was directly transferred into glutamine-free medium and was able to grow at comparable rates without requiring further adaptation. Cells compensated the lack of glutamine by increasing their consumption of glutamate and aspartate. PMID- 20931605 TI - Assessing contaminated sediments in the context of multiple stressors. AB - Sediments have a major role in ecosystem functioning but can also act as physical or chemical stressors. Anthropogenic activities may change the chemical constituency of sediments and the rate, frequency, and extent of sediment transport, deposition, and resuspension. The importance of sediments as stressors will depend on site ecosystem attributes and the magnitude and preponderance of co-occurring stressors. Contaminants are usually of greater ecological consequence in human-modified, depositional environments, where other anthropogenic stressors often co-occur. Risk assessments and restoration strategies should better consider the role of chemical contamination in the context of multiple stressors. There have been numerous advances in the temporal and spatial characterization of stressor exposures and quantification of biological responses. Contaminated sediments causing biological impairment tend to be patchy, whereas more pervasive anthropogenic stressors, such as alterations to habitat and flow, physical disturbance, and nutrient addition, may drive large scale ecosystem responses. A systematic assessment of relevant ecosystem attributes and reference conditions can assist in understanding the importance of sediments in the context of other stressors. Experimental manipulations then allow for the controlled study of dominant stressors and the establishment of causal links. This approach will result in more effective management of watersheds and waterways. PMID- 20931606 TI - Effects of ferrous sulfate, inoculum history, and anionic form on lead, zinc, and copper toxicity to Acidithiobacillus caldus strain BC13. AB - The current study reports the single and combined toxicities of Pb, Zn, and Cu to Acidithiobacillus caldus strain BC13. The observed half-maximal inhibitory concentrations (IC50), +/- 95% confidence intervals, for Pb, Zn, and Cu were 0.9 +/- 0.1 mM, 39 +/- 0.5 mM, and 120 +/- 8 mM, respectively. The observed minimum inhibitory concentrations (MIC) for Pb, Zn, and Cu were 7.5 mM, 75 mM, and 250 mM, respectively. When metals were presented in binary mixtures, the toxicities were less than additive. For example, when 50% of the Pb MIC and 50% of the Cu MIC were presented together, the specific growth rate was inhibited by only 59 +/ 3%, rather than 100%. In addition, the presence of ferrous iron in the growth media decreased Pb and Zn toxicity to A. caldus strain BC13. The importance of inoculum history was evaluated by pre-adapting cultures through subsequent transfers in the presence of Pb, Zn, and Cu at their respective IC50s. After pre adaptation, cultures had specific growth rates 39 +/- 11, 32 +/- 7, and 28 +/- 12% higher in the presence of Pb, Zn, and Cu IC50s, respectively, compared with cultures that had not been pre-adapted. In addition, when cells exposed to the MICs of Pb, Zn, and Cu were harvested, washed, and re-inoculated into fresh, metal-free medium, they grew, showing that the cells remained viable with little residual toxicity. Finally, metal chlorides showed more toxicity than metal sulfates, and studies using sodium chloride or a mixture of metal sulfates and sodium chloride suggested that this was attributable to an additive combination of the metal and chloride toxicities. PMID- 20931607 TI - Zinc oxide-engineered nanoparticles: dissolution and toxicity to marine phytoplankton. AB - It is now widely recognized that dissolution plays an important role in metallic nanoparticle toxicity, but to what extent remains unclear. In the present study, it was found that ZnO-engineered nanoparticle (ZnO-EN) toxicity to the marine diatom Thalassiosira pseudonana could be solely explained by zinc ion (Zn(2+) ) release. This is based on comparable inhibitive effects from ZnO-EN addition media, with or without the ultrafiltration through a 3-kD membrane, and from the media in which only Zn(2+) was added. Considering the importance of dissolution in ZnO-EN toxicity, Zn(2+) release kinetics was systematically examined under different conditions for the first time. It was found to be mainly influenced by pH as well as the specific surface area of the nanoparticles. In contrast, natural organic compounds either enhance or reduce Zn(2+) release, depending on their chemical composition and concentration. Compared with deionized water, ZnO EN dissolution rates were accelerated in seawater, whereas ZnO-EN concentration itself only had a very small effect on Zn(2+) release. Therefore, dissolution as affected by several physicochemical factors should not be neglected in the effects, behavior, and fate of ENs in the environment. PMID- 20931608 TI - Ecotoxicological effects of diuron and chlorotoluron nitrate-induced photodegradation products: monospecific and aquatic mesocosm-integrated studies. AB - The ecotoxicological impact of nitrate-induced photodegradation products of diuron and chlorotoluron was studied through monospecific biotests conducted in conjunction with experiments in outdoor aquatic mesocosms. Organisms representing three trophic levels were used: two heterotrophic microorganisms, the luminescent bacterium Vibrio fischeri and the ciliated protozoa Tetrahymena pyriformis, and one metazoa, the gastropod Lymnaea stagnalis. Among the variety of the phenylurea photoproducts, the N-formylated ones appeared clearly more toxic than the parent compounds towards the microorganisms, whereas the nitroderivatives showed a similar toxicity. Using photodegraded solutions of diuron, toxicity was maintained or even increased during disappearance of the initial herbicide, demonstrating that some of the photoproducts may have an impact additively or in synergy. Enzymatic biomarker assays performed on Lymnaea stagnalis exposed under monospecific conditions showed significant effects, due to the combination of nitrate with the pesticide and its photoproducts. A positive impact on snail fecundity was observed with chlorotoluron both under monospecific laboratory and integrated mesocosm conditions. Oviposition stimulation took place when first- and second-generation photoproducts were predominant. PMID- 20931609 TI - Growth, abnormalities, and mortality of tadpoles of American toad exposed to combinations of malathion and nitrate. AB - American toad tadpoles (Bufo americanus) were exposed to malathion and nitrate in a fully factorial experiment that crossed four concentrations of malathion ranging between 0 and 1,000 ug malathion/L, and five concentrations of nitrate ranging from 0 to 16 mg NO(3) -N/L to identify single and interactive effects. In this 21-d experiment, we recorded tadpole length, mass, survivorship, and frequencies of diamond-shaped and stiff-tail abnormalities. Malathion increased frequency of diamond-shaped and stiff-tail abnormalities, and negatively affected survivorship, but did not affect tadpole size. Nitrate did not affect survivorship but did have sublethal effects, including effects on tadpole length and the frequency of both abnormalities. The interaction of malathion and nitrate has no effect on survivorship or tadpole size but did affect the frequency of abnormalities, with nitrate reducing malathion's effect. Results of the present study suggest that at the environmentally realistic concentrations used in our experiment, malathion has both lethal and sublethal effects, but nitrate had only sublethal effects on American toad tadpoles. The combination of malathion and nitrate had limited effects at the tested concentrations under laboratory conditions. However, the effect of the combined treatments on the frequency of tadpole developmental abnormalities suggests that such interactions may play a role under field conditions, in which pesticide and nitrate fertilizers are typically applied simultaneously. PMID- 20931611 TI - Preparation and characterization of molecularly imprinted microspheres for dibutyl phthalate recognition in aqueous environment. AB - Molecularly imprinted microspheres (MIMs) were prepared by suspension polymerization for the binding and recognition of dibutyl phthalate (DBP). DBP was used as the template molecule, methacrylic acid as the functional monomer, ethylene dimethacrylate (EDMA) as the linking agent, PVA as the dispersing agent, and Span 60 as the surfactant. The MIMs were characterized with electron microscope scanning and rebinding experiments. The Scatchard plot revealed that the template-polymer system has a two-site binding behavior with dissociation constants of 4.05 and 0.515 mmol/L. The MIMs exhibited the highest selective rebinding to DBP at 736.85 MUg/g. The recoveries of the MIM-SPE column for DBP extraction was 94.75-101.9% with the RSD of 1.5-7.3%, indicating the feasibility of the prepared MIMs for DBP extraction. Finally, the method developed was used to analyze the trace levels of phthalate in aqueous environment samples. PMID- 20931610 TI - CMV in critically ill patients: pathogen or bystander? AB - Despite broad variability in study populations, methodologies for CMV detection, and analytic methods used, multiple studies have documented frequent CMV infection in non-immunocompromised adults with critical illness due to a variety of causes. Higher rates of CMV infection in studies of seropositive patients suggest that reactivation of latent infection rather than primary infection is the main mechanism in this setting. Risk factors for CMV reactivation (other than seropositivity) have not been clearly defined and there does not appear to be a consistent association with severity of illness. Furthermore, CMV reactivation in this setting has been associated with important adverse clinical outcomes, including increased duration of mechanical ventilation, longer length of stay and all-cause mortality. There are several biologically plausible mechanisms that could link CMV reactivation with adverse outcomes, including: direct lung injury (CMV pneumonia), amplification of inflammation systemically and within the lung, or predisposition to other nosocomial infections, but clinical data in the ICU setting are limited. Further observational studies are unlikely to significantly advance our understanding of the role of CMV in critically ill patients. Given the significant impact of critical illness, limited current therapeutic options, the availability of generally well-tolerated antiviral options for CMV, and the clinical data supporting a possible pathogenic role for CMV, there is a strong rationale for a randomised controlled trial of CMV prevention as a novel means of improving the outcomes of critically ill patients. PMID- 20931612 TI - Application of liquid chromatography in polymer non-ionic antistatic additives analysis. AB - This article investigates the applicability of HPLC-UV, ultra performance LC evaporative light-scattering detection (UPLC-ELSD), HPLC-ESI(+)-MS and HPLC hybrid linear ion trap (LTQ) Orbitrap MS for the analysis of different non-ionic antistatic additives, Span 20, Span 60, Span 65, Span 80, Span 85 (sorbitan fatty acid esters), Atmer 129 (glycerol fatty acid ester) and Atmer 163 (ethoxylated alkylamine). Several alkyl chain length or different degrees of esterification of polyol derivatives can be present in commercial mixtures of these polymer additives. Therefore, their identification and quantification is complicated. Qualitative composition of the studied compounds was analysed by MS. HPLC-UV, UPLC-ELSD and HPLC-LTQ Orbitrap MS methods were applied to the quantitative determination of the different Spans, Atmer 129 and Atmer 163, respectively. Quality parameters of these methods were established and no derivatization was necessary. PMID- 20931613 TI - Characterisation of blends of polyisoprene and polystyrene by on-line hyphenation of HPLC and (1) H-NMR: LC-CC-NMR at critical conditions of both homopolymers. AB - Blends of polystyrene (PS) and polyisoprene (PI) were analysed by on-line hyphenation of LC at critical conditions and (1) H-NMR. Chromatography at critical conditions was established for both PS and PI. At both critical conditions, a perfect separation into the blend components was achieved. By operating at critical conditions of one blend component and size exclusion mode for the other it is possible to determine the molar mass using a suitable calibration. By using NMR as a detector, the microstructure of PI can be identified, quantified and the chemical composition of the blends can be calculated by monitoring the signal intensities of the olefinic protons of isoprene and the aromatic protons of PS. PMID- 20931614 TI - Sicilian lemon oil: Composition of volatile and oxygen heterocyclic fractions and enantiomeric distribution of volatile components. AB - A total of 92 samples of Sicilian lemon oils (Citrus limon (L.) Burm. f.) produced from September 2008 to June 2009, industrially cold-pressed by different extraction techniques (Brown Oil Extractor and Food Machinery Corporation), were analyzed by GC-flame ionization detector (FID) and GC/MS-LRI to investigate the volatile fraction; by RP-HPLC/PDA to determine the non-volatile components and by enantio-GC-FID to determine the enantiomeric ratios of 12 volatile components. This study provides a detailed investigation on the composition of Sicilian lemon essential oils industrially produced during a productive season, with the aim to recognize quality parameters for the characterization of this product. The results obtained are discussed to evaluate seasonal variation, influence of the extraction techniques, and are compared with those obtained for samples produced during different seasons. PMID- 20931615 TI - Do abnormalities in regional cerebral blood flow in anorexia nervosa resolve after weight restoration? AB - OBJECTIVE: Previous studies have demonstrated localised abnormalities of cerebral blood flow in anorexia nervosa, suggesting reduction of cerebral activity and function in specific regions. There is debate as to whether such findings are secondary to starvation or indicative of a primary abnormality predating the illness, representing an underlying biological substrate. This small study, the first in early onset anorexia nervosa, reports findings of regional cerebral blood flow (rCBF) at both baseline and follow up. METHOD: Nine participants who had previously undergone rCBF studies at the start of treatment, had a repeat scan at an average of 4.2 years later. RESULTS: Seven out of the nine had persisting reduced cerebral blood flow in one area of the brain, predominantly the medial temporal region. DISCUSSION: These data suggest that in the majority of cases rCBF does not return to normal following weight restoration. The implications for future research are explored. PMID- 20931616 TI - Acetic acid denaturing pulsed field capillary electrophoresis for RNA separation. AB - Based on our previous work of in-capillary denaturing polymer electrophoresis, we present a study of RNA molecular separation up to 6.0 kilo nucleotide by pulsed field CE. This is the first systematic investigation of electrophoresis of a larger molecular mass RNA in linear hydroxyethylcellulose (HEC) under pulsed field conditions. The parameters that may influence the separation performance, e.g. gel polymer concentration, modulation depth and pulse frequency, are analyzed in terms of resolution and mobility. For denaturing and separating RNA in the capillary simultaneously, 2 M acetic acid was added into the HEC polymer to serve as separation buffer. Result shows that (i) in pulsed field conditions, RNA separation can be achieved in a wide range of concentration of HEC polymer, and RNA fragments between 0.3 and 0.6 kilo nucleotide are sensitive to the polymer concentration; (ii) under certain pulsed field conditions, RNA fragments move linearly as the modulation depth increases; (iii) 12.5 Hz is the resonance frequency for RNA reorientation time and applied frequency. PMID- 20931617 TI - New method for prefractionation of plasma for proteomic analysis. AB - The depth of proteome analysis is severely limited in complex samples with a wide dynamic range of protein abundance such as plasma. Removal of high-abundance proteins should reveal the signal of lower abundance plasma proteins. However, smaller proteins may be part of larger protein complexes and hence the removal of proteins involved in complexes with high-abundance proteins such as albumin may inhibit the search for disease biomarkers. Prefractionation of a sample divides it into fractions of reduced complexity, allowing improved detection of lower abundance proteins. Using a prefractionation device, which employs GradiflowTM technology, we were able to separate small volume plasma samples into multiple fractions based on the molecular weight and/or charge. The resulting samples of reduced complexity were directly compatible with 2-DE. The use of this prefractionation machine may therefore be useful in the hunt for disease biomarkers. PMID- 20931618 TI - An automated instrument for human STR identification: design, characterization, and experimental validation. AB - The microfluidic integration of an entire DNA analysis workflow on a fully integrated miniaturized instrument is reported using lab-on-a-chip automation to perform DNA fingerprinting compatible with CODIS standard relevant to the forensic community. The instrument aims to improve the cost, duration, and ease of use to perform a "sample-to-profile" analysis with no need for human intervention. The present publication describes the operation of the three major components of the system: the electronic control components, the microfluidic cartridge and CE microchip, and the optical excitation/detection module. Experimental details are given to characterize the level of performance, stability, reliability, accuracy, and sensitivity of the prototype system. A typical temperature profile from a PCR amplification process and an electropherogram of a commercial size standard (GeneScan 500TM, Applied Biosystems) separation are shown to assess the relevance of the instrument to forensic applications. Finally, we present a profile from an automated integrated run where lysed cells from a buccal swab were introduced in the system and no further human intervention was required to complete the analysis. PMID- 20931619 TI - Capillary electrophoresis for analysis of microheterogeneous glutelin subunits in rice (Oryza sativa L.). AB - Glutelin, the major storage protein of rice seed, consists of microheterogenous subunits and partially exists in a macromolecular form that is polymerized by intersubunit disulfide bonds. In order to analyze the glutelin subunits using high-throughput CE, we first identified a sample preparation procedure suitable for CE. The polymerized glutelin treated with a reductant could not dissociate into its constituent monomer subunits when it was dissolved in an acidic solution. However, the glutelin dissociated into its subunits and component alpha and beta polypeptides when it was denatured and reduced by an appropriate amount of urea and 2-mercaptoethanol at a specific incubation time and temperature. The molecular species of the completely dissociated alpha and beta polypeptides were identified and quantitatively analyzed by CE using glutelin mutants. The CE analysis also demonstrated that the actual subunit variation in terms of the charge and/or size of the beta polypeptides is much smaller than predicted when compared with that of alpha polypeptides, even under denaturing and reducing condition. Thus, the combined analytical system described here will be useful for basic and applied research, such as the kinetic characterization of higher-order structure and the quantitative evaluation of glutelin in a large number of diverse rice varieties. PMID- 20931620 TI - Immunonutrition in gastrointestinal surgery. AB - BACKGROUND: Patients undergoing major gastrointestinal surgery are at increased risk of developing complications. The use of immunonutrition (IN) in such patients is not widespread because the available data are heterogeneous, and some show contradictory results with regard to complications, mortality and length of hospital stay. METHODS: Randomized controlled trials (RCTs) published between January 1985 and September 2009 that assessed the clinical impact of perioperative enteral IN in major gastrointestinal elective surgery were included in a meta-analysis. RESULTS: Twenty-one RCTs enrolling a total of 2730 patients were included in the meta-analysis. Twelve were considered as high-quality studies. The included studies showed significant heterogeneity with respect to patients, control groups, timing and duration of IN, which limited group analysis. IN significantly reduced overall complications when used before surgery (odds ratio (OR) 0.48, 95 per cent confidence interval (c.i.) 0.34 to 0.69), both before and after operation (OR 0.39, 0.28 to 0.54) or after surgery (OR 0.46, 0.25 to 0.84). For these three timings of IN administration, ORs of postoperative infection were 0.36 (0.24 to 0.56), 0.41 (0.28 to 0.58) and 0.53 (0.40 to 0.71) respectively. Use of IN led to a shorter hospital stay: mean difference -2.12 (95 per cent c.i. -2.97 to -1.26) days. Beneficial effects of IN were confirmed when low-quality trials were excluded. Perioperative IN had no influence on mortality (OR 0.90, 0.46 to 1.76). CONCLUSION: Perioperative enteral IN decreases morbidity and hospital stay but not mortality after major gastrointestinal surgery; its routine use can be recommended. PMID- 20931621 TI - In vivo and in vitro antibacterial activity of acanthospermal B, a sesquiterpene lactone isolated from Acanthospermum hispidum. AB - Acanthospermal B (AcB), the major sesquiterpene lactone (SL) of Acanthospermum hispidum, an herb widely spread in Argentina, is a selective antibacterial agent against Enterococcus faecalis and Staphylococcus aureus, but inactive on Gram negative and Lactobacillus. Methicillin-resistant Staphylococcus aureus (MRSA) is one of the main microorganisms involved in human chronic infection. A balb?c mouse skin infection model was developed to reproduce the lesions caused by acute and chronic infections produced by MRSA. After determination of the maximum concentration of AcB unable to produce tissular injury after intradermal injection, the anti-MRSA effect of AcB was evaluated on skin, liver and spleen tissues of infected mice. AcB, at doses of 2.5 mg/kg, produced a ten times decrease of MRSA growth in skin infection. In addition, the same dose prevented the dissemination to liver and/or spleen. AcB also displayed a bacteriostatic effect, in vitro, on MRSA cultures at 50 ug/mL that seems to be caused by partial denaturation of total bacterial DNA and/or inhibition of the PCR reaction in not denaturized DNA. Finally, total MRSA cell wall lysis occurred at a concentration of 100 ug/mL of AcB after 2 h of exposure. PMID- 20931622 TI - Changes in activity and interest in the third and fourth age: associations with health, functioning and depressive symptoms. AB - This study examines the changes in activity investment among older adults and the role of these changes in the relationship between health limitations and depression. Residents of six senior living facilities (N = 178) completed questionnaires including the Geriatric Depression Scale, health and functioning measures and the Revised Change in Activity and Interest Index (CAII-R) which measures self-perceived changes in the level of investment in social and leisure activities among older adults. Respondents indicated more disengagement from CAII R subscales Active Instrumental (AI) and Active Social (AS) and increased engagement in Passive Social Spiritual. Fourth Age adults (age 80+) reported greater reductions in AI than Third Age adults (age 64-79). Reduced AS investment had the strongest association with depression and mediated the relationship between poor health or functioning and depression. These categories of activity may guide occupational therapy practitioners and other health providers in selecting the focus of intervention for older clients according to their identified life stage. The study provides evidence of distinct differences in interests within the parameters of normal aging and a baseline from which to assess the impact of illness and disability on the activity choices for clients in different life stages. PMID- 20931623 TI - Simultaneous determination of three naphthoquinones in the leaves of Impatiens balsamina L. by reversed-phase high-performance liquid chromatography. AB - INTRODUCTION: Naphthoquinones; lawsone (1), lawsone methyl ether (2) and methylene-3,3'-bilawsone (3) are the main active compounds of Impatiens balsamina leaves. OBJECTIVE: To develop and validate an HPLC method for simultaneous quantitative determination of 1-3 in I. balsamina leaf extracts. METHODOLOGY: The method utilised a Supelco(r) C(18) column (5 um, 4.6 * 150 mm) at 25 degrees C with the mixture of 2% aqueous acetic acid : methanol (gradient elution as follows: 0-10 min, 25 : 75; 10-20 min, 32 : 68; 20-35 min, 55 : 45) as the mobile phase at a flow-rate of 1 mL/min, and UV detection at 280 nm. The parameters of linearity, repeatability, reproducibility, accuracy specificity and sensitivity of the method were evaluated. RESULTS: The recovery of the method was 96-101% and linearity (r(2) >= 0.9995) was obtained for all naphthoquinones. A high degree of specificity, as well as repeatability and reproducibility (RSD less than 5%), were also achieved. PMID- 20931624 TI - An efficient strategy based on MAE, HPLC-DAD-ESI-MS/MS and 2D-prep-HPLC-DAD for the rapid extraction, separation, identification and purification of five active coumarin components from Radix Angelicae Dahuricae. AB - INTRODUCTION: Further studies of active coumarin components in Radix Angelicae Dahuricae (AE) are absolutely essential to provide data on pharmacology, toxicology and quality for innovative drug candidates. Thus, the preparation of active component standards and the administration of coumarin monomers should be carried out. The isolation of the low-level active components from complex Traditional Chinese Medicine (TCM) samples necessitates the development of rapid, simple and economical modern extraction, separation, identification and purification methods. OBJECTIVE: To develop an efficient strategy for the rapid extraction, separation, identification and purification of coumarins from AE. METHODOLOGY: First, active coumarins in AE were extracted with microwave-assisted extraction (MAE) after the extraction conditions were optimised. Second, gradient extraction methods with MAE were used to partially purify AE. Third, a high performance liquid chromatography-diode array detection-electrospray ionisation tandem mass spectrometry (HPLC-DAD-ESI-MS/MS) method was applied for the preliminary on-line identification and screening of the main coumarins in AE extract. Finally, a two-dimensional preparative high-performance liquid chromatography-diode array detection (2D-prep-HPLC-DAD) system was developed for further preparative separation of those target components. RESULTS: Altogether 10 coumarins have been identified and five of them including xanthotoxol, osthenol, oxypeucedanin hydrate, byakangelicin and imperatorin were deemed as target components for the preparative isolation. All of the five isolated coumarins were at high purities of over 99% and the production rate was much higher than the traditional methods. CONCLUSION: The present paper demonstrates that these consecutive approaches are very useful for to isolate chemical constituents from TCM. PMID- 20931625 TI - An alternative method for irones quantification in iris rhizomes using headspace solid-phase microextraction. AB - INTRODUCTION: The essential oil obtained from iris rhizomes is one of the most precious raw materials for the perfume industry. Its fragrance is due to irones that are gradually formed by oxidative degradation of iridals during rhizome ageing. OBJECTIVE: The development of an alternative method allowing irone quantification in iris rhizomes using HS-SPME-GC. METHODOLOGY: The development of the method using HS-SPME-GC was achieved using the results obtained from a conventional method, i.e. a solid-liquid extraction (SLE) followed by irone quantification by CG. RESULTS: Among several calibration methods tested, internal calibration gave the best results and was the least sensitive to the matrix effect. The proposed method using HS-SPME-GC is as accurate and reproducible as the conventional one using SLE. These two methods were used to monitor and compare irone concentrations in iris rhizomes that had been stored for 6 months to 9 years. CONCLUSION: Irone quantification in iris rhizome can be achieved using HS-SPME-GC. This method can thus be used for the quality control of the iris rhizomes. It offers the advantage of combining extraction and analysis with an automated device and thus allows a large number of rhizome batches to be analysed and compared in a limited amount of time. PMID- 20931626 TI - Solid-phase extraction of liquiritin and glycyrrhizin from licorice using porous alkyl-pyridinium polymer sorbent. AB - INTRODUCTION: Liquiritin and glycyrrhizin are valuable components of licorice. An effective separation and determination procedure is needed to separate the liquiritin and glycyrrhizin from the licorice extract. METHODOLOGY: A polymer confined, ionic liquid sorbent was developed using a process involving polymerisation and modification. The obtained porous particles were used as a sorbent in a solid-phase extraction process to isolate liquiritin and glycyrrhizin from licorice with different washing and elution solvents. The porous alkyl-pyridinium polymer sorbent was compared with the C(18) sorbent. RESULTS: A simple and convenient method was established to the selectively separate and determinate of liquiritin and glycyrrhizin using a porous ionic liquid-based polymer coupled with HPLC. Additionally, this study evaluated the application of this sorbent for the detection of these two compounds in commercial medicines. CONCLUSION: This method was a viable tool that was compatible with the existing HPLC methods and was used to separate and analyse the content of liquiritin and glycyrrhizin in licorice. PMID- 20931627 TI - Atherosclerosis in systemic lupus: the role of antiphospholipid antibodies needs strict diagnostic criteria to be evaluated. Comment on the article by Urowitz et al. PMID- 20931628 TI - Seawater spray injury to Quercus acutissima leaves: crystal deposition, stomatal clogging, and chloroplast degeneration. AB - Effects of seawater spray on leaf structure were investigated in Quercus acutissima by electron microscopy and X-ray microanalysis. Two-year-old seedlings of Q. acutissima were sprayed with seawater and kept in a greenhouse maintained at 25 degrees C. The most recognizable symptoms of seawater-sprayed seedlings included leaf necrosis, crystal deposition, stomatal clogging, and chloroplast degeneration. Field emission scanning electron microscopy revealed that the leaf surface was covered with additional layers of remnants of seawater spray. Composed of sodium and chloride, cube-shaped crystals (halite) were prevalently found on trichomes and epidermis, and formed aggregates. Meanwhile, wedge-shaped crystals were deposited on epidermis and consisted of calcium and sulfur. As a result of stomatal clogging by crystal deposition on the abaxial surface, it was conceivable that plant respiration became severely hampered. Transmission electron microscopy showed degenerated cytoplasm of seawater-sprayed leaves. It was common to observe severe plasmolysis and disrupted chloroplasts with a reduced number of thylakoids in grana. These results indicate that foliar applications of seawater were sufficient to induce necrosis of Q. acutissima seedlings as an abiotic disturbance factor. PMID- 20931629 TI - Solution-based in situ synthesis and fabrication of ultrasensitive CdSe photoconductors. PMID- 20931630 TI - Silicon nanowires for photovoltaic solar energy conversion. AB - Semiconductor nanowires are attracting intense interest as a promising material for solar energy conversion for the new-generation photovoltaic (PV) technology. In particular, silicon nanowires (SiNWs) are under active investigation for PV applications because they offer novel approaches for solar-to-electric energy conversion leading to high-efficiency devices via simple manufacturing. This article reviews the recent developments in the utilization of SiNWs for PV applications, the relationship between SiNW-based PV device structure and performance, and the challenges to obtaining high-performance cost-effective solar cells. PMID- 20931631 TI - Scales to assess sleep impairment in Parkinson's disease: critique and recommendations. AB - There is a broad spectrum of sleep disturbances observed in Parkinson's disease (PD). A variety of scales have been applied to the evaluation of PD sleep and wakefulness, but only a small number have been assessed specifically for clinimetric properties in the PD population. The movement disorder society has commissioned this task force to examine these scales and to assess their use in PD. A systematic literature review was conducted to explore the use of sleep scales in PD and to determine which scales qualified for a detailed critique. The task force members, all of whom have extensive experience in assessing sleep in PD reviewed each of the scales using a structured proforma. Scales were categorized into recommended, suggested and listed according to predefined criteria. A total of 48 potential scales were identified from the search and reviewed. Twenty-nine were excluded because they did not meet review criteria or were variations of scales already included, leaving 19 scales that were critiqued and rated by the task force based on the rating criteria. Only six were found to meet criteria for recommendation or suggestion by the task force: the PD sleep scale (PDSS) and the Pittsburgh sleep quality index (PSQI) are recommended for rating overall sleep problems to screen and to measure severity, the SCOPA-sleep (SCOPA) is recommended for rating overall sleep problems both to screen and to measure severity, and for rating daytime sleepiness; the Epworth sleepiness scale (ESS) is recommended for rating daytime sleepiness to screen and to measure severity; the inappropriate sleep composite score (ISCS) is suggested for rating severe daytime sleepiness or sleep attacks to screen and to measure severity; and the Stanford sleepiness scale (SSS) is suggested for rating sleepiness and to measure severity at a specific moment. The task force does not recommend the development of new scales, but emphasizes the need for educational efforts to train physicians in sleep interview techniques and polysomnography. PMID- 20931632 TI - Motor complications in Parkinson's disease: ten year follow-up study. AB - Parkinson's disease (PD) can be symptomatically controlled with standard treatments; however, after a few years, this response typically declines and most patients develop motor complications. We carried out a prospective practice-based study to evaluate the evolution appearance and evolution of motor complications in 64 de novo PD patients over 5 years and in 38 PD patients over 10 years. We studied untreated patients from initial assessment at basal conditions and evaluated every 6 months thereafter with treatment (levodopa versus other drugs). The follow-up assessments were performed with the Unified Parkinson's Disease Rating Scale (UPDRS). At each assessment, patients were monitored regarding the development of dyskinesias, motor fluctuations, freezing, loss of postural reflexes, and cognitive impairment. We observed a significant improvement in UPDRS scores during the first year, then a progressive decline, more evident after the third year. Motor complications increased after the third year, and at the end of the survey (tenth year); drug-induced dyskinesias and motor fluctuations were experienced (71.1 and 94.7%, respectively). After the first decade, many complications arose from the non-levodopa-responsive features of the disease (cognitive impairment was present in 52.6% and gait freezing in 71.1%). Initial medication may influence medium-term complications but not long-term problems. Most long-term disabling problems of PD were related to non-levodopa responsive features. PMID- 20931633 TI - Low anaerobic threshold and increased skeletal muscle lactate production in subjects with Huntington's disease. AB - Mitochondrial defects that affect cellular energy metabolism have long been implicated in the etiology of Huntington's disease (HD). Indeed, several studies have found defects in the mitochondrial functions of the central nervous system and peripheral tissues of HD patients. In this study, we investigated the in vivo oxidative metabolism of exercising muscle in HD patients. Ventilatory and cardiometabolic parameters and plasma lactate concentrations were monitored during incremental cardiopulmonary exercise in twenty-five HD subjects and twenty five healthy subjects. The total exercise capacity was normal in HD subjects but notably the HD patients and presymptomatic mutation carriers had a lower anaerobic threshold than the control subjects. The low anaerobic threshold of HD patients was associated with an increase in the concentration of plasma lactate. We also analyzed in vitro muscular cell cultures and found that HD cells produce more lactate than the cells of healthy subjects. Finally, we analyzed skeletal muscle samples by electron microscopy and we observed striking mitochondrial structural abnormalities in two out of seven HD subjects. Our findings confirm mitochondrial abnormalities in HD patients' skeletal muscle and suggest that the mitochondrial dysfunction is reflected functionally in a low anaerobic threshold and an increased lactate synthesis during intense physical exercise. PMID- 20931634 TI - Amino acid starvation sensitizes cancer cells to proteasome inhibition. AB - We explored the crosstalk between protein degradation and synthesis in cancer cells. The tumorigenic cell line, MCF7, showed enhanced proteasome activity compared to the nontumorigenic line, MCF10A. Although there was no difference in the sensitivity of MCF7 and MCF10A cells to proteasome inhibition in complete growth medium, combining proteasome inhibition with amino acid deprivation led to reduced protein synthesis and survival of MCF7 cells, with a lesser effect on MCF10A cells. Additional cancer cell lines (including CAG and A431) could be strongly sensitized to proteasome inhibition by concomitant amino acid deprivation, whereas others were completely resistant to proteasome inhibition. We hypothesize that protein catabolism contributes to the pool of free amino acids available for protein synthesis, leading to a crucial role of the proteasome in cell survival during amino acid depletion, in some tumor cell lines. PMID- 20931635 TI - Identification of targets of specific miRNAs by selective amplification of Ago2 associated mRNA. AB - To study the function of a miRNA, it is necessary to identify its target genes. The most common methods to reveal miRNA target genes rely on ectopically expressed tagged Ago2 and nonphysiological overexpression or inhibition of the miRNA of interest. To uncover the natural association between miRNAs and their target genes, we isolated endogenous Ago2 protein followed by a selective strategy, which only amplified target genes of the selected miRNA from the purified RNA-induced silencing complex by miRNA specific primers. This enabled us to identify the mRNAs regulated by miRNAs of interest. Our data demonstrated that this strategy is effective and highly credible. Moreover, our results showed the evidence of efficient miRNA target sites in 5' untranslated regions and open reading frames of target mRNAs. PMID- 20931636 TI - Integrating replication-based selection strategies in dynamic covalent systems. AB - In the past 15 years, the chemistry of reversible covalent bond formation (dynamic covalent chemistry (DCC)) has been exploited to engineer networks of interconverting compounds known as dynamic combinatorial libraries (DCLs). Classically, the distribution of library components is governed by their relative free energies, and so, processes that manipulate the free energy landscape of the DCL can influence the distribution of library members. Within the same time frame, the design and implementation of molecules capable of copying themselves- so-called replicators--has emerged from the field of template-directed synthesis. Harnessing the nonlinear kinetics inherent in replicator behavior offers an attractive strategy for amplification of a target structure within a DCL and, hence, engendering high levels of selectivity within that library. The instructional nature of replicating templates also renders the combination of replication and DCC a potential vehicle for developing complex reaction networks; a prerequisite for the development of the emerging field of systems chemistry. This Concept article explores the role of kinetically and thermodynamically controlled processes within different DCC frameworks. The effects of embedding a replicating system within these DCC frameworks is explored and the consequences of the different topologies of the reaction network for amplification and selectivity within DCLs is highlighted. PMID- 20931637 TI - Postoperative magnetic resonance imaging characterization of slings for female stress urinary incontinence. AB - PURPOSE: The aim was to characterize different types of slings such as autologous rectus fascia (ARF), porcine dermis (PD) and tension-free vaginal tape (TVT) in the early postoperative period with regard to its visibility and location by using magnetic resonance imaging (MRI). MATERIALS AND METHODS: Between October 2003 and June 2007, total of 60 patients underwent MRI after a sling procedure. Thirty-six patients had ARF slings. Twelve patients had a PD sling and 12 had a TVT. All patients had pelvic MRI 6-8 hr postoperatively. Six patients in the ARF sling group had both preoperative and postoperative images at 6 hr and 3 months. MRI images were analyzed with regard to visibility and location. All data were collected prospectively. RESULTS: ARF slings were clearly visible in both T1W and T2W images. ARF appeared as low signal intensity area with surrounding high signal intensity due to fat attached to the rectus fascia in the MRI images obtained 6 hr after the procedure. Although the fatty component of the sling was diminished but was still visible on MRI scan 3 months postoperatively. On the other hand PD and TVT sling materials were not visible by MRI. Most of the ARF slings were located just below the bladder neck. CONCLUSIONS: The ARF sling is easily identifiable on MRI in the early postoperative period primarily because of the fat attached to the autologous rectus fascia. However, depiction of the PD and TVT slings in the early postoperative period is very poor. PMID- 20931638 TI - High-grade atypical epithelial cells in pancreatic mucinous cysts are a more accurate predictor of malignancy than "positive" cytology. AB - BACKGROUND: The Sendai guidelines for risk assessment of malignancy in patients with mucinous cysts lists "positive" cytology as a high-risk feature. In the current study, the authors hypothesized that a cytological threshold of high grade atypical epithelial cells (AEC) is a more accurate predictor of malignancy. METHODS: The clinical, radiological, and cytological data of 112 patients with histologically confirmed mucinous cysts of the pancreas were reviewed. Cytology slides were blindly reviewed and cells were classified as benign, AEC, or malignant. On histology, neoplasms were grouped as benign (low-grade and moderate dysplasia) and malignant (high-grade dysplasia/carcinoma in situ and invasive carcinoma). RESULTS: There were 92 patients with an intraductal papillary mucinous neoplasm (IPMN) and 20 with a mucinous cystic neoplasm; 39 were malignant and 73 were benign (42 with low-grade dysplasia and 31 with moderate dysplasia). Only 28% (11 of 39) of the malignant cysts were cytologically malignant with a sensitivity of 29%, a specificity of 100%, and an accuracy of 75%. AEC detected 17 additional cancers (44% of all malignant cysts; 16% more than detected on the basis of "positive" cytology). By using AEC as a surgical triage threshold, the sensitivity was 72%, the specificity was 85%, and the accuracy was 80%, with similar values for small (<= 3 cm) branch duct IPMN. Nine of 73 (12%) benign cysts were identified with AEC, 4 of which had moderate dysplasia. AEC had a positive predictive value of 87% for the detection of a mucinous cyst with moderate dysplasia or worse. CONCLUSIONS: AEC are a more accurate predictor of malignancy than "positive" cytology in aspirates of pancreatic mucinous cysts, including small branch duct IPMN. AEC warrant a "suspicious" interpretation for appropriate surgical triage. PMID- 20931639 TI - Unexpected hydrobromic acid-catalyzed C-C bond-forming reactions and facile synthesis of coumarins and benzofurans based on ketene dithioacetals. AB - Hydrobromic acid was found to be a unique catalyst in C-C bond-forming reactions with ketene dithioacetals. Distinctly different from other acids (including Lewis and Bronsted acids), the remarkable catalytic performance of hydrobromic acid in catalytic amounts was observed in the "acid"-catalyzed reactions of readily available functionalized ketene dithioacetals 1 with various electrophiles. Under the catalysis of 0.1 equivalents of hydrobromic acid, the reaction of 1 with carbonyl compounds 2a-l gave polyfunctionalized penta-1,4-dienes 3 or conjugated dienes 4 in good to excellent yields. The reaction tolerated a broad range of substituents on both the ketene dithioacetals 1 and the carbonyl compounds 2. Application of this efficient C-C bond-forming method generated coumarins 5 and benzofurans 7 under mild, metal-free conditions by hydrobromic acid-catalyzed reactions of 1 with salicylaldehydes 2m-o and p-quinones 6a-d, respectively. A new reactive species, a sulfur-stabilized carbonium ylide, formed depending on the nature of the counterion, and this was proposed as the key intermediate in the unique catalysis of hydrobromic acid. PMID- 20931640 TI - Noble gas matrices may change the electronic structure of trapped molecules: the UO(2)(Ng)(4) [Ng=Ne, Ar] case. PMID- 20931641 TI - Palladium-catalyzed cross-coupling of aryl chlorides and tosylates with hydrazine. PMID- 20931642 TI - Oxidation of alkyl trifluoroborates: an opportunity for tin-free radical chemistry. PMID- 20931644 TI - The x-ray structure of the adduct between NAMI-A and carbonic anhydrase provides insights into the reactivity of this metallodrug with proteins. PMID- 20931643 TI - Cooperative, heparan sulfate-dependent cellular uptake of dimeric guanidinoglycosides. AB - Oligoarginine and guanidinium-rich molecular transporters have been shown to facilitate the intracellular delivery of a diverse range of biologically relevant cargos. Several such transporters have been suggested to interact with cell surface heparan sulfate proteoglycans as part of their cell-entry pathway. Unlike for other guanidinium-rich transporters, the cellular uptake of guanidinoglycosides at nanomolar concentrations is exclusively heparan sulfate dependent. As distinct cells differ in their expression levels and/or the composition of cell-surface heparan sulfate proteoglycans, one might be able to exploit such differences to selectively target certain cell types. To systematically investigate the nature of their cell-surface interactions, monomeric and dimeric guanidinoglycosides were synthesized by using neomycin, paromomycin, and tobramycin as scaffolds. These transporters differ in the number and 3D arrangement of their guanidinium groups. Their cellular uptake was measured by flow cytometry in wild-type and mutant Chinese hamster ovary cells after the corresponding fluorescent streptavidin-phycoerythrin-Cy5 conjugates had been generated. All derivatives showed negligible uptake in mutant cells lacking heparan sulfate. Decreasing the number of guanidinium groups diminished uptake, but the three dimensional arrangement of these groups was less important for cellular delivery. Whereas conjugates prepared with the monomeric carriers showed significantly reduced uptake in mutant cells expressing heparan sulfate chains with altered patterns of sulfation, conjugates prepared with the dimeric guanidinoglycosides could overcome this deficiency and maintain high levels of uptake in such deficient cells. This finding suggests that cellular uptake depends on the valency of the transporter and both the content and arrangement of the sulfate groups on the cell-surface receptors. Competition studies with chemically desulfated or carboxy-reduced heparin derivatives corroborated these observations. Taken together, these findings show that increasing the valency of the transporters retains heparan sulfate specificity and provides reagents that could distinguish different cell types based on the specific composition of their cell-surface heparan sulfate proteoglycans. PMID- 20931645 TI - C12orf48, termed PARP-1 binding protein, enhances poly(ADP-ribose) polymerase-1 (PARP-1) activity and protects pancreatic cancer cells from DNA damage. AB - To identify novel therapeutic targets for aggressive and therapy-resistant pancreatic cancer, we had previously performed expression profile analysis of pancreatic cancers using microarrays and found dozens of genes trans-activated in pancreatic ductal adenocarcinoma (PDAC) cells. Among them, this study focused on the characterization of a novel gene C12orf48 whose overexpression in PDAC cells was validated by Northern blot and immunohistochemical analysis. Its overexpression was observed in other aggressive and therapy-resistant malignancies as well. Knockdown of C12orf48 by siRNA in PDAC cells significantly suppressed their growth. Importantly, we demonstrated that C12orf48 protein could directly interact with Poly(ADP-ribose) Polymerase-1 (PARP-1), one of the essential proteins in the repair of DNA damage, and positively regulate the poly(ADP-ribosyl)ation activity of PARP-1. Depletion of C12orf48 sensitized PDAC cells to agents causing DNA damage and also enhanced DNA damage-induced G2/M arrest through reduction of PARP-1 enzymatic activities. Hence, our findings implicate C12orf48, termed PARP-1 binding protein (PARPBP), or its interaction with PARP-1 to be a potential molecular target for development of selective therapy for pancreatic cancer. PMID- 20931646 TI - Lipidomics era: accomplishments and challenges. AB - Lipid mediators participate in signal transduction pathways, proliferation, apoptosis, and membrane trafficking in the cell. Lipids are highly complex and diverse owing to the various combinations of polar headgroups, fatty acyl chains, and backbone structures. This structural diversity continues to pose a challenge for lipid analysis. Here we review the current state of the art in lipidomics research and discuss the challenges facing this field. The latest technological developments in mass spectrometry, the role of bioinformatics, and the applications of lipidomics in lipid metabolism and cellular physiology and pathology are also discussed. PMID- 20931647 TI - Transitin is required for the differentiation of avian QM7 myoblasts into myotubes. AB - Transitin is a nestin-like intermediate filament protein co-expressed with vimentin in the precursor cells of the myogenic and neurogenic lineages of the avian embryo. To understand its role in myogenesis, stable cell lines expressing transitin-targeted siRNAs were derived from the quail muscle cell line QM7. When cells were cultured in differentiation medium, we found that transitin knockdown prevented myoblast fusion and myotube formation. MyoD mRNA could be detected in transitin siRNA-transfected cells, but upregulation of myogenin and desmin expression was impaired compared to control cells. In addition, transitin siRNA cells maintain high levels of Pax7 expression suggesting that QM7 myoblasts into which transitin expression has been attenuated display a muscle progenitor cell phenotype (Pax7(+)/MyoD(+)/myogenin(-)/desmin(-)). These observations indicate that transitin plays an important role in the initiation of the myogenic program in avian muscle progenitor cells in acting downstream of MyoD and upstream of myogenin during the lineage progression. PMID- 20931649 TI - Fluorescent whole-mount method for visualizing three-dimensional relationships in intact and regenerating adult newt spinal cords. AB - Adult newts have the remarkable ability to regenerate their spinal cords after a complete transection injury. To understand this process, we have developed a method for visualizing the cellular and molecular events during regeneration in whole-mount preparations using fluorescent probes (streptavidins and antibodies) and confocal microscopy. This method was optimized by varying parameters associated with fixation, tissue trimming, fluorescent probe penetration, and clearing and represents a significant advance in our ability to observe the intact and regenerating newt spinal cord. These methods should also be widely applicable to the study of other newt tissues and adult tissues from other model systems. PMID- 20931648 TI - Dermoskeleton morphogenesis in zebrafish fins. AB - Zebrafish fins have a proximal skeleton of endochondral bones and a distal skeleton of dermal bones. Recent experimental and genetic studies are discovering mechanisms to control fin skeleton morphogenesis. Whereas the endochondral skeleton has been extensively studied, the formation of the dermal skeleton requires further revision. The shape of the dermal skeleton of the fin is generated in its distal growing margin and along a proximal growing domain. In these positions, dermoskeletal fin morphogenesis can be explained by intertissue interactions and the function of several genetic pathways. These pathways regulate patterning, size, and cell differentiation along three axes. Finally, a common genetic control of late development, regeneration, and tissue homeostasis of the fin dermoskeleton is currently being analyzed. These pathways may be responsible for the similar shape obtained after each morphogenetic process. This provides an interesting conceptual framework for future studies on this topic. PMID- 20931650 TI - Ultrasound demonstration of Struthers' ligament. AB - The supracondylar process is a bony spur at the anteromedial surface of the distal humerus. It is associated with the Struthers' ligament, running from its apex to the medial epicondyle. Symptoms may occur due to fracture and entrapment of nerves (most frequently the median nerve) and/or blood vessels underneath the structures. We report a case in which we used MRI and high-frequency ultrasound to investigate the supracondylar process, the Struthers' ligament, and its surrounding structures. Ultrasound is a useful alternative to MRI during the workup of potential entrapment syndromes. PMID- 20931651 TI - Bilateral round ligament varicosities mimicking an inguinal hernia in pregnancy: case report. AB - A 22-year-old pregnant woman presented with a painful swelling in the right groin. Sonography was performed to confirm a presumptive diagnosis of inguinal hernia based on physical examination. Gray-scale sonography examination revealed bilateral inguinal cystic lesion expanding with the Valsalva maneuver. Color Doppler imaging demonstrated multiple prominent vessels with retrograde venous flow during Valsalva maneuver. Bilateral round ligament varicosities were diagnosed and inguinal hernia was excluded by sonographic findings. Round ligament varicosities should be considered in the differential diagnosis of groin swelling during pregnancy. PMID- 20931654 TI - Monoclonal anti-CD8 therapy induces disease amelioration in the K/BxN mouse model of spontaneous chronic polyarthritis. AB - OBJECTIVE: CD8+ T cells are part of the T cell pool infiltrating the synovium in rheumatoid arthritis (RA). However, their role in the pathogenesis of RA has not been fully delineated. Using the K/BxN mouse model of spontaneous chronic arthritis, which shares many similarities with RA, we studied the potential of CD8+ T cell depletion with monoclonal antibodies (mAb) to stop and reverse the progression of experimental arthritis. METHODS: CD8+ T cells from the blood and articular infiltrate of K/BxN mice were characterized for cell surface phenotypic markers and for cytokine production. Additionally, mice were treated with specific anti-CD8 mAb (YTS105 and YTS169.4), with and without thymectomy. RESULTS: CD8+ T cells from the peripheral blood and joints of K/BxN mice were mainly CD69+ and CD62L-CD27+ T cells expressing proinflammatory cytokines (interferon-gamma [IFNgamma], tumor necrosis factor alpha [TNFalpha], interleukin 17a [IL-17A], and IL-4), and granzyme B. In mice receiving anti-CD8 mAb, the arthritis score improved 5 days after treatment. Recovery of the CD8+ T cells was associated with a new increase in the arthritis score after 20 days. In thymectomized and anti-CD8 mAb-treated mice, the arthritis score improved permanently. Histologic analysis showed an absence of inflammatory infiltrate in the anti-CD8 mAb-treated mice. In anti-CD8 mAb-treated mice, the serologic levels of TNFalpha, IFNgamma, IL-6, and IL-5 normalized. The levels of the disease related anti-glucose-6-phosphate isomerase antibodies did not change. CONCLUSION: These results indicate that synovial activated effector CD8+ T cells locally synthesize proinflammatory cytokines (IFNgamma, TNFalpha, IL-17, IL-6) and granzyme B in the arthritic joint, thus playing a pivotal role in maintaining chronic synovitis in the K/BxN mouse model of arthritis. PMID- 20931657 TI - Cellular response after crush injury in adult zebrafish spinal cord. AB - Zebrafish proves to be an excellent model system to study spinal cord regeneration because it can repair its disengaged axons and replace lost cells after injury, allowing the animal to make functional recovery. We have characterized injury response following crush injury, which is comparable to the mammalian mode of injury. Infiltrations of blood cells during early phases involve macrophages that are important in debris clearance and probably in suppression of inflammatory response. Unlike mammals where secondary injury mechanisms lead to apoptotic death of both neurons and glia, here we observe a beneficial role of apoptotic cell death. Injury-induced proliferation, presence of radial glia cells, and their role as progenitor all contribute to cellular replacement and successful neurogenesis after injury in adult zebrafish. Together with cell replacement phenomenon, there is creation of a permissive environment that includes the absence or clearance of myelin debris, presence of Schwann cells, and absence of inflammatory response. PMID- 20931658 TI - Subcellular phosphoproteomics. AB - Protein phosphorylation represents one of the most extensively studied post translational modifications, primarily due to the emergence of sensitive methods enabling the detection of this modification both in vitro and in vivo. The availability of enrichment methods combined with sensitive mass spectrometry instrumentation has played a crucial role in uncovering the dynamic changes and the large expanding repertoire of this reversible modification. The structural changes imparted by the phosphorylation of specific residues afford exquisite mechanisms for the regulation of protein functions by modulating new binding sites on scaffold proteins or by abrogating protein-protein interactions. However, the dynamic interplay of protein phosphorylation is not occurring randomly within the cell but is rather finely orchestrated by specific kinases and phosphatases that are unevenly distributed across subcellular compartments. This spatial separation not only regulates protein phosphorylation but can also control the activity of other enzymes and the transfer of other post translational modifications. While numerous large-scale phosphoproteomics studies highlighted the extent and diversity of phosphoproteins present in total cell lysates, the further understanding of their regulation and biological activities require a spatio-temporal resolution only achievable through subcellular fractionation. This review presents a first account of the emerging field of subcellular phosphoproteomics where cell fractionation approaches are combined with sensitive mass spectrometry methods to facilitate the identification of low abundance proteins and to unravel the intricate regulation of protein phosphorylation. PMID- 20931659 TI - Xenopus sonic hedgehog guides retinal axons along the optic tract. AB - The role of classic morphogens such as Sonic hedgehog (Shh) as axon guidance cues has been reported in a variety of vertebrate organisms (Charron and Tessier Lavigne [2005] Development 132:2251-2262). In this work, we provide the first evidence that Xenopus sonic hedgehog (Xshh) signaling is involved in guiding retinal ganglion cell (RGC) axons along the optic tract. Xshh is expressed in the brain during retinal axon extension, adjacent to these axons in the ventral diencephalon. Retinal axons themselves express Patched 1 and Smoothened co receptors during RGC axon growth. Blocking Shh signaling causes abnormal ventral pathfinding, and targeting errors at the optic tectum. Misexpression of exogenous N-Shh peptide in vivo also causes pathfinding errors. Retinal axons grown in culture respond to N-Shh in a dose-dependent manner, either by decreasing extension at lower concentrations, or retracting axons in the presence of higher doses. These data suggest that Shh signaling is required for normal RGC axon pathfinding and tectal targeting in the developing visual system of Xenopus. We propose that Shh serves as a ventral optic tract repellent that helps to define the caudal boundary for retinal axons in the diencephalon, and that this signaling is also required for initial target recognition at the optic tectum. PMID- 20931661 TI - Underdiagnosis of posttraumatic stress disorder in at risk youth. AB - Three studies examined the diagnosis of posttraumatic stress disorder (PTSD) in agencies treating at risk youth. Studies 1 and 2 (1999) found that baseline PTSD diagnosis was rare in a residential and an outpatient agency (2.3% and 5.4%, respectively) whereas trauma-focused interviews identified PTSD in 47.7% and 44.6% of these clients. Subsequent training efforts increased awareness of PTSD and recognition of unique issues in assessing at risk youth. Study 3 (2009) reexamined PTSD diagnosis rates in these agencies 10 years later and found that the residential agency had an increased rate of PTSD diagnosis (10.8%), whereas PTSD diagnosis remained rare in the outpatient agency (4.0%). Suggestions are offered for increased accuracy in the diagnosis of PTSD and complex PTSD with at risk youth. PMID- 20931662 TI - Prazosin treatment of trauma nightmares and sleep disturbance in soldiers deployed in Iraq. AB - Trauma nightmares and sleep disturbance impair combat soldiers' functioning. The alpha-1 adrenoreceptor antagonist prazosin has been demonstrated effective for these symptoms in Vietnam veterans. Thirteen soldiers seeking relief from distressing trauma nightmares impairing military function in northern Iraq in 2006 received prazosin alone or in combination with other psychotropics. Mean prazosin dose was 4.1 (SD = 2.2) mg before bed. Six soldiers improved markedly and 3 moderately on the Clinical Global Impression of Change Ratings of distressing dreams decreased from an average of 7.0 (SD = 0.7) to 2.9 (SD = 3.0, p < .001) and those of disturbed sleep from 6.7 (SD = 0.9) to 3.7 (SD = 2.4, p < .001). Prazosin appears effective and well tolerated in the desert warfare environment. PMID- 20931663 TI - The relationship between somatization and posttraumatic symptoms among immigrants receiving primary care services. AB - Traumatic experiences and somatization are related in studies on complex trauma, though this relation is rarely studied in immigrants. The relationship between somatization and self-reported traumatic experiences and posttraumatic symptoms in patients attending a primary care service for immigrants was studied. The sample consisted of 101 patients attending a primary healthcare service dedicated to immigrants. Participants completed two self-assessment questionnaires specifically designed for use in transcultural research: the Bradford Somatic Inventory and the Harvard Trauma Questionnaire. Both were translated and back translated into eight languages. Somatization was significantly related to traumatic events and posttraumatic symptoms. In primary care centers for immigrants, physicians should give particular attention to somatization as a possible sign of unreported posttraumatic symptoms. PMID- 20931660 TI - Somatic cell nuclear transfer efficiency: how can it be improved through nuclear remodeling and reprogramming? AB - Fertile offspring from somatic cell nuclear transfer (SCNT) is the goal of most cloning laboratories. For this process to be successful, a number of events must occur correctly. First the donor nucleus must be in a state that is amenable to remodeling and subsequent genomic reprogramming. The nucleus must be introduced into an oocyte cytoplasm that is capable of facilitating the nuclear remodeling. The oocyte must then be adequately stimulated to initiate development. Finally the resulting embryo must be cultured in an environment that is compatible with the development of that particular embryo. Much has been learned about the incredible changes that occur to a nucleus after it is placed in the cytoplasm of an oocyte. While we think that we are gaining an understanding of the reorganization that occurs to proteins in the donor nucleus, the process of cloning is still very inefficient. Below we will introduce the procedures for SCNT, discuss nuclear remodeling and reprogramming, and review techniques that may improve reprogramming. Finally we will briefly touch on other aspects of SCNT that may improve the development of cloned embryos. PMID- 20931664 TI - Impact of drug interactions, dosage, and duration of therapy on the risk of hip fracture associated with benzodiazepine use in older adults. AB - PURPOSE: To determine how concomitant use of potentially interacting drugs, drug dosage, and duration of therapy modify the risk of hip fracture associated with use of benzodiazepines and benzodiazepine-related drugs (BDZ) in older adults. METHODS: A nested case-control study was conducted in Medicare patients 65 years or older, enrolled in the Pennsylvania drug assistance program (PACE) between 1994 and 2005. We included 17,198 patients with a hip fracture leading to hospitalization and 85,990 controls matched on hospitalization (index date). BDZ and interacting drug use within 2 weeks preceding the index date was determined using information on date of drug dispensing, days supplied, quantity dispensed, and strength. Date of the first BDZ prescription within the year preceding the index date was used as surrogate for duration of therapy. RESULTS: While the adjusted relative risk (RR) for overall BDZ use and hip fracture was 1.2 (95% confidence interval 1.1, 1.2), the RRs for concomitant use of alprazolam, lorazepam, and zolpidem and their interacting drugs were 1.5 (1.3, 1.7), 1.9 (1.7, 2.2), and 1.7 (1.4, 2.0), and 2.1 (1.5, 2.8) for BDZ use initiated within 14 days preceding the index date. RR increased with increasing BDZ dose and was highest for defined daily BDZ doses >1 [RR: 1.3 (1.2, 1.5)]. CONCLUSIONS: BDZ associated hip fracture risk increases with concomitant use of interacting drugs, higher doses, and is highest at initiation. Clinicians should avoid concomitant use of BDZ and interacting drugs, because their impact on hip fracture risk is at least additive. PMID- 20931665 TI - Figulla PFO occluder versus Amplatzer PFO occluder for percutaneous closure of patent foramen ovale. AB - BACKGROUND: Percutaneous closure of patent foramen ovale (PFO) has been shown safe and feasible using several devices. The Occlutech Figulla single layer PFO Occluder (FPO) constitutes an alternative to the Amplatzer PFO Occluder (APFO). OBJECTIVES: We report our experience with both devices in a single-center case control study. METHODS: Twenty patients undergoing percutaneous PFO closure using an FPO for secondary prevention of paradoxical embolism or diving were blindly matched with 20 patients receiving an APFO during the same time period. Contrast transesophageal echocardiography (TEE) was performed 6 months after device implantation to assess for residual shunting and device-associated thrombus. RESULTS: Patient baseline characteristics were well matched by study design. Procedural success was 95% with FPO vs. 100% for APFO (P = 1.0), with 3 (15%) peri-procedural complications with FPO vs. none with APFO (P = 0.24). These comprised one asymptomatic device embolization in the descending aorta with percutaneous retrieval, one transient ischemic attacks, and one suspected device endocarditis. Contrast TEE at 6 months showed significantly more residual shunts in the FPO-group (39% vs. 0%; P = 0.01). Two FPO patients with a moderate residual shunt underwent implantation of a second device (APFO 25 mm) vs. none in the APFO group (P = 0.48). No thrombi were observed in either group. During 1.7 +/- 0.7 years of follow-up, no death or recurrent embolic event occurred. CONCLUSIONS: According to this single-center case-control study, PFO closure with the FPO appears less efficacious than with the APFO. PMID- 20931666 TI - Physiological assessment of renal artery stenosis: comparisons of resting with hyperemic renal pressure measurements. AB - OBJECTIVES: We compared resting and hyperemic pressure gradients induced by intrarenal papaverine for the assessment of renal artery stenosis (RAS). We also investigated the incidence of the QT interval prolongation and ventricular arrhythmias. BACKGROUND: In the coronary circulation, maximal hyperemia is essential in determining the significance of a stenosis. In the renal circulation, the role of maximal hyperemia for the assessment of RAS has not been established. METHODS: In 55 patients with RAS (67 RAS), resting P(d)/P(a) ratio (the ratio between distal renal pressure to the aortic pressure), renal fractional flow reserve (FFR), and resting and hyperemic systolic gradients (RSG and HSG, respectively) were measured with a pressure guidewire. In a subset of 16 patients, renal vein renin activity (RVRA) was measured. RESULTS: HSG was significantly greater than RSG (20 +/- 14 mm Hg vs. 9.0 +/- 13 mm Hg, respectively; P < 0.001). Renal FFR was significantly lower than baseline P(d)/P(a) ratio (0.91 +/- 0.06 vs. 0.94 +/- 0.06 vs. respectively; P < 0.001). RVRA increased from 50 +/- 66% at rest to 122 +/- 112% at hyperemia, P < 0.01. At HSG of 21 mm Hg or renal FFR of 0.90, RVRA increased markedly (120%), but RVRA increased modestly (18%) when RSG was 16 mm Hg or resting P(d)/P(a) ratio was 0.93. The corrected QT intervals at baseline vs. hyperemia were not significantly different (433 +/- 26 vs. 436 +/- 25 msec, respectively; P = NS); no episodes of ventricular arrhythmias were noted. CONCLUSIONS: Renin production, an index of renal ischemia, was markedly greater at hyperemia than at rest, suggesting that RAS, with either an HSG of 21 mm Hg or a renal FFR of 0.90, can be considered a hemodynamically significant stenosis. Intrarenal papaverine neither prolonged the QT interval nor induced ventricular arrhythmias and the safety of which will need to be corroborated in a large study. (c) 2010 Wiley-Liss, Inc. PMID- 20931667 TI - Oral sirolimus after bare metal stent implantation: a glimpse to the future. PMID- 20931668 TI - Large sample inference for an assay quality measure used in high-throughput screening. PMID- 20931669 TI - In vitro antimicrobial susceptibility of Propionibacterium acnes isolated from acne patients in northern Mexico. AB - BACKGROUND: Antimicrobials are essential in acne therapy. In the last decades, Propionibacterium acnes has become resistant to different antibiotics. OBJECTIVE: To determine antimicrobial susceptibility patterns of P. acnes to frequently used drugs. MATERIALS AND METHODS: Cutaneous lesion samples were obtained from 50 patients with acne vulgaris, which were cultured in anaerobic media to demonstrate the presence of P. acnes. After that, antimicrobial susceptibility tests to tetracycline, minocycline, doxycycline, erythromycin, azithromycin, clindamycin, trimethoprim/sulfamethoxazole (SXT) and levofloxacin were performed. RESULTS: In the general study group, resistance to azithromycin was 82%, the most prevalent one (P < 0.05), followed by trimethoprim/sulfamethoxazole (68%) and erythromycin (46%). On the other hand, all strains isolated were susceptible to minocycline. Resistance bias were similar when subgroups with and without the previous antimicrobial therapy were performed, finding a low prevalence of resistance to tetracyclines and levofloxacin in both groups. CONCLUSIONS: In our region, P. acnes is highly resistant to azithromycin, SXT, erythromycin and clindamycin; and being very susceptible to minocycline, levofloxacin and tetracycline, in vitro in both groups: with and without the previous antibiotic use. To our knowledge, high resistance prevalence to azithromycin and SXT has never been reported. PMID- 20931670 TI - Clear cell acanthoma: a rare clinical diagnosis prior to biopsy. AB - BACKGROUND: Clear cell acanthoma is a rare, benign epidermal tumor with a clinical hybrid appearance and a distinct histological one. It is frequently mistaken for other clinical lesions. OBJECTIVE: To evaluate the frequency that clear cell acanthoma was listed in the clinical differential diagnosis of histologically confirmed specimens. METHODS: A regional dermatopathology lab database was evaluated from January 1998 through March 2008 for histologically diagnosed cases of clear cell acanthoma. Clinical data that was submitted with these cases including differential diagnoses was analyzed. RESULTS: During this time period of review, 411 histologically confirmed cases of clear cell acanthoma were identified. This entity was listed as a diagnostic possibility in 11 (2.7%) of the cases. CONCLUSION: Clear cell acanthoma was rarely listed amongst the differential diagnosis of biopsy proven specimens. This may be due to a variable clinical appearance with overlapping features of several other lesions making it difficult to distinguish, or an entity that is rare and not frequently suspected. Additional studies with dermatoscopy may help to further delineate the reasons for the low diagnostic sensitivity. PMID- 20931671 TI - Analysis of epidemiology, clinical features and management of erysipelas. AB - BACKGROUND: Erysipelas is a superficial form of cellulitis affecting the upper dermis and superficial lymphatics. The widespread use of antibiotics may affect clinical findings and response to therapy of infectious disorders. The purpose of the study was to investigate the epidemiological, clinical, and laboratory features of erysipelas and to compare the results of treatment with penicillin vs. other antibiotic regimens. METHODS: All charts of erysipelas patients treated at the University Hospital of Heraklion, Crete, Greece from 1994 to 2002 were retrospectively studied. RESULTS: Median age of the 99 patients was 54.5 years; 59% were females. The most frequent site involved was the lower extremity (76%), followed by the face (17%) and upper extremity (6%). In 61 patients (62%), a possible entry portal was identified. The most common manifestation of erysipelas was local symptoms and signs (pain, erythema, and swelling) in all patients, together with elevated erythrocyte sedimentation rate (ESR) (60%). Fever was present in 25% of patients. The most commonly used antibiotic was intravenous penicillin G (64%). In the penicillin group, mean duration of fever after treatment initiation was shorter than in the nonpenicillin group (1.7 vs. 4.5 days, P = 0.002). Both treatment failures and recurrences were the same between the two groups. DISCUSSION: The diagnosis of erysipelas can be based on careful examination for local signs and symptoms. The role of ESR in primary diagnosis needs further investigation. Penicillin seems to preserve its fundamental role in the treatment of disease. PMID- 20931672 TI - Dermoscopy as a diagnostic tool in demodicidosis. AB - BACKGROUND: The in vivo demonstration of Demodex infestation is traditionally based on the microscopic identification of Demodex mites, which is time consuming and requires specific equipment and a trained observer. OBJECTIVE: The aim of this study was to describe for the first time the use of polarized-light dermoscopy for the diagnosis of demodicidosis in patients with variable clinical presentations. METHODS: A total of 72 patients with variable facial eruptions were examined clinically, microscopically, and dermoscopically for the presence of Demodex mites. RESULTS: Of the 72 patients, 55 were found to have demodicidosis. In 54 patients, the dermoscopy examination yielded a specific picture consisting of Demodex "tails" and Demodex follicular openings. In patients with an inflammatory variant of demodicidosis, reticular horizontal dilated blood vessels were also visualized. Microscopically, skin scrapings demonstrated Demodex in 52 patients. Overall, the dermoscopy findings showed excellent agreement with the microscopy findings (kappa value 0.86, 95% CI 0.72 0.99, P < 0.001). In the remaining 17 patients, there was no evidence of Demodex infestation either microscopically or dermoscopically. LIMITATIONS: The study was not blinded. As there are no standards for the diagnosis of demodicidosis, our results were based on criteria developed by our research group. CONCLUSIONS: This is the first description of the specific dermoscopic findings associated with variable clinical presentations of demodicidosis. Dermoscopy may serve as a valuable tool for the real-time validation of Demodex infestation and the evaluation and follow-up of affected patients. PMID- 20931673 TI - Cutaneous disorders in uremic patients on hemodialysis: an Egyptian case controlled study. AB - BACKGROUND: We studied the prevalence of mucocutaneous disorders in uremic adults and children on hemodialysis (HD) vs. controls, in Egypt. METHODS: A total of 206 Egyptians with uremia (163 adults and 43 children) undergoing HD, and 199 healthy controls (161 adults and 38 children), were examined for mucocutaneous abnormalities. RESULTS: Specific cutaneous diseases associated with renal insufficiency were found in five adults, including acquired perforating dermatosis and pseudo-porphyria. Non-specific abnormalities included xerosis (54%), pallor (42.2%), nail changes (34.9%), hair changes (34%), pruritus (32%), hyper-pigmentation (22.2%), coated tongue (14.1%), ecchymosis (1.5%), and gingival hypertrophy (1.5%). Disorders found significantly more often in uremics than controls included pallor, nail changes, hair changes, pruritus, hyperpigmentation and coated tongue in adults (P < 0.05), and nail changes, hair changes, and hyper-pigmentation in children (P < 0.05). The prevalence of each mucocutaneous abnormality was similar in uremic adults and children except for pallor [more common in adults (P = 0.001)], and hyper-pigmentation [more common in children (P = 0.003)]. A greater number of hepatitis C virus-positive than negative adult uremics had hyper-pigmentation (P < 0.05), and more diabetic uremics had pruritus than did non-diabetics (P < 0.05). CONCLUSION: Mucocutaneous disorders occur in adults and children with uremia, some of which are specific associations with the underlying renal disease. Occurrence of some of the non specific abnormalities, such as xerosis, ecchymosis, and gingival hypertrophy, may be coincidental or associated with factors other than renal insufficiency. PMID- 20931674 TI - [The French-speaking Society of Pneumology recommendations on the management of COPD]. PMID- 20931675 TI - Proceedings of the 9th International Symposium on Chromosomal Aberrations: New insights into chromosomal aberrations. July11-12, 2009. St Goar, Germany. PMID- 20931677 TI - [Abstracts of the 57th Meeting of the Japanese Society of Clinical Pathology. September 9-12, 2010. Tokyo, Japan]. PMID- 20931676 TI - Regulatory Control and Standardization of Allergenic Extracts. Proceedings of the 12th International Paul-Ehrich-Seminar. September 24-27, 2008. Bad Homburg, Germany. PMID- 20931678 TI - [Abstracts of the 103rd Annual Meeting of the Japanese Society of Animal Reproduction. September 2-4, 2010. Aomori, Japan]. PMID- 20931679 TI - Abstracts of the 2010 Triological Society Combined Section Meetings. April 30-May 1, 2010. Las Vegas, Nevada, USA. PMID- 20931680 TI - [Symposium on Asbestos and Asbestos-related Diseases. Split, 6 December 2008]. PMID- 20931681 TI - Endovascular repair of abdominal aortic aneurysm. PMID- 20931682 TI - Hospital-acquired infections due to gram-negative bacteria. PMID- 20931683 TI - CardioPulse. The first European Society of Cardiology Association is born. AB - Jen Taylor reports on the European Association of Echocardiography now in its 18th year. PMID- 20931684 TI - Clinical, pathologic, and ultrastructural studies of progressive macular hypomelanosis. AB - BACKGROUND: Progressive macular hypomelanosis (PMH), a condition of uncertain etiology, is characterized by asymptomatic hypopigmented macules, predominantly located on the trunk. To date, the study of this disease has been sporadic and there are still no clinical diagnostic criteria. The aim of this study was to investigate the histopathologic and ultrastructural characteristics of PMH, and propose the clinical diagnostic criteria of PMH. METHODS: The Wood's lamp and Confocal Laser Scanning Microscopy were used to observe the lesions' features. Skin biopsies were used for hematoxylin and eosin staining, melanin staining, antibodies staining of S-100 protein, tyrosinase-related protein-1(TRP-1) and tyrosinase (T311), and also for ultra-structural study. Melanocytes were isolated and cultured from the lesions. RESULTS: Under Wood's lamp examination, the lesions of PMH showed punctiform red fluorescence. Confocal Laser Scanning Microscopy observation of the lesion showed that its "pigmented ring" around the dermal papillae was intact, but its melanin content was decreased compared with the surrounding normal skin. Ferrous sulfate staining showed that melanin content in the lesion of PMH was significantly decreased compared with the normal skin (P < 0.05). S-100 staining showed that the number of positive cells in the basal layer had no statistical significance (P > 0.05) between the lesion areas (8.25 +/- 0.96) and the surrounding normal skin (8.75 +/- 1.71). TRP-1 staining showed no significant difference between lesion areas (4.25 +/- 0.96) and the surrounding normal skin (4.50 +/- 1.29) (P > 0.05), and T311 staining also showed no difference between lesion areas (4.01 +/- 0.87) and the surrounding normal skin (4.30 +/- 1.05) (P > 0.05). Ultra-structural studies revealed a large reduction in the number of mature melanosome from PMH lesions. There were many membrane-bound groups in PMH lesions with normal appearance the margin, which contained a number of smaller type II-IV melanosomes, which were distributed in clusters. No degradation of melanosomes was present in the lysosomal compartments of PMH lesions. When melanocytes from the PMH lesions were cultured in vitro, the morphology of those melanocytes showed no difference compared with normal melanocytes. CONCLUSION: As a result of the above findings, we discussed and summarized the PMH's clinical diagnostic criteria. PMID- 20931685 TI - Human leukocyte antigen (HLA) and single nucleotide polymorphisms (SNPs) tumor necrosis factor (TNF)-alpha -238 and -308 as genetic markers of susceptibility to psoriasis and severity of the disease in a long-term follow-up Brazilian study. AB - BACKGROUND: The strongest genetic marker for psoriasis is Cw*06. Polymorphisms in the tumor necrosis factor (TNF)-alpha promoter region, especially replacement of guanine with adenine in positions -238 and -308 are related to higher TNF-alpha production and higher risk for psoriasis in Caucasoid populations, not found in Asians. We performed a case-control study of 69 patients with psoriasis type I and 70 controls, characterized clinical progression along 10-years of follow-up in mild or severe disease and determined HLA class I, II, and TNF single nucleotide polymorphisms (SNPs) -238 and -308 polymorphisms to demonstrate whether these polymorphisms may be genetic risk for susceptibility to psoriasis or severity of the disease in Brazilians. METHODS: Polymorphisms were identified using PCR/SSP. Alleles, genotypes, and haplotypes frequencies were compared using Fisher's test. RESULTS: More severe disease was found in male patients. It may be suggested that alleles B*37, Cw*06, Cw*12, and DRB1*07 were associated with severe disease course, while B*57 with mild disease. No statistical difference was found between the patients and controls regarding polymorphisms frequencies in TNF SNPs. This study pointed to a higher TNF-238 G/G genotype frequency (OR: 3.21; CI: 1.06-9.71; P = 0.04) in the group with severe disease. CONCLUSIONS: Polymorphisms in the TNF-alpha SNPs do not seem to be a more important genetic risk factor for psoriasis than the already known Cw*06 in Brazilian patients, but these markers may be related to clinical manifestations. PMID- 20931686 TI - Beliefs and perceptions of Arab vitiligo patients regarding their condition. AB - BACKGROUND: Patients' beliefs about their illness can result in positive and/or negative implications for the management of their disease. To examine the beliefs held by vitiligo patients about their condition and to explore the potential factors that might influence such beliefs. METHODS: The illness perception questionnaire (IPQ) was translated into the particular regional language (Arabic) and administered to adult vitiligo patients visiting our Dermatology Department, from 2006 to 2008. Demographic and illness details were obtained. RESULTS: We recruited 164 vitiligo patients (91 male subjects). The mean age was 27 years (SD = 13, range 15-57 years). It was believed that stress, altered immunity, and heredity were the cause of vitiligo by 33%, 26%, and 24% of the respondents respectively. Eighty-four percent and 28% believed in fate and evil eye as a cause of their illness respectively. Forty-two percent believed that their illness had a major effect on their lives and 44% believed that vitiligo had strongly affected the way others see them. For both beliefs, this was independent of the gender. Thirty-seven percent reported that they do not understand their illness. Six percent believed that their disease was contagious while 12% were not sure. Fifty-four and 57% reported feeling depressed and anxious respectively, because of their disease. This was more common in female patients (P = 0.019 and 0.031 respectively). CONCLUSION: Misconceptions and negative attitudes are widespread among vitiligo patients. The lack of disease-related understanding and the existence of anxiety and depression require targeted health education and psychosocial support. PMID- 20931687 TI - Professionalism. PMID- 20931688 TI - AABB and FDA: a shared history of patient safety. PMID- 20931689 TI - Transfusion med illustrated: Ceftriaxone-induced acute hemolytic anemia. PMID- 20931690 TI - Abstracts of the AWHONN (Association of Women's Health, Obstetric and Neonatal Nurses) National Meeting. September 25-29, 2010. Las Vegas, Nevada, USA. PMID- 20931691 TI - How does sipuleucel-T alter our clinical practice? PMID- 20931692 TI - Walter Clement Noel-first patient described with sickle cell disease. PMID- 20931693 TI - Pandemic influenza-a timeline. PMID- 20931694 TI - The quality of health insurance service delivery for kidney transplant recipients: a patient perspective. AB - Increased attention has been devoted to improving quality care in kidney transplantation. The discourse on quality care has focused on transplant center metrics and other clinical parameters. However, there has been little discussion on the quality of health insurance service delivery, which may be critical to kidney recipients' access to transplantation and immunosuppression. This paper describes and provides a framework for characterizing kidney transplant recipients' positive and negative interactions with their insurers. A consecutive cohort of kidney recipients (n = 87) participated in semistructured interviews on their interactions with insurance agencies. Patients reported negative (37%) and/or neutral or positive (79%) interactions with their insurer (a subset [16%] reported both). Perceived negative experiences included: poor service, logistical difficulties with confusing and time-consuming paperwork, poor communication, rude behavior and concerns about adequate coverage. Positive experiences related to: having good coverage, a simple application process, straightforward transactions and helpful communication. Findings suggest that even when patients have insurance coverage, difficult interactions with insurers and limited skills in navigating insurance options may limit their access to needed medications and health services. Future research is needed to test this hypothesis in a larger population. PMID- 20931695 TI - The molecular phenotype of kidney transplants. AB - Microarray studies of kidney transplant biopsies provide an opportunity to define the molecular phenotype. To facilitate this process, we used experimental systems to annotate transcripts as members of pathogenesis-based transcript sets (PBTs) representing biological processes in injured or diseased tissue. Applying this annotation to microarray results revealed that changes in single molecules and PBTs reflected a large-scale coordinate disturbance, stereotyped across various diseases and injuries, without absolute specificity of individual molecules or PBTs for rejection. Nevertheless, expression of molecules and PBTs was quantitatively specific: IFNG effects for rejection; T cell and macrophage transcripts for T cell-mediated rejection; endothelial and NK transcripts for antibody-mediated rejection. Various diseases and injuries induced the same injury-repair response, undetectable by histopathology, involving epithelium, stroma and endothelium, with increased expression of developmental, cell cycle and apoptosis genes and decreased expression of differentiated epithelial features. Transcripts reflecting this injury-repair response were the best correlates of functional disturbance and risk of future graft loss. Late biopsies with atrophy-fibrosis, reflecting their cumulative burden of injury, displayed more transcripts for B cells, plasma cells and mast cells. Thus the molecular phenotype is best described in terms of three elements: specific diseases, including rejection; the injury-repair response and the cumulative burden of injury. PMID- 20931696 TI - An integrated view of molecular changes, histopathology and outcomes in kidney transplants. AB - Data-driven approaches to deteriorating kidney transplants, incorporating histologic, molecular and HLA antibody findings, have created a new understanding of transplant pathology and why transplants fail. Transplant dysfunction is best understood in terms of three elements: diseases, the active injury-repair response and the cumulative burden of injury. Progression to failure is mainly attributable to antibody-mediated rejection, nonadherence and glomerular disease. Antibody-mediated rejection usually develops late due to de novo HLA antibodies, particularly anti-class II, and is often C4d negative. Pure treated T cell mediated rejection does not predispose to graft loss because it responds well, even with endothelialitis, but it may indicate nonadherence. The cumulative burden of injury results in atrophy-fibrosis (nephron loss), arterial fibrous intimal thickening and arteriolar hyalinosis, but these are not progressive without ongoing disease/injury, and do not explain progression. Calcineurin inhibitor toxicity has been overestimated because burden-of-injury lesions invite this default diagnosis when diseases such as antibody-mediated rejection are missed. Disease/injury triggers a stereotyped active injury-repair response, including de-differentiation, cell cycling and apoptosis. The active injury repair response is the strongest correlate of organ function and future progression to failure, but should always prompt a search for the initiating injury or disease. PMID- 20931697 TI - [Biceps tendon in rotator cuff lesions - the surgeon may decide]. PMID- 20931698 TI - Markets or incentives: terminology is critical. PMID- 20931699 TI - [Not Available]. PMID- 20931700 TI - [Not Available]. PMID- 20931702 TI - Retraction: Intron-1 rs3761548 is related to the defective transcription of Foxp3 in psoriasis through abrogating E47/c-Myb binding. PMID- 20931701 TI - [Not Available]. PMID- 20931703 TI - One step closer. HHS announces two EHR certification bodies. PMID- 20931704 TI - They're in the money--now. Some IT projects are getting stimulus funds faster. PMID- 20931705 TI - Deadly trend. Arkansas accident was eighth air medical crash in '10. PMID- 20931706 TI - Going global. Two architecture firms announce consolidation deals. PMID- 20931707 TI - Uncertain future for MedCath. PMID- 20931708 TI - When compromise was allowed. Despite his faults, Rosty knew how to reach out and make a deal. PMID- 20931709 TI - More, but possibly less. Medicaid expansion will add revenue, but state budget woes could force cuts. PMID- 20931710 TI - Obesity. How colds can make kids fat. PMID- 20931711 TI - Surefil SDR Flow. PMID- 20931712 TI - Dietary fluoride supplements. PMID- 20931713 TI - Sustaining shared hope for breast cancer survivors. PMID- 20931714 TI - CLR 2010-2011 needs a "fix". PMID- 20931716 TI - Refinancing time. Investor-owned companies look for cheaper debt. PMID- 20931715 TI - Cracking down. Agencies unveil new fraud-detection procedures. PMID- 20931717 TI - More advanced degrees ... but not enough to ease nursing faculty shortage. PMID- 20931718 TI - As the recession recedes. Data show extent of the damage, but the public safety net has done its job. PMID- 20931719 TI - Prevention through intervention. Programs use training, patient education to help head off suicide attempts. PMID- 20931720 TI - Kaiser tries to explain it all for you with new site. PMID- 20931721 TI - Endovascular repair of abdominal aortic aneurysm. PMID- 20931722 TI - Endovascular repair of abdominal aortic aneurysm. PMID- 20931723 TI - Hospital-acquired infections due to gram-negative bacteria. PMID- 20931724 TI - CardioPulse. Climbing the academic ladder in the UK is structured to ensure that trainees learn everything within the cardiology curriculum and yet still have time for research. PMID- 20931726 TI - CardioPulse. Company success stories: Medtronic: From a garage workshop to a billion-dollar enterprise. AB - Freelance medical journalist, Emma Wilkinson, MA, talks to Rob ten Hoedt, vice president of Medtronic's cardiovascular business in Western Europe, about the growth of the world's largest medical device company. PMID- 20931727 TI - Charges billed to third parties for prescription drugs furnished by VA to a veteran for a nonservice-connected disability. Final rule. AB - This document amends the medical regulations of the Department of Veterans Affairs (VA) concerning ''reasonable charges'' for medical care or services provided or furnished by VA to a veteran for a nonservice-connected disability. More specifically, VA amends the regulations regarding charges billed for prescription drugs not administered during treatment by changing the billing formula to reflect VA's actual drug costs for each drug rather than using a national average drug cost for all prescriptions dispensed. The revised formula for calculating reasonable charges for prescription drug costs will also continue to include an average administrative cost for each prescription. The purpose is to provide VA with a more accurate billing methodology for prescription drugs. PMID- 20931728 TI - [History of combined modality therapy for esophageal cancer in Japan]. PMID- 20931729 TI - [Endoscopic surgical procedures for gastric cancer-EMR and ESD-]. PMID- 20931730 TI - [Current topics on molecular targeting drugs for gastric cancer]. PMID- 20931731 TI - [Itching behind the eyelid]. PMID- 20931732 TI - Recent case developments in health law. "Willful modulation of brain activity in disorders of consciousness": legal and ethical ramifications. PMID- 20931733 TI - [Rosiglitazone]. PMID- 20931734 TI - [Should functional disorders be treated in psychiatric services?]. PMID- 20931735 TI - [Depression and fatigue in chronic disease]. PMID- 20931736 TI - Oncologic drugs advisory committee recommends withdrawing approval for bevacizumab use in breast cancer treatment. PMID- 20931737 TI - Young adults and the Affordable Care Act of 2010. AB - The Patient Protection and Affordable Care Act includes several provisions that promise to stem the rapidly rising tide of uninsured young adults, one of the largest uninsured segments of the population. These include the ability to enroll in a parent's health plan up to age 26, beginning in September 2010; significant expansion in eligibility for Medicaid, beginning in 2014; and the creation of health insurance exchanges with subsidized private insurance for people with low and moderate incomes, also beginning in 2014. Of the 14.8 million uninsured young adults, up to 12.1 million may gain subsidized insurance once all the law's provisions go into effect in 2014: 7.2 million may gain coverage under Medicaid and 4.9 million may gain subsidized private coverage through the insurance exchanges. In addition, about 1 million uninsured young adults are expected to join their parents' policies over the next three years. PMID- 20931738 TI - The long and winding road to clinical success in gene therapy. PMID- 20931739 TI - Paul Dudley White: "Our Hearts Were Young and Gay". PMID- 20931740 TI - Young policies to an elder population: challenges for the Health Sector. PMID- 20931741 TI - Clinical practice. PMID- 20931742 TI - [Long non-coding RNA and inhibition of the immune system]. PMID- 20931743 TI - Chemotherapy-related delayed bilateral spontaneous pneumothorax and lung fibrosis: methotrexate or cyclophosphamide, or both? PMID- 20931744 TI - Acute respiratory distress following intravenous injection of trichloroethylene. PMID- 20931745 TI - Subcutaneous emphysema of the lower eyelid as a complication of nasal continuous positive airway pressure. PMID- 20931746 TI - Complementary and alternative medicine. PMID- 20931747 TI - Patient information about options for treatment: Methods of a national audit of information provision in chronic kidney disease. AB - The new CARI guidelines for 'Acceptance onto dialysis' suggest patients with chronic kidney disease are referred to a nephrologist at an estimated glomerular filtration rate of <30 ml/min per 1.73 m2, to allow 3-6 months for pre-dialysis education, creation of dialysis access, and planned initiation of renal replacement therapy or conservative management. Similarly, international guidelines recommend education for patients and their families occurs 6 to 12 months prior to the predicted onset of end stage kidney disease or during Stage 4 or Stage 5 chronic kidney disease. However, some patients commencing treatment may not receive information about their options at a time that facilitates effective and informed decision making or that enables consideration of treatment other than centre-based haemodialysis. Implementation of chronic kidney disease education guidelines has not been widely reported and there are few published studies that assess the provision and delivery of information about all treatment options. Patient INformation about Options for Treatment (PINOT) is a prospective national audit of the type and timing of information provided by renal units to incident pre-emptive transplant, dialysis and conservatively managed patients over a 3-month period. PINOT will assess the patient and unit characteristics associated with timely information provision and highlight any regional variation in treatments offered. PMID- 20931748 TI - Anti-inflammatory treatment for post-diarrhoeal haemolytic-uraemic syndrome with central nervous system involvement. PMID- 20931749 TI - End-stage kidney disease after mushroom poisoning and abo-incompatible liver transplantation. PMID- 20931750 TI - Transhepatic placement of haemodialysis catheter: A solution for vascular access exhaustion. PMID- 20931752 TI - [Strategy of molecular drug design: activity and druggability]. AB - Intrinsic activity and druggability represent two essences of innovative drugs. Activity is the fundamental and core virtue of a drug, whereas druggability is essential to translate activity to therapeutic usefulness. Activity and druggability are interconnected natures residing in molecular structure. The pharmaceutical, pharmacokinetic and pharmacodynamic phases in vivo can be conceived as an overall exhibition of activity and druggability. Druggability actually involves all properties, except for intrinsic activity, of a drug. It embraces physico-chemical, bio-chemical, pharmacokinetic and toxicological characteristics, which are intertwined properties determining the attributes and behaviors of a drug in different aspects. Activity and druggability of a drug are endowed in the chemical structure and reflected in the microscopic structure and macroscopic property of a drug molecule. The lead optimization implicates molecular manipulation in multidimensional space covering activity, physicochemistry, biochemistry, pharmacokinetics and safety, and embodies abundant contents of medicinal chemistry. PMID- 20931753 TI - [The action of p38 MAP kinase and its inhibitors on endometriosis]. AB - Endometriosis, an oestrogen-dependent disorder, is related to inflammation, p38 Mitogen activated protein kinases (p38 MAPK) can be activated by sex hormone and inflammatory factors, which plays an important role in many cellular reactions such as apoptosis, proliferation, inflammation and stresses, etc. Many studies showed that p38 MAPK was participated directly in regulating the pathogenesis of endometriosis. The special regulatory action of p38 MAPK on sex hormone and inflammation may help us to understand the intricate endometriosis pathological hypothesis. p38 MAPK inhibitors play a key role in the the study of endometriosis, and show great promise for the future. Blocking and regulating the expression of p38 MAPK on the signal transduction pathway level may hope to be a new strategy to prevent and treat endometriosis. PMID- 20931754 TI - [Theory of selectivity of RP-LC C18 column and its application]. AB - In recent years, more and more researchers focus on the selectivity of RP-HPLC columns. Among these columns, C18 column is the most commonly used the column. Yet even the same filler can not give us the same separation effect with the columns of different brands and different types, therefore, it is important to choose the suitable HPLC column for carrying out an experiment. After study in recent years, some column classification, selection methods (e.g.: column parameter method, F value method) have been achieved and contributed to the finding of suitable columns and reducing the blindness of column selection. This paper summarizes the advantages of these methods and their limitations in the application process, and gives some advice and expectations to pharmaceutical analysis works based on the works of other researchers. PMID- 20931755 TI - [Advances in the study of polymeric micelles used in oral administration]. AB - Polymeric micelles which are self-assembled from amphiphilic copolymers are thermodynamically stable, and they can solubilize hydrophobic drugs by the hydrophilic core. Many excellent active compounds are confined because of general low oral bioavailability due to poor solubility. Take into account from the two points above, polymeric micelles may be used as proper oral carrier to improve the dissolubility of hydrophobic drugs, and enhance the permeation though gastrointestinal tract, therefore, the pharmacodynamics is elevated. Meanwhile, the segments in copolymers are multivariate, so many kinds of micelles can be obtained, such as, pH- or thermo- sensitive as well as mucoadhesive ones. The modified micelles can alter drug release profiles while solubilizing them, that is why the oral bioavailability increase further. In this review, recent progress of polymeric micelles used in oral administration is summarized, and the prospect of polymeric micelles' application in this field is also evaluated. PMID- 20931756 TI - [Effects of oligomeric grape seed proanthocyanidins on isoproterenol-induced cardiac remodeling in rats]. AB - The purpose of this study is to evaluate the effect of oligomeric grape seed proanthocyanidins (GSP) on isoproterenol (ISO)-induced cardiac remodeling in rats. ISO was given subcutaneously (5 mg x kg(-1), sc, 7 days) to induce cardiac remodeling in rats. Therapeutic groups were given GSP (50, 100, and 150 mg x kg( 1)) after ISO treatment. After 2 weeks intervention, heart rate (HR), left ventricular systolic pressure (LVSP), left ventricular end-diastolic pressure (LVEDP), rate of rise of left ventricular pressure (+/- dp/dt(max)) were examined. The myocardial hypertrophy index was expressed as heart weight/body weight (HW/BW) and left ventricle weight/body weight (LVW/BW), the histological changes were investigated by HE and Van Gieson stain. SOD activity and MDA content in serum, contents of hydroxyproline (Hyp) in the left ventricular tissue were assayed by xanthinoxidase method, thiobarbituric acid (TBA) method and alkaline hydrolysis method, respectively. After the onset of ISO-treatment, GSP therapy potently improved cardiac function, inhibited myocardial hypertrophy, improved cardiac pathology change, decreased the myocardial cross-section area (CSA), collagen volume fraction (CVF) and perivascular circumferential collagen area (PVCA), reduced the content of Hyp in the left ventricular tissue, inhibited the decrease of SOD activity and increase of MDA content in serum. GSP possess protective effect against ISO induced cardiac remodeling in rats, this may be related to reducing the oxidative stress and improving antioxidant capacity. PMID- 20931757 TI - [Comparison of the antitumor activities of immunoconjugates composed of lidamycin and monoclonal antibody fab' fragment with different linkers]. AB - To investigate the antitumor activities of the immunoconjugates composed of anti type IV collagenase monoclonal antibody Fab' fragment and lidamycin (LDM) prepared with different linkers. The immunoconjugates were prepared by linking Fab' to lysine-69 of LDM apoprotein by SPDP, LCSPDP, SMBS or SSMPB as the intermediate drug linkers. Immunoreactivities of the conjugates were determined by ELISA. The cytotoxicities of the conjugates were examined by clonogenic assay. In vivo antitumor effects of the conjugates were evaluated in nude mice bearing subcutaneously implanted HT-1080 tumor. ELISA assay showed that the conjugates retained part of the immunoreactivity of 3G11 against the antigen. The cytotoxicities of the Fab'-SMBS-LDM and Fab'-SSMPB-LDM to HT-1080 cells were significantly potent, compared with Fab'-SPDP-LDM, Fab'-LCSPDP-LDM and free LDM. In animal models at the same condition, free LDM, Fab'-SPDP-LDM and Fab'-LCSPDP LDM inhibited the growth of HT-1080 tumor by 70.9%, 74.8% and 72.3%, while Fab' SMBS-LDM and Fab'-SSMPB-LDM reached 78.0% and 87.7%, respectively. The median survival time of the mice treated with free LDM, Fab'-SPDP-LDM and Fab'-LCSPDP LDM were prolonged by 71.9%, 82.2% and 107.5%, respectively, compared with that of untreated group. Whereas, the median survival time of Fab'-SMBS-LDM and Fab' SSMPB-LDM were prolonged by 145.2% and 165.8%, respectively, indicating that Fab' SSMPB-LDM was more effective than Fab'-SMBS-LDM in tumor suppression and life span prolongation. Fab'-SSMPB-LDM has more marked selective antitumor efficacy and lower toxicity, and might be a novel candidate for cancer therapy. PMID- 20931758 TI - [Silence of VEGFR2 expression mediated by PEI/siRNA complexes]. AB - The aim of this paper is to report the study on gene silencing efficiency of siRNA targeted against mouse VEGFR2 (siVEGFR2) in vitro mediated by polyethyleneimine (PEI) and its anti-tumor effect in vivo. CY3-labeled siRNA was compounded into PEI and transfected into MS1 cells. Confocal microscopy was used to image the subcellular distribution of siRNA in MS1 cells. Semi-quantitative RT PCR and Western blotting were used to evaluate VEGFR2 gene silencing induced by siVEGFR2/PEI complexes. A tumor-bearing nude mice model was established to compare the anti-tumor effect after delivered by local and systemic routes. siVEGFR2/PEI complex-transfected cells exhibited much fluorescence in cytoplasm with no evidence of nuclear accumulation. The expression levels of VEGFR2 mRNA and protein in PEI-transfected cells were significantly down-regulated compared with that in blank group, the silencing efficiency were 28.2% and 23.6% respectively. The tumor sizes in mice intratumorally injected with siVEGFR2/PEI complexes (189.429 +/- 17.562 mm3) were reduced definitely compared to that in mice injected with siVEGFR2/PEI complexes via vein route (315.507 +/- 20.491 mm3), or to saline groups (365.844 +/- 20.713 mm3). The study demonstrated that PEI could effectively transfect siRNA into cells and silence the VEGFR2 gene expression. Intratumoral delivery is more suitable for non-targeted modified PEI/siRNA complexes to inhibit the tumor growth in vivo. The present data lay a solid foundation to further study on the gene silencing mechanism for PEI medicated RNAi and its anti-tumor efficiency in vivo. PMID- 20931759 TI - [Binding capability of lidamycin apoprotein to human breast cancer detected by tissue microarrays]. AB - This study is to investigate the binding capability of lidamycin apoprotein (LDP), an enediyne-associated apoprotein of the chromoprotein antitumor antibiotic family, to human breast cancer and normal tissues, the correlation of LDP binding capability to human breast cancer tissues and the expression of tumor therapeutic targets such as VEGF and HER2. In this study, the binding capability of LDP to human breast cancer tissues was detected with tissue microarray. The correlation study of LDP binding capability to human breast tumor tissues and relevant therapeutic targets was performed on breast cancer tissue microarrays. Immunocytochemical examination was used to detect the binding capability of LDP to human breast carcinoma MCF-7 cells. As a result, tissue microarray showed that LDP staining of 73.2% (30/41) of breast cancer tissues was positive, whereas that of 48.3% (15/31) of the adjacent normal breast specimens was positive. The difference between the tumor and normal samples was significant (Chi2 = 4.63, P < 0.05). LDP immunoreactivity in breast cancer correlated significantly with the overexpression of VEGF and HER2 (P < 0.001 and < 0.01, r = 0.389 and 0.287, respectively). Determined with confocal immunofluorescent analysis, LDP showed the binding capability to mammary carcinoma MCF-7 cells. It is demonstrated that LDP can bind to human breast cancer tissues and there is significant difference between the breast cancer tissues and the corresponding normal tissues. Notably, the binding reactivity shows positive correlation with the expression of VEGF and HER2 in breast carcinoma tissues. The results imply that LDP may have a potential use as targeting drug carrier in the research and development of new anticancer therapeutics. This study may provide reference for drug combination of LDM and other therapeutic agents. PMID- 20931760 TI - [Characteristics of boningmycin induced cellular senescence of human tumor cells]. AB - Cellular senescence is one of the important steps against tumor. This study was to observe the characteristics of boningmycin induced senescence of human tumor cells. MIT method and clone formation assay were used to detect the growth inhibitory effect. Cellular senescence was detected with senescence-associated beta-galactosidase staining. Cell cycle distribution and accumulation of intracellular reactive oxygen species (ROS) were analyzed with flow cytometry. Protein expression was detected by Western blotting. The results showed that the growth-inhibitory effect of boningmycin was obviously stronger on human oral epithelial carcinoma KB cells than that on non-small cell lung cancer A549 cells. Comparison to the similar action of doxorubicin, that boningmycin induced the features of cellular senescence in both cell lines, its due to the arrest at G2/M phase and an increase of ROS level. The molecular senescence marker P21 increased significantly after boningmycin treatment at a dosage of 0.1 micromol x L(-1), whereas a higher concentration of it induced apoptosis. The results indicated that cellular senescence induced by boningmycin was one of its mechanisms in tumor suppression. PMID- 20931761 TI - [vWF improves secretion and activity of intein spliced BDD-FVIII]. AB - As synthesized by vascular endothelial cells and megakaryocytes, the von Willebrand factor (vWF) plays an important hemostatic role in the binding to and stabilizing blood coagulation factor VIII (FVIII) and preventing its enzymatic degradation. Our recent work demonstrated intein can efficiently ligate BDD-FVIII (B-domaim deleted FVIII) posttranslationally by protein trans-splicing after transfer of split BDD-FVIII gene by a dual-vector system. In this study we investigated the effect of vWF on secretion and activity of intein-ligated BDD FVIII. We observed the levels of full-length BDD-FVIII antigen secreted into culture supernatant by ELISA and their activity by Coatest assay after transfection of cultured 293 cells with intein-fused BDD-FVIII heavy- and light chain genes simultaneously with the vWF gene co-transfected. The data showed that the amount of full-length BDD-FVIII protein and their bioactivity in vWF gene co transfected cell supernatant were 235 +/- 21 ng x mL(-1) and 1.98 +/- 0.2 u x mL( 1), respectively, greater than that of non-vWF co-transfected cell (110 +/- 18) ng x mL(-1) and 1.10 +/- 0.15 u x nL(-1)) or just BDD-FVIII gene transfected control cell (131 +/- 25 ng x mL(-1) and 1.22 +/- 0.18 u x mL(-1)) indicating the benefit of vWF gene co-transfection in the secretion and activity of intein spliced BDD-FVIII protein. It provided evidence that vWF gene co-transfer may be useful to improve efficacy of gene therapy for hemophilia A in protein splicing based split FVIII gene transfer. PMID- 20931762 TI - [Three different drug interaction mathematical models used to evaluate the cytotoxicity of SAHA and arsenic trioxide in combination]. AB - To clarify the source of deviations of drug combination effects evaluated with different drug interaction mathematical models, the cytotoxicity of SAHA and arsenic trioxide and their combinations were observed in a series of human cancer cell lines and a normal cell line. The combined effects were evaluated with three drug interaction models: Loewe Additivity (LA), Bliss Independence (BI) and Chou's Median Effect Model. The evaluations with three different models were further compared with each other. We demonstrated that when dose-response curves were fitted with the same method, similar evaluated results for drug combinations would be derived with different models. The deviations of evaluated effects of drug combinations were attributed to different curve fitting methods used rather than the models themselves. The effects of drug combinations showed discrepancies on different cell lines, and at different combined drug concentrations on same cell line. PMID- 20931763 TI - [The characterization on the site of vindoline binding to human serum albumin]. AB - In this paper, the fluorogenic property of vindoline was exploited and, as a probe, used to analyze the interaction of vindoline with HSA by fluorescence and absorption spectra in combination with molecular modeling under a simulated physiological conditions. The evidences from synchronous fluorescence and absorption spectroscopes showed the effect of vindoline on the microenvironment around HSA in aqueous solution. Data obtained by the fluorescence spectroscopy indicated that binding of vindoline with HSA leads to dramatic enhancement of the fluorescence emission intensity. The binding constants and the number of binding sites between vindoline and HSA at different temperatures (303, 310 and 317 K) were calculated according to the data obtained from fluorescence titration. Molecular docking was performed to reveal the possible binding mode or mechanism and suggested that vindoline can bind strongly to HSA. It is considered that vindoline binds to HSA mainly by a hydrophobic interaction and there are four hydrogen bonds interactions between the drug and the residues Ala291, Arg222, Arg218 and Lys195, separately. Fluorescent displacement measurements confirmed that vindoline bind HSA on site II. The thermodynamic parameters obtained (the enthalpy change deltaH0 and the entropy change deltaS0 were calculated to be 10.30 kJ x mol(-1) and 79.98 J x mol(-1) x K(-1), respectively, according to the Van't Hoff equation) suggested that hydrophobic and electrostatic interaction is the predominant intermolecular forces stabilizing the complex. PMID- 20931764 TI - QSAR, docking studies and pharmacophore identification of phenylmethyl phenoxy propyl amino propanoic acid derivatives as leukotriene A4 hydrolase inhibitors. AB - The enzyme leukotriene A4 (LTA4) plays an important role as precursor of slow reactive substances as LTC4, LTD4, and LTE4. It is an attractive target for molecular modeling and QSAR study. Our effort is mainly focused on exploring the SAR for inhibitors of the LTA4 hydrolase through docking study, pharmacophore modeling and molecular descriptor study. The binding of these small molecules on LTA4 hydrolase enzyme was described by the models developed on 2D molecular descriptors, with good predictive power (39 compounds, 6 descriptors, r2 0.98, SEE 0.167, F-value 268.53, q2 0.90, r2 adj 0.97, P-value < 0.0001, SD of residuals 0.15). Docking studies were employed to presume the probable binding conformation of these analogues and exploring the SAR for the compounds. The novel pharmacophore represents the ligand features that are involved in interactions with the target protein, as well as the space around the ligand occupied by the protein. The efforts are aimed to discover the SAR for the inhibitors of LTA4 hydrolase through techniques of QSAR, docking and pharmacophore. PMID- 20931765 TI - Sulfur-containing amides from Entada phaseoloides. AB - To study the chemical constituents of the Entada phaseoloides (L.) Merr., seeds of Entada phaseoloides were extracted with 70% ethanol at room temperature. Isolation and purification were performed by silica gel, reversed-phase silica gel column chromatography and semi-preparative HPLC. Structures of the pure compounds were established on the basis of spectral analysis. Four sulfur containing amide compounds were isolated from the n-BuOH-soluble fraction and identified as entadamide A-beta-D-glucopyranosyl-(1-->3)-beta-D-glucopyranoside (1), entadamide A (2), entadamide A-beta-D-glucopyranoside (3) and clinacoside C (4). Compound 1 is a new compound. Compound 4 is isolated from the genus Entada for the first time. PMID- 20931766 TI - [LC-MSn analysis of metabolites of 1,2-[bis (1,2-benzisoselenazolone-3(2H) ketone)]-ethane, a novel anti-cancer agent in rat]. AB - This study is to elucidate the metabolic pathway of 1,2-[bis (1,2 benzisoselenazolone-3 (2H)-ketone)]-ethane (BBSKE) in rats. Rats were administrated with a single dose of BBSKE 200 mg x kg(-1). The metabolites in rat urine, feces, bile and plasma were identified by LC-MSn analysis. The characterization of fragment ions from LC-MSn chromatography and mass spectrometry was applied to the investigation of structures of metabolites. Three phase I metabolites were detected in rat urine and feces. Two of them were also found in plasma and one existed in bile. These products were derived from oxidized, methylated and S-methylated BBSKE, separately. One phase II glucuronide of BBSKE was also found in bile. Therefore, it is possible that BBSKE was metabolized by oxidization, methylation and glucuronidation. PMID- 20931767 TI - [Internal standard method to determine the recovery of nicotine in microdialysis]. AB - The paper reports the evaluation of the feasibility of using internal standard method for the determination of nicotine recovery in microdialysis in vitro. This in vitro experiment included two conditions. Nicotine and codeine phosphate were dissolved in Ringer's solution. Nicotine, codeine phosphate and the mixture of them were perfused through the CMA30 linear probe separately to calculate the proportion of the recovery (or delivery) of nicotine to that of codeine phosphate. And then codeine was perfused through the probe which was immersed in nicotine solution with different concentrations to calculate the proportion, too. In another condition nicotine was dissolved in rat plasma. The rat plasma protein binding rate was determined by using retrodialysis and internal standard method in vitro. The results are as follows: the proportion of the recovery (or delivery) of nicotine to that of codeine phosphate was fairly stable. The delivery of codeine was independent of nicotine concentration in the external medium. Protein binding rate determined by retrodialysis was almost the same as that determined by internal standard method. It suggests that the internal standard method is an effective way in the determination of nicotine recovery and codeine phosphate can be used as the internal standard. PMID- 20931768 TI - [Pharmacokinetics of ginsenosides Rg1 and its metabolites in rats]. AB - To study the pharmacokinetics of ginsenosides Rg1 and its metabolites after iv and oral administration in Wistar rats, the LC-MS/MS method was selected to determine ginsenosides Rg1 and its metabolites in plasma and their pharmacokinetic parameters were calculated. After oral administration of ginsenosides Rg1 to rats, ginsenosides Rg1, Rh1, F1 and protopanaxatriol (Ppt) could be detected in plasma. Their Tmax were 0.92, 3.64, 5.17, and 7.30 h, respectively; MRT were 2.68, 5.06, 6.65, and 5.33 h, respectively; AUC(o-t), were 2 363.5, 4 185.5, 3 774.3, and 396.2 ng x mL(-1) x h, respectively. After iv administration of ginsenosides Rg1 to rats, ginsenosides Rg1, Rh1 and FI could be detected in plasma. Their T1/2betaS were 3.12, 5.87, and 6.87 h, respectively; MRTs were 1.92, 5.99, and 7.13 h, respectively; AUCo-tS were 1 454.7, 597.5, and 805.6 ng x mL(-1) x h, respectively. So, it can be concluded that after oral administration, the amounts of metabolites were higher than the prototype in vivo, and the distribution and elimination of the metabolites were relatively slow. After iv administration, the amount of prototype were higher than that of the metabolites in vivo, and the distribution and elimination of the metabolites were relatively slow. PMID- 20931769 TI - [Identification of main related substances in potassium sodium dehydroandrographolide succinate]. AB - To identify the structure of three related substances in potassium sodium dehydroandrographolide succinate (PSDS), an HPLC preparation method was used to separate the impurities. These main impurities were identified using LC ESI/TOFMS, LC-ESI/MSn, NMR, UV and IR. One of the main impurities was a hydrolyzed and oxidized product of PSDS, which has not been reported previouely. The other two impurities were hydrolyzed products of PSDS after losing different succinic acids. The results indicate that PSDS can be easily hydrolyzed and oxidized. It should be stored at cool and dry places. PMID- 20931770 TI - Using extended Wilson model to study the relationship between critical relative humidity and solubility of electrolytes. AB - Based on thermodynamic principle, the critical relative humidity of electrolytes is closely related to their solubility. The authors explored the relationship theoretically and calculated critical relative humidity of 21 electrolytes from their solubility in the light of Raoult's law and extended Wilson model. The results indicate that the critical relative humidity values calculated by Raoult's law can not accord with the reported ones and there is a systematic error in the high concentration range; while these calculated by extended Wilson model are comparable to the reported ones. PMID- 20931771 TI - [Intestinal absorption of the effective components of Schisandra chinensis Baill by rats single-pass perfusion in situ]. AB - The aim of the study is to investigate rat intestinal absorption behavior of three main active components, schisandrol A, schisandrin A and schisandrin B in Schisandra chinensis Baill extracts in intestine of rats. With phenol red as the indicator, in situ single pass intestinal perfusion (SPIP) model was used and the concentrations of three main active components in perfusion solution of different intestinal segments (duodenum, jejunum, ileum, and colon) were determined by HPLC in combination with diode array detection. The results showed that the absorption rate constant (Ka) and effective permeability values (Peff) of three main active components in Schisandra chinensis Baill extracts had significant difference (P < 0.05) at different concentrations of perfusion solution, the Ka and Peff first increased and then decreased with the increase of drug concentration, the middle concentration was higher than those of the other two concentrations. The saturate absorption phenomena were observed, and it suggested that the transport mechanisms of three main active components in vivo were similar to active transport or facilitated diffusion. Three active components can be well absorbed in all of the intestinal segments, while duodenum is the best absorption region. The Ka and Peff of three active components in jejunum and ileum had no significant difference (P > 0.05). The absorption of the three active components displayed significant difference (P < 0.05) at different intestinal segments of rats. Schisandrin A had the best absorption in duodenum. The Ka and Peff among three active components were sequenced as follows: schisandrin A > schisandrin B > schisandrol A in other intestinal segments, and there is significant difference (P < 0.05) between them. PMID- 20931772 TI - [Gene transfer system mediated by PEI-cholesterol lipopolymer with lipid microbubbles]. AB - The properties of polyethyleneimine-cholesterol cationic lipopolymer (PEI-Chol) as gene carries and its gene transfer efficiency in vitro with lipid microbubbles were presented in this paper. PEI-Chol lipopolymer was synthesized by linking cholesterol chloroformate to the amino groups of branched poly(ethyleneimine) (PEI) of 1 800. The structure and molecular weight of PEI-Chol were confirmed by IR, 1H NMR and MADI-TOF-MS (matrix-assisted laser desorption/ionization time-of flight tandem mass spectrometry), respectively. The average molecular weight of PEI-Chol was approximately 2 000. The gene delivery system of bubble/PEI-Chol/DNA was constructed by mixed PEI-Chol/pDNA (N/P 10:1) complexes with lipid microbubbles (2-8 microm) which were prepared by DPPC, DSPE-PEG2000 and perfluoropropane with the reverse phase evaporation technique. pEGFP-Cl (enhanced green fluorescent protein) was used as report gene to investigate the DNA condensing ability of PEI-Chol lipopolymer by agarose gel electrophoresis. And their cytotoxicity and in vitro transfer efficiency of different complexes were compared with each other in A549 and MCF-7. The results indicated PEI-Chol lipopolymer can condense plasmid DNA when N/P ratio upto 4, PEI-Chol complexes and bubble/PEI-Chol/DNA complexes were nontoxic to A549 and MCF-7 when formulated at the N/P ratio of 10/1 as determined by MTT assay. This bubble/PEI-Chol/DNA delivery system provided good transfer efficiency with other desirable characteristics such as against-precipitation of plasma proteins. In conclusion, bubble/PEI-Chol/DNA complex is a novel non-viral gene delivery system. PMID- 20931773 TI - [Development of microsatellites of Dendrobium officinale and its application in purity identification of germplasm]. AB - Simple sequence repeat (SSR) was used to investigate the genetic diversity and structure of Dendrobium officinale. A total of 15 primer pairs with stable and repeatable polymorphism were screened out from 60 SSR primer pairs developed by the method of microsatellite enrichment by magnetic beads. Forty-eight samples of Dendrobium officinale were analyzed in genetic polymorphism. These loci were polymorphic and displayed 3 to 9 alleles per locus with a mean number of 6.1. The observed and expected heterozygosities ranged from 0.60 to 0.85 and from 0.49 to 0.85 respectively. The polymorphic information content (PIC) of each SSR locus varied from 0.437 to 0.829 with an average of 0.702. Fifteen primer pairs were used in Dendrobium cross-species amplification and totally 13 primer pairs were proved to have the transferability in D. officinale related species. In addition, 500 tissue culture plantlets of D. officinale were tested for purity identification by means of PCR amplification with four SSR primer pairs. The results showed that SSR technique is a feasible, simple and inexpensive method for determining adulterants in germplasm identification. PMID- 20931774 TI - [A quantitation method for andrographolide and dehydroandrographolide by X-ray powder diffraction Fourier fingerprint pattern technique]. AB - The powder X-ray diffraction Fourier fingerprint pattern technique was used to develop a new quantitation method for the analysis of andrographolide and dehydroandrographolide. And the high performance liquid chromatography method was used to evaluate the quantity of andrographolide and dehydroandrographolide. The relationship of diffraction peak intensity and content of andrographolide and dehydroandrographolide was investigated. The powder X-ray diffraction Fourier fingerprint pattern analysis technique can be used to evaluate the quantity of andrographolide and dehydroandrographolide in the herb simultaneously. PMID- 20931775 TI - [Strategies of the study on herb genome program]. AB - Herb Genome Program (HerbGP) includes a series of projects on whole genome sequencing (WGS) and post-genomics research of medicinal plants with unique secondary metabolism pathways or/and those of great medical and pharmaceutical importance. In this paper, we systematically discussed the strategy of HerbGP, from species selection, whole-genome sequencing, assembly and bioinformatics analysis, to postgenomics research. HerbGP will push study on Chinese traditional medicines into the front field of life science, by selecting a series of plants with unique secondary metabolism pathways as models and introducing "omics" methods into the research of these medicinal plants. HerbGP will provide great opportunities for China to be the leader in the basic research field of traditional Chinese medicine. HerbGP shall also have significant impacts on the R&D of natural medicines and the development of medicinal farming by analysis of secondary metabolic pathways and selection of cultivars with good agricultural traits. PMID- 20931776 TI - [Progress in the study of heat shock protein 90 inhibitors]. AB - Heat shock protein 90 is a new target of antitumor drug, the inhibitor of Hsp90 fight against tumor by destroy and degrade the structure of protein. In recent years, looking for Hsp90 inhibitor is not only via structure modifying of natural products, but also via high throughput screening and computer aided drug design to find and synthesize new kinds of Hsp90 inhibitor. Anyway, Hsp90 inhibitor has considered as an important biology target and to pay more and more attention. This review describes recent developments of small molecule Hsp90 inhibitors. PMID- 20931777 TI - [Advances in the study of Candida albicans gene mutation on azole drug resistance]. AB - Gene mutation of Candida albicans is one of the main causes for azole drug resistance. Different types of variation play different roles in promoting the process of drug resistance. ERG series of gene mutations primarily affect the ergosterol synthesis pathway. When the regulatory factors TAC1 for CDR1 gene and Mrr1 for MDR1 gene generate mutations, the expression level of drug efflux pump protein in Candida albicans may be changed. In addition, gene copy number variation is also gaining attention. Therefore, the research of mutation resistance-associated genes has a positive meaning to explore the mechanism of drug resistance in Candida albicans. PMID- 20931778 TI - [Mechanisms and strategies for targeting drugs to myocardial ischemic regions]. AB - The ischemic heart disease has been endangering human health seriously. Although there are many kinds of anti-ischemic drugs, most of them are lacking in tissue specificity, which together with a remarkably reduced blood circulation in the ischemic zone often lead to a quite low drug distribution in the targets. Myocardial ischemia can cause a lot of pathophysiological changes, such as the enhanced permeability of the endothelial cell membrane, the up-regulated expression of various cell adhesion molecules on endothelium, the exposure of intracellular antigenic components, the decrease of pH within the ischemic zone, and so on. To date, some of these changes have been exploited with limited success to gain the passive, active and physicochemical targeting of diagnostic or therapeutic drugs to myocardial ischemic regions. However, more effective delivery strategies are still eagerly needed. Here, we reviewed and discussed the potential targeting-delivery mechanisms and strategies, used or may be used in the future, for myocardial ischemic regions. PMID- 20931779 TI - [Effects of alcohol exposure during pregnancy on dendritic spine and synapse of visual cortex in filial mice]. AB - The prenatal ethanol exposure induced the alterations of dendritic spine and synapse in visual cortex and their long-term effect would be investigated in mice from P0 to P30. Pregnant mice were intubated ethanol daily from E5 through the pup's birth to establish mode of prenatal alcohol abuse. The dendritic spines of pyramidal cells in visual cortex of pups were labeled with DiI diolistic assay, and the synaptic ultrastructure was observed under transmission electron microscope. Prenatal alcohol exposure was associated with a significant decrease in the number of dendritic spines of pyramidal neurons in the visual cortex and an increase in their mean length; ultrastructural changes were also observed, with decreased numbers of synaptic vesicles, narrowing of the synaptic cleft and thickening of the postsynaptic density compared to controls. Prenatal alcohol exposure is associated with long-term changes in dendritic spines and synaptic ultrastructure. The changes were dose-dependent with long term effect even at postnatal 30. PMID- 20931780 TI - Protective effect of edaravone against renal ischemia/reperfusion injury and compared with ischemic postconditioning in rats. AB - The aim of this study is to clarify whether edaravone postconditioning had protective effect against renal ischemia/reperfusion injury and to compare the protective effect between ischemic postconditioning and edaravone postconditioning. Rats were subjected to 45 min ischemia followed by 24 h reperfusion. The rats were randomly assigned to seven groups: a sham-operated control group, an ischemia/reperfusion group, an ischemic postconditioning group, a normal saline vehicle postconditioning group and an edaravone postconditioning (1, 3, and 6 mg x kg(-1)) group. Renal function was assessed by serum creatinine and BUN concentration, while histological damage of renal tissue was assessed with HE staining. MDA content and SOD activity of renal tissue were determined. TUNEL staining was performed to analyze the apoptosis of the tubular epithelial cells, the protein level of Bcl-2 and Bax in renal tissue was examined by Western blotting. Compared to the ischemia/reperfusion group, edaravone postconditioning significantly decreased serum creatinine and BUN concentration, and ameliorated histological damage of renal tissue. MDA was less after 24 h reperfusion in the edaravone postconditioning group than that in the ischemia/reperfusion group, consistent with an increase in SOD activity. In addition, edaravone postconditioning decreased TUNEL-positive cells and Bax expression, and increased Bcl-2 expression. Results detected in the edaravone postconditioning group showed no significant difference from the ischemic postconditioning group. Edaravone administered during the last 3 min of ischemia, prior to reperfusion induces a pharmacological postconditioning in vivo against renal ischemia/reperfusion injury in rats. This protection is similar to that observed with ischemic postconditioning. PMID- 20931781 TI - [Effect of ketamine on transient outward potassium current of isolated human atrial myocytes]. AB - The effects of ketamine on transient outward potassium current (I(to)) of isolated human atrial myocytes were investigated to understand the mechanism of part of its effects by whole-cell patch-clamp. Atrial myocytes were enzymatically isolated from specimens of human atrial appendage obtained from patients under going cardiac valve displacing. Ito is recorded in voltage-clamp modes using the patch-clamp technique at room temperature. Currents signals were recorded by an Axopatch 200B amplifier with the Digidata 1322A-pClamp 9.0 data acquisition system. Ketamine decreased I(to) of human atrial myocytes in a dose-dependent manner. The current-voltage curve was significantly lowered, 30, 100, 300, and 1000 micromol x L(-1) ketamine decreased respectively I(to) current density about (13.62 +/- 0.04)%, (38.92 +/- 0.05)%, (72.24 +/- 0.10)% and (83.84 +/- 0.05)% at the potential of 50 mV, with an IC50 of 121 micromol x L(-1). The I(to) activation curve, inactivation curve and the recovery curve were not altered by ketamine. So, ketamine concentration-dependently decreased I(to) of human atrial myocytes. PMID- 20931782 TI - [Involvement of Wnt/beta-catenin signaling in tripchlorolide protecting against oligomeric beta-amyloid-(1-42)-induced neuronal apoptosis]. AB - This study is to explore whether the Wnt/beta-catenin signaling pathway is involved in the process of tripchlorolide (T4) protecting against oligomeric Abeta(1-42)-induced neuronal apoptosis. Primary cultured cortical neurons were used for the experiments on day 6 or 7. The oligomeric Abeta(1-42) (5 micromol x L(-1) for 24 h) was applied to induce neuronal apoptosis. Prior to treatment with Abeta(1-42) for 24 h, the cultured neurons were pre-incubated with T4 (2.5, 10, and 40 nmol x L(-1)), Wnt3a (Wnt signaling agonists) and Dkk1 (inhibitors) for indicated time. Then the cell viability, neuronal apoptosis, and protein levels of Wnt, glycogen synthase kinase 3beta (GSK3beta), beta-catenin and phospho-beta catenin were measured by MTT assay, TUNEL staining and Western blotting, respectively. The result demonstrated that oligomeric Abeta(1-42) induced apoptotic neuronal cell death in a time- and dose-dependent manner. Pretreatment with T4 significantly increased the neuronal cell survival and attenuated neuronal apoptosis. Moreover, oligomeric Abeta(1-42)-induced phosphorylation of beta-catenin and GSK3beta was markedly inhibited by T4. Additionally, T4 stabilized cytoplasmic beta-catenin. These results indicate that tripchlorolide protects against the neurotoxicity of Abeta by regulating Wnt/beta-catenin signaling pathway. This may provide insight into the clinical application of tripchlorolide to Alzheimer's disease. PMID- 20931783 TI - Synthesis and in vitro antibacterial activity of 7-(4-alkoxyimino-3-methyl-3 methylaminopiperidin-1-yl)quinolones. AB - To explore new agents of quinolone derivatives with high antibacterial activity, 7-(4-alkoxyimino-3-methyl-3-methylaminopiperidin-1-yl)quinolones were designed and synthesized, and their activity against gram-positive and gram-negative strains was tested in vitro. Sixteen target compounds were obtained. Their structures were established by 1H NMR, HRMS and X-ray crystallographic analysis. Compounds 14k and 14m-14o show good antibacterial activity against the tested five gram-positive strains and five gram-negative strains (MIC: 0.25-16 micromg x mL(-1)), of which the most active compound 14o is 8-fold more potent than levofloxacin against S. pneumoniae (MIC: 4 microg x mL(-1)), and comparable to levofloxacin against S. aureus, S. epidermidis, E. faecalis and E. coli (MIC: 0.25-1 microg x mL(-1)), but generally less potent than gemifloxacin. PMID- 20931784 TI - [Design, synthesis and antidepressive activity of duloxetine derivatives]. AB - In this paper, duloxetine was chosen as the lead compound. The pharmacophores with 5-HT(1A) antagonism activity were used to replace the naphthyl of duloxetine. A series of duloxetine derivatives had been designed and synthesized and whose structures were confirmed with elemental analysis, MS and H NMR. All synthesized compounds were tested by tail suspension test and forced swimming test in vivo. The test results revealed that most of the compounds have shown better activity than duloxetine at the same dosage. Some of them are worth to be studied further. PMID- 20931785 TI - [Two new phenolic acids from Drynariae rhizoma]. AB - To study the chemical constituents of Drynariae Rhizoma, nine phenolic acids were isolated from a 70% ethanol extract by using a combination of various chromatographic techniques including column chromatography over silica gel, ODS, Sephadex LH-20, and semi-preparative HPLC. By spectroscopic techniques including 1H NMR, 13C NMR, 2D NMR, and HR-ESI-MS, these compounds were identified as 4, 4' dihydroxy-3, 3'-imino-di-benzoic acid (1), protocatechuic acid (2), gallic acid (3), p-hydroxybenzoic acid (4), (E)-caffeic acid (5), ethyl trans-3, 4 dihydroxycinnamate (6), caffeic acid 4-O-beta-D-glucopyranoside (7), p-coumaric acid 4-O-beta-D-glucopyranoside (8), and 23(S)-12-O-caffeoyl-12-hydroxyllauric acid glycerol ester (9), separately. Among them, 1 and 9 are new compounds, and 3, 4, and 6 were isolated from Drynaria species for the first time. PMID- 20931786 TI - A new phenylpropanoid glycoside from Cirsium setosum. AB - To study the chemical constituents of Cirsium setosum (Willd.) MB., 70% ethanol extract of the aerial parts was subjected to column chromatography. One new phenylpropanoid glycoside, sinapyl alcohol 9-O-(E)-p-coumaroyl-4-O-beta-D glucopyanoside (1) was isolated, along with three known compounds: lycoperodine-1 (2), apigenin-7-O-(6"-(E)-p-coumaroyl)-beta-D-galactopyranoside (3) and quercetin (4). The structures were elucidated on the basis of spectral and chemical evidence. Compound 2 was obtained from Cirsium genus for the first time, compounds 3 and 4 were obtained from this plant for the first time. PMID- 20931787 TI - [Application of Fourier amplitude sensitivity test in Chinese healthy volunteer population pharmacokinetic model of tacrolimus]. AB - In this study, we evaluated the influence of different variance from each of the parameters on the output of tacrolimus population pharmacokinetic (PopPK) model in Chinese healthy volunteers, using Fourier amplitude sensitivity test (FAST). Besides, we estimated the index of sensitivity within whole course of blood sampling, designed different sampling times, and evaluated the quality of parameters' and the efficiency of prediction. It was observed that besides CL1/F, the index of sensitivity for all of the other four parameters (V1/F, V2/F, CL2/F and k(a)) in tacrolimus PopPK model showed relatively high level and changed fast with the time passing. With the increase of the variance of k(a), its indices of sensitivity increased obviously, associated with significant decrease in sensitivity index for the other parameters, and obvious change in peak time as well. According to the simulation of NONMEM and the comparison among different fitting results, we found that the sampling time points designed according to FAST surpassed the other time points. It suggests that FAST can access the sensitivities of model parameters effectively, and assist the design of clinical sampling times and the construction of PopPK model. PMID- 20931788 TI - [Simultaneous determination of peimine and peiminine in rat plasma by LC-MS/MS and its application in the pharmacokinetic study]. AB - To establish an LC-MS/MS method for simultaneous determination of peimine and peiminine in rat plasma after oral and intravenous administration of Fritillaria thunbergii Miq. extract, the pharmacokinetic parameters were calculated as well. Peimine, peiminine and internal standard carbamazepine were extracted from plasma with liquid-liquid extraction by ethyl acetate, then separated on a Luna C18 column by using acetonitrile-water containing 10 mmol x L(-1) ammonium formate (35:65), as mobile phase. The electrospray ionization (ESI) source was applied and operated in positive ion mode. Peimine was detected at m/z 432.4 --> 414.4, peiminine at m/z 430.4 --> 412.4 and carbamazepine (IS) at 237.1 --> 194.2. The linear calibration curves were obtained at the concentration range of 0.8-800 ng x mL(-1) for peimine and peiminine. The extraction recoveries were 94.1%-105.3% and 85.8%-98.6%, respectively. The precisions, accuracy and stability of the analytes meet the requirements. The method was shown to be effective, convenient, and suitable for simultaneous pharmacokinetic study of peimine and peiminine in rat. PMID- 20931789 TI - [Multidimensional spatial triangular area as an index for the evaluation of the release-absorption correlation of multiple component traditional Chinese medicines]. AB - The paper is aimed to provide a novel index, named as multidimensional spatial triangular area, for the evaluation of the release-absorption correlation of multiple component traditional Chinese medicines (TCMs). The applicability of the method was demonstrated by the example data. The method and standard practice for evaluation of the release-absorption correlation for western medicines with single compound could not be applied to TCMs with multiple components. The release percentage or absorption percentage of the multiple components for TCMs at the sampling time was a point in the multidimensional space. The area of the triangle formed byt the sequential three points represented the changing characteristics of the components' release and absorption kinetics. The side lengths of the triangle could be calculated from the spatial distances between each two of the sequential three points. Then the triangle area could be obtained by the side lengths. The in vitro release-in vivo absorption correlation of the multiple components could be represented by the correlation between the integrating values of the release triangle areas and that of the absorption triangle areas. The results of the examples indicated that the multidimensional spatial triangular area method could treat the multiple components in a holistic way, in line with the holism the hi he TCMs. Therefore, the multidimensional spatial triangular area method provided new methodology for the release absorption correlation of the TCMs with multiple components. PMID- 20931790 TI - Disposition and tissue distribution of imatinib in a liposome formulation after intravenous bolus dose to mice. AB - Imatinib is an efficacious anticancer drug with a spectrum of potential antitumour applications limited by poor biodistribution at therapeutic concentrations to the tissues of interest. We assess the pharmacokinetic and tissue distribution profile of imatinib in a liposome formulation. Its single dose (6.25 mg x kg(-1)) in a liposome formulation was administered iv to male mice. Imatinib concentration was measured in plasma, spleen, liver, kidney and brain using a HPLC assay. Non-compartmental pharmacokinetic approach was used to assess the disposition parameters. The plasma disposition profile was biphasic with a plateau-like second phase. The AUC(0-->infinity) was 11.24 microg x h x mL(-1), the elimination rate constant (k(el)) was 0.348 h(-1) and the elimination half life (t(1/2)) was 2.0 h. The mean residence time (MRT) was 2.59 h, V(SS) was 1.44 L x kg(-1) and clearance was 0.56 L x h x kg(-1). Liver achieved the highest tissue exposure: CMAX = 18.72 microg x mL(-1); AUC(0-->infinity)= 58.18 microg x h x mL(-1) and longest t(1/2) (4.29 h) and MRT (5.31 h). Kidney and spleen AUC(0- >infinity) were 47.98 microg x h x mL(-1) and 23.46 microg x h x mL(-1), respectively. Half-life was 1.83 h for the kidney and 3.37 h for the spleen. Imatinib penetrated into the brain reaching approximately 1 microg x g(-1). Upon correction by organ blood flow the spleen showed the largest uptake efficiency. Liposomal imatinib presented extensive biodistribution. The drug uptake kinetics showed mechanism differences amongst the tissues. These findings encourage the development of novel imatinib formulations to treat other cancers. PMID- 20931791 TI - [Kinetic study on dissociation of amylose/salicylic acid compound using non isothermal method]. AB - The inclusion compound of amylose and salicylic acid (SA) was prepared by a sealed temperature control method, and the formation of the inclusion compound was confirmed by IR spectrum and powder X-ray diffraction. The kinetic parameters of dissociation of amylose/SA compound were studied by the nonisothermal method which was defined as a relationship between the dissociation ratio and time. The values of activation energy (Ea) and frequency factors (InA) were calculated by a nonlinear least-square method. In this study, the formation of the inclusion compound of amylose/SA was confirmed by IR spectrum powder X-ray diffraction. SA existed in a molecule form in the spiral stouction of amylose. The dissociation of amylose/SA compound was attributed to first order reaction. The values of Ea calculated by the nor-isothermal method were 21.71 and 22.41 kJ x mol(-1) at heating rate 5 and 10 degrees C x h(-1), respectively. The corresponding isothermal method value of Ea was 22.17 kJ x mol(-1); the calculated InA values were 9.32 and 10.08 at heating rate 5 and 10 degrees C x h(-1), respectively. The corresponding isothermal method lnA value was 9.26. The results were in good agreement with Ea values and lnA values by isothermal method. These results indicated that the non-isothermal method described in this study could be adequately used for the stability study of inclusion compound and was a rapid and accurate method for the determination of kinetic parameters. PMID- 20931792 TI - [Preparation of scopolamine hydrobromide nanoparticles-in-microsphere system]. AB - This study is to prepare scopolamine hydrobromide nanoparticles-in-microsphere system (SH-NiMS) and evaluate its drug release characteristics in vitro. SH nanoparticles were prepared by ionic crosslinking method with tripolyphosphate (TPP) as crosslinker and chitosan as carrier. Orthogonal design was used to optimize the formulation of SH nanoparticles, which took the property of encapsulation efficiency and drug loading as evaluation parameters. With HPMC as carrier, adjusted the parameters of spray drying technique and sprayed the SH nanoparticles in microspheres encaposulated by HPMC was formed and which is called nanoparticles-in-microsphere system (NiMS). SH-NiMS appearances were observed by SEM, structure was obsearved by FT-IR and the release characteristics in vitro were evaluated. The optimized formulation of SH nanoparticles was TPP/CS 1:3 (w/w), HPMC 0.3%, SH 0.2%. The solution peristaltic speed of the spray drying technique was adjusted to 15%, and the temperature of inlet was 110 degrees C. The encapsulation product yeild, drug loading and particle sizes of SH-NiMS were 94.2%, 20.4%, and 1256.5 nm, respectively. The appearances and the structure of SH-NiMS were good. The preparation method of SH-NiMS is stable and reliable to use, which provide a new way to develop new dosage form. PMID- 20931793 TI - [Synthesis of polyrotaxane-camptothecin conjugates and evaluation of its anti tumor effect]. AB - To prepare polyrotaxane-camptothecin conjugates and evaluate its anti-tumor effect, polyrotaxane-camptothecin conjugates were successfully synthesized, and the release behavior was performed; MTT assay and cell morphology were used to examine the inhibition of cells' proliferation effect in vitro. The experimental study of the antitumor effect on S180 mice in vivo was also performed to further evaluate the anti-tumor effect of conjugate. The result showed polyrotaxane camptothecin conjugates can effectively inhibit the proliferation in a dose dependent effect. In vivo study and cell morphology observation of S180 mice showed significant decrease in growth of tumor, degree of tumor infiltration and blood vessel number. The result indicated anti-tumor mechanism may be through affect the angiogenesis and reduced blood supply to tumor cells and then leading to necrosis. PMID- 20931794 TI - Authentication of Curcuma species (Zingiberaceae) based on nuclear 18S rDNA and plastid trnK sequences. AB - Curcuma drugs have been used discriminatingly for invigorating blood circulation, promoting digestion, and as a cholagogic in China. However, there is confusion about the drug's botanical origins and clinical uses because of morphological similarity of Curcuma plants and drugs. Comparative sequencing of the 18S rRNA gene in nuclear ribosomal DNA (rDNA) and trnK gene in chloroplast DNA (cpDNA) was carried out in order to examine interspecies phylogeny and to identify ultimately Curcuma species. A total of a hundred of accessions of eighteen species were analyzed. This resulted in an aligned matrix of 1810 bp for 18S rDNA and 2 800 bp for trnK. 18S rDNA sequence divergence within the ingroup ranged from 0-0.05%, trnK ranged from 0-0.19%. One base transversion-substituted site (from cytosine to thymine) was observed from the upstream of 18S rDNA at nucleotide position 234 in C. kwangsiensis and Japanese population of C. zedoaria which have separated genetic distance to other Curcuma taxa. Two noncoding regions embedded in trnK intron showed higher variability, including nucleotide substitutions, repeat insertion and deletions. Based on consensus of relationship, eighteen major lineages within Curcuma are recognized at the species level. The results suggest that Curcuma is monophyletic with 100% bootstrap support and sister to the genera Hedychium and Zingiber. The trnK sequences showed considerable variations between Curcuma species and thus were revealed as a promising candidate for barcoding of Curcuma species, which provide valuable characters for inferring relationship within species but are insufficient to resolve relationships among closely related taxa. PMID- 20931795 TI - In-silico study of 4-methylsulfinyl-3-butenyl isothiocyanate binding to tubulin induces A549 cells apoptosis. PMID- 20931796 TI - [Protective effect of hydroxysafflor yellow A against acute lung injury induced by oleic acid and lipopolysaccharide in rats]. AB - This study is to investigate the pharmacological effect and mechanism of action of hydroxysafflor yellow A (HSYA) on acute lung injury (ALI). The rat ALI was induced by oleic acid and lipopolysaccharide (LPS) injection. The incidence of acidosis, PaO2 (arterial blood oxygen pressure), W/D (wet weight/dry weight) and lung index (LI) were measured. Electron microscope and optical microscope were applied to observe lung morphological changes in rat. RT-PCR was used to determine TNF-alpha and ICAM-1 mRNA level. Inhibition effect of HSYA on plasma inflammatory cytokine expression was measured by ELISA. HSYA could alleviate pulmonary edema, reduce acidosis, keep PaO2 from descending, inhibit inflammatory cell infiltration, inhibit rat lung TNF-alpha and ICAM-1 mRNA expression and plasma IL-6 and IL-1beta level elevation. HSYA is an effective ingredient to remit ALI induced by oleic acid and LPS in rat. PMID- 20931797 TI - [Work report of the President of the Federacion Mexicana de Ginecologia y Obstetricia 2007-2009]. PMID- 20931798 TI - [Impact of office hysteroscopy in patients with a history of two or more failed cycles of IVF-ET and pre-ICSI in assisted an reproduction center]. AB - BACKGROUND: Many couples fail to achieve pregnancy instead repeated FIV-TE-ICSI cycles. Good quality embryos for successful pregnancy rates should not be count apart over endometrial receptivity. OBJECTIVE: To assess the impact of office hysteroscopy in a group of patients with two or more previous failed cycles of FIV-TE-ICSI in an assisted reproduction center. MATERIAL AND METHOD: Retrospective case control study in patients with problems to conceive in two or more previous failed FIV-TE-ICSI cycles instead good quality embryos and an apparently normal uterine cavity. They were divided in two groups: A with no hysteroscopy perfomed, and 8 with hysteroscopy. Second group was divided in 81 (without pathologic findings) and 82 (with intrauterine abnormalities). Demographic variables were analized, hysteroscopic findings, good quality embryos transferred, biochemical and clinical pregnancies and perinatal results in all groups. RESULTS: No significant differences were found in demographic variables analyzed among patient with or without office hysteroscopy. Intrauterine abnormalities were found in 16 (64%) patients of group 82. No significant statistical differences were found respect biochemical, clinical pregnancies or live birth new born. CONCLUSIONS: Instead previous diagnosis of an apparently normal uterine cavity, pathologic abnormalities were found in a significant number of patients. We observed an improvement in pregnancy rates in patients in with HC was realized previous to FIV-TE-ICSI, particularly on those were endometrial pathology was found and corrected, even though the study sample did not allowed to reach results with statistical difference. PMID- 20931799 TI - [Differing response to GnRH antagonists in cycles of ovarian hyperstimulation plus intrauterine insemination]. AB - OBJECTIVE: To compare two flexible protocols of GnRHant in OH plus IUI vs a control group without GnRHant. MATERIALS AND METHODS: Randomized controlled trial 90 infertile patients were analyzed in 116 cycles of IUI. Cycles were randomized in 3 groups; group 1: started GnRHant when the leading follicle reached 14mm, group 2: when it reached 16mm and group 3: without GnRHant hormonal determinations were done during OH. Main outcomes were: premature LH raise incidence, premature luteinization (PL) and pregnancy rate per cycle. RESULTS: Premature LH rise incidence was 2.6% (3 cycles) and PL 6% (7 cycles). Group 1 didn't present cycles with LH rise or PL, groups 2 and 3 presented LH rise in 3.1% and 1.8% and PL in 12.5% and 5.4% respectively. Pregnancy rate with GnRHant was 16.4% (95% IC 8.1-28.1) vs. 7.2% (95% le 2.0-17.5%) without GnRHant (group 3) (p = 0.16): groups 1 and 2 represented a pregnancy rate of 20.6% (95% IC 7.9 39.7) and 12.5% (95% IC 3.5-28.9%) respectively (p = 0.49). Mature follicles number reached meaning difference between all groups (p = 0.04) specially between groups 1 and 2 (p = 0.02). CONCLUSIONS: A trend to elevate pregnancy rates was observed with GnRHant specially with when it was started when leading follicle reached 14 mm (p > 0.05). Starting GnRHant with 16 mm was not totally usefully to prevent PL. PMID- 20931800 TI - [Potential treatment of infertility with second ejaculate]. AB - OBJECTIVE: To compare the changes that occurs in the spermatic parameters when a second ejaculate is obtained in the first 60 minutes in patients with a different seminal quality. MATERIAL AND METHOD: Infertile patient from andrology service were asked to provide a second sample within 1 hours of the first. All the patients had poor semen characteristics in volumen, density, motility or total motile cells. RESULTS: The patients were divided in subgroup; hipospermia (n = 75), oligospermic (n = 46), asthenospermic (n = 111) and teratospermic (n = 157). A benefic effect from a second ejaculate sample was observed in patients with asthenosperia, oligospermic and a total motile sperm count less than 10 million (p < 0.05). CONCLUSIONS: The second ejaculate must be considered as an alternative in some infertile patients that are looking for an spontaneous pregnancy or in patients that will require an assisted reproductive techniques and have poor seminal parameters. PMID- 20931801 TI - [Combined hormonal contraception in cycles artificially extended]. AB - OBJECTIVE: To compare the bleeding patterns, satisfaction and tolerability of 3 different contraceptive in an extended regimens in the service of Family Planning of the North Central Hospital of PEMEX. MATERIAL AND METHODS: Healthy, adult women with desire of contraception for one year (N 120) were randomly assigned to receive oral contraceptive drospirenone/ethinyl E2 (group1), the norelgestromin/ethinyl E2 transdermal patch (group 2) and vaginal ring etonogestrel/ ethinyl E2 (group 3) in an extended regimen (42 consecutive days, 1 hormone-free week). Study assessments were conducted at scheduled visits at the time of initial screening, at baseline after 1, 3, 6, and 12 months. Subjects recorded menstrual associated symptoms bleeding data and completed satisfaction questionnaires. Subjects and investigators provided overall assessments of the regimens. RESULTS: Extended use of 3 different contraceptive resulted in fewer bleeding days in every group (66.6%, 55% and 58.3% P 0.0024), and less mastalgia and menstrual pain. Subjects were highly satisfied with three regimens (93.3%, 96.6% and 91.6% P 0.00421). Although not mayor adverse events were reported with this regimen, there was an increase in spotting days; it decreased with each successive cycle of therapy. Efficacy and safety were similar to those reported for traditional cycle. CONCLUSION: Extended-contraceptive regimen delays menses and reduces bleeding, a profile that may be preferred by women who seek flexibility with their contraceptive method. PMID- 20931802 TI - [Effect of post-abortion interpregnancy interval on obstetric and perinatal outcomes]. AB - BACKGROUND: The interval between pregnancies is important because it allows the mother to recover after an obstetric event. OBJECTIVE: To evaluate if postabortion short interpregnancy intervals affect the obstetrics and perinatal outcome. MATERIAL AND METHODS: A cases and controls study was carried out. We studied 858 patients with a history of early pregnancy loss in the previous pregnancy, of which 286 were cases (interval postabortion < or = 6 months) and 572 controls (interval postabortion > 6 months). Abortion, preterm birth and perinatal outcomes: apgar < or = 7, morbidity, mortality, and weight of newborns were analyzed. RESULTS: The risk of abortion was similar in both groups (14.68% and 13.28%, for the cases and controls respectively (OR: 1.12; IC 95%: 0.75 1.69), and there were no differences in preterm birth (5.59% vs 8.21%; OR: 0.66; IC 95%: 0.37-1.19). Apgar was similar between the groups; there were not differences in the perinatal morbidity (RM: 0.77; IV 95%: 0.27-2.17; p = 0.8005), mortality (RM: 1.14; IC 95%: 0.33-3.94; p = 0.9145) and weight of the newborns between cases and control group. CONCLUSIONS: A short interpregnancy interval less than or equal to six months is not a risk factor for adverse obstetrical and perinatal outcome. PMID- 20931803 TI - [Prevalence of maternal sadness and its associated factors]. AB - BACKGROUND: Frequently occur emotional changes during pregnancy and postpartum. These changes can produce feelings of sadness, anxiety, or fear. In most women, these feelings called "maternity blues" or "baby blues" disappear quickly, if they do not disappear or worsen, they are catalogued as postpartum depression. OBJECTIVE: To determine the prevalence of maternity blues and the associated factors. MATERIAL AND METHOD: In a cross-sectional study, women at immediate postpartum were recruited. It was applied face-to face the Edinburgh test for determining maternity blues. Other registered data were: maternal age, education level, parity, death sons, history of depressive episodes, sleeping disorders, and if the pregnancy was planned or unplanned. The statistical analysis included arithmetic mean, percentages, Chi2, Student t test; and logistic regression analysis for determining the associated factors with the maternity blues. An alpha value was set at 0.05. RESULTS: Overall 1,134 women, 21 of them (1.8%) were diagnosed as maternity blues. The significant factors associated with maternity blues were: the history of death sons, p < 0.002; depressive episodes, p < 0.001; and sleeping disorders, p < 0.003. CONCLUSION: The frequency of maternity blues is low in our population. The associated factors with this disease should be identified during antenatal care in order to offer special care to these women, in order to avoid the complications associated with this entity. PMID- 20931805 TI - [Critical assessment of current therapy of threatened abortion. 1954]. PMID- 20931806 TI - [Third revision of the National Consensus on Diagnosis and Treatment of Breast Cancer (first of three parts)]. PMID- 20931804 TI - [Sonographic ovarian vascularization and volume in women with polycystic ovary syndrome treated with clomiphene citrate and metformin]. AB - OBJECTIVE: To measure the vascularization and ovarian volume with three dimensional sonography in patients diagnosed of polycystic ovary syndrome with stimulated ovulation treatment, and to analyse the differences between the patients treated with clomiphen citrate versus clomiphen citrate and metformin. MATERIAL AND METHOD: Therty patients were studied. Twenty ovulation cycles were obtained with clomiphen citrate and 17 with clomiphen citrate plus merformin (added in case of obesity or hyperglucemy/hyperinsulinemia). Ovarian volumes and vascular indexes were studied with 3D-sonography and results were analysed by treatment. RESULTS: There were no statistical differences of ovarian volume by treatment along the cycles, although bigger volume were found in ovulatory cycles compared to non-ovulatory ones (20,36 versus 13,89 ml, p = 0,026). No statistical differences were also found concerning vascular indexes, neither by treatment nor by the obtention of ovulation in the cycle. CONCLUSIONS: Ovarian volume and vascular indexes measured with three-dimensional sonography in patients diagnosed of polycystic ovary syndrome do not show differents values in patients treated with clomiphen citrate alone versus clomiphen citrate plus metformin. PMID- 20931807 TI - [Clinical practice guideline. Female sexual dysfunctions: intervention and treatment. Colegio Mexicano de Especialistas en Ginecologia y Obstetricia]. PMID- 20931809 TI - [Ultrastructural aspects of the HIV-1 infection in human placental villi with zidovudine treatment]. AB - BACKGROUND: HIV patients with normal placental villi can suffer degenerative changes, the hormones that maintain pregnancy (HCG and progesterone) are diminishing, the pH of blood and oxygen tensions lower. OBJECTIVE: To demonstrate ultrastructural degenerative changes in placental villi at term of pregnant women infected by HIV-1 with zidovudine treatment. MATERIAL AND METHOD: Four placentas at term from seropositive mothers were analyzed; three specimens of each one were processed with conventional transmission electron microscopy. The results were compared with four control cases. RESULTS: Particles belonging to the viral structure associated with the microvilli of the syncytium and cytoplasmic regions were found. Were observed: interruptions of syncytial plasma membrane, syncytial edema; loss of ribosomes at level of RER, disappearance of mitochondria, Golgi complex, RER, lysosomes and cytoplasmic filaments, dissolution of hyaloplasmic matrix, filopodiums of syncytial membrane, aggregated nuclear heterochromatin and dilated perinuclear cistern. Macrophagues had numerous particles into cytoplasm, probably pertaining to electron dense material contained in the viral nucleocapsid, also observed in the stromal region close to the endothelium of the villus. Some myofibroblasts were detected suffering a process of cellular death with cariorexis event. CONCLUSIONS: These changes indicate that the cytopathic effect spreads from peripheral syncytium to stromal zone suggesting that the damaged placental barrier don't have the better conditions for the transmission of gases, nutrients and metabolites toward fetal circulation. PMID- 20931810 TI - [Laparoscopic radical hysterectomy with lymphatic mapping and sentinel lymph node biopsy in early cervical cancer]. AB - BACKGROUND: in patients with early-stage cervical cancer (FIGO IA, IB2 and IIA), the incidence of lymph node metastases is up to 15%; the majority of early cervical cancer patients with pelvic and para-aortic lymphadenectomy does not benefit with the procedure and are at risk of associated morbidity (linfocyst, lymphedema, vascular or nerve damage). OBJECTIVE: To describe the experience and usefulness of lymphatic mapping and sentinel lymph node with total laparoscopic radical hysterectomy in early stage cervical cancer. PATIENTS AND METHOD: Retrospective study in patients with diagnosis of cervical cancer in early stage, submitted to laparoscopic radical hysterectomy with lymphatic mapping and sentinel lymph node biopsy. We analyzed sentinel lymph node identification, false negative rate and surgical variables. RESULTS: in 36 months 15 patients were included, two in IA2 FIGO stage, twelve IB1 and one IIA; thirteen patients were mapping with combined technique and two only with dye. The sentinel lymph node identification rate was 87% (two failures in the patients using only blue dye); the false negative rate was 0%. CONCLUSION: Laparoscopic radical hysterectomy with lymphatic mapping is a secure technique for patients with early stage cervical cancer; it allows the correct identification of lymph node status as the principal prognostic factor. We recommend the use of combined technique (radiocolloid tracer and blue dye) for best rate sentinel lymph node identification. PMID- 20931811 TI - [Impact of perinatal mortality in multiple pregnancies over total perinatal mortality in a hospital in Monterrey, Nuevo Leon]. AB - BACKGROUND: The incidence of multiple pregnancies has increased on the last decade resulting in a rise of premature and underweight newborns infants, with increase of the perinatal morbidity and mortality. OBJECTIVE: To determine the impact of perinatal mortality of multiple pregnancies in the total perinatal mortality. PATIENTS AND METHOD: perinatal mortality rate of multiple pregnancies treated in the Unidad Medica de Alta Especialidad No. 23, Monterrey, Nuevo Leon (Mexico) were analized, from 2002 to 2008. The prevalence of multiple pregnancies, the rate of premature births, the incidence of low-birth weight products and perinatal mortality was estimated. The difference between overall mortality and multiple pregnancy rate was measured by chi2. RESULTS: Of the 144,114 births, there were 1076 (0.8%) fetal deaths and 1,617 (1.10%) neonatal deaths. There were 110 high-order fetal pregnancies (more than three fetuses): 92 triplets, 14 quadruplets, 3 quintuplets and 1 sextuplet, producing a total of 353 newborns. Multiple pregnancies represent 2.8% (59/2093) of the total perinatal mortality (p = 0.3). 79.9% (1674/2093) of the total perinatal mortality were newborns weighing less than 2500 g. In the group of multiple pregnancies, all perinatal deaths occurred in products weighing less than 2500 g. CONCLUSIONS: The perinatal mortality of multiple pregnancies does not impact significantly overall perinatal mortality. PMID- 20931812 TI - [Risk factors associated with maternal mortality in the State of Morelos, Mexico]. AB - INTRODUCTION: Maternal mortality is a public health issue. The causes of maternal mortality are directly related to accessibility, opportunity, costs and quality of obstetric and perinatal services. OBJECTIVE: To describe the characteristics of maternal deaths and analyze the risk factors associated with these deaths in the State of Morelos (Mexico). MATERIAL AND METHOD: a cross-sectional epidemiological, observational, descriptive, retrospective study of 94 cases of maternal deaths registered in the Morelos health services, from 2000 to 2004. Hospitalized and non-hospitalized maternal deaths characteristics were compared. RESULTS: Of 94 maternal deaths, 81.9% were classified as hospitalized (66.7% in public hospitals) and 13.8% as non-hospitalized. 73 (77.6%) deaths occurred during the postpartum period. Most women did not have any medical service (76.7%). There were 77 cases (81.9%) of direct maternal death and 12 (18.1%) indirect. The risk of non-hospitalized maternal death in women 35 to 40 years old was three times higher, with incomplete primary education or none 10.9 and without medical service 3.6 times. CONCLUSIONS: Most deaths were in hospitals, the main causes were hypertensive disorders of pregnancy, childbirth and postpartum and obstetric hemorrhage, events related to the quality of health services. It is necessary to develop more efficient prenatal programs, with focus in maternal and child risk. PMID- 20931813 TI - [Genetic and hormonal effects on sexual differentiation. Paradoxically women require androgens and men estrogens]. AB - It had been established that the sexual structure of a person was determined by the type of hormonal production, what gave biological specificity of the estrogens to women and androgens to men, but recently this functional specificity has lost base due to the biological activity described in different tissues of men and women, today known as endocrine paradox. There are hormonal events that show the need of estrogens to correct development in men and androgens to women. In men the absence of effect of the estrogens produces deficient ossification of skeleton, persistence of the growth cartilage and osteoporosis in adult men. In women the production of androgens by suprarenal glandules is required to obtain the complete feminization. In women with chirurgic-induced menopause, the relation between androgens and the stimulation of sexual response has been established. It has been described a hormone called kisspeptin, that it is attributed the potential to initiate the puberty because stimulates the hypothalamus; in absence of this hormone the women do not present their secondary sex characters, remaining immature sexually. The understanding of individuals needs of androgens and estrogens contribute to improve the control and care of the patient with hormonal deficiencies in any phase of the life. PMID- 20931814 TI - [Assessment of current procedures in the treatment of preeclampsia. 1955]. PMID- 20931816 TI - New accountability measures could mean sea change for QI. AB - Research, evidence-based practices are emphasized. Measures should address a process proximate to desired outcome. Changes should strengthen the hand of quality managers. PMID- 20931815 TI - [Clinical practice guideline. Female sexual dysfunctions: sexual pain disorders. Colegio Mexicano de Especialistas en Ginecologla y Obstetricia]. PMID- 20931817 TI - Electronic tablets help provide information. AB - Opportunities for improvement discovered through questionnaires. Use of e-tablets boosts patient satisfaction, say leaders. Color-coding of symptoms quickly alerts staff to any problems. PMID- 20931818 TI - Hospital uses service for follow-up calls. AB - San Juan Regional Medical Center contracted nurses to make discharge follow-up calls 24/7. Hospital identifies trends through calls. Calls escalated to hospital nurse if there are medication or clinical problems. PMID- 20931819 TI - Provide better ED discharge planning. AB - Hospitals need to look more closely at an integration of community resources and mental health resources. Extend hospital/ED discharge planning to environmental assessments. One of the most common medication problems in therapeutic duplication. PMID- 20931820 TI - Collaboration on capacity management. AB - Representatives from two hospitals developed a systematic approach to capacity management that allows for each hospital to create variances to meet its needs. Huddles vary by hospitals. The hospitals track time frames at different points of care. PMID- 20931821 TI - [Neurohormonal effects following treatment with dopamine. More advantages or disadvantages?]. AB - Due to a big amount of dopaminergic receptors set in the vertebrate central nervous system (CNS), endogenously freed dopamine determines motor and cognitive activities of an organism. It influences neurohormonal regulation of the body, among all, other catecholamines' production; it also regulates kidney's functioning, the cardiovascular system and alimentary canal. Dopamine (a natural catecholamine) containing specimens are often used for the sake of intensive medical care. A particular effect, which is natriuretic, inotropic and vasopressive, is expected under inpatient treatment conditions depending on a selected dose. In practice, however, a potential influence of such treatment on neurohormonal processes, among all, an impact on hypothalamo-hypophyseal-adrenal axis is rarely taken into account. Considering numerous adverse events, a risk of renal failure development and blood redistribution disorders in the mucous membrane of the gastrointestinal tract, a negative impact on the respiratory system, as well as in the event of insufficient evidence for dopamine's effectiveness in both prevention and acute renal failure) treatment, dopamine's implementation in so called diuretic doses is controversial. Its implementation as a drug with the vasopressor effect must be reconsidered and individualised. PMID- 20931822 TI - [Comparison of treatment effectiveness of implantable cardioverter defibrillator in patients undergoing defibrillation threshold testing at the time of implantation versus no defibrillation threshold testing]. AB - Inability to perform defibrillation threshold (DFT) testing during implantable cardioverter defibrillator (ICD) implantation due to comorbidities may influence long-term survival. MATERIAL AND METHODS: Retrospective review (2005-2007) identified 142 patients undergoing ICD implantation without DFT testing (No-DFT group). A control group consisting of 290 patients undergoing standard DFT testing (DFT group) was compared to the first group in terms of appropriate shocks, clinical shock efficacy and all-cause mortality. The primary and secondary prophylactic therapy were performed to the estimation. RESULTS: DFT testing was withheld due to atrial fibrillation with inability to exclude left atrial thrombus, left ventricular thrombus, congestive heart disease and(or) ischemia, hypotension and absent of anesthesiologist. The No-DFTgroup had a similar appropriate shock rate, but lower total survival (79.1% vs. 91.2%, p = 0.01) than the DFT group. In secondary prophylactic therapy, the No-DFT group had a higher incidence of sudden death (7.6% vs. 4.3%, p = 0.03) compared to the DFT group. CONCLUSIONS: The overall mortality was higher in the No-DFT group and number of sudden death in secondary prophylactic therapy. DFT testing should therefore remain the standard of care. Nevertheless, ICD therapy should not be withheld in patients who meet appropriate implant criteria simply on the basis of clinical scenarios that preclude routine DFT testing. PMID- 20931823 TI - [Influence of low-molecular-weight heparin on the life quality of patients after intravascular medical procedures in comparison to patients who were treated with oral anticoagulants]. AB - Atherosclerosis is the illness of arteries which causes changes in vessels leading to their narrowing and then to their closure. Men are mainly attacked by illnesses of arteries. There are several factors which can intensify these illnesses such as: diabetes, smoking cigarettes, diet rich in cholesterol, arterial hypertension. Chronic ischemia of lower extremities is the most frequent illness with which patients notify. Patients with long-standing atherosclerotic process are usually afflicted with thrombotic ischemia. The life quality is the term that can have many meanings. It can be treated objectively or subjectively. In the first case we deal with the quality of life and in the second one with the feeling of life quality. Considering the problem we can base on the level of fulfilling the norm or on riches of obtained experience. The term life quality is significantly connected with the process of cognitive assessment of the individual. The quality of life of patients who were subjected to intravascular medical procedures considerably changes. The continuation of surgical treatment is pharmacotherapy which is connected with administering to patients low molecular-weight heparin or oral antithrombotic medicine. The aim of the study was an evaluation of quality of life of patient after intravascular medical procedures, at which continued treatment was low-molecular-weight heparin and comparison of received results with subjective feeling of quality of life among ill across passing, treated oral anticoagulants medicines. MATERIAL AND METHODS: A number of 50 patients participated in the research. The most numerous group was made up of people aged 51-60 (20 people, 40%), 15 patients (30%) were over 61 years old, 7 ill (14%) were aged 41-50, 5 people (10%) were aged 31-40 and 3 patients (6%) were aged 20-30. Tested patients were selected randomly. The largest number of people (54%) came from the cities with more than 50 thousand inhabitants. People living in the towns with less than 50 thousand inhabitants made up a bit smaller group (30%). A questionnaire of pain assessment according to the NRS scale was used in the research (from 1 to 10; 1 means: "I do not feel pain", 10: "unbearable pain") as well as EuroQol 4D--a questionnaire of health state and quality of life assessment. The questionnaire consisted of 20 questions and was filled in voluntarily. RESULTS: Conducted research has shown that the life quality of patients who were treated with low-molecular-weight heparin changed for better in higher degree than patients who were treated with oral antithrombotic medicine. PMID- 20931824 TI - [Diagnostic significance of tuberculin skin test in BCG vaccinated population]. AB - There is some data on the influence of the BCG vaccination on the TST (tuberculin skin test) but most of them are focused on the population vaccinated only one time. The aim of the study was to describe the relation between vaccination scheme and TST in polish population. MATERIAL AND METHODS: TST was performed in 114 patient with active, culture confirmed tuberculosis and 100 medical student at the beginning of the study as a control group. RESULTS: In our investigation there was no statistically important differences of the TST size between Tb patients and control group. CONCLUSION: In polish population it is not possible to estimate the cutoff value of TST size that could be used to differentiate between TB infection and reaction to vaccination. PMID- 20931825 TI - [Anxiety, depression and polymorphism of the gene encoding superoxide dismutase in patients with chronic obstructive pulmonary disease]. AB - Chronic obstructive pulmonary disease (COPD) is a severe systemic disease leading to circulatory and respiratory failure. COPD is also a risk factor for the onset of anxiety and mood disturbances. Identification of the correlates of emotional disturbances in the course of COPD can make it possible, on the one hand, to prevent mental and behavioral disorders early in the course of this serious somatic disease, and on the other hand, to institute appropriate treatment. The aim of the study was to determine the correlation between the polymorphism of manganese superoxide dismutase signal peptide and the severity of anxiety and depression in COPD patients. MATERIAL AND METHODS: The study group consisted of 57 patients with grade I, II and III COPD according to GOLD criteria. The control group consisted of 63 healthy nicotine addicts. In all the subjects, the genotype of position 9 of manganese superoxide dismutase signal peptide was determined, depression severity was measured with Beck Depression Scale, and anxiety as a trait and as a state was measured with Spielberg State/Trait Anxiety Inventory (STAI). RESULTS: Among COPT patients, 16 subjects were found to have Ala/Ala genotype, 23 Val/Ala and 18 Val/Val. In the smokers' group Ala/Ala genotype was found in 29 cases, Val/Ala in 27 and Val/Val in 7. The distribution of genotype frequencies differed between the groups. In COPD patients, the mean depression severity assessed according to Beck Scale amounted to (16.52 +/- 5.63) and was higher than in smokers without COPD (13.85 +/- 4.24, p = 0.003828). The average severity of anxiety as a trait and as a state did not differ significantly in both groups. Among COPD patients, the mean severity of depressive disorders in subjects with Val/ Val genotype was 21.27 +/- 4.32 and was significantly higher than in those with Val/Ala (15.22 +/- 5.29) and Ala/Ala (12.87 +/- 3.72) genotypes. The severity of anxiety as a trait in COPD patients reached 7.72 +/- 1.21 in the subgroup with Val/Val genotype and was also higher than in those with Val/Ala genotype (6.69 +/- 1.48) and with Ala/Ala genotype (5.87 +/- 1.14). A similar correlation was observed for anxiety as a state (subjects with Val/Val genotype 6.78 +/- 1.06, with Val/Ala genotype 6.18 +/- 1.01 and with Ala/ Ala genotype 5.88 +/- 1.41). Among healthy smokers, the mean severities of depression, anxiety as a trait and anxiety as a state did not differ in subjects with different genotypes. CONCLUSIONS: The study has demonstrated that the severity of depression is higher in COPD patients than in the group of healthy smokers. In the group of patients with COPD, Val/Val genotype at position 9 of MnSOD signal peptide is associated with more severe depression, anxiety as a trait and anxiety as a state in comparison with patients who have Val/Ala and Ala/Ala genotypes. No similar correlations were found in healthy smokers. PMID- 20931826 TI - [Significance of serum concentrations of pro- and anti-inflammatory cytokines in identification of patients with Crohn's disease]. AB - A simple, non-invasive examination separating patients with irritable bowel syndrome from those affected by Crohn's disease (CD) has not been found, so far. Immune disturbances associated with release of various cytokines play an important role in CD pathogenesis. The aim of the study was to investigate the diagnostic efficacy of serum levels of broad panel of pro- and anti-inflammatory cytokines in differentiation between patients with CD and intact bowel. MATERIAL AND METHODS: To the study were included 57 patients with established diagnosis of ileo-coecal CD (according to endoscopic, radiologic and histopathologic criteria) and 21 subjects with no organic bowel pathology. Serum concentrations of CRP and proinflammatory (IL-1beta, IL-6, TNF-alpha) and anti-inflammatory (IL-10, IL-1, IL-1RA, IL-6sR, TNF-alpha R2) cytokines were measured by immunoenzymatic method in both groups. RESULTS: Serum levels of IL-1beta, IL-6, IL-10, TNF-alpha and TNF alpha R2 were significantly different in CD patients than in control group. Among these cytokines TNF-alpha serum level showed the highest discriminative diagnostic efficacy between both groups. The diagnostic efficacies of CRP (cut off value was 4.25 mg/dl) and TNF-alpha (cut-off value 2.5 microg/ml) were similar, showing respectively an accuracy of 81% and 74%, sensitivity of 79% and 65% and specificity of 89% and 100%. CONCLUSION: TNF-alpha showed the highest diagnostic efficacy in differentiating patients with CD from healthy subjects, however, the TNF-alpha does not exceed diagnostic value of CRP. PMID- 20931827 TI - [Is autosomal dominant polycystic kidney disease associated with asymptomatic bacteriuria?]. AB - Urinary tract infections (UTIs) are a common complication in patients with autosomal dominant polycystic kidney disease (ADPKD). Asymptomatic bacteriuria (AB) is a factor predisposing to UTI in other populations. The aim of the study was to determine whether AB is more frequent in a group of ADPKD patients with normal kidney function and no diabetes than in a healthy control group. MATERIAL AND METHODS: A group of 49 ADPKD patients (19 men and 30 women) with normal kidney function (creatinine level < 1.35 mg/dl) and no diabetes, with an average age of 35.9 +/- 11.1 years was compared with a group of 50 healthy controls (22 men, 28 women) with similar age (36.7 +/- 9.2 years). All subject were evaluated using medical history and physical examination, urine culture, urinalysis (biochemical and morphological), kidney ultrasonography, oral glucose tolerance test (with 75 g of glucose) and serum creatinine testing. RESULTS: UTIs were significantly more frequent in medical history of ADPKD patients than in control group (26% vs. 0%, p < 0.001). Asymptomatic bacteriuria was found in 2% of ADPKD patients and in 4% of control group (p = 0.69). The presence of protein in urinalysis was observed in 6% of ADPKD and in none of the control patients. Other urine measurements like pH, specific gravity, and morphological examination were normal and did not substantially differ between groups. The kidneys of ADPKD patients were significantly longer than in control group (p < 0.001). CONCLUSIONS: Asymptomatic bacteriuria is not present more frequently in ADPKD patients with normal kidney function and no diabetes, than in healthy people. PMID- 20931828 TI - [Influence of vegetarian diet on serum values of homocysteine and total antioxidant status in children]. AB - The vegetarian diet may play a preventive role in the development of chronic diseases such as coronary heart and cardiovascular disease. However increase of homocysteine (Hcy) concentration in peoples avoiding animal products may contribute to an increased atherosclerotic risk in these subjects. Recent evidence has suggested that role of hyperhomocysteinemia in atherogenesis is associated with process of autooxidation, which can promote the production of hydroxyl radicals, resulting in oxidative modification of low density lipoprotein and endothelium injury. The oxidant-antioxidant imbalance depends not only on the amount of enhanced free oxygen species but also insufficiency of antioxidant defence system. Total antioxidant status (TAS) expresses capacity for scavenging of free radicals minimizes oxidative damage. The aim of this study was to asses concentrations of homocysteine and total antioxidant status in serum of children on vegetarian and omnivorous diet. We also studied levels of vitamin A (retinol) and vitamin E (alpha-tocopherol) particular components of TAS. MATERIAL AND METHODS: The study included 35 children, aged 5-16 who had been referred to Institute of Mother and Child for dietary consultation. From those, 17 were lacto ovo-vegetarians and 18 omnivores. Dietary constituents were analyzed using the nutritional programme Dietetyk2 and completed with supplementation data. Concentration of homocysteine was estimated in serum with fluorescence polarization immunoassay and TAS by colorimetric method. Levels of vitamin A and E were determined using high-pressure liquid chromatography (HPLC). RESULTS: The mean concentration of homocysteine was similar in both studied groups (vegetarians: 6.13 +/- 1.01 micromol/l vs. omnivores: 5.45 +/- 0.98 micromol/l). In vegetarian children serum level of TAS was significantly lower (1.21 +/- 0.06 mmol/I) as compared to those in non-vegetarian ones (1.30 +/- 0.05 mmol/l, p < 0.0001), but remained within the physiological range (1.16-1.40 mmol/l). The mean concentrations of vitamins A and E in serum of vegetarians were lower than observed in omnivores group, but only in case of alpha-tocopherol the difference was statistically significant (vegetarians: 15.58 +/- 4.12 vs. omnivores: 18.41 +/- 3.10; p < 0.05). CONCLUSION: In studied group of children on lacto-ovo vegetarian diet, serum concentrations of homocysteine are normal and daily food intake of antioxidants and their level in blood are sufficient for preserving adequate total antioxidant status. PMID- 20931829 TI - [Morphological conditions of dysphonia in patients with vocal folds edema]. AB - Disorders of voice quality are mostly influenced by organic changes in larynx. In the assessment of ultrastructure of vocal fold mucosa the most useful is the technique of transmission electron microscopy (TEM). The organic dysphonia is diagnosed by the perceptual, endoscopic (VLS) and stroboscopic (VLSS) assessment of larynx and acoustic assessment. The aim of the study was to determine morphological changes and voice quality disorders in patients with edema of larynx. MATERIAL AND METHODS: 40 patients with vocal folds edema (I group) and 10 patients with no pathological changes of larynx (II group) were included in the study. The morphological assessment of vocal folds mucosa was carried out with the usage of transmission electron microscopy (TEM). The voice quality was examined by the subjective and objective methods. The endoscopic and stroboscopic (VLS and VLSS) examination of larynx and acoustic analysis of voice were carried out. RESULTS: Morphological changes of vocal folds mucosa were observed. Epithelial cells showed features of vacuolar degeneration. Moreover enlargement of intercellular spaces, small rugosity of basal membrane and inflammatory infiltration of stroma, a large number of blood vessels and a cumulation of elastic and collagenous fibers were observed. CONCLUSIONS: Stillness of vocal folds influenced disorders of voice quality with features of dysphonia. The endoscopic and stroboscopic examination of larynx clinically shows the morphological changes of vocal folds mucosa. Simple and non-invasive acoustic examination of voice in patients with edema of larynx objectively confirms the subjectively registered dysphonia. PMID- 20931830 TI - [Assessment of speech and linguistic disorders in patients with cochlear implant- preliminary results]. AB - Cochlear Implant (CI) is the most advanced technical solution in the treatment of profound hearing loss and deafness in patients of all age groups. The aim of the study was to analyse the speech and linguistic disorders in adults with pre- and postlingual deafness rehabilitated with Cochlear implant (CI). MATERIAL AND METHODS: 21 adults with pre- (I group) and postlingual (II group) deafness deriving no benefit from hearing aids participated in this study. Phonatory organ was examined by endoscopy (VLS) and stroboscopy (VLSS). Test of Auditory Perception (TSS) was conducted directly after the activation of speech processor and after rehabilitation. The logopedic assessment before and after CI was based on the examination of motoric activity of articulatory organs, type of respiration, loudness of speech and the assessment of articulation. The linguistic assessment of grammatical and lexical aspect was carried out. The prosodic elements of speech were also analysed. RESULTS: Stroboscopic examination pointed to hypofunction of larynx in patients with prelingual deafness and hyperfunction--in postlingual deafness. The values of TSS were improved after CI, especially in patients with postlingual deafness. The most severe disorders of the efficiency of articulatory organs were observed in patients with prelingual deafness before CI. In the group of prelingually deaf patients disorders of the articulation of vowels and consonants as well as the lexical and grammatical aspect of speech were improved after CI. The correctness of syntax and inflection, development of active vocabulary, improvement of prosodic elements of speech were noticed in patients with postlingual deafness after CI. CONCLUSIONS. Patients with postlingual deafness achieved better results of rehabilitation in auditory perception than prelingually deaf patients. The linguistic improvement of grammatical and lexical aspect was noticed especially in prelingually deaf patients after implantation. This group of patients achieved also the significant progress in prosodic elements of speech in comparison with the results before implantation. PMID- 20931831 TI - [Radiological evaluation of elongated styloid process]. AB - It is commonly forgotten that the osseous link between the tympanie and styloid part of the styloid process occurs in the fourth decade of life, and only then, the exact full lenght of the styloid process can be evaluated. Orthopantomography is a allowing to investigate the length of the process and to define it's relation to the other parts of the skull. The aim of the study was the length of the styloid process after it's complete ossification by means of orthopantomographs. MATERIAL AND METHODS: A group of 200 patients, 119 female and 81 male, aged 40 and more (mean age 53.5 years) was investigated by means of orthopantomographs taken with Kodak 8000 digital camera. The length of the process was defined by considering it's ratio to the mandibular foramen and to the angle of the mandible. RESULTS: Ortopantomographs of 35.5% of the patients presented the process projecting above the mandibular foramen. In 8.5% of those cases, the process was not visible, being partly covered by the images of other skeletal structures. In 58% of the cases, the apex of the process was situated between the mandibular foramen and the angle of the mandible, and in 6.5% of the cases, it was placed below the mandibular angle. In most of the cases, the styloid processes on both sides of the skull were symmetrical. CONCLUSIONS: In the patients studies, 93.5% of the cases were considered physiological; they fell into the first two categories described above. It was concluded that the range of the length of the styloid process below the mandibular angle may be regarded as elongated, thus favouring the incidence of the Eagle Syndrome. PMID- 20931832 TI - [Transient left ventricular dysfunction syndrome or an aborted myocardial infarction? Analysis of six cases]. AB - Transient left ventricular dysfunction (LVDS) is a syndrome of unknown etiology resembling acute coronary syndrome (ACS). The aim of this study was to prospectively assess the course of the acute phase of illness, recovery and prognosis after LVDS. MATERIAL AND METHODS: We prospectively evaluated six women hospitalized due to suspected ACS who have had: elevated levels of troponin T the absence of critical stenoses of coronary arteries in coronary angiography, and akinesis of apical and adjacent segments in ventriculography and/or echocardiography. We analyzed: the clinical course of acute phase, the level of markers of myocardial necrosis and the parameters of electrocardiogram, echocardiography, angiography and cardiac magnetic resonance imaging (MRI). RESULTS: LVSD was diagnosed in six women out of the 1768 patients (0.3%) hospitalized in our department from 2007 to 2009 with an initial diagnosis of ACS. These were women aged 52 to 68 years (average 58 +/- 6 years), without typical risk factors for coronary disease, admitted due to retrosternal pain, preceded by a strong stress. Symmetrical, negative T waves were observed in the ECG in most cases and the troponin T level was elevated in all (from 0.06 to 0.8 ng/ml, mean 0.35 +/- 0.3 ng/ml). Wall motion abnormalities with a reduced ejection fraction (EF) to 20-40% (mean 32 +/- 8%) were observed on echocardiography and/or ventriculography. Coronary angiography showed no hemodynamically significant stenoses of the coronary arteries in any patient. During a mean follow-up period of 12 +/- 1 months (range from 5 to 24 months) all patients recovered completely. Left ventricular contractility had normalized in a few weeks (mean EF 62 +/- 2.5%). A resolution of ECG changes was observed in each case but delayed up to several months MRI performed several months after the acute event showed no scarring within the left ventricular walls. There were no relapses or deaths. CONCLUSIONS: LVDS is a rare clinical entity, which resemble the symptoms of ACS, occurring in postmenopausal women, with a good long-term prognosis. Similar diagnostic criteria cause difficulties--in some cases it is difficult to clearly distinguish LVDS from an aborted myocardial infarction. PMID- 20931833 TI - [The use of human immunoglobulins--adverse reactions]. AB - The primary immunodeficiency, mainly humoral immunity, secondary immunodeficiency and autoimmune diseases are the indications for immunoglobulins substitution. The prolonged substitution in primary immunodeficiency includes regular intravenous infusion of immunoglobulins in 0.4-0.6 g/kg of body weight every 21-28 days. The purpose of such substitution is decrease of frequency and diminishes the clinical course of infections. The high-dose use of immunoglobulins (1-2 g/kg body weight) is preferred in autoimmune diseases based on suppressive and anti-inflammatory activity of immunoglobulins. The subcutaneous administration of immunoglobulins is an alternative to intravenous way, but the singular dose (0.1 g/kg body weight) is too low for suppressive and anti-inflammatory activity of immunoglobulins, so this substitution is indicated in primary immunodeficiency only. The adverse events of immunoglobulins differentiate because of time of occurrence and clinical character. The rapid symptoms occurred just after beginning of infusion and often present the clinical features of anaphylactoid reaction. During the infusion the occurring adverse symptoms are mild and the life-threatening situations are very rare. The next periods of typical adverse reaction are 24-48 hrs after infusion, 72 hrs and later. The mechanisms leading to adverse reaction to immunoglobulins are based on presence of IgG dimmers, stimulating high production of pro-inflammatory cytokines by immunocompetent cells. High level of cytokines is associated with high fever, chills, flu-like symptoms, feeling malaise and sick. The reaction of anti-IgA antibodies present in patient serum with IgA in immunoglobulins preparation is responsible for moderate and severe adverse clinical symptoms. The late adverse events present the symptoms of aseptic meningo-encephalitis. In case of adverse events the stopping of infusion, additions saline/ glucose infusion, anti-histaminic drugs of I and II generation and steroids are used. Severe adverse events are indication for withdraw the immunoglobulins intravenous infusions. In these patients the subcutaneous way of immunoglobulins substitution is an alternative with hope that low singular dose and slow uptake may be better tolerated. PMID- 20931834 TI - [Genotyping of Mycobacterium tuberculosis. An overview of the major research techniques (Part I)]. AB - The recent development of molecular biology methods has substantially improved the identification of many bacterial pathogens, both at the species and strain level. Microbial strain genotyping refers to the process of discriminating among individuals within particular species based on the detection of genomic DNA polymorphisms by means of different molecular markers. Genetic variability arises mainly from genetic recombinations and spontaneous mutations. Each genotyping assay yields strain-specific genetic profiles, allowing assessment of inter strain relationships. The ability to differentiate between strains, the so-called discriminatory power of particular genotyping methods depends heavily on the type and level of polymorphism detected. In the case of tuberculosis, a wide variety of methods have already been implemented to genotype its causative agent Mycobacterium tuberculosis. Most of these methods are based on the polymorphic repetitive DNA sequences in tubercle bacilli genome. This review briefly recapitulates the major research techniques used for genotyping of M. tuberculosis. PMID- 20931835 TI - [Genotyping of Mycobacterlum tuberculosis. An overview of the major research techniques (Part II)]. AB - At present, molecular typing methods of Mycobacterium tuberculosis have become increasingly integrated into the epidemiological studies of tuberculosis. Molecular typing is a process of discriminating between strains of tubercle bacilli, based on the detection of genomic DNA polymorphisms, most frequently associated with repetitive DNA elements. The ability to assess the inter-strain genetic relationships provides a powerful means of resolving a number of epidemiological issues, such as tracing of chains of transmission, determining sources of infection, differentiating recent transmission from reactivation and reinfection from relapse or treatment failure, detecting laboratory cross contaminations, monitoring the geographic distribution and spread of particular genetic strains (including those of special epidemiological importance), or investigating the evolution of M. tuberculosis. In this review, some major techniques used for genotyping of M. tuberculosis were summarized, as well as selected examples of the application of molecular epidemiological studies to the clinical practice. PMID- 20931836 TI - [Rehabilitation of patients following subarachnoid haemorrhage as a result of ruptured intracranial aneurysms]. AB - The aim of the present paper is to discuss how neuropsychological impairments affect the functioning of patients in the aftermath of aneurysmal SAH and to highlight the need for complex professional rehabilitation services for this group of patients. Following the acute stage of illness, when treatment efforts are focused on life-saving measures, a significant proportion of patients are left with long-term consequences of cerebral damage in the form of specific cognitive impairments or emotional changes. The resultant functional deficits require specialist treatment, but few patients have sufficient knowledge in this regard to allow them to seek help and the availability of specialist services is frequently restricted only to large centres of population. Patients and their families usually do not know where to turn in the face of a sudden, life threatening illness, which changes their lives diametrically, still less, what kind of specialist help might be available to them. Bearing in mind the needs of patients and their families, there are but few centers offering cognitive therapy or other forms of psychotherapeutic intervention, that are funded under the auspices of the National Health Fund (NFZ). Furthermore, healthcare policies do not place high priority on employing adequately trained psychological therapists in neurosurgical or neurological departments, and the lack of effective cooperation between specialists from different disciplines places significant limitations on the effective rehabilitation of patients who have undergone SAH. In the following article we review the opportunities for effective rehabilitation in order to optimize the functioning of patients with brain damage following SAH. PMID- 20931837 TI - [Responses of medicinal plant to drought stress and controlled experiment]. AB - Progress in the studies on responses of medicinal plants to drought stress including changes of appearance, physiological adaptation, biochemistry response and molecular mechanisms were summarized. Committed steps of controlled experiment of medicinal plants to drought stress were proposed considering the characteristics of medicinal plants, which will provide rationale basis for clear elaboration of the responses of medicinal plant to the drought stress. PMID- 20931838 TI - [Cloning and expression of fibrinolytic enzyme cDNA sequence from Eupolyphaga sinensis]. AB - OBJECTIVE: To obtain the cDNA sequence encoding fibrinolytic enzyme from Eupolyphaga sinensis and express it in prokaryotic and eukaryotic expression system. METHOD: The primers were designed according to the cDNA of other animals'fibrinolytic enzyme. The cDNA sequence was cloned by RT-PCR and 3 RACE. RESULT: Sequence analysis revealed that the length of the cDNA fragment was 672 bp and encoded a protein of 224 amino acid residues, the N end amino acid sequence residues was IVGG in accordance with other fibrinolytic enzyme. The cDNA sequence was expressed in E. coli, inactive protein was obtained. While expressed in Pichia pastoris, recombinant protein had fibrinolytic activity. CONCLUSION: The cDNA sequence of fibrinolytic enzyme from E. sinensis Walker was cloned and expressed for the first time and it proved a good basis for further functional study of the enzyme. PMID- 20931839 TI - [Breeding of new varieties "zhongchai no. 2" and "zhongchai no. 3" of Bupleurum chinense]. AB - OBJECTIVE: To breed new varieties with better uniformity and commercial quality as well as higher saikosaponin contents. METHOD: The excellent germplasm resources were selected from "zhongchai no. 1" population. Single plant method was applied to get better varieties. All the breeding material was investigated according to morphological characters, agronomic characters and the contents of saikosaponin a and saikosaponin d. The experiments of comparative test and varieties regional test were carried out. RESULT: The bred new varieties of "zhongchai No. 2" and "zhongchai No. 3" had better uniformity. The dark brown roots ratios of the two varieties were 83.2%, 89.9%, respectively. The contents of saikosaponins (a + d) of the two varieties reached 1.31%, 1.02%, respectively. CONCLUSION: "zhongchai No. 2" and " zhongchai No. 3" both had the advantages of better uniformity, darker brown roots and higher saikosaponin contents. PMID- 20931840 TI - [Principal component analysis and cluster analysis of inorganic elements in Erodium stephanianum from different areas]. AB - OBJECTIVE: To explore the characteristics of inorganic elements in Erodium stephanianum. METHOD: The content of elements such as Li, B, Na, Mg, Al, Si, K, Ca, Ti, V, Cr, Mn, Fe, Ni, Cu, Zn, Ga, Br, Rb, Sr, Ba, La, Ce and Rb in ten E. stephanianum samples were determined by means of ICP/MS. The results were used for the development of element distribution diagram. The principal component analysis of SPSS and Q-type cluster analysis were applied for the study of characteristic elements in E. stephanianum. RESULT: Five principal components which accounted for over 91% of the total variance were extracted from the original data. The analysis results showed that Al, Ti, V, Fe, La, Ce, Li, Ga and Ba may be the characteristic elements in E. stephanianum; The results of Q-type cluster analysis showed that the samples could be clustered reasonably into two groups, and the elemental distribution characteristics were related to the ecology and origins of E. stephanianum. CONCLUSION: The principal component analysis and Q-type cluster analysis could be used in data processing in inorganic elements. PMID- 20931841 TI - [Cultural characteristics of mycelia of Ganoderma gibbosum]. AB - To study the cultural characteristics of mycelia of Ganoderma gibbosum, a medicinal fungus used in China. The growth rate and biomass of G. gibbosum mycelia were measured under different temperature, lightning carbon and nitrogen sources conditions. It showed that the optimal growth temperature for mycelia was 25 degrees C. Darkness was beneficial for mycelium growth. The initial pH 5.5 was suitable. The sucrose was the best carbon source and yeast extract the best nitrogen source, the optimal carbon-nitrogen ratio 60:2. These conclusions will offer references for further artificial cultivation and liquid fermentation. PMID- 20931842 TI - [Study on stability and degradation kinetics of ketoprofen-paeonol conjugate]. AB - OBJECTIVE: To study the stability and degradation kinetics of Ketoprofen-Paeonol conjugate (Ket-Pae). METHOD: RP-HPLC method was used to determine the solubility and partition coefficient of Ket-Pae. Stability test was carried out to investigate the factors affecting Ket-Pae. The kinetic studies of Ket-Pae degradation were conducted in different pH buffer solutions and 80% rat plasma at 37 degrees C. RESULT: Ket-Pae showed significant degradation phenomenon at high temperature. The solubility of Ket-Pae was decreased about 200 to 300 times compared with parent drugs in water while the lnP increased about 4 times. The degradation curve displayed a V-shape, and kept maximum stability at week acidic (pH 5.0, t(1/2) = 11.4 d). Ket-Pae degraded quickly with very short half life of 1.3 min in plasma, therefore easily released ketoprofen and paeonol. CONCLUSION: The lipophilicity of Ket-Pae is increased, its stability is affected by temperature and pH value. PMID- 20931843 TI - [Studies on changes of in vitro and in vivo material base of Shaoyao Gancao decoction based on HPLC-DAD-ESI-MS]. AB - OBJECTIVE: To study the changes of the in vitro and in vivo material base of Shaoyao Gancao decoction (SGD) based on HPLC-DAD-ESI-MS, and confirm the migrational constituents in plasma. METHOD: Kormasil C18, (4.6 mm x 250 mm, 5 microm with protection column) was employed; acetonitrile and 0.5% acetic acid/water was used as mobile phase for gradient elution, flow rate was set at 0.8 mL x m min(-1), column temperature was 25 degrees C, and methanol was used to remove the protein. A LCQdeca mass spectrometer system equipped with an electrospray ionization iontrap source was used as the detector and operated in the positive ion mode. Ions was scanned from the m/z 100 to m/z 1000, and characteristic ion were secondary schizolysised to obtain data of second order MS. RESULT: The main constitutes of SGD were peoniflorin, Catechin-5-O-glucoside, albiflorin, liquiritin and glycyrrhizic acid etc, and glucosides were found in the plasma samples of rats administered with SGD, which were glucuronide conjunctions of liquiritigenin and isoliquiritigenin. CONCLUSION: Liquid chromatography-mass spectrometry technology provides a convenient and high speed method to analyze the migrational constituents of plasma of rats administered with SGD, therefore, it has a good value in studies on the changes in the material base of traditional Chinese medicine (TCM). PMID- 20931844 TI - [Researches on relationships between main active ingredients and physical and chemical parameters of dangguibuxue decoction]. AB - OBJECTIVE: To study relationships between the main active ingredients and physical and chemical parameters of dangguibuxue decoction, and to explore the feasibility of characterization the quality of decoction by physical and chemical parameters. METHOD: Solutions of ferulic acid and astragaloside with different concentrations were prepared, of which physical and chemical parameters such as surface tension, pH value and conductivity, etc were determined at 25 degrees C. And polynomial regression analysis was used to analyze these data. RESULT: With the increase of concentration of ferulic acid, pH value was decreased and conductivity was increased. And surface tension was decreased in the aqueous solution of astragaloside. In the combined solution of ferulic acid and astragaloside, ferulic acid was the main influencing pH value and conductivity, while astragaloside was the main factor influencing surface tension. CONCLUSION: On one hand, astragaloside concentration has a significant correlation with surface tension, but almost no correlation with pH value and conductivity. On the other hand, ferulic acid concentration has a strong correlation with pH value and conductivity, but almost no correlation with surface tension. In addition, each parameter has strong anti-interference ability and almost didn't change with the addition of another material. These preliminary results suggested that such characteristic parameters could be used to characterize the decoction quality. PMID- 20931845 TI - [Simultaneous isolation and purification of gallic acid and brevifolincarboxylic acid from Polygonum capitatum by high-speed counter-current chromatography]. AB - OBJECTIVE: To isolate and purify gallic acid and brevifolincarboxylic acid simultaneously by high-speed counter-current chromatography (HSCCC) from a crude extract of Polygonum capitatum. METHOD: The biphasic solvent system composed of ethyl acetate-n-butanol-0.44% acetic acid (3:1:5) was used at a flow rate of 2.0 mL x min(-1), while the aqueous phase was selected as the mobile phase and the apparatus was rotated at 860 r x min(-1). The effluent was detected at 272 nm. RESULT: 51.5 mg of gallic acid and 5.9 mg of brevifolincarboxylic acid were separated from 1.07 g of the crude extract with the purities of 99.7% and 97.5%, respectively, while brevifolincarboxylic acid was obtained firstly from the genus Polygonum. The structures of the compounds were identified by ultraviolet spectrometry (UV), infra-red spectrometry (IR), liquid chromatography/mass spectrometry (LC/MS), time-of-flight mass spectrometry( TOF-MS), 1H-nuclear magnetic resonance (NMR) and 13C-NMR. CONCLUSION: This method is feasible and rapid for isolation and purification of gallice acid and brevifolincarboxylil acid. PMID- 20931846 TI - [Extraction, isolation and purification for ginkgolide B]. AB - OBJECTIVE: To establish a simple extraction, isolation and purification method for ginkgolide B from ginkgo leaf. METHOD: The optimum conditions of extraction, isolation and purification were studied by taking the transfer rate of ginkgolide B as index. RESULT: Ginkgo leaf was extracted with 70% ethanol for three times, the extracts were concentrated to remove ethanol and diluted by water till the crude drug density reached 0.1 g x mL(-1). The dilution was adsorbed with HPD-450 macroporous resin. The impurities were eluted with 20% ethanol and ginkgolide B was eluted with 80% ethanol. Then the 80% ethanol eluant was concentrated and crystallized. Finally the crude crystals were recrystallized with isopropanol. The purity of the ginkgolide B recrystallization was 95%. CONCLUSION: The process was stable and easy to operate, which was suited to industrialized production. PMID- 20931847 TI - [Detection of bacterial endotoxin content in eight kinds of injection by cytokine revulsion]. AB - OBJECTIVE: By using RAW 264.7 macrophage cell line, we studied the dose-effect relationship of endotoxin induced RAW 264.7 cells to release TNF-alpha, and then detected the content of endotoxin in 8 kinds of injections, so that we can investigate the feasibility and the interference factors of the novel test. METHOD: By using endotoxin of different concentrations to induce RAW 264. 7 cells to release TNF-a, we drew the curve of dose-effect relationship between endotoxin and generated TNF-alpha. Then we detected the content of TNF-alpha in yuxingcao, shuanghuanglian, qingkailing, gegensu, xiangdan, qianrongmei and jiangxianmei injections and shuanghuanglian powder injection, and calculated their content of endotoxin. RESULT: The endotoxin could induce the cells to release TNF-alpha in a good dose-dependent manner, even at a very low concentration. In the range of maximum available dilution multiple, the content of endotoxin in the rest 7 kinds of injections was less than 1.0 EU x mL(-1) except qingkailing injection of two batch. CONCLUSION: Cytokine revulsion has the advantage of wide detection range, high sensitivity, simple operation, and the detected endotoxin is of bioactivity. This method provides another technical mean for pyrogen test of injections. PMID- 20931848 TI - [A novel lignan dimer from stems of Kadsura heteroclita]. AB - As a part of our search for bioactive material, the chemical investigation of the stems of Kadsura heteroclita led up to the isolation of a new lignan, heteroclitin R. The structure was elucidated on the basis of nuclear magnetic resonance spectroscopic data. Heteroclitin R was a new compound as a lignan dimer obtained from Schisandraceae family for the first time. PMID- 20931849 TI - [Hasubanan type alkaloids in Stephania hernandifolia]. AB - OBJECTIVE: To study the hasubanan type alkaloids in Stephania hernandifolia. METHOD: The dried herbs of S. hernandifolia. were extracted with 95% ethanol. After removal of the solvent, the residue was first partitioned between acid water and petroleum ether, then the aqueous layer was basified and extracted with chloroform to obtain crude alkaloids. Column chromatograghic methods with on silica gel, Rp-18, MCI CHP 20P, Sephadex LH-20 were applied for the isolation and purification of the crude alkaloid fraction. The structures were elucidated by their physicochemical properties and spectral data. RESULT: Nine hasubanan type alkaloids were obtained and identified as aknadinine(1), longanone(2), stephasunoline (3), N-methylstephuline(4), epistephamiersine(5), prostephabyssine(6), aknadilactam(7), dihydroepistephamiersine(8), hasubanonine(9). CONCLUSION: Compounds 2-8 were isolated from this plant for the first time. PMID- 20931850 TI - [Chemical constituents from root barks of Morus atropurpurea]. AB - OBJECTIVE: To study the chemical constituents from the root barks of Morus atropurpurea. METHOD: The chemical constituents from the 70% ethanol extract of M. atropurpurea were isolated and purified by column chromatographic methods. Their structures were identified by physico-chemical properties as well as spectral data. RESULT: Fifteen compounds were isolated and identified as sanggenol O(1), kuwanon S(2), moracin C(3), mulberrofuran A(4), mulberrofuran B(5), mulberrofuran C(6), mulberrofuran G(7), mulberroside A(8), mulberroside C(9), 1-deoxynojirimycin(10), 2-O-alpha-D-galactopyranosyl-1 deoxynojirimycin(11), fagomine(12), betulinic acid(13), ursolic acid(14) and beta sitosterol(15). CONCLUSION: Compounds 1-6 and 8-13 were isolated from M. atropurpurea for the first time. PMID- 20931851 TI - [Investigation on relationship between flavonoid content and inhibitory ability to nitrosamine synthesis for eleven Chinese herbal medicines]. AB - The eleven Chinese herbal medicine containing flavonoids are applied as raw materials to explore the relationship between the inhibitory ratio of nitrosamine synthesis, the scavenging ratio of nitrite and the flavonoid content in the samples. The inhibitory ratio of nitrosamine synthesis and the scavenging ratio of nitrite of the 11 herbal medicines, Vit C and rutin were determined in intro compare with Vit C and the standard ample of rutin. The results indicate that each sample exhibits certain ability to inhibitiory nitrosamine synthesis. Among these samples, Honeysuckle flower is found to be of best effects, its inhibitory ratio and scavenging ratio reaches 78.5% and 60.5%, respectively. Except kudzuvine root, the other samples with higher content of flavonoid result in a higher inhibitory or scavenging ratio, and the relative coefficient reaches a value of 0.9338 and 0.9272, respectively, displaying notable positive correlation. The concentrations of IC50 (g x L(-1)) of flavonoid extracted from honeysuckle, rutin and VC were 0.013, 0.022 and 0.187, respectively. While the inhibitory ratio of synthesis of nitrosamines reached 50%, and those were 0.042, 0.024 and 0.041, respectively. While scavenging ratio of nitrite reaches 50%. The inhibitory ratio of synthesis of nitrosamine of flavonoids extracted from honeysuckle flower is higher than that of Vit C and rutin, and the scavenging ratio of nitrite is similar to that of Vit C. PMID- 20931852 TI - [Determination of methyl nonyl ketone in volatile oil from herbs of Houttuynia cordata by GC-MS]. AB - OBJECTIVE: To develop a GC-MS method for the determination of methyl nonyl ketone in the volatile oil from the herbs of Houttuynia cordata. METHOD: The sample was split in the 240 degrees C injection port, with 20:1 split ratio, and separated on a DB-5 (30 m x 0.25 mm, 0.25 microm film thickness) fused silica column with helium as the carrier gas. The temperature program was as follows: 100 degrees C for 2 min, the 5 degrees C x min(-1) to 150 degrees C, then 15 degrees C x min( 1) to 200 degrees C, and kept for 10 min. The MS transfer line temperature was set to 250 degrees C, the MS source temperature was set to 200 degrees C. The ionization mode was electron ionization (EI) and the selective ion monitor mode was used. RESULT: A good linear relationship was constructed over the injection amount range of 5.5-110 ng of methyl nonyl ketone. The average recovery was 98.9%, and RSD was 2. 2%. CONCLUSION: The developed method was sensitive, accurate, and can be used for the determination of methyl nonyl ketone in the volatile oil and for the quality control of H. cordata. PMID- 20931853 TI - [Determination of biological activity of extract from hirudo by N-benzoyl-L arginine ethyl ester]. AB - As a potent anticoagulant, leech a traditional Chinese medicine, has become increasing topics. Hirudin, which is the primary effective component in leech, is a specific and efficient inhibitor of thrombin, mainly used in prevention and treatment of thrombus on the clinic practice. However, there is still no accurate and convenient method reported about the determination of it's biological activity. This paper reported a method for the determination of the biological activity the of extract from hirudo. The extra thrombin, which was not inhibited by hirudin in the extract from hirudo, reacted with N-benzoyl-L-arginine ethyl ester and was determined. The biological activity of the hirudo extract was determined, indirectly. The linear of calibration curve and accuracy were both perfect, the method was accurate and reliable. PMID- 20931854 TI - [Dracorhodin perchlorate inhibit high glucose induce serum and glucocorticoid induced protein kinase 1 and fibronectin expression in human mesangial cells]. AB - OBJECTIVE: To investigate the effect of dracorhodin perchlorate (DP) on inhibiting high glucose-induced serum and glucocorticoid induced protein kinase 1 (SGK1) and fibronectin (FN) expression in human mesangial cells (HMC), and its mechanism of prevention and treatment on renal fibrosis in diabetic nephropathy (DN) . METHOD: The HMC were divided into normal glucose group (NG group, 5.5 mmol x L(-1) D-glucose), normal glucose +low DP group (NG + LDP group, 5.5 mmol x L( 1) D-glucose +7.5 micromol x L(-1) DP), normal glucose +high DP group (NG + HDP group, 5.5 mmol x L(-1) D-glucose + 15 micromol x L(-1) DP), high glucose group (HG group,25 mmol x L(-1) D-glucose), high glucose +low DP group (HG + LDP group, 25 mmol x L(-1) D-glucose + 7.5 micromol x L(-1) DP)and high glucose +high DP group (HG +HDP group, 25 mmol x L(-1) D-glucose + 15 micromol x L(-1) DP). Each group was examined at 24 hours. The levels of SGK1 and FN mRNA was detected by real-time fluorescence quantitative PCR,and the expression of SGK1 and FN protein was detected by Western blot or indirect immunofluorescence. RESULT: A basal level of SGK1 and FN in HMC were detected in NG group, and the level of SGK1 and FN mRNA and protein were not evidently different compared to that of NG group adding 7.5 micromol x L(-1) DP for 24 hours. On the other hand, the levels of SGK1 and FN mRNA and protein were obviously decreased by adding 15 micromol x L( 1) DP for 24 hours. Compared to NG group, the levels of SGK1 and FN mRNA and protein were increased in HG group after stimulating for 24 hours (P < 0.01). Compared to HG group, the level of SGK1 and FN mRNA and protein were evidently reduced in HG + LDP and HG + HDP groups by adding 7.5 micromol x L(-1) DP and 15 micromol x L(-1) DP for 24 hours (P < 0.01). CONCLUSION: Dracorhodin perchlorate can inhibit high glucose-induced serum and glucocorticoid induced protein kinase 1 (SGK1) and fibronectin(FN) expression in human mesangial cells, and this may be part of the mechanism of preventing and treating renal fibrosis of DN. PMID- 20931855 TI - [Effect of tectorigenin on MCP-1 and ICAM-1 mRNA expression in injured vascular endothelial cells]. AB - OBJECTIVE: To observe the protective effect of tectorigenin on the vascular endothelial cells(VEC) injured by oxidant low density lipoprotein-cholesterol and the expression of MCP-1 and ICAM-1 mRNA, and explore the mechanism of anti atherosclerosis. METHOD: The VEC of rat was cultured in vitro and the 100 mg x L( 1) ox-LDL inducing oxidant injured model was used in this study. Different dosage tectorigenin was added into VEC and the activity of VEC was observed by MTT colorimetry. The expression of MCP-1 and ICAM-1 mRNA in VEC was detected by RT PCR. RESULT: Tectorigenin had significantly protective effect on the VEC injured by ox-LDL and obviously inhibited the excessive expression of MCP-1 and ICAM-1 mRNA in VEC. CONCLUSION: It was the critical mechanism of anti-atherosclerosis that tectorigenin prevented the VEC oxidant injured and inhibited the excessive expression of MCP-1 and ICAM-1. PMID- 20931856 TI - [Comparative study on acute toxicity and pharmacological effect of huoxiang zhengqi microemulsion and huoxiang zhengqi tincture]. AB - OBJECTIVE: To compare the acute toxicity and the pharmacological effect of Huoxiang Zhengqi microemulsion and Huoxiang Zhengqi tincture. METHOD: The acute toxicities of Huoxiang Zhengqi microemulsion and Huoxiang Zhengqi tincture were observed by the test of maximum dose in mice and the antidiarrheal effects of them were evaluated by ED50 values of the diarrhea index, the serum levels of gastrin and motilin in the mice diarrhea model induced by senna. RESULT: The acute toxicity of Huoxiang Zhengqi tincture was much higher than that of Huoxiang Zhengqi microemulsion and the ED50 values of the two formulations were similar. CONCLUSION: The microemulsion of Huoxiang Zhengqi prescription was much safer than that of tincture, but the antidiarrheal effects of them in diarrhea model induced by senna were similar. PMID- 20931857 TI - [Difference of hypaconitine concentration in serum between cold-deficiency and normal mice]. AB - OBJECTIVE: To investigate the difference of hypaconitine concentration in serum between normal and cold-deficiency mice after administration of aconite decoction. To analyze how the toxic dose of aconite decoction correlate to the metabolic environment. METHOD: Prepared cold-deficiency mice model, treated normal and cold-deficiency mice with aconite decoction for 14 days continuously, and then detected hypaconitine concentration in serum by HPLC along with survival ratio of mice on the first, seventh and fourteenth day. RESULT: After administration of aconite decoction for 14 days, the hypaconitine concentration in serum of cold-deficiency mice is close to that in normal mice. It showed aconite decoction has the ability of regulating metabolism environment, the hypaconitine concentration in serum of normal mice was higher on the seventh and fourteenth day than that on first day. It showed that aconite decoction can disturb metabolism environment of normal mice. It was also been observed that the range of variation of hypaconitine concentration in cold-deficiency mice was minor than that in normal mice during the fourteen days' administration. CONCLUSION: The difference of serum concentration in normal and cold-deficiency mice showed that there were different metabolic environments in two mice models, and the metabolic environment changed during administration. These results showed that the different toxic doses of aconite decoction were partially due to the different metabolic environments. PMID- 20931858 TI - [Influence of tongxie prescription on CRF expression in spinal cord and brain of hypersensitive viscera rats]. AB - OBJECTIVE: To investigate the distribution and expression of corticotropin releasing factor (CRF) in spinal cord, hypothalamus and third ventricle of cerebrum, of the hypersensitive viscera rats, and to research on the mechanism of CRF in the hypersensitive vicera signal conduction pathway in IBS (irritable bowel syndrome) and to investigate possible active mechanisms of tongxie prescription on IBS. METHOD: Forty SD rats were divided randomly into three groups. The rats of model No. 1 were sensitized by injecting egg albumin into abdominal cavity. The rats of model No. 2 were sensitised by conditional stimulus and unconditional stimulus. The two model groups were both divided randomly into two groups. The five groups were given intragastric administration with Tongxie prescription or normal saline for four weeks. Then quantitative analysis of CRF in the lumbosacral spinal cord and brain of rats were achieved by immunohistochemical method and computerized image system. RESULT: The sensitivity of the groups being treated with tongxie prescription were much lower than the model groups (P < 0.01). The immunohistochemical method showed that CRF was expressed in the lumbar intumescentia of spinal cord, hypothalamus and the diaphragmatic surface of third ventricle of cerebrum. The CRF positive index of the model groups was higher than that of the blank group (P < 0.01). The CRF positive index of the healing groups was lower than that of the model groups (P < 0.01). The CRF positive index of the healing groups was higher than that of the blank group (P < 0.01). CONCLUSION: The two model rats evoked by two different stimulation both appeared visceral hypersensitivity state. CRF is related to stress. The increase of CRF expression in the lumbar intumescentia of spinal cord, hypothalamus and the diaphragmatic surface of third ventricle of cerebrum showed that CRF is critical to the introduce of stimulus signal of vicera. Tongxie prescription can significantly decrease CRF expression. This is one mechanism to decrease sensitivity of hypersensitive viscera rats. PMID- 20931859 TI - [Metabolism, transformation and distribution of Coptis chinensis total alkaloids in rat]. AB - OBJECTIVE: To determine the pharmacokinetics, distribution and mutual transformation of the total alkaloids, jatrorrhizine, coptisine, berberine and palmatine from Coptis chinensis in rats. METHOD: After the total alkaloids and berberine were fed into rats, their contents in plasma, tissues and gastrointestinal tract were determined by reversed-phase HPLC. RESULT: The peak times of berberine in blood were 2.0 h (Cmax 3.7 mg x L(-1)) and 5.0 h Cmax 2.8 mg x L(-1)), respectively. Berberine in rat blood can be transformed into jatrorrhizine. After the rats were fed with the total alkaloids by gavage, the content of berberine was decreased monotonously, while coptisine, palmatine and jatrorrhizine contents were increased gradually in the stomach, it speculated that berberine may be transformed into jatrorrhizine in the stomach. Animal experiments showed that berberine and palmatine were mainly distributed in the lungs of animals, followed by the distribution in the liver, while jatrorrhizine and coptisine was mainly in the liver, then in the lungs. CONCLUSION: Berberine could transform into jatrorrhizine. The mechanism on the appearance of two maximum blood concentration of berberine in blood could be explained with the propulsion of the gastrointestinal tract partly. PMID- 20931860 TI - Protective effect of effective part of Acanthopanacis senticosus on damage of PC12 cells induced by MPP+. AB - The purpose of our research was to evaluate the protective effect of the effective part of Acanthopanacis senticosus (AS) on the damage of PC12 cells induced by MPP+, an in vitro cell model for Parkinson's disease. Cell viability and apoptosis of PC12 cells induced by MPP' were assayed by MTT and flow cytometry respectively in the presence or absence of the effective part of AS. The contents of lactate dehydrogenase (LDH), nitric oxide (NO), nitric oxide synthase (NOS) and malondialdehyde (MDA) were determined by UV spectrophotometer. Our study showed that the survival rate of PC12 cells was markedly increased while cell apoptosis was decreased in the range of 200 to 400 mg x L(-1) of the effective part of AS. The contents of LDH, NO, NOS, MDA were reduced. Our experimental results indicated that the effective part of AS had the protective effect on the damage of PC12 cells induced by MPP+. The underlying mechanisms might be the combination of reduction of LDH leakage and decreases in the contents of NO, NOS and MDA, and finally prevent the apoptosis in PC12 cells and increase the cell survival rate. PMID- 20931861 TI - [Present status and sustainable development of Dendrobium officinale industry]. AB - OBJECTIVE: To understand the present status and characteristics of Dendrobium officinale industry and to provide a rationale for the sustainable industrial development. METHOD: Based on references and an on-site investigation of main Dendrobium officinale-producing enterprises and market, to analyze main existing problems and to propose suggestions for sustainable development. RESULT: More than 10 provinces and regions are involved in the production around the center of Zhejiang and Yunnan provinces. These two provinces are different from each other in development pattern. Yunnan adopts a mode of companies minus farmer households but Zhejiang mainly employs a mode that a leading company establishes a production base with production, processing and marketing combined together. Zhejiang mode is characterized by high tech, high investment, high risk and high return. Existence of non-genuine species, stagnancy in development and application of varieties and techniques for quality control and a narrow channel for marketing are the key problems limiting sustainable development of the industry. CONCLUSION: The key to sustainable development of the industry is to establish a technological alliance to speed up development of common techniques and application of integrated innovations, to strengthen self-discipline and monitoring of production, and to expand sales market. PMID- 20931862 TI - [Rationality analysis on current validity period of preparations in medical institutions]. AB - The rationality of current validity period of the preparations in medical institutions was analyzed. Based on the discussion of the main functions of the validity period in administration admission and the essential principles for the reasonable enactment of the validity period, author suggested that the validity period should be amended as 5 years in order to exert more effectively on administration admission of the preparation of medical institution. PMID- 20931863 TI - [Lignocellulose degrading bacteria and their genes encoding cellulase/hemicellulase in rumen--a review]. AB - Rumen of ruminant animals is known as a natural reactor involved in highly efficient lignocelluloses degradation. Rumen fibrolytic microbes have attracted an increasing attention for their potential value in biofuel research. Studies on rumen microbes have traditionally entailed the isolation of fibrolytic bacteria and subsequent analysis of fibrolytic enzymes. Developments in genomic and metagenomic approaches have made it possible to isolate directly genes and gene clusters encoding fibrolytic activities from rumen samples, permitting a global analysis of mechanisms of degradation of lignocellulose in rumen. Research in this field shows that lignocellulose degradation in rumen is a complex process involving a number of different microbes and is effected by a huge array of hydrolytic enzymes in a concerted fashion. This review briefly summarizes results from recent studies, especially metagenomic studies, on lignocellulose degradation in rumen. PMID- 20931864 TI - [Advances in lactamases from microbes--a review]. AB - gamma-Lactamase belongs to the amidase. The (+) gamma-lactamses can be applied in the kinetic resolution of racemic gamma-lactam, which can produce (-) gamma lactam efficiently. The (-) gamma-lactam enantiomer is an important synthon for the synthesis of carbocyclic nucleosides. Up to now seven strains of microbes were reported that produced gamma-lactamses. The crystal structure of (-) lactamase from Aureoacterium sp. was resoluted, and the catalytic mechanism based on the structure data analysis was alike with the alpha/beta hydrolase family. However, no structure data and mechanism theory is available for (+) lactamase till now. The future works focus on protein engineering of the gamma-lactamase to improve the catalysis of the protein, elucidation of the catalytic mechanism of the gamma-lactamase and the functions of the gamma-lactamase in vivo. PMID- 20931865 TI - [Diversity and bioactivity of cultured actinomycetes in Sichuan and Yunnan area]. AB - OBJECTIVE: In order to discover new leader compounds, the diversity and some bioactivities of cultured actinomycetes from Sichuan and Yunnan were studied. METHODS: In total 250 soil samples were collected from forest of Huangjin, Emei and Qingcheng Mountains, Jiuzhaigou in Sichuan, and Xishuangbanna in Yunnan. Actinomycetes in these samples were isolated and identified. Bioactivities of isolated strains were determined. RESULTS: In total 2676 strains of actinomycetes were isolated from these samples. The 16S rRNA gene sequences of 98 selected strains were determined, and the phylogenetic analysis was carried out. 13, 5, 9 and 20 genera were identified from Forest of Huangjin, Emei and Qingcheng Mountains (one sample area), Jiuzhaigou, and Xishuangbanna respectively. The diversity of Xishuangbanna was the richest. That of Emei and Qingcheng Mountains was monotone, and only five genera were isolated. Antimicrobial activities of 169 selected strains against 11 bacteria and fungi were tested using agar well diffusion method, and genes of type I and II polyketide synthases (PKS I, PKS II), non-ribosomal peptide synthase (NRPS) and polygene cytochrome P450 hydroxylase (CYP) were detected by PCR. High rate of antimicrobial activity and the synthesis genes of four antibiotic existed in these actinomyctes. CONCLUSION: In sample-collecting areas, the poorer human beings disturbance, the richer the diversity of actinomycetes. For isolation of actinomycetes, author advocate using of " extreme" conditions, although it may got small number of actinomycetes, but the proportion of unknown actinomycetes was greater. Gram-negative bacteria and fungi could be inhibited by adding inhibitors in media. PMID- 20931866 TI - [Screening of harmine tolerance/degrading bacteria from camel rumen]. AB - OBJECTIVE: Peganum harmala, a famous traditional Chinese drug, contains a variety of alkaloids and toxic for many animals. Camels mainly live in desert or semi desert areas, with the robust gastrointestine system in digesting various feed including toxic plants without disease symptoms. METHODS: Camel rumen content was used as the inoculant to inoculate medium M98-5 which contains 100 mg x L(-1) harmin and cultivated for 5 days. Upto 5 subculturings, strains that could degrading or tolerant harmine were isolated. Their conversion activity was determined by thin-layer chromatography. The taxonomic position of the strains were identified based on 16S rRNA sequences analysis. RESULTS: 15 out of the 29 isolates have harmine degrading activity. Most of the isolates are identified as the members of the Genera Lactobacillus (16 strains, 55%), Shigella (7 strains, 24%) and Bacillus (4 strains, 13.8%). Only one strain belong to genus Enterococcus and one belong to genus Megasphaera. CONCLUSION: The results indicated that the harmine tolerance/degrading communities of camel rumen are limited and only Lactobacillus have harmine-degrading activity. PMID- 20931867 TI - [Cloning and analysis of the telomeres of five Streptomyces linear plasmids]. AB - OBJECTIVE: Streptomyces strains were isolated from soil samples of Tibet, five small linear plasmids were detected by pulsed-field gel electrophoresis. OBJECTIVE: Cloning, sequencing and analysis of telomeres of these plasmids. METHODS: The telomeres were cloned by a modified procedure--"alkaline treatment and enzyme digestion in gels". RESULTS: Telomeres of five linear plasmids were cloned and sequenced. Compared with the typical Streptomyces telomeres, the newly identified telomeres contained multiple palindromes, but some could not "fold back" of their first conserved palindrome I with the internal palindromes to form a "super-hairpin", and palindromes of some telomeres did not contain the 3-nt "loop". CONCLUSION: New telomere sequences were cloned by a modified procedure. Both folding-back of the telomere palindromes and 3-nt loop of palindromes varied among telomeres. PMID- 20931868 TI - [Genetic manipulation system for tiacumicin producer Dactylosporangium aurantiacum NRRL 18085]. AB - OBJECTIVE: To optimize the production of tiacumicin B in Dactylosporangium aurantiacum NRRL 18085, we developed a genetic manipulation system for disrupting genes involved in tiacumicin biosynthesis. METHODS: We developed a method of conjugation to transfer exotic DNA pSET152 into D. aurantiacum NRRL 18085. Using the PCR-targeting system, we disrupted a putative tiacumicin halogenase gene in vitro by "in-frame deletion" in E. coli, and then the resulting cosmid was transferred into D. aurantiacum NRRL 18085 by conjugation. RESULTS: The putative tiacumicin halogenase gene in D. aurantiacum NRRL 18085 was disrupted by in-frame deletion from a double-crossover recombination event. The resulting mutant strain lost the ability to produce tiacumicin B. CONCLUSION: We developed a genetic manipulation system for D. aurantiacum NRRL 18085, enabling the functional characterization of tiacumicin biosynthetic genes in vivo, and we offered a positive example for other Actinobacteria lacking an appropriate genetic manipulation system. PMID- 20931869 TI - [Effects of environmental stress on secondary metabolites of Aspergillus ochraceus LCJ11-102 associated with the coral Dichotella gemmacea]. AB - OBJECTIVE: To explore the secondary metabolites of fungus Aspergillus ochraceus LCJ11-102 associated with the coral Dichotella gemmacea under environmental stress and to obtain characteristic compounds with biological activities. METHODS: A nutrient-deprived culture medium (biomimetic culture) and a high salt culture medium were used for fermentation. Fingerprints of HPLC of the fermentation broth were used to investigate the diversity of secondary metabolites. Compounds were isolated by column chromatography on silica gel, Sephadex LH-20, and preparative HPLC. Their structures were identified by spectroscopic analyses and the modified Mosher's method. RESULTS: Different secondary metabolites were produced by A. ochraceus LCJ11-102 under two different culture conditions. (R)-mellein (1), (5,6-trans, 8,9-threo-) -9-chloro-8-hydroxy 8, 9-deoxyaspyrone (2), (5,6-erythro-, 8,9-threo-) -9-chloro-8-hydroxy-8, 9 deoxyasperlactone (3), and (5S, 6R, 9S)-dihydroaspyrone (4) were identified from the biomimetic cultures, and R (+) -semi-vioxanthin (5) was identified from the high salt cultures, respectively. CONCLUSION: Environmental stress obviously induces microbes to produce different secondary metabolites. And biomimetic culture is an effective approach to obtain active chloro compounds from marine microorganisms. PMID- 20931870 TI - [Effect of YDL080C gene deletion on higher alcohols production in Saccharomyces cerevisiae haploids]. AB - OBJECTIVE: The deletion of pyruvate decarboxylase-like enzyme gene (YDL080C gene) in industrial Saccharomyces cerevisiae haploids a-8 and alpha-22 were respectively constructed, and the effect of YDL080C gene deletion on the production of higher alcohols, especially isoamyl alcohol, was investigated in high gravity ethanol fermentation. METHODS: Upper and down stream fragments YA (460 bp) and YB (630 bp) of YDL080C gene were amplified by PCR using the genomic DNA of S. cerevisiae haploids a-8 and alpha-22, respectively; KanMX marker for G418 resistance from plasmid pUG6 was cloned by PCR. Fragments YA, YB and KanMX were respectively inserted into the same plasmid pUC19 using EcoRI and KpnI, KpnI and BamHI, and KpnI sites in the order of YA-KanMX-YB to construct the recombined vector pUC-YABK. The recombinant cassette YA-KanMX-YB was cloned from plasmid pUC YABK by PCR and respectively transformed into industrial yeast haploid a-8 and alpha-22. By the double homologous recombination, YDL080C gene deletion mutants were constructed and selected by the growth extent on YEPD agar plates containing 600 microg/mL G418. At the end of high gravity ethanol fermentation, fermentation performance and higher alcohols production of parental haploids and their mutants were determined. RESULTS: YDL080C deletion mutants were respectively selected from their corresponding parental haploid a-8 and alpha-22. The alcohol fermentation results showed that higher alcohols, especially isoamyl alcohol, were almost invariable among the mutants and their corresponding parental haploids. However, mutants yielded more amount of ethanol of 0.6 (%, v/v) and 0.4 (%, v/v) over its parental haploid, respectively. CONCLUSION: Deletion of YDL080C gene in S. cerevisiae haploids has no noticeable effect on decreasing the production of higher alcohols, especially isoamyl alcohol, but it seems to somehow increase the production of ethanol. PMID- 20931871 TI - [Isolation and identification of an endophytic fungus of Polygonatum cyrtonema and its antifungal metabolites]. AB - OBJECTIVE: Endophytic fungi in medicinal plants produce a variety of bioactivity compounds. In this study, an endophytic fungus zjqy610 with antifungal activity was isolated from Polygonatum cyrtonema in Zhejiang Qingyuan Baishanzu Mountain nature reserve. METHODS: Strain zjqy610 was identified as Penicillium canescens based on the morphology and its rDNA sequence analysis. Three antifungal compounds were isolated from the fermentation broth of zjqy610 through normal phase silica gel column chromatography and gel (Sephadex LH-20) column chromatography, traced by ultraviolet light or iodine vapor with bioassay-guided fractionation. RESULTS: These three compounds were elucidated as o acetylbenzeneamidinocarboxylic acid (zjqy610B-g-3), griseofulvin (zjqy610D-4) and naphtho [1,2-b] furan-3-carboxylic acid, 4-hydroxy-5-methoxy-2-methyl-(zjqy610F 2) based on mass spectrometry and nuclear magnetic resonance spectroscopy. The antifungal activity assays showed that the three compounds had inhibitory to variety of plant pathogenic fungi. Compound zjqy610D-4 had strong antifungal activity against Botrytis cinerea, Colletotrichum orbiculare, Didymella bryoniae and Sclerotinia sclerotiorum. EC50 was 0.68, 0.38, 0.91 and 0.61 mg/L, respectively. CONCLUSION: Zjqy610D-4 is deserved to develop an agricultural antibiotics. PMID- 20931873 TI - [Identification of almA genes involved in long-chain alkane degradation by Alcanivorax hongdengensis A-11-3]. AB - OBJECTIVE: The aim of this study is to identify of genes involved in long-chain (LC) alkane degradation in Alcanivorax hongdengensis A-11-3. METHODS: PCR was applied to obtain Flavin-binding monooxygenase genes, then quantitative real-time polymerase chain reaction (Q-RT-PCR) and RT-PCR were applied to analyze gene expression in response to different LC-alkanes and pristane. RESULTS: Two homologues, almA1 and almA2, were obtained. They showed 58.6% and 53.2% similarities with almA of Acinetobacter sp. Strain DSM 17874, respectively, at amino acid level. Enhanced expression of almA1 genes was observed when strain A 11-3 grew with long chain alkanes (C28 to C32), in sodium acetate medium. However, the induction expression was not observed in the case of C9-C22 alkanes. Similarly, almA2 was induced by long chain alkanes (C24 to C34). In addition, it was also induced by the branched alkane pristane. CONCLUSION: AlmA genes were mostly responsible for the degradation of long-chain alkanes and pristane in strain A-11-3. PMID- 20931872 TI - [Screening and characterization of antibacterial and cytotoxic marine bacteria associated with Karlodinium micrum]. AB - OBJECTIVE: Antibacterial and cytotoxic activities were screened for marine bacteria which have been isolated from Karlodinium micrum, in order to obtain potential strains with antibacterial and cytotoxic activities. METHODS: In total 38 bacteria isolated from Karlodinium micrum were screened by agar-screening and MTT methods. The 16S rRNA genes were amplified from the genome DNA of those bacteria positive for both antibacterial and cytotoxic activities, which were cloned into pMD18-T vector for sequencing analysis. RESULTS: Twenty-five isolates had antimicrobial activity and 5 isolates (W-14-2, W-2-2, W-12, E-8-2 and W-4) had cytotoxicity. Molecular phylogenetic analysis of marine bacteria with cytotoxicity based on 16S rRNA sequences indicated that they exhibited the highest similarity (98%, 99%, 99%, 98% and 99%, respectively) to the 16S rRNA fragments of Alteromonas alvinellae, Stappia aggregata, Pelagibaca bermudensis, Marinobacter kribbensis and Maribacter dokdonensis. CONCLUSION: The bacteria with bioactivity in Karlodinium micrum were abundant. We obtained five strains positive for both antibacterial and cytotoxic activities, which provide a clue to understanding the mechanism of toxin biosynthesis in Karlodinium micrum based on epiphytic and endophytic bacteria. PMID- 20931874 TI - [Purification and characterization of ferulic acid esterase from Penicillium citrinum]. AB - OBJECTIVE: Extracellular feruloyl esterase (EC 3.1.1.73) from Penicillium citrinum culture filtrates was studied. The effect of feruloyl esterases on the enzymatic hydrolysis of brewer's spent grain was also investigated. METHODS: Feruloyl esterase was purified to homogeneity by ammonium sulfate precipitation, ion-exchange chromatography with a DEAE-Sepharose Fast Flow column, and column chromatography with a Phenyl-Sepharose 6 Fast Flow column. RESULTS: The purified homogeneous preparation of native feruloyl esterase had a molecular mass of 58 kDa by native-PAGE and a subunit molecular mass of 31 kDa by SDS-PAGE. The optimum enzymatic activity was achieved at pH 6.0 and 45 - 65 degrees C. The enzyme was stable at pH from 5.0 to 6.0 and temperature from 25 to 55 degrees C. The enzymatic activity was slightly enhanced by Mg2+, Fe2+, Mn2+, Ca2+, and Na+, whereas it was slightly inhibited by Zn2+, strongly inhibited by Cu2+, and completely inhibited by Hg2+ and phenylmethanesulfonyl fluoride. EDTA had a slight influence on the enzymatic activity. The determination of k(cat)/K(m) revealed that the enzyme hydrolyzed methyl p-coumarate, methyl sinapate, methyl ferulate, methyl caffeate, and the values were 823, 416, 103, and 0, respectively. The k(cat)/K(m) values showed that the enzyme hydrolyzed MpCA faster and more efficiently than all the other substrates. When the crude feruloyl esterase was used to hydrolyze the brewer's spent grain, about 7.2% of the alkaline-extractable ferulic acid could be released, with the concentration of 5 u feruloyl esterase /g. CONCLUSION: A feruloyl esterase was discovered. Its biochemical characteristics were different from what has been reported in literature. This provided an important basis for the exploitation of a feruloyl esterase. PMID- 20931875 TI - [Effect of environmental factors on bacterial community in Lake Dongping sediment]. AB - OBJECTIVE: In order to investigate the effect of environmental factors on the bacterial composition of Lake Dongping sediment. METHODS: We set six sampling points in Lake Dongping and sampled once in July and once October. Terminal Restriction Fragment Length Polymorphism (T-RFLP) method was used to analyze the bacterial diversity. Ammonium nitrogen (NH4(+)-N) , nitrate nitrogen (NO3(-)-N) , total nitrogen (TN), total phosphorus (TP), total organic carbon (TOC) and water depth were measured. RESULTS: T-RFLP profiles showed high similarity among samples. However, bacterial diversity indices were significant difference in various samples. The richness, diversity, and evenness in samples which were collected in dry season (October) were generally higher than those in wet season (July), and the bacterial species dominance was higher in wet season than that in dry season. Principal Component Analysis showed that the structure of bacterial communities in sample 2B was marked different from the other samples. The results of Canonical Correspondence Analysis suggested that the abundance of 558 bp T-RF was negatively correlated with NH4(+)-N, NO3(-)-N, TN, TP and TOC, but positively correlated with TOC/TN and the water depth; the abundance of 64.5, 164, 509, and 543 bp T-RFs were positively correlated with NH4(+)-N, NO3(-)-N, TN, TOC, TOC/TN and the water depth. The dominant bacteria in Lake Dongping sediments were Firmicutes and Proteobacteria. CONCLUSION: Environmental factors affect bacterial diversity of Lake Dongping sediments, although affect less on indigenous bacteria. PMID- 20931876 TI - [Construction of microbial metagenomic library and screening of a nematicidal protease gene in greenhouse cucumber soil infested with root-knot nematodes]. AB - OBJECTIVE: In order to search novel nematicidal protease genes, a metagenomic fosmid library was constructed and screened by uncultured method. METHODS: Density gradient centrifugation was used to extract and purify total greenhouse soil microbial DNA. After end-repair, ligation, packing and transformation, metagenomic fosmid library was constructed. At the same time, in order to screen the library, function-driven screening was used as a potential strategy, skim milk was served as substrate and root-knot nematodes as targets. RESULTS: The library contained 31,008 clones with the average insert fragment of 36.5 kb, including 1.13 Gbp microbial genetic information, so it was suitable for large scale microbial functional gene screening. By the function-driven screening, fosmid clone pro12 which contained the nematicidal protease gene was screened. Then, subclones were constructed and screened. A subclone named espro124a5 was screened. After analysis of gene structure, espro124a5 is a secreted extracellular protease and a database search for homologies revealed it possessed 45% identities with peptidase S15 from Maricaulis maris MCS10 (accession no. YP_ 756822 at NCBI). It is a novel serine protease. Besides these, it has the serine protease-conserved catalytic triad residues, Asp469, His541 and the catalytic nucleophile Ser348. CONCLUSION: DNA obtained from the method of Nycodenz density gradient centrifugation had high purity, long fragment, and can meet the requirements of constructing metagenomic fosmid library. At the same time, the metagenomic fosmid library contains a lot of microbial genetic information, which is suitable for the screening of the other microbial genetic resources. PMID- 20931877 TI - [Establishment and application of a high-throughput model for screening alpha glucosidase inhibitors]. AB - OBJECTIVE: Targeted at the important enzyme in human glucose metabolic pathway, the purpose of this paper is to establish alpha-glucosidase inhibitors high throughput screening model. METHODS: Pichia pastoris expression system was used to clone and express the human alpha-maltase glucosidase. Using the catalytic properties of enzyme to establish alpha-glucosidase inhibitor screening model. This model was applied in screening of actinomycete metabolites library. The taxonomic status of positive strains were analyzed by constructing 16S rRNA phylogenetic tree. RESULTS: The N-terminal catalytic domain of human alpha maltase glucosidase was successfully cloned and expressed for the first time. The high-throughput screening model of alpha-glucosidase inhibitors was established. A natural product library containing metabolites from nearly 2000 actinomycetes was screened, 20 alpha-maltase glucosidase inhibitor producing strains were obtained finally, of which, 19 strains initially identified as Streptomyces, and showed taxonomically rich diversity. CONCLUSION: The alpha-glucosidase inhibitor high-throughput screening model has high practical value, this work laid the foundation for developing new hypoglycemic drugs. PMID- 20931878 TI - [Comparison of six detection methods for classical swine fever virus]. AB - OBJECTIVE: We investigated the advantages and disadvantages of six methods to detect classical swine fever virus (CSFV). METHODS: We used six methods, including the virus isolation, colloidal gold immunochromatographic assay (CGIA), antigen-capture ELISA (AC-ELISA), reverse transcription-polymerase chain reaction (RT-PCR), TaqMan real-time RT-PCR (RT-qPCR) and reverse transcription-loop mediated isothermal amplification assay (RT-LAMP), to detect CSFV in 50 samples parallelly. RESULTS: The results showed that 13 samples were detected positive by RT-qPCR and RT-LAMP, 11 by PCR, 10 by virus isolation, 9 by AC-ELISA and 8 by CGIA, and 8 samples were detected positive and 37 samples negative by the six methods. CONCLUSION: These results indicated that the 3 RNA-amplification assays could be used as the first choice for detection of CSFV due to the high sensitivity, while they were vulnerable to false positive results arising from sample to sample contaminations or from other contaminated sources. Although the virus isolation was time-consuming, it was still considered the "gold standard" and was indispensable for confirming CSF outbreaks. The rest two methods, AC ELISA and CGIA, yielded the results in a short time yet their performance was hampered by a low sensitivity. Therefore, they were mainly used for herd diagnosis and not suitable for individual test for CSFV infection. PMID- 20931879 TI - [Ultrasonic treatment of soil samples for actinomycete isolation]. AB - OBJECTIVE: We used ultrasonic to treat soil samples to isolate rare actinomycetes strains. METHODS: We collected and suspended soil samples from mix tropical-rain forest in Xishuangbanna. Farther, we treated the soil suspension with ultrasound for 10 to 120 s and used the plate dilution method to isolate actinomycetes. After got pure colonies, we sequenced their 16S rRNA gene sequences and calculated to put in phylogenetic analysis. The isolates were identified to the genus. We treated 10 kinds of common and identified Streptomyces with 1 - 5 min using ultrasonic, and then were cultured to measure their survival rate. RESULTS: The soil suspensions treated with different times by the ultrasonic, actinomycetes gradual increased in the number and types. Ultrasonic treating of known Streptomyces with 0-5 min, there was no significant effect on the survival number of Streptomyces. CONCLUSION: The ultrasonic treating with soil suspensions for 40 s can significantly increase the total number of actinomycetes and the types of rare actinomycetes. Thereby, it is an economic and simple method to apparently increase the types of rare actinomycetes in the isolation. PMID- 20931880 TI - [Cloning, sequencing and identification of replication origin of Rhodococcus linear plasmid pNSL1]. AB - Two linear plasmids, pNSL1 and pNSL1, were detected from Rhodocuccus sp. NS1. OBJECTIVE: Cloning, sequencing and identification of replication origin of the Rhodococcus linear plasmid pNSL1. METHODS: Large amount of linear plasmid DNA was recovered from pulsed-field gels for shotgun-cloning and sequencing, and identification of its replication locus. RESULTS: The complete nucleotide sequence of pNSL1 consisted of 117252 bp, including the conserved 1282-bp telomere sequences among Rhodococcus linear plasmids. pNSL1 encoded 103 open reading frames, including functions of replication, maintenance and transfer etc. A locus, pNSL1. 038 and upstream 767-bp non-coding sequence, was identified for autonomous replication by cloning in an E. coli vector and introduced by electroporation into Nocardia coralline 4. 1037. CONCLUSION: Cloning and sequencing of Rhodococcus linear plasmid pNSL1, and identification of its replication origin. PMID- 20931881 TI - [Isolation PQQ biosynthesis gene cluster from Gluconobacter oxydans based on sorbose-dehydrogenase activity]. AB - OBJECTIVE: To isolate PQQ biosynthesis gene cluster from Gluconobacter oxydans H24 based on sorbose-dehydrogenase activity. METHODS: A library of Gluconobacter oxydans H24 genomic DNA was constructed with host strains Escherichia coli JM109s, which was integrated of sdh gene at the ptsG site on the chromosome of JM109. By detecting sorbose-dehydrogenase activity, clone of PQQ biosynthesis was isolated and subcloned. RESULTS: A positive clone was isolated from Gluconobacter oxydans H24 genomic DNA library. Within the 5,400-base-pair DNA fragment five reading frames are presented, corresponding to five of the pqq genes (pqqABCDE). The nucleotide and amino acid sequence showed highly homology to pqq genes of other bacteria. CONCLUSION: The pqqABCDE gene cluster was successfully isolated from Gluconobacter oxydans H24 by sorbose dehydrogenase activity. PMID- 20931882 TI - [Preparation and characterization of monoclonal antibodies specific for FlaA protein of Campylobacter jejuni]. AB - OBJECTIVE: We expressed and purified Campylobacter jejuni flagellin FlaA protein to develop monoclonal antibodies (mAbs) against this protein. METHODS: The C. jejuni flaA gene was amplified and inserted into the expression plasmids, pET30a (+) and pGEX-6p-1. The purified rHis-FlaA protein was used as an immunogen in 8 week-old BALB/c mice, and injected subcutaneously. The purified rGST-FlaA protein used as a detecting antigen for screening mAbs against FlaA was prepared by using a denaturation and renaturation technique. The specificity of mAbs was characterized by Dot-ELISA and Western blot assays. RESULTS: The recombinant expression plasmids, pET30a (+)-flaA and pGEX-6p-1-flaA were obtained. The sizes of the recombinant proteins, rHis-FlaA and rGST-FlaA, were consistent with their predicted size. Specific reaction was found between FlaA positive serum and expressed protein by Western-blot assay, confirming its identification as a Campylobacter jejuni immunogen. Three hybridoma cell lines, designated 2D12, 5A12 and 6A9, secreting mAbs against FlaA were obtained. Their immunoglobulin subclasses were IgG2a, IgG1 and IgG1, respectively. The ELISA titers of the ascites fluid were 1:102 400, 1:102 400 and 1:51 200, respectively. Western blot analysis confirmed that the three mAbs reacted with the rHis-FlaA fusion protein but not the His tag. The Dot-ELISA results demonstrated that the three mAbs only with FlaA and not the tags for the expression vectors. CONCLUSION: The successful preparation of three mAbs specific for the FlaA protein lays the foundation for further study regarding the biological characteristics of FlaA and the pathogenesis of C. jejuni. PMID- 20931883 TI - Coverage, recission reviews to get tougher in some states under reform. PMID- 20931884 TI - Pay raises in store for clinical executives. PMID- 20931885 TI - Defined contribution. Magic bullet? PMID- 20931886 TI - When is a brand a generic? In a contract with a PBM. PMID- 20931887 TI - $10B to study payment systems. PMID- 20931888 TI - Provenge approval means sensitive coverage decisions. PMID- 20931889 TI - Interim federal high-risk groups may far exceed $5B allocation. PMID- 20931890 TI - Social media are your friends. Interview by John Marcille. PMID- 20931891 TI - Helping Hispanics means improving preventive care. PMID- 20931892 TI - Holistic care management requires IT integration. PMID- 20931893 TI - Strengthening diuretics' role in hypertension. PMID- 20931894 TI - Program keeps dually-eligible adults out of nursing home. PMID- 20931895 TI - New players enter field of regenerative medicine. PMID- 20931896 TI - PPACA causes short-term increases in costs. PMID- 20931897 TI - Uphill battle. As number of uninsured rises, effort to repeal healthcare overhaul gets tougher. AB - The latest Census Bureau figures on the number of uninsured Americans gave more fuel to those behind the new healthcare law. The statistics show 50.7 million had no health insurance in 2009. "The economic downturn has affected everyone so it is not surprising that more people are without insurance," says Richard Umbdenstock, left, of the AHA. PMID- 20931898 TI - Bumpy ride for stocks. But hospital investors see reform as positive. PMID- 20931899 TI - Privacy, please. AHIMA voices concern over proposed privacy rule changes. PMID- 20931900 TI - Outsourcing sees stimulus effect. Health reform, ailing economy prompt a closer look at use of contractors. PMID- 20931901 TI - Who says it's hyperbolic? Midterm campaigns are bringing out the healthcare crazy talk. PMID- 20931902 TI - More than words. Hospital culture must change at its core to truly improve safety. PMID- 20931903 TI - Physician disciplinary actions by state. Ranked by total board actions in 2009. PMID- 20931904 TI - Domestic violence: its prevalence and profile. PMID- 20931905 TI - Acute toxicity and diuretic studies of the roots of Asparagus racemosus Willd in rats. AB - OBJECTIVE: Asparagus racemosus Willd has been used as diuretic in Ayurveda but has not been validated by a suitable experimental model. Hence the present study was undertaken. MATERIALS AND METHODS: The study was carried out with an aqueous extract of the roots of Asparagus racemosus utilizing three doses viz 800 mg/kg, 1600 mg/kg and 3200 mg/kg for its diuretic activity in comparison with standard drug (furosemide) and control (normal saline) rats after doing acute toxicity study. RESULTS: Acute toxicity study showed no fatality even with the highest dose and the diuretic study revealed significant diuretic activity (p < 0.05) in the dose of 3200 mg/kg. CONCLUSION: Asparagus racemosus showed diuretic activity at a 3200 mg/kg dose without acute toxicity. PMID- 20931906 TI - The Jamaica Injury Surveillance System: a profile of the intentional and unintentional injuries in Jamaican hospitals. AB - BACKGROUND: Injuries in Jamaica are a major public health problem as demonstrated by a hospital based computerized injury surveillance system established in 1999 that provides a risk profile for injuries. SUBJECTS AND METHOD: Injury data from 2004 were selected to provide an annual profile, as comprehensive injury data were available from nine public hospitals. These nine public hospitals provide care for 70% of the Jamaicans admitted to hospitals annually. RESULTS: Data are presented on unintentional injuries where falls caused 44%, lacerations 27% and accidental blunt injuries were 17% of these. For motor vehicle related injuries, 55% were sustained while commuting by motorcars, 17% while riding motorbikes/bicycles and 16% of those injured were pedestrians. Most violence related injuries were due to fights (76%) with acquaintances (47%) who used sharp objects (40%) to inflict the injury. CONCLUSION: The Jamaica Injury Surveillance System (JISS) data, augmented by data collected on injuries from the health centres and the sentinel surveillance system, give a measure of the magnitude of the impact of injuries on the health services. The JISS provides data on the profile of injuries seen and treated at health facilities in Jamaica. In collaboration with police data and community-based surveys, it can be used to complete the risk profiles for different types of injuries. The data generated at the parish, regional and national levels form the basis for the design and monitoring of prevention programmes, as well as serve to support and evaluate policy, legislative control measures and measures that impact on interventions. PMID- 20931907 TI - Seroprevalence of toxoplasmosis, leptospirosis and brucellosis in sugarcane field workers in Trinidad and Tobago. AB - Sugarcane field-workers, like rice field-workers, livestock farmers and abattoir workers are known to be occupationally exposed to zoonotic agents. The study determined the seroprevalence of immunoglobulins to Toxoplasma gondii (IgM), Leptospira spp (IgM) and Brucella abortus (IgG) in sugarcane field-workers across weighing stations in the island of Trinidad. In addition, the association of risk factors to infections by the three zoonoses was investigated. Blood samples were collected from consenting apparently healthy sugarcane field-workers across the island of Trinidad. Current/acute infection in individuals was determined in the sera of individuals using the enzyme immunoassay (EIA) for T gondii IgM antibodies, enzyme-linked immunosorbent assay (ELISA) for Leptospira spp IgM immunoglobulins and both buffered plate agglutination test (BPAT) and competitive ELISA for B abortus IgG antibodies. The seroprevalence of IgM immunoglobulins to T gondii was 15.7% (64 of 407) and to Leptospira spp was 0.7% (5 of 704) and the difference was statistically significant (p 0 < 0.05; chi2). All 704 samples tested for B abortus IgG immunoglobulins were negative. All risk factors (age, gender race and type of work done) were not statistically significantly (p > 0.05; chi2) associated with infections by T gondii and Leptospira spp. It was concluded that sugarcane field-workers in Trinidad were at high risk of acute toxoplasmosis and, to a lesser extent, to leptospirosis. The fact that the four risk factors studied were not significantly associated with T gondii and Leptospira spp infections suggests that they may not be important in the epidemiology of both diseases in the population studied. PMID- 20931908 TI - The prevalence of domestic violence within different socio-economic classes in Central Trinidad. AB - OBJECTIVES: Domestic violence is a medical and social issue that often leads to negative consequences for society. This paper examines the association between the prevalence of domestic violence in relation to the different socio-economic classes in Central Trinidad. The paper also explores the major perceived causes of physical abuse in Central Trinidad. SUBJECTS AND METHODS: Participants were selected using a two-stage stratified sampling method within the Couva district. Households, each contributing one participant, were stratified into different socioeconomic classes (SES Class) and each stratum size (or its share in the sample) was determined by the portion of its size in the sampling frame to the total sample; then its members were randomly selected. The sampling method attempted to balance and then minimize racial, age, cultural biases and confounding factors. The participant chosen had to be older than 16-years of age, female and a resident of the household. If more than one female was at home, the most senior was interviewed. RESULTS: The study found a statistically significant relationship between verbal abuse (p = 0.0017), physical abuse (p = 0.0012) and financial abuse (p = 0.001) and socio-economic class. For all the socio-economic classes considered, the highest prevalence of domestic violence occurred amongst the working class and lower middle socio-economic classes. The most prominent reasons cited for the physical violence was drug and alcohol abuse (37%) and communication differences (16.3%). These were the other two main perceived causes of the violence. The power of the study was 0.78 and the all strata prevalence of domestic violence was 41%. CONCLUSIONS: Domestic violence was reported within all socio-economic class groupings but it was most prevalent within the working class and lower middle socio-economic classes. The major perceived cause of domestic violence was alcohol/drug abuse. PMID- 20931909 TI - Trauma: the burden of a preventable problem. AB - Trauma is a leading cause of morbidity and mortality in developing countries and we reviewed the demographics and cost of trauma in a Jamaican population. This is a retrospective, descriptive analytical study of all trauma patients aged 25 to 29-years who presented to the University Hospital of the West Indies (UHWI) during the study period, January 2001 to December 2005. Data were extracted from the Trauma Registry and analysed. Seven hundred and fifteen patients were included in the specified age group over the five-year period. The median age of the patients was 27 years and the median hospital stay was 3 days. There was a 4:1 ratio of males to females and 49.7% of injuries were caused by penetrating wounds. Motor vehicle accidents occurred in 22.4% of cases. Head injuries occurred in 13.6% of cases, long bone fractures in 16.5% and internal injury to chest or abdominal organs in 15.9% of cases. Craniotomy or thoracotomy was undertaken in 4% of cases, Open Reduction Internal Fixation (ORIF) or bone immobilization in 11% and laparotomy in 8% of cases. The mean injury severity scores (ISS) was 4 while 5% of patients had ISS greater than 15. More than 60% of patients underwent diagnostic X-rays, 8% had abdominal imaging (CT scan or ultrasound) and 9.5% underwent head CT scan. The in-hospital mortality was 4.2%. The median hospital bill charged was US$320.00 and the median amount paid by the patients was US$50.00. At the start of the new millennium, penetrating trauma accounted for almost 50% of cases at UHWI with the majority of costs associated with trauma-care being state funded. PMID- 20931910 TI - Small babies on a small island: survival of very low birthweight infants in Antigua and Barbuda 1986 to 2006. AB - INTRODUCTION: Recent attention has been focussed on pregnancy outcomes in developing countries, with the publication of the World Health Organization Report 2005, Make Every Mother and Child Count and the Neonatal Survival Series from the Lancet in 2005. Scant outcome data from the smaller islands of the Caribbean exist for very low birthweight (VLBW) babies (birthweight < 1500 g). PATIENTS AND METHODS: A retrospective review of mortality data on VLBW babies in Antigua and Barbuda was performed. Antigua and Barbuda had a population of 71 500 with per capita income of (US) $6054 dollars in 1998. In November 1985, a neonatal Special Care Nursery (SCN) was established. The survival to discharge from SCN for VLBW babies was reviewed from January 1986 to December 2006. RESULTS: There were 26 455 babies born from 1986 to 2006; 344 (1.3%) were VLBW babies. Survival to SCN discharge was 45% from 1986 to 1992, 46% from 1993 to 1999, and increased to 60% from 2000 to 2006 (p < 0.05 compared with the first two time-periods). Babies from 1000 to 1499 g accounted for 64% of VLBW babies and survival to SCN discharge was 60% from 1986 to 1992, 58% from 1993 to 1999, and increased to 83% from 2000 to 2006 (p < 0.01 compared with the first time period; p < 0.001 compared with the second). Babies < 1000g accounted for 36% of VLBW babies and survival to SCN discharge was 10% from 1986 to 1992, increased to 25% from 1993 to 1999 and to 28% from 2000 to 2006 (trend of p < 0.10 compared with first time period). Conservative newborn care only was available. Antenatal steroids were given from 2000 to 2006. CONCLUSION: The outlook for VLBW babies using conservative newborn care techniques has significantly improved over 21 years in Antigua and Barbuda. PMID- 20931911 TI - HTLV-1 related knowledge, attitude and behaviour patterns among mothers who participated in the Jamaica Breastfeeding Intervention Study (1996-2000). AB - Human T-cell Lymphotropic Virus type-1 (HTLV-1), the first human retrovirus associated with a malignant disease, is endemic in Jamaica. Vertical transmission and sexual intercourse are the major routes of transmission. Women are at greater risk of contracting the virus as it is more efficiently transmitted from male to female than in the reverse. Prevention of transmission is best achieved by health education on safe practices. The study aims to document the knowledge, attitude and behaviour pattern (KABP) of a group of women five years after they had participated in a mother-to-child transmission of HTLV-1 risk reduction study. A cross-sectional study was conducted using a 46-point structured interviewer administered questionnaire to capture data from 88 mothers. Overall knowledge scores were computed and four rating categories created. There were large deficiencies in the knowledge and practice of women at risk of being infected with HTLV-1. Only 58% knew that HTLV-1 is sexually transmitted. A minority was aware of HTLV-1 associated diseases: Adult T-cell lymphoma/leukaemia (ATL) 30.7%; Tropical Spastic Paraparesis (TSP) -42%; Infective dermatitis -42%). Ten (11.4%) believed that HTLV-1 infection can cause HIV/AIDS and only 33% knew that there was no cure for the virus. Most women (88.6%) continued to have unprotected sex. Controlling HTLV-1 spread must be based on interrupting transmission. In Jamaica, donated blood is screened for HTLV-1 and sharing of infected needle is an insignificant mode of transmission. However although safe practices in breastfeeding and sexual intercourse are proven ways to reduce HTLV-1 transmission, these data show that knowledge and safe practices among those at risk may not be retained and health education will need to be sustained. PMID- 20931912 TI - What does the medical student know about eye donation/corneal transplant? The University of Nigeria scenario. AB - OBJECTIVE: The study was designed to determine the knowledge of eye donation and corneal transplant among final year medical students of The University of Nigeria, Enugu Campus (UNEC). METHODS: Self-administered structured questionnaires were distributed to the members of the final year (graduating) class of the Medical College of UNEC in June 2007. Responses were obtained to questions bordering on eye donation and corneal transplant. RESULTS: One hundred and thirty-one students out of 183 eligible students participated in the study (response rate = 71.6%). One hundred and four students (79.4%) were aware of eye donation/corneal transplant. However 95 students (72.5%) were not aware that the eyes can only be removed from a dead donor. Eighty-four students (64.1%) were not aware that eyes with cataract could be donated. Eighty-seven (66.4%) students were not willing to pledge their eyes for donation. CONCLUSION: Medical students lack adequate knowledge about some aspects of eye donation and corneal transplantation. This may be a predictor of the level of awareness among the general public. Concerted innovative education and information dissemination strategies are required at this stage of national development to address the misconceptions surrounding eye donation and corneal transplant. There is a need to target medical students as future motivators, counsellors and eye donors. This should help advance the eye donation rates in Nigeria whenever the plans for the establishment of an eye-bank are finalized. PMID- 20931913 TI - Students' perception of the 'educational climate' at the Faculty of Medical Sciences, The University of the West Indies, Jamaica. AB - BACKGROUND: In 2001, the Faculty of Medical Sciences at the Mona Campus of The University of the West Indies (UWI) introduced a restructured curriculum in keeping with advances in the philosophy of medical education. OBJECTIVES: To explore the quality of the educational environment in the Undergraduate Medical Programme at the Mona campus of the UWI to identify areas for improvement and examine for any differences in student perception in a transitional medical curriculum. METHODS: The Dundee Ready Education Environment Measure (DREEM) was self-administered and completed anonymously during April 2004 by 278 (70%) undergraduate medical students (cohorts 2004 - 2007) registered in the Faculty of Medical Sciences, Mona Campus, Jamaica. RESULTS: The overall mean DREEM score was 102.80 +/- 21.88 (maximum score 200; the higher the score, the more favourable the perception) and there was no significant difference by year of study. Teacher knowledge was highly rated by students but this was overshadowed by concerns about attitudes and behaviour toward students. The quality of the learning atmosphere was poorly rated with general concerns of an overcrowded curriculum, time-table issues and lack of adequate support systems to deal with student stress. CONCLUSIONS: Curriculum managers must identify strategies to improve the student-centredness and student-friendliness of the school's educational environment. PMID- 20931914 TI - Client characteristics associated with failure to complete residential treatment at a multicultural drug and alcohol treatment facility in Antigua, West Indies. AB - The purpose of this study is to compare the demographic and clinical characteristics of clients leaving treatment prior to completion of the 29-day residential stay at a multicultural addiction treatment centre. The charts of 446 clients (62% from the United States of America, 29% from the Caribbean region, 9% European) were reviewed. The mean age was 39.7 years, 33% female, with 91% using alcohol, 49% using cocaine, 25% using opioids (single drug 27%, poly-drug use 73%), with mean 13.1 years of harmful use, 33% using prescribed mental health medications and 46% having had prior residential treatment. Of 446 clients, 76 (17%) did not complete treatment stay. A comparison of clients leaving early and those completing stay revealed no difference in age (38.6 vs 39.9 years) or years of harmful use (11.7 vs 13.4 years). There were trends toward those leaving to be more often female (42 vs 31%, p < 0.10) and non-Caribbean (20% American or European vs 12% Caribbean, p < 0.10). Clients who left early were more likely to use opioids (41 vs 22%, p < 0.001) and less likely to use alcohol/sedative (83 vs 1%, p < 0.02). Cocaine/stimulant use did not differ (49 vs 49%). Those leaving treatment early had greater use of mental health medications (50 vs 29%, p < 0.001). Prior treatment was not significantly different (53 vs 44%). An analysis of the 128 clients from the Caribbean region showed 15 clients (12%) failed to complete treatment. Those leaving treatment early were more likely to be female (53 vs 26%, p < 0.05), had a trend toward being younger (35.6 vs 39.9 years, p = 0.19) and had fewer years of harmful use (8.1 vs 13.1, p < 0.02). Ethnicity (73 vs 74% African) and alcohol/sedative (87 vs 94%), cocaine/stimulant (53 vs 65%), and opioid use (0 vs 4%) did not differ. Those leaving were more likely to use mental health medication (47 vs 12%, p < 0.001) and there was a trend toward prior treatment (40 vs 23%, p < 0.10). PMID- 20931915 TI - Pathology and therapeutic results in patients with intraosseous ganglia of the carpal bone. AB - This study evaluated the pathology and therapeutic results of seven patients with intraosseous ganglia of the carpal bone. The mean age at the time of surgery was 27.6 years. The lesions were localized in the proximal carpal row in six patients and in the distal carpal row in only one. Surgical treatment was performed in all patients with good bone union. None had pain during activity or at rest and no recurrence had occurred. The intraosseous ganglia in four patients was of the idiopathic type, and in the other three patients was of the penetrating type. Although intraosseous ganglia of the carpal bone is reported as a rare disease, there were 159 cases in the literature. The pathology was intra- or extraosseous development, showing variation, but most cases were localized in the proximal carpal row. PMID- 20931916 TI - Supporting cancer patients in Jamaica--a needs assessment survey. AB - OBJECTIVE: Global cancer incidence is rising rapidly particularly in the developing world where a majority of people present with advanced disease. In the English-speaking Caribbean, there is very little published data on the needs of cancer patients, their caregivers or those of allied health professionals. The research team sought to redress this balance by undertaking a needs assessment survey in the South Eastern Health Region of Jamaica to identify unmet needs and to make recommendations for improved service delivery. METHODS: A mixed methods, cross-sectional study design was used involving formal and semi-formal interviews and focus group discussions. RESULTS: The study results indicated that there were significant barriers to accessing healthcare. These included prohibitive costs of diagnosis and treatment, a mistrust of and poor communication with doctors, compounded by people's fears, belief in folk wisdom and lack of knowledge about cancer. Recommendations offered by the study participants focussed on a community based model of support to address the multiple needs of people facing life limiting illness and their caregivers. Healthcare practitioners recommended the development of specific policies, targeting, in particular improved drug availability and palliative care education in order to guide development of appropriate services for the large numbers of cancer patients in need. CONCLUSION: A multiplicity of unmet needs was identified by cancer patients, their caregivers and allied health professionals. Recommendations by study participants and the authors echoed the guidelines as set out by the World Health Organization (WHO) in its 1990 Public Health Model for the integration of palliative care into existing healthcare systems. PMID- 20931917 TI - Red cell transfusion practices and the impact of phlebotomy in an adult intensive care unit in Trinidad--a prospective observational study. AB - OBJECTIVES: To determine the pattern of current red cell transfusion practices in an adult intensive care unit (ICU) in Trinidad and the impact of phlebotomy on transfusions. METHODS: A prospective observational study was conducted over a six month period to include all patients who received transfusions in the ICU of Port of-Spain General Hospital, Trinidad. Demographic data including age, gender and weight were recorded. Clinical data recorded were the admission APACHE II scores, daily phlebotomy volumes, haemoglobin levels, transfusions and outcome during the first thirty days following ICU admission. Patients were grouped according to diagnoses and transfusion patterns. RESULTS: Of 134 patients admitted, 40 (29.8%) were transfused packed red cells 18 (29%) of the requests were for single unit transfusion. The mean phlebotomy volume was 13.5 +/- 4.3 (SD) mL day. The adjusted phlebotomy volume to body weight did not correlate with the amount of transfusions. The mean haemoglobin level for triggering blood transfusion was 6.73 g dL. The mean transfusion rate was 2.9 +/- 1.8 (SD) units per patient. Ten per cent of the patients received more than 5 units. Twenty nine per cent of the units were transfused on the first day of ICU admission and 69% were transfused during the first week of LCU stay. CONCLUSIONS: Transfusion practices in the study ICU pointed towards a restrictive strategy, although there were some inappropriate transfusions. The phlebotomy volumes did not contribute towards transfusion requirements. PMID- 20931918 TI - Pharmacovigilance: healthcare professionals' role in benefits versus harm analysis of drugs use. AB - Monitoring the negative effect of drugs is a concept that all healthcare professionals would be aware of as part of their professional responsibility. However since 1968, it has evolved into a structured science called 'Pharmacovigilance'. This review aims to sensitize Caribbean healthcare professionals to the global pharmacovigilance network of the World Health Organization and how their active involvement at the national level is imperative to the benefit versus harm evaluation of drugs. PMID- 20931919 TI - An intense influenza pandemic--possible subtype of H5N1: its implications for Jamaica. AB - Using two different attack rates, 20% and 30%, the paper attempts to project several possible outcomes for the Jamaican economy in the event of a severe pandemic. In addition to forecasting the possible loss in man hours for the economy, the study uses the Monte Carlo modelling technique to provide estimates of the death and hospitalization rates among the 0-19, 20-64 and 65(+)-year age cohorts while extra-polating the demand for healthcare providers. PMID- 20931920 TI - Substance abuse treatment--the special needs populations. PMID- 20931921 TI - Duodenal fibrosarcoma mimicking Franz tumour complicated by post-resection chylous ascites. AB - This case report presents a young woman who underwent a Whipples resection for a large pan-creato-duodenal tumour. Pathology and immunohistochemical analysis of the tumour suggest duodenal fibrosarcoma. The patient's postoperative management was complicated by chylous ascites. A brief literature review is given to highlight this unusual case. PMID- 20931922 TI - Jaundice post laparoscopic cholecystectomy. AB - In just over 20 years, laparoscopic cholecystectomy has emerged as the standard therapy for cholelithiasis and is now being performed with increased safety. However an uncommon complication of this technique has been jaundice even in patients without iatrogenic bile duct injury. We report on two cases where this complication occurred and review the literature on this topic. PMID- 20931923 TI - Childhood bruxism: a clinical review and case report. AB - The present case report refers to a patient who reported to the department with the complaint of teeth grinding (Bruxism). A brief review of the literature is reported concerning the aetiology, clinical diagnosis and the therapeutic approach of the disease. PMID- 20931924 TI - Keratosis palmoplantaris associated with early-onset periodontitis: a case report. AB - Keratosis palmoplantaris associated with periodontopathy or Papillon Lefevre syndrome is a very rare genetic disorder with autosomal recessive mode of inheritance and is characterized by hyperkeratosis of the palms and soles and early onset of a severe destructive periodontitis. The clinical presentation, differential diagnosis, therapeutic and periodontal management of an 8-year old male child diagnosed with this syndrome is discussed. PMID- 20931925 TI - Citalopram related euprolactinaemic galactorrhoea: a case report. PMID- 20931926 TI - Skin eruption and thrombocytopaenia in a woman with glaucoma: a case report. AB - Antibiotic and non-antibiotic sulphonamides are often prescribed. Although chemical differences make cross-reactivity rare, reactions may be severe in patients allergic to sulphur. Adverse reactions are common with sulphonamides but low platelets and skin changes are rarely associated with eye-drops for glaucoma. A woman treated with dorzolamide and timolol presented with disseminated eruption. On admission, her physical examination was unremarkable except for the skin changes and severe thrombocytopaenia was detected. Skin biopsy showed hyperkeratosis, acanthosis, perivascular and periadnexal infiltrates with no vasculitis. After discontinuation of eye-drops, the eruption improved but low platelets persisted. Skin changes reappeared with use of dapsone which suggested sulphonamide cross-reactivity. PMID- 20931927 TI - The usefulness of latissimus dorsi transfer for reconstruction for malignant fibrous histiocytoma in the infraspinatus muscle region: a case report. AB - Malignant fibrous histiocytoma (MFH) is a type of highly malignant soft tissue sarcoma with a predilection for the extremities of adults. We report a patient with MFH in the infraspinatus muscle for which wide resection including total resection of the infraspinatus muscle was performed, followed by transfer of the latissimus dorsi muscle for shoulder reconstruction in a one-stage operation with good postoperative function. PMID- 20931928 TI - Solitary metastasis of the patella in the differential diagnosis of anterior knee pain. PMID- 20931929 TI - A case of pulmonary oedema induced by suffocation. AB - A 57-year old female civilian was suffocated by an intruder The victim (experienced severe dyspnoea) but violently resisted the assault. Two hours after this event, on admission to a Trauma Centre, she demonstrated left facial swelling with low percutaneous oxygen saturation. Chest X-ray and computed tomography demonstrated pulmonary oedema. This improved dramatically within a short time and she was discharged on the 5th hospital day. Pulmonary oedema induced by suffocation has been reported only rarely. The possible mechanisms by which pulmonary oedema might form after the relief of airway obstruction are discussed. PMID- 20931930 TI - A comparison of cisplatin and carboplatin: a short review. PMID- 20931931 TI - A short review summarizing literature on immediate measures to prevent sexually transmitted diseases: focusing on current conditions in Japan. PMID- 20931932 TI - Improvement of total health measures in Mie Prefecture, Japan Mie. PMID- 20931933 TI - First steps along the road to meaningful use. PMID- 20931934 TI - Meaningful use: the long road. CIOs prepare for ramped-up requirements in later stages. PMID- 20931935 TI - Meaningful use: front-runners. On the long road toward meaningful use, these four organization all gave themselves a head start. PMID- 20931936 TI - Split screen: CIOs help their physicians with meaningful use. Limited resources and crunched timeframes mean more attention on the needs of employed physicians. PMID- 20931937 TI - Is ICD-10 a quality initiative? Innovators will use ICD-10 to further their business models and clinical capabilities. PMID- 20931938 TI - Taking it to the clouds. The image movement of Montana starts sharing images via cloud-based solution. PMID- 20931940 TI - Evidence-based Order sets and CPOE. Interview by Mark Hagland. PMID- 20931939 TI - KLAS 2010 mid-term performance review: beyond the numbers. Under the gun. PMID- 20931941 TI - Benefits of an early start with EMR. The early roll-out of an EMR system was met with skepticism, but has resulted in higher performance and patient care quality. PMID- 20931942 TI - Meaningful use anxiety. Interview by Mark Hagland. PMID- 20931943 TI - Tracking the evolution of HIEs. Interview by Mark Hagland. PMID- 20931944 TI - Where healthcare reform Meets HIE. Interview by Mark Hagland. PMID- 20931945 TI - Oklahoma to build statewide HIE. Interview by Jennifer Prestigiacomo. PMID- 20931946 TI - Hiring your replacement. Finding senior-level talent who will one day step into your shoes is the most important hiring decision you can make. PMID- 20931948 TI - Ab initio study of hydrazinyl radical: toward a DMBE potential energy surface. AB - A series of stationary structures of the hydrazinyl radical have been characterized by optimization at the CCSD(T)/cc-pVTZ level of theory. CCSD(T)/aug cc-pVXZ single-point calculations have also been carried out at the optimized geometries with basis sets of different cardinal numbers (X = T, Q), which were used to obtain accurate energies via extrapolation to the complete basis set limit. A discussion on the analytical modeling of the potential energy surface of hydrazinyl is also presented. PMID- 20931949 TI - Ab initio study of the VUV-induced multistate photodynamics of formaldehyde. AB - Although formaldehyde, H2CO, has been extensively studied there are still several issues not-well understood, specially regarding its dynamics in the VUV energy range, mainly due to the amount of nonadiabatic effects governing its dynamics. Most of the theoretical work on this molecule has focused on vertical excitation energies of Rydberg and valence states. In contrast to photodissociation processes involving the lowest-lying electronic states below 4.0 eV, there is little known about the photodynamics of the high-lying electronic states of formaldehyde (7-10 eV). One question of particular interest is why the (pi, pi*) electronic state is invisible experimentally even though it corresponds to a strongly dipole-allowed transition. In this work we present a coupled multisurface 2D photodynamics study of formaldehyde along the CO stretching and the symmetric HCH bending motion, using a quantum time-dependent approach. Potential energy curves along all the vibrational normal modes of formaldehyde have been computed using equation-of-motion coupled cluster including single and double excitations with a quadruply augmented basis set. In the case of the CO stretching coordinate, state-averaged complete active space self-consistent field followed by multireference configuration interaction was used for large values of this coordinate. 2D (for the CO stretching coordinate and the HCH angle) and 3D (including the out-of-plane distortion) potential energy surfaces have been computed for several Rydberg and valence states. Several conical intersections (crossings between potential energy surfaces of the same multiplicity) have been characterized and analyzed and a 2D 5 * 5 diabatic model Hamiltonian has been constructed. Based on this Hamiltonian, electronic absorption spectra, adiabatic and diabatic electronic populations and vibrational densities have been obtained and analyzed. The experimental VUV absorption spectrum in the 7-10 eV energy range is well reproduced, including the vibrational structure and the high irregularity in the regime of strong interaction between the (pi, pi*) electronic state and neighboring Rydberg states. PMID- 20931950 TI - Mechanistic aspects of radiation-induced oligomerization of 3,4 ethylenedioxythiophene in ionic liquids. AB - Thiophene and its disubstituted derivatives, such as 3,4-ethylenedioxythiophene (EDOT), 3,4-dimethoxythiophene (DMT), 3,4-propylenedioxythiophene (PDOT), and 3,4 butylenedioxythiophene (BuDOT) were oxidized in organic solvents and in ionic liquid 1-butyl-3-methylimidazolium hexafluorophosphate (BMIM(+)PF6-) at RT and under cryogenic conditions. Their radical cations were spectrally characterized at 77 K. Annealing of the irradiated matrix, which triggers the diffusion processes, led to spontaneous oligomerization. The oxidative coupling between a radical cation and a neutral monomer was identified as the first step of the oligomerization process. The scale of oligomerization could be extended by the addition of chloroform, which acts as a dissociative electron scavenger, whereas the dichloromethylperoxyl radicals formed in the reaction with the dissolved oxygen act as secondary oxidizing agents. PMID- 20931951 TI - Correlated ab initio spin densities for larger molecules: orbital-optimized spin component-scaled MP2 method. AB - The performance of the orbital-optimized MP2 method (OO-MP2) and its spin component-scaled variant is investigated for the prediction of atomic and molecular hyperfine coupling constants (hfccs). The calculated hfccs are compared to experimental as well as to CCSD(T) reference results. The OO-MP2 isotropic hfccs for a series of small radicals are almost of CCSD quality but are obtained with iterative O (N5) effort. The dipolar hfccs are less well predicted by the OO MP2 methods, whereas spin-component scaling improves the description of the hyperfine structure. The spin contamination in the OO-MP2 wave function is drastically reduced compared to the standard unrestricted Hartree-Fock wave function. The applicability of the OO-MP2 to fairly large systems is demonstrated for the solvated p-benzosemiquinone radical anion, where calculations with almost 2000 basis functions have been performed. PMID- 20931952 TI - Theoretical study on the thermodynamic properties and self-decomposition of methylbenzenediol isomers. AB - Alkylated hydroxylated aromatics are major constituents of various types of fuels, including biomass and low-rank coal. In this study, thermochemical parameters are obtained for the various isomeric forms of methylbenzenediol isomers in terms of their enthalpies of formation, entropies, and heat capacities. Isodesmic work reactions are used in quantum chemical computations of the reaction enthalpies for O-H and H2C-H bond fissions and the formation of phenoxy- and benzyl-type radicals. A reaction potential energy on the singlet state surface surface is mapped out for the unimolecular decomposition of the 3 methylbenzene-1,2-diol isomer. According to the calculated high pressure-limit reaction rate constants, concerted hydrogen molecule elimination from the methyl group and the hydroxyl group, in addition to intermolecular H migration from the hydroxyl group, dominates the unimolecular decomposition at low to intermediate temperatures (T <= 1200 K). At higher temperatures, O-H bond fission and concerted water elimination are expected to become the sole decomposition pathways. PMID- 20931953 TI - The quadrupole moment of substituted cyclopentadienyl anions. AB - Previous work in our group on the cation binding of substituted cyclopentadienyl anions (Cp) showed the curious result that Cp traceless electric quadrupole moments (Theta(zz)) are almost all positive. Probing this issue further here we show that substituted Cp Theta(zz) values are always significantly more positive than the analogous substituted benzenes. Given the nature of aromatic Theta(zz) values, this is the opposite of what would be predicted. Furthermore, we show that the quadrupole moments of Cp anions do not behave as one would expect based on Cp substitutions. Unlike the quadrupole moments of substituted benzenes, which generally become more negative with the addition of electron-donating groups and more positive with the addition of electron-withdrawing groups, Cp quadrupole moments become more positive when any substituent is added, regardless of the electron-donating/withdrawing nature of the substituent. To explain these results we propose a model where the anionic Cp pi-electron density repels the substituent electron density toward the molecular periphery and AIM calculations support this view. PMID- 20931954 TI - Intramolecular vibrational energy redistribution in aromatic molecules of type C6H5X (X = H, D, F, Cl, CH3, CF3). AB - Femtosecond IR pump UV probe spectroscopy was employed in the gas phase to study intramolecular vibrational energy redistribution (IVR) in benzene and five monosubstituted derivatives thereof. After selective excitation of the first overtone of the ring CH-stretch vibration, all molecules showed the same two-step redistribution dynamics characteristic for nonstatistical IVR. The nature of the substituent influences mainly the second, slower IVR component. The presence of an internal rotor does not alter the redistribution rate or pathway compared to that of a monatomic substituent of equal mass. Coupling order model calculations reflect the experimental trends well if the polyatomic substituents are regarded as decoupled from the intra-ring dynamics and modeled as point masses. PMID- 20931955 TI - Nonadiabatic reaction of energetic molecules. AB - Energetic materials store a large amount of chemical energy that can be readily converted into mechanical energy via decomposition. A number of different ignition processes such as sparks, shocks, heat, or arcs can initiate the excited electronic state decomposition of energetic materials. Experiments have demonstrated the essential role of excited electronic state decomposition in the energy conversion process. A full understanding of the mechanisms for the decomposition of energetic materials from excited electronic states will require the investigation and analysis of the specific topography of the excited electronic potential energy surfaces (PESs) of these molecules. The crossing of multidimensional electronic PESs creates a funnel-like topography, known as conical intersections (CIs). CIs are well established as a controlling factor in the excited electronic state decomposition of polyatomic molecules. This Account summarizes our current understanding of the nonadiabatic unimolecular chemistry of energetic materials through CIs and presents the essential role of CIs in the determination of decomposition pathways of these energetic systems. Because of the involvement of more than one PES, a decomposition process involving CIs is an electronically nonadiabatic mechanism. Based on our experimental observations and theoretical calculations, we find that a nonadiabatic reaction through CIs dominates the initial decomposition process of energetic materials from excited electronic states. Although the nonadiabatic behavior of some polyatomic molecules has been well studied, the role of nonadiabatic reactions in the excited electronic state decomposition of energetic molecules has not been well investigated. We use both nanosecond energy-resolved and femtosecond time resolved spectroscopic techniques to determine the decomposition mechanism and dynamics of energetic species experimentally. Subsequently, we employ multiconfigurational methodologies (such as, CASSCF, CASMP2) to model nonadiabatic molecular processes of energetic molecules computationally. Synergism between experiment and theory establishes a coherent description of the nonadiabatic reactivity of energetic materials at a molecular level. Energetic systems discussed in this Account are nitramine- and furazan-based species. Both energetic species and their respective model systems, which are not energetic, are studied and discussed in detail. The model systems have similar molecular structures to those of the energetic species and help significantly in understanding the decomposition behavior of the larger and more complex energetic molecules. Our results for the above systems of interest confirm the existence of CIs and energy barriers on the PESs of interest. The presence of the CIs and barriers along the various reaction coordinates control the nonadiabatic behavior of the decomposition process. The detailed nature of the PESs and their CIs consequently differentiate the energetic systems from model systems. Energy barriers to the chemically relevant low-lying CIs of a molecule determine whether that molecule is more or less "energetic". PMID- 20931956 TI - Infrared optical activity: electric field approaches in time domain. AB - Vibrational circular dichroism (VCD) spectroscopy provides detailed information about the absolute configurations of chiral molecules including biomolecules and synthetic drugs. This method is the infrared (IR) analogue of the more popular electronic CD spectroscopy that uses the ultraviolet and visible ranges of the electromagnetic spectrum. Because conventional electronic CD spectroscopy measures the difference in signal intensity, problems such as weak signal and low time-resolution can limit its utility. To overcome the difficulties associated with that approach, we have recently developed femtosecond IR optical activity (IOA) spectrometry, which directly measures the IOA free-induction-decay (FID), the impulsive chiroptical IR response that occurs over time. In this Account, we review the time-domain electric field measurement and calculation methods used to simultaneously characterize VCD and related vibrational optical rotatory dispersion (VORD) spectra. Although conventional methods measure the electric field intensity, this vibrational technique is based on a direct phase-and amplitude measurement of the electric field of the chiroptical signal over time. This method uses a cross-polarization analyzer to carry out heterodyned spectral interferometry. The cross-polarization scheme enables us to selectively remove the achiral background signal, which is the dominant noise component present in differential intensity measurement techniques. Because we can detect the IOA FID signal in a phase-amplitude-sensitive manner, we can directly characterize the time-dependent electric dipole/magnetic dipole response function and the complex chiral susceptibility that contain information about the angular oscillations of charged particles. These parameters yield information about the VCD and VORD spectra. In parallel with such experimental developments, we have also calculated the IOA FID signal and the resulting VCD spectrum. These simulations use a quantum mechanical/molecular mechanical molecular dynamics (QM/MM MD) method and calculate the electric dipole/magnetic dipole cross-correlation function in the time domain. Although many quantum chemistry calculation approaches can only consider a limited number of geometry-optimized conformations of chiral molecules in a gas phase, this computational method includes the solute-solvent interactions and the inhomogeneous distributions of solute conformers in condensed phases. A subsequent Fourier transformation of the chiral response function produced a theoretical VCD spectrum in the entire mid-IR frequency range. Directly comparing theory and experiment, we demonstrate quantitative agreement between frequency-tunable femtosecond IOA measurements and QM/MM MD simulations of (1S)-beta-pinene in CCl(4) solution. We anticipate that these direct IOA measurement and calculation methods will be applied to the studies of equilibrium chiroptical properties and structure determinations. These methods provide tools to investigate ultrafast structural dynamics of chiral systems with unprecedented time resolution. PMID- 20931957 TI - Self-assembled terplexes for targeted gene delivery with improved transfection. AB - To improve transfection efficiency and to incorporate target ligands to the gene delivery systems, heparin and heparin-biotin were introduced to complexes of polyamidoamine dendrimer and DNA (PAMAM/DNA) via electrostatic interactions to form self-assembled PAMAM/DNA/heparin and PAMAM/DNA/heparin-biotin terplexes, respectively. The self-assembled terplexes were characterized by agarose gel electrophoresis and particle size analysis. The MTT assay indicated that, after incorporation of heparin and heparin-biotin, the terplexes exhibited decreased cytotoxicity. In addition, as compared with PAMAM/DNA and PAMAM/DNA/heparin complexes, the PAMAM/DNA/heparin-biotin complexes exhibited much higher cellular uptake into HeLa cells due to the specific interactions between biotin and biotin receptors on HeLa cells, which led to the enhanced transfection activity. The PAMAM/DNA/heparin-biotin complexes would be a promising targeting gene delivery system. PMID- 20931958 TI - Cold gelation of alginates induced by monovalent cations. AB - A new reversible gelation pathway is described for alginates in aqueous media. From various samples differing by their mannuronic/guluronic content (M/G), both enthalpic and viscoelastic experiments demonstrate that alginates having a high M content are able to form thermoreversible assemblies in the presence of potassium salts. The aggregation behavior is driven by the low solubility of M-blocks at low temperature and high ionic strength. In semidilute solutions, responsive assemblies induce a strong increase of the viscosity below a critical temperature. A true physical gel is obtained in the entangled regime, although the length scale of specific interactions between M-blocks decreases with increasing density of entanglements. Cold setting takes place at low temperatures, below 0 degrees C for potassium concentrations lower than 0.2 mol/kg, but the aggregation process can be easily shifted to higher temperatures by increasing the salt concentration. The self-assembling process of alginates in solution of potassium salts is characterized by a sharp gelation exotherm and a broad melting endotherm with a large hysteresis of 20-30 degrees C between the transition temperatures. The viscoelastic properties of alginate gels in potassium salts closely depend on thermal treatment (rate of cooling, time, and temperature of storage), polymer and salt concentrations, and monomer composition as well. In the case of alginates with a high G content, a similar aggregation behavior is also evidenced at higher salt concentrations, but the extent of the self-assembling process remains too weak to develop a true gelation behavior in solution. PMID- 20931959 TI - Microfluidic immunosensor with micromagnetic beads coupled to carbon-based screen printed electrodes (SPCEs) for determination of Botrytis cinerea in tissue of fruits. AB - A wide range of plant species, including economically important crops such as vegetables, ornamentals, bulbs, and fundamentally fruits, can be affected by gray mold caused by the fungal pathogen Botrytis cinerea . This paper describes the development of a microfluidic immunosensor with micromagnetic beads (MMBs) coupled to carbon-based screen-printed electrodes (SPCEs) for the rapid and sensitive quantification of B. cinerea in apple (Red Delicious), table grape (pink Moscatel), and pear (William's) tissues. The detection of B. cinerea was carried out using a competitive immunoassay method based on the use of purified B. cinerea antigens immobilized on 3-aminopropyl-modified MMBs. The total assay time was 40 min, and the calculated detection limit was 0.008 MUg mL(-1). Moreover, the intra- and interassay coefficients of variation were below 7%. The developed method allowed detects B. cinerea even in asymptomatic fruits and promises to be particularly useful for application in the agricultural industry. PMID- 20931960 TI - Multialkylation of aqueous ammonia with alcohols catalyzed by water-soluble Cp*Ir ammine complexes. AB - Novel water-soluble Cp*Ir-ammine complexes have been synthesized, and a new and highly atom-economical system for the synthesis of organic amines using aqueous ammonia as a nitrogen source has been developed. With a water-soluble and air stable Cp*Ir-ammine catalyst, [Cp*Ir(NH(3))(3)][I](2), a variety of tertiary and secondary amines were synthesized by the multialkylation of aqueous ammonia with theoretical equivalents of primary and secondary alcohols. The catalyst could be recycled by a facile procedure maintaining high activity. A one-flask synthesis of quinolizidine starting with 1,5,9-nonanetriol was also demonstrated. This new catalytic system would provide a practical and environmentally benign methodology for the synthesis of various organic amines. PMID- 20931961 TI - Effects of deamidation on structure and functional properties of barley hordein. AB - Deamidated hordeins of various deamidation degree (DD) ranging from 0.7 to 40% were prepared using an alkaline method. The hordein peptide bond cleavage, secondary structure, surface charge and hydrophobicity as well as their solubility, emusifying and foaming properties were studied as a function of DD value. SDS-PAGE, size exclusion chromatography (SEC) and Fourier transform infrared (FTIR) results suggest that limited deamidation (<= 4.7%) could dissociate hordein aggregates, leading to great increase of the protein solubility and surface hydrophobicty. A further increase of the DD value greater than 4.7% resulted in extensive protein hydrolysis and a marked change of protein secondary structure. The optimal functionalities were obtained at a narrow DD range (2.4-4.7%), where hordein samples demonstrated significantly improved solubility and the emulsifying and foaming properties at both acidic and neutral pHs. These results suggest that deamidated hordein would be an excellent candidate to be developed as an emulsifying and foaming ingredient. PMID- 20931962 TI - Simple combustion production and characterization of octahydro[60]fullerene with a non-IPR C60 cage. AB - For the first time an easier, operable combustion method is employed for the synthesis of non-IPR fullerene, and an octahydro[60]fullerene with a non-IPR C(60) cage (C(60) isomer (#1809)C(60)) produced by combustion is isolated and characterized by MS, UV-vis, IR, and NMR spectroscopies in combination with DFT calculations. This finding shows that, in addition to chlorine, hydrogen can be an ample cataloreactant for the production of non-IPR fullerene derivatives under such conditions as arc-burning and diffusion combustion. PMID- 20931963 TI - Discovery of a novel 5-HT(3) antagonist/5-HT(1A) agonist 3-amino-5,6,7,8 tetrahydro-2-{4-[4-(quinolin-2-yl)piperazin-1-yl]butyl}quinazolin-4(3H)-one (TZB 30878) as an orally bioavailable agent for irritable bowel syndrome. AB - We have prepared a series of quinazolinone derivatives linked with piperazinylquinoline for the treatment of irritable bowel syndrome (IBS). Using pharmacophore analysis, we designed and synthesized compounds which bind to both serotonin receptor subtype 1A (5-HT(1A)) and subtype 3 (5-HT(3)). Quinazolinone derivatives with a sulfur atom in the linker showed high affinity in in vitro assays, but low in vivo activity. Focusing on the linker to improve the pharmacokinetic profile, the sulfur atom in the linker was replaced with a methylene group. Further optimization led to the discovery of compound 17m (TZB 30878) ( J. Pharmacol. Exp. Ther. 2007 , 322 , 1315 - 1323 , Patent WO2005082887 (A1), 2005 ), a novel 5-HT(1A) agonist/5-HT(3) antagonist in the 3 aminoquinazolinone series. In in vivo functional assays, 17m dose dependently inhibited the Bezold-Jarisch reflex and induced 5-HT(1A)-mediated behaviors, and in an IBS animal model, 17m significantly inhibited stress-induced defecation. Pretreatment by WAY-100635 (5-HT(1A) antagonist) significantly attenuated but did not abolish the inhibitory effects of 17m. These results suggested that 17m exerted inhibitory effects via both 5-HT(1A) agonistic and 5-HT(3) antagonistic activities and that 17m would be useful as a therapeutic agent for IBS. PMID- 20931964 TI - Remarkable effect of bimetallic nanocluster catalysts for aerobic oxidation of alcohols: combining metals changes the activities and the reaction pathways to aldehydes/carboxylic acids or esters. AB - Selective oxidation of alcohols catalyzed by novel carbon-stabilized polymer incarcerated bimetallic nanocluster catalysts using molecular oxygen has been developed. The reactivity and the selectivity were strongly dependent on the combination of metals and solvent systems; aldehydes and ketones were obtained by the gold/platinum catalyst in benzotrifluoride, and esters were formed by the gold/palladium catalyst in methanol. To the best of our knowledge, this is the first example that the reaction pathway has been changed dramatically in gold catalysis by combining with a second metal. The differences in the activity and the selectivity are considered to be derived from the difference in the structure of the bimetallic clusters. PMID- 20931965 TI - Nanopod formation through gold nanoparticle templated and catalyzed cross-linking of polymers bearing pendant propargyl ethers. AB - A novel method for synthesizing polymer nanopods from a linear polymer bearing pendant propargyl ether groups, using gold nanoparticles as both the template and the catalyst for the cross-linking reaction, is reported. The transformations involved in the cross-linking process are unprecedented on the surface of a gold particle. A tentative cross-linking mechanism is proposed. PMID- 20931967 TI - Quantitative characterization of multicomponent polymers by sample-controlled thermal analysis. AB - This paper explores the potential of sample-controlled thermal analysis (SCTA) in order to perform compositional analysis of multicomponent polymeric materials by means of thermogravimetric experiments. In SCTA experiments, the response of the sample to the temperature determines the evolution of the temperature by means of a feedback system; thus, what is controlled is not the temperature-time profile, as in conventional analysis, but rather the evolution of the reaction rate with time. The higher resolving power provided by the technique has been used for determining the composition of polymer blends composed of polyvinyl chloride (PVC) and different commercial plasticizers, a system where the individual components have very similar thermal stabilities, thereby rendering useless thermogravimetric experiments run under conventional conditions. Different SCTA procedures, such as constant rate thermal analysis (CRTA), which has received special attention, and high-resolution and stepwise isothermal analysis have been tested, and the results obtained have been compared with linear heating rate technique. It has been proven that CRTA can be used to effectively determine the exact composition of the blend. PMID- 20931966 TI - Ribozymes and riboswitches: modulation of RNA function by small molecules. AB - Diverse small molecules interact with catalytic RNAs (ribozymes) as substrates and cofactors, and their intracellular concentrations are sensed by gene regulatory mRNA domains (riboswitches) that modulate transcription, splicing, translation, or RNA stability. Although recognition mechanisms vary from RNA to RNA, structural analyses reveal recurring strategies that arise from the intrinsic properties of RNA such as base pairing and stacking with conjugated heterocycles, and cation-dependent recognition of anionic functional groups. These studies also suggest that, to a first approximation, the magnitude of ligand-induced reorganization of an RNA is inversely proportional to the complexity of the riboswitch or ribozyme. How these small molecule binding induced changes in RNA lead to alteration in gene expression is less well understood. While different riboswitches have been proposed to be under either kinetic or thermodynamic control, the biochemical and structural mechanisms that give rise to regulatory consequences downstream of small molecule recognition by RNAs mostly remain to be elucidated. PMID- 20931968 TI - Field-free remobilization of proteins after isoelectric focusing in packed capillaries. AB - Pressure-driven remobilization without an applied electric field is shown to be possible with capillary isoelectric focusing using packed capillaries. The capillary dimensions are 100 MUm i.d. and 2 cm in length, and the packing is made of 0.9 MUm nonporous silica particles that are chemically modified with a brush layer of polyacrylamide. Both reversible and irreversible adsorption are shown to be negligible. The packed capillaries eliminate the problem of unwanted hydrodynamic flow between reservoirs. Three proteins are focused: trypsin inhibitor, carbonic anhydrase II, and myoglobin. The time required for focusing in the packed capillaries is increased by only a factor of 2 compared to the open capillary, giving complete focusing in less than 15 min at 200 V/cm. The packed capillaries allow the use of higher electric fields, with resolution continually increasing up to at least 1500 V/cm. The packing obstructs diffusional broadening after the field is turned off: for trypsin inhibitor, D = 6.1(+/-0.3) * 10(-8) cm(2)/s for the packed capillary vs D = 28.8(+/-0.3) * 10(-8) cm(2)/s for the open capillary. The broadening contributed by the packing during remobilization is from eddy diffusion, and it is described by its plate height, H, which is the variance per unit length: H = sigma(2)/L = 0.64 MUm. This limits the resolution to 0.1 pH units for the 2 cm capillary having a pH range of 3-10, giving a theoretical peak capacity of 47. PMID- 20931969 TI - Circular dichroism and voltammetry, assisted by multivariate curve resolution, and mass spectrometry of the competitive metal binding by phytochelatin PC5. AB - The competitive binding of Cd(2+) and Pb(2+) by the phytochelatin (gammaGlu-Cys)5 Gly (PC5) has been examined by several analytical techniques. Positive-mode electrospray ionization mass spectrometry (ESI-MS) is used to determine the stoichiometries of the complexes, while voltammetric and spectroscopic data are analyzed by multivariate curve resolution with alternating least-squares (MCR ALS) and some recently developed chemometric tools, which allows one to follow the displacement induced by Cd(2+) or Pb(2+) in the binding of Pb(2+) or Cd(2+), respectively, by PC5, and to obtain a complete overview of the processes involved. Differential pulse polarography (DPP) signals of these systems present, besides overlapping peaks due to free metal ion and metal complexes, interference of mercury anodic signals. Circular dichroism (CD) spectroscopy is a useful complementary technique due to the absence of these types of signals and its selective response to different species. A tentative complexation/electrochemical model is proposed for Cd(2+) and Pb(2+) competition toward PC5 complexation. The formation of the previously unreported ternary CdPb(PC5) complex was suggested by DPP and CD spectroscopy experiments and confirmed by ESI-MS. PMID- 20931970 TI - Sterols as anticancer agents: synthesis of ring-B oxygenated steroids, cytotoxic profile, and comprehensive SAR analysis. AB - The cytotoxicity of oxysterols was systematically studied in tumor and normal cells. Synthetic strategies to prepare this library included oxidations at ring B and a new method to yield 6beta-hemiphthalates directly from Delta(5)-steroids. Most oxysterols were cytotoxic and showed selectivity toward cancer cells, LAMA 84 cells (leukemia) being particularly sensitive to 4, 8, 22, and 27 (IC(50) < 5.6 MUM). The structural requirements to induce selective toxicity are discussed to shed light on the development of new anticancer drugs. PMID- 20931971 TI - Discovery of dual inducible/neuronal nitric oxide synthase (iNOS/nNOS) inhibitor development candidate 4-((2-cyclobutyl-1H-imidazo[4,5-b]pyrazin-1-yl)methyl)-7,8 difluoroquinolin-2(1H)-one (KD7332) part 2: identification of a novel, potent, and selective series of benzimidazole-quinolinone iNOS/nNOS dimerization inhibitors that are orally active in pain models. AB - Three isoforms of nitric oxide synthase (NOS), dimeric enzymes that catalyze the formation of nitric oxide (NO) from arginine, have been identified. Inappropriate or excessive NO produced by iNOS and/or nNOS is associated with inflammatory and neuropathic pain. Previously, we described the identification of a series of amide-quinolinone iNOS dimerization inhibitors that although potent, suffered from high clearance and limited exposure in vivo. By conformationally restricting the amide of this progenitor series, we describe the identification of a novel series of benzimidazole-quinolinone dual iNOS/nNOS inhibitors with low clearance and sustained exposure in vivo. Compounds were triaged utilizing an LPS challenge assay coupled with mouse and rhesus pharmacokinetics and led to the identification of 4,7-imidazopyrazine 42 as the lead compound. 42 (KD7332) (J. Med. Chem. 2009, 52, 3047 - 3062) was confirmed as an iNOS dimerization inhibitor and was efficacious in the mouse formalin model of nociception and Chung model of neuropathic pain, without showing tolerance after repeat dosing. Further 42 did not affect motor coordination up to doses of 1000 mg/kg, demonstrating a wide therapeutic margin. PMID- 20931972 TI - Anti-obesity effect of phosphatidylinositol on diet-induced obesity in mice. AB - The aim of this study is to investigate the biodistribution of phosphatidylinositol (PI) after oral administration and its anti-obesity effect. When a suspension of radiolabeled PI was orally administered to mice and the biodistribution was examined, PI radioactivity accumulated in the liver compared to myo-inositol radioactivity at 48 h or later after administration. Then, a PI suspension was orally administered to diet-induced obesity (DIO) mice every 4 days, and the anti-obesity effect of PI was examined. As a result, PI suppressed the body weight increase of DIO mice and significantly reduced the plasma levels of aspartate aminotransferase (AST) and cholesterol. Furthermore, PI regulated the expression of some genes in the liver involved in lipid synthesis and metabolism. The present study demonstrated that PI accumulated in the liver after oral administration and exerted its anti-obesity effect on DIO by regulating the expression of certain genes involved in lipid metabolism in the liver. PMID- 20931973 TI - Structural stability of carbon nanotube films: the role of bending buckling. AB - In films, mats, buckypaper, and other materials composed of carbon nanotubes (CNTs), individual CNTs are bound together by van der Waals forces and form entangled networks of bundles. Mesoscopic dynamic simulations reproduce the spontaneous self-assembly of CNTs into continuous networks of bundles and reveal that the bending buckling and the length of CNTs are the two main factors responsible for the stability of the network structures formed by defect-free CNTs. Bending buckling of CNTs reduces the bending energy of interconnections between bundles and stabilizes the interconnections by creating effective barriers for CNT sliding. The length of the nanotubes is affecting the ability of van der Waals forces of intertube interactions to counterbalance the internal straightening forces acting on curved nanotubes present in the continuous networks. The critical length for the formation of stable network structures is found to be ~120 nm for (10,10) single-walled CNTs. In the simulations where the bending buckling is artificially switched off, the network structures are found to be unstable against disintegration into individual bundles even for micrometer long CNTs. PMID- 20931974 TI - Particle lithography from colloidal self-assembly at liquid-liquid interfaces. AB - Particle lithography has been extensively used as a robust and cost-effective method to produce large-area, close-packed arrays of nanometer scale features. Many technological applications, including biosensing, require instead non-close packed patterns in order to avoid cross-talk between the features. We present a simple, scalable, single-step particle lithography process that employs colloidal self-assembly at liquid-liquid interfaces (SALI) to fabricate regular, open particle lithography masks, where the size of the features (40 to 500 nm) and their separation can be independently controlled between 3 and 10 particle diameters. Finally we show how the process can be practically employed to produce diverse biosensing structures. PMID- 20931976 TI - Spray-dried oil powder with ultrahigh oil content. AB - We report a new facile route to the production of solid oil powders with an oil weight content of as high as 90% or beyond. The proposed method starts from a standard protein-stabilized oil-in-water emulsion in which a protein monolayer absorbed at the oil-water interface is successively cross linked by a thermal treatment. The emulsion is then spray dried as for ordinary emulsions, however without the addition of hydrocolloids typically needed when spray drying liquid oil dispersions. This leads to a final solid oil powder in which the total mass is constituted of oil, proteins, and eventual buffer salts and in which the elasticity of the cross-linked protein monolayer is alone sufficient to stabilize the powder and to limit any oil leakage. To best illustrate the potential in food applications and to preserve the food-grade nature of the constituents, we have used thermal denaturation at 80 degrees C for 15 min to cross link a beta lactoglobulin-stabilized olive oil-in-water emulsion and to produce the corresponding solid oil powder. Because of the simplicity and flexibility of the proposed pathway, the present method can be used inexpensively to convert any type of hydrophobic liquid into the corresponding solid powder and is then particularly suitable for cosmetic, pharmaceutical, medical, biotechnological, and food applications. PMID- 20931977 TI - Hydride ion transfer from ruthenium(II) complexes in water: kinetics and mechanism. AB - Reactions of hydride complexes of ruthenium(II) with hydride acceptors have been examined for Ru(terpy)(bpy)H(+), Ru(terpy)(dmb)H(+), and Ru(eta(6) C(6)Me(6))(bpy)(H)(+) in aqueous media at 25 degrees C (terpy = 2,2';6',2'' terpyridine, bpy = 2,2'-bipyridine, dmb = 4,4'-dimethyl-2,2'-bipyridine). The acceptors include CO(2), CO, CH(2)O, and H(3)O(+). CO reacts with Ru(terpy)(dmb)H(+) with a rate constant of 1.2 (0.2) * 10(1) M(-1) s(-1), but for Ru(eta(6)-C(6)Me(6))(bpy)(H)(+), the reaction was very slow, k <= 0.1 M(-1) s( 1). Ru(terpy)(bpy)H(+) and Ru(eta(6)-C(6)Me(6))(bpy)(H)(+) react with CH(2)O with rate constants of (6 +/- 4) * 10(6) and 1.1 * 10(3) M(-1) s(-1), respectively. The reaction of Ru(eta(6)-C(6)Me(6))(bpy)(H)(+) with acid exhibits straightforward, second-order kinetics, with the rate proportional to [Ru(eta(6) C(6)Me(6))(bpy)(H)(+)] and [H(3)O(+)] and k = 2.2 * 10(1) M(-1) s(-1) (MU = 0.1 M, Na(2)SO(4) medium). However, for the case of Ru(terpy)(bpy)H(+), the protonation step is very rapid, and only the formation of the product Ru(terpy)(bpy)(H(2)O)(2+) (presumably via a dihydrogen or dihydride complex) is observed with a k(obs) of ca. 4 s(-1). The hydricities of HCO(2)(-), HCO(-), and H(3)CO(-) in water are estimated as +1.48, -0.76, and +1.57 eV/molecule (+34, 17.5, +36 kcal/mol), respectively. Theoretical studies of the reactions with CO(2) reveal a "product-like" transition state with short C-H and long M-H distances. (Reactant) Ru-H stretched 0.68 A; (product) C-H stretched only 0.04 A. The role of water solvent was explored by including one, two, or three water molecules in the calculation. PMID- 20931978 TI - Importance of equilibrium fluctuations between most stable conformers in the control of the reaction mechanism. AB - Hydrolysis of closely related compounds show how subtle structural differences markedly change reaction mechanisms. While in the hydrolysis of 3-acetoxy-2 naphthoic acid (3AC2NA) the reacting groups rotate freely, favoring intramolecular general base catalysis, the 1-acetoxy-2-naphthoic acid (1AC2NA) isomer is caged in an energy wall that freezes a conformation suitable for intramolecular nucleophilic attack, in contrast to the results expected for reactions governed largely by electronic effects. The results highlight the importance of the dynamics of equilibrium fluctuations between most stable conformers in the control of the reaction mechanism, (i) promoting the nucleophilic attack in 1AC2NA by allowing the most stable conformers to equilibrate only via rotation in a direction that intercepts the reaction coordinate and (ii) favoring a general base-catalyzed water attack in 3AC2NA by favoring equilibration via rotation that allows inclusion of a water molecule in a proper position for reaction. PMID- 20931979 TI - Regulation of local structure and composition of binary disulfide and thiol self assembled monolayers using nanografting. AB - Nanografting is used to create spatial confinement, which enables regulation of self-assembly reaction pathways and outcome. The degree and outcome of this regulation is revealed using binary self-assembled monolayers (SAMs) of organothiols and disulfides. In naturally grown systems, these SAMs have more complex morphology when compared with corresponding binary alkanethiol SAMs. Taller molecules form nanodomains of ellipsoidal cap in shape. These domains arrange in various irregular geometries, including 1D worm-like and 2D branches. This observation differs from binary alkanethiol SAMs, where nanodomains are separated and randomly dispersed. During nanografting, more homogeneous morphology was observed compared with naturally grown layers. By varying nanoshaving speed, the nanodomain structure can be regulated from randomly dispersed to more heterogeneous and, finally, to near natural growth. This trend is very similar to mixed alkanethiol systems, where the domain size and separation increase with increasing speed. Different from the alkanethiol systems, the observed structural variations are due to the changes in surface composition, in addition to domain size, shape, and arrangement. PMID- 20931981 TI - Self-assembly of a hexameric aggregate of a lipophilic calix[4]pyrrole resorcinarene hybrid in solution: a diffusion NMR study. AB - The lipophilic calix[4]pyrrole-resorcinarene hybrid 1b, the extended analogue of resorcin[4]arene 2b, was synthesized for the first time, and its self-assembly in solution was studied using (1)H and diffusion NMR. It was found that 1b self assembles to hexameric aggregates in CDCl(3) solution. The interaction of trialkylamine guests with the hexameric aggregate of 1b was explored, and it appears that under the conditions used in the present study these guests interact with the external faces of the hexameric aggregate of 1b. PMID- 20931980 TI - Identification of non-peptide malignant brain tumor (MBT) repeat antagonists by virtual screening of commercially available compounds. AB - The malignant brain tumor (MBT) repeat is an important epigenetic-code "reader" and is functionally associated with differentiation, gene silencing, and tumor suppression. (1-3) Small molecule probes of MBT domains should enable a systematic study of MBT-containing proteins and potentially reveal novel druggable targets. We designed and applied a virtual screening strategy that identified potential MBT antagonists in a large database of commercially available compounds. A small set of virtual hits was purchased and submitted to experimental testing. Nineteen of the purchased compounds showed a specific dose dependent protein binding and will provide critical structure-activity information for subsequent lead generation and optimization. PMID- 20931984 TI - Cost of wind energy: comparing distant wind resources to local resources in the midwestern United States. AB - The best wind sites in the United States are often located far from electricity demand centers and lack transmission access. Local sites that have lower quality wind resources but do not require as much power transmission capacity are an alternative to distant wind resources. In this paper, we explore the trade-offs between developing new wind generation at local sites and installing wind farms at remote sites. We first examine the general relationship between the high capital costs required for local wind development and the relatively lower capital costs required to install a wind farm capable of generating the same electrical output at a remote site,with the results representing the maximum amount an investor should be willing to pay for transmission access. We suggest that this analysis can be used as a first step in comparing potential wind resources to meet a state renewable portfolio standard (RPS). To illustrate, we compare the cost of local wind (~50 km from the load) to the cost of distant wind requiring new transmission (~550-750 km from the load) to meet the Illinois RPS. We find that local, lower capacity factor wind sites are the lowest cost option for meeting the Illinois RPS if new long distance transmission is required to access distant, higher capacity factor wind resources. If higher capacity wind sites can be connected to the existing grid at minimal cost, in many cases they will have lower costs. PMID- 20931982 TI - Lung cancer serum biomarker discovery using glycoprotein capture and liquid chromatography mass spectrometry. AB - Targeted glycoproteomics represents an attractive approach for conducting peripheral blood based cancer biomarker discovery due to the well-known altered pattern of protein glycosylation in cancer and the reduced complexity of the resultant glycoproteome. Here we report its application to a set of pooled nonsmall cell lung cancer (NSCLC) case sera (9 adenocarcinoma and 6 squamous cell carcinoma pools from 54 patients) and matched controls pools, including 8 clinical control pools with computed tomography detected nodules but being nonmalignant as determined by biopsy from 54 patients, and 8 matched healthy control pools from 106 cancer-free subjects. The goal of the study is to discover biomarkers that may enable improved early detection and diagnosis of lung cancer. Immunoaffinity subtraction was used to first deplete the topmost abundant serum proteins; the remaining serum proteins were then subjected to hydrazide chemistry based glycoprotein capture and enrichment. Hydrazide resin in situ trypsin digestion was used to release nonglycosylated peptides. Formerly N-linked glycosylated peptides were released by peptide-N-glycosidase F (PNGase F) treatment and were subsequently analyzed by liquid chromatography (LC)-tandem mass spectrometry (MS/MS). A MATLAB based in-house tool was developed to facilitate retention time alignment across different LC-MS/MS runs, determination of precursor ion m/z values and elution profiles, and the integration of mass chromatograms based on determined parameters for identified peptides. A total of 38 glycopeptides from 22 different proteins were significantly differentially abundant across the case/control pools (P < 0.01, Student's t test) and their abundances led to a near complete separation of case and control pools based on hierarchical clustering. The differential abundances of three of these candidate proteins were verified by commercially available ELISAs applied in the pools. Strong positive correlations between glycopeptide mass chromatograms and ELISA measured protein abundance was observed for all of the selected glycoproteins. PMID- 20931986 TI - Influence of beta-substituents in aldol reactions of boron enolates of beta alkoxy methylketones. AB - Moderate to good levels of substrate-based 1,5-syn-stereocontrol could be achieved in the boron-mediated aldol reactions of beta-tert-butyl methylketones with achiral aldehydes, independent of the nature of the beta-alkoxy protecting group (P = PMB or TBS). The analysis of the relative energies of the transition structures by theoretical calculations using the density functional B3LYP shows relative energies favoring the corresponding OUT-1,5-SYN transition structures, explaining the observed 1,5-syn stereoinduction. PMID- 20931985 TI - Efficient microwave-assisted synthesis of human islet amyloid polypeptide designed to facilitate the specific incorporation of labeled amino acids. AB - A cost-efficient, time-reducing solid-phase synthesis of the amyloidogenic, 37 residue islet amyloid polypeptide (IAPP) is developed using two pseudoprolines (highlighted blue in sequence) in combination with microwave technology. A yield twice that obtained with conventional syntheses is realized. The utility of this protocol is demonstrated by the synthesis of a (13)C(18)O-labeled Ser-20 IAPP variant, a prohibitively expensive and chemically challenging site to label via other protocols. TEM analysis shows the peptide forms normal amyloid (abstract image). PMID- 20931987 TI - Efficient synthesis of 1-sulfonyl-1,2,3-triazoles. AB - An efficient room-temperature method for the synthesis of 1-sulfonyl-1,2,3 triazoles from in situ generated copper(I) acetylides and sulfonyl azides is described. The copper(I) thiophene-2-carboxylate (CuTC) catalyst produces the title compounds under both nonbasic anhydrous and aqueous conditions in good yields. PMID- 20931988 TI - Measurements of the absolute absorption cross sections of the A<-X transition in organic peroxy radicals by dual-wavelength cavity ring-down spectroscopy. AB - We demonstrate an experimental method for the accurate measurement of the absorption cross section of transient species, such as organic peroxy radicals in which the concentration of the radicals is determined via the absorption of a stable coproduct that is produced stochiometrically. The requirements for the experimental apparatus, a dual-wavelength cavity ring-down spectrometer, and the chemical protocol for transient species generation are discussed. The capability of this approach is demonstrated by measuring the peak absorption cross section of the ethyl peroxy radical, C22H5O2, whose value for the A<-X electronic transition at 7596 cm-1 (lambda = 1316.5 nm) is found to be sigma(p)(EP) = 5.29(20) * 10-21 cm2. These present results are compared to those obtained from other methods of measurement of sigma(p)(EP). Possible random and systematic errors are discussed. PMID- 20931989 TI - Simulation studies on hydrogen sorption and its thermodynamics in covalently linked carbon nanotube scaffold. AB - Carbon nanotubes are potential hydrogen storage materials because of their large surface area and high sorbate-surface interaction energy due to the curvature effect. However, single walled carbon nanotubes bundle up tightly, so most of their surface areas become inaccessible for adsorption. As a solution, spacer molecules can be used to hold the tubes at a distance from each other in a scaffolded structure. Here, using grand canonical Monte Carlo simulation, we show that scaffolds can achieve high sorption capacity. We analyze the sorption capacity of (6, 6), (9, 9), (12, 12), (15, 15), (18, 18), and (21, 0) tube scaffolds with linker distances along the c-axis ranging from 8.14 to 24.4 A, as a function of tube diameter and spacer density, for various temperatures and pressures. In order to explore additional avenues to further improve the sorption capacity, we studied surface functionalized and Li(+) ion decorated nanotube scaffolds. We also report the thermodynamics of sorption based on isosteric heat. PMID- 20931990 TI - Nucleation pathways of clathrate hydrates: effect of guest size and solubility. AB - Understanding the microscopic mechanism of nucleation of clathrate hydrates is important for their use in hydrogen storage, CO(2) sequestration, storage and transport of natural gas, and the prevention of the formation of hydrate plugs in oil and gas pipelines. These applications involve hydrate guests of varied sizes and solubility in water that form different hydrate crystal structures. Nevertheless, molecular studies of the mechanism of nucleation of hydrates have focused on the single class of small hydrophobic guests that stabilize the sI crystal. In this work, we use molecular dynamics simulations with a very efficient coarse-grained model to elucidate the mechanisms of nucleation of clathrate hydrates of four model guests that span a 2 orders of magnitude range in solubility in water and that encompass sizes which stabilize each one a different hydrate structure (sI and sII, with and without occupancy of the dodecahedral cages). We find that the overall mechanism of clathrate nucleation is similar for all guests and involves a first step of formation of blobs, dense clusters of solvent-separated guest molecules that are the birthplace of the clathrate cages. Blobs of hydrophobic guests are rarer and longer-lived than those for soluble guests. For each guest, we find multiple competing channels to form the critical nuclei, filled dodecahedral (5(12)) cages, empty 5(12) cages, and a variety of filled large (5(12)6(n) with n = 2, 3, and 4) clathrate cages. Formation of empty dodecahedra is an important nucleation channel for all but the smallest guest. The empty 5(12) cages are stabilized by the presence of guests from the blob in their first solvation shell. Under conditions of high supercooling, the structure of the critical and subcritical nuclei is mainly determined by the size of the guest and does not reflect the cage composition or ordering of the stable or metastable clathrate crystals. PMID- 20931992 TI - Photoactivated antimicrobial activity of carbon nanotube-porphyrin conjugates. AB - We report the design of antimicrobial nanocomposite films based on conjugates of multiwalled carbon nanotubes (MWNT) and protoporphyrin IX (PPIX) that are highly effective against Staphylococcus aureus (S. aureus) upon irradiation with visible light. S. aureus infections can lead to life-threatening situations, especially when caused by antibiotic-resistant strains. While the light-activated antimicrobial activity of porphyrins against such pathogens is well-known, a facile way to incorporate porphyrins into coatings may lead to their more effective use. To that end, we decided to synthesize and characterize MWNT-PPIX conjugates which combine the biocidal capacity of porphyrins with the mechanical strength of MWNTs. The conjugates could effectively deactivate S. aureus cells in solution upon irradiation with visible light. We also designed large area nanocomposite films comprised of the MWNT-PPIX conjugates that showed potent antimicrobial activity. These MWNT-PPIX conjugates represent a facile strategy for the design of antimicrobial and antifouling coatings. PMID- 20931991 TI - Paraoxon-induced protein expression changes to SH-SY5Y cells. AB - SH-SY5Y neuroblastoma cells were examined to determine changes in protein expression following exposure to the organophosphate paraoxon (O,O-diethyl-p nitrophenoxy phosphate). Exposure of SH-SY5Y cells to paraoxon (20 MUM) for 48 h showed no significant change in cell viability as established using an MTT assay. Protein expression changes from the paraoxon-treated SH-SY5Y cells were determined using a comparative, subproteome approach by fractionation into cytosolic, membrane, nuclear, and cytoskeletal fractions. The fractionated proteins were separated by 2D-PAGE, identified by MALDI-TOF mass spectrometry, and expression changes determined by densitometry. Over 400 proteins were separated from the four fractions, and 16 proteins were identified with altered expression >=1.3-fold including heat shock protein 90 (-1.3-fold), heterogeneous nuclear ribonucleoprotein C (+2.8-fold), and H(+) transporting ATP synthase beta chain (-3.1-fold). Western blot analysis conducted on total protein isolates confirmed the expression changes in these three proteins. PMID- 20931993 TI - Ultradense, deep subwavelength nanowire array photovoltaics as engineered optical thin films. AB - A photovoltaic device comprised of an array of 20 nm wide, 32 nm pitch array of silicon nanowires is modeled as an optical material. The nanowire array (NWA) has characteristic device features that are deep in the subwavelength regime for light, which permits a number of simplifying approximations. Using photocurrent measurements as a probe of the absorptance, we show that the NWA optical properties can be accurately modeled with rigorous coupled-wave analysis. The densely structured NWAs behave as homogeneous birefringent materials into the ultraviolet with effective optical properties that are accurately modeled using the dielectric functions of bulk Si and SiO2, coupled with a physical model for the NWA derived from ellipsometry and transmission electron microscopy. PMID- 20931994 TI - Energy loss of the electron system in individual single-walled carbon nanotubes. AB - We characterize the energy loss of the nonequilibrium electron system in individual metallic single-walled carbon nanotubes at low temperature. Using Johnson noise thermometry, we demonstrate that, for a nanotube with Ohmic contacts, the dc resistance at finite bias current directly reflects the average electron temperature. This enables a straightforward determination of the thermal conductance associated with cooling of the nanotube electron system. In analyzing the temperature- and length-dependence of the thermal conductance, we consider contributions from acoustic phonon emission, optical phonon emission, and hot electron outdiffusion. PMID- 20931995 TI - The influence of strong electron and hole doping on the Raman intensity of chemical vapor-deposition graphene. AB - Electrochemical charging has been applied to study the influence of doping on the intensity of the various Raman features observed in chemical vapor-deposition grown graphene. Three different laser excitation energies have been used to probe the influence of the excitation energy on the behavior of both the G and G' modes regarding their dependence on doping. The intensities of both the G and G' modes exhibit a significant but different dependence on doping. While the intensity of the G' band monotonically decreases with increasing magnitude of the electrode potential (positive or negative), for the G band a more complex behavior has been found. The striking feature is an increase of the Raman intensity of the G mode at a high value of the positive electrode potential. Furthermore, the observed increase of the Raman intensity of the G mode is found to be a function of laser excitation energy. PMID- 20931996 TI - Synthesis of nitrogen-doped graphene films for lithium battery application. AB - We demonstrate a controlled growth of nitrogen-doped graphene layers by liquid precursor based chemical vapor deposition (CVD) technique. Nitrogen-doped graphene was grown directly on Cu current collectors and studied for its reversible Li-ion intercalation properties. Reversible discharge capacity of N doped graphene is almost double compared to pristine graphene due to the large number of surface defects induced due to N-doping. All the graphene films were characterized by Raman spectroscopy, transmission electron microscopy, and X-ray photoemission spectroscopy. Direct growth of active electrode material on current collector substrates makes this a feasible and efficient process for integration into current battery manufacture technology. PMID- 20931997 TI - Enantioselective synthesis of alpha-fluoro-beta(3)-amino esters: synthesis of enantiopure, orthogonally protected alpha-fluoro-beta(3)-lysine. AB - The scope of a tandem conjugate addition-fluorination sequence performed on alpha,beta-unsaturated esters using the enantiopure lithium amide derived from (S)-N-benzyl-N-(alpha-methylbenzyl)amine, and the electrophilic fluorinating agent N-fluorobenzenesulfonimide has been investigated. Using this method, alpha fluoro-beta(3)-amino esters can be obtained in up to quantitative yield and 80:20 to >99:1 dr. This simple methodology does not rely on the use of alpha-amino acids from the chiral pool and thus provides the potential for the preparation of enantiopure alpha-fluoro-beta(3)-amino acids with a wide variety of side chains. Its utility was demonstrated through the synthesis of orthogonally protected (2S,3S)-alpha-fluoro-beta(3)-lysine. PMID- 20931998 TI - Self-assembled 1-octadecanethiol monolayers on graphene for mercury detection. AB - We report studies on surface modification of graphene with 1-octadecanethiol and its application as heavy metal sensors. The alkanethiol molecules can self assemble into large-scale highly ordered monolayers on single-layer graphene regardless of the roughness of graphene surfaces inherited from the underlying amorphorous silicon oxide (SiO2) dielectric substrates. Atomically resolved scanning tunneling microscopy imaging of modified graphene sheets on SiO2 was conducted to reveal configuration details of the self-assembled structure. Functionalization of graphene field effect transistors (Gra-FETs) with 1 octadecanethiol was realized and successfully explored for mercury(II) (Hg2+) detection at 10 ppm. PMID- 20932000 TI - HER2/neu antibody conjugated poly(amino acid)-coated iron oxide nanoparticles for breast cancer MR imaging. AB - Superparamagnetic iron oxide nanoparticles are widely used as nanoprobes for magnetic resonance imaging (MRI). Water-soluble iron oxide nanoparticles were synthesized by coating iron oxide nanoparticles with a hydrophilic, biocompatible, biodegradable poly(amino acid) derivative, poly(2-hydroxyethyl aspartamide) graft copolymer for negative contrast enhancement on T2 weighted MRI. HER2/neu antibodies were conjugated on the surface of poly(amino acid) coated iron oxide nanoparticles for the detection of breast cancer. The antibody grafted iron oxide nanoparticles (PAION-Ab) were about 31.1 nm in diameter. The T2 relaxivity of PAION-Ab was 246 L.mmol(-1).sec(-1) greater than that of the commercial product such as Feridex. PAION-Ab showed low cytotoxicity even at relatively high concentrations. Furthermore, Prussian blue staining and in vitro MRI study with SKBR-3, breast cancer cells overexpressing HER2/neu receptors indicated that PAION-Ab exhibited excellent cancer cell detection ability and enhanced signal intensities in the T2-weighted image. PMID- 20932001 TI - Time trend analysis of atmospheric POPs concentrations in the Great Lakes region since 1990. AB - Using a multiple linear regression model of the concentrations of several persistent organic pollutants in the atmospheric vapor and particle phases and in precipitation, we have analyzed a data set of about 700,000 values to determine the rate at which these concentrations are decreasing. These concentrations were measured as part of the Integrated Atmospheric Deposition Network (IADN), which has operated several sites near the North American Great Lakes since 1991. The pollutants measured include 83 polychlorinated biphenyl congeners, 17 polycyclic aromatic hydrocarbons, and 24 organochlorine pesticides. In the approach used here, for each of the three phases, the concentrations of a specific chemical at all the sites were combined and fitted with a regression incorporating the sine and cosine of the Julian Day (relative to 1 January 1990 and with a periodicity of one year) and the population living and working within a 25-km radius of the sampling site. Partial residuals were then calculated for each datum, all of the residuals for the three phases were combined, and an overall halving time was calculated from them. This relatively simple approach indicated that the concentrations of PCBs in air around the Great Lakes are decreasing with an overall halving time of 17 +/- 2 years, which is slow for a substance that was banned about 35 years ago. Phenanthrene, chrysene, and endosulfan showed halving times on the order of 10 years. The concentrations of several organochlorine pesticides were decreasing more rapidly; for example alpha- and gamma-HCH (lindane) have halving times of about 3.5 years. PMID- 20932002 TI - N-nitrosodimethylamine occurrence, formation and cycling in clouds and fogs. AB - The occurrence, source, and sink processes of N-nitrosodimethylamine (NDMA) have been explored by means of combined laboratory, field, and model studies. Observations have shown the occurrence of NDMA in fogs and clouds at substantial concentrations (7.5-397 ng L(-1)). Laboratory studies were conducted to investigate the formation of NDMA from nitrous acid and dimethylamine in the homogeneous aqueous phase. While NDMA was produced in the aqueous phase, the low yields (<1%) observed could not explain observational concentrations. Therefore gaseous formation of NDMA with partitioning to droplets likely dominates aqueous NDMA formation. Box-model calculations confirmed the predominant contributions from gas phase formation followed by partitioning into the cloud droplets. Measurements and model calculations showed that while NDMA is eventually photolyzed, it might persist in the atmosphere for hours after sunrise and before sunset since the photolysis in the aqueous phase might be much less efficient than in the gas phase. PMID- 20932003 TI - p38 MAPK activation, DNA damage, cell cycle arrest and apoptosis as mechanisms of toxicity of silver nanoparticles in Jurkat T cells. AB - To identify potential harmful effects of silver nanoparticles (AgNPs) on human health, a comprehensive toxicity assay was conducted on human Jurkat T cells, using oxidative stress-related endpoint. The effect of Ag ions was also investigated and compared with that of AgNPs, as it is anticipated that Ag ions will be released from AgNPs, which may be responsible for their toxicity. Cell viability tests indicated high sensitivity of Jurkat T cells when exposed to AgNPs compared to Ag ions; however, both AgNPs and Ag ions induce similar levels of cellular reactive oxygen species during the initial exposure period and; after 24 h, they were increased on exposure to AgNPs compared to Ag ions, which suggest that oxidative stress may be an indirect cause of the observed cytotoxicity of AgNPs. AgNPs exposure activates p38 mitogen-activated protein kinase through nuclear factor-E2-related factor-2 and nuclear factor-kappaB signaling pathways, subsequently inducing DNA damage, cell cycle arrest and apoptosis. Selective toxicity of AgNPs on Jurkat T cells suggests that rigorous toxicity evaluation should be conducted using various different cell types and biological systems prior to the widespread use of AgNPs. PMID- 20932004 TI - In situ observations of nanoparticle early development kinetics at mineral-water interfaces. AB - The early development of nanoparticles at mineral-water interfaces exerts crucial influences on the sequestration and transport of aqueous toxic species originating from both natural and anthropogenic sources. Homogeneous and heterogeneous nucleation often occur simultaneously, making it difficult to sort out whether toxic species are transported as free species, sorbed on nanoparticle surfaces, or trapped between aggregated nanoparticles. Here, using a newly developed X-ray scattering setup, we show how homogeneous nucleation and growth can be quantitatively separated from heterogeneous processes under aqueous conditions in real-time. Under conditions found in acid-mine-drainage (at pH 3.6 and [Fe(3+)] = 10(-4) M), heterogeneous nucleation of iron oxide nanoparticles on quartz dominated homogeneous nucleation by a factor of 192 (by particle volume). The smallest heterogeneously formed nanoparticles had radii of 1.7 +/- 0.5 nm, significantly smaller than the size estimated using classical nucleation theory (CNT). Based on the data, the dominant nucleation and growth mechanisms of iron oxide nanoparticles depending on ionic strength were presented. Our findings have implications for the formation and transport of nanoparticles, and thus toxins, in both environmental and biological systems. PMID- 20932005 TI - Aromaticity and relative stabilities of azines. AB - The most refined nucleus-independent chemical shift index (NICS(0)(pizz)) and the extra cyclic resonance energies (ECREs), based on the block localized wave function (BLW) method, show that the aromaticity of all azines is like that of benzene. The same is true for aza-naphthalenes relative to naphthalene. The lower relative energies of isomers with vicinal N's are due to the weakness of NN bonds rather than to reduced aromaticity. PMID- 20932006 TI - Electronic structures of single-walled carbon nanotubes encapsulating ellipsoidal C70. AB - The molecular orientation of ellipsoidal C(70) in single-walled carbon nanotubes (SWCNTs) depends on the tube diameter (d(t)). Photoluminescence (PL) studies reveal that the fullerene encapsulation effects on the optical transition energy of SWCNTs are significantly different for C(70) and C(60) at d(t) = 1.405-1.431 nm. This indicates that the transition from the "lying" alignment to the "standing" alignment occurs at d(t) ~ 1.41 nm and the electronic states of SWCNTs are very sensitive to the interspacing between the encapsulated molecules and the SWCNTs. The present findings suggest that the electronic structure of SWCNTs is tunable not only by alternating the encapsulated molecules but also by controlling their molecular orientations, thus paving the way for development of novel SWCNT-based devices. PMID- 20932007 TI - Synthesis of redox active ferrocene-modified phospholipids by transphosphatidylation reaction and chronoamperometry study of the corresponding redox sensitive liposome. AB - The design of stable redox active liposomes where the organometallic electroactive pendent was covalently bound to the phospholipid headgroup through a phospholipase D (PLD)-catalyzed transphosphatidylation reaction between a choline-bearing phospholipid and a primary alcohol containing a ferrocene derivative is reported. The functionalization of a liposome surface with this organometallic redox phospholipid allowed the study of membrane-bound electrochemical reactions, which are important in the design of redox-sensitive liposome delivery systems. PMID- 20932008 TI - Detection of telomerase activity in high concentration of cell lysates using primer-modified gold nanoparticles. AB - Although the telomeric repeat amplification protocol (TRAP) has served as a powerful assay for detecting telomerase activity, its use has been significantly limited when performed directly in complex, interferant-laced samples. In this work, we report a modification of the TRAP assay that allows the detection of high-fidelity amplification of telomerase products directly from concentrated cell lysates. Briefly, we covalently attached 12 nm gold nanoparticles (AuNPs) to the telomere strand (TS) primer, which is used as a substrate for telomerase elongation. These TS-modified AuNPs significantly reduce polymerase chain reaction (PCR) artifacts (such as primer dimers) and improve the yield of amplified telomerase products relative to the traditional TRAP assay when amplification is performed in concentrated cell lysates. Specifically, because the TS-modified AuNPs eliminate most of the primer-dimer artifacts normally visible at the same position as the shortest amplified telomerase PCR product apparent on agarose gels, the AuNP-modified TRAP assay exhibits excellent sensitivity. Consequently, we observed a 10-fold increase in sensitivity for cancer cells diluted 1000-fold with somatic cells. It thus appears that the use of AuNP-modified primers significantly improves the sensitivity and specificity of the traditional TRAP assay and may be an effective method by which PCR can be performed directly in concentrated cell lysates. PMID- 20932009 TI - 5-Piperazinyl-3-sulfonylindazoles as potent and selective 5-hydroxytryptamine-6 antagonists. AB - As part of our efforts to develop agents for CNS diseases, we have been focused on the 5-HT(6) receptor in order to identify potent and selective ligands for cognitive enhancement. Herein we report the identification of a novel series of 5 piperazinyl-3-sulfonylindazoles as potent and selective 5-HT(6) antagonists. The synthesis, SAR, and pharmacokinetic and pharmacological activities of some of the compounds including 3-(naphthalen-1-ylsulfonyl)-5-(piperazin-1-yl)-1H-indazole (WAY-255315 or SAM-315) will be described. PMID- 20932010 TI - Design and synthesis of 2-arylbenzimidazoles and evaluation of their inhibitory effect against Chlamydia pneumoniae. AB - Chlamydia pneumoniae is an intracellular bacterium that responds poorly to antibiotic treatment. Insufficient antibiotic usage leads to chronic infection, which is linked to disease processes of asthma, atherosclerosis, and Alzheimer's disease. The Chlamydia research lacks genetic tools exploited by other antimicrobial research, and thus other approaches to drug discovery must be applied. A set of 2-arylbenzimidazoles was designed based on our earlier findings, and 33 derivatives were synthesized. Derivatives were assayed against C. pneumoniae strain CWL-029 in an acute infection model using TR-FIA method at a concentration of 10 MUM, and the effects of the derivatives on the host cell viability were evaluated at the same concentration. Fourteen compounds showed at least 80% inhibition, with only minor changes in host cell viability. Nine most potential compounds were evaluated using immunofluorescence microscopy on two different strains of C. pneumoniae CWL-029 and CV-6. The N-[3-(1H-benzimidazol-2 yl)phenyl]-3-methylbenzamide (42) had minimal inhibitory concentration (MIC) of 10 MUM against CWL-029 and 6.3 MUM against the clinical strain CV-6. This study shows the high antichlamydial potential of 2-arylbenzimidazoles, which also seem to have good characteristics for lead compounds. PMID- 20932011 TI - Probing the spontaneous membrane insertion of a tail-anchored membrane protein by sum frequency generation spectroscopy. AB - In addition to providing a semipermeable barrier that protects a cell from harmful stimuli, lipid membranes occupy a central role in hosting a variety of biological processes, including cellular communications and membrane protein functions. Most importantly, protein-membrane interactions are implicated in a variety of diseases and therefore many analytical techniques were developed to study the basis of these interactions and their influence on the molecular architecture of the cell membrane. In this study, sum frequency generation (SFG) vibrational spectroscopy is used to investigate the spontaneous membrane insertion process of cytochrome b(5) and its mutants. Experimental results show a significant difference in the membrane insertion and orientation properties of these proteins, which can be correlated with their functional differences. In particular, our results correlate the nonfunctional property of a mutant cytochrome b(5) with its inability to insert into the lipid bilayer. The approach reported in this study could be used as a potential rapid screening tool in measuring the topology of membrane proteins as well as interactions of biomolecules with lipid bilayers in situ. PMID- 20932012 TI - Structural phase control in self-catalyzed growth of GaAs nanowires on silicon (111). AB - Au free GaAs nanowires with zinc blende structure, free of twin planes and with remarkable aspect ratios, have been grown on (111) Si substrates by molecular beam epitaxy. Nanowires with diameters down to 20 nm are obtained using a thin native oxide layer on the Si substrates. We discuss how the structural phase distribution along the wire length is controlled by the effective V/III ratio and temperature at the growth interface and explain how to obtain a pure twin plane free zinc blende structure. PMID- 20932014 TI - Total synthesis of (-)-callipeltoside A. AB - A total synthesis of (-)-callipeltoside A (1) has been achieved. The core macrocycle was made via a dual macrolactonization/pyran hemiketal formation reaction, developed to circumvent issues related to the reversible nature of acylketene formation from beta-keto lactone substrates. Initial approaches to the core of the natural product that revolved around ring-closing metathesis (RCM) and relay ring-closing metathesis (RRCM) reactions are also described. PMID- 20932015 TI - Oxygen atom transfer reactions from isolated (oxo)manganese(V) corroles to sulfides. AB - A series of five free-base corroles were metalated and brominated to form 10 manganese(III) corroles. Two of the free-base corroles and six manganese(III) corroles were analyzed by X-ray crystallography, including one complex that may be considered a transition-state analogue of oxygen atom transfer (OAT) from (oxo)manganese(V) to thioansisole. Oxidation by ozone allowed for isolation of the 10 corresponding (oxo)manganese(V) corroles, whose characterization by (1)H and (19)F NMR spectroscopy and electrochemistry revealed a low-spin and triply bound manganese-oxygen moiety. Mechanistic insight was obtained by investigating their reactivity regarding stoichiometric OAT to a series of p-thioanisoles, revealing a magnitude difference on the order of 5 between the beta-pyrrole brominated (oxo)manganese(V) corroles relative to the nonbrominated analogues. The main conclusion is that the (oxo)manganese(V) corroles are legitimate OAT agents under conditions where proposed oxidant-coordinated reaction intermediates are irrelevant. Large negative Hammett rho constants are obtained for the more reactive (oxo)manganese(V) corroles, consistent with expectation for such electrophilic species. The least reactive complexes display very little selectivity to the electron-richness of the sulfides, as well as a non-first order dependence on the concentration of (oxo)manganese(V) corrole. This suggests that disproportionation of the original (oxo)manganese(V) corrole to (oxo)manganese(IV) and (oxo)manganese(VI) corroles, followed by substrate oxidation by the latter complex, gains importance when the direct OAT process becomes progressively less favorable. PMID- 20932013 TI - Highly stereoselective and scalable anti-aldol reactions using N-(p dodecylphenylsulfonyl)-2-pyrrolidinecarboxamide: scope and origins of stereoselectivities. AB - A highly enantio- and diastereoselective anti-aldol process (up to >99% ee, >99:1 dr) catalyzed by a proline mimetic-N-(p-dodecylphenylsulfonyl)-2 pyrrolidinecarboxamide-has been developed. Catalyst loading as low as 2 mol % can be employed. Use of industry-friendly solvents for this transformation as well as neat reaction conditions have been demonstrated. The scope of this transformation on a range of aldehydes and ketones is explored. Density functional theory computations reveal that the origins of enhanced diastereoselectivity are due to the presence of nonclassical hydrogen bonds between the sulfonamide, the electrophile, and the catalyst enamine that favor the major anti-Re aldol TS in the Houk-List model. PMID- 20932016 TI - Visible-light-driven Cu(II)-(Sr(1-y)Na(y))(Ti(1-x)Mo(x))O3 photocatalysts based on conduction band control and surface ion modification. AB - Band-gap narrowing is generally considered to be a primary method in the design of visible-light-active photocatalysts because it can decrease the photo threshold to lower energies. However, controlling the valence band by up-shifting the top of the band or inducing localized levels above the band results in quantum efficiencies under visible light much lower than those under UV irradiation (such as those reported for N-doped TiO(2): Science 2001, 293, 269. J. Phys. Chem. B 2003, 107, 5483). Herein, we report a systematic study on a novel, visible-light-driven photocatalyst based on conduction band control and surface ion modification. Cu(II)-(Sr(1-y)Na(y))(Ti(1-x)Mo(x))O(3) photocatalysts were prepared by a soft chemical method in combination with an impregnation technique. It is found that Mo(6+) as well as Na(+) doping in the SrTiO(3) can lower the bottom of the conduction band and effectively extend the absorption edge to the visible light region. The Cu(II) clusters grafted on the surface act as a co-catalyst to efficiently reduce the oxygen molecules, thus consuming the excited electrons. Consequently, photocatalytic decomposition of gaseous 2 propanol into CO(2) is achieved, that is, CH(3)CHOHCH(3) + (9)/(2)O(2) -> 3CO(2) + H(2)O. For Cu(II)-(Sr(1-y)Na(y))(Ti(1-x)Mo(x))O(3) at x = 2.0% under visible light irradiation, the maximum CO(2) generation rate can reach 0.148 MUmol/h; the quantum efficiency under visible light is calculated to be 14.5%, while it is 10% under UV light irradiation. Our results suggest that high visible light photocatalytic efficiency can be achieved by combining conduction band control and surface ion modification, which provides a new approach for rational design and development of high-performance photocatalysts. PMID- 20932017 TI - Discovery of biphasic thermal unfolding of ompc with implications for surface loop stability. AB - Escherichia coli outer membrane protein C (osmoporin) is a close homologue of OmpF or matrix porin, expressed under conditions of high osmolarity or ionic strength. Despite the fact that the proteins display very similar structures (rmsd = 0.78 A), the channel activities (gating or selectivity) of the two proteins are markedly different, and compared to OmpF, there is much less published information about the stability and folding of OmpC. In this paper, we report a structural study of nine OmpC mutations that affect channel size and voltage gating. The secondary and tertiary structural analysis by circular dichroism (CD) indicated that the single-amino acid substitutions have little impact on the protein fold. However, a thermal denaturation study using CD and differential scanning calorimetry shows that different mutations lead to varied levels of destabilization, with the largest showing a 15 degrees C lower T(m) than the wild type and a 40% reduction in DeltaH(cal). CD thermal denaturation measurements revealed that OmpC unfolds in a biphasic process, in which only the second phase is affected by the known mutations. The first stage of unfolding was shown to be reversible and separate from the main unfolding and loss of trimeric structure occurring in the second phase, leaving the flexible extracellular loops as the likely site of unfolding. The first phase is abolished as OmpC becomes more stable at lower pH. PMID- 20932018 TI - Volume-based thermoelasticity: consequences of the (near) proportionality of isothermal compressibility to formula-unit volume. AB - Groups of structurally related materials, including the alkali halides, exhibit a proportionality of isothermal compressibility to formula-unit volume. The relationship has recently been explored by Glasser and by Recio et al. In this paper, we present the consequences of such proportionality on the relationships of Born-Lande and Born-Mayer parameters to the formula-unit volume. These relationships have then been tested separately on (i) alkali (excluding cesium) halides and (ii) cesium halides. We conclude that the equations fit the NaCl-type materials satisfactorily, but less well for the CsCl-type materials, and that the Born-Mayer equation is more applicable. These results confirm the conclusion that volume is intimately linked to thermodynamic quantities, as already demonstrated by our development of volume-based thermodynamics (VBT). PMID- 20932019 TI - Aluminosilicate relatives: Chalcogenoaluminogermanates Rb(3)(AlQ(2))(3)(GeQ(2))(7) (Q = S, Se). AB - The new compounds Rb(3)(AlQ(2))(3)(GeQ(2))(7) [Q = S (1), Se (2)] feature the 3D anionic open framework [(AlQ(2))(3)(GeQ(2))(7)](3-) in which aluminum and germanium share tetrahedral coordination sites. Rb ions are located in channels formed by the connection of 8, 10, and 16 (Ge/Al)S(4) tetrahedra. The isostructural sulfur and selenium derivatives crystallize in the space group P2(1)/c. 1: a = 6.7537(3) A, b = 37.7825(19) A, c = 6.7515(3) A, and beta = 90.655(4) degrees . 2: a = 7.0580(5) A, b = 39.419(2) A, c = 7.0412(4) A, beta = 90.360(5) degrees , and Z = 2 at 190(2) K. The band gaps of the congruently melting chalcogenogermanates are 3.1 eV (1) and 2.4 eV (2). PMID- 20932020 TI - Facile syntheses of silylene nickel carbonyl complexes from Lewis base stabilized chlorosilylenes. AB - Two silylene nickel carbonyl complexes of composition L.Ni(CO)(3) (1) {L = PhC(NtBu)(2)SiCl} and L'(2).Ni(CO)(2) (2) { L' = RSiCl(2), R = (1,3-bis-(2,6 diisopropylphenyl)imidazol-2-ylidene)} were prepared by reacting 1 equivalent of Ni(CO)(4) with 1 equivalent of heteroleptic chlorosilylene L for 1 and with 2 equivalents of carbene stabilized dichlorosilylene L' for 2 in toluene at room temperature. Both complexes 1 and 2 were characterized by single-crystal X-ray analysis, NMR and IR spectroscopy, EI-MS spectrometry, and elemental analysis. PMID- 20932021 TI - Asymmetric synthesis of 3,4-diaminocyclohexanol and endo-7 azabicyclo[2.2.1]heptan-2-amine. AB - Hydroboration of (1R,2R)-bis[(S)-1-phenylethylamino]cyclohex-4-ene and its derivatives with several borane reagents gave diastereomeric mixtures of the 3,4 diaminocyclohexanol derivatives. Cyclization of the prevalent diastereomer with the R configuration of the newly formed stereocenter under Mitsunobu conditions, followed by reductive removal of the N-substituents, gave the optically pure endo 7-azabicyclo[2.2.1]heptane-2-amine. PMID- 20932022 TI - Total synthesis of (-)-nakadomarin A. AB - A concise diastereoselective total synthesis of (-)-nakadomarin A has been completed in 21 steps from D-pyroglutamic acid. Key steps include an enecarbamate Michael addition/furan-N-acyliminium ion cascade cyclization to provide the tetracyclic core and ring-closing alkyne and alkene metatheses to construct the fifteen- and eight-membered azacycles, respectively. PMID- 20932023 TI - Lithium salts of [1,12-dialkyl-CB11Me10]- anions. AB - We report the syntheses of several [1-R-CB(11)-Me(11)](-) and [1-R-12-R'-CB(11) Me(10)](-) anions (R, R' = alkyl) and the solubilities of their lithium salts in cyclohexane. These solutions are of interest as Lewis acid catalysts. The new anions are not directly accessible by methylation with methyl triflate because of intervening triflyloxy substitution on one or more boron vertices. The difficulty has been circumvented in two ways. Either (i) an iodo substituent is first introduced into position 12, permitting a clean decamethylation, and then replaced with a methyl by reaction with trimethylaluminum or (ii) the offending triflyloxy substituents are replaced with methyls by reaction with trimethylaluminum. PMID- 20932024 TI - Iridium metal complexes containing N-heterocyclic carbene ligands for blue-light emitting electrochemical cells. AB - A new series of cationic blue-emitting, heteroleptic iridium(III)-based metal complexes were systematically synthesized using two 4,6-difluorophenylpyridine ligands as well as one methyl- or n-butyl-substituted bisimidazolium salt carbene type ligand. In degassed CH(2)Cl(2), all complexes display highly efficient, blue phosphorescence (lambda(max) ~ 452 nm; emission quantum yield ~ 0.30) at room temperature and also show blue emission in a thin film. The measured photophysical properties of the complexes have been rationalized with the help of quantum-chemical calculations. Because of the high solubility of the complexes, solution-processed devices, light-emitting electrochemical cells (LEECs), were made. The results showed that true blue emission and short turn-on time is achieved when an ionic conductor, tetrabutylammonium trifluoromethanesulfonate, was used as the matrix for the film containing the emitters. These iridium complexes and the described devices are the bluest materials ever reported and the first case of LEECs based on carbene ligands. PMID- 20932026 TI - Ferromagnetically coupled cobalt-benzene-cobalt: the smallest molecular spin filter with unprecedented spin injection coefficient. AB - Here, we predict that the ferromagnetically coupled cobalt-benzene-cobalt system will act as the smallest molecular spin filter with unprecedented spin injection coefficient. To validate our in-silico observation, we have performed state-of the-art nonequilibrium Green's function calculations and analyzed the density of states of cobalt at the relativistic and nonrelativistic level of theory. Remarkably, we found that unpaired 3d electrons of cobalt are not participating in the spin transport process like other transition metal containing multidecker complexes. Instead, an admixture of the outer-sphere 4s and 4p orbitals of cobalt along with the 2p orbital of carbon of the benzene moiety is contributing to the singly occupied highest molecular orbital in the majority spin channel that creates a path for coherent spin transport leading to the extremely high spin injection coefficient of the system. The absence of the 3d electrons of cobalt in the spin transport process has been carefully examined, and it was found that the nodal structure of the 3d orbital of cobalt is not at all suitable for bonding in the cobalt-benzene-cobalt system. The whole study indicates that the underlying mechanism of the spin filter action in cobalt-benzene-cobalt is completely distinctive from the other known materials. PMID- 20932025 TI - High-affinity glycopolymer binding to human DC-SIGN and disruption of DC-SIGN interactions with HIV envelope glycoprotein. AB - Noncovalent interactions between complex carbohydrates and proteins drive many fundamental processes within biological systems, including human immunity. In this report we aimed to investigate the potential of mannose-containing glycopolymers to interact with human DC-SIGN and the ability of these glycopolymers to inhibit the interactions between DC-SIGN and the HIV envelope glycoprotein gp120. We used a library of glycopolymers that are prepared via combination of copper-mediated living radical polymerization and azide-alkyne [3+2] Huisgen cycloaddition reaction. We demonstrate that a relatively simple glycopolymer can effectively prevent the interactions between a human dendritic cell associated lectin (DC-SIGN) and the viral envelope glycoprotein gp120. This approach may give rise to novel insights into the mechanisms of HIV infection and provide potential new therapeutics. PMID- 20932027 TI - Thermochemistry of Lewis adducts of BH3 and nucleophilic substitution of triethylamine on NH3BH3 in tetrahydrofuran. AB - The thermochemistry of the formation of Lewis base adducts of BH(3) in tetrahydrofuran (THF) solution and the gas phase and the kinetics of substitution on ammonia borane by triethylamine are reported. The dative bond energy of Lewis adducts were predicted using density functional theory at the B3LYP/DZVP2 and B3LYP/6-311+G** levels and correlated ab initio molecular orbital theories, including MP2, G3(MP2), and G3(MP2)B3LYP, and compared with available experimental data and accurate CCSD(T)/CBS theory results. The analysis showed that the G3 methods using either the MP2 or the B3LYP geometries reproduce the benchmark results usually to within ~1 kcal/mol. Energies calculated at the MP2/aug-cc-pVTZ level for geometries optimized at the B3LYP/DZVP2 or B3LYP/6 311+G** levels give dative bond energies 2-4 kcal/mol larger than benchmark values. The enthalpies for forming adducts in THF were determined by calorimetry and compared with the calculated energies for the gas phase reaction: THFBH(3) + L -> LBH(3) + THF. The formation of NH(3)BH(3) in THF was observed to yield significantly more heat than gas phase dative bond energies predict, consistent with strong solvation of NH(3)BH(3). Substitution of NEt(3) on NH(3)BH(3) is an equilibrium process in THF solution (K ~ 0.2 at 25 degrees C). The reaction obeys a reversible bimolecular kinetic rate law with the Arrhenius parameters: log A = 14.7 +/- 1.1 and E(a) = 28.1 +/- 1.5 kcal/mol. Simulation of the mechanism using the SM8 continuum solvation model shows the reaction most likely proceeds primarily by a classical S(N)2 mechanism. PMID- 20932028 TI - Supramolecular interactions probed by 13C-13C solid-state NMR spectroscopy. AB - We present a robust solid-state NMR approach for the accurate determination of molecular interfaces in insoluble and noncrystalline protein-protein complexes. The method relies on the measurement of intermolecular (13)C-(13)C distances in mixtures of [1-(13)C]glucose- and [2-(13)C]glucose-labeled proteins. We have applied this method to Parkinson's disease-associated alpha-synuclein fibrils and found that they are stacked in a parallel in-register arrangement. Additionally, intermolecular distance restraints for the structure determination of the fibrils at atomic resolution were measured. PMID- 20932029 TI - Molecular detection of targeted major histocompatibility complex I-bound peptides using a probabilistic measure and nanospray MS3 on a hybrid quadrupole-linear ion trap. AB - A nanospray MS(3) method deployed on a quadrupole linear ion trap hybrid can detect targeted peptides with high dynamic range and high sensitivity from complex mixtures without separations. The method uses a recognition algorithm that is a modification of the relative (Kullback-Leibler, KL) entropy characterization of probabilistic distance to detect if reference MS(3) fragmentation patterns are components of acquired MS(3) spectra. The recognition reflects the probabilistic structure of physical MS measurements unlike the Euclidean or inner product metrics widely used for comparing spectra. It capably handles spectra with a significant chemical ion background in contrast to the Euclidean metric or the direct relative entropy. The full nanospray MS(3) method allows both the detection and quantitation of targets without the need to obtain isotopically labeled standards. By avoiding chromatographic separations and its associated surface losses, the detection can be applied to complex samples on a very limited material scale. The methodology is illustrated by applications to the medically important problem of detecting targeted major histocompatibility complex (MHC) I associated peptides extracted from limited cell numbers. PMID- 20932032 TI - Functional comparison of esterified and free forms of conjugated linoleic acid in high-fat-diet-induced obese C57BL/6J mice. AB - This study investigated the effects of dietary conjugated linoleic acid (CLA), in the form of free fatty acid (FFA-CLA) or triacylglycerol (TG-CLA), on serum and liver lipid composition and gene expression associated with lipogenesis and beta oxidation in high-fat-diet (HFD)-induced obese C57BL/6J mice. Animals were fed a control diet, HFD, HFD supplemented with 2% FFA-CLA, or HFD supplemented with 2% TG-CLA for 8 weeks. Supplementation with both forms of CLA significantly reduced the weights of whole body and adipose tissue and was positively associated with significant liver enlargement. Both forms of CLA significantly decreased serum TG concentration, but had no effect on total cholesterol levels, which were increased in mice fed HFD. There was a prominent increase in serum alanine aminotransferase (ALT) levels in mice that received either form of CLA. TG accumulation and lipogenic gene expression, including the expression of genes for fatty acid synthase (FAS), acetyl-coenzyme A carboxylase (ACC), and malic enzyme, were significantly lower in the livers of mice that received TG-CLA as compared to FFA-CLA. The gene expressions of sterol regulatory element binding protein-1c (SREBP-1c) in both liver and adipose tissue were suppressed in mice that were fed either form of CLA as compared to the mice fed HFD alone, whereas there were no increases in the levels of expression of beta-oxidation-related genes. These findings demonstrated that free and esterified forms of CLA have differing effects on liver and adipose tissue lipogenesis. PMID- 20932033 TI - Urinary excretion of (Epi)catechins in rats fed different berries or berry products. AB - (Epi)catechins are associated with many health benefits in humans. However, their bioavailability, excretory pattern, and extent of conjugation in animals fed different sources or levels in the diet are not well documented. Two experiments were conducted to investigate the urinary excretion of (epi)catechins after feeding of different types of berries or different levels of the same berry source to rats. Experiment 1 investigated the effects of feeding a commercially available concentrated cranberry powder (CCP) at three different levels, 3.3, 6.6, and 33 g/kg of diet, whereas experiment 2 investigated the effect of feeding freeze-dried whole cranberry (CB), blueberry (BB), or black raspberry (BRB) powder at 50 g/kg of diet. Both experiments had an AIN-93-based control and a high-fructose diet (53-65% of the diet) to which was added three levels of CCP in experiment 1 and CB, BB, and BRB in experiment 2. (Epi)catechins were excreted as free and conjugated in both intact and methylated forms. Excretion of conjugated (epi)catechins was as high as 60% of the total consumed in some cases. A majority of both catechins and epicatechins excreted in the urine was in a methylated form. Excretion of epicatechins, including their methylated forms, ranged from 30 to 47% of the ingested amount, whereas that of catechins, including their methylated forms, ranged from 9 to 31%. Urinary excretion of (epi)catechins was dose dependent and increased with the amount of (epi)catechins present in the diet. On the basis of the excretory pattern of (epi)catechins in the urine, data suggested that the bioavailability of epicatechins may be higher than that of catechins and that (epi)catechins may be more available from blueberries compared to cranberries. PMID- 20932034 TI - Homogeneous esterification of poplar wood in an ionic liquid under mild conditions: characterization and properties. AB - Wood meal was completely dissolved under constant conditions (130 degrees C, 6 h) in the ionic liquid 1-butyl-3-methylimidazolium chloride ([C4mim]Cl), and the various factors and potential mechanism of the homogeneous esterification of wood in this reaction medium were mainly studied. The physicochemical properties of the esterified wood were also investigated. It has been shown that highly substituted wood esters could be obtained by reacting wood dissolved in [C(4)mim]Cl with octanoyl chloride in the presence of triethylamine as a neutralizer. The weight percent gain was arranged from 121.5% to 297.4%. All reactions were performed under mild conditions, low excess of reagent, and a short reaction time compared to the heterogeneous chemical modification. Meanwhile, characterization of the derivatives confirmed that the homogeneous esterification was successfully processed. It was also found that thermal stability and morphological properties of the esterified wood were significantly different from those in previous reports. Octanoylation of wood meal in the [C(4)mim]Cl homogeneous system reduced the initial temperature of their thermal degradation and decreased the thermal stability compared to those in unmodified wood meal. Furthermore, the fibrillar appearance of wood meal changed into a relatively more homogeneous macrostructure of the esterfied wood. All these results suggested that homogeneous esterification of poplar wood in [C(4)mim]Cl would enhance the compatibility and improve the processability of wood with synthetic polymers. PMID- 20932035 TI - Intramolecular NH...Pt interactions of platinum(II) diimine complexes with phenyl ligands. AB - Pt(pipNC)(2)(phen) [pipNC(-) = 1-(piperidylmethyl)phenyl anion; phen = 1,10 phenanthroline] was prepared by the reaction of cis-Pt(pipNC)(2) with phen. Crystallographic and (1)H NMR data establish that the phen ligand is bidentate, whereas each piperidyl ligand is monodentate and bonded to the platinum at the ortho position of the phenyl group. Acidic conditions allowed for isolation of the salts of diprotonated Pt(pipNHC)(2)(diimine)(2+) adducts (diimine = phen, 2,2'-bipyridine, or 5,5'-ditrifluoromethyl-2,2'-bipyridine). Crystallographic and spectroscopic data for the diprotonated complexes are consistent with H...Pt interactions (2.32-2.51 A) involving the piperidinium groups, suggesting that the metal center behaves as a Bronsted base. Metal-to-ligand (diimine) charge transfer states of Pt(pipNHC)(2)(phen)(2+) in solution are strongly destabilized (>2500 cm(-1)) relative to Pt(pipNC)(2)(phen), in keeping with the notion that NH...Pt interactions effectively reduce the electron density at the metal center. Though N...Pt interactions in Pt(pipNC)(2)(phen) appear to be weaker than those found for outer-sphere two-electron reagents, such as Pt(pip(2)NCN)(tpy)(+) [pip(2)NCN(-) = 1,3-bis(piperidylmethylphenyl anion; tpy = 2,2':6',2' terpyridine], each of the Pt(pipNC)(2)(diimine) complexes undergoes diimine ligand dissociation to give back cis-Pt(pipNC)(2) and free diimine ligand. Electrochemical measurements on the deprotonated complexes suggest that the piperidyl groups help to stabilize higher oxidation states of the metal center, whereas protonation of the piperidyl groups has a destabilizing influence. PMID- 20932036 TI - Charged states of alpha,omega-dicyano beta,beta'-dibutylquaterthiophene as studied by in situ ESR UV-vis NIR spectroelectrochemistry. AB - The influence of the molecular structure on the stabilization of charged states was studied in detail by in situ ESR UV-vis NIR spectroelectrochemistry at a novel alpha,omega-dicyano substituted beta,beta'-dibutylquaterthiophene (DCNDBQT) and the electrochemically generated cation and anion radicals have been proved for the first time. The voltammetry of DCNDBQT results in two separate oxidation steps with the reversible first one. The experimental absorption maxima at 646 and 1052 nm together with the calculated ones (by DFT method) as well as an ESR signal at the first anodic step prove the presence of a radical cation. Three additional optical bands (554, 906, and 1294 nm for CT-transition) can be attributed to the formation of cation radical dimer. The dicationic structure formed in the second oxidation step is not stable. The stabilization proceeds via a dimer formation in two chemical follow-up reactions. The existence of the dimeric structures was proved by ex situ MALDI TOF mass spectrometry. As the substitution by cyano groups opens the route to cathodic reductions, DCNDBQT shows a single quasi-reversible reduction step. Here, the in situ ESR UV-vis NIR spectroelectrochemical measurements and theoretical calculations let us confirm the electrochemical generation of an anion radical. As we found a low number of anion radicals by quantitative ESR spectroelectrochemistry and an appearance of additional bands in the UV-vis NIR absorption spectra, the formation of dimeric structures must be considered and was corroborated by mass spectrometry. The role of dimerization in the reaction mechanism of the DCNDBQT oxidation and reduction are discussed in general. The experimental results were interpreted using the quantum chemical calculations based on density functional theory. PMID- 20932037 TI - Synthesis, structure, and binding property of pentiptycene-based rigid tweezer like molecules. AB - A series of pentiptycene-derived rigid tweezer-like molecules have been efficiently synthesized, and their structures have been determined by NMR, MS spectra, and X-ray analysis. Moreover, it was also found that molecular tweezer 15 showed efficient binding ability toward C(60). PMID- 20932038 TI - Comment on "Atomic and molecular parity nonconservation and sum frequency generation solutions to the Ozma problem". PMID- 20932039 TI - Effects of surface properties of different substrates on fine structure of plasma polymerized SiOCH films prepared from hexamethyldisiloxane (HMDSO). AB - In this study, Doppler broadening energy spectroscopy (DBES) combined with slow positron beam was used to discuss the effect of substrate types on the fine structure of a plasma-polymerized SiOCH layer as a function of depth. From the SEM pictures, the SiOCH films formed on different substrates showed hemispherical macrostructures, and the deposition rate was dependent on the mean pore size. It appears that the morphology of the plasma-polymerized SiOCH films was associated with the porosity-related characteristics of the substrate such as the size/shape of pores. As deposited on the MCE-022 substrate (mixed cellulose esters membrane with a mean pore size of 0.22 MUm) with a nodular structure, the SiOCH films had pillar-like structures and high gas permeabilities. DBES results showed that the SiOCH films deposited on different substrates were composed of three layers: the SiOCH bulk layer, the transition layer, and the substrate. It was observed that the microstructure of the SiOCH films was affected layer by layer; a higher surface pore size in the substrates induced thicker transition layers with higher microporosities and led to thinner bulk layers having higher S parameter values during the plasma polymerization. It was also observed that the change in O(2)/N(2) selectivity was consistent with the DBES analysis results. The gas separation performance and DBES analysis results agreed with each other. PMID- 20932040 TI - Imaging ice-like structures formed on HOPG at room temperature. AB - In this work, ice was viewed at the nanoscale by scanning an atomic force microscopy tip over a highly oriented pyrolytic graphite (HOPG) surface in air. At low scan velocities, the tip exhibited stick-slip motion with a period of 0.13 nm corresponding to the scanner step; at higher velocities, the HOPG lattice and the periodicity of the ice were visible. A hexagonal structure with a 0.45 +/- 0.04 nm periodicity was observed in which the distance between the second neighbors of the HOPG coincided with the distance of the first neighbors for the ice-like arrangement. Small water clusters were also nucleated with an ice-Ic structure (0.34 +/- 0.03 nm), and thus, the ice layers consisted of extensive sets composed of arrangements of hexamers and tetramers. PMID- 20932041 TI - Reversible pH-controlled switching of poly(methacrylic acid) grafts for functional biointerfaces. AB - Responsive polymeric brushes of poly(methacrylic acid) (PMAA) were grafted from silicon surfaces using controlled surface-initiated atom-transfer radical polymerization (SI-ATRP). The growth kinetics of PMAA was investigated with respect to the composition of the ATRP medium by grafting the polymer in mixtures of water and methanol with different ratios. The dissociation behavior of the polymer layers was characterized by FTIR titration after incubating the polymer grafted substrates in PBS buffer solutions with different pH values. PMAA layers show a strong pH-dependent behavior with an effective pK(a) of the bulk polymer brush of 6.5 +/- 0.2, which is independent of the polymer brush thickness and methanol content of the ATRP grafting medium. The pH-induced swelling and collapse of the grafted polymer layers were quantified in real time by in situ ellipsometry in liquid environment. Switching between polymer conformations at pH values of 4 and 8 is rapid and reversible, and it is characterized by swelling factors (maximum thickness/minimum thickness) that increase with decreasing the methanol content of the SI-ATRP medium. PMID- 20932042 TI - Hydrated cation speciation at the muscovite (001)-water interface. AB - Charged materials in aqueous systems interact according to their interfacial properties, typically described by the electrical double layer (EDL). Distributions of divalent metal cations at the muscovite (001)-solution interface observed using resonant anomalous X-ray reflectivity demonstrate an unexpected complexity with respect to the EDL structure. Three forms of adsorbed cations can coexist: the classical inner-sphere and outer-sphere complexes and a third "extended" outer-sphere complex located farther from the surface. Their relative proportions are controlled by the energy balance among cation hydration, interface hydration, and electrostatic attraction. Systematic trends in coverage and position establish the defining role of cation hydration in stabilizing the multiple coexisting species. PMID- 20932043 TI - Domino imino-aldol-aza-Michael reaction: one-pot diastereo- and enantioselective synthesis of piperidines. AB - Addition of alpha-arylmethylidene- or alpha-alkylidene-beta-keto ester enolate to N-activated aldimines via the imino aldol pathway followed by intramolecular aza Michael reaction in a domino fashion has been developed, and a highly diastereoselective route to substituted piperidines is reported. Enantiopure piperidines are synthesized from chiral sulfinyl imines. Formation and the observed stereoselectivity of the products have been rationalized by mechanistic and computational studies. PMID- 20932044 TI - Band alignment tuning in twin-plane superlattices of semiconductor nanowires. AB - The band alignments of twin-plane superlattices in semiconductor nanowires are systematically investigated on the basis of density functional calculations. Our calculations demonstrate that for nanowires with small diameters the quantum confinement effect is prominent within wurtzite structure regions and the energy gap in wurtzite-structured nanowires is remarkably larger than that including zinc-blende structure. This results in the straddling band alignment, in which both electrons and holes are confined in zinc-blende structure region. The analysis using a simple tight-binding methods also clarifies that the straddling band alignments can be realized when the diameters of nanowires are less than 4-8 nm, leading to full control of band alignments by varying the nanowire diameter. Our results provide the ability of band-alignment tuning and open new possibilities for band engineering. PMID- 20932045 TI - Vesicle adsorption on mesoporous silica and titania. AB - Lipid bilayer formation via vesicle fusion on mesoporous silica and mesoporous titania was investigated using quartz crystal microbalance with dissipation monitoring (QCM-D) and fluorescent recovery after photobleaching (FRAP). Results showed that lipid bilayers were formed on mesoporous silica and that intact vesicle adsorption was obtained on mesoporous titania. From the FRAP results, it could be concluded that the lipid bilayer was fluid; however, it had a smaller diffusivity constant compared to bilayers supported on a nonporous silica. PMID- 20932046 TI - Wafer scale homogeneous bilayer graphene films by chemical vapor deposition. AB - The discovery of electric field induced band gap opening in bilayer graphene opens a new door for making semiconducting graphene without aggressive size scaling or using expensive substrates. However, bilayer graphene samples have been limited to MUm(2) size scale thus far, and synthesis of wafer scale bilayer graphene poses a tremendous challenge. Here we report homogeneous bilayer graphene films over at least a 2 in. * 2 in. area, synthesized by chemical vapor deposition on copper foil and subsequently transferred to arbitrary substrates. The bilayer nature of graphene film is verified by Raman spectroscopy, atomic force microscopy, and transmission electron microscopy. Importantly, spatially resolved Raman spectroscopy confirms a bilayer coverage of over 99%. The homogeneity of the film is further supported by electrical transport measurements on dual-gate bilayer graphene transistors, in which a band gap opening is observed in 98% of the devices. PMID- 20932047 TI - Conductive path formation in the Ta2O5 atomic switch: first-principles analyses. AB - The conductive path formed by the interstitial Cu or oxygen vacancies in the Ta(2)O(5) atomic switch were investigated in detail by first-principles methods. The calculated results indicated that the defect state induced by the interstitial Cu is located just at the Fermi level of the Cu and Pt electrodes in the Cu/Ta(2)O(5)/Pt heterostructure and that a conduction channel is formed in the Ta(2)O(5) film via the interstitial Cu. On the other hand, oxygen vacancies in Ta(2)O(5) do not form such a conduction channel because of the lower energy positions of their defect states. The above results suggest that the conductive path could be formed by interstitial Cu in the Ta(2)O(5) atomic switch, whereas the oxygen vacancies do not contribute to the formation of the conductive path. PMID- 20932048 TI - Hexaazaphenalene derivatives: one-pot synthesis, hydrogen-bonded chiral helix, and fluorescence properties. AB - Symmetric hexaazaphenalenes (R = phenyl and tert-butyl) have been synthesized by one-pot condensations of corresponding amidine hydrochlorides with tricyanomethanide. The hexaazaphenalenes are linked with each other by a N-H...N hydrogen-bonding interaction in the crystalline states. Interestingly, a planar and achiral tert-butylated derivative was crystallized in a chiral space group with assembly of one-handed helical hydrogen-bonded chains. Hexaazaphenalenyl anions were isolated as air- and water-stable tetraethyl ammonium salts. PMID- 20932049 TI - Dynamical friction effects on the photoisomerization of a model protonated Schiff base in solution. AB - Photoisomerization involving a conical intersection (CI) for a model protonated Schiff base (PSB) in modeled water and acetonitrile solvents is examined with the inclusion of energy- and momentum-transfer effects described via a generalized Langevin equation (GLE) frictional approach and surface-hopping dynamics. Short time GLE frictional effects on the model's three coordinates, the intramolecular bond length alternation and torsional PSB coordinates and a solvent coordinate, eliminate several unphysical features associated with a no-friction inertial description and have the general feature of accelerating nonadiabatic transitions to the ground electronic state. The inertial prediction of equal probability formation of ground-state trans and cis isomer products subsequent to the Franck Condon excitation of the ground cis isomer is replaced by the GLE prediction of a preferential higher proportion of ground-state trans isomer, that is, a successful cis to trans photoreaction. This preference is solvent-dependent and is enhanced in water solvent with its higher friction intensity and short time scales. For the fast water solvent motion, the nonadiabatic transitions to the S(0) ground state are centered around the CI seam (which is due to the solvent coordinate's role as a tuning coordinate), facilitating direct transitions to the ground-state trans isomer. In contrast, for the slower acetonitrile solvent motion, the decay occurs, on average, away from the CI seam in regions with a finite free-energy gap between the excited and ground states, resulting in reduced trans isomer production. Some directions for the extension of the model description are also discussed. PMID- 20932050 TI - Organocatalytic preparation of simple beta-hydroxy and beta-amino esters: low catalyst loadings and gram-scale synthesis. AB - A combined amino- and N-heterocyclic carbene (NHC)-catalyzed one-pot reaction sequence for the synthesis of simple enantioenriched beta-hydroxy and beta-amino esters using commercially available catalysts at low catalyst loadings has been developed. The desired products were obtained in high yield and excellent enantiopurity. The generation of quaternary stereocenters and application in gram scale synthesis were also realized, with no requirements of inert or anhydrous reaction conditions, thus making this transformation a highly practical protocol. PMID- 20932051 TI - Molecular dynamics simulations and instantaneous normal-mode analysis of the vibrational relaxation of the C-H stretching modes of N-methylacetamide-d in liquid deuterated water. AB - Nonequilibrium molecular dynamics (MD) simulations and instantaneous normal mode (INMs) analyses are used to study the vibrational relaxation of the C-H stretching modes (nu(s)(CH3)) of deuterated N-methylacetamide (NMAD) in aqueous (D2O) solution. The INMs are identified unequivocally in terms of the equilibrium normal modes (ENMs), or groups of them, using a restricted version of the recently proposed Min-Cost assignment method. After excitation of the parent nu(s)(CH3) modes with one vibrational quantum, the vibrational energy is shown to dissipate through both intramolecular vibrational redistribution (IVR) and intermolecular vibrational energy transfer (VET). The decay of the vibrational energy of the nu(s)(CH3) modes is well fitted to a triple exponential function, with each characterizing a well-defined stage of the entire relaxation process. The first, and major, relaxation stage corresponds to a coherent ultrashort (tau(rel) = 0.07 ps) energy transfer from the parent nu(s)(CH3) modes to the methyl bending modes delta(CH3), so that the initially excited state rapidly evolves into a mixed stretch-bend state. In the second stage, characterized by a time of 0.92 ps, the vibrational energy flows through IVR to a number of mid range-energy vibrations of the solute. In the third stage, the vibrational energy accumulated in the excited modes dissipates into the bath through an indirect VET process mediated by lower-energy modes, on a time scale of 10.6 ps. All the specific relaxation channels participating in the whole relaxation process are properly identified. The results from the simulations are finally compared with the recent experimental measurements of the nu(s)(CH3) vibrational energy relaxation in NMAD/D2O(l) reported by Dlott et al. (J. Phys. Chem. A 2009, 113, 75.) using ultrafast infrared-Raman spectroscopy. PMID- 20932052 TI - Scanning tunneling microscopy, spectroscopy, and nanolithography of epitaxial graphene chemically modified with aryl moieties. AB - The reduction of diazonium salts has recently been proposed as a robust covalent modification scheme for graphene surfaces. While preliminary studies have provided indirect evidence that this strategy decorates graphene with aryl moieties, the molecular ordering and conformation of the resulting adlayer have not been directly measured. In this Article, we report molecular-resolution characterization of the adlayer formed via the spontaneous reduction of 4 nitrophenyl diazonium (4-NPD) tetrafluoroborate on epitaxial graphene on SiC(0001) using ultrahigh vacuum (UHV) scanning tunneling microscopy (STM) and spectroscopy (STS). An atomically flat inhomogeneous layer of covalently bonded organic molecules is observed after annealing the chemically treated surface at ~500 degrees C in UHV. STM and STS results indicate that the adlayer consists predominantly of aryl oligomers that sterically prevent uniform and complete covalent modification of the graphene surface. The adsorbed species can be selectively desorbed by the STM tip above a threshold sample bias of -5 V and tunneling current of 1 nA, thus enabling the fabrication of a diverse range of graphene nanopatterns at the sub-5 nm length scale. PMID- 20932053 TI - Strontium nitrate extraction to ionic liquids by a crown ether: a molecular dynamics study of aqueous interfaces with C4mim+- vs C8mim+-based ionic liquids. AB - In order to gain microscopic insights into the extraction mechanism of strontium cations by 18-crown-6 (18C6) to room temperature ionic liquids (ILs), we simulated by molecular dynamics (MD) strontium complexes in neat ionic liquids and at their interfaces with water. We compared two ILs, based on the PF(6)(-) anion and either 1-butyl-3-methylimidazolium (C(4)mim(+)) or 1-octyl-3 methylimidazolium (C(8)mim(+)) cations. Regarding the complexes, two states were considered: charged [Sr?18C6](2+) vs neutral [Sr?18C6,(NO(3))(2)], where the nitrates are either fully dissociated or coordinated to Sr. In "dry" or "humid" [C(4)mim][PF(6)] and in "dry" [C(8)mim][PF(6)] IL, the neutral complex is found to be the most stable one. In the binary IL/water solutions, the charged complexes mostly partition to the aqueous phase, whereas the neutral [Sr?18C6,(NO(3))(2)] complexes are more concentrated in the interfacial domain. The aqueous solutions in contact with the ionic liquids contain C(4)mim(+), but almost no C(8)mim(+) ions, supporting a classical extraction mechanism to [C(8)mim][PF(6)] and an ion exchange mechanism to [C(4)mim][PF(6)]. Furthermore, remarkable events occurred during the dynamics, where complexes were extracted to the IL phases. When compared to the interfacial landscapes obtained with the same solutes at a classical organic liquid (chloroform)/water interface, those with ILs allow us to better understand specific features of liquid-liquid extraction to ILs. PMID- 20932054 TI - Steady-state kinetic mechanism and reductive half-reaction of D-arginine dehydrogenase from Pseudomonas aeruginosa. AB - D-arginine dehydrogenase from Pseudomonas aeruginosa catalyzes the oxidation of D arginine to iminoarginine, which is hydrolyzed in solution to ketoarginine and ammonia. In the present study, we have genetically engineered an untagged form of the enzyme that was purified to high levels and characterized in its kinetic properties. The enzyme is a true dehydrogenase that does not react with molecular oxygen. Steady-state kinetic studies with D-arginine or D-histidine as substrate and PMS as the electron acceptor established a ping-pong bi-bi kinetic mechanism. With the fast substrate D-arginine a dead-end complex of the reduced enzyme and the substrate occurs at high concentrations of D-arginine yielding substrate inhibition, while the overall turnover is partially limited by the release of the iminoarginine product. With the slow substrate D-histidine the initial Michaelis complex undergoes an isomerization involving multiple conformations that are not all equally catalytically competent for the subsequent oxidation reaction, while the overall turnover is at least partially limited by flavin reduction. The kinetic data are interpreted in view of the high-resolution crystal structures of the iminoarginine--and iminohistidine--enzyme complexes. PMID- 20932055 TI - DNA-directed self-assembly of gold nanoparticles onto nanopatterned surfaces: controlled placement of individual nanoparticles into regular arrays. AB - A method for the templated DNA-directed self-assembly of individual gold nanoparticles (AuNPs) into discrete nanostructures is described. The templating nanostructures consisted of a linear configuration of six metal dots with a center-to-center dot distance of 55 nm, fabricated by means of electron beam lithography. The 40 nm DNA-capped AuNPs were immobilized onto this templating nanostructure to produce a linear configuration of six adjacent AuNPs. The geometry of the templating nanostructure was found to be critically important for the successful direction of a single nanoparticle onto individual adsorption sites. For optimized template structures the immobilization efficiency of nanoparticles onto the individual adsorption sites was found to be 80%. The nonspecific association of nanoparticles with specifically adsorbed nanoparticles and the between adsorption of nanoparticles, bridging two individual adsorption sites, were the two main defects observed in the immobilized assemblies. Less than 1% of all surface confined AuNPs adsorbed nonspecifically in the areas between the self-assembled regular arrays. PMID- 20932056 TI - Efficient subfractionation of gram-negative bacteria for proteomics studies. AB - Proteomics studies of pathogenic bacteria are an important basis for biomarker discovery and for the development of antimicrobial drugs and vaccines. Especially where vaccines are concerned, it is of great interest to explore which bacterial factors are exposed on the bacterial cell surface and thus can be directly accessed by the immune system. One crucial step in proteomics studies of bacteria is an efficient subfractionation of their cellular compartments. We set out to compare and improve different protocols for the fractionation of proteins from Gram-negative bacteria into outer membrane, cytoplasmic membrane, periplasmic, and cytosolic fractions, with a focus on the outer membrane. Overall, five methods were compared, three methods for the fast isolation of outer membrane proteins and two methods for the fractionation of each cellular compartment, using Escherichia coli BL21 as a model organism. Proteins from the different fractions were prepared for further mass spectrometric analysis by SDS gel electrophoresis and consecutive in-gel tryptic digestion. Most published subfractionation protocols were not explicitly developed for proteomics applications. Thus, we evaluated not only the separation quality of the five methods but also the suitability of the samples for mass spectrometric analysis. We could obtain high quality mass spectrometry data from one-dimensional SDS PAGE, which greatly reduces experimental time and sample amount compared to two dimensional electrophoresis methods. We then applied the most specific fractionation technique to different Gram-negative pathogens, showing that it is efficient in separating the subcellular proteomes independent of the species and that it is capable of producing high-quality proteomics data in electrospray ionization mass spectrometry. PMID- 20932057 TI - Population proteomics of the European Hake (Merluccius merluccius). AB - We report the novel use of proteomics to investigate protein variation among populations of the European hake (Merluccius merluccius). The liver and brain extracts of 18 hake (N = 36) captured in the Mediterranean Sea, Cantabrian Sea, and Atlantic Ocean were examined by 2D/DIGE and mass spectrometry. Significant differences in protein expression among populations were revealed by 84 spots obtained in the gels for the liver and 145 spots for the brain. Population groups of samples were defined by multivariate analysis (PCA and hierarchical clustering). According to protein expression levels and the functions of the 55 candidate protein spots identified, which showed significant expression differences, highest population discrimination was rendered by brain proteins involved in cell signaling and metabolism/energy and by liver proteins involved in protein fate. Finally, we present a statistically robust framework to accurately classify individuals according to their population of origin. Thus, purposely identified protein isoforms were found to be competent at discriminating populations. These results suggest the possibility of identifying protein biomarkers related to environmental changes in a nonmodel species such as the hake and pave the way for more extensive research on protein variation among populations of marine fishes. PMID- 20932058 TI - (1)H NMR-based metabonomic investigation of the effect of two different exercise sessions on the metabolic fingerprint of human urine. AB - Physical exercise modifies animal metabolism profoundly. Until recently, biochemical investigations related to exercise focused on a small number of biomolecules. In the present study, we used a holistic analytical approach to investigate changes in the human urine metabolome elicited by two exercise sessions differing in the duration of the rest interval between repeated efforts. Twelve men performed three sets of two 80 m maximal runs separated by either 10 s or 1 min of rest. Analysis of pre- and postexercise urine samples by (1)H NMR spectroscopy and subsequent multivariate statistical analysis revealed alterations in the levels of 22 metabolites. Urine samples were safely classified according to exercise protocol even when applying unsupervised methods of statistical analysis. Separation of pre- from postexercise samples was mainly due to lactate, pyruvate, hypoxanthine, compounds of the Krebs cycle, amino acids, and products of branched-chain amino acid (BCAA) catabolism. Separation of the two rest intervals was mainly due to lactate, pyruvate, alanine, compounds of the Krebs cycle, and 2-oxoacids of BCAA, all of which increased more with the shorter interval. Metabonomics provides a powerful methodology to gain insight in metabolic changes induced by specific training protocols and may thus advance our knowledge of exercise biochemistry. PMID- 20932059 TI - Intermolecular interaction in water hexamer. AB - The origin of the intermolecular interaction, especially the many-body interaction, in eight low-lying water hexamer structures (prism, cage, book-1, book-2, cyclic-chair, bag, cyclic-boat-1, and cyclic-boat-2) is unraveled using the localized molecular orbital energy decomposition analysis (LMO-EDA) method at the second-order Moller-Plesset perturbation (MP2) level of theory with a large basis set. It is found that the relative stabilities of these hexamer structures are determined by delicate balances between different types of interaction. According to LMO-EDA, electrostatic and exchange interactions are strictly pairwise additive. Dispersion interaction in these water hexamer structures is almost pairwise additive, with many-body effects varying from -0.13 to +0.05 kcal/mol. Repulsion interaction is roughly pairwise additive, with many-body effects varying from -0.84 to -0.62 kcal/mol. Polarization interaction is not pairwise additive, with many-body effects varying from -13.10 to -8.85 kcal/mol. PMID- 20932060 TI - Proteome of metastatic canine mammary carcinomas: similarities to and differences from human breast cancer. AB - Mammary tumors are a major health threat to women and female dogs. In both, metastasis of the primary tumor to distant organs is the most common cause of tumor-related death. Nevertheless, the molecular mechanisms of tumor metastasis are far from being understood, and it is still unknown why some human and canine carcinomas metastasize and others do not. Using 2D-DIGE and MALDI-TOF-MS we identified 21 proteins with significant changes (fold change >1.5; p < 0.05) in protein expression between metastasizing (n = 6) and nonmetastasizing (n = 6) canine mammary carcinomas. Quantitative RT-PCR was used to identify transcriptional or post-transcriptional regulation of protein expression. Up regulated proteins in metastatic carcinomas included proliferating cell nuclear antigen, ferritin light chain, bomapin, tropomyosin 3, thioredoxin-containing domain C5, adenosin, ornithine aminotransferase, coronin 1A, RAN-binding protein 1,3-phosphoglycerate dehydrogenase, and eukaryotic translation elongation factor 1. Down-regulated proteins in metastatic carcinomas included calretinin, myosin, light chain 2, peroxiredoxin 6, maspin, ibrinogen beta chain, vinculin, isocitrate dehydrogenase 1, tropomyosin 1, annexin A5, and Rho GTPase activating protein 1. Interestingly, 19 of these 21 proteins have been described with a malignancy-associated expression in human breast cancer and other human cancer types before. Further investigations are now necessary to test whether these markers are of prognostic value for canine mammary carcinomas and whether their expression is directly involved in canine mammary carcinogenesis or represent solely a secondary reactive phenotype. PMID- 20932061 TI - The C-terminus of nucleolin promotes the formation of the c-MYC G-quadruplex and inhibits c-MYC promoter activity. AB - Nucleolin, the most abundant nucleolar phosphoprotein of eukaryotic cells, is known primarily for its role in ribosome biogenesis and cell proliferation. It is, however, a multifunctional protein that, depending on the cellular context, can drive either cell proliferation or apoptosis. Our laboratory recently demonstrated that nucleolin can function as a repressor of c-MYC transcription by binding to and stabilizing the formation of a G-quadruplex structure in a region of the c-MYC promoter responsible for controlling 85-90% of c-MYC's transcriptional activity. In this study, we investigate the structural elements of nucleolin that are required for c-MYC repression. The effect of nucleolin deletion mutants on the formation and stability of the c-MYC G-quadruplex, as well as c-MYC transcriptional activity, was assessed by circular dichroism spectropolarimetry, thermal stability, and in vitro transcription. Here we report that nucleolin's RNA binding domains 3 and 4, as well as the arginine-glycine glycine (RGG) domain, are required to repress c-MYC transcription. PMID- 20932062 TI - Binding of reduced nicotinamide adenine dinucleotide phosphate destabilizes the iron-sulfur clusters of human mitoNEET. AB - The outer mitochondrial membrane protein mitoNEET is a cellular target of the antidiabetic drug pioglitazone. Binding of pioglitazone stabilizes the protein against [2Fe-2S] cluster release. Here, we report that reduced nicotinamide adenine dinucleotide phosphate (NADPH) can bind to homodimeric mitoNEET, influencing the stability of the [2Fe-2S] cluster that is bound within a loop region (Y71-H87) in each subunit. Nuclear magnetic resonance (NMR) and isothermal titration calorimetry experiments demonstrated that NADPH binds weakly to mitoNEET(44-108), a soluble domain of mitoNEET containing residues 44-108. Visible-UV absorption measurements revealed the destabilizing effect of NADP binding on the [2Fe-2S] clusters. Disruption of the three-dimensional structure of mitoNEET(44-108) as a result of decomposition of the iron-sulfur clusters was observed by NMR and circular dichroism experiments. Binding of NADPH facilitated release of the iron-sulfur clusters from the protein at pH<=7.0. Residues K55 and H58 of each subunit of mitoNEET were shown to be involved in NADPH binding. NADPH binding may perturb the interactions of K55 and H58 from one subunit with H87' and R73', respectively, from the other subunit, thereby interfering with [2Fe-2S] cluster binding. This may account for the destabilization effect of NADPH binding on the [2Fe-2S] clusters. PMID- 20932063 TI - Anaesthetic-related neuroprotection: intravenous or inhalational agents? AB - In designing the anaesthetic plan for patients undergoing surgery, the choice of anaesthetic agent may often appear irrelevant and the best results obtained by the use of a technique or a drug with which the anaesthesia care provider is familiar. Nevertheless, in those surgical procedures (cardiopulmonary bypass, carotid surgery and cerebral aneurysm surgery) and clinical situations (subarachnoid haemorrhage, stroke, brain trauma and post-cardiac arrest resuscitation) where protecting the CNS is a priority, the choice of anaesthetic drug assumes a fundamental role. Treating patients with a neuroprotective agent may be a consideration in improving overall neurological outcome. Therefore, a clear understanding of the relative degree of protection provided by various agents becomes essential in deciding on the most appropriate anaesthetic treatment geared to these objectives. This article surveys the current literature on the effects of the most commonly used anaesthetic drugs (volatile and gaseous inhalation, and intravenous agents) with regard to their role in neuroprotection. A systematic search was performed in the MEDLINE, Cumulative Index to Nursing and Allied Health Literature (CINHAL(r)) and Cochrane Library databases using the following keywords: 'brain' (with the limits 'newborn' or 'infant' or 'child' or 'neonate' or 'neonatal' or 'animals') AND 'neurodegeneration' or 'apoptosis' or 'toxicity' or 'neuroprotection' in combination with individual drug names ('halothane', 'isoflurane', 'desflurane', 'sevoflurane', 'nitrous oxide', 'xenon', 'barbiturates', 'thiopental', 'propofol', 'ketamine'). Over 600 abstracts for articles published from January 1980 to April 2010, including studies in animals, humans and in vitro, were examined, but just over 100 of them were considered and reviewed for quality. Taken as a whole, the available data appear to indicate that anaesthetic drugs such as barbiturates, propofol, xenon and most volatile anaesthetics (halothane, isoflurane, desflurane, sevoflurane) show neuroprotective effects that protect cerebral tissue from adverse events- such as apoptosis, degeneration, inflammation and energy failure--caused by chronic neurodegenerative diseases, ischaemia, stroke or nervous system trauma. Nevertheless, in several studies, the administration of gaseous, volatile and intravenous anaesthetics (especially isoflurane and ketamine) was also associated with dose-dependent and exposure time-dependent neurodegenerative effects in the developing animal brain. At present, available experimental data do not support the selection of any one anaesthetic agent over the others. Furthermore, the relative benefit of one anaesthetic versus another, with regard to neuroprotective potential, is unlikely to form a rational basis for choice. Each drug has some undesirable adverse effects that, together with the patient's medical and surgical history, appear to be decisive in choosing the most suitable anaesthetic agent for a specific situation. Moreover, it is important to highlight that many of the studies in the literature have been conducted in animals or in vitro; hence, results and conclusions of most of them may not be directly applied to the clinical setting. For these reasons, and given the serious implications for public health, we believe that further investigation- geared mainly to clarifying the complex interactions between anaesthetic drug actions and specific mechanisms involved in brain injury, within a setting as close as possible to the clinical situation--is imperative. PMID- 20932064 TI - The pharmacoeconomics of cognitive enhancers in moderate to severe Alzheimer's disease. AB - Alzheimer's disease is associated with a substantial economic impact on patients, their caregivers and society. Due to the current rise in the aging population, the prevalence and impact of Alzheimer's disease are expected to increase greatly. The cost of caring for someone with Alzheimer's disease is magnified in the more severe stages of the disease. There are four cognitive enhancers commonly used for the treatment of Alzheimer's disease: three cholinesterase inhibitors (donepezil, rivastigmine and galantamine) and one NMDA receptor antagonist (memantine). Of these, donepezil and memantine have been approved in many countries as pharmacological treatments for moderate to severe Alzheimer's disease, while donepezil, rivastigmine and galantamine are approved treatments for mild to moderate Alzheimer's disease. While cost effectiveness has been well studied in mild to moderate Alzheimer's disease, the cost-benefit information for drug therapy in moderate to severe Alzheimer's disease is less clear. This article reviews the pharmacoeconomic data available on these four drugs, with a specific focus on moderate to severe Alzheimer's disease, including economic burden, cost drivers, clinical outcomes and pharmacoeconomic studies. A key driver of the cost of Alzheimer's disease is the severity of the disease, indicating that the ability to stabilize the disease state is a potential source of cost savings. Drug therapies that can limit increases in behavioural problems and cognitive and functional impairment, and postpone institutionalization without an increase in longevity may serve to reduce the economic burden on Alzheimer's disease patients. The data suggest that, while the available, approved agents offer only modest improvements in clinical outcomes, they could be cost-effective treatments for moderate to severe Alzheimer's disease when viewed from the societal perspective. For memantine and donepezil, data are available that suggest that the cost of these drugs is offset by the clinical and societal benefits provided by slowing the progression of Alzheimer's disease. While there are few head-to-head comparison trials, the similarity in costs of the treatments and efficacy against placebo suggest that cost effectiveness will not be substantially different among treatments. More studies that examine longitudinal resource utilization and its relationship to drug treatment in the moderate to severe stages are needed to clarify cost benefit in this population and possibly differentiate between individual medications. PMID- 20932065 TI - Innovative delivery systems for migraine: the clinical utility of a transdermal patch for the acute treatment of migraine. AB - Migraine is a disabling, painful primary headache disorder that is associated with various combinations of neurological, gastrointestinal, autonomic and pain symptoms. Gastrointestinal disturbances associated with migraine, including nausea and vomiting, affect a majority of migraineurs and often result in a delay in taking or avoidance of pharmacological intervention. Gastric stasis and vomiting may lead to delayed or inconsistent absorption of orally administered medications. Many migraineurs awake early in the morning with their attack progressing and already associated with nausea and vomiting. As a result, there is a need for a novel, non-invasive, non-oral delivery system for fast and effective acute treatment of migraine. There are two non-oral delivery systems currently available in the US for the acute treatment of migraine: three nasal sprays and two injectable formulations. Although nasal sprays depend partially on nasal mucosal absorption, a significant amount of drug is swallowed, transits the stomach and is absorbed in the small intestine, which is not as rapid or effective a route of delivery for those migraineurs with gastric stasis. Sumatriptan is rapidly absorbed by subcutaneous injection with or without a needle, but the invasiveness and discomfort of the delivery, the high incidence of adverse events and the high recurrence rate all limit its use for many patients. Iontophoretic delivery of medication is a non-invasive transdermal approach that uses small amounts of electrical current to promote rapid movement of the ionized drug through the skin and into the systemic circulation. This delivery bypasses hepatic first-pass metabolism and also avoids gastric transit delay and slowing of small intestinal absorption associated with gastrointestinal stasis in migraineurs. Two pharmacokinetic studies have demonstrated that iontophoretic transdermal delivery of sumatriptan results in rapid and consistent achievement of therapeutic plasma concentrations. These studies also suggest that, by avoiding patient exposure to a rapid rise in and high plasma concentrations of sumatriptan as seen with injectable sumatriptan, transdermal delivery using iontophoresis may significantly reduce typical triptan-related adverse events. A large, randomized, double-blind, placebo-controlled, multicentre clinical trial showed statistically significant efficacy, good tolerability and virtually no triptan-related adverse events. Iontophoretic delivery of sumatriptan, with a novel transdermal patch device, offers patients a migraine-specific medication that is non-invasive and non-oral. Clinically, transdermal delivery provides rapid and effective relief of migraine while bypassing the gastrointestinal tract, with minimal classic triptan-related adverse effects. This unique approach facilitates the rapid absorption of this migraine-specific triptan, which should improve the chances of consistently achieving a therapeutic plasma concentration of sumatriptan, resulting in effective migraine relief. PMID- 20932068 TI - Ocular adverse effects of common psychotropic agents: a review. PMID- 20932069 TI - Effects of two administration schemes of intramuscular clodronic acid on bone mineral density: a randomized, open-label, parallel-group study. AB - BACKGROUND: Clodronic acid is a bisphosphonate used in the prevention and treatment of postmenopausal bone loss. Previous evidence suggests a direct dose response relationship for the densitometric effect of clodronic acid. Therefore, as it is widely accepted that a reduction in the dosing frequency of bisphosphonates may improve adherence and therefore therapeutic outcomes, an increase in the interval between consecutive administrations of clodronic acid might be associated with a concomitant increase in the overall bisphosphonate dose received. However, to our knowledge, a direct comparison of the effects of intramuscular clodronic acid 100 mg once weekly with a regimen consisting of a higher dose and a longer interval between two consecutive administrations is still lacking. OBJECTIVE: This study compared the increase in bone mineral density (BMD) achieved with two different administration schemes of intramuscular clodronic acid (100 mg once weekly and 200 mg every 2 weeks) in patients with postmenopausal osteoporosis. STUDY DESIGN AND SETTING: This randomized, open label, parallel-group trial was conducted in the Osteoporosis and Instrumental Diagnosis Center 'OsteoArticolar' (University of Siena, Siena, Italy) between January 2007 and December 2009. PATIENTS: Consecutive women aged 50-80 years with postmenopausal osteoporosis, diagnosed >=5 years prior to inclusion in the study, were eligible for participation in this study. INTERVENTION: Patients were randomized to receive either intramuscular clodronic acid (Clasteon(r)) 100 mg (group A) + lidocaine (lignocaine) once weekly or intramuscular clodronic acid 100 mg + lidocaine for two consecutive days every 2 weeks (group B), for 2 years. RESULTS: In total, 30 patients were randomized to group A and 30 patients to group B. Significant increases in mean +/- SD BMD of the lumbar spine versus baseline values were observed in both groups at 1 and 2 year(s) from treatment initiation (group A - year 1: +2.8% +/- 1.7%, p < 0.05; year 2: +3.5% +/- 2.2%, p < 0.01; group B - year 1: +2.7% +/- 2.1%, p < 0.05; year 2: +3.9% +/- 2.2%, p < 0.01). Mean +/- SD BMD at the femoral neck also significantly increased versus baseline in group A at both timepoints (year 1: +2.3% +/- 1.9%, p < 0.05; year 2: +2.5% +/- 1.9%, p < 0.05), while the increase reported in group B was significant only after 2 years of treatment (year 1: +1.9% +/- 2.2%; year 2: +2.8% +/- 1.8%; p < 0.05). Significant mean +/- SD increases in total femur BMD were observed only in group A at 2 years (+2.4% +/- 1.9, p < 0.05). No differences between study groups were reported. Two non-traumatic vertebral fractures were observed in group A (6.6%) and three in group B (10.0%). Treatment was well tolerated; mild pain at injection site was observed in three patients (one in group A, 3.3%; two in group B, 6.6%). CONCLUSION: This randomized study suggests, for the first time to the author's knowledge, a similar effect of intramuscular clodronic acid 100 mg once weekly and 200 mg every 2 weeks (two 100 mg administrations on two consecutive days) on BMD in women with postmenopausal osteoporosis. The administration of intramuscular clodronic acid 200 mg every 2 weeks may therefore represent a new therapeutic option in the treatment of postmenopausal osteoporosis. PMID- 20932066 TI - Dopamine receptor agonists for the treatment of early or advanced Parkinson's disease. AB - Dopamine receptor agonists are indicated for the symptomatic treatment of early, moderate or advanced Parkinson's disease as well as for the reduction of levodopa related motor complications. Ergolinic dopamine agonists, such as bromocriptine or pergolide, were initially developed and marketed, and then non-ergolinic dopamine agonists, such as pramipexole and ropinirole, were introduced, reducing the risk of drug-induced fibrotic reactions. Once-daily, controlled-release oral and transdermal formulations have been developed aiming at providing more stable 24-hour plasma drug concentrations and more convenient administration. A disease modifying effect of dopamine agonists has not been demonstrated clinically. As with any other drug, dopamine agonists can also cause adverse drug reactions, which can be related or unrelated to dopaminergic hyperactivation. Dopaminergic reactions include nausea, hallucinations, confusion and orthostatic hypotension, among others, which were readily identified in pre-marketing clinical trials. During post-marketing surveillance, important adverse reactions were identified, such as daytime somnolence, impulse-control disorders and heart valve fibrosis. Other issues, including the efficacy of dopamine agonists for the treatment of non-motor symptoms, remain under evaluation. PMID- 20932070 TI - Effects of adalimumab versus placebo on risk of symptom worsening in psoriasis and subsequent impacts on health-related quality-of-life: analysis of pooled data from two randomized, double-blind, placebo-controlled, multicentre clinical trials. AB - BACKGROUND: Rates and impacts of worsening symptoms in patients with psoriasis have not been well characterized. OBJECTIVES: To assess the risk of clinically relevant worsening of psoriasis symptoms in patients treated with adalimumab versus placebo and to determine the health-related quality-of-life (HRQOL) impacts of such worsening. METHODS: The cumulative incidence of worsening was compared for adalimumab (40 mg every other week following an 80 mg induction dose) versus placebo using data from two phase III randomized, placebo-controlled trials (CHAMPION and REVEAL). Clinically relevant worsening of psoriasis was defined as a follow-up visit with a >=25% increase in the Psoriasis Area and Severity Index (PASI) from baseline or a >=5-unit increase in the Dermatology Life Quality Index from baseline during the initial 16-week double-blind treatment periods. Patients with versus without worsening were compared in terms of pain, work productivity and activity impairment (WPAI) and the mental and physical component summary (MCS and PCS) scores of the Short-Form 36 Health Survey. A subgroup analysis was performed for patients with PASI 10-20 at baseline. RESULTS: The 17-week risk of clinically relevant worsening was 37.0% (95% CI 26.1, 46.3) for placebo (n = 445) and 4.2% (95% CI 2.0, 6.3) for adalimumab-treated patients (n = 914) [p < 0.0001]. Patients with versus without worsening experienced substantially increased pain, increased WPAI and greater impairment in MCS and PCS. Results were similar for patients with PASI 10-20 at baseline. LIMITATIONS: The short study duration may not reflect long-term outcomes. CONCLUSION: Clinically relevant worsening of psoriasis symptoms was associated with substantial worsening of HRQOL. Adalimumab treatment was associated with a substantially reduced risk of clinically relevant worsening. PMID- 20932073 TI - Consortium for Blood Group Genes (CBGG): 2009 report. AB - Consortium for Blood Group Genes is a worldwide organization whose goal is to have a vehicle to interact, establish guidelines, operate a proficiency program, and provide education for laboratories involved in DNA and RNA testing for the prediction of blood group, platelet, and neutrophil antigens. Currently, the consortium operates with representatives from Brazil, Canada, and the United States. Membership is voluntary with the expectation that members actively contribute to discussions involving blood group genetics. This year witnessed a change in the standing committee membership and the institution of a representative for the human platelet antigens group. Looking forward, the consortium sees challenges for the nomenclature of blood group alleles and user required specifications for laboratory information systems to store genotype information. PMID- 20932071 TI - Aspirin and antiplatelet agent resistance: implications for prevention of secondary stroke. AB - Oral antiplatelet drugs, including aspirin, clopidogrel and extended-release dipyridamole, are widely prescribed for the secondary prevention of vascular events, including stroke. Despite the benefits of antiplatelet therapy, 10-20% of patients experience a recurrent vascular event while taking antiplatelet medication. This article discusses the concept of antiplatelet resistance in general, focusing on aspirin resistance in particular, as a poorly defined cause of recurrent vascular events. Factors such as the lack of a standardized method to diagnose aspirin resistance and a poor clinical correlation with laboratory assays make the treatment of aspirin nonresponders difficult. In addition, there are confounding conditions such as diabetes mellitus that can affect aspirin resistance and determine a different course of treatment for these patients. Other antiplatelet options may also have resistant subpopulations; thus, alternative strategies for the secondary stroke patient must be explored. PMID- 20932074 TI - The Duffy blood group system: a review. AB - Duffy was the first blood group mapped to an autosome (chromosome 1) using cytogenetic studies. Duffy antigens are located on a glycoprotein that can be found on erythrocytes and other cells throughout the body. Fy(a) and Fy(b) are products of their respective alleles (FY*A, FY*B). Fy(x) characterized by weak Fy(b) expression, is a result of an additional mutation in FY*B. The Fy(a-b-) phenotype, most commonly found in Blacks, occurs primarily as a result of GATA promoter region mutation upstream of the FY allele. This mutation prevents expression of Duffy glycoprotein on erythrocytes only, while permitting expression of nonerythroid cells. Other antigens include Fy3, Fy5, and Fy6. Antibodies to Duffy antigens are usually clinically significant and have been reported to cause hemolytic disease of the fetus and newborn. This review provides a general overview of the Duffy blood group system, including the role of the Duffy glycoprotein as a chemokine receptor (Duffy antigen receptor for chemokines) and in malarial infection. PMID- 20932075 TI - RHCE*ceAR encodes a partial c (RH4) antigen. AB - Thr Rh blood group system is highly complex both in the number of discreet antigens and in the existence of partial antigens, especially D and e. Recently, several partial c antigens have been reported. Here we report findings on an African American man with sickle cell disease whose RBCs typed C+c+ and whose plasma contained anti-c. Hemagglutination tests, DNA extraction, PCR-RFLP, reticulocyte RNA isolation, RT-PCR cDNA analyses, cloning, and sequencing were performed by standard procedures. RBCs from the patient typed C+c+ but his plasma contained alloanti-c. DNA analyses showed the presence of RHCE*Ce in trans to RHCE*ceAR with RHD*D and RHD*Weak D type 4.2.2. The amino acid changes on RhceAR are such that C+c+ patient made alloanti-c. This case shows that RhceAR carries a partial c antigen and illustrates the value of DNA testing as an adjunct to hemagglutination to aid in antibody identification in unusual cases. PMID- 20932076 TI - The Gerbich blood group system: a review. AB - Antigens in the Gebrich blood group system are expressed on glycophorin C (GPC) and glycophorin D (GPD), which are both encoded by a single gene, GYPC. The GYPC gene is located on the long arm of chromosome 2, and Gebrich antigens are inherited as autosomal dominant traits. There are 11 antigens in the Gebrich blood group system, six of high prevalence (Ge2, Ge3, Ge4, GEPL [Ge10*], GEAT [Ge11*], GETI [Ge12*]) and five of low prevalence (Wb [Ge5], Ls(a) [Ge6], An(a) [Ge7], Dh(a) [Ge8], GEIS [Ge9]). GPC and GPD interact with protein 4.1R, contributing stability to RBC membrane. Reduced levels of GPC and GPD are associated with hereditary elliptocytosis, and Gebrich antigens act as receptors for the malarial parasite Plasmodium falciparum. Anti-Ge2 and anti-Ge3 have caused hemolytic transfusion reactions, and anti-Ge3 has produced hemolytic disease of the fetus and newborn (HDFN). PMID- 20932077 TI - Application of real-time PCR and melting curve analysis in rapid Diego blood group genotyping. AB - The paucity of appropriate reagents for serologic typing of the Diego blood group antigens has prompted the development of a real-time PCR and melting curve analysis for Diego blood group genotyping. In this study, we phenotyped 4326 donor blood samples for Di(a) using semiautomated equipment. All 157 Di(a+) samples were then genotyped by PCR using sequence-specific primers (PCR-SSP) for DI*02 because of anti-Di(b) scarcity. Of the 4326 samples, we simultaneously tested 160 samples for Di(a) and Di(b) serology, and DI*01 and DI*02 by PCR-SSP and by real-time PCR. We used the same primers for Diego genotyping by real-time PCR and PCR-SSP. Melting curve profiles obtained using the dissociation software of the real-time PCR apparatus enabled the discrimination of Diego alleles. Of the total samples tested, 4169 blood donors, 96.4 percent (95% confidence interval [CI], 95.8-96.9%), were homozygous for DI*02 and 157, 3.6 percent (95% CI, 3.1%-4.2%), were heterozygous DI*01/02. No blood donor was found to be homozygous for DI*01 in this study. The calculated DI*01 and DI*02 allele frequencies were 0.0181 (95% CI, 0.0173-0.0189) and 0.9819 (95% CI, 0.9791 0.9847), respectively, showing a good fit for the Hardy-Weinberg equilibrium. There was full concordance among Diego phenotype results by PCR-SSP and real-time PCR. DI*01 and DI*02 allele determination with SYBR Green I and thermal cycler technology are useful methods for Diego determination. The real-time PCR with SYBR Green I melting temperature protocol can be used as a rapid screening tool for DI*01 and DI*02 blood group genotyping. PMID- 20932078 TI - The Dombrock blood group system: a review. AB - The Dombrock blood group system (Do) consists of two antithetical antigens (Do(a) and Do(b)) and five antigens of high prevalence (Gy(a), Hy, Jo(a), DOYA, and DOMR). Do antigens are carried on the Dombrock glycoprotein, which is attached to the RBC membrane via glycosylphosphatidylinositol linkage. The gene (DO, ART4) encoding the Do glycoprotein, located on the short arm of chromosome 12, has been cloned and sequenced, allowing the molecular basis of the various Do phenotypes to be determined. Do(a) and Do(b) have a prevalence that makes them useful as genetic markers; however, the paucity of reliable anti-Do(a) and anti-Do(b) has prevented this potential from being realized. The ease with which these antigens can be predicted by analysis of DNA opens the door for such studies to be carried out. Anti-Do(a) and anti-Do(b) are rarely found as a single specificity, but they have been implicated in causing hemolytic transfusion reactions. This review is a synthesis of our current knowledge of he Dombrock blood group system. PMID- 20932079 TI - Rural mental health workforce difficulties: a management perspective. AB - INTRODUCTION: The recruitment, retention and training of mental health workers is of major concern in rural Australia, and the Gippsland region of Victoria is no exception. Previous studies have identified a number of common factors in these workforce difficulties, including rurality, difficulties of access to professional development and training, and professional and personal isolation. However, those previous studies have often focused on medicine and been based on the perspectives of practitioners, and have almost ignored the perspectives of managers of rural mental health services. The study reported in this article sought to contribute to the development of a more sustainable and effective regional mental health workforce by complementing earlier insights with those of leading administrators, managers and senior clinicians in the field. METHODS: The study took a qualitative approach. It conducted semi-structured in-person interviews with 24 managers of health/mental-health services and senior administrators and clinicians working in organisations of varying sizes in the public and private sectors. Thematic content analysis of the transcribed interviews identified core difficulties these managers experienced in the recruitment, retention and training of employees. RESULTS: The study found that some of the issues commonly resulting in difficulties in recruiting, retaining and developing a trained workforce in rural areas, such as rurality (implying personal and professional isolation, distances to deliver service and small organisations) and a general shortage of trained personnel, are significant in Gippsland. Through its focus on the perspectives of leaders in the management of rural mental health services, however, the study found other key issues that contribute to workforce difficulties. Many, including the unattractive nature of mental health work, the fragmented administration of the mental health system, short-term and tied funding, and shortcomings in training are external to organisations. Interviewees indicated that these issues make it difficult for organisations to support personnel in ways that enhance personal and professional satisfaction and so retention and, in turn, the capacity to recruit new employees. Participants also highlighted issues internal to the organisation. The tensions that flow from the systemic forces require highly creative leadership to negotiate the numerous policy changes, diverse sources of funding, training regimens, worker cohorts and models of care. Managers must nurture the capacity of their own organisation to respond flexibly to the demands, by establishing a responsive culture and structure. They must also encourage the collaboration of their other organisations in their sub-regional grouping and the development of a regional sensibility. CONCLUSION: The approach taken by the study, particularly its focus on a management perspective, revealed that the difficulties experienced are the product of a core tension between a growing demand for mental health care, emerging specialities and technological advances in the field, and a diminished systemic capacity to support organisations in meeting the demand. Resolving this core tension is a key to the maintenance of a sustainable and effective workforce in Gippsland, and the role of management is crucial to that resolution. PMID- 20932080 TI - Initial experience with retroperitoneoscopic microwave ablation of clinical T(1a) renal tumors. AB - PURPOSE: To evaluate the feasibility, safety, and efficacy of retroperitoneoscopic microwave ablation (MWA) for clinical stage T(1a) (cT(1a)) renal tumors. PATIENTS AND METHODS: Consecutive renal cell carcinomas (RCCs) managed since April 2006 with a minimal follow-up of 12 months were included. A total of 23 tumors in 22 patients were managed with laparoscopic MWA. A cooled shaft needle antenna was inserted into the tumor under direct visual guidance. Microwaves were emitted at 50 W for 8 minutes and prolonged as necessary to ensure complete tumor kill. Short-term efficacy was assessed by contrast-enhanced CT at 1, 3, and 6 months, and every 6 months thereafter. RESULTS: Pathologic analysis revealed low-grade clear-cell RCC in all patients. Mean tumor size was 2.8 cm (range 0.9-4.0 cm). Excluding 5 lost patients, the initial ablation was successful in 17 (94.4%) of 18 tumors. One patient with an incomplete ablation lesion under strict surveillance had no evidence of disease progression at 31 months of follow-up. No recurrence was observed at a median follow-up of 20 months (range 12-45 mos). All 17 remaining patients had no clinical or radiographic evidence of disease at last follow-up. In addition, complications were mild and tolerable (18.2%), and there was no significant deterioration of renal function. CONCLUSIONS: Retroperitoneoscopic MWA appears to be a safe and effective technique for cT(1a) RCC in selected patients. Additional follow-up is needed to assess long-term effectiveness. PMID- 20932081 TI - Coculture of osteoblasts and endothelial cells: optimization of culture medium and cell ratio. AB - Vascularization strategies in cell-based bone tissue engineering depend on optimal culture conditions. The present study aimed to determine optimal cell culture medium and cell ratio for cocultures of human marrow stromal cells (HMSCs) and human umbilical vein endothelial cells (HUVECs) in view of both osteogenic and angiogenic outcome parameters upon two-dimensional and three dimensional culture conditions. Cultures were performed in four different media: osteoblastic cell proliferation medium, osteogenic medium (OM), endothelial medium, and a 1:1 mixture of the latter two media. Mineralization within the cocultures was observed only in OM. Subsequent experiments in OM showed that alkaline phosphatase activity, mineralization, and CD31(+) staining were highest for cocultures at a 50:50 HMSC/HUVEC ratio. Therefore, the results from the present study show that a HMSC/HUVEC coculture ratio of 50:50 in OM is the best combination to obtain both osteogenic and angiogenic differentiation. PMID- 20932082 TI - Improved detection of nonmuscle invasive urothelial carcinoma of the bladder using pirarubicin endoscopy: a prospective, single-center preliminary study. AB - BACKGROUND AND PURPOSE: Fluorescence cystoscopy (FC) with intravesical instillation of a photosensitizing agent has emerged as an adjunctive and safe diagnostic tool with high sensitivity and reasonable specificity; however, it has not been widely accepted, because it is time-consuming and expensive. The aim of the present study was to determine whether the use of the fluorescent dye pirarubicin [(2"R)-4'-O-tetrahydropyranyl doxorubicin] (THP) in endoscopy can improve detection of nonmuscle invasive urothelial carcinoma of the bladder. PATIENTS AND METHODS: Forty-eight patients with known or suspected bladder urothelial carcinoma were enrolled in this prospective study between January 2008 and April 2009. The Storz D-light system was used to detect fluorescence 15 minutes after intravesical instillation with 30 mg THP. Endoscopic findings, histopathologic evaluation of biopsy lesions, and adverse effects of THP were recorded. RESULTS: After THP uptake, the lesions appear bright orange under white light, and produce bright red fluorescence under blue light. Among 238 biopsies evaluated (84 malignant, 20 dysplasia, and 134 benign), sensitivity of overall tumors, carcinoma in situ (CIS), and dysplasia detection using FC was 96% (81/84), 100% (6/6), and 90% (18/20), respectively. The specificity of FC was 74.7% (115/154), and its false-positive rate was 32.5% (39/120). No significant systemic side effects or allergic reactions were observed other than a few cases of mild cystitis. CONCLUSION: THP endoscopy may improve the detection of nonmuscle invasive urothelial carcinoma of the bladder, especially CIS and flat lesions. Results indicate that THP is a promising fluorescent dye for diagnosis and follow-up of nonmuscle invasive bladder carcinoma. Moreover, it is inexpensive, easily available, simple to administer, and is associated with few side effects. PMID- 20932083 TI - Public knowledge and beliefs about diarrheal disease. AB - Sixty percent of the U.S. population experiences acute diarrheal illness each year, but little is understood regarding public knowledge and beliefs about the causes and treatment of these diseases. We performed a telephone survey of 2117 Tennessee residents regarding knowledge and practices associated with diarrheal illness. Bloody stool, dehydration, and persistent symptoms were the most common reasons for which the respondents would seek medical care. Although most acute diarrheal disease is self-limited, overuse of antimicrobials for treatment is common. Few people believed that stool cultures (4.5%) or antibiotics (6.9%) are routinely necessary for diarrhea. Over 60% of respondents believed that food is the most common source of diarrhea. Three-fourths believed that it is normal for uncooked meat to contain bacteria, and 45% believed it is legal to sell such products. These results have implications for medical providers, regulators, and public health in the management and prevention of diarrheal disease. PMID- 20932084 TI - Differentiation of Salmonella enteritidis isolates by fluorescent amplified fragment length polymorphism. AB - Salmonella Enteritidis is responsible for human gastroenteritis outbreaks worldwide, and the molecular characterization of isolates is an important tool for epidemiological studies. Fluorescent amplified fragment length polymorphism (FAFLP) analysis was performed on 31 Salmonella Enteritidis strains from South Brazil isolated from human, foods, swine, broiler carcasses, and other poultry related samples to subtype isolates in comparison to pulsed-field gel electrophoresis (PFGE) analysis. Five strains of Salmonella Enteritidis from different geographical regions, Salmonella Enteritidis ATCC 13076, and four isolates of different Salmonella serovars were also tested. Among the 41 isolates tested, 96 polymorphic AFs and 40 distinct profiles were obtained, displaying a Simpson's index of diversity of 0.99; whereas the PFGE analysis presented 13 patterns and the resulting Simpson's index was 0.55. Nine FAFLP and seven PFGE clusters could be inferred based in Dice similarity coefficient. FAFLP clustering readily identified different serotypes of Salmonella but did not distinguish isolates epidemiologically nonrelated or distinct phage types. Therefore, these results indicate that FAFLP is a rapid method for epidemiological investigations of Salmonella outbreaks, presenting a high discriminatory power for subtyping of Salmonella Enteritidis. PMID- 20932085 TI - A new and preliminary three-dimensional perspective: proteomes of optimization between OSCC and OLK. AB - BACKGROUND: principally 80 percent of the malignant oral tumors are the Oral Squamous Cell Carcinoma (OSCC), which require quantities of such sacrifices as deformity, malfunction, recurrence, metastasis, deterioration, and mortality in common cases of failing to antedate diagnosis. Similarly critical is the Oral Leukoplakia (OLK) among precancerous lesions of oral mucosa. It would also be of interest for scholars and clinicians to target the discrimination as seizing up OLK intimate to OSCC. OBJECTIVE: through bioinformatics technology, the research in narration worked to establish a three-dimensional discriminate database from high throughput data of protein fingerprints from serum, saliva, and tissue samples of OSCC and OLK patients as a preliminary step towards integrated group proteins biomarker discovery and to further understanding of corresponding tumorgenesis and proteomics. METHODS: differential proteomic patterns in serum, saliva, and tissue between OSCC patients or OSCC tissues and OLK were detected by SELDI-TOF-MS technology, and discriminatively analyzed by ZUCI-PDAS (Zhejiang University Cancer Institute ProteinChip Data Analysis System) with Support Vector Machines (SVM) and cross validation. Additionally, Laser Capture Micro-dissection technology was utilized in the tissue research. RESULTS: mass/charge proteomes of optimization obtained from the samples were, respectively, 4162 with 6886 of 87.82%, 92.86%, 66.67% as the sensitivity, specificity, and accuracy for serum difference; m/z 5818, 4617 with 3884 of all 100% as the sensitivity, specificity, and accuracy for saliva difference; and m/z 3738, 11366 of 96.29%, 100.00%, 85.71% as the sensitivity, specificity, and accuracy for tissue difference between OSCC and OLK patients. CONCLUSIONS: within the fields of clinical biomarker application and bioinformatics utilization, as well as the exploitation and popularization of modern discriminate analysis technology, to determine preventative and therapeutic stage and prognosis of OSCC and OLK, the proteomes of optimization for discrepancy are suggested to be directly enrolled in clinical application without protein identification. PMID- 20932086 TI - Comparison of probabilistic and deterministic predictions of time to growth of Listeria monocytogenes as affected by pH and temperature in food. AB - Stochastic models are useful for estimating the risk of foodborne illness and they can be integrated, besides other sources of variability, into microbial risk assessment. A stochastic approach to evaluate growth of two strains of Listeria monocytogenes influenced by different factors affecting microbial growth (pH and storage temperature) was performed. An individual-based approach of growth through optical density measurements was used. From results obtained, histograms of the lag phase were generated and distributions were fitted. Histograms presented increased variation when the factors applied were suboptimal for L. monocytogenes and they were combined. The extreme value distribution was ranked as the best one in most cases, whereas normal was the poorest fitting distribution. To evaluate the influence of pH and storage temperature on L. monocytogenes CECT 5672 in real food, commercial samples of courgette and carrot soup were inoculated with this pathogen. It was able to grow in both soups at storage temperatures from 4 degrees C to 20 degrees C. Using the distributions adjusted, predictions of time to growth (102 cfu/g) of L. monocytogenes were established by Monte Carlo simulation and they were compared with deterministic predictions and observations in foods. PMID- 20932087 TI - Viable but nonculturable state of foodborne pathogens in grapefruit juice: a study of laboratory. AB - Several foodborne human pathogens, when exposed to harsh conditions, enter viable but nonculturable (VBNC) state; however, still open is the question whether VBNC pathogens could be a risk for public health, because, potentially, they can resuscitate. Moreover, cultural methods for food safety control were not able to detect VBNC forms of foodborne bacteria. Particularly, it has not been established whether food chemophysical characteristics can induce VBNC state in contaminating pathogen bacterial populations, especially in food, such as salads and fresh fruit juices, not subjected to any decontamination treatment. In this preliminary study, we intentionally contaminated grapefruit juice to determine whether pathogen bacteria could enter VNBC state. In fact, grapefruit juice contains natural antimicrobial compounds, has an average pH of about 3 and low content in carbohydrates. Such characteristics make grapefruit juice a harsh environment for microbial survival. For this purpose, Escherichia coli O157:H7, Salmonella enterica serovar Typhimurium ATCC 14028, Listeria monocytogenes ATCC 7644, and Shigella flexneri ATCC 12022, at two different inoculum sizes, have been used. Viability by the LIVE/DEAD BacLight Bacterial Viability kit and culturability by plate counts assay were monitored, whereas "resuscitation" of nonculturable populations was attempted by inoculation in nutrient-rich media. The data showed that L. monocytogenes lost both culturability and viability and did not resuscitate within 24 h independently on inoculum size, whereas E. coli O157:H7 was able to resuscitate after 24 h but did not after 48 h. Salmonella Typhimurium and S. flexneri, depending on inoculum size, lost culturability but maintained viability and were able to resuscitate; moreover, S. flexneri was still able to form colonies after 48 h at high inoculum size. In conclusion, entry into VBNC state differs on the species, depending, in turn, on inoculum size and time of incubation. PMID- 20932088 TI - Efficacy of high-intensity pulsed light for the microbiological decontamination of chicken, associated packaging, and contact surfaces. AB - The efficacy of high-intensity light pulse (HILP) technology (3 Hz, maximum of 505 J/pulse, and a pulse duration of 360 MUs) for the decontamination of raw chicken and associated packaging and surface materials was investigated. Its ability to reduce microbial counts on raw chicken through plastic films was also examined. Complete inactivation of Campylobacter spp., Escherichia coli, and Salmonella Enteritidis in liquid was achieved after 30 sec HILP treatment. Reductions of 3.56, 4.69, and 4.60 log10 cfu/cm2) were observed after 5 sec HILP treatment of Campylobacter jejuni, E. coli, and Salmonella Enteritidis inoculated onto packaging materials and contact surfaces, respectively. The greatest reductions on inoculated chicken skin were 1.22, 1.69, and 1.27 log10 cfu/g for C. jejuni, E. coli, and Salmonella Enteritidis, respectively. Corresponding reductions on inoculated skinless breast meat were 0.96, 1.13, and 1.35 log10 cfu/g. The effectiveness of HILP treatment for reducing microbial levels on chicken increased as the film thickness decreased. HILP treatments of 2 sec did not significantly affect the color of raw chicken although treatments of 30 sec impacted color. This study has shown HILP to be an effective method for the decontamination of packaging and surface materials. Additionally, it has demonstrated the potential of HILP to be used as a decontamination method for packaged chicken. PMID- 20932089 TI - Antibacterial activity of the essential oil of Satureja wiedemanniana against Bacillus species isolated from chicken meat. AB - The antimicrobial activity of the essential oil (EO) of Satureja wiedemanniana against Bacillus spp. isolated from chicken meat was investigated. Thirty-seven Bacillus strains were isolated from 15 chicken meat samples and examined for proteolytic and lipolytic activities by agar well diffusion assay. Of 37 Bacillus isolated from raw chicken samples, which based on a clear zone diameter of >= 6 mm in agar well diffusion assays for proteolytic activity, 19 Bacillus strains were selected for this study. Bacillus licheniformis T11(1) and Bacillus lentus T10(14) have high proteolytic activity (14.0 mm zone diameter), whereas B. licheniformis T4(2) and Bacillus mycoides T 5(5) have high lipolytic activity (12.0 mm zone diameter). Thirty-two components representing 98.10% of the composition of the S. wiedemanniana EO were identified using gas chromatography/mass spectrometry. Both S. wiedemanniana EO and its main component p-cymene exhibited strong antimicrobial activity against some Bacillus strains. The results of this study confirmed the possibility of using S. wiedemanniana EO as a protective agent to chicken meat. But, detail studies are still needed to elucidate the effects of S. wiedemanniana EO against other spoilage microorganisms. PMID- 20932090 TI - Effect of chlorine dioxide gas on Salmonella enterica inoculated on navel orange surfaces and its impact on the quality attributes of treated oranges. AB - Microorganisms, including pathogens of public health significance, have been shown to contaminate orange juice during the mechanical extraction of juice. The problem gets exacerbated when washed oranges have high initial microbial load, due to an insufficient postharvest treatment. The objective of this study was to investigate the reduction of Salmonella enterica on orange surfaces using ClO2 gas treatments to achieve a 5 log reduction, consistent with the recommendations of the U.S. Department of Agriculture-National Advisory Committee on Microbiological Criteria for Foods. A mixed culture of four Salmonella strains, isolated from previous orange juice outbreaks, was spot inoculated onto orange skin surface areas. The oranges were then treated with 0.1, 0.3, and 0.5 mg/L ClO2 gas for 2-14 minutes at 22 degrees C and 90%-95% relative humidity. Surviving bacteria on treated areas were recovered and enumerated over treatment time on a nonselective medium, tryptic soy agar, followed by culturing onto a selective medium, xylose lysine deoxycholate agar. A >5 log reduction of Salmonella per sample of orange surface was observed with 0.1 and 0.3 mg/L ClO2 gas treatments at 14 minutes and a similar log reduction was observed at 0.5 mg/L ClO2 gas at 10 minutes. This result demonstrates that the treatment of oranges with ClO2 gas is a promising technology that could be successfully employed for the treatment of whole oranges to reduce the risk of Salmonella outbreaks in orange juice. PMID- 20932091 TI - Minimally invasive repair of spontaneous intracranial hypotension. AB - Spontaneous spinal CSF leakage with the development of intracranial hypotension is a well-described entity. Cerebrospinal fluid leaks, mostly from the thoracic spine, are the major cause of spontaneous intracranial hypotension (SIH). Conservative treatment options include hydration, oral caffeine, and epidural blood patching. Alternatively, open surgical correction of meningeal diverticula is a therapeutic option. The authors describe 4 cases of spontaneous spinal CSF leakage producing symptoms of intracranial hypotension. All patients had multiple spinal diverticula with an identified leaking level. The patients were treated using a minimally invasive approach via surgical correction of the meningeal diverticulum. PMID- 20932092 TI - Dr. Henry Head and lessons learned from his self-experiment on radial nerve transection. AB - In this paper the authors aim to review Dr. Henry Head's famous and dramatic nerve sectioning experiment. They discuss the implications of his experimental approach as well as the effect his experiment had on the field of neurology. Henry Head was a prominent British neurologist who contributed greatly to the understanding of the sensory examination through an experiment in which he had his own radial nerve transected. Head carefully documented the sensory changes following the sectioning. He hypothesized the existence of two separate sensory systems: protopathic and epicritic. Head was one of the first scientists to speculate on sensory dissociation, and his writings generated both enthusiasm and controversy. Although the ethical issue of self-experimentation was raised by his bold experiment and many aspects of his investigations and conclusions have been criticized, Head undoubtedly contributed important clinical lessons to neurology. Arguably, Henry Head's greatest contribution was the realization that the neurological portion of the sensory examination was anything but straightforward. PMID- 20932093 TI - Impact of individual intracranial arterial aneurysm morphology on initial obliteration and recurrence rates of endovascular treatments: a multivariate analysis. AB - OBJECT: The goal was to investigate whether morphological features of aneurysms can be identified that determine initial success and recurrence rates of coiled aneurysms of the basilar artery tip, the posterior communicating artery (PCoA), and the anterior communicating artery. METHODS: The authors evaluated 202 aneurysms in connection with their pretreatment morphological features including size, neck-to-dome ratio, angulation of the aneurysm in relation to the parent artery, orientation of the aneurysm dome, and associated anatomical variations. The mean follow-up was 19 months (range 6-96 months) after endovascular coil occlusion. Using multivariate logistic regression, probabilities for initial complete occlusion and long-term stability of the treatment were calculated. RESULTS: Recanalization occurred in 49 of 202 cases. Favorable factors for long term stability included small aneurysms with small necks. However, additional factors related to local hemodynamic forces could be identified for the different aneurysm locations, which may influence initial success rates and long-term stability of aneurysm treatment with endovascular coiling. These factors were a medial dome orientation and a symmetrical disposition of both A(1) segments (for the anterior communicating artery), a posteroinferior dome orientation and a small-size PCoA (for the PCoA), and a cranial symmetrical fusion (for the basilar artery tip). CONCLUSIONS: A detailed pretreatment analysis of morphological features of aneurysms may help to determine those aneurysms that are more prone to recurrence, which could add to the treatment decision and the follow-up algorithm. PMID- 20932094 TI - Schwannomatosis, sporadic schwannomatosis, and familial schwannomatosis: a surgical series with long-term follow-up. Clinical article. AB - OBJECT: The aim of this study was to provide disease-specific information about schwannomatosis in its different forms and to present 2 particular cases of malignant schwannomas in the context of familial schwannomatosis (FS). METHODS: The authors analyzed patients with pathologically defined schwannomas and identified those with varied forms of schwannomatosis. Each case was retrospectively analyzed for patient sex and age, number of operations and tumors excised, symptoms, location and size of tumors, extent of resection, nerve function pre- and postoperatively, complications, other nonsurgically treated tumors, malignancy, results of brain MR imaging, and follow-up data. RESULTS: One hundred fifty-eight patients underwent the excision of 216 schwannomas. One hundred forty-two patients presented with solitary schwannomas, 2 had neurofibromatosis Type 2 (NF2), and 14 presented with schwannomatosis. The average follow-up was 52 months. Six individuals had sporadic schwannomatosis, whereas 8 had the familial form of the disease. These 14 patients had an average age of 28.3 years at the time of disease onset (median 27.5 years) and 35.4 years at the time of the first operation (median 37 years) Thirteen of the 14 patients with schwannomatosis experienced pain as the first symptom. Eight (57%) of the 14 patients presented with at least 1 tumor in the spinal canal or attached to the spinal nerve roots. Malignant schwannomas developed in 2 patients from the same family during the follow-up. CONCLUSIONS: Patients suffering from schwannomatosis tend to be younger than those presenting with solitary schwannomas. Therefore, individuals presenting at a young age with multiple schwannomas but not meeting the criteria for NF2 should prompt the physician to suspect schwannomatosis. Patients with schwannomatosis who report pain should be exhaustively examined. The spine is affected in the majority of patients, and MR imaging of the spine should be part of the routine evaluation. Rapid enlargement of schwannomas in the context of FS should raise suspicion of malignant transformation. PMID- 20932095 TI - A 3-tier classification of cerebral arteriovenous malformations. Clinical article. AB - OBJECT: The authors propose a 3-tier classification for cerebral arteriovenous malformations (AVMs). The classification is based on the original 5-tier Spetzler Martin grading system, and reflects the treatment paradigm for these lesions. The implications of this modification in the literature are explored. METHODS: Class A combines Grades I and II AVMs, Class B are Grade III AVMs, and Class C combines Grades IV and V AVMs. Recommended management is surgery for Class A AVMs, multimodality treatment for Class B, and observation for Class C, with exceptions to the latter including recurrent hemorrhages and progressive neurological deficits. To evaluate whether combining grades is warranted from the perspective of surgical outcomes, the 3-tier system was applied to 1476 patients from 7 surgical series in which results were stratified according to Spetzler-Martin grades. RESULTS: Pairwise comparisons of individual Spetzler-Martin grades in the series analyzed showed the fewest significant differences (p < 0.05) in outcomes between Grades I and II AVMs and between Grades IV and V AVMs. In the pooled data analysis, significant differences in outcomes were found between all grades except IV and V (p = 0.38), and the lowest relative risks were found between Grades I and II (1.066) and between Grades IV and V (1.095). Using the pooled data, the predictive accuracies for surgical outcomes of the 5-tier and 3-tier systems were equivalent (receiver operating characteristic curve area 0.711 and 0.713, respectively). CONCLUSIONS: Combining Grades I and II AVMs and combining Grades IV and V AVMs is justified in part because the differences in surgical results between these respective pairs are small. The proposed 3-tier classification of AVMs offers simplification of the Spetzler-Martin system, provides a guide to treatment, and is predictive of outcome. The revised classification not only simplifies treatment recommendations; by placing patients into 3 as opposed to 5 groups, statistical power is markedly increased for series comparisons. PMID- 20932096 TI - Extensive craniocervical pneumocranium. AB - The authors report the first case of extensive craniocervical pneumocranium causing mass effect, without any associated extradural pneumatocele. The patient presented with frontal headaches and unusual sensations in his left ear. He was found to have large pneumocranium involving his left frontal, temporal, parietal, and occipital bones as well as the atlas. He underwent a craniectomy with replacement of the pneumatized bone with titanium mesh, and mastoidectomy with obliteration of the mastoid air cells. This case is discussed in the context of the literature to date. A review of the literature shows that trauma is not a common cause of pneumocranium, with most cases occurring spontaneously. The authors believe that a combined neurosurgical-otological approach is beneficial in such cases. PMID- 20932097 TI - Successful obliteration and shrinkage of giant partially thrombosed basilar artery aneurysms through a tailored flow reduction strategy with bypass surgery. AB - OBJECT: The authors evaluated the efficacy of a new flow reduction strategy for giant partially thrombosed upper basilar artery (BA) aneurysms, for which proximal parent artery occlusion is not always effective. METHODS: Eight consecutive patients with severely symptomatic, partially thrombosed, giant upper BA aneurysms were treated with a tailored flow reduction strategy, or received conservative therapies. The flow reduction strategy comprised isolation of several branches from the upper BA at their origins with bypasses in addition to parent artery occlusion. RESULTS: The median follow-up period of all 8 patients was 15.0 months (range 4-31 months). In 6 patients treated with flow reduction, the mean decrease in residual blood lumen was -10.7 mm (95% CI -19.7 to -1.7 mm; p = 0.029) and the mean decrease in diameter of the aneurysms was -11.5 mm (95% CI -25.1 to 2.1 mm; p = 0.082). Complete or virtually complete thrombosis was achieved in all but 1 aneurysm (83%) and shrinkage was observed in 4 (67%). In those in whom complete or virtually complete thrombosis was achieved, significant shrinkage of the aneurysm was observed (mean decrease in diameter -14.8 mm; 95% CI -28.8 to -0.8 mm; p = 0.043). Improvement or stabilization of symptoms occurred in 67% of the patients who received flow reduction treatment. Both patients who received conservative treatment had unfavorable outcomes. CONCLUSIONS: The flow reduction strategy is effective at promoting complete thrombosis of the aneurysm. This strategy can also induce shrinkage of the aneurysm if successful thrombosis is achieved. Although the neurological outcome of the treatment appears favorable considering its intractable nature, further study of the treatment is necessary to confirm its clinical efficacy and safety. PMID- 20932098 TI - Assessment of morbidity following resection of cingulate gyrus gliomas. Clinical article. AB - OBJECT: The morbidity associated with resection of tumors in the cingulate gyrus (CG) is not well established. The goal of the present study is to define the short- and long-term morbidity profile associated with resection of gliomas within this region. METHODS: Ninety consecutive patients with gliomas involving the CG were analyzed. Resections were classified by zones corresponding to functionally defined regions of the CG as follows: Zone I (perigenual, anterior), Zone II (midcingulate), Zone III (posterior), and Zone IV (retrosplenial). Basic demographic, imaging, operative details, and pre- and postoperative neurological examinations were recorded for each patient. Patients in whom neurological morbidity was documented during their initial postoperative examination who did not completely improve by the 6-month follow-up examination were considered to have a permanent deficit. For each patient with surgery-related morbidity, postoperative MR imaging and operative notes were reviewed, and the cortical regions incorporated in the surgical trajectory were recorded. The analysis was carried out for tumors confined to the CG (> 90% of tumor contained within the CG) as well as those involving the CG but extending into adjacent cortical structures. RESULTS: Analysis of the entire patient cohort demonstrated that 29% of patients experienced a new or worsened neurological deficit immediately after surgery. The most common deficits were supplementary motor area (SMA) syndrome (20%), weakness (6%), and sensory changes (2%). All patients with an SMA syndrome in our series had intentional resection of SMA as part of the surgical approach. Patients with resections including Zone II or III had a higher rate of total morbidity and SMA syndrome than patients with Zone I resections (p < 0.05). Only 4% of patients had a persistent neurological deficit at 6 months postoperatively. A similar morbidity profile was observed in the subset analysis of patients with tumors confined to the CG, with no additional morbidity related to known cingulate-specific functions. CONCLUSIONS: Resection of gliomas involving the CG can be performed with minimal, predictable long-term morbidity (< 5%). Surgical morbidity is primarily a function of surgical trajectory rather than the particular cingulate region resected. PMID- 20932099 TI - The intracranial denticulate ligament: anatomical study with neurosurgical significance. AB - OBJECT: Knowledge of the detailed anatomy of the craniocervical junction is important to neurosurgeons. To the authors' knowledge, no study has addressed the detailed anatomy of the intracranial (first) denticulate ligament and its intracranial course and relationships. METHODS: In 10 embalmed and 5 unembalmed adult cadavers, the authors performed posterior dissection of the craniocervical junction to expose the intracranial denticulate ligament. Rotation of the spinomedullary junction was documented before and after transection of unilateral ligaments. RESULTS: The first denticulate ligament was found on all but one left side and attached to the dura of the marginal sinus superior to the vertebral artery as it pierced the dura mater. The ligament always traveled between the vertebral artery and spinal accessory nerve. On 20% of sides, it also attached to the intracranial vertebral artery and, histologically, blended with its adventitia. In general, this ligament tended to be thicker laterally and was often cribriform in nature medially. The hypoglossal nerve was always superior to the ligament, which always concealed the ventral roots of the C-1 spinal nerve. The posterior spinal artery traveled posterior to this ligament on 93% of sides. On one left side, the ascending branch of the posterior spinal artery traveled anterior to the ligament and the descending branch traveled posterior to it. Following unilateral transection of the intracranial denticulate ligament, rotation of the spinomedullary junction was increased by approximately 25%. CONCLUSIONS: Knowledge of the relationships of the first denticulate ligament may prove useful to the neurosurgeon during procedures at the craniocervical junction. PMID- 20932100 TI - Long-term outcome after resection of brainstem hemangioblastomas in von Hippel Lindau disease. AB - OBJECT: Brainstem hemangioblastomas are frequently encountered in patients with von Hippel-Lindau (VHL) disease. These tumors can cause significant morbidity, and their optimal management has not been defined. To better define the outcome and management of these tumors, the authors analyzed the long-term results in patients who underwent resection of brainstem hemangioblastomas. METHODS: Consecutive patients with VHL disease who underwent resection of brainstem hemangioblastomas with a follow-up of 12 months or more were included in this study. Serial functional assessments, radiographic examinations, and operative records were analyzed. RESULTS: Forty-four patients (17 male and 27 female) underwent 51 operations for resection of 71 brainstem hemangioblastomas. The most common presenting symptoms were headache, swallowing difficulties, singultus, gait difficulties, and sensory abnormalities. The mean follow-up was 5.9 +/- 5.0 years (range 1.0-20.8 years). Immediately after 34 operations (66.7%), the patients remained at their preoperative functional status; they improved after 8 operations (15.7%) and worsened after 9 operations (17.6%) as measured by the McCormick scale. Eight (88.9%) of the 9 patients who were worse immediately after resection returned to their preoperative status within 6 months. Two patients experienced functional decline during long-term follow-up (beginning at 2.5 and 5 years postoperatively) caused by extensive VHL disease-associated CNS disease. CONCLUSIONS: Generally, resection of symptomatic brainstem hemangioblastomas is a safe and effective management strategy in patients with VHL disease. Most patients maintain their preoperative functional status, although long-term decline in functional status may occur due to VHL disease-associated progression. PMID- 20932101 TI - Combined paracetamol and amitriptyline adsorption to activated charcoal. AB - Objectives. High-gram drug doses seen in multiple-drug poisonings might be close to the adsorption capacity of activated charcoal (AC). The aim was to determine the maximum adsorption capacities (Q(m)) of amitriptyline and paracetamol, separately and in combination, to AC. Methods. ACs (Carbomix(r) and Norit Ready To-Use) were tested in vitro. At pH 1.2 and pH 7.2, 0.250 g AC and paracetamol and/or amitriptyline were mixed and incubated. The AC: drug ratios were 10:1, 5:1, 3:1, 2:1, and 1:1. The mixed-drug adsorption vials contained the same AC: paracetamol ratios, but amitriptyline was added as fixed dose (0.080 g) to all samples. Drug concentrations in the liquid phase were analyzed using high performance liquid chromatography (HPLC)/UV-detection. Results. Q(m), amitriptyline, were 0.49 g/g Carbomix(r) and 0.70 g/g Norit Ready-To-Use, and Q(m), paracetamol, were 0.63 g/g Carbomix(r) and 0.72 g/g Norit Ready-To-Use. The tested pH differences had minor effect on the adsorption. The mixed-drug adsorption showed about 40% Q(m) reduction of each drug with increasing amounts of drug/g AC, but the total gram of drug adsorbed to AC was increased compared to one-drug conditions. Conclusion. The adsorption of the two compounds to AC seems to compete resulting in lower maximum adsorption capacity for both drugs when mixed. However, a great adsorptive capacity was noted and might be explained by adsorption of the drugs to different AC surface sites. Furthermore, the Norit Ready-To-Use preparation, with less volume and total weight for the same AC dose as Carbomix(r), showed a higher Q(m). This might be clinically significant in terms of preventing nausea, vomiting, and subsequent aspiration. PMID- 20932102 TI - Azadirachtin poisoning: a case report. AB - The use of neem-based products is widespread in the Indian Subcontinent. Neem based pesticides obtained from neem kernels are considered natural and safe. The toxic effects of ingestion and overdose of this pesticide in adults have not been described in this literature. We report the case of a 35-year-old lady who had consumed Azadirachtin in an attempt of deliberate self-harm. The patient had features of neurotoxicity because of Azadirachtin requiring intensive medical care with mechanical ventilation. The patient survived the overdose with no long lasting side effects of the toxin. PMID- 20932103 TI - Multiplying the serum aminotransferase by the acetaminophen concentration to predict toxicity following overdose. AB - CONTEXT: The first available predictors of hepatic injury following acetaminophen (APAP) overdose are the serum APAP and aminotransferases [AT, i.e., aspartate (AST) aminotransferase or alanine (ALT) aminotransferase]. OBJECTIVE: We describe the initial value, rate of change, and interrelationship between these biomarkers in patients who develop hepatotoxicity despite treatment following acute overdose. A new parameter, the APAP * AT multiplication product, is proposed for early risk stratification. METHODS: We conducted a descriptive study of individuals selected from a multicenter retrospective cohort of patients hospitalized for APAP poisoning. We selected those acute APAP overdose patients who subsequently developed AT > 1,000 IU/L. Rising serum AT values were compared to simultaneously measured (or estimated) falling serum APAP. The APAP * AT was expressed relative to initiation of acetylcysteine therapy and grouped by time to meeting hepatotoxicity criteria. RESULTS: In the 94 cases studied, serum APAP concentrations were still appreciable [median 570 (interquartile range (IQR) 314 983) MUmol/L] at the time of the first measured AT [211 (77-511) IU/L at 15.3 (12.1-19.2) h post-ingestion], yielding an initial APAP * AT of 99,000 (52,000 240,000) MUmol * IU/L(2). Because serum AT rose rapidly (doubling time 9.5 h ) and APAP fell slowly (half-life 4.8 h), the multiplication product remained elevated during the first 12-24 h of antidotal therapy, especially among patients who developed earlier hepatotoxicity (AT > 1,000 IU/L). DISCUSSION AND CONCLUSIONS: The APAP * AT multiplication product, calculated at the time of presentation and after several h of antidotal therapy, holds promise as a new risk predictor following APAP overdose. It requires neither graphical interpretation nor accurate time of ingestion, two limitations to current risk stratification. PMID- 20932104 TI - Public awareness of heart attack symptoms: what should we look for and how will it help? PMID- 20932105 TI - Back to the future: of fevers and failures. PMID- 20932107 TI - Is allopurinol a potential new treatment for angina pectoris? PMID- 20932108 TI - Statin loading before percutaneous coronary intervention: proposed mechanisms and applications. AB - Statin therapy reduces the risk of cardiovascular events in patients with coronary artery disease. Recent in vitro and in vivo studies demonstrated a LDL independent action of these class of drugs, which appears in modulating endothelial function, inflammation and thrombosis. Periprocedural myocardial infarction and contrast-induced nephropathy after percutaneous coronary intervention (PCI), associated with worse outcome on long-term follow-up, are both complications related to inflammatory pathogenetic mechanisms. Randomized studies demonstrated a beneficial effect of short-term statin pretreatment in reducing periprocedural cardiac marker release in patients undergoing PCI. Statin therapy before elective PCI reduces periprocedural myocardial infarction in patients with stable angina. Furthermore, an acute loading with a high dose of atorvastatin prevents myocardial damage in patients with acute coronary syndromes undergoing early PCI (<48 h). In patients already on chronic statin therapy, a reload with high-dose statins was associated with a significant improvement on 30 day major adverse cardiac event rates. Furthermore, statin therapy at the time of PCI significantly decreased the incidence of contrast-induced nephropathy. This evidence suggests an 'upstream administration' of short-term, high-dose statins in all patients undergoing PCI. PMID- 20932109 TI - Hemodynamically complicated ST-segment elevation myocardial infarction: presentation and treatment. AB - When ST-segment elevation myocardial infarction is complicated by hemodynamic instability, clinical evaluation alone cannot be relied upon for accurate assessment. Invasive hemodynamic monitoring with a pulmonary artery catheter and intra-arterial catheter should, therefore, be performed to gauge impaired hemodynamics in such patients and make necessary changes in therapy. There are several hemodynamic disturbances that can occur after ST-segment elevation myocardial infarction including pulmonary congestion, cardiogenic shock and mechanical complications such as left-ventricular free-wall rupture, ventricular septal defect or papillary muscle rupture. Patients with hemodynamic compromise should be admitted to the coronary care unit and therapy should be initiated with drugs such as vasodilators, diuretics and positive-inotropic agents, based on hemodynamic data provided by the invasive catheter. Intra-aortic balloon counterpulsation should be used for those who fail to achieve hemodynamic stability with medical therapy. Coronary angiography should be considered for all patients who are hemodynamically unstable provided they are candidates for aggressive care, followed by coronary revascularization in those with suitable anatomy. Operative repair should be performed promptly when a surgically correctable mechanical lesion is identified. PMID- 20932110 TI - Screening value of N-terminal pro-B-type natriuretic peptide as a predictor of perioperative cardiac events after noncardiac surgery. AB - Preoperative cardiac risk assessment is the cornerstone of rationale perioperative management that guides invasive surgical interventions. In addition to clinical risk factors, a simple screening biomarker would be useful for identifying those surgical patients who might benefit from additional cardiac testing or therapeutic interventions. Preoperative plasma levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP) are predictors of cardiac events after noncardiac surgery. NT–proBNP is synthesized in the ventricular myocardium in response to ventricular wall stress. To further increase the diagnostic accuracy of NT-proBNP for preoperative screening, it is important to identify confounding factors that influence NT-proBNP levels and their interaction with identifying risks for adverse cardiac events. Moreover, until now the available data from previous studies has been unable to consistently recognize the optimal discriminatory threshold for NT-proBNP. Currently, the ongoing DECREASE-VI study is conducted to evaluate whether current preoperative risk stratification can be improved by incorporating NT-proBNP measurements. PMID- 20932111 TI - Stress Doppler echocardiography in valvular heart diseases: utility and assessment. AB - This article is a review on the role of stress echocardiography in valvular heart diseases, describing what the validated indications are, how to perform the test and the utility of performing this examination. Most valve diseases are characteristically dynamic and this dynamic component is best appreciated by exercise Doppler echocardiography. Dobutamine stress echocardiography is also useful in patients with severe aortic stenosis and left ventricular dysfunction. The main advantage of stress echocardiography is to concomitantly allow the evaluation of symptoms, exercise capacity and the hemodynamic consequences of valve diseases, especially in patients with severe valve diseases who deny symptoms or present equivocal symptoms. It also provides important prognostic information and may help to optimize surgical timing in difficult cases. Whether these data should be integrated in the management of patients needs further validation. PMID- 20932112 TI - An overview of surgery options for congenital coronary artery anomalies. AB - Congenital and acquired coronary artery anomalies are associated with significant morbidity and mortality and can be sudden in onset. The spectrum of congenital lesions include anomalous origin from the pulmonary artery, critical left main stenosis/atresia, coronary artery fistulas, anomalous aortic origin and intramyocardial courses. The spectrum of acquired lesions include Kawasaki disease, late postoperative obstructions in patients who had coronary artery surgical manipulations and iatrogenic injuries that can occur in the catheterization laboratory or the operating room. Surgical therapies for ischemic syndromes associated over the long term of these anomalies are presented herein. PMID- 20932113 TI - Surgery for carcinoid heart disease: current outcomes, concerns and controversies. AB - Cardiac involvement in patients with carcinoid disease is a well-recognized pathology. Early reports described right-sided heart involvement. More recently, both right- and left-sided heart disease have been reported. Progress of the treatment of carcinoid disease is leading to an increase in the number of patients presenting for surgery to treat valvular dysfunction. owing to improvements in the prognosis of the basic disease, valve replacement surgery is now a reasonable option in patients with severe valvular dysfunction. This article provides an overview of carcinoid heart disease with an emphasis on current outcomes, concerns and controversies associated with the surgical management of this disease. PMID- 20932115 TI - Role of myeloperoxidase in cardiology. AB - Myeloperoxidase (MPO) is an enzyme found in myeloid cells, particularly in neutrophils, and to a lesser extent in monocytes and tissue macrophages. MPO plays an important role in the host defense against bacteria and viruses. Since MPO is also an important enzyme in the inflammatory process, and inflammation is a key component in the development and progression of atherosclerotic and other forms of cardiovascular disease, there is ongoing interest in the use of MPO as a biomarker in different fields of cardiology. We aimed to review the current state of literature regarding the role of MPO in cardiovascular disease, especially highlighting the practical implications of the fast growing data from clinical studies. PMID- 20932116 TI - Headache and cardiovascular disease: old symptoms, new proposals. AB - Evidence of a link between headache symptoms and cardiovascular disease has rapidly grown in recent years and it is of utmost importance for the cardiologist and neurologist to be aware of this intimate connection. A brief overview of different cardiovascular diseases (namely hypertension, stroke, coronary heart disease, patent foramen ovale, atrial septal defects, atrial septal aneurisms, mitral valve prolapse, and aortic and carotid disease) that may be related to headache is presented in this article. Proposed pathophysiological mechanisms for this association and landmark studies are reviewed and discussed. PMID- 20932117 TI - Acute coronary syndrome cohort definition: troponin versus ICD-9-CM codes. AB - AIM: To determine the accuracy of troponin laboratory results versus International Classification of Diseases clinical modification codes (ICD-9-CM) in identifying acute coronary syndrome (ACS) rule-out (R/O) patients who present to emergency departments (EDs). MATERIALS & METHODS: Retrospective data analysis and chart review (to establish gold standard) were conducted on ED patients. Data retrieved from a clinical data warehouse were reviewed to identify patients with two or more troponins within 24 h of ED registration and ICD-9-CM codes consistent with ACS R/O. RESULTS: Of 329 charts reviewed, 17 were determined to be ACS R/O. A total of 31 out of 329 (9.42%, 95% CI: 6.26-12.58%) had two or more troponins with a sensitivity of 100% (95% CI: 77.08-100%) and specificity of 95.51% (95% CI: 92.42-97.43%). A total of 32 out of 329 patients (9.73%, 95% CI: 6.53-12.93%) had R/O ICD-9-CM codes with a sensitivity of 76.47% (95% CI: 49.76 83.00%) and specificity of 93.91% (95% CI: 90.50-96.19%). All 17 gold-standard ACS R/O patients were identified using troponins while ICD-9-CM identified 13 out of 17. CONCLUSION: Clinical data (two troponins) availability is timelier and compares well with billing data (ICD-9-CM codes) in ACS R/O patient identification. Clinical data use may be generalized to identify other disease specific cohorts for clinical research. PMID- 20932119 TI - An evaluation of biocompatibility of indigenously produced pure titanium: an experimental study in rabbits. AB - The indigenously produced pure titanium dental implants are economical and useful for common human use in India. The aim of this study is to test the biocompatibility of the indigenously produced pure titanium dental implant material obtained from the Defense Metallurgical Research Laboratory, Hyderabad, India, and the Institute of Nuclear Medicine and Allied Science, Delhi, India. An experimental study in rabbits was done to study the amount of ordered bone formation around the screw and cylinder type of indigenously produced pure titanium metal implant specimens. The experimental animals were killed at 4, 6, 8, 12, and 16 weeks from the date of implantation. The histopathological examination of the animals killed at 16 weeks demonstrates the presence of osteoblastic cell proliferation and early ordered bone formation toward the implant site, indicating signs of osseointegration of both screw- and cylinder type indigenously produced pure titanium specimens. PMID- 20932114 TI - Peroxisome proliferator-activated receptors, metabolic syndrome and cardiovascular disease. AB - Metabolic syndrome (MetS) is a constellation of risk factors including insulin resistance, central obesity, dyslipidemia and hypertension that markedly increase the risk of Type 2 diabetes (T2DM) and cardiovascular disease (CVD). The peroxisome proliferators-activated receptor (PPAR) isotypes, PPARalpha, PPARdelta/beta and PPARgamma are ligand-activated nuclear transcription factors, which modulate the expression of an array of genes that play a central role in regulating glucose, lipid and cholesterol metabolism, where imbalance can lead to obesity, T2DM and CVD. They are also drug targets, and currently, PPARalpha (fibrates) and PPARgamma (thiazolodinediones) agonists are in clinical use for treating dyslipidemia and T2DM, respectively. These metabolic characteristics of the PPARs, coupled with their involvement in metabolic diseases, mean extensive efforts are underway worldwide to develop new and efficacious PPAR-based therapies for the treatment of additional maladies associated with the MetS. This article presents an overview of the functional characteristics of three PPAR isotypes, discusses recent advances in our understanding of the diverse biological actions of PPARs, particularly in the vascular system, and summarizes the developmental status of new single, dual, pan (multiple) and partial PPAR agonists for the clinical management of key components of MetS, T2DM and CVD. It also summarizes the clinical outcomes from various clinical trials aimed at evaluating the atheroprotective actions of currently used fibrates and thiazolodinediones. PMID- 20932120 TI - Edentulous maxillary arch fixed implant rehabilitation using a hybrid prosthesis made of micro-ceramic-composite: case report. AB - The prosthetic treatment of patients with an edentulous maxilla opposing mandibular natural teeth is one of the most challenging endeavors that face clinicians. Occlusal forces from the opposing natural teeth may cause fractures in the maxillary prosthesis and also result in advanced bone loss of the edentulous maxilla. With the presence of extreme gagging reflex, the treatment may become more complicated. This article describes and illustrates the 2-stage surgical and prosthetic treatment of a patient with an edentulous maxilla opposing natural teeth. In the beginning, the patient was treated with 4 implants and a maxillary implant-supported overdenture. The extreme gagging reflex and the occlusal forces from the mandibular natural teeth obligated the team a second stage surgical and prosthetic treatment, which included increasing the number of implants after bilateral sinus lifting in the posterior maxilla and fabricating a maxillary fixed hybrid prosthesis made of micro-ceramic composite that yielded a satisfactory result. PMID- 20932121 TI - Stress analysis in platform-switching implants: a 3-dimensional finite element study. AB - The aim of this study was to evaluate the influence of the platform-switching technique on stress distribution in implant, abutment, and peri-implant tissues, through a 3-dimensional finite element study. Three 3-dimensional mandibular models were fabricated using the SolidWorks 2006 and InVesalius software. Each model was composed of a bone block with one implant 10 mm long and of different diameters (3.75 and 5.00 mm). The UCLA abutments also ranged in diameter from 5.00 mm to 4.1 mm. After obtaining the geometries, the models were transferred to the software FEMAP 10.0 for pre- and postprocessing of finite elements to generate the mesh, loading, and boundary conditions. A total load of 200 N was applied in axial (0 degrees ), oblique (45 degrees ), and lateral (90 degrees ) directions. The models were solved by the software NeiNastran 9.0 and transferred to the software FEMAP 10.0 to obtain the results that were visualized through von Mises and maximum principal stress maps. Model A (implants with 3.75 mm/abutment with 4.1 mm) exhibited the highest area of stress concentration with all loadings (axial, oblique, and lateral) for the implant and the abutment. All models presented the stress areas at the abutment level and at the implant/abutment interface. Models B (implant with 5.0 mm/abutment with 5.0 mm) and C (implant with 5.0 mm/abutment with 4.1 mm) presented minor areas of stress concentration and similar distribution pattern. For the cortical bone, low stress concentration was observed in the peri-implant region for models B and C in comparison to model A. The trabecular bone exhibited low stress that was well distributed in models B and C. Model A presented the highest stress concentration. Model B exhibited better stress distribution. There was no significant difference between the large diameter implants (models B and C). PMID- 20932122 TI - Influence of prognostic risk indicators on osseointegrated dental implant failure: a matched case-control analysis. AB - Dental implant treatment is an important therapeutic modality with documented long-term success for replacement of missing teeth. However, dental implants can be susceptible to disease conditions or healing complications that may lead to implant loss. This case-control study identified several risk indicators associated with failure such as smoking and alcohol consumption. The use of postoperative antibiotics or wide-diameter implants may significantly reduce implant failure. Knowledge of patient-related risk factors may assist the clinician in proper case selection and treatment planning. PMID- 20932123 TI - Acrylic resin polymerization in direct contact to the abutment and the temperature at bone-implant interface: a pilot in vitro study. AB - Three autopolymerizing acrylic resins were applied to a titanium alloy abutment connected to 2 different diameters of an implant. The implants were embedded in fresh iliac bone of sheep in a 37 degrees C water bath. Temperature changes were recorded via embedded thermocouples at the cervical (T1) and apical (T2) regions of the implant surface. Polymerization temperature of acrylic resins did not seem to exceed the critical threshold of 47 degrees C. PMID- 20932124 TI - Maintenance requirements associated with mandibular implant overdentures: clinical results after first year of service. AB - The aim of this clinical study was to evaluate the prosthodontic maintenance requirements during the first year of service of mandibular overdentures supported by interforaminal implants and to assess the influence of attachment type, implant number, and bite force on these requirements. Fifty-nine patients treated with mandibular implant overdentures between the years 2004 and 2009 and appearing in the 12th-month recall were included in this study. The overdentures constituted 4 groups: 2 single interforaminal implants (1 group with locator and 1 group with ball attachments), 3 single interforaminal implants, 3 splinted interforaminal implants (bar), and 4 splinted interforaminal implants (bar). During the examination, prosthetic parameters such as occlusion, tissue adaptation, condition of the retentive mechanism (matrice and patrice), and the condition of the denture-bearing tissues were evaluated and recorded. No statistically significant relation was found between attachment type, bite force values, implant number, and the occurring complications except the need for relining, which was found significantly more in the ball attachments than in other attachment groups (P = .03). After 12 months following the overdenture insertion, there seems to be no relation between occurring complications and patient-related factors, such as maximum bite force, age, and gender, as well as factors related to the overdentures such as number and type of attachments. PMID- 20932125 TI - Implant-supported prosthesis misalignment related to the dental arch: a 14-year clinical follow-up. AB - The purpose of this study was to warn the dental community about a possible problem in function with partial implant-supported prostheses used for long periods. The misalignment between natural teeth and the implant-supported prosthesis on teeth 11 and 12, observed in a 14-year clinical follow-up, illustrates the fact. The metal-ceramic crowns were placed in 1995 after a rigorous occlusal adjustment. Evaluations were made at 4, 6, 9, and 14 years, when it was noticed that the restorations were positioned palatally and extruded in comparison with the natural teeth. After 9 years, a greater discrepancy was noticed, with anterior occlusion and esthetic changes. The possible causes have been discussed: occlusal problems, parafunctional habits, and natural movement. The first 2 options were discarded after clinical analysis and diagnosis. Therefore, the natural movement probably deriving from an interaction of mechanical and genetic factors might have been the cause. The implants do not have periodontal ligaments but rather ankylosis, so they do not suffer those movements. This case emphasizes the need to inform patients that implants can last more than 10 years in function, but this is not the case with restorations, which lose function and esthetics and must be replaced. PMID- 20932126 TI - Nasopalatine canal position relative to the maxillary central incisors: a cone beam computed tomography assessment. AB - The aim of this study was to determine the proximity of the nasopalatine canal (NPC) to the maxillary central incisor root (MCIR). The study included 120 cone beam computed tomography scans obtained from the Center for Implant Dentistry, Loma Linda University, between June 2006 and September 2009. They were equally distributed into six groups: (1) 21- to 40-year-old men, (2) 21- to 40-year-old women, (3) 41- to 60-year-old men, (4) 41- to 60-year-old women, (5) 61- to 80 year-old men, and (6) 61- to 80-year-old women. The closest distances between the NPC and the MCIR (NPC-to-MCIR) were measured at the midroot (bisecting palatal cementoenamel junction to root apex) and the apex levels. Differences between the groups were analyzed using a t test and 1-way analysis of variance at a significance level of alpha = .05. The overall mean NPC-to-MCIR distances at the midroot and apex levels were 3.05 +/- 1.64 and 5.22 +/- 1.56 mm, respectively. The modes of the NPC-to-MCIR distances at the midroot and apex levels were in the range of 1.01-2.00 mm and 4.01-5.00 mm, respectively. The mean NPC-to-MCIR distance was significantly greater in men than in women at the midroot level (P < .05) but not at the apex level (P > .05). The mean NPC-to-MCIR distance was significantly shorter for the youngest age group than the other two age groups at the midroot level (P < .05). However, at the apex level, the youngest age group had a significantly shorter distance compared with the oldest age group (P < .05) but not the middle age group (P > .05). The results of this study suggest that, to avoid NPC penetration, more care must be exercised during immediate implant placement at the midroot level of a maxillary central incisor in women and younger patients because of the root proximity to the NPC. Tapered implants may also be beneficial in such situations. PMID- 20932128 TI - Ultrasound scan and magnetic resonance imaging for the diagnosis of adenomyosis: systematic review comparing test accuracy. AB - BACKGROUND: Adenomyosis is a common condition that causes substantial morbidity. Until recently, the reference standard for a definitive diagnosis was histology of hysterectomy specimens. Ultrasound and magnetic resonance imaging (MRI) may allow accurate non-invasive diagnosis. OBJECTIVE: To compare the diagnostic accuracy of these techniques. DESIGN: Systematic review with meta-analysis. POPULATION: Women who had ultrasound and/or MRI, and whose results were compared with a reference standard. METHODS: Electronic searches were conducted in literature databases from database inception to 2010. The reference lists of known relevant articles were searched for further articles. Selected studies reported data on ultrasound and/or MRI with histological confirmation of diagnosis. Two reviewers independently selected articles without language restrictions, and extracted data in the form of 2 * 2 tables. We computed sensitivity and specificity for individual studies and pooled these results in a meta-analysis. We also performed meta-regression to examine how the index tests compared on diagnostic accuracy. RESULTS: Twenty-three articles (involving 2,312 women) satisfied the inclusion criteria. Transvaginal ultrasound had a pooled sensitivity of 72% (95% CI 65-79%), specificity of 81% (95% CI 77-85%), positive likelihood ratio of 3.7 (95% CI 2.1-6.4) and negative likelihood ratio of 0.3 (95% CI 0.1-0.5). MRI had a pooled sensitivity of 77% (95% CI 67-85%), specificity of 89% (95% CI 84-92%), positive likelihood ratio of 6.5 (95% CI 4.5 9.3), and negative likelihood ratio of 0.2 (95% CI 0.1-0.4). The results show that a correct diagnosis was obtained more often with MRI. CONCLUSION: Transvaginal ultrasound and MRI show high levels of accuracy for the non-invasive diagnosis of adenomyosis. PMID- 20932129 TI - The effect of laser preexposure on seeding endothelial cells to a biomaterial surface. AB - OBJECTIVE: In this study, the possible effect of low-level laser (LLL) on improving the adhesion of endothelial cells (ECs) to a biomaterial substrate was evaluated. BACKGROUND DATA: Despite the numerous studies regarding the effects of LLL on biologic systems, the influence of LLL on the binding between cells and materials was rarely investigated. MATERIALS AND METHODS: A low-power He-Ne laser apparatus with a continuous wavelength of 632.8 nm (a maximum power output of 50 mW) was used. The average irradiation energy on cells was 1.18 J/cm(2). Cell morphology and the concentrations of nitric oxide and calcium after laser exposure were measured. Biomedical grade poly(carbonate)urethane (PU) was synthesized and used to prepare microporous vascular grafts. ECs exposed to laser were harvested and seeded on the PU grafts. No further exposure was given. RESULTS: LLL could change the morphology and increase the matrix secretion of ECs, and such effects persisted when preexposed cells were harvested and seeded to another substrate. The number of ECs attached on the biomaterial substrate was not affected. Preexposed ECs on the PU graft, however, were, on average, more resistant to flushing (i.e., greater cell retention). CONCLUSION: ECs were pretreated with LLL before being seeded onto the PU biomaterial vascular grafts. The retention of LLL-preexposed ECs on the graft surface was enhanced, but not as significantly as that of ECs preexposed to low-intensity ultrasound. PMID- 20932130 TI - Clinical evaluation of Er:YAG, Nd:YAG, and diode laser therapy for desensitization of teeth with gingival recession. AB - OBJECTIVES: The aim of this study was to evaluate the effectiveness of three types of lasers, Er:YAG, Nd:YAG, and GaAlAs (Diode), as dentin desensitizers, as well as to determine both the immediate and late therapeutic effects on teeth with gingival recessions. MATERIALS AND METHODS: The study was conducted on 24 patients with 96 teeth with Miller's class I or class II gingival recessions with clinically elicitable dentin hypersensitivity (DH) divided into three test groups: (A) Er:YAG, 2,940 nm, 60 mJ/pulse, 2 Hz, 20 s; (B) Nd:YAG, 1,064 nm, 100 mJ/pulse, 15 Hz, 100 s, (C) diode; 808 nm, 100 mW, 20s; and one control group (d) control not irradiated. DH was assessed by means of air stimulus. A visual analogue scale (VAS) was used to measure DH. The selected teeth in three groups received laser therapy for three sessions. The measurements were performed before each treatment session and at 30 min after the laser application (immediate effect), and additional measurements were also performed at 15, 30, and 60 days after the conclusion of treatment (late effect) to assess the extent of desensitization obtained with the different laser devices. RESULTS: Significant reduction of DH occurred at all times measured during the three treatment sessions in groups treated with Er:YAG, Nd:YAG, and diode lasers. Comparing the means of the responses in the three treatment sessions of the four groups, Group b showed a higher degree of desensitization in teeth with gingival recession compared with the other groups (p < 0.001). The immediate and late therapeutic effects of group b were more evident compared with the other groups. CONCLUSIONS: The Er:YAG, Nd:YAG, and diode lasers can be used to reduce DH. Nd:YAG laser irradiation is more effective in the treatment of DH than are Er:YAG and diode laser. Within the limitations of the present study, the Nd:YAG laser seems to be a suitable tool for successful reduction of DH, especially because the 3-month results of this treatment modality are promising. PMID- 20932131 TI - Two rovers to the same site on Mars, 2018: possibilities for cooperative science. PMID- 20932132 TI - A call for intervention research to overcome barriers to women's enrollment in outpatient cardiac rehabilitation programs. PMID- 20932133 TI - The unique role of U.S. foundations in international family planning and reproductive health. AB - This article reviews the unique historic and contemporary role of U.S. philanthropies in supporting international family planning and reproductive health (FPRH) programs, including how priorities are set, strategies developed, and activities funded. We then discuss the FPRH situation in sub-Saharan Africa today, where needs are the most urgent and where, increasingly, foundations are focusing their resources. We describe one case study exhibiting good philanthropic practice and conclude with thoughts about what the future holds for foundations in international FPRH. We find that as leaders in the field of FPRH, foundations have the ability to stay committed to their goals of championing the reproductive health and rights of individuals under dynamic circumstances. Although every policy environment offers opportunities and constraints, foundations, with their grantee partners, have a range of tools to foster and guide social change. As circumstances change, foundations have to be willing and able both to reassess where they provide added value and to take risks through innovative strategies. PMID- 20932134 TI - 3rd Annual Symposium on Self Monitoring of Blood Glucose (SMBG) Applications and Beyond, May 7-8, 2010, London, UK. PMID- 20932135 TI - VoiceRelease. AB - VoiceRelease is a progressively structured treatment system that aims to release the voice through muscle tension reduction by manual therapy, thereby facilitating healthy voice production. The VoiceRelease treatment should closely interact with functional voice training and should therefore be carried out by the speech-language therapist (SLT). The aim of this paper is not to present the treatment in detail, but to describe the benefits of using the techniques in the voice clinic and to argue that laryngeal manual therapy complements the skills of the SLT and that it in a natural and integrated way applies to the treatment of voice problems. In order to comply with the present skills of the SLT, VoiceRelease is progressively structured in four levels. PMID- 20932136 TI - Colorectal cancer: cetuximab, KRAS, BRAF, PIK3CA mutations and beyond. PMID- 20932138 TI - Antiviral therapy for hepatitis C is associated with improved clinical outcomes in patients with advanced fibrosis. AB - End-stage liver disease from hepatitis C is a leading cause of decompensated cirrhosis, hepatocellular carcinoma, liver transplantation and liver-related deaths. The goals of antiviral therapy are to prevent these sequelae and prolong life. Clinical trials of alpha-interferons and ribavirin have used sustained viral response as an outcome because it is considered synonymous with cure and is assumed to be associated with decreasing complications caused by cirrhosis. However, it is only recently that data has emerged supporting this assumption. This study demonstrates that meaningful clinical end points are seen in patients who achieve a sustained virologic response (SVR) with a reduction in liver related deaths, rates of hepatocellular carcinoma (HCC) and liver-related complications. None of the patients who achieved SVR developed variceal bleeding. The rates of HCC were significantly lower in the SVR group, but six cases of HCC occurred in the SVR group, underscoring the importance of continued surveillance in hepatitis C virus patients with SVR who have advanced fibrosis or cirrhosis. PMID- 20932139 TI - Advances and challenges in studying hepatitis C virus in its native environment. AB - Approximately 2% of the worldwide population is infected with hepatitis C virus (HCV), the major causative agent of non-A, non-B hepatitis. Although substantial progress has been made in developing tools to dissect the viral life cycle, most in vitro studies rely on hepatoma cell lines, which are functionally disparate from the natural in vivo target of the virus - hepatocytes. To gain insights into virus-host interactions, there is a need for HCV-model systems that more closely mimic the physiological environment of the liver. Here, we discuss recent advances in culture and detection systems that facilitate the study of HCV in primary cells. Use of these new models may help bridge the gap between in vitro studies and clinical research. PMID- 20932140 TI - Developing better treatments in hepatocellular carcinoma. AB - The marked heterogeneity of hepatocellular carcinoma (HCC), particularly with regard to the etiology and severity of the underlying cirrhosis, makes clinical trial design in this disease very challenging. In addition, despite the global burden of HCC, there have been relatively few randomized studies. The major advance in medical therapy in HCC has been the benefit of sorafenib, as demonstrated in two Phase III studies. However, the benefit is small, and new therapies to augment or replace sorafenib are urgently needed. These newer therapies, as well as the progress made in two important areas - clinical trial design and molecular characterization - are the subject of this article. PMID- 20932141 TI - Defining primary bile acid diarrhea: making the diagnosis and recognizing the disorder. AB - Chronic diarrhea due to bile acid malabsorption may be considered as contributing to the diagnosis when it results from secondary causes, such as ileal resection affecting the enterohepatic circulation. However, the primary form (also known as idiopathic bile acid malabsorption) is not well recognized as a common condition and patients are left undiagnosed. Primary bile acid diarrhea can be diagnosed by the nuclear medicine 75Se-homocholyltaurine (SeHCAT) test, although this is unavailable or underutilized in many settings. A systematic review suggests that approximately 30% of patients who would otherwise be diagnosed with diarrhea predominant irritable bowel syndrome or functional diarrhea have abnormal SeHCAT retention. Serum 7alpha-hydroxy-4-cholesten-3-one can also be measured to show increased bile acid synthesis. The reasons for the lack of recognition of primary bile acid diarrhea are discussed, and these are compared with the other common cause of malabsorption, celiac disease. The lack of a clear pathophysiological mechanism has been a problem, but recent evidence suggests that impaired feedback control of hepatic bile acid synthesis by the ileal hormone FGF19 results in overproduction of bile acids. The identification of FGF19 as the central mechanism opens up new areas for development in the diagnosis and treatment of primary bile acid diarrhea. PMID- 20932142 TI - The Duke Abdominal Assessment Scale: initial experience. AB - Plain abdominal radiographs are the current standard imaging modality of choice in the evaluation of patients with clinically suspected necrotizing enterocolitis. The time interval between radiographic exams varies with the severity of disease and may range from every 6 h to every 24 h. Radiographs are often also obtained at any point of acute clinical deterioration. Evaluation of the abdominal radiographic series is critical as the findings may alter patient management and can be an indication for surgical intervention. For these reasons, it is essential that the radiographic findings are communicated to the referring neonatologist in a clear and consistent manner. Inherent variability and lack of consistency in radiology reporting makes it difficult for the referring clinician to incorporate radiographic reports into his/her treatment algorithm. Assigning abdominal radiographic findings in necrotizing enterocolitis to a numerical scale that increases as the disease progresses provides objective terminology in lieu of subjective descriptors and may facilitate communication to our clinical colleagues. With this task in mind, the Duke Abdominal Assessment Scale was created as a 10-point numerical scale of plain film bowel gas pattern findings designed to reflect progressive disease and increased certainty of the diagnosis of necrotizing enterocolitis. PMID- 20932143 TI - Thiopurine therapy in inflammatory bowel disease. AB - The thiopurines azathioprine and 6-mercaptopurine have been used in the treatment of Crohn's disease and ulcerative colitis for over 40 years. Randomized controlled trials have supported their use in the treatment of active disease, as well as for the maintenance of disease remission. Presently, the most debated issues surrounding the thiopurines include: the role of thiopurine methyltransferase and metabolite-adjusted dosing in enhancing efficacy and minimizing toxicity; the timing of thiopurine use, that is, earlier versus later use during the course of the disease; the selection of thiopurine monotherapy versus combination therapy with an anti-TNF-alpha; agent; and the safety profile of thiopurines. Accumulated evidence has supported the safety of 6 mercaptopurine/azathioprine use in pregnancy and lactation. Thiopurine therapy in inflammatory bowel diseases is associated with an increased risk of lymphoproliferative disorders. Factoring their proven efficacy over a broad range of clinical scenarios within Crohn's disease and ulcerative colitis together with their overall safety profile and convenient and inexpensive once-daily oral administration, azathioprine and 6-mercaptopurine remain among the mainstays of Crohn's disease and ulcerative colitis therapy. PMID- 20932144 TI - Impact of Clostridium difficile on inflammatory bowel disease. AB - Clostridium difficile infection (CDI) has been increasing in incidence among those with underlying inflammatory bowel disease (IBD) and is associated with substantial morbidity, the need for surgery and even mortality. The similar clinical presentation between CDI and a flare of underlying IBD makes prompt diagnosis essential to prevent deterioration which would accompany an escalation of immunosuppression in the absence of appropriate antibiotic therapy. Classical risk factors (antibiotic or healthcare exposure) or clinical findings (pseudomembranes) may not be found in many IBD patients with CDI and should not be considered essential for entertaining the diagnosis. Enzyme immunoassays detecting both toxins A and B remain the most widely used test for diagnosis and have acceptable sensitivity, but may require testing of multiple samples in select situations. Both vancomycin and metronidazole appear to be effective and treatment with oral vancomycin is preferred in those with severe disease, including those who require hospitalization. Appropriate infection control measures are essential to restrict patient-to-patient spread within healthcare environments and to prevent recurrences. Several novel therapies are currently under study, including new antibiotic agents and monoclonal antibodies targeted against the toxins. There is a need to broaden these studies to the IBD population. There is also the need to prospectively examine whether CDI has long term disease-modifying consequences in those with underlying IBD. PMID- 20932145 TI - Cholangiocarcinoma: an endoscopist's perspective. AB - The incidence of cholangiocarcinoma is on the rise. This may be related in part to higher detection rates secondary to sophisticated endoscopic modalities. These tumors pose a significant diagnostic dilemma. High index of suspicion, careful interpretation of serum markers and utilization of endoscopic techniques, including endoscopic retrograde cholangiopancreatography and endoscopic ultrasound, help to establish the diagnosis. Imaging modalities are crucial in the evaluation of these tumors. They help to define the extent of the native lesion, which may dictate its resectability, as well as evaluate for metastasis. Therapeutic options are somewhat limited, short of surgical resection. Newer chemotherapeutic agents, as well as endoscopy-targeted therapy, may improve the overall treatment success rate, although experience is somewhat limited at this time. Endoscopic intervention is essential for palliation. PMID- 20932146 TI - Recent advances in liver imaging. AB - Liver surgery remains a difficult challenge in which preoperative data analysis and strategy definition may play a significant role in the success of the procedure. Medical image processing led to a major improvement of patient care by guiding the surgical gesture. From this initial data, new technologies of virtual reality and augmented reality can increase the potential of such images. The 3D modeling of the liver of patients from their CT scan or MRI thus allows an improved surgical planning. Simulation allows the procedure to be simulated preoperatively and offers the opportunity to train the surgical gesture before carrying it out. These three preoperative steps can be used intraoperatively thanks to the development of augmented reality, which consists of superimposing the preoperative 3D modeling of the patient onto the real intraoperative view of the patient and his/her organs. Augmented reality provides surgeons with a transparent view of the patient. This facilitated the intraoperative identification of the vascular anatomy and the control of the segmental arteries and veins in liver surgery, thus preventing intraoperative bleeding. It can also offer guidance due to the virtual improvement of their real surgical tools, which are tracked in real-time during the procedure. During the surgical procedure, augmented reality, therefore, offers surgeons a transparent view of their patient, which will lead to the automation of the most complex maneuvers. The new ways of processing and analyzing liver images have dramatically changed the approach to liver surgery. PMID- 20932147 TI - Nonalcoholic steatohepatitis: risk factors and diagnosis. AB - Nonalcoholic steatohepatitis (NASH) represents the progressive form of nonalcoholic fatty liver disease with greater potential to lead to liver-related morbidity and mortality. Diagnosing NASH mandates more intensive clinical management and consideration for clinical trials. Currently, the diagnosis of NASH requires a liver biopsy, which is invasive, with drawbacks in sampling and interpretation error. Clinical risk factors for NASH include diabetes and the metabolic syndrome; however, these are not sufficiently predictive of the condition by themselves. Routine liver aminotransaminase levels are not reliable; however, novel plasma hepatocyte apoptosis markers, either alone or in combination with clinical risk factors, are potential noninvasive diagnostic tools for the future. PMID- 20932148 TI - The enteric nervous system as a regulator of intestinal epithelial barrier function in health and disease. AB - The intestinal epithelia proliferate and differentiate along the crypt villus axis to constitute a barrier cell layer separating some 1013 potentially harmful bacteria from a sterile mucosal compartment. Strict regulatory mechanisms are required to maintain a balance between the appropriate uptake of luminal food components and proteins, while constraining the exposure of the mucosal compartment to luminal antigens and microbes. The enteric nervous system is increasingly recognized as such a regulatory housekeeper of the epithelial barrier integrity, in addition to its ascribed immunomodulatory potential. Inflammation affects both epithelial integrity and barrier function and, in turn, loss of barrier function perpetuates inflammatory conditions. The observation that inflammatory conditions affect enteric neurons may add to the dysregulated barrier function in chronic disease. Here, we review the current understanding of the regulatory role of the nervous system in the maintenance of barrier function in healthy state, or during pathological conditions of, for instance, stress induced colitis, surgical trauma or inflammation. We will discuss the clinical potential for advances in understanding the role of the enteric nervous system in this important phenomenon. PMID- 20932150 TI - Use of intraoral welding to stabilize dental implants in augmented sites for immediate provisionalization: a case report. AB - Immediate implant rehabilitation of edentulous arches may be somewhat problematic because of anatomic situations involving insufficient bone thickness or height and tooth position. The aim of this report was to present a retrospective case series of dental implants placed into augmented sites (split crest or sinus augmentation) that were stabilized with an intraorally welded framework at the time of immediate provisionalization. An intraoral welding unit was used to join and stabilize implants as an orthopedic splint to break down forces applied on provisional restorations during healing and osseointegration. This approach allows for the immediate provisionalization of implants in bone-defective areas where multiple implant systems have been enacted. Forty-eight implants in 16 patients were inserted, welded together to a titanium framework, and immediately provisionalized during the same surgery in which split-crest or sinus augmentation procedures were performed. After removing the welded frameworks, 1 of 48 implants failed; the failed implant was associated with a sinus augmentation procedure. Intraoral welding stabilization may be a predictable procedure to allow immediate loading in augmented areas during healing time and to stabilize implants against nonaxial forces, thereby reducing the number of surgical and prosthetic sessions and making patients comfortable and accustomed to immediate fixed provisional and definitive restorations. PMID- 20932151 TI - Metal-ceramic screw-retained implant fixed partial denture with intraoral luted framework to improve passive fit. AB - Passive fit of a long-span screw-retained implant prosthesis is an important criteria for the success of the restoration. This article describes a technique for fabricating a ceramometal implant fixed dental prosthesis (FDP) for a long span partially edentulous situation by altering the conventional screw-retained design. The possibility of a passive fit is maximized by intraoral luting of the cast frame to milled abutments, and the potential framework distortion during fabrication is compensated to a major extent. Retrievability is ensured by screw retention of the prosthesis to the implants. Compared with conventional porcelain fused to metal screw-retained FDP, this prosthesis is relatively inexpensive to fabricate. PMID- 20932152 TI - Tooth movement after infrared laser phototherapy: clinical study in rodents. AB - OBJECTIVES: The aim of this research was to investigate the influence of low power laser on tooth movement in rats. BACKGROUND: Tooth movement is closely related to the process of bone remodeling. The biologic result, with the application of a force to the tooth, is bone absorption on the pressure side and neoformation on the traction side of the alveolar bone. The laser photobiomodulation is capable of providing an increase in cellular metabolism, blood flow, and lymphatic drainage. METHODS: Thirty young-adult male Wistar rats weighing between 250 and 300 g were divided into two groups, control and experimental, containing 15 animals each. The animals received orthodontic devices calibrated to release a force of 40 g/F, with the purpose of moving the first upper molar mesially. Low-intensity laser, wavelength 790 nm, was used in the experimental group; the dose was 4.5 J/cm(2) per point, mesial and distal, on the palatal side, 11 J/cm(2) on the buccal side, and this procedure was repeated every 48 h, totaling nine applications. The active movement was clinically evaluated after 7, 13, and 19 days. RESULTS AND CONCLUSION: The results showed no statistically significant difference, p = 0.079 (T0-T7), p = 0.597 (T7-T13), and p = 0.550 (T13-T19) between the laser and control groups on the amount of tooth movement in the different times evaluated. It may be concluded that laser phototherapy, with the parameters in the present study, did not significantly increase the amount of tooth displacement during induced orthodontic movement in rodents. PMID- 20932153 TI - Clarithromycin accumulation by phagocytes and its effect on killing of Aggregatibacter actinomycetemcomitans. AB - BACKGROUND: Clarithromycin inhibits several periodontal pathogens and is concentrated inside gingival fibroblasts and epithelial cells by an active transporter. We hypothesized that polymorphonuclear leukocytes (PMNs) and less mature myeloid cells possess a similar transporter for clarithromycin. It is feasible that clarithromycin accumulation inside PMNs could enhance their ability to kill Aggregatibacter actinomycetemcomitans (previously Actinobacillus actinomycetemcomitans). METHODS: To test the first hypothesis, purified PMNs and cultured HL-60 cells were incubated with [(3)H]-clarithromycin. Clarithromycin transport was assayed by measuring changes in cell-associated radioactivity over time. The second hypothesis was examined with PMNs loaded by incubation with clarithromycin (5 MUg/ml). Opsonized bacteria were incubated at 37 degrees C with control and clarithromycin-loaded PMNs. RESULTS: Mature human PMNs, HL-60 cells differentiated into granulocytes, and undifferentiated HL-60 cells all took up clarithromycin in a saturable manner. The kinetics of uptake by all yielded linear Lineweaver-Burk plots. HL-60 granulocytes transported clarithromycin with a K(m) of ~250 MUg/ml and a V(max) of 473 ng/min/10(6) cells, which were not significantly different from the values obtained with PMNs. At steady state, clarithromycin levels inside HL-60 granulocytes and PMNs were 28- to 71-fold higher than extracellular levels. Clarithromycin-loaded PMNs killed significantly more A. actinomycetemcomitans and achieved shorter half-times for killing than control PMNs when assayed at a bacteria-to-PMN ratio of 100:1 (P <0.04). At a ratio of 30:1, these differences were not consistently significant. CONCLUSIONS: PMNs and less mature myeloid cells possess a transporter that takes up and concentrates clarithromycin. This system could help PMNs cope with an overwhelming infection by A. actinomycetemcomitans. PMID- 20932154 TI - Implant stability and peri-implant parameters in free vascularized iliac graft transplantation patients: report of three ameloblastoma cases. AB - BACKGROUND: Ameloblastoma, a benign but locally aggressive tumor, accounts for 9% to 11% of all odontogenic tumors. Radical procedures, including resection, are performed. To restore functions after resection, free vascularized iliac grafts followed by a dental implant-supported prosthesis are used as a successful treatment option. The aim of this case report is to evaluate the peri-implant clinical status and stability of dental implants placed in patients with advanced stage mandibular ameloblastomas. METHODS: Examinations of three patients revealed extensive ameloblastomas, and hemimandibulectomies were performed. Six months after surgeries, two to four dental implants were placed. After 6 months of healing, one fixed prosthesis and two removable prostheses were delivered. The stability of implants was evaluated at the surgical baseline and 1, 3, 6, 9, and 12 months after surgery by resonance-frequency (RF) analysis. Peri-implant clinical parameters (i.e., plaque index [PI], gingival index [GI], gingival bleeding time index [GBTI], and peri-implant probing depth [PD]) were recorded at the delivery of the prosthesis and at follow-ups at 1, 3, and 6 months. RESULTS: Nine implants that supported one removable prosthesis and two fixed prostheses were placed. RF analysis revealed no significant changes in implant stability during 12 months of follow-up. Peri-implant clinical parameters (PI, GI, and GBTI) showed slight improvements during follow-up. Although advancements were observed in 6 months, PDs were found to be deeper than optimal measurements for the whole observation time. CONCLUSION: The implant-supported prosthetic rehabilitation of patients with ameloblastomas reconstructed with free vascularized iliac crest grafts can be a predictive alternative for improving the quality of life of patients in which a high implant stability and acceptable peri implant health may be achieved. PMID- 20932155 TI - Subantimicrobial-dose doxycycline and cytokine-chemokine levels in gingival crevicular fluid. AB - BACKGROUND: The present randomized, double-masked, placebo-controlled, parallel arm study examines the impact of adjunctive subantimicrobial-dose doxycycline (SDD) on the local inflammatory response through cytokine and chemokine levels in gingival crevicular fluid (GCF) samples from patients with chronic periodontitis. METHODS: Forty-six patients with chronic periodontitis received scaling and root planing with or without adjunctive SDD. GCF samples were collected and clinical parameters including probing depth, clinical attachment level, gingival index, and plaque index were recorded every 3 months for 12 months. GCF tumor necrosis factor-alpha, interleukin (IL)-6, IL-4, IL-10, IL-13, IL-17, macrophage inhibitory protein 1alpha, macrophage inhibitory protein 1beta, monocyte chemoattractant protein 1, and regulated on activated normal T-cell expressed and secreted protein levels were determined by xMAP multiplex immunoassay. RESULTS: Significant improvements were observed in all clinical parameters in both groups over 12 months (P <0.0125), whereas the SDD group showed significantly better reduction in gingival index, probing depth, and gain in clinical attachment compared to the placebo group (P <0.05). Decrease in IL-6 in the SDD group was significantly higher compared to the placebo group at 6 and 9 months in deep pockets (P <0.05), whereas tumor necrosis factor-alpha was significantly reduced in moderately deep pockets (P <0.05). SDD resulted in a stable IL-4 and IL-10 response while reducing the monocyte chemoattractant protein 1 levels at 3 months (P <0.05). CONCLUSIONS: These results show that SDD, as an adjunct to non surgical periodontal therapy, stabilizes the inflammatory response by promoting the suppression of proinflammatory cytokines and increasing the anti-inflammatory cytokines. The chemokine activity would account for the regulation of the inflammatory response to SDD therapy. PMID- 20932156 TI - Periodontitis prevalence and severity in Indonesians with type 2 diabetes. AB - BACKGROUND: The prevalence of diabetes mellitus type 2 (DM2) in Indonesia is high and still rising. Periodontitis is associated with DM2. No study has investigated this association in Indonesia, nor has any study investigated this association using a variety of methods to operationalize periodontitis. The present study compares prevalence and severity of periodontitis in patients with DM2 to healthy controls, using different methods to operationalize periodontitis. METHODS: A total of 78 subjects with DM2 and 65 healthy control subjects underwent a full mouth periodontal screening assessing probing depth, gingival recession, plaque index, and bleeding on probing. Using these measurements, the prevalence and severity of periodontitis was operationalized in various ways. Differences in the prevalence and severity of periodontitis between subjects with DM2 and healthy subjects were analyzed using univariate analyses. In regression analyses, the prevalence and severity of periodontitis were predicted on the basis of DM2 presence, controlling for confounders and effect modification. RESULTS: Prevalence of periodontitis was significantly higher in subjects with DM2 compared to healthy subjects, showing odds ratios of 5.0 and 6.1. Likewise, periodontitis severity was significantly higher in subjects with DM2. CONCLUSION: Indonesian subjects with DM2 had more prevalent and more severe periodontitis than healthy Indonesian subjects, independent of confounding factors or the methods used to operationalize periodontitis. PMID- 20932157 TI - The effect of low-level laser therapy as an adjunct to non-surgical periodontal treatment. AB - BACKGROUND: The aim of this study is to evaluate the effect of low-level laser therapy (LLLT) as an adjunct to non-surgical periodontal therapy of smoking and non-smoking patients with moderate to advanced chronic periodontitis. METHODS: All 36 systemically healthy patients who were included in the study initially received non-surgical periodontal therapy. The LLLT group (n = 18) received GaAlAs diode laser therapy as an adjunct to non-surgical periodontal therapy. A diode laser with a wavelength of 808 nm was used for the LLLT. Energy density of 4 J/cm(2) was applied to the gingival surface after periodontal treatment on the first, second, and seventh days. Each of the LLLT and control groups was divided into two groups as smoking and non-smoking patients to investigate the effect of smoking on treatment. Gingival crevicular fluid samples were collected from all patients and clinical parameters were recorded on baseline, the first, third, and sixth months after treatment. Matrix metalloproteinase-1, tissue inhibitor matrix metalloproteinase-1, transforming growth factor-beta1, and basic-fibroblast growth factor levels in the collected gingival crevicular fluid were measured. RESULTS: The primary outcome variable in this study was change in gingival bleeding and inflammation. At all time points, the LLLT group showed significantly more improvement in sulcus bleeding index (SBI), clinical attachment level, and probing depth (PD) levels compared to the control group (P <0.001). There were clinically significant improvements in the laser-applied smokers' PD and SBI levels compared to smokers to whom a laser was not applied, between the baseline and all time points (P <0.001) (SBI score: control group 1.12, LLLT group 1.49; PD: control group 1.21 mm, LLLT group 1.46 mm, between baseline and 6 months). Transforming growth factor-beta1 levels and the ratio of matrix metalloproteinase-1 to tissue inhibitor matrix metalloproteinase-1 decreased significantly in both groups at 1, 3, and 6 months after periodontal therapy (P <0.001). Basic-fibroblast growth factor levels significantly decreased in both groups in the first month after the treatment, then increased in the third and sixth months (P <0.005). No marker level change showed significant differences between the groups (P <0.05). CONCLUSION: LLLT as an adjunctive therapy to non-surgical periodontal treatment improves periodontal healing. PMID- 20932158 TI - Clinical and histologic evaluation of a granular bovine bone biomaterial used as an adjunct to GTR with a bioresorbable bovine pericardium collagen membrane in the treatment of intrabony defects. AB - BACKGROUND: The aim of the present study is to evaluate the clinical and histologic healing of deep intrabony defects treated with guided tissue regeneration (GTR) with a collagen membrane from bovine pericardium and implantation of granular bovine bone biomaterial. METHODS: Thirty patients with one deep, combined 1- and 2-wall intrabony defect exhibiting a probing depth >=6 mm and an associated intrabony defect >=3 mm were treated with GTR with a bioresorbable collagen membrane from bovine pericardium and adjunct implantation of a granular bovine bone biomaterial. The clinical results were evaluated 1 and 3 years after surgery. In addition, five teeth fulfilling the inclusion criteria but scheduled for extraction because of advanced periodontitis or restorative considerations were treated similarly and then extracted along with a portion of their surrounding periodontal tissues for histologic evaluation 6 months after surgery. RESULTS: Healing was uneventful in all patients. Significant clinical improvements were observed at 1 and 3 years postoperatively (P <0.01; probing depth averaged 4.4 +/- 1.6 and 4.7 +/- 1.4 mm and clinical attachment level gain was 3.9 +/- 1.4 and 3.5 +/- 1.3 mm, respectively). The histologic evaluation revealed formation of new cellular cementum and new periodontal ligament in four of the five cases. In general, the xenograft particles seemed to be mostly embedded in connective tissue without any evidence of new bone formation. CONCLUSION: GTR treatment of intrabony defects with the collagen membrane from bovine pericardium and adjunct implantation of the new bovine bone biomaterial may result in significant clinical improvements that can be maintained over a period of 3 years, and regeneration of cementum and periodontal ligament, but without bone formation. PMID- 20932159 TI - Enhanced ridge preservation by bone mineral bound with collagen-binding synthetic oligopeptide: a clinical and histologic study in humans. AB - BACKGROUND: The ridge-preservation technique has been applied with membrane alone or membrane plus graft. Synthetic peptides, mimicking bioactive growth factor or extracellular matrix protein, have been attempted to provide an active surface of the biomaterials in inducing bone formation while alleviating the limitations of whole protein such as short half-life, immunologic responses. The aim of the present clinical study is to examine the osteogenic effect of synthetic oligopeptide-coated bone mineral compared to bone graft without peptide when applied with collagen membrane in a ridge-preservation technique. METHODS: Synthetic oligopeptide from the collagen-binding domain of osteopontin was chemically synthesized and coated onto the surface of bone mineral particulates. Ridge preservations were performed at 44 extraction sites in 42 patients (20 males and 22 females). Analyses of clinical parameters and histomorphometric evaluations were conducted to compare the osteogenic effects of the grafts between baseline and 6 months. RESULTS: In the bone grafts of the control group treated without synthetic peptide, new bone formation was only seen around borders and basal areas. However, new bone was observed broadly in the defects of the test group treated with synthetic peptide-coated bone mineral, as seen not only at peripheries but also in the central and coronal parts of bone cores in the defects. The average percentage of new bone formation was significantly higher in the test group (5.3% +/- 8.3% versus 10.4% +/- 4.6%). The contact percentages between the graft particles and the new bone were 8.2% +/- 11.3% for the control group and 20.4% +/- 7.5% for the test group (P <0.05). CONCLUSIONS: The ridge-preservation approach using synthetic oligopeptide-coated bone mineral with collagen membrane effectively prevented the resorption of hard tissue with higher bone-to-graft contact, and the oligopeptide-coated bone may be a choice for ridge-preservation procedures while assuring new bone formation. PMID- 20932160 TI - Seasonal carryover effects following the administration of cortisol to a wild teleost fish. AB - Stress can have sublethal effects that are manifested either immediately or at spatial or temporal scales that are removed from the stress event (i.e., carryover effects). We tested whether a short-term elevation of plasma cortisol would result in seasonal carryover effects in wild largemouth bass Micropterus salmoides. Using exogenous hormone implants, we raised circulating cortisol concentrations in a group of wild fish for approximately 5 d in October 2007. We then compared activity (velocity, distance traveled) of cortisol-treated animals with that of sham-treated and control animals throughout the winter using an automated acoustic telemetry array. Immediately following treatment, the cortisol treated fish showed increased activity relative to controls. However, this difference disappeared following the cessation of the elevation of circulating cortisol. During the winter of 2007 to 2008, the lake experienced a nearly complete winterkill event, providing insight into how a transient stress response can influence the response of wild animals to subsequent challenges. Most fish carrying acoustic transmitters succumbed during this winterkill event, but cortisol-treated fish died earlier than fish in other groups and showed a decrease in activity relative to controls and sham-treated fish before mortality. This study provides preliminary evidence of seasonal carryover effects in wild fish and yields insight into the ecological consequences of stress across broad temporal scales. PMID- 20932161 TI - Maxillofacial anatomy: the mandibular symphysis. AB - Placement of dental implants in the anterior mandible is considered by many clinicians to be a relatively low-risk procedure. However, hemorrhagic episodes following implant placement in the mandibular symphysis are regularly reported and can have serious consequences. The use of high-resolution focused cone beam scanners has given us the ability to visualize the intricate neurovascular network of the intraforaminal region without distortion and in greater detail. Knowledge of the arterial supply and navigated implant placement in the mandibular symphysis can help to avoid these potentially life-threatening emergencies. PMID- 20932162 TI - Downward vascular translocation of a green fluorescent protein-tagged strain of Dickeya sp. (Biovar 3) from stem and leaf inoculation sites on potato. AB - Translocation of a green fluorescent protein (GFP)-tagged Dickeya sp. from stems or from leaves to underground parts of potato plants was studied in greenhouse experiments. Thirty days after stem inoculation, 90% of plants expressed symptoms at the stem base and 95% of plants showed browning of internal stem tissue. The GFP-tagged Dickeya sp. was detected by dilution plating in extracts of the stem interiors (100%), stem bases (90%), roots (80%), stolons (55%), and progeny tubers (24%). In roots, the GFP-tagged Dickeya sp. was found inside and between parenchyma cells whereas, in stems and stolons, the GFP-tagged Dickeya sp. was found in the xylem vessels and protoxylem cells. In progeny tubers, this strain was detected in the stolon end. Thirty days after leaf inoculation, the GFP tagged Dickeya sp. was detected in extracts of 75% of the leaves, 88% of the petioles, 63% of the axils, and inside 25% of the stems taken 15 cm above the ground level. UV microscopy confirmed the presence of the GFP-tagged Dickeya sp. inside petioles and in the main leaf veins. No blackleg or aerial stem rot and no translocation of the GFP-tagged Dickeya sp. to underground plant parts was observed. The implications for contamination of progeny tubers are discussed. PMID- 20932163 TI - Invasion of Phytophthora infestans at the landscape level: how do spatial scale and weather modulate the consequences of spatial heterogeneity in host resistance? AB - Strategic spatial patterning of crop species and cultivars could make agricultural landscapes less vulnerable to plant disease epidemics, but experimentation to explore effective disease-suppressive landscape designs is problematic. Here, we present a realistic, multiscale, spatiotemporal, integrodifference equation model of potato late blight epidemics to determine the relationship between spatial heterogeneity and disease spread, and determine the effectiveness of mixing resistant and susceptible cultivars at different spatial scales under the influence of weather. The model framework comprised a landscape generator, a potato late blight model that includes host and pathogen life cycles and fungicide management at the field scale, and an atmospheric dispersion model that calculates spore dispersal at the landscape scale. Landscapes consisted of one or two distinct potato-growing regions (6.4-by-6.4-km) embedded within a nonhost matrix. The characteristics of fields and growing regions and the separation distance between two growing regions were investigated for their effects on disease incidence, measured as the proportion of fields with >=1% severity, after inoculation of a single potato grid cell with a low initial level of disease. The most effective spatial strategies for suppressing disease spread in a region were those that reduced the acreage of potato or increased the proportion of a resistant potato cultivar. Clustering potato cultivation in some parts of a region, either by planting in large fields or clustering small fields, enhanced the spread within such a cluster while it delayed spread from one cluster to another; however, the net effect of clustering was an increase in disease at the landscape scale. The planting of mixtures of a resistant and susceptible cultivar was a consistently effective option for creating potato growing regions that suppressed disease spread. It was more effective to mix susceptible and resistant cultivars within fields than plant some fields entirely with a susceptible cultivar and other fields with a resistant cultivar, at the same ratio of susceptible to resistant potato plants at the landscape level. Separation distances of at least 16 km were needed to completely prevent epidemic spread from one potato-growing region to another. Effects of spatial placement of resistant and susceptible potato cultivars depended strongly on meteorological conditions, indicating that landscape connectivity for the spread of plant disease depends on the particular coincidence between direction of spread, location of fields, distance between the fields, and survival of the spores depending on the weather. Therefore, in the simulation of (airborne) pathogen invasions, it is important to consider the large variability of atmospheric dispersion conditions. PMID- 20932164 TI - Baseline sensitivity and resistance-risk assessment of Phytophthora capsici to iprovalicarb. AB - Iprovalicarb has been used to control Phytophthora capsici, a devastating pathogen of many economically important crops. To evaluate the risk of fungicide resistance, 158 isolates of P. capsici were examined for sensitivity to iprovalicarb by measuring mycelial growth. Values of effective concentrations for 50% mycelial growth inhibition varied from 0.2042 to 0.5540 MUg/ml and averaged 0.3923 (±0.0552) MUg/ml, with a unimodal distribution. This is the first report of P. capsici isolates highly resistant to iprovalicarb (resistance factor >100). Resistance of the isolates was stable through 10 transfers on iprovalicarb free medium, and most resistant isolates had the same level of fitness (mycelial growth, zoospore production, and virulence) as their corresponding parents, indicating that iprovalicarb resistance was independent from other general growth characters. There was cross-resistance among all tested carboxylic acid amide (CAA) fungicides, including iprovalicarb, flumorph, dimethomorph, and mandipropamid, but not with non-CAA fungicides, including azoxystrobin, chlorothalonil, cymoxanil, etridiazole, metalaxyl, and zoxamide. Based on the present results, resistance risk of P. capsici to CAAs could be moderate and resistance management should be considered. PMID- 20932165 TI - Periodicity in host availability does not account for evolutionary branching as observed in many plant pathogens: an application to Gaeumannomyces graminis var. tritici. AB - Periodicity in host availability is common in agricultural systems. Although it is known to have profound effects on plant pathogen abundance, the evolutionary consequences of periodicity for the pathogen population have not previously been analyzed. An epidemiological model incorporating periodic absence of the host crop is combined with the theory of adaptive dynamics to determine whether or not seasonality in host presence plays a role in the occurrence of evolutionary branching, leading to coexisting yet genetically distinct pathogen phenotypes. The study is motivated and illustrated by the specific example of take-all disease of wheat, caused by the pathogen Gaeumannomyces graminis var. tritici, for which two coexisting but genetically distinct types and a trade-off related to seasonality in host presence have been identified. Numerical simulations are used to show that a trade-off between the pathogen transmission rate and the survival of the pathogen between cropping seasons cannot account for the evolutionary branching observed in many pathogens. Model elaborations show that this conclusion holds for a broad range of putative mechanisms. Although the analysis is motivated and illustrated by the specific example of take-all of wheat, the results apply to a broad range of pathogens. PMID- 20932166 TI - Identification and characterization of a novel etiological agent of mango malformation disease in Mexico, Fusarium mexicanum sp. nov. AB - The primary objective of this study was to characterize Fusarium spp. associated with the economically devastating mango malformation disease (MMD) in Mexico. In all, 142 Fusarium strains were isolated from symptomatic mango inflorescences and vegetative tissues in eight geographically diverse Mexican states from 2002 through 2007. Initially, all the Mexican isolates were screened for genetic diversity using appolymerase chain reaction and random amplified polymorphic DNA markers and were grouped into seven distinct genotypes. Based on results of these analyses, evolutionary relationships and species limits of the genetically diverse MMD-associated Fusarium spp. were investigated using multilocus DNA sequence data and phylogenetic species recognition. Maximum parsimony analyses of a five-locus data set comprising 5.8 kb of aligned DNA sequence data indicated that at least nine phylogenetically distinct Fusarium spp. within the Gibberella fujikuroi species complex are associated with MMD, including one species within the African clade (Fusarium pseudocircinatum), two species within the Asian clade (F. mangiferae and F. proliferatum), and at least six species within the American clade (F. sterilihyphosum and five undescribed Fusarium spp.). Molecular phylogenetic analyses indicate that a novel genealogically exclusive lineage within the American clade was the predominant MMD associate in Mexico. This new Fusarium sp. caused MMD and could be distinguished from all other known species morphologically by the production of mostly sterile, coiled hyphae which are typically associated with sporodochial conidiophores together with unbranched or sparsely branched aerial conidiophores. Koch's postulates were completed for isolates of the new species on nucellar seedlings of mango cv. Ataulfo. This pathogen is formally described herein as F. mexicanum. PMID- 20932167 TI - Variation in pathogenicity and aggressiveness of Erysiphe necator from different Vitis spp. and geographic origins in the eastern United States. AB - Eastern North America is considered the center of diversity for many Vitis spp. and for the grape powdery mildew pathogen, Erysiphe necator. However, little is known about populations of E. necator from wild Vitis spp. We determined the phenotypic variation in pathogenicity and aggressiveness of E. necator among isolates from wild and domesticated Vitis spp. from diverse geographic regions in the eastern United States. To test pathogenicity, we inoculated 38 E. necator isolates on three wild Vitis spp., two commercially grown hybrids and the European wine grape, Vitis vinifera. V. rotundifolia (muscadine grape) was the only host species on which complete host specialization was evident; it was only susceptible to isolates collected from V. rotundifolia. All isolates, regardless of source host, were pathogenic on the other Vitis spp. We found no differences in components of aggressiveness latent period and lesion size among isolates from different source hosts when inoculated on V. vinifera, which is highly susceptible to powdery mildew. However significant variation was evident among isolates on the more resistant V. labruscana 'Niagara'. Isolates from the wild species V. aestivalis were the most aggressive, whereas isolates from V. vinifera were not more aggressive than isolates from other source hosts. Greater aggressiveness was also detected among isolates from the southeastern United States compared with isolates from the northeastern United States. PMID- 20932168 TI - Mitochondrial haplotype analysis as a tool for differentiating isolates of Verticillium dahliae. AB - The ability to monitor mitochondrial background in Verticillium dahliae may provide an additional tool for population studies and monitoring clonal populations. Published mitochondrial genome sequences of V. dahliae (DQ351941) were used to design primers for amplification of spacer regions for assessment of mitochondrial haplotype differences among isolates. Five regions were examined (5,229 bp, or 19% of the total genome size) for 30 isolates representing a range in vegetative compatibility group (VCG), host, and geographic origin. Observed differences among isolates were due to single nucleotide polymorphisms, different numbers of bases in specific homopolymeric regions, and copies of subrepeated sequences. When the differences observed for each locus were totaled there were 28 total groupings; when the results of each locus for individual isolates were combined there were 15 mitochondrial haplotypes. Some of the observed groupings correlated with VCG. For example, five VCG-1A and VCG-1B isolates from California, Spain, and Greece had identical haplotypes; however, this was not observed for VCG-2 or VCG-4 isolates. While some VCG-2 isolates also were identical and fell into a single haplotype, five haplotypes were found for this group (five other haplotypes were observed for other isolates that had not been characterized to VCG but grouped with VCG-2 isolates in the phylogenetic analysis). Likewise, five VCG-4 isolates fell into four mitochondrial haplotypes, one of which was identical to the largest VCG-2 grouping. A heterokaryon self incompatible isolate that was reported in the literature to cluster with VCG-2 isolates by amplified fragment length polymorphism analysis was identical with VCG-1 isolates for four of the five loci, but was intermediate between VCG-1 and VCG-2 in the haplotype analysis. Phylogenetic analysis with these regions revealed the mitochondrial background of VCG-1 and VCG2-B to be monophyletic but VCG-2A and VCG-4 could not be separated. The results obtained indicate that there is variation in mitochondrial haplotypes and this type of analysis may be a useful for characterization of isolates. While data from all five regions was used for the haplotype separation in this study, depending on the VCG or the level of variability observed within a population it is possible to use fewer loci. PMID- 20932169 TI - A statistical model to detect asymptomatic infectious individuals with an application in the Phytophthora alni-induced alder decline. AB - In some diseases-in particular, tree root infection-stages of infection and inoculum production level and timing are not readily observable because of uncertainty or time lags in symptom appearance. Here, we pose a criterion, based on relative hazard of disease symptoms, to discriminate between healthy and asymptomatic infected individuals. We design a statistical procedure to estimate the criterion for a 6-year survey of alder decline along a northeastern French river. Individual tree symptom hazard was modeled with Cox's regression model, taking estimation of local infection pressure as a risk factor. From an inoculum production experiment, we thereafter assessed the inoculum production level of target trees, including symptomatic and asymptomatic trees ranked according to their symptoms hazard. Using receiver operating characteristic methods, we first evaluated the criterion performance and determined the discrimination threshold to sort out asymptomatic individuals into healthy and infected. Then, we highlighted the fact that the infected asymptomatic trees were among the major inoculum producers whereas severely declining and dead trees were found to be poor inoculum sources. PMID- 20932171 TI - Tolerance and safety of nifurtimox in patients with chronic chagas disease. AB - BACKGROUND: Nifurtimox has been used to treat Chagas disease for 40 years, but tolerance and safety data in adults are scarce. We aimed to evaluate nifurtimox tolerance and safety in a cohort of Trypanosoma cruzi-infected adult patients in a country of nonendemicity. METHODS: This observational study included all consecutive adults patients who were given a diagnosis of T. cruzi infection from June through December 2008. Eligible patients received nifurtimox at 10 mg/kg/day for 60 days, with regular medical and biological follow-up. Adverse events (AEs) were recorded according to Common Terminology Criteria for Adverse Events, version 3.0. RESULTS: Eighty-one patients received nifurtimox. Eight were lost to follow-up during treatment, and 41 (56.2%) completed the 60-day course. All premature treatment terminations were caused by AEs; 97.5% of patients suffered from AEs, mostly expected (90.5%) and not severe. Gastrointestinal symptoms predominated. Six (7.4%) patients presented with a suspected unexpected serious adverse reaction: drug reaction with eosinophilia and systemic symptoms (n = 3), Quincke edema (n = 1), acute myocarditis (n = 1), and anaphylaxis (n = 1). Patients with 3 or more AEs had an increased risk of premature treatment termination (hazard ratio, 8.42; 95% confidence interval, 1.6-45.5). CONCLUSION: Nifurtimox is poorly tolerated among adults with chronic Chagas disease, resulting in a low treatment completion rate. Considering the significant risk of serious AEs, close monitoring is required, which may be difficult to implement in poor rural areas of countries of endemicity. The safety and efficacy of nifurtimox and benznidazole should be compared to improve current therapeutic recommendations, and pharmacovigilance systems should be enhanced. PMID- 20932170 TI - Poor clinical outcome for meningitis caused by Haemophilus influenzae serotype A strains containing the IS1016-bexA deletion. AB - Since the introduction of Haemophilus influenzae type b (Hib) conjugate vaccines, meningitis caused by serotypes other than Hib has gained in importance. We conducted active hospital-based surveillance for meningitis over an 11-year period in Salvador, Brazil. H. influenzae isolates were serotyped and analyzed by polymerase chain reaction, pulsed-field gel electrophoresis, and DNA sequencing to identify strains with a specific deletion (IS1016) in the bexA gene (IS1016 bexA). We identified 43 meningitis cases caused by non-type b H. influenzae: 28 (65%) were caused by type a (Hia), 9 (21%) were caused by noncapsulated strains, and 3 (7%) each were caused by types e and f. Hia isolates clustered in 2 clonal groups; clonal group A strains (n = 9) had the IS1016-bexA deletion. Among children <5 years of age, meningitis caused by Hia from clonal group A had higher case-fatality than meningitis caused by clonal group B. Despite small numbers, these results indicate that the presence of the IS1016-bexA deletion is associated with enhanced virulence in non-type b H. influenzae. PMID- 20932172 TI - Kinematic analysis of lingual movements during consonant productions in dysarthric speakers with Friedreich's ataxia: A case-by-case analysis. AB - Articulatory kinematics were investigated using electromagnetic articulography (EMA) in four dysarthric speakers with Friedreich's ataxia (FRDA). Specifically, tongue-tip and tongue-back movements were recorded by the AG-200 EMA system during production of the consonants /t/ and /k/ as produced within a sentence utterance and during a rapid syllable repetition task. The results obtained for each of the participants with FRDA were individually compared to those obtained by a control group (n = 10). Results revealed significantly greater movement durations and increased articulatory distances, most predominantly during the approach phase of consonant production. A task difference was observed with lingual kinematics more disturbed during the syllable repetition task than during the sentence utterance. Despite expectations of slowed articulatory movements in FRDA dysarthria, the EMA data indicated that the observed prolongation of consonant phase durations was generally associated with greater articulatory distances, rather than slowed movement execution. PMID- 20932173 TI - TGF-beta1 promoted MMP-2 mediated wound healing of anterior cruciate ligament fibroblasts through NF-kappaB. AB - The adult human anterior cruciate ligament (ACL) has poor functional healing response. Transforming growth factor (TGF)-beta1 enhances the wound repair by stimulating matrix proteins deposition as well as the proliferation and migration of cells. However, the function of the TGF-beta1-induced matrix metalloproteinases' (MMPs) activities in the wound healing process is poorly understood. In this study, exogenous MMP-2 is added to mimic the TGF-beta1 induced MMP-2 expression. Role of NF-kappaB pathway is further examined. Our results show that TGF-beta1 induces dramatic elevation of MMP-2 activities and the MMP-2/tissue inhibitors of metalloproteinases ratio. Furthermore, the exogenous MMP-2 significantly promoted in vitro wound healing abilities of ACL fibroblasts that are significantly blocked with the addition of its inhibitors. TGF-beta1 also increases the proliferation of ACL fibroblasts whereas MMP-2 alone does not, indicating that MMP-2 activities are not involved in the proliferation. TGF-beta1-induced MMP-2 activity is inhibited by Bay11-7082 and Bay11-7085 (NF kappaB inhibitors). Our results demonstrate that increased TGF-beta1 facilitates the ACL healing process by promoting the fibroblasts migration and proliferation. The migration process is mediated by MMP-2 and NF-kappaB pathway is involved in TGF-beta1-mediated MMP-2 release. PMID- 20932175 TI - Fate of vena saphena magna stump after endovenous laser ablation with 980-nm diode laser: 12-month follow-up. AB - OBJECTIVE: The aim of this study was to investigate the fate of VSM stump and its relation to the incidence of thrombosis during a-12 mo follow-up. BACKGROUND DATA: Varicose veins are a common problem. There are several treatment alternatives available. Conventional surgical treatment is associated with high recurrence and complications. However, with the recent development of minimal invasive surgery, various techniques have been developed. Endovenous laser ablation (EVLA) is one of these techniques, which has proven to be safe and effective. Since EVLA is safe and has minor adverse reactions, residual VSM stump and its association with thrombosis after EVLA has not been well studied in literature. MATERIALS AND METHODS: Sixty-nine patients underwent EVLA with a 980 nm diode laser (Ceralas D, Biolitec AG, Jena, Germany), and retrospectively obtained data were analyzed over a 12-mo period. Twenty-six patients were excluded due to the lack of follow-up. All EVLA procedures were performed by the same surgeon, who has experience of EVLA. Laser power was set at 10-15 W depending on the size of targeted vein. The saphenous vein was percutaneously punctured with an 18-gauge needle under ultrasonography guidance. Patients were reassessed at 1 wk, and at 3, 6, and 12 mo after the procedure. RESULTS: Technical success was accomplished in all patients. One patient had flow signals with patent segment of the VSM visualized by venous duplex ultrasonography at 1 mo, which persisted until the 12-mo follow-up. None of the patients developed acute deep-venous thrombosis. CONCLUSIONS: The present study shows that residual VSM stump-length measurement differences at 7 d and 12 mo were statistically significant. In future, large-scale studies are needed, focusing on the proper position of the catheter tip to the saphenofemoral junction and timing the intervals of follow-up after EVLA. PMID- 20932176 TI - The use of the 308-nm excimer laser for the treatment of psoriasis. AB - OBJECTIVE: The objective was to study the effectiveness of the 308-nm excimer laser for the treatment of various forms of localized stable psoriasis. BACKGROUND: Recent reports show that 308-nm excimer laser may be an effective and safe method for the treatment of localized stable psoriasis. METHODS: A retrospective chart review was performed of a population-based group of 98 patients with various forms of localized stable psoriasis treated with excimer laser. Of these, 41 were male, and 57 were female patients. Ages ranged from 10 to 84 years (mean, 51.4 years). Patients who completed at least 10 sessions were included unless they had achieved >70% improvement in PASI scores before 10 treatments. The initial dose was determined by the MED (minimal erythema dose), and the dose was raised gradually in a stepwise fashion. RESULTS: Significant improvement (>=70%) was achieved by 59 (60.2%) patients; they needed an average cumulative dose of 6.46 J/cm(2), and an average of 17 sessions. Twenty-four (24.5%) patients achieved good improvement (50% to 70%); the average cumulative dose needed was 5.36 J/cm(2), and the average number of sessions required was 12. Side effects were limited to sunburn-like reaction. CONCLUSION: The 308-nm excimer laser is an effective and safe modality for the treatment of psoriasis, with good results achieved in a relatively short time. PMID- 20932177 TI - Getting it right. PMID- 20932174 TI - Cyclin-dependent kinases (cdks) and the DNA damage response: rationale for cdk inhibitor-chemotherapy combinations as an anticancer strategy for solid tumors. AB - IMPORTANCE OF THE FIELD: The eukaryotic cell division cycle is a tightly regulated series of events coordinated by the periodic activation of multiple cyclin-dependent kinases (cdks). Small-molecule cdk-inhibitory compounds have demonstrated preclinical synergism with DNA-damaging agents in solid tumor models. An improved understanding of how cdks regulate the DNA damage response now provides an opportunity for optimization of combinations of cdk inhibitors and DNA damaging chemotherapy agents that can be translated to clinical settings. AREAS COVERED IN THIS REVIEW: Here, we discuss novel work uncovering multiple roles for cdks in the DNA-damage-response network. First, they activate DNA damage checkpoint and repair pathways. Later their activity is turned off, resulting in cell cycle arrest, allowing time for DNA repair to occur. Recent clinical data on cdk inhibitor-DNA-damaging agent combinations are also discussed. WHAT THE READER WILL GAIN: Readers will learn about novel areas of cdk biology, the complexity of DNA damage signaling networks and clinical implications. TAKE HOME MESSAGE: New data demonstrate that cdks are 'master' regulators of DNA damage checkpoint and repair pathways. Cdk inhibition may therefore provide a means of potentiating the clinical activity of DNA-damaging chemotherapeutic agents for the treatment of cancer. PMID- 20932178 TI - Zenker's diverticulum: the diagnostic power of ultrasound. PMID- 20932179 TI - Evaluation of iodine nutritional status in Tehran, Iran: iodine deficiency within iodine sufficiency. AB - BACKGROUND: Production of iodized salt in Iran for household consumption began in 1990. Previous studies have reported sustainable elimination of iodine deficiency disorders in Iran. The aim of this study was to evaluate the iodine nutritional status in Tehran in 2009. METHODS: In this cross-sectional study, 383 Tehranian households were enrolled through randomized cluster sampling and a total of 639 adult subjects (242 men and 397 women), aged 19 and over, participated. A 24-hour urine sample was collected for measurement of urinary iodine, sodium, and creatinine concentrations using the digestion method, flame photometry, and autoanalyzer assay, respectively. Salt intake was estimated and iodine content of household salt was measured by titration. RESULTS: Median (interquartile range) iodine content of household salt and urinary iodine concentration (UIC) in Tehran were 21.2 (3.2-31.7) parts per million and 70.0 (34.0-131.2) MUg/L, respectively. There was no statistically significant difference in 24-hour UICs between men and women. Median (interquartile range) daily salt intake was 7.6 (5.5-9.8) g, which was not different in the two genders. According to the WHO/ICCIDD/UNICEF classification, 11.2%, 25.9%, 26.7%, 25.1%, 8.0%, and 3.2% of participants had UIC <20, 20-49, 50-99, 100-199, 200-299, and >300 MUg/L, respectively. CONCLUSIONS: Mild iodine deficiency has recurred in Tehranians. The results emphasize the need for continuous monitoring in all regions, even in a country with iodine sufficiency. PMID- 20932181 TI - Pooled analysis of two case-control studies in New Caledonia and French Polynesia of body mass index and differentiated thyroid cancer: the importance of body surface area. AB - BACKGROUND: New Caledonia and French Polynesia have among of the world highest thyroid cancer incidence rates. Studies have demonstrated a relationship between anthropometric parameters and the prevalence of cancer. In this study we evaluated further the relationship between body mass index (BMI) and other anthropometric parameters on the incidence of thyroid cancer in the New Caledonia and French Polynesia populations. METHODS: We performed a pooled analysis of two case-control studies in New Caledonia and French Polynesia. We included a total of 554 cases (65 men and 489 women) of differentiated thyroid cancers and 776 population control subjects matched on sex, age, and study. Anthropometric factors (height, weight, BMI, body fat percentage [BF%], and body surface area [BSA]), at age 18 and before diagnosis, were analyzed by conditional logistic regression, adjusting for other independent risk factors. RESULTS: A high proportion of cases (73%) were overweight (25-29.9 kg/m(2)) or obese (>=30 kg/m(2)) before diagnosis of thyroid cancer (against 57% of control subjects). An increased risk of thyroid cancer was observed with greater height, weight, BMI, BF%, and BSA. The association of thyroid cancer risk with height, weight, BMI, and BF% did not remain when adjustment was made for BSA. By comparison, the odds ratios for the highest versus the lowest quartile of BSA at age 18 were 3.97 (95% confidence interval, 2.57-6.15; p < 0.001) for women and 4.06 (95% confidence interval, 1.03-16.06; p = 0.04) for men. The association between thyroid cancer risk and each of anthropometric factors did not depend on tumor size or menopausal status before diagnosis. CONCLUSION: Among anthropometric factors, BSA plays a dominant role in thyroid cancer risk and explains the apparent role of BMI. PMID- 20932180 TI - Prevalence of malignant tumors and adenomatous lesions detected by ultrasonographic screening in patients with autoimmune thyroid diseases. AB - BACKGROUND: Thyroid ultrasonography (US) is the most sensitive method for detecting thyroid nodules, and US-guided aspiration biopsy is the most accurate diagnostic procedure for thyroid nodules. We performed this retrospective study to establish the prevalence of thyroid nodules in Graves' disease and patients with Hashimoto's thyroiditis at the time of their initial visit. METHODS: We performed thyroid US as routine screening in 1652 patients with Graves' disease and 2036 Hashimoto's thyroiditis and performed US-guided fine-needle aspiration biopsy when the diameter of a nodule >1 cm or a nodule was suspected of being malignant. RESULTS: The prevalence of papillary carcinoma in the patients with Hashimoto's thyroiditis was higher than in the patients with Graves' disease (1.77% vs. 0.97%), and two patients with Hashimoto's thyroiditis (0.098%) were found to have malignant lymphoma. Adenomatous lesions were observed more frequently in the patients with Hashimoto's thyroiditis than in the patients with Graves' disease. The prevalence of adenomatous lesions increased in an age dependent manner in both the patients with Graves' disease and those with Hashimoto disease; and adenomatous lesions were more frequent in younger patients with Hashimoto' s thyroiditis than in those with Graves' disease. CONCLUSIONS: The prevalence of both thyroid papillary cancer and adenomatous lesions was greater in the patients with Hashimoto's thyroiditis than in those with Graves' disease; and adenomatous lesions were more frequent in younger patients with Hashimoto's thyroiditis. We recommend performing US at the time of the initial visit in patients with autoimmune thyroid disease, who have a high prevalence of thyroid papillary carcinoma, to detect malignant thyroid tumors and adenomatous lesions. PMID- 20932182 TI - Enhanced liver regeneration following acute hepatectomy by low-level laser therapy. AB - OBJECTIVE: The aim of the present study was to investigate the effect of low level laser therapy (LLLT) on liver regeneration following hepatectomy. BACKGROUND: LLLT has been found to modulate various biological processes. MATERIALS AND METHODS: Twelve mature male rats were used. The liver was exposed, and 70% of it was excised. The rats were assigned randomly to two groups: control, non-laser treated, and experimental, laser-treated (diode [Ga-Al-As] laser 804 nm) group. For determination of newly formed blood vessels and proliferating cells, 5-Bromo-2'deoxyuridine (BrdU) was injected intraperitoneally. The rats were sacrificed 2 d post hepatectomy, and histological sections from each liver were processed for analysis of new blood vessel formation using BrdU immunostaining kit. Mesenchymal stem cells (MSCs) were assessed using c-kit immunostaining. BrdU-labeled cells were counted as for estimation of newly formed hepatic cells. RESULTS: It was found that the number of proliferating cells (BrdU positive cells) per area in the regenerating regions of the livers were significantly (p < 0.01) 2.6-fold higher in the laser-treated rats than in the control non-laser-treated rats. The density of the newly formed blood vessels and c-kit immunopositive cells in the regenerating area of the laser-treated livers was significantly (p < 0.01) 3.3- and 2.3-fold respectively higher than the control non-laser treated livers. CONCLUSION: It is concluded that LLLT following acute hepatectomy most probably stimulates a significant enhancement of liver regeneration conducive to both the formation of new hepatocytes and MSCs and angiogenesis in the regenerating liver. PMID- 20932183 TI - Influence of laser (lambda670 nm) and dexamethasone on the chronology of cutaneous repair. AB - OBJECTIVE: This study aimed to assess the effect of LLLT associated with and without dexamethasone on inflammation and wound healing in cutaneous surgical wounds. BACKGROUND: Limited studies are directed at the possible interference of laser photobiomodulation on the formation of myofibroblasts, associated with an antiinflammatory drug. METHODS AND MATERIALS: Standard skin wounds were performed on 80 Wistar rats, distributed into four groups: no treatment (sham group), laser only (lambda670 nm, 9 mW, 0.031 W/cm(2), 4 J/cm(2), single dose after surgery), dexamethasone only (2 mg/kg 1 h before surgery), and laser with dexamethasone. Tissue was examined histologically to evaluate edema, presence of polymorphonuclear, mononuclear cells, and collagen. The analysis of myofibroblasts was assessed by immunohistochemistry and transmission electron microscopy. The intensity was rated semiquantitatively. RESULTS: The results showed that laser and dexamethasone acted in a similar pattern to reduce acute inflammation. Collagen synthesis and myofibroblasts were more intense in the laser group (p = 0.048), whereas animals treated with dexamethasone showed lower results for these variables. In a combination of therapies, the synthesis of collagen and actin and desmin-positive cells was less than laser group. CONCLUSIONS: Laser was effective in reducing swelling and polymorphonuclear cells and accelerated tissue repair, even in the presence of dexamethasone. PMID- 20932184 TI - Effectiveness of non-ablative three dimensional (3D) skin rejuvenation: a retrospective study involving 46 patients. AB - BACKGROUND: Three dimensional (3D) skin rejuvenation is proposed to be effective for all skin layers. The aim of this concept is to treat sun spots with broad band pulse light; large pores, fine lines and vascular lesions with a long-pulsed 1064 nm neodymium-yttrium-aluminum-garnet (Nd:YAG) laser system and skin ptosis and laxity with a 1100-1800 nm infrared light source. OBJECTIVE: In this study, 46 patients treated with the 3D skin rejuvenation procedure were retrospectively evaluated to assess the effectiveness of the 3D procedure according to both patient and doctor satisfaction. METHODS: The 3D procedure was carried out over the course of five sessions with 15 day intervals between sessions. Results were judged by an experienced laser dermatologist both by direct patient examination and by comparison of "before" and "after" photographs. Results were ranked into five categories ranging from 0 to 4. At the final control, the patients were also asked to rate their satisfaction with the procedure in five categories, ranging from 0 to 4. RESULTS: All of our patients showed improvement, with an overall patient satisfaction score of 2.65. Female patients were more satisfied than male patients. Patient and doctor satisfaction scores were generally correlated. CONCLUSIONS: Our clinical results indicate that the 3D procedure is an effective nonsurgical skin rejuvenation method. PMID- 20932185 TI - Effect of laser (670 nm) on healing of wounds covered with occlusive dressing: a histologic and biomechanical analysis. AB - OBJECTIVES: To analyze the effects of low-level laser therapy (LLLT), 670 nm, with doses of 4 and 7 J/cm(2), on the repair of surgical wounds covered by occlusive dressings. BACKGROUND DATA: The effect of LLLT on the healing process of covered wounds is not well defined. MATERIALS AND METHODS: For the histologic analysis with HE staining, 50 male Wistar rats were submitted to surgical incisions and divided into 10 groups (n = 5): control; stimulated with 4 and 7 J/cm(2) daily, for 7 and 14 days, with or without occlusion. Reepithelization and the number of leukocytes, fibroblasts, and fibrocytes were obtained with an image processor. For the biomechanical analysis, 25 rats were submitted to a surgical incision and divided into five groups (n = 5): treated for 14 days with and without occlusive dressing, and the sham group. Samples of the lesions were collected and submitted to the tensile test. One-way analysis of variance was performed, followed by post hoc analysis. A Tukey test was used on the biomechanical data, and the Tamhane test on the histologic data. A significance level of 5% was chosen (p <= 0.05). RESULTS: The 4 and 7J/cm(2) laser with and without occlusive dressing did not alter significantly the reepithelization rate of the wounds. The 7 J/cm(2) laser reduced the number of leukocytes significantly. The number of fibroblasts was higher in the groups treated with laser for 7 days, and was significant in the covered 4 J/cm(2) laser group. CONCLUSIONS: Greater interference of the laser-treatment procedure was noted with 7 days of stimulation, and the occlusive dressing did not alter its biostimulatory effects. PMID- 20932186 TI - Low-level laser intensity application in masseter muscle for treatment purposes. AB - OBJECTIVE: This study evaluated with histochemical analysis how the number of laser applications can affect the masseter muscle. BACKGROUND: In dentistry today, the laser is used in patients with temporomandibular disorders (TMDs), mainly for radiating pain in the masticatory muscles, whose origins may be associated with malocclusion, although the laser effects are not well understood on the cellular level. MATERIALS AND METHODS: Thirty mice (HRS/J lineage) were randomly distributed into groups according to the number of laser applications (three, six, and 10). For each group of laser applications (experimental, n = 5), it was considered the control group (n = 5), which was not irradiated. All animals inhaled halothane (2-bromo-2-chloro-1, 1, 1-trifluoroethane, minimum 99%, Sigma Aldrich, India) before each laser irradiation performed on the left masseter muscle region, on alternate days with 20 J/cm(2), 40 mW, for 20 sec. The muscle samples were collected for histochemical analysis with succinate dehydrogenase (SDH) enzyme 72 h after the last application. RESULTS: (a) A decrease in area of light fibers type (35.91% +/- 6.9%; 32.08% +/- 6.3%, and 27.88% +/- 6.3%), according to the increase of laser applications (p < 0.05); (b) significant increase (p < 0.05) in the area of intermediate fibers, with an increase of laser application (11.08% +/- 3.9%; 16.52% +/- 5.7%, and 15.96% +/- 3.9%), although the increase with 10 applications was small; (c) area increase of dark fibers in the group with three laser applications (0.16% +/- 0.3%) (p < 0.05), and in groups with six and 10 laser applications, respectively (9.68% +/- 6.0% and 9.60% +/- 4.0%). CONCLUSIONS: The SDH enzyme activity revealed that the number of laser applications increases the metabolic pattern of the muscle fibers. A minimal difference in metabolic activity between six and 10 applications of a laser suggests that further analyses should be done to confirm that six applications are enough to produce the same clinical effects, thereby contributing data to professionals from different fields in regard to the cost benefit ratio of this therapy. PMID- 20932187 TI - Effects of ozone and ND:YAG laser pretreatment on bond strength of self-etch adhesives to coronal and root dentin. AB - OBJECTIVES: The aim of this study was to evaluate the effects of two different disinfection treatments--ozone and Nd:YAG laser application--on shear-bond strength (SBS) of self-etch adhesives to coronal and root dentin. MATERIALS AND METHODS: Sixty extracted human canines were ground flat, exposing the coronal and root dentin surfaces, and randomly divided into three groups. The surfaces were untreated (Control) or treated with ozone (HealOzone, KaVo) or Nd:YAG laser (Fidelis III, Fotona). Coronal and root dentins of 10 teeth of each group were treated with a two-step self-etch adhesive (Clearfil SE Bond, Kuraray Medical; SE), whereas the remaining 10 teeth were treated with a one-step self-etch adhesive (Clearfil Tri-S Bond, Kuraray Medical; S3). A resin composite (Clearfil Majesty Esthetics, Kuraray Medical) was then placed, and SBS was tested with a universal testing machine. Failure modes were determined under a stereomicroscope. The mean SBS values of each group were calculated, and data were subjected to statistical analysis (p = 0.05). RESULTS: For the coronal dentin, Control/SE showed significantly higher values than Control/S3, Ozone/S3, and Nd:YAG/S3. Although Ozone/SE showed significantly higher values than Nd:YAG/S3 (p < 0.05), the differences within the other groups were not significant for the root dentin (p > 0.05). Comparison of two dentin substrates in each group did not show any significant difference except for Control/SE, in which coronal dentin showed higher SBS. The failure modes of all groups were mainly adhesive. CONCLUSION: Pretreatments with Ozone or Nd:YAG laser did not impair the SBS of both of the self-etch adhesives used to coronal and root dentin. PMID- 20932188 TI - Stem cell research Italy: genesis of a society. PMID- 20932189 TI - Immediate effect of acupuncture at Sanyinjiao (SP6) and Xuanzhong (GB39) on uterine arterial blood flow in primary dysmenorrhea. AB - OBJECTIVE: The objective of this study was to compare immediate effect of acupuncture at SP6 on uterine arterial blood flow in primary dysmenorrhea with that of GB39. DESIGN: This was a prospective, randomized clinical trial. SETTING: Sixty-six (66) patients with primary dysmenorrhea from the Affiliated Hospital of Shangdong University of Traditional Chinese Medicine were recruited. INTERVENTIONS: The SP6 group (n =32) was treated with manual acupuncture at bilateral SP6 for 5 minutes after obtaining needling sensation (de qi) during the period of menstrual pain, whereas the control group (n = 34) was needled at GB39 of both sides for 5 minutes when they suffered menstrual pain. MAIN OUTCOME MEASURES: Differences in pulsatility index (PI), resistance index (RI), and ratio of systolic peak and diastolic peak (A/B) in uterine arteries were the main outcome measures. RESULTS: Highly significant reductions were observed in the SP6 treatment group 5 minutes after treatment in menstrual pain scores (8.17 +/- 1.90 versus 11.20 +/- 2.66; p < 0.001), values of PI (1.75 +/- 0.48 versus 2.32 +/- 0.70; p < 0.001), RI (0.72 +/- 0.11 versus 0.78 +/- 0.07; p < 0.001), and A/B (4.33 +/- 1.37 versus 5.23 +/- 1.67; p < 0.001). Compared with the GB39 control group, patients in the SP6 treatment group showed significant reductions in 5 minutes after treatment in the changes of menstrual pain scores (3.03 +/- 2.36 versus 0.00 +/- 0.29; p < 0.001), values of PI (0.57 +/- 0.42 versus -0.10 +/- 0.58; p < 0.001), RI (0.06 +/- 0.08 versus -0.03 +/- 0.15; p < 0.01), and A/B (0.90 +/- 0.87 versus 0.23 +/- 1.02; p < 0.01). There were no significant changes in menstrual pain scores, values of PI, RI, or A/B before and after treatment in the GB39 control group (p > 0.05). No adverse events from treatment were reported. CONCLUSIONS: This study suggests that needling at SP6 can immediately improve uterine arterial blood flow of patients with primary dysmenorrhea, while GB39 does not have these effects. PMID- 20932190 TI - Robot-assisted laparoscopic sacral colpopexy: initial experience in a high-volume laparoscopic reference center. AB - PURPOSE: To describe the surgical technique of robot-assisted sacral colpopexy (RASCP) and to assess its feasibility and safety in a high-volume laparoscopic center. PATIENT AND METHODS: 12 women with symptomatic urogenital prolapse with or without concomitant urinary stress incontinence were treated with RASCP by one surgeon at our institution. The preoperative workup involved a detailed urologica and gynecologic history and physical examination to determine the type, the degree of the prolapse and the presence of concomitant stress urinary incontinence. RESULTS: Mean operative time was 144 minutes (range 120-180 min). No conversion to a laparoscopic or open procedure was necessary. The mean patient age was 57.1 years old (range 44-79). The mean estimated blood loss was 60 mL (range 20-200 mL). The mean catheterization time was 2 days, and the mean hospital stay was 3.4 days (range 3-4 d). At a mean follow-up of 19.1 months (range 8-28 mos), no recurrence of the prolapse occurred. CONCLUSION: RASCP for treatment of patients with urogenital prolapse is a feasible alternative to open and laparoscopic procedures. It procures an anatomic repositioning of the pelvic organs. The short-term results and the complication rates are similar with gold standard techniques. PMID- 20932191 TI - The influence of ultrasound probe orientation on prostate cancer detection rate during transrectal ultrasonography-guided prostate biopsy. AB - PURPOSE: We aim to determine whether end-fire probe orientation (and therefore image orientation and biopsy needle direction) during transrectal ultrasonography guided prostate biopsy has an effect on the prostate cancer (PCa) detection rate, the number of positive biopsy cores, the proportion of diseased tissue in the samples obtained, and the Gleason score. We compared two different axial image protocols and a sagittal image protocol for PCa yield. We hypothesize that axial probe methods direct more of the biopsy needle through the peripheral zone, the principal site for PCa, and therefore improve PCa yield. PATIENTS AND MATERIALS: A total of 441 patients underwent systematic 12-core biopsy using three different methods by six radiologists at our institution. An axial method using probe angulation, an axial method using probe rotation, and a sagittal method were compared. RESULTS: The axial-angulation method was used in 166 men, the axial rotation method was used in 125 men, and the sagittal method was used in 150 men. Overall, 58.3% had PCa detected. Axial-rotation techniques showed a 17% greater PCa yield and significantly increased the number of positive biopsy cores relative to the sagittal method (P < 0.001) for all patients and for those with a prostate-specific antigen level <10 ng/mL. Of those with PCa, the number of positive cores, proportion of diseased tissue, and Gleason score were also significantly elevated using this technique (P < 0.05). CONCLUSION: This study suggests that axial techniques have the potential to increase carcinoma yield and Gleason score, through a greater yield in positive core number and proportion of diseased tissue in the samples obtained. PMID- 20932192 TI - Microsomal epoxide hydrolase gene polymorphisms and susceptibility to chronic obstructive pulmonary disease in the Tunisian population. AB - It is well known that cigarette smoking is the major risk factor for chronic obstructive pulmonary disease (COPD). However, only 10%-20% of chronic heavy cigarette smokers develop symptomatic disease, which suggests the presence of genetic susceptibility. Microsomal epoxide hydrolase (EPHX1) is an enzyme involved in the protective mechanism against oxidative stress. It has been reported that gene polymorphisms of this enzyme may be associated with variations in EPHX1 activity. In this study, we aimed at investigating the relationship between EPHX1 polymorphisms and susceptibility to COPD in the Tunisian population. EPHX1 exon 3 (rs1051740, Tyr113His) and exon 4 (rs2234922, His139Arg) polymorphisms were genotyped by polymerase chain reaction followed by restriction fragment length polymorphism analysis. These techniques were used to examine a total of 416 Tunisian individuals, including 182 blood donors and a group of 234 COPD patients. All subjects were not related. An increased risk for COPD was observed in subjects with EPHX1 His113-His113 genotype (odds ratio = 2.168; confidence interval 1.098-4.283; p = 0.02386). However, multivariate logistic regression analysis showed no significant relationship between the mutant genotype and the disease after adjustment for sex, age, body mass index, smoking status, and pack-year smoking (odds ratio = 1.524; confidence interval, 0.991 6.058; p = 0.06137). Regarding the two subtypes of COPD, our investigations demonstrated that there is no significant correlation between exon 3 polymorphism and the chronic bronchitis subgroup (p = 0.09034). The relation between exon 3 polymorphism and emphysema was significant in the univariate analysis (p = 0.02257), but no association was found after controlling for classic risk factors (p = 0.06273). In conclusion, our results showed that there is a weak relation between 113His genotype and COPD, and no apparent relation between 139Arg and COPD in the studied Tunisian population. PMID- 20932193 TI - An Internet misadventure: bloodroot salve toxicity. AB - INTRODUCTION: Bloodroot (Sanguinaria canadensis) is a perennial flowering plant native to North America. Sanguinarine, a benzylisoquinoline alkaloid, is a powerful escharotic contained in the root. Herbalists prescribe bloodroot for multiple conditions including skin lesions and sore throats. We report 2 patients who treated skin lesions with bloodroot to untoward effect. CASE REPORT 1: A 53 year-old man with unremarkable medical history developed a 5-mm papule on his chest that gradually blackened. The patient searched the Internet for "herbal cures" and found bloodroot salve as a therapy for skin lesions. The patient applied bloodroot black salve for 10 days. After 6 months the remaining lesion resumed increasing in size. The patient restarted bloodroot treatments despite intense pain. After 6 weeks the lesion doubled, became ulcerated and purulent, prompting presentation to the Emergency Department. Pathological examination of the lesion revealed malignant melanoma. CASE REPORT 2: A 42-year-old man with a history of metastatic colon cancer developed palpable subcutaneous nodules on the anterior abdominal wall. The patient's mother searched the Internet for cancer salves and purchased black and yellow bloodroot salve. After 8 days, feces were noted discharging from an ulcer where the salve was applied. The patient was admitted for total parenteral nutrition until the enterocutaneous fistula healed. DISCUSSION: Bloodroot is widely available on the Internet and easily purchased. Web sites discuss the efficacy of bloodroot in treating skin cancer. The cases describe attempts to self-treat skin lesions with unregulated Internet therapy. Lack of regulation of information on the Internet allows alternative therapies to be promoted without full consideration of potential toxicity. Greater awareness of agents with such potential for danger needs to be available to health care providers, and the taking of such remedies should always be discussed with the supervising physician. PMID- 20932194 TI - Radioprotective effects of Aegle marmelos (L.) Correa (Bael): a concise review. AB - The effective use of radiotherapy in cancer cure and palliation is compromised by the side-effects resulting from radiosensitivity of bordering normal tissues, which are invariably exposed to the cytotoxic effects of ionizing radiation during treatment. In this situation, use of radioprotective compounds that can protect normal tissues against radiation injury are of immense use. In addition to protecting normal tissue these compounds will also permit use of higher radiation doses to obtain better cancer control and possible cure. However, to date, no ideal radioprotectors are available as most synthetic compounds are toxic at their optimal concentrations and have produced little success in clinics. Radiation ill-effects are principally the result of generation of free radicals, and the antioxidant compounds that counter them are supposed to be of immense use in preventing them. In Ayurveda, the traditional Indian system of medicine, several plants have been observed to avert/ameliorate free radical mediated ailments--an effect that has been documented--and such plants have recently been the focus of attention. Aegle marmelos (L.) Correa (Bael), commonly known as bael, has been used since antiquity for treating various ailments, some of which are now known to be the result of oxidative stress. In studies spanning nearly a decade, it has been observed that bael prevented radiation-induced ill effects, and the results of these studies indicate that it has the potential to be an effective, nontoxic radioprotective agent. In this current review, for the first time, an attempt is made to summarize these observations and to discuss the plausible reasons responsible for bael's radioprotective effects. PMID- 20932195 TI - A systematic review of randomized controlled trials using music therapy for children. AB - BACKGROUND: Music therapy is a promising approach widening the potential applications of psychotherapy. Music influences both, psychologic and physiologic parameters, and children are especially responsive to this form of therapy. Many aspects of its action mechanisms remain to be elucidated, underscoring the need for evidence-based medicine (EBM) for clinical use of music therapy. AIMS: This review seeks to highlight some of the issues of music therapy research and to initiate a discussion about the need for international multicenter cooperation to bring scientifically sound evidence of the benefits of music therapy in pediatric patients. METHODS: Scientific bibliographic databases were searched for randomized controlled trials on use of music therapy for children. Identified articles were evaluated according to criteria for scientific quality. RESULTS: Twenty-eight studies were identified. Most of the trials were biased by the number of participants, and some trials showed the need to improve design of control groups. Indeed, the novelty of this area of study has produced a large number of different studies (with variability in diagnoses, interventions, control groups, duration, and/or outcome parameters), and there is a need for a more homogeneous and systematic approach. Available studies highlight the need to address reproducibility issues. CONCLUSIONS: This analysis identifies the need for a subsequent series of clinical studies on the efficacy of music in the pediatric population, with more focus on eligibility criteria with respect to EBM and reproducibility. PMID- 20932196 TI - Bilateral posterior scleritis: an idiopathic painless presentation. AB - PURPOSE: To describe a presentation of painless posterior scleritis. METHODS: This study was an interventional case report. An 18-year-old boy was admitted to the authors' clinic with symptoms of low degree of vision and no ocular pain. Ophthalmologic examination, ocular ultrasonography, magnetic resonance imaging, fundus fluorescein angiography (FFA), optical coherence tomography (OCT), thoracic radiography, abdominal sonography, and laboratory testing were carried out and the results were evaluated. RESULTS: OCT revealed bilateral exudative retinal detachment. Diffuse bilateral posterior scleral thickening and serous retinal detachment were found in B-scan ultrasonography, suggesting posterior scleritis. Laboratory findings and imaging disclosed no systemic disease. The patient responded to oral prednisolone 60 mg once daily. CONCLUSIONS: The case reported here indicates that pain is not always present in posterior scleritis. PMID- 20932197 TI - Acute superior mesenteric artery syndrome and pancreatitis in anorexia nervosa. AB - OBJECTIVE: The aim of this paper is to describe the presentation and clinical management of a patient with anorexia nervosa complicated by superior mesenteric artery syndrome and pancreatitis, and discuss the association between these conditions. METHOD: We present a case report and briefly review the relevant literature. RESULTS: A 17-year-old girl with undiagnosed anorexia nervosa presented acutely with abdominal symptoms and vomiting. After numerous investigations, she was diagnosed with the rare condition of superior mesenteric artery syndrome and pancreatitis, leading to a prolonged hospital admission and management on both an acute medical/surgical ward and an eating disorders unit. CONCLUSIONS: Anorexia nervosa has been associated with superior mesenteric artery syndrome and pancreatitis. Clinical awareness of these conditions can result in prompt diagnosis and optimal management of these patients. PMID- 20932198 TI - Mind the evidence gap: do we have any idea about how to integrate the treatment of anorexia nervosa into the Australian mental health context? AB - OBJECTIVE: The aim of this paper is to review recent developments in the treatment of anorexia nervosa (AN) and how this translates to clinical and population-based care in the Australian context. CONCLUSIONS: Overall, there is a paucity of high-quality research into treatments for AN, albeit that a number of biological and psychological interventions show promise as avenues for further research. There are significant impediments to the provision of comprehensive longitudinal care for people with AN within Australian mental health services. Evaluation of novel strategies, such as home-based support, is required as part of enhancing options for Australians suffering with AN and their families. PMID- 20932199 TI - Dementia in Aboriginal Australians. PMID- 20932200 TI - Young rural people at risk for schizophrenia: time for mental health services to translate research evidence into best practice of care. AB - Early intervention into prodromal schizophrenia has shown promise, but controversy continues regarding the ethical acceptability of identifying a group of 'ultra high risk' individuals of whom only 30 to 50% will develop a psychotic disorder. With well developed early intervention services this group faces the possibility of being labelled as 'pre-psychotic', a condition for which the well known stigma associated with the diagnosis of schizophrenia or bipolar disorder is likely to be associated. In addition, the use of potent antipsychotic and other medications (albeit usually at lower doses than those used for those with manifest psychosis) mandates consideration of the risks associated with their use and neurological and metabolic side effects. The potential for iatrogenic morbidity in the 'false positive' group must be weighed against the need of the 'true positives' identified through screening and assessment. Current evidence for the concept of 'at-risk mental state' was reviewed within a neurodevelopmental framework, including emerging data on the effectiveness of early intervention for the purpose of providing recommendations for community mental health services. The review suggests that different treatment strategies may be appropriate depending on the clinical stage of the condition as long as the benefits of intervention outweigh its risk burden. It further suggests that the severity of psychoses and the evidence of its early onset in utero and its acceleration in adolescence positions 'ultra high risk' intervention as a core model for early intervention for young people by teasing apart the symptomatic components of the 'prepsychotic state' and ensuring the population is reaching targeted mental health services for screening. The model is not restricted to the delivery of intervention for 'pre-psychotic' young people but is applicable for targeted programmes for a number of clinical groups considered at 'ultra high risk'. However, only further research in naturalistic populations embedded in clinical practice and ideally conducted in partnership of mental health services with academic research institutions will help clarify potential risks of early identification and intervention and assist in updating and making more explicit the clinical guidelines services will use in approaching those in the 'ultra high risk' group. PMID- 20932201 TI - Organ transplantation and magical thinking. AB - Organ transplantation can provide important treatment benefits in a variety of situations. While a number of live donor procedures are now possible, procurement of organs from dead donors remains the mainstay of transplant programmes. However, cadaveric donation rates remain much lower than anticipated, and some patients who receive organs struggle to adapt to their new body. The reasons for this are not entirely explained by rational or logical means. This paper uses concepts drawn from magical thinking to try to explain some of the less apparent issues at play within the process of cadaveric organ transplantation, including both the donation and receiving of organs. Three themes are explored as potentially relevant: superstitions and rituals around death and the dead body, incorporation and the meanings attached to the transplanted organ, and survivor guilt. All three are shown to be relevant for some part of the transplantation process in at least a minority of cases. It is therefore suggested that focusing not only on the logical and scientific, but also on the ambiguous and magical may enhance the organ donation process and thus increase donation rates and the psychological adjustment of transplant recipients. PMID- 20932202 TI - Factors associated with dementia in Aboriginal Australians. AB - OBJECTIVE: Although the prevalence of dementia in remote living Aboriginal Australians is one of the highest in the world, the factors associated with dementia in this population are yet to be examined. This study was designed to determine the demographic, lifestyle and clinical factors associated with dementia in Aboriginal Australians living in the Kimberley region of Western Australia. METHOD: A total of 363 Aboriginal Australians aged over 45 years from the Kimberley region were selected by semi-purposeful sampling. The factors analysed for association with dementia were age, sex, education, smoking, chewing tobacco, alcohol, head injury, heart disease, hypertension, diabetes, previous stroke, epilepsy, falls, mobility, incontinence, urinary problems, vision and hearing. This exposure data was collected from participants' and informants' reports using the Kimberley Indigenous Cognitive Assessment and specialist review, and medical records. RESULTS: Factors associated with dementia included older age, male gender (OR 3.1, 95%CI 1.4, 6.8) and no formal education (OR 2.7, 95%CI 1.1, 6.7) and after adjusting for age, sex and education, dementia was associated with current smoking (OR 4.5, 95%CI 1.1, 18.6), previous stroke (OR 17.9, 95%CI 5.9, 49.7), epilepsy (OR 33.5, 95%CI 4.8, 232.3), head injury (OR 4.0, 95%CI 1.7, 9.4), and poor mobility, incontinence and falls. CONCLUSIONS: Interventions aimed at better management or prevention of the modifiable factors identified could reduce dementia risk in Aboriginal populations. PMID- 20932203 TI - Acceptability of an emotional and behavioural screening tool for children in Aboriginal Community Controlled Health Services in urban NSW. AB - OBJECTIVE: To assess the acceptability and face validity of the Strengths and Difficulties Questionnaire (SDQ) in Aboriginal community controlled health services (ACCHOs) located in the greater Sydney region. METHODS: A qualitative study was conducted in three ACCHOs located within the greater Sydney region in 2008-2009. A semi-structured approach was used in focus groups and small group interviews (n = 47) to elicit participants' views on the appropriateness of the SDQ and any additional issues of importance to Aboriginal child and adolescent mental health. RESULTS: The SDQ was found to cover many important aspects of Aboriginal child and adolescent mental health, however, the wording of some questions was considered ambiguous and some critical issues are not explored. The peer relationships subscale did not appear to fit well with Aboriginal concepts of the relative importance of different interpersonal relationships. CONCLUSION: Overall the SDQ was acceptable in ACCHOs in Sydney; however, changes to the wording of some questions and the response scale may be indicated to improve cultural appropriateness and clarity. A further set of issues which are not covered by any commonly used screening tools but are of critical importance to Aboriginal child and adolescent mental health should also be considered by clinicians. PMID- 20932204 TI - Changes in the prevalence of major depression in an Australian community sample between 1998 and 2008. AB - OBJECTIVE: To identify changes in the prevalence of major depression between 1998, 2004 and 2008 in South Australia. METHODS: Face-to-face Health Omnibus surveys were conducted in 1998, 2004 and 2008 with approximately 3000 participants aged 15 years and over, who were random and representative samples of the South Australian population. Each survey used the same methodology. Outcome measures were: major depression as detected by the Mood module of the Primary Care Evaluation of Mental Disorders instrument; mental health literacy by recognition and exposure to classical symptoms of depression; and health status using the SF-36 Physical and Mental Component summaries. RESULTS: There was a significant increase in the prevalence of major depression from 6.8% (95%CI: 5.9% 7.7%) to 10.3% (95%CI: 9.2%-11.4%; chi2 24.59, p < 0.001) between 1998 and 2008. Significant increases were observed in males aged 15-29 and females aged 30-49 years. There was no significant increase in any other sub-group. The strongest predictor of major depression was health status. Participants with poor/fair mental health literacy were 37% less likely to be classified with major depression. CONCLUSIONS: The prevalence of major depression increased significantly in South Australia over the last decade and there was a reduction in mental health status and an increase in persons reporting poor health. Unexpectedly, having poor or fair mental health literacy was significantly protective for major depression. Ideally, public health initiatives should result in an improvement in health, but this did not appear to have occurred here. PMID- 20932205 TI - Treatment outcomes and predictors of drop out for problem gamblers in South Australia: a cohort study. AB - OBJECTIVES: Recent prevalence studies in Australia, the USA and Canada have estimated 1-2% of the adult population meet the diagnostic criteria for problem or pathological gambling. The Statewide Gambling Therapy Service (SGTS) provides treatment for problem gamblers in key metropolitan and rural regions in South Australia. The aims of this study were two-fold: to analyse the short and mid term outcomes following treatment provided by SGTS and to identify factors associated with treatment drop-out. METHOD: A cohort of treatment seeking problem gamblers was recruited through SGTS in 2008. Repeated outcome measures included problem gambling screening, gambling related cognitions and urge. Treatment drop out was defined as participants attending three or less treatment sessions, whilst potential predictors of drop-out included perceived social support , anxiety and sensation-seeking traits. RESULTS: Of 127 problem gamblers who participated in the study, 69 (54%) were males with a mean age of 43.09 years (SD = 12.65 years) and with 65 (52%) reporting a duration of problem gambling greater than 5 years. Follow up time for 50% of participants was greater than 8.9 months and, overall, 41 (32%) participants were classified as treatment drop-outs. Results indicated significant improvement over time on all outcome measures except alcohol use for both treatment completers and drop-outs, although to a lesser extent for the treatment drop-out group. A significant predictor of treatment drop-out was sensation-seeking traits. CONCLUSION: These results will inform future treatment planning and service delivery, and guide research into problem gambling including aspects of treatment drop-out. PMID- 20932206 TI - Factors associated with medication non-adherence in patients suffering from schizophrenia: a cross-sectional study in a universal coverage health-care system. AB - OBJECTIVE: To quantify the factors associated with non-adherence to medication among stable patients suffering from schizophrenia in the context of universal access to care. METHODS: This naturalistic, multicentric study was conducted in 15 French public hospitals in a region of south-eastern France during a 1 week period in 2008. All consecutive outpatients with stable schizophrenia were recruited. Adherence was assessed with the 10-item Drug Attitude Inventory (DAI). Measures included socio-demographic characteristics, clinical characteristics, insight using the Scale to assess Unawareness of Mental Disease (SUMD), and therapeutic alliance using the Patient Session Questionnaire (PSQ). Regression models were used to identify the risk factors associated with non-adherence. RESULTS: The study included 291 patients, 30% of whom were considered to be non adherent. Non-adherence increased with duration of untreated psychosis (DUP) (OR = 1.12, 95%CI = 1.03-1.22), lack of insight only for the dimension 'effect of medication' (OR = 3.23, 95%CI = 1.05-9.89), and a low level of therapeutic alliance (OR = 0.45, 95%CI = 0.32-0.64). Individuals prescribed atypical antipsychotic drugs were more likely to be adherent than those prescribed typical antipsychotics (OR = 0.37, 95%CI = 0.13-1.0). CONCLUSIONS: DUP, prescription of typical antipsychotics, therapeutic alliance and insight were the most important features associated with non-adherence. This study also suggests that economic factors such as the service delivery system should not be neglected in public strategies aimed at addressing problems of non-adherence in non-universal coverage health systems. PMID- 20932207 TI - Who cares? A profile of people who care for relatives with a mental disorder. AB - OBJECTIVE: To profile the Australian adults who are caring for a relative with a mental disorder. METHOD: Data came from the 2007 National Survey of Mental Health and Wellbeing 2007 (NSMHWB), a nationally representative household survey of 8841 individuals aged between 16 and 85 years. RESULTS: Many people act as carers: 15% of the Australian adult population, or nearly 2.4 million individuals. The strongest predictors of being a carer are being female and being in a relatively older age bracket. Carers provide a range of emotional and practical supports to close relatives with a range of mental disorders, most notably high prevalence disorders. Their relatives' health problems cause them considerable worry, anxiety and depression, and their caring role can be associated with high financial costs. CONCLUSIONS: Carers are significant stakeholders in the mental health system. Providing support for carers is crucial, particularly because their own mental health and well-being may be affected by their care-giving role. The nature of this support should take into account their large numbers, their profile and the role they perform. PMID- 20932208 TI - Randomized controlled trial of Internet cognitive behavioural treatment for social phobia with and without motivational enhancement strategies. AB - OBJECTIVE: The present study (Shyness 7) has two aims: Firstly, to replicate an earlier trial showing that a self-guided Internet treatment for social phobia is efficacious, and secondly, to examine whether the addition of self-guided motivational enhancement strategies improves completion rates and clinical outcomes. METHOD: Randomized controlled trial (RCT) of self-guided Internet-based cognitive behavioural treatment (iCBT), or iCBT plus self-guided motivational enhancement strategies (iCBT+MS), was conducted. An intention-to-treat and last observation carried forward model was used for data analyses. The participants consisted of 108 volunteers with social phobia. The iCBT intervention consisted of two online lessons about symptoms and treatment of anxiety disorders and six lessons about management of social phobia (the Shyness programme) with complex automated reminders. The motivational intervention was based on traditional techniques including understanding and exploring ambivalence about change using a cost-benefit analysis, developing and resolving discrepancy between values and symptoms, and enhancing self-efficacy for change. The main outcome measures were the Social Interaction Anxiety Scale and Social Phobia Scale. RESULTS: More iCBT+MS group participants completed the eight lessons than iCBT group participants (75% versus 56%, respectively), but there were no between-group differences in outcome measures at post-treatment or at 3 month follow up. Large mean within-groups effect sizes (Cohen's d) for the two social phobia measures were found for both the iCBT and iCBT+ MS groups (1.1 and 0.95, respectively), which were sustained at 3 month follow up (1.06 and 1.07, respectively). Both iCBT and iCBT+MS group participants reported that the procedures were highly acceptable. CONCLUSIONS: Both self-guided versions of the Shyness programme were reliably efficacious, confirming that people with social phobia may significantly benefit from a highly structured self-guided intervention. The addition of motivational techniques increased completion rates but did not improve clinical outcomes or acceptability. PMID- 20932209 TI - Patterns of alcohol use and associated physical and lifestyle characteristics according to new Australian guidelines. AB - OBJECTIVE: To describe the pattern of alcohol consumption and associated physical and lifestyle characteristics in a population-based sample of Australian men. METHOD: A community-based age-stratified random sample of 1420 men (median age 56 years, range 20-93) participating in the Geelong Osteoporosis Study, an epidemiological study set in south-eastern Australia. Daily alcohol intake was ascertained from a detailed food frequency questionnaire and categorized according to the Australian National Health and Medical Research Council 2009 guidelines (non-drinkers, greater than zero but <= 2 drinks per day, > 2 drinks per day), with a standard drink equivalent to 10 g of ethanol. Anthropometry was measured and lifestyle factors self-reported. Body composition was determined using dual energy absorptiometry. Socio-economic status was categorized according to the Australian Bureau of Statistics data. Results were age standardized to the Australian male population figures. RESULTS: The median daily ethanol consumption was 12 g (IQR 2-29) per day with a range of 0-117 g/day. The age-standardized proportion of non-drinkers was 8.7%, 51.5% consumed up to two drinks per day (<= 20 g ethanol/day), and 39.9% exceeded 2 standard drinks per day (> 20 g ethanol/day). Alcohol consumption was positively associated with cigarette smoking, weight, higher SES and inversely with age and physical activity. CONCLUSIONS: Approximately, 40% of Australian men consume alcohol at levels in excess of current recommendations, which in combination with other risk factors may adversely impact upon health. PMID- 20932210 TI - Relationship between subjective experiences and psychopathological dimensions in schizophrenia. AB - OBJECTIVE: Subjective experiences are subtle, self-experienced disturbances, a thorough description of which is provided within the framework of the concept of basic symptoms. Recent studies have shown that subjective experiences have important diagnostic implications for schizophrenia and related disorders. The purpose of the present study was to examine the relationship between subjective experiences and psychopathological dimensions in schizophrenia. METHOD: Sixty seven outpatients with schizophrenia were evaluated. Subjective experiences were comprehensively assessed using the Frankfurt Complaint Questionnaire (FCQ). Symptoms of schizophrenia were evaluated using the Manchester Scale (MS). Pearson's partial correlation analysis was performed between the FCQ and the MS scores, controlling for the influence of extrapyramidal adverse effects. RESULTS: The analysis revealed that the MS positive symptom score had significant positive correlations with the FCQ total score and subscales scores. The MS negative symptom score did not have significant correlations with the FCQ scores. CONCLUSIONS: The results of our study suggest that subjective experiences are significantly associated with positive symptomatology in schizophrenia, suggesting that they may share a common underlying neural basis. Future prospective studies are necessary to confirm the stability of these relationships and to explore the diagnostic and therapeutic implications of subjective experiences in a diverse group of patients at different stages of illness. PMID- 20932211 TI - Mobile phones, suicide and prognostication. PMID- 20932212 TI - Khat concerns in Australia: hyperbole or understated? PMID- 20932214 TI - News from CROES: time for acknowledgment. PMID- 20932213 TI - Mortality, prescribing patterns and intensive case management in community mental health care. PMID- 20932215 TI - Laparoscopic radical versus laparoscopic partial nephrectomy for clinical T1bN0M0 renal tumors: comparison of perioperative, pathological, and functional outcomes. AB - AIM: To compare outcomes in patients treated with laparoscopic partial nephrectomy (LPN) and laparoscopic radical nephrectomy (LRN) for clinical T1bN0M0 renal masses. MATERIALS AND METHODS: Between 2002 and 2008, 33 and 52 consecutive patients who underwent LPN and LRN, respectively, for clinical stage T1bN0M0 tumors were retrospectively identified from a prospectively maintained database of 450 patients undergoing laparoscopic renal surgery. Perioperative, pathological, and postoperative outcomes were compared. RESULTS: The two groups of patients were similar in age, sex, and body-mass index. Mean radiographic tumor size was smaller (4.8 vs. 5.2 cm, p = 0.04) in the LPN group. Mean operative time (228 vs. 175 minutes, p < 0.0001) and mean estimated blood loss (233 vs. 112 mL, p = 0.003) were higher in the LPN group. Intraoperative complication rates of 15.2% versus 5.7% (p = 0.28) and postoperative complication rates of 24.2% versus 13.5% (p = 0.20) were observed in the LPN and LRN groups, respectively. Overall median follow-up was 15 and 21 months for the LPN and LRN cohorts, respectively. A 12.5% and 29.3% decline in estimated glomerular filtration rate was observed (p = 0.002), and 30.3% compared with 55.7% of patients developed an estimated creatinine clearance (eCrCl) < 60 mL/minutes after treatment (p = 0.04) for LPN and LRN, respectively. There were no differences in pathological stage distribution between the two groups. In the LPN group there were no local or systemic recurrences, and one positive surgical margin was observed. One patient developed metastatic disease in the LRN group. CONCLUSIONS: LPN for T1b renal tumors provides superior intermediate-term preservation of renal function compared with LRN. Continued follow-up of these patients is required to evaluate oncological outcomes. PMID- 20932221 TI - Prevention of breast cancer (Part II): risk reduction strategies. AB - Until recently, the best protection against breast cancer mortality was early diagnosis through mammographic screening. However, the possibility that breast cancer in some cases can be prevented has come to light over the past 30 years. Various risk reduction strategies of breast cancer have been explored including lifestyle modification, prophylactic surgeries, and the use of chemopreventive agents. This article is the second portion of a two-part series on breast cancer prevention, and will focus its discussion on the available risk reduction interventions that have been shown to prevent breast cancer in women considered high risk for the disease. (See Part I in Cancer Investigation, 28:743-750, 2010) PMID- 20932222 TI - Long-term safety of duloxetine during open-label compassionate use treatment of patients who completed previous duloxetine clinical trials. AB - PURPOSE: To provide duloxetine for the treatment of major depressive disorder (MDD), generalized anxiety disorder (GAD), fibromyalgia (FM) and diabetic peripheral neuropathic pain (DPNP) to patients who had previously completed a duloxetine clinical study and for whom, in the opinion of the investigator, no effective alternative therapy was available. METHODS: Adult outpatients who had previously completed a duloxetine study for the treatment of MDD, GAD, DPNP, or FM received duloxetine 30 mg to 120 mg daily up until its local commercial availability. Safety analyses included treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), AEs reported as reason for discontinuation, and vital signs. No efficacy measures were collected. RESULTS: Of 667 patients enrolled, 282 (42.3%) were still participating at the time the drug was made commercially available in their countries. Most patients had previously participated in a duloxetine MDD study (76.2%); were female (68.1%) and Caucasian (94.9%). The median duration of exposure was 328 days (range 3-1718 days). The most common reasons for discontinuation were patient decision (25.3%), adverse event (8.4%), and lack of efficacy (8.4%). Of the 86 SAEs experienced by 46 patients, most (including one death) were judged by the investigator to be unrelated to duloxetine treatment. The most common TEAEs were in the System Organ Class of gastrointestinal (28.3%), nervous system (28.0%), and psychiatric (25.8%) and were predominantly mild to moderate in severity. Increases of systolic blood pressure (1.9 mm Hg) and pulse rate (2.2 bpm) at endpoint were reported. CONCLUSION: The safety data from this long-term compassionate use study of duloxetine were consistent with previous experience and revealed no new safety signals. LIMITATIONS: The limitations include: lack of a control arm, no efficacy data were collected to assess the long-term efficacy, the results may not necessarily generalize to other ethnic groups as most patients were Caucasians, and lack of consistency in regard to duration of exposure at study entry as patients came from different trials with different study designs. CLINICAL TRIAL REGISTRY ID: www.clinicaltrials.gov--NCT00071708. PMID- 20932223 TI - A prospective, observational study describing the haematological response in patients undergoing chemotherapy treated by tri-weekly darbepoetin alfa for anaemia. AB - OBJECTIVE: This prospective, observational study investigated the haematological response to darbepoetin alfa (DA) administered every three weeks for the treatment of anaemia. Response was also assessed according to baseline characteristics including iron, folate and vitamin B12 status. RESEARCH DESIGN AND METHODS: Anaemic adult patients with malignant non-myeloid cancer, starting or having already undergone chemotherapy received DA on day of inclusionand were followed up for up to 24 weeks. Concentration of haemoglobin (Hb), as well as iron, vitamin B12 and folate status where available, were recorded at inclusion, after a treatment period of 9 weeks and up to a maximum of 24 weeks or cessation of DA treatment, whichever was sooner. MAIN OUTCOME MEASURES: The main outcome measure assessed in this study was the percentage of patients reaching a Hb concentration of at least 11 g/dL at least once at any time during the study. RESULTS: A total of 2912 patients were included. The mean Hb concentration increased from 10.0 g/dL at inclusion to 11.4 g/dL at 9 weeks and 11.8 g/dL at 24 weeks. In 74.6% of patients the target Hb level of 11.0 g/dL or above was reached. After initiation of DA treatment, 9.5% of patients required a blood transfusion by week 9, and 5.6% thereafter. Vitamin B12 and folate status were unknown for 80.3% of patients and the iron status for 73.2% of patients. Compared with patients who remained untreated for vitamin B12 or folate deficiency, a higher percentage of patients with vitamin status within normal limits achieved the target Hb concentration. However, achievement of target Hb level appeared not to be affected by iron status. CONCLUSIONS: In this study, the mean Hb level increased in anaemic cancer patients treated with DA and the majority of patients achieved the target Hb level. In contrast to the recommendations of guidelines (EORTC) encouraging the measurement of iron and vitamin levels, the present study demonstrated that data were not routinely collected for these factors. PMID- 20932224 TI - Oral salmon calcitonin--pharmacology in osteoporosis. AB - IMPORTANCE OF THE FIELD: Osteoporosis is a slow progressive disease with develops over decades, and where intervention is needed for an extended number of years. This highlights the need for safe intervention possibilities, which have sustained beneficial effects post-treatment. AREAS COVERED IN THIS REVIEW: Articles on salmon calcitonin appearing on Pubmed from 1960 until today, with focus on a newly developed oral formulation showing increased exposure and efficacy compared with nasal formulation is reviewed. The second half focuses on long-term phenomena, such as bone quality and resolution effects. The final part discusses potential additional benefits of salmon calcitonin. WHAT THE READER WILL GAIN: Insight into the clinical development of an orally formulated peptide, as well as a detailed understanding of why this approach could revive salmon calcitonin as a treatment for osteoporosis. TAKE HOME MESSAGE: The oral formulation of salmon calcitonin provides additional benefits and increased efficacy on bone based on Phase I and II clinical trials data, as compared with the nasal formulation. Hence, the results on the ongoing Phase III fracture trial are awaited with great interest. PMID- 20932225 TI - CD133(+) cells isolated from various sources and their role in future clinical perspectives. AB - BACKGROUND: CD133 is a member of a novel family of cell surface glycoproteins. Initially, the expression of CD133 antigen was seen only in the hematopoietic derived CD34(+) stem cells. At present, CD133 expression is demonstrated in undifferentiated epithelium, different types of tumors and myogenic cells. CD133(+) neurosphere cells isolated from brain are able to differentiate into both neurons and glial cells. These data suggested that CD133 could be a specific marker for various stem and progenitor cell populations. OBJECTIVES: The main goal would be to describe the role for CD133 as a marker of stem cells able to engraft and differentiate, to form functional non-hematopoietic adult lineages and contribute to disease amelioration via tissue regeneration. RESULTS/CONCLUSION: In conclusion, since the rise of CD133 antigen as a suitable stem cell marker, the possible use of CD133(+) stem cells in therapeutic applications has opened a new promising field in the treatment of degenerating diseases. The human circulating cells expressing the CD133 antigen behave as a stem cell population capable of commitment to hematopoietic, endothelial and myogenic lineages. CD133 cell therapy may represent a promising treatment for many diseases. PMID- 20932226 TI - Regulatory T cells in HBV and HCV liver diseases: implication of regulatory T lymphocytes in the control of immune response. AB - IMPORTANCE OF THE FIELD: Hepatic cirrhosis is a frequent consequence of chronic hepatitis infection (HBV and HCV) or alcohol abuse and the most common cause of hepatocellular carcinoma (HCC). Currently, liver transplantation remains the only effective therapeutic approach for cirrhosis-related HCC patients. The evolution of the pathology strongly depends on immunological mechanisms. AREAS COVERED IN THIS REVIEW: Despite the presence of specific T cells, viral chronic infection and continuous tumor growth suggest a failure of immune control. It appears that direct suppression of antiviral or antitumor effector cells by regulatory T cells plays a pivotal role in the impairment of immune response. Several types of regulatory T cells have been described, natural regulatory T cells (nTreg) and induced-type 1 regulatory T cells (Tr1) being the best characterized. WHAT THE READER WILL GAIN: Currently, there is no evidence for a direct implication of regulatory T cells in the evolution of hepatitis, especially concerning chronic infection, cirrhosis late stage and HCC progress. However, recent studies show that regulatory T cells are implicated in the modulation of HBV- and HCV associated immune response, thus, promoting HCC progress. TAKE HOME MESSAGE: Therefore, nTreg and Tr1 cells seem to play an important role in the control of immune response leading to chronic hepatitis infection and progression of the pathology to cirrhosis and HCC. PMID- 20932227 TI - The P413L chromogranin B variation in French patients with sporadic amyotrophic lateral sclerosis. AB - Chromogranins interact with mutant forms of superoxide dismutase 1 (SOD1) responsible for a portion of familial amyotrophic lateral sclerosis (ALS). A particular variation (P413L) in the chromogranin B gene, CHGB, has been recently associated with an earlier age at onset in both familial and sporadic ALS. The aim of our study was to evaluate the P413L chromogranin variation in French patients with sporadic amyotrophic lateral sclerosis. We developed a High Resolution DNA Melting (HRM) protocol to analyse the P413L variation in the CHGB gene in 540 French patients with sporadic ALS and 504 controls. The clinical characteristics of patients were analysed in relation to their genotype. Results showed that our study on a large cohort of French-Caucasian patients with SALS and controls failed to confirm an increased frequency of the 413L variant in SALS patients. This frequency was 5.3% in the SALS population and 5.5% in the control group. Moreover, we did not observe a previous observation of a difference of age at onset between T-allele carriers and non-carriers (median age of onset 60.4 vs. 62.0 years of age, respectively). Thus, our findings do not support the 413L variant of rs742710 as a risk factor for sporadic ALS in the French population. PMID- 20932228 TI - Acute starvation in C57BL/6J mice increases myocardial UCP2 and UCP3 protein expression levels and decreases mitochondrial bio-energetic function. AB - Associations between uncoupling protein (UCP) expression and functional changes in myocardial mitochondrial bio-energetics have not been well studied during periods of starvation stress. Our aim was to study the effects of acute starvation, for 24 or 48 h, on combined cardiac mitochondrial function and UCP expression in mice. Isolated heart mitochondria from female mice starved for 48 h compared to that from mice fed revealed a significantly (p < 0.05) decreased adenosine diphosphate-to-oxygen ratio, a significantly increased proton leak and an increased GTP inhibition on palmitic acid-induced state 4 oxygen consumption (p < 0.05). These bio-energetic functional changes were associated with increases in mitochondrial UCP2 and UCP3 protein expression. In conclusion, our findings suggest that increased UCP2 and UCP3 levels may contribute to decreased myocardial mitochondrial bio-energetic function due to starvation. PMID- 20932229 TI - Personal care products and endocrine disruption: A critical review of the literature. AB - This article reviews laboratory and epidemiological research into the endocrine disruptive effects of components of personal care products, namely, phthalate esters, parabens, ultraviolet (UV) filters, polycyclic musks, and antimicrobials. High doses of phthalates in utero can produce “phthalate syndrome,” demasculinizing effects in male rat offspring due to impaired testosterone production by fetal testes. However, evidence linking phthalate exposure to similar effects in humans appears inconclusive. Furthermore, phthalate exposure derived from personal care products is within safe limits and its principal bioavailable phthalate, diethyl phthalate (DEP), does not produce “phthalate syndrome.” Parabens exhibit very weak estrogen activity in vitro and in vivo, but evidence of paraben-induced developmental and reproductive toxicity in vivo lacks consistency and physiological coherence. Evidence attempting to link paraben exposure with human breast cancer is nonexistent. Select UV filters at high doses produce estrogenic, antithyroid, and other effects in rats in vivo. Again, no evidence links UV filter exposure to endocrine disruptive effects in humans. Some polycyclic musks weakly bind to estrogen, androgen, or progestin receptors and exhibit primarily antagonistic activity in vitro, which for the most part, has yet to be confirmed in vivo in mammals. The antimicrobials triclocarban and triclosan evoke weak responses mediated by aryl hydrocarbon, estrogen, and androgen receptors in vitro, which require confirmation in vivo. Preliminary observations suggest a novel interaction between triclocarban and testosterone. In conclusion, although select constituents exhibit interactions with the endocrine system in the laboratory, the evidence linking personal care products to endocrine disruptive effects in humans is for the most part lacking. PMID- 20932230 TI - Biphasic interactions between a cationic dendrimer and actin. AB - Gene delivery systems face the problem not only of the route toward the cell and tissues in question, but also of the molecularly crowded environment of both the cytoplasm and the nucleus itself. One of the physical barriers in the cytoplasm for diffusing nanoparticles is an actin network. Here, we describe the finding that a self-fluorescent sixth generation cationic dendrimer (6 nm in diameter) interacts reversibly and possibly electrostatically with actin filaments in vitro. Not only does this interaction slow the diffusion of the dendrimer but it also affects actin polymerization in a biphasic manner. At low concentrations the dendrimer behaves like a G-binding actin protein, retarding actin polymerization, whereas at high concentrations the dendrimer acts as a nucleating protein accelerating the polymerization. Thus in vivo the diffusion of a dendrimer carrier such as this has both physical and chemical elements: by decreasing polymerization it might accelerate its own transport, and by enhancing actin polymerization retard it. This finding suggests that such a dendrimer may have a role as an anticancer agent through its inhibitory effect on actin polymerization. PMID- 20932231 TI - Targeted delivery of large fusion protein into hippocampal neurons by systemic administration. AB - Targeted delivery of proteins into the hippocampus has not yet been achieved. Here, we show that systemic administration of the beta-galactosidase, fused to a 43-amino-acid peptide derived from rabies virus glycoprotein (RVG), results in targeted delivery of the fusion protein into the hippocampal neurons. This approach may enable the development of protein therapy for neurodegenerative diseases, such as Alzheimer's disease. This result may open new possibilities in using neurotropic virus glycoprotein-derived peptides for targeted delivery of therapeutic molecules into local brain regions. PMID- 20932232 TI - Wheelchair propulsion biomechanics and wheelers' quality of life: an exploratory review. AB - PURPOSE. To provide an overview of associations between wheelchair propulsion biomechanics for both everyday and racing wheelchairs, wheeling-related upper limb injuries, and quality of life of manual wheelchair users through a synthesis of the available information. METHODS. A search of publications was carried out in PubMed and SportsDiscus databases. Studies on wheelchair propulsion biomechanics, upper limb injuries associated with wheelchair propulsion and quality of life of wheelchair users were identified. Relevant articles cited in identified articles but not cited in PubMed or SportsDiscus were also included. RESULTS. Wheelchair sports participation has positive impact on quality of life and research in racing wheelchair biomechanics can indirectly promote the visibility of wheelchair sports. The impact of pushrim-activated power-assisted wheelchairs (a hybrid between manual and battery-powered wheelchairs) and geared manual wheels on wheelers' everyday life were discussed. CONCLUSIONS. The study of wheelchair propulsion biomechanics focuses on how a wheelchair user imparts power to the wheels to achieve mobility and the accumulated knowledge can help to improve wheelchair users' mobility, reduce physical stress associated with wheelchair propulsion, and as a result, enhance quality of life. PMID- 20932233 TI - Functioning and disability in stroke. AB - PURPOSE: To describe functioning and disability in patients with stroke according to the model endorsed by the International Classification of Functioning Disability and Health (ICF) in a rehabilitation hospital. METHODS: Adult patients with stroke were consecutively enrolled. The Functional Independence Measure (FIM) and the WHO Disability Assessment Schedule II (WHO-DAS II) were administered in individual sessions. ICF checklist was applied on the basis of medical documentation and rehabilitation team meetings. Descriptive analyses were performed to report on FIM and WHO-DAS II scores. ICF categories reported as a problem by more than 20% of patients were described in detail. RESULTS: Patients (197 in total) were mainly men, aged about 60, with average FIM score of 75. Within ICF Body Functions component 32 categories were applied in at least 20% of the patients, 5 within Body Structures, 27 within Activities and Participation and 7 within Environmental Factors. CONCLUSIONS: ICF represents a new integrative tool to help professionals dealing with stroke. The checklist captures the various sequels of stroke in terms of impairments, activity limitations and participation restrictions. It shows the extensive need for rehabilitation, whereby it facilitates consideration of the patient' needs. PMID- 20932234 TI - Bioengineering assessment of acupuncture, part 8: innovative moxibustion. AB - The actual Chinese character for acupuncture, translated literally, means "acupuncture-moxibustion." This shows the enormous importance of moxibustion in Asia for thousands of years. In this review article, the history of the burning of mugwort (moxatherapy) is briefly described. In addition, new technical methods such as new infrared-moxa or laser-moxa devices, electrobian stone moxibustion, and the investigations of a new needle-moxa system using high-tech methods such as thermography, laser Doppler flowmetry, and laser Doppler imaging are presented. PMID- 20932235 TI - Quality assessment in magnetic resonance images. AB - Assessing quality of medical images is critical because the subsequent course of actions depend on it. Extensive use of clinical magnetic resonance (MR) imaging warrants a study in image indices used for MR images. The quality of MR images assumes particular significance in the determination of their reliability for diagnostics, response to therapies, synchronization across different imaging cycles, optimization of interventional imaging, and image restoration. In this paper, we review various techniques developed for the assessment of MR image quality. The reported quality indices can be broadly classified as subjective/objective, automatic/semi-automatic, region-of-interest/non-region-of interest-based, full-reference/no-reference and HVS incorporated/non-HVS incorporated. The trade-of across the various indices lies in the computational complexity, assumptions, repeatability, and resemblance to human perception. Because images are eventually viewed by the human eye, it is found that it is important to incorporate aspects of human visual response, sensitivity, and characteristics in computing quality indices. Additionally, no-reference metrics are the most relevant due to the lack of availability of a golden standard against which images could be compared. Techniques that are objective and automatic are preferred for their repeatability and to eliminate avoidable errors due to factors like stress, which arise in human intervention. PMID- 20932237 TI - Classical approaches and intelligent systems in ventilation management: a survey. AB - Ventilation management is the ongoing process of adjusting ventilator support according to patients' needs. The present article is a review of the published work on the modeling of respiration physiology or the ventilation management process for supporting the critical task of ventilation. The focus of the survey is the application of soft computing--intelligent methods for the development of clinical decision support systems (CDSS). The necessity of CDSS in critical care and more specifically in ventilation management is discussed, and important characteristics are highlighted. PMID- 20932236 TI - Molecular networks in drug discovery. AB - Despite the dramatic increase of global spending on drug discovery and development, the approval rate for new drugs is declining, due chiefly to toxicity and undesirable side effects. Simultaneously, the growth of available biomedical data in the postgenomic era has provided fresh insight into the nature of redundant and compensatory drug-target pathways. This stagnation in drug approval can be overcome by the novel concept of polypharmacology, which is built on the fundamental concept that drugs modulate multiple targets. Polypharmacology can be studied with molecular networks that integrate multidisciplinary concepts including cheminformatics, bioinformatics, and systems biology. In silico techniques such as structure- and ligand-based approaches can be employed to study molecular networks and reduce costs by predicting adverse drug reactions and toxicity in the early stage of drug development. By amalgamating strides in this informatics-driven era, designing polypharmacological drugs with molecular network technology exemplifies the next generation of therapeutics with less of target properties and toxicity. In this review, we will first describe the challenges in drug discovery, and showcase successes using multitarget drugs toward diseases such as cancer and mood disorders. We will then focus on recent development of in silico polypharmacology predictions. Finally, our technologies in molecular network analysis will be presented. PMID- 20932238 TI - Are microfluidics-based blood viscometers ready for point-of-care applications? A review. AB - In recent years, the engineering of blood viscometers for the diagnosis, prognosis, and prevention of cardiovascular and other diseases has been the subject of significant research interest. Conventional blood viscometers such as rotational viscometers and capillary viscometers typically rely on mechanical techniques in quantifying whole-blood viscosity, a process in which resistance to blood flow is measured in response to an applied force. The direct applicability of conventional viscometers as point-of-care diagnostic and clinical tools is subject to several limitations mainly related to their macro-structural features that augment the sampling size and reduce portability. The development of new fabrication technologies to scale down experimental processes has opened up the reality of miniaturizing existing concepts of blood viscometers into microchips, and paves the road for future development of blood viscometers. These micro-blood viscometers are advantageous because they use very small sample volumes for quick, routine clinical purposes. The easy fabrication of microsystems and large scale production not only result in a lower cost, but also render these devices portable and disposable, both of which are highly desirable for clinical applications. The underlying challenges of these devices are associated with red blood cell clogging, measurement stability, reliability, and reproducibility. The present review discusses the state-of-the-art and emerging trends in the field of microfluidics to provide elegant solutions for quantifying blood viscosity with vastly improved efficacy and with the potential for use at the patient's bedside. PMID- 20932239 TI - Computer-aided diagnosis of knee-joint disorders via vibroarthrographic signal analysis: a review. AB - The knee is the lower-extremity joint that supports nearly the entire weight of the human body. It is susceptible to osteoarthritis and other knee-joint disorders caused by degeneration or loss of articular cartilage. The detection of a knee-joint abnormality at an early stage is important, because it helps increase therapeutic options that may slow down the degenerative process. Imaging based arthrographic modalities can provide anatomical images of the joint cartilage surfaces, but fail to demonstrate the functional integrity of the cartilage. Knee-joint auscultation, by means of recording the vibroarthrographic (VAG) signal during bending motion of a knee, could be used to develop a noninvasive diagnostic tool. Computer-aided analysis of VAG signals could provide quantitative indices for screening of degenerative conditions of the cartilage surface and staging of osteoarthritis. In addition, the diagnosis of knee-joint pathology by means of VAG signal analysis may reduce the number of semi-invasive diagnostic arthroscopic examinations. This article reviews studies related to VAG signal analysis, first summarizing the pilot studies that demonstrated the diagnostic potential of knee-joint auscultation for the detection of degenerative diseases, and then describing the details of recent progress in analysis of VAG signals using temporal analysis, frequency-domain analysis, time-frequency analysis, and statistical modeling. The decision-making methods used in the related studies are summarized, followed by a comparison of the diagnostic performance achieved by different pattern classifiers. The final section is a perspective on the future and further development of VAG signal analysis. PMID- 20932240 TI - Conundrum and therapeutic potential of curcumin in drug delivery. AB - Turmeric, the source of the polyphenolic active compound curcumin (diferuloylmethane), has been used extensively in traditional medicine since ancient times as a household remedy against various diseases, including hepatic disorders, cough, sinusitis, rheumatism, and biliary disorders. In the past few decades, a number of studies have been done on curcumin showing its potential role in treating inflammatory disorders, cardiovascular disease, cancer, AIDS, and neurological disorders. However, the main drawback associated with curcumin is its poor aqueous solubility and stability in gastrointestinal fluids, which leads to poor bioavailability. Multifarious novel drug-delivery approaches, including microemulsions, nanoemulsions, liposomes, solid lipid nanoparticles, microspheres, solid dispersion, polymeric nanoparticles, and self microemulsifying drug-delivery systems have been used to enhance the bioavailability and tissue-targeting ability of curcumin. These attempts have revealed promising results for enhanced bioavailability and targeting to disease such as cancer, but more extensive research on tissue-targeting and stability related issues is needed. Tissue targeting and enhanced bioavailability of curcumin using novel drug-delivery methods with minimum side effects will in the near future bring this promising natural product to the forefront of therapy for the treatment of human diseases such as cancer and cardiovascular ailments. We provide a detailed analysis of prominent research in the field of curcumin drug delivery with special emphasis on bioavailability-enhancement approaches and novel drug-delivery system approaches. PMID- 20932241 TI - Inhalational therapy for pulmonary arterial hypertension: current status and future prospects. AB - This review summarizes the pathophysiology and current therapeutic and drug delivery strategies for pulmonary arterial hypertension (PAH), a rare but devastating disorder of the pulmonary circulation affecting 50,000 to 100,000 persons in the United States. Chief clinical features of PAH include increased mean pulmonary arterial pressure (>25 mm Hg) and right ventricular and smooth muscle hypertrophy. A wide variety of agents have been studied for use as anti PAH drugs, including prostacyclin analogues, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors, to name a few. However, a major shortcoming of anti-PAH medications is their short half-lives, requiring them to be administered via parenteral routes, which lead to undesirable side effects, including systemic vasodilation. Inhalational delivery of anti-PAH drugs provides an attractive alternative to conventional routes, with ease of administration and minimal systemic vasodilation. Recently, the U.S. Food and Drug Administration approved inhalable iloprost (Ventavis(r)), a prostacyclin analogue, for PAH treatment. Other drugs being studied for their potential in inhalable PAH therapy include PGE1, treprostinil, vasoactive intestinal peptide, and fasudil. Controlled release inhalable delivery systems for anti-PAH medications have also been proposed to facilitate long-term and selective vasodilation of pulmonary arteries. Extensive studies are warranted to develop safe and effective drug delivery systems that will provide a better quality of life to patients. PMID- 20932242 TI - A need for reorganization of the Food and Drug Administration. AB - The associate director for science and medicine in the Office of Drug Safety at the Food and Drug Administration (FDA), Dr. David Graham, reported that the FDA was incapable of protecting Americans from unsafe drugs. In testimony to the Senate Finance Committee, he stated that the FDA has let the American people down and betrayed public trust. Drastic changes and measures within the FDA must be made to ensure the safety of American consumers of drugs, products, and medical devices. Efforts such as the introduction of the Grassley-Dodd Bill, allowing the FDA to order immediate drug recall or increased risk warnings, followed by the FDA Safety Act of 2007, are still not enough to ensure the safety and efficacy of drugs, biological products, and medical devices that the American public use every day. In this report, we describe past and present efforts by congressional leaders, FDA representatives, and American citizens to effect changes within the FDA in order to protect America from unsafe drugs and medical devices. We describe our own struggles in passing a citizen?s petition to ban cornstarch in medical gloves, and the lack of response and responsibility that the FDA has displayed. PMID- 20932243 TI - Revolutionary advances in the diagnosis of vitamin D deficiency. AB - Vitamin D deficiency has bee associated with bone diseases, cardiovascular diseases, cancer, and multiple sclerosis. Recent clinical studies have pointed out that these diseases could be prevented by either adequate sun exposure or oral vitamin D3 supplementation. In an effort to prevent these illnesses, emergency physicians and other clinicians must be aware of technological advances in the measurement of serum concentrations of 25-hydroxyvitamin D. Realizing the importance of diagnosing vitamin D deficiency, we reviewed the following advanced diagnostic techniques: liquid chromatography tandem mass spectrometry, radioimmunoassay, and DiaSorin's immunochemiluminometric automated analyzer LIASION(r). On the basis of this review, we have found that each of these diagnostic tests has documented limitations, and therefore we recommend an international standardization of these assays to accurately diagnose vitamin D deficiency. PMID- 20932244 TI - Protective role of zinc in ameliorating arsenic-induced oxidative stress and histological changes in rat liver. AB - The aim of present work was to gain insight into the role of dietary zinc in ameliorating the adverse effects caused by arsenic on rat liver. Male Wistar rats received arsenic alone in the form of sodium arsenite in drinking water at a dose level of 100 ppm, zinc alone in the form of zinc sulfate in drinking water at a dose level of 227 mg/L, or arsenic + zinc treatments in the combined group for a total duration of 3 months. Arsenic treatment resulted in a significant increase in lipid peroxidase (LPO); however, glutathione (GSH) levels and the activities of superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR), and catalase (CAT) were found to be significantly decreased following arsenic treatment. Furthermore, arsenic treatment resulted in a significant decrease in hepatic zinc levels. Histological studies showed well differentiated signs of focal hepatitis, lobular inflammation, prominent hepatocyte degeneration, and severe periportal necrosis. Administration of zinc to arsenic-treated rats significantly decreased the level of LPO but increased the level of GSH compared with arsenic-treated rats. Further, the zinc level and activities of SOD, GPx, GR, and CAT were found to be significantly increased following zinc treatment. The administration of zinc to arsenic-treated rats caused signs of improvement in liver histoarchitecture, but a few focal areas of degeneration and necrosis were still occasionally seen. In conclusion, the results of this study suggest that zinc can be beneficial against arsenic-induced hepatotoxicity in rats. PMID- 20932245 TI - Protective effect of Alstonia scholaris against radiation-induced clastogenic and biochemical alterations in mice. AB - We studied the radioprotective effect of Alstonia scholaris bark extract (ASE) on cytogenetic alterations in the form of chromosomal aberrations and micronuclei induction in bone marrow. For this purpose, one group of male Swiss albino mice was exposed to 2.5 Gy gamma radiation to serve as the irradiated control, while the other group received ASE (100 mg/kg bwt/d) orally for 5 consecutive days 30 min before irradiation to serve as the experimental group. Results indicated that dicentrics and chromosomal exchanges were increased at 12 h post-exposure in both groups, followed by a gradual decline and then disappearance by d 15 and 7, respectively. However, the occurrence of chromatid breaks and acentric fragments was also maximum at 12 h, and later decreased without attaining the normal value, even up to the last necropsy interval. The percentage of such aberrations was significantly less in the ASE-pretreated irradiated animals. The incidence of chromosome breaks and centric rings kept increasing up to d 1, but then declined gradually and reached zero beginning at d 7; they were significantly lower in the ASE-treated irradiated group at the early intervals. A significant decrease in glutathione (GSH) and an increase in lipid peroxidation were observed after radiation exposure in untreated controls, whereas ASE-pretreated irradiated animals exhibited a significant increase in GSH and a decrease in lipid peroxidation; however, the values remained below normal. The results from the present study suggest that ASE pretreatment provides protection against radiation induced chromosomal damage and micronuclei induction in the bone marrow of mice. PMID- 20932246 TI - Diallyl disulfide induces caspase-dependent apoptosis via mitochondria-mediated intrinsic pathway in B16F-10 melanoma cells by up-regulating p53, caspase-3 and down-regulating pro-inflammatory cytokines and nuclear factor-kappabeta-mediated Bcl-2 activation. AB - Diallyl disulfide (DADS) is a major organo-sulfur compound derived from garlic (Allium sativum), which inhibits the proliferation of various types of cancer cells. In this study we investigated the effect of DADS on the induction of apoptosis, as well as its regulatory effect on the activation of transcription factors in B16F-10 melanoma cells. Treatment of B16F-10 cells with nontoxic concentrations of DADS resulted in the presence of apoptotic bodies and induced DNA fragmentation in a dose-dependent manner. Cell-cycle analysis revealed that the occurrence of the sub-G1 peak was significantly elevated in DADS-treated cells. DADS treatment also down-reguated Bcl-2 expression and up-regulated p53, caspase-9, and caspase-3 expression in B16F-10 melanoma cells. The study also reveals that DADS inhibited the activation and nuclear translocation of p65, p50, and c-Rel subunits of nuclear factor (NF)-B and other transcription factors, such as c-fos, activated transcription factor-2, and cyclic adenosine monophosphate response element-binding protein, in B16F-10 melanoma cells The pro-inflammatory cytokine production and gene expression of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, and granulocyte-macrophage colony-stimulating factor (GM-CSF) were down-regulated in DADS-treated cells compared with control B16F-10 metastatic melanoma cells. DADS induces caspase-dependent apoptosis through a mitochondria-mediated intrinsic pathway in B16F-10 melanoma cells by activating p53 and caspase-3 gene expression and suppressing pro-inflammatory cytokines and NF-B-mediated Bcl-2 activation. PMID- 20932247 TI - Anti-tumor activity of Aloe vera against DMBA/croton oil-induced skin papillomagenesis in Swiss albino mice. AB - Human populations are increasingly exposed to various carcinogens such as chemicals, radiation, and viruses in the environment. Chemopreventive drugs of plant origin are a promising strategy for cancer control because they are generally nontoxic or less toxic than synthetic che-mopreventive agents, and can be effective at different stages of carcinogenesis. The present investigation was undertaken to explore the antitumor activity of topical treatment with aloe vera (Aloe vera) gel, oral treatment with aloe vera extract, and topical and oral treatment with both gel and extract in stage-2 skin carcinogenesis in Swiss albino mice induced by 7,12-dim ethylbenz(a)anthracene (DMBA) and promoted croton (Croton tiglium) oil. The animals were randomly divided into 4 groups and treated as follows: Group I, DMBA + croton oil only (controls); Group II, DMBA + croton oil + topical aloe vera gel; Group III, DMBA + croton oil + oral aloe vera extract; Group I V, DMBA + croton oil + topical aloe vera gel + oral aloe vera extract. Results showed that body weight was significantly increased from 78.6% in the control group (Group I) to 92.5%, 87.5%, and 90.0% in Groups II, III, and I V, respectively. A 100% incidence of tumor development was noted in Group I, which was decreased to 50%, 60%, and 40% in Groups II, III, and I V, respectively. Also in Groups II, III, and IV, the cumulative number of papillomas was reduced significantly from 36 to 12, 15, and 11; tumor yield from 3.6 to 1.2, 1.5, and 1.1; and tumor burden from 3.6 to 2.4, 2.50, and 2.75, respectively, after treatment with aloe vera. Conversely, the average latent period increased significantly from 4.9 (Group I) to 5.23, 5.0, and 6.01 weeks in Groups II, III, and I V, respectively. We conclude that aloe vera protects mice against DMBA/croton oil-induced skin papillomagenesis, likely due to the chemopreventive activity of high concentrations of antioxidants such as vitamins A, C, and E; glutathione peroxidase; several isozymes of superoxide dismutase; the minerals selenium and zinc; and polysaccharides in aloe vera. PMID- 20932248 TI - Regulation and gene expression of heme synthesis under heavy metal exposure- review. AB - Environmental pollution of heavy metals is very abundant nowadays from industry, chemicals, old paints, and pipes or resulting from previous contaminants accumulating in the food chain. Most of the iron demands of the body are needed for heme synthesis and assembly, but iron is also required for Fe-S cluster proteins and other redox enzymes. Heme is an essential, iron-binding molecule used as a prosthetic group of hemoproteins or as a regulator in multiple cellular pathways. In this review, we focused on the effect of exposure to heavy metals, such as Pb, Ga, Cu, Kd, Hg and Al, on heme synthesis as the main iron sequestering process of the human body. These metals compete with iron on transporters, reduce the cellular iron pool and moreover, bind to proteins, and cause physical and mental disturbances. Heavy metals mainly impair various aspects of the heme synthesis pathway: gene expression, enzyme activity, and iron integration into protoporphyrin IX. Main risk factors are described as well as effects on iron dependent processes in order to increase public awareness to the distribution of heavy metals in our close environment and the harsh consequences of exposure, even in low doses. PMID- 20932249 TI - Endotoxin contamination of Agaricus blazei Murrill extract enhances murine immunologic responses and inhibits the growth of sarcoma 180 implants in vivo. AB - Agaricus blazei Murrill, a native mushroom of Brazil, has been reported to be an immunoreactant with anti-tumor effect. There are many reports on the anti-tumor effect of Agaricus blazei Murrill; however, the precise mechanism of its effect is not fully understood. In this study, we tried to confirm the anti-tumor effect of Agaricus blazei Murrill against Sarcoma 180 cells in a mouse model and found that an inhibitory effect on tumor growth was induced by peritoneal injection of a freeze-dried, hot water extract of Agaricus blazei Murrill (FAG). We noted that there were differences among each sample in terms of anti-tumor activity. We hypothesized that this was because some contaminants of FAG were affecting the anti-tumor activity. We evaluated cytokine secretion from mouse peritoneal cells incubated with FAG. While high interleukin-6 and tumor necrosis factor-alpha secretions were observed in response to crude FAG, they were dramatically decreased by the removal of endotoxin from the FAG using an endotoxin-specific polymyxin B-conjugated affinity column. The reductions were synergistically recovered by adding an amount of lipopolysaccharide equivalent to the amount of contaminated endotoxin. Thus, these data suggest that the contaminated endotoxin of Agaricus blazei Murrill may act as an immunomodulator of anti-tumor activity. PMID- 20932250 TI - Molecular structure of transient receptor potential vanilloid type 1 ion channel (TRPV1). AB - Elaboration of the structure of TRPV1 and its functional relationship with channel activity is a work in progress, with much remaining to be done before the structure-function relationship of TRPV1 is comprehensively elicited. The result is that the present state of knowledge can reasonably be described as a patch work of insightful data where major deficits in knowledge remain and where meaningful general conclusions cannot be reliably drawn. This is unfortunate, given that this ion channel has been convincingly implicated in a wide range of physiological functions and pathological conditions. Moreover, the development of therapeutic strategies which target TRPV1 depends on the knowledge of this receptor's structure and its relationship with channel function. Here, we offer a description of the present state of knowledge in relation to this complex subject. PMID- 20932251 TI - A "cute" desensitization of TRPV1. AB - Capsaicin and other vanilloids selectively excite and subsequently desensitize pain-conducting nerve fibers (nociceptors) and this process contributes to the analgesic (and thus therapeutically relevant) effects of these compounds. Such a desensitization process is triggered by the activation of the transient receptor potential vanilloid subtype 1 receptor channels (TRPV1) that open their cationic pores, permeable to sodium, potassium and calcium (Ca(2+)) ions. Depending on the duration of capsaicin exposure and the external calcium concentration, the Ca(2+) influx via TRPV1 channels desensitizes the channels themselves, which, from the cellular point of view, represents a feedback mechanism protecting the nociceptive neuron from toxic Ca(2+) overload. The 'acute desensitization' accounts for most of the reduction in responsiveness occurring within the first few (~20) seconds after the vanilloids are administered to the cell for the first time. Another form of desensitization is 'tachyphylaxis', which is a reduction in the response to repeated applications of vanilloid. The wealth of pathways following TRPV1 activation that lead to increased intracellular Ca(2+) levels and both forms of desensitization is huge and they might utilise just about every known type of signalling molecule. This review will not attempt to cover all historical aspects of research into all these processes. Instead, it will try to highlight some new challenging thoughts on the important phenomenon of TRPV1 desensitization and will focus on the putative mechanisms that are thought to account for the acute phase of this process. PMID- 20932252 TI - Possible consequences of blocking transient receptor potential vanilloid. AB - The cloning of the first sensory Transient Receptor Potential (TRP) channel, TRPVanilloid 1 (TRPV1) in 1997, initiated a new era of pain research and coincided with the Decade of Pain Control and Research promulgated by the United States Congress. When cloned, TRPV1 channel was shown to be predominantly expressed in nociceptors (C- and Adelta-fibers) and are activated by physical and chemical stimuli. Channel function can be amplified by transcriptional upregulation and posttranslational modification by proinflammatory agents. Indeed, TRPV1 gene disruption confirms that it is involved in transmitting inflammatory thermal hypersensitivity, but not acute thermal or mechanical pain sensitivity. Based on its distribution and functions, TRPV1 is considered as an ideal target for developing small molecule antagonists. Now, there is a growing body of evidence that TRPV1 is expressed in non-sensory neurons and non-neuronal cells. This raises the possibility of unwanted effects that may result from targeting TRPV1. A major consequence of TRPV1 blockade that has come to light in clinical trials following administration of antagonists is hyperthermia. This observation has threatened the abandonment of TRPV1 antagonists, although they are proven to be useful in certain modalities of pain. In this review, we will discuss the expression and functions of TRPV1 in various organ systems and highlight the consequences that might be associated with blocking the receptor. PMID- 20932253 TI - TRPV1 function in health and disease. AB - The transient receptor potential vanilloid type 1 ion channel (TRPV1) was identified as a receptor responsible for mediating the intense burning sensation following exposure to heat greater than approximately 43 degrees C., or capsaicin, the pungent ingredient of hot chilli peppers. More importantly, however, it has been shown that TRPV1 plays a pivotal role in the development of the burning pain sensation associated with inflammation in peripheral tissues. More recently, there has been a virtual avalanche of sightings of TRPV1 on the anatomical landscape, coupled with association of TRPV1 with a wide range of non pain-related physiological and pathological conditions. Here, we consider the continuously expanding set of functions in both health and disease which TRPV1 is understood to subserve at present. The widespread expression of TRPV1 in the human suggests that, in addition to the development of burning pain associated with acute exposure to heat or capsaicin, and with inflammation, TRPV1 may also be involved in an array of vitally important functions, such as those of the urinary tract, the respiratory and auditory systems. Moreover, TRPV1 could also be involved in the maintenance of body and cell homeostasis, metabolism, regulation of hair growth, and development of cancer. Thus, controlling TRPV1 function may possess the potential of providing exciting opportunities for therapeutic interventions. At the same time, however, the widespread distribution of these ion channels introduces a tremendous complication in developing a drug to serve in one disease context which may have profound implications for normal TRPV1 functioning in other non-pathological contexts. PMID- 20932254 TI - TRPV1 and synaptic transmission. AB - Transient Receptor Potential Vanilloid Type 1 is a prominent "pain" receptor expressed in sensory afferent neurons. TRPV1 on peripheral nerve terminals detects a variety of noxious stimuli generated at sites of injury and inflammation, and in turn, drives the excitation and sensitization of C-fibers neurons. Significantly, TRPV1 is also located on the central terminals of sensory neurons projecting to the spinal cord and brainstem. These TRPV1 channels appear to stimulate the secretion of glutamate. Further, TRPV1 is expressed diffusely in the brain and there is emerging evidence for TRPV1 modulating transmission at various brain synapses. Here we discuss our current understanding of the potential roles for TRPV1 in synaptic transmission. PMID- 20932255 TI - Regulation of nociceptive transmission at the periphery via TRPA1-TRPV1 interactions. AB - TRPV1 and TRPA1 have traditionally been considered to function independently from each other as homomers, but their extensive co-expression in sensory neurons and recent evidence suggest that these channels can functionally interact and may form a complex as part of their normal function. Although TRPA1 and TRPV1 do not absolutely require interaction to maintain function in expression systems or even sensory neurons, their heteromerization may still result in dramatic effects on channel biophysical properties, pharmacology, signaling, regulation, and ultimately function. Understanding the regulation and functional significance of TRPA1-TRPV1 interaction is of tremendous clinical importance since first, both channels are the potential molecular targets for numerous therapeutic drugs; and second, TRPA1-TRPV1 co-expression is far more specific for nociceptive sensory neurons than expression patterns of TRPA1 or TRPV1 considered separately. PMID- 20932256 TI - TRPM8, a sensor for mild cooling in mammalian sensory nerve endings. AB - Temperature sensing is a crucial feature of the nervous system, enabling organisms to avoid physical danger and choose optimal environments for survival. TRPM8 (Transient Receptor Potential Melastatin type 8) belongs to a select group of ion channels which are gated by changes in temperature, are expressed in sensory nerves and/or skin cells and may be involved in temperature sensing. This channel is activated by a moderate decrease in temperature, with a threshold of approximately 25 degrees C in heterologous expression systems, and by a variety of natural and synthetic compounds, including menthol. While the physiological role of TRPM8 as a transducer of gentle cooling is widely accepted, its involvement in acute noxious cold sensing in healthy tissues is still under debate. Although accumulating evidence indicates that TRPM8 is involved in neuropathic cold allodynia, in some animal models of nerve injury peripheral and central activation of TRPM8 is followed by analgesia. A variety of inflammatory mediators, including bradykinin and prostaglandin E(2), modulate TRPM8 by inhibiting the channel and shifting its activation threshold to colder temperatures, most likely counteracting the analgesic action of TRPM8. While important progress has been made in unraveling the biophysical features of TRPM8, including the revelation of its voltage dependence, the precise mechanism involved in temperature sensing by this channel is still not completely understood. This article will review the current status of knowledge regarding the (patho)physiological role(s) of TRPM8, its modulation by inflammatory mediators, the signaling pathways involved in this regulation, and the biophysical properties of the channel. PMID- 20932257 TI - TRPM8: from cold to cancer, peppermint to pain. AB - Temperature perception is vital for cellular and metabolic homeostasis, avoidance, and survival. In the primary afferent nerve terminal, select members of the transient receptor potential (TRP) family of ion channels reside and convert thermal stimuli into neuronal activity. The cold and menthol receptor, TRPM8, is the predominant thermoceptor for cellular and behavioral responses to cold temperatures. Remarkably, this single molecular sensor of cold, that responds at a discrete thermal threshold in vitro (approximately 28 degrees C), enables sensory afferents to respond to distinct, yet varied thermal thresholds (approximately 28 to <5 degrees C). Thus, unlike other thermally-gated TRP channels which are activated at either innocuous or noxious temperatures, TRPM8 provides perception of both pleasantly cool and painfully cold. In addition to this diversity in sensory signaling, TRPM8 has an emerging role in a variety of biological systems, including thermoregulation, cancer, bladder function, and asthma. Here we summarize some key points related to TRPM8 and its potential as a drug target to treat a wide variety of physiological conditions. Nonetheless, it remains to be seen how this single "cool" molecule can serve in such a multitude of biological processes. PMID- 20932258 TI - The emerging pharmacology of TRPM8 channels: hidden therapeutic potential underneath a cold surface. AB - Transient receptor potential melastatin 8 (TRPM8) is a non-selective cation channel activated by cold temperature and cooling agents. TRPM8 is expressed in a subpopulation of cold-sensitive sensory neurons, as well as in the male urogenital system. TRPM8 is markedly upregulated in prostate cancer and in other tumors such as breast adenocarcinoma and melanoma. Moreover, recent studies suggest the potential involvement of TRPM8 channels in the pathophysiology of cold nociception and cold allodynia. This has led to a strong interest in the pursuit of novel modulators of TRPM8 channels. This review highlights our current knowledge of TRPM8 pharmacology and modulation mechanisms, detailing structural features important for TRPM8 gating by different agonists, the mechanism of antagonism by different compounds and the potential relevance of TRPM8 for treatment of various pathological conditions. PMID- 20932259 TI - TRPM6 and TRPM7: A Mul-TRP-PLIK-cation of channel functions. AB - Unique among ion channels, TRPM6 and TRPM7 garnered much interest upon their discovery as the first ion channels to possess their own kinase domain. Soon after their identification, the two proteins were quickly linked to the regulation of magnesium homeostasis. However, study of their physiological functions in mouse and zebrafish have revealed expanding roles for these channel kinases that include skeletogenesis and melanopore formation, thymopoiesis, cell adhesion, and neural fold closure during early development. In addition, mutations in the TRPM6 gene constitute the underlying genetic defect in hypomagnesemia with secondary hypocalcemia, a rare autosomal-recessive disease characterized by low serum magnesium accompanied by hypocalcemia. Depletion of TRPM7 expression in brain, on the other hand, proved successful in mitigating much of the cellular devastation that accompanies oxygen-glucose deprivation during ischemia. The aim of this review is to summarize the data emerging from molecular genetic, biochemical, electrophysiological, and pharmacological studies of these unique channel-kinases. PMID- 20932260 TI - TRP channels in the digestive system. AB - Several of the 28 mammalian transient receptor potential (TRP) channel subunits are expressed throughout the alimentary canal where they play important roles in taste, chemo- and mechanosensation, thermoregulation, pain and hyperalgesia, mucosal function and homeostasis, control of motility by neurons, interstitial cells of Cajal and muscle cells, and vascular function. While the implications of some TRP channels, notably TRPA1, TRPC4, TRPM5, TRPM6, TRPM7, TRPV1, TRPV4, and TRPV6, have been investigated in much detail, the understanding of other TRP channels in their relevance to digestive function lags behind. The polymodal chemo- and mechanosensory function of TRPA1, TRPM5, TRPV1 and TRPV4 is particularly relevant to the alimentary canal whose digestive and absorptive function depends on the surveillance and integration of many chemical and physical stimuli. TRPV5 and TRPV6 as well as TRPM6 and TRPM7 appear to be essential for the absorption of Ca(2+) and Mg(2+), respectively, while TRPM7 appears to contribute to the pacemaker activity of the interstitial cells of Cajal, and TRPC4 transduces smooth muscle contraction evoked by muscarinic acetylcholine receptor activation. The implication of some TRP channels in pathological processes has raised enormous interest in exploiting them as a therapeutic target. This is particularly true for TRPV1, TRPV4 and TRPA1, which may be targeted for the treatment of several conditions of chronic abdominal pain. Consequently, blockers of these TRP channels have been developed, and their clinical usefulness has yet to be established. PMID- 20932262 TI - Sub-cellular distribution and translocation of TRP channels. AB - Cellular electrical activity is the result of a highly complex processes that involve the activation of ion channel proteins. Ion channels make pores on cell membranes that rapidly transit between conductive and non-conductive states, allowing different ions to flow down their electrochemical gradients across cell membranes. In the case of neuronal cells, ion channel activity orchestrates action potentials traveling through axons, enabling electrical communication between cells in distant parts of the body. Somatic sensation -our ability to feel touch, temperature and noxious stimuli- require ion channels able to sense and respond to our peripheral environment. Sensory integration involves the summing of various environmental cues and their conversion into electrical signals. Members of the Transient Receptor Potential (TRP) family of ion channels have emerged as important mediators of both cellular sensing and sensory integration. The regulation of the spatial and temporal distribution of membrane receptors is recognized as an important mechanism for controlling the magnitude of the cellular response and the time scale on which cellular signaling occurs. Several studies have shown that this mechanism is also used by TRP channels to modulate cellular response and ultimately fulfill their physiological function as sensors. However, the inner-working of this mode of control for TRP channels remains poorly understood. The question of whether TRPs intrinsically regulate their own vesicular trafficking or weather the dynamic regulation of TRP channel residence on the cell surface is caused by extrinsic changes in the rates of vesicle insertion or retrieval remain open. This review will examine the evidence that sub-cellular redistribution of TRP channels plays an important role in regulating their activity and explore the mechanisms that control the trafficking of vesicles containing TRP channels. PMID- 20932261 TI - Pharmacological modulation of diacylglycerol-sensitive TRPC3/6/7 channels. AB - Members of the classic type of transient receptor potential channels (TRPC) represent important molecules involved in hormonal signal transduction. TRPC3/6/7 channels are of particular interest as they are components of phospholipase C driven signalling pathways. Upon receptor-activation, G-protein-mediated stimulation of phospholipase C results in breakdown of phosphatidylinositides leading to increased intracellular diacylglycerol and inositol-trisphosphate levels. Diacylglycerol activates protein kinase C, but more interestingly diacylglycerol directly activates TRPC2/3/6/7 channels. Molecular cloning, expression and characterization of TRP channels enabled reassignment of traditional inhibitors of receptor-dependent calcium entry such as SKF-96365 and 2-APB as blockers of TRPC3/6/7 and several members of non-classic TRP channels. Furthermore, several enzyme inhibitors have also been identified as TRP channel blockers, such as ACA, a phospholipase A(2) inhibitor, and W-7, a calmodulin antagonist. Finally, the naturally occurring secondary plant compound hyperforin has been identified as TRPC6-selective drug, providing an exciting proof of concept that it is possible to generate TRPC-selective channel modulators. The description of Pyr3 as the first TRPC3-selective inhibitor shows that not only nature but also man is able to generate TRP-selective modulators. The review summarizes the data on pharmacological modification of TRPC3/6/7. Sheds lights on the current knowledge and historical development of pharmacological modulators of TRPC3/6/7. Our analysis indicates that Pyr3 and hyperforin provide promising core structures for the development of new, skeletive and more potent modulators of TRPC3/6/7 activity. PMID- 20932263 TI - Methodological considerations to understand the sensory function of TRP channels. AB - Transient Receptor Potential channels are exquisite molecular transducers of multiple physical and chemical stimuli, hence the raising interest to study their relevance to Sensory Biology. Here we discuss a number of aspects of the biophysical and pharmacological properties of TRP channels, which we consider essential for a clear understanding of their sensory function in vivo. By examining concrete examples extracted from recent literature we illustrate that TRP channel research is a field in motion, and that many established dogmas on biophysical properties, drug specificity and physiological role are continuously reshaped, and sometimes even dismantled. PMID- 20932264 TI - Exercise and cardiovascular disease. AB - Cardiovascular disease is the main cause of death in the United States. Although it is recognized that moderate intensity long-term exercise can decrease the chances of dying from cardiovascular disease by favorably modifying risk factors such as hypertension, obesity, hyperlipidemia, and insulin resistance, physical activity also enhances longevity by mechanisms independent of these risk factors. This review briefly summarizes what is known about the inflammatory nature of atherosclerosis and how long-term aerobic exercise can reduce the atherogenic activity of endothelial cells, blood mononuclear cells, and adipose tissue. PMID- 20932265 TI - Atherosclerotic coronary heart disease-epidemiology, classification and management. AB - Atherosclerotic coronary heart disease (CHD) is a major health problem worldwide. Epidemiological studies have identified the role of several modifiable and non modifiable risk factors in the pathogenesis of CHD. Aggressive risk modification has led to a significant improvement in the morbidity and mortality from CHD. However, there is a growing need to identify better modalities of risk prediction in CHD. Many of these newer risk markers, currently under evaluation, are based on the newer concept that atherosclerosis is more than merely a problem of lipid imbalance. There has been a recent shift in the paradigm towards inflammation and oxidative stress as the key drivers in the pathophysiology of atherosclerosis and its complications. Further understanding of this complex interplay of lipid and inflammatory factors is likely to pave way to a better understanding of this disease and its myriad complications. PMID- 20932266 TI - Atrial fibrillation: the emerging role of inflammation and oxidative stress. AB - Atrial fibrillation (AF) remains the most commonly encountered sustained arrhythmia in clinical practice and contributes to increased morbidity and mortality. Management of AF poses a challenge due to the refractory nature of the arrhythmia and the associated thromboembolic complications. Recent studies have implicated both systemic and local cardiac inflammation in the development as well as persistence of AF. This has been validated by the occurrence of high levels of systemic markers of inflammation in patients with post operative as well as chronic AF. High levels of markers of oxidative stress have also been found in patients with chronic AF when compared with controls, indicating a role of systemic reactive oxidative species in the perpetuation of this arrhythmia. Renin angiotension system (RAS) is believed to be unregulated in AF and may contribute to the pathogenesis of AF by producing a state of cardiac or systemic oxidative stress and /or inflammation. In this review, we aim to discuss the emerging evidence linking inflammation, and oxidative stress with AF. PMID- 20932267 TI - The inflammation paradigm and coronary artery disease: What Celsus, Virchow and gene knock outs have taught us. AB - Atherosclerotic vascular disease is a major cause of morbidity and mortality throughout the world. The clinical manifestations include coronary artery disease and myocardial infarction, cerebrovascular disease, renovascular disease and peripheral vascular disease. Initially considered a bland occlusive disease mediated to a great extent by lipids, atherosclerosis can now be considered an inflammatory disease, in its own right. This has led to a paradigm shift in disease management. We have come a long way since the time of Celsus, Galen, Virchow, Rokitansky and others when the components of the inflammatory cascade were first described. The development of mouse knock out models, improved molecular approaches to studying atheromatous blood vessels and development of sophisticated imaging and biomarker studies have enhanced our understanding of the molecular pathways in atherosclerosis. This brief review will attempt to weave together the historical, biochemical, immunological and molecular developments that have led to our current understanding of a deadly but treatable and potentially preventable disease. PMID- 20932268 TI - Homocysteine, cardiovascular inflammation, and myocardial remodeling. AB - Chronic heart failure is a major public health problem causing considerable morbidity and mortality. Recent studies have shown that an elevated plasma level of homocysteine is a strong independent risk factor for heart failure, in addition to atherosclerotic disease. Preclinical studies have demonstrated that induced hyperhomocysteinemia acts via multiple pathogenic mechanisms, including inflammation and oxidative stress, to promote adverse cardiac remodeling and failure. However, clinical studies have not conclusively shown a causative relation between hyperhomocysteinemia and cardiovascular disease. This article will review current data concerning homocysteine and its pathogenic relationship to heart failure. PMID- 20932270 TI - Neurology residency training in Europe--the current situation. AB - INTRODUCTION: Little is known about neurological training curricula in Europe. A joint approach by the European Federation of Neurological Societies (EFNS), the Union of European Medical Specialists/European Board of Neurology and the European Association of Young Neurologist and Trainees was established to explore the spectrum of neurology training in Europe. METHODS: In 2006, a questionnaire based survey on neurology curricula as well as demographic data was designed by WS and WG and distributed by the EFNS to the national delegates of the EFNS, which comprises all European countries and Israel. RESULTS: By 2009, delegates from 31 of 41 countries (representing 76% of 505 million) had returned the questionnaire. A total of 24,165 specialists (46% women) were registered in the 31 countries. This corresponds to an average of 6.6 neurologists per 100,000 inhabitants (range 0.9-17.4/100,000 inhabitants). Duration of training in Europe was on average 4.9,years, ranging from 3 to 6,years. The number of residents interested in neurological training exceeded the amount of available training positions. Performance of neurological trainees was regularly assessed in 26 countries (84%), usually by recurrent clinical evaluation. Board examinations were held in 23 countries (74%). Interim examinations were performed in three countries, exit examinations in 14 and both interim and exit examination in 6. Considerable differences were also found in manpower (0.9-17.4 neurologists/100,000 inhabitants) and working conditions (e.g. average weekly working hours ranging from 30-80 h/month). We found a significant positive correlation between manpower and theoretical training hours. CONCLUSION: Considerable differences exist in training curricula of European countries. These data might provide the basis for European training and quality assurance initiatives. PMID- 20932269 TI - Atherosclerosis-related functions of C-reactive protein. AB - C-reactive protein (CRP) is secreted by hepatocytes as a pentameric molecule made up of identical monomers, circulates in the plasma as pentamers, and localizes in atherosclerotic lesions. In some cases, localized CRP was detected by using monoclonal antibodies that did not react with native pentameric CRP but were specific for isolated monomeric CRP. It has been reported that, once CRP is bound to certain ligands, the pentameric structure of CRP is altered so that it can dissociate into monomers. Accordingly, the monomeric CRP found in atherosclerotic lesions may be a stationary, ligand-bound, by-product of a ligand-binding function of CRP. CRP binds to modified forms of low-density lipoprotein (LDL). The binding of CRP to oxidized LDL requires acidic pH conditions; the binding at physiological pH is controversial. The binding of CRP to enzymatically-modified LDL occurs at physiological pH; however, the binding is enhanced at acidic pH. Using enzymatically-modified LDL, CRP has been shown to prevent the formation of enzymatically-modified LDL-loaded macrophage foam cells. CRP is neither pro atherogenic nor atheroprotective in ApoE-(/)- and ApoB100(/)100Ldlr -(/)- murine models of atherosclerosis, except in one study where CRP was found to be slightly atheroprotective in ApoB100(/)100Ldlr -(/)- mice. The reasons for the ineffectiveness of human CRP in murine models of atherosclerosis are not defined. It is possible that an inflammatory environment, such as those characterized by acidic pH, is needed for efficient interaction between CRP and atherogenic LDL during the development of atherosclerosis and to observe the possible atheroprotective function of CRP in animal models. PMID- 20932271 TI - Do-it-yourself genetic testing. AB - We developed a computational screen that tests an individual's genome for mutations in the BRCA genes, despite the fact that both are currently protected by patents. PMID- 20932272 TI - Improved healing response in delayed unions of the tibia with low-intensity pulsed ultrasound: results of a randomized sham-controlled trial. AB - BACKGROUND: We compared the healing response of tibial delayed unions between subjects treated with low-intensity pulsed ultrasound (LIPUS) (n = 51) and subjects treated with a sham device (n = 50). Fracture age was >= 4 months in all cases. Study personnel and participants were blinded to random treatment assignment throughout the study. METHODS: This multi-center randomized sham controlled trial was undertaken at six hospitals in Germany. Adult patients who had sustained a tibial shaft fracture that subsequently showed inadequate progress toward healing (i.e., delayed union) were enrolled and randomized to receive either LIPUS (Exogen 2000/2000+, Smith & Nephew GmbH, Schenefeld, Germany) or an identical nonoperative sham device. The daily treatment duration was 20 minutes, for a period of 16 weeks. Subjects randomly assigned to active treatment had the ultrasound pressure wave signal set at the following parameters: 1.5 MHz frequency, 1 kHz repetition rate, 200 MUs pulse duration, 30 mW/cm2 spatial intensity. Progress toward healing was estimated from changes in bone mineral density (BMD) and gap area as determined from computed tomography scans. Intention-to-treat analysis was conducted using a multiple imputation methodology. RESULTS: Based on log-transformed data, mean improvement in BMD was 1.34 (90% confidence interval (CI) 1.14 to 1.57) times greater for LIPUS-treated subjects compared to sham (p = 0.002). A mean reduction in bone gap area also favored LIPUS treatment (p = 0.014). CONCLUSIONS: These findings demonstrate significantly greater progress toward bone healing after LIPUS treatment compared to no LIPUS treatment in subjects with established delayed unions of the tibia. PMID- 20932273 TI - Male mate choice scales female ornament allometry in a cichlid fish. AB - BACKGROUND: Studies addressing the adaptive significance of female ornamentation have gained ground recently. However, the expression of female ornaments in relation to body size, known as trait allometry, still remains unexplored. Here, we investigated the allometry of a conspicuous female ornament in Pelvicachromis taeniatus, a biparental cichlid that shows mutual mate choice and ornamentation. Females feature an eye-catching pelvic fin greatly differing from that of males. RESULTS: We show that allometry of the female pelvic fin is scaled more positively in comparison to other fins. The pelvic fin exhibits isometry, whereas the other fins (except the caudal fin) show negative allometry. The size of the pelvic fin might be exaggerated by male choice because males prefer female stimuli that show a larger extension of the trait. Female pelvic fin size is correlated with individual condition, suggesting that males can assess direct and indirect benefits. CONCLUSIONS: The absence of positive ornament allometry might be a result of sexual selection constricted by natural selection: fins are related to locomotion and thus may be subject to viability selection. Our study provides evidence that male mate choice might scale the expression of a female sexual ornament, and therefore has implications for the understanding of the relationship of female sexual traits with body size in species with conventional sex-roles. PMID- 20932274 TI - Financing the Millennium Development Goals for health and beyond: sustaining the 'Big Push'. AB - Many of the Millennium Development Goals are not being achieved in the world's poorest countries, yet only five years remain until the target date. The financing of these Goals is not merely insufficient; current evidence indicates that the temporary nature of the financing, as well as challenges to coordinating its delivery and directing it to the most needy recipients, hinder achievement of the Goals in countries that may benefit most. Traditional approaches to providing development assistance for health have not been able to address both prevalent and emergent public health challenges captured in the Goals; these challenges demand sustained forms of financial redistribution through a coordinated mechanism. A global social health protection fund is proposed to address recurring failures in the modern aid distribution mechanism. Such a Fund could use established and effective strategies for aid delivery to mitigate many financial problems currently undermining the Millennium Development Goals initiative. PMID- 20932275 TI - Decisions at the end of life: have we come of age? AB - Decision making is a complex process and it is particularly challenging to make decisions with, or for, patients who are near the end of their life. Some of those challenges will not be resolved - due to our human inability to foresee the future precisely and the human proclivity to change stated preferences when faced with reality. Other challenges of the decision-making process are manageable. This commentary offers a set of approaches which may lead to progress in this field. One clearly desirable approach can and should be used more often than it is: the routine inclusion of discussions about the goals of care and documentation with all patients who have a poor prognosis. The match between a patient's goals and the care received should be the gold standard for quality palliative care.Planning for future situations is necessary but hard. In order to achieve efficient elicitation and documentation of advance care planning, research is needed on each individual's thresholds for transitioning from curative to palliative intent and on the trajectory of changed preferences when illness occurs. Another clearly desirable approach is the documentation and use of community preferences, so that proxies making decisions without guidance from the patient can at least know what the majority of people considering similar situations chose to do.Part of the challenge of achieving 'quality dying' may have to do with the still current (mainly Western) tendency to a death-denying culture and the inability of dying people to enter into the dying role. Awareness of the tasks of the dying role and the provision of time and space for those tasks during the delivery of medical care is essential. Medicine needs to continue to enhance the existential maturity of our profession, our patients and the cultures in which we practice. This state of mind should provide for decisions made with a more settled acceptance of mortality and with more awareness of the necessary connection to our survivors and next generation that mortality creates. Specific interventions, such as Dignity Therapy and advance care planning, may aid this state of mind. PMID- 20932276 TI - LATS2 is de-methylated and overexpressed in nasopharyngeal carcinoma and predicts poor prognosis. AB - BACKGROUND: LATS2, which encodes a novel serine/threonine kinase, is known to be important in centrosome duplication and in the maintenance of genomic stability. Recently, a potential role for LATS2 in cancer has been reported. In breast cancer and acute lymphoblastic leukemia (ALL), LATS2 mRNA is downregulated and has been suggested to be a tumor suppressor. However, the role of LATS2 in nasopharyngeal carcinoma has not been investigated. In this study, we aimed to investigate the expression pattern of LATS2 and its clinicopathological involvement in nasopharyngeal carcinoma to understand its effect on cell survival. METHODS: Using quantitative real time PCR and immunoblotting, the expression of LATS2 was detected in nasopharyngeal carcinoma cell lines and in the immortalized nasopharyngeal epithelial cell line NP69. Using immunohistochemistry, we analyzed LATS2 protein expression in 220 nasopharyngeal carcinoma cases. The association of LATS2 protein expression with the clinicopathological characteristics and the prognosis of nasopharyngeal carcinoma were subsequently assessed. Using methylation specific PCR, we detected the methylation status of the LATS2 promoter. RNA interference was performed by transfecting siRNA to specifically knock down LATS2 expression in 5-8F and CNE2. RESULTS: LATS2 protein was detected in 178 of 220 (80.91%) cases of nasopharyngeal carcinoma. LATS2 overexpression was a significant, independent prognosis predictor (P = 0.037) in nasopharyngeal carcinoma patients. Methylation specific PCR revealed that 36.7% (11/30) of nasopharyngeal carcinoma tissues and all of the chronic nasopharyngeal inflammation samples were methylated. Functional studies showed that the suppression of LATS2 expression in nasopharyngeal carcinoma (5-8F and CNE2) cell lines by using specific small interfering (siRNA) resulted in the inhibition of growth, induction of apoptosis and S-phase cell cycle increase. Overexpression of LATS2 in NP69 stimulated cell proliferation. CONCLUSIONS: Our results indicate that LATS2 might play a role in the tumorigenesis of nasopharyngeal carcinoma by promoting the growth of nasopharyngeal carcinoma cells. Transfection with specific siRNA might be feasible for the inhibition of growth, induction of apoptosis and S phase increase in nasopharyngeal carcinoma. PMID- 20932277 TI - Global Health Education: a cross-sectional study among German medical students to identify needs, deficits and potential benefits (Part 1 of 2: Mobility patterns & educational needs and demands). AB - BACKGROUND: In recent years, education and training in global health has been the subject of recurring debate in many countries. However, in Germany, there has been no analysis of the educational needs or demands of medical students, or the educational deficits or potential benefits involved in global health education. Our purpose is to analyse international health elective patterns of medical students enrolled at German universities and assess whether or how they prepare for their electives abroad. We examine the exposure of medical students enrolled at German universities to training courses in tropical medicine or global health and assess students' perceived needs and demands for education in global health. METHODS: Cross-sectional study among medical students in Germany including all 36 medical schools during the second half of the year 2007. All registered medical students were eligible to participate in the study. Recruitment occurred via electronic mailing-lists of students' unions. We developed a web-based, semi structured questionnaire to capture students' international mobility patterns, preparation before electives, destination countries, exposure to and demand for global health learning opportunities. RESULTS: 1126 online-replies were received and analysed from all registered medical students in Germany (N = 78.067). 33.0% of all respondents (370/1126) declared at least one international health elective and of these, 36.0% (133/370) completed their electives in developing countries. 36.0% (131/363) did not prepare specifically at all, 59.0% (214/363) prepared either by self-study or declared a participation in specific preparation programmes. 87.8% of 5th and 6th year students had never participated in a global health course and 72.6% (209/288) had not completed a course in tropical medicine. 94.0% (861/916) endorsed the idea of introducing global health into medical education. CONCLUSION: Students in our sample are highly mobile during their studies. International health electives are common, also in developing countries. Formal preparation beyond self-study is virtually non-existent amongst our sample and the participation rate in courses of tropical medicine or global health is appallingly low. We have identified unmet perceived needs and the demand for more learning opportunities in global health in our sample, urging for reforms to adjust curricula to a globalising world. PMID- 20932278 TI - Global Health Education: a cross-sectional study among German medical students to identify needs, deficits and potential benefits (Part 2 of 2: Knowledge gaps and potential benefits). AB - BACKGROUND: In Germany, educational deficits or potential benefits involved in global health education have not been analysed till now. OBJECTIVE: We assess the importance medical students place on learning about social determinants of health (SDH) and assess their knowledge of global health topics in relation to (i) mobility patterns, their education in (ii) tropical medicine or (iii) global health. METHODS: Cross-sectional study among medical students from all 36 medical schools in Germany using a web-based, semi-structured questionnaire. Participants were recruited via mailing-lists of students' unions, all medical students registered in 2007 were eligible to participate in the study. We captured international mobility patterns, exposure to global health learning opportunities and attitudes to learning about SDH. Both an objective and subjective knowledge assessment were performed. RESULTS: 1126 online-replies were received and analysed. International health electives in developing countries correlated significantly with a higher importance placed on all provided SDH (p <= 0.006). Participation in tropical medicine (p < 0.03) and global health courses (p < 0.02) were significantly associated with a higher rating of 'culture, language and religion' and the 'economic system'. Global health trainings correlated with significantly higher ratings of the 'educational system' (p = 0.007) and the 'health system structure' (p = 0.007), while the item 'politics' was marginally significant (p = 0.053).In the knowledge assessment students achieved an average score of 3.6 (SD 1.5; Mdn 4.0), 75% achieved a score of 4.0 or less (Q25 = 3.0; Q75 = 4.0) from a maximum achievable score of 8.0. A better performance was associated with international health electives (p = 0.032), participation in tropical medicine (p = 0.038) and global health (p = 0.258) courses. CONCLUSION: The importance medical students in our sample placed on learning about SDH strongly interacts with students' mobility, and participation in tropical medicine and global health courses. The knowledge assessment revealed deficits and outlined needs to further analyse education gaps in global health. Developing concerted educational interventions aimed at fostering students' engagement with SDH could make full use of synergy effects inherent in student mobility, tropical medicine and global health education. PMID- 20932279 TI - Gene expression profiling in the stress control brain region hypothalamic paraventricular nucleus reveals a novel gene network including amyloid beta precursor protein. AB - BACKGROUND: The pivotal role of stress in the precipitation of psychiatric diseases such as depression is generally accepted. This study aims at the identification of genes that are directly or indirectly responding to stress. Inbred mouse strains that had been evidenced to differ in their stress response as well as in their response to antidepressant treatment were chosen for RNA profiling after stress exposure. Gene expression and regulation was determined by microarray analyses and further evaluated by bioinformatics tools including pathway and cluster analyses. RESULTS: Forced swimming as acute stressor was applied to C57BL/6J and DBA/2J mice and resulted in sets of regulated genes in the paraventricular nucleus of the hypothalamus (PVN), 4 h or 8 h after stress. Although the expression changes between the mouse strains were quite different, they unfolded in phases over time in both strains. Our search for connections between the regulated genes resulted in potential novel signalling pathways in stress. In particular, Guanine nucleotide binding protein, alpha inhibiting 2 (GNAi2) and amyloid beta (A4) precursor protein (APP) were detected as stress regulated genes, and together with other genes, seem to be integrated into stress responsive pathways and gene networks in the PVN. CONCLUSIONS: This search for stress-regulated genes in the PVN revealed its impact on interesting genes (GNAi2 and APP) and a novel gene network. In particular the expression of APP in the PVN that is governing stress hormone balance, is of great interest. The reported neuroprotective role of this molecule in the CNS supports the idea that a short acute stress can elicit positive adaptational effects in the brain. PMID- 20932280 TI - Association between actual weight status, perceived weight and depressive, anxious symptoms in Chinese adolescents: a cross-sectional study. AB - BACKGROUND: The purpose of this study was to describe actual measured weight and perceived weight and to explore associations with depressive, anxiety symptoms in school adolescents in China. METHODS: A sample of 1144 Chinese adolescents was randomly selected from four schools in Wuhan, China, including 665 boys and 479 girls with ages ranging between 10 and 17 years. Actual measured weight and height and perceived weight status were compared to anxiety and depressive symptoms measured using the revised Self-Rating Anxiety Scale and Children's Depression Inventory. A general linear model was used to compare differences in psychological symptoms among the teenagers with different measured and perceived weights. RESULTS: When compared with standardized weight tables (WHO age- and gender-specific body mass index (BMI) cutoffs (2007 reference)), girls were more likely to mis-perceive themselves as overweight, whereas more boys misclassified their weight status as underweight. The adolescents who perceived themselves as overweight were more likely to experience depressive and anxiety symptoms (except girls) than those who perceived themselves as normal and/or underweight. However, no significant association was found between depressive and anxiety symptoms actual measured weight status. CONCLUSIONS: Perceived weight status, but not the actual weight status, was associated with psychological symptoms. PMID- 20932281 TI - Analysis of X-ray structures of matrix metalloproteinases via chaotic map clustering. AB - BACKGROUND: Matrix metalloproteinases (MMPs) are well-known biological targets implicated in tumour progression, homeostatic regulation, innate immunity, impaired delivery of pro-apoptotic ligands, and the release and cleavage of cell surface receptors. With this in mind, the perception of the intimate relationships among diverse MMPs could be a solid basis for accelerated learning in designing new selective MMP inhibitors. In this regard, decrypting the latent molecular reasons in order to elucidate similarity among MMPs is a key challenge. RESULTS: We describe a pairwise variant of the non-parametric chaotic map clustering (CMC) algorithm and its application to 104 X-ray MMP structures. In this analysis electrostatic potentials are computed and used as input for the CMC algorithm. It was shown that differences between proteins reflect genuine variation of their electrostatic potentials. In addition, the analysis has been also extended to analyze the protein primary structures and the molecular shapes of the MMP co-crystallised ligands. CONCLUSIONS: The CMC algorithm was shown to be a valuable tool in knowledge acquisition and transfer from MMP structures. Based on the variation of electrostatic potentials, CMC was successful in analysing the MMP target family landscape and different subsites. The first investigation resulted in rational figure interpretation of both domain organization as well as of substrate specificity classifications. The second made it possible to distinguish the MMP classes, demonstrating the high specificity of the S1' pocket, to detect both the occurrence of punctual mutations of ionisable residues and different side-chain conformations that likely account for induced fit phenomena. In addition, CMC demonstrated a potential comparable to the most popular UPGMA (Unweighted Pair Group Method with Arithmetic mean) method that, at present, represents a standard clustering bioinformatics approach. Interestingly, CMC and UPGMA resulted in closely comparable outcomes, but often CMC produced more informative and more easy interpretable dendrograms. Finally, CMC was successful for standard pairwise analysis (i.e., Smith-Waterman algorithm) of protein sequences and was used to convincingly explain the complementarity existing between the molecular shapes of the co-crystallised ligand molecules and the accessible MMP void volumes. PMID- 20932282 TI - Effect of dietary intervention on serum lignan levels in pregnant women - a controlled trial. AB - BACKGROUND: Mother's diet during pregnancy is important, since plant lignans and their metabolites, converted by the intestinal microflora to enterolignans, are proposed to possess multiple health benefits. Aim of our study was to investigate whether a dietary intervention affects lignan concentrations in the serum of pregnant women. METHODS: A controlled dietary intervention trial including 105 first-time pregnant women was conducted in three intervention and three control maternity health clinics. The intervention included individual counseling on diet and on physical activity, while the controls received conventional care. Blood samples were collected on gestation weeks 8-9 (baseline) and 36-37 (end of intervention). The serum levels of the plant lignans 7-hydroxymatairesinol, secoisolariciresinol, matairesinol, lariciresinol, cyclolariciresinol, and pinoresinol, and of the enterolignans 7-hydroxyenterolactone, enterodiol, and enterolactone, were measured using a validated method. RESULTS: The baseline levels of enterolactone, enterodiol and the sum of lignans were higher in the control group, whereas at the end of the trial their levels were higher in the intervention group. The adjusted mean differences between the baseline and end of the intervention for enterolactone and the total lignan intake were 1.6 ng/ml (p = 0.018, 95% CI 1.1-2.3) and 1.4 ng/mg (p = 0.08, 95% CI 1.0-1.9) higher in the intervention group than in the controls. Further adjustment for dietary components did not change these associations. CONCLUSION: The dietary intervention was successful in increasing the intake of lignan-rich food products, the fiber consumption and consequently the plasma levels of lignans in pregnant women. TRIAL REGISTRATION: ISRCTN21512277, http://www.isrctn.org. PMID- 20932283 TI - Mutational spectrum of the SPG4 (SPAST) and SPG3A (ATL1) genes in Spanish patients with hereditary spastic paraplegia. AB - BACKGROUND: Hereditary Spastic Paraplegias (HSP) are characterized by progressive spasticity and weakness of the lower limbs. At least 45 loci have been identified in families with autosomal dominant (AD), autosomal recessive (AR), or X-linked hereditary patterns. Mutations in the SPAST (SPG4) and ATL1 (SPG3A) genes would account for about 50% of the ADHSP cases. METHODS: We defined the SPAST and ATL1 mutational spectrum in a total of 370 unrelated HSP index cases from Spain (83% with a pure phenotype). RESULTS: We found 50 SPAST mutations (including two large deletions) in 54 patients and 7 ATL1 mutations in 11 patients. A total of 33 of the SPAST and 3 of the ATL1 were new mutations. A total of 141 (31%) were familial cases, and we found a higher frequency of mutation carriers among these compared to apparently sporadic cases (38% vs. 5%). Five of the SPAST mutations were predicted to affect the pre-mRNA splicing, and in 4 of them we demonstrated this effect at the cDNA level. In addition to large deletions, splicing, frameshifting, and missense mutations, we also found a nucleotide change in the stop codon that would result in a larger ORF. CONCLUSIONS: In a large cohort of Spanish patients with spastic paraplegia, SPAST and ATL1 mutations were found in 15% of the cases. These mutations were more frequent in familial cases (compared to sporadic), and were associated with heterogeneous clinical manifestations. PMID- 20932284 TI - Predicting enzyme targets for cancer drugs by profiling human metabolic reactions in NCI-60 cell lines. AB - BACKGROUND: Drugs can influence the whole metabolic system by targeting enzymes which catalyze metabolic reactions. The existence of interactions between drugs and metabolic reactions suggests a potential way to discover drug targets. RESULTS: In this paper, we present a computational method to predict new targets for approved anti-cancer drugs by exploring drug-reaction interactions. We construct a Drug-Reaction Network to provide a global view of drug-reaction interactions and drug-pathway interactions. The recent reconstruction of the human metabolic network and development of flux analysis approaches make it possible to predict each metabolic reaction's cell line-specific flux state based on the cell line-specific gene expressions. We first profile each reaction by its flux states in NCI-60 cancer cell lines, and then propose a kernel k-nearest neighbor model to predict related metabolic reactions and enzyme targets for approved cancer drugs. We also integrate the target structure data with reaction flux profiles to predict drug targets and the area under curves can reach 0.92. CONCLUSIONS: The cross validations using the methods with and without metabolic network indicate that the former method is significantly better than the latter. Further experiments show the synergism of reaction flux profiles and target structure for drug target prediction. It also implies the significant contribution of metabolic network to predict drug targets. Finally, we apply our method to predict new reactions and possible enzyme targets for cancer drugs. PMID- 20932286 TI - The quest for universal access to effective malaria treatment: how can the AMFm contribute? AB - Access to quality assured artemisinin-based combination therapy (ACT) has remained very low in most malaria endemic countries. A number of reasons, including unaffordable prices, have contributed to the low accessibility to these life-saving medicines. The Affordable Medicines Facility-Malaria (AMFm) is a mechanism to increase access to quality assured ACT. The AMFm will use price signals and a combination of public and private sector channels to achieve multiple public health objectives: replacing older and increasingly ineffective anti-malarial medicines, such as chloroquine and sulphadoxine-pyrimethamine with ACT, displacing oral artemisinin monotherapies from the market, and prolonging the lifespan of ACT by reducing the likelihood of resistance to artemisinin.Access to medicines frameworks paint a broad picture of dimensions of access to medicines and juxtapose components that enhance or hinder access to medicines. Access requires various activities--funding, institutions, interventions, and thinking--from public and private actors at global, national, and local levels. This paper examines, within access to medicines frameworks, the role of the AMFm across and within each dimension and discusses how the AMFm can help to solve access bottlenecks. PMID- 20932285 TI - Circulating retinol binding protein 4 in critically ill patients before specific treatment: prognostic impact and correlation with organ function, metabolism and inflammation. AB - INTRODUCTION: Hyperglycemia and insulin resistance are well-known features of critical illness and impact the mortality rate, especially in sepsis. Retinol binding protein 4 (RBP4) promotes insulin resistance in mice and is systemically elevated in patients with obesity and type 2 diabetes. We investigated the potential role of RBP4 in critically ill patients. METHODS: We conducted a prospective single-center study of serum RBP4 concentrations in critically ill patients. One hundred twenty-three patients (85 with sepsis, 38 without sepsis) were studied at admission to a medical intensive care unit (ICU) before initiation of specific intensive care treatment measures and compared to 42 healthy nondiabetic controls. Clinical data, various laboratory parameters and metabolic and endocrine functions were assessed. Patients were followed for approximately 3 years. RESULTS: Serum RBP4 was significantly reduced in ICU patients, independently of sepsis, as compared to healthy controls (P < 0.001). Patients with liver cirrhosis as the primary underlying diagnosis for ICU admission had significantly lower RBP4 levels as compared with other ICU patients. Accordingly, in all ICU patients, serum RBP4 closely correlated with liver function and increased with renal failure. No significant differences of serum RBP4 concentrations in septic patients with pulmonary or other origins of sepsis or nonseptic patients could be revealed. Acute phase proteins were inversely correlated with RBP4 in sepsis patients. RBP4 did not differ between patients with or without obesity or preexisting diabetes. However, serum RBP4 levels correlated with endogenous insulin secretion (C-peptide) and insulin resistance (HOMA index). Low serum RBP4 upon admission was an adverse predictor of short-term survival in the ICU, but was not associated with overall survival during long-term follow-up. CONCLUSIONS: Serum RBP4 concentrations are significantly reduced in critically ill patients. The strong associations with hepatic and renal function, insulin resistance and acute mortality collectively suggest a role of RBP4 in the pathogenesis of critical illness, possibly as a negative acute phase reactant, and allow a proposition as a potential novel biomarker for ICU patients. PMID- 20932287 TI - Gene expression in a paleopolyploid: a transcriptome resource for the ciliate Paramecium tetraurelia. AB - BACKGROUND: The genome of Paramecium tetraurelia, a unicellular model that belongs to the ciliate phylum, has been shaped by at least 3 successive whole genome duplications (WGD). These dramatic events, which have also been documented in plants, animals and fungi, are resolved over evolutionary time by the loss of one duplicate for the majority of genes. Thanks to a low rate of large scale genome rearrangement in Paramecium, an unprecedented large number of gene duplicates of different ages have been identified, making this organism an outstanding model to investigate the evolutionary consequences of polyploidization. The most recent WGD, with 51% of pre-duplication genes still in 2 copies, provides a snapshot of a phase of rapid gene loss that is not accessible in more ancient polyploids such as yeast. RESULTS: We designed a custom oligonucleotide microarray platform for P. tetraurelia genome-wide expression profiling and used the platform to measure gene expression during 1) the sexual cycle of autogamy, 2) growth of new cilia in response to deciliation and 3) biogenesis of secretory granules after massive exocytosis. Genes that are differentially expressed during these time course experiments have expression patterns consistent with a very low rate of subfunctionalization (partition of ancestral functions between duplicated genes) in particular since the most recent polyploidization event. CONCLUSIONS: A public transcriptome resource is now available for Paramecium tetraurelia. The resource has been integrated into the ParameciumDB model organism database, providing searchable access to the data. The microarray platform, freely available through NimbleGen Systems, provides a robust, cost-effective approach for genome-wide expression profiling in P. tetraurelia. The expression data support previous studies showing that at short evolutionary times after a whole genome duplication, gene dosage balance constraints and not functional change are the major determinants of gene retention. PMID- 20932288 TI - A systematic review of PET and PET/CT in oncology: a way to personalize cancer treatment in a cost-effective manner? AB - BACKGROUND: A number of diagnostic tests are required for the detection and management of cancer. Most imaging modalities such as computerized tomography (CT) are anatomical. However, positron emission tomography (PET) is a functional diagnostic imaging technique using compounds labelled with positron-emitting radioisotopes to measure cell metabolism. It has been a useful tool in studying soft tissues such as the brain, cardiovascular system, and cancer. The aim of this systematic review is to critically summarize the health economic evidence of oncologic PET in the literature. METHODS: Eight electronic databases were searched from 2005 until February 2010 to identify economic evaluation studies not included in previous Health Technology Assessment (HTA) reports. Only full health economic evaluations in English, French, or German were considered for inclusion. Economic evaluations were appraised using published quality criteria for assessing the quality of decision-analytic models. Given the variety of methods used in the health economic evaluations, the economic evidence has been summarized in qualitative form. RESULTS: From this new search, 14 publications were identified that met the inclusion criteria. All publications were decision analytic models and evaluated PET using Fluorodeoxyglucose F18 (FDG-PET). Eight publications were cost-effectiveness analyses; six were cost-utility analyses. The studies were from Australia, Belgium, Canada, France, Italy, Taiwan, Japan, the Netherlands, the United Kingdom, and the United States. In the base case analyses of these studies, cost-effectiveness results ranged from dominated to dominant. The methodology of the economic evaluations was of varying quality. Cost-effectiveness was primarily influenced by the cost of PET, the specificity of PET, and the risk of malignancy. CONCLUSIONS: Owing to improved care and less exposure to ineffective treatments, personalized medicine using PET may be cost effective. However, the strongest evidence for the cost-effectiveness of PET is still in the staging of non-small cell lung cancer. Management decisions relating to the assessment of treatment response or radiotherapy treatment planning require further research to show the impact of PET on patient management and its cost-effectiveness. Because of the potential for increased patient throughput and the possible greater accuracy, the cost-effectiveness of PET/CT may be superior to that of PET. Only four studies of the cost-effectiveness of PET/CT were found in this review, and this is clearly an area for future research. PMID- 20932289 TI - Improved variant discovery through local re-alignment of short-read next generation sequencing data using SRMA. AB - A primary component of next-generation sequencing analysis is to align short reads to a reference genome, with each read aligned independently. However, reads that observe the same non-reference DNA sequence are highly correlated and can be used to better model the true variation in the target genome. A novel short-read micro realigner, SRMA, that leverages this correlation to better resolve a consensus of the underlying DNA sequence of the targeted genome is described here. PMID- 20932290 TI - The IGNITE (investigation to guide new insight into translational effectiveness) trial: Protocol for a translational study of an evidenced-based wellness program in fire departments. AB - BACKGROUND: Worksites are important locations for interventions to promote health. However, occupational programs with documented efficacy often are not used, and those being implemented have not been studied. The research in this report was funded through the American Reinvestment and Recovery Act Challenge Topic 'Pathways for Translational Research,' to define and prioritize determinants that enable and hinder translation of evidenced-based health interventions in well-defined settings. METHODS: The IGNITE (investigation to guide new insights for translational effectiveness) trial is a prospective cohort study of a worksite wellness and injury reduction program from adoption to final outcomes among 12 fire departments. It will employ a mixed methods strategy to define a translational model. We will assess decision to adopt, installation, use, and outcomes (reach, individual outcomes, and economic effects) using onsite measurements, surveys, focus groups, and key informant interviews. Quantitative data will be used to define the model and conduct mediation analysis of each translational phase. Qualitative data will expand on, challenge, and confirm survey findings and allow a more thorough understanding and convergent validity by overcoming biases in qualitative and quantitative methods used alone. DISCUSSION: Findings will inform worksite wellness in fire departments. The resultant prioritized influences and model of effective translation can be validated and manipulated in these and other settings to more efficiently move science to service. PMID- 20932291 TI - Women's experiences of wearing therapeutic footwear in three European countries. AB - BACKGROUND: Therapeutic footwear is recommended for those people with severe foot problems associated with rheumatoid arthritis (RA). However, it is known that many do not wear them. Although previous European studies have recommended service and footwear design improvements, it is not known if services have improved or if this footwear meets the personal needs of people with RA. As an earlier study found that this footwear has more impact on women than males, this study explores women's experiences of the process of being provided with it and wearing it. No previous work has compared women's experiences of this footwear in different countries, therefore this study aimed to explore the potential differences between the UK, the Netherlands and Spain. METHOD: Women with RA and experience of wearing therapeutic footwear were purposively recruited. Ten women with RA were interviewed in each of the three countries. An interpretive phenomenological approach (IPA) was adopted during data collection and analysis. Conversational style interviews were used to collect the data. RESULTS: Six themes were identified: feet being visibly different because of RA; the referring practitioners' approach to the patient; the dispensing practitioners' approach to the patient; the footwear being visible as different to others; footwear influencing social participation; and the women's wishes for improved footwear services. Despite their nationality, these women revealed that therapeutic footwear invokes emotions of sadness, shame and anger and that it is often the final and symbolic marker of the effects of RA on self perception and their changed lives. This results in severe restriction of important activities, particularly those involving social participation. However, where a patient focussed approach was used, particularly by the practitioners in Spain and the Netherlands, the acceptance of this footwear was much more evident and there was less wastage as a result of the footwear being prescribed and then not worn. In the UK, the women were more likely to passively accept the footwear with the only choice being to reject it once it had been provided. All the women were vocal about what would improve their experiences and this centred on the consultation with both the referring practitioner and the practitioner that provides the footwear. CONCLUSION: This unique study, carried out in three countries has revealed emotive and personal accounts of what it is like to have an item of clothing replaced with an 'intervention'. The participant's experience of their consultations with practitioners has revealed the tension between the practitioners' requirements and the women's 'social' needs. Practitioners need greater understanding of the social and emotional consequences of using therapeutic footwear as an intervention. PMID- 20932292 TI - Genome profiling of ERBB2-amplified breast cancers. AB - BACKGROUND: Around 20% of breast cancers (BC) show ERBB2 gene amplification and overexpression of the ERBB2 tyrosine kinase receptor. They are associated with a poor prognosis but can benefit from targeted therapy. A better knowledge of these BCs, genomically and biologically heterogeneous, may help understand their behavior and design new therapeutic strategies. METHODS: We defined the high resolution genome and gene expression profiles of 54 ERBB2-amplified BCs using 244K oligonucleotide array-comparative genomic hybridization and whole-genome DNA microarrays. Expression of ERBB2, phosphorylated ERBB2, EGFR, IGF1R and FOXA1 proteins was assessed by immunohistochemistry to evaluate the functional ERBB2 status and identify co-expressions. RESULTS: First, we identified the ERBB2 C17orf37-GRB7 genomic segment as the minimal common 17q12-q21 amplicon, and CRKRS and IKZF3 as the most frequent centromeric and telomeric amplicon borders, respectively. Second, GISTIC analysis identified 17 other genome regions affected by copy number aberration (CNA) (amplifications, gains, losses). The expression of 37 genes of these regions was deregulated. Third, two types of heterogeneity were observed in ERBB2-amplified BCs. The genomic profiles of estrogen receptor positive (ER+) and negative (ER-) ERBB2-amplified BCs were different. The WNT/beta-catenin signaling pathway was involved in ER- ERBB2-amplified BCs, and PVT1 and TRPS1 were candidate oncogenes associated with ER+ ERBB2-amplified BCs. The size of the ERBB2 amplicon was different in inflammatory (IBC) and non inflammatory BCs. ERBB2-amplified IBCs were characterized by the downregulated and upregulated mRNA expression of ten and two genes in proportion to CNA, respectively. IHC results showed (i) a linear relationship between ERBB2 gene amplification and its gene and protein expressions with a good correlation between ERBB2 expression and phosphorylation status; (ii) a potential signaling cross-talk between EGFR or IGF1R and ERBB2, which could influence response of ERBB2-positive BCs to inhibitors. FOXA1 was frequently coexpressed with ERBB2 but its expression did not impact on the outcome of patients with ERBB2-amplified tumors. CONCLUSION: We have shown that ER+ and ER- ERBB2-amplified BCs are different, distinguished ERBB2 amplicons in IBC and non-IBC, and identified genomic features that may be useful in the design of alternative therapeutical strategies. PMID- 20932293 TI - Reducing errors in health care: cost-effectiveness of multidisciplinary team training in obstetric emergencies (TOSTI study); a randomised controlled trial. AB - BACKGROUND: There are many avoidable deaths in hospitals because the care team is not well attuned. Training in emergency situations is generally followed on an individual basis. In practice, however, hospital patients are treated by a team composed of various disciplines. To prevent communication errors, it is important to focus the training on the team as a whole, rather than on the individual. Team training appears to be important in contributing toward preventing these errors. Obstetrics lends itself to multidisciplinary team training. It is a field in which nurses, midwives, obstetricians and paediatricians work together and where decisions must be made and actions must be carried out under extreme time pressure.It is attractive to belief that multidisciplinary team training will reduce the number of errors in obstetrics. The other side of the medal is that many hospitals are buying expensive patient simulators without proper evaluation of the training method. In the Netherlands many hospitals have 1,000 or less annual deliveries. In our small country it might therefore be more cost-effective to train obstetric teams in medical simulation centres with well trained personnel, high fidelity patient simulators, and well defined training programmes. METHODS/DESIGN: The aim of the present study is to evaluate the cost effectiveness of multidisciplinary team training in a medical simulation centre in the Netherlands to reduce the number of medical errors in obstetric emergency situations. We plan a multicentre randomised study with the centre as unit of analysis. Obstetric departments will be randomly assigned to receive multidisciplinary team training in a medical simulation centre or to a control arm without any team training.The composite measure of poor perinatal and maternal outcome in the non training group was thought to be 15%, on the basis of data obtained from the National Dutch Perinatal Registry and the guidelines of the Dutch Society of Obstetrics and Gynaecology (NVOG). We anticipated that multidisciplinary team training would reduce this risk to 5%. A sample size of 24 centres with a cluster size of each at least 200 deliveries, each 12 centres per group, was needed for 80% power and a 5% type 1 error probability (two-sided). We assumed an Intraclass Correlation Coefficient (ICC) value of maximum 0.08.The analysis will be performed according to the intention-to-treat principle and stratified for teaching or non-teaching hospitals.Primary outcome is the number of obstetric complications throughout the first year period after the intervention. If multidisciplinary team training appears to be effective a cost effective analysis will be performed. DISCUSSION: If multidisciplinary team training appears to be cost-effective, this training should be implemented in extra training for gynaecologists. TRIAL REGISTRATION: The protocol is registered in the clinical trial register number NTR1859. PMID- 20932294 TI - Effects of supplemental fish oil on resting metabolic rate, body composition, and salivary cortisol in healthy adults. AB - BACKGROUND: To determine the effects of supplemental fish oil (FO) on resting metabolic rate (RMR), body composition, and cortisol production in healthy adults. METHODS: A total of 44 men and women (34 +/- 13y, mean+SD) participated in the study. All testing was performed first thing in the morning following an overnight fast. Baseline measurements of RMR were measured using indirect calorimetry using a facemask, and body composition was measured using air displacement plethysmography. Saliva was collected via passive drool and analyzed for cortisol concentration using ELISA. Following baseline testing, subjects were randomly assigned in a double blind manner to one of two groups: 4 g/d of Safflower Oil (SO); or 4 g/d of FO supplying 1,600 mg/d eicosapentaenoic acid (EPA) and 800 mg/d docosahexaenoic acid (DHA). All tests were repeated following 6 wk of treatment. Pre to post differences were analyzed using a treatment X time repeated measures ANOVA, and correlations were analyzed using Pearson's r. RESULTS: Compared to the SO group, there was a significant increase in fat free mass following treatment with FO (FO = +0.5 +/- 0.5 kg, SO = -0.1 +/- 1.2 kg, p = 0.03), a significant reduction in fat mass (FO = -0.5 +/- 1.3 kg, SO = +0.2 +/- 1.2 kg, p = 0.04), and a tendency for a decrease in body fat percentage (FO = 0.4 +/- 1.3% body fat, SO = +0. 3 +/- 1.5% body fat, p = 0.08). No significant differences were observed for body mass (FO = 0.0 +/- 0.9 kg, SO = +0.2 +/- 0.8 kg), RMR (FO = +17 +/- 260 kcal, SO = -62 +/- 184 kcal) or respiratory exchange ratio (FO = -0.02 +/- 0.09, SO = +0.02 +/- 0.05). There was a tendency for salivary cortisol to decrease in the FO group (FO = -0.064 +/- 0.142 MUg/dL, SO = +0.016 +/- 0.272 MUg/dL, p = 0.11). There was a significant correlation in the FO group between change in cortisol and change in fat free mass (r = -0.504, p = 0.02) and fat mass (r = 0.661, p = 0.001). CONCLUSION: 6 wk of supplementation with FO significantly increased lean mass and decreased fat mass. These changes were significantly correlated with a reduction in salivary cortisol following FO treatment. PMID- 20932295 TI - S110, a novel decitabine dinucleotide, increases fetal hemoglobin levels in baboons (P. anubis). AB - BACKGROUND: S110 is a novel dinucleoside analog that could have advantages over existing DNA methyltransferase (DNMT) inhibitors such as decitabine. A potential therapeutic role for S110 is to increase fetal hemoglobin (HbF) levels to treat beta-hemoglobinopathies. In these experiments the effect of S110 on HbF levels in baboons and its ability to reduce DNA methylation of the gamma-globin gene promoter in vivo were evaluated. METHODS: The effect of S110 on HbF and gamma globin promoter DNA methylation was examined in cultured human erythroid progenitors and in vivo in the baboon pre-clinical model. S110 pharmacokinetics was also examined in the baboon model. RESULTS: S110 increased HbF and reduced DNA methylation of the gamma-globin promoter in human erythroid progenitors and in baboons when administered subcutaneously. Pharmacokinetic analysis was consistent with rapid conversion of S110 into the deoxycytosine analog decitabine that binds and depletes DNA. CONCLUSION: S110 is rapidly converted into decitabine, hypomethylates DNA, and induces HbF in cultured human erythroid progenitors and the baboon pre-clinical model. PMID- 20932296 TI - The association between retraction of the torn rotator cuff and increasing expression of hypoxia inducible factor 1alpha and vascular endothelial growth factor expression: an immunohistological study. AB - BACKGROUND: Differing levels of tendon retraction are found in full-thickness rotator cuff tears. The pathophysiology of tendon degeneration and retraction is unclear. Neoangiogenesis in tendon parenchyma indicates degeneration. Hypoxia inducible factor 1alpha (HIF) and vascular endothelial growth factor (VEGF) are important inducers of neoangiogenesis. Rotator cuff tendons rupture leads to fatty muscle infiltration (FI) and muscle atrophy (MA). The aim of this study is to clarify the relationship between HIF and VEGF expression, neoangiogenesis, FI, and MA in tendon retraction found in full-thickness rotator cuff tears. METHODS: Rotator cuff tendon samples of 33 patients with full-thickness medium-sized rotator cuff tears were harvested during reconstructive surgery. The samples were dehydrated and paraffin embedded. For immunohistological determination of VEGF and HIF expression, sample slices were strained with VEGF and HIF antibody dilution. Vessel density and vessel size were determined after Masson-Goldner staining of sample slices. The extent of tendon retraction was determined intraoperatively according to Patte's classification. Patients were assigned to 4 categories based upon Patte tendon retraction grade, including one control group. FI and MA were measured on standardized preoperative shoulder MRI. RESULTS: HIF and VEGF expression, FI, and MA were significantly higher in torn cuff samples compared with healthy tissue (p < 0.05). HIF and VEGF expression, and vessel density significantly increased with extent of tendon retraction (p < 0.05). A correlation between HIF/VEGF expression and FI and MA could be found (p < 0.05). There was no significant correlation between HIF/VEGF expression and neovascularity (p > 0.05) CONCLUSION: Tendon retraction in full-thickness medium sized rotator cuff tears is characterized by neovascularity, increased VEGF/HIF expression, FI, and MA. VEGF expression and neovascularity may be effective monitoring tools to assess tendon degeneration. PMID- 20932297 TI - Categorizing and comparing psychophysical detection strategies based on biomechanical responses to short postural perturbations. AB - BACKGROUND: A fundamental unsolved problem in psychophysical detection experiments is in discriminating guesses from the correct responses. This paper proposes a coherent solution to this problem by presenting a novel classification method that compares biomechanical and psychological responses. METHODS: Subjects (13) stood on a platform that was translated anteriorly 16 mm to find psychophysical detection thresholds through a Adaptive 2-Alternative-Forced Choice (2AFC) task repeated over 30 separate sequential trials. Anterior posterior center-of-pressure (APCoP) changes (i.e., the biomechanical response R(B)) were analyzed to determine whether sufficient biomechanical information was available to support a subject's psychophysical selection (R(Psi)) of interval 1 or 2 as the stimulus interval. A time-series-bitmap approach was used to identify anomalies in interval 1 (a1) and interval 2 (a2) that were present in the resultant APCoP signal. If a1 > a2 then R(B) = Interval 1. If a1 < a2, then R(B)= Interval 2. If a2-a1 < 0.1, R(B) was set to 0 (no significant difference present in the anomaly scores of interval 1 and 2). RESULTS: By considering both biomechanical (R(B)) and psychophysical (R(Psi)) responses, each trial run could be classified as a: 1) HIT (and True Negative), if R(B) and R(Psi) both matched the stimulus interval (SI); 2) MISS, if R(B) matched SI but the subject's reported response did not; 3) PSUEDO HIT, if the subject signalled the correct SI, but R(B) was linked to the non-SI; 4) FALSE POSITIVE, if R(B) = R(Psi), and both associated to non-SI; and 5) GUESS, if R(B) = 0, if insufficient APCoP differences existed to distinguish SI. Ensemble averaging the data for each of the above categories amplified the anomalous behavior of the APCoP response. CONCLUSIONS: The major contributions of this novel classification scheme were to define and verify by logistic models a 'GUESS' category in these psychophysical threshold detection experiments, and to add an additional descriptor, "PSEUDO HIT". This improved classification methodology potentially could be applied to psychophysical detection experiments of other sensory modalities. PMID- 20932298 TI - The prevalence of angina symptoms and association with cardiovascular risk factors, among rural, urban and rural to urban migrant populations in Peru. AB - BACKGROUND: Rural-to-urban migration in low- and middle-income countries causes an increase in individual cardiovascular risk. Cost-effective interventions at early stages of the natural history of coronary disease such as angina may stem an epidemic of premature coronary deaths in these countries. However, there are few data on the prevalence of angina in developing countries, whilst the understanding the aetiology of angina is complicated by the difficulty in measuring it across differing populations. METHODS: The PERU MIGRANT study was designed to investigate differences between rural-to-urban migrant and non migrant groups in specific cardiovascular disease risk factors. Mass-migration seen in Peru from 1980s onwards was largely driven by politically motivated violence resulting in less 'healthy migrant' selection bias. The Rose angina questionnaire was used to record chest pain, which was classified definite, possible and non-exertional. Mental health was measured using the General Health Questionnaire (GHQ-12). Mantel-Haenszel odds ratios (adjusted for age, sex, cardiovascular disease risk factors and mental health) were used to assess the risk of chest pain in the migrant and urban groups compared to the rural group, and further to assess the relationship (age and sex-adjusted) between risk factors, mental health and chest pain. RESULTS: Compared to the urban group, rural dwellers had a greatly increased likelihood of possible/definite angina (multi-adjusted OR 2.82 (1.68- 4.73)). Urban and migrant groups had higher levels of risk factors (e.g. smoking--20.1% urban, 5.5% rural). No diabetes was seen in the rural dwellers who complained of possible/definite angina. Rural dwellers had a higher prevalence of mood disorder and the presence of a mood disorder was associated with possible/definite angina in all three groups, but not consistently with non-exertional chest pain. CONCLUSION: Rural groups had a higher prevalence of angina as measured by Rose questionnaire than migrants and urban dwellers, and a higher prevalence of mood disorder. The presence of a mood disorder was associated with angina. The Rose angina questionnaire may not be of relevance to rural populations in developing countries with a low pre-test probability of coronary disease and poor mental health. PMID- 20932299 TI - Dynamic transcriptomic profiles of zebrafish gills in response to zinc depletion. AB - BACKGROUND: Zinc deficiency is detrimental to organisms, highlighting its role as an essential micronutrient contributing to numerous biological processes. To investigate the underlying molecular events invoked by zinc depletion we performed a temporal analysis of transcriptome changes observed within the zebrafish gill. This tissue represents a model system for studying ion absorption across polarised epithelial cells as it provides a major pathway for fish to acquire zinc directly from water whilst sharing a conserved zinc transporting system with mammals. RESULTS: Zebrafish were treated with either zinc-depleted (water = 2.61 MUg L-1; diet = 26 mg kg-1) or zinc-adequate (water = 16.3 MUg L-1; diet = 233 mg kg-1) conditions for two weeks. Gill samples were collected at five time points and transcriptome changes analysed in quintuplicate using a 16K oligonucleotide array. Of the genes represented the expression of a total of 333 transcripts showed differential regulation by zinc depletion (having a fold change greater than 1.8 and an adjusted P-value less than 0.1, controlling for a 10% False Discovery Rate). Down-regulation was dominant at most time points and distinct sets of genes were regulated at different stages. Annotation enrichment analysis revealed that 'Developmental Process' was the most significantly overrepresented Biological Process GO term (P = 0.0006), involving 26% of all regulated genes. There was also significant bias for annotations relating to development, cell cycle, cell differentiation, gene regulation, butanoate metabolism, lysine degradation, protein tyrosin phosphatases, nucleobase, nucleoside and nucleotide metabolism, and cellular metabolic processes. Within these groupings genes associated with diabetes, bone/cartilage development, and ionocyte proliferation were especially notable. Network analysis of the temporal expression profile indicated that transcription factors foxl1, wt1, nr5a1, nr6a1, and especially, hnf4a may be key coordinators of the homeostatic response to zinc depletion. CONCLUSIONS: The study revealed the complex regulatory pathways that allow the organism to subtly respond to the low-zinc condition. Many of the processes affected reflected a fundamental restructuring of the gill epithelium through reactivation of developmental programs leading to stem cell differentiation. The specific regulation of genes known to be involved in development of diabetes provides new molecular links between zinc deficiency and this disease. The present study demonstrates the importance of including the time dimension in microarray studies. PMID- 20932300 TI - Molecular and phylogenetic characterization of the sieve element occlusion gene family in Fabaceae and non-Fabaceae plants. AB - BACKGROUND: The phloem of dicotyledonous plants contains specialized P-proteins (phloem proteins) that accumulate during sieve element differentiation and remain parietally associated with the cisternae of the endoplasmic reticulum in mature sieve elements. Wounding causes P-protein filaments to accumulate at the sieve plates and block the translocation of photosynthate. Specialized, spindle-shaped P-proteins known as forisomes that undergo reversible calcium-dependent conformational changes have evolved exclusively in the Fabaceae. Recently, the molecular characterization of three genes encoding forisome components in the model legume Medicago truncatula (MtSEO1, MtSEO2 and MtSEO3; SEO = sieve element occlusion) was reported, but little is known about the molecular characteristics of P-proteins in non-Fabaceae. RESULTS: We performed a comprehensive genome-wide comparative analysis by screening the M. truncatula, Glycine max, Arabidopsis thaliana, Vitis vinifera and Solanum phureja genomes, and a Malus domestica EST library for homologs of MtSEO1, MtSEO2 and MtSEO3 and identified numerous novel SEO genes in Fabaceae and even non-Fabaceae plants, which do not possess forisomes. Even in Fabaceae some SEO genes appear to not encode forisome components. All SEO genes have a similar exon-intron structure and are expressed predominantly in the phloem. Phylogenetic analysis revealed the presence of several subgroups with Fabaceae-specific subgroups containing all of the known as well as newly identified forisome component proteins. We constructed Hidden Markov Models that identified three conserved protein domains, which characterize SEO proteins when present in combination. In addition, one common and three subgroup specific protein motifs were found in the amino acid sequences of SEO proteins. SEO genes are organized in genomic clusters and the conserved synteny allowed us to identify several M. truncatula vs G. max orthologs as well as paralogs within the G. max genome. CONCLUSIONS: The unexpected occurrence of forisome-like genes in non-Fabaceae plants may indicate that these proteins encode species-specific P-proteins, which is backed up by the phloem-specific expression profiles. The conservation of gene structure, the presence of specific motifs and domains and the genomic synteny argue for a common phylogenetic origin of forisomes and other P-proteins. PMID- 20932301 TI - Mutations that permit residual CFTR function delay acquisition of multiple respiratory pathogens in CF patients. AB - BACKGROUND: Lung infection by various organisms is a characteristic feature of cystic fibrosis (CF). CFTR genotype effects acquisition of Pseudomonas aeruginosa (Pa), however the effect on acquisition of other infectious organisms that frequently precede Pa is relatively unknown. Understanding the role of CFTR in the acquisition of organisms first detected in patients may help guide symptomatic and molecular-based treatment for CF. METHODS: Lung infection, defined as a single positive respiratory tract culture, was assessed for 13 organisms in 1,381 individuals with CF. Subjects were divided by predicted CFTR function: 'Residual': carrying at least one partial function CFTR mutation (class IV or V) and 'Minimal' those who do not carry a partial function mutation. Kaplan Meier estimates were created to assess CFTR effect on age of acquisition for each organism. Cox proportional hazard models were performed to control for possible cofactors. A separate Cox regression was used to determine whether defining infection with Pa, mucoid Pa or Aspergillus (Asp) using alternative criteria affected the results. The influence of severity of lung disease at the time of acquisition was evaluated using stratified Cox regression methods by lung disease categories. RESULTS: Subjects with 'Minimal' CFTR function had a higher hazard than patients with 'Residual' function for acquisition of 9 of 13 organisms studied (HR ranging from 1.7 to 3.78 based on the organism studied). Subjects with minimal CFTR function acquired infection at a younger age than those with residual function for 12 of 13 organisms (p-values ranging: < 0.001 to 0.017). Minimal CFTR function also associated with younger age of infection when 3 alternative definitions of infection with Pa, mucoid Pa or Asp were employed. Risk of infection is correlated with CFTR function for 8 of 9 organisms in patients with good lung function (>90%ile) but only 1 of 9 organisms in those with poorer lung function (<50%ile). CONCLUSIONS: Residual CFTR function correlates with later onset of respiratory tract infection by a wide spectrum of organisms frequently cultured from CF patients. The protective effect conferred by residual CFTR function is diminished in CF patients with more advanced lung disease. PMID- 20932302 TI - Live lecture versus video podcast in undergraduate medical education: A randomised controlled trial. AB - BACKGROUND: Information technology is finding an increasing role in the training of medical students. We compared information recall and student experience and preference after live lectures and video podcasts in undergraduate medical education. METHODS: We performed a crossover randomised controlled trial. 100 students were randomised to live lecture or video podcast for one clinical topic. Live lectures were given by the same instructor as the narrator of the video podcasts. The video podcasts comprised PowerpointTM slides narrated using the same script as the lecture. They were then switched to the other group for a second clinical topic. Knowledge was assessed using multiple choice questions and qualitative information was collected using a questionnaire. RESULTS: No significant difference was found on multiple choice questioning immediately after the session. The subjects enjoyed the convenience of the video podcast and the ability to stop, review and repeat it, but found it less engaging as a teaching method. They expressed a clear preference for the live lecture format. CONCLUSIONS: We suggest that video podcasts are not ready to replace traditional teaching methods, but may have an important role in reinforcing learning and aiding revision. PMID- 20932303 TI - Physical activity in US Blacks: a systematic review and critical examination of self-report instruments. AB - BACKGROUND: Physical activity self-report instruments in the US have largely been developed for and validated in White samples. Despite calls to validate existing instruments in more diverse samples, relatively few instruments have been validated in US Blacks. Emerging evidence suggests that these instruments may have differential validity in Black populations. PURPOSE: This report reviews and evaluates the validity and reliability of self-reported measures of physical activity in Blacks and makes recommendations for future directions. METHODS: A systematic literature review was conducted to identify published reports with construct or criterion validity evaluated in samples that included Blacks. Studies that reported results separately for Blacks were examined. RESULTS: The review identified 10 instruments validated in nine manuscripts. Criterion validity correlations tended to be low to moderate. No study has compared the validity of multiple instruments in a single sample of Blacks. CONCLUSION: There is a need for efforts validating self-report physical activity instruments in Blacks, particularly those evaluating the relative validity of instruments in a single sample. PMID- 20932304 TI - Is there an association between mild cognitive impairment and dietary pattern in Chinese elderly? Results from a cross-sectional population study. AB - BACKGROUND: Diet has an impact on cognitive function in most prior studies but its association with Mild Cognitive Impairment (MCI) in Chinese nonagenarians and centenarians has not been explored. METHODS: 870 elder dujiangyan residents aged 90 years or more in 2005 census were investigated at community halls or at home. They underwent the Mini-Mental State Examination (MMSE) for assessment of cognitive function and replied to our questionnaire comprised of 12 food items and other risk factors. MCI was defined by two steps: first, subjects with post stroke disease, Alzheimer's disease or Parkinson's disease and MMSE< 18 were excluded; and then subjects were categorized as MCI (MMSE scores between 19 and 24) and normal (MMSE scores between 25 and 30). Logistic regression models were used to analyze the association between diet and the prevalence of MCI. The model was adjusted for gender, ages, systolic blood pressure, diastolic blood pressure, body mass index, fasting plasma glucose, total cholesterol, triglycerides, high density lipoprotein cholesterol and low-density lipoprotein cholesterol, smoking habits, alcohol and tea consumption, educational levels and exercise in baseline dietary assessment. RESULTS: 364 elderly finally included, 108 (38.71%) men and 171 (61.29%) women of whom were classified as MCI. A significant correlation between MCI and normal in legume was observed (OR, 0.84; 95%CI, 0.72-0.97), and also in animal oil (any oil that obtained from animal substances) (OR, 0.93; 95%CI, 0.88-0.98). There was no statistical difference of other food items between normal and MCI. CONCLUSIONS: Among Chinese nonagenarians and centenarians, we found there were significant associations between inadequate intake of legume and animal oil and the prevalence of MCI. No significant correlation between other food items and the prevalence of MCI were demonstrated in this study. PMID- 20932305 TI - A mutational analysis and molecular dynamics simulation of quinolone resistance proteins QnrA1 and QnrC from Proteus mirabilis. AB - BACKGROUND: The first report on the transferable, plasmid-mediated quinolone resistance determinant qnrA1 was in 1998. Since then, qnr alleles have been discovered worldwide in clinical strains of Gram-negative bacilli. Qnr proteins confer quinolone resistance, and belong to the pentapeptide repeat protein (PRP) family. Several PRP crystal structures have been solved, but little is known about the functional significance of their structural arrangement. RESULTS: We conducted random and site-directed mutagenesis on qnrA1 and on qnrC, a newly identified quinolone-resistance gene from Proteus mirabilis. Many of the Qnr mutants lost their quinolone resistance function. The highly conserved hydrophobic Leu or Phe residues at the center of the pentapeptide repeats are known as i sites, and loss-of-function mutations included replacement of the i site hydrophobic residues with charged residues, replacing the i-2 site, N terminal to the i residues, with bulky side-chain residues, introducing Pro into the beta-helix coil, deletion of the N- and C-termini, and excision of a central coil. Molecular dynamics simulations and homology modeling demonstrated that QnrC overall adopts a stable beta-helix fold and shares more similarities with MfpA than with other PRP structures. Based on homology modeling and molecular dynamics simulation, the dysfunctional point mutations introduced structural deformations into the quadrilateral beta-helix structure of PRPs. Of the pentapeptides of QnrC, two-thirds adopted a type II beta-turn, while the rest adopted type IV turns. A gap exists between coil 2 and coil 3 in the QnrC model structure, introducing a structural flexibility that is similar to that seen in MfpA. CONCLUSION: The hydrophobic core and the beta-helix backbone conformation are important for maintaining the quinolone resistance property of Qnr proteins. QnrC may share structural similarity with MfpA. PMID- 20932306 TI - Effect of neutrophil elastase and its inhibitor EPI-hNE4 on transepithelial sodium transport across normal and cystic fibrosis human nasal epithelial cells. AB - BACKGROUND: Hyperactivity of the epithelial sodium (Na+) channel (ENaC) and increased Na+ absorption by airway epithelial cells leading to airway surface liquid dehydration and impaired mucociliary clearance are thought to play an important role in the pathogenesis of cystic fibrosis (CF) pulmonary disease. In airway epithelial cells, ENaC is constitutively activated by endogenous trypsin like serine proteases such as Channel-Activating Proteases (CAPs). It was recently reported that ENaC activity could also be stimulated by apical treatment with human neutrophil elastase (hNE) in a human airway epithelial cell line, suggesting that hNE inhibition could represent a novel therapeutic approach for CF lung disease. However, whether hNE can also activate Na+ reabsorption in primary human nasal epithelial cells (HNEC) from control or CF patients is currently unknown. METHODS: We evaluated by short-circuit current (Isc) measurements the effects of hNE and EPI-hNE4, a specific hNE inhibitor, on ENaC activity in primary cultures of HNEC obtained from control (9) and CF (4) patients. RESULTS: Neither hNE nor EPI-hNE4 treatments did modify Isc in control and CF HNEC. Incubation with aprotinin, a Kunitz-type serine protease inhibitor that blocks the activity of endogenous CAPs, decreased Isc by 27.6% and 54% in control and CF HNEC, respectively. In control and CF HNEC pretreated with aprotinin, hNE did significantly stimulate Isc, an effect which was blocked by EPI-hNE4. CONCLUSIONS: These results indicate that hNE does activate ENaC and transepithelial Na+ transport in both normal and CF HNEC, on condition that the activity of endogenous CAPs is first inhibited. The potent inhibitory effect of EPI-hNE4 on hNE-mediated ENaC activation observed in our experiments highlights that the use of EPI-hNE4 could be of interest to reduce ENaC hyperactivity in CF airways. PMID- 20932307 TI - Dietary fatty acid composition alters 11beta-hydroxysteroid dehydrogenase type 1 gene expression in rat retroperitoneal white adipose tissue. AB - The enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) amplifies intracellular glucocorticoid action by converting inactive glucocorticoids to their active forms in vivo. Adipose-specific overexpression of 11beta-HSD1 induces metabolic syndrome in mice, whereas 11beta-HSD1 null mice are resistant to it. Dietary trans and saturated fatty acids (TFAs and SFAs) are involved in the development of metabolic syndrome, whereas polyunsaturated fatty acids (PUFA) offer protection against this. Here, we report the effects of chronic feeding of different diets containing vanaspati (TFA rich), palm oil (SFA rich) and sunflower oil (PUFA rich) at 10%level on 11beta-HSD1 gene expression in rat retroperitoneal adipose tissue. 11beta-HSD1 gene expression was significantly higher in TFA rich diet-fed rats compared to SFA rich diet-fed rats, which in turn was significantly higher than PUFA rich diet-fed rats. Similar trend was observed in the expression of CCAAT-enhancer binding protein-alpha (C/EBP-alpha), the main transcription factor required for the expression of 11beta-HSD1. We propose that TFAs and SFAs increase local amplification of glucocorticoid action in adipose tissue by upregulating 11beta-HSD1 by altering C/EBP-alpha-gene expression. The increased levels of glucocorticoids in adipose tissue may lead to development of obesity and insulin resistance, thereby increasing the risk of developing metabolic syndrome. PMID- 20932308 TI - Structural and antimicrobial properties of human pre-elafin/trappin-2 and derived peptides against Pseudomonas aeruginosa. AB - BACKGROUND: Pre-elafin/trappin-2 is a human innate defense molecule initially described as a potent inhibitor of neutrophil elastase. The full-length protein as well as the N-terminal "cementoin" and C-terminal "elafin" domains were also shown to possess broad antimicrobial activity, namely against the opportunistic pathogen P. aeruginosa. The mode of action of these peptides has, however, yet to be fully elucidated. Both domains of pre-elafin/trappin-2 are polycationic, but only the structure of the elafin domain is currently known. The aim of the present study was to determine the secondary structures of the cementoin domain and to characterize the antibacterial properties of these peptides against P. aeruginosa. RESULTS: We show here that the cementoin domain adopts an alpha helical conformation both by circular dichroism and nuclear magnetic resonance analyses in the presence of membrane mimetics, a characteristic shared with a large number of linear polycationic antimicrobial peptides. However, pre elafin/trappin-2 and its domains display only weak lytic properties, as assessed by scanning electron micrography, outer and inner membrane depolarization studies with P. aeruginosa and leakage of liposome-entrapped calcein. Confocal microscopy of fluorescein-labeled pre-elafin/trappin-2 suggests that this protein possesses the ability to translocate across membranes. This correlates with the finding that pre-elafin/trappin-2 and elafin bind to DNA in vitro and attenuate the expression of some P. aeruginosa virulence factors, namely the biofilm formation and the secretion of pyoverdine. CONCLUSIONS: The N-terminal cementoin domain adopts alpha-helical secondary structures in a membrane mimetic environment, which is common in antimicrobial peptides. However, unlike numerous linear polycationic antimicrobial peptides, membrane disruption does not appear to be the main function of either cementoin, elafin or full-length pre-elafin/trappin-2 against P. aeruginosa. Our results rather suggest that pre-elafin/trappin-2 and elafin, but not cementoin, possess the ability to modulate the expression of some P.aeruginosa virulence factors, possibly through acting on intracellular targets. PMID- 20932309 TI - Freeze-thaw treatment effects on the dynamic mechanical properties of articular cartilage. AB - BACKGROUND: As a relatively non-regenerative tissue, articular cartilage has been targeted for cryopreservation as a method of mitigating a lack of donor tissue availability for transplant surgeries. In addition, subzero storage of articular cartilage has long been used in biomedical studies using various storage temperatures. The current investigation studies the potential for freeze-thaw to affect the mechanical properties of articular cartilage through direct comparison of various subzero storage temperatures. METHODS: Both subzero storage temperature as well as freezing rate were compared using control samples (4 degrees C) and samples stored at either -20 degrees C or -80 degrees C as well as samples first snap frozen in liquid nitrogen (-196 degrees C) prior to storage at -80 degrees C. All samples were thawed at 37.5 degrees C to testing temperature (22 degrees C). Complex stiffness and hysteresis characterized load resistance and damping properties using a non-destructive, low force magnitude, dynamic indentation protocol spanning a broad loading rate range to identify the dynamic viscoelastic properties of cartilage. RESULTS: Stiffness levels remained unchanged with exposure to the various subzero temperatures. Hysteresis increased in samples snap frozen at -196 degrees C and stored at -80 degrees C, though remained unchanged with exposure to the other storage temperatures. CONCLUSIONS: Mechanical changes shown are likely due to ice lens creation, where frost heave effects may have caused collagen damage. That storage to -20 degrees C and -80 degrees C did not alter the mechanical properties of articular cartilage shows that when combined with a rapid thawing protocol to 37.5 degrees C, the tissue may successfully be stored at subzero temperatures. PMID- 20932310 TI - Genome-wide association reveals genetic effects on human Abeta42 and tau protein levels in cerebrospinal fluids: a case control study. AB - BACKGROUND: Alzheimer's disease (AD) is common and highly heritable with many genes and gene variants associated with AD in one or more studies, including APOE epsilon2/epsilon3/epsilon4. However, the genetic backgrounds for normal cognition, mild cognitive impairment (MCI) and AD in terms of changes in cerebrospinal fluid (CSF) levels of Abeta1-42, T-tau, and P-tau181P, have not been clearly delineated. We carried out a genome-wide association study (GWAS) in order to better define the genetic backgrounds to these three states in relation to CSF levels. METHODS: Subjects were participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI). The GWAS dataset consisted of 818 participants (mainly Caucasian) genotyped using the Illumina Human Genome 610 Quad BeadChips. This sample included 410 subjects (119 Normal, 115 MCI and 176 AD) with measurements of CSF Abeta1-42, T-tau, and P-tau181P Levels. We used PLINK to find genetic associations with the three CSF biomarker levels. Association of each of the 498,205 SNPs was tested using additive, dominant, and general association models while considering APOE genotype and age. Finally, an effort was made to better identify relevant biochemical pathways for associated genes using the ALIGATOR software. RESULTS: We found that there were some associations with APOE genotype although CSF levels were about the same for each subject group; CSF Abeta1-42 levels decreased with APOE gene dose for each subject group. T-tau levels tended to be higher among AD cases than among normal subjects. From adjusted result using APOE genotype and age as covariates, no SNP was associated with CSF levels among AD subjects. CYP19A1 'aromatase' (rs2899472), NCAM2, and multiple SNPs located on chromosome 10 near the ARL5B gene demonstrated the strongest associations with Abeta1-42 in normal subjects. Two genes found to be near the top SNPs, CYP19A1 (rs2899472, p = 1.90 * 10(-7)) and NCAM2 (rs1022442, p = 2.75 * 10(-7)) have been reported as genetic factors related to the progression of AD from previous studies. In AD subjects, APOE epsilon2/epsilon3 and epsilon2/epsilon4 genotypes were associated with elevated T-tau levels and epsilon4/epsilon4 genotype was associated with elevated T-tau and P-tau181P levels. Pathway analysis detected several biological pathways implicated in Normal with CSF beta-amyloid peptide (Abeta1-42). CONCLUSIONS: Our genome-wide association analysis identified several SNPs as important factors for CSF biomarker. We also provide new evidence for additional candidate genetic risk factors from pathway analysis that can be tested in further studies. PMID- 20932312 TI - Associations of supermarket accessibility with obesity and fruit and vegetable consumption in the conterminous United States. AB - BACKGROUND: Limited access to supermarkets may reduce consumption of healthy foods, resulting in poor nutrition and increased prevalence of obesity. Most studies have focused on accessibility of supermarkets in specific urban settings or localized rural communities. Less is known, however, about how supermarket accessibility is associated with obesity and healthy diet at the national level and how these associations differ in urban versus rural settings. We analyzed data on obesity and fruit and vegetable (F/V) consumption from the Behavioral Risk Factor Surveillance System for 2000-2006 at the county level. We used 2006 Census Zip Code Business Patterns data to compute population-weighted mean distance to supermarket at the county level for different sizes of supermarket. Multilevel logistic regression models were developed to test whether population weighted mean distance to supermarket was associated with both obesity and F/V consumption and to determine whether these relationships varied for urban (metropolitan) versus rural (nonmetropolitan) areas. RESULTS: Distance to supermarket was greater in nonmetropolitan than in metropolitan areas. The odds of obesity increased and odds of consuming F/V five times or more per day decreased as distance to supermarket increased in metropolitan areas for most store size categories. In nonmetropolitan areas, however, distance to supermarket had no associations with obesity or F/V consumption for all supermarket size categories. CONCLUSIONS: Obesity prevalence increased and F/V consumption decreased with increasing distance to supermarket in metropolitan areas, but not in nonmetropolitan areas. These results suggest that there may be a threshold distance in nonmetropolitan areas beyond which distance to supermarket no longer impacts obesity and F/V consumption. In addition, obesity and food environments in nonmetropolitan areas are likely driven by a more complex set of social, cultural, and physical factors than a single measure of supermarket accessibility. Future research should attempt to more precisely quantify the availability and affordability of foods in nonmetropolitan areas and consider alternative sources of healthy foods besides supermarkets. PMID- 20932311 TI - PLCgamma-activated signalling is essential for TrkB mediated sensory neuron structural plasticity. AB - BACKGROUND: The vestibular system provides the primary input of our sense of balance and spatial orientation. Dysfunction of the vestibular system can severely affect a person's quality of life. Therefore, understanding the molecular basis of vestibular neuron survival, maintenance, and innervation of the target sensory epithelia is fundamental. RESULTS: Here we report that a point mutation at the phospholipase Cgamma (PLCgamma) docking site in the mouse neurotrophin tyrosine kinase receptor TrkB (Ntrk2) specifically impairs fiber guidance inside the vestibular sensory epithelia, but has limited effects on the survival of vestibular sensory neurons and growth of afferent processes toward the sensory epithelia. We also show that expression of the TRPC3 cation calcium channel, whose activity is known to be required for nerve-growth cone guidance induced by brain-derived neurotrophic factor (BDNF), is altered in these animals. In addition, we find that absence of the PLCgamma mediated TrkB signalling interferes with the transformation of bouton type afferent terminals of vestibular dendrites into calyces (the largest synaptic contact of dendrites known in the mammalian nervous system) on type I vestibular hair cells; the latter are normally distributed in these mutants as revealed by an unaltered expression pattern of the potassium channel KCNQ4 in these cells. CONCLUSIONS: These results demonstrate a crucial involvement of the TrkB/PLCgamma-mediated intracellular signalling in structural aspects of sensory neuron plasticity. PMID- 20932313 TI - Inheritance and identification of molecular markers associated with a novel dwarfing gene in barley. AB - BACKGROUND: Dwarfing genes have widely been used in barley breeding program. More than 30 types of dwarfs or semidwarfs have been reported, but a few has been exploited in barley breeding because pleiotropic effects of dwarfing genes cause some undesired traits. The plant architecture of newly discovered dwarfing germplasm "Huaai 11" consisted of desirable agronomic traits such as shortened stature and early maturity. Genetic factor controlling the plant height in dwarf line Huaai 11 was investigated. RESULTS: The Huaai 11 was crossed with tall varieties Monker, Mpyt, Zhenongda 3, Zaoshu 3, Advance, Huadamai 1, Huadamai 6, Hyproly and Ris01508. All the F1 plants displayed tall trait. Both tall and dwarf plants appeared in all the F2 populations with a 3:1 segregation ratio, suggesting that dwarfism of Huaai 11 is controlled by a single recessive gene, btwd1. Allelism test indicated that this dwarfing gene in the Huaai 11 is nonallelic with the gene br, uzu, sdw1 and denso. Using a double haploid population derived from a cross of Huadamai 6 and Huaai 11 and SSR markers the novel dwarfing gene was mapped onto the long arm of chromosome 7H, and closely linked to Bmac031 and Bmac167 with genetic distance of 2.2 cM. CONCLUSION: Huaai 11 is a new source of dwarf for broadening the genetic base of dwarfism. This dwarf source was controlled by a recessive dwarfing gene btwd1, was mapped onto the long arm of chromosome 7H. PMID- 20932314 TI - Quantification of myocardial perfusion by cardiovascular magnetic resonance. AB - The potential of contrast-enhanced cardiovascular magnetic resonance (CMR) for a quantitative assessment of myocardial perfusion has been explored for more than a decade now, with encouraging results from comparisons with accepted "gold standards", such as microspheres used in the physiology laboratory. This has generated an increasing interest in the requirements and methodological approaches for the non-invasive quantification of myocardial blood flow by CMR. This review provides a synopsis of the current status of the field, and introduces the reader to the technical aspects of perfusion quantification by CMR. The field has reached a stage, where quantification of myocardial perfusion is no longer a claim exclusive to nuclear imaging techniques. CMR may in fact offer important advantages like the absence of ionizing radiation, high spatial resolution, and an unmatched versatility to combine the interrogation of the perfusion status with a comprehensive tissue characterization. Further progress will depend on successful dissemination of the techniques for perfusion quantification among the CMR community. PMID- 20932315 TI - Genes encoding critical transcriptional activators for murine neural tube development and human spina bifida: a case-control study. AB - BACKGROUND: Spina bifida is a malformation of the neural tube and is the most common of neural tube defects (NTDs). The etiology of spina bifida is largely unknown, although it is thought to be multi-factorial, involving multiple interacting genes and environmental factors. Mutations in transcriptional co activator genes-Cited2, p300, Cbp, Tfap2alpha, Carm1 and Cart1 result in NTDs in murine models, thus prompt us to investigate whether homologues of these genes are associated with NTDs in humans. METHODS: Data and biological samples from 297 spina bifida cases and 300 controls were derived from a population-based case control study conducted in California. 37 SNPs within CITED2, EP300, CREBBP, TFAP2A, CARM1 and ALX1 were genotyped using an ABI SNPlex assay. Odds ratios and 95% confidence intervals were calculated for alleles, genotypes and haplotypes to evaluate the risk for spina bifida. RESULTS: Several SNPs showed increased or decreased risk, including CITED2 rs1131431 (OR = 5.32, 1.04~27.30), EP300 rs4820428 (OR = 1.30, 1.01~1.67), EP300 rs4820429 (OR = 0.50, 0.26~0.50, in whites, OR = 0.7, 0.49~0.99 in all subjects), EP300 rs17002284 (OR = 0.43, 0.22~0.84), TFAP2A rs3798691 (OR = 1.78, 1.13~2.87 in Hispanics), CREBBP rs129986 (OR = 0.27, 0.11~0.69), CARM1 rs17616105 (OR = 0.41, 0.22~0.72 in whites). In addition, one haplotype block in EP300 and one in TFAP2A appeared to be associated with increased risk. CONCLUSIONS: Modest associations were observed in CITED2, EP300, CREBBP, TFAP2A and CARM1 but not ALX1. However, these modest associations were not statistically significant after correction for multiple comparisons. Searching for potential functional variants and rare causal mutations is warranted in these genes. PMID- 20932316 TI - The Alberta population-based prospective evaluation of the quality of life outcomes and economic impact of bariatric surgery (APPLES) study: background, design and rationale. AB - BACKGROUND: Extreme obesity affects nearly 8% of Canadians, and is debilitating, costly and ultimately lethal. Bariatric surgery is currently the most effective treatment available; is associated with reductions in morbidity/mortality, improvements in quality of life; and appears cost-effective. However, current demand for surgery in Canada outstrips capacity by at least 1000-fold, causing exponential increases in already protracted, multi-year wait-times. The objectives and hypotheses of this study were as follows: 1. To serially assess the clinical, economic and humanistic outcomes in patients wait-listed for bariatric care over a 2-year period. We hypothesize deterioration in these outcomes over time; 2. To determine the clinical effectiveness and changes in quality of life associated with modern bariatric procedures compared with medically treated and wait-listed controls over 2 years. We hypothesize that surgery will markedly reduce weight, decrease the need for unplanned medical care, and increase quality of life; 3. To conduct a 3-year (1 year retrospective and 2 year prospective) economic assessment of bariatric surgery compared to medical and wait-listed controls from the societal, public payor, and health-care payor perspectives. We hypothesize that lower indirect, out of pocket and productivity costs will offset increased direct health-care costs resulting in lower total costs for bariatric surgery. METHODS/DESIGN: Population-based prospective cohort study of 500 consecutive, consenting adults, including 150 surgically treated patients, 200 medically treated patients and 150 wait-listed patients. Subjects will be enrolled from the Edmonton Weight Wise Regional Obesity Program (Edmonton, Alberta, Canada), with prospective bi-annual follow-up for 2 years. Mixed methods data collection, linking primary data to provincial administrative databases will be employed. Major outcomes include generic, obesity-specific and preference-based quality of life assessment, patient satisfaction, patient utilities, anthropometric indices, cardiovascular risk factors, health care utilization and direct and indirect costs. DISCUSSION: The results will identify the spectrum of potential risks associated with protracted wait times for bariatric care and will quantify the economic, humanistic and clinical impact of surgery from the Canadian perspective. Such information is urgently needed by health-service providers and policy makers to better allocate use of finite resources. Furthermore, our findings should be widely-applicable to other publically-funded jurisdictions providing similar care to the extremely obese. TRIAL REGISTRATION: Clinicaltrials.gov NCT00850356. PMID- 20932317 TI - Frameshift mutation hotspot identified in Smith-Magenis syndrome: case report and review of literature. AB - Smith-Magenis syndrome (SMS) is a complex syndrome involving intellectual disabilities, sleep disturbance, behavioural problems, and a variety of craniofacial, skeletal, and visceral anomalies. While the majority of SMS cases harbor an ~3.5 Mb common deletion on 17p11.2 that encompasses the retinoic acid induced-1 (RAI1) gene, some patients carry small intragenic deletions or point mutations in RAI1. We present data on two cases of Smith-Magenis syndrome with mutation of RAI1. Both cases are phenotypically consistent with SMS and RAI1 mutation but also have other anomalies not previously reported in SMS, including spontaneous pneumothoraces. These cases also illustrate variability in the SMS phenotype not previously shown for RAI1 mutation cases, including hearing loss, absence of self-abusive behaviours, and mild global delays. Sequencing of RAI1 revealed mutation of the same heptameric C-tract (CCCCCCC) in exon 3 in both cases (c.3103delC one case and and c.3103insC in the other), resulting in frameshift mutations. Of the seven reported frameshift mutations occurring in poly C-tracts in RAI1, four cases (~57%) occur at this heptameric C-tract. Collectively, these results indicate that this heptameric C-tract is a preferential hotspot for single nucleotide insertion/deletions (SNindels) and therefore, should be considered a primary target for analysis in patients suspected for mutations in RAI1. We expect that as more patients are sequenced for mutations in RAI1, the incidence of frameshift mutations in this hotspot will become more evident. PMID- 20932318 TI - Aggressive mammary carcinoma progression in Nrf2 knockout mice treated with 7,12 dimethylbenz[a]anthracene. AB - BACKGROUND: Activation of nuclear factor erythroid 2-related factor (Nrf2), which belongs to the basic leucine zipper transcription factor family, is a strategy for cancer chemopreventive phytochemicals. It is an important regulator of genes induced by oxidative stress, such as glutathione S-transferases, heme oxygenase-1 and peroxiredoxin 1, by activating the antioxidant response element (ARE). We hypothesized that (1) the citrus coumarin auraptene may suppress premalignant mammary lesions via activation of Nrf2/ARE, and (2) that Nrf2 knockout (KO) mice would be more susceptible to mammary carcinogenesis. METHODS: Premalignant lesions and mammary carcinomas were induced by medroxyprogesterone acetate and 7,12-dimethylbenz[a]anthracene treatment. The 10-week pre-malignant study was performed in which 8 groups of 10 each female wild-type (WT) and KO mice were fed either control diet or diets containing auraptene (500 ppm). A carcinogenesis study was also conducted in KO vs. WT mice (n = 30-34). Comparisons between groups were evaluated using ANOVA and Kaplan-Meier Survival statistics, and the Mann-Whitney U-test. RESULTS: All mice treated with carcinogen exhibited premalignant lesions but there were no differences by genotype or diet. In the KO mice, there was a dramatic increase in mammary carcinoma growth rate, size, and weight. Although there was no difference in overall survival, the KO mice had significantly lower mammary tumor-free survival. Also, in the KO mammary carcinomas, the active forms of NF-kappaB and beta-catenin were increased ~2-fold whereas no differences in oxidized proteins were observed. Many other tumors were observed, including lymphomas. Interestingly, the incidences of lung adenomas in the KO mice were significantly higher than in the WT mice. CONCLUSIONS: We report, for the first time, that there was no apparent difference in the formation of premalignant lesions, but rather, the KO mice exhibited rapid, aggressive mammary carcinoma progression. PMID- 20932319 TI - A direct comparison of the KBTM Basecaller and phred for identifying the bases from DNA sequencing using chain termination chemistry. AB - BACKGROUND: Relatively recently, the software KBTM Basecaller has replaced phred for identifying the bases from raw sequence data in DNA sequencing employing dideoxy chemistry. We have measured quantitatively the consequences of that change. RESULTS: The high quality sequence segment of reads derived from the KBTM Basecaller were, on average, 30-to-50 bases longer than reads derived from phred. However, microbe identification appeared to have been unaffected by the change in software. CONCLUSIONS: We have demonstrated a modest, but statistically significant, superiority in high quality read length of the KBTM Basecaller compared to phred. We found no statistically significant difference between the numbers of microbial species identified from the sequence data. PMID- 20932320 TI - Nano to micro delivery systems: targeting angiogenesis in brain tumors. AB - Treating brain tumors using inhibitors of angiogenesis is extensively researched and tested in clinical trials. Although anti-angiogenic treatment holds a great potential for treating primary and secondary brain tumors, no clinical treatment is currently approved for brain tumor patients. One of the main hurdles in treating brain tumors is the blood brain barrier - a protective barrier of the brain, which prevents drugs from entering the brain parenchyma. As most therapeutics are excluded from the brain there is an urgent need to develop delivery platforms which will bypass such hurdles and enable the delivery of anti angiogenic drugs into the tumor bed. Such delivery systems should be able to control release the drug or a combination of drugs at a therapeutic level for the desired time. In this mini-review we will discuss the latest improvements in nano and micro drug delivery platforms that were designed to deliver inhibitors of angiogenesis to the brain. PMID- 20932322 TI - Isolated cystic tuberculosis of scapula; case report and review of literature. AB - Tubercular osteomylitis of scapula is extremely rare. The isolated involvement of this flat bone without any primary focus confuses the surgeon with other pathology and as a result there is always delay in diagnosis. This article discusses about an isolated multicystic tubercular lesion of scapula which remained untreated for about two years as the primary physician biased with the history of trauma and suspected it to be a post-traumatic hematoma. MRI picture was deceptive. Finally, diagnosis was established by fine needle aspiration which showed typical epitheloid granuloma on histology. Lack of awareness and nonspecific radiological picture may cause delay in diagnosis of scapular tuberculosis. Tuberculosis is an important consideration in isolated scapular swelling particularly in endemic regions and the histological diagnosis by fine needle aspiration may be helpful in cases of doubtful radiological pictures. PMID- 20932321 TI - The potential of nanomedicine therapies to treat neovascular disease in the retina. AB - Neovascular disease in the retina is the leading cause of blindness in all age groups. Thus, there is a great need to develop effective therapeutic agents to inhibit and prevent neovascularization in the retina. Over the past decade, anti VEGF therapeutic agents have entered the clinic for the treatment of neovascular retinal disease, and these agents have been effective for slowing and preventing the progression of neovascularization. However, the therapeutic benefits of anti VEGF therapy can be diminished by the need for prolonged treatment regimens of repeated intravitreal injections, which can lead to complications such as endophthalmitis, retinal tears, and retinal detachment. Recent advances in nanoparticle-based drug delivery systems offer the opportunity to improve bioactivity and prolong bioavailability of drugs in the retina to reduce the risks associated with treating neovascular disease. This article reviews recent advances in the development of nanoparticle-based drug delivery systems which could be utilized to improve the treatment of neovascular disease in the retina. PMID- 20932323 TI - "Summary Page": a novel tool that reduces omitted data in research databases. AB - BACKGROUND: Data entry errors are common in clinical research databases. Omitted data are of particular concern because they are more common than erroneously inserted data and therefore could potentially affect research findings. However, few affordable strategies for their prevention are available. METHODS: We have conducted a prospective observational study of the effect of a novel tool called "Summary Page" on the frequency of correction of omitted data errors in a radiation oncology research database between July 2008 and March 2009. "Summary Page" was implemented as an optionally accessed screen in the database that visually integrates key fields in the record. We assessed the frequency of omitted data on the example of the Date of Relapse field. We considered the data in this field to be omitted for all records that had empty Date of Relapse field and evidence of relapse elsewhere in the record. RESULTS: A total of 1,156 records were updated and 200 new records were entered in the database over the study period. "Summary Page" was accessed for 44% of all updated records and for 69% of newly entered records. Frequency of correction of the omitted date of cancer relapse was six-fold higher in records for which "Summary Page" was accessed (p = 0.0003). CONCLUSIONS: "Summary Page" was strongly associated with an increased frequency of correction of omitted data errors. Further, controlled, studies are needed to confirm this finding and elucidate its mechanism of action. PMID- 20932324 TI - p27(Kip1) deficiency promotes prostate carcinogenesis but does not affect the efficacy of retinoids in suppressing the neoplastic process. AB - BACKGROUND: p27 is a cell cycle suppressor gene, whose protein is a negative regulator of cyclin/cdk complexes. p27 is also a potential target of retinoids in cancer prevention studies. In benign prostate hyperplasia (BPH), and in most carcinomas, p27(Kip1) is down-regulated, suggesting its potential resistance to retinoids. To test this hypothesis, we examined the efficacy of 9-cis retinoic acid (9cRA) to suppress prostate cell proliferation (PECP) and carcinogenesis in p27(Kip1) deficient mice. METHODS: p27(Kip1) deficient (-/-), heterozygous (+/-) and homozygous (+/+) mice were treated for 7 days with testosterone, 9cRA, or with both, and cell proliferation in dorsolateral prostate (DLP) was determined by BrdU labeling. Prostate carcinogenesis was induced by N-Methyl-N-Nitrosourea (MNU) and hormone stimulation. RESULTS: PECP in DLP of two-month-old mice of all genotypes was similar but significantly increased in old p27-/- mice only. Testosterone treatment increased PECP in all three p27 genotypes with the highest values in p27-/- mice. p27(Kip1) deficiency did not affect the response of PEC to 9cRA and to 9cRA+testosterone. The decrease of p27(Kip1) in p27+/- and p27-/- mice progressively increased the incidence and frequency of PIN and tumors. 9cRA suppressed PIN in all three p27 genotypes and this was associated with decreased PECP and increased cellular senescence. CONCLUSIONS: This data indicates that p27(Kip1) deficiency promotes prostate cell proliferation and carcinogenesis but does not affect 9cRA's potential to suppress prostate carcinogenesis, suggesting that patients with PIN and carcinomas lacking or having a low level of p27(Kip1) expression may also benefit from clinical trials with retinoids. PMID- 20932325 TI - Identification of differences in human and great ape phytanic acid metabolism that could influence gene expression profiles and physiological functions. AB - BACKGROUND: It has been proposed that anatomical differences in human and great ape guts arose in response to species-specific diets and energy demands. To investigate functional genomic consequences of these differences, we compared their physiological levels of phytanic acid, a branched chain fatty acid that can be derived from the microbial degradation of chlorophyll in ruminant guts. Humans who accumulate large stores of phytanic acid commonly develop cerebellar ataxia, peripheral polyneuropathy, and retinitis pigmentosa in addition to other medical conditions. Furthermore, phytanic acid is an activator of the PPAR-alpha transcription factor that influences the expression of genes relevant to lipid metabolism. RESULTS: Despite their trace dietary phytanic acid intake, all great ape species had elevated red blood cell (RBC) phytanic acid levels relative to humans on diverse diets. Unlike humans, chimpanzees showed sexual dimorphism in RBC phytanic acid levels, which were higher in males relative to females. Cultured skin fibroblasts from all species had a robust capacity to degrade phytanic acid. We provide indirect evidence that great apes, in contrast to humans, derive significant amounts of phytanic acid from the hindgut fermentation of plant materials. This would represent a novel reduction of metabolic activity in humans relative to the great apes. CONCLUSION: We identified differences in the physiological levels of phytanic acid in humans and great apes and propose this is causally related to their gut anatomies and microbiomes. Phytanic acid levels could contribute to cross-species and sex-specific differences in human and great ape transcriptomes, especially those related to lipid metabolism. Based on the medical conditions caused by phytanic acid accumulation, we suggest that differences in phytanic acid metabolism could influence the functions of human and great ape nervous, cardiovascular, and skeletal systems. PMID- 20932326 TI - Development of mental health first aid guidelines for Aboriginal and Torres Strait Islander people experiencing problems with substance use: a Delphi study. AB - BACKGROUND: Problems with substance use are common in some Aboriginal communities. Although problems with substance use are associated with significant mortality and morbidity, many people who experience them do not seek help. Training in mental health first aid has been shown to be effective in increasing knowledge of symptoms and behaviours associated with seeking help. The current study aimed to develop culturally appropriate guidelines for providing mental health first aid to an Aboriginal or Torres Strait Islander person who is experiencing problem drinking or problem drug use (e.g. abuse or dependence). METHODS: Twenty-eight Aboriginal health experts participated in two independent Delphi studies (n = 22 problem drinking study, n = 21 problem drug use; 15 participated in both). Panellists were presented with statements about possible first aid actions via online questionnaires and were encouraged to suggest additional actions not covered by the content. Statements were accepted for inclusion in the guidelines if they were endorsed by >= 90% of panellists as either 'Essential' or 'Important'. At the end of the two Delphi studies, participants were asked to give feedback on the value of the project and their participation experience. RESULTS: From a total of 735 statements presented over two studies, 429 were endorsed (223 problem drinking, 206 problem drug use). Statements were grouped into sections based on common themes (n = 7 problem drinking, n = 8 problem drug use), then written into guideline documents. Participants evaluated the Delphi method employed, and the guidelines developed, as useful and appropriate for Aboriginal and Torres Strait Islander people. CONCLUSIONS: Aboriginal health experts were able to reach consensus about culturally appropriate first aid for problems with substance use. Many first aid actions endorsed in the current studies were not endorsed in previous international Delphi studies, conducted on problem drinking and problem drug use in non-Indigenous people, highlighting the need for culturally specific first aid strategies to be employed when assisting Aboriginal or Torres Strait Islander people. PMID- 20932327 TI - Effect of omega-3 and omega-9 fatty acid rich oils on lipoxygenases and cyclooxygenases enzymes and on the growth of a mammary adenocarcinoma model. AB - BACKGROUND: Nutritional factors play a major role in cancer initiation and development. Dietary polyunsaturated fatty acids (PUFAs) have the ability to induce modifications in the activity of lipoxygenase (LOX) and cyclooxygenase (COX) enzymes that affect tumour growth. We studied the effect of two diets enriched in 6% Walnut and Peanut oils that are rich in omega-3 and omega9 PUFAs respectively on a murine mammary gland adenocarcinoma as compared with the control (C) that received commercial diet. RESULTS: Peanut oil enriched diet induced an increase in membrane arachidonic acid (AA) content and the cyclooxygenase enzyme derived 12-HHT (p < 0.05) and simultaneously showed decrease in 12-LOX, 15-LOX-2, 15-LOX-1 and PGE activities (p < 0.05) that corresponded to higher apoptosis and lower mitosis seen in this group (p < 0.05). Furthermore, Peanut oil group showed lower T-cell infiltration (p < 0.05), number of metastasis (p < 0.05) and tumour volume (p < 0.05) and longer survival rate compared to other groups. CONCLUSIONS: The results of the present study showed that Peanut oil-enriched diet protects against mammary cancer development by modulating tumour membrane fatty acids composition and LOX and COX enzyme activities. PMID- 20932328 TI - Genome-wide regulation of innate immunity by juvenile hormone and 20 hydroxyecdysone in the Bombyx fat body. AB - BACKGROUND: Insect innate immunity can be affected by juvenile hormone (JH) and 20-hydroxyecdysone (20E), but how innate immunity is developmentally regulated by these two hormones in insects has not yet been elucidated. In the silkworm, Bombyx mori, JH and 20E levels are high during the final larval molt (4 M) but absent during the feeding stage of 5(th) instar (5 F), while JH level is low and 20E level is high during the prepupal stage (PP). Fat body produces humoral response molecules and hence is considered as the major organ involved in innate immunity. RESULTS: A genome-wide microarray analysis of Bombyx fat body isolated from 4 M, 5 F and PP uncovered a large number of differentially-expressed genes. Most notably, 6 antimicrobial peptide (AMP) genes were up-regulated at 4 M versus PP suggesting that Bombyx innate immunity is developmentally regulated by the two hormones. First, JH treatment dramatically increased AMP mRNA levels and activities. Furthermore, 20E treatment exhibited inhibitory effects on AMP mRNA levels and activities, and RNA interference of the 20E receptor EcR-USP had the opposite effects to 20E treatment. CONCLUSION: Taken together, we demonstrate that JH acts as an immune-activator while 20E inhibits innate immunity in the fat body during Bombyx postembryonic development. PMID- 20932329 TI - CTD small phosphatase like 2 (CTDSPL2) can increase epsilon- and gamma-globin gene expression in K562 cells and CD34+ cells derived from umbilical cord blood. AB - BACKGROUND: A potential strategy for treatment of sickle cell disease (SCD) and beta-thalassemia in adults is reactivation of the epsilon- and gamma-globin genes in the adult. We aimed to identify trans-activators of epsilon- and gamma-globin expression and provide new candidate targets for effective treatment of sickle cell disease (SCD) and beta-thalassemia through activation of epsilon- and gamma globin genes in adults. RESULTS: We identified a CTD small phosphatase like 2 (CTDSPL2) gene that had higher transcription levels in umbilical cord blood (UCB) than in adult bone marrow (BM). Also, transcription of the CTDSPL2 gene increased significantly during erythroid differentiation. Further, we found that overexpression of CTDSPL2 could obviously improve the expression of epsilon- and gamma-globin genes in K562 cells. Meanwhile, the repression of CTDSPL2 by RNA interference decreased expression of epsilon- and gamma-globin genes but did not inhibit the increase of globin gene expression during K562 erythroid differentiation. In addition, the enforced expression of CTDSPL2 gene mediated by lentiviruses could also increase epsilon- and gamma-globin gene expression during erythroid differentiation of CD34+ cells derived from UCB. CONCLUSION: CTDSPL2 gene can obviously improve the expression of epsilon- and gamma-globin genes in K562 cells and CD34+ cells derived from UCB. Our study provides a new candidate target for effective treatment of SCD and beta-thalassemia. PMID- 20932330 TI - Genome-wide analysis of the effect of histone modifications on the coexpression of neighboring genes in Saccharomyces cerevisiae. AB - BACKGROUND: Neighboring gene pairs in the genome of Saccharomyces cerevisiae have a tendency to be expressed at the same time. The distribution of histone modifications along chromatin fibers is suggested to be an important mechanism responsible for such coexpression. However, the extent of the contribution of histone modifications to the coexpression of neighboring genes is unclear. RESULTS: We investigated the similarity of histone modification between neighboring genes using autocorrelation analysis and composite profiles. Our analysis showed that neighboring genes had similar levels or changes of histone modifications, especially those transcribed in the same direction. The similarities, however, were restricted to 1 or 2 neighboring genes. Moreover, the expression of a gene was significantly correlated with histone modification of its neighboring gene(s), but this was limited to only 1 or 2 neighbors. Using a hidden Markov model (HMM), we found more than 2000 chromatin domains with similar acetylation changes as the cultures changed and a considerable number of these domains covered 2-4 genes. Gene pairs within domains exhibited a higher level of coexpression than random pairs and shared similar functions. CONCLUSIONS: The results of this study suggest that similar histone modifications occur within only a small local chromatin region in yeast. The modifications generally have an effect on coexpression with only 1 or 2 neighboring genes. Some blocking mechanism(s) might strictly restrain the distribution of histone modifications in yeast. PMID- 20932331 TI - MiR-339-5p inhibits breast cancer cell migration and invasion in vitro and may be a potential biomarker for breast cancer prognosis. AB - BACKGROUND: MicroRNAs (miRNAs) play an important role in the regulation of cell growth, differentiation, apoptosis, and carcinogenesis. Detection of their expression may lead to identifying novel markers for breast cancer. METHODS: We profiled miRNA expression in three breast cancer cell lines (MCF-7, MDA-MB-231, and MDA-MB-468) and then focused on one miRNA, miR-339-5p, for its role in regulation of tumor cell growth, migration, and invasion and target gene expression. We then analyzed miR-339-5p expression in benign and cancerous breast tissue specimens. RESULTS: A number of miRNAs were differentially expressed in these cancer cell lines. Real-time PCR indicated that miR-339-5p expression was downregulated in the aggressive cell lines MDA-MB-468 and MDA-MB-231 and in breast cancer tissues compared with benign tissues. Transfection of miR-339-5p oligonucleotides reduced cancer cell growth only slightly but significantly decreased tumor cell migration and invasion capacity compared with controls. Real time PCR analysis showed that BCL-6, a potential target gene of miR-339-5p, was downregulated in MDA-MB-231 cells by miR-339-5p transfection. Furthermore, the reduced miR-339-5p expression was associated with an increase in metastasis to lymph nodes and with high clinical stages. Kaplan-Meier analyses found that the patients with miR-339-5p expression had better overall and relapse-free survivals compared with those without miR-339-5p expression. Cox proportional hazards analyses showed that miR-339-5p expression was an independent prognostic factor for breast cancer patients. CONCLUSIONS: MiR-339-5p may play an important role in breast cancer progression, suggesting that miR-339-5p should be further evaluated as a biomarker for predicting the survival of breast cancer patients. PMID- 20932332 TI - Recurrent post-partum coronary artery dissection. AB - Coronary artery dissection is a rare but well-described cause for myocardial infarction during the post-partum period. Dissection of multiple coronary arteries is even less frequent. Here we present a case of recurrent post-partum coronary artery dissections. This unusual presentation poses unique problems for management. A 35 year-old female, gravida 3 para 2, presented with myocardial infarction 9 weeks and 3 days post-partum. Cardiac catheterization demonstrated left anterior descending (LAD) dissection but an otherwise normal coronary anatomy. The lesion was treated with four everolimus eluting stents. Initially the patient made an unremarkable recovery until ventricular fibrillation arrest occurred on the following day. Unsynchronized cardioversion restored a normal sinus rhythm and repeat catheterization revealed new right coronary artery (RCA) dissection. A wire was passed distally, but it was unclear whether this was through the true or false lumen and no stents could be placed. However, improvement of distal RCA perfusion was noted on angiogram. Despite failure of interventional therapy the patient was therefore treated conservatively. Early operation after myocardial infarction has a significantly elevated risk of mortality and the initial dissection had occurred within 24 hours. This strategy proved successful as follow-up transthoracic echocardiography after four months demonstrated a preserved left ventricular ejection fraction of 55-60% without regional wall motion abnormalities. The patient remained asymptomatic from a cardiac point of view. PMID- 20932333 TI - HIV-1 subtype distribution in the Gambia and the significant presence of CRF49_cpx, a novel circulating recombinant form. AB - BACKGROUND: Detailed local HIV-1 sequence data are essential for monitoring the HIV epidemic, for maintaining sensitive sequence-based diagnostics, and to aid in designing vaccines. RESULTS: Reported here are full envelope sequences derived from 38 randomly selected HIV-1 infections identified at a Gambian clinic between 1991 and 2009. Special care was taken to generate sequences from circulating viral RNA as uncloned products, either by limiting dilution or single genome amplification polymerase chain reaction (PCR). Within these 38 isolates, eight were subtyped as A and 18 as CRF02_AG. A small number of subtype B, C, D viruses were identified. Surprising, however, was the identification of six isolates with subtype J-like envelopes, a subtype found normally in Central Africa and the Democratic Republic of the Congo (DRC), with gag p24 regions that clustered with subtype A sequences. Near full-length sequence from three of these isolates confirmed that these represent a novel circulating recombinant form of HIV-1, now named CRF49_cpx. CONCLUSIONS: This study expands the HIV-1 sequence database from the Gambia and will provide important data for HIV diagnostics, patient care, and vaccine development. PMID- 20932334 TI - In silico modeling indicates the development of HIV-1 resistance to multiple shRNA gene therapy differs to standard antiretroviral therapy. AB - BACKGROUND: Gene therapy has the potential to counter problems that still hamper standard HIV antiretroviral therapy, such as toxicity, patient adherence and the development of resistance. RNA interference can suppress HIV replication as a gene therapeutic via expressed short hairpin RNAs (shRNAs). It is now clear that multiple shRNAs will likely be required to suppress infection and prevent the emergence of resistant virus. RESULTS: We have developed the first biologically relevant stochastic model in which multiple shRNAs are introduced into CD34+ hematopoietic stem cells. This model has been used to track the production of gene-containing CD4+ T cells, the degree of HIV infection, and the development of HIV resistance in lymphoid tissue for 13 years. In this model, we found that at least four active shRNAs were required to suppress HIV infection/replication effectively and prevent the development of resistance. The inhibition of incoming virus was shown to be critical for effective treatment. The low potential for resistance development that we found is largely due to a pool of replicating wild type HIV that is maintained in non-gene containing CD4+ T cells. This wild-type HIV effectively out-competes emerging viral strains, maintaining the viral status quo. CONCLUSIONS: The presence of a group of cells that lack the gene therapeutic and is available for infection by wild-type virus appears to mitigate the development of resistance observed with systemic antiretroviral therapy. PMID- 20932335 TI - Construction of an almond linkage map in an Australian population Nonpareil x Lauranne. AB - BACKGROUND: Despite a high genetic similarity to peach, almonds (Prunus dulcis) have a fleshless fruit and edible kernel, produced as a crop for human consumption. While the release of peach genome v1.0 provides an excellent opportunity for almond genetic and genomic studies, well-assessed segregating populations and the respective saturated genetic linkage maps lay the foundation for such studies to be completed in almond. RESULTS: Using an almond intraspecific cross between 'Nonpareil' and 'Lauranne' (N x L), we constructed a moderately saturated map with SSRs, SNPs, ISSRs and RAPDs. The N x L map covered 591.4 cM of the genome with 157 loci. The average marker distance of the map was 4.0 cM. The map displayed high synteny and colinearity with the Prunus T x E reference map in all eight linkage groups (G1-G8). The positions of 14 mapped gene-anchored SNPs corresponded approximately with the positions of homologous sequences in the peach genome v1.0. Analysis of Mendelian segregation ratios showed that 17.9% of markers had significantly skewed genotype ratios at the level of P < 0.05. Due to the large number of skewed markers in the linkage group 7, the potential existence of deleterious gene(s) was assessed in the group. Integrated maps produced by two different mapping methods using JoinMap(r) 3 were compared, and their high degree of similarity was evident despite the positional inconsistency of a few markers. CONCLUSIONS: We presented a moderately saturated Australian almond map, which is highly syntenic and collinear with the Prunus reference map and peach genome V1.0. Therefore, the well-assessed almond population reported here can be used to investigate the traits of interest under Australian growing conditions, and provides more information on the almond genome for the international community. PMID- 20932336 TI - Misty Mountain clustering: application to fast unsupervised flow cytometry gating. AB - BACKGROUND: There are many important clustering questions in computational biology for which no satisfactory method exists. Automated clustering algorithms, when applied to large, multidimensional datasets, such as flow cytometry data, prove unsatisfactory in terms of speed, problems with local minima or cluster shape bias. Model-based approaches are restricted by the assumptions of the fitting functions. Furthermore, model based clustering requires serial clustering for all cluster numbers within a user defined interval. The final cluster number is then selected by various criteria. These supervised serial clustering methods are time consuming and frequently different criteria result in different optimal cluster numbers. Various unsupervised heuristic approaches that have been developed such as affinity propagation are too expensive to be applied to datasets on the order of 106 points that are often generated by high throughput experiments. RESULTS: To circumvent these limitations, we developed a new, unsupervised density contour clustering algorithm, called Misty Mountain, that is based on percolation theory and that efficiently analyzes large data sets. The approach can be envisioned as a progressive top-down removal of clouds covering a data histogram relief map to identify clusters by the appearance of statistically distinct peaks and ridges. This is a parallel clustering method that finds every cluster after analyzing only once the cross sections of the histogram. The overall run time for the composite steps of the algorithm increases linearly by the number of data points. The clustering of 106 data points in 2D data space takes place within about 15 seconds on a standard laptop PC. Comparison of the performance of this algorithm with other state of the art automated flow cytometry gating methods indicate that Misty Mountain provides substantial improvements in both run time and in the accuracy of cluster assignment. CONCLUSIONS: Misty Mountain is fast, unbiased for cluster shape, identifies stable clusters and is robust to noise. It provides a useful, general solution for multidimensional clustering problems. We demonstrate its suitability for automated gating of flow cytometry data. PMID- 20932337 TI - Drug-induced mild therapeutic hypothermia obtained by administration of a transient receptor potential vanilloid type 1 agonist. AB - BACKGROUND: The use of mechanical/physical devices for applying mild therapeutic hypothermia is the only proven neuroprotective treatment for survivors of out of hospital cardiac arrest. However, this type of therapy is cumbersome and associated with several side-effects. We investigated the feasibility of using a transient receptor potential vanilloid type 1 (TRPV1) agonist for obtaining drug induced sustainable mild hypothermia. METHODS: First, we screened a heterogeneous group of TRPV1 agonists and secondly we tested the hypothermic properties of a selected candidate by dose-response studies. Finally we tested the hypothermic properties in a large animal. The screening was in conscious rats, the dose response experiments in conscious rats and in cynomologus monkeys, and the finally we tested the hypothermic properties in conscious young cattle (calves with a body weight as an adult human). The investigated TRPV1 agonists were administered by continuous intravenous infusion. RESULTS: Screening: Dihydrocapsaicin (DHC), a component of chili pepper, displayed a desirable hypothermic profile with regards to the duration, depth and control in conscious rats. Dose-response experiments: In both rats and cynomologus monkeys DHC caused a dose-dependent and immediate decrease in body temperature. Thus in rats, infusion of DHC at doses of 0.125, 0.25, 0.50, and 0.75 mg/kg/h caused a maximal DeltaT ( degrees C) as compared to vehicle control of -0.9, -1.5, -2.0, and -4.2 within approximately 1 hour until the 6 hour infusion was stopped. Finally, in calves the intravenous infusion of DHC was able to maintain mild hypothermia with DeltaT > -3 degrees C for more than 12 hours. CONCLUSIONS: Our data support the hypothesis that infusion of dihydrocapsaicin is a candidate for testing as a primary or adjunct method of inducing and maintaining therapeutic hypothermia. PMID- 20932338 TI - An appeal to humanity: legal victory in favour of North America's only supervised injection facility: Insite. AB - Canada's federal government has once again failed to shut North America's only authorized supervised injection facility: Insite. A majority ruling issued by the BC Court of Appeal on 15 January 2010 upheld an earlier British Columbia Supreme Court ruling in 2008 that protected the rights of injection drug users (IDUs) to access Insite as a health facility as per the Charter of Rights and Freedoms component of the Constitution of Canada. The majority decision from Honourable Madam Justices Rowles, Huddart and Smith also established a jurisdictional victory safeguarding Insite as most appropriately run under the authority of the province of British Columbia rather than the federal Government of Canada. The Federal Government has appealed the case to the Supreme Court of Canada. A hearing date has been set for 12 May 2011. The appeal will be a legal one but even more so, it will be an appeal to humanity. PMID- 20932339 TI - Low hospital admission rates for respiratory diseases in children. AB - BACKGROUND: Population-based data on hospital admissions for children aged 0-17 years concerning all respiratory diseases are scarce. This study examined hospital admissions in relation to the preceding consultations in general practice in this age group. METHODS: Data on children aged 0-17 years with respiratory diseases included in the Second Dutch National Survey of General Practice (DNSGP-2) were linked to all hospital admissions in the Dutch National Medical Registration. Admission rates for respiratory diseases were calculated. Data were analysed using multivariate logistic regression. RESULTS: Of all 79,272 children within the DNSGP-2, 1.8% were admitted to hospital for any respiratory diagnosis. The highest admission rates per 1000 children were for chronic disease of tonsils and adenoids (12.9); pneumonia and influenza (0.97); and asthma (0.92). Children aged 0-4 years and boys were admitted more frequently. Of children with asthma, 2.3% were admitted for respiratory diseases. For asthma, admission rates varied by urbanisation level: 0.47/1000 children/year in cities with <= 30,000 inhabitants, 1.12 for cities with >= 50,000 inhabitants, and 1.73 for the three largest cities (p = 0.002). Multivariate logistic regression showed that within two weeks after a GP consultation, younger age (OR 0.81, 95% CI 0.76 0.88) and more severe respiratory diseases (5.55, 95% CI 2.99-8.11) predicted hospital admission. CONCLUSIONS: Children in the general population with respiratory diseases (especially asthma) had very low hospital admission rates. In urban regions children were more frequently admitted due to respiratory morbidity. For effectiveness studies in a primary care setting, hospital admission rates should not be used as quality end-point. PMID- 20932340 TI - Clinical characteristics of depression among adolescent females: a cross sectional study. AB - BACKGROUND: Adolescents rarely seek psychiatric help; they even hesitate to disclose their feelings to their parents. However; the adolescents especially the females experience depressive symptoms more frequently than general population. Do they experience classic depressive symptoms? Are there symptoms specific to this subpopulation? AIM OF THE STUDY: Through this study, the authors aimed to estimate the prevalence of depressive disorders in Egyptian adolescent female students. They also expected a characteristic profile of symptoms for the adolescent females. However available literature provides no guidance in the description of this profile of symptoms. METHODS: A number of 602 adolescent females were interviewed, and subjected to General Health Questionnaire (GHQ); Children Depression Inventory (CDI), Structured Clinical Interview for DSM-IV Axis-I Disorders (SCID-I), then Hamilton Rating Scale for Depression (Ham-D). Results were analyzed by the use of SPSS-15. RESULTS: The study revealed the prevalence of depression in the sample of the study to be 15.3% (measured by CDI), and 13.3% (measured by SCID-I). Fatigue was the most common presenting depressive symptom (81.3%), in addition to other emotional, cognitive and physiological symptoms. Suicidal ideations were the most common suicidal symptoms in depressed adolescent females (20%), with 2.5% serious suicidal attempts. CONCLUSIONS: The somatic symptoms were by far the most common presenting symptom for female adolescents suffering from depressive disorders. Depressive phenomena including unexplained fatigue, decreased energy, psychomotor changes, lack of concentration, weight changes and suicidal ideations may be the presenting complaints instead of the classic sad mood. PMID- 20932341 TI - Phase 1 safety and tolerability study of BMP-7 in symptomatic knee osteoarthritis. AB - BACKGROUND: There are no proven therapies that modify the structural changes associated with osteoarthritis (OA). Preclinical data suggests that intra articular recombinant human BMP-7 (bone morphogenetic protein-7) has reparative effects on cartilage, as well as on symptoms of joint pain. The objective of this study was to determine the safety and tolerability as well as dose-limiting toxicity and maximal tolerated dose of intra-articular BMP-7. The secondary objectives were to determine the effect on symptomatic responses through 24 weeks. METHODS: This was a Phase 1, double-blind, randomized, multi-center, placebo-controlled, single-dose escalation safety study consisting of 4 dosing cohorts in participants with knee OA. Each cohort was to consist of 8 treated participants, with treatment allocation in a 3:1 active (intra-articular BMP-7) to placebo ratio. Eligible participants were persons with symptomatic radiographic knee OA over the age of 40. The primary objective of this study was to determine the safety and tolerability of BMP-7 including laboratory assessments, immunogenicity data and radiographic assessments. Secondary objectives were to determine the proportion of participants with a 20%, 50%, and 70% improvement in the WOMAC pain and function subscales at 4, 8, 12, and 24 weeks. Other secondary outcomes included the change from baseline to 4, 8, 12, and 24 weeks for the OARSI responder criteria. RESULTS: The mean age of participants was 60 years and 73% were female. All 33 participants who were enrolled completed the study and most adverse events were mild or moderate and were similar in placebo and BMP-7 groups. The 1 mg BMP-7 group showed a higher frequency of injection site pain and there was no ectopic bone formation seen on plain x-rays. By week 12, most participants in both the BMP-7 and placebo groups experienced a 20% improvement in pain and overall the BMP-7 group was similar to placebo with regard to this measurement. In the participants who received 0.1 mg and 0.3 mg BMP-7, there was a trend toward greater symptomatic improvement than placebo. The other secondary endpoints showed similar trends including the OARSI responder criteria for which the BMP-7 groups had more responders than placebo. CONCLUSIONS: There was no dose limiting toxicity identified in this study. The suggestion of a symptom response, together with the lack of dose limiting toxicity provide further support for the continued development of this product for the treatment of osteoarthritis. PMID- 20932342 TI - Healthcare workers as parents: attitudes toward vaccinating their children against pandemic influenza A/H1N1. AB - BACKGROUND: Both the health care workers (HCWs) and children are target groups for pandemic influenza vaccination. The coverage of the target populations is an important determinant for impact of mass vaccination. The objective of this study is to determine the attitudes of HCWs as parents, toward vaccinating their children with pandemic influenza A/H1N1 vaccine. METHODS: A cross-sectional questionnaire survey was conducted with health care workers (HCWs) in a public hospital during December 2009 in Istanbul. All persons employed in the hospital with or without a health-care occupation are accepted as HCW. The HCWs who are parents of children 6 months to 18 years of age were included in the study. Pearson's chi-square test and logistic regression analysis was applied for the statistical analyses. RESULTS: A total of 389 HCWs who were parents of children aged 6 months-18 years participated study. Among all participants 27.0% (n = 105) reported that themselves had been vaccinated against pandemic influenza A/H1N1. Two third (66.1%) of the parents answered that they will not vaccinate their children, 21.1% already vaccinated and 12.9% were still undecided. Concern about side effect was most reported reason among who had been not vaccinated their children and among undecided parents. The second reason for refusing the pandemic vaccine was concerns efficacy of the vaccine. Media was the only source of information about pandemic influenza in nearly one third of HCWs. Agreement with vaccine safety, self receipt of pandemic influenza A/H1N1 vaccine, and trust in Ministry of Health were found to be associated with the positive attitude toward vaccinating their children against pandemic influenza A/H1N1. CONCLUSIONS: Persuading parents to accept a new vaccine seems not be easy even if they are HCWs. In order to overcome the barriers among HCWs related to pandemic vaccines, determination of their misinformation, attitudes and behaviors regarding the pandemic influenza vaccination is necessary. Efforts for orienting the HCWs to use evidence based scientific sources, rather than the media for information should be considered by the authorities. PMID- 20932343 TI - Disrupted postnatal lung development in heme oxygenase-1 deficient mice. AB - BACKGROUND: Heme oxygenase (HO) degrades cellular heme to carbon monoxide, iron and biliverdin. The HO-1 isoform is both inducible and cyto-protective during oxidative stress, inflammation and lung injury. However, little is known about its precise role and function in lung development. We hypothesized that HO-1 is required for mouse postnatal lung alveolar development and that vascular expression of HO-1 is essential and protective during postnatal alveolar development. METHODS: Neonatal lung development in wildtype and HO-1 mutant mice was evaluated by histological and molecular methods. Furthermore, these newborn mice were treated with postnatal dexamethasone (Dex) till postnatal 14 days, and evaluated for lung development. RESULTS: Compared to wildtype littermates, HO-1 mutant mice exhibited disrupted lung alveolar structure including simplification, disorganization and reduced secondary crest formation. These defects in alveolar development were more pronounced when these mice were challenged with Dex treatment. Expression levels of both vascular endothelial and alveolar epithelial markers were also further decreased in HO-1 mutants after Dex treatment. CONCLUSIONS: These experiments demonstrate that HO-1 is required in normal lung development and that HO-1 disruption and dexamethasone exposure are additive in the disruption of postnatal lung growth. We speculate that HO-1 is involved in postnatal lung development through modulation of pulmonary vascular development. PMID- 20932344 TI - A profile of prognostic and molecular factors in European and Maori breast cancer patients. AB - BACKGROUND: New Zealand Maori have a poorer outcome from breast cancer than non Maori, yet prognostic data are sparse. The objective of this study was to quantify levels of prognostic factors in a cohort of self-declared Maori and European breast cancer patients from Christchurch, New Zealand. METHODS AND RESULTS: Clinicopathological and survival data from 337 consecutive breast cancer patients (27 Maori, 310 European) were evaluated. Fewer tumours were high grade in Maori women than European women (p = 0.027). No significant ethnic differences were detected for node status, tumour type, tumour size, human epidermal growth factor receptor, oestrogen and progesterone receptor (ER/PR) status, or survival.In addition, tumour and serum samples from a sub-cohort of 14 Maori matched to 14 NZ European patients were analyzed by immunohistochemistry and enzyme linked immunosorbent assay for molecular prognostic factors. Significant correlations were detected between increased grade and increased levels of hypoxia inducible factor-1 (HIF-1alpha), glucose transporter-1 (GLUT-1), microvessel density (MVD) and cytokeratins CK5/6 (p < 0.05). High nodal status correlated with reduced carbonic anhydrase IX (CA-IX). Negative ER/PR status correlated with increased GLUT-1, CA-IX and MVD. Within the molecular factors, increased HIF-1alpha correlated with raised GLUT-1, MVD and CK5/6, and CK5/6 with GLUT-1 and MVD (p < 0.05). The small number of patients in this sub-cohort limited discrimination of ethnic differences. CONCLUSIONS: In this Christchurch cohort of breast cancer patients, Maori women were no more likely than European women to have pathological or molecular factors predictive of poor prognosis. These data contrast with data from the North Island NZ, and suggest potential regional differences. PMID- 20932345 TI - The efficacy of preoperative PET/CT for prediction of curability in surgery for locally advanced gastric carcinoma. AB - BACKGROUND: The benefits of preoperative 18FDG-PET/CT for gastric cancer remain uncertain. The aim of this study was to investigate the effects of preoperative 18FDG-PET/CT on the surgical strategy for locally advanced gastric cancer retrospectively. METHODS: From January 2007 to November 2008, 18FDG-PET/CT was performed in 142 patients who had been diagnosed with advanced gastric cancer by computed tomography or gastrofiberscope findings. RESULTS: Detection rates were 88.7% (126/142) for primary tumors and 24.6% (35/142) for local lymph nodes (LN). Nine patients with metastatic lesions underwent induction chemotherapy without operation. Of 133 patients subjected to operation, positive FDG uptake in primary tumors (p=0.047) and local lymph nodes (p<0.001) was related to non-curable operations. The mean standard uptake value (SUV) of primary tumors of patients who underwent non-curable operations was significantly higher than that of patients with curable operations (p=0.001). When the SUV was greater than 5 and FDG uptake of LN was positive, non-curable operations were predicted with a sensitivity of 35.2%, a specificity of 91.0% and an accuracy of 76.7%. CONCLUSIONS: High SUV of the primary tumor and positive FDG uptake in local lymph nodes at PET/CT could predict non-curative resection in locally advanced gastric cancer. Therefore, information from preoperative PET/CT can help physician decisions regarding other modalities without laparotomy. PMID- 20932346 TI - A genome-wide SNP-association study confirms a sequence variant (g.66493737C>T) in the equine myostatin (MSTN) gene as the most powerful predictor of optimum racing distance for Thoroughbred racehorses. AB - BACKGROUND: Thoroughbred horses have been selected for traits contributing to speed and stamina for centuries. It is widely recognized that inherited variation in physical and physiological characteristics is responsible for variation in individual aptitude for race distance, and that muscle phenotypes in particular are important. RESULTS: A genome-wide SNP-association study for optimum racing distance was performed using the EquineSNP50 Bead Chip genotyping array in a cohort of n = 118 elite Thoroughbred racehorses divergent for race distance aptitude. In a cohort-based association test we evaluated genotypic variation at 40,977 SNPs between horses suited to short distance (<= 8 f) and middle-long distance (> 8 f) races. The most significant SNP was located on chromosome 18: BIEC2-417495 ~690 kb from the gene encoding myostatin (MSTN) [P(unadj.) = 6.96 x 10-6]. Considering best race distance as a quantitative phenotype, a peak of association on chromosome 18 (chr18:65809482-67545806) comprising eight SNPs encompassing a 1.7 Mb region was observed. Again, similar to the cohort-based analysis, the most significant SNP was BIEC2-417495 (P(unadj.) = 1.61 x 10-9; P(Bonf.) = 6.58 x 10-5). In a candidate gene study we have previously reported a SNP (g.66493737C>T) in MSTN associated with best race distance in Thoroughbreds; however, its functional and genome-wide relevance were uncertain. Additional re sequencing in the flanking regions of the MSTN gene revealed four novel 3' UTR SNPs and a 227 bp SINE insertion polymorphism in the 5' UTR promoter sequence. Linkage disequilibrium was highest between g.66493737C>T and BIEC2-417495 (r2 = 0.86). CONCLUSIONS: Comparative association tests consistently demonstrated the g.66493737C>T SNP as the superior variant in the prediction of distance aptitude in racehorses (g.66493737C>T, P = 1.02 x 10-10; BIEC2-417495, P(unadj.) = 1.61 x 10-9). Functional investigations will be required to determine whether this polymorphism affects putative transcription-factor binding and gives rise to variation in gene and protein expression. Nonetheless, this study demonstrates that the g.66493737C>T SNP provides the most powerful genetic marker for prediction of race distance aptitude in Thoroughbreds. PMID- 20932347 TI - Increased accumulation of hypoxia-inducible factor-1alpha with reduced transcriptional activity mediates the antitumor effect of triptolide. AB - BACKGROUND: Hypoxia-inducible factor-1alpha (HIF-1alpha), a critical transcription factor to reduced O2 availability, has been demonstrated to be extensively involved in tumor survival, aggressive progression, drug resistance and angiogenesis. Thus it has been considered as a potential anticancer target. Triptolide is the main principle responsible for the biological activities of the Traditional Chinese Medicine tripterygium wilfordii Hook F. Triptolide possesses great chemotherapy potential for cancer with its broad-spectrum anticancer, antiangiogenesis, and drug-resistance circumvention activities. Numerous biological molecules inhibited by triptolide have been viewed as its possible targets. However, the anticancer action mechanisms of triptolide remains to be further investigated. Here we used human ovarian SKOV-3 cancer cells as a model to probe the effect of triptolide on HIF-1alpha. RESULTS: Triptolide was observed to inhibit the proliferation of SKOV-3 cells, and meanwhile, to enhance the accumulation of HIF-1alpha protein in SKOV-3, A549 and DU145 cells under different conditions. Triptolide did not change the kinetics or nuclear localization of HIF-1alpha protein or the 26 S proteasome activity in SKOV-3 cells. However, triptolide was found to increase the levels of HIF-1alpha mRNA. Unexpectedly, the HIF-1alpha protein induced by triptolide appeared to lose its transcriptional activity, as evidenced by the decreased mRNA levels of its target genes including VEGF, BNIP3 and CAIX. The results were further strengthened by the lowered secretion of VEGF protein, the reduced sprout outgrowth from the rat aorta rings and the inhibitory expression of the hypoxia responsive element driven luciferase reporter gene. Moreover, the silencing of HIF-1alpha partially prevented the cytotoxicity and apoptosis triggered by triptolide. CONCLUSIONS: The potent induction of HIF-1alpha protein involved in its cytotoxicity, together with the suppression of HIF-1 transcriptional activity, indicates the great therapeutic potential of triptolide as an anticancer drug. Meanwhile, our data further stress the possibility that HIF-1alpha functions in an unresolved nature or condition. PMID- 20932348 TI - Altered resting-state connectivity in subjects at ultra-high risk for psychosis: an fMRI study. AB - BACKGROUND: Individuals at ultra-high risk (UHR) for psychosis have self disturbances and deficits in social cognition and functioning. Midline default network areas, including the medial prefrontal cortex and posterior cingulate cortex, are implicated in self-referential and social cognitive tasks. Thus, the neural substrates within the default mode network (DMN) have the potential to mediate self-referential and social cognitive information processing in UHR subjects. METHODS: This study utilized functional magnetic resonance imaging (fMRI) to investigate resting-state DMN and task-related network (TRN) functional connectivity in 19 UHR subjects and 20 matched healthy controls. The bilateral posterior cingulate cortex was selected as a seed region, and the intrinsic organization for all subjects was reconstructed on the basis of fMRI time series correlation. RESULTS: Default mode areas included the posterior/anterior cingulate cortices, the medial prefrontal cortex, the lateral parietal cortex, and the inferior temporal region. Task-related network areas included the dorsolateral prefrontal cortex, supplementary motor area, the inferior parietal lobule, and middle temporal cortex. Compared to healthy controls, UHR subjects exhibit hyperconnectivity within the default network regions and reduced anti correlations (or negative correlations nearer to zero) between the posterior cingulate cortex and task-related areas. CONCLUSIONS: These findings suggest that abnormal resting-state network activity may be related with the clinical features of UHR subjects. Neurodevelopmental and anatomical alterations of cortical midline structure might underlie altered intrinsic networks in UHR subjects. PMID- 20932349 TI - Pharmacokinetics of artemether and dihydroartemisinin in healthy Pakistani male volunteers treated with artemether-lumefantrine. AB - BACKGROUND: Artemether-lumefantrine is one of the most widely used anti-malarial drug combinations in the world with excellent tolerability and cure rates in adult and paediatric patients with uncomplicated falciparum malaria. The aim of this study was to evaluate the pharmacokinetics of artemether and its active metabolite, dihydroartemisinin, in healthy Pakistani volunteers. METHODS: Twelve healthy male Pakistani subjects, aged 20 to 50, were recruited into the study. A fixed oral combination of artemether-lumefantrine (80-480 mg) was given as a single oral dose. Frequent blood samples were collected and artemether and dihydroartemisinin were quantified in human plasma using solid-phase extraction and liquid chromatography coupled with tandem mass spectrometry. Drug concentration-time data were evaluated with non-compartmental analysis. RESULTS: Observed maximum concentrations (mean +/- SD) of artemether and dihydroartemisinin were 184 +/- 100 ng/mL and 126 +/- 46 ng/mL, respectively. These concentrations were reached at 1.56 +/- 0.68 hr and 1.69 +/- 0.59 hr, respectively, after drug intake. The terminal elimination half-life of artemether and dihydroartemisinin were 2.00 +/- 0.71 hr and 1.80 +/- 0.31 hr, respectively. Apparent volume of distribution and oral clearance for artemether were estimated to 666 +/- 220 L and 257 +/- 140 L/hr. The same parameters were estimated to 702 +/- 220 L and 269 +/- 57 L/hr for dihydroartemisinin. CONCLUSIONS: The overall pharmacokinetic properties of artemether and dihydroartemisinin in healthy Pakistani subjects are comparable to healthy subjects and patients from other populations. PMID- 20932350 TI - Cost-effectiveness of recurrence risk guided care versus care as usual in women who suffered from early-onset preeclampsia including HELLP syndrome in their previous pregnancy (the PreCare study). AB - BACKGROUND: Preeclampsia and HELLP syndrome may have serious consequences for both mother and fetus. Women who have suffered from preeclampsia or the HELLP syndrome, have an increased risk of developing preeclampsia in a subsequent pregnancy. However, most women will develop no or only minor complications. In this study, we intend to determine cost-effectiveness of recurrence risk guided care versus care as usual in pregnant women with a history of early-onset preeclampsia. METHODS/DESIGN: We developed a prediction model to estimate the individual risk of recurrence of early-onset preeclampsia and the HELLP syndrome. In a before-after study, pregnant women with preeclampsia or HELLP syndrome in their previous pregnancy receiving care as usual (before introduction of the prediction model) will be compared with women receiving recurrence risk guided care (after introduction of the prediction model). Eligible and pregnant women will be recruited at six university hospitals and seven large non-university tertiary referral hospitals in the Netherlands. The primary outcome measure is the recurrence of early-onset preeclampsia or HELLP syndrome in women allocated to the regular monitoring group. For the economic evaluation, a modelling approach will be used. Costs and effects of recurrence risk guided care with those of care as usual will be compared by means of a decision model. Two incremental cost-effectiveness ratios will be calculated: 1) cost per Quality Adjusted Life Year (mother unit of analysis) and 2) cost per live born child (child unit of analysis). DISCUSSION: This is, to our knowledge, the first study that evaluates prospectively the efficacy of a multivariable prediction rule for recurrent hypertensive disease in pregnancy. Results of this study could either be integrated into the current guideline on Hypertensive Disorders in Pregnancy, or be used to develop a new guideline. PMID- 20932352 TI - High dietary niacin intake is associated with decreased chromosome translocation frequency in airline pilots. AB - Experimental studies suggest that B vitamins such as niacin, folate, riboflavin, vitamin B6 and vitamin B12 may protect against DNA damage induced by ionising radiation (IR). However, to date, data from IR-exposed human populations are not available. We examined the intakes of these B vitamins and their food sources in relation to the frequency of chromosome translocations as a biomarker of cumulative DNA damage, in eighty-two male airline pilots. Dietary intakes were estimated by using a self-administered semi-quantitative FFQ. Translocations in peripheral blood lymphocytes were scored by using fluorescence in situ hybridisation whole-chromosome painting. Negative binomial regression was used to estimate rate ratios and 95 % CI, adjusted for age and occupational and lifestyle factors. We observed a significant inverse association between translocation frequency and dietary intake of niacin (P = 0.02): adjusted rate ratio for subjects in the highest tertile compared with the lowest tertile was 0.58 (95 % CI 0.40, 0.83). Translocation frequency was not associated with total niacin intake from food and supplements as well as dietary or total intake of folate, riboflavin or vitamin B6 or B12. However, the adjusted rate ratios were significant for subjects with >= median compared with < median intake of whole grains (P = 0.03) and red and processed meat (P = 0.01): 0.69 (95 % CI 0.50, 0.96) and 1.56 (95 % CI 1.13, 2.16), respectively. Our data suggest that a high intake of niacin from food or a diet high in whole grains but low in red and processed meat may protect against cumulative DNA damage in IR-exposed persons. PMID- 20932351 TI - Specific antibody responses against membrane proteins of erythrocytes infected by Plasmodium falciparum of individuals briefly exposed to malaria. AB - BACKGROUND: Plasmodium falciparum infections could lead to severe malaria, principally in non-immune individuals as children and travellers from countries exempted of malaria. Severe malaria is often associated with the sequestration of P. falciparum-infected erythrocytes in deep micro-vascular beds via interactions between host endothelial receptors and parasite ligands expressed on the surface of the infected erythrocyte. Although, serological responses from individuals living in endemic areas against proteins expressed at surface of the infected erythrocyte have been largely studied, seldom data are available about the specific targets of antibody response from travellers. METHODS: In order to characterize antigens recognized by traveller sera, a comparison of IgG immune response against membrane protein extracts from uninfected and P. falciparum infected red blood cells (iRBC), using immunoblots, was performed between non exposed individuals (n = 31) and briefly exposed individuals (BEI) (n = 38) to malaria transmission. RESULTS: Immune profile analysis indicated that eight protein bands from iRBC were significantly detected more frequently in the BEI group. Some of these antigenic proteins were identified by an original immuno proteomic approach. CONCLUSION: Collectively, these data may be useful to characterize the singular serological immune response against a primary malaria infection in individuals briefly exposed to transmission. PMID- 20932353 TI - Development of nutritional iron deficiency in growing male rats: haematological parameters, iron bioavailability and oxidative defence. AB - Despite Fe deficiency having been widely studied, the sequence of events in its development still remains unclear. The aim of the present study was to elucidate the effects of nutritional Fe-deficiency development on haematological parameters, Fe bioavailability and the enzymes involved in oxidative defence in recently weaned male Wistar albino rats. Control (C) and Fe-deficient (ID) groups were fed the AIN-93 G diet with a normal Fe level (45 mg/kg diet) or with a low Fe level (5 mg/kg diet), respectively, for 20, 30 or 40 d. At day 20 serum Fe, serum ferritin and the saturation of transferrin decreased drastically, decreasing further in the course of Fe-deficiency development for the saturation of transferrin. The development of Fe deficiency did not affect plasma thiobarbituric acid-reactive substance production, or catalase (CAT) and glutathione peroxidase (GPx) activities in erythrocyte cytosol. Fe deficiency diminished hepatic Fe content and CAT and GPx activities in hepatic cytosol only at day the 20. However, in spite of the minor Fe deposits in the brain of ID rats, the CAT and GPx activities in the brain cytosolic fraction did not differ in any of the studied periods v. control rats. These results show that brain is a tissue that does not seem to depend on Fe levels for the maintenance of antioxidant defence mechanisms in the course of nutritional Fe deficiency. PMID- 20932354 TI - The fat and protein fractions of freshwater clam ( Corbicula fluminea) extract reduce serum cholesterol and enhance bile acid biosynthesis and sterol excretion in hypercholesterolaemic rats fed a high-cholesterol diet. AB - We investigated whether the fat and protein fractions of freshwater clam (Corbicula fluminea) extract (FCE) could ameliorate hypercholesterolaemia in rats fed a high-cholesterol diet. We also explored the mechanism and the components that exert the hypocholesterolaemic effect of FCE. The doses of the fat and protein fractions were equivalent to those in 30 % FCE. The fat and protein fractions of FCE, two major components of FCE, significantly reduced the serum and hepatic cholesterol levels. The fat fraction more strongly reduced serum cholesterol levels than the same level of total FCE. The excretion of faecal neutral sterols increased in rats fed the total the FCE and the fat fraction of FCE. On the other hand, faecal bile acid levels were greater in rats fed the total FCE and the fat and protein fractions of FCE than in control animals. The hepatic gene expression of ATP-binding cassette transporter G5 and cholesterol 7alpha-hydroxylase was up-regulated by the administration of the total FCE and both the fat and protein fractions of FCE. These results showed that the fat and protein fractions of FCE had hypocholesterolaemic properties, and that these effects were greater with the fat fraction than with the protein fraction. The present study indicates that FCE exerts its hypocholesterolaemic effects through at least two different mechanisms, including enhanced excretion of neutral sterols and up-regulated biosynthesis of bile acids. PMID- 20932355 TI - Sexual size dimorphism, sex ratio and the relationship between seasonality and water quality in four species of Gordiida (Nematomorpha) from Catamarca, Argentina. AB - A total of 687 adult nematomorphs of four species of Gordiida: Chordodes brasiliensis (393 specimens), Noteochorododes cymatium (47 specimens), N. talensis (162 specimens) and Pseudochordodes dugesi (85 specimens) were collected during a period of 1 year from El Simbolar stream, Argentina. Free-living worms were abundant during autumn and spring, but their number decreased during winter and summer. Males were shorter and significantly more abundant than females. The presence of N. cymatium, N. talensis and P. dugesi was correlated with water temperature and these species were most abundant in winter and spring. The presence of C. brasiliensis was correlated with flow rate and pH; this species was more abundant in autumn and winter. These four species are sympatric. PMID- 20932356 TI - Presence of individual (residual) symptoms during depressive episodes and periods of remission: a 3-year prospective study. AB - BACKGROUND: Residual depressive symptomatology constitutes a substantial risk for relapse in depression. Treatment until full remission is achieved is therefore implicated. However, there is a lack of knowledge about the prevalence of (1) residual symptoms in general and (2) the individual residual symptoms in particular. METHOD: In a 3-year prospective study of 267 initially depressed primary care patients we established per week the presence/absence of the individual DSM-IV depressive symptoms during subsequent major depressive episodes (MDEs) and episodes of (partial) remission. This was accomplished by means of 12 assessments at 3-monthly intervals with the Composite International Diagnostic Interview (CIDI). RESULTS: In general, residual depressive symptomatology was substantial, with on average two symptoms present during remissions. Three individual symptoms (cognitive problems, lack of energy and sleeping problems) dominated the course of depression and were present 85-94% of the time during depressive episodes and 39-44% of the time during remissions. CONCLUSIONS: Residual symptoms are prevalent, with some symptoms being present for almost half of the time during periods of remission. Treatment until full remission is achieved is not common practice, yet there is a clear need to do so to prevent relapse. Several treatment suggestions are made. PMID- 20932357 TI - Multiple pathways of inhibition shape bipolar cell responses in the retina. AB - Bipolar cells (BCs) are critical relay neurons in the retina that are organized into parallel signaling pathways. The three main signaling pathways in the mammalian retina are the rod, ON cone, and OFF cone BCs. Rod BCs mediate incrementing dim light signals from rods, and ON cone and OFF cone BCs mediate incrementing and decrementing brighter light signals from cones, respectively. The outputs of BCs are shaped by inhibitory inputs from GABAergic and glycinergic amacrine cells in the inner plexiform layer, mediated by three distinct types of inhibitory receptors: GABA(A), GABA(C), and glycine receptors. The three main BC pathways receive distinct forms of inhibition from these three receptors that shape their light-evoked inhibitory signals. Rod BC inhibition is dominated by slow GABA(C) receptor inhibition, while OFF cone BCs are dominated by glycinergic inhibition. The inhibitory inputs to BCs are also shaped by serial inhibitory connections between GABAergic amacrine cells that limit the spatial profile of BC inhibition. We discuss our recent studies on how inhibitory inputs to BCs are shaped by receptor expression, receptor properties, and neurotransmitter release properties and how these affect the output of BCs. PMID- 20932358 TI - Evidence of alpha 7 nicotinic acetylcholine receptor expression in retinal pigment epithelial cells. AB - Some evidence suggests that retinal pigment epithelium (RPE) can express nicotinic acetylcholine receptors (nAChRs) as described for other epithelial cells, where nAChRs have been involved in processes such as cell development, cell death, cell migration, and angiogenesis. This study is designed to determine the expression and activity of alpha7 nAChRs in RPE cells. Reverse transcriptase (RT)-PCR was performed to test the expression of nicotinic alpha7 subunit in bovine RPE cells. Protein expression was determined by Western blot and by immunocytochemistry. Expression of nicotinic alpha7 subunits was also analyzed in cryostat sections of albino rat retina. Changes in protein expression were tested under hypoxic conditions. Functional nAChRs were studied by examining the Ca2+ transients elicited by nicotine and acetylcholine stimulation in fura-2-loaded cells. Expression of endogenous modulators of nAChRs was analyzed by RT-PCR and Western blot in retina and RPE. Cultured bovine RPE cells expressed nicotinic receptors containing alpha7 subunit. RT-PCR amplified the expected specific alpha7 fragment. Western blotting showed expression at the protein level, with a specific band being found at 57 kDa in both cultured and freshly isolated RPE cells. Expression of nAChRs was confirmed for cultured cells by immunofluorescence. Immunohistochemistry confirmed alpha7 receptor expression in rat RPE retina. alpha7 receptor expression was down-regulated by long-term hypoxia. A small subpopulation of RPE cultured cells showed functional nAChRs, as evidenced by the selective response elicited by nicotine and acetylcholine stimulation. Expression of the endogenous nicotinic receptors' modulator lynx1 was confirmed in bovine retina and RPE, and expression of lynx1 and other endogenous nicotinic receptor modulators (SLURP1 and RGD1308195) were also confirmed in rat retina. These results suggest that nAChRs could have a significant role in RPE, which may not be related to the traditional role in nerve transmission but could more likely be related to the nonneuronal cholinergic system in the eye. PMID- 20932359 TI - Effects of fixational saccades on response timing in macaque lateral geniculate nucleus. AB - Even during active fixation, small eye movements persist that might be expected to interfere with vision. Numerous brain mechanisms probably contribute to discounting this jitter. Changes in the timing of responses in the visual thalamus associated with fixational saccades are considered in this study. Activity of single neurons in alert monkey lateral geniculate nucleus (LGN) was recorded during fixation while pseudorandom visual noise stimuli were presented. The position of the stimulus on the display monitor was adjusted based on eye position measurements to control for changes in retinal locations due to eye movements. A method for extracting nonstationary first-order response mechanisms was applied, so that changes around the times of saccades could be observed. Saccade-related changes were seen in both amplitude and timing of geniculate responses. Amplitudes were greatly reduced around saccades. Timing was retarded slightly during a window of about 200 ms around saccades. That is, responses became more sustained. These effects were found in both parvocellular and magnocellular neurons. Timing changes in LGN might play a role in maintaining cortical responses to visual stimuli in the presence of eye movements, compensating for the spatial shifts caused by saccades via these shifts in timing. PMID- 20932360 TI - Stepped care cognitive behavioural therapy for children with anxiety disorders: a new treatment approach. AB - BACKGROUND: The current nonrandomized clinical trial explored changes over time in children with an anxiety disorder during stepped care, manual-based cognitive behaviour therapy (CBT). METHODS: Clinically anxious children (8-12 years, n = 133) and their parents participated in child focused CBT (10 sessions). If assessments indicated additional treatment was necessary, participants could step up to a second and possibly third treatment phase (each 5 sessions) including more parental involvement. RESULTS: After the first treatment phase 45% of the Intention-To-Treat sample was free of any anxiety disorder; after the second and third phase an additional 17% and 11% respectively. In total, 74% of the children no longer met criteria for any anxiety disorder following treatment. Child and parent reported anxiety and depression symptoms of children improved significantly during all treatment phases, as well as child reported anxiety sensitivity and negative affect. Children participating in more treatment showed significant improvements during additional treatment phases, indicating that late change occurred for the subgroup that had not changed during the first phase. CONCLUSIONS: Stepped care offers a standardized, assessment based, yet tailored treatment approach for children with anxiety disorders. A more intensive treatment is offered when initial CBT is insufficient, providing children additional opportunities to reach the desired outcome. PMID- 20932361 TI - Histological and stereological characterization of brown trout (Salmo trutta f. fario) trunk kidney. AB - The large variability in kidney morphology among fish makes it difficult to build a "universal" model on its function and structure. Therefore, a morphological study of brown trout trunk kidney was performed, considering potential seasonal and sex effects. Three-year-old specimens of both sexes were collected at four stages of their reproductive cycle. Kidney was processed for light and electron microscopy. The relative volumes of renal components, such as renal corpuscles and different nephron tubules, were estimated by stereological methods. Qualitatively, the general nephron structure of brown trout was similar to that described for other glomerular teleost species. Quantitatively, however, differences in the relative volume of some renal components were detected between sexes and among seasons. Particularly, highest values of vacuolized tubules and new growing tubules were observed after spawning, being more relevant in females. Despite seasonal changes, more linear correlations were found between those parameters and the reno-somatic index than the gonado-somatic index. Thus, we verified that some brown trout renal components undergo sex dependent seasonal variations, suggesting a morphological adaptation of the components to accomplish physiological needs. These findings constitute a baseline for launching studies to know which factors govern the morphological variations and their functional consequences. PMID- 20932362 TI - The safety and efficacy of laparoscopic surgical staging and debulking of apparent advanced stage ovarian, fallopian tube, and primary peritoneal cancers. AB - OBJECTIVES: To describe our experience with laparoscopic primary or interval tumor debulking in patients with presumed advanced ovarian, fallopian tube, or peritoneal cancers. METHODS: This is a retrospective analysis of a prospective case series. Women with presumed advanced (FIGO stage IIC or greater) ovarian, fallopian tube, or primary peritoneal cancers deemed appropriate candidates for laparoscopic debulking by the primary surgeon(s) were recruited. RESULTS: The study comprised 32 patients who underwent laparoscopic evaluation. Seventeen underwent total laparoscopic primary or interval cytoreduction, with 88.2% optimal cytoreduction. Eleven underwent diagnostic laparoscopy and conversion to laparotomy for cytoreduction, with 72.7% optimal cytoreduction. Four patients had biopsies, limited cytoreduction, or both. In the laparoscopy group, 9 patients have no evidence of disease (NED), 6 are alive with disease (AWD), and 2 have died of disease (DOD), with mean follow-up time of 19.7 months. In the laparotomy group, 3 patients are NED, 5 are AWD, and 3 are DOD, with mean follow-up of 25.8 months. Estimated blood loss and length of hospital stay were less for the laparoscopy group (P=0.008 and P=0.03), while operating time and complication rates were not different. Median time to recurrence was 31.7 months for the laparoscopy group and 21.5 months for the laparotomy group (P=0.3). CONCLUSIONS: Laparoscopy can be used for diagnosis, triage, and debulking of patients with advanced ovarian, fallopian tube, or primary peritoneal cancer and is technically feasible in a well-selected population. PMID- 20932363 TI - Complications associated with two laparoscopic procedures used in the management of rectal endometriosis. AB - BACKGROUND: To evaluate intra- and postoperative complications associated with laparoscopic management of rectal endometriosis by either colorectal segmental resection or nodule excision. METHODS: During 39 consecutive months, 46 women underwent laparoscopic management of rectal endometriosis and were included in a retrospective comparative study. The distinguishing feature of the study is that the choice of the surgical procedure is not related to the characteristics of the nodule. RESULTS: Colorectal segmental resection with colorectal anastomosis was carried out in 15 patients (37%), while macroscopically complete rectal nodule excision was performed in 31 women (63%). No intraoperative complications were recorded. In the colorectal resection group, 3 women (18%) had a bladder atony (spontaneously regressive in 2 women), 4 women (24%) experienced chronic constipation, one had an anastomosis leakage (6%), while 2 women (13%) had acute compartment syndrome with peripheral sensory disturbance. In the nodule excision group, 1 woman (4%) developed transitory right obturator nerve motor palsy. Based on both postoperative pain and improvement in quality of life, all 29 women in the excision group (100%) and 14 women in the colorectal resection group (82%) would recommend the surgical procedure to a friend suffering from the same disease. CONCLUSION: Our study suggests that carrying out colorectal segmental resection in rectal endometriosis is associated with unfavourable postoperative outcomes, such as bladder and rectal dysfunction. These outcomes are less likely to occur when rectal nodules are managed by excision. Information about complications related to both surgical procedures should be provided to patients managed for rectal endometriosis and should be taken into account when a decision is being made about the most appropriate treatment of rectal endometriosis in each case. PMID- 20932364 TI - Total laparoscopic hysterectomy for uteri over one kilogram. AB - INTRODUCTION: Laparoscopic hysterectomy for large fibroid uteri is technically a difficult procedure. In this article, we report our experience with fibroid uteri >1 kg in weight. MATERIALS AND METHODS: An intent-to-treat study. RESULTS: From 2003 to 2009, 13 patients were successfully treated for large fibroid uteri with postoperative specimens weighing >1000 g. Four patients had total abdominal hysterectomy, one patient had laparoscopically assisted vaginal hysterectomy, and 8 patients had total laparoscopic hysterectomy. The last 6 cases were total laparoscopic hysterectomy cases. CONCLUSION: With experience and specialized techniques, total laparoscopic hysterectomy can replace abdominal hysterectomy for large uteri. PMID- 20932365 TI - Transvaginal application of a laparoscopic bipolar cutting forceps to assist vaginal hysterectomy in extremely obese endometrial cancer patients. AB - INTRODUCTION: The purpose of this report is to evaluate our experience with transvaginal application of a laparoscopic bipolar cutting forceps to assist vaginal hysterectomy in extremely obese women with endometrial cancer in whom obesity precluded LAVH/BSO and lymphadenectomy and vaginal obesity limited visualization and exposure. MATERIALS AND METHODS: We performed a retrospective review and identified 6 consecutive cases. No cases were excluded. A laparoscopic 33-cm Plasma Kinctic (PK) cutting forceps with a 5-mm diameter was applied transvaginally to coagulate and cut the uterosacral and cardinal ligaments, uterine vasculature, and ovarian ligaments. The uterus was delivered vaginally. Staging lymphadenectomy was not performed. RESULTS: Median age was 51 years, median weight was 405 lbs, and median BMI was 66 kg/m2. Five of 6 cases were successfully performed vaginally (83%). Median operative time was 1 hour 10 minutes, median blood loss was 500 mL, and pain was only discomforting. All patients were discharged the day after surgery. There were no complications. At median follow-up of 1 year, all patients were alive with no evidence of disease. CONCLUSION: It is our opinion that the transvaginal application of a laparoscopic bipolar cutting forceps can successfully assist vaginal hysterectomy in extremely obese endometrial cancer patients who cannot tolerate LAVH/BSO and lymphadenectomy and vaginal obesity limits visualization and exposure. PMID- 20932366 TI - Immediate laparoscopic nontransvesical repair without omental interposition for vesicovaginal fistula developing after total abdominal hysterectomy. AB - BACKGROUND AND OBJECTIVE: We conducted this study to evaluate the feasibility and efficacy of immediate laparoscopic nontransvesical repair without omental interposition for vesicovaginal fistula (VVF) developing after total abdominal hysterectomy (TAH), which causes not only social and economic misery for the patient but also considerable stress to the physicians who perform the surgery. METHODS: We performed a retrospective review of 5 women who underwent immediate laparoscopic nontransvesical repair without omental interposition for VVFs, developing after TAH from October 2007 to March 2009. In terms of laparoscopic procedure, cystoscopy was performed to confirm the location of fistula and ureteral openings, initially. Without opening the bladder, the fistula tract was identified, and the bladder was dissected from the vagina. The bladder defect was closed by using intracorporeal, continuous, and double-layer suturing, laparoscopically. The vaginal defect was closed using interrupted and single layer suturing, vaginally. A Foley catheter was inserted for 2 weeks and removed after bladder integrity was confirmed with a retrograde cystogram. RESULTS: The median age and body mass index of the patients were 47 years and 22.3 kg/m2, respectively. Operating time, hemoglobin change, and hospital stay were 95 minutes, 1.1 g/dL, and 5 days, respectively. There were no complications or laparoconversions. During follow-up (median 56.1 weeks; range 26.6 to 74.0), there was no evidence of recurrence. CONCLUSIONS: Immediate laparoscopic nontransvesical repair without omental interposition might be an effective, feasible alternative to the traditional methods in select patients with small sized (<1 cm) VVF developing after TAH. PMID- 20932367 TI - Hydrothermal endometrial ablation can reduce the need for hysterectomy and transfusion. AB - Women seeking emergency care for severe uterine hemorrhage with profound anemia often undergo transfusion dilatation curettage and ultimately hysterectomy. The purpose of this article is to describe a modern conservative approach to treating persistent uterine hemorrhage unresponsive to medical therapy, avoiding transfusion and allowing for nonemergent future therapy without the potential complications of transfusion. Six patients with unremitting uterine bleeding were included in the study performed in the Department of Gynecology at an academically affiliated general hospital. Patients underwent successful hydrothermal endometrial ablation after failed medical therapy. This procedure is effective in controlling severe uterine bleeding in patients with large intrauterine fibroids; thus, the number of women being transfused can be significantly reduced. PMID- 20932368 TI - Saving time during laparoscopy using a new, wall anchoring trocar device. AB - OBJECTIVE: Safe and reliable access systems are crucial in laparoscopy, and trocar dislodgement is still a common and frustrating problem. Wall emphysema can occur besides the risky prolongation of the surgical procedure. Wall-anchoring components provide a better hold of the device. This comparative analysis assesses the frequency of dislodgement and a time-sparing effect on the intervention of 3 different trocar systems, including an innovation in the field of access-providing systems. METHODS: Patients who underwent laparoscopy for various gynecological indications were included and randomized consecutively into 3 groups according to the access system used in the intervention: (A) trocar fitted with a spiral thread on the sleeve, (B) trocar with plain sleeve, (C) trocar as in B together with a fixator. This novelty is installed on the trocar before insertion and then sutured to the abdominal wall. Intervention time, frequency of trocar corrections, and the time loss through correction were registered. Standard statistical analyses were performed. RESULTS: The cohort comprised 131 patients; 51 patients were consecutively randomized into group A, 38 into group B, and 42 into group C. Mean intervention time was different, shortest in C and highest in B. Frequency of interruption of the intervention due to adjustment of the device and time loss through adjustment was lowest in group C (fixator + plain sleeve) and highest in group B (plain-sleeve) (0.47 vs 0.29, P<0.05 and 2.13 minutes vs 0.69 minutes, P<0.05). CONCLUSION: Wall-anchoring components lead to higher stability of ports and have a time-sparing effect. Comparing the 2 trocar groups with wall-anchoring properties (trocar with thread fitted sleeve vs fixator + trocar with plain sleeve), the mean operation time was lowest in the fixator group, and the time-saving effect was higher. PMID- 20932369 TI - Initial surgeon training for single port access surgery: our first year experience. AB - BACKGROUND: We have developed a single port access (SPA) surgical technique that allows for procedures to be done through a single umbilical port incision <20 mm in length. For a new approach to be universally beneficial, it needs to be easily learned and applied. METHODS: Single port access abdominal procedures are performed through one umbilical incision where skin and soft tissue flaps are raised from the underlying fascia to allow insertion of up to 4 instruments. Fifty surgeons with varying degrees of laparoscopic training participated in SPA training programs at Drexel University to learn and apply the SPA technique through participation in an animate (porcine) laboratory. RESULTS: All surgeons successfully performed the SPA access technique without difficulty and completed the cholecystectomy in <55 minutes (average, 42). Eight surgeons successfully performed placement of a cholangiogram catheter. All recognized the value of a formal training symposium to learn SPA techniques before performing SPA procedures in their practice. CONCLUSIONS: The SPA technique has been successfully shown to be an approach that is easily learned and accomplished. We believe this is a necessary and important bridge towards proficiency in performing SPA procedures in clinical patients. PMID- 20932370 TI - Comparison of laparoscopy training using the box trainer versus the virtual trainer. AB - BACKGROUND AND OBJECTIVES: To evaluate whether training on a virtual reality laparoscopic simulator improves the performance on a laparoscopic box trainer. METHODS: Twenty-six subjects were trained using a box trainer, and 17 participants were trained using a virtual simulator. Participants in the experimental group completed 1 session of 5 exercises on the box trainer, 4 sessions on the virtual simulator, and a final session on the box trainer. Participants in the control group completed 6 sessions of 5 exercises on the box trainer alone. Exercises were monitored and scored for time and accuracy. Participants completed a self-evaluation survey after each session and a user satisfaction questionnaire at the end of the training. RESULTS: No significant difference existed between the 2 groups in improvement of accuracy. Pegboard time (P=0.0110) and pattern cutting time (P=0.0229) were the only exercise parameters that improved significantly more in the control group compared with the experimental group. The experimental group developed more interest in a surgical field as a result of their experience than the control group did (70.6% vs 53.8%, respectively). CONCLUSION: The virtual simulator is a reasonable alternative to the box trainer for laparoscopic skills training. PMID- 20932371 TI - Failure of mesenteric defect closure after Roux-en-Y gastric bypass. AB - BACKGROUND AND OBJECTIVES: Bowel obstructions following Roux-en-Y gastric bypass (RYGB) are a significant issue often caused by internal herniation. Controversy continues as to whether mesenteric defect closure is necessary to decrease the incidence of internal hernias after RYGB. Our purpose was to evaluate the effectiveness of closing the mesenteric defect at the jejunojejunostomy in patients who underwent RYGB by examining this potential space at reoperation for any reason. METHODS: We retrospectively reviewed medical records of patients undergoing surgery after RYGB from August 1999 to October 2008 to determine the status of the mesentery at the jejunojejunostomy. RESULTS: Eighteen patients underwent surgery 2 to 19 months after open (n=8) or laparoscopic (n=10) RYGB. All patients had documented suture closure of their jejunojejunostomy at the time of RYGB. Permanent (n=12) or absorbable (n=6) sutures were used for closures. Patients lost 23.6 kg to 62.1 kg before a reoperation was required for a ventral hernia (n=8), cholecystectomy (n=4), abdominal pain (n=4), or small bowel obstruction (n=2). Fifteen of the 18 patients had open mesenteric defects at the jejunojejunostomy despite previous closure; none were the cause for reoperation. CONCLUSION: Routine suture closure of mesenteric defects after RYGB may not be an effective permanent closure likely due to the extensive fat loss and weight loss within the mesentery. PMID- 20932372 TI - Early results of trans-oral endoscopic plication and revision of the gastric pouch and stoma following Roux-en-Y gastric bypass surgery. AB - OBJECTIVE: A new technique for endoscopic plication and revision of the gastric pouch (EPRGP) for patients who underwent gastric bypass (RGB) surgery was evaluated in patients with severe GERD, dumping syndrome, failure of weight loss, or all of these. PATIENTS AND METHODS: Patients underwent EPRGP over a 12-month period. The StomaphyX device (Endogastric Solutions, Redmond, WA) was utilized over a standard flexible gastroscope. Patients were kept on a liquid diet for 1 week. RESULTS: The study included 64 patients with a mean age of 48 years who underwent 67 procedures. EPRGP was performed an average of 5 years after RGB. The mean preoperative BMI was 39.5 kg/m2. The primary indications for the procedure were inadequate weight loss, dumping syndrome (42), and GERD (15). The mean follow-up period was 5.8 months (range, 3 to 12). The average operative time was 50 minutes, with a significant reduction with increased operator experience. There were only 2 (3%) intraoperative complications during the early period (equipment failure), which did not result in any morbidity. All symptoms from dumping syndrome or reflux improved, with no further operative-related complications. The mean weight loss was 7.3 kg. CONCLUSIONS: This study demonstrates the technical feasibility, safety, and efficacy of EPRGP. PMID- 20932373 TI - Gastric plication can reduce slippage rate after laparoscopic gastric banding. AB - BACKGROUND: Laparoscopic insertion of a gastric band for weight reduction is increasingly performed in obese and morbidly obese patients. Complication rates after gastric band insertion are reduced by using certain techniques. PATIENTS AND METHODS: This was a prospective study of all patients who underwent laparoscopic adjustable gastric band (LAGB) insertion at our unit. This procedure is performed through the classical 4-port technique and the use of a liver retractor. The pars flaccida method is performed in all patients, and the gold finger, a malleable instrument, is used to guide the band through the retroesophageal window in patients with difficult anatomy. Band slippage is avoided by using 2 types of gastric plication, depending on the anatomical characteristics of the stomach. Outcomes and morbidity are recorded, and patients are followed up in outpatient clinics. RESULTS: Laparoscopic adjustable gastric band (LAGB) insertion was performed in 464 patients. A single consultant surgeon performed all procedures over a 2-year period. From August 2005 through August 2007, 380 (81.89%) women and 84 (18.10%) men were included in this study. The mean age was 41 years (range, 21 to 62). The mean body mass index was 43 (range, 35 to 62). Morbidity included dysphagia, epigastric pain, port displacement, port infection, erosion, and acute respiratory distress. Only one (0.21%) case of band slippage was reported. The mean follow-up was 26 months (range, 18 to 42). CONCLUSION: Laparoscopic gastric plication adds greater security and provides optimum gastric band placement. It is an effective method to reduce slippage after gastric band insertion. PMID- 20932374 TI - Single-incision sleeve gastrectomy using a novel technique for liver retraction. AB - INTRODUCTION: Laparoscopic sleeve gastrectomy has rapidly gained popularity in the field of bariatric surgery, mainly due to its low morbidity and mortality. Traditionally, 4 to 6 trocars are used. Single-access surgery has emerged as an attempt to decrease incisional morbidity and enhance cosmetic benefits. We present our initial 7 patients undergoing single-incision laparoscopic sleeve gastrectomy using a novel technique for liver retraction. METHODS: Patients who underwent single-incision laparoscopic sleeve gastrectomy between March 2009 and May 2009 were analyzed. A 4-cm left paramedian incision was used. Laparoscopic sleeve gastrectomy was performed in a standard fashion using a 40 French bougie. RESULTS: Seven patients underwent single-incision sleeve gastrectomy at the University of Illinois at Chicago. They were all female with a mean age of 34 years. Preoperative BMI was 49 kg/m2 (range, 39 to 64). There were no intraoperative complications. Mean operative time was 103 minutes. Estimated blood loss was minimal. All 7 patients were discharged on postoperative day 2 and were doing well without any complications at 3.1 +/- 0.7 months after surgery. CONCLUSION: Single-incision laparoscopic sleeve gastrectomy is safe and feasible and can be performed without changing the existing principles of the procedure. Our technique for internal liver retraction provides adequate exposure and is reproducible. Development of improved standard instrumentation is required for this technique to become popular. PMID- 20932375 TI - Transvaginal repair of a large chronic porcine ventral hernia with synthetic mesh using NOTES. AB - BACKGROUND: Ventral incisional hernias still remain a common surgical problem. We tested the feasibility of transvaginal placement of a large synthetic mesh to repair a porcine hernia. METHODS: Seven pigs were used in this survival model. Each animal had creation of a 5-cm hernia defect and underwent a transvaginal repair of the defect with synthetic mesh. A single colpotomy was made using a 12 cm trocar for an overtube. The mesh was cut to size and placed through the trocar. A single-channel gastroscope with an endoscopic atraumatic grasper was used for grasping sutures. Further fascial sutures were placed every 5 cm. RESULTS: Mesh repair was feasible in all 7 animals. Mean operative time was 133 minutes. Technical difficulties were encountered. No gross contamination was seen at the time of necropsy. However, 5 animals had positive mesh cultures; 7 had positive cultures in the rectouterine space in enrichment broth or on direct culture. CONCLUSION: Transvaginal placement of synthetic mesh to repair a large porcine hernia using NOTES is challenging but feasible. Future studies need to be conducted to develop better techniques and determine the significance of mesh contamination. PMID- 20932376 TI - Laparoscopic incisional hernia repair with fibrin glue in select patients. AB - BACKGROUND AND OBJECTIVE: Laparoscopic treatment of incisional hernias can be performed using different types of fixation devices and prosthesis. We present a case series of 19 patients with incisional hernias with a diameter of < 6 cm, who underwent laparoscopic repair using Hi-tex dual-side mesh, positioned intraperitoneally, fixed to the abdominal wall by fibrin glue (Tissucol). METHODS: Nineteen patients with incisional hernias < 6 cm in diameter were enrolled in this study and treated laparoscopically with Hi-tex and Tissucol. Surgical complications and patient outcomes were assessed with a clinical follow up. RESULTS: Laparoscopic repair of incisional hernias by using Hi-tex mesh affixed to the parietal wall with fibrin glue was feasible and easy in patients with parietal defects < 6 cm in diameter. Mean operating time was 30 minutes. Mean hospital stay was 1.5 days. Almost no postoperative pain, major surgical complications, seroma formation, relapses, or prosthesis infection occurred during a mean follow-up of 20 months. CONCLUSIONS: In select patients, Hi-tex mesh affixed using fibrin glue allows laparoscopic repair of incisional hernias with very good patient outcomes, especially in terms of postoperative pain and seroma formation. PMID- 20932377 TI - Laparoscopic common bile duct exploration in patients with gallstones and choledocholithiasis. AB - OBJECTIVES: To compare the effectiveness of laparoscopic common bile duct exploration in patients with failed endoscopic retrograde cholangiopancreatography (ERCP). METHODS: This is a descriptive, comparative study. Patients with an indication of common bile duct exploration between February 2005 and October 2008 were included. We studied 2 groups: Group A: patients with failed ERCP who underwent LCBDE plus LC. Group B: patients with common bile duct stones managed with the 1-step approach (LCBDE + LC) with no prior ERCP. RESULTS: Twenty-five patients were included. Group A: 9 patients, group B: 16 patients. Success rate, operative time, and hospital stay were as follows: group A 66% vs group B 87.5%; group A 187 minutes vs 106 minutes; group A 4.5 days vs 2.3 days; respectively. CONCLUSION: Patients with failed ERCP should be considered as high-complex cases in which the laparoscopic procedure success rate decreases, and the conversion rate increases considerably. PMID- 20932378 TI - Laparoscopic-assisted management of impalpable testis in patients older than 10 years. AB - OBJECTIVE: Cryptorchidism affects 1% of male births. The majority of patients with undescended testis are identified and treated in childhood, but a significant proportion of them especially in third-world countries are neglected and present late. Herein, we present our initial experience of managing impalpable testis in older children and adults with laparoscopic assistance. PATIENTS AND METHODS: This study was conducted from 2003 through 2008 at LUMHS Jamshoro. Thirty-two patients with 40 impalpable testes were included in this study. Diagnostic laparoscopy was performed in 32 anesthetized patients. Laparoscopic-assisted orchiopexy or orchiectomy was performed in patients with intraabdominal testis. Testicular vessels and vas deferens were mobilized and after obtaining sufficient length were brought through the posterior wall of the inguinal canal by creating a neo-inguinal ring medial to the epigastric vessels after a small inguinal incision. RESULTS: Of 40 impalpable testis, ultrasound localized 16 (40%) of them, and on laparoscopy, 36 (90%) were localized, 30 (75%) as intraabdominal and in 6 (15%) cases vas and vessels were entering into the internal inguinal ring (intracanalicular). The remaining 4 patients were diagnosed as having vanishing testis (anorchia). Laparoscopic orchiectomy was performed in 14 (35%) of these testes, while single-stage laparoscopic-assisted orchiopexy using Prentiss' maneuver was performed in 16 (40%) testis. No major complications occurred. Seven testes were associated with ipsilateral hernias and were simultaneously repaired laparoscopically. CONCLUSION: Laparoscopic-assisted single-stage orchiopexy is a safe and successful procedure for intraabdominal testis in adolescents and older patients. The additional benefit of shortening the usual course of spermatic cord was beneficial to fix the testis in the scrotum without tension. PMID- 20932379 TI - Secured independent tools in peritoneoscopy. AB - BACKGROUND AND OBJECTIVES: Secured independent tools are being introduced to aid in peritoneoscopy. We present a simple technique for anchoring instruments, powered lights, and micro machines through the abdominal wall. METHODS: We used a laparoscopic trainer, micro alligator clips with one or two 2-0 nylon tails and cables for engines and lights. The above instruments were introduced via a 12-mm or 15-mm port. Clips were placed for traction, retraction and exposure, lights for illumination, and motors for potential work. A laparoscopy port closure or suture passer was introduced percutaneously to grab and extract the tails or cables outside of the simulated abdominal cavity. The engines and lights were powered by a direct electric current (DC) plugged into exteriorized cables. RESULTS: We used 2 to 3 clips for each, and engines performed well. CONCLUSION: This basic simulation adds independent instruments, lights, and engines. We replaced cannulas with threads or cables in an attempt to limit the number of ports. This technique further opens the door for innovations in wired machines in laparoscopy, single-port laparoscopy, or natural orifice surgery. PMID- 20932380 TI - Laparoscopic intragastric removal of giant trichobezoar. AB - BACKGROUND AND OBJECTIVES: Gastric bezoars are a rare clinical entity, most commonly observed in patients with mental or emotional illness. Large bezoars can be difficult to remove laparoscopically without extending a port incision. METHODS: We report the case of a large symptomatic trichobezoar with Rapunzel syndrome that occurred in a 17-year-old girl who had trichotillomania. RESULTS: The bezoar was removed laparoscopically, in piecemeal fashion, through a gastrotomy port. This procedure did not require an extension of any incision, nor did it require the contents of the stomach to directly touch the incision, thereby reducing the risk of infection. The patient was discharged home, on the fourth postoperative day, free of any complications. CONCLUSION: This case illustrates the safety of the laparoscopic approach in the removal of large gastric bezoars. In considering use of this approach, the potentially long operative time must be weighed against the benefits of both minimal risk of infection and minimal incisions. PMID- 20932381 TI - Laparoscopic treatment of gastric bezoar. AB - A seventeen-year-old female presented with a symptomatic abdominal mass that was diagnosed by barium meal and computed tomography to be a gastric bezoar. She underwent laparoscopic removal of the bezoar, through an anterior wall gastrostomy in an endobag, which was extracted piecemeal through a 4-cm upper midline incision. The technique is described with a review of a few previous laparoscopic-assisted cases. PMID- 20932382 TI - Iatrogenic combined bile duct and right hepatic artery injury during single incision laparoscopic cholecystectomy. AB - BACKGROUND: Numerous recent reports describe the performance of laparoscopic procedures through a single incision. Although the feasibility of this approach for a variety of procedures is currently being established, little data are available regarding safety. CASE REPORT: A 65-year-old female patient who was transferred from an outside institution had undergone a single incision laparoscopic cholecystectomy that resulted in biliary tract and vascular injuries. METHODS: The patient was transferred with a known bile duct injury on the first postoperative day following single incision laparoscopic cholecystectomy. Review of her magnetic resonance imaging and percutaneous transhepatic cholangiogram studies showed a Bismuth type 3 bile duct injury. Hepatic angiogram demonstrated an occlusion of the right hepatic artery with collateralization from the left hepatic artery. She was initially managed conservatively with a right-sided external biliary drain, followed 6 weeks later by a Hepp-Couinaud procedure to reconstruct the biliary tract. CONCLUSION: As new techniques evolve, it is imperative that safety, or potential side effects, or both safety and side effects, be monitored, because no learning curve is established for these new techniques. In these initial stages, surgeons should have a low threshold to add additional ports when necessary to ensure that procedures are completed safely. PMID- 20932383 TI - Laparoscopic excision of a large hepatic cyst. AB - Benign congenital liver cysts are rare in the pediatric population and often present a challenge in the diagnosis. Therefore, with recent advances in the field of minimally invasive surgery, this technique may be ideal in achieving both diagnosis and curative resection. We describe the case of a 2-month-old female initially referred for an antenatal ultrasound in the third trimester revealing a 7-cm intraabdominal cystic lesion of unknown origin. She was found to have a 10-cm hepatic cyst successfully treated by laparoscopic surgery. Our approach consisted of complete cyst excision along with its attached hepatic parenchyma. We recommend this technique as safe and feasible. PMID- 20932384 TI - Emergency intraperitoneal onlay mesh repair of incarcerated spigelian hernia. AB - BACKGROUND AND OBJECTIVES: Spigelian hernia is a rare cause of incarcerated ventral abdominal hernia that may pose a diagnostic dilemma. However, with the increasing utilization of double contrast computed tomography (CT) for undiagnosed small bowel obstruction in a virgin abdomen, more such cases are being diagnosed with increasing confidence. Furthermore, with the rapid expansion of the indications for minimal access surgery in emergency situations, these rare emergencies are increasingly tackled using a laparoscopic approach leading to swift patient recovery and discharge. METHODS: We present the case of an emergency intraperitoneal onlay mesh (IPOM) repair of Spigelian hernia, causing acute small bowel obstruction in a 55-year-old man with liver disease and ascites that was diagnosed using a CT scan. We conducted a search of Medline, Embase, Science Citation Index, Current Contents, PubMed, and the Cochrane Database to review the history of laparoscopic repair of Spigelian hernia and its various advancements, which are briefly presented here. RESULTS: The hernia was successfully reduced using laparoscopy, revealing a moderate-size defect in the linea semilunaris. The hernial defect was repaired with a composite mesh that was tacked into position. The patient was discharged from the hospital on the second postoperative day. CONCLUSIONS: Spigelian hernia in an emergency setting can be easily and swiftly repaired using the IPOM method utilizing a composite mesh. PMID- 20932385 TI - Symptomatic Bochdalek hernia in an adult. AB - BACKGROUND AND OBJECTIVES: Bochdalek hernias are congenital diaphragmatic defects resulting from the failure of posterolateral diaphragmatic foramina to fuse in utero. Symptomatic Bochdalek hernias in adults are infrequent and may lead to gastrointestinal dysfunction or severe pulmonary disease. We describe our experience with this rare entity. METHODS: A retrospective chart review was performed on a single patient for data collection purposes. RESULTS: The patient is a morbidly obese 53-year-old female who presented with epigastric pain and diffuse abdominal tenderness. Computed tomography scans of the chest and abdomen revealed a small posterior diaphragmatic defect containing gastric fundal diverticulum. Laboratory work and imaging revealed no other findings. Laparoscopic repair of the Bochdalek hernia was done via an abdominal approach and utilized primary closure with an AlloDerm patch apposed to the defect. The patient has had significant clinical improvement and continues to do well at 9 months postoperatively. CONCLUSION: Laparoscopic repair of symptomatic adult Bochdalek hernias can be performed successfully and may result in significant clinical improvement. PMID- 20932386 TI - Laparoscopic enterolithotomy is a valid option to treat gallstone ileus. AB - Gallstone ileus is a well-recognized clinical entity. It usually affects elderly female patients, and very often diagnosis can be delayed resulting in high morbidity and mortality. An abdominal x-ray and computed tomographic (CT) scan of the abdomen may show classical radiological features of small bowel obstruction, pneumobilia, and an ectopic gallstone. Laparotomy and enterlithotomy with or without definite biliary surgery is an established treatment. Since 1992, many cases of laparoscopic-assisted enterolithotomy have been reported. Only a few cases of a totally laparoscopic approach have been documented. We present the case of a 75-year-old lady who presented with features of intestinal obstruction. A plain x-ray of the abdomen and a CT scan confirmed the classical features of gallstone ileus. A totally laparoscopic enterolithotomy was performed using 6 ports. A 6-cm gallstone was retrieved through a longitudinal enterotomy. The transverse closure of the enterotomy was performed with intracorporeal suturing, resulting in an uneventful postoperative recovery. We suggest that a CT scan helps in the early diagnosis of the cause of intestinal obstruction, and totally laparoscopic enterolithomy with intracorporeal enterotomy repair is a valid, safe option. PMID- 20932387 TI - Single incision laparoscopic splenectomy in a 5-year-old with hereditary spherocytosis. AB - BACKGROUND: Single incision laparoscopic surgery (SILS) is an emerging technique that has been used as an approach for appendectomy, cholecystectomy, and splenectomy. We describe the technique of single incision laparoscopic splenectomy for hypersplenism in a 5-year-old boy with spherocytosis. CASE REPORT: The patient required blood transfusions for anemia secondary to hypersplenism. His spleen measured 9.8 cm in cranio-caudal length on ultrasound. SILS splenectomy was performed through a 2-cm umbilical incision by using 3 ports. The splenic attachments were taken down using an electrosurgical sealing and cutting device, and the hilum was transected with an endosurgical stapler. The spleen was placed in an endosurgical bag, morcellated, and removed from the abdomen via the umbilical incision without complications. Operative time was 84 minutes; blood loss was minimal. CONCLUSION: SILS splenectomy is feasible in pediatric patients. More experience is needed to assess advantages and disadvantages compared with the standard laparoscopic approach. PMID- 20932388 TI - Postoperative bowel herniation in a 5-mm nonbladed trocar site. AB - BACKGROUND: Incisional hernias are a rare complication of laparoscopic surgery, with a reported incidence of <1%. CASE REPORT: We describe a case of bowel herniation and strangulation involving a 5-mm trocar site. CONCLUSION: Although there is growing literature supporting fascial closure of abdominal port sizes >= 10 mm, there is sparse data to suggest closure of 5-mm port sites. Our case illustrates that in appropriate clinical scenarios, the possibility of a strangulated hernia involving a 5-mm port site warrants consideration. PMID- 20932389 TI - Aberrant mesoappendix vasculature: a unique cause of partial small bowel obstruction. AB - Small bowel obstructions are most frequently caused by hernias or adhesive bands. However, there have been several rare reported cases of mechanical small bowel obstructions caused by loops of bowel or vascular bands. We describe a case of a 30-year-old woman with a clinical presentation suggestive of appendicitis. Laparoscopic evaluation showed an aberrant vessel looping around the small bowel extending from the lateral anterior abdominal wall to the mesoappendix, resulting in a partial small bowel obstruction. We review the literature relating to bowel obstructions resulting from bowel knots and vascular bands. To our knowledge, this is the first reported case of a small bowel obstruction caused by an aberrant intraabdominal vessel. PMID- 20932390 TI - Villous mucinous cystadenoma of the appendix in a postmenopausal woman. AB - OBJECTIVE: To present the case of a postmenopausal woman, who was suspected of having an ovarian cyst. Instead, a cystadenoma of the appendix was discovered during laparoscopy. METHODS: A 64-year-old postmenopausal nulliparous woman was admitted to our hospital because of a cystic lesion, which had been detected in the course of a routine gynecological examination. The patient underwent vaginal ultrasound, magnetic resonance tomography, and laparoscopy. RESULTS: During vaginal ultrasound, a dumbbell-shaped anechogenic cystic structure 70 x 32 x 22 mm in diameter was found in the region of the right adnexa. Magnetic resonance tomography revealed no additional information. During diagnostic laparoscopy, the cystic lesion was found to be a distended appendix. A laparoscopic appendectomy was performed. Subsequent histological analysis revealed a villous mucinous cystadenoma of the appendix with low-grade intraepithelial neoplasia. CONCLUSION: Gynecologists should routinely consider this disease in the differential diagnosis of right lower dumbbell abdominal cysts. Eleven percent to 20% of mucoceles are caused by mucinous cystadenocarcinomas, which carry the risk of peritoneal tumor implantation caused by rupture or laparoscopic resection. Therefore, it should be mandatory that a general surgeon be involved in the laparoscopic procedure and the conversion to laparotomy for resection of the structure. PMID- 20932391 TI - An unusual presentation of a severely calcified parasitic leiomyoma in a postmenopausal woman. AB - We report the case of a calcified parasitic leiomyoma in a 51-year-old postmenopausal woman with lower abdominal discomfort. She had no history of surgery. Workup confirmed a calcified leiomyoma. On laparoscopy, the mass was separate from the uterus and adhered to the bowel and bladder. Histopathological examination confirmed a calcified leiomyoma. A calcified parasitic leiomyoma in a postmenopausal woman is rare. Most prior cases were in persons with a history of a laparoscopic myomectomy. The diagnosis can be made by radiological findings. Laparoscopic excision is the treatment of choice in such cases. PMID- 20932392 TI - Robotic management of pheochromocytoma of the vesicoureteric junction. AB - Pheochromocytoma of the urinary bladder is rare, presenting usually with hypertension, hematuria and syncopal attacks. Such cases have usually been managed with open or laparoscopic partial cystectomy. We present a case of bladder pheochromocytoma that had unusual presenting symptoms, a paraneoplastic manifestation and was successfully managed with robotic technique. PMID- 20932393 TI - Robot-assisted laparoscopic ureterolysis: case report and literature review of the minimally invasive surgical approach. AB - OBJECTIVES: To evaluate our case of robot-assisted ureterolysis (RU), describe our surgical technique, and review the literature on minimally invasive ureterolysis. METHODS: One patient managed with robot-assisted ureterolysis for idiopathic retroperitoneal fibrosis was identified. The chart was analyzed for demographics, operative parameters, and immediate postoperative outcome. The surgical technique was assessed and modified. Lastly, a review of the published literature on ureterolysis managed with minimally invasive surgery was performed. RESULTS: One patient underwent robot-assisted ureterolysis at our institution in 2 separate settings. Operative time (OR) decreased from 279 minutes to 191 minutes. Estimated blood loss (EBL) was less than 50 mL. The patient has been free of symptoms and both renal units are unobstructed. According to the published literature, 302 renal units underwent successful laparoscopic ureterolysis (LU), and 6 renal units underwent RU. There were 9 open conversions (all in LU). Mean OR in LU was 248 minutes for unilateral and 386 minutes for bilateral cases. In RU, mean OR was 220 minutes for unilateral and 390 minutes for bilateral cases. EBL averaged 200 mL in LU and 30 mL in RU. CONCLUSIONS: Our data reveal that robot-assisted ureterolysis is safe and feasible. Published data demonstrate the advantages of minimally invasive surgery. PMID- 20932394 TI - Child and parental acceptance of preformed metal crowns. AB - AIM: To assess child and parent acceptance of preformed metal crowns (PMCs). STUDY DESIGN: This was a service evaluation using a child- and parent-centred self-report questionnaire in a convenience sample of hospital patients. METHODS: Questionnaires were developed with serviceusers and issued to 98 children who had received a PMC on a primary molar within the paediatric dentistry clinic, Sheffield Dental Hospital, UK. Children used a pictorial Likert scale to rate their treatment experience and views on PMCs. Parents were also asked to complete a 5-item questionnaire, to explore their attitudes towards the PMC and how they felt their child had coped with treatment. Both children and parents were invited to comment in a free-text box on any other issues relating to PMCs. Clinical data were extrapolated from the child's dental records as follows: child's age and gender; status of clinician who had placed the PMC (staff or student), and technique for PMC placement (Hall technique or conventional). RESULTS: 62 questionnaires were completed (63% response rate). The mean age of the child participants was 6.6 years (SD+/-1.51; range=3.8-10.3), and 65% (n=40) were male. Most children found the clinical procedure acceptable with 54.8% (n=34) reporting it was 'really easy', with no significant differences according to placement technique, or the experience level of the operator (P<0.05, chi-squared test). Only 4.8% (n=3) of parents expressed strong objections to the appearance. Both children and parents felt the clinical rationale had been fully explained to them (88.7%, n=55 and 100%, n=62 respectively). Themes commonly identified from the children's accounts related to specialness, function and recollections of the treatment, with the perception that PMCs were valued for being different. CONCLUSIONS: This study revealed that PMCs were mainly viewed favourably by children and their parents. Clinicians who have been reluctant to use this restorative approach may be encouraged by these findings. However, communication and clinical expertise are paramount in ensuring children and parents have positive treatment experiences and attitudes towards PMCs. PMID- 20932395 TI - Short communication: Influence of preformed metal crowns (Hall technique) on the occlusal vertical dimension in the primary dentition. AB - AIM: This was to investigate the measure of propping, or occlusal interference and opening the bite after placement of preformed metal crowns (PMC) using the Hall technique and in how many days it took for the open bite to return to normal. METHODS: For this study school children living in the rain forest of Suriname were selected. The distance between the tip of the mandibular and maxillary primary canines was measured just before and after treatment with PMCs and again after 15 and 30 days. RESULTS: In 48 children the mean distance between the canine tips reduced from 2.45 mm before to 0.54 mm directly after treatment. After 15 days the distance increased again to 1.96 mm and after 30 days (with the remaining 8 patients) to 2.75 mm. The reduction of the overbite seems to be caused by intrusion of the crowned molar and its antagonist. CONCLUSION: Although the overbite had equilibrated after 30 days, additional research is necessary in a larger study to draw more decisive conclusions. PMID- 20932396 TI - ART class II restoration loss in primary molars: re-restoration or not? AB - AIM: The purpose of this study was to find an answer as to what to do with Atraumatic Restorations (ART) failures: re-restore or leave the preparation further unfilled? STUDY DESIGN: Cross sectional study. METHODS: In 2006, 804 children in Kenya each had one proximal cavity treated using the ART approach. Out of the original group of 192 children, who had lost their restorations but still had the treated molars in situ, were selected for further study in 2008. The length of time that the restorations had been in situ was known while the colour, hardness and the extent of infected dentine was then evaluated and documented. STATISTICS: Analysis of the data obtained was conducted using SPSS 16.0. Chi Square tests were performed with the variables of hardness, colour and infected dentine, and a 5% confidence interval was used. The Spearman's Rank Correlation Coefficient was also calculated. RESULTS: The results showed that 66% of the molars that had lost restorations had hard dentine, 78% of the preparations showed dark dentine and 50.7% appeared to have no infected dentine. These percentages increased with the increase in the survival time of the restorations. CONCLUSIONS: It is not always necessary to re-restore primary molars after ART restoration loss. Further research is necessary to confirm these findings. PMID- 20932397 TI - Efficiency of different polyacrylic acid concentrations on the smear layer, after ART technique, by Scanning Electron Microscopy (SEM). AB - AIM: To assess the efficiency of different polyacrylic acid concentrations on the removal of the smear layer after caries removal with hand and rotary instruments in affected dentine of primary teeth. STUDY DESIGN: In vitro study. METHODS: Six exfoliated primary molars with carious lesions were divided into two groups for caries removal: (1) hand instrument or (2) low speed bur. Each tooth was cut into four pieces. One piece assigned as control surface and the other three surfaces were actively treated with either 40% Fuji IXGP Liquid (GC America), or 40% Fuji IXGP Liquid diluted with water, and 25% Ketac Molar(TM) Conditioner (3M-ESPE). Surfaces were prepared for scanning electron microscopy (SEM). All images were submitted to an analysis by an experienced SEM professional, regarding presence or absence of smear layer and dentinal demineralization pattern. Chi-squared test was carried out (5% significance). RESULTS: There was no difference concerning the presence of a smear layer in relation to the method of caries removal, and 40% Fuji IXGP diluted with water causes a higher demineralization when compared with the control group of teeth (p=0.01). CONCLUSION: Treatments with polyacrylic acid are indicated prior to glass ionomer cement application in primary teeth. PMID- 20932398 TI - Dental caries prevalence in children with cleft lip/palate aged between 6 months and 6 years in the West of Scotland. AB - AIM: To compare the prevalence of dental caries in children with cleft lip/palate with national data at the same age. METHOD: Ethical approval was granted from the West of Scotland Ethics Committee. Children attending the Oral Orthopaedic Clinic were examined for caries according to the criteria of the British Association for the Study of Community Dentistry (BASCD) by two trained and calibrated examiners (KB, RW). Subjects were divided into five age groups: 0.5-1.49; 1.5-2.49; 2.5 3.49; 3.5-4.49 and 4.5-6.0 years. Mean dmft scores were compared with available national data (National Dental Inspection Program of Scotland) for nursery [NDIP 3-year-old survey 2008, unpublished] and 5-year-old children in Scotland [NDIP, 2008]. RESULTS: 209 subjects were examined (participation rate of 87.4%); 45.9% were female, 54.1% male; 21 children (10%) had a recognised syndrome and were reported separately. Cleft Palate (CP) was the most commonly occurring cleft in both syndromic and non-syndromic groups, followed in decreasing numbers by Unilateral Cleft Lip and Palate (UCLP), Bilateral Cleft Lip and Palate (BCLP), Unilateral Cleft Lip (UCL) and Bilateral Cleft Lip (BCL). The only age group with a significantly higher level of dental caries compared with national data was the 4.5-6.0 year-olds where only 37.2% of the children with clefts were caries free compared with the national figure of 57.7% (p=0.004). This same age group had a mean dmft for the cleft group of 3.24 compared with 1.86 nationally. The other age groups had similar dmft and percentages of subjects caries free compared with the national data. The differences did not reach significance. Caries was more common in the anterior teeth of the youngest two age groups, but in the posterior teeth of the two oldest age groups. CONCLUSION: By the age of 4.5 years, children with cleft lip/palate in the West of Scotland have significantly more caries than their non-cleft peers. PMID- 20932399 TI - Effect of CD4+ lymphocyte count, viral load, and duration of taking anti retroviral treatment on presence of oral lesions in a sample of South African children with HIV+/AIDS. AB - AIMS: This was to determine the presence and types of oral mucosal lesions in a sample of HIV(+)/AIDS South African children taking antiretroviral therapy and to investigate the relationship between CD4(+) lymphocyte counts, viral load, duration of taking antiretroviral therapy (DART), and age on presence of oral lesions. METHODS: The samples consisted of 56 South African children aged 0-4 years (mean age =7.09 years) with HIV(+)/AID, infected at birth. Subjects were divided into two groups according to the presence of oral lesions with test group (patients with oral lesions) and control group (patients with no oral lesions). Children were also divided into two groups, those <6 years and those >6 years old to study the effect of age on presence of lesions. RESULTS: Oral Candidiasis was the most common lesion reported in 19/56 children, followed by Recurrent Herpetic Infection in 9 children. Other lesions such as Kaposi's sarcoma, Multifocal Epithelial Hyperplasia, Oral Hairy Leukoplakia, Linear Gingival Erythema, and oral ulceration were also present. A statistical significant difference in CD4(+) lymphocyte count (p value 0.005), and viral load (p value 0.002) was found between the oral lesion and no oral lesion groups, those with oral lesions having a significantly higher viral load and lower CD4+ count. No statisticaly significant difference between the two groups in terms of the DART effect (p value 0.811) was found. Furthermore, there was no effect of age groups on the presence of lesions in children with HIV(+)/AIDS. CONCLUSION: This study contributes to the relatively scant literature on the prevalence of oral lesions in children with HIV infection in South Africa and also the relationship of these lesions to the viral load and CD4(+) lymphocyte counts. PMID- 20932400 TI - Validation of a Greek version of the oral health impact profile (OHIP-14) in adolescents. AB - AIM: To evaluate the validity and reliability of the Greek version of the Oral Health Impact Profile (OHIP-14) (short form) in adolescents. METHODS: A total of 112 healthy adolescents (15-18 years) from various socioeconomic backgrounds were randomly selected and participated in a clinical oral examination conducted by a calibrated dentist and on the same day a face to face interview was held for assessing the psychometric properties of the OHIP-14 in Greek adolescents. RESULTS: Cronbach's coefficient, was used to evaluate the internal consistency of the instrument and a value of a=0.8 was found indicating exceptional internal consistency. Discriminant validity and convergent validity was assessed and the inter-item correlation coefficients ranged from -0.01 to 0.8 and the item-total correlation coefficients varied from 0.17 to 0.6. Important statistical correlations were also observed between the OHIP-14 and all the clinical measures, confirming that the questionnaire can distinguish between individuals with and without impacts on their oral health. The OHIP-14 total score proved to have high associations with both self-perceived oral health status (rs=0.36; p=0.01) and self-assessment of oral satisfaction (rs=0.4; p=0.01). Examination of the relationship between these parameters and the score of each domain also lead to similar results. CONCLUSIONS: The Greek version of OHIP-14 instrument was found to be a valid and reliable instrument for assessing oral health-related quality of life in Greek adolescents. PMID- 20932401 TI - Short communication: In vitro assessment of erosive potential of energy drinks. AB - AIM: This in vitro study was to evaluate the endogenous pH, titratable acidity, total soluble solids content (TSSC) and nonreducing sugars of energy drinks. METHODS: Nine energy drinks (Bad Boy Power Drink, Red Bull, Red Bull Sugar Free, Flying Horse, Burn, Night Power, Flash Power, Flying Horse Light and 220V) were evaluated by a randomised experiment with 3 repetitions on each sample. pH analysis performed by potentiometry and buffering capacity was assessed by dilution of each drink. Increments of 0.1 N KOH were titrated until neutrality reached. TSSC readings were performed by Brix refractometry using an Abbe refractometer. RESULTS: pH values ranged from 1.52 (Flash Power) to 3.20 (Red Bull) and all drinks showed pH 5.5. Titratable acidity values ranged from 0.56 (220V) to 1.04 (Bad Boy Power Drink). Flying Horse Light presented the lowest TSSC content (1.66%) and Flying Horse presented the highest (12.58%). Non reducing sugars values ranged from 0.00% (Red Bull Sugar Free and Flying Horse Light) to 54.33% (Flying Horse). CONCLUSION: The energy drinks evaluated have a high erosive potential, as they present low pH and a high non-reducing sugar content. PMID- 20932402 TI - Case report: Rehabilitation of a child with dentinogenesis imperfecta and congenitally missing lateral incisors. AB - BACKGROUND: Dentinogenesis imperfecta is one of the most common hereditary disorders of dentine formation. Opalescent teeth composed of irregularly formed and undemineralised dentine that obliterates pulp chambers and root canals characterize it. Complete-coverage crowns are usually the preferred restoration for patients with this condition. CASE REPORT: A 9 year-old girl presented with dentinogenesis imperfecta, congenitally missing maxillary lateral incisors and maxillary right permanent second molar retention. TREATMENT: The treatment comprised an initial approach to allow the correct eruption of the retained second molar. The use of low-fusion metal ceramic restorations comprised a second stage to improve the aesthetic appearance and decrease the risk of overload on teeth with limited value. FOLLOW-UP: The patient has been recalled regularly and at the last visit, 10 years after initial prosthetic treatment, no problems or signs of complications have occurred. The patient is now aged 25 years and is still satisfied with the prosthetic rehabilitation. CONCLUSION: This case illustrates the need for appropriate and timely restorative treatment to prevent deterioration of the dentition. This case will also demonstrate that low-fusion metal ceramic restoration is a viable esthetic treatment option for today's patients. PMID- 20932403 TI - Point. Routine use of postoperative intravesical chemotherapy after TURBT-should it be done? PMID- 20932404 TI - Counter-point. Routine use of perioperative intravesical chemotherapy after TURBT: against. PMID- 20932405 TI - Editorial comment. PMID- 20932406 TI - Editorial comment. PMID- 20932407 TI - Editorial comment. PMID- 20932408 TI - A population-based comparison of cancer-control rates between radical and partial nephrectomy for T1A renal cell carcinoma. AB - OBJECTIVES: To complement existing data with population-based cancer control outcomes that account for the effect of other-cause mortality (OCM). Cancer control rates are virtually equivalent between partial (PN) and radical nephrectomy (RN) for patients with T1aN0M0 renal cell carcinoma (RCC). To date, only 6 studies from centers of excellence examined cancer control rates after PN vs RN for T1aN0M0 RCC. OCM was unaccounted for in those studies, which may introduce a bias. We relied on the surveillance, epidemiology, and end results (SEER) database and assessed cancer-specific mortality (CSM) after either PN or RN for T1aN0M0 RCC, in competing-risks models. METHODS: Between 1988 and 2004, the SEER-9 database identified 1622 PN (22.3%) and 5658 RN (77.7%) T1aN0M0 RCC. Competing-risks regression models, controlling for OCM and matched for age, year of surgery, tumor size, and Fuhrman grade, addressed the effect of nephrectomy type (PN vs RN) on CSM. RESULTS: At 5 years, in a PN and RN matched-population controlling for OCM, CSM after PN and RN was respectively 1.8% vs 2.5% (P = .5). The CSM rates in this cohort for patients aged >= 70 years were respectively 1.0% and 3.4% (P = .7). CONCLUSIONS: This competing-risks population-based analysis confirmed the CSM equivalence between PN and RN for T1aN0M0 RCC and showed virtually perfect CSM-free rates (97.5% or better) even in older patients. PMID- 20932409 TI - Editorial comment. PMID- 20932411 TI - Dose-ranging study of the luteinizing hormone-releasing hormone receptor antagonist cetrorelix pamoate in the treatment of patients with symptomatic benign prostatic hyperplasia. AB - OBJECTIVE: To compare the efficacy of 4 dosage regimens of cetrorelix pamoate, a sustained release formulation that allows for more convenient dosing, in patients with symptomatic benign prostatic hyperplasia (BPH). Repeated dosing with cetrorelix acetate was shown to be active in the treatment of BPH symptoms. METHODS: Double-blind, randomized, multicenter study was undertaken among patients with International Prostate Symptom Score (IPSS) >= 13. After a single blind placebo run-in phase of 4 weeks, treatment was administered at 2-week intervals as follows: 30 + 30 mg, 30 + 30 + 30 mg, 60 + 30, 60 + 60 mg cetrorelix pamoate, or matching placebo. Patients were followed-up for 28 weeks after randomization. RESULTS: A statistically significant overall difference was found with respect to the primary variable, the IPSS (P <= .001). Optimal results, a 4 point improvement in IPSS in excess of the changes observed in the placebo group, were achieved with a starting dose of 60 mg cetrorelix pamoate followed by a dose of 30 mg 2 weeks later. In all dosage groups, the symptomatic improvement was paralleled by an increase in uroflow. There was a marked dissociation between only moderate and transient testosterone suppression and the persisting effects on BPH signs and symptoms. Tolerability was good at all cetrorelix dosages. CONCLUSIONS: Intramuscular injections of 60 and 30 mg of cetrorelix pamoate within 2 weeks provide rapid symptomatic improvements of BPH that are sustained for the following 6 months. PMID- 20932412 TI - Editorial comment. PMID- 20932413 TI - Editorial comment. PMID- 20932415 TI - Buccal mucosa graft for ureteral stricture substitution: initial experience. AB - OBJECTIVES: To evaluate the use of buccal mucosa tubal graft for reconstruction of extensive ureteral stricture. MATERIAL AND METHODS: Between April 2006 and July 2008, 5 patients (mean age, 51.2 years) underwent reconstructive ureteral surgery for ureteral obstruction using buccal mucosa graft. The indication of surgery was extensive ureteral stricture of a 4.4-cm average length (range, 3.5 5.0). The site of stricture was in the proximal and the middle ureter in 3 and 2 patients, respectively. The causes of stricture were postinflammatory (3 cases) and iatrogenic after ureteroscopic procedures for impacted stones (2 cases). RESULTS: All 5 patients underwent successful ureteral defect replacement using buccal mucosal tube. The intraoperative course was uneventful without any major complications. Mean operative time was 106 minutes (range, 85-130). With a mean follow-up of 24 months (range, 14-39), the operated kidneys showed no obstruction. CONCLUSIONS: Oral buccal mucosal tubal graft for reconstruction of extensive ureteral stricture is a good available option. Although the results of this initial experience are encouraging, a bigger series and longer follow-up is recommended to evaluate our procedure. PMID- 20932417 TI - Editorial comment. PMID- 20932419 TI - Editorial comment. PMID- 20932421 TI - Editorial comment. PMID- 20932423 TI - Editorial comment. PMID- 20932424 TI - A novel technique for repair of testicular rupture after blunt trauma. AB - OBJECTIVE: To present a simple technique for the repair of a ruptured testis after blunt trauma when extruded but viable testicular tissue prevents closure of the testicular capsule during surgical exploration. Preservation of viable testicular tissue is important because the risk of impaired fertility and hormone function is minimized. METHODS: A 25-year-old male sustained a ruptured right testis confirmed by ultrasound. Testicular exploration was performed and hematoma evacuated. Extruded but viable testicular tissue was identified and preserved. The free edges of parietal tunica vaginalis was used to create a "neocapsule" around the testis and extruded tissue. RESULTS: There were no postoperative complications. Follow-up Doppler ultrasound scan at 3 months showed a viable testis with no atrophic changes. CONCLUSIONS: This technique avoids the loss of extruded but viable testicular tissue and may reduce the risk of impaired fertility and hormone function, without compromising the goals of scrotal exploration. PMID- 20932425 TI - Re: Hara et al.: Decline of the red cell blood count in patients receiving androgen deprivation therapy for localized prostate cancer: impact of ADT on insulin-like growth factor 1 and erythropoesis. (Urology 2010;75:1441-1445). PMID- 20932427 TI - Re: Hong et al.:Twenty-four hour and spot urine metabolic evaluations: correlations versus agreements. (Urology 2010;75:1294-1298). PMID- 20932429 TI - Prostate-specific antigen self-testing among British Association of Urological Surgeons (BAUS) consultant urologists. PMID- 20932431 TI - Re: Hong et al.: Detection of subclinical carbon dioxide embolism by transesophageal echocardiography during laparoscopic radical prostatectomy (Urology 2010;75:581-584). PMID- 20932432 TI - Conservative surgery for early stage cervical cancer: who should we offer it to? PMID- 20932433 TI - How does public policy impact cervical screening and vaccination strategies? AB - OBJECTIVES: To examine the current approaches to cervical screening and points to consider for improving HPV vaccination acceptance and uptake in the US. METHODS: An expert forum was conducted September 12-13, 2008, by the Society of Gynecologic Oncologists including 56 experts in cervical cancer and titled "Future Strategies of Cervical Cancer Prevention: What Do We Need to Do Now to Prepare?". RESULTS: Cervical cancer prevention has primarily relied on screening paradigms but vaccination against human papillomavirus (HPV), the cause of the disease, is a primary preventative measure that has been recommended by all cervical cancer screening stakeholders. Guidelines for vaccination are developed by national advisory groups, but successful implementation requires a supportive infrastructure and the cooperation of providers, clinicians, and patients. HPV vaccination has been available in the United States (US) since 2006 and screening practices have been updated to also include HPV genotyping. However, many clinicians fail to adhere to the guidelines for HPV testing (and HPV co-testing) as part of cervical cancer screening, and vaccination coverage has been poor among females aged 11 and 12, the group for which vaccination is recommended by all organizations. CONCLUSIONS: The data reviewed and presented in this session of the "Future Strategies of Cervical Cancer Prevention. What Do We Need to do Now to Prepare?". The Forum suggests that the policies influencing HPV vaccination and screening need to be reassessed at multiple levels in order to achieve more effective implementation and regular use. PMID- 20932434 TI - Diagnosis and monitoring of abdominal aortic aneurysm: current status and future prospects. Foreword. PMID- 20932436 TI - [Dermatology, proctology or infectiology: The necessity of a multidirectional approach]. PMID- 20932437 TI - [Suppurations of the perineal and gluteal region: An aetiological study of 60 cases]. AB - BACKGROUND: The gluteal region is a complex area of the body that may be the seat of several diseases with dermatological manifestations. The purpose of this series was to study the aetiological profile of suppurative lesions of the gluteal region in patients in Morocco. PATIENTS AND METHODS: A retrospective study was carried out on patients presenting suppuration of the gluteal region hospitalised in our department between 1987 and 2008. The epidemiological, clinical and aetiological data for 60 cases were reviewed. Skin biopsies with bacterial, fungal and histological studies, as well as bacterial and fungal cultures of pus and anorectal examination, were performed for all patients. RESULTS: We examined the files for 44 males and 16 females; mean age was 44 years (range: 13 to 70 years) and the average duration of illness was 6.5 years. The various aetiologies were as follows: hidradenitis suppurativa (27 cases), cutaneous tuberculosis (10 cases), Crohn's disease (nine cases), phlegmon carbuncle (eight cases), tumours (four cases) and deep mycosis (two cases). Medical and surgical treatments were aetiological. DISCUSSION: There are various aetiologies of suppurations of the gluteal region. In Morocco, hidradenitis suppurativa, cutaneous tuberculosis and Crohn's disease are the most frequent causes. Multidisciplinary management is essential. PMID- 20932438 TI - [A retrospective efficacy and safety study of UVB-TL01 phototherapy and PUVA therapy in palmoplantar psoriasis]. AB - BACKGROUND: Topical therapy is generally insufficient in palmoplantar psoriasis. UVBTL01 phototherapy is a therapeutic alternative and we conducted a retrospective study of the efficacy and safety of this approach and of PUVA therapy in palmoplantar psoriasis. PATIENTS AND METHODS: All patients treated with UVBTL01 or PUVA therapy from November 2001 to April 2008 were included in the study. Phototherapy was given three times a week. Evaluation was performed after 20 sessions, again after 30 sessions and then at the end of the treatment. Therapeutic outcome was classed as "failure", "slight improvement" or "improvement or clear skin". RESULTS: UVBTL01 phototherapy and PUVA therapy were effective, with "improvement or clear skin" in respectively 52% and 61% of cases and "slight improvement" in 16% and 23% of cases at the end of the treatment. With UVBTL01, adverse effects occurred in 20% of cases (erythema 18%, first degree burns 7%) and treatment was discontinued as a result in only 4% of cases. Adverse effects occurred in 50% in patients on PUVA therapy, mainly due to methoxypsoralen intake. CONCLUSION: UVBTL01 phototherapy and PUVA therapy are efficacious treatments in palmoplantar psoriasis; UVBTL01 phototherapy involves fewer constraints and has fewer adverse effects. PMID- 20932435 TI - Diagnosis and monitoring of abdominal aortic aneurysm: current status and future prospects. AB - Abdominal aortic aneurysm (AAA) remains an important cause of morbidity and mortality in elderly men, and prevalence is predicted to increase in parallel with a global aging population. AAA is commonly asymptomatic, and in the absence of routine screening, diagnosis is usually incidental when imaging to assess unrelated medical complaints. In the absence of approved diagnostic and prognostic markers, AAAs are monitored conservatively via medical imaging until aortic diameter approaches 50-55 mm and surgical repair is performed. There is currently significant interest in identifying molecular markers of diagnostic and prognostic value for AAA. Here we outline the current guidelines for AAA management and discuss modern scientific techniques currently employed to identify improved diagnostic and prognostic markers. PMID- 20932439 TI - [Contribution of the cryosurgery in the management of xeroderma pigmentosum]. AB - BACKGROUND: Basal cell carcinoma (BCC) occurs frequently in young patients with xeroderma pigmentosum (XP). Because tumours are multiple and usually found on the face, alternatives to surgery are proposed. The purpose of this study was to evaluate the efficacy of cryosurgery for BCC in XP patients. PATIENTS AND METHODS: This was a retrospective study that included all instances of BCC occurring in XP patients treated by cryosurgery between January 2002 and October 2008. RESULTS: Forty-five cases of primary facial BCC and one case of relapsing BCC (16 on the cheeks, 11 on the nose, six on the face and five on the inner edge of the eye area) were treated by cryosurgery in 18 XP patients (average age: 18.7 years; sex ratio: 0.5). Mean carcinoma size was 10mm. Thirty-six tumours were nodular and 10 were nodular and ulcerated. Follow-up ranged from 16 to 60 months (mean: 30 months). Complications were rare. Cosmetic results were satisfactory. We noted 10 cases of hypopigmentation (21.7%) and one notch on the nose following treatment for recurrent BCC on a radiotherapy scar. Relapse occurred in one case (2.17%). CONCLUSION: Because of its simplicity, its good safety, its sparing of skin and its reliability of oncological outcome, cryosurgery is the treatment of choice for CBC in XP patients. PMID- 20932440 TI - [Management of cutaneous T-cell lymphomas: Recommendations of the French Cutaneous Lymphoma Group]. AB - BACKGROUND: Classification of diagnostic methods, of initial staging and of the treatment of primary cutaneous T-cell lymphomas, particularly the most common epidermotropic forms, constitutes an essential step in rationalising therapeutic practice and in evaluating the results of treatment. PATIENTS AND METHODS: We carried out an analysis of the literature and of existing recommendations in order to create recommendations regarding the diagnosis, initial staging and treatment of primary T-cell lymphomas. RESULTS: We present the key elements of diagnosis and initial staging. The selected therapeutic strategy, which necessarily changes over time, must avoid both unnecessarily aggressive early treatment as well as an overly timid therapeutic approach that could allow lesions to rapidly progress towards more advanced stages. Regular reassessment of the benefit/risk ratio is necessary and involves the use of first- and second line measures, in which it is difficult to establish any hierarchy, with the current tendency favouring in particular combined therapy as second-line treatment in order to limit the toxicity of each individual constituent drug within the combination. The creation of a national SPC marks significant progress in difficult cases. CONCLUSION: As a result of the offer, limited level of proof in existing studies, which are generally unsatisfactory in terms of methodology, the new recommendations described herein are timely and should be updated regularly in accordance with advances in knowledge. The organisation of clinical trials and validation of the scoring systems currently being developed should be encouraged. PMID- 20932441 TI - [Topical imiquimod for the treatment of anogenital warts in an infant]. AB - BACKGROUND: Treatment of anogenital warts (AW) in children and infants is painful because of the destructive techniques involved, as a result of which general anaesthesia may be required. For adults, topical imiquimod is an efficient and well-tolerated product used for these lesions. Here, we report a case demonstrating the benefits of topical imiquimod in the treatment of AW in infant. PATIENTS AND METHODS: A ten-month-old infant was presenting large AW in the inguinal and perianal folds for a period of two months, which persisted despite one month of treatment with podophyllotoxin. After a month of daily application of imiquimod, the AW was completely cured, with no recurrence at six months. DISCUSSION: In the literature, we found four similar case reports concerning the efficacy and safety of topical imiquimod for AW in infants. Although topical imiquimod is not licensed for paediatric use, these case reports highlight the benefits of this approach in infants. PMID- 20932442 TI - [Leg ulcerations and sunitinib]. AB - BACKGROUND: Sunitinib is an antiangiogenic tyrosine kinase inhibitor indicated in the treatment of metastatic renal cancer and gastrointestinal stromal tumours (GIST). We report a case of leg ulcer apparently triggered by this drug and we discuss the potential implication of the antiangiogenic effect of sunitinib in ulcer genesis. CASE REPORT: A 73-year-old woman with a history of deep venous thrombosis of the lower limbs was treated with sunitinib for renal cancer with hepatic and pulmonary secondaries. While on this treatment, she developed painful ulcers of the right lower limb, despite having never previously presented leg ulceration. On discontinuation of sunitinib, the lesions improved, and resumption of this drug, even at a lower dosage, resulted in relapse of her ulcers. DISCUSSION: Although questions may legitimately be asked about the contribution of the patient's venous condition, withdrawal of sunitinib followed by a positive rechallenge tend to suggest the role of this drug in recurrence of ulcers. Their recurrence despite the decreased dosage of the drug points to a nondose-dependent pathogenic mechanism. PMID- 20932443 TI - [Atypical cutaneous Fusarium infection in an immunocompetent patient]. AB - INTRODUCTION: Fusarium are filamentous saprophytic brown fungi found in soil, on plants and outdoors. Invasive, necrotic fusarial skin infections are rare and are found in immunodepressed subjects. We report a case in a woman with no discernible immune deficiency. PATIENTS AND METHODS: A 24-year-old woman in good general health, pregnant at 34 weeks amenorrhoea, consulted for ulcerating, budding lesions with a necrotic centre over her entire body, but mainly localised on the cheeks and four limbs. The diagnosis of fusariosis due to Fusarium oxysporum was made on the basis of direct examination and repeated skin biopsy culture. All investigations were normal, and in particular, the patient had no detectable immune deficiency. Treatment was extremely difficult. The patient received amphotericin B, then voriconazole and terbinafine, ketoconazole and finally liposomal amphotericin. DISCUSSION: In immunocompetent subjects, fusarial species generally colonise the corneal layers of the skin. Our case was special in terms of the clinical aspect of the pseudotumoural lesions with a necrotic centre in an immunocompetent woman and in terms of the difficulty in treating her. PMID- 20932444 TI - [Congenital erythropoeietic porphyria treated by haematopoietic stem cell allograft]. AB - BACKGROUND: Congenital erythropoietic porphyria (CEP) is a genodermatosis associated uroporphyrinogen III synthase deficit that results in porphyrin accumulation in various organs, particularly the skin. It is the most severe form of porphyria associated with haemolytic anaemia and cutaneous phototoxicity. We report a severe case of CEP treated by allogeneic bone marrow transplantation. CASE REPORT: A one-year-old child presented erythrodontia and scarring on exposed areas. The diagnosis of CEP was confirmed by the decline of uroporphyrinogen III synthase activity. Demonstration of p.Cys73Arg mutation confirmed the severity of the disease. Allogeneic bone marrow transplantation resulted in persistent resolution of clinical signs 25 months after grafting. DISCUSSION: Symptomatic treatment is ineffective in this serious disease associated with early mortality. 11 of the 13 patients treated by allogeneic hematopoietic stem cell graft, including our patient, continued to be asymptomatic an average of seven years after transplantation. CONCLUSION: This new case confirms the role of allogeneic hematopoietic stem cell grafting in the treatment of congenital erythropoietic porphyria. PMID- 20932445 TI - [Porphyria cutanea tarda in a child undergoing bone marrow grafting]. AB - BACKGROUND: Porphyria cutanea tarda (PCT) is rare in childhood and association with bone marrow transplant has occasionally been reported. PATIENTS AND METHODS: A 13-year-old boy was referred to our department for bullous lesions on sun exposed areas. His past medical history revealed acute biphenotypic leukaemia with complete remission after allogeneic hematopoietic stem cell transplantation (unrelated donor). Complications of bone marrow transplant comprised anaemia (treated by blood transfusions), primary cytomegalovirus (CMV) infection, pulmonary aspergillosis and acute digestive graft-versus-host disease. The diagnosis of type I sporadic PCT was based on high levels of porphyria and normal erythrocytic uroporphyrinogen decarboxylase activity. The bullous lesions disappeared on bleeding, but the patient subsequently developed sclerodermiform lesions. DISCUSSION: An association between PCT and bone marrow transplant has been reported previously in two independent cases, of which one involved a child. The causative role of bone marrow transplantation in the development of PCT could be related to several triggering factors: primary CMV infection, hepatotoxic drugs, blood transfusion and possible chronic hepatic graft-versus-host disease. CONCLUSION: We report the second case in a child of type I PCT associated with bone marrow transplantation. This new case reinforces the hypothesis of a non random relationship between the two conditions. PMID- 20932446 TI - [Ingrown nail: A new cause of chronic perionyxis]. AB - BACKGROUND: Retronychia is the phenomenon of ingrown nail resulting in inflammation of the proximal subungual fold and is a newly described entity. Herein, we report a new case revealed through chronic proximal perionyxis. PATIENTS AND METHODS: A 52-year-old woman followed up for hypothyroidism, for which she was receiving treatment, consulted for pain in the lateral fold of the left big toe that had been ongoing for four months and for which glomic tumour was the suspected cause. Questioning revealed repeated microtrauma due to wearing of tight shoes and lack of growth of the toenail over the previous four months (in contrast with the contralateral toenail). Examination showed painful proximal perionyxis of the left big toe, with discharge from the subungual fold. Ultrasound examination of the subungual fold revealed effusion of fluid around the matrix, and this was confirmed by MRI. Surgical avulsion of the nail was carried out, and recovery was complete. DISCUSSION: Retronychia is the result of a loss of continuity between the nail plate and the nail matrix, generally as a result of mechanical factors (distal trauma). However, unlike onychomadesis or Beau's lines, there is a disturbance of alignment between the two parts of the nail, which is normally maintained by the proximal subungual fold. This prevents newly formed nail from progressing towards the distal part of the plate, which itself is pushed into the nail bed and forced towards the proximal fold, causing inflammation of the latter structure. In our case, the pain recorded in the lateral fold was misleading, hence the ultimately unnecessary use of MRI to rule out the hypothesis of glomic tumour. Paronychia, discontinuation of nail growth and weeping through the subungual fold all argued in favour of a diagnosis of retronychia, which was confirmed by surgery. Surgical nail removal is the curative treatment for retronychia and results in complete cure without relapse or occurrence. CONCLUSION: Retronychia should be suspected in the event of persistent proximal perionyxis, particularly in a setting of trauma with interrupted nail growth. Nail avulsion constitutes both a diagnostic and a therapeutic procedure. PMID- 20932447 TI - [Tacrolimus mouthwash as second-line treatment for erosive oral lichen planus]. PMID- 20932448 TI - [Subacute anaemia: An unusual presentation of giant melanoma]. PMID- 20932449 TI - [Clinical assessment of the risk of bacteremia and the value of skin cultures during Stevens-Johnson syndrome and toxic epidermal necrolysis]. PMID- 20932450 TI - [Childhood vitiligo]. PMID- 20932451 TI - [Eccrine poroma and porocarcinoma]. PMID- 20932452 TI - [Bluish nodule]. PMID- 20932453 TI - [The role of small interfering RNA (siRNA) in genodermatoses]. PMID- 20932454 TI - [Milia en plaque of the mucous surface of the lip: A complication of piercing]. PMID- 20932455 TI - [Trichoblastic carcinoma on the lip]. PMID- 20932456 TI - [Eventration and methotrexate in psoriasis]. PMID- 20932457 TI - Social relations in older adults: Secular trends and longitudinal changes over a 16-year follow-up. AB - Drawing on population studies in Finland, we investigated secular trends and longitudinal changes in social relations. The cohort comparison data comprised on 974 persons aged 65-69 years from three cohorts born between 1919 and 1939 and interviewed in 1988, 1996 and 2004. Longitudinal analyses were conducted for 635 persons aged 65-74 years over a 16-year follow-up at three measurement points. Social relations were studied on the basis of frequency seeing one's offspring, perceptions of the sufficiency of these contacts, and by asking whom the participants considered as their closest person and how often and in how many tasks they helped someone. The cohort comparisons showed that the frequency of seeing one's offspring had decreased in the most recent cohort and that the number of contacts was considered more inadequate. Longitudinal analyses showed that although the proportion of children as the closest persons increased, meetings with them became fewer. Helping others was more common in the last cohort, but in the longitudinal analyses it decreased with age. Finnish people at retirement help others more than before, but they do not meet their offspring as often as they would like. Measures are needed for action to promote intergenerational exchange in older adults on both individual and societal level. PMID- 20932458 TI - Sudden cardiac death: an 11-year postmortem analysis in the region of Epirus, Greece. AB - The aim of the study was to determine the rate of sudden cardiac death in people aged between 1 and 80 years, and to investigate its etiology. All autopsies performed during an 11-year period were reviewed. Circumstances of death, individual's information, and post-mortem findings were determined. Among 1254 sudden death autopsies performed during the study period, 688 cases were recognized as sudden cardiac death (79.8% males). The estimated annual frequency of sudden cardiac death in the region of Epirus was 18.6/100,000. The major cause of death was ischemic heart disease (82%), and in 2.6%, death was unexplained. Among our study's total population, 4.1% were <35 years old. The estimated annual rate of sudden cardiac death in the population 1-35 years old was 1.78/100,000. The most common etiology in that age group was atherosclerosis (17.8%), myocarditis (10.7%), and cardiomyopathies (10.7%), whereas 39.3% exhibited structurally normal heart. Although ischemic heart disease accounts for most of sudden cardiac death episodes, many other causes contribute. Most sudden deaths in the young were "unascertained". The likely cause of death in these cases might be a primary arrhythmogenic disorder. Correct identification of such cases at autopsy will enable an appropriate clinical screening of surviving relatives. PMID- 20932460 TI - Extracellular production of recombinant proteins using bacterial autotransporters. AB - Escherichia coli is still a very popular host for the production of recombinant proteins at an analytical or industrial scale. Secretion of the proteins into the culture medium or display at the cell surface would be preferred in many applications but is hampered by the complex two-layered cell envelope. The autotransporter pathway is used by E. coli to secrete virulence factors via a relatively simple but efficient and specific mechanism. Here we discuss recent progress in the structural and mechanistic analysis of this pathway and the implications for future development of a versatile platform for secretion and display of heterologous proteins. PMID- 20932461 TI - Development of a cardiopulmonary exercise prognostic score for optimizing risk stratification in heart failure: the (P)e(R)i(O)dic (B)reathing during (E)xercise (PROBE) study. AB - BACKGROUND: Cardiopulmonary exercise testing (CPET) provides powerful information on risk of death in heart failure (HF). We sought to define the relative and additive contribution of the 3 landmark (CPET) prognostic markers--peak oxygen consumption (VO2), minute ventilation/carbon dioxide production (VE/VCO2) slope, and exercise periodic breathing (EPB)-to the overall risk of cardiac death and to develop a prognostic score for optimizing risk stratification in HF patients. METHODS AND RESULTS: A total of 695 stable HF patients (average LVEF: 25 +/- 8%) underwent a symptom-limited CPET maximum test after familiarization and were prospectively tracked for cardiac mortality. At multivariable Cox analysis EPB emerged as the strongest prognosticator. Using a statistical bootstrap technique (5000 data resamplings), point estimates, and 95% confidence intervals were obtained. Thirty-two configurations were adopted to classify patients into a given cell, according to EPB presence or absence and values of the 2 other covariates. Configurations without EPB and with VE/VCO2 slope <=30 were not significantly different from 0 (reference value). Statistical power of configurations increased with higher VE/VCO2 slope and lower peak VO2. This prompted us to formulate a score including EPB as a discriminating variable, the (P)e(R)i(O)dic (B)reathing during (E)xercise (PROBE), which ranges between -1 and 1, with zero as reference configuration, that would help to optimize the prognostic accuracy of CPET-derived variables. The greatest PROBE score impact was provided by EPB, followed by VE/VCO2 slope, whereas peak VO2 added minimal prognostic power. CONCLUSIONS: EPB with an elevated VE/VCO2 slope leads to the highest and most precise PROBE score, whereas no additional risk information emerges when EPB is present with a peak VO2 <=10 mL O2.kg-1.min-1. PROBE score appears to provide a step forward for optimizing CPET use in HF prognostic definition. PMID- 20932462 TI - Heart rate predicts mortality in patients with heart failure and preserved systolic function. AB - BACKGROUND: Elevated resting heart rates have been associated with increased mortality and morbidity in patients with heart failure and decreased left ventricular ejection fraction (EF). It is unclear, though, if this association applies to those with heart failure and preserved EF. METHODS AND RESULTS: We determined outcome for 685 consecutive patients with a prior diagnosis of heart failure and a preserved EF (>50%) documented on echocardiography at 1 of 3 laboratories. Patients with non-sinus rhythm were excluded from the analysis. We determined adjusted mortality rates at 1 year after the echocardiogram. The mean age of the cohort was 70 +/- 11 years. Of the 685 included patients, 87% had a history of hypertension, 50% had diabetes, and the mean EF was 60% +/- 6%. All cause mortality at 1 year was significantly lower in the group with heart rate below 60 beats/min (10%) when compared with the group with heart rates between 60 and 70 beats/min (18%), 71-90 beats/min (20%), and >90 beats/min (35%) (P < .0001). After adjustment for patient history, demographics, laboratory values, and echocardiographic findings, the hazard ratios for total mortality (relative to a heart rate of <60) were 1.26 (95% CI, 0.88-1.80) for HR 60-69, 1.47 (95% CI, 1.02-2.07) for HR 70-90, and 2.00 (95% CI, 1.31-3.04) for HR>90 (P = .01 across all groups). CONCLUSIONS: These data suggest that an elevated resting heart rate is a marker for increased mortality in patients with heart failure and preserved systolic function. Heart rate may be useful in these patients for improved cardiovascular risk assessment. PMID- 20932463 TI - Clinical features of myocardial triglyceride in different types of cardiomyopathy assessed by proton magnetic resonance spectroscopy: comparison with myocardial creatine. AB - BACKGROUND: Myocardial lipid overstorage may produce cardiomyopathy, leading to dysfunction, but advanced heart failure may cause lipolysis via sympathetic nerve activation. In the failing heart, the creatine kinase system may also be impaired. The aims of this study were to assess myocardial triglyceride (TG) and creatine (CR) in different types of cardiomyopathy and to investigate whether they are related to the severity of cardiac dysfunction. METHODS AND RESULTS: In patients with hypertrophic cardiomyopathy (HCM, n = 8), dilated cardiomyopathy (DCM, n = 12) or ischemic cardiomyopathy (ICM, n = 10), and normal subjects (NML, n = 22), myocardial TG and CR were evaluated using proton magnetic resonance spectroscopy. To assess cardiac sympathetic nerve activity, myocardial MIBG (a radioactive guanethidine analog) uptake was measured in DCM. Myocardial TG was significantly lower in hypertrophic cardiomyopathy (HCM) (1.92 +/- 0.99 MUmol/g), but higher in ICM (7.59 +/- 4.36 MUmol/g) than in NML hearts (4.05 +/- 1.94 MUmol/g). There was no significant difference in TG between DCM (4.84 +/- 6.45 MUmol/g) and NML. Myocardial CR in HCM (20.4 +/- 8.4 MUmol/g), DCM (14.8 +/- 4.8 MUmol/g), and ICM (19.4 +/- 6.3 MUmol/g) was significantly lower than that in NML hearts (27.1 +/- 4.3 MUmol/g). Overall, myocardial CR correlated positively with the severity of heart failure estimated by ejection fraction or myocardial BMIPP (a radioactive fatty acid analog) uptake, but TG did not. In DCM, myocardial TG correlated with body mass index, but not with MIBG uptake. CONCLUSIONS: Myocardial TG may be related to the specific cause of disease rather than the severity of cardiac dysfunction. In contrast, myocardial CR reflects the severity of heart failure despite different pathoetiologic mechanisms of dysfunction. In DCM, myocardial TG may be affected by an overweight state rather than cardiac sympathetic nerve dysfunction. Thus, myocardial CR has a closer relationship to heart failure severity than does myocardial TG. PMID- 20932464 TI - Patient perspectives on decision making in heart failure. AB - BACKGROUND: Patients with heart failure (HF) face an array of challenging decisions involving medications, devices, and transplants. The goal of this qualitative study was to describe patients' perceptions surrounding difficult decisions along with factors that influenced their decisions. METHODS AND RESULTS: We studied 22 patients with symptomatic HF from the University of Colorado Hospital using in-depth, semistructured interviews. We used descriptive theme analysis in an iterative process to analyze responses to the question: "Can you tell me about any important or difficult decisions you have had to make about your heart condition?" Two distinct decision-making styles emerged: active (55%) and passive (45%). Active decision makers identified interventions such as implantable cardioverter-defibrillators, medications, and transplants to be the most difficult decisions and weighed concerns for side effects, family, and quality of life. Passive decision makers generally did not identify a difficult decision and described factors such as trust in God, trust in the physician, and power of the physician as reasons for their passivity. CONCLUSIONS: Patients with HF use active and passive decision styles in their approach to medical decision making. Future work should investigate communication techniques to assure that passive decision makers receive health care that is concordant with their values. PMID- 20932465 TI - Right ventricular dysfunction is a strong predictor of developing atrial fibrillation in acutely decompensated heart failure patients, ACAP-HF data analysis. AB - BACKGROUND: Heart failure and atrial fibrillation (AFib) are the twin epidemics of modern cardiovascular disease. The incidence of new-onset AFib in acute decompensated heart failure (ADHF) patients is difficult to predict and the short and long-term outcomes of AFib in a cohort of patients admitted with ADHF are unknown. METHODS AND RESULTS: A total of 904 patients admitted with ADHF were studied. Incidence of AFib on admission was recorded and a multivariate analysis was performed using echocardiographic parameters to specify the predictors of AFib incidence in this cohort. In 904 ADHF patients (57% male, mean age 69 +/- 14 years), 81% had history of hypertension, 40% were diabetics, and 51% were smokers. A total of 63% of the patients had known heart failure (HF) with mean ejection fraction of 34% +/- 21%, and 33% of the patients had ischemic cardiomyopathy as the etiology of HF. Echocardiographic parameters were: left atrial (LA) diameter 4.5 +/- 0.8 cm, left ventricular end-systolic 4.1 +/- 1.3 cm, left ventricular end-diastolic 5.3 +/- 1.1 cm. Right ventricular dysfunction (RVD) was present in 34% of the patients. A total of 191 (21%) patients subsequently developed AFib with two thirds of the cases occurring in patients with RVD. Using a univariate analysis, older age (OR 1.02; P < .0001), history of HF (OR 2.93; P < .0001), LA dilation (OR 1.58; P < .0001), the presence of left ventricular hypertrophy (OR 3.01, P < .0001), and RVD (OR 4.93; P < .00001) were the strongest predictors for AFib. Controlling for LA size and left ventricular hypertrophy using a forward stepwise regression, RVD remained the strongest predictor (OR 4.45; P < .0001). Patients with RVD had more events (cardiac readmission and mortality) than those with normal RV (56% versus 38%; P < .00001), notably; all-cause mortality was 4.7%/year in the abnormal RV group versus 2.9%/year in the normal RV group; P < .05. RV function analyses by echocardiography further risk stratified these patients based on their rhythm categorizing those patients with abnormal RV and AFib as the ones with the worse prognosis. CONCLUSION: RV dysfunction is a strong predictor for developing AFib in acutely decompensated systolic failure patients. Patients with AFib and RVD have the worse outcome specially when is combined with LV dysfunction, therefore; evaluation of RV function may substantiate the difference in HF prognosis. PMID- 20932466 TI - Causes of breathing inefficiency during exercise in heart failure. AB - BACKGROUND: Patients with heart failure (HF) develop abnormal pulmonary gas exchange; specifically, they have abnormal ventilation relative to metabolic demand (ventilatory efficiency/minute ventilation in relation to carbon dioxide production [V(E)/VCO2]) during exercise. The purpose of this investigation was to examine the factors that underlie the abnormal breathing efficiency in this population. METHODS AND RESULTS: Fourteen controls and 33 moderate-severe HF patients, ages 52 +/- 12 and 54 +/- 8 years, respectively, performed submaximal exercise (~65% of maximum) on a cycle ergometer. Gas exchange and blood gas measurements were made at rest and during exercise. Submaximal exercise data were used to quantify the influence of hyperventilation (PaCO2) and dead space ventilation (V(D)) on V(E)/VCO2. The V(E)/VCO2 relationship was lower in controls (30 +/- 4) than HF (45 +/- 9, P < .01). This was the result of hyperventilation (lower PaCO2) and higher V(D)/V(T) that contributed 40% and 47%, respectively, to the increased V(E)/VCO2 (P < .01). The elevated V(D)/V(T) in the HF patients was the result of a tachypneic breathing pattern (lower V(T), 1086 +/- 366 versus 2003 +/- 504 mL, P < .01) in the presence of a normal V(D) (11.5 +/- 4.0 versus 11.9 +/- 5.7 L/min, P = .095). CONCLUSIONS: The abnormal ventilation in relation to metabolic demand in HF patients during exercise was due primarily to alterations in breathing pattern (reduced V(T)) and excessive hyperventilation. PMID- 20932468 TI - Chk-ing in and Chk-ing out: kinase compartmentalization comes to checkpoint control. AB - Checkpoints are the sentinels of cell-cycle progression. In this issue of Molecular Cell, Yaffe and colleagues (Reinhardt et al., 2010) show that spatial and temporal resolution of Chk1 and MK2, checkpoint kinases with identical substrate specificity, are necessary to signal different aspects of DNA damage signaling. PMID- 20932467 TI - Chronic alternate-day fasting results in reduced diastolic compliance and diminished systolic reserve in rats. AB - BACKGROUND: Based on animal experiments and limited data from the few human trials, alternate-day fasting (ADF) resulted in weight loss, prolonged life, reduced metabolic risk factors for diabetes and cardiovascular diseases, and reduced prevalence of age-related diseases. The present study is the first comprehensive examination of the long-term effects of ADF on general cardiovascular fitness in rats. METHODS AND RESULTS: Four-month-old male Sprague Dawley rats were started on ADF or continued on ad libitum diets and followed for 6 months with serial echocardiography. A comprehensive hemodynamic evaluation including a combined dobutamine-volume stress test was performed at the end of the study, and hearts were harvested for histological assessment. The 6-month long ADF diet resulted in a 9% reduction (P < .01) of cardiomyocyte diameter and 3-fold increase in interstitial myocardial fibrosis. Left ventricular chamber size was not affected by ADF and ejection fraction was not reduced, but left atrial diameter was increased 16%, and the ratio of early (E) and late atrial (A) waves, in Doppler-measured mitral flow was reduced (P < .01). Pressure-volume loop analyses revealed a "stiff" heart during diastole in ADF rats, whereas combined dobutamine and volume loading showed a significant reduction in left ventricular diastolic compliance and a lack of increase in systolic pump function, indicating a diminished cardiac reserve. CONCLUSION: Chronic ADF in rats results in development of diastolic dysfunction with diminished cardiac reserve. ADF is a novel and unique experimental model of diet-induced diastolic dysfunction. The deleterious effect of ADF in rats suggests that additional studies of ADF effects on cardiovascular functions in humans are warranted. PMID- 20932469 TI - Should INO stay or should INO Go: a DNA "zip code" mediates gene retention at the nuclear pore. AB - In this issue of Molecular Cell, Brickner and colleagues (Light et al., 2010) identify a DNA sequence that mediates transcriptional memory and retention of recently active INO1 at the nuclear pore complex. PMID- 20932470 TI - The special delivery of a tail-anchored protein: why it pays to use a dedicated courier. AB - The membrane-spanning C-terminal regions in tail-anchored proteins must be recognized and delivered posttranslationally to the endoplasmic reticulum or mitochondrial membrane. A paper in this issue of Molecular Cell (Wang et al., 2010) and another recent report (Mariappan et al., 2010) delineate early steps in this pathway. PMID- 20932471 TI - CRL4(Cdt2) regulates cell proliferation and histone gene expression by targeting PR-Set7/Set8 for degradation. AB - PR-Set7/Set8 is a cell-cycle-regulated enzyme that monomethylates lysine 20 of histone H4 (H4K20). Set8 and monomethylated H4K20 are virtually undetectable during G1 and S phases of the cell cycle but increase in late S and in G2. We identify CRL4(Cdt2) as the principal E3 ubiquitin ligase responsible for Set8 proteolytic degradation in the S phase of the cell cycle, which requires Set8 PCNA interaction. Inactivation of the CRL4-Cdt2-PCNA-Set8 degradation axis results in (1) DNA damage and the induction of tumor suppressor p53 and p53 transactivated proapoptotic genes, (2) delayed progression through G2 phase of the cell cycle due to activation of the G2/M checkpoint, (3) specific repression of histone gene transcription and depletion of the histone proteins, and (4) repression of E2F1-dependent gene transcription. These results demonstrate a central role of CRL4(Cdt2)-dependent cell-cycle regulation of Set8 for the maintenance of a stable epigenetic state essential for cell viability. PMID- 20932472 TI - CRL4(Cdt2)-mediated destruction of the histone methyltransferase Set8 prevents premature chromatin compaction in S phase. AB - The proper coordination between DNA replication and mitosis during cell-cycle progression is crucial for genomic stability. During G2 and mitosis, Set8 catalyzes monomethylation of histone H4 on lysine 20 (H4K20me1), which promotes chromatin compaction. Set8 levels decline in S phase, but why and how this occurs is unclear. Here, we show that Set8 is targeted for proteolysis in S phase and in response to DNA damage by the E3 ubiquitin ligase, CRL4(Cdt2). Set8 ubiquitylation occurs on chromatin and is coupled to DNA replication via a specific degron in Set8 that binds PCNA. Inactivation of CRL4(Cdt2) leads to Set8 stabilization and aberrant H4K20me1 accumulation in replicating cells. Transient S phase expression of a Set8 mutant lacking the degron promotes premature H4K20me1 accumulation and chromatin compaction, and triggers a checkpoint mediated G2 arrest. Thus, CRL4(Cdt2)-dependent destruction of Set8 in S phase preserves genome stability by preventing aberrant chromatin compaction during DNA synthesis. PMID- 20932474 TI - Exo1 competes with repair synthesis, converts NER intermediates to long ssDNA gaps, and promotes checkpoint activation. AB - Ultraviolet (UV) light induces DNA-damage checkpoints and mutagenesis, which are involved in cancer protection and tumorigenesis, respectively. How cells identify DNA lesions and convert them to checkpoint-activating structures is a major question. We show that during repair of UV lesions in noncycling cells, Exo1 mediated processing of nucleotide excision repair (NER) intermediates competes with repair DNA synthesis. Impediments of the refilling reaction allow Exo1 to generate extended ssDNA gaps, detectable by electron microscopy, which drive Mec1 kinase activation and will be refilled by long-patch repair synthesis, as shown by DNA combing. We provide evidence that this mechanism may be stimulated by closely opposing UV lesions, represents a strategy to redirect problematic repair intermediates to alternative repair pathways, and may also be extended to physically different DNA damages. Our work has significant implications for understanding the coordination between repair of DNA lesions and checkpoint pathways to preserve genome stability. PMID- 20932473 TI - DNA damage activates a spatially distinct late cytoplasmic cell-cycle checkpoint network controlled by MK2-mediated RNA stabilization. AB - Following genotoxic stress, cells activate a complex kinase-based signaling network to arrest the cell cycle and initiate DNA repair. p53-defective tumor cells rewire their checkpoint response and become dependent on the p38/MK2 pathway for survival after DNA damage, despite a functional ATR-Chk1 pathway. We used functional genetics to dissect the contributions of Chk1 and MK2 to checkpoint control. We show that nuclear Chk1 activity is essential to establish a G(2)/M checkpoint, while cytoplasmic MK2 activity is critical for prolonged checkpoint maintenance through a process of posttranscriptional mRNA stabilization. Following DNA damage, the p38/MK2 complex relocalizes from nucleus to cytoplasm where MK2 phosphorylates hnRNPA0, to stabilize Gadd45alpha mRNA, while p38 phosphorylates and releases the translational inhibitor TIAR. In addition, MK2 phosphorylates PARN, blocking Gadd45alpha mRNA degradation. Gadd45alpha functions within a positive feedback loop, sustaining the MK2 dependent cytoplasmic sequestration of Cdc25B/C to block mitotic entry in the presence of unrepaired DNA damage. Our findings demonstrate a critical role for the MK2 pathway in the posttranscriptional regulation of gene expression as part of the DNA damage response in cancer cells. PMID- 20932475 TI - A cytoplasmic ATM-TRAF6-cIAP1 module links nuclear DNA damage signaling to ubiquitin-mediated NF-kappaB activation. AB - As part of the genotoxic stress response, cells activate the transcription factor NF-kappaB. The DNA strand break sensor poly(ADP-ribose)-polymerase-1 (PARP-1) and the kinase ataxia telangiectasia mutated (ATM) act as proximal signal mediators. PARP-1 assembles a nucleoplasmic signalosome, which triggers PIASy-mediated IKKgamma SUMOylation. ATM-dependent IKKgamma phosphorylation and subsequent ubiquitination were implicated to activate the cytoplasmic IkappaB kinase (IKK) complex by unknown mechanisms. We show that activated ATM translocates in a calcium-dependent manner to cytosol and membrane fractions. Through a TRAF binding motif, ATM activates TRAF6, resulting in Ubc13-mediated K63-linked polyubiquitin synthesis and cIAP1 recruitment. The ATM-TRAF6-cIAP1 module stimulates TAB2-dependent TAK1 phosphorylation. Both nuclear PARP-1- and cytoplasmic ATM-driven signaling branches converge at the IKK complex to catalyze monoubiquitination of IKKgamma at K285. Our data indicate that exported SUMOylated IKKgamma acts as a substrate. IKKgamma monoubiquitination is a prerequisite for genotoxic IKK and NF-kappaB activation, but also promotes cytokine signaling. PMID- 20932477 TI - Dynamic control of yeast MAP kinase network by induced association and dissociation between the Ste50 scaffold and the Opy2 membrane anchor. AB - Membrane localization of the Ste11 MAPKKK is essential for activation of both the filamentous growth/invasive growth (FG/IG) MAP kinase (MAPK) pathway and the SHO1 branch of the osmoregulatory HOG MAPK pathway, and is mediated by binding of the Ste50 scaffold protein to the Opy2 membrane anchor. We found that Opy2 has two major (CR-A and CR-B), and one minor (CR-D), binding sites for Ste50. CR-A binds Ste50 constitutively and can transmit signals to both the Hog1 and Fus3/Kss1 MAPKs. CR-B, in contrast, binds Ste50 only when Opy2 is phosphorylated by Yck1/Yck2 under glucose-rich conditions and transmits the signal preferentially to the Hog1 MAPK. Ste50 phosphorylation by activated Hog1/Fus3/Kss1 MAPKs downregulates the HOG MAPK pathway by dissociating Ste50 from Opy2. Furthermore, Ste50 phosphorylation, together with MAPK-specific protein phosphatases, reduces the basal activity of the HOG and the mating MAPK pathways. Thus, dynamic regulation of Ste50-Opy2 interaction fine-tunes the MAPK signaling network. PMID- 20932476 TI - ATM- and NEMO-dependent ELKS ubiquitination coordinates TAK1-mediated IKK activation in response to genotoxic stress. AB - Activation of the transcription factor NF-kappaB by multiple genotoxic stimuli modulates cancer cell survival. This response is mediated by a conserved pathway involving the nuclear ATM kinase and cytoplasmic IkappaB kinase (IKK); however, the molecular link between them remains incompletely understood. Here we show that ATM activates the IKK kinase TAK1 in a manner dependent on IKKgamma/NEMO and ELKS (a protein rich in glutamate, leucine, lysine, and serine). K63-linked polyubiquitination of ELKS, dependent on the ubiquitin ligase XIAP and the conjugating enzyme UBC13, allows ELKS association with TAK1 via its ubiquitin binding subunits TAB2/3. Although NEMO mutants defective in ubiquitin binding permit ATM-dependent TAK1 activation, they block NEMO association with ELKS and IKK activation. Thus, ATM- and NEMO-dependent ubiquitination of ELKS leads to the ubiquitin-dependent assembly of TAK1/TAB2/3 and NEMO/IKK complexes, resulting in IKK and NF-kappaB activation following genotoxic stimuli. PMID- 20932478 TI - A WD-repeat protein stabilizes ORC binding to chromatin. AB - Origin recognition complex (ORC) plays critical roles in the initiation of DNA replication and cell-cycle progression. In metazoans, ORC associates with origin DNA during G1 and with heterochromatin in postreplicated cells. However, what regulates the binding of ORC to chromatin is not understood. We have identified a highly conserved, leucine-rich repeats and WD40 repeat domain-containing protein 1 (LRWD1) or ORC-associated (ORCA) in human cells that interacts with ORC and modulates chromatin association of ORC. ORCA colocalizes with ORC and shows similar cell-cycle dynamics. We demonstrate that ORCA efficiently recruits ORC to chromatin. Depletion of ORCA in human primary cells and embryonic stem cells results in loss of ORC association to chromatin, concomitant reduction of MCM binding, and a subsequent accumulation in G1 phase. Our results suggest ORCA mediated association of ORC to chromatin is critical to initiate preRC assembly in G1 and chromatin organization in post-G1 cells. PMID- 20932479 TI - Interaction of a DNA zip code with the nuclear pore complex promotes H2A.Z incorporation and INO1 transcriptional memory. AB - DNA "zip codes" in the promoters of yeast genes confer interaction with the NPC and localization at the nuclear periphery upon activation. Some of these genes exhibit transcriptional memory: after being repressed, they remain at the nuclear periphery for several generations, primed for reactivation. Transcriptional memory requires the histone variant H2A.Z. We find that targeting of active INO1 and recently repressed INO1 to the nuclear periphery is controlled by two distinct and independent mechanisms involving different zip codes and different interactions with the NPC. An 11 base pair memory recruitment sequence (MRS) in the INO1 promoter controls both peripheral targeting and H2A.Z incorporation after repression. In cells lacking either the MRS or the NPC protein Nup100, INO1 transcriptional memory is lost, leading to nucleoplasmic localization after repression and slower reactivation of the gene. Thus, interaction of recently repressed INO1 with the NPC alters its chromatin structure and rate of reactivation. PMID- 20932480 TI - Phosphorylation-dependent regulation of PSF by GSK3 controls CD45 alternative splicing. AB - Signal-induced alternative splicing of the CD45 gene in human T cells is essential for proper immune function. Skipping of the CD45 variable exons is controlled, in large part, by the recruitment of PSF to the pre-mRNA substrate upon T cell activation; however, the signaling cascade leading to exon exclusion has remained elusive. Here we demonstrate that in resting T cells PSF is directly phosphorylated by GSK3, thus promoting interaction of PSF with TRAP150, which prevents PSF from binding CD45 pre-mRNA. Upon T cell activation, reduced GSK3 activity leads to reduced PSF phosphorylation, releasing PSF from TRAP150 and allowing it to bind CD45 splicing regulatory elements and repress exon inclusion. Our data place two players, GSK3 and TRAP150, in the complex network that regulates CD45 alternative splicing and demonstrate a paradigm for signal transduction from the cell surface to the RNA processing machinery through the multifunctional protein PSF. PMID- 20932481 TI - Structural basis for translational stalling by human cytomegalovirus and fungal arginine attenuator peptide. AB - Specific regulatory nascent chains establish direct interactions with the ribosomal tunnel, leading to translational stalling. Despite a wealth of biochemical data, structural insight into the mechanism of translational stalling in eukaryotes is still lacking. Here we use cryo-electron microscopy to visualize eukaryotic ribosomes stalled during the translation of two diverse regulatory peptides: the fungal arginine attenuator peptide (AAP) and the human cytomegalovirus (hCMV) gp48 upstream open reading frame 2 (uORF2). The C terminus of the AAP appears to be compacted adjacent to the peptidyl transferase center (PTC). Both nascent chains interact with ribosomal proteins L4 and L17 at tunnel constriction in a distinct fashion. Significant changes at the PTC were observed: the eukaryotic-specific loop of ribosomal protein L10e establishes direct contact with the CCA end of the peptidyl-tRNA (P-tRNA), which may be critical for silencing of the PTC during translational stalling. Our findings provide direct structural insight into two distinct eukaryotic stalling processes. PMID- 20932482 TI - Proteasomal degradation is transcriptionally controlled by TCF11 via an ERAD dependent feedback loop. AB - Coordinated regulation of the ubiquitin-proteasome system (UPS) is crucial for the cell to adjust its protein degradation capacity to changing proteolytic requirements. We have shown previously that mammalian cells upregulate proteasome gene expression in response to proteasome inhibition. Here, we report the identification of the transcription factor TCF11 (long isoform of Nrf1) as a key regulator for 26S proteasome formation in human cells to compensate for reduced proteolytic activity. Under noninducing conditions, TCF11 resides in the endoplasmic reticulum (ER) membrane. There, TCF11 is targeted to ER-associated protein degradation requiring the E3 ubiquitin ligase HRD1 and the AAA ATPase p97. Proteasome inhibitors trigger the accumulation of oxidant-damaged proteins and promote the nuclear translocation of TCF11 from the ER, permitting activation of proteasome gene expression by binding to antioxidant response elements in their promoter regions. Thus, we uncovered the transcriptional control loop regulating human proteasome-dependent protein degradation to counteract proteotoxic stress caused by proteasome inhibition. PMID- 20932483 TI - Should microbicides be controlled by women or by physicians? AB - In 2007, nearly 7000 new cases of HIV infection occurred each day. There is a constant increase in the proportion of women newly infected with HIV in the global population; this increase is particularly high in some areas of the world such as sub-Saharan Africa. Microbicides are products that are being developed to empower women against HIV. First- and second-generation microbicides are broad spectrum products that include surface active agents, vaginal defense enhancers, and blocking agents. Third-generation microbicides are HIV-specific and include replication and entry inhibitors formulated as gels or as vaginal rings. However, there is a concern that antiretroviral-based microbicides could lead to drug resistance if they are used by HIV-positive women who are unaware of their HIV status. To reach the highest number of women possible, microbicides should be available over-the-counter, which might not be the case with antiretroviral-based formulations. In contrast, non-antiretroviral-based microbicides will have the advantage of being initiated and controlled by women themselves and they will not jeopardize the use of life-saving drugs. PMID- 20932484 TI - The case for case reports. PMID- 20932485 TI - Pulmonary cryptococcosis misdiagnosed as smear-negative pulmonary tuberculosis with fatal consequences. AB - HIV-associated pulmonary cryptococcosis is under diagnosed, and may progress to fatal meningoencephalitis. We present a case of HIV-associated pulmonary Cryptococcus neoformans infection, initially mis-diagnosed as smear-negative pulmonary TB, which progressed to fatal cryptococcal meningitis. Autopsy series suggest that pulmonary cryptococcosis is common in African AIDS patients, and, due to limited diagnostic capacity, often mis-diagnosed as smear negative TB. Serum cryptococcal antigen testing may facilitate diagnosis in such cases. PMID- 20932486 TI - Infective endocarditis caused by Streptococcus bovis complicated by a superior mesenteric artery mycotic aneurysm and systemic septic emboli in a patient with colon diverticulitis. AB - To date, Streptococcus bovis endocarditis complicated by a superior mesenteric artery mycotic aneurysm and systemic septic emboli in a patient with colon diverticulitis has never been reported. A 46-year-old man, with a history of colon diverticulitis identified by diagnostic colon fiberscope and with hypertension, presented with a 14-day history of intermittent fever. An echocardiogram revealed severe mitral regurgitation with two large floating vegetations attached to both mitral leaflets. A blood culture grew S. bovis. Abdominal pain and left leg weakness developed 10 days after admission. Computerized tomography identified a 5*3cm mycotic aneurysm, and angiography revealed a saccular aneurysm at the distal branch of the superior mesenteric artery. A duplex study revealed an intravascular mass at the left femoral artery bifurcation. The patient accordingly underwent surgical resection of the mycotic aneurysm, removal of the mycotic thrombi, and mitral valve replacement. The patient's recovery was unremarkable. PMID- 20932487 TI - Coxiella burnetii infection of left atrial thrombus mimicking an atrial myxoma. AB - Infection of intracardiac thrombi is extremely unusual. Coxiella burnetii is a well-recognized etiologic agent of negative-blood culture endocarditis and vascular graft infection. Herein we describe the first reported case, to our knowledge, of C. burnetii infection of a large left-sided intracardiac thrombus that was initially misdiagnosed as an atrial myxoma. Diagnosis was confirmed by direct immunofluorescence assay, electron microscopy, and C. burnetii-specific polymerase chain reaction analysis performed on tissue sections of the thrombus. PMID- 20932488 TI - Laparoscopic surgery for rectal cancer. PMID- 20932489 TI - Laparoscopic surgery for rectal cancer. PMID- 20932491 TI - Functional imaging for head and neck cancer. PMID- 20932492 TI - Reconstruction of the maxilla and midface: introducing a new classification. AB - Most patients requiring midface reconstruction have had ablative surgery for malignant disease, and most require postoperative radiotherapy. This type of facial reconstruction attracts controversy, not only because of the many reconstructive options, but also because dental and facial prostheses can be very successful in selected cases. This Personal View is based on a new classification of the midface defect, which emphasises the increasing complexity of the problem. Low defects not involving the orbital adnexae can often be successfully treated with dental obturators. For the more extensive maxillary defects, there is consensus that a free flap is required. Composite flaps of bone and muscle harvested from the iliac crest with internal oblique or the scapula tip with latissimus dorsi can more reliably support the orbit and cheek than soft-tissue free flaps and non-vascularised grafts, and also enable an implant-borne dental or orbital prosthesis. Nasomaxillary defects usually require bone to augment the loss of the nasal bones, but orbitomaxillary cases can be managed more simply with local or soft-tissue free flaps. We review the current options and our own experience over the past 15 years in an attempt to rationalise the management of these defects. PMID- 20932493 TI - Drugs of abuse and human placenta. AB - Drugs of abuse such as cocaine and amphetamines, when used by pregnant women, exert deleterious effects on the fetus. These drugs produce their effects through inhibition of the serotonin transporter, norepinephrine transporter, and dopamine transporter. The inhibition can occur in the pregnant mother as well as in the fetus. These events contribute to the detrimental effects of these drugs on the fetus. However, the role of placenta, which serves as the link between the pregnant mother and the fetus, in the process remains understudied. It has been assumed that the placenta did not play any direct role in the process except that it allowed the passage of these drugs from maternal circulation into fetal circulation. This was before the discovery that the placenta expresses two of the three monoamine transporters. The serotonin transporter and the norepinephrine transporter are expressed on the maternal-facing side of the syncytiotrophoblast, thus exposed to the inhibitory actions of cocaine and amphetamines if present in maternal blood. Inhibition of these transporters in the placenta could lead to elevation of serotonin and norepinephrine in the intervillous space that may cause uterine contraction and vasoconstriction, resulting in premature delivery, decreased placental blood flow, and intrauterine growth retardation. Thus, the placenta is actually a direct target for these abusable drugs. Since the placental serotonin transporter and norepinephrine transporter are also inhibited by many antidepressants, therapeutic use of these drugs in pregnant women may have similar detrimental effects on placental function and fetal growth and development. PMID- 20932494 TI - Effect of methamphetamine on expression of HIV coreceptors and CC-chemokines by dendritic cells. AB - The United States is currently experiencing an entangled epidemic of HIV infection and use of different drugs of abuse, especially of methamphetamine (Meth). Blood monocyte-derived dendritic cells (DC) are the first line of defense against HIV-1 infection, and are the initial target of HIV-1 infection in injection drug users. DC-SIGN present on dendritic cells is the first molecule that facilitates HIV-1 infection independent of CD4 or HIV coreceptors. AIMS: The aim of this study was to evaluate whether Meth acts as a cofactor in the pathogenesis of HIV-1 infection. MAIN METHODS: Monocyte derived DCs, obtained from normal subjects were cultured with and without Meth+/-HIV-1B, followed by analyzing the gene and protein expression by real-time quantitative polymerase chain reaction (RT-PCR) and fluorescence-activated cell-sorting analyses, respectively. KEY FINDINGS: Our results show that Meth significantly enhances HIV infection, and downregulates the gene expression of chemokines and costimulatory molecules with reciprocal upregulation of HIV coreceptors and DC-SIGN by dendritic cells. SIGNIFICANCE: Better understanding of the role of Meth in HIV-1 disease susceptibility and the mechanism through which Meth mediates its effects on HIV-1 infection may help to devise novel therapeutic strategies against HIV-1 infection in Meth using HIV-1 infected population. PMID- 20932496 TI - Prion protein self-interactions: a gateway to novel therapeutic strategies? AB - Transmissible spongiform encephalopathies (TSEs) or prion diseases are fatal neurodegenerative disorders and include among others Creutzfeldt-Jakob disease in humans, bovine spongiform encephalopathy (BSE) in cattle, and scrapie in sheep. The central event in disease development in TSEs is the refolding of the normal host-encoded cellular prion protein (PrP) into abnormal and disease associated prion protein. The agent is thought to consist mainly or exclusively of these pathologically folded PrP molecules. The exact molecular mechanisms underlying this process and the role of normal PrP in the conversion to pathological isoforms of PrP are still poorly understood. The highly conserved PrP gene structure and organisation however, suggests that its function is important, even though PrP knockout mice appear to develop normally. Conversion of normal PrP is initiated by interaction with abnormal PrP (or "agent") resulting in refolding of normal PrP into new pathological PrP ("agent replication"). Normal PrP was shown to interact/bind with many different molecules including metal ions, nucleic acids, several (receptor) proteins, and the prion protein itself. The processes underlying agent replication (normal to abnormal PrP conversion) are most likely initiated by selective interaction between PrP molecules and potentially influenced by chaperone molecules. Thus far no vaccine, disease reversing therapeutic compounds or strategies (cure) exists, although there are some compounds capable of slowing the progression of prion disease. Studies towards interference to date have primarily focussed on inference with the interaction between normal and pathological isoforms of PrP in order to develop therapeutic strategies or find compounds capable of inhibiting prion propagation. Most described strategies are either directed at depletion of normal PrP and thus preventing pathological PrP formation and accumulation, or are based on preventing interaction between normal and abnormal PrP. Other therapeutic strategies focus on selective (self-)interaction of normal PrP molecules. Increased understanding of these interactions and the processes in which normal PrP plays a (active) role, could potentially lead to new modes of inhibiting prion protein conversion in which the physiological function(s) of normal PrP is retained. Ultimately this may lead to therapeutic strategies that are effective not only as a prophylactic but also in later stages of prion disease development. Here we review the data underlying these PrP-based approaches. PMID- 20932497 TI - World Pneumonia Day: fighting pneumonia with safe and affordable vaccines. PMID- 20932495 TI - Efflux transporters- and cytochrome P-450-mediated interactions between drugs of abuse and antiretrovirals. AB - Multidrug regimens and corresponding drug interactions cause many adverse reactions and treatment failures. Drug efflux transporters: P-gp, MRP, BCRP in conjunction with metabolizing enzymes (CYPs) are major factors in such interactions. Most effective combination antiretrovirals (ARV) therapy includes a PI or a NNRTI or two NRTI. Coadministration of such ARV may induce efflux transporters and/or CYP3A4 resulting in sub-therapeutic blood levels and therapeutic failure due to reduced absorption and/or increased metabolism. A similar prognosis is true for ARV-compounds and drugs of abuse combinations. Morphine and nicotine enhance CYP3A4 and MDR1 expression in vitro. A 2.5 fold rise of cortisol metabolite was evident in smokers relative to nonsmokers. Altered functions of efflux transporters and CYPs in response to ARV and drugs of abuse may result in altered drug absorption and metabolism. Appropriate in vitro models can be employed to predict such interactions. Influence of genetic polymorphism, SNP and inter-individual variation in drug response has been discussed. Complexity underlying the relationship between efflux transporters and CYP makes it difficult to predict the outcome of HAART as such, particularly when HIV patients taking drugs of abuse do not adhere to HAART regimens. HIV(+) pregnant women on HAART medications, indulging in drugs of abuse, may develop higher viral load due to such interactions and lead to increase in mother to child transmission of HIV. A multidisciplinary approach with clear understanding of mechanism of interactions may allow proper selection of regimens so that desired therapeutic outcome of HAART can be reached without any side effects. PMID- 20932498 TI - Peruvian FSWs: understanding HPV and barriers to vaccination. AB - Vaccine acceptability and vaccine-related knowledge data were collected from female sex workers (FSWs) in Lima, Peru to determine their awareness of HPV and barriers to the potential acceptability of HPV vaccine. FSWs were found to have low knowledge of HPV, HPV vaccine, and cervical cancer. Due to high reported sexual exposure, FSWs are likely at increased risk of cervical cancer, and should have access to HPV vaccine. FSWs should be targeted for HPV education campaigns and barriers to vaccination should be addressed. Future studies should assess HPV prevalence in this population and examine retention issues for vaccine dose completion. PMID- 20932499 TI - Down-regulation of IL-6 production by astaxanthin via ERK-, MSK-, and NF-kappaB mediated signals in activated microglia. AB - In this study, we investigated the effect of astaxanthin on IL-6 in activated microglial cells because excessive interleukin-6 (IL-6) production by activated brain microglia has been linked to many neurological disorders and proper regulation of IL-6 is critical for maintaining brain homeostasis. Astaxanthin inhibited lipopolysaccharide (LPS)-stimulated IL-6 mRNA and protein in BV-2 microglial cells. Moreover, LPS-induced p-IKKalpha, p-IkappaBalpha, and p-NF kappaB p65 levels were all suppressed by astaxanthin. The translocation of p-NF kappaB p65 from the cytosol into the nucleus and transcriptional activity were inhibited by astaxanthin. IL-6 expression and NF-kappaB transcriptional activation were inhibited by astaxanthin, as well as inhibitors of NF-kappaB and MAPK in LPS-stimulated BV-2 microglial cells. Consistent with these findings, astaxanthin down-regulated the activation of p-extracellular signal-regulated kinase 1/2 (p-ERK1/2) and p-mitogen- and stress-activated protein kinase 1(p MSK1), but not of p-c-jun N-terminal kinase (p-JNK). Astaxathin also decreased IL 6 mRNA and protein levels in LPS-stimulated primary microglial cells, RAW264.7 macrophages, and peritoneal macrophages. In addition, IL-6 suppression through astaxanthin-induced down-regulation of p-ERK1/2, p-MSK1, and p-NF-kappaB p65 occurred in microglial cells stimulated with LPS or stromal derived factor (SDF) 1alpha. Astaxathin also inhibited the secretion and mRNA expression of IL-6 in SDF-1alpha-stimulated microglial cells. SDF-1alpha-stimulated ERK1/2, MSK1, and NF-kappaB p65 phosphorylation were reduced by astaxanthin. Therefore, our results suggest that astaxanthin regulates IL-6 production through a p-ERK1/2-MSK-1- and p-NF-kappaB p65-dependent pathway in activated microglial cells. PMID- 20932500 TI - Visualizing the temporal dynamics of spatial information processing responsible for the Simon effect and its amplification by inhibition of return. AB - Research has shown that the Simon effect is larger for targets suffering from inhibition of return (IOR). We used speed-accuracy trade-off (SAT) methodology to explore the temporal dynamics underlying this interaction. In Experiment 1, a new method for sorting the data was used to reveal a monotonic decay in the impact of task-irrelevant location information that is responsible for the Simon effect. In Experiment 2, we show that IOR delays both task-relevant identity and task irrelevant location codes; a relatively longer delay for location than identity codes accounts for the effect of IOR on the Simon effect. When location information was made task-relevant in Experiment 3, IOR delayed the accumulation of this information by about the same amount as when location was irrelevant. The results suggest that IOR, therefore, has a greater effect on location than identity information. PMID- 20932501 TI - Managing chronic heart failure patient in chronic kidney disease. AB - Management of systolic heart failure can be particularly challenging in patients with chronic kidney disease, especially those who are not yet receiving dialysis. Few clinical trials have been performed in this particular population, so management is directed by evidence from studies of patients with limited or no renal impairment. Their heightened risk for many treatment complications mandates additional considerations regarding drug selection, dosing, and monitoring. Subspecialty consultation is driven by patient instability or disease progression, intolerance of standard treatment, or need for device placement. PMID- 20932502 TI - Implementation of high sensitivity cardiac troponin T measurement in the emergency department. AB - BACKGROUND: we examined the diagnostic performance of high sensitivity cardiac troponin T (cTnThs) measurement and its ability to predict risk in unselected patients presenting to the emergency department with acute chest pain. METHODS: we conducted a retrospective analysis of 137 consecutive patients with chest pain (age range, 66 +/- 16 years; 64% male). A final diagnosis of acute myocardial infarction was made using the "old" (cTnT fourth-generation assay, >= 0.04 microg/L) or the "new" cutpoint (cTnThs >= 0.014 microg/L). RESULTS: the adjudicated final diagnosis of acute myocardial infarction significantly increased from 20 to 35 patients (a 75% increase) and troponin-positive nonvascular cardiac chest pain from 10 to 30 (a 200% increase) using cTnThs. The number of patients with unstable angina or troponin-negative nonvascular cardiac chest pain significantly decreased (P <.05). Diagnostic performance of cTnThs levels at admission was significantly higher compared to cTnT levels (area under the curve [AUC] 0.85 vs AUC 0.70; P <.05). cTnThs levels below the detection limit (<0.003 microg/L) had a negative predictive value of 100% to exclude acute myocardial infarction. The event rate during 6 months of follow-up was low in patients with cTnThs levels <0.014 microg/L, while patients with cTnT levels >= 0.04 MUg/L were at increased, and patients with cTnThs >= 0.014 MUg/L and cTnT <0.04 microg/L at intermediate risk of death or recurrent myocardial infarction (P = .002). Risk was highest in chest pain patients with dynamic changes of cTnThs levels >30%. CONCLUSION: the introduction of cTnThs assay displays an excellent diagnostic performance for the workup of patients with chest pain at the time of their initial presentation. Even small increases of cTnThs indicate increased risk for death or myocardial infarction during follow-up. PMID- 20932503 TI - Mental nerve neuropathy: frequently overlooked clinical sign of hematologic malignancies. PMID- 20932505 TI - Office management of the patient with chronic cough. AB - Chronic cough is a common complaint in the ambulatory setting and can result in significant compromise in quality of life and, uncommonly, is a presenting symptom of serious or life-threatening disease. Although there are many potential causes, an organized approach to diagnosis that may include therapeutic trials of select medications can establish the diagnosis in over 90% of presenting patients. Management hinges on accurate etiologic diagnosis. Consultation with a pulmonologist, otolaryngologist, or allergist is indicated in selected cases where diagnosis is unclear or specific therapy is mandated. PMID- 20932504 TI - Management of atrial fibrillation: translating clinical trial data into clinical practice. AB - Atrial fibrillation is a supraventricular tachyarrhythmia with significant consequences in terms of morbidity and mortality. In light of the limitations of available pharmacologic treatment options (suboptimal efficacy plus safety and tolerability issues), atrial fibrillation management should be individualized based on patient characteristics and comorbidities that could influence response to specific management approaches. The importance of adequate anticoagulation should not be overlooked. This review provides a practical guide for primary care physicians, internists, and cardiologists on current management strategies for atrial fibrillation, based on recent guidelines and current clinical data. PMID- 20932506 TI - Focus on cystic fibrosis and other disorders evidenced in fetuses with sonographic finding of echogenic bowel: 16-year report from Brittany, France. AB - OBJECTIVE: Pregnancies medical follow-up and ultrasonography development have enabled detection of fetal echogenic bowel, a sign associated with various pathologies, including cystic fibrosis. Based on the long experience of a region where cystic fibrosis is frequent (Brittany, France), we describe disorders diagnosed in fetal echogenic bowel fetuses and assess ultrasonography ability in detecting cystic fibrosis in utero. STUDY DESIGN: We reviewed the cases of fetal echogenic bowel diagnosed in pregnant women living in Brittany and referred for CFTR gene analysis over the 1992-2007 period (n = 289). RESULTS: A disorder was diagnosed in 32.2% of the fetuses, cystic fibrosis being the most commonly identified (7.6%). We also found digestive malformations (7.0%), chromosomal abnormalities (3.7%), and maternofetal infections (3.7%). Combining these data with our ongoing newborn screening program since 1989 showed that ultrasonography enabled diagnosis of 10.7% of the cystic fibrosis cases. CONCLUSION: This study highlights the importance of pregnancy ultrasound examinations and their efficiency in detecting cystic fibrosis. PMID- 20932507 TI - Biochemical and biophysical predictors of the response to the induction of labor in nulliparous postterm pregnancy. AB - OBJECTIVE: The objective of the study was to evaluate the clinical, sonographic, and hormonal variables that influence the success of labor induction in nulliparous postterm pregnancies. STUDY DESIGN: Fifty nulliparous women with a single postterm pregnancy receiving a slow-release prostaglandin estradiol pessary were prospectively enrolled, and clinical characteristics were analyzed in relation to success of induction of labor. Clinical, sonographic, and hormonal variables were analyzed by univariate statistical analysis and multivariate logistic regression for the prediction of successful induction. RESULTS: The group of patients delivering within 24 hours differed significantly from the remaining patients by higher Bishop scores, body mass indices, estradiol serum concentrations, estriol to estradiol ratios, and shorter cervices. The combination of cervical length and estriol to estradiol ratio achieved a sensitivity of 100% (95% confidence interval, 71.3-100%) and a specificity of 94.1% (95% confidence interval, 80.3-99.1%). CONCLUSION: Cervical length and the estriol to estradiol ratio represent good predictive indicators of the response to the induction of labor in postterm pregnancies. PMID- 20932508 TI - Comparison of central corneal thickness measurement using ultrasonic pachymetry, rotating Scheimpflug camera, and scanning-slit topography. AB - PURPOSE: To evaluate and compare central corneal thickness measurements using rotating Scheimpflug camera, scanning-slit topography, and ultrasound pachymetry in virgin, healthy corneas. DESIGN: Prospective, observational, cross-sectional study. METHODS: Central corneal thickness in 157 healthy eyes of 157 patients without ocular abnormalities other than refractive errors was measured, in a sequential order, once with rotating Scheimpflug camera and scanning-slit topography and 3 times with ultrasound pachymetry as the last part of examination. All measurements were performed by a single experienced examiner. The results from scanning-slit topography are given with and without correction for "acoustic correction factor" of 0.92. RESULTS: The average measurements of central corneal thickness by rotating Scheimpflug imaging, scanning-slit pachymetry, and ultrasound were 537.15 +/- 32.98 MUm, 542.06 +/- 39.04 MUm, and 544.07 +/- 34.75 MUm, respectively. The mean differences between modalities were 6.92 MUm between rotating Scheimpflug and ultrasound (P < .0001), 2.01 MUm between corrected scanning-slit and ultrasound (P = .204), and 4.91 MUm between corrected scanning-slit and rotating Scheimpflug imaging (P = .001). According to Bland-Altman analysis, highest agreement was between ultrasonic and rotating Scheimpflug pachymetry. CONCLUSIONS: In the assessment of normal corneas, rotating Scheimpflug topography measures central corneal thickness values with higher agreement to ultrasound pachymetry. PMID- 20932509 TI - Association of Wnt3A gene variants with non-syndromic cleft lip with or without cleft palate in Chinese population. AB - OBJECTIVE: non-syndromic cleft lip with or without cleft palate (NSCLP) is one of the most common birth defects all over the world. Both genetic and environmental factors may contribute to NSCLP. Recent studies have demonstrated that Wnt/beta catenin signalling pathway is required for lip and palate formation. WNT family may play an important role in the development of NSCLP. This study aimed to evaluate the association between Wnt3A gene polymorphisms and NSCLP in Chinese population from Northwest China. DESIGN: 216 patients with NSCLP and 233 normal controls were genotyped for two SNPs of Wnt3A by PCR-RFLP. Both SNPs genotype frequencies were analysed between cases group and controls group. RESULTS: the frequencies of rs752107 TT and rs3121310 AA were significantly higher in NSCLP cases group (7.4%, 15.3%) than that in controls group (2.1%, 9.5%) with p value=0.013, 0.014, corrected p value (p-corr) <0.05 and with odds ratio (OR)=3.49, 95% confidence interval [CI]: 1.244-9.79, OR=2.27, 95% CI: 1.17-4.38, respectively; the frequency of rs3121310 GA was also higher in NSCLP cases group (57.4%) than in controls group (52.0%) with p-value=0.042 and OR=1.56 (95% CI: 1.02-2.39). And the frequency of rs752107 TT of Wnt3A showed higher risk in female patients, while the frequency of A allele of rs3121310 showed stronger association in male patients. CONCLUSIONS: this is the first report that two SNPs of Wnt3A (rs752107 and rs3121310) are significantly associated with NSCLP in Chinese population. These findings provide a context for understanding the genetic aetiology of NSCLP. PMID- 20932510 TI - Interferon-gamma +874A/T polymorphism in relation to generalized chronic periodontitis and the presence of periodontopathic bacteria. AB - BACKGROUND: Interferon gamma (IFN-gamma) is one of the key regulatory cytokines that has a significant effect on immune responses. It may be important in the chronic inflammatory diseases such as periodontitis in which increased IFN-gamma levels were found. The aim of this study was to analyze +874A/T polymorphism in the IFN-gamma gene and its associations with the presence of periodontopathic bacteria and susceptibility to generalized chronic periodontitis (CP). METHODS: A total of 498 unrelated Czech white subjects were included in the present study. Genomic DNA was obtained from the peripheral blood of 244 patients with CP and 254 healthy subjects. The IFN-gamma +874A/T polymorphism was determined by amplification refractory mutation system-polymerase chain reaction (ARMS-PCR). Subgingival bacterial colonization (A. actinomycetemcomitans, P. gingivalis, P. intermedia, T. forsythia, T. denticola, P. micros, F. nucleatum in subgingival pockets) was investigated by the DNA-microarray based periodontal pathogen detection kit in a subgroup of subjects (N=110). RESULTS: Our results showed no differences in the allele and genotype frequencies of the IFN-gamma +874A/T polymorphism between patients with CP and controls (P>0.05). Although we found significant differences in the occurrence of periodontal bacteria between patients with CP and healthy controls (from P<0.00001 to P<0.05), no significant association between IFN-gamma +874A/T polymorphism and periodontal pathogens was observed in any group. CONCLUSIONS: In conclusion, these findings indicate that putative functional variant in the IFN-gamma is not associated with susceptibility to chronic periodontitis or microbial composition in the Czech population. PMID- 20932511 TI - Parental fear of negative child evaluation in child social anxiety. AB - Parental anxiety has been linked to child anxiety in various studies. However, specific mechanisms responsible for this relationship in the context of child social anxiety are still largely unknown. A potential mediator between parental and child social anxiety may be parental fear of negative child evaluation (FNCE). To investigate this concept, we collected self-reported data from families with 9- to 16-year old children in a non-clinical sample (458 mother child dyads and 336 father-child dyads). While both paternal and maternal FNCE predicted child social anxiety, only maternal FNCE mediated the association between maternal and child social anxiety. Maternal report of FNCE was also found to mediate the association between maternal social anxiety and general childhood emotional problems but not externalising problems. Overall, this study is the first to identify a mediator variable that may explain the association between mother and child social anxiety in school-age children. The results shed new light on the mechanisms by which fear and anxiety may be transmitted across generations. PMID- 20932512 TI - The impact of group leaders' behaviour on parents acquisition of key parenting skills during parent training. AB - BACKGROUND: Parent training (PT) is identified as the most effective intervention for the treatment of conduct disorder (CD). Intervention observational outcomes are often reported as summarised composite scores, providing an overview of overall construct change. METHODS AND AIMS: Parents of children aged 3-5 years identified 'at risk' of developing CD were randomly allocated to either PT intervention or waiting list control group. Parent and child behaviours were assessed before and after the intervention period. The current paper aims to establish which individual observed parenting categories change as a result of PT, and which specific observed leader categories predict these changes. RESULTS: Controlling for baseline scores, ANCOVA demonstrated changes in parent praise and reflective behaviours as significant post-intervention. One-way ANOVAs demonstrated higher levels of leader praise and reflective behaviours resulted in greater change in parental praise and reflective behaviours respectively. Regression analyses indicated these leader behaviours predict positive change in parental praise and reflective behaviours for intervention families. CONCLUSIONS: Composite observational scores provide an account of behaviour constructs, whereas individual behaviour categories provide an insight into the core components of these constructs. The results suggest praise and reflection as key leader behaviours that influence the mechanisms of change in parenting behaviours as a result of PT. PMID- 20932514 TI - Degradation of carbohydrate moieties of arabinogalactan-proteins by glycoside hydrolases from Neurospora crassa. AB - Arabinogalactan-proteins (AGPs) are a family of plant proteoglycans having large carbohydrate moieties attached to core-proteins. The carbohydrate moieties of AGPs commonly have beta-(1->3)(1->6)-galactan as the backbone, to which other auxiliary sugars such as l-Ara and GlcA are attached. For the present study, an alpha-L-arabinofuranosidase belonging to glycoside hydrolase family (GHF) 54, NcAraf1, and an endo-beta-(1->6)-galactanase of GHF 5, Nc6GAL, were identified in Neurospora crassa. Recombinant NcAraf1 (rNcAraf1) expressed in Pichia pastoris hydrolyzed radish AGPs as well as arabinan and arabinoxylan, showing relatively broad substrate specificity toward polysaccharides containing alpha-L arabinofuranosyl residues. Recombinant Nc6GAL (rNc6GAL) expressed in P. pastoris specifically acted on beta-(1->6)-galactosyl residues. Whereas AGP from radish roots was hardly hydrolyzed by rNc6GAL alone, beta-(1->6)-galactan side chains were reduced to one or two galactan residues by a combination of rNcAraf1 and rNc6GAL. These results suggest that the carbohydrate moieties of AGPs are degraded by the concerted action of NcAraf1 and Nc6GAL secreted from N. crassa. PMID- 20932515 TI - Circulating nucleic acids in type 1 diabetes may modulate the thymocyte turnover rate. AB - The autoimmunity of type 1 diabetes is associated with T-cell hyperactivity. Current study was designed to examine the effect of circulating ribonucleic acids (RNAs), isolated from type 1 diabetic patients on proliferative, apoptotic and inflammatory potential of rat thymocytes. Rat thymocytes were assayed for proliferating nuclear cell antigen (PCNA), Bcl-2, Bax and NF-kappaB level, using the flow cytometric and fluorometric assays. Cells were allocated into groups, treated with RNAs purified from plasma of juvenile diabetics, adult type 1 diabetic patients, control healthy children, healthy adult persons, nucleic acids and polynucleotide standards (RNA, polyC, PolyA, PolyIC, and CpG). The upregulation of PCNA and Bcl-2 protein and downregulation of Bax protein and NF kappaB was shown when the thymocytes where incubated with RNA purified from plasma of juvenile type 1 diabetic patients. The dysregulation of inflammatory cascade and central tolerance may be a defect in autoimmune diseases related to innate immunity leading to corresponding alteration in adaptive immune response. PMID- 20932516 TI - Preterm birth and exposure to air pollutants during pregnancy. AB - BACKGROUND: Research has shown that prenatal exposure to air pollutants may have a detrimental effect on fetal development, with the strength of the relationship depending on the effect being studied. The evidence to date, however, is insufficient to establish a direct causal link between such exposure and preterm delivery. This study evaluates the specific effect of prenatal exposure to NO(2) and benzene on preterm births. METHODS: The population under study comprised 785 pregnant women who formed part of the INMA cohort in Valencia, Spain (2003-2005). Multiple regression models were used for mapping outdoor nitrogen dioxide (NO(2)) and benzene levels throughout the area. Individual exposure was assigned as the estimated outdoor levels at each woman's home measured during each trimester as well as throughout the entire pregnancy. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated in order to assess the association between preterm birth and exposure to NO(2) and benzene. The shape of the exposure response curve between air pollution and the risk of preterm birth was analyzed with a flexible approach, introducing a natural cubic spline for air pollution levels into the model. RESULTS: Pregnant women exposed to NO(2) and benzene have an increased risk of preterm birth. This risk was shown to be significant when women were exposed to NO(2) levels >46.2 MUg/m(3) during the second and third trimesters as well as throughout the entire pregnancy and to benzene levels >2.7 MUg/m(3) throughout the entire pregnancy. CONCLUSION: These results suggest that maternal exposure to traffic-related air pollution is associated with preterm birth. PMID- 20932513 TI - From reactive to proactive and selective control: developing a richer model for stopping inappropriate responses. AB - A better understanding of the neural systems underlying impulse control is important for psychiatry. Although most impulses are motivational or emotional rather than motoric per se, it is research into the neural architecture of motor response control that has made the greatest strides. This article reviews recent developments in the cognitive neuroscience of stopping responses. Most research of this kind has focused on reactive control-that is, how subjects stop a response outright when instructed by a signal. It is argued that reactive paradigms are limited as models of control relevant to psychiatry. Instead, a set of paradigms is advocated that begins to model proactive inhibitory control-that is, how a subject prepares to stop an upcoming response tendency. Proactive inhibitory control is generated according to the goals of the subject rather than by an external signal, and it can be selectively targeted at a particular response tendency. This may have wider validity than reactive control as an experimental model for stopping inappropriate responses. PMID- 20932517 TI - [Legibility of the patient information sheet after its review by the clinical research ethics committees]. PMID- 20932518 TI - The effect of paternal age on assisted reproduction outcome. AB - OBJECTIVE: To summarize the current knowledge about the association between paternal age and assisted reproductive technology (ART) outcomes. In contrast to the extensive investigation of the relationship between maternal age and the success of ART, there are few studies examining the effect of paternal age on ART outcomes. DESIGN: Systematic review of the literature. By means of a PubMed literature search using the phrases "paternal age", "male age", and "assisted reproductive technology", we identified articles that investigated the role of male age in in vitro reproduction techniques. RESULT(S): The 10 studies included in this review did not show a clear correlation between advanced paternal age and rates of fertilization, implantation, pregnancy, miscarriage, and live birth. Paternal age was not found to affect embryo quality at the cleavage stage (days 2 3). However, a significant decrease in blastocyst embryo formation was associated with increased paternal age, probably reflecting male genomic activation within the embryo. Except for volume, characteristics of semen such as motility, concentration, and morphology did not decrease with age. CONCLUSION(S): There is insufficient evidence to demonstrate an unfavorable effect of paternal age on ART outcomes. Further study with well-defined entry criteria and uniform reporting of outcomes is needed to investigate the subject. PMID- 20932519 TI - Pancreatic hemangioma mimicking a malignant pancreatic cyst. PMID- 20932520 TI - The effect of haematoma aspiration on intra-articular pressure and pain relief following Mason I radial head fractures. AB - BACKGROUND: The aspiration of the accompanying haematoma by Mason type I radial head fractures is advocated by several authors to achieve an analgesic effect. The purpose of this study was to investigate the effect of haematoma aspiration on intra-articular pressure and on pain relief after Mason I radial head fractures. MATERIALS AND METHODS: A total of 16 patients (10 men and six women, age 23-47 years) with an isolated Mason I radial head fracture were subjected to haematoma paracentesis. Initially, intra-articular pressure was measured by using the Stryker Intra-Compartmental Pressure Monitor System. After haematoma aspiration, a new pressure measurement without moving the needle was performed. Pain before and after haematoma aspiration was evaluated by using an analogue 10 point pain scale. RESULTS: Intra-articular elbow pressure prior to haematoma aspiration varied from 49 to 120 mmHg (median, 76.5 mmHg), while following aspiration, it ranged from 9 to 25 mmHg (median, 17 mmHg). The median quantity of the aspired blood was 2.75 ml (range, 0.5-8.5 ml). Patients reported a decrease in the visual analogue score (VAS) for pain from 5.5 (4-8) before to 2.5 (1-4) after aspiration. Decrease for both pressure and pain was statistically significant (p=0.005). CONCLUSION: The formation of an intra-articular haematoma in the elbow joint following an undisplaced Mason I radial head fracture leads to a pronounced increase of the intra-articular pressure accompanied by intense pain for the patient. The aspiration of the haematoma results in an acute pressure decrease and an immediate patient relief. PMID- 20932521 TI - Cement augmentation of intertrochanteric fractures stabilised with intramedullary nailing. AB - We studied 80 patients (56 females) with an average age of 84 years (range 80 94). All patients were suffering from osteoporosis (1 or 2 Singh score) and had an unstable intertrochanteric fracture, defined as a fracture with three fragments or more. Patients were divided in group A (40 patients), treated by a cement augmentation technique and group B (40 patients) treated by Gamma Nail conventional technique. Augmentation was performed with MetilMetacrilate (Mendec Spine, Tecres) inserted through the cannulated cephalic screw at its apex. Such parameters were evaluated as the length of operating time, early functional recovery using the Harris hip score, assessment with radiography of the TAD index and development of implant related complications. The HHS average score was 48.2 and 49.31 after 1 month post-operation, 54.37 and 53.56 after 3 months, 54.71 and 56.42 after 6 months, 57.91 and 59.86 after 12 months, in groups A and B, respectively. The average drop of haemoglobin was 1.55 g/dL and 1.05 g/dL, in groups A and B, respectively. Except one joint penetration with the guide wire and some small amount of cement leakage, no other complications (infection, screw cut out and femoral head necrosis) were observed. We believe that in femoral intertrochanteric fractures cement augmentation could improve the mechanical stability of the implant, ensuring early functional recovery. PMID- 20932522 TI - Triceps-sparing versus olecranon osteotomy for ORIF: analysis of 67 cases of intercondylar fractures of the distal humerus. AB - The purpose of this study was to compare the triceps-sparing approach with olecranon osteotomy regarding their effects on the functional outcomes of intercondylar fractures of the distal humerus managed with open reduction and internal fixation (ORIF), by reviewing 67 cases of intercondylar distal humerus fractures surgically managed with either of the approaches during 2001-2009. The medical records and radiographs of 30 male and 37 female patients, with a mean age of 44.5 years (range, 16-77) and a mean follow-up time of 34.3 months (range, 6-89), were retrospectively reviewed. Flexion, extension, arc of flexion/extension, pronation, supination, arc of pronation/supination and the Mayo Elbow Performance Score (MEPS) were used to assess the functional outcomes of intercondylar distal humerus fractures treated with ORIF through the triceps sparing approach or olecranon osteotomy. According to the AO Foundation (AO) classification, there were 10 cases of C1, 28 cases of C2 and 29 cases of C3 fractures. At the time of review, all fractures had united. Although there was no overall statistically significant difference in the average flexion, extension, arc of flexion/extension, pronation, supination and arc of pronation/supination between the triceps-sparing group (n=34) and the olecranon osteotomy group (n=33), patients above 60 years of age tended to have more extension loss (mean 22.9 degrees , range 0-55 degrees ) after ORIF via the triceps-sparing approach, compared with any other surgical approach/age combination group. In the triceps sparing group, although only 37.5% of patients over the age of 60 years obtained excellent/good MEPS, the rate increased to 100% in patients aged less than 40 years of age (P<0.05). By contrast, the rate of excellent/good MEPS remained above 80% in all age groups of patients treated with ORIF via olecranon osteotomy. In conclusion, ORIF via the triceps-sparing approach confers inferior functional outcomes for intercondylar distal humerus fractures in patients over the age of 60 years, for whom the olecranon osteotomy approach may be a better choice. However, for patients less than 60 years of age, especially those less than 40 years of age, either approach confers satisfactory outcomes. PMID- 20932523 TI - Comparison of soft-tissue serum markers in stable intertrochanteric fracture: dynamic hip screw versus proximal femoral nail-A preliminary study. AB - DESIGN: Prospective randomised comparative study. OBJECTIVES: To analyse and compare serum soft-tissue marker differences after dynamic hip screw (DHS)and proximal femoral nail (PFN) fixation of stable intertrochanteric fractures in the elderly. MATERIALS AND METHODS: Twenty elderly patients (>60 years old) with a stable intertrochanteric fracture were enrolled in this study. Patients were divided into two groups of 10 each according to the device used (DHS or PFN). All 20 patients had a stable intertrochanteric fracture, and all were operated on by the same surgeon using minimal invasive approach. A biochemical comparison of soft-tissue serum markers was performed. The serum markers examined were haemoglobin (Hb), haematocrit (Hct), creatine kinase (CK), myoglobin (MYO), troponin I and C-reactive protein (CRP), and their levels were determined before surgery, and 1, 8, 16, 24, 36, 48 and 72 h after surgery. Differences between the DHS and PFN groups were compared. RESULTS: No inter-group differences were observed with respect to preoperative demographics,operation time, incision length or blood loss. In terms of serum markers, both methods showed similar patterns of change for CK, MYO and CRP pre- to post-operatively. In addition, pre and postoperative Hb and Hct levels were similar. Furthermore, no inter-group differences were observed between the absolute values of serum markers at any point. CONCLUSION: The absolute values and temporal changes of serum markers were similar in the two study groups. These findings suggest that DHS and PFN fixation of stable intertrochanteric fractures produce similar levels of soft-tissue damage. PMID- 20932524 TI - Nurses' work environment and intent to leave in Lebanese hospitals: implications for policy and practice. AB - BACKGROUND: The dual burden of nursing shortages and poor work environments threatens quality of patient care and places additional pressures on resource stretched health care systems, particularly in the Eastern Mediterranean Region (EMR). There is a paucity of research in the EMR examining the quality of nurses' work environment and its association to nurses' intent to leave their jobs/countries. OBJECTIVES: Systematically examine the characteristics of nurses' work environment and their relation to nurses' intent to leave their jobs within the context of Lebanon. A secondary objective is to assess the utility and validity of the NWI-R within the context of the EMR. METHODS: A cross-sectional survey design was utilized to survey a total of 1793 registered nurses in 69 Lebanese hospitals. The survey instrument included questions on nurses' background, hospital characteristics, intent to leave, and the Revised Nurse Working Index (NWI-R). Data analysis included descriptive statistics for demographic characteristics, t-test and ANOVA to assess differences in agreement scores, and a multinomial logistic regression model to predict intent to leave. Thematic analysis of open-ended questions was utilized to extract themes that fit under issues relating to nurses' work environment in Lebanese hospitals. RESULTS: The NWI-R subscale with the lowest mean score related to control. Younger nurses had lower scores on organizational support and career development. Regression analysis revealed that for every 1 point score decrease on career development there was a 93% increase in likelihood of reporting intent to leave country. Likewise, for every 1 point score decrease on participation there was an observed 51% and 53% increase in likelihood of reporting intent to leave country and hospital, respectively. Findings show that hospital characteristics (size, accreditation status and presence of a recruitment and retention strategy) were significantly associated with NWI-R subscales. CONCLUSIONS: Participation, control and career development were key work environment challenges contributing to the attrition on nurses from Lebanese hospitals. Although some of the issues identified are country specific, others would certainly be relevant to other countries in the EMR. Addressing these challenges would require a strong and coordinated action from governments, professional bodies, policy makers and health managers. PMID- 20932525 TI - Effect of short-chain alcohols on surfactant-mediated reversed-phase liquid chromatographic systems. AB - The behaviour of beta-blockers in a reversed-phase liquid chromatographic (RPLC) column with mobile phases containing a short-chain alcohol (methanol, ethanol or 1-propanol), with and without the surfactant sodium dodecyl sulphate (SDS), was explored. Two surfactant-mediated RPLC modes were studied, where the mobile phases contained either micelles or only surfactant monomers at high concentration. Acetonitrile was also considered for comparison purposes. A correlation was found between the effects of the organic solvent on micelle formation (monitored by the drop weight procedure) and on the nature of the chromatographic system (as revealed by the retention, elution strength and peak shape of beta-blockers). When SDS is added to the mobile phase, the free surfactant monomers bind the C18 bonded chains on the stationary phase, forming an anionic layer, which attracts strongly the cationic beta-blockers. The retention is modified as a consequence of the solving power of the organic solvent, micelles and surfactant monomers. The molecules of organic solvent bind the micelles, modify their shape, and may avoid their formation. They also bind the monomers of surfactant, desorbing them from the stationary phase, which affects the retention. The remaining surfactant covers the free silanols on the siliceous support, avoiding the interaction with the cationic solutes. The retention of beta-blockers results from a combination of electrostatic and hydrophobic interactions, the latter being weaker compared to the hydro-organic system. The peak efficiencies and asymmetries are excellent tools to probe the surfactant layer on the stationary phase in an SDS/organic solvent system. The peaks will be nearly symmetrical wherever enough surfactant coats the stationary phase (up to 60% methanol, 40% ethanol, 35% 1-propanol, and 50% acetonitrile). PMID- 20932526 TI - Charge heterogeneity of a therapeutic monoclonal antibody conjugated with a cytotoxic antitumor antibiotic, calicheamicin. AB - A robust and highly reproducible capillary isoelectric focusing (cIEF) method for the evaluation of charge heterogeneity of monoclonal antibody (mAb) pharmaceutical which contains covalently bound antitumor compounds was developed using a combination of commercially available dimethylpolysiloxane-coated capillary and carrier ampholyte. In order to optimize major analytical parameters for robust mobilization, experimental responses from three pI markers were selected. The optimized method gave excellent repeatability and intermediate precision in estimated pI values of charge variants with relative standard deviations (RSDs) of not more than 0.06% and 0.95%, respectively, when using IgG(4) as a model. Furthermore, RSDs of charge variant compositions were less than 5.0%. These results suggest that the proposed method can be a powerful tool for reproducible evaluation of charge variants of both naked mAbs and their conjugates with high resolution, and it is applicable to quality testing and detailed characterization in the pharmaceutical industry. In addition, it should be noticed that the method provided non-linear pH gradient within the tested ranges, from pI 9.50 to 3.78, and the pH gradient caused the inconsistency of estimated pI ranges between cIEF and gel IEF. This result indicates that selecting appropriate pI markers based on the target pI ranges of charge variants for each mAb related pharmaceutical is highly recommended for the precise determination of pI values. PMID- 20932527 TI - Continuous separation of copper ions from a mixture of heavy metal ions using a three-zone carousel process packed with metal ion-imprinted polymer. AB - In this study, a three-zone carousel process based on a proper molecular imprinted polymer (MIP) resin was developed for continuous separation of Cu(2+) from Mn(2+) and Co(2+). For this task, the Cu (II)-imprinted polymer (Cu-MIP) resin was synthesized first and used to pack the chromatographic columns of a three-zone carousel process. Prior to the experiment of the carousel process based on the Cu-MIP resin (MIP-carousel process), a series of single-column experiments were performed to estimate the intrinsic parameters of the three heavy metal ions and to find out the appropriate conditions of regeneration and re-equilibration. The results from these single-column experiments and the additional computer simulations were then used for determination of the operating parameters of the MIP-carousel process under consideration. Based on the determined operating parameters, the MIP-carousel experiments were carried out. It was confirmed from the experimental results that the proposed MIP-carousel process was markedly effective in separating Cu(2+) from Mn(2+) and Co(2+) in a continuous mode with high purity and a relatively small loss. Thus, the MIP carousel process developed in this study deserves sufficient attention in materials processing industries or metal-related industries, where the selective separation of heavy metal ions with the same charge has been a major concern. PMID- 20932528 TI - Novel calcium-alginate capsules with aqueous core and thermo-responsive membrane. AB - Novel calcium-alginate (Ca-alginate) capsules with aqueous core and thermo responsive membrane are successfully prepared by introducing a co-extrusion minifluidic approach, and the thermo-responsive gating characteristics of Ca alginate capsule membranes embedded with poly(N-isopropylacrylamide) (PNIPAM) microspheres are investigated systematically. The experimental results show that the prepared Ca-alginate capsules are highly monodisperse, and the average diameter and membrane thickness of Ca-alginate capsules are about 2.96 mm and 0.11 mm respectively. The Ca-alginate capsule membranes exhibit desired thermo responsive gating property. With increasing the content of PNIPAM microspheres embedded in the Ca-alginate capsule membranes, the thermo-responsive gating coefficient of the capsule membranes increases simply. When solute molecules diffuse through the capsule membrane, the thermo-responsive gating coefficient is significantly affected by the molecular weight of solute molecules. PMID- 20932529 TI - Synthesis of tailored core-brush polymer particles via a living radical polymerization and architecture of colloidal crystals. AB - Narrow disperse core-brush polymer nanoparticles (BP) were synthesized by grafting from photo-induced atom transfer radical polymerization (ATRP) of 2 hydroxyethyl methacrylate (HEMA) from N,N-diethyldithiocarbamate (DC) groups of core-shell particle surface. We constructed colloidal crystals of these particles by depositing on glass substrate. By variation of the particle size, the brilliant color could be varied throughout the visible spectrum. We locked also permanently such colloidal crystals by cross-linking of poly(2-hydroxyethyl methacrylate) (PHEMA) brush phases with glutaraldehyde. The peak wavelength (lambda(max)) in the reflection spectra agreed well with the bandgap position for light incident on the (1 1 1) face of face-centered cubic (fcc) lattice according to Bragg's law. PMID- 20932530 TI - Dendritic cell internalization of foam-structured fluorescent mesoporous silica nanoparticles. AB - In this paper, foam-structured fluorescent mesoporous silica nanoparticles (FMSNs) are produced in a sol-gel method with the introduction of a phosphonate functional group. It is found that the phosphonate functionalized FMSNs with the foam structure minimizes the aggregation of FMSNs in solution. The average particle size of the FMSNs without and with phosphonate functionalization is 46.3 +/- 5 nm and 60.5 +/- 8 nm in diameter, respectively. The latter one exhibits higher fluorophore loading capacity (~67 +/- 2.5%). The excitation wavelength (lambda(ex)) of FMSNs is observed at 526 nm, approximate 12 nm larger in the Stoke-shift compared to the free organic dye at 494/514 nm. Furthermore, the photostability of the hydrophobic fluorophore is greatly improved by the FMSNs with the foam structure. In addition, the dose-dependent nature of FMSN uptake is assessed for the immune cells, the bone marrow-derived dendritic immune cells (BMDCs). Our results indicate that approximately 42% of BMDCs are able to take up foam-structured FMSNs (>5 MUg/ml) without decreasing the viability of BMDCs. Thus, the phosphonate functionalized FMSNs with the foam structure are suitable to be used for many biomedical applications, especially in cell tracking. PMID- 20932531 TI - An experimental test of the fractal model for drainage of foam films. AB - Drainage of foam films with different radii (50-150 MUm), stabilized by hexathylene glycol dodecyl ether C(12)E(6) and in a presence of 0.024 M NaCl, were analyzed in the light of a recent dynamic fractal classification of [1]. The latter accounts for the effect of film surface corrugations developed during the film drainage. For simplicity, the film surface mobility is neglected since the presence of surfactants reduces dramatically the film surface velocity. The magnitude of surface non-homogeneities, caused by the film drainage, is accounted via a dynamic fractal dimension parameter alpha being spanned between zero and two. Depending on the alpha-value the film drains by different kinetic laws. For example, if the thin film is planar alpha=2 and it drains according to the Reynolds law; if alpha=1 the film contains an axisymmetric dimple causing faster drainage; if alpha=1/2 the film exhibits number of asymmetric dimples and the film drains even faster; finally if alpha=0 the film contains spatially uncorrelated domains causing the fastest possible drainage. The present analysis of experimental data suggests that the parameter alpha is inversely proportional to the film radius R and it is independent of the type and concentration of surfactants. A semi-empirical model for alpha is proposed, thus completing the generic dynamic fractal classification. PMID- 20932532 TI - Facile fabrication of mechanochromic-responsive colloidal crystal films. AB - This paper presents a simple approach to fabricate a reversible mechanochromic responsive crystal film based on the room-temperature film-formation of monodisperse polymer latex by the aid of nanosilica particles. In this approach, when the "soft" colloidal polymer spheres were blended with colloidal silica particles and then cast on a substrate, followed by drying at room temperature for self-assembly, an elastic crystal film was directly obtained. This crystal film has not only reversible and repeatable mechanochromic-responsive property, but also tunable color and peak position covering almost entire visible spectral region, depending upon the sizes of polymer spheres and strains. This optical response is attributed to the variation of lattice spacing during deformation. PMID- 20932533 TI - Application of rod-shaped cellulose nanocrystals in polyacrylamide hydrogels. AB - Rod-shaped cellulose nanocrystals (CNCs) were manufactured and used to reinforce polyacrylamide (PAM) hydrogels through in situ free-radical polymerization. The gelation process of the nanocomposite hydrogels was monitored on a rheometer using oscillatory shear. The chemical structure, morphology, swelling property, and compression strength of the formed gels were investigated. A possible mechanism for forming hydrogels was proposed. The results showed that CNCs accelerated the formation of hydrogels and increased the effective crosslink density of hydrogels. Thus CNCs were not only a reinforcing agent for hydrogel, but also acted as a multifunctional cross-linker for gelation. The shear storage modulus, compression strength and elastic modulus of the nanocomposite hydrogels were significantly improved because of good dispersion of CNCs in PAM as well as enhanced interfacial interaction between these two components. Among the CNC contents used, a loading of 6.7 w/w% led to the maximum mechanical properties for nanocomposite hydrogels. PMID- 20932534 TI - Effect of phosphate on phenanthrene sorption in soils. AB - Phosphate is ubiquitous in the environment. However, its impact on sorption of hydrophobic organic compounds in soils has received little attention. Some effects of phosphate on phenanthrene sorption were investigated in this study using two Chinese soils with contrasting properties. The presence of phosphate significantly decreased the capacity and increased the nonlinearity of phenanthrene sorption in the soils, and this sorption-inhibiting effect was more significant at high phosphate concentration. The influence of phosphate on phenanthrene sorption in the soils was governed by the release of dissolved organic carbon (DOC), particularly higher-molecular-weight and highly aromatic DOC, which tended to be enhanced in the presence of phosphate (p<0.01) as evidenced by size exclusion chromatography and specific UV absorbance analysis. Atomic force microscopy and zeta potential analysis reveal that the ringed microaggregates of DOC were disrupted into larger condensed microaggregates and the solid interfaces tended to be more hydrophilic in the presence of phosphate which also inhibited the accumulation of phenanthrene in the soils. This study for the first time points to an important role of phosphate in the sorption of phenanthrene in soils and provides substantial evidence for the mechanisms involved using a combination of microscopic and chromatographic techniques. PMID- 20932535 TI - Influence of the ionic strength and solid/solution ratio on Ca(II)-for-Na+ exchange on montmorillonite. Part 1: Chemical measurements, thermodynamic modeling and potential implications for trace elements geochemistry. AB - Na/Ca ion-exchange isotherms were performed on a Na-saturated montmorillonite for different constant normalities of the aqueous chloride solution and at two solid/solution ratios. The experimental data suggest that the affinity of Na(+) for the solid increases with total normality and m/V ratio and that a significant proportion of CaCl(+) is also sorbed. A thermodynamic modeling procedure with one sorption site and three sorbed cations (Na(+), Ca(2+) and CaCl(+)) was applied to interpret the data. We show that by accounting for the activities of aqueous species, the experimental data obtained at different total normalities for a given solid/solution ratio can be fitted using a unique set of selectivity coefficient values. However, when the m/V ratio is decreased from 25 to 2.5 g/L, an increase in the log Kc(Na(+)/Ca(2+)) of up to 0.4 +/- 0.05 was required to interpret the data with a constant log Kc(Na(+)/CaCl(+)) value. The same behavior concerning the increase in the log Kc(Na(+)/Ca(2+)) with a m/V ratio decrease was observed when using a multi-site model taking into account the specific sorption of H(+). The results clearly indicate that the Na(+)/Ca(2+) selectivity coefficients strongly depend on the solid/solution ratio but are independent of the exchanger composition and the total normality of the solution. Such findings provide possible pitfalls when using selectivity coefficients obtained in diluted suspension to assess the sorption in compacted clayrocks and allow a better prediction of the sorption of trace elements in competition with major cations. PMID- 20932536 TI - Surface modification of glass plates and silica particles by phospholipid adsorption. AB - The effect of phospholipid adsorption on the hydrophobicity of glass plates and on the surface charge of silica particles using contact angle and electrophoretic mobility measurements, respectively, was investigated. Deposition of successive statistical monolayers of dipalmitoylphosphatidylcholine (DPPC) on the glass surface showed zig-zag changes of water contact angle, especially on the first few monolayers. This behavior is qualitatively coherent with the oscillations observed in zeta potential values for increasing DPPC concentration. The results indicate that the phospholipid is adsorbed vertically on the plates, exposing alternately its polar head and non-polar hydrocarbon chains in successive layers. On the other hand, experiments conducted on glass plates prior hydrophobized by contact with n-tetradecane suggest that DPPC molecules may to some extent dissolve in the relatively thick n-alkane film and then expose their polar heads over the film surface thus producing polar electron-donor interactions. The effect of both DPPC and dioleoylphosphatidylcholine (DOPC) on the electrokinetic potential of silica spheres confirms adsorption of the phospholipids, leading to a decrease in the (originally negative) zeta potential of silica and even reversal of its sign to positive at acidic pH. Hydrophobic interactions between phospholipid molecules in the medium and those already adsorbed may explain the overcharging. The adsorption of neutral phospholipids may reduce the zeta potential as a consequence of the shift of the electrokinetic or slip plane. The effect is more evident in the case of DOPC, suggesting a less efficient packing of this phospholipid because of the presence of double bonds in its molecule, which in fact is well known. PMID- 20932537 TI - Absorption and transport properties of ultra-fine cellulose webs. AB - Characterization of transport and absorption properties of nanofiber webs is a challenge, because in many cases the material is soft and cannot withstand the stresses exerted by the standard instruments. In this paper, we report on development of a new technique for materials characterization. We propose to conduct wicking and permeability experiments for full characterization of the nanowebs. As an example, we used electrospun cellulose acetate nanowebs. The wicking experiments showed very good reproducibility, demonstrating the square root-of-time dependence of wetting front position vs time. The prefactor depends on a product of capillary pressure and materials permeability. We developed a technique to independently measure the permeability of small samples of nanowebs. Wicking and permeability data allow one to estimate the pore size; SEM micrographs confirmed the obtained estimates of pore radius. In general, the proposed method allows one to characterize the transport and absorption parameters of the nanofibrous materials for which the standard procedures are inapplicable. PMID- 20932538 TI - Thermoresponsive unimolecular micelles with a hydrophobic dendritic core and a double hydrophilic block copolymer shell. AB - Biocompatible stimuli-responsive unimolecular polymeric micelles have attracted much interest due to their unique structures and potential applications in biomedical fields such as drug delivery and tissue engineering. Here, we report the preparation of dendritic unimolecular polymeric micelles with temperature sensitive shells via reversible addition-fragmentation transfer (RAFT) technique. A multi-arm star amphiphilic copolymer (H40-PDEA) with a hydrophobic hyperbranched polyester (Boltorn H40) as the core and the grafted poly(N,N diethylacrylamide) (PDEA) as the shell was prepared using H40 based macroRAFT agent. And a dendritic unimolecular polymer (H40-PDEA-PDMA) with a double hydrophilic block copolymer (DHBC) [PDEA-b-poly(2-(dimethylamino)ethyl methacrylate) (PDEA-b-PDMA)] as the dual thermoresponsive shells was synthesized by H40-PDEA based macroRAFT agent. Both H40-PDEA and H40-PDEA-PDMA have a reversible phase transition behavior in aqueous solution. In particular, the unimolecular polymeric micelles H40-PDEA-PDMA with double thermoresponsive shells exhibit a two-stage phase transition behavior. Laser light scattering (LLS), UV vis transmittance, excimer fluorescence measurements, and micro-differential scanning calorimetry (micro-DSC) were used in combination to probe the conformational changes of chains located at the inner layer and outer corona during the phase transition process. PMID- 20932539 TI - Oxidative stress in children affected by epileptic encephalopathies. AB - Oxidative stress may lead to abnormal peroxidation of membrane lipids, oxidation of sulfhydryl groups and disruption of nucleic acids. Experimental and clinical studies suggested that free radicals may be involved in the pathogenesis of epilepsy. Three groups of patients were considered in the study. Group 1 (N=34) included patients affected by epileptic encephalopathy; Group 2 (N=31) included those affected by idiopathic epilepsy syndromes and under valproic acid (VPA) monotherapy, and Group 3 (N=22) represented by healthy controls. All patients and healthy children underwent blood withdrawals to evaluate redox status by measuring levels of F2-isoprostanes (F2-iso), advanced oxidative protein products (AOPP), non-protein binding iron (NPBI), thiols (-SH groups), and total hydroperoxides (TH). In comparison to the controls, Group 1 patients showed significantly higher plasma levels of F2-iso, AOPP, and TH. By contrast, no differences there were in the plasma NPBI concentrations. Again, no statistical differences there were in the plasma levels of the oxidative stress markers between patients from Group 2 and normal subjects. Our study showed that patients with epileptic encephalopathy have increased levels of oxidative stress markers. By contrast, normal redox status was observed in patients with idiopathic epilepsy syndromes under long-term VPA monotherapy. PMID- 20932540 TI - Comparative analysis of the early transcriptome of Brucella abortus--infected monocyte-derived macrophages from cattle naturally resistant or susceptible to brucellosis. AB - Brucellosis is a worldwide zoonotic infectious disease that has a significant economic impact on animal production and human public health. We characterized the gene expression profile of B. abortus-infected monocyte-derived macrophages (MDMs) from naive cattle naturally resistant (R) or susceptible (S) to brucellosis using a cDNA microarray technology. Our data indicate that (1) B. abortus induced a slightly increased genome activation in R MDMs and a down regulated transcriptome in S MDMs, during the onset of infection, (2) R MDMs had the ability to mount a type 1 immune response against B. abortus infection which was impaired in S cells, and (3) the host cell activity was not altered after 12 h post-B. abortus infection in R MDMs while the cell cycle was largely arrested in infected S MDMs at 12 h p.i. These results contribute to an improved understanding of how host responses may be manipulated to prevent infection by brucellae. PMID- 20932541 TI - Serum acute phase proteins as biomarkers of pleuritis and cranio-ventral pulmonary consolidation in slaughter-aged pigs. AB - The purpose of this study was to investigate the relationship between the existence of lung lesions in pigs at slaughter and the concentration of the serum acute phase proteins (APP), haptoglobin (Hp), pig-major acute protein (Pig-MAP) and C-reactive protein (CRP). A total of 24 pig farms were selected out of a larger farm database previously screened to study risk factors associated with pleuritis and cranio-ventral pulmonary consolidation (CVPC) lesions at slaughter aged pigs in Spain. The farms were classified as "pleuritis negative (P-) or positive (P+)" and as "CVPC negative (M-) or positive (M+)" and divided into four groups according to a 2X2 factorial design (P-M-, P-M+, P+M-, P+M+). Also at slaughter, blood from 20 randomly selected pigs from each farm was collected. Obtained serum samples were used to measure acute phase proteins. All APP concentrations were significantly higher for M+ farms than for M- ones. However, only Hp and Pig-MAP showed significantly higher concentrations for P+ farms than for P- ones. Pig-MAP was the most sensitive biomarker since it was able to clearly discriminate between P-/P+ and M-/M+ groups (p<0.001 in both cases). Hp was an excellent marker for pleuritis and good for CVPC lesions. CRP was able to discriminate for CVPC lesions but not for pleuritis. The present results indicate that Pig-MAP and, possibly Hp, may be used as potential markers to characterise and discriminate respiratory lesions in swine herds at slaughter. PMID- 20932542 TI - Inflammation, insulin resistance, lipid disturbances, anthropometrics, and metabolic syndrome in morbidly obese patients: a case control study comparing laparoscopic Roux-en-Y gastric bypass and laparoscopic sleeve gastrectomy. AB - BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) is a common bariatric procedure that has several advantages over Roux-en-Y gastric bypass, but data on the effectiveness of this procedure on metabolic syndrome have rarely been reported. METHODS: This case control study compared the incidence of low grade systemic inflammation, insulin resistance, anthropometrics, lipid disturbances, and metabolic syndrome in 12 patients undergoing laparoscopic Roux-en-Y gastric bypass (LRYGBP) and 10 patients undergoing LSG, matched for age, sex, body mass index (BMI), and HbA1c. RESULTS: At 6 months after surgery, there was no significant difference in any of the parameters investigated. Metabolic syndrome improved in all five patients undergoing LRYGBP and in 4 out of 6 patients undergoing LSG (ns). At 1 year after surgery, patients in the LRYGBP group had a significantly lower BMI (32.6 +/- 5.1 vs 36.5 +/- 2.5 kg/m(2); P < .05) and percent of excess BMI lost (70.1 +/- 20.5 vs 55.3 +/- 12.8; P < .05), and had significantly lower plasma levels of C-reactive protein (2.3 +/- 1.5 vs 5.1 +/- 4.6 mg/L; P < .05), total cholesterol (4.7 +/- 1 vs 5.6 +/- 0.3 mmol/L; P < .001) and LDL cholesterol (2.7 +/- 0.7 vs 3.7 +/- 0.3 mmol/L; P < .001). Remission of metabolic syndrome was significantly less common after LSG at 1 year than LRYGBP (3 vs 0 patients; P < .05). CONCLUSION: In this limited study patients undergoing LRYGBP demonstrated significantly lower BMIs, improved lipid profiles, decreased systemic low-grade inflammation and less metabolic syndrome than those with LSG at 1-year follow-up. PMID- 20932543 TI - Technical, economic and environmental assessment of sludge treatment wetlands. AB - Sludge treatment wetlands (STW) emerge as a promising sustainable technology with low energy requirements and operational costs. In this study, technical, economic and environmental aspects of STW are investigated and compared with other alternatives for sludge management in small communities (<2000 population equivalent). The performance of full-scale STW was characterised during 2 years. Sludge dewatering increased total solids (TS) concentration by 25%, while sludge biodegradation lead to volatile solids around 45% TS and DRI(24h) between 1.1 and 1.4 gO(2)/kgTS h, suggesting a partial stabilisation of biosolids. In the economic and environmental assessment, four scenarios were considered for comparison: 1) STW with direct land application of biosolids, 2) STW with compost post-treatment, 3) centrifuge with compost post-treatment and 4) sludge transport to an intensive wastewater treatment plant. According to the results, STW with direct land application is the most cost-effective scenario, which is also characterised by the lowest environmental impact. The life cycle assessment highlights that global warming is a significant impact category in all scenarios, which is attributed to fossil fuel and electricity consumption; while greenhouse gas emissions from STW are insignificant. As a conclusion, STW are the most appropriate alternative for decentralised sludge management in small communities. PMID- 20932545 TI - The effect of UV/H2O2 treatment on biofilm formation potential. AB - Greater Cincinnati Water Works (GCWW) evaluated the efficacy of ultraviolet light/hydrogen peroxide advanced oxidation (UV/H(2)O(2)) for reducing trace organic contaminants in natural water with varying water qualities. A year-long UV/H(2)O(2) pilot study was conducted to examine a variety of seasonal and granular activated carbon (GAC) breakthrough conditions. The UV pilot-scale reactors were set to consistently achieve 80% atrazine degradation, allowing comparison of low pressure (LP) and medium pressure (MP) lamp technologies for by product formation. Because hydroxyl radicals react non-selectively with organic compounds, unintended by-product formation occurred. Total assimilable organic carbon (AOC) concentration increased through the reactors from 14 to 33% on average, depending on water quality. Natural organic matter (NOM) contains the precursors for AOC production, so when post-GAC water (versus conventionally treated water) served as reactor influent, less AOC was produced. No appreciable difference in AOC concentration was observed between LP and MP UV reactors. The Spirillum strain NOX fraction of the AOC increased from 50 to 65% on average, depending on the quality of the water. The increase in this fraction of AOC occurred because oxidation of NOM yielded smaller more assimilable organic compounds such as organic acids that are necessary for NOX growth. The Pseudomonas fluorescens strain P17 AOC concentration increased only when conventionally treated plant water was used as pilot influent. This organism thrives in waters of differing organic energy sources, but does not thrive well in carboxylic acids alone. The CONV water had more overall TOC that could contribute to higher P17 AOC counts. Biofilm coupon studies indicated that biofilms with greater heterotrophic plate counts were observed in the granular activated carbon (GAC) effluent streams receiving UV/H(2)O(2) pre-treatment. Biofilm coupon studies additionally indicated that the effluent stream of the GAC column proceeded by the MP reactor exhibited more viable biofilm than the other GAC effluent streams based on an ATP-bioluminescence method. The increased viability of the biofilm produced by the MP UV reactor is likely a result of the multiple UV wavelengths and higher energy input characteristic of this technology. PMID- 20932546 TI - Effects of aeration patterns on the flow field in wastewater aeration tanks. AB - Due to the high energy input of aeration, the spatial distribution of air diffusers largely determines the flow field in aeration tanks. This has consequences on the efficiency of the aeration system, the performance of the aeration tank and on tank operation and control. This paper deals with these effects applying both Computational Fluid Dynamics (CFD) enhanced with a biokinetic model and full scale validation using velocity and reactive tracer measurements with high temporal and spatial resolution. It is shown that small changes in the diffuser arrangement drastically change the overall flow field. Using different aeration patterns in the same tank may lead to large scale instabilities in the flow field that lower plant performance and produce strong variations in concentration signals impeding their use for plant control. CFD is a valuable tool to analyze the interaction of flow field and aeration and their effects on plant performance and operation. But, in complex flow situations experimental validation is needed and strongly suggested. PMID- 20932547 TI - Assessment of dietary exposure to PCDD/F and dioxin-like PCB in infant formulae available on the EU market. AB - In infant period, human milk and infant formulae are the major sources of exposure to dioxins (polychlorinated dibenzo-p-dioxins (PCDD) and dibenzofurans (PCDFs) and dioxin-like polychlorinated biphenyls (PCB). Since in many parts of Europe the mothers are increasingly reluctant to breastfeed their babies, the main objective of the present study is to assess the level of exposure of non breast-fed infants during their early development. Consequently, the concentration levels of PCDD/F and dioxin-like PCB were determined in industrial infant formulae including "starting" (aged 0-4months) and "follow-on" (after 4months) products of milk formula, soy formula and hypoallergenic infant formula, available on the EU market. Furthermore, dietary exposure to dioxin of exclusively formula-fed infants was assessed at each month from 0 to 9months. The results suggest that dietary exposure to dioxins via formulae is higher when consuming "starting" than "follow-on" infant formulae on a body-weight basis. Estimated dietary exposure after 4months of age was always below the lowest range of the Tolerable Daily Intake (TDI) of 1pg WHO-TEQkg(-1)bwd(-1) and Provisional Tolerable Monthly Intake (PTMI) of 70pg WHO-TEQkg(-1)bwmonth(-1). The highest estimated cumulative dietary exposure to PCDD/F and dioxin-like PCB was obtained considering infants of 0-1months fed with the "starting" hypoallergenic infant formula (2.8pg WHO-TEQkg(-1)bwd(-1) and 84pg WHO-TQkg(-1)bwmonth(-1)). However, these elevated levels are much lower than those observed in some studies in breast-fed infants. The study can be used for further risk assessments in regard to infant exposure. PMID- 20932548 TI - Occurrence of priority hazardous PAHs in water, suspended particulate matter, sediment and common eels (Anguilla anguilla) in the urban stretch of the River Tiber (Italy). AB - This study investigated the occurrence of polycyclic aromatic hydrocarbons (PAHs) in water, suspended particulate matter (SPM), bed sediment and common eels (Anguilla anguilla) in the urban stretch of the River Tiber (Italy). The selected PAHs, fluoranthene, benzo(b)fluoranthene, benzo(k)fluoranthene, benzo(a)pyrene, benzo(g,h,i)perylene, indeno(1,2,3-cd)pyrene, belong to the EC priority list of dangerous substances. SPM was found to be the most polluted compartment, with values ranging from 1663.1 to 15472.9 ngg(-1) (Sigma(6)PAHs), followed by sediment samples, from 157.8 to 271.6 ngg(-1) and by aqueous samples, from 23.9 to 72.0 ngL(-1). The distribution coefficient (K(d)) showed a good correlation with particle organic carbon (OC) content, while K(oc) values experimentally measured for sediment/SPM deviated from those predicted by K(ow), implying that for very hydrophobic compounds, K(ow) alone may not be an appropriate descriptor of all the thermodynamic forces involved in their sorption to aquatic particles. Some selected PAH ratios indicated that PAHs in the River Tiber come mainly from pyrolitic sources and vehicular traffic. Concentrations of individual PAHs in muscles of common eels varied from 0.8 to 7.0 ngg(-1) wet wt. and the calculated toxicity equivalent concentration (TEQ, 1.8 ngg(-1) wet wt.) of total PAHs fell below the recommended screening value (SV) in US EPA guidelines, suggesting no concern for human consumption. PMID- 20932549 TI - Extractability and mobility of mercury from agricultural soils surrounding industrial and mining contaminated areas. AB - This study focussed on a comparison of the extractability of mercury in soils with two different contamination sources (a chlor-alkali plant and mining activities) and on the evaluation of the influence of specific soil properties on the behaviour of the contaminant. The method applied here did not target the identification of individual species, but instead provided information concerning the mobility of mercury species in soil. Mercury fractions were classified as mobile, semi-mobile and non-mobile. The fractionation study revealed that in all samples mercury was mainly present in the semi-mobile phase (between 63% and 97%). The highest mercury mobility (2.7 mg kg(-1)) was found in soils from the industrial area. Mining soils exhibited higher percentage of non-mobile mercury, up to 35%, due to their elevated sulfur content. Results of factor analysis indicate that the presence of mercury in the mobile phase could be related to manganese and aluminium soil contents. A positive relation between mercury in the semi-mobile fraction and the aluminium content was also observed. By contrary, organic matter and sulfur contents contributed to mercury retention in the soil matrix reducing the mobility of the metal. Despite known limitations of sequential extraction procedures, the methodology applied in this study for the fractionation of mercury in contaminated soil samples provided relevant information on mercury's relative mobility. PMID- 20932550 TI - Occurrence and fate of the human pharmaceutical metabolite ritalinic acid in the aquatic system. AB - To investigate the occurrence and fate of ritalinic acid - the main human metabolite of the psychostimulant drug methylphenidate - in the aquatic environment, a HPLC-electrospray-MS/MS method for the quantification of ritalinic acid in wastewater, surface water and bank filtrate was developed. Carbamazepine known as very stable in the aquatic environment was analyzed as anthropogenic marker in parallel. Furthermore, the removal of ritalinic acid was studied in a sewage treatment plant using an activated sludge system during a field study and in lab-scale plants. In good agreement between lab-scale and field studies a low removal rate of 13% and 23%, respectively, was determined. As a consequence, the concentration of ritalinic acid in the wastewater effluents were in the range of <50-170 ngL(-1) which corresponds to a mean specific load per capita of 17.7 MUgd(-1). Ritalinic acid has further been detected in German rivers at concentrations of 4-23 ngL(-1) and in bank filtrate samples in 100-850 m distance from the river up to 5 ngL(-1) demonstrating the widespread occurrence of this stable metabolite in the aquatic environment. A comparison to available sales data shows that a significant amount of methylphenidate applied can be found in waters as ritalinic acid. PMID- 20932551 TI - Enhancement by anthraquinone-2-sulphonate of the photonitration of phenol by nitrite: implication for the photoproduction of nitrogen dioxide by coloured dissolved organic matter in surface waters. AB - Anthraquinone-2-sulphonate (AQ2S) under UVA irradiation is able to oxidise nitrite to (.)NO(2) and to induce the nitration of phenol. The process involves the very fast reactions of the excited triplet state (3)AQ2S(*) and its 520-nm absorbing exciplex with water, at different time scales (ns and MUs, respectively). Quinones are ubiquitous components of coloured dissolved organic matter (CDOM) in surface waters and AQ2S was adopted here as a proxy of CDOM. Using a recently developed model of surface-water photochemistry, we found that the oxidation of nitrite to (.)NO(2) by (3)CDOM(*) could be an important (.)NO(2) source in water bodies with high [NO(2)(-)] to [NO(3)(-)] ratio, for elevated values of column depth and NPOC. PMID- 20932552 TI - Evaluation of the noncovalent binding interactions between polycyclic aromatic hydrocarbon metabolites and human p53 cDNA. AB - The binding of reactive polycyclic aromatic hydrocarbon (PAH) metabolites, formed enzymatically, to DNA is a crucial step in PAH carcinogenesis in vivo. We investigated the noncovalent binding interactions between 11 PAH metabolites and human p53 complementary DNA (p53 cDNA) using the fluorescence displacement method and molecular docking analysis. All of the examined metabolites predominantly interacted with p53 cDNA by intercalation instead of groove binding. The dissociation constants ranged from 0.02 to 12.34MUM. Of the metabolites tested, 1 hydroxypyrene and 3-hydroxybenzo[a]pyrene showed the strongest binding affinities to DNA, while 2-naphthol was the weakest DNA intercalator. The intercalation of the metabolites was stabilized by stacking the PAH phenyl rings with the DNA base pairs and the formation of hydrogen bonds between the oxide or hydroxyl groups on the metabolites, and DNA bases or backbones. The binding of the metabolites to DNA showed some sequence selectivity. The binding affinities and hydrogen bonds for 3-hydroxybenzo[a]pyrene, benzo[a]pyrene-4,5-dihydroepoxide (BPE) and benzo[a]pyrene-r-7,t-8-dihydrodiol-t-9,10-epoxide (BPDE) differed. It seems that the functional groups on the periphery of the PAH aromatic ring play crucial roles in regulating its binding affinity with DNA. Although it was difficult to determine the correlation between DNA noncovalent binding affinity and carcinogenicity for some of the PAH metabolites, the present study improved our understanding of the formation of PAH metabolite-DNA adducts. PMID- 20932553 TI - Osteoprotegerin is higher in peripheral arterial disease regardless of glycaemic status. AB - INTRODUCTION: Peripheral arterial disease (PAD) and type 2 diabetes mellitus (DM) are both associated with excessive vascular calcification and elevated levels of inflammatory markers IL-6 and hsCRP. The recently identified Osteoprotegerin(OPG)/RANKL/TRAIL pathway has been implicated in vascular calcification, but data on levels in PAD and effect of co-existent DM are lacking. MATERIALS AND METHODS: 4 groups of patients were recruited - 26 with PAD and DM, 35 with DM alone, 22 with PAD alone, and 21 healthy individuals. Serum OPG, RANKL, TRAIL, hsCRP and IL-6 were measured using commercial ELISA assays. Presence and severity of PAD was defined using ankle brachial index (ABI). RESULTS: Serum OPG (7.4+/-0.3 vs.5.8+/-0.2 pmol/l, p<0.0001), TRAIL (95.5+/-5.2 ng/ml vs. 76.2+/-4.4 ng/ml, p=0.006), hsCRP (2.6+/-0.3 vs. 1.8+/-0.3 mg/l, p=0.048), and IL-6 (4.1+/-0.4 vs. 2.9+/-0.4 pg/ml, p=0.06) were higher in patients with PAD. There was no difference in RANKL. Only OPG was significantly higher in PAD and DM (7.2+/-0.3 pmol/l) and PAD alone (7.7+/-0.4 pmol/l) compared to DM only (5.8+/-0.3 pmol/l) and healthy controls (5.6+/-0.4 pmol/l), p<0.01, but OPG was no higher in those with DM plus PAD versus those with PAD alone (p<0.3). Only OPG was associated with PAD severity, correlating negatively with ABI (r=-0.26, p=0.03), independent of age, gender, glycaemic status, hsCRP and IL 6. CONCLUSIONS: PAD is associated with higher serum OPG, regardless of the co existence of DM. This finding, in addition to its correlation with severity of PAD, suggests that OPG may be a novel marker for the presence and severity of PAD, possibly by reflecting the degree of underlying vascular calcification. PMID- 20932554 TI - Involvement of heparanase in vaginal and cesarean section deliveries. AB - BACKGROUND: Heparanase is an endo-beta-D-glucuronidase dominantly involved in cell invasion, tumor angiogenesis and metastasis. Recently, we demonstrated increased levels of heparanase, tissue factor pathway inhibitor (TFPI)-2 and vascular endothelial growth factor (VEGF)-A in early miscarriages (Nadir et al., Thromb Res, 2010). Herein, we investigated the role of heparanase in third trimester placentas, in correlation to tissue factor (TF), TFPI, TFPI-2, and VEGF A. METHODS: Twenty five third-trimester placenta samples (weeks 36-41) were studied applying real time RTPCR and immunostaining. Ten cases were placentas of elective cesarean sections, 8 cases were of normal vaginal deliveries and 7 samples were placentas of intra-uterine growth restriction (IUGR) fetuses. Skin and lung tissues of heparanase over-expressing mice and heparanase knock-out mice were subjected to immunostaining. RESULTS: Sections obtained from vaginal and IUGR placentas revealed 2 folds increased levels of heparanase, TFPI-2 and VEGF-A compared to placentas from elective cesarean sections in maternal decidua as well as in fetal placenta elements. Interestingly, abundance of TFPI staining in the intra-villous blood was observed in placentas of vaginal and IUGR deliveries. Heparanase effect on TFPI release to the blood was supported by immunostaining of heparanase over-expressing and heparanase knock-out mice tissues. CONCLUSIONS: In regard to our previous data on early pregnancy losses, the present data strengthen the understanding that in placental vascular complications levels of heparanase, TFPI-2 and VEGF-A increase. In the process of delivery, heparanase may have a regulatory role on TFPI release to fetal circulation. PMID- 20932556 TI - Modulation of adrenergic responses of human vas deferens by K+ channel inhibitors. AB - OBJECTIVES: The present study was designed to evaluate the role of K(+) channels in the adrenergic responses of human vas deferens as well as the intervention of dihydropyridine-sensitive Ca(2+) channels on modulation of adrenergic responses by K(+) channel inhibitors. METHODS: Ring segments of the epididymal part of the vas deferens were taken from 32 elective vasectomies and mounted in organ baths for isometric recording of tension. We then studied the effects of K(+) channel blockers on neurogenic and norepinephrine-induced contractile responses. RESULTS: Addition of tetraethylammonium (TEA, 10(-3) M), a nonspecific K(+) channel blocker, or charybdotoxin (10(-7) M), a nonselective inhibitor of large- and intermediate-conductance Ca(2+)-activated K(+) channel, increased the contractile responses to norepinephrine and electrical field stimulation-induced contractions (P < .01), whereas iberiotoxin (10(-7) M), a selective blocker of large conductance Ca(2+)-activated K(+) channels, apamin (10(-6) M), a blocker of small conductance Ca(2+)-activated K(+) channels, or glibenclamide (10(-5) M), an inhibitor of ATP-sensitive K(+) channels, were without effect. TEA- and charybdotoxin-induced potentiation of contractions elicited by electrical field stimulation and norepinephrine was blocked by L-type Ca(2+) channel blocker nifedipine (10(-6) M). CONCLUSIONS: The results suggest that charybdotoxin sensitive, but iberiotoxin-insensitive, K(+) channels are activated by stimulation with norepinephrine and electrical field stimulation to counteract the adrenergic-induced contractions of human vas deferens. Thus, inhibition of these channels increases significantly the contraction, an effect that appears to be mediated by an increase in Ca(2+) entry through L-type voltage-dependent Ca(2+) channels. PMID- 20932557 TI - Unnecessary imaging for the staging of low-risk prostate cancer is common. AB - OBJECTIVE: To quantify the rate of overuse of preoperative imaging procedures in a referral cohort of low-risk patients. International evidence-based best practice guidelines discourage routine imaging for staging purposes in low-risk patients with newly diagnosed prostate cancer. MATERIAL AND METHODS: An institutional database comprised of all patients undergoing robotic-assisted laparoscopic prostatectomy was queried for "low-risk" patients between May 2005 and January 2010. "Low-risk" was defined by the most inclusive criteria for imaging recommendations: prostate-specific antigen <=10 ng/mL and Gleason score <=6. We defined staging imaging as a bone scan, computed tomography (CT) of the pelvis or endorectal magnetic resonance imaging performed after the diagnosis of prostate cancer and before prostatectomy for the indication of "prostate cancer." Six-hundred seventy-seven patients were identified as having low-risk disease and comprised our study population. RESULTS: Of the 677 patients identified as low risk, 328 (48%) underwent at least one preoperative imaging procedure despite the guideline recommendations. Two-hundred two of 677 (30%) patients were administered at least 2 of the 3 modalities, and 18/677 (3%) patients received all 3 imaging examinations before prostatectomy. Suspicious results from the CT (7/265%, 2.7%) or bone scan (21/241%, 8.7%) resulted in 27 patients undergoing additional radiographic imaging, none of which resulted in suspicious lesions requiring intervention or biopsy. CONCLUSIONS: Despite international evidence based guidelines for the staging of newly diagnosed prostate cancer patients, many urologists continue to refer low-risk patients for unnecessary imaging studies. This may place the patient at increased risk from radiation or contrast exposure and places an unnecessary financial burden on the patient and health care system. PMID- 20932558 TI - Electroejaculatory stimulation for male infertility secondary to spinal cord injury: the Irish experience in National Rehabilitation Hospital. AB - OBJECTIVES: To examine the success rate of electroejaculatory stimulation in patients with acquired spinal injuries in a single Irish institution. The use of electroejaculatory stimulation is of benefit in patients with spinal cord injury who wish to have children. METHODS: A retrospective review of the Hospital In Patient Enquiry scheme database and the patients' medical notes was performed. Any patient who had undergone electroejaculatory stimulation in the past 14 years was included. The quality of semen obtained and the pregnancy rate were assessed in relation to several variables, including patient age and level of spinal injury. RESULTS: From 1994 to 2008, 31 patients (29 patients with acquired spinal injury and 2 patients with a congenital spinal abnormality) had undergone electroejaculatory stimulation as a method of providing semen for assisted conception. Of the 31 patients, 6 had requested cryopreservation of their semen for future use and were therefore excluded from the pregnancy rate analysis. Of the 25 patients who had used the semen, 9 (36%) were successful in achieving pregnancy that resulted in living offspring. The semen analysis results were available for 15 patients. Three patients (one each with contaminated semen, poor semen quality, and an abandoned procedure) required testicular biopsy to extract viable sperm and subsequently achieved pregnancy. Lower spinal lesions (below T10) were associated with lower rates of pregnancy after electroejaculatory stimulation. One patient developed autonomic dysreflexia during the procedure, which was therefore abandoned. CONCLUSIONS: Electroejaculatory stimulation is an effective method of obtaining semen for reproductive purposes and is an option for fertility preservation in patients with spinal cord injury-related anejaculation. PMID- 20932559 TI - Sex-sorted bovine spermatozoa and DNA damage: I. Static features. AB - This study examined the static response of Spermatozoa DNA Fragmentation (SDF) after sex selection in bulls using a MoFlo((r)) SX (Beckman Coulter, Miami FL) spermatozoa sorter to produce three different subpopulations: 1) Spermatozoa bearing X- chromosomes with a purity of 95%, 2) Spermatozoa bearing Y-chromosomes with a purity of 95%, and 3) non-viable spermatozoa. The static response of SDF refers to the baseline values observed for DNA damage when analyzed pre- and post sex-sorting. Results showed that while the baseline level SDF in pre-sorted bull spermatozoa samples ranged from 5.3% to 11% with an average of 7.9% +/- 2.1%, the level of SDF obtained in X- and Y-chromosome sorted samples was much lower (3.1% +/- 1.9%) and statistical differences were obtained after comparing both groups (P < 0.01). Spermatozoa containing a fragmented DNA molecule tend to be accumulated in the non-viable subpopulation. The baseline SDF level in X- and Y chromosome sorted subpopulations is reduced, by 63% on average when compared to the values obtained in the neat semen sample. Different bulls exhibit unique SDF reduction efficiencies via the X- and Y-chromosome sex selection process. PMID- 20932560 TI - Immunohistochemical localization of aromatase during the development and atresia of ovarian follicles in prepubertal horses. AB - Ovarian steroidogenesis from the neonatal to pubertal period in horses is poorly understood. This study was designed to immunolocalize cytochrome P450 aromatase in the ovarian follicles of slaughtered fillies ages approximately (I) 6-9 mo (<10MF); (II) 1 y (1YF); and (III) 1.5 y (1.5YF). The ovaries of adult mares were used as controls. In each age group, immunoreactivity for P450arom was observed in the mural granulosa of nonatretic follicles >5 mm in diameter. Staining intensity was dependent on the size and morphology of the follicle. In nonatretic follicles 5-10 mm in diameter, the reaction was weak and heterogeneous, while most intense staining was observed in preovulatory follicles. In follicles (diameter <20 mm) in the groups <10MF and 1YF, the reaction was less intense than in adult mare follicles of similar size. In each age group, several follicles with early or advanced signs of atresia exhibited a heterogeneous staining pattern, which subsequently disappeared in late atretic follicles. No immunoreactivity was detected in the theca interna, preantral follicle, or stroma cells. Our observations reveal that the mural granulosa of viable follicles in fillies about 6-18 mo old contains aromatase, indicating that the ovary is capable of estrogen synthesis. Immunoreactivity for P450arom was dependent on follicle size and disappeared in atretic follicles. PMID- 20932561 TI - Immunolocalization of the hyaluronan receptor CD44 in the reproductive tract of the mare. AB - Hyaluronan (HA), a glycosaminoglycan, is a major component of the pericellular matrix which envelopes mammalian cells. Binding of hyaluronan to one of its specific receptors, CD44, modulates transduction of intracellular signals which direct a variety of processes, including embryogenesis, wound healing, inflammation, and neoplasia. Since regulation of these processes is critical to equine reproductive success, localization of constitutive CD44 expression was evaluated by immunohistochemical methods in ovarian, oviductal, and uterine tissues from healthy mares. Ovarian stroma contained thecal cells with varying CD44 immunopositivity. Follicular and granulosa cells of some antral and atretic follicles were positive for CD44. In the oviduct, the luminal epithelium was variably positive for CD44, with overall decreasing intensity of immunostaining from the infundibulum to the isthmus. The CD44 molecule was expressed strongly by surface epithelial cells of the uterine endometrium, but was present only rarely among cells of uterine glands. In addition, CD44 was expressed by smooth muscle cells of vascular walls, oviduct, and uterus. Since CD44 is known to modulate cell movement and differentiation, and was present at multiple sites in the reproductive tract of normal mares, we inferred there may be an important role for the HA-CD44 signaling pathway in reproductive function and inflammation. PMID- 20932563 TI - The neural basis of the right visual field advantage in reading: an MEG analysis using virtual electrodes. AB - Right-handed participants respond more quickly and more accurately to written words presented in the right visual field (RVF) than in the left visual field (LVF). Previous attempts to identify the neural basis of the RVF advantage have had limited success. Experiment 1 was a behavioral study of lateralized word naming which established that the words later used in Experiment 2 showed a reliable RVF advantage which persisted over multiple repetitions. In Experiment 2, the same words were interleaved with scrambled words and presented in the LVF and RVF to right-handed participants seated in an MEG scanner. Participants read the real words silently and responded "pattern" covertly to the scrambled words. A beamformer analysis created statistical maps of changes in oscillatory power within the brain. Those whole-brain maps revealed activation of the reading network by both LVF and RVF words. Virtual electrode analyses used the same beamforming method to reconstruct the responses to real and scrambled words in three regions of interest in both hemispheres. The middle occipital gyri showed faster and stronger responses to contralateral than to ipsilateral stimuli, with evidence of asymmetric channeling of information into the left hemisphere. The left mid fusiform gyrus at the site of the 'visual word form area' responded more strongly to RVF than to LVF words. Activity in speech-motor cortex was lateralized to the left hemisphere, and stronger to RVF than LVF words, which is interpreted as representing the proximal cause of the RVF advantage for naming written words. PMID- 20932562 TI - Effects of tasks on BOLD signal responses to sentence contrasts: Review and commentary. AB - Functional neuroimaging studies of syntactic processing have been interpreted as identifying the neural locations of parsing and interpretive operations. However, current behavioral studies of sentence processing indicate that many operations occur simultaneously with parsing and interpretation. In this review, we point to issues that arise in discriminating the effects of these concurrent processes from those of the parser/interpreter in neural measures and to approaches that may help resolve them. PMID- 20932565 TI - Fracture toughness of two dentin adhesives. AB - PURPOSE: Test the hypothesis that a self-etching adhesive is more likely to fail at the dentin-adhesive interface than an etch-and-rinse adhesive. MATERIALS AND METHODS: Forty-eight composite-dentin short rod chevron-notched specimens were prepared. XP Bond and G Bond were used as adhesives. After 7 days in distilled water at 37 degrees C, each specimen was tested (cross-head speed=0.05 mm/min). Fractured surfaces were inspected and characterized as interfacial failures, composite failures or a combination of interfacial and composite failures. The fracture toughness values (K(IC)) of the two adhesives were compared (Student's t test and Weibull statistics). RESULTS: Of the specimens bonded with XP Bond, 50% failed at the dentin-adhesive interface, 42% at both the dentin-adhesive and composite interface and 8% in the composite alone. Of the specimens bonded with G Bond, 41% failed at the dentin-adhesive interface, 53% at both the dentin adhesive and composite interface and 6% in the composite alone. The K(IC) values of the two adhesives differed significantly (p<0.05). XP Bond had a K(IC) of 0.77+/-0.11 MNm(-3/2) (n=17), while G Bond a K(IC) of 0.62+/-0.21 MNm(-3/2) (n=12). CONCLUSION: The high percentage of mixed failures did not support the hypothesis that the dentin-adhesive interface is clearly less resistant to fracture than the adhesive-composite interface. The finding that cracks occurred in 6-8% in the composite suggests that defects within the composite or at the adhesive-composite interface are important variables to consider in adhesion testing. PMID- 20932564 TI - A new method to test the fracture probability of all-ceramic crowns with a dual axis chewing simulator. AB - OBJECTIVES: The purpose of this study was to validate a new laboratory method to test all-ceramic systems with regard to the proportion of failures. METHODS: Sixteen standardized mandibular molar crowns consisting of two different materials (IPS Empress, IPS e.max Press) were adhesively luted on CAD/CAM milled PMMA abutments (first lower molar, circular chamfer). All crowns were loaded applying an eccentric force in a Willytec chewing simulator (steel stylus, O 2.4 mm, 2 mm lateral movement from fossa to cuspal tip) with stepwise increase of the load (3, 5, 9 kg, 100,000 cycles each, 0.8 Hz) and simultaneous thermocycling (5 degrees C/55 degrees C*417 per phase). Another four crowns of each material were subjected to force measurements with a 3D force sensor during dynamic loading of each loading phase using two different lateral movements (from fossa to cusp and vice versa). RESULTS: The cumulative forces for the three directions in space were much higher compared to the static load of the chewing simulator (maximal force at 3 kg 60 N, 5 kg 160 N, 9 kg 240 N). There was no statistically significant difference in the mean or maximal force between the two materials or two different lateral movements. During dynamic loading, no fractures occurred in the molar crowns made of IPS e.max Press, whereas 50% of the IPS Empress crowns showed failures (75% fractures and 25% chippings) (log-rank test p=0.002). Most of the Empress crowns fractured during the third loading phase (9 kg). CONCLUSIONS: The forces that the dead weights exerted during dynamic loading were 2-3 times higher than those during static loading. None of the lithium disilicate ceramic molar crowns fractured, whereas half of the leucite reinforced molar crowns failed during dynamic loading. PMID- 20932566 TI - NHS reform: untried remedies for misdiagnosed problems? PMID- 20932567 TI - Polyplex micelles prepared from omega-cholesteryl PEG-polycation block copolymers for systemic gene delivery. AB - Polyplex micelles formed with plasmid DNA (pDNA) and poly(ethylene glycol) (PEG) block-poly{N-[N-(2-aminoethyl)-2-aminoethyl]aspartamide} [PAsp(DET)] exhibit effective endosomal escaping properties based on di-protonation of diamine side chains with decreasing pH, which improves their transfection efficiency and thus are promising candidates for local in vivo gene transfer. Here, PEG-PAsp(DET) polyplex micelles were further improved as in vivo systemic vectors by introduction of cholesterol (Chole) into the omega-terminus of PEG-PAsp(DET) to obtain PEG-PAsp(DET)-Chole. Introduction of the cholesterol resulted in enhanced association of block copolymers with pDNA, which led to increased stability in proteinous medium and also in the blood stream after systemic injection compared to PEG-PAsp(DET) micelles. The synergistic effect between enhanced polymer association with pDNA and increased micelle stability of PEG-PAsp(DET)-Chole polyplex micelles led to high in vitro gene transfer even at relatively low concentrations, due to efficient cellular uptake and effective endosomal escape of block copolymers and pDNA. Finally, PEG-PAsp(DET)-Chole micelles achieved significant suppression of tumor growth following intravenous injection into mice bearing a subcutaneous pancreatic tumor using therapeutic pDNA encoding an anti angiogenic protein. These results suggest that PEG-PAsp(DET)-Chole micelles can be effective systemic gene vectors for treatment of solid tumors. PMID- 20932569 TI - Biodegradable CpG DNA hydrogels for sustained delivery of doxorubicin and immunostimulatory signals in tumor-bearing mice. AB - Immunostimulatory CpG DNA was self-assembled to form DNA hydrogels for use as a sustained delivery system for both intercalated doxorubicin (DXR) and immunostimulatory CpG motifs for cancer treatment. X-shaped DNA (X-DNA) was designed as a building unit, and underwent ligation to form DNA hydrogels. Two types of X-DNA were constructed using four oligodeoxynucleotides each, one containing six potent CpG motifs (CpG X-DNA) and the other with none (CpG-free X DNA). CpG X-DNA was more effective than its components or the CpG-free counterpart in terms of the production of tumor necrosis factor-alpha from murine macrophage-like RAW264.7 cells, as well as maturation of the murine dendritic DC2.4 cells. The cytotoxic effects of X-DNA, DXR and their complexes were examined in a co-culture system of colon26/Luc cells, a murine adenocarcinoma clone stably expressing firefly luciferase, and RAW264.7 cells. DXR/CpG X-DNA showed the highest ability to inhibit the proliferation of colon26/Luc cells. DXR was slowly released from CpG DNA hydrogels. Injections of DXR/CpG DNA hydrogels into a subcutaneous colon26 tumor effectively inhibited tumor growth. These results show that CpG DNA hydrogels are an effective sustained system for delivery of immunostimulatory signals to TLR9-positive immune cells and DXR to cancer cells. PMID- 20932568 TI - Cell-cell signaling in co-cultures of macrophages and fibroblasts. AB - The foreign body response (FBR) comprises a general, ubiquitous host tissue-based reaction to implanted materials. In vitro cell-based models are frequently employed to study FBR mechanisms involving cell signaling responses to materials. However, these models often study only one cell type, identify only limited signals, and cannot accurately represent the complexity of in vivo inflammatory signaling. To address this issue, a cell co-culture system involving two primary effector cells of the FBR, macrophages and fibroblasts, was employed. Cell-cell signaling systems were monitored between these cell types, including long-term 1) culture of one cell type in conditioned media from the other cell type, 2) non contacting cell co-cultures (paracrine signaling), and 3) contact co-cultures (juxtacrine signaling) of primary- and secondary-derived cells. Cell culture media and cell images were collected on Days 1, 2, 3, 7, 14, and 21 and changes in soluble protein secretion, cellular behavior, and morphology were assessed. Primary- and secondary-derived cells responded uniquely during each signaling scenario and to one another. In general higher in vitro fidelity to FBR-like responses was found in primary cell co-cultures compared to their mono-cultures and all secondary cell cultures. PMID- 20932570 TI - Infarct stabilization and cardiac repair with a VEGF-conjugated, injectable hydrogel. AB - Injectable scaffolds made of biodegradable biomaterials can stabilize a myocardial infarct and promote cardiac repair. Here, we describe the synthesis of a new, temperature-sensitive, aliphatic polyester hydrogel (HG) conjugated with vascular endothelial growth factor (VEGF) and evaluate its effects on cardiac recovery after a myocardial infarction (MI). Seven days after coronary ligation in rats, PBS, HG, or HG mixed or conjugated with VEGF (HG + VEGF or HG-VEGF, respectively) was injected around the infarct (n = 8-11/group). Function was evaluated by echocardiography at multiple time points. Pressure-volume measurements were taken and infarct morphometry and blood vessel density were assessed at 35 days after injection. HG-VEGF provided localized, sustained VEGF function. Compared with outcomes in the PBS group, fractional shortening, ventricular volumes, preload recruitable stroke work, and end-systolic elastance were all preserved (p < 0.05) in the HG and HG + VEGF groups, and further preserved in the HG-VEGF group. Conjugated VEGF also produced the highest blood vessel density (p < 0.05). The infarct thinned and dilated after PBS injection, but was smaller and thicker in hearts treated with HG (p < 0.05). Our temperature sensitive HG attenuated adverse cardiac remodeling and improved ventricular function when injected after an MI. VEGF delivery enhanced these effects when the VEGF was conjugated to the HG. PMID- 20932571 TI - Surface plasmonic gold nanorods for enhanced two-photon microscopic imaging and apoptosis induction of cancer cells. AB - Two-photon microscopy powered by a femtosecond laser is a promising tool for luminescence imaging and localized microsurgery of cancers. However, the high energy required to destruct cells limits its medical applications. In this work, gold nanorods were conjugated with transferrin for efficient targeting, two photon luminescence imaging and enhanced microsurgery of cancer cells. Due to the large two-photon excitation cross section of gold nanorods, gold nanorods are a hundred times more efficient than Fluorescein isothiocyanate (FITC), a common molecular dye, in three-dimensional imaging of cancer cells. The enhanced light absorption and energy conversion by gold nanorods enable treatment of cells with energy fluences two orders of magnitude below that in the absence of gold nanorods. By manipulating the energy fluence, apoptosis of cancer cells has been achieved. At a same power density, the energy fluence for apoptosis induction is less than 20% of that for necrosis. Gold nanorods-enhanced luminescence imaging coupled with apoptosis induction of cancer cells provides a medically safe femtosecond laser-based imaging and microsurgery system for cancer diagnosis and treatment. PMID- 20932572 TI - Recombinant self-assembling peptides as biomaterials for tissue engineering. AB - Synthetic nanostructures based on self-assembling systems that aim to mimic natural extracellular matrix are now being used as substrates in tissue engineering applications. Peptides are excellent starting materials for the self assembly process as they can be readily synthesised both chemically and biologically. P11-4 is an 11 amino acid peptide that undergoes triggered self assembly to form a self-supporting hydrogel. It exists as unimers of random coil conformations in water above pH 7.5 but at low pH adopts an antiparallel beta sheet conformation. It also self-assembles under physiological conditions in a concentration-dependent manner. Here we describe an unimer P11-4 production system and the use of a simple site-directed mutagenesis approach to generate a series of other P11-family peptide expression vectors. We have developed an efficient purification strategy for these peptide biomaterials using a simple procedure involving chemical cleavage with cyanogen bromide then repeated filtration, lyophilisation and wash steps. We report peptide-fusion protein yields of ca. 4.64 g/L and we believe the highest reported recovery of a recombinant self-assembling peptide at 203 mg/L of pure recombinant P11-4. This peptide forms a self-supporting hydrogel under physiological conditions with essentially identical physico-chemical properties to the chemically synthesised peptide. Critically it also displays excellent cytocompatibility when tested with primary human dermal fibroblasts. This study demonstrates that high levels of a series of recombinant self-assembling peptides can be purified using a simple process for applications as scaffolds in tissue engineering. PMID- 20932573 TI - Study of the therapeutic benefit of cationic copolymer administration to vascular endothelium under mechanical stress. AB - Pulmonary edema and the associated increases in vascular permeability continue to represent a significant clinical problem in the intensive care setting, with no current treatment modality other than supportive care and mechanical ventilation. Therapeutic compound(s) capable of attenuating changes in vascular barrier function would represent a significant advance in critical care medicine. We have previously reported the development of HPMA-based copolymers, targeted to endothelial glycocalyx that are able to enhance barrier function. In this work, we report the refinement of copolymer design and extend our physiological studies to demonstrate that the polymers: 1) reduce both shear stress and pressure mediated increase in hydraulic conductivity, 2) reduce nitric oxide production in response to elevated hydrostatic pressure and, 3) reduce the capillary filtration coefficient (K(fc)) in an isolated perfused mouse lung model. These copolymers represent an important tool for use in mechanotransduction research and a novel strategy for developing clinically useful copolymers for the treatment of vascular permeability. PMID- 20932574 TI - Differential redistribution of Ca2+-handling proteins during polarisation of MDCK cells: Effects on Ca2+ signalling. AB - The spatial organisation of the Ca(2+) signal in microdomains enables the regulation of various processes in specific regions of the cell and is essential for the versatility of cell responses to various stimuli. Ca(2+) signals can be independently regulated in the cytoplasm and in the nucleoplasm. Increases in the concentration of Ca(2+) in the nucleus can have specific effects different from those due to increases of Ca(2+) in the cytoplasm. We investigated the influence of cell polarity on the subcellular distribution of molecules responsible for intracellular Ca(2+) homeostasis (Ca(2+) release channels, Ca(2+) pumps and Ca(2+) binding proteins) and its influence on the intracellular Ca(2+) signal in MDCK cells with respect to its cytoplasmic or nucleoplasmic localisation. The intracellular Ca(2+) store was largely reorganised during cell polarisation, with a differential redistribution of IP3R, Ca(2+)-binding proteins and SERCA between the nuclear envelope and the periphery of the cell. This was accompanied by morphological changes in cell shape, which condense the cytoplasm around the nucleus, and in the shape of the nucleus, resulting in invaginations of the nuclear envelope. This facilitates Ca(2+) exchanges between the cytoplasm and the nucleoplasm, and preserves the ability to generate nucleoplasmic Ca(2+) transients in agonist-stimulated polarised MDCK cells. PMID- 20932575 TI - Calcium regulates cyclic compression-induced early changes in chondrocytes during in vitro cartilage tissue formation. AB - A single application of cyclic compression (1kPa, 1Hz, 30min) to bioengineered cartilage results in improved tissue formation through sequential catabolic and anabolic changes mediated via cell shape changes that are regulated by alpha5beta1 integrin and membrane-type metalloprotease (MT1-MMP). To determine if calcium was involved in this process, the role of calcium in regulating cell shape changes, MT1-MMP expression and integrin activity in response to mechanical stimulation was examined. Stimulation-induced changes in cell shape and MT1-MMP expression were abolished by chelation of extracellular calcium, and this effect was reversed by re-introduction of calcium. Spreading was inhibited by blocking stretch-activated channels (with gadolinium), while retraction was prevented by blocking the L-Type voltage-gated channel (with nifedipine); both compounds inhibited MT1-MMP upregulation. Calcium A23187 ionophore restored cellular response further supporting a role for these channels. Calcium regulated the integrin-mediated signalling pathway, which was facilitated through Src kinase. Both calcium- and integrin-mediated pathways converged on ERK-MAPK in response to stimulation. While both integrins and calcium signalling mediate chondrocyte mechanotransduction, calcium appears to play the major regulatory role. Understanding the underlying molecular mechanisms involved in chondrocyte mechanotransduction may lead to the development of improved bioengineered cartilage. PMID- 20932576 TI - Cumulative risk exposure and mental health symptoms among maltreated youth placed in out-of-home care. AB - OBJECTIVE: Maltreated children placed in out-of-home care are at high risk for exhibiting symptoms of psychopathology by virtue of their exposure to numerous risk factors. Research examining cumulative risk has consistently found that the accumulation of risk factors increases the likelihood of mental health problems. The goal of the current study was to elucidate the relation between cumulative risk and mental health symptomatology. METHODS: The study consisted of a sample of 252 maltreated youths (aged 9-11) placed in out-of-home care. RESULTS: Analyses confirmed the high-risk nature of this sample and identified seven salient risk variables. The cumulative risk index comprised of these seven indicators was a strong predictor of mental health symptoms, differentiating between children who scored in the clinical range with regard to mental health symptoms and those who did not. Finally, the data supported a linear model in which each incremental increase in cumulative risk was accompanied by an increase in mental health problems. CONCLUSION: This is the first known study to examine cumulative risk within a sample of youths in out-of-home care. PMID- 20932577 TI - The occurrence of nickel and other elements in tissues of the hip joint. AB - Nickel is applied in the production of surgical instruments and compounds of nickel affect the osseous tissue. The objective of this study was to determine the contents of nickel and 11 elements in tissues of a hip joint obtained from inhabitants of the Upper-Silesian Industrial Area. The samples were collected intra-operatively during Total Hip Replacement procedures, in most cases the indication for the surgery was hip osteoarthritis. Concentrations of nickel and 11 trace elements were measured with a Pye Unicam SP-9 acetylene-oxygen flame atomic absorption spectrometer (AAS). Additional analyses were conducted to identify the correlations occurring between these elements. The average content of trace elements in the hip joint was as follows (mg kg(-1)): Cd 0.66, Cr 7.58, Cu 8.43, Mn 0.79, Pb 3.75, Ni 4.82, Fe 252.13, Zn 75.65, Mg 1306.19, K 3938.67, Na 7484.52, Ca 49485.44. The study demonstrated that the content of nickel and the other elements was diversified, depending on the element of the hip joint, gender and the type of affection the endoprosthesis-plasty was performed for. PMID- 20932578 TI - A school peer mediation program as a context for exploring therapeutic jurisprudence (TJ): Can a peer mediation program inform the law? AB - This paper reports an exploratory study of a school peer mediation program implemented as an alternative way to manage bullying and other destructive conflict. The study explores the effects of the program on the well-being of members of the school community by examining perceptions of students, staff and a sample of parents and former students. Drawing on therapeutic jurisprudence (TJ) the study explores whether the component parts of the program, separately or together, promote intended or unintended therapeutic effects. The preliminary findings of the study emphasise the importance of peer mediation training and suggest that existing scholarship in the area of school conflict resolution and peer mediation, when viewed through a TJ lens, may provide valuable insights into how to optimally configure programs for development and adoption in schools and other community settings. The study highlights the lack of attention paid by the legal system to valuable scholarship in the area of school conflict resolution and peer mediation, which may have implications for the understanding and development of legal processes and the law in general. PMID- 20932579 TI - Sex crime legislation: Proactive and anti-therapeutic effects. AB - Therapeutic jurisprudence may have its major role within law practice, but analysis of the law from a therapeutic perspective is a task that should not be neglected; how a piece of legislation is designed and formulated certainly influences the therapeutic outcome of a legal process. This article uses sex legislation as an example to demonstrate how the old rape law based on coercion has anti-therapeutic effects on rape victims. If the law requires resistance, it implies that a woman is sexually available until she resists physically, resulting in an attitude that a woman reporting rape without injuries should be mistrusted. This mistrust of the victim and the victim's attendant feelings of self-blame aggravate the victim's trauma. On the other hand, a modern rape law based on lack of consent gives the signal that a woman is not available until she has given her consent, resulting in a different starting position for the investigation. Since the will of the victim must be respected, the victim herself must be respected in the legal process. Furthermore, being able to tell one's story in a respectful atmosphere can be more important for the well-being of the victim than the outcome of the reported case. PMID- 20932580 TI - The plague and macular degeneration. PMID- 20932581 TI - The Ahmed Baerveldt Comparison Study methodology, baseline patient characteristics, and intraoperative complications. AB - PURPOSE: The Ahmed Baerveldt Comparison (ABC) Study compares the long-term outcomes and complications of the Ahmed glaucoma valve (AGV; model FP7; New World Medical, Los Ranchos, CA) and the Baerveldt glaucoma implant (BGI; model 101-350; Abbott Medical Optics, Abbott Park, IL). DESIGN: Multicenter, randomized, controlled clinical trial. PARTICIPANTS: Two hundred seventy-six glaucoma patients at 16 clinical centers worldwide who were 18 to 85 years of age with inadequately controlled intraocular pressure (IOP; >=18 mmHg) in whom placement of an aqueous shunt was planned. METHODS: Study patients were randomized to undergo implantation of an AGV or a BGI. MAIN OUTCOME MEASURES: Failure, defined as IOP >21 mmHg or not reduced by 20% less than baseline or IOP <=5 mmHg (2 consecutive visits after 3 months), additional glaucoma surgery, removal of the implant, or loss of light perception vision. RESULTS: A total of 276 patients were enrolled between October 2006 and April 2008, including 143 in the AGV group and 133 in the BGI group. The mean age+/-standard deviation (SD) of patients enrolled was 63+/-14 years, and 52% were male. The mean baseline IOP+/-SD was 31.5+/-11.8 mmHg. Except for a 13% higher prevalence of hypertension in the AGV group, no significant differences in baseline demographic or ocular characteristics were observed between the study groups. Intraoperative complications occurred in 11 (8%) patients in the AGV group and in 16 (12%) patients in the BGI group (P = 0.31). CONCLUSIONS: The ABC Study should yield valuable prospective data comparing 2 commonly used aqueous shunts in clinical practice. PMID- 20932582 TI - Interim clinical outcomes in the collaborative bleb-related infection incidence and treatment study. AB - PURPOSE: To introduce the Collaborative Bleb-related Infection Incidence and Treatment Study and to provide an interim, 2.5-year follow-up report of the findings. This prospective study sought to determine the incidence, severity, and prognosis of bleb-related infection and to investigate the efficacy of the antibacterial therapy in preventing it. DESIGN: Prospective cohort study. PARTICIPANTS: A total of 908 eyes of 908 glaucoma patients who had undergone mitomycin C-augmented trabeculectomy or trabeculectomy combined with phacoemulsification and intraocular lens implantation performed at 34 clinical centers. METHODS: Outcomes were measured at 6-month intervals, with special attention to bleb-related infections, and data for 2.5 years of follow-up result were summarized. MAIN OUTCOME MEASURES: The incidence and severity of bleb related infection. RESULTS: Of the 908 eyes, 9 eyes developed a bleb-related infection. The Kaplan-Meier survival analysis revealed that the probability of development of bleb-related infection was 1.5+/-0.6% (cumulative probability +/- standard error) at the 2.5-year follow in the trabeculectomy cases and 1.4+/-1.0% in the combined surgery cases. It was 1.5% in both cases with a limbal-based flap and in those with a fornix-based flap. It was significantly different between cases with bleb leakage and those without it (P = 0.037; log-rank test). CONCLUSIONS: The cumulative probability of bleb-related infection was prospectively determined to be 1.5+/-0.6% in eyes treated with mitomycin C augmented trabeculectomy or trabeculectomy combined with phacoemulsification and intraocular lens implantation at the 2.5-year follow-up in the Collaborative Bleb related Infection Incidence and Treatment Study. PMID- 20932584 TI - The outcome of corneal transplantation in infants, children, and adolescents. AB - OBJECTIVE: To examine factors affecting penetrating corneal graft survival and visual outcomes in patients aged less than 20 years. DESIGN: Large prospective, cohort study. PARTICIPANTS: Records of 14 865 followed penetrating corneal grafts in 11 929 patients were searched to identify 765 grafts in 640 patients aged younger than 20 years of age at the time of graft. METHODS: Records submitted to the Australian Corneal Graft Registry by 381 ophthalmic surgeons and 253 follow up practitioners from May 1985 to June 2009 were analyzed using Kaplan-Meier survival plots and Cox proportional hazards regression analysis. MAIN OUTCOMES MEASURES: Probability of corneal graft survival and Snellen acuity at the time of most recent follow-up and at defined intervals post-graft. RESULTS: Infants (<5 years) exhibited poorer graft survival than children aged 5 to 12 years. Adolescents (13-19 years) exhibited better corneal graft survival than other age groups; 86% of grafts in adolescents were for keratoconus. Factors significantly affecting corneal graft survival in pediatric patients included indication for graft, graft inflammation, history of intraocular surgery, vascularization, rejection episodes, post-graft operative procedures, and refractive surgery. Fourteen percent of pediatric grafts failed, of which 65% failed within 2 years post-graft. Forty-four percent of failures were due to unknown causes (18) or irreversible rejection (30). CONCLUSIONS: Corneal grafts for keratoconus in adolescents show excellent survival. Infants exhibit poor graft survival and visual outcomes, especially those undergoing transplantation for Peters' anomaly. Corneal graft survival and visual outcomes vary more by indication for graft than recipient age. The major reason for graft failure is irreversible rejection. Corneal transplantation improves overall bilateral vision in pediatric patients. PMID- 20932583 TI - Treatment outcomes in the Ahmed Baerveldt Comparison Study after 1 year of follow up. AB - PURPOSE: To determine the relative efficacy and complications of the Ahmed glaucoma valve (AGV) model FP7 (New World Medical, Ranchos Cucamonga, CA) and the Baerveldt glaucoma implant (BGI) model 101-350 (Abbott Medical Optics, Abbott Park, IL) in refractory glaucoma. DESIGN: Multicenter, randomized, controlled clinical trial. PARTICIPANTS: Two hundred seventy-six patients, including 143 in the AGV group and 133 in the BGI group. METHODS: Patients 18 to 85 years of age with refractory glaucoma having intraocular pressure (IOP) of 18 mmHg or more in whom an aqueous shunt was planned were randomized to undergo implantation of either an AGV or a BGI. MAIN OUTCOME MEASURES: The primary outcome was failure, defined as IOP >21 mmHg or not reduced by 20% from baseline, IOP <=5 mmHg, reoperation for glaucoma or removal of implant, or loss of light perception vision. Secondary outcomes included mean IOP, visual acuity, use of supplemental medical therapy, and complications. RESULTS: Preoperative IOP (mean+/-standard deviation [SD]) was 31.2+/-11.2 mmHg in the AGV group and 31.8+/-12.5 mmHg in the BGI group (P = 0.71). At 1 year, mean+/-SD IOP was 15.4+/-5.5 mmHg in the AGV group and 13.2+/-6.8 mmHg in the BGI group (P = 0.007). The mean+/-SD number of glaucoma medications was 1.8+/-1.3 in the AGV group and 1.5+/-1.4 in the BGI group (P = 0.071). The cumulative probability of failure was 16.4% (standard error [SE], 3.1%) in the AGV group and 14.0% (SE, 3.1%) in the BGI group at 1 year (P = 0.52). More patients experienced early postoperative complications in the BGI group (n = 77; 58%) compared with the AGV group (n = 61; 43%; P = 0.016). Serious postoperative complications associated with reoperation, vision loss of >=2 Snellen lines, or both occurred in 29 patients (20%) in the AGV group and in 45 patients (34%) in the BGI group (P = 0.014). CONCLUSIONS: Although the average IOP after 1 year was slightly higher in patients who received an AGV, there were fewer early and serious postoperative complications associated with the use of the AGV than the BGI. PMID- 20932585 TI - When paranoia fails to enhance self-esteem: explicit and implicit self-esteem and its discrepancy in patients with persecutory delusions compared to depressed and healthy controls. AB - The hypothesis that persecutory delusions function to enhance self-esteem implies that patients will show normal explicit, but low implicit self-esteem. As evidence for this has been inconsistent, our study assessed delusional state, explicit and implicit self-esteem and depression in a large sample (n=139) of schizophrenia patients with acute persecutory delusions (n=28), patients with remitted persecutory delusions (n=31), healthy controls (n=59), and depressed controls (n=21). Patients with delusions and patients with depression both showed decreased levels of explicit, but normal levels of implicit self-esteem when compared to healthy controls. The direct comparison of levels of explicit and implicit self-esteem within each group revealed that healthy controls had higher explicit than implicit self-esteem, while the converse pattern was found for depressed controls. No discrepancy between explicit and implicit self-esteem was found for acute deluded or remitted patients with schizophrenia. Although these findings do not support the hypothesis that delusions serve to enhance self esteem, they underline the relevance of low self-esteem in patients with persecutory delusions and point to the necessity of enhancing self-esteem in therapy. PMID- 20932586 TI - Bactericidal activity of porcine neutrophil secretions. AB - Antimicrobial proteins in neutrophil granules exert their bactericidal activity both within the neutrophil phagolysosome and as components of neutrophil extracellular traps. This study evaluated the bactericidal activity of porcine neutrophil secretions against four bacterial pathogens of swine. Porcine neutrophils were treated with or without phorbol myristate acetate (PMA), then the resulting supernatants were incubated with Escherichia coli K-12, Streptococcus suis, Actinobacillus suis, or Pasteurella multocida, and the surviving colony forming units were enumerated. Supernatants of PMA-activated neutrophils killed an average of 95% of E. coli K-12 cells, relative to supernatants from untreated neutrophils. Inhibition of elastase activity using chloromethylketone (CMK) prior to PMA stimulation significantly reduced the bactericidal activity of the neutrophil supernatants; 57% of the PMA-induced bactericidal activity against E. coli K-12 was estimated to be elastase dependent. The same neutrophil supernatants had lower bactericidal activity against S. suis, A. suis, and P. multocida, with 30%, 36% and 13% reduction in bacterial numbers, respectively. The cathelicidin porcine myeloid antimicrobial peptide (PMAP)-36 and lactotransferrin were among the proteins identified in the supernatants of PMA-stimulated neutrophils by mass spectrometry. These findings imply that elastase-activated proteins, such as cathelicidins, are partially responsible for the bactericidal effect of porcine neutrophil secretions, but non elastase-dependent proteins such as lactoferrin may also contribute. Further, the secretions of activated neutrophils were effective in killing the avirulent E. coli K-12 but were less effective against the other bacteria tested, suggesting that these pathogens may have evolved mechanisms to resist neutrophil-mediated killing. PMID- 20932587 TI - Chorda tympani nerve function in children: relationship to otitis media and body mass index. AB - OBJECTIVE/HYPOTHESIS: A relationship between acute otitis media and elevated body mass index has recently been reported. Intriguingly, it was postulated that this relationship may result from altered chorda tympani nerve function impacting taste sensation and eating habits. We sought to test this directly by measuring chorda tympani nerve function in children with and without a previous history of acute otitis media and to determine the relationship to body mass index. STUDY DESIGN: Retrospective cohort study. METHODS: Institutional research ethics board approval was obtained. Study participants included 142 children (5-18 years of age) who were recruited from an otolaryngology outpatient clinic at a tertiary academic pediatric hospital between May and August 2009. Children were excluded if they were not able to communicate effectively, younger than age 5, or had developmental disabilities. Body mass index was calculated and the history of previous otologic disease carefully elicited from the caregivers. Electrogustometric threshold, a validated measure of chorda tympani function, was obtained bilaterally in each child. Children were divided into cohorts based on the number of acute otitis media episodes, and electrogustometry thresholds were compared between cohorts. RESULTS: Electrogustometric thresholds were successfully obtained in all children. There was no significant relationship between chorda tympani nerve function and history of acute otitis media. Similarly, there was no significant association between the history of otitis media and body mass index. CONCLUSION: This study did not demonstrate any effect of previous acute otitis media history on chorda tympani nerve function. Furthermore, it did not demonstrate a relationship between acute otitis media and elevated body mass index. This is counter-evidence to the previous hypothesis that increasing acute otitis media is responsible for increasing childhood obesity through alteration in chorda tympani nerve function. PMID- 20932588 TI - Mid-life and late-life vascular risk factors and dementia in Korean men and women. AB - Dementia is one of the most important neurological disorders in the elderly population. The significance of vascular risk factors for dementia remains controversial. This study aimed to determine the effects of vascular risk factors, such as blood pressure, diabetes and smoking in the mid-life or the late life on dementia risk. The data in this prospective cohort study came from 3252 dementia events occurring over 14 years among 848,505 Koreans aged 40-95 years insured by the National Health Insurance Corporation who had a biennial medical evaluation during 1992-1995. Data on clinical dementia during the period 1993 2006 were examined in relation to vascular risk factors. The age adjusted incidence per 100,000 was 31.9 for men and 45.0 for women, respectively. In multivariate Cox proportional hazard models, diabetes increased the risk of either dementia in Alzheimer's disease or vascular dementia in men and women, controlling for age, hypertension, total cholesterol, alcohol drinking, and smoking. Hypertension also increased vascular dementia in both men [Hazard ratio (HR)=2.6, 95% confidence interval (CI)=1.7-3.8] and women (HR=2.3, 95%CI=1.6 3.3). The association of hypertension or diabetes on risk of vascular dementia, however, among the group aged older than 65 was attenuated but remained as significant in men. There was no interaction between hypertension and diabetes on the risk of dementia. This study demonstrates that diabetes and hypertension increased the risk of vascular dementia. Treatment for these risk factors may reduce the risk of vascular dementia. PMID- 20932589 TI - Sexual life and self-esteem in married elderly. AB - The elderly population in South Korea is increasing. But traditionally in Korea, there is a tendency for the elderly to be cautious and sensitive to how their children view them, and younger generations tend to consider elderly sexuality to be a subject of taboo. Nevertheless, a person's sexual life is a general condition that affects the body, mental health and personality. Therefore, it is important to examine the relationship between the actual conditions of sexual life of elderly and self-esteem during old age. Sexual life was important for 38.5% of the research subjects and very important for 23.7%. Sexual partners were spouses for 93.4%. The self-esteem range was 20-38 with an average of 28.23. Those who were maintaining a sexual life had significantly higher self-esteem than those who were not (t=2.222, p=0.028). Those who felt very satisfied with their current sexual life had a significantly higher self-esteem than those who did not (F=2.824, p=0.028). The results show that it is important to have sexual life in late life. It will be necessary to develop and apply programs that will actively support elderly sexual life, as well as continue research in this area. PMID- 20932590 TI - A new risk score predicting 1- and 5-year mortality following acute myocardial infarction Soroka Acute Myocardial Infarction (SAMI) Project. AB - BACKGROUND: Risk stratification of patients following acute myocardial infarction (AMI), in order to identify patients whose clinical outcomes can be improved through specific medical interventions, is needed. OBJECTIVES: Development and validation of a prognostic tool comprising a variety of non-cardiovascular co morbidities, to predict mortality of hospital survivors after AMI. METHODS: The study cohort included 2773 consecutive patients with AMI who were discharged live from the Soroka University Medical Center between 2002 and 2004. Two-thirds were used obtain the model (training set) and one-third to validate it (validation set). Data were collected from the hospital's routine computerized information systems. The primary outcome was post-discharge 1-year all-cause mortality. The weight of each variable in the final score was computed based on the odds ratio values of the multivariate model. Additionally, the ability of the index to predict 5-year mortality was assessed. RESULTS: These are comprised of the following parameters: 4 points - age >75 years, abnormal echocardiography findings; 3 points - at least one of following: gastro-intestinal hemorrhage, COPD, malignancy, alcohol or drug addiction, neurological disorders, psychiatric disorders; 2 points - no echocardiography results, renal diseases, anemia, hyponatremia; -3 points for PCI or thrombolytic therapy; -6 points - CABG; -2 points - obesity. The c-statistics for 1-year all-cause mortality were 0.86 and 0.83 in the training and validation sets, respectively. The c-statistics for 5 year mortality was 0.858 for both sets combined. CONCLUSIONS: The new score is a simple robust tool for predicting mortality in patients discharged alive following AMI. PMID- 20932591 TI - Acute heart failure: when standard therapy fails--an interdisciplinary challenge. PMID- 20932592 TI - Analysis of Escherichia coli cell damage induced by HPCD using microscopies and fluorescent staining. AB - Cellular damage of Escherichia coli (E. coli) induced by high pressure carbon dioxide (HPCD) at 37-57 degrees C and 10-30 MPa for 5-75 min was investigated using scanning electronic microscopy (SEM), transmission electronic microscopy (TEM), confocal laser scanning microscopy (CLSM), and fluorospectrophotometer (FSM). HPCD-induced alterations in the morphology and the intracellular organization of E. coli cells was more susceptible to HPCD. A vast majority of HPCD-treated E. coli cells with seemingly intact morphology sustained severe damage in their intracellular organization. CLSM suggested that initial disruption of the outer membrane and later permeabilization of the cytoplasmic membrane of HPCD-treated E. coli cells was a consecutive and progressive process. These results were confirmed by FSM with the probes PI and SYTO 9. The membrane fluidity of HPCD-treated E. coli cells decreased as suggested by increased fluorescence polarization using FSM with the probe 1,6-diphenyl-1,3,5-hexatriene (DPH). The temperatures of 37, 42 and 47 degrees C alone showed no impact on the outer membrane and membrane fluidity of E. coli cells whereas 57 degrees C alone had greater impact on them. Combined with HPCD, the temperatures of 37, 42 and 47 degrees C disrupted the outer membrane of E. coli cells without damage to the cytoplasmic membrane and of 57 degrees C damaged the cytoplasmic membrane, but all these temperatures decreased the membrane fluidity of E. coli cells. Higher temperature increased HPCD-induced outer membrane disruption and the cytoplasmic membrane damage and decreased the membrane fluidity. PMID- 20932593 TI - Concentrations of viable airborne fungal spores and trichloroanisole in wine cellars. AB - In wineries, unwanted microorganisms present not only hygienic problems but also have a negative influence on wine quality. An evaluation of Austrian/Styrian wine cellars with regard to the volume and the composition of the mycoflora is very important both for the process of wine production and for occupational safety. Thirty-six wine cellars of 20 vintners were investigated with regard to microorganisms in the air and on material surfaces. Moreover, the presence of trichloroanisole in the air was determined by means of solid-phase micro extraction. Microorganisms were sampled using the six-stage Andersen-Cascade impactor. The results showed that the concentrations of xerophilic fungi in the air of cellars with large visible mold areas (> 80%) reached values up to 1.4 * 104 colony forming units per m3. In the wine cellars fourteen predominant fungal genera were found in the indoor air, the most frequent was Penicillium. Trichloroanisole was detected in the air of wine cellars with large visible moldy patches. The spore concentrations in the cellar air were two times higher in cellars with Zasmidium cellare growth than in cellars without Z. cellare. These results will serve as a database for further studies. PMID- 20932594 TI - Evolution of hepatitis B genotype C viral quasi-species during hepatitis B e antigen seroconversion. AB - BACKGROUND & AIMS: Although the evolution of viral quasi-species may be related to the pathological status of disease, little is known about this phenomenon in hepatitis B, particularly with respect to hepatitis B e antigen (HBeAg) seroconversion. METHODS: Nucleotide sequences of the hepatitis B virus (HBV) X/precore/core region was analyzed at five time-points in four groups of chronic hepatitis B patients, interferon-induced seroconverters (IS, N = 9), interferon non-responders (IN, N = 9), spontaneous seroconverters (SS, N = 9), and non seroconverters (SN, N = 9) followed during 60 months on an average. Only patients with genotype C were studied. RESULTS: Analysis of 1800 nucleotide sequences showed that there was no statistical difference between the nucleotide genetic distances of seroconverters (IS and SS; 6.9 * 10-3 substitutions (st)/site and 6.7 * 10-3 st/site, respectively) and those of non-seroconverters (IN and SN; 5.3 * 10-3 st/site and 3.8 * 10-3 st/site, respectively) before seroconversion. Compared to non-seroconverters (IN and SN; 5.1 * 10-3 st/site and 5.9 * 10-3 st/site, respectively), the sequence diversity of seroconverters (IS and SS; 10.9 * 10-3 st/site and 9.9 * 10-3 st/site, respectively) was significantly higher after seroconversion (p < 0.05), and was higher in seroconverters after seroconversion than before seroconversion (p < 0.05), while this changed very little in non-seroconverters during the observation period. Phylogenetic trees showed greater complexity in secoconverters than non-seroconverters. Parsimony based estimation of the direction of sequence change between descendants and ancestors before HBeAg seroconversion, revealed higher frequencies of transversional A to T substitution in seroconverters (0.06 vs. 0.02, p = 0.0036) that coincided with the dynamics of quasi-species possessing A1762T mutation. CONCLUSIONS: The distinctly greater viral diversity in HBeAg seroconverters after seroconversion could be related to escape mutants resulting from stronger selection pressure. PMID- 20932595 TI - Small molecule scavenger receptor BI antagonists are potent HCV entry inhibitors. AB - BACKGROUND AND AIMS: ITX 5061 is a clinical stage small molecule compound that promotes high-density lipoprotein (HDL) levels in animals and patients by targeting the scavenger receptor BI protein pathway. Since SR-BI is a known co receptor for HCV infection, we evaluated these compounds for their effects on HCV entry. METHODS: We obtained ITX 5061 and related compounds to characterize their interaction with SR-BI and effects on HCV entry and infection. RESULTS: We confirmed that a tritium-labeled compound analog (ITX 7650) binds cells expressing SR-BI, and both ITX 5061 and ITX 7650 compete for HDL-mediated lipid transfer in an SR-BI dependent manner. Both molecules inhibit HCVcc and HCVpp infection of primary human hepatocytes and/or human hepatoma cell lines and have minimal effects on HCV RNA replication. Kinetic studies suggest that the compounds act at an early post-binding step. CONCLUSIONS: These results suggest that the ITX compounds inhibit HCV infection with a mechanism of action distinct from other HCV therapies under development. Since ITX 5061 has already been evaluated in over 280 patients with good pharmacokinetic and safety profiles, it warrants proof-of-concept clinical studies in HCV infected patients. PMID- 20932596 TI - Distinct roles for non-muscle myosin II isoforms in mouse hepatic stellate cells. AB - BACKGROUND & AIMS: Upon liver injury, hepatic stellate cells (HSCs) undergo dramatic morphological and functional changes including migration and contraction. In the present study, we investigated the role of myosin II isoforms in the development of the contractile phenotype of mouse HSCs, which are considered therapeutic targets to decrease portal hypertension and fibrosis. METHODS: We characterized the expression of myosin IIA and IIB in primary mouse HSCs and addressed their function by gene knock-down using isoform-specific siRNAs. RESULTS: We found that myosin IIA and IIB are differentially expressed and localized and have clearly different functions in HSCs. Myosin IIA is mainly located in the subcortical area of quiescent HSCs and at alpha-SMA-containing stress fibres after activation, while myosin IIB is located in the cytoplasm and at the edge of protrusions of quiescent HSCs, at stress fibres of activated cells, and at the leading edge of lamellipodia. Knock-down of myosin IIA in HSCs influences cell size and shape, results in the disruption of stress fibres and in a decrease of focal adhesions, and inhibits contractility and intra-cellular Ca(2+) release but increases cell migration. Myosin IIB contributes to the extension of lamellipodia and cell spreading but has no direct role in stress fibres and focal adhesion formation, contraction, or intra-cellular Ca(2+) signalling. CONCLUSIONS: In mouse HSCs, myosin IIA and IIB clearly fulfil distinct roles. Our results provide an insight into the contractile machinery of HSCs, that could be important in the search for new molecules to treat portal hypertension. PMID- 20932597 TI - Transjugular intrahepatic portosystemic shunt for portal vein thrombosis with symptomatic portal hypertension in liver cirrhosis. AB - BACKGROUND & AIMS: Data on the management of portal vein thrombosis (PVT) in patients with decompensated cirrhosis are extremely limited, particularly in the cases of the transjugular intrahepatic portosystemic shunt (TIPS). We assessed the outcome of TIPS for PVT in patients with cirrhosis and symptomatic portal hypertension and determined the predictors of technical success and survival. METHODS: In the retrospective study, 57 consecutive patients receiving TIPS were enrolled between December 2001 and September 2008. All were diagnosed with chronic PVT, and 30 had portal cavernoma. Indications for TIPS were variceal hemorrhage (n = 56) and refractory ascites (n = 1). RESULTS: TIPS were successfully placed in 75% of patients (43/57). The independent predictors of technical success included portal cavernoma, and the degree of thrombosis within the main portal vein (MPV), the portal vein branches, and the superior mesenteric vein. Only one patient died of severe procedure-related complication. The cumulative 1-year shunt dysfunction and hepatic encephalopathy rates were 21% and 25%, respectively. The cumulative 1- and 5-year variceal re-bleeding rates differed significantly between the TIPS success and failure groups (10% and 28% versus 43% and 100%, respectively; p = 0.0004), while the cumulative 1- and 5 year survival rates were similar between the two groups (86% and 77% versus 78% and 62%, respectively; p = 0.34). The independent predictor of survival in PVT patients with decompensated cirrhosis was the degree of MPV occlusion (hazard ratio 0.189, 95% CI 0.042-0.848). CONCLUSIONS: TIPS should be considered a safe and feasible alternative therapy for chronic PVT in selected patients with decompensated cirrhosis. Both technical success and survival were closely associated with the degree of MPV occlusion. PMID- 20932598 TI - Reliability of transient elastography for the detection of fibrosis in non alcoholic fatty liver disease and chronic viral hepatitis. AB - BACKGROUND & AIMS: Transient elastography (TE) is validated in chronic hepatitis C (CHC) to evaluate hepatic fibrosis; however, limited data are available in chronic hepatitis B (CHB) and non-alcoholic fatty liver disease (NAFLD). This prospective study is aimed to assess the accuracy and the efficacy of TE for the detection of fibrosis in patients with chronic liver disease of different etiology and to evaluate the effect of steatosis on the liver stiffness measurement (LSM). METHODS: TE was performed in 219 consecutive patients with chronic liver disease (35% CHC, 32% CHB, and 33% NAFLD) within 6 months of the liver biopsy. RESULTS: LSM was related to the fibrosis stage in each group (CHC: p = 0.596, p < 0.001; CHB: p = 0.418, p < 0.001; NAFLD: p = 0.573, p < 0.001), but the correlation was less strong in CHB and NAFLD than in CHC patients. In CHB patients with histological cirrhosis (F4), the median stiffness value was almost two times lower than in patients with severe fibrosis (F3). In NAFLD patients with advanced fibrosis (F3) and severe steatosis (> 33%), the LSM values were lower than expected and were similar to those of patients with initial fibrosis (F1) and fat < 33%. TE underestimated the stage of fibrosis in 75% of patients with F3 and steatosis > 33%. At multiple logistic regression analysis, in CHC and CHB patients, LSM was the only predictive variable of severe fibrosis/cirrhosis (OR = 1.42, p = 0.003 and OR = 1.354, p = 0.003, respectively), while in NAFLD subjects BMI and AST (OR = 1.433, p = 0.002 and OR = 1.053, p = 0.020, respectively) but not LSM were independently related with advanced fibrosis and cirrhosis. CONCLUSIONS: This study confirms that TE can be considered a valid support to detect fibrosis in chronic liver disease related to HCV but it should be interpreted cautiously in CHB and NAFLD patients, where host or disease related factors may modify its accuracy. PMID- 20932599 TI - Hepcidin in human iron disorders: therapeutic implications. AB - The discovery of hepcidin has triggered a virtual explosion of studies on iron metabolism and related disorders, the results of which have profoundly changed our view of human diseases associated with excess of iron, iron deficiency or iron misdistribution. Not only has new light been shed on the pathogenesis of these disorders, but therapeutic applications from these advances are now foreseen. The notion that hepcidin excess or deficiency may contribute to the dysregulation of iron homeostasis in hereditary and acquired iron disorders raises the possibility that hepcidin-lowering or enhancing agents may be an effective strategy for curing the main consequences of hepcidinopathies, anemia or iron overload, respectively. Experimental pre-clinical and clinical studies have shown that hepcidin antibodies, agonists or antagonists, cytokine receptor antibodies and small-molecules that modify hepcidin expression also reverse iron abnormalities in vivo, in a number of disease models. While future studies addressing safety and long-term efficacy of hepcidin-targeted treatments will clarify risks and benefits, a new era has begun based on the treatment of disorders of iron homeostasis through the modulation of its regulatory hormone, hepcidin. PMID- 20932600 TI - Short term physiological implications of NBPT application on the N metabolism of Pisum sativum and Spinacea oleracea. AB - The application of urease inhibitors in conjunction with urea fertilizers as a means of reducing N loss due to ammonia volatilization requires an in-depth study of the physiological effects of these inhibitors on plants. The aim of this study was to determine how the urease inhibitor N-(n-butyl) thiophosphoric triamide (NBPT) affects N metabolism in pea and spinach. Plants were cultivated in pure hydroponic culture with urea as the sole N source. After 2 weeks of growth for pea, and 3 weeks for spinach, half of the plants received NBPT in their nutrient solution. Urease activity, urea and ammonium content, free amino acid composition and soluble protein were determined in leaves and roots at days 0, 1, 2, 4, 7 and 9, and the NBPT content in these tissues was determined 48h after inhibitor application. The results suggest that the effects of NBPT on spinach and pea urease activity differ, with pea being most affected by this treatment, and that the NBPT absorbed by the plant caused a clear inhibition of the urease activity in pea leaf and roots. The high urea concentration observed in leaves was associated with the development of necrotic leaf margins, and was further evidence of NBPT inhibition in these plants. A decrease in the ammonium content in roots, where N assimilation mainly takes place, was also observed. Consequently, total amino acid contents were drastically reduced upon NBPT treatment, indicating a strong alteration of the N metabolism. Furthermore, the amino acid profile showed that amidic amino acids were major components of the reduced pool of amino acids. In contrast, NBPT was absorbed to a much lesser degree by spinach plants than pea plants (35% less) and did not produce a clear inhibition of urease activity in this species. PMID- 20932601 TI - Both HY5 and HYH are necessary regulators for low temperature-induced anthocyanin accumulation in Arabidopsis seedlings. AB - The roles of two bZIP transcription factors LONG HYPOCOTYL 5 (HY5) and HY5 HOMOLOG (HYH) in inducing anthocyanin accumulation during low temperature treatment were studied in Arabidopsis. In all seedlings tested, low temperature significantly induced anthocyanin accumulation only in the presence of light. In the absence of HY5 or HYH, the low temperature-induced anthocyanin accumulation was significantly impaired compared to that of the wild type. Moreover, in the double mutant hy5hyh, no significant anthocyanin accumulation was induced by low temperature even in light, suggesting that the low temperature-induced anthocyanin accumulation was mediated by HY5/HYH. Through the RT-PCR assay, expressions of several "early" genes in anthocyanin biosynthetic pathway, chalcone synthase (CHS), chalcone isomerase (CHI), flavanone 3-hydroxylase (F3H), were up-regulated by low temperature in a manner that is at most partially dependent on HY5/HYH, whereas dihydroflavanol reductase (DFR), a "late" gene, was found to be up-regulated in a manner that was almost fully dependent on HY5/HYH. Thus, up-regulation of DFR in a HY5/HYH-dependent manner may address the question of why low temperature-induced anthocyanin accumulation relies upon light. In addition, we found that HY5/HYH expression was enhanced by low temperature in wild type Col-0, implying that low temperature induces anthocyanin accumulation, at least in part, through enhancing HY5/HYH protein levels. Collectively, our data suggest that HY5 and HYH are two necessary regulators that play a pivotal role during low temperature-induced anthocyanin accumulation in Arabidopsis seedlings. PMID- 20932602 TI - [Perianal herpes simplex in a patient with Crohn's disease treated with infliximab]. PMID- 20932603 TI - [Primary pancreatic lymphoma diagnosed by endoscopic ultrasound-guided fine needle aspiration biopsy]. AB - Although primary pancreatic lymphoma (PPL) is a rare malignant tumor, the correct diagnosis is essential since their therapeutic management differs from other pancreatic tumors. The fine needle aspiration cytology guided by endoscopic ultrasonography (EUS-FNA) is currently the preferred technique for the diagnosis of neoplasms of the pancreas, being of particular interest in those pancreatic lesions with atypical characteristics or presentation. However, the usefulness of EUS-FNA in the PPL has been poorly studied because of the rarity of this entity. We report a case of a patient with HIV infection and PPL diagnosed by EUS-FNA. PMID- 20932605 TI - [Clinical microbiology laboratory and imported parasitic diseases]. AB - Imported parasitosis represents an increasingly frequent diagnostic challenge for microbiology laboratories. A surge in immigration and international travel has led to a rise in the number of imported cases of parasitosis, and this trend is expected to continue in the future. The present article addresses this challenge by reviewing recommended diagnostic approaches and tests. Currently, microscopy is always recommended when analysing blood samples for parasites. If malaria is suspected, rapid antigen testing (including at least HRP2 antigen) should also be performed. The work-up for suspected leishmaniasis should include serology, culture, and in selected cases detection of antigen in urine. In suspected Chagas disease, two different serological tests should be performed. PCR for blood protozoa is highly sensitive, although it cannot be used to rule out Chagas disease, since this condition may be present without parasitemia. Accurate diagnosis of intestinal amebiasis usually requires PCR or antigen detection tests. In helminthiasis, traditional microscopy may need to be complemented with other tests, such as agar plate culture for strongyloidiasis, Og4C3 antigen detection for bancroftian filariasis, and antibody detection test for filariasis and schistosomiasis. PMID- 20932606 TI - [Road-rage in the general population]. AB - OBJECTIVE: To analyze the prevalence of road rage in the general population and the sociodemographic factors associated with this phenomenon. METHODS: A total of 2,500 interviews were carried out in the population of Castile and Leon aged 14 70 years. Road rage was evaluated in the year prior to the survey using a test with eight questions. RESULTS: One-third (31.1%) of the interviewees reported they had experienced a situation involving road rage during the previous 12 months (26.8% on more than one occasion). Among these episodes, 2.6% involved "serious" aggressors. In drivers, the probability of experiencing road rage increased in line with the number of kilometers driven per week (odds ratio [OR]=1.52), decreased as the age of the driver increased (OR=0.975), and was highest in men (OR=1.287), university graduates (OR=1.408), and persons living in towns with over 10,000 inhabitants (OR=1.25). CONCLUSIONS: The results of this study show that road rage affects almost a third of the general population of Castile and Leon, which would amply justify the adoption of prevention and/or reduction measures. PMID- 20932607 TI - A regio- and stereoselective 1,3-dipolar cycloaddition for the synthesis of novel spiro-pyrrolothiazolyloxindoles and their antitubercular evaluation. AB - The 1,3-dipolar cycloaddition of azomethine ylides derived from substituted isatins and 1,3-thiazolane-4-carboxylic acid to a series of 2-(arylmethylene)-2,3 dihydro-1H-inden-1-ones afforded twenty nine novel spiro pyrrolothiazolyloxindoles regio- and stereoselectively in moderate yields. These compounds were screened for their in vitro activity against Mycobacterium tuberculosis H37Rv (MTB) using agar dilution method. Among 29 compounds screened, spiro[5.3']-5'-nitrooxindole-spiro-[6.3"]-2,3-dihydro-1H-inden-1"-one-7-(2,3 dichlorophenyl)tetrahydro-1H-pyrrolo[1,2-c][1,3]thiazole, was found to be the most active compound with MIC of 2.8 MUM against MTB, being 1.67 and 2.70 times more active than ciprofloxacin and ethambutol respectively. PMID- 20932608 TI - Synthesis and antitubercular activity of new mefloquine-oxazolidine derivatives. AB - In this work, we report the synthesis and the antitubercular evaluation of 16 new mefloquine derivatives, formed from reactions between mefloquine and benzaldehydes, with the activity expressed as the minimum inhibitory concentration (MIC) in MUM. The compounds were non-cytotoxic and exhibited an important activity (12.6 MUM). The appreciable activity of these compounds can be considered an important finding for the rational design of new leads for anti-TB compounds. PMID- 20932609 TI - Synthesis of novel chiral Delta2-isoxazoline derivatives related to ABT-418 and estimation of their affinity at neuronal nicotinic acetylcholine receptor subtypes. AB - The enantiopure diastereomeric Delta2-isoxazoline derivatives (2S,5'R)-5a-10a and (2S,5'S)-5b, (2S,5'S)-9b, (2S,5'S)-11b, which are structural analogues of both ABT-418 2 and oxyimino ethers (S)-3 and (Z)-(S)-4, were synthesized through cycloaddition reactions involving nitrile oxides as 1,3-dipoles and (S)-N-Boc-2 vinylpyrrolidine-13 as the dipolarophile. The absolute configuration was unequivocally assigned to target compounds by means of an X-ray analysis. The derivatives under study were assayed at neuronal acetylcholine nicotinic receptors (nAChRs), where they showed a meaningful reduction in affinity at the heteromeric alpha4beta2 subtype when compared to the reference molecules. Conversely, anti (2S,5'S)-5b and syn (2S,5'R)-10a isomers showed an affinity for the alpha7 nAChRs comparable to that observed for the model compound ABT-418. PMID- 20932611 TI - Clinical negligence and duty of candour. AB - The Department of Health is considering imposing a legal duty of candour on health care providers to ensure that an apology and explanation are given to patients when errors occur during medical treatment. This aims to improve quality of care and reduce adverse events during medical treatment. We present the current system of clinical negligence and the future of medical ethics. We discuss relevant cases with regard to duty of candour, and highlight the existence of serious imbalances in which patients' rights and corresponding ethical duties of professionals predominate over the responsibilities of patients themselves. It is known that most adverse events arise because of multiple factors for which no individual should be blamed. To improve healthcare services there is a need for a system in which lessons can be learnt from mistakes, and services can be improved in the interest of patient safety, and for transparency in the broad principles on which the decisions are based within which clinical performance is supervised and monitored. PMID- 20932610 TI - An international comparison of Korean and Chinese nursing students with nursing curricula and educational outcomes. AB - AIM: The aim of this study was to compare Korean and Chinese nursing students with respect to their nursing curricula and educational outcomes including critical thinking, professionalism, leadership, communication skills, and nursing practice skills. METHODS: Data were collected from 762 nursing college students (355 in Korea and 407 in China) using the validated self-report questionnaires. The instruments were translated into Chinese for the Chinese students. FINDINGS: Korea offered various nursing courses more focused on specific nursing compared to China. With respect to critical thinking skills, the Korean students had significantly higher scores than the Chinese students. The Chinese students had significantly higher scores than the Korean students on the professionalism and communication skills. There were no differences between the groups in scores of leadership and nursing practice skills. CONCLUSION AND RECOMMENDATIONS: This study provides preliminary information on cross-national nursing educational outcomes. A comparison of educational outcomes among nursing students of other countries as well as China will determine differences in nursing educational outcomes that the nursing program is located in, and an international flow of students through the nursing educational should develop a general direction for nursing education. PMID- 20932612 TI - Effectiveness of an internet-based intervention enhancing Finnish parents' parenting satisfaction and parenting self-efficacy during the postpartum period. AB - BACKGROUND: The postpartum period presents several challenges related to learning infant care tasks, getting to know the infant and fulfilling self-expectations as parents. There is a need to evaluate the effectiveness of information-technology based interventions that support parenting during this period. OBJECTIVE: To evaluate the effectiveness of an internet-based intervention to support mothers' and fathers' parenting satisfaction and parenting self-efficacy (PSE). DESIGN: A quasi-experimental design with a non-equivalent control group and repeated measures. SETTING: Two public maternity hospitals (intervention/control) in southern Finland. PARTICIPANTS: A convenience sample of mothers and/or fathers (n = 1300 families). The inclusion criteria were primipara or multipara, and at least one parent willing to participate. Multiple birth, non-Finnish speaking and early discharge parents receiving home visits were excluded. A total of 500 mothers and 242 fathers returned complete sets of questionnaires. INTERVENTION: The intervention offered online support for parenting, breast feeding and infant care beginning from the middle of pregnancy. It comprised an information database, a peer discussion forum and expert advice. MEASUREMENTS: Outcomes were measured by the Evaluation Subscale of the What Being the Parent of a New Baby is Like-Revised and parenting self-efficacy instruments after childbirth and six to eight weeks post partum. FINDINGS: Both intervention and control mothers' parenting satisfaction and PSE increased significantly during the postpartum period. Fathers' parenting satisfaction and PSE also increased, but this change was only significant in the case of PSE. Both parents felt that their affective skills related to PSE were the weakest after childbirth. During the postpartum period, affective skills improved more than cognitive and behavioural skills. Different groups of mothers and different groups of fathers showed an equally positive change in parenting satisfaction and PSE. CONCLUSION: Both intervention and control mothers' and fathers' parenting satisfaction and PSE became more positive during the postpartum period. However, no intervention effects were found. In the future, it would be interesting to study longer-term effects and more specific groups of parents. The results indicate that online support has the potential to reach parents from diverse backgrounds. More research is needed on gender differences and user preferences. More interactive methods are needed to support parents' affective skills related to PSE. PMID- 20932613 TI - Empowerment in the midwifery context--a concept analysis. AB - OBJECTIVE: The concept empowerment is difficult to understand, define and translate into different contexts. Therefore, the purpose of this paper was to analyze the empowerment concept in the midwifery context, focused on the childbearing period, aimed at clarifying its meaning in order to enable comprehension and use in clinical practice, education and research. DESIGN: Semi structured interviews and written text. SETTING: Prenatal clinics, delivery and maternity wards in western Sweden. PARTICIPANTS: Nine midwives and 12 couples. MEASUREMENTS AND FINDINGS: A concept analysis was undertaken according to the hybrid model which consists of the theoretical, fieldwork and analytical phases. After a literature review, the concept was empirically elucidated in the fieldwork phase. The final step was to describe criteria and attributes, illustrative cases, antecedents and consequences of the concept. The following tentative criteria and attributes of empowerment in the midwifery context are described: developing a trustful relationship; starting an awareness process, making it possible to reflect on the changing situation; acting based on the parents' situation on their own terms, getting them involved and able to make informed choices; confirming the personal significance of becoming parents. Finally, empowerment in the midwifery context was redefined. KEY CONCLUSION: Midwives use empowerment in education and research as well as strategies on both the micro and macro levels in practice. IMPLICATIONS FOR PRACTICE: Empirical findings from the concept analysis confirm the concept's relevance in the midwifery context. PMID- 20932614 TI - The definition of species richness used by species sensitivity distributions approximates observed effects of salinity on stream macroinvertebrates. AB - The risk of chemicals for ecological communities is often forecast with species sensitivity distributions (SSDs) which are used to predict the concentration which will protect p% of species (PCp value). However, at the PCp value, species richness in nature would not necessary be p% less than at uncontaminated sites. The definition of species richness inherent to SSDs (contaminant category richness) contrasts with species richness typically measured in most field studies (point richness). We determine, for salinity in eastern Australia, whether these definitions of stream macroinvertebrate species richness are commensurable. There were strong relationships (r2>=0.87) between mean point species, family and Ephemeroptera, Trichoptera and Plecoptera species richness and their respective contamination category richness. Despite differences in the definition of richness used by SSDs and field biomonitoring, their results in terms of relative species loss from salinity in south-east Australia are similar. We conclude that in our system both definitions are commensurable. PMID- 20932615 TI - Effects of C60 nanoparticle exposure on earthworms (Lumbricus rubellus) and implications for population dynamics. AB - Effects of C60 nanoparticles (nominal concentrations 0, 15.4 and 154 mg/kg soil) on mortality, growth and reproduction of Lumbricus rubellus earthworms were assessed. C60 exposure had a significant effect on cocoon production, juvenile growth rate and mortality. These endpoints were used to model effects on the population level. This demonstrated reduced population growth rate with increasing C60 concentrations. Furthermore, a shift in stage structure was shown for C60 exposed populations, i.e. a larger proportion of juveniles. This result implies that the lower juvenile growth rate due to exposure to C60 resulted in a larger proportion of juveniles, despite increased mortality among juveniles. Overall, this study indicates that C60 exposure may seriously affect earthworm populations. Furthermore, it was demonstrated that juveniles were more sensitive to C60 exposure than adults. PMID- 20932616 TI - The functional and physiological status of Gammarus fossarum (Crustacea; Amphipoda) exposed to secondary treated wastewater. AB - Climate change scenarios predict lower flow rates during summer that may lead to higher proportions of wastewater in small and medium sized streams. Moreover, micropollutants (e.g. pharmaceuticals and other contaminants) continuously enter aquatic environments via treated wastewater. However, there is a paucity of knowledge, whether extended exposure to secondary treated wastewater disrupts important ecosystem functions, e.g. leaf breakdown. Therefore, the amphipod shredder Gammarus fossarum was exposed to natural stream water (n=34) and secondary treated wastewater (n=32) for four weeks in a semi-static test system under laboratory conditions. G. fossarum exposed to wastewater showed significant reductions in feeding rate (25%), absolute consumption (35%), food assimilation (50%), dry weight (18%) and lipid content (22%). Thus, high proportions of wastewater in the stream flow may affect both the breakdown rates of leaf material and thus the availability of energy for the aquatic food web as well as the energy budget of G. fossarum. PMID- 20932617 TI - Distribution of perfluorochemicals between sera and milk from the same mothers and implications for prenatal and postnatal exposures. AB - The levels of six perfluorocarboxylates (PFCAs), four perfloroalkylsulfonates (PFASs), and one sulfonamide were measured in paired samples of maternal serum, umbilical cord serum, and breast milk. The maternal and cord sera were strongly correlated with each other for all measured compounds (r>0.5 and p<0.01). Nevertheless, there was a significant difference in compound composition profile between the two sera matrices, with a more depletion of the longer chain compounds in cord serum. The transfer efficiency values from maternal to cord serum (TFCS/MS) decreased by 70% with each increasing unit of -CF2 chain within a PFCA group, and for perfluorooctanesulfonate (PFOS), by a half compared to perfluorooctanoate (PFOA). In contrast to the strong correlation in concentrations between the two sera matrices, the pattern of compounds in breast milk differed considerably with those in sera. Accordingly, compound- and matrix specific transfer must be considered when assessing prenatal and postnatal exposure. PMID- 20932618 TI - Acetylcholinesterase activity in the terrestrial snail Xeropicta derbentina transplanted in apple orchards with different pesticide management strategies. AB - Apple orchards are highly manipulated crops in which large amounts of pesticides are used. Some of these pesticides lack target specificity and can cause adverse effects in non-target organisms. In order to evaluate the environmental risk of these products, the use of transplanted sentinel organisms avoids side-effects from past events and facilitate comparison of multiple sites in a short time. We released specimens of the terrestrial snail Xeropicta derbentina in each 5 of two kinds of apple orchards with either conventional or organic management strategies plus in a single abandoned orchard. After one month, individuals were retrieved in order to measure acetylcholinesterase (AChE) activity. Mean values of AChE activity were significantly reduced in all conventional apple orchards compared to the others. Results show that the measurement of biomarkers such as AChE inhibition in transplated X. derbentina could be useful in the environmental risk assessment of post-authorized pesticides. PMID- 20932619 TI - Antagonism of phenanthrene cytotoxicity for human embryo lung fibroblast cell line HFL-I by green tea polyphenols. AB - Polycyclic aromatic hydrocarbons (PAHs) have been detected in some commercial teas around the world and pose a threat to tea consumers. However, green tea polyphenols (GTP) possess remarkable antioxidant and anticancer effects. In this study, the potential of GTP to block the toxicity of the model PAH phenanthrene was examined in human embryo lung fibroblast cell line HFL-I. Both GTP and phenanthrene treatment individually caused dose-dependent inhibition of cell growth. A full factorial design experiment demonstrated that the interaction of phenanthrene and GTP significantly reduced growth inhibition. Using the median effect method showed that phenanthrene and GTP were antagonistic when the inhibitory levels were less than about 50%. Apoptosis and cell cycle detection suggested that only phenanthrene affected cell cycle significantly and caused cell death; GTP lowered the mortality of HFL-I cells exposed to phenanthrene; However, GTP did not affect modulation of the cell cycle by phenanthrene. PMID- 20932620 TI - Behaviour of arsenic in forested catchments following a high-pollution period. AB - Due to high availability of adsorption sites, forested catchments could be net sinks for pollutant arsenic both during the period of increasing and decreasing pollution. We tested this hypothesis along a north-south pollution gradient in spruce die-back affected areas of Central Europe. For two water years (2007 2008), we monitored As fluxes via spruce-canopy throughfall, open-area precipitation, and runoff in four headwater catchments (Czech Republic). Since 1980, atmospheric As inputs decreased 26 times in the north, and 13 times in the south. Arsenic export by runoff was similar to atmospheric inputs at three sites, resulting in a near-zero As mass balance. One site exhibited a net export of As (2.2 g ha(-1) yr(-1)). In contrast, the preceding period (1995-2006) showed much higher As fluxes, and higher As export. Czech catchments do not serve as net sinks of atmospheric As. A considerable proportion of old industrial arsenic is flushed out of the soil. PMID- 20932621 TI - An economic evaluation of erythropoiesis-stimulating agents in CKD. AB - BACKGROUND: The objective was to determine the cost-effectiveness of treating anemic patients with chronic kidney disease (CKD) with erythropoiesis-stimulating agents (ESAs) to a low (9-10.9 g/dL), intermediate (11-12 g/dL), or high (> 12 g/dL) hemoglobin level target compared with a strategy of managing anemia without ESAs. STUDY DESIGN: Cost-utility analysis. SETTING & PARTICIPANTS: Publicly funded health care system. Anemic patients with CKD, overall and stratified into dialysis-/non-dialysis-dependent subgroups. MODEL, PERSPECTIVE, & TIMEFRAME: Decision analysis, health care payer, patient's lifetime. MAIN OUTCOME: Cost per quality-adjusted life-year (QALY) gained. RESULTS: For dialysis patients, compared with anemia management without ESAs, using ESAs to target a low hemoglobin level is associated with a cost per QALY of $96,270. Given a lack of direct trials comparing low and intermediate targets, significant uncertainty exists between these strategies. Treatment to a high hemoglobin target was always associated with worse clinical outcomes and higher costs compared with a low hemoglobin target. Results were similar in non-dialysis-dependent patients with CKD, with a cost per QALY for a low target compared with no ESA of $147,980. LIMITATIONS: Given limitations in the available randomized controlled trials, we were able to model only 4 treatment strategies, balancing the need to consider relevant targets with the requirement for accurate estimates of clinical effect. We assumed that the efficacy of the different strategies would continue over a patient's lifetime. CONCLUSIONS: Using ESAs to target a hemoglobin level > 12 g/dL is associated with worse clinical outcomes and significant additional cost compared with using ESAs to target lower hemoglobin levels (9-12 g/dL). Given a lack of studies comparing low (9-10.9 g/dL) and intermediate (11-12 g/dL) hemoglobin targets for clinical outcomes, including quality of life, the most cost-effective hemoglobin level target within the range of 9-12 g/dL is uncertain, although aiming for higher targets within this range will lead to higher costs. PMID- 20932622 TI - Spontaneous remission of IgA nephropathy associated with resolution of hepatitis A. AB - Although most cases of immunoglobulin A (IgA) nephropathy are idiopathic, several diseases are associated with IgA nephropathy. Of these, chronic liver disease resulting from hepatitis B or C virus infection has been reported as a secondary cause of IgA nephropathy. Recently, hepatitis A virus (HAV)-associated kidney disease has received attention because acute kidney injury can occur as a complication of HAV infection, generally caused by acute tubular necrosis or interstitial nephritis. However, unlike IgA nephropathy related to hepatitis B or C, HAV-associated IgA nephropathy is extremely rare and long-term outcomes have not been reported yet. We describe a case of spontaneous remission of IgA nephropathy associated with serologically documented HAV infection. The patient presented with microhematuria and moderate proteinuria, but acute kidney injury did not occur during active hepatic injury. Kidney biopsy specimens clearly showed mesangial IgA deposits with intact tubules and interstitium. Serum liver enzyme levels returned to reference values 1 month after the onset of acute hepatitis, but urinary protein excretion remained increased. Approximately 1 year later, urinary abnormalities were resolved and a second biopsy showed no mesangial IgA deposits. These findings suggest that IgA nephropathy can transiently accompany HAV infection, but may not progress to chronic glomerulonephritis after recovery from HAV. PMID- 20932623 TI - Socioeconomic variation in the impact of obesity on health-related quality of life. AB - There is evidence that obesity has a negative impact on health-related quality of life (HRQL). However, little attention has been paid to variations in this impact between population groups. This study investigates the relationship between HRQL and obesity, and whether or not this relationship varies by socioeconomic status (SES). Data were taken from four rounds of the Health Survey for England (2003 2006; n = 33,716) for persons aged 16 and above. Banded total annual household income is regressed against a comprehensive set of SES indicators using interval regression. We use the equivalised predicted values from this model, categorised into quartiles, as our measure of SES. We regress EQ-5D scores against interactions between body mass index and SES categories. Obesity is negatively correlated with HRQL. The negative impact of obesity is greater in people from lower SES groups. Overweight and obese people in lower SES groups have lower HRQL than those of normal weight in the same SES group, and have lower HRQL than those in higher SES groups of the same weight. This trend is also observed after controlling for individual and household characteristics, although the statistical significance and magnitude of effects is diminished. PMID- 20932624 TI - [2nd international course of the ACREP (Reconstructive and esthetic surgery association of Picardie) on perforated flaps]. PMID- 20932626 TI - Atipic electrocardiographic manifestation of pulmonary embolism. PMID- 20932627 TI - Are patients brain-dead after successful resuscitation from cardiac arrest suitable as organ donors? A systematic review. AB - AIM: To compare the outcome of organs retrieved from patients brain dead due to cardiac arrest (CA) with that of organs retrieved from patients brain dead due to other causes (non-CA). METHODS: Systematic review. Clinical studies comparing the outcome of patients and organs retrieved from donors brain dead after being resuscitated from cardiac arrest with that of patients and organs retrieved from donors brain dead not due to cardiac arrest were considered for inclusion. Full text articles were searched on MEDLINE, EmBASE, Cochrane Register of Controlled Trials and Cochrane Register of Systematic Reviews. MAIN OUTCOME MEASURE: One year patient or organ survival rate. RESULTS: Four studies fulfilling inclusion criteria were found and three had sufficient quality to be included in final analysis. A total of 858 organs were transplanted from 741 donors. Since the transplanted organs (heart, liver, kidney, lung and intestine) were different in the three studies, metanalysis was not performed. There were no significant differences in 1-year survival rates between CA and non-CA groups. No significant differences were reported for 5-year survival rates, early recovery of transplanted organ function, and organ rejection rates. CONCLUSION: Survival rates of kidneys, livers, hearts and intestines retrieved from CA donors were not significantly different from that of organs transplanted from non-CA donors. Patients brain dead after having been resuscitated from cardiac arrest can be considered as potential donors for organ transplantation. PMID- 20932628 TI - Retention into internship of resuscitation skills learned in a medical student resuscitation program incorporating an Immediate Life Support course. AB - AIMS: This study describes the acquisition and retention of resuscitation skills by medical students during and following a vertically integrated training program incorporating an Immediate Life Support course (ILS): and the skills demonstrated by interns on entry to clinical practice. METHODS: Yearly resuscitation workshops were held in the final 3 years of a 6-year undergraduate medical curriculum. These consisted of a basic life support course in year 4; a resuscitation workshop including shock-advisory defibrillation in year 5; and an ILS course in year 6. A medical student cohort was tested during the course and at the beginning of internship. RESULTS: Before year 5 training, an average of 36.6% of students passed each criterion and this increased to 72.3% 10 weeks after training. Prior to the ILS course (approximately 6-18 months following year 5 training), this proportion had decreased to 35.2%; and on retesting as interns the proportion was 64.1%, with delay between ILS training and testing of between 3 and 9 months. The proportion of interns correctly performing airway opening, initial rescue breathing and ventilation technique was lower than other measured skills. Those with ILS training performed better in initial rescue breaths (p=0.03), ventilation technique (p=0.04), and recommencement of CPR without delay following defibrillation (p=0.02). CONCLUSIONS: A vertically integrated undergraduate resuscitation course appears to reinforce the maintenance of resuscitation skills until internship. Skills are maintained for at least 6-9 months following an ILS course. This may be due to the ILS course embedding the skills more thoroughly. PMID- 20932630 TI - Platonin mitigates acute lung injury in haemorrhagic shock rats. AB - AIM OF THE STUDY: Enhanced oxidative stress and inflammatory response are crucial in mediating the development of acute lung injury induced by haemorrhagic shock with resuscitation. Platonin, a potent antioxidant, possesses potent anti inflammation capacity. We sought to elucidate whether platonin could mitigate acute lung injury in haemorrhagic shock/resuscitation rats. METHODS: Seventy-two adult male rats were randomized to receive haemorrhagic shock/resuscitation (HS), HS plus platonin (10, 50, or 100MUg/kg intravenous injection immediately after resuscitation), sham instrumentation (Sham), or Sham plus platonin (100MUg/kg) (n=12 in each group). Haemorrhagic shock was induced by blood drawing and mean blood pressure was maintained at 40-45mmHg for 120min. Then, resuscitation was achieved by shed blood/saline mixtures re-infusion. After monitoring for another 8h, rats were sacrificed. RESULTS: Arterial blood gas and histological findings, in concert with assays of leukocyte infiltration (polymorphonuclear leukocytes/alveoli ratio and myeloperoxidase activity) and lung water content (wet/dry weight ratio), confirmed that haemorrhagic shock/resuscitation caused significant lung injury. Significant increases in concentrations of inflammatory molecules (chemokine, cytokine, and prostaglandin E(2)) as well as nitric oxide and malondialdehyde in lung tissues confirmed that haemorrhagic shock/resuscitation elicited inflammatory response and imposed oxidative stress in rats. Platonin at the dosages of 50 and 100MUg/kg, but not 10MUg/kg, significantly attenuated the inflammatory response and oxidative stress induced by haemorrhagic shock/resuscitation. Most important, platonin at the dosages of 50 and 100MUg/kg, but not 10MUg/kg, significantly mitigated the lung injury induced by haemorrhagic shock/resuscitation. CONCLUSIONS: Platonin mitigates acute lung injury in haemorrhagic shock/resuscitation rats. PMID- 20932631 TI - Continuous capnography and focused echocardiographic evaluation during resuscitation--additional criteria for cessation of treatment out-of-hospital cardiac arrest. PMID- 20932632 TI - Chest compression: not as effective on dental chair as on the floor. PMID- 20932633 TI - Constructing genuine savings indicators for Ireland, 1995-2005. AB - In this paper we compute the genuine savings indicators for the Republic of Ireland over the period 1995-2005. We expand and improve existing World Bank's estimates by: a) using data collected from official Irish sources; b) employing the net present value method to assess resource depreciation; c) including external costs from SO(2) and NOx emissions; and d) estimating human capital accumulation using the returns to education. We also perform a sensitivity analysis to check the robustness of our estimates to different assumptions and parameters. Our estimates are consistently smaller than the World Bank's and negative in the first years of the period considered. PMID- 20932634 TI - Estimating the volatilization of ammonia from synthetic nitrogenous fertilizers used in China. AB - Although it has long been recognized that significant amounts of nitrogen, typically in the form of ammonia (NH(3)) applied as fertilizer, are lost to the atmosphere, accurate estimates are lacking for many locations. In this study, a detailed, bottom-up method for estimating NH(3) emissions from synthetic fertilizers in China was used. The total amount emitted in 2005 in China was estimated to be 3.55 Tg NH(3)-N, with an uncertainty of +/- 50%. This estimate was considerably lower than previously published values. Emissions from urea and ammonium bicarbonate accounted for 64.3% and 26.5%, respectively, of the 2005 total. The NH(3) emission inventory incorporated 2448 county-level data points, categorized on a monthly basis, and was developed with more accurate activity levels and emission factors than had been used in previous assessments. There was considerable variability in the emissions within a province. The NH(3) emissions generally peaked in the spring and summer, accounting for 30.1% and 48.8%, respectively, of total emissions in 2005. The peaks correlated with crop planting and fertilization schedules. The NH(3) regional distribution pattern showed strong correspondence with planting techniques and local arable land areas. The regions with the highest atmospheric losses are located in eastern China, especially the North China Plain and the Taihu region. PMID- 20932635 TI - Magnetic composite prepared from palm shell-based carbon and application for recovery of residual oil from POME. AB - Magnetic separation combined with adsorption by activated carbon has been found to be a useful method for removing pollutants. In this paper, the use of palm shell as a source of activated carbon for the removal and recovery of oil from palm oil mill effluent (POME) is studied. In the first part of the study, the properties of samples of activated carbon prepared from palm shell under a variety of different conditions were characterized for their hydrophobicity, surface areas and pore size distribution. The most effective of the activated carbon samples was prepared by impregnation with ZnCl(2) followed by combined physical/chemical activation under carbon dioxide flow at 800 degrees C. Four grams of these samples adsorbed 90% of the oil from 50 mL POME. In the second part, the palm shell-based carbon samples were given magnetic properties by the technique of iron oxide deposition. Ninety-four percent of the activated carbon/iron oxide composite containing the adsorbed oil could be extracted from the POME by a magnetic bar of 0.15 T. Four grams of the composite can remove 85% of oil from 50 mL POME and a total of 67% of the initial oil can then be recovered by hexane extraction. Powder X-ray diffractometry showed the presence of magnetite and maghemite in the activated carbon/iron oxide composite. PMID- 20932636 TI - Mapping socio-economic scenarios of land cover change: a GIS method to enable ecosystem service modelling. AB - We present a GIS method to interpret qualitatively expressed socio-economic scenarios in quantitative map-based terms. (i) We built scenarios using local stakeholders and experts to define how major land cover classes may change under different sets of drivers; (ii) we formalized these as spatially explicit rules, for example agriculture can only occur on certain soil types; (iii) we created a future land cover map which can then be used to model ecosystem services. We illustrate this for carbon storage in the Eastern Arc Mountains of Tanzania using two scenarios: the first based on sustainable development, the second based on 'business as usual' with continued forest-woodland degradation and poor protection of existing forest reserves. Between 2000 and 2025 4% of carbon stocks were lost under the first scenario compared to a loss of 41% of carbon stocks under the second scenario. Quantifying the impacts of differing future scenarios using the method we document here will be important if payments for ecosystem services are to be used to change policy in order to maintain critical ecosystem services. PMID- 20932637 TI - Decreasing rate and extent of lymph node staging in patients undergoing radical prostatectomy may undermine the rate of diagnosis of lymph node metastases in prostate cancer. AB - BACKGROUND: At radical prostatectomy (RP), pelvic lymph node dissection (PLND) represents the most accurate staging procedure for the presence of lymph node (LN) metastases. OBJECTIVE: We evaluated the rate of PLND use and its lymph node count (LNC) over the last two decades. We also tested the relationship between LNC and the rate of pN1 stage. DESIGN, SETTING, AND PARTICIPANTS: Between 1988 and 2006, 130,080 RPs were recorded in 17 Surveillance Epidemiology and End Results registries. MEASUREMENTS: The statistical significance of temporal trends was evaluated with the chi-square trend test. Separate univariable and multivariable regression analyses tested the relationship between predictors and two end points: (1) lack of LN staging (pNx) and (2) presence of LN metastases (pN1). RESULTS AND LIMITATIONS: Stage pNx was recorded in 25.9% of patients, and pNx rate was higher in more contemporary years (30.1% in 2000-2006 vs 20.8% in 1988-1993; multivariable p < 0.001). When PLND was performed, an average of 7.4 LNs (median: 6) were removed. The average LNC decreased from 12.0 nodes (median: 12) in 1988 to 6.0 nodes (median: 4) in 2006. Overall pN1 rate was 3.4% and decreased from 10.7% to 3.1% between 1988 and 2006 (p < 0.001). LNC was an independent predictor of pN1 stage (multivariable p < 0.001). CONCLUSIONS: An increasingly larger proportion of prostate cancer patients remain without LN staging at RP. Fewer LNs were removed at PLND over time, resulting in fewer patients diagnosed with pN1 stage at RP. The impact of this phenomenon on cancer control outcomes is still to be verified. PMID- 20932638 TI - Fault detection using dynamic time warping (DTW) algorithm and discriminant analysis for swine wastewater treatment. AB - This paper proposes a diagnosis system using dynamic time warping (DTW) and discriminant analysis with oxidation-reduction potential (ORP) and dissolved oxygen (DO) values for swine wastewater treatment. A full-scale sequencing batch reactor (SBR), which has an effective volume of 20 m(3), was auto-controlled, and the reaction phase was performed by a sub-cycle operation consisting of a repeated short cycle of the anoxic-aerobic step. Using ORP and DO profiles, SBR status was divided into four categories of normal and abnormal cases; these were influent disturbance, aeration controller fault, instrument trouble and inadequate raw wastewater feeding. Through the DTW process, difference values (D) were determined and classified into seven cases. In spite of the misclassification of high loading rates, the ORP profile provided good diagnosis results. However, the DO profiles detected five misclassifications that indicated different statuses. After the DTW process, several statistical values, including maximum value, minimum value, average value, standard deviation value and three quartile values, were extracted and applied to establish the discriminant function. The discriminant analysis allows one to classify seven cases with a percentage of 100% and 92.7% for ORP and DO profiles, respectively. Consequently, the study showed that ORP profiles are more efficient than DO profiles as diagnosis parameters and DTW diagnosis algorithms and discriminants. PMID- 20932639 TI - Evaluation of blends bauxite-calcination-method red mud with other industrial wastes as a cementitious material: properties and hydration characteristics. AB - Red mud is generated from alumina production, and its disposal is currently a worldwide problem. In China, large quantities of red mud derived from bauxite calcination method are being discharged annually, and its utilization has been an urgent topic. This experimental research was to evaluate the feasibility of blends red mud derived from bauxite calcination method with other industrial wastes for use as a cementitious material. The developed cementitious material containing 30% of the bauxite-calcination-method red mud possessed compressive strength properties at a level similar to normal Portland cement, in the range of 45.3-49.5 MPa. Best compressive strength values were demonstrated by the specimen RSFC2 containing 30% bauxite-calcination-method red mud, 21% blast-furnace slag, 10% fly ash, 30% clinker, 8% gypsum and 1% compound agent. The mechanical and physical properties confirm the usefulness of RSFC2. The hydration characteristics of RSFC2 were characterized by XRD, FTIR, (27)Al MAS-NMR and SEM. As predominant hydration products, ettringite and amorphous C-S-H gel are principally responsible for the strength development of RSFC2. Comparing with the traditional production for ordinary Portland cement, this green technology is easier to be implemented and energy saving. This paper provides a key solution to effectively utilize bauxite-calcination-method red mud. PMID- 20932640 TI - Biodegradation of anthracene by Aspergillus fumigatus. AB - An anthracene-degrading strain, identified as Aspergillus fumigatus, showed a favorable ability in degradation of anthracene. The degradation efficiency could be maintained at about 60% after 5d with initial pH of the medium kept between 5 and 7.5, and the optimal temperature of 30 degrees C. The activity of this strain was not affected significantly by high salinity. Exploration on co metabolism showed that the highest degradation efficiency was reached at equal concentration of lactose and anthracene. Excessive carbon source would actually hamper the degradation efficiency. Meanwhile, the strain could utilize some aromatic hydrocarbons such as benzene, toluene, phenol etc. as sole source of carbon and energy, indicating its degradation diversity. Experiments on enzymatic degradation indicated that extracellular enzymes secreted by A. fumigatus could metabolize anthracene effectively, in which the lignin peroxidase may be the most important constituent. Analysis of ion chromatography showed that the release of anions of A. fumigatus was not affected by addition of anthracene. GC-MS analysis revealed that the molecular structure of anthracene changed with the action of the microbe, generating a series of intermediate compounds such as phthalic anhydride, anthrone and anthraquinone by ring-cleavage reactions. PMID- 20932641 TI - Ultrasonic recovery of copper and iron through the simultaneous utilization of Printed Circuit Boards (PCB) spent acid etching solution and PCB waste sludge. AB - A method was developed to recover the copper and iron from Printed Circuit Boards (PCB) manufacturing generated spent acid etching solution and waste sludge with ultrasonic energy at laboratory scale. It demonstrated that copper-containing PCB spent etching solution could be utilized as a leaching solution to leach copper from copper contained PCB waste sludge. It also indicated that lime could be used as an alkaline precipitating agent in this method to precipitate iron from the mixture of acidic PCB spent etching solution and waste sludge. This method provided an effective technique for the recovery of copper and iron through simultaneous use of PCB spent acid solution and waste sludge. The leaching rates of copper and iron enhanced with ultrasound energy were reached at 93.76% and 2.07% respectively and effectively separated copper from iron. Followed by applying lime to precipitate copper from the mixture of leachate and rinsing water produced by the copper and iron separation, about 99.99% and 1.29% of soluble copper and calcium were settled as the solids respectively. Furthermore the settled copper could be made as commercial rate copper. The process performance parameters studied were pH, ultrasonic power, and temperature. This method provided a simple and reliable technique to recover copper and iron from waste streams generated by PCB manufacturing, and would significantly reduce the cost of chemicals used in the recovery. PMID- 20932642 TI - Removal of 1-naphthylamine from aqueous solution by multiwall carbon nanotubes/iron oxides/cyclodextrin composite. AB - The adsorption of 1-naphthylamine on multiwall carbon nanotubes/iron oxides/beta cyclodextrin composite (denoted by MWCNTs/iron oxides/CD) prepared by using plasma-induced grafting technique was investigated by batch technique under ambient conditions. The effect of contact time, pH, adsorbent content, temperature and initial 1-naphthylamine concentration, on 1-naphthylamine adsorption to MWCNTs/iron oxides/CD was examined. The adsorption of 1 naphthylamine on MWCNTs/iron oxides/CD was dependent on pH, adsorbent content, and temperature. The 1-napthylamien was adsorbed rapidly at the first 50h, and thereafter attained the adsorption saturation at 80h. The adsorption kinetic data were well described by the pseuso-second-order rate model. The adsorption isotherms were fitted by the Langmuir model better than by the Freundlich model. The maximum adsorption capacity of 1-naphthylamine was 200.0mg/g. The adsorption thermodynamic parameters of standard enthalpy (DeltaH(0)), standard entropy changes (DeltaS(0)), and standard free energy (DeltaG(0)) were calculated from temperature dependent adsorption isotherms. The values of DeltaH(0) and DeltaG(0) suggested that the adsorption of 1-naphthylamine on MWCNTs/iron oxides/CD was endothermic and spontaneous. The electron-donor-acceptor interaction, Hydrophobic interaction, and Lewis acid-base interaction may play an important role in 1 naphthylamine adsorption. The results show that MWCNTs/iron oxides/CD is a promising magnetic nanomaterial for the preconcentration and separation of organic pollutants from aqueous solutions in environmental pollution cleanup. PMID- 20932643 TI - Polysiloxane surface modified with bipyrazolic tripodal receptor for quantitative lead adsorption. AB - A new silica gel compound modified N,N-bis(3,5-dimethylpyrazol-1-ylmethyl) amine (SiN(2)Pz) was synthesized and characterized by elemental analysis, FT-IR, (13)C NMR of the solid state, nitrogen adsorption-desorption isotherm, BET surface area and BJH pore sizes. The new surface exhibits good chemical and thermal stability determined by thermogravimetry curves (TGA). The effect of pH and stirring time on the adsorption of Pb(II) were studied. The process of metal retention was followed by batch method and the optimum pH value for the quantitative adsorption of this toxic metal ion was 7. At this pH value, the new functionalized polysiloxane presents further improvements and shows higher affinity (123mg of Pb(2+)/g of silica) for the effective adsorption of Pb(II) compared to others described sorbents. The extracted amounts of Pb(II) were determined by atomic absorption measurements. PMID- 20932644 TI - Inputting history of heavy metals into the inland lake recorded in sediment profiles: Poyang Lake in China. AB - The temporal and spatial distribution of heavy metals (Cd, Hg, Pb, As and Cr) in Poyang Lake, the largest freshwater lake (3050 km(2)) in China, were studied based on the sedimentary profiles. For this purpose, eight sedimentary cores were selected which located at lake area, outfall of lake and the main branch rivers, respectively. High-resolution profiles with interval 2 cm were used for analyzing the concentration of metals, and the ages of them were determined by (210)Pb and (137)Cs isotopic dating. While studying the change of metals concentration with the age in profile, it is found that the concentration of them in sediments was influenced not only by the sources in history but also by the sediment types. Based on this detailed work, the inventory and burden of heavy metals per decade were estimated in lake area during the past 50 years. Significantly, rivers contribution ratio per decade was estimated to distinguish each river's contribution of heavy metals into lake while river-flux in history and metals concentration in profiles were considered as calculating factors. So, our research provides a proof to well understand the sedimentary history and the inputting history of heavy metals from main rivers into an inland lake. PMID- 20932645 TI - Role of the NKCC1 co-transporter in sensitization of spinal nociceptive neurons. AB - The Na(+), K(+), 2Cl(-) co-transporter type 1 (NKCC1) plays a pivotal role in hyperalgesia associated with inflammatory stimuli. NKCC1 contributes to maintain high [Cl(-)](i) in dorsal root ganglia (DRG) neurons which cause primary afferent depolarization (PAD) when GABA(A) receptors are activated. Enhanced GABA-induced depolarization, through increased NKCC1 activity, has been hypothesized to produce orthodromic spike activity of sufficient intensity to account for touch induced pain. In the present study, we investigate this hypothesis using in vivo electrophysiology on rat dorsal horn neurons; the effects of spinal blockade of NKCC1 on intraplantar capsaicin-induced sensitization of dorsal horn neurons were examined. Single wide dynamic range (WDR) and nociceptive specific (NS) neuron activity in the dorsal horn was recorded using glass microelectrodes in anesthetized rats. Dorsal horn neurons with a receptive field on the plantar surface of the hindpaw were studied. Neuronal responses to mechanical stimuli (brush, von Frey filaments) were recorded ten minutes before intraplantar injection of 0.3 ml 0.1% capsaicin (CAP), 40 min after CAP and 15 min after local application of the NKCC1 blocker bumetanide (BTD; 500 MUM) on the spinal cord. After CAP, low and high threshold stimulation of the cutaneous receptive field produced a significant enhancement in spike frequency over pre-CAP values in both WDR and NS neurons. Spinal BTD application reduced the spike frequency to baseline levels as well as attenuated the CAP-induced increases in background activity. Our data support the hypothesis that NKCC1 plays an important role in the sensitization of dorsal horn neurons following a peripheral inflammatory insult. PMID- 20932647 TI - The prevalence of Cryptosporidium, and identification of the Cryptosporidium horse genotype in foals in New York State. AB - To date, little is known about the prevalence, genotypes and zoonotic potential of Cryptosporidium spp. affecting horses, especially in North America. A cross sectional study was conducted in New York, USA between February 25th and May 1st 2009. Fecal samples were collected from three hundred and forty nine 1-10-week old foals and their dams on 14 different broodmare farms. All fecal samples were screened for Cryptosporidium spp. using a direct immunofluorescence assay (DFA). DNA extraction and PCR-RFLP analysis of the small-subunit (SSU) rRNA gene were performed on all the foal samples. PCR-positive samples were subtyped by DNA sequencing of the 60-kDa glycoprotein (gp60) gene. On DFA, 13/175 (7.4%) foal samples and 3/174 (1.7%) mare samples were designated positive for Cryptosporidium spp., whereas on SSU rRNA-based PCR, 9/175 (5.1%) foal samples were positive. Cryptosporidium PCR-positive foals were significantly older (13-40 days, median age of 28 days) compared with negative foals (4-67 days, median 18 days, p=0.02). The number of foals with diarrhea or soft feces was not significantly different between positive and negative foals (p=0.09). PCR-RFLP analysis of the SSU rRNA gene and DNA sequencing of the gp60 gene identified the parasite as subtype VIaA14G2 of the horse genotype. This is the first report of a group of foals affected with the Cryptosporidium horse genotype, which has recently been detected in humans. As other contemporary molecular studies have identified C. parvum in foals, it seems that equine cryptosporidiosis should be considered a zoonosis. PMID- 20932646 TI - Are prognostic indicators for poor outcome different for acute and chronic low back pain consulters in primary care? AB - Few studies have investigated whether prognostic indicators, which contribute to the transition from acute to chronic low back pain (LBP), are also those which contribute to continuing persistence of chronic LBP. We compared the contribution of physical, psychological and social indicators to predicting disability after one year between consulters with LBP of less than 3 months duration and more than 3 months duration. Data from two large prospective cohort studies of consecutive patients consulting with LBP in general practices were merged, providing complete data for 258 cases with acute/subacute LBP and 668 cases with chronic LBP at 12 months follow-up. There were significant differences between the two LBP groups in baseline characteristics and clinical course of disability, assessed by Roland Morris Disability Questionnaire, during the year of follow-up. Adjusted associations between potential prognostic indicators and disability at 12months were carried out in the two LBP subgroups. The final multivariable regression models showed that being non-employed, having widespread pain, a high level of Chronic Pain Grade, and catastrophising were the strongest prognostic indicators for disability at 12 months in both LBP groups. Fear of pain was significantly associated with disability in chronic LBP. Importantly, beyond baseline disability, the effect size of the other prognostic indicators for poor outcome was rather low. These findings must continue to challenge researchers to identify useful early predictors of outcome in persons with disabling back pain, as screening and targeted treatment approaches are dependent upon prognostic indicators with clinical significance. PMID- 20932648 TI - Early administration of trimetazidine may prevent or ameliorate diabetic cardiomyopathy. AB - Diabetic cardiomyopathy is a type of cardiac dysfunction resulting from diabetes, independent of vascular or valvular pathology. It clinically manifests initially as asymptomatic diastolic dysfunction and then progresses to symptomatic heart failure. Two major contributors to the development of diabetic cardiomyopathy, which are unique to diabetes, are hyperglycemia and diabetes-related alterations in myocardial metabolism. Diabetes mellitus is characterized by reduced glucose and lactate metabolism and enhanced fatty acid metabolism, which are the early consequences of the disease. Studies on the effect of intensive glucose control on heart failure events in patients with diabetes have been conducted with neutral results. However, no study on the effect of metabolic modulators on the prevention of heart failure has been reported. Trimetazidine, a 3-ketoacyl coenzyme A thiolase (3-KAT) inhibitor, shifts cardiac energy metabolism from free fatty acid oxidation to glucose oxidation by inhibiting mitochondrial long-chain 3-KAT, and is used clinically as an effective antianginal agent. Studies have shown that trimetazidine improves heart function in patients with idiopathic cardiomyopathy and in diabetic patients with cardiac ischemia or heart failure. In addition to being effective, trimetazidine has only mild side effects. Therefore, instead of routine administration of trimetazidine for the treatment of diabetic cardiomyopathy, we hypothesize that the early application of trimetazidine may prevent or ameliorate diabetic cardiomyopathy. In addition to life style modifications, ACEI, ARB, and beta-blockers, which have been recommended in the past, trimetazidine should be administered to those patients with impaired glucose tolerance or patients in the early course of diabetes. In this way, we may reduce the prevalence of heart failure and improve the long-term survival of patients with diabetes through early normalization of the myocardial substrate metabolism. PMID- 20932649 TI - Wine, sirtuins and nephroprotection: not only resveratrol. AB - Resveratrol (RSV), a red wine component, and red wine itself exert cardio- and nephroprotective effects by modulating the Nitric Oxide system (NO). It has been shown that one of the main actions resulting from NO modulation is sirtuin regulation, especially SIRT-1 regulation. Elucidating both upstream and downstream molecular mechanisms of the SIRT-1 pathway is an open field of investigation that can explain its role not only in long-term processes, such as aging, but also in short-term processes, such as protection against ischemic damage. Our hypothesis suggests the importance of investigating compounds that are routine dietary components and do not necessarily contain RSV. Their nephroprotective activity could involve not only eNOS-dependent, but also NO dependent but eNOS-independent mechanisms, or other molecular alternative signaling systems. PMID- 20932650 TI - First evaluation of the biologic effectiveness factors of boron neutron capture therapy (BNCT) in a human colon carcinoma cell line. AB - PURPOSE: DNA lesions produced by boron neutron capture therapy (BNCT) and those produced by gamma radiation in a colon carcinoma cell line were analyzed. We have also derived the relative biologic effectiveness factor (RBE) of the neutron beam of the RA-3- Argentine nuclear reactor, and the compound biologic effectiveness (CBE) values for p-boronophenylalanine ((10)BPA) and for 2,4-bis (alpha,beta dihydroxyethyl)-deutero-porphyrin IX ((10)BOPP). METHODS AND MATERIALS: Exponentially growing human colon carcinoma cells (ARO81-1) were distributed into the following groups: (1) BPA (10 ppm (10)B) + neutrons, (2) BOPP (10 ppm (10)B) + neutrons, (3) neutrons alone, and (4) gamma rays ((60)Co source at 1 Gy/min dose-rate). Different irradiation times were used to obtain total absorbed doses between 0.3 and 5 Gy (+/-10%) (thermal neutrons flux = 7.5 10(9) n/cm(2) sec). RESULTS: The frequency of micronucleated binucleated cells and the number of micronuclei per micronucleated binucleated cells showed a dose-dependent increase until approximately 2 Gy. The response to gamma rays was significantly lower than the response to the other treatments (p < 0.05). The irradiations with neutrons alone and neutrons + BOPP showed curves that did not differ significantly from, and showed less DNA damage than, irradiation with neutrons + BPA. A decrease in the surviving fraction measured by 3-(4,5-dimetiltiazol-2-il)-2,5 difeniltetrazolium bromide (MTT) assay as a function of the absorbed dose was observed for all the treatments. The RBE and CBE factors calculated from cytokinesis block micronucleus (CBMN) and MTT assays were, respectively, the following: beam RBE: 4.4 +/- 1.1 and 2.4 +/- 0.6; CBE for BOPP: 8.0 +/- 2.2 and 2.0 +/- 1; CBE for BPA: 19.6 +/- 3.7 and 3.5 +/- 1.3. CONCLUSIONS: BNCT and gamma irradiations showed different genotoxic patterns. To our knowledge, these values represent the first experimental ones obtained for the RA-3 in a biologic model and could be useful for future experimental studies for the application of BNCT to colon carcinoma. PMID- 20932651 TI - Phase I trial of hypofractionated intensity-modulated radiotherapy with temozolomide chemotherapy for patients with newly diagnosed glioblastoma multiforme. AB - PURPOSE: To determine the maximal tolerated biologic dose intensification of radiotherapy using fractional dose escalation with temozolomide (TMZ) chemotherapy in patients with newly diagnosed glioblastoma multiforme. METHODS AND MATERIALS: Patients with newly diagnosed glioblastoma multiforme after biopsy or resection and with adequate performance status, bone marrow, and organ function were eligible. The patients underwent postoperative intensity-modulated radiotherapy (IMRT) with concurrent and adjuvant TMZ. All patients received a total dose of 60 Gy to the surgical cavity and residual tumor, with a 5-mm margin. IMRT biologic dose intensification was achieved by escalating from 3 Gy/fraction (Level 1) to 6 Gy/fraction (Level 4) in 1-Gy increments. Concurrent TMZ was given at 75 mg/m(2)/d for 28 consecutive days. Adjuvant TMZ was given at 150-200 mg/m(2)/d for 5 days every 28 days. Dose-limiting toxicity was defined as any Common Terminology Criteria for Adverse Events, version 3, Grade 3-4 nonhematologic toxicity, excluding Grade 3 fatigue, nausea, and vomiting. A standard 3+3 Phase I design was used. RESULTS: A total of 16 patients were accrued (12 men and 4 women, median age, 69 years; range, 34-84. The median Karnofsky performance status was 80 (range, 60-90). Of the 16 patients, 3 each were treated at Levels 1 and 2, 4 at Level 3, and 6 at Level 4. All patients received IMRT and concurrent TMZ according to the protocol, except for 1 patient, who received 14 days of concurrent TMZ. The median number of adjuvant TMZ cycles was 7.5 (range, 0-12). The median survival was 16.2 months (range, 3-33). One patient experienced vision loss in the left eye 7 months after IMRT. Four patients underwent repeat surgery for suspected tumor recurrence 6-12 months after IMRT; 3 had radionecrosis. CONCLUSIONS: The maximal tolerated IMRT fraction size was not reached in our study. Our results have shown that 60 Gy IMRT delivered in 6-Gy fractions within 2 weeks with concurrent and adjuvant TMZ is tolerable in selected patients with a T(1)-weighted enhancing tumor <6 cm. PMID- 20932652 TI - Dynamics of delayed p53 mutations in mice given whole-body irradiation at 8 weeks. AB - PURPOSE: Ionizing irradiation might induce delayed genotoxic effects in a p53 dependent manner. However, a few reports have shown a p53 mutation as a delayed effect of radiation. In this study, we investigated the p53 gene mutation by the translocation frequency in chromosome 11, loss of p53 alleles, p53 gene methylation, p53 nucleotide sequence, and p53 protein expression/phosphorylation in p53(+/+) and p53(+/-) mice after irradiation at a young age. METHODS AND MATERIALS: p53(+/+) and p53(+/-) mice were exposed to 3 Gy of whole-body irradiation at 8 weeks of age. Chromosome instability was evaluated by fluorescence in situ hybridization analysis. p53 allele loss was evaluated by polymerase chain reaction, and p53 methylation was evaluated by methylation specific polymerase chain reaction. p53 sequence analysis was performed. p53 protein expression was evaluated by Western blotting. RESULTS: The translocation frequency in chromosome 11 showed a delayed increase after irradiation. In old irradiated mice, the number of mice that showed p53 allele loss and p53 methylation increased compared to these numbers in old non-irradiated mice. In two old irradiated p53(+/-) mice, the p53 sequence showed heteromutation. In old irradiated mice, the p53 and phospho-p53 protein expressions decreased compared to old non-irradiated mice. CONCLUSION: We concluded that irradiation at a young age induced delayed p53 mutations and p53 protein suppression. PMID- 20932653 TI - Objective and longitudinal assessment of dermatitis after postoperative accelerated partial breast irradiation using high-dose-rate interstitial brachytherapy in patients with breast cancer treated with breast conserving therapy: reduction of moisture deterioration by APBI. AB - PURPOSE: To objectively evaluate the radiation dermatitis caused by accelerated partial breast irradiation (APBI) using high-dose-rate interstitial brachytherapy. PATIENTS AND METHODS: The skin color and moisture changes were examined using a newly installed spectrophotometer and corneometer in 22 patients who had undergone APBI using open cavity implant high-dose-rate interstitial brachytherapy (36 Gy in six fractions) and compared with the corresponding values for 44 patients in an external beam radiotherapy (EBRT) control group (50-60 Gy in 25-30 fractions within 5-6 weeks) after breast conserving surgery. RESULTS: All values changed significantly as a result of APBI. The extent of elevation in a* (reddish) and reduction in L* (black) values caused by APBI were similar to those for EBRT, with slightly delayed recovery for 6-12 months after treatment owing to the surgical procedure. In contrast, only APBI caused a change in the b* values, and EBRT did not, demonstrating that the reduction in b* values (yellowish) depends largely on the surgical procedure. The changes in moisture were less severe after APBI than after EBRT, and the recovery was more rapid. The toxicity assessment using the Common Toxicity Criteria, version 3, showed that all dermatitis caused by APBI was Grade 2 or less. CONCLUSION: An objective analysis can quantify the effects of APBI procedures on color and moisture cosmesis. The radiation dermatitis caused by APBI using the present schedule showed an equivalent effect on skin color and a less severe effect on moisture than the effects caused by standard EBRT. PMID- 20932654 TI - Genome-wide association study to identify single nucleotide polymorphisms (SNPs) associated with the development of erectile dysfunction in African-American men after radiotherapy for prostate cancer. AB - PURPOSE: To identify single nucleotide polymorphisms (SNPs) associated with erectile dysfunction (ED) among African-American prostate cancer patients treated with external beam radiation therapy. METHODS AND MATERIALS: A cohort of African American prostate cancer patients treated with external beam radiation therapy was observed for the development of ED by use of the five-item Sexual Health Inventory for Men (SHIM) questionnaire. Final analysis included 27 cases (post treatment SHIM score <=7) and 52 control subjects (post-treatment SHIM score >=16). A genome-wide association study was performed using approximately 909,000 SNPs genotyped on Affymetrix 6.0 arrays (Affymetrix, Santa Clara, CA). RESULTS: We identified SNP rs2268363, located in the follicle-stimulating hormone receptor (FSHR) gene, as significantly associated with ED after correcting for multiple comparisons (unadjusted p = 5.46 * 10(-8), Bonferroni p = 0.028). We identified four additional SNPs that tended toward a significant association with an unadjusted p value < 10(-6). Inference of population substructure showed that cases had a higher proportion of African ancestry than control subjects (77% vs. 60%, p = 0.005). A multivariate logistic regression model that incorporated estimated ancestry and four of the top-ranked SNPs was a more accurate classifier of ED than a model that included only clinical variables. CONCLUSIONS: To our knowledge, this is the first genome-wide association study to identify SNPs associated with adverse effects resulting from radiotherapy. It is important to note that the SNP that proved to be significantly associated with ED is located within a gene whose encoded product plays a role in male gonad development and function. Another key finding of this project is that the four SNPs most strongly associated with ED were specific to persons of African ancestry and would therefore not have been identified had a cohort of European ancestry been screened. This study demonstrates the feasibility of a genome-wide approach to investigate genetic predisposition to radiation injury. PMID- 20932655 TI - Lung density changes after stereotactic radiotherapy: a quantitative analysis in 50 patients. AB - PURPOSE: Radiologic lung density changes are observed in more than 50% of patients after stereotactic body radiotherapy (SBRT) for lung cancer. We studied the relationship between SBRT dose and posttreatment computed tomography (CT) density changes, a surrogate for lung injury. METHODS AND MATERIALS: The SBRT fractionation schemes used to treat Stage I lung cancer with RapidArc were three fractions of 18 Gy, five fractions of 11 Gy, or eight fractions of 7.5 Gy, prescribed at the 80% isodose. Follow-up CT scans performed at less than 6 months (n = 50) and between 6 and 9 months (n = 30) after SBRT were reviewed. Posttreatment scans were coregistered with baseline scans using a B-spline deformable registration algorithm. Voxel-Hounsfield unit histograms were created for doses between 0.5 and 50 Gy. Linear mixed effects models were used to assess the effects of SBRT dose on CT density, and the influence of possible confounders was tested. RESULTS: Increased CT density was associated with higher dose, increasing planning target volume size, and increasing time after SBRT (all p < 0.0001). Density increases were apparent in areas receiving >6 Gy, were most prominent in areas receiving >20 Gy, and seemed to plateau above 40 Gy. In regions receiving >36 Gy, the reduction in air-filled fraction of lung after treatment was up to 18%. No increase in CT density was observed in the contralateral lung receiving >=3 Gy. CONCLUSIONS: A dose-response relationship exists for quantitative CT density changes after SBRT. A threshold of effect is seen at low doses, and a plateau at highest doses. PMID- 20932657 TI - Prospective phase I-II trial of helical tomotherapy with or without chemotherapy for postoperative cervical cancer patients. AB - PURPOSE: To investigate, in a prospective trial, the acute and chronic toxicity of patients with cervical cancer treated with surgery and postoperative intensity modulated radiotherapy (RT) delivered using helical tomotherapy, with or without the administration of concurrent chemotherapy. PATIENTS AND METHODS: A total of 24 evaluable patients entered the study between March 2006 and August 2009. The indications for postoperative RT were tumor size, lymphovascular space invasion, and the depth of cervical stromal invasion in 15 patients; 9 patients underwent postoperative RT because of surgically positive lymph nodes. All patients underwent pelvic RT delivered with helical tomotherapy and intracavitary high dose-rate brachytherapy. Treatment consisted of concurrent weekly platinum in 17, sequential carboplatin/Taxol in 1, and RT alone in 6. The patients were monitored for acute and chronic toxicity using the Common Toxicity Criteria, version 3.0. RESULTS: The median follow-up was 24 months (range, 4-49). At the last follow-up visit, 23 patients were alive and disease free. Of the 24 patients, 12 (50%) experienced acute Grade 3 gastrointestinal toxicity (anorexia in 5, diarrhea in 4, and nausea in 3). One patient developed acute Grade 4 genitourinary toxicity (vesicovaginal fistula). For patients treated with concurrent chemotherapy, the incidence of acute Grade 3 and 4 hematologic toxicity was 71% and 24%, respectively. For patients treated without concurrent chemotherapy, the incidence of acute Grade 3 and 4 hematologic toxicity was 29% and 14%, respectively. Two long-term toxicities occurred (vesicovaginal fistula at 25 months and small bowel obstruction at 30 months). The overall and progression-free survival rate at 3 years for all patients was 100% and 89%, respectively. CONCLUSION: The results of our study have shown that postoperative external RT for cervical cancer delivered with helical tomotherapy and high-dose-rate brachytherapy and with or without chemotherapy is feasible, with acceptable acute and chronic toxicity. PMID- 20932656 TI - Phase II study of neoadjuvant bevacizumab and radiotherapy for resectable soft tissue sarcomas. AB - PURPOSE: Numerous preclinical studies have demonstrated that angiogenesis inhibitors can increase the efficacy of radiotherapy (RT). We sought to examine the safety and efficacy of bevacizumab (BV) and RT in soft tissue sarcomas and explore biomarkers to help determine the treatment response. METHODS AND MATERIALS: Patients with >=5 cm, intermediate- or high-grade soft tissue sarcomas at significant risk of local recurrence received neoadjuvant BV alone followed by BV plus RT before surgical resection. Correlative science studies included analysis of the serial blood and tumor samples and serial perfusion computed tomography scans. RESULTS: The 20 patients had a median tumor size of 8.25 cm, with 13 extremity, 1 trunk, and 6 retroperitoneal/pelvis tumors. The neoadjuvant treatment was well tolerated, with only 4 patients having Grade 3 toxicities (hypertension, liver function test elevation). BV plus RT resulted in >=80% pathologic necrosis in 9 (45%) of 20 tumors, more than double the historical rate seen with RT alone. Three patients had a complete pathologic response. The median microvessel density decreased 53% after BV alone (p <.05). After combination therapy, the median tumor cell proliferation decreased by 73%, apoptosis increased 10.4-fold, and the blood flow, blood volume, and permeability surface area decreased by 62-72% (p <.05). Analysis of gene expression microarrays of untreated tumors identified a 24-gene signature for treatment response. The microvessel density and circulating progenitor cells at baseline and the reduction in microvessel density and plasma soluble c-KIT with BV therapy also correlated with a good pathologic response (p <.05). After a median follow-up of 20 months, only 1 patient had developed local recurrence. CONCLUSIONS: The results from the present exploratory study indicated that BV increases the efficacy of RT against soft tissue sarcomas and might reduce the incidence of local recurrence. Thus, this regimen warrants additional investigation. Gene expression profiles and other tissue and circulating biomarkers showed promising correlations with treatment response. PMID- 20932658 TI - Phase II study of chemoradiotherapy with 5-fluorouracil and cisplatin for Stage II-III esophageal squamous cell carcinoma: JCOG trial (JCOG 9906). AB - PURPOSE: In this Phase II study, we evaluated the efficacy and toxicity of chemoradiotherapy (CRT) with cisplatin (CDDP) and 5-fluorouracil (5-FU) for Stage II-III esophageal squamous cell carcinoma (ESCC). PATIENTS AND METHODS: Patients with clinical Stage II-III (T1N1M0 or T2-3N0-1M0) thoracic ESCC were enrolled between April 2000 and March 2002. Chemotherapy comprised two courses of protracted infusion of 5-FU (400 mg/m(2)/day) on Days 1-5 and 8-12, and 2-h infusion of CDDP (40 mg/m(2)) on Days 1 and 8; this regimen was repeated every 5 weeks. Concurrent radiotherapy involved 60-Gy irradiation (30 fractions) for 8 weeks with a 2-week break. Responders received two courses of 5-FU (800 mg/m(2)/day) on Days 1-5 and CDDP (80 mg/m(2)) on Day 1. Final analysis was conducted in March 2007. Survival and late toxicities were monitored for 5 years. RESULTS: The characteristics of the 76 patients enrolled were as follows: median age, 61 years; male/female, 68/8; performance status 0/1, 59/17 patients; Stage IIA/IIB/III, 26/12/38 patients. Of the 74 eligible patients, 46 (62.2%) achieved complete response. Median survival time was 29 months, with 3- and 5-year survival rates of 44.7% and 36.8%, respectively. Acute toxicities included Grade 3/4 esophagitis (17%), nausea (17%), hyponatremia (16%), and infection without neutropenia (12%). Late toxicities comprised Grade 3/4 esophagitis (13%), pericardial (16%) and pleural (9%) effusion, and radiation pneumonitis (4%), causing 4 deaths. CONCLUSIONS: CRT is effective for Stage II-III ESCC with manageable acute toxicities and can provide a nonsurgical treatment option. However, further improvement is required for reduction in late toxicity. PMID- 20932659 TI - Long-term results after high-dose radiotherapy and adjuvant hormones in prostate cancer: how curable is high-risk disease? AB - PURPOSE: To analyze long-term outcome and prognostic factors for high-risk prostate cancer defined by National Comprehensive Cancer Network criteria treated with high-dose radiotherapy and androgen deprivation in a single institution. METHODS AND MATERIALS: A total of 306 patients treated between 1995 and 2007 in a radiation dose-escalation program fulfilled the National Comprehensive Cancer Network high-risk criteria. Median International Commission on Radiation Units and Measurements radiation dose was 78 Gy (range, 66.0-84.1 Gy). Long-term androgen deprivation (LTAD) was administered in 231 patients, short-term androgen deprivation (STAD) in 59 patients, and no hormones in 16 patients. The Phoenix (nadir plus 2 ng/mL) consensus definition was used for biochemical control. Multivariate analysis was performed to determine the independent prognostic impact of clinical and treatment factors. Median follow-up time was 64 months (range, 24-171 months). RESULTS: The actuarial overall survival at 5 and 10 years was 95.7% and 89.8%, respectively, and the corresponding biochemical disease-free survival (bDFS) was 89.5% and 67.2%, respectively. Fourteen patients (4.6%) developed distant metastasis. Multivariate analysis showed that Gleason score>7 (p=0.001), pretreatment prostate-specific antigen (PSA) level>20 ng/mL (p=0.037), higher radiation dose (p=0.005), and the use of adjuvant LTAD vs. STAD (p=0.011) were independent prognostic factors affecting bDFS in high-risk disease. The 5 year bDFS for patients treated with LTAD plus radiotherapy dose>78 Gy was 97%. CONCLUSIONS: For high-risk patients the present series showed that the use of LTAD in conjunction with higher doses (>78 Gy) of radiotherapy was associated with improved biochemical tumor control. We observed that the presence of Gleason sum>7 and pretreatment PSA level>20 ng/mL in the same patient represents a 6.8 times higher risk of PSA failure. These men could be considered for clinical trials with addition of novel agents. PMID- 20932660 TI - Preliminary experience in treatment of papillary and macular retinoblastoma: evaluation of local control and local complications after treatment with linear accelerator-based stereotactic radiotherapy with micromultileaf collimator as second-line or salvage treatment after chemotherapy. AB - PURPOSE: To determine the local control and complication rates for children with papillary and/or macular retinoblastoma progressing after chemotherapy and undergoing stereotactic radiotherapy (SRT) with a micromultileaf collimator. METHODS AND MATERIALS: Between 2004 and 2008, 11 children (15 eyes) with macular and/or papillary retinoblastoma were treated with SRT. The mean age was 19 months (range, 2-111). Of the 15 eyes, 7, 6, and 2 were classified as International Classification of Intraocular Retinoblastoma Group B, C, and E, respectively. The delivered dose of SRT was 50.4 Gy in 28 fractions using a dedicated micromultileaf collimator linear accelerator. RESULTS: The median follow-up was 20 months (range, 13-39). Local control was achieved in 13 eyes (87%). The actuarial 1- and 2-year local control rates were both 82%. SRT was well tolerated. Late adverse events were reported in 4 patients. Of the 4 patients, 2 had developed focal microangiopathy 20 months after SRT; 1 had developed a transient recurrence of retinal detachment; and 1 had developed bilateral cataracts. No optic neuropathy was observed. CONCLUSIONS: Linear accelerator based SRT for papillary and/or macular retinoblastoma in children resulted in excellent tumor control rates with acceptable toxicity. Additional research regarding SRT and its intrinsic organ-at-risk sparing capability is justified in the framework of prospective trials. PMID- 20932661 TI - Improved correlation of the neuropathologic classification according to adapted world health organization classification and outcome after radiotherapy in patients with atypical and anaplastic meningiomas. AB - PURPOSE: To evaluate the correlation between the 1993 and 2000/2007 World Health Organization (WHO) classification with the outcome in patients with high-grade meningiomas. PATIENTS AND METHODS: Between 1985 and 2004, 73 patients diagnosed with atypical or anaplastic meningiomas were treated with radiotherapy. Sections from the paraffin-embedded tumor material from 66 patients (90%) from 13 different pathology departments were re-evaluated according to the first revised WHO classification from 1993 and the revised classifications from 2000/2007. In 4 cases, the initial diagnosis meningioma was not reproducible (5%). Therefore, 62 patients with meningiomas were analyzed. RESULTS: All 62 tumors were reclassified according to the 1993 and 2000/2007 WHO classification systems. Using the 1993 system, 7 patients were diagnosed with WHO grade I meningioma (11%), 23 with WHO grade II (37%), and 32 with WHO grade III meningioma (52%). After scoring using the 2000/2007 system, we found 17 WHO grade I meningiomas (27%), 32 WHO grade II meningiomas (52%), and 13 WHO grade III meningiomas (21%). According to the 1993 classification, the difference in overall survival was not statistically significant among the histologic subgroups (p=.96). Using the 2000/2007 WHO classifications, the difference in overall survival became significant (p=.02). Of the 62 reclassified patients 29 developed tumor progression (47%). No difference in progression-free survival was observed among the histologic subgroups (p=.44). After grading according to the 2000/2007 WHO classifications, significant differences in progression-free survival were observed among the three histologic groups (p=.005). CONCLUSION: The new 2000/2007 WHO classification for meningiomas showed an improved correlation between the histologic grade and outcome. This classification therefore provides a useful basis to determine the postoperative indication for radiotherapy. According to our results, a comparison of the published data for future treatment decision making remains difficult when the histologic diagnosis has not been based on the new improved classification system. PMID- 20932662 TI - Early side effects of three-dimensional conformal external beam accelerated partial breast irradiation to a total dose of 40 Gy in one week (a phase II trial). AB - PURPOSE: Several accelerated partial breast irradiation (APBI) techniques are described in the literature, and apparently, the three-dimensional (3D)-conformal technique is being used increasingly. Nonetheless, the optimal radiation dose is not yet known. Here, we report feasibility and early toxicities of APBI delivering 40 Gy over 5 days, in a phase II trial. METHODS AND MATERIALS: From October 2007 to September 2008, 25 patients with pT1N0 cancer received 3D conformal APBI. The prescribed radiation dose was 40 Gy in 4-Gy fractions given twice daily. This technique used two minitangents and an "en face" electron field. Toxicities were systematically assessed at 1, 2, and 6 months and then once every 6 months. RESULTS: The planning tumor volume for evaluation (PTV_EVAL) coverage was adequate: the mean dose to the PTV_EVAL was 41.8 Gy (range, 41-42.4 Gy). Mean doses to the ipsilateral lung and heart were 1.6 Gy (range, 1.0-2.3 Gy) and 1.2 Gy (range, 1.0-1.6 Gy), respectively. One and two months after completion of APBI, most patients had no or mild erythema (n=16 patients at 1 month; n=25 patients at 2 months); none of these patients developed moist desquamation. After a median follow-up of 12 months, only 1 patient had a significant moderate field contracture (grade 2). Other reported late toxicities were grade 1. CONCLUSIONS: 3D-conformal APBI (with two minitangents and an "en face" electron field) using a total dose of 40 Gy in 10 fractions twice daily over 5 days achieved appropriate PTV_EVAL coverage and offered significant sparing of normal tissue. Early tolerance was excellent. PMID- 20932663 TI - Dependence of cell survival on iododeoxyuridine concentration in 35-keV photon activated Auger electron radiotherapy. AB - PURPOSE: To measure and compare Chinese hamster ovary cell survival curves using monochromatic 35-keV photons and 4-MV x-rays as a function of concentration of the radiosensitizer iododeoxyuridine (IUdR). METHODS AND MATERIALS: IUdR was incorporated into Chinese hamster ovary cell DNA at 16.6 +/- 1.9%, 12.0 +/- 1.4%, and 9.2 +/- 1.3% thymidine replacement. Cells were irradiated from 1 to 8 Gy with 35-keV synchrotron-generated photons and conventional radiotherapy 4-MV x-rays. The effects of the radiation were measured via clonogenic survival assays. Surviving fraction was plotted vs. dose and fit to a linear quadratic model. Sensitization enhancement ratios (SER(10)) were calculated as the ratio of doses required to achieve 10% surviving fraction for cells without and with DNA incorporated IUdR. RESULTS: At 4 MV, SER(10) values were 2.6 +/- 0.1, 2.2 +/- 0.1, and 1.5 +/- 0.1 for 16.6%, 12.0%, and 9.2% thymidine replacement, respectively. At 35 keV, SER(10) values were 4.1 +/- 0.2, 3.0 +/- 0.1, and 2.0 +/ 0.1, respectively, which yielded SER(10) ratios (35 keV:4 MV) of 1.6 +/- 0.1, 1.4 +/- 0.1, and 1.3 +/- 0.1, respectively. CONCLUSIONS: SER(10) increases monotonically with percent thymidine replacement by IUdR for both modalities. As compared to 4-MV x-rays, 35-keV photons produce enhanced SER(10) values whose ratios are linear with percent thymidine replacement and assumed to be due to Auger electrons contributing to enhanced dose to DNA. Although this Auger effectiveness factor is less than the radiosensitization factor of IUdR, both could be important for the clinical efficacy of IUdR radiotherapy. PMID- 20932664 TI - Clinical validation of atlas-based auto-segmentation of multiple target volumes and normal tissue (swallowing/mastication) structures in the head and neck. AB - PURPOSE: To validate and clinically evaluate autocontouring using atlas-based autosegmentation (ABAS) of computed tomography images. METHODS AND MATERIALS: The data from 10 head-and-neck patients were selected as input for ABAS, and neck levels I-V and 20 organs at risk were manually contoured according to published guidelines. The total contouring times were recorded. Two different ABAS strategies, multiple and single subject, were evaluated, and the similarity of the autocontours with the atlas contours was assessed using Dice coefficients and the mean distances, using the leave-one-out method. For 12 clinically treated patients, 5 experienced observers edited the autosegmented contours. The editing times were recorded. The Dice coefficients and mean distances were calculated among the clinically used contours, autocontours, and edited autocontours. Finally, an expert panel scored all autocontours and the edited autocontours regarding their adequacy relative to the published atlas. RESULTS: The time to autosegment all the structures using ABAS was 7 min/patient. No significant differences were observed in the autosegmentation accuracy for stage N0 and N+ patients. The multisubject atlas performed best, with a Dice coefficient and mean distance of 0.74 and 2 mm, 0.67 and 3 mm, 0.71 and 2 mm, 0.50 and 2 mm, and 0.78 and 2 mm for the salivary glands, neck levels, chewing muscles, swallowing muscles, and spinal cord-brainstem, respectively. The mean Dice coefficient and mean distance of the autocontours vs. the clinical contours was 0.8 and 2.4 mm for the neck levels and salivary glands, respectively. For the autocontours vs. the edited autocontours, the mean Dice coefficient and mean distance was 0.9 and 1.6 mm, respectively. The expert panel scored 100% of the autocontours as a "minor deviation, editable" or better. The expert panel scored 88% of the edited contours as good compared with 83% of the clinical contours. The total editing time was 66 min. CONCLUSION: Multiple-subject ABAS of computed tomography images proved to be a useful novel tool in the rapid delineation of target and normal tissues. Although editing of the autocontours is inevitable, a substantial time reduction was achieved using editing, instead of manual contouring (180 vs. 66 min). PMID- 20932665 TI - Repeat gamma knife radiosurgery for trigeminal neuralgia. AB - PURPOSE: Repeat gamma knife stereotactic radiosurgery (GKRS) for recurrent or persistent trigeminal neuralgia induces an additional response but at the expense of an increased incidence of facial numbness. The present series summarized the results of a repeat treatment series at Wake Forest University Baptist Medical Center, including a multivariate analysis of the data to identify the prognostic factors for treatment success and toxicity. METHODS AND MATERIALS: Between January 1999 and December 2007, 37 patients underwent a second GKRS application because of treatment failure after a first GKRS treatment. The mean initial dose in the series was 87.3 Gy (range, 80-90). The mean retreatment dose was 84.4 Gy (range, 60-90). The dosimetric variables recorded included the dorsal root entry zone dose, pons surface dose, and dose to the distal nerve. RESULTS: Of the 37 patients, 81% achieved a >50% pain relief response to repeat GKRS, and 57% experienced some form of trigeminal dysfunction after repeat GKRS. Two patients (5%) experienced clinically significant toxicity: one with bothersome numbness and one with corneal dryness requiring tarsorraphy. A dorsal root entry zone dose at repeat treatment of >26.6 Gy predicted for treatment success (61% vs. 32%, p = .0716). A cumulative dorsal root entry zone dose of >84.3 Gy (72% vs. 44%, p = .091) and a cumulative pons surface dose of >108.5 Gy (78% vs. 44%, p = .018) predicted for post-GKRS numbness. The presence of any post-GKRS numbness predicted for a >50% decrease in pain intensity (100% vs. 60%, p = .0015). CONCLUSION: Repeat GKRS is a viable treatment option for recurrent trigeminal neuralgia, although the patient assumes a greater risk of nerve dysfunction to achieve maximal pain relief. PMID- 20932666 TI - Prolongation of total treatment time because of infrequently missed days of treatment is not associated with inferior biochemical outcome after dose escalated radiation therapy for prostate cancer. AB - PURPOSE: Prolongation of treatment time with radiation therapy (RT) is associated with inferior disease control for many rapidly proliferating tumors, but it is uncertain whether the same effect is seen in prostate cancer. METHODS AND MATERIALS: 596 patients underwent with curative-intent RT for adenocarcinoma of the prostate. By National Comprehensive Cancer Network criteria, men were classified as having low-risk (30%), medium-risk (40%), or high-risk (30%) disease. The median RT dose was 72 Gy. Androgen-deprivation therapy (ADT) was used in 45%. The idealized treatment time was defined as the total elapsed time (including weekends) to complete treatment if started on a Monday. Missed days of treatment, defined as the number of days beyond the idealized treatment time, was recorded for all patients. Missed days were added to the end of therapy resulting in a longer treatment time. Analysis was conducted for missed days and other standard prognostic variables against freedom from biochemical failure (FFBF). RESULTS: The median number of missed days was 2 (range, -3 to 22). With a median follow-up of 51 months, men with 5 or more missed days had similar 4-year FFBF rates (79% vs. 83% in men with <5 missed days, p = 0.0809), especially in the subset of men receiving 74 Gy or greater (89% for both groups, p = 0.8008). Analysis of missed days was performed for the subsets of dose, ADT, and risk category. Men without ADT had a lower FFBF rate with more missed days (p = 0.0030), but this association was not seen in men treated to a dose of 74 Gy or greater (p = 0.7425). On multivariate analysis, dose (p = 0.0010), T stage (p = 0.0145), and prostate-specific antigen level (p < 0.0001) were associated with FFBF, but Gleason score (p = 0.1351) and missed days (p = 0.3767) were not. CONCLUSIONS: Slight prolongation of treatment time (e.g., <=7 days) was not associated with inferior FFBF, especially in men receiving an RT dose of 74 Gy or greater. PMID- 20932667 TI - Induction chemotherapy and continuous hyperfractionated accelerated radiotherapy (chart) for patients with locally advanced inoperable non-small-cell lung cancer: the MRC INCH randomized trial. AB - PURPOSE: Recent clinical trials and meta-analyses have shown that both CHART (continuous hyperfractionated accelerated radiation therapy) and induction chemotherapy offer a survival advantage over conventional radical radiotherapy for patients with inoperable non-small cell-lung cancer (NSCLC). This multicenter randomized controlled trial (INCH) was set up to assess the value of giving induction chemotherapy before CHART. METHODS AND MATERIALS: Patients with histologically confirmed, inoperable, Stage I-III NSCLC were randomized to induction chemotherapy (ICT) (three cycles of cisplatin-based chemotherapy followed by CHART) or CHART alone. RESULTS: Forty-six patients were randomized (23 in each treatment arm) from 9 UK centers. As a result of poor accrual, the trial was closed in December 2007. Twenty-eight patients were male, 28 had squamous cell histology, 34 were Stage IIIA or IIIB, and all baseline characteristics were well balanced between the two treatment arms. Seventeen (74%) of the 23 ICT patients completed the three cycles of chemotherapy. All 42 (22 CHART + 20 ICT) patients who received CHART completed the prescribed treatment. Median survival was 17 months in the CHART arm and 25 months in the ICT arm (hazard ratio of 0.60 [95% CI 0.31-1.16], p = 0.127). Grade 3 or 4 adverse events (mainly fatigue, dysphagia, breathlessness, and anorexia) were reported for 13 (57%) CHART and 13 (65%) ICT patients. CONCLUSIONS: This small randomized trial indicates that ICT followed by CHART is feasible and well tolerated. Despite closing early because of poor accrual, and so failing to show clear evidence of a survival benefit for the additional chemotherapy, the results suggest that CHART, and ICT before CHART, remain important options for the treatment of inoperable NSCLC and deserve further study. PMID- 20932668 TI - Radiation-induced liver fibrosis is mitigated by gene therapy inhibiting transforming growth factor-beta signaling in the rat. AB - PURPOSE: We determined whether anti-transforming growth factor-beta (TGF-beta) intervention could halt the progression of established radiation-induced liver fibrosis (RILF). METHODS AND MATERIALS: A replication-defective adenoviral vector expressing the extracellular portion of human TbetaRII and the Fc portion of immunoglobulin G fusion protein (AdTbetaRIIFc) was produced. The entire rat liver was exposed to 30 Gy irradiation to generate a RILF model (RILFM). Then, RILFM animals were treated with AdTbetaRIIFc (1 * 10(11) plaque-forming units [PFU] of TbetaRII), control virus (1 * 10(11) PFU of AdGFP), or saline. Delayed radiation liver injury was assessed by histology and immunohistochemistry. Chronic oxidative stress damage, hepatic stellate cell activation, and hepatocyte regeneration were also analyzed. RESULTS: In rats infected with AdTbetaRIIFc, fibrosis was significantly improved compared with rats treated with AdGFP or saline, as assessed by histology, hydroxyproline content, and serum level of hyaluronic acid. Compared with AdGFP rats, AdTbetaRIIFc-treated rats exhibited decreased oxidative stress damage and hepatic stellate cell activation and preserved liver function. CONCLUSIONS: Our results demonstrate that TGF-beta plays a critical role in the progression of liver fibrosis and suggest that anti TGF-beta intervention is feasible and ameliorates established liver fibrosis. In addition, chronic oxidative stress may be involved in the progression of RILF. PMID- 20932669 TI - Randomized trial of postoperative adjuvant therapy in Stage II and III rectal cancer to define the optimal sequence of chemotherapy and radiotherapy: 10-year follow-up. AB - PURPOSE: To determine the optimal sequence of postoperative adjuvant chemotherapy and radiotherapy in patients with Stage II or III rectal cancer. METHODS AND MATERIALS: A total of 308 patients were randomized to early (n = 155) or late (n = 153) radiotherapy (RT). Treatment included eight cycles of chemotherapy, consisting of fluorouracil 375 mg/m(2)/day and leucovorin 20 mg/m(2)/day, at 4 week intervals, and pelvic radiotherapy of 45 Gy in 25 fractions. Radiotherapy started on Day 1 of the first chemotherapy cycle in the early RT arm and on Day 1 of the third chemotherapy cycle in the late RT arm. RESULTS: At a median follow up of 121 months for surviving patients, disease-free survival (DFS) at 10 years was not statistically significantly different between the early and late RT arms (71% vs. 63%; p = 0.162). A total of 36 patients (26.7%) in the early RT arm and 49 (35.3%) in the late RT arm experienced recurrence (p = 0.151). Overall survival did not differ significantly between the two treatment groups. However, in patients who underwent abdominoperineal resection, the DFS rate at 10 years was significantly greater in the early RT arm than in the late RT arm (63% vs. 40%; p = 0.043). CONCLUSIONS: After the long-term follow-up duration, this study failed to show a statistically significant DFS advantage for early radiotherapy with concurrent chemotherapy after resection of Stage II and III rectal cancer. Our results, however, suggest that if neoadjuvant chemoradiation is not given before surgery, then early postoperative chemoradiation should be considered for patients requiring an abdominoperineal resection. PMID- 20932670 TI - Prognostic value of pretreatment carcinoembryonic antigen after definitive radiotherapy with or without concurrent chemotherapy for squamous cell carcinoma of the uterine cervix. AB - PURPOSE: To evaluate whether pretreatment carcinoembryonic antigen (CEA) levels have a prognostic role in patients after definitive radiotherapy for squamous cell carcinoma (SCC) of the uterine cervix. METHODS AND MATERIALS: A retrospective study of 550 patients was performed. The SCC antigen (SCC-Ag) and CEA levels were regarded as elevated when they were >=2 and >=5 ng/mL, respectively. A total of 208 patients underwent concurrent chemoradiotherapy (CCRT). The Kaplan-Meier method was used to calculate the distant metastasis (DM), local failure (LF), disease-free survival (DFS), and overall survival (OS) rates. Multivariate analysis was performed using the Cox proportional hazards model. The hazard ratio (HR) with 95% confidence interval (CI) was evaluated for the risk of a poor prognosis. RESULTS: Compared with the patients with normal CEA/SCC-Ag levels, CEA levels >=10 ng/mL but without elevated SCC-Ag levels was an independent factor for LF (HR, 51.81; 95% CI, 11.51-233.23; p < .001), DM (HR, 6.04; 95% CI, 1.58-23.01; p = .008), DFS (HR, 10.17; 95% CI, 3.18-32.56; p < .001), and OS (HR, 5.75; 95% CI, 1.82-18.18; p = .003) after RT alone. However, no significant role for CEA was noted in patients with SCC-Ag levels >=2 ng/mL. In patients undergoing CCRT, a CEA level >=10 ng/mL was an independent factor for LF (HR, 2.50; 95% CI, 1.01-6.21; p = .047), DM (HR, 3.41; 95% CI, 1.56-7.46; p = .002), DFS (HR, 2.73; 95% CI, 1.39-5.36; p = .003), and OS (HR, 3.93; 95% CI 1.99 7.75; p < .001). A SCC-Ag level of >=40 ng/mL was another prognostic factor for DM, DFS, and OS in patients undergoing not only CCRT, but also RT alone. The 5 year OS rate for CCRT patients with CEA <10 ng/mL and >=10 ng/mL was 75.3% and 35.8%, respectively (p < .001). CCRT was an independent factor for better OS (HR, 0.69; 95% CI, 0.50-0.97; p = .034). CONCLUSION: Pretreatment CEA levels in patients with SCC of the uterine cervix provide complementary information for predicting LF, DM, DFS, and OS, except for in patients with abnormal SCC-Ag levels before RT alone. More aggressive therapy might be advisable for patients with CEA levels of >=10 ng/mL. PMID- 20932671 TI - Combining carbon ion radiotherapy and local injection of alpha-galactosylceramide pulsed dendritic cells inhibits lung metastases in an in vivo murine model. AB - PURPOSE: Our previous report indicated that carbon ion beam irradiation upregulated membrane-associated immunogenic molecules, underlining the potential clinical application of radioimmunotherapy. The antimetastatic efficacy of local combination therapy of carbon ion radiotherapy and immunotherapy was examined by use of an in vivo murine model. METHODS AND MATERIALS: Tumors of mouse squamous cell carcinoma (NR-S1) cells inoculated in the legs of C3H/HeSlc mice were locally irradiated with a single 6-Gy dose of carbon ions (290 MeV/nucleon, 6-cm spread-out Bragg peak). Thirty-six hours after irradiation, alpha galactosylceramide-pulsed dendritic cells (DCs) were injected into the leg tumor. We investigated the effects on distant lung metastases by counting the numbers of lung tumor colonies, making pathologic observations, and assessing immunohistochemistry. RESULTS: The mice with no treatment (control) presented with 168 +/- 53.8 metastatic nodules in the lungs, whereas the mice that received the combination therapy of carbon ion irradiation and DCs presented with 2.6 +/- 1.9 (P = 0.009) at 2 weeks after irradiation. Immunohistochemistry showed that intracellular adhesion molecule 1, which activates DCs, increased from 6 h to 36 h after irradiation in the local tumors of the carbon ion-irradiated group. The expression of S100A8 in lung tissue, a marker of the lung pre-metastatic phase, was decreased only in the group with a combination of carbon ions and DCs. CONCLUSIONS: The combination of carbon ion radiotherapy with the injection of alpha-galactosylceramide-pulsed DCs into the primary tumor effectively inhibited distant lung metastases. PMID- 20932672 TI - Parameters favorable to intraprostatic radiation dose escalation in men with localized prostate cancer. AB - PURPOSE: To identify , within the framework of a current Phase I trial, whether factors related to intraprostatic cancer lesions (IPLs) or individual patients predict the feasibility of high-dose intraprostatic irradiation. METHODS AND MATERIALS: Endorectal coil MRI scans of the prostate from 42 men were evaluated for dominant IPLs. The IPLs, prostate, and critical normal tissues were contoured. Intensity-modulated radiotherapy plans were generated with the goal of delivering 75.6 Gy in 1.8-Gy fractions to the prostate, with IPLs receiving a simultaneous integrated boost of 3.6 Gy per fraction to a total dose of 151.2 Gy, 200% of the prescribed dose and the highest dose cohort in our trial. Rectal and bladder dose constraints were consistent with those outlined in current Radiation Therapy Oncology Group protocols. RESULTS: Dominant IPLs were identified in 24 patients (57.1%). Simultaneous integrated boosts (SIB) to 200% of the prescribed dose were achieved in 12 of the 24 patients without violating dose constraints. Both the distance between the IPL and rectum and the hip-to-hip patient width on planning CT scans were associated with the feasibility to plan an SIB (p = 0.002 and p = 0.0137, respectively). CONCLUSIONS: On the basis of this small cohort, the distance between an intraprostatic lesion and the rectum most strongly predicted the ability to plan high-dose radiation to a dominant intraprostatic lesion. High-dose SIB planning seems possible for select intraprostatic lesions. PMID- 20932673 TI - Thymidylate synthase gene polymorphism affects the response to preoperative 5 fluorouracil chemoradiation therapy in patients with rectal cancer. AB - PURPOSE: This study aims to correlate thymidylate synthase (TS) gene polymorphisms with the tumor response to preoperative 5-fluorouracil (5-FU)-based chemoradiation therapy (CRT) in patients with rectal cancer. METHODS AND MATERIALS: Forty-four patients with rectal cancer treated with 5-FU-based preoperative CRT were prospectively enrolled in this study. Thymidylate synthase expression and TS gene polymorphisms were evaluated in tumor obtained before preoperative CRT and were correlated with the pathologic response, as assessed by histopathologic staging (pTNM) and tumor regression grade. RESULTS: Patients exhibited 2R/3R and 3R/3R tandem repeat polymorphisms in the TS gene. With regard to TS expression in these genotypes, 2R/3RC and 3RC/3RC were defined as the low expression group and 2R/3RG, 3RC/3RG, and 3RG/3RG as the high-expression group. There was no significant correlation between TS expression and tumor response. There was no significant difference in the tumor response between patients homozygous for 3R/3R and patients heterozygous for 2R/3R. However, 13 of 14 patients in the low-expression group with a G>C single-nucleotide polymorphism (SNP) (2R/3RC [n = 5] or 3RC/3RC [n = 9]) exhibited a significantly greater tumor downstaging rate, as compared with only 12 of 30 patients in the high-expression group without the SNP (2R/3RG [n = 10], 3RC/3RG [n = 9], or 3RG/3RG [n = 11]) (p = 0.001). The nodal downstaging rate was also significantly greater in this low expression group, as compared with the high-expression group (12 of 14 vs. 14 of 30, p = 0.014). However, there was no significant difference in the tumor regression grade between these groups. CONCLUSIONS: This study suggests that SNPs within the TS enhancer region affect the tumor response to preoperative 5-FU based CRT in rectal cancer. PMID- 20932674 TI - High-risk prostate cancer with Gleason score 8-10 and PSA level <=15 ng/mL treated with permanent interstitial brachytherapy. AB - PURPOSE: With widespread prostate-specific antigen (PSA) screening, there has been an increase in men diagnosed with high-risk prostate cancer defined by a Gleason score (GS) >=8 coupled with a relatively low PSA level. The optimal management of these patients has not been defined. Cause-specific survival (CSS), biochemical progression-free survival (bPFS), and overall survival (OS) were evaluated in brachytherapy patients with a GS >=8 and a PSA level <=15 ng/mL with or without androgen-deprivation therapy (ADT). METHODS AND MATERIALS: From April 1995 to October 2005, 174 patients with GS >=8 and a PSA level <=15 ng/mL underwent permanent interstitial brachytherapy. Of the patients, 159 (91%) received supplemental external beam radiation, and 113 (64.9%) received ADT. The median follow-up was 6.6 years. The median postimplant Day 0 minimum percentage of the dose covering 90% of the target volume was 121.1% of prescription dose. Biochemical control was defined as a PSA level <=0.40 ng/mL after nadir. Multiple parameters were evaluated for impact on survival. RESULTS: Ten-year outcomes for patients without and with ADT were 95.2% and 92.5%, respectively, for CSS (p = 0.562); 86.5% and 92.6%, respectively, for bPFS (p = 0.204); and 75.2% and 66.0%, respectively, for OS (p = 0.179). The median post-treatment PSA level for biochemically controlled patients was <0.02 ng/mL. Multivariate analysis failed to identify any predictors for CSS, whereas bPFS and OS were most closely related to patient age. CONCLUSIONS: Patients with GS >=8 and PSA level <=15 ng/mL have excellent bPFS and CSS after brachytherapy with supplemental external beam radiotherapy. The use of ADT did not significantly impact bPFS, CSS, or OS. PMID- 20932675 TI - Acute and late toxicity after dose escalation to 82 GyE using conformal proton radiation for localized prostate cancer: initial report of American College of Radiology Phase II study 03-12. AB - PURPOSE: Several randomized trials have shown a benefit of dose escalation to 78 to 79 Gy for men treated with external radiation for localized prostate cancer. Single-institution data suggest a benefit with even higher doses. American College of Radiology 03-12 is a Phase II trial testing the safety and efficacy of 82 GyE (Gray equivalent) delivered with conformal proton radiation. METHODS AND MATERIALS: From 2003-2006, 85 men with localized prostate cancer were accrued to American College of Radiology 03-12. Eighty-four were eligible for analysis. They were treated with conformal proton radiation alone to a total dose of 82 GyE. The study was designed to test whether the rate of 18-month Grade 3+ late toxicity was greater than 10%. RESULTS: The median follow-up was 31.6 months. Regarding treatment-related acute toxicity, there were 39 Grade 1 cases (46%), 19 Grade 2 cases (23%) and 2 Grade 3 cases (2%). Regarding genitourinary/gastrointestinal toxicity, there were 42 Grade 1 cases (50%), 12 Grade 2 cases (14%) and 1 Grade 3 case (1%). Regarding late toxicity, there were 28 Grade 1 cases (33%), 22 Grade 2 cases (26%), 6 Grade 3 cases (7%), and 1 Grade 4 case (1%). The late genitourinary/gastrointestinal rates were the same. The estimated rate of Grade 3+ late toxicity at 18 months was 6.08%. CONCLUSIONS: Although not free of late toxicity, 82 GyE at 2 GyE per fraction delivered with conformal proton radiation did not exceed the late morbidity target tested in this trial. There was sufficient morbidity, however, that this may be the maximal dose that can be delivered safely with this technique and fractionation. PMID- 20932676 TI - Evaluation of radiation dose and image quality for the Varian cone beam computed tomography system. AB - PURPOSE: To compare the image quality and dosimetry on the Varian cone beam computed tomography (CBCT) system between software Version 1.4.13 and Version 1.4.11 (referred to as "new" and "old" protocols, respectively, in the following text). This study investigated organ absorbed dose, total effective dose, and image quality of the CBCT system for the head-and-neck and pelvic regions. METHODS AND MATERIALS: A calibrated Farmer chamber and two standard cylindrical Perspex CT dosimetry phantoms with diameter of 16 cm (head phantom) and 32 cm (body phantom) were used to measure the weighted cone-beam computed tomography dose index (CBCTDIw) of the Varian CBCT system. The absorbed dose of different organs was measured in a female anthropomorphic phantom with thermoluminescent dosimeters (TLD) and the total effective dose was estimated according to International Commission on Radiological Protection (ICRP) Publication 103. The dose measurement and image quality were studied for head-and-neck and pelvic regions, and comparison was made between the new and old protocols. RESULTS: The values of the new CBCTDIw head-and-neck and pelvic protocols were 36.6 and 29.4 mGy, respectively. The total effective doses from the new head-and-neck and pelvic protocols were 1.7 and 8.2 mSv, respectively. The absorbed doses of lens for the new 200 degrees and old 360 degrees head-and-neck protocols were 3.8 and 59.4 mGy, respectively. The additional secondary cancer risk from daily CBCT might be up to 2.8%. CONCLUSIONS: The new Varian CBCT provided volumetric information for image guidance with acceptable image quality and lower radiation dose. This imaging tool gave a better standard for patient daily setup verification. PMID- 20932677 TI - Can 18-FDG-PET during radiotherapy replace post-therapy scanning for detection/demonstration of tumor response in head-and-neck cancer? AB - PURPOSE: In routine practice, the tumor response in head-and-neck cancer (HNC) is assessed 3-4 months after radiotherapy (RT). We compared the results of fluorodeoxyglucose-positron emission tomography (FDG-PET) during (47 Gy) and 4 months after RT. METHODS AND MATERIALS: In 40 patients with HNC, PET was performed before (PET1), at the end of Week 4 (47 Gy) (PET2), and 4 months after RT (PET3). Visual analysis classified patients as having a complete response (CR) or a non-CR (NCR). The sensitivity, specificity, accuracy, negative predictive value, and positive predictive value for PET2 and PET3 were determined. The 2 year overall survival (OS) rate for a CR and NCR was calculated for both response evaluation points. RESULTS: After a median follow-up of 26 months, 10 patients had died, 6 had residual disease, and 24 remained disease free. The overall sensitivity, specificity, negative predictive value, positive predictive value, and accuracy of PET2 vs. PET3 for the detection of a CR was 28.6%, 81.8%, 31.0%, 80.0%, and 42.5% vs. 78.6%, 75.0%, 60.0%, 88.0%, and 77.5%, respectively. The 2 year OS rate determined at 47 Gy was 90.0% and 71.8% for a CR and NCR, respectively, and did not appear to be significantly different (p = .50). For the study, at 4 months, the OS was significantly better in the CR group (91.8%) than in the NCR group (49.9%; p = .0055). CONCLUSION: The high specificity and positive predictive value for the evaluation of tumor response with PET2 and PET3 might avoid unnecessary salvage surgery in patients with a CR. In contrast to PET3, the sensitivity of PET 2 was low, and the difference in OS between the CR and NCR groups was not significantly different. Therefore, the evaluation of the tumor response with FDG-PET at 4 months after RT completion cannot be replaced by FDG-PET during RT at 47 Gy. PMID- 20932678 TI - Online adaptive radiotherapy for muscle-invasive bladder cancer: results of a pilot study. AB - PURPOSE: To determine the advantages and disadvantages of daily online adaptive image-guided radiotherapy (RT) compared with conventional RT for muscle-invasive bladder cancer. METHODS AND MATERIALS: Twenty-seven patients with T2-T4 transitional cell carcinoma of the bladder were treated with daily online adaptive image-guided RT using cone-beam computed tomography (CBCT). From day 1 daily soft tissue-based isocenter positioning was performed using CBCT images acquired before treatment. Using a composite of the initial planning CT and the first five daily CBCT scans, small, medium, and large adaptive plans were created. Each of these adaptive plans used a 0.5-cm clinical target volume (CTV) to planning target volume expansion. For Fractions 8-32, treatment involved daily soft tissue-based isocenter positioning and selection of suitable adaptive plan of the day. Treating radiation therapists completed a credentialing program, and one radiation oncologist performed all the contouring. Comparisons were made between adaptive and conventional treatment on the basis of CTV coverage and normal tissue sparing. RESULTS: All 27 patients completed treatment per protocol. Bladder volume decreased with time or fraction number (p < 0.0001). For the adaptive component (Fractions 8-32) the small, medium, large, and conventional plans were used in 9.8%, 49.2%, 39.5%, and 1.5% of fractions, respectively. For the adaptive strategy, 2.7% of occasions resulted in a CTV V95 <99%, compared with 4.8% of occasions for the conventional approach (p = 0.42). Mean volume of normal tissue receiving a dose >45 Gy was 29% (95% confidence interval, 24-35%) less with adaptive RT compared with conventional RT. The mean volume of normal tissue receiving >5 Gy was 15% (95% confidence interval, 11-18%) less with adaptive RT compared with conventional RT. CONCLUSIONS: Online adaptive radiotherapy is feasible in an academic radiotherapy center. The volume of normal tissue irradiated can be significantly smaller without reducing CTV coverage. PMID- 20932679 TI - Results of the 2005-2008 Association of Residents in Radiation Oncology survey of chief residents in the United States: clinical training and resident working conditions. AB - PURPOSE: To document clinical training and resident working conditions reported by chief residents during their residency. METHODS AND MATERIALS: During the academic years 2005 to 2006, 2006 to 2007, and 2007 to 2008, the Association of Residents in Radiation Oncology conducted a nationwide survey of all radiation oncology chief residents in the United States. Chi-square statistics were used to assess changes in clinical training and resident working conditions over time. RESULTS: Surveys were completed by representatives from 55 programs (response rate, 71.4%) in 2005 to 2006, 60 programs (75.9%) in 2006 to 2007, and 74 programs (93.7%) in 2007 to 2008. Nearly all chief residents reported receiving adequate clinical experience in commonly treated disease sites, such as breast and genitourinary malignancies; and commonly performed procedures, such as three dimensional conformal radiotherapy and intensity-modulated radiotherapy. Clinical experience in extracranial stereotactic radiotherapy increased over time (p < 0.001), whereas clinical experience in endovascular brachytherapy (p <0.001) decreased over time. The distribution of gynecologic and prostate brachytherapy cases remained stable, while clinical case load in breast brachytherapy increased (p = 0.006). A small but significant percentage of residents reported receiving inadequate clinical experience in pediatrics, seeing 10 or fewer pediatric cases during the course of residency. Procedures involving higher capital costs, such as particle beam therapy and intraoperative radiotherapy, and infrequent clinical use, such as head and neck brachytherapy, were limited to a minority of institutions. Most residency programs associated with at least one satellite facility have incorporated resident rotations into their clinical training, and the majority of residents at these programs find them valuable experiences. The majority of residents reported working 60 or fewer hours per week on required clinical duties. CONCLUSIONS: Trends in clinical training and resident working conditions over 3 years are documented to allow residents and program directors to assess their residency training. PMID- 20932680 TI - Evaluation of the planning target volume in the treatment of head and neck cancer with intensity-modulated radiotherapy: what is the appropriate expansion margin in the setting of daily image guidance? AB - PURPOSE: To compare patterns of disease failure among patients treated with intensity-modulated radiotherapy (IMRT) in conjunction with daily image-guided radiotherapy (IGRT) for head and neck cancer, according to the margins used to expand the clinical target volume (CTV) to create a planning target volume (PTV). METHODS AND MATERIALS: Two-hundred and twenty-five patients were treated with IMRT for squamous cell carcinoma of the head and neck. Daily IGRT scans were acquired using either kilovoltage or megavoltage volumetric imaging prior to each delivered fraction. The first 95 patients were treated with IMRT with 5-mm CTV-to PTV margins. The subsequent 130 patients were treated using 3-mm PTV expansion margins. RESULTS: Two-year estimates of overall survival, local-regional control, and distant metastasis-free survival were 76%, 78%, and 81%, respectively. There were no differences with respect to any of these endpoints among patients treated with 5-mm and 3-mm PTV expansion margins (p > 0.05, all). The 2-year local regional control rate for patients treated with IMRT with 5-mm and 3-mm PTV margins was 78% and 78%, respectively (p = 0.96). Spatial evaluation revealed no differences in the incidences of marginal failures among those treated with 5-mm and 3-mm PTV margins. CONCLUSIONS: The use of 3-mm PTV expansion margins appears adequate and did not increase local-regional failures among patients treated with IMRT for head and neck cancer. These data demonstrate the safety of PTV reduction of less than 5 mm and support current protocols recommending this approach in the setting of daily IGRT. PMID- 20932681 TI - Use of the Charlson combined comorbidity index to predict postradiotherapy quality of life for prostate cancer patients. AB - PURPOSE: To determine the impact of pretreatment comorbidity on late health related quality of life (HRQoL) scores after patients have undergone combined radiotherapy for prostate cancer, including high-dose rate brachytherapy boost and hormonal deprivation therapy. METHODS AND MATERIALS: Results from the European Organization for Research and Treatment of Cancer QLQ-C30 questionnaire survey of 158 patients 5 years or more after completion of therapy were used from consecutively accrued subjects treated with curative radiotherapy at our institution, with no signs of disease at the time of questionnaire completion. HRQoL scores were compared with the Charlson combined comorbidity index (CCI), using analysis of covariance and multivariate regression models together with pretreatment factors including tumor stage, tumor grade, pretreatment prostate specific antigen level, neoadjuvant hormonal treatment, diabetes status, cardiovascular status, and age and Charlson score as separate variables or the composite CCI. RESULTS: An inverse correlation between the two HRQoL domains, long-term global health (QL) and physical function (PF) scores, and the CCI score was observed, indicating an impact of comorbidity in these function areas. Selected pretreatment factors poorly explained the variation in functional HRQoL in the multivariate models; however, a statistically significant impact was found for the CCI (with QL and PF scores) and the presence of diabetes (with QL and emotional function). Cognitive function and social function were not statistically significantly predicted by any of the pretreatment factors. CONCLUSIONS: The CCI proved to be valid in this context, but it seems useful mainly in predicting long-term QL and PF scores. Of the other variables investigated, diabetes had more impact than cardiovascular morbidity on HRQoL outcomes in prostate cancer. PMID- 20932682 TI - Severe pulmonary toxicity after myeloablative conditioning using total body irradiation: an assessment of risk factors. AB - PURPOSE: To assess factors associated with severe pulmonary toxicity after myeloablative conditioning using total body irradiation (TBI) followed by allogeneic stem cell transplantation. METHODS AND MATERIALS: A total of 101 adult patients who underwent TBI-based myeloablative conditioning for hematologic malignancies at Duke University between 1998 and 2008 were reviewed. TBI was combined with high-dose cyclophosphamide, melphalan, fludarabine, or etoposide, depending on the underlying disease. Acute pulmonary toxicity, occurring within 90 days of transplantation, was scored using Common Terminology Criteria for Adverse Events version 3.0. Actuarial overall survival and the cumulative incidence of acute pulmonary toxicity were calculated via the Kaplan-Meier method and compared using a log-rank test. A binary logistic regression analysis was performed to assess factors independently associated with acute severe pulmonary toxicity. RESULTS: The 90-day actuarial risk of developing severe (Grade 3-5) pulmonary toxicity was 33%. Actuarial survival at 90 days was 49% in patients with severe pulmonary toxicity vs. 94% in patients without (p < 0.001). On multivariate analysis, the number of prior chemotherapy regimens was the only factor independently associated with development of severe pulmonary toxicity (odds ratio, 2.7 per regimen). CONCLUSIONS: Severe acute pulmonary toxicity is prevalent after TBI-based myeloablative conditioning regimens, occurring in approximately 33% of patients. The number of prior chemotherapy regimens appears to be an important risk factor. PMID- 20932683 TI - Effect of radiotherapy planning complexity on survival of elderly patients with unresected localized lung cancer. AB - PURPOSE: To evaluate whether complex radiotherapy (RT) planning was associated with improved outcomes in a cohort of elderly patients with unresected Stage I-II non-small-cell lung cancer (NSCLC). METHODS AND MATERIALS: Using the Surveillance, Epidemiology, and End Results registry linked to Medicare claims, we identified 1998 patients aged >65 years with histologically confirmed, unresected stage I-II NSCLC. Patients were classified into an intermediate or complex RT planning group using Medicare physician codes. To address potential selection bias, we used propensity score modeling. Survival of patients who received intermediate and complex simulation was compared using Cox regression models adjusting for propensity scores and in a stratified and matched analysis according to propensity scores. RESULTS: Overall, 25% of patients received complex RT planning. Complex RT planning was associated with better overall (hazard ratio 0.84; 95% confidence interval, 0.75-0.95) and lung cancer-specific (hazard ratio 0.81; 95% confidence interval, 0.71-0.93) survival after controlling for propensity scores. Similarly, stratified and matched analyses showed better overall and lung cancer-specific survival of patients treated with complex RT planning. CONCLUSIONS: The use of complex RT planning is associated with improved survival among elderly patients with unresected Stage I-II NSCLC. These findings should be validated in prospective randomized controlled trials. PMID- 20932684 TI - Weight gain in advanced non-small-cell lung cancer patients during treatment with split-course concurrent chemoradiotherapy is associated with superior survival. AB - BACKGROUND: Preoperative concurrent chemoradiotherapy (CRT) is an accepted treatment for potentially resectable, locally advanced, non-small-cell lung cancer (NSCLC). We reviewed a decade of single institution experience with preoperative split-course CRT followed by surgical resection to evaluate survival and identify factors that may be helpful in predicting outcome. METHODS AND MATERIALS: All patients treated with preoperative split-course CRT and resection at Rush University Medical Center (RUMC) between January 1999 and December 2008 were retrospectively analyzed. Endpoints included overall survival (OS), progression-free survival (PFS), local-regional progression-free survival (LRPFS), and distant metastasis-free survival (DMFS). Patient and treatment related variables were assessed for correlation with outcomes. RESULTS: A total of 54 patients were analyzed, 76% Stage IIIA, 18% Stage IIIB, and 6% oligometastatic. The pathologic complete response (pCR) rate was 31.5%, and the absence of nodal metastases (pN0) was 64.8%. Median OS and 3-year actuarial survival were 44.6 months and 50%, respectively. Univariate analysis revealed initial stage (p < 0.01) and percent weight change during CRT (p < 0.01) significantly correlated with PFS/OS. On multivariate analysis initial stage (HR, 2.4; 95% CI, 1.18-4.90; p = 0.02) and percent weight change (HR, 0.79; 95% CI, 0.67-0.93; p < 0.01) maintained significance with respect to OS. There were no cases of Grade 3+ esophagitis, and there was a single case of Grade 3 febrile neutropenia. CONCLUSIONS: The strong correlation between weight change during CRT and OS/PFS suggests that this clinical parameter may be useful as a complementary source of predictive information in addition to accepted factors such as pathological response. PMID- 20932685 TI - Ocular response of choroidal melanoma with monosomy 3 versus disomy 3 after iodine-125 brachytherapy. AB - PURPOSE: To report the ocular response of choroidal melanoma with monosomy 3 vs. disomy 3 after (125)I brachytherapy. METHODS AND MATERIALS: We evaluated patients with ciliochoroidal melanoma managed with fine needle aspiration biopsy immediately before plaque application for (125)I brachytherapy between January 1, 2005 and December 31, 2008. Patients with (1) cytopathologic diagnosis of melanoma, (2) melanoma chromosome 3 status identified by fluorescence in situ hybridization, and (3) 6 or more months of follow-up after brachytherapy were sorted by monosomy 3 vs. disomy 3 and compared by Kruskal-Wallis test. RESULTS: Among 40 ciliochoroidal melanomas (40 patients), 15 had monosomy 3 and 25 had disomy 3. Monosomy 3 melanomas had a median greatest basal diameter of 12.00 mm and a median tumor thickness of 6.69 mm before brachytherapy; at a median of 1.75 years after brachytherapy, median thickness was 3.10 mm. Median percentage decrease in tumor thickness was 48.3%. Disomy 3 melanomas had a median greatest basal diameter of 10.00 mm and median tumor thickness of 3.19 mm before brachytherapy; at a median of 2.00 years after brachytherapy, median tumor thickness was 2.37 mm. The median percentage decrease in tumor thickness was 22.7%. Monosomy 3 melanomas were statistically greater in size than disomy 3 melanomas (p < 0.001) and showed a greater decrease in tumor thickness after brachytherapy (p = 0.006). CONCLUSION: In this study, ciliochoroidal melanomas with monosomy 3 were significantly greater in size than disomy 3 melanoma and showed a significantly greater decrease in thickness at a median of 1.75 years after brachytherapy. The greater decrease in monosomy 3 melanoma thickness after brachytherapy is consistent with other malignancies in which more aggressive pathology has been shown to be associated with a greater initial response to radiotherapy. PMID- 20932686 TI - Preliminary results of whole brain radiotherapy with concurrent trastuzumab for treatment of brain metastases in breast cancer patients. AB - PURPOSE: To assess the use of trastuzumab concurrently with whole brain radiotherapy (WBRT) for patients with brain metastases from human epidermal growth factor receptor-2-positive breast cancer. METHODS AND MATERIALS: Between April 2001 and April 2007, 31 patients with brain metastases from human epidermal growth factor receptor-2-positive breast cancer were referred for WBRT with concurrent trastuzumab. At brain progression, the median age was 55 years (range, 38-73), and all patients had a performance status of 0-2. The patients received trastuzumab 2 mg/kg weekly (n = 17) or 6 mg/kg repeated every 21 days (n = 14). In 26 patients, concurrent WBRT delivered 30 Gy in 10 daily fractions. In 6 patients, other fractionations were chosen because of either poor performance status or patient convenience. RESULTS: After WBRT, radiologic responses were observed in 23 patients (74.2%), including 6 (19.4%) with a complete radiologic response and 17 (54.8%) with a partial radiologic response. Clinical responses were observed in 27 patients (87.1%). The median survival time from the start of WBRT was 18 months (range, 2-65). The median interval to brain progression was 10.5 months (range, 2-27). No Grade 2 or greater acute toxicity was observed. CONCLUSION: The low toxicity of trastuzumab concurrently with WBRT should probably not justify delays. Although promising, these preliminary data warrant additional validation of trastuzumab as a potential radiosensitizer for WBRT in brain metastases from breast cancer in the setting of a clinical trial. PMID- 20932687 TI - Late patient-reported toxicity after preoperative radiotherapy or chemoradiotherapy in nonresectable rectal cancer: results from a randomized Phase III study. AB - PURPOSE: Preoperative chemoradiotherapy (CRT) is superior to radiotherapy (RT) in locally advanced rectal cancer, but the survival gain is limited. Late toxicity is, therefore, important. The aim was to compare late bowel, urinary, and sexual functions after CRT or RT. METHODS AND MATERIALS: Patients (N = 207) with nonresectable rectal cancer were randomized to preoperative CRT or RT (2 Gy * 25 +/- 5-fluorouracil/leucovorin). Extended surgery was often required. Self reported late toxicity was scored according to the LENT SOMA criteria in a structured telephone interview and with questionnaires European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30), International Index of Erectile Function (IIEF), and sexual function-vaginal changes questionnaire (SVQ). RESULTS: Of the 105 patients alive in Norway and Sweden after 4 to 12 years of follow-up, 78 (74%) responded. More patients in the CRT group had received a stoma (73% vs. 52%, p = 0.09). Most patients without a stoma (7 of 12 in CRT group and 9 of 16 in RT group) had incontinence for liquid stools or gas. No stoma and good anal function were seen in 5 patients (11%) in the CRT group and in 11 (30%) in the RT group (p = 0.046). Of 44 patients in the CRT group, 12 (28%) had had bowel obstruction compared with 5 of 33 (15%) in the RT group (p = 0.27). One-quarter of the patients reported urinary incontinence. The majority of men had severe erectile dysfunction. Few women reported sexual activity during the previous month. However, the majority did not have concerns about their sex life. CONCLUSIONS: Fecal incontinence and erectile dysfunction are frequent after combined treatment for locally advanced rectal cancer. There was a clear tendency for the problems to be more common after CRT than after RT. PMID- 20932688 TI - Stereotactic body radiotherapy versus surgery for medically operable Stage I non small-cell lung cancer: a Markov model-based decision analysis. AB - PURPOSE: To compare the quality-adjusted life expectancy and overall survival in patients with Stage I non-small-cell lung cancer (NSCLC) treated with either stereotactic body radiation therapy (SBRT) or surgery. METHODS AND MATERIALS: We constructed a Markov model to describe health states after either SBRT or lobectomy for Stage I NSCLC for a 5-year time frame. We report various treatment strategy survival outcomes stratified by age, sex, and pack-year history of smoking, and compared these with an external outcome prediction tool (Adjuvant! Online). RESULTS: Overall survival, cancer-specific survival, and other causes of death as predicted by our model correlated closely with those predicted by the external prediction tool. Overall survival at 5 years as predicted by baseline analysis of our model is in favor of surgery, with a benefit ranging from 2.2% to 3.0% for all cohorts. Mean quality-adjusted life expectancy ranged from 3.28 to 3.78 years after surgery and from 3.35 to 3.87 years for SBRT. The utility threshold for preferring SBRT over surgery was 0.90. Outcomes were sensitive to quality of life, the proportion of local and regional recurrences treated with standard vs. palliative treatments, and the surgery- and SBRT-related mortalities. CONCLUSIONS: The role of SBRT in the medically operable patient is yet to be defined. Our model indicates that SBRT may offer comparable overall survival and quality-adjusted life expectancy as compared with surgical resection. Well-powered prospective studies comparing surgery vs. SBRT in early stage lung cancer are warranted to further investigate the relative survival, quality of life, and cost characteristics of both treatment paradigms. PMID- 20932689 TI - Preferential effect of synchrotron microbeam radiation therapy on intracerebral 9L gliosarcoma vascular networks. AB - PURPOSE: Synchrotron microbeam radiation therapy (MRT) relies on spatial fractionation of the incident photon beam into parallel micron-wide beams. Our aim was to analyze the effects of MRT on normal brain and 9L gliosarcoma tissues, particularly on blood vessels. METHODS AND MATERIALS: Responses to MRT (two arrays, one lateral, one anteroposterior (2 * 400 Gy), intersecting orthogonally in the tumor region) were studied during 6 weeks using MRI, immunohistochemistry, and vascular endothelial growth factor Western blot. RESULTS: MRT increased the median survival time of irradiated rats (*3.25), significantly increased blood vessel permeability, and inhibited tumor growth; a cytotoxic effect on 9L cells was detected 5 days after irradiation. Significant decreases in tumoral blood volume fraction and vessel diameter were measured from 8 days after irradiation, due to loss of endothelial cells in tumors as detected by immunochemistry. Edema was observed in the normal brain exposed to both crossfired arrays about 6 weeks after irradiation. This edema was associated with changes in blood vessel morphology and an overexpression of vascular endothelial growth factor. Conversely, vascular parameters and vessel morphology in brain regions exposed to one of the two arrays were not damaged, and there was no loss of vascular endothelia. CONCLUSIONS: We show for the first time that preferential damage of MRT to tumor vessels versus preservation of radioresistant normal brain vessels contributes to the efficient palliation of 9L gliosarcomas in rats. Molecular pathways of repair mechanisms in normal and tumoral vascular networks after MRT may be essential for the improvement of such differential effects on the vasculature. PMID- 20932690 TI - Craniospinal irradiation techniques: a dosimetric comparison of proton beams with standard and advanced photon radiotherapy. AB - PURPOSE: To evaluate the dosimetric benefits of advanced radiotherapy techniques for craniospinal irradiation in cancer in children. METHODS AND MATERIALS: Craniospinal irradiation (CSI) using three-dimensional conformal radiotherapy (3D CRT), tomotherapy (TOMO), and proton beam treatment (PBT) in the scattering mode was planned for each of 10 patients at our institution. Dosimetric benefits and organ-specific radiation-induced cancer risks were based on comparisons of dose volume histograms (DVHs) and on the application of organ equivalent doses (OEDs), respectively. RESULTS: When we analyzed the organ-at-risk volumes that received 30%, 60%, and 90% of the prescribed dose (PD), we found that PBT was superior to TOMO and 3D-CRT. On average, the doses delivered by PBT to the esophagus, stomach, liver, lung, pancreas, and kidney were 19.4 Gy, 0.6 Gy, 0.3 Gy, 2.5 Gy, 0.2 Gy, and 2.2 Gy for the PD of 36 Gy, respectively, which were significantly lower than the doses delivered by TOMO (22.9 Gy, 4.5 Gy, 6.1 Gy, 4.0 Gy, 13.3 Gy, and 4.9 Gy, respectively) and 3D-CRT (34.6 Gy, 3.6 Gy, 8.0 Gy, 4.6 Gy, 22.9 Gy, and 4.3 Gy, respectively). Although the average doses delivered by PBT to the chest and abdomen were significantly lower than those of 3D-CRT or TOMO, these differences were reduced in the head-and-neck region. OED calculations showed that the risk of secondary cancers in organs such as the stomach, lungs, thyroid, and pancreas was much higher when 3D-CRT or TOMO was used than when PBT was used. CONCLUSIONS: Compared with photon techniques, PBT showed improvements in most dosimetric parameters for CSI patients, with lower OEDs to organs at risk. PMID- 20932691 TI - Model-based radiation dose correction for yttrium-90 microsphere treatment of liver tumors with central necrosis. AB - PURPOSE: The objectives of this study were to model and calculate the absorbed fraction phi of energy emitted from yttrium-90 ((90)Y) microsphere treatment of necrotic liver tumors. METHODS AND MATERIALS: The tumor necrosis model was proposed for the calculation of phi over the spherical shell region. Two approaches, the semianalytic method and the probabilistic method, were adopted. In the former method, the range--energy relationship and the sampling of electron paths were applied to calculate the energy deposition within the target region, using the straight-ahead and continuous-slowing-down approximation (CSDA) method. In the latter method, the Monte Carlo PENELOPE code was used to verify results from the first method. RESULTS: The fraction of energy, phi, absorbed from (90)Y by 1-cm thickness of tumor shell from microsphere distribution by CSDA with complete beta spectrum was 0.832 +/- 0.001 and 0.833 +/- 0.001 for smaller (r(T) = 5 cm) and larger (r(T) = 10 cm) tumors (where r is the radii of the tumor [T] and necrosis [N]). The fraction absorbed depended mainly on the thickness of the tumor necrosis configuration, rather than on tumor necrosis size. The maximal absorbed fraction phi that occurred in tumors without central necrosis for each size of tumor was different: 0.950 +/- 0.000, and 0.975 +/- 0.000 for smaller (r(T) = 5 cm) and larger (r(T) = 10 cm) tumors, respectively (p < 0.0001). CONCLUSIONS: The tumor necrosis model was developed for dose calculation of (90)Y microsphere treatment of hepatic tumors with central necrosis. With this model, important information is provided regarding the absorbed fraction applicable to clinical (90)Y microsphere treatment. PMID- 20932692 TI - Influence of prostatic edema on 131Cs permanent prostate seed implants: a dosimetric and radiobiological study. AB - PURPOSE: To study the influence of prostatic edema on postimplant physical and radiobiological parameters using (131)Cs permanent prostate seed implants. METHODS AND MATERIALS: Thirty-one patients with early prostate cancer who underwent (131)Cs permanent seed implantation were evaluated. Dose-volume histograms were generated for each set of prostate volumes obtained at preimplantation and postimplantion days 0, 14, and 28 to compute quality indices (QIs) and fractional doses at level x (FD(x)). A set of equations for QI, FD(x), and biologically effective doses at dose level D(x) (BED(x)) were defined to account for edema changes with time after implant. RESULTS: There were statistically significant differences found between QIs of pre- and postimplant plans at day 0, except for the overdose index (ODI). QIs correlated with postimplant time, and FD(x) was found to increase with increasing postimplant time. With the effect of edema, BED at different dose levels showed less improvement due to the short half-life of (131)Cs, which delivers about 85% of the prescribed dose before the prostate reaches its original volume due to dissipation of edema. CONCLUSIONS: Results of the study show that QIs, FD(x), and BEDs at the level of D(x) changed from preneedle plans to postimplant plans and have statistically significant differences (p < 0.05), except for the ODI (p = 0.106), which suggests that at the time of (131)C seed implantation, the effect of edema must be accounted for when defining the seed positions, to avoid the possibility of poor dosimetric and radiobiologic results for (131)Cs seed implants. PMID- 20932693 TI - Ulnocarpal epiphyseal arthrodesis for recurrent deformity after centralization for radial longitudinal deficiency. AB - PURPOSE: To report our results for ulnocarpal epiphyseal arthrodesis for recurrent or late-presenting wrist deformity in patients with radial longitudinal deficiency, using both objective data and long-term subjective follow-up evaluation. METHODS: A retrospective review of our surgical logs between 1970 and 2007 identified 12 postcentralization patients treated with ulnocarpal epiphyseal arthrodesis, and 1 patient (who had reached skeletal maturity) treated with traditional ulnocarpal arthrodesis. Indications for the arthrodesis included postcentralization recurrence of radial angulation to greater than 45 degrees , an inability to actively extend the wrist to within 25 degrees of neutral (ie, 25 degrees of flexion), or both. We collected objective and radiographic data on all 12 patients by chart review at a mean of 89 months (range, 2-472 mo) after arthrodesis. We collected subjective data from 9 patients at a mean of 160 months (range, 14-602 mo) after arthrodesis. RESULTS: Ulnocarpal union was obtained in 11 wrists at an average of 4 months (range, 2-6 mo); the 1 case of nonunion was treated successfully with revision arthrodesis. The mean radial angulation position was 20 degrees after arthrodesis (range, 0 degrees to 35 degrees ), an average improvement of 42 degrees . The mean position of wrist fusion was 11 degrees of flexion (range, 0 degrees to 35 degrees of flexion), an average improvement of 7 degrees . The mean postoperative Disabilities of the Arm, Shoulder, and Hand score was 24.5 (SD, 12.3; range, 6.8-36.4). Final postoperative Visual Analog Score rating for function averaged 8 (range, 4-10); for appearance, it averaged 7 (range, 5-10), and for pain, it averaged 1 (range, 0-5). CONCLUSIONS: Ulnocarpal and epiphyseal arthrodesis are appropriate surgical procedures to stabilize the carpus in postcentralization patients with recurrent or late-presenting wrist deformity. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 20932694 TI - Altered gene expression in umbilical cord mononuclear cells in preterm infants with periventricular leukomalacia. AB - AIM: Periventricular leukomalacia (PVL) is one of the most important causes of adverse outcome of preterm infants. We hypothesized that inflammatory or some other specific pathways will have been activated at birth in preterm infants who later develop PVL. The aim of this study is to examine the difference in mRNA expression in umbilical cord blood according to the presence or absence of PVL. METHODS: A total of 61 umbilical cord blood samples were collected from preterm infants with gestational age less than 33 weeks together with the patients' medical information during perinatal period. RNA expression patterns in the collected cord bloods were analyzed by microarray. On the basis of cranial ultrasonography and brain MRI examination, 3 infants (4.9%) were diagnosed as cystic PVL and selected as the subjects. Five patients who showed similar perinatal factors to those of infants with PVL but did not show PVL were selected as the normal control. RESULTS: Five of the 15 up-regulated genes are coding ribosomal proteins, and another encodes a translation elongation factor. Three of the 7 down-regulated genes encode proteins that may be related to immune response and/or inflammation. CONCLUSIONS: Up-regulation of the ribosomal proteins may indicate an activation of lymphocytes during the fetal period. PMID- 20932695 TI - Esophageal injury in fatal rear-impact collisions. AB - Neck injuries resulting from motor vehicle collisions (MVC), often referred to as whiplash trauma and injury, often demonstrate little or no evidence of significant tissue damage. In rare instances, however, serious injury to the anterior neck organ injuries can result from such trauma. The present study describes esophageal injury associated with rear-impact collisions, based on a unique case report, review of the scientific literature and a query in the National Automotive Sampling System (NASS) database of the US National Highway Traffic Safety Administration. The Medline search and present case study totaled five cases of rear-impact collision-related serious esophageal injury (laceration or rupture). In the four published cases all patients survived, whereas in the presented case study, the patient died due to mediastinitis and sepsis. The NASS query revealed an additional three cases out of a total of 55,926 investigated crashes. All three cases were associated with fatalities. Although no anatomical or bioengineering studies have presented data on the behavior of the esophagus during rear-impact whiplash loading, sudden tensile and/or compressive forces is the likely explanation of injury, often in combination with a local fracture of a vertebral body. In these 8 cases significant esophageal injury carried a substantial (50%) risk of mortality. Clinicians should be aware of the potential for significant complications in the whiplash trauma-exposed patient who complains of chest pain, mid-thoracic pain, discomfort in the neck and throat, respiratory distress, or hoarseness. For those forensic specialists involved in whiplash cases these study results highlight the need to consider esophageal injuries as a rare but potential consequence of whiplash trauma. PMID- 20932696 TI - Scanning electron microscopy as an auxiliary method in the study of exhumed bones. AB - Scanning electron microscopy (SEM) has been used in forensic science in many ways. The reports of cases in which SEM has been used as an auxiliary method in the investigation of exhumed bones are rare. In this article, we report an exhumation that was made to determine if a seized weapon could have been used in a homicide. We used SEM to analyze a fracture in the interior of the skull of the victim. The findings described in this article showed us that it is possible to develop new researches in this field. PMID- 20932697 TI - Moyamoya disease in children. AB - Moyamoya disease is an uncommon cerebrovascular disease characterized by progressive steno-occlusive changes in the terminal internal carotid arteries (ICA) and their main branches, associated with the development of moyamoya vessels. The incidence of the disease is high in east Asia, especially in Japan and Korea. The familial form accounts for 10-15%. Moyamoya disease has two age distribution peaks at around 5 and 40years. Most pediatric patients exhibit transient ischemic attacks or infarction. Headache and involuntary movements are serious symptoms associated with pediatric moyamoya disease. MRI and MR angiography (MRA) are useful and non-invasive methods for diagnosing or monitoring moyamoya disease. Cerebral angiography is still the gold standard for a diagnosis, however, it is not mandatory when MRI and MRA show typical findings of moyamoya disease; steno-occlusive changes at the ends of ICA and an abnormal vascular network in the basal ganglia. Other MRI findings have been reported, including T2 shortening in the white matter, the ivy sign on fluid-attenuated inversion recovery (FLAIR) images, and medullary streaks on FLAIR or enhanced T1 weighted images. PMID- 20932698 TI - The HAMLET case: what can we learn from a misfolded protein that triggers tumour cell death? PMID- 20932699 TI - Magnetic resonance imaging of pontine capillary telangectasia. AB - Capillary telangectasia (CTS) is a vascular malformation, characterized by multiple thin-walled vascular channels, interposed between normal brain parenchyma. It has been hypothesized that CTS is an acquired lesion caused by other underlying venous anomalies but this theory is still debated. The clinical symptoms of CTS are described to be rather mild. In most cases CTS is not detectable by computed tomography and among imaging techniques, nowadays magnetic resonance imaging (MRI) represents the standard of reference in diagnosing this pathology. Usually, by analyzing the different signal characteristics it is possible to perform a differential diagnosis between CTS and the other pathologies that may affect the pons and the use of diffusion-weighted and Gradient-echo sequences increase the MRI specificity. PMID- 20932700 TI - Diffusion-weighted MR imaging in comparison to integrated [18F]-FDG PET/CT for N staging in patients with lung cancer. AB - PURPOSE: The purpose of this study was to prospectively determine the diagnostic accuracy of diffusion-weighted imaging (DWI) using MRI in the staging of thoracic lymph nodes in patients with lung cancer, and to compare the performance to that of PET/CT. PATIENTS AND METHOD: 20 consecutive patients (pts) with histologically proven lung cancer were included in this study. In all pts FDG-PET/CT was routinely performed to stage lung carcinoma. Additionally, MRI (1.5T) was performed including native T1w, T1w post contrast medium, T2w, and DWI sequences. Regarding the N stage based on the results of the PET/CT there were 5 patients with N0, 3 patients with N1, 5 patients with N2 and 7 patients with N3. Image analysis was performed by two radiologists (R1 and R2), respectively. The reviewers had to chose between 1 (at least one lymph node within a station is malignant) or 0 (no lymph nodes suspicious for malignancy). First the T1 post contrast sequence was analyzed. In a second step the DWI sequence (b=800) was analyzed. Both steps were performed in a blinded fashion. RESULTS: MR imaging with or without DWI only agreed with the results of the PET/CT regarding the N stage in 80% of the patients-15% were understaged and 5% overstaged. There was excellent interobserver agreement; the N-staging result only differed in 1 patient for DWI, resulting in correlation coefficients of 0.98 for DWI and 1.0 for MRI. Compared to PET-CT MRI overstaged one and understaged 4 patients, while DWI overstaged one and understaged 3 patients. This resulted in correlation coefficients of 0.814 (R1 and R2) for MRI and 0.815 (R1) and 0.804 (R2) for DWI. Regarding the ADC values there were no significant differences between ipsilateral hilar (1.03 mm(2)/s +/- 0.13), subcarinal (0.96 mm(2)/s+/-0.24), ipsilateral mediastinal (1.0mm(2)/s +/- 0.18), contralateral mediastinal (0.93 mm(2)/s +/- 0.23) and supraclavicular (0.9 mm(2)/s +/- 0.23) lymph nodes. CONCLUSION: Diffusion-weighted imaging does not show a clear advantage over conventional MR protocols in the N-staging of lung cancer. MRI with or without DWI shows a moderately correlation with PET/CT with a tendency for understaging. PMID- 20932701 TI - Evaluation of skin exposure during cerebral CT perfusion studies on a phantom. AB - OBJECTIVES: To evaluate the skin dose during cerebral CT perfusion on a phantom, and estimate the weighted CT dose index (CTDIw) to maximum skin dose conversion factors for four types of CT scanners. STUDY DESIGN: We evaluated the relationship between surface dose during cerebral CT perfusion and distance from the scan center in the x-y plane using a 64-multidetector row CT scanner. Skin doses were also assessed with 4 different 64-multidetector CT scanners. RESULTS: The surface doses decreased with the distance from the scan center in the x-y plane. The surface doses at the points 6 cm and 10 cm from the scan center in the x-y plane were different from the dose at the point 8 cm by about 15%. CTDIw and skin doses differed among the CT scanners (CTDIw, 143-590 mGy; averaged temporal skin dose, 126-590 mGy). For all the four types of CT scanner, the doses increased in the following order: occipital point 0.05) the normalization of proinflammatory cytokines or neuroendocrine hormones produced following LPS. Collectively, these results indicate that maternal stress impacts aspects of the proinflammatory cytokine and stress hormone response in their progeny following LPS dosing of the offspring. This response is potentially responsible in part for the resultant changes to SAA production. Because several of the changes observed here are dependent on pig gender, these results are also the first evidence that inherent epigenetic factors coupled with maternal stress impact the cumulative response to stress and LPS in young pigs. PMID- 20932704 TI - Magnetic resonance imaging-guided breast biopsies: tips and tricks. PMID- 20932705 TI - Two-stage exchange for infected resurfacing arthroplasty: use of a novel cement spacer technique. AB - Infection after total hip arthroplasty is a devastating complication. A 2-stage reimplantation with antibiotic-impregnated interval spacer is typically recommended. We present a case of infected resurfacing hip arthroplasty treated with a novel cement spacer technique. The aim was to avoid the introduction of the infection into the femoral medullary canal with the use of a conventional stemmed antibiotic cement spacer. Reimplantation was accomplished routinely, and the patient remains infection-free at 9 months. PMID- 20932706 TI - Fixed versus rotating platform total knee arthroplasty: a prospective, randomized, single-blind study. AB - The purpose of this randomized, single-blind clinical trial was to compare a rotating platform (RP) total knee arthroplasty to a fixed-bearing (FB) total knee arthroplasty. Ninety-five knees in 69 patients were implanted by 2 surgeons. There were no significant differences in the preoperative demographics. At a minimum of 2-year follow-up, clinical outcomes and complication rates were similar, with the exception that the RP group had significantly better stair climbing scores (P = .04). Postoperative range of motion was equally good in both groups (FB knees, 1 degrees -125 degrees ; RP knees, 1-126 degrees ). There were no bearing dislocations in the RP group. In conclusion, this RP design performs at least as well as the FB version, and the RP patients reported better stair climbing ability. Enthusiasm for this finding should be tempered by the relatively small sample size. PMID- 20932707 TI - Patients prefer a bicruciate-retaining or the medial pivot total knee prosthesis. AB - Four-hundred forty patients underwent staged bilateral total knee arthroplasty using a different prosthesis on each side. Prostheses used were anterior posterior cruciate-retaining (ACL-PCL), posterior cruciate-retaining (PCL), Medial Pivot (MP), posterior cruciate-substituting (PS), and mobile bearing (MB). At the 2-year evaluation, we asked "Which is your better knee overall?" Responses were as follows: 89.1% preferred the ACL-PCL to the PS and 76.2% preferred the MP to the PS. The ACL-PCL and the MP were preferred equally. The MP was preferred over the PCL by 76.0%, and 61.4% preferred the MP over the MB. The PS and PCL were preferred equally. Range of motion, pain relief, alignment, and stability did not vary significantly by prosthesis used. Patients with bilateral total knee arthroplasties preferred retention of both cruciates with use of the ACL-PCL prosthesis or substituting with an MP prosthesis. PMID- 20932708 TI - Early results of 827 trabecular metal revision shells in acetabular revision. AB - We evaluated the survival of 827 acetabular revisions with Trabecular Metal Revision Shell using data from a nationwide arthroplasty register. The mean age of the patients was 69.1 years. The 3-year overall survivorship was 92% (95% confidence interval, 88-95), which coincides with earlier reports. Revision rate for aseptic loosening was only 2%. The most common reason for revision was dislocation of the prosthesis with or without malposition of the socket (60%). Age was found to have significant effect on cup survivorship: each additional year in age decreased the risk of revision by 2.4% (95 % confidence interval, 0.1 4.7; P = .044). We found no differences in survival rates between aseptic and septic revisions. Furthermore, sex, diagnosis, and hospital volume did not affect the survival. PMID- 20932709 TI - Design and primary application of computer-assisted, patient-specific navigational templates in metal-on-metal hip resurfacing arthroplasty. AB - Total hip resurfacing arthroplasty is increasingly being used. One of its goals is to closely mimic the normal anatomy and normal biomechanics of the hip joint. Prosthesis location has a large impact on implant survival and patient function; but in conventional hip resurfacing arthroplasty, precise positioning sometimes cannot be achieved. We describe a novel method for ensuring accurate prosthesis implantation in hip resurfacing arthroplasty by means of 3-dimensional reconstruction and reverse engineering. PMID- 20932710 TI - A cautionary tale from critical care: resolution of myoclonus after fentanyl rotation to hydromorphone. PMID- 20932711 TI - Anti-TNFalpha therapy and control of chronic pain in ankylosing spondylitis. PMID- 20932712 TI - Isolated infrarenal caval disruption secondary to minimal blunt trauma. AB - Injuries to the inferior vena cava (IVC) are highly lethal and are usually associated with gunshot wounds. Blunt injury to the IVC is a rare entity that is usually located in the retrohepatic space. We present the case of an infrarenal caval disruption in a 9-year-old as a result of minimal blunt trauma. A computed tomography scan showed that the patient had a large retroperitoneal hematoma associated with IVC disruption and proximal thrombus just below the renal veins. There was no evidence of either arterial or other intra-abdominal injuries. The patient had a fall in hematocrit and abdominal tenderness prompting operative exploration. Before laparotomy, bilateral balloon occlusion devices were placed in both femoral veins. The patient was noted to have a total disruption of his IVC just above the origin of his iliac veins. The anterior two-third of the IVC was avulsed, thus leaving the posterior portion against the retroperitoneum. Given the patient's hemodynamic instability and amount of venous damage, the IVC was oversewn and a damage control operation was undertaken. The following day, the patient was brought back to the operating room for a second-look laparotomy and abdominal closure. A pathologic examination revealed a high-grade spindle cell sarcoma. Blunt injury to the IVC is a rare entity and its location outside of the retrohepatic space should alert the surgeon to a potential underlying malignant etiology. PMID- 20932713 TI - Aortic transection and diverting bypass as treatment of repetitive recurrent abdominal aortic false aneurysm rupture in a patient with Behcet's disease. AB - Abdominal aortic false aneurysms in patients with Behcet's disease have been reported frequently and repaired successfully by various procedures; however, anastomotic false aneurysms have often been reported to occur after the operation. In this article, we report a case of four-time repetitive, recurrent suprarenal abdominal aortic false aneurysm ruptures that lasted for 7 years. The location of this aneurysm was not easy to repair not only by open surgical procedures but by endovascular stent because the aortic defect was too close to the visceral arterial branches. The last operation consisted of primary repair of aortic defect, transection of abdominal aorta at the level of supraceliac aorta with end closure, and a thoracic aorta to abdominal aorta bypass with Dacron graft. An 8-year follow-up revealed no more abdominal aortic aneurysm recurrence. PMID- 20932714 TI - The success of endovascular therapy for all TransAtlantic Society Consensus graded femoropopliteal lesions. AB - BACKGROUND: Advances in technology and practice have led to increased endovascular management of all TransAtlantic Society Consensus (TASC)-graded lesions. This study aims to evaluate the success of endovascular therapy in the management of TASC-graded femoropopliteal lesions. METHODS: Patients undergoing endovascular treatment for femoropopliteal lesions between July 1999 and August 2008 were divided by TASC scores and evaluated for primary, assisted-primary, and secondary patency rates at 12 and 24 months. Secondary endpoints included limb loss and postoperative complications. RESULTS: A total of 499 femoropopliteal lesions in 427 patients were treated with endovascular interventions. Score distribution for TASC type A, type B, type C, and type D lesions was 26 (5.2%), 140 (28.1%), 168 (33.7%), and 165 (33.1%), respectively. Primary, assisted primary, and secondary patency rates at 24 months were 77.7 +/- 3.2%, 78.9 +/- 3.2%, and 86.7 +/- 2.6%, respectively, for TASC type A + B lesions, 76.0 +/- 3.3%, 77.2 +/- 3.2%, and 85.0 +/- 2.8%, respectively, for TASC type C lesions, and 61.2 +/- 3.8%, 61.2 +/- 3.8%, and 78.2 +/- 3.2%, respectively, for TASC type D lesions. Compared with TASC type A + B and TASC type C lesions, TASC type D lesions were associated with worse primary and assisted-primary patency rates. However, there was no statistically significant difference in secondary patency between TASC type A + B and TASC type D lesions. The TASC score was not a significant predictor of postoperative complication rates. The 24-month limb salvage rate in patients with TASC type D lesions presenting with critical limb ischemia was 71.9 +/- 8.0%. CONCLUSION: It was observed that all femoropopliteal lesions can be safely and effectively managed with endovascular therapy. Although TASC type D lesions do have lower primary and assisted-primary patency rates, high secondary patency rates comparable with other TASC scores can be achieved with effective prevention of limb loss. These data provide evidence to support endovascular therapy as primary management for all femoropopliteal lesions regardless of the TASC score. PMID- 20932715 TI - Gender differences of children's developmental trajectory from 6 to 60 months in the Taiwan Birth Cohort Pilot Study. AB - The parental report instrument is the most efficient developmental detection method and has shown high validity with professional assessment instruments. The reliability and validity of the Taiwan Birth Cohort Study (TBCS) 6-, 18- and 36 month scales have already been established. In this study, the reliability and validity of the 60-month scale was tested. The gender differences in children's longitudinal gross motor, fine motor, language and social development were also investigated. Using the dataset from the Taiwan Birth Cohort Pilot Study (TBCS p), 2048 infants were followed up when they were 6-, 18-, 36- and 60-month-old. At the final stage, 1620 children were followed up. Development of the children was measured using the TBCS 6-, 18-, 36-, and 60-month developmental scales. The reconstructed TBCS 60-month scale yielded 16 items measuring children's development in the four dimensions of gross motor, fine motor, language and social. The scale yielded an internal consistency of 0.39-0.71. Structural equation modeling also showed good construct and predictive validity, in that the 6-, 18-, and 36-month scales were predictive of the 60-month scale. No gender differences between the gross motor dimension was found. Gender had an effect on the fine motor dimension at 36 and 60 months, language dimension at 36 months, and social dimension at 18, 36 and 60 months. Gender had a transient effect in language development and social development a continuous effect from 18 to 60 months. Thus different gender norms may need to be established to prevent misdiagnosis. The TBCS scale is a valid and reliable developmental screening instrument that can be used in continuous surveillance of children's development in community and clinical settings from 6 months to 5 years of age. PMID- 20932716 TI - Impaired myocardial radial function in asymptomatic patients with type 2 diabetes mellitus: a speckle-tracking imaging study. AB - BACKGROUND: Diabetic cardiomyopathy has been characterized by an early impairment of left ventricular (LV) longitudinal function as opposed to preserved LV radial function. METHODS: Conventional echocardiography and longitudinal (epsilon(L)) and radial (epsilon(R)) systolic strain assessed by speckle-tracking imaging were obtained in 114 type 2 diabetic patients and 88 age-matched controls. RESULTS: LV ejection fraction was similar in diabetic patients and controls. The presence of subclinical LV systolic dysfunction in diabetic patients was demonstrated by lower values of midwall fractional shortening (18% +/- 3% vs 20% +/- 3%, P = .006), epsilon(L) (-19% +/- 3% vs -22% +/- 2%, P < .001), and epsilon(R) (50% +/- 16% vs 56% +/- 12%, P = .003) compared with controls. On multivariate analysis, factors predicting strain values were diabetes (P = .001) and gender (P = .001) for epsilon(L) and diabetes (P = .003) for epsilon(R). CONCLUSION: Diabetic patients without overt heart disease display subclinical alteration of both radial and longitudinal LV systolic function even after adjustment for blood pressure, age, and body mass index. PMID- 20932717 TI - Gaussian mixtures on tensor fields for segmentation: applications to medical imaging. AB - In this paper, we introduce a new approach for tensor field segmentation based on the definition of mixtures of Gaussians on tensors as a statistical model. Working over the well-known Geodesic Active Regions segmentation framework, this scheme presents several interesting advantages. First, it yields a more flexible model than the use of a single Gaussian distribution, which enables the method to better adapt to the complexity of the data. Second, it can work directly on tensor-valued images or, through a parallel scheme that processes independently the intensity and the local structure tensor, on scalar textured images. Two different applications have been considered to show the suitability of the proposed method for medical imaging segmentation. First, we address DT-MRI segmentation on a dataset of 32 volumes, showing a successful segmentation of the corpus callosum and favourable comparisons with related approaches in the literature. Second, the segmentation of bones from hand radiographs is studied, and a complete automatic-semiautomatic approach has been developed that makes use of anatomical prior knowledge to produce accurate segmentation results. PMID- 20932718 TI - Expression level of a pancreatic neo-antigen in beta cells determines degree of diabetes pathogenesis. AB - It is not fully understood how the expression level of autoantigens in beta cells impacts autoimmune diabetes (T1D) development. Earlier studies using ovalbumin and also insulin had shown that secreted antigens could enhance diabetes development through facilitated presentation by antigen presenting cells. Here we sought to determine how the expression level of a membrane bound, non-secreted or cross-presented neo-antigen, the glycoprotein (GP) of lymphocytic choriomeningitis virus (LCMV), would influence T1D. We found that an RIP-LCMV transgenic mouse line exhibiting higher levels of beta cell GP expression developed more severe diabetes after LCMV infection or transfer of high numbers of activated autoreactive T cells. Importantly, all beta cells were lost and a significant increase in morbidity and mortality from T1D was noted. Insulitis and accumulation of autoaggressive CD8 cells was more profound in the RIP-LCMV-GP high-expressor line. Interestingly, the additional introduction of neo-antigen specific CD4(+) helper or regulatory T cells was able to influence diabetogenesis positively or negatively. We conclude that a higher degree of autoantigen expression results in increased diabetes susceptibility. Therefore, autoantigens such as insulin that are expressed at higher levels in beta cells might have a more profound impact on diabetes pathogenesis. PMID- 20932719 TI - CXCL10 promotes liver fibrosis by prevention of NK cell mediated hepatic stellate cell inactivation. AB - Chemokines, such as CXCL10, promote hepatic inflammation in chronic or acute liver injury through recruitment of leukocytes to the liver parenchyma. The CXCL10 receptor CXCR3, which is expressed on a subset of leukocytes, plays an important part in Th1-dependent inflammatory responses. Here, we investigated the role of CXCL10 in chemically induced liver fibrosis. We used carbon tetrachloride (CCl(4)) to trigger chronic liver damage in wildtype C57BL/6 and CXCL10-deficient mice. Fibrosis severity was assessed by Sirius Red staining and intrahepatic leukocyte subsets were investigated by immunohistochemistry. We have further analyzed hepatic stellate cell (HSC) distribution and activation and investigated the effect of CXCL10 on HSC motility and proliferation. In order to demonstrate a possible therapeutic intervention strategy, we have examined the anti-fibrotic potential of a neutralizing anti-CXCL10 antibody. Upon CCl(4) administration, CXCL10-deficient mice showed massively reduced liver fibrosis, when compared to wildtype mice. CXCL10-deficient mice had less B- and T lymphocyte and dendritic cell infiltrations within the liver and the number and activity of HSCs was reduced. In contrast, natural killer (NK) cells were more abundant in CXCL10 deficient mice and granzyme B expression was increased in areas with high numbers of NK cells. Further detailed analysis revealed that HSCs express CXCR3, respond to CXCL10 and secrete CXCL10 when stimulated with IFNgamma. Blockade of CXCL10 with a neutralizing antibody exhibited a significant anti-fibrotic effect. Our data suggest that CXCL10 is a pro-fibrotic factor, which participates in a crosstalk between hepatocytes, HSCs and immune cells. NK cells seem to play an important role in controlling HSC activity and fibrosis. CXCL10 blockade may constitute a possible therapeutic intervention for hepatic fibrosis. PMID- 20932721 TI - Subjective cognitive impairment: functional MRI during a divided attention task. AB - BACKGROUND: Individuals with subjective cognitive impairment (SCI) have persistent memory complaints but normal neurocognitive performance. For some, this may represent a pre-mild cognitive impairment (MCI) stage of Alzheimer's disease (AD). Given that attentional deficits and associated brain activation changes are present early in the course of AD, we aimed to determine whether SCI is associated with brain activation changes during attentional processing. METHODS: Eleven SCI subjects and 10 controls completed a divided attention task during functional magnetic resonance imaging. RESULTS: SCI and control groups did not differ in sociodemographic, neurocognitive or behavioural measures. When group activation during the divided attention task was compared, the SCI group demonstrated increased activation in left medial temporal lobe, bilateral thalamus, posterior cingulate and caudate. CONCLUSION: This pattern of increased activation is similar to the pattern of decreased activation reported during divided attention in AD and may indicate compensatory changes. These findings suggest the presence of early functional changes in SCI; longitudinal studies will help to further elucidate the relationship between SCI and AD. PMID- 20932720 TI - PBC screen: an IgG/IgA dual isotype ELISA detecting multiple mitochondrial and nuclear autoantibodies specific for primary biliary cirrhosis. AB - A dual isotype (IgG, IgA) enzyme-linked immunosorbent assay (ELISA) designed to provide enhanced detection of primary biliary cirrhosis (PBC)-specific autoantibodies against both major mitochondrial and nuclear antigens has been developed and recently become commercially available. The assay (PBC Screen) simultaneously detects IgG and IgA autoantibodies to the immunodominant portions of the 3 major mitochondrial (MIT3) and nuclear (gp210, and sp100) antigens. The aim of this study was to compare the performance of the PBC Screen to the combined performance obtained with individual IgG ELISAs to MIT3, gp210, and sp100 on a large group of selected patients from multiple centers. A total of 1175 patients with PBC and 1232 subjects without PBC were evaluated. Non-PBC groups included healthy controls (624) as well as individuals with autoimmune hepatitis (281), primary sclerosing cholangitis (77), viral hepatitis (91 hepatitis B and 98 hepatitis C), other liver diseases (31), and other infectious or autoimmune diseases (30). The PBC Screen at the receiver operator characteristic optimized cutoff of 27.8 units, had an overall sensitivity of 83.8%, specificity of 94.7% and area under curve of 0.9212. This was similar to the specificity of 96.1% obtained by the combined results of individual MIT3, sp100, and gp210 IgG ELISAs (kappa index at 0.898). Of the 253 PBC patients without AMA detectable by immunofluorescence, 113 (44.7%) were interpreted as positive for PBC-specific autoantibodies. In conclusion, the PBC Screen is an appropriate first-line test for the diagnosis of PBC, including for patients negative for markers assessed using conventional methods. PMID- 20932722 TI - The contribution of a mobile mental health unit to the promotion of primary mental health in rural areas in Greece: a 2-year follow-up. AB - During the 2 years of the mobile mental-health unit's operation in Northwestern Greece, the referrals increased rapidly with 29.4% of patients never having received mental-health care before, while hospitalizations and relapses reduced significantly, indicating that community-oriented programs can contribute greatly to successfully addressing the needs of patients in remote rural areas. PMID- 20932723 TI - Interaction force measurement between E. coli cells and nanoparticles immobilized surfaces by using AFM. AB - To better understand environmental behaviors of nanoparticles (NPs), we used the atomic force microscopy (AFM) to measure interaction forces between E. coli cells and NPs immobilized on surfaces in an aqueous environment. The results showed that adhesion force strength was significantly influenced by particle size for both hematite (alpha-Fe(2)O(3)) and corundum (alpha-Al(2)O(3)) NPs whereas the effect on the repulsive force was not observed. The adhesion force decreased from 6.3+/-0.7nN to 0.8+/-0.4nN as hematite NPs increased from 26nm to 98nm in diameter. Corundum NPs exhibited a similar dependence of adhesion force on particle size. The Johnson-Kendall-Roberts (JKR) model was employed to estimate the contact area between E. coli cells and NPs, and based on the JKR model a new model that considers local effective contact area was developed. The prediction of the new model matched the size dependence of adhesion force in experimental results. Size effects on adhesion forces may originate from the difference in local effective contact areas as supported by our model. These findings provide fundamental information for interpreting the environmental behaviors and biological interactions of NPs, which barely have been addressed. PMID- 20932724 TI - The formation of non-soluble complexes between polyethyleneimine-anions and their potential use to isolate enzymes. AB - The aqueous solution behavior of polyethyleneimine (a synthetic cationic polymer) in the presence of anions with two or more electrical charges (citrate, phosphate, sulphate, malate, malonate and succinate) was studied by means of turbidimetry and light scattering. Polyethyleneimine forms non-soluble complexes with these anions, which behave as a pseudo-polyampholyte with an isoelectrical pH value dependent on the type of anion. The effect of pH, polymer concentration and ionic strength on the non-soluble complexes formation was examined. The complex precipitation pH range was between 3.5 and 8.0 and also depended on the type of anion. The complex formation was inhibited by the ionic strength in agreement with the electrostatic mechanism of the non-soluble complex formation. Model proteins with isoelectric pH from 1 to 10 were assayed in orden to be precipitated by these complexes. It was found that the non-soluble polyethyleneimine-anion complexes have the property to precipitate macromolecules charged with an opposite electrical charge. PMID- 20932725 TI - [Osteoarticular tuberculosis: a differential diagnosis of idiopathic juvenile arthritis]. AB - We report a case of extrapulmonary tuberculosis with oligoarthritis and synovitis in a 6-year-old girl with undiagnosed disseminated tuberculosis. CLINICAL CASE: The child, adopted from Ethiopia, was admitted to the pediatric rheumatology unit for suspected idiopathic juvenile arthritis. She presented with clinical signs of subacute arthritis of the right knee. Joint symptoms began insidiously and followed a short period of fever and pain in the right hip. Clinical examination showed voluminous cervical lymphadenitis, night sweats, and a moderate alteration of the child's general condition. The medical history revealed that since her arrival in France, 2 years before, she had had febrile subacute pneumonia. A review of the chest x-ray diagnosed primary pulmonary tuberculosis. An intradermal tuberculin test confirmed the diagnosis with a phlyctenular response and a diameter exceeding 20mm. Additional evaluation showed cervical lymphadenitis and intense synovitis of the right hip and knee joints. With an appropriate antitubercular regimen, her condition improved within a few months. After 1 year of treatment, magnetic resonance imaging (MRI) showed normalization of the impaired joints with no functional sequelae. DISCUSSION: Although the spine is a common target for osteoarticular tuberculosis (OAT), peripheral involvement in this case underlines the polymorphism of OAT in children. It illustrates a case of OAT strictly located to the synovial membranes, which usually occurs in one-third of OAT cases. In addition, MRI showed tenosynovitis of the quadriceps. The child presented with unilateral oligoarthritis instead of chronic insidious monoarthritis or symmetrical oligoarthritis as usually described in pediatric OAT. When available, MRI is the best way to evaluate OAT lesions. Mycobacterium tuberculosis can be isolated from sputum, gastric aspiration, and joint fluid or synovial biopsy. Histological lesions can reveal advanced tuberculosis with the presence of caseous follicular lesions. Rapid bacterial detection using polymerase chain reaction remains insufficiently useful in those situations. The recommended therapeutic regimen consists of 3 months with four antitubercular agents (rifampicin, isoniazid, pyrazinamide, and ethambutol) followed by 9 months of a dual therapy (isoniazid, rifampicin). PMID- 20932726 TI - Oramoeba fumarolia gen. nov., sp. nov., a new marine heterolobosean amoeboflagellate growing at 54 degrees C. AB - An amoeba strain was isolated from marine sediment taken from the beach near a fumarole in Italy. The trophozoites of this new marine species transforms into flagellates with variable numbers of flagella, from 2 to 10. The strain forms round to oval cysts. This thermophilic amoeboflagellate grows at temperatures up to 54 degrees C. Molecular phylogenetic analysis of the small subunit ribosomal DNA (SSU rDNA) places the amoeboflagellate in the Heterolobosea. The closest relatives are Stachyamoeba sp. ATCC50324, a strain isolated from an ocean sample, and Vrihiamoeba italica, a recent isolate from a rice field. Like some other heterolobosean species, this new isolate has a group I intron in the SSU rDNA. Because of the unique place in the molecular phylogenetic tree, and because there is no species found in the literature with similar morphological and physiological characteristics, this isolate is considered to be a new genus and a new species, Oramoeba fumarolia gen. nov., sp. nov. PMID- 20932728 TI - High-intensity focused ultrasound for prostate cancer: a systematic review. AB - High-intensity focused ultrasound (HIFU) has recently been promoted as a non invasive treatment option for prostate cancer. This systematic review sought to evaluate the evidence comparing it with standard treatment in patients with localised prostate cancer. The literature review included searches of MEDLINE, EMBASE, the Cochrane Library, annual meetings' abstracts and websites of evidence based practice guideline producers. Studies were included if they were randomised controlled trials comparing HIFU with current management approaches, or were meta analyses, systematic reviews or practice guidelines addressing HIFU. No randomised controlled trials or meta-analyses were identified. Seven systematic reviews and two practice guidelines were identified; neither contained randomised controlled trials. Adjusting the selection criteria to include case series found 34 clinical studies of HIFU. Twenty-nine evaluated HIFU as the primary treatment and five examined HIFU as salvage treatment for recurrence after radiotherapy. In most studies the outcomes used to determine efficacy were negative biopsy rates or prostate-specific antigen (PSA) levels. Among the 29 studies of HIFU as the primary treatment, negative biopsy rates ranged from 35 to 95% in 21 studies, a PSA nadir of <=0.5 ng/ml ranged from 55 to 91% in 10 studies and mean PSA nadirs ranged from 0 to 1.9 ng/ml in 17 studies. Five studies reported 5-year disease free survival rates ranging from 55 to 95%. Among five studies of HIFU as salvage treatment, negative biopsy rates ranged from 73 to 84% in four studies, a PSA nadir of <=0.5 ng/ml ranged from 57 to 66% in three studies and mean PSA nadirs were 1.97 and 2.38 ng/ml in two studies, respectively. Current evidence on HIFU use in prostate cancer patients is of low quality, rendering it difficult to draw conclusions about its efficacy. Until results from case series are confirmed in prospective studies, the widespread use of HIFU is not supported. PMID- 20932729 TI - Tinospora cordifolia ameliorates urotoxic effect of cyclophosphamide by modulating GSH and cytokine levels. AB - Cyclophosphamide (CP) is a commonly used anti-cancer drug which causes toxicity by its reactive metabolites. In this study we investigated the effect of Tinospora cordifolia on urotoxicity induced by acute dose of CP using Swiss albino mice model. Administration of an alcoholic extract of the plant T. cordifolia (Family: Menispermaceae) (200 mg/kg i.p.) for 5 days reduced CP (1.5 mmol/kg body wt. i.p.) induced urotoxicity as evident from the morphological analysis of bladder, decreased the relative bladder and liver weights and also decreased level of urea nitrogen and protein in blood as well as urine. Severely inflamed and dark coloured urinary bladders of the CP alone treated animals were found to be normalized by the treatment of T. cordifolia. GSH content, which was drastically reduced by CP administration in both bladder and liver was enhanced by treatment with T. cordifolia. Histopathological analysis of the bladder of CP alone-treated group showed severe necrotic damage where as the T. cordifolia treated group showed normal bladder architecture. The lowered levels of cytokines IFN-gamma, IL-2, after CP treatment were found to be increased in treated animals. At the same time the level of pro-inflammatory cytokine TNF-alpha, which was elevated during CP administration, was significantly reduced by extract administration. This study clearly demonstrates uroprotective role of T. cordifolia from CP induced toxicities by modulating GSH and pro-inflammatory cytokine levels. PMID- 20932731 TI - Vascularity of the hip labrum during the foetal period. AB - Tears of the hip labrum have been recognized as a cause of hip pain and clicking. It has been reported that labrum tears are associated with increased microvessel formation. The purpose of this study was to identify the regional vascularity of the acetabular labrum during late foetal development. The acetabular labrum was examined from 21 formalinized foetuses of the age 5th to 10th months of gestation (mean 6.4+/-0.99). The acetabulum of each specimen was anatomically prepared and divided into four quadrants. The number of blood vessels in labrum quadrants was counted during microscopic examination. A total of 599 of blood vessels were found in all specimens: 159 in quadrant I, 150 in quadrant II, 127 in quadrant III and 163 in quadrant IV. The capsular part of the labrum contained 357 vessels and the articular part contained 242. The total number of blood vessels within the capsular parts of all specimens (357) was significantly greater than the number within the articular parts (242) (p<0.028). There was some evidence to suggest that with increasing foetal age, the number of blood vessels in the labrum decreased. However, taking into consideration the number of vessels in particular quadrants of the labrum, the great frequency of labral tears in the anterosuperior part of the labrum could not be explained. PMID- 20932730 TI - Urban air pollution produces up-regulation of myocardial inflammatory genes and dark chocolate provides cardioprotection. AB - Air pollution is a serious environmental problem. Elderly subjects show increased cardiac morbidity and mortality associated with air pollution exposure. Mexico City (MC) residents are chronically exposed to high concentrations of fine particulate matter (PM(2.5)) and PM-associated lipopolysaccharides (PM-LPS). To test the hypothesis that chronic exposure to urban pollution produces myocardial inflammation, female Balb-c mice age 4 weeks were exposed for 16 months to two distinctly different polluted areas within MC: southwest (SW) and northwest (NW). SW mice were given either no treatment or chocolate 2g/9.5 mg polyphenols/3 times per week. Results were compared to mice kept in clean air. Key inflammatory mediator genes: cyclooxygenase-2 (COX-2), interleukin-1beta (IL-1beta), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha), and the LPS receptor CD14 (cluster of differentiation antigen 14) were measured by real-time polymerase chain reaction. Also explored were target NFkappaB (nuclear factor kappaB), oxidative stress and antioxidant defense genes. TNF-alpha, IL-6, and COX 2 were significantly increased in both NW and SWMC mice (p=0.0001). CD14 was up regulated in SW mice in keeping with the high exposures to particulate matter associated endotoxin. Chocolate administration resulted in a significant down regulation of TNF-alpha (p<0.0001), IL-6 (p=0.01), and IL-1beta (p=0.02). The up regulation of antioxidant enzymes and the down-regulation of potent oxidases, toll-like receptors, and pro-apoptotic signaling genes completed the protective profile. Exposure to air pollution produces up-regulation of inflammatory myocardial genes and endotoxin plays a key role in the inflammatory response. Regular consumption of dark chocolate may reduce myocardial inflammation and have cardioprotective properties in the setting of air pollution exposures. PMID- 20932732 TI - Patterns of tail breakage in the ladder snake (Rhinechis scalaris) reflect differential predation pressure according to body size. AB - Predator-prey interactions are key factors in the evolution of defensive tactics. In snakes, shy organisms from which direct evidence of predator-prey interactions is difficult to obtain, injuries are potential indicators of both the nature and frequency of interactions. We studied the incidence of tail breakage and body scarring in the ladder snake, Rhinechis scalaris, an actively foraging Mediterranean snake, and tested several hypotheses that link body injuries and snake life-history traits, mainly under sexual and ontogenetic aspects. Evidence is presented supporting an ontogenetic shift in the frequency of tail breakage, with the incidence of tail loss increasing as a logistic function of snake size. We relate this finding to the adaptive significance of ontogenetic shifts in dorsal pattern and the reaction of snakes to approaching predators; small individuals are more likely to remain immobile than are medium to large individuals, the former aided by a concealing dorsal pattern with transverse lines, and the latter by a striped pattern. This species exhibited sex differences in body scarring but not in tail breakage, nor did we encounter evidence to suggest that snakes experience multiple tail breaks over time, thus failing to support the sexual difference and multiple tail breakage hypotheses. Moreover, we failed to find a lower frequency of body scarring than tail breakage; hence, our results do not afford evidence that frequency of tail breakage represents an inefficiency of predators in catching or dispatching ophidian prey. PMID- 20932733 TI - Intra-sex dimorphism in crayfish females. AB - A unique cycle of female form alternation has been revealed in an experimental population of Orconectes limosus during a year-long observation. Significant cyclic changes observed in chelae length, width, and robustness, as well as in abdomen width, demonstrated a form alternation similar to that in conspecific males. Small females alternate between sexually active and sexually inactive forms with a short time interval between successive molts as well as different growth patterns of some body parts. Form alternation efficiently produces larger chelae, abdomen, and body dimensions, especially the molt to form I (sexually active). Larger females that undergo only a single annual molt do not alter between forms and are sexually active. They grow slowly and lose chelae robustness. The cycle of form alternation, consisting of two molts per year, may facilitate the effective utilization of resources to increase the size of body parts important to survival and reproduction. PMID- 20932734 TI - The generation and maintenance of serum alloantibody. AB - Donor-specific alloantibodies (DSA) mediate hyperacute and acute antibody mediated rejection (AMR), which can lead to early graft damage and loss, and are also associated with chronic AMR and reduced long-term graft survival. Such alloantibodies can be generated by previous exposure to major histocompatibility (MHC) antigens (usually via blood transfusions, previous allografts or pregnancy) or can occur de novo after transplantation. Recent studies also suggest that non MHC antibodies, including those recognising major histocompatibility complex class I-related chain A (MICA), MICB, vimentin, angiotensin II type I receptor may also have an adverse impact on allograft outcomes. In this review, we consider how the dose, route and context of antigen exposure influences DSA induction and describe factors which control the generation, maintenance and survival of alloantibody-producing plasma cells. Finally, we discuss the implications of these variables on therapeutic approaches to DSA. PMID- 20932735 TI - Interface between hemostasis and adaptive immunity. AB - Stress induced activation or denudation of the endothelium elicits arrest and activation of platelets with attendant triggering of coagulation, culminating in a physical barrier to limit blood loss. Recently, coagulation-activated osteopontin, chemerin, and protease-activated receptor signaling, as well as platelet-derived molecules including platelet factor 4, serotonin, P-selectin, and CD154 (CD40L) have been revealed as new links between hemostasis and adaptive immunity. The initiation of hemostasis establishes a local state of inflammation that serves as an adjuvant system for antigen presentation, consequently influencing the onset and functional characteristics of an evolving adaptive immune response. In this context, the hemostatic system and its associated signaling pathways warrant further study as novel therapeutic targets that may enhance, abrogate, or otherwise selectively direct the adaptive immune response. PMID- 20932736 TI - Health-related quality of life in patients by COPD severity within primary care in Europe. AB - Pan-European data on health-related quality of life (HRQL) in chronic obstructive pulmonary disease (COPD) are lacking. This cross-sectional epidemiological study evaluated health status in 1817 COPD patients from an 'all-comers' primary care population in seven European countries (87% stable disease; 13% with current exacerbation) using: St George's Respiratory Questionnaire-COPD specific (SGRQ C), the short form health survey (SF-12) and the Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue scale. Mean total score for SGRQ was 44.7 +/- 19.4 showing marked impairment of HRQL. Scores differed little between countries (range 39.2-50.1). Impairment was associated with the severity of airway obstruction, but within each GOLD stage the variation (SD) was wide [Stage I: 38.5 +/- 19.3 (n = 223); Stage II: 40.4 +/- 18.1 (n = 868); Stage III: 50.2 +/- 18.6 (n = 551); Stage IV: 58.6 +/- 17.7 (n = 144)]. Patients suffering an exacerbation had a worse SGRQ score (54.9 +/- 19.3) than those with stable disease (43.3 +/- 19.0). The presence of >=3 co-morbidities (CM) was also associated with a significantly worse score (49.9 +/- 19.1) vs. 1-2 CM (42.1 +/- 19.1) or no CM (42.3 +/- 18.6). Findings with the SF-12 and FACIT-F results were consistent with those from the SGRQ-C. This large observational primary care study shows that health status is significantly impaired in COPD patients of all severities, even in those with mild airway obstruction. Within each GOLD stage of severity there is considerable heterogeneity in HRQL impairment among patients. (Study number: 111749). PMID- 20932737 TI - Technical and environmental long-term properties of industrial residues--summary of field and laboratory investigations. AB - In Sweden, use of industrial residues is still hindered by concern for their long term properties. A three-year research project was therefore initiated aiming to (1) identify the crucial processes of ageing related to the usefulness of residues in roads; (2) investigate the consequences of these processes for technical and environmental properties of the residues, and (3) propose a method for accelerated ageing to predict the long-term properties. This paper gives an overview of the project methodology, a summary of the test results and references to papers where further details are given. The project, running through 2006 2008, compared naturally aged samples of two residues used as sub-bases in existing asphalt paved roads with samples of fresh residues from producers' piles. Steel slag of electric arc furnace (EAF) type and municipal solid waste incinerator (MSWI) bottom ash were chosen. The samples were thoroughly characterised in order to identify which ageing processes had been crucial. The results showed that: - Bottom ash from the pavement edge was more aged than bottom ash from the road centre. However, no difference in pH was found, instead the differences were caused by differences in water exposure. - Steel slag from the pavement edge showed traces of carbonation and leaching processes, whereas slag from the road centre was identical to fresh slag. - Water exposure to the subbase materials after ten years in an asphalt paved road was calculated to less than 0.1-0.5 litres per kg. - Ageing reactions in steel slag and MSWI bottom ash, ready for use, were too small to be verified by laboratory measurement of deformation properties under loaded conditions. An accelerated ageing test for steel slag was set up to achieve the carbonation (decrease in pH) and leaching that was observed in the pavement edge material. An accelerated ageing test for bottom ash was set up to achieve the pozzolan reactions that were observed in SEM analyses of in situ specimens. It is recommended to use uncrushed particles when properties of aged material are studied, in order to preserve the original particle surfaces. PMID- 20932738 TI - Fabrication of an oxytetracycline molecular-imprinted sensor based on the competition reaction via a GOD-enzymatic amplifier. AB - A highly sensitive molecular-imprinted polymer sensor (MIP sensor) for ultratrace oxytetracycline (OTC) determination was prepared based on the competition reaction between template molecule OTC and glucose oxidase (GOD)-labeled OTC (GOD OTC). Sensitivity improved dramatically due to the detection of a huge amount of enzyme catalytic production, which was inversely proportional to template molecule concentration. The MIP sensor was characterized by alternating current impedance spectroscopy and cyclic voltammetry, and its voltammetric behavior was also verified. Experimental conditions including isolation, incubation, and competition were optimized. OTC can be determined at concentrations between 0 and 4.0*10(-7) mol/L with a detection limit of 3.30*10(-10) mol/L by the differential pulse voltammetry technique. The MIP sensor showed high sensitivity, selectivity, reproducibility, and good recovery in sample determination. PMID- 20932739 TI - Prognostic determinants in epithelioid sarcoma. AB - BACKGROUND: Epithelioid sarcoma (ES) is a rare soft tissue neoplasm that usually arises in the distal extremities of young adults, presents a high rate of recurrences and metastases and frequently poses diagnostic dilemmas. In order to identify markers useful for patient stratification purposes, we investigated the prognostic impact of clinical and molecular patient characteristics, including the status of SMARCB1 tumour suppressor gene, in a consecutive series of ES cases. METHODS: Kaplan-Meier survival curves were compared by the log-rank test. Immunophenotyping and SMARCB1 protein expression were analysed by immunohistochemistry or western blotting in 40 ES patients for which tumour material was available. Cases lacking SMARCB1 protein expression were investigated for the presence of gene mutations and gene deletions by exon sequencing, fluorescent in situ hybridization and quantitative PCR. RESULTS: FNCLCC tumour grade 3 and proximal-type histology significantly correlated with shorter overall survival (log-rank p=0.0046 and p=0.0001, respectively). We identified loss of SMARCB1 protein expression in the majority of ES cases (25/40, 62.5%), including 24/34 (71%) adult cases but only 1/6 (17%) paediatric/adolescent cases (p=0.02, two-tailed Fisher's exact test). The absence of protein is strongly correlated with SMARCB1 gene deletion (p=0.003, two-tailed Fisher's exact test). We observed a trend towards the correlation between SMARCB1 inactivation and both higher tumour grading and a clinical course of the disease characterised by the occurrence of multiple relapses/metastasis. CONCLUSION: These data show that both tumour grading and subtype are prognostic factors in ES. Loss of SMARCB1 protein expression in ES is a frequent occurrence mediated by gene deletion events, thus pointing to a crucial role of SMARCB1 in ES genesis. Analysis of SMARCB1 status in ES warrants prospective investigation as a prognostic marker and therapeutic target. PMID- 20932740 TI - Breast cancer in pregnancy: recommendations of an international consensus meeting. AB - PURPOSE: To provide guidance for clinicians about the diagnosis, staging and treatment of breast cancer occurring during an otherwise uncomplicated pregnancy. METHODS: An international expert Panel convened to address a series of questions identified by a literature review and personal experience. Issues relating to the diagnosis and management of breast cancer after delivery were outside the scope. RESULTS: There is a paucity of large and/or randomized studies. Based on cohort studies, case series and case reports, the recommendations represent the best available evidence, albeit of a lower grade than is optimal. RECOMMENDATIONS: In most circumstances, serious consideration should be given to the option of treating breast cancer whilst continuing with the pregnancy. Each woman should ideally be referred to a centre with sufficient expertise, given a clear explanation of treatment options. Most diagnostic and staging examinations can be performed adequately and safely during pregnancy. Treatment should however be adapted to the clinical presentation and the trimester of the pregnancy: surgery can be performed during all trimesters of pregnancy; radiotherapy can be considered during the first and second trimester but should be postponed during the third trimester; and standard chemotherapies can be used during the second and third trimester. Since neonatal morbidity mainly appears to be related to prematurity, delivery should not be induced before 37 weeks, if at all possible. CONCLUSIONS: The treatment of breast cancer in pregnancy should be executed by experienced specialists in a multidisciplinary setting and should adhere as closely as possible to standard protocols. PMID- 20932741 TI - Organ specific regulation of tumour invasiveness and gelatinolytic activity at the invasive front. AB - Proteolytic enzymes play a complex role in tumour growth and invasion. To explore the impact of tumour stroma on invasiveness and expression of proteolytic enzymes, we used a xenograft mouse model where tumours in tongue and skin were established from various human cancer cell lines. Gelatinolytic activity in the tumours was investigated by a novel in situ zymography technique which enables high image resolution. In vivo and in vitro expression of various proteolytic enzymes were analysed at transcriptional and protein level using RT-qPCR, immunohistochemistry and SDS-PAGE substrate zymography. At the mRNA level all cell lines were found to express MMP-2, -7, -14, uPA and uPAR. In addition, two out of three cell lines expressed MMP-9. Histological analyses revealed that tongue tumours had an invasive growth pattern, associated with reduced E-cadherin expression. In contrast, the skin tumours established from the same cell lines were non-invasive. Tongue tumours of all cell lines showed strong gelatinolytic activity especially at the invasive front, which was not seen in the non-invasive skin tumours. Our results show a close relationship between tumour invasiveness and gelatinolytic activity at the tumour front. Furthermore, in our model, both invasiveness and activity of tumour-associated proteolytic enzymes were more dependent on the tumour microenvironment than on inherent properties of the cancer cells. PMID- 20932742 TI - Altered CD94/NKG2A and perforin expression reduce the cytotoxic activity in malignant pleural effusions. AB - CD94/NKG2A is an inhibitory receptor expressed by NK cells and cytotoxic lymphocytes and, upon activation by HLA-E, downregulates the cytolytic activities of these cells thus representing a tumour immune escape mechanism. This study was aimed at assessing whether cytotoxic lymphocytes (CD8+) and NK cells from malignant pleural effusions have a deregulated expression of CD94/NKG2A. The expression of membrane CD94/NKG2A and perforin was evaluated by flow-cytometry in CD8+ and NK cells from pleural effusions and autologous peripheral blood of cancer (n=19) and congestive heart failure (CHF) (n=11) patients. Intracellular CD94/NKG2A expression was evaluated by flow-cytometry in pleural effusion CD8+ and NK cells from cancer patients (n=10). Cytotoxic activity against cancer cells exerted by pleural and autologous peripheral blood T lymphocytes from cancer patients was assessed by flow-cytometry assay. Pleural CD8+ from cancer patients showed a reduced expression of membrane CD94/NKG2A and perforin when compared to autologous peripheral blood and CHF pleural effusions. Reduced numbers of NK cells were present in pleural effusions from both cancer and CHF patients. Pleural NK from cancer patients showed a reduced expression of membrane CD94/NKG2A and perforin when compared to autologous peripheral blood. Pleural T lymphocytes from cancer patients exhibited a reduced cytotoxic activity against cancer cells when compared to autologous peripheral blood T lymphocytes. The intracellular expression of CD94/NKG2A in CD8+ and NK cells from cancer patients was higher than membrane expression. In conclusion, this study provides compelling evidences of new mechanisms underlying the reduced host defence against cancer within the pleural space. PMID- 20932743 TI - Understanding interactive characteristics of bioelectricity generation and reductive decolorization using Proteus hauseri. AB - This first-attempt study quantitatively explored interactive characteristics of bioelectricity generation and dye decolorization in air-cathode single-chamber microbial fuel cells (MFCs) using indigenous Proteus hauseri ZMd44. After approx. 15 cycles (30 days) acclimatization in dye-bearing cultures, P. hauseri could express its stable capability of simultaneous bioelectricity generation and color removal (SBP&CR) in MFCs. Evidently, appropriate acclimation strategy for formation of the electrochemically active anodic biofilm played a crucial role to enhance the performance of SBP&CR in MFCs. Gradually increased supplementations of C.I. reactive blue 160 resulted in progressively decreased decay rate of bioelectricity generation. That is, a dye decolorized in a faster rate would result in a lower capability for bioelectricity generation and vice versa. In addition, a reduced dye with less toxicity potency (e.g., 2-aminophenol) might work as a redox mediator of electron transport to anodic biofilm for bioelectricity generation in MFCs. PMID- 20932744 TI - Synthesis and antihyperlipidemic activity of novel coumarin bisindole derivatives. AB - A series of novel coumarin bisindole heterocycles were synthesized following an uncommon method and evaluated for their antihyperlipidemic activity in hyperlipidemic hamster model. Among 12 compounds tested, the compound 5e showed potent antihyperlipidemic activity and was found to decrease the plasma triglyceride levels (TG) by 55%, total cholesterol (TC) by 20%, accompanied by an increase in HDL-C/TC ratio by 42% in hyperlipidemic rats to a greater degree than some of the reference statins. PMID- 20932745 TI - Synthesis and pharmacological activity of 1,3,6-trisubstituted-4-oxo-1,4 dihydroquinoline-2-carboxylic acids as selective ET(A) antagonists. AB - A series of 1,3,6-trisubsituted-4-oxo-1,4-dihyroquinoline-2-carboxylic acid analogs (2a-m) were designed and synthesized and their pharmacological activity determined, with the objective to better understand their SAR as potential ET(A) selective inhibitors. Most of the compounds displayed significant ET(A) antagonist activity having IC(50) for inhibition of binding of the [(125)I]ET-1 to ET(A) receptor <10 nM, with good selectivity for ET(A) antagonism over ET(B) receptor. Based on the in vitro results, SAR of this series of compounds requires an alkoxy substituent at the 6-position to be a straight and saturated chain up to three carbons long, since substitution of unsaturated and branched alkyloxy groups results in decrease in ET(A) antagonist activity. In this series, compound 2c (6-O-n-propyl analog) was found to be most potent (IC(50)=0.11 nM) with ET(B)/ET(A) selectivity of 8303. PMID- 20932746 TI - Discovery of cell-active phenyl-imidazole Pin1 inhibitors by structure-guided fragment evolution. AB - Pin1 is an emerging oncology target strongly implicated in Ras and ErbB2-mediated tumourigenesis. Pin1 isomerizes bonds linking phospho-serine/threonine moieties to proline enabling it to play a key role in proline-directed kinase signalling. Here we report a novel series of Pin1 inhibitors based on a phenyl imidazole acid core that contains sub-MUM inhibitors. Compounds have been identified that block prostate cancer cell growth under conditions where Pin1 is essential. PMID- 20932747 TI - The rational design of a novel potent analogue of the 5'-AMP-activated protein kinase inhibitor compound C with improved selectivity and cellular activity. AB - We have designed and synthesized analogues of compound C, a non-specific inhibitor of 5'-AMP-activated protein kinase (AMPK), using a computational fragment-based drug design (FBDD) approach. Synthesizing only twenty-seven analogues yielded a compound that was equipotent to compound C in the inhibition of the human AMPK (hAMPK) alpha2 subunit in the heterotrimeric complex in vitro, exhibited significantly improved selectivity against a subset of relevant kinases, and demonstrated enhanced cellular inhibition of AMPK. PMID- 20932748 TI - Catharanthine C16 substituent effects on the biomimetic coupling with vindoline: preparation and evaluation of a key series of vinblastine analogues. AB - The examination of the catharanthine C16 substituent effects on the Fe(III) promoted biomimetic coupling reaction with vindoline is detailed, confirming the importance of the presence of a C16 electron-withdrawing substituent, and establishing an unanticipated unique role (>10-fold) that the C16 methyl ester plays in the expression of the natural product properties. Thus, replacement of the vinblastine C16' methyl ester with an ethyl ester (10-fold), a cyano group (100-fold), an aldehyde (100-fold), a hydroxymethyl group (1000-fold) or a primary carboxamide (>1000-fold) led to surprisingly large reductions in cytotoxic activity. PMID- 20932749 TI - Identification of a sulfonoquinovosyldiacylglyceride from Azadirachta indica and studies on its cytotoxic activity and DNA binding properties. AB - Chromatographic separation of the methanolic extract of the leaves of Azadirachta indica led to the isolation of a sulfonoglycolipid characterized as a sulfonoquinovosyldiacylglyceride (SQDG), by extensive 2D NMR and mass spectral analysis. SQDG induces apoptosis in a dose dependent manner with IC(50) 8.3 MUM against acute lymphoblastic leukemia (ALL) MOLT-4 cell lines. The compound showed significant DNA binding properties as evidenced by the enhancement of melting temperature and perturbation of the characteristic B-form in CD evidence of calf thymus DNA. The DNA binding was also characterized by isothermal calorimetry where a predominantly enthalpy driven binding to CT DNA was revealed. PMID- 20932750 TI - 1,2-diamino-ethane-substituted-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepines as TRPV1 antagonists with improved properties. AB - Based upon a previously reported lead compound 1, a series of 1,2-diamino-ethane substituted-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepines were synthesized and evaluated for improved physiochemical and pharmacokinetic properties while maintaining TRPV1 antagonist activity. Structure-activity relationship studies directed toward improving the aqueous solubility (pH 2 and fasted-state simulated intestinal fluid (SIF)) and rat pharmacokinetics led to the discovery of compound 13. Aqueous solubility of compound 13 (pH 2 >=237 MUg/mL and SIF=11 MUg/mL) was significantly improved over compound 1 (pH 2=5 MUg/mL and SIF=0.5 MUg/mL). In addition, compound 13 afforded improved rat pharmacokinetics (CL=0.7 L/kg/h) compared to compound 1 (CL=3.1 L/kg/h). Compound 13 was orally bioavailable and afforded a significant reversal of carrageenan-induced thermal hyperalgesia at 5 and 30 mg/kg in rats. PMID- 20932751 TI - CWJ-081, a novel 3-arylisoquinoline derivative, induces apoptosis in human leukemia HL-60 cells partially involves reactive oxygen species through c-Jun NH2 terminal kinase pathway. AB - In the present study, we investigated the effect of a novel 3-arylisoquinoline derivative 3-(6-ethyl-benzo[1,3]dioxol-5-yl)-7,8-dimethoxy-2-methyl-2H isoquinolin-1-one (CWJ-081) on the induction of apoptosis and the putative molecular mechanism of its action in human leukemia cells. Treatment with CWJ-081 exhibited a characteristic feature of apoptosis including externalization of phosphatidylserine and formation of DNA fragmentation in human leukemia cell lines (HL-60, U-937, K-562). In addition, stimulation of HL-60 cells with CWJ-081 induced a series of intracellular events: (1) the activations of caspase-8, -9, and -3; (2) the cleavage of poly (ADP-ribose) polymerase-1 (PARP-1); (3) the loss of mitochondrial membrane potential (DeltaPsi(m)); (4) the release of cytochrome c; and (5) the modulation of Bcl-2 family proteins. We further demonstrated that CWJ-081 induces reactive oxygen species (ROS) production and c-Jun NH(2)-terminal kinase (JNK) activation. Pretreatment with the antioxidant N-acetyl-L-cysteine (NAC) markedly inhibited the CWJ-081-induced JNK activation and apoptosis. Moreover, CWJ-081-induced apoptosis was suppressed in the presence of SP600125, a specific JNK inhibitor. Taken together, these data suggest that CWJ-081 induces apoptosis via the mitochondrial apoptotic pathway in HL-60 cells, and ROS mediated JNK activation plays a key role in the CWJ-081-induced apoptosis. PMID- 20932752 TI - Synthesis and antifungal activity of a novel series of 13-(4 isopropylbenzyl)berberine derivatives. AB - By replacing the methyl group of 13-(4-isopropylbenzyl)berberine 2 with various acyl, alkyl, and benzyl groups via the demethylated intermediate, 13-(4 isopropylbenzyl)berberrubine 4, a novel series of 9-O-alkyl-13-(4 isopropylbenzyl)berberine derivatives was synthesized and examined for antifungal activities against various human pathogenic fungi. The introduction of various alkyl groups led to enhanced antifungal activity but that of acyl groups resulted in decrease of the activity. Among them, 9-O-butyl-13-(4 isopropylbenzyl)berberine 6d exhibited the most potent antifungal activities against Cryptococcus neoformans, Candida species (MIC=0.25-1 MUg/ml), and Aspergillus species (MIC=2-4 MUg/ml). The compound was found to be relatively safe up to 900 mg/kg in oral administration to mice. PMID- 20932753 TI - Tetrasubstituted naphthalene diimide ligands with selectivity for telomeric G quadruplexes and cancer cells. AB - A series of tetrasubstituted naphthalene diimide compounds with N methylpiperazine end groups has been synthesized and evaluated as G-quadruplex ligands. They have high affinity and selectivity for telomeric G-quadruplex DNA over duplex DNA. CD studies show that they induce formation of a parallel G quadruplex topology. They inhibit the binding of hPOT1 and topoisomerase IIIalpha to telomeric DNA and inhibit telomerase activity in MCF7 cells. The compounds have potent activity in a panel of cancer cell lines, with typical IC(50) values of ~0.1 MUM, and up to 100-fold lower toxicity in a normal human fibroblast cell line. PMID- 20932754 TI - Synthesis and biological evaluation of furoxan-based nitric oxide-releasing derivatives of glycyrrhetinic acid as anti-hepatocellular carcinoma agents. AB - A series of novel furoxan-based nitric oxide (NO)-releasing derivatives of glycyrrhetinic acid (GA) were designed, synthesized, and evaluated for their in vitro cytotoxicity against human hepatocellular carcinoma (HCC) and non-tumor liver cells. Five furoxan/GA hybrids, 7b-d, 7f, and 7g, displayed potent cytotoxicity against HCC cells (IC(50): 0.25-1.10 MUM against BEL-7402 cells and 1.32-6.78 MUM against HepG2 cells), but had a little effect on the growth of LO2 cells, indicating that these compounds had selective cytotoxicity against HCC cells. Furthermore, these compounds produced high concentrations of NO in HCC cells, but low in LO2 cells and treatment with hemoglobin partially reduced the cytotoxicity of the hybrid in HCC cells. Apparently, the high concentrations of NO produced by NO donor moieties and the bioactivity of GA synergistically contribute to the cytotoxicity, but the NO is a major player against HCC cells in vitro. Potentially, our findings may aid in the design of new chemotherapeutic reagents for the intervention of human HCC at clinic. PMID- 20932755 TI - Polymerase-directed synthesis of C5-ethynyl locked nucleic acids. AB - Modified nucleic acids have considerable potential in nanobiotechnology for the development of nanomedicines and new materials. Locked nucleic acid (LNA) is one of the most prominent nucleic acid analogues reported so far and we herein for the first time report the enzymatic incorporation of LNA-U and C5-ethynyl LNA-U nucleotides into oligonucleotides. Phusion High Fidelity and KOD DNA polymerases efficiently incorporated LNA-U and C5-ethynyl LNA-U nucleotides into a DNA strand and T7 RNA polymerase successfully accepted the LNA-U nucleoside 5'-triphosphate as substrate for RNA transcripts. PMID- 20932756 TI - Lupane-type triterpenoids from the steamed leaves of Acanthopanax koreanum and their inhibitory effects on the LPS-stimulated pro-inflammatory cytokine production in bone marrow-derived dendritic cells. AB - Two new compounds, (20R)-3alpha-hydroxy-29-dimethoxylupan-23,28-dioic acid (1) and 3alpha-hydroxylup-20(29)-ene-23,28-dioic acid 28-O-[beta-D-glucopyranosyl-(1 >6)-beta-D-glucopyranosyl] ester (2), and eight known lupane-type triterpenoids (3-10), were isolated from steamed leaves of Acanthopanax koreanum. Chemical structures were determined using a combination of spectroscopic analyses and chemical reactivity. Compounds 1-10 were evaluated for their inhibitory activities on lipopolysaccharide (LPS)-stimulated interleukin (IL)-12 production in bone marrow-derived dendritic cells (BMDCs). Compound 1 exhibited inhibitory activity with IC(50) value of 26.5 MUM on IL-12 production, compared with IC(50) value of 29.6 MUM for the positive control. Compound 1 also showed significant suppression of LPS-stimulated IL-6 and tumor necrosis factor-alpha (TNF-alpha) production. PMID- 20932757 TI - Synthesis and bioevaluation of aryl-guanidino polyamine conjugates targeting the polyamine transporter. AB - Aryl-guanidino polyamine conjugates were prepared to evaluate their recognition for polyamine transporter (PAT) via a-difluoromethylornithine (DFMO) and spermidine (SPD)-treated B16 cell lines. The potent synergistic effects of DFMO on guanidino polyamine conjugates indicated that the presence of DFMO strongly facilitates the transport of conjugates into cells via PAT on cell membrane. The apoptotic mechanisms of triamine conjugates 10 and 1 (with and without guanidine groups) revealed that they induced apoptosis of Hela cells through the mitochondrial pathway associated with lysosomes, while DFMO strongly synergizes the function of 10 without changing the apoptotic route. Taken together, guanidino polyamine conjugates can target PAT for transport as normal polyamine ones, and the presence of guanidine in the polyamine vectors does not seem to alter the cellular targets of the conjugates, which may depend mainly on the pharmacophore. PMID- 20932758 TI - Development of novel inhibitors targeting HIF-1alpha towards anticancer drug discovery. AB - Hypoxia-inducible factor-1alpha (HIF-1alpha) is a critical regulatory protein of cellular response to hypoxia, and regulates the transcription of many genes involved in key aspects of cancer biology, including immortalization, maintenance of stem cell pools, cellular dedifferentiation, vascularization, and invasion/metastasis. HIF-1alpha has been implicated in the regulation of genes involved in angiogenesis, for example, VEGF and is associated with tumor progression. In the last decade, over expression of HIF-1alpha has been demonstrated in many common human cancers and emerging as a validated target for anticancer drug discovery. Here we report the discovery of newly designed and synthesized pyridylpyrimidine based potent and selective inhibitors of HIF 1alpha. P2630 has been found as potent antiproliferative, antiangiogenic and orally efficacious compound in PC-3 xenograft mice model. PMID- 20932759 TI - 4,5-Dihydro-1H-pyrazolo[4,3-h]quinazolines as potent and selective Polo-like kinase 1 (PLK1) inhibitors. AB - A series of 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivatives was optimized as Polo-like kinase 1 inhibitors. Extensive SAR afforded a highly potent and selective PLK1 compound. The compound showed good antiproliferative activity when tested in a panel of tumor cell lines with PLK1 related mechanism of action and with good in vivo antitumor efficacy in two xenograft models after i.v. administration. PMID- 20932760 TI - A new insight on the hypochlorous acid scavenging mechanism of tryptamine and tryptophan derivatives. AB - The reaction mechanisms of hypochlorous acid (HOCl) with several tryptophan and tryptamine derivatives, previously reported to scavenge this powerful oxidant, was investigated to determine whether ionic or radical pathways were involved. For this purpose, the reaction of tryptamine and tryptophan derivatives with HOCl was optimized and some compounds were isolated by HPLC and their structures assigned. In order to prevent possible radical reaction pathway, experiments have been carried in the presence of the radical trap TEMPO (2,2,6,6 tetramethylpiperidine-1-oxyl). The obtained results show that the reaction mechanisms are influenced by the type of structure and that a complex pathway is involved, in which both ionic and radical mechanisms can occur. PMID- 20932761 TI - Solid-phase synthesis and screening of N-acylated polyamine (NAPA) combinatorial libraries for protein binding. AB - Inhibitors for protein-protein interactions are challenging to design, in part due to the unique and complex architectures of each protein's interaction domain. Most approaches to develop inhibitors for these interactions rely on rational design, which requires prior structural knowledge of the target and its ligands. In the absence of structural information, a combinatorial approach may be the best alternative to finding inhibitors of a protein-protein interaction. Current chemical libraries, however, consist mostly of molecules designed to inhibit enzymes. In this manuscript, we report the synthesis and screening of a library based on an N-acylated polyamine (NAPA) scaffold that we designed to have specific molecular features necessary to inhibit protein-protein interactions. Screens of the library identified a member with favorable binding properties to the HIV viral protein R (Vpr), a regulatory protein from HIV, that is involved in numerous interactions with other proteins critical for viral replication. PMID- 20932762 TI - Flavonoids from Dracocephalum tanguticum and their cardioprotective effects against doxorubicin-induced toxicity in H9c2 cells. AB - Two new flavonoids, ladanetin-6-O-beta-(6"-O-acetyl)glucoside (1) and pedalitin 3'-O-beta-glucoside (2), together with 15 known compounds (3-17), were isolated from the whole plants of Dracocephalum tanguticum. Their structures were established on the basis of extensive spectroscopic (IR, MS, 2D NMR) data analysis and by the comparison with spectroscopic data reported in the literature. Antioxidant capacities of the isolated substances were determined using the 1,1-diphenyl-2-picrylhydrazyl (DPPH), ferrous ions, and ABTS(.)(+) radical in vitro assay, and their cytoprotective activities were also tested on doxorubicin (DOX)-induced toxicity in H9c2 cardiomyocytes. Among all the tested compounds, luteolin-7-O-beta-D-glucopyranoside (7) exhibited both strong antioxidative effect and high protective activity against DOX-induced toxicity. Further investigation found 7 could decrease DOX-induced death of H9c2 cell, reduce LDH and CK level, and inhibit the elevated intracellular concentration of ROS and [Ca(2+)](i). The preliminary structure-activity relationships (SAR) of these compounds revealed the Delta(2,3) double bond on C-ring and 3',4'-di-OHs on B-ring with a flavone skeleton such as luteolin and its derivatives, were necessary for their cardioprotective effects. PMID- 20932763 TI - Coordination of segments reorientation during on-the-spot turns in healthy older adults in eyes-open and eyes-closed conditions. AB - Turning has frequent occurrence in everyday activities. Despite the prevalence of turning in everyday life and the challenge it poses to older adults, there is far less known about the multisegmental control of turning than the control of standing and straight walking, especially in elderly individuals. The purpose of this study was to examine the timing and sequence of segments reorientation in healthy older adults during 90 degrees on-the-spot turns. The role of vision on segments coordination was also examined by testing the participants in eyes-open and eyes-closed conditions. When turning on-the-spot, healthy elderly reoriented their head, shoulder and pelvis simultaneously, followed by foot displacement. This was a robust behavior not affected by visual condition. Axial segments turned slower and more synchronously when vision was not available. While all segments started to turn together in both visual conditions, head turned faster and reached its peak velocity earlier than shoulder and pelvis. However, the difference in segmental velocity and the time to reach the peak velocity was smaller in eyes-closed than eyes-open condition. Without vision, the functional importance of a faster head turn is diminished. Participants may have adopted a tighter control of segments to simplify the control of movement by reducing the degrees of freedom. PMID- 20932764 TI - Comment on "Efficacy and safety of different doses of intravenous tissue plasminogen activator in Chinese patients with ischemic stroke". PMID- 20932765 TI - Visual failure and recovery after thrombosis of a giant carotid ophthalmic aneurysm following vascular bypass and carotid artery ligation. AB - Thrombosis via Hunterian ligation, with or without high-flow bypass, is the definitive treatment for unclippable giant aneurysms; however, secondary deterioration may occur. We present a 67-year-old woman with an unclippable giant (33mm) carotid ophthalmic aneurysm. High-flow external carotid artery to middle cerebral artery bypass and proximal cervical internal carotid artery Hunterian ligation achieved complete thrombosis. Subsequent expansion of the thrombosed aneurysm created mass effect with hydrocephalus, leading to marked cognitive and visual decline. Aneurysmal decompression led to improved vision and near-normal neurological function. PMID- 20932766 TI - Synthesis and antitumour activity of glycyrrhetinic acid derivatives. AB - Glycyrrhetinic acid (GA) is one of many interesting triterpenoic acids showing anticancerogenic potential. GA is known to trigger apoptosis in tumour cell lines, although GA has a low cytotoxicity. In our study we were able to prepare derivatives of GA that show lowered the IC(50) values as determined by a sulforhodamine B (SRB) assay using 15 different human tumour cell lines. Thus, combining an ester group combined with the presence of an amino acid moiety led to a ca. 60-fold improved antitumor activity. Experiments on mouse embryonic fibroblasts (NiH3T3) revealed that these compounds showed a better selectivity for tumour cells compared to the parent compound GA. An apoptotic effect of some of these compounds was determined using an acridine orange/ethidium bromide (AO/EB) test and DNA laddering experiments. PMID- 20932767 TI - Building a MCHR1 homology model provides insight into the receptor-antagonist contacts that are important for the development of new anti-obesity agents. AB - Melanin-concentrating hormone (MCH) regulates feeding and energy homeostasis through interaction with its receptor, the melanin-concentrating receptor 1 (MCHR1), making it a target in the treatment of obesity. Molecular modeling and docking studies were performed in order to find a binding model for the docking of two new series of MCHR1 antagonists to the receptor. Results suggested interactions between the ligands and two glutamines (Gln5.42 and Gln6.55) not conserved in many of the GPCRs family members. Histamine 3 receptor (HRH3) presents two apolar residues in the aforementioned positions and the available biological data against this receptor supported the role of the two glutamines in the binding of antagonists to the MCHR1. This knowledge could be useful in the development of new, more active and more selective MCHR1 antagonists. PMID- 20932768 TI - A demonstration of the effectiveness of a single aberration correction per optical slice in beam scanned optically sectioning microscopes. AB - In this paper we report the use of adaptive optics to correct for sample induced aberrations in optical microscopy, crucially comparing individual pixel-by-pixel correction against a single correction for an entire optical section. Sample induced optical aberrations in slices of rat brain tissue were corrected with a deformable membrane mirror. Using axial resolution measurements, we demonstrate that a single aberration correction per optical slice achieves around 80% of the maximum possible improvement compared to individual pixel-by-pixel correction in both confocal and multiphoton microscopy. A single aberration correction per depth, compared to pixel-by-pixel aberration correction, significantly decreases scan times and therefore reduces photobleaching and phototoxic effects enabling more rapid microscopy with active aberration correction. The results confirm that the use of a "look-up" table, based upon sample type and depth, may be the most practical way of implementing adaptive optic aberration correction in beam scanning optical sectioning microscopy. PMID- 20932769 TI - Extracorporeal membrane oxygenation as a bridge to lung transplantation in a patient with persistent severe porto-pulmonary arterial hypertension following liver transplantation. AB - Idiopathic pulmonary artery hypertension (IPAH) is a progressive disease with a dismal prognosis and lung transplantation is often the only option for patients, who do not respond to pharmacological therapy. We report the use of an extracorporeal membrane oxygenation (ECMO) system in a 49-year-old woman with primary pulmonary hypertension, previously liver transplanted. The patient, listed for lung transplantation, developed respiratory and circulatory failure despite maximal pharmacological therapy and was successfully bridged to emergent bilateral lung transplantation with veno-arterial ECMO. Emergent veno-arterial ECMO was able to rescue the patient and bridge her to bilateral lung transplantation and should therefore be an option for patients with PAH and circulatory collapse. PMID- 20932770 TI - Reconstruction of the free margin of the anterior mitral leaflet with autologous pericardium in active infected endocarditis. AB - In patients with active infective endocarditis mitral valve repair is better than mitral valve replacement, but it remains a challenge when there has been massive destruction of the rough zone of the anterior leaflet. We report a technical modification of mitral valve repair for advanced active infective endocarditis in which a widely infected rough zone and the chordae were successfully replaced with autologous pericardium and multiple artificial chordae. The procedure described here is capable of improving the prospects of mitral valve repair in advanced infective endocarditis. PMID- 20932771 TI - Giant anterior chest-wall basal-cell carcinoma. PMID- 20932772 TI - Acute Leriche syndrome due to the thrombus in the left ventricle. PMID- 20932773 TI - TNF-alpha levels are not increased in inflamed patients carrying the CCR5 deletion 32. AB - BACKGROUND AND AIMS: Recently we reported on a genetically predisposed protection from C-reactive protein (CRP) related mortality in dialysis patients carrying the functional CC-chemokine receptor 5 deletion 32 allele (CCR5Delta32) mutation. Since CCR5Delta32 is associated with a less pro-inflammatory immune response in mice, we hypothesized that the observed protection is (in part) due to a less pro inflammatory cytokine profile. METHODS: Cross-sectional observational study including 263 incident dialysis patients aged 18-70years, without clinical signs of infection and/or acute vasculitis. TNF-alpha, IL-6, IL-10 and hsCRP levels were determined and studied in relation to the CCR5 genotype. RESULTS: In the presence of elevated hsCRP, IL-6 concentration was higher irrespective of the CCR5 genotype. However, in patients with the CCR5 deletion, TNF-alpha did not differ in the presence/absence of elevated hsCRP and was not correlated with hsCRP levels in carriers of the CCR5Delta32 polymorphism. CONCLUSIONS: A possible underlying mechanism of the impact of CCR5Delta32 genotype on inflammation driven mortality in dialysis patients could be a reduced Th1 immune response as represented by decreased TNF-alpha levels. PMID- 20932774 TI - Photoinduced dissociation of heparin-derived oligosaccharides controlled by charge location. AB - The development of strategies based on mass spectrometry to help for deep structural analysis of acidic oligosaccharides remains topical. We thus examined the dissociation behavior of deprotonated ions of heparin-derived di- to tetra saccharides under UV irradiation at 220 nm. Depending on the ionization state of the carboxylic groups, an oxidized species issued from electron photodetachment was observed in complement to photoinduced fragmentation of precursor ions. The influence of the charge location in the oligosaccharide dianions on the balance between photodissociation and electron photodetachment is examined and a way to direct the relaxation pathways, (i.e., dissociation versus electron detachment), is proposed using sodium adducts. The oxidized species was subjected to activated electron photodetachment (activated-EPD) leading to complementary informative fragment ions to those issued from photodissociation. Directed photoinduced dissociation at 220 nm and activated-EPD should complement the more conventional CAD and IRMPD activation modes for deeper structural analysis of acidic oligosaccharides-derived anions. PMID- 20932775 TI - Analysis of patellar stabilizers muscles and patellar kinematics in anterior knee pain subjects. AB - Patella stabilizer muscle response and patellar kinematics were evaluated in 19 women with anterior knee pain (AKP) and 20 healthy women during maximum voluntary isometric contraction (MVIC) with the knee positioned at 15 degrees , 30 degrees and 45 degrees flexion during open (OKC) and closed (CKC) kinetic chain exercises. Patellar kinematics was evaluated through patellar tilt and displacement, and the electrical activity of patellar stabilizers through the root mean square normalized during MVIC and OKC with the knee at 90 degrees flexion. Data revealed that the vastus medialis oblique muscle (VMO) was more active in the control group compared to the AKP group during OKC exercises with the knee at 45 degrees flexion. However, no difference in the patellar kinematics was observed between these groups; nevertheless, the correlation between these parameters also showed, with the knee at 45 degrees flexion, that lateral patellar tilt increase was associated with a reduction in the activity of lateral patellar stabilizers in the control group and with an increase in the VMO activity in the AKP group. In conclusion, electrical activity is an important factor in evaluating AKP and in AKP treatment evolution. PMID- 20932776 TI - Automated quantification of aortoaortic and aortoiliac angulation for computed tomographic angiography of abdominal aortic aneurysms before endovascular repair: preliminary study. AB - The degree of angulation of abdominal aortic aneurysms (AAAs) has emerged as an important factor in assessing eligibility for endovascular aneurysm repair (EVAR). The authors developed an automatic algorithm that reduces variability of measurement of aortoiliac angulation. For highly structured manual methods, intraobserver variability was 8.2 degrees +/- 5.0 (31% +/- 20) and interobserver variability was 5.6 degrees +/- 2.5 (20% +/- 9.1) compared with 0.6 degrees +/- 0.8 (2.2% +/- 3.6) (intraobserver) and 0.4 degrees +/- 0.4 (1.4% +/- 1.9) (interobserver) for the automatic algorithm (P < .01). In phantoms, the automatically measured angles were equivalent to reference values (P < .05). This algorithm was also faster than manual methods and has the potential to enhance the clinical utility and reliability of computed tomographic angiography for preoperative assessment for EVAR. PMID- 20932777 TI - Memory and consciousness: trace distinctiveness in memory retrievals. AB - The aim of this article was to provide experimental evidence that classical dissociation between levels of consciousness associated with memory retrieval (i.e., implicit or explicit) can be explained in terms of task dependency and distinctiveness of traces. In our study phase, we manipulated the level of isolation (partial vs. global) of the memory trace by means of an isolation paradigm (isolated words among non-isolated words). We then tested these two types of isolation in a series of tasks of increasing complexity: a lexical decision task, a recognition task, and a free recall task. The main result of this study was that distinctiveness effects were observed as a function of the type of isolation (level of isolation) and the nature of the task. We concluded that trace distinctiveness improves subsequent access to the trace, while the level of trace distinctiveness also appears to determine the possibility of conscious or explicit retrieval. PMID- 20932778 TI - Brain imaging of the self--conceptual, anatomical and methodological issues. AB - In this paper we consider two major issues: conceptual-experimental approaches to the self, and the neuroanatomical substrate of the self. We distinguish content- and processed-based concepts of the self that entail different experimental strategies, and anatomically, we investigate the concept of midline structures in further detail and present a novel view on the anatomy of an integrated subcortical-cortical midline system. Presenting meta-analytic evidence, we show that the anterior paralimbic, e.g. midline, regions do indeed seem to be specific for self-specific stimuli. We conclude that future investigation of the self need to develop novel concepts that are more empirically plausible than those currently in use. Different concepts of self will require novel experimental designs that include, for example, the brain's resting state activity as an independent variable. Modifications of both conceptual and anatomical dimensions will allow an empirically more plausible account of the relationship between brain and self. PMID- 20932779 TI - The role of the self in mindblindness in autism. AB - Since its inception the 'mindblindness' theory of autism has greatly furthered our understanding of the core social-communication impairments in autism spectrum conditions (ASC). However, one of the more subtle issues within the theory that needs to be elaborated is the role of the 'self'. In this article, we expand on mindblindness in ASC by addressing topics related to the self and its central role in the social world and then review recent research in ASC that has yielded important insights by contrasting processes relating to both self and other. We suggest that new discoveries lie ahead in understanding how self and other are interrelated and/or distinct, and how understanding atypical self-referential and social-cognitive mechanisms may lead to novel ideas as to how to facilitate social-communicative abilities in ASC. PMID- 20932780 TI - The effect of biceps reattachment site. AB - BACKGROUND: We hypothesize that an anatomic repair of the distal biceps tendon would recreate native tendon moment arm and forearm rotation, while a nonanatomic insertion would compromise moment arm and forearm rotation. METHODS: Isometric supination torque was measured at 60 degrees of pronation, neutral, and 60 degrees of supination for the native distal biceps tendon and 4 repair points in 6 cadaveric specimens using a computer controlled elbow simulator. The slope of the regression line fitted to the torque versus biceps load data was used to define the moment arm for each attachment location. Range of motion testing was performed by incrementally loading the biceps, while measuring the supination motion generated using a digital goniometer. RESULTS: Tendon location and forearm position significantly affected the moment arm of the biceps (P < .05). Anatomic repair in all forearm positions showed no significant difference from the native insertion. Moment arm for an anterior center repair was significantly lower in supination (-97%) and neutral (-27%) and also produced significantly less supination motion. No difference was observed between all tendon locations in pronation. CONCLUSIONS: Reattachment of the biceps to its anatomic location, as opposed to a more anterior central position, is critical in reestablishing native tendon biomechanics. Clinically, these findings would suggest that patients with a biceps repair might experience the most weakness in a supinated position without experiencing a deficit in the pronated forearm. PMID- 20932781 TI - Radial head prosthesis micromotion characteristics: Partial versus fully grit blasted stems. AB - BACKGROUND: Compared to fully textured prosthetic stems, partial texturing lessens bone loss due to stress shielding and makes removal easier. However, initial press-fit stability is necessary for bone ingrowth. HYPOTHESIS: There is no significant difference in the initial stability of radial head prostheses that are partially grit-blasted compared to those that are fully grit-blasted. MATERIALS AND METHODS: Cadaveric radii were implanted with partial or fully grit blasted radial head prostheses. Micromotion of the stem at the isthmus of the canal and stem tip were measured under circumstances simulating eccentric loads. RESULTS: Micromotion was not significantly different in the fully grit-blasted stems (isthmus, 11 +/- 1 MUm; tip, 21 +/- 2 MUm) and partially grit-blasted stems (isthmus, 13 +/- 2 MUm; tip, 25 +/- 2 MUm) (P = 0.4). The direction of loading had no effect on micromotion characteristics in either the fully or partially grit-blasted stems (P = .07). DISCUSSION: Micromotion is comparable in partially and fully grit-blasted radial head prosthetic stems. For both stem surfaces, micromotion was well within the range that is conducive for bone ingrowth. A partially textured stem might have less bone loss due to stress shielding, making it easier to remove without destroying bone. CONCLUSION: The initial stability of a radial head stem that is partially grit-blasted only at the proximal end is comparable to that of a radial head stem that is grit-blasted along its entire length. PMID- 20932782 TI - Glenoid spherical orientation and version. AB - HYPOTHESIS: Glenoid orientation likely plays an important role in shoulder mechanics and has been associated with glenohumeral instability, rotator cuff tears, and total shoulder arthroplasty outcome. Glenoid version and inclination measurements are widely used, but these measurements are 2-dimensional, and orientation of the central face must be inferred from 2 points on the outer rim. This study tested the hypothesis that sphere fitting provides an optimal assessment of glenoid face 3-dimensional orientation, and clinically important differences will exist in some individuals between sphere fit orientation and traditional version measurement. MATERIALS AND METHODS: Computed tomography scans of 20 normal glenoids were obtained. Glenoid version was measured from resliced, pure transverse images at a series of glenoid heights. Separately, the 3 dimensional surface of each glenoid face was reconstructed. A sphere was fit to the glenoid face, and its orientation was described by 2 angles analogous to version and inclination. RESULTS: "Sphere fit version" averaged -3.2 degrees +/- 3.4 degrees (negative indicating retroversion), and "sphere fit inclination" averaged 1.3 degrees +/- 4.7 degrees . Absolute differences between sphere fit version and the standard mid-glenoid version averaged 1.5 degrees (maximum 4.0 degrees ) across patients. The glenoids were, on average, 5.5 degrees more retroverted at the 80% height than at the 20% height. DISCUSSION: Three dimensional aspects of the glenoid, including the spiraling twist evidenced by increased retroversion superiorly, are accounted for in this novel sphere-fitting approach for assessing glenoid orientation. CONCLUSIONS: For most normal glenoids, midglenoid version appears to provide an adequate measure of glenoid central face orientation. Sphere fitting has potential utility in optimizing glenoid implant alignment in total shoulder arthroplasty. PMID- 20932783 TI - The effects of two analgesic regimes on behavior after abdominal surgery in Steller sea lions. AB - This study examined the effects of two non-steroidal anti-inflammatory drug (NSAID) treatment protocols on the behavioral responses of juvenile Steller sea lions after abdominal surgery. Sea lions were randomly assigned to one of two treatments designed to control post-operative pain. The flunixin group (n=6) received flunixin meglumine (1mg/kg) administered as a single intramuscular (IM) injection before extubation from surgery. The carprofen group (n=5) received carprofen (4.4 mg/kg) as an IM injection before extubation, then orally at 24, 48 and 72 h after surgery. Seven behaviors related to post-operative pain were monitored by observers, blinded to treatment, for a total of 10 days (3 days pre , day of surgery, and 6 days post-surgery). All seven behaviors changed after surgery regardless of NSAID treatment, two of which returned to baseline within 6 days of surgery. Only one behavior was mildly affected by analgesic treatment: sea lions in the carprofen group tended to spend less time lying down in Days 1-3 following surgery (i.e., the days which they received oral carprofen). These results suggested that neither treatment, at the dose administered, was effective in controlling pain in the days following this surgery. PMID- 20932784 TI - Prevalence and antimicrobial susceptibility of Salmonella infections in free range pigs. AB - The prevalence of Salmonella spp. infection was determined in 67 free-range pig herds in southern Spain. Microbiological assessment was performed on ileocolic lymph nodes collected at slaughter according to ISO 6579:2002 procedures. Overall, 33% of herds were infected and the prevalence of infection was 5.3%. Salmonella spp. serovars most frequently isolated were Anatum and Typhimurium, although uncommon serovars such as Hessarek and Mikawasima were also detected. Isolates were tested against 16 antimicrobial agents and exhibited resistance to streptomycin (46%), tetracycline (30%), sulphonamides (25%) and ampicillin (23%) by the break-point method. Multi-drug resistance, defined as resistance to >= 4 antimicrobials, was 36%. PMID- 20932785 TI - mRNA expression of canine ATP10C, a P4-type ATPase, is positively associated with body condition score. AB - Mouse and human Atp10c genes are strong candidates for changes in bodyweight and glucose homeostasis. Using comparative genomic analysis, a novel canine P4-type ATPase, ATP10C, was identified. Expression of ATP10C was compared between sex matched lean (body condition score, BCS<8; n=7) and obese (BCS?8, n=8) client owned dogs of comparable ages. Canine ATP10C is highly expressed in visceral and subcutaneous fat at approximately 3-fold levels compared to the omental adipose depot. There was a 5-fold significant increase (P<0.0001) in mRNA expression of ATP10C in dogs with a BCS?8. PMID- 20932786 TI - The incidence and distribution of peripheral caries in the cheek teeth of horses and its association with diastemata and gingival recession. AB - Although considered relatively common in horses, there is little information on the prevalence, distribution and aetiology of peripheral caries of the equine cheek teeth (CT). The objective of this study was to investigate a possible association between this lesion and diastemata or 'gaps' between the CT which facilitate the entrapment of food material. Video recordings of oroscopic examinations of all dental cases at an equine hospital over a 3-year period were reviewed, and the location of all diastemata, peripheral caries, trapped food, and of gingival recession were recorded. A total of 108 cases met study inclusion criteria and 298 diastemata and 445 CT with peripheral caries were noted. Diastemata were found predominantly in the mandibular arcades (80%) and 75% of animals had at least one diastema. Peripheral caries was uniformly distributed between the maxillary and mandibular CT, being most prevalent on the most caudal three teeth (87%). Overall, diastemata were not associated with peripheral caries at either a tooth or individual patient level. However, a highly significant association was found between the presence of trapped food within diastemata and gingival recession. PMID- 20932787 TI - Recombinant small ruminant lentivirus subtype B1 in goats and sheep of imported breeds in Mexico. AB - Nucleotide sequences of small ruminant lentiviruses (SRLVs) were determined in sheep and goats, including progeny of imported animals, on a farm in Mexico. On the basis of gag-pol, pol, env and LTR sequences, SRLVs were assigned to the B1 subgroup, which comprises caprine arthritis-encephalitis virus (CAEV)-like prototype sequences mainly from goats. In comparison with CAEV-like env sequences of American and French origin, two putative recombination events were identified within the V3-V4 and V4-V5 regions of the env gene of a full length SRLV sequence (FESC-752) derived from a goat on the farm. PMID- 20932788 TI - Reference values of mechanical and thermal pain tests in a pain-free population. AB - Quantitative sensory tests are widely used in human research to evaluate the effect of analgesics and explore altered pain mechanisms, such as central sensitization. In order to apply these tests in clinical practice, knowledge of reference values is essential. The aim of this study was to determine the reference values of pain thresholds for mechanical and thermal stimuli, as well as withdrawal time for the cold pressor test in 300 pain-free subjects. Pain detection and pain tolerance thresholds to pressure, heat and cold were determined at three body sites: (1) lower back, (2) suprascapular region and (3) second toe (for pressure) or the lateral aspect of the leg (for heat and cold). The influences of gender, age, height, weight, body-mass index (BMI), body side of testing, depression, anxiety, catastrophizing and parameters of Short-Form 36 (SF-36) were analyzed by multiple regressions. Quantile regressions were performed to define the 5th, 10th and 25th percentiles as reference values for pain hypersensitivity and the 75th, 90th and 95th percentiles as reference values for pain hyposensitivity. Gender, age and/or the interaction of age with gender were the only variables that consistently affected the pain measures. Women were more pain sensitive than men. However, the influence of gender decreased with increasing age. In conclusion, normative values of parameters related to pressure, heat and cold pain stimuli were determined. Reference values have to be stratified by body region, gender and age. The determination of these reference values will now allow the clinical application of the tests for detecting abnormal pain reactions in individual patients. PMID- 20932789 TI - Mental stress and psychosocial factors at work in relation to multiple-site musculoskeletal pain: a longitudinal study of kitchen workers. AB - Among 385 female kitchen workers, we examined (1) whether mental stress and psychosocial factors at work (job control, skill discretion, supervisor support, co-worker relationships, and hurry) predict multiple-site musculoskeletal pain (MSP; defined as pain at >= 3 of seven sites) and (2) reversedly, whether MSP predicts these psychosocial factors. Data were collected by questionnaire at 3 month intervals during 2 years. Trajectory analysis was applied. Four trajectories of MSP prevalence emerged: Low, Descending, Ascending, and High. For the psychosocial factors, a two-trajectory model (Ascending or High vs. Low) yielded the best fit. In logistic regression analysis, with the Low MSP trajectory as reference, poor co-worker relationships (odds ratio [OR] 3.9), mental stress (3.1) and hurry (2.1) at baseline predicted belonging to the High MSP trajectory. Also MSP at baseline predicted the trajectories (Ascending vs. Low) of low job control (2.2) and mental stress (3.2). Adverse changes in most psychosocial factors were associated with belonging to the High (ORs between 2.3 and 8.6) and Ascending (2.7-5.5) MSP trajectories. In generalized estimating equations, time-lagged by 3 months, all psychosocial factors but two predicted MSP (1.4-2.1), allowing, e.g. for MSP at baseline, and vice versa, MSP predicted low job control, low supervisor support, and mental stress (1.4-2.0), after adjustment for e.g. the relevant psychosocial factor at baseline. In conclusion, we found that several psychosocial factors predicted MSP and that MSP predicted several psychosocial factors. The results suggest a cumulative process in which adverse psychosocial factors and MSP influence each other. PMID- 20932790 TI - Application of compressed sensing to in vivo 3D 19F CSI. AB - This study shows how applying compressed sensing (CS) to (19)F chemical shift imaging (CSI) makes highly accurate and reproducible reconstructions from undersampled datasets possible. The missing background signal in (19)F CSI provides the required sparsity needed for application of CS. Simulations were performed to test the influence of different CS-related parameters on reconstruction quality. To test the proposed method on a realistic signal distribution, the simulation results were validated by ex vivo experiments. Additionally, undersampled in vivo 3D CSI mouse datasets were successfully reconstructed using CS. The study results suggest that CS can be used to accurately and reproducibly reconstruct undersampled (19)F spectroscopic datasets. Thus, the scanning time of in vivo(19)F CSI experiments can be significantly reduced while preserving the ability to distinguish between different (19)F markers. The gain in scan time provides high flexibility in adjusting measurement parameters. These features make this technique a useful tool for multiple biological and medical applications. PMID- 20932791 TI - Case-control study to determine risk factors for diarrhea among children during a large outbreak in a country with a high prevalence of HIV infection. AB - OBJECTIVES: Between January and March of 2006, over 35 000 diarrhea cases and 532 deaths were reported among children aged <5 years in Botswana. We conducted an investigation to characterize the outbreak, identify risk factors for diarrhea, and recommend control strategies. METHODS: We enrolled children <5 years of age presenting to the emergency department between March 2 and March 20, 2006. Cases had >=3 loose stools per day and no antecedent diarrhea among household members. Controls had had no diarrhea since January 1, 2006. We conducted a multivariate logistic regression analysis controlling for socioeconomic status, age, and maternal HIV status. RESULTS: Forty-nine cases with median age of 12 months (range 0-45 months) and 61 controls with median age of 24 months (range 0-59 months) were enrolled; 33 (30%) were born to HIV-positive mothers. Case-parents were more likely to report storing household drinking water (adjusted odds ratios (AOR) 3.9, 95% confidence interval (CI) 1.2-15.7). Lack of hand washing after using the toilet or latrine (AOR 4.2, 95% CI 1.1-20.4) was more likely to be reported by case-parents. Case-children were less likely to be currently breastfeeding (AOR 30.3, 95% CI 2.0-1000.0). Five (10%) case-patients and no control-patients died. Multiple causal pathogens were identified. CONCLUSIONS: During this diarrhea outbreak in a country with a national program to prevent mother-to-child transmission of HIV, ill children were less likely to be breastfed and more likely to have been exposed to environmental factors associated with fecal contamination. These findings underscore the importance of adequate access to safe water, sanitation, hygiene, and nutrition education among populations using breast milk substitutes. PMID- 20932792 TI - Nonlinear ultrasonic standing waves: two-dimensional simulations in bubbly liquids. AB - We present the results of numerical predictions for analyzing the behavior of nonlinear ultrasonic standing waves in two-dimensional cavities filled with bubbly liquids. The model we solve accounts for nonlinearity, dissipation, and dispersion of the two-dimensional media due to the bubbles. The numerical simulations are based on a finite-difference scheme. They consider the bubbles evenly distributed in the liquid. Results are shown for high-amplitude signals. They make it possible to observe how the linear modes turn into multi-frequency nonlinear fields. PMID- 20932793 TI - Potassium sorbate as an efficient and green catalyst for Knoevenagel condensation. AB - Potassium sorbate has been utilized as a novel, efficient and green catalyst for the Knoevenagel condensation of aromatic aldehydes with active methylene compounds to afford substituted ole-fins through the conventional stirring or under ultrasound irradiation. Improvements were observed by carrying out the reactions under ultrasound irradiation. The advantages of this procedure are mild reaction conditions, high yields, cleaner reaction profiles and operational simplicity. PMID- 20932794 TI - Portable measurement system for the objective evaluation of the spasticity of hemiplegic patients based on the tonic stretch reflex threshold. AB - The clinical scales used for the evaluation of the spasticity have some drawbacks, in spite of their simplicity and ease of assessment, and their inter- and intra-rater reliability remains controversial. The aim of this study is to develop a portable system for the objective and reliable evaluation of the spasticity based on the K-means clustering of the tonic stretch reflex threshold (TSRT) and to compare the discrimination performance of the level of spasticity determined by our method with that by the conventional modified Ashworth scale (MAS). Fifteen hemiplegic patients (7 males and 8 females, age: 63.5+/-15.6) participated in the study. The average and standard deviation values of the TSRTs were 127.9+/-1.6, 121.8+/-1.5 and 117.9+/-1.3 in groups G1, G2 and G3, respectively, and there were significant differences between the TSRTs of each group (p<0.05). Also, our groups classified by the criteria of the TSRT had a strong negative correlation (r=-0.95, r(2)=0.90, p<0.05) between the level of spasticity and TSRTs. These results demonstrated that our system could be clinically more useful for the quantitative and reliable discrimination of the spasticity than the conventional MAS. PMID- 20932796 TI - Combating evolution with intelligent design: the neoglycoside ACHN-490. AB - The challenge posed by increasing levels of drug-resistant bacteria world-wide is manifest, and must be dealt with both by new approaches to the use of existing antibiotics and by the introduction of novel drugs. ACHN-490 is the first neoglycoside, or next-generation aminoglycoside, to begin clinical development. ACHN-490 was designed to target key pathogens, particularly gram-negative organisms and those resistant to older antibiotics. ACHN-490 demonstrates promising in vitro activity against wild-type and resistant bacteria while retaining the favorable bactericidal and synergistic properties of the aminoglycoside class. These attributes, along with the results of Phase 1 studies of ACHN-490 injection, suggest that ACHN-490 may help to fill the growing unmet need for new antibacterial agents. PMID- 20932795 TI - The functional role of cross-frequency coupling. AB - Recent studies suggest that cross-frequency coupling (CFC) might play a functional role in neuronal computation, communication and learning. In particular, the strength of phase-amplitude CFC differs across brain areas in a task-relevant manner, changes quickly in response to sensory, motor and cognitive events, and correlates with performance in learning tasks. Importantly, whereas high-frequency brain activity reflects local domains of cortical processing, low frequency brain rhythms are dynamically entrained across distributed brain regions by both external sensory input and internal cognitive events. CFC might thus serve as a mechanism to transfer information from large-scale brain networks operating at behavioral timescales to the fast, local cortical processing required for effective computation and synaptic modification, thus integrating functional systems across multiple spatiotemporal scales. PMID- 20932797 TI - Development and evaluation of an adult use-of-time instrument with an energy expenditure focus. AB - Measurement in behavioural epidemiology depends on high resolution and precise and accurate measures of the behaviour of interest. Few questionnaires in the adult population are able to simultaneously collect the multidimensional information that is emerging as being important in the relationship between behaviour and health. This project had two objectives: (1) to develop an adult version of the computer-delivered Multimedia Activity Recall for Children and Adolescents (MARCA), a 24-h activity recall instrument that can measure use-of time and estimate energy expenditure and (2) to determine the test-retest reliability and convergent validity of the developed adult MARCA. Thirty-eight healthy subjects (mean+/-SD, 31.7+/-12.1 yr) completed two recalls of the adult MARCA within 24-h and accelerometer counts were measured on 30 of the subjects. Bland-Altman analysis and intraclass correlation coefficients (ICC) were used to quantify the test-retest reliability of the adult MARCA. Spearman rank correlation coefficients (rho) were used to quantify convergent validity of the adult MARCA compared to accelerometer counts. The test-retest reliability coefficients of the adult MARCA were high with intra-class coefficients ranging from 0.99 to 1.00. Moderate to strong validity was observed for physical activity level (PAL) (MET.min score of accelerometer wear time) and accelerometer counts per minute (rho=0.72). The adult MARCA is a valid and reliable self-report measure of use-of-time and energy expenditure, capable of a wide variety of flexible use-of-time analyses related to a wide range of behaviours. PMID- 20932798 TI - Effect of a carbohydrate mouth rinse on maximal sprint performance in competitive male cyclists. AB - There is evidence that rinsing the mouth with a carbohydrate (CHO) solution can improve endurance performance. The goal of this study was to investigate whether a CHO mouth rinse can improve the performance of a maximal sprint effort. Fourteen competitive male cyclists (64.0+/-5.6 mL kg(-1) min(-1) (mean+/-SD)) each completed the following 5-s mouth rinse trials in a randomised counter balanced order; (a) 6.4% maltodextrin solution [Mal], (b) 7.1% glucose solution [Glu], (c) water [Wa] and (d) a control trial with no rinse [Con]. Each participant then performed a 30-s maximal sprint effort on a cycle ergometer. Glu, Mal and Wa trials were not significantly different from Con across all indicators of sprint performance (maximal power output, mean power output over 0 30, 0-10, 10-20, and 20-30s), nausea or fatigue level (p>0.05). These findings suggest that the use of a 5-s mouth rinse with an isoenergetic amount of either maltodextrin or glucose is not beneficial for maximal sprint performance. PMID- 20932799 TI - Treatment-related peripheral neuropathy in multiple myeloma: the challenge continues. AB - Introduction of the proteasome inhibitor bortezomib and the immunomodulatory drugs thalidomide and lenalidomide has substantially improved outcomes for patients with multiple myeloma. As a result, these drugs have become cornerstones of current antimyeloma treatment regimens. However, after several years of clinical experience it has become apparent that peripheral neuropathy is the most common and potentially disabling non-haematological side-effect associated with thalidomide and bortezomib. Maximising treatment benefit while preserving quality of life therefore requires a careful balance between achieving optimum activity and minimising toxicity, including neuropathy, to further enhance efficacy. In this review, we discuss all aspects of drug-induced peripheral neuropathy in myeloma, with a particular focus on thalidomide and bortezomib. PMID- 20932801 TI - BEI Resources: a biological resource center for parasitologists. PMID- 20932800 TI - p53 post-translational modification: deregulated in tumorigenesis. AB - The p53 tumor suppressor protein has well-established roles in monitoring various types of stress signals by activating specific transcriptional targets that control cell cycle arrest and apoptosis, although some activities are also mediated in a transcription-independent manner. Here, we review the recent advances in our understanding of the wide spectrum of post-translational modifications that act as epigenetic-like codes for modulating specific functions of p53 in vivo and how deregulation of these modifications might contribute to tumorigenesis. We also discuss future research priorities to further understand p53 post-translational modifications and the interpretation of genetic data in appreciation of the increasing evidence that p53 regulates cellular metabolism, autophagy and many unconventional tumor suppressor activities. PMID- 20932802 TI - Is the quality of assisted reproduction treatment better in some countries than others? PMID- 20932803 TI - Increased safety leads to less restrictive use of plasma transfusions. PMID- 20932804 TI - The status of pathogen-reduced plasma. AB - Efforts to reduce the risk of transfusion-transmitted infectious diseases began more than 4 decades ago with testing donated blood for syphilis. During the subsequent 4 decades, the number of recognized blood-borne transmissible agents and new laboratory tests has proliferated to a logistical breaking point. Further, the number of "emerging agents" which might enter the donor population is increasing continuously. In the search for an alternative to the laboratory testing strategy, pathogen-reduction technologies have emerged as the most promising. The model for this paradigm is pasteurization of a bottle of cow's milk. No matter what infective agent may be present in freshly collected cow's milk, pasteurization, i.e., a generic purification process can eliminate all potential infectivity, while preserving its essential biological properties--and an affordable cost. Several manufacturers have undertaken the challenge of developing a pathogen-reduction technology for blood components. Some novel technologies have proven successful for pooled plasma derivatives such as immune globulins, coagulation factor concentrate concentrates and albumin. The greatest challenge is finding a technology that is suitable for red blood cell and platelet components, whereas significant progress has been made already for pathogen-reduced plasma products. The present review addresses the status of implementation of pathogen-reduced plasma products in the global market. Some blood centers and hospital blood banks in Europe and the Middle East have begun to distribute pathogen-reduced plasma, but no pathogen-reduced plasma product is presently approved by the US Food and Drug Administration. While many observers in the United States focus on the regulatory process as the impediment to widespread implementation, the real challenge will be paying the surcharge for the pathogen-reduction process - an as yet unspecified figure - but likely to add a very substantial amount to the annual healthcare budget. PMID- 20932805 TI - Efficacy and safety of artemether-lumefantrine compared with quinine in pregnant women with uncomplicated Plasmodium falciparum malaria: an open-label, randomised, non-inferiority trial. AB - BACKGROUND: Malaria in pregnancy is associated with maternal and fetal morbidity and mortality. In 2006, WHO recommended use of artemisinin-based combination treatments during the second or third trimesters, but data on efficacy and safety in Africa were scarce. We aimed to assess whether artemether-lumefantrine was at least as efficacious as oral quinine for the treatment of uncomplicated falciparum malaria during the second and third trimesters of pregnancy in Mbarara, Uganda. METHODS: We did an open-label, randomised, non-inferiority trial between October, 2006, and May, 2009, at the antenatal clinics of the Mbarara University of Science and Technology Hospital in Uganda. Pregnant women were randomly assigned (1:1) by computer generated sequence to receive either quinine hydrochloride or artemether-lumefantrine, and were followed up weekly until delivery. Our primary endpoint was cure rate at day 42, confirmed by PCR. The non inferiority margin was a difference in cure rate of 5%. Analysis of efficacy was for all randomised patients without study deviations that could have affected the efficacy outcome. This study was registered with ClinicalTrials.gov, number NCT00495508. FINDINGS: 304 women were randomly assigned, 152 to each treatment group. By day 42, 16 patients were lost to follow-up and 25 were excluded from the analysis. At day 42, 137 (99.3%) of 138 patients taking artemether lumefantrine and 122 (97.6%) of 125 taking quinine were cured-difference 1.7% (lower limit of 95% CI -0.9). There were 290 adverse events in the quinine group and 141 in the artemether-lumefantrine group. INTERPRETATION: Artemisinin derivatives are not inferior to oral quinine for the treatment of uncomplicated malaria in pregnancy and might be preferable on the basis of safety and efficacy. FUNDING: Medecins Sans Frontieres and the European Commission. PMID- 20932806 TI - Pyospermia in an adult cohort with persistent lower urinary tract symptoms and a history of ablated posterior urethral valve. AB - PURPOSE: To assess for the presence of lower urinary tract symptoms and abnormal semen parameters in adults with a history of PUV. MATERIALS AND METHODS: The study involved 29 male patients, aged 17-51 (mean 21.5 years), with a history of PUV. Ten had more severe symptoms of frequency, urgency and enuresis, and agreed to detailed study. Medical history, urine analysis, ultrasonography and voiding cystourethrogram were completed for all. Magnetic resonance imaging of the bladder, prostate, seminal vesicles and ejaculatory ducts, ultrasonography of the prostate, as well as semen analysis and culture, and measurement of serum levels of follicle-stimulating hormone, luteinizing hormone and testosterone were performed on the 10/29 patients with severe symptoms. RESULTS: Of the 8/10 patients who provided acceptable semen culture data, 88% (7/8) showed significant bacterial growth and pyospermia. On semen analysis, 3/8 patients had profound decreases in sperm count, 6/8 < 50% motility and 4/8 <= 30% normal forms. pH range for semen was 7.2-7.8 (mean 7.45). For all 10 patients, follicle stimulating and luteinizing hormone values were within normal range. Elongation of the prostate was the only radiologic variant of the sex accessory structures. CONCLUSION: A significant finding of pyospermia and bacterial growth in semen culture is reported in a subpopulation of young men with a history of PUV and severe lower urinary tract symptoms. This may have an impact on fertility. PMID- 20932807 TI - Quantifying the variability of financial disclosure information reported by authors presenting at annual spine conferences. AB - BACKGROUND CONTEXT: In recent years, greater attention has been directed toward determining how potential financial conflicts of interest may affect the integrity of biomedical research. To address this issue, various disclosure policies have been adopted in an attempt to increase the transparency of this process. However, the consistency of such reporting among spine surgeons remains unknown. This study quantifies the variability in the self-reported disclosures of individual authors presenting at multiple spine conferences during the same year. METHODS: The author disclosure information published for the 2008 North American Spine Society (NASS), Cervical Spine Research Society (CSRS), and Scoliosis Research Society (SRS), conferences were compiled into a database. We evaluated the disclosure policy for each society and compared the disclosure listings of authors who presented at more than one of these meetings. RESULTS: Disclosure records were available for 1,231 authors at NASS, 550 at CSRS, and 642 at SRS. Of these individuals, 278 (NASS), 129 (CSRS), and 181 (SRS) presented at one of the other conferences and 40 presented at all three conferences. North American Spine Society and CSRS required disclosure of all financial relationships, whereas SRS only requested disclosures pertinent to authors' presentations. Of the 153 authors who presented at the NASS and CSRS meetings, 51% exhibited discrepancies in their disclosure information. In contrast, only 9% of the 205 individuals whose data was listed at both the NASS and SRS conferences demonstrated irregularities. Similarly, 18% of the 56 authors who had provided information to both CSRS and SRS were inconsistent in their reporting. CONCLUSIONS: These findings emphasize the significant variability that currently exists in the reporting of financial conflicts of interest by authors who presented at three major spine conferences within the past year. We believe these discrepancies are likely because of confusion regarding what relationships should be acknowledged in certain situations and the clear lack of uniformity among the disclosure policies established by these various associations. CLINICAL RELEVANCE: This study evaluates financial conflicts of interests in clinical research. PMID- 20932808 TI - Treatment of facial cutaneous carcinoma with high-dose rate contact brachytherapy with customized molds. AB - BACKGROUND: The main treatment given for initial stage facial epitheliomas is surgery, although there are alternatives. We present our results with Ir-192 high dose rate (HDR) contact brachytherapy. METHODS AND MATERIALS: Fifty-one epitheliomas, with a mean size of 1.5 cm and a maximum thickness of 3mm, were treated with HDR contact brachytherapy by means of customized molds, with plastic tubes on bolus for flat surfaces and on wax molds for the nose. A total dose of 48-57 Gy, 3-4 Gy/fraction three times a week, was administered. RESULTS: After a median followup of 45 months, five tumors relapsed (9.8%), four of them on the tip of the nose. The 5-year actuarial local control rate was 89%, 100% for flat surfaces, and 83% for the nose. All of them were salvaged with surgery. The treatment was well tolerated, 21.6% developed severe acute toxicity, with good or very good late cosmetic results. CONCLUSION: HDR contact brachytherapy is a good alternative to treat facial epitheliomas with a maximum thickness of 3mm. Tip of the nose tumors are not well covered with this technique and a different procedure is required. PMID- 20932809 TI - Local control and visual acuity following treatment of medium-sized ocular melanoma using a contact eye plaque: a single surgeon experience. AB - PURPOSE: To evaluate the outcomes of choroidal melanoma in (CM) patients treated with (125)I episcleral plaque brachytherapy and to compare our single surgeon results with the multi-institutional Collaborative Ocular Melanoma Study (COMS). METHODS AND MATERIALS: A review was performed of all CM patients treated with (125)I episcleral plaque brachytherapy by ophthalmologist in accordance with established COMS guidelines. RESULTS: The records of 35 patients were reviewed. The median longest basal tumor diameter and apical tumor height was 13.5 and 7.8mm, respectively. Median dose to the apex was 8609 cGy at a median dose rate of 92 cGy/h. At a median followup of 45 months, 35 patients had local control and 33 had successful organ preservation. At 5 years, the local control rate was 100%, and the eye preservation rate was 94%. Five patients developed hepatic metastasis at a median of 58 months, and 2 succumbed from disease. The 5-year survival rate was 84%, and the 5-year rate of death with histopathologically confirmed metastasis was 15%. Of the 22 patients with at least 3 years of followup, 68% had a visual acuity in the treated eye of 20/200 or worse. CONCLUSION: Excellent local control, eye preservation rates, and survival outcomes following (125)I episcleral plaque application for CM can be optimized by having an experienced ophthalmologist place the plaques. Additionally, hepatic metastasis can occur more than 5 years postimplant regardless of local control; therefore, longer systemic staging should be considered. PMID- 20932810 TI - Measurement of dose perturbation around shielded ovoids in high-dose-rate brachytherapy. AB - PURPOSE: To analyze the effect of tungsten shields present in a Fletcher-Suit Delclos ovoid by comparing the dose distribution computed by a treatment planning system (TPS) to the delivered dose distribution measured by radiochromic film dosimetry. METHODS AND MATERIALS: Gafchromic/EBT films were carefully wrapped around the caps (diameter 20-25 mm) of shielded as well as unshielded ovoids, including their anterior and posterior ends. The ovoids were irradiated to a dose of 300 cGy using a high-dose rate remote afterloading unit. The films were scanned using Vidar VXR-16 Scanner. The dose distribution in the planes above, below, and on the sides of the ovoid were compared with the dose distribution computed by TPS, which does not account for the presence of shields. RESULTS: The dose distributions obtained about the unshielded ovoid from film dosimetry was in order of what is computed by TPS (90% measurements +/- 5%, maximum 8%). The dose reduction in the anterior part of the shielded ovoid affects maximally the dose to the bladder where a reduction up to 20% was noted. The reduction of dose in the posterior part of the ovoid, which is designed to shield rectum was as high as 23%. Where the shields are not present, insignificant difference in the measured and computed dose values was noticed. CONCLUSIONS: The TPS may substantially overestimate the dose to the bladder and rectum, including regions that lie in the shadow of the solid angle subtended by the shields if it does not account for the presence of tungsten shields. PMID- 20932811 TI - High-dose rate interstitial brachytherapy using two weekly sessions of 10 Gy each for patients with locally advanced cervical carcinoma. AB - PURPOSE: To evaluate the feasibility of high-dose rate interstitial brachytherapy (HDR-IBT) using two weekly sessions of 10 Gy in combination to pelvic external beam radiation therapy (EBRT) for patients with locally advanced cervical carcinoma. METHODS AND MATERIALS: Between the year 2005 and 2007, 42 patients with locally advanced cervical carcinoma (International Federation of Gynecology and Obstetrics Stage IIB-IVA), not suitable for intracavitary radiotherapy after completing EBRT, were enrolled in this prospective study. Two weekly sessions of HDR-IBT with 10 Gy each were delivered 1 week after pelvic EBRT. Various parameters studied for evaluating the feasibility were procedure-related complications, delayed radiation toxicity, and recurrence-free survival. RESULTS: International Federation of Gynecology and Obstetrics stage distribution of patients was as follows: Stage IIB (10), Stage IIIB (27), and Stage IVA (5). A total of 84 HDR-IBT procedures were performed in these 42 patients. Each session of brachytherapy treatment (from needle insertion to removal of template) was completed in less than 4 h. Frequency of various procedure-related complications were as follows: hematuria (3.5%), deep vein thrombosis (0%), and visceral puncture (0%). Overall delayed radiation toxicity (Grade III-IV) was 9%. Median followup was 23 months. The 3-y overall survival for all stages was 47% and the 3 y recurrence-free survival for stage IIB, IIIB, and IVA was 67%, 34%, and 20%, respectively. CONCLUSION: Our clinical results have shown that weekly HDR-IBT schedule (10 Gy * 2) is associated with low toxicity, decent local control, and survival rates thereby proving its clinical feasibility. PMID- 20932812 TI - Chronic infection with Toxoplasma gondii causes myenteric neuroplasticity of the jejunum in rats. AB - Toxoplasma gondii is an aetiological agent of toxoplasmosis, which commonly causes diarrhoea in a number of species. This observation and the parasite's affinity for the nervous tissue support the theory that T. gondii infection may affect the myenteric neurons. The aim of this study was to evaluate the changes caused by T. gondii (genotype III) in the myenteric neurons of the jejunum in rats. Fifteen rats were distributed into three groups: control (CG), inoculated for 30 days (G30) and inoculated for 90 days (G90). Rats from the G30 and G90 groups received an oral inoculum with 500 oocysts from a genotype III (M7741) T. gondii strain. At 180 days of age, all animals were anaesthetised and euthanised. Whole mounts were stained by using Giemsa (total population) and NADPH-diaphorase (nitrergic subpopulation) histochemistry. Maintenance of the width, length, area and neuronal density was observed; there was neuronal atrophy in the G30 group and a tendency to hypertrophy in the G90 group. Rats inoculated orally with sporulated oocysts did not show clinical illness or macroscopic or microscopic lesions, as do the majority of animal species. Therefore, infection was confirmed by a serum agglutination test; 30 days of infection caused increased weight gain and atrophy of myenteric neurons. At 90 days post-infection, weight gain became normal, and myenteric neurons hypertrophied. PMID- 20932813 TI - Metabolic analysis of guava (Psidium guajava L.) fruits at different ripening stages using different data-processing approaches. AB - Gas chromatography coupled with time-of-flight mass spectrometry and principal component analysis were used to obtain the metabolite profiles of guava (Psidium guajava) fruits. Results with two types of data-processing software, ChromaTOF and AMDIS, were compared to explain the differences between the samples. There were some differences in score and loading plot patterns of PCA as well as in the composition of the metabolites. However, little difference was observed in the type of metabolites detected and identified using either type of software. Both the flesh and peel of premature and mature white guava fruits were compared for the analysis of the metabolite profiles. Malic acid, aspartic acid, and glucose were the major metabolites distinguishing the different parts of guava fruits in the PCA loading plot. In addition, the metabolic profiles of the fruits revealed significant changes in some metabolites during ripening. The major components contributing to the separation were serine, citric acid, fructose, sucrose, and some unknowns. In particular, sucrose, fructose, serine and citric acid were related to the ripening of guava fruits. Fructose and sucrose were increased whereas citric acid was decreased during guava fruit ripening. PMID- 20932814 TI - [Chilaiditi syndrome: a single X-ray is diagnostic]. PMID- 20932815 TI - Hierarchical Y-SNP assay to study the hidden diversity and phylogenetic relationship of native populations in South America. AB - Studying the Y chromosomes of indigenous tribes of Ecuador revealed a lack of strategic SNP assays to examine the substructure of South American native populations. In most studies dealing with South American samples so far only the most common Y-SNP M3 of haplogroup Q was analyzed, because this is known to define a founder group in South America. Studies of SNPs ancestral to Q-M3 (Q1a3a) to confirm the results or the typing of Q subclades have often been neglected. For this reason we developed a SNaPshot assay, which allows first for a hierarchical testing of all main haplogroups occurring in South American populations and second for a detailed analysis of haplogroups Q and C thought having ancient Asian descent. We selected 16 SNPs from the YCC haplogroup tree and established two multiplexes. The first multiplex ("SA Major") includes 12 Y SNPs defining the most frequent haplogroups occurring in South America (M42, M207, M242, M168, M3, M145, M174, M213, RPS4Y711, M45, P170, and M9). The second multiplex ("SA SpecQ") contains Y-SNPs of haplogroup Q, especially of the subclade Q-M3 (M19, M194, P292, M3, and M199). Within our Ecuadorian sample, haplogroup Q-M3 (xM19, M194, P292, and M199) was predominant, but we also found haplogroup E and R, which can be attributed to recent admixture. Moreover, we found four out of 65 samples, which were tested to be haplogroup C3* (C-M217) the modal haplogroup in Mongolians and widespread in indigenous populations of the Russian Far East as well as in Eastern Asia. This haplogroup is not known to be the result of recent admixture and has been found only one time before in South America. Since haplogroup C occurs in Asia and in North America (C3b or C-P39), we assume that these C-lineages are ancient as well. Therefore, we established a third multiplex ("SA SpecC"), which allows the further subtyping of haplogroup C, mainly of subclade C3 defined by the Y-SNP M217 (M407, M48, P53.1, M217, P62, RPS4Y711, M93, M86, and P39). Altogether, these three multiplexes cover the most frequent haplogroups in South America and allow for a maximal resolution of the Y chromosomal SNP diversity in Amerindian population samples. PMID- 20932816 TI - STR sequence analysis for characterizing normal, variant, and null alleles. AB - DNA sequence variation is known to exist in and around the repeat region of short tandem repeat (STR) loci used in human identity testing. While the vast majority of STR alleles measured in forensic DNA laboratories worldwide type as "normal" alleles compared with STR kit allelic ladders, a number of variant alleles have been reported. In addition, a sequence difference at a polymerase chain reaction (PCR) primer binding site in the DNA template can cause allele drop-out (i.e., a "null" or "silent" allele) with one set of primers and not with another. Our group at the National Institute of Standards and Technology (NIST) has been sequencing variant and null alleles supplied by forensic labs and cataloging this information on the NIST STRBase website for the past decade. The PCR primer sequences and strategy used for our STR allele sequencing work involving 23 autosomal STRs and 17 Y-chromosome STRs are described along with the results from 111 variant and 17 null alleles. PMID- 20932817 TI - Post-traumatic arteriovenous fistula of the hepatic pedicle. AB - Hepatico-portal fistula (HPF) is a rare condition, most often of post-traumatic or iatrogenic origin and occasionally secondary to a ruptured aneurysm of the hepatic artery into the portal vein. HPF in extrahepatic locations often results in portal hypertension (PHT). While Doppler ultrasound, CT angiography, and magnetic resonance angiography are usually demonstrative, arteriography remains indispensable to clarify the exact anatomical configuration. In the treatment of these arteriovenous (AV) fistulas, open surgical approaches have increasingly given way to radiological embolization techniques, especially in intrahepatic locations, but surgery remains indicated for AV fistulas of the hepatic pedicle where maintenance of hepatic arterial flow is a priority of treatment. We report a patient who had an AV fistula of the hepatic pedicle with resultant PHT presenting 5 years after open abdominal trauma. Treatment was surgical; the immediate and long-term postoperative course was uneventful with regression of PHT. Through analysis of this case and a review of the literature, we discuss the clinical, paraclinical, therapeutic, and prognostic features of this lesion. PMID- 20932818 TI - Improving community participation to eliminate lymphatic filariasis in American Samoa. AB - In 2000, the American Samoa Department of Health initiated a campaign of annual mass drug administration (MDA) with albendazole and diethylcarbamazine (DEC) to eliminate transmission of filariasis. Drug coverage was well below prescribed targets in the first three campaigns, ranging from 24 to 52% of the total population. Evaluation findings from a variety of formative research methods identified opportunities to improve MDA coverage and ensuing program modifications resulted in increased drug coverage of 65-71% in the following four annual distributions. Partnering with churches for drug distribution and using multiple media channels for health promotion led to sustained program improvements. With the increased emphasis on the use of mass distribution for delivery of drugs for a number of neglected tropical diseases, other programs may benefit from a similar approach. PMID- 20932819 TI - Monitoring membrane binding and insertion of peptides by two-color fluorescent label. AB - Herein, we developed an approach for monitoring membrane binding and insertion of peptides using a fluorescent environment-sensitive label of the 3-hydroxyflavone family. For this purpose, we labeled the N-terminus of three synthetic peptides, melittin, magainin 2 and poly-l-lysine capable to interact with lipid membranes. Binding of these peptides to lipid vesicles induced a strong fluorescence increase, which enabled to quantify the peptide-membrane interaction. Moreover, the dual emission of the label in these peptides correlated well with the depth of its insertion measured by the parallax quenching method. Thus, in melittin and magainin 2, which show deep insertion of their N-terminus, the label presented a dual emission corresponding to a low polar environment, while the environment of the poly-l-lysine N-terminus was rather polar, consistent with its location close to the bilayer surface. Using spectral deconvolution to distinguish the non hydrated label species from the hydrated ones and two photon fluorescence microscopy to determine the probe orientation in giant vesicles, we found that the non-hydrated species were vertically oriented in the bilayer and constituted the best indicators for evaluating the depth of the peptide N-terminus in membranes. Thus, this label constitutes an interesting new tool for monitoring membrane binding and insertion of peptides. PMID- 20932820 TI - Microglial activation is a major contributor to neurologic dysfunction in thiamine deficiency. AB - In Wernicke's encephalopathy and thiamine deficiency (TD), the cause of this brain disorder, development of inflammation is an important aspect of the disease process. How this pathological mechanism relates to the neurologic impairment associated with TD, however, remains unclear. A key feature of the inflammatory process is the activation of microglia. In the present study, we evaluated the role of microglial activation in the pathophysiology of TD by examining the relationship between levels of CD11b/c and CD68, two proteins associated with microglial activation, and neurological dysfunction under conditions of TD. Rats with TD showed large increases in expression of both CD11b/c and CD68 in the vulnerable thalamus and inferior colliculus, with no change in mRNA levels in the relatively non-vulnerable frontal cortex. These alterations in CD11b/c and CD68 expression were reflected in dramatic upregulation of both proteins by immunoblotting and immunohistochemical methods. Co-treatment of rats with TD and the anti-inflammatory drug minocycline prevented microglial activation, and onset of neurological changes, including loss of righting reflex, was delayed by approximately 39h, compared to animals with TD alone. In addition, co-treatment of rats with TD and N-acetylcysteine prevented the increase in CD11b/c and CD68, but did not alter the onset of neurological impairment. These results suggest that microglial activation plays a role in the development of neurological impairment in TD and possibly Wernicke's encephalopathy, and that while development of oxidative stress may be involved in microglial activation, the basis of this neurologic dysfunction is likely to be multifactorial in nature. PMID- 20932821 TI - CYP2E1 enhances ethanol-induced lipid accumulation but impairs autophagy in HepG2 E47 cells. AB - The regulation and function of autophagy and lipid metabolism have recently been reported to be reciprocally related. Macroautophagy mediates the breakdown of lipids stored in lipid droplets. An inhibition of autophagy leads to the development of a fatty liver. We evaluated the ability of CYP2E1 to modulate the effects of ethanol on lipid accumulation and autophagy in vitro. The E47 HepG2 cell which expresses CYP2E1 was treated with ethanol at 50, 100 and 150mM for 4 or 5days. Ethanol-induced lipid accumulation and an increase of triglycerides (TG) in E47 cells to a greater extent than in control C34 cells which do not express CYP2E1. In contrast, autophagy (LC3 II/LC3 I ratio) was significantly induced by ethanol in C34 cells to a greater extent than in E47 cells. P62 was significantly increased in E47 cells after ethanol treatment. Thus, there is a reciprocal relationship between the effects of ethanol on lipid accumulation and autophagy in the CYP2E1-expressing cells. Inhibition of autophagy by 3 methyladenine (3MA), increased lipid accumulation and TG levels in C34 cells which display elevated autophagy, but enhanced lipid accumulation and TG level to a lesser extent in E47 cells which displayed lower autophagy. Ethanol induced CYP2E1 activity and oxidative stress in E47 cells compared with C34 cells. These experiments suggest that the expression of CYP2E1 may impair autophagy formation which contributes to lipid accumulation in the liver. We hypothesize that CYP2E1 induced oxidative stress promotes the accumulation of lipid droplets by ethanol and this may be responsible for the suppression of autophagy in the liver. PMID- 20932822 TI - The cap'n'collar transcription factor Nrf2 mediates both intrinsic resistance to environmental stressors and an adaptive response elicited by chemopreventive agents that determines susceptibility to electrophilic xenobiotics. AB - Transcription factor Nrf2 regulates genes encoding drug-metabolising enzymes and drug transporters, as well as enzymes involved in the glutathione, thioredoxin and peroxiredoxin antioxidant pathways. Using mouse embryonic fibroblast (MEF) cells from Nrf2(+/+) and Nrf2(-/-) mice, in conjunction with the 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cytotoxicity assay, we have shown that loss of Nrf2 diminishes the intrinsic resistance of mutant fibroblasts towards isothiocyanates (i.e. sulforaphane), epoxides (i.e. (2S,3S)-( )-3-phenylglycidol, ethyl 3-phenylglycidate and styrene-7,8-epoxide), peroxides, hydroquinones and quinones (i.e. tert-butylhydroperoxide, tert-butylhydroquinone and 2,3-dimethoxynaphthoquinone), NaAsO(2), and various mutagens, including beta propiolactone, cisplatin, mechlorethamine and methyl methanesulfonate to ~50% of that observed in equivalent wild-type cells. Exposure of Nrf2(+/+) fibroblasts, but not Nrf2(-/-) fibroblasts, to a non-toxic dose (3MUmol/l) of the chemopreventive agent sulforaphane (Sul) stimulated an adaptive response that, 18h after first being subjected to the isothiocyanate, caused an induction of between 2- and 10-fold in the levels of mRNA for glutamate-cysteine ligase catalytic (Gclc) and modifier (Gclm) subunits, glutathione S-transferases and NAD(P)H:quinone oxidoreductase-1 (Nqo1); this was accompanied by an increase in total glutathione of between 1.5- and 1.9-fold. Pre-treatment of Nrf2(+/+) MEF cells with 3MUM Sul for 18h prior to challenge with xenobiotics, conferred between 2.0- and 4.0-fold protection against isothiocyanates, reactive carbonyls, peroxides, quinones, NaAsO(2), and the anticancer nitrogen mustard chlorambucil, but pre-treatment with 3MUM Sul produced no such increased tolerance in Nrf2(-/-) MEF cells. The inducible resistance towards acrolein, cumene hydroperoxide and chlorambucil, produced by pre-treating wild-type fibroblasts with 3MUM Sul, was dependent on glutathione because simultaneous pre-treatment with 5MUmol/l buthionine sulfoximine abolished the increased tolerance of these xenobiotics. However, inducible resistance towards menadione that occurred upon pre-treatment with 3MUM Sul was independent of glutathione and may be due to upregulation of Nqo1. Thus Nrf2 controls cellular resistance against electrophiles. PMID- 20932823 TI - Role of serum amyloid P in skin graft survival and wound healing in burned patients receiving skin grafts. AB - BACKGROUND: Recent studies in animal models suggest that serum amyloid P (SAP) can affect burn wound healing. However, the role of SAP in a clinical setting remains unknown. METHODS: We enrolled 88 patients with third degree burn wounds. All the patients were candidates for auto-skin graft procedure using stamp skin graft. The complete graft healing time and the number of survived grafts were recorded. Serum SAP levels were assessed 1 day before operation. RESULTS: There was no significant difference in SAP level between controls and patients. There were no significant differences noted among the patients with different burn surface area. However, when the patients in each group were stratified by SAP levels, the mean complete healing time of grafted wound and the mean numbers of survived skin grafts were significantly different. Spearman's analyses showed that the serum SAP levels negatively correlated with the complete wound healing time and mean numbers of survived skin grafts. Logistic regression analysis showed that the serum SAP levels and mean numbers of survived skin grafts were potent independent factors contributing to wound healing. CONCLUSIONS: The results of this study suggest that the serum SAP levels may be an easy detected predictor for the healing of burn wounds. PMID- 20932824 TI - A de novo mutation in NKX2.5 associated with atrial septal defects, ventricular noncompaction, syncope and sudden death. AB - BACKGROUND: Mutations in transcription factor NKX2.5 cause congenital heart disease (CHD). We identified a CHD family with atrial septal defects (ASDs), atrioventricular block, ventricular noncompaction, syncope and sudden death. Our objective is to identify the disease-causing mutation in the CHD family. METHODS: Direct DNA sequence analysis was used to identify the CHD mutation. The functional effects of the mutation were characterized by a luciferase reporter assay and immunostaining. RESULTS: A novel, de novo 2-bp insertion (c.512insGC) was identified in exon 2 of NKX2.5. Mutation c.512insGC co-segregates with CHD in the family, and is not present in 200 controls. Functional studies indicate that the c.512insGC mutation impedes nuclear localization of NKX2.5 and causes a total loss of transactivation activity of NKX2.5. Furthermore, no NKX2.5 mutation was identified in 125 sporadic Chinese CHD patients. CONCLUSIONS: (1) NKX2.5 mutation c.512insGC is associated with ASDs, syncope and sudden death. It is the second de novo mutation identified in NKX2.5. (2) NKX2.5 mutations are rare in sporadic CHD patients. (3) This study for the first time identifies association between a NKX2.5 mutation and ventricular noncompaction. Our results significantly expand the phenotypic spectrum of NKX2.5 mutations. PMID- 20932825 TI - The PPARgamma ligand ciglitazone regulates androgen receptor activation differently in androgen-dependent versus androgen-independent human prostate cancer cells. AB - The androgen receptor (AR) regulates growth and progression of androgen-dependent as well as androgen-independent prostate cancer cells. Peroxisome proliferator activated receptor gamma (PPARgamma) agonists have been reported to reduce AR activation in androgen-dependent LNCaP prostate cancer cells. To determine whether PPARgamma ligands are equally effective at inhibiting AR activity in androgen-independent prostate cancer, we examined the effect of the PPARgamma ligands ciglitazone and rosiglitazone on C4-2 cells, an androgen- independent derivative of the LNCaP cell line. Luciferase-based reporter assays and Western blot analysis demonstrated that PPARgamma ligand reduced dihydrotestosterone (DHT)-induced increases in AR activity in LNCaP cells. However, in C4-2 cells, these compounds increased DHT-induced AR driven luciferase activity. In addition, ciglitazone did not significantly alter DHT-mediated increases in prostate specific antigen (PSA) protein or mRNA levels within C4-2 cells. siRNA-based experiments demonstrated that the ciglitazone-induced regulation of AR activity observed in C4-2 cells was dependent on the presence of PPARgamma. Furthermore, overexpression of the AR corepressor cyclin D1 inhibited the ability of ciglitazone to induce AR luciferase activity in C4-2 cells. Thus, our data suggest that both PPARgamma and cyclin D1 levels influence the ability of ciglitazone to differentially regulate AR signaling in androgen-independent C4-2 prostate cancer cells. PMID- 20932826 TI - Efficacy of olfactory ensheathing cells to support regeneration after spinal cord injury is influenced by method of culture preparation. AB - Olfactory ensheathing cells (OEC) have been shown to stimulate regeneration, myelination and functional recovery in different spinal cord injury models. However, recent reports from several laboratories have challenged this treatment strategy. The discrepancy in results could be attributed to many factors including variations in culture protocols. The present study investigates whether the differences in culture preparation could influence neuroprotective and growth promoting effects of OEC after transplantation into the injured spinal cord. Primary OEC cultures were purified using method of differential cell adhesion (a OEC) or separated with immunomagnetic beads (b-OEC). After cervical C4 hemisection in adult rats, short-term (3 weeks) or long-term (7 weeks) cultured OEC were transplanted into the lateral funiculus at 1mm rostral and caudal to the transection site. At 3-8 weeks after transplantation, labeled OEC were mainly found in the injection sites and in the trauma zone. Short-term cultured a-OEC supported regrowth of rubrospinal, raphaespinal and CGRP-positive fibers, and attenuated retrograde degeneration in the red nucleus. Short-term cultured b-OEC failed to promote axonal regrowth but increased the density of rubrospinal axons within the dorsolateral funiculus and provided significant neuroprotection for axotomized rubrospinal neurons. In addition, short-term cultured OEC attenuated sprouting of rubrospinal terminals. In contrast, long-term cultured OEC neither enhanced axonal growth nor prevented retrograde cell death. The results suggest that the age of OEC in culture and the method of cell purification could affect the efficacy of OEC to support neuronal survival and regeneration after spinal cord injury. This article is part of a Special Issue entitled: Understanding olfactory ensheathing glia and their prospect for nervous system repair. PMID- 20932827 TI - Attenuation of CNS inflammatory responses by nicotine involves alpha7 and non alpha7 nicotinic receptors. AB - A considerable number of in vivo studies have demonstrated that the cholinergic system can dampen the peripheral immune response, and it is thought that the alpha7-nicotinic acetylcholine receptor (nAChR) subtype is a key mediator of this process. The goal of the present study was to determine if nicotine modulates immunological mechanisms known to be involved in the development of experimental autoimmune encephalomyelitis (EAE), a mouse model for CNS autoimmune disease, via alpha7-nAChRs. Here we show that nicotine exposure attenuates EAE severity and that this effect is largely abolished in nAChR alpha7 subunit knock-out mice. However, nicotine exposure partially retains the ability to reduce lymphocyte infiltration into the CNS, inhibit auto-reactive T cell proliferation and helper T cell cytokine production, down-regulate co-stimulatory protein expression on myeloid cells, and increase the differentiation and recruitment of regulatory T cells, even in the absence of alpha7-nAChRs. Diverse effects of nicotine on effector and regulatory T cells, as well as antigen-presenting cells, may be linked to differential expression patterns of nAChR subunits across these cell types. Taken together, our data show that although alpha7-nAChRs indeed seem to play an important role in nicotine-conferred reduction of the CNS inflammatory response and protection against EAE, other nAChR subtypes also are involved in the anti-inflammatory properties of the cholinergic system. PMID- 20932829 TI - In vitro and in vivo activity of three sesquiterpenes against L(3) larvae of Anisakis type I. AB - In order to investigate the possible use of terpenic derivatives to treat anisakiasis caused by L(3) larvae of Anisakis, we studied the in vitro and in vivo larvicidal activity of three sesquiterpenes (nerolidol, farnesol and elemol). In vitro experiments included the histological study of larval damage and in vivo studies the measurement of myeloperoxidase activity in rat gastrointestinal tract after administration of the sesquiterpenes. In the in vitro assays, the most active compound against the L(3) larvae was nerolidol, followed by farnesol; both caused the death of all nematodes, which showed cuticle changes and intestinal wall rupture. In the in vivo assays, only 20% of infected rats treated with nerolidol or farnesol showed gastric wall lesions in comparison to 86.6% of control animals. According to these results, nerolidol and farnesol are good candidates for further research as biocidal agents against L(3) larvae of Anisakis type I. PMID- 20932828 TI - Wind-up of stretch reflexes as a measure of spasticity in chronic spinalized rats: The effects of passive exercise and modafinil. AB - Spasticity is a common disorder following spinal cord injury that can impair function and quality of life. While a number of mechanisms are thought to play a role in spasticity, the role of motoneuron persistent inward currents (PICs) is emerging as pivotal. The presence of PICs can be evidenced by temporal summation or wind-up of reflex responses to brief afferent inputs. In this study, a combined neurophysiological and novel biomechanical approach was used to assess the effects of passive exercise and modafinil administration on hyper-reflexia and spasticity following complete T-10 transection in the rat. Animals were divided into 3 groups (n=8) and provided daily passive cycling exercise, oral modafinil, or no intervention. After 6weeks, animals were tested for wind-up of the stretch reflex (SR) during repeated dorsiflexion stretches of the ankle. H reflexes were tested in a subset of animals. Both torque and gastrocnemius electromyography showed evidence of SR wind-up in the transection only group that was significantly different from both treatment groups (p<0.05). H-reflex frequency dependent depression was also restored to normal levels in both treatment groups. The results provide support for the use of passive cycling exercise and modafinil in the treatment of spasticity and provide insight into the possible contribution of PICs. PMID- 20932830 TI - Toxicity effect of the acaricide fipronil in semi-engorged females of the tick Rhipicephalus sanguineus (Latreille, 1806) (Acari: Ixodidae): preliminary determination of the minimum lethal concentration and LC(50). AB - Chemical acaricides, especially fipronil (active ingredient of Frontline(r)), are still the most effective method to control tick populations. In this study, the effectiveness of fipronil was assessed in semi-engorged females of the tick Rhipicephalus sanguineus. A protocol for an in vitro bioassay (AIT) was developed, and the LC(50) (lethal concentration 50%) and 95% confidence interval were determined. Ticks were immersed in Petri dishes with different concentrations of fipronil or distilled water for 2 min, dried, and placed in an incubator for 7 days. Dead R. sanguineus females treated with the 14 concentrations of fipronil were counted daily. Mortality results were compared with the Probit analysis, and the LC(50) and 95% confidence interval were calculated, g (95): LC(50) = 9.647 (4.711 to 13.470). This study was aimed at developing a more appropriate and updated protocol for an in vitro bioassay (AIT- adult immersion test), and providing information on the toxic potential of fipronil (elimination of ectoparasites with lower concentrations) and sensitivity of ticks, especially R. sanguineus, a pest of great interest, due to its occurrence in urban environments. PMID- 20932831 TI - Grb14 inhibits FGF receptor signaling through the regulation of PLCgamma recruitment and activation. AB - To decipher the mechanism involved in Grb14 binding to the activated fibroblast growth factor receptor (FGFR), we used the bioluminescence resonance energy transfer (BRET) technique and the Xenopus oocyte model. We showed that Grb14 was recruited to FGFR1 into a trimeric complex containing also phospholipase C gamma (PLCgamma). The presence of Grb14 altered FGF-induced PLCgamma phosphorylation and activation. Grb14-FGFR interaction involved the Grb14-SH2 domain and the FGFR pY766 residue, which is the PLCgamma binding site. Our data led to a molecular model whereby Grb14 binding to the phosphorylated FGFR induces a conformational change that unmasks a PLCgamma binding motif on Grb14, allowing trapping and inactivation of PLCgamma. PMID- 20932832 TI - Golgi-localized KIAA0725p regulates membrane trafficking from the Golgi apparatus to the plasma membrane in mammalian cells. AB - Mammals have three members of the intracellular phospholipase A(1) protein family (phosphatidic acid preferring-phospholipase A(1), p125, and KIAA0725p). In this study, we showed that KIAA0725p is localized in the Golgi, and is rapidly cycled between the Golgi and cytosol. Catalytic activity is important for targeting of KIAA0725p to Golgi membranes. RNA interference experiments suggested that KIAA0725p contributes to efficient membrane trafficking from the Golgi apparatus to the plasma membrane, but is not involved in brefeldin A-induced Golgi-to endoplasmic reticulum retrograde transport. PMID- 20932833 TI - Consolidation of glycosyl hydrolase family 30: a dual domain 4/7 hydrolase family consisting of two structurally distinct groups. AB - In this work glycosyl hydrolase (GH) family 30 (GH30) is analyzed and shown to consist of its currently classified member sequences as well as several homologous sequence groups currently assigned within family GH5. A large scale amino acid sequence alignment and a phylogenetic tree were generated and GH30 groups and subgroups were designated. A partial rearrangement in the GH30 defining side-associated beta-domain contributes to the differentiation of two major groups that contain up to eight subgroups. For this CAZy family of Clan A enzymes the dual domain fold is conserved, suggesting that it may be a requirement for evolved function. This work redefines GH family 30 and serves as a guide for future efforts regarding enzymes classified within this family. PMID- 20932834 TI - Gastrin increases its own synthesis in gastrointestinal cancer cells via the CCK2 receptor. AB - The involvement of the gastrointestinal hormone gastrin in the development of gastrointestinal cancer is highly controversial. Here we demonstrate a positive feedback loop whereby gastrin, acting via the CCK2 receptor, increases its own expression. Such an autocrine loop has not previously been reported for any other gastrointestinal hormone. Gastrin promoter activation was dependent on the MAP kinase pathway and did not involve Sp1 binding sites or epidermal growth factor receptor transactivation. As the treatment of gastrointestinal cancer cells with amidated gastrin led to increased expression of non-amidated gastrins, the positive-feedback loop may contribute to the sustained increase in circulating gastrins observed in colorectal cancer patients. PMID- 20932835 TI - A novel secreted metzincin metalloproteinase from Bacillus intermedius. AB - The mprBi gene from Bacillus intermedius 3-19 encoding a novel secreted metalloproteinase was identified. The mpriBi gene was expressed in an extracellular proteinase-deficient Bacillus subtilis BG 2036 strain and the corresponding protein was characterized biochemically. The 19 kDa MprBi protein was purified to homogeneity and sequenced by mass spectroscopy and Edman degradation methods. Amino acid sequence analysis of MprBi identified an active site motif HEYGHNFGLPHD and a conserved structural component Met-turn, both of which are unique features of the metzincin clan. Furthermore, MprBi harbors a number of distinct sequence elements characteristic of proteinase domains in eukaryotic adamalysins. We conclude that MprBi and similar proteins from other Bacillus species form a novel group of metzincin metalloproteinases in prokaryotes. PMID- 20932836 TI - Regulation of the connexin 43 promoter in the brook trout testis: role of the thyroid hormones and cAMP. AB - Gap junctions are critical for spermatogenesis. They are composed of integral proteins, the connexins. In mammals, a loss of Cx43 expression results in the inhibition of spermatogenesis. We have shown that Cx43 is expressed in the Sertoli cells of rainbow trout and that cAMP and triiodothyronine (T(3)) regulate testicular Cx43 expression in brook trout testis. The objective of this study was to determine if cAMP and T(3) act at the level of the cx43 promoter to regulate its expression. A 607 bp 5' flanking sequence of the cx43 promoter was obtained by Genome Walking. A TATA box was predicted to be located between positions -36 and -30 relative to the transcriptional initiation site. 5'-Rapid amplification of cDNA ends indicated a single transcriptional start site. Single C/EBP (-164 to -156) and tr-beta (-112 to -107) response elements were identified and electrophoretic mobility shift assays indicated the presence of competitive protein binding sites at each region. Immortalized rainbow trout gonadal cell line (RTG-2) which express cx43 and tr-beta transcripts were transfected with a vector containing the Cx43 promoter inserted into a luciferase expression vector. Transactivation of the reporter genes was stimulated by either cAMP or T(3). Sequential deletion and point mutations in either the C/EBP or tr-beta response element indicated that T(3) but not cAMP directly induced luciferase transactivation of the luciferase gene by acting on different sites of the Cx43 promoter. Together, these data indicate that T(3) stimulates cx43 expression via direct regulation of gene transcription. PMID- 20932837 TI - Phytochemicals and reproductive function in wild female Phayre's leaf monkeys (Trachypithecus phayrei crepusculus). AB - Female reproduction is known to be influenced by food availability and its impact on energetic status. However, emerging evidence suggests that the phytochemical content of food may also be an important factor. Here, we investigated this hypothesis, presenting 20 months of data on fecal progestin (fP) patterns in wild female Phayre's leaf monkeys (Trachypithecus phayrei crepusculus). We examined whether (a) the availability of Vitex (a plant known to contain phytochemicals) might be linked to seasonal fP levels, (b) fP levels were associated with female reproductive performance, and (c) reproductive performance might also be linked with energetic status (as measured by physical condition). We collected fecal samples (N=2077) from 10 adult females to analyze estrogen (fE) and progestin (fP) metabolites, behavioral data from 7 cycling females to determine receptivity, and monthly data on Vitex availability and female physical condition. Seasonally elevated fP levels were found in all females, with higher levels when Vitex leaves and fruits were abundant. During the period of high progestins, females had longer cycle lengths and follicular phases, while receptive periods did not change. Nevertheless, when ovulations occurred, females were more likely to conceive. On the other hand, conceptions were also more likely when physical condition was improving, suggesting that the effects of phytochemicals and energetic status on reproduction may be difficult to separate. Although our results support the predicted effects of Vitex on endocrine and reproductive function, future studies with detailed feeding data and chemical analyses of plants are needed to confirm this finding. PMID- 20932838 TI - Endocrine correlates of pregnancy in the ring-tailed lemur (Lemur catta): implications for the masculinization of daughters. AB - Female ring-tailed lemurs (Lemur catta) are Malagasy primates that are size monomorphic with males, socially dominate males, and exhibit a long, pendulous clitoris, channeled by the urethra. These masculine traits evoke certain attributes of female spotted hyenas (Crocuta crocuta) and draw attention to the potential role of androgens in lemur sexual differentiation. Here, hormonal correlates of prenatal development were assessed to explore the possibility that maternal androgens may shape the masculine morphological and behavioral features of developing female lemurs. Maternal serum 17alpha-hydroxyprogesterone, dehydroepiandrosterone sulphate (DHEA-S), ?4 androstenedione (androst-4-ene 3,17,dione), testosterone, and 17beta-estradiol were charted throughout the 19 pregnancies of 11 ring-tailed lemurs. As in spotted hyenas, lemur pregnancies were associated with an immediate increase in androgen concentrations (implicating early maternal derivation), followed by continued increases across stages of gestation. Pregnancies that produced singleton males, twin males, or mixed-sex twins were marked by greater androgen and estrogen concentrations than were pregnancies that produced singleton or twin females, especially in the third trimester, implicating the fetal testes in late-term steroid profiles. Concentrations of DHEA-S were mostly below detectable limits, suggesting a minor role for the adrenals in androgen biosynthesis. Androgen concentrations of pregnant lemurs bearing female fetuses, although less than those of pregnant hyenas, exceeded preconception and postpartum values and peaked in the third trimester. Although a maternal (and, on occasion, fraternal) source of androgen may exist for fetal lemurs, further research is required to confirm that these steroids would reach the developing female and contribute to her masculinization. PMID- 20932839 TI - Oxytocin receptors in the nucleus accumbens shell are involved in the consolidation of maternal memory in postpartum rats. AB - Female rats with maternal experience display a shorter onset of maternal responsiveness compared to those with no prior experience. This phenomenon called 'maternal memory' is critically dependent on the nucleus accumbens (NA) shell. We hypothesized that activation of OT receptors in the NA shell facilitates maternal memory. In Experiment 1, postpartum female rats given 1 hour of maternal experience were infused following the experience with either a high or low dose of an OT antagonist into the NA shell and tested for maternal behavior after a 10 day pup isolation period. Females receiving a high dose of the antagonist showed a significantly longer latency to exhibit full maternal behavior after the pup isolation period compared to females that received vehicle or a high dose of antagonist in a control region. In Experiment 2, postpartum female rats were infused with either a high or low dose of OT into the NA shell after a 15-minute maternal experience and tested for maternal behavior after a 10-day pup isolation period. There were no significant differences between the females infused with OT and females treated with a vehicle infused into the NA shell or with OT infused into the control region. One possible reason for a lack of facilitation is a floor effect, since females in the control groups displayed a rapid maternal response after the pup isolation period. These findings suggest that OT receptors, likely in combination with other neurotransmitters, in the NA shell play a role in the consolidation of maternal memory. PMID- 20932840 TI - Flow cytometric methods for prenatal and neonatal diagnosis. AB - Flow cytometry offers a promising alternative to the current methods of amniocentesis or chorionic villus sampling (CVS) for fetal cell sorting for prenatal diagnosis. While flow cytometric methods have been greatly improved to be more sensitive at detecting fetal cells within the maternal circulation, there are still several challenges that need to be overcome before application in prenatal diagnosis. However, flow cytometry is a powerful tool that can be used to enhance molecular testing and other diagnostic testing modalities in prenatal and neonatal diagnosis. It remains the gold standard to identify cellular immunodeficiencies and, for some immunological disorders with established biomarkers, flow cytometric assays can be used to make a definitive diagnosis. In this review, the advantages and disadvantages of using MACS and FACS analysis for fetal cell sorting are discussed. This review also includes an overview of the current flow cytometric assays and biomarkers that may be used for prenatal and neonatal diagnosis of common immunological and hematological abnormalities and the role of flow cytometry in treatment monitoring after bone marrow and stem cell transplantation. PMID- 20932841 TI - Effects of photoperiodically induced reproductive diapause and cold hardening on the cold tolerance of Drosophila montana. AB - Coping with seasonal and daily variation in environmental conditions requires that organisms are able to adjust their reproduction and stress tolerance according to environmental conditions. Females of Drosophila montana populations have adapted to survive over the dark and cold winters at high latitudes and altitudes by spending this season in photoperiodically controlled reproductive diapause and reproducing only in spring/summer. The present study showed that flies of a northern population of this species are quite tolerant of low temperatures and show high seasonal and short-term plasticity in this trait. Culturing the flies in short day length (nearly all females in reproductive diapause), as well as allowing the flies to get cold hardened before the cold treatment, increased the cold tolerance of both sexes both in chill coma recovery time test and in mortality assay. Chill coma recovery time test performed for the females of two additional D. montana populations cultured in a day length where about half of the females enter diapause, also showed that diapause can increase female cold tolerance even without a change in day length. Direct linkage between diapause and cold tolerance was found in only two strains representing a high altitude population of the species, but the phenomenon will certainly be worth of studying in northern and southern populations of the species with larger data sets. PMID- 20932842 TI - In vivo passages of heterologous Beauveria bassiana isolates improve conidial surface properties and pathogenicity to Nilaparvata lugens (Homoptera: Delphacidae). AB - In entomopathogenic hyphomycetes, desired candidates against the brown planthopper, Nilaparvata lugens (a sap-sucking rice pest in Asia), are lacking. In this study, 21 Beauveria bassiana isolates from heterologous host insects showed low pathogenicity to third-instar nymphs sprayed at the high concentration of ~ 1000 conidia/mm(2), causing only 2-23% mortalities. Of those, three isolates killed significantly more nymphs (up to 45-62%) after two in vivo passages but no more after further passage. Conidial hydrophobicity rates (H(r)), zeta potentials (P(z)), and subtilisin-like protease (Pr1) activities (A(p)) of these isolates showed the same trends in the three host passages (N: 0-3). In multivariate correlation, the variables N, H(r) and P(z) were found contributing 89% to the mortality variation (r(2)=0.89). Significant positive correlations were also found between H(r) and N (r(2)=0.64), P(z) and N (r(2)=0.52), A(p) and N (r(2)=0.51), H(r) and A(p) (r(2)=0.45), and P(z) and A(p) (r(2)=0.57), respectively. However, irregular changes of H(r) and P(z) occurred in four other isolates, whose pathogenicity to N. lugens was not enhanced by repeated host passages, resulting in no correlation between the variables. Our data indicate that the conidial surface properties H(r) and P(z) associated with cuticle adhesion reflect the heterologous host-induced adaptation and help to select fungal candidates against N. lugens from repeated in vivo passages. PMID- 20932843 TI - Interactions of two insect pathogens, Paranosema locustae (Protista: Microsporidia) and Metarhizium acridum (Fungi: Hypocreales), during a mixed infection of Locusta migratoria (Insecta: Orthoptera) nymphs. AB - Locusta migratoria nymphs were fed Paranosema locustae spores and/or surface treated with Metarhizium acridum 3 (assay 1), 6 (assay 2) or 9 days (assay 3) post microsporidia application (p.m.a.). These three dates corresponded to the key phases of P. locustae development: (a) mass proliferation, (b) transition to sporogenesis and (c) onset of spore maturation, respectively. As a result, locust mortality due to mixed treatment increased slower, equally and faster, as compared to mortality expected from the combination of two pathogens in assays 1 3, respectively. However, a statistically significant difference in survival times was observed only in assay 3, indicating that only at the phase of spore maturation microsporidia drastically increase locust susceptibility to fungal infection. Analysis of perished nymphs showed that fungal treatment 3 days p.m.a. impeded development of microsporidia. Fungal sporulation on locust cadavers was not affected by co-occurring microsporidiosis. PMID- 20932844 TI - The KdpD/KdpE two-component system of Photorhabdus asymbiotica promotes bacterial survival within M. sexta hemocytes. AB - Many bacteria persist within phagocytes, deploying complex sets of tightly regulated virulence factors to manipulate and survive within host cells. So far, no single factor has been identified that is sufficient to allow intracellular persistence of an otherwise non-pathogenic bacterium. Here we report that the two component KdpD/KdpE sensor kinase/response regulator of the insect and human pathogen Photorhabdus asymbiotica (Pa) is sufficient to allow a harmless laboratory strain of E. coli to resist phagocytic killing and persist within insect hemocytes, ultimately killing the insect. Screening of a cosmid library of Pa in E. coli by injection into the moth Manduca sexta, previously identified three overlapping clones which caused the insect to cease feeding and subsequently die. Transposon mutagenesis revealed a cosmid encoded kdp high affinity potassium pump regulon was responsible for this phenotype. Gentamycin protection assays and confocal microscopy revealed the cosmid clones were persisting inside insect hemocytes far longer than control bacteria. Cloning and expression of PakdpD/kdpE alone into E. coli recapitulated the phenotype. Bioassay results and transcriptional analysis of various E. coli kdp mutants harboring the Pa kdp genes confirmed that Pa KdpD/KdpE was able to induce the E. coli kdp pump structural genes in response to exposure to insect hemocytes but not blood plasma alone. The finding that Pa KdpD/KdpE can facilitate resistance of E. coli to phagocytic killing suggests a central role for potassium in this process, supporting previous work implicating potassium sensing in virulence of other bacteria and also in the normal process of protease killing of engulfed bacteria by neutrophils. PMID- 20932845 TI - Substrate-specific kinetics of Dicer-catalyzed RNA processing. AB - The specialized ribonuclease Dicer plays a central role in eukaryotic gene expression by producing small regulatory RNAs-microRNAs (miRNAs) and short interfering RNAs (siRNAs)-from larger double-stranded RNA (dsRNA) substrates. Although Dicer will cleave both imperfectly base-paired hairpin structures (pre miRNAs) and perfect duplexes (pre-siRNAs) in vitro, it has not been clear whether these are mechanistically equivalent substrates and how dsRNA binding proteins such as trans-activation response (TAR) RNA binding protein (TRBP) influence substrate selection and RNA processing efficiency. We show here that human Dicer is much faster at processing a pre-miRNA substrate compared to a pre-siRNA substrate under both single and multiple turnover conditions. Maximal cleavage rates (V(max)) calculated by Michaelis-Menten analysis differed by more than 100 fold under multiple turnover conditions. TRBP was found to enhance dicing of both substrates to similar extents, and this stimulation required the two N-terminal dsRNA binding domains of TRBP. These results demonstrate that multiple factors influence dicing kinetics. While TRBP stimulates dicing by enhancing the stability of Dicer-substrate complexes, Dicer itself generates product RNAs at rates determined at least in part by the structural properties of the substrate. PMID- 20932846 TI - The vertical distribution of phytoplankton in stratified water columns. AB - What determines the vertical distribution of phytoplankton in different aquatic environments remains an open question. To address this question, we develop a model to explore how phytoplankton respond through growth and movement to opposing resource gradients and different mixing conditions. We assume stratification creates a well-mixed surface layer on top of a poorly mixed deep layer and nutrients are supplied from multiple depth-dependent sources. Intraspecific competition leads to a unique strategic equilibrium for phytoplankton, which allows us to classify the distinct vertical distributions that can exist. Biomass can occur as a benthic layer (BL), a deep chlorophyll maximum (DCM), or in the mixed layer (ML), or as a combination of BL+ML or DCM+ML. The ML biomass can be limited by nutrients, light, or both. We predict how the vertical distribution, relative resource limitation, and biomass of phytoplankton will change across environmental gradients. We parameterized our model to represent potentially light and phosphorus limited freshwater lakes, but the model is applicable to a broad range of vertically stratified systems. Increasing nutrient input from the sediments or to the mixed layer increases light limitation, shifts phytoplankton towards the surface, and increases total biomass. Increasing background light attenuation increases light limitation, shifts the phytoplankton towards the surface, and generally decreases total biomass. Increasing mixed layer depth increases, decreases, or has no effect on light limitation and total biomass. Our model is able to replicate the diverse vertical distributions observed in nature and explain what underlying mechanisms drive these distributions. PMID- 20932847 TI - Strengthening strong reciprocity. PMID- 20932848 TI - Spatiotemporally modulated Vestigial gradient by Wingless signaling adaptively regulates cell division for precise wing size control. AB - In animal development, the growth of a tissue or organ is timely arrested when it reaches the stereotyped correct size. How this is robustly controlled remains poorly understood. The prevalent viewpoint, which is that morphogen gradients, due to their organizing roles in development, are directly responsible for growth arrest, cannot explain a number of observations. Recent findings from studies of the Drosophila wing have revealed that the interpretation of the Wingless gradient requires signaling-induced self-inhibition and that cell proliferation is controlled by graded vestigial expression. These findings highlight a growth control mechanism that involves Wingless regulated vestigial expression, but a question is whether they can quantitatively explain the observed precision and robustness of wing size control. Quantitative and systematic investigation into Wingless signaling using a mathematical model has elucidated two points. First, negative regulation of the Vestigial gradient by Wingless signaling makes vestigial expression precise and robust. Second, weak Wingless signaling in a primarily small wing pouch causes a short and steep Vestigial gradient, which stimulates more cell divisions and leads to a significant expansion of the wing pouch; however, strong Wingless signaling in a primarily large wing pouch causes a long and smooth Vestigial gradient, which stimulates fewer cell divisions and results in a slight expansion of the wing pouch. These results substantially decipher an inherent mechanism of tissue and organ size control. Our model explains, and is supported by, a number of experimental observations. PMID- 20932849 TI - The proteinase/proteinase-activated receptor-2/transient receptor potential vanilloid-1 cascade impacts pancreatic pain in mice. AB - AIMS: Proteinase-activated receptor-2 (PAR2) and transient receptor potential vanilloid-1 (TRPV1) are co-localized in the primary afferents, and the trans activation of TRPV1 by PAR2 activation is involved in processing of somatic pain. Given evidence for contribution of PAR2 to pancreatic pain, the present study aimed at clarifying the involvement of TRPV1 in processing of pancreatic pain by the proteinase/PAR2 pathway in mice. MAIN METHODS: Acute pancreatitis was created by repeated administration of cerulein in conscious mice, and the referred allodynia/hyperalgesia was assessed using von Frey filaments. Injection of PAR2 agonists into the pancreatic duct was achieved in anesthetized mice, and expression of Fos in the spinal cord was determined by immunohistochemistry. KEY FINDINGS: The established referred allodynia/hyperalgesia following cerulein treatment was abolished by post-treatment with nafamostat mesilate, a proteinase inhibitor, and with capsazepine, a TRPV1 antagonist, in mice. Injection of trypsin, an endogenous PAR2 agonist, or SLIGRL-NH(2), a PAR2-activating peptide, into the pancreatic duct caused expression of Fos protein in the spinal superficial layers at T8-T10 levels in the mice. The spinal Fos expression caused by trypsin and by SLIGRL-NH(2) was partially blocked by capsazepine, the former effect abolished by nafamostat mesilate. SIGNIFICANCE: Our data thus suggest that the proteinase/PAR2/TRPV1 cascade might impact pancreatic pain, in addition to somatic pain, and play a role in the maintenance of pancreatitis-related pain in mice. PMID- 20932850 TI - 7-ketocholesteryl-9-carboxynonanoate induced nuclear factor-kappa B activation in J774A.1 macrophages. AB - AIMS: 7-Ketocholesteryl-9-carboxynonanoate (oxLig-1), a lipid moiety of oxidized low-density lipoprotein (oxLDL), has been reported to be a crucial ligand of beta2-glycoprotein I (beta(2)-GPI), and plays a potential role in the development of atherosclerosis (AS), however, the role of the sole oxLig-1 in the development of AS remains unclear. MAIN METHODS: Expression and phosphorylation levels of several proteins, such as nuclear factor-kappaB (NF-kappaB), protein kinase C (PKC), IkappaBalpha and inter-cellular adhesion molecule 1 (ICAM-1) were determined by Western blot; nuclear localization of NF-kappaB was studied by immunocytochemistry; NF-kappaB activation was assayed by electrophoretic mobility shift assay (EMSA); and expressions of genes associated with AS process were investigated by Mouse Atherosclerosis RT(2) Profiler PCR Array assay. KEY FINDINGS: The present work indicated that oxLig-1 induced IkappaBalpha phosphorylation and results in the nuclear translocation of NF-kappaB in J774A.1 macrophages. Moreover, oxLig-1-induced NF-kappaB DNA binding activity was detected by EMSA. Indeed, oxLig-1 led to the activation of PKC prior to activating NF-kappaB. The treatment of oxLig-1 in J774A.1 macrophages up regulates the expression of NF-kappaB target genes including ICAM-1. SIGNIFICANCE: OxLig-1 on the oxLDL plays an important role in AS process, as evidenced by the NF-kappaB activation and up-regulation of genes involved in AS development in oxLig-1 challenged J774A.1 macrophages. PMID- 20932851 TI - Testosterone is essential for cocaine sensitization in male rats. AB - Most studies agree that males and females respond differently to drugs of abuse. In females, estradiol enhances the behavioral response to cocaine. However, studies on the role of testosterone and the locomotor response to psychostimulants in the male rat are inconclusive. Our study was designed to determine the behavioral effects of testosterone on the development and persistence of cocaine sensitization in male rats. We tested different doses of cocaine (10, 15 and 30mg/kg) to determine which dose induced locomotor sensitization in intact (INT) and gonadectomized (GDX) animals. We also investigated if GDX males with testosterone replacement (GDX-T) showed a similar locomotor response to cocaine as INT males. Our data showed that gonadectomy enhanced the locomotor response to a single cocaine injection. This effect was not observed in gonadectomized rats that received testosterone replacement. However, GDX rats did not show a progressive increase in their locomotor response to repeated cocaine administration (15 and 30mg/kg) (sensitization) as did INT and GDX-T animals. It is possible that in GDX males, the initial high locomotor response to cocaine creates a ceiling effect that limits further increase in cocaine-induced hyperactivity. These findings indicate that testosterone not only modulates the behavioral response to a single and to repeated cocaine injections, but is also essential for male rats to become sensitized to cocaine. PMID- 20932852 TI - Chronic stress, energy balance and adiposity in female rats. AB - Stress preferentially increases the consumption of high fat foods in women, suggesting the interaction of these two factors may disproportionately predispose women toward excess weight gain. In the present study, female rats were exposed to a chronic high fat or chow diet and were exposed to 4weeks of chronic variable stress (CVS) or served as home cage controls. Control females exposed to a high fat diet displayed many symptoms of the metabolic syndrome including increased body weight gain, total and visceral adiposity and insulin and leptin concentrations relative to all groups. However, CVS-high fat, CVS chow and control chow groups had similar body weight gain and caloric efficiency. This finding suggests that CVS increases energy expenditure much more in females exposed to a high fat diet relative to those fed a standard chow diet. The CVS high fat group had increased adiposity and increased circulating leptin and insulin concentrations, despite the fact that their body weight did not differ from the controls. These results underscore the importance of assessing the degree of adiposity, rather than body weight alone, as an index of overall metabolic health. Overall, the data indicate that in female rats, chronic stress prevents high fat diet related increases in body weight, but does not prevent high fat diet induced increases in adiposity when compared to chow-fed females. PMID- 20932853 TI - Effects of undernourishment on the hypothalamic orexinergic system. AB - The present study examined the effects of a severely restricted diet during the pre- and postnatal periods with later nutritional rehabilitation on orexin hypothalamic neurons in male and female Wistar rats. Immunocytochemistry was used to reveal orexin-immunoreactive (orexin-ir) cells in the ventromedial hypothalamus (VMH), dorsomedial hypothalamus (DMH), lateral hypothalamic area (LH) and the perifornical nucleus (PF). Dietary restriction decreased the number of orexin-ir cells in the LH, whereas DMH or PF orexin-ir populations were not affected in either male or female rats. Nutritional rehabilitation resulted in a differential recovery that depended on the period during which rehabilitation occurred and on the sex of the animal. In summary, our study suggests that the hypothalamic nuclei implicated in eating behavior present a differential vulnerability to adverse environmental conditions during development. Specifically, among the studied nuclei only the LH orexin-ir cells were sensitive to severe food deprivation during development in male and female rats. These results suggest that starvation interferes with developmental events that occur during CNS sexual differentiation. PMID- 20932854 TI - Peptidomic dissection of the skin secretion of Phasmahyla jandaia (Bokermann and Sazima, 1978) (Anura, Hylidae, Phyllomedusinae). AB - The systematic investigation of the peptidic composition of the skin secretion of Phasmahyla jandaia, a phyllomedusine anuran endemic to the southern region of the Espinhaco range in Brazil, is herein reported. By means of de novo interpretation of tandem mass spectrometric data, Edman N-terminal sequencing and similarity searches, 57 peptides - including phylloseptins, dermaseptins stricto sensu, dermatoxins, hyposins, tryptophyllins, caerulein-related, bradykinin-related, bradykinin potentiating, tyrosine-rich, and opioid peptides - were sequenced. Moreover, five peptide families without significant similarity to other known molecules were verified. Differently from most Phyllomedusinae genera, the molecular diversity in the skin of representatives of Phasmahyla remained unprospected until now. Therefore, besides disclosing novel natural variants of number of bioactive peptides, the present study contributes to the understanding of the evolution of biochemical characters of the phyllomedusines. PMID- 20932855 TI - Palytoxin action on the Na(+),K(+)-ATPase and the disruption of ion equilibria in biological systems. AB - Palytoxin-group toxins (PlTX) exert their potent biological activity by altering mechanisms of ion homeostasis in excitable and non-excitable tissues. This review will describe major aspects that led to the relatively early identification of the Na(+),K(+)-ATPase as the molecular target and receptor of the toxin in sensitive systems. The importance of this pump in the normal functioning of animal cells has driven extensive investigative efforts. The recognized molecular mechanism of action of PlTX involves its binding to the extracellular portion of alpha subunit of this plasma membrane protein, which converts an enzyme carrying ions against their concentration gradients at the expense of chemical energy (ATP) into a non-selective cation channel, allowing passive flow of ions following their concentration gradients. More recent findings have indicated that PlTX would interfere with the normal strict coupling between inner and outer gates of the pump controlling the ion access to the Na(+),K(+)-ATPase, allowing the gates to be simultaneously open. The ability of PlTX to make internal portions of the Na(+),K(+)-ATPase accessible to relatively large molecules has been exploited to characterize the structure-function relationship of the pump, leading to a better understanding of its ion translocation pathway. Thus, forty years from the isolation of this potent marine biotoxin, a considerable understanding of its mode of action and of its potential as a research tool have been achieved and are the basis for promising future advancement in the characterization of biological systems and their alteration by PlTX. PMID- 20932856 TI - Decision-theoretic models of visual perception and action. AB - Statistical decision theory (SDT) and Bayesian decision theory (BDT) are closely related mathematical frameworks used to model ideal performance in a wide range of visual and motor tasks. Their elements (gain function, likelihood, prior) are readily interpretable in terms of information available to the observer. We briefly describe SDT and BDT and then review recent work employing them as models of biological perception or action. We emphasize work that employs gain functions and priors as independent or dependent variables. At one extreme, Bayesian decision theory allows the experimenter to compute ideal performance in specific tasks and compare human performance to ideal (Geisler, 1989). No claim is made that visual processing is in any sense "Bayesian". At the other extreme, researchers have proposed Bayesian decision theory as a process model of "perception as Bayesian inference" (Knill & Richards, 1996). We end by discussing how possible ideal models are related to imperfect, actual observers and how the "Bayesian hypothesis" can be tested experimentally. PMID- 20932858 TI - Intraplantar injection of bergamot essential oil induces peripheral antinociception mediated by opioid mechanism. AB - This study investigated the effect of bergamot essential oil (BEO) containing linalool and linalyl acetate as major volatile components in the capsaicin test. The intraplantar injection of capsaicin (1.6 MUg) produced a short-lived licking/biting response toward the injected paw. The nociceptive behavioral response evoked by capsaicin was inhibited dose-dependently by intraplantar injection of BEO. Both linalool and linalyl acetate, injected into the hindpaw, showed a significant reduction of nociceptive response, which was much more potent than BEO. Intraperitoneal (i.p.) and intraplantar pretreatment with naloxone hydrochloride, an opioid receptor antagonist, significantly reversed BEO and linalool-induced antinociception. Pretreatment with naloxone methiodide, a peripherally acting MU-opioid receptor preferring antagonist, resulted in a significant antagonizing effect on antinociception induced by BEO and linalool. Antinociception induced by i.p. or intrathecal morphine was enhanced by the combined injection of BEO or linalool. The enhanced effect of combination of BEO or linalool with morphine was antagonized by pretreatment with naloxone hydrochloride. Our results provide evidence for the involvement of peripheral opioids, in the antinociception induced by BEO and linalool. Combined administration of BEO or linalool acting at the peripheral site, and morphine may be a promising approach in the treatment of clinical pain. PMID- 20932859 TI - Degree of crosslinking of collagen at interfaces: adhesion and shear rheological indicators. AB - Work of adhesion (DeltaW) and surface rheology at solid/air and solution/air interface have been used as indicators to study the stabilization of collagen by different crosslinking agents like basic chromium sulfate (BCS), tannic acid, catechin and formaldehyde. The results show that an increase in rate of DeltaW would promote adsorption while a decrease leads to hindered adsorption. Shear rheological studies on collagen demonstrate an increase in both shear viscosity and elasticity with time while for collagen with polyphenols like catechin and tannic acid there is an unusual breakdown of these values. A correlation between the rheological properties and the work of adhesion suggests that the time frame in which the viscoelastic behavior is initiated for collagen with different crosslinking agents determines the final macroscopic property of the protein. The study attempts to quantify the degree of crosslinking of collagen through the dynamics and strength of the water molecules in the assembly of hydrated protein and the crosslinking agents. PMID- 20932860 TI - Towards a comprehensive human cell-surface immunome database. AB - The human immune system is a complex machinery involving numerous proteins. Proteins located at the cell surface of immune cells are of particular relevance due not only to their participation in the network of interactions that regulate the immune response but also to their potential as excellent targets for diagnostic and therapeutic interventions. The main objective of this project is to generate a comprehensive database of the human cell-surface proteins expressed in immune cells and lymphoid tissues. For this purpose, we have integrated information collected from primary literature, databases and electronic information sources. This manually curated database includes the gene symbol and name of the protein, describes the family that each protein belongs to, indicates their type of extracellular domains, and compiles data regarding their expression. Thus far we have identified and catalogued 1015 genes and proteins. The largest families in this compendium are the Ig superfamily with 195 members (~20%) and the G-protein coupled receptor superfamily with 147 members (~14%). Other abundant families include the C-type lectin and the cytokine receptor families with 43 and 42 members respectively (4%). About 25% of the proteins belong to minor families and approximately 4% lack any clear family assignment. More than 60% of the genes encode proteins without a CD number. This database will serve to boost the production of new monoclonal antibodies and to stimulate studies aimed at characterizing the function of these proteins in the immune system as well as identifying potential new biomarkers and therapeutic targets. PMID- 20932857 TI - New aspects of melanocortin signaling: a role for PRCP in alpha-MSH degradation. AB - The role of the central melanocortin system in the regulation of energy metabolism has received much attention during the past decade since gene mutations of key components in melanocortin signaling cause monogenic forms of obesity in animals and humans. In the arcuate nucleus of the hypothalamus the prohormone proopiomelanocortin (POMC) is posttranslationally cleaved to produce alpha-melanocyte stimulating hormone (alpha-MSH), a peptide with anorexigenic effects upon activation of the melanocortin receptors (MCRs). alpha-MSH undergoes extensive post-translational processing and its in vivo activity is short lived due to rapid degradation. The enzymatic process that controls alpha-MSH inactivation is incompletely understood. Recent evidence suggests that prolyl carboxypeptidase (PRCP) is an enzyme responsible for alpha-MSH degradation. As for many key melanocortin peptides, gene mutation of PRCP causes a change in the metabolic phenotype of rodents. This review summarizes the current knowledge on the melanocortin system with particular focus on PRCP, a newly discovered component of the melanocortin system. PMID- 20932861 TI - Identification of cytomegalovirus (CMV)pp65 antigen-specific human monoclonal antibodies using single B cell-based antibody gene cloning from melanoma patients. AB - Recently, because of highly advanced protein engineering technology, beyond the chimeric antibody, highly humanized and fully human antibody development is becoming crucial in the medical field. In the last decade, investigational approaches using clinical samples for fully human antibody production have been performed, but there are still problems with efficiency and accuracy, which should be solved. In the present study, based on novel IgG antibody-measuring ELISA and antibody gene copy number-quantitative PCR, a human single B cell RT PCR-mediated IgG monoclonal antibody (mAb) gene cloning method was established, and CMVpp65-specific human mAbs were successfully identified. Quantitative PCR for the human IgG mRNA copy number per cell demonstrated that the detection range was 10-250copies/cell. CMVpp65(+)surfaceIgG(+) B cells were collected from melanoma patients who showed high titers of serum anti-CMVpp65 IgG antibody. RT PCR was successful in 64% (IGH) and 84% (beta-actin) of 88 single B cells. Finally, both IGH and IGL gene amplifications in the same cell were successful in 21 single cells, and 18 IgG antibody genes specific for CMVpp65 antigen were cloned. Four of 13 recombinant human single-chain fragment variable (scFv) antibodies showed strong responses to full-length CMVpp65 protein. These results suggested that the current fully human mAb production procedure through antibody titer screening by ELISA, single B cell RT-PCR-based antibody gene cloning, and the making of scFv recombinant antibody is an efficient method of therapeutic antibody development. PMID- 20932862 TI - Modeling Sjogren's syndrome with Id3 conditional knockout mice. AB - The Id3 gene has been shown to play important roles in the development and function of broad tissue types including B and T cells. Id3 deficient mice develop autoimmune disease similar to human Sjogren's syndrome. Both B and T lymphocytes have been implicated to contribute to the disease phenotype in this disease model. In order to gain a better understanding of individual cell types in this disease model, we generated an Id3 conditional allele. An LckCre transgene was used to induce Id3 deletion in developing T cells. We showed that the Id3 gene was efficiently disrupted in early thymocyte development prior to T cell receptor (TCR)-mediated positive selection. Consequently, thymocyte maturation was impaired in the conditional knockout mice. These mice developed exocrinopathy starting at two months of age and subsequently exhibited high incidence of lymphocyte infiltration to salivary glands between eight and 12 months of age. This progressive feature of disease development is very similar to those observed in Id3 germline knockout mice. This study establishes a new model for investigating the relationship between T cell development and autoimmune disease. Our observation provides an experimental case that autoimmune disease may be induced by acquired mutation in developing T cells. PMID- 20932863 TI - DNA biosensor for detection of Neisseria gonorrhoeae causing sexually transmitted disease. AB - A sequence-specific electrochemical sexually transmitted disease (STD) sensor based on self-assembled monolayer of thiolated DNA probe specific to target opa gene for detection of Gonorrhoea, a sexually transmitted disease has been fabricated. 6-Mercapto-1-hexanol (MCH) has been used as a blocking agent to facilitate oligos "stand" up at the surface, a configuration favoring subsequent DNA hybridization and to repel non-specific adsorption of undesired DNA. The results of differential pulse voltammetric studies of this STD sensor reveal low detection limit (1.0 * 10(-18)M) and a wide dynamic range (from 1.0 * 10(-6)M to 0.5 * 10(-18)M) arising due to the stable hybridization using methylene blue as an electro-active DNA hybridization indicator. The experimental results with genomic DNA, clinical patient sample of Neisseria gonorrhoeae, culture of non-N. gonorrhoeae Neisseria species (NgNS) and gram negative bacteria indicate that the fabricated sensor is specific to this STD. PMID- 20932864 TI - beta-Glucosidase catalyzed synthesis of octyl-beta-D-glucopyranoside using whole cells of Pichia etchellsii in micro aqueous media. AB - Octyl-beta-D-glucopyranoside was synthesized by transglucosylation between p nitrophenyl beta-D-glucopyranoside (pNPG) and octanol as an acceptor using whole cells of thermo tolerant yeast Pichia etchellsii displaying cell wall bound beta glucosidase. Effect of several parameters such as glucosyl donor concentration, enzyme units and initial water activity was studied to optimize product yield. An initial water activity interval of 0.33-0.64 was favorable and increase in total enzyme units had marginal effect on conversion yield. An empirical model was developed to describe the relationship between various parameters and octyl glucoside yield. These factors were combined in a batch replacement strategy whereby octyl-beta-D-glucopyranoside was synthesized in 4h to a concentration of 30 mM (9.25 mg/ml) with a conversion yield of nearly 70% with pNPG as a glucosyl donor. Quantitative analysis was done by a highly reproducible reverse-phase high performance liquid chromatography (RP-HPLC) method and detection was achieved using refractive index detector. The structure of the product was confirmed by 13C and 1H NMR spectroscopy. Additional products like octyl diglucoside were also formed, the structure of which was confirmed by mass spectrometry. PMID- 20932865 TI - Phage display technology for stem cell delivery and systemic therapy. AB - Advances in the technology for phage display in vivo have set the stage for a new ligand-directed pharmacology with broad implications for both treatment and molecular imaging of patients, and for the elucidation of molecular mechanisms of action, particularly in carcinogenesis. This technology identifies specific molecular complexes, mainly small peptide and gene-based therapeutic and imaging agents, effective in experimental animals and patients. The unbiased identification of molecular targets on the surfaces of blood vessels and parenchymal cells in preselected specific organs and tissues raises the prospect of an increased understanding of animal and human cellular and vascular proteomics. In this review, we focus on the delivery of phage-based agents via stem and progenitor cells, important delivery vehicles contributing to the growing impact of phage display on modern medicine. PMID- 20932866 TI - Skin peptide and cDNA profiling of Australian anurans: genus and species identification and evolutionary trends. AB - Host defense peptides of 35 species of Australian frogs from the hylids Cyclorana and Litoria, and the myobatrachids Crinia, Limnodynastes and Uperoleia have been identified. The biological activities of the majority of these peptides have been determined and include hormones, neuropeptides, opioids, immunomodulators, membrane active peptides [including antimicrobial, anticancer, antiviral (enveloped viruses like HIV and Herpes) and antifungal peptides], neuronal nitric oxide synthase inhibitors, pheromones and individual peptides with other specific activities. The host defense peptide skin profile can be diagnostic at both the species and higher taxonomic levels; for example, species of Crinia, Litoria and Uperoleia each produce quite different types of peptides. Species of Cyclorana and Limnodynastes are more difficult to characterize by skin peptides alone: species of both genera produce similar peptides with no apparent activity. The skin peptide profiles of frogs from the genera Crinia, Litoria and Uperoleia may be used together with morphological and cognate methods, to differentiate between sub-species and even different population clusters of the same species. Nucleotide sequencing of cDNAs of precursors (pre-pro peptides) of bioactive peptides from the skin glands of various species of the genus Litoria show that the majority of these peptides originated from a single ancestor gene before the break away of Australia from Gondwana. The exceptions are the caerulein neuropeptides {e.g. caerulein [pEQDY(SO(3)H)TGWMDF(NH(2))]} which have a different origin to that of other Litoria peptides. Disulfide containing peptides from skin glands of species of Crinia show a different evolutionary route to peptides from species of Litoria. PMID- 20932867 TI - Endomorphin-1 prevents lipid accumulation via CD36 down-regulation and modulates cytokines release from human lipid-laden macrophages. AB - CD36 is a scavenger receptor known to play a critical role in the development of atherosclerosis by mediating the uptake of oxidized low-density lipoproteins (oxLDL) by macrophages, thus leading to foam cell formation. It is now generally recognized that the immune system has a pivotal role in the pathogenesis of atherosclerosis, whose progression is determined by ongoing inflammatory reactions. Recently, several studies pointed out that opioid peptides exert anti inflammatory activities. Therefore the aim of the present study was to evaluate a possible endomorphin-1 (EM-1) immunomodulatory activity on human foam cells. Our results showed that EM-1 reduced Nile Red-stained lipid droplets content, decreased the expression of CD36 receptor and modulated tumor necrosis factor alpha (TNF-alpha) and interferon-gamma (IFN-gamma) release from lipid-laden macrophages. Furthermore, Naloxone, an opioid receptors antagonist, reverted the anti-atherogenic and anti-inflammatory observed effects of EM-1. These data demonstrated, for the first time, an unprecedented ability of EM-1 to act as a novel modulator for macrophage-to-foam cell transformation, and for inflammatory cytokines profile, suggesting possible novel endomorphin-based anti atherosclerotic approaches for the prevention and treatment of atherosclerosis. PMID- 20932868 TI - Investigation of endogenous soybean food allergens by using a 2-dimensional gel electrophoresis approach. AB - As part of the safety assessment of genetically modified (GM) soybean, 2 dimensional gel electrophoresis analyses were performed with the isoxaflutole and glyphosate tolerant soybean FG72, its non-GM near-isogenic counterpart (Jack) and three commercial non-GM soybean lines. The objective was to compare the known endogenous human food allergens in seeds in the five different soybean lines in order to evaluate any potential unintended effect(s) of the genetic modification. In total, 37 protein spots representing five well known soybean food allergen groups were quantified in each genotype. Qualitatively, all the allergenic proteins were detected in the different genetic backgrounds. Quantitatively, among 37 protein spots, the levels of accumulation of three allergens were slightly lower in the GM soybean than in the non-GM counterparts. Specifically, while the levels of two of these three allergens fell within the normal range of variation observed in the four non-GM varieties, the level of the third allergen was slightly below the normal range. Overall, there was no significant increase in the level of allergens in FG72 soybean seeds. Therefore, the FG72 soybean can be considered as safe as its non-GM counterpart with regards to endogenous allergenicity. Additional research is needed to evaluate the biological variability in the levels of endogenous soybean allergens and the correlation between level of allergens and allergenic potential in order to improve the interpretation of these data in the safety assessment of GM soybean context. PMID- 20932869 TI - The evaluation of drug rechallenge: the casopitant Phase III program. AB - Drug rechallenge (or reinitiation), following an event of drug-induced liver injury, is associated with 13% mortality in prospective series. Rechallenge generally results in much more rapid injury than the initial liver event. The neurokinin-1 antagonist casopitant or its placebo was administered cyclically with ondansetron and dexamethasone in two randomized chemotherapy-induced nausea and vomiting clinical trials in nearly 3000 subjects. Grade 3 ALT elevations were observed in up to 2% of subjects receiving casopitant or placebo treatment. Similar rates of positive rechallenge were observed in the casopitant 8/29 (28%) and placebo groups 2/8 (25%), with no Grade 4 ALT elevations, hypersensitivity or liver-related serious adverse events. Publishing available rechallenge data (positive and negative) will advance our clinical understanding. Rechallenge should only be considered when the potential drug benefit exceeds the risk. PMID- 20932870 TI - Autoantibodies reacting with vasopressin and oxytocin in relation to cortisol secretion in mild and moderate depression. AB - BACKGROUND: Abnormal vasopressin (VP) and oxytocin (OT) signaling may contribute to the altered activity of the hypothalamo-pituitary-adrenal (HPA) axis in major depression; however, the underlying mechanisms remain uncertain. This study characterized plasma levels and affinities of OT- and VP-reactive autoantibodies (autoAbs) in relation to disease severity and plasma cortisol response to physical exercise in patients with mild and moderate depression and healthy controls. METHODS: Physical exercise was used to elicit plasma cortisol response in 23 male patients with depression and 20 healthy controls and plasma samples were obtained before and after the exercise. Just before the exercise, patients and controls were evaluated by the Montgomery and Asberg Depression Rating Scale (MADRS) and divided according to depression severity (14 mild and 9 moderate). Plasma levels of total and free VP- and OT-reactive IgG, IgA and IgM autoAbs were measured by ELISA and affinity of IgG and IgM autoAbs were measured by plasmon resonance technique at baseline before the exercise and analyzed with relation to the MADRS and cortisol response. Immunohistochemistry was used to evaluate autoAbs binding to the rat hypothalamus. RESULTS: Plasma levels of OT- and VP reactive total IgG autoAbs were lower in patients with moderate depression vs. controls and patients with mild depression. Plasma levels of both OT- and VP-free IgG autoAbs were negatively correlated with MADRS scores. Affinity values of IgG and IgM autoAbs for both OT and VP displayed 100 fold variability among patients or controls but no significant group differences were found. Patients with moderate depression displayed blunted response of cortisol secretion to physical exercise. Baseline levels of VP total IgG and IgM autoAbs correlated negatively and VP-free IgG autoAbs correlated positively with plasma cortisol after physical exercise. Immunostaining of magnocellular hypothalamic neurons of the supraoptic and paraventricular nuclei by plasma IgG was present in 35% of the depression and in 14% of the controls groups, but this staining was not abolished by plasma preabsorption with OT or VP peptides. CONCLUSION: These data show that changes of levels but not affinity of OT- and VP-reactive autoAbs can be associated with the altered mood in subjects with moderate depression and that levels of VP-reactive autoAbs are associated with cortisol secretion. PMID- 20932871 TI - Preventive effect of Coptis chinensis and berberine on intestinal injury in rats challenged with lipopolysaccharides. AB - Coptis chinensis has been used in traditional Chinese medicine to treat inflammatory symptoms. Berberine is the main alkaloid compound of C. chinensis. This study utilized a typical lipopolysaccharide (LPS) injured model to investigate the effects of C. chinensis aqueous extract (CCAE) and berberine (major active ingredient in CCAE) in the gut-derived sepsis. In rats, pretreatment with different doses of berberine (30 or 120 mg/kg bw, i.g.; BBR30 or BBR120) or CCAE (containing 9.9% berberine; 300 mg/kg bw, i.g.; CCAE300) prior to the administration of LPS (20 mg/kg bw, i.p.) significantly suppressed the increased tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and nitrite oxide (NO) in plasma as well as the activation of toll-like receptor 4 (TLR4) and nuclear factor-kappaB (NF-kappaB) in ileum. In addition, CCAE300 and BBR30 markedly elevated the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px); significantly prevented the increased malondialdehyde (MDA), NO and villi injury in ileum compared with the negative control. Collectively, CCAE300 and BBR30 reduced the LPS-induced intestinal damage by elevating the activities of SOD and GSH-Px and by suppressing the activation of TLR4 and NF-kappaB in ileum. These results indicate that CCAE and berberine are promising agents for preventing sepsis and its complications. PMID- 20932872 TI - Ergothioneine protects against neuronal injury induced by cisplatin both in vitro and in vivo. AB - The neuroprotective effects of ergothioneine (EGT) against cisplatin toxicity were investigated both in vitro and in vivo. For in vitro study, two types of neuronal cells, primary cortical neuron (PCN) cells and rat pheochromocytoma (PC12) cells, were incubated with EGT (0.1-10.0 MUM) for 2 h followed by incubation with 0.5 MUM cisplatin for 72 h. Results show that cisplatin markedly decreased the proliferation of PC12 cells and strongly inhibited the growth of axon and dendrite of PCN cells, but these effects were significantly prevented by EGT. For in vivo study, CBA mice were orally administered with 2 or 8 mg EGT/kg body weight for 58 consecutive days and were injected i.p. with 5mg cisplatin/kg body weight on days 7, 9 and 11. We found that EGT significantly restored the learning and memory deficits in mice treated with cisplatin evaluated by active and passive avoidance tests. EGT also significantly prevented brain lipid peroxidation, restored acetylcholinesterase (AChE) activity and maintained glutathione/glutathione disulfide ratio in brain tissues of mice treated with cisplatin. These results demonstrate that EGT protects against cisplatin-induced neuronal injury and enhances cognition, possibly through the inhibition of oxidative stress and restoration of AChE activity in neuronal cells. PMID- 20932873 TI - Parenteral paradichlorobenzene exposure reduces sperm production, alters sperm morphology and exhibits an androgenic effect in rats and mice. AB - Rats and mice (8 animals per species per group) were injected subcutaneously or intraperitoneally with paradichlorobenzene (PDCB) at doses of 0, 100, 200 and 400 mg/kg/day, 4-5 days a week, for 8 weeks (for rats) and either 2 or 6 weeks (for mice). Prostate and seminal vesicle weights were significantly increased in PDCB treated rats but not in mice. Major histopathologic injuries were not found in testis and epididymis of both species. Daily sperm production was depressed in both species in a dose-response manner. Serum testosterone levels were not significantly changed in both species. Sperm morphology was evaluated in rats intraperitoneally administered PDCB at a dose of 800 mg/kg. Abnormal sperms with reduced hook, bent neck, coiled flagellum, bent flagellum and bent flagellum tip were significantly increased in treated rats. In Hershberger assay, PDCB administration increased weights of ventral prostate gland, seminal vesicle, levator ani/bulbocavernosus muscle and glans penis in castrated rats, and also weights of ventral prostate gland and glans penis in castrated mice. PDCB and 2,5 dichlorophenol (the major metabolite) did not bind androgen receptor (AR) up to 10 mM. In conclusion, PDCB affects sperm production and morphology but is somewhat androgenic independently from AR binding in rats and mice. PMID- 20932874 TI - Regional changes in purines and selected purinergic receptors in immature rat brain exposed to lead. AB - Lead (Pb) toxicity still remains a significant health problem, since it was recognized as a potent neurodevelopmental toxin. Regarding the fact that in the nervous system ATP is not only the energy source but also acts as a signaling molecule outside the cell, it was of interest to investigate both the level of purines and expression of purinergic receptors in different regions of immature rat brain under Pb toxicity conditions. We examined the expression of A1 receptor which is involved in neuroprotective mechanisms, and P2X7R receptor related to the inflammatory and neurodegenerative processes. Expression of receptors' protein was analysed using immunoblotting method whereas HPLC method was used to measure the levels of purines. We observed the features of energetic stress in all examined brain structures expressed by decrease in ATP and ADP levels and AEC ratio. However, in forebrain cortex, the observed changes were milder than in cerebellum and hippocampus. Enhanced expression of A1R and high increase of adenosine (Ado) level, suggest the proper function of protective mechanisms mediated by Ado. We have found that hippocampus is most vulnerable to Pb toxicity, both due to the high energy depletion and the pattern of expression of investigated receptors. Enhanced expression of P2X7R and connexin 43 (Cx43) in glial fraction (GPV), suggests the involvement of astrocytic pool of cells into the pathological changes observed in this structure of Pb-exposed immature rat brains. PMID- 20932875 TI - Evolving experience-dependent robust behaviour in embodied agents. AB - In this work, based on behavioural and dynamical evidence, a study of simulated agents with the capacity to change feedback from their bodies to accomplish a one legged walking task is proposed to understand the emergence of coupled dynamics for robust behaviour. Agents evolve with evolutionary-defined biases that modify incoming body signals (sensory offsets). Analyses on whether these agents show further dependence to their environmental coupled dynamics than others with no feedback control is described in this article. The ability to sustain behaviours is tested during lifetime experiments with mutational and sensory perturbations after evolution. Using dynamical systems analysis, this work identifies conditions for the emergence of dynamical mechanisms that remain functional despite sensory perturbations. Results indicate that evolved agents with evolvable sensory offset depends not only on where in neural space the state of the neural system operates, but also on the transients to which the inner-system was being driven by sensory signals from its interactions with the environment, controller, and agent body. Experimental evidence here leads discussions on a dynamical systems perspective on behavioural robustness that goes beyond attractors of controller phase space. PMID- 20932876 TI - Characterization of the zebrafish (Danio rerio) mineralocorticoid receptor. AB - Comparison between evolutionarily distant receptors can provide critical insights into both structure and function. Sequence comparison between the mineralocorticoid receptors (MR) of the zebrafish (zMR) and human (hMR) reveals a high degree of sequence conservation in the major functional domains. We isolated a zMR cDNA to contrast the transcriptional response to a range of ligands and to establish whether a teleost MR exhibits the amino/carboxyl-terminal interaction (N/C-interaction) previously reported for the hMR. Aldosterone, deoxycorticosterone (DOC) and cortisol induced zMR transcriptional activity with similar efficacy to that observed with the hMR. The hMR antagonist, spironolactone, acted as an agonist with the zMR. The zMR exhibited an N/C interaction in response to aldosterone but, in contrast to the hMR, cortisol and DOC predominantly stimulated the interaction in the zMR. Conservation of the N/C interaction between evolutionarily distant MR provides evidence of functional significance. PMID- 20932877 TI - Expression of cyclooxygenase-2 and prostaglandin receptor EP4b mRNA in the ovary of the medaka fish, Oryzias latipes: possible involvement in ovulation. AB - In vitro ovulation of mature medaka ovarian follicles was inhibited by inhibitors of cyclooxygenase (COX) or by an antagonist of the prostaglandin E(2) receptor (EP). Of the three medaka COX genes, ptgs2 was most dominantly expressed in the fish ovary. The ptgs2 transcript was detected in all sizes of growing follicles. In a 24-h spawning cycle, large-sized follicles contained ptgs2 mRNA at a fairly constant level. The levels of COX enzyme activity and prostaglandin E(2) were also constant in the large-sized follicles during the spawning cycle. The expression of prostaglandin E(2) receptor EP4b (ptger4b) mRNA was drastically upregulated in the large-sized follicles as the ovulation time approached. The current results indicate that prostaglandin E(2), which might be produced by COX 2, is involved in the ovulation of medaka, and that EP4b is likely the receptor responsible for exerting the action of prostaglandin E(2) in the process. PMID- 20932878 TI - Intrinsically organized network for word processing during the resting state. AB - Neural mechanisms underlying word processing have been extensively studied. It has been revealed that when individuals are engaged in active word processing, a complex network of cortical regions is activated. However, it is entirely unknown whether the word-processing regions are intrinsically organized without any explicit processing tasks during the resting state. The present study investigated the intrinsic functional connectivity between word-processing regions during the resting state with the use of fMRI methodology. The low frequency fluctuations were observed between the left middle fusiform gyrus and a number of cortical regions. They included the left angular gyrus, left supramarginal gyrus, bilateral pars opercularis, and left pars triangularis of the inferior frontal gyrus, which have been implicated in phonological and semantic processing. Additionally, the activations were also observed in the bilateral superior parietal lobule and dorsal lateral prefrontal cortex, which have been suggested to provide top-down monitoring on the visual-spatial processing of words. The findings of our study indicate an intrinsically organized network during the resting state that likely prepares the visual system to anticipate the highly probable word input for ready and effective processing. PMID- 20932879 TI - Anti-inflammatory effects of serum isolated from animals on intermittent feeding in C6 glioma cell line. AB - Multiple sclerosis (MS) is a demyelinating disease of the CNS. Early inflammation leads to later destruction of myelin in MS. Dietary restriction (DR) produces anti-inflammatory and immunomodulatory effects in many species. Based on the reported anti-inflammatory effects of DR, we investigated whether sera collected from rats fed on intermittent feeding (IF, a type of DR) diet could modulate cytokine secretion and matrix metalloproteinase (MMP-2) activity that are involved in MS pathogenesis. Cytokine levels (IL-6 and TGF-beta1) were measured in supernatant from C6 glioma cell line cultures treated with IF and AL fed animals' sera by enzyme-linked immunosorbent assay (ELISA) and MMP-2 activity was detected by gelatin zymography. Our results indicated that sera of animals on IF diet significantly reduced IL-6 (p<0.05) and increased TGF-beta1 (p<0.05) production by C6 glioma cells. A significant decrease (p<0.05) in MMP-2 activity was also found. These results indicate anti-inflammatory and immunomodulatory activity in the sera of animals on IF regimen on cells involved in multiple sclerosis pathogenesis. Further studies on the detection of factors responsible for such activities and their mechanism of action in MS pathogenesis are recommended. PMID- 20932880 TI - Effect of different frequencies of music on blood pressure regulation in spontaneously hypertensive rats. AB - The effect of different frequencies of music on brain function was investigated through measurement of blood pressure in spontaneously hypertensive rats (SHR). Previous studies indicated that exposure to Mozart's music (K. 205) leads to increased calcium/calmodulin-dependent dopamine synthesis in the brain, and that the subsequent increase in dopamine reduces blood pressure via D(2) receptors. The present study demonstrated that the blood pressure-reducing response was dependent on the frequency, and was markedly greater at 4 k-16 kHz compared with lower frequencies. These findings suggest that music containing high-frequency sounds stimulates dopamine synthesis, and might thereby regulate and/or affect various brain functions. PMID- 20932881 TI - Age-related differences in human corticospinal excitability during simple reaction time. AB - Age-related declines in central processing may delay the facilitation of corticospinal (CS) tracts that underlie emergence of voluntary responses to external stimuli. To explore this effect, single pulse transcranial magnetic stimulation (TMS) was applied to the left motor cortex at different latencies from the go-signal (auditory tone) during a simple reaction time (SRT) task with the right or left thumb [i.e. right (RHM) or left hand move (LHM)]. Motor evoked potentials (MEPs) in the right abductor pollicis brevis (APB) were recorded from eleven healthy right-handed participants (aged 22-65; six young adults and five old adults). Both age groups showed significant facilitation of CS excitability approximately 100-120 ms from the onset of the go-signal in the RHM SRT that occurred before the onset of EMG voluntary burst, with no evidence for motor slowing in old adults. Old adults demonstrated a significant facilitation of MEPs in the time that preceded the go-signal for RHM SRT and a marked depression of CS excitability in preparation for the LHM SRT that was sustained up to 80 ms after the onset of the go-signal. Both effects were not seen in young adults. While the small number of participants may hinder the generality of the present observations, this pilot study suggests for the first time that old adults implemented selective tuning of CS excitability prior to the onset of the go command to speed up their response generation. PMID- 20932882 TI - Within-subject comparison of degree of delay discounting using titrating and fixed sequence procedures. AB - Different procedures are often used across experiments to estimate the degree of delay discounting, a common measure of impulsivity. In all procedures, participants indicate their choice between a reward available immediately and one available after a delay. The present experiment determined whether there are differences in the degree of discounting for a hypothetical $100 produced by a procedure that titrates the immediate amount (titrating sequence procedure) versus a procedure that presents a fixed sequence of immediate amounts (fixed sequence procedure) using a within-subject design. The adult human participants showed no significant differences in degree of discounting between procedures as assessed by a hyperboloid model and the Area Under the Curve. Furthermore, the Area Under the Curve values from the two procedures showed a strong positive correlation. These findings suggest there may be no systematic difference between the degree of delay discounting as estimated by the titrating sequence and fixed sequence procedures. Given the apparent similarities in the results, it appears researchers may be justified in basing their choice of which procedure to use on convenience. PMID- 20932883 TI - Involvement of transient receptor potential melastatin-related 7 (TRPM7) channels in cadmium uptake and cytotoxicity in MC3T3-E1 osteoblasts. AB - Exposure to cadmium (Cd) disrupts bone metabolism, causing osteoporosis. Impaired vitamin D metabolism was initially proposed as the underlying mechanism, yet recent studies argue for the direct effect of Cd on bone cells. This study aimed at characterizing (109)Cd uptake and cytotoxicity in MC3T3-E1 osteoblasts. Time dependent accumulation of (109)Cd was observed with a 50% lethal concentration (LC(50)) of 9.6 +/- 1.2 MUM at 24-h. Reducing extracellular calcium (Ca) or magnesium (Mg) increased Cd cytotoxicity. The presence of Ca, Mg, zinc or gadolinium decreased (109)Cd uptake suggesting the involvement of non-selective cationic channels. The Mg-sensitive part of (109)Cd uptake increased at acidic pH, a condition known to stimulate TRPM7 channel activity. Stimulating TRPM7 channel activity by cellular Mg starvation enhanced (109)Cd uptake. Silencing TRPM7 channel expression abolished the Mg-sensitive and the Mg starvation-induced uptake indicating that TRPM7 is involved in Cd transport in osteoblasts. PMID- 20932884 TI - 1H NMR-based metabolic profiling of naproxen-induced toxicity in rats. AB - The dose-dependent perturbations in urinary metabolite concentrations caused by naproxen toxicity were investigated using 1H NMR spectroscopy coupled with multivariate statistical analysis. Histopathologic evaluation of naproxen-induced acute gastrointestinal damage in rats demonstrated a significant dose-dependent effect. Furthermore, principal component analysis (PCA) of 1H NMR from rat urine revealed a dose-dependent metabolic shift between the vehicle-treated control rats and rats treated with low-dose (10 mg/kg body weight), moderate-dose (50 mg/kg), and high-dose (100 mg/kg) naproxen, coinciding with their gastric damage scores after naproxen administration. The resultant metabolic profiles demonstrate that the naproxen-induced gastric damage exhibited energy metabolism perturbations that elevated their urinary levels of citrate, cis-aconitate, creatine, and creatine phosphate. In addition, naproxen administration decreased choline level and increased betaine level, indicating that it depleted the main protective constituent of the gastric mucosa. Moreover, naproxen stimulated the decomposition of tryptophan into kynurenate, which inhibits fibroblast growth factor-1 and delays ulcer healing. These findings demonstrate that 1H NMR-based urinary metabolic profiling can facilitate noninvasive and rapid diagnosis of drug side effects and is suitable for elucidating possible biological pathways perturbed by drug toxicity. PMID- 20932885 TI - Different effects of l- and d-menthol on the microstructure of ceramide 5/cholesterol/palmitic acid bilayers. AB - The optical activity of transdermal permeation enhancers is one of the crucial factors for the enhancement of drug permeation via the skin. We investigated the effects of optically active menthols on a lipid bilayer model composed of ceramide 5, cholesterol, and palmitic acid. We first examined the fluidizing effects of l- and d-menthols on the lipid bilayers. The fluorescence anisotropy and thermodynamic parameters, such as the transition temperature and transition enthalpy, were significantly reduced by treatment with the optically active menthols. The effects of d-menthol were stronger than those of l-menthol. To discuss further, we also performed a detergent insolubility study and measured wide angle X-ray scattering. The amount of liquid-ordered phase membranes in the bilayers was significantly reduced by treatment with d-menthol. Whereas, l menthol did not affected to the liquid-ordered phase membranes. The apparent ratio of orthorhombic hydrocarbon chain packing was substantially reduced by treatment with l-menthol. Thus, the distinct effects of optically active menthols on lipid bilayers were clarified: l-menthol acts on orthorhombic hydrocarbon chain packing with high selectivity, whereas d-menthol has no such specific effect. These findings extend our understanding of the mechanisms by which menthols affect the intercellular lipids in the stratum corneum. PMID- 20932886 TI - Penetration and distribution of PLGA nanoparticles in the human skin treated with microneedles. AB - This study was designed to investigate the penetration and the distribution of poly(d,l-lactic-co-glycolic acid) (PLGA) nanoparticles in the human skin treated with microneedles. Fluorescent nanoparticles were prepared to indicate the transdermal transport process of the nanoparticles. Permeation study was performed on Franz-type diffusion cells in vitro. The distribution of nanoparticles was visualized by confocal laser scanning microscopy (CLSM) and quantified by high performance liquid chromatography (HPLC). CLSM images showed that nanoparticles were delivered into the microconduits created by microneedles and permeated into the epidermis and the dermis. The quantitative determination showed that (i) the permeation of nanoparticles into the skin was enhanced by microneedles, but no nanoparticle reached the receptor solution; (ii) much more nanoparticles deposited in the epidermis than those in the dermis; (iii) the permeation was in a particle size-dependent manner; and (iv) the permeation increased with the nanoparticle concentration increasing until a limit value was reached. These results suggested that microneedles could enhance the intradermal delivery of PLGA nanoparticles. The biodegradable nanoparticles would sustain drug release in the skin and supply the skin with drug over a prolonged period. This strategy would prove to be useful for topical drug administration. PMID- 20932887 TI - The use of medicinal plants in self-care in the Agonlin region of Benin. AB - AIM OF THE STUDY: To investigate the extent and type of medicinal plants used in self-care by the inhabitants of the Agonlin community in the Republic of Benin. MATERIALS AND METHODS: A semi-structured questionnaire was used to interview a total of one thousand mothers. RESULTS: The prevalence rate of the use of herbal medicines in self-care was found to be 51.04%. One hundred and fourteen (114) plant species belonging to 69 families were reported, each with their local names, medicinal use, and parts used. Of all the indications of the identified plants, fever, headache, abdominal pain, and vomiting were the most frequently reported, with malaria treatment recording the highest usage of plant remedies (22%). The plant part most frequently used was the leaves. CONCLUSIONS: This study showed that self-care using medicinal plants is a major part of health care in the Agonlin area. PMID- 20932888 TI - Ethanol extract of seeds of Oenothera odorata induces vasorelaxation via endothelium-dependent NO-cGMP signaling through activation of Akt-eNOS-sGC pathway. AB - AIM OF STUDY: The vasorelaxant effect of ethanol extract of seeds of Oenothera odorata (Onagraceae) (one species of evening primroses) (ESOO) and its mechanisms involved were defined. MATERIALS AND METHODS: Changes in vascular tension, guanosine 3',5'-cyclic monophosphate (cGMP) levels, and Akt expression were measured in carotid arterial rings from rats. Seeds of Oenothera odorata were extracted with ethanol (94%) and the extract was filtered, concentrated and stored at -70 degrees C. RESULTS: ESOO relaxed endothelium-intact, but not endothelium-denuded, carotid arterial rings in a concentration-dependent manner. Similarly, ESOO increased cGMP levels of the carotid arterial rings. Pretreatment of endothelium-intact arterial rings with L-NAME, an inhibitor of nitric oxide synthase (NOS), or ODQ, an inhibitor of soluble guanylyl cyclase (sGC), blocked the ESOO-induced vasorelaxation and increase in cGMP levels. Nominally Ca(2+) free but not L-typed Ca(2+) channel inhibition attenuated the ESOO-induced vasorelaxation. Thapsigargin, Gd(3+), and 2-aminoethyl diphenylborinate, modulators of store-operated Ca(2+) entry (SOCE), significantly attenuated the ESOO-induced vasorelaxation and increase in cGMP levels. Further, wortmannin, an inhibitor of Akt, attenuated the ESOO-induced vasorelaxation and increases in cGMP levels and phosphorylated Akt2 expression. K(+) channel blockade with TEA, 4 aminopyridine, and glibenclamide attenuated the ESOO-induced vascular relaxation. CONCLUSION: Taken together, the present study demonstrates that ESOO relaxes vascular smooth muscle via endothelium-dependent NO-cGMP signaling through activation of the Akt-eNOS-sGC pathway. PMID- 20932889 TI - Acute and sub-chronic oral toxicity studies of an aqueous stem bark extract of Pterocarpus soyauxii Taub (Papilionaceae) in rodents. AB - Pterocarpus soyauxii Taub (Papilionaceae) is used in Cameroonian traditional medicine and pharmacopoeia to treat hypertension, diabetes, gastrointestinal parasitizes and cutaneous diseases. AIM OF THE STUDY: The present investigation was carried out to evaluate the safety of an aqueous stem bark extract of Pterocarpus soyauxii by determining toxicity after acute and sub-chronic oral administration in male and female rodents. MATERIALS AND METHODS: The acute toxicity test was conducted in mice. An aqueous extract of barks was administrated by gavage in single doses of 2.5-12.5 g/kg. General behaviour and mortality were examined for up to 7 days. The sub-chronic toxicity test was performed in rats. The plant extract was administered by daily gavage of 150-600 mg/kg for 42 days. Body weight, food and water intakes were followed weekly. Haematological, biochemical and organ parameters were determined at the end of the 42-day administration. RESULTS: In the acute study in mice, oral administration of the aqueous extract of Pterocarpus soyauxii caused dose dependent general behaviour adverse effects and mortality. The no-observed adverse effect level (NOAEL) of the extract was 5.0 g/kg. The lowest-observed adverse effect level (LOAEL) was 7.5 mg/kg. Mortality increased with the dose, LD(50) was>10.75 g/kg for the mouse. In the sub-chronic study in rats, daily oral administration of the aqueous extract of Pterocarpus soyauxii did not result in death or significant changes in haematological or biochemical parameters, excepted increased hepatic catalase activity (P<0.05) at the dose of 600 mg/kg. No alteration was observed in body weight, food and water intake. Liver, kidney, lung and pancreas histopathology did not reveal morphological alteration. CONCLUSIONS: The results showed that the aqueous stem bark extract of Pterocarpus soyauxii Taub had very low toxicity in oral acute high dose administration and no toxicity in oral sub-chronic low dose administration and indicate that the plant could be considered safe for oral medication. PMID- 20932890 TI - In vitro detection of contact allergens: development of an optimized protocol using human peripheral blood monocyte-derived dendritic cells. AB - Allergic contact dermatitis is a delayed T-cell mediated allergic response associated with relevant social and economic impacts. Animal experiments (e.g. the local lymph node assay) are still supplying most of the data used to assess the sensitization potential of new chemicals. However, the 7th amendment to the EU Cosmetic Directive will introduce a testing ban for cosmetic ingredients after 2013. In vitro alternative methods are thus being actively developed. Although promising results have been obtained with cell lines, their reduced functionality and inherent genomic instability led us to reinvestigate the use of peripheral blood monocyte-derived dendritic cells (PBMDCs) for the establishment of a reliable in vitro sensitization test. To solve the issues associated with the use of primary cells, the culture and exposure conditions (cytokine concentrations, incubation time, readout, pooled vs. single donors and cytotoxicity) were re assessed and optimized. Here we propose a stable and reproducible protocol based on PBMDCs. This should allow a wider acceptance of PBMDCs as a reliable test system for the detection of human skin sensitizers and the inclusion of this protocol in an integrated testing strategy. PMID- 20932891 TI - Genotoxicity of marine sediments in the fish hepatoma cell line PLHC-1 as assessed by the Comet assay. AB - The main goal of this study was to test the usefulness of the Comet assay in the PLHC-1 hepatoma fish cell line as a tool for detecting the presence of genotoxic compounds in contaminated marine sediments. The system has been tested using both model chemicals (benzo[a]pyrene (B[a]P) and ethyl methanesulfonate (EMS)) and extracts of sediment samples obtained with solvent dichloromethane/methanol. For all of the analysed sediment extracts as well as for the model chemicals a concentration dependent genotoxic effect was observed. The sediment with the highest observed genotoxic potential was additionally extracted using various solvents in order to test which class of compounds, according to their polarity, is most responsible for the observed genotoxic effect. Non-polar solvents (cyclohexane and dichloromethane) yielded stronger genotoxic effect but the highest level of DNA damage was determined after exposure to sediment extract obtained with the solvent mixture dichloromethane/methanol which extracts a wide range of contaminants. Our results indicate that the PLHC-1 cell line is a suitable in vitro model in sediment genotoxicity assessment and encourage the use of fish cell lines as versatile tools in ecogenotoxicology. PMID- 20932892 TI - Chemoprotective effect of N-acetylcysteine (NAC) on cellular oxidative damages and apoptosis induced by nano titanium dioxide under UVA irradiation. AB - The chemoprotective effect of N-acetylcysteine (NAC), a sulfhydryl-containing antioxidant, on nano titanium dioxide (nano-TiO(2)) induced oxidative stress and apoptosis in human keratinocyte (HaCaT) cells was assessed. HaCaT cells were pretreated with NAC followed by treatment with 200 MUg/ml nano-TiO(2), then exposed to ultraviolet A (UVA, 365 nm) for 1 h and cultured for 24 h. Intracellular reactive oxygen species (ROS) and nitric oxide (NO) formation, mitochondrial membrane potential (MMP), apoptosis and the content of the lipid peroxidation product malondialdehyde (MDA) were measured. Keratin 6 (K6) mRNA expression was also analyzed. The results showed that NAC strongly inhibited ROS and NO production in nano-TiO(2) treated cells. The extent of lipid peroxidation was also decreased in the presence of NAC. In addition, NAC suppressed nano TiO(2) induced apoptosis and increased K6 mRNA expression. The results indicated that NAC could prevent oxidative stress and apoptosis induced by nano-TiO(2) in HaCaT cells. PMID- 20932893 TI - Development of a mechanistic SAR model for the detection of phototoxic chemicals and use in an integrated testing strategy. AB - Phototoxicity is of increasing concern in dermatology, since modern lifestyle is often associated with exposure to sunlight. The most commonly reported process is via oxidative reactions. Therefore characterizing the "photo-pro-oxidant" potential of a compound early in its industrial development is of utmost interest, especially for compounds likely to undergo sunlight exposure in skin. Today there is a need for filtering compounds to be tested in the 3T3 neutral red uptake in vitro test for phototoxicity since testing requires resources. A computational model aiming at predicting the mechanisms that imply the generation of reactive oxygen species was developed using a diverse set of 56 chemicals having 3T3 NRU data. An historical mechanistic (Q)SAR model developed for polycyclic aromatic hydrocarbons was used to derive the new mechanistic model: descriptors were selected upfront to describe the modeled phenomenon. The historical parabolic relationships between phototoxicity and the energy gap (E(GAP)) between energies of the highest occupied molecular orbital and the lowest unoccupied molecular orbital was confirmed. The model predicts chemicals to be "phototoxic or photodegradable", or "non-phototoxic and non photodegradable". A four-step testing strategy is proposed to enable the reduction of experimental testing with the in silico model implemented as a first screen. PMID- 20932894 TI - Preservation of hepatocellular functionality in cultures of primary rat hepatocytes upon exposure to 4-Me2N-BAVAH, a hydroxamate-based HDAC-inhibitor. AB - Great efforts are being put in the development/optimization of reliable and highly predictive models for high-throughput screening of efficacy and toxicity of promising drug candidates. The use of primary hepatocyte cultures, however, is still limited by the occurrence of phenotypic alterations, including loss of xenobiotic biotransformation capacity. In the present study, the differentiation stabilizing effect of a new histone deacetylase inhibitor 5-(4 dimethylaminobenzoyl)-aminovaleric acid hydroxamide (4-Me(2)N-BAVAH), a structural Trichostatin A (TSA)-analogue with a more favourable pharmaco toxicological profile, was studied at a genome-wide scale by means of microarray analysis. Several genes coding for xenobiotic biotransformation enzymes were found to be positively regulated upon exposure to 4-Me(2)N-BAVAH. For CYP1A1/2B1/3A2, these observations were confirmed by qRT-PCR and immunoblot analysis. In addition, significantly higher 7-ethoxyresorufin-O-deethylase and 7 pentoxyresorufin-O-dealkylase activity levels were measured. These effects were accompanied by an increased expression of CCAAT/enhancer binding protein alpha and hepatic nuclear factor (HNF)4alpha, but not of HNF1alpha. Finally, 4-Me(2)N BAVAH was found to induce histone H3 acetylation at the proximal promoter of the albumin, CYP1A1 and CYP2B1 genes, suggesting that chromatin remodelling is directly involved in the transcriptional regulation of these genes. In conclusion, histone deacetylase inhibitors prove to be efficient agents for better maintaining a differentiated hepatic phenotype in rat hepatocyte cultures. PMID- 20932895 TI - Oxidatively damaged proteins in the early stage of testicular toxicities in male rats by orally administered with a synthetic oestrogen, diethylstilbestrol. AB - The molecular mechanism of severe adverse effects of the endocrine disruptor diethylstilbestrol (DES) on reproductive organs is not currently understood. The effects of DES on testicular proteins were studied in adult male rats orally treated with 0.35 and 3.5mg DES/kg every two days for two weeks before the manifestation of morphological toxicities. Two up-regulated proteins (glutamine synthetase and chaperonin containing TCP1), two down-regulated proteins (thioredoxin-like 1 and testis-specific autoantigen) and two proteins with altered isoelectric points (protein disulfide isomerase [PDI a3] and enolase 1) were identified in DES groups. Carbonylation of PDI a3 was detected. A significant decrease in PDI activity and significant increases in caspase-12 and calpain activities were also found in the group. It is suggested that testicular toxicity by DES was initiated by the down-regulation of thioredoxin-like-1 leading to the cellular redox inbalances, and the resultant oxidative modification of several important proteins involved in protein foldings. PMID- 20932896 TI - S1 to S2 hind- and forelimb projections in the agouti somatosensory cortex: axon fragments morphological analysis. AB - The integration of cutaneous, proprioceptive, and motor information in area S2 seems to be essential for manual object recognition and motor control. Part of the inputs to S2 comes from area S1. However no detailed investigations of the morphology of this projection are available. In the present study we describe and quantify the morphology of axon fragments of S1 to S2 ipsilateral projections in the agouti somatosensory cortex. Two groups of projecting axon arbors in S2 were individually reconstructed in three dimensions using Neurolucida, after a single electrophysiological guided BDA injection in either the forelimb (n=4) or the hindlimb (n=4). Electrophysiological mapping was performed 15 days after injections, allowing the localization of S2. Cluster analysis of 40 fragments after hindlimb and 40 after forelimb distinguished two clusters of terminals designated as type I and type II. On average, Type I fragments had greater surface areas and segment lengths than type II fragments, whereas type II fragments had higher number of terminal boutons, number of segments and branching points/mm than type I fragments. Type I corresponded to 58% of the axons projecting from the hindlimb representation in S1 whereas 63% of the sample originating from the forelimb representation in S1 corresponded to type II axons. The results suggest possible parallel processing by two stereotyped classes of axon terminals in the S1 to S2 projections that may represent at least part of the circuitry groundwork associated with distinct somatomotor skills of these limbs in agoutis. PMID- 20932897 TI - Sustained lung activity of a novel chimeric protein, SOD2/3, after intratracheal administration. AB - Delivery of recombinant superoxide dismutase to the lung is limited by its short half-life and poor tissue penetration. We hypothesized that a chimeric protein, SOD2/3, containing the enzymatic domain of manganese superoxide dismutase (SOD2) and the heparan-binding domain of extracellular superoxide dismutase (SOD3), would allow for the delivery of more sustained lung and pulmonary vascular antioxidant activity compared to SOD2. We administered SOD2/3 to rats by intratracheal (i.t.), intraperitoneal (i.p.), or intravenous (i.v.) routes and evaluated the presence, localization, and activity of lung SOD2/3 1 day later using Western blot, immunohistochemistry, and SOD activity gels. The effect of i.t. SOD2/3 on the pulmonary and systemic circulation was studied in vivo in chronically catheterized rats exposed to acute hypoxia. Active SOD2/3 was detected in lung 1 day after i.t. administration but not detected after i.p. or i.v. SOD2/3 administration or i.t. SOD2. The physiologic response to acute hypoxia, vasoconstriction in the pulmonary circulation and vasodilation in the systemic circulation, was enhanced in rats treated 1 day earlier with i.t. SOD2/3. These findings indicate that i.t. administration of SOD2/3 effectively delivers sustained enzyme activity to the lung as well as pulmonary circulation and has a longer tissue half-life compared to native SOD2. Further testing in models of chronic lung or pulmonary vascular diseases mediated by excess superoxide should consider the longer tissue half-life of SOD2/3 as well as its potential systemic vascular effects. PMID- 20932899 TI - Lymphatic ontogeny and effect of hypoplasia in developing lung. AB - The pulmonary lymphatic vasculature plays a vital role in maintaining fluid homeostasis required for efficient gas exchange at capillary alveolar barriers and contributes to lung fluid clearance at birth. To further understanding of pulmonary lymphatic function at birth, lineage-tracing analysis of mouse lung was used. Lineage analysis confirmed that lymphatic endothelial cells (LEC) bud from extrapulmonary lymphatics and demonstrated that LEC migrate into developing lung along precise pathways. LEC cluster first in the primary bronchovascular region then along the secondary broncho-arterial regions and along veins. Small lymphatic vessels in distal lung develop from LEC that have migrated into lung mesenchyme from the extrapulmonary lymphatics. Finally, proximal and distal lymphatics remodel to form vessels with lumens in stereotypical locations. Loss of function analysis with lung-specific expression of a secreted form of the extracellular domain of vascular endothelial growth factor receptor-3 (dnR3) caused significant embryonic pulmonary lymphatic hypoplasia with fourfold reduction in distal LEC. Lung-specific expression of dnR3 did not affect blood vascular development, overall lung organogenesis or lymphatic development in other organs. Neonatal mice with pulmonary lymphatic hypoplasia developed respiratory distress with significantly increased mortality. During the transition to air breathing, lymphatic hypoplasia adversely affected fetal lung fluid clearance as determined by wet/dry weight analysis and morphometric analysis of bronchovascular cuffing and mesenchymal thickening. Surfactant synthesis was unaffected. Together, these data demonstrate that lung lymphatics develop autonomously and that pulmonary lymphatic hypoplasia is detrimental to survival of the neonate due to impaired lung fluid clearance. PMID- 20932898 TI - Calcium-mediated mechanisms of cystic expansion. AB - In this review, we will discuss several well-accepted signaling pathways toward calcium-mediated mechanisms of cystic expansion. The second messenger calcium ion has contributed to a vast diversity of signal transduction pathways. We will dissect calcium signaling as a possible mechanism that contributes to renal cyst formation. Because cytosolic calcium also regulates an array of signaling pathways, we will first discuss cilia-induced calcium fluxes, followed by Wnt signaling that has attributed to much-discussed planar cell polarity. We will then look at the relationship between cytosolic calcium and cAMP as one of the most important aspects of cyst progression. The signaling of cAMP on MAPK and mTOR will also be discussed. We infer that while cilia-induced calcium fluxes may be the initial signaling messenger for various cellular pathways, no single signaling mediator or pathway is implicated exclusively in the progression of the cystic expansion. This article is part of a Special Issue entitled: Polycystic Kidney Disease. PMID- 20932900 TI - Predicting the clinical effect of a short acting bronchodilator in individual patients using artificial neural networks. AB - Artificial neural networks were used in this study to model the relationships between in vitro data, subject characteristics and in vivo outcomes from N=18 mild-moderate asthmatics receiving monodisperse salbutamol sulphate aerosols of 1.5, 3 and 6 MUm mass median aerodynamic diameter in a cumulative dosing schedule of 10, 20, 40 and 100 MUg. Input variables to the model were aerodynamic particle size (APS), body surface area (BSA), age, pre-treatment forced expiratory volume in one-second (FEV(1)), forced vital capacity, cumulative emitted drug dose and bronchodilator reversibility to a standard salbutamol sulphate 200 MUg dose MDI (REV(%)). These factors were used by the model to predict the bronchodilator response at 10 (T10) and 20 (T20) min after receiving each of the 4 doses for each of the 3 different particle sizes. Predictability was assessed using data from selected patients in this study, which were set aside and not used in model generation. Models reliably predicted DeltaFEV(1)(%) in individual subjects with non-linear determinants (R(2)) of >= 0.8. The average error between predicted and observed DeltaFEV(1)(%) for individual subjects was <4% across the cumulative dosing regimen. Increases in APS and drug dose gave improved DeltaFEV(1)(%). Models also showed trends towards improved responses in younger patients and those having greater REV(%), whilst BSA was also shown to influence clinical effect. These data show that APS can be used to discriminate predictably between aerosols giving different bronchodilator responses across a cumulative dosing schedule, whilst patient characteristics can be used to reliably estimate clinical response in individual subjects. PMID- 20932901 TI - Computer simulations for bioequivalence trials: selection of analyte in BCS drugs with first-pass metabolism and two metabolic pathways. AB - The objective of this work is to use a computer simulation approach to define the most sensitive analyte for in vivo bioequivalence studies of all types of Biopharmaceutics Classification System (BCS) drugs undergoing first-pass hepatic metabolism with two metabolic pathways. A semi-physiological model was developed in NONMEM VI to simulate bioequivalence trials. Four BCS classes (from Class I to IV) of drugs, with three possible saturation scenarios (non-saturation, saturation and saturation of only the major route of metabolism), two (high or low) dose schemes, and six types of pharmaceutical quality for the drug products were simulated. The number of investigated scenarios was 144 (4 * 3 * 2 * 6). The parent drug is the most sensitive analyte for bioequivalence trials in all the studied scenarios. Metabolite data does not show sensitivity to detect differences in pharmaceutical quality or it gives the same information as the parent compound. An interesting point to notice is the case of class I drugs administered at a high dose when the principal metabolic route is saturated and the secondary one is not saturated. In this case a substantial reduction in dissolution rate (as it could occur in the case of a prolonged release formulation developed as a line extension of an immediate release formulation) leads to a considerable increase in the AUC of the major metabolite whose formation is saturated supporting the need to require pharmacokinetic and clinical data for new prolonged release medicinal products. PMID- 20932902 TI - Assessment of gastrointestinal pH, fluid and lymphoid tissue in the guinea pig, rabbit and pig, and implications for their use in drug development. AB - Laboratory animals are often used in drug delivery and research. However, basic information about their gastrointestinal pH, fluid volume, and lymphoid tissue is not completely known. We have investigated these post-mortem in healthy guinea pigs, rabbits and pigs, to assess their suitability for pre-clinical studies by comparing the results with reported human literature. The mean gastric pH (fed ad libitum) was 2.9 and 4.4 in guinea pig and pig, respectively. In contrast, a very low pH (1.6) was recorded in the rabbits. The small intestinal pH was found in the range of 6.4-7.4 in the guinea pigs and rabbits, whereas lower pH (6.1-6.7) was recorded in the pig, which may have consequences for ionisable or pH responsive systems when tested in pig. A relatively lower pH than in the small intestine was found in the caecum (6.0-6.4) and colon (6.1-6.6) of the guinea pig, rabbit and the pig. The water content in the gastrointestinal tract of guinea pig, rabbit and pig was 51g, 153g and 1546g, respectively. When normalized to the body weight, the guinea pig, had larger amounts of water compared to the rabbit and the pig (guinea pig>rabbit>pig); in contrast, a reverse order was found when normalized to per unit length of the gut (guinea pig0.0001) and adiponectin (p=0.0002) were higher and lower in obese children respectively. OPG was lower in obese children (p=0.01), being inversely related to free leptin (p=0.009), total body and truncal fat mass (both p=0.01). RANKL was inversely related to free leptin in children with prior fracture (p=0.03). CTx was higher in obese children (p=0.003). Free leptin was positively associated with both CTx (p=0.03) and P1NP (p=0.02). DKK1 was inversely related to adiponectin (p=0.02). CONCLUSION: Bone formation relative to resorption was reduced in obese children; this difference was accentuated in those with prior fracture. Adipokines may regulate these changes. Osteoprotegerin may play a fundamental role in the failure of obese children to accrue bone mass appropriately. PMID- 20932950 TI - WITHDRAWN: Characterization of botulinum progenitor neurotoxin A complexes by blue native gel electrophoresis and mass spectrometry. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 20932949 TI - Lithium chloride attenuates BMP-2 signaling and inhibits osteogenic differentiation through a novel WNT/GSK3- independent mechanism. AB - Lithium inhibition of glycogen synthase kinase3 (GSK3) activity has been shown to mimic the canonical WNT signaling. Analogous to WNT, lithium prevents GSK3 mediated phosphorylation of cytosolic transcription factor beta-catenin and its subsequent degradation by the proteasome complex. Although stabilization of beta catenin in osteoblasts has been shown to promote bone mass accrual in a mouse model, several studies reported inhibitory effects of lithium supplements on the osteogenic differentiation of cultured mesenchymal stem cells. One possible explanation for these apparent contradictory findings might be that lithium affects the differentiation of osteoblast progenitors through additional signaling events, which independently or in concert with WNT signaling, affect the bone resorption activities in vivo. In the current study, we used murine MC3T3-E1 pre-osteoblasts and a pluripotent mesenchymal cell line C2C12 to investigate lithium effects during the early stages of osteoblast differentiation. We demonstrate here that lithium inhibits BMP-2 signaling to affect osteogenic differentiation in both cell lines. Lithium treatment reduces BMP-2-induced SMAD 1,5,8 phosphorylation in both MC3T3-E1 and C2C12 cells without affecting their dephosphorylation. Additionally, in MC3T3-E1 cells, lithium attenuates BMP-2-induced osteogenic differentiation through GSK3 inhibition; while in C2C12 cells, these negative effects of lithium ions on BMP-2 signaling do not rely on GSK3 inhibition or activation of canonical WNT signaling. Our work suggests the presence of a novel GSK3/WNT-independent mechanism of lithium action during the early stages of osteogenic differentiation. PMID- 20932951 TI - Histamine and tele-methylhistamine quantification in cerebrospinal fluid from narcoleptic subjects by liquid chromatography tandem mass spectrometry with precolumn derivatization. AB - An ultra-performance liquid chromatography tandem mass spectrometry (UPLCTM MS/MS) assay was developed for the simultaneous analysis of histamine, its major metabolite tele-methylhistamine, and an internal standard (N-tele-(R)-alpha dimethylhistamine) from human cerebrospinal fluid (CSF) samples. The method involves derivatization of primary amines with 4-bromobenzenesulfonyl chloride and subsequent analysis by reversed phase liquid chromatography with mass spectrometry detection and positive electrospray ionization. The separation of derivatized biogenic amines was achieved within 3.5 min on an Acquity(r) BEH C(18) column by elution with a linear gradient of acetonitrile/water/formic acid (0.1%). The assay was linear in the concentration range of 50-5000 pM for each amine (5.5-555 pg/ml for histamine and 6.25-625 pg/ml for tele-methylhistamine). For repeatability and precision determination, coefficients of variation (CVs) were less than 11.0% over the tested concentration ranges, within acceptance criteria. Thus, the developed method provides the rapid, easy, highly sensitive, and selective requirement to quantify these amines in human CSF. No significant difference was found in the mean +/- standard error levels of these amines between a group of narcoleptic patients (histamine=392 +/- 64 pM, tele methylhistamine=2431 +/- 461 pM, n=7) and of neurological control subjects (histamine=402 +/- 72 pM, tele-methylhistamine=2209 +/- 463 pM, n=32). PMID- 20932952 TI - Enzymes of the mevalonate pathway of isoprenoid biosynthesis. AB - The mevalonate pathway accounts for conversion of acetyl-CoA to isopentenyl 5 diphosphate, the versatile precursor of polyisoprenoid metabolites and natural products. The pathway functions in most eukaryotes, archaea, and some eubacteria. Only recently has much of the functional and structural basis for this metabolism been reported. The biosynthetic acetoacetyl-CoA thiolase and HMG-CoA synthase reactions rely on key amino acids that are different but are situated in active sites that are similar throughout the family of initial condensation enzymes. Both bacterial and animal HMG-CoA reductases have been extensively studied and the contrasts between these proteins and their interactions with statin inhibitors defined. The conversion of mevalonic acid to isopentenyl 5-diphosphate involves three ATP-dependent phosphorylation reactions. While bacterial enzymes responsible for these three reactions share a common protein fold, animal enzymes differ in this respect as the recently reported structure of human phosphomevalonate kinase demonstrates. There are significant contrasts between observations on metabolite inhibition of mevalonate phosphorylation in bacteria and animals. The structural basis for these contrasts has also recently been reported. Alternatives to the phosphomevalonate kinase and mevalonate diphosphate decarboxylase reactions may exist in archaea. Thus, new details regarding isopentenyl diphosphate synthesis from acetyl-CoA continue to emerge. PMID- 20932953 TI - Ketoconazole and miconazole alter potassium homeostasis in Saccharomyces cerevisiae. AB - The effects of ketoconazole and miconazole uptake on K(+) transport and the internal pH of Saccharomyces cerevisiae were studied. The uptake of both drugs was very fast, linear with concentration and not dependent on glucose, indicating entrance by diffusion and concentrating inside. Low (5.0MUM) to intermediate concentrations (40MUM) of both drugs produced a glucose-dependent K(+) efflux; higher ones also produced a small influx of protons, probably through a K(+)/H(+) exchanger, resulting in a decrease of the internal pH of the cells and the efflux of material absorbing at 260nm and phosphate. The cell membrane was not permeabilized. The K(+) efflux with miconazole was dependent directly on the medium pH. This efflux results in an increased membrane potential, responsible for an increased Ca(2+) uptake and other effects. These effects were not observed with two triazolic antifungals. A decrease of the Zeta (zeta) potential was observed at low concentrations of miconazole. Although the main effect of these antifungals is the inhibition of ergosterol synthesis, K(+) efflux is an important additional effect to be considered in their therapeutic use. Under certain conditions, the use of single mutants of several transporters involved in the movements of K(+) allowed to identify the participation of several antiporters in the efflux of the cation. PMID- 20932955 TI - Activation of astrocytes in the spinal cord contributes to the development of bilateral allodynia after peripheral nerve injury in rats. AB - Activation of spinal cord microglia and astrocytes after peripheral nerve injury contributes to the development of behavioral hypersensitivity. Suppression of spinal cord glial activation attenuates the development of nerve injury-induced allodynia. The contribution of spinal cord glia to existing allodynia, however, is not known. We investigated whether intrathecally administered propentofylline, a glial inhibitor, reverses existing allodynia after nerve injury. Male Sprague Dawley rats underwent L5 spinal nerve transection, and mechanical allodynia was assessed by measuring hind paw withdrawal thresholds bilaterally using von Frey filaments. Rats received either saline or propentofylline (1, 3, and 10 MUg/d) for 7 days (days 0-7) by intrathecal infusion with an osmotic minipump. Other groups of rats received either intrathecal infusion of saline or propentofylline (10 MUg/d) for 7 days on days 14-21 or 60-67 after surgery. After completing the intrathecal infusion, lumbar spinal cord sections were assessed for immunostaining of astrocytic glial fibrillary acidic protein and microglial OX 42. Propentofylline infusion on days 0-7 suppressed development of allodynia in both the ipsilateral and contralateral hind paws in a dose-dependent manner. Propentofylline treatment on days 14-21 or 60-67 did not reverse existing allodynia. Propentofylline infusion (10 MUg/d) inhibited astrocytic activation bilaterally on days 0-7, 14-21, and 60-67 and inhibited microglial activation on days 14-21 but not on days 0-7 and 60-67. These results suggest that activation of spinal glia, especially astrocytes, dominantly contributes to the development of neuropathic pain and also to mirror-image pain. PMID- 20932954 TI - Effects of individual segmental trisomies of human chromosome 21 syntenic regions on hippocampal long-term potentiation and cognitive behaviors in mice. AB - As the genomic basis for Down syndrome (DS), human trisomy 21 is the most common genetic cause of intellectual disability in children and young people. The genomic regions on human chromosome 21 (Hsa21) are syntenic to three regions in the mouse genome, located on mouse chromosome 10 (Mmu10), Mmu16, and Mmu17. Recently, we have developed three new mouse models using chromosome engineering carrying the genotypes of Dp(10)1Yey/+, Dp(16)1Yey/+, or Dp(17)1Yey/+, which harbor a duplication spanning the entire Hsa21 syntenic region on Mmu10, Mmu16, or Mmu17, respectively. In this study, we analyzed the hippocampal long-term potentiation (LTP) and cognitive behaviors of these models. Our results show that, while the genotype of Dp(17)1Yey/+ results in abnormal hippocampal LTP, the genotype of Dp(16)1Yey/+ leads to both abnormal hippocampal LTP and impaired learning/memory. Therefore, these mutant mice can serve as powerful tools for further understanding the mechanism underlying cognitively relevant phenotypes associated with DS, particularly the impacts of different syntenic regions on these phenotypes. PMID- 20932956 TI - Brain-derived neurotrophic factor (BDNF) and polysialylated-neural cell adhesion molecule (PSA-NCAM): codistribution in the human brainstem precerebellar nuclei from prenatal to adult age. AB - Occurrence and distribution of the neurotrophin brain-derived neurotrophic factor (BDNF) and polysialylated-neural cell adhesion molecule (PSA-NCAM), a neuroplasticity marker known to modulate BDNF signalling, were examined by immunohistochemistry in the human brainstem precerebellar nuclei at prenatal, perinatal and adult age. Western blot analysis performed in human brainstem showed for both molecules a single protein band compatible with the molecular weight of the dimeric form of mature BDNF and with that of PSA-NCAM. Detectability of both molecules up to 72h post-mortem was also assessed in rat brain. In neuronal perikarya, BDNF-like immunoreactivity (LI) appeared as intracytoplasmic granules, whereas PSA-NCAM-LI appeared mostly as peripheral staining, indicative of membrane labelling; immunoreactivity to both substances also labelled nerve fibres and terminals. BDNF- and PSA-NCAM-LI occurred in the external cuneate nucleus, perihypoglossal nuclei, inferior olive complex, arcuate nucleus, lateral reticular formation, vestibular nuclei, pontine reticulotegmental and paramedian reticular nuclei, and pontine basilar nuclei. With few exceptions, for both substances the distribution pattern detected at prenatal age persisted later on, though the immunoreactivity appeared often higher in pre- and full-term newborns than in adult specimens. The results obtained suggest that BDNF operates in the development, maturation, maintenance and plasticity of human brainstem precerebellar neuronal systems. They also imply a multiple origin for the BDNF-LI of the human cerebellum. The codistribution of BDNF- and PSA-NCAM-LI in analyzed regions suggests that PSA-NCAM may modulate the functional interaction between BDNF and its high and low affinity receptors, an issue worth further analysis, particularly in view of the possible clinical significance of neuronal trophism in cerebellar neurodegenerative disorders. PMID- 20932957 TI - Natural antioxidants synergistically enhance the anticancer potential of AP9-cd, a novel lignan composition from Cedrus deodara in human leukemia HL-60 cells. AB - Antioxidants have been used as adjuvant with anticancer therapy to synergize the potential of the anti-neoplastic therapeutics. Based on the fact, we have studied the effect of three natural antioxidants curcumin, silymarin and acteoside on AP9 cd (standardized lignan composition from Cedrus deodara) induced cytotoxicity in human leukemia HL-60 cells. The antioxidant potential of individual test compounds was first evaluated with ferric reducing antioxidant power (FRAP) test, which revealed that all four molecules behave as antioxidants. The apoptotic potential of AP9-cd was significantly enhanced in HL-60 cells in the presence of curcumin, silymarin and acteoside. It was confirmed by using various models like MTT assay, DNA fragmentation, nuclei condensation, sub-Go DNA population, Annexin V-FITC binding, ROS depletion and immunoblotting in HL-60 cells. AP9-cd and individual antioxidants alone at low doses (10MUg and 10MUM, respectively) have meager or no cytotoxicity in HL-60 cells, whereas in mutual combinations, there were 2-3 times enhancement in Annexin-V-FITC and sub-Go DNA population. Moreover, prominent DNA ladders were observed at low doses of AP9-cd in combinations with various antioxidants. The Hoechst staining of the nucleus also revealed the same results for the HL-60 cells treated with AP9-cd and different antioxidants. The molecular diagnostics revealed that the combinations induced a strong antioxidant effect which was correlated with the downregulation of NF-kappaB expression in the nucleus. Out of the three antioxidants, curcumin was found to be more potent than acteoside and silymarin in terms of enhancing the apoptotic potential of AP9 cd. These results propose an important role of natural antioxidant as adjuvant to enhance the anticancer potential of AP9-cd and more likely other anti-neoplastic therapeutics. PMID- 20932958 TI - Interaction of 1,3,4-thiadiazolium mesoionic derivatives with mitochondrial membrane and scavenging activity: Involvement of their effects on mitochondrial energy-linked functions. AB - The aim of this work was to assess the significance of the interaction of the 1,3,4-thiadiazolium derivatives MI-J, MI-4F and MI-2,4diF with mitochondrial membrane and their effects on energy-linked functions. Mitochondrial swelling in the absence of substrate was inhibited by all derivatives; however, the fluorine derivatives were most effective. MI-4F decreased swelling by ~32% even at the lowest concentration (65 nmol mg(-1) protein), reaching ~67% at the concentration of 130 nmol mg(-1) protein. Swelling of mitochondria in the presence of oxidizable substrates was also strongly decreased by all derivatives. This effect was more pronounced when using glutamate plus malate, and also fluorine derivatives, which promoted complete inhibition at all concentrations (6.5-130 nmol mg(-1) protein). Swelling occurred when succinate was the substrate in the presence of MI-J (6.5-65 nmol mg(-1) protein); however, the shrinkage rate was strongly decreased. MI-4F and MI-2,4diF also inhibited swelling, with total inhibition occurring at a concentration of 65 nmol mg(-1) protein. Lipid peroxidation induced by Fe(3+)-ADP/2-oxoglutarate in isolated mitochondria was inhibited time- and dose-dependently by the derivatives, reaching complete inhibition at the highest concentration (80 nmol mg(-1) protein). However, when lipid peroxidation was initiated by peroxyl radicals generated from AAPH, the inhibition was less intense, reaching ~50%, ~40% and ~58% with MI-J, MI-4F and MI 2,4diF (80 nmol mg(-1) protein), respectively. The mesoionic compounds also showed superoxide radical scavenging ability of ~22%, ~32% and ~40% (80 nmol mg( 1) protein), respectively. Fluorescence polarization experiments showed that the derivatives are able to enter the bilayer, decreasing its fluidity in the hydrophobic DMPC membrane region and ordering the fluid phase. Our results suggest that MI-J, MI-4F and MI-2,4diF interact significantly, albeit in different modes, with mitochondrial membrane, and that fluorine derivatives seem to alter the membrane's properties more markedly. PMID- 20932959 TI - Sub-chronic administration of doxorubicin to Wistar rats results in oxidative stress and unaltered apoptotic signaling in the lung. AB - Despite the vast published data on cardiac toxicity, there is still little work done regarding the toxicity of the antineoplastic agent Doxorubicin (DOX) in the lung. The aim of the present work was to determine if DOX causes alterations in selected apoptotic proteins and oxidative stress in the lung, in a similar manner to what occurs in the heart. For that purpose, lungs from Wistar-Han rats sub chronically treated with vehicle or DOX for seven weeks were collected and analyzed concerning several proteins involved in mitochondrial permeabilization and apoptotic pathways, including p53, Bax and Bcl-2 and different oxidative stress markers. After sub-chronic DOX treatment, no alterations in lung proteins involved in mitochondrial membrane permeabilization or caspase 3 and 9-like activities were found. Nevertheless, an increase in malondialdehyde levels and a decrease in the lung concentration of vitamin E were detected, despite no alterations in reduced and oxidized glutathione. The results obtained indicate for the first time that lungs from DOX-treated rats appear to be susceptible to increased lipid peroxidation, which can explain some cases of DOX-induced lung toxicity. PMID- 20932960 TI - Naringenin, a flavanone inhibits the proliferation of cerebrally implanted C6 glioma cells in rats. AB - Tumor cells are able to survive and proliferate in spite of their increased oxidative stress. This was taken as a hint for the implication of oxidants/antioxidants in the proliferation of glial-tumor cells. In the present study, an anti-proliferative effect of Naringenin, an antioxidant against cerebrally implanted C6 glioma cells in rats has been investigated. The status of lipid peroxidation/antioxidants, expressions of protein kinase C, nuclear factor kappaB, cyclin D1, cyclin dependent kinase 4, proliferating cell nuclear antigen, vascular endothelial growth factor, argyophillic nucleolar organizing regions and histopathology of brain tissues of control and experimental rats were analyzed. On supplementation of naringenin (50mg/kg BW for 30 days) to glioma induced rats, there was a reduction in lipid peroxidation with an increased antioxidant status. There was a significant decrease in the expressions of protein kinase C, nuclear factor kappaB, cyclin D1 and cyclin dependent kinase 4 on naringenin treatment. Further, the drug could modulate the glial-tumor cell proliferation as evidenced from the histopathological findings, argyophillic nucleolar organizing regions staining, proliferating cell nuclear antigen and vascular endothelial growth factor immunostaining. The findings suggest that naringenin could underlie the inhibition of glial tumor cell proliferation in C6 glioma models of rat. PMID- 20932961 TI - Protective role of arzanol against lipid peroxidation in biological systems. AB - This study examines the protective effect of arzanol, a pyrone-phloroglucinol etherodimer from Helichrysum italicum subsp. microphyllum, against the oxidative modification of lipid components induced by Cu(2+) ions in human low density lipoprotein (LDL) and by tert-butyl hydroperoxide (TBH) in cell membranes. LDL pre-treatment with arzanol significantly preserved lipoproteins from oxidative damage at 2h of oxidation, and showed a remarkable protective effect on the reduction of polyunsaturated fatty acids and cholesterol levels, inhibiting the increase of oxidative products (conjugated dienes fatty acids hydroperoxides, 7beta-hydroxycholesterol, and 7-ketocholesterol). Arzanol, at non-cytotoxic concentrations, exerted a noteworthy protection on TBH-induced oxidative damage in a line of fibroblasts derived from monkey kidney (Vero cells) and in human intestinal epithelial cells (Caco-2), decreasing, in both cell lines, the formation of oxidative products (hydroperoxides and 7-ketocholesterol) from the degradation of unsaturated fatty acids and cholesterol. The cellular uptake and transepithelial transport of the compound were also investigated in Caco-2 cell monolayers. Arzanol appeared to accumulate in Caco-2 epithelial cells. This phenol was able to pass through the intestinal Caco-2 monolayers, the apparent permeability coefficients (P(app)) in the apical-to-basolateral and basolateral to-apical direction at 2h were 1.93+/-0.36*10(-5) and 2.20+/-0.004*10(-5)cm/s, respectively, suggesting a passive diffusion pathway. The results of the work qualify arzanol as a potent natural antioxidant with a protective effect against lipid oxidation in biological systems. PMID- 20932962 TI - Chlorinated and brominated phosphatidylcholines are generated under the influence of the Fenton reagent at low pH-a MALDI-TOF MS study. AB - Lipid (phospholipid) oxidation is an increasingly important research topic due to the significant physiological relevance. The Fenton reaction, i.e. the transition metal catalyzed decomposition of H(2)O(2) is frequently used to generate hydroxyl radicals (HO*). Lipids with unsaturated fatty acyl residues are primarily converted by HO* radicals into peroxides. In contrast, chloro- and bromohydrins as well as dihalogenides are formed by the addition of HOCl or HOBr to the olefinic groups of the fatty acyl residues of lipids or under the influence of the enzyme myeloperoxidase (MPO) from Cl(-) and H(2)O(2). We will show here by using MALDI-TOF MS for product analysis that halogenated products may also be generated in the presence of the Fenton reagent, if either FeCl(2) or FeBr(2) is used. In the presence of FeSO(4), however, peroxides are exclusively generated. It will also be shown that the generation of halogen-containing products is a competing reaction with the cleavage of the double bond under generation of the corresponding aldehyde or carboxylic acid that is favored at prolonged incubation times and at elevated pH. PMID- 20932963 TI - New pH-sensitive liposomes containing phosphatidylethanolamine and a bacterial dirhamnolipid. AB - Phosphatidylethanolamine-based pH-sensitive liposomes of various compositions have been described as efficient systems for cytoplasmic delivery of molecules into cells. Incorporation of an amphiphile of appropriate structure is needed for the stabilization and performance of these vesicles. Among the wide variety of interesting activities displayed by Pseudomonas aeruginosa dirhamnolipids (diRL), is their capacity to stabilize bilayer structures in phosphatidylethanolamine systems. In this work, X-ray scattering, dynamic light scattering, fluorescence spectroscopy and fluorescence microscopy have been used to study the structure and pH-dependent behaviour of phosphatidylethanolamine/diRL liposomes. We show that diRL, in combination with dioleoylphosphatidylethanolamine (DOPE), forms stable multilamellar and unilamellar liposomes. Acidification of DOPE/diRL vesicles leads to membrane destabilization, fusion, and release of entrapped aqueous vesicle contents. Finally, DOPE/diRL pH-sensitive liposomes act as efficient vehicles for the cytoplasmic delivery of fluorescent probes into cultured cells. It is concluded that DOPE/diRL form stable pH-sensitive liposomes, and that these liposomes are incorporated into cultured cells through the endocytic pathway, delivering its contents into the cytoplasm, which means a potential use of these liposomes for the delivery of foreign substances into living cells. Our results establish a new application of diRL as a bilayer stabilizer in phospholipid vesicles, and the use of diRL-containing pH-sensitive liposomes as delivery vehicles. PMID- 20932964 TI - AFM study of the thermotropic behaviour of supported DPPC bilayers with and without the model peptide WALP23. AB - Temperature-controlled Atomic Force Microscopy (TC-AFM) in Contact Mode is used here to directly image the mechanisms by which melting and crystallization of supported, hydrated DPPC bilayers proceed in the presence and absence of the model peptide WALP23. Melting from the gel L(beta)' to the liquid-crystalline L(alpha) phase starts at pre-existing line-type packing defects (grain boundaries) in absence of the peptide. The exact transition temperature is shown to be influenced by the magnitude of the force exerted by the AFM probe on the bilayer, but is higher than the main transition temperature of non-supported DPPC vesicles in all cases due to bilayer-substrate interactions. Cooling of the fluid L(alpha) bilayer shows the formation of the line-type defects at the borders between different gel-phase regions that originate from different nuclei. The number of these defects depends directly on the rate of cooling through the transition, as predicted by classical nucleation theory. The presence of the transmembrane, synthetic model peptide WALP23 is known to give rise to heterogeneity in the bilayer as microdomains with a striped appearance are formed in the DPPC bilayer. This striated phase consists of alternating lines of lipids and peptide. It is shown here that melting starts with the peptide-associated lipids in the domains, whose melting temperature is lowered by 0.8-2.0 degrees C compared to the remaining, peptide-free parts of the bilayer. The stabilization of the fluid phase is ascribed to adaptations of the lipids to the shorter peptide. The lipids not associated with the peptide melt at the same temperature as those in the pure DPPC supported bilayer. PMID- 20932965 TI - Serum tartrate-resistant acid phosphatase 5b (TRACP5b) activity as a biomarker for bone metastasis in non-small cell lung cancer patients. AB - BACKGROUND: Diagnosis and follow-up of bone metastasis (BMet) in non-small cell lung cancer (NSCLC) patients usually rely on symptoms and image studies. A serum marker of bone resorption may improve the quality of treatment in such patients. Tartrate-resistant acid phosphatase 5b (TRACP5b) is a specific marker for osteoclasts and we proposed it can be used as a marker of BMet in NSCLC patients. METHODS: In November 2002 till August 2008 serum samples were obtained from 141 newly diagnosed stage IIIA, IIIB or IV NSCLC patients and 41 normal subjects. All patients received baseline bone scintinography examination and evaluation of clinical symptoms as a standard of BMet diagnosis. Patients were divided into 2 groups by having BMet (Group I, n = 72) or not (Group II, n = 69). An in-house immunoassay using a TRACP-specific monoclonal antibody, 14G6, was used to measure the serum TRACP5b activity at pH 6.1. RESULTS: The mean serum TRACP5b activities of Group I, Group II and normal subjects were 3.50 +/- 2.2 3U/l, 2.09 +/- 0.72 U/l and 2.33 +/- 0.52 U/l, respectively. After adjusting for age, stage, gender, and histology in a generalized linear model, Group I has significantly higher TRACP5b activity than Group II (p < 0.001). The receiver operating characteristic analysis established a cutoff value of 2.551 U/l to identify BMet in NSCLC patients with a sensitivity of 63.9% and a specificity of 76.8%. TRACP5b activity declined in patients who responded to treatment (p = 0.047), and elevated in patients who developed new BMet (p = 0.05). CONCLUSIONS: Serum TRACP5b activity test is a potentially useful adjunct in diagnosing and monitoring BMet in NSCLC. Further study is warranted to establish its real value in diagnosis and monitoring of BMet in NSCLC patients. PMID- 20932966 TI - HDL-C concentration is related to markers of absorption and of cholesterol synthesis: Study in subjects with low vs. high HDL-C. AB - BACKGROUND: The antiatherogenic functions of high density lipoprotein (HDL-C) include its role in reverse cholesterol transport, but to what extent the concentration of HDL-C interferes with the whole-body cholesterol metabolism is unknown. Therefore, we measured markers of body cholesterol synthesis (desmosterol and lathosterol) and of intestinal cholesterol absorption (campesterol and beta-sitosterol) in healthy subjects that differ according to their plasma HDL-C concentrations. METHODS: Healthy participants presented either low HDL-C (< 40 mg/dl, n=33, 17 male and 16 female) or high HDL-C (> 60 mg/dl, n=33, 17 male and 16 female), BMI< 30 kg/m2, were paired according to age and gender, without secondary factors that might interfere with their plasma lipid concentrations. Plasma concentrations of non-cholesterol sterols were measured by the combined GC-MS analysis. RESULTS: Plasma desmosterol did not differ between the two groups; however, as compared with the high HDL-C participants, the low HDL-C participants presented higher concentration of lathosterol and lower concentration of the intestinal cholesterol absorption markers campesterol and beta-sitosterol. CONCLUSION: Plasma concentrations of HDL, and not the activities of LCAT and CETP that regulate the reverse cholesterol transport system, correlate with plasma sterol markers of intestinal cholesterol absorption directly, and of cholesterol synthesis reciprocally. PMID- 20932967 TI - Individual blastomeres of 16- and 32-cell mouse embryos are able to develop into foetuses and mice. AB - Cell and developmental studies have clarified how, by the time of implantation, the mouse embryo forms three primary cell lineages: epiblast (EPI), primitive endoderm (PE), and trophectoderm (TE). However, it still remains unknown when cells allocated to these three lineages become determined in their developmental fate. To address this question, we studied the developmental potential of single blastomeres derived from 16- and 32-cell stage embryos and supported by carrier, tetraploid blastomeres. We were able to generate singletons, identical twins, triplets, and quadruplets from individual inner and outer cells of 16-cell embryos and, sporadically, foetuses from single cells of 32-cell embryos. The use of embryos constitutively expressing GFP as the donors of single diploid blastomeres enabled us to identify their cell progeny in the constructed 2n<->4n blastocysts. We showed that the descendants of donor blastomeres were able to locate themselves in all three first cell lineages, i.e., epiblast, primitive endoderm, and trophectoderm. In addition, the application of Cdx2 and Gata4 markers for trophectoderm and primitive endoderm, respectively, showed that the expression of these two genes in the descendants of donor blastomeres was either down- or up-regulated, depending on the cell lineage they happened to occupy. Thus, our results demonstrate that up to the early blastocysts stage, the destiny of at least some blastomeres, although they have begun to express markers of different lineage, is still labile. PMID- 20932968 TI - CYP18A1, a key enzyme of Drosophila steroid hormone inactivation, is essential for metamorphosis. AB - Ecdysteroids are steroid hormones, which coordinate major developmental transitions in insects. Both the rises and falls in circulating levels of active hormones are important for coordinating molting and metamorphosis, making both ecdysteroid biosynthesis and inactivation of physiological relevance. We demonstrate that Drosophila melanogaster Cyp18a1 encodes a cytochrome P450 enzyme (CYP) with 26-hydroxylase activity, a prominent step in ecdysteroid catabolism. A clear ortholog of Cyp18a1 exists in most insects and crustaceans. When Cyp18a1 is transfected in Drosophila S2 cells, extensive conversion of 20-hydroxyecdysone (20E) into 20-hydroxyecdysonoic acid is observed. This is a multi-step process, which involves the formation of 20,26-dihydroxyecdysone as an intermediate. In Drosophila larvae, Cyp18a1 is expressed in many target tissues of 20E. We examined the consequences of Cyp18a1 inactivation on Drosophila development. Null alleles generated by excision of a P element and RNAi knockdown of Cyp18a1 both result in pupal lethality, possibly as a consequence of impaired ecdysteroid degradation. Our data suggest that the inactivation of 20E is essential for proper development and that CYP18A1 is a key enzyme in this process. PMID- 20932970 TI - Phage ESCape: an emulsion-based approach for the selection of recombinant phage display antibodies. AB - Antibody phage display technology is a well established method for selecting specific antibodies against desired targets. Although phage display is the most widely used method of generating synthetic antibodies, it is laborious to perform multiple selections with different antigens simultaneously using conventional manual methods. We have developed a novel approach to the identification and isolation of cells secreting phage encoding desirable antibodies that utilizes compartmentalization and Fluorescence Activated Cell Sorting (FACS). This method, termed Phage Emulsion, Secretion, and Capture (ESCape), allows us to individually query each phage against the antigen. Here, we demonstrate the ability of Phage ESCape to identify novel scFvs against a phosphopeptide epitope of the Her2 kinase from a phage display library containing approximately 10(8) synthetically diversified antibodies. Clones were analyzed by monoclonal phage ELISA against the Her2 phosphopeptide, and positive binders were identified as those showing a signal greater than 3-fold higher than the background signal against an irrelevant antigen. We isolated antibodies recognizing the phosphopeptide in a single round of selection by Phage ESCape, but the strength and specificity of the hits was substantially improved when the library was pre-enriched by a single round of biopanning. By minimizing the selection rounds required for phage display and using a FACS machine as a 'colony picker' equivalent, Phage ESCape has the potential to dramatically increase the throughput of in vitro screening methods. PMID- 20932969 TI - Aqueous humor rapidly stimulates myocilin secretion from human trabecular meshwork cells. AB - Myocilin, a protein associated with the development of glaucoma, is expressed in most eye tissues with highest expression observed in trabecular meshwork cells. In culture, primary human trabecular meshwork cells incubated in 10% fetal bovine serum have reduced myocilin expression compared to in vivo, but incubation in human aqueous humor, their normal in vivo nutrient source, restores myocilin expression to near in vivo levels. To investigate the mechanism by which human aqueous humor stimulates myocilin accumulation in conditioned media from normal human trabecular meshwork cells, three independent trabecular meshwork cell lines were cultured in Dulbecco's Modified Eagle's Medium (DMEM) containing various supplements: fetal bovine serum (10%), human serum (0.2%), porcine aqueous humor (50%), bovine serum albumin (0.1%), dexamethasone (10(-7)M), human aqueous humor (50%) or heat-inactivated human aqueous humor (50%). Conditioned media from cultured primary trabecular meshwork cells following incubation in human aqueous humor showed significant accumulation of myocilin in a time- (15 min) and dose dependent manner (half maximal effective concentration ~ 30%) while intracellular myocilin levels decreased. Minimal myocilin accumulation was observed in conditioned media isolated from trabecular meshwork cells cultured in DMEM containing fetal bovine or human serum, bovine serum albumin, porcine aqueous humor, dexamethasone or DMEM alone. Heat inactivation of human aqueous humor nearly eliminated human aqueous humor-stimulated myocilin secretion. Inhibitors of new protein synthesis, gene transcription, the endoplasmic reticulum/Golgi system and endocytic/exocytic secretory pathways failed to inhibit human aqueous humor-stimulated myocilin secretion. Using immunolabeling and transmission electron microscopy, myocilin was found associated with 70-90 nm vesicle-like structures within the cytoplasm of human aqueous humor treated trabecular meshwork cells. These studies suggest that myocilin secretion from trabecular meshwork cells occurs in a Golgi-independent manner following human aqueous humor treatment. Heat-labile factors in human aqueous humor are responsible for the time- and dose-dependent release of myocilin from vesicle-like structures within the cytoplasm of trabecular meshwork cells. PMID- 20932971 TI - Nitric oxide/cGMP signaling in the corpora allata of female grasshoppers. AB - The corpora allata (CA) of various insects express enzymes with fixation resistant NADPHdiaphorase activity. In female grasshoppers, juvenile hormone (JH) released from the CA is necessary to establish reproductive readiness, including sound production. Previous studies demonstrated that female sound production is also promoted by systemic inhibition of nitric oxide (NO) formation. In addition, allatotropin and allatostatin expressing central brain neurons were located in close vicinity of NO generating cells. It was therefore speculated that NO signaling may contribute to the control of juvenile hormone release from the CA. This study demonstrates the presence of NO/cGMP signaling in the CA of female Chorthippus biguttulus. CA parenchymal cells exhibit NADPHdiaphorase activity, express anti NOS immunoreactivity and accumulate citrulline, which is generated as a byproduct of NO generation. Varicose terminals from brain neurons in the dorsal pars intercerebralis and pars lateralis that accumulate cGMP upon stimulation with NO donors serve as intrinsic targets of NO in the CA. Both accumulation of citrulline and cyclic GMP were inhibited by the NOS inhibitor aminoguanidine, suggesting that NO in CA is produced by NOS. These results suggest that NO is a retrograde transmitter that provides feedback to projection neurons controlling JH production. Combined immunostainings and backfill experiments detected CA cells with processes extending into the CC and the protocerebrum that expressed immunoreactivity against the pan-neural marker anti HRP. Allatostatin and allatotropin immunopositive brain neurons do not express NOS but subpopulations accumulate cGMP upon NO-formation. Direct innervation of CA by these peptidergic neurons was not observed. PMID- 20932972 TI - Potassium fluxes across the blood brain barrier of the cockroach, Periplaneta americana. AB - Potassium fluxes across the blood-brain barrier of the cockroach Periplaneta americana were measured using the scanning ion-selective microelectrode technique. In salines containing 15 mM or 25 mMK(+), an efflux of K(+) from the ganglia of isolated nerve cords was counterbalanced by an influx across the connectives. Metabolic inhibition with CN(-) resulted in an increase in K(+) efflux across both the ganglia and the connectives. Depletion of K(+) by chilling the nerve cords in K(+)-free saline was associated with subsequent K(+) influx across the connectives in K(+)-replete saline at room temperature. There were dramatic increases in K(+) efflux across both ganglia and connectives when the nerve cords were exposed to the pore-forming antibiotic amphotericin B. K(+) fluxes across the ventral nerve cord were also altered when paracellular leakage was augmented by transient exposure to 3M urea. K(+) efflux was reduced by the K(+) channel blockers Ba(2+) and tetraethylammonium or by exposure to Ca(2+)-free saline and K(+) efflux from the ganglia was increased by addition of ouabain to the bathing saline. The results provide direct support for a model proposing that K(+) is cycled through a current loop between the ganglia and the connectives and that both the Na(+)/K(+)-ATPase and K(+) channels are implicated in extracellular K(+) homeostasis within the central nervous system. PMID- 20932973 TI - A novel unstructured scaffold based on 4EBP1 enables the functional display of a wide range of bioactive peptides. AB - Target validation using protein aptamers enables the characterization of a specific function of a target protein in an environment that resembles native conditions as closely as possible. A major obstacle to the use of this technology has been the generation of bioactive aptamers, which is dependent on the choice of scaffold. Constraining binding peptides within a particular scaffold does not necessarily result in binding aptamers, as suboptimal presentation of peptides can occur. It is therefore understandable that different peptides might require different scaffolds for optimal presentation. In this article, we describe a novel scaffold protein that bypasses the conventional requirement for scaffolds to have known rigid structures and yet successfully presents several peptides that need to adopt a wide range of conformations for binding to their target protein. Using an unstructured protein, 4EBP1, as scaffold, we successfully construct binding aptamers to three different target proteins: Mdm2, proliferating cell nuclear antigen, and cyclin A. The Mdm2-binding aptamer constructed using 4EBP1 as scaffold demonstrates better stability and bioactivity compared to that constructed using thioredoxin as scaffold. This new scaffold protein, which makes it relatively easy to create bioactive aptamers based on known interaction sequences, will greatly facilitate the aptamer approach to target validation. PMID- 20932974 TI - Biosynthesis of isoprenoids: crystal structure of the [4Fe-4S] cluster protein IspG. AB - IspG protein serves as the penultimate enzyme of the recently discovered non mevalonate pathway for the biosynthesis of the universal isoprenoid precursors, isopentenyl diphosphate and dimethylallyl diphosphate. The enzyme catalyzes the reductive ring opening of 2C-methyl-D-erythritol 2,4-cyclodiphosphate, which affords 1-hydroxy-2-methyl-2-(E)-butenyl 4-diphosphate. The protein was crystallized under anaerobic conditions, and its three-dimensional structure was determined to a resolution of 2.7 A. Each subunit of the c(2) symmetric homodimer folds into two domains connected by a short linker sequence. The N-terminal domain (N domain) is an eight-stranded beta barrel that belongs to the large TIM barrel superfamily. The C-terminal domain (C domain) consists of a beta sheet that is flanked on both sides by helices. One glutamate and three cysteine residues of the C domain coordinate a [4Fe-4S] cluster. Homodimer formation involves an extended contact area (about 1100 A(2)) between helices 8 and 9 of each respective beta barrel. Moreover, each C domain contacts the N domain of the partner subunit, but the interface regions are small (about 430 A(2)). We propose that the enzyme substrate binds to the positively charged surface area at the C terminal pole of the beta barrel. The C domain carrying the iron-sulfur cluster could then move over to form a closed conformation where the substrate is sandwiched between the N domain and the C domain. This article completes the set of three-dimensional structures of the non-mevalonate pathway enzymes, which are of specific interest as potential targets for tuberculostatic and antimalarial drugs. PMID- 20932975 TI - Rapid odorant release in mammalian odour binding proteins facilitates their temporal coupling to odorant signals. AB - We have measured the effect of rat odorant-binding protein 1 on the rates of ligand uptake and liquid-to-air transfer rates with a set of defined odorous compounds. Comparison of observed rate constants (k(obs)) with data simulated over a wide range of different kinetic and thermodynamic regimes shows that the data do not agree with the previously held view of a slow off-rate regime (k(off) <0.0004 s(-1)). We propose that a rapid k(off) would be a necessary requirement for such a system, since slow odorant-release rates would result in significant decorrelation between the olfactory world and odour perception. PMID- 20932976 TI - Probing designability via a generalized model of helical bundle geometry. AB - Because the space of folded protein structures is highly degenerate, with recurring secondary and tertiary motifs, methods for representing protein structure in terms of collective physically relevant coordinates are of great interest. By collapsing structural diversity to a handful of parameters, such methods can be used to delineate the space of designable structures (i.e., conformations that can be stabilized with a large number of sequences)-a crucial task for de novo protein design. We first demonstrate this on natural alpha helical coiled coils using the Crick parameterization. We show that over 95% of known coiled-coil structures are within 1-A C(alpha) root mean square deviation of a Crick-ideal backbone. Derived parameters show that natural geometric space of coiled coils is highly restricted and can be represented by "allowed" conformations amidst a potential continuum of conformers. Allowed structures have (1) restricted axial offsets between helices, which differ starkly between parallel and anti-parallel structures; (2) preferred superhelical radii, which depend linearly on the oligomerization state; (3) pronounced radius-dependent a- and d-position amino acid propensities; and (4) discrete angles of rotation of helices about their axes, which are surprisingly independent of oligomerization state or orientation. In all, we estimate the space of designable coiled-coil structures to be reduced at least 160-fold relative to the space of geometrically feasible structures. To extend the benefits of structural parameterization to other systems, we developed a general mathematical framework for parameterizing arbitrary helical structures, which reduces to the Crick parameterization as a special case. The method is successfully validated on a set of non-coiled-coil helical bundles, frequent in channels and transporter proteins, which show significant helix bending but not supercoiling. Programs for coiled-coil parameter fitting and structure generation are provided via a web interface at http://www.gevorggrigoryan.com/cccp/, and code for generalized helical parameterization is available upon request. PMID- 20932977 TI - Full-length structures of BenM and two variants reveal different oligomerization schemes for LysR-type transcriptional regulators. AB - BenM, a LysR-type transcriptional regulator (LTTR) from the bacterium Acinetobacter baylyi, responds synergistically to benzoate and cis,cis-muconate. With these effectors, BenM activates gene expression during benzoate consumption. Without effectors, BenM represses transcription. Here, X-ray crystallography was used to determine the full-length structures of BenM and two variants that activate transcription without benzoate or cis,cis-muconate: BenM(R156H) and BenM(E226K). Previous studies indicate that these regulators function as tetramers. Here, interconnections between subunits in the crystals prevented the formation of a closed oligomer and highlighted the inherent flexibility of this multidomain regulator. Nevertheless, analysis of subunit interfaces suggested the functional significance of key interactions. The structures of BenM and its variants were nearly identical, implying that transcriptional differences rely on factors beyond major conformational changes defined solely by sequence. Comparisons of BenM with other LTTRs, including unpublished structures in the Protein Data Bank, revealed extensive variation in the relative orientations of DNA-binding domains (DBDs) and effector-binding domains (EBDs). To form dimers, different LTTRs used similar interfaces between two EBDs, each containing two subdomains: EBD-I and EBD-II. Surprisingly, the dimers used three substantially different schemes to form higher-order oligomers. In one scheme used by BenM, oligomer assembly involved contacts between the EBD-II regions and the DBD regions of adjacent subunits. In another scheme, there were no contacts between the EBDs; only the DBDs were involved in tetramer formation. In the third scheme, the oligomer interface involved DBD and EBD-I/EBD-II contacts. These diverse schemes demonstrate novel variation in the oligomeric structures of individual LTTRs within this large and important family. PMID- 20932978 TI - Mouse ApoM displays an unprecedented seven-stranded lipocalin fold: folding decoy or alternative native fold? AB - Mouse apolipoprotein M (m-apoM) displays a 79% sequence identity to human apolipoprotein M (h-apoM). Both proteins are apolipoproteins associated with high density lipoproteins, with similar anticipated biological functions. The structure of h-apoM has recently been determined by X-ray crystallography, which revealed that h-apoM displays, as expected, a lipocalin-like fold characterized by an eight-stranded beta-barrel that encloses an internal fatty-acid-binding site. Surprisingly, this is not true for m-apoM. After refolding from inclusion bodies, the crystal structure of m-apoM (reported here at 2.5 A resolution) displays a novel yet unprecedented seven-stranded beta-barrel structure. The fold difference is not caused by a mere deletion of a single beta-strand; instead, beta-strands E and F are removed and replaced by a single beta-strand A' formed from residues from the N-terminus. Molecular dynamics simulations suggest that m apoM is able to adopt both a seven-stranded barrel structure and an eight stranded barrel structure in solution, and that both folds are comparably stable. Thermal unfolding simulations identify the position where beta-strand exchange occurs as the weak point of the beta-barrel. We wonder whether the switch in topology could have a biological function and could facilitate ligand release, since it goes hand in hand with a narrowing of the barrel diameter. Possibly also, the observed conformation represents an on-pathway or off-pathway folding intermediate of apoM. The difference in fold topology is quite remarkable, and the fold promiscuity observed for m-apoM might possibly provide a glimpse at potential cross-points during the evolution of beta-barrels. PMID- 20932979 TI - Pathogenic mutations in the hydrophobic core of the human prion protein can promote structural instability and misfolding. AB - Transmissible spongiform encephalopathies, or prion diseases, are caused by misfolding and aggregation of the prion protein PrP. These diseases can be hereditary in humans and four of the many disease-associated missense mutants of PrP are in the hydrophobic core: V180I, F198S, V203I and V210I. The T183A mutation is related to the hydrophobic core mutants as it is close to the hydrophobic core and known to cause instability. We used extensive molecular dynamics simulations of these five PrP mutants to compare their dynamics and conformations to those of the wild type PrP. The simulations highlight the changes that occur upon introduction of mutations and help to rationalize experimental findings. Changes can occur around the mutation site, but they can also be propagated over long distances. In particular, the F198S and T183A mutations lead to increased flexibility in parts of the structure that are normally stable, and the short beta-sheet moves away from the rest of the protein. Mutations V180I, V210I and, to a lesser extent, V203I cause changes similar to those observed upon lowering the pH, which has been linked to misfolding. Early misfolding is observed in one V180I simulation. Overall, mutations in the hydrophobic core have a significant effect on the dynamics and stability of PrP, including the propensity to misfold, which helps to explain their role in the development of familial prion diseases. PMID- 20932980 TI - Reduced models for the pacemaker dynamics of cardiac cells. AB - We introduce three- and two-dimensional biophysical models of cardiac excitability derived from a 14-dimensional model of the sinus venosus [Rasmusson, R., et al., 1990. Am. J. Physiol. 259, H352-369]. The reduced models capture normal pacemaking dynamics with a small complement of ionic currents. The two dimensional model bears some similarities with the Morris-Lecar model [Morris, C., Lecar, H., 1981. Biophysical Journal, 35, 193-213]. Because they were reduced from a biophysical model, both models depend on parameters that were obtained from experimental data. Even though the correspondence with the original model is not exact, parameters may be adjusted to tune the reductions to fit experimental traces. As a consequence, unlike other generic low-dimensional models, the models introduced here provide a means to relate physiologically relevant characteristics of pacemaker potentials such as diastolic depolarization, plateau, and action potential frequency, to biophysical variables such as the relative abundance of membrane channels and channel kinetic rates. In particular, these models can lead to an explicit description of how the shape of cardiac action potentials depends on the relative contributions and states of inward and outward currents. By being physiologically derived and computationally efficient, the models presented in this article are useful tools for theoretical studies of excitability at the cellular and network levels. PMID- 20932981 TI - Historical effect in the territoriality of ayu fish. AB - Ayu fish form algae-feeding territories in a river during a non-breeding (growing) season. We build a cost-benefit theory to describe the breakdown and formation of territory. In the early stage of a growing season, all fish hold territories at low densities. Once all territory sites are occupied, excess fish become floaters. When fish density further increases, a phase transition occurs: all the territories suddenly break down and fish form a school. In contrast, when the fish density is decreased, territories are suddenly formed from the school. Both theory and experiments demonstrate that ayu should exhibit a historical effect: the breakdown and formation processes of territory are largely different. In particular, the theory in formation process predicts a specific fish behavior: an "attempted territory holder" that tries to have a small territory emerges just before the formation of territory. PMID- 20932982 TI - Comparison of the effects of erythropoietin and its carbamylated derivative on behaviour and hippocampal neurogenesis in mice. AB - Erythropoietin (EPO), a well known haematopoietic growth factor, possesses neuroprotective and neurotrophic effects which have been recently reported to improve cognition and to modulate emotional processing. We investigated the effects of EPO and of its non-erythropoietic carbamylated derivative (CEPO) on memory- and emotion-related behaviour in the adult mouse. Locomotor activity, memory performances (place and object recognition tasks), anxiety- (light/dark transition test) and despair-like behaviours (tail suspension test) were assessed over 6 weeks of repeated EPO or CEPO administration (40 MUg/kg, twice a week). Given the potential involvement of hippocampal neurogenesis in memory, we also assessed the effects of EPO and CEPO on neurogenesis in the dentate gyrus. Both treatments improved spatial and non-spatial recognition memory and increased the number of NeuN/BrdU double-labeled cells in the dentate gyrus. These effects seem to be, at least partly, independent from an haematopoietic action since administration of CEPO leads to the similar results. Moreover, CEPO decreased, albeit modestly, despair-related behaviour and tended to decrease anxiety-like behaviour. These results suggest that CEPO is as an attractive molecule for the treatment of neuropsychiatric diseases associating memory and/or emotional disorders. PMID- 20932983 TI - Kainic acid-induced neurodegeneration and activation of inflammatory processes in organotypic hippocampal slice cultures: treatment with cyclooxygenase-2 inhibitor does not prevent neuronal death. AB - In the postnatal rodent hippocampus status epilepticus (SE) leads to age- and region-specific excitotoxic neuronal damage, the precise mechanisms of which are still incompletely known. Recent studies suggest that the activation of inflammatory responses together with glial cell reactivity highly contribute to excitotoxic neuronal damage. However, pharmacological tools to attenuate their activation in the postnatal brain are still poorly elucidated. In this study, we investigated the role of inflammatory mediators in kainic acid (KA)-induced neuronal damage in organotypic hippocampal slice cultures (OHCs). A specific cyclooxygenase-2 (COX-2) inhibitor N-[2-(cyclohexyloxy)-4-nitrophenyl] methanesulfonamide (NS-398) was used to study whether or not it could ameliorate neuronal death. Our results show that KA treatment (24 h) resulted in a dose dependent degeneration of CA3a/b pyramidal neurons. Furthermore, COX-2 immunoreactivity was pronouncedly enhanced particularly in CA3c pyramidal neurons, microglial and astrocyte morphology changed from a resting to active appearance, the expression of the microglial specific protein, Iba1, increased, and prostaglandin E2 (PGE2) production increased. These indicated the activation of inflammatory processes. However, the expression of neither proinflammatory cytokines, i.e. tumour necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1beta), nor the anti-inflammatory cytokine IL-10 mRNA was significantly altered by KA treatment as studied by real-time PCR. Despite activation of an array of inflammatory processes, neuronal damage could not be rescued either with the combined pre- and co-treatment with a specific COX-2 inhibitor, NS-398. Our results suggest that KA induces activation of a repertoire of inflammatory processes in immature OHCs, and that the timing of anti-inflammatory treatment to achieve neuroprotection is a challenge due to developmental properties and the complexity of inflammatory processes activated by noxious stimuli. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'. PMID- 20932984 TI - An automatic-voluntary dissociation and mental imagery disturbance following a cerebellar lesion. AB - The cerebellum receives signals from, and sends signals to, the parietal cortex and instances of cerebellocerebral diaschisis indicate that some behaviours are controlled through this circuitry. Not all aspects of action control associated with the parietal cortex have been reported in patients with cerebellar damage though. Presented here is a case study of a cerebellar patient whose action deficits appear to be associated with both cerebellar and parietal functions. AM was 27 years old and eight years previously he had an operation to remove a cystic cerebellar tumour. He was tested on his ability to carry out motor imagery, make instructed and spontaneous actions, and intrinsic and extrinsic movements. Similar to ideomotor apraxia patients AM showed an automatic-voluntary dissociation where his motor control was better on spontaneous actions than instructed ones. He also had poor motor imagery timing. However, unlike apraxia patients he was equally poor at controlling body-related and object-related actions and his performance improved without vision. The presence of problems more commonly associated with parietal cortex functions suggest that the cerebellum is involved in a broader spectrum of action abilities than previously thought. PMID- 20932985 TI - Poly(I:C) reduces expression of JAM-A and induces secretion of IL-8 and TNF-alpha via distinct NF-kappaB pathways in human nasal epithelial cells. AB - Human nasal epithelium is an important physical barrier and innate immune defense protecting against inhaled substances and pathogens. Toll-like receptor (TLR) signaling, which plays a key role in the innate immune response, has not been well characterized in human nasal epithelial cells (HNECs), including the epithelial tight junctional barrier. In the present study, mRNAs of TLR1-10 were detected in hTERT-transfected HNECs, which can be used as an indispensable and stable model of normal HNECs, similar to primary cultured HNECs. To investigate the changes of tight junction proteins and the signal transduction pathways via TLRs in HNECs in vitro, hTERT-transfected HNECs were treated with TLR2 ligand P(3)CSK(4), TLR3 ligand poly(I:C), TLR4 ligand LPS, TLR7/8 ligand CL097, TLR8 ligand ssRNA40/LyoVec, and TLR9 ligand ODN2006. In hTERT-transfected HNECs, treatment with poly(I:C) significantly reduced expression of the tight junction protein JAM-A and induced secretion of proinflammatory cytokines IL-8 and TNF alpha. Both the reduction of JAM-A expression and the induction of secretion of IL-8 and TNF-alpha after treatment with poly(I:C) were modulated by distinct signal transduction pathways via EGFR, PI3K, and p38 MAPK and finally regulated by a TLR3-mediated NF-kappaB pathway. The control of TLR3-mediated signaling pathways in HNECs may be important not only in infection by viral dsRNA but also in autoimmune diseases caused by endogenous dsRNA released from necrotic cells. PMID- 20932987 TI - Palytoxins and cytoskeleton: An overview. AB - Cytoskeleton is a dynamic structure essential for a wide variety of normal cellular processes, including the maintenance of cell shape and morphology, volume regulation, membrane dynamics and signal transduction. Cytoskeleton is organized into microtubules, actin meshwork and intermediate filaments. Actin has been identified as a major target for destruction during apoptosis and is also important under pathological conditions such as cancers. Several natural compounds actively modulate actin organization by specific signaling cascades being useful tools to study cytoskeleton dynamics. Palytoxin is a large bioactive compound, first isolated from zoanthids, with a complex structure and different analogs such as ostreocin-D or ovatoxin-a. This toxin has been identified as a potent tumor promoter and cytotoxic molecule, which leads to actin filament distortion and triggers cell death or apoptosis. In this review we report the findings on the involvement of palytoxin and analogues modulating the actin cytoskeleton within different cellular models. PMID- 20932986 TI - A possible mechanism for the decrease in serum thyroxine level by phenobarbital in rodents. AB - Effects of phenobarbital (PB) on the levels of serum thyroid hormones such as total thyroxine (T(4)) and triiodothyronine were examined in male mice, hamsters, rats, and guinea pigs. One day after the final administration of PB (80 mg/kg, intraperitoneal, once daily for 4 days), significant decreases in the levels of the serum total T(4) and free T(4) occurred in mice, hamsters, and rats, while a significant decrease in the level of serum triiodothyronine was observed in hamsters and rats among the animals examined. In addition, a significant decrease in the level of serum thyroid-stimulating hormone was observed in only hamsters among the rodents examined. Significant increases in the level and activity of hepatic T(4)-UDP-glucuronosyltransferase (UGT1A) after the PB administration occurred in mice, hamsters, and rats, while the increase in the amount of biliary [(125)I]T(4)-glucuronide after an intravenous injection of [(125)I]T(4) to the PB pretreated animals occurred only in rats. In mice, rats, and hamsters, but not guinea pigs, PB pretreatment promoted the clearance of [(125)I]T(4) from the serum, led to a significant increase in the steady-state distribution volumes of [(125)I]T(4), and raised the concentration ratio (Kp value) of the liver to serum and the liver distribution of [(125)I]T(4). The present findings indicate that the PB-mediated decreases in the serum T(4) level in mice, hamsters, and rats, but not guinea pigs, occur mainly through an increase in the accumulation level of T(4) in the liver. PMID- 20932988 TI - "The King is dead": Checkmating ion channels with tethered toxins. AB - The quickest possible checkmate in the game of chess requires two moves using a pawn and the queen. Metaphorically speaking, the pawn (a membrane tether) and the queen (a toxin) work together to checkmate an ion channel within a neuronal circuit. This strategy termed "tethered toxin" (t-toxin) is based on the use of genetically encoded peptide toxins that are anchored to the cell-membrane via a glycolipid or transmembrane tether. Because of their mode of action at the cell surface, t-toxins act only on ion channels and receptors of the cell that is expressing the t-toxin, and not on identical receptors present in neighboring cells that do not express the t-toxin. In this mini-review we discuss the design of these genetic tools and their application for cell-specific and temporal manipulation of ion channel-mediated activities in vivo. PMID- 20932989 TI - Visual deficits in anisometropia. AB - Amblyopia is usually associated with the presence of anisometropia, strabismus or both early in life. We set out to explore quantitative relationships between the degree of anisometropia and the loss of visual function, and to examine how the presence of strabismus affects visual function in observers with anisometropia. We measured optotype acuity, Pelli-Robson contrast sensitivity and stereoacuity in 84 persons with anisometropia and compared their results with those of 27 persons with high bilateral refractive error (isoametropia) and 101 persons with both strabismus and anisometropia. All subjects participated in a large-scale study of amblyopia (McKee et al., 2003). We found no consistent visual abnormalities in the strong eye, and therefore report only on vision in the weaker, defined as the eye with lower acuity. LogMAR acuity falls off markedly with increasing anisometropia in non-strabismic anisometropes, while contrast sensitivity is much less affected. Acuity degrades rapidly with increases in both hyperopic and myopic anisometropia, but the risk of amblyopia is about twice as great in hyperopic than myopic anisometropes of comparable refractive imbalance. For a given degree of refractive imbalance, strabismic anisometropes perform considerably worse than anisometropes without strabismus--visual acuity for strabismics was on average 2.5 times worse than for non-strabismics with similar anisometropia. For observers with equal refractive error in the two eyes there is very little change in acuity or sensitivity with increasing (bilateral) refractive error except for one extreme individual (bilaterally refractive error of -15 D). Most pure anisometropes with interocular differences less than 4D retain some stereopsis, and the degree is correlated with the acuity of the weak eye. We conclude that even modest interocular differences in refractive error can influence visual function. PMID- 20932990 TI - Receptive fields for smooth pursuit eye movements and motion perception. AB - Humans use smooth pursuit eye movements to track moving objects of interest. In order to track an object accurately, motion signals from the target have to be integrated and segmented from motion signals in the visual context. Most studies on pursuit eye movements used small visual targets against a featureless background, disregarding the requirements of our natural visual environment. Here, we tested the ability of the pursuit and the perceptual system to integrate motion signals across larger areas of the visual field. Stimuli were random-dot kinematograms containing a horizontal motion signal, which was perturbed by a spatially localized, peripheral motion signal. Perturbations appeared in a gaze contingent coordinate system and had a different direction than the main motion including a vertical component. We measured pursuit and perceptual direction discrimination decisions and found that both steady-state pursuit and perception were influenced most by perturbation angles close to that of the main motion signal and only in regions close to the center of gaze. The narrow direction bandwidth (26 angular degrees full width at half height) and small spatial extent (8 degrees of visual angle standard deviation) correspond closely to tuning parameters of neurons in the middle temporal area (MT). PMID- 20932991 TI - Contextual flanks' tilting and magnitude of illusion of extent. AB - The "centroid" explanation of the Muller-Lyer and similar illusions of extent supposes the perceptual positional shifts of the stimulus terminators in direction of the centers-of-masses of adjacent contextual flanks. In the present study, the validity of the assumption was tested in psychophysical examination of illusory figures comprising the Muller-Lyer wings or arcs of a circle as the contextual objects. In experiments, the illusion magnitude changes evoked by the tilting of stimulus flanks have been measured. A good resemblance between the experimental data and theoretical predictions was obtained that strongly supports the idea of local positional shifts and serves in favor of "centroid" explanation of illusions investigated. PMID- 20932992 TI - The influence of orientation and contrast flicker on contour saliency of outlines of everyday objects. AB - One of the most important tasks of the visual system is the extraction of edges and object contours, and the integration of discrete elements to form a coherent global percept. A great deal is known about the spatial properties of contour extraction, but less is known about the dynamics and spatio-temporal aspects. We used Gabor-rendered outlines of real-world objects, where we could manipulate low level properties, such as element orientation and phase, while incorporating higher-level properties, such as object complexity and identity, to study dynamic relationships in object detection. First we manipulated the time available for integration by changing back and forth between coherent and non-coherent orientations of the contour elements. We then manipulated contrast flicker by reversing the spatial phase of the Gabor elements at various frequencies. We found similar results to earlier studies on contour detection: detection was better for contrast flicker than for orientation flicker, and detection performance was curvature-dependent for orientation flicker but not for contrast flicker. Our results support the existence of at least two temporal frequency channels in the visual system, one low-pass and one band-pass peaking around 10 12 Hz. In addition, we found that object properties, such as identity and complexity, affected detection performance. PMID- 20932994 TI - Effects of anabolic androgenic steroids and social subjugation on behavior and neurochemistry in male rats. AB - Early abuse and anabolic androgenic steroids (AAS) both increase aggression. We assessed the behavioral and neurochemical consequences of AAS, alone or in combination with social subjugation (SS), an animal model of child abuse. On P26, gonadally intact male rats began SS consisting of daily pairings with an adult male for 2 weeks followed by daily injections of the AAS, testosterone on P40. As adults, males were tested for sexual and aggressive behaviors towards females in various hormonal conditions and inter-male aggression in a neutral setting using home or opponent bedding. Neurotransmitter levels were assessed using HPLC. Results showed that AAS males displayed significantly more mounts toward sexually receptive, vaginally obstructed females (OBS) and displayed significantly more threats towards ovariectomized females. SS males mounted OBS females significantly less and were not aggressive toward females. The role of olfactory cues in a neutral setting did not affect aggression regardless of treatment. AAS significantly increased brainstem DOPAC and NE. SS decreased 5HIAA, DA, DOPAC, and NE in brainstem. 5HIAA was significantly increased in the prefrontal cortex of all experimental groups. We conclude that AAS and SS differentially affect behavior towards females as well as neurotransmitter levels. PMID- 20932993 TI - Visually guided navigation: head-mounted eye-tracking of natural locomotion in children and adults. AB - The current study showed that visual fixation of obstacles is not required for rapid and adaptive navigation of obstacles. Children and adults wore a wireless, head-mounted eye-tracker during a visual search task in a room cluttered with obstacles. They spontaneously walked, jumped, and ran through the room, stepping up, down, and over obstacles. Both children and adults navigated adaptively without fixating obstacles, however, adults fixated less often than children. We discuss several possibilities for why obstacle navigation may shift from foveal to peripheral control over development. PMID- 20932995 TI - Cervical cancer screening among urban immigrants by region of origin: a population-based cohort study. AB - OBJECTIVES: We compared the prevalence of appropriate cervical cancer screening among screening-eligible immigrant women from major geographic regions of the world and native-born women. METHODS: We determined the proportion of women who were screened during the three-year period of 2006-2008 among 2.9 million screening-eligible women living in urban centres in Ontario, Canada. In multivariate analyses, we adjusted for numerous variables including age, neighbourhood-level income, and prenatal visits during the study period. RESULTS: 61.3% of women were up-to-date on cervical cancer screening. Screening rates were lowest among women from South Asia when compared to the referent group (Canadian born women and immigrants who arrived before 1985) (adjusted rate ratio 0.81, 95% CI [0.80-0.82] among women aged 18-49 years, adjusted rate ratio 0.67 [0.65-0.69] among women aged 50-66 years). Of the older South Asian women living in the lowest-income neighbourhoods and not in a primary care enrollment model, 21.9% had been appropriately screened. In contrast, among Canadian-born women living in the highest-income neighbourhoods and in a primary care enrollment model, 79.0% had been appropriately screened. CONCLUSION: Efforts to reduce cervical cancer screening disparities should focus on women living in the lowest-income neighbourhoods and women from South Asia. PMID- 20932996 TI - Induction of transposase and polyprotein RNA levels in disseminated neoplastic hemocytes of soft-shell clams: Mya arenaria. AB - In Prince Edward Island, a high mortality of soft-shell clams Mya arenaria was found to be related to the disease known as disseminated neoplasia (DN). However, the molecular mechanisms by which hemocytes of clams are transformed in the course of DN remain by far unknown. This study aims at identifying the transcripts involved in the development of the disease. Four subtractive cDNA sequence libraries were generated and more than 200,000 reads were obtained. Following similarity searches in genome databases, the transcripts were assigned to cellular functions including mitochondrial respiration, structural proteins, cytoskeleton, nucleic acid regulation, general metabolism, signal transduction, apoptosis, cell cycle regulation, as well as virus transcripts. The expression levels of transposase and polyprotein genes were evaluated in clams with various percentages of tetraploid hemocytes. Data have shown that expression levels were significantly higher in clams with a high percentage of tetraploid hemocytes. These results reinforce the hypothesis of endogenous retrotransposon involvement in the etiology of the disease. Further investigations are needed, however, to elucidate the role of transposase and polyprotein in the disease development. PMID- 20932997 TI - Vasodilatation in the rat dorsal hindpaw induced by activation of sensory neurons is reduced by paclitaxel. AB - Peripheral neuropathy is a major side effect following treatment with the cancer chemotherapeutic drug paclitaxel. Whether paclitaxel-induced peripheral neuropathy is secondary to altered function of small diameter sensory neurons remains controversial. To ascertain whether the function of the small diameter sensory neurons was altered following systemic administration of paclitaxel, we injected male Sprague Dawley rats with 1mg/kg paclitaxel every other day for a total of four doses and examined vasodilatation in the hindpaw at day 14 as an indirect measure of calcitonin gene related peptide (CGRP) release. In paclitaxel treated rats, the vasodilatation induced by either intradermal injection of capsaicin into the hindpaw or electrical stimulation of the sciatic nerve was significantly attenuated in comparison to vehicle-injected animals. Paclitaxel treatment, however, did not affect direct vasodilatation induced by intradermal injection of methacholine or CGRP, demonstrating that the blood vessels' ability to dilate was intact. Paclitaxel treatment did not alter the compound action potentials or conduction velocity of C-fibers. The stimulated release of CGRP from the central terminals in the spinal cord was not altered in paclitaxel injected animals. These results suggest that paclitaxel affects the peripheral endings of sensory neurons to alter transmitter release, and this may contribute to the symptoms seen in neuropathy. PMID- 20932998 TI - Prosthetic joint infection: recent developments in diagnosis and management. AB - Over the past years there has been a significant increase in the number of joint prosthesis replacements worldwide. The most serious complication of joint prosthesis is infection with an incidence of 1.5-2.5% for primary interventions and up to 20% for revision procedures. The mortality rate ranges between 1% and nearly 3%. The economic cost of this complication is up to $50,000 per patient and $250,000 million per year. A major issue in the management of prosthetic joint infection (PJI) is the relative difficulty in making a diagnosis so to cause a significant effect on the prognosis. Goals of the treatment are to eradicate infection, prevent its recurrence and preserve mechanical joint function. In this review we focus on the value of traditional and newer diagnostic tests and we discuss management and preventive strategies. European networks are needed to define the best diagnostic and treatment strategies in order to reduce future challenge posed by PJIs. PMID- 20932999 TI - Prevalence of single, double, and triple infections of HIV, HCV and HBV among the MSM community in Pakistan. PMID- 20933000 TI - Citrobacter koseri meningitis: another freediving risk? AB - We present a rare case of meningitis caused by Citrobacter koseri in an immunocompetent adult who had recently been freediving. Middle ear pressure changes from this recreational activity, and the subsequent inflammatory response, are likely to have provided this environmental organism access to the central nervous system, and thus the ability to cause clinically significant infection. PMID- 20933001 TI - Comparison of the Cepheid XpertTM MRSA assay with culture in a low prevalence setting in The Netherlands. PMID- 20933002 TI - Time-frequency analysis using damped-oscillator pseudo-wavelets: Application to electrophysiological recordings. AB - The damped-oscillator pseudo-wavelet is presented as a method of time-frequency analysis along with a new spectral density measure, the data power. An instantaneous phase can be defined for this pseudo-wavelet, and it is easily inverted. The data power measure is tested on both computer generated data and in vivo intrahippocampal electrophysiological recordings from a rat. The data power spectral density is found to give better time and frequency resolution than the more conventional total energy measure, and additionally shows intricate time frequency structure in the rat that is altered in association with the emergence of epilepsy. With epileptogenesis, the baseline theta oscillation is severely degraded and is absorbed into a broader gamma band. There are also broad 600 Hz and 2000 Hz bands which localize to hippocampal layers that are distinct from those of the theta and gamma bands. The 600 Hz band decreases in prominence with epileptogenesis while the 2000 Hz band increases in prominence. The origins of these high frequency bands await further study. In general, we find that the damped-oscillator pseudo-wavelet is easy to use and is particularly suitable for problems where a wide range of oscillator frequencies is expected. PMID- 20933003 TI - An algorithm for real-time detection of spike-wave discharges in rodents. AB - The automatic real-time detection of spike-wave discharges (SWDs), the electroencephalographic hallmark of absence seizures, would provide a complementary tool for rapid interference with electrical deep brain stimulation in both patients and animal models. This paper describes a real-time detection algorithm for SWDs based on continuous wavelet analyses in rodents. It has been implemented in a commercially available data acquisition system and its performance experimentally verified. ECoG recordings lasting 5-8h from rats (n=8) of the WAG/Rij strain were analyzed using the real-time SWD detection system. The results indicate that the algorithm is able to detect SWDs within 1s with 100% sensitivity and with a precision of 96.6% for the number of SWDs. Similar results are achieved for 24-h ECoG recordings of two rats. The dependence of accuracy and speed of detection on program settings and attributes of ECoG are discussed. It is concluded that the wavelet based real-time detecting algorithm is well suited for automatic, real-time detection of SWDs in rodents. PMID- 20933004 TI - First human hNT neurons patterned on parylene-C/silicon dioxide substrates: Combining an accessible cell line and robust patterning technology for the study of the pathological adult human brain. AB - In this communication, we describe a new method which has enabled the first patterning of human neurons (derived from the human teratocarcinoma cell line (hNT)) on parylene-C/silicon dioxide substrates. We reveal the details of the nanofabrication processes, cell differentiation and culturing protocols necessary to successfully pattern hNT neurons which are each key aspects of this new method. The benefits in patterning human neurons on silicon chip using an accessible cell line and robust patterning technology are of widespread value. Thus, using a combined technology such as this will facilitate the detailed study of the pathological human brain at both the single cell and network level. PMID- 20933005 TI - Label-free in vivo optical imaging of functional microcirculations within meninges and cortex in mice. AB - Abnormal microcirculation within meninges is common in many neurological diseases. There is a need for an imaging method that is capable of monitoring dynamic meningeal microcirculations, preferably decoupled from cortical blood flow. Optical microangiography (OMAG) is a recently developed label-free imaging method capable of producing 3D images of dynamic blood perfusion within micro circulatory tissue beds at an imaging depth up to ~2 mm, with an unprecedented imaging sensitivity to blood flow at ~4 MUm/s. In this paper, we demonstrate the utility of OMAG in imaging the detailed blood flow distributions, at a capillary level resolution, within the meninges and cortex in mice with the cranium left intact. Using a thrombotic mouse model, we show that the OMAG can yield longitudinal measurements of meningeal vascular responses to the insult and can decouple these responses from those in the cortex, giving valuable information regarding the localized hemodynamics along with the dynamic formation of thrombotic event. The results indicate that OMAG can be a useful tool to study therapeutic strategies in preclinical animal models in order to mitigate various pathologies that are mainly related to the meningeal circulations. PMID- 20933006 TI - A novel multicomponent stimulus device for use in olfactory experiments. AB - Olfactory studies have expanded beyond the study of single compound odor perception to explore the processing of complex mixtures and blends. The spatiotemporal presentation of blend stimuli is a challenging task requiring volatiles with diverse chemical and physical properties to be presented as a unified stimulus. This not only necessitates accurate control of the timing and homogeneity of the odor stream, but requires attention to the concentration of each blend component presented. We have developed a novel, multicomponent stimulus system for use in olfactory experiments that is capable of presenting up to 8 different odors simultaneously or in sequence at defined concentrations and time scales. Each odor is separated to minimize physical or chemical interactions, and stimulations are performed from a saturated headspace of the odor solution. Stimulus concentrations can be measured empirically or estimated using common gas laws. Photoionization detector measurements show that stimuli could be presented as cohesive blends or single components at frequencies of at least 10Hz without leakage or contamination. Solid phase microextraction measurements also show that the concentration of each component could be equilibrated through regulation of each component line's flow rate based on the different partial vapor pressures of the odorants. This device provides a unique method for introducing complex volatile mixtures for olfactory studies in a variety of animal taxa and allows for accurate control of odor intensities in both time and space. PMID- 20933007 TI - ScoreCentre: a computer program to assist with collection and calculation of BBB locomotor scale data. AB - The Basso, Beattie and Bresnahan (BBB) Locomotor Rating Scale is a standardized assessment scale for use in experimental spinal cord injury (SCI) research. This paper describes a computer program, ScoreCentre, which aims to simplify the recording and handling of BBB locomotor scale data. The program assists with the recording of observational data from open-field testing and then automatically calculates BBB scores. Possible errors associated with data entry and manual calculation of scores are thus essentially eliminated. In addition, significant time is saved by the automated derivation of scores and subscores and elimination of the need to manually transfer data from paper records to a computer. ScoreCentre can also be used as a training aid, to help familiarize users with the BBB scale and to explore how changes in the observations impact on overall BBB score. ScoreCentre includes simple experiment management functions such as control of trial blinding, administration of drugs in a blinded fashion and longitudinal data analysis. ScoreCentre provides all the advantages of electronic records, such as ease of use, analysis and archiving, and allows the elimination of paper records if appropriate. When paper records are required, for example for archiving and auditing, they can be automatically produced by ScoreCentre. ScoreCentre will assist with both the learning and use of the BBB locomotor scale, thus facilitating the use of this standardized outcome measure in SCI research. ScoreCentre is available to download from www.rmeonline.net/scorecentre. PMID- 20933008 TI - Tonic BCR signaling represses receptor editing via Raf- and calcium-dependent signaling pathways. AB - Light chain receptor editing is an important mechanism that prevents B cell self reactivity. We have previously shown that tonic signaling through the BCR represses RAG expression at the immature B cell stage, and that initiation of light chain rearrangements occurs in the absence of these tonic signals in an in vitro model of B cell development. To further test our hypothesis we studied the effect of itpkb deficiency (itpkb(-/-) mice) or Raf hyper-activation (Raf-CAAX transgenic mice), two mutations that enhance BCR signaling, on receptor editing in an in vivo model. This model relies on transferring bone marrow from wild-type or mutant mice into mice expressing an anti-kappa light chain transgene. The anti kappa transgene induces receptor editing of all kappa light chain expressing B cells, leading to a high frequency of lambda light chain expressing B cells. Anti kappa transgenic recipients of bone marrow from itpkb(-/-) or Raf-CAAX mice showed lower levels of editing to lambda light chain than did non-transgenic control recipients. These results provide evidence in an in vivo model that enhanced BCR signaling at the immature B cell stage of development suppresses light chain receptor editing. PMID- 20933009 TI - Grape seed proanthocyanidin extract (GSPE) differentially regulates Foxp3(+) regulatory and IL-17(+) pathogenic T cell in autoimmune arthritis. AB - Grape seed proanthocyanidin extract (GSPE), which is the antioxidant derived from grape seeds, has been reported to possess a variety of potent properties. We have previously shown that GSPE attenuates collagen-induced arthritis. However the mechanism by which GSPE regulates the immune response remains unclear, although it may involve effects on the regulation of pathogenic T cells in autoimmune arthritis. To clarify this issue, we have assessed the effects of GSPE on differential regulation of Th17 and regulatory T (Treg) cells subsets in vitro in mouse and human CD4(+) T cells. We observed that GSPE decreased the frequency of IL-17(+)CD4(+)Th17 cells and increased induction of CD4(+)CD25(+)forkhead box protein 3 (Foxp3)(+) Treg cells. In vivo, GSPE effectively attenuated clinical symptoms of established collagen-induced arthritis in mice with concomitant suppression of IL-17 production and enhancement of Foxp3 expression (type II collagen-reactive Treg cells) in CD4(+) T cells of joints and splenocytes. The presence of GSPE decreased the levels of IL-21, IL-22, IL-26 and IL-17 production by human CD4(+) T cells in a STAT3-dependent manner. In contrast, GSPE induces Foxp3(+) Treg cells in humans. Our results suggest that GSPE possesses a reciprocal control over IL-17 and Foxp3. By potently regulating inflammatory T cell differentiation, GSPE may serve as a possible novel therapeutic agent for inflammatory and autoimmune diseases, including rheumatoid arthritis. PMID- 20933010 TI - New B-cell CD molecules. AB - B cells not only play a pivotal role in humoral immunity, but also are involved in a broad spectrum of immune responses, including antigen presentation and T cell function regulation. The identification of cell-surface CD molecules derived from a series of Human Leukocyte Differentiation Antigens (HLDA) Workshops has been instrumental to the discovery and functional characterization of human B cell populations. Moreover, many events regulating B-cell development, activation, and effector functions are orchestrated by these cell-surface molecules. During the Ninth HLDA Workshop (HLDA9) eighteen new CDs were allocated to cell-surface molecules expressed on B cells: CD210a (IL10RA), CD215 (IL15RA), CD270 (TNFRSF14), CD307a (FCRL1), CD307b (FCRL2), CD307c (FCRL3), CD307d (FCRL4), CD351 (FCAMR), CD352 (SLAMF6), CD353 (SLAMF8), CD354 (TREM1), CD355 (CRTAM), CD357 (TNFRSF18), CD358 (TNFRSF21), CD360 (IL21RA), CD361 (EVI2B), CD362 (SDC2), and CD363 (S1PR1). Here we present their expression patterns on leukocytes, including T lymphocytes, NK cells, granulocytes, monocytes, plasmacytoid and monocyte-derived dendritic cells, and several B-cell subsets. These new CD molecules are expressed on B cells at various stages of differentiation; from bone marrow precursor pro-B cells to plasma cells. Three of them, CD307a, CD307b and CD307d, exhibit a B-cell restricted expression pattern, whereas the rest are also present on other leukocytes. In this paper we also review the structural characteristics, expression, and function of these new CD molecules. The availability of monoclonal antibodies directed against novel B cell-surface molecules will have broad implications not only for B-cell biology, but also for the development of new diagnostic and therapeutic tools. PMID- 20933011 TI - FCRL6 receptor: expression and associated proteins. AB - FCRL6 receptor is a more recently identified representative of the FCRL family. We generated a panel of mouse mAbs to baculovirus-derived recombinant FCRL6 protein. The clone 7B2 was found to specifically recognize a 63kDa protein expressed preferentially on the surface of CD8 T and CD56 NK cells in human peripheral blood and spleen. The clone 7B2 reacts with FCRL6 in Western blotting, FACS, and immunohistochemistry. In the T cell lineage, FCRL6 functions in antigen experienced cells. Mitogenic stimulation of PB leukocytes in vitro resulted in an abrogation of the FCRL6 gene expression. We found a significant decrease in the FCRL6 gene expression in peripheral T cells of patients with certain autoimmune and blood diseases, and its upregulation at the late stages of HIV infection. Study of the FCRL6 association with signaling molecules showed its ability to recruit SHP-1, SHP-2, SHIP-1, and SHIP-2 phosphatases, and also adaptor protein Grb2 through phosphorylated cytoplasmic tyrosines. The current results demonstrate inhibitory potential of FCRL6 and suggest its possible involvement in modulation of CTL effector functions in various immune disorders. PMID- 20933012 TI - Analysis of HLDA9 mAbs on plasmacytoid dendritic cells. AB - Dendritic cells are a heterogeneous population of bone marrow derived leucocytes that play a crucial role in both pathogen recognition and the initiation of primary T cell immune responses. Plasmacytoid dendritic cells (pDCs), also known as natural interferon-producing cells, comprise one of two major human dendritic cell subsets that strongly influences immune balance. pDCs remain a poorly characterized subset. Several studies have suggested the existence of a close phenotypic and functional relationship between B-cells and pDCs. The surface reactivity of a panel of 96 monoclonal antibodies submitted to the ninth Human Leukocyte Differentiation Antigens workshop (HLDA9) B cell section was analyzed using pDCs as target cells. The results showed that eight of the mAbs reacted positively on pDCs: CD86, CD229, CD319, CD305, CD184, CD84, CD85g and FcERIa, confirming previously published reports. Interestingly, this study also revealed the expression of eight surface molecules not previously described on pDCs, including CD352(NTBA), CD272(BTLA), CD357(GITR), CD48, CD270(HVEM), Galectin-3, CD148, and CD361. The present report summarizes the expression of these molecules on freshly isolated pDCs. Significantly, we have identified several new molecules expressed by these intriguing cells, ones we believe will open new avenues for the study of pDC functionality and their role in human health and diseases. PMID- 20933013 TI - Expression of SLAM (CD150) cell-surface receptors on human B-cell subsets: from pro-B to plasma cells. AB - The SLAM (CD150) family receptors are leukocyte cell-surface glycoproteins involved in leukocyte activation. These molecules and their adaptor protein SAP contribute to the effective germinal center formation, generation of high affinity antibody-secreting plasma cells, and memory B cells, thereby facilitating long-term humoral immune response. Multi-color flow cytometric analysis was performed to determine the expression of CD48 (SLAMF2), CD84 (SLAMF5), CD150 (SLAM or SLAMF1), CD229 (Ly9 or SLAMF3), CD244 (2B4 or SLAMF4), CD319 (CRACC, CS1, or SLAMF7), and CD352 (NTB-A or SLAMF6) on human cell lines and B-cell subsets. The following subsets were assessed: pro-B, pre-B, immature B, and mature-B cells from bone marrow; transitional and B1/B2 subsets from peripheral blood; and naive, pre-germinal center, germinal center, memory, plasmablasts, and plasma cells from tonsil and spleen. All receptors were expressed on B cells, with the exception of CD244. SLAM family molecules were widely distributed during B-cell development, maturation and terminal differentiation into plasmablasts and plasma cells, but their expression among various B-cell subsets differed significantly. Such heterogeneous expression patterns suggest that SLAM molecules play an essential and non-redundant role in the control of humoral immune responses. PMID- 20933014 TI - Monoclonal antibody-based triple antibody sandwich-enzyme-linked immunosorbent assay and immunocapture reverse transcription-polymerase chain reaction for Odontoglossum ringspot virus detection. AB - Odontoglossum ringspot virus (ORSV) infects numerous commercially important orchids and causes significant losses worldwide. The coat protein (CP) gene of ORSV was cloned and expressed in Escherichia coli by using the pET-32a expression vector, and the expression of recombinant protein was confirmed by Western blotting using anti-ORSV antibodies. The recombinant protein was purified using Ni-NTA agarose, and the purified protein was used as an immunogen to produce monoclonal antibodies (MAbs) and polyclonal antibodies (PAbs). Five murine MAbs against ORSV CP were obtained. Among them, two MAbs (6B4 and 1D1) also reacted with TMV CP. The triple antibody sandwich enzyme-linked immunosorbent assay (TAS ELISA) and immunocapture reverse transcription-polymerase chain reaction (IC-RT PCR) methods using the MAb (8A5) were then developed for sensitive, specific, and rapid detection of ORSV. TAS-ELISA and IC-RT-PCR could detect ORSV in the infected leaf saps with dilutions of 1:10,240 and 1:81,920 (w/v, g mL(-1)), respectively. TAS-ELISA and IC-RT-PCR detections indicated that ORSV was prevalent in orchids in the Zhejiang Province of China. PMID- 20933015 TI - Detection and discrimination of members of the family Luteoviridae by real-time PCR and SYBR(r) GreenERTM melting curve analysis. AB - This study investigated the suitability of a two step real-time RT-PCR melting curve analysis as a tool for the detection and discrimination of nine species in the plant virus family Luteoviridae, being Soybean dwarf virus [SbDV], Bean leafroll virus [BLRV], Beet chlorosis virus [BChV], Beet mild yellowing virus [BMYV], Beet western yellows virus [BWYV], Cereal yellow dwarf virus-RPV [CYDV RPV], Cucurbit aphid-borne yellows virus [CABYV], Potato leafroll virus [PLRV] and Turnip yellows virus [TuYV]. Melting temperature and shape of the melting peak were analysed for 68 bp and 148 bp coat protein gene amplicons using SYBR(r) GreenERTM fluorescent dye. Specific melting peaks with unique melting temperature were observed for the various species of the family Luteoviridae using the 68 bp amplicon, but not with the 148 bp amplicon. Due to the high variability of sequences for some members of this family, different melting temperatures were also observed between different isolates of the species CYDV-RPV and TuYV. Nevertheless, discrimination between species was achieved for SbDV, BLRV, BChV, BMYV, CABYV and either PLRV or BWYV. Melting curve analysis, in this study, is a faster and more discriminatory alternative to gel electrophoresis of end-point PCR products for the detection of Luteoviridae infection. PMID- 20933016 TI - Detection and differentiation of tick-borne encephalitis virus subtypes by a reverse transcription quantitative real-time PCR and pyrosequencing. AB - Tick-borne encephalitis (TBE) virus causes one of the most important flaviviral infections of the human central nervous system in Europe and Asia. In recent years the rate of TBE infection has been raising and the virus has been spreading to new areas. Currently, the diagnosis of TBE is based on detection of specific antibodies in patients' sera which appear as late as about 2 weeks post infection. For a timely diagnosis of TBE virus infections and epidemiological studies, a TBE virus-specific reverse transcription quantitative real-time PCR (RT-qPCR) followed by pyrosequencing was developed. The assay is based on one degenerated primer pair detecting all three human-pathogenic TBE virus subtypes with a detection limit of 10 copies. Even though primers and probe are highly degenerated, the assay is specific for TBE virus species and detects all subtypes with a comparable sensitivity. Furthermore, TBE virus RT-qPCR could be carried out as one-step or two-step assay. RT-qPCR can be followed by pyrosequencing which allows a rapid subtyping of TBE viruses. For detection purposes an internal control to monitor RNA extraction, cDNA synthesis and amplification is included. In summary, the method is sensitive, highly specific and easy-to-handle tool for the detection and differentiation of TBE virus in the early phase of illness or in TBE host animal species and ticks. PMID- 20933017 TI - Adaptation of a Madin-Darby canine kidney cell line to suspension growth in serum free media and comparison of its ability to produce avian influenza virus to Vero and BHK21 cell lines. AB - Madin-Darby canine kidney (MDCK) cells are currently considered for influenza vaccine manufacturing. A drawback of these cells is their anchorage dependent growth, which greatly complicates process scale-up. In this paper a novel MDCK cell line (MDCK-SFS) is described that grows efficiently in suspension and retained high expression levels of both alpha-2,6 and alpha-2,3 sialic acid receptors, which bind preferably to human and avian influenza viruses, respectively. The production of avian influenza virus by BHK21, Vero and MDCK-SFS cell lines was compared. Although BHK21 cells consisted of two populations, one of which lacks the alpha-2,3 receptor, they supported the replication of two influenza strains to high titres. However, BHK21 cells are generally not applicable for influenza production since they supported the replication of six further strains poorly. MDCK-SFS cells yielded the highest infectious virus titres and virus genome equivalent concentration for five of the eight influenza strains analyzed and the highest hemagglutination activity for all eight virus strains. Taken together with their suitability for suspension growth this makes the MDCK-SFS cell line potentially useful for large scale influenza virus production. PMID- 20933018 TI - New in vitro method for evaluating antiviral activity of acyclic nucleoside phosphonates against plant viruses. AB - A new method was developed for testing antiviral compounds against plant viruses based on rapidly growing brassicas in vitro on liquid medium. This method enables exchange of media containing tested chemicals in various concentrations and simultaneous evaluation of their phytotoxicity and antiviral activity. While using ribavirin as a standard for comparison, phytotoxicity and ability of the acyclic nucleotide analogues (R)-PMPA, PMEA, PMEDAP, and (S)-HPMPC to eliminate ssRNA Turnip yellow mosaic virus (TYMV) were evaluated by this method. Double antibody sandwich ELISA and real-time PCR were used for relative quantification of viral protein and nucleic acid in plants. Ribavirin had the most powerful antiviral effect against TYMV. On the other hand, (R)-PMPA and PMEA had no antiviral effect and almost no phytotoxicity compared to the control. (S)-HPMPC and PMEDAP showed moderate antiviral effect, accompanied by higher phytotoxicity. The tested compounds can be screened within 6-9 weeks in contrast to the 6 months for traditionally used explants on solid medium. The method enables large-scale screening of potential antivirals for in vitro elimination of viruses from vegetatively propagated crops and ornamentals. PMID- 20933019 TI - The effects of pentylenetetrazol, chlordiazepoxide and caffeine in rats tested in the elevated plus-maze depend on the experimental illumination. AB - The so-called anxiolytic and anxiogenic drugs are considered to cause, respectively, increases and decreases in plus-maze open arm exploration, without modifying locomotor activity occurring in the closed arms in an elevated plus maze when the animals are tested in an illuminated environment. Simply testing animals in the dark also increases open arm exploration, which may be interpreted as an anxiolytic effect. We investigated the effects of two GABAergic drugs, pentylenetetrazol (10 and 20 mg/kg) and chlordiazepoxide (1.5 and 3 mg/kg), and one non-GABAergic drug, caffeine (10 and 30 mg/kg) on anxiety levels of rats tested in the elevated plus-maze under two illumination conditions, light or dark. All animals explored more the open arms in the dark. In the light, pentylenetetrazol decreased open arm exploration while chlordiazepoxide had the opposite effect. Neither pentylenetetrazol nor chlordiazepoxide had any effect in the dark. Caffeine, increased open arms exploration in both illumination conditions. These results indicate that light triggers aversion, a response mediated by GABA since the GABAergic drugs, but not caffeine, were ineffective when the rats were tested in the dark. PMID- 20933020 TI - Neurobiology of decision-making in adolescents. AB - The study examined the relationship between risk-taking behavior during selection of monetary rewards and activations in the anterior cingulate cortex (ACC), orbitofrontal cortex (OFC) and medial prefrontal cortex (mPFC), brain regions that are associated with decision-making. Thirty-three adolescents with no personal or family history of any psychiatric illness were administered the Wheel of Fortune (WOF) task using a functional magnetic resonance imaging protocol. The WOF is a computerized two-choice, probabilistic monetary reward task. Selection of a reward, particularly a low-probability/high-magnitude reward choice, induced greater activations in dorsal ACC, ventrolateral OFC and mPFC than the control condition. Although similar findings have been reported by earlier studies, the results from this study were not impacted by reaction times and expected values and persisted even after controlling for sociodemographic factors. Post hoc analysis revealed greater activation of ACC and mPFC in response to selection of rewards of larger magnitude than those of smaller magnitude when the probability of reward was maintained constant. Adolescents with greater frequency of high risk behavior (defined as low-probability/high-magnitude reward choice) had lower activation of ACC, OFC and mPFC than those who engaged in this behavior less frequently. These findings suggest individual differences in prefrontal cortical function with regards to decision-making process in adolescents. PMID- 20933021 TI - Sickness behaviors following medial frontal cortical contusions in male rats. AB - Behaviors associated with sickness (food consumption, weight maintenance, exploratory activity and grooming frequency) were examined on post-surgical days 1, 3, 5, 7 and 9 in male rats treated with progesterone (4 mg/kg) and/or vehicle. Rats with medial frontal cortex contusions showed reduced food consumption on days 1 and 3 (p < 0.01), reduced weight maintenance on days 1, 3, 5, 7 and 9 (p < 0.01), reduced grooming frequency on day 1 (p < .01), and reduced exploratory activity on day 1 (p < 0.01), after injury compared to sham rats. Contusion induced behaviors were not attenuated with 5 days of progesterone treatment (p > 0.05). Progesterone did reduce lesion size at 9 days after injury (p < 0.05). Our results suggest sickness behaviors occur after traumatic brain injury and that they might not respond to some neurosteroidal agents. PMID- 20933022 TI - Behavioral characterization of a mutant mouse strain lacking D-amino acid oxidase activity. AB - D-amino acid oxidase (DAO), an enzyme that degrades d-serine, has been suggested as a susceptibility factor for schizophrenia. Here we sought to understand more about the behavioral consequence of lacking DAO and the potential therapeutic implication of DAO inhibition by characterizing a mouse strain (ddY/DAO(-)) lacking DAO activity. We found that the mutant mice showed enhanced prepulse inhibition responses (PPI). Intriguingly, DAO-/- mice had increased sensitivity to the PPI-disruptive effect induced by the competitive NMDA antagonist, SDZ 220 581. In the 24-h inhibitory avoidance test, DAO-/- mice were not different from DAO+/+ mice during the recall. In Barnes Maze, we found that DAO-/- mice had a shortened latency to enter the escape tunnel. Interestingly, although these mice were hypoactive when tested in a protected open field, they showed a profound increase of activity on the edge of the unprotected open field of the Barnes Maze even with the escape tunnel removed. This increased edge activity does not appear to be related to a reduced level of anxiety given that there were no significant genotype effects on the measures of anxiety-like behaviors in two standard animal models of anxiety, elevated plus maze and novelty suppressed feeding. Our data suggest that DAO-/- mice might have altered functioning of NMDARs. However, these results provide only modest support for manipulations of DAO activity as a potential therapeutic approach to treat schizophrenia. PMID- 20933023 TI - Central injections of noradrenaline induce reinstatement of cocaine seeking and increase c-fos mRNA expression in the extended amygdala. AB - We recently reported that central injections of noradrenaline (NA) induce reinstatement of cocaine seeking in rats. Here, we replicate and extend our finding to an additional dose of NA and show that it is associated with the induction of c-fos mRNA expression (a marker of neuronal activation) in functionally relevant brain regions, including the bed nucleus of the stria terminalis and central nucleus of the amygdala. PMID- 20933025 TI - Effect of shape and size of polymer particles on cellular internalization. PMID- 20933024 TI - Metabolic control of mitochondrial biogenesis through the PGC-1 family regulatory network. AB - The PGC-1 family of regulated coactivators, consisting of PGC-1alpha, PGC-1beta and PRC, plays a central role in a regulatory network governing the transcriptional control of mitochondrial biogenesis and respiratory function. These coactivators target multiple transcription factors including NRF-1, NRF-2 and the orphan nuclear hormone receptor, ERRalpha, among others. In addition, they themselves are the targets of coactivator and co-repressor complexes that regulate gene expression through chromatin remodeling. The expression of PGC-1 family members is modulated by extracellular signals controlling metabolism, differentiation or cell growth and in some cases their activities are known to be regulated by post-translational modification by the energy sensors, AMPK and SIRT1. Recent gene knockout and silencing studies of many members of the PGC-1 network have revealed phenotypes of wide ranging severity suggestive of complex compensatory interactions or broadly integrative functions that are not exclusive to mitochondrial biogenesis. The results point to a central role for the PGC-1 family in integrating mitochondrial biogenesis and energy production with many diverse cellular functions. This article is part of a Special Issue entitled: Mitochondria and Cardioprotection. PMID- 20933026 TI - Intravital microscopy as a tool to study drug delivery in preclinical studies. AB - The technical developments in the field of non-linear microscopy have made intravital microscopy one of the most successful techniques for studying physiological and pathological processes in live animals. Intravital microscopy has been utilized to address many biological questions in basic research and is now a fundamental tool for preclinical studies, with an enormous potential for clinical applications. The ability to dynamically image cellular and subcellular structures combined with the possibility to perform longitudinal studies have empowered investigators to use this discipline to study the mechanisms of action of therapeutic agents and assess the efficacy on their targets in vivo. The goal of this review is to provide a general overview of the recent advances in intravital microscopy and to discuss some of its applications in preclinical studies. PMID- 20933029 TI - Biological and structural characteristics of the binding peptides from the sporozoite proteins essential for cell traversal (SPECT)-1 and -2. AB - The sporozoite microneme proteins essential for cell traversal, SPECT-1 and SPECT 2, are considered attractive pre-erythrocytic immune targets due to the key role they play in crossing of the malaria parasite across the dermis and the liver sinusoidal wall, prior to invasion of hepatocytes. In this study, the sequences of SPECT-1 and SPECT-2 were mapped using 20 mer-long synthetic peptides to identify high-activity binding peptides (HABPs) to HeLa cells. 17 HABPs with enzyme sensitive bindings to HeLa cells were identified: 3 predominantly alpha helical in SPECT-1, and 10 alpha-helical and 4 beta-turns/random coils in SPECT 2. Immunofluorescence assays (IFA) with antibodies raised in rabbits against chemically synthesized B-cell epitopes suggests the presence of these two proteins in the micronemes and in sporozoite membrane. (1)H NMR studies showed that HABPs located in the membrane-attack complex/perforin (MACPF) domain of SPECT-2 share high similarity with the 3D structure of C8alpha. Altogether, the results highlight the potential of including HABPs from SPECT-1 and SPECT-2 as components of a fully effective multistage, multiepitopic, minimal subunit-based synthetic vaccine against Plasmodium falciparum malaria. PMID- 20933027 TI - Nuclear receptor coregulators as a new paradigm for therapeutic targeting. AB - The complex function and regulation of nuclear receptors cannot be fully understood without a thorough knowledge of the receptor-associated coregulators that either enhance (coactivators) or inhibit (corepressors) transcription. While nuclear receptors themselves have garnered much attention as therapeutic targets, the clinical and etiological relevance of the coregulators to human diseases is increasingly recognized. Aberrant expression or function of coactivators and corepressors has been associated with malignant and metabolic disease development. Many of them are key epigenetic regulators and utilize enzymatic activities to modify chromatin through histone acetylation/deacetylation, histone methylation/demethylation or chromatin remodeling. In this review, we showcase and evaluate coregulators--such as SRCs and ANCCA--with the most promising therapeutic potential based on their physiological roles and involvement in various diseases that are revealed thus far. We also describe the structural features of the coactivator and corepressor functional domains and highlight areas that can be further explored for molecular targeting. PMID- 20933028 TI - Sulfated cholecystokinin-8 activates phospho-mTOR immunoreactive neurons of the paraventricular nucleus in rats. AB - The serin/threonin-kinase, mammalian target of rapamycin (mTOR) was detected in the arcuate nucleus (ARC) and paraventricular nucleus of the hypothalamus (PVN) and suggested to play a role in the integration of satiety signals. Since cholecystokinin (CCK) plays a role in the short-term inhibition of food intake and induces c-Fos in PVN neurons, the aim was to determine whether intraperitoneally injected CCK-8S affects the neuronal activity in cells immunoreactive for phospho-mTOR in the PVN. Ad libitum fed male Sprague-Dawley rats received 6 or 10 MUg/kg CCK-8S or 0.15M NaCl ip (n=4/group). The number of c Fos-immunoreactive (ir) neurons was assessed in the PVN, ARC and in the nucleus of the solitary tract (NTS). CCK-8S increased the number of c-Fos-ir neurons in the PVN (6 MUg: 103 +/- 13 vs. 10 MUg: 165 +/- 14 neurons/section; p<0.05) compared to vehicle treated rats (4 +/- 1, p<0.05), but not in the ARC. CCK-8S also dose-dependently increased the number of c-Fos neurons in the NTS. Staining for phospho-mTOR and c-Fos in the PVN showed a dose-dependent increase of activated phospho-mTOR neurons (17 +/- 3 vs. 38 +/- 2 neurons/section; p<0.05), while no activated phospho-mTOR neurons were observed in the vehicle group. Triple staining in the PVN showed activation of phospho-mTOR neurons co-localized with oxytocin, corresponding to 9.8 +/- 3.6% and 19.5 +/- 3.3% of oxytocin neurons respectively. Our observations indicate that peripheral CCK-8S activates phospho-mTOR neurons in the PVN and suggest that phospho-mTOR plays a role in the mediation of CCK-8S's anorexigenic effects. PMID- 20933030 TI - Central nesfatin-1 reduces the nocturnal food intake in mice by reducing meal size and increasing inter-meal intervals. AB - Nesfatin-1 is well established to reduce food intake upon brain injection in rats, while in mice its anorexigenic action and brain expression are largely unexplored. We characterized the influence of intracerebroventricular (icv) and peripheral (intraperitoneal, ip, subcutaneous, sc) injection of nesfatin-1 on dark phase ingestive behavior using an automated feeding monitoring system and co localized NUCB2/nesfatin-1 immunoreactivity in the associated brain areas. Nesfatin-1 (0.3, 1 or 3 MUg/mouse, icv) caused a dose-related reduction of 4-h dark phase food intake by 13%, 27%, and 46% respectively. Nesfatin-1 (3 MUg/mouse, icv) action had a 2-h delayed onset, 82% peak inhibition occurring at 3-4h post-injection and was long lasting (30% reduction for 12h period post injection). Nesfatin-1 (3 MUg/mouse, icv)-treated mice had a 46% lower meal frequency associated with 2-times longer inter-meal intervals and a 35% reduction in meal size compared to vehicle during the 1-4h post-injection (p<0.05). NUCB2/nesfatin-1-immunopositive neurons were found in hypothalamic (supraoptic, paraventricular, arcuate, dorsomedial, lateral) and brainstem (dorsal vagal complex) feeding regulatory nuclei. When injected peripherally, neither food intake nor feeding microstructure parameters were altered. These results demonstrate that NUCB2/nesfatin-1 is prominently expressed in mouse hypothalamus and medulla and acts in the brain to curtail the dark phase feeding by inducing satiation and satiety indicated by reduced meal size and prolonged inter-meal intervals respectively. The lack of nesfatin-1 effect when injected peripherally at a 23-times higher dose indicates a primarily central site of the anorexigenic action for nesfatin-1 in mice. PMID- 20933031 TI - Hippocampal lipids linked to spatial memory in the C57BL/6J mouse. AB - Although the role of individual brain lipids for learning and memory has been reported, no systematic approach associating brain lipids with spatial memory has been carried out. It was therefore the aim of the study to determine brain lipids in hippocampus of mice forming and yoked controls that did not form spatial memory using the probe trial as the endpoint. 10 animals were trained in the Morris water maze (MWM) and 10 mice were serving as yoked controls i.e. no platform was used during the whole experiment. Hippocampal tissue lipids were extracted and data were acquired with Fourier transformation ion cyclotron resonance mass spectrometry (LTQ-FT) coupled to HPLC. Glycerophosphatidylethanolamines (18:0/22:6, 18:0/20:4 and 18:1/18:1), plasmalogens (16:0-10/22:6 and 18:0-10/22:6) and ceramides (18:0) showed higher levels in the trained group, while glycerolysophosphatidylcholines (16:0, 18:1, 18:0, 20:4), sphingomyelins (16:0, 24:1), ether linked glycerophosphatidylcholines (16:0-10/18:0), glycerophosphatidylcholines (16:0/18:1, 16:0/18:0, 18:0/18:1, 38:7, 18:1/20:1, 20:4/20:4, 22:1/18:1, 22:0/18:1, 20:4/22:6, 22:6/22:6), glucosylceramide (24:1) and plasmalogen (18:0 10/20:1) revealed lower levels in the trained group. Decreased levels of certain species of lysophosphatidylcholine, sphingomyelin, plasmenylphosphatidylcholine, phosphatidylcholine, glycosylceramide and plasmalogen at the probe trial for spatial memory may indicate catabolism in terms of consumption during this process. Increased hippocampal levels of long chain highly unsaturated phosphatidylethanolamines, plasmalogens and ceramides may reflect increased synthesis or decreased degradation at the endpoint of memory testing, probably representing interactions in the brain lipid pathways. The study shows pathways involved in spatial memory, may propose the use of individual brain lipids as probable cognitive enhancers and forms the basis for further studies on the role of brain lipids per se. PMID- 20933032 TI - TDP-43 physically interacts with amyotrophic lateral sclerosis-linked mutant CuZn superoxide dismutase. AB - Mutations in the CuZn superoxide dismutase (SOD1) and TAR DNA-binding protein 43 (TDP-43) genes are linked to familial amyotrophic lateral sclerosis, ALS1 and ALS10, respectively. In addition, TDP-43 is a major component protein of the ubiquitinated aggregates observed in sporadic ALS (SALS) patients. However, it remains unclear whether these ALS groups partly have a shared pathogenesis. In the present study, we demonstrate that mutant SOD1, but not wild-type SOD1, interacts with TDP-43 by co-immunoprecipitation assays using cultured cells and G93A mutant SOD1 transgenic mice. The region responsible for this interaction within SOD1 is the dimer interface, namely, the N- and C-terminal regions. Deletion mutants of TDP-43 with or without nuclear localization sequence interacted with mutant SOD1. Cell fractionation assays using cultured cells showed that mutant SOD1 was localized in the cytosolic fraction but not in the nuclear fraction. TDP-43 was detected both in the nuclear and cytosolic fractions, suggesting that mutant SOD1 interacts with TDP-43 in the cytoplasm. Mutant SOD1 overexpression led to an increased amount of mutant SOD1 and, to some extent, its interacting proteins including TDP-43 in the detergent-insoluble fraction. These results indicate that mutant SOD1 could affect the solubility/insolubility of its interacting proteins including TDP-43 through physical interactions. Our findings may contribute to the understanding of links among SALS, ALS1 and ALS10. PMID- 20933033 TI - alpha-Tocopherol quinone inhibits beta-amyloid aggregation and cytotoxicity, disaggregates preformed fibrils and decreases the production of reactive oxygen species, NO and inflammatory cytokines. AB - Alzheimer's disease (AD) is a complex, multifactorial neurodegenerative disease. The aggregation of beta-amyloid (Abeta) into extracellular fibrillar deposition is a pathological hallmark of AD. The Abeta aggregate-induced neurotoxicity, inflammatory reactions and oxidative stress are linked strongly to the etiology of AD. The currently available hitting-one-target drugs are insufficient for the treatment of AD. Therefore, finding multipotent agents able to modulate multiple targets simultaneously is attracting more attention. Previous studies indicated that vitamin E or its constituent such as alpha-tocopherol (alpha-T) was able to attenuate the effects of several pathogenetic factors in AD. However, ineffective or detrimental results were obtained from a number of clinical trials of vitamin E. Here, we showed that naturally synthesized RRR-alpha-tocopherol quinone (alpha TQ), a main derivative of alpha-T, could inhibit Abeta42 fibril formation dose dependently. Further investigations indicated that alpha-TQ could attenuate Abeta42-induced neurotoxicity toward SH-SY5Y neuroblastoma cells, disaggregate preformed fibrils and interfere with natural intracellular Abeta oligomer formation. Moreover, alpha-TQ could decrease the formation of reactive oxygen species (ROS) and NO, and modulate the production of cytokines by decreasing TNF alpha and IL-1beta and increasing IL-4 formation in microglia. Taken together, alpha-TQ targeting multiple pathogenetic factors deserves further investigation for prevention and treatment of AD. PMID- 20933034 TI - Hypoxia induces up-regulation of progranulin in neuroblastoma cell lines. AB - Progranulin (PGRN) is a widely expressed multifunctional protein, involved in regulation of cell growth and cell cycle progression with a possible involvement in neurodegeneration. We looked for PGRN regulation in three different human neuroblastoma cell lines, following exposure to two different stimuli commonly associated to neurodegeneration: hypoxia and oxidative stress. For gene and protein expression analysis we carried out a quantitative RT-PCR and western blotting analysis. We show that PGRN is strongly up-regulated by hypoxia, through the mitogen-actived protein kinase (MAPK)/extracellular signal-regulated kinase (MEK) signaling cascade. PGRN is not up-regulated by H(2)O(2)-induced oxidative stress. These results suggest that PGRN in the brain could exert a protective role against hypoxic stress, one of principal risk factors involved in frontotemporal dementia pathogenesis. PMID- 20933035 TI - Activation of the neurokinin-1 receptor in rat spinal astrocytes induces Ca2+ release from IP3-sensitive Ca2+ stores and extracellular Ca2+ influx through TRPC3. AB - Substance P (SP) plays an important role in pain transmission through the stimulation of the neurokinin (NK) receptors expressed in neurons of the spinal cord, and the subsequent increase in the intracellular Ca(2+) concentration ([Ca(2+)](i)) as a result of this stimulation. Recent studies suggest that spinal astrocytes also contribute to SP-related pain transmission through the activation of NK receptors. However, the mechanisms involved in the SP-stimulated [Ca(2+)](i) increase by spinal astrocytes are unclear. We therefore examined whether (and how) the activation of NK receptors evoked increase in [Ca(2+)](i) in rat cultured spinal astrocytes using a Ca(2+) imaging assay. Both SP and GR73632 (a selective agonist of the NK1 receptor) induced both transient and sustained increases in [Ca(2+)](i) in a dose-dependent manner. The SP-induced increase in [Ca(2+)](i) was significantly attenuated by CP-96345 (an NK1 receptor antagonist). The GR73632-induced increase in [Ca(2+)](i) was completely inhibited by pretreatment with U73122 (a phospholipase C inhibitor) or xestospongin C (an inositol 1,4,5-triphosphate (IP(3)) receptor inhibitor). In the absence of extracellular Ca(2+), GR73632 induced only a transient increase in [Ca(2+)](i). In addition, H89, an inhibitor of protein kinase A (PKA), decreased the GR73632 mediated Ca(2+) release from intracellular Ca(2+) stores, while bisindolylmaleimide I, an inhibitor of protein kinase C (PKC), enhanced the GR73632-induced influx of extracellular Ca(2+). RT-PCR assays revealed that canonical transient receptor potential (TRPC) 1, 2, 3, 4 and 6 mRNA were expressed in spinal astrocytes. Moreover, BTP2 (a general TRPC channel inhibitor) or Pyr3 (a TRPC3 inhibitor) markedly blocked the GR73632-induced sustained increase in [Ca(2+)](i). These findings suggest that the stimulation of the NK-1 receptor in spinal astrocytes induces Ca(2+) release from IP(3-)sensitive intracellular Ca(2+) stores, which is positively modulated by PKA, and subsequent Ca(2+) influx through TRPC3, which is negatively regulated by PKC. PMID- 20933036 TI - Lactate levels in the brain are elevated upon exposure to volatile anesthetics: a microdialysis study. AB - Anesthetic agents have well-defined pharmacological targets but their effects on energy metabolism in the brain are poorly understood. In this study, we examined the effects of different anesthetics on extracellular lactate and glucose levels in blood, CSF and brain of the mouse. In vivo-microdialysis was used to monitor extracellular energy metabolites in the brain of awake mice and during anesthesia with seven different anesthetic drugs. In separate groups, lactate and glucose concentrations in blood and CSF were measured for each anesthetic. We found that anesthesia with isoflurane caused a large increase of extracellular lactate levels in mouse striatum and hippocampus (300-400%). Pyruvate levels also increased while glucose and glutamate levels were unchanged. This effect was dose dependent and was mimicked by other gaseous anesthetics such as halothane and sevoflurane but not by intravenous anesthetics. Ketamine/xylazine and chloral hydrate caused 2-fold increases of glucose levels in mouse blood and brain while lactate levels were only moderately increased. Propofol caused a minor increase of extracellular glucose levels while pentobarbital had no effect on either lactate or glucose. Volatile anesthetics also increased lactate levels in blood and CSF by 2-3-fold but had no effect on plasma glucose. Further experiments demonstrated that lactate formation by isoflurane in mouse brain was independent of neuronal impulse flow and did not involve ATP-dependent potassium channels. We conclude that volatile anesthetics, but not intravenous anesthetics, cause a specific, dose-dependent increase in extracellular lactate levels in mouse brain. This effect occurs in the absence of ischemia, is independent of peripheral actions and is reflected in strongly increased CSF lactate levels. PMID- 20933037 TI - Up-regulation of serum- and glucocorticoid-induced protein kinase 1 in the brain tissue of human and experimental epilepsy. AB - Several studies have shown that serum- and glucocorticoid-induced protein kinase 1(SGK1) can regulate both glutamate receptors and glutamate transporters and may participate in the regulation of neuroexcitability in neuronal diseases. In our previous study, we analyzed differential gene expression in the anterior temporal neocortex of drug-refractory epilepsy patients relative to control patients using a complementary DNA microarray and found that the SGK1 gene was up-regulated more than twofold in the brain tissues of epileptic patients. In the current study, we measured SGK1 expression in the brain tissues of humans and in an experimental model of rat epilepsy in order to explore the relationship between SGK1 expression and epilepsy. The SGK1 expression was detected in thirty human brain tissues derived from patients undergoing operation for drug-refractory epilepsy and was also detected in eight samples from autopsies. Meanwhile, we investigated SGK1 expression during the epileptic process in rats using immunofluorescence, RT PCR and western blot analysis. SGK1 expression was enhanced in the temporal neocortex of patients with drug-refractory epilepsy and was also highly expressed in the rat brain during different phases of the epileptic process. SGK1 expression was also related with the elevation of EAAT3, which expression reduced after knockdown SGK1. These results provide new insight into the potential role of SGK1 in the pathophysiology of epilepsy. PMID- 20933038 TI - Improved in silico prediction of carcinogenic potency (TD50) and the risk specific dose (RSD) adjusted Threshold of Toxicological Concern (TTC) for genotoxic chemicals and pharmaceutical impurities. AB - The Threshold of Toxicological Concern (TTC) is a level of exposure to a genotoxic impurity that is considered to represent a negligible risk to humans. The TTC was derived from the results of rodent carcinogenicity TD50 values that are a measure of carcinogenic potency. The TTC currently sets a default limit of 1.5 MUg/day in food contact substances and pharmaceuticals for all genotoxic impurities without carcinogenicity data. Bercu et al. (2010) used the QSAR predicted TD50 to calculate a risk specific dose (RSD) which is a carcinogenic potency adjusted TTC for genotoxic impurities. This promising approach is currently limited by the software used, a combination of MC4PC (www.multicase.com) and a Lilly Inc. in-house software (VISDOM) that is not available to the public. In this report the TD50 and RSD were predicted using a commercially available software, SciQSAR (formally MDL-QSAR, www.scimatics.com) employing the same TD50 training data set and external validation test set that was used by Bercu et al. (2010). The results demonstrate the general applicability of QSAR predicted TD50 values to determine the RSDs for genotoxic impurities and the improved performance of SciQSAR for predicting TD50 values. PMID- 20933039 TI - Human biomonitoring as a pragmatic tool to support health risk management of chemicals--examples under the EU REACH programme. AB - REACH requires health risk management for workers and the general population and introduced the concept of Derived No-Effect Level (DNEL). DNELs must be derived for all substances that are classified as health hazards. As with analogues to other health-risk based guidance values, such as reference doses (RfDs) and tolerable daily intakes (TDIs), risk to health is considered negligible if the actual exposure is less than the DNEL. Exposure assessment is relatively simple for occupational situations but more complex for the general public, in which exposure may occur via multiple pathways, routes, and media. For such complex or partially defined exposure scenarios, human biomonitoring gives a snapshot of internal or absorbed dose of a chemical and is often the most reliable exposure assessment methodology as it integrates exposures from all routes. For human risk management human biomonitoring data can be interpreted using the recently developed concept of Biomonitoring Equivalents (BE). Basically, a BE translates an established reference value into a biomarker concentration using toxicokinetic data. If the results of an exposure assessment using human biomonitoring indicate that the levels measured are below the DNEL-based BE (BE(DNEL)), it would indicate that the combined exposure via all potential exposure routes is unlikely to pose a risk to human health and that health risk management measures might not be needed. Hence, BEs do not challenge existing risk assessments but rather build upon them to help risk management, the ultimate goal of any risk assessment. A challenge in implementing this approach forms the limited availability of toxicokinetic information for many substances. However, methodologies such as generic physiologically-based toxicokinetic models, which allow estimation of biomarker concentrations based on physicochemical properties, are being developed for less data-rich chemicals. Use of BE by regulatory authorities will allow initial screening of population exposure to chemicals to identify those chemicals requiring more detailed risk and exposure assessment, assisting in priority setting and ultimately leading to improved product stewardship and risk management. PMID- 20933040 TI - Contrasting substitution patterns between HA proteins of avian and human influenza viruses: Implication for monitoring human influenza epidemics. AB - The HA1 domain of influenza A viruses is critical for immune escape and host receptor recognition. However, the association between HA1 evolution and host species-specific adaptations remains unclear. We have identified the amino acid sites that are related to the host species-specific adaptations by systematically comparing the evolutionary dynamics of HA1 between human and avian hosts for both H1N1 and H3N2 viruses. We can thus refine the "positively selected sites" in the HA1 domain of these two virus subtypes to those that occur only in humans. We further demonstrate that the refined sets can accurately reflect influenza epidemics. Our retrospective study shows that when substitutions occur at more than three out of these identified sites in the same year, an epidemic is very likely to occur. Therefore, our approach could potentially be used in determining whether new influenza vaccines are needed. PMID- 20933041 TI - CpG oligodeoxynucleotides containing GACGTT motifs enhance the immune responses elicited by a goose parvovirus vaccine in ducks. AB - Recombinant parvovirus VP2 (rVP2) was formulated with different types of adjuvant, including aluminum adjuvant and CpG oligodeoxynucleotides (ODNs), and the immunological responses after vaccination in ducks were examined. In comparison with the control group, production of rVP2-specific antibodies, expression of cytokines in peripheral blood mononuclear cells (PBMC) stimulated by rVP2, and percentage of CD4(+)/CD8(+) cells in PBMC were significantly increased in ducks immunized with rVP2 formulated with CpG ODNs containing 3 copies of GACGTT motif. CpG ODNs with GACGTT motifs might be used to improve the efficacy of vaccines for ducks. PMID- 20933043 TI - Agomelatine in the treatment of panic disorder. PMID- 20933042 TI - Public vaccination programmes against hepatitis B in The Netherlands: assessing whether a targeted or a universal approach is appropriate. AB - To date, the policy to control hepatitis B in the Netherlands is to vaccinate specific risk groups, rather than all children. Low incidence of the disease has fueled debate whether such a targeted vaccination strategy or rather a universal strategy, as recommended by the World Health Organization, is appropriate. The standard framework for assessing whether a particular vaccination should be included in a public programme, as recently proposed by the Health Council of the Netherlands (HCN), was applied to the various options for hepatitis B vaccination. This framework includes seven selection criteria, grouped under five thematic headings: seriousness and extent of the disease burden, effectiveness and safety of the vaccination, acceptability of the vaccination, efficiency of the vaccination, and priority of the vaccination. From about 1990 the disease burden has stayed more or less the same over time and careful assessment has made it clear that the targeted approach has failed to reach a significant part of the risk groups. Models suggest that the public health benefits obtained through targeted programmes could be augmented considerably by universal vaccination. Based on the assessment that universal vaccination means better protection for high-risk groups as well as the whole population, the HCN calls for universal immunisation, even though hepatitis B to a large extent is limited to specific high-risk groups. Should the Netherlands adopt universal vaccination, several immunisation programmes targeted to high-risk groups will, however, remain of crucial importance for years to come. PMID- 20933044 TI - A case of porencephalic cyst in a schizophrenic patient with history of postnatal encephalitis. PMID- 20933045 TI - The respiratory allergen glutaraldehyde in the local lymph node assay: sensitization by skin exposure, but not by inhalation. AB - Previously, a selection of low molecular weight contact and respiratory allergens had tested positive in both a skin and a respiratory local lymph node assay (LLNA), but formaldehyde was negative for sensitization by inhalation. To investigate whether this was due to intrinsic properties of aldehyde sensitizers, the structurally related allergen glutaraldehyde (GA) was tested. BALB/c mice were exposed by inhalation to 6 or 18ppm GA (respiratory LLNA), both generated as a vapor and as an aerosol. Other groups received 0.25% or 2.5% GA on the skin of the ears (skin LLNA). Lymphocyte proliferation and cytokine production were measured in the draining lymph nodes. GA was positive in the skin LLNA and its cytokine profile (IL-4/IFN-gamma) skewed towards a Th2-type immune response with increasing dose. Inhalation exposure did not result in increased lymphocyte proliferation or increased cytokine levels, despite comparable tissue damage (irritation) in the skin and respiratory tract. We hypothesize that the highly reactive and hydrophilic GA oligomerizes in the protein-rich mucous layer of the respiratory tract, which impedes sensitization but still facilitates local irritation. Within the context of risk assessment in respiratory allergy, our results stress the importance of prevention of skin--besides inhalation-- exposure to aldehydes like GA. PMID- 20933046 TI - Trial of protective effect of fissure sealants, in vivo, on the palatal surfaces of anterior teeth, in patients suffering from erosion. AB - OBJECTIVES: Previous work has shown protection to eroded teeth offered by a resin based adhesive lasted up to three months. The hypothesis investigated in this study was whether application of a fissure sealant would offer longer protection. METHODS: Seventeen adult patients with palatal tooth wear were recruited and written consent obtained. Metal discs were cemented on the palatal surfaces of all upper anterior teeth following previously published techniques. Alternate teeth within each subject were randomly chosen and coated with a clear fissure sealant using previously published methods. The uncoated teeth were used as controls. Accurate impressions were taken in custom made trays and repeated at 3, 6, 9, 12 and 20 months and scanned using a non-contacting laser profilometer. RESULTS: The mean (standard deviation) thickness of the fissure sealant was 290 MUm (500) at the start and after 3 months a mean thickness of 120 MUm (260) remained. At this point the control surfaces showed a mean 70 MUm (113) of tooth wear. At 6 and 9 months the mean wear for control teeth was higher at 120 MUm (114) and 110 MUm (114) than sealed teeth at 50 MUm (260) and 60 MUm (440), respectively. A comparison of paired sites within subjects at their final visit indicated a statistically significant difference in wear between the sealed and control teeth (p=0.016). CONCLUSIONS: The use of fissure sealant to protect palatal dentine surfaces may have a role in prevention of tooth wear for up to a period of nine months. PMID- 20933047 TI - Four-year clinical evaluation of Class II nano-hybrid resin composite restorations bonded with a one-step self-etch and a two-step etch-and-rinse adhesive. AB - OBJECTIVE: The objective of this prospective clinical trial was to evaluate the 4 year clinical performance of an ormocer-based nano-hybrid resin composite (Ceram X; Dentsply/DeTrey) in Class II restorations placed with a one-step self-etch (Xeno III; Dentsply/DeTrey) and two-step etch-and-rinse adhesive (Ivoclar Vivadent). METHODS: Seventy-eight participants received at random at least two, as similar as possible, Class II restorations of the nano-hybrid resin composite bonded with either a single step self-etch adhesive or a control 2-step etch-and rinse adhesive. The 165 restorations were evaluated using slightly modified USPHS criteria at baseline and then yearly during 4 years. RESULTS: 162 restorations were evaluated at 4 years. Postoperative sensitivity was observed in 6 patients (3 Xeno III, 3 Exite) between 1 and 3 weeks. Eleven failed restorations (6.8%) were observed during the follow up. Seven in the one-step self-etch adhesive group (7.7%) and four in the 2-step etch-and-rinse group (5.6%). This resulted in non-significant different annual failure rates of 1.9% and 1.4%, respectively. Fracture of restoration was the main reason for failure. CONCLUSION: The ormocer based nano-hybrid resin composite showed a good clinical performance in Class II cavities during the 4 year evaluation. No significant difference was seen in overall clinical effectiveness between the two adhesives. PMID- 20933049 TI - Selective constraints, molecular recombination structure and phylogenetic reconstruction of isometric plant RNA viruses of the families Luteoviridae and Tymoviridae. AB - In an effort to enhance the knowledge on molecular evolution of currently the known members of the families Luteoviridae and Tymoviridae, in-depth molecular investigations in the entire genome of 147 accessions retrieved from the international databases, were carried out. Two algorithms (RECCO and RDP version 3.31beta) adapted to the mosaic structure of viruses were utilized. The recombination frequency along the sequences was dissected and demonstrated that the three virus genera of the family Luteoviridae comprise numerous members subjected to recombination. It has pointed out that the major viruses swapped a few but long genomic segments. In addition, in Barley yellow dwarf virus, heredity material might be exchanged between two different serotypes. Even more, putative recombination events occurred between two different genera. Based on Fisher's Exact Test of Neutrality, positive selection acting on protein expression was detected only in the poleroviruses Cereal yellow dwarf virus, Potato leafroll virus and Wheat yellow dwarf virus. In contrast, several components of the family Tymoviridae were highly recombinant. Genomic portion exchange arose in many positions consisting of short fragments. Furthermore, no positive selection was detected. The evolutionary history showed, in the Luteoviridae, that all screened isolates split into three clusters corresponding to the three virus genera forming this family. Moreover, in the serotype PAV of Barley yellow dwarf virus, two major clades corresponding to PAV-USA and PAV China, were delineated. Similarly, in the Tymoviridae, all analyzed isolates fell into four groups corresponding to the three virus genera composing this family along with the unclassified Tymoviridae. Inferred phylogenies reshuffled the existing classification and showed that Wheat yellow dwarf virus-RPV was genetically closely related to Cereal yellow dwarf virus and the unclassified Tymoviridae Grapevine syrah virus-1 constituted an integral part of the genus Marafivirus. PMID- 20933048 TI - Solvent composition of one-step self-etch adhesives and dentine wettability. AB - OBJECTIVES: Our aim was to determine the wettability of dentine by four commercial self-etch adhesives and evaluate their spreading rate on the dentine surface. Any correlation with chemical composition was sought, particularly with the amount of solvent or HEMA present in the adhesive. The adhesives used were AdheSE One, Optibond All.In.One, Adper Easy Bond and XenoV. METHODS: Chemical compositions were determined by proton nuclear magnetic resonance (NMR) spectroscopy of the adhesives dissolved in dimethylsulfoxide. Apparent contact angles for sessile drops of adhesives were measured on dentine slices as a function of time for up to 180s. The water contact angles were determined for fully polymerised adhesives. RESULTS: All adhesives were water-based with total solvent contents ranging from 27% to 73% for HEMA-free adhesives, and averaging 45% for HEMA containing adhesives. The contents in hydrophobic groups decreased as water contents increased. No differences were found in the adhesive contact angles after 180s even though the spreading rates were different for the products tested. CONCLUSION: Water contact angles differed significantly but were not correlated with HEMA or solvent presence. Manufacturers use different approaches to stabilise acid co-monomer ingredients in self-etch adhesives. Co-solvents, HEMA, or acrylamides without co-solvents are used to simultaneously etch and infiltrate dentine. A large proportion of water is necessary for decalcification action. PMID- 20933050 TI - The disulfiram metabolites S-methyl-N,N-diethyldithiocarbamoyl sulfoxide and S methyl-N,N-diethylthiocarbamoyl sulfone irreversibly inactivate betaine aldehyde dehydrogenase from Pseudomonas aeruginosa, both in vitro and in situ, and arrest bacterial growth. AB - Betaine aldehyde dehydrogenase from the human opportunistic pathogen Pseudomonas aeruginosa (PaBADH) catalyzes the irreversible, NAD(P)(+)-dependent oxidation of betaine aldehyde, producing glycine betaine, an osmoprotectant. PaBADH participates in the catabolism of choline and likely in the defense against the osmotic and oxidative stresses to which the bacterium is exposed when infecting human tissues. Given that choline or choline precursors are abundant in infected tissues, PaBADH is a potential drug target because its inhibition will lead to the build up of the toxic betaine aldehyde inside bacterial cells. We tested the thiol reagents, disulfiram (DSF) and five DSF metabolites-diethyldithiocarbamic acid (DDC), S-methyl-N,N-diethyldithiocarbamoyl sulfoxide (MeDDTC-SO) and sulfone (MeDDTC-SO(2)), and S-methyl-N,N-diethylthiocarbamoyl sulfoxide (MeDTC-SO) and sulfone (MeDTC-SO(2))-as inhibitors of PaBADH and P. aeruginosa growth. As in vitro PaBADH inhibitors, their order of potency was: MeDDTC-SO(2)>DSF>MeDTC SO(2)>MeDDTC-SO>MeDTC-SO. DDC did not inactivate the enzyme. PaBADH inactivation by DSF metabolites (i) was not affected by NAD(P)(+), (ii) could not be reverted by dithiothreitol, and (iii) did not affect the quaternary structure of the enzyme. Of the DSF metabolites tested, MeDTC-SO(2) and MeDDTC-SO produced significant in situ PaBADH inactivation and arrest of P. aeruginosa growth in choline containing media, in which the expression of PaBADH is induced. They had no effect in media lacking choline, indicating that PaBADH is their main intracellular target, and that arrest of growth is due to accumulation of betaine aldehyde. The in vitro and in situ kinetics of enzyme inactivation by these two compounds were very similar, indicating no restriction on their uptake by the cells. MeDDTC-SO(2) and DSF have no inhibitory effects in situ, probably because their high reactivity towards intracellular nonessential thiols causes their depletion. Our results support that PaBADH is a promising target to treat P. aeruginosa infections, and that some DSF metabolites might be of help in this aim. PMID- 20933052 TI - MicroRNA-146a disrupts hematopoietic differentiation and survival. AB - OBJECTIVE: MicroRNAs (miRNAs) are short noncoding RNAs capable of exerting dramatic effects by postranscriptionally regulating numerous messenger RNA targets. Toll-like receptor-4 (TLR-4) activation by lipopolysaccharide (LPS) induces the expression of three miRNAs in myeloid cells. The aim of this study was to investigate the in vivo consequences of expressing one of the LPS-induced miRNA, miR-146a, in bone marrow cells. MATERIAL AND METHODS: The role of miR-146a in hematopoiesis was investigated by using retroviral infection and overexpression of miR-146a in mouse hematopoietic stem/progenitor cells, followed by bone marrow transplantations. RESULTS: miR-146a is mainly expressed in primitive hematopoietic stem cells and T lymphocytes. Overexpression of miR-146a in hematopoietic stem cells, followed by bone marrow transplantation, resulted in a transient myeloid expansion, decreased erythropoiesis, and impaired lymphopoiesis in select anatomical locations. Enforced expression of miR-146a also impaired bone marrow reconstitution in recipient mice and reduced survival of hematopoietic stem cells. CONCLUSIONS: Our results indicate that miR-146a, an LPS-induced miRNA, regulates multiple aspects of hematopoietic differentiation and survival. Furthermore, the consequences of miR-146a expression in hematopoietic cells mimics some of the reported effects with acute LPS exposure. PMID- 20933051 TI - Maintenance of HSC by Wnt5a secreting AGM-derived stromal cell line. AB - OBJECTIVE: The microenvironment wherein hematopoietic stem cells (HSC) reside orchestrates HSC self-renewal vs. differentiation decisions. Stromal cells derived from ontogenically divergent hematopoietic microenvironments can support HSC in vitro and have been used to decipher factors that influence HSC fate decisions. Employing stromal cell lines derived from the aorta-gonad-mesonephros and embryonic liver, we aim to identify secreted factors that maintain/expand HSC in vitro. MATERIALS AND METHODS: We cultured murine lineage antigen-negative (Lin(-)) bone marrow cells in transwells above the UG26-1B6, urogenital ridge-, and EL08-1D2, embryonic liver-derived cell lines. We, also, performed real-time quantitative PCR analysis to identify differentially expressed genes from the Wnt family of proteins in ontogenically different stromal cell lines. RESULTS: Lin(-) murine bone marrow cells maintained for 3 weeks in transwells above UG26-1B6 but not EL08-1D2 cells contained competitive repopulating HSC. Addition of as few as 25% UG26-1B6 cells to EL08-1D2 feeders led to maintenance of HSC in noncontact cultures, validating soluble factors are secreted by the UG26-1B6 cells. As we found that Wnt5a was significantly higher expressed in UG26-1B6 than EL08-1D2 cells, we added Wnt5a to EL08-1D2 transwell cultures or an antibody against Wnt5a to UG26-1B6 transwell cultures. Addition of Wnt5a to EL08-1D2 transwell cultures restored maintenance of HSC, whereas addition of an anti-Wnt5a antibody to UG26 1B6 transwell cultures inhibited maintenance of competitive repopulating HSC. CONCLUSIONS: We demonstrate that stromal cell lines generated from embryonic microenvironments provide a tool to identify secreted proteins that play a role in the maintenance of HSC, and that at least one of the factors produced by UG26 1B6 cells responsible for preserving HSC is Wnt5a. PMID- 20933053 TI - Endogenously elevated androgens alter the developmental programming of the hypothalamic-pituitary axis in male mice. AB - Transgenic male mice that express human chorionic gonadotropin (hCG) alpha and beta subunits constitutively hypersecrete hCG and produce elevated levels of androgens. The aim of this study was to characterize the hypothalamic-pituitary function of these transgenic (hCGalphabeta+) males by focusing on FSH regulation. Serum FSH levels and pituitary mRNA expression of Fshb, Lhb, Cga, Gnrhr and Esr1 were reduced, whereas Fst expression was increased in prepubertal hCGalphabeta+ males as compared with wild-type. In the hypothalamus, Cyp19a1 expression, GnRH concentration and ex-vivo GnRH pulsatility were elevated in prepubertal hCGalphabeta+ mice, whereas Kiss1 expression was decreased prepubertally and Gad67 expression was elevated neonatally. The effect of androgens on the developmental programming of the hypothalamic-pituitary axis of hCGalphabeta+ males was evaluated by perinatal and prepubertal antiandrogen (flutamide) administration. Our studies identified a critical window between gestational day 18 and postnatal day 14, during which chronically elevated androgens and/or their locally produced metabolites activate the hypothalamus and concomitantly shut down the gonadotropin axis. PMID- 20933054 TI - Modulation of Bcl-2-related protein expression in pancreatic beta cells by pro inflammatory cytokines and its dependence on the antioxidative defense status. AB - Pro-inflammatory cytokines are key mediators in the selective and progressive destruction of insulin-producing beta cells during type 1 diabetes development. However, the mechanisms of cytokine-induced beta cell apoptosis are not fully understood. This study demonstrates that pro-inflammatory cytokines strongly modified the expression of the anti-apoptotic protein Bcl-2 and the pro-apoptotic BH3-only proteins Bad, Bim, and Bid in primary rat islets and insulin-producing RINm5F cells. Overexpression of mitochondrially located catalase (MitoCatalase) specifically increased basal Bcl-2 and decreased basal Bax expression, suppressed cytokine-mediated reduction of Bcl-2, and thereby prevented the release of cytochrome c, Smac/DIABLO and the activation of caspase-9 and -3. Thus, cytokine mediated decrease of Bcl-2 expression and the sequentially changed Bax/Bcl-2 ratio are responsible for the release of pro-apoptotic mitochondrial factors, activation of caspase-9, and ultimately caspase-3. These results indicate that activation of the intrinsic/mitochondrial apoptosis pathway is essential for cytokine-induced beta cell death and the mitochondrial generation of reactive oxygen species, in particular mitochondrial hydrogen peroxide, differentially regulates the Bax/Bcl-2 ratio. PMID- 20933055 TI - Age related strategic differences in processing irrelevant information. AB - Deficient control of irrelevant information with greater age can be demonstrated in paradigms like inhibition of return (IOR). IOR is a mechanism to protect the organism from redirecting attention to a previously scanned irrelevant location and is assumed to be generated slower but to a comparable amount with increasing age. We investigated this putative deficit by means of event-related potentials (ERPs). As expected, IOR developed later in older subjects. In the cue-related ERPs, young subjects showed a large frontocentral N2 (reflecting control or inhibition) which was virtually absent in the old subjects. Instead, the older subjects showed a P3b, reflecting controlled processing of information. Thus, older adults process irrelevant stimuli more like relevant ones, thereby overloading their information processing system. PMID- 20933056 TI - An image fusion algorithm based on multi-resolution decomposition for functional magnetic resonance images. AB - This paper presents a new functional image fusion algorithm which is the combination of SPM and ICA using multi-resolution decomposition. Firstly, we designed the fMRI experiments and obtained the fMRI image data from different experimental conditions. The brain activated regions were extracted by the SPM and ICA methods respectively. Secondly, by constructing the Laplacian pyramids of the source image, a new fusion rule based on the salience and matching measure is proposed in various resolutions. Finally, the fused functional images are reconstructed by the inverse Laplacian pyramid transformation. The results show that the algorithm can retain the details of the source images and pinpoint exactly the brain functional area associated with the hand action, thus outperforming SPM or ICA for functional regions extraction. PMID- 20933057 TI - No association between the KCNH1, KCNJ10 and KCNN3 genes and schizophrenia in the Han Chinese population. AB - Schizophrenia is a common severe mental illness affecting 0.3-2.0% of the world's population. The potassium channels are thought to have a role in modulating electrical excitability in neurons, regulating calcium signaling in oligodendrocytes and regulating action potential duration in presynaptic terminals and GABA release. Previous studies have reported that some potassium channel genes might be candidate genes for susceptibility to schizophrenia. In the present study, we chose three potassium channel genes, KCNH1, KCNJ10, KCNN3 to investigate the role of potassium channels in schizophrenia by genotyping 23 SNPs (9 in KCNH1, 5 in KCNJ10 and 9 in KCNN3) in a Han Chinese sample consisting of 893 schizophrenia patients and 611 healthy controls. No significant difference in allelic or genotypic frequency was revealed between schizophrenia patients and healthy individuals. Nor was a significant difference in haplotypic distribution detected. MDR analysis revealed no gene-gene interaction within the three potassium channel genes. Our study suggests that the 23 SNPs within the three potassium genes we examined do not play a major role in schizophrenia in the Han Chinese population. PMID- 20933058 TI - Anti-neuroinflammation effect of ginsenoside Rbl in a rat model of Alzheimer disease. AB - The present work explored the anti-neuroinflammation effects of Ginseng Rb1 in a rat model of Alzheimer disease produced by ventricle injection of Abeta1-42. Abeta1-42 injection induces loss of learning and memory behavior of rats in Morris water maze, which could be reversed with Rb1 treatment. Further, Rb1 reversed the changes in several direct or indirect neuroinflammation markers in the hippocampus, suggesting that this could be a potential underlying mechanism and a way to develop anti-aging drugs. PMID- 20933059 TI - Spatial coding of touch at the fingers: Insights from double simultaneous stimulation within and between hands. AB - We studied the effect of tactile double simultaneous stimulation (DSS) within and between hands to examine spatial coding of touch at the fingers. Participants performed a go/no-go task to detect a tactile stimulus delivered to one target finger (e.g., right index), stimulated alone or with a concurrent non-target finger, either on the same hand (e.g., right middle finger) or on the other hand (e.g., left index finger=homologous; left middle finger=non-homologous). Across blocks we also changed the unseen hands posture (both hands palm down, or one hand rotated palm-up). When both hands were palm-down DSS interference effects emerged both within and between hands, but only when the non-homologous finger served as non-target. This suggests a clear segregation between the fingers of each hand, regardless of finger side. By contrast, when one hand was palm-up interference effects emerged only within hand, whereas between hands DSS interference was considerably reduced or absent. Thus, between hands interference was clearly affected by changes in hands posture. Taken together, these findings provide behavioral evidence in humans for multiple spatial coding of touch during tactile DSS at the fingers. In particular, they confirm the existence of representational stages of touch that distinguish between body-regions more than body-sides. Moreover, they show that the availability of tactile stimulation side becomes prominent when postural update is required. PMID- 20933061 TI - Binding and intracellular routing of the plant-toxic lectins, lanceolin and stenodactylin. AB - BACKGROUND: The present research studied the interaction of two ribosome inactivating proteins (RIPs) from Adenia genus with HeLa cells. Namely, lanceolin and stenodactylin were examined in comparison to volkensin, another toxic two chain RIP from Adenia genus. METHODS: The binding, endocytosis, intracellular routing, degradation and exocytosis were investigated by measuring the distribution of radiolabelled RIP and by determining its cytotoxicity. RESULTS: Stenodactylin was the most toxic, resulting in the greater inhibition of protein synthesis and cell death. Lanceolin and stenodactylin bound to cells with comparable affinity and have a similar number of binding sites (10(5)/cell). The uptake of lanceolin and stenodactylin was 13 and 36 times greater, respectively, than that reported for volkensin. The two toxins bound to cell membrane receptors via their lectin B chain, were endocytosed through a clathrin-independent pathway, were internalised in a manner independent from endosomal acidification, and required routing through the Golgi apparatus, as reported for modeccin and volkensin. Stenodactylin showed greater uptake, exocytosis and re-uptake of non degraded RIP than lanceolin and volkensin, whereas volkensin had the highest residual activity after being released from the cell. CONCLUSIONS: The high cytotoxicity of RIPs from the Adenia genus may depend on the following: high affinity binding to the cell and efficient endocytosis, intracellular routing that appears similar to that of other ricin-like toxic RIPs, partial resistance to proteolysis, and, regarding stenodactylin, high accumulation in cell. GENERAL SIGNIFICANCE: The data provide a model that could lead to new strategies for anti cancer therapy and neuroscience studies. PMID- 20933060 TI - Screening for calcium channel modulators in CLN3 siRNA knock down SH-SY5Y neuroblastoma cells reveals a significant decrease of intracellular calcium levels by selected L-type calcium channel blockers. AB - BACKGROUND: Defects of the CLN3 gene on chromosome 16p12.1 lead to the juvenile form of neuronal ceroid-lipofuscinosis (JNCL, Batten Disease), the most common recessive inherited neurodegenerative disorder in children. Dysregulation of intracellular calcium homeostasis in the absence of a functional CLN3 protein (CLN3P, Battenin) has been linked to synaptic dysfunction and accelerated apoptosis in vulnerable neuronal cells. Prolonged increase of intracellular calcium concentration is considered to be a significant trigger for neuronal apoptosis and cellular loss in JNCL. METHODS: We examined the potential effect of 41 different calcium channel modulators on intracellular calcium concentration in CLN3 siRNA knock down SH-SY5Y neuroblastoma cells. RESULTS: Six drugs belonging to the group of voltage dependent L-type channel blockers show significant lowering of the increased intracellular calcium levels in CLN3 siRNA knock down cells. CONCLUSIONS: Our studies provide important new data suggesting possible beneficial effects of the tested drugs on calcium flux regulated pathways in neuronal cell death. Therapeutic intervention in this untreatable disease will likely require drugs that cross the blood-brain barrier as did all of the positively screened drugs in this study. GENERAL SIGNIFICANCE: Better comprehension of the mechanism of neurodegeneration in rare recessive disorders, such as neuronal ceroid-lipofuscinoses, is likely to help to better understand mechanisms involved in more complex genetic neurodegenerative conditions, such as those associated with aging. PMID- 20933062 TI - A common neural system is activated in hearing non-signers to process French sign language and spoken French. AB - We used functional magnetic resonance imaging to investigate the areas activated by signed narratives in non-signing subjects naive to sign language (SL) and compared it to the activation obtained when hearing speech in their mother tongue. A subset of left hemisphere (LH) language areas activated when participants watched an audio-visual narrative in their mother tongue was activated when they observed a signed narrative. The inferior frontal (IFG) and precentral (Prec) gyri, the posterior parts of the planum temporale (pPT) and of the superior temporal sulcus (pSTS), and the occipito-temporal junction (OTJ) were activated by both languages. The activity of these regions was not related to the presence of communicative intent because no such changes were observed when the non-signers watched a muted video of a spoken narrative. Recruitment was also not triggered by the linguistic structure of SL, because the areas, except pPT, were not activated when subjects listened to an unknown spoken language. The comparison of brain reactivity for spoken and sign languages shows that SL has a special status in the brain compared to speech; in contrast to unknown oral language, the neural correlates of SL overlap LH speech comprehension areas in non-signers. These results support the idea that strong relationships exist between areas involved in human action observation and language, suggesting that the observation of hand gestures have shaped the lexico-semantic language areas as proposed by the motor theory of speech. As a whole, the present results support the theory of a gestural origin of language. PMID- 20933063 TI - Identification, characterization and expression analysis of MicroRNAs and their targets in the potato (Solanum tuberosum). AB - MicroRNAs (miRNAs) are recognized as a class of important post-transcriptional expression regulators that act on their target genes by degradation of target mRNAs or by inhibition of target protein translation. Compared with the current numbers of identified miRNAs for other species in the plant kingdom, a large number of potential miRNAs remains to be identified in potato. In this study, using a newly modified comparative genome strategy, a total of 202 potential potato miRNAs were identified, which belong to 78 families. miR162, miR167, and miR396 are highly expressed in all tested organs. miR372 is highly expressed in flowers. A total of 1094 miRNA targets were predicted and some of them encode transcription factors as well as genes that function in stress response, signal transduction, and a variety of other metabolic processes. Gene ontology (GO) analysis implicates that these targets are involved in 545 biological processes. Of those processes, 28 are related to potato defense mechanisms against bacteria, viruses, and fungi, the metabolism of molecules such as carbon, sucrose, starch, and lipid, and the development of primary and lateral roots. Pathway enrichment analysis, based on the Kyoto Encyclopedia of Genes and Genomes (KEGG), demonstrates that the identified miRNAs participated in 98 metabolism networks, some of which include sucrose metabolism, fatty acid metabolism, amino acid metabolism, carbon fixation, and the biosynthesis of plant hormones. PMID- 20933064 TI - Dermal uptake and excretion of 14C-toluene diisocyante (TDI) and 14C-methylene diphenyl diisocyanate (MDI) in male rats. Clinical signs and histopathology following dermal exposure of male rats to TDI. AB - Polyurethanes (PU) are polymers made with diisocyanates such as MDI (4,4' methylene diphenyl diisocyanate) and TDI (2,4-toluene diisocyanate and 2,6 toluene diisocyanate). Investigations have been undertaken with MDI and TDI to assess dermal uptake and resulting systemic exposure. Absorption, distribution and excretion of MDI was studied in rats using a single dermal administration of (14)C-MDI dissolved in acetone at nominal 165 mg/kg body weight and 15 mg/kg bw (4.0 and 0.4 mg/cm(2)) and intradermal injection of (14)C-MDI dissolved in corn oil at nominal 1.4 mg/kg bw. Dermal absorption of (14)C-MDI (at both doses) was low; at or below 1% of the applied dose. Considerable amounts of the applied radioactivity were found at the application site which could not be washed off. By intradermal administration of (14)C-MDI approximately 66% of applied radioactivity remained at the application site with approximately 26% recovered in excreta, cage wash, tissues and carcass. The absorption, distribution and excretion of 2,4-TDI was studied in rats following a single dermal administration of radiolabelled (14)C-2,4-TDI at nominal 350 mg/kg body weight (12 mg/cm(2)). Dermal absorption of (14)C-2,4-TDI was at or below 1% of the applied dose. Considerable amounts of the applied radioactivity were found at the application site which could not be washed off. In summary the results show that dermal uptake of MDI and TDI is very low. Due to the chemical reactivity of isocyanates it can be expected that small amounts which might be absorbed will react with tissue constituents directly at the exposed skin area, or will be converted to adducts with biomacromolecules or to biologically inactive oligoureas. Overall it is concluded that, following dermal exposure to MDI and TDI, systemic exposures and resulting toxicity, other than the known sensitization, can be expected to be very low. In addition studies were performed with dermal application of unlabelled 2,4 and 2,6 TDI to check the availability and fate of this chemical on rat skin surface and to assess possible tissue damage. These experiments showed that unchanged test material can be detected on rat skin for up to 8h if not washed off. Dermal treatment with 2,4 or 2,6 TDI was associated with irritation with increased severity over a 48 h period after washing with a decontaminant solution. PMID- 20933065 TI - Lactational transfer of bisphenol A in Sprague-Dawley rats. AB - Bisphenol A (BPA), an important industrial chemical to which humans are exposed on a daily basis, has long been associated with endocrine disruption in experimental animal models. Such exposures are of concern, particularly during fetal and early neonatal periods, because of greater vulnerability of developing organs to aberrant endocrine signaling. Although rarely reported, information about internal exposures to the receptor-active aglycone form of BPA during the perinatal period is essential to accurate assessment of potential risks. Lactating Sprague-Dawley dams were treated by daily gavage with 100 MUg/kg bw d6 BPA starting at birth. Conjugated and aglycone forms of BPA were then measured by using LC/MS/MS in milk from lactating dams on PND 7 and in serum from dams and their pups on PND 10. All samples were collected 1h after dosing, a time selected to produce nearly maximal levels. While aglycone BPA was detected in all dam serum and milk samples, none was detected in pup serum (<0.2 nM). Doses delivered to pups lactationally, estimated from milk concentrations and body weights, were 300-fold lower than the dose administered to the dams. Similarly, serum concentrations of total BPA in pups were 300-fold lower than those in their dams. Furthermore, plasma concentrations of total BPA in PND 10 rat pups were 500-fold lower than peak levels achieved following direct oral delivery of the same dose to the same age pups. These findings of significant dose attenuation for the active aglycone form of BPA, relative to that of the dam, suggest high potency for toxicological effects derived exclusively from lactational transfer. Alternatively, studies that include lactational exposure and report minimal effects from BPA should consider the possibility that inadequate internal exposures were achieved during the critical postnatal period. PMID- 20933066 TI - Optimization of formulation and process variable of nanosuspension: An industrial perspective. AB - The objective of this study was to identify and optimize formulation and process variables affecting characteristic and scale up of nanosuspension manufacturing process on bead mill considering industrial perspective. Box-Behnken design was used for this study. Formulation factors evaluated were ratio of polymer to drug and ratio of surfactant to drug, whereas process parameters were milling time and milling speed. Responses measured in this study include zeta potential and, particle size distribution d(90). The ANOVA test reveals that ratio of polymer to drug and milling speed has significant effect on zeta potential whereas milling time and milling speed has significant effect on the particle size distribution of nanosuspension. The X-RD pattern of drug milled at high and low speed reveals no form conversion when compared to unmilled drug. The Box-Behnken design used in this study helped in identifying the factors affecting the particle size distribution d(90), zeta potential and, scalability of nanosuspension. The derived polynomial equation and contour graph aid in predicting the values of selected independent variables for preparation of optimum nanosuspension formulations with desired properties. PMID- 20933067 TI - Confocal laser scanning microscopy (CLSM) based evidence for cell permeation by mono-4-(N-6-deoxy-6-amino-beta-cyclodextrin)-7-nitrobenzofuran (NBD-beta-CyD). AB - Beta-cyclodextrin (beta-CyD), amantadine and glucose were fluorescently tagged with 4-chloro-7-nitrobenz-2-oxa-1,3-diazole (NBD chloride) to afford NBD-beta CyD, NBD-amantadine and NBD-glucose, respectively. NBD-beta-CyD/amantadine and beta-CyD/NBD-amantadine inclusion complexes were prepared. Fluorescence emission maxima (lambda(max) 544nm) and relative fluorescence intensities for NBD-beta-CyD and NBD-beta-CyD/amantadine were virtually identical, precluding the use of emission spectrum shifts for distinguishing free NBD-beta-CyD from the complex. Intracellular accumulation of NBD-beta-CyD was studied in HepG2 and SK-MEL-24 cells using confocal laser scanning microscopy (CLSM). No major differences were observed between uptake of NBD-beta-CyD and NBD-beta-CyD/amantadine. Serum proteins did not perturb uptake, whereas temperature-dependent uptake, indicative of cell entry via diffusion, was observed. Intracellular distribution favoured mitochondria, with less fluorescent material present in cytoplasm and none in cell nuclei. No experimental evidence of NBD-beta-CyD breakdown to NBD-glucose was found upon chromatographic analysis of incubation mixtures, providing additional evidence of intact NBD-beta-CyD entry into these cells. Endocytosis and/or cholesterol-independent membrane modulation are discussed as possible mechanisms for the transmembrane passage of NBD-beta-CyD. PMID- 20933068 TI - Release of paeonol-beta-CD complex from thermo-sensitive poly(N isopropylacrylamide) hydrogels. AB - By preparing an inclusion complex of paeonol (PAE) with beta-cyclodextrin (beta CD), this study investigated its release behavior from thermo-sensitive poly(N isopropylacrylamide) (PNIPAAm) hydrogels. The PAE-beta-CD complex was prepared via coprecipitation. According to differential scanning calorimeter (DSC) and X ray diffraction (XRD) results, the solid PAE-beta-CD complex was found in the amorphous state, indicating that each PAE molecule was encapsulated by a beta-CD molecule. The change of chemical shifts of H3 and H5 in proton nuclear magnetic resonance (H NMR) spectra indicated that PAE was inside the CD cavity. PNIPAAm hydrogels containing different cross-linker contents were then synthesized and had a similar lowest critical solution temperature (LCST) of around 33 degrees C. Experimental results of swelling and deswelling indicated that increasing the cross-linker content of the hydrogel decreased the swelling ratio and increased the water retention. According to experimental results of PAE-beta-CD complex release, the release rate at 45 degrees C (>LCST) was higher than at 25 degrees C (